metal-catalyzed amidation

at SciVerse ScienceDirect

Tetrahedron 68 (2012) 9867e9923

Contents lists available

Tetrahedron

journal homepage: www.elsevier .com/locate/ tet

Tetrahedron report number 993

Metal-catalyzed amidation

Sudipta Roy *, Sujata Roy, Gordon W. Gribble *

Department of Chemistry, Dartmouth College, 6128 Burke, Hanover, NH 03755, USA

a r t i c l e i n f o

Article history:Received 17 July 2012Available online 6 September 2012

* Corresponding authors. E-mail addresses: sroysm

0040-4020/$ e see front matter � 2012 Elsevier Ltd.http://dx.doi.org/10.1016/j.tet.2012.08.065

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 98682. Palladium-catalyzed preparation of secondary and tertiary amides using gaseous CO . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9869

2.1. From aryl iodides and bromides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 98692.2. From vinyl iodides and bromides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 98792.3. From aryl and vinyl triflates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 98802.4. From aryl chlorides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 98802.5. From vinyl tosylates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9883

3. Palladium-catalyzed preparation of Weinreb amides using gaseous CO . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 98843.1. From aryl iodides and bromides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 98843.2. From vinyl iodides and triflates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9885

4. Palladium-catalyzed preparation of secondary and tertiary amides using Mo(CO)6 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 98864.1. From aryl iodides and bromides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 98864.2. From vinyl bromides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 98894.3. From aryl and vinyl triflates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 98894.4. From vinyl phosphates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 98894.5. From aryl and vinyl chlorides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9889

5. Palladium-catalyzed preparation of N-benzylamides using BnNH2eW(CO)5 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 98906. Palladium-catalyzed preparation of Weinreb amides using W(CO)6 or Mo(CO)6 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .98917. Palladium-catalyzed preparation of tertiary amides using DMF . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 98928. Palladium-catalyzed preparation of tertiary amides using carbamoylsilane . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 98949. Palladium-catalyzed preparation of secondary and tertiary amides using ex situ generated CO . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9894

10. Palladium-catalyzed preparation of tertiary amides from organostannanes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 989611. Palladium-catalyzed preparation of secondary, tertiary, and Weinreb amides from boronic acids and derivatives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 989612. Palladium-catalyzed preparation of primary amides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 989913. Palladium-catalyzed preparation of sulfonamides and amide derivatives via aminocarbonylation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .990114. Preparation of heterocycles via palladium-catalyzed aminocarbonylation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 990315. Molybdenum-mediated amidation of aryl iodides and bromides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 990816. Nickel-catalyzed amidation of aryl iodides and bromides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .991117. Palladium and ruthenium co-catalyzed amidation using N-(2-pyridyl)formamide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .991318. Rhodium-catalyzed intramolecular aminocarbonylation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .991519. Amidation via CeH activation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .9916

References and notes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9921Biographical sketch . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9923

[email protected] (S. Roy), [email protected] (G.W. Gribble).

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http://dx.doi.org/10.1016/j.tet.2012.08.065



S. Roy et al. / Tetrahedron 68 (2012) 9867e99239868

1. Introduction

The amide functionality is an important and pervasive structuralmotif in pharmacologically active molecules, agrochemicals, pep-tides, and polymers.1 Representative pharmaceuticals that containaryl/heteroaryl amide functionality are shown in Figs. 1e3. Due to

OMe

Cl

NH

OS

HN

HN

O

O

O Cl

H2N OMe

NH

O NEt2 MeO

MeOOMe

NH

O

O

NMe2

NH

O

N

SO

Me

ONO2

O

NH

N

NMe

NHMe

N N

N

CO2HNH

O CO2H

NMe

NN

N

N NH2H2N

NH

O CO2H

NH

HNN

NH2

O

CO2H

NH

O

Cl

NO2

Cl

OH Cl

O

NH

O

H2N

NH

O NEt2

NH

OHN

N N

N

Me

CF3

N N

Me

NH

O

NN

HOCO2H

CO2H

HN

O

Ph

O

N

N

NH

Me

NH

O HN

O

OF3C

F3C

O

O

NN

NHNNH

O

O

Ph

O

NH

MeOH

OH

SPh

N

H

H

OHN Me

MeMe

Niclocide (Niclosamide) Pronestyl/Procanbid (Procainamide) Bezalip (Bezafibrate)

Glyburide (Glibenclamide) Reglan (Metoclopramide) Tebamide/ Tigan (Trimethobenzamide) Alinia/Kidonax (Nitazoxanide)

Gleevec/Glivec (Imatinib) Viracept (Nelfinavir) Rheumatrex/Trexall (Methotrexate) Alimta (Pemetrexed)

22

2

Colazal/Colazide (Balsalazide)Tasigna (Nilotinib)

2

Vaprisol (Conivaptan) Tambocor (Flecainide)

Onon/Azlaire (Pranlukast)4

CO2H

Me Me

H2N OEt

NH

O NO2N

OH

NH2

OOHHN

MeBnN

H

O

Me

Me

HN

NH

Me

Cidine/Cintapro (Cinitapride) Trandate/ Normodyne (Labetalol)Matulane/Indicarb (Procarbazine)

OMe

NH

OEtO2S N

Et

H2N

Amitrex/ Solian (Amisulpride)

Fig. 1. Representative aryl amide pharmaceuticals.

the unique hydrogen bonding ability of amides, as both acceptorand donor (when NH is present), the synthesis of amide analoguesof the ‘hit/lead’ molecule(s) is frequently involved in drug-discov-ery programs. The most common synthesis of aryl and heteroarylamides involves the coupling of carboxylic acids with amines in thepresence of a coupling agent (e.g., EDC, HOBt, CDI, HATU, BOP)(Scheme 1).2 The coupling of activated carboxylic acids, such as acidchlorides, esters, or mixed anhydrides, with amines is also oftenused for the same purpose.

Along with recent progress in metalation reactions,3,4 the metal-mediated synthesis of amides has emerged as an attractive alterna-tive for thepreparationof numerous amide-basedmolecules.5,6 Thus,the coupling of organolithiums (or organomagnesiums) with iso-cyanates7,8 and the coupling of organolithiums (or organocuprates)with carbamoyl chlorides9,10 are now frequently used to synthesizesecondary and tertiary aryl/heteroaryl amides (Scheme 2). Nickel-

catalyzed coupling of organomagnesiums with carbamoyl chloridesis also known.11 The use of (trimethylsilyl)isocyanate in the couplingwith organolithiums affords the corresponding primary amides.12

A one-pot synthesis of aryl/heteroaryl primary amides was recentlyreported utilizing the coupling of organozinc halides with tri-chloroacetyl isocyanate (Scheme 3).13

Noteworthy is the one-pot preparation of heteroaryl amidesfrom the corresponding heteroaryl chlorides via sequential SNAr-oxidation using diethylaminoacetonitrile derivatives as the amidesynthons (Scheme 4).14a Another SNAr-oxidation-displacementstrategy, using malononitrile as the carbonyl synthon, was also ap-plied for the same purpose.14b Likewise, 1-(4,5-dichloroimidazolyl)acetonitrile was used as the carbonyl synthon for the synthesis of2-pyrazinone-3-carboxamides.15

Although the aforementioned metal-mediated methods areeffective in constructing the aryl/heteroaryl amide units, the useof organolithium, organomagnesium, or organozinc reagents isoften unsuitable for the introduction of the amide functionality ata late-stage in the synthetic sequence due to the vulnerability ofmany functional groups to the highly basic or nucleophilic con-ditions. To the contrary, the relatively mild palladium-catalyzedamidation methods accommodate a large variety of functional

N

PhHN

O

Ph

F

Me

Me

CO2H

HO

HO

N

N

Me

NH

O

SHN

O O HN

O

N

NNH

O HN

O

Ph

B(OH)2

Me

Me

NHOFNH

Me

MeO

NH

NEt2

NN

N

HN

O

H2NO Cl

Cl

ONMe2

S

NHN

MeMe

O O

Me

NH

O

N

HN

N

NN

CH3

ONH

NMe

NN N

NN

O

NH2

Me

O

CF3

NH

O

ON

Me OMe

NH

ON

CH2

NN

NH

NH

NH

NH2

OMe

Lipitor (Atorvastatin) Glucotrol (Glipizide)

Velcade (Bortezomib)

Sutent (Sunitinib)

Rhythmy (Rilmazafone)Rescriptor (Delavirdine)

Kytril/ Sancuso (Granisetron)

Temodar/Temodal (Temozolomide)Arava (Leflunomide) Vergentan/Litican (Alizapride) Frova (Frovatriptan)

Fig. 2. Representative heteroaryl amide pharmaceuticals.

N

HNO

O Me

MeONH

OS

O

OMe

O2N

HOOH

NEt2

O

CN

N

N

Me NO

Me

Me

Me

NH2

NH2O

O

NH2O

O

NH OH

Me

Me

N

O

NHO

O

NH2

N

NH

O

NO

N

NMe

Cl

SH2N O

O NH

ON

MeF N

N

O Me

NCO2Et

Ambien/Stilnox (Zolpidem)

Nevanac (Nepafenac)

Tenormin (Atenolol)

Comtan (Entacapone)

Accolate (Zafirlukast)

Revlimid (Lenalidomide)

Gastrozepin (Pirenzepine)

Lozol/ Natrilix (Indapamide) Romazicon (Flumazenil)

Fig. 3. Representative aryl amide related pharmaceuticals.

O

OHAr

O

NArR1

R2

coupling agent

R1R2NH

Scheme 1.

S. Roy et al. / Tetrahedron 68 (2012) 9867e9923 9869

groups and, in theory, can be carried out at any point in thesynthesis.

In this review, we discuss various metal-catalyzed amidationand related reactions of aryl and heteroaryl halides that allowregioselective introduction of the amide functionality. We alsobriefly present representative preparations of heterocycles viaaminocarbonylation and amidation via CeH activations.

2. Palladium-catalyzed preparation of secondary and tertiaryamides using gaseous CO

2.1. From aryl iodides and bromides

Heck first reported the palladium-catalyzed three-componentsynthesis of primary and secondary amides using aryl halides,primary amines, and gaseous CO under atmospheric pressure(Scheme 5).16 Although an additional tertiary amine, tri-n-butyl-amine, was used with aniline to neutralize the HBr produced in thereaction mixture, it was not necessary for aminocarbonylation in-volving stronger primary and secondary aliphatic amines. In gen-eral, these aminocarbonylations proceed more rapidly than theanalogous alkoxycarbonylation for the synthesis of aryl esters. Thereaction of 4-nitrobromobenzene with aniline produced a urea by-

(Het)Ar/Ar Br / HR–Li

(Het)Ar/Ar Li

R–NCO

O

NClR1

R2

O

NHR(Het)Ar/Ar

O

N(Het)Ar/ArR1

R2

(or LDA)

Scheme 2.

(Het)Ar/Ar ZnX

O

NCOCl3C O

NH2(Het)Ar/ArO

N(Het)Ar/ArZnCl

CCl3

O

i)

ii) K2CO3, MeOH rt, 12 h

via

60–99%(X = Cl, Br, I)

THF, –20 °C to rt, 2 h

Scheme 3.

O

NEt2(Het)Ar (Het)ArCN

NEt2

i) NaHMDSEt2N-CH2-CNTHF, rt, 10 h

via

55–79%oxidant used: TMSO OTMS or NiO2•H2O

ii) oxidant, rt, 10 h

(Het)Ar Cl

O

NH

(Het)Ar(n-Pr)

(Het)ArCN

CN

via

i) NaH, NC-CH2-CNTHF, rt, 12 h

ii) n-PrNH2, oxidant

rt, 15 min29–67%

oxidant used: AcOOH

Scheme 4.

Ar–BrO

NH

ArPh

O

NH

ArPh

O

NH

ArBn

Ar = 4-OMe-Ph, 76%Ar = 4-NO2-Ph, 57%Ar = 4-CO2Me-Ph, 86%Ar = 3-pyridyl, 65%Ar = 2-thienyl, 63%

PhNH2, CO (1 atm)

PhNH2, CO (1 atm)

BnNH2, CO (1 atm)

Ar = Ph, 94%

Ar = Ph, 79%

Condition A: 1.5 mol% PhPdBr(PPh3)2, n-Bu3N (1.1 eq), 100 °C, 3.5 h.Condition B: 1.5 mol% PdBr2(PPh3)2, n-Bu3N (1.1 eq), 100 °C, 2–10 h.

Condition A

Condition B

Condition B

Scheme 5.


product along with the desired N-phenyl-4-nitrobenzamide due topalladium-catalyzed reduction of the nitro group under theseconditions; however, the rate of urea formation was much slowerthan the desired aminocarbonylation.

The widely accepted mechanism of palladium-catalyzed ami-nocarbonylation is shown in Fig. 4. Oxidative addition of aryl halideto in situ generated Pd(0) species followed by CO-insertion into thearyl carbonepalladium bond produces the acylpalladium complex.

Nucleophilic addition of amine to the acylpalladium complex fol-lowed by reductive elimination of amide regenerates Pd(0). Ingeneral, electron-rich ligands facilitate oxidative addition andprevent precipitation of Pd-black or formation of Pd-carbonylclusters due to ligation of multiple CO ligands. Also, bidentateligands are often more effective than monodentate ligands in Pd-catalyzed carbonylation of aryl halides due to their greater abilityto prevent catalyst poisoning. However, the problematic step in the

O

NArR1

R2

Ar–X

II IILnPd

NR1R2

OAr

LnPdAr

X

IILnPd

X

OAr

CO

LnPd(0)

R2R2NH + Base

LnPd(II)

Base•HX

Fig. 4. Mechanism of palladium-catalyzed aminocarbonylation.

RNH

N

I

R n-BuNHMe, CO (2 bar)

conditions

R'-NH2, CO (2 bar)(for R = H)

Conditions: 4 mol% PdCl2(dppf)•CH2Cl2,

conditions

Scheme

XNH

HN N R

HN S

95%

n-BuNH2, CO (25 ba

, CO (25

Condition B

, CO (25 b

(X = 6-Br)

(X = 4-Br)

93%

Condition A: 1 mol% PdCl2(PhCN)2, 3 mol% dCondition B: 5 mol% PdCl2(PhCN)2, 15 mol%

Condition A

Condition A

(X = 4-Br, 5-Br, 7-Br

R = Bn, Me : 91–9

Scheme


catalytic cycle can be the nucleophilic addition of amine to acyl-palladium complex. Thus, in the case of sluggish amine addition,the aroylpalladium complex is susceptible to decompositionthereby resulting in ineffective catalysis.

Using PdCl2(PhCN)2 and dppf catalysteligand combination (Pd/L¼1:3), Beller reported palladium-catalyzed aminocarbonylation ofunprotected bromoindoles [dppf¼1,10-bis(diphenylphosphino)fer-rocene] (Scheme 6).17 The nucleophilic attack of bromoindoles viathe indole nitrogen onto the acylpalladium complex is significantlyslower than the amine used for the carbonylations; thus, the desiredindole-amides were obtained in excellent yields. However, thePdCl2(PPh3)2edppf combination, lower CO pressure, or lower tem-perature were all ineffective for this transformation. A higher cata-lyst loading was required for thiomorpholine to maximize the yieldof the corresponding amide. Buchstaller reported the amino-carbonylation of unprotected 3-iodoindazole using a lower COpressure (Scheme7).18 Interestingly, higher COpressure lowered theyield of indazole-amides. Nonetheless, de-iodinated indazoles wereformed as themajor side-products in all cases, even under lower CO(2 bar) pressure. Notably, the formation of indazol-1-yl(1H-indazol-3-yl)methanonewas observed in the absence of primary/secondaryamines in the reaction medium due to nucleophilic attack of theindazole nitrogen onto the acylpalladium complex.

NH

N

ON

n-Bu

MeR = H, 71%R = 4-Me, 30%R = 5-OMe, 32%R = 5-NO2, 38%R = 6-OMe, 51%R = 6-NO2, 31%

NH

N

ONHR'

R' = n-Pr, 44%R' = Bn, 46%

5 mol% dppf, Et3N (1.4 eq), THF, 110 °C.

7.

O

N

NR

NH

HN

O(n-Bu)

NH

N O

NH

r)

bar)

ar)

ppf, Et3N (1.2 eq), toluene, 130 °C, 20 h.dppf, Et3N (1.2 eq), toluene, 130 °C, 20 h.

)

9%

S

6.


While studying Pd-catalyzed double carbonylation, Uozumi re-ported room temperature aminocarbonylation of iodobenzeneswith tri-n-butylamine in the presence of di(m-chloro)bis(h3-allyl)dipalladium(II), triphenylphosphine (Pd/L¼1:2), and DBU inTHF under atmospheric CO to afford N-butylbenzamides (Table 1,entry 1).19 Interestingly, double carbonylation was strongly favoredin the presence of DABCO in THF, even under atmospheric

Table 1Room temperature aminocarbonylation of iodobenzenes under atmospheric CO

IR R

NH

O(n-Bu)

R

O

O

HN

(n-Bu)+

3 mol% [PdCl(allyl)]26 mol% PPh3

base (3 eq), solventrt, 12 h

n-BuNH2, CO (1 atm)

Entry R Base Solvent Isolated yield (%)

Amide Ketoamide

1 H DBU THF 72 <12 H DABCO THF 7 863 H DABCO DMSO 62 184 4-OMe DABCO THF 6 875 3-Me DABCO THF 10 856 3-Cl DABCO THF 77 137 4-CF3 DABCO THF 98 <1

CO pressure (entry 2), while the DABCOeDMSO combination pro-moted monocarbonylation (entry 3) under similar conditions.The electronic nature of the aryl iodide also plays a major role indetermining this selectivity. Thus, the electron-rich 4-iodoanisolepredominantly gave the corresponding ketoamide (keto-carbox-amide) (entry4)while theelectron-deficient4-iodobenzotrifluorideproduced the amide (carboxamide) exclusively (entry 6). A mecha-nism of double carbonylation is shown in Fig. 5.

O

ArN

OR2

R1

Ar–X

II IILnPd

OAr

ONR1R2

LnPdAr

X

IILnPd

X

OAr

COCO

LnPd(0)

R1R2NH + Base

LnPd(II)

Base•HX

Fig. 5. Mechanism of palladium-catalyzed double carbonylation.

Kondo reported the effect of P(t-Bu)3 ligand on the Pd-catalyzedaminocarbonylation of 1-iodo-4-nitrobenzene with pyrrolidine.20

Exclusive formation of amide was observed using thePd2(dba)3ePPh3eDBUeTHF system at room temperature under at-mospheric CO pressure (Table 2, entry 1). Use of dppf, dppp orPCy3 as the ligand also displayed the same trend (entries 2e4) [dppp:

1,3-bis(diphenylphosphino)propane]. However, predominant for-mation of the ketoamide was observed with P(t-Bu)3 as the ligand(used as tetrafluoroborate) along with Pd2(dba)3 or by using com-mercially available Pd(t-Bu3P)2 (entries 5 and 6). In contrast, DABCOor Cs2CO3 as the base significantly favored the formation of amidewhen used with catalytic Pd2(dba)3eP(t-Bu)3$HBF4 or Pd(t-Bu3P)2,respectively (entries 7 and 8).

Kollar reported the aminocarbonylation of 2- and 3-iodopyridineand iodopyrazine with representative primary/secondary aminesand amino acid esters.21 Whereas 2-iodopyridine and iodopyrazineexclusively afforded the corresponding amides (Scheme 8),3-iodopyridine produced a mixture of amides and ketoamides un-der similar conditions (Scheme 9). Notably, even at higher COpressure (40 atm), the reactions of iodopyrazine with methyl gly-cinate and methyl alaninate did not even produce trace amounts ofthe corresponding ketoamides (Scheme 9). Thus, the substratestructures play a significant role in determining the selectivitytoward single and double CO-insertions. Of note, Horino reportedpartial aminocarbonylation of 2,6-dibromopyridine to afford themonoamide in 28e65% yield.22

Using Xantphos as the ligand, Buchwald reported a convenientpreparation of a variety of substituted benzamides via Pd-catalyzedaminocarbonylation of aryl bromides with primary and secondaryamines [Xantphos: 4,5-bis(diphenylphosphino)-9,9-dimethylxan-thene] (Scheme 10).23 The desired amides were obtained inexcellent yields in most cases, although a relatively higher tem-perature (100 �C) was essential for the sterically challenging ortho-substituted aryl bromides. Use of triethylamine as the base alsoprovided good yields of the benzamides.

McNulty and co-workers used bis(di-tert-butylphosphino)-o-xylene (dtbpx) and 1,3,5,7-tetra-methyl-6-phenyl-2,4,8-trioxa-6-phosphaadamantane (PA-Ph) as the supporting ligands in the Pd-catalyzed aminocarbonylation of bromobenzenes with diethyl-amine (Scheme 11).24 However, a higher CO pressure was requiredfor the success of these reactions. Qu and co-workers appliedmonodentate di-tert-butylphosphinoferrocene in the Pd-catalyzedaminocarbonylation of heteroaryl halides with chiral amines(Scheme 12).25 In the event, using the air-stable P(Fc)(t-Bu)2$HBF4,the amideswere obtained in good yields from2-bromopyridine and2-bromopyrimidine. While the Pd/ligand¼1:2 ratio proved to besufficient in most cases, a slightly higher amount of ligand(Pd/L¼1:3)was necessary for the challenging substrates to suppresscatalyst deactivation. Notably, Xantphos and P(t-Bu)3$HBF4 showedsimilar reactivity to P(Fc)(t-Bu)2$HBF4 in some instances although

N

X

(X = CH)

NN

OR2

R1

conditions50 °C, 22-72 h

R1 = H, R2 = t-Bu, 70%R1 = H, R2 = CH2CO2Me, 61%R1 = H, R2 = Ph, 20%R1R2 = -(CH2)5-, 83%R1R2 = -(CH2)2-O-(CH2)2-, 80%

I

R1R2NH, CO (1 atm)

N

N

N

OR2

R1R1 = H, R2 = t-Bu, 85%R1 = H, R2 = Ph, 8%R1R2 = -(CH2)5-, 81%R1R2 = -(CH2)2-O-(CH2)2-, 83%

conditions50 °C, 22 h

R1R2NH, CO (1 atm)(X = N)

Conditions: 2.5 mol% Pd(OAc)2, 5 mol% PPh3, Et3N–DMF.

Scheme 8.

N+

N

N

OR1

R2

ON

OR2

R1

N

X I

(X = CH)


R1R2NH, CO (1 atm)

34%60%32%

44%22%43%

R1 = H, R2 = t-BuR1R2 = -(CH2)5-R1R2 = -(CH2)2-O-(CH2)2-

N+

N

N

OR1

R2

ON

OR2

R1


R1R2NH, CO (40 atm)

7%15%

71%68%

R1 = H, R2 = CH2CO2MeR1 = H, R2 = CH(Me)CO2Me

N

N+

N

NN

OR1

R2

ON

OR2

R1(X = N)


R1R2NH, CO (40 atm)

78%82%

0%0%

R1 = H, R2 = CH2CO2MeR1 = H, R2 = CH(Me)CO2Me

(X = CH)

Conditions: 2.5 mol% Pd(OAc)2, 5 mol% PPh3, Et3N–DMF.

Scheme 9.

Table 2Room temperature aminocarbonylation of 1-iodo-4-nitrobenzene

O2N

I

O2N

N

O

O2N

ON

O+pyrrolidine, CO (1 atm)

Pd-catalyst, ligandbase, THF, rt

Entry Pd-catalyst/ligand Base Product distribution (% by 1H NMR)

Iodide Amide Ketoamide

1 Pd2(dba)3þ2PPh3 DBU, 3 h 0 100 02 Pd2(dba)3þdppf DBU, 14 h 0 100 03 Pd2(dba)3þdppp DBU, 14 h 0 100 04 Pd2(dba)3þ2PCy3 DBU, 24 h 0 100 05 Pd2(dba)3þ2[P(t-Bu)3$HBF4] DBU, 3 h 0 10 806 Pd(t-Bu3P)2 DBU, 2 h 0 12 807 Pd2(dba)3þ2[P(t-Bu)3$HBF4] DABCO, 24 h 17 68 158 Pd(t-Bu3P)2 Cs2CO3, 1.5 h 0 75 25


RX

Br

RN

OR1

R = 3,5-di-Me, R1 = H, R2 = Bn, 95%R = 3-Cl, R1 = H, R2 = Ph, 98%R = 4-OMe, R1 = R2 = n-Bu, 87%R = 4-OMe, R1R2 = -(CH2)2-O-(CH2)2-, 87%R = 3-CO2Me, R1R2 = -(CH2)5, 83%

conditions, 80 °CNa2CO3 (3 eq)

R1R2NH, CO (1 atm)

(X = CH)

R = 2,4-di-Me, R1 = H, R2 = n-Hex, 91%R = 2-OMe, R1 = H, R2 = Bn, 94%R = 2-CO2Me, R1R2 = -(CH2)2-O-(CH2)2-, 84%R = 2,4-di-Me, R1R2 = -(CH2)2-O-(CH2)2-, 86%

R2

RN

OR1R1R2NH, CO (1 atm)

(X = CH)

R2

RX

N

OR1R1R2NH, CO (1 atm)

(X = CH, N)

R2

conditions, 100 °CNa2CO3 (3 eq)

conditions, 80 °CEt3N (3 eq)

X = CH, R = 4-CN, R1 = Me, R2 = Ph, 97%X = N, R = H, R1 = R2 = n-Bu, 78%

Conditions: 2 mol% Pd(OAc)2, 2 mol% Xantphos, toluene, 15 h.

Scheme 10.

Br

R R

NEt2

O

O O

O P

MePh

Me

Me

Me

PA-Ph

P(t-Bu)2

P(t-Bu)2dtbpx83–86%

Condition A: 2.5 mol% Pd(OAc)2, 5 mol% dtbpx, Cs2CO3 (1.5 eq), DMF, 80 °C, 6–8 h.Condition B: 3 mol% Pd(OAc)2, 3 mol% PA-Ph, Cs2CO3 (1.5 eq), DMF, 80 °C, 6–7 h.

Et2NH, CO (40-45 psi)

Condition A or B

(R = Me, NO2)

Scheme 11.

Pt-Bu

t-Bu

Z

Y

X Ph

NH2EtO2C •HCl

HN

O

R1

R2

N

Y HN

O

CO2Et

Ph

Fe

Condition A: 3 mol% Pd(OAc)2, 6 mol% P(Fc)(t-Bu)2•HBF4, i-Pr2NEt (4 eq), MeCN.Condition B: 3 mol% Pd(OAc)2, 9 mol% P(Fc)(t-Bu)2•HBF4, i-Pr2NEt (4 eq), MeCN.

Condition A120 °C, 4 h

P(Fc)(t-Bu)2

Y = CH, 91%Y = N, 74%

Condition B120 °C, 4–5 h

(X = I)

(X = Br)

CO (50 psi)

CO (100–200 psi)

(Y = Z = CH)

(Z = N)

R2

NH2R1

R1 = Ph, R2 = Me, 87%R1 = CO2Et, R2 = Ph, 82%

Scheme 12.


CataCXium A, QPhos, dppb, and dcpb were ineffective. [CataCXiumA: di(1-adamantyl)-n-butylphosphine; QPhos: 1,2,3,4,5-pentaphe-nyl-10-(di-tert-butylphosphino)ferrocene; dppb: 1,4-diphenylphos-phinobutane; dcpb: dicyclohexylphosphinobutane].

Using a continuous flow reactor (X-Cube), Csajagi and co-workers carried out aminocarbonylation of halogenated aryl car-boxylic acids on polymer-supported tetrakis(triphenylpho-

sphine)palladium (Scheme 13).26 The combination Et3NeTHF wassuperior as the base and solvent for this purpose. Thus, gaseous COwas introduced from an external cylinder to the solution of halide,amine, and Et3N in THF (with 0.5 mL/min flow rate at 100 �C and30 bar) in X-Cube and the liquidegas mixture was subsequentlypassed through the pre-heated commercially available CatCarts�cartridges that were loaded with immobilized palladium catalysts.

YZ

R1 = H, R2 = c-Hex, Y = 4-CO2H : 73%R1 = H, R2 = c-Hex, Y = 3-CO2H : 61%R1 = H, R2 = Bn, Y = 4-CO2H : 69%R1 = H, R2 = t-Bu, Y = 4-CO2H : 50%R1 = H, R2 = 2-Me-Ph, Y = 4-CO2H : 58%R1R2 = -(CH2)4-, Y = 4-CO2H : 81%R1R2 = -(CH2)4-, Y = 3-CO2H : 61%

X

(X = I, Z = CH)

conditionsX-Cube

R1R2NH, COY

N

OR2

R1

YN

N

OR2

R1R1 = H, R2 = Bn, Y = 5-CO2H : 32%R1 = H, R2 = Bn, Y = 3-CO2H : 30%R1R2 = -(CH2)4-, Y = 3-CO2H : 56%

Conditions: Polymer-supported Pd(PPh3)4, Et3N, THF, 100 °C, 30 bar.

(X = Br, Z = N)

conditionsX-Cube

R1R2NH, CO

Scheme 13.


These high-efficiency aminocarbonylations were completed in lessthan 2 min considering the residence time on immobilized Pd-catalyst where the reaction took place.

Nacci and co-workers used a benzothiazole-carbene-based Pd-catalyst for the aminocarbonylation of bromobenzenes (and chlo-robenzenes) in ionic liquids (Scheme 14).27 Interestingly, only tetra-n-butylammonium bromide (TBAB) gave good results under these

X

R R

NEt2

O

N

S

Me

PdI

I

N

S

Me

Et2NH, CO (1 atm)

X = Br : R = H, 85%X = Br : R = OMe, 93%X = Cl : R = COMe, 17%X = Cl : R = NO2, 39%

Pd-catalyst

4 mol% Pd-catalyst8 mol% PPh3

Et3N, TBAB, DMA130–140 °C, 5–10 h

Scheme 14.

conditions while tetra-n-butylammonium chloride (TBAC) andtetra-n-butylammonium iodide (TBAI) were ineffective. The ionicliquids having less coordinating anions such as tosylate and tetra-fluoroborate were not suitable for these aminocarbonylations. Sig-nificantly, this air- andmoisture-stable Pd-catalyst couldbe recycledseveral times without major loss in catalytic activity. McNulty alsoreported mild aminocarbonylation in ionic liquids under atmo-spheric CO pressure (Scheme 15).28 Interestingly, a bromide effectwas observed by these researchers while screening a range of

RBr Et2NH, CO (1 atm)

RNEt2

O

PC6H13

C6H13C6H13

C14H29

Br4 mol% Pd(OAc)2

8 mol% dppfEt3N (2 eq), Br–PSIL

60 °C, 6–8 hR = Me, 81%R = NO2, 85%

trihexyl(tetradecyl)-phosphonium bromide

Br-PSIL:

Scheme 15.

phosphonium salt ionic liquids (PSIL), involving a range of commonanions in combination with trihexyl(tetradecyl)phosphonium cat-ion. Thus, trihexyl(tetradecyl)phosphonium bromide is superior forthese aminocarbonylations. In fact, control experiment conducted ina bromide-containing media confirmed the existence of the acylbromide intermediate. In the presence of an amine nucleophile, theacyl bromide presumably affords the amide via pathway b (Fig. 6).

Bhanage reported the aminocarbonylation of aryl iodides inwater (Scheme 16).29 Primary, secondary, and aromatic amines, in-cluding sterically challenging ortho-substituted anilines, gave goodyields of the corresponding amides, even with a low (0.5 mol %)catalyst loading.

Petricci reported microwave-assisted Pd-catalyzed amino-carbonylation of aryl bromides (Scheme 17).30 While DIPEAwas the

superior base for the aminocarbonylation of aliphatic amines,Cs2CO3 provided better results for the less nucleophilic anilines.These researchers also successfully carried out microwave-assistedaminocarbonylation of aryl iodides under heterogeneous catalyticconditions (Scheme 18).31 No ancillary ligand was used in thesereactions. Nonetheless, the amides were isolated in good yieldsafter simple filtration (to remove the catalyst) of the reactionmixture. The catalyst could be recycled twice without any signifi-cant decrease in catalytic activity.

The Pd-catalyzed aminocarbonylation of 2-iodoanisole withrepresentative primary, secondary amines and amino acid estersunder atmospheric CO pressure afforded the corresponding amidesin good yields (Scheme 19).32 However, double carbonylation of2-iodoanisole was only observed at a higher CO pressure(40e60 bar), predominantly providing the corresponding ketoa-mides. In contrast, aminocarbonylation of related ortho-alkoxy aryl

Fig. 6. Bromide effect in Pd-catalyzed aminocarbonylation.

RI

0.5 mol% Pd(OAc)Et3N (2 eq)

H2O, 100 °C, 8 h

R = H, R1 = H, R2 = Ph (96%)R = H, R1 = H, R2 = 4-OMe-Ph (84%)R = H, R1 = H, R2 = 3-CF3-Ph (91%)R = H, R1 = H, R2 = 2-Me-Ph (92%)

R1R2NH, CO (100 p

R = R = R = R =

Scheme

I R1R2NH, CO (130 psi)

R R

N

O

10% Pd-CDBU (3 eq), DMF

130 °C, MW, 20 min

R2

Scheme

RBr

R

O

R1R2NH, CO (120 psi)

5 mol% PdCl2(PPh3)2i-Pr2NEt (3 eq), THF130 °C, MW, 20 min

10 mol% PdCl2(PPh3)2Cs2CO3 (3 eq), THF120 °C, MW, 30 min

ArNH2, CO (120 psi)R

O

Scheme


iodides, such as 5-chloro-7-iodo-8-methoxyquinoline and 8-benzyloxy-5-chloro-7-iodoquinoline with tert-butylamine re-quired a high pressure (60 bar) of CO to afford the correspondingamides; only trace amounts of ketoamides resulting from doublecarbonylation were detected in these reactions. However, similaraminocarbonylation of 5-chloro-8-hydroxy-7-iodoquinoline (anortho-hydroxy aryl iodide) with tert-butylamine and piperidinecompletely failed under atmospheric pressure and even at60 bar; the de-iodinated product was isolated nearly quantitatively.On the other hand, the Pd-catalyzed aminocarbonylation of8-benzyloxy-5,7-diiodoquinoline using tert-butylamine underatmospheric CO pressure successfully produced the corresponding5-amidoquinoline (Scheme 20).33 However, a higher CO pressure(80 bar) was required to afford the corresponding 5,7-diamidoquinoline in moderate yield. In contrast, similar amino-carbonylation using piperidine, morpholine, and aniline was regio-selective at higher CO pressure (80 bar) and exclusively afforded thecorresponding 5-amidoquinolines. As observed previously, theaminocarbonylation of the ortho-hydroxy derivative, 5,7-diiodo-8-hydroxyquinoline, was unsuccessful under similar conditions andthe corresponding de-iodinated 8-hydroxyquinoline was obtainedas the major product.

2R

N

OR1si)

R2

4-OMe, R1 = H, R2 = Ph (94%)4-NO2, R1 = H, R2 = 3-CF3-Ph (62%)2-Me, R1 = H, R2 = Bn (86%)4-Me, R1R2 = -(CH2)2-O-(CH2)2- (82%)

16.

R1

R = H, R1 = H, R2 = Ph, 95%R = H, R1 = H, R2 = 4-OMe-Bn, 75%R = OMe, R1 = H, R2 = 4-OMe-Bn, 60%R = CO2Et, R1 = H, R2 = 4-OMe-Bn, 75%R = H, R1R2 = -(CH2)2-O-(CH2)2-, 80%R = OMe, R1R2 = -(CH2)2-O-(CH2)2-, 80%R = CO2Et, R1R2 = -(CH2)2-O-(CH2)2-, 90%

18.

NR1

R2

R = 4-F, Ar = 2-Cl-4-NO2-Ph, 75%R = 4-Et, Ar = 2-Me-3-NO2-Ph, 82%R = 4-F, Ar = 2-imidazolyl, 90%R = 4-Et, Ar = 2-thiazolyl, 85%R = 4-Et, Ar = 3-quinolinyl, 70%

R = 4-F, R1R2 = -(CH2)2-N(Ph)-(CH2)2-, 88%R = 4-Et, R1R2 = -(CH2)2-O-(CH2)2-, 85%R = 4-Et, R1 = H, R2 = 4-OMe-Bn, 88%

NH

Ar

17.

I

ORN

Cl

I

OMe

OMe

N

OR1R2

ORN

ClN

OR1R2

R1R2NH, CO (1 bar)

R1 = H, R2 = t-Bu, 60%R1 = H, R2 = CH2CO2Me, 80%R1R2 = -(CH2)5-, 80%R1R2 = -(CH2)2-O-(CH2)2-, 71%


R1R2NH, CO (60 bar)


R = H, R1 = H, R2 = t-Bu, 0%R = Me, R1 = H, R2 = t-Bu, 72%R = Bn, R1 = H, R2 = t-Bu, 62%

O

R1R2NH, CO (40 bar)


N

O

OMe

R2

R1R1 = H, R2 = t-Bu, 55%R1 = H, R2 = CH2CO2Me, 70% (at 60 bar)R1R2 = -(CH2)5-, 67%R1R2 = -(CH2)2-O-(CH2)2-, 73%

Conditions: 2.5 mol% Pd(OAc)2, 5 mol% PPh3, Et3N−DMF.

Scheme 19.

NOBn

IO

NH

Ph

NOBn

IO

NR1

R2

NOBn

IIN

OBn

IO

NH

(t-Bu)

NOBn

O

NH

(t-Bu)HN

O

(t-Bu)

R1R

2= -(CH

2)5-, -(CH

2)2-O-(CH

2)2-

t-BuNH2CO (1 bar)

conditions, 70 h

76%

conditions, 70 h

47%

Conditions: 2.5 mol% Pd(OAc)2, 5 mol% PPh3, Et3N−DMF, 50 °C.

t-BuNH2CO (80 bar)

PhNH2CO (80 bar)

conditions, 70 h

86−87%

conditions, 25 h

R1R2NHCO (80 bar)

81%

Scheme 20.


A variety of p- and m-substituted benzamide-C-ribonucleosideswere prepared in good yields via the Pd-catalyzed amino-carbonylation of TBS-protected 3- and 4-bromophenyl-C-ribonu-cleoside under atmospheric CO pressure (Scheme 21).34 Thehydrochloride salts of methylamine and dimethylamine were used

O

TBSO

TBSO

OTBS

O

TBSO

TBSO

OTBS

R1R2NH, CO (1 atm)

5 mol% Pd(OAc)210 mol% Xantphos

K3PO4 (4 eq)toluene, 80 °C, 2−4 h

XN

OR1

R2

79−95%

R1 = H, R2 = Me, c-Pr, c-Hex, Bn;R1 = R2 = Me; R1 = R2 = n-Bu;

R1R2 = -(CH2)4-, -(CH2)5-, -(CH2)2-O-(CH2)2-

(X = 3-Br / 4-Br)

Scheme 21.

for the preparation of the corresponding benzamides. The sodiumsalts of N,N-dimethylaminoethylamine and N-methylpiperazinewere used as the nucleophiles in the aminocarbonylation of bro-mobacteriochlorin (Scheme 22).35 A stoichiometric amount ofPd(PPh3)4 was necessary to ensure complete substitution of the

dibromide because a catalytic amount of palladium providedmultiple products along with a large amount of unreacted dibro-mide. Nonetheless, bacteriochlorin-amides were obtained in onlymoderate yields due to unavoidable double carbonylation underthe applied conditions.

Representative examples of the regioselective introduction ofthe amide functionality via aminocarbonylation of aryl/heteroaryliodides and bromides using gaseous CO are shown in Table 3. Ingeneral, these aminocarbonylations were carried out in the pres-ence of catalytic Pd(OAc)2ePPh3 or PdCl2(PPh3)2.

NNH

N HN

BrMe

Me

Br

Me

Me

NR1R2, 70 °C to rt, 30 min NNH

N HN

MeMe

Me

Me

O N

NO R1

R2

i) Pd(PPh3)4 (1 eq), CO (1 atm)DMF-toluene (1:1), 70 °C, 2 h

ii) Na

R1 = H, R2 = CH2CH2NMe2, 53%R1R2 = -(CH2)2-N(Me)-(CH2)2, 47%

R2

R1

Scheme 22.

Table 3Aminocarbonylation of aryl/heteroaryl halides using gaseous CO

Entry AreX, conditions Amide YieldRef.

1

I

NH

N

HO2C

O

Me

NH

NO

MeN

O

NHO2C

87%36a

R1R2NH, CO (15 psi), PdCl2(PPh3)2, (c-Hex)2NH, anisole, 100 �C

2

NH

O

I

Cl

O

Me

Me

NMe

H

NH

O Cl

O

Me

Me

NMe

H

NH

O N

N

68%36b

(Het)AreNH2, CO (1 atm), PdCl2(PPh3)2, Et3N, DMF, 95 �C

3O

N

Ph I

Me

ON

Ph

Me

ONH

Ph

79%36c,d

RNH2, CO (1 atm), PdCl2(PPh3)2, DMF, D

4

S

O

O

I

SO2Me

S

O

O

ONH

N O

SO2Me

3

84%36e

RNH2, CO (1 atm), Pd(OAc)2, PPh3, Et3N, DMF, 80 �C

5

N

N

N

N

(i-Pr)

NH

I

MeO

N

N

N

N

(i-Pr)

NH

O

HN

R

MeO

(R = i-Pr, i-Bu)

90e95%36f

RNH2, CO, Pd(PPh3)4, Et3N, THF, 50 �C


Table 3 (continued )


6

N

N

N

N

(i-Pr)

NH

I

Ar

N

N

N

N

(i-Pr)

NH

O

Ar

HN

(i-Pr)

(Ar = 4-OMe-Ph, 4-Cl-Ph)

76e77%36f

RNH2, CO, Pd(PPh3)4, Et3N, THF, 50 �C

7 Br

Me

HN

OMe

Me

HN

OMe

O

N

O

Cl80e85%37a

R1R2NH, CO, Pd(OAc)2, PPh3, DBU, DMF, 125 �C

8Br

OBn

N

NMe

Me

OBn

N

NMe

MeNMe2

O

95%37b,c

R1R2NH, CO (6 bar), Pd(OAc)2, PPh3, DMAP, DMF, 130 �C

9

N

NMe

Br

Ph

N

NMe

Ph

NMe2

O

69%37d

R1R2NH, CO (6 bar), Pd(OAc)2, PPh3, Et3N, THF, 120 �C

10

N

NMe

MeBr

OBn

N

NMe

Me

OBn

NMe2

O

81%37e

R1R2NH, CO (10 bar), Pd(OAc)2, PPh3, Et3N, THF, 120 �C

11

NN

NMe

Me

HN

MeEt

Br

NN

NMe

Me

HN

MeEt

NMe2

O

66%37f

R1R2NH, CO (6 bar), Pd(OAc)2, PPh3, THF, 120 �C


2.2. From vinyl iodides and bromides

In his original report, Heck described the preparation of acryl-amides via the Pd-catalyzed aminocarbonylation of vinyl iodidesand bromides under atmospheric CO pressure (Scheme 23).16 Thetransformation was found to be highly stereospecific and, thus,provided the corresponding amides with retention of configurationfrom the cis- and trans-vinylic halide precursors. Importantly, the

aminocarbonylation of 2-chloropropene with aniline produced thecorresponding amide in 74% yield under similar conditions[PdCl2(PPh3)2, 100 �C, 10 h]; however, a high CO pressure (600 psi)was required.

Under atmospheric CO pressure, the Pd-catalyzed amino-carbonylation of a-iodostyrene and a,a0-diiodo-1,4-divinylbenzenewith primary, secondary amines and amino acid esters afforded thecorresponding N-substituted phenylacrylamides in high yields

R'

R

Br R'

R

NHPhO

R'R

I

R

NHPhO

PhNH2, CO (1 atm)

Condition A: 1.5 mol% PdI2(PPh3)2, n-Bu3N (1.1 eq), 100 °C, 1−1.5 h.Condition B: 1.5 mol% PdBr2(PPh3)2, n-Bu3N (1.1 eq), 60−100 °C, 1−4 h.

R = H, R' = Ph;R = R' = Me;

R = Me, R' = CO2Me80−88%

PhNH2, CO (1 atm)

Condition A

R = Et, R' = Et70−71%

Condition B

R'

Scheme 23.


(Scheme 24).38 The aminocarbonylation of 10,4-diiodostyrene withprimary and secondary amines under atmospheric CO pressureeffected substitutions of both vinyl and aryl iodides (Scheme 25).39

To the contrary, with amino acid esters as the nucleophiles thesereactions are highly chemoselective under atmospheric CO pres-sure and afforded only the (4-iodophenyl)acrylamides. However,conducting the aminocarbonylation of 10,4-diiodostyrene withthese amino acid esters at higher CO pressure (40 bar) pre-dominantly produced the corresponding diamides. Likewise, theaminocarbonylation of (4-iodophenyl)acrylamide with glycinemethyl ester under a higher CO pressure (40 bar) effected sub-stitution of aryl iodide.

I

II

R1R2NH, CO (1 bar) N

OR2

R1 R1 = H, R2 = t-Bu, 83%R1 = H, R2 = Ph, 70%R1 = H, R2 = CH2CO2Me, 76%R1 = H, R2 = CH(Me)CO2Me, 72%R1R2 = -(CH2)5-, 79%

N

OR2

R1

N

OR1

R2

R1 = H, R2 = t-Bu, 80%R1 = H, R2 = CH2CO2Me, 70%R1R2 = -(CH2)5-, 75%

R1R2NH, CO (1 bar)

conditions

Conditions: 2.5 mol% Pd(OAc)2, 5 mol% PPh3, Et3N−DMF, 50 °C, 22 h.

conditions

Scheme 24.

Variations of Heck’s protocol have been used by researchers toinstall regioselectively amide functionality into the target mole-cules (Table 4, entries 1e4).

2.3. From aryl and vinyl triflates

Ortar and co-workers prepared amides via the Pd-catalyzedaminocarbonylation of aryl and vinyl triflates under atmosphericCO pressure (Scheme 26).42 Representative examples of the ami-nocarbonylation of aryl and vinyl triflates using similar conditionsare shown in Table 5. Likewise, the synthesis of 11C-labeled amideswas achieved via the aminocarbonylationof aryl triflates using a lowconcentration of [11C]-carbon monoxide.43 Lithium bromide wasused as an additive along with Pd(PPh3)4 to facilitate this reaction.

2.4. From aryl chlorides

Similar to many other Pd-catalyzed reactions, aryl chlorides areunreactive toward carbonylation reactions. Using chelate-stabilized

and electron-rich Pd(dippp)2 as the catalyst, Milstein reportedaminocarbonylation of chlorobenzenes with di-n-propylamine(Scheme 27).46 Excess amine was used for these reactions (withoutany additional base) to afford the amides in high yields. Similarresults were obtained with [Pd(OAc)2þ2(dippp)] that presumablygenerated Pd(dippp)2. For these aminocarbonylations, dippp (1,3-diisopropylphosphinopropane) was found to be uniquely supe-rior, as related ligands, such as dppp, dppe, dmpe [or the mono-dentate phosphine ligands, e.g., PPh3, P(i-Pr)3, PMe3], wereineffective (dippb and dippe showed low activity). The highelectron-density of the ligand in Pd(dippp)2 presumably promotesthe oxidative addition of aryl chloride to Pd(0). Furthermore,

a chelate effect seems to facilitate both the reductive eliminationand the CO-insertion steps.

Perry and Wilson studied Pd-catalyzed aminocarbonylation ofelectron-deficient chlorobenzenes with aniline using NaI as theadditive (Scheme 28).47 Acceleration of the rate of amidation wasobserved in the presence of NaI. While KI exhibited comparableactivity, TBAI showed low activity. However, electron-rich arylchlorides were generally unreactive under these conditions.

Using 1-[2-(dicyclohexylphosphanyl)ferrocenyl]ethyldicycloh-exylphosphane ligand in combination of PdCl2(PhCN)2 catalyst,Beller reported aminocarbonylation of chlorobenzene with di-n-propylamine under atmospheric CO pressure (Scheme 29).48 Infact, this particular JosiPhos-type chelating ligand displayed su-perior performance compared to similar ligands. Like the baseNa2CO3, sodium acetate (NaOAc) showed promising results inscreening experiments. Later, these researchers reported thatthe dppf ligand could be used in the aminocarbonylation of 2-chloropyridine, 2-chloroisoquinoline, and 4-chloro-7-trifluorome-thylquinoline with N-benzylpiperazine (Scheme 30).49 Although

I

conditions

I

I

N

OR2

R1

N

OR2

R1

N

OR2

R1R1R2NH, CO (1 bar)

conditions

R1R2NH, CO (1 bar)

R1 = H, R2 = t-Bu, 55%R1R2 = -(CH2)5-, 84%

R1 = H, R2 = CH2CO2Me, 89%R1 = H, R2 = CH(Me)CO2Me, 90%R1 = H, R2 = CH(i-Pr)CO2Me, 77%R1R2 = -CH(CO2Me)-(CH2)3-, 90%

conditions

N

OR2

R1

N

OR2

R1R1R2NH, CO (40 bar)

R1 = H, R2 = CH2CO2Me, 56%R1 = H, R2 = CH(Me)CO2Me, 64%R1 = H, R2 = CH(i-Pr)CO2Me, 61%R1R2 = -CH(CO2Me)-(CH2)3-, 55%

Conditions: 2.5 mol% Pd(OAc)2, 10 mol% PPh3, Et3N−DMF, 50 °C, 24 h.

Scheme 25.

Table 4Aminocarbonylation of vinyl halides using gaseous CO

Entry ReX, conditions Amide YieldRef.

1 OS

Me

I

O

H

HNBoc

OS

MeO

H

HN

HNO

Boc 65%40a

RNH2, CO (8 bar), PdCl2(PPh3)2, MeCN, D

2 N

O

Bn

OH

O

IN

O

Bn

HO

NH

O

Br

64%40b

(i) RNH2, CO, Pd(OAc)2, PPh3, Et3N, DMF, 40 �C(ii) NH3 in MeOH (for deformylation)

3

O

BrO2N

MeMe

O

O2N

MeMe

OHN CN

299%41a

RNH2, CO (1 atm), Pd(OAc)2, PPh3, KI (1 equiv), DMF, 130 �C, 1 h

4

NO O

Br

NH

Me

Me

NO O

NH

Me

Me

ON N Ph

70%41b

R1R2NH, CO, Pd(OAc)2, CataCXium A, Et3N, dioxane, 100 �C


Ar OTf

OTfMe

Me

AcO

O

NAr

Me

Me

AcO

ONEt2

Ar = 4-OMe-Ph, 59%Ar = 3-OMe-Ph, 68%Ar = 2-naphthyl, 70%3 mol% Pd(OAc)2

6 mol% dppfDMF, 60−80 °C, 1−2 h

R1R2NH, CO (1 atm)[R1R2 = -(CH2)5-]

3 mol% Pd(OAc)26 mol% PPh3DMF, rt, 1 h

Et2NH, CO (1 atm)

91%

Scheme 26.

RCl

RN(n-Pr)2

OP(i-Pr)2

P(i-Pr)2(n-Pr)2NH, CO (70 psi)

R = H, 87%R = 3-Me, 80%

1 mol% Pd(dippp)2DMF, 150 °C, 20 h (dippp)

Scheme 27.

Table 5Aminocarbonylation of aryl and vinyl triflates using gaseous CO

Entry R/AreOTf, conditions Amide YieldRef.

1

NN

OTf

NO2

NN

NO2

N

O

NMe61%44a

R1R2NH, CO, Pd(dba)2, Et3N, DMF, 80 �C

2 NMe

Me OTf NMe

MeO

HNNHPh

70%44b

RNH2, CO, Pd(OAc)2, dppf, Et3N

3

OTf

NMeO2CBr

NMeO2CBr

O HN Br

74%45a

RNH2, CO, Pd(PPh3)4

4 O

OOTf

MeMe

O

OMe

Me

NEt2

O

60%45b

R1R2NH, CO (1 atm), Pd(OAc)2, PPh3, Et3N, Et2NHeDMF (1:5), rt, 24 h


ClNHPh

O

3 mol% PdCl2(PPh3)26 mol% dppe

DBU (3 eq), NaI (1.2 eq)DMAC, 115 °C, 24 h

PhNH2, CO (5 psi)

R = SO2Ph, 91%R = CF3, 78%R = CN, 62%R = COPh, 82%R = CO2Me, 59%R = OMe, 0%

R R

Scheme 28.

PCy2

MePCy2

Ph Cl Ph N

O(n-Pr)

(n-Pr) Fe

n-Pr2NH, CO (1 bar)

65% Ligand

0.5 mol% PdCl2(PhCN)22 mol% ligand

Na2CO3 (3 eq), DMF145 °C, 4 Å MS, 16 h

Scheme 29.

(Het)Ar Cl (Het)Ar

O

NN

Bn1 mol% PdCl2(PhCN)2

3 mol% dppf, Et3N (1.2 eq)toluene, 130 °C, 20 h

[(Het)Ar = 2-pyridyl, 1-isoquinolinyl, 7-CF3-4-quinolinyl]

R1R2NH, CO (25 bar)

85−99% (GC yields)[R1R2 = -(CH)2-N(Bn)-(CH2)2-]

Scheme 30.

O

NArR1

R2Ar−Cl

IILnPd

Ar

Cl

IILnPd

Cl

OAr

CO

PhO

O

O

ArPh

LnPd(0)

LnPd(II)

Ph−OH+

PhO

R1R2NH+

PhO

+ Cl

Fig. 7. NaOPh-assisted Pd-catalyzed aminocarbonylation of aryl chlorides.


a higher CO pressure (25 bar) was applied to these reactions,selective monocarbonylation of 2,5-dichloropyridine wassuccessfully carried out (95% GC yield) at a lower CO pressure(10 bar).

Using sodium phenoxide (NaOPh) as an acyl transfer agent,Buchwald developed Pd-catalyzed aminocarbonylation of arylchlorides under atmospheric CO pressure (Scheme 31).50 Theelectron-richbulkychelating ligand1,3-bis(dicyclohexylphosphino)propane was suitable for this purpose and used as its air-stabletetrafluoroborate salt [dcpp$2HBF4]. Primary, secondary, and aro-matic amines successfully participated in this aminocarbonylationwith a variety of aryl and heteroaryl chlorides. Even a stericallychallenging ortho-substituted aryl chloride provided the corre-sponding amide in good yield. In this aminocarbonylation protocol,sodium phenoxide (NaOPh) significantly facilitated the catalyticprocess by transferring the acyl group from the palladium center tothe amine via a phenyl ester intermediate (Fig. 7). Indeed, the in-termediacy of the ester intermediate (phenyl 3-methoxybenzoate)during amidation was confirmed by in situ IR spectroscopy viamonitoring the reaction mixture of 3-chloroanisole, di-n-

(Het

Ar =Ar =Ar =Ar =Ar =Ar =Ar =

(Het)Ar/Ar ClR1R2NH, CO (1 atm)

2 mol% Pd(OAc)24−5 mol% dcpp•2HBF4NaOPh (2 eq), 4 Å MS

DMSO, 100−120 °C, 15 h

Scheme

butylamine, and NaOPh under catalytic conditions at 120 �C. In ad-dition, rapid conversion of phenyl 3-methoxybenzoate to the amideby di-n-butylamine was observed (in DMSO at 120 �C) in the pres-ence of NaOPh (1 equiv) whereas the same transformation wassluggish in the absence of NaOPh.

The Pd-catalyzed aminocarbonylation of 2-bromo-4,6-dichloropyridine with dimethylamine at 70 �C afforded regiose-lectively the monoamide (Scheme 32).51 But, conducting the re-action at a higher temperature promoted the aminocarbonylationat both C-2 and C-6 to give the bis-amide in moderate yield.

2.5. From vinyl tosylates

The Pd-catalyzed aminocarbonylation has also been success-fully extended to vinyl tosylates. Using catalytic Pd(OAc)2 and

)Ar/Ar N

OR1

R2

PCy2

PCy2

4-OMe-Ph, R1 = H, R2 = Bn, 98%3-CN-Ph, R1 = H, R2 = Bn , 65%2-thienyl, R1 = H, R2 = n-Hex, 99%3-pyridyl, R1 = H, R2 = Ph, 92%4-Me-Ph, R1 = R2 = n-Bu, 79%3-OMe-Ph, R1R2 = -(CH2)2-O-(CH2)2-, 88%3-CO2t-Bu, R1R2 = -(CH2)2-O-(CH2)2-, 75%

(dcpp)

31.

NBr Cl

NH2Cl

N Cl

NH2Cl

Me2N

O

N

NH2Cl

O

Me2N NMe2

O

59%

83%

conditions, 70 °C

Me2NH (2 M in THF)CO (6 bar)

conditions, 100 °C

Me2NH (2 M in THF)CO (6 bar)

Conditions: 10 mol% Pd(OAc)2, PPh3 (0.74 eq), Et3N (2.4 eq), THF, 4 h.

Scheme 32.


SkewPhos (bdpp), Reeves reported the preparation of a variety ofa,b-unsaturated amides from the corresponding vinyl tosylates(Scheme 33).52 Both primary and secondary amines as well asaniline successfully participated under these conditions to affordthe amides in good yields. The aminocarbonylation of 2-phenyl-1-cyclohexenyl tosylate, a fully substituted vinyl tosylate, with ben-zylamine also gave the corresponding amide in 75% yield. Ina screening experiment, the ligand efficiency was found to be:skewphos>dcpp>dppp>dppb>dppf>dppe. The use of hydrazineas the nucleophile with naphthalene-2-tosylate afforded the acylhydrazone in moderate yield.


OTs


N

OR1

R2

N

OR1

R2

PPh2

PPh2

Me

MeR1 = H, R2 = t-Bu, 61%R1 = H, R2 = 4-OMe-Bn, 79%R1 = Me, R2 = Bn, 83%R1 = R2 = n-Bu, 95%R1R2 = -(CH2)4-, 73%R1R2= -(CH2)2-O-(CH2)2-, 75%R1 = H, R2 = NHPh, 46%

SkewPhos (bdpp)

Conditions: 1 mol% Pd(OAc)2, 2 mol% SkewPhos, K3PO4 (3 eq), 4 Å MS, toluene, 100 °C, 14−24 h.

R1 = H, R2 = Ph, 91%R1 = H, R2 = 4-OMe-Bn, 85%conditions

conditions

Scheme 33.

3. Palladium-catalyzed preparation of Weinreb amides usinggaseous CO


Zhuang and co-workers used Pd-catalyzed aminocarbonylationto prepare a Weinreb amide from an aryl bromide and N,O-dime-thylhydroxylamine hydrochloride (Scheme 34).53 A high CO pres-sure (200 psi) was used for this transformation.

BrBnN

OMeO

Me

BnMeONH(Me)•HCl

CO (200 psi)

10 mol% PdCl2PPh3 (0.6 eq)Et3N (4 eq)

NMP, 120 °C, 40 h73%

Scheme 34.

Using Xantphos as the ligand, Buchwald and co-workers pre-paredWeinreb amides via Pd-catalyzed aminocarbonylation of arylbromides under atmospheric CO pressure (Scheme 35).23,54 Thewide bite angle (110 �) and flexible coordinating backbone(97�e133�) of Xantphos were found to be crucial for the catalystactivity and stability. Thus, the ligands with bite angles rangingfrom 92� to 108�, such as DPEphos, dppf, dppb, dppp, and BINAP,were ineffective under the same conditions [DPEphos: bis(2-diphenylphosphinophenyl)ether]. Both electron-deficient andelectron-rich aryl bromides gave good yields of the correspondingWeinreb amides. However, a higher temperature and increased

amount of Xantphos (Pd/L¼1:2) were required for sterically chal-lenging ortho-substituted aryl bromides. While sodium carbonate(and triethylamine in some instances) was the preferred base formeta- and para-substituted aryl bromides, potassium phosphatewas superior for ortho-substituted aryl bromides. Several sensitivefunctionalities, such as cyano, nitro, ester, and tert-butyl carbamate,are well-tolerated in this transformation. While toluene was thesuitable solvent in most cases, m-xylene was also used for a fewortho-substituted substrates (such as 2-bromobenzotrifluoride and2-cyclohexylbromobenzene and 2-bromo-3-methylpyridine) so asto conduct the reaction at a higher temperature. In addition, thereaction of 4-chlorobenzonitrile with N,O-dimethylhydroxylaminehydrochloride afforded the Weinreb amide under similar condi-tions (at 105 �C).

Kollar and co-workers prepared Weinreb amides from iodo-benzene and 2-iodothiophene (Scheme 36).55 A higher CO pressure(60 bar) was essential as no effective conversion to the expectedWeinreb amides was observed under atmospheric CO pressure. 2-Iodopyridine and related derivatives as well as 2-iodoimidazolefailed to provide the Weinreb amides under these conditions.

BrR

R

R

NOMe

O

Me

NOMe

O

Me

Condition A: 2 mol% Pd(OAc)2, 2 mol% Xantphos, toluene, 5−22 h.Condition B: 2.5−3 mol% Pd(OAc)2, 5−6 mol% Xantphos, toluene, 20 h.

R = 3-CN, 88%R = 3-NO2, 87%R = 3-CO2Me, 88%R = 4-Cl, 87%R = 4-OMe, 89%R = 4-N(Me)Boc, 95%

R = 2,5-di-Me, 87%R = 2-CN, 84%R = 2-CO2Me, 80%R = 2-OMe, 81%

MeONH(Me)•HClCO (1 atm)

(for o-substituted)

(for m-/p-substituted)

Condition A (Pd:L = 1:1)

Na2CO3 (3 eq), 80 °C


Condition B (Pd:L = 1:2)

K3PO4 (3 eq), 100 °C

Scheme 35.


3.2. From vinyl iodides and triflates

Kollar and co-workers also converted vinyl iodides to the cor-responding Weinreb amides (Scheme 37).55 In contrast to the

Ar I Ar = Ph, 82% (in 20 h)Ar = 2-thienyl, 67% (in 110 h)


Ar NOMe

O

Me

MeONH(Me)•HClCO (60 bar)

conditions, 50 °C

Scheme 36.

negative results with aryl iodides, partial conversions (20e60%) ofvinyl iodides to Weinreb amides were observed under atmosphericCO pressure. In fact, excellent transformation of 1-(1-iodovinyl)naphthalene into the expected Weinreb amides was observed un-der atmospheric COpressure in 20 h (83% yield; 86% yield at 60 bar).

Using the Pd(OAc)2eXantphoseNa2CO3 combination, Prandireported synthesis of lactam-, lactone-, and thiolactone-derivedWeinreb amides from the corresponding triflates at room tem-perature (Scheme 38).56 Similar to aryl bromide substrates,

IR

Conditions: 2.5 mol% Pd(OAc)2

MeONH(Me)•HClCO (40−60 bar)

conditions, 50 °CR

Scheme

Z

OTfO

Z


nconditions, rt

Conditions: 2 mol% Pd(OAc)2, 2 mol% Xantp

n

Scheme

Xantphos (Pd/L¼1:1) was essential for the aminocarbonylation ofthese triflates, as other bidentate ligands, such as dppp or dppf,were ineffective. Of note, the carbonylative coupling of these tri-flates with morpholine at room temperature also provided the

corresponding amides in moderate to excellent yields (57e90%).Later, Prandi and co-workers applied these conditions to thepreparation of a Weinreb amide from N-methylindole-2-triflate(Scheme 39).57 However, a higher catalyst loading was used inthis case.

Earlier, the room temperature preparation of theWeinreb amidefrom an vinyl triflate under atmospheric CO pressure was reportedby Funk where a large excess of N,O-dimethylhydroxylaminewas used in the presence of excess Pd(OAc)2, dppp, and Et3N

R = 4-t-Bu, 87% (in 20 h)R = 2-Me, 85% (in 72 h)

, 5 mol% PPh3, Et3N−DMF.

NOMe

O

Me

37.

NOMe

Me

n = 1, Z = NTs, 75%n = 2, Z = NTs, 64%n = 2, Z = NBoc, 78%n = 2, Z = NCO2Me, 68%n = 3, Z = NCbz, 72%n = 2, Z = O, 76%n = 2, Z = S, 70%n = 2, Z = CH2, 58%

hos, Na2CO3 (3 eq), THF.

38.

NMe

OTfNMe

N

O

MeOMe


65%

conditions, rt

Conditions: 5 mol% Pd(OAc)2, 5 mol% Xantphos, Na2CO3 (3 eq), THF.

Scheme 39.


(Scheme 40).58 The successful transformation of a steroidal triflateinto the Weinreb amide was also achieved using N,O-dimethylhy-droxylamine hydrochloride in the presence of catalyticPd(OAc)2ePPh3 (Scheme 41).59

O

OOTf

MeMe

O

HEtS

O

OMe

Me

O

HEtS

N

OMe

OMe91%

MeONH(Me)CO (1 atm)

conditions, rt

Conditions: 2 eq Pd(OAc)2, 2 eq dppp, Et3N (4 eq), DMF.

Scheme 40.

O

O

Me OTf

Conditions: 8 mol% Pd(OAc)2, 15 m

MeONH(Me)•HCO (1 atm)

87%

conditions, 60

Scheme

R

X

R

R

R'−NH2, Mo(CO)6

Conditions: 3.7 mol% Herrmann's palladacyc10 mol% BINAP, 4 M aq K2CO3 (diglyme, MW, 150 °C, 15 min.

(X = I, Br)R1R2NH, Mo(CO)6

conditions

conditions

(R' = n-Bu)

[R1R

2= -(CH

2)5-]

Scheme

4. Palladium-catalyzed preparation of secondary and tertiaryamides using Mo(CO)6


Larhed and co-workers used solid molybdenum hexacarbonyl togenerate CO in situ undermicrowave that was subsequently used inthe Pd-catalyzed aminocarbonylation of aryl iodides and bromides(Scheme 42).60 In their initial experiments with solid Mo(CO)6 asthe CO-source, they used Herrmann’s palladacycle [trans-di(m-acetato)bis[o-(di-o-tolyl-phosphino)benzyl]dipalladium(II)] as thePd-catalyst and BINAP as the ligand. Diglyme as the solvent and 4 Maqueous K2CO3 were particularly effective to prevent the pre-cipitation of solid molybdenummetal on the glass surface (which isa leading cause of thermal cracking of glass due to extrememicrowave absorption). The liberation of CO from Mo(CO)6 ata constant rate was observed at 150 �C and, therefore, the amino-carbonylations were carried out at 150 �C. Although the reaction ofnon-hindered primary and secondary amines with both electron-rich and electron-deficient aryl halides gave good yields of thecorresponding amides, low yields were encountered with aromaticamines and hindered amines under similar conditions. Notably,both 10% PdeC and Pd(OAc)2 were found to be quite effective as thePd-catalyst in the aminocarbonylation of aryl iodides, but werecompletely ineffective for aryl bromides.

Wannberg and Larhed subsequently modified their Mo(CO)6aminocarbonylation protocol to expand the substrate scope forthese reactions (Scheme 43).61 In the modified protocol, they used

O

O

MeO

NMe

OMe

ol% PPh3, Et3N (10 eq), DMF.

Cl

°C

41.

N

O

NH

O(n-Bu)

PPd

O OPd

OO

Me

Me

PAr Ar

Ar Ar(Ar = o-tolyl)

R = OMe, 65-66%R = Me, 66-69%R = CF3, 74-75%R = Ac, 76-83%

Herrmann's palladacycle

le,3.5 eq),

R = OMe, 69-70%R = Me, 71-72%R = CF3, 75-78%R = Ac, 77-79%

42.

(X = I)

R = H, R1 = H, R2 = Ph, 85%R = 4-OMe, R1 = H, R2 = Ph, 87%R = 4-CF3, R1 = H, R2 = Ph, 86%R = 2-Me, R1 = H, R2 = Ph, 84%R = H, R1 = H, R2 = CH2CO2t-Bu, 64%R = H, R1 = H, R2 = CH2CO2H, 50%R = H, R1 = H, R2 = CH(i-Bu)CO2H, 46%R = H, R1R2= -(CH2)5-, 81%

(X = Br) R = 4-OMe, R1 = H, R2 = Ph, 68%R = 4-OMe, R1 = H, R2 = Bn, 92%R = 4-CF3, R1 = H, R2 = Ph, 53%R = 4-CF3, R1 = H, R2 = Bn, 95%R = 2-Me, R1 = H, R2 = Ph, 85%

X

N

O

R2

R1R1R2NH, Mo(CO)6

10 mol% Pd(OAc)2DBU (3 eq), THF

100 °C, MW, 15 min

5 mol% palladacycleDBU (3 eq), THF

150 °C, MW, 15 min

R

R1R2NH, Mo(CO)6

R

N

O

R2

R1R

Scheme 43.


DBU as the base and THF as the solvent, conditions that were almostuniformly effective for a wide range of substrates. The DBU inducedthe CO-liberation from solid Mo(CO)6 at room temperature. In fact,the pressure of the reaction mixture increased to w4 bar at 100 �Cin the presence of both DBU and solid Mo(CO)6 [<2 bar withoutDBU and Mo(CO)6]. The formation of an unstable Mo-intermediatewas proposed for this DBU-accelerated CO-generation (Fig. 8).

Mo(CO)6 ΔMo(DBU)2(CO)4 + 2CO

DBU (excess)

Fig. 8. DBU-accelerated CO-generation from Mo(CO)6.

BrR

R = H, 78−87%R = 4-OMe, 75−84%R = 4-CF3, 74−83%R = 4-Me, 86−88%R = 2-Me, 70−74%

N

OR1R1R2NH, Mo(CO)6

Conditions: 5 mol% Herrmann's palladacycle, Na2CO3 (3 eq), 170 °C, MW, 10 min.

water, conditions

[R1 = H, R2 = n-Bu; R1R2 = -(CH2)5-]

R R2

Scheme 45.

Furthermore, this modification eliminated the need for high-boiling and water-soluble diglyme, thus providing easier isolationand higher yields of benzamides in many cases. While Pd(OAc)2was able to catalyze the aminocarbonylation of aryl iodides, it wasineffective for aryl bromides; thus, Herrmann’s palladacycle wasemployed for the aryl bromides. Both electron-rich and electron-deficient aryl iodides and bromides successfully participated inthe aminocarbonylation under these modified conditions. Bothprotected and unprotected glycine underwent aminocarbonylationwith aryl iodides, although a higher amount of DBU (6 equiv) wasrequired. Nonetheless, the aminocarbonylation of iodobenzenewith unprotected L-leucine afforded the corresponding amidewithout any racemization. In addition to Mo(CO)6, other Group-VImetal carbonyl complexes, such as Cr(CO)6 and W(CO)6, are alter-native CO-sources for these reactions.

Using allylamine and Mo(CO)6 in the Pd-catalyzed amino-carbonylation of aryl iodides and bromides under microwave

NH2, Mo(CO)6

Ar

Ar X

7 mol% Pd(OAc)2DBU (3 eq), dioxane125 °C, MW, 10 min

NH2, Mo(CO)6

2.5 mol% palladacycle7 mol% [(t-Bu)3PH]BF4

DBU (3 eq), dioxane140 °C, MW, 15 min

Ar

(X = I)

(X = Br)

Scheme

heating, Larhed and co-workers prepared the correspondingN-allylbenzamides, in reactions scalable up to a 25 mmol scale(Scheme 44).62 Notably, phosphine-free aminocarbonylation of aryliodides was successfully carried out in the presence of Pd(OAc)2 andDBU in THF. On the other hand, tri-tert-butylphosphonium tetra-fluoroborate was used with Herrmann’s palladacycle for the arylbromides to afford N-allylbenzamides in good yields. While theester functionality tolerated this transformation, nitro-containingaryl halides were reduced to the corresponding aniline and ortho-amino substituted aryl halides gave a low yield of the amide due tocatalyst deactivation. The maximum CO pressure detected at anypoint during the course of these reactions was 3 bar, which, ofcourse, gradually decreases during the reaction due to the con-sumption of CO in the amidation. Of note, no significant side-product resulting from a Heck reaction of aryl halides and allyl-amine was detected under these conditions.

The microwave-assisted Pd-catalyzed aminocarbonylation ofaryl bromides using Mo(CO)6 was also successfully implemented inan aqueous medium (Scheme 45).63 Both electron-rich andelectron-deficient as well as ortho-substituted aryl bromides

NH

OAr = Ph, 73%Ar = 4-OMe-Ph, 81%Ar = 2-Me-Ph, 76%Ar = 2-thienyl, 76%Ar = 3-furyl, 72%

NH

OAr = 2-thienyl, 72%Ar = 2-furyl, 76%Ar = 3-furyl, 66%Ar = 4-COPh, 43%Ar = 4-CO2Et, 56%

44.


engage in aminocarbonylation with a variety of primary and sec-ondary amines to produce the corresponding benzamides. Notably,the aminocarbonylation of aryl bromides strongly dominated overthe hydroxycarbonylation even though reactions were conductedin water. Later, Larhed extended this rapid aminocarbonylationprotocol to aryl iodides and chlorides (Scheme 46).64

Ar NH

O(n-Bu)

Ar X

N

OR1

R2Me

N

OR1

R2Me

Ar NH

O(n-Bu)

Ar = Ph, 88%Ar = 4-OMe-Ph, 81%Ar = 4-CF3-Ph, 92%Ar = 2-Me-Ph, 65%Ar = 1-naphthyl, 83%Ar = 3-thienyl, 84%

n-BuNH2, Mo(CO)6

waterCondition A

R1 = H, R2 = Bn, 78%R1= H, R2 = c-Hex, 68%R1 = R2 = n-Bu, 52%R1R2= -(CH2)5-, 61%R1R2= -(CH2)4-, 68%

(X = I)

(X = I)

Ar = Ph, 76%Ar = 4-OMe-Ph, 74%Ar = 4-CF3-Ph, 84%Ar = 2-Me-Ph, 77%Ar = 1-naphthyl, 82%Ar = 3-thienyl, 64%

(X = Cl)

Condition A: 5 mol% Pd(OAc)2, Na2CO3 (3 eq), 110 °C, MW, 10 min.Cobdition B: 5 mol% Herrmann's palladacycle, 10 mol% [(t-Bu)3PH]BF4, Na2CO3 (3 eq), 170 °C, MW, 10−30 min.

(X = Cl)

R1 = H, R2 = Bn, 81%R1= H, R2 = c-Hex, 64%R1 = R2 = n-Bu, 44%R1R2= -(CH2)5-, 79%R1R2= -(CH2)4-, 78%

R1R2NH, Mo(CO)6

waterCondition A

n-BuNH2, Mo(CO)6water

Condition B

R1R2NH, Mo(CO)6

waterCondition B

(Ar = 4-Me-Ph)(Ar = 4-Me-Ph)

Scheme 46.

Using conventional heating, Yamazaki and Kondo preparedbenzamides from aryl iodides and bromides using solid Mo(CO)6 asthe CO-synthon (Scheme 47).65 A ligand exchange presumably fa-cilitated the CO-liberation from Mo(CO)6 in this case (Fig. 9). Al-

RX

R1R2NH, Mo(CO)6R

N

OR1

R2

R = H, R1 = H, R2 = Bn, 47%R = 4-CO2Et, R1 = H, R2 = Bn, 85%R = 4-OMe, R1 = H, R2 = CH(Ph)2, 73%R = 4-CO2Et, R1R2= -(CH2)2-O-(CH2)2-, 78%R = 4-OMe, R1R2 = -(CH2)2-O-(CH2)2-, 72%

(X = I)

(X = Br)

RN

OR1

R2

R = H, R1 = H, R2 = Bn, 57%R = 4-CO2Et, R1 = H, R2 = Bn, 88%R = 4-OMe, R1 = H, R2 = Bn, 12%R = 3-OMe, R1 = H, R2 = Bn, 70%

Condition A: 10 mol% Pd(OAc)2, 10 mol% BINAP, Cs2CO3 (1 eq), toluene−MeCN, 80 °C, 1 h.Condition B: 10 mol% Pd(OAc)2, 20 mol% BINAP, Cs2CO3 (1 eq), toluene−MeCN, 80 °C, 1 h.

Condition A

R1R2NH, Mo(CO)6

Condition B

Scheme 47.

Mo(CO)6 ΔMo(MeCN)3(CO)3 + 3CO

MeCN

Fig. 9. MeCN-assisted CO-liberation from Mo(CO)6.

though the benzamides were obtained inmoderate to high yields inmost cases, electron-rich 4-bromoanisole gave an unusually lowyield of the corresponding amide. This protocol was also applied inthe aminocarbonylation of polymer-supported aryl halides as wellas in the aminocarbonylation involving amino-resins where theamides were conveniently isolated in good purity after cleavagefrom the resin. Earlier, Takahashi described the Pd-catalyzed ami-nocarbonylation of aryl iodides with polymer-supported primaryamines and gaseous CO (15 atm).66

Queiroz and co-workers also used conventional heating for thePd-catalyzed aminocarbonylation where Mo(CO)6 was used as theCO-source (Scheme 48).67 DBUwas the base and the reactions werecarried out at 100e125 �C in dioxane.

In the presence of Pd(t-Bu3P)2 catalyst, Pd-catalyzed amino-carbonylation of 4-iodoanisole with n-butylamine was carried out

by Iizuka and Kondo using CO generated from Mo(CO)6 at roomtemperature (Scheme 49).20 Whereas the base DABCO producedthe amide as the major product, DBU facilitated the double car-bonylation to produce predominately the ketoamide.

The aminocarbonylation of aryl iodides and bromides usingMo(CO)6 as the CO-source has been widely used for the

S

X

Ar−NH2, Mo(CO)6

S

ONHAr

SNHAr

O

S

ONHAr

Condition A: 10 mol% Pd(OAc)2, Mo(CO)6, DBU (3 eq). dioxane.Condition B: 4 mol% Herrmann's palladacycle, 8 mol% [(t-Bu)3PH]BF4, DBU (0.7 eq), dioxane.

(X = 2-I)

(X = 3-I)

(X = 3-Br)

Condition A, 110 °C, 1 hAr = 4-OMe-Ph, 65%Ar = 4-CN-Ph, 70%

Ar = 3-pyridyl, 55%Ar = 2-pyridyl, 44%

Ar = 2,4-di-OMe-Ph, 86%Ar = 4-F-Ph, 70%Ar = 4-CN-Ph, 63%Ar = 3-CN-Ph, 45%Ar = 3-pyridyl, 15 % (in 3 h)Ar = 2-pyridyl, 0% (in 6 h)

SNHAr

O

(X = 2-Br)

Ar = 4-OMe-Ph, 66%

Ar−NH2, Mo(CO)6Condition A, 110 °C, 3 h

Ar−NH2, Mo(CO)6Condition B, 125 °C, 1 h

Ar−NH2, Mo(CO)6

Condition B, 125 °C, 1 h

Scheme 48.

I

MeO

Pd(t-Bu3P)2, DABCOTHF, rt, 24 h MeO

NH

O(n-Bu)

MeO

O HN

O(n-Bu)

n-BuNH2, Mo(CO)6

67%

70%

Pd(t-Bu3P)2, DBUTHF, rt, 24 h

n-BuNH2, Mo(CO)6

Scheme 49.


regioselective installation of the amide functionality. A few repre-sentative examples are shown in Table 6.

4.2. From vinyl bromides

Using solid Mo(CO)6 as the CO-generator, Larhed and co-workers achieved the aminocarbonylation of vinyl bromides(Scheme 50).72 The corresponding amides were likewise obtainedin good yields.

4.3. From aryl and vinyl triflates

The Pd-catalyzed aminocarbonylation of aryl triflates to thecorresponding amides was also effective using Mo(CO)6 as theCO-source (Scheme 51).73 The use of XPhos as the ligand, instead of[(t-Bu)3PH]BF4, produced better results in this reaction. Althoughelectron-rich triflates afforded good yields of the correspondingamides, slightly lower yields were obtained for electron-deficienttriflates, presumably due to the reduction of the triflate. Stericallychallenging 2-methylphenyl triflate provided a modest yield.DMAP was very effective in increasing the yield of those reactionsinvolving less nucleophilic and sterically hindered amines. Acting

as an acyl transfer agent, DMAP presumably afforded an acylpyr-idinium intermediate that was activated toward nucleophilic attackby the amines (Fig. 10). A dry solvent (dioxane) was highly rec-ommended to prevent the hydrolysis of triflates at the hightemperature.

Applying similar conditions to vinyl triflates, Larhed reportedthe preparation of the corresponding amides (Scheme 52).72 Infact, these reactions were efficiently carried out at a relativelylower temperature (60e80 �C) using Pd(OAc)2 as the catalyst.Inert atmosphere is necessary to obtain the amides in highyields.

4.4. From vinyl phosphates

Vinyl phosphates participate in the Pd-catalyzed amino-carbonylationusingMo(CO)6 as theCO-liberating agent (Scheme53).72

Compared to vinyl triflates, a high temperature is required for thisconversion.

4.5. From aryl and vinyl chlorides

Both electron-rich and electron-deficient aryl chloridesserve as useful substrates for the microwave-assisted Pd-cata-lyzed aminocarbonylations using Mo(CO)6 as the CO-source(Scheme 54).74 Sterically confronting ortho-substituted arylchlorides also react under these conditions. Reaction of aryl/heteroaryl chlorides with allylamine afforded the correspond-ing amides as the major product, instead of the productsresulting from a Heck reaction.62 Likewise, vinyl chloridesproduced the corresponding amides in moderate yields(Scheme 55).72

Larhed described one example of microwave-assisted amino-carbonylation of an aryl tosylate using Mo(CO)6.73 Thus, the re-action of naphthalene-2-tosylate with piperidine in the presence ofHerrmann’s palladacycle, XPhos, and Cs2CO3 produced the desiredamide in 55% yield. Unfortunately, similar conditions failed forother tosylates.

Table 6Aminocarbonylation of aryl halides using solid Mo(CO)6


1 NH

Ar

CO2EtAr

O

I

NH

Ar

CO2EtAr

O

ONHR

(Ar = 4-OMe-Ph)

R¼2,4-di-OMeeBn, 80%68

RNH2, Mo(CO)6, Pd(OAc)2, DBU, THF, 100 �C, MW, 40 min

R¼Me, 65%68

2HN

NHO

Me CO2Et

BrHN

NHO

Me CO2EtO

NHR

R¼n-Bu, 87%69

RNH2, Mo(CO)6, Herrmann’s palladacycle, [(t-Bu)3PH]BF4,DBU, THF, 130e140 �C, MW, 15 min

R¼Ph, 83%69

R¼Bn, 78%69

3HN

NHO

Me CO2Et

Br

HNNH

O

Me CO2Et

NOFor 3-Br: 71%69

R1R2NH, Mo(CO)6, Herrmann’s palladacycle, [(t-Bu)3PH]BF4,DBU, THF, 130e140 �C, MW, 15 min

For 2-Br: 21%69

4 N

BrPh

OMe N

Ph

OMe

NH

OBn

61%70

RNH2, Mo(CO)6, Herrmann’s palladacycle, [(t-Bu)3PH]BF4,DBU, MeCN, 170 �C, MW, 25 min

5 N

Br

MeO

NMeO

N

OR1

R2

R1R2¼e(CH2)2eN(i-Pr)e(CH2)2e, 97%71

R1R2NH, Mo(CO)6, Herrmann’s palladacycle [(t-Bu)3PH]BF4,DBU, THF, 125 �C, MW, 6 min

R1R2¼e(CH2)2eN(Boc)e(CH2)2e, 78%71

R1R2¼e(CH2)2eOe(CH2)2e, 82%71

6

N

N

Br

R N

NR

N

O

N(i-Pr)

R¼OMe, 88%71

R1R2NH, Mo(CO)6, Herrmann’s palladacycle [(t-Bu)3PH]BF4,DBU, THF, 125 �C, MW, 6 min

R¼H, 51%71

BrPh

Br

NH

Ph

OR

NH

OBn

RNH2, Mo(CO)6

R = Bn, 64%R = n-Hex, 72%

BnNH2, Mo(CO)6

Conditions: 2.5 mol% Herrmann's palladacycle, 5 mol% [(t-Bu)3PH]BF4,DBU (3 eq), THF, 140 °C, MW, 20 min.

conditions

conditions

73%

Scheme 50.


5. Palladium-catalyzed preparation of N-benzylamides usingBnNH2eW(CO)5

Using a tungsteneamine complex, Ren and Yamane synthesizeda series of N-benzylamides from the corresponding aryl iodides andbromides (Scheme 56).75 The air-stable solid BnNH2eW(CO)5 wasprepared from W(CO)6 in two steps. While the amides were ob-tained in good yields in the presence of Pd(OAc)2eP(o-tol)3eK2CO3,this transformation was ineffective in the absence of Pd-catalyst orligand. For aryl bromides, longer reaction times and higher catalystloading were required to maximize the amide yield. Among otherGroup-VI metal benzylamine complexes, BnNH2eMo(CO)5 pro-vided the benzamide from iodobenzene in excellent yield, butBnNH2eCr(CO)5 was onlymoderately effective. Like K2CO3, LiHMDSwas quite effective for this transformation. In contrast to the

OTf

MeO

MeO

MeO

Conditions: 2.5 mol% Pd(OAc)2, 7

R1R2NH, Mo(CO)6

conditions60 °C, MW, 20 min

R1R2NH, Mo(CO)6


Scheme

OTfR

R

N

O

R2

R1

Me

N

O R = H, 74%R = 4-OMe, 78%R = 4-CF3, 63%R = 4-Me, 93%R = 3-Me, 79%R = 2-Me, 49%

R1R2NH, Mo(CO)6

conditions, Cs2CO3 (3 eq)

R1R2NH, Mo(CO)6conditions, Cs2CO3 (3 eq)

DMAP (2 eq)(R = 4-Me)

[R1R

2= -(CH

2)5-]

R1 = H, R2 = Ph, 70%R1 = H, R2 = Bn, 92%R1 = H, R2 = t-Bu, 68%R1 = R2 = n-Bu, 51%

Conditions: 2.5 mol% Herrmann's palladacycle, 7.5 mol% XPhos, dioxane, 160 °C, MW, 20 min.

Scheme 51.

O

NArR1

R2

Ar−OTf

IILnPd

Ar

OTf

IILnPd

OTf

OAr

CO

NMe2N

NO

ArMe2N

LnPd(0)

LnPd(II)

+Base•H

R1R2NH+

Base

+ OTf

Me2N N

Fig. 10. DMAP-assisted Pd-catalyzed aminocarbonylation.

ORPO

OO

Ph

PhR

N

OR

R2

R1R2NH, Mo(CO)6

Conditions: 2.5 mol% Herrmann's palladacycleDBU (3 eq), THF, 170 °C, MW, 20

conditions

Scheme 5


acylpalladium(II) intermediate [LnPd(COAr)X] that forms in thePd-catalyzed aminocarbonylation using solid Mo(CO)6 or gaseousCO, these reactions presumably proceed via a carbamoylpalladiu-m(II) intermediate [LnPd(Ar)(CONHBn)] that is formed in thetransmetalation of LnPd(Ar)X with carbamoyltungstate.

6. Palladium-catalyzed preparation of Weinreb amides usingW(CO)6 or Mo(CO)6

Using W(CO)5 as the CO-generator, Odell reported themicrowave-assisted Pd-catalyzed synthesis of Weinreb amidesfrom aryl bromides (Scheme 57).76 In contrast to Yamane’s protocolas mentioned previously, no pre-formed tungsteneamine complexwas used in this case. Although these conditions were operationalfor a wide variety of aryl bromides (except ortho-substituted ones)and were compatible with conventional heating, only traceamounts of Weinreb amides were obtained from aryl iodides underthese conditions. Instead, a similar Mo(CO)5-mediated protocolwas found to be effective for Pd-catalyzed conversion of aryliodides to Weinreb amides. Although a low yield was obtainedwith 4-iodobenzotrifluoride under these conditions, due to theundesired reduction of aryl iodide, the sterically challenging2-iodotoluene provided the corresponding Weinreb amide in good

N

OR1

R2

N

OR1

R2

R1 = H, R2 = Bn, 67%R1 = H, R2 = n-Hex, 62%

.5 mol% XPhos, DBU (3 eq), THF.

R1 = H, R2 = Ph, 78%R1R2 = -(CH2)4-, 73%

52.

1

R = t-Bu, R1 = H, R2 = n-Hex, 47%R = t-Bu, R1 = H, R2 = Bn, 75%R = t-Bu, R1 = H, R2 = Ph, 42%R = adamantyl, R1 = H, R2 = n-Hex, 51%R = adamantyl, R1 = H, R2 = Bn, 62%R = adamantyl, R1R2 = -(CH2)4-, 27%

, 5 mol% [(t-Bu)3PH]BF4,min.

3.

R'−NH2, Mo(CO)6

R1R2NH, Mo(CO)6Ar N

O

Ar NH

OR'

Ar = 4-OMe-Ph, R' = Bn, 86%Ar = 4-CF3-Ph, R' = Bn, 89%Ar = 4-CO2Me-Ph, R' = Bn, 62%Ar = 2,6-di-Me-Ph, R' = Bn, 81%Ar = 4-CF3-Ph, R' = Ph, 64%

Condition A

Condition A

Ar = 4-OMe-Ph, 69%Ar = 2,6-di-Me-Ph, 51%Ar = 4-CO2Me-Ph, 74%

Condition A: 2.5 mol% Herrmann's palladacycle, 5 mol% [(t-Bu)3PH]BF4,DBU (3 eq), THF, 170 °C, MW, 15−25 min.

Condition B: 2.5−3.5 mol% Herrmann's palladacycle, 7−9 mol% [(t-Bu)3PH]BF4,DBU (3 eq), dioxane, 140−160 °C, MW, 15−20 min.

Ar ClNH2, Mo(CO)6 N

HAr

OAr = Ph, 67%Ar = 2-thienyl, 69%Ar = 3-furyl, 73%Condition B

[R1R2 = -(CH2)5-]

Scheme 54.

RNH2, Mo(CO)6 R = Bn, 61%R = n-Hex, 61%

Conditions: 2.5 mol% Herrmann's palladacycle, 5 mol% [(t-Bu)3PH]BF4,DBU (3 eq), THF, 170 °C, MW, 20 min.

conditions

ClNH

OR

Scheme 55.

NH2

W(CO)5Bn

Ar X

W(CO)6

NH2

W(CO)5Bn

Et4NCl[Et4N]

O

NH

ArBn

O

NH

ArBn

[ClW(CO)5]Bn–NH2

NH2

W(CO)5Bn

Ar = Ph, 95%Ar = 4-OMe-Ph, 95%Ar = 4-COMe-Ph, 85%Ar = 4-Br-Ph, 84%

Ar = 4-CO2Et-Ph, 64%Ar = 4-vinyl-Ph, 63%Ar = 1-naphthyl, 81%Ar = 2-naphthyl, 86%Ar = 3-thienyl, 63%

Condition A

Condition A: 5 mol% Pd(OAc)2, 10 mol% P(o-tol)3, K2CO3 (1.1 eq), THF, reflux, 13 20 h.Condition B: 10 mol% Pd(OAc)2, 20 mol% P(o-tol)3, K2CO3 (1.1 eq), THF, reflux, 48 84 h.

(X = I)

Condition B

(X = Br)

diglyme, 140 °C EtOH, rt

Scheme 56.


yield. However, N-methylbenzamide was obtained as a by-productin these reactions due to aminocarbonylation of aryl halides withmethylamine that was generated in situ via the reduction of N,O-dimethylhydroxylamine. Indeed, the reduction of N,O-dime-thylhydroxylamine to methylamine was quite prominent in ami-nocarbonylation involving less-reactive aryl bromides. ThePd-catalyzed synthesis of N-methyl-2-aminopyridine amides(MAP-amides) from aryl halides was also developed by Odell usingMo(CO)6 under similar conditions.

The microwave-assisted preparation of a Weinreb amide fromp-tolyl triflate via Pd-catalyzed aminocarbonylation using Mo(CO)6has also been accomplished (Scheme 58).73

7. Palladium-catalyzed preparation of tertiary amides usingDMF

Indolese and co-workers prepared N,N-dimethylbenzamideand N-methylbenzamide via Pd-catalyzed aminocarbonylation of

3-bromobenzotrifluoride with DMF and N-methylformamide,respectively, under CO (5 bar) atmosphere (Scheme 59).77 Imidaz-ole or DMAP acted as both base and acyl transfer agent to facilitatethe amide formation (Fig. 11). Notably, N,N-dimethylacetamide(DMAC) as an alternative to DMF afforded a low yield of the amide.

Hallberg and co-workers employed DMF as the CO-source in thePd-catalyzed aminocarbonylation of aryl bromides under micro-wave conditions (Scheme 60).78 These reactions were carried out inthe presence of imidazole and potassium tert-butoxide where the

MeONH(Me)•HClW(CO)6

Ar X

MeONH(Me)•HClMo(CO)6

Ar N

OOMe

Me

Ar N

OOMe

MeCondition A

(X = Br)

Condition A: 7.5 mol% Pd(OAc)2, 15 mol% Xantphos, DMAP (2 eq), K3PO4 (6 eq), dioxane, 120 °C, MW, 20 min.Condition B: 5 mol% Pd(OAc)2, 10 mol% Xantphos, DMAP (2 eq), K3PO4 (6 eq), dioxane, 110 °C, MW, 10 min.

Condition B

Ar = Ph, 70%Ar = 4-OMe-Ph, 57%Ar = 4-CF3-Ph, 37%Ar = 4-COMe-Ph, 70%Ar = 2-Me-Ph, 20%Ar = 2-naphthyl, 87%Ar = 3-quinolinyl, 84%

Ar = Ph, 80%Ar = 4-OMe-Ph, 82%Ar = 4-CF3-Ph, 39%Ar = 4-COMe-Ph, 74%Ar = 2-Me-Ph, 69%Ar = 2-naphthyl, 84%

(X = I)

Scheme 57.

OTf

Me

N

O

Me

OMe

Meconditions

Conditions: 2.5 mol% Herrmann's palladacycle, 7.5 mol% XPhos,Cs2CO3 (5 eq), dioxane, 160 °C, MW, 20 min.

67%

MeONH(Me)•HCl, Mo(CO)6

Scheme 58.

BrF3C

O

X, CO (5 bar)NMe

Me

F3CNH

OMe

F3CN

OMe

Me

1 mol% PdCl2(PPh3)2DMAP (1 eq)

dioxane, 120 °C, 18 h

1 mol% Pd(OAc)26 mol% PPh3

imidazole (1 eq)120 °C, 18 h

(DMF/DMAC as solvent)

for X = H: 89%for X = Me: 35%

78%

O

H, CO (5 bar)NH

Me

Scheme 59.

O

NArMe

MeAr−Br

IILnPd

Ar

Br

IILnPd

Br

OAr

COO

HNMe

Me

NO

ArN

LnPd(0)

LnPd(II)

+CO

HNN

+ HBr

NHN

Fig. 11. Pd-catalyzed synthesis of N,N-dimethylbenzamides using DMF.


latter base promoted the decomposition of DMF to generate carbonmonoxide in situ. In the absence of an amine nucleophile,4-bromotoluene afforded the corresponding N,N-dimethylbenza-mide. However, in the presence of excess amine, the amino-carbonylation of bromobenzene and electron-rich aryl bromidesafforded the corresponding amides in good yields. A large excess ofamine suppressed the competing side-reaction of aryl halides withdimethylamine that is generated in situ from the decomposition ofDMF. Nonetheless, electron-deficient aryl bromides failed to par-ticipate in the aminocarbonylation under these conditions. In fact,the competing BuchwaldeHartwig amination was strongly favoredfor these aryl bromides. The proposed mechanism for this trans-formation is shown in Fig. 12. The nucleophilic catalyst imidazolepresumably acted as an acyl transfer agent to form the acylimida-zole intermediate, which produces the amide upon the reactionwith the amine. While dppf and BINAP supported the efficient

production of amides, the monodentate ligands PPh3 and P(o-tol)3were ineffective.

Hiyama described the Pd-catalyzed preparation of N,N-dime-thylbenzamides using DMF and POCl3 (Scheme 61).79 No base wasused in these CO-free reactions, and a variety of iodobenzenessuccessfully engage in this reaction. However, these conditionswere ineffective for aryl bromides. The proposed mechanism forthis transformation suggests the addition of LnPd(Ar)X to the imi-nium salt [Me2Nþ]CHCl] that was formed in situ from DMF andPOCl3. Other possible mechanisms were ruled out since the cou-pling did not work for other DMF-related substrates, such asbenzaldehyde, formamide, N-methylformamide, N,N-dimethylace-tamide, and n-butyl formate. Lewis acids, such as BF3$OEt2, SnCl4,and TiCl4, were also ineffective for this transformation. This trans-formation was also reported by Bhanage using a heterogeneouscatalyst (Scheme 62).80 The catalyst was recycled and reused threetimes without significant loss of catalytic activity. Notably, the nitrogroup tolerated these conditions and the corresponding benzamidewas obtained in 66% yield.

RN

OR1

R2

R = H, R1 = H, R2 = Bn, 82%R = 4-OMe, R1 = H, R2 = Bn, 70%R = 4-Me, R1 = H, R2 = Bn, 76%R = 4-Me, R1 = H, R2 = Ph, 77%R = 2-Me, R1 = H, R2 = Bn, 94%R = 4-Me, R1R2= -(CH2)2-O-(CH2)2-, 78%

Br

O

R1R2NH, H NMe2R

5 mol% Pd(OAc)25 mol% dppf

KOt-Bu (1.5 eq)imidazole (1 eq)

190 °C, MW, 15−20 min

Scheme 60.

O

NArR1

R2

Ar−Br

IILnPd

Ar

BrO

NMe 2H

t-BuOII

LnPdBr

OAr

ΔΔCO

HNN

NO

ArN

LnPd(0)

LnPd(II)

+ HBr

Me2NHR1R2NH

NHN

Fig. 12. Pd-catalyzed aminocarbonylation using DMF as the CO-source.

I

O

Me2N HR R

O

NMe22.5 mol% Pd2(dba)3

POCl3 (2 eq)120 °C, 10−36 h

R = 4-Me, 92%R = 4-OMe, 87%R = 4-CO2Et, 72%R = 2-Me, 89%R = 4-Br, 84%

Scheme 61.

R = H, 76%R = 4-OMe, 70%R = 4-NO2, 66%R = 2-Me, 73%R = 4-Br, 63%

I

O

Me2N HR R

O

NMe210 mol% Pd−CPOCl3 (2 eq)140 °C, 24 h

Scheme 62.


Bhanage and co-workers also used a variety of N-substitutedformamides as the amide source (and solvent) in the Pd-catalyzedaminocarbonylation of aryl iodides and bromides (Scheme 63).81

Electron-rich, electron-deficient, and ortho-substituted aryl ha-lides afforded good yields of the expected amides. However,a higher temperature and an increased catalyst loading were re-quired for aryl bromides. A variety of functional groups, such aseOH, eNO2, eCOMe, were well-tolerated under these conditions.Various N-substituted formamides, including cyclic formamides (1-formylpiperidine and 4-formylmorphine), were effective for this

transformation. While Xantphos and dppf were suitable for thistransformation, dppe, dppp, and dppb failed to produce the amidesunder similar conditions.

8. Palladium-catalyzed preparation of tertiary amides usingcarbamoylsilane

Cunico and Maity synthesized N,N-dimethylamides via thePd-catalyzed coupling of aryl/heteroaryl bromides and chlorideswith an N,N-dimethylcarbamoylsilane (Scheme 64).82 Althoughbis(tri-tert-butylphosphine)palladium(0) was effective for arylbromides and chlorides, the coupling of iodobenzene with thecarbamoylsilane in the presence of Pd(t-Bu3P)2 provided the amidein very low yield (8% after 14 h). In contrast, Pd(PPh3)4 affordeda moderate yield (60% after 14 h) under the same coupling condi-tions. Pd(PPh3)4 also afforded amides in good yields in the couplingof aryl bromides with the carbamoylsilane, except for the stericallychallenging bromomesitylene. However, it was ineffective forchlorobenzenes. Notably, 2-bromopyridine successfully partici-pated in this transformation and produced the correspondingamide in good yield. These researchers also applied these condi-tions to alkenyl bromides and chlorides to afford the correspondingenamides (Scheme 65).83

9. Palladium-catalyzed preparation of secondary and tertiaryamides using ex situ generated CO

Using a sealed and interconnected two-chamber reaction set-up, Lindhardt and Skrydstrup reported the Pd-catalyzed

N

OMe

Me

N

OR1

R2

R

O

N HR1

R2

O

N HMe

Me

XR

N

OR1

R2

N

OMe

MeRCondition A

R = H, 93%R = 4-OMe, 92%R = 4-NO2, 96%R = 4-COMe, 93%R = 4-OH, 88%R = 2-OMe, 78%

(X = I)

R = H, 72%R = 2-OMe, 67%

R1 = H, R2 = n-Bu, 81%R1 = H, R2 = Bn, 88%R1 = H, R2 = Ph, 82%R1 = Me, R2 = Ph, 85%R1 = R2 = n-Bu, 90%R1, R2 = -(CH2)5-, 92%R1 = H, R2 = n-Bu, 70%

R1 = H, R2 = Ph, 59%R1 = Me, R2 = Ph, 52%R1 = R2 = n-Bu, 71%

Condition A: 3 mol% Pd(OAc)2, 6 mol% Xantphos, POCl3 (2 eq), 135 °C, 6 h.Condition B: 5 mol% Pd(OAc)2, 10 mol% Xantphos, POCl3 (2 eq), 165 °C, 24 h.

Condition A

(X = I, R = H)

O

N HMe

Me

Condition B

(X = Br)

O

N HR1

R2

Condition B

(X = Br, R = H)

Scheme 63.

Ar X

O

Me2N SiMe3

Ar NMe2

O

X = Br : Ar = Ph, 82%X = Br : Ar = 4-OMe-Ph, 76%X = Br : Ar = 4-CO2Me-Ph, 74%X = Br : Ar = 2,4-6-tri-Me-Ph, 92%X = Br : Ar = 2-thienyl, 87%X = Br : Ar = 3-furyl, 61%X = Br : Ar = 2-pyridyl, 68%X = Cl : Ar = Ph, 74%X = Cl : Ar = 4-OMe-Ph, 78%

2 4 mol% Pd(t-Bu3P)2toluene, 100 °C, 5–

–11 h

Scheme 64.

XNMe2

O

(X = Br : 74%)(X = Cl : 79%)

O

Me2N SiMe3

2−4 mol% Pd(t-Bu3P)2toluene, 100 °C, 5−11 h

Scheme 65.

Ar N

OR1

R25 mol% Pd(dba)2

10 mol% PPh3Et3N (2 eq), dioxane, 80 °C(Chamber A+B: Δ, 16−20 h)

R1R2NH, CO (generated ex-situ)

5 mol% Pd(dba)25 mol% P(t-Bu)3DIPEA (1.5 eq)dioxane, 80 °C

Ar I

MeO

Cl (1 eq)Chamber A

(CO generation chamber)

Chamber B(aminocarbonylation chamber)

Scheme 66.


aminocarbonylation of aryl iodides and bromides using CO that wasgenerated ex situ from solid 9-methyl-9H-fluorene-9-carbonylchloride (Scheme 66).84 9-Methyl-9H-fluorene-9-carbonyl chlo-ride was synthesized from commercially available 9-fluorenone infour steps via 9-methyl-9H-fluorene. The Pd-catalyzed decarbon-ylation of 9-methyl-9H-fluorene-9-carbonyl chloride produced thenon-volatile 9-methylene-fluorene by-product in the CO-generation chamber to provide clean CO for the amino-carbonylation. A high degree of CO-capture during the amino-carbonylation process was also attained in this protocol. In fact, 4-methoxy-N-hexylbenzamide was obtained in 96% yield from 4-bromoanisole using this CO-synthon as the limiting agent, in-dicating nearly quantitative CO-capture in the aminocarbonylationprocess. The high yield of amides also signified essentially stoi-chiometric conversion of 9-methyl-9H-fluorene-9-carbonyl chlo-ride into 9-methylene-fluorene, which was converted to 9-methyl-9H-fluorene (precursor of the carbonyl chloride) via Pd-catalyzedhydrogenation. This protocol was also very useful for the synthe-sis of 13C-labeled amides using 13C-labeled acid chloride as the13CO-source. Whereas aminocarbonylation of aryl iodides wascarried out in the presence of Pd(dba)2, PPh3, and Et3N in dioxane(Scheme 66), aryl bromides were aminocarbonylated usingPd(dba)2, CataCXium A, and Na2CO3 in toluene (Scheme 67).84

Several medicinally useful compounds and their 13C-labeled de-rivatives were prepared in high yields using these conditions(Tables 7 and 8). Of note, toluene is also suitable for this decar-bonylation reaction by promoting the nearly quantitative CO-re-lease from the carbonyl chloride.

Although palladium-catalyzed decarbonylation generally requiresheating, 9-methyl-9H-fluorene-9-carbonyl chloride is capable of re-leasing CO at room temperature. Thus, combining this room temper-aturePd-catalyzeddecarbonylationwithKondo’saminocarbonylationprotocol (cf. Scheme 49), 4-methoxy-N-hexylbenzamide was ob-tained from iodoanisole in high yield (Scheme 68).84 Changing thebase toDBU, theanalogousketoamidewasalsoprepared ingoodyield.Both decarbonylation and aminocarbonylation were the outcome inTHF using a slight excess of carbonyl chloride as the CO-source.

Ar N

OR1

R25 mol% Pd(dba)2

10 mol% cataCXium ANa2CO3 (3 eq), toluene, 80 °C

(Chamber A+B: Δ, 16−20 h)


5 mol% Pd(dba)25 mol% P(t-Bu)3DIPEA (1.5 eq)toluene, 80 °C

Ar Br

MeO

Cl (1 eq)Chamber A



Scheme 67.

Table 7Aminocarbonylation of aryl iodides using ex situ generated CO

Entry AreI Amide Yielda (%)

1IMeO

MeO

MeO

MeO

NH

O

R

[R = -O-(CH2)2-NMe2]

94

2I

O

O

O

O N

O

N(i-Pr)

83

3

I

OMe

X

H2NNH

ONEt2X

H2N OMe (X = Cl, Br)

63e65

4

N

I

N

NH

ONEt2 86

a Based on CO as the limiting agent.

Table 8Aminocarbonylation of aryl bromides using ex situ generated CO

Entry AreBr Amide Yielda (%)

1BrO

O

O

O

N

O

83

2Br

NH2 NH

O

84

3

Br

ONH2

Cl

Cl

O

NHO

79b

a Based on CO as the limiting agent.b DMAP (0.25 equiv) was used along with Na2CO3 (3 equiv).

I

MeO

MeO

NH

O(n-Hex)

MeO

O HN

O

conditionsDABCO (2 eq)

THF, rt, 48 h

n-HexNH2CO (1.25 eq)

conditionsDBU (2 eq)

THF, rt, 48 h

n-HexNH2CO (2.5 eq)

86%

68%

Conditions: 2 mol% Pd(dba)2, 4 mol% [(t-Bu)3PH]BF4.

(n-Hex)

[CO generated ex-situ from 9-methylfluorene-9-carbonyl chlorideusing 2 mol% Pd(dba)2, 2 mol% P(t-Bu)3, DIPEA (1.5 eq) THF at rt]

Scheme 68.


Using a similar two-chamber set-up, Lindhardt and Skrydstrupreported the Pd-catalyzed aminocarbonylation of 2-pyridyl tosy-lates using CO that was generated ex situ from pivaloyl chloride viaPd-catalyzed decarbonylation (Scheme 69).84 With only a slight

excess of pivaloyl chloride (1.5 equiv) as the CO-synthon, the cor-responding amides were obtained in good yields in the presence ofcatalytic Pd(dba)2 and 1,10-bis(diisopropylphosphino)ferrocene(Di-PrPF). Primary, secondary, and aromatic amines successfullyreact in this fashion. Even the presence of hydroxyl on the aminenucleophile was tolerated under these conditions. Use of a sub-stoichiometric amount of pivaloyl chloride (0.75 equiv) also affor-ded a good yield of product (79%) in the aminocarbonylation of 2-pyridyl tosylate with n-hexylamine.

Using air-stable solid silacarboxylic acids, such as MePh2SiCO2Has the CO-source in the two-chamber CO-releasing set-up, thisresearch group reported the aminocarbonylation of an aryl iodideto afford the corresponding amide in 82% yield (Scheme 70).85 ThePd-catalyzed decarbonylation of MePh2SiCO2H, prepared from thecorresponding chlorosilane via lithiation followed quenchingwith CO2, was performed using KF in dioxane. Other silacarboxylicacids, such as Me2PhSiCO2H and (t-Bu)Ph2SiCO2H, were also ef-fective CO-generators that can be subsequently used in the ami-nocarbonylation process. Even at room temperature, rapidCO-release from MePh2SiCO2H was observed and, thus, a ketoa-mide was obtained in 91% yield in just 2 h via the double carbon-ylation of ethyl 4-iodobenzoate with pyrrolidine. This group hasalso reported the preparation of a 13C-labeled benzamide usinga sub-stoichiometric amount of 13C-labeled silacarboxylic acid(Scheme 71).85

10. Palladium-catalyzed preparation of tertiary amides fromorganostannanes

The Pd-catalyzed coupling of aryl- and vinylorganostannanewith N-methyl-N-phenylcarbamoyl chloride gave the correspond-ing amides in moderate to good yields (Scheme 72).86 However, thearyl ester functionality was not suitable for this transformation.Only the (E)-isomer was obtained from the coupling of thecarbamoyl chloride with a (E)- and (Z)-mixture (80:20) ofstyryltributylstannane.

11. Palladium-catalyzed preparation of secondary, tertiary,and Weinreb amides from boronic acids and derivatives

Kristensen described the synthesis of various ortho-substitutedbenzamides via the Pd-catalyzed coupling of ortho-substitutedarylboronic acid neopentylglycol esters with carbamoyl chlorides(Scheme 73).87 Whereas CsF was an effective base for this trans-formation, excess carbamoyl chloride (2 equiv) was required tomaximize the yield of the amides due to slow conversion of carba-moyl chloride to carbamoyl fluoride during the reaction. Similar to

IMOMO

MeO2C

SiMeO

OH (1.5 eq)

IEtO2CPd(t-Bu3P)2, DBU

THF, rt, 2 h

O

EtO2C

O

N

MOMO

MeO2C

N

O

5 mol% Pd(dba)210 mol% PPh3

Et3N (2 eq), dioxane, 70 °C(Chamber A+B: Δ, 16 h)


KF (1.1 eq)dioxane, 70 °C

82%

Chamber A(CO generation chamber)


R1R2NH, CO (3.0 eq)

(CO generated ex-situ from MePh2SiCO2H at rt)

91%

N

O

Scheme 70.

IMeO

O

Si CMeO

OH (0.83 eq)

C

MeO

NH

OCl

Cl

O

5 mol% Pd(OAc)210 mol% CataCXium A

DBU (2 eq), toluene, 70 °C(Chamber A+B: Δ, 21 h)


KF (1.1 eq)toluene, 70 °C



13

13

74%

13

Scheme 71.

Me MeMe

OCl (1.5 eq)

RN OTs

RN

N

OR2

R1

3 mol% Pd(dba)23 mol% Di-PrPF

DIPEA (2 eq), dioxane, 80 °C(Chamber A+B: Δ, 20 h)


R = 3-Me, R1 = H, R2 = n-Hex, 82%R = 5-Cl, R1 = H, R2 = n-Hex, 85%R = 5-CF3, R1 = H, R2 = n-Hex, 64%R = H, R1 = H, R2 = Ph, 48%R = H, R1 = Me, R2 = CH(Me)-CH(OH)Ph, 67%R = H, R1R2 = -(CH2)2-N(2-OH-Ph)-(CH)2-, 88%

1 mol% Pd(dba)21 mol% P(t-Bu)3DIPEA (1 eq)dioxane, 80 °C



Scheme 69.


R/Ar SnBu3

O

N ClMe

PhO

NR/ArMe

Ph

Ar = Ph, 81%Ar = 4-OMe-Ph, 57%Ar = 4-CO2Me-Ph, 0%Ar = 3-furyl, 73%Ar = (E)-styryl, 67%R = vinyl, 74%R = 1-ethoxyvinyl, 65%

4 mol% PdCl2(PPh3)2toluene, 100 °C, 2−8 h

Scheme 72.

RB

O

OMe

Me

O

N ClR'

R'

O

N ClX

O

NR'

R'R

O

NX

R R = H, X = O, 79%R = Cl, X = O, 94%R = CN, X = O, 87%R = Ph, X = O, 76%R = OMe, X = O, 86%R = NHBoc, X = O, 79%R = F, X = NMe, 74%

R = H, R' = Et, 85%R = OMe, R' = Et, 74%R = CO2Et, R' = Et, 51%R = CN, R' = Me, 93%

Conditions: 3 mol% PdCl2(PPh3)2, CsF (2 eq), THF, reflux, 16 h.

conditions

conditions

Scheme 73.


acyclic alkyl carbamoyl chlorides, 4-methylpiperazine-1-carbonylchloride and morpholine-1-carbonyl chloride afforded benzamidesin good yields. Using these conditions, Murafuji and Sugihara effec-ted the coupling of azulene-2-boronic acid pinacol ester with car-bamoyl chlorides to afford the corresponding amides (Scheme 74).88

BO

OMe

Me

MeMe

O

N ClR1

R2

N

O

R2

R13 mol% PdCl2(PPh3)2

CsF (2 eq)THF, 80 °C, 23 h

R1 = R2 = Me, 63%R1R2 = -(CH2)2O(CH2)2-, 66%

Scheme 74.

Duan and Deng were able to couple arylboronic acids with N,N-dibutylcarbamoyl chloride to afford N,N-di(n-butyl)benzamides(Scheme 75).89 A catalytic amount of Cu2O along with the Pd-catalyst increased the yield. Both electron-rich and electron-deficient arylboronic acids participate under these conditions togive the benzamides in excellent yields. Only a moderate yieldresulted for the coupling of an ortho-substituted arylboronic acid.

Ar B(OH)2

O

N Cl(n-Bu)

(n-Bu)Ar3 mol% Pd(PPh3)4

6 mol% Cu2OK3PO4•3H2O (3.3 eq)toluene, 80 °C, 24 h

Scheme

The ‘copper-free’ Pd-catalyzed coupling of phenyl- and styr-ylboronic acid with N,N-benzylcarbamoyl chloride was reported byTakemoto (Scheme 76).90 These conditions were developed for thecoupling of alkylboranes, generated in situ from the 9-BBN hydro-boration of terminal olefins, with carbamoyl chlorides to afford theamides in a one-pot fashion. The couplings were conducted underanhydrous basic conditions to prevent the hydrolysis of carbamoylchloride. While Cs2CO3 is highly effective for these transformations,CsF, K3PO4, and K2CO3 are ineffective. Carbamoyl chlorides derivedfrom dialkyl amines, cyclic amines, and even from an amino acidsuccessfully couple to a variety of alkylboranes.

Herr and co-workers used the coupling of arylboronic acids andN-methoxy-N-methylcarbamoyl chloride to prepare Weinreb am-ides (Scheme 77).91 Both electron-rich and electron-deficientarylboronic acids undergo this transformation. Potassium organo-trifluoroborates also produced the corresponding Weinreb amidesin the presence of PdCl2(PPh3)2 and Na2CO3.

Andrus and co-workers synthesized the benzamides usinga four-component Pd-catalyzed coupling of arylboronic acids, aryldiazonium tetrafluoroborates, ammonia, and CO (Scheme 78).92

The active NHCePd catalyst was formed in situ from an imidazo-lium N-heterocyclic carbene ligand and palladium acetate. Thecoupling of potassium phenyltrifluoroborate and phenylboronicacid pinacol ester with aryl diazonium tetrafluoroborates alsoafforded the corresponding amides in comparable yields; however,

N

O(n-Bu)

(n-Bu)

Ar = Ph, 93%Ar = 4-OMe-Ph, 86%Ar = 4-CF3-Ph, 87%Ar = 4-COMe-Ph, 89%Ar = 2-Me-Ph, 60%

75.

Ar B(OH)2

O

N ClBn

Bn

R/Ar

BR/Ar

Ar N

OBn

Bn

O

NR1

R2

R/Ar

i) 9-BBN, THF0 °C to rt, 2 h

R = n-Bu, R1 = R2 = Bn, 72%R = CH2TMS, R1 = R2 = Bn, 74%R = CH2OBn, R1 = R2 = Bn, 80%R = CH(OMOM)Ph, R1 = R2 = Bn, 86%Ar = Ph, R1 = R2 = Me, 87%Ar = Ph, R1R2 = -(CH2)2O(CH2)2-, 62%

5 mol% Pd(PPh3)4Cs2CO3 (1.5 eq)THF, reflux, 16 h

Ar = Ph, 94%Ar = (E)-styryl, 96%

ii) R1R2NC(O)Cl5 mol% Pd(PPh3)4Cs2CO3 (1.5 eq)reflux, 16 h

hydroboration amidation

Scheme 76.

Ar B(OH)2

O

N ClMeO

MeAr N

OOMe

Me

Ar = 4-OMe-Ph, 89%Ar = 3-CO2Et-Ph, 87%Ar = (E)-styryl, 76%Ar = 5-indolyl, 78%Ar = 3-pyridyl, <5%

5 mol% PdCl2(PPh3)2K3PO4•H2O (2 eq)EtOH, 65 °C, 1−7 h

Scheme 77.

Ar' N2+BF4

-

Ar NH

OAr'

N N+

i-Pr

i-Pr

i-pr

i-Pr

Cl-

2 mol% Pd(OAc)24 mol% NHC-ligandNH3-saturated THF

rt, 3−6.5 hAr = Ph, Ar' = Ph, 83%Ar = 4-OMe-Ph, Ar' = Ph, 86%Ar = (E)-styryl, Ar' = Ph, 80%Ar = Ph, Ar' = 2-Me-Ph, 82%Ar = Ph, Ar' = 2-OMe-Ph, 64%

N,N-bis(2,6-diisopropylphenyl)-4,5-dihydroimidazolium

chloride

CO (5 atm)Ar B(OH)2

Scheme 78.


a longer reaction time was necessary in some cases. The Pd-catalyzed coupling of arylboronic acids and isocyanates has alsobeen used for the preparation of benzamides (Scheme 79).93

12. Palladium-catalyzed preparation of primary amides

Morera and Ortar synthesized primary amides via Pd-catalyzedcarbonylation of aryl iodides and triflates using HMDS as an

Ar'-NCO

5 mol% Pd(OAc)220 mol% PPh3THF, rt, 40 h

Ar B(OH)2 Ar NH

OAr'

Scheme

ammonia synthon (Scheme 80).94 The amides were obtained ingood yields after hydrolytic work-up. Although PPh3 was thesuitable ligand for this aminocarbonylation of a majority of aryliodides, it was ineffective for some aryl triflates. However, thebidendate dppp was suitable for these unreactive aryl triflates. Theaminocarbonylation of vinyl iodides and triflates also afforded thecorresponding primary amides in good yields. DMPU was used asthe solvent for the aminocarbonylation of vinyl iodides and

Ar = Ph, Ar' = Ph, 64%Ar = 4-(t-Bu)-Ph, Ar' = Ph, 52%Ar = 4-Br-Ph, Ar' = Ph, 32%Ar = 3,4-di-OMe-Ph, Ar' = Ph, 49%Ar = Ph, Ar' = 3-Cl-4-Me-Ph, 56%Ar = 4-(t-Bu)-Ph, Ar' = 3-Cl-4-Me-Ph, 56%

79.

Ar X

i) NH(SiMe3)2, CO (1 atm)

ii) MeOH, aq H2SO4

3 mol% PdCl26 mol% PPh3

DMF, 80 °C, 1−1.5 h

O

NH2Ar

Ar = Ph, 76%Ar = 4-OMe-Ph, 76%Ar = 4-CO2Me-Ph, 88%Ar = 1-naphthyl, 94%

(X = I)

Ar = 1-naphthyl, 86%Ar = 4-OMe-Ph, 80%5 mol% PdCl2

5 mol% dpppDMF, 80−100 °C, 2.5−4 h

i) NH(SiMe3)2, CO (1 atm)

ii) MeOH, aq H2SO4

O

NH2Ar

(X = OTf)

Scheme 80.


triflates to suppress side reactions involving DMF. A similaraminocarbonylation protocol was later employed for thesynthesis of primary amides from aryl bromides and aryl triflates(Table 9).95

Table 9Pd-catalyzed aminocarbonylation using HMDS as the ammonia synthon

Entry AreBr/OTf, conditions Amide YieldRef.

1

Br

Nn-Pr

MeO

MeO

2 Nn-Pr

MeO

MeO

2

NH2

O

69%95a

HMDS, CO, Pd(OAc)2, dppp, i-Pr2NEt, DMF, 110 �C, 24 h

2

Me

OMe

OTfOTBS

Me

OMe

OTBS

NH2

O

95%95b

HMDS, CO, PdCl2(dppf)$CH2Cl2, DMF, 100 �C, 1 h

Using formamide as the ammonia source, Indolese developeda Pd-catalyzed aminocarbonylation of aryl- and heteroaryl bro-mides to afford the corresponding primary aromatic amides(Scheme 81).77 A nucleophilic Lewis base, such as DMAP, imid-azole, or PPY, was used as the acyl transfer agent to facilitate the

Ar NH2

OAr = 3-CF3-Ph, 71%Ar = 4-Me-Ph, 82%Ar = (E)-styryl, 73%Ar = 4-COMe-Ph, 34%Ar = 2-pyridyl, 66%

1 mol% PdCl2(PPh3)2DMAP (1 eq)


O

H, CO (5 bar)H2N

Ar Br

1 mol% PdCl2(PPh3)24-pyrrolidinopyridine (1 eq)

DMAC, 120 °C, 18 h

O

NH2, CO (5 bar)H2NAr = 3-CF3-Ph, 52%

Ar NH2

O

Scheme 81.

aminocarbonylation (PPY: 4-pyrrolidinopyridine). The amidesdid not form in the absence of CO; only the dehalogenatedarenes were obtained as the major products in this case. Forless-reactive aryl halides, an increased amount of ligand (up toPd/L¼1:8) was required for catalyst stabilization to maximize theyields. With a Pd/L¼1:5 ratio, 2-chloropyridine led to the cor-responding amide in 80% yield. Whereas PPh3 was suitable forthis transformation, bidentate BINAP, DPEPhos, dppb, and dppfwere not. Attempts to use urea as the ammonia synthon alsoproduced the benzamide from 3-bromobenzotrifluoride, albeit inlow yields. DMAC was used as the solvent in this case due to lowsolubility of urea in dioxane. A possible mechanism of primaryamide formation via Pd-catalyzed aminocarbonylation is shownin Fig. 13. Acyl transfer by DMAP from acylpalladium complex toformamide and subsequent decomposition of the resulting im-ides under basic conditions afforded the primary amides. Later, itwas found that triethylamine could be used as the base in theaminocarbonylation of 3-bromobenzotrifluoride, which pro-duced the primary amide in high yield after basic work-up(Scheme 82).96 Notably, these researchers isolated the aroyl

acylimides by conducting the Pd-catalyzed aminocarbonylationof aryl bromides in the presence of triethylamine and a sub-sequent acidic work-up (these acylimides readily hydrolyze un-der aqueous basic conditions).

Alterman reported the microwave-assisted synthesis of pri-mary aromatic amides via Pd-catalyzed aminocarbonylation ofaryl bromides using formamide as a source of both NH3 and CO,and as the solvent (Scheme 83).97 Potassium tert-butoxide was therequired base for the decomposition of formamide to generate COand NH3 in situ. Imidazole was used as the acyl transfer agent topromote the aminocarbonylation. In fact, no benzamide was ob-tained in the absence of imidazole, indicating the intermediacy ofthe key acylimidazole in this process. Under these conditions,good yields of the primary benzamides were obtained after a shortreaction time (<7 min), even from 2-bromotoluene. 4-Iodotoluenealso furnished the corresponding amide in 79% yield under theseconditions. A proposed mechanism of the reaction is shown inFig. 14.

Beller described the synthesis of primary aromatic amides viaPd-catalyzed aminocarbonylation of aryl bromides using gaseousNH3 and CO (Scheme 84).98 These reactions were conducted under

Ar−Br

IILnPd

Ar

BrMe2N N

IILnPd

Br

OAr

CO

NMe2N

NO

ArMe2N

LnPd(0)

LnPd(II)

+Base•H

+Base

+ Br

O

H2N H

O

NH

HAr

O

NH2Ar

O− CO

Fig. 13. Pd-catalyzed aminocarbonylation using formamide as NH3-synthon.

BrR R

NH2

OO

NH2H

5 mol% Pd(OAc)25 mol% dppf

imidazole (1 eq)KOt-Bu (1.5 eq)

180 °C, MW, 400 s

R = H, 83%R = 4-OMe, 74%R = 4-CF3, 84%R = 4-CN, 52%R = 2-Me, 86%

Scheme 83.

Ar Br1 mol% PdCl2(PPh3)2

Et3N (1 eq)dioxane, 120 °C, 18 h

O

H, CO (5 bar)H2N

Ar NH2

O

Ar = 3-CF3-Ph, 82%

Scheme 82.


relatively low pressures of NH3 and CO, whereas ammonia servesa dual role as the nucleophile to afford the amides and as the baseto regenerate the palladium catalyst. The ligands dppf, dppp,XantPhos, diop, and dppb gave good yields of the primary benza-mides, but dppe, dpppe, and dppm and other commercially avail-able monodentate ligands were ineffective. Although phenyltriflate was converted to the benzamide in high yield, aryl chloridesrequired higher temperature (130e150 �C) and increased catalystloading. Benzyl chlorides were also converted to the correspondingamides using CO and ammonia.

Starting with phenols, a Pd-catalyzed synthesis of primaryaromatic amides via in situ formation of aryl nonaflates was re-ported by Beller (Scheme 85).99 In general, aryl nonaflates aremore stable than triflates, and yet are more reactive than theirtosylate and mesylate analogues. Accommodating nonaflate for-mation and aminocarbonylation in a one-pot process, a variety ofphenols were successfully converted to the primary benzamidesunder relatively mild conditions. Whereas 3-pyridinol affordednicotinamide in 85% yield, only a small amount of amide wasobtained from 4-pyridinol under these conditions. Phenols bearingeNO2 or eCHO functionality also gave low yields (5e15%) of the

corresponding amides. A proposed mechanism of the reaction isshown in Fig. 15.

Lindhardt and Skrydstrup synthesized primary aromatic amidesvia Pd-catalyzed aminocarbonylation of aryl bromides using solidprecursors for both ammonia and carbonmonoxide (Scheme 86).100

Thus, using a sealed interconnected two-chamber system, theseresearchers generated CO ex situ from solid 9-methyl-9H-fluorene-9-carbonyl chloride and allowed it to react in the amino-carbonylation (NH3 generated from ammonium carbamate). Bothelectron-rich and electron-deficient aryl bromides, even 4-bromobenzaldehyde and 4-bromobenzonitrile, produced the pri-mary amides in good yields. Among the tested tosylates, pyridine-2-tosylate afforded the amide in 77% yield whereas pyridine-3-tosylate and pyridine-4-tosylate did not provide the amides underthese conditions. Low conversion rates were also observed for arylchlorides.

Previously, Foldes and co-workers used ammonium carbamateas the ammonia surrogate in the Pd-catalyzed aminocarbonylationof steroidal alkenyl iodides (Scheme 87).101 Depending on the re-activity of these iodides, the reactions were conducted either underatmospheric or higher CO pressure. In general, acceleration of thereaction and increase in yield were observed by conducting thereaction at a higher CO pressure.

This group also prepared primary amides using a Pd-catalyzedaminocarbonylation and deprotection sequence (Scheme 88).102

In this two-step sequence, aminocarbonylation of aryl/alkenyl io-dides with tert-butylamine first gave the corresponding aryl/alkenyl N-tert-butyl amides, which were subsequently treated withtert-butyldimethylsilyl triflate to furnish the primary amides aftercleavage of the tert-butyl group. Of note, the deprotection was in-effective for the steroidal substrates bearing eOH and eNHfunctionalities.

Using hydroxylamine as the ammonia synthon and solidMo(CO)6 as the CO-source, Larhed described the microwave-assisted Pd-catalyzed synthesis of primary aromatic amides(Scheme 89).103 No aryl hydroxamic acid by-product, resulting fromdirect aminocarbonylation of the aryl halide with hydroxylamine,was detected under these conditions. However, a decrease in theprimary benzamide yield was observed by conducting the amino-carbonylation of aryl iodides at temperatures higher than110e130 �C. The aminocarbonylation of p-tolyl triflate also pro-duced the corresponding primary amide under these conditions,albeit in low yield (Scheme 90).73 Likewise, lower yields of ben-zamides were observed from aryl bromides with ammoniumchloride as the ammonium source (Scheme 91).103

13. Palladium-catalyzed preparation of sulfonamides andamide derivatives via aminocarbonylation

Pd-catalyzed carbonylation of 3-bromotoluene with benzene-sulfonamide was briefly studied by Schnyder and Indolese (Scheme92).96 Using a slight excess of triethylamine, they observed w70%conversion of the aryl bromide, producing the desired product in66% yield. Thus, the use of excess base (>2 equiv) is suggested forfull conversion of aryl bromide to product.

Larhed later developed a microwave-assisted synthesis ofaryl acyl sulfonamides via Pd-catalyzed carbonylation of aryl io-dides and bromides using Mo(CO)6 as the solid CO-source(Scheme 93).104 Regardless of substitution pattern, a variety ofaryl iodides and bromides provided good yields of the corre-sponding acyl sulfonamides. During their synthesis of potentialHCV NS3 protease inhibitors, Sandstrom and co-workers usedthese conditions to prepare targeted aryl acyl sulfonamides(Scheme 94).105 The conversion of p-tolyl triflate to the corre-sponding aryl acyl sulfonamides was also reported by Larhed(Scheme 95).73

O

NH2Ar Ar−Br

IILnPd

Ar

BrO

NMe2HNH

N

t-BuOII

LnPdBr

OAr

ΔΔCONH3

Me2NH

HNN

NO

ArN

LnPd(0)

LnPd(II)

+ HBr

Fig. 14. Pd-catalyzed aminocarbonylation using formamide as CO- and NH3-source.

NH3 (2 bar), CO (2 bar)Ar NH2

O Ar = Ph, 85%Ar = 4-(t-Bu)-Ph, 88%Ar = 1-naphthyl, 90%

Ar Br2 mol% Pd(OAc)2

3 mol% dppfdioxane, 100 °C, 16 h

Scheme 84.

C4F9SO2F (1 eq), DBU (1 eq)NH3 (2 bar), CO (2 bar)

Ar NH2

OAr OH

1 mol% [Pd(cinnamyl)Cl]22 mol% DPEphos

MeCN, 80 °C, 16 h

Ar = Ph, 78%Ar = 4-OMe-Ph, 83%Ar = 4-SMe-Ph, 52%Ar = 4-CF3-Ph, 82%Ar = 4-OCF3-Ph, 97%Ar = 1-naphthyl, 61%Ar = 2-naphthyl, 97%Ar = 3-pyridyl, 85%Ar = 4-pyridyl, 9%

Scheme 85.


The synthesis of a variety of aryl- and heteroaryl acyl sulfon-amides, via Pd-catalyzed carbonylation of aryl bromides, wasreported by Roberts (Scheme 96).106 These reactions werecarried out under microwave conditions using either gaseousCO (65 psi) or solid Mo(CO)6 as the CO-source. Both electron-richand electron-deficient aryl bromides, except the bulkier 2-cyclohexylbromobenzene, gave good yields of the correspondingproducts. Iodobenzene also underwent this transformation. Witha longer reaction time (20 h), 4-chlorobenzonitrile affordeda moderate yield of the acyl sulfamide. However, unactivatedaryl chlorides, such as 3-methoxychlorobenzene, did not producethe expected products under these conditions. The addition ofDMAP was found to be beneficial for the transformation ofortho-substituted aryl bromides to acyl sulfonamides usingMo(CO)6.

A microwave-assisted synthesis of aryl and heteroaryl N-acylureas, via Pd-catalyzed carbonylation, was reported by Roberts(Scheme 97).107 With slight adjustments in reaction conditions,this protocol was successful in the carbonylative coupling of var-ious aryl/heteroaryl bromides with urea. Both gaseous CO or solidMo(CO)6 were successfully used in the synthesis of these N-acylureas. Although aryl chlorides were inert under these conditions,activated aryl chlorides afforded low to moderate yield of thecorresponding aryl N-acyl ureas (Scheme 98).107 Of note, a one-

step synthesis of insecticide diflubenzuron was achieved (in45% yield) via the carbonylative coupling of 2-bromo-1,3-difluorobenzene with (4-chlorophenyl)urea under similarconditions.

Using solid Mo(CO)6 as the CO-source, Larhed and co-workersperformed Pd-catalyzed carbonylation of aryl iodides and bro-mides with substituted hydrazines (Scheme 99).108 Notably, theconsumption of the aryl iodides occurred within 5 min in mostcases, except for electron-rich 4-iodoanisole. A shorter reactiontime was suggested to prevent the decomposition of products.However, aryl chlorides were inert under these conditions. ThePd-catalyzed aminocarbonylation of aryl and alkenyl iodides withaminophosphonate afforded the corresponding amides in goodyields (Scheme 100).109 Only trace ketoamide by-products weredetected under these conditions.

Ar−OHC4F9SO2F

DBUAr−ONf

II IILnPd

H

ONfLnPd

Ar

ONf

O

NH2Ar IILnPd

ONf

OAr

CO

LnPd(0)

LnPd(II)

Base•HONf

Base

NH3

Fig. 15. Pd-catalyzed synthesis of primary aromatic amides from phenols.

O

ONH4, CO (generated ex-situ)H2N

Ar NH2

O

5 mol% Pd(dba)2, 5 mol% JosiphosNaHCO3 (1.3 eq), dioxane, 100 °C

(Chamber A+B: Δ, 20 h)

Ar = 4-Me-Ph, 99%Ar = 4-OTs-Ph, 88%Ar = 4-CN-Ph, 90%Ar = 4-COMe-Ph, 96%Ar = 4-CHO-Ph, 65%Ar = 2-Me-Ph, 86%Ar = 3-pyridyl, 89%

5 mol% Pd(dba)25 mol% [(t-Bu)3PH]BF4DIPEA (1.5 eq)dioxane, 100 °C

Ar Br

MeO

Cl (1.3 eq)Chamber A



Scheme 86.

NOR

I O

ONH4H2N

NOR

ONH2

R = H, 91%R = Me, 90%

5 mol% Pd(OAc)210 mol% PPh3Et3N (1.3 eq)


CO (6 bar)

IO

ONH4H2N



CO (1 bar)

ONH2

71%

Scheme 87.


14. Preparation of heterocycles via palladium-catalyzedaminocarbonylation

Banandco-workersprepared isoindolinonesvia thePd-catalyzedintramolecular aminocarbonylation of N-benzyl-2-bromobenz-ylamine under atmospheric CO pressure (Scheme 101).110 The re-lated six- and seven-memberedbenzolactamswere also synthesizedusing similar conditions.

The Pd-catalyzed aminocarbonylation of 2-iodobenzylamineafforded 1-isoindolinone (Scheme 102).111 An increased yield of1-isoindolinone was realized with a primary amine additivesuch as tert-butylamine. Furthermore, a series of N-substituted1-isoindolinones were prepared by Kollar and co-workers viaPd-catalyzed aminocarbonylation of 2-iodobenzyl bromide usingexcess primary amines (and amino acid esters) under atmosphericCO pressure.111 A proposed mechanism for this transformation isshown in Fig. 16. Grigg demonstrated the use of palladium nano-particles, generated from a palladacycle, for the synthesis of iso-indolinones from 2-iodobenzyl bromide.112

Another synthesis of isoindolinones was realized by Cho andRen via the Pd-catalyzed carbonylative cyclization of imines, gen-erated in situ from 2-bromobenzaldehyde and primary amines(Scheme 103).113 Later, this protocol was used to synthesizehydroisoindolinones.114

Ban applied Pd-catalyzed intramolecular aminocarbonylation tothe synthesis of 1,4-benzodiazepines (Scheme 104).115 Utilizing Pd-catalyzed aminocarbonylation, Ban also developed a one-step

synthesis of 1,4-benzodiazepines and quinazolinones from2-iodoaniline.116, 117 While 2-pyrrolidinone furnished the corre-sponding dihydropyrrolo[2,1-b]quinazolin-9-one in 52% yield,2-piperidone afforded only 3% yield of the corresponding productunder similar conditions. Nonetheless, the coupling of N-carbme-thoxy-2-iodoaniline and N-acetyl-2-iodoaniline with tryptamineprovided high yields of the corresponding quinazoline-2,4-dioneand quinazolin-4-one, respectively (Scheme 105).117 Likewise, thesynthesis of 2,3,4,5-tetrahydro-2,4-benzodiazepine-1,3-dione wasaccomplished by Ferraccioli and co-workers via Pd-catalyzed car-bonylative cyclization of a (o-iodobenzyl)urea under atmosphericCO pressure (Scheme 106).118

The synthesis of 1,8-naphthalimides was reported by Kollar viapalladium-catalyzed aminocarbonylation of 1,8-diiodonaphthalenewith various primary amines and amino acid esters (Scheme107).119 The optimal ratio for amine to diiodide was 1:1, as theuse of excess amine instead provided the 1,8-dicarboxamides as themajor products.

Using hydrazines as the nucleophile, Kollar studied Pd-catalyzedsynthesis of 3,4-dihydro-1-phthalazinones from 2-iodobenzylbromide (Scheme 108).120 While the reaction of 2-iodobenzylbromide with methylhydrazine afforded 3-methyl-3,4-dihydrophthalazin-1-one, a similar reaction of 2-iodobenzyl bro-mide with phenylhydrazine produced 2-phenyl-3,4-dihydrophthalazin-1-one as the major product. For methylhy-drazine, the initial nucleophilic attack on the benzylic positionoccurred through the more nucleophilic nitrogen, whereas

Me

Me

H

I

RI

R

MeO H

N

Me

H

(t-Bu)

NH

O(t-Bu)

TBDMSOTf

TBDMSOTfR

NH2

O

MeO

NH2

Me

H

R = H, 85%R = 4-OMe, 58%R = 3-NO2, 72%

74−91%


toluene, 60 °C, 8 h95%

toluene, 60 °C, 8 h

98%

(t-Bu)NH2, CO (1 bar)




(t-Bu)NH2, CO (1 bar)

Scheme 88.

RX

RNH2

OR = H, 75%R = 4-OMe, 71%R = 4-CF3, 80%R = 2-Me, 78%

RNH2

OR = H, 77%R = 4-OMe, 78%R = 4-CF3, 76%R = 2-Me, 84%

NH2OH•HCl, Mo(CO)6




(X = I)

(X = Br)

Conditions: 5 mol% Herrmann's palladacycle, 10 mol% [(t-Bu)3PH]BF4,DBU (1 eq), i-Pr2NEt (2 eq), dioxane.

Scheme 89.

OTf

Me

NH2

O

Me



Conditions: 2.5 mol% Herrmann's palladacycle, 7.5 mol% XPhos,Cs2CO3 (5 eq), dioxane.

55%

Scheme 90.

Ar NH2

ONH4Cl, Mo(CO)6conditions

150 °C, MW, 20 min

Conditions: 5 mol% Herrmann's palladacycle, 10 mol% [(t-Bu)3PH]BF4,DBU (1 eq), i-Pr2NEt (2 eq), dixoxne.

Ar = Ph, 69%Ar = 1-naphthyl, 55%Ar Br

Scheme 91.

BrMe MeNH

OS PhO

OH2NSO2Ph, CO (5 bar)

1 mol% PdCl2(PPh3)24 mol% PPh3Et3N (1.05 eq)

dioxane, 120 °C, 15 h66% (~ 70% conversion)

Scheme 92.


phenylhydrazine primarily added in the opposite sense. Likewise,reaction with 1,2-dimethylhydrazine and 1,1-dimethylhydrazineafforded 2,3-dimethyl-3,4-dihydro-1-phthalazinone and 3-methyl-3,4-dihydro-1-phthalazinone, respectively. The loss ofmethyl iodide from the resulting quaternary salt provided 1-(2-iodobenzyl)-1-methylhydrazine, which subsequently engaged inthe aminocarbonylation to furnish the final product.

Grigg and co-workers synthesized a series of 3-substitutedisoindolin-1-ones via a novel aminocarbonylationeMichael addi-tion cascade.121 Thus, the reaction of aryl iodides, bearing a Michaelacceptor at the ortho-position, with aliphatic or aromatic amines inthe presence of a Pd-catalyst under CO atmosphere gave the cor-responding isoindolinones in good yields (Scheme 109). Aryl io-dides bearing an enamide at the ortho-position also provide thecorresponding products via the same cascade (Scheme 110).121 Thisgroup extended the protocol to mono- and di-substituted hydra-zines to afford either the isoindolones via a 5-exo-trig cyclizationthrough the amidic nitrogen or the phthalazones via a 6-exo-trigcyclization through the non-amidic nitrogen (Scheme 111).122

Cacchi and Marinelli achieved a one-pot synthesis of 2-aryl and2-vinylbenzoxazin-4-ones using Pd-catalyzed aminocarbonylationas the key step (Scheme 112).123 Under their optimized conditions,the coupling of 2-iodoaniline with an aryl iodide or alkenyl triflatein the presence of Pd(PPh3)4 and K2CO3 under atmospheric COpressure afforded the corresponding benzoxazinones. The car-bonylation was highly chemoselective in providing the key anilide,

SO

RNH

OAr

Ar = Ph, R = 4-Me-Ph, 80%Ar = 4-OMe-Ph, R = 4-Me-Ph, 88%Ar = 4-CF3-Ph, R = 4-Me-Ph, 76%Ar = 2-Me-Ph, R = 4-Me-Ph, 88%Ar = 1-naphthyl, R = 4-Me-Ph, 74%Ar = 2-thienyl, R = 4-Me-Ph, 65%Ar = 4-Me-Ph, R = 4-Br-Ph, 84%Ar = 4-Me-Ph, R = Me, 72%Ar = 4-Me-Ph, R = CF3, 71%

Ar X

H2NSO2R, Mo(CO)6

Condition A: 1 mol% Pd(OAc)2, DBU (3 eq), dioxane.Condition B: 5 mol% Herrmann's palladacycle, 10 mol% [(t-Bu)3PH]BF4,

DBU (3 eq), dioxane.

Ar = Ph, R = 4-Me-Ph, 95%Ar = 4-OMe-Ph, R = 4-Me-Ph, 93%Ar = 4-CF3-Ph, R = 4-Me-Ph, 95%Ar = 2-Me-Ph, R = 4-Me-Ph, 93%Ar = 1-naphthyl, R = 4-Me-Ph, 96%Ar = 2-thienyl, R = 4-Me-Ph, 79%Ar = 4-Me-Ph, R = Me, 88%Ar = 4-Me-Ph, R = CF3, 80%

(X = I)

(X = Br)

SO

RNH

OAr

Condition A110 °C, MW, 15 min

H2NSO2R, Mo(CO)6

Condition B140 °C, MW, 15 min

Scheme 93.

N

HN

O

O

O(t-Bu)

NHBoc

ArBr

N

HN

O

O

O(t-Bu)

NHBoc

Ar O

NH

SO2R

N

OMe

Ph

(9 examples : 35–62%)

Herrmann’s palladacycle[(t-Bu)3PH]BF4DBU, dioxane

MW, 140 °C, 15 min

(R = Ph, Me, c-Pr, Bn, 4-OMe-Ph, 4-CF3-Ph, 2-thienyl)

H2NSO2R, Mo(CO)6

Ar =

Scheme 94.

OTf

Me

NH

O

Me

NH2SO2Me, Mo(CO)6


Conditions: 2.5 mol% Herrmann's palladacycle, 7.5 mol% XPhos,Cs2CO3 (3 eq), dioxane.

62%

SO2Me

Scheme 95.


which bears an ortho-iodophenyl functionality, that underwenta second carbonylation followed by base-mediated intramolecularnucleophilic attack of the amide oxygen to the acylpalladium(II)complex to afford the benzoxazinone by regenerating Pd(0)catalyst.

Using aryl bromides and 2-bromoanilines as the starting mate-rials, Beller developed another similar synthesis of 2-arylbenzox-azinones that involved two sequential Pd-catalyzed carbonylationsfollowed by an intramolecular cyclization (Scheme 113).124 As seenin the previous case, the initial oxidative addition was highly che-moselective toward the aryl/heteroaryl bromides rather than to theelectron-rich 2-bromoanilines, a factor that directed formation ofthe 2-arylbenzoxazinones. Although di(1-adamantyl)-n-butyl-phosphine was used as the ligand along with the Pd(OAc)2 catalyst,PCy3 and P(t-Bu)3 were also effective for this transformation. 3-Bromobenzothiophene and N-methyl-5-bromoindole underwentthis domino process with 2-bromoaniline to afford the corre-sponding 2-heteroarylbenzoxazinones in good yields. The proposed

mechanism for this transformation is shown in Fig. 17. In fact, N-(2-bromophenyl)benzamide, the key intermediate for the synthesisof 2-phenylbenzoxazinone, was isolated and treated separatelyunder the same Pd-catalyzed conditions; 2-phenylbenzoxazinonewas obtained in 92% yield from this isolated intermediate.

The synthesis of fused isoquinolinones via a one-pot Pd-cata-lyzed carboxyamidation and aldol condensation cascade was re-ported by Alper (Scheme 114).125 In these three-componentreactions, aryl halides, carrying an active methylene group at theortho-position (e.g., ethyl 2-iodophenylacetate, 2-iodopheny-lacetonitrile, and 2-iodobenzyl phenyl sulfone) were treated withlactams under CO atmosphere in the presence of a Pd-catalyst.Intramolecular in situ aldol condensation of the amide, resultingfrom the carbonylative coupling of aryl iodide and lactam, affordedthe fused isoquinolinones. Although K2CO3 was suitable for mostcases, the stronger base Cs2CO3 was essential for the electron-richsubstrates, such as ethyl 2-(2-iodo-4,5-dimethoxyphenyl)acetateand ethyl 3,4-methylenedioxy-6-iodophenylacetate, in order toachieve a successful aldol reaction and to furnish the fused iso-quinolines. However, KOt-Bu and Et3N were ineffective for thiscascade. The proposed reaction mechanism for this transformationis shown in Fig. 18. Later, they extended this protocol for thesynthesis of oxazolo- and pyrazoloisoquinolinones.126 Thus, thereaction of aryl iodides, bearing an active methylene moiety atthe ortho-position [e.g., ethyl 2-(2-iodophenylethyl)acetateand 2-iodophenyl acetonitrile] with oxazolidinones and pyr-azolidinones gave the corresponding products (Scheme 115). Inaddition, 2-iodobenzyl sulfones with a bromo or chloro substituentalso participated in this cascade. Likewise, the reaction of aryl

SNN

H

O O

Ar

O

R2

Ar Br

Condition A100 °C, MW, 4 h

Ar = Ph, R1R2 = -(CH2)4-, 92%Ar = 4-OMe-Ph, R1R2 = -(CH2)4-, 80%Ar = 4-CN-Ph, R1R2 = -(CH2)4-, 80%Ar = 2-Me-Ph, R1R2 = -(CH2)4-, 83%Ar = 3-pyridyl, R1R2 = -(CH2)4-, 56%Ar = 4-CN-Ph, R1 = H, R2 = Me, 75%Ar = 4-CN-Ph, R1 = H, R2 = Ph, 50%

Condition B100 °C, MW, 2.5 h

Ar = Ph, R1R2 = -(CH2)4- , 78%Ar = 4-OMe-Ph, R1R2 = -(CH2)4- , 88%Ar = 4-CF3-Ph, R1R2 = -(CH2)4- , 73%Ar = 2-F-Ph, R1R2 = -(CH2)4- , 78%Ar = 3-furyl, R1R2 = -(CH2)4-, 84%Ar = 3-pyridyl, R1R2 = -(CH2)4-, 74%Ar = Ph, R1 = H, R2 = Me, 91%Ar = Ph, R1 = H, R2 = Ph, 72%

SNN

H

O O

Ar

O

R2

R1

R1

Ar = 2-Cl-Ph, R1R2 = -(CH2)4- , 20% (56% with DMAP additive)Ar = 2-Me-Ph, R1R2 = -(CH2)4- , 0% (60% with DMAP additive)Ar = 2-OMe-Ph, R1R2 = -(CH2)4- , 0% (68% with DMAP additive)

Condition A: 10 mol% PdCl2(dppf)•CH2Cl2, Et3N (3 eq), DMAP (1 eq), dioxane.Condition B: 10 mol% Herrmann's palladacycle, 20 mol% [(t-Bu3)PH]BF4, DBU (3 eq), dioxane.

NH2SO2NR1R2, CO (65 psi)

NH2SO2NR1R2, Mo(CO)6

Scheme 96.

O

NNH

Ar

O

O

NNH

Ar

O

O

NH2N

O

NH2N

Ar Br

O

R2R1N NH2

O

NH2N

Mo(CO)6

O

NNH

Ar

O

O

HN NH

O

NH2N

O

NNH

Ar

O

O

NNH R2

R1Ph

O

Ph

O

N NH

O

Ar = Ph, 74%Ar = 4-OMe-Ph, 50%Ar = 4-CF3-Ph, 60%Ar = 4-CN-Ph, 74%Ar = 4-Cl-Ph, 72%Ar = 3-thienyl, 75%Ar = 3-furyl, 85%Ar = 3-pyridyl, 76%Ar = 3-quinolinyl, 89%

Ar = 2-Me-Ph, 90%Ar = 2-OMe-Ph, 90%Ar = 2-F-Ph, 89%Ar = 2,6-di-F-Ph, 0%

Ar = 2,6-di-F-Ph, 50%Ar = 2,6-di-Me-Ph, 4%

R1 = H, R2 = Me, 91%R1 = H, R2 = Bn, 58%R1 = H, R2 = Ph, 57%R1 = R2 = Me, 62%

n

n

Ar = Ph, 83%Ar = 4-OMe-Ph, 55%Ar = 4-CF3-Ph, 60%Ar = 2-Me-Ph, 78%Ar = 3-thienyl, 60%

Condition A: 10 mol% PdCl2(dppf)•CH2Cl2, Et3N (3 eq), dioxane, 100 °C, MW, 4 h.Condition B: 10 mol% PdCl2(dppf)•CH2Cl2, Et3N (3 eq), DMAP (1 eq), dioxane, 100 °C, MW, 7 h.Condition C: 10 mol% Pd(OAc)2, 15 mol% Xantphos, Et3N (1 eq), dioxane, 100 °C, MW, 4 h.Condition D: 10 mol% Herrmann's palladacycle, 20 mol% [(t-Bu)3PH]BF4, DBU (3 eq), DMAP (1 eq),

dioxane, 100 °C, MW, 2.5 h.

Condition A

CO (65 psi)

Condition B

CO (65 psi)

Condition C

CO (65 psi)

Condition D

Condition A

CO (65 psi)

Condition A

CO (65 psi)

(Ar = Ph)

(Ar = Ph)

n = 1, 64%n = 2, 51%

Scheme 97.


bromides, bearing an active methylene group at the ortho-position[e.g., ethyl 2-(2-bromophenyl)acetate and 2-bromobenzyl phenylsulfone], withN-phenylpyrazolidinones gave the expected products(Scheme 116). However, a higher CO pressure, higher catalyst load-ing, and higher temperature were required for aryl bromides thanrequired for the aryl iodides.

Alper also developed a Pd-catalyzed synthesis of 1,4-benzo- andpyrido-oxazepinones via one-pot sequential ring-opening and

cyclocarbonylation of N-tosylaziridines with 2-halophenols/pyr-idinol (Scheme 117).127 This chemistry was carried out using10 mol % benzyltriethylammonium chloride (TEBA) additive alongwith Pd(OAc)2ePPh3eCs2CO3. This domino process worked for2-bromophenols where 18-crown-6 was used as the additive in thepresence of 3 mol % PdCl2(PPh3)2, 6 mol % dppf, and K2CO3 (3 equiv)in DMF at a higher temperature (130 �C for 48 h) and under higherCO pressure (400 psi). The suggested mechanism for this

A

Cl

NC

O

NH2NO

NNH

O

ANCconditions

CO (65 psi) A = CH, 68%A = N, 35%

conditions: 10 mol% PdCl2(dppf)•CH2Cl2, Et3N (3 eq), dioxane, 100 °C, MW, 20 h.

Scheme 98.

X

(X = I)

(X = Br)

Condition A: 10 mol% Pd(OAc)2, DBU (3 eq), air, THF.Condition B: 2.5 mol% Herrmann's palladacycle, 10 mol% [(t-Bu)3PH]BF4, air, THF.

H2N−NH−R', Mo(CO)6 NH

O HN

R'

(R' = COPh)

R = Me, 57%R = OMe, 50%R = CF3, 43%

R' = COPh, 57−78%R' = COBn, 48−59%R' = Boc, 40−45%

(R = Me, OMe, CF3)

R

RCondition A110 °C, MW, 5−15 min

H2N−NH−R', Mo(CO)6Condition B

130 °C, MW, 5 min

NH

O HN

R'

R

Scheme 99.

Ph

PNH O

OEtOEtAr

O

Ph

PNH O

OEtOEt

O

Ar = Ph, 72%Ar = 2-thienyl, 76%

R = H, R' = H, 82%R = H, R' = t-Bu, 80%R = Me, R' = H, 43% (at 40 bar)

I

R RR' R'

H2NCH(Ph)P(O)(OEt)2CO (40 bar)

conditions50 °C, 20−40 h


H2NCH(Ph)P(O)(OEt)2CO (1 bar)


Ar−I

Scheme 100.

BrHN

CO (1 atm)

2 mol% Pd(OAc)24 mol% PPh3

n-Bu3N (1.1 eq)100 °C, 26 h

Rn n

N

O

R

n = 1, R = Bn, 63%n = 2, R = Bn, 65%n = 3, R = Bn, 63%n = 1, R = H, 38%n = 3, R = H, 41%

Scheme 101.


transformation is shown in Fig. 19 where the reaction sequence isinitiated by the base-catalyzed ring-opening of N-tosylaziridines by2-halophenols or 2-halopyridinols followed by intramolecularaminocarbonylation. Utilizing this palladium-catalyzed tandemring-opening/aminocarbonylation sequence, this group accom-plished the one-pot synthesis of 1,4-benzothiazepin-5-ones from2-iodothiophenols andN-tosylaziridines (Scheme 118).128 Althoughno additive was used in this case, these reactions were carried outat a higher CO pressure (500 psi). The JohnPhos ligand waseffective for this transformation, but the commonly usedXantphos, binap, and dppf were either only moderately active or

completely ineffective. As shown in Fig. 19, the reaction sequence isinitiated by base-catalyzed ring-opening of N-tosylaziridines by 2-iodothiophenols.

Staben and Blaquiere synthesized fully substituted 1,2,4-triazoles using the Pd-catalyzed carbonylative coupling of aryl/heteroaryl iodides with amidines followed by an in situ cyclizationwith mono-substituted hydrazines (Scheme 119).129 Both electron-rich and electron-deficient aryl and heteroaryl iodides engaged inthe Pd-catalyzed coupling with alkyl, aryl, and heteroaryl amidinesto afford the intermediates that underwent cyclization with alkyl,aryl, or heteroaryl hydrazines. Triazole formation was completely

I

Br

Et3N•HBr

I

NHR

LnPdI

CO

II

LnPdI

O

NHRII

NR

LnPd

O

Et3N

II

O

N R

Et3N•HI

LnPd(0)

LnPd(II)

RNH2+

Et3N

NHR

Fig. 16. Pd-catalyzed synthesis of isoindolinones from 2-iodobenzyl bromide.

I

Br

Conditions: 2.5 mol% Pd(OAc)2, 5 mol% PPh3, Et3N−DMF, 50 °C.

N

O

R

R = t-Bu, 89% (in 90 h)R = Ph, 85% (in 48 h)R = CH2CO2Me, 89% (in 24 h)R = CH(Me)CO2Me, 82% (in 24 h)

I

NH2NH

O

76% (89% with t-BuNH2 additive)

RNH2, CO (1 bar)

conditions, 24−90 h

CO (1 bar)

conditions, 70 h

Scheme 102.

Br

CHON

O

RRNH2, CO (10 atm)

4 mol% PdCl2(PhCN)28 mol% PPh3

DMF, 100 °C, 24 h

via

Br

NR

R = Ph, 81%R = 4-OMe-Ph, 77%R = 4-Cl-Ph, 76%R = 2-Me-Ph, 86%R = 2,6-di-Me-Ph, 78%R = 3-pyridyl, 61%

R = Ph, 55%R = 4-OMe-Ph, 37%R = 4-Cl-Ph, 59%R = 2-Me-Ph, 75%

Br

CHON

O

RRNH2, CO (10 atm)

4 mol% PdCl2(PhCN)2DMF, 60 °C, 10 h

Scheme 103.


regioselective in all cases. Aqueous hydrazine led to 5-aryl-1H tri-azoles under these conditions, albeit in moderate yield.

15. Molybdenum-mediated amidation of aryl iodides andbromides

Using a molybdenumecarbonyl amine complex, Ren andYamane synthesized N-benzylbenzamides from aryl iodides orbromides (Scheme 120).130 TheN-benzyl aryl amideswere obtainedin good yields even though no palladium catalyst was used for thistransformation. An analogous tungsten complex was also effectivefor this transformation, but to a lesser extent. However, only traceamounts of benzamides were obtained using a chromium complex.Both electron-rich and electron-deficient aryl iodides and bromides,

irrespective of substitution pattern, produced the correspondingamides in good yields (based on the molybdenumeamine complexas the limiting reagent). Apparently due to the coordinationbetween pyridine nitrogen and molybdenum, low yields of amideswere obtained from 2-bromopyridine. Benzyl and alkenyl bromidesunderwent coupling with this molybdenumecarbonyl amine com-plex. In contrast to Pd-catalyzed aminocarbonylation of aryl halidesusing the tungsteneamine complex, the molybdenumecarbonylamine complex mediated protocol afforded the amides in goodyields within a short reaction time (w3 h). Likewise, the molybde-numecarbonyl pyrrolidine complex providedN-benzoylpyrrolidinefrom iodobenzene in excellent yield (91%).

Apart from the aforementioned N-benzyl aryl/heteroaryl am-ides, a similar protocol was later used by Ren and Yamane for the

I

NH2

HN

MeO2CN

NH

O

O

N

N

O R

CO (3 atm)

conditionsn = 1, 79%n = 2 ,18%n

n

Conditions: cat Pd(OAc)2−PPh3, K2CO3, HMPA, 110−120 °C, 12−24 h.

Br

N

Cl

Me

O HN

R

N

N

O

OMe

RCl

R = Ac, 48%R = Bn, 30%

CO (4−5 atm)

10 mol% Pd(OAc)2PPh3 (1 eq)

n-Bu3N (1.7 eq), HMPA110 °C, 40 h

HN

R

CO (3−5 atm)

conditions

n

O

n = 1, R = CO2Me, 37%n = 1, R = H, 52%n = 2, R = H, 3%

n

Scheme 104.

I

NH

O

OMe H2NAr

I

NH

Me

O

N

NH

O

O

NH

N

N

ONH

Me

, CO (1 atm)

Conditions: cat Pd(OAc)2−PPh3, K2CO3, HMPA, 110−120 °C, 12−24 h.

91%

77%

conditions

(Ar = 3-indolyl)

H2NAr

, CO (1 atm)

conditions

(Ar = 3-indolyl)

Scheme 105.

I

NHN

OR'

R

(R = n-Bu, R' = Ph)

CO (1 atm)

10 mol% Pd(PPh3)4KOAc (1.5 eq)

DMF, 80 °C, 2.5 h

N

N

O R'

O

R

92%

Scheme 106.


synthesis of a variety of amides from the carbonylative coupling ofaryl/heteroaryl halides with amines in the presence of Mo(CO)6, tri-n-butylamine, and Et4NCl (Scheme 121).131 Although no Pd-catalystwas required for this transformation, no amide was obtained in theabsence of Et4NCl. Both electron-rich and electron-deficient aryliodides afforded excellent yields of the corresponding amides in

most cases. Anilines, alkyl amines, acyclic and cyclic secondaryamines were successfully aminocarbonylated under these condi-tions. In addition, pyrrole, indazole, and carbazole also behave asnucleophiles in the carbonylative coupling of iodobenzene to fur-nish the corresponding amides. Interestingly, only a trace amountof amide was obtained from the coupling of 3-chloropyridine withbenzylamine while 2-bromo- and 2-chloropyridine provided35e45% yield of the corresponding amides. Furthermore, the car-bonylative coupling of 2-chloro-5-iodopyridine with benzylamineproduced N-benzyl-5-iodopicolinamide in 53% yield, instead of theanticipated N-benzyl-6-chloronicotinamide. Benzyl bromide alsoafforded the corresponding amide in moderate yield upon couplingwith benzylamine. A relatively lower temperature (80e100 �C) wasalso sufficient for the aminocarbonylation of alkenyl iodides andbromides than that required for aryl iodides/bromides. Notably, useof W(CO)6 in the aminocarbonylation of iodobenzene with ben-zylamine also afforded an excellent (90%) yield of N-benzylbenza-mide under these conditions.

Ren and Yamane prepared primary benzamides via themolybdenum-catalyzed carbonylation of iodobenzenes with aque-ous ammonia (Scheme 122).131 3-Bromothiophene and (E)-styrylbromide afforded the corresponding primary amides under theseconditions. Their earlier effort using a tungsteneammonia complex,prepared from W(CO)5Cl�NEt4 and aqueous ammonia, gave theprimary benzamide from iodobenzene, albeit in low yield.130 Theintramolecular molybdenum-catalyzed aminocarbonylation of 2-iodobenzylamine and (2-iodophenyl)ethyl amine afforded the ex-pected benzolactams in moderate yields (Scheme 123).131

Using microwave-irradiation in the molybdenum-mediatedcarbonylative coupling of aryl iodides and bromides with amines,Roberts and co-workers synthesized a variety of primary, second-ary, and tertiary amides (Scheme 124).132 These conversions werecarried out without any palladium catalyst and even in the absenceof tri-n-butylamine. Both electron-rich and electron-deficient aryland heteroaryl halides as well as ortho-substituted aryl halidesreacted with benzylamine in the presence of stoichiometricMo(CO)6 (Scheme 125).132 While the aforementioned Mo(CO)6-mediated reactions required high temperatures (160e200 �C), the

I

IN

O

O

R

R = Ph, 80% (in 42 h)R = Bn, 82% (in 42 h)R = t-Bu, 0% (in 42 h)R = CH2CO2Me, 77% (in 90 h)R = CH(Me)CO2Me, 78% (in 90 h)R = CH(i-Pr)CO2Me, 69% (in 90 h)

2.5 mol% Pd(OAc)25 mol% PPh3Et3N−DMF

50 °C, 42−90 h

RNH2, CO (40 bar)

Scheme 107.

NHN

OPh

NNH

O

Me

I

NH

NH Ph

NH2NMe

Me

NH

H2N Ph

I

Br

NH

H2N Me

NH

NH

Me Me

I

NMe

NH R

I

NMe

NH2Me

Br I

NMe

NH2

NN

OMe

Me

NNH

O

Me85%52%

82% 66%

conditions: 2.5 mol% Pd(OAc)2, 5 mol% PPh3,Et3N−DMF, 50 °C.

− MeBr

via

(R = H, Me)

via

via

CO (1 bar)conditions




Scheme 108.

I

X

RNH2, CO (1 atm)

X

NH

OR

N

O

R

X

amino-carbonylation

MichaelAddition

X = CO2Me, R = Ph, 75%X = CO2Me, R = Bn, 91%X = CN, R = Bn, 69%X = COMe, R = Bn, 61%X = COPh, R = Bn, 70%X = CO2Me, R = c-Pr, 79%X = CO2Me, R = CH2(4-pyridyl), 95%X = CO2Me, R = CH2CH2(3-indolyl), 69%

10 mol% Pd(OAc)220 mol% PPh3Cs2CO3 (2 eq)


Scheme 109.


same transformations were performed at lower temperatures(130e150 �C) using Mo(CO)5Cl$NEt4 that was prepared in situ byheating Mo(CO)6 and Et4NCl under microwave. Cyclic secondaryamines, aniline, and even ammonia behaved well under theseconditions.

Utilizing the molybdenum-mediated carbonylations of aryl io-dide as a key step, Roberts developed the microwave-assistedsynthesis of quinazolin-4(3H)-ones (Scheme 126) and quinazolin-2,4-diones (Scheme 127).133 Thus, the reaction of (2-iodophenyl)-phenylcarbodiimide with primary and secondary aminesafforded quinazolin-4(3H)-ones as a single regioisomer via thecyclocarbonylation of a guanidine intermediate. Although the

carbonylative cyclization of the guanidine intermediate occurredthrough the NH-aryl center rather than the NH-alkyl center in thepresence of primary and cyclic secondary amines, the use of am-monia as the nucleophile exclusively afforded the otherregioisomer under similar conditions (carbonylative cyclizationusing eNH2 instead of NH-aryl). The reaction of (2-iodophenyl)-phenylcarbodiimide with aniline in the presence of Mo(CO)6 andEt4NCl afforded only a 10% yield of the corresponding4-quinazolinone, although the yield was later increased to 56%using Mo(CO)5Cl$NEt4. For the preparation of quinazolin-2,4-diones, ureas bearing a 2-iodophenyl functionality were used.Although similar yields of the products were obtained using

I

Condition A: 2.5 mol% Pd2(dba)3, 20 mol% P(o-furyl)3, Cs2CO3 (2 eq), toluene, 90 °C, 18 h.Condition B: 2 mol% PdCl2(PPh3)2, 12 mol% P(o-furyl)3, Cs2CO3 (2 eq), dioxane, 110 °C , 18 h.

N

O

R

N

O

N

O

Condition A:R = 2-pyridyl, 86%R = 4-pyridyl, 92%R = CH2CH2(3,4-di-OMe-Ph), 85%

Condition B:R = COMe, 62%R = SO2Ph, 56%R = COCF3, 60%

Condition A or B

RNH2, CO (1 atm)

Scheme 110.

I

X

N

O

NH

X

R

NN

O

X

R

R'

H2N-NHR, CO (1 atm)

Condition A: 3−5 mol% Pd(OAc)2, 6−10 mol% PPh3, Cs2CO3 (2 eq),toluene, 90 °C , 3−18 h. (MeCN co-solvent for R = CH

2CF

3)

Condition B: 2.5 mol% Herrmann's palladacycle, Cs2CO3 (2-3 eq),DMF, 60−100 °C, 1.5−4.5 h. (H

2O for co-solvent R = R' = Et)

Condition A

RNH-NHR', CO (1 atm)

X = CO2Me, R = Ph, 50%X = CO2Me, R = 2,4-di-F-Ph, 60%X = COMe, R = 2,4-di-F-Ph, 50%X = CN, R = 2,4-di-F-Ph, 52%X = CO2Me, R = CH2CF3, 68%

X = CO2Me, R = Ph, R' = Ac, 55%X = COMe, R = Ph, R' = Ac, 60%X = CN, R = Ph, R' = Ac, 43%X = CO2Me, R = R' = Et, 55%

Condition B

Scheme 111.

RI

I

H2N

OTf

R

R

O

N

O

O

N

O

R

, CO (1 atm)

5 mol% Pd(PPh3)4K2CO3 (5 eq)

MeCN, 60 °C, 21−27 h

R = 4-OMe, 72%R = 3-NO2, 62%R = 4-COMe, 85%R = 2-OMe, 29%

50−55% (R = Ph, t-Bu)

I

H2N , CO (1 atm)

5 mol% Pd(PPh3)4K2CO3 (5 eq)

MeCN, 60 °C, 18 h

O

N

O

ArH

LnPdI

B

Scheme 112.


stoichiometric amounts of Mo(CO)6 and Et4NCl or in situ preparedMo(CO)5Cl$NEt4, low yields of the products were obtained whenonly Mo(CO)6 (in the absence of Et4NCl) or sub-stoichiometricamounts of Mo(CO)5Cl$NEt4 was used.

16. Nickel-catalyzed amidation of aryl iodides and bromides

Nickel-catalyzed aminocarbonylation of alkenyl bromides wasinitially reported by Corey using Ni(CO)4.134 Later, Lee and co-workers used the nickel-catalyzed coupling of aryl iodides andbromides with DMF for the preparation of N,N-dimethylbenza-mides (Scheme 128).135 While these reactions were carried out in

dioxane, an excess of DMF (at least 10 equiv) is required to furnishthe amides in high yields. The combination of Ni(OAc)2$4H2O withan air- and moisture-stable phosphite ligand (Pd/L¼1:1) in thepresence of NaOMe was most effective for this transformation.Although Xantphos and t-Bu3P showed moderate to good activity,phosphine ligands, such as PCy3, PPh3, dppf, and even P(OEt)3 wereineffective. Other nickel catalysts, such as NiCl2, Ni(acac)2, andNi(COD)2 or non-alkoxide bases were ineffective for this trans-formation. In general, electron-rich aryl iodides provided betteryields than the electron-deficient aryl iodides; for the latter thedehalogenated product was obtained as one of the major products.Sterically hindered 2-iodotoluene afforded a moderate yield of the

Br

Br

H2N , CO (5 bar)

6 mol% Pd(OAc)212 mol% P(Bu)(Ad)2

DIPEA (4 eq)toluene, 110 °C, 20 h

(Ad = adamantyl)

O

N

O

R

R

R'

R'

R = H, R ' = H, 86%R = 4-OMe, R' = H, 83%R = 4-CF3, R' = H, 78%R = 4-CO2(t-Bu), R' = H, 70%R = 4-Cl, R' = H, 91%R = 2-Me, R' = H, 74%R = H, R' = 4-Me, 81%

Scheme 113.

Z

I

HN

O N

O

Z

n

n

, CO (200 psi)

3 mol% Pd(OAc)213.5 mol% PPh3

K2CO3 (3 eq)THF, 80 °C, 24 h

Z = CO2Et, n = 1, 95%Z = CO2Et, n = 2, 75%Z = CO2Et, n = 3, 65%Z = CN, n = 1, 95%Z = SO2Ph, n = 1, 90%

Scheme 114.

O

NH

ArBrO

N

O

Ar

Ar−Br

IIIIIILnPd

BrNH

ArO

LnPdAr

BrLnPd

NH

O Ar

Br

LnPdBr

O

NH

O Ar

IILnPd

Br

OAr

II COCO

Base NH2 + Base

Br

LnPd(II)

LnPd(0)

Base•HX

LnPd(II)

LnPd(0)

Base•HX

Cycle 1Cycle 2O

N

O

ArH

LnPdBr

B

Fig. 17. Pd-catalyzed synthesis of 2-arylbenzoxazinones.

IIII

N

O

LnPdI

IILnPd

I

O

CO

LnPd(0)

+ Base

LnPd(II)

Base•HX

Z

I

ZZ

NH

O

Z

LnPdN

OZO

O

N

O

Z

Aldol

Fig. 18. Pd-catalyzed synthesis of fused isoquinolinones.


I

Z

HNX

Y

O N

OX

YZ

, CO (100 psi)

1.5 mol% PdCl2(PPh3)21.5 mol% PPh3Cs2CO3 (3 eq)THF, 80 °C, 4 h

Z = CO2Et; X = CH(Me), CH(Et), CH(i-Pr); Y = O : 41−65%Z = CO2Et; X = NPh, NMe; Y = CH2, CH(Me) : 70−78%Z = CN; X = NPh, NMe; Y = CH2, CH(Me) : 75−84%Z = SO2Ph; X = NPh, NMe; Y = CH2, CH(Me) : 41−60%

Scheme 115.

Br

Z

HNX

O N

O

X

Z

, CO (200 psi)

3 mol% Pd2(dba)312 mol% [(t-Bu)3PH]BF4

Cs2CO3 (3 eq)toluene, 110 °C, 24 h

Z = CO2Et, 66%Z = SO2Ph, 43%

(X = NPh)

Scheme 116.

X I

OH

R

N Ts

N Ts XR N

O

O Ts

R'

XR N

O

O Ts

n

n

n = 1−2, X = CH, R = H, 71−76%n = 1−2, X = N, R = H, 70−77%%n = 1, X = CH, R = CO2Me, 92%n = 1, X = CH, R = Ph, 94%n = 1, X = CH, R = Me, 58%n = 1, X = CH, R = t-Bu, 55%

Conditions: 1.5 mol% PdCl2(PPh3)2, 1.5 mol% PPh3, K2CO3 (3 eq), 10 mol% TEBA, THF, 80 °C, 24 h.

, CO (200 psi)

X = CH, R = H, R' = Bn, 74%X = N, R = H, R' = Bn, 71%X = CH, R = CO2Me, R' = Bn, 92%X = CH, R = t-Bu, R' = Bn, 64%

conditions

, CO (200 psi)

conditions

R'

Scheme 117.


corresponding amide. Interestingly, a nearly quantitative yield ofamide was obtained from the coupling of 2-bromoanisole withDMF, whereas 3- and 4-bromoanisole afforded only 82% and 62%yields of the amides, respectively. 2-Bromo-6-methoxynaphth-alene provided a nearly quantitative yield of the amide, while 1-bromo- and 2-bromonaphthalene produced the amides in 64%and 72% yields, respectively. An increased catalyst loading (10 mol% of catalyst and ligand) was required with 3-bromothiophene tomaximize the yield of the corresponding amide. Lee extended thisnickel-catalyzed coupling to various formamides that afforded thecorresponding aryl amides from aryl bromides in moderate to goodyields (Scheme 129).136 The steric bulk of the formamide de-rivatives played a major role in this coupling. Less bulky formam-ides gave higher yields whereas bulky formamides provided theamides only in moderate yields, even with higher catalyst loading.The base KOMe was more effective than NaOMe for thecoupling of sterically hindered formamides. Nonetheless, N,N-diethylformamide, N,N-diisopropylformamide, and even tert-butylformamide were completely ineffective under these

conditions, but the cyclic formamides, such as formylpiperidine andformylmorpholine, did couple with aryl bromides. The coupling ofN-methylformamide with an aryl bromide bearing an ortho-phenylgroup afforded a higher yield of the amide than the yield of theamide obtained from similar coupling with 2-bromoanisole.

The nickel-catalyzed coupling of aryl bromides with isocyanatesgave the corresponding secondary amides (Scheme 130).137 Ingeneral, bromoarenes afforded higher yields of the amides thaniodoarenes, presumably due to the greater tendency of iodoarenesto undergo competing reductive homo dimerization under theseconditions. Applying similar conditions to the coupling of 1,3-iodoesters with isocyanates, Cheng and co-workers prepared a se-ries ofN-substituted phthalimides (Scheme 131). Catalytic Et3Nwasused for these reactions alongwith catalytic Ni(dppe)Br2edppe andzinc.

The synthesis of novel bis(isoindolinone)s was also reported viaa nickel-catalyzed sequential cyclocarbonylation and dimerizationof 2,6-dichlorophenylimines.138

17. Palladium and ruthenium co-catalyzed amidation usingN-(2-pyridyl)formamide

Using catalytic PdCl2 and Ru3(CO)12, Chang and co-workerswere able to couple aryl iodides with N-(2-pyridyl)formamide(Scheme 132).139 N-(2-Pyridyl)formamide presumably acts as theCO as well as amine source. In fact, quantitative formation of2-aminopyridine was observed within 2 h from the decarbon-ylation of N-(2-pyridyl)formamide in acetonitrile above 130 �C inthe presence of 3 mol % Ru3(CO)12. Amidation did not occur in theabsence of either Pd- or Ru-catalyst. Various aryl iodides, eventhose bearing a free phenolic eOH group, were converted to thecorresponding N-(2-pyridyl)benzamides; however, aryl bromidesand aryl chlorides failed to react under these conditions.

II

N

O

O

Ts

LnPdN

O

OTs

OH

IN Ts

IILnPd

I

O

O

NHTs

II

O

IHN

Ts

LnPdI

O

HNTs

CO

LnPd(0)

Base

LnPd(II)

Base•HI

K2CO3TEBA

Fig. 19. Pd-catalyzed synthesis of 1,4-benzoxazepinones.

N Ts

I

SH

R

N Ts

R'

R N

S

O Ts

R N

S

O Ts

Ph

n

n

, CO (500 psi)

Condition A (for n = 1, 3)

Condition B (for n = 2)

n = 1, R = H, 79%n = 2, R = H, 93%n = 3, R = H, 64%n = 1, R = Me, Cl, 74-75%n = 2, R = Me, Cl, 94-95%

R = H, R' = Ph, 68%

Condition A: 4 mol% Pd(OAc)2, 4 mol% JohnPhos, K2CO3 (3 eq), dioxane, 100 °C, 17 h.Condition B: 4 mol% Pd(OAc)2, 4 mol% JohnPhos, Et3N (3 eq), THF, 100 °C, 17 h.

, CO (500 psi)

Condition A

Scheme 118.

XAr

R

HN NH2

N

ONH2Ar

R

AcOH

R'HN NH2N

NNAr

R'

R

5 mol% Pd(OAc)25 mol% Xantphos

Et3N−DMF80−100 °C, 2 h

1. 2.

(1.5−3 eq)

Ar = 4-OMe-Ph, R = Ph, R' = i-Pr, 79%Ar = 4-OMe-Ph, R = 4-pyridyl, R' = i-Pr, 54%Ar = N-Me-4-pyrazolyl, R = Ph, R' = i-Pr, 52%Ar = 4-OMe-Ph, R = Me, R' = i-Pr, 74%Ar = 4-Br-Ph, R = Me, R' = i-Pr, 56%Ar = 4-CF3-Ph, R = Me, R' = Ph, 69%Ar = 4-OMe-Ph, R = Me, R' = 2-pyridyl, 63%Ar = 4-OMe-Ph, R = Me, R' = H, 65%

CO (1 atm)

Scheme 119.


NH2

Bn(OC)5Mo

Ar X

O

NH

ArBn

O

NH

ArBn

Conditions: n-Bu3N (1.1 eq), diglyme, 120−150 °C, 1−3 h. (no Pd-catalyst)

Ar = Ph, 95%Ar = 4-OMe-Ph, 95%Ar = 3-OMe-Ph, 80%Ar = 2-OMe-Ph, 88%Ar = 2-naphthyl, 95%Ar = 1-naphthyl, 87%

(X = I)

(X = Br)

Ar = 4-COMe-Ph, 89%Ar = 4-CO2Et-Ph, 88%Ar = 3-thienyl, 91%Ar = 2-pyridyl, 49%Ar = (E)-styryl, 93%Ar = Bn, 78%

conditions

NH2

Bn(OC)5Mo

conditions

Scheme 120.

O O

NH

ArBn

Ar X

O

NH

ArBn

NH

ArR

O

NArR1

R2

Ar = Ph, R = Ph, 79%Ar = Ph, R = Bn, 97%Ar = 4-OMe-Ph, R = Bn, 96%Ar = 2-OMe-Ph, R = Bn, 91%Ar = 4-COMe-Ph, R = Bn, 95%Ar = 1-naphthyl, R = Bn, 93%Ar = Ph, R = 4-OMe-Ph, 85%Ar = Ph, R = 4-CO2Me-Ph, 64%Ar = Ph, R = t-Bu, 90%

RNH2Mo(CO)6 (0.2 eq)

conditions

(X = I)

Ar = Ph, R1R2 = -(CH2)4-, 83%Ar = Ph, R1R2 = -(CH2)5-, 90%Ar = Ph, R1 = Me, R2 = Bn, 91%

BnNH2Mo(CO)6 (0.2 eq)

conditions

(X = Br)

Ar = 2-naphthyl, 97%Ar = 3-thienyl, 94%Ar = 2-pyridyl, 45% (at 90 °C)Ar = Bn, 52%Ar = (E)-styryl, 85% (at 80 °C)

BnNH2Mo(CO)6 (0.2 eq)

conditions

(X = Cl)

Ar = 2-pyridyl, 35%Ar = 2-(5-iodopyridyl), 53%Ar = 3-pyridyl, traceAr = 2-quinolinyl, 61% (at 90 °C)

R1R2NHMo(CO)6 (0.2 eq)

conditions

(X = I)

Conditions: n-Bu3N (1.1 eq), Et4NCl (0. 2 eq), diglyme, 140−150 °C, 0.5−7 h.

Scheme 121.

Ar X

NH3(OC)5W O

NH2Ar

O

NH2Ar

n-Bu3N, diglyme140−150 °C, 8 h

X = I : Ar = Ph, 91%X = I : Ar = 4-OMe-Ph, 75%X = I : Ar = 4-COMe-Ph, 50%X = Br : Ar = 3-thienyl, 54%X = Br : Ar = (E)-styryl, 76%

NH3 (aq)Mo(CO)6 (0.2 eq)

diglyme150 °C, 1-4 h

X = I : Ar = Ph, 40%

Scheme 122.


18. Rhodium-catalyzed intramolecular aminocarbonylation

Using aldehydes as the CO-source, Morimoto and Kakiuchi syn-thesized benzolactams via a rhodium-catalyzed intramolecularaminocarbonylation of aryl bromides and chlorides, containing anortho-alkylamine group (Scheme 133).140 While electron-deficient

pentafluorobenzaldehyde and cinnamaldehyde smoothly un-derwent Rh-catalyzed decarbonylation to generate rhodiumcarbonyl in situ and subsequently to afford isoindolinonefrom N-tosyl-2-bromobenzylamine in high yields, benzaldehyde, 4-methoxybenzaldehyde, 4-trifluoromethylbenzaldehyde, 2-napthal-dehyde, and decanal failed to react as desired. Paraformaldehyde

O

NArR1

R2

R1R2NHMo(CO)5Cl•NEt4

BnNH2Mo(CO)5Cl•NEt4

Ar X

O

NH2Ar

BnNH2Mo(CO)5Cl•NEt4

NH3 (aq)Mo(CO)5Cl•NEt4

O

NH

ArBn

O

NH

ArBn

dioxane130 °C, MW, 4 h

(X = I)

Ar = Ph, 95%Ar = 4-OMe-Ph, 90%Ar = 3-Cl-Ph, 98%Ar = 2-Me-Ph, 98%Ar = 3-thienyl, 97%

Ar = Ph, 91%Ar = 4-OMe-Ph, 81%Ar = 3-Cl-Ph, 96%Ar = 2-Me-Ph, 79%Ar = 3-pyridyl, 87%Ar = (E)-styryl, 85%

Ar = Ph, R1R2 = -(CH2)4-, 96%Ar = Ph, R1 = H, R2 = Ph, 99%Ar = Ph, R1 = H, R2 = Boc, 51%

Ar = Ph, 75%


(X = Br)


(X = I)


(X = I)

Scheme 125.

I

NH2n

n-Bu3N (1.1 eq)Et4NCl (0. 2 eq), diglyme

120−140 °C, 1−2 h

NH

O

62−70%

Mo(CO)6 (0.2 eq)

n

(n = 1−2)

Scheme 123.

Ar X

BnNH2, Mo(CO)6


BnNH2, Mo(CO)6

(X = I)

(X = Br)

O

NH

ArBn

O

NH

ArBn

Ar = Ph, 84%Ar = 4-OMe-Ph, 84%Ar = 3-Cl-Ph, 99%Ar = 2-Me-Ph, 93%Ar = 3-thienyl, 98%

Ar = Ph, 92%Ar = 4-OMe-Ph, 87%Ar = 2-Me-Ph, 98%Ar = 3-pyridyl, 92%Ar = (E)-styryl, 89%


Scheme 124.


(10 equiv) afforded 69% yield of the benzolactam from N-tosyl-2-bromobenzylamine under similar conditions. Benzolactam forma-tion is somewhat specific for aryl alkyl amines bearing an (N)-tosylgroup as the analogous compounds bearing (N)-H, (N)-acetyl, (N)-benzyl, and (N)-PMB did not furnish the desired product. However,N-Boc-2-bromobenzylamine gave the corresponding lactam in 53%yield in 48 h using pentafluorobenzaldehyde as the CO-source.

I

NC

NPh

I

NH

N

NR1

Ph

R2

R1R2NHMo(CO)6 (1 eq)

Et4NCl (1 eq), dioxane130−150 °C, MW, 2−4 h

Scheme 1

Some related catalytic systems, such as RhCl(CO)(PPh3)2 and[RhCl(cod)]2edppe also showed moderate to good activity. The Rh-catalyzed cyclocarbonylation of N-tosyl-2-bromobenzylamine inthe presence of gaseous CO (1 atm) afforded the benzolactam in 87%yield in 18 h (vs 92% yield in 10 h using pentafluorobenzaldehyde).Recently, this group reported an asymmetric synthesis of3-substituted isoindolinones by applying similar conditions on chiralbromobenzylamines (Scheme 134).141 Use of formaldehyde as theCO-synthon afforded 3-substituted isoindolinones with excellent ee,albeit in lower yields.

19. Amidation via CeH activation

Orito reported the phosphine-free synthesis of five- and six-membered benzolactams from N-alkyl-u-arylalkylamines viaPd-catalyzed CeH activation (Scheme 135).142 These reactions wereexecuted in the presence of catalytic Pd(OAc)2eCu(OAc)2 undera mixed COeair atmosphere. The rate of five-membered ring for-mation was much faster than six-membered ring formation underthese conditions.

Chatani and co-workers prepared phthalimides using a ru-thenium-catalyzed aminocarbonylation via the activation ofCeH bonds in benzamides, bearing a (2-pyridinyl)methylamine

moiety (Scheme 136).143 Ethylene was used as a hydrogen ac-ceptor and the phthalimides did not form in the absence ofethylene. Other known hydrogen acceptors, such as norborneneand methyl acrylate, were ineffective. Addition of H2O (2 equiv)was crucial to generate active catalytic species (low yields wereobtained in the absence of H2O). A variety of para-substitutedbenzamides were converted to the corresponding phthalimides

N

N

OPh

NR1

R2

R1 = H, R2 = i-Pr, 88%R1 = H, R2 = Bn, 56%R1 = H, R2 = t-Bu, 52%R1R2 = -(CH2)4-, 92%R1R2 = -(CH2)5-, 54%R1R2 = -(CH2)2-O-(CH2)2-, 55%

26.

(X = I)

O

NMe2H

Ar X

Ar N

OMe

Me

Ar N

OMe

Me

Conditions: 5 mol% Ni(OAc)2•4H2O, 5 mol% phosphite ligand, NaOMe (4 eq), dioxane, 110 °C, 12 h.

Ar = 4-OMe-Ph, 99%Ar = 4-CF3-Ph, 11%Ar = 4-Me-Ph, 98%Ar = 2-Me-Ph, 68%Ar = 1-napththyl, 45%

conditions

O

t-Bu

t-BuP3

phosphite ligand

Ar = H, 98%Ar = 4-Me-Ph, 99%Ar = 4-OMe-Ph, 62%Ar = 3-OMe-Ph, 82%Ar = 2-OMe-Ph, 99%Ar = 4-Ph, 85%Ar = 2-Ph, 87%Ar = 1-naphthyl, 64%Ar = 2-naphthyl, 72%Ar = 2-(6-methoxynaphthyl), 97%

(X = Br)

O

NMe2H

conditions

Scheme 128.

I

NH

NH

OR N

H

N

OR

ODMF, MW, 150 °C, 5 h

R = Et, 64−65%R = Bn, 54−58%

Mo(CO)6 (1 eq), Et4NCl (1 eq)or

Mo(CO)5Cl•NEt4 (1 eq)

Scheme 127.

O

NH

HMe

RBr

O

NHX

O

NH

H

R

R

R

N

O

X

NH

OMe

NH

O

(5 eq)

R = 4-Me, X = CH2, 68%R = 4-Me, X = O, 51%R = 2-Me, X = CH2, 58%R = 2-Me, X = O, 41%R = 2-OMe, X = CH2, 41%R = 2-OMe, X = O, 35%

NaOMe (2 eq)Condition A

(4 eq)R = H, 65%R = 4-t-Bu, 94%R = 4-Me, 89%R = 3-OMe, 43%R = 2-OMe, 56%

R = H, 99%R = 4-Me, 92%R = 4-OMe, 68%R = 2-OMe, 53%R = 2-Ph, 82%

Condition A: 1 mol% Ni(OAc)2•4H2O, 1 mol% phosphite ligand, diglyme, 110 oC, 10 h.Condition B: 2 mol% Ni(OAc)2•4H2O, 2 mol% phosphite ligand, diglyme, 110 oC, 10 h.Condition C: 5 mol% Ni(OAc)2•4H2O, 5 mol% phosphite ligand, diglyme, 110 oC, 10 h.

(3 eq)

KOMe (3 eq)Condition B

KOMe (4 eq)Condition C

O

t-Bu

t-BuP3

phosphite ligand

Scheme 129.


under these conditions. The (2-pyridyl)methylamine moiety ef-fectively coordinates with the catalyst as a bidentate N,N-donorfor the carbonylation at the CeH bond. Thus, the related benza-mides bearing (3-pyridyl)methylamine, (4-pyridyl)methylamine,

N-methyl-(2-pyridyl)methylamine, and (2-pyridyl)ethylaminedid not undergo carbonylation of the CeH bond. For the meta-substituted benzamides, bearing the (2-pyridyl)methylaminemoiety, the carbonylation preferentially occurred at the sterically

I

OMe

O

R−NCON

O

O

Rconditions

Conditions: 10 mol% Ni(dppe)Br2, 10 mol% dppe,Et3N (0.1 eq), Zn (2 eq), MeCN, 80 °C, 36 h.

R = c-Hex, 88%R = Bn, 79%R = Ph, 61%R = 4-Cl-Ph, 53%R = Si(OEt)3, 79%

Scheme 131.

NNH

H

O

IR

5 mol% PdCl25 mol% Ru3(CO)12NaHCO3 (1.5 eq)

MeCN, 135 °C, 4−10 h

R NH

O

NR = H, 58%R = 4-Me, 76%R = 4-OMe, 62%R = 4-COMe, 83%R = 6-OH, 57%

Scheme 132.

Ar BrR−NCO

O

NH

ArR

Conditions: 10 mol% Ni(dppe)Br2, 10 mol% dppe, Zn (2 eq), MeCN, 80 °C, 16 h.

conditions

Ar = Ph, R = c-Hex, 71%Ar = Ph, R = 4-Me-Ph, 64%Ar = 2-naphthyl, R = 4-Me-Ph, 51%

Scheme 130.

HN

Ts

X

N

O

Ts

N

O

Ts

n

n

for R = C6F5, n = 1 : 92% (10 h)for R = C6F5, n = 2 : 84% (in 25 h)for R = C6F5, n = 3 : 66% (in 48 h)for R = styryl, n = 1 : 93% (in 10 h)for R = styryl, n = 2 : 93% (in 20 h)for R = styryl, n = 3 : 17% (in 48 h)

(X = Br)

n

for R = C6F5, n = 1 : 82% ( in 24 h)for R = styryl, n = 1 : 91% (in 8 h)

Conditions: 2.5 mol% [RhCl(cod)2], 5 mol% dppp, K2CO3 (2 eq), xylene, 130 °C.

O

H (5 eq)R

conditions

(X = Cl)O

H (5 eq)R

conditions

Scheme 133.

O

H (5 eq)C6F5

HN

Ts

Br

Ar

R1

R2

N

O

Ts

Ph

N

O

Ts

Ar

Conditions: 5 mol% [RhCl(cod)2], 10 mol% dppp, K2CO3 (2 eq), xylene, 130 °C.

conditions, 5−10 h

Ar = Ph, 89% (99% ee)

Ar = 4-OMe-Ph, 84% (99% ee)

Ar = 4-CF3-Ph, 81% (99% ee)

Ar = 2-Me-Ph, 88% (95% ee)

R1 = H, R2 = OMe, 75% (98% ee)

R1 = H, R2 = F, 91% (99% ee)

R1 = OMe, R2 = H, 87% (99% ee)

R1 = F, R2 = H, 84% (99% ee)

(R1 = R2 = H)

O

H (5 eq)C6F5

conditions, 15−60 h(Ar = Ph)

R1

R2

Scheme 134.


less hindered ortho-position, except for a meta methyl-substituted benzamide. Steric effects seemed to dominate overelectronic effects in governing the regioselectivity in these meta-substituted benzamides.

Kakiuchi described ruthenium-catalyzed regioselective amino-carbonylation via aromatic CeH bond cleavage (Scheme 137).144

Carbamoyl chlorides were used for this regioselective installationof tertiary amides. No additional oxidant was needed for this

HHN

O

NR

5 mol% Ru3(CO)12H2O (2 eq)

ethylene (7 atm)toluene, 160 °C, 24 h

N

NR

O

O R = H, 77%R = OMe, 69%R = CO2Me, 82%R = COMe, 78%R = CN, 84%R = Br, 87%

CO (10 atm)

HHN

O

N5 mol% Ru3(CO)12

H2O (2 eq)ethylene (7 atm)


N

N

O

OCO (10 atm)

X

Y

X

Y

+ NO

O

NH

X

Y

68% (1:1) X = Me, Y = H84% (14:1) X = OMe, Y = H86% (>20:1) X = NMe2, Y = H82% (20:1) X = COMe, Y = H73% (11:1) X = OMe, Y = Me

Scheme 136.

HN

Rn

H CO (1 atm)

5 mol% Pd(OAc)250 mol% Cu(OAc)2air, toluene, 120 °C

n = 1 : 87% (in 2 h)n = 2 : 64% (in 24 h)

Nn

O

R

(R = n-Pr)

Scheme 135.

N

H

O

NClR1

R2

Conditions: 10 mol% RuCl2(PPh3)2, toluene, 120 °C, 24 h.

H

H

NN

O

N O

N

O

NClR'

R'RR

O

NClMe

Me

NO

NR1 R2

RNMe2

O

N

R1 = R2 = Me, 94%R1 = R2 = Ph, 97%

R1R2 = -(CH2)2-O-(CH2)2-, 90%

R = H, R' = Me, 68%R = H, R' = Et, 57%R = H, R' = Ph, 74%R = 4-OMe, R' = Me, 83%

(2.5 eq)

R = 2-Me, 75%R = 2-CO2Et, 63%R = 3-CF3, 76% (in 48 h)R = 3-Me, 84% (in 48 h)

K2CO3 ( 2.5 eq)conditions

(5 eq)

(2.5 eq)

K2CO3 ( 5 eq)conditions

K2CO3 ( 2.5 eq)conditions

R'

R'

R'R'

Scheme 137.


catalytic CeH aminocarbonylation. Thus, the reaction of benzo[h]quinoline with N,N-dimethylcarbamoyl chloride or N,N-diphe-nylcarbamoyl chloride in the presence of catalyst RuCl2(PPh3)3 andK2CO3 afforded the N,N-disubstituted amide at the C-10 position.

A similar morpholine amide was also obtained in very high yield.The aminocarbonylation of 2-phenylpyridine with N,N-dimethyl-,N,N-diethyl-, and N,N-diphenylcarbamoyl chloride gave the corre-sponding diamides. While 2-(4-methoxyphenyl)pyridine also gavethe diamide in excellent yield, the related o- and m-substitutedarylpyridines afforded only the monoamides. Installation of theamides occurred at the sterically less hindered site for the meta-substituted arylpyridines. The N-methylimidazolyl group also acted

as an ortho-directing group and gave only the monoamide in 58%yield from N-methyl-2-phenylimidazole.

Kuninobu and Takai synthesized phthalimidines via Re-catalyzed CeH activation (Scheme 138).145 Insertion of

RH

N(t-Bu)

R'−NCOR N

HN (t-Bu)

R'

O

3 mol% [ReBr(CO)3(thf)]2ClCH2CH2Cl, reflux, 24 h

R = H, R' = Ph, 97%R = H, R' = 4-OMe-Ph, 81%R = H, R' = 4-CF3-Ph, 94%R = 4-OMe, R' = Ph, 80%R = 4-CF3, R' = Ph, 87%R = 2-Me, R' = Ph, 51%

Scheme 138.

X

Nt-Bu

HPh−NCO

X Nt-Bu

HPh−NCO

X N(t-Bu)

NH-Ph

O

X

N(t-Bu)

NH-Ph

O

H3O+

H3O+ X

O

NH-Ph

O

H

X O

NH-Ph

O

H

X = S, 77%X = O, 36%X = N(Me), 80%

2.5 mol% [ReBr(CO)3(thf)]2ClCH2CH2Cl, reflux, 24 h

X = S, 92%X = O, 63%

2.5 mol% [ReBr(CO)3(thf)]2ClCH2CH2Cl, reflux, 24 h

Scheme 139.

H

NR−NCO

NHAc

H R−NCO

NHAc

H

Ph

R−NCO

R−NCO

NNH−R

O

NHAc

NH−R

O

N

N

Ph

OR

Me

NHAc

NH−R

O

Ph

NHAc

NH−R

O

Ph

R = n-Hex, 76%R = Bn, 68%R = Ph, 60%R = c-Hex, 76%R = 1-adamantyl, 48%

R = Ph, 85%R = 4-OMe-Ph, 72%R = 4-CF3-Ph, 84%

Condition A: 5 mol% [Cp*RhCl2]2, 20 mol% AgSbF6, CH2Cl2, 75 °C, 24 h.Condition B: 5 mol% [Cp*Rh(MeCN)3(SbF6)2], THF, 75 °C, 16 h.Condition C: 5 mol% [Cp*Rh(MeCN)3(SbF6)2], THF, rt, 16 h.Condition D: 5 mol% [Cp*Rh(MeCN)3(SbF6)2], THF, 105 °C, 16 h.

Condition A

Condition B

R = n-Hex, 96%R = Ph, 96%R = c-Hex, 84%R = 1-adamantyl, 40%

Condition C

R = Ph, 96%

Condition D

via

Scheme 140.


isocyanates into the ortho CeH bond of tert-butyl aldimine pro-ceeded smoothly at 90 �C. While [ReBr(CO)3(THF)]2 affordedphthalimidines in excellent yields, Re(CH3)(CO)5, Ru3(CO)12,RuH2(CO)(PPh3)3, and RhCl(PPh3)3 were ineffective. Although alkylisocyanates did not participate in this transformation, bothelectron-rich and electron-deficient aryl isocyanates provided goodyields of corresponding phthalimidines. Phenylisothiocyanate didnot participate in the coupling with aldimine. Using the directingimine functionality, Kuninobu and Takai also reported Re-catalyzedthe amidation via activation of ortho CeH bond in representativeheteroaryl aldimines (Scheme 139).146

Bergman and Ellman reported the amidation of aryl halides,bearing an ortho-directing group, using isocyanates via the Rh(III)-catalyzed activation of a CeH bond (Scheme 140).147 A room tem-perature preparation of enamides has also been reported undersimilar conditions. Conducting the reactions at a higher tempera-ture provided a one-pot synthesis of pyrimidin-4-ones via in situcyclodehydration of enamides.

Insummary,metal-catalyzedamidationsarebecoming increasinglyrecognized as anattractive and important alternative to classical amidecoupling involvingcarboxylicacidsandcarboxylic acidderivativeswithamines. Using palladium-catalyzed aminocarbonylation, the amide


group can be regioselectively introduced into targetmolecules, even ata late stage of the synthesis. The extensive commercial availability ofhalogenated building blocks compared to the less available aryl/het-eroaryl carboxylic acids and derivatives, and combined with the rela-tively facile preparation of halogenated scaffolds as amide precursorsadds considerable advantage to these metal-catalyzed methods. Theamidation protocols summarized in this review afford valuablemeans for the exploration of the diversity space in the drug-discovery landscape. Moreover, the examples of aminocarbon-ylation-based synthesis of novel heterocycles further extend thescope of this chemistry.

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S. Roy et al. / Tetrahed
Biographical sketch

Sudipta Roy completed his undergraduate studies (first class, first division) inChemistry (Honors) at Presidency College (University of Calcutta), India. He obtainedhis Master’s degree from the Indian Institute of Technology (IIT)dBombay. He earneda Ph.D. in Organic Chemistry at Dartmouth College in 2006, working under the super-vision of Professor Gordon Gribble. After post-doctoral work with Professors RichardLarock and George Kraus at Iowa State University, he worked at AMRI. He has co-authored 20 publications including a review on Aromatic Trifluoromethylation anda book-chapter in ‘Metalation of Azoles and Related Five-Membered Ring Heterocycles’ fo-cusing on N-arylation, lithiation, magnesiation, and CeC cross-coupling reactions ofpyrazoles and indazoles. He has also co-authored a book-chapter on Fluorinated Imid-azoles and Benzimidazoles in Fluorine in Heterocyclic Chemistry (to be published), and isa named inventor on two patent applications. His current research interests includesynthetic methodology, heterocyclic chemistry, organometallic chemistry, organo-fluorine chemistry, natural product synthesis, and medicinal chemistry.

Sujata Roy obtained her Bachelor’s degree studying Chemistry (Honors) in PresidencyCollege (University of Calcutta), India. After receiving her Master’s degree from the In-dian Institute of Technology (IIT)dKharagpur (99 percentile in GATE), she joined Dart-mouth College from where she earned a Ph.D. in Organic Chemistry in 2007 workingunder the supervision of Professor Gordon Gribble. After post-doctoral work with Pro-fessor Richard Larock at Iowa State University, she joined AMRI. She has co-authored15 publications including a book-chapter on ‘Metalation of Pyrazoles and Indazoles’and a review titled ‘Trifluoromethylation of Aryl and Heteroaryl Halides’ that was recog-nized in the ‘Top-25 most cited articles’ as published in Tetrahedron (2010e2011) andlisted in ‘Top-25 Hottest Tetrahedron articles’ for 2011. Her current research interestsinclude synthetic methodology, heterocyclic chemistry, organometallic chemistry, or-ganofluorine chemistry, and medicinal chemistry.

Gordon W. Gribble is a native of San Francisco, California, and completed his undergraduate education at the University of California at Berkeley in 1963. He earned a Ph.D. inOrganic Chemistry at the University of Oregon in 1967. After a National Cancer Institute Postdoctoral Fellowship at the University of California, Los Angeles, he joined the facultyof Dartmouth College in 1968 where has been Full Professor of Chemistry since 1980. He served as Department Chair from 1988 to 1991. In 2005, he was named to the inauguralendowed Chair as ‘The Dartmouth Professor of Chemistry.’ Dr. Gribble has published 320 papers in natural product synthesis, synthetic methodology, heterocyclic chemistry, naturalorganohalogen compounds, and synthetic triterpenoids, one of which is currently in Phase 3 clinical trials for the treatment of chronic kidney disease. Since 1995 he has co-editedthe annual series ‘Progress in Heterocyclic Chemistry’, and the second edition of ‘Palladium in Heterocyclic Chemistry’, co-authored with Jack Li, was published in 2007. As a homewinemaker for the past 30 years, he has a strong interest in the chemistry of wine and winemaking.

metal-catalyzed amidation

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