acylation and related transformations alan r. katritzky, kazuyuki suzuki, ashraf a. abdel- fattah,...

Acylation and Related TransformationsAcylation and Related TransformationsAlan R. Katritzky, Kazuyuki Suzuki, Ashraf A. Abdel-

Fattah, Rachel Witek, Chunming Cai

University of Florida, Center for Heterocyclic compounds

Lecture presented in 2005

Reviews of Benzotriazole Chemistry

Early Reviews:

• [91T2683] “Benzotriazole: A novel Synthetis Auxiliary”

• [94ACA31] “Benzotriazole-Stabilized Carbanions: Generation, Reactivity, and Synthetic Utility

• [94Sip] “Benzotriazole as a Synthetic Auxiliary: Benzotriazolylalkylations and Benzotriazole Mediated Heteroalkylation”

• [94CSRsub] “Benzotriazole Mediated Arylalkylation and Heteroalkylation”

Review Comprehensive through 1996:

• [98CR409] “Properties and Synthetic Utility of N-Substituted Benzotriazoles” (includes 403 references of which 253 are from our group)

More Recent Reviews:

• [98AA33] “Benzotriazole-Based Reagents for Efficient Organic Synthesis”

• [99T8263] “Benzannulations

• [98CCCC599] “Michael Additions of Benzotriazole-Stabilized Carbanions”

• [98T2647] “ The Generation and Reactions of Non-Stabilized a-Aminocarbanions”

• [00PAC1597] “Designing Efficient Routes to Polyfunctionality”

• [01SL458] “The preparation of Mono-, 1,1-Di-, trans-1,2-Di- and Tri-Substituted Ethylenes by Benzotriazole Methodology”

• [03CEJ4586] “Benzotriazole:An Ideal Synthetic Auxiliary”

1

Acylation in Organic SynthesisAcylation in Organic Synthesis

• Scope: on

– Nitrogen Amides, especially peptides

– Sulfur Thiol esters

– Oxygen Esters

– Carbon Ketones

• Reagents for Acylation — Activated Derivatives of Carboxylic Acid

– Acid chloride or Anhydride

– Activated ester or Amide

– From acid via non-isolated activated derivatives

2

•Disadvantages of Common Acylation Agents– Sensitivity to water — precludes use of aqueous solutions– Problems in handling, storage, weighing– Lack of chiral stability– Incompatibility of other functionality

• Acylazoles or Azolides — Staab ca. 1961

– Especially acylimidazoles

NN

O

RWidely used

Preparation of N-AcylbenzotriazolesPreparation of N-Acylbenzotriazoles direct from Carboxylic Acidsdirect from Carboxylic Acids

1. Use of Counter-attack reagent

2. Via Sulfinyl-bisbenzotriazole

3

RO

OMeSO2Bt R

O

O SO2MeBt R

O

Bt

+

(or p-CH3C6H4SO2Bt)Any salts

as Na+ or Et3NH+

+- MeSO3

BtH SOCl2 SO

BtBt

RO

OH

2BtH HCl

RO

BtSO2 BtH+

4 mols 1 mol

+

Unstable

+ +

(00JOC8210)

(03S2795)

RCOBt mp Yield

87-89 88

149-151 84

146-147 76

215-216 90

136-137 92

232-234 88

205 82

191 92

189 54

164-166 95

4

RCOBt mp Yield

HCOBt 94-96 71

CH3COBt 49-51 92

C2H5COBt 73-74 92

C3H7COBt 62-63 79

n-C4H9COBt 42-44 83

Me2CHCOBt Oil 91

tBuCOBt 71-72 94

tBuCH2COBt 56-57 83

C5H11COBt Oil 96

n-C15H31COBt 54-55 89

tBuCH2CHMeCH2COBt 157-158 86

PhCH2COBt 65-66 84

Ph2CHCOBt 88-89 89

PhCH2CH2COBt 63-64 84

PhCOBt 112-113 93

4-CH3C6H4COBt 123-124 91

2-CH3OC6H4COBt 96-97 72

4-CH3OC6H4COBt 104 93

N-AcylbenzotriazolesN-Acylbenzotriazoles: Aliphatic, : Aliphatic,

173-175 92

171-173 97

161-162 75

98-100 91

OCOBt

SCOBt

NCOBt

COBtNH

NCOBt

N COBt

COBtN

N

NH

COBt

COBt

COBtBtOC

COBtBtOC

N

COBtBtOC

COBt

COBt

MeO

COBt

HeteroaromaticHeteroaromaticAromatic,Aromatic,RCOBt mp Yield

4-ClC6H4CH2COBt 90-91 64

3-ClC6H4COBt 120-121 74

4-ClC6H4COBt 138-139 74

4-BrC6H4COBt 142-143 93

4-FC6H4COBt 119 98

4-NO2C6H4COBt 193-194 83

4-Et2NC6H4COBt 86-87 85

4-HOC6H4COBt 199-200 84CCl3COBt 78 98

CF3COBt 89-91 70

CF3CF2CF2COBt oil 86

BtCOCOBt 163-164 92

BtCOBt 182-184 90

N-AcylbenzotriazolesN-AcylbenzotriazolesFrom Unsaturated, Functionalized and Bis-acidsFrom Unsaturated, Functionalized and Bis-acids

RCOBt mp Yield

oil 83

CH3CH=CHCOBt 87-88 86

PhCH=CHCOBt 151-152 96

HC≡ CCOBt 99-100 83

PhC≡ CCOBt 124-125 92

87-88 86

BrCH2COBt 91-92 87

Cl2CHCOBt 87-88 86

CH3OCH2COBt 103-104 96

PhSCH2COBt 103-104 90

PhCOCOBt 72-73 72

174-175 82

BtCO(CH2)4COBt 170-171 75

BtCO(CH2)18COBt 121-122 63

MeO2C(CH2)3COBt 51-52 87

300 77

COBt

COBtCl

BtOC COBt

5

RCOBt mp Yield

223-225 94

247 16

188-189 60

158-160 80

98-100 40

142-144 98

159-160 87

104-105 98

Bt

O

Bt

O

BtS

O

Bt

O

BtO

O

Bt

O

Bt

O

Bt

O

Bt

O

Bt

O

Bt SS

OBt

O

Bt

OBt

O

O

BtO

Bt

RCOBt mp Yield

142-144

169-170

95

98

183-184 96

244-245 90

136-137 98

183 65

196-197 95

118-120 56

91-92

165-167

86

59

O COBt

S COBt

COBtCl

COBtO2N

COBtMeO

MeO

MeO

COBtO

HO

COBtS

SCOBt

OCOBt

COBtCOBtBtOC

6N-Acylbenzotriazole Derivatives from N-Protected Amino Acids (No Extra Functionality)-All solid, m.p.s in range of 50~180 oC.

Amino Acid

N-Protecting Group

Structure of N-Acylbenzotriazole

Yield ee.*

L-Gly Cbz Cbz-Gly-Bt 99 >97

L-Ala Boc Boc-Ala-Bt 61 >97

L-Ala Cbz Cbz-L-Ala-Bt 95 >97

L-Ala Fmoc Fmoc-L-Ala-Bt 79 >97

L-Ala Tfa Tfa-L-Ala-Bt 76 >97

D-Ala Cbz Cbz-D-Ala-Bt 90 >97

DL-Ala Cbz Cbz-DL-Ala-Bt 94 >97

L-Val Boc Boc-L-Val-Bt 83 >97

L-Val Cbz Cbz-L-Val-Bt 91 >97

* e.e. values were estimated in NMR and HPLC analysis by preparing a dipeptide for each N-aminoacylbenzotriazoles.

Amino Acid

N-Protecting Group


Yield ee.*

L-Phe Boc Boc-L-Phe-Bt 81 >97

L-Phe Cbz Cbz-L-Phe-Bt 88 >97

L-Phe Fmoc Fmoc-L-Phe-Bt 83 >97

L-Phe Tfa Tfa-L-Phe-Bt 82 >97

L-Leu Boc Cbz-L-Leu-Bt 66 >97

L-Leu Cbz Cbz-L-Leu-Bt 95 >97

L-Ileu Cbz Cbz-L-Ileu-Bt 95 >97

L-Pro Cbz Cbz-L-Pro-Bt 74 >97

(04S2645)(04S1806)(05S397)(In Preparation)

NN-Acylbenzotriazole Derivatives-Acylbenzotriazole Derivatives from from NN-Protected -Protected Amino Acids with FunctionalityAmino Acids with Functionality

(05S397) (In Preparation)


Functionality Yield ee.a

Cbz-L-Trp-Bt Indole NH 95 >97

Cbz-L-Tyr-Bt Phenol OH 86 >97

Cbz-L-Gln-Bt Amide NH2 72 >97

Cbz-L-Cys-Bt SH 76 >97

Cbz-L-Asn-Bt Amide NH2 72 >97

Cbz-L-Asp(OMe)-Bt CO2Me 82 >97

Cbz-L-Met-Bt CH2SMe 95 >99

Cbz-L-His-Bt Imidazole NH 70b >95c



Fmoc-L-Trp-Bt Indole NH 90 >97

Fmoc-L-Met-Bt CH2SMe 87 >97

Fmoc-L-Ser-Bt Alcoholic OH 68 >97

Tfa-L-Asp(OMe)-Bt CO2Me 80 >97

Tfa-L-Glu(OMe)-Bt CO2Me 82 >97

Di-Bt derivatives



Z-L-Cystine-Bt S-S dimer 90 >97

Z-L-Asp-diBt Two COBt 87 >97

Z-L-Glu-diBt Two COBt 68 >97

a: e.e. values were estimated in NMR and HPLC analysis by preparing a dipeptide for each N-aminoacylbenzotriazoles. b; Characterized as amides. c; Determined on amides in NMR

7

NN-Acylbenzotriazole Derivatives-Acylbenzotriazole Derivatives from from NN-Protected Dipeptides-Protected Dipeptides

R1

Z

O

NHNHO

HO

R2R1

Z

O

NHNHO

Bt

R2BtH, SOCl2

THF, -10oC

Entry Product Yield (%) Mp (oC) e.e.*

1 Z-L-Ala-L-Phe-Bt 90 148149 95

2 Z-L-Phe-L-Ala-Bt 85 180181 95

3 Z-L-Phe-D-Ala-Bt 90 156157 95

4 Z-L-Trp-L-Ala-Bt 78 176177 95

5 Z-L-Trp-L-Trp-Bt 76 152154 95

6 Z-L-Met-L-Ala-Bt 85 104105 95

7 Z-L-Met-D-Ala-Bt 87 135137 95

*e.e. was estimated in 1H NMR.

8

(04S2645)(04S1806)(05S397)

Virtues of AcylbenzotriazolesVirtues of Acylbenzotriazoles

Preparation: (i) RCOCl + BtH + base RCOBt

(ii) RCO2H + NEt3 + BtSO2Me [RCOOSO2Me + Bt] RCOBt

(iii) RCO2H + BtH (3 equiv) + SOCl2 RCOBt (via BtSOBt)

Scope Prepared from a very wide range of Acids (see previous slides)

9

Advantages: (i) Solids, highly crystalline compounds (ii) Soluble in organic solvents (iii) Non-hydroscopic, stable in air, can be weighed out, and stored indefinitely (iv) Can be used in aqueous media (v) Compatible with wide range of functionality (vi) Chirally stable for long periods (vii) Selectivity (e.g. diketones, not vinyl esters) (viii) Prepared directly from RCO2H in near quantitative yields (ix) Benzotriazole reagent easily recovered and recycled

Utility: (i) Peptide synthesis in aqueous media(ii) Peptide synthesis with diverse unprotected functionality(iii) Efficient S-acylation(iv) O-Acylation(v) Wide range of C-acylation

N-AcylationN-Acylation:Amides from N-acylbenzotriazoles

Primary amides RCONH2

R Yield(%)

C6H5 100

2-CH3OC6H4 100

3-ClC6H4 87

4-NO2C6H4 1002-Furanyl 1001-Naphthyl 1002-Pyridyl 1003-Pyridyl 1004-Pyridyl 1002-Pyrazinyl 100

PhCH2 100

PhCH2CH2 85

Ph2CH 90

n-C4H9 72

Secondary amides RCONHRR R’ Yield(%)

4-ClC6H5 EtCH(CH3) 95

4-ClC6H4 C6H5 75

4-Et2C6H4 n-C4H9 92

C6H5 t-C4H9 75

2-Furanyl n-C4H9 94

1-Naphthyl n-C4H9 92

2-Pyridyl 4-CH3OC6H5 83

4-Pyridyl EtCH(CH3) 100

2-Pyrazinyl (CH3)3C 100

Ph2CH C6H5 70Tertiary amides RCONRRR R’ R” Yield(%)

4-CH3C6H4 C2H5 C2H5 100

4-NO2C6H4 (CH2)4 96

C6H5 (CH2)4 100

2-CH3OC6H4 (CH2)4 98

2-Furanyl C2H5 C2H5 51

1-Naphthyl (CH2)4 94

4-Pyridyl (CH2)4 100

PhCH2 (CH2)4 99

Ph2CH (CH2)5 68

(00JOC8210)For reactions with Wang resin linked amines see 02BMCL1809

10

11Chiral Integrity of Peptide SynthesisChiral Integrity of Peptide SynthesisPreparation of N-(Boc acylamino)amides

1H NMR of Boc-Valine derivatives (02Arkivoc(viii)134)

Boc NH

O

Bt

R

Me

PhH2N

Boc NH

O

HN

R

Ph

Me

1. The NMR method 2. The chiral column methodHPLC: Performed on Beckman system gold with Chirobiotic T column, detection at 254 nm, flow rate of 1.0 mL/min, and MeOH/H2O (50:50)

L,L R.Time L,D R.Time

Cbz-L-Tyr-L-Phe-OH

10.8 Cbz-L-Tyr-D-Phe-OH

11.7

Cbz-L-Trp-L-Ala-OH

11.0 Cbz-L-Trp-D-Ala-OH

12.9

Fmoc-L-Trp-L-Ala-OH

11.1 Fmoc-L-Trp-D-Ala-OH

13.6

Cbz-L-Cys-L-Phe-OH

11.5 Cbz-L-Cys-D-Phe-OH

24.3

Cbz-L-Met-L-Ala-OH

10.9 Cbz-L-Met-D-Ala-OH

15.9

Cbz-L-Gln-L-Phe-OH

12.9 Cbz-L-Gln-D-Phe-OH

15.9

R.Time = Retention Time

(05S397)

Methods of Peptide PreparationMethods of Peptide Preparation

O

BtNH

R1

Cbz

O

OHH2N

R2Et3N O

HNNH

R1

CbzO

HO

R2+

CH3CN/H2O

r.t. 0.5 h

85~98%

O

BtNH

R1

Cbz

O

HNH2N

R2Et3N O

HNNH

R1

CbzO

HN

R2+

CH3CN/H2O

r.t. 0.5~1.0hO

HO

R3

OHO

R3

85~98%

Stepwise coupling:

O

HNNH

R1

CbzO

Bt

R2

O

OHH2N

R3

O

HNNH

R1

CbzO

HO

R2

O

HNNH

R1

CbzO

HN

R2

OHO

R3

BtH, SOCl2

0 oC

R1 = CH2Ph, R2 = Me, 85%

R1 = Me, R2 = CH2Ph, 90% 92~95%

Fragment coupling:

O

HNNHO

Bt

Cbz

Ph O

HNH2NO

HO

Et3N

O

HNNHCbzO

HN

OHN

O

HO

Ph

+CH3CN/H2O

r.t. 2.0h

86%

12

(04S2645)

Preparation of DipeptidesPreparation of DipeptidesChiral Dipeptides Yield(%) ee.a

Cbz-L-Ala-L-Phe-OH 90 >97

Cbz-L-Ala-L-Ser-OH 85 >97

Cbz-L-Ala-L-Trp-OH 97 >97

Cbz-L-Val-L-Phe-OH 98 >97

Cbz-L-Val-L-Trp-OH 96 >97

Cbz-L-Phe-L-Ala-OH 98 >97

Cbz-L-Phe-L-Val-OH 95 >97

Cbz-L-Phe-L-Phe-OH 98 >97

Cbz-L-Phe-L-Ser-OH 96 >97

Cbz-L-Tyr-L-Phe-OH 86 >97

Cbz-L-Tyr-L-Trp-OH 98 60

Cbz-L-Trp-L-Ala-OH 90 >97

Cbz-L-Trp-L-Cys-OH 86 >97

Cbz-L-Trp-L-Ser-OH 86 >97

Cbz-L-Trp-L-Trp-OH 85 >97

Cbz-L-Cys-L-Ala-OH 98 >97

13

Cbz-L-Met-L-Ala-OH 95 >97

Cbz-L-Met-D-Ala-OH 95 >97

Cbz-L-Met-L-Met-OH 95 >97

Cbz-L-Met-L-Trp-OH 82 >97

Cbz-L-Met-L-Glu-OH 60 >97

Cbz-L-Gln-L-Phe-OH 72 >97

Cbz-L-Gln-L-Gln-OH 47 >97

Cbz-L-Gln-L-Val-OH 95 >97

Fmoc-L-Trp-L-Ala-OH 70 >97

Fmoc-L-Trp-L-Ser-OH 87 >97

Fmoc-L-Met-L-Ser-OH 88 >97

Fmoc-L-Met-L-Glu-OH 93 >97

a:e.e. value was estimated by 1H NMR and HPLC analysis.

(05S397) (In Preparation)

Diastereomeric mixture of Dipeptide

Yield

Cbz-L-Tyr-DL-Phe-OH 86

Cbz-L-Trp-DL-Ala-OH 98

Cbz-L-Cys-DL-Ala-OH 71

Cbz-L-Met-DL-Ala-OH 72

Cbz-L-Gln-DL-Phe-OH 74

Fmoc-L-Trp-DL-Ala-OH 68

Preparation of Tri-, Preparation of Tri-,

Tripeptides Yield (%) ee.a

Cbz-L-Ala-L-Gly-L-Leu-OH 93 >97

Cbz-L-Ala-L-Phe-L-Trp-OH 95 >97

Cbz-L-Val-L-Gly-L-Leu-OH 85 >97

Cbz-L-Phe-L-Gly-L-Gly-OH 98 >97

Cbz-L-Phe-L-Ala-L-Ala-OH 92 >97

Cbz-L-Phe-L-Ala-L-Ser-OH 94 >97

Cbz-L-Trp-L-Ala-L-Cys-OH 86 >97

Cbz-L-Trp-L-Trp-L-Try-OH 87 33

Cbz-L-Met-L-Ala-L-Ala-OH 86 >97

Cbz-L-Met-L-Ala-L-Ser-OH 83 64

Cbz-L-Met-L-Ala-L-Trp-OH 92 60

Cbz-DL-Ala-L-Gly-L-Leu-OH 94 b

Cbz-L-Met-DL-Ala-L-Ala-OH 86 b

Tetrapeptides Yield (%) ee.*

Cbz-L-Phe-L-Ala-L-Gly-L-Leu-OH 86 >97

Cbz-L-Ala-L-Phe-L-Gly-L-Leu-OH 85 >97

a:The ee. value was estimated by 1H NMR and HPLC analysis. b; Diastereomeric mixture

14

(04S2645)(In progress)

and Tetraand Tetra-Peptides-Peptides

Synthesis of Weinreb amides and Hydroxamic acidsSynthesis of Weinreb amides and Hydroxamic acids15a

O

BtR1

O

NR1+ HN

R3

OR2OR2

R3

Et3N, THF

r.t.

R1: alkyl, aromatic

R2: H, Et, Bn

R3: H, Me

Weinreb amides: 24 examples (64-94%) Hydroxamic acids: 6 examples (61-91%)

O

BtNH

R1

N

R2H2N

HOEtOH

O

ONH

R1

NNH2

R2

EtOH

N

NO

R2NH25 oC

Pg = Boc, Cbz, Fmoc

Amino acid with R: alanine, valine, phenylalanine, methionine, tryptophan, and glutamine

R2: p-tolyl, benzyl, p-pyridyl

Bt = benzotriazol-1-yl

reflux

R

PgPg Pg

18 examples(average yield 88%)Can be isolated

5 min

Synthesis of Chiral Synthesis of Chiral 1,2,4-Oxadiazoles1,2,4-Oxadiazoles

(02ARK39) (03S2777)

(05ARK, In press)

15b

O

BtR1 R2 S

O

O

NH2

NaH

THF

O

NH

R1 SO

O

R2

+

R1: Aromatic and amino acid derivatives

R2SO2NH2: MeSO2NH2, p-MeC6H4SO2NH2, and acetazolamide

18 examples (78-98%)

O

BtR1 +

R1: Aromatic X = O, 10 examples (84-98%)X = S, 8 examples (85-97%)

HX NH2

X = O, R2 = Me

X = S, R2 = H

O

N

1) M.W. 80 oC, 10min

2) M.W. 80 oC, 2min

SOCl2

R2

R2R2

R2

R1

N-Acylation of SulfonamidesN-Acylation of Sulfonamides

Microwave-assisted Preparation of Oxazolines and ThiazolinesMicrowave-assisted Preparation of Oxazolines and Thiazolines

(02ARK14)

(04JOC811)

SS-Acylation -Acylation

Previous methods and their difficulties

(i) Acyl halides with thiol sodium salts low yields

(ii) Couplings of acyl halides and thiols with catalysts (thallium, tin mercaptides, or Zinc) limited by substrate specificity

(iii) Activation of RCO2H by diphosgene or polyphosphate ester low

yield, harsh conditions

(iv) Use of thiocyanate, instead of thiol limited by availability of S.M.

(v) Couplings of RCO2H and thiols with carbodiimides (e.g. DCC)

difficulty in removal of urea.

16

SS-Acylation-AcylationSynthesis of Thiol esters

RO

Bt

HS R'

Et3N

RO

S R'CH2Cl2, r.t.

*The crude product was obtained in 90% yield.

R of reactant

RCOBt R

O

S Ph

Yield %

RO

SPh

Yield %

RO

SCO2Et

Yield %

RO

SCO2H

Yield % C6H5 (1a) 92 98 93 97

2-MeOC6H4 (1b) 99 99 85 92

2-pyridyl (1c) 90 85 90 35*

2-indolyl (1d) 93 95 93 89

2-furyl (1e) 93 89 87 88

4-Et2NC6H4 (1f) 86 96 91 82

m-C6H4 (1g) 90 85 98 96

O

BtNH

Ph

Pg

HS RO

SNH

Ph

PgR

CH2Cl2 / Et3N (cat.)

1h., 25oC

Pg = Boc, Cbz

Pg-Phe-SR Yield (%) mp (oC)

Boc-Phe-SPh 76 102103

Boc-Phe-SCH2Ph 97 9293

Boc-Phe-SCH2CO2Et 85 7778

Cbz-Phe-SPh 86 100101

Cbz-Phe-SCH2Ph 93 119120

Cbz-Phe-SCH2CO2Et 84 5556

Cbz-Phe-SCH2CO2H 94 9899

17

(04S1806)

OO-Acylation -Acylation 18

O

H

HO

H

HO

H

OHOHH

H

OH

O

H

HO

H

HO

H

OHOHH H

O O

HN

PgR

D-Glucose

Pg = Fmoc, CBZ

Bt

O

NH

R

ZO

H

H HO

NH

R

Z

CholesterolMicrowaves

65 oC, 20 min+

Z = PhCH2OCO-

R = L-Me2CH- (88%), L-PhCH2- (82%) D-PheCH2- (84%)

Bt

O

NH

R

ZO

O

NH

R

Z

NerolMicrowaves

65 oC, 20 min+

R = L-3-IndolylCH2- (XX%) L-CH3SCH2CH2- (XX%)

(Unpublished work)

O-Acylated steroids, terpenes, sugars, and lipids

CC-Acylation (i) Aryl and Heteroaryl Rings-Acylation (i) Aryl and Heteroaryl Rings

O

O

BtR

TiCl4or ZnBr2O

R

O

5 examples54~98% (Average 79%)

S SR

O


N

X

TiCl4

N

X

R

O

X = H, Me

7 examples for X = H21~91% (Average 56%)7 examples for X = Me51~94% (Average 70%)

N

Si(i-Pr)3

TiCl4

N

Si(i-Pr)3

O

R


N

X

TiCl4

N

X

X = H, Me

7 examples for X = H15~92% (Average 66%)7 examples for X = Me27~92% (Average 69%)

R

O

(03JOC5720)(04CCA175)

19

R1

NH

Bt

O

PGN

R2

AlCl3

CH2Cl2, 20 °C

R1

NH O

PGN

R2

PG = Tfa, R1 = Phenyl

PG= Tfa, R1 = H

PG = Fmoc, R1 = Phenyl

PG = Fmoc, R1 = indol-3-yl

PG = Fmoc, R1 = CH2SMe

R2 = H

R2 = Me

5 examples for R2 = H

52~82% (Average 70%)

5 examples for R2 = Me

41~78% (Average 60%)

R1

NH

Bt

O

PGAlCl3

CH2Cl2, 20 °C

R1

NH O

PG

PG = Tfa, R1 = Phenyl

PG= Tfa, R1 = H

PG = Fmoc, R1 = Phenyl

PG = Fmoc, R1 = indol-3-yl

PG = Fmoc, R1 = CH2SMe

R2 = H

R2 = Me

5 examples for R2 = H

63~87% (Average 79%)

5 examples for R2 = Me

40~90% (Average 62%)

NR2

NR2

(In progress)

CC-Acylation (ii) Ketones, -Acylation (ii) Ketones, O

R2 R3

R1O

O

R2 R3

O

BtR1

LDA

(00JOC3679)

16 examples

(Average isolated yield 75%)

R3 SO2

R2

O

BtR1

n-BuLiO2S

R3

OR1

R2(03JOC1443)

18 examples


R1 = alkyl or arylR2 +R3 = alkyl or alicyclic

NH

R1O

N

R2

O

BtR1

LDA

R3R2

R3 (00S2029)

16 examples


NO2

R2

O

BtR1

t-BuOK

O

R1NO2

R2

(In Progress)

14 examples


20

R1 = alkyl or (hetero)aryl

R2 = hydrogen, alkyl,

vinyl or aryl

R3 = alkyl or aryl

R1 = alkyl or (hetero)aryl

R2 = hydrogen, or alkyl

R1 = alkyl, alkenyl or aryl

R2 = alkyl, or aryl

R3 = alkyl (acyclic or alicyclic)

Sulfones,Sulfones, Nitrocompounds and IminesNitrocompounds and Imines

CC-Acylation (iii) Heteroaryl Alkyl Groups-Acylation (iii) Heteroaryl Alkyl Groups

R2

Het R1

O

Bt

LDA R2

Het O

R1 R2

Het OH

R1(In Progress)

21

Entry

Het

R1 of R1COBt

R2 of HetCH2R

2 Yield (%)

(keto +enol) Keto/ enol

(%)

1 Pyridin-2-yl (CH3)2CHCH2 H 65 69/ 31 2 Pyridin-2-yl CH3(CH2)2CH2 H 56 67/ 33 3 Pyridin-2-yl PhCH=CH H 65 50/ 50 4 Pyridin-2-yl Ph H 78 59/ 41 5 Pyridin-2-yl 4-ClC6H4 H 83 38/ 62 6 Pyridin-2-yl Furan-2-yl H 84 68/ 32 7 Pyridin-2-yl Thiophen-2-yl H 68 85/ 15 8 Pyridin-2-yl Pyridin-3-yl H 72 16/ 84 9 Pyridin-2-yl 4-ClC6H4 Ph 95 58/ 42 10 Quinolin-2-yl Ph H 91 8/ 92 11 Quinolin-4-yl 4-ClC6H4 H 87 100/ 0 12 Quinolin-4-yl 4-NO2C6H4 H 72 100/ 0 13 Quinolin-4-yl Thiophen-2-yl H 66 100/ 0 14 Pyrimidin-4-yl Thiophen-2-yl H 80 50/ 50 15 Pyrimidin-4-yl Furan-2-yl H 50 50/ 50

CC-Acylation (iv) -Acylation (iv) -Keto Esters-Keto Esters

O

H3CCO2Et

R2

BtR1

O

NaHCO2Et

R2

COCH3

R1CO

O

R1

R2

CO2Et

1

2

43

O

H3C

O

BtR1

R2

O

NaH

OH

R1 R2

OO

R1 R2

O

5

2

6

(04JOC6617)

22

Entry

R1

R2

Yield (%)

(keto +enol)

enol

(%)

6a Ph Me 55 94

6b 4-MeC6H4 4-MeC6H4 97 97

6c 2-Thienyl 2-Thienyl 100 88

6d 4-MeC6H4 2-Furyl 52 94

Entry

R1

R2

Yield (%) (keto +enol)

Keto (%)

4a Ph H 76 83 4b 4-ClC6H4 H 84 78 4c 4-MeC6H4 H 85 86 4d 2-Furyl H 70 93 4e 4-Pyridyl H 71 39 4f n-C5H11 H 58 92 4g 4-MeC6H4 Me 76 100 4h n-C5H11 Me 52 93 4i 2-Furyl Me 71 100 4j 2-Thienyl Me 60 100 4k 2-Pyridyl Me 60 100 4l Ph Me 54 100

4m (Ph)2CH Me 51 100 4n 2-Furyl Bn 69 100 4o 2-Thienyl Bn 71 100 4p Ph Bn 65 100 4q Ph- Bn 54 0 4r 4-ClC6H4 Bn 53 100

and and -Diketones-Diketones

ThioamidesThioamides

R

S

YHN

R1

R2+

Route C

Y= Cl, OEt, Im, Bt

S

R NR1

R2

Route A

Route B

Route C

O

R NR1

R2

(Im)2CS

P2S5 or Lawesson's Reagent

PhN+

O-

Me

S

R NR1

R2

Routes

A (i)

A (ii)RMgX

RLi

RMgX

S

NMe

MeCl

R2 N C S

S

S

S

NR1

R2N R1

R2

Routes

B (i)

B (ii)

B (iii)

NiCl2(dppe)

23

Drawbacks of Route A:(i) Lawesson’s reagent is expensive, and the large amount of reagent-derived byproducts which accompany its reactions can only be removed by chromatography. (ii) 1,1-thiocarbonyl diimidazole is unstable and decomposes after 28 days of storage at room temperature.

Drawbacks of Route B:(i) Necessity of synthesizing thiocarbamic acid thioanhydride.(ii) Instability of alkyl isothiocyanates.(iii) Use of expensive metal catalyst and lack of commercially available thiocarbamoyl chlorides with substituents other than N,N-dimethyl.

Benzotriazole-Based Thioacylation Benzotriazole-Based Thioacylation ReagentsReagents

CS2R MgBrTHF R

S

SMgBr

BtCl

R

S

Bt

RCSBt: Synthesis of Thioacylbenzotriazoles from Grignards

R % Yield4-Tolyl 634-Methoxyphenyl

89Phenyl 76

RR1NCSBt: Preparation of Thiocarbamoylbenzotriazoles

S

ClCl NN

N

SiMe3

S

BtBt

+

1

NHRS

NBtR

R1

R1

2

2 R R1 % Yield MP (oC)

a Cyclohexyl H 85 128–130a

b Furfuryl H 94 119–120a

c (R)-Methylbenzyl H 87 oila

d Phenethyl H 89 112–113

e t-Butyl H 60 61–63

f 1,5-Dimethylhexyl H 87 oila

g -CH2CO2CH3 H 76 129–130

h 2,3-Dihydroindolyl =R1 84 123–124

i Pyrrolidinyl =R1 76 86–87

j Phenyl Methyl 92 137–138

k Ethyl Ethyl 98 oil

l n-Butyl Methyl 76 oil

S

Bt Bt SH R S

S

RBt Bt

S

Bt

S R

11

+ +

R1

a) Phenylb) Benzylc) Acetyl ethyl esterd) Isopropyl

46%42%63% 0%

21%44%trace90%

1RSCSBt: Synthesis of Alkyl/Arylthiothiocarbonylbenzotriazoles

S

Bt Bt OH R O

S

RBt

1

R1 = Ethyl (19%) 2-Naphthyl (87%) 3-Pyridinyl (66%) 1-Naphthyl (81%) Phenyl (83%)

1+

ROCSBt: Synthesis of Alkyl/Aryloxythiocarbonylbenzotriazoles

24

N

S

R

N N

NO2

NH2

NH2O2NNH

OR

NH2

NO2

RCOCl 1)P2S5

2) HONO

Preparation of Thiocarbonyl-1H-6-nitrobenzotriazoles

(96JOC9045) 6 examples:56-67 % yields(99JOC1065) 9 examples: 48-55 % yields(Unpublished results) 7 examples: 44-78% yields

Rapoport’s method for the

O

S

NR

RO

SnBuLi

O

S

BtRR2NH

1

Thioacylations with Benzotriazole Reagents Thioacylations with Benzotriazole Reagents ([04JOC2976] and unpublished work)

R

S

NR1

R2

R1R2NH

R

S

Bt

Synthesis of Thioureas from Thiocarbamoylbenzotriazoles

6 Examples: average isolated yield 87 %

S

NH

BtR NH

R2

R3

Et3N S

NH

NRR2

R3

+

Synthesis of Thioamides from Thioacylbenzotriazoles

15 examples: average yield 89 %

NHR2

S

NNH

R2

R1 R1

S

Bt Bt

R NH21)

2)

R

Bis-(benzotriazolyl)methanethione One-pot Syntheses of Thioureas:


Synthesis of Thioamides, Thiocarbamates, and Dithiocarbamates from Thiocarbamoylbenzotriazoles

N

S

RBt

R

N

S

R

RR

R-M(X)

N

S

R

RRO

N

S

R

RRS

2

11

2 2

1

2

1ROH

RSH

2 Note: R2 = H,No Reaction


2 examples: 59 and 60 % yields

9 examples: average isolated yield 71%

73% yield

R =R1 Morpholinyl 70%R = Benzyl R1 = H 85%

Thionesters and Thiocarbamates from Aryloxythioacylbenzotriazoles

25

Imidoylation-ScopeImidoylation-Scope• Scope: on

- Nitrogen ---Amidines, Guanidines

- Carbon ------Imines

- Sulfur ------Imidothioformate

RNH Bt

NR

R Bt

NR

Bt Bt

NR

a b c

NNH

R R''

R'

NNH

NH

R''

R'

R''

Amidines Guanidines

N

Cl

N

EtO

H

N

TfO

H

R2

R1

R2

R1

+

BF4-

R2

R1

+

OTf -

Imidoyl chlorides Imidate fluoroborates Iminium triflates

26

• Agents for imidoylation

- Imidolyating agents

Imidoyl chlorides, imidate fluoroborates,

and iminium triflates

- Guanidylating agents

Will be discussed in detail later

• Benzotriazole derivatives for imidoylations

- (a) Imidoylbenzotriazoles

- (b) (bis-benzotriazol-1-yl-methylene)amines

- (c) benzotriazole-1-carboxamidines

Reagents for the Preparation of AmidinesReagents for the Preparation of Amidines

• Conventional methods • Preparation of Imidoylbenzotriazoles

O

NH

N

Cl

N

EtO

H

N

TfO

H

N

N

NH

R2

R2

R1

R2

R1

+

BF4

_

R2

R1

+

OTf_

1

2

3

R2

R1R3

R4

R3 R4

R1

• Imidoyl chlorides are generally prepared in situ, but they are extremely labile toward hydrolysis and side reactions have been reported at elevated temperatures.

• Iminium triflates and imidate fluoroborates require handling under inert atmosphere and cannot be isolated or purified.

N

Bt

NH

O

R1R2

NH

O

R1R2

NOH

R1 R2

O

BtR1

NH

O

R1R2

R2

R1

Bt2SO

PPh3/BtCl

BtTs

R2NCO

BtR1

R2NC/BF3

BtHPOCl3, NEt3

95H231, 10 examples Yield: 15-75%

90CB1545, 8 examples

Yield: 38-96%

04JOC5108, 9 examples

Yield: 40-90%

01JOC2865

11 examples

Yield: 87-99%

01JOC1043

6 examples

Yield: 71-99%

99OL577, 12 examples

Yield: 20-87%

27

Imidoylbenzotriazoles are good substitutesfor imidoyl chlorides.

A Facile Preparation Method for Imidoylbenzotriazoles

Entry R1 R2 Yield (%) Entry R1 R2 Yield (%)

6a Me Ph 75 (B) 6j Ph Ph 88 (A)

6b Me p-Tolyl 65 (B) 6k p-Tolyl p-Tolyl 82 (A)

6c Bn p-Tolyl 62 (B) 6l 2-furyl p-Tolyl 84 (A)

6d Bn Bn 56 (B) 6m Ph p-MeOC6H4 82 (A)

6e PhCH2CH2 p-Tolyl 64 (B) 6n Ph Bn 93 (A)

6f PhCH2CH2 PhCH2 57 (B) 6o p-MeOC6H4 Bn 78 (A)

6g n-C6H13 p-Tolyl 57 (B) 6p Ph 2-Furylmethyl 84 (A)

6h Ph 2-Pyridyl 76 (A) 6q 2-furyl Cyclohexyl 95 (A)

6i p-O2NC6H4 Ph 88 (A) 6r p-O2NC6H4 Bn 79 (A)

Conditions for Route A and B

• Route A: amide (1 eq) + SOCl2 (2 eq) + BtH (4 eq); Solvent, CHCl3; Microwave, 80 oC, 80 W, 10 min.

• Route B: 1) amide (1 eq) + (COCl)2 + pyridine (1 eq), 0 oC, 15 min; solvent, CH2Cl2

2) BtH (2 eq), room temperature, 4 h

N

R1Bt

R2

N

R1Bt

R2

NHR2R1

O

BtH + SOCl2

route A

i (COCl)2, PyH ii BtH

route B

R1 = Alkyl R1 = Aryl

28

R1

NR

AcOH, microwaves

120 oC, 120 W, 10 minR1

NR

Bt

+R3R2

HN N

R2

R3

7a-p

Entry R R1 R2 R3 Yield (%)

7a Ph Me -(CH2)2O(CH2)2- 76

7b Ph Me Ph Me 74

7c Ph Me Et Et 88

7d Ph Me Bn H 77

7e Ph Me p-Tolyl H 89

7f Ph Ph Et Et 71

7g Ph Ph -(CH2)2O(CH2)2- 63

7h Ph Ph Ph Me 72

7i Ph Ph p-Tolyl H 66

7j 2-Furyl p-Tolyl -(CH2)2O(CH2)2- 74

7k 2-Furyl p-Tolyl Et Et 77

7l Bn p-Tolyl Et Et 86

7m Bn p-Tolyl p-Tolyl H 90

7n n-C6H13 p-Tolyl -(CH2)2O(CH2)2- 78

7o n-C6H13 p-Tolyl Et Et 88

7p Bn Bn -(CH2)2O(CH2)2- 75

Preparation of Polysubstituted AmidinesPreparation of Polysubstituted Amidines

•Reaction took place under microwave irradiation, and just needed 10 minutes to finish.

• Acetic acid acts as a solvent, catalyst, and reactant.

• 15 amidines are listed here with good to excellent yields.

• Most amidines were isolated as acetic acid salts.

• The examples obtained showed the versatility of the method.

29

ArHN

S

NHAr

R

N PPh3

BocHN

NHBoc

S

BocHN

NBoc

SMe

H2N

NHBoc

S

H2N

NR1

SMe

HgCl2 , TEA,

DMF, 60oC

N Me

Cl

I

N

NH

N NR2

R1

HN

R

N

N

Cl

O

Cl

NH2R

H2N

NR1

SO3H

R1HN

NH

SMe

R1HN

NR1

N N

R1HN

NTf

NHR1

R1N

O

NR1

2a-j

+aR1 = Alkyl

Et2O, 0oC

bR1 = Boc, Cbz

DCM, 20oC

cR1 = Boc, Cbz

THF, 20oC

dR1 = Ph, Pr

MeCN, 20oC

eR1 = Mtr, Pmc

Hg(ClO4)2 , TEA

f

g

hEDCl, TEA,

DCM, 20oC

iR1 = Ar

t-BuOH, heat

j

R = Ar, 4

R1= Ar, Alk;

R2 = H

THF, reflux

1 3 5

2a

2b

2c

2d

2e

2f

2g

2h

2i

2j

H2N

NH2+

Bt Bt

NR

Cl

TsO

6 7

• Reagents 6–7 both guanylate primary and secondary amines under mild conditions in high yields.

• Benzotriazole-1-carboxamidinium tosylate 6 afforded guanidines under mild conditions, in moderate to good yields (55-86%).

• Benzotriazolylcarboximidoyl chlorides 7 are stable, odorless, and convenient to handle. They afforded guanidines in moderate yields (68-69%).

Literature reagents

Disadvantages:• These reagents must be synthetically prepared, most of them in a multi-step sequence.• Harsh reaction conditions are required in some cases to deprotect the protecting groups• A large excess of starting amines is in need at times to reach completion of the reaction.• Low reactivity at times

Early Bt derivatives

95SC1173 01JOC2854

30Guanidylating Agents and First Bt- Literature

Second Generation Bt-Mediated Preparation of GuanidinesSecond Generation Bt-Mediated Preparation of Guanidines

Bt N

N O

N N

N O

8b

R1

R2

R3

R1

R2

R3

R4

R5

R4NHR5

a''-o''

Entry R1 R2 Yield (%)

a H Ph 80

b H n-C5H11 74

c H Bn 68

d -(CH2)4- 71

e -(CH2)2O(CH2)2- 68

f ipr ipr 68

Bt Bt

NHBt

NH

NR1

R2

R1NHR2

THF rt

8a (65%) a-f

Entry R1 R2 R3 R4 Yield

a’ -(CH2)2O(CH2)2- Ph H 64

b’ -(CH2)2O(CH2)2- p-Tolyl H 74

c’ -(CH2)2O(CH2)2- Bn H 71

d’ -(CH2)2O(CH2)2- Ph Me 85

e’ -(CH2)4- Ph H 68

f’ -(CH2)4- 4-MeOC6H4 H 60

g’ iPr iPr 4-MeOC6H4 H 48

(00JOC8080)

Entry R1 R2 R3 R4 R5 Y (%)

a’’ -(CH2)5- Ph 4-MeOC6H4 H 68

b’’ -(CH2)5- Ph (CH2)2O(CH2)2 78

c’’ -(CH2)5- Ph Ph H 76

d’’ -(CH2)5- Ph n-Bu H 84

e’’ iPr iPr Et PhC2H4 H 51

f’’ iPr iPr Et Bn H 50

g’’ iPr iPr Et i-Bu H 56

h’’ iPr iPr Et 4-MeOC6H4 H 70

i’’ iPr iPr Ph Ph H 60

j’’ iPr iPr Ph Bn H 78

k’’ (CH2)2O(CH2)2 4-MeOC6H4 (CH2)2O(CH2)2 84

l’’ (CH2)2O(CH2)2 2-Furyl PhC2H4 H 81

m’’ (CH2)2O(CH2)2 2-Furyl p-Tolyl H 79

n’’ (CH2)2O(CH2)2 4-ClC6H4 MeO2CCH(Ph)

H 70

o’’ (CH2)2O(CH2)2 4-ClC6H4 -(CH2)4- 78(01S897)

31

N

NH

NR1

R2

R3

R4

R3NHR4

THF, Reflux

a'-g'

Recent Bt-based Guanidylating AgentsRecent Bt-based Guanidylating Agents

Bt

Bt

S

Bt

RBt

N

BtS

R1 NH

RBtN

R1 NH

R N PPh3

R N PPh3

9

10

12

11a-f

13a-l

10

R1NH2

12a R1 = Bn, 98 %

12b R1 = i-Pr, 95 %

12c R1 = Ph, 90 %

12d R1 = n-Bu, 98 %

10a R = Ph

10b R = p-Tol

10c R = C6H4CN-m

10d R = C6H4CO2Et

10e R = C6H4Cl-p

10f R = COPh

10g R = C6H2(Me)3-2,4,6

12e R1 = (CH2)2Ph, 93 %

12f R1 = (CH2)5CH, 95 %

12g R1 = CH2CH(CH3)CH2CH3, 98 %

12h R1 = 2-furylmethyl, 91 %

Preparation

Bt

BtN

R Bt

NHN

R

R1

NH

NHN

R

R1

R1

R1NH2

HN

HNN

R

NH2

NH2

NN

N

BtR N C R1N

11

Toluene, reflux 1h

Toluene, reflux 1h

16a-e

= Bt

15a-e

R1NH2

Preparation of symmetrical and cyclic trisubstituted guanidines

5 examples, 79-91%

5 examples, 77-96%

R1HN

BtN

R R1HN

NN

R

R3

R2

R1HN

HNN

R

R2

R2NH2

R3NHR2

13

Toluene, reflux 12h

Toluene, reflux 1h

17a-f

18a-h

NN

N= Bt

6 examples, 67-96 %

8 examples, 71-99%

• Starting materials 11 and 13 were prepared through a novel method with good yields

Preparation of substituted unsymmetrical guanidines

32

Imidolylation at SulfurImidolylation at Sulfur

N

Bt

N

R1

R2

R3

R4

N

N

S

R1

R2

R3

R4 R5R5SHNaOMe

THF, Reflux16-18h

R1 R2 R3 R4 R5 Yield (%)

a H -(CH2)2O(CH2)2- 2,5-Cl2C6H3 4-MeC6H4 44

b H -(CH2)2O(CH2)2- 2,5-Cl2C6H3 C6H5CH2 53

c H Me Ph 2,5-Cl2C6H3 Ph 92

d H -(CH2)2O(CH2)2- 4-NO2C6H4 4-MeC6H4 44

e H -(CH2)2O(CH2)2- C6H5CH2 4-MeC6H4 46

f H -(CH2)2O(CH2)2- C6H5CH2 4-tBu-2-MeC6H3 75

g iBu -(CH2)2O(CH2)2- 3-NO2C6H4 4-Me C6H4 59

(01JOC2865)

R1 R2 R3 Yield (%)

a 4-MeC6H4 Ph iPr 90

b Me Ph iPr 77

c 4-MeC6H4 4 Ph PhCH2 91

d Me Ph PhCH2 94

N

Bt

N

SR3SHNaOMe

THF, Reflux16-18hR1

R2

R1

R2 R3

(95H231)

33

Imidoylation at Carbon (Ketones)Imidoylation at Carbon (Ketones)

N

BtN N

X

N

X

R1

R2

R1

R2

+

LDATHF, -78 oC

Overnight

12a: X=O2b: X=S

3

01JOC4041

entry R1 R2 X Yield (%)

3a Ph Ph O 85

3b Ph Ph S 79

3c Ph 4-ClC6H4 O 87

3d Ph 4-ClC6H4 S 88

3e Ph 4-BrC6H4 O 89

3f Ph 4-BrC6H4 S 98

3g 4-MeC6H4 Ph O 82

3h 4-MeC6H4 Ph S 91

3i 4-MeC6H4 4-BrC6H4 O 96

3j 4-MeC6H4 4-BrC6H4 S 89

3k Ph 4-MeOC6H4 O 84

3l Ph 4-MeOC6H4 S 85

3m 4-MeC6H4 4-MeOC6H4 O 85

3n 4-MeC6H4 4-MeOC6H4 S 84

34

1-Cyanobenzotriazole1-CyanobenzotriazoleA Safe and Convenient Source of +CNA Safe and Convenient Source of +CN

N

NMe2

NBr

N+

NMe2

N

Br-

BtHN

NN

N

NBrN-

NN

Na+

Preparation of 1-Cyanobenzotriazole1-Cyanobenzotriazole

76% 90%

1-Cyanobenzotriazole as a 1-Cyanobenzotriazole as a NN-Cyanating Reagent-Cyanating Reagent

1-Cyanobenzotriazole as a 1-Cyanobenzotriazole as a CC-Cyanating Reagent-Cyanating Reagent

Hughes et al. (98JOC401) 5 examples: 30-66 %

Bt CN2.

1. LDAAr

CN

CNAr

CN

NC Bt CN

CN

CCH CHN

nBuLi

Drechsler et al. (01JCSPT(2)581) 70% yield

Bt CN NCN

R1R+ NHR

R1 R = H

chlorobenzene

(91RRC573) 7 examples: 84-96 % yields

Whitten et al. (88S470)(91RRC573)

35

Classical Preparation of Sulfonamides:

RS

Cl

O

OR NH2 R

SNH

R

O

O

base+

Disadvanges of Using Sulfonyl Chlorides:

• Highly reactive and hygroscopic Problematic to store• Requires a base for reactions• Many are difficult to access.

Synthetic Equivalents to sulfonyl chlorides:

N N+

S

O

O

CH3

-OTfClS

O

ONH N

TfOCH3

+

Preparation of SulfonylbenzotriazolesPreparation of Sulfonylbenzotriazoles (04JOC1849)

MgBr

S Li

Li

N

Li

MgCl

R M

93

82

65

20

71

Mp(0C)

133-134

143-144

117-119

oil

131-132

of RSO2BtYield (%)

MgCl

N

N

Li

N Li

N

Li

O Li

R M Yield (%)

75

80

71

41

83

Mp(0C)

107-109

147-150

oil

132-135

128-129

of RSO2Bt

R M SO2R S

OMgBr

O

BtClR S

O

O

BtNEt3

+

Sulfonylbenzotriazoles: Preparation

O’Connell, J. F. and Rapoport, H. (92JOC4775)

36

Advantages over existing methods:

• no need for added base • reaction proceeds at ambient temperatures • Less reactive and more selective than sulfonyl chlorides• Selectively sulfonylate a 10 amine over the 20 • Selectively sulfonylate aliphatic amines over aromatic amines

S

O

O

NN N

Ph

NH2R

ArOH

SR

O

O

NH

R

SR

O

O

N R

R

SR

O

O

O Ar

NH

R R1

1

1

1

22

THF/RT

Benzotriazole-Assisted SulfonylationBenzotriazole-Assisted Sulfonylation ([94SC205] and [04JOC1849])

Generation of Sulfonamides from Sulfonylbenzotriazoles

SO

O NH

SO

O N

S SO

O N

NS

O

O

N

S

O

ON

89

72

85

Cyclohexylamine,THF/25 0C/18 h

N-Methylbenzyl-amine,

THF/25 0C/15 h

Piperidine,THF/25 0C/42 h

YieldAmine/Conditions Sulfonamide

99Piperidine,THF/25 0C/20 h

(%)

Piperidine,DMF/80 0C/48 h 99

R S

O

OBt

NH

R2R1

RS

O

ON

R1

R2

S SO

O NH

NO

N

N

S

O

O

N

N

SN

O

OH

O SO

O NH

91

64

80

Morpholine,DMF/80 0C/24 h

1, 5- dimethyl-hexylamine,

DMF/80 0C/24 h

Phenethylamine,DMF/80 0C/48 h

992-Aminopentane,DMF/80 0C/24 h

Yield (%) Amine/Conditions Sulfonamide

3 examples: 87-93% yields



37

38Coworkers in Benzotriazole Chemistry 1987-2005Argentina

Laura Moyano

Australia

Darren CundyScott HendersonRichard MusgraveNassem PeerzadaPaul SavageAdam WellsStuart Barrow

Austria

Isolde Puschmann

Azerbaijan

Novruz AkhmedovRena Akhmedova

Belgium

Annie MayenceChris StevensJ.-J. Vanden Eynde

Brazil

Alessandro Soares

China

Weilang BaoChunming CaiXiaohong CaiHe-Xi ChangJie ChenJun ChenKe ChenYaxing ChenDai ChengXilin CuiWeihong DuWei-Qiang FanYunfeng FangDaming FengHai Ying HeQing-Mei HongXiang HongTan Bao HuangZhizhen HuangFu Bao Ji

Yu JiJinlong JiangRong JiangXiangfu LanHengyuan LangKam Wah LawJinqung LiLingfei LiuQiu-He LongZiwei LuPing LueZhushou LuoRexiat MaimaitMing QiGuofang QiuHuimin SongHui TaoHongbin TuJin WangJunquan WangMingyi WangXiaoling WangZuoquan WangHong WuJiaxing WuJing Wu Linghong XieYongjiang XuBaozhen YangHongfang Yang Zhijun YangGuo-Wei YaoJiangchao YaoYeyi YinYanhua YuGui-Fen ZhangLianhao ZhangSuoming ZhangYongmin ZhangYuming ZhangZhongxing ZhangHongyan ZhaoXiaoming ZhaoDazhi ZhongLie Zhu

Columbia

Rodrigo AboniaHenry Insuasty

Egypt

Ahmed El-SayedSaad El-ZemityAbdel Haleem HusseinFatma MahniAshraf Abdel-FattahSamia Agamy

France

Sophie BusontChristophe ChassaingCatherine GarotJeremy KisterStephane LedouxYves LeGallOlivier LingibeDaphne MonteuxJean-Luc MoutouDavid PleynetDelphine SemenzinGeoffroy Sommen

Germany

Michael ArendTorsten BlitzkeNicole ClemensPeter CzerneySebastian HoffmanAldo JesorkaSimona JurczykJens KoeditzThomas Kurz

Ghana

Augustine Donkor

Greece

John GallosK. Yannakopoulou

Hungary

Ferenc SotiLaszlo Urogdi

India

Parul AngrishM. BalasubramanianVandana GuptaRitu JainJamshed LamSuman MajumderNegeshwar MalhotraKavita ManjuT. MayelvagananNabin MeherShamal MehtaPrabhu MohapatraSatheesh NairSubbu PerumalMungala RaoNavayath ShobanaSandeep SinghSanjai SinghShaleindra SinghSrinivasa Rao TalaAjith Dain ThomasSutha VellaichamyAkhilesh Verma

Jamaica

Keisha Gay Hylton

Japan

Kunihiko AkutagawaYasuhisa MatsukawaKazuyuki SuzukiIchiro Takahashi

Jordan

Shibli Bayyuk

Lebanon

Niveen Khashab

New Zealand

Peter Steel

Nigeria

Clara Fali

Palestine

Abd Ferwanah

Panama

Herman Odens

Poland

Piotr BarczynskiJoanna BorowieckaJacek BrzezinskiZofia Dega-SzafranJacek DoskoczBarbara GaluszkaKrzysztof IndzikAndrzej JizwiakW. KuzmierkiewiczZbigniew NajzarekMaria PaluchowskaJuliusz PernakBoguslaw PilarskiBogumila RachwalStanislaw RachwalDanuta RasalaFrank SaczewskiJadwiga SoloduchoMirek SzafranMaria SzajdaLeszek Wrobel

Pakistan

Amir AfridiMuhammad Latif

Romania

Diana AslanMircea DarabantuIon GhivirigaDaniela OniciuDorin ToaderIoan Silberg

Russia

Sergey BobrovZoya DemyanetsOlga DeniskoMikhail GordeevAnna GromovaAlexy IgnatchenkoYekaterina Kovalenko

Alexander LesinValery MortikovGeorgiy NikonovIrina ScherbakovaAlexander ShestopalovSergei VerinMichael VoronkovVladimir Vvedensky

Slovenia

Sonja Strah

So. Africa

Jaco BreytenbachNazira Karodia

So. Korea

Young-Seuk HongYoung Soo Gyong

Spain

Pilar CabildoJusto Cobo-DomingoBalbino ManchenoAlfredo Pastor-del-CastilloOlga Rubio-Teresa

Sudan

Ahmad Yagoub

Switzerland

Frederick Brunner

Syria

Mohammed Soleiman

Togo

Rufine Akue-Gedu

Turkey

Alaettin GuvenDeniz Hur

UK

Steve AllinRichard BarcockMike BlackAndy BriggsMartin ButtonKevin Doyle

John GreenhillDennis HallPhilip HarrisGregory HitchingsPeter LeemingJulian LevellJulie Thomson

Ukraine

Sergei BelyakovAnna DenisenkoSergei DenisenkoKonstantin KirichenkoNatalie KirichenkoAlexander MitrokhinBoris RogovoyAlina SilinaLarisa SerdyukAlexander SorochinskyDmytro TymoshenkoAnatoly Vakulenko

USA

Ken CasterJanet CusidoTerry DavisChris DiebertM. Drewniak-DeyrupRachel Fuller-WitekKenny HeckAmy HaydenCraig HughesGlen NobleRick OffermanPhilip PhelphreyDaniel NicolsValerie RodriguezJames RogersJohn StevensDoug TathamAdam VincekChavon Wilkerson

39Katritzky Group Financial Support 1987-20053M Corporation

St. Paul, MN; Austin, TX

Harlow, UK; Ferrania, Italy

Abbott Laboratories, IL

Affymax

Agrevo, Germany

Aldrich/Sigma-Aldrich, WI

Aldrich Zeneca

Amgen, CA

Arcadia, Denmark

Army, Research Office, NJ

Athena, CA

Aventis Crop Science

BASF, Ludwigshafen, Germany

Bayer, CT

BioVitrum

Boehringer, Ingelheim, CT

Bristol-Myers Squibb, CT

Centaur, CA

Ciba-Geigy, NC

Coelacanth, NJ

COR Therapeutics, CA

Cyanamid, NJ

Dow Agroscience

Dow-Elanco, IN

Dupont Agro Chem, DE

Dupont Pharma

Eli Lilly

Exxon Corporation, now ExxonMobil

Baton Rouge, LA; Linden, NJ

Clinton, NJ; Abingdon, UK

Fisons, NY

Flexsys, OH

FMC Corporation, NJ

Geo-Centers, NJ

Glaxo-Wellcome, UK & France

ImClone, NY

Inspire Pharmaceuticals, NC

Jansen

Lancaster, UK and Gainesville, FL

Lion Biosciences, CA

L’Oreal Paris, France

Maxim Pharmaceuticals

Merck, NJ

Millenium

Monsanto, Nutrasweet, IL

New Technology, IL

Namiki Shoji, Japan

NeurogesX, CA

Nippon Soda, Japan

Novartis Crop Protection, NC

NSF, Washington DC

Nutrasweet, IL

Organon, NetherlandsParke-Davis, MIPfizer, CN

Pharmacia-Upjohn, MI

Pharmos, Alachua, FL

Procter and Gamble, OH, FL; UK

Reilly Industries, IN

Renovis, S. Francisco, CA

Rhone-Poulenc, Research Triangle, NC

Rohm and Haas, PA

RW Johnson Research, NJ

Samsung, Korea

Sandoz, NC

Schering-Plough, NJ

Scriptgen

SDS Biotech, Japan

Senomyx

Smith Klein Beecham

SPECS, Holland

Solutia, St. Louis, MO

Sterling Winthrop Inc., PA

Trega Biosciences, CA

Tularik, CA

Univ Alabama

Upjohn Corp., MI

US Navy, Research Office, CA

US Army

US Department of Agriculture

Warner-Lambert, MI

Zeneca, UK

acylation and related transformations alan r. katritzky, kazuyuki suzuki, ashraf a. abdel- fattah,...

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