chapter 1 suzuki-miyaura and heck cross coupling...

Chapter 1

Suzuki-Miyaura and Heck Cross Coupling

Reactions

X

R

B(OH)2

K2CO3, TCA-Pd(0),

R

71-95%

X = I & Br

CO2Et,

N(CH2CH2CN)3 / NH(CH2CH2CN)2

R

30-96%

Pd (OAc)2CO2Et

110 oC 80 oC / microwave

H2O

R = NO2, NH2, Cl,

OH, OCH3, CH3

R = NO2, Cl, COCH3,

OH, OCH3, CH3

Development of cyanoalkylamine------------- Chapter 1

37

Development of cyanoalkylamine as interface reagent for cross coupling reactions

1.1 Introduction:

The transition metal catalyzed carbon-carbon cross coupling reactions such as Suzuki and

Heck are very important in organic synthesis. These reactions can be performed in organic

solvents, water and ionic liquids. The problem in water mediated reactions such as

solubility of substrates has been overcome to some extent by the use of phase-transfer

catalyst, additive and water soluble catalyst [Bedford et al. (2003); De Vasher et al.

(2004)]. Water-cosolvents like H2O-MeOH, H2O-CH3COCH3, H2O-toluene and H2O-PEG

have also been used to resolve this problem [Liu et al. (2005); Phan and Styring (2008)].

But there is still need to search some alternative which can give good performance in water

mediated reactions. In this regard our main aim was to develop an alternative which has

the property to bring the substrate and catalyst at a common surface for the high

performance of reaction, hence behaving as an interface reagent.

An interface is a shared boundary or connection (either physical or logical) between two

dissimilar objects or systems through which information is passed. This term is used in

many fields including chemistry, geology, electronics, computers and telecommunications.

In chemistry it refers to the common surface between two distinct phases.

Cyanoalkylamines such as tris(2-cyanoethyl) amine (TCA) and bis(2-cyanoethyl)amine

(DCA) have interesting properties such as low melting point, high boiling point, solubility

in water and polar or non-polar solvents. TCA can also be referred as interface reagent due

to its ability to bring the substrates and catalyst in a common surface for providing

favourable pathway for the chemical reaction. Substrates and catalyst interact at the

common surface followed by activation and reaction to give the products. In addition to

this, it also acts as base and reaction media in Heck cross coupling reaction.

Previously TCA and DCA have been synthesized through reaction of acrylonitrile with

ammonium salts or ammonia gas in water (Scheme 1 and 2) [Dinslaken (1977); Smiley

(1993)].

+CNNH4OAc

CH3COOH, H2O

105 oC, 24 hN

CN

CN

CN

TCA

Scheme 1. Synthesis of TCA from ammonium acetate and acrylonitrile


38

NH3 (gas) +CN bubble column reactor

H2OHN

DCACN

CN

Scheme 2. Synthesis of DCA from ammonia and acrylonitrile

Some others methods are also available but in most of the cases large ratio of polar solvent,

high pressure, longer reaction time and large volume is required. So there is need to

develop an ecofriendly method for their synthesis. Earlier TCA was used as an additive in

plasticized poly (vinyl acetate) coating to increase tenstile strength, as a ligand in the

preparation of silver macrocyclic [Erxleben (2002)] and as a promoter in catalytic

oxidation of alkyl aromatic hydrocarbon to aromatic carboxylic acids. TCA can be

hydrolyzed to nitrilotripropionic acid which is useful as boiler scale inhibitor and remover

[Tsou et al. (1985)]. DCA is also a valuable starting material for various important

syntheses. It can be converted by hydrogenation into dipropylene-amine which is

employed as hardener for epoxide resins [Dinslaken (1977)]. But TCA and DCA were not

applied extensively to improve stability of transition metal catalyst and as a base in organic

synthesis.

1.1 Carbon-carbon cross coupling reactions:

The metal catalyzed cross coupling reactions (Suzuki and Heck) are powerful methods for

C-C bond formation and for the synthesis of heterocycles, natural products and

pharmaceuticals (Figure 1) [Bakherad et al. (2009)]. Biaryls which are found in polymers,

biologically active compounds, ligands and various electronic materials can be easily

synthesized using Suzuki cross coupling reaction [Billingsley et al. (2006)]. The Heck

arylation of olefin is also one of the most important C-C bonds forming reaction used in

the synthesis of several biologically active cinnamates, coumarians and flavonoids [Bianco

et al. (2004)].

X

R

X=I, Br and Cl

+ R'R'Metal Catalyst

base, solvent

R' = boronic acid, olefin

Figure 1. General outline for Suzuki and Heck cross coupling reactions


39

1.2.1 Palladium-catalyzed Suzuki cross coupling reactions:

Suzuki cross coupling is important palladium-catalyzed carbon-carbon bond forming

reaction. The first example of this reaction has been reported by Suzuki group in 1981

[Miyaura et.al. (1981)]. Further many modifications have been made in this reaction by

using water soluble Pd(0) catalyst [Casalnuovo and Calabrese (1990)] and water as solvent

[Badone et al. (1997); Bumagin and Bykov (1997)]. The use of amphiphilic polymer

supported palladium catalyst, ionic liquids and phosphine ligands have also been reported

[Uozumi et al. (1999); Mathews et al. (2000); Urgaonkar et al. (2002); Yamada et al.

(2002)]. The problems that arise in water mediated reaction such as solubility of substrates

and stability of the metal catalysts have been overcome to some extent by the use of phase-

transfer catalysts, additives and water soluble ligands [Leadbeater and Marco (2002);

Bedford et al. (2003); De Vasher et al. (2004)]. Varoius phosphine free ligands such as N-

heterocyclic carbenes [Wang et al. (2004); Kim et al. (2005); Shi and Qian (2005)], N, O

or N, N-bidentate ligands [Lai et al. (2005); Mino et al. (2005)] and simple amines [Tao

and Boykin (2004); Li et al. (2005)] have also been used in the Suzuki cross coupling

reactions. Pd(OAc)2 in a mixture of water and poly(ethylene glycol) (PEG) [Liu et al.

(2005)] as well as in TBAB and PEG-400 [Liu et al. (2006)] has been investigated as an

active catalyst for Suzuki cross coupling reaction and afforded corresponding products in

moderate to excellent yields (Scheme 3).

R1+

B(OH)2

XPd(OAC)2

R1

R2

R2

X = I,Br,Cl

R1 = NO2,OMe

R2 = H, OMe

PEG

Scheme 3. Suzuki cross coupling reactions catalyzed by Pd(OAc)2

Suzuki cross coupling reaction using PdCl2 or Pd(OAc)2 along with KOH in water has

been reported at low palladium loading [Korolev and Bumagin (2006)]. Li et al. have

synthesized the water-soluble Pd(OAc)2/guanidine catalyst from Pd(OAc)2 and 1,1,3,3-

tetramethyl-2-n-butylguanidine. The catalyst has been applied in Suzuki cross coupling

reaction to afford the corresponding coupling products in good to excellent yields (Scheme

4) [Li et al. (2007)].


40

X

R

B(OH)2

R1

Bu N

N N

Pd(OAc)2K2CO3,H2O

R1

R

+

X = I,Br, Cl

R = OCH3,NO2,CHO,CH3,COCH3

R1 = H, OCH3,Cl,CH3,CF3

Scheme 4. Suzuki cross coupling reaction of aryl halides in aqueous solution

Imidazolium and pyridinium based ionic liquids with ether/polyether substituent have been

evaluated as solvents for palladium-catalyzed Suzuki cross coupling reactions due to better

stabilization of the palladium catalyst in these solvents (Scheme 5) [Yang et al. (2008)].

R+

B(OH)2

Na2CO3, 100 oC, IL

X

R1

X = I,Br

R = NO2,CN,OMe, COOH

PdCl2 (CH3CN)2

Scheme 5. Suzuki cross coupling reaction in ionic liquid

The Suzuki cross coupling reaction with Pd(OAc)2-H2O-CH3COCH3 [Liu et al. (2006)]

has been investigated by Liu. Similarly a non-symmetrical salen type palladium catalyst

that is readily immobilized onto merrifield resin in H2O-toluene [Phan and Styring (2008)]

has also been used in Suzuki cross coupling reaction (Scheme 6). In both processes,

toluene or acetone has been used as co-solvent in water mediated reaction to improve the

yield.

+

B(OH)2

H2O-Toluene or H2O-CH3COCH3

XPalladium catalyst

R1

X= I,Br

R1 R2

R2

R1 = OH,CHO,CNR2 = H, OCH3

Scheme 6. Suzuki cross coupling reactions of aryl halides using cosolvents

De Souza et al. have reported the PEG-H2O-Pd/BaSO4 system as a suitable catalyst for

Suzuki cross coupling reactions of halobenzenes with boronic acids (Scheme 7). The

catalytic system was recycled up to six times, showing a continuous slight decrease in

activity [De Souza et al. (2009)].


41

+

B(OH)2

XPd / BaSO4

R1

X= I,Br

R1 R2

R2

R1 = H,CH3O,NO2

R2 = H, Br

PEG-H2O, 80 oC

Scheme 7. Suzuki cross coupling reaction in PFG-H2O

Suzuki cross coupling reaction using bis(imino)pyridine palladium(II) complexes [Liu et

al. (2009); Liu et al. (2010)] has also been investigated. Similarly, palladacyclic catalyst in

pure aqueous buffer [Marziale et al. (2010); Marziale et al. (2011)] was found to be

efficient for Suzuki cross coupling reaction at room temperature (Scheme 8).

+

B(OH)2

X

R1X= I, Br

R2R1

R2

R1 = OH,COOH,COCH3

R2 = H, COOH

Palladium catalyst

H2O

Scheme 8. Aqueous Suzuki cross coupling reactions of aryl halides

In another instance, a series of nitrile functionalized pyrrolidinium based ionic liquids have

been prepared and characterized by spectroscopic methods and X-ray crystallography. Cui

et al. have investigated the application of these ionic liquids for Suzuki cross coupling

reaction as a media (Scheme 9) [Cui et al. (2010)].

R+

B(OH)2

IL,110 oC

X

R1

X = I,Br

R = NO2,CN,OMe, H

PdCl2, Na2CO3 (aq.)

Scheme 9. Nitrile functionalized ionic liquids promoted Suzuki coupling reaction

A monodentate palladium-sulphur ligand catalytic system for the Suzuki cross coupling

reaction has been investigated and found to be effective under aerobic conditions. The

sulphur ligand was recovered by column chromatography with good catalytic activity of

the recycled ligand (Scheme 10) [Li et al. (2010)]. In the same manner, palladium-

catalyzed Suzuki cross coupling reaction of aryl bromides and chlorides in water using

phosphine-palladium complex has been developed. The catalyst could be recycled for at

least three times inspite of its homogeneous nature [Fihri et al. (2011)].


42

+

B(OH)2

X

R1

X= I, Br, Cl

R2R1

R2

R1 = OMe,COCH3, Cl,NO2

R2 = H, OMe, Me

Pd(OAc)2, Ligand

H2O or i-PrOH / H2O

K2CO3, 100 oC

Scheme 10. Ligand promoted Suzuki coupling reactions of aryl halides in water

In addition to this, palladium complex bearing half-salen ligand with PdCl2 has been

established as efficient catalyst for Suzuki cross coupling reaction [Liu et al. (2010)].

Suzuki cross coupling reaction using a series of β-ketoamine ligands with different steric

and electronic substituents which in situ complexed to PdCl2 has been investigated under

aerobic conditions in EtOH-H2O solvent system (Scheme 11) [Zhou et al. (2011)]. The

catalytic studies indicated that β-ketoamines are effective ligands for Suzuki cross coupling

reaction under aerobic condition.

+

B(OH)2

XPdCl2, Ligand

R1

X= Br

R1

R1 = CH3,Cl,NO2,OCH3

EtOH-H2O, 60 oC

Scheme11. Suzuki cross coupling reactions of aryl halides using β-ketoamine ligands

Godoy et al. have synthesized Pd(II) complexes containing sulfonate functionalized N-

heterocyclic carbene ligands which adopted a monodentate, bis-chelating and pincer

coordination form. These complexes have been used in the Suzuki cross coupling reaction

in water and in iPrOH/water (Scheme 12) [Godoy et al. (2011)]. It has been found that

mixture of solvents allowed effective coupling of various nonactivated bromoarenes.

+

B(OH)2

XPalladium complex

R1

X= Br, Cl

R1

R1 = CH3, H, COCH3, OCH3

H2O/ iPrOH, K2CO3

Scheme12. Palladium-catalyzed Suzuki cross coupling reactions of aryl halides

Recently, an in situ generated catalytic system based on PdCl2 and sodium sulfate has been

developed which exhibited excellent catalytic activity in the Suzuki cross coupling reaction

at room temperature in water under ligand free condition (Scheme 13) [Mondal and Bora

(2012)].


43

+

B(OH)2

X

R1X= Br

R2R1

R2

R1 = OMe,COCH3, H, NO2

R2 = H, OMe

PdCl2, Na2SO4

H2O or i-PrOH

K2CO3

Scheme13. Suzuki cross coupling reactions using in situ generated catalyst

Moreover, palladium (II) pyridoxal hydrazone complexes bearing triphenylphosphine has

been synthesized through the reaction of [PdCl2(PPh3)2] and substituted pyridoxal

hydrazone ligands (generally abbreviated as H2L) in methanol under reflux. Among them,

one of complex [C33H27BrN3O3PPd] was found to be excellent in Suzuki cross coupling

reaction of aryl bromides [Pandiarajan and Ramesh (2012)].

1.2.2 Palladium-catalyzed Heck cross coupling reaction:

Palladium-catalyzed Heck cross coupling reaction has been discovered initially by Heck

and Mizoroki in 1970’s [Mizoroki et al. (1971); Heck and Nolley (1972)]. After this

various ligands such as carbene [Herrmann et al. (1995)], thiolate [Bergbreiter et al.

(1999)] and phosphines [Littke et al. (1999); Shaughnessy et al. (1999); Ehrentraut et al.

(2000); Feuerstein et al. (2001)] have been explored in this reaction. Monodentate or

bidentate N-heterocyclic carbenes and non-supported or supported palladium salts have

also been utilized for Heck cross coupling reaction [Yang et al. (2001); De Vries et al.

(2003); Yao et al. (2003); Horniakova et al. (2004); Crudden et al. (2005); Karimi and

Enders (2006)]. Heck cross coupling reaction has also been carried out in ionic liquids

[Carmichael et al. (1999); Okubo et al. (2002); Calo et al. (2003)] and in an aqueous-ionic

liquid biphasic reaction medium based on high-melting-point hydrophobic

alkylammonuim tetrafluoroborates [Zou et al.(2003)]. Xie et al. have described Pd/C-

catalyzed, microwave assisted Heck cross coupling reaction in ionic liquid 1-octanyl-3-

methylimidazolium tetrafluoroborate ([OMIm]BF4) in absence of phosphine ligand [Xie et

al. (2004)]. The ionic liquid containing catalyst system was used five times with slight loss

of activity. Xiao et al. have reported the application of ionic liquid, a monoquaternary

product arising from the reaction of 2,2’-diimidazole with iodobutane as solvent and ligand

for the Heck cross coupling reaction (Scheme14) [Xiao et al. (2004)].


44

X

R+IL, 100 oC

PdCl2, Na2CO3

X = I,ClR = Ar, CO2CH3

R

Scheme14. Palladium-catalyzed Heck cross coupling reaction in ILs

Additionally, Heck cross coupling reaction of aryl halides with olefins has been carried out

by Gerritsma et al. in the presence of phosphonium salt ionic liquid such as

trihexyl(tetradecyl)phosphonium chloride (THP-Cl) (Scheme 15). The phosphonium ionic

liquids provided a recyclable reaction media and active palladium catalytic species

[Gerritsma et al. (2004)].

X

R+ NaOAc or Et3N

Pd(OAc)2 , THP-Cl

X = I,Br

R1

R1= OCH3,CH3,CNR = Ar, CO2CH3

R1

R

Scheme15. Phosphonium salt ionic liquid promoted Heck cross coupling reaction

In the same manner, phosphine free palladium-catalyzed Heck cross coupling reactions

using triethanolamine [Li and Wang (2006)], functionalized ionic liquid [Zhou and Wang

(2006)] and bronsted acid-base ionic liquids (GILs) based on guanidine and acetic acid [Li

et al. (2006)] have been demonstrated which act as reusable base, ligand and reaction

media for the reaction (Scheme16).

X

R+ N(CH2CH2OH)3 or GIL

Pd(OAc)2 or PdCl2

X = I,Br,Cl

R1

R1= H,OCH3, COCH3,CN,NO2

R = Ar, CN,CO2C2H5

R1

R

Scheme 16. Palladium-catalyzed Heck cross coupling reaction

Liu et al. have reported an efficient and recyclable functionalized ionic liquid (FILs)

network of [BMIM][TPPMS] and [BMIM][OAc], PdCl2(CH3CN)2 that catalyzed the Heck

cross coupling reaction (Scheme 17). It has been demonstrated that [BMIM][OAc] played

the role of base as well as synergic ligand with [BMIM][TPPMS]. The FILs of


45

[BMIM][TPPMS] and [BMIM][OAc] jointly contributed to activity and stability of the

palladium catalyst [Liu et al. (2006)].

X

R+

Pd(II) / [BMIM][TPPMS]

X = I,Br

R1

R1= H,OCH3,CH3,NO2

R = Ar, CO2C2H5

R1

R

[BMIM][OAc]

Scheme 17. Heck cross coupling reaction in FILs system

Wang et al. have synthesized pyrazolyl-functionalized imidazolium-based ionic liquids

bearing alkyl and polyfluoroalkyl substituents and applied them in the Heck cross coupling

reaction using a hemilabile pyrazolylfunctionalized (N-heterocyclic carbene)palladium

complex as a catalyst precursor (Scheme 18) [Wang et al. (2007)].

X

R+ Na2CO3, 120 oC

Palladium catalyst

X = I

R1

R1 = H, OCH3,CH3, NO2, F R = Ar, CO2Bu

R1

R

Scheme 18. Palladium catalyzed Heck cross coupling reaction in ILs

Further approaches involved the use of supported materials, palladium nanoparticles as

heterogeneous catalyst and ligands in aqueous phase [Evdokimov and Bumagin (2007);

Zheng and Zhang (2007); Qiao et al. (2008); Xu et al. (2008); Evangelisti et al. (2009);

Firouzabadi et al.(2009)]. Palladium-catalyzed Heck cross coupling reaction in the

multifunctionalized ionic liquid compositions (MFILC) has also been reported. The PdCl2-

MFILC catalytic system was reused seven times without loss of activity (Scheme 19) [Wan

et al. (2008)].

X

COOEt+

X = I,Br

R1

R1= H,OCH3,CH3,NO2

R1

COOEt

PdCl2-MFILC

130 oC

Scheme 19. Heck cross coupling reaction in MFILs system

In another instance, palladium-catalyzed Heck cross coupling reaction of aryl halides in

the presence of tetrabutylammonium acetate (TBAA) [Calo et al. (2009)] as optimal base


46

and tetrabutylammonium bromide (TBAB) as optimal solvent have been developed which

afforded corresponding products in good yield (Scheme 20).

+

X Palladium catalyst

X= Br

R1 R1

RTBAB

R1= H,OCH3,CH3

R = Ar

R TBAA

Scheme 20. Palladium-catalyzed Heck cross coupling reactions of aryl halides

Wan et al. have demonstrated the P,N-donor functionalized imidazolium salt as a bidentate

ligand for palladium-catalyzed Heck cross coupling reaction in ionic liquid which derived

efficient and recyclable catalytic system even after seven reuses without loss of activity

(Scheme 21) [Wan et al. (2009)].

X

COOR,+

X = I,Br

R1

R1= H,OCH3,CH3,NO2

R' = C2H5, CH3

R1

COOR'

PdCl2, Ligand

[BMim]PF6,110 oC

Scheme 21. Palladium-catalyzed Heck cross coupling reaction

Heck cross coupling reaction in the presence of task specific ionic liquid based on

ethanolamine functionalized quaternary ammonium salt [Wang et al. (2009)] and an

amino-functionalized ionic liquid using Pd submicron powder in [bmim][PF6] [Liu et al.

(2010)] has been reported. Amino functionalized ionic liquid has also been investigated as

ligand and base for Heck cross coupling reaction (Scheme 22).

+

X

R = Ph,COOEtR1 = H,OMe, CN,CF3

X= I, Br

R1

Palladium catalyst

Ionic liquid or TSILR1

R

R

Scheme 22. Heck cross coupling reactions in ionic liquids

In addition to this, the utility of water-soluble Pd(NH3)2Cl2/cationic 2,2’-bipyridyl system

[Huang et al. (2010)] and 1,3,2,4-diazadiphosphetidine, oligomer [(PhNH)P2(NPh)2]2NPh


47

(L1) as base and ligand in Pd(II) catalyzed Heck cross coupling reaction of aryl halides has

been described [Iranpoor et al. (2010)]. Recently polystyrene-supported schiff base

palladium (II) catalyst [Islam et al. (2011)], ortho-palladated complex in a nonaqueous

ionic liquid [Hajipour and Rafiee (2011)] and Pd exchanged supported in 12-

tungstophosphoric acid has been successfully investigated for Heck cross coupling reaction

which can be further reused [Pathan and Patel (2012)]. Heck cross coupling reaction in

hydrophobic fluorous ionic liquid which can be reused at least five times catalyzed by Pd-

nanoparticles formed in situ from Pd(OAc)2 has also been reported [Gaikwad et al.

(2012)]. Petrovic et al. have reported that triethanolammonium acetate [(TEA)(HOAc)]

acted as multifunctional ionic liquid providing a good reaction medium, base, precatalyst-

precursor and mobile support for the active palladium species in a phosphine-free Heck

cross coupling reaction (Scheme 23). The reaction of PdCl2 with [TEA][HOAc] provided

an effective ionic liquid-palladium catalytic system for the Heck cross coupling reaction

which could be recovered and recycled [Petrovic et al. (2012)].

+

X

R = COOEt, COOCH3, COOC4H9

X= I, Br

PdCl2, 110 oCR

RTEA-HOAc

Scheme 23. Heck cross coupling reaction in [TEA][HOAc]

In view of the above literature precedents, it would be apparent that a majority of the

approaches for carbon-carbon bond formation employ ligands which are expensive or

require multiple steps for their synthesis. Although there have been efforts to devise new

catalytic systems, but these catalytic systems suffer from drawbacks such as moisture

sensitivity and use of various additives. Although ionic liquids offer some advantages over

organic solvents, but most of them require tedious steps for preparation and their

environmental safety is still debated. In this context, it would be highly desirable to

develop a ligand free mild methodology. So we have investigated the applications of

cyanoalkylamines (TCA and DCA) as reaction media in Heck cross coupling reactions and

interface reagent in water mediated Suzuki cross coupling reaction.

1.3 Result and Discussion:

1.3.1 Aza-Micheal reaction:

A green synthesis of cyanoalkylamine on silica surface under solvent free milder condition

was developed through aza-Michael reaction. Initially, silica surface was chosen to


48

investigate aza-Michael reaction of ammonium hydroxide (30% aq. sol.) with acrylonitrile.

Ammonium hydroxide and acrylonitirle in 1:4 molar ratio gave highest yield of TCA.

Moderate yield of 1 was observed under acidic alumina and in presence of toluene (Table

1).

Table 1. Aza-Michael reaction under different conditions

NH4OH +CN

80 oC,15h

SiO2 HN

CN

CN

orN

CN

CN

CN

1 2

Entry Product Yield (%)a

1

2

1

2

80b, 70c, 55d

80b

aIsolated Yield, bSiO2, cAl2O3, dToluene

When ammonium hydroxide and acrylonitrile were added in 1:2 and 1:3 molar ratio,

mixture of products 1 and 2 were obtained. Interestingly, equimolar mixture (1:1) of

ammonium hydroxide and acrylonitrile gave highest yield of 2 (Table 1).

1.3.2 Preparation and characterization of TCA-Pd:

In earlier reports, nitrile functionalized ionic liquid has been used for the formation of

palladium nanoparticles and their stabilization. It has been demonstrated that nitrile group

enhances the catalytic stability and prevent aggregation [Fei et al. (2007)]. When TCA was

treated with Pd(OAc)2 at 80 oC for 30 minute, the brown colour of solution changed to

blackish. The in situ conversion of Pd(II) to Pd(0) (Figure 2) was monitored by UV-Visible

absorption spectrophotometer (Figure 3).

NNCPd(OAc)2 +

80 oC

30 min NCN

NC PdOAc

OAc

NNC

CN

CN

CN

C

C

N

N

Pd(0) NCN

C

C

N

N

Figure 2. In situ formation of palladium(0) nano/microparticle stabilized by TCA


49

Figure 3. UV-Vis absorption spectrometric studies of in situ conversion of Pd(II) to Pd(0).

Reagents and conditions: (a) TCA in DMF; (b) Pd(OAc)2 in DMF at initial stage; (c)

TCA+ Pd(OAc)2 after 1-2 min at rt (recorded in DMF); (d) after heated at 80 oC for 30 min

TCA+Pd(0) (recorded in DMF).

FT-IR spectra of TCA and TCA-Pd also showed the binding of nitrile moiety with

palladium (Figure 4). The two νCN stretching vibration bands at 2243 cm-1

and 2360 cm-1

in

infrared spectra of TCA-Pd demonstrated the presence of uncoordinated (or weakly

bounded) cyano group and metal bounded nitrile respectively.

Figure 4. (a) FT-IR spectra of TCA (b) FT-IR spectra of TCA-Pd

Surface studies of TCA and TCA-Pd were also performed to see the formation of

nano/microparticles of Pd(0) stabilized by TCA (Figure 5).


50

Figure 5. (a) Scanning electron micrographs (SEM) of TCA surface (b) SEM of TCA-

Pd(0) surface

1.3.3 Suzuki cross coupling reaction using TCA-Pd:

First time TCA was used as a stabilizer of Pd(0) nano/microparticles in water mediated

Suzuki cross coupling reaction. Due to interesting physicochemical properties of TCA, it

behaves as an interface reagent to bring the substrates (such as Pd(0), hydrophobic

compounds, base and water) on a common surface to interact with each other to give high

performance of reaction. The Suzuki cross coupling reaction of 4-bromotoluene and

phenyl boronic acid in water with in situ prepared TCA-Pd under microwave irradiation

for 5 minute gave corresponding product 3 in 81% yield (Table 2, entry 1). Similar

reaction under conventional condition gave 3 in 80% yield after 8 h. 3-Hydroxy

bromobenzene and 4-nitrobromobenzene coupled rapidly in excellent yield (Table 2,

entries 2, 3). Different aryl bromides substituted with methoxy and amino groups were

found suitable under conventional and microwave heating conditions (Table 2, entries 4,

5). Selective bromo coupled product of 3-chlorobromobenzene was observed under both

the conditions (Table 2, entry 6). 1, 4-Dibromobenzene under same conditions gave major

disubstituted product (Table 2, entry 7).

The reaction was further extended for the coupling reaction of aryl bromides with different

arylboronic acids. The result indicated that the electron deficient 3,4-dichlorophenyl

boronic acid afforded the corresponding product with moderate yield (Table 2, entry 8).

Different aryl iodides such as 1-iodonaphthalene, 4-hydroxyiodobenzene and 4-

methyliodobenzene also gave corresponding coupled products with different boronic acids

in good yield (Table 2, entries 9-12) under both the conditions.

a b


51

Table 2. Suzuki cross coupling of different aryl halides in water with TCA-Pd(0)

X B(OH)2

+TCA-Pd(0), K2CO3

RR R'R' 80 oC, 6-8 h

X = I & Br MW, 5-7 min.H2O

aIsolated Yield

Entry Products

Yield(%)a

1

2

4

5

6

OH

Cl

Cl

3

12

11

10

80

75

90

89

7

8

9

10

Cl

OCH3

NO2

OH

NH2

8

6

5

4

7

9

80

85

93

91

95

75

3

81

91

89

88

77

94

71

88

89

77

Conventional Microwave

Br

Br

BrO2N

BrH3CO

Br

HO

H2N

Br

Br

Br

I

Reactants

Cl

Br

HO

I

Cl

Cl

10

3

90

80

11

12

86

76

I

I


52

1.3.4 TCA and DCA promoted Heck cross coupling reaction:

TCA and DCA were applied as efficient base, ligand (N, N-ligand) and reaction medium in

palladium-catalyzed Heck cross coupling reaction (Figure 4).

Figure 4. TCA and DCA act as base, ligand and reaction media

As a model case, the reaction of 4-iodotoluene with ethyl acrylate was selected to optimize

the conditions under different proportions of TCA and DCA (Table 3). Through these

studies 4 equivalent of TCA was found suitable as a media and base for Heck cross

coupling reaction of 4-iodotoluene (Table 3). Under similar reaction condition, 4

equivalent of DCA gave low yield of corresponding product as compare to TCA (Table 3).

Table 3. Optimization study for Heck cross coupling reaction

I

+

Entry Solvent Yielda (%)

1

2 TCA (2eq.)

110 oC, 12h

Pd (OAc)2, TCA/DCACO2EtCO2Et

70

40

aIsolated Yield, eq.= equivalent

3 TCA (4eq.) 95

TCA (1eq.)

13

DCA (2eq.)4 35

DCA (4eq.) 705

1-Iodonahthalene and 4-iodophenol underwent Heck cross coupling reaction under same

condition and afforded corresponding coupled products (Table 4, entries 2 and 3).


53

Table 4. TCA or DCA promoted Heck cross coupling reaction of different aryl halides

X

R

CO2Et

R

CO2Et+

110 oC, 12-20 h

X = I & Br 30-96 %

Pd (OAc)2, TCA/DCA

aIsolated yield, Entries 10-14,reaction is carried out with DCA

Entry Products Yield (%)a

1

2

3

4

5

6

7

CO2Et

HO

CO2Et

CO2Et

MeO

HO

O2N

CO2Et

CO2Et

CO2Et

CO2Et

13

14

15

13

16

14

17

95

90

96

65

60

45

55

8

9

10

11

12

13

14

55

70

66

35

70

65

30

H3COC

Cl

HO

Cl

CO2Et

CO2Et

CO2Et

CO2Et

CO2Et

CO2Et

18

19

15

19

13

14

MeO

CO2Et16

I

HO I

I

Br

MeO Br

HO Br

O2N Br

Reactants

I

I

Br

H3COC Br

MeO Br

HO I

Br

Cl

Cl

Different aryl bromides were also investigated to explore the substrate scope of the present

process. For 4-bromotoluene and 4-bromoanisole, corresponding coupling products 13 and


54

16 were obtained in 60-65% yields (Table 4, entries 4 and 5). On the other hand 4-

bromophenol gave the cross coupled product 14 in 45% yield (Table 4, entry 6). Reactions

of nitro, chloro and keto substituted bromo arenes with ethyl acrylate gave the

corresponding Heck cross coupling products 17-19 in 55-70% yields (Table 4, entries 7, 8

and 9). DCA was not found to be suitable reaction media for Heck cross coupling reaction

of aryl bromides and the probable reason might be due to its less basic nature than TCA

(Table 4, entry 10 and 11). But Heck cross coupling reaction of aryl iodides in DCA (4 eq.)

gave 14 and 15 in 65-70% yields which could be considered as a good conversion under

this mild basic condition (Table 4, entry 12-14).

1.4 Conclusion:

A silica mediated aza-Michael reaction of ammonium hydroxide and acrylonitrile was

carried out to produce TCA and DCA. First time TCA was applied in water mediated

Suzuki cross coupling reaction and could be referred as interface reagent. Further TCA and

DCA applied as a reaction media, ligand and base in Heck cross coupling reaction. The

solubility and high boiling point were found to be very interesting properties to use TCA in

water mediated and microwave assisted reactions. Simultaneously, due to property of TCA

as a stabilizer of nano/microparticles in reaction media, it could be used in different metal

catalyzed organic transformations.

1.5 Experimental Section:

1.5.1 General Procedure:

All reagents of high quality were purchased from Sigma Aldrich. Silica gel (350 mesh size)

was procured from SD Fine-chem Ltd. Aluminium oxide (basic, 70-290 mesh size) was

purchased from SRL Pvt. Ltd. Toluene was freshly distilled before use and dried over 4Ao

molecular sieves. Commercial reagents and solvents were of analytical grade and were

purified by standard procedures prior to use. Thin layer chromatography was performed

using precoated silica gel plates 60F254. Microwave reactions were carried out using a

CEM Discover focused microwave (2450 MHz, 300W). 1H and

13C-NMR spectra were

recorded using a Bruker Avance 300 spectrometer operating at 300 MHz (1H) and 75 MHz

(13

C). Spectra were recorded at 25 °C in CDCl3 [residual CHCl3 (δH 7.24 ppm) or CDCl3

(δC 77.00 ppm) as international standard] with TMS as internal standard. Chemical shifts

were recorded in δ (ppm) relative to the TMS signal, coupling constants (J) are given in Hz

and multiplicities of signals are reported as follows: s, singlet; d, doublet; t, triplet; m,


55

multiplet; br, broad singlet. Mass spectra were recorded on a Waters Q-TOF-MS with

electro spray ionisation (ESI) in Waters Masslynx software. Each sample was dissolved in

acetonitrile:water (50:50) and directly injected into the ESI source at a flow rate of

5μL/min.

1.5.2 Procedure for synthesis of tris-(β-cyanoethyl) amine (TCA) (1) using silica:

N

CN

CN

CN

Ammonium hydroxide (30% aq. sol.) (2.7 ml, 28.5 mmol) and acrylonitrile

(6.04 g, 114.1 mmol) was added to freely flowing silica and the reaction mixture was

stirred at room temperature for 1 h and then heated to 80 oC for 15 h. The progress of

reaction was monitored on TLC. After completion of reaction, the mixture was extracted

with ethyl acetate 2-3 times and the combined organic layer was evaporated and

crystallized in ethanol at 0 oC to yield 1 as a white solid (5.38 g, 80.4%), mp 49-50

oC;

1H

NMR (300 MHz, CDCl3-d1) δ 2.47-2.52 (m, 6H), 2.89-2.93 (m, 6H); 13

C NMR (75 MHz,

CDCl3-d1) δ 19.28 (3C), 44.52 (3C), 118.95 (3CN); HRMS (ESI) data: m/z calcd for

[M+H]+

C9H13N4 177.2263, obsd. 177.2264.

1.5.3 Procedure for TCA synthesis using alumina:

N

CN

CN

CN

Ammonium hydroxide (30% aq. sol.) (278 µl, 2.8 mmol) and acrylonitrile

(605.4 mg, 11.41 mmol) was added to freely flowing alumina and the reaction mixture was

stirred at room temperature for 1 h and then heated to 80 oC for 15 h. The progress of

reaction was monitored on TLC. After completion of reaction, the mixture was extracted

with ethyl acetate 2-3 times and the combined organic layer was evaporated to yield 1 as a

white solid (468 mg, 69.91%).

1.5.4 Procedure for TCA synthesis using toluene:

To a solution of ammonium hydroxide (30% aq. sol.) (277.9 µl, 2.8 mmol) in toluene (0.5

ml), acrylonitrile (605 mg, 11.4 mmol) was added and the reaction mixture was stirred at

80 oC for 15 h. The progress of reaction was monitored on TLC. After completion of

reaction, the mixture was diluted with ethyl acetate and solvent was evaporated to yield 1

as a white solid (370 mg, 55%).


56

1.5.5 Procedure for synthesis of bis-(β-cyanoethyl) amine (DCA) (2) using silica:

HN

CN

CN Ammonium hydroxide (30% aq. sol.) (2.7 ml, 28.5 mmol) and acrylonitrile

(1.51 g, 28.5 mmol) was added to freely flowing silica and the reaction mixture was stirred

at room temperature for 1 h and then heated to 80 oC for 15 h. The progress of reaction was

monitored on TLC. After completion of reaction, the mixture was extracted with ethyl

acetate 2-3 times and the combined organic layer was evaporated to yield 2 as a light

yellowish liquid (1.37 g, 79.5%); 1H NMR (300 MHz, CDCl3-d1) δ 1.88 (s, 1H), 2.40-2.44

(m, 4H), 2.79-2.83 (m, 4H); 13

C NMR (75 MHz, CDCl3-d1) δ 18.27 (2C), 43.95 (2C),

118.54 (2CN). HRMS (ESI) data: m/z calcd for [M+ H]+ C6H9N3 124.1638, obsd.

124.1637.

1.5.6 Procedure for synthesis of 4-methylbiphenyl (3) from Suzuki cross coupling:

A mixture of 4-bromotoluene (100 mg, 0.58 mmol), phenylboronic acid

(91.86 mg, 0.76 mmol) and K2CO3 (161.42 mg, 1.2 mmol) in H2O (0.5 ml) was added to in

situ prepared TCA (240 mg) stabilized Pd(0) (from Pd(OAc)2: 6.55 mg, 0.03 mmol) in a

round bottom flask. The mixture was stirred at 80 oC for 8 h. Upon completion, the

reaction mixture was allowed to cool at room temperature and extracted with diethyl ether

(3x10 ml). The combined organic phase was dried with Na2SO4, evaporated under reduced

pressure and purified by silica gel column chromatography (hexane:EtOAc :: 99:1) to give

3 as a white solid (79 mg, 80%), mp 43-44 oC;

1H NMR (300 MHz, CDCl3-d1) δ 2.37 (s,

3H), 7.20-7.21 (m, 2H), 7.37-7.42 (m, 2H), 7.46-7.48 (d, 2H), 7.54-7.57 (m, 3H); 13

C NMR

(75 MHz, CDCl3-d1) δ 21.49, 127.37 (2C), 127.56 (3C), 129.11 (2C), 129.87 (2C), 137.41,

138.75, 141.55.

OH

3-Hydroxybiphenyl (4): Prepared as described for 3; Starting from 3-

bromophenol (100 mg, 0.57 mmol) gave, after purification with silica gel column

chromatography (hexane:EtOAc :: 92:8) 4 as a brownish solid (91 mg, 93%), mp 75-78 oC;

1H NMR (300 MHz, CDCl3-d1) δ 6.55 (s, 1H), 7.03-7.06 (m, 1H), 7.29 (m, 1H), 7.36-7.38

(m, 1H), 7.46 (m, 1H), 7.49 (m, 1H), 7.53-7.62 (m, 2H), 7.72-7.74 (m, 2H); 13

C NMR (75

MHz, CDCl3-d1) δ 114.58, 114.75, 120.23, 127.49 (2C), 127.89, 129.17 (2C), 130.48,

141.03, 143.36, 156.77.


57

NO2

4-Nitrobiphenyl (5): Prepared as described for 3; Starting from 4-

nitrobromobenzene (100 mg, 0.49 mmol) gave, after purification with silica gel column

chromatography (hexane:EtOAc :: 95:5) 5 as a white solid (90 mg, 91%), mp 113-115 oC;

1H NMR (300 MHz, CDCl3-d1) δ 7.46-7.51 (m, 3H), 7.60-7.63 (m, 2H), 7.70-7.76 (m,

2H), 8.26-8.32 (m, 2H); 13

C NMR (75 MHz, CDCl3-d1) δ 124.45 (2C), 127.73 (2C), 128.14

(2C), 129.28, 129.51 (2C), 139.09, 147.41, 147.97.

OCH3

4-Methoxybiphenyl (6): Prepared as described for 3; Starting from

4-bromoanisole (100 mg, 0.54 mmol) gave, after purification with silica gel column


1H

NMR (300 MHz, CDCl3-d1) δ 3.89 (s, 3H), 7.01 (m, 2H), 7.34 (m, 1H), 7.45-7.47 (m, 2H),

7.56-7.58 (m, 4H); 13

C NMR (75 MHz, CDCl3-d1) δ 55.73, 114.62 (2C), 127.26 (3C),

127.04 (2C), 129.12 (2C), 134.20, 141.25, 159.58.

NH2

3-Aminobiphenyl (7): Prepared as described for 3; Starting from 3-

bromoaniline (100 mg, 0.58 mmol) gave, after purification with silica gel column


1H NMR (300 MHz, CDCl3-d1) δ 3.70 (s, 2H), 6.74 (d, J = 7.6 Hz, 1H), 6.98 (brs, 1H),

7.10 (d, J = 7.2 Hz, 1H), 7.28-7.53 (m, 1H), 7.44 (d, J = 6.5 Hz, 1H), 7.49-7.54 (m, 2H),

7.66-7.68 (m, 2H); 13

C NMR (75 MHz, CDCl3-d1) δ 114.38 (2C), 117.72 (2C), 127.62

(2C), 129.17 (2C), 131.10, 141.88, 142.90, 147.29.

Cl

3-Chlorobiphenyl (8): Prepared as described for 3; Starting from 3-

chlorobromobenzene (100 mg, 0.52 mmol) gave, after purification with silica gel column

chromatography (hexane:EtOAc :: 98:2) 8 as a colourless liquid (79 mg, 80%); 1H NMR

(300 MHz, CDCl3-d1) δ 7.36-7.41 (m, 3H), 7.44-7.51 (m, 3H), 7.59-7.66 (m, 3H); 13

C

NMR (75 MHz, CDCl3-d1) δ 125.68, 127.50 (2C), 127.65 (2C), 128.25, 129.29 (2C),

130.37, 135.04, 140.19, 143.52.

4-Phenylbiphenyl (9): Prepared as described for 3; Starting from

1,4 dibromobenzene (100 mg, 0.42 mmol) gave, after purification with silica gel column


58


1H NMR (300 MHz, CDCl3-d1) δ 7.37-7.40 (m, 2H), 7.42-7.52 (m, 4H), 7.67-7.71 (m,

8H); 13

C NMR (75 MHz, CDCl3-d1) δ 127.47 (4C), 127.76 (2C), 127.92 (4C), 129.23 (4C),

140.53 (2C), 141.11 (2C).

1.5.7 Procedure for synthesis of 4-methyl-3’, 4’-dichlorobiphenyl (10):

Cl

Cl A mixture of 4-iodotoluene (100 mg, 0.45 mmol), 3,4-

dichlorophenylboronic acid (111.62 mg, 0.58 mmol) and K2CO3 (124.38 mg, 0.90 mmol)

in water (0.5 ml) was added to in situ prepared TCA (240 mg) stabilized Pd(0) (from

Pd(OAc)2: 5.05 mg, 0.02 mmol) in a round bottom flask. The mixture was stirred at 80 oC

for 6 h. Upon completion, the reaction mixture was allowed to cool at room temperature

and extracted with diethyl ether (3x10 ml). The combined organic phase was dried with

Na2SO4, evaporated under reduced pressure and purified by silica gel column

chromatography (hexane:EtOAc :: 99:1) to give 10 as a white solid (95 mg, 89%), mp 70-

71 oC;

1H NMR (300 MHz, CDCl3-d1) δ 2.43 (s, 3H), 7.28 (m, 2H), 7.45 (m, 4H), 7.68 (m,

1H); 13

C NMR (75 MHz, CDCl3-d1) δ 19.32, 126.50, 127.12 (2C), 129.06, 130.09 (2C),

130.97, 131.31, 133.11, 136.19, 138.44, 141.52.

1-Phenylnaphthalene (11): Prepared as described for 10; Starting from 1-

iodonaphthalene (100 mg, 0.39 mmol) gave, after purification with silica gel column

chromatography (hexane:EtOAc :: 98:2) 11 as a colourless liquid (72 mg, 90%); 1H NMR

(300 MHz, CDCl3-d1) δ 7.55-7.62 (m, 9H), 7.97-8.08 (m, 3H); 13

C NMR (75 MHz, CDCl3-

d1) δ 125.11, 125.76 (2C), 126.66, 126.96, 127.37, 129.99 (4C), 129.81 (2C), 131.37,

133.54, 140.00, 140.50.

OH4-Hydroxybiphenyl (12): Prepared as described for 10; Starting

from 4-iodophenol (100 mg, 0.45 mmol) gave, after purification with silica gel column


1H NMR (300 MHz, CDCl3-d1) δ 5.00 (s, 1H), 6.93 (m, 2H), 7.34-7.45 (m, 2H), 7.51-7.56

(m, 5H); 13

C NMR (75 MHz, CDCl3-d1) δ 116.06 (2C), 127.13 (3C), 128.80 (2C), 129.13

(2C), 134.45, 141.16, 155.47.


59

1.5.8 Procedure for Suzuki cross coupling reaction under microwave condition:

A mixture of 4-nitrobromobenzene (100 mg, 0.49 mmol), phenylboronic acid (77.65 mg,

0.63 mmol), K2CO3 (135.44 mg, 0.98 mmol) in water (0.5 ml) was added to in situ

prepared TCA (240 mg) stabilized Pd(0) (from Pd(OAc)2: 5.50 mg, 0.02 mmol) in a round

bottom flask. The mixture was irradiated under microwave system at 80 oC for 5 minute.

Upon completion, the reaction mixture was allowed to cool at room temperature and

extracted with diethyl ether (3x10 ml). The combined organic phase was dried with

Na2SO4, evaporated under reduced pressure and purified by silica gel column

chromatography (hexane:EtOAc :: 95:5) yielded 5 as a white solid (87 mg, 89%). Melting

point and NMR data are same as described for 5 above.

Compounds 3-12 were also prepared under microwave conditions following the same

method as described for 5.

1.5.9 Procedure for synthesis of ethyl-3-(4-methylphenyl)acrylate (13) from Heck

reaction:

CO2Et

A mixture of palladium acetate (5.05 mg, 0.02 mmol), 4-iodotoluene

(100 mg, 0.45 mmol), ethyl acrylate (135.14 mg, 1.37 mmol) and TCA (322.43 mg, 1.83

mmol) was stirred at 110 oC for 12 h and the progress of reaction was monitored by TLC.

After completion of reaction, the crude reaction mixture was diluted with ethyl acetate.

The organic layer was evaporated under reduced pressure. The obtained residue was

purified by silica gel column chromatography (hexane:EtOAc :: 99:1) yielded 13 as a

colourless liquid (83 mg, 95%); 1H NMR (300 MHz, CDCl3-d1) δ 1.37-1.46 (m, 3H), 2.44

(s, 3H), 4.30-4.39 (m, 2H), 6.48 (dd, J = 15.9, 7.5 Hz, 1H), 7.27-7.29 (m, 2H), 7.48-7.52

(m, 2H), 7.75 (dd, J = 15.9, 7.5 Hz, 1H); 13

C NMR (75MHz, CDCl3-d1) δ 14.44, 21.52,

60.48, 117.33, 128.15 (2C), 129.71 (2C), 131.89, 140.69, 144.68, 167.26; HRMS (ESI)

data: m/z calcd for [M+H]+

C12H14O2 191.2463, obsd.191.2462.

HO

CO2Et

Ethyl-3-(4-hydroxyphenyl)acrylates (14): Prepared as described

for 13; Starting from 4-iodophenol (100 mg, 0.45 mmol) gave, after purification with silica

gel column chromatography (hexane:EtOAc :: 92:8) 14 as a colourless liquid (78.5 mg,

90%); 1H NMR (300 MHz, CDCl3-d1) δ 1.32-1.37 (m, 3H), 4.26-4.32 (m, 2H), 6.30 (d, J =

15.9 Hz, 1H), 6.90-6.93 (m, 2H), 7.40-7.42 (m, 2H), 7.66 (d, J = 15.9 Hz, 1H); 13

C NMR

(75 MHz, CDCl3-d1) δ 14.24, 58.58, 115.15, 116.06 (2C), 126.51, 130.11 (2C), 145.39,


60

158.77, 168.63; HRMS (ESI) data: m/z calcd for [M+ H]+

C11H12O3 193.2191, obsd.

193.2191.

CO2Et

Ethyl-3-(naphthalene-5-yl) acrylates (15): Prepared as described for

13; Starting from 1-iodonaphthalene (100 mg, 0.39 mmol) gave, after purification with

silica gel column chromatography (hexane:EtOAc :: 98:2) 15 as a colourless liquid (85 mg,

96%); 1H NMR (300 MHz, CDCl3-d1) δ 1.40-1.43 (m, 3H), 4.31-4.38 (m, 2H), 6.56 (d, J =

15.7 Hz, 1H), 7.48-7.63 (m, 3H), 7.80 (d, J = 7.1, 1H), 7.88-7.92 (m, 2H), 8.22 (d, J = 8.0,

1H), 8.56 (d, J =15.7 Hz, 1H); 13

C NMR (75 MHz, CDCl3-d1) δ 14.80, 61.04, 121.33,

123.82, 125.40, 125.88, 126.63, 127.26, 129.13, 130.31, 131.81, 132.23, 134.07, 142.03,

167.33; HRMS (ESI) data: m/z calcd for [M+ H]+

C15H14O2 227.2784 , obsd. 227.2749.

1.5.10 Procedure for synthesis of ethyl-3-(4-methoxyphenyl)acrylates (16):

MeO

CO2Et

A mixture of palladium acetate (11.9 mg, 0.05 mmol), 4-

bromoanisole (100 mg, 0.53 mmol), ethyl acrylate (160.37 mg, 1.60 mmol) and TCA

(751.8 mg, 4.27 mmol) was stirred at 110 oC for 15 h and monitored by TLC. After

completion of reaction, the crude reaction mixture was diluted with ethyl acetate. The

organic layer was evaporated under vacuum. The obtained residue was purified by silica

gel column chromatography (hexane:EtOAc :: 98:2) yielded 16 as a colourless liquid (66

mg, 60%); 1H NMR (300 MHz, CDCl3-d1) δ 1.36-1.46 (m, 3H), 3.92 (s, 3H), 4.31-4.40 (m,

2H), 6.40 (dd, J = 15.9, 6.2 Hz, 1H), 6.98-7.02 (m, 2H), 7.55-7.59 (m, 2H), 7.74 (dd, J

=15.9, 6.02 Hz, 1H); 13

C NMR (75 MHz, CDCl3-d1) δ 14.74, 55.73, 60.70, 114.72 (2C),

117.75, 126.77, 129.47 (2C), 144.64, 161.76, 167.72; HRMS (ESI) data: m/z calcd for

[M+ H]+

C12H14O3 207.2457, obsd. 207.2456.

O2N

CO2Et

Ethyl-3-(4-nitrophenyl)acrylates (17): Prepared as described

for 16; Starting from 1-bromo-4-nitrobenzene (100 mg, 0.49 mmol) gave, after purification

with silica gel column chromatography (hexane:EtOAc :: 95:5) 17 as a white solid (60 mg,

55%), mp 131-133 oC;

1H NMR (300 MHz, CDCl3-d1) δ 1.32-1.37 (m, 3H), 4.25-4.33 (m,

2H), 6.55 (d, J =16.0, 1H), 7.65-7.73 (m, 3H), 8.22-8.25 (m, 2H); 13

C NMR (75 MHz,

CDCl3-d1) δ 14.36, 60.82, 118.31, 123.44 (2C), 128.73 (2C), 140.72, 141.69, 148.59,

166.09; HRMS (ESI) data: m/z calcd for [M+ H]+

C11H11NO4 222.2173, obsd. 222.2172.


61

H3COC

CO2Et

Ethyl-3-(4-acetylphenyl)acrylates (18): Prepared as

described for 16; Starting from 1-(4-bromophenyl)ethanone (100 mg, 0.50 mmol) gave,

after purification with silica gel column chromatography (hexane:EtOAc :: 96:4) 18 as a

yellow solid (60 mg, 55%), mp 44-46 oC;

1H NMR (300 MHz, CDCl3-d1) δ 1.29-1.35 (m,

3H), 2.55 (s, 3H), 4.22-4.27 (m, 2H), 6.50 (d, J = 16.0 Hz, 1H), 7.57-7.59 (m, 2H), 7.67 (d,

J = 16.0 Hz, 1H), 7.93-7.95 (m, 2H); 13

C NMR (75 MHz, CDCl3-d1) δ 14.66, 29.66, 61.12,

118.54, 128.48 (2C), 129.21 (2C), 138.37, 139.18, 143.35, 166.82, 197.65; HRMS (ESI)

data: m/z calcd for [M+ H]+

C13H14N3 219.2564, obsd. 219.2564.

Cl

CO2Et

Ethyl-3-(3-chlorophenyl)acrylates (19): Prepared as described for

16; Starting from 1-bromo-3-chlorobenzene (100 mg, 0.52 mmol) gave, after purification

with silica gel column chromatography (hexane:EtOAc :: 98:2) 19 as a colourless liquid

(77 mg, 70%); 1H NMR (300 MHz, CDCl3-d1) δ 1.31-1.36 (m, 3H), 4.23-4.30 (m, 2H),

6.43 (d, J = 16.0 Hz, 1H), 7.31-7.37 (m, 2H), 7.39-7.50 (m, 2H), 7.60 (d, J = 16.0 Hz, 1H);

13C NMR (75 MHz, CDCl3-d1) δ 14.41, 60.78, 118.25, 126.32, 127.90, 130.19 (2C),

135.04, 136.46, 143.03, 166.64; HRMS (ESI) data: m/z calcd for [M+ H]+

C11H11ClO2

211.6645, obsd. 211.6631.

Compounds 13, 14, 15, 16, 19 (Table 4, entries 10-14) were also prepared by using DCA

(4 eq.) following the same methods described for TCA.

1.6 References:

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Bakherad, M., Keivanloo, A., Bahramian, B. and Hashemi, M. (2009). Copper-free

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under aerobic conditions. Tetrahedron Letter 50 (14): 1557-59.

Bedford, R. B., Blake, M. E., Butts, C. P. and Holder, D. (2003). The Suzuki coupling of

aryl chlorides in TBAB-water mixtures. Chemical Communications 466-67.

Bergbreiter, D. E., Osburn, P. L. and Liu, Y. S. (1999). Tridentate SCS palladium(II)

complexes: new, highly stable, recyclable catalysts for the Heck reaction. Journal

of American Chemical Society 121: 9531-38.


62

Bianco, A., Cavarischia, C. and Guiso, M. (2004). The Heck coupling reaction using aryl

vinyl ketones: synthesis of flavonoids. European Journal of Organic Chemistry

2894-98.

Billingsley, K. L., Anderson, K. W. and Buchwald, S. L. (2006). A highly active catalyst

for Suzuki-Miyaura cross-coupling reactions of heteroaryl compounds.

Angewandte Chemie International Edition 45 (21): 3484-88.

Bumagin, N. A. and Bykov, V. V. (1997). Ligandless palladium catalyzed reactions of

arylboronic acids and sodium tetraphenylborate with aryl halides in aqueous media.

Tetrahedron 53: 14437-450.

Calo, V., Nacci, A., Monopoli, A., Laera, S. and Cioffi, N. (2003). Pd nanoparticles

catalyzed stereospecific synthesis of β-aryl cinnamic esters in ionic liquids. Journal

of Organic Chemistry 68: 2929-33.

Calo, V., Nacci, A., Monopoli, A. and Cotugno, P. (2009). Heck reactions with palladium

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NMR spectra of some compounds

1H NMR (in CDCl3) spectrum of Tris-(β-cyanoethyl) amine

13C NMR (in CDCl3) spectrum of Tris-(β-cyanoethyl) amine


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HRMS(ESI) of Tris-(β-cyanoethyl) amine

1H NMR ((in CDCl3) spectrum of Bis-(β-cyanoethyl) amine


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13

C NMR ((in CDCl3) spectrum of Bis-(β-cyanoethyl) amine

HRMS(ESI) of Bis-(β-cyanoethyl) amine


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1H NMR (in CDCl3) spectrum of 4-Methoxybiphenyl

13

C NMR (in CDCl3) spectrum of 4-Methoxybiphenyl


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1H NMR (in CDCl3) spectrum of Ethyl-3-(4-hydroxyphenyl)acrylates

13

C NMR (in CDCl3) spectrum of Ethyl-3-(4-hydroxyphenyl)acrylates


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HRMS(ESI) of Ethyl-3-(4-hydroxyphenyl)acrylates

chapter 1 suzuki-miyaura and heck cross coupling...

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