Ionic Liquid assisted metal free decarboxylation of...

Ionic Liquid assisted …… Chapter 2

91

Ionic Liquid assisted metal free decarboxylation of heteroaryl and aryl carboxylic acid derivatives under microwave irradiation

2.1 Introduction

The removal of a carboxyl group (-COOH), usually in the form of carbon dioxide is termed

as decarboxylation. It is a fundamental organic transformation widely used in synthesis or

mechanistic investigation of organic compounds [Patai (1969)]. Some salient applications

of decarboxylation reactions are briefly described below:

2.2 Significance of decarboxylation

2.2.1 Role in biosynthetic pathways

In the biochemical milieu, decarboxylation is a ubiquitous step for transformation of amino

acids into various other secondary metabolites using specific enzymes termed

decarboxylases [Liu and Zhang (2006)]. More importantly, nature has also employed

decarboxylation as a central tool for linking metabolic pathways like glycolysis and citric

acid cycle, whereby, pyruvate is decarboxylated into acetyl CoA which subsequently enters

the citric acid cycle (Figure 1) [Nelson and Cox (2009)]. In this way, it commits pyruvate

to enter the citric acid cycle, where it is either used as a substrate for oxidative

phosphorylation, or is converted to citrate for export to the cytosol.

Figure 1. Decarboxylation as a central tool for linking two different metabolic pathways

H3C C C O-

O O

H3C C S CoA

O

acetyl-CoA

+ CO2HSCoA

NAD+NADH

to Citric Acid Cycle

from Glycolysis

Oxidative Decarboxylation

Pyruvate


92

2.2.2 Decarboxylation as an enabling tool for synthesis of bioactive compounds and

carbon chain shortening

Decarboxylation has also been extensively employed in organic synthesis for accessing a

wide range of biologically active compounds. It constitutes one of the final steps for several

classical transformations like Reissert, Fischer and Rees-Moody reactions for synthesis of

2-unsubstituted indoles (Scheme 1) [Jones and Chapman (1993)]. Similarly, the well

known Knoevenagal-Doebner [Dale and Hennis (1958)] and Perkin condensation [Solladie

et al. (2003)] also involve a removal of carboxyl function for synthesis of styrenes and

stilbenes respectively (Scheme 1). On the other hand, decarboxylation is also one of the

few reactions enabling cleavage of C-C bonds [Payette and Yamamoto (2008)] which are

other wise quite stable to synthetic manipulations.

Scheme 1. Utility of decarboxylative transformations in synthesis of biologically important compounds i) Indoles, ii) Styrenes, iii) Stilbenes

2.2.3 Decarboxylative coupling as a new strategy for C-C bond formation

Recently, decarboxylation has emerged as a pivotal element to design conceptually newer

carbon-carbon bond forming strategies [Baudoin (2007)]. The immense interest in such

decarboxylative couplings is mainly because carboxylic acids offer an easily available and

economical alternative to the expensive organometallic/organohalide reagents

conventionally used for cross coupling reactions. Thus, pioneering efforts by Meyers et al.

has lead to the utilization of aromatic acids as novel organohalide equivalents for eventual

Heck type coupling with olefins [Myers et al. (2002); Tanaka and Myers (2004)]. On the

other hand, Gooßen and others have shown that benzoic acids can also serve as versatile

NH

COOH NH

COOH

COOH

i)

ii)

iii)

R

R

R R

R

R


93

organometallic reagent equivalents for efficient coupling with aryl halides [Gooßen et al.

(2006); Gooßen et al. (2007)], diaryliodonium salts [Becht and Drian (2008)] and indoles

[Cornella et al. (2009)] etc. (Scheme 2).

Scheme 2. Decarboxylation based C-C coupling using carboxylic acid synthons as i) organohalide equivalents, ii) organometallic equivalents

In view of their above mentioned importance, there has been an upsurge of interest

in developing newer decarboxylation approaches. However, the removal of carboxyl group

has remained one of the most difficult transformations often requiring prior activation by

metal catalysts as well as the use of harsh organic bases [Cohen and Schambach (1970);

Lisitsyn (2007)]. In particular, the seminal work of Shepard et al., wherein, a combination

of copper catalyst and quinoline provided a quintessential reagent system for

decarboxylation has remained a prominent hallmark [Shepard et al. (1930)]. Later on, some

variants of above protocol as well as other metal promoted methodologies have also been

developed for decarboxylative synthesis of important targets like indoles, styrenes,

stilbenes and aromatic derivatives.

2.3 Reported methods for decarboxylation reactions

A brief description of the prevalent approaches for decarboxylation of heteroaromatic,

cinnamic acid and aromatic carboxylic acid derivatives is presented below:

2.3.1 Decarboxylation of N-heteroaryl carboxylic acids

Jones et al. used a combination of quinoline/Cu salt in sealed tube for decarboxylation of

indole-2-carboxylic acids under microwave irradiation (Scheme 3) [Jones and Chapman

(1993)].

NO2

COOH

NO2

X

COOH

+

+

i)

ii)

X = Br, I etc.


94

Scheme 3

Similarly, the decarboxylation of indole-2-carboxylic ester (Ethyl 3-cyano-1-methoxy-1H-

2-indolecarboxylate) has been accomplished through a two step sequence involving initial

hydrolysis using LiOH followed by quinoline/Cu promoted decarboxylation of resulting

indole-2-carboxylic acids (Scheme 4) [Selvakumar and Rajulu (2004)]. The above protocol

was further applied towards the total synthesis of some bioactive alkaloids possessing 2-

unsubstituted indole framework.

Scheme 4

In the same vein, Gan et al. employed quinoline/Cu combination for decarboxylation of

indole-2-carboxylic acid which was in turn obtained from Fischer indole cyclization

approach (Scheme 5) [Gan et al. (1997)]. The resulting indole was further used for total

synthesis of Tryprostatin A, a potential inhibitor of indoleamine 2,3-dioxygenase.

Scheme 5

On the other hand, a silver catalyzed protocol for protodecarboxylation of various

heteroaromatic acids has been reported using Ag2CO3/AcOH (Scheme 6) [Lu et al. (2009)].

Scheme 6

Cu powder, Quinoline

NH

MW, sealed tubeCOOHR

R = OMe, Cl etc.

NH

R

N COOEt

OMe

CNi) LiOH, DMF-H2O (3:1)

ii) Quinoline/Cu powder, 220oC N

OMe

CN

NH

COOH

CH3 Cu/Quinoline

NH

CH3

MeO MeOreflux

N N

DMSO, 140oC Ag2CO3/AcOH

COOH


95

Maehara et al. disclosed a Pd catalyzed decarboxylation of indole-2-carboxylic acid and

demonstrated its application for regioseleective synthesis of 3 vinylated indoles (Scheme 7)

[Maehara et al. (2008)].

Scheme 7

2.3.2 Decarboxylation of Cinnamic acids

Walling et al. investigated the decarboxylation of substituted cinnamic acids using various

copper salts and found that copper powder in boiling quinoline accelerated the

decarboxylation of cinnamic acids into corresponding styrenes (Scheme-8) [Walling and

Wolfstrin (1947)].

Scheme 8

In another report, the antimitotic cis-combretastatin A-4 was synthesized via

decarboxylation of corresponding α-phenyl cinnamic acid ((E)-3-(3′-Hydroxy-4′-

methoxyphenyl)-2-(3′′,4′′,5′′-trimethoxyphenyl)prop-2-enoic acid) using a combination of

Cu/quinoline (Scheme 9) [Gaukroger et al. (2001)].

Scheme 9

An enzymatic decarboxylation of 4-hydroxy cinnamic acids into 4-vinylphenol was

achieved using the para-hydroxycinnamic acid decarboxylase (Scheme 10) [Bassat et al.

(2007)].

N COOH

Me

Pd(OAc)2/Cu(OAc)2. H2O

N

Me

CO2Bu

MS-4 Ao /LiOAc DMAc

CO2Bu+

COOH

RR

Quinoline, >250 oC

Cu powder

R= Cl, Br, NO2,OMe

OMe

OMe

MeO

OH

OMeCu powderQuinoline

200oC

HOOC

OMe

OMe

MeO

OH

OMe


96

Scheme 10

Nomura et al. reported the decarboxylation of hydroxylated cinnamic acids into

corresponding styrenes using amine bases (Scheme-11) [Nomura et al. (2005)].

Scheme 11

A microwave assisted decarboxylation of hydroxy substituted α-phenyl cinnamic acids

into corresponding stilbenes using a combination of methylimidazole and piperidine has

been disclosed (Scheme 12) [Kumar et al. (2007)].

Scheme 12

Similarly, DBU promoted decarboxylation of hydroxyl cinnamic acids has been reported

using basic aluminium oxide as solid support (Scheme 13) [Bernini et al. (2007)].

Scheme 13

OH

O

HO HO

pHCA decarboxylase

aqueous buffer, pH 6, toluene

OH

O

R2

R1

R2

R1R3 R3

Et3N

MW

R1 = OH, R2 = R3 = H, OMe etc.

HO

R2

R3

R1

HO

R2

R3

R1

R1= R2= R3 = H, OMe

MIm/Piperidine

MWCOOH PEG

OH

O

HO

R2

R3

R1

HO

R2

R3

R1

R1= R2= R3 = H, OMe

DBU, basic Al2O3

hydroquinone, MW


97

2.3.3 Decarboxylation of aromatic acids

The decarboxylation of ortho/para nitro substituted phenyl acetic acids was achieved using

K2CO3 in DMF (Scheme-14) [Bull et al. (1996)].

Scheme 14

The photodecarboxylation of acetoyl substituted phenyl acetic acids was investigated in

water:AcCN (1:1) solvent system and a photolytic mechanism was proposed (Scheme 15)

[Xu and Wan (2000)]. Further, it was hypothesized that α-arylpropionic acids,

constituents of nonsteroidal anti-inflammory drugs (NSAIDs) might also be metabolized

via an analogous oxidative decarboxylative pathway.

Scheme 15

On the other hand, decarboxylation of 3,5-dichloro-4-hydroxy-benzoic acid into the

pharmaceutically important 2,6-dichlorophenol was achieved using Cu2O/quinoline

(Scheme-16) [Mukhopadhyay and Chandalia (1999)].

Scheme 16

A catalytic protocol for decarboxylation of 4-hydroxy substituted benzoic acids has been

reported using Pd in combination with diphosphine ligand (Scheme 17) [Magro et al.

(2009)].

Scheme 17

COOH

HO HO

Pd(OAc)2

PBut2

PBut2

toluene, 140oC

55oCK2CO3

COOH

X X = NO2 X

DMF

HOOC

OO

hv

1:1 (H2O-AcCN) (pH=7)

COOH

220oC

Cu2O, quinoline

Cl Cl

OH

Cl Cl

OH


98

Similarly, a palladium catalyzed decarboxylation of various bis-ortho-substituted aromatic

acids has been developed and the methodology was also found to be applicable on hindered

carboxylic acids (Scheme 18) [Dickstein et al. (2007)].

Scheme 18

In another report, the decarboxylation of naphthyl carboxylic acid was achieved using Pd/C

under hydrothermal conditions (Scheme 19) [Matsubara et al. (2004)].

Scheme 19

Recently, Gooßen et al. found that a silver based catalyst system was effective in

promoting protodecarboxylation of ortho substituted aromatic acids (Scheme 20) [Gooßen

et al. (2009)].

Scheme 20

On the other hand, Meyers et al. developed a palladium catalyzed sequential

decarboxylation of aromatic acids which was followed by a Heck type coupling with

alkenes (Scheme 21) [Myers et al. (2002)]. The use of ortho-substituted benzoic acids as

Scheme 21

Pd/CH2O, 250oC, 4-5 MPa

14h

COOH

K2CO3, NMP, 120 oC

OH

O

R RR = OMe, Cl, Br, NO2, etc

10% AgOAc

OMe

COOH

OMe

MeO

OMe

OMe

MeOPd(OCOCF3)2, CF3COOH

5% DMSO/DMF, 70oC

OH

OCH3

H3C CH3

CH3

H3C CH3

Pd(OCOCF3)2Ag2CO3+

5% DMSO-DMF, 120oC


99

substrates besides Ag2CO3 as base and DMSO (5% v/v) in DMF as solvent was found to

be critical for success of above reaction.

In a complementary strategy, Gooßen et al. utilized nitro substituted benzoic acids as

organometallic reagent equivalents which under palladium catalysis undergo

decarboxylation-coupling with aryl halides to furnish the biaryls (Scheme 22) [Gooßen et

al. (2007)].

Scheme 22

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

prevalent decarboxylation approaches employ harsh reaction conditions involving metal

catalysts and/or strong bases. For instance, the rampant use of copper/quinoline based

decarboxylation approach is known to generate environmentally hazardous residues besides

sometimes providing a poor to moderate yield of desired product due to the propensity for

concomitant side reactions [Locatelli et al. (2005)]. In addition, it also entails an extra step

involving neutralization with an excess of acid. Although there have been noteworthy

efforts to devise more benign decarboxylation conditions with various improvements,

however, these have also been found to be constrained by an indispensable usage of either

different metals like silver [Gooßen et al. (2009)], palladium [Dickstein et al. (2007)],

mercury [Moseley and Gilday (2006)] or specialized techniques involving supercritical

water-Pd/C etc [Matsubara et al. (2004)]. On the other hand, the biocatalytic methods

exhibit limited generality. In this context, it would be highly desirable if a mild and metal-

free methodology for decarboxylation of a wide range of substrates could be devised.

2.4 Ionic Liquids

The emergence of new enabling technologies often provides a fresh stimulus to approach

longstanding problems. Ionic liquids have recently emerged as one of the leading reaction

medium besides being a central element of green chemical practices [Sheldon (2005);

Welton (1999)]. As discussed in the introduction section, the usage of room temperature

R

Br

R = CH3, CF3, COOEt, NO2

+K2CO3, NMP, 160oC

NO2

+ CO2

NO2

OH

OPd(acac)2, CuI, 1,10-phenanthroline

R


100

ionic liquids (RTIL’s) have provided a beneficial approach due to several attendant benefits

like low volatility, high thermal stability besides their remarkable ability to promote a wide

array of organic transformations [Wasserscheid and Welton (2008); Welton (1999)]. In

addition, there has been much recent interest in developing “catalyst free” organic

transformations in neat ionic liquids, wherein, the classical necessity of an additional metal

or acid/base catalyst stands removed [Meciarova et al. (2007); Parvulescu and Hardacre

(2007)].

2.5 Results and Discussion

In order to realize the objective of developing a mild and metal-free decarboxylation

approach, it was envisaged to explore the catalytic ability of ionic liquids [Wasserscheid

and Welton (2008)]. To the best of our knowledge, room temperature ionic liquids have not

been systematically explored to promote decarboxylative transformations apart from some

initial mechanistic reports [Oswald et al. (2005); Wong and Wu (2006)]. Initially, indole-2-

carboxylic acid was chosen as the model substrate, as these constitute one of the most

useful precursors for synthesis of immensely important 2-unsubstituted indole scaffolds

[Jones and Chapman (1993)]. Consequently, indole-2-carboxylic acid (1a) was treated with

ionic liquid 1-butyl-3-methylimidazolium hydroxide [bmim]OH (Table 1, entry 1) under

microwave irradiation (MW).

The above reaction condition

was found to provide the

expected 1b (60% yield) at

240oC optimized

temperature. Subsequently,

various other ionic liquids

were screened (Table 1) for

further increasing the

reaction performance.

Interestingly, the use of

neutral ionic liquid 1-hexyl-

3-methylimidazolium-

Entry Ionic liquid yieldc (%)reaction time [min]

1

1-butyl-3-methylimidazolium chloride

25 60

4

1-butyl-3-methylimidazolium hexafluorophosphate

25 5

3

1-butyl-3-methylimidazolium tetrafluoroborate

25 traces

2

1-butyl-3-methylimidazolium bromide

25 49

5

1-hexyl-3-methylimidazolium bromide

25 72

1-butyl-3-methylimidazolium hydroxide

8

1-methylimidazolium p-toluenesulfonic acid

40 ndd

Table 1. Effect of different ionic liquids on decarboxylation of 1a under microwave.a

1-methylimidazole

20 746

7 20 79

Ionic liquid

NH

NH

MW,COOH

1a 1b

aCEM monomode microwave. bWater (8 mmol). cIsolated yield. d Not detected.General condition:1a (1.2 mmol), ionic liquid (1.5 ml) under MW for 15-40 min (250W, 240 °C)

1-hexyl-3-methylimidazolium bromide + water b9 15 88

240 °C, 15-40 min,


101

bromide [hmim]Br (Table 1, entry 7) was found to provide expected 1b in comparatively

superior yield (79%) as compared to that obtained with basic and acidic ionic liquids.

In the course of our further attempts to enhance the reaction yield it was reasoned that

decarboxylation might have been hindered by the well known tendency of ionic liquids to

trap carbon dioxide [Wahelgren et al. (2006)]. However, application of simultaneous

evacuation using either a vacuum assembly or nitrogen purging to aid the release of

liberated carbon dioxide also proved futile. Thereafter, it was planned to use ionic liquid in

conjunction with water as some recent reports had disclosed the beneficial role of such a

combination for various organic transformations [Liao et al. (2005); Zhao et al. (2006)] It

was fascinating to note that addition of water (Table 1, entry 9) did indeed improve the

reaction performance as 1b was obtained in 88% yield in a reduced reaction time of 15 min

at 240oC. The presence of water might have favored decarboxylation as it allowed

increased mass transfer of an otherwise viscous reaction mixture [Liao et al. (2005); Zhao

et al. (2006)]. Moreover, the widely recognized hydrophilic nature of above ionic liquid

[Welton (1999)] apparently prevented any appreciable loss of water upon MW irradiation,

thereby, preventing any adverse effect on reaction performance. On the other hand, a

further increase in amount of water didn’t help as it prevented the reaction mixture to attain

required temperature for decarboxylation.

It is also worthwhile to mention that after work up, the recovered ionic liquid was reused as

such for three consecutive cycles to afford 88%, 82% and 75% yield of 1b, thereby,

demonstrating the recyclability of ionic liquid for above decarboxylation. In order to

ascertain the specific role of microwave irradiation, the developed decarboxylation of 1a

was also attempted under conventional heating in oil bath at similar temperature (240oC),

however, the expected 1b was obtained in only 31% yield after 6 hr of heating along with

some unreacted starting material besides blackening of reaction mixture. The foregoing

result highlights the utility of microwave irradiation in ionic liquid assisted

decarboxylation.

Subsequently, the applicability of developed method on various other N-heteroaryl

carboxylic acids was evaluated. It would be apparent from Table 2 that the above protocol

was effective for decarboxylation of diverse nitrogen containing heteroaryl carboxylic acids

possessing indole (Table 2, entries 2, 5-6), indazole (Table 2, entry 3) and quinoline (Table


102

2, entry 4) moieties under metal-free conditions. Importantly, the developed protocol also

facilitated a useful one pot hydrolysis-decarboxylation of indole carboxylic esters (Table 2,

entries 5-6) as such transformations are usually carried out via a two step base induced

hydrolysis-decarboxylation approach. Further the above result assumes significance as the

total synthesis of alkaloid natural products often involves the removal of a carboxylic ester

moiety from indole nucleus [Gan et al. (1997); Selvakumar and Rajulu (2004)]. On the

other hand, the indole-3-phenyl acetic acids (Table 3, entries 7-9) were also rapidly

Substrate (a)

NH

NH

COOH

NH N

HCOOH

Cl Cl

NH

N

COOH

NH

N

N COOH N

Reaction time [min]

Entry Product (b)

Table 2. Decarboxylation of N-heteroaryl carboxylic acids using neat [hmim]Br under MW a without any catalyst.

Yieldb (%)

1

2

15 88

83

85

864

3

15

15

15

NH

COOCH3

NMe

5 75

6

15

15 41NMe

COOCH3

1b

a CEM monomode microwave.b Yield of pure isolated product. General condition: substrate 1a-6a (1.2 mmol),[hmim]Br (1.5 ml), water (8 mmol); MW: (250W, 240 °C), Published in Adv. Synth. Catal. 2008, 350, 2910-2910.

Substrate (a)

Reaction time (min)

Entry Product (b)

Table 3. Decarboxylation of indole indole-3-acetic acids using neat [hmim]Br under MW a without any catalyst.

Yieldb (%)

7

8

9

a CEM monomode microwave.b Yield of pure isolated product. General condition: substrate 7a-9a (1.2 mmol), [hmim]Br (1.5 ml), water (8 mmol); MW: (250W, 240 °C).

NH

COOHNH

CH3

N

COOH

N

CH3

CH3 CH3

NH

COOH

NH

CH3

CH3CH3

90

82

49

15

15

15


103

decarboxylated using these conditions.

Having developed a neat [hmim]Br/water promoted metal free decarboxylation protocol for

N-heteroaryl carboxylic acids (Table 2-3, entries 1-9), it was decided to extend the same

towards decarboxylation of α,β-unsaturated aryl carboxylic acids i.e hydroxycinnamic acids

as these are precursors of various industrially and medicinally important hydroxy styrenes

[Crouzet et al. (1997)]. It may be mentioned that a few protocols [Bernini et al. (2007);

Nomura et al. (2005)] disclose such a synthesis of hydroxy styrenes, however, these have

been constrained either by the susceptibility of product styrenes towards polymerization or

usage of strong organic bases. Thus, a mixture of 4-hydroxy-3,5-dimethoxy cinnamic acid

(10a) and neat [hmim]Br/water was irradiated under MW (150oC optimized temperature, 30

min) to provide canolol (10b), an anticancer compound [Cao et al. (2008)] in 34% yield.

Similarly, 4-hydroxy-3-methoxy cinnamic acid (11a) also provided the corresponding

styrene 11b in 36% yield. In order to further enhance the yield of hydroxystyrenes (10b-

11b), the addition of a small amount of base was envisaged as such a combination has been

earlier found to improve the performance of various ionic liquid mediated transformations

[Meciarova et al. (2007)]. Consequently, 10a (Table 4, entry 10) was treated with

[hmim]Br using various mild bases like aq. NaHCO3, KHCO3 etc. under MW and

gratifyingly the [hmim]Br–aq. NaHCO3 (20 mol%) combination was found to provide 10b

in an improved 67% yield. Thereafter, this protocol was applied on various other cinnamic

acids (Table 4). Significantly, it provided an improved decarboxylative access towards

industrially important hydroxy styrenes including 4-vinyl guaiacol (Table 4, entry 11), a

FEMA GRAS (Flavor and Extract Manufacturer΄s Association; Generally Regarded As

Safe) approved flavoring agent [Sinha et al. (2007)]. It would also be evident from Table 4

that an ortho or para hydroxy substitution at aromatic ring provided a comparatively

favorable condition for decarboxylation as compared to 3-hydroxy counterpart (Table 4,

entry 20). The foregoing result is presumably due to the well known resonance stabilization

provided by the ortho/para quinomethide [Nomura et al. (2005); Sinha et al. (2007)].

The above success with 4 or 2-hydroxy substituted cinnamic acids motivated us to explore

the hitherto unrealized metal/quinoline free decarboxylation of methoxylated cinnamic

acids like 15a (Table 4, entry 15) with no 4 or 2-hydroxy substitution. However, no product

(15b) could be detected when 15a was treated with a combination of [hmim]Br and aq.


104

NaHCO3 under microwave irradiation even after 60 min of MW while the starting material

remained unreacted. Similarly, the replacement of NaHCO3 with stronger bases like

methylimidazole, piperidine etc. also proved futile for improving the reaction performance.

R1R2

R'OR3

R4

COOH

R1R2

R'OR3

R4

OMeOMe

COOH

OMeOMe OH

MeO

MeO

COOH

OHMeO

MeO

HOMeO

O O

HO

COOH

HO

Table 4. Decarboxylation of cinnamic acid derivatives using [hmim]Br-base under microwave irradiation.a

Entry Substrate (a)

Reaction time (min)

Product (b)

Yieldb (%)

10

13

12

11

15

14

OMeMeO

16

17

18

19

50d

20 14b 27e

30 6d

21 3c

R1-R4 = OMe, OH etc.R' = H, CH3 etc

[hmim]Br - base

aCEM Discover microwave. b Yield of pure isolated product. General condition: substrate (entries 10-14, 18-19) (1.5 mmol), [hmim]Br (1.5 ml), water (8 mmol), NaHCO3 (20 mol%) under microwave for 4-30 min (150W, 140°C); in case of entries 15-17 and 20-21: DBU (1.5 mmol) was used in place of NaHCO3 while rest of the conditions were same. c Based on GC-MS analysis. d After the formation of styrene (11b) in 4 min (MW) as described in general condition above, dimethyl sulphate (2 mmol), water (5 ml), sodium hydroxide (2 mmol ) were added to the same pot and the mixture stirred at ice bath for 30 min to obtain 17b. e NaOH (1.5 mmol) was used instead of NaHCO3. Published in Adv. Synth. Catal. 2008, 350, 2910-2910.

HOOMe

COOHMeO

HOOMe

MeO

HOOMe

COOH

HOOMe

HO

COOH

HO

COOH

HO

HO

HO

HOCOOH

OH OHCOOH

OMe OMeMeO MeO

20OH

COOH

OH

2016b'

15b'

20 6c

17b'5c

30

67

60

50

69

4

4

4

4

7

20

64

5c19

5c 19

4

MW, 140 °C

+ +

++

++

MeO

MeO11a


105

Consequently the use of a hindered base like DBU (pKa = 12) was envisaged as it has been

reported for an efficient albeit metal catalyzed decarboxylation of unsaturated fatty acids

[Hori et al. (1981)]. Surprisingly, the treatment of 15a with a combination of [hmim]Br-

DBU under microwave irradiation for 20 min provided the first metal-free decarboxylation

of methoxylated cinnamic acid (Table 4, entry 15). The above result was especially

interesting as a subsequent literature search revealed that DBU in the absence of ionic

liquid had earlier proved to be ineffective for promoting decarboxylation of similar

methoxylated substrates under microwave conditions [Bernini et al. (2007)]. In this

context, it appears plausible that it is the unique combination of ionic liquid with DBU that

provides an effective system for promoting decarboxylation of 15a even in the absence of a

metal catalyst. Moreover, 15a also underwent a novel simultaneous decarboxylation and

demethylation to give an unexpected side product 2-hydroxy-4-methoxy styrene (15b', 5%

yield). It would be apparent from Table 4, the above [hmim]Br-DBU system was also

found to be applicable for decarboxylation of other methoxylated cinnamic acids 16-17a

(Table 4) into methoxy styrenes (16b-17b). Interestingly, 16a underwent a concurrent

demethylation to give 2-hydroxy-3-methoxy styrene (16b') as the major product. In order to

further increase the yield of methoxylated styrene 17b, it was planned to develop a one pot

decarboxylation-methylation of corresponding hydroxy cinnamic acid. Thus, 4-hydroxy-3-

methoxy cinnamic acid 11a upon decarboxylation with [hmim]Br-aq. NaHCO3 protocol

provided corresponding styrene 11b (as revealed by comparison with standard on TLC).

Thereafter, the obtained 11b was methylated by addition of dimethyl sulfate (2 mmol),

water (5 ml), sodium hydroxide (2 mmol) in the same pot and reaction mixture stirred in ice

bath for 30 min to provide the corresponding 3,4-dimethoxy styrene 17b (Table 4, entry 18)

in 50% yield. On the other hand, coumarin 19a (Table 4) also provided the corresponding

styrene 14b through a simultaneous hydrolysis-decarboxylation (Table 4, entry 19).

However, the above reaction required prior addition of a few drops of sodium hydroxide

(1.5 mmol) to [hmim]Br for initial hydrolysis of lactone ring to be followed by subsequent

decarboxylation of resulting cinnamic acid.

After the above success with hydroxycinnamic acids (Table 4, entries 10-21), it was

planned to apply the ionic liquid based strategy for decarboxylation of hydroxy substituted

α–phenylcinnamic acids into biologically important hydroxystilbenes [Baur and Sinclair


106

(2006); Likhtenshtein (2009)]. Hence, α-phenyl-4-hydroxycinnamic acid 22a was treated

with [hmim]Br under MW irradiation (30 min), wherein, the corresponding stilbene was

obtained in 84% yield. However, when above method using neat [hmim]Br or even its

combination with NaHCO3 or DBU was applied on various other α–phenylcinnamic acids

like α -phenyl-4-hydroxy-3-methoxycinnamic acid (23a) or α -phenyl-4,4’-dihydroxy-3-

methoxycinnamic acid (24a), the corresponding stilbenes 23b-24b were obtained in

comparatively lower yield (upto 41%) after 45 min of MW irradiation. Consequently,

various other ionic liquids from Table 1 were screened and neat ionic liquid [Hmim]PTSA

was surprisingly found to be effective for decarboxylation of 23a (Table 5, 72% yield),

while 22b was obtained in 86% yield (Table 5, entry 22). Similarly, the other α-phenyl-4-

Table 5. Decarboxylation of a-phenylcinnamic acid derivatives using [hmim]PTSA under microwave irradiationa without any catalyst.

Entry Substrate (a)

Reaction time (min)

Product (b)

Yieldb (%)

22

23

R1-R9 = H, OMe, OH, OCOCH3 etc.R' = H, COCH3 etc

aCEM Discover microwave. b Yield of pure isolated product. General condition: substrate (entries 22-28) (0.83 mmol), [Hmim]PTSA (2 g), water (8 mmol), under microwave for 60-90 min (160W, 155°C). Published in Adv. Synth. Catal. 2008, 350, 2910-2910.

MW, 155oC

[hmim]PTSA/H2O

HO

R1R2

HOR3

R4

R6R5

R9

R7

R8

R1R2

R'OR3

R4

R6R5

R9

R7

R8

COOH

COOH

C6H5

MeO

HO

COOH

C6H5

MeO

HO

COOH

C6H4 (4-OH)

HO

COOH

C6H4(3-OMe)

HO

COOH

C6H4 (4-OMe)

H3COCO

COOH

C6H5

MeO

H3COCO

COOH

C6H5

MeO

HO

C6H5

MeO

HO

C6H5

MeO

HO

C6H4 (4-OH)

HO

C6H4(3-OMe)

HO

C6H4 (4-OMe)MeO

HO

C6H5

MeO

HO

C6H5

60

90

90

90

90

70

80

86

72

65

70

71

79

67

24

25

26

27

28


107

hydroxycinnamic acids (Table 5, entries 24-26) also underwent decarboxylation into

corresponding stilbenes (upto 79% yield) without the addition of any catalyst. Moreover,

the above conditions were also conducive for a useful one pot two step deacetylation-

decarboxylation of acetylated α-phenylcinnamic acids (Table 5, entries 27-28).

With an ionic liquid based decarboxylation platform for synthesis of indoles, styrenes and

stilbenes (Tables 2-5) in hand, it was planned to extend the methodology towards aromatic

acids which are known to be immensely useful synthons [Baudoin (2007); Myers et al.

(2002)]. It is pertinent to mention that decarboxylation of aromatic acids has been widely

recognized to be one of the most challenging transformations which requires either an

indispensable use of transition metals [Dickstein et al. (2007); Myers et al. (2002)] or

specialized reaction conditions involving Pd-supercritical water [Matsubara et al. (2004)]

etc. Thus, it was initially planned to explore a neat ionic liquid assisted metal-free

decarboxylation of 3,5-dichloro-4-hydroxy benzoic acid (29a) into 2,6-dichlorophenol, a

pharmaceutically important phenol [Mukhopadhyay and Chandalia (1999)]. In this context,

a survey of reaction temperature revealed that treatment of 29a with [hmim]Br/water at

190oC under 25 min of MW (200W) was effective to provide corresponding phenol 29b in

31% yield. Similarly, the above protocol was beneficial for efficient decarboxylation of

ortho/para nitro substituted phenyl acetic acids 30b-31b into synthetically useful alkyl nitro

benzenes (85 and 78% yield respectively) [Bull et al. (1996)] without addition of any

catalyst. On the other hand, a low yield (23%) was obtained in case of 2-chloro-4-

nitrobenzoic acid 32a (32b). In the course of further efforts for improving the reaction

performance, the role of a combination of [hmim]Br with aq. NaHCO3 was evaluated.

Hence, 29a was treated with [hmim]Br and NaHCO3 (20 mol%) and gratifyingly 29b was

obtained in an improved 61% yield (Table 6, entry 29). Similarly, the above [hmim]Br-

aq.NaHCO3 reagent system also enhanced the reaction performance of 30a and 31a as the

corresponding decarboxylated products were obtained in comparatively shorter reaction

times as compared to the case with neat [hmim]Br (Table 6, entries 30-31). In addition, the

treatment of nitro substituted carboxylic acid (32a) (Table 6, entry 32) under above reaction

conditions also furnished the corresponding 32b in an improved 55% yield. It is worthwhile

to mention that above approach provides a useful addition as such substrates have recently

been much explored for decarboxylative couplings [Gooßen et al. (2006); Gooßen et al.


108

(2007)]. Curiously, the 4-nitrobenzoic acid (Table 6, entry 33) underwent decarboxylation

in longer reaction time of 45 min with 15% yield along with formation of some esterified

side products. Similarly, other nitro substituted benzoic acid (Table 6, entries 34-35) didn’t

undergo efficient decarboxylation. Interestingly, diphenyl acetic acid underwent facile

decarboxylation (Table 6, entry 37), however, no product formation was detected in the

Cl Cl

COOH

Me O

COOH

ndd

COOH

93

COOH

ndc-d

ndd

NO 2

S COOH Sndc-d

COOH

NO 2 NO 2

x

R'

x

R

MW, 190oC

COOH

O2N O2N

NO 2

COOH

Table 6. Decarboxylation of aromatic acid derivatives using [hmim]Br-aq. NaHCO3 under microwave irradiation.a

Reaction time(min)

Entry Product (b)

Yield (%)bSubstrate (a)

X= OH, NO2, ClR' = H, CH3, CH2-C6H5

[hmim]Br- aq. NaHCO3

X= NO2, ClR = COOH, CH2COOH etc.

aCEM Discover monomode microwave. bYield of pure isolated product. c based on GC-MS analysis. dNot detected. General condition: substrate (entries 29-40) (2.1 mmol), [hmim] Br (1.5 ml), water (8 mmol), NaHCO3 (20 mol %) under microwave for 5-60 min (200W, 190oC). Published in Adv. Synth. Catal. 2008, 350, 2910-2920.

COOH

O2N O2NCl Cl

15

32

60

ndd

34

36

45

24c

33

35

45

15c

5520

37

38

45

40 45

39

29

OHCl Cl

COOH

OH

Cl Cl

O2N

CH 3

O2N

COOH30

31

92

84

5

5

45

CH 3COOH

NO 2 NO 2

20

45

61

Me O


109

case of biphenyl-4-carboxylic acid, 4-methoxy benzoic acid or thiophene-2-carboxylic acid

(Table 6, entries 38-40). On the other hand, the developed methodology was found to be

amenable towards decarboxylation of diverse 4-hydroxy benzoic acids (Table 7, entries 41-

45) into industrially important flavoring agents like syringol, guaiacol [Crouzet et al.

(1997)] and anti-oxidant catechol [Cao et al. (2008)]. Thus, it would be apparent from

Table 6-7 that the presence of a 4-hydroxy or 2-chloro/4-nitro substitution at the aromatic

ring is necessary for a metal-free decarboxylation to proceed under above conditions.

After examining the substrate scope of developed ionic liquid based metal-free

decarboxylation strategy, it was interesting to evaluate its mechanistic implications. In

particular, the unprecedented decarboxylation of various indole and aromatic acid

derivatives under catalyst free conditions using neat ionic liquid appeared noteworthy.

Similarly, though the decarboxylation of hydroxy cinnamic acid derivatives and nitro

benzene derivatives appears to be facilitated in part by the peculiar resonance stabilization

COOH

HOHO

COOH

HO

COOH

HOHO

COOH

HOHO

OMe

MeO

OMe

MeO

HOHOOMe

OMe

HO HO

COOH

42

15 54

44

45

50

56

43

15

15HO

aCEM Discover monomode microwave. bYield of pure isolated product. c based on GC-MS analysis. dNot detected. General condition: substrate (entries 41-45) (2.1 mmol),[hmim] Br (1.5 ml), water (8 mmol), NaHCO3 (20 mol %) under microwave for 15 min (200W, 190oC) Published in Adv. Synth. Catal. 2008, 350, 2910-2910.

x

R'

x

R

MW, 190oC

Table 7. Decarboxylation of 4-hydroxy substituted aromatic acids using [hmim]Br-aq. NaHCO3 under microwave irradiation.a

Reaction time(min)

Entry Product (b)

Yield (%)bSubstrate (a)

X= OHR' = H, CH3

[hmim]Br- aq. NaHCO3

X= OHR = COOH, CH2COOH etc.


110

in these systems [Gooβen et al. (2006); Sinha et al. (2007)], however, the above

stabilization has also been usually reported following an initial base/acid catalyzed step. In

this context, a general mechanistic pathway (Figure 2) for neat ionic liquid catalyzed

decarboxylation plausibly involves an initial ionic liquid promoted formation of

carboxylate anion which is facilitated in part by the enhanced dissociation constants of aryl

acids in presence of ionic liquids. Subsequently, the ionic liquid facilitates efficient

absorption of microwave energy to provide the decarboxylated product.

Figure 2

2.6 Conclusion

In summary, ionic liquids have been found to be efficient catalysts cum solvents for metal

and quinoline free decarboxylation of diverse N-heteroaryl and aryl carboxylic acids under

microwave irradiation in aqueous condition. The methodology showed wide substrate

scope towards synthesis of pharmacologically and industrially important aromatic

compounds including indoles, styrenes, stilbenes, nitro or hydroxy arene derivatives. In the

case of indole carboxylic acids and α-phenylcinnamic acids, decarboxylation proceeded

well in neat [hmim]Br and [Hmim]PTSA respectively. On the other hand, addition of a

mild base like aq. NaHCO3 to [hmim]Br was found to improve the decarboxylation of

cinnamic and aromatic acid substrates. The developed methodology offers several inherent

Br-

-CO2

resonance stabilisationby nitrogen/oxygen at aromatic ring

Decarboxylated product

H

R

RCOOH

RC

N NC6H13

Br-

+

O

O-

H+

Microwave

R = Indoles, Aryl ethenes andArene derivatives

N NC6H13++


111

advantages like reduction in waste and hazards, recyclability of reagent system, short

reaction times besides ease of product recovery.

2.7 Experimental Section 2.7.1 General Procedure The starting materials were reagent grade (purchased from Merck and Sigma Aldrich)

except α-phenylcinnamic acid derivatives which were prepared through previously reported

Perkin reaction of respective benzaldehydes [Sinha et al. (2007)] and fully characterized by 1H and 13C NMR. The ionic liquids were purchased (Merck and Acros) or synthesized

using an earlier reported procedure [Nockemann et al. (2005)]. The purity of ionic liquids

was checked by 1H NMR before their use. The solvents used for isolation/purification of

compounds were obtained from commercial sources (Merck) and used without further

purification. 1H (300 MHz) and 13C (75.4 MHz) NMR spectra were recorded on a Bruker

Avance-300 spectrometer. GC-MS analysis was undertaken using a Shimadzu-2010

spectrometer. CEM Discover© focused microwave (2450 MHz, 300W) was used wherever

mentioned. The temperature of reactions in microwave experiments was measured by an

inbuilt infrared temperature probe that determined the temperature on the surface of

reaction flask. The sensor is attached in a feedback loop with an on-board microprocessor

to control the temperature rise rate. In the case of conventional heating in oil bath, the

temperature of reaction mixture was monitored by an inner thermometer.

2.7.2 Optimization of reaction conditions 2.7.2.1 Decarboxylation of N-heteroaryl carboxylic acids 2.7.2.1.1 Decarboxylation of indole-2-carboxylic acid (1a) using [bmim]OH (Table 1, entry 1) A mixture of indole-2-carboxylic acid (0.2 g, 1.2 mmol) and [bmim]OH (1.5 ml) was

irradiated under focused microwave system in parts (250W, 240oC) for 15 min. After the

completion of reaction (on TLC basis), the reaction mixture was cooled and extracted with

ethyl acetate (3x10 ml) and the ionic liquid left as residue. The combined organic layer was

washed with brine, dried (anhyd. Na2SO4) and vacuum evaporated to obtain a crude


112

product which was purified on silica-gel (60-120 mesh size) column with a 1:10 mixture of

ethylacetate and hexane to provide 1b (0.087g, 60% yield).

Indole (Table 1, entry 1)

White solid, m. p. 51-53°C (lit. m. p. 52–54°C) [Jones and Chapman (1993)], 1H NMR δ

(CDCl3, 300 MHz) 7.93 (1H, s), 7.70 (1H, d, J=7.67 Hz), 7.35 (1H, d, J=8.07 Hz), 7.25-

7.11 (3H, m), 6.57 (1H, s); 13C NMR δ (CDCl3, 75.4 MHz) 135.8, 127.9, 124.3, 122.0,

120.8, 119.9, 111.2 and 102.6.

2.7.2.1.2 Decarboxylation of 1a using various other ionic liquids [Hmim]PTSA,

[bmim]PF6, [bmim]BF4, [bmim]Cl, [bmim]Br, [hmim]Br) (Table 1, entries 2-7)

Indole-2-carboxylic acid (0.2 g, 1.2 mmol) was treated separately with the following ionic

liquids (1.5 ml each); [Hmim]PTSA, [bmim]PF6, [bmim]BF4, [bmim]Cl, [bmim]Br,

[hmim]Br under the microwave conditions mentioned in preceding section. After the

completion of reaction, each of the reaction mixture was worked up as mentioned in the

preceding section. The column purification (Silica-gel (60-120 mesh size)) of crude mixture

of a majority of above reactions with a 1:10 mixture of ethylacetate and hexane provided

the desired 1b in traces to 79% yield. However, an enhanced yield (88%) of 1b was

obtained in the case when [hmim]Br was used.

2.7.2.1.3 Optimized procedure for decarboxylation of 1a using combination of

[hmim]Br-H2O (Table 1, entry 9)

A mixture of indole-2-carboxylic acid (1.2 mmol), [hmim]Br (1.5 ml) and water (8 mmol)

was irradiated under focused microwave system in parts (250W, 240oC) for 15 min. After

the completion of reaction, the reaction mixture was worked up and purified as mentioned

in section 2.7.2.1.1 to provide the desired 1b (0.127g, 88% yield) whose NMR (1H and 13C) spectrum matched well with that obtained in section 2.7.2.1.1.

The above procedure was also followed for decarboxylation of various other

heteroaromatic acids (Table 2, entries 2-6; Table 3, entries 7-9).

NH


113

5-Chloro-indole 2b (2b, Table 2)

White solid, m. p. 70-73°C (lit. m. p. 70–72°C) [Gu et al. (2007)], 1H NMR δ (CDCl3, 300

MHz) 8.11 (1H, s), 7.56 (1H, s), 7.25 (1H, d, J=8.51 Hz), 7.16-7.08 (2H, m), 6.44 (1H, s); 13C NMR δ (CDCl3, 75.4 MHz) 134.1, 128.9, 125.4, 122.3, 120.1, 112.0 and 102.4.

Indazole (3b, Table 2)

White solid, m. p. 146-148°C (lit. m. p 147–149°C) [Lukin et al. (2006)], 1H NMR δ

(CD3COCD3, 300 MHz) 12.25 (1H, s), 7.99 (1H, s), 7.72 (1H, d, J=7.67 Hz), 7.53 (1H, d,

J=8.07 Hz), 7.31 (1H, t, J=7.67 Hz), 7.08 (1H, t, J=7.67 Hz); 13C NMR δ (CD3COCD3,

75.4 MHz) 140.4, 133.7, 126.0, 123.4, 120.5, 120.3 and 109.9.

Quinoline (4b, Table 2)

Light yellow liquid [Reddy and Ganesh (2000)], 1H NMR δ (CDCl3, 300 MHz) 8.76 (1H,

s), 8.01 (1H, d, J=8.88 Hz), 7.95 (1H, d, J=8.48 Hz), 7.63 (1H, d, J=8.48 Hz), 7.57 (1H, t,

J=7.27 Hz), 7.38 (1H, t, J=7.67 Hz), 7.21-7.16 (1H, m); 13C NMR δ (CDCl3, 75.4 MHz)

149.9, 148.2, 136.0, 129.3, 128.2, 127.7, 126.5 and 121.0.

1-Methylindole (6b, Table 2)

Light yellow liquid [Gu et al. (2007)], 1H NMR δ (CDCl3, 300 MHz) 7.74 (1H, d, J=7.87

Hz), 7.42 (1H, d, J=8.23 Hz), 7.34-7.28 (1H, m), 7.22-7.17 (1H, m), 7.12 (1H, d, J=3.11

Hz); 6.58 (1H, d, J=3.11 Hz); 3.84 (3H, s); 13C NMR δ (CDCl3, 75.4 MHz) 137.1, 129.2,

128.9, 121.9, 121.3, 119.7, 109.6, 101.3 and 32.8.

NH

Cl

NH

N

N

N

CH3


114

3-Methylindole (7b, Table 3)

White solid, m. p. 94-97°C (lit. m. p. 93–95°C) [Jensen et al. (1995)], 1H NMR δ (CDCl3,

300 MHz) 7.74 (1H, s), 7.59 (1H, d, J=7.27 Hz), 7.31 (1H, d, J=7.27 Hz), 7.21-7.09 (2H,

m), 6.91 (1H, s), 2.33 (3H, s); 13C NMR δ (CDCl3, 75.4 MHz) 136.3, 128.3, 121.9, 121.6,

119.1, 118.9, 111.7, 111.0 and 9.7.

1,3-Dimethylindole (8b, Table 3)

Colorless liquid [Jefford et al. (1984)], 1H NMR δ (CDCl3, 300 MHz) 7.60 (1H, d, J=8.07

Hz), 7.30-7.24 (2H, m), 7.16-7.10 (1H, m), 6.81 (1H, s), 3.71 (3H, s), 2.35 (3H, s); 13C

NMR δ (CDCl3, 75.4 MHz) 137.0, 128.7, 126.6, 120.5, 119.0, 118.5, 110.1, 109.0, 32.5

and 9.6.

2,3-Dimethylindole (9b, Table 3)

Colorless viscous liquid [An et al. (1997)], 1H NMR δ (CDCl3, 300 MHz) 7.52 (1H, d,

J=6.46 Hz), 7.23 (1H, d, J=1.86 Hz), 7.15-7.10 (2H, m), 2.32 (3H, s), 2.25 (3H, s); 13C

NMR δ (CDCl3, 75.4 MHz) 135.0, 130.74, 129.35, 120.78, 118.94, 117.87, 110.15, 106.80,

11.15 and 8.34.

2.7.2.2 Optimization of conditions for decarboxylation of cinnamic acids 2.7.2.2.1 Decarboxylation of 4-hydroxy-3,5-dimethoxy cinnamic acid (10a) using combination of [hmim]Br and water A mixture of 4-Hydroxy-3,5-dimethoxy cinnamic acid (10a, 0.34 g, 1.5 mmol), [hmim]Br

(1.5ml) and water (8 mmol) was irradiated under focused microwave system in parts

NH

CH3

N

CH3

CH3

NH

CH3

CH3


115

(150W, 140 °C) for 4 min. The reaction mixture was worked up and purified as mentioned

in section 2.7.2.1.1 and 10b was obtained in 34% yield (0.09 g).

4-Hydroxy-3,5-dimethoxy styrene (10b, Table 4)

Colorless liquid [Nomura et al. (2005)], 1H NMR δ (CDCl3, 300 MHz) 6.58 (2H, s), 6.55-

6.50 (1H, m), 5.56 (1H, d, J=17.76 Hz), 5.09 (1H, d, J=10.90 Hz), 3.83 (6H, s); 13C NMR δ

(CDCl3, 75.4 MHz) 147.1, 136.8, 134.8, 129.2, 111.8, 103.0 and 56.2.

2.7.2.2.2 Decarboxylation of 10a using combination of [hmim]Br/H2O and various

inorganic bases

The reaction was performed in the same manner as described in section 2.7.2.2.1, however,

various bases like NaOAc, KHCO3, K2CO3 each were explored in combination with

[hmim]Br and water. Each of the above reactions upon completion and work up as

mentioned in section 2.7.2.1.1 led to a lower yield of 10b.

2.7.2.2.3 Final optimized procedure for decarboxylation of 10a using combination of

[hmim]Br/water and NaHCO3 (Table 4, entry 10)

A mixture of 4-hydroxy-3,5-dimethoxy cinnamic acid (10a, 0.34 g, 1.5 mmol), [hmim]Br

(1.5ml), water (8 mmol) and 20 mol% NaHCO3 (0.42 mmol) was irradiated under focused

microwave system in parts (150W, 140 °C) for 4 min. The reaction mixture was worked up

and purified as mentioned in section 2.7.2.2.1 and 10b was obtained in an optimum 67%

yield (0.18 g). The spectral data (1H and 13C NMR) of above 10b matched well with that

obtained in section 2.7.2.2.1.

The above procedure was also followed for decarboxylation of various other cinnamic

acids (Table 4, entries 11-14, 18-19). However, in the case of entries 15-17 and 20-21

(Table 4), DBU (1.5 mmol) was used in place of NaHCO3 while rest of the conditions

were the same as in section 2.7.2.2.3.

MeO

HO

OMe


116

4-Hydroxy-3-methoxy styrene (11b, Table 4)

Colorless viscous liquid [Nomura et al. (2005)], 1H NMR δ (CDCl3, 300 MHz) 6.88-6.81

(3H, m), 6.63-6.54 (1H, m), 5.68 (1H, s), 5.71 (1H, d, J=17.56 Hz), 5.09 (1H, d, J=10.92

Hz), 3.84 (3H, s); 13C NMR δ (CDCl3, 75.4 MHz) 146.6, 145.6, 136.6, 103.3, 120.1, 114.4.

111.4, 108.1 and 55.9.

3,4-Dihydroxy styrene (12b, Table 4)

Colorless viscous liquid [Nomura et al. (2005)], 1H NMR δ (CDCl3, 300 MHz) 6.95 (1H, d,

J=7.16 Hz), 6.69 (1H, d, J=7.16 Hz), 6.67 (1H, s), 6.61-6.39 (1H, m), 5.63 (1H, d, J=16.8

Hz), 5.29 (1H, d, J=11.2 Hz); 13C NMR δ (CDCl3, 75.4 MHz) 144.4, 143.6, 136.2, 128.9,

121.1, 118.9, 114.3 and 112.1.

4-Hydroxy styrene (13b, Table 4)

Colorless liquid [Nomura et al. (2005)], 1H NMR δ (CDCl3, 300 MHz) 7.25 (2H, d, J=8.07

Hz), 6.75 (2H, d, J=8.87 Hz), 6.63-6.54 (1H, m), 5.56 (1H, d, J=17.36 Hz), 5.52 (1H, s),

5.07 (1H, d, J=10.50 Hz); 13C NMR δ (CDCl3, 75.4 MHz) 155.4, 136.2, 130.6, 127.6, 115.4

and 111.6.

2-Hydroxy styrene (14b, Table 4)

Colorless oil [Nomura et al. (2005)], 1H NMR δ (CDCl3, 300 MHz) 7.38 (1H, d, J=7.67

Hz), 7.15-7.07 (1H, m), 6.99-6.91 (1H, m), 6.89-6.86 (1H, m), 6.76 (1H, d, J=8.48 Hz),

5.74 (1H, d, J=17.67 Hz), 5.33 (1H, d, J=11.30 Hz); 13C NMR δ (CDCl3, 75.4 MHz) 152.9,

131.5, 128.9, 127.3, 125.0, 120.9, 115.9 and 115.6.

HO

OMe

HO

HO

HO

OH


117

2,4-Dimethoxy styrene (15b, Table 4)

Colorless liquid [Shin et al. (2001)], 1H NMR δ (CDCl3, 300 MHz), 7.42 (1H, d, J=8.23

Hz), 7.01-6.92 (1H, m), 6.51-6.45 (2H, m), 5.67 (1H, d, J=17.75 Hz), 5.18 (1H, d, J=11.16

Hz), 3.85 (3H, s), 3.83 (3H, s); 13C NMR δ (CDCl3 75.4 MHz) 160.9, 158.2, 131.6, 127.6,

120.3, 112.6, 105.1, 98.8 and 55.7.

2-Hydroxy-3-methoxy styrene (16b′, Table 4)

Colorless liquid [Ingemarsson (1998)], 1H NMR δ (CDCl3, 300 MHz) 7.11 (1H, d, J=1.83

Hz), 7.08-6.99 (1H, m), 6.86 -6.77 (2H, m), 5.91 (1H, s), 5.86 (1H, d, J =17.56 Hz), 5.35

(1H, d, J=11.34 Hz), 3.91 (3H, s); 13C NMR δ (CDCl3, 75.4 MHz) 147.0, 143.7, 131.6,

124.3, 119.7, 119.2, 115.2, 110.0 and 56.5.

2.7.2.3 Optimization of conditions for decarboxylation of α-phenylcinnamic acids 2.7.2.3.1 Decarboxylation of α-phenyl-4-hydroxy-3-methoxycinnamic acid (23a) using

[hmim]Br/water alone or its combination with various bases (23a was taken in place of

22a as the decarboxylation of former proved difficult using [hmim]Br/base)

A mixture of α-phenyl-4-hydroxy-3-methoxycinnamic acid (23a, 0.23 g, 0.83 mmol),

[hmim]Br (1.5 ml) and water (8 mmol) was irradiated under focused microwave system in

parts (200W, 190°C) for 45 min. The reaction mixture was worked up and purified as

mentioned in section 2.7.2.1.1 and 23b was obtained in only 20% yield. Subsequently, the

above reaction was also conducted using other bases like NaHCO3 or DBU, however, the

yield of 23b was found to increase upto 41% only.

4-Hydroxy-3-methoxy stilbene (23b)

HO

OMe

MeO OMe

OMe

OH


118

White solid, m. p. 130-132 °C (lit. m. p 132–134°C) [Sinha et al. (2007)], 1H NMR δ

(CDCl3, 300 MHz) 7.45 (2H, d, J=7.41 Hz), 7.32-7.27 (2H, m), 7.21-7.16 (1H, m), 7.02-

6.85 (5H, m), 5.66(1H, s), 3.89(3H, s); 13C NMR δ (CDCl3, 75.4MHz). 146.7, 145.6, 137.6,

130.0, 128.7, 127.2, 126.5, 126.2, 120.5, 114.6, 108.3 and 55.9.

2.7.2.3.2 Optimized procedure for decarboxylation of α-phenyl-4-hydroxy-3-

methoxycinnamic acid (23a) using [Hmim]PTSA (Table 5, entry 23)

A mixture of 23a (0.23 g, 0.83 mmol), [Hmim]PTSA (2 g) and water (8 mmol) was

irradiated under focused microwave system in parts (200W, 190°C) for 90 min. The

reaction mixture was worked up and purified as mentioned in section 2.7.2.1.1 and 23b was

obtained in an optimum 72% yield (0.18 g). The spectral data (1H and 13C NMR) of above

obtained 23b matched well with that obtained in section 2.7.2.3.1.

The above procedure was also followed for decarboxylation of various other α-phenyl

cinnamic acids (Table 5, entries 22, 24-28).

4-Hydroxy stilbene; (22b,Table 5)

White solid, m. p. 184-186 °C (lit. m. p 185–187°C) [Sinha et al. (2007)], 1H NMR δ

(MeOD, 300 MHz) 7.40 (2H, d, J=7.68 Hz), 7.31 (2H, d, J=8.51 Hz), 7.24-7.19 (2H, m),

7.12-7.08 (1H, m), 7.02 (1H, d, J=16.74 Hz), 6.90 (1H, d, J=16.74 Hz), 6.72 (2H, d, J=8.51

Hz); 13C NMR δ (MeOD 75.4 MHz) 157.0, 137.9, 129.1, 128.2, 128.1, 127.5, 126.6, 125.8,

125.4 and 115.1.

4,4′-Dihydroxy-3-methoxy stilbene; (24b, Table 5)

Brown solid; (m. p. 210-214°C) [Kumar et al. (2007)], 1H NMR δ (CD3COCD3, 300 MHz)

HO

HO

MeO

OH


119

8.36 (1H, s), 7.61 (1H, s), 7.33 (2H, d, J=9.3 Hz), 7.12 (1H, s), 6.97-6.92 (3H, m), 6.77-

6.72 (3H, m), 3.81 (3H, s); 13C NMR δ (CD3COCD3, 75.4 MHz) 156.8, 147.6, 146.2, 130.0,

129.5, 127.4, 125.9, 125.7, 119.8, 115.5, 115.0, 108.9 and 55.3.

4-Hydroxy-3′-methoxy stilbene (25b, Table 5)

White solid m. p. 133–135°C (lit. m. p 131–134°C) [Sinha et al. (2007)], 1H NMR δ

(CD3COCD3, 300 MHz) 8.46 (1H, s), 7.39 (2H, d, J=8.51 Hz), 7.20–7.13 (1H, m), 7.07–

7.04 (3H, m), 6.97 (1H, d, J=16.14 Hz), 6.80 (2H, d, J=8.51 Hz), 6.74 (1H, d, J=7.14 Hz),

3.74 (3H, s); 13C NMR δ (CD3COCD3, 75.4 MHz) 160.1, 157.4, 139.4, 129.5, 129.0, 128.7,

127.9, 125.5, 118.7, 115.5, 112.7, 111.3 and 54.6.

4-Hydroxy-3,4′-dimethoxy stilbene (26b, Table 5)

White solid, m. p. 164-167°C (lit. m. p 163–166°C) [Sinha et al. (2007)], 1H NMR δ

(CDCl3, 300 MHz) 7.37 (2H, d, J=8.48 Hz), 6.95-6.92 (2H, m), 6.84-6.81 (5H, m), 3.88

(3H, s), 3.76 (3H, s); 13C NMR δ (CDCl3, 75.4 MHz) 159.0, 146.7, 145.2, 130.3, 127.4,

126.6, 126.1, 120.1, 114.5, 114.1, 108.0, 55.9 and 55.3.

2.7.2.4 Optimization of conditions for decarboxylation of aromatic acid derivatives

2.7.2.4.1 Decarboxylation of 3,5-dichloro-4-hydroxy benzoic acid (29a) using

[hmim]Br/water

A mixture of 3,5-dichloro-4-hydroxy benzoic acid (29a, 0.43g, 2.1 mmol), [hmim]Br (1.5

ml) and water (8 mmol) was irradiated under focused microwave system in parts (200W,

190°C) for 25 min. The reaction mixture was worked up and purified as mentioned in

section 2.7.2.1.1 and 29b was obtained in 31% yield.

2,6-Dichlorophenol (29b)

OH

ClCl

HO

OMe

HO

MeO

OMe


120

White solid, m. p. 67-70°C (lit. m. p 68-69°C) [Mukhopadhyay and Chandalia (1999)], 1H

NMR δ (CDCl3, 300 MHz) 7.29 (2H, d, J=8.05 Hz), 6.86-6.78 (1H, m), 5.92 (1H, s); 13C

NMR δ (CDCl3 75.4 MHz) 148.3, 131.7, 129.3 and 121.5.

2.7.2.4.2 Optimized procedure for decarboxylation of 3,5-dichloro-4-hydroxy benzoic

acid (29a) using combination of [hmim]Br/water and NaHCO3 (Table 6, entry 29)

A mixture of 3,5-dichloro-4-hydroxy benzoic acid (29a, 0.43 g, 2.1 mmol), [hmim]Br (1.5

ml), water (8 mmol) and 20 mol% NaHCO3 (0.42 mmol) was irradiated under focused

microwave system in parts (200W, 190°C) for 20 min. The reaction mixture was worked up

and purified as mentioned in section 2.7.2.1.1 and 29b was obtained in an optimum 61%

yield. The spectral data (1H and 13C NMR) of above obtained 10b matched well with that

obtained in section 2.7.2.4.1.

The above procedure was also followed for decarboxylation of various other aromatic

acids (Table 6, entries 30-40; Table 7, entries 41-45)

4-Nitrotoluene (30b, Table 6)

Light yellow solid, m. p. 50-52°C (lit. m. p 51–54°C) [Bull et. al. (1996)], 1H NMR δ

(CDCl3, 300 MHz) 8.15 (2H, d, J= 8.48 Hz), 7.35 (2H, d, J=8.48 Hz), 2.48 (3H, s); 13C

NMR δ (CDCl3, 75.4 MHz) 146.5, 146.3, 130.1, 123.9 and 21.9.

2-Nitrotoluene (31b, Table 6)

Yellow liquid [Bull et. al. (1996)], 1H NMR δ (CDCl3, 300 MHz) 7.89 (1H, d, J=8.23 Hz),

7.44-7.40 (1H, m), 7.27 (2H, d, J=4.94 Hz), 2.52 (3H, s); 13C NMR δ (CDCl3 75.4 MHz)

149.2, 133.5, 133.0, 132.7, 126.9, 124.6 and 20.4.

CH3

O2N

CH3

NO2


121

3-Chloronitrobenzene (32b, Table 6)

Viscous yellow liquid [Mendonca et al. (2005)], 1H NMR δ (CDCl3, 300 MHz) 8.14 (1H,

s), 8.07 (1H, d, J=8.48 Hz), 7.62 (1H, d, J=8.48 Hz), 7.46-7.41 (1H, m); 13C NMR δ

(CDCl3, 75.4 MHz) 148.8, 135.4, 134.7, 130.4, 123.8 and 121.7.

The compounds 33-36b were detected on GC-MS basis (Table 6, entries 33-36).

Diphenylmethane (37b, Table 6)

Colorless liquid [Kim and Ahn (2003)], 1H NMR δ (CDCl3, 300 MHz) 7.27-7.25 (4H, m),

7.17-7.14 (6H, m), 3.95 (2H, s); 13C NMR δ (CDCl3, 75.4 MHz) 141.1, 129.3, 128.5, 126.1

and 42.0.

The compounds 38-40b were detected on GC-MS basis (Table 6, entries 38-40).

Phenol (41b, Table 7)

Colorless liquid [Dorfner et al. (2003)], 1H NMR δ (CDCl3, 300 MHz) 7.38-7.33 (2H, m),

7.10-7.05 (1H, m), 7.02-6.98 (2H, m), 6.80 (1H, s); 13C NMR δ (CDCl3, 75.4 MHz) 156.0,

130.7, 121.9 and 116.4.

2,6-Dimethoxyphenol (42b, Table 7)

White solid, m. p 52-56°C (lit. m. p. 54-56°C) [Guillen and Ibargoitia (1998)], 1H NMR δ

(CDCl3, 300 MHz) 6.84-6.79 (1H, m), 6.61 (2H, d, J=8.42 Hz), 5.55 (1H, s), 3.92 (6H, s); 13C NMR δ (CDCl3, 75.4 MHz) 147.6, 135.3, 119.4, 105.3 and 56.6.

O2N Cl

HO

HO

OMe

MeO


122

2-Methoxyphenol (43b, Table 7)

Colorless liquid [Dorfner et al. (2003)], 1H NMR δ (CDCl3, 300 MHz) 7.06-7.03 (1H, m),

6.98-6.92 (3H, m), 5.98 (1H, s), 3.90 (3H, s); 13C NMR δ (CDCl3, 75.4 MHz) 147.1, 146.1,

121.9, 120.6, 115.1, 111.3 and 56.3.

2-Hydroxyphenol (44b, Table 7)

White solid [Dorfner et al. (2003)], m. p. 102-103°C (lit. m. p. 105°C), 1H NMR δ

(CD3COCD3, 300 MHz) 7.86 (2H, s), 6.86-6.80 (2H, m), 6.71-6.65 (2H, m); 13C NMR δ

(CD3COCD3 75.4 MHz) 145.4, 120.6 and 116.1.

2.8 References

An, J., Bagnell, L., Cablewski, T., Strauss, C. R. and Trainor, R. W. (1997). Applications

of high-temperature aqueous media for synthetic organic reactions. Journal of

Organic chemistry 62: 2505–2511.

Bassat, A. B., Breinig, S., Crum, G. A., Huang, L., Altenbaugh, A. L. B., Rizzo, N. R.,

Trotman, J., Vannelli, T., Sariaslani, F. S. and Haynie, S. L. (2007). Preparation of 4-

vinylphenol using pHCA decarboxylase in a two-solvent medium. Organic Process

Research Development 11: 278–285.

Baudoin, O. (2007). New approaches for decarboxylative biaryl coupling. Angewandte

Chemie International Edition 46:1373-1375.

Baur, J. A. and Sinclair, D.A. (2006). Therapeutic potential of resveratrol: the in vivo

evidence. Nature Reviews Drug Discovery 5: 493-506.

HO

OMe

HO

HO


123

Becht, J. M. and Drian, C. L. (2008). Biaryl synthesis via decarboxylative Pd-catalyzed

reactions of arenecarboxylic acids and diaryliodonium triflates. Organic Letters 10:

3161-3164.

Bernini, R., Mincione, E., Barontini, M., Provenzano, G. and Setti, L. (2007). Obtaining

4-vinylphenols by decarboxylation of natural 4-hydroxycinnamic acids under

microwave irradiation .Tetrahedron 63: 9663-9667.

Bull, D. J. Fray, M. J., Mackenny, M. C. and Malloy K. A. (1996). Facile decarboxylation

of nitrobenzene acetic acids as a convenient route to alkylnitro benzenes

Synlett: 647-648.

Cao, X., Tsukamoto, T., Seki, T., Tanaka, H., Morimura, S., Cao, L., Mizoshita, T., Ban

H., Toyoda, T., Maeda, H., and Tatematsu, M. (2008). 4-Vinyl-2, 6 dimethoxyphenol

(canolol) suppresses oxidative stress and gastric carcinogenesis in Helicobacter

pylori-infected carcinogen-treated Mongolian gerbils .International Journal of

Cancer 122: 1445-1454.

Cohen, T. and Schambach, R. A. (1970). Copper quinoline decarboxylation.

Journal of the American Chemical Society 92: 3189-3190.

Cornella, J., Lu, P. and Larrosa, I. (2009). Intermolecular decarboxylative direct C-3

arylation of indoles with benzoic acids. Organic Letters 11: 5506–5509.

Crouzet, J., Sakho, M. and Chassagne, D. (1997). In : Barberan, F. A. T., Robins, R.J.

(eds). Phytochemistry of fruit and vegetables. pp 112-120. Oxford University Press,

Oxford.

Dale, W. J. and Hennis, H. E. Substituted styrenes 3. (1958). The synthesis and some

chemical properties of the vinylphenols. Journal of the American Chemical Society

80: 3645-3649.

Dickstein, J. S., Mulrooney , C.A., Brein, E. M. O., Morgan, B.J. and Kozlowiski, M.C.

(2007). Development of a catalytic aromatic decarboxylation reaction. Organic

Letters 9: 2441-2444.


124

Dorfner, R., Ferge, K. T., Zimmermann, A. R. and Yeretzian, C. (2003). Real-time

monitoring of 4-vinylguaiacol, guaiacol, and phenol during coffee roasting by

resonant laser ionization time-of-flight mass spectrometry. Journal of Agriculture and

Food Chemistry 51: 5768–5773.

Gan, T., Liu, R., Yu, P., Zhao, S. and Cook, J. M. (1997). Enantiospecific synthesis of

optically active 6-methoxytryptophan derivatives and total synthesis of tryprostatin

A1, Journal of Organic Chemistry 62: 9298-9304.

Gaukroger, K., Hadfield, J. A., Hepworrth, L.A., Lawrwncen, N. J. and Mc Gown, A.T.

(2001). Novel syntheses of cis and trans isomers of combretastatin A-4. Journal of

Organic Chemistry 66: 8135-8138.

Gooßen, L. J, Deng, G. and Levy, L. M. (2006). Synthesis of biaryls via Catalytic

Decarboxylative Coupling. Science 313: 662-664

Gooßen, L. J., Linder, C., Rodrıguez, N., Lange, P. P. and Fromm, A. (2009). Silver-

catalysed protodecarboxylation of carboxylic acids, Chemical Communications:

7173–7175

Gooßen, L. J., Rodrıguez, N., Melzer, B., Linder, C., Deng, G. and Levy, L. M. (2007).

Biaryl synthesis via Pd-catalyzed decarboxylative coupling of aromatic carboxylates

with aryl halides. Journal of the American Chemical Society 129: 4824-4833.

Gu, Y., Ogawa, C. and Kobayashi, S., (2007). Silica-supported sodium sulfonate with

ionic liquid: a neutral catalyst system for Michael reactions of indoles in water.

Organic Letters 91: 175-178.

Guillen, M. D. and Ibargoitia, M. L. (1998). New components with potential antioxidant

and organoleptic properties, detected for the first time in liquid smoke flavoring

preparations. Journal of Agriculture and Food Chemistry 46: 1276–1285.

Hori, Y., Nagano, Y. and Taniguchi, H. (1981). Decarboxylation of carboxylic acids

using diazabicycloalkenes and, if desired, also a simple copper salt, as the means for


125

decarboxylation. US Patent, 4262157.

Ingemarsson, A. (1998). Slow pyrolysis of spruce and pine samples studied with GC/MS

and GC/FTIR/FID. Chemosphere 36: 2879-2889.

Jefford, C. W., Jaggi, D., Boukovolas, J., Kohmoto, S. and Bernardinelli, G. (1984).

The reaction of singlet oxygen with 1, 3-dimethylindole in the presence of aldehydes–

formation of 1, 2, 4-Trioxanes. Helvetica Chemica Acta 67: 1104-1111.

Jensen, M. T., Cox, R. P and Jenson, B. B. (1995). 3-Methylindole (Skatole ) and indole

introduction by mixed populations of pig feacal bacteria. Applied Environmental

Microbiology 61: 3180-3184.

Jones, G. B. and Chapman B. J. (1993). Decarboxylation of indole-2-carboxylic acids:

improved procedures. Journal of Organic Chemistry 58: 5558-5559.

Kim, D. S. and Ahn, W. S. (2003). Diphenylmethane synthesis using ionic liquids as

lewis acid catalyst .Korean Journal of Chemical Engineering 20:39-43.

Kumar, V., Sharma, A., Sharma, A. and Sinha, A. K. (2007). Remarkable synergism in

methylimidazole-promoted decarboxylation of substituted cinnamic acid derivatives

in basic water medium under microwave irradiation: a clean synthesis of

hydroxylated (E)-stilbenes. Tetrahedron 63: 7640-7646.

Liao, M. C., Duan, X. H. and Liang, Y. M. (2005). Ionic liquid/water as a recyclable

medium for Tsuji-Trost reaction assisted by microwave. Tetrahedron Letters 46:

3469-3472.

Likhtenshtein, G. (2009). Stilbenes: Applications in Chemistry, Life Sciences and

Materials. Wiley-VCH. Weinheim.

Lisitsyn, A. S. (2007). 2,2 '-Bipyridine and related N-chelants as very effective promoters

for Cu catalysts in the decarboxylation. Applied Catalysis A General 332: 166-170.


126

Liu, A. and Zhang, H. (2006). Transition metal-catalyzed nonoxidative decarboxylation

reactions. Biochemistry 45: 10407-10411.

Locatelli, G. A., Savio, M., Forti, L., Shevelev, I., Ramadan, N. K., Stevala, L. A.,

Vanini, V., Ubscher, U. H., Spadari, S. and Maga, G. (2005). Inhibition of

mammalian DNA polymerases by resveratrol: mechanism and structural

determinants. Biochemical Journal 389: 259-268.

Lukin, K., Hsu, M. C., Fernando, D. and Leanna, M. R. (2006). New practical synthesis

of indazoles via condensation of o-fluorobenzaldehydes and their o-methyloximes

with hydrazine. Journal of Organic Chemistry 71: 8166-8172.

Lu, P., Sanchez, C., Cornella, J. and Larrosa, I. (2009). Silver-catalyzed

protodecarboxylation of heteroaromatic carboxylic acids. Organic Letters 11: 5710-

5713.

Maehara, A., Tsurugi, H., Satoh, T. and Miura, M. (2008). Regioselective C-H

functionalization directed by a removable carboxyl group: palladium-catalyzed

vinylation at the unusual position of indole and related heteroaromatic rings. Organic

Letters 10: 1159-1162.

Magro, A. A. N., Eastham, G. R. and Hamilton, D. J. C. (2009). Preparation of phenolic

compounds by decarboxylation of hydroxybenzoic acids or desulfonation of

hydroxybenzenesulfonic acid, catalysed by electron rich palladium complexes, Dalton

Transactions: 4683-4688.

Matsubara, S., Yokota, Y. and Oshima, K. (2004). Palladium-catalyzed decarboxylation

and decarbonylation under hydrothermal conditions: Decarboxylative deuteration.

Organic Letters 6: 2071-2073.

Meciarova, M., Toma, S. and Kotrusz, P. (2007). Michael additions of methylene active

compounds to chalcone in ionic liquids without any catalyst: The peculiar properties

of ionic liquids. Chemistry- A European Journal 13: 1268-1272.


127

Mendonca, G. F., Magalhaes, R. R. and Mattos, M. C. S. D. (2005). Trichloroisocyanuric

acid in H2SO4: An efficient superelectrophilic reagent for chlorination of isatin and

benzene derivatives. Journal of Brazilian Chemical Society 16: 695-698.

Moseley, J. D. and Gilday, J. P. (2006). The mercury-mediated decarboxylation (Pesci

reaction) of naphthoic anhydrides investigated by microwave synthesis. Tetrahedron

62: 4690-4697.

Mukhopadhyay, S. and Chandalia, S. B. (1999). Oxidative chlorination, desulphonation,

or decarboxylation to synthesize pharmaceutical intermediates: 2, 6-dichlorotoluene,

2, 6-dichloroaniline, and 2, 6-dichlorophenol.Organic Process Research and

Development 3: 10-16.

Myers, A. G., Tanka, D. and Mannion M. R. (2002). Development of a decarboxylative

palladation reaction and its use in a Heck-type olefination of arene carboxylates.

Journal of the American Chemical Society 124: 11250-11251.

Nelson D. L. and Cox, M. M. (2009). Lehninger principles of biochemistry, 5th edition W

H Freeman & Co., New York.

Nockemann, P., Binnemans, K. and Driesen, K. (2005).Purification of imidazolium ionic

liquids for spectroscopic applications. Chemical Physics Letters 415: 131-136.

Nomura, E., Hosoda, A., Mori, H. and Taniguchi, H. (2005). Rapid base-catalyzed

decarboxylation and amide-forming reaction of substituted cinnamic acids via

microwave heating. Green Chemistry 7: 863-866.

Oswald, M. F., Parsons, A. F., Yang, W. and Bowden, M. (2005). Combined

dealkoxycarbonylation and lactonisation of unsaturated malonates in ionic liquids.

Tetrahedron Letters 46: 8087-8089.

Parvulescu, V. I. and Hardacre, C. (2007). Catalysis in ionic liquids. Chemical Reviews

107: 2615-2665.

Patai, S. (1969). The Chemistry of Carboxylic Acids and Esters, Wiley-VCH, New York.


128

Payette, J. N. and Yamamoto, H. (2008). Nitrosobenzene-mediated C-C bond cleavage

reactions and spectral observation of an oxazetidin-4-one Ring System, Journal of the

American Chemical Society 130: 12276–12278.

Reddy, B. M. and Ganesh, I. (2000). Vapour phase synthesis of quinoline from aniline

and glycerol over mixed oxide catalysts. Journal of Molecular Catalysis A- Chemical

151: 289-293.

Selvakumar, N. and Rajulu, G. G. (2004). Efficient total syntheses of phytoalexin and

(+/-)-paniculidine B and C based on the novel methodology for the preparation of 1-

methoxyindoles. Journal of Organic Chemistry 69: 4429-4432.

Sheldon, R. A. (2005). Green solvents for sustainable organic synthesis: State of the

art. Green Chemistry 7: 267–278.

Shepard, A. F., Winslow, N. R. and Johnson, J. R. (1930). The simple halogen derivatives

of furan. Journal of the American Chemical Society 52: 2083-2090.

Shin, W. S., Padias, A. B. and Hall, H. K. (2001). Homopolymerization and [2+4]/[3+2]

cycloaddition in the reaction of nitroethylene with vinyl ethers. Journal of Polymer

Science: Polymer Chemistry 39: 1886-1891.

Sinha, A. K., Sharma, A. and Joshi, B. P. (2007). One-pot two-step synthesis of 4-

vinylphenols from 4-hydroxy substituted benzaldehydes under microwave irradiation:

a new perspective on the classical Knoevenagel-Doebner reaction. Tetrahedron 63:

960-965.

Sinha, A. K., Kumar, V., Sharma, A., Sharma, A. and Kumar, R. (2007). Unusual, mild

and convenient one-pot two-step access to (E) stilbenes from hydroxy-substituted

benzaldehydes and phenylacetic acids under microwave activation: a new facet of the

classical Perkin reaction. Tetrahedron 63: 11070-11077.

Solladie, G., Jacope, Y. P. and Maignan, J. (2003). A re-investigation of resveratrol

synthesis by Perkins reaction. Application to the synthesis of aryl cinnamic acids.

Tetrahedron 59: 3315–3321.


129

Takemoto, M. and Achiwa, K. (2001). Synthesis of styrenes through the biocatalytic

decarboxylation of trans-cinnamic acids by plant cell cultures. Chemical and

Pharmaceutical Bulletin 49: 639-641.

Tanaka, D. and Myers, A. G. (2004). Heck-Type arylation of 2-Cycloalken-1-ones with

arylpalladium intermediates formed by decarboxylative palladation and by aryl iodide

insertion. Organic Letters 6: 433–436.

Wahelgren, U., Tsushima, S. and Grenthe, I. (2006). The Journal of Physical Chemistry B

110: 9262-9269.

Walling, C. and Wolfstrin, K. B. (1947). Substituted styrenes. I. The decarboxylation of

substituted cinnamic acids. Journal of the American Chemical Society 69: 852-854.

Wasserscheid, P. and Welton, T. (eds). (2008). Ionic liquids in synthesis. Wiley-VCH.

Weinheim.

Welton, T.(1999). Room temperature ionic liquids. Solvents for synthesis and catalysis.

Chemical Reviews 99: 2071-2083.

Wong, F. M. and Wu, W. (2006). Accelerated decarboxylation of 1, 3-dimethylorotic

acid in ionic liquid. Bioorganic Chemistry 34: 99-104.

Xu, M. and Wan, P. (2000). Efficient photodecarboxylation of aroyl-substituted

phenylacetic acids in aqueous solution: a general photochemical reaction. Chemical

Communications: 2147-2148.

Zhao, Y. B., Yan, Z. Y. and Liang, Y. M., (2006). Efficient synthesis of 1, 4-disubstituted

1,2,3-triazoles in ionic liquid/water system. Tetrahedron Letters 47: 1545-1549.


130

1H NMR (in CDCl3) spectrum of 1,3-dimethyl indole (8b, Table 3)

13C NMR (in CDCl3) spectrum of 1,3-dimethyl indole (8b, Table 3)

3456789 ppm

200 180 160 140 120 100 80 60 40 20 ppm

N

CH3

CH3


131

1H NMR (in CDCl3) spectrum of 3,5-dimethoxy-4-hydroxy styrene (10b, Table 4)

13C NMR (in CDCl3) spectrum of 3,5-dimethoxy-4-hydroxy styrene (10b, Table 4)

3.03.54.04.55.05.56.06.57.07.5 ppm

6080100120140160180 ppm

HO

OCH3

H3CO


132

1H NMR (in MeOD) spectrum of 4-hydroxy stilbene (22b, Table 5)

13C NMR (in MeOD) spectrum of 4-hydroxy stilbene (22b, Table 5)

45678 ppm

180 160 140 120 100 80 60 40 20 ppm

HO


133

OH

ClCl

1H NMR (in CDCl3) spectrum of 2,5-dichlorophenol (29b, Table 6)

13C NMR (in CDCl3) spectrum of 2,5-dichlorophenol (29b, Table 6)

2.53.03.54.04.55.05.56.06.57.07.58.0 ppm

5060708090100110120130140150160170 ppm

Ionic Liquid assisted metal free decarboxylation of...

Documents

Transcript of Ionic Liquid assisted metal free decarboxylation of...