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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
Ionic Liquid assisted …… Chapter 2
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
Ionic Liquid assisted …… Chapter 2
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.
Ionic Liquid assisted …… Chapter 2
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
Ionic Liquid assisted …… Chapter 2
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
Ionic Liquid assisted …… Chapter 2
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
Ionic Liquid assisted …… Chapter 2
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
Ionic Liquid assisted …… Chapter 2
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
Ionic Liquid assisted …… Chapter 2
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
Ionic Liquid assisted …… Chapter 2
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,
Ionic Liquid assisted …… Chapter 2
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
Ionic Liquid assisted …… Chapter 2
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
Ionic Liquid assisted …… Chapter 2
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.
Ionic Liquid assisted …… Chapter 2
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
Ionic Liquid assisted …… Chapter 2
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
Ionic Liquid assisted …… Chapter 2
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
Ionic Liquid assisted …… Chapter 2
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.
Ionic Liquid assisted …… Chapter 2
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
Ionic Liquid assisted …… Chapter 2
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.
Ionic Liquid assisted …… Chapter 2
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++
Ionic Liquid assisted …… Chapter 2
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
Ionic Liquid assisted …… Chapter 2
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
Ionic Liquid assisted …… Chapter 2
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
Ionic Liquid assisted …… Chapter 2
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
Ionic Liquid assisted …… Chapter 2
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
Ionic Liquid assisted …… Chapter 2
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
Ionic Liquid assisted …… Chapter 2
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
Ionic Liquid assisted …… Chapter 2
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
Ionic Liquid assisted …… Chapter 2
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
Ionic Liquid assisted …… Chapter 2
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
Ionic Liquid assisted …… Chapter 2
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
Ionic Liquid assisted …… Chapter 2
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.
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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
Ionic Liquid assisted …… Chapter 2
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
Ionic Liquid assisted …… Chapter 2
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
Ionic Liquid assisted …… Chapter 2
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