N-heterocyclic carbene-mediated hydroacylation-Sonogashira/Heck/Suzuki coupling in a single pot: A new cascade reaction

Article abstract of DOI:10.1039/c2ob06950d

A dually NHC-catalyzed reaction cascade comprising an initial hydroacylation of an activated ketone and subsequent Sonogashira/Heck/Suzuki coupling in the same pot is reported. The reaction mechanism and scope of the methodology is presented.

Full text of DOI:10.1039/c2ob06950d

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PAPER
N-heterocyclic carbene-mediated hydroacylation–Sonogashira/Heck/Suzuki
coupling in a single pot: A new cascade reaction†
M. Sreenivasulu,a,b K. Siva Kumar,a P. Rajender Kumar,a K. B. Chandrasekharb and Manojit Pal*c
Received 19th November 2011, Accepted 23rd November 2011
DOI: 10.1039/c2ob06950d
A dually NHC-catalyzed reaction cascade comprising an initial hydroacylation of an activated ketone and
subsequent Sonogashira/Heck/Suzuki coupling in the same pot is reported. The reaction mechanism and
scope of the methodology is presented.
Introduction
Although hydroacylation of alkenes using aldehydes as acyl
donors is common in the literature1, an analogous process invol-
ving aldehydes and carbonyl groups was not explored as a new
synthetic tool until 2006.2 Thus hydroacylation of α-keto esters
(2) with aldehydes (1) was carried out using N-heterocyclic
carbenes (NHCs) as organocatalysts and the methodology was
further improved by using activated ketones as substrates.3 Being
Scheme 1 NHC-mediated one-pot hydroacylation–Sonogashira/Heck/
Suzuki coupling.
environmentally benign and atom economical chemical trans-
formations these methodologies are attractive and of particular
interest. Palladium catalyzed C–C bond forming reactions such
Results and discussion
as Sonogashira, Heck or Suzuki reactions on the other hand have
While
1,3-bis(2,4,6-trimethylphenyl)imidazolium
chloride
emerged as powerful tools in modern organic synthesis4
especially in the synthesis of natural products, bioactive mol-
ecules and organic material. The use of NHCs as alternatives to
phosphine ligands in these cross-coupling reactions5–7 have been
explored and studied with the major focus on the Suzuki reac-
tion.8,9 Avariety of bulky NHC ligands have been reported to be
effective for efficient Suzuki coupling involving chloroarenes at
elevated and room temperature.10–14 Intriguingly, the combination
of NHC-mediated hydroacylation and subsequent Pd-catalyzed
cross-coupling reactions in the same pot is not common in the
literature. Herein, we report first NHC-organocatalyzed one-pot
hydroacylation–Sonogashira/Heck/Suzuki coupling under mild
conditions (Scheme 1). We envisioned that in addition to partici-
pating in the usual hydroacylation process the NHC ligand
would facilitate the subsequent Pd-catalyzed cross-coupling reac-
tions of the iodo derivative generated in situ in the same pot.
(IMes·HCl) in combination with triethylamine was identified as
an efficient source of NHC in our previous study3 it was
however not clear if the same combination would be effective
for subsequent Pd-catalyzed C–C bond forming reactions in the
same pot. Our initial objective therefore was to identify appropri-
ate N-heterocyclic salts suitable for one-pot hydroacylation–
Sonogashira/Heck/Suzuki coupling under mild conditions. We
choose to assess hydroacylation–Sonogashira coupling initially
for this purpose. Accordingly, a few N-heterocyclic salts based
on five-membered rings containing two hetero atoms (e.g. A–D,
Fig. 1) were examined for their effect on the reaction of 4-iodo-
benzaldehyde (1a), methyl-2-(4-bromophenyl)-2-oxoacetate (2a)
and phenyl acetylene (3a) in the presence of Pd(OAc)2, CuI,
Et3N in THF (Table 1).
aCustom Pharmaceutical Services, Dr Reddy’s Laboratories Limited,
Bollaram Road, Miyapur, Hyderabad, 500 049, India
bDepartment of Chemistry, Jawaharlal Nehru Technological University
of Anantapur, Anantapur, 515 002 Andhra Pradesh, India
cInstitute of Life Sciences, University of Hyderabad Campus,
Gachibowli, Hyderabad, 500 046 Andhra Pradesh, India.
E-mail: manojitpal@rediffmail.com
†Electronic supplementary information (ESI) available: 1H and 13C
NMR, MS and HRMS data of all new compounds. See DOI: 10.1039/
c2ob06950d
Fig. 1 N-heterocyclic salts as source of NHC.
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Table 1 NHC-mediated hydroacylation–Sonogashira coupling of 1a
with 2aa
Table 2 NHC-mediated hydroacylation–Sonogashira couplinga
Yield (%)b
Ketone (2)
Entry X & Y =
Alkynes (3)
R =
Products
(4)
Time (h);
yieldb (%)
Entry
NHC ligands (mol%)
Time (h)
1.
2.
3.
4.
5.
6.
A (15)
A (10)
A (0.5)
B (10)
C (10)
D (10)
5
5
10
10
15
15
58
61
12
38
16
22
1.
2.
3.
H; Br 2a
2a
2a
C6H5-3a
CH3(CH2)5-3b
4a
4b
4c
4; 61
5; 68
6;58
3c
4.
2a
4d
4; 71
a The reaction was carried out using 1a (0.43 mmol), 2a (0.646 mmol),
3a (0.646 mmol), NHC ligand (A–D), Pd(OAc)2 (0.022 mmol), CuI
(0.043 mmol) and Et3N (1.08 mmol) in THF (5 mL) at 28–32 °C under
nitrogen. b Isolated yield.
3d
3a
5.
6.
7.
8.
Cl; H 2b
2b
2b
2b
2b
2b
2b
2b
2b
4e
4f
4; 66
5; 58
4; 78
4; 75
5; 61
4; 62
4; 62
4; 70
6; 59
HOCH2CH2-3e
ClCH2(CH2)2-3f 4g
CH3(CH2)3-3g 4h
CH3(OH)CH-3h 4i
3c
3d
9.
10.
11.
12.
13.
4j
4k
4l
As evident from Table 1 the sterically encumbered 1,3-bis
(2,4,6-trimethylphenyl)imidazolium chloride (A) facilitated the
hydroacylation–Sonogashira coupling to afford the expected
product 4a (entry 1, Table 1). While the reaction was completed
within 5 h when 15 mol% of A was used it was observed that a
lower quantity of A i.e. 10 mol% was also effective providing
the same yield of 4a (entry 2, Table 1). However, further
decrease of A decreased the product yield substantially (entry 3,
Table 1). The other salts e.g. 1,3-dimethyl-1H-imidazol-3-ium
iodide (B) afforded 4a in low yield (entry 4, Table 1) whereas
thiazolium salts C and D provided 4a in poor yields even after
15 h (entries 5 & 6, Table 1). In all these reactions 0.022 mmol
of Pd(OAc)2 in combination with CuI (0.043 mmol) was used
for the alkynylation step. The yield of 4a was decreased when
0.011 mmol of Pd(OAc)2 was used and 4a was not formed in the
absence of either of Pd(OAc)2 or CuI indicating the need of Pd–
Cu catalysts to facilitate the alkynylation step. In a separate study
the hydroacylated product i.e. 1-(4-bromophenyl)-2-methoxy-2-
oxoethyl-4-iodobenzoate isolated from the reaction of 1a and 2a
was treated with 3a in the presence of Pd(OAc)2, CuI, Et3N in
THF at 28–32 °C when formation of 4a was not observed even
after 12 h. The formation of 4a was also not observed when the
reaction was carried out at refluxing temperature (65–67 °C)
suggesting the additional role played by the NHC in the
Sonogashira step.
2-NO2C6H4-3i
4m
3j
14.
2b
C2H5CH(OH)-
3k
CH3(CH2)4-3l
3b
4n
4; 63
15.
16.
2b
2b
4o
4p
4; 79
4; 75
a All the reactions were carried out using 1a (0.43 mmol),
(0.646 mmol), 3 (0.646 mmol), NHC ligand A (0.044 mmol), Pd(OAc)2
(0.022 mmol), CuI (0.043 mmol) and Et3N (1.08 mmol) in THF (5 mL)
at 28–32 °C under nitrogen. b Isolated yield.
2
Scheme 2 The use of o- and m-iodo benzaldehyde (1b and 1c) in
NHC-mediated hydroacylation–Sonogashira coupling.
Having established the optimum reaction conditions for the
NHC-mediated hydroacylation–Sonogashira coupling we then
examined the further scope and generality of this process.
benzaldehyde (1b and 1c, Scheme 2) in the present reaction and
the corresponding products were isolated in good yields.
Thus a range of terminal alkynes (3) possessing different sub-
stituents were employed which provided the desired alkyne
derivatives (4) in good yields (Table 2). The presence of a aryl,
alkyl, cycloalkyl, pyridyl, hydroxyalkyl, chloroalkyl or naphthyl
group in the alkyne 3 was well tolerated in the present one-pot
reaction. The presence of bromo or chloro on the aromatic ring
of 2 was also tolerated. In comparison to the earlier report8
the present Sonogashira coupling proceeded under milder
conditions. We also examined the use of o- and m-iodo
Encouraged by these results we then examined the posibility
of conducting hydroacylation–Heck couplings in a single pot.
Initially, a reaction was carried out using 1a, 2a, and methyl
acrylate (R′ = CO2Me, 5a) in the presence of the Et3N, NHC
ligand A, Pd(OAc)2 in THF at 28–32 °C. The reaction proceeded
smoothly to give the corresponding product 6a in 65% yield.
Thus the use of other alkenes was examined and the results are
summarised in Table 3. All these reactions required 10–15 h for
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Table 3 NHC-mediated hydroacylation–Heck couplinga
Table 4 NHC-mediated hydroacylation–Suzuki couplinga
Boronic acids (7)
Entry Ketone (2) Ar =
Time (h);
Alkenes (5)
Entry Ketone (2) R′ =
Time (h);
Products (6) yieldb (%)
Products (8) yieldb (%)
1.
2a
8a
8; 66
6; 69
1.
2.
3.
4.
5.
6.
2a
2a
2a
2b
2b
2b
CH3OCO-5a
C2H5OCO-5b
t-BuOCO-5c
5a
5b
5c
6a
6b
6c
6d
6e
6f
15; 65
14; 71
14; 64
14; 70
10; 65
12; 74
7a
2.
2a
8b
7b
7a
a All the reactions were carried out using 1a (0.43 mmol),
(0.646 mmol), 5 (1.72 mmol), NHC ligand A (0.044 mmol), Pd(OAc)2
(0.022 mmol), and Et3N (1.08 mmol) in THF (5 mL) at 28–32 °C under
nitrogen. b Isolated yield.
2
3.
4.
2b
2b
8c
8d
8; 66
7; 69
7cc
5.
2b
8e
7; 71
7d
a All the reactions were carried out using 1a (0.43 mmol),
2
(0.646 mmol), 7 (0.646 mmol), NHC ligand A (0.044 mmol), Pd(OAc)2
(0.022 mmol) and Et3N (1.08 mmol) in THF (5 mL) at 28–32 °C under
nitrogen. b Isolated yield. c The boronic acid 7c was added after 3h.
Scheme 3 The use of 1b and 1c in NHC-mediated hydroacylation–
Heck coupling.
completion but remarkably did not require any heating to
provide the desired alkene derivatives 6. Both the benzaldehyde
1b and 1c participated well in the present reaction (Scheme 3).
1
Based on H NMR data all the alkenes prepared were character-
ized as the E-isomer (J = 15.6–16 Hz).†
We also examined the possibility of conducting hydroacyla-
tion–Suzuki coupling in a single pot and the results are presented
in Table 4. Once again the process showed remarkable selectivity
towards iodo over bromo and chloro, though NHC-mediated
Suzuki reactions involving chloro or bromoarenes are known in
the literature. While a number of functional groups present in the
boronic acid 7 were tolerated the reactant 7c however was added
Scheme 5 Generation of Pd(II)-NHC complex X.
to the reaction mixture 3 h later (entry 4, Table 4) to avoid its
participation in the initial hydroacylation process. Like earlier
reactions both the benzaldehyde 1b and 1c participated in the
present process to give the desired products (Scheme 4).
To understand the role of NHC both in the Heck and Suzuki
steps separate experiments were carried out in absence ligand A.
Thus the hydroacylated product isolated from the reaction of 1a
and 2a was treated separately with alkene 5a, Pd(OAc)2 and
Et3N in THF at 28–32 °C under nitrogen. No formation of
desired product was observed after 15 h and only trace amount
of the product 6a was detected after 48h. Similarly, the same
hydroacylated product was treated with boronic acid 7a,
Pd(OAc)2 and Et3N in THF at 28–32 °C under nitrogen. While
the reaction proceeded in this case only 30% conversion was
observed after 8 h. All these observations clearly suggest that the
ligand A played a key role in step 2 of both the hydroacylation–
Heck and hydroacylation–Suzuki reactions. Based on these
Scheme 4 The use of 1b and 1c in NHC-mediated hydroacylation–
Suzuki couplings.
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observations and the results presented in Table 1 a plausible
mechanism can be proposed for the present one-pot hydroacyla-
tion–coupling reaction (Scheme 2). It is known that appropriate
imidazolium salts react with Pd(OAc)2 to generate the corre-
sponding Pd(II)-NHC complexes12 depending on the presence or
absence of a base. However, it was still not clear if a diligated
Pd-complex catalyzed the cross-coupling reactions.15 Addition-
ally, a monoligated Pd-complex generated from Pd(OAc)2 has
been used for the Suzuki reaction of aryl chlorides.16 In the
present reaction the ligand A (half equiv) initially participates in
the organocatalyzed addition of aldehyde 1a, converted to acyl
anion equivalent by umpolung along with the regioselective
reduction of the keto group of 2 and then acylation of the
alcohol formed along with the regeneration of the NHC.2,3 The
regenerated NHC then reenters into the catalytic cycle of hydroa-
cylation process.
The remaining half equivalent of A reacts with Pd(OAc)2 to
form the complex X (Scheme 5) that actually catalyzes the sub-
sequent C–C bond forming reaction. Thus the iodoarene deriva-
tive generated in situ as a result of the hydroacylation process
undergoes Sonogashira, Heck or Suzuki coupling depending on
the reactants and reaction conditions employed. Various studies
have suggested that steric bulk and the electronic nature of the
NHC ligand play a key role in the overall performance of the Pd-
NHC catalyst in the Suzuki reaction.9 The reported mechanism
for Pd-catalyzed cross-coupling reactions involve three important
steps: oxidative addition, transmetallation and reductive elimin-
ation. While the electronic nature of the ligand may not be vital
for facile oxidative insertion into the relatively labile C–I bond
(towards Pd-catalyst) the steric bulk however seemed to aid the
reductive elimination of the coupled product along with regener-
ation of the catalyst. Since the ligand possessing too much steric
bulk can affect the rate of oxidative addition adversely, a balance
between steric and electronic factors have been suggested to
achieve optimum activity of the Pd-NHC catalyst generated
in situ. The Pd center of complex X seemed to have a balanced
electronic character and steric crowding necessary for facile oxi-
dative addition as well as reductive elimination.
4-iodobenzaldehyde as an acyl donor that allowed subsequent
coupling reactions in the same pot facilitated by the NHC ligand.
With its multiple bond-forming ability the present cascade reac-
tion represents an attractive option for the rapid construction of
compound library based on small organic molecules.
Experimental
General methods
Unless stated otherwise, reactions were performed under nitro-
gen atmosphere using oven dried glassware. Reactions were
monitored by thin layer chromatography (TLC) on silica gel
plates (60 F254), visualizing with ultraviolet light or iodine
spray. Flash chromatography was performed on silica gel
(230–400 mesh) using distilled hexane, ethyl acetate and THF.
1H NMR and 13C NMR spectra were determined in DMSO-d6
or CD3OD solution by using 400 and 100 (or 50) MHz spec-
trometers, respectively. Proton chemical shifts (δ) are relative to
tetramethylsilane (TMS, δ = 0.00) as internal standard and
expressed in ppm. Spin multiplicities are given as s (singlet), d
(doublet), t (triplet) and m (multiplet) as well as b (broad). Coup-
ling constants (J) are given in Hertz. Infrared spectra were
recorded on a FT-IR spectrometer. Melting points were deter-
mined using melting point apparatus and are uncorrected. MS
spectra were obtained on a mass spectrometer. High-resolution
mass spectra (HRMS) were recorded using electron ionization
(EI) mass spectrometry. The ketones i.e. methyl-2-(2-chlorophe-
nyl)-2-oxoacetate and methyl 2-(4-bromophenyl)-2-oxoacetate
were prepared according to known procedures.22 The 4-iodo ben-
zaldehyde, all alkynes and alkenes, palladium(II)acetate, boronic
acids and imidazolium salt are purchased and used directly.
A typical procedure for one-pot NHC mediated hydroacylation
and Sonogashira reactions
To a mixture of imidazolium salt A (14.8 mg, 0.044 mmol) and
4-iodobenzaldehyde (100 mg, 0.43 mmol) in THF (5.0 mL) tri-
ethylamine (109 mg, 1.08 mmol), methyl 2-(4-bromophenyl)-2-
oxoacetate (157.1 mg, 0.646 mmol), palladium(II)acetate
(4.84 mg, 0.022 mmol), copper iodide (8.2 mg, 0.043 mmol)
were added, followed by phenyl acetylene (66.0 mg,
0.646 mmol) under a nitrogen atmosphere. The mixture was then
stirred at 28–32 °C for 4 h (monitored by TLC). After com-
pletion of the reaction the mixture was concentrated under
vacuum and the residue was purified by flash chromatography on
silica gel (230–400 mesh) using 10–20% EtOAc-hexane.
Overall, the present single step method i.e. hydroacylation–
Sonogashira/Heck/Suzuki coupling in a single pot provided a
series of O-acyl derivatives of analogues of mandelic acid ester.
Notably mendelic acid has been used as an antibacterial agent
particularly in the treatment of urinary tract infections.17 4-Sub-
stituted benzoic acids on the other hand have been explored for
their inhibitory effect on the biosynthesis of fatty acids and
sterols.18 Due to our long standing interest in bioactive mol-
ecules19,20 we thought that combining mandelic acid or its ana-
logues with a variety of 4-substituted benzoic acids could
provide a library of small molecules of potential pharmacological
significance. The diversity based 2-aryloxy esters21 presented
here therefore may have medicinal value.
1-(4-Bromophenyl)-2-methoxy-2-oxoethyl-4-(phenylethynyl)
benzoate (4a)
This compound was purified by using 10% EtOAc/hexane to
give the title compound (118.1 mg) as an off white solid; mp
(DSC) 122.7 °C; Rf = (1 : 3 EtOAc/hexane); IR (cm−1, KBr)
2950, 2214, 1755, 1716, 1260, 763; 1H NMR (400 MHz,
DMSO-d6): δ 8.07 (2H, d, J = 8.0 Hz, C6H4), 7.75 (2H, d, J =
8.0 Hz, C6H4), 7.70 (2H, d, J = 8.4 Hz, p-BrC6H4),7-62-7.60
(2H, m, C6H5), 7.59 (2H, d, J = 8.4 Hz, p-BrC6H4), 7.47–7.45
Conclusions
In conclusion, 1,3-bis(2,4,6-trimethylphenyl)imidazolium chlor-
ide has been identified as a single NHC ligand for facile one-pot
hydroacylation–Sonogashira/Heck/Suzuki coupling under mild
reaction conditions. The reaction involved the use of 2-, 3- or
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(3H, m, C6H5), 6.29 (1H, s, CH), 3.70 (3H, s, OCH3); 13C NMR
(100 MHz, DMSO-d6): δ 52.7, 73.9, 88.3, 92.7, 121.5, 122.8,
127.7, 128.1, 128.8 (2C), 129.4 (2C), 129.7, 129.8 (2C), 131.6
(2C), 131.8, 131.9 (2C), 133.0, 164.3, 168.6; mass (ES) m/z
449.1 (M + 1); HRMS (ESI) calculated for C24H18O4Br
(M + H]+ 449.0447; found 449.0388.
1-(2-Chlorophenyl)-2-methoxy-2-oxoethyl-4-(phenylethynyl)
benzoate (4e)
This compound was purified by using 10% EtOAc/hexane to
give the title compound (115.2 mg) as an off white solid; mp
(DSC) 102.09 °C; Rf 0.63(1 : 3 EtOAc/hexane); IR (film) 2218,
1755, 1716, 1260, 763 cm−1; 1H NMR (400 MHz, DMSO-d6): δ
8.05 (2H, d, J = 7.60 Hz, C6H4), 7.74 (2H, d, J = 7.60 Hz,
C6H4), 7.68 (2H, d, J = 7.6, O-ClC6H4), 7.60–7.62 (2H, m,
O-ClC6H4), 7.50–7.53 (5H, m, C6H5), 6.63 (1H, s, CH), 3.74
(3H, s, OCH3); 13C NMR (50 MHz, DMSO-d6): δ 52.9, 71.4,
121.5 (2C), 127.9 (2C), 128.8 (2C), 129.3 (2C), 129.7 (2C),
130.0 (2C), 130.2 (2C), 131.5 (2C), 131.8 (2C), 133.0 (2C),
164.1, 167.9; mass (ES) m/z 405.20 (M + 1); HRMS (ESI) cal-
culated for C24H18O4Cl[M + H]+ 405.0885; found 405.0894.
1-(4-Bromophenyl)-2-methoxy-2-oxoethyl-4-(oct-1-yn-1-yl)
benzoate (4b)
This compound was purified by using 10% EtOAc/hexane to
give the title compound (134.0 mg) as light yellow colour oil; Rf
= (1 : 3 EtOAc/hexane); IR (cm−1, KBr) 2954, 2226, 1760,
1
1727, 1255, 766; H NMR (400 MHz, DMSO-d6): δ 7.99 (2H,
d, J = 8.8 Hz, C6H4), 7.69 (2H, d, J = 8.4 Hz, C6H4), 7.57–7.53
(4H, m, p-BrC6H4), 6.27 (1H, s, CH), 3.69 (3H, s, OCH3);
2.49–2.46 (2H, t, J = 7.6 Hz), 1.57–1.52 (2H, m, CH2),
1.45–1.41 (2H, m, CH2), 1.39–1.23 (4H, m, CH2), 0.89–.85
(3H, m, CH3); 13C NMR (100 MHz, DMSO-d6): δ 13.8, 18.7,
21.9, 27.8, 27.9, 30.7, 52.7, 73.7, 79.8, 95.0, 122.7, 127.3,
128.9, 129.6 (2C), 129.8 (2C), 131.6 (2C), 131.9 (2C), 133.0,
164.4, 168.6. Mass (ES) m/z 457.2 (M + 1); HRMS (ESI) calcu-
lated for C24H26O4Br[M +H]+ 457.1023; found 457.1014.
1-(2-Chlorophenyl)-2-methoxy-2-oxoethyl-4-(4-hydroxybut-1-yn-
1-yl) benzoate (4f)
This compound was purified by using 15% EtOAc/hexane to
give the title compound (93.1 mg) as a light yellow oil; Rf 0.21
(1 : 3 EtOAc/hexane); IR (film) 3420, 2954, 2233, 1732, 1255,
1
766 cm−1; H NMR (400 MHz, DMSO-d6): δ 7.97 (2H, d, J =
8.4 Hz, C6H4), 7.59–7.64 (2H, m, O-ClC6H4c), 7.57 (2H, d, J =
8.4 Hz, C6H4), 7.46–7.50 (2H, m, O-ClC6H4), 6.60 (1H, s, CH),
5.75 (1H, b, OH), 3.73 (3H, s, OCH3), 3.61 (2H, m, CH2), 2.61
(2H, t, J = 6.8 Hz, CH2); 13C NMR (100 MHz, DMSO-d6): δ
23.4, 53.0, 59.5, 71.4, 80.4, 93.1, 127.4, 128.0, 128.9, 129.7
(2C), 130.1, 130.2 (2C), 131.4, 131.7, 131.9, 133.2, 164.3,
168.1; mass (ES) m/z 390.3 (M + 18); HRMS (ESI) calculated
for C20H18O5Cl[M + H]+ 373.0839; found 373.0843.
1-(4-Bromophenyl)-2-methoxy-2-oxoethyl-4-
(1-hydroxycyclohexyl)ethynyl) benzoate (4c)
This compound was purified by using 10% EtOAc/hexane to
give the title compound (117.5 mg) as an off white solid; mp
(DSC) 137.2 °C; Rf 0.37 (1 : 3 EtOAc/hexane); IR (cm−1, KBr)
1
3517, 2933, 2222, 1718, 1695, 1303, 754; H NMR (400 MHz,
DMSO-d6): δ 8.01 (2H, d, J = 8.8 Hz, C6H4), 7.70 (2H, d, J =
8.4 Hz, C6H4), 7.58–7.55 (4H, m, p-BrC6H4), 6.28(1H, s, CH),
5.55 (1H, s, OH), 3.69 (3H, s, OCH3), 1.8–1.23 (10H, m, CH2
1-(2-Chlorophenyl)-2-methoxy-2-oxoethyl-4-(5-chloropent-1-yn-
1-yl) benzoate (4g)
13C NMR (100 MHz, DMSO-d6): δ 22.5, 22.7, 24.6,
cyclohexanol);
This compound was purified by using 15% EtOAc/hexane to
give the title compound (136.2 mg) as a light yellow oil; Rf 0.59
(1 : 3 EtOAc/hexane); IR (film) 2955, 2229, 1759, 1255,
24.8, 52.7, 66.9, 73.8, 81.8, 122.8, 127.7 (2C), 128.1 (2C),
129.6 (2C), 129.8 (2C), 131.6 (2C), 131.9 (2C), 132.9, 164.3,
168.5; mass (ES) m/z 471.3 (M + 1); HRMS (ESI) calculated for
C24H24O5Br (M + H]+ 471.0808; found 471.0807.
1
766 cm−1; H NMR (400 MHz, DMSO-d6): δ 7.98 (2H, d, J =
7.6 Hz, C6H4), 7.60–7.69 (4H, m, O-ClC6H4c), 7.46–7.59 (2H,
m, C6H4), 6.60 (1H, s, CH), 3.75–3.79 (2H, t, J = 6.4 Hz, CH2),
3.73 (3H, s, OCH3), 2.61–2.65 (2H, t, J = 6.8 Hz, CH2),
1.99–2.49 (2H, t, J = 6.8 Hz, CH2); 13C NMR (100 MHz,
DMSO-d6): δ 16.2, 30.7, 44.1, 52.9, 71.4, 80.4, 93.2, 127.5,
127.9, 128.5, 129.6 (2C), 130.0, 130.2, 131.4, 131.6, 131.8,
133.1 (2C), 164.2, 168.0; mass (ES) m/z 405.20 (M + 1); HRMS
(ESI) calculated for C21H19O4Cl2 [M + H]+ 405.0600; found
405.0660.
1-(4-Bromophenyl)-2-methoxy-2-oxoethyl-4-(pyridin-
2-ylethynyl) benzoate (4d)
This compound was purified by using 15% EtOAc/hexane to
give the title compound (138.0 mg) as an off white solid; mp
(DSC) 134.6 °C; Rf 0.20 (1 : 3 EtOAc/hexane); IR (cm−1, KBr)
2951, 2219, 1757, 1730, 1276,770; 1H NMR (400 MHz,
DMSO-d6): δ 8.65 (1H, m, C5H4N), 8.1 (2H, J = 7.6 Hz,
C6H4),7.92 (1H, m, C5H4N), 7.81 (2H, J = 8.4 Hz, C6H4), 7.70
(1H, d, J = 8.4 Hz, C5H4N),7.68 (2H, d, J = 8.4 Hz, p-BrC6H4),
7.59 (2H, J = 8.0 Hz, p-BrC6H4), 7.48 (1H, m, C6H4), 6.30(1H,
s, CH), , 3.69 (3H, s, OCH3); 13C NMR (100 MHz, DMSO-d6):
δ 52.7, 73.9, 87.0, 91.9, 122.8, 124.0, 126.7, 127.6, 128.7 (2C),
129.8 (2C), 129.9 (2C), 131.9 (2C), 132.2, 132.9, 136.9, 141.6,
150.3, 164.2, 168.5; mass (ES) m/z 450.0 (M + 1); HRMS (ESI)
calculated for C23H17NO4Br [M + H]+ 450.0338; found
450.0341.
1-(2-Chlorophenyl)-2-methoxy-2-oxoethyl-4-(hex-1-yn-1-yl)
benzoate (4h)
This compound was purified by using 10% EtOAc/hexane to
give the title compound (124.5 mg) as a light yellow oil; Rf 0.77
(1 : 3 EtOAc/hexane); IR (film) 2932, 2229, 1732, 1255,
1
766 cm−1; H NMR (400 MHz, DMSO-d6): δ 7.98 (2H, d, J =
8.4 Hz, C6H4), 7.55 (2H, d, J = 8.4 Hz, C6H4), 7.48 (4H, m,
O-ClC6H4c), 6.60 (1H, s, CH), 3.73 (3H, s, OCH3), 2.45–2.49
1674 | Org. Biomol. Chem., 2012, 10, 1670–1679
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1-(2-Chlorophenyl)-2-methoxy-2-oxoethyl-4-((2-nitrophenyl)
ethynyl) benzoate (4l)
(2H, m, CH2), 1.51–1.58 (2H m, CH2), 1.40–1.47 (2H, m, CH2),
0.89–0.93 (3H, t, J = 7.2 Hz, CH3); 13C NMR (100 MHz,
DMSO-d6): δ 13.9, 18.8, 21.8, 30.4, 53.4, 71.8, 80.3, 95.4,
127.7, 128.4, 129.3, 130.1, 130.5, 130.6, 131.8 (2C), 132.1,
132.2 (2C), 133.6, 164.7, 168.5; mass (ES) m/z 385.20 (M + 1);
HRMS (ESI) calculated for C22H22O4Cl [M + H]+ 385.1216;
found 385.1207.
This compound was purified by using 10% EtOAc/hexane to
give the title compound (135.7 mg) as an orange colour solid;
mp (DSC) 180.53 °C; Rf 0.37 (1 : 3 EtOAc/hexane); IR (film)
1
2954, 1752, 1718, 1490, 1390, 756 cm−1; H NMR (400 MHz,
DMSO-d6): δ 8.68 (2H, d, J = 8.8 Hz, O-NO2C6H4), 8.19 (2H,
d, J = 8.4 Hz, C6H4), 7.82-7.84 (1H, m, O-NO2C6H4),
7.71–7.76 (2H, m, C6H4), 7.68–7.70 (2H, m, O-ClC6H4),
7.60–7.62 (1H, m, O-NO2C6H4), 7.46–7.54 (2H, m, O-ClC6H4),
6.64 (1H, s, CH), 3.74 (3H, s, OCH3); 13C NMR (100 MHz,
DMSO-d6): δ 52.9, 71.5, 114.2, 121.8, 122.7, 127.5, 127.9,
129.0 (2C), 129.5, 130.0 (2C), 130.2 (2C), 130.6, 131.0, 131.3,
131.5, 131.9, 133.0, 135.2, 147.3, 164.12, 168.0; mass (ES) m/z
450.20 (M + 1); HRMS (ESI) calculated for C24H17NO6Cl
[M + H]+ 450.0752; found 450.0744.
1-(2-chlorophenyl)-2-methoxy-2-oxoethyl-4-(3-hydroxybut-1-yn-
1-yl) benzoate (4i)
This compound was purified by using 15% EtOAc/hexane to
give the title compound (98.0 mg) as a light yellow oil; Rf 0.26
(1 : 3 EtOAc/hexane); IR (film) 3467, 2954, 1741, 1222,
1
756 cm−1; H NMR (400 MHz, DMSO-d6): δ 7.98 (2H, d, J =
8.4 Hz, C6H4), 7.61–7.66 (2H, m, O-ClC6H4), 7.59 (2H, d, J =
8.4 Hz, C6H4), 7.45–7.53 (2H, m, O-ClC6H4), 6.60 (1H, s, CH),
5.56 (1H, b, OH), 4.60–4.65 (1H, q, J = 6.8 Hz, CHOH), 3.73
̲
1-(2-Chlorophenyl)-2-methoxy-2-oxoethyl-4-((6-
methoxynaphthalen-2-yl)ethynyl) benzoate (4m)
(3H, s, OCH3), 1.40 (3H, d, J = 6.4 Hz, CH3); 13C NMR
(50 MHz, CD3OD): δ 25.0, 53.8, 59.4, 73.4, 83.6, 96.7, 129.1,
130.2, 130.3, 131.2 (2C), 131.4, 131.6, 132.5 (2C), 133.2,
133.9, 135.7, 166.7, 170.6; mass (ES) m/z 373.10 (M + 1);
HRMS (ESI) calculated for C20H18O5Cl [M + H]+ 373.0854;
found 373.0843.
This compound was purified by using 10% EtOAc/hexane to
give the title compound (123.3 mg) as a pale yellow colour
solid; mp (DSC) 161.57 °C; Rf 0.53 (1 : 3 EtOAc/hexane); IR
1
(film) 1741, 1719, 1268,, 1088, 767 cm−1; H NMR (400 MHz,
DMSO-d6): δ 8.17 (1H, S, CHnaphthalene), 8.07 (2H, d, J = 8.4
Hz, C6H4), 7.85–7.88 (2H, m, CHnaphthalene), 7.74–7.76 (2H, d, J
= 8.4 Hz, C6H4), 7.68 (1H, d, J = 9.2 Hz, CHnaphthalene),
7.59–7.62 (2H, m, O-ClC6H4), 7.48–7.59 (2H,m, O-
ClC6H4),7.39 (1H, s, CH(naphthalene)), 7.25 (1H, d, J = 8.8,
CHnaphthalene), 6.63 (1H, s, CH), 3.9 (3H, s, OCH3 naphthalene),
3.74 (3H, s, OCH3); 13C NMR (100 MHz, DMSO-d6): δ 52.9,
55.3, 71.4, 106.1, 119.5, 127.2 (2C), 127.3 (2C), 128.0 (2C),
128.4 (2C), 129.5 (2C), 129.8 (2C), 130.0, 130.2, 131.4 (2C),
131.6, 131.7, 133.1 (2C), 134.3 (2C), 168.03, 174.8; mass (ES)
m/z 485.30 (M + 1); HRMS (ESI) calculated for C29H22O5Cl
[M + H]+ 485.1156; found 485.1156.
1-(2-Chlorophenyl)-2-methoxy-2-oxoethyl-4-((1-
hydroxycyclohexyl)ethynyl) benzoate (4j)
This compound was purified by using 10% EtOAc/hexane to
give the title compound (113.5 mg) as a light yellow oil; Rf 0.38
(1 : 3 EtOAc/hexane); IR (film) 3411, 2934, 1729, 1256,
1
754 cm−1; H NMR (400 MHz, DMSO-d6): δ 7.98 (2H, d, J =
8.4 Hz, C6H4), 7.59–7.65 (2H, m, O-ClC6H4), 7.58 (2H, d, J =
8.8 Hz, C6H4), 7.45–7.52 (2H, m, O-ClC6H4), 6.60 (1H, s, CH),
5.75 (1H, b, OH), 3.73 (3H, s, OCH3), 1.47–1.66 (10H, m, CH2
13C NMR (100 MHz, DMSO-d6): δ 22.5, 22.7, 24.6,
cyclohexanol);
24.8, 52.9, 67.0, 71.4, 81.8, 98.8, 127.6, 127.9, 128.2, 129.7
(2C), 130.0 (2C), 130.2, 131.4 (2C), 131.6, 131.7, 133.1, 164.2,
168.0; mass (ES) m/z 427.3 (M + 1); HRMS (ESI) calculated for
C24H24O5Cl [M + H]+ 427.1310; found 427.1312.
1-(2-Chlorophenyl)-2-methoxy-2-oxoethyl-4-(3-hydroxypent-1-
yn-1-yl) benzoate (4n)
This compound was purified by using 15% EtOAc/hexane to
give the title compound (105.0 mg) as a light brown oil; Rf 0.33
(1 : 3 EtOAc/hexane); IR (film) 3416, 2932, 1732, 1254,
1
766 cm−1; H NMR (400 MHz, DMSO-d6): δ 8.0 (2H, d, J =
1-(2-Chlorophenyl)-2-methoxy-2-oxoethyl-4-(pyridin-2-
ylethynyl) benzoate (4k)
8.4 Hz, C6H4), 7.61–7.65 (2H, m, ClC6H4), 7.52–7.59 (2H, m,
O-ClC6H4), 7.46–7.50 (2H, m, O-ClC6H4), 6.60 (1H, s, CH),
5.75 (1H, b, OH), 4.43 (1H, t, J = 6.4 Hz, CHaliphatic), 3.73 (3H,
s, OCH3), 1.65–1.69 (2H, m, CH2), 0.95–0.99 (3H, t, J = 7.2
Hz, CH3); 13C NMR (50 MHz, DMSO-d6): δ 9.6, 30.5, 53.0,
62.1, 71.4, 82.2, 96.2, 127.7, 128.0, 128.1, 129.7, 130.0, 130.2
(2C), 131.4(2C), 131.6, 131.8, 133.1, 164.2, 166.0; mass (ES)
m/z 387.20 (M + 1); HRMS (ESI) calculated for C21H20O5Cl [M
+ H]+ 387.1000; found 387.0999.
This compound was purified by using 15% EtOAc/hexane to
give the title compound (108.4 mg) as a light yellow oil; Rf 0.21
(1 : 3 EtOAc/hexane); IR (film) 3467, 2954, 1741, 1222,
1
756 cm−1; H NMR (400 MHz, DMSO-d6): δ 8.63–8.65 (1H,
m, C5H4N), 8.07(2H, d, J = 8.0 Hz, C6H4), 7.91 (1H, m,
C5H4N), 7.81 (2H, d, J = 8.0 Hz, C6H4), 7.72 (1H, d, J = 8.0
Hz, O-ClC6H4), 7.60–7.68 (2H, m, C5H4N), 7.44–7.53 (3H, m,
O-ClC6H4), 6.63 (1H, s, CH), 3.74 (3H, s, OCH3); 13C NMR
(100 MHz, DMSO-d6): δ 52.9, 71.5, 87.0, 91.9, 124.0, 126.8,
127.6, 127.9, 128.6 (2C), 129.8, 130.0, 130.2, 131.3, 131.5,
132.2 (2C), 133.0, 136.9, 141.6, 150.2, 164.1, 167.9; mass (ES)
m/z 406.10 (M + 1); HRMS (ESI) calculated for C23H17NO4Cl
[M + H]+ 406.0858; found 406.0846.
1-(2-Chlorophenyl)-2-methoxy-2-oxoethyl-4-(hept-1-yn-1-yl)
benzoate (4o)
This compound was purified by using 10% EtOAc/hexane to
give the title compound (135.8 mg) as a light yellow colour oil;
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 1670–1679 | 1675

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Rf 0.74 (1 : 3 EtOAc/hexane);IR (film) 2955, 1760, 1727, 1254,
753 cm−1;1H NMR (400 MHz, DMSO-d6): δ 7.97 (2H, d, J =
8.4 Hz, C6H4), 7.61–7.65 (2H, m, C6H4), 7.55 (2H, d, J = 8.4
Hz, O-ClC6H4), 7.44–7.52 (2H, m, O-ClC6H4), 6.60 (1H, s,
CH), 3.72 (3H, s, OCH3), 2.44–2.48 (2H, t, J = 6.8 Hz, CH2),
1.52–1.59 (2H, m, CH2), 1.28–1.40 (4H, m, CH2), 0.90–0.87
(3H, t, J = 6.8 Hz, CH3); 13C NMR (50 MHz, DMSO-d6): δ
13.8, 18.6, 21.5, 27.6, 30.5, 52.9, 71.3, 79.8, 95.0, 127.2, 127.9,
128.8, 129.6, 129.9, 130.1 (2C), 131.3, 131.5, 131.6 (2C),
133.0, 164.1, 167.9; mass (ES) m/z 399.20 (M + 1); HRMS
(ESI) calculated for C23H23O4Cl [M + H]+ 399.1358; found
399.1363.
130.1, 130.2, 131.3, 131.5, 131.7, 133.0, 136.4, 164.0, 167.9;
mass (ES) m/z 385.20 (M + 1); HRMS (ESI) calculated for
C22H22O4Cl [M + H]+ 385.1207; found 385.1190.
A typical procedure for one-pot NHC mediated hydroacylation
and Heck reactions
To a mixture of imidazolium salt (14.8 mg, 0.044 mmol) and 4-
iodobenzaldehyde (100 mg, 0.43 mmol) in THF (5.0 mL) tri-
ethylamine (109 mg, 1.08 mmol), methyl 2-(4-bromophenyl)-2-
oxoacetate (157.1 mg, 0.646 mmol) palladium(II)acetate
(4.84 mg, 0.022 mmol) were added, followed by methyl acrylate
(148.4 mg, 1.72 mmol) under a nitrogen atmosphere. The
mixture was then stirred at 28–32 °C for 15 h (monitored the
reaction by TLC). After completion of the reaction the mixture
was concentrated under vacuum and the residue was purified by
flash chromatography on silica gel (230–400 mesh) using
10–20% EtOAc/hexane.
1-(2-Chlorophenyl)-2-methoxy-2-oxoethyl-4-(oct-1-yn-1-yl)
benzoate (4p)
This compound was purified by using 10% EtOAc/hexane to
give the title compound (133.6 mg) as a light yellow colour oil;
Rf 0.74 (1 : 3 EtOAc/hexane); IR (film) 2954, 2226, 1760, 1727,
1255, 766 cm−1;1H NMR (400 MHz, DMSO-d6): δ 7.97 (2H, d,
J = 8.4 Hz, C6H4), 7.61–7.65 (2H, m, C6H4), 7.55 (2H, d, J =
7.6 Hz, O-ClC6H4), 7.44–7.52 (2H, m, O-ClC6H4), 6.60 (1H, s,
CH), 3.72 (3H, s, OCH3), 2.44–2.48 (2H, t, J = 6.8 Hz, CH2),
1.52–1.59 (2H, m, CH2), 1.28–1.40 (6H, m, CH2), 0.89–0.85
(3H, t, J = 6.8 Hz, CH3); 13C NMR (50 MHz, DMSO-d6): δ
13.8, 18.7, 21.9, 27.9, 30.7, 52.9, 71.3, 79.8, 95.0, 127.2, 127.9,
128.9 (2C), 129.6 (2C), 130.0 (2C), 130.2, 131.4, 131.6, 131.7,
133.0, 164.2, 168.0; mass (ES) m/z 413.0 (M + 1); HRMS (ESI)
calculated for C24H26O4Cl [M + H]+ 413.1515; found 413.1520.
(E)-1-(4-Bromophenyl)-2-methoxy-2-oxoethyl-4-(3-methoxy-
3-oxoprop-1-en-1-yl) benzoate (6a)
This compound was purified by using 10% EtOAc/hexane to
give the title compound (121.0 mg) as a light yellow colour oil;
Rf 0.36 (1 : 3 EtOAc/hexane); IR (cm−1, KBr) 1H NMR
(400 MHz, DMSO-d6): δ 8.05 (2H, d, J = 7.6 Hz, C6H4), 7.92
(2H, d, J = 8.4 Hz, C6H4), 7.76 (1H, d, J = 16 Hz, CHethylene),
7.71 (2H, d, J = 8.4 Hz p-BrC6H4), 7.58 (2H, d, J = 8.0 Hz, p-
BrC6H4)); 6.83 (1H, d, J = 16 Hz, CHethylene), 6.29 (1H, s, CH),
3.75 (3H, s, OCH3), 3.72 (3H, s, OCH3); 13C NMR (100 MHz,
DMSO-d6): δ 51.6, 52.7, 73.8, 120.8, 122.7, 128.7 (2C), 129.5
(2C), 129.8 (2C), 129..9, 131.8 (2C), 133.0, 139.1, 142.8, 164.4,
166.2, 168.5; mass (ES) m/z 433.2 (M + 1); HRMS (ESI) calcu-
lated for C20H18O6Br [M + H]+ 433.0296; found 433.0287.
1-(2-Chlorophenyl)-2-methoxy-2-oxoethyl 2-(hex-1-yn-1-yl)
benzoate (4q)
This compound was purified by using 10% EtOAc/hexane to
give the title compound (116.2 mg) as a light yellow oil; Rf 0.76
(1 : 3 EtOAc/hexane); 1H NMR (400 MHz, DMSO-d6): δ
7.97–795 (2H, d, J = 8.0 Hz, C6H4), 7.55 (2H, d, J = 8.0 Hz,
C6H4), 7.48–7.53 (4H, m, O-ClC6H4c), 6.60 (1H, s, CH), 3.72
(3H, s, OCH3), 2.45–2.50 (2H, m, CH2), 1.52–1.54 (2H m,
CH2), 1.28–1.44 (2H, m, CH2), 0.89–0.93 (3H, t, J = 7.2 Hz,
CH3); 13C NMR (100 MHz, DMSO-d6): δ 13.9, 18.7, 21.9,
30.7, 52.9, 71.3, 79.8, 95.0, 127.2, 127.9, 128.9, 129.6(2C),
130.1, 130.2, 131.4(2C), 131.7 (2C), 133.0, 164.2, 168.0; mass
(ES) m/z 385.20 (M + 1); HRMS (ESI) calculated for
C22H22O4Cl [M + H]+ 385.1207; found 385.1195.
(E)-1-(4-bromophenyl)-2-methoxy-2-oxoethyl-4-(3-ethoxy-3-
oxoprop-1-en-1-yl) benzoate (6b)
This compound was purified by using 10% EtOAc/hexane to
give the title compound (136.5 mg) as a light yellow colour oil;
1
Rf 0.44 (1 : 3 EtOAc/hexane); H NMR (400 MHz, DMSO-d6):
δ 8.05 (2H, d, J = 8.4 Hz, C6H4), 7.92 (2H, d, J = 8.4 Hz,
C6H4), 7.74 (1H, d, J = 16 Hz, CHethylene), 7.70 (2H, d, J = 8.8
Hz, p-BrC6H4), 7.58 (2H, d, J = 8.0 Hz, p-BrC6H4), 6.81 (1H, d,
J = 16.0 Hz, CHethylene), 6.28 (1H, s, CH), 4.20–4.24 (2H, q, J =
7.6 Hz, CH2), 3.69 (3H, s, OCH3), 1.32–1.36 (3H, t, J = 7.6 Hz,
OCH2CH3
);13C NMR (100 MHz, DMSO-d6): δ 14.1, 52.7,
̲
1-(2-Chlorophenyl)-2-methoxy-2-oxoethyl 3-(hex-1-yn-1-yl)
benzoate (4r)
60.2, 73.8, 121.2, 122.7, 128.7 (2C), 129.5 (2C), 129.7, 129.8
(2C), 131.8 (2C), 133.0, 139.2, 142.7, 164.4, 165.8, 168.5; mass
(ES) m/z 447.2 (M
+ 1); HRMS (ESI) calculated for
This compound was purified by using 10% EtOAc/hexane to
give the title compound (119.5 mg) as light yellow oil; Rf 0.77
(1 : 3 EtOAc/hexane); H NMR (400 MHz, DMSO-d6): δ 7.97
C21H20O6Br [M + H]+ 447.0493; found 447.0443.
1
(2H, d, J = 8.0 Hz, C6H4), 7.7 (2H, d, J = 8.0 Hz, C6H4),
7.67–7.5 (4H, m, O-ClC6H4c), 6.62 (1H, s, CH), 3.73 (3H, s,
OCH3), 2.46–2.42 (2H, t, J = 7.7 Hz, CH2), 1.52–1.55 (2H m,
CH2), 1.44–1.46 (2H, m, CH2), 0.88–0.93 (3H, t, J = 7.2 Hz,
CH3); 13C NMR (100 MHz, DMSO-d6): δ 13.4, 18.2, 21.4,
30.0, 52.9, 71.4, 79.2, 92.3, 127.9, 128.7, 128.8, 129.4, 130.0,
(E)-1-(4-bromophenyl)-2-methoxy-2-oxoethyl-4-(3-(tert-butoxy)-
3-oxoprop-1-en-1-yl) benzoate (6c)
This compound was purified by using 10% EtOAc/hexane to
give the title compound (131.0 mg) as light yellow colour oil; Rf
1
0.53 (1 : 3 EtOAc/hexane); H NMR (400 MHz, DMSO-d6): δ
1676 | Org. Biomol. Chem., 2012, 10, 1670–1679
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(E)-1-(2-chlorophenyl)-2-methoxy-2-oxoethyl 2-(3-ethoxy-3-
oxoprop-1-enyl) benzoate (6g)
8.03 (2H, d, J = 8.4 Hz, C6H4), 7.89 (2H, d, J = 8.4 Hz, C6H4),
7.71 (2H, d, J = 8.4 Hz, p-BrC6H4), 7.64 (1H, d, J = 16 Hz,
CHethylene), 7.58(2H, d, J = 8.8 Hz, p-BrC6H4), 6.70 (1H, d, J =
16.4 Hz, CHethylene), 6.28 (1H, s, CH), 3.69 (3H, s, OCH3), 1.49
(9H, s, O(CH3)3);13C NMR (100 MHz, DMSO-d6): δ 27.7 (3C),
52.7, 73.8, 80.3, 122.7, 122.8, 128.6 (2C), 129.3 (2C), 129.8
(2C), 129.9, 131.9 (2C), 133.0, 139.3, 141.9, 164.4, 165.1,
168.5; mass (ES) m/z 497.2 (M+23); HRMS (ESI) calculated for
C23H22O6Br [M − H]+ 473.0619; found 473.0600.
This compound was purified by using 10% EtOAc/hexane to
give the title compound (120.0 mg) as light yellow colour oil. Rf
0.46 (1 : 3 EtOAc/hexane);1H NMR (400 MHz, DMSO-d6): δ
8.04 (2H, d, J = 8.4 Hz,C6H4), 7.92 (2H, d, J = 8.4 Hz, C6H4),
7.74 (1H, d, J = 16 Hz, CHethylene), 7.59–7.68(2H, m, O-
ClC6H4), 7.49–7.53 (2H, m, O-ClC6H4); 6.80 (1H, d, J = 16 Hz,
CHethylene),6.62 (1H, s, CH), 4.2–4.24(2H, m, CH2), 3.73 (3H, s,
OCH3), 1.25–1.28(3H, t, J = 7.2 Hz, CH3); 13C NMR
(100 MHz, DMSO-d6): δ 14.1, 52.9, 60.2, 71.4, 121.2, 127.9,
128.7 (2C), 129.4 (2C), 129.9, 130.0, 130.2, 131.3, 131.6,
133.0, 139.2, 142.7, 164.2, 165.7, 168.0; mass (ES) m/z 403.2
(M + 1); HRMS (ESI) calculated for C21H20O6Cl [M + H]+
403.0948; found 403.0932.
(E)-1-(2-chlorophenyl)-2-methoxy-2-oxoethyl-4-(3-methoxy-3-
oxoprop-1-en-1-yl) benzoate (6d)
This compound was purified by using 10% EtOAc/hexane to
give the title compound (117.3 mg) as a light yellow colour oil;
1
Rf 0.38 (1 : 3 EtOAc/hexane); H NMR (400 MHz, DMSO-d6):
δ 8.03 (2H, d, J = 8.4 Hz, C6H4), 7.91 (2H, d, J = 8.8 Hz,
C6H4), 7.73 (1H, d, J = 16 Hz, CHethylene), 7.59–7.68(2H, m, O-
ClC6H4), 7.45–7.53 (2H, m, O-ClC6H4); 6.80 (1H, d, J = 16 Hz,
CHethylene),6.60 (1H, s, CH), 3.75 (3H, s, OCH3), 3.72 (3H, s,
OCH3); 13C NMR (50 MHz, DMSO-d6): δ 51.6, 52.9, 71.4,
120.8, 127.9, 128.7 (2C), 129.4 (2C), 129.8, 130.0, 130.1,
131.3, 131.6, 133.0, 139.1, 142.8, 164.2, 166.2, 167.9; mass
(E)-1-(2-chlorophenyl)-2-methoxy-2-oxoethyl 3-(3-ethoxy-
3-oxoprop-1-enyl) benzoate (6h)
This compound was purified by using 10% EtOAc/hexane to
give the title compound (123.2 mg) as light yellow colour oil. Rf
0.47 (1 : 3 EtOAc/hexane);1H NMR (400 MHz, DMSO-d6): δ
8.26(1H, s, C6H4), 8.12 (2H, d, J = 8.0 Hz, C6H4), 7.78 (1H, d,
J = 16 Hz, CHethylene), 7.52–7.58 (1H, m, C6H4), 7.60–7.70 (2H,
m, O-ClC6H4, 7.48–7.51 (2H, m, O-ClC6H4); 6.75 (1H, d, J =
16 Hz, CHethylene), 6.64 (1H, s, CH), 4.18–4.23 (2H, m, CH2),
3.73 (3H, s, OCH3), 1.25–1.28 (3H, t, J = 7.2 Hz, CH3); 13C
NMR (100 MHz, DMSO-d6): δ 14.1, 52.9, 60.3, 71.4, 125.0,
125.4 126.6, 127.1, 128.0, 128.9, 130.0, 130.2, 131.3, 131.7,
133.1, 138.4, 143.5, 145.6, 164.4, 165.7, 168.1; mass (ES) m/z
403.2 (M + 1); HRMS (ESI) calculated for C21H20O6Cl
[M + H]+ 403.0948; found 403.0930.
(ES) m/z 389.2 (M
+ 1); HRMS (ESI) calculated for
C20H18O6Cl[M + H]+ 389.0783; found 389.0792.
(E)-1-(2-chlorophenyl)-2-methoxy-2-oxoethyl-4-(3-ethoxy-3-
oxoprop-1-en-1-yl) benzoate (6e)
This compound was purified by using 10% EtOAc/hexane to
give the title compound (112.8 mg) as a light yellow colour oil.
Rf 0.46 (1 : 3 EtOAc/hexane);1H NMR (400 MHz, CDCl3): δ
8.11 (2H, d, J = 8.8 Hz, C6H4), 7.69 (1H, d, J = 16 Hz,
CHethylene), 7.60 (2H, d, J = 8.4 Hz, C6H4), 7.45–7.57 (2H, m,
O-ClC6H4), 7.32–7.38 (2H, m, O-ClC6H4); 6.70 (1H, s, CH),
6.51 (1H, d, J = 15.6 Hz, CHethylene), 4.25-4.30 (2H, q, J = 6.8
Hz, CH2), 3.79 (3H, s, OCH3), 1.32–1.36 (3H, t, J = 6.8 Hz,
OCH3); 13C NMR (50 MHz, DMSO-d6): δ 14.1, 52.9, 60.2,
71.4, 121.2, 127.9, 128.7 (2C), 129.4 (2C), 129.9, 130.0, 130.2,
131.3, 131.6, 133.0, 139.2, 142.7, 164.2, 165.8, 168.0;
mass (ES) m/z 403.2 (M + 1); HRMS (ESI) calculated for
C21H20O6Cl [M + H]+ 403.0945; found 403.0948.
A typical procedure for one-pot NHC mediated hydroacylation
and Suzuki reaction
To a mixture of imidazolium salt (14.8 mg, 0.044 mmol) and
4-iodobenzaldehyde (100 mg, 0.43 mmol) in THF (5.0 mL) was
added triethylamine (109 mg, 1.08 mmol), methyl 2-(4-bromo-
phenyl)-2-oxoacetate (157.1 mg, 0.646 mmol), palladium(II)
acetate (4.84 mg, 0.022 mmol) followed by 3-(hydroxyl methyl)
phenyl boronic acid (98.2 mg, 0.646 mmol) under a nitrogen
atmosphere. The mixture was then stirred at 28–32 °C for 8 h
(monitored by TLC). After completion the reaction mixture was
concentrated under vacuum and the residue was purified by flash
chromatography on silica gel (230–400 mesh) using 10-20%
EtOAc/hexane.
(E)-1-(2-chlorophenyl)-2-methoxy-2-oxoethyl-4-(3-(tert-butoxy)-
3-oxoprop-1-en-1-yl) benzoate (6f)
This compound was purified by using 10% EtOAc/hexane to
give the title compound (137.4 mg) as a light yellow colour oil;
1
Rf 0.56 (1 : 3 EtOAc/hexane); H NMR (400 MHz, DMSO-d6):
δ 8.02 (2H, d, J = 8.4 Hz, C6H4), 7.89 (2H, d, J = 8.4 Hz,
C6H4), 7.65 (1H, d, J = 16 Hz, CHethylene),7.59–7.45 (4H, m, O-
ClC6H4), 6.69 (1H, d, J = 15.6 Hz, CHethylene), 6.28 (1H, s,
CH), 3.73 (3H, s, OCH3), 1.49 (9H, s, (CH3)3); 13C NMR
(100 MHz, DMSO-d6): δ 27.6 (3C), 52.5, 71.1, 80.3, 122.7,
122.8, 128.6 (2C), 129.3 (2C), 129.7, 129.8 (2C), 131.9 (2C),
133.0, 139.3, 141.9, 164.1, 164.7, 167.8; mass (ES) m/z 431.3
(M + 1); HRMS (ESI) calculated for C23H24O6Cl [M + H]+
431.1263; found 431.1261.
1-(4-Bromophenyl)-2-methoxy-2-oxoethyl-3′-(hydroxymethyl)-
[1,1′-biphenyl]-4-carboxylate (8a)
This compound was purified by using 15% EtOAc/hexane to
give the title compound (130.0 mg) as a light brown color oil. Rf
1
0.38 (2 : 3 EtOAc/hexane); H NMR (400 MHz, DMSO-d6): δ
8.12 (2H, d, J = 8.4 Hz, C6H4), 7.87 (2H, d, J = 8.4 Hz, C6H4),
7.71 (1H, d, J = 8.8 Hz, C6H4 benzyl), 7.71(2H, d, J = 8.8 Hz,
p-BrC6H4),7.63 (1H, s, C6H4 benzyl), 7.6 (2H, d, J = 8.4 Hz,
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1-(2-Chlorophenyl)-2-methoxy-2-oxoethyl-4′-fluoro-3′-methyl-
[1,1′-biphenyl]-4-carboxylate (8e)
p-BrC6H4), 7.47 (1H, d, J = 7.6 Hz, C6H4 benzyl), 7.40 (1H, d, J
= 8.0 Hz, C6H4 benzyl), 6.30 (1H, s, CH), 5.30 (1H, b, OH), 4.59
(2H, s, CH2), 3.70 (3H, s, OCH3); 13C NMR (100 MHz,
DMSO-d6): δ 52.7, 65.2, 73.7, 122.7, 125.0, 125.4, 126.6,
127.1, 127.2, 128.9 (2C), 129.8 (2C), 130.1 (2C), 131.9 (2C),
133.1, 138.5, 143.5, 145.6, 164.8, 168.7; mass (ES) m/z 476.9
(M+23); HRMS(ESI) calculated for C23H18O5Br [M − H]+
453.0378; found 453.0338.
This compound was purified by using 20% EtOAc/hexane to
give the title compound (126.3 mg) as a light brown color oil; Rf
0.6 (2 : 3 EtOAc/hexane);1H NMR (400 MHz, DMSO-d6): δ
8.08 (2H, d, J = 8.4 Hz, C6H4), 7.85 (2H, d, J = 8.0 Hz, C6H4),
7.60–7.71 (4H, m, O-ClC6H4), 7.59–7.50 (2H, m, p-FC6H3),
7.29–7.25 (1H, m, p-FC6H3), 6.63 (1H, s, CH), 3.74 (3H, s,
OCH3), 2.32 (3H, s, CH313C NMR (100 MHz, DMSO-d6): δ
14.3, 53.0, 71.3, 113.3, 115.3, 115.5, 115.7, 125.0, 125.1, 126.4,
126.5, 128.0, 130.1, 130.2, 130.4, 131.4, 131.7, 133.1, 134.8,
144.6, 164.6, 168.2; mass (ES) m/z 413.2 (M + 1); HRMS (ESI)
calculated for C23H19O4FCl [M + H]+ 413.0949; found
413.0956.
1-(4-Bromophenyl)-2-methoxy-2-oxoethyl-4-(furan-2-yl)
benzoate (8b)
This compound was purified by using 20% EtOAc/hexane to
give the title compound (123.0 mg) as an off white solid; mp
(DSC) 109.6 °C; Rf 0.40 (2 : 3 EtOAc/hexane);1H NMR
(400 MHz, DMSO-d6): δ 8.07 (2H, d, J = 8.8 Hz, C6H4), 7.88
(2H, d, J = 8.4 Hz, C6H4), 7.87 (1H, d, J = 1.6 Hz, CHfuran),
7.71 (2H, d, J = 8.8 Hz, p-BrC6H4), 7.6 (2H, d, J = 7.6 Hz, p-
BrC6H4), 7.20 (1H, d, J = 3.6 Hz, CHfuran), 6.8 (1H, dd, J1 = 1.6
1-(2-Chlorophenyl)-2-methoxy-2-oxoethyl-3′-(hydroxymethyl)
biphenyl-2-carboxylate (8f)
This compound was purified by using 15% EtOAc/hexane to
give the title compound (106.2 mg) as light brown color oil. Rf
0.4 (2 : 3 EtOAc/hexane); 1H NMR (400 MHz, DMSO-d6): δ
8.10 (2H,d,J = 8.4 Hz, C6H4), 7.86 (2H, d, J = 8.0 Hz, C6H4),
7.68–7.60 (4H, m, C6H4 benzyl), 7.45–7.51(4H, m, O-ClC6H4);
6.63 (1H, s, CH), 5.30–5.28 (1H, t, J = 6.0 Hz, OH), 4.59 (2H,
d, J = 5.6 Hz, CH2), 3.74 (3H, s, OCH3); 13C NMR (100 MHz,
DMSO-d6): δ 52.9, 62.7, 71.3, 125.0, 125.4, 126.6, 127.1, 128.0
(2C), 128.9 (2C), 130.0 (2C), 130.2 (2C), 131.3, 131.7, 133.1,
138.4, 143.5, 145.6, 164.6, 168.1; mass (ES) m/z 428.2 (M +
18); HRMS (ESI) calculated for C23H20O5Cl [M + H]+
411.0999; found 411.0998.
Hz, J2 = 2.0 Hz CHfuran), 6.27 (1H, s, CH), 3.69 (3H, s,
l
OCH3);13C NMR (100 MHz, DMSO-d6): δ 52.7, 73.7, 108.9,
112.5, 122.7, 123.5, 126.7 (2C), 129.8 (2C), 130.2 (2C), 131.9
(2C), 133.1, 134.9, 144.4, 151.7, 164.5, 168.7; mass (ES) m/z
415.1 (M + 1); HRMS (ESI) calculated for C20H16O5Br[M +
H]+ 415.0173; found 415.0181
1-(2-Chlorophenyl)-2-methoxy-2-oxoethyl-3′-(hydroxymethyl)-
[1,1′-biphenyl]-4-carboxylate (8c)
This compound was purified by using 15% EtOAc/hexane to
give the title compound (116.8 mg) as a light brown color oil; Rf
0.40 (2 : 3 EtOAc/hexane); IR (cm−1, KBr) 3543, 2949, 2344,
1
1-(2-Chlorophenyl)-2-methoxy-2-oxoethyl-3′-(hydroxymethyl)
biphenyl-3-carboxylate (8g)
1749, 1709, 1260, 756; H NMR (400 MHz, DMSO-d6): δ 8.11
(2H, d, J = 8.4 Hz, C6H4), 7.87 (2H, d, J = 8.0 Hz, C6H4),
7.68–7.60 (4H, m, C6H4 benzyl), 7.54–7.50 (2H, m, O-ClC6H4),
7.49–7.38(2H, m, O-ClC6H4); 6.63 (1H, s, CH), 5.30–5.28 (1H,
t, J = 6.0 Hz, OH), 4.59 (2H, d, J = 5.6 Hz, CH2), 3.74 (3H, s,
OCH3); 13C NMR (100 MHz, DMSO-d6): δ 52.9, 62.7, 71.3,
125.0, 125.4, 126.6, 127.1, 128.0 (2C), 128.9 (2C), 130.0 (2C),
130.2 (2C), 131.3, 131.7, 133.1, 138.4, 143.5, 145.6, 164.6,
168.1; mass (ES) m/z 411.1 (M + 1); HRMS (ESI) calculated for
C23H20O5Cl [M + H]+ 411.1004; found 411.0999.
This compound was purified by using 15% EtOAc/hexane to
give the title compound (113 mg) as light brown color oil. Rf 0.4
1
(2 : 3 EtOAc/hexane); H NMR (400 MHz, DMSO-d6): δ 8.22
(1H, s, C6H4 benzyl), 8.03 (2H, d, J = 8.4 Hz, C6H4), 7.93 (2H, d,
J = 8.0 Hz, C6H4), 7.68–7.60 (3H, m, C6H4 benzyl), 7.57–7.50
(2H, m, O-ClC6H4), 7.48–7.37(2H, m, O-ClC6H4); 6.65 (1H, s,
CH), 5.28–5.25 (1H, t, J = 6.0 Hz, OH), 4.59 (2H, d, J = 5.6
Hz, CH2), 3.74 (3H, s, OCH3); 13C NMR (100 MHz, DMSO-
d6): δ 52.9, 62.7, 71.4, 124.8, 125.1, 126.1, 127.3, 127.9, 128.3,
128.9(2C), 129.7, 130.0, 130.2, 131.3, 131.7, 132.3, 133.1,
138.6, 141.0, 144.0, 164.7, 168.1; mass (ES) m/z 411.2 (M + 1);
HRMS (ESI) calculated for C23H20O5Cl [M + H]+ 411.0999;
found 411.1001.
1-(2-Chlorophenyl)-2-methoxy-2-oxoethyl-4′-formyl-
[1,1′-biphenyl]-4-carboxylate (8d)
This compound was purified by using 20% EtOAc/hexane to
give the title compound (121.5 mg) as a light brown color oil; Rf
0.35 (2 : 3 EtOAc/hexane); IR (cm−1, KBr) 2955, 2150, 1753,
Acknowledgements
1
1766, 1262, 772; H NMR (400 MHz, DMSO-d6): δ 10.08 (1H,
s, CHO), 8.14 (2H, d, J = 8.4 Hz, C6H4), 8.00 (2H, d, J = 8.8
Hz, C6H4), 7.96–7.87 (4H, m, C6H4 benzaldehyde), 7.69–7.60 (2H,
m, O-ClC6H4), 7.54–7.46 (2H, m, O-ClC6H4); 6.65 (1H, s, CH),
3.74 (3H, s, OCH3); 13C NMR (100 MHz, DMSO-d6): δ 52.9,
71.4, 127.7 (2C), 127.8 (2C), 128.0 (2C), 128.1 (2C), 130.0
(2C), 130.2 (2C), 131.3, 131.6, 133.1, 135.8, 144.0, 144.2,
164.4, 168.0, 192.7; mass (ES) m/z 409.2 (M + 1); HRMS(ESI)
calculated for C23H18O5Cl [M + H]+ 409.0842; found 409.0843.
The authors (M. S. and K. S. K.) thank Dr Vilas Dahanukar for
constant support and the analytical group of DRL for spectral
data.
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