An efficient method for the preparation of mono α-aryl derivatives of diethyl malonate and ethyl cyanoacetate using ethyl-1-imidazole carbamate (EImC)

Article abstract of DOI:10.1016/j.tetlet.2011.12.067

An efficient method for the synthesis of mono α-aryl derivatives of diethyl malonate and ethyl cyanoacetate using ethyl-1-imidazole carbamate (EImC) has been described. Using this method many sterically hindered and highly substituted mono α-aryl derivatives of diethyl malonate and ethyl cyanoacetate were synthesized in high yield.

Full text of DOI:10.1016/j.tetlet.2011.12.067

Tetrahedron Letters 53 (2012) 1060–1062
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
An efficient method for the preparation of mono a-aryl derivatives
of diethyl malonate and ethyl cyanoacetate using ethyl-1-imidazole
carbamate (EImC)
Manoranjan Behera a, R. Venkat Ragavan a, , M. Sambaiah a, Balaiah Erugu a, J. Rama Krishna Reddy a,b
,
⇑
K. Mukkanti b, Satyanarayana Yennam a
a Chemistry services, GVK Biosciences Pvt. Ltd, Plot No. 28, IDA, Nacharam, Hyderabad 500 076, A.P., India
b Chemistry Division, Institute of Science and Technology, JNT University, Kukatpally, Hyderabad 500 072, A.P., India
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient method for the synthesis of mono
etate using ethyl-1-imidazole carbamate (EImC) has been described. Using this method many sterically
a
-aryl derivatives of diethyl malonate and ethyl cyanoac-
Received 17 November 2011
Revised 15 December 2011
Accepted 16 December 2011
Available online 24 December 2011
hindered and highly substituted mono
were synthesized in high yield.
a-aryl derivatives of diethyl malonate and ethyl cyanoacetate
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Ethyl-1-imidazole carbamate
LiHMDS
Mono-a-aryl derivatives of diethyl
malonate and ethyl cyanoacetate
The century old alkylation chemistry of diethyl malonate and
related compounds continue to see wide use in organic synthesis.1
dium-catalyzed coupling of enolates with aryl halides.15 Another
important protocol involves arylation of activated methylene com-
pounds mediated by copper salts.16 Recently, proline has also been
used along with CuI for c-arylation of diethyl malonate.17 But some
of the methods suffer from serious drawbacks and limitations viz.
long reaction times, the high cost of Pd catalyst and the need for
stoichiometric amounts of copper salts.18 Hartwig reported that
di-alkyl malonate did not react with pyridyl halides or halobenzo-
nitriles in the presence of palladium catalysts.19
a
-Aryl malonates have been used as effective modulators in mam-
malian cell membranes and as enzyme inhibitors.2 For the synthe-
sis of highly functionalized compounds containing quaternary
centers3; malonate chemistry remains the method of choice. A
broad range of synthetically valuable materials is derived from
a
-aryl malonates.4–7 For example,
potential in the synthesis of
-Aryl carboxylic acids and acid derivatives comprise an impor-
a
-aryl malonates have a notable
a
-aryl carboxylic acids.8
a
Among other reagents for arylation of diethyl malonate, Jeff’s
group has used ethyl cyanoformate and phenyl acetic acid ester
tant class of organic molecules. There has been much interest in
these molecules because of their occurrence in a myriad of natural
products and wide applications in pharmaceutical chemistry.9
to prepare the
a
-aryl malonate.20 Recently, the same method has
been used for the preparation of 1,3-porpane diamine derivatives21
But it was not generalized for various substrates. Also there are few
reports using diethyl carbonate. But the main disadvantage is that
one has to use large excess of diethyl carbonate and base.22
a-Aryl acetic acids (e.g., indomethancin, sulindac, ibufenca, dicofe-
nac) and -aryl propionic acids (e.g., ibuprofen, naproxen, ketopro-
a
fen) are two main categories of nonsteroidal anti-inflammatory
drugs (NSAIDS).10 Aryl cyanoacetates can be used to generate a vari-
ety of nitrogen containing products such as amino alcohols11 and
b-amino acids12 while also being valuable as chiral shift reagents.13
Among the many methods available14 for the synthesis of
a-aryl
compounds, a great deal of attention has been given to the palla-
COOEt
N
EtOOC COOEt
N COOEt
2
⇑
Corresponding author. Tel.: +91 6628 1348; fax: +91 6628 1505.
E-mail addresses: ragavachem@gmail.com, venkatragavan.r@gvk.bio.com
LiHMDS, THF
3a
1a
(R. Venkat Ragavan).
Scheme 1. Synthesis of diethyl 2-phenyl malonate (2a).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.12.067

M. Behera et al. / Tetrahedron Letters 53 (2012) 1060–1062
1061
Table 2
Synthesis of mono
During our research program on preparation of heterocycles we
needed to synthesize number of -aryl compounds with various
degrees of substituent on aromatic ring. Intrigued by the finding
of Saprong et al23 that methyl imidazole carbamate (MImC) can
be used for the esterification and amidation of carboxylic acids,
we ventured to explore the potential use of ethyl imidazole carba-
a-aryl diethyl malonates
a
Entry
1
Substrate
Product
Yielda (%)
COOEt
EtOOC COOEt
81
76
75
69
3a
1a
COOEt
EtOOC COOEt
mate (EImC) for the preparation of
Herein, we wish to report that EImC24 can be used efficiently for
the preparation of -aryl diethyl malonate and ethyl cyanoacetate
a-aryl malonate derivatives.
3b
2
3
4
1b
OCH3
COOEt
Cl
1c
a
OCH3
EtOOC COOEt
starting from the phenyl acetic acid ester (Scheme 1). Ethyl-1-
imidazole carbamate (EImC) 2 was prepared by treating ethyl chlo-
roformate with imidazole in the presence of triethylamine in DCM
in very good yield. Initially, phenyl acetic acid ethyl ester 1a was
chosen as model substrate. Thus, when compound 1a was reacted
with EImC in the presence of LiHMDS in THF at 0 °C for 6 h, the
compound 3a was obtained with 44% yield along with some un-
wanted product. When we repeated the same reaction at À78 °C,
better yield was obtained and no by product was observed. 1H
NMR of compound 3a clearly shows the characteristic peak at 4.6
as singlet besides ester and aromatic peaks.
To optimize the reaction conditions, various bases and solvents
were screened whose results are summarized in Table 1. Among
the bases screened we found that LiHMDS produced the best yield,
while KHMDS gave 67% yield. Use of sodium hydride and potas-
sium tert-butoxide resulted in poor yield and also 10–20% of unre-
acted phenyl acetic acid ethyl ester was recovered in both the
cases. Among the solvents screened we observe that both the sol-
vents viz. THF and toluene are good for these reactions.
F
F
Cl
3c
COOEt
EtOOC COOEt
3d
1d
OCF3
COOEt
OCF3
EtOOC COOEt
5
78
1e
F
COOEt
Cl
3e
F
F
F
EtOOC COOEt
Cl
Cl
Cl
6
7
72
77
3f
1f
Cl
COOEt
F
1g
Cl
EtOOC COOEt
F
F
F
3g
COOEt
EtOOC COOEt
Once the reaction condition was standardized, various highly
substituted phenyl acetic acid ethyl esters were reacted with EImC
(2) to give the compounds 3a–p (Table 2)25 The required phenyl
acetic acid ethyl esters were either commercially available or pre-
pared from corresponding acids by esterification with EtOH in the
8
9
78
65
1h
3h
Cl
COOEt
Cl
EtOOC COOEt
presence of cat. H2SO4. All compounds 4–17 were well character-
13
1i
ized by 1H NMR, IR and
C NMR (for unknown compounds).
3i
The purity of all compound were measured by LC–MS analysis.
It is noteworthy to mention here that previously inaccessible
pyridine analogues and benzonitrile analogues were synthesized
in very good yield (entries 14–16).
COOEt
EtOOC COOEt
10
11
12
75
80
82
3j
1j
As indicated in Table 2, sterically hindered analogues (entries 1,
3 and 6) and substrates having the strong electron withdrawing
groups (entries 5, 10 and 15) gave the products in very good yield
without any difficulties. We did not observe the self condensed
products of phenyl acetic acid ethyl esters in any of the cases.
Using the condition above, ortho-substitution is tolerated to give
the products in good yield.
CF3
COOEt
CF3
EtOOC COOEt
3k
1k
COOEt
F
1l
Br
COOEt
EtOOC COOEt
F
3l
Similar approach was adapted to synthesize26 the mono
a-aryl
derivatives of ethyl cyanoacetate (Scheme 2) and the results are gi-
ven in Table 3. All the substrates reacted well under these condi-
tions and did not produce any by products. Also, we did not
observe the hydrolysis of cyano group in this condition.
Br
EtOOC COOEt
F
1m
F
13
14
15
75
84
In conclusion, we developed an efficient and simple method to
3m
Cl
EtOOC COOEt
synthesize the mono
a-aryl diethyl malonates and mono a-aryl
Cl
COOEt
ethyl cyanoacetates in good yield using LiHMDS and EImC.
1n
3n
N
N
Table 1
Effect of solvent and base on the yield of 3a
COOEt
F
1o
CN
COOEt
EtOOC COOEt
Yielda (%)
F
3o
Entry
Base
Solvent
72
79
1
2
3
4
5
6
LiHMDS (1 M in THF)
KHMDS (1 M in THF)
LiHMDS (1 M in THF)
NaH
THF
THF
THF
THF
THF
Toluene
81
67
44b
42
33
78
CN
EtOOC COOEt
t-BuOK
16
LiHMDS (1 M in THF)
3p
1p
N
N
a
Isolated yield.
Reaction performed at 0 °C.
b
a
Isolated yield.

1062
M. Behera et al. / Tetrahedron Letters 53 (2012) 1060–1062
Okada, H.; Nakamata, K.; Yamamoto, T.; Sekine, F. Heterocycles 1996, 43, 1031;
N
CN
EtOOC CN
N COOEt
(d) Patel, R.; Banerjee, A.; Chu, L.; Brozozowski, D.; Nanduri, V.; Laszlo J. Am. Oil.
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8. Carey, F. A.; Sunderberg, R. J. Advanced Organic Chemistry Part B: Reaction and
Synthesis; Plenum Press: New York, 1990. pp 13–16.
2
LiHMDS, THF
4a
5a
F
F
Scheme 2. Synthesis of ethyl 2-cyano-2-(4-fluorophenyl) acetate (5a).
9. (a) Sheldrick, G. M.; Jones, P. G.; Kennard, O.; Williams, D. H.; Smith, G. A.
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Table 3
Synthesis of mono
a-aryl ethyl cyanoacetates
S. No
Substrate
Product
Yielda (%)
68
CN
EtOOC CN
1
4a
5a
F
F
CN
EtOOC CN
F
4b
F
2
3
71
73
5b
Br
CN
Br
EtOOC CN
F
4c
F
5c
Cl
CN
Cl
EtOOC CN
4
5
81
78
5d
EtOOC CN
5e
OMe
4d
CN
4e
OMe
18. (a) Jiang, Y.; Wu, N.; Wu, H.; He, M. Synlett 2005, 2731; (b) Fox, J. M.; Huang, X.;
Chieff, A.; Buchwald, S. L. J. Am. Chem. Soc. 2000, 122, 1360; (c) Culkin, D. A.;
Hartwig, J. F. J. Am. Chem. Soc. 2001, 123, 5816.
a
Isolated yield.
19. Beare, N. A.; Hartwig, J. F. J. Org. Chem. 2002, 67, 541.
20. Katz, C. E.; Aube, J. J. Am. Chem. Soc. 2003, 125, 13948.
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Urdiales, E.; Gotor-Fernandez, V.; Gotor, V. J. Org. Chem. 2009, 74, 2571.
22. (a) Richon, A. B.; Maragoudakis, M. E.; Wasvary, J. S. J. Med. Chem. 1982, 25, 745;
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1996, 43, 1031.
Acknowledgments
We are grateful to GVK Biosciences Pvt. Ltd for the financial
support and analytical data. We thank Dr. Balram Patro for his
encouragement and motivation.
23. Heller, S. T.; Sarpong, R. Org. Lett. 2010, 12, 4572.
24. Heller, S. T.; Sarpong, R. Tetrahedron 2011, 67, 8851.
25. Typical experimental for preparation of compound 3a: To a stirred solution of
phenyl acetic acid ethyl ester 1a (1 g, 6.09 mmol) in THF (10 mL) was added
LiHMDS (9.1 ml, 1 M sol. in THF, 7.31 mmol) at À78 °C and the reaction
mixture was stirred at this temperature for 30 min. Ethyl-1-imidazole
carboxylate 2 (1.2 g, 9.146 mmol) in dry THF (3 ml) was added drop wise to
the reaction mixture at À78 °C and stirred at rt for 3 h. The reaction mixture
was quenched with saturated ammonium chloride solution and extracted with
ethyl acetate. The combined organic layer was washed with water, saturated
brine solution and dried over Na2SO4. The solvent was evaporated under
reduced pressure and the crude product was chromatographed on a silica gel
column. Elution with 4% ethyl acetate/pet ether gave the pure compound 3a
(1.1 g, 81% yield) as a colorless liquid.
26. Typical experimental for preparation of compound 5a: To a stirred solution of
compound 4a (700 mg, 5.18 mmol) in THF (10 mL) was added LiHMDS (6.2 ml,
1 M sol. in THF, 6.2 mmol) at 0 °C and the reaction mixture was stirred at this
temperature for 30 min. Ethyl-1-imidazole carboxylate 2 (870 mg, 6.22 mmol)
in dry THF (3 ml) was added drop wise to the reaction mixture at 0 °C and
stirred at rt for 4 h. The reaction mixture was quenched with saturated
ammonium chloride solution and extracted with ethyl acetate. The combined
organic layer was washed with water, saturated brine solution and dried over
Na2SO4. The solvent was evaporated under reduced pressure and the crude
product was chromatographed on a silica gel column. Elution with 10% ethyl
acetate/pet ether gave the pure compound 5a (720 mg, 68% yield) as a colorless
liquid.
Supplementary data
Supplementary data (copies of 1H NMR & 13C NMR and LC–MS
of the compounds) associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.12.067.
References and notes
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