A microwave-accelerated esterification of α,β-unsaturated acids with alkyl or aryl carbonochloridate and triethylamine in acetonitrile as a novel esterifying reagent mixture

Article abstract of DOI:10.1002/hlca.200590058

An efficient synthesis of α,β-unsaturated esters by treatment of the corresponding acids with alkyl or aryl carbonochloridate, triethylamine, and acetonitrile was accomplished for the first time under microwave irradiation for 10 min. The esters 1b-24b were isolated in 71-97% yield.

Full text of DOI:10.1002/hlca.200590058

Helvetica Chimica Acta ± Vol.88 (2005)
811
A Microwave-Accelerated Esterification of a,b-Unsaturated Acids with Alkyl
or Aryl Carbonochloridate and Triethylamine in Acetonitrile as a Novel
Esterifying Reagent Mixture1)
by Vinod Pathania, Anuj Sharma, and Arun K. Sinha*
Natural Plant Products Division, Institute of Himalayan Bioresource Technology, Palampur (H.P.) ± 176061,
India (phone: ‡ 911894-230426; fax: ‡ 911894-230433; e-mail: aksinha08@rediffmail.com)
An efficient synthesis of a,b-unsaturated esters by treatment of the corresponding acids with alkyl or aryl
carbonochloridate, triethylamine, and acetonitrile was accomplished for the first time under microwave
irradiation for 10 min.The esters 1b ± 24b were isolated in 71 ± 97% yield.
Introduction. ± In the last decade, a lot of environmentally friendly protocols have
come into fore, and most importantly among them is organic synthesis under
microwave irradiation, due to a lot of benefits inherent in microwaves [1].As a
corollary, some microwave-assisted esterifications of a,b-unsaturated acids have been
‡
reported with various reagents such as H /alcohol [2], potassium hydrogensulfate [3],
silicotungstic acid [4], montomorrillonite KSF clay/H2SO4 [5], PdCl2/P(o-Tol)3/
(bmim)PF6/Et3N (bmim ˆ 1-butyl-3-methylimidazolium) [6] and polymer-supported
O-alkyl- or O-benzylisourea [7].Esterifications of a,b-unsaturated acids under
microwave irradiation, beside being environmentally friendly, are also marked by a
considerable reduction in reaction time in comparison to conventional [8] esterifica-
tions.In this regard, some of the methods drew our attention to the possibility to
employ then in our case.Unfortunately, the promisingly high-yielding and attractive
esterification of carboxylic acids with O-benzylisourea [7] as reagent is limited by the
commercial unavailability of O-benzylisourea.Similarly, microwave-assisted esterifi-
‡
cation of cinnamic acids with H /alcohol [2] also appears to be attractive; however,
‡
when applied to 3-(2,4,5-trimethoxyphenyl)prop-2-enoic acid (1a) in H /alcohol, the
method was not compatible [9] because of poor solubility of 1a in the alcohol and rapid
evaporation of alcohol during microwave irradiation, resulting in the isolation of
unreacted starting material.Hence, an efficient and mild protocol for esterification of a
wide range of substituted a,b-unsaturated acids remains a desirable target.We report
herein a microwave-assisted synthesis of a,b-unsaturated esters utilizing commercially
available alkyl or aryl carbonochloridates, Et3N, and MeCN as a novel esterifying
mixture, resulting in moderate to high yields (71 ± 97%) after only 10 min (Scheme 1).
Results and Discussion. ± During our endeavor on microwave-assisted synthesis of
bioactive compounds [10] including cinnamic acid derivatives [11], we realized that
transforming cinnamic acids into their derivatives in basic medium is advantageous
1
)
IHBT communication No.0452.
ꢀ 2005 Verlag Helvetica Chimica Acta AG, Zürich

812
Helvetica Chimica Acta ± Vol.88 (2005)
Scheme 1
since it catalyzes the reaction and facilitates dissolution of cinnamic acids.Hence, after
‡
the failure of esterification with H /alcohol under microwave irradiation, we focused
our attention on alkyl or aryl carbonochloridate/base mixtures [12], which have been
reported as a mild and well-exploited economical reagents for the preparation of a
large number of organic molecules.However, to the best of our knowledge,
esterification with alkyl or aryl carbonochloridate has not yet been achieved under
microwave irradiation.Initially, 3-(2,4,5-trimethoxyphenyl)prop-2-enoic acid ( 1a) was
added to a mixture of CH2Cl2, Et3N, and ethyl carbonochloridate which upon
microwave irradiation (960 W) for 4 min provided ethyl 3-(2,4,5-trimethoxyphenyl)-
prop-2-enoate (1b) in 30% yield.Addition of a catalytic amount of N,N-dimethylpy-
ridin-4-amine (DMAP) [12b] to the same initial mixture did not enhance the yield of
1b but made workup more difficult (bumping of the reaction mixture after evaporation
of CH2Cl2).Various solvents were tested in the above reaction such as CHCl 3, dioxane,
and THF but none of them improved the yield of 1b (Table 1).Similarly, DMF having a
high boiling point and high dielectric constant [13], both assumed to be suitable for this
reaction, did only marginally enhance the yield of 1b to 37%.
Table 1. Effect of Solvent and Ethyl Carbonochloridate (EtOCOCl)/Triethylamine Ratioa) in the Esterification
of 3-(2,4,5-Trimethoxyphenyl)prop-2-enoic Acid (1a) into Ethyl 3-(2,4,5-Trimethoxyphenyl) Prop-2-enoate (1b)
under Microwave Irradiation (960 W)
Microwave irradiation
Solvent
EtOCOCl [mol-equiv.]
Yield [%]
2 min
4 min
4 min
4 min
4 min
4 min
4 min
10 min
10 min (ice bath)
10 min (ice bath)
10 min (ice bath)
10 min (ice bath)
300 min (conventional)
CH2Cl2
CH2Cl2
THF
CHCl3
1,4-dioxane
DMF
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
2
30
no improvement
25
28
21
37
45
no improvement
52
68
88
no improvement
64
3
excess
3
a) The amount of Et3N was kept constant (3 mol-equiv.) in all experiments because it is the minimum amount
required for dissolution of 1a.
Surprisingly, the use of MeCN [14] as a solvent increased the yield of 1b to 45%
within 4 min of irradiation; thus, MeCN appeared to be the most suitable solvent for

Helvetica Chimica Acta ± Vol.88 (2005)
813
the reaction (Table 1).But no further increase in the yield could be achieved even upon
prolonged periods of exposure (up to 10 min).Although we assumed that the
combination of Et3N and ethyl carbonochloridate should retard evaporation of the
thermolabile ethyl carbonochloridate to some extent under microwave irradiation, the
persistently low product yield suggested that some evaporation of either ethyl
carbonochloridate or esterified product was occurring.Hence, irradiations at various
low-power levels (180 ± 600 W) were explored, but there was no significant improve-
ment in the yield of 1b.This suggested that high magnetron-input power (700 ± 960 W)
led to evaporation of product, whereas a low input-power level (180 ± 600 W) was
insufficient for satisfactory esterification rates of 1a.Thus, the above irradiations were
performed in an ice bath for a prolonged time under high magnetron-input power
(960 W) inside the microwave oven, indeed, the cooling should condense the volatile
products but not adversely influence the superheating [15] effects associated with
microwaves.Finally, the microwave-assisted (960 W) reaction of 1a with ethyl
carbonochloridate/Et3N 1:1 (mol ratio) in MeCN under ice-bath cooling provided
an 88% yield of 1b in an optimized time of 10 min (Table 1).The use of 1,8-
diazabicyclo[5.4.0]undec-7-ene (DBU) or pyridine in place of Et3N was also effective;
however, there was no significant increase in yield of the product 1b.
Under conventional conditions, the reaction of 1a with ethyl carbonochloridate/
Et3N in MeCN at room temperature (5 h) under N2 gave product 1b in 64% yield; no
yield improvement was achieved even upon refluxing for 10 h.
The reaction of cinnamic acid 1a and ethyl carbonochloridate proceeds via the
unstable intermediate carboxylic carbonic anhydride, which spontaneously releases
carbon dioxide [12][16] and forms ethyl cinnamate 1b (Scheme 2).We studied the
mechanism in more detail by performing a series of experiments wherein 1a was first
activated with ethyl carbonochloridate/Et3N to form intermediate anhydride, which
upon addition of MeOH or isobutylamine did not form any methyl cinnamate or N-
Scheme 2

814
Helvetica Chimica Acta ± Vol.88 (2005)
isobutylcinnamamide, respectively (Scheme 2).Instead, in both cases, ethyl cinnamate
1b was exclusively obtained, thus confirming that the esterification mechanism is
intramolecular rather than intermolecular.Performing the above experiment under
microwave irradiation also confirms the involvement of an intramolecular mechanism
for the formation of ester 1b.
The microwave-assisted esterification was applied to the preparation of a large
number of esters [17] from a variety of structurally different a,b-unsaturated acids, i.e.,
from 2a ± 26a, and different alkyl and aryl carbonochloridates to determine the scope
and limitation of the method; the corresponding esters 2b ± 24b were isolated in
moderate to high yield (71 ± 97%; Table 2).Thus, a,b-unsaturated acids containing a 2-
furyl or 1-naphthyl substituent, or a phenyl substituent carrying electron-withdrawing
or electron-releasing groups all successfully reacted under the given esterification
conditions.However, in case of the OH-substituted cinnamic acid 25a and 26a, no ester
25b and 26b, respectively, was formed even after prolonged irradiation time; some by-
product was isolated which could not be elucidated.All esters 1b ± 24b were
characterized by spectroscopic techniques, and the data were in accordance with the
reported values [18].
Table 2. Alkyl Carbonochloridate Assisted Esterification of a,b-Unsaturated Acids 1a ± 26a into a,b-Unsaturated
Esters 1b ± 24b under Microwave Irradiation (960 W)
R
R'
Reaction time [min]
Yield [%]
1b
2b
3b
4b
5b
6b
7b
8b
9b
10b
11b
12b
13b
14b
15b
16b
17b
18b
19b
20b
21b
22b
23b
24b
25b
26b
2,4,5-trimethoxyphenyl
2,4,5-trimethoxyphenyl
3,4,5-trimethoxyphenyl
2,3,4-trimethoxyphenyl
3,4-dimethoxyphenyl
3,4-dimethoxyphenyl
3,4-dimethoxyphenyl
3,5-dimethoxyphenyl
2,5-dimethoxyphenyl
Ph
4-methoxyphenyl
4-methoxyphenyl
4-methoxyphenyl
4-methoxyphenyl
3-methoxyphenyl
4-methylphenyl
Ph
Et
Me
Et
Et
Et
Me
Bu
Et
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
20
20
88
82
83
85
84
86
91
85
84
82
88
84
82
96
86
79
74
76
97
84
86
76
84
71
±
Et
Ph
Me
Et
Bu
Ph
Et
Me
Et
Me
Et
Me
Et
Me
Et
Me
Et
Et
Ph
4-nitrophenyl
4-chlorophenyl
4-bromophenyl
3-chlorophenyl
1-naphthyl
2-furyl
4-hydroxy-3-methoxyphenyl
3-hydroxyphenyl
±

Helvetica Chimica Acta ± Vol.88 (2005)
815
Conclusions. ± A novel and efficient microwave-assisted conversion of the a,b-
unsaturated acids 1a ± 26a with alkyl or aryl carbonochloridate and Et3N in MeCN into
the corresponding esters 1b ± 24b was developed, furnishing the latter in 71 ± 97% yield
within 10 min.The method may find utility as an alternative to the currently available
protocols.
Two of us (A. S. and V. P. ) are indebted to CSIR and UGC, Delhi, for the award of SRF (A. S.) and JRF
(V. P. ), respectively. The authors gratefully acknowledge the Director of I.H.B.T., Palampur, for his kind
cooperation and encouragement.
Experimental Part
General.Alkyl (methyl, ethyl or butyl) and phenyl carbonochloridate of reagent grade and MeCN of HPLC
grade (Merck) were used without further purification.A Kenstar domestic microwave oven (2450 MHz, 960 W)
was used for reactions.Mp.:.
Mettler FP80 micromelting point apparatus; uncorrected.IR Spectra: Perkin-
Elmer spectrophotometer.NMR Spectra: Bruker Avance-300 spectrometer; 1H at 300 and 13C at 75.4 MHz;
CDCl3 soln.
Esterification of Substituted a,b-Unsaturated Acids: General Procedure.The a,b-unsaturated acid
(0.005 mol) in an Erlenmayer flask (loose funnel at the top) was dissolved in Et3N (0.015 ± 0.017 mol) and
MeCn (5 ± 6 ml) and alkyl or aryl carbonochloridate (0.015 mol) was added. The mixture was placed in an ice
bath and irradiated in the microwave oven for 10 min, with a pause of 15 s after every 2 min.After completion of
the reaction (TLC monitoring), the mixture was cooled, washed with AcOEt (3 Â 10 ml), and filtered.The
combined AcOEt layer was washed with dil.HCl (2 Â 10 ml), sat.NaHCO (2 Â 10 ml), and sat.NaCl soln,.
3
dried (Na2SO4), and evaporated: pure (by NMR) ester, i.e., no column chromatography (CC) was required,
except for phenyl cinnamates 10b and 14b which were subjected to CC (silica gel, hexane/AcOEt 9 :1) as the
crude products were comparatively impure.Spectroscopic and physical data of esters 1b ± 24b were in
accordance with the reported values [18 ± 33].
REFERENCES
[1] N.F.K.Kaiser, U.Bremberg, M.Larhed, C.Moberg, A.Hallberg,
Lidstrom, J.Tierney, B.Wathey, J.Westman, Tetrahedron 2001, 57, 9225; M.Larhed, A.Hallberg, Drug
Discov. Today 2001, 6, 406; A.K.Bose, M.S.Manhas, S.N.Ganguly, A.H.Sharma, B.K.Banik, Synthesis
2002, 11, 1578; K.J.Watkins, Chem. Eng. News 2002, 80, 17; N.E.Leadbeater, H.M.Torenius, J. Org.
Angew. Chem.,Int. Ed. 2000, 39, 3596; P.
Â
Chem. 2002, 67, 3145; L.Botella, C.Na jera, Tetrahedron Lett. 2004, 60, 5563; N.Kaval, W.Dehaen, P.
Â
Matyus, E.V.Eycken, Green Chem. 2004, 6, 125.
[2] A.K.De, A.Mitra, N.Karchaudhuri, Ind. J. Chem.,Sect. B 2000, 39, 311.
[3] S.Ling, D.Lu, Guangdong Huagong 2003, 30, 12 (Chem.Abstr. 2004, 140, 28744).
[4] J.Li, S.Wang, Henna Shitan Daxue Xuebao,Ziran Kexueban 2003, 31, 111 (Chem.Abstr. 2004, 140, 28744).
[5] S.K.Dewan, R.Singh, J. Ind. Council Chemists 2003, 20, 1 (Chem.Abstr. 2004, 140, 374892).
[6] K.S.A.Vallin, P.Emilsson, M.Larhed, A.Hallberg,
J. Org. Chem. 2002, 67, 6243.
[7] S.Crosignani, P.D.White, B.Linclau, Org. Lett. 2002, 4, 2961; S.Crosignani, P.D.White, R.Steinauer, B.
Linclau, Org. Lett. 2003, 5, 853.
[8] A.Galat, J. Am. Chem. Soc. 1946, 68, 376; U.Tataki, I.Suso, T.Matsuhisa, I.Hara, US. .Patent 4661620,
1987; S.F.Jonathan, K.Hisashi, M.P.G.Gerard, J.K.T.Richard,
Synlett 2002, 8, 1293; O.Uchikawa, K.
Fukatsu, R.Tokunoh, M.Kawada, K.Matsumoto, Y.Imai, S.Hinuma, K.Kato, H.Nishikawa, K.Hirai, M.
Miyamoto, S.Ohkawa, J. Med. Chem. 2002, 45, 4222; S.Crosignani, P.D.White, R.Steinauer, B.Linclau,
Â
Org. Lett. 2003, 5, 853; A.Palma, B.A.Frontana-Uribe, J.Ca rdenas, M.Saloma, Electrochem. Commun.
2003, 5, 455; N.N.Karade, S.G.Shirodkar, R.A.Potrekar,
Fiorini, A.Palmieri, Tetrahedron Lett. 2004, 45, 7027.
[9] A.K.Sinha, B.P.Joshi, A.Sharma, J.K.Kumar, V.K.Kaul,
Synth. Commun. 2004, 34, 391; R.Ballini, D.
Nat. Prod. Res. 2003, 17, 419.
[10] A.K.Sinha, B.P.Joshi, R.Acharya,
Patent, 6544390, 2003.
Chem. Lett. 2003, 32, 780; A.K.Sinha, B.P.Joshi, R.Dogra, U.S.
[11] A.Sharma, B.P.Joshi, A.K.Sinha,
Chem. Lett. 2003, 32, 1186.

816
Helvetica Chimica Acta ± Vol.88 (2005)
[12] a) J.M.Domagala, Tetrahedron Lett. 1980, 21, 4997; b) S.Kim, Y.C.Kim, J.I.Lee, Tetrahedron Lett. 1983,
24, 3365; c) S. Kim, J.I. Lee, Y.C. Kim, J. Org. Chem. 1985, 50, 560; d) O.Rahman, T.Kihlberg, B.
Langstrom, J. Org. Chem. 2003, 68, 3558; e) M.Sugiura, N.Yamaguchi, K.Asai, I.Maeba, Tetrahedron
Ï
Lett. 2003, 44, 6241; f) P.Hus ek, J. Chromatogr. B 1993, 615, 334.
[13] A.K.Bose, M.S.Manhas, M.Ghosh, M.Shah, V.S.Raju, S.S.Bari, S.N.Newaz, B.K.Banik, A.G.
Chaudhary, K.J.Barakat, J. Org. Chem. 1991, 56, 6968.
[14] R.P.Unnikrishnan, S.D.Endalkachew, S.V.Rajendra,
Tetrahedron Lett. 2002, 43, 2909; H.K.Jong, L.
Synth. Commun. 2004, 34, 1223; N.N.
Sangku, K.Mu-Gil, S.P.Yong, C.Sung-Kyu, K.Byoung-Mog,
Karade, S.G.Shirodkar, R.A.Potrekar, Synth. Commun. 2004, 34, 391.
[15] H.M. Kingston, L.B. Jassie, ꢁIntroduction to Microwave Sample Preparation Theory and Practiceꢂ,
American Chemical Society, Washington, D.C., 1988; K.G.Kabza, B.R.Chapados, J.L.McGrath,
J. Org.
Chem. 2000, 65, 1210.
Ï
[16] W.C.Shieh, S.Dell, O.Repic , J. Org. Chem. 2002, 67, 2188.
[17] ꢁDictionary of Organic Compoundsꢂ, Chapman & Hall, Mack Printing Company, Eastern Pennsylvania,
New York, 1982; ꢁDictionary of Natural Productsꢂ, Chapman & Hall Chemical Database, 2-6 Boundary
Row, London SE18 HN, 1994.
[18] L.H.Klemm, D.R.Olson, J. Org. Chem. 1973, 38, 3390; H.Rapoport, D.Weller, R.D.Cless, U.S.Patent,
4435572, 1984; ꢁHandbook of Proton-NMR, Spectra and Dataꢂ, Asahi Research Center, Academic Press,
Inc., Tokyo, 1987; W. R. Bowman, E. Mann, J. Parr, J. Chem. Soc.,Perkin Trans. 1 2000, 2991; H.Saito, M.
Kasai, M.Morimoto, E.Kobayashi, Y.Uosaki, Y.Kanda, H.Sano, US. .Patent, 5117006, 1992.
[19] V.L.Pardini, S.K.Sakata, R.R.Vargas, H.Viertler,
[20] M.Carmignani, A.R.Volpe, F.D.Monache, B.Botta, R.Espinal, S.C.De Bonnevaux, C.De Luca, M.
Botta, F.Corelli, A.Tafi, G.Ripanti, G.D.Monache, J. Med. Chem. 1999, 42, 3116.
Tetrahedron Lett. 1982, 23, 889; T.Iliefski, S.Li, K.Lundquist,
J. Braz. Chem. Soc. 2001, 12, 223.
[21] Y.Oikaw, T.Yoshioka, O.Yonemitsu,
Tetrahedron Lett. 1998, 39, 2413.
[22] F.Xu, R.D.Tillyer, D.M.Tschaen, E.J.J.Grabowski, P.J.Reider,
Tetrahedron: Asymmetry 1998, 9, 1651;
D.Penningt, M.A.Russell, B.B.Chen, H.Y.Chen, B.N.Desai, S.H.Docter, D.J.Edwards, G.J.Gesicki,
C.D.Liang, J.W.Malecha, S.S.Yu, V.W.Engleman, S.K.Freeman, M.L.Hanneke, K.E.Shannon, M.M.
Westlin, G.A.Nickels, Bioorg. Med. Chem. Lett. 2004, 14, 1471.
[23] L.H.Klemm, R.A.Klemm, P.S.Santhanam, D.V.White,
[24] H.M.S.Kumar, M.S.Kumar, S.Joyasawal, J.S.Yadav,
J. Org. Chem. 1971, 36, 2169.
Tetrahedron Lett. 2003, 44, 4287.
[25] V.T.Ramakrishnan, J.Kagan, J. Org. Chem. 1970, 35, 2901.
[26] D.K.Barma, A.Kundu, A.Bandyopadhyay, A.Kundu, B.Sangras, A.Briot, C.Mioskowski, J.R.Falck,
Tetrahedron Lett. 2004, 45, 5917.
[27] T.Ohno, Y.Ishino, Y.Sumagari, I.Nishiguchi, J. Org. Chem. 1995, 60, 458.
[28] H.X.Wei, S.H.Kim, G.Li, Tetrahedron 2001, 57, 3869; A.M.S.Silva, I.Alkorta, J.Elguero, V.L.M.Silva,
J. Mol. Struct. 2001, 595.
[29] R.B.Andrew, C.G.IV Louis,
Synlett 2004, 738; T.J.Speed, J.P.McIntyre, D.M.Thamattoor,
J. Chem.
Edu. 2004, 81, 1355.
[30] J.J.Bloomfield, R.Fuchs, J. Org. Chem. 1961, 26, 2993; A.B.Charette, M.K.Janes, H.Lebel, Tetrahedron:
Asymmetry 2003, 14, 867.
[31] G.Li, H.X.Wei, S.H.Kim,
Tetrahedron 2001, 57, 8407.
Â
[32] A.Costa, C.Na jera, J.M.Sansano, J. Org. Chem. 2002, 67, 5216.
[33] H.Tanaka, S.Takamuku, H.Sakurai, Bull. Chem. Soc. Jpn. 1979, 52, 801; Z.Wang, F.R.W.McCourt, D.A.
Holden, Macromolecules 1992, 25, 1576.
Received November 4,2004