Catalytic synthesis of 3-alkoxyacrylic acid esters under neat conditions

Article abstract of DOI:10.1080/00397910903029875

Triethylamine or Ph₃P (0.05 eq.) was found to catalyze the addition of alcohols to alkyl propiolates. The reaction occurred much more rapidly without solvent than in solvent. The E/Z ratio was relative to the reaction temperature. Water was fou

Full text of DOI:10.1080/00397910903029875

Synthetic Communications1, 40: 980–983, 2010
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910903029875
CATALYTIC SYNTHESIS OF 3-ALKOXYACRYLIC ACID
ESTERS UNDER NEAT CONDITIONS
Junhua Wang,1 Honglin Wang,2 and Hongmin Ren1
1Institute of Marine Material Science and Engineering, Shanghai Maritime
University, Shanghai, China
2School of Chemistry, Yunnan University, Kunming, China
Triethylamine or Ph3P (0.05 eq.) was found to catalyze the addition of alcohols to alkyl
propiolates. The reaction occurred much more rapidly without solvent than in solvent.
The E/Z ratio was relative to the reaction temperature. Water was found to inhibit the
reaction.
Keywords: 3-Alkoxyacrylic acid ester; catalytic; neat conditions
3-Alkoxyacrylic acid esters, in particular, methyl 3-methoxyacrylate[1] and ethyl
3-ethoxyacrylate,[2] are valuable building blocks for the synthesis of many important
compounds, for example, 2-aminothiozole-5-carboxylates,[3] an intermediate of
ceftibuten. Furthermore, many useful compounds contain the structural unit of
3-alkoxyacrylic acid ester.[4]
The general synthetic route to 3-alkoxyacrylic acid esters involves the addition
of the relevant alcohols to alkyl propiolates in the presence of solvents and stoichio-
metric amines.[5] Herein, we report a catalytic synthesis of 3-alkoxyacrylic acid esters
under neat conditions (Scheme 1).
We studied the reaction between ethanol and ethyl propiolate as a model
(Table 1). The addition of alkyl propiolate to a mixture of the catalyst and alcohol
was essential: alternative orders of addition afforded poor conversion (<20%).
Triethylamine (0.05 eq.) catalyzed the reaction to completion, but 0.01 eq. of triethy-
lamine almost did not work (Table 1, entry 3).
Generally a mixture of (E)- and (Z)-isomers was obtained. The E=Z ratio was
relative to the reaction temperature. The greater the reaction temperature, the more
(E)-isomer was afforded (entries 4 and 5). The reaction was exothermic. Water was
found to inhibit the reaction, and 95% EtOH did not add to alkyl propiolate under
such conditions (entry 6).
Received January 21, 2009.
Address correspondence to Junhua Wang, Mailbox A25, Shanghai Maritime University, 1550
Haigang Avenue, Lingang New Town, Shanghai 201306, China. E-mail: chemwoods@yahoo.com.cn
980

CATALYTIC SYNTHESIS OF 3-ALKOXYACRYLIC ACID ESTERS
981
Scheme 1. The catalyzed addition of alcohols to alkyl propiolates under neat conditions.
Table 1. Screening of reaction conditions of the solvent-free addition of ethanol to ethyl propiolate
Ratio of
EtOH=propiolate
Et3N
(eq.)
Temperature
(ꢀC)
Reaction time
(h)
Yield
(%)
Ratio of
E=Za
Entry
1
2
3
4
5
6
2
0.1
0–24
0–8
3
94
95
6.3
2.3
—
2
0.05
0.01
0.05
0.05
0.05
0.5
1
2
1.2
8–10
24–40
30–64
0–8
<10
94
0.5
0.5
1
>20
>20
—
1.2
1.2 (95% EtOH)
93
<10
aDetermined by 1H NMR.
Scheme 2. As a comparison, the reaction was run in TBME (0.5 M).
Under neat conditions, the reaction occurred rapidly and usually completed
within 30 min. As a comparison, the reaction in tert-butyl methyl ether (TBME)
(0.5 M) took much longer than in neat conditions (Scheme 2).
Phosphines also catalyze the addition of alcohols to alkyl propiolates.[6] To our
knowledge, these reported procedures use additional solvents except for one case
involving fluorous phosphines.[7] We found that Ph3P can also catalyze this reaction
in neat conditions, affording similar results.
In conclusion, 0.05 eq. of triethylamine or Ph3P catalyzed the addition of alco-
hols to alkyl propiolates. Under neat conditions, the reaction occurred much more
rapidly than in solvent. Our procedure minimizes the waste and labor and shortened
the reaction time dramatically. These advantages could be significant in the case of
large-scale synthesis.
EXPERIMENTAL
All chemicals were purchased from commercial suppliers and used as received.
1
NMR spectra were recorded on a Varian 300 instrument. The H chemical shifts
were obtained in CDCl3 with tetramethylsilane (TMS) as standard.

982
J. WANG, H. WANG, AND H. REN
Typical Procedure
Ethyl propiolate (4.90 g, 50.00 mmol) was added dropwise to a stirred solution
of triethylamine (0.25 g, 2.50 mmol, 0.05 eq.) in absolute ethanol (2.76 g, 60.00 mmol,
1.2 eq.) in a water bath. The temperature of the reaction mixture rose to 40ꢀC gradu-
ally. After the addition completed, the resulting mixture was stirred for 30 min.
Triethylamine and slightly excessive ethanol were removed on a rotarator. The
residual was (E)-ethyl 3-ethoxyacrylate, which was pure enough for many purposes.
Further purification by distillation afforded a colorless liquid. Yield: 94%.
(E)-Ethyl 3-ethoxyacrylate[8]
1
Colorless liquid, bp 36–38ꢀC=3 mmHg. H NMR: d 7.60 (d, J ¼ 12.3 Hz, 1H),
5.19 (d, J ¼ 12.6 Hz, 1H), 4.17 (q, J ¼ 6.9 Hz, 2H), 3.91 (q, J ¼ 7.2 Hz, 2H), 1.35 (t,
J ¼ 6.9 Hz, 3H), 1.28 (t, J ¼ 7.2 Hz, 3H).
(E)-Methyl 3-methoxyacrylate[9]
Colorless liquid, bp 161–162ꢀC. 1H NMR: d 7.64 (d, J ¼ 12.6 Hz, 1H), 5.20 (d,
J ¼ 12.6 Hz, 1H), 3.71 (s, 3H), 3.70 (s, 3H).
ACKNOWLEDGMENTS
We thank the Natural Science Fund of China (Grant No. 20772142) and
Shanghai Maritime University Fund (No. 2009156) for financial support.
REFERENCES
1. For examples, see (a) Tate, E. W.; Zard, S. Z. Efficient construction of polycyclic alkaloid
synthetic precursors by a xanthate-free radical addition and Mannich cyclization cascade.
Tetrahedron Lett. 2002, 43, 4683; (b) Wilkinson, J. A.; Ardes-Guisot, N.; Ducki, S.;
Leonard, J. Towards the total synthesis of tangutorine by intramolecular Diels–Alder
reaction. Tetrahedron Lett. 2005, 46, 8053.
2. For examples, see (a) Ohmoto, K.; Yamamoto, T.; Okuma, M.; Horiuchi, T.; Imanishi, H.;
Odagaki, Y.; Kawabata, K.; Sekioka, T.; Hirota, Y.; Matsuoka, S.; Nakai, H.; Toda, M.
Development of orally active nonpeptidic inhibitors of human neutrophil elastase. J. Med.
Chem. 2001, 44, 1268; (b) Cao, Y.-Q.; Wu, G.-Q.; Li, Y.-B.; Dai, Z.; Chen, B.-H. Practical
preparation of esters and thioacetates from alkyl halides and carboxylates or thioacetate
catalyzed by PEG400 without solvent. Synth. Commun. 2006, 36, 3353; (c) Gavrin, L.
K.; Lee, A.; Provencher, B. A.; Massefski, W. W.; Huhn, S. D.; Ciszewski, G. M.; Cole,
D. C.; McKew, J. C. Synthesis of pyrazolo[1,5-alpha]pyrimidinone regioisomers. J. Org.
Chem. 2007, 72, 1043.
3. Zhao, R. L.; Gove, S.; Sundeen, J. E. A new facile synthesis of 2-aminothiazole-5-
carboxylates. Tetrahedron Lett. 2001, 42, 2101.
4. For examples, see (a) Matsuo, G.; Matsukura, H.; Hori, N.; Nakata, T. Synthetic studies
on brevetoxin-B, part 1: Stereoselective synthesis of the ABC-ring system. Tetrahedron
Lett. 2000, 41, 7673; (b) Ariza, X.; Costa, A. M.; Faja, M.; Pineda, O.; Vilarrasa, J.
New protecting groups for 1,2-diols (Boc- and Moc-ethylidene): Cleavage of acetals with
bases. Org. Lett. 2000, 2, 2809; (c) Lee, E.; Choi, S. J.; Kim, H.; Han, H. O.; Kim, Y.

CATALYTIC SYNTHESIS OF 3-ALKOXYACRYLIC ACID ESTERS
983
K.; Min, S. J.; Son, S. H.; Lim, S. M.; Jang, W. S. Total synthesis of ambruticin. Angew.
Chem. Int. Ed. Engl. 2002, 41, 176; (d) Kamimura, A.; Mitsudera, H.; Matsuura, K.;
Omata, Y.; Shirai, M.; Yokoyama, S.; Kakehi, A. Stereoselective construction of multisub-
stituted tetrahydrofurans via three-component condensation reaction. Tetrahedron 2002,
58, 2605; (e) Lee, E.; Song, H. Y.; Kang, J. W.; Kim, D.-S.; Jung, C.-K.; Joo, J. M.
Lasonolide A: Structural revision and synthesis of the unnatural (ꢁ)-enantiomer. J. Am.
Chem. Soc. 2002, 124, 384.
5. For examples, see (a) Hiramatsu, N.; Takahashi, N.; Noyori, R.; Mori, Y. A stereoselective
route to multisubstituted tetrahydropyrans by vinyl radical cyclization. Tetrahedron 2005,
61, 8589; (b) Pradilla, R. F. de la; Montero, C.; Tortosa, M. Sulfinyl-mediated chirality
transfer in diastereoselective Claisen rearrangements. Org. Lett. 2002, 4, 2373; (c) Sato,
K.; Sasaki, M. Studies toward the total synthesis of gambieric acids, potent antifungal
polycyclic ethers: Convergent synthesis of the CDEFG-ring system. Org. Lett. 2005, 7,
2441; (d) Sato, K.; Sasaki, M. Convergent synthesis of the BCDEFGHIJ-ring polyether
core of gambieric acids, potent antifungal polycyclic ethers. Tetrahedron 2007, 63, 5977.
6. For examples, see (a) Sato, K.; Sasaki, M. Convergent synthesis of the BCDEFGHIJ-ring
polyether core of gambieric acids, potent antifungal polycyclic ethers. Tetrahedron 2007, 63,
5977; (b) Inoue, M.; Miyazaki, K.; Ishihara, Y.; Tatami, A.; Ohnuma, Y.; Kawada, Y.;
Komano, K.; Yamashita, S.; Lee, N.; Hirama, M. Total synthesis of ciguatoxin and
51-hydroxyCTX3C. J. Am. Chem. Soc. 2006, 128, 9352.
7. Wende, M.; Gladysz, J. A. Fluorous catalysis under homogeneous conditions without
fluorous solvents: A ‘‘greener’’ catalyst recycling protocol based upon temperature-
dependent solubilities and liquid=solid phase separation. J. Am. Chem. Soc. 2003, 125,
5861.
8. Regnouf de Vains, J.-B.; Lehn, J.-M.; Ghermani, N. E.; Dusausoy, O.; Dusausoy, Y.;
Papet, A.-L.; Marsura, A.; Friant, P.; Rivail, J. L. Synthesis, theoretical conformational
study, and x-ray structures of 2,20-dimethyl-4,40-bipyrimidine and 6,60-dimethyl-2,20-
bipyrazine. New J. Chem. 1994, 18, 701.
9. Konkol, M.; Schmidt, H.; Steinborn, D. Iridium-catalyzed addition of methanol to
terminal alkynes. J. Mol. Catal. A: Chem. 2007, 269, 119.

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copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written
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