Regiochemistry of the reaction of 2-acylcyclohexanones with trimethyl orthoformate: A convenient one-pot method to obtain 7,7-dimethoxy alkanoate methyl esters

Article abstract of DOI:10.1055/s-1999-2725

The regiochemistry of the reaction of 2-acylcyclohexanones [containing 2-acyl groups, C(O)R, where R = Me, Et, CH₂Ph, CF₃, Ph and OMe] with trimethyl orthoformate to obtain the corresponding acetal derivative is reported. Compounds w

Full text of DOI:10.1055/s-1999-2725

LETTER
789
Regiochemistry of the Reaction of 2-Acylcyclohexanones with Trimethyl
Orthoformate: A Convenient One-Pot Method to Obtain 7,7-Dimethoxy
Alkanoate Methyl Esters
Marcos A. P. Martins,* Giovani P. Bastos, Adilson P. Sinhorin, Alex F. C. Flores, Helio G. Bonacorso, Nilo Zanatta
Departamento de Química, Universidade Federal de Santa Maria, 97.105-900 Santa Maria, RS, Brazil
Fax +55 55 2208031; E-mail: mmartins@base.ufsm.br http://www.ufsm.br/nuquimhe
Received 14 March 1999
Abstract: The regiochemistry of the reaction of 2-acylcyclohex-
anones [containing 2-acyl groups, C(O)R, where R = Me, Et,
CH2Ph, CF3, Ph and OMe] with trimethyl orthoformate to obtain the
corresponding acetal derivative is reported. Compounds with R =
alkyl groups showed to be convenient synthons for a one-pot meth-
od to obtain 7,7-dimethoxy alkanoate methyl esters under mild
conditions. The results of the reaction of 2-acetylcyclopentanone,
-heptanone and -octanone with trimethyl orthoformate are also re-
ported.
Key words: acetals, β-diketones, 2-acylcycloalkanones, trimethyl
orthoformate, reverse claisen condensation
b-Alkoxyvinyl halomethyl ketones or -diketone deriva-
tives are used by our research group as precursors for the
synthesis of 5-, 6- and 7-membered heterocycles.1,2 These
Scheme
precursors have been synthesized by the haloacetylation
of enol ethers.3-5 As a part of our research program, we de-
veloped the synthesis of -alkoxyvinyl trihalomethyl ke-
tones or -diketone derivatives from the trihaloacetylation
of enol ethers generated in situ4,5 from the respective ace-
perature (25-30 °C), after which time it was neutralized
tals, as an alternative one-pot procedure with great advan-
tages over the direct acylation of enol ethers. However,
during the preparation of the 2-acetyl cyclohexanone di-
methyl acetal, cleavage of the cyclohexanone ring afford-
ing 7,7-dimethoxyoctanoate methyl ester was observed.
Although cleavage of the cyclohexanone ring (reverse
Claisen condensation) was observed by several authors6
(e.g., the synthesis of 7-oxoalkanoic acid derivatives from
the reaction of acylcyclohexanones with sodium hydrox-
ide), we have not found reported in the literature the re-
verse Claisen condensation under mild conditions and in
a one-pot procedure to obtain 7-oxoalkanoate ester acetal
derivatives. The aim of this work is to determine the effect
of the acyl group on the regiochemistry of the acetaliza-
tion and the optimization of the reaction conditions to ob-
tain 7,7-dimethoxy alkanoate methyl esters. The reaction
of 2-acetylcyclopentanone, -heptanone and -octanone
with trimethyl orthoformate was also studied (Scheme).
with dry sodium carbonate and the products 5-9 were pu-
rified by distillation (Table).
In the case of cyclohexanone derivatives 2a-f, the regio-
chemistry of the reaction was governed by the electronic
substituent effect of R. When R is Me, Et or CH2Ph, the
cleavage of the cyclohexanone ring (C1-C2 bond) was ob-
served and 7,7-dimethoxyalkanoate methyl esters 9a-c
were obtained. On the other hand, when R is Ph, CF3 or
OMe, 2-acyl cyclohexanone dimethyl acetals 6d-f were
obtained. These results suggest that RC(O) groups with a
large electron withdrawing effect led to the cleavage of
the cyclohexanone ring and the RC(O) groups with an at-
tenuated electron withdrawing effect led to the cyclohex-
anone dimethyl acetals.
The reaction of cyclopentanone 1a with trimethyl ortho-
formate leads to the isolation of acetal 5a, and the cyclo-
heptanone 3a led to the acetal 7a by cleavage of C2-
COMe bond. The reaction of cyclooctanone derivative 4a
leads to the isolation of acetal 8a, similar to products 6d-
f obtained from cyclohexanone derivatives 2d-f. Thus,
while 2-acetylcyclohexanone 2a and 2-acetylcyclohep-
tanone 3a react with trimethyl orthoformate to give the re-
verse Claisen products 9a (with cleavage of C1-C2 bond)
and 7a (with cleavage of C2-COMe bond), respectively;
the reaction of 2-acetylcyclopentanone 1a and 2-acetylcy-
2-Acyl cycloalkanones 1a-f, 2a, 3a, 4a were synthesized
from the reaction of the cycloalkanone enamine derivative
with the respective acyl halide or anhydride as reported by
Stork et al. .7 The reaction of 1-4 with trimethyl orthofor-
mate and p-toluenesulfonic acid in methanol as solvent
was carried out in a molar ratio 1:1.5:0.01, respectively.
The reaction mixture was kept for 24 hours at room tem-
Synlett 1999, No. 6, 789–791 ISSN 0936-5214 © Thieme Stuttgart · New York

790
M. A. P. Martins et al.
LETTER
clooctanone 4a react with trimethyl orthoformate to give References and Notes
acetals 5a and 8a, respectively, with no C-C bond cleav-
(1) Martins, M.A.P.; Zoch, A.N.; Bonacorso, H.G.; Zanatta, N.;
Clar, G. J. Heterocycl. Chem. 1995, 32, 739.
Martins, M.A.P.; Flores, A.F.C.; Freitag, R.A.; Zanatta, N. J.
Heterocycl. Chem. 1995, 32, 731.
age.
Selected physical and spectral data of 5a, 6d-f, 7a, 8a, 9a-
c are presented in the Table.8
Martins, M.A.P.; Flores, A.F.C.; Freitag, R.A.; Zanatta, N. J.
Heterocycl. Chem. 1996, 33, 1223.
Martins, M.A.P.; Siqueira, G.M.; Bastos, G. P.; Zanatta, N. J.
Heterocycl. Chem. 1996, 33, 1.
Martins, M.A.P.; Freitag, R.A.; Flores, A.F.C.; Zanatta, N.
Synthesis 1995, 1491.
Synthesis of 7,7-Dimethoxyalkanoate Methyl Esters
9a-c and Cycloalkanone Derivatives 5a, 6d-f, 7a, 8a;
General Procedure:
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(2) Zanatta, N.; Pacholski, I.L.; Blanco, I.; Martins, M.A.P.
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Trimethyl orthoformate (16.4 mL, 150 mmol) and p-tolu-
enesulfonic acid (0.15g, 0.78 mmol) in dry methanol (30
mL) were added to an Erlenmeyer flask (250 mL) with 2-
acyl cycloalkanone 1-4 (100 mmol) and the mixture was
Zanatta, N.; Madruga, C.C.; Clerici, E.; Martins, M.A.P. J.
Heterocycl. Chem. 1995, 32, 735.
o
kept for 24 hours at room temperature (25-30 C). The
mixture was neutralized with sodium carbonate and fil-
tered. The solvent was removed in vacuo and products 5a,
6d-f, 7a, 8a, 9a-c were purified by distillation, (see Ta-
ble).
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Acknowledgement
The authors thank the Conselho Nacional de Desenvolvimento
Científico e Tecnológico (CNPq / PADCT), Fundação de Amparo
à Pesquisa do Estado do Rio Grande do Sul (FAPERGS) for finan-
cial support. The fellowships from CNPq, CAPES and FAPERGS
are also acknowledged.
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LETTER
A Convenient One-Pot Method to Obtain 7,7-Dimethoxy Alkanoate Methyl Esters
791
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were used as obtained from commercial suppliers without
further purification. Yields listed in the Table are of isolated
compounds and all boiling points are uncorrected. Elemental
analysis was carried out on an Elemental Analysensysteme
Vario EL apparatus. 1H and 13C NMR spectra were recorded
on a Bruker DPX-200 (1H at 200.13 MHz and 13C at 50.32
MHz), 298 K, digital resolution of 0.01 ppm, 0.5 M in
chloroform-d1/TMS.
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Article Identifier:
1437-2096,E;1999,0,06,0789,0791,ftx,en;S08598ST.pdf
Synlett 1999, No. 6, 789–791 ISSN 0936-5214 © Thieme Stuttgart · New York