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D. Sarma et al. / Tetrahedron Letters 47 (2006) 3957–3958
Table 1. endocarboxy/exocarboxy Ratiosa,b for the reaction of 1 with 2a in different solvents and for the reactions of 1 with 2b and 2c in water alone
Solvent
endocarboxy/exocarboxy Isolated yield % Solvent
endocarboxy/exocarboxy Isolated yield (%)
Water
Methanol
Ethanol
Propan-1-ol
Butan-1-ol
Ethylene carbonate
Reaction 1 + 2b in water 0.40c
1.28
2.09
1.85
1.78
1.84
1.95
78
60
58
55
50
50
60
DMSO
Nitrobenzene
Formamide
N-Methylformamide
Ethylene glycol
n-Heptane
Reaction 1 + 2c in water 1.97d
2.29
1.73
2.09
2.57
2.14
0.97
62
49
69
65
68
35
85
a Also implies the same as exomt/endomt
.
b An average of triplicate data with a standard deviation of 0.03.
c From Ref. 9.
d From Ref. 10.
in propan-1-ol, butan-1-ol, ethanol, ethylene carbonate,
methanol, formamide, ethylene glycol and DMSO
increases by 35%, 39%, 44%, 44%, 52%, 63%, 67% and
68%, respectively, as compared to that in water alone.
References and notes
1. (a) Hoffman, R.; Woodward, R. B. J. Am. Chem. Soc.
1965, 87, 4388–4389; (b) Hoffman, R.; Woodward, R. B.
J. Am. Chem. Soc. 1965, 87, 4389–4390.
2. Saur, J.; Sustmann, R. Angew. Chem., Int. Ed. Engl. 1980,
19, 779–807.
3. Garcia, J. I.; Mayoral, J. A.; Salvetella, L. Acc. Chem. Res.
2000, 33, 658–664, and references cited therein.
4. Rideout, D. C.; Breslow, R. J. Am. Chem. Soc. 1980, 102,
7816–7817.
5. For example see: Breslow, R. Acc. Chem. Res. 1991, 24,
159–164.
6. Berson, J. A.; Hamlet, Z.; Mueller, W. A. J. Am. Chem.
Soc. 1962, 84, 297–304.
The methyl group is more hydrophobic than the carboxyl-
ate group, so the hydrophobic packing of the methyl
group in the transition state would lead to more endomt
,
corresponding to more exocarboxy. This is exactly what
one finds in this water-mediated reaction of 1 with 2a.
This suggests that hydrophobic effects influence the
stabilization of the geometry of the transition states. A
similar change in the endocarboxy/exocarboxy selectivity
was observed for the exo-selective reaction of 1 with
methyl methacrylate 2b (Scheme 1) in water9 (Table 1)
and organic solvents.6,7 In the absence of methyl group
substitution, as in the reaction of 1 with methyl acrylate,
2c (Scheme 1), hydrophobic interactions become less
important and SOIs direct the reaction to be endocarboxy
selective leading to a higher endocarboxy/exocarboxy ratio
in water (Table 1).6,10
7. Kobuke, Y.; Fueno, T.; Furukawa, J. J. Am. Chem. Soc.
1970, 92, 6548–6553.
8. Compound 1 was freshly cracked from its dimer just
before its use. Compound 2a was prepared by heating
freshly crystallized trans-crotonic acid with methanol and
sulfuric acid for 18 h using the procedure given elsewhere.7
Deionized water was used for carrying out the reactions.
The organic solvents (purity > 99+%, spectrophotometric
grade) were used in the investigation. In a typical run,
0.6 mL (7.24 mmol) of freshly cracked 1 was transferred
into 5 mL of solvent. Then 0.6 mL (6.44 mmol) of 2a was
dissolved in 5 mL of the solvent. The solution containing 1
was added to the solution containing 2a. The reaction
mixture was magnetically stirred at 27 °C for about 12 h.
The stereochemical assignments were made by condensing
crotonic acid with 1 and the resultant endo and exo bicylic
acids separated by iodolactonization as described by
Evans, D. A.; Chapman, K. T.; Bisaha, J. J. Am. Chem.
Soc. 1988, 110, 1238–1256; The 1H NMR spectrum of the
endo ester is also reported by Ikota, N. Chem. Pharm. Bull.
1989, 37, 2219–2221, The products were analyzed by gas
chromatography using a CP SIL 5CB column. The
retention times for the endo and exo products were 8.411
and 8.278 min, respectively. GC analyses of the individual
isomers were found to be 8.633 min for the endo and
8.249 min for the exo ester. GC and NMR were also used
to check the dimerization of 1, which was found to be
negligible.
The endocarboxy/exocarboxy values in water were checked
after every 30 min before the completion of the reaction
to yield the ratio as 1.28 0.08 (an average of six read-
ings) indicating that selective decomposition of either
endo or exo-product did not take place. Also the sepa-
rated endo and exo products were kept in water for
the same time without any change suggesting that the
endo product (56%) did not convert into the exo isomer
(44%) and vice versa.
In summary, it is possible to invoke the role of hydro-
phobic packing to explain the stereoselectivity of a
Diels–Alder reaction in water.
Acknowledgements
The authors thank Professor R. Breslow and an anony-
mous reviewer for making useful suggestions on this
work. D.S. and S.S.D. thank CSIR, New Delhi, for
awarding them Research Fellowships.
9. Deshpande, S. S.; Kumar, A. Tetrahedron 2002, 58, 8759–
8762.
10. Pawar, S. S.; Phalgune, U.; Kumar, A. J. Org. Chem.
1999, 64, 7055–7060.