M. N. Masuno, T. F. Molinski / Tetrahedron Letters 42 (2001) 8263–8266
8265
Table 2. Apparent zero-order rates for cationic triethylsil-
ane reductions of enamide 2a (initial c=70–90 mM, T=
−10°C) in TFA
presumed to be catalyzed by trace acid in the NMR
solvent and proceeded at a rate that was observed to be
dependent upon the initial concentration of starting
material. Under the same conditions, spontaneous
dimerization was not seen in the electron-poor enamide
2f suggesting that suitably electron-rich arenes are
required as electrophilic acceptors in this reaction.
Reagentsa
Rate (mol dm−3 s−1
)
Et3SiH–TFA
Et3SiD–TFA
Et3SiH–TFA-d1
7.12×10–5
7.10×10–5
6.80×10–6
In summary, we have described a new preparation of
phenethylamine carbamates by mild cationic reduction
of the corresponding enamide. This reaction should find
utility in preparation of biologically active phenethy-
lamines. The facile nature of the reaction is a conse-
quence of the high electrophilicity of N-(alkoxy-
carbonyl)enamines.
a Initial concentrations. CF3COOH(D); ꢀ12 M; Et3SiH(D) ꢀ1 M
The lack of dependence of the rate of reduction on
enamide concentration suggests that the rate-limiting
step does not involve the protonation of enamide, nor
hydride transfer from silane.10 While more detailed
analysis of this kinetic isotope effect on the reduction is
beyond the scope of this communication, the kinetic
isotope effect is highly suggestive that the rate-limiting
step possibly involves dissociation of TFA prior to
proton transfer to the enamide (Fig. 1, path a).
Acknowledgements
We are grateful to Michael Toney, UC Davis, Depart-
ment of Chemistry, for helpful discussions and the staff
of the UC Riverside Mass Spectrometry Laboratory for
MS spectra. This work was supported by NIH (GM
57560).
Another possible explanation for both the rate and
kinetic isotope effect is protonation followed by a slow,
rate-limiting C-2C-1 migration of hydride, then fast
Et3SiH reduction of the incipient cation (ii, Fig. 1, path
b), however, the expected isotope effects for 1,2-2H
migration should be much smaller than those observed.
Alternatively, since the reaction is two-phase, we can-
not discount the possibility that rate-limiting physical
processes occur at the liquid–liquid interface.
References
1. Hoffman, B.; Lefkowitz, R. J. In The Pharmacological
Basis of Therapeutics; 8th ed.; Goodman, A. G.; Rall, T.
W.; Nies, A. S.; Taylor, P.; Eds.; Pergamon: New York,
1990; Chapter 10.
2. CNS Neurotransmitters and Neuromodulators: Dopamine;
Stone, T. W., Ed; CRC Press: Boca Raton, 1996.
3. (a) Rizzacasa, M. A.; Sargent, M. V.; Skelton, B. W.;
White, A. H. Aust. J. Chem. 1990, 43, 79; (b) Corey, E.
J.; Gin, D. Y. Tetrahedron Lett. 1996, 40, 7163; (c)
Corey, E. J.; Gin, D. Y. J. Am. Chem. Soc. 1996, 118,
9202.
4. For a recent examples see, (a) Couladouros, E. A.; Mout-
sos, V. I. Tetrahedron Lett. 1999, 40, 7027–7030; (b)
Bailey, K. L.; Molinski, T. F. Western Regional Meeting
of the American Chemical Society, San Francisco, CA,
25–28 October 2000; (c) Rettig, M.; Sigrist, A.; Re´tey, J.
Helv. Chim. Acta 2000, 83, 2246–2265; (d) Nakazato, A.;
Ohta, K.; Sekiguchi, Y.; Okuyama, S.; Chaki, S.;
Kawashima, Y.; Hatayama, K. J. Med. Chem. 1999, 42,
1076–1087; (e) Somanathan, R.; Rivero, I. A.; Gama, A.;
Ochoa, A.; Aguirre, G. Synth. Commun. 1998, 28, 2043–
2048.
Classical cationic silane reductions of vinyl com-
pounds,11 even N-enelactams,12 usually proceed slowly
(12–50 h) or require elevated temperatures (]50°C).
Conversely, we find that reduction of the N-(alkoxycar-
bonyl)enamines, 2, are efficient at −10°C. The ease of
reduction of these N-vinyl carbamates is clearly related
to the high electrophilicity of N-acyliminium ion, i (Fig.
1), a property that manifested itself in other ways.
For example, when 2b was left to stand in CDCl3
solution at room temperature, spontaneous dimeriza-
tion to 7 (purified yield, ꢀ23%) and other products was
observed. This electrophilic aromatic substitution,
which was also observed for 2c and 2d but not 2f, was
5. (a) Albini, A.; Fasani, E.; Dacrema, L. M. JCS Perkin
Trans. 1980, 2738–2742; (b) Slopianka, M.; Gossauer, A.
Liebigs Ann. Chem. 1981, 2258–2265.
6. (a) Kazlauskas, R.; Lidgard, R. O.; Murphy, P. T.; Wells,
R. J.; Blount, J. F. Aust. J. Chem. 1981, 34, 765–786; (b)
Mack, M.; Molinski, T. F.; Buck, E. D.; Pessah, I. N. J.
Biol. Chem. 1994, 269, 23236–23349; (c) Pessah, I. N.;
Molinski, T. F.; Meloy, T. D.; Wong, P.; Buck, E. D.;
Allen, P. D.; Mohr, F. C.; Mack, M. M. Am. J. Physiol.
1997, 41, C601–C614; (d) Chen, L.; Molinski, T. F.;
Pessah, I. N. J. Biol. Chem. 1999, 274, 32603–32612.
7. Jessup, P. J.; Petty, C. B.; Roos, J.; Overman, L. E. In
Coll. Vol. Org. Syn.; Vol. 6, pp. 95–101.
Figure 1. Two possible mechanisms of cationic enamide
reduction in the presence of CF3COOH and Et3SiH.