M. C. Willis, G. N. Brace / Tetrahedron Letters 43 (2002) 9085–9088
9087
(strategic research fund) for their support of this study.
The EPSRC Mass Spectrometry Service at the Univer-
sity of Wales Swansea is also thanked for their
assistance.
References
1. For general reviews on enamine chemistry, see: (a)
Whitesell, J. K. In Comprehensive Organic Synthesis;
Trost, B. M.; Fleming, I. Eds.; Oxford: Pergamon, 1991;
(b) Cook, A. G., Ed., Enamines; New York: Marcel
Decker, 1988.
Scheme 2.
2. For example: (a) Aznar, F.; Valde´s, C.; Cabal, M.-P.
Tetrahedron Lett. 2000, 41, 5683; (b) Hird, N. W.; Irie,
K.; Nagai, K. Tetrahedron Lett. 1997, 38, 7111.
3. For an example, see: Abdel-Magid, A. F.; Carson, K. G.;
Harris, B. D.; Maryanoff, C. A.; Shah, R. D. J. Org.
Chem. 1996, 61, 3849.
4. White, W. A.; Weingarten, H. J. Org. Chem. 1967, 32,
213.
5. Martin, S. F.; Gompper, R. J. Org. Chem. 1974, 39, 2814.
6. For a review on the uses and preparations of triflate
derivatives, see: Ritter, K. Synthesis 1993, 735.
7. For reviews, see: (a) Hartwig, J. F. In Modern Amination
Methods; Ricci, A. Ed.; Weinheim: Wiley-VCH, 2000; (b)
Wolfe, J. P.; Wagaw, S.; Marcoux, J.-F.; Buchwald, S. L.
Acc. Chem. Res. 1998, 31, 805; (c) Muci, A. R.; Buch-
wald, S. L. Top. Curr. Chem. 2002, 219, 131.
Scheme 3.
The effectiveness of a second vinyl triflate was also
examined; reaction of tetralone derived triflate 7 under
the standard reaction conditions, followed by direct
reduction provided the corresponding enamine in 100%
conversion and the isolated amine 8 in 66% yield
(Scheme 2).
8. During the course of this study an example of an
intramolecular palladium catalysed coupling between a
vinyl bromide and an amide was reported; Kozawa, Y.;
Mori, M. Tetrahedron Lett. 2002, 43, 111; an example of
the intermolecular palladium catalysed coupling of vinyl
bromides and azoles has also recently appeared: Lebedev,
A. Y.; Izmer, V. V.; Kazyul’kin, D. N.; Beletskaya, I. P.;
Voskoboynikov, A. Z. Org. Lett. 2002, 4, 623.
The direct hydrolysis of enol triflates to the analogous
ketones is not a straightforward transformation; direct
reaction under either basic or acidic conditions gener-
ally results in decomposition.15 Our observations that
the enamines prepared by the palladium catalysed CꢀN
bond forming process were prone to hydrolysis pre-
sented the possibility of adapting this method to a mild
triflate hydrolysis procedure. Triflate 1 was reacted
under the standard conditions to provide the corre-
sponding morpholine derived enamine. This was then
treated with an acetic acid/water/THF mix to deliver
the parent ketone 9 in 73% yield (Scheme 3).
9. Wolfe, J. P.; Tomori, H.; Sadighi, J. P.; Yin, J.; Buch-
wald, S. L. J. Org. Chem. 2000, 65, 1158.
10. (a) Yin, J. J.; Buchwald, S. L. J. Am. Chem. Soc. 2002,
124, 6043; (b) Hamann, B. C.; Hartwig, J. F. J. Am.
Chem. Soc. 1998, 120, 7369.
11. Yang, B. H.; Buchwald, S. L. Org. Lett. 1999, 1, 35.
12. Starting triflate recovered in 93% yield.
In summary, we have shown that vinyl triflates can
undergo palladium catalysed CꢀN bond formation to
deliver the corresponding enamines in excellent conver-
sions. Isolation of the enamines proved difficult, how-
ever they were successfully reduced in situ to deliver the
corresponding amines. Alternatively, the process can be
employed as a mild triflate hydrolysis procedure
whereby the crude enamines are reacted with aqueous
acid to provide the corresponding ketone. These mild
methods should find application where acidic condi-
tions must be avoided. Efforts to expand the range of
the process and to include vinyl halide substrates are
underway and will be reported in due course.
13. General procedure; To an oven dried flask, Pd(OAc)2 (8
mg, 0.035 mmol) and rac-BINAP (33 mg, 0.052 mmol)
were added under nitrogen. The flask was flushed with
nitrogen, before the triflate (0.70 mmol) and amine (1.40
mmol) were added. The mixture was taken up in dry
toluene (1.40 ml) and Cs2CO3 (0.45 g, 1.40 mmol) was
added. The reaction was stirred at 80°C for 20 h under
nitrogen. After cooling, the reaction mixture was diluted
with Et2O (10 ml) and the suspension filtered through a
celite pad. The precipitate was washed with Et2O (20 ml)
and the filtrate was reduced in vacuo. The crude product
was subjected to 1H NMR spectroscopy for determina-
tion of the percentage conversion to product, or taken
immediately into the next reaction.
14. Selected NMR data for isolated amines; Table 2, entry 1:
2:1 mix of diastereomers, major isomer, lH (CDCl3, 300
MHz) 0.85 (9H, s), 1.00–1.12 (1H, m), 1.29–1.42 (6H, m),
1.93–2.04 (2H, m), 2.09–2.14 (1H, m), 2.36–2.46 (4H, m),
Acknowledgements
We thank the University of Bath and AstraZeneca