Table 2 Variation of the vinyl bromide componenta
and diversity-oriented synthesis.12 This new reactivity pattern
described for vinyl halides, delivering products substituted cine
to the original C–X bond, should complement the traditional C–
C based coupling processes resulting in ipso-substitution. This
new process has the potential to find application in diversity-
oriented synthesis where it is advantageous if a functional group
can be transformed into structurally and topologically distinct
products using related reactions. Efforts to expand the general
process to alternative reactions and to develop asymmetric
variants are underway and will be reported in due course.
This work was supported by the EPSRC and Syngenta. The
EPSRC Mass Spectrometry Service at the University of Wales,
Swansea is also thanked for their assistance.
Entry
1
Vinyl halide
Yield (%)b
76
Notes and references
2
3
81
89
‡ General procedure for the addition of a-bromostyrene to alkylidene
malonates: A flask was charged with Pd(OAc)2 (3 mg, 0.01 mmol, 1
mol%), (rac)-BINAP (19 mg, 0.03 mmol, 3 mol%), toluene (4 mL) under
a nitrogen atmosphere and heated to 80 ◦C until the solution became
homogeneous (5 min). The reaction was cooled to rt, a-bromostyrene
(130 lL, 1.0 mmol), pyrrolidine (85 lL, 1.02 mmol) and sodium tert-
butoxide (106 mg, 1.1 mmol) were added and the reaction heated to
80 ◦C for 3 h. The reaction was cooled to rt, and the alkylidine malonate
(1.2–2.0 mmol) in toluene (1 mL) was added, and the reaction was
allowed to stir for 20 h at rt. The reaction was quenched with sat. NH4Cl
(1 mL) and partitioned between EtOAc (20 mL) and H2O (10 mL).
The aqueous phase was extracted with EtOAc (3 × 10 mL) and the
organic portions combined, washed with H2O (10 mL), sat. NaCl (10
mL), dried (MgSO4) and reduced in vacuo. The residue was purified by
column chromatography (SiO2) to produce the desired compound. See
the electronic supplementary information for characterisation of all new
compounds.
4
5
6
76
80
73c
1 A. De Meijere and F. Diederich, Metal-catalyzed Cross-coupling
Reactions, 2nd edn., Wiley-VCH, New York, 2004.
2 Palladium Reagents and Catalysts: New Perspectives for the 21st
Century, ed. J. Tsuji, Wiley, Chichester, 2004.
3 For recent reviews on Pd catalysed C–O and C–N bond formation,
see: (a) A. R. Muci and S. L. Buchwald, Top. Curr. Chem., 2002, 219,
131; (b) J. F. Hartwig, in Handbook of Organopalladium Chemistry
for Organic Synthesis, ed. E. Negishi, Wiley, New York, 2002; (c) D.
Prim, J.-M. Campagne, D. Joseph and B. Andrioletti, Tetrahedron,
2002, 58, 2041–2075.
4 For a recent review on the synthesis of enamines and enol ether using
metal mediated coupling reactions, see: J. R. Dehli, J. Legros and C.
Bolm, Chem. Commun., 2005, 973–986.
5 (a) J. K. Whitesell, in Comprehensive Organic Synthesis, ed.
B. M. Trost and I. Fleming, Pergamon, Oxford, 1991; (b) Enamines:
Synthesis, Structure and Reactions, 2nd edn., ed. A. G. Cook, Marcel
Decker, New York, 1987; (c) G. Stork, A. Brizzolara, H. Landesman,
J. Szmuszkovicz and R. Terrell, J. Am. Chem. Soc., 1963, 85, 207–222.
6 (a) J. Barluenga, M. A. Ferna´ndez, F. Aznar and C. Valde´s, Chem.
Commun., 2002, 2362–2363; (b) J. Barluenga, M. A. Ferna´ndez,
F. Aznar and C. Valde´s, Chem. Eur. J., 2004, 10, 494–507; (c) J.
Barluenga, M. A. Ferna´ndez, F. Aznar and C. Valde´s, Chem.
Commun., 2004, 1400–1401; (d) J. Barluenga, F. Aznar, P. Moriel
and C. Valde´s, Adv. Synth. Catal., 2004, 346, 1697–1701.
7 M. C. Willis and G. N. Brace, Tetrahedron Lett., 2002, 43, 9085–9088.
8 S. J. Blarer and D. Seebach, Chem. Ber., 1983, 116, 2250.
9 Weaker bases such as Cs2CO3 or K3PO4 were not effective. Similarly,
the ligands DPEphos and Xantphos delivered no enamine product.
10 D. W. Old, J. P. Wolfe and S. L. Buchwald, J. Am. Chem. Soc., 1998,
120, 9722–9723.
7 X = Cl
8d X = Cl
9 X = I
58
87
77
84
10 X = OTf
a Conditions: vinyl halide (1.0 equiv.), pyrrolidine (1.0 equiv.), Pd(OAc)2,
(1 mol%), (rac)-BINAP (3 mol%), NaOtBu (1.1 equiv.), toluene, 80 ◦C;
then diethyl ethylidene malonate (1.2 equiv.), rt, 20 h. b Isolated yields.
c Product obtained as a 4 : 1 mixture of diastereoisomers, as determined
1
by H NMR spectroscopy. d Pd2dba3 (1 mol%) and ligand 1 employed
(3 mol%).
using (rac)-BINAP could be employed with the vinyl chloride
example, the amination was considerably slower, resulting in
only a 58% yield of the final product (entry 7). A more efficient
reaction, producing a 87% yield, could be achieved by the use of
biphenyl ligand 1 in combination with Pd2dba3 (entry 8).10
In summary, we have demonstrated that by using palladium
catalysis to convert vinyl halides to enamines, they can be
employed as nucleophilic components in a series of Michael
addition reactions. A range of alkyl and aryl substituents are
tolerated on both the vinyl bromide and alkylidene malonate
substrates, to provide substituted Michael adducts in high
yield. The ability to unveil a reactive functional group using
mild and selective reagents is attractive in both combinatorial11
11 Molecular Diversity and Combinatorial Chemistry: Principles and
Applications, ed. M. C. Pirrung, Elsevier, 2004.
12 M. D. Burke and S. L. Schreiber, Angew. Chem., Int. Ed., 2004, 43,
46–58.
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 0 9 4 – 3 0 9 5
3 0 9 5