H. J. Davies et al. / Tetrahedron Letters 48 (2007) 1461–1464
Table 2. Generality of the reaction processa
1463
observed whereas in the DMF:H2O mixture (9:1) the
adduct was isolated in an excellent 84% yield. Less electron
deficient aldehyde substrates were found to be slower, in
line with the observations of others, the reaction of fur-
furaldehyde and methyl vinyl ketone taking 4 days to
reach completion (Table 2, entry 12, 89%).
Entry
ArCHO
Product
Yield
OH
O
CHO
CHO
1b
67
F
F
OH
O
In accordance with the observations of Shi, examination
of each of the adducts prepared in this study (Tables 1
and 2) by HPLC on a chiral stationary phase showed
each to be racemic.
2c
87
42
F
F
OH
O
O
CHO
3b
In summary, we have found that in the proline/imidaz-
ole catalysed Baylis–Hillman reaction between methyl
vinyl ketone and aldehydes, the nature of the solvent
is crucial for effective catalyst activity. Addition of small
amounts of water brings about more effective reaction
with a solvent mixture of DMF:H2O (9:1) being opti-
mal. This solvent mixture is effective with a variety of
substrates within the reaction, with yields being substan-
tially lower in the absence of water. Increasing or
decreasing the amount of water present is detrimental
to the observed yield. Due to the significant amount of
interest in this type of Baylis–Hillman reaction and its
potential for the development of an asymmetric variant,
the incorporation of water in the reaction medium
appears also to be an important factor in optimising
catalyst activity.
O2N
NO2
O2N
NO2
OH
CHO
NO2
4c
81
O2N
O2N
NO2
OH
O
CHO
5b
56
80
Cl
Cl
Cl
Cl
Cl
Cl
OH
O
CHO
Cl
6c
Cl
O
OH
Acknowledgements
CHO
NO2
7b
58
73
The authors wish to thank the EPSRC for financial sup-
port, and the HRMS service at Swansea for analyses.
NO2
OH
O
CHO
NO2
8c
References and notes
NO2
1. (a) List, B. Chem. Commun. 2006, 819–824; (b) Seayad, J.;
List, B. Org. Biomol. Chem. 2005, 3, 719–724; (c)
Berkessel, A.; Gro¨ger, H. Asymmetric Organocatalysis;
Wiley-VCH: Weinheim, Germany, 2005; (d) Dalko, P. I.;
Moisan, L. Angew. Chem., Int. Ed. 2004, 43, 5138–5175;
(e) Methot, J. L.; Roush, W. R. Adv. Synth. Catal. 2004,
346, 1035–1050; (f) Clarke, M. L. Lett. Org. Chem. 2004,
1, 292–296; (g) Armstrong, A. Angew. Chem., Int. Ed.
2004, 43, 1460–1462; (h) France, S.; Guerin, D. J.; Miller,
S. J.; Lectka, T. Chem. Rev. 2003, 103, 2985–3012; (i)
Schreiner, P. R. Chem. Soc. Rev. 2003, 32, 289–296; (j)
Dalko, P. I.; Moisan, L. Angew. Chem., Int. Ed. 2001, 40,
3726–3748.
F
F
OH
O
F
CHO
F
F
9b
0
F
F
F
F
F
F
F
F
F
OH
O
CHO
F
10c
84
F
F
F
F
F
2. For some recent advances in organocatalysis see: (a)
Kocˇovsky´, P., Malkov, A. V., Eds.; Tetrahedron 2006, 62,
243–502; (b) Houk, K. N., List, B., Eds.; Acc. Chem. Res.
2004, 37, 487–631.
3. (a) Baylis, A. B.; Hillman, M. E. D. German Patent
2,155,113, 1972; Chem. Abstr. 1972, 77, 34174; (b)
Hillman, M. E. D.; Baylis, A. B. US Patent 3,743,669,
1972; Chem. Abstr. 1972, 77, 34174q; (c) Morita, K.;
Suzuki, Z.; Hirose, H. Bull. Chem. Soc. Jpn. 1968, 41,
2815.
4. For reviews see: (a) Berkessel, A.; Gro¨ger, H. Asymmetric
Organocatalysis; Wiley-VCH: Weinheim, Germany, 2005;
(b) Basavaiah, D.; Rao, A. J.; Satyanarayana, T. Chem.
Rev. 2003, 103, 811–892; (c) Langer, P. Angew. Chem., Int.
Ed. 2000, 39, 3049–3052.
OH
O
O
O
11b,d
33
89
CHO
O
O
OH
O
12c,d
CHO
a All reactions performed at 1 M concentration at 25 ꢁC for 24 h except
entries 11 and 12.
b Reactions performed in DMF.
c Reactions performed in DMF:H2O (9:1).
d Reactions performed for 90 h.