Phosphoramide-Catalyzed EnantioselectiVe Allylation
is often the case in asymmetric catalysis, the success of this
endeavor relies on the combination of empirical experimentation
and careful mechanistic analysis. We describe below the
interplay of mechanistic and synthetic studies that have led to
the development of a highly enantioselective and general
catalytic asymmetric allylation reaction.15
TABLE 1. Allylation of Benzaldehyde, Using Allyltrichlorosilane
with Additivesa
additive
(equiv)
t1/2,b
min
conversion,
% (time)
yield,c
%
entry
solvent
Results
1
2
3
4
5
6
7
8
9
DMF (1.0)
DMF (2.0)
HMPA (1.0)
C6D6
C6D6
C6D6
C6D6
CDCl3
CD3CN
C6D6
CD3CN
CDCl3
d8-THF
83 (70 h)
82 (48 h)
1. Survey of Achiral Lewis Base Promoters. Although DMF
18
26
77
71
85
86
promoted the addition of allylic trichlorosilanes to aldehydes,
the necessity of using this agent as the solvent precluded an
efficient catalytic process. Thus, as the point of entry, we
assayed the ability of other Lewis bases to function as promoters
for the addition in stoichiometric quantities. The initial survey
included a variety of Lewis bases in the addition of allyltri-
chlorosilane 1a to benzaldehyde 2 at room temperature. The
d
TPPA (1.0)
HMPA (1.0)
HMPA (1.0)
HMPA (0.1)
HMPA (0.2)
HMPA (0.1)
HMPA (0.1)
63 (4 min)
63 (4 min)
60 (46 h)
80 (80 h)
20 (1 h)
529
397
69
1
0
350
80 (124 h)
a
Reactions run at 1.0 M concentration. b Reaction monitored by 1
H
1
reaction conversion was monitored by H NMR spectroscopy,
NMR. c Yield of isolated product after complete consumption of 2.
d Tripiperidinophosphoric triamide.
and in some cases, the yield of isolated product was determined
(Table 1). In the absence of any Lewis base additive, no reaction
was observed in C6D6 solution. Whereas DMF is an effective
allylation promoter when used as solvent, 1.0 and 2.0 equiv of
DMF in benzene are relatively ineffective, requiring 70 and 48
h to accomplish ca. 82% conversion (Table 1, entries 1 and 2).
It was found that hexamethylphosphoric triamide (HMPA) was
much more effective than DMF as a promoter for the addition;
benzene ca. 60% conversion was achieved in 46 h with 0.1 equiv
of HMPA, and in other solvents, the reaction proceeded, but
stalled in all three cases suggesting the intervention of product
inhibition. It was especially encouraging that the reaction could
be carried out with a substoichiometric amount of HMPA, which
provided the foundation for development of a more efficient,
catalytic process.
16
5
0% conversion was observed after 18 min (entry 2). The more
hindered phosphoramide, tris(piperidino)phosphoric triamide
TPPA), was a slightly less potent promoter. Other strongly basic
additives such as dimethyl sulfoxide and pyridine N-oxide were
Next, alkylphosphonic and alkylphosphinic amides18 with
different steric and electronic properties were surveyed in these
additions (Scheme 3). The allylation of benzaldehyde with 1a
was carried out with 10 mol % of the promoter at 1.0 M in
CDCl3 for 1 h, and the formation of product was monitored by
(
17
found to be incompatible with the trichlorosilane reagent. The
effect of the solvent on reaction rate was also examined in the
allylation promoted by HMPA. The reactions in CDCl3 and CD3-
CN were even faster than those in C6D6; 63% conversion was
observed within 4 min and high yields of the product could be
obtained. Finally, the potential of using substoichiometric
amounts of the promoter was demonstrated in entries 7-10. In
1
H NMR spectroscopy.
SCHEME 3
(13) For preliminary communications see: (a) Denmark, S. E.; Coe, D.
M.; Pratt, N. E.; Griedel, B. D. J. Org. Chem. 1994, 59, 6161-6163. (b)
Denmark, S. E.; Fu, J. J. Am. Chem. Soc. 2000, 122, 12021-12022. (c)
Denmark, S. E.; Fu, J. J. Am. Chem. Soc. 2001, 123, 9488-9489.
(14) Other chiral Lewis bases have also been employed as promoter in
the allylation reaction. For leading references to various promoter structures
see: (a) Iseki, K.; Mizuno, S.; Kuroki, Y.; Kobayashi, Y. Tetrahedron 1999,
5
5, 977-988. (b) Hellwig, J.; Belser, T.; Muller, J. F. K. Tetrahedron Lett.
2
001, 42, 5417-5419. (c) Nakajima, M.; Saito, M.; Shiro, M.; Hashimoto,
S. J. Am. Chem. Soc. 1998, 120, 6419-6420. (d) Malkov, A. V.; Bell, M.;
Orsini, M.; Pernazza, D.; Massa, A.; Hermann, P.; Meghani, P.; Kocovsky,
P. J. Org. Chem. 2003, 68, 9659-9668. (e) Shimada, T.; Kina, A.; Ikeda,
S.; Hayashi, T. Org. Lett. 2002, 4. 2799-2801. (f) Chataigner, I.; Piarulli,
U.; Gennari, C. Tetrahedron Lett. 1999, 40, 3633-3634. (g) Angell, R.
M.; Barrett, A. G. M.; Braddock, D. C.; Swallow, S.; Vickery, B. D. Chem.
Commun. 1997, 919-920. (h) Massa, A.; Malkov, A. V.; Kocovsky, P.;
Scettri, A. Tetrahedron 2003, 44, 7179-7181. (i) Traverse, J. F.; Zhao,
Y.; Hoveyda, A. H.; Snapper, M. L. Org. Lett. 2005, 7, 3151-3154. (j)
Pignataro, L.; Benaglia, M.; Cinquini, M.; Cozzi, F.; Celentano, G. Chirality
With 10 mol % of HMPA, the addition of 1a to benzaldehyde
gave 20% conversion after 1 h at room temperature. The
2
005, 17, 396-403. (k) M u¨ ller, C. A.; Hoffart, T.; Holbach, M.; Reggelin,
M. Macromolecules 2005, 38, 5375-5380. (l) Nakajima, M.; Kotani, S.;
Ishizuka, T.; Hashimoto, S. Tetrahedron Lett. 2005, 46, 157-159.
(17) After our studies other laboratories have successfully employed
DMSO and more complex heteroaromatic N-oxides as stoichiometric
promoters and catalysts for allylation. See refs 12f, 14c, and 14h.
(18) For the preparation of phosphorus amides see: (a) Razvodovskaya,
L. V.; Grapov, A. F.; Mel’nikov, N. N. Zh. Obshch. Khim. 1969, 39, 1260-
1263. (b) Bollinger, J.-C.; Faure, R.; Yvernault, T. Can. J. Chem. 1983,
61, 328-333. (c) Ulrich, H.; Tucker, B.; Sayigh, A. A. R. J. Org. Chem.
1967, 32, 1360-1362. (d) Koizumi, T.; Haake, P. J. Am. Chem. Soc. 1973,
95, 8073-8079. (e) Burg, A. B.; Slota, P. J. J. Am. Chem. Soc. 1960, 82,
2145-2148. (f) Hanessian, S.; Bennani, Y. L.; Leblanc, Y. Heterocycles
1993, 35, 1411-1424.
(15) This paper focuses on the allylation reaction with monophosphor-
amides and those relevant mechanistic studies. The following paper focuses
on the development of bisphosphoramides as catalysts.
(16) General references on the properties and the application of phos-
phoramides: (a) Normant, H. Russ. Chem. ReV. (Engl. Transl.) 1970, 39,
9
90-1049. (b) Jensen, W. B. Chem. ReV. 1978, 78, 1-22. (c) Reichardt,
C. SolVents and SolVent Effects in Organic Chemistry; VCH: Weinheim,
Germany, 1988. (d) Luteric, G. F.; Ford, W. T. J. Org. Chem. 1977, 42,
8
20-825. (e) Gutmann, V. The Donor-Acceptor Approach to Molecular
Interaction; Plenum: New York, 1978.
J. Org. Chem, Vol. 71, No. 4, 2006 1515