Table 1. Optimization of the Annulation of (Sa)-1 with
Benzaldehyde and tert-Butyl Carbamate
entry Lewis acid time (h) solvent yield (%) of 2aa
drc
1
2
3
4
5
6
7
8
9
TMSOTf
TMSOTf
TiCl4
TiCl4
TfOH
48
48
48
48
48
48
72
72
72
DCM
EtCN
DCM
EtCN
DCM
EtCN
DCM
MeCN
EtCN
9
41
<5
33
44
47
14
56
67
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
Figure 1. Open transition state model. For detailed analysis on the
proposed transition states, see Supporting Information.
TfOH
by activating an aldehyde in the presence of an amine with
a Lewis acid. After screening a number of amines, benzyl
amines, hydrazones, and acetamides were found to be
unreactive under a variety of conditions, and the use of
sulfonamides resulted in a complex mixture of products.
Carbamates proved to be the most effective amine source
for iminium ion formation. When allenylsilane (Sa)-1 was
exposed to benzaldehyde in the presence of tert-butyl
carbamate and a Lewis acid activator, the major product
obtained was dihydropyrrole 2a.
The optimal Lewis acid for iminium ion formation was
found to be BF3·OEt2. Attempts to catalyze the reaction with
Sc(OTf)3 resulted in the recovery of the starting materials,
while TiCl4, TfOH, and TMSOTf provided lower yields (see
Table 1). Use of an excess of Lewis acid led to decomposi-
tion of the products, and using substoichiometric amounts
of Lewis acid resulted in incomplete reactions. No protode-
silylation product was isolated under any of the reaction
conditions, suggesting that the vinylsilane product is robust.
Polar nitrile solvents (MeCN, EtCN) were found to give the
highest yields for the [3 + 2] annulation reactions.9 In all
cases a single diastereomer was observed as determined by
NMR analysis. The best yields were obtained when the
iminium ion was formed in situ, by treatment of a solution
of aldehyde and carbamate with Lewis acid at -78 °C. The
allenylsilane was then added dropwise, and the resulting
solution was warmed to -40 °C.
BF3·OEt2
BF3·OEt2
BF3·OEt2
a Isolated yields after purification over silica gel. All reactions run with
1.2 equiv of Lewis acid at -78 to -40 °C except for entry 8, which was
run at -40 °C. c Diastereomeric ratios were determined by 1H NMR analysis
on crude material.
yield and selectivity.6 Racemic allenes have been used in a
variety of additions to imines, resulting in [3 + 2] and [4 +
2] annulation products, many with high diastereoselectivity
and enantiomeric excess due to the use of chiral catalysts.7
In addition, a few reports containing examples of allenylsi-
lanes being used in [3 + 2] annulations with iminium ions
are available, but they show a limited substrate scope and
selectivity. In interest of complete transparency, Danheiser
was the first to demonstrate a [3 + 2] annulation of racemic
allenylsilanes with ꢀ-alkoxylactams, affording pyrrolizinones
as the major products.5 More recently, Akiyama reported a
Cu(I)-catalyzed cycloaddition to afford dihydroproline de-
rivatives.8 The purpose of this communication is to report
our initial studies on the use of chiral allenylsilanes in
annulations with N-acyl iminuim ions generated in situ from
carbamates and aldehydes.
We have recently reported an efficient synthesis of highly
enantioenriched allenylsilane (Sa)-1 and its enantiomer. That
sequence, from the corresponding propargylic alcohol,
utilized a lipase resolution followed by a Johnson orthoester
Claisen rearrangement. These reagents can be accessed on
a multigram scale (>15 g) with >95% ee.3
The stereochemical course of the [3 + 2] annulation can
be described by either an antiperiplanar or synclinal transition
state, where the axial chirality of the allenylsilane (Sa)-1 is
transferred to the si face of the iminium ion (see Figure 1).
The antiperiplanar transition state limits the gauche interac-
tions, while the synclinal transition state places the R group
of the iminium ion furthest from the incoming allenylsilane.
The absolute sterechemistry of the products is based on the
addition to the allene being anti to the carbon-silicon bond.10
Several conditions were explored for the addition of these
allenylsilanes to iminium ions, which were formed in situ
(6) (a) Panek, J. S.; Jain, N. F. J. Org. Chem. 1994, 59, 2674–2675. (b)
Schaus, J. V.; Jain, N. F.; Panek, J. S. Tetrahedron 2000, 56, 10263–10274.
(c) Lipomi, D. J.; Panek, J. S. Org. Lett. 2005, 7, 4701–4704. (d) Restorp,
P.; Fischer, A.; Somfai, P. J. Am. Chem. Soc. 2006, 128, 12646–12647.
(7) (a) Depature, M.; Grimaldi, J.; Hatem, J. Eur. J. Org. Chem. 2001,
941–946. (b) Ma, S.; Gao, W. Org. Lett. 2002, 4, 2989–2992. (c) Kaden,
S.; Brockmann, M.; Reissig, H.-U. HelV. Chim. Acta 2005, 88, 1826–1838.
(d) Wurz, R. P.; Fu, G. C. J. Am. Chem. Soc. 2005, 127, 12234–12235. (e)
Castellano, S.; Fiji, H. D. G.; Kinderman, S. S.; Watanabe, M.; de Leon,
P.; Tamanoi, F.; Kwon, O. J. Am. Chem. Soc. 2007, 129, 5843–5845. (f)
Fuchibe, K.; Hatemata, R.; Akiyama, T. Tetrahedron Lett. 2005, 46, 8563–
8566. (g) Fang, Y.-Q.; Jacobsen, E. N. J. Am. Chem. Soc. 2008, 130, 5660–
5661.
The [3 + 2] annulations were successful for a variety of
aldehydes (see Table 2). Aromatic aldehydes typically
(9) All reactions were run until the allene was consumed, as determined
by TLC analysis. Reactions run in a variety of other solvent systems,
including THF, diethyl ether, toluene, and hexanes, produced little or no
desired product.
(8) Daidouji, K.; Fuchibe, K.; Akiyama, T. Org. Lett. 2005, 7, 1051–
1053.
(10) Marshall, J. A.; Maxson, K. J. Org. Chem. 2000, 65, 630–633.
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