Toward a versatile allylation reagent: Practical, enantioselective allylation of acylhydrazones using strained silacycles

Article abstract of DOI:10.1021/ja035001g

A highly practical method for the enantioselective allylation of acylhydrazones has been developed. The previously reported strained silacycle reagent 1 reacts with a wide variety of acylhydrazones to give the hydrazide products with good enantioselectivi

Full text of DOI:10.1021/ja035001g

Published on Web 07/18/2003
Toward a Versatile Allylation Reagent: Practical, Enantioselective Allylation
of Acylhydrazones Using Strained Silacycles
Richard Berger, Philippe M. A. Rabbat, and James L. Leighton*
Department of Chemistry, Columbia UniVersity, New York, New York 10027
Received March 5, 2003; E-mail: leighton@chem.columbia.edu
The development of practical enantioselective syntheses of chiral
amines is of great importance to synthetic organic and medicinal
chemistry. Despite much effort directed at enantioselective aldehyde
allylation and crotylation, the development of chiral reagents and
catalysts for the enantioselective allyl(crotyl)ation of aldimine
derivatives has lagged behind. While creative and noteworthy
advances have been recorded,1,2 a truly practical and general method
remains elusive. We recently reported a conceptually new and
practical class of allylsilane reagents (e.g., 1) for aldehyde allylation
that derive their reactivity from ring strain-induced Lewis acidity,3
and it was of interest to investigate these reagents in the context of
aldimine allylation reactions (Scheme 1).
restored (entry 12). The 2-pyrrolyl acetylhydrazone was also a
problematic substrate (entry 13). While the mechanistic basis for
the poor selectivity in this case is less obvious, the corresponding
N-Boc pyrrole was prepared. This substrate proved very effective,
albeit sluggish, resulting in product of 92% ee (entry 14). Finally,
although aliphatic aldehyde-derived hydrazones generally provide
only low to moderate enantioselectivities, the pivalaldehyde-derived
substrate is an exception, providing the highest enantioselectivity
observed to date (97% ee, entry 15).
Table 1. Enantioselective Allylation of Acylhydrazones
Scheme 1
Several imine derivatives of benzaldehyde were subjected to
reaction with 1, and in no case was any allylation observed (Scheme
2). Kobayashi has reported that benzoylhydrazones undergo smooth
allylation with allyltrichlorosilane especially in the presence of
Lewis basic solvents such as DMF.4 Reaction of benzoylhydrazone
2a with allylsilane 1 in CH2Cl2 at 0 °C led to hydrazide 3a in 51%
yield and in 69% ee. A series of aroyl- and alkanoylhydrazones of
benzaldehyde were prepared and reacted with allylsilane 1.
Significant variations in enantioselectivity were observed (e.g.,
pivaloylhydrazone 2b gave 3b in only 40% ee), and optimal results
were obtained with the simple acetylhydrazone 2c. Optimization
revealed CH2Cl2 as the solvent of choice and 10 °C as the optimal
reaction temperature. Under these conditions, the reaction of 1 and
2c proceeded to give 3c in 86% yield and 88% ee.5
Scheme 2
a Enantiomeric excess was determined by chiral HPLC. b 40% of
recovered starting material was isolated as well.
In a demonstration of the practicality of this reaction, the
reactions of two substrates were carried out on a 5 g scale (Scheme
3). Only 1.2 equiv of reagent 1 was employed, the products were
isolated without chromatography, and highly enantiomerically
enriched materials (g98% ee) were obtained in good yield upon a
single recrystallization. Combined with the experimentally trivial
preparation of reagent 1,6 these data establish the true practicality
As outlined in Table 1, a wide variety of aromatic and hetero-
cyclic aldehyde-derived acetylhydrazones performed admirably in
the reaction (entries 1-10). An exception was the 3-pyridyl
acetylhydrazone, which was allylated in only 23% ee (entry 11).
Hypothesizing that the Lewis basic nitrogen was interacting with
the Lewis acidic silicon, we screened the 2-chloropyridyl substrate
and were delighted to find that most of the lost selectivity was
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J. AM. CHEM. SOC. 2003, 125, 9596-9597
10.1021/ja035001g CCC: $25.00 © 2003 American Chemical Society

C O M M U N I C A T I O N S
Scheme 6
of this reaction, despite the only moderately high enantioselectivities
of some of the substrates.
Scheme 3
We have developed a highly practical enantioselective allylation
of acetylhydrazones. The reagent is trivially prepared in bulk and
is stable to storage. The products may be isolated without
chromatography and in high ee by simple recrystallization. A
mechanistic paradigm distinct from aldehyde allylation has been
established, and more effective Lewis base-containing imine
derivatives may be imagined.
The observations (1) that of the aldimine derivatives screened,
only acylhydrazones undergo allylation and (2) that the structure
of the acyl group has a dramatic effect on the reaction (see Scheme
2) suggest a secondary interaction between the Lewis basic amide
and the Lewis acidic silane. This in turn calls into question whether
the ring strain-induced Lewis acidity in reagents such as 1, which
has been shown to be necessary for aldehyde allylation,2a is
necessary in the reactions with acylhydrazones. We prepared
allylsilane 4 and have found that it indeed allylates acetylhydrazone
2c, albeit with reduced efficiency (Scheme 4). We may thus
conclude that strain-induced Lewis acidity, while helpful for
efficiency, is not necessary for acylhydrazone allylation, in stark
contrast to the corresponding aldehyde allylations.7
Acknowledgment. We are grateful to Merck Research Labo-
ratories for unrestricted research support and fellowship support
of R.B. J.L.L. is the recipient of a Pfizer Award for Creativity in
Organic Chemistry.
Supporting Information Available: Experimental procedures,
characterization data, and stereochemical proofs (PDF). This material
is available free of charge via the Internet at http://pubs.acs.org.
Scheme 4
References
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cis-Crotylsilane and trans-crotylsilane (S,S)-5a,b were prepared
and reacted with benzoylhydrazone 2a, giving anti-hydrazide 6a
in 81% yield with 96:4 dr and 95% ee and syn-hydrazide 6b in
89% yield with 95:5 dr and 97% ee, respectively (Scheme 5). In
addition to establishing the superior performance of the crotylation
reagents 5, these results are mechanistically revealing. As shown,
two-point binding/double activation of the type proposed is
completely consistent with the unusual observation of an anti
product from a cis-crotylsilane, and a syn from a trans-crotylsilane.
Kobayshi has made similar observations in the additions of crotyl-
trichlorosilanes to benzoylhydrazones,4 and related observations
have been made during studies of intramolecular aldehyde crotyl-
silylations.8
(2) For reviews of enantioselective amine synthesis by nucleophilic addition
to imines, see: (a) Enders, D.; Reinhold, U. Tetrahedron: Asymmetry
1997, 8, 1895-1946. (b) Bloch, R. Chem. ReV. 1998, 98, 1407-1438.
(c) Kobayashi, S.; Ishitani, H. Chem. ReV. 1999, 99, 1069-1094. (d)
Puentes, C. O.; Kouznetsov, V. J. Heterocycl. Chem. 2002, 39, 595-
614.
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J. Am. Chem. Soc. 2002, 124, 7920-7921. (b) Kubota, K.; Leighton, J.
L. Angew. Chem., Int. Ed. 2003, 42, 946-948.
(4) (a) Kobayashi, S.; Hirabayashi, R. J. Am. Chem. Soc. 1999, 121, 6942-
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Scheme 5
(5) Reagent 1 is an inseparable 2:1 mixture of diastereomers (see ref 3a).
When 2c was reacted in separate experiments with 0.5 and 5.0 equiv of
1, 3c was obtained in 85.4% and 87.5% ee, respectively. These data are
inconsistent with the possibility that the diastereomers of 1 react
independently with significantly different rates and enantioselectivities
and suggest instead that they interconvert and react by a common pathway
or pathways.
(6) The preparation of reagent 1 was recently carried out on ∼150 g scale in
An important consequence of this mechanism is that Lewis basic
groups other than acylhydrazones might be expected to promote
the reaction. Indeed, aldimine 7 was prepared and, upon reaction
with allylsilane 1, gave amine 8 in 31% yield and 50% ee (Scheme
6). Albeit unoptimized, this reaction stands in contrast to the
corresponding benzylimine, which does not undergo allylation with
allylsilane 1 (see Scheme 2).
92% yield. See the Supporting Information.
(7) Allylsilane 4 is unreactive with aldehydes even at 50 °C.
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1995, 281-282. (b) Chemler, S. R.; Roush, W. R. J. Org. Chem. 1998,
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68, 1319-1333. (d) Wang, X.; Meng, Q.; Nation, A. J.; Leighton, J. L.
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