Preparation of silyl substituted crotylzinc reagents and their highly diastereoselective addition to carbonyl compounds

Article abstract of DOI:10.1039/b802157k

Readily prepared β-silyl substituted crotylzinc reagents undergo highly selective allylation of carbonyl compounds leading to syn-homoallylic alcohols. The Royal Society of Chemistry.

Full text of DOI:10.1039/b802157k

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Preparation of silyl substituted crotylzinc reagents and their highly
diastereoselective addition to carbonyl compoundsw
Matthew D. Helm, Peter Mayer and Paul Knochel*
Received (in Cambridge, UK) 6th February 2008, Accepted 6th March 2008
First published as an Advance Article on the web 19th March 2008
DOI: 10.1039/b802157k
Readily prepared b-silyl substituted crotylzinc reagents undergo
highly selective allylation of carbonyl compounds leading to
syn-homoallylic alcohols.
Allylation reactions of carbonyl compounds with allylic orga-
nometallic reagents are of huge importance in organic synth-
esis.1 The allylation reaction is one of the best methods for the
controlled synthesis of quaternary centres. Recently we have
reported the use of zinc dust in the presence of lithium chloride
in THF as a cheap and convenient method for the synthesis of
Fig. 1
substituted allylic zinc reagents from allyl chlorides or phos-
phonates.2 Allylation reactions with carbonyl compounds at
A variety of alkyl substituted aldehydes were investigated
ꢀ78 1C provided mostly the anti isomers. To extend this
(5–7, Fig. 2). In all cases, we were delighted to observe very
methodology to the preparation of syn-homoallylic alcohols
high diastereoselectivity and the steric properties of the alde-
we have investigated the possibility of using steric hindrance
hyde appeared to have no bearing on the diastereoselectivity.
on the 2-position of the allyl chloride, through the presence of
Reaction with functionalised benzaldehyde derivatives showed
a silyl group. The resulting allylic zinc reagents should under-
a high level of tolerance towards sensitive functional groups
go highly syn-selective allylation of aldehydes and ketones
such as free amino, chloro and nitro groups (8–9, Fig. 2). In
(Fig. 1). The use of silyl substituted allyl-chromium reagents
the cases involving nitro substituted, more electron deficient,
has been investigated previously, however, moderate levels of
aldehydes lower diastereoselectivity was observed (9, Fig. 2
diastereoselectivity were observed.3
and 15–16, Scheme 2). The addition to acetophenones was also
We decided to concentrate our initial studies using a mixture
highly selective and again the tolerance towards sensitive
of readily available trimethylsilyl substituted allyl chlorides4
functional groups was remarkable, with substrates containing
1a and 1b (Scheme 1). In the presence of zinc powder (10
azide and bromo functional groups proceeding smoothly
equiv.) and LiCl (3 equiv.), we observed a smooth insertion
(10 to 12, Fig. 2).
reaction in which complete consumption of the starting mate-
Reaction of 1.1 equiv of 2 with p-nitrobenzaldehyde gave
rials was observed in 18 h at 25 1C and provided organozinc
homoallylic alcohol 15 in 89% yield with a diastereoselectivity
species 2 in 78% yield as determined by iodometic titration.
Remarkably, addition of 1.1 equiv. of this reagent to benzal-
dehyde (1 equiv.) at ꢀ78 1C gave the allylation product 3 as a
1
single diastereomer as distinguishable by H-NMR. Protode-
silylation of the allylation product 3 via a carbon to oxygen
silyl migration promoted by sodium hydride in THF/HMPA5
gave the expected syn-homoallylic alcohol 4 in 86% yield
(Scheme 1). The remarkable diastereoselectivity observed in
this reaction must be attributed to the fact that only a single
allylic zinc species (E-isomer) is formed during the insertion.
This is highly unusual as previous examples of conformation-
ally stable allylzinc reagents have relied upon either conforma-
tional rigidity, coordination or stereoelectronic factors.1,2,6
Ludwig-Maximilians-Universitat Munchen, Department Chemie und
¨
Biochemie, Butenandtstr. 5-13, Haus F, D-81377 Munchen, Germany.
¨
¨
E-mail: Paul.Knochel@cup.uni-muenchen.de; Fax: (+)49-89-2180-
77680; Tel: (+)49-89-2180-77681
w Electronic supplementary information (ESI) available: Further
experimental details; crystallographic data in CIF format
(CCDC 673535). See DOI: 10.1039/b802157k
Scheme 1
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Fig. 2 Addition of trimethylsilyl substituted allyl zinc 2 to functionalised aldehydes and ketones.7
Notes and references
z CCDC 673535.
1 For allyl metal additions see: S. R. Chemler and W. R. Roush, in
Modern Carbonyl Chemistry, ed. J. Otera, Wiley-VCH, Weinheim,
2000; S. E. Denmark and N. G. Almstead, in Modern Carbonyl
Chemistry, ed. J. Otera, Wiley-VCH, Weinheim, 2000; Stereoselec-
tive Synthesis, Methods of Organic Chemistry (Houben-Weyl), ed.
G. Helmchen, R. W. Hoffmann, J. Mulzer and E. Schaumann,
Thieme, Stuttgart, E21 edn, 1996; I. Marek and G. Sklute, Chem.
Commun., 2007, 1683; M. Yasuda, K. Hirata, M. Nishino, A.
Yamamoto and A. Baba, J. Am. Chem. Soc., 2002, 124, 13442; A.
N. Thadani and R. A. Batey, Org. Lett., 2002, 4, 3827; S. W. Li and
R. A. Batey, Chem. Commun., 2004, 1382; C. T. Buse and C. H.
Heathcock, Tetrahedron Lett., 1978, 1865; Y. Yamamoto, H. Ya-
tagai, Y. Naruta and K. Maruyama, J. Am. Chem. Soc., 1980, 102,
7107.
Scheme 2
2 H. Ren, G. Dunet, P. Mayer and P. Knochel, J. Am. Chem. Soc.,
2007, 129, 5376.
of 89 : 11 (Scheme 2). Careful recrystallisation from ethyl
acetate and pentane gave only the major isomer which was
identified as the cis isomer through X-ray analysis.z Forma-
tion of the triethylsilyl substituted allylic zinc 14 also pro-
ceeded smoothly (Scheme 2). Addition of 14 (1.1 equiv.) to
p-nitrobenzaldehyde (1 equiv.) gave the allylation product 16
(Scheme 2) in 80% yield with a diastereoselectivity of 94 : 6.
This increase in stereoselectivity may be best explained by the
increased steric hindrance of the silyl group of 14 compared to
2 (Scheme 2).
3 D. M. Hodgson and C. Wells, Tetrahedron Lett., 1992, 33, 4761; S.
Nowotny, C. E. Tucker, C. Jubert and P. Knochel, J. Org. Chem.,
1995, 60, 2762; see also the use of silyl substituted allylstannanes: Y.
Nishigaichi, N. Ishida, M. Nishida and A. Takuwa, Tetrahedron
Lett., 1996, 37, 3701.
4 T. H. Chan and B. S. Ong, J. Org. Chem., 1978, 43, 2994; T. H.
Chan, E. Mychajlowshij, B. S. Ong and D. N. Harpp, J. Org.
Chem., 1978, 43, 1526.
5 F. Sato, M. Kusakabe and Y. Kobayashi, J. Chem. Soc., Chem.
Commun., 1984, 1130.
6 F. Lambert, B. Kirschleger and J. Villie
1991, 405, 273; F. Lambert, B. Kirschleger and J. Villie
Organomet. Chem., 1991, 406, 71.
´
ras, J. Organomet. Chem.,
´
ras, J.
In conclusion, we have demonstrated that the new b-silyl
substituted allylic zinc reagent 2 undergoes highly diastereo-
selective additions to acetophenones and aldehydes. Further
extensions of this methodology are currently under way in our
laboratory.
7 To further examine the scope of this methodology some further
experiments were conducted. Reaction of 2 with 4-formyl-benzoic
acid methyl ester gave the allylation product in 88% yield with a
diastereoselectivity of 92 : 8. Reaction of 2 with p-anisaldehyde gave
an unstable product which decomposed upon attempted isolation.
Reaction of 2 with 4-acetyl-benzaldehyde gave a complex mixture of
products containing the aldehyde allylation products and the
a-addition product as the major contingent with traces of ketone
allylation products. See ESIw for further details.
We would like to thank the SFB (749) and the Alexander
von Humboldt foundation for financial assistance and Umi-
core AG (Angleur, Belgium) for the generous gift of zinc dust.
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This journal is The Royal Society of Chemistry 2008
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