Asymmetric synthesis of α-amino allyl, benzyl, and propargyl silanes by metalation and rearrangement

Article abstract of DOI:10.1021/ol034397y

(Matrix presented) Metalation of a Boc-protected N-silylamine α to nitrogen results in migration of the silicon from nitrogen to carbon (reverse aza-Brook rearrangement), yielding an α-amino silane. The Boc group acts initially as a metalation-directing g

Full text of DOI:10.1021/ol034397y

ORGANIC
LETTERS
2003
Vol. 5, No. 11
1859-1861
Asymmetric Synthesis of r-Amino Allyl,
Benzyl, and Propargyl Silanes by
Metalation and Rearrangement
Scott McN. Sieburth,*,†,‡ Heather K. O’Hare,‡ Jiayi Xu,‡ Yanping Chen,‡ and
Guodong Liu†
Department of Chemistry, Temple UniVersity, Philadelphia, PennsylVania 19122,
and Department of Chemistry, State UniVersity of New York at Stony Brook,
Stony Brook, New York 11794-3400
sieburth@astro.temple.edu
Received March 6, 2003
ABSTRACT
Metalation of a Boc-protected N-silylamine r to nitrogen results in migration of the silicon from nitrogen to carbon (reverse aza-Brook
rearrangement), yielding an r-amino silane. The Boc group acts initially as a metalation-directing group and then to stabilize the nitrogen
anion, providing a driving force for the rearrangement. In the presence of (−)-sparteine, the new chiral center is formed in >90% ee from allyl,
benzyl, and propargylamines.
Allylsilanes and other â,γ-unsaturated silanes1 have received
extensive attention as reagents and synthetic intermediates
because of annulation reactivity2,3 and their predictable SE2′
nucleophilicity.4 Transfer of stereochemistry in these reac-
tions, when chirality lies between the silicon and the
unsaturation, is generally high.5
merically pure precursors6 and by catalytic asymmetric
synthesis.7
During our study of silicon-based peptidomimetics as
novel pharmaceuticals,8 we have explored methods for
R-aminosilane preparation9 and describe here the use of the
reverse aza-Brook rearrangement as a convergent and ef-
ficient approach to such structures. The R-aminosilanes are
produced as versatile Boc-protected primary amines.
Construction of optically active allylsilanes, with carbon
as the stereogenic atom, has been achieved from enantio-
(5) Recent examples: Arefolov, A.; Panek, J. S. Org. Lett. 2002, 4,
2397-2400. Chabaud, L.; Landais, Y.; Renaud, P. Org. Lett. 2002, 4, 4257-
4260. Yamaguchi, R.; Tanaka, M.; Matsuda, T.; Okano, T.; Nagura, T.;
Fujita, K.-i. Tetrahedron Lett. 2002, 43, 8871-8874.
(6) Bhushan, V.; Lohray, B. B.; Enders, D. Tetrahedron Lett. 1993, 34,
5067-5070. Jain, N. F.; Cirillo, P. F.; Schaus, J. V.; Panek, J. S. Tetrahedron
Lett. 1995, 36, 8723-8726. Suginome, M.; Matsumoto, A.; Ito, Y. J. Am.
Chem. Soc. 1996, 118, 3061-3062. Bru¨mmer, O.; Ru¨ckert, A.; Blechert,
S. Chem. Eur. J. 1997, 3, 441-446.
(7) Hayashi, T.; Iwamura, H.; Uozumi, Y. Tetrahedron Lett. 1994, 35,
4813-4816. Hatanaka, Y.; Goda, K.-i.; Yamashita, F.; Hiyama, T.
Tetrahedron Lett. 1994, 35, 7981-7982. Davies, H. M. L.; Hansen, T.;
Rutberg, J.; Bruzinski, P. R. Tetrahedron Lett. 1997, 38, 1741-1744.
(8) Sieburth, S. McN.; Nittoli, T.; Mutahi, A. M.; Guo, L. Angew. Chem.,
Int. Ed. 1998, 37, 812-814. Chen, C.-A.; Sieburth, S. McN.; Glekas, A.;
Hewitt, G. W.; Trainor, G. L.; Erickson-Viitanen, S.; Garber, S. S.; Cordova,
B.; Jeffrey, S.; Klabe, R. M. Chem. Biol. 2001, 8, 1161-1166. Mutahi, M.
wa; Nittoli, T.; Guo, L.; Sieburth, S. McN. J. Am. Chem. Soc. 2002, 124,
7363-7375. Kim, J.; Glekas, A.; Sieburth, S. McN. Bioorg. Med. Chem.
Lett. 2002, 12, 3625-3627.
† Temple University.
‡ State University of New York at Stony Brook.
(1) Reviews: Chan, T. H.; Fleming, I. Synthesis 1979, 761-786.
Fleming, I.; Dunogue`s, J.; Smithers, R. Org. React. (N.Y.) 1989, 37, 57-
575. Masse, C. E.; Panek, J. S. Chem. ReV. 1995, 95, 1293-1316. Sarkar,
T. K. In Houben-Weyl Methods of Molecular Transformation; Fleming, I.,
Ed.; Georg Thieme Verlag: New York, 2000; Vol. 4, pp 837-925.
(2) Danheiser, R. L.; Dixon, B. R.; Gleason, R. W. J. Org. Chem. 1992,
57, 6094-6097. Knoelker, H.-J.; Foitzik, N.; Goesmann, H.; Graf, R.; Jones,
P. G.; Wanzl, G. Chem. Eur. J. 1997, 3, 538-551. Peng, Z. H.; Woerpel,
K. A. Org. Lett. 2000, 2, 1379-1381.
(3) Recent examples: Angle, S. R.; El-Said, N. A. J. Am. Chem. Soc.
2002, 124, 3608-3613. Peng, Z.-H.; Woerpel, K. A. Org. Lett. 2002, 4,
2945-2948. Angle, S. R.; Belanger, D. S.; El-Said, N. A. J. Org. Chem.
2002, 67, 7699-7705.
(4) Fleming, I.; Dunogue`s, J.; Smithers, R. Org. React. (N.Y.) 1989, 37,
57-575. Sarkar, T. K. In Houben-Weyl Methods of Molecular Transforma-
tion; Fleming, I., Ed.; Georg Thieme Verlag: New York, 2000; Vol. 4, pp
837-925.
10.1021/ol034397y CCC: $25.00 © 2003 American Chemical Society
Published on Web 05/01/2003

triflate, as described by Roby and Voyer17 gave 4 in good
yield. While somewhat moisture sensitive, this product is
readily purified by crystallization or chromatography over
alumina. Treatment of 4 at -78 °C with sec-butyllithium
and warming to ca. -40 °C followed by a standard workup
gave R-aminosilane 7 in high yield. Voyer et al. have shown
that carbanion intermediate 5 (TMS, TBS, and TIPS instead
of triphenylsilyl) can be trapped with deuterium or carbon
dioxide without silicon migration, to give other useful
products.18
The Boc group of silane 7 can be removed with trifluo-
roacetic acid, but sodium iodide/chlorotrimethylsilane in
acetonitrile19 is a more general procedure for acid-sensitive
products (see below).
The new stereogenic center in 7 can also be prepared
enantioselectively. Deprotonation of 4 with a mixture of sec-
butyllithium and (-)-sparteine in ether led to 7 with 66%
ee (Mosher derivative). Changing the solvent from ether to
toluene improved the ee value to 97%. This solvent-
dependent selectivity is similar to that reported by Beak et
al.20 and suggests that the deprotonation is the stereochem-
istry-determining step.
Scheme 1. Brook and aza-Brook Rearrangement
The anion-mediated migration of silicon from carbon to
oxygen (Brook rearrangement10), Scheme 1, transforming an
alkoxide (1a) to a carbanion (2a), has been studied for more
than forty years.11 The equilibrium of this organosilane-
alkoxide/silyl ether-carbanion rearrangement is driven by
the relative stabilities of the anions and the strengths of the
silicon-carbon and silicon-oxygen bonds (ca. 375 and 475
kJ/mol, respectively12). Useful versions of the reverse Brook
rearrangement have been developed for the synthesis of
R-hydroxy silanes (protonated 1a).13 Both ionic and radical14
Brook rearrangements are known, although the former are
by far the most common.
The aza-Brook rearrangement (1b f 2b) has been studied
almost as long as the oxygen-based original,15 but the high
basicity of nitrogen anion 1b leads to side reactions, reducing
its utility. Derivatization of an amine with a Boc group,
however, greatly acidifies the nitrogen, providing a driving
force favoring 1b, as well as acting as a metalation-directing
group.9a,16
When benzylamine was replaced with allylamine to give
9, Scheme 3, rearrangement gave the product of 1,2-
Scheme 3. Allyl Amines 9 Yields Only 1,2-Migration
Product, whereas Dianion Gives Only Silylation of
(Z)-γ-Product 12
Scheme 2. Metalation/Rearrangement of Benzylamine
rearrangement, allylsilane 10. Use of the (-)-sparteine-sec-
butyllithium complex in toluene gave this allylsilane with
>90% ee. Only 1,2-migration of the silicon was observed
for these reactions. This contrasts with the product derived
from silylation of dianion 11 by Resek and Beak where
reaction with chlorotrimethylsilane gave only silyl enamide
12.21,22 The absolute stereochemistry of 10b was determined
to be (S)- by X-ray crystallography of a derivative (Scheme
5).
Benzylamine 3 is a typical example, Scheme 2. Treatment
with di-tert-butyl dicarbonate followed by triphenylsilyl
(9) (a) Sieburth, S. McN.; Somers, J. J.; O’Hare, H. K. Tetrahedron 1996,
52, 5669-5682. (b) Sieburth, S. McN.; Somers, J. J.; O’Hare, H. K.; Hewitt,
G. W. Appl. Organomet. Chem. 1997, 11, 337-343. (c) Hewitt, G. W.;
Somers, J. J.; Sieburth, S. McN. Tetrahedron Lett. 2000, 41, 10175-10179.
(10) Brook, A. G. Acc. Chem. Res. 1974, 7, 77-84. Moser, W. H.
Tetrahedron 2001, 57, 2065-2084. Fleming, I.; Lawrence, A. J.; Richard-
son, R. D.; Surry, D. S.; West, M. C. HelV. Chim. Acta 2002, 85, 3349-
3365.
Scheme 4. Propargyl Amine Derivative 13 Rearranges to
Propargylaminosilane 14
(11) Brook, A. G. J. Am. Chem. Soc. 1958, 80, 1886-1889.
(12) Walsh, R. Thermochemistry. In The Chemistry of Organic Silicon
Compounds; Patai, S., Rappoport, Z., Eds.; John Wiley & Sons: New York,
1989; Vol. 1, pp 371-391.
(13) Linderman, R. J.; Ghannam, A. J. Am. Chem. Soc. 1990, 112, 2392-
2398.
(14) Schiesser, C. H.; Styles, M. L. J. Chem. Soc., Perkin Trans. 2 1997,
2335-2340.
(15) Brook, A. G.; Duff, J. M. J. Am. Chem. Soc. 1974, 96, 4692-4693.
Duff, J. M.; Brook, A. G. Can. J. Chem. 1977, 55, 2589-2600.
(16) Barberis, C.; Voyer, N. Tetrahedron Lett. 1998, 39, 6807-6810.
The use of a propargylamine gave a similar outcome,
Scheme 4.23 This anion of 13, more stabilized than those
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Org. Lett., Vol. 5, No. 11, 2003

are altered.24c To test the influence of the amino and silyl
groups on the alkene reactivity of 10b, it was subjected to
nitrile oxide cycloaddition, Scheme 5. Little diastereoselec-
tivity was observed; however, the major product 15 led to
the crystal structure shown in Scheme 5, with the absolute
stereochemistry found to be (1S,5R)-, as shown. Asymmetric
rearrangement products from benzyl and propargylamines
using (-)-sparteine (Schemes 2 and 4, respectively) are
assumed to have the same (S)- absolute stereochemistry.
Transformation of an R-amino-R-vinylsilane to a pyrro-
lidine derivative was examined, Scheme 6. Rearrangement
Scheme 5. Addition of Phenyl Nitrile Oxide to Allylsilane 10
Gives a Mixture of Diastereomersa
Scheme 6. Methathesis Converts Silane 19 to Dihydropyrrole
20
a Crystallography of 15 identified the absolute stereochemistry.
derived from 4 and 9, is slower to rearrange, taking several
hours at -40 °C. Following metalation, holding compound
13 for 1 h at -40 °C gave a 50% conversion to the
rearrangement product. Nevertheless, the rearrangement
proceeds with high enantioselectivity. Removal of the Boc
group of 14 and conversion of the amine a Mosher amide
found the product to have 98% ee.
Several R-aminoallylsilanes have been described previ-
ously but generally not as primary amine derivatives.24 In
the case of R-dialkylamino allylsilanes, the reactivity patterns
of TBS-protected allyl carbamate 17 gave 18 in good yield.
N-Allylation of 18 gave 1,6-diene 19, which when treated
with Grubbs first-generation catalyst25 rapidly gave dihy-
dropyrrole 20 in high yield. This product proved to be
somewhat air sensitive, undergoing oxidation upon standing
to yield the corresponding N-Boc 2-silylpyrrole.
The metalation and rearrangement chemistry described
here is the first general method for preparing R-substituted
R-aminesilanes. As protected primary amines, they can be
readily converted to primary, secondary, and tertiary amines
(see Schemes 2 and 6). The use of (-)-sparteine to prepare
the new stereogenic center led to high levels of asymmetric
induction in all cases tested. The newly reported equivalent
to (+)-sparteine26 should allow either antipode to be avail-
able.
(17) Roby, J.; Voyer, N. Tetrahedron Lett. 1997, 38, 191-194. Kauch,
M.; Hoppe, D. Can. J. Chem. 2001, 79, 1736-1746.
(18) Voyer, N.; Roby, J.; Chenard, S.; Barberis, C. Tetrahedron Lett.
1997, 38, 6505-6508. Barberis, C.; Voyer, N. Synlett 1999, 1106-1108.
Barberis, C.; Voyer, N.; Roby, J.; Chenard, S.; Tremblay, M.; Labrie, P.
Tetrahedron 2001, 57, 2965-2972.
(19) Olah, G. A.; Narang, S. C. Tetrahedron 1982, 38, 2225-2277. Olah,
G. A.; Narang, S. C.; Gupta, B. G. B.; Malhotra, R. Synthesis 1979, 61-
62.
(20) Wu, S.; Lee, S.; Beak, P. J. Am. Chem. Soc. 1996, 118, 715-721.
(21) Resek, J. E.; Beak, P. Tetrahedron Lett. 1993, 34, 3043-3046. See
also: Weisenburger, G. A.; Faibish, N. C.; Pippel, D. J.; Beak, P. J. Am.
Chem. Soc. 1999, 121, 9522-9530. See also: Whisler, M. C.; Beak, P. J.
Org. Chem. 2003, 68, 1207-1215. For a related silylation of amine-
substituted allyl anion, see: Corriu, R. J. P.; Huynh, V.; Moreau, J. J. E. J.
Organomet. Chem. 1983, 259, 283-293.
Acknowledgment. Acknowledgment is made to the NIH,
the NSF, and the donors of the Petroleum Research Fund,
administered by the American Chemical Society, for support
of this research. We are grateful to Professors Joseph Lauher
(Stony Brook) and Donald Titus (Temple University) for
assistance with the crystal structure determination.
(22) For a similar rearrangement but in the other direction, see: Honda,
T.; Mori, M. J. Org. Chem. 1996, 61, 1196-1197.
(23) For a recent study of propargyl alcohol reverse Brook rearrangement
and enantioselective synthesis, see: Sakaguchi, K.; Fujita, M.; Suzuki, H.;
Higashino, M.; Ohfune, Y. Tetrahedron Lett. 2000, 41, 6589-6592.
(24) (a) Primary amine: Chen, S.-F.; Ho, E.; Mariano, P. S. Tetrahedron
1988, 44, 7013-7026. Secondary and tertiary amines: (b) Ahlbrecht, H.;
Eichler, J. Synthesis 1974, 672-674. (c) Corriu, R. J. P.; Huynh, V.; Moreau,
J. J. E. J. Organomet. Chem. 1983, 259, 283-293. (d) Yamamoto, Y.;
Yatagai, H.; Saito, Y. J. Org. Chem. 1984, 49, 1096-1104. (e) Honda, T.;
Satoh, S.-i.; Mori, M. Organometallics 1995, 14, 1548-1550. (f) Weisen-
burger, G. A.; Beak, P. J. Am. Chem. Soc. 1996, 118, 12218-12219. (g)
Parisi, M.; Solo, A.; Wulff, W. D.; Guzei, I. A.; Rheingold, A. L.
Organometallics 1998, 17, 3696-3700.
Supporting Information Available: Procedures and
characterization data for all new compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
OL034397Y
(25) Grubbs, R. H.; Chang, S. Tetrahedron 1998, 54, 4413-4450. Trnka,
T. M.; Grubbs, R. H. Acc. Chem. Res. 2001, 34, 18-29.
(26) Dearden, M. J.; Firkin, C. R.; Hermet, J.-P. R.; O’Brien, P. J. Am.
Chem. Soc. 2002, 124, 11870-11871.
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