A R T I C L E S
Furrow and Myers
structural data (fortunately, also from an aromatic aldehyde:
3-cyano-5-(4-pyridyl)pyrid-[1H]-2-one-6-carboxaldehyde).17 In
addition, as discussed in the Introduction, Klingebiel and co-
workers have previously reported X-ray structural data for the
N-tert-butyldiphenylsilylhydrazone derivative of the aliphatic
ketone pinacolone.7c Comparisons among the three structures
are instructive. For example, comparison of the TBSH derivative
of p-tolualdehyde with the prior structure of a simple hydrazone
derivative reveals that the silylhydrazone has a shorter C(1)-
N(1) bond (1.272 vs 1.297 Å), a longer N(1)-N(2) bond (1.365
vs 1.317 Å), and a C(2)-C(1)-N(1) bond angle that is closer
to an idealized trigonal geometry (122.0° vs 116.6°), all of which
are consistent with the view that the silylhydrazone derivative
has reduced conjugation of the lone pair localized on N(2) with
the imine π-system relative to the simple hydrazone. The
nitrogen bearing the tert-butyldimethylsilyl group appears to
be essentially planar, and the N-N-Si bond angle is 121.7°.
Silylamines are known to exhibit a high degree of planarity,
which has been interpreted as evidence of a partial multiple
bond between silicon and nitrogen.18 To the extent that the lone
pair of N(2) in the structure of Figure 1 is involved in multiple
bonding with the silicon atom, reduced conjugation with the
imine π-bond would be expected19 and is supported by the
structural evidence. Comparisons between the TBSH structure
and the prior silylhydrazone structure reveal similar C(1)-N(1)
bond lengths (1.272 vs 1.274 Å, respectively) and similar Si-N
bond lengths (1.730 vs 1.728 Å), but the TBSH derivative is
found to have a shorter N-N bond length (1.365 vs 1.401 Å).7c
potassium hydroxide2a,21 or their heating with sodium ethoxide
in ethanol in a sealed tube at temperatures of 160-200 °C.2b
Numerous modifications to these procedures have been intro-
duced over the years,22 but the most commonly employed
protocol, reported in 1946 by Huang-Minlon, involves heating
of crude hydrazone derivatives with alkali in a high-boiling
ethereal solvent such as diethylene glycol, typically at temper-
atures of 195-200 °C.23 In addition to the Huang-Minlon
procedure, other modifications of the Wolff-Kishner reduction
are occasionally employed in synthesis.24
In a mechanistic study of the Huang-Minlon modification of
the Wolff-Kishner reduction, Szmant et al. found that a
minimum temperature of ∼190 °C was necessary to achieve a
reasonable rate of reduction.25 Two independent reports, from
Cram et al. in 1962,26 and from Henbest and co-workers in
1963,4a outlined reaction conditions that allowed the Wolff-
Kishner reduction to be conducted successfully at temperatures
as low as 23 °C. Cram et al. reported that the slow addition of
solutions of pure aldehyde- and ketone-derived hydrazones to
a solution of potassium tert-butoxide in dimethyl sulfoxide at
23 °C afforded reduction products in yields ranging from 64%
for camphor hydrazone to 90% for benzophenone hydrazone.
Subsequent studies showed that the use of a protic cosolvent
such as 2-(2-butoxyethoxy)ethanol27 or tert-butyl alcohol28 leads
to an increase in the rate of reduction under the Cram conditions.
Henbest and co-workers reported an alternative procedure in
which hydrazones were added in a single portion to a suspension
of potassium tert-butoxide in toluene at 100-110 °C to effect
Wolff-Kishner reduction.4a These reduced-temperature modi-
fications of the Wolff-Kishner reduction have not been
exploited to any great extent in organic synthesis, presumably
due to the necessity to preform and isolate the sensitive
hydrazone substrates and, in the case of Cram’s conditions, to
Applications of TBSH Derivatives in Synthesis. The lability
of nitrogen-silicon bonds toward cleavage under a wide range
of different reaction conditions suggested that TBSH derivatives
might transform as simple hydrazones do in the many known
applications of hydrazones in organic synthesis.20 This sup-
position has been found to have substantial merit, as illustrated
in the applications detailed below.
(21) (a) Kishner, N. Zh. Russ. Fiz.-Khim. O-Va., Chast. Khim. 1912, 44, 1754.
(b) Cook, A. H.; Linstead, R. P. J. Chem. Soc. 1934, 946. (c) Barrett, J.
W.; Linstead, R. P. J. Chem. Soc. 1935, 436. (d) Asahina, Y.; Nogami, H.
Chem. Ber. 1935, 68, 1500.
(22) For a recent review, see (a) Hutchins, R. O.; Hutchins, M. K. In
ComprehensiVe Organic Synthesis; Trost, B. M. Ed.; Pergamon Press:
Oxford, U.K., 1991; Vol. 8, pp 327-362. For reviews covering the early
advances in the Wolff-Kishner reduction, see (b) Todd, D. Org. React.
1948, 4, 378-422. (c) Buu-Ho¨ı, N. P.; Hoa´n, N.; Xuong, N. D. Recl. TraV.
Chim. Pays-Bas, 1952, 71, 285. (d) Huang-Minlon Sci. Sinica 1961, 10,
711. (e) Reusch, W. In Reduction; Augustine, R. L., Ed.; Dekker: New
York, 1968; pp 171-211.
(A) Reduced-Temperature Wolff-Kishner Reductions.
The reduction of carbonyl compounds to hydrocarbons via the
corresponding hydrazones was first reported by Kishner in
19112a and soon thereafter by Wolff in 1912.2b Early procedures
described the addition of preformed hydrazones to hot solid
(23) (a) Huang-Minlon. J. Am. Chem. Soc. 1946, 68, 2487. (b) Huang-Minlon.
J. Am. Chem. Soc. 1949, 71, 3301. For an account of the circumstances
surrounding the serendipitous discovery of the Huang-Minlon modification,
see (c) Fieser, L. F.; Fieser, M. In Topics in Organic Chemistry; Reinhold:
New York, 1963; p 258. For recent examples in synthesis, see (d)
Gambacorta, A.; Fabrizi, G.; Bovicelli, P. Tetrahedron 1992, 48, 4459. (e)
Paquette, L. A.; Schulze, M. M.; Bolin, D. G. J. Org. Chem. 1994, 59,
2043. (f) Kuck, D. Chem. Ber. 1994, 127, 409. (g) Desmae¨le, D.; Mekouar,
K.; d’Angelo, J. J. Org. Chem. 1997, 62, 3890-3901. (h) Toyota, M.; Wada,
T.; Fukumoto, K.; Ihara, M. J. Am. Chem. Soc. 1998, 120, 4916. (i)
Srikrishna, A.; Reddy, T. J. J. Chem. Soc., Perkin Trans. 1 1998, 2137. (j)
Srikrishna, A.; Vijaykumar, D. J. Chem. Soc., Perkin Trans. 1 1999, 1265.
(k) Toyota, M.; Wada, T.; Ihara, M. J. Org. Chem. 2000, 65, 4565. (l)
Hsu, D.-S.; Liao, C.-C. Org. Lett. 2003, 5, 4741. For detailed experimentals,
see (m) Durham, L. J.; McLeod, D. J.; Cason, J. Organic Syntheses;
Wiley: New York, 1963; Collect. Vol. 4, p 510. (n) Hu¨nig, S.; Lu¨cke, E.;
Brenniger, W. Organic Syntheses; Wiley: New York, 1973; Collect. Vol.
5, p 533.
(24) See, for example, (a) Confalonieri, G.; Marotta, E.; Rama, F.; Righi, P.;
Rosini, G.; Serra, R.; Venturelli, F. Tetrahedron 1994, 50, 3235. (b) Mander,
L. N.; Owen, D. J.; Twitchen, B. Aust. J. Chem. 1996, 49, 249. (c)
Srikrishna, A.; Vijaykumar, E. J. Chem. Soc., Perkin Trans. 1 2000, 2583.
(25) (a) Szmant, H. H.; Harnsberger, H. F.; Butler, T. J.; Barie, W. P. J. Am.
Chem. Soc. 1952, 74, 2724. (b) Szmant, H. H.; Harmuth, C. M. J. Am.
Chem. Soc. 1964, 86, 2909.
(26) Cram, D. J.; Sahyun, M. R. V.; Knox, G. R. J. Am. Chem. Soc. 1962, 84,
1734.
(27) Szmant, H. H.; Roman, M. N. J. Am. Chem. Soc. 1966, 88, 4034.
(28) Szmant, H. H.; Birke, A.; Lau, M. P. J. Am. Chem. Soc. 1977, 99, 1863.
(17) Stockley, M.; Clegg, W.; Fontana, G.; Golding, B. T.; Martin, N.; Rigoreau,
L. J. M.; Smith, G. C. M.; Griffin, R J. Bioorg. Med. Chem. Lett. 2001,
11, 2837.
(18) (a) Hedberg, K. J. Am. Chem. Soc. 1955, 77, 6491. (b) Ebsworth, E. A.
V.; Hall, J. R.; MacKillop, M. J.; McKean, D. C.; Sheppard, N.; Woodward,
L. A. Spectrochim. Acta 1958, 13, 202. (c) Glidewell, G.; Rankin, D. W.
H.; Robiette, A. G.; Sheldrick, G. M. J. Mol. Struct. 1969, 4, 215. (d)
Wilkov, L. V.; Tarasenko, N. A. Chem. Commun. 1969, 1176. For crystal
structures of monoalkylsilylamines, see (e) Clegg, W.; Klingebiel, U.;
Neemann, J.; Sheldrick, G. M.; Vater, N. Acta Crystallogr., Sect. B: Struct.
Sci. 1981, 37, 987. (f) Wiedenbruch, M.; Pan, Y.; Peters, K.; von Schnering,
H. G. Chem. Ber. 1989, 122, 885. (g) Schaefer, W. P.; Cotter, W. D.;
Bercaw, J. E. Acta Crystallogr., Sect. C: Cryst. Struct. Commun. 1993,
49, 1489. (h) Memmler, H.; Gade, L. H.; Lauher, J. W. Inorg. Chem. 1994,
33, 3064. (i) Alcalde, M. I.; Go´mez-Sal, M. P.; Royo, P. Organometallics
1999, 18, 546. (j) Renner, P.; Galka, C. H.; Gade, L. H.; Radojevic, S.;
McPartlin, M. J. Chem. Soc., Dalton Trans. 2001, 964. (k) Renner, P.;
Galka, C. H.; Gade, L. H.; Radojevic, S.; McPartlin, M. Eur. J. Inorg.
Chem. 2001, 1425. (l) Renner, P.; Galka, C. H.; Gade, L. H.; Radojevic,
S.; McPartlin, M. Inorg. Chem. Commun. 2001, 4, 191. (m) Gade, L. H.;
Renner, P.; Memmler, H.; Fecher, F.; Galka, C. H.; Laubender, M.;
Radojevic, S.; McPartlin, M.; Lauher, J. W. Chem.-Eur. J. 2001, 7, 2563.
(19) Colvin, E. Silicon in Organic Synthesis; Butterworth: London, 1981; pp
10-13.
(20) The mechanistic details of the timing of Si-N bond cleavage are of interest,
and likely will differ from application to application, but fall outside the
scope of the present work.
9
5440 J. AM. CHEM. SOC. VOL. 126, NO. 17, 2004