Highly efficient methodology for the reductive coupling of aldehyde tosylhydrazones with alkyllithium reagents [4]

Full text of DOI:10.1021/ja981918h

J. Am. Chem. Soc. 1998, 120, 8891-8892
8891
Scheme 1
Highly Efficient Methodology for the Reductive
Coupling of Aldehyde Tosylhydrazones with
Alkyllithium Reagents
Andrew G. Myers* and Mohammad Movassaghi
DiVision of Chemistry and Chemical Engineering
California Institute of Technology
Pasadena, California 91125
min, acetic acid (1.25 equiv) was added, followed by trifluoro-
ethanol (TFE, 5.0 mL), and the resulting solution was warmed
to 23 °C to induce diazene formation and elimination of
dinitrogen. The reaction was complete within 8 h at 23 °C. After
extractive isolation and chromatography on silica gel, the coupled
product was obtained as a colorless oil (133 mg, 95%). 1H and
13C NMR analysis showed that the coupled product was a single
diastereomer, demonstrating that epimerization of the aldehyde-
derived stereocenter did not occur throughout the sequence of
tosylhydrazone formation, silylation, and coupling. Entries 6, 7,
and 9-12 of Table 1 were also shown to proceed without
detectable epimerization, reinforcing the potential utility of the
method for asymmetric synthesis using “R-chiral” aldehydes.5
Recent advances in the preparation of (stereochemically) complex
primary alkyllithium reagents further extend the potential of the
method in asymmetric synthesis, as illustrated by entries 6, 8,
and 10.6
Prior studies support the pathway shown in Scheme 1 as the
likely sequence for the present coupling chemistry: 1,2-addition
of the alkyllithium reagent and protonation of the adduct followed
by elimination of p-toluenesulfinic acid, protodesilylation, and
loss of dinitrogen.2 That the latter step proceeds by a radical
pathway was established unequivocally by trapping of the
intermediate free radical with TEMPO, by intramolecular radical
cyclization experiments (see the Supporting Information), and by
the observation of fragmentation within the substrate of entry 13.7
A particularly noteworthy feature of the coupling chemistry
described is the overall efficiency of the process (Table 1), a
sequence initiated by 1,2-addition of the alkyllithium reagent. The
latter step is no doubt facilitated relative to additions to the anionic
intermediates formed from nonsilylated tosylhydrazones4 by the
fact that the silylated tosylhydrazone is a neutral species; however,
the X-ray crystal structure of N-tert-butyldimethylsilyl 1-naph-
thaldehyde tosylhydrazone (Figure 1) suggests that there may be
other beneficial factors associated with N-silylation as well. The
sulfonamide nitrogen is found to be nearly planar, a common
feature within silylated amines but not within sulfonylhydrazones.8
The bulky tert-butyldimethylsilyl group is adjacent to the imino
lone pair, while the arenesulfonyl group is syn coplanar with the
aldimine hydrogen atom. This places one of the sulfonyl oxygens
in a nearly ideal orientation to direct the addition of an
organolithium reagent to the imine group. The least basic
organometallic reagent observed to add efficiently to a silylated
tosylhydrazone is the amide enolate of entry 5 (addition at -20
ReceiVed June 2, 1998
Aldehyde tosylhydrazones are nearly ideal synthetic intermedi-
ates; they are readily available, stable, and frequently crystalline
compounds that can be stored indefinitely, whereas the parent
aldehydes cannot, being susceptible to autoxidation, self-
condensation, and hydration.1 In this work, we describe a new
and efficient process for the construction of C-C σ bonds by
the reductive coupling of aldehyde tosylhydrazones with alkyl-
lithium reagents.
In an earlier study we reported that aldehyde tosylhydrazones
are readily N-tert-butyldimethylsilylated, in quantitative yield, and
that the resultant derivatives undergo 1,2-addition of vinyllithium
reagents to form olefinic products in a process involving,
ultimately, [3,3]-sigmatropic elimination of dinitrogen from an
allylic diazene intermediate.2 In this work, we show that saturated
(sp3-hybridized) alkyllithium reagents (typically, 1.2 equiv) add
to N-tert-butyldimethylsilyl aldehyde tosylhydrazones at -78 °C
and that the resultant adducts can be made to extrude dinitrogen
in a free-radical process,3 leading to a net reductive coupling
reaction that often proceeds with remarkable overall efficiency
(Scheme 1, Table 1). These features distinguish the present
methodology from the important precedents of Vedejs et al., who
reported the reductive coupling of (nonsilylated) aldehyde tosyl-
hydrazones with alkyllithium reagents (g3 equiv, 20-61% yield)
by an anionic fragmentation pathway,4a and of Bertz, who
described the coupling of nonepimerizable aldehyde tosylhydra-
zones with cuprate reagents, also by anionic fragmentation.4b
Sequential treatment of aldehyde tosylhydrazones (0.2 M in
tetrahydrofuran, THF) with triethylamine (1.3 equiv) and tert-
butyldimethylsilyl trifluoromethanesulfonate (TBSOTf, 1.2 equiv)
at -78 °C followed by the addition of methanol (1.3 equiv),
dilution with hexanes, and immediate washing of the cold reaction
solution with saturated aqueous sodium bicarbonate solution, and
then brine, drying over magnesium sulfate, and concentration
affords the silylated tosylhydrazones in quantitative yield.2
Because of their propensity to hydrolyze upon exposure to silica
gel, these intermediates are used directly in the coupling reactions,
without purification. Entry 8 (Table 1) is illustrative of a typical
coupling protocol: a solution of (2S)-1-lithio-2-methyl-3-phen-
ylpropane (0.378 mmol, 1.2 equiv) in diethyl ether (1.0 mL) at
-78 °C was added to a solution of N-tert-butyldimethylsilyl (2S)-
3-(tert-butyldiphenylsilyloxy)-2-methylpropanal tosylhydrazone
(147 mg, 0.315 mmol) in THF (1.5 mL) at -78 °C. After 15
(5) For preparations of “R-chiral” aldehydes and alkyl iodides used in entries
6-8 and 10, see: (a) Myers, A. G.; Yang, B. H.; Chen, H.; McKinstry, L.;
Kopecky, D. J.; Gleason, J. L. J. Am. Chem. Soc. 1997, 119, 6496. (b) Myers,
A. G.; Yang, B. H.; Chen, H.; Kopecky, D. J. Synlett 1997, 457.
(6) Noncommercial alkyllithiums were generated either by lithium-iodide
exchange (Table 1 entries 1, 2, 6, and 8-10) or by deprotonation (Table 1
entries 4 and 5): (a) Bailey, W. F.; Punzalan, E. R. J. Org. Chem. 1990, 55,
5404. (b) Negishi, E.-i.; Swanson, D. R.; Rousset, C. J. J. Org. Chem. 1990,
55, 5406. (c) For a review of ortho-metalation, see: Snieckus, V. Chem. ReV.
1990, 90, 879.
(1) (a) Shapiro, R. H. Org. React. 1975, 23, 405. (b) Adlington, R. M.;
Barrett, A. G. M. Acc. Chem. Res. 1983, 16, 55. (c) Bertz, S. H.; Dabbagh,
G. J. Org. Chem. 1983, 48, 116.
(2) Myers, A. G.; Kukkola, P. J. J. Am. Chem. Soc. 1990, 112, 8208.
(3) (a) Kosower, E. M. Acc. Chem. Res. 1971, 4, 193. (b) Tsuji, T.;
Kosower, E. M. J. Am. Chem. Soc. 1971, 93, 1992. (c) Myers, A. G.;
Movassaghi, M.; Zheng, B. J. Am. Chem. Soc. 1997, 119, 8572. (d) Myers,
A. G.; Movassaghi, M.; Zheng, B. Tetrahedron Lett. 1997, 38, 6569.
(4) (a) Vedejs, E.; Stolle, W. T. Tetrahedron Lett. 1977, 135. (b) Bertz, S.
H. Tetrahedron Lett. 1980, 21, 3151. For other examples of reductive coupling
of aldehyde tosylhydrazones with organometallic reagents, see: (c) Vedejs,
E.; Dolphin, J. M.; Stolle, W. T. J. Am. Chem. Soc. 1979, 101, 249. (d)
Chandrasekhar, S.; Takhi, M.; Yadav, J. S. Tetrahedron Lett. 1995, 36, 307.
(e) Chandrasekhar, S.; Takhi, M.; Yadav, J. S. Tetrahedron Lett. 1995, 36,
5071.
(7) Newcomb, M. Tetrahedron 1993, 49, 1151.
(8) (a) Hedberg, K. J. Am. Chem. Soc. 1955, 77, 6491. (b) Ebsworth, E.
A. V.; Murray, E. K.; Rankin, D. W. H.; Robertson, H. E. J. Chem. Soc.,
Dalton Trans. 1981, 1501. (c) Anderson, D. G.; Rankin, D. W. H.; Robertson,
H. E.; Gundersen, G.; Seip, R. J. Chem. Soc., Dalton Trans. 1990, 161. (d)
Mitzel, N.; Schier, A.; Schmidbaur, H. Chem. Ber. 1992, 125, 2711. (e) Mitzel,
N. W.; Reide, J.; Schier, A.; Paul, M.; Schmidbaur, H. Chem. Ber. 1993,
126, 2027.
S0002-7863(98)01918-0 CCC: $15.00 © 1998 American Chemical Society
Published on Web 08/15/1998

8892 J. Am. Chem. Soc., Vol. 120, No. 34, 1998
Communications to the Editor
Table 1. Reductive Coupling of Aldehyde Tosylhydrazones with
Alkyllithiums
Figure 1.
silylated aldehyde tosylhydrazones (see entries 3, 7, 12, and 13),
the efficiency of alkyllithium addition to the imino carbon
apparently diminishes when the tosylhydrazone component
becomes excessively hindered, as in the case of 1-adamantan-
ecarboxaldehyde tosylhydrazone, where competitive ortho-lithia-
tion of the tolyl group occurs upon attempted addition of
n-butyllithium.9 The use of triisopropylbenzenesulfonyl (trisyl)
hydrazones10 in such cases alleviates this problem, but does
necessitate that the addition reactions be conducted at somewhat
warmer temperatures (0 °C, entry 14). The facility of enolization
(see the Supporting Information) precludes the extension of the
present methodology to silylated ketone tosylhydrazones.
Where possible, [3,3]-sigmatropic elimination of dinitrogen is
preferred over radical fragmentation of the intermediate monoalkyl
diazene.3c Such is believed to be the case for aryllithium adducts
(entry 11) and intermediates arising from aromatic aldehyde
substrates (entries 15 and 16). The isonaphthalene product of
entry 15 is sufficiently stable to be isolated, but the isotoluene
intermediates of entries 11 and 16 are not, undergoing isomer-
ization in situ to form the indicated aromatic products. Rearo-
matization is believed to involve protonation of the isotoluene
ring, a proposal supported by the greater rate (and efficiency) of
rearomatization of the electron-rich substrate of entry 16 versus
that of entry 11.
Carbon-carbon σ bonds that link saturated centers are seldom
targeted for retrosynthetic disconnection in current practice, largely
because of the paucity of reliable methodology to accomplish such
bond formations directly. Indirect sequences, such as C-C π
bond formation followed by hydrogenation, are much more
commonly employed for fragment assembly about a C-C σ bond.
The methodology described herein offers an alternative to such
two-step sequences and, further, provides an efficient construction
of σ bonds to quaternary and aromatic centers, not possible by
olefination-hydrogenation routes. The compatibility of the
present methodology with “R-chiral” aldehydes, sterically hin-
dered alkyllithiums and aldehydes, and the mild reaction condi-
tions and overall efficiency of the transformation make this
coupling chemistry a potentially powerful addition to existing
carbon-carbon (sp3-sp3) bond-forming processes.
Acknowledgment. Financial support from the National Science
Foundation is gratefully acknowledged. We thank Dr. Michael Day and
Dr. Lawrence Henling for obtaining X-ray crystallographic data and Dr.
John Greeves for HRMS data.
Supporting Information Available: Experimental details and ana-
lytical data for the products of Table 1, procedures for preparation of
aldehyde tosylhydrazones, X-ray data, and other supporting data refer-
enced (22 pages, print/PDF). See any current masthead page for ordering
information and Web access instructions.
JA981918H
°C); lithium acetylides and Grignard reagents examined thus far
have been found to react not at all or very slowly.
Although hindered alkyllithium reagents such as tert-butyl-
lithium readily undergo reductive coupling with a range of
(9) ortho-Lithiation is followed by N f C silyl transfer (see the Supporting
Information).
(10) Chamberlin A. R.; Stemke, J. E.; Bond, F. T. J. Org. Chem. 1978,
43, 147.