reactions, including both displacement and addition reactions.
Presumably, 1 decomposes to cyanide and acetone under the
reaction conditions. It was thought that similar conditions
may effect the hydrocyanation of nitroalkenes 2.
Scheme 2. Proposed Mechanism for Formation of 4
A range of nitroalkenes 2 were synthesized by the Et3N-
catalyzed Henry reaction9 followed by dehydration using MsCl
and DIPEA (Scheme 1).10 After some experimentation, con-
Scheme 1. Synthesis of Nitroalkenes 2 and Hydrocyanation
to the nitroalkene, followed by elimination of H-CN, as the
resulting alkene in 4 is not in conjugation with the nitro
group. The actual mechanistic explanation may be more
complex as the isolated alkene has a vicinal coupling constant
of 10.4 Hz that suggests a cis configuration. Dilution of the
reaction resulted in much longer reaction times and no
significant decrease in dimer formation. Reverse and slow
addition (syringe pump) of the nitroalkene to the mixture of
KCN, 18-C-6, and 1, followed by further addition of 1 (1.2
equiv) led to comparable yields of desired 3 (entries 4, 5,
and 7).
jugate addition of cyanide was achieved by the addition of 1 to
a solution of 2 with catalytic (10 mol %) quantities of KCN
and 18-C-6 in MeCN at room temperature (Table 1).
Hydrocyanation of trisubstituted nitroalkenes led to 1:1
diastereomeric mixtures (entries 2 and 5). The synthesis
of tetrasubstituted nitroalkenes from the condensation of
1° nitroalkanes with ketones leads to an unfavorable Henry
reaction. To investigate the hydrocyanation of tetrasub-
stituted nitroalkenes, we synthesized the literature com-
pound 1-nitro-2-methylcyclohex-1-ene (entry 8) from
2-chloro-2-methylcyclohexanone,12 via the oxidation of
the corresponding oxime.13 Hydrocyanation led to the
isolation of diastereomerically pure syn-6 in 84% yield,
and its structure was confirmed by single crystal X-ray
diffraction. This diastereoisomer presumably arises through
protonation from the thermodynamically more stable chair
form 714 of the nitronate to give the equatorial nitro
function in 6 (Scheme 3).
To gain some insight into the general mechanism for the
hydrocyanation of nitroalkenes control reactions were per-
formed in the absence of 18-C-6 or 1 and in the absence of
both 18-C-6 and KCN. In all three cases, no reaction was
found to occur. This indicates that the in situ generated HCN,
formed from the cyanide anion abstracting a proton from
the acetone cyanohydrin (1), is very important for the reaction
to proceed.
Table 1. Substrate Scope 3a
a All reactions carried out with 1 (1.2 equiv), 18-C-6 (0.1 equiv), and
KCN (0.1 equiv) in MeCN at rt. b Nitroalkene added via syringe pump
over a 5 h period to 1, 18-C-6, and KCN in MeCN followed by further
addition of 1 (1.2 equiv) in MeCN at rt.
Good yields were obtained except in the cases of linear
nitroalkenes (entries 4, 5, and 7) where none of the desired
product 3 could be isolated under the standard conditions.
Instead, a variety of byproducts were formed, and in the case
n
of 2 (R ) Pn, R′ ) H), we isolated the dimer 4 in 23%
To demonstrate the utility of these ꢀ-nitronitriles as
building blocks in synthesis, we have investigated functional
group interconversions of 8 (Scheme 4). The nitro group was
reduced with Zn/HCl, and the crude material Boc protected
yield (Scheme 2).11 The mechanism for its formation could
arise from conjugate deprotonation by the cyanide ion to give
nitronate 5, followed by conjugate addition to the starting
material (Scheme 2). This mechanism is preferred over the
nitronate derived from conjugate addition of cyanide adding
(12) Singh, V. S.; Gupta, S. M. L. Curr. Sci. 1981, 50, 816.
(13) Sakakibara, T.; Ikeda, Y.; Sudoh, R. Bull. Chem. Soc. Jpn. 1982,
55, 635.
(9) Fieser, L. F.; Gates, M. J. Am. Chem. Soc. 1946, 68, 2249.
(10) Melton, J.; McMurry, J. E. J. Org. Chem. 1975, 40, 2138.
(11) A similar dimer from entry 1 was isolated in 3% yield from a 3.5
mmol scale reaction.
(14) Values of CN ) 0.84 kJ/mol: (a) Jensen, F. R.; Bushweller, C. H.;
Beck, B. H. J. Am. Chem. Soc. 1969, 91, 344vs CH3 ) 7.28 kJ/mol: Booth,
H.; Everett, J. R. J. Chem. Soc., Perkin 2 1980, 255.
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Org. Lett., Vol. 10, No. 18, 2008