2
C.W. Downey et al. / Tetrahedron Letters xxx (xxxx) xxx
which may allow in situ formation of the silyl ketene imine nucleo-
phile [10–12] in equilibrium amounts prior to addition of the
acetal, [10–12] led to generally superior results (Eq. (3)).
ð4Þ
ð5Þ
ð3Þ
Table 1 illustrates the scope of this one-pot reaction. The opti-
mized reaction conditions were highly effective for reactions of
acetals derived from benzaldehyde derivatives, generally providing
yields from 80 to 100%. The electron-poor nitrobenzaldehyde deri-
vative, however, suffered from low conversion and the bulk of the
mass balance in the unpurified reaction mixture consisted of the
parent aldehyde. Notably, the electron-poor (4-trifluoromethyl)
benzaldehyde derivative afforded 87% yield of the desired product,
which suggests that the electron deficiency of the 4-nitro deriva-
tive may not be responsible for its poor reactivity. Some substrates
reacted more efficiently when hexane was added as a cosolvent,
including two halogenated derivatives (entries 4,5). The 4-chloro-
and 4-bromobenzaldehyde derivatives reacted somewhat slug-
gishly at room temperature, but smoothly afforded the desired
product when heated to 70 °C for 2 h. Attempts to synthesize het-
eroaryl-substituted nitriles resulted only in decomposition of the
electrophile (entry 8), but some reactivity was observed for the
purely aliphatic cyclohexyl substrate (entry 9). When the elec-
tron-rich dimethyl acetal derived from p-anisaldehyde was sub-
jected to the reaction conditions, an intractable reaction mixture
Based on the success of the reactions of acetonitrile with acet-
als, the application of this method to the cyanomethylation of
nitrone electrophiles was targeted in order to provide products
that can act as b-amino acid precursors [13]. Yoshimura and
Tanino have shown that
a-substituted nitriles can be converted
to their silyl ketene imines in situ prior to addition to nitrones,
but the use of acetonitrile itself has not been addressed in this con-
text. Based upon our previous success with nitrone electrophiles
under silylative conditions [14] and the successful development
of the dimethyl acetal methodology described above, a standard
set of reaction conditions was rapidly established. Acetonitrile
again proved viable as both reaction solvent and substrate, but
reactivity was somewhat sluggish due to the poor solubility of
the nitrone electrophiles. To combat this problem, a small amount
of CH Cl (~10% by volume) was added to the reaction mixture,
2
2
and high conversion to the b-(silyloxy)aminonitrile was observed
dominated by the
a,b-unsaturated nitrile product was observed,
(Eq. (6)).
in analogy to previously reported results [7].
The scope of this reaction is not limited to the examples illu-
strated in Table 1. For example, when benzaldehyde dimethyl
acetal was added to a mixture of propionitrile, TMSOTf, and i-Pr -
2
ð6Þ
NEt, the b-methoxynitrile was provided as a mixture of diastereo-
mers in 73% yield (Eq. (4)). When the acetal featured alkenyl
substitution, a notable change in chemoselectivity occurred. Cinna-
maldehyde dimethyl acetal was subjected to the standard reaction
conditions, but elimination occurred under the reaction conditions
A variety of nitrones reacted under similar conditions, as illu-
strated in Table 2. Nitrones derived substituted from benzalde-
hydes proved to be excellent substrates, providing the
conveniently protected products in 65–84% yield (entries 1–6).
Even the electron-rich p-anisyl nitrone, which is particularly prone
to rearrangement to the N-aryl amide at warmer temperatures
to yield the a,b,c,d-unsaturated nitrile (Eq. (5)).
[
14b], reacted efficiently at room temperature. Heteroaryl substi-
tution, which was incompatible with the acetal reactions described
above, provided no obstacle in the nitrone case and both the furyl
and thienyl substrates reacted in acceptable yield (entries 7–8). In
further contrast with the acetal electrophiles, a cinnamyl nitrone
Table 1
Reaction of acetonitrile with various dimethyl acetals.
Table 2
Addition of acetonitrile to various nitrones.
Entry
R
Product
Yield (%)b
1
2
3
4
5
6
7
8
9
Ph
4-(NO
4-(CF
4-ClPh
4-BrPh
4-MePh
2-naphthyl
2-thienyl
Cy
1a
1b
1c
1d
1e
1f
1g
1h
1i
100
36
Yield (%)b
Entry
R
T (°C)
t
Product
2
)Ph
)Ph
1
2
3
4
5
6
7
8
9
Ph
4-(NO
4-FPh
0
23
0
23
23
23
0
23
0
2 h
2 h
2 h
2 h
16 h
2 h
2 h
16 h
2 h
2 h
4a
4b
4c
4d
4e
4f
4g
4h
4i
84
65
85
66
78
83
53
80
64
76
3
87
c,d
85
2
)Ph
c,d
92
c
86
4-BrPh
c
81
4-MePh
4-MeOPh
2-furyl
2-thienyl
cinnamyl
Cy
e
0
24
a
2
Reaction conditions: 1. MeCN (2.5 mL), TMSOTf (2.06 mmol), i-Pr NEt
1.12 mmol), rt, 1 h. 2. Acetal (1.0 mmol), 16 h.
Isolated yield after chromatography.
Hexane (12.5 mL) was added as a cosolvent.
After addition of the acetal, the reaction was heated to reflux (70 °C) for 2 h.
Decomposition of the acetal was observed.
(
10
23
4j
b
c
a
Reaction conditions: nitrone (1.00 mmol), MeCN (10 mL), CH
2 2
Cl (1 mL), i-
d
Pr NEt (1.50 mmol), TMSOTf (1.40 mmol).
2
e
b
Isolated yield after chromatography.
Downey, C. Wade
