acylcyanation - α-amino nitrile - Brønsted acid catalysis - organocatalysis - acetyl
cyanide
<P>The Strecker reaction of imines with HCN provides one of the most efficient methods
for the preparation of α-amino nitriles, which are useful intermediates in the synthesis
of α-amino acids.
[
1]
However, the Strecker reaction has limitations in particular due to the volatile and
highly toxic nature of HCN. In this regard, trimethylsilyl cyanide (TMSCN) offers
certain advantages. However, due to its high toxicity and price, access to alternative
cyanation reagents is desirable. For example, acyl cyanides are not only less toxic
and readily available but also have already been used in the acylcyanation of carbonyl
compounds.
[
2]
Surprisingly however, while the reaction of acetyl cyanide and analogous α-oxonitriles
with aldehydes and ketones has been studied extensively in recent years, its reaction
with imines has been significantly less investigated. Thus in 1958, Dornow et al.
first reported the reaction of acyl cyanides with imines and later described a triethylamine-catalyzed
version.
[
3]
Survey of the literature reveals that there are no other catalytic versions of this
atom-economic yet rarely used approach to α-amino nitriles.
[
4]
</P><P>Recently, Brønsted acid and hydrogen-bonding catalysis have emerged as powerful
strategies for organocatalysis.
[
5]
Inspired by these studies and realizing the potential of the acylcyanation of imines
for the synthesis of α-amino acids, we were encouraged to investigate the catalytic
addition of acyl cyanides to imines (Scheme
[
1]
).</P>
Scheme 1 Catalytic acylcyanation of imines
<P>Initial experiments focused on the examination of different catalysts for this
transformation (Table
[
1]
).
[
6]
While the highly acidic TFA (trifluoroacetic acid) did not give any conversion in
dichloromethane (entry 1), moderately acidic phenylphosphinic acid
3a gave good conversion (entry 2). In the context of these studies we then found that
the reaction cannot only be catalyzed by stronger, specific acid catalysts but also
by hydrogen-bonding-type, general acid catalysts.
[
7]
</P>
Table 1 Catalytic Acylcyanation of Imine 1a
<TD VALIGN="TOP" COLSPAN="5">
</TD>
<TD VALIGN="TOP">
Entrya
</TD><TD VALIGN="TOP">
Catalyst
</TD><TD VALIGN="TOP">
mol%
</TD><TD VALIGN="TOP">
Time (h)
</TD><TD VALIGN="TOP">
Conv. (%)b
</TD>
<TD VALIGN="TOP">
1
</TD><TD VALIGN="TOP">
TFA
</TD><TD VALIGN="TOP">
20
</TD><TD VALIGN="TOP">
72
</TD><TD VALIGN="TOP">
0
</TD>
<TD VALIGN="TOP">
2
</TD><TD VALIGN="TOP">
3a
</TD><TD VALIGN="TOP">
20
</TD><TD VALIGN="TOP">
24
</TD><TD VALIGN="TOP">
90
</TD>
<TD VALIGN="TOP">
3
</TD><TD VALIGN="TOP">
3b
</TD><TD VALIGN="TOP">
10
</TD><TD VALIGN="TOP">
24
</TD><TD VALIGN="TOP">
99
</TD>
<TD VALIGN="TOP">
4
</TD><TD VALIGN="TOP">
3b
</TD><TD VALIGN="TOP">
2
</TD><TD VALIGN="TOP">
24
</TD><TD VALIGN="TOP">
98
</TD>
<TD VALIGN="TOP">
5
</TD><TD VALIGN="TOP">
3b
</TD><TD VALIGN="TOP">
1
</TD><TD VALIGN="TOP">
24
</TD><TD VALIGN="TOP">
93
</TD>
<TD COLSPAN="20">
</TD></TR><TR><TD VALIGN="TOP" COLSPAN="5">
a All reactions were performed using 0.1 mmol of imine 1a and 0.15 mmol of acetyl cyanide (2).
b Determined by GC.
</TD>
<P>We identified Schreiner’s thiourea catalyst
3b, in particular, to be highly efficient in promoting the reaction (entry 3).
[
8]
In each instance, the reaction was carried out with 1.5 equivalents of acetyl cyanide.
Decreasing the catalyst loading from 10 mol% to 2 mol% essentially preserved the conversion
(entry 4). Reducing the catalyst loading to only 1 mol% reduced the yield somewhat
(entry 5).
[
9]
Consequently, either 2 mol% or 5 mol% of catalyst
3b was used in subsequent experiments.</P><P>Using dichloromethane as the solvent and
thiourea
3b as the catalyst (2-5 mol%), we decided to explore the scope of this reaction (Table
[
2]
). It turned out that the selected reaction conditions are broadly useful for a variety
of different substrates. Both aromatic aldimines (entries 1-4) with electron-donating
or -withdrawing substituents, as well as heteroaromatic aldimines (entries 5 and 6),
can be used with similar efficiencies. Furthermore, aliphatic branched, unbranched,
and unsaturated aldimines can also be employed to give moderate to good yields (entries
7-10).</P>
Table 2 Catalytic Acylcyanation of Various Imines
<TD VALIGN="TOP" COLSPAN="4">
</TD>
<TD VALIGN="TOP">
Entrya
</TD><TD VALIGN="TOP">
R
</TD><TD VALIGN="TOP">
Time (h)
</TD><TD VALIGN="TOP">
Yield (%)b
</TD>
<TD VALIGN="TOP">
1
</TD><TD VALIGN="TOP">
Ph
</TD><TD VALIGN="TOP">
24
</TD><TD VALIGN="TOP">
88
</TD>
<TD VALIGN="TOP">
2
</TD><TD VALIGN="TOP">
4-MeOC6H4
</TD><TD VALIGN="TOP">
24
</TD><TD VALIGN="TOP">
84
</TD>
<TD VALIGN="TOP">
3
</TD><TD VALIGN="TOP">
4-ClC6H4
</TD><TD VALIGN="TOP">
24
</TD><TD VALIGN="TOP">
79
</TD>
<TD VALIGN="TOP">
4
</TD><TD VALIGN="TOP">
2-ClC6H4
</TD><TD VALIGN="TOP">
24
</TD><TD VALIGN="TOP">
83
</TD>
<TD VALIGN="TOP">
5
</TD><TD VALIGN="TOP">
2-Furyl
</TD><TD VALIGN="TOP">
24
</TD><TD VALIGN="TOP">
67
</TD>
<TD VALIGN="TOP">
6
</TD><TD VALIGN="TOP">
3-Pyridyl
</TD><TD VALIGN="TOP">
24
</TD><TD VALIGN="TOP">
96
</TD>
<TD VALIGN="TOP">
7c
</TD><TD VALIGN="TOP">
i-Pr
</TD><TD VALIGN="TOP">
48
</TD><TD VALIGN="TOP">
76
</TD>
<TD VALIGN="TOP">
8c
</TD><TD VALIGN="TOP">
t-Bu
</TD><TD VALIGN="TOP">
48
</TD><TD VALIGN="TOP">
64
</TD>
<TD VALIGN="TOP">
9c
</TD><TD VALIGN="TOP">
1-Cyclohexenyl
</TD><TD VALIGN="TOP">
48
</TD><TD VALIGN="TOP">
82
</TD>
<TD VALIGN="TOP">
10c
</TD><TD VALIGN="TOP">
t-BuCH2
</TD><TD VALIGN="TOP">
48
</TD><TD VALIGN="TOP">
81
</TD>
<TD COLSPAN="20">
</TD></TR><TR><TD VALIGN="TOP" COLSPAN="4">
a All reactions were performed using 2 mol% of the catalyst unless otherwise stated.
b Yields of pure product after silica gel column chromatography.
c 5 mol% of the catalyst.
</TD>
<P>Mechanistically, the reaction may proceed via an initial reaction of the imine
with acetyl cyanide to form an acyl iminium-cyanide ion pair. Its recombination to
product
4 may be urea-catalyzed.</P><P>In summary, we have developed a new efficient and potentially
useful variant of the Strecker reaction, the general Brønsted acid catalyzed acylcyanation
of imines with acetyl cyanide as a new cyanide source. The operational simplicity,
practicability, and mild reaction conditions render it an attractive approach for
the generation of different
N-acyl α-amino nitriles. Further studies in our laboratory aim at expanding the scope
of the reaction to include ketimines and at developing an asymmetric catalytic version.
[
10]
</P>