acylcyanation - α-amino nitriles - multicomponent reactions - organocatalysis - acyl
cyanides
<P>Discovered in 1850,
[
1 ]
the Strecker reaction has been identified as one of the most powerful multicomponent
reactions and has a central importance in organic synthesis.
[
2 ]
This three-component coupling of aldehydes, amines, and hydrogen cyanide to give α-amino
nitriles provides a practical method in the synthesis of α-amino acids (Scheme
[
1 ]
, eq. 1). Multicomponent reactions
[
3 ]
such as the Strecker reaction are often useful due to their high atom economy, selectivity,
environmental friendliness, and formation of low levels of by-products. However,
the Strecker reaction has drawbacks in particular due to the volatile and highly toxic
nature of HCN. In this regard trimethyl cyanide (TMSCN) offers certain advantages.
However, due to its high toxicity and high 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 acylcyanation of carbonyl compounds.
[
4 ]
In the course of our investigation of Brønsted acid catalyzed reactions of imines,
[
5 ]
we recently developed a new efficient and potentially useful variant of the Strecker
reaction, the Brønsted acid catalyzed acylcyanation of imines with acetyl cyanide
(
1a ) as a new cyanide source.
[
6 ]
After screening different Brønsted acid catalysts,
[
7 ]
thio urea catalyst
5 developed earlier by Schreiner et al.
[
8 ]
turned out to be a highly efficient catalyst for this rarely used and yet highly atom
economic reaction.
[
9 ]
</P><P>We reasoned that a useful extension of our catalytic imine acylcyanation would
be avoiding the isolation of the preformed imine intermediate entirely and developing
a one-pot three-component acylcyanation (or acyl-Strecker reaction) of amines, aldehydes,
and acyl cyanides (Scheme
[
1 ]
, eq. 2). Such a reaction would not only simplify our approach towards α-amino acid
derivatives but also provide a potentially useful entry towards molecular diversity
if assortments of reagents were used. We were aware that the irreversible reaction
of acyl cyanide and amine to give an amide would threaten our concept but hoped to
avoid this side reaction by sequencing the reagent additions in a suitable order.</P>
Scheme 1
Table 1 Optimizing the Reaction Conditions for the One-Pot, Three-Component Acylcyanation
<TD VALIGN="TOP" COLSPAN="4">
<TD VALIGN="TOP">
Entrya
</TD><TD VALIGN="TOP">
Catalyst 5 (mol%)
</TD><TD VALIGN="TOP">
Additive
</TD><TD VALIGN="TOP">
Conversion (%)b
</TD>
<TD VALIGN="TOP">
1
</TD><TD VALIGN="TOP">
5
</TD><TD VALIGN="TOP">
MgSO4
</TD><TD VALIGN="TOP">
86
</TD>
<TD VALIGN="TOP">
2
</TD><TD VALIGN="TOP">
5
</TD><TD VALIGN="TOP">
5 Å MS
</TD><TD VALIGN="TOP">
92
</TD>
<TD VALIGN="TOP">
3c
</TD><TD VALIGN="TOP">
5
</TD><TD VALIGN="TOP">
5 Å MS
</TD><TD VALIGN="TOP">
99
</TD>
<TD VALIGN="TOP">
4c
</TD><TD VALIGN="TOP">
1
</TD><TD VALIGN="TOP">
5 Å MS
</TD><TD VALIGN="TOP">
70
</TD>
<TD VALIGN="TOP">
5c
</TD><TD VALIGN="TOP">
0
</TD><TD VALIGN="TOP">
5 Å MS
</TD><TD VALIGN="TOP">
42
</TD>
<TD COLSPAN="20">
a Reaction condition: aldehyde 2a , amine 3a , additive, and catalyst 5 were stirred together at 0 °C for 2 h before acetyl cyanide 1a (1.5 equiv) was added.
b Determined by GC.
c Aldehyde 2a , amine 3a , additive, and catalyst 5 were stirred together at r.t. for 2 h before acetyl cyanide (1a , 1.5 equiv) was added at 0 °C.
<P>Our initial investigations focused on finding appropriate conditions
[
10 ]
for the three-component reaction of benzaldehyde (
2a ), benzyl amine (
3a ) and acetyl cyanide (
1a , Table
[
1 ]
). According to our findings in the two-component version we used dichloromethane
as the solvent. We were pleased to find good conversion at our initial attempt using
MgSO
4 as the drying agent (entry 1). Interestingly, use of 5 Å MS as the drying agent further
improved the conversion (entry 2). The best result was obtained when the mixture of
aldehyde, amine, additive, and catalyst were stirred together at room temperature
before the addition of acetyl cyanide at 0 °C (entry 3). Lowering the catalyst loading
further resulted in lower yields and side product (
N -benzyl acetamide) formation although a significant background reaction was observed
(entries 4 and 5).</P><P>After establishing suitable reaction condition, we decided
to explore the scope of this new three-component reaction. First, a variety of different
aldehydes
2a -
j was examined with benzyl amine
3a as the amine component and acetyl cyanide
1a as the cyanide source (Table
[
2 ]
, entries 1-10). Both aromatic aldehydes (entries 1-4) with electron-donating or -withdrawing
substituents, as well as heteroaromatic aldehydes (entries 5 and 6) can be used with
similar efficiencies. Furthermore, aliphatic branched, unbranched, and unsaturated
aldehydes can also be employed to give moderate to good yields (entries 7-10).</P>
Table 2 Three-Component Acylcyanation of Different Aldehydes
<TD VALIGN="TOP" COLSPAN="4">
<TD VALIGN="TOP">
Entrya
</TD><TD VALIGN="TOP">
R2
</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">
36
</TD><TD VALIGN="TOP">
80
</TD>
<TD VALIGN="TOP">
2
</TD><TD VALIGN="TOP">
4-MeOC6 H4
</TD><TD VALIGN="TOP">
36
</TD><TD VALIGN="TOP">
82
</TD>
<TD VALIGN="TOP">
3
</TD><TD VALIGN="TOP">
4-ClC6 H4
</TD><TD VALIGN="TOP">
48
</TD><TD VALIGN="TOP">
73
</TD>
<TD VALIGN="TOP">
4
</TD><TD VALIGN="TOP">
2-Naph
</TD><TD VALIGN="TOP">
36
</TD><TD VALIGN="TOP">
83
</TD>
<TD VALIGN="TOP">
5
</TD><TD VALIGN="TOP">
2-furyl
</TD><TD VALIGN="TOP">
36
</TD><TD VALIGN="TOP">
76
</TD>
<TD VALIGN="TOP">
6
</TD><TD VALIGN="TOP">
3-pyridyl
</TD><TD VALIGN="TOP">
36
</TD><TD VALIGN="TOP">
84
</TD>
<TD VALIGN="TOP">
7
</TD><TD VALIGN="TOP">
i -Pr
</TD><TD VALIGN="TOP">
36
</TD><TD VALIGN="TOP">
78
</TD>
<TD VALIGN="TOP">
8
</TD><TD VALIGN="TOP">
t -Bu
</TD><TD VALIGN="TOP">
48
</TD><TD VALIGN="TOP">
48
</TD>
<TD VALIGN="TOP">
9
</TD><TD VALIGN="TOP">
1-cinnamyl
</TD><TD VALIGN="TOP">
36
</TD><TD VALIGN="TOP">
85
</TD>
<TD VALIGN="TOP">
10
</TD><TD VALIGN="TOP">
n -Pent
</TD><TD VALIGN="TOP">
36
</TD><TD VALIGN="TOP">
82
</TD>
<TD COLSPAN="20">
a Aldehyde 2 (0.5 mmol), amine 3a (0.5 mmol), 5 Å MS (150 mg) and catalyst (0.025 mmol) were stirred together at r.t.
for 2 h before acetyl cyanide (0.75 mmol) was added at 0 °C.
b Isolated yield after silica gel column chromatography.
<P>A variety of amines were studied next with benzaldehyde (
2a ) as the aldehyde component and acetyl cyanide (
1a ) as the cyanide source (Table
[
3 ]
, entries 1-6). It turned out that the three-component acylcyanation processes works
well with several amines. Both benzyl amines with electron-rich or electron-poor phenyl
group can be used with similar efficiencies (entries 2, 3). Furfuryl amine having
a heteroaromatic moiety (entry 4) can also be employed. Noteworthy, the reaction also
affords products with allyl amine or even with a simple alkyl amine (entries 5 and
6).</P><P>In addition to acetyl cyanide, heptanoyl cyanide as another commercially
available acyl cyanide has also been used with similar reactivity (Table
[
3 ]
, entry 7).</P>
Table 3 Three-Component Acylcyanation with Different Amines and Acylcyanides
<TD VALIGN="TOP" COLSPAN="5">
<TD VALIGN="TOP">
Entrya
</TD><TD VALIGN="TOP">
R1
</TD><TD VALIGN="TOP">
R3
</TD><TD VALIGN="TOP">
Time (h)
</TD><TD VALIGN="TOP">
Yield (%)b
</TD>
<TD VALIGN="TOP">
1
</TD><TD VALIGN="TOP">
Me
</TD><TD VALIGN="TOP">
1-NaphCH2
</TD><TD VALIGN="TOP">
36
</TD><TD VALIGN="TOP">
77
</TD>
<TD VALIGN="TOP">
2
</TD><TD VALIGN="TOP">
Me
</TD><TD VALIGN="TOP">
4-ClC6 H4 CH2
</TD><TD VALIGN="TOP">
36
</TD><TD VALIGN="TOP">
81
</TD>
<TD VALIGN="TOP">
3
</TD><TD VALIGN="TOP">
Me
</TD><TD VALIGN="TOP">
4-MeOC6 H4 CH2
</TD><TD VALIGN="TOP">
36
</TD><TD VALIGN="TOP">
78
</TD>
<TD VALIGN="TOP">
4
</TD><TD VALIGN="TOP">
Me
</TD><TD VALIGN="TOP">
furfuryl
</TD><TD VALIGN="TOP">
48
</TD><TD VALIGN="TOP">
76
</TD>
<TD VALIGN="TOP">
5
</TD><TD VALIGN="TOP">
Me
</TD><TD VALIGN="TOP">
allyl
</TD><TD VALIGN="TOP">
48
</TD><TD VALIGN="TOP">
68
</TD>
<TD VALIGN="TOP">
6
</TD><TD VALIGN="TOP">
Me
</TD><TD VALIGN="TOP">
n -Pent
</TD><TD VALIGN="TOP">
36
</TD><TD VALIGN="TOP">
75
</TD>
<TD VALIGN="TOP">
7
</TD><TD VALIGN="TOP">
n -Hex
</TD><TD VALIGN="TOP">
Bn
</TD><TD VALIGN="TOP">
36
</TD><TD VALIGN="TOP">
72
</TD>
<TD COLSPAN="20">
a Aldehyde 2a (0.5 mmol), amine 3 (0.5 mmol), 5 Å MS (150 mg), and catalyst 5 (0.025 mmol) were stirred together at r.t. for 2 h before the acyl cyanide 1 (0.75 mmol) was added at 0 °C.
b Isolated yield after silica gel column chromatography.
<P>In summary, we have developed a new efficient and potentially useful variant of
the three-component one-pot Strecker reaction using acyl cyanides as cyanide source.
Its rather broad scope, operational simplicity, practicability, and mild reaction
conditions render it an attractive approach for the generation of diverse assortments
of α-amido nitriles. Besides the use of our reaction in the preparation of α-amino
acids, it may find place in medicinal chemistry due to its potential diversity. Further
studies in our laboratory aim at expanding the scope of the reaction to include ketones
and at developing an asymmetric catalytic version.</P>
General Procedure for the One-Pot Three-Component Acylcyanation
<P>The aldehyde
2 (0.5 mmol), amine
3 (0.5 mmol), 5 Å MS (150 mg) and catalyst
5 (5 mol%) was taken in a dry Schlenk flask. Then 2 mL dry CH
2 Cl
2 was added to the mixture and stirred at r.t. for 2 h. The flask was cooled to 0 °C
and stirred for 10 min. Then 50 µL of acetyl cyanide
1a (0.75 mmol) was added to the mixture and stirred for 36-48 h at 0 °C. The mixture
was directly subjected to silica gel column chromatography to give the pure corresponding
product. All compounds were fully characterized on the basis of
1 H NMR,
13 C NMR and HRMS. Compound
4a : colorless liquid.
1 H NMR (400 MHz, CDCl
3 ): δ = 7.44-7.38 (m, 5 H), 7.31-7.24 (m, 3 H), 7.14-7.07 (m, 3 H), 4.58 (d,
J = 17.6 Hz, 1 H), 4.49 (d,
J = 12.9 Hz, 1 H), 2.14 (s, 1 H).
13 C NMR (100 MHz, CDCl
3 ): δ = 171.3, 135.3, 131.9, 129.1, 128.8, 128.4, 127.4, 125.9, 116.1, 49.2, 48.3,
21.7. HRMS (EI):
m /
z calcd for [MH]
+ 264.126062; found: 264.126260.</P>
Acknowledgment <P>We thank Degussa, Merck, Saltigo, and Wacker for the donation of chemicals and
Novartis for a Young Investigator award to BL. Our work was supported by the Max-Planck-Gesellschaft,
the Deutsche Forschungsgemeinschaft (Priority Program 1179
Organocatalysis ), and the Fonds der Chemischen Industrie.</P>
