Catalytic one-pot, three-component acyl-strecker reaction

Article abstract of DOI:10.1055/s-2007-968008

Different aldehydes and amines react with acyl cyanides in the presence of a catalytic amount of the Schreiner thiourea catalyst to give the corresponding N-acyl amino nitriles in high yields. The scope of the reaction is broad and both aromatic and aliphatic aldehydes and amines can readily be used. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-968008

318
LETTER
Catalytic One-Pot, Three-Component Acyl-Strecker Reaction
Catalytic
O
ne-
u
Pot, Three-C
b
omponent
A
h
cyl-Strecker
aReaction s Chandra Pan, Benjamin List*
Max-Planck-Institut für Kohlenforschung, Kaiser-Wilhelm-Platz 1, 45470 Mülheim an der Ruhr, Germany
Fax +49(208)3062999; E-mail: list@mpi-muelheim.mpg.de
Received 20 October 2006
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.
Abstract: Different aldehydes and amines react with acyl cyanides
in the presence of a catalytic amount of the Schreiner thiourea cata-
lyst to give the corresponding N-acyl amino nitriles in high yields.
The scope of the reaction is broad and both aromatic and aliphatic
aldehydes and amines can readily be used.
NH2
CN
O
Key words: acylcyanation, a-amino nitriles, multicomponent reac-
classical Strecker
reaction
NH3
+
+
HCN
(1)
(2)
tions, organocatalysis, acyl cyanides
R
H
+
R
O
R2
O
O
R3
Discovered in 1850,1 the Strecker reaction has been iden-
tified as one of the most powerful multicomponent reac-
tions and has a central importance in organic synthesis.2
This three-component coupling of aldehydes, amines, and
hydrogen cyanide to give a-amino nitriles provides a
practical method in the synthesis of a-amino acids
(Scheme 1, eq. 1). Multicomponent reactions3 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 carbo-
nyl 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 acyl-
cyanation 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
three-component
acylcyanation
N
R2
+
R3
CN
R1
H
H2N
R1
CN
Scheme 1
Our initial investigations focused on finding appropriate
conditions10 for the three-component reaction of benz-
aldehyde (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 MgSO4 as the drying agent (entry 1). Interestingly,
use of 5 Å MS as the drying agent further improved the
Table 1 Optimizing the Reaction Conditions for the One-Pot,
Three-Component Acylcyanation
H
H
F3C
N
N
CF3
S
O
CF3
Ph
CF3
5
O
O
Me
N
Ph
+
+
H2N
Me
CN Ph
H
CH2Cl2,
0 °C, 24 h
Ph
CN
1a
2a
3a
4a
Entrya
Catalyst 5 (mol%)
Additive
MgSO4
5 Å MS
5 Å MS
5 Å MS
5 Å MS
Conversion (%)b
1
5
5
5
1
0
86
92
99
70
42
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 sim-
plify our approach towards a-amino acid derivatives but
also provide a potentially useful entry towards molecular
diversity if assortments of reagents were used. We were
2
3c
4c
5c
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.
SYNLETT 2007, No. 2, pp 0318–0320
0
1.
0
2.
2
0
0
7
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.
Advanced online publication: 24.01.2007
DOI: 10.1055/s-2007-968008; Art ID: G31706ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Catalytic One-Pot, Three-Component Acyl-Strecker Reaction
319
conversion (entry 2). The best result was obtained when Noteworthy, the reaction also affords products with allyl
the mixture of aldehyde, amine, additive, and catalyst amine or even with a simple alkyl amine (entries 5 and 6).
were stirred together at room temperature before the
In addition to acetyl cyanide, heptanoyl cyanide as an-
addition of acetyl cyanide at 0 °C (entry 3). Lowering the
other commercially available acyl cyanide has also been
catalyst loading further resulted in lower yields and side
used with similar reactivity (Table 3, entry 7).
product (N-benzyl acetamide) formation although a
significant background reaction was observed (entries 4
and 5).
Table 3 Three-Component Acylcyanation with Different Amines
and Acylcyanides
O
After establishing suitable reaction condition, we decided
to explore the scope of this new three-component reac-
tion. 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, en-
tries 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).
R3
O
O
R3
5 (5 mol%)
R1
Ph
N
+
+
H2N
R1
CN
Ph
H
5 Å MS, CH2Cl2, 0 °C
CN
1
2a
3
4
Entrya
R1
R3
Time (h) Yield (%)b
1
2
3
4
5
6
7
Me
Me
Me
Me
Me
Me
1-NaphCH2
4-ClC6H4CH2
4-MeOC6H4CH2
furfuryl
36
36
36
48
48
36
36
77
81
78
76
68
75
72
Table 2 Three-Component Acylcyanation of Different Aldehydes
allyl
O
n-Pent
Bn
O
O
5 (5 mol%)
Me
N
Bn
n-Hex
Bn
+
+
H2N
R2
H
Me
CN
5 Å MS,
CH2Cl2, 0 °C
R2
CN
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.
1a
2
3a
4
Entrya
R2
Ph
Time (h)
36
Yield (%)b
b Isolated yield after silica gel column chromatography.
1
2
80
82
73
83
76
84
78
48
85
82
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, practicabil-
ity, and mild reaction conditions render it an attractive
approach for the generation of diverse assortments of
a-amido nitriles. Besides the use of our reaction in the
preparation of a-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.
4-MeOC6H4
4-ClC6H4
2-Naph
2-furyl
36
3
48
4
36
5
36
6
3-pyridyl
i-Pr
36
7
36
8
t-Bu
48
9
1-cinnamyl
n-Pent
36
10
36
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.
General Procedure for the One-Pot Three-Component Acyl-
cyanation
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 CH2Cl2 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 mL 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.
b Isolated yield after silica gel column chromatography.
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.
1
All compounds were fully characterized on the basis of H NMR,
1
13C NMR and HRMS. Compound 4a: colorless liquid. H NMR
(400 MHz, CDCl3): d = 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). 13C NMR (100 MHz, CDCl3): d = 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.
Synlett 2007, No. 2, 318–320 © Thieme Stuttgart · New York

320
S. C. Pan, B. List
LETTER
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Acknowledgment
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.
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Synlett 2007, No. 2, 318–320 © Thieme Stuttgart · New York

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