Redox-neutral α-cyanation of amines

Article abstract of DOI:10.1021/ja308009g

α-Aminonitriles inaccessible by traditional Strecker chemistry are obtained in redox-neutral fashion by direct amine α-cyanation/N-alkylation or alternatively, α-aminonitrile isomerization. These unprecedented transformations are catalyzed by simple carboxylic acids.

Full text of DOI:10.1021/ja308009g

Communication
pubs.acs.org/JACS
Redox-Neutral α‑Cyanation of Amines
Longle Ma, Weijie Chen, and Daniel Seidel*
Department of Chemistry and Chemical Biology, Rutgers, The State University of New Jersey, Piscataway, New Jersey 08854, United
States
S
* Supporting Information
ABSTRACT: α-Aminonitriles inaccessible by traditional
Strecker chemistry are obtained in redox-neutral fashion by
direct amine α-cyanation/N-alkylation or alternatively, α-
aminonitrile isomerization. These unprecedented trans-
formations are catalyzed by simple carboxylic acids.
he exceptional versatility of α-aminonitriles continues to
T
inspire the development of methods that provide access to
these valuable building blocks.1 While the classic Strecker
reaction2,3 remains an important tool in this regard, α-
aminonitriles that are part of a ring system cannot easily be
prepared by this methodology. A particularly attractive
alternative approach to α-aminonitriles such as 2 is the
replacement of an amine α-C−H bond with a C−CN bond
(1 → 2, eq 1). Previous efforts to develop such methods have
The notion that iminium ions such as 8 are accessible from
their corresponding α-aminonitriles led us to consider the
possibility of a novel α-aminonitrile isomerization (Figure 1).
relied on oxidative approaches,4,5 including electrochemical
methods.6 Photoredox catalysis has recently emerged as a
promising tool for oxidative amine α-cyanation, although this
strategy has largely been limited to N-aryl tetrahydroisoquino-
lines and N,N-dialkylanilines.7 Here we report a conceptually
new strategy for the α-cyanation of amines (eq 2). In contrast
to previous approaches, this method is redox-neutral8 and does
not require metal-based catalysts.
As part of a program to develop novel reactions of amines
and amino acids for the rapid buildup of molecular complex-
ity,9,10 we recently reported a decarboxylative version of the
classic Strecker reaction (eq 3).9g Specifically, we found that α-
amino acids such as proline react with aldehydes and TMSCN
to form cyclic α-aminonitriles (e.g., 5a) rapidly under
microwave irradiation. We also discovered that α-aminonitrile
7 reacts with proline to form 5a (eq 4). This reaction most
likely proceeds via reaction of proline with iminium ion pair 8,
which is thought to be present in equilibrium with α-
aminonitrile 7.
Figure 1. Potential pathways for α-aminonitrile isomerization.
The ability to generate cyclic α-aminonitriles such as 5a from
6a, which is readily available by standard Strecker chem-
istry,11,12 would represent a significant advance as this would
enable the use of simple amines as starting materials in place of
amino acids. As outlined in Figure 1, a number of potential
pathways can be considered that would result in the desired
isomerization process.
α-Aminonitrile 6a may isomerize to 5a simply by heating in
the absence of any additives (noncatalyzed pathway). Iminium
ion 9, which is expected to be present in low equilibrium
concentrations, could be transformed into azomethine ylide 10
via iminium α-deprotonation by the relatively basic cyanide
counteranion. The thus formed HCN would subsequently
Received: August 11, 2012
Published: September 10, 2012
© 2012 American Chemical Society
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Journal of the American Chemical Society
Communication
protonate azomethine ylide 10 at the benzylic position,
resulting in the formation of the new iminium ion 11, the
direct precursor of α-aminonitrile 5a.13,14 A base catalyzed
pathway can be envisioned as a variation of this isomerization
process. In this case, similar intermediates are accessed with the
difference being that the initial deprotonation of iminium ion 9
is achieved by an external base more basic than cyanide.
The perhaps most promising approach for α-aminonitrile
isomerization is a carboxylic acid catalyzed pathway (Figure 1).
Here, the cyanide anion of 9 is protonated by a carboxylic acid
catalyst to form iminium ion 12. The carboxylate anion could
subsequently deprotonate the iminium α-proton to give
azomethine ylide 10 which goes on to form α-aminonitrile
5a. Alternatively, N,O-acetal 13, which is expected to exist in
equilibrium with 12, could eliminate carboxylic acid to form
azomethine ylide 10 via a concerted pathway. A closely related
mechanism was proposed by Yu et al.15 as part of a
computational investigation of Tunge’s benzoic acid catalyzed
formation of N-alkyl pyrroles from 3-pyrroline.10i Independ-
ently, we have recently shown by means of intramolecular [3 +
2] trapping experiments that azomethine ylides are likely
intermediates in this and other carboxylic acid catalyzed redox-
isomerization processes.9d
%) led to almost complete isomerization to the desired α-
aminonitrile 5a. Specifically, 5a and 6a were isolated in an 18:1
ratio in 84% combined yield (entry 3).18 A number of other
aliphatic and aromatic carboxylic acid catalysts exhibited a very
similar but slightly inferior performance (entries 4−7).
Carboxylic acids with increased acidities resulted in less
favorable product ratios or led to poor yields. Diphenylphos-
phate was completely ineffective as a catalyst (entry 11).
Shorter reaction times led to lower levels of isomerization
(entries 12−13), whereas prolonged exposure to microwave
irradiation did not serve to improve product ratios but rather
led to slightly reduced yields (entry 14). Exchange of toluene
for xylenes as the solvent made virtually no difference (entry
15), whereas the degree of isomerization was substantially
lower in acetonitrile (entry 16). Interestingly, very little
isomerization was observed in n-butanol (entry 17), the solvent
that was previously found to be optimal in the decarboxylative
Strecker reaction. Lastly, reaction temperatures below 200 °C
led to incomplete isomerization and higher temperatures
resulted in partial substrate decomposition (entries 18−20).
In some cases, 1,3-dibenzylpyrrole was observed as a minor
byproduct of the isomerization process.10c
Having identified convenient conditions for α-aminonitrile
isomerization, we next sought to develop a one-pot approach to
the synthesis of 5a. Upon exposing a mixture of pyrrolidine,
benzaldehyde, TMSCN and benzoic acid (20 mol %) in
toluene to microwave irradiation at 200 °C for 30 min, 5a and
6a were obtained in a 9:1 ratio and 62% combined yield (eq 6).
Different catalysts were tested in the proposed α-aminonitrile
isomerization, using 6a as a model substrate (Table 1).16
Interestingly, brief exposure of 6a to microwave irradiation at
200 °C led to some isomerization in the absence of any
additives (entry 1). The addition of triethylamine had no
discernible effect on the outcome of the isomerization (entry
2).17 Gratifyingly, a catalytic amount of benzoic acid (20 mol
a
Table 1. Evaluation of Isomerization Conditions
Upon further experimentation, we found that it is advantageous
to perform the direct α-cyanation of pyrrolidine as a two- rather
than three-component reaction, using readily available
cyanohydrins as starting materials (eq 7). In this instance, 2-
ethylhexanoic acid (2-EHA) slightly outperformed benzoic acid
as the catalyst. The scope of this reaction with regard to the
cyanohydrin is summarized in Table 2.
Cyanohydrins derived from aromatic aldehydes with various
substitution patterns provided α-aminonitriles 5 with favorable
regioselectivities and in good yields. A number of hetero-
aromatic substituents were also well tolerated. Cyanohydrins
derived from aliphatic aldehydes provided less favorable
product ratios. This is perhaps due to a lower ionization
propensity of the regular Strecker products. Interestingly,
benzophenone-derived cyanohydrin provided α-aminonitrile 5p
in essentially regioisomerically pure form.
Importantly, the redox-neutral α-cyanation is applicable to
amines other than pyrrolidine. For instance, piperidine readily
underwent N-alkylation/α-cyanation when exposed to benzal-
dehyde cyanohydrin in the presence of 2-ethylhexanoic acid (eq
8). Products 14 and 15 were obtained in a favorable 15:1 ratio
in 61% overall yield. An increased temperature was required in
this case as a reaction performed at 200 °C provided compound
15 as the major product. Azepane underwent the correspond-
ing reaction at 220 °C to give products 16 and 17 in an 11:1
ratio and 79% combined yield (eq 9).19
temperature
time
ratio
yield
(%)
entry
catalyst
[°C]
[min]
5a/6a
1
−
NEt3
200
200
200
200
200
200
200
200
200
200
200
200
200
200
200
200
200
150
180
250
20
20
20
20
20
20
20
20
20
20
20
5
1:5
91
2
1:4
ND
84
3
PhCO2H
18:1
10:1
16:1
15:1
12:1
16:1
7:1
4
MeCO2H
84
5
2-Ethylhexanoic acid
Pivalic acid
4-MeO-benzoic acid
4-NO2-benzoic acid
Chloroacetic acid
CF3CO2H
84
6
70
7
86
8
43
9
13
10
11
12
13
14
1:2
ND
ND
90
Diphenylphosphate
PhCO2H
<1:20
11:1
13:1
17:1
18:1
4:1
PhCO2H
10
30
20
20
20
20
20
20
86
PhCO2H
77
b
15
PhCO2H
79
c
16
d
PhCO2H
ND
ND
ND
79
17
PhCO2H
1:1
18
19
20
PhCO2H
1:2
PhCO2H
13:1
9:1
PhCO2H
41
a
Reactions were performed on a 0.25 mmol scale. Product ratios were
determined by H NMR analysis of the crude reaction mixture. Yield
corresponds to combined, isolated yields of both regioisomers. ND:
1
A reaction of tetrahydroisoquinoline with benzaldehyde
cyanohydrin gave rise to predominantly one of the three
b
c
d
not determined. In xylenes. In acetonitrile. In n-butanol.
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Journal of the American Chemical Society
Communication
a
prepared sample of 20 was exposed to the previously optimized
isomerization conditions (eq 11). Indeed, α-aminonitrile 18
was again obtained as the major product.21 However, the
efficiency of this process was rather poor, and 4-benzylisoqui-
noline was obtained as a byproduct in 17% yield.
Table 2. Scope of the Direct α-Cyanation of Pyrrolidine
As shown in eq 12, a reaction of 2-methyl-pyrrolidine
provided a mixture of products 21 (52%, dr = 4.8:1)22 and 22
product
5/6
ratio
5/6
yield
(%)
entry
R
R′
b
1
Ph
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
a
b
c
d
e
f
18:1
86
80
67
94
41
87
79
85
89
85
60
64
82
62
74
78
40
2
3
4
4-Me-C6H4
4-MeO-C6H4
4−Cl-C6H4
4-NO2−C6H4
3−Cl-C6H4
3-Me-C6H4
2−Br-C6H4
mesityl
16:1
11:1
>20:1
1.4:1
>20:1
19:1
c
5
6
7
g
h
i
8
>20:1
>20:1
18:1
9
10
11
12
13
14
15
16
1-naphthyl
3-pyridyl
j
k
l
>20:1
20:1
2-furyl
2-thienyl
m
n
o
p
q
>20:1
1:1.4
1:3
(11%). Only trace amounts of the regular Strecker product
were observed. Although acyclic α-aminonitriles are readily
obtained by standard Strecker chemistry, we conducted a
reaction with N-benzylmethylamine to probe the reactivity of
this substrate class (eq 13). In this instance, 23 was obtained as
the sole product in 81% yield.
In summary, we have introduced a conceptually new strategy
for the direct α-cyanation of amines, a reaction that provides
rapid access to synthetically valuable α-aminonitriles not
accessible by traditional Strecker chemistry. The overall
transformation was rendered redox-neutral via the combination
of a reductive N-alkylation with an oxidative α-functionaliza-
tion. Further applications of this uncommon mode of
azomethine ylide reactivity are the subject of ongoing
investigations.
CO2Et
CH2CH2Ph
cyclohexyl
Ph
1:5
d
17
Ph
>20:1
a
b
c
See footnote (a) in Table 1. Reaction time was 30 min. Performed
as a three-component reaction according to eq 6. No heating element
was used. Benzoic acid was used as the catalyst.
d
ASSOCIATED CONTENT
* Supporting Information
Experimental procedures and characterization data. This
material is available free of charge via the Internet at http://
pubs.acs.org.
■
S
possible regioisomeric products (eq 10). Interestingly, 18 was
isolated as the major product, resulting from the functionaliza-
AUTHOR INFORMATION
Corresponding Author
seidel@rutchem.rutgers.edu
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported in part by the National Science
Foundation (Grant CHE-0911192). D.S. is a fellow of the
Alfred P. Sloan Foundation and the recipient of an Amgen
Young Investigator Award. We thank Mr. Tian Zhou (Rutgers
University) for conducting preliminary computational studies.
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