A novel oxidative transformation of α-aminonitriles to amides

Article abstract of DOI:10.1246/cl.2002.122

A novel oxidative transformation of α-aminonitriles to amides is reported. Oxidation of α-aminonitriles with peracid, followed by basic treatment affords, amides in good yields. A mechanistic aspect of this transformation is also discussed.

Full text of DOI:10.1246/cl.2002.122

122
Chemistry Letters 2002
A Novel Oxidative Transformation of ꢀ-Aminonitriles to Amides
Satoshi Yokoshima, Tetsuji Kubo, Hidetoshi Tokuyama, and Tohru Fukuyamaꢀ
Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033
(Received October 31, 2001; CL-011084)
A novel oxidative transformation of ꢀ-aminonitriles to
date (DEPC) to yield various ꢀ-aminonitriles 5 in 67–88% yields
(eq 2). ꢀ-Aminonitriles obtained were then subjected to the
oxidative transformation according to the following procedure:
To a solution of ꢀ-aminonitrile 5 in acetonitrile-water (4 : 1) was
added mCPBA (1.2 equiv) at 0 ꢁC. Upon disappearance of the
starting material (10–20 min), the solution was treated with
dimethyl sulfide (1.0equiv). 7 After stirring for 15 min, aqueous
potassium hydroxide (3 M, 5.0equiv) was added and stirring was
continued for several hours. Extraction with ethyl acetate and
purification by silica gel chromatography afforded the corre-
sponding amide.
amides is reported. Oxidation of ꢀ-aminonitriles with peracid,
followed by basic treatment affords, amides in good yields. A
mechanistic aspect of this transformation is also discussed.
ꢀ-Aminonitrile is a valuable functional group since it can be
used as an acyl anion equivalent in the umpolung synthesis,1 a
masked hemiaminal functionality,2 and a precursor of hydro-
xylamines.3 In the course of our investigation of total synthesis of
gelsemine (1),4 we planned to construct ꢁ-lactam 4 by conjugate
addition of ꢀ-aminonitrile anion and the subsequent conversion
to the lactam. While the expected conjugate addition took place
quite smoothly, we confronted a major problem in an efficient
conversion of ꢀ-aminonitrile 3 into lactam 4. This transformation
could initially be carried out by a two-step procedure, namely,
hydrolysis of ꢀ-aminonitrile 3 in the presence of silver nitrate in
acetonitrile-water followed by oxidation of the resulting hemi-
aminal with pyridinium dichromate (PDC), albeit in low yield.
After extensive investigation, we fortuitously found that this
transformation could be executed in one-pot by oxidation with m-
chloroperbenzoic acid (mCPBA) followed by treatment with base
(eq 1).5 In this communication, we describe this novel
transformation of ꢀ-aminonitriles to amides and its mechanistic
aspects as well.
CN
(EtO)2P(O)CN
R"
R"
HN
+
(2)
RCHO
R
N
THF
rt
R’
R’
5a-g
7
8
Some representative results are summarized in Table 1. ꢀ-
Aminonitriles 5a-d, derived from cyclic amines, morpholine or
pyrrolidine, with either aliphatic or aromatic aldehyde, could be
transformed into the corresponding amides in good yields (entries
1-4). While the reaction of 5e, prepared from N-benzylmethyl-
amine, gave the desired amide in good yield, the corresponding
aminonitrile 5f (R ¼ Ph) afforded amide in low yield. In addition,
reaction of the aniline derivative 5g did not proceed to give any
CO
O
2 R"
Table 1. Oxidative transformation of aminonitriles
NC
NC
Me
O
R
R
Time/ha Yield
N
Entry
Substrate
CN
Product
O
N
N
N
Me
R
N
R
N
OCOPh
O
R’
O
O
2
3
5a R = CH2CH2Ph
5b R = Ph
6a R = CH2CH2Ph
6b R = Ph
3
1.5
1
2
82
73
O
O
CN
O
O
R
N
R
N
R
N
NH
N
N
Me
Me
3
4
5
2
89
78
5c R = CH2CH2Ph
5d R = Ph
6c R = CH2CH2Ph
6d R = Ph
O
OCOPh
Gelsemine (1)
O
CN
Me
4
Me
R
N
Scheme 1. A Plan for construction of ꢁ-lactam.
R
N
Bn
Bn
mCPBA; Me2S;
CN
O
7
3
89
33
5
6
5e R = CH2CH2Ph
5f R = Ph
6e R = CH2CH2Ph
6f R = Ph
KOH aq
R"
R"
(1)
R
N
R
N
O
CN
Me
CH3CN-H2O
R’
R’
Me
6
Ph
N
Ph
N
5
Ph
Ph
_
7
5g
6g
0
We carried out model studies using ꢀ-aminonitriles prepared
according to Shioiri’s procedure.6 Thus, aldehydes 7 were
condensed with secondary amines 8 by diethyl phosphorocyani-
aReaction time for basic treatment.
Copyright Ó 2002 The Chemical Society of Japan

Chemistry Letters 2002
123
desired amide.
NC
O
N
O
O
A proposed mechanism of the reaction is shown in Scheme 2.
m-Chloroperbenzoic acid oxidation of ꢀ-aminonitrile 5 is
expected to give N-oxide 9. Subsequent base treatment would
cause a Polonovsky-type elimination8 to afford a cyanoiminium
ion 10,9 which should undergo hydrolysis via cyanohydrin 11 to
yield amide 6. During the optimization of the reaction conditions,
we observed some side reactions that support the intermediacies
of 9, 10, and 11. The reaction of ꢀ-aminonitrile 5a using sodium
bicarbonate in THF-water afforded ꢀ,ꢂ-unsaturated nitrile 12 (eq
3), which might have been generated via Cope elimination of N-
oxide 5a. In contrast, the reaction using DBU as base in THF-
water yielded enamine 13 (eq 4), which would be derived from
cyanoiminium ion 10a. When excess amount of mCPBA was not
quenched with dimethyl sulfide, hydroxylamine 15 and methyl
ester 16 were obtained (eq 5). Further oxidation of hemiaminal
11e, followed by fragmentation of the resulting N-oxide 14,
mCPBA;
Et3N
MOM
MOM
N
N
N
Me
Me
(6)
THF-H2O
rt
OCOPh
OCOPh
83
3'
4'
would give the hydroxylamine 15. Methyl ester 16 would be
derived from the corresponding acylcyanide by methanolysis.
Having obtained the basic information on the desired
transformation with model compounds, we then applied the
reaction conditions to the highly functionalized ꢀ-aminonitrile 30
(eq 6). Gratifyingly, the desired transformation proceeded quite
smoothly to afford the lactam 40 in 83% yield, which could be
converted to (þ)-gelsemine in several steps.4
In summary, we have developed a novel oxidative transfor-
mation of ꢀ-aminonitriles into amides. Because of the ready
availability of ꢀ-aminonitriles from aldehydes, the present
method would serve as a versatile amide formation reaction.
mCPBA; Me2S;
NC
O
KOH aq
R'
R'
R
N
R
N
CH3CN-H2O (4:1)
0
R''
R''
5
6
The present work is dedicated to Professor Teruaki
Mukaiyama on the occasion of his 75th birthday.
mCPBA
HCN
NC
NC
CN
References and Notes
O
+OH
R'
OH
R'
R'
1
D. J. Ager, ‘‘Formyl and Acyl Anions,’’ in ‘‘Umpoled
Synthons,’’ ed. by T. A. Hase, Wiely, New York (1987).
For an example in total synthesis of natural products, see: T.
Fukuyama and J. J. Nunes, J. Am. Chem. Soc., 110, 5196
(1988).
R
N
R
N
R
N
HO
R''
R''
R''
9
10
11
2
Scheme 2. A proposed reaction mechanism.
mCPBA;
NaHCO3
CN
3
4
5
H. Tokuyama, T. Kuboyama, A. Amano, T. Yamashita, and
T. Fukuyama, Synthesis, 2000, 1299.
S. Yokoshima, H. Tokuyama, and T. Fukuyama, Angew.
Chem., Int. Ed., 39, 4073 (2000).
R
R’
R’’
R
5a
N
CN (3)
THF-H2O
rt
H
H
O
9a
12
Although several oxidative transformations of ꢀ-aminoni-
triles to amides have been reported, they need harsh
conditions or are lack of generality, see; a) T.-H. Chuang,
C.-C. Yang, C.-J. Chang, and J.-M. Fang, Synlett, 1990, 733.
b) C.-C. Yang, H.-M. Tai, and P.-J. Sun, Synlett, 1997, 812.
S. Harusawa, Y. Hamada, and T. Shioiri, Tetrahedron Lett.,
1979, 4663.
It was necessary to quench excess mCPBA with dimethyl
sulfide because undesired oxidation of an intermediate in the
later step lowered the yields.
mCPBA;
DBU
CN
CN
R
R’
R
R’
5a
5e
(4)
N
N
THF-H2O
rt
R’’
10a
R’’
13
6
7
mCPBA;
DBU
CN
R’
N R’’
O
CN
mCPBA
R’
R
N
R
HO
MeOH-H2O
rt
O
R’’
H
14
11e
8
9
For a review of Polonovski reaction, see: D. Grierson, Org.
React., 39, 85 (1990), and references therein.
The elimination occurred with complete regioselectivity
because of higher acidity of the ꢀ-proton of the nitrile group.
HO
N
R’
(5)
+
RCO2Me
R’’
16
15