Ru(II)-Pheox catalyzed N-H insertion reaction of diazoacetamides: Synthesis of N-substituted α-aminoamides

Article abstract of DOI:10.1016/j.tetlet.2012.06.134

An efficient protocol for the preparation of α-aminoamides was developed via the Ru(II)-dm-Pheox catalyzed N-H insertion reaction of various diazoacetamides with several amines, including aniline. This catalytic N-H insertion reaction was also applied to the synthesis of 2-(2-methylquinolin-4- ylamino)-N-phenylacetamide, a potential antileishmanial agent.

Full text of DOI:10.1016/j.tetlet.2012.06.134

Tetrahedron Letters 53 (2012) 4862–4865
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Ru(II)-Pheox catalyzed N–H insertion reaction of diazoacetamides: synthesis of
N-substituted
a-aminoamides
⇑
Soda Chanthamath, Songkharm Thongjareun, Kazutaka Shibatomi, Seiji Iwasa
Department of Environmental and Life Sciences, Toyohashi University of Technology, 1-1, Tempaku-cho, Toyohashi, Aichi 441-8580, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient protocol for the preparation of a-aminoamides was developed via the Ru(II)-dm-Pheox cat-
Received 30 April 2012
Revised 21 June 2012
Accepted 28 June 2012
Available online 5 July 2012
alyzed N–H insertion reaction of various diazoacetamides with several amines, including aniline. This
catalytic N–H insertion reaction was also applied to the synthesis of 2-(2-methylquinolin-4-ylamino)-
N-phenylacetamide, a potential antileishmanial agent.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Ruthenium catalyst
N–H insertion reaction
Diazoacetamide
a-Aminoamide
a
-Aminoamide structural moieties are found in a wide range of
Table 1
naturally occurring organic compounds and pharmaceuticals.1
a-
Optimization of catalytic N–H insertion reaction of diazoacetamide 2a with N-
methylaniline 1aa
Aminoamides have been widely employed as intermediates,2 organ-
ocatalysts,3 and catalyst ligands4 in organic synthesis. Hence,
O
O
catalyst
NH
N2
N
numerous methods for the construction of
a
-aminoamides have
-aminoamides
a-aminonitriles synthesized via
+
N
N
been developed in the past decade.5 Traditionally,
a
solvent, RT
are prepared by hydrolysis of the
1a
2a
3a
−
the Strecker reaction,6 but the drawbacks of this approach include
toxicity issues such as HCN which must be generated in situ from
cyanide salts and the requirement of harsh reaction conditions.
PF6
(NCCH3)4
+
Ru
N
Nucleophilic substitutions of amino acid derivatives and/or
genated amides with amines are often employed for the synthesis of
-aminoamides, but the synthesis of N-aryl-substituted -aminoa-
mides has not been attempted frequently because the arylamines
a-halo-
O
Ru(II)-dm-Pheox
a
a
Entry
Catalyst
Solvent
Time
Yieldb (%)
1
2
3
4
5
6
7
8
Ru(II)-dm-Pheox
Ru(II)-dm-Pheox
Ru(II)-dm-Pheox
Ru(II)-dm-Pheox
Ru(II)-dm-Pheox
Ru(II)-dm-Pheox
Ru(II)-dm-Pheox
Ru(II)-dm-Pheox
Ru(II)-dm-Pheox
Rh2(OAc)4
Toluene
H2O
CH3OH
CH3OH
THF
10 min
30 min
20 h
73
77
70
78
89
80
89
97
89
61
42
R1
N
O
Previous reports
X= O, CH2
R1
N
O
O
24 h
R3
R3
R3
or
5 min
10 min
5 min
5 min
5 min
5 min
48 h
R2
C
R2
R2
O
O
H2
Et2O
[M] catalyst
NHR1R2
N2
R3
Acetone
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
X
R1
N
9c
10d
11d
α
-Aminoamides as useful
bioactive compounds
N
R4
This work
X= NR4
Cul
a
Performed at RT using 0.5 mol % of catalyst in Ar atmosphere with 2 equiv N-
Scheme 1. Transition-metal-catalyzed N–H insertion of
pounds into amine derivatives.
a-diazocarbonyl com-
methylaniline 1a and N-benzyl-N-methyldiazoacetamide 2a.
b
Isolated yield.
Carried out with 1 equiv of N-methylaniline 1a.
Carried out with 5 mol % of catalyst.
c
d
⇑
Corresponding author. Tel.: +81 532 44 6817; fax: +81 523 44 6817.
E-mail address: iwasa@ens.tut.co.jp (S. Iwasa).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.06.134

S. Chanthamath et al. / Tetrahedron Letters 53 (2012) 4862–4865
4863
precursors have low nucleophilicity.7 Therefore, the development of
Table 2
Ru(II)-dm-Pheox catalyzed N–H insertion reaction of N-methylaniline 1a with various
novel efficient synthetic routes to N-substituted
highly desirable.
a-aminoamides is
diazoacetamides 2a–ea
O
Ru(II)-dm-Pheox
(0.5 mol%)
O
Among the various methods for C–N bond formation, insertion
of an -diazocarbonyl compound into an N–H bond is one of the
straightforward routes to
-amino acid derivatives.8 While there
are numerous reports on the successful synthesis of -aminoke-
tones and -aminoesters from diazoketones and diazoesters,
respectively, there is no report on the use of diazoacetamide for
the synthesis of -aminoamides by N–H insertion (Scheme 1), ex-
R1
R1
N
NH
N2
+
a
N
R2
N
R2
CH2Cl2, RT, 5 min
a
a
(2 equiv)
1a
2a-e
3a-e
a
Entry
Diazoacetamide (R1, R2)
Product
Yieldb (%)
a
1
2
2a (Bn, Me)
2b (Bn, H)
2c (Bn, Bn)
2d (Ph, H)
2e (Et, Et)
3a
3b
3c
3d
3e
97
82
84
93
89
cept for that by Muthusamy and co-workers on the Rh2-based N–H
insertion of 3-diazopiperidin-2-ones.9 Herein, we report an effi-
3
4c
5
cient protocol for the preparation of N-substituted a-aminoamides
through the Ru(II)-catalyzed N–H insertion of diazoacetamides
into amine derivatives.
a
Performed at RT using 0.5 mol % Ru(II)-dm-Pheox in Ar atmosphere with
2 equiv N-methylaniline 1a and diazoacetamides 2a–e.
The present study on the N–H insertion reaction of diazoaceta-
b
Isolated yield.
mides, which would be a powerful tool for constructing
a-aminoa-
C
Because diazoacetamide 2d couldn’t dissolve in CH2Cl2, thus we used acetone as
mides, was inspired by our previous study on the efficient use of
the solvent.
Table 3
Ru(II)-dm-Pheox catalyzed N–H insertion of diazoacetamide 2a into various amines 1a and 4a–h
R1
N
Ru(II)-dm-Pheox
O
O
R1
(0.5 mol%)
N2
+
R2
N
N
NH
R2
CH2Cl2, RT, 5 min
1a, 4a-h
2a
3a, 5a-i
(2 equiv)
Entry
1
Amine
Product
Yielda (%)
97
O
NH
N
1a
3a
N
O
NH
N
4a
5a
2
3
98
94
N
O
N
NH
N
4b
5b
MeO
Cl
MeO
Cl
O
NH
N
4c
5c
N
4
90
O
NH
N
4d
N
5d
5
6
7
48
95
96
O2N
Ph
O2N
Ph
Ph
Ph
N
O
O
4e
N
H
5e
N
N
Ph
Ph
Ph
N
H
Ph
4f
N
N
5f
N
O
4g
H
5g
8
92
78
85
N
NH2
NH2
O
O
H
N
4h
4h
9b
5h
5i
N
H
N
10c
N
H
a
b
c
Isolated yield.
Reaction was carried out using 3 mol % Ru(II)-dm-Pheox for 1 h because a long reaction time was required when using 0.5 mol % of the catalyst.
Performed in acetone for 30 min using diazoacetamide 2d.

4864
S. Chanthamath et al. / Tetrahedron Letters 53 (2012) 4862–4865
Ru(II)-Pheox catalyst in the carbene transfer reactions of diazoace-
tates to furnish cyclopropanes.10
easy access to a-aminoamide derivatives, which are important
building blocks for the synthesis of natural products and pharma-
ceuticals. In addition, we successfully used this catalytic N–H
insertion reaction and obtained 2-(2-methylquinolin-4-ylamino)-
N-phenylacetamide, a potential antileishmanial agent, in high yield
(96%) within 5 min under mild reaction conditions.
Initially, we evaluated the catalytic activity of Ru(II)-dm-Pheox
catalyst11 in various solvents for the intermolecular N–H insertion
reaction of N-methylaniline 1a with N-benzyl-N-methyldiazoace-
tamide 2a, as shown in Table 1. Dichloromethane was the best
solvent (Table 1, entry 8) since the reaction in this case gave 3a
in 97% yield, in the presence of 0.5 mol % Ru(II)-dm-Pheox catalyst.
Acknowledgment
Interestingly, the catalyst could afford
a-aminoamide 3a in high
yield (77%) even in water at room temperature (Table 1, entry 2).
The yield was slightly decreased when the reaction was performed
with 1 equiv of N-methylaniline 1a to diazoamide 2a (entry 9).
Rh2(OAc)4 and CuI also catalyzed the N–H insertion of diazoaceta-
mide 2a with N-methylaniline 1a to give moderate yields (entries
10 and 11).
This study was supported by a Grant-in-Aid for Scientific Re-
search (C) (No. 23550179) from Japan Society for the Promotion
of Science.
Supplementary data
Under the optimized conditions, N–H insertion reactions with
various N-substituted diazoacetamides were examined (Table 2).
All the N-substituted diazoacetamides participated in the reaction
Supplementary data (experimental procedures, detailed prod-
uct characterization data, compound spectra) associated with this
article can be found, in the online version, at http://dx.doi.org/
10.1016/j.tetlet.2012.06.134.
to afford the corresponding
a-aminoamides in high yields (82–
97%) in 5 min. Further, the reactivity of the N–H insertion was lar-
gely unaffected even when diazoacetamide 2c having two bulky
benzyl substituents was used.
References and notes
N–H insertion reactions of various amines, including secondary,
aliphatic, and aromatic amines, with 2a in the presence of Ru(II)-
dm-Pheox (0.5 mol %) at room temperature were also examined,
as shown in Table 3. Electron-donating and electron-withdrawing
arylamine derivatives could easily undergo insertion reactions
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with 2a to give the corresponding
a-aminoamides in high yields
(90–98%; entries 1–4 and 6). The only exception was the reaction
with p-nitroaniline 4d, in which case the product yield was low
(48%) and dimers were formed (entry 5), probably because the
electron density of p-nitroaniline is lower than that of the other
arylamines shown in Table 3. Simple secondary amines such as
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dibenzyl and dipropyl amines also afforded the corresponding
a-
aminoamides in high yields (entries 7 and 8). Interestingly, aniline,
which has lower nucleophilicity than do other primary and sec-
ondary amines, could be successfully used in the insertion reaction
with diazoacetamides 2a and 2d to afford the corresponding
aminoamides in high yields (entries 9 and 10).
Encouraged by the efficiency of the Ru(II)-dm-Pheox catalyzed
N–H insertion reaction of diazoacetamides with amines, we sought
to examine the utility of this method for the synthesis of 2-(2-meth-
ylquinolin-4-ylamino)-N-phenylacetamide 7, which was reported
to be a potential antileishmanial agent by Sahu et al. in 200212
(Scheme 2). We used 4-aminoquinaldine 6 as the amine substrate
and carried out the N–H insertion with N-phenyldiazoacetamide
2d in the presence of Ru(II)-dm-Pheox catalyst under the optimized
a-
conditions. The desired a-aminoamide 7 was obtained in high yield
(96%) within a very short time (5 min).
In conclusion, we have established an efficient protocol for the
preparation of N-substituted
a-aminoamides through the Ru(II)-
dm-Pheox catalyzed N–H insertion reaction of various diazoaceta-
6. Strecker, A. Justus Liebigs Ann. Chem. 1850, 75, 27.
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O
NH2
Ru(II)-dm-Pheox
H
N
O
(0.5 mol%)
N
H
N2
+
N
H
acetone
RT,5 min
N
N
7
6 (2 equiv)
2d
96% yield
Antileishmanial agent
Scheme 2. Synthesis of 2-(2-methylquinolin-4-ylamino)-N- phenylacetamide 7 via
Ru(II)-dm-Pheox catalyzed N–H insertion of diazoacetamide 2d into 4-aminoquin-
aldine 6.

S. Chanthamath et al. / Tetrahedron Letters 53 (2012) 4862–4865
4865
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