Direct synthesis of α-amino amides from N-alkyl amines by the copper-catalyzed oxidative Ugi-type reaction

Article abstract of DOI:10.1055/s-0031-1290319

α-Amino amides can be accessed directly form N-alkyl amines by the isocyanide-compatible oxidative copper-peroxide conditions even in the presence of water. Various functional groups are tolerated in the reaction, leading to the synthesis of various -amin

Full text of DOI:10.1055/s-0031-1290319

LETTER
409
Direct Synthesis of a-Amino Amides from N-Alkyl Amines by the
Copper-Catalyzed Oxidative Ugi-Type Reaction
S
a
ynthesis of
a
-Am
i
ino Am
n
ides
f
rom
N
-Alkyl
Y
A
mines e,a,b Chunsong Xie,*a Rui Huang,b Jinhua Liu*b
Research Center of Biomedicine and Health, Hangzhou Normal University, Hangzhou 310012, P. R. of China
Fax +86(571)28865630; E-mail: chunsongxie@hznu.edu.cn
b
College of Materials, Chemistry and Chemical Engineering, Hangzhou Normal University, Hangzhou 310012, P. R. of China
E-mail: ljh@hznu.edu.cn
Received 20 October 2011
ated amidation of tetrahydroisoquinolines developed by
Zhu et al.,8a and the singlet-oxygen-mediated three-com-
ponent reaction of N-alkyl amines, isocyanides, and car-
boxylic acids reported by Chi and his coworkers.8b
Abstract: a-Amino amides can be accessed directly form N-alkyl
amines by the isocyanide-compatible oxidative copper–peroxide
conditions even in the presence of water. Various functional groups
are tolerated in the reaction, leading to the synthesis of various a-
amino amides in moderate yield. A plausible mechanism is pro-
posed in which an oxidative Ugi-type three-component pathway is
supposed to be involved.
On the other hand, copper catalysis had proven to be com-
patible with isocyanides, and a variety of transformations,
such as insertion into alcohol, had been developed under
aerobic conditions.10 During our work on the transition-
metal-catalyzed saturated C–H bond activation, we devel-
oped mild oxidative conditions that had proven to be com-
patible with isocyanides.11 By using this newly developed
copper–peroxide system, we had developed a novel meth-
od for the synthesis of a-amino imides from tertiary
amines, isocyanides, and carboxylic acids. However,
since the amide moiety in the products were blocked by
acyl groups, modification of the imides required further
transformations. Thus, we wondered whether it was pos-
sible to directly synthesize a-amino amides from N-alkyl
amines by expanding upon the above-mentioned reac-
tions.
Key words: a-amino amide, isocyanide, Ugi reaction, copper catal-
ysis, multicomponent reaction
a-Amino amides are structurally ubiquitous units in many
biologically active compositions.1 They have also been
widely used as precursors for the synthesis of a variety of
medicinal heterocycles.2 Thereafter, the synthesis of a-
amino amides has attracted wide attention, and many
promising methods have been reported.3 Among these
methods, Ugi reaction represented one of the most effi-
cient and widely used method, and many variants had
been developed.4 From the viewpoint of mechanism,
these reactions were typically initiated by the dehydration
formation of imines from primary amines and carbonyl
components, and hence providing easy accesses to a-ami-
no amides from primary amines. However, in some cases
the primary amine precursors are not readily available,
and/or the dehydration formation of imines is not so effi-
cient,5,6 normally these strategies will be incompetent. So
the development of novel synthetic methods for the syn-
thesis of a-amino amides from readily available materials
is still of much significance.
We commenced our investigation by performing the reac-
tion between N,N-dimethylaniline 1a and isocyanide 2a in
the presence of 10 mol% CuBr and 240 mol% TBHP (70
wt% aq) at 60 °C for six hours, and pleasingly found that
the a-amino amide 3aa was indeed produced, albeit in a
low yield (Table 1, entry 1). The addition of some mono-
dentate ligands such as Ph3P, pyridine, and N-methyl im-
idazole had proven to be slightly advantageous with
slightly higher yields from 10–21% being delivered
(Table 1, entries 2–4). It was found that elevating the re-
action temperature to be 80 °C was beneficial for the reac-
tion, and a moderate yield (45%) could be obtained when
using Ph3P as the ligand (Table 1, entries 5 and 6). Biden-
tated ligands like N1,N2-dimethylethane-1,2-diamine and
dppe [1,2-bis(diphenylphosphino)ethane] had proven to
be less active ligands and gave lower yields (30% and
19%) than Ph3P (Table 1, entries 7 and 8). A similar result
had also been obtained when an electron-rich monoden-
tate phosphorus ligand like PCy3 was used in the reaction
(Table 1, entry 9). The screening of copper catalysts had
revealed that CuCl was the most effective catalyst, giving
a higher yield (57%) than other copper complexes such as
CuI, CuCl2, CuBr2, and Cu(OAc)2·H2O (Table 1, entries
10–14). Further increasing the reaction temperature
seemed to have little effect on the reaction, and a compa-
rable yield (58%) was provided when the reaction was
It is known that besides the dehydration of primary
amines and carbonyls, the imines (or iminiums) can also
be produced by the oxidation of N-alkyl amines.7 As a re-
sult in recent years, the oxidative Ugi-type reactions based
on the dehydrogenative formation of imine or iminium in-
termediates from N-alkyl amines had attracted wide atten-
tion.8 However, mainly because that the isocyanides,
which are the key components in Ugi-type reactions, have
proven to be sensitive to oxidants,9 the searching for mild
conditions that are compatible with isocyanides has just
achieved limited success. To the best of our knowledge,
the typical two successful examples were the IBX-medi-
SYNLETT 2012, 23, 409–412
x
x.
x
x.
2
0
1
2
Advanced online publication: 25.01.2012
DOI: 10.1055/s-0031-1290319; Art ID: W57711ST
© Georg Thieme Verlag Stuttgart · New York

410
X. Ye et al.
LETTER
performed in a sealed tube at 100 °C (Table 1, entry 15). ing various substituted a-amino amides in moderate
Shortening the reaction time had proven to be detrimental, yields. For example, N,N-dimethylanilines bearing elec-
and just a 52% yield was given when the reaction time was tron-donating groups such as methyl and ethyl at the 4-po-
shortened to three hours (Table 1, entry 16). However, sition were subjected to reaction with isocyanide 2a,
further elongation of the reaction time seemed to be of no giving a-anilino amides 3ba and 3ca in 53% and 30%
use either, and a 58% yield was delivered when conducted yields (Table 2, entries 2 and 3). Meanwhile, N,N-dimeth-
the reaction for 12 hours (Table 1, entry 17). It should be ylaniline bearing an electron-withdrawing substituent
noted that the reaction could also proceed smoothly when such as Br (1d) could also undergo reaction, resulting in
using TBHP in decane as the oxidant, indicating that wa- the a-anilino amide 3da in 55% yield (Table 2, entry 4). It
ter as solvent was not a necessity for the reaction (Table 1, was noteworthy that the halogen atom (Br), which had
entry 18).
proven to be quite reactive in the copper catalysis,12 could
be tolerated in the reaction, and thus made the further
transformation of the thus-synthesized a-amino amide
feasible.
With the optimal conditions in hand, we next investigated
the scope of the reaction, and the results are summarized
in Table 2. Various N,N-dimethylanilines were proven to
be reliable reaction partners with isocyanide 2a, produc- Moreover, N,N-dimethylanilines having substituents on
the 3-position of phenyl had also been used in the reaction
Table 1 Optimization of Reactions Conditionsa
and delivered 43% and 60% yield, respectively, when the
substituent was methyl and chloro (Table 2, entries 5 and
6). Once again the halogen atom survived in the reaction,
enabling the further derivation of the product on this site.
Besides, the ortho-substituted N,N-dimethylanilines, such
Me
N
Me
Me
[Cu], L
N
+
TsCH2NC
TBHP in H2O
MeCN, 6 h
2a
O
NHCH2Ts
1a
3aa
Table 2 Reaction Scopea
Entry Copper
Ligand
Temp Yield
R2
(°C)
60
60
60
60
80
80
80
80
80
80
80
80
80
80
100
80
80
80
(%)b
R2
N
CuCl, Ph3P
+ R3NC
R1
N
1
2
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuCl
CuI
–
9
R1
TBHP in H2O
MeCN, 80 °C, 6 h
Me
2
O
NHR3
1
Ph3P
11
21
10
25
45
30
19
20
57
48
44
56
35
58
52
58
50
3
3
pyridine
Entry 1
R1
H
R2
2
R3
Product Yield
(%)b
4
N-methylimidazole
5
pyridine
1
2
1a
Me
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2b
2c
2d
TsCH2
TsCH2
TsCH2
TsCH2
TsCH2
TsCH2
TsCH2
TsCH2
TsCH2
TsCH2
TsCH2
TsCH2
Bn
3aa
3ba
3ca
3da
3ea
3fa
3ga
3ha
3ia
57
53
30
55
43
60
40
50
27
61
42
26
46
54
35
6
Ph3P
1b
1c
1d
1e
1f
4-Me Me
7
MeHNCH2CH2NHMe
3
4-Et
4-Br
Me
Me
8
dppe
Cy3P
Ph3P
Ph3P
Ph3P
Ph3P
Ph3P
Ph3P
Ph3P
Ph3P
Ph3P
4
9
5
3-Me Me
3-Cl Me
2-Me Me
10
11
12
13
14
15c
16d
17e
18f
6
7
1g
1h
1i
CuCl2
CuBr2
8
2-Cl
2-Ph
2-I
H
Me
Me
Me
Ph
9
Cu(OAc)2·H2O
CuCl
10
11c
12
13d
14d
15d
1j
3ja
3ka
3la
1k
1l
CuCl
H
Bn
CuCl
1a
1d
1a
H
Me
Me
Me
3ab
3dc
CuCl
4-Br
H
t-Bu
a Reaction conditions: 1a (2.0 mmol), 2a (1.0 mmol), copper (0.1
mmol), ligand (0.1 mmol), peroxide (2.4 mmol).
b Isolated yields.
2,6-Me2C6H3 3ad
a Reaction conditions: 1 (2.0 mmol), 2 (1.0 mmol), CuCl (0.1 mmol),
Ph3P (0.1 mmol), TBHP (2.4 mmol).
b Isolated yields.
c The reaction was performed in a sealed tube.
d The reaction time was 3 h.
c The reaction time was 48 h.
e The reaction time was 12 h.
d The ligand was 2,2¢-bipyridyl.
f The oxidant was TBHP (5–6 M) in decane.
Synlett 2012, 23, 409–412
© Thieme Stuttgart · New York

LETTER
Synthesis of a-Amino Amides from N-Alkyl Amines
411
R2
R2
CuCl2
Ln
LnCu
N
N
OH
N
R1
R1
1
+
R2
t-BuOOH
III
R2
t-BuOH
+
H2O
N
R1
H2O
O
R2
N+
R2
NHR3
–CuLn
–CuLn
3
N
R1
R1
N
R3
I
II
R3
C
N
2
Scheme 1 Proposed mechanism
as N,N,2-trimethylaniline (1g), 2-chloro-N,N-dimethyla- a-amino amide products 3. In the whole of this procedure,
niline (1h), 2-phenyl-N,N-dimethylaniline (1i), and 2- the solvent water seems to have no effect on the reaction,
iodo-N,N-dimethylaniline (1j) could also proceed this re- and this is quite consistent with the fact that the reaction
action smoothly, producing various a-arylamino amides can also be conducted under the promotion of the TBHP
bearing ortho substituents in 27–61% yield (Table 2, en- in decane solution.
tries 7–10). It should be pointed out that the halogens,
even the reactive iodine, could be well tolerated in the
reaction. This is especially significant because the thus-
synthesized ortho-halogenated a-arylamino amides have
In summary, we have developed a novel and straightfor-
ward synthesis of a-amino amides from readily accessible
N-alkylamine materials.14 The reaction can be performed
under mild and neutral conditions, affording aimed a-ami-
proven to be good precursors for the synthesis of many
no amides in moderate yields. Various functionalities, es-
medicinally important heterocycles.2c
pecially the transformable halogens, have proven to be
Furthermore, N,N-diarylalkylamine, such as N-methyl-N- compatible with this reaction, therefore making this trans-
phenylaniline (1k), was found to be able to undergo the formation attractive for the synthesis of various potential
reaction, producing the a-diarylamino amide product in medicinal heterocycles. Further investigations on the ap-
42% yield (Table 2, entry 11). Unsymmetrical N,N-di- plication of this strategy are currently ongoing in our lab-
alkylaniline such as N-methyl-N-benzylaniline (1l) was oratory.
also subjected in the reaction, affording the amidation
product 3la at the less steric side as major product in 26%
yield (Table 2, entry 12).
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
On the other hand, the direct introduction of other isocy-
anides such as benzyl isocyanide (2b), tert-butyl isocy-
Acknowledgment
anide (2c), and aryl isocyanide (2d), had proven to be
sluggish. However, after changing the ligand from mono-
phosphorus ligand Ph3P to the bidentate nitrogen ligand
The authors gratefully thank the grant support from the Zhejiang
Provincial Natural Science Foundation of China (Y4090408) and
2,2¢-bipyridyl, the reaction turned to be better, affording the Hangzhou City Research Project (20090331N04).
various a-amino amides with different substitutions on
the amide nitrogen in moderate yields (Table 2, entries
13–15).
References and Notes
(1) (a) Dolle, R. E. Mol. Diversity 1998, 3, 199. (b) Weber, L.
On the basis of the above-mentioned results and some pre-
Curr. Med. Chem. 2002, 9, 2085. (c) Hulme, C.; Gore, V.
Curr. Med. Chem. 2003, 10, 51. (d) Sexton, K. E.; Lee, H.
vious reports,7a,13 a plausible mechanism for this Ugi-type
reaction has been proposed as depicted in Scheme 1. As
an initial of the cascade events, the N-alkyl amines 1 were
transformed into electrophilic iminiums I under the pro-
motion of copper and peroxide. In the course of this trans-
formation, nucleophilic water might be generated. Then
the tandem nucleophilic attack of isocyanides 2 and water
produced the iminal intermediates III. At the end, the im-
inal III would isomerize into amide, producing the final
T.; Massa, M.; Padia, J.; Patt, W. C.; Liao, P.; Pontrello, J.
K.; Roth, B. D.; Spahr, M. A.; Ramharack, R. Bioorg. Med.
Chem. 2003, 11, 4827. (e) Beguin, C.; LeTiran, A.; Stables,
J. P.; Voyksnerc, R. D.; Kohn, H. Bioorg. Med. Chem. 2004,
12, 3079.
(2) (a) Iden, H. S.; Lubell, W. D. J. Comb. Chem. 2008, 10, 691.
(b) Cuny, G.; Bois-Choussy, M.; Zhu, J. P. J. Am. Chem.
Soc. 2004, 126, 14475. (c) Erb, W.; Neuville, L.; Zhu, J. P.
J. Org. Chem. 2009, 74, 3109.
© Thieme Stuttgart · New York
Synlett 2012, 23, 409–412

412
X. Ye et al.
LETTER
(3) (a) Porter, J. R.; Wirschun, W. G.; Kuntz, K. W.; Snapper,
M. L.; Hoveyda, A. H. J. Am. Chem. Soc. 2000, 122, 2657.
(b) Takamura, M.; Hamashima, Y.; Usuda, H.; Kanai, M.;
Shibasaki, M. Angew. Chem. Int. Ed. 2000, 39, 1650.
(c) Lin, Y. S.; Alper, H. Angew. Chem. Int. Ed. 2001, 40,
779. (d) Wang, M. X.; Lin, S. J. J. Org. Chem. 2002, 67,
6542. (e) Alcaide, B.; Almendros, P.; Aragoncillo, C. Chem.
Eur. J. 2002, 8, 3646. (f) Ntaganda, R.; Milovic, T.;
Tiburcioz, J.; Thadani, A. N. Chem. Commun. 2008, 4052.
(g) Loser, R.; Frizler, M.; Schilling, K.; Gutschow, M.
Angew. Chem. Int. Ed. 2008, 47, 4331. (h)Noorduin, W. L.;
Izumi, T.; Millemaggi, A.; Leeman, M.; Meekers, H.;
Van Enckevort, W. J. P.; Kellogg, R. M.; Kaptein, B.; Vlieg,
E.; Blackmond, D. G. J. Am. Chem. Soc. 2008, 130, 1158.
(i) Hirner, S.; Somfai, P. J. Org. Chem. 2009, 74, 7798.
(4) (a) Domling, A.; Ugi, I. Angew. Chem. Int. Ed. 2000, 39,
3168. (b) Dömling, A. Chem. Rev. 2006, 106, 17.
(c) El Kaim, L.; Grimaud, L. Tetrahedron 2009, 65, 2153.
(d) Lygin, A. V.; Meijere, A. Angew. Chem. Int. Ed. 2010,
49, 9094.
(5) (a) Henriques, A.; Kan, C.; Chiaroni, A.; Riche, C.; Husson,
H. P. J. Org. Chem. 1982, 47, 803. (b) Han-ya, Y.;
Tokuyama, H.; Fukuyama, T. Angew. Chem. Int. Ed. 2011,
50, 4884.
(6) Tanaka, Y.; Hasui, T.; Suginome, M. Org. Lett. 2007, 9,
4407.
(7) (a) Li, C. J. Acc. Chem. Res. 2009, 42, 335. (b) Murahashi,
S.-I.; Komiya, N.; Terai, H. Angew. Chem. Int. Ed. 2005, 44,
6931. (c) Rajendra, P. D.; Subbarayappa, A. Adv. Synth.
Catal. 2011, 353, 1695. (d) Nicolaou, K. C.; Mathison, C. J.
N.; Montagnon, T. Angew. Chem. Int. Ed. 2003, 42, 4077.
(e) Nicolaou, K. C.; Mathison, C. J. N.; Montagnon, T.
J. Am. Chem. Soc. 2004, 126, 5192.
(8) (a) Ngouansavanh, T.; Zhu, J. P. Angew. Chem. Int. Ed.
2007, 46, 5775. (b) Jiang, G. X.; Chen, J.; Huang, J. S.; Che,
C. M. Org. Lett. 2009, 11, 4568.
(9) (a) Brioche, J.; Masson, G.; Zhu, J. P. Org. Lett. 2010, 12,
1432. (b) Feuer, H.; Rubinstein, H.; Nielsen, A. T. J. Org.
Chem. 1958, 23, 1107. (c) Saegusa, T.; Kobayashi, S.; Ito,
Y. Bull. Chem. Soc. Jpn. 1970, 43, 275.
(10) (a) Saegusa, T.; Ito, Y.; Kobayashi, S.; Hirota, K.; Takeda,
N. Can. J. Chem. 1969, 47, 1217. (b) Saegusa, T.; Ito, Y.;
Kobayashi, S.; Takeda, N.; Hirota, K. Tetrahedron Lett.
1967, 8, 521. (c) Saegusa, T.; Ito, Y.; Kobayashi, S.;
Takeda, N.; Hirota, K. Tetrahedron Lett. 1967, 8, 1273.
(11) Ye, X.; Xie, C. S.; Pan, Y. Y.; Han, L. H.; Xie, T. Org. Lett.
2010, 12, 4240.
(12) (a) Ley, S. V.; Thomas, A. W. Angew. Chem. Int. Ed. 2003,
42, 5400. (b) Evano, G.; Blanchard, N.; Toumi, M. Chem.
Rev. 2008, 108, 3054.
(13) (a) Boess, E.; Sureshkumar, D.; Sud, A.; Wirtz, C.; Fares, C.;
Klussmann, M. J. Am. Chem. Soc. 2011, 133, 8106. (b) Li,
Z.; Bohle, S.; Li, C.-J. Proc. Natl. Acad. Sci. U.S.A. 2006,
103, 8928. (c) Ghobrial, M.; Schnurch, M.; Mihovilovic,
M. D. J. Org. Chem. 2011, 76, 8781.
(14) Representative Procedure for the Three-Component
Reaction
Into an oven-dried flask, N,N-dimethylaniline (1a, 242 mg,
2.0 mmol), 1-(isocyanomethylsulfonyl)-4-methylbenzene
(2a, 195 mg, 1.0 mmol), CuCl (10 mg, 0.1 mmol), Ph3P (26
mg, 0.1 mmol), and TBHP (70% aq, 2.4 mmol) were added
at r.t.. Under the protection of N2, MeCN (5 mL) was added,
and the reaction mixture was allowed to react at 80 °C for 6
h. After the end of the reaction, the mixture was filtered
through a pad of Celite, and the filtrate was concentrated
until the solvent was completely removed. The residue was
then separated on a silica gel column, and the final product
was obtained as a yellow powder (190 mg, 57%). 1H NMR
(400 MHz, CDCl3, TMS): d = 7.72 (d, J = 8.8 Hz, 2 H),
7.29–7.35 (m, 3 H), 7.27 (m, 1 H), 6.89 (t, J = 7.4 Hz, 1 H),
6.68 (d, J = 7.6 Hz, 2 H), 4.69 (d, J = 7.2 Hz, 2 H), 3.75 (s,
2 H), 2.99 (s, 3 H), 2.46 (s, 3 H). 13C NMR (100 MHz,
CDCl3): d = 170.4, 149.0, 145.6, 133.7, 130.0, 129.5, 128.9,
119.3, 113.4, 59.8, 58.6, 40.1, 21.8. HRMS (EI): m/z calcd
for C17H20N2O3S [M]+: 332.1195; found: 332.1186.
Synlett 2012, 23, 409–412
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