Copper-catalyzed synthesis of α-amino imides from tertiary amines: Ugi-type three-component assemblies involving direct functionalization of sp3 C-Hs adjacent to nitrogen atoms

Article abstract of DOI:10.1021/ol101576q

Figure Presented. α-Amino imides can be accessed straightforwardly from tertiary amines through copper-catalyzed three-component reactions involving the direct functionalization of sp³ C-Hs adjacent to nitrogen atoms. This reaction has demonstrated a tolerance to a wide range of functionalizations and can be performed under very mild conditions. A plausible mechanism has been proposed in which an Ugi-type cascade assembly has been included.

Full text of DOI:10.1021/ol101576q

ORGANIC
LETTERS
2010
Vol. 12, No. 19
4240-4243
Copper-Catalyzed Synthesis of r-Amino
Imides from Tertiary Amines: Ugi-Type
Three-Component Assemblies Involving
Direct Functionalization of sp3 C-Hs
Adjacent to Nitrogen Atoms
Xin Ye,†,‡ Chunsong Xie,*,† Yuanyuan Pan,†,‡ Laihong Han,†,‡ and Tian Xie*,†
Research Center of Biomedicine and Health, and College of Materials, Chemistry and
Chemical Engineering, Hangzhou Normal UniVersity, Hangzhou 310012, P. R. China
chunsongxie@hznu.edu.cn; tianxie@hznu.edu.cn
Received July 8, 2010
ABSTRACT
r-Amino imides can be accessed straightforwardly from tertiary amines through copper-catalyzed three-component reactions involving the
direct functionalization of sp3 C-Hs adjacent to nitrogen atoms. This reaction has demonstrated a tolerance to a wide range of functionalizations
and can be performed under very mild conditions. A plausible mechanism has been proposed in which an Ugi-type cascade assembly has
been included.
R-Amino amides have been constantly found in many natural
products and pharmaceuticals.1 They have also been inten-
sively used as intermediates for the synthesis of many
heterocycles.2 Moreover, the utilization of them as organo-
catalysts and catalyst ligands has attracted much attention.3,4
Traditionally, these motifs could be prepared straightfor-
wardly by the Ugi reaction involving the imines generated
in situ from the amines and aldehydes.5,6 However, due to
the involvement of acyl migration as the key step (the Mumm
rearrangement), the classic Ugi reaction usually required
primary amines and therefore showed limited success in the
preparation of R-nonacylamino amides.7 To address this
limitation, Suginome et al. developed the acid-free Ugi-type
three-component reaction which had proven to be applicable
to secondary amines.8 Nevertheless, these reactions mecha-
nistically had to be performed under the promotion of
aminoborane, which needed to be presynthesized and used
in a stoichiometric amount. Hence, the development of novel
access to R-amino amides, especially the R-nonacylamino
amides, from readily available materials is still of much
significance.
† Research Center of Biomedicine and Health.
‡ College of Materials, Chemistry and Chemical Engineering.
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10.1021/ol101576q  2010 American Chemical Society
Published on Web 09/09/2010

In recent years, oxidative isocyanide-based multicompo-
nent reactions have become a challenge since isocyanides
are known to be sensitive toward a variety of oxidants.9
Synthesis of R-amino amides by IBX (2-iodoxybenzoic acid)
mediated oxidative Ugi-type three-component reaction has
already been achieved by Zhu and his co-workers.10 On the
other hand, transition-metal-catalyzed direct functionalization
of unactivated sp3 C-Hs has attracted wide attention mainly
for its atom-economical significance.11,12 Among the various
methods that have been developed,13-18 copper-catalyzed
strategies for the activation of sp3 C-Hs R to nitrogens under
the promotion of peroxides have been well documented.19
A variety of nucleophiles such as terminal alkynes,20
nitromethanes and malonates,21 indoles,22 naphthols,23
amides,24 phosphonates,25 as well as silyl enol ethers26 have
been successfully used for the direct functionalization of
saturated C-Hs in amines. Considering that the iminiums
can be readily accessed from the activation of the sp3 C-Hs
R to nitrogens in amines by coppers as described by Li and
his co-workers,19 we assumed that the R-amino amide
frameworks were able to be synthesized conveniently by the
three-component assemblies of saturated amines with iso-
cyanides and carboxylic acids under the promotion of copper
and peroxides.
As an initial study of our investigations, we performed
the reaction of N,N-dimethylbenzenamine 1a with 1-(iso-
cyanomethylsulfonyl)-4-methylbenzene 2a and benzoic acid
3a under the promotion of 10 mol % CuBr and 150 mol %
TBHP (tert-butyl hydroperoxide in decane) in MeCN at 40
°C for 6 h. To our delight, the reaction indeed occurred,
affording the isolable R-amino imide product 4aa and
R-amino amide 4ab in 19% and 14% yields (Scheme 1). To
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Scheme 1. Initial Experiment
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achieve a better performance, we next conducted an opti-
mization on the reaction conditions, and the results are
summarized in Table 1.
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In view of the structural difference between 4aa and 4ab,
we deduced that 4ab might be produced by the reaction of
1a and 2a with H2O which was formed in situ under the
above reaction conditions. So we next added 4 Å MS
(molecular sieves) into the reaction mixture and found that
the formation of 4ab was successfully inhibited (Table 1,
entry 1). To improve the reaction efficiency further, we next
introduced the N1,N2-dimethylethane-1,2-diamine and 2-(py-
ridin-2-yl)pyridine as bidentate ligands and discovered that
the latter was superior, with a 32% yield of 4aa being
delivered (Table 1, entries 2 and 3). Screening of the copper
catalysts had revealed that CuCl worked best (Table 1, entries
4-7). On the other hand, other peroxides such as benzoyl
peroxide, tert-butyl perbenzoate, and 2-(tert-butylperoxy)-
2-methylpropane had proven to be less effective oxidants
(Table 1, entries 8-10). When employing tert-butyl perben-
zoate and 2-(tert-butylperoxyl)-2-methylpropane as the reac-
tion promoters, only a trace amount of the desired product
4aa was provided. Optimization of the reaction temperature
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Org. Lett., Vol. 12, No. 19, 2010
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Table 1. Optimizationa
Table 2. Scope of the Three-Component Reactiona
yield
b
entry
conditions
%
1
CuBr, TBHP, 40 °C
18
CuBr, TBHP, N1,N2-dimethylethane-1,2-diamine,
2
40 °C
10
CuBr, TBHP, 2-(pyridin-2-yl)pyridine,
3
40 °C
32
CuI, TBHP, 2-(pyridin-2-yl)pyridine,
4
40 °C
67
CuBr2, TBHP, 2-(pyridin-2-yl)pyridine,
5
40 °C
43
CuCl2, TBHP, 2-(pyridin-2-yl)pyridine,
6
40 °C
50
CuCl, TBHP, 2-(pyridin-2-yl)pyridine,
7
40 °C
68
CuCl, (PhCO2)2, 2-(pyridin-2-yl)pyridine,
8
40 °C
54
CuCl, PhCO3-t-Bu, 2-(pyridin-2-yl)pyridine,
9
40 °C
trace
trace
84
CuCl, (t-BuO)2, 2-(pyridin-2-yl)pyridine,
10
11
12
40 °C
CuCl, TBHP, 2-(pyridin-2-yl)pyridine,
60 °C
CuCl, TBHP, 2-(pyridin-2-yl)pyridine,
80 °C
78
a Reaction conditions: 1a (2.0 mmol), 2a (1.0 mmol), 3a (1.5 mmol),
copper catalysts (0.1 mmol), ligands (0.1 mmol), peroxides (1.5 mmol),
MeCN (5.0 mL). b Isolated yields based on 2a.
had revealed that elevating the temperature was beneficial
for the reaction, and a higher yield (84%) could be obtained
when the reaction was performed at 60 °C (Table 1, entry
11). However, further increasing the temperature seemed to
be disadvantageous, and just a 78% yield of 4aa was afforded
while the reaction was carried out at 80 °C (Table 1, entry
12).
With the optimal conditions in hand, we next studied the
scope of the three-component reaction, and the results are
illustrated in Table 2. Various N,N-dimethylanilines bearing
both electron-donating substituents (Table 2, entries 1 and
2) and an electron-withdrawing substituent (Table 2, entry
3) at the 4-positions had proven to be reliable substrates for
the three-componnet reaction, leading to the synthesis of
R-arylamino imides in good yields. It was noteworthy that
Br could be well tolerated in the copper-catalyzed reaction
since it had been proven to be rather reactive for copper
catalysis27 and therefore making the further modification of
the as-synthesized R-arylamino imide convenient.
a Reaction conditions: amines (2.0 mmol), isocyanides (1.0 mmol), acids
(1.5 mmol), CuCl (0.1 mmol), 2,2′-bipyridyl (0.1 mmol), TBHP (1.5 mmol),
MeCN (5.0 mL), 60 °C, 6 h. b Isolated yields based on isocyanides. c The
reaction time was 24 h.
Moreover, N,N-dimethylanilines bearing both electron-
donating and electron-withdrawing groups at both 3- and
2-postions had also been used as reaction partners with
isocyanide 2a and carboxylic acid 3a, yielding various
R-arylamino imides in moderate to good yields (Table 2,
entries 4-8). Similarly, the halogen atom Cl had proven to
be compatible in the reaction and would allow further
functionalization of the products.
In addition, N-phenyl piperidine 1j, which had both R
C-H bonds and ꢀ C-H bonds, was also able to proceed
with the three-component reaction, affording the R C-H
bond transformation product, albeit with a relatively lower
(27) (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.
4242
Org. Lett., Vol. 12, No. 19, 2010

yield (24%, Table 2, entry 9). Besides these, N,N-diaryl
alkylamines such as N-methyl-N-phenylbenzenamine 1k
were likewise found able to undergo the reaction, producing
the R-diphenylamino imide in a 37% yield (Table 2, entry
10).
On the other hand, various isocyanides including alkyl
isocyanide 2b and 2c as well as aryl isocyanide 2d had also
been subjected to the three-component reaction and proved
to be reliable reaction partners with tertiary amines and
carboxylic acid 3a with moderate to good yields delivered
(Table 2, entries 11-15). Substituted benzoic acids such as
4-methylbenzoic acid 3b could also work with tertiary amine
1b and isocyanide 2a and provided a moderate yield (42%,
Table 2, entry 16).
and liberated the copper species. Lastly, owing to the fact
that the nitrogens of the amines had been blocked, the
migration of the acyls to the nitrogens of the isonitrile would
occur,28 producing the R-amino imide products 4. However,
in the absence of molecular sieves, the water which was
generated in the first step would competitively react with I
and 2, affording the byproduct 4ab.
In conclusion, we have reported a novel three-component
assembly involving the copper-catalyzed activations of sp3
C-Hs adjacent to nitrogens. Notably, the reaction could be
conducted under mild conditions and demonstrated a toler-
ance to a broad range of functional groups, leading to the
synthesis of R-amino imides from tertiary amines in a concise
manner. On the basis of the results, a possible reaction
mechanism has been proposed. Further research on the
asymmetric synthesis of the R-amino amides and detailed
mechanistic explanation, as well as applications of this
assembly in organic synthesis, are now ongoing in our
laboratory.
On the basis of the above results, a plausible mechanism
has been proposed as depicted in Scheme 2. As an initial
Scheme 2. Proposed Mechanism
Acknowledgment. The authors gratefully thank the grant
support from the Zhejiang Provincial Natural Science
Foundation of China (Y4090408) and the Zhejiang Provincial
Major Project of China (2007C01004-2). Financial support
from the Hangzhou City Research Project (20090331N04)
and the Hangzhou Normal University Research Program
(YS05203121) is simultaneously acknowledged by Dr. C.-
S. Xie.
Supporting Information Available: General experimental
procedures and spectroscopic data (1H NMR, 13C NMR, and
HRMS) for the corresponding products. This material is
available free of charge via the Internet at http://pubs.acs.org.
step of the cascade events, the N,N-dialkyl amines 1 were
converted into copper-iminium complexes I under the
promotion of copper and peroxides. Then the tandem
nucleophilic additions of isocyanides 2 and the formed
carboxylates generated the imino anhydride intermediates II
OL101576Q
(28) Similar transfer of acyls to the nitrogens of isonitriles had already
been reported in ref 7b and the following reference: Ugi, I.; Steinbruckner,
C. Chem. Ber. 1961, 94, 2802.
Org. Lett., Vol. 12, No. 19, 2010
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