Copper-catalyzed intramolecular C(sp3)-H and C(sp2)-H amidation by oxidative cyclization

Article abstract of DOI:10.1002/anie.201311105

The first copper-catalyzed intramolecular C(sp³)-H and C(sp ²)-H oxidative amidation has been developed. Using a Cu(OAc) ₂ catalyst and an Ag₂CO₃ oxidant in dichloroethane solvent, C(sp³)-H

Full text of DOI:10.1002/anie.201311105

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Angewandte
Communications
DOI: 10.1002/anie.201311105
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C H Activation
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Copper-Catalyzed Intramolecular C(sp ) H and C(sp ) H Amidation
by Oxidative Cyclization**
Zhen Wang, Jizhi Ni, Yoichiro Kuninobu,* and Motomu Kanai*
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Abstract: The first copper-catalyzed intramolecular C(sp ) H
methods for forming lactams. We selected a direct intra-
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and C(sp ) H oxidative amidation has been developed. Using
a Cu(OAc)2 catalyst and an Ag2CO3 oxidant in dichloroethane
solvent, C(sp ) H amidation proceeded at a terminal methyl
group, as well as at the internal benzylic position of an alkyl
chain. This reaction has a broad substrate scope, and various b-
lactams were obtained in excellent yield, even on gram scale.
Use of CuCl2 and Ag2CO3 under an O2 atmosphere in dimethyl
sulfoxide, however, leads to 2-indolinone selectively by C(sp )
molecular C H amidation as an alternative synthetic method.
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Although there are several reports of intramolecular C(sp )
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3
H amidation,[7] examples of intramolecular C(sp ) H amida-
tion are still rare. The few examples include: a) rhodium-
À
À
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catalyzed C(sp ) H amidation at internal positions of alkyl
chains, such as benzylic and tertiary positions (Figure 2a);[8]
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b) palladium-catalyzed allylic C(sp ) H amidation (Fig-
2
3
ure 2b);[9] and c) palladium-catalyzed C(sp ) H amidation
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H amidation. Kinetic isotope effect (KIE) studies indicated
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that C H bond activation is the rate-determining step. The 5-
methoxyquinolyl directing group could be removed by oxida-
tion.
L
actams (cyclic amides) and related compounds are impor-
tant partial structures of natural products, such as penicillin
and cephalosporin, and drugs such as ezetimibe[1] and
piperacillin[2] (b-lactam antibiotics, Figure 1). The Beckmann
rearrangement,[3] Schmidt reaction,[4] cyclization of amino
acids,[5] and iodolactamization[6] are well-known synthetic
Figure 2. Examples of transition-metal-catalyzed intramolecular
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C(sp ) H amidation. Mbs=(4-methoxyphenyl)sulfonyl, oct=octane,
Ts =4-toluenesulfonyl.
at terminal and internal positions (Figure 2c).[7f,10] Intramo-
Figure 1. Examples of b-lactam antibiotics.
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lecular C(sp ) H amidation using first-row transition-metal
catalysts, however, has not been reported. We report herein
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the first copper-catalyzed intramolecular C(sp ) H [and
2
[11]
[*] Z. Wang, J. Ni, Prof. Dr. Y. Kuninobu, Prof. Dr. M. Kanai
Graduate School of Pharmaceutical Sciences, The University of
Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033 (Japan)
E-mail: kuninobu@mol.f.u-tokyo.ac.jp
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C(sp ) H] amidation using a bidentate directing group.
The amidation reaction proceeds at both terminal and
internal C(sp ) H bonds with broad substrate generality.
Although substrate generality is slightly narrower than the
palladium-catalyzed reaction originally developed by Chen
and co-workers and Daugulis and co-workers,[7f,10] it is
noteworthy that the first-row transition-metal copper can
promote the identical reaction.
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kanai@mol.f.u-tokyo.ac.jp
Prof. Dr. Y. Kuninobu, Prof. Dr. M. Kanai
ERATO (Japan) Science and Technology Agency (JST), Kanai Life
Science Catalysis Project, Tokyo 113-0033 (Japan)
[**] This work was supported in part by ERATO from JST.
Treatment of the amide 1a with a catalytic amount of
CuCl and Ag2CO3 as an oxidant in dimethyl sulfoxide at
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201311105.
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Table 1: Investigation of several solvents and copper catalysts.
Table 2: Investigation of substrate scope.
Entry
Solvent
Catalyst
Yield [%][a]
1
DMSO
CuCl
17
2
3
acetonitrile
DMF
CuCl
CuCl
trace
19
4
benzonitrile
CuCl
41
5
6
7
8
1,2-dichloroethane
chlorobenzene
tert-butyl methyl ether
toluene
CuCl
CuCl
CuCl
CuCl
47
42
trace
31
9
1,4-dioxane
CuCl
40
10
11
12
13
14
15
16
17
18
19
octane
CuCl
CuBr
CuI
CuCN
CuSCN
CuF2
CuCl2
CuBr2
Cu(OAc)2
Cu(OPiv)2
33
50
38
52
93
43
55
45
1,2-dichloroethane
1,2-dichloroethane
1,2-dichloroethane
1,2-dichloroethane
1,2-dichloroethane
1,2-dichloroethane
1,2-dichloroethane
1,2-dichloroethane
1,2-dichloroethane
82
79
1
[a] Yield determined by H NMR of the crude mixture using 1,1,2,2-
tetrachloroethane as an internal standard. DMF= N,N,-dimethylform-
amide, DMSO=dimethylsulfoxide, Piv=pivaloyl.
1408C for 24 hours gave the b-lactam 2a in only 17% yield
(Table 1, entry 1). To improve the yield of 2a, several solvents
and catalysts were investigated (Table 1). The best solvent
and catalyst were 1,2-dichloroethane and CuSCN (or Cu-
(OAc)2), respectively (entries 14 and 18). In this reaction, b-
À
lactam formation through C H amidation at the terminal
methyl group was predominant, and g-lactam through inter-
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nal methylene C H amidation was not detected at all.
Although CuSCN was more reactive than Cu(OAc)2
(Table 1), its applicability to other substrates was unsatisfac-
tory. Therefore, we investigated the substrate scope using
Cu(OAc)2 as the catalyst (Table 2). For substrates 1b–g, the
amidation reaction proceeded selectively at a methyl group
(entries 1–6). For the phenacyl amide substrate 1h, the
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reaction proceeded at both C(sp ) H and C(sp ) H bonds,
thus affording a mixture of the b-lactam 2h and 2-indolinone
3h, with 2h as the preferred product (entry 7). The reaction
Yields of product are given within parentheses. The yields are those of
isolated products. [a] Diastereomeric ratio of 2.3:1.
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also proceeded at an internal benzylic C(sp ) H bond
À
(entries 8–17). The selectivity between methyl C H and
À
benzyl C H bonds was moderate (ca. 1:2, entries 8–15), but
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benzyl C H amidation was the predominant pathway in
a concerted metalation-deprotonation (CMD) pathway
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[14]
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entries 16 and 17. The reaction also proceeded using an amide
with a cleavable 5-methoxyquinolyl directing group, thus
producing the b-lactam 2s in high yield (entry 18).
[C(sp ) H bond activation];
4) reaction between B and
acetic acid to give C by the elimination of CO2 and H2O;
5) reductive elimination to give a b-lactam and copper species
CuOAc; and 6) oxidation of the CuOAc species with Ag2CO3
to regenerate Cu(OAc)(CO3).[12] After the first cycle, the
reaction proceeds through steps 2–6.
Considering the beneficial effects of acetate anions on
reactivity (Table 1), we propose the following mechanism for
the formation of b-lactams (Scheme 1): 1) oxidation of
a copper salt Cu(OAc)2 with Ag2CO3;[12] 2) formation of the
copper amide intermediate A by elimination of acetic acid;[13]
3) formation of a the metalacyclic intermediate B through
Next, we performed a deuterium-labeling experiment to
gain insight into the rate-determining step for the formation
of b-lactams. Treatment of the amide 1d or deuterated amide
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Interestingly, the reaction of 1h was C(sp ) H selective
when the reaction conditions were slightly modified [Eq. (5)].
Thus, treatment of 1h in the presence of the CuCl2 catalyst
and Ag2CO3 in dimethyl sulfoxide under an O2 atmosphere at
1408C for 24 hours produced the 2-indolinone 3h and b-
lactam 2h in 89% and 4% yields, respectively. This result is in
sharp contrast to the result shown in entry 7 of Table 2, where
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Scheme 1. A proposed mechanism for the intramolecular C(sp ) H
amidation.
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C(sp ) H amidation was the preferred reaction pathway.
[D6]-1d with a copper catalyst and oxidant gave the corre-
sponding b-lactams 2d and [D5]-2d in 16% and 5.6% yields,
respectively, after 1 hour [Eqs. (1) and (2)]. The kinetic
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In summary, we succeeded in intramolecular C(sp ) H
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and C(sp ) H amidation under copper catalysis. Although
there are a few examples of palladium-catalyzed intramolec-
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ular C H amidation, this is the first example of copper-
3
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catalyzed C(sp ) H amidation. The reaction proceeded at
a terminal methyl group, as well as at the internal benzylic
position of an alkyl chain. This reaction has broad substrate
scope, and b-lactams were obtained in high yield even on
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isotope effect value was 2.6, thus supporting our notion that
gram scale. 2-Indolinone was also synthesized by C(sp ) H
[15]
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C H bond activation is the rate-determining step.
amidation by slightly modifying the optimized reaction
conditions for C(sp ) H amidation. Because the 5-methoxy-
quinolyl directing group could be removed by oxidation, this
reaction could become a useful method for the synthesis of b-
lactams and 2-indolinones. Attempts to improve the position
selectivity and catalyst activity are ongoing in our group.
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The reaction could be performed on gram scale without
significantly changing the efficiency [Eq. (3)]. Thus, treat-
ment of 1.50 g of 1 f with Cu(OAc)2 and AgCO3 gave 1.22 g of
2 f in 81% yield, which is comparable to the yield shown in
entry 5 of Table 2 (1 f: 33.2 mg).
Experimental Section
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Gram-scale procedure for copper-catalyzed intramolecular C(sp ) H
amidation: A mixture of 2-ethyl-2-methyl-4-phenyl-N-(8-quinolinyl)-
butanamide (1 f, 1.50 g, 4.65 mmol), Cu(OAc)2 (169 mg, 0.930 mmol),
Ag2CO3 (3.84 g, 13.9 mmol), and 1,2-dichloroethane (46.5 mL) was
stirred at 1408C for 24 h under argon atmosphere. Then, the reaction
mixture was cooled to room temperature, and was subjected to
column chromatography on silica gel (hexane/ethyl acetate = 8:1, ca.
2.0 L) without removing 1,2-dichloroethane to give 3-ethyl-3-phe-
nethyl-1-(8-quinolinyl)-2-azetidinone (2 f, 1.22 g, 81% yield).
A residual directing group in the products decreases the
practicality of the transformation. According to Chenꢀs
finding, the 5-methoxyquinolyl group can be cleaved under
oxidative conditions [Eq. (4)].[10d] Treatment of the b-lactam
2s with ceric ammonium nitrate (CAN) afforded the depro-
tected b-lactam 4 in 67% yield without opening the sensitive
b-lactam scaffold [Eq. (4)].
Received: December 21, 2013
Published online: February 24, 2014
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