Copper-Catalyzed Formal [4 + 1] Cycloaddition of Benzamides and Isonitriles via Directed C-H Cleavage

Article abstract of DOI:10.1021/acs.orglett.5b01986

A copper-catalyzed formal [4 + 1] cycloaddition of benzamides and isonitriles via 8-aminoquinoline-directed C-H cleavage has been developed. The reaction proceeds well even in the presence of a base metal catalyst, CuBr·SMe₂, alone to deliver the corresponding 3-iminoisoindolinones in good yields. Moreover, the unique acceleration effects of diphenyl sulfide are also disclosed.

Full text of DOI:10.1021/acs.orglett.5b01986

Letter
pubs.acs.org/OrgLett
Copper-Catalyzed Formal [4 + 1] Cycloaddition of Benzamides and
Isonitriles via Directed C−H Cleavage
Kazutaka Takamatsu, Koji Hirano,* and Masahiro Miura*
Department of Applied Chemistry, Faculty of Engineering, Osaka University, Suita, Osaka 565-0871, Japan
S
* Supporting Information
ABSTRACT: A copper-catalyzed formal [4 + 1] cyclo-
addition of benzamides and isonitriles via 8-aminoquinoline-
directed C−H cleavage has been developed. The reaction
proceeds well even in the presence of a base metal catalyst,
CuBr·SMe2, alone to deliver the corresponding 3-iminoisoin-
dolinones in good yields. Moreover, the unique acceleration
effects of diphenyl sulfide are also disclosed.
sonitriles constitute an important class of compounds in
organic synthesis because they are unique, versatile, and useful
was detrimental. Particularly, diglyme gave a much cleaner result,
and the GC yield reached 77% after 24 h (entry 7). Subsequent
evaluations of additives identified unique acceleration effects of
Ph2S: the addition of Ph2S allowed the reaction to complete
within 7 h at 170 °C, and 3aa was obtained in 88% GC yield (74%
isolated yield) with recovery of Ph2S (>94%, by GC analysis)
(entry 9). Without any sulfides, no full conversion occurred even
at 170 °C (entry 10).10 The structure of 3aa, including (E)-
geometry of the imine moiety, was unambiguously confirmed by
X-ray analysis.11 Some additional observations are to be noted:
both MnO2 and O2 were necessary for a satisfactory yield (entries
11 and 12); even with excess CuBr·SMe2 or Cu(OAc)2, the yield
of 3aa was low to moderate in the absence of the above-
mentioned two oxidants (entries 13 and 14); the copper salt was
essential for the cycloaddition (entry 15); the 8-aminoquinoline
moiety in 1a was critical, and other monodentate and bidentate
functional groups did not work at all under the conditions in
entry 9 (A−C, Table 1); as a general trend, excess 2a (>0.75
mmol) significantly dropped the rate (data not shown).
I
C1 sources as well as good equivalents to toxic carbon monoxide.
Particularly, there are many successful reports of cycloaddition
reactions with isonitriles for the synthesis of a variety of N-
heterocycles.1 Additionally, they are frequently employed as a C1
coupling partner in the metal-catalyzed C−H functionalization.2
However, to date, only noble palladium3 and rhodium4
complexes, in conjunction with stoichiometric Cu or Ag
oxidants, are known to catalyze this type of transformation.5
Thus, further development of direct cycloaddition with
isonitriles in base metal catalysis is very appealing. Herein, we
report a copper-catalyzed formal cycloaddition of benzamides
and isonitriles via an 8-aminoquinoline-directed C−H cleavage.
The reaction proceeds smoothly even in the presence of a copper
catalyst alone to deliver the cycloadducts, 3-iminoisoindoli-
nones,6 in good yields. This is the first successful example of the
copper-catalyzed C−H functionalization with isonitriles, to the
best of our knowledge.
Recently, our group7 and others8 have focused on inexpensive,
less toxic, and abundant copper salts and developed a number of
copper-mediated C−H functionalization reactions. In particular,
nitrogen-based directing groups allow such common metal
species to serve as good alternatives to precious transition
elements (e.g., Pd and Rh) and sometimes unique activators for
otherwise challenging C−H transformations. During our
continuous studies on this chemistry, we attempted a copper-
catalyzed direct cycloaddition of benzamide 1a (0.25 mmol) that
bears the 8-aminoquinoline-based bidentate coordination group9
and xylyl-substituted isonitrile 2a (0.38 mmol) (Table 1). In an
early experiment, the desired 3-iminoisoindolinone 3aa was
formed in 56% GC yield upon treatment of 1a with 2a in the
presence of a Cu(OAc)2 catalyst, AcOH, and activated MnO2
under O2 (1 atm, balloon) in DMF at 150 °C (entry 1). Some
other copper salts also promoted the reaction (entries 2−5), with
Cu(OAc)2 and CuBr·SMe2 proving to be optimal (entries 1 and
3). Utilizing CuBr·SMe2 with better reproducibility, we next
investigated the solvent effects (entries 6−8): aprotic polar
DMSO and diglyme also worked well, while less polar o-xylene
With the optimized conditions in hand (Table 1, entry 9), we
then performed the copper-catalyzed formal [4 + 1] cyclo-
addition of various benzamides 1 with isonitrile 2a (Scheme 1).
In addition to the simple 1a, electron-donating tert-butyl and
methoxy groups at the para position were tolerated, and the
corresponding iminoisoindolinones 3ba and 3ca were obtained
in 73% and 63% yields, respectively. The copper catalysis also
accommodated electron-withdrawing trifluoromethyl (3da),
chloro (3ea), and bromo (3fa) substituents, but they showed
somewhat lower efficiency and generally required a longer
reaction period to full conversion. A similar trend was observed
in the case of the methyl substituent at the congested ortho
position (3ga). The reaction of meta-substituted substrates
occurred preferably at the more sterically accessible C−H (3ha/
3ha′ and 3ia/3ia′),12 except for the meta-chlorobenzamide (3ja/
3ja′). Also note that the regioisomers could be readily separated
Received: July 10, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b01986
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Table 1. Optimization Studies for Copper-Catalyzed Formal
[4 + 1] Cycloaddition of Benzamide 1a and Isonitrile 2a
Scheme 1. Products in Copper-Catalyzed Formal [4 + 1]
a
a
Cycloaddition of Various Benzamides 1 and Isonitriles 2
additives
b
entry
1
Cu
(equiv)
conditions
3aa, % yield
Cu(OAc)2
MnO2 (2.0)
DMF, 150 °C
7 h, O2
56
2
CuI
MnO2 (2.0)
MnO2 (2.0)
MnO2 (2.0)
MnO2 (2.0)
MnO2 (2.0)
MnO2 (2.0)
MnO2 (2.0)
DMF, 150 °C
4 h, O2
27
57
37
trace
61
77
2
3
CuBr·SMe2
CuCl
DMF, 150 °C
7 h, O2
4
DMF, 150 °C
4 h, O2
5
Cu(OTf)2
CuBr·SMe2
CuBr·SMe2
CuBr·SMe2
CuBr·SMe2
CuBr
DMF, 150 °C
4 h, O2
6
DMSO, 150 °C
7 h, O2
7
diglyme, 150 °C
24 h, O2
8
o-xylene, 150 °C
4 h, O2
9
MnO2 (2.0)
Ph2S (1.0)
MnO2 (2.0)
diglyme, 170 °C
7 h, O2
88 (74)
53
0
10
11
12
diglyme, 170 °C
7 h, O2
CuBr·SMe2
CuBr·SMe2
CuBr·SMe2
Cu(OAc)2
none
Ph2S (1.0)
diglyme, 170 °C
4 h, O2
MnO2 (2.0)
Ph2S (1.0)
Ph2S (1.0)
diglyme, 170 °C
7 h, N2
29
2
c
13
diglyme, 170 °C
7 h, N2
c
14
Ph2S (1.0)
diglyme, 170 °C
7 h, N2
32
0
15
MnO2 (2.0)
Ph2S (1.0)
diglyme, 170 °C
7 h, O2
a
Reaction conditions: Cu (0.050 mmol), AcOH (0.25 mmol),
additives, 1a (0.25 mmol), 2a (0.38 mmol), solvent (1.5 mL), O2 (1
b
atm, balloon) or N2. Yield estimated by GC method. Yield of isolated
c
product given in parentheses. With 0.50 mmol of Cu.
a
Conditions: CuBr·SMe2 (0.050 mmol), AcOH (0.25 mmol), Ph2S
(0.25 mmol), activated MnO2 (0.50 mmol), 1 (0.25 mmol), 2 (0.38
mmol), diglyme (1.5 mL), O2 (1 atm, balloon). Yields of isolated
from each other by silica gel column chromatography. Higher
condensed naphthalene (3ka/3ka′ and 3la) and phenanthrene
(3ma) compounds were also applicable substrates. Moreover,
some heteroarenes participated in the direct cycloaddition:
indole- (3na), benzothiophene- (3oa), pyrrole- (3pa), and
pyridine- (3qa) fused iminoisoindolinone analogues were
formed in synthetically acceptable yields. In the cases of the
pyrrole and pyridine (3pa and 3qa), the starting amides were
recovered in ca. 10% (by GC and GCMS analysis), but the rest
could not be identified. On the other hand, the isonitrile was
relatively limited in scope,13 but bulky tert-butyl- and 1-
adamantyl-substituted isonitriles could be employed (3ab,11
3ac, 3hc/3hc′, 3ic, and 3qc). Particularly, the coupling of 1i with
b
products are given. The reaction time is shown in parentheses. On a
2.5 mmol scale. Regioisomeric ratios. Both isomers could be isolated
by column chromatography. Without Ph2S. Q = 8-quinolinyl, Xyl =
c
d
2,6-dimethylphenyl.
1-adamantylisonitrile (2c) formed the single regioisomer 3ic in
76% yield.14 It is also noteworthy that the catalytic reaction could
be conducted on a 2.5 mmol scale without any difficulties (3aa),
thus indicating the good reliability and practicality of the present
process.
B
DOI: 10.1021/acs.orglett.5b01986
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
A proposed mechanism for the reaction of 1a with 2a is shown
in Scheme 2. The initial off-cycle oxidation of CuBr·SMe2 (I) and
early stage of the reaction with 1a-d5 (1 h), both the product and
recovered starting material did not lose any deuteriums (eq 1),
thus suggesting the irreversible C−H cleavage under catalytic
conditions. Additionally, the competitive and parallel reactions
gave large KIE values of 3.5 and 5.8, respectively (eq 2). Thus, the
C−H cleavage would be involved in the rate-determining step.
However, further efforts are essential for clarification of the
mechanism.19
Scheme 2. Plausible Mechanism (X = Br or OAc, L = Xyl-NC
(2a) or R2S)
The iminoisoindolinone products 3 could be easily trans-
formed into various 1,2-dicarboxylic acid derivatives (Scheme 4).
Scheme 4. Transformation of Products
coordination of the isonitrile 2a and sulfides form the active
copper complex 4. Subsequent deprotonation of relatively acidic
NH in 1a15 generates the key N,N-bidentately chelated
metalacycle 5, which is apparently supported by control
experiments with other benzamides A−C (Table 1). The ortho
C−H cleavage (5 → 6) is followed by the insertion of the
isonitrile to the C−Cu moiety16 to afford the intermediate 7.
Productive reductive elimination is then induced by the
oxidation into Cu(III) species,17 en route to the cycloadduct
3aa (7 → 8 → 9). Reoxidation of the liberated Cu(I) 9 by MnO2
and/or O2 regenerates the starting 4 to complete the catalytic
cycle. The (E)-geometry of the imine moiety in 3aa can be
thermodynamically controlled by the steric repulsion between
the Xyl group and quinoline ring. Given the critical effects of
MnO2 and O2 even under stoichiometric conditions (entries 13
and 14 in Table 1), they can work in both oxidation steps (7 → 8
and 9 → 4). Although the exact role of the external Ph2S still
remains unclear, it can suppress the formation of inactive,
isonitrile-overcoordinated copper 4′, which is consistent with
some phenomena observed in the optimization studies: the
reduced reaction rate in the presence of excess isonitriles and
nearly quantitative recovery of Ph2S.18
The xylyl-substituted 3aa was hydrolyzed upon treatment with
HNO3 aq. affording the N-quinolinylphthalimide 10. Subsequent
ethanolysis and aminolysis furnished diethyl phthalate (11) and
phthalamide (12), respectively, in good overall yields.
Furthermore, the reaction of 3ac with hydrazine provided the
corresponding 4-aminophthalazinone skeleton 13, which
frequently occurs in bioactive molecules.20
In conclusion, we have developed a copper-catalyzed formal [4
+ 1] cycloaddition of benzamides and isonitriles via directed C−
H cleavage. Suitable oxidants (i.e., activated MnO2 and O2) and a
Ph2S additive enable the first Cu catalysis in the aromatic C−H
coupling with isonitriles.21 The products can also be readily
converted to useful acyclic and cyclic compounds. Our ongoing
work seeks to uncover the detailed mechanism and develop
relevant Cu-based C−H activation catalysts.
ASSOCIATED CONTENT
* Supporting Information
■
S
To shed some light onto the C−H cleavage step, we
performed deuterium-labeling experiments (Scheme 3). At an
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.5b01986.
Scheme 3. Deuterium-Labeling Experiments
Detailed experimental procedures, characterization data of
compounds (PDF)
CIF file of 3ab (CIF)
CIF file of 3aa (CIF)
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: k_hirano@chem.eng.osaka-u.ac.jp.
*E-mail: miura@chem.eng.osaka-u.ac.jp.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
This work was supported by JSPS KAKENHI Grant Nos.
15K13696 (Grant-in-Aid for Exploratory Research) and
■
C
DOI: 10.1021/acs.orglett.5b01986
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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15H05485 (Grant-in-Aid for Young Scientists (A)) to K.H. and
24225002 (Grant-in-Aid for Scientific Research (S)) to M.M.
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D
DOI: 10.1021/acs.orglett.5b01986
Org. Lett. XXXX, XXX, XXX−XXX