Copper-catalyzed aerobic dehydrogenative cyclization of N-methyl-N-phenylhydrazones: Synthesis of cinnolines

Article abstract of DOI:10.1002/anie.201204339

O₂ leading the way: The title reaction proceeds through an oxidation/cyclization sequence, thus representing the first copper-catalyzed coupling reaction of hydrazones through a C sp 3-H bond functionalization process (see scheme; DMF=N,N'-dimethylformamide, Py=pyridine). The method provides an environmentally friendly and atom-efficient approach to biologically active cinnoline derivatives. Copyright

Full text of DOI:10.1002/anie.201204339

Angewandte
Chemie
DOI: 10.1002/anie.201204339
Synthetic Methods
Copper-Catalyzed Aerobic Dehydrogenative Cyclization of N-Methyl-
N-phenylhydrazones: Synthesis of Cinnolines**
Guangwu Zhang, Jinmin Miao, Yan Zhao, and Haibo Ge*
À
Selective carbon–carbon (C C) bond formation is one of the
most important processes in organic chemistry since it enables
key steps in the synthesis of complex organic molecules from
bacterial, anticancer, antifungal, antihypertensive, antiinflam-
matory, and antiulcer activities.[14]
Our investigation began with the oxidative cyclization of
À
simple precursors. Traditionally, the construction of C C
1-methyl-1-phenyl-2-(1-phenylethylidene)hydrazine
(1a)
bonds relies primarily on prefunctionalized substrates, which
usually requires additional synthetic steps, and thus reduces
the overall efficiency of this transformation.[1] For this reason,
À
with catalytic CuSO4 in the presence of O2 (1 atm). To our
delight, the cyclization reaction was successful with DMF,
DMA, or DCE as the solvent, albeit in low yields (Table 1,
entries 1–3). An extensive catalyst screening showed that
although other CuII and CuI sources could catalyze the
C C bond formation reactions through transition-metal-
catalyzed direct functionalization of relatively unreactive
À
C H bonds have emerged as a major topic of research in
organic chemistry.[2] Among them, copper-catalyzed aerobic
dehydrogenative coupling reactions from two carbon–hydro-
Table 1: Optimization of reaction conditions.[a]
À
gen (C H) bonds have received renewed interest in recent
years with the following inherent advantages: maximizing
atom economy by avoiding prefunctionalization of the
coupling partners, and avoidance of toxic by-products with
molecular oxygen as the sole oxidant.[3]
Entry Cu source
(mol%)
Additives
(equiv)
Solvent Yield
[%][b]
Since the discovery of the Glaser reaction or the oxidative
dimerization of terminal alkynes[4] over 140 years ago, many
1
2
3
4
5
6
7
CuSO4 (20)
CuSO4 (20)
CuSO4 (20)
CuSO4 (20)
CuSO4 (20)
CuSO4 (20)
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
DMF
DMA
DCE
37
32
30
À
efforts have been devoted to this field to construct new C C
bonds. A number of copper-catalyzed aerobic dehydrogen-
CH3CN <5
DMSO trace
À
À
ative coupling reactions through a Csp H or Csp2 H bond
functionalization process have been developed, including
oxidative dimerization of phenols,[5] naphthols,[6] and elec-
tron-deficient arenes,[7] cross-coupling of terminal alkynes
with electron-deficient arenes,[8] and intramolecular dehydro-
genative cylization of anilides.[9] In comparison, the develop-
ment of copper-catalyzed aerobic dehydrogenative coupling
at sp3-carbon atoms is still in its infancy and the current
advances suffer severely from restricted substrate scope,
namely substrates with the sp3-carbon atom adjacent to
a heteroatom[10] or malonic amide derivative.[11] In our
continued efforts toward the development of transition-
metal-catalyzed coupling reactions on novel substrates,[12]
herein we report N-methyl-N-phenylhydrazones as unprece-
dented substrates for copper-catalyzed aerobic intramolecu-
lar dehydrogenative cyclization for the formation of cinno-
lines,[13] a privileged structure in many medicinal compounds
with a broad range of biological activities including anti-
NMP
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
trace
0
8
9
Cu(OAc)2 (20)
CuBr2 (20)
CuCl2 (20)
CuF2 (20)
Cu(OH)2CO3 (20)
Cu(TFA)2 (20)
Cu(OTf)2 (20)
CuI (20)
CuBr·DMS (20)
CuSO4 (20)
CuSO4 (20)
CuSO4 (20)
CuSO4 (20)
CuSO4 (10)/
CuI (10)
22
20
19
17
16
15
12
25
22
73
55
47
43
42
10
11
12
13
14
15
16
17
18
19
20
21
Py (3.5)/CF3SO3H (1) DMF
Py (3.5)/TsOH (1) DMF
Py (3.5)/CF3CO2H (1) DMF
Py (3.5)/AcOH (1)
Py (3.5)/PhCO2H (1)
DMF
DMF
22
CuSO4 (1.5)/
CuI (7.5)
Py (3.5)/CF3SO3H (1) DMF
Py (3.5)/CF3SO3H (1) DMF
Py (3.5)/CF3SO3H (1) DMF
83(80)[c]
70
23
CuSO4 (1.5)/
CuI (5)
CuSO4 (1.5)/
CuI (7.5)
24[d]
20
[*] Dr. G.-W. Zhang, J.-M. Miao, Y. Zhao, Prof. Dr. H.-B. Ge
Department of Chemistry and Chemical Biology, Indiana University
Purdue University Indianapolis, Indianapolis, IN 46202 (USA)
E-mail: geh@iupui.edu
[a] Reaction conditions: 1a (0.3 mmol), Cu source, additive, O2 (1 atm),
3 mL of solvent, 1108C, 14 h unless otherwise noted. [b] Yields and
conversions are based on 1a, and determined by 1H NMR analysis of the
crude reaction mixture using dibromomethane as the internal standard.
[c] Yield of isolated product. [d] Under air. DCE=1,2-dichloroethane,
DMF=N,N’-dimethylformamide, DMA=dimethylacetamide,
DMS=dimethylsulfide, DMSO=dimethylsulfoxide, Py=pyridine,
Tf =trifluoromethanesulfonyl, TFA=trifluoroacetic acid.
[**] We gratefully acknowledge Indiana University Purdue University
Indianapolis for financial support. The Bruker 500 MHz NMR was
purchased using funds from an NSF-MRI award (CHE-0619254).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201204339.
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cyclization of 1a, none of these catalysts improved the yield
(entries 8–16). Upon realizing that the addition of a nucleo-
philic base could facilitate the demethylation, screening of
different bases (pyridine, DMAP, DABCO, etc.) was carried
out. Unfortunately, none of these bases improved the yield.
However, the yield was increased by the addition of an acid
along with excess pyridine, and the optimal results were
obtained with 1 equivalent of CF3SO3H and 3.5 equivalent of
pyridine (entry 22).
from this ring, and good to high yields of product were
obtained with both electron-donating or electron-withdraw-
ing substituents (R1) on either the para, meta, and ortho po-
sitions, with the exception of 2o. The meta-OMe-, Me-, or Br-
substituted substrates gave a mixture of para and ortho-
substituted products (2h–j) with a preference for the p-
substituted products, whereas substrates bearing the more
hindered iPr group and the electron-withdrawing CN group
provided only the p-substituted products (2k and 2l, respec-
tively). As expected, halogens (F, Cl, and Br) were tolerated
under the current reaction system, thus allowing further
manipulation of the initial products. In contrast, there is an
electronic effect resulting from substituents (R2) on the other
phenyl ring (2q–z). Generally, electron-donating groups on
this ring provide higher yields than those with electron-
withdrawing groups. It is noted that replacement of this
phenyl group with an alkyl group gave only a trace amount of
product as a result of the decomposition of the starting
material under the oxidative conditions. It was also observed
that this reaction failed with the introduction of an alkyl
group on the carbon atom a to the imine moiety.
As shown in Table 2, this transformation is compatible
with electron-rich and electron-deficient N-phenyl rings (2b–
o). There is no apparent electronic or steric effect resulting
Table 2: Substrate scope.[a,b]
It is noteworthy that under the current reaction condi-
tions, a small amount of 2-(N-methyl-N-phenylhydrazono)-2-
phenylacetaldehyde (3) was isolated along with the desired
product 2a from the reaction of 1a. Furthermore, treatment
of 3 under the cyclization reaction conditions provided 1a in
90% yield (Scheme 1).
Scheme 1. Cyclization of 2-(N-methyl-N-phenylhydrazono)-2-phenyl-
acetaldehyde (3).
To further probe the reaction mechanism, deuterium-
labeling experiments were conducted (Scheme 2). No signifi-
cant kinetic isotope effect was observed in the reaction of
À
[D1]-1a, thus suggesting that the arene Csp2 H bond cleavage
might not be involved in the rate-determining step.[15]
Scheme 2. Deuterium-labeling experiments.
Based on the above observations, a reaction mechanism
for the cyclization of 1a is proposed (Scheme 3). It is believed
that this transformation starts with the oxidation of 1a into 3
through a copper-catalyzed process in the presence of
oxygen.[16] Copper-assisted Friedel–Crafts-type cyclization of
3 generates the intermediate G.[17] Activation of G by
a copper species, followed by loss of the hydroxy group, and
a methyl group by nucleophilic substitution by pyridine,
provides the desired product 2a.
[a] Reaction conditions: 1 (0.3 mmol), CuSO4 (1.5 mol%), CuI
(7.5 mol%), Py (3.5 eq), CF3SO3H (1.0 eq), O2 (1 atm), 3 mL of DMF,
1108C, 14 h unless otherwise noted. [b] Yield of isolated product. [c] The
reaction was run at 1508C for 20 h. [d] The reaction was run at 958C for
48 h.
2
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In summary, an efficient copper-catalyzed aerobic intra-
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Csp3 H oxidation, cyclization, and aromatization processes.
This transformation is the first example of copper-catalyzed
À
coupling reactions of hydrazones through a Csp3 H bond
functionalization pathway. This novel method provides an
efficient access to cinnoline derivatives.
Experimental Section
A 50 mL Schlenk tube was charged with N-methyl-N-phenylhydra-
zones (1, 0.3 mmol), CuSO4 (1.0 mg, 0.0045 mmol), CuI (4.2 mg,
0.0225 mmol), Py (84.4 mL, 1.05 mmol), and DMF (2.7 mL). Then
a solution of CF3SO3H (26.5 mL, 0.3 mmol) in DMF (0.3 mL) was
slowly added. The tube was evacuated and filled with 1 atm O2, and
stirred rigorously at 1108C (unless otherwise noted) for 14–48 h.
After removal of the solvent, the residue was purified by flash
chromatography on silica gel (gradient eluent of 5% EtOAc and 1%
Et3N in hexanes, v/v) to yield the desired product as a colorless or
pale-yellow solid.
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Received: June 4, 2012
Published online: && &&, &&&&
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À
Keywords: C C coupling · copper · heterocycles · oxygen ·
synthetic methods
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4
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Synthetic Methods
G.-W. Zhang, J.-M. Miao, Y. Zhao,
H.-B. Ge*
&&&& — &&&&
Copper-Catalyzed Aerobic
Dehydrogenative Cyclization of N-Methyl-
N-phenylhydrazones: Synthesis of
Cinnolines
O2 leading the way: The title reaction
proceeds through an oxidation/cycliza-
tion sequence, thus representing the first
copper-catalyzed coupling reaction of
DMF=N,N’-dimethylformamide, Py=
pyridine). The method provides an envi-
ronmentally friendly and atom-efficient
approach to biologically active cinnoline
derivatives.
À
hydrazones through a Csp3 H bond func-
tionalization process (see scheme;
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