Copper-Catalyzed aerobic intramolecular dehydrogenative cyclization of n,n-disubstituted hydrazones through C sp 3 -H functionalization

Article abstract of DOI:10.1002/anie.201209618

An aerobic activity: The title reaction proceeds through an oxidation/cyclization/aromatization sequence under an atmosphere of O ₂ (see scheme; DBU=1,8-diazabicyclo[5.4.0]undec-7-ene, DCE=1,2-dichloroethane, DMS=dimethylsulfide). This coupling

Full text of DOI:10.1002/anie.201209618

Angewandte
Chemie
DOI: 10.1002/anie.201209618
Heterocycles
Copper-Catalyzed Aerobic Intramolecular Dehydrogenative
À
Cyclization of N,N-Disubstituted Hydrazones through Csp3
Functionalization**
H
Guangwu Zhang, Yan Zhao, and Haibo Ge*
The development of methods for selective carbon–carbon
(C-C) bond formation is of paramount importance in organic
synthesis.[1] As major approaches, nucleophilic substitution
and addition, Friedel–Crafts-type reactions, and cross-cou-
pling reactions often require the use of prefunctionalized
starting materials, which add additional costs and generate
stoichiometric amounts of metal salts as waste. Therefore, the
The requirement of an ideal internal nucleophile for the
intramolecular cyclization led us to consider N,N-disubsti-
tuted hydrazones as potential substrates. Although the
copper-catalyzed oxidative coupling reaction of hydrazones
has not been explored, it was reported that hydrazines could
be oxidized by rhodium(III) to form the corresponding
iminium ion intermediates, which could then undergo cyclo-
addition with an electron-deficient alkene.[8] It is envisioned
that if the selective oxidation of the nitrogen atom of
a hydrazone is feasible by a copper source and an external
oxidant, the in situ generated iminium ion intermediate could
be trapped intramolecularly by nucleophilic addition of an
enamine-type substructure, the tautomer of the imine moiety,
to form a dihydropyrazole structure. Furthermore, the initial
dihydropyrazole product could be aromatized to pyrazole
under the oxidative conditions. On the basis of this design,
copper-catalyzed aerobic intramolecular cyclization of N,N-
À
construction of C C bonds through the direct use of
À
unfunctionalized substrates through C H bond functionali-
zation has attracted considerable attention, and significant
progress has been achieved in recent years.[2] Among these
approaches, copper-catalyzed aerobic dehydrogenative cou-
pling provides a powerful method for the direct functional-
ization at sp3 carbon atoms a to amines or ethers.[3]
In 1993, Miura and co-workers reported the first example
of this transformation by coupling N,N-dimethylanilines with
alkynes in low to moderate yields.[4] Li and co-workers, as well
as others have recently made significant progress in this area
by expanding the substrate scope.[5] It is well accepted that an
iminium ion intermediate is formed through amine oxidation
by a copper source in the presence of an oxidant by a single-
electron transfer (SET) process. The resulting iminium ion
intermediate then acts as an electrophile for the subsequent
nucleophilic addition.[6] The studies on the substrate scope
showed that nitroalkanes, alkynes, cyanides, malonic esters,
ketones, a,b-unsaturated carbonyl compounds, and electron-
rich (hetero)arenes are all suitable nucleophiles. Further-
more, certain secondary amines, namely the N-aryl-substi-
tuted a-amino esters, ketones, and amides,[7] are also compat-
ible under the oxidative conditions, and further improved
product diversity. However, current progress is limited only to
the intermolecular case, termed as the cross dehydrogenative
coupling (CDC).[6a] In our continuing efforts toward the
development of green chemistry for chemical syntheses,
herein, we report the realization of the first example of this
transformation in an intramolecular manner.
À
disubstituted hydrazones by a double Csp3 H bond function-
alization was developed and is reported here. This unprece-
dented transformation provides an efficient approach for the
synthesis of pyrazoles, a privileged structure and prevalent
motif in medicinal compounds and many biologically active
natural products.[9] It is worth mentioning that current
syntheses of 1,3,5-trisubstituted pyrazoles rely primarily on
the cyclization of hydrazines with 1,3-dicarbonyl compounds,
and in spite of providing a powerful approach, it often suffers
from poor regioselectivity.
We recently reported the copper-catalyzed aerobic dehy-
drogenative cyclization of N-phenylhydrazones for the for-
mation of cinnolines via a-imino aldehyde intermediates.[10] It
was envisioned that replacement of the N-phenyl with an
alkyl group could favor the selective oxidation of the amine
moiety, and lead to subsequent cyclization. Thus, we began
our investigation with the oxidative cyclization of 1-benzyl-1-
isopropyl-2-(1-phenylethylidene)hydrazine (1a) with cata-
lytic CuBr·DMS in the presence of 1.1 equivalents of
Cs2CO3 as the base and 1 atm of O2 as the oxidant at 1358C
(Table 1). After an extensive solvent screening, DCE was
proven to be optimal, albeit with a low yield (entry 1). It was
noticed that decomposition of starting material also occurred
under the above reaction conditions. Therefore, screening of
different additives to inhibit decomposition of 1a was carried
out, and it was found that DBU could alleviate the problem
although the reaction yield was only slightly increased
(entry 2). Further optimization showed that this reaction
could be improved by the addition of a catalytic amount of KI,
which presumably facilitates the cyclization (entry 3). To our
delight, the addition of DMS as the cosolvent significantly
[*] Dr. G.-W. Zhang, 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
[**] 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).
We also would like to thank Jinmin Miao for providing several
starting materials.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201209618.
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Table 1: Optimization of reaction conditions.[a]
Table 2: Scope: N substituents.[a,b]
Entry Cu source (mol%) Additives (equiv)
Cosolvent Yield [%][b]
1
2
3
4
5
6
7
8
CuBr·DMS (10)
CuBr·DMS (10)
CuBr·DMS (10)
CuBr·DMS (10)
CuBr·DMS (10)
CuBr·DMS (10)
CuBr·DMS (10)
(CuOTf)2·
–
–
–
–
15
22
DBU (0.3)
DBU (0.3)/KI (0.5)
DBU (0.3)/KI (0.5) DMS
–
DBU (0.3)
KI (0.5)
DBU (0.3)/KI (0.5) DMS
33
80 (77)[c]
DMS
DMS
DMS
46
67
53
73
benzene (5)
9
CuI (10)
DBU (0.3)/KI (0.5) DMS
DBU (0.3)/KI (0.5) DMS
DBU (0.3)/KI (0.5) DMS
DBU (0.3)/KI (0.5) DMS
DBU (0.3)/KI (0.5) DMS
DBU (0.3)/KI (0.5) DMS
DBU (0.3)/KI (0.5) DMS
70
66
68
72
70
69
75
10
11
12
13
14
15
Cu(OTf)2 (10)
Cu(OAc)2 (10)
CuBr2 (10)
CuCl2 (10)
CuSO4 (10)
Cu(TFA)2 (10)
[a] Reaction conditions: 1a (0.3 mmol), Cu source, Cs2CO3 (1.1 equiv),
additive, O2 (1 atm), 3 mL of solvent, 1358C, 5 h. [b] Yields and
conversions are based on 1a, determined by 1H NMR spectroscopy of
the crude reaction mixture using dibromomethane as the internal
standard. [c] Yield of the isolated product. DBU=1,8-diazabicyclo-
[5.4.0]undec-7-ene, DMS=dimethylsulfide, TFA=trifluoroacetate.
enhanced the tolerance of the substrate to the oxidative
conditions and improved the efficiency of this transformation,
thus providing the desired product 2a in 80% yield (entry 4).
In addition, other copper(I) or copper(II) sources could also
effectively catalyze this reaction under the above modified
reaction conditions (entries 9–15).
With the optimized reaction conditions in hand, we then
carried out a study on the substrate scope with respect to the
the amine moiety (Table 2). As expected, both electron-
donating and electron-withdrawing groups on the phenyl ring
are compatible under the current catalytic system (2b–m). In
addition, halogens (F, Cl, and Br) are also tolerated, and thus
allow additional transformation of the initial products.
Furthermore, there is no apparent electronic or steric effect
on this ring since good to high yields of the desired products
were observed for substrates with either electron-donating or
electron-withdrawing groups at the para, meta, and ortho
positions. It is also noted that the isopropyl group can be
replaced with another alkyl or phenyl group (2n–r), and thus
allows the synthesis of pyrazoles having different substitution
patterns.[11] Interestingly, with 1-benzyl-1-methyl-2-(1-phenyl-
ethylidene)hydrazine as the substrate, two products (2pa and
2pb) were obtained, which were likely resulted from the
competitive oxidation between the benzyl and methyl groups
under the oxidative reaction conditions.
[a] Reaction conditions: 1 (0.3 mmol), CuBr·DMS (10 mol%), Cs2CO3
(1.1 equiv), DBU (30 mol%), KI (50 mol%), O2 (1 atm), 3 mL solvent
(DCE/DMS=10:1, v/v), 1358C, 5 h. [b] Yield of the isolated product.
were observed with substrates having very strong electron-
withdrawing groups (2y and 2ab), presumably as a result of
the instability of the starting materials under the oxidative
reaction conditions. As expected, halogens (F, Cl, and Br)
were also well tolerated. Furthermore, good yields of desired
products were also obtained with the naphthalene substrates
(2af and 2ag). Unfortunately, a-substituted 1-benzyl-1-iso-
propyl-2-(1-phenylethylidene)hydrazines
and
aliphatic
hydrazones were not well tolerated under the current catalyst
system because of the competitive decomposition of starting
materials (2ah and 2ai).
Next, the substrate scope with regard to the imine moiety
was carried out. As shown in Table 3, a wide variety of aryl
groups having either an electron-donating or electron-with-
drawing substituent on the ring were tolerated under the
current reaction conditions (2s–ae). Although there is no
apparent electronic or steric effect on this ring, lower yields
On the basis of previous reports,[6a,b,12] a plausible reaction
mechanism is proposed (Scheme 1). It is believed that the
reaction is initiated by oxidation of the amine on 1 to form the
iminium ion intermediate B via the intermediate A (rou-
te a).[3a,h] Alternatively, the intermediate B could also be
generated through tautomerization of 1 to form the inter-
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Table 3: Scope: Imine moiety.[a,b]
intermediate I, presumably by a KI-assisted process. The
intermediate I is then aromatized to form the pyrazole 2
under the oxidative conditions (route c). Alternatively, inter-
mediate I could be formed by tautomerization of B to the
enamine-type structure G followed by subsequent oxidation
and radical cyclization (route d).[3g,14]
To further probe the reaction mechanism, a time-depen-
dent study of copper-catalyzed oxidative cyclization of 1-
benzyl-1-methyl-2-(1-phenylethylidene)hydrazine (1q) was
carried out.[15] It was noticed that the intermediate 3 was
rapidly formed during the reaction (within 10 min), and then
completely consumed. Furthermore, treatment of this inter-
mediate under standard reaction conditions gave 2q in nearly
quantitative yield (Scheme 2a). Furthermore, the addition of
excess TEMPO has no apparent effect on this intramolecular
cyclization reaction (Scheme 2b).[16] Based on the above
observations, it is believed that the mechanism of this reaction
proceeds by route a and then route c as shown in Sche-
me 1.[3a,5a,e]
Scheme 2. Control experiments. TEMPO=2,2,6,6-tetramethylpiperidin-
1-oxyl.
In summary, we have developed an efficient copper-
catalyzed aerobic intramolecular dehydrogenative cyclization
[a] Reaction conditions: same as in Table 2. [b] Yield of the isolated
product.
À
reaction of N,N-disubstituted hydrazones by Csp3 H oxida-
tion, cyclization, and aromatization. This transformation is
the first example of an intramolecular copper-catalyzed
dehydrogenative coupling reaction via an iminium ion
mediate C, followed by oxidation[3g] and subsequent 1,5-H
shift[13] and oxidation (route b). Tautomerization of the imine
moiety on B to the enamine-type structure G and subsequent
intramolecular cyclization provides the dihydropyrazole
À
intermediate by a Csp3 H bond functionalization pathway.
This novel method provides a complementary, environmen-
Scheme 1. Plausible reaction mechanism.
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tally friendly, and atom-efficient approach to accessing
pyrazole derivatives. Additional mechanistic investigation of
this transformation is currently underway in our laboratory.
Experimental Section
A 50 mL Schlenk tube was charged with an N,N-disubstituted
hydrazone (1, 0.3 mmol), CuBr·DMS (6.1 mg, 0.03 mmol), KI
(24.9 mg, 0.15 mmol), DBU (13.3 mL, 0.09 mmol), Cs2CO3 (107 mg,
0.33 mmol), and the solvent mixture of DCE and DMS (10:1, v/v;
3.0 mL). The vial was then evacuated and filled with 1 atm O2, and
stirred rigorously at 1358C for 5 h. After removal of the solvent, the
residue was purified by flash chromatography on silica gel (gradient
eluent of 2% EtOAc in hexanes, v/v) to give the desired product.
Received: December 1, 2012
Published online: January 23, 2013
À
Keywords: C H activation · copper · cyclization · heterocycles ·
oxygen
.
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