Access to the Cinnoline Scaffold via Rhodium-Catalyzed Intermolecular Cyclization under Mild Conditions

Article abstract of DOI:10.1021/acs.orglett.6b02103

Herein, we report Rh(III)-catalyzed, N-amino (hydrazine)-directed C-H functionalization with α-diazo-β-ketoesters for access to the cinnoline scaffold. A diverse set of nondiscriminating conditions obtained for a highly efficient test transformation prompted use of a substrate-replacement technique for an in-depth search of experimental parameter space and pinpointing of the optimized conditions. A successive C-H activation/C-C coupling/intramolecular dehydration mechanistic sequence is proposed. The ability to perform gram-scale synthesis proves the synthetic utility of this simple, yet efficient, method.

Full text of DOI:10.1021/acs.orglett.6b02103

Letter
pubs.acs.org/OrgLett
Access to the Cinnoline Scaffold via Rhodium-Catalyzed
Intermolecular Cyclization under Mild Conditions
Chao Song, Chen Yang, Feifei Zhang, Jinhu Wang, and Jin Zhu*
Department of Polymer Science and Engineering, School of Chemistry and Chemical Engineering, State Key Laboratory of
Coordination Chemistry, Nanjing National Laboratory of Microstructures, Collaborative Innovation Center of Chemistry for Life
Sciences, Nanjing University, Nanjing 210093, China
S
* Supporting Information
ABSTRACT: Herein, we report Rh(III)-catalyzed, N-amino (hydra-
zine)-directed C−H functionalization with α-diazo-β-ketoesters for
access to the cinnoline scaffold. A diverse set of nondiscriminating
conditions obtained for a highly efficient test transformation
prompted use of a substrate-replacement technique for an in-depth
search of experimental parameter space and pinpointing of the
optimized conditions. A successive C−H activation/C−C coupling/
intramolecular dehydration mechanistic sequence is proposed. The
ability to perform gram-scale synthesis proves the synthetic utility of this simple, yet efficient, method.
he cinnoline skeleton is common in fluorescent chemicals
chromenes,11 isoquinolines,12 furans,13 indazoles,14 and cinno-
lines,15 etc. Despite synthetic advances achieved for cinnoline
scaffold, various bulky protecting groups were adopted for initial
protection of one or both of the nitrogen atoms and subsequent
removal along with the formation of C−N bond (Scheme 2, eqs
b15b and d15d) or retained in the products requiring additional
T
and biologically active and other functional molecules.1−5
For example, some of its derivatives (Scheme 1) exhibit
Scheme 1. Functional Molecules Containing the Cinnoline
Skeleton
Scheme 2. Schematic of Transition-Metal-Catalyzed C−H
Functionalization Reactions for Cinnoline Synthesis
fluorescent properties for cell-based imaging,2 antitrypanoso-
miasis activity,3 inhibitory activity toward Bruton’s tyrosine
kinase,4 and antiallergic activities.5 Various synthetic methods
have been developed for such a two nitrogen atom bearing
heterocycle that primarily include diazonium-based annulation6
and aryl−halogen-based C−C and C−N coupling reactions,7
etc.8 However, their synthetic utility is restricted due to various
drawbacks: (1) extra preparation steps for the installation of
multiple functionalities undermining the step economy, (2)
harsh reaction conditions limiting the substrate scope, and (3)
demands for nitrogen protection compromising the atom
efficiency. In addition, 1-substituted cinnoline derivatives,
which are also important bioactive molecules,2,3,5 cannot be
generated by direct modification of cinnoline, and very few
synthetic methods were reported on this kind of cinnoline
derivatives.7b,9
Transition-metal-catalyzed C−H functionalization has
Received: July 18, 2016
emerged as a useful tool for heterocycle synthesis,10−15 including
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b02103
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Organic Letters
Letter
deprotection steps (Scheme 2, eqs a15a and c15c). In addition,
large amount of acids (Scheme 2, eqs a, b, and d), multiple
additional transition metal salts (Scheme 2, eqs a−d), and high
temperature (Scheme 2, eqs a−c) were necessary for the
transformations. The end products of these methods are limited
in substitution patterns, and therefore, further development of
C−H functionalization-based methods for expansion of the
cinnoline structural diversity is warranted.
Recently, we have initiated a program for N-amino group
(hydrazine)-directed C−H bond functionalization reactions.
The amino group functioned as an internal oxidant for the access
of indole and ortho-alkenylated aniline derivatives.16 The
remarkable reactivity of the directing system translates into
mild reaction conditions for the synthesis of nitrogen-containing
compounds. We envisioned that that N−N bond would remain
intact after coupling with redox-neutral partners and the retained
amino group could be further used for the formation of a
heterocycle when an intramolecular cyclization reaction can
proceed. Herein, we report on the synthesis of the cinnoline
scaffold through the use of C−H activation of 1-alkyl-1-
phenylhydrazines and α-diazo-β-ketoesters as the redox-neutral
coupling partners. After the formation of the C−C bond, a formal
dehydration reaction occurs between amino and keto groups and
allows the generation of 1-alkyl-1,4-dihydrocinnolines. This
synthetic protocol features an atom- and step-economic
intermolecular cyclization of simple substrates under mild
conditions, with water and nitrogen gas as the only side
products, furnishing the target products in high yields.
test substrate). Since there were only slight differences between
the yields under these conditions (termed primary conditions),
we used the substrate-replacement (SURE) technique for
identifying a broadly applicable condition. The SURE technique
basically involves a replacement of substrate, further optimiza-
tion of reaction conditions (termed secondary conditions), and a
secondary validation on the original substrate. Additional rounds
of substrate replacement, reaction condition optimization, and
back validation can be solicited when desired. The idea is to
perform an in-depth search in the experimental parameter space
and eliminate the selection of a randomly obtained reaction
condition as the so-called “optimized” condition for all
substrates. As a proof-of-concept demonstration of the synthetic
utility of our proposed SURE technique, we replaced the test
substrate from 1a with a supposedly less reactive p-cyano-
substituted substrate, 1g. When the aforementioned conditions
were examined (Table S1, entries 1−5), the yields significantly
dropped to below 60%. Then different amounts of additives were
examined (Table S1, entries 6−10), and the yield eventually
reached 89% yield when 10 mol % of LiOAc was used as the sole
additive. We then applied these optimized conditions to the
reaction of 1a and 2a for secondary validation (Table 1, entry
12), and an excellent 94% yield was obtained. In addition, a
reduction in catalyst loading could also provide a satisfactory 97%
yield for 1a (Table 1, entry 13). However, under these
conditions, the yield decreased to 77% for 1g (Table S1, entry
11). Finally, a control experiment omitting the rhodium catalyst
proved it to be essential in this reaction (Table 1, entry 14).
Overall, the reaction conditions were quite switchable for
moderately reactive substrates as 1a, exhibiting great perform-
ance under acidic (Table 1, entry 6), basic (Table 1, entries 8 and
9), and near-neutral (Table 1, entries 12 and 13) conditions.
With the SURE-delivered optimized conditions in hand, we
commenced to explore the scope of 1-alkyl-1-phenylhydrazine
substrates. We employed 2a as the coupling partner and
examined various substituents (Scheme 3). For para substitu-
ents, both electron-donating groups (1b and 1f) and electron-
withdrawing groups (1c−e and 1g,h) participated in the
reaction, affording good to excellent yields in 8 h. Impressive
were the substrates 1a and 1d, both of which reached high yields
above 90% under a lower catalyst loading of 1 mol %. For a highly
reactive substrate 1f, the expected product 3f could be obtained
in 89% yield in 4 h. The meta-substituted substrates were also
effective in this reaction, and regiospecificity was observed in
almost all of the products. For methyl substitution, only the para-
position of the methyl group was reactive, and we gained 3i in
98% yield using 1 mol % of catalyst in 16 h. In comparison, for
fluoro and chloro substituents, single products reacting at their
ortho-position were isolated. However, the bromo substituent
offered a product mixture of ortho/para regioisomers at higher
temperature in 67% yield (trace product at room temperature).
The regioselectivity can be rationalized by the inherent higher
reactivity at the ortho position, but steric effects take control
(reactive site at para position) when the substituent is too bulky.
Ortho substitution was also compatible, as proved by 1-(o-
fluorophenyl)-1-methylhydrazine, which provided a 90% yield of
3m. A change of substituent on the aryl-linked nitrogen (defined
as 1-nitrogen) was then investigated. Both 1-alkyl (1a,n,p) and 1-
aryl (1o) phenylhydrazines participated well in the reaction,
offering ∼90% yields. For 1-benzyl-1-phenylhydrazine (1p), a
substrate bearing highly reactive benzyl C−H bonds, no reaction
was observed on this position, and the expected product 3p was
obtained in 86% yield. Furthermore, we carried out a gram-scale
We initiated our investigations by examining [RhCp*Cl2]2-
catalyzed reactions of 1-methyl-1-phenylhydrazine (1a) and
ethyl 2-diazo-3-oxobutanoate (2a). According to our previous
work16a and the screen of solvents (Table 1, entries 1−6), we
selected 2 mol % of [RhCp*Cl2]2 as the catalyst and MeOH as
the solvent. Acetic acid and acetates were used to improve the
catalytic performance (Table 1, entries 6−10). To our
satisfaction, HOAc, NaOAc, and KOAc conditions all offered
excellent >80% yields (termed primary validation on the original
a,b
Table 1. Optimization of Reaction Conditions
entry
solvent
DCE
additive (mol %)
yield (%)
1
HOAc (100)
HOAc (100)
HOAc (100)
HOAc (100)
HOAc (100)
HOAc (100)
LiOAc (100)
NaOAc (100)
KOAc (100)
CsOAc (100)
46
0
2
CH3CN
THF
3
0
4
toluene
1,4-dioxane
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
0
5
0
6
92
62
84
89
67
0
7
8
9
10
11
12
LiOAc (10)
LiOAc (10)
LiOAc (10)
94
97
0
c
13
d
14
a
Conditions: 1a (0.25 mmol, 1 equiv), 2a (1.1 equiv), solvent (1 mL).
Isolated yields. With 1 mol % of [RhCp*Cl2]2. Without
b
c
d
[RhCp*Cl2]2.
B
DOI: 10.1021/acs.orglett.6b02103
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Organic Letters
Letter
a,b
coordination of thienyl sulfur atom to rhodium catalyst, 2j
showed a lower 60% yield. Additionally, with the derivatization of
a cyclopropyl group (2l) on the coupling partner, 72% yield was
obtained, and no ring-opening product was observed.
Scheme 3. Substrate Scope of 1-Alkyl-1-phenylhydrazines
Furthermore, the mechanism of this reaction system was
examined by hydrogen−deuterium exchange experiments and
kinetic isotope effect (KIE) studies (Scheme 5). Treating 1a
Scheme 5. Mechanistic Studies
a
Conditions: 1a−p (0.25 mmol, 1 equiv), 2a (1.1 equiv), MeOH (1
b
c
d
mL). Isolated yields. With 1 mol % of [RhCp*Cl2]2. 75% yield at
under standard conditions in CD3OD solvent resulted in an
approximately 2% deuterium substitution in the ortho position of
the substrate, and the reversal test using 1a-d3 as the starting
material in CH3OH gave almost the same ratio of exchange. This
low efficiency of H−D exchange revealed the C−H activation
step in this reaction to be close to irreversible. We then carried
out a KIE test through intermolecular competition between 1a
and 1a-d3 with 2a under standard conditions.17 The KIE value
was determined as 4.9 by the calculation of the yield ratio of 3a to
3a-d2 through 1H NMR analysis. This high KIE value indicated
that the C−H activation step was likely rate-determining in the
catalytic process.
e
f
10 mmol scale. Reaction time: 4 h. Reaction time: 16 h.
g
Temperature: 50 °C.
reaction of 1a and 2a under standard conditions, and 3a was
isolated in 75% yield, which promised this synthetic method as a
useful tool in practical synthetic contexts.
We then examined an array of α-diazo-β-ketoester coupling
partners (Scheme 4). 1-Methyl-1-phenylhydrazine (1a) was
a,b
Scheme 4. Substrate Scope of α-Diazo-β-ketoesters
In our previous work, the mechanism of C−H activation step
of 1-alkyl-1-phenylhydrazine substrates was well investigated.16a
Based on this understanding and the observations in the
mechanism studies, we proposed a mechanism of this reaction
in Scheme 6 using 1a and 2a as the model reactants. Initially, the
rhodium catalyst dimer experienced a ligand exchange to form a
reactive acetate rhodium species. It then coordinated the amino
group of the substrate 1a and activated the ortho C−H bond of
Scheme 6. Proposed Mechanism
a
Conditions: 1a (0.25 mmol, 1 equiv), 2b−l (1.1 equiv), MeOH (1
b
c
mL). Isolated yields. Temperature: 50 °C.
adopted as the C−H activation substrate. Phenyl substitutions on
the keto group were first studied. p-Methyl (2c), p-fluoro (2d),
and p-methoxy (2g) substituents invariably gave a ∼80% yield.
Simple phenyl (2b) and p-bromo (2f) phenyl substitutions also
achieved good yields above 60%. However, with the change of
substituent to either p-chloro (2e) or p-methoxycarbonyl (2h),
the yield dropped to below 60%. Fortunately, with the
adjustment of temperature to 50 °C, these coupling reactants
attained excellent yields up to 90%. Other aromatic substitutions,
including furyl (2i), thienyl (2j), and naphthyl (2k), were also
compatible in this reaction. The furyl and naphthyl ones offered
excellent ∼90% yields. However, likely due to the strong
C
DOI: 10.1021/acs.orglett.6b02103
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Organic Letters
Letter
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compound 2a formed a carbene species, bound to rhodium atom,
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ASSOCIATED CONTENT
* Supporting Information
■
S
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Experimental procedure, characterization of the products
(PDF)
1H and 13C NMR spectra of selected products (PDF)
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AUTHOR INFORMATION
Corresponding Author
■
*E-mail: jinz@nju.edu.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We gratefully acknowledge support from the National Natural
Science Foundation of China (21425415, 21274058) and the
National Basic Research Program of China (2015CB856303).
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