A general method to diverse cinnolines and cinnolinium salts

Article abstract of DOI:10.1002/chem.201300155

Rhodium catalysis: A highly efficient and general method has been established to prepare cinnolines, cinnolinium salts, and polycyclic cinnolinium salts through the rhodium(III)-catalyzed oxidative C-H activation/cyclization of azo compounds with alkynes (see scheme). Key features of this methodology include the unprecedented capacity to create both cinnoline and cinnolinium frameworks. Copyright

Full text of DOI:10.1002/chem.201300155

COMMUNICATION
DOI: 10.1002/chem.201300155
A General Method to Diverse Cinnolines and Cinnolinium Salts
Dongbing Zhao, Qian Wu, Xiaolei Huang, Feijie Song, Taiyong Lv, and Jingsong You*[a]
Cinnolines and cinnolinium salts represent pharmaceuti-
cally and biologically important structures with anticancer,
antimicrobial, antiinflammatory, antiparasitic, trypanocidal,
and foliar herbicide activities as well as structural motifs
with optical and luminescent characteristics (Scheme 1).[1,2]
Very recently, two significant contributions were made for
the synthesis of cinnolines independently by Willis and Ge.[4]
Willis et al. disclosed a two-step reaction sequence for the
synthesis of cinnolines through the copper-catalyzed annula-
tion of 2-(2-bromoalkenyl)aryl bromide with diethyl-1,2-hy-
drazinedicarboxylate and subse-
quent aromatization (Scheme 2,
route B).[4a] Ge et al. developed
the copper-catalyzed intramo-
lecular dehydrogenative cycliza-
tion of N-methyl-N-phenylhy-
drazones to give cinnolines
3
À
through sequential
C
N
oxidation, cyclization, and aro-
matization (Scheme 2, rou-
te C).[4b] However, both of
these catalytic methods were
not yet extended to the prepa-
ration of cinnolinium salts.
Compared with cinnolines, the
synthesis of cinnolinium salts is
less developed. Traditionally, 2-
alkylcinnolinium salts could be
synthesized by alkylation of the
corresponding cinnolines, which
frequently leads to a mixture of
1-
and
2-alkylcinnolinium
Scheme 1. Selected pharmaceutically and biologically active molecules and photoelectric materials with the
cinnoline or cinnolinium structural motif.
salts.[5] However, 2-arylcinnoli-
nium salts cannot be obtained
by direct N-arylation of cinno-
However, accessible and efficient synthetic methods for
these privileged structures are surprisingly under-represent-
ed. Traditional strategies for the preparation of cinnolines
usually suffer from limited substrate scope and nontrivial
multistep reaction sequences (Scheme 2, route A).[3]
lines.[6] To the best of our knowledge, there is still no transi-
tion-metal-catalyzed version describing the formation of cin-
nolinium salts. In particular, none of the previously reported
routes have a singularly high capacity for the synthesis of
both cinnolines and cinnolinium salts. Undoubtedly, the de-
velopment of a general and efficient route to both cinno-
lines and cinnolinium salts with easily tunable substitution
patterns is highly warranted to enable a set of diverse scaf-
folds.
[a] Dr. D. Zhao,+ Q. Wu,+ X. Huang, Dr. F. Song, T. Lv, Prof. Dr. J. You
Key Laboratory of Green Chemistry and Technology of Ministry
of Education, College of Chemistry, and State Key Laboratory
of Biotherapy, West China Medical School
Sichuan University, 29 Wangjiang Road
In recent years, it has become increasingly important to
construct various heterocycles by transition-metal-catalyzed
À
(including Pd, Rh, Ru, etc.) ortho-directed C H bond acti-
Chengdu 610064 (P. R. China)
Fax : (+86)28-85412203
E-mail: jsyou@scu.edu.cn
vation and subsequent functionalization to the directing
groups.[7–9] By using different types of imines as the directing
[+] These authors contributed equally to this work.
group, Fagnou, Chiba, and Cheng et al. have independently
III
À
developed versatile Rh -catalyzed chelation-assisted C H
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201300155.
bond activation strategies to synthesize isoquinolines[8k,p]
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that 10 mol% of Ag2CO3 in
combination with NaBF4
(2.0 equiv) as the counteranion
could afford 3a in 96% yield
by using CuACHTNUTRGNE(NUG OAc)2 (2.0 equiv)
as the oxidant (Table 1 and
Table S1, entry 11 in the Sup-
porting Information).
The counteranions are critical
for regulating the properties of
quaternary ammonium salts,
such as melting point, density,
viscosity, solubility, fluorescence
characteristics, and electrocon-
ductivity.[11] Thus, it stimulated
us to develop a concise route to
the cinnolinium salts with dif-
ferent counteranions. Gratify-
ingly, the coupling of azoben-
zene (1a) with diphenylacety-
lene (2a) could smoothly give
the cinnolinium salts 3 with di-
verse counteranions, such as
BF4 , NO3 , NTf2 , SbF6 , and
OTfÀ through an extra addition
of stoichiometric alkali metal
salts with different anions
(Table 1). Notably, the nitrate
salt 3b has excellent water solu-
bility, which may offer a pre-
condition for the application in
biological systems.
Scheme 2. Existing routes for the formation of cinnolines. PG=protecting group.
À
À
À
À
Scheme 3. RhIII-catalyzed C H bond activation strategy to isoquinolines, isoquinolinium salts, cinnolines, and
cinnolinium salts.
À
and isoquinolinium salts[8t] (Scheme 3). However, the utility
of this concept for the synthesis of cinnolines and cinnolini-
um salts has not yet been documented. Along the same
lines, we envisioned that we could develop a general route
to diverse cinnolines and cinnolinium salts with complete
control of the substituent pattern through the rhodiumACTHUNTGRNEUNG(III)-
À
catalyzed oxidative C H activation/cyclization of azo com-
pounds with various alkynes (Scheme 3).
Our initial investigation focused on the coupling of azo-
benzene (1a) with diphenylacetylene (2a; for screening of
reaction conditions, see Table S1 in the Supporting Informa-
tion). The cinnolinium salt 3a was obtained in 98% isolated
yield in the presence of [RhCl
(2.0 mol%), AgBF4 (1.0 equiv), and CuAHCUTNGTRENNUNG
(Cp*)]2 (Cp*=C5Me5)
(OAc)2 (1.0 equiv) in
tert-amyl alcohol at 1108C for 3 h (see Table S1, entry 4 in
the Supporting Information). The structure of 3a was con-
firmed to contain a cinnolinium cation and a tetrafluorobo-
rate anion by single-crystal X-ray analysis (Figure 1).[10] Con-
sidering the high cost of the silver source, we envisioned
whether the amount of AgBF4 could be reduced to the sub-
stoichiometric level. Subsequently, we were pleased to find
Figure 1. ORTEP diagrams of 3a, 4r, and 6 f. Thermal ellipsoids are
shown at the 50% probability level.
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A General Method to Diverse Cinnolines and Cinnolinium Salts
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Table 1. Preparation of the cinnolinium salts 3 with different counteranions.[a]
zation, and desilylation [Eq. (1)]. The previous re-
search demonstrated that the reaction failed when
bis(trimethylsilyl)acetylene was reacted with the cy-
clopalladated azobenzene complexes.[6]
To further establish the validity of the methodol-
ogy, we tried to synthesize neutral cinnolines. After
extensive efforts we found that treatment of N-tert-
butyl-aryldiazene with the dialkyl-substituted
alkyne gave 3,4-dialkyl-substituted cinnolines
(Table 4, 6a–d). However, surprisingly we found
that N-tert-butyl-aryldiazene could not give the de-
sired neutral cinnolines when diaryl alkynes were
[a] MX: NaBF4, NaNO3, LiNTf2, NaSbF6, or NaOTf. Tf=trifluoromethanesulfonyl,
t-AmylOH=tert-amyl alcohol.
Subsequently, we examined the scope of internal alkynes
and azo compounds in the oxidative cross-coupling/cycliza-
tion. Overall, we were pleased with the generality of this
method. As shown in Table 2, various azo compounds and
internal alkynes proceeded smoothly to afford the desired
À
cinnolinium salts in satisfactory yields. For example, the re-
actions occurred preferentially at the more sterically accessi-
ble position when a meta-substituent was attached to the
phenyl ring of the azo compounds (Table 2, 4a). The aryl
group was installed at the 3-position of the cinnolinium salts
when an unsymmetrical alkyl aryl alkyne was employed
(Table 2, 4r and 4s). The structure of 4r was confirmed by
an X-ray analysis of single crystals (Figure 1).[10] The synthe-
sis of unsymmetrical 3,4-bis(aliphatic)-substituted cinnolini-
um salts is a challenging task. It is important to stress that
the reaction of an enyne with an azobenzene exclusively
yielded the 3-alkenyl cinnolinium regioisomer under the op-
timized reaction conditions (Table 2, 4u), which could offer
an opportunity to unsymmetrical 3,4-bis(aliphatic)-substitut-
ed cinnolinium salts through a simple hydrogenation. In par-
ticular, this method was remarkably compatible with a varie-
ty of important functional groups such as halogens, hydrox-
yl, ester, acetyl, nitrile, and methoxy groups, which could be
subjected to further synthetic transformations (Table 2, 4b–
h, 4j–m, 4p, and 4t).
employed as the substrate. Instead, the sequential C H acti-
À
vation/cyclization/C H activation/cyclization cascade occur-
red to afford a variety of 5,6,13-trisubstituted isoquinolino-
AHCTUNGTREG[NNUN 2,1-b]cinnolinium tetrafluoroborates (Table 4, 6e–g), which
were confirmed by an X-ray analysis of single crystals of 6 f
(Figure 1).[10] These novel polycyclic cinnolinium salts would
find potential applications in materials science.
To afford the structurally diverse neutral cinnolines, we
tried to remove the alkyl group from 2-alkyl cinnolinium
salts. Upon treatment of the 2-methyl cinnolinium salt 4i in
pyridine at 1408C, the corresponding 3,4-diphenyl cinnoline
7a was obtained in 96% yield (Table 5). According to this
method, we obtained various cinnolines including 3,4-diaryl-
substituted, 3-aryl-4-alkyl-substituted, and monosubstituted
cinnolines, which constituted an unprecedented route to
neutral cinnolines with diverse substituent patterns incorpo-
rated and demonstrates the high-throughput of the method-
ology.
Although a more detailed investigation of the reaction
mechanism is currently underway, we proposed a plausible
catalytic cycle illustrated in Scheme 4.[8] The catalytic pro-
One of the commonly encountered limitations of the ex-
isting rhodium-catalyzed oxidative synthesis of N-heterocy-
cles is the difficulty to incorporate terminal alkynes. As a
result, it is challenging to construct monosubstituted hetero-
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
lowed by coordination with an azo compound to generate
cycles. Fortunately, the terminal alkynes, such as phenyl
ACHTUNGTNERaNUNG cet-
ACHTUNGTRENNUNGylene, could undergo this type of oxidative cross-coupling/
cyclization with azo compounds to give the monosubstituted
cinnolinium salts 5 while the solvent was changed to di-
chloroethane (DCE) and the reaction time was prolonged
to 20 h in the presence of stoichiometric AgBF4. As shown
in Table 3, both alkyl and aryl-substituted terminal alkynes
gave the desired cinnolinium salts in yields of 75–83%. In
addition, the regioselectivity of insertion was highly predict-
able with the terminal end located at the 4-position of cin-
nolinium salts.
To our delight, our synthetic strategy could be applied to
the synthesis of 3,4-unsubstituted 2-arylcinnolinium salts by
the reaction of azobenzene with 1,2-bis(trimethylsilyl)-
À
Scheme 4. Proposed mechanism for the RhIII-catalyzed synthesis of cin-
nolinium salts.
ACHTUNGTRENNUNGethyne, which underwent a sequential C H activation, cycli-
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Table 2. Scope of internal alkynes and azo compounds in the oxidative
cross-coupling/cyclization.[a]
Table 3. Reactions of azo compounds with terminal alkynes.
Table 4. Preparation of neutral cinnolines and polycyclic cinnolinium
salts by starting from N-tert-butyl-aryldiazene.[a]
[a] For the detailed reaction conditions, see the Supporting Information.
Table 5. Demethylation of 2-methyl cinnolinium salts to diverse cinno-
lines.
[a] Reactions were carried out by using [RhCl
2ACHTUNGTREN(NNUG Cp*)]2 (2.0 mol%), Cu-
ACHTUNGTRENNUNG
pound (0.30 mmol), and internal alkyne (0.25 mmol) in t-AmylOH
(1.5 mL) at 1108C for 16 h.
the five-membered rhodacycle intermediate A through an
À
ortho-directed C H bond activation. Subsequently, the
seven-membered rhodacycle intermediate C was formed
À
C H activation/cyclization of azo compounds with alkynes,
through regioselective insertion of an alkyne into the rhodi-
which exhibits an unprecedented capacity to install versatile
functional groups at various positions of the cinnoline ring.
The catalytic protocol can be extended to synthesize polycy-
2
(sp2) bond
À
um–carbon bond of the intermediate B. C
(sp ) N
reductive elimination of C gave the cinnolinium salt and RhI
À
species, which was oxidized by Cu
(OAc)2 to regenerate the
clic cinnolinium salts through twice ortho-directed C H acti-
RhIII species.
vation and cyclization. In this work, we have overcome a
series of barriers: 1) the obstacle for establishing the catalyt-
ic cycle due to the high stability and general unreactivity of
the cyclometalated azobenzene complexes,[6] 2) the installa-
In summary, we have developed a highly efficient and
general method to create both cinnoline and cinnolinium
frameworks through the rhodiumACTHNUGRTNEUNG(III)-catalyzed oxidative
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[6] Heck and co-workers reported the synthesis of 2-arylcinnolinium
salts through the cyclization of alkynes with cyclopalladated azoben-
zene complexes. However, the catalytic version of the reaction proc-
ess could not be established, see: G. Wu, A. L. Rheingold, R. F.
Heck, Organometallics 1987, 6, 2386.
tion of a facile leaving group as one N-substitutent of azo
compounds to afford the neutral cinnolines, 3) the regiose-
À
lectivity control including the activation of aryl C H bonds
and the insertion of unsymmetrical alkynes, 4) the hindrance
of insertion of terminal alkynes, and 5) the competitive reac-
tion from the rhodium-catalyzed addition of alkynes with
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Acknowledgements
This work was supported by the National Basic Research Program of
China (973 Program, 2011CB808600), and grants from the National NSF
of China (nos. 21025205, 21272160, and 21021001). We thank the Centre
of Testing & Analysis, Sichuan University for NMR spectroscopic meas-
urements.
Keywords: catalysis
· cinnolines · cinnolinium salts ·
heterocycles · rhodium
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Received: January 16, 2013
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A General Method to Diverse Cinnolines and Cinnolinium Salts
COMMUNICATION
Heterocycles
D. Zhao, Q. Wu, X. Huang, F. Song,
T. Lv, J. You* ................. &&&& — &&&&
Rhodium catalysis: A highly efficient
and general method has been estab-
lished to prepare cinnolines, cinnoli-
nium salts, and polycyclic cinnolinium
tion of azo compounds with alkynes
A General Method to Diverse Cinno-
lines and Cinnolinium Salts
(see scheme). Key features of this
methodology include the unprece-
dented capacity to create both cinno-
line and cinnolinium frameworks.
salts through the rhodiumACTHNUTRGNE(NUG III)-cata-
À
lyzed oxidative C H activation/cycliza-
Chem. Eur. J. 2013, 00, 0 – 0
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
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These are not the final page numbers!