Multicomponent Coupling Cyclization Access to Cinnolines via in Situ Generated Diazene with Arynes, and α-Bromo Ketones

Article abstract of DOI:10.1021/acs.orglett.5b03236

A transition-metal-free multicomponent coupling cyclization reaction was explored involving arynes, tosylhydrazine, and α-bromo ketones. The reaction proceeds via a formal [2 + 2 + 2] cycloaddition, giving access to cinnoline derivatives in moderate yields under mild conditions. Three chemical bonds were formed-two C-N bonds and one C-C bond-in a single step.

Full text of DOI:10.1021/acs.orglett.5b03236

Letter
pubs.acs.org/OrgLett
Multicomponent Coupling Cyclization Access to Cinnolines via in
Situ Generated Diazene with Arynes, and α‑Bromo Ketones
Wen-Ming Shu, Jun-Rui Ma, Kai-Lu Zheng, and An-Xin Wu*
Key Laboratory of Pesticide & Chemical Biology, Ministry of Education, College of Chemistry, Central China Normal University,
Hubei, Wuhan 430079, P. R. China
S
* Supporting Information
ABSTRACT: A transition-metal-free multicomponent cou-
pling cyclization reaction was explored involving arynes,
tosylhydrazine, and α-bromo ketones. The reaction proceeds
via a formal [2 + 2 + 2] cycloaddition, giving access to
cinnoline derivatives in moderate yields under mild conditions.
Three chemical bonds were formedtwo C−N bonds and
one C−C bondin a single step.
Scheme 1. Strategic Access to Cinnolines
n the past decades, arynes have emerged as powerful synthons
widely used in the synthesis of heterocycles and complex
I
natural products.1 This is mainly because of the introduction of
2-(trimethylsilyl)aryl triflates as aryne precursors, which allow
arynes to be generated under mild and easily controlled
conditions, such as treatment with fluoride.2 Arynes can also
proceed to various chemical reactions, including nucleophilic
addition,3 cycloaddition,4 annulation,5 coupling,6 insertion,7 and
others.8 When transition metals, such as palladium and nickel,
were introduced into benzyne chemistry, many unprecedented
transformations (such as [2 + 2 + 2] cycloaddition) were quickly
developed.9
Cinnoline is an important nitrogen-containing heterocyclic
compound, and its derivatives exhibit widespread potent
biological and pharmaceutical activities, such as inhibitory
activity toward CSF-1R, inhibited ulceration, anti-inflammatory,
antitumor, and anticancer activity (Figure 1).10
As cinnoline analogues exhibit superior properties, there are
various approaches for the synthesis of cinnolines.11 In recent
years, Ge and co-workers reported distinguished work for the
synthesis of cinnolines by copper-catalyzed aerobic dehydrogen-
ative cyclization (Scheme 1a).12 In addition, the You group
developed a general route to cinnolines through the rhodium-
catalyzed oxidative C−H activation/cyclization reaction
(Scheme 1b).13 Furthermore, Willis and co-workers exploited a
copper-catalyzed tandem C−N bond formation reaction for the
efficient synthesis of functionalized cinnolines (Scheme 1c).14
More recently, Reddy and co-workers developed a directed C−H
activation strategy for the synthesis of benzo[c]cinnolines
through a sequential C−C and C−N bond formation.15 Herein,
a transition-metal-free multicomponent coupling cyclization
reaction was developed for direct access to cinnolines (Scheme
Received: November 9, 2015
Figure 1. Selected biologically active cinnoline derivatives.
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b03236
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Letter
a
1d). Advantages of this method include the use of commercially
available starting materials, mild reaction conditions, and the
formation of three chemical bonds in a single step.
Scheme 2. Scope of α-Bromo Ketones
Our initial investigations of this new route to cinnolines
focused on the three-component reaction of 2-(trimethylsilyl)-
phenyl triflate (1a) and tosylhydrazine (2) with α-bromoaceto-
phenone (3a). The desired product, 3-phenylcinnoline (4aa),
was furnished with 34% yield when the reaction proceeded in the
presence of 3.0 equiv of CsF at 80 °C for 3 h in CH3CN (entry 1).
Encouraged by the aforementioned result, other reaction
conditions were investigated, and the results are summarized in
Table 1. First, the amount of CsF was examined (entries 1−4).
a
Table 1. Optimization of the Reaction Conditions
b
entry
solvent
CsF (equiv)
temp (°C)
yield (%)
1
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
dioxane
THF
3
5
6
8
8
8
8
8
8
8
8
8
8
8
80
80
80
80
rt
34
2
46
3
57
4
63
a
Reactions were carried out with 1a (0.5 mmol, 1.0 equiv), 2 (0.75
mmol, 1.5 equiv), 3 (0.5 mmol, 1.0 equiv), and CsF (8.0 equiv) in the
CH3CN (4 mL) at 90 °C for 3 h in a sealed tube. Isolated products.
5
24
6
40
60
70
90
80
70
80
80
80
46
7
51
8
60
detected. In addition, when the substituents were heterocyclic
(2-benzofuryl) and alkyl (methyl) groups, the desired products
4an and 4ao were not afforded. The structure of 4aa was
identified by single-crystal X-ray diffraction (see Supporting
Information (SI)).
9
69
trace
27
10
11
12
13
14
DCE
trace
35
toluene
EtOAc
Encouraged by the results described above, the scope of 2-
(trimethylsilyl)aryl triflates (1) was subsequently examined
(Scheme 3). First, symmetrically substituted aryne precursor
14
a
Reaction conditions: 1a (0.1 mmol, 1.0 equiv), 2 (0.15 mmol, 1.5
equiv), 3a (0.1 mmol, 1.0 equiv), CsF (0.8 mmol, 8.0 equiv), and
solvent (2 mL) for 3 h in a sealed tube. Isolated yields.
b
a
Scheme 3. Scope of 2-(Trimethylsilyl)aryl Triflates
The desired product 4aa was satisfactorily afforded in 63% yield
when 8.0 equiv of CsF were used in CH3CN at 80 °C (entry 4).
Additionally, lowering the reaction temperature did not increase
the yields of 4aa (entries 5−8). However, increasing the
temperature to 90 °C resulted in the best yield (entry 9).
Subsequently, various solvents were screened, revealing that
CH3CN was the best choice for the reaction. A satisfactory yield
of the desired product 4aa was not obtained in other solvents
(dioxane, THF, DCE, toluene, and EtOAc) (entries 10−14).
After optimizing the reaction conditions, we explored the
substrate scope of α-bromo ketones (3), as shown in Scheme 2. It
is noteworthy that the electronic properties of the substituents
on the aromatic ring system were shown to have a significant
influence on the efficiency of this transformation. The α-bromo
ketones bearing electron-neutral (H), electron-donating (4-Me,
3-OMe, 4-OMe), and halo-substituted (4-F, 3-Cl, 4-Cl, 3,4-2Cl,
4-Br) groups attached to the benzene ring transformed smoothly
into corresponding products in moderate to good yields (56%−
70%; 4aa−4ai). Much to our satisfaction, β-naphthyl and
biphenyl group substrates were also compatible, giving the
expected products 4al and 4am in 69% and 43% yield,
respectively. However, the electron-withdrawing groups (4-
CN, 4-NO2) have a negative effect on this reaction, and the
desired product 4aj had a low yield (48%), and 4ak was not
a
Isolated products.
1b was explored, and the corresponding product 4ba was
obtained in moderate yield (43%). Moreover, when nonsym-
metrical arynes derived from precursors 1d and 1e were used in
the annulation, the products 4da/4da′ and 4ea/4ea′ were
afforded as a mixture of two isomers in good yields (61% and
66%, respectively). However, the reaction of the 3-methoxy
substituted aryne precursor 1c gained the sole regioisomers, and
B
DOI: 10.1021/acs.orglett.5b03236
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Letter
the corresponding products 4ca−4cf were obtained in 35%−
57% yields.
Scheme 5. A Possible Mechanism
To gain insight into the reaction process, control experiments
were performed (Scheme 4). The reaction of benzyne precursor
a
Scheme 4. Control Experiments
8 could be reduced by diazene A, transforming into
diphenylhydrazine 7.18,21
a
Isolated products.
We further explored the application of cinnolines in organic
synthesis as shown in Scheme 6 (4aa as an example). 3-
1a with tosylhydrazone 516,17 did not afford the target product
4aa under standard conditions. This result identified that
compound 5 may not be the intermediate for this reaction (eq
1). Furthermore, the reaction between 1a and 2 proceeded
smoothly to give 1-methyl-4-(phenylsulfonyl)benzene 6 in 75%
yield together with small amounts of diphenylhydrazine 7 (12%)
(eq 2). When 3.0 equiv of 1a and 1.0 equiv of 2 participated in
this reaction, the main product was also compound 6 with a trace
of 7 and a small quantity of (E)-1,2-diphenyldiazene 8 (7%) (eq
3). Moreover, the compound 8 could be reduced to 7 in 52%
yield in the presence of tosylhydrazine 2 (eq 4). It was proven
that diazene could be in situ generated in this reaction. In
addition, other α-halo ketones have also been checked under
standard conditions. The desired product 4aa was not afforded
when using α-chloroacetophenone 9 as a substrate (eq 5).
However, the product 4aa was obtained in 38% yield in the
presence of α-iodoacetophenone 10 (eq 6).
a
Scheme 6. Synthetic Application (4aa as an Example)
a
Isolated products.
Phenylcinnoline 4aa transformed into 3-phenylcinnolin-4-ol 12
in moderate yield (59%) through three-step reactions.10a Certain
literature10a,d indicates that the cinnolin-4-ols are also very useful
building blocks for the construction of pharmacologically active
cinnoline derivatives.
On the basis of the above-mentioned experimental results, a
possible reaction mechanism for this reaction is proposed as
shown in Scheme 5 (using 4aa as an example). Initially, 2-
(trimethylsilyl)phenyl triflate 1a furnishes the benzyne 1a′ in the
presence of CsF. Meanwhile, tosylhydrazine 2 decomposes into
the 4-methylbenzenesulfinate anion 11 and intermediate diazene
A in the presence of CsF.18 Subsequently, the diazene A reacts
with benzyne 1a′ and α-bromoacetophenone 3a through a
coupling annulation reaction to afford intermediate B.19 Finally,
intermediate B is converted to the desired product 4aa through
an aromatization reaction with elimination of H2O. On the other
hand, in the absence of 3a, the decomposed 4-methylbenzene-
sulfinate anion 11 and diazene A could capture benzyne 1a′ to
give 1-methyl-4-(phenylsulfonyl)benzene 6, and (E)-1,2-
diphenyldiazene 8, respectively.20 The (E)-1,2-diphenyldiazene
In summary, we have developed a novel transition-metal-free
multicomponent coupling cyclization reaction for the efficient
and convenient synthesis of cinnoline derivatives by simple
treatment with CsF in the absence of catalyst. This method
allows the formation of new C−C and C−N bonds in a single
step. Further studies on this method for the synthesis of other
bioactive compounds and applications are in progress in our
laboratory.
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.5b03236.
C
DOI: 10.1021/acs.orglett.5b03236
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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Experimental procedures, product characterizations,
crystallographic data, and copies of the 1H and 13C
NMR spectra (PDF)
X-ray data for 4aa (CIF)
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AUTHOR INFORMATION
Corresponding Author
■
*E-mail: chwuax@mail.ccnu.edu.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We are grateful to the National Natural Science Foundation of
China (Grants 21272085, and 21472056) for financial support.
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