Direct C-H Cyanoalkylation of Quinoxalin-2(1H)-ones via Radical C-C Bond Cleavage

Article abstract of DOI:10.1021/acs.orglett.7b03984

An efficient synthesis of cyanoalkylated heteroarenes via iron-catalyzed direct C-H cyanoalkylation of heteroarenes has been developed. Structurally diverse cyanoalkyl motifs generated through C-C bond cleavage of cyclobutanone oxime esters have been intr

Full text of DOI:10.1021/acs.orglett.7b03984

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Direct C−H Cyanoalkylation of Quinoxalin-2(1H)‑ones via Radical
C−C Bond Cleavage
Lin Yang, Pin Gao, Xin-Hua Duan, Yu-Rui Gu, and Li−Na Guo*
Department of Chemistry, School of Science, and MOE Key Laboratory for Nonequilibrium Synthesis and Modulation of Condensed
Matter, Xi’an Jiaotong University, Xi’an 710049, China
S
* Supporting Information
ABSTRACT: An efficient synthesis of cyanoalkylated heteroarenes via iron-catalyzed direct C−H cyanoalkylation of
heteroarenes has been developed. Structurally diverse cyanoalkyl motifs generated through C−C bond cleavage of cyclobutanone
oxime esters have been introduced into quinoxalin-2(1H)-ones, flavone, benzothiazoles, and caffeine in good to excellent yields.
Remarkably, less-strained cyclopentanone and unstrained cyclohexanone oxime esters were also amenable substrates in this
cyanoalkylation reaction.
bond cleavage process.6 Furthermore, the radical and
uinoxalin-2(1H)-ones are a privileged class of structural
Q motifs found in various bioactive natural products as
palladium-catalyzed ring-opening cleavage of cyclobutanone
well as pharmaceutical compounds.1 Because of their significant
oxime derivatives has emerged as an efficient strategy to
introduce a γ-cyanoalkyl substituent bearing larger aliphatic or
functionalized chains into organic molecules via C−C bond
cleavage.7,8 For instance, Zard and co-workers reported the first
ring opening of cyclobutanone oxime derivatives via a radical
process (Figure 1).7a More recently, some elegant C−C bond
biological properties, chemists have devoted much effort to the
synthesis of these aza-heterocycles.2 One of the traditional
methods involves construction of the heterocyclic ring via an
intermolecular cyclization of 1,2-diaminobenzene and a suitable
partner.2a On the other hand, direct modification of easily
available quinoxalin-2(1H)-ones provides facile alternatives to
more complex molecules.3 In this field, catalytic direct C3−H
functionalization of quinoxalin-2(1H)-ones has emerged as an
attractive approach to 3-substituted quinoxalin-2(1H)-ones,
which usually exhibit significant pharmaceutical properties.3a,c
Recently, several important advances have been reported,
including radical C3−H arylation, phosphonation, amination,
and acylation of quinoxalin-2(1H)-ones. However, C−H
alkylation of quinoxalin-2(1H)-ones is still rare.3 Because of
their importance, it is desirable and in demand to introduce
alkyl substituents, especially those bearing functional groups, at
the 3-position of quinoxalin-2(1H)-ones, which would probably
promote their applications in new drug discovery and
development.1
Cyanoalkyl moieties not only widely exist in a variety of
natural products and pharmaceuticals, but also are a class of
versatile building blocks in organic synthesis.4 Therefore,
efficient incorporation of a cyanoalkyl group into structurally
diverse molecules has attracted much attention.5 Recently, the
radical cyanoalkylation reaction has proven to be a powerful
tool to achieve this goal. For example, simple acetonitrile has
been developed as an efficient cyanomethyl precursor in many
radical cross-coupling and cyclization reactions through a C−H
Figure 1. Generation of iminyl radicals via C−C bond cleavage.
cleavages of cyclobutanone oxime derivatives have been
established by transition metal or photoredox catalysis.7c−j In
this field, our group disclosed a Ni-catalyzed cyanoalkylation of
heteroaromatic N-oxides and quinones.9a In addition, we also
demonstrated that the γ-cyanoalkyl radicals generated from
cyclobutanone oxime esters can react efficiently with activated
alkenes, furnishing cyanoalkylated oxindoles and dihydroqui-
Received: December 22, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b03984
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
nolin-2(1H)-ones.9b Compared with extensive α-cyanoalkyla-
tion reactions, γ-cyanoalkylation reactions have been less
exploited at present.5 Herein we report a simple and efficient
Fe-catalyzed C−H cyanoalkylation of quinoxalin-2(1H)-ones
with cyclobutanone oxime esters.
Scheme 1. Scope of Quinolin-2(1H)-ones
Initially, quinoxalin-2(1H)-one 1a and cyclobutanone
pentafluorobenzoyl oxime 2a were chosen as model substrates
to optimize the reaction conditions (Table 1).10 When the
a
Table 1. Optimization of the Reaction Conditions
b
entry
deviation from above
yield (%)
1
2
15 mol % FeCl2 as the catalyst
15 mol % Fe(OAc)2 as the catalyst
15 mol % FeSO4·7H2O as the catalyst
15 mol % Fe powder as the catalyst
15 mol % Cu(acac)2 as the catalyst
15 mol % Ni(acac)2 as the catalyst
1,4-dioxane as the solvent
80
72
85
75
65
15
90
87
90
36
trace
3
4
5
6
7
8
CH3NO2 as the solvent
9
EtOH as the solvent
10
11
DMF as the solvent
a
An inseparable 1:1 mixture of 6- and 7-methylquinoxalin-2(1H)-ones
without catalyst
was used as the substrate.
a
Reaction conditions: 15 mol % catalyst, 1a (0.45 mmol 1.5 equiv), 2a
b
(0.3 mmol, 1.0 equiv), CH3CN (1.5 mL), 100 °C, 18 h, N2. Yields of
isolated products.
converted to the desired product 3m in 61% yield. Notably, the
representative quinolin-2(1H)-one N,6-dimethylquinolin-
2(1H)-one (1n) also led to the anticipated product 3n in
60% yield. Satisfactorily, treatment of 2-phenylchromen-4-one
(1o) with 2a delivered the desired product 3o in 40% yield.
Next, we turned our attention to investigate the cyanoalky-
lation of quinoxalin-2(1H)-one 1a with various cyclobutanone
oxime esters 2 (Scheme 2). A variety of cyclobutanone oxime
esters containing aryl, benzyl, and alkyl groups at the 3-position
reacted well to give the target products 4a−f in good to
excellent yields. It is noteworthy that 3-cyano, carbamate
(NHBoc), and benzyloxy cyclobutanone oxime esters also
survived well, leading to the desired products 4g−i in good
yields. In addition, 3,3-disubstituted oxime esters also
participated well in this reaction, affording the desired products
4j and 4k in 72% and 81% yield, respectively. The substrate
derived from oxetan-3-one was also amenable, producing the
desired product 4l in 48% yield. Notably, the reaction of 1a
with 2,3-disubstituted cyclobutanone oxime ester 2n gave the
desired product 4m in moderate yield with excellent
regioselectivity.
Furthermore, oxime esters derived from norcamphor and
tricyclo[5.2.1.0(2,6)]decan-8-one also gave the desired prod-
ucts 6a and 6b in 74% and 62% yield, respectively (Scheme 3).
Remarkably, cyclopentanone oxime ester 5c without any
substituent at the α-position also successfully delivered the
cyanoalkylated product 6c in 52% yield, representing a rare
example of ring-opening/coupling of less-strained cyclo-
pentanone oxime esters.7,8 Inspired by these results, we tried
to exploit the feasibility of the more challenging unstrained
cyclohexanone oxime ester. To our delight, simple oxime ester
5d was also applicable, leading to the expected product 6d,
albeit in low yield (Scheme 3). For cyclopentanone and
model reaction was carried out using 15 mol % Fe(acac)2 as the
catalyst in MeCN at 100 °C for 18 h, the desired 3-
cyanopropylated product 3a was isolated in 93% yield. Then
a variety of iron catalysts, including FeCl2, Fe(OAc)2, FeSO4·
7H2O, and Fe powder, were tested for this reaction. All of these
iron catalysts were effective but gave lower yields than
Fe(acac)2 (Table 1, entries 1−4). During the catalyst screening,
we found that Cu(acac)2 afforded a 65% yield of 3a, but
Ni(acac)2 gave only a 15% yield of 3a (entries 5 and 6). Next,
other reaction parameters were surveyed. Among the solvents
tested, 1,4-dioxane, CH3NO2, and EtOH were suitable, whereas
DMF proved to be less effective (entries 7−10). Furthermore,
O-acyl oximes bearing different protecting groups, including
BzO, 4-FBzO, and 4-NO2BzO, were also examined, but all of
them resulted in somewhat low yields (see Table S1 in the
Supporting Information). Finally, a control experiment revealed
that only a trace amount of 3a was formed in the absence of
iron catalyst (entry 11).
After the optimal conditions were determined, we first
examined the substrate scope of quinoxalin-2(1H)-ones 1 with
oxime ester 2a (Scheme 1). Various quinoxalin-2(1H)-ones
bearing electron-donating and electron-withdrawing groups on
the aromatic rings engaged in this reaction efficiently, affording
the corresponding 3-cyanopropylated products 3b−i in
moderate to good yields. A series of functional groups
including fluoro, chloro, bromo, nitro, and ester were well-
tolerated under the optimal conditions. Besides the methyl
group, substrates with other protecting groups such as n-propyl,
benzyl, and acetate groups were also efficient substrates,
furnishing the corresponding products 3j−l in 49−74% yield.
N-Unsubstituted quinoxalin-2(1H)-one was also successfully
B
DOI: 10.1021/acs.orglett.7b03984
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Organic Letters
Letter
Scheme 2. Scope of Cyclobutanone Oxime Esters
Scheme 4. Synthesis of 3a on a Gram Scale and Direct C−H
Cyanoalkylation of Benzothiazoles and Caffeine
68% yield, respectively. 3-Cyanoalkylated caffeine 10a was
obtained in 49% yield under the modified conditions.
Finally, several control experiments were performed to gain
insight into the reaction mechanism. Radical trapping experi-
ments were conducted first by addition of TEMPO or BHT to
the reaction of 1a and 2a, respectively (eqs 1 and 2). Addition
Scheme 3. Ring Opening of Cyclopentanone and
Cyclohexanone Oxime Esters
of TEMPO (1.0 equiv) significantly suppressed this cyanoalky-
lation reaction, and the cyanoalkyl-TEMPO adduct 11a was
isolated in 64% yield. Moreover, the radical inhibitor BHT (1.0
equiv) also led to an obvious decrease in the isolated yield.
These results indicate that radical intermediates are involved in
this transformation. On the other hand, radical clock
experiments were designed and performed. Treatment of
cyclobutanone oxime esters 12a and 12b containing double
bonds with 1a delivered the ring-closing products 13a and 13b
in 53% and 65% yield, respectively (eqs 3 and 4). These results
are in favor of radical pathway for this transformation.
However, the spirocyclic substrate 12c afforded the product
13c in 89% yield with no ring-expanded product observed (eq
5). A possible mechanism is proposed in Scheme 5. First,
single-electron reduction of 2a by Fe(II) affords iminyl radical
I, which is transformed into cyanoalkyl radical II through C−C
bond cleavage.7 Subsequently, radical addition of II to 1a leads
to radical intermediate III, which undergoes single-electron
oxidation by Fe(III) followed by loss of H+ to afford the
product 3a.
cyclohexanone oxime esters 5c and 5d, FeSO4·7H2O gave
better yields than Fe(acac)2.
To further demonstrate the applicability of this cynoalkyla-
tion reaction, a gram-scale reaction was carried out under the
standard conditions (Scheme 4). Satisfactorily, the reaction of
1a and 2a proceeded smoothly to afford the target product 3a
in 80% isolated yield. Furthermore, the C−H bonds of
benzothiazole and caffeine could also be directly cynoalkylated
by using Fe(OTf)3 instead of Fe(acac)2 as the catalyst.
Treatment of benzothiazoles 7a and 7b with 2a gave the
corresponding 2-cynoalkylated products 8a and 8b in 69% and
C
DOI: 10.1021/acs.orglett.7b03984
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Letter
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S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b03984.
Experimental procedures and spectroscopic data for new
compounds (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: guoln81@xjtu.edu.cn.
ORCID
Li−Na Guo: 0000-0002-9789-6952
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support from the Natural Science Basic Research Plan
in Shaanxi Province of China (2016JZ002), the National
Natural Science Foundation of China (21602168), and the
Fundamental Research Funds of the Central Universities
(zrzd2017001, xjj2016056, and 1191329724) is greatly
appreciated.
(9) (a) Gu, Y.-R.; Duan, X.-H.; Yang, L.; Guo, L.-N. Org. Lett. 2017,
19, 5908. (b) Wu, J.; Zhang, J.-Y.; Gao, P.; Xu, S.-L.; Guo, L.-N. J. Org.
Chem. 2018, 83, 1046.
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DOI: 10.1021/acs.orglett.7b03984
Org. Lett. XXXX, XXX, XXX−XXX