Isobutyl Nitrite-Mediated Synthesis of Quinoxalines through Double C?H Bond Amination of N-Aryl Enamines

Article abstract of DOI:10.1002/adsc.201800928

An efficient and metal-free double C?H bond amination of N-aryl enamines using isobutyl nitrite (IBN) has been developed. This method enables the preparation of functionalized quinoxalines in good to excellent yields and tolerates a variety of N-aryl enamines with diverse functional substituents. Mechanistic studies revealed the presence of a key β-imino oxime ester intermediate. A quinoxaline derivative could be prepared from β-carbonyl ester in one-pot sequence on a gram scale. Finally, two important quinoxaline scaffolds were easily prepared in moderate yields over two steps. (Figure presented.).

Full text of DOI:10.1002/adsc.201800928

Title:
Isobutyl Nitrite-Mediated Synthesis of Quinoxalines through
Double C−H Bond Amination of N-Aryl Enamines
Authors: Yan-Xiao JIAO, Lin-Su Wei, Chun-Yang Zhao, KAI WEI,
Dong-Liang Mo, Cheng-Xue Pan, and Gui-Fa SU
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201800928
Link to VoR: http://dx.doi.org/10.1002/adsc.201800928

Advanced Synthesis & Catalysis
10.1002/adsc.201800928
UPDATE
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Isobutyl Nitrite-Mediated Synthesis of Quinoxalines through
Double C−H Bond Amination of N-Aryl Enamines
Yan-Xiao Jiao, Lin-Su Wei, Chun-Yang Zhao, Kai Wei, Dong-Liang Mo,* Chen-Xue
Pan,* and Gui-Fa Su*
a
State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources, Ministry of Science and
Technology of China; School of Chemistry and Pharmaceutical Sciences, Guangxi Normal University, 15 Yu Cai Road,
Guilin 541004, China. E-mail: moeastlight@mailbox.gxnu.edu.cn; chengxuepan@163.com; gfysglgx@163.com
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
Abstract. An efficient and metal-free double C−H bond
amination of N-aryl enamines using isobutyl nitrite (IBN)
has been developed. This method enables the preparation of
functionalized quinoxalines in good to excellent yields and
tolerates a variety of N-aryl enamines with diverse
functional substituents. Mechanistic studies revealed the
presence of a key β-imino oxime ester intermediate. A
quinoxaline derivative could be prepared from β-carbonyl
ester in one-pot sequence on a gram scale. Finally, two
important quinoxaline scaffolds were easily prepared in
moderate yields over two steps.
Figure 1. Some Bioactive Quinoxaline-contianing
Compounds
Many elegant strategies have been developed to
prepare quinoxaline scaffolds. However, these
strategies typically use ortho-phenylenediamines or
[3]
ortho-functionalized anilines as starting materials.
C−H amination is an efficient and direct strategy for
the preparation of nitrogen containing compounds,
because it avoids pre-functionalized starting
Keywords: Amination; N-Aryl enamine; C−N Bond
formation; C−H Functionalization; Quinoxaline
[4]
materials.
Many
transition
metal-catalyzed
strategies for the construction of C−N bonds via
[5]
direct C−H functionalization have been developed.
However, metal-free C−H functionalization
approaches are also desirable; these approaches meet
the purity requirements of biological and medicinal
chemistry research, and thereby complement metal-
Quinoxaline is one of the most important nitrogen
heterocyclic scaffolds. It plays an important role in
medicinal chemistry, and commonly occurs in
[6]
catalyzed methods.
Transition metal-catalyzed
pharmaceuticals, because of its good biological
synthesis
of
activity.[
1]
Examples of bioactive quinoxaline-
quinoxalines via C−H amination using diverse
containing compounds include the PDGF receptor
inhibitor, Topo-II poison, and antitumor antibiotics,
such as AG1295, XK469, PAQ, and CQS, which are
shown in Figure 1.[ Strategies for the efficient
preparation of quinoxalines using simple conditions
and readily available starting materials are highly
desirable.
nitrogen reagents has received considerable
[7]
attention. However, only a few metal-free strategies
[8]
have been reported. For example, a 2014 report by
Zhang and co-workers detailed the metal-free
synthesis of 3-trifluoromethylquinoxalines from N-
aryl enamines and nitromethane in a one-pot reaction
2]
[
8a]
(Scheme 1-A).
However, this approach suffered
from complicated additives such as KI, CsOAc and
tert-butyl hydroperoxide, and is run in HOAc at
120 °C.
Me
Me
N
N
N
O
As demonstrated in recent reports, nitrous esters,
COOH
NH2
N
Cl
O
such as tert-butyl nitrite (TBN) and iso-butyl nitrite
(
IBN), are a new type of nitrogen reagent for the
AG1295
XK469
[9]
construction of C−N bonds. In 2014, Jiao’s group
Cl
3
developed a novel metal-free amination of C(sp )–H
H N
N
N
N
2
2
and C(sp )–H bonds. This approach was used to
O
S
prepare 2-quinoxaline N-oxides from N-aryl
N
N
O
ketimines using TBN (3.0 equiv.) in MeCN (Scheme
H
[10]
PAQ
CQS
1-B).
Although this is a simple and efficient
method to construct the quinoxaline N-oxide skeleton,
1
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Advanced Synthesis & Catalysis
10.1002/adsc.201800928
it required the use of TiCl
4
/NaI reductive reagents.
of TBAB in Ac
2
O did not improve the yield of 3aa
[11]
During the course of our research, we found that
quinoxaline could be obtained via consecutive
condensation and N-arylation reactions under Lewis
acid conditions. However, an oxime starting material
and stoichiometric quantities of Lewis acid were
required. Inspired by Jiao’s work, and based on our
(Table 1, entry 13). The yield of 3aa decreased at
lower temperatures, and at room temperature the
reaction did not occur. Enamine 1a was recovered
from the room temperature reaction (Table 1, entries
14-16). To our delight, when 2.0 equiv. of Ac O was
2
used as an additive, 3aa was produced in 78% in
MeCN and 73% yield in toluene. 2a was observing as
a minor product in both of these conditions (Table 1,
[12]
group’s nitrosation studies using TBN,
we
surmised that quinoxalines could be synthesized
directly from N-aryl enamines through nitrosation, to
afford a β-imino oxime ester, and subsequent
cyclization. Here, we describe an efficient and metal-
free method to synthesize quinoxalines in a one-pot
entries 17-18). These results indicated that Ac O
2
promoted the formation of 3aa. Therefore, the
optimal conditions for the formation of 3aa was IBN
in Ac O at reflux (Table 1, entry 12).
2
2
reaction via the double C(sp )–H bond amination of
N-aryl enamines using IBN (Scheme 1-C).
Table 1. Optimization of the Reaction Conditions.a
A) Zhang's group, metal-free C-H amination of N-arylenamines with MeNO2
H
H
N
N
N
conditions
N
CF3
N
CF3
R1
+
KI, TBHP
N
O
CO Et
N
2
CO Et
2
R
+
MeNO2
R
CO2Et
R1
CsOAc, HOAc, 120 °C
N
H H
1aa
2a
3aa
3aa%b
double sp2 C-H
B) Jiao's group, TBN-mediated double C-H amination to access quinoxaline in two steps
2a%b
entry “N” / additive / solvent / temp
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
TBN / TBAB / MeCN / 60 °C 52
46
37
42
40
46
38
25
22
31
29
51
94
93
90
41
-
N
Ar
Me
N
Ar
N
Ar
TBN (3.0 equiv.)
TiCl4/NaI
DCM
R
R
R
TBN / TBAB/ MeCN / 25 °C
IBN / TBAB / MeCN / 60 °C
IBN / TBAF / MeCN / 60 °C
IBN / TBAB / MeCN / reflux
IBN / - / MeCN / reflux
IBN / - / DCE / reflux
IBN / - / THF / reflux
IBN / - / toluene / reflux
IBN / - / DMF / reflux
41
20
21
27
27
41
47
13
16
11
-
H
TBAB, MeCN, 60 °C
N
N
sp2 C-H + sp3 C-H
O
N
Ar
23 examples
R
38-83% yields
N
via O
C) This work, IBN-mediated double C-H amination to access quinoxaline in one-pot reaction
H
N
H
N
R1
R1
R1
IBN
N
R
R
R
Ac2O
EWG
N
EWG
EWG
H H
H N
0
1
2
3
4
5
6
7
8
double sp2 C-H
OAc
via
IBN / - / HOAc / reflux
IBN / - / Ac
IBN / TBAB / Ac
2
O / reflux
O / reflux
Scheme 1. Metal-Free C−H Aminations to Access
Quinoxalines.
2
-
IBN / - / Ac
IBN / - / Ac
IBN / - / Ac
2
2
2
O / 80 °C
O / 60 °C
O / 25 °C
-
-
-
Initially, N-aryl enamine 1aa was chosen as a
model substrate and the efficiency of formation of
quinoxaline 3aa was examined. The substrate was
treated with TBN and the additive tetra-n-
butylammonium bromide (TBAB) in MeCN at 60 °C.
The desired quinoxaline 3aa was obtained in 46%
yield, but quinoxaline N-oxide 2a was also produced
in 52% yield (Table 1, entry 1). Lowering the
temperature to 25 °C, decreased the total yield of
both 2a and 3aa (Table 1, entry 2). To our surprise,
when TBN was replaced with IBN, quinoxaline 3aa
was obtained as the major product, in 42% yield,
while quinoxaline N-oxide 2a was only afforded in
c
c
IBN / Ac
IBN / Ac
2
O / MeCN / reflux
O / toluene / reflux
11
<5
78
73
1
2
a)
Reaction conditions: 1aa (0.5 mmol), TBN or IBN (0.5
mmol, 1.0 equiv.), additive (0.025 mmol, 5 mol%), solvent
b)
c)
(
2
2.0 mL), 2−24 h; isolated yield; Ac O (2.0 equiv.).
With the optimized conditions in hand, the scope
of N-aryl enamines 1 for preparing quinoxalines was
explored. As shown in Table 2, various substituents
on the aniline moiety of the enamine were
investigated. Substrates with electron-donating and
electron-withdrawing groups at the ortho-, meta-, and
para-positions of the aniline afforded the
corresponding quinoxalines 3aa-3ao in good yields;
however, the substrates with electron-withdrawing
groups required longer reaction times (3ac, 3ae, 3af,
2
0% yield (Table 1, entry 3). Using tetra-n-
butylammonium fluoride (TBAF) as an additive did
not affect the yield significantly (Table 1, entry 4).
The total yield of 2a and 3aa was improved slightly
when TBAB was removed or when the reaction was
increased to reflux (Table 1, entries 5-6). Solvent
screening revealed that 2a was afforded as the major
product in DCE and THF, while 3aa was obtained as
the major product in toluene, DMF and HOAc (Table
3
ak and 3am). When enamines 1ad and 1ae, with a
methoxy and trifluoromethyl groups at their aryl
meta-position, respectively, were subjected to the
optimal conditions, only the regioisomers 3ad and
3
ae were obtained (87% and 84% yields,
1
, entries 8-11). Pleasingly, in Ac
was obtained in 94% yield and quinoxaline N-oxide
a was not observed (Table 1, entry 12). The addition
2
O, quinoxaline 3aa
respectively). However, enamine 1af, with a fluoro
group at the meta-position of its aryl ring, produced a
mixture of 3af-1 and 3af-2 in a 1.3:1 ratio. A 1:2 ratio
2
2
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Advanced Synthesis & Catalysis
10.1002/adsc.201800928
of quinoxaline 3am-1 and 3am-2 was also observed.
Next, a variety of R1 and electron-withdrawing
groups (EWG) were evaluated. Aryl and alkyl groups
and its conversion to 3aa did not involve a radical
process. No reaction took place using N-arylimine 1n
as substrate (Scheme 2-6). When enamine 1o was
subjected to the optimal conditions, product 3oa was
not observed while N-phenylacetamide was obtained
in 60% yield (Scheme 2-7).
1
were well tolerated at the R position and afforded the
desired products in good yields (3ba-ga). The EWG
substituent could be an ester, a ketone, or a cyano
group (3ha-ja). When acetylenedicarboxylates
containing alkyl, alkene, and alkyne groups were
used, the corresponding quinoxalines were also
obtained in good yields (3ka-ma). The structure of
N
Ph
N
Ph
IBN
(1)
Ac O, reflux
N
O
2
CO Et
2
N
2
CO Et
3aa
2
a
quinoxaline 3 was further confirmed by X-ray
H
N
N
Ph
N
Ph
diffraction analysis of compound 3ma.[13]
IBN (1.0 equiv)
Ac2O, rt
(2)
CO Et
2
CO Et
2
OH
4, 96%
Table 2. Scope of N-Aryl Enamines 1.a,b
1aa
H
R1
H
N
TEMPO (2.0 equiv)
IBN (1.0 equiv)
N
Ph
R1
N
Ph
N
IBN (1.0 equiv)
Ac2O, reflux
+
R
R
(3)
(4)
N
N
3
EWG
N
CO Et
EWG
Ac2O, rt
2
1
CO2Et
NO
OH
, 18%
R
1aa
4
5,71%
N
Ph
N
Ph
R
N
Ph
CO2Et
N
Ph
F
N
Ph
+
N
Ph
+
N
N
Ph
N
CO2Et
N
CO Et
N
N
CO2Et
N
CO2Et
N
N
Ph
Ac O (2.0 equiv)
2
2
3
aa, 94%
R = Me, 3ab, 85%
R = CF3, 3ac, 90%
F
3af-1
3af-2
R = OMe, 3ad, 87%
2% (1.3:1) c
reflux, 4 h
8
R = CF , 3ae, 84%
3
N
CO Et
CO
CO Et
2
2
Et
2
Br
OAc
6, 83%
Me
N
Ph
OH
4
N
Ph
N
Ph
CO Et
R = OMe, 3ag, 88%
R = Me, 3ah, 87%
R = Br,
R = F,
3aa, 10%
2
Ac O, reflux
3ai, 83%
3aj, 88%
N
CO2Et
R
N
CO2Et
F
N
2
N
Ph
95%
Me
N
N
Ph
CO Et
3
ak, 86%
3al, 89%
(
5)
N
Ph
Cl
F
N
Ph
CO2Et
N
CO Et
MeO
MeO
N
Ph
CO2Et
2
N
Ph
CO2Et
2
OAc
90%
F
N
CO2Et
N
3aa
N
6
N
TEMPO (2.0 equiv)
Cl
3
am-1
7% (1:2) d
R
3am-2
3an, 87%
9
3ao, 94%
Ac2O, reflux
IBN (1.0 equiv)
Ac2O, reflux
N
CO Me
N
N
CO Me
2
2
N
N
Me
CO2Et
N
Et
CO2Et
N
Me
(6)
MeO
Br
1n
N
CO2Et
N
N
3na, 0%
N
CO2Et
R = OMe, 3ba, 84%
R = Cl, 3ca, 81%
3fa, 81%
3
ea, 66%
3ga, 82%
H
N
H
N
N
H
R = F,
3da, 79%
IBN (1.0 equiv)
Ac2O, reflux
Me
N
CO2R
CO2R
+
(7)
N
Me
N
Me
N
Ph
CN
CO Me
N
CO2Me
O
2
N
Me
1o
N
N
N
3oa, 0%
60%
R = Me, 3ka, 68%
R =
R =
O
3
ha, 54%
O
3ia, 67%
3ja, 82%
, 3la, 70%
3ma, 74%
,
Scheme 2. Mechanistic Studies.
a)
Reaction conditions: 1 (0.5 mmol), IBN (0.5 mmol, 1.0
equiv.), Ac O (2.0 mL), 2−18 h; isolated yield.
2
b)
Based on the experimental results, a possible
mechanism for the formation of quinoxaline 3aa from
N-aryl enamine 1aa was proposed (Scheme 3). First,
IBN is easily split into an •NO and an i-BuO• radical
upon heating. The addition of an •NO radical to
enamine 1aa gives intermediate A, which rapidly
reacts with the i-BuO• radical to afford intermediate
B and i-BuOH. Intermediate B then undergoes a
Control experiments were performed to study the
mechanism of formation of quinoxaline 3aa (Scheme
[14]
2
). When quinoxaline N-oxide 2a was subjected to
the optimal conditions, quinoxaline 3aa was not
observed. This indicated that quinoxaline N-oxide 2a
was unlikely to be the intermediate in the formation
of quinoxaline 3aa (Scheme 2-1). When 1aa was
[
9f,15]
[
1,3]-H migration to yield oxime 4.
Esterification
treated with IBN in Ac O at room temperature, oxime
2
of oxime 4 with Ac
2
O generates compound 6, which
undergoes a 6πe-azacyclization to yield intermediate
4
was obtained in 96% yield and quinoxaline 3aa was
[16]
not observed (Scheme 2-2). The treatment of 1aa
C. Finaly, elimination of HOAc affords product
aa. Alternatively, N−O bond cleavage of 6 and
electrophilic cyclization under high reaction
temperatures affords intermediate D.
undergoes aromatization to yield product 3aa. The
key role of Ac O might be the production of ester 6,
thereby facilitating quinoxaline formation.
with radical trapping reagent TEMPO afforded oxime
3
4
and the N-nitroso compound 5 in 18% and 71%
[17]
yield, respectively (Scheme 2-3). These results
suggested that the nitrosation of enamine 1aa
involved a radical process. When oxime 4 was treated
Finally, D
2
with Ac O at reflux for 4 h, compound 6 was
2
obtained in 88% yield and quinoxaline 3aa was
obtained in 10% yield (Scheme 2-4). Finally, when
compound 6 was refluxed in Ac O, with and without
2
the addition of TEMPO, quinoxaline 3aa was
afforded in 95% and 90% yield, respectively (Scheme
2
-5). These results revealed that compound 6 was the
key intermediate in the formation of quinoxaline 3aa,
3
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Advanced Synthesis & Catalysis
10.1002/adsc.201800928
i-BuONO
N
1
) SOCl2
i-BuO
H
N
N
Ph
2
) AlCl3, rt
N
H
N
Ph
Ph
i-BuO
N
N
Ph
N
N
Ph
O
NO
KOH
9, 46%
N
O
CO Et
EtOH, r.t
2
CO2H
CO Et
N
O
CO2Et
i-BuOH
CO2Et
N
N
Ph
OAc
2
1) SOCl2
HO
97%
8
1
aa
B
3aa
O
A
[1,3]-H
O
2)
10, 38%
,
Pyr, DMAP
N
Ph
N
Ph
N
Ph
Ac O
OAc
Aza-e
cyclization
2
N
CO Et
N
CO2Et
2
N
CO Et
H
2
OAc
C
OAc
6
HOAc
OH
4
Scheme 5. Applications of Quinoxaline 3aa.
HOAc
Ph
OAc
Ph
In summary, we have developed a IBN-mediated
N
N
N
2
double C(sp )−H bond functionalization of N-aryl
CO Et
N
CO Et
2
2
enamines to prepare various functionalized
quinoxalines in good to excellent yields. Mechanistic
studies revealed that the reaction proceeded through a
β-imino oxime ester intermediate. Furthermore, a
target quinoxaline was easily converted into two
important quinoxaline scaffolds in two steps and in
moderate yields.
3
aa
D
H
Scheme 3. Proposed Mechanism.
To further demonstrate the utility of this method, a
one-pot preparation of quinoxaline 3aa from β-
carbonyl ester 7 was conducted on a gram scale. As
shown in Scheme 4. 1.92 g of compound 7 could be
condensed with PhNH
phenyl enamine 1aa. Then, IBN and Ac
to the mixture, yielding 2.3 g of quinoxaline 3aa in
2% yield in a one-pot reaction. This protocol
provides a facile approach to access quinoxalines.
Experimental Section
2
under heating, leading to N-
2
O was added
General procedure for the synthesis of quinoxaline 3aa.
To a 10 mL round-bottom flask equipped with a magnetic
stirring bar were added N-aryl enamine 1aa (0.5 mmol),
8
2
IBN (0.5 mmol, 1.0 equiv.) and Ac O (2.0 mL). The
reaction mixture was stirred at room temperature for 10
min, and then was refluxed until the reaction was
completed as monitored by TLC (2–18 h). At this time, the
O
N
N
Ph
reaction was quenched by H O (10 mL) and extracted with
2
PhNH2
IBN
CO Et
EtOAc (3 × 10 mL). Then, the combined organic layers
2
Ph
TsOH, EtOH
Ac2O, reflux
2 4
were dried over Na SO and filtered. The solvent was
CO Et
2
evaporated under reduced pressure and the crude product
was purified by flash column chromatography on silica gel
with eluents (EtOAc/petroleum) to give product 3aa as a
7
3aa
(
1.92 g, 10 mmol)
(
2.3 g, 82% yield)
1
yellow solid (0.127 g, 94%), mp: 65−66 °C. H NMR (500
MHz, CDCl
3
) δ 8.26–8.20 (m, 2H), 7.91–7.83 (m, 2H),
Scheme 4. Gram Scale Preparation of Quinoxaline 3aa.
7
2
.80–7.72 (m, 2H), 7.58–7.48 (m, 3H), 4.36 (q, J = 7.1 Hz,
13
3
H), 1.20 (t, J = 7.1 Hz, 3H); C NMR (125 MHz, CDCl )
δ 166.6, 152.3, 145.8, 142.3, 139.9, 137.8, 131.7, 130.6,
1
29.6, 129.4, 128.7, 128.6, 62.4, 13.8; HRMS (ESI) m/z
calcd for C17
Na [M+Na]+ 301.0948; found
01.0968.
Indeno[1,2-b]quinoxaline derivatives constitute a
large number of potential bioactive agents.
[18]
14 2 2
H N O
3
Because our method proved to be efficient in the
preparation of quinoxalines, the transformation of
Acknowledgements
3
aa to the indeno[1,2-b]quinoxaline scaffold was
investigated. As shown in Scheme 5, hydrolysis of
This work was supported by National Natural Science
Foundation of China (21602037, 21462008), Natural Science
quinoxaline 3aa with KOH afforded acid 8 in 97%
yield. The reaction of 8 with SOCl
intramolecular acylation gave
b]quinoxaline 9 in 46% yield. Meanwhile, treatment
2
, and followed by
Foundation
of
Guangxi
(2016GXNSFFA380005,
indeno[1,2-
2017GXNSFDA198045), the State Key Laboratory for Chemistry
and Molecular Engineering of Medicinal Resources
(
CMEMR2018-A1), Guangxi Medical Talent Highland (201705)
of 8 with SOCl
2
and sequential esterification with 4-
and the “oversea 100 Talents Program” of Guangxi Higher
(
1
hydroxymethyl) phenyl acetate, afforded compound
Education.
0 in 38% yield. Analogues of compound 10 have
been demonstrated that this group of quinoxalines
possesses antimycobacterial activity against M.
tuberculosis (Mtb).[ The transformations reported
here will allow access to these quinoxalines,
furthering their potential use in pharmaceuticals.
References
19]
[
1] Some selected reviews on quinoxalines, see: a) S.
Tariq, K. Somakala, and M. Amir, Eur. J. Med. Chem.
2
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M. V. N. de Souza, Anti-Cancer Agents in Med. Chem.
2
2
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014, 85, 688; d) L. Martin, L. Lutsen, D. Vanderzande,
and W. Maes, Org. Biomol. Chem. 2013, 11, 5866; e)
4
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Advanced Synthesis & Catalysis
10.1002/adsc.201800928
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Advanced Synthesis & Catalysis
10.1002/adsc.201800928
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6
This article is protected by copyright. All rights reserved.

Advanced Synthesis & Catalysis
10.1002/adsc.201800928
UPDATE
Isobutyl Nitrite-Mediated Synthesis of
Quinoxalines through Double C−H Bond
Amination of N-Aryl Enamines
N
N
H
N
R1
EWG Ac2O, reflux
R1
N
IBN (1.0 equiv)
O
R
45% yield in two steps
R
Adv. Synth. Catal. Year, Volume, Page – Page
H
H
N
EWG
N
N
Ph
OAc
2
5 examples
up to 97% yield
O
O
Yan-Xiao Jiao, Lin-Su Wei, Chun-Yang Zhao, Kai
Wei, Dong-Liang Mo,* Chen-Xue Pan,* and Gui-
Fa Su*
3
7% yield in two steps
7
This article is protected by copyright. All rights reserved.