Benzofurazan N-Oxides as Mild Reagents for the Generation of α-Imino Gold Carbenes: Synthesis of Functionalized 7-Nitroindoles

Article abstract of DOI:10.1021/acs.orglett.9b02893

An efficient gold-catalyzed [3 + 2] annulation of benzofurazan N-oxides with ynamides has been developed, which provides a concise and regioselective access to highly functionalized 7-nitroindoles. Although N-oxides are often considered as oxygen transfer

Full text of DOI:10.1021/acs.orglett.9b02893

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Benzofurazan N‑Oxides as Mild Reagents for the Generation of
α‑Imino Gold Carbenes: Synthesis of Functionalized 7‑Nitroindoles
Wei Xu, Yulong Chen, Ali Wang, and Yuanhong Liu*
State Key Laboratory of Organometallic Chemistry, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic
Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 345 Lingling Lu, Shanghai 200032, People’s
Republic of China
S
* Supporting Information
ABSTRACT: An efficient gold-catalyzed [3 + 2] annulation of benzofurazan N-oxides with ynamides has been developed,
which provides a concise and regioselective access to highly functionalized 7-nitroindoles. Although N-oxides are often
considered as oxygen transfer reagents in gold catalysis, benzofurazan N-oxide was found to act as a facile precursor for an α-
imino gold carbene intermediate. Benzofurazan can also react with ynamides to afford quinoxaline N-oxides via a [4 + 2]
annulation process.
7-Nitroindoles are important heterocyclic units that exist as the
core structures of numerous biologically active molecules.1−4
For example, 7-nitroindole a exhibits potent xanthine oxidase
inhibitory activity1 (Figure 1). 7-Nitroindole b serves as a chk2
conditions. Therefore, it is highly desirable to develop efficient
methods for the synthesis of 7-nitroindoles from easily
available starting materials under mild reaction conditions.
In recent years, gold-catalyzed oxygen6 and nitrene7−16
transfer reactions have attracted considerable attention due to
their wide applications in the construction of diversely
functionalized carbo- or heterocycles (Scheme 1, eqs 1 and
2). Mechanistically, these reactions proceed through the
nucleophilic attack of the oxygen or nitrogen atom from the
nucleophilic reagents on the alkynes followed by elimination of
a neutral organic framework. In this context, N-oxides such as
pyridine- and quinoline-N-oxides have been commonly
employed as oxygen transfer reagents to trigger a facile
generation of highly electrophilic α-oxo gold-carbene inter-
mediates.6 On the other hand, great achievements have also
been made based on the development of novel nitrene transfer
reagents. For example, azides,7 2H-azirines,8 N-iminopyridium
ylides,9 isoxazoles,10 benzoisoxazoles,11 1,4,2-dioxazoles,12 4,5-
dihydro-1,2,4-oxadiazoles,13 triazapentalene,14 benzo[d]-
isoxazoles,15 and sulfilimines16 have been disclosed to show
high reactivities in nitrene transfer reactions reported by
Gagosz, Davies, Zhang, Ye, Hashmi, Liu, us, and others. In
these reactions, α-imino gold-carbene complexes have been
recognized as possible reaction intermediates. However, to the
best of our knowledge, N-oxides have never been used as the
precursors of α-imino gold-carbene intermediates. During our
studies on the use of N−O-containing heterocycles as α-imino
Figure 1. Biologically active 7-nitroindole derivatives.
inhibitor for the treatment of cancer.2 7-Nitroindole c with a
pyrimidine ring was found to be an inhibitor of DYRK1A and
CLK1 kinases, which displays in vitro antiproliferative
activities.3 Compound d shows good MT1 and MT2 affinities,
which may be involved in the vasoconstrictor activities on
animal vessels.4 However, only limited methods are available
for the synthesis of 7-nitroindoles such as direct nitration of
indoles,5a,b nitration of 7-chloroindoles,5c Fischer indole
synthesis of o-nitrophenylhydrazones,5d,e cyclization of 1,2-
dinitrobenzene with vinylmagnesium bromides, etc.5f These
methods usually suffer from various disadvantages such as low
regioselectivity, limited substrate scope, and harsh reaction
Received: August 15, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b02893
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Scheme 1. Generation of α-Oxo/Imino Gold Carbenes
Table 1. Optimization of the Reaction Conditions
a
1
gold-carbene precursors,12,13,15b we envisioned that if an N-
oxide reagent derived from N−O heterocycles bearing an
additional nucleophilic site is used as the substrate, the
reaction pathway might be altered since both the N+−O− and
the other nucleophilic moiety can attack the alkyne. We are
therefore quite interested in clarifying whether an α-oxo gold-
carbene would still be formed by using these substrates and its
transformations. To test our hypothesis, benzofurazan N-oxide
was chosen as the appropriate substrate (Scheme 1, eq 3).
Benzofurazan N-oxides are easily available heterocyclic
compounds17 which have been used for the synthesis of
quinoxaline 1,4-di-N-oxides through the reaction with 1,3-
dicarbonyl compounds18a,b and 2H-benzimidazole 1,3-dioxi-
des.18c However, these heterocycles have not been applied in
gold-catalyzed reactions. Herein, we report our success on
gold-catalyzed cyclization of benzofurazan N-oxides with
ynamides, which provides an efficient route to 7-nitroindole
derivatives. Interestingly, the expected oxygen transfer reaction
did not take place; instead, an α-imino gold-carbene
intermediate II was produced to deliver a [3 + 2] annulation
product. In addition, we find that benzofurazan19 can also react
with ynamides to afford quinoxaline N-oxides via an α-imino
gold-carbene intermediate III (Scheme 1, eq 4).
We initially focused on the cyclization of ynamide 1a with
benzofurazan N-oxide 2a in the presence of various gold
catalysts. To our delight, when in situ prepared PPh3AuNTf2
was employed as the catalyst, 7-nitroindole 3a could be formed
at room temperature in 73% yield within 4 h (Table 1, entry
1). The results indicated that an efficient N−O bond cleavage
occurred during the process. Since the steric and electronic
effects of the ligands played an important role in gold-catalyzed
reactions, we expected that the yield of 3a might be improved
by variation of the ligands on gold. By changing the catalyst to
Yields were determined by H NMR using 1,3,5-trimethoxybenzene
b
c
as an internal standard. [Substrate] = 0.1 M. Isolated yield. The
solvent became viscous. 1.0 equiv of 1a and 1.2 equiv of 2a were
used. 50 °C. 98% NMR yield of unreacted 1a was observed.
d
e
f
JohnPhosAu(MeCN)SbF6 (catalyst A), a significant increase
of the yield was observed (entry 2, 97%). The use of more
crowded tBuXPhos (catalyst B) resulted in a slight decrease in
yield (entry 3). N-Heterocyclic carbene gold(I) complex C
(IPrAuNTf2) provided 3a in 72% yield (entry 4). Gold(III)
complexes such as PicAuCl2 (catalyst D) or AuBr3 could also
catalyze the reaction, furnishing 3a in 78−82% yields (entries
5−6). When the reactions were performed in other solvents
such as THF, DCM, MeCN, or toluene, 3a was formed in up
to 71% yield (entries 7−10). The results indicated that DCE
was the best solvent (compared with entry 2). It was noted
that, in the case of THF, the reaction mixture became viscous
as the reaction proceeded. Possibly partial polymerization of
THF occurred as being initiated by some cation species and
propagated by a cationic mechanism.20 Turning the ratio of
1a:2a to 1:1.2 gave a lower yield of 3a (entry 11, 78%).
Employing AgSbF6 or HNTf2 as the catalyst afforded 3a in
≤20% yields (entries 12−13). The reaction did not take place
in the absence of any catalyst, even at 50 °C for 24 h (entry
14).
With the optimized reaction conditions in hand (Table 1,
entry 2), the scope of this novel cycloaddition reaction was
examined. The scope of ynamides 1 was first studied by using
2a as the reaction partner (Scheme 2). Tosyl-protected
substrate 1b gave 3b in a lower yield of 78% (compared
with 3a). In the case of Ns-protected ynamide 1c, the product
3c precipitated easily from the reaction medium due to its low
solubility, which can be simply purified by filtration and
B
DOI: 10.1021/acs.orglett.9b02893
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Letter
sterically encumbered o-Br substituted aryl ring could also be
easily transformed to the desired product 3j in 66% yield. A
heteroaryl-substituted ynamide such as a 2-thienyl-substituted
one was well compatible, which also required PicAuCl2 to
afford a satisfactory yield (3k). Ynamide with a 1-naphthyl
substituent proceeded smoothly (3l). When alkyl-substituted
ynamide was used, the desired 7-nitroindole 3m was not
observed, instead, vinyl imine 5 was formed in 31% yield via
1,2-H shift. The reaction could be applied to natural product
related derivatives. For example, ynamides derived from
1,3,5(10)-estratrien-3-ol-17-one or formononetin transformed
to 3n and 3o in moderate to high yields. Furthermore, when
benzofurazan N-oxide 2b with a methoxy substituent at the R3
position was employed, 4-OMe-substituted 3p was obtained in
60% yield, along with a small amount of a byproduct 3p′ and
alkyne hydration product (ca. 12% combined yield). It is
suggested that 3p′ is a 7-nitroindole isomer in which the MeO
group locates at the C-5 position due to the tautomerization of
the substrate 2b.21 To demonstrate the utility of the product,
reduction of 3a under the conditions of cat. Pd/HCO2NH4
was performed, which delivered 7-aminoindole 4 in 90% yield.
The structures of 7-nitroindoles 3 were confirmed by X-ray
crystallographic analyses of 3b (CCDC-1940164) and 3p
(CCDC-1940167).
Scheme 2. Synthesis of 7-Nitroindoles by Gold-Catalyzed [3
+ 2] Annulations
a
To compare the reactivity of benzofurazan N-oxide 2 and
benzofurazan 6, we next investigated the gold-catalyzed
reactions of 6a with ynamides (Scheme 3). To our delight,
Scheme 3. Scope of Gold-Catalyzed [4 + 2] Annulations
a
with Ynamides
a
Isolated yields. Only the yields of 8 which could be purified by
b
column chromatography are given. 8a was also isolated in 15% yield.
c
a
b
8e was also isolated in 25% yield.
Isolated yields. 5 mol % Pd/CaCO3, 5.0 equiv of HCO2NH4,
c
EtOH, reflux. Reaction was performed at 50 °C. [Substrate] = 0.033
d
e
M. 1 mmol scale. 5 mol % PicAuCl2 was used as the catalyst.
f
quinoxaline N-oxides 7 could be formed in the presence of
tBuXPhosAu(MeCN)SbF6 (catalyst B). Quinoxaline derivative
8 was also observed as a side product in most cases. Obviously,
8 can be envisioned to be formed during the oxidative reaction
of quinoxaline N-oxide 7 with ynamide (vide infra). A series of
ynamides were smoothly converted into the corresponding
quinoxaline N-oxides. Tosyl and mesyl groups on nitrogen
were well tolerated (7a, CCDC-1940169; 7b). Electron-
withdrawing groups (e.g., p-F and p-Cl) on the aryl ring of
the ynamides were compatible (7c and 7d), while electron-
donating groups (e.g., p-OMe) resulted in a low yield of 7e
(17%), along with the formation of 8e in 25% yield. The
results indicated that electron-rich ynamides turned out to be
easily oxidized by N-oxide 7. Cyclopropyl-substituted ynamide
afforded 7f in 49% yield.
[Substrate] = 0.05 M.
washing (42% yield). These results suggest that the protecting
groups on nitrogen have a dramatic impact on the product
yields. N-Benzyl substituted ynamide was also compatible
(3d). Next, the substituent effects of the aryl groups on
ynamide terminus were investigated. Electron-donating groups
such as p-methyl and p-methoxy on the aryl ring were well
suited, furnishing 3e and 3f in 90% and 86% yields,
respectively. Substrates bearing electron-withdrawing groups
such as p-F and p-Cl worked well, leading to 3g−3h in 66−
88% yields. In addition, a reaction of 1g on 1 mmol scale also
provided a high yield of 3g. Several products were observed
under the standard conditions when ynamide 1i with a p-
CO2Et-substituted aryl group was used as the substrate.
Switching the gold catalyst to PicAuCl2 was found to give
better results, leading to 3i in 75% yield. A substrate bearing a
Interestingly, when the above reaction (for example, 1b with
6a) was carried out at 80 °C, quinoxaline N-oxide 7a was
almost consumed, furnishing quinoxaline 8a (CCDC-
C
DOI: 10.1021/acs.orglett.9b02893
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1940168) in 84% yield and 2,5-diaminofuran 9 (CCDC-
1940166) in 45% yield (based on 6a) (Scheme 4, eq 5). To
Scheme 6. Possible Reaction Mechanism
Scheme 4. Formation of 2,5-Diaminofuran
understand the reaction outcome between ynamide 1 and N-
oxide 7, the reaction of 1b with 7a was also performed
(Scheme 4, eq 6). The same products of 8a and 9 were
formed. The results indicated that 7a acts as an oxidant to
initiate an oxygen transfer reaction with ynamide. The in situ
generated α-oxo gold carbene Int-2 is trapped by an additional
ynamide molecule to deliver the furan product 9. According to
the literature, when ynamide was oxidized by 8-methylquino-
line N-oxide, only the over-oxidized product of α-ketoimide
was observed.22 Thus, quinoxaline N-oxide displays unique
reactivity compared to well-used N-oxides.
and N-oxide 7 (Scheme 6, eq 8). Initially, ynamide 1 is
activated by gold to afford keteniminium ion intermediate Int-
4, which is attacked by the imino nitrogen of 2a to give an
intermediate Int-5. Ring fragmentization of Int-5 affords the α-
imino gold carbene Int-6. Subsequent nucleophilic attack of
the phenyl ring on gold carbene leads to intermediate Int-7.
This is followed by aromatization and deauration to give the
product 3.24,25 When benzofurazan 6a is used, Int-9 is formed
through the nucleophilic attack of the imino nitrogen on
intermediate Int-4. Int-9 fragmentizes into the α-imino gold
carbene Int-10 via N−O bond cleavage. Then nucleophilic
attack of the nitroso nitrogen to gold-carbene26 followed by
elimination of the gold catalyst leads to the products 7.
In summary, we have developed a novel and efficient
protocol for the synthesis of 7-nitroindoles through gold-
catalyzed [3 + 2] annulations of benzofurazan N-oxides with
ynamides. Although N-oxides are often considered as oxygen
transfer reagents, benzofurazan N-oxide was found to act as a
facile precursor to initiate the generation of an α-imino gold
carbene intermediate. In addition, gold-catalyzed reactions of
benzofurazans with ynamides provide quinoxaline N-oxides via
[4 + 2] annulation process. Further extensions by exploring the
reactivity of N-oxides derived from other N−O heterocycles
are currently underway in our laboratory.
To further explore the utility of benzofurazan derivatives in
gold catalysis, we also made efforts to examine their reactions
with propargyl esters (Scheme 5). Interestingly, a four-
Scheme 5. Reaction of Propargyl Esters with 2a or 6a
component reaction involving two molecules of benzolyl-
protected substrate 10a and two molecules of benzofurazan N-
oxide 2a was observed, leading to the product 11 (CCDC-
1940163) bearing o-nitroaniline moieties in 22% yield.
Reaction of 10a with benzofurazan 6a resulted in the
formation of N-OBz protected benzimidazole 12a in 39%
yield. 2-Naphthyl-substituted propargyl ester 10b underwent a
similar reaction with 6a (12b in 30% yield, CCDC-1940165).
Possible reaction mechanisms for these transformations are
shown in the Supporting Information. Both reactions involve
the nucleophilic attack of the nitrogen moiety of benzofurazan
N-oxide or benzofurazan to a vinyl gold carbene intermediate
generated through 1,2-acyloxy migration of propargyl ester.23
Based on the above results, a possible reaction mechanism is
given for the formation of 7-nitroindole 3 (Scheme 6, eq 7)
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b02893.
■
S
Experimental details, spectroscopic characterization of
all new compounds (PDF)
Accession Codes
CCDC 1940163−1940169 contain the supplementary crys-
tallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
D
DOI: 10.1021/acs.orglett.9b02893
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Letter
Wolff Rearrangement of Oxidatively Generated α-Oxo Gold
Carbenes: An Effective Approach to Silylketenes. Angew. Chem., Int.
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Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
(7) Gorin, D. J.; Davis, N. R.; Toste, F. D. Gold(I)-Catalyzed
Intramolecular Acetylenic Schmidt Reaction. J. Am. Chem. Soc. 2005,
127, 11260−11261.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: yhliu@sioc.ac.cn.
ORCID
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Jones, M. P.; Davies, P. W. Alkynyl Thioethers in Gold-Catalyzed
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R. L.; Liu, R.-S. Development of Gold-catalyzed [4 + 1] and [2 +
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Yuanhong Liu: 0000-0003-1153-5695
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the National Key Research and Development
Program (2016YFA0202900), the National Natural Science
Foundation of China (21572256), the Science and Technology
Commission of Shanghai Municipality (18XD1405000), the
Strategic Priority Research Program of the Chinese Academy
of Sciences (XDB20000000), and the Shanghai Institute of
Organic Chemistry (sioczz201807) for financial support.
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F
DOI: 10.1021/acs.orglett.9b02893
Org. Lett. XXXX, XXX, XXX−XXX