Transition-Metal-Free Synthesis of N-Hydroxy Oxindoles by an Aza-Nazarov-Type Reaction Involving Azaoxyallyl Cations

Article abstract of DOI:10.1002/anie.201607177

A novel transition-metal-free method to construct N-hydroxy oxindoles by an aza-Nazarov-type reaction involving azaoxyallyl cation intermediates is described. A variety of functional groups were tolerated under the weak basic reaction conditions and at room temperature. A one-pot process was also developed to make the reaction even more practical. This method provides alternative access to oxindoles and their biologically active derivatives.

Full text of DOI:10.1002/anie.201607177

Angewandte
Communications
Chemie
International Edition: DOI: 10.1002/anie.201607177
German Edition: DOI: 10.1002/ange.201607177
Heterocycle Synthesis
Transition-Metal-Free Synthesis of N-Hydroxy Oxindoles by an Aza-
Nazarov-Type Reaction Involving Azaoxyallyl Cations
Wenzhi Ji, Yahu A. Liu, and Xuebin Liao*
Abstract: A novel transition-metal-free method to construct
N-hydroxy oxindoles by an aza-Nazarov-type reaction involv-
ing azaoxyallyl cation intermediates is described. A variety of
functional groups were tolerated under the weak basic reaction
conditions and at room temperature. A one-pot process was
also developed to make the reaction even more practical. This
method provides alternative access to oxindoles and their
biologically active derivatives.
O
xindoles are widely present in natural products,[1] and also
in pharmacologically active compounds such as NMDA
antagonists,[2] calcium channel blockers,[3] and agents with
anti-angiogenic,[4] anticancer,[5] and analgesic effects[6]
(Figure 1). Past decades have seen the development of
Scheme 1. Access to oxindoles from a-halo anilides.
a-halo anilides,[10a,b] but the reaction conditions were very
harsh and problematic with some substrates (Scheme 1a).
Some of the other preparations of oxindoles from a-halo
anilides include Buchwaldꢁs synthesis of oxindoles by a palla-
[11a]
À
dium-catalyzed C H functionalization
and Leiꢁs nickel-
catalyzed cyclization.[11p] Recently, Yu and co-workers
reported another method to convert 2-bromoanilides, con-
taining two electron-withdrawing substituents, into 3,3-dis-
ubstituted oxindoles by visible-light-promoted photoredox
catalysis.[9t] However, most of these reactions require costly
metal catalysts which can contaminate products.
Transition-metal-free reactions have emerged in recent
À
À
years as important methods for the formation of C C, C N,
[12]
À
À
C O, and even C S bonds. Although typical examples of
metal-free cyclizations to prepare oxindoles are processes
involving radicals,[9a–e] a potassium tert-butoxide promoted
synthesis of oxindoles reported by the group of Bolm was
believed to proceed through an SNAr reaction.[13] Addition-
ally, both the groups of Zhu[14] and Zhao[15] developed metal-
free approaches to oxindoles using a hypervalent iodine(III)
reagent, but the reaction has limited scope and requires an
external oxidant. Herein, we describe a transition-metal-free
and oxidant-free access to oxindoles under mild reaction
conditions.
Figure 1. Representative natural products and pharmacologically active
compounds containing oxindole core.
numerous methods to synthesize oxindoles containing a vari-
ety of functionalities,[7] and these methods include the
derivatization of either isatin or indoles,[8] radical cyclizations
of aniline derivatives,[9] Friedel–Crafts-type cyclizations,[10]
and transition-metal-mediated reactions,[11,9n] among others.
One of the most efficient modes to construct oxindoles is their
conversion from a-halo anilides (Scheme 1). As early as the
1930s, Stollꢀ et al. used AlCl3 to promote cyclization from
Azaoxyallylic cations are reactive intermediates which
have not yet been studied extensively. In the 1960s, the
azaoxyallyl cation was first suggested as an intermediate when
Sheehan studied a-lactam chemistry.[16] In 1993, the group of
Kikugawa showed evidence for azaoxyallyl cation intermedi-
ates,[17] but there had not been much progress until Jeffrey and
co-workers reported the first practical [4+3] cycloaddition
involving azaoxyallyl cations.[18,19] Very recently, the groups of
Jeffrey[20] and Wu,[21] and ourselves[22] reported a dearomative
[3+2] cycloaddition of azaoxyallyl cationic intermediates. Our
group has also explored the application of azaoxyallyl cations
as synthons in synthetic approaches towards (Æ)-minfien-
sine.[22] Considering that this intermediate could be trapped by
[*] W. Ji, Prof. Dr. X. Liao
School of Pharmaceutical Sciences, Collaborative Innovation Center
for Diagnosis and Treatment of Infectious Diseases
Tsinghua University (China)
E-mail: liaoxuebin@mail.tsinghua.edu.cn
Dr. Y. A. Liu
Medicinal Chemistry, Genomics Institute of the Novartis Research
Foundation, San Diego, CA 92121 (USA)
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under:
http://dx.doi.org/10.1002/anie.201607177.
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a benzene ring to construct an oxindole skeleton, we initiated
our screenings to generate azaoxyallyl cations from anilides
under mild reaction conditions: a KHCO3/1,1,1,3,3,3-hexa-
fluoro-2-propanol (HFIP) system. It was found that the
substituent on the anilide nitrogen atom is a key factor, as no
reaction occurred when the substituent was H, methyl,
methoxy, or benzyl (Table 1, entries 1–4). To our delight,
Table 1: Optimization of the reaction conditions.[a]
Entry
R
Base
Solvent
Yield [%][b]
1
2
3
4
5
6
7
8
9
H
Me
Bn
KHCO3
KHCO3
KHCO3
KHCO3
KHCO3
Et3N
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
THF
n.r.
n.r.
n.r.
n.r.
90
83
52
no
no
no
no
OMe
OH
OH
OH
OH
OH
OH
OH
K2CO3
KHCO3
KHCO3
KHCO3
KHCO3
CH2Cl2
MeCN
toluene
10
11
[a] Reaction conditions: 7 (0.3 mmol, 1.0 equiv) and base (1.1 equiv) in
solvent (2 mL) at room temperature (RT) for 5 h. [b] The yield is that of
isolated product. n.r.=no reaction, no=no desired product 8,
THF=tetrahydrofuran.
Scheme 2. Substrate scope for the reaction. Yield is that of the isolated
product. X=Br. Reaction conditions: 10 (0.3 mmol, 1.0 equiv), and
KHCO3 (1.1 equiv) in HFIP (2 mL) at room temperature (RT) for 5 h.
[a] Reaction time: 12 h. [b] X=Cl. 12 h.
when a-bromo-N-hydroxy anilide (7, R=OH) was subjected
to the system,[20–22] the desired oxindole 8 (R =OH) was
obtained in 90% yield (entry 5). Thus, 7 (R=OH) was chosen
as the model substrate for the initial survey. Replacing KHCO3
with either K2CO3 or Et3N as the base resulted in lower yield
(entries 6 and 7). The solvent was so crucial that the reaction
conducted in common solvents gave the elimination product 9
as the main product without forming 8 (entries 8–11).
subsequent evaporation of the ether solvent and addition of
HFIP. The reaction mixture was then stirred for another
5 hours at room temperature, thus resulting in the desired
product 8a in 68% yield. Because various phenylhydroxyl-
amines and acyl halides are either commercially available or
can be prepared readily, this one-pot procedure is more
practical than the two-step method, albeit in lower, but
acceptable yield (11g, 11q, 11r, 11u–z).
Having identified the optimized reaction conditions, we
next explored the substrate scope. A variety of N-hydroxy
anilides were subjected to the KHCO3/HFIP reaction system
(Scheme 2). Functional groups such as methyl, methoxy,
halogens, ester, nitrile, or hydroxy were found to be well
tolerated in the system (11a–m). The position of substituents
at the para, meta, or ortho positions did not affect the
reaction. The substituted anilides with electron-withdrawing
groups tended to have poor yields (11i,j). Spiro-oxindoles
(11n,o) with five-membered or six-membered rings were
readily prepared in this method. Both 3-monosubstituted and
3,3-disubstituted substrates gave oxindoles in good yields
(11p–t), but the former (11p–s) reacted more slowly (12 h)
than did the latter (11t). Besides a-bromo-N-hydroxy ani-
lides, a-chloro-N-hydroxy anilide (11r) also reacted smoothly.
Since N-hydroxy anilides can be prepared readily by
reacting phenylhydroxylamine (12) with either acyl chloride
or bromide,[23] we turned our attention to testing the
possibility of a one-pot process for the synthesis of 11 and 8
(Scheme 3). In the one-pot process, 2-bromo-2-methylpropa-
noyl bromide (13; R2 = R3 = Me, X1 = X2 = Br) was added
dropwise to a mixture of 12 and KHCO3 in ether, with
Given the versatility of the one-pot process, it was applied
to the synthesis of the progesterone receptor antagonist
5
[24](Scheme 4). The synthesis began with treatment of N-(4-
bromophenyl)hydroxylamine (14) with the acyl bromide 15 in
a one-pot process to give the oxindole 11 f in 55% yield. The
oxindole 11 f was then reacted with the boronic acid 16 under
Suzuki coupling conditions to afford the precursor 17 in 72%
yield.[25] Cleavage of the N O bond of 17 afforded 5 in 81%
À
yield.[26]
It was found that when the substituent on the anilide
nitrogen atom was either H, methyl, benzyl, or methoxy, the
reaction did not afford the desired product 8. In addition, an
attempt with N-benzyl-2-bromo-N-hydroxy-2-methylpropa-
namide (18) under the standard reaction conditions to
prepare the six-membered ring compound 19 gave the
olefin 20 in almost quantitative yield without even trace
amount of 19 formed (Scheme 5). Thus, the reactivity of 7 can
possibly be ascribed to the nitrogen atom attached directly to
the benzene ring. Based on these results and previous
mechanistic studies of azaoxyally cations,[17–21] we hereby
2
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Scheme 6. Proposed pathway of the reaction.
evidence to support this proposed mechanism is that the
anilides substituted with electron-withdrawing groups [EtOC-
(O) and CF3] formed the desired products in poor yields
(Scheme 2; 11i,j). In addition, use of HFIP as the solvent is
the key, since it presumably stabilizes the transition state
through hydrogen-bond interactions with the oxygen atom of
the azaoxyallyl cation.[18–21,27]
To conclude, we developed
a transition-metal-free
method to construct oxindoles by an aza-Nazarov-type
reaction involving azaoxyallyl cation intermediates. The
reaction can be carried out under very mild reaction
conditions and has broad functional-group tolerance. In
addition, a one-pot procedure was developed to make the
method yet more practical. This reaction provides an alter-
native access to oxindoles and their biologically active
derivatives. More detailed mechanistic studies are ongoing
and will be reported in due course.
Scheme 3. One-pot process. Yield is that of the isolated product. The
yield within parentheses is the overall yield of the two-step process
when the reaction was carried out in a stepwise fashion. Reaction
conditions: X1 or X2 =Br or Cl. a) 12 (0.5 mmol, 1.0 equiv), 13
(1.1 equiv) and KHCO3 (1.2 equiv) in Et2O (3 mL) at 08C for 1 h and at
room temperature (RT) for 1 h, followed by removal of solvent.
b) KHCO3 (1.1 equiv) in HFIP (3 mL) at RT for 5 h.
Acknowledgments
This work was supported by the Collaborative Innovation
Center for Diagnosis and Treatment of Infectious Diseases,
the Tsinghua-Peking Centre for Life Sciences and “1000
Talents Recruitment Program”.
Keywords: azaoxyallylic cations · cyclizations · heterocycles ·
oxindoles · synthetic methods
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Received: July 25, 2016
Published online: && &&, &&&&
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Communications
Heterocycle Synthesis
W. Ji, Y. A. Liu, X. Liao*
&&&& — &&&&
Transition-Metal-Free Synthesis of N-
Hydroxy Oxindoles by an Aza-Nazarov-
Type Reaction Involving Azaoxyallyl
Cations
A bit weak: In the title reaction, a variety
of functional groups are tolerated under
weakly basic reaction conditions and at
room temperature. This method provides
alternative access to oxindoles and their
biologically active derivatives. FG=func-
tional group, HFIP=1,1,1,3,3,3-hexa-
fluoro-2-propanol.
Angew. Chem. Int. Ed. 2016, 55, 1 – 5
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!