Metal- and Oxidant-Free Modular Approach to Access N-Alkoxy Oxindoles via Aryne Annulation

Article abstract of DOI:10.1021/acs.orglett.8b01972

An unprecedented metal- and oxidant-free (intermolecular) approach to access N-alkoxy oxindoles via [3 + 2] cycloadition of in situ generated electrophilic species viz. aryne and (putative) aza-oxyallyl cation is reported. This approach is amenable to both C3-unsubstituted as well as C3-substituted oxindoles. A one-pot manipulation further makes this reaction highly practical. The versatility of this approach was demonstrated through valuable synthetic transformations.

Full text of DOI:10.1021/acs.orglett.8b01972

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Metal- and Oxidant-Free Modular Approach To Access N‑Alkoxy
Oxindoles via Aryne Annulation
Ritesh Singh,*,†,‡ Kommu Nagesh,‡,§ Doddapaneni Yugandhar,‡,§ and AVG Prasanthi‡,§
†Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Raebareli-229010,
UP, India
‡Organic Synthesis and Process Chemistry Division, CSIR-Indian Institute of Chemical Technology, Hyderabad-500007, Telangana,
India
S
* Supporting Information
ABSTRACT: An unprecedented metal- and oxidant-free (intermolecular)
approach to access N-alkoxy oxindoles via [3 + 2] cycloadition of in situ
generated electrophilic species viz. aryne and (putative) aza-oxyallyl cation
is reported. This approach is amenable to both C3-unsubstituted as well as
C3-substituted oxindoles. A one-pot manipulation further makes this
reaction highly practical. The versatility of this approach was demonstrated
through valuable synthetic transformations.
xindoles are an important scaffold in natural products1
free reaction conditions for the construction of oxindoles.
Existing methods typically are radical initiated intramolecular
Oand pharmaceutics, which are endowed with manifold
bioactivities such as anticancer,2a analgesic effects,2b calcium
transformations using anilide as starting materials (which
channel blockers,2c etc. Consequently, during past decades
requires preassembly of desired substitutents and thus are
multistep) which require harsh reaction conditions (high
several elegant strategies have appeared to construct this
temperature and/or strong oxidants) and are limited to C3-
coveted moiety with different functionalities through various
disubstituted oxindoles (eq 1; Scheme 1).4b,6a−c,l,9 Although
pathways such as a Friedel−Craft type reaction,4 transition
Zhu4a and Zhao10 developed metal-free methods via alternate
metal catalyzed cyclization,5 and radical cyclization,6 besides
pathways, requirement of external oxidants (hypervalent
derivatization of bicyclic isatin/indole.3 Additionally, oxindoles
iodine(III)) was necessary for efficiency. Very recently, an
elegant transition-metal-free approach was reported by Liao et
al. (through aza-Nazarov cyclization), but requires exotic
often serve as a versatile intermediate for synthesis of various
natural products7 as well as biologically active compounds (eq
3; Scheme 1).8 Owing to its profound importance, recently,
fluorinated solvent for its success and limited to C3-substituted
N-hydroxy oxindoles.11 In light of the above-mentioned
there has been growing interest in the development of metal-
limitations, development of newer and sustainable methods
under benign conditions to access diversified oxindoles is
highly desirable (eq 2; Scheme 1).
Scheme 1. Previous Reports and Our Approach for
Oxindole Synthesis
On the other hand, cycloaddition with α-haloamides via an
aza-oxyallyl cation intermediate has lately garnered significant
attention.12 It participates as 3 units (2π electron) in formal [3
+ 2] cycloadditions showing a reactivity profile similar to a well
established electrophilic oxy-allyl cation13 and act as a LUMO
partner with their counterparts which are often electron-rich
and polar systems. Likewise, arynes with their highly
electrophilic character and low-lying LUMO have forged
their place in organic synthesis as an efficient, 2 unit participant
in formal [3 + 2] cycloadditions (as 4π + 2π) with 1,3-dipoles
for construction of a five-membered ring.14 Despite significant
progress in the 1,3 dipolar cycloaddition reaction with arynes,
[3 + 2] cycloaddition based on the 2π + 2π electron system is
Received: June 26, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b01972
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
unconceived. More importantly realization of α-unsubstituted
haloamides as a putative aza-oxyallyl cation synthon is hitherto
unknown.12c Therefore, in an attempt to provide a metal-/
oxidant-free route, herein, disclosed is our envisioned novel
intermolecular disconnection approach to access both C3-
unsubstituted and C3-substituted N-alkoxy oxindoles under
extremely mild reaction conditions where the first successful
realization of conceptually novel [3 + 2] [2π + 2π] formal
cycloaddition of two in situ generated electrophilic species has
been achieved.24
Our work commenced with screening of various parameters
in order to search for the ideal reaction conditions for an
efficient and successful cycloaddition of aryne precursor, 2-
(trimethylsilyl) aryl triflate 1a with α-haloamide 2 (Table 1).
revealed KF/18-c in itself was sufficient to promote the
reaction with equal efficiency (entry 5). No reaction without
18-c proved the necessity of F− under the phase transfer
system (PTS) to act as both nucleophile and base (entry 6).
An increase in aryne concentration (2 equiv) significantly
improved the yield of product 3a (entry 7). Subsequent
screening with different F−(PTS) sources demonstrated
tetrabutyl ammonium fluoride (TBAF) as the best reagent
for the dual role of base and nucleophile, perhaps due to
greater basicity and solubility in THF (entries 8−10). Other
solvents (diethyl ether, CF3CH2OH (TFE), (CF3)2CHOH
(HFIP), and CH2Cl2) screened proved futile, and no desired
product 3a was observed in any case (entries 11−13). Diluting
the reaction further helped in achieving the best yield of the
product 3a with a reaction time of just 30 min (entries 14−
16). No reaction was observed with N-Bn substituted substrate
2b; this indicated requirement of a N-alkoxy substituent for
stabilization of a putative aza-oxyallyl cation. Reaction without
addition of molecular sieves provided a lower yield of 3a,
indicating the detrimental effect of adventitious moisture in the
reaction medium (entry 18). With optimized reaction
conditions in hand, we then studied the scope and limitation
of this novel process for C3-unsubstituted oxindole synthesis.
As shown in Scheme 2, C3-unsubstituted oxindoles with
different N-substituents (OMe, O-Et, O-t-Butyl, OCH2C6F5,
a
Table 1. Optimization of [3 + 2] Cycloaddition
substrate
(equiv)
temp
3a
b
entry
F− (equiv)
solvent
THF
THF
THF
THF
(°C)
(%)
c
1
1a:2a (1.1:1) CsF (2.2)
1a:2a (1.1:1) CsF (2.2)
1a:2a (1.1:1) KF (2)
rt
0
0
0
0
20
5
c
2
c
3
c
Scheme 2. . Reaction Scope toward C3-Unsubstituted
Oxindoles
4
1a:2a (1.1:1) KF/18-c
30
(2.2)
5
6
1a:2a (1.1:1) KF/18-c
THF
THF
0
0
31
(4.2)
1a:2a (1.1:1) KF or CsF
NR
(6)
7
8
9
10
11
12
13
14
15
1a:2a (2:1)
1a:2a (2:1)
1a:2a (2:1)
1a:2a (2:1)
1a:2a (2:1)
1a:2a (2:1)
1a:2a (2:1)
1a:2a (2:1)
1a:2a (2:1)
KF/18-c (6) THF
TBAT (6) THF
CsF/18-c (6) THF
0
0
0
0
0
0
0
0
0
69
52
55
74
NR
NR
0
TBAF (6)
TBAF (6)
TBAF (6)
TBAF (6)
TBAF (6)
TBAF (6)
THF
TFE/HFIP
ether
CH2Cl2
THF (0.05 M)
82
85
THF
(0.025 M)
16
17
1a:2a (2:1)
1a:2b (2:1)
1a:2a (2:1)
TBAF (6)
TBAF (6)
TBAF (6)
THF
0
0
0
84
(0.015 M)
THF
(0.025 M)
THF
(0.025 M)
NR
71
d
18
a
1
a
Regioselectivity determined from crude H NMR.
Reactions were conducted in a Schlenk tube under argon at 0 °C
with 1a, 2, F− source, and 4 Å MS (200 wt %), in anhydrous THF, 30
b
c
min (see SI for details). Isolated yields. With K2CO3 (2 equiv).
and O-allyl) were readily generated using this cycloaddition
strategy in high yields (entries 3b−h). Noteworthily, N-OMe
substituted α-bromoamides which have previously failed to
participate in the cycloaddition process with dienes12c were
efficiently incorporated to achieve the desired oxindole (3b).
Thereafter, to observe the steric and electronic effect on this
cycloaddition process, several symmetrical/unsymmetrical
aryne precursors were tested. Both electron-donating (OMe)
and electron-withdrawing (F) group substituted symmetrical
arynes provided excellent yields of the desired oxindoles
(entries 3i and 3j). Bulky 2-naphthyl aryne also smoothly gave
the desired cycloaddition product in good yield (entry 3k).
Interestingly 3-OMe substituted aryne gave a single
regioisomer of the oxindole product15 with nucleophilic attack
(from N of aza-oxyallyl cation, 2a) on the m-position (entry
d
Without 4 Å MS. NR = No Reaction. TBAT = Tetrabutyl-
ammonium difluorotriphenylsilicate.
Our initial attempt with N-OBn substituted bromoaceta-
mide derivative 2a using CsF as the F− source and K2CO3 as
the base in anhydrous THF failed to give any desired product
when the reaction was conducted at room temperature (messy
reaction mixture, entry 1). However, conducting the reaction
at 0 °C with the same reagents pleasingly gave the desired C3-
unsubstituted N-benzyloxy oxindole 3a, albeit in low yield
(entry 2). In an attempt to increase the yield, combination of
KF/K2CO3 did not show any improvement (entry 3);
however, addition of 18-crown [6] (18-c) gave a better yield
(entry 4). A control reaction conducted in the absence of base
B
DOI: 10.1021/acs.orglett.8b01972
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
3l). Surprisingly, the corresponding benzyne with a small 3-Me
substituent gave high selectivity for the product arising from m-
attack (entry 3n/3n′), perhaps due to the additive steric effect
of the N-substituent on 2a. Expectedly, no steric or electronic
effect on 4-Me and the modest electronic effect on 4-OMe/4-F
substituted aryne was observed giving a mixture of two isomers
in each case (entries 3o/3o′, 3p/3p′, and 3q/3q′,
respectively). A single product was obtained from the 1-
naphthyl aryne owing to sterics (entry 3m).
In order to make this protocol more practical, the feasibility
of a one-pot process was then tested. Consequently, in a vessel
containing methoxylamine hydrochloride (OMeNH2·HCl)
and Et3N in anhydrous THF at 0 °C bromoacetyl bromide
was added dropwise, and the reaction was allowed to stir at 0
°C. After 3 h, 4 Å MS, TBAF, and an aryne precursor, 1a, was
added sequentially and the reaction was further stirred for 30
min at the same temperature, affording 3b, without
significantly affecting the yield (80%). In fact, N-OMe oxindole
constitutes a vital core in Gelsemium alkaloids as well as
Phytoalexins, wherein compound 3b serves as a prime
intermediate for total syntheses of Gelsemine,7b Gelsedilam,7a
Gelsemoxonine,16 and Wasalexins1e (Scheme 3). Notably, this
is the first intermolecular metal-/oxidant-free report for C3-
unsubstituted oxindole.17
groups) substituted N-alkoxy oxindoles were readily accessed
by reacting various arynes with corresponding monoalkyl α-
bromoamides 4, in very good yields under standard reaction
conditions (s.r.c.) (entries 5a−j). A similar regioselectivity
pattern was observed as in the case for the aforementioned C3-
unsubstituted oxindoles (shown in Scheme 2) (entries 5k−
5o). Surprisingly, an attempt to obtain C3-aryl substituted
(entry 5p) as well as C3-dimethyl substituted oxindole 7 using
amide 6 via this approach failed (eq 2), perhaps due to the
steric effect. Instead, uncyclized products 8 and 9 from
respective N- and O-attack of the putative aza-oxyallyl cation
were obtained in a 2:1 ratio. Of note, the reactivity trend of α-
haloamides observed in this work is in sharp contrast to their
reactivity trend observed in literature, where dialkyl substituted
haloamides (6) react faster and successfully (at ambient
temperature) as compared to monoalkyl (4) and unsubstituted
haloamides (2), respectively.12c,d
However, in our quest to utilize this strategy to access C3-
disubstituted N-alkoxy oxindoles, a one-pot, two-step strategy
was adopted, where 1a was first reacted with bromoamide 2a.
Under s.r.c., after the stipulated time, THF was removed and
the crude obtained was then treated with MeI in DMSO, using
potassium tert-butoxide (tBuOK) as base, which furnished C3-
dimethyl substituted oxindole 7 in very good yield at rt (eq 3,
Scheme 5).
Scheme 3. One-Pot Manipulation of 3b
Scheme 5. Application toward C3-Disubstituted Oxindoles
Next, we investigated the efficiency of this method for the
synthesis of C3-substituted N-alkoxy oxindoles. As summarized
in Scheme 4, C3-monoalkyl (methyl, ethyl, and n-butyl
Scheme 4. Reaction Scope toward C3-Substituted Oxindoles
a
Yield in parentheses was obtained in one-pot reaction starting from 1
and corresponding α-bromoamide (see SI for details).
The synthetic utility of this cycloaddition strategy was
further demonstrated by synthesizing C3-aryl substituted
quaternary carbon centered N-alkoxy oxindoles. Consequently,
C3-monoalkyl substituted oxindoles (5a and 5g) were treated
t
with electrophile 1a in DMSO using BuOK as the base and
KF/18-c as the F− source, which provided C3-phenyl
substituted quaternary stereocentered N-benzyloxy oxindoles
(10 and 11) in excellent yields. This approach was readily
extended to synthesize biologically important C3-biaryl
substituted oxindole 1218 from 3a under similar reaction
conditions (eq 4, Scheme 5). Importantly, a one-pot
maneuvered protocol makes this process highly efficient and
practical (see Supporting Information (SI) for details).
In view of the observed reactivity of various bromoamides,
with arynes (vide supra), plausible reaction pathways have been
delineated for product formation (Scheme 6). Upon
generation of aryne from 1a, it could react with either the
open aza-oxyallyl cation intermediate A21a or its valence
tautomer (closed intermediate), α-lactam B,20a,b generated
simultaneously under s.r.c. via pathways (a) and (b),
respectively, to provide the desired oxindoles.
a
1
Regioselectivity determined from crude H NMR
C
DOI: 10.1021/acs.orglett.8b01972
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 6. Putative Reaction Pathways for Oxindole
Synthesis
Scheme 8. Large Scale Synthesis of 3a, Versatility of N-
Protecting Group, and Further Synthetic Applications
with α-haloamides. Realization of synthetically unexplored
unsubstituted α-bromoamide, as a putative aza-oxyallyl cation
synthon, is a notable feature in this report. Further, it is a rare
system that does not require fluorinated solvents for successful
cycloaddition with α-haloamides, perhaps owing to highly
reactive arynes as the coupling partner. Detailed mechanistic
insight along with asymmetric manipulation of this novel
transformation is currently underway and will be reported in
due course.
However, in view of previous reports20 where α-lactam has
been proposed under a similar reaction medium (ether) and
involved in a subsequent rearrangement,20c a concerted
cycloaddition with transient α-lactam B generated from
substrates 2a and 4 (via intermediate A) is assumed to be
more favorable (pathway b), to give the desired products 3a
and 5f respectively, as compared to concerted or stepwise
cycloaddition with intermediate A, while α-dimethyl sub-
stituted bromo amide 6 would follow path b or c via cyclic
intermediates B and C respectively, leading to unsaturated
products 8 and 9. Observation of imidate 9 is consistent with
involvement of aza-oxyallyl cations, as observed in the
successful cycloaddition of α-dimethyl haloamide in earlier
reports.12f−h,21b,c,d
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b01972.
Preparation and characterization information; HPLC
In order to shed some light on the possibility of the stepwise
nucleophilic addition/elimination pathway in this trans-
formation (see Scheme S1 in SI), an optically pure amide
1321e was treated with 1a under s.r.c., which furnished racemic
product 5f (Scheme 7; see Figures S1−S4 in SI), clearly
1
chromatograms; H, 13C, and 19F NMR (PDF)
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: riteshsingh@niperraebareli.edu.in; ritesh.cdri@gmail.
com.
Scheme 7. Mechanistic Insight Using Chiral Substrate
ORCID
Ritesh Singh: 0000-0002-2000-6800
Author Contributions
§K.N., D.Y., and A.V.G.P. contributed equally.
Notes
indicating formation of an aza-oxyallyl cation as the
intermediate in the current cycloaddition (at least in α-
mono-/disubstituted bromoamides).22
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
A gram scale synthesis of 3a (eq 5, Scheme 8), besides
deprotection of the N-protecting group to access N−OH
(entry 3a′, eq 6, Scheme 8) and N−H (entry 5f′, eq 7, Scheme
8) oxindoles, was also demonstrated on substrates 3a and 5f
respectively. The synthetic utility of this method was further
shown by efficient transformation of 3h in to N-alkoxy indole
14, a bioactive scaffold,23 via reductive dehydration and a drug
analog (Semaxanib), 15, via Knoevenagel condensation (eq 8,
Scheme 8).
R.S. thanks DST (Department of Science and Technology),
New Delhi for an INSPIRE Faculty (Award No. IF15-CH-
179) grant. Prof. Takayoshi Suzuki (KPUM, Japan) is highly
acknowledged for kind support. Dr. S. J. S. Flora (Director
NIPER-R) is acknowledged for support and encouragement.
This is NIPER-R/Communication/043.
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intermolecular approach to access both C3-unsubstituted and
C3-substituted oxindoles via [3 + 2] cycloaddition of arynes
D
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intermediate/α-lactam in this cycloaddition (see Scheme S2 in SI).
E
DOI: 10.1021/acs.orglett.8b01972
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Organic Letters
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However, no solid evidence is there at this stage to conclusively
distinguish between the possible mechanisms; hence, we believe both
could contribute toward the observed products 3.
(23) Jump, S. M.; Kung, J.; Staub, R.; Kinseth, M. A.; Cram, E. J.;
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(24) During the course of the preparation of this manuscript, an
aryne-based approach for a different class of oxindole derivatives was
reported by: Pandya, V. G.; Mhaske, S. B. Org. Lett. 2018, 20, 1483.
F
DOI: 10.1021/acs.orglett.8b01972
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