Aerobic Radical-Cascade Alkylation/Cyclization of α,β-Unsaturated Amides: an Efficient Approach to Quaternary Oxindoles

Article abstract of DOI:10.1002/anie.201603809

An efficient method for the aerobic radical-cascade alkylation/cyclization of α,β-unsaturated amides to afford functionalized oxindoles with a C3 quaternary stereocenter is described. The process is based on the generation of valuable alkyl radicals throu

Full text of DOI:10.1002/anie.201603809

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International Edition: DOI: 10.1002/anie.201603809
German Edition: DOI: 10.1002/ange.201603809
Synthetic Methods
Aerobic Radical-Cascade Alkylation/Cyclization of a,b-Unsaturated
Amides: an Efficient Approach to Quaternary Oxindoles
Promita Biswas, Subhasis Paul, and Joyram Guin*
Abstract: An efficient method for the aerobic radical-cascade
alkylation/cyclization of a,b-unsaturated amides to afford
functionalized oxindoles with a C3 quaternary stereocenter is
described. The process is based on the generation of valuable
oxindole scaffold.[6] Although, significant advances have been
made in the construction of oxindoles with C3 quaternary
stereocenters by intercepting alkyl radicals with N-arylacryl-
amides, the existing methods generally require a metal
catalyst, stoichiometric oxidant, and/or toxic solvent.[7] As
a consequence, the development of an efficient and econom-
ical method to such compounds under benign conditions
would be highly desirable. It has been reported that the
aerobic oxidation of aldehydes involves an acyl radical
intermediate.[8] We thus hypothesized that an alkyl radical
may be obtained through decarbonylation of the acyl radical
generated by aldehyde auto-oxidation under suitable reaction
conditions.[9,10] The in situ generated alkyl radical is expected
to react with N-alkyl-N-arylacrylamide to form a new carbon-
centered radical intermediate that upon intramolecular
cyclization with the aromatic ring would deliver the desired
oxindole (Scheme 1). Herein, we report the successful
À
alkyl radicals through sustainable aerobic C H activation of
aldehydes followed by decarbonylation using O2 as the sole
oxidant. This method features a broad substrate scope,
inexpensive alkyl radical precursors, and convenient reagents.
Finally, the method was successfully applied to the synthesis of
alkyl analogues of tetrahydrofuranoindoline and (Æ)-esermet-
hole.
C
ascade reactions initiated by intermolecular addition of
a carbon-centered radical to an olefin enable the efficient
construction of multiple carbon–carbon bonds in a single
chemical operation with generally high functional-group
compatibility.[1,2] The synthetic potential of this strategy has
been well established in the synthesis of complex natural
products.[3] However, a major disadvantage of this process is
access to the free-radical intermediates, in particular alkyl
radicals, which typically requires pre-functionalized sub-
strates and undesirable reagents and/or reaction condi-
tions.[2,3] Therefore, an environmentally friendly method for
a free-radical-cascade reaction involving alkyl radicals gen-
erated from readily available precursors by a more conven-
ient and efficient approach is still in great demand.
À
In our recent report on the C H alkylation of hetero-
aromatic bases,[4] we demonstrated an efficient method for the
generation of valuable alkyl radicals through aldehyde auto-
oxidation. Despite this work, the scope of this simple
alkylation technique needs to be further expanded with
other radical acceptors to establish the synthetic power of the
method. Hence, we became interested in developing an
alkylation/cyclization cascade reaction with alkyl radicals
generated through aerobic oxidation of an aldehyde, which
may offer easy access to functionalized cyclic compounds
under mild reaction conditions.
Scheme 1. An aerobic radical alkylation/cyclization cascade of N-alkyl-
N-arylacrylamide.
N-Arylacrylamides have recently received considerable
attention as radical acceptors in developing free-radical-
initiated addition/cyclization cascades to synthesize function-
alized oxindole moieties,[5] since large numbers of bioactive
natural products and pharmaceutical molecules contain an
realization of this approach to the preparation of various
quaternary oxindoles with alkyl functionalities in good yields.
The method employs inexpensive aldehydes as alkyl radical
precursors, O2 as the sole oxidant, and ethyl acetate as a green
solvent.
The concept presented in Scheme 1 was established from
the results obtained from the reaction between 2-ethylbutanal
1a and N-alkyl-N-arylacrylamide 2a under various reaction
conditions in the presence of O2 (1 atm.). The optimized
reaction conditions revealed that the oxindole 3 could indeed
be obtained in 73% yield of isolated product when using
8 equiv of 1a and ethyl acetate as the solvent after 39 h (see
[*] P. Biswas, S. Paul, Dr. J. Guin
Department of Organic Chemistry
Indian Association for the Cultivation of Science
2A & 2B Raja S. C. Mullick Road, Jadavpur, Kolkata-700032 (India)
E-mail: ocjg@iacs.res.in
Supporting information for this article can be found under:
http://dx.doi.org/10.1002/anie.201603809.
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Table 1: Reaction scope with respect to the aldehyde.[a]
method. For asymmetrical substrates with substituents at the
m position of the aromatic ring, the formation of regioisomers
was observed, with low selectivity. The reaction furnished the
oxindole 31 in 65% yield when the benzene ring of the
substrate was replaced with a naphthalene moiety. Impor-
tantly, various functionalized aza-oxindoles (32–36) were
synthesized in moderate to good yields when using N-
pyridine-substituted methacrylamide. Substrates with differ-
ent N substituents, such as ethyl, benzyl, phenyl, and ester
groups, could be converted into the desired products 37–40 in
good yields. However, unprotected NH arylmethacrylamide
was found to be completely ineffective for this transformation
(see the Supporting Information).
The synthetic utility of this method was demonstrated in
the preparation of alkyl-substituted tetrahydrofuranoindoline
and pyrrolidinoindoline moieties, which could be easily
converted into alkyl analogues of naturally occurring alka-
loids such as (Æ)-physovenine, and (Æ)-physostigmine. This
family of alkaloids exhibit inhibitory activity against acetyl-
cholinesterase and butyrylcholinesterase.[12] Furthermore,
(À)-physostigmine has been used for the treatment of
glaucoma and severe anticholinergic toxicity.[13] The synthesis
was initiated by performing the key radical-cascade alkyla-
tion/cyclization of conjugated amide 41 (prepared as pre-
sented in Scheme 2) with various structurally diverse alde-
[a] All the reactions were carried out with amide 2a (1.0 equiv),
aldehydes 1a–h (8–12 equiv), EtOAc (0.1–0.2m) for 48 h. Yields of
isolated products are given. [b] Combined yields are given. [c] The
diastereoisomeric ratio (d.r.) was determined by 1H NMR analysis of the
sample.
the Supporting Information). With the optimized reaction
conditions, the scope of the transformation was evaluated
with different aliphatic aldehydes (Table 1). Symmetrically a-
substituted aldehydes furnished the corresponding 3,3’-dia-
lkylated oxindoles 3 and 4 in good yields. Unsymmetrical a-
branched aldehydes reacted with equal efficiency, delivering
the oxindoles 5–7 in a 1:1 mixture of two diastereoisomers.
Cyclohexyl substituted oxindole 8 was obtained in moderate
yield when the reaction was performed with cyclohexanecar-
boxaldehyde. Interestingly, the reaction enabled the synthesis
of highly sterically demanding oxindole 9, which has two
alternative quaternary centers, in good yield when using
pivaldehyde as the tert-butyl radical precursor. The reaction
was found to be less efficient with a linear aldehyde, affording
the desired product 10 in 15% yield.[11] The much lower
reactivity of the linear aldehyde towards alkylation can be
explained by the fact that decarbonylation of the primary acyl
radical to form the corresponding alkyl radical is energetically
less favorable.[9b]
We then directed our attention toward exploring the
scope of this transformation with a broad range of N-alkyl-N-
arylacrylamides with varying substituents on both the aro-
matic ring and the nitrogen center (Table 2). Substrates with
a methyl substituent at any position of the aryl moiety
exhibited good reactivity under the optimized reaction
conditions (11–16). Varying the electronic properties of the
substrate from electron-donating (methoxy) to electron-with-
drawing (cyano, ester, trifluoromethyl) substituents made no
considerable difference to the yields of the final products (17–
22). Halide substituents at the o, m, and p positions of the
aromatic ring were well tolerated in this transformation (23–
29). Importantly, oxindole 30, which bears a sensitive iodo
functionality, could be prepared in 65% yield by this simple
Scheme 2. Synthesis of alkylated tetrahydrofuranoindolines and alkyl
analogues of (Æ)-esermethole. Reaction conditions: a) Et3N, CH2Cl2,
12 h, RT, 67%; b) aldehydes (8.0 equiv), O2 (1 atm.), EtOAc (1.0 mL,
0.2m), 48 h, 1158C; c) LiAlH4 (4.0 equiv), THF, 1 h, RT; d) i. MeN-
H2·EtOH (33%), 48 h, 708C, 79–92% (50–52); ii. LiAlH4 (8.0 equiv),
THF, 3 h, 708C. THF=tetrahydrofuran.
hydes, furnishing the desired products 42–45 in good yields
(54–70%). Reduction of oxindoles 42–45 with LiAlH4
delivered tetrahydrofuranoindolines 46–49, which can be
easily converted into the (Æ)-physovenine analogues.[14]
Furthermore, alkyl analogues of (Æ)-esermethole (53–55)
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Table 2: Reaction scope with respect to the amide.
[a] Unless otherwise indicated, all the reactions were carried out with N-alkyl-N-arylacrylamides 2b–2ae (1.0 equiv), 1a (8–10 equiv), EtOAc (0.2m) for
40–90 h. Yields of isolated products are given. [b] The regioisomeric ratios refer to the isolated products and the structure of the major isomer is
drawn. [c] Combined yields are given.
were synthesized from oxindoles 42–44 by amidation followed
by LiAlH4 reduction. Compounds 53–55 may serve as
precursors for the synthesis of (Æ)-physostigmine ana-
logues.[14]
To shed light on the mechanism of the reaction, several
control experiments were carried out (see the Supporting
Information). The reaction gave only trace amounts of the
desired product under argon atmosphere, thus suggesting that
O2 is absolutely necessary for this transformation. However,
a much lower yield of the desired product was observed when
the reaction was performed using a O2 balloon. This result
indicates that a higher concentration of O2 in the reaction
mixture may be detrimental to the process. Furthermore, the
reaction did not provide any desired product in the presence
of 2,2,6,6-tetramethyl-l-piperidinoxyl (TEMPO), presumably
owing to the involvement of various radical intermediates in
this process. Based on the above observations and literature
precedent, a possible reaction mechanism for the aerobic
alkylation/cyclization cascade reaction is depicted in
Scheme 3. The acyl radical generated from aldehyde auto-
oxidation delivers the corresponding alkyl radical through
decarbonylation. The alkyl radical thus formed reacts with
electron-deficient N-alkyl-N-arylacrylamide to provide the
Scheme 3. A proposed reaction mechanism.
new carbon-centered radical intermediate A. Intramolecular
cyclization of A with an aromatic ring gives cyclohexadienyl
radical B, which furnishes the desired oxindole after rear-
omatization with O2 or a hydroperoxide radical.
In conclusion, we have developed an unprecedented and
efficient method for the aerobic radical alkylarylation of
À
electron-deficient amides through dual C H bond function-
alization under metal- and peroxide-free conditions. The
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different alkyl-functionalized oxindoles with a C3 quaternary
stereocenter, as well as analogues of biologically important
naturally occurring alkaloid such as (Æ)-esermethole.
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Acknowledgements
We gratefully acknowledge the generous financial support
received from Science and Engineering Research Board,
India (No. SB/S5/GC-08/2014) and CSIR for fellowship to
P. B. and S.P.
Keywords: alkylation · cascade reactions · cyclization ·
oxindoles · radical reactions
How to cite: Angew. Chem. Int. Ed. 2016, 55, 7756–7760
Angew. Chem. 2016, 128, 7887–7891
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Received: April 20, 2016
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