Construction of Quaternary Carbon Center via NHC Catalysis Initiated by an Intermolecular Heck-Type Alkyl Radical Addition

Article abstract of DOI:10.1021/acs.orglett.1c01400

A quaternary carbon center containing an oxindole motif is constructed via NHC-catalyzed transition-metal and aldehyde-free intermolecular Heck-type alkyl radical addition initiated annulation. This redox-neutral protocol also features a simple procedure, broad substrate scope, good functional group tolerance and could be smoothly amplified to a gram scale. The mechanism study shows that the reaction possibly undergoes two folds of SET processes with an NHC radical cation intermediate involved.

Full text of DOI:10.1021/acs.orglett.1c01400

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Letter
Construction of Quaternary Carbon Center via NHC Catalysis
Initiated by an Intermolecular Heck-Type Alkyl Radical Addition
Lanjun Su, Huan Sun,* Jikai Liu,* and Chengming Wang*
Cite This: Org. Lett. 2021, 23, 4662−4666
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ABSTRACT: A quaternary carbon center containing an oxindole
motif is constructed via NHC-catalyzed transition-metal and
aldehyde-free intermolecular Heck-type alkyl radical addition
initiated annulation. This redox-neutral protocol also features a
simple procedure, broad substrate scope, good functional group
tolerance and could be smoothly amplified to a gram scale. The
mechanism study shows that the reaction possibly undergoes two folds of SET processes with an NHC radical cation intermediate
involved.
itrogen-containing heterocycles with quaternary carbon
centers.4−6 To date, well-reported protocols are mainly based
Ncenters are ubiquitous in nature. They are one of the on transition-metal catalysis (Scheme 1, a).4,6b While
transition-metal catalysts do provide remarkable efficiency for
these transformations, they also suffer from high costs and
toxicity, harsh reaction conditions, and poor selectivity. In this
context, the demands for developing metal-free access to 3,3′-
disubstituted oxindoles5 have steadily increased since they
meet the current fundamental research goals for sustainable,
green, and clean organic synthesis.
most abundant and important classes of useful building blocks
in organic synthesis.1 In particular, 3,3′-disubstituted oxindole
is an attractive structural motif found in numerous natural
products and biologically active molecules as shown in Figure
1.2
Today, N-heterocyclic carbenes (NHCs) have wide
applications involving in numerous important processes in
organic synthesis,7 coordination chemistry,8 and materials
science.9 However, the chemistry of NHCs greatly depends on
aldehydes or other substrates containing active carbonyl
functional group (such as acyl fluoride or α,β-unsaturated
ester).7 For example, it is well-known that NHCs can either be
directly used for umpolung of aldehyde functional groups or
form the acyl azolium intermediates and work as electrophiles.
Therefore, the exploration and development of new reactivity
pathways which expand the range of suitable reaction partners
beyond the traditional aldehydes is of great importance to this
research field. In recent years, Ohmiya and others reported a
series of novel NHC-catalyzed radical coupling reactions.10
However, the scope of these transformations is still limited to
aldehyde compounds. Recently, Severin et al. revealed that the
NHC catalyst could undergo a SET process with oxidizing
Lewis acids to afford NHC radical cation (Scheme 1, b).11
Moreover, our group has just disclosed the first NHC-
Figure 1. Selected drugs containing sulfone motifs.
Over the past few decades, the synthesis of oxindoles
containing quaternary carbon atoms is still one of the central
issues in organic synthesis because the reaction to construct
quaternary carbon atoms usually suffers from the problem of
steric hindrance.3 Despite many efforts, current reported
methods still do not allow the efficient synthesis of this type
of functionalized quaternary carbon atoms. As a result, organic
chemists continue to search for more straightforward and
sustainable ways to prepare various oxindoles containing
quaternary carbon centers with diversified functional groups.
Among them, intermolecular radical addition to N-arylacyla-
mides followed by tandem cyclization is one of the simplest
and direct methods to construct such quaternary carbon
Received: April 23, 2021
Published: June 3, 2021
https://doi.org/10.1021/acs.orglett.1c01400
© 2021 American Chemical Society
Org. Lett. 2021, 23, 4662−4666
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a
Scheme 1. Synthesis of Oxindoles with Quaternary Carbon
Centers
Table 1. Conditions Optimization
b
entry
solvent
MeCN
toluene
DMSO
n-Bu2O
1, 4-dioxane
1, 4-dioxane
1, 4-dioxane
1, 4-dioxane
1, 4-dioxane
1, 4-dioxane
1, 4-dioxane
1, 4-dioxane
1, 4-dioxane
1, 4-dioxane
1, 4-dioxane
catalyst
base
yield (%)
1
2
3
4
5
6
7
8
NHC A
NHC A
NHC A
NHC A
NHC A
NHC A
NHC A
NHC A
NHC A
NHC A
NHC B
NHC C
NHC D
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
DBU
67
15
14
43
86
9
34
16
45
38
56
<5
<5
ND
ND
Et3N
NaOAc
NaHCO3
t-BuOK
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
9
10
11
12
13
14
15
NHC A
a
Reaction on a 0.25 mmol scale, using 1a (1.0 quiv.), 2a (1.5 equiv),
NHC (20 mol %), base (2.0 equiv), solvent (0.25 mL), 110 °C, under
b
N2, 24 h. NMR yield. ND = not detected. For structures of NHC
catalysts A−D, see:
reaction had a good functional group tolerance and an
acceptable substrate scope. Various acrylamides 1a−h with a
broad substitution pattern and different electronic natures at
the ortho-, meta-, and para-positions on the phenyl ring can be
well applied, thus smoothly affording the related oxindole
products (3a−h) in middle to good yields. It was worth noting
that substrates containing fluorine atoms (1f, 1g), which
widely distribute in many drugs,12 were also nicely compatible
with this radical process. Substrates with different N-protecting
substituents, such as methyl, ethyl, benzyl, phenyl, and p-
methylphenyl groups, all could be efficiently converted into the
desired products (3a, 3i−m) in acceptable yields. Next,
different radical precursors were tested. Among them, α-bromo
esters 1n−p, α-bromo keto 1q, α-bromo nitriles 1r−s, and
even CX4 (X = Cl, Br) 1t−u all work well to generate the
oxindoles with related quaternary carbon centers (3n−u). In
particular, more sterically hindered substrate 1v also afforded
related cyclization product 3v, thus further extending the scope
of this conversion. Currently, other halogen compounds, such
as benzyl bromide, allyl bromide, and 2-bromopentane all
failed to give the desired products. Chiral NHCs were also
tested; however, no ee values were detected (for details, see the
Supporting Information).
catalyzed aldehydes and active carbonyl group free intra-
molecular radical cyclization reaction, thus broadening the
scope of NHC catalysis (Scheme 1, c).5d Herein, we report an
example of NHC-catalyzed intermolecular Heck-type alkyl radical
addition initiated intramolecular annulation reaction leading to
the rapid and efficient construction of quaternary carbon center at
the 3-position of oxindoles.
Initial condition optimization was performed with N-phenyl
acylamide 1a and α-bromo ester 2a in the presence of NHC
catalyst A and Cs2CO3 in MeCN under argon (Table 1).
Gratifyingly, the cyclization product 3a was obtained in 67%
yield (entry 1). This yield can be further improved to 86%
when tends to 1,4-dioxane (entry 5). Other solvents, such as
toluene, DMSO, and n-Bu2O, all dramatically decreased the
yields (entries 2−4). Among the organic and inorganic bases
screened, Cs2CO3 is the best one (entries 5−10). The
structure of the NHC catalysts also plays an important role
in this reaction, as was illustrated in entries 5, 11−13 (for more
details, see the Supporting Information). The reactions were
totally shut down in the absence of NHC catalyst or base
(entries 14 and 15). Finally, the best reaction conditions were
defined as 1a (1.0 equiv), 2a (1.5 equiv), NHC A (20 mol %),
and Cs2CO3 (2.0 equiv) in 1,4-dioxane at 110 °C.
Next, we investigated the regioselectivity of the cyclization
process of this transformation. Asymmetric disubstituted N-
arylacylamide 1w with different aromatic rings can smoothly
undergo this reaction and only gave the pyridinyl moiety
cyclization product 3w (Scheme 2, a), thus indicating the
excellent selectivity of the alkyl radical addition/annulation
process toward the heterocycle. However, the reaction of N-
The scopes and limitations of this intermolecular radical
addition initiated oxindole synthesis were carefully examined,
and the results are summarized in Table 2. Generally, this
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Letter
a
Table 2. Substrate Scope
Scheme 2. Selectivity of the Cyclization Process
Scheme 3. Gram-Scale Synthesis
Scheme 4. Reduction of the Product
and amide in 3a can be efficiently reduced to N-methyl
indoline 4a with a free hydroxyl in good yield upon treatment
with LiAlH4 in toluene,4d which provides the possibility for
further structure modification.
A series of experiments were carried out in order to shed
light on the reaction mechanism. When the reaction mixtures
were exposed to various radical scavengers, such as TEMPO
and O2, substantially diminished yields were obtained, thus
indicating the possible involvement of radical intermediates
(Scheme 5). Moreover, the observation of BHT-adduct 4b
further confirmed the generation of related radical inter-
mediate, which is possibly produced under the action of NHC
catalyst, and thus initiated the reaction by adding onto the
double bond followed by subsequent annulation reactions (for
more details, see the Supporting Information).
a
b
Isolated yield. Reaction at 130 °C using NHC A (40% mol), 2 (3.0
equiv), and Cs2CO3 (3.0 equiv).
Based on the above experiments and reported literatur-
es,5d,11,13,14 we proposed a mechanism for this transformation
(Scheme 6). Initially, sterically hindered NHC could serve as a
single-electron reductant and donate one electron to α-bromo
ester 2a, as proven by Severin et al.11 and our recent work,5d
giving rise to the formation of persistent NHC radical cation B
and related α-carbon radical A, which can be trapped by
external addition of BHT. Downstream carbon radical A added
onto the CC double bond would generate radical C, which
then quickly underwent another intramolecular radical
addition to form intermediate D. Next, a base-promoted
aryl acrylamide 1x with a different electronic nature at the
para-position on the phenyl ring mainly afforded a related
mixture of the cyclization products 3x−3y (Scheme 2, b).
In addition, the reaction can be effectively scaled up to 1 g
with similar synthetic efficiency (Scheme 3), which further
exhibited the practical application of this NHC-catalyzed
transformation.
This method allowed quick access to a series of free hydroxyl
molecules containing indoline motifs (Scheme 4). For
example, the both carbonyl functional groups of the ester
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Scheme 5. Radical-Capture Experiments
General experimental procedures, characterization data,
1
and copies of H, 19F and 13C NMR spectra for all
compounds (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
Huan Sun − School of Pharmaceutical Sciences, South-Central
University for Nationalities, Wuhan 430074, China;
Email: sunh15@163.com
Jikai Liu − School of Pharmaceutical Sciences, South-Central
University for Nationalities, Wuhan 430074, China;
orcid.org/0000-0001-6279-7893; Email: liujikai@
mail.scuec.edu.cn
Chengming Wang − Department of Chemistry, College of
Chemistry and Materials Science, Jinan University,
Guangzhou 511443, China; orcid.org/0000-0002-0201-
1526; Email: cmwang2019@jnu.edu.cn
Scheme 6. Proposed Mechanism
Author
Lanjun Su − School of Pharmaceutical Sciences, South-Central
University for Nationalities, Wuhan 430074, China
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c01400
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by National Natural Science
Foundation of China (81803395), Hubei Provincial Natural
Science Foundation of China (2018CFB222), and the
Fundamental Research Funds for the Central Universities
(21620318, 2019QNGG22, CZY20023). C.W. also thanks
Jinan University (start-up fund) for additional support.
homolytic aromatic substitution (HAS) reaction13,14 occurred
smoothly accompanied by the second SET process and
followed by deprotonation of D. Finally, the oxindole products
with quaternary carbon centers were efficiently accessed and
the catalytic cycle was successfully fulfilled.
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ASSOCIATED CONTENT
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