KOH-mediated stereoselective alkylation of 3-bromooxindoles for the synthesis of 3,3′-disubstituted oxindoles with two contiguous all carbon quaternary centres

Article abstract of DOI:10.1039/d0nj06283a

The stereoselective synthesis of 3,3′-disubstituted oxindoles having all-carbon quaternary stereocenters has been achieved using KOH as a base with an excellent diastereomeric ratio (98?:?2). The practicability of the present methodology has been validated with the synthesis of a series of substrates in good to excellent yields. The aesthetic simplicity, accessibility, and eco-friendly base (KOH) have prompted the broader application of the present methodology in organic synthesis.

Full text of DOI:10.1039/d0nj06283a

NJC
View Article Online
View Journal
COMMUNICATION
KOH-mediated stereoselective alkylation of
3-bromooxindoles for the synthesis of
3,30-disubstituted oxindoles with two contiguous
all carbon quaternary centres†
Cite this: DOI: 10.1039/d0nj06283a
Received 28th December 2020,
Accepted 31st March 2021
Manju Devi, Amol P. Jadhav and Ravi P. Singh
*
DOI: 10.1039/d0nj06283a
rsc.li/njc
The stereoselective synthesis of 3,30-disubstituted oxindoles having all- stereocenters on the o-azaxylylenes,7 installing contiguous stereo-
carbon quaternary stereocenters has been achieved using KOH as a centers is quite a herculean task and relatively less explored. In
base with an excellent diastereomeric ratio (98 : 2). The practicability of addition, an alternative method to generate the carbon nucleo-
the present methodology has been validated with the synthesis of a phile can be by simple dearomatization of indoles;8 however, due
series of substrates in good to excellent yields. The aesthetic simplicity, to the planar structure of indole, the interaction with the electro-
accessibility, and eco-friendly base (KOH) have prompted the broader phile becomes challenging. The indole dearomatization strategy
application of the present methodology in organic synthesis.
was first introduced in 1954 by Woodward to synthesize indole-
nine type scaffolds using Pictet Spengler reaction.9 Further develop-
ment in indole dearomatization remained dormant for about three
decades till Magnus and Kuehne demonstrated the efficacy of indole
dearomatization in the total synthesis of strychnos alkaloids using
transannular Mannich reaction.10 Later on, various synthetic meth-
odologies were developed using indole dearomatization for the total
synthesis of natural products and industrially essential molecules.8e
Among these, alkylative dearomatization of indole has aroused
specific interest due to its utility in the synthesis of indole alkaloids
containing a C3 all-carbon quaternary center. A thorough literature
Introduction
Indoline scaffolds with a C3 all-carbon quaternary stereocenter
are one of the most commonly observed heterocyclic scaffolds
in nature.1 While the unique C3 stereocenter imparts
unmatched bioactivity, it also poses synthetic hardship.2 The
quaternary stereocenter is challenging to recreate due to the
substituents on the carbon center that cause high steric
repulsions.2a Even more challenging is the generation of
a vicinal all-carbon quaternary stereocenter.2b Despite many
efforts, only
a limited number of approaches such as
alkylation3 and cycloaddition4 reactions have been successfully
used for the synthesis of such structural motifs to date. One
approach that has been recently used is the formation of
o-azaxylylenes from 3-haloindoles as an intermediate and its
exploration in various transformations that can provide direct
access to 3-functionalized 2-oxindole derivatives.5 While the
reaction has been developed for the non-stereoselective synthesis
of 3-functionalized 2-oxindole, the diastereoselective version is yet
to be developed. Recently, several base promoted approaches
where carbon nucleophiles and heteroatom-based nucleophiles
have been added to the o-azaxylylenes have been reported
(Fig. 1).5,6 Interestingly, while it is easier to install single
Department of Chemistry, Indian Institute of Technology, Delhi, Hauz Khas,
New Delhi-110016, India. E-mail: ravips@chemistry.iitd.ac.in
† Electronic supplementary information (ESI) available. CCDC 2039264. For ESI
and crystallographic data in CIF or other electronic format see DOI: 10.1039/
d0nj06283a
Fig. 1 Methods for the synthesis of 3,30-dialkyl substituted oxindoles.
This journal is © The Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2021
New J. Chem.

View Article Online
Communication
NJC
Table 1 Optimization of the reaction conditionsa
survey suggests that even with a demanding synthetic utility of
alkylative dearomatization, only a few reports are witnessed. For
instance, in 2004, Funk and co-workers reported the synthesis of
perophoramidine using the alkylative dearomatization strategy, and
later in 2012, the synthesis of communesin-F was also reported
following the same protocol.6b,g Later in 2016, Bisai and co-workers
reported the synthesis of dimeric 2-oxindoles consisiting of a vicinal
all-carbon quaternary stereocenter, which is an active intermediate
in the total synthesis of (+)-folicanthine.6e Recently, the Feng group
have reported the synthesis of b-alkyl nitriles from dearomatization
of indol-2-ones having two contiguous stereocentres that provide
easy access to the synthesis of pyrroloindolines.6c Although the
present literature precedences demonstrate that such Michael addi-
tion and similar azaxylylene addition reactions are quite extensively
used in organic transformation utilizing a metal catalyst, the devel-
opment of a more economical and environmentally benign
approach is still awaited. We believe that a more economical version
will have a tremendous impact as commonly used reactions
generate more toxic and difficult to dispose off waste in large
quantities over scarce reactions that may not generate such waste
in any significant quantities. Hence the development of more
novel and general synthetic methodologies toward such structural
motifs is urgently needed. Herein we report the synthesis of 3,
30-disubstituted oxindoles having all-carbon quaternary stereo-
Entry Base
Solvent Temp (1C) Yieldb (%) drc (anti/syn)
1
2
3
4
5
6
7
8
DIPEA
DBU
DABCO
K3PO4
CPME r.t.
CPME r.t.
CPME r.t.
CPME r.t.
51
46
n.d
65
59
62
55
68
78
n.d
60
70
70
76
71
n.d.
45
60 : 40
60 : 40
—
78 : 22
65 : 35
74 : 26
60 : 40
77 : 23
80 : 20
—
85 : 15
93 : 7
93 : 7
97 : 3
95 : 5
—
Na3PO4ꢀ12H2O CPME r.t.
Cs2CO3
DIPEA
K3PO4
Cs2CO3
KOtBu
KOH
CPME r.t.
CH2Cl2 r.t.
CH2Cl2 r.t.
CH2Cl2 r.t.
CH2Cl2 r.t.
CH2Cl2 r.t.
9
10d
11d
12d
13d
14d
15d
16d
17d
KOH
KOH
KOH
KOH
KOH
KOH
CH2Cl2 0
CH2Cl2 ꢁ10
CH2Cl2 ꢁ20
CH2Cl2 ꢁ40
C6H14
PhMe
ꢁ20
ꢁ20
93 : 7
a
All reactions were performed with 1a (0.2 mmol), 2a (0.24 mmol), and
b
c
base (0.4 mmol) in solvent (2.0 mL) for 6 h. Isolated yield. Diaster-
eomeric ratios were determined by 1H NMR of the crude reaction
centers using
base KOH.
a cheap, readily available, and eco-friendly
d
mixtures. Stirred for 3 h.
With KOH as an optimal base, the reaction temperature was
screened to achieve the best reaction yields. By decreasing the
Result and discussion
We started our investigation by a model reaction between reaction temperature to 0 1C, an increase in reactivity and
3-benzyl-3-bromooxindole 1a and 3-methylindole 2a in CPME selectivity of the reaction was observed with 70% yield and
(cyclopentyl methyl ether) as a solvent and using DIPEA as a 93 : 7 dr (Table 1, entry 12). Decreasing the reaction tempera-
base at room temperature. The reaction proceeded smoothly to ture to ꢁ20 1C results in the formation of 3a in 76% yield with
give the desired product 3a in 51% yield with a diastereomeric 97 : 3 dr (Table 1, entry 14), and decreasing the reaction
ratio (dr) of 60 : 40 (Table 1, entry 1). Furthermore, the reaction temperature to ꢁ40 1C affects the reaction yields and dr
was examined with a hindered base such as DBU; however, a negatively (Table 1, entry 15). Various solvents were also
decrease in reactivity was observed (Table 1, entry 2). When the screened for improvement in yields, and dr. However, a hydro-
reaction was carried out with DABCO as a base, no product carbon solvent like hexane did not yield any product formation
formation was observed. (Table 1, entry 3). In the presence of (Table 1, entry 16), while toluene afforded good diastereoselec-
inorganic bases such as K3PO4, Na3PO4ꢀ12H2O, and Cs2CO3 tivity (93 : 7) with poor reaction yield (Table 1, entry 17). Con-
only a substantial improvement in the dr of the adduct 3a with clusively, using KOH as a base in DCM solvent at ꢁ20 1C affords
moderate yield was observed (Table 1, entries 4–6). When the the best reaction outcome for the stereoablative alkylation of
solvent was changed from CPME to DCM, no considerable 3-benzyl-3-bromooxindole using 3-methylindole to afford 3a
change in the reactivity and selectivity of the reaction was with 76% yield and 97 : 3 dr. Furthermore, the substrate scope
observed (Table 1, entries 7 and 8). On using Cs2CO3 as a base has been examined using the above-mentioned reaction stan-
in DCM, the reaction yielded the desired product 3a in 78% dards unless otherwise noted.
yield with 80 : 20 dr (Table 1, entry 9). Interestingly, sterically
Having the optimized reaction conditions in hand, the sub-
hindered non-nucleophilic bases like KOtBu failed to catalyze strate scope has been explored using various 3-substituted-3-
the reaction, and no product formation was observed (Table 1, bromooxindoles. The reaction proceeds smoothly under standard
entry 10). However, the other strong alkali metal base, reaction conditions concerning both electron-donating and
KOH, showed better results for the stereoselective alkylation electron-withdrawing groups (-ortho, -meta and -para position) to
of 3-bromooxindole. By using KOH as a base, a significant afford their corresponding products in good to excellent yields
reduction in the reaction time and improvement in dr were and dr (Table 2, entries 3a–3j). Notably, no dehalogenation has
observed. The reaction was completed in half the reaction time been observed in the case of halogenated oxindoles (3b–d) that
(3 h) to afford 3a in 60% yield with 85 : 15 dr (Table 1, entry 11). enables the further elaboration of the molecular skeleton using
New J. Chem.
This journal is © The Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2021

View Article Online
NJC
Communication
Table 2 Stereoablative alkylation of various 3-bromooxindoles 1 with
various substituted indoles 2abc
Scheme 1 Gram scale alkylation reaction.
optimized reaction conditions to afford their corresponding
products in good yields (62–68%) with 98 : 2 dr (Table 2, entries
3m–3n). The indoles bearing –Cl or –OMe groups on the phenyl
ring of indole also reacted smoothly under the optimised reaction
conditions and afforded their corresponding products in accepta-
ble yields and excellent dr (97 : 3). Furthermore, the steric effect of
bulky substituents at the C3 position of indole was examined using
3-isopropyl indole as a model substrate. Unfortunately, the reaction
did not proceed under the optimized reaction conditions, and
starting materials were recovered successfully. However, the N-Boc
protected 1H-indole 3-ethylamine afforded the corresponding
product 3q in 67% yields with lower dr value. The decrease in
the reaction yields might be attributed to the steric effect of the
–alkylNHBoc group. Conclusively, the steric effect on the C3
position of indole significantly affected its reactivity when a bulkier
group than methyl was imposed.
Furthermore, the gram scale alkylation of 1a was done by
treating 2 mmol of 1a with 2.4 mmol of 2a yielding the product
3a in 71% yield and without deterioration in diastereoselec-
tivity (Scheme 1).
Finally, a plausible reaction pathway has been proposed
based on literature precedent6b,g for the stereoablative alkyla-
tion of bromooxindoles with indoles (Scheme 2). The first step
involves the formation of an o-azaxylylene B intermediate from
3-bromooxindole A in the presence of a base (KOH). The
intermediate B undergoes conjugate addition11 reaction with
indole C to give the intermediate E that undergoes intra-
molecular proton abstraction to give final product 3. Notably,
the intermediate B might undergo Diels–Alders reaction with
a
All reactions were carried out with 1 (0.2 mmol), 2a (0.24 mmol), and
b
KOH (0.4 mmol) in CH2Cl2 (2.0 mL) at ꢁ20 1C for 3 h. Isolated yield.
c
Diastereomeric ratios determined by 1H NMR of crude reaction mixtures.
transition metal-based coupling reactions. The relative stereo-
chemistry of 3c was assigned to be anti- by single-crystal X-ray
analysis (see ESI† for details). Interestingly, the heteroaryl group
substituted oxindoles gave a slightly lower yield (55%) with 95 : 5 dr
as compared to its other aryl-substituted analogs. Similarly, the C3
substitution on indole also affects the yields of reaction and results
in a subsequent decrease in the reaction yield (60%, 98 : 2 dr) on
changing the substituent from methyl to ethyl (3l). After the
successful synthesis of substrates concerning different substitu-
tions on oxindole, the effect of substitution on the C2 position of
indoles was further examined on the reaction yields and dr.
Delightfully, the C2, C3 disubstituted indoles also react under Scheme 2 Plausible reaction mechanism.
This journal is © The Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2021
New J. Chem.

View Article Online
Communication
NJC
4 (a) B. M. Trost, N. Cramer and S. M. Silverman, J. Am. Chem.
Soc., 2007, 129, 12396–12397; (b) J. N. Payette and
H. Yamamoto, J. Am. Chem. Soc., 2007, 129, 9536–9537;
(c) L. Gao, G.-S. Hwang and D. H. Ryu, J. Am. Chem. Soc.,
2011, 133, 20708–20711; (d) Z.-Y. Cao, X. Wang, C. Tan,
X.-L. Zhao, J. Zhou and K. Ding, J. Am. Chem. Soc., 2013, 135,
8197–8200; (e) K. Ohmatsu, N. Imagawa and T. Ooi, Nat. Chem.,
2014, 6, 47–51; ( f ) A. Jolit, P. M. Walleser, G. P. A. Yap and
M. A. Tius, Angew. Chem., Int. Ed., 2014, 53, 6180–6183.
5 (a) X. Liu, P. Wang, L. Bai, D. Li, L. Wang, D. Yang and
R. Wang, ACS Catal., 2018, 8, 10888–10894; (b) X.-L. Liu,
J. Yue, S. Chen, H.-H. Liu, K.-M. Yang, T.-T. Feng and
Y. Zhou, Org. Chem. Front., 2019, 6, 256–262.
6 (a) K. Kawasaki, D. Aoki and H. Otsuka, Macromol. Rapid
Commun., 2020, 41, 1900460; (b) J. R. Fuchs and R. L. Funk,
J. Am. Chem. Soc., 2004, 126, 5068–5069; (c) J. Zheng, L. Lin,
L. Dai, Q. Tang, X. Liu and X. Feng, Angew. Chem., Int. Ed.,
2017, 56, 13107–13111; (d) C. Wu, G. Li, W. Sun, M. Zhang,
L. Hong and R. Wang, Org. Lett., 2014, 16, 1960–1963; (e) S. De,
M. K. Das, A. Roy and A. Bisai, J. Org. Chem., 2016, 81,
12258–12274; ( f ) Y.-L. Huang, W.-H. Bao, W.-W. Ying,
W.-T. Chen, L.-H. Gao, X.-Y. Wang, G.-P. Chen, G.-P. Ge and
W.-T. Wei, Synlett, 2018, 1485–1490; (g) J. Belmar and
R. L. Funk, J. Am. Chem. Soc., 2012, 134, 16941–16943.
7 (a) A. P. Jadhav, A. Manchanda, M. K. Jaiswal and
R. P. Singh, Adv. Synth. Catal., 2017, 359, 3917–3921;
(b) X. Bai, Z. Jing, Q. Liu, X. Ye, G. Zhang, X. Zhao and
Z. Jiang, J. Org. Chem., 2015, 80, 12686–12696; (c) J. Zuo,
Z.-J. Wu, J.-Q. Zhao, M.-Q. Zhou, X.-Y. Xu, X.-M. Zhang and
W.-C. Yuan, J. Org. Chem., 2015, 80, 634–640; (d) J. Zuo,
Y.-H. Liao, X.-M. Zhang and W.-C. Yuan, J. Org. Chem., 2012,
77, 11325–11332; (e) X. Xie, L. Jing, D. Qin, W. He, S. Wu,
L. Jin and G. Luo, RSC Adv., 2014, 4, 11605–11609.
indole C to give the intermediate D that undergoes ring open-
ing to give intermediate E and finally undergoes intramolecular
proton abstraction to give the final product 3.
Conclusions
In conclusion, we have developed a KOH mediated strategy for
the stereoselective synthesis of 3,30-disubstituted oxindoles having
all-carbon quaternary stereocenters from 3-bromooxindoles and
3-substituted indoles in good to excellent yields and diastereoselec-
tivity up to 98 : 2. The substrate scope has been examined concern-
ing different substitutions on 3-bromooxindoles, and 3-methyl
indole, which resulted in their corresponding products in good
yields and diastereotopic ratio that indeed enables the synthesis of a
library of heteroaromatics.
Conflicts of interest
There are no conflicts to declare.
Acknowledgements
This research was supported by the DST-India (EMR/2017/
000319), CSIR [02(0254)/16/EMR-II], and DAE (201804BRE02
RP04978-BRNS). MD is grateful to the CSIR, New Delhi, India,
for a JRF. The authors thank Dr Pawan Kumar for help in
prepartion of the manuscript. The authors acknowledge DST-
FIST for providing the mass spectrometer facility.
Notes and references
1 (a) A. R. Katritzky and C. W. Rees, Comprehensive Hetero-
cyclic Chemistry, Pergamon Press, Ltd, Headington Hill Hall,
Oxford OX3 OBW, England, 1984; (b) R. Long, J. Huang,
J. Gong and Z. Yang, Nat. Prod. Rep., 2015, 32, 1584–1601;
(c) R. M. Lemieux and A. I. Meyers, J. Am. Chem. Soc., 1998,
120, 5453–5457; (d) L. E. Overman, D. V. Paone and
B. A. Stearns, J. Am. Chem. Soc., 1999, 121, 7702–7703;
(e) B. M. Trost and M. Osipov, Angew. Chem., Int. Ed.,
2013, 52, 9176–9181.
8 For review see; (a) W. Zi, Z. Zuo and D. Ma, Acc. Chem. Res.,
2015, 48, 702–711; (b) D. Zhang, H. Song and Y. Qin, Acc.
Chem. Res., 2011, 44, 447–457For research articles see; ;
(c) S. B. Gohain, M. Basumatary, P. K. Boruah, M. R. Das and
A. J. Thakur, Green Chem., 2020, 22, 170–179; (d) H.-L. Cui,
S.-W. Liu and X. Xiao, J. Org. Chem., 2020, 85, 15382–15395;
(e) J.-C. Yi, C. Liu, L.-X. Dai and S.-L. You, Chem. – Asian J.,
2017, 12, 2975–2979; ( f ) S. P. Roche, J.-J. Youte Tendoung
and B. Treguier, Tetrahedron, 2015, 71, 3549–3591 and
references therein. ; (g) C. Zheng and S.-L. You, Nat. Prod.
Rep., 2019, 36, 1589; (h) S. P. Roche, J. J. Y. Tendoung and
B. Treguier, Tetrahedron, 2015, 71, 3549–3591.
2 (a) D. Liu, G. Zhao and L. Xiang, Eur. J. Org. Chem., 2010,
3975–3984; (b) E. A. Peterson and L. E. Overman, Proc. Natl.
Acad. Sci. U. S. A., 2004, 101, 11943–11948.
¨
3 (a) C. Uyeda, A. R. Rotheli and E. N. Jacobsen, Angew. Chem.,
Int. Ed., 2010, 49, 9753–9756; (b) H. Mitsunuma,
M. Shibasaki, M. Kanai and S. Matsunaga, Angew. Chem.,
Int. Ed., 2012, 51, 5217–5221; (c) K. Ohmatsu, Y. Ando and
T. Ooi, J. Am. Chem. Soc., 2013, 135, 18706–18709;
9 R. B. Woodward, M. P. Cava, W. D. Ollis, A. Hunger,
I. U. Daeniker and K. Schenker, J. Am. Chem. Soc., 1954, 76,
4749–4751.
(d) S. Ghosh, S. Bhunia, B. N. Kakde, S. De and A. Bisai, 10 (a) P. Magnus, M. Giles, R. Bonnert, C. S. Kim, L. McQuire,
Chem. Commun., 2014, 50, 2434–2437; (e) H. Yang, K.-S. Cao
and W.-H. Zheng, Chem. Commun., 2017, 53, 3737–3740;
( f ) S. J. Han, F. Vogt, J. A. May, S. Krishnan, M. Gatti,
S. C. Virgil and B. M. Stoltz, J. Org. Chem., 2015, 80, 528;
(g) J. Qiu, J.-X. Zhang, S. Liu and X.-J. Hao, Tetrahedron Lett.,
A. Merritt and N. Vicker, J. Am. Chem. Soc., 1992, 114,
4403–4405; (b) P. Magnus, M. Giles, R. Bonnert, G. Johnson,
L. McQuire, M. Deluca, A. Merritt, C. S. Kim and N. Vicker,
J. Am. Chem. Soc., 1993, 115, 8116–8129; (c) M. E. Kuehne and
F. Xu, J. Org. Chem., 1993, 58, 7490–7497.
˜
2013, 54, 300–302; (h) I. Olaizola, R. A. A. Abdine, 11 For review see; D. Trubitson and T. Kangera, Symmetry,
H. Dhimane and P. I. Dalko, Synthesis, 2017, 391–396. 2020, 12, 1184–1214.
New J. Chem.
This journal is © The Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2021