Oxidative dimerization of 2-oxindoles promoted by KOtBu-I2: Total synthesis of (±)-folicanthine

Article abstract of DOI:10.1021/acs.orglett.5b00032

A transition-metal-free oxidative coupling of 2-oxindoles has been demonstrated in the presence of 1.2 equiv each of potassium tert-butoxide and iodine. The method yields a diverse range of structurally different homo- and heterodimerized 2-oxindoles bearing vicinal all-carbon quaternary centers of great synthetic importance. A radical-driven pathway has been tentatively proposed.

Full text of DOI:10.1021/acs.orglett.5b00032

Letter
pubs.acs.org/OrgLett
Oxidative Dimerization of 2‑Oxindoles Promoted by KOtBu‑I2: Total
Synthesis of ( )-Folicanthine
Santanu Ghosh, Saikat Chaudhuri, and Alakesh Bisai*
Department of Chemistry, Indian Institute of Science Education and Research, Bhopal - 462 066, MP, India
S
* Supporting Information
ABSTRACT: A ‘transition-metal-free’ oxidative coupling of 2-oxindoles has been demonstrated in the presence of 1.2 equiv each
of potassium tert-butoxide and iodine. The method yields a diverse range of structurally different homo- and heterodimerized 2-
oxindoles bearing vicinal all-carbon quaternary centers of great synthetic importance. A radical-driven pathway has been
tentatively proposed.
C2-Symmetric1 dimeric cyclotryptamine alkaloids (1a−c, Figure
1) with a labile C3a−C3a′ σ-bond possess a diverse array of
palladation of indole (Scheme 1). We envisioned that
folicanthine 1b and related cyclotryptamine alkaloids can be
Scheme 1. Pd-Catalyzed Oxidative Dimerization
synthesized from a common intermediate ( )-2 (Figure 1),
which in turn can be accessed from a direct oxidative coupling of
2-oxindole ( )-4 (Figure 1). Herein, we report an expeditious
entry to dimeric 2-oxindoles bearing a variety of esters (8 and 9)
and alkyl functionality (2) via a direct oxidative coupling of 3-
substituted 2-oxindoles (6, 7, and 4) promoted by KOtBu-I2,
under mild conditions.
Figure 1. Selected bis-indole alkaloids (1a−c) with C2-symmetry.
biological activities.2 It is the presence of two vicinal all-carbon
quaternary stereocenters in these alkaloids which are a challenge
to the synthetic community, and hence they are attractive
synthetic targets.3 One of the plausible biogenetic pathways to
achieve this involves a direct C−C bond formation via oxidative
coupling4,5 of two C−H bonds. Synthetic approaches in this
direction are mainly concentrated toward the dimerization of 2-
oxindoles such as 3a6a,b and 3b6c (Figure 1). However, these
methods generally afford dimeric 2-oxindole products in poor to
moderate yields, which might be due to the associated difficulty
in the formation of a C−C bond containing a vicinal all-carbon
quaternary center. Other approaches to dimeric cyclotryptamine
alkaloids include direct oxidative dimerization of 3-substituted
indoles.7a−c,8
Initially, we thought to synthesize the dimeric 2-oxindoles10
possessing bisesters functionalities (8 and 9) via a Pd-catalyzed
oxidative coupling11 of 2-oxindole derivatives (6 and 7) (Scheme
1). We envisioned that, in the presence of a suitable base, ( )-6a
would generate enolate 10 (Scheme 2), which upon subsequent
ligand exchange with Pd(OAc)2 could lead to the formation of
Pd(II) intermediate 11c via the intermediacy of 11a and 11b.
Ultimately, the direct coupling of two C−H bonds of 2-oxindoles
( )-6a could be achieved following a reductive elimination
pathway. The process can be catalytic in the presence of a
In 2010, Shi et al. demonstrated an oxidative homodimeriza-
tion of indole derivatives toward 3,3′-linked bis-indole scaffolds
(5) via Pd-catalysis,9 where authors proposed formation of C-3
Received: January 5, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b00032
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Organic Letters
Letter
efficient to afford 8a in 66−68% yields with dr 2.0:1 (entries 6
and 7). Also, tBuOK was found to be superior over other bases
such as Cs2CO3 and tBuONa used in this reaction (entries 8−9).
Surprisingly, the same reaction, when performed in the
absence of Pd(II) (entry 10, Table 1), afforded 8a in 84% yield
with dr 1.9:1. A brief solvent screening showed that nonpolar
solvent such as toluene (entry 11) was inferior to polar aprotic
solvents such as dimethyl sulfoxide (DMSO) and N,N-
dimethylformamide (DMF) (entries 12−13), yielding 8a in
74% and 81% isolated yields, respectively, with almost similar dr.
Scheme 2. Our Initial Hypothesis
t
Optimization using different bases such as BuONa, Na2CO3,
K2CO3, and Cs2CO3 revealed that the product 8a can be
obtained in the range of 62−75% isolated yields with up to 2.4:1
dr (entries 14−17).13 These results prompted us to revise our
hypothesis of the Pd(II)-catalyzed sequence shown in Scheme 2.
Since, palladium does not play a significant role in the reaction of
6a to dimeric 8a, we proposed a more reasonable alternative
route involving a radical mediated intermolecular oxidative
coupling. A single electron transfer (SET) from enolate 10 to an
oxidant leads to the formation of radical intermediate 12a
(Scheme 3).14 The latter has the resonating structure, a 3° radical
sacrificial oxidant, which would help bring back the active catalyst
Pd(II).
Preliminary experiments were performed with N-methyl-2-
oxindole-3-methylcarboxylate (6a) in the presence of 1.2 equiv
of tBuOK as base and 1.2 equiv of various oxidants using 10 mol
% Pd(OAc)2 as the catalyst in DMF at 0 °C−rt. Several oxidants
such as FeCl3, Cu(OAc)2, iodosobenzene diacetate (PIDA), bis-
trifluoroacetate iodoxybenzene (PIFA), and I2 were screened in
the coupling reaction. It was found that molecular iodine12 was
the best oxidant to afford ( )-and meso-8a in 61% isolated yield
(dr 1.9:1) in 20 min (Table 1, entries 1−5). Switching to THF as
solvent, the yield was further increased to 68% (dr 1.9:1) (entry
6). We observed that Pd(OAc)2 and Pd(TFA)2 were equally
Scheme 3. Revised Proposed Pathway of Dimerization
Table 1. Optimization of Oxidative Coupling
(12b) at the pseudobenzylic position, which simply dimerizes to
afford expected product 8a (Scheme 3). In fact, a reaction
between tBuOK and iodine is known to produce tBuOI,15 which
is reported to be a good radical initiator in a variety of organic
transformations.16,17
In addition to iodine, simple oxidants such as N-halo
succinimides such as NIS18 and NBS also afforded product 8a
in 83% and 69% yields, respectively, with dr 1.6:1 (Table 2,
entries 1−2) and we did not observe any traces of halides 13a−b.
Interestingly, well-known oxidizing agents, such as PIDA and
PIFA,19 which follow a radical mechanism, also afforded dimeric
product 8a in 45−52% yields (entries 3−4). Thus, based on this
a
b
sl. no. solvent
base
oxidants
FeCl3
time
1 h
yield (%)
dr
c
1
2
3
4
5
6
7
8
9
DMF
DMF
DMF
DMF
DMF
THF
THF
THF
THF
THF
PhMe
DMSO
DMF
THF
THF
THF
THF
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
Cs2CO3
NaOtBu
KOtBu
KOtBu
KOtBu
KOtBu
NaOtBu
Na2CO3
K2CO3
Cs2CO3
−
−
−
c
c
c
c
c
d
c
c
e
Cu(II)
1 h
trace
f
PIDA
PIFA
I2
30 min
30 min
20 min
20 min
20 min
40 min
40 min
15 min
30 min
15 min
15 min
15 min
15 min
15 min
15 min
43
1.4:1
1.3:1
1.9:1
1.9:1
2.0:1
2.0:1
1.2:1
1.9:1
1.3:1
1.7:1
1.9:1
1.1:1
1.5:1
2.4:1
1.9:1
f
38
61
68
66
I2
I2
f
I2
51
f
I2
46
Table 2. Optimization of Intramolecular-Dehydrogenative
Coupling
10
11
12
13
14
15
16
17
I2
84
f
I2
31
I2
74
81
62
68
75
72
I2
I2
I2
I2
a
b
entry
oxidants
time
yield (%)
dr
I2
1
2
3
4
NIS
15 min
15 min
25 min
25 min
83
69
1.5:1
1.6:1
1.7:1
1.4:1
a
NBS
PIDA
PIFA
Reactions were carried out on a 0.25 mmol of 6a in the presence of
0.30 mmol of base and oxidants in 1 mL of solvent at 0−25 °C, and
isolated yields of 8a are reported. Dr determined from H NMR of
unpurified reaction mixture. 10 mol % Pd(OAc)2 was used as catalyst.
10 mol % Pd (TFA)2 was used as catalyst. Cu(OAc)2·H2O was used
as oxidant. Mixture of products for rest of the mass balance.
c
52
b
c
1
45
c
d
e
a
b
1
Isolated yields of 8a. Dr determined from H NMR of unpurified
f
c
reaction mixture. Mixture of products for rest of the mass balance.
B
DOI: 10.1021/acs.orglett.5b00032
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Organic Letters
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evidence, it is quite reasonable to understand that our
methodology follows a radical mediated process.
With the optimized conditions, we then explored the substrate
scope using a variety of N-alkyl-2-oxindole-3-carboxylates (6, see
Supporting Information for synthetic procedure) to afford
dimeric 2-oxindoles. As evidenced from Figure 2, a variety of
Figure 3. Substrate scope with various allylic type esters.
Scheme 4. Scope of Heterodimerization
Figure 2. Substrate scope of oxidative dimerization.
dimeric 2-oxindoles sharing vicinal all-carbon quaternary centers
(8a−r) were obtained in 62−84% yields with a dr up to 3.9:1.
The dr of the products can be further improved to >20:1
following recrystallization in a few cases to afford active isomer
( )-8.20
To further extend the scope, a variety of N-methyl and benzyl
substituted 2-oxindole-3-carboxylates (7, see Supporting In-
formation for detailed method) having allyl, methallyl, prenyl,
and geranyl esters with a diversely substituted 2-oxindole core
were subjected to standard coupling conditions, and the results
are shown in Figure 3.
efficient platform for the synthesis of unsymmetrical dimeric
indole alkaloids.
Apart from this, different N-protected substrates, such as 3-
methyl-N-Boc-2-oxindole 15a, also undergo dimerization with-
out an event to afford 14a in 73% with an ∼1.1:1 dr (Figure 4)
thus increasing the scope of the method even further. However,
the reaction faced limitations with substrate 16a, leading to 45−
50% recovery of starting material along with decomposition of
the rest of the mass balance (Figure 4). In the case of 2-oxindole
17, the starting material was consumed but no expected product
was isolated and always a multitude spots on TLC were observed.
These results also suggested a tertiary radical is probably
responsible for the oxidative coupling.
Notably, Nb-phth protected N-methyl-2-oxindole ( )-4
afforded dimeric 2 in 56% yield with ∼1.2:1 dr, which on
subsequent deprotection of the phthalimido group followed by
carbamate protection afforded 19 in 70% yield with ∼1.2:1 dr.
The major trans isomer was separated in column chromatog-
raphy followed by Red-Al treatment affording ( )-folicanthine
1b in 68% yield (see Supporting Information for details).
In summary, we have developed a novel and efficient oxidative
coupling protocol which allows the synthesis of a structurally
diverse range of dimeric 2-oxindoles with vicinal quaternary
centers. The reaction is mediated by KOtBu and I2 under mild
conditions, and additional research will focus on the develop-
Rewardingly, a variety of dimeric 2-oxindoles 9a−l were
prepared in good yields with a dr up to 2.8:1. Importantly, these
dimeric 2-oxindoles are potential substrates that can provide
access to enantioenriched bis-2-oxindoles with vicinal all-carbon
quaternary stereocenters21,22 under the influence of a catalytic
nonracemic Pd-complex.23 Later, a search for a more generalized
dimerization protocol prompted us to carry out heterodimeriza-
tion of two structurally different N-alkyl-2-oxindole-3-carbox-
ylates (Scheme 4). Consequently, we observed that an efficient
heterodimerization could also be realized under optimized
conditions (see Supporting Information for details). When two
different ester substrates were subjected to 1.2 equiv of each
KOtBu and I2, heterodimerized products 9m−n were obtained in
50−52% yield with a moderate dr of 2.4:1. In addition, we also
isolated homodimerized products in these processes in ∼10−
13% yields (Scheme 4). We have also seen that an isolated yield
of the heterodimerization product is dependent on the
concentration of the reaction medium. With the dilution, an
isolated yield of 9m also increased (see Supporting Information
for details). These heterodimerized skeletons represent an
C
DOI: 10.1021/acs.orglett.5b00032
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Organic Letters
Letter
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of simple bases, such as tBuONa, Na2CO3, K2CO3, and Cs2CO3, under
the optimized conditions.
ASSOCIATED CONTENT
* Supporting Information
General experimental procedures and analytical data for all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
■
S
(14) The vinyloxy radical has been proposed earlier by Baran and co-
workers: Richter, J. M.; Whitefield, B. W.; Maimone, T. J.; Lin, D. W.;
Castroveijo, P. M.; Baran, P. S. J. Am. Chem. Soc. 2007, 129, 12857.
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M.; Barton, D. H. R. J. Am. Chem. Soc. 1964, 86, 1528.
(16) We sincerely thank the reviewers for their valuable suggestions to
validate the reactions using a preformed well-known radical generator
tBuOI.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: alakesh@iiserb.ac.in.
Notes
(17) We have also conducted the oxidative dimerization in the
t
presence of in situ generated BuOI (see Supporting Information for
details) and found that oxidative dimerized products can be obtained in
synthetically useful yields.
The authors declare no competing financial interest.
(18) For use of NIS as an oxidant in an oxidative bond-forming
reaction, see: (a) West, S. P.; Bisai, A.; Lim, A. D.; Narayan, R. R.;
Sarpong, R. J. Am. Chem. Soc. 2009, 131, 11187. (b) Foo, K.; Newhouse,
T.; Mori, I.; Takayama, H.; Bran, P. S. Angew. Chem., Int. Ed. 2011, 50,
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(19) For a recent example, see: Wang, J.; Yuan, Y.; Xiong, R.; Zhang-
Negrerie, D.; Du, Y.; Zhao, K. Org. Lett. 2012, 14, 2210.
(20) The major diastereomer of our oxidative process is the active one,
which was confirmed from HPLC analysis of one of the products (9a).
(21) The dimeric 2-oxindoles of the type 9a can be converted to C2-
symmetric 2-oxindoles with vicinal all-carbon quaternary stereocenters.
See our report: Ghosh, S.; Bhunia, S.; Kakde, B. N.; De, S.; Bisai, A.
Chem. Commun. 2014, 50, 2434.
(22) For pioneering work on enantioselective double decarboxylative
allylations, see: (a) Trost, B. M.; Osipov, M. Angew. Chem., Int. Ed. 2013,
52, 9176. (b) Enquist, J. A., Jr.; Stoltz, B. M. Nature 2008, 453, 1228.
(23) For Pd-catalyzed asymmetric prenylations and geranylations, see:
Trost, B. M.; Malhotra, S.; Chan, W. H. J. Am. Chem. Soc. 2011, 133,
7328.
ACKNOWLEDGMENTS
■
Financial support from the DST (SR/S1/OC-54/2011) and the
CSIR [02(0013)/11/EMR-II], Govt. of India is gratefully
acknowledged. S.G. and S.C. thank the CSIR and UGC, New
Delhi, for the SRF and JRF, respectively.
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DOI: 10.1021/acs.orglett.5b00032
Org. Lett. XXXX, XXX, XXX−XXX