Synthesis of 2-oxindoles via 'transition-metal-free' intramolecular dehydrogenative coupling (IDC) of sp2 C-H and sp3 C-H bonds

Article abstract of DOI:10.3762/bjoc.12.111

The synthesis of a variety of 2-oxindoles bearing an all-carbon quaternary center at the pseudo benzylic position has been achieved via a 'transition-metal-free' intramolecular dehydrogenative coupling (IDC). The construction of 2-oxindole moieties was carried out through formation of carbon-carbon bonds using KOt-Bu-catalyzed one pot C-alkylation of β-N-arylamido esters with alkyl halides followed by a dehydrogenative coupling. Experimental evidences indicated toward a radical-mediated path for this reaction.

Full text of DOI:10.3762/bjoc.12.111

Synthesis of 2-oxindoles via 'transition-metal-free'
intramolecular dehydrogenative coupling (IDC) of
sp2 C–H and sp3 C–H bonds
Nivesh Kumar‡, Santanu Ghosh‡, Subhajit Bhunia and Alakesh Bisai*
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2016, 12, 1153–1169.
Department of Chemistry, Indian Institute of Science Education and
Research Bhopal, Bhopal Bypass Road, Bhauri, Bhopal – 462 066,
Madhya Pradesh, India
doi:10.3762/bjoc.12.111
Received: 13 February 2016
Accepted: 16 May 2016
Published: 08 June 2016
Email:
Alakesh Bisai* - alakesh@iiserb.ac.in
This article is part of the Thematic Series "C–H
Functionalization/activation in organic synthesis".
* Corresponding author ‡ Equal contributors
Keywords:
Guest Editor: R. Sarpong
C−H functionalization; intramolecular dehydrogenative coupling (IDC);
iodine; N-iodosuccinimide; oxidants; 2-oxindoles
© 2016 Kumar et al; licensee Beilstein-Institut.
License and terms: see end of document.
Abstract
The synthesis of a variety of 2-oxindoles bearing an all-carbon quaternary center at the pseudo benzylic position has been achieved
via a ‘transition-metal-free’ intramolecular dehydrogenative coupling (IDC). The construction of 2-oxindole moieties was carried
out through formation of carbon–carbon bonds using KOt-Bu-catalyzed one pot C-alkylation of β-N-arylamido esters with alkyl
halides followed by a dehydrogenative coupling. Experimental evidences indicated toward a radical-mediated path for this reaction.
Introduction
The C−H functionalization is an attractive synthetic strategy metal catalysts for efficient reactions, which are sometimes
used in organic synthesis for the development of atom- and undesirable [17-21]. Therefore, an alternate strategy to carry out
step-economical routes [1-10]. In recent years it was witnessed these transformations under 'transition-metal-free' conditions
a mushrooming growth in the number of reports in the litera- has recently gained immense importance.
ture owing to the efficiency of the oxidative coupling of two
C–H bonds [also termed as cross-dehydrogenative-coupling 2-Oxindoles having all carbon quaternary centres at the
(CDC)] in the formation of C–C bonds [11-16]. This was facili- pseudobenzylic position are common structural scaffolds in
tated by the introduction of transition metals in organic synthe- many naturally occurring alkaloids of biological relevance [22-
sis providing an amazing tool to explore these oxidative cou- 25]. These heterocyclic motifs especially exist in indole alka-
pling reactions in an efficient manner. However, despite the as- loids with a wide spectrum of biological and pharmacological
sociated advantages, these methodologies require one or two properties and hence are very attractive as well as challenging
1153

Beilstein J. Org. Chem. 2016, 12, 1153–1169.
synthetic targets [26]. Selected examples for the synthesis of a C-alkylation followed by an oxidative construction of the C–C
2-oxindole include an intramolecular homolytic aromatic substi- bond (Scheme 1) [46]. Applying the aforementioned strategy,
tution on the aryl ring by an amidyl radical formed by homol- we were able to synthesize several 3-alkyl-2-oxindoles bearing
ysis of a C–X bond [27-30], single electron transfer (SET) to a ester functionalities at the pseudobenzylic position from β-N-
α-halo anilides followed by halide elimination [31,32], and the arylamido allyl, methallyl, dimethylallyl, and geranyl esters.
formation of an aryl radical followed by a 1,5-hydrogen atom Here, in this article, we disclose the scope and limitations of
translocation [33,34]. Out of these strategies, the initial two 'transition-metal-free' IDC of Csp2-H and Csp3-H using iodine
require specifically functionalized precursors such as the pres- and N-iodosuccinimide (NIS) as oxidants. In addition, we have
ence of an o-halogen, an o-selenium, or an o-xanthate, respec- also demonstrated the synthetic utility of oxidative coupling
tively. One of the direct approaches to 2-oxindoles could be a products in the syntheses of 3-substituted-2-oxindoles, via a
one-electron oxidation of an amide enolate as shown in decarboxylative protonation on 2-oxindoles bearing an
Scheme 1. Toward this end, in 2009, Kündig and co-workers benzylester or para-methoxybenzyl ester at the 3-position in
have developed a novel route to 3,3-disubstituted-2-oxindoles presence of a catalytic amount of Pd on activated charcoal. We
while working on asymmetric synthesis of 3,3-disubstituted-2- have also shown the direct installation of allyl, prenyl, reverse-
oxindoles via a Pd-catalyzed (chiral N-heterocyclic carbene as prenyl, or geranyl groups at the 3-position of 2-oxindole using
ligands) intramolecular α-arylation of an amide [35-37]. For this Pd-catalyzed decarboxylative strategies [47].
'intramolecular dehydrogenative coupling' (IDC) of Csp2-H and
Csp3-H they used 2.2 equiv of CuCl2 and 5 equiv of NaOt-Bu Results and Discussion
[38,39].
We decided to use iodine as an oxidant for the synthesis of
2-oxindoles [48-53], starting from β-N-arylamido ester 3a and
In the same year, Taylor and co-workers independently re- methyl iodide as the substrates (Table 1). An elaborate optimi-
ported synthesis of 2-oxindoles in the presence of zation study suggested that the methylation can be done in the
Cu(OAc)2·H2O as oxidant (Scheme 1) [40-44]. Experimental presence of 1.2 equivalents of KOt-Bu and 1.1 equivalents of
evidence suggests involvement of a free-radical process in the methyl iodide. This was accompanied with an oxidative cou-
addition of α-carbonylalkyl radicals to the phenyl ring. The pling using 1.2 equivalents of KOt-Bu and iodine to afford the
α-carbonylalkyl radicals were formed by Cu(II)-mediated oxi- desired product in 65% yield (Table 1, entries 1 and 2). Optimi-
dation of the respective enolate precursors. In 2010, Yu and zation studies in search of suitable solvent, potential bases,
co-workers have reported the synthesis of 3-acetyloxindoles via oxidants etc. yielded the desired product in good yields i.e.
Ag2O-mediated intramolecular oxidative coupling [45]. For the 85%, 88%, and 90% in THF, dioxane, and DMSO, respectively
past few years, our group is engaged in the development of effi- (Table 1, entries 3, 5, and 8). However, in non-polar aromatic
cient methodologies for the synthesis of 2-oxindoles with solvents like xylene, benzene, and toluene, poor yields
intriguing ring systems. To this end, recently, we have reported (43–49%, Table 1, entries 4, 6, and 7) of products were ob-
a transition-metal-free ‘intramolecular-dehydrogenative-cou- served with reactions being unclean (mixture of products) [54].
pling' (IDC) strategy to access such 2-oxindole moieties through KOt-Bu was superior over other bases used in this reaction like
Scheme 1: Synthesis of 2-oxindoles via oxidative processes.
1154

Beilstein J. Org. Chem. 2016, 12, 1153–1169.
Table 1: Optimization of intramolecular-dehydrogenative-coupling (IDC)a.
entry
solvent
base
Alkylations at 25 °C
oxidants
time
% 4ab,c
1.
2.
DMF
DMF
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
NaH
20 min
20 min
30 min
45 min
20 min
50 min
45 min
20 min
20 min
2 h
1.5 equiv I2
1.2 equiv I2
1.2 equiv I2
1.2 equiv I2
1.2 equiv I2
1.2 equiv I2
1.2 equiv I2
1.2 equiv I2
1.2 equiv I2
1.2 equiv I2
–
6 h
3 h
65%
62%
85%
49%d
88%
43%d
45%d
90%
33%
–e
3.
THF
3 h
4.
xylene
dioxane
benzene
toluene
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
1 h
5.
2 h
6.
2 h
7.
1 h
8.
30 min
30 min
30 min
–
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
NaOMe
K2CO3
CS2CO3
t-BuONa
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
1 hf
–
2 h
1.5 equiv I2
1.5 equiv I2
1.2 equiv I2
0.6 equiv I2
0.3 equiv I2
1.2 equiv PIDA
1.2 equiv DBDMHh
1.2 equivICl
1.2 equiv NIS
1.2 equiv NBS
1.2 equiv NCS
1.0 equivTCICAi
0.5 equivTCICAi
30 min
30 min
30 min
1 h
26%g
–g
30 min
15 min
15 min
15 min
15 min
15 min
15 min
15 min
15 min
15 min
15 min
15 min
90%
54%
29%
82%
16%g
69%
84%
75%
58%
62%
56%
1 h
30 min
30 min
30 min
30 min
30 min
30 min
30 min
30 min
a Entries 1–18 have been reproduced from our preliminary communication (reference [46]. bReactions were carried out on a 0.25 mmol of 3a with
0.275 mmol of methyl iodide in presence of 0.30 mmol of base in 1 mL of solvent at 25 °C for specified time for alkylations and 0.275 mmol of oxidant
in presence of 0.30 mmol of base under heating at 110 °C for oxidative coupling steps, unless noted otherwise. cIsolated yields of 4a after column
chromatography. dMixture of products were observed for rest of the mass balance. eC-methylation as major product. fStarting material was recovered
(92%). gDecomposition of starting materials. hDBDMH (1,3-dibromo-5,5-dimethylhydantoin) as oxidant. iTCICA (trichloroisocyanuric acid).
NaH, NaOMe, K2CO3, Cs2CO3, and NaOt-Bu (Table 1, entries iodine or NIS, no product was formed. Eventually, the combina-
9–13). Among other metal-free oxidants, iodosobenzenediac- tion of 1.2 equivalents of iodine (conditions A) or NIS (condi-
etate (PIDA), DBDMH (1,3-dibromo-5,5-dimethylhydantoin), tions B) were found to be the best and chosen for further studies
and ICl afforded 2-oxindole 4a in 82%, 16%, and 69%, respec- (Table 1, entries 14 and 20).
tively (Table 1, entries 17–19). Later, we turned our attention to
N-halo succinimides as potential oxidants in our methodology Next, the substrate scope of the reaction was explored as shown
[53]. Interestingly, N-iodosuccinimide (NIS), N-bromosuccin- in Figure 1. A variety of substrates were prepared by a cou-
imide (NBS), and N-chlorosuccinimide (NCS) afforded 4a in pling reaction of N-methyl arylamines and monoalkyl
84%, 75%, and 58% yields, respectively (Table 1, entries malonates/cyanoacetic acids. Under optimized conditions A and
20–22). However, trichloroisocyanuric acid (TCICA) is found B, various β-N-arylamido esters and nitriles (3) were subjected
to be inefficient in oxidative coupling and afforded 56–62% to a one-pot alkylations using 1.2 equivalents of KOt-Bu to
yields of 4a (Table 1, entries 23 and 24). In the absence of produce C-alkylated intermediate 5 followed by oxidative cou-
1155

Beilstein J. Org. Chem. 2016, 12, 1153–1169.
Figure 1: Substrates scope of one-pot ‘transition-metal-free’ IDC. The syntheses of compounds 4a–s according to method A have been reproduced
from reference [46]. Conditions A: KOt-Bu, iodine; conditions B: KOt-Bu, NIS.
1156

Beilstein J. Org. Chem. 2016, 12, 1153–1169.
pling using 1.2 equivalents iodine or NIS. Gratifyingly, it was arylamido p-methoxybenzyl ester as starting materials for the
found that a range of β-N-arylamido esters (3a–s) and β-N- oxidative coupling reaction shown in Figure 2. Towards this
arylamido ketones (3t–x) underwent intramolecular dehydro- end, β-N-aryl amido benzylester or β-N-arylamido p-methoxy-
genative coupling (IDC) under both conditions A and B to benzyl ester 3 were subjected to an one pot alkylation to
afford a wide range of 2-oxindoles (4a–x) having an all-carbon generate the intermediate 7 followed by oxidative coupling
quaternary center in high yields. However, we observed that in reaction using our optimized conditions A and B to furnish
case of 2-oxindoles 4v and 4k, a two-step protocol is necessary, products of type (±)-6 in good yields (Figure 2). For the synthe-
where in first step C-alkylation of β-N-arylamido ketone was sis of compound (±)-6g, we followed a two-step protocol: In
carried out using 1.2 equivalents of KOt-Bu to afford products first step a C-alkylation of β-N-arylamido benzylester in pres-
5v and 5k, respectively (Figure 1), followed by a second oxida- ence of 1.2 equivalents of NaH and alkylating agent afford
tive coupling reaction in the presence of iodine or NIS.
compound (±)-7g in good yields (74%), followed by an oxida-
tive coupling in presence of 1.2 equivalents of KOt-Bu and
We envisioned that the oxidative coupling products containing iodine or NIS as oxidant.
benzyl or p-methoxybenzyl ester could be effective intermedi-
ates for the synthesis of 3-monosubstituted 2-oxindoles via Next, we focussed our attention to prenylated, reverse-prenyl-
deprotection of the benzyl group followed by decarboxylative ated, and geranylated hexahydropyrrolo[2,3-b]indole alkaloids
protonation in presence of a catalytic amount of Pd on acti- showing broad biological activities [55-61]. For the synthesis of
vated charcoal under hydrogenolysis. Thus, we explored the these compounds, we thought of utilizing the Pd-catalyzed
substrate scope using β-N-arylamido benzyl ester or β-N- decarboxylative strategy to install the prenyl, reverse-prenyl, or
Figure 2: Further substrates scope of one-pot ‘transition metal-free’ IDC. Conditions A: KOt-Bu, iodine; conditions B: KOt-Bu, NIS.
1157

Beilstein J. Org. Chem. 2016, 12, 1153–1169.
geranyl group at the 3-position of 2-oxindole starting from the Noticeably, we could directly construct the 2-oxindoles with a
corresponding β-amido esters such as 8 [47]. This further ex- geranyl group at the 3-position using geranyl bromide as an
tended the methodology to a variety of β-N-arylamido esters alkylating agent. Upon a subsequent oxidative coupling step,
containing allyl, methallyl, dimethylallyl, and geranyl ester products in good yields (8q–s, Figure 3) were formed using
groups (9). It is noteworthy that, the substrate of type 9 could conditions A. Later, the IDC was extended to substrates having
undergo smooth IDC in the presence of iodine (conditions A) to β-N-arylamido geranyl esters to afford compounds 8t–v
provide an access to compounds 8 in synthetically useful yields (Figure 3). These compounds could be excellent substrates for
(Figure 3).
carrying out Tsuji–Trost decarboxylative geranylations/reverse-
Figure 3: Substrates scope of ‘transition-metal-free’ IDC using KOt-Bu/I2. Reproduced from [46].
1158

Beilstein J. Org. Chem. 2016, 12, 1153–1169.
geranylations [62,63]. However, conditions B (NIS) were found There are a large number of indole alkaloids bearing a
unsuccessful in case of β-N-arylamidoallyl, methallyl, dimethyl- 3-arylated-2-oxindole moiety that are known for their various
allyl, and geranyl esters 9. We speculate that the olefin func- biological activities [65-67]. In a quest for such structural scaf-
tionality of substrates might be reacting with NIS (conditions B) folds, C-arylated substrates (±)-11a–d were subjected to stan-
faster than iodine (conditions A). Although our iodine-medi- dard reaction conditions to afford compound 12a–d (Scheme 2).
ated IDC is successful in most of the cases, however, in few To our pleasure, C-arylated β-N-arylamidoesters (±)-11a–d
cases we have seen moderate yields of products. Thus, we afforded products (±)-12a–d in 59–89% yield after 1 h under
decided to carry out IDC in the presence of organic bases as conditions A and B.
well.
Our synthetic methodology was further explored in the con-
Thus, for an alternative approach to 2-oxindoles bearing allyl, struction of spiro-fused oxindole ring systems (Scheme 3). The
methallyl, dimethylallyl, and geranyl esters, we were interested spiro-fused oxindoles such as coerulescine (15a) [68-72], hors-
for IDC using simple organic bases such as triethylamine, pyri- filine (15b) [73], and elacomine (16), are prevalently found in a
dine, and DABCO (Table 2) [64]. It was found that IDC can huge number of indole-based alkaloids having analgesic proper-
operate in the presence of organic bases to afford products only ties. Our oxidative methodology offered us a direct access to the
in 25–34% yields of 2-oxindoles (Table 2, entries 1, 2 and 4). core structures of these alkaloids under the optimized IDC
These reactions were always associated with unreacted starting conditions in high yields (Scheme 3).
material (28–51%) and decomposition of the rest of the mass
balance. Interestingly, when the base was changed to DBU Next, we thought of carrying out the IDC without alkylations of
(using 1.5 equiv DBU and 1.2 equiv of iodine) the desired compounds 3a and b and 17a and b (Scheme 4). Unfortunately,
2-oxindole was isolated in 82% (conditions C).
we could not isolate products due to decomposition under opti-
mized IDC conditions. It was noticed that changing the solvent
With this result in hand, we thought of exploring IDC using to THF effected very fast (within 5 minutes) dimerization of 3a
C-alkylated substrates 10. For this purpose, a variety of C-alky- and b at room temperature to afford 18a and b as sole products
lated β-N-arylamidoallyl, methallyl, dimethylallyl, and geranyl in 91–93% yield and in up to >20:1 dr (Scheme 4). This shows
esters 10 were synthesized in good yields as per Figure 4. These that formation of a stabilized tertiary radical probably facili-
substrates were then utilized in IDC-promoted by DBU/I2 and tates the IDC process for the syntheses of 2-oxindoles.
the results are summarized in Figure 5. Interestingly, under this
conditions, we can synthesize a variety of 2-oxindoles 8 in However, if a tertiary radical is responsible for the oxidative
moderate to good yields.
process, then one would realize the formation of dimeric
Table 2: IDC in the presence of organic bases. Reproduced from [46].
entry
base
time
% of 8j
% of 10j
1.
2.
3.
4.
pyridine
Et3N
12 h
12 h
29
25
82
34
30
28
–
DBU
40 min
12 h
DABCO
51
aReactions were carried out on a 0.25 mmol of 10j using 0.50 mmol of base and 0.275 mmol of iodine in 1 mL of solvent for specified time.
1159

Beilstein J. Org. Chem. 2016, 12, 1153–1169.
Figure 4: C-Alkylation of anilides using KOt-Bu.
2-oxindoles sharing vicinal all-carbon quaternary centers from loids 22a and b, see, Scheme 5) [74-77], sharing a vicinal all-
dimeric β-N-arylamidoesters 18a and b (Scheme 4). The reason carbon quaternary stereogenic centers with extreme steric
behind our interest towards this direction was due to the preva- congestion at the C3a–C3a' σ-bond as well as the attendant
lence of various dimeric cyclotryptamine alkaloids containing lability of this linkage. Under the optimized conditions, one-pot
3a,3a'-bis-pyrrolo[2,3-b]indole subunits (core structure of alka- dimerization of β-N-arylamido ester 3a and b and 9a took place
1160

Beilstein J. Org. Chem. 2016, 12, 1153–1169.
Figure 5: Substrates scope of ‘transition-metal-free’ IDC of C-alkylated anilides using DBU/I2.
in the presence of 1.2 equivalents of KOt-Bu and I2 followed by consecutive carbon–carbon bonds. X-ray crystal structure deter-
a double IDC on treatment with 1.2 equivalents of KOt-Bu and mination of (±)-19b proved the outcome of the reaction unam-
I2 affording the dimeric 2-oxindoles (±)-19a–c in poor to mod- biguously. It was noteworthy to observe Pd-catalyzed highly
erate yields (26–45% yield and 2:1 dr) along with 15–18% enantio-, chemo-, and diastereoselective double decarboxyla-
isolation of dimeric β-N-arylamidoesters (±)-18a–c (Scheme 5). tive allylations on dimeric β-N-arylamido allyl ester 19c to yield
This transformation is an efficient one-pot formation of three the enantiopure compounds of type 20a and b in good yields
1161

Beilstein J. Org. Chem. 2016, 12, 1153–1169.
Scheme 2: Oxidative coupling of C-arylated anilides (±)-11a–d. The synthesis of 12b as per method A has been reproduced from reference [46].
Scheme 3: Synthesis of spirocyclic product through IDC The synthesis of 14 as per method A has been reproduced from reference [46]. Conditions
A: KOt-Bu, iodine; conditions B: KOt-Bu, NIS.
Scheme 4: Dimerization of β-N-aryl-amidoesters 3a and b. Reproduced from [46].
1162

Beilstein J. Org. Chem. 2016, 12, 1153–1169.
Scheme 5: Synthesis of dimeric 2-oxindoles utilizing IDC. The syntheses of 19a and b have been reproduced from [46].
[78-81]. Especially, enantioenriched 20b is the advanced inter- tion of 23d takes place to afford the final product of the oxida-
mediate for the total syntheses of 3a,3a'-bispyrrolo[2,3-b]indole tive coupling reaction.
alkaloids, chimonanthine (22a), folicanthine (22b), and their re-
arranged skeleton such as calycanthine (22c) (Scheme 5) [78].
Kündig et al. in their oxidative coupling process using 2.2
equivalent of CuCl2 showed that it is important to have a
In all the cases, IDC was feasible with substrates having substit- tertiary carbon α- to the amide for the process to be radical
uents at the carbon atom α- to the amides. This gave a clue for a mediated [38,39]. Also, it is well evident from literature that the
radical-mediated process where a single electron transfer (SET) oxidation processes using Mn(OAc)3 as oxidant follow a radical
mechanism might be operating. A tentative mechanism has pathway [82-86]. In fact, the reaction of 3a also afforded
been proposed in Scheme 6, the reaction can adopt a SET mech- 2-oxindole 4a in 69% yield when the oxidative coupling was
anism leading to the intermediate 23a, after C-alkylation. Com- carried out in presence of 1.2 equiv of Mn(OAc)3 (Scheme 7).
pound 23a in turn gets converted into intermediate aryl radical A similar result was also observed when reaction was carried
23b. From this intermediate another intermediate aryl carbocat- out using C-methyl β-N-arylamido ester 5a (Scheme 7) [82-86].
ion 23c is formed by transferring a single electron to the
oxidant. Carbocation 23c is stabilized by the amide nitrogen as However, one can’t rule out the possibility of a substitution
shown in 23d. Eventually, in the presence of base, rearomatiza- reaction on C-iodo product 24 from the adjacent aryl group
1163

Beilstein J. Org. Chem. 2016, 12, 1153–1169.
Scheme 6: Plausible mechanism of ‘transition-metal-free’ IDC The mechanistic consideration in Scheme 6 has been reproduced from [46].
Scheme 7: Intramolecular-dehydrogenative-coupling (IDC) of 3a and 5a. Reproduced from [46].
(Scheme 8). Thus, the possibilty of the addition at the 2-posi- at the sterically congested tertiary iodide 24. However, to our
tion of electron-rich N-acylated aniline 3a to the tertiary iodide surprise, when C-iodination of 5a was carried out at rt, we
intermediate was also investigated. Towards this, we thought of found that it also afforded 2-oxindole 4a in 30–39% yield along
synthesizing the C-iodo intermediate using N-iodosuccinimide with 43–52% of recovered starting material (Scheme 8) and no
(NIS) or ICl in the presence of a base. Surprisingly, our all trace of C-iodide 24 was observed. These results suggest that,
effort to prepare C-iodo compound 24 in the presence of KOt- NIS and ICl also acts as oxidants and helping in a single elec-
Bu as a base only led to formation of 2-oxindole 4a in 72% and tron transfer (SET) in the oxidative coupling reaction [87,88]. It
69% yields, respectively (Scheme 8). Along the same line, is also well evident in the literature that, these can also be used
C-methyl β-N-arylamido ester 5a also afforded product 4a in as oxidants in variety of oxidative coupling reactions [87,88].
80–85% yield when the reaction was carried out at elevated Further, oxidative coupling of 5a was carried out in presence of
temperature (Scheme 8). We thought there could be the possi- well-known t-BuOI, which generally goes through a radical-
bility of a substitution reaction of iodide compound 24 pre- mediated pathway [89,90]. Towards this, when the oxidative
pared in-situ to form directly 2-oxindole 4a under elevated tem- coupling was carried out in presence of in situ generated t-BuOI
perature. Thus, it was decided to carry out the C-iodination at [91], the reaction afforded oxidative coupling product (±)-4a in
room temperature, where substitution reactions would be 68% yield, which is also probably indicating a radical pathway
unlikely, considering the fact that the substitution has to occur of the reaction (Scheme 8).
1164

Beilstein J. Org. Chem. 2016, 12, 1153–1169.
Scheme 8: IDC of 3a and 5a using different oxidants. Reproduced from [46].
Shifting our attention towards the synthetic application of our products (±)-25a–h in excellent yields (Scheme 9 and
IDC methodology, we put forward our effort towards the syn- Scheme 10).
thesis of 3-alkylated or arylated 2-oxindoles. Towards this, we
subjected to react, the oxidative coupling products (±)-6, (±)- Later, we envisioned that the oxidative coupling products
12c and d having benzyl (Bn) or p-methoxybenzyl (PMB) having allyl, methallyl, dimethylallyl esters after Trost–Tsuji
esters with a catalytic amount of Pd on activated charcoal (10% decarboxylative allylations could serve as an interesting plat-
Pd on charcoal) under atmospheric pressure of hydrogen gas in form for complex natural product synthesis after further synthe-
MeOH/EtOH (Scheme 9).
tic elaboration and functionalization. A few substrates were
treated under decarboxylative allylation (DcA) conditions in the
Interestingly, we observed that the oxidative coupling products presence of 10 mol % of Pd(PPh3)4 in refluxing tetrahydro-
undergo deprotection of benzyl or p-methoxybenzyl group and furan (7–8 h), which afforded products 26a–d in up to 99%
provided the intermediate carboxylic acid, followed by yield (Scheme 11). Interestingly, oxidative coupling products
decarboxylative protonation in the same pot gave us the desired with dimethylallyl esters 8j underwent smooth decarboxylative
1165

Beilstein J. Org. Chem. 2016, 12, 1153–1169.
Scheme 9: Synthesis of 3-substituted-2-oxindoles from benzyl esters.
Scheme 10: 3-Substituted-2-oxindoles from p-methoxybenzyl esters.
prenylation and reverse-prenylation in the presence of 5 mol % a ‘transition-metal-free’ intramolecular dehydrogenative cou-
of Pd2(dba)3 and 15 mol % dppp in refluxing toluene (7–8 h, pling (IDC) strategy. The methodology has been broadly
96% yields) to afford prenylated (27a) and reverse-prenylated applied to a wide range of substrates affording 2-oxindoles in
(27b) structures in 64% and 32% yield, respectively good yields in a facile one-pot C-alkylation concomitant with
(Scheme 11) [92,93]. These structures commonly occur in many oxidative coupling strategy. These products serve as a great
hexahydropyrrolo[2,3-b]indole-based alkaloids.
synthetic platform for several indole-based natural products.
The methodology demonstrated here has several advantages: (i)
C-alkylations can be carried in same pot; (ii) simple oxidants
Conclusion
In summary, we have successfully demonstrated the synthesis like iodine and N-iodosuccinimide (NIS) could be used in the
of 2-oxindoles bearing an all-carbon quaternary center applying absence of any transition metal which may be toxic and (iii)
1166

Beilstein J. Org. Chem. 2016, 12, 1153–1169.
Scheme 11: Synthetic elaboration using Tsuji–Trost reactions. Reproduced from [46].
substrates with a scope of further functionalization work equally for predoctoral fellowships. We sincerely thank Dr. Subahdip
well. The easy handling and the low cost of the reagents De, Dr. Badrinath N. Kakde, and Dr. Amit Adhikary for prelim-
involved in this synthetic methodology offers profound oppor- inary studies. Facilities from the Department of Chemistry,
tunities to expand and explore the use of IDC in organic synthe- IISER Bhopal is gratefully acknowledged.
sis. Further applications of this strategy are under active investi-
References
1. Dyker, G., Ed. Handbook of C-H Transformations: Applications in
gation in our laboratory.
Organic Synthesis; 2005; Vol. 2.
Supporting Information
2. Stuart, D. R.; Fagnou, K. Science 2007, 316, 1172.
doi:10.1126/science.1141956
Supporting Information File 1
3. Ashenhurst, J. A. Chem. Soc. Rev. 2010, 39, 540.
Copies of 1H, and13C NMR spectra for all new compounds.
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-12-111-S1.pdf]
doi:10.1039/B907809F
4. Le Bras, J.; Muzart, J. Chem. Rev. 2011, 111, 1170.
doi:10.1021/cr100209d
5. Rossi, R.; Bellina, F.; Lessi, M. Synthesis 2010, 4131.
doi:10.1055/s-0030-1258262
6. Scheuermann, C. J. Chem. – Asian J. 2010, 5, 436.
doi:10.1002/asia.200900487
Acknowledgements
Financial support from the Department of Science and Technol-
ogy (DST) through FAST-TRACK scheme (SB/FT/CS-54/
2011) and the Council of Scientific and Industrial Research
(CSIR) [02(0013)/11/EMR-II], Govt. of India is gratefully ac-
knowledged. N.K., S.G., and S.B. thank the CSIR, New Delhi,
7. You, S.-l.; Xia, J.-B. Top. Curr. Chem. 2010, 292, 165.
doi:10.1007/128_2009_18
8. Newhouse, T.; Baran, P. S.; Hoffmann, R. W. Chem. Soc. Rev. 2009,
38, 3010. doi:10.1039/b821200g
1167

Beilstein J. Org. Chem. 2016, 12, 1153–1169.
9. Gaich, T.; Baran, P. S. J. Org. Chem. 2010, 75, 4657.
doi:10.1021/jo1006812
37.Jia, Y.-X.; Katayev, D.; Bernardinelli, G.; Seidel, T. M.; Kündig, E. P.
Chem. – Eur. J. 2010, 16, 6300. doi:10.1002/chem.201000031
38.Jia, Y. X.; Kündig, E. P. Angew. Chem., Int. Ed. 2009, 48, 1636.
doi:10.1002/anie.200805652
10.Hendrickson, J. B. J. Am. Chem. Soc. 1975, 97, 5784.
doi:10.1021/ja00853a023
11.Cho, S. H.; Kim, J. Y.; Kwak, J.; Chang, S. Chem. Soc. Rev. 2011, 40,
5068. doi:10.1039/c1cs15082k
See for oxidative coupling using 2.2 equiv of CuCl2.
39.Dey, C.; Kündig, E. P. Chem. Commun. 2012, 3064.
doi:10.1039/c2cc17871k
12.Yeung, C. S.; Dong, V. M. Chem. Rev. 2011, 111, 1215.
doi:10.1021/cr100280d
40.Perry, A.; Taylor, R. J. K. Chem. Commun. 2009, 3249.
doi:10.1039/b903516h
13.McGlacken, G. P.; Bateman, L. M. Chem. Soc. Rev. 2009, 38, 2447.
doi:10.1039/b805701j
See for oxidative coupling using 1.0 equiv of Cu(OAc)2·H2O.
41.Pugh, D. S.; Klein, J. E. M. N.; Perry, A.; Taylor, R. J. K. Synlett 2010,
934. doi:10.1055/s-0029-1219392
14.Liu, C.; Zhang, H.; Shi, W.; Lei, A. Chem. Rev. 2011, 111, 1780.
doi:10.1021/cr100379j
15.Siemsen, P.; Livingston, R. C.; Diederich, F. Angew. Chem., Int. Ed.
2000, 39, 2632.
42.Klein, J. E. M. N.; Perry, A.; Pugh, D. S.; Taylor, R. J. K. Org. Lett.
2010, 12, 3446. doi:10.1021/ol1012668
doi:10.1002/1521-3773(20000804)39:15<2632::AID-ANIE2632>3.0.CO
;2-F
See for coupling using 5–10 mol % of Cu(OAc)2·H2O.
43.Moody, C. L.; Franckevičius, V.; Drouhin, P.; Klein, J. E. M. N.;
Taylor, R. J. K. Tetrahedron Lett. 2012, 53, 1897.
doi:10.1016/j.tetlet.2012.01.120
16.Li, C.-J. Acc. Chem. Res. 2009, 42, 335. doi:10.1021/ar800164n
17.Li, Z.; Bohle, D. S.; Li, C.-J. Proc. Natl. Acad. Sci. U. S. A. 2006, 103,
8928. doi:10.1073/pnas.0601687103
44.Pugh, D. S.; Taylor, R. J. K. Org. Synth. 2012, 89, 438.
doi:10.15227/orgsyn.089.0438
18.Li, C.-J.; Li, Z. Pure Appl. Chem. 2006, 78, 935.
doi:10.1351/pac200678050935
45.Yu, Z.; Ma, L.; Yu, W. Synlett 2010, 2607. doi:10.1055/s-0030-1258584
46.Ghosh, S.; De, S.; Kakde, B. N.; Bhunia, S.; Adhikary, A.; Bisai, A.
Org. Lett. 2012, 14, 5864. doi:10.1021/ol302767w
See for a preliminary communication from our group.
47.Trost, B. M.; Malhotra, S.; Chan, W. H. J. Am. Chem. Soc. 2011, 133,
7328. doi:10.1021/ja2020873
19.Yoo, W.-J.; Li, C.-J. Top. Curr. Chem. 2010, 292, 281.
doi:10.1007/128_2009_17
20.Zhang, Y.; Li, C.-J. J. Am. Chem. Soc. 2006, 128, 4242.
doi:10.1021/ja060050p
See for metal-free CDC.
21.Uyanik, M.; Ishihara, K. ChemCatChem 2012, 4, 177.
doi:10.1002/cctc.201100352
See for Pd-catalyzed asymmetric prenylations and geranylations.
48.Smit, W. A.; Bochkov, A. F.; Caple, R. Organic Synthesis: The Science
behind the Art; Royal Society of Chemistry: Cambridge, 1998.
49.Corey, E. J.; Cheng, X.-M. The Logic of Chemical Synthesis; John
Wiley & Sons: New York, 1995.
22.Marti, C.; Carreira, E. M. Eur. J. Org. Chem. 2003, 2209.
doi:10.1002/ejoc.200300050
23.Klein, J. E. M. N.; Taylor, R. J. K. Eur. J. Org. Chem. 2011, 6821.
doi:10.1002/ejoc.201100836
50.Magdziak, D.; Meek, S. J.; Pettus, T. R. R. Chem. Rev. 2004, 104,
1383. doi:10.1021/cr0306900
24.Roth, G. J.; Heckel, A.; Colbatzky, F.; Handschuh, S.; Kley, J.;
Lehmann-Lintz, T.; Lotz, R.; Tontsch-Grunt, U.; Walter, R.; Hilberg, F.
J. Med. Chem. 2009, 52, 4466. doi:10.1021/jm900431g
25.Rudrangi, S. R. S.; Bontha, V. K.; Manda, V. R.; Bethi, S.
Asian J. Res. Chem. 2011, 4, 335.
51.Zhdankin, V. V.; Stang, P. J. Chem. Rev. 2008, 108, 5299.
doi:10.1021/cr800332c
52.Bisai, A.; West, S. P.; Sarpong, R. J. Am. Chem. Soc. 2008, 130, 7222.
doi:10.1021/ja8028069
26.Trost, B. M.; Brennan, M. K. Synthesis 2009, 3003.
doi:10.1055/s-0029-1216975
53.West, S. P.; Bisai, A.; Lim, A. D.; Narayan, R. R.; Sarpong, R.
J. Am. Chem. Soc. 2009, 131, 11187. doi:10.1021/ja903868n
54.Kantak, A. A.; Potavathri, S.; Barham, R. A.; Romano, K. M.;
DeBoef, B. J. Am. Chem. Soc. 2011, 133, 19960.
doi:10.1021/ja2087085
27.Nishio, T.; Iseki, K.; Araki, N.; Miyazaki, T. Helv. Chim. Acta 2005, 88,
35. doi:10.1002/hlca.200490294
28.Axon, J.; Boiteau, L.; Boivin, J.; Forbes, J. E.; Zard, S. Z.
Tetrahedron Lett. 1994, 35, 1719. doi:10.1016/0040-4039(94)88328-9
29.Murphy, J. A.; Tripoli, R.; Khan, T. A.; Mail, U. W. Org. Lett. 2005, 7,
3287. doi:10.1021/ol051095i
Due to electron-rich species, aromatic solvents can take part in
oxidative coupling reactions. See for an example.
55.Jensen, B. S. CNS Drug Rev. 2002, 8, 353.
30.Teichert, A.; Jantos, K.; Harms, K.; Studer, A. Org. Lett. 2004, 6, 3477.
doi:10.1021/ol048759t
doi:10.1111/j.1527-3458.2002.tb00233.x
56.Oleynek, J. J.; Sedlock, D. M.; Barrow, C. J.; Appell, K. C.; Casiano, F.;
Haycock, D.; Ward, S. J.; Kaplita, P.; Gillum, A. M. J. Antibiot. 1994,
47, 399. doi:10.7164/antibiotics.47.399
31.Zhu, J.; Zhang, W.; Zhang, L.; Liu, J.; Zheng, J.; Hu, J. J. Org. Chem.
2010, 75, 5505. doi:10.1021/jo1005262
32.Ju, X.; Liang, Y.; Jia, P.; Li, W.; Yu, W. Org. Biomol. Chem. 2012, 10,
498. doi:10.1039/C1OB06652H
57.Yu, Q.-S.; Holloway, H. W.; Flippen-Anderson, J. L.; Hoffman, B.;
Brossi, A.; Greig, N. H. J. Med. Chem. 2001, 44, 4062.
doi:10.1021/jm010080x
33.Khan, T. A.; Tripoli, R.; Crawford, J. J.; Martin, C. G.; Murphy, J. A.
Org. Lett. 2003, 5, 2971. doi:10.1021/ol035173i
34.Beckwith, A. L. J.; Bowry, V. W.; Bowman, W. R.; Mann, E.; Parr, J.;
Storey, J. M. D. Angew. Chem., Int. Ed. 2004, 43, 95.
doi:10.1002/anie.200352419
58.Yu, Q.-S.; Zhu, X.; Holloway, H. W.; Whittaker, N. F.; Brossi, A.;
Greig, N. H. J. Med. Chem. 2002, 45, 3684. doi:10.1021/jm010491d
59.Luo, W.; Yu, Q.-S.; Zhan, M.; Parrish, D.; Deschamps, J. R.;
Kulkarni, S. S.; Holloway, H. W.; Alley, G. M.; Lahiri, D. K.; Brossi, A.;
Greig, N. H. J. Med. Chem. 2005, 48, 986. doi:10.1021/jm049309+
60.Kobayashi, J.; Ishibashi, M. Alkaloids 1992, 41, 41.
61.Lin, H.; Danishefsky, S. J. Angew. Chem., Int. Ed. 2003, 42, 36.
doi:10.1002/anie.200390048
35.Kündig, E. P.; Seidel, T. M.; Jia, Y.-X.; Bernardinelli, G.
Angew. Chem., Int. Ed. 2007, 46, 8484. doi:10.1002/anie.200703408
36.Jia, Y.-X.; Hillgren, J. M.; Watson, E. L.; Marsden, S. P.; Kündig, E. P.
Chem. Commun. 2008, 4040. doi:10.1039/b810858g
1168

Beilstein J. Org. Chem. 2016, 12, 1153–1169.
62.Okada, M.; Sato, I.; Cho, S. J.; Dubnau, D.; Sakagami, Y. Tetrahedron
2006, 62, 8907. doi:10.1016/j.tet.2006.06.074
85.Corey, E. J.; Kang, M. J. Am. Chem. Soc. 1984, 106, 5384.
doi:10.1021/ja00330a076
See for the isolation of geranylated hexahydropyrrolo[2,3-b]indole
alkaloids.
86.Iqbal, J.; Bhatia, B.; Nayyar, N. K. Chem. Rev. 1994, 94, 519.
doi:10.1021/cr00026a008
63.Rochfort, S. J.; Moore, S.; Craft, C.; Martin, N. H.; Van Wagoner, R. M.;
Wright, J. L. C. J. Nat. Prod. 2009, 72, 1773. doi:10.1021/np900282j
64.One-pot alkylations followed by dehydrogenative-coupling was
unsuccessful, thus, IDC was carried out C-alkylated substrates such as
10.
87.Newhouse, T.; Lewsi, C. A.; Eastman, K. J.; Baran, P. S.
J. Am. Chem. Soc. 2010, 132, 7119. doi:10.1021/ja1009458
88.Foo, K.; Newhouse, T.; Mori, I.; Takayama, H.; Baran, P. S.
Angew. Chem., Int. Ed. 2011, 50, 2716. doi:10.1002/anie.201008048
89.Akhtar, M.; Barton, D. H. R. J. Am. Chem. Soc. 1964, 86, 1528.
doi:10.1021/ja01062a016
65.Burgett, A. W. G.; Li, Q.; Wei, Q.; Harran, P. G. Angew. Chem., Int. Ed.
2003, 42, 4961. doi:10.1002/anie.200352577
90.Montoro, R.; Wirth, T. Org. Lett. 2003, 5, 4729. doi:10.1021/ol0359012
91.Preparation of t-BuOI: A flame-dried round-bottom flask was charged
with 0.6 mmol of t-BuONa in 0.5 mL of benzene. To this solution was
added 0.6 mmol of I2 at room temperature. This solution was directly
used for the oxidative coupling (see, reference [90]).
92.Ruchti, J.; Carreira, E. M. J. Am. Chem. Soc. 2014, 136, 16756.
doi:10.1021/ja509893s
66.Nicolaou, K. C.; Hao, J.; Reddy, M. V.; BheemaRao, P.; Rassias, G.;
Snyder, S. A.; Huang, X.; Chen, D. Y.-K.; Brenzovich, W. E.;
Guiseppone, N.; Giannakakou, P.; O’Brate, A. J. Am. Chem. Soc.
2004, 126, 12897. doi:10.1021/ja040093a
67.Wu, Q.-X.; Crew, M. S.; Draskovic, M.; Sohn, J.; Johnson, T. A.;
Tenney, K.; Valeriote, F. A.; Yao, X.-J.; Bjeldanes, L. F.; Crews, P.
Org. Lett. 2010, 12, 4458. doi:10.1021/ol101396n
68.Francke, W.; Kitching, W. Curr. Org. Chem. 2001, 5, 233.
doi:10.2174/1385272013375652
93.Thandavamurthy, K.; Sharma, D.; Porwal, S. K.; Ray, D.;
Viswanathan, R. J. Org. Chem. 2014, 79, 10049.
doi:10.1021/jo501651z
69.Rosenberg, S.; Leino, R. Synthesis 2009, 2651.
doi:10.1055/s-0029-1216892
70.Edmondson, S.; Danishefsky, S. J.; Sepp-Lorenzino, L.; Rosen, N.
J. Am. Chem. Soc. 1999, 121, 2147. doi:10.1021/ja983788i
71.Deppermann, N.; Thomanek, H.; Prenzel, A. H. G. P.; Maison, W.
J. Org. Chem. 2010, 75, 5994. doi:10.1021/jo101401z
72.Trost, B. M.; Brennan, M. K. Org. Lett. 2006, 8, 2027.
doi:10.1021/ol060298j
License and Terms
This is an Open Access article under the terms of the
Creative Commons Attribution License
(http://creativecommons.org/licenses/by/2.0), which
permits unrestricted use, distribution, and reproduction in
any medium, provided the original work is properly cited.
73.De, S.; Das, M. K.; Bhunia, S.; Bisai, A. Org. Lett. 2015, 17, 5922.
doi:10.1021/acs.orglett.5b03082
See for our approach using a thiourea catalyzed aldol reaction with
paraformaldehyde.
The license is subject to the Beilstein Journal of Organic
Chemistry terms and conditions:
74.May, J. A.; Stoltz, B. M. Tetrahedron 2006, 62, 5262.
doi:10.1016/j.tet.2006.01.105
(http://www.beilstein-journals.org/bjoc)
75.Steven, A.; Overman, L. E. Angew. Chem., Int. Ed. 2007, 46, 5488.
doi:10.1002/anie.200700612
76.Schmidt, M. A.; Movassaghi, M. Synlett 2008, 313.
doi:10.1055/s-2008-1032060
The definitive version of this article is the electronic one
which can be found at:
77.Ghosh, S.; Chaudhuri, S.; Bisai, A. Org. Lett. 2015, 17, 1373.
doi:10.1021/acs.orglett.5b00032
doi:10.3762/bjoc.12.111
78.Ghosh, S.; Chaudhuri, S.; Bisai, A. Chem. – Eur. J. 2015, 21, 17479.
doi:10.1002/chem.201502878
See for an enantioselective approach using a key Pd-catalyzed
decarboxylative allylation from our group.
79.Overman, L. E.; Paone, D. V.; Stearns, B. A. J. Am. Chem. Soc. 1999,
121, 7702. doi:10.1021/ja991714g
See for an asymmetric sequential processes to set a vicinal all-carbon
quaternary stereocenter.
80.Trost, B. M.; Osipov, M. Angew. Chem., Int. Ed. 2013, 52, 9176.
doi:10.1002/anie.201302805
81.Ghosh, S.; Bhunia, S.; Kakde, B. N.; De, S.; Bisai, A. Chem. Commun.
2014, 50, 2434. doi:10.1039/c3cc49064e
82.Heiba, E. I.; Dessau, R. M.; Koehl, W. J., Jr. J. Am. Chem. Soc. 1968,
90, 2706. doi:10.1021/ja01012a051
See for a Mn(III)-mediated radical process.
83.Bush, J. B., Jr.; Finkbeiner, H. J. Am. Chem. Soc. 1968, 90, 5903.
doi:10.1021/ja01023a048
84.Nikishin, G. I.; Vinogradov, M. G.; Fedorova, T. M.
J. Chem. Soc., Chem. Commun. 1973, 693.
doi:10.1039/C39730000693
1169