Intramolecular-Dehydrogenative-Coupling (IDC) reactions
by utilizing the C(sp2)-H bond with a C(sp3)-H bond. Herein,
we envisioned a DDQ (2,3-dichloro-5,6-dicyanobenzo-
quinone) mediated direct CꢀH functionalization of β-N-
arylamido ester (3a) to carry out an IDC of a C(sp2)-H bond
ortho to the N-alkylanilides with an internal C(sp3)-H bond
of active methine (3a) without using any metal based oxidant.
Employing DDQ-mediated strategy of oxidative cou-
pling,10 we set forth to investigate the possibility of an IDC
to transform β-N-arylamido ester of the type 3a into 4a
(Scheme 1). Mechanistically, a single electron transfer
(SET) from the anion (prepared in situ from 3a by the
treatment of KOtBu) to DDQ may generate a Kþ.DDQ
radical (6a) and a radical 5a (Scheme 2), which could in turn
form an intermediate aryl radical 5b. The latter, following
another SET to 6a could form Kþ.DDQ anion (6b) and an
intermediate aryl carbocation 5c, which can be stabilized
by amide nitrogen (see 5d). Eventually, abstraction of a
R-hydrogen from the iminium intermediate 5d in the presence
of 6b with resultant rearomatization leads to the desired oxi-
dative coupling product (4a) and Kþ of p-quinol derivative 6c.
respectively [see, Supporting Information (SI) for details].9b
No product was formed in the absence of DDQ, or PIDA,
or PIFA. Since, KOtBu is also known to promote alkylation
of 7a (Scheme 3),9a we thought to carry out a simultaneous
C-alkylation of β-N-arylamido ester (7a) using KOtBu and
methyl iodide accompanied with a DDQ-mediated dehy-
drogenative-coupling in a one-pot protocol (Scheme 3).
Scheme 3. One-pot C-alkylation and IDC Mediated by DDQ
To establish a standard reaction protocol, we selected
β-N-arylamido ester (7a) and methyl iodide as model substrates.
Exhaustive optimization studies [see, SI for details] revealed
that methylation of 7a could be done in presence of 1.2 equiv
of KOtBu and 1.1 equiv of methyl iodide, concomitant with
oxidative coupling using 1.2 equiv of KOtBu and 1.1 equiv of
DDQ to afford the desired product in 85% yield (Scheme 3).
In order to explore the synthetic viability of this oxida-
tive coupling, we then extended it to various β-N-arylamido
esters 7 [see, SI for details] and alkyl halides. As shown
in Figure 1, a wide range of 2-oxindoles (4aꢀn) could
be obtained in good yields. Gratifyingly, β-N-arylamido
esters (7) with different substituents including allyl,
methallyl, dimethylallyl, and geranyl, tolerate the standard
reaction conditions well to afford a variety of 2-oxindoles
4qꢀz (Figure 1) in good yields. This prompted us to examine
the versatility of our approach by extending it to substrates
like 8a, which in turn provides an entry to spiro-fused
2-oxindoles 9 in 72% yield. The essence of spiro-fused
2-oxindole is evident from a range of natural products
including coerulescine (10a) and horsfiline (10b) (Scheme4).11
Under optimized conditions, a few more substrates have
alsobeenexaminedasshown inFigure2. Weobservedthat
compounds 7a and 11a were not suitable for IDC and
simply led to the decomposition, probably indicating the
involvement of tertiary radical in the oxidative coupling
process. Unprotected amides such as 8b and 11b were also
leading to multiple spots on TLC. We speculate that this
might be due to the involvement of competitive reactions
of nitrogen and carbon centered radical species.12
Scheme 2. Proposed Mechanism for DDQ-mediated IDC
Initially, we embarked on our studies taking C-methyl
β-N-phenylamido methylester 3a as substrate and charged
it with 1.2 equiv of KOtBu at rt followed by treatment with
1.1 equiv DDQ in DMSO to afford product 4a in 89%
yield in 30 min. Similarly, in case of other oxidants such
as iodosobenzene diacetate (PIDA) and [bis(trifluoro-
acetoxy) iodo]benzene (PIFA) which could also follow a
SET mechanism, we found that the reaction worked
equally efficient to afford 4a in 80% and 86% yields,
(6) For reviews on 2-oxindoles, see: (a) Millemaggi, A.; Taylor,
R. J. K. Eur. J. Org. Chem. 2010, 4527. For a review on asymmetric
catalytic oxindole syntheses, see: (b) Zhou, F.; Liu, Y. L.; Zhou, J. A.
Adv. Synth. Catal. 2010, 352, 1381. (c) For synthesis of 2-oxindoles via a
Friedel-Crafts alkylations from our group, see: Ghosh, S.; Kinthada, L.
K.; Bhunia, S.; Bisai, A. Chem. Commun. 2012, 10132.
The subset of 2-oxindoles constitutes a common struc-
tural motif in many biologically active alkaloids and there-
fore has gained significant attention from synthetic
community. A wide range of hexahydropyrroloindolines
(7) For oxidative coupling using 2.2 equiv of CuCl2, see: (a) Jia, Y. X.;
€
Kundig, E. P. Angew. Chem., Int. Ed. 2009, 48, 1636. (b) Dey, C.;
€
€
Kundig, E. P. Chem. Commun. 2012, 3064. (c) Dey, C.; Kundig, E. P.
Chem. Commun. 2012, 3064.
(10) (a) Buckle, D. R. Encyclopaedia of Reagent for Organic Synthesis;
Paquette, L. A., Ed.; John Wiley & Sons: Chichester, UK, 1995; Vol. 3, p 1699. (b)
Patir, S.; Erturk, E. J. Org. Chem. 2011, 76, 335. (c) Ying, B.-P.; Trogden,
B. G.; Kohlman, D. T.; Liang, S. X.; Xu, Y.-C. Org. Lett. 2004, 6, 1523.
(11) (a) Deppermann, N.; Thomanek, H.; Prenzel, A. H. G. P.;
Maison, W. J. Org. Chem. 2010, 75, 5994. (b) Trost, B. M.; Brennan,
M. K. Org. Lett. 2006, 8, 2027.
(8) For oxidative coupling using 1.0 equiv of Cu(OAc)2.H2O, see: (a)
Perry, A.; Taylor, R. J. K. Chem. Commun. 2009, 3249. (b) Franckevicius,
V.; Cuthbertson, J. D.; Pickworth, M.; Pugh, D. S.; Taylor, R. J. K. Org.
Lett. 2011, 13, 4264. For coupling using 5ꢀ10 mol% of Cu(OAc)2.H2O,
see: (c) Klein, J. E. M. N.; Perry, A.; Pugh, D. S.; Taylor, R. J. K. Org. Lett.
2010, 12, 3446. (d) Moody, C. L.; Franckevicius, V.; Drouhin, P.; Klein, J.
E. M. N.; Taylor, R. J. K. Tetrahedron. Lett. 2012, 53, 1897.
€
(12) Richter, J. M.; Whitefield, B. W.; Maimone, T. J.; Lin, D. W.;
Castroviejo, M. P.; Baran, P. S. J. Am. Chem. Soc. 2007, 129, 12857.
(13) Wang, Y. -H.; Long, C.-L.; Yang, F.-M.; Wang, X.; Sun, Q.-Y.;
Wang, H.-S.; Shi, Y.-N.; Tang, G.-H. J. Nat. Prod. 2009, 72, 1151.
(9) (a) For I2-mediated IDC, see: Ghosh, S.; De, S.; Kakde, B. N.;
Bhunia, S.; Adhikary, A.; Bisai, A. Org. Lett. 2012, 14, 5864. (b) We
sincerely thank the reviewers for their valuable suggestions to check IDC
using oxidants which could also follow a SET.
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