Pd-catalyzed cascade carbopalladation-annulation reaction of 3-(2-iodobenzyl)-indoles into fused 6/5/7/6- and 6/5/5/6- heterocyclic systems

Article abstract of DOI:10.1039/b919991h

Polycyclic indole structures, possessing fused seven-membered rings were efficiently synthesized via the Pd-catalyzed intramolecular carbopalladation- annulation of 3-(2-iodobenzyl)-indoles and alkynes. A remarkable base effect on the chemoselectivity of this transformation has been found: switching from Et₃N to CsOAc completely reverses the reaction path to intramolecular cyclization forming fused five-membered rings.

Full text of DOI:10.1039/b919991h

View Article Online / Journal Homepage / Table of Contents for this issue
This article was published as part of the
2009 ‘Catalysis in Organic
Synthesis’ web theme issue
Showcasing high quality research in organic chemistry
Please see our website
(http://www.rsc.org/chemcomm/organicwebtheme2009)
to access the other papers in this issue.

COMMUNICATION
www.rsc.org/chemcomm | ChemComm
Pd-catalyzed cascade carbopalladation-annulation reaction
of 3-(2-iodobenzyl)-indoles into fused 6/5/7/6- and
6/5/5/6- heterocyclic systemsw
Natalia Chernyak, David Tilly, Zhou Li and Vladimir Gevorgyan*
Received (in College Park, MD, USA) 25th September 2009, Accepted 27th October 2009
First published as an Advance Article on the web 17th November 2009
DOI: 10.1039/b919991h
Polycyclic indole structures, possessing fused seven-membered
rings were efficiently synthesized via the Pd-catalyzed intra-
molecular carbopalladation-annulation of 3-(2-iodobenzyl)-indoles
and alkynes. A remarkable base effect on the chemoselectivity of
this transformation has been found: switching from Et3N to
CsOAc completely reverses the reaction path to intramolecular
cyclization forming fused five-membered rings.
efficiently on polysubstituted electron-rich o-halobiaryls,
however, to the best of our knowledge, this annulations
strategy has never been used for construction of fused hetero-
cyclic frameworks. Thus, we explored this concept toward
assembly of fused derivatives of indole.
First, 3-benzoyl derivative 4a was examined in arylation/
cyclization reaction with 5-decyne (Scheme 2). However,
formation of the targeted seven-membered heterocycle 5 was
not observed. Instead, tetracyclic indenone 3a, a product of
intramolecular arylation, was obtained in 80% yield. The
related reaction on indole derivatives is precedented. Thus,
it was reported that isomeric 2-benzoyl indole undergoes
intramolecular cyclization under palladium catalysis to
produce indenoindolone.6 We decided to explored the scope
of this novel mode of intramolecular arylation reaction
(Table 1). Thus, cyclization of 4a provided slightly better yields
Polycyclic derivatives of indole have received increasing attention
due to their high importance in modern science, particularly
in bio-related fields.1 Tricyclic and tetracyclic derivatives of
indole, possessing seven-membered rings, are used as direct
precursors in synthesis of anti-histaminic and anti-inflammatory
compounds.1h–k Although numerous methods have been devel-
oped for assembly of these polycyclic frameworks, they are
generally lengthy or require employment of stoichiometric
amounts of organometallic reagents, which largely limits their
scope.2–4 Accordingly, development of alternative catalytic
methods for assembly of these important heterocyclic cores is
justified. Herein we wish to report the Pd-catalyzed intermole-
cular cascade annulations reactions of iodobenzyl derivatives of
indole 1 with alkynes leading to the formation of polycyclic fused
seven-membered heterocycles 2 and five-membered structures 3.
We envisioned that the intermolecular cascade arylation/
cyclization reaction of haloaryl heterocycles 1 with alkynes
might be an attractive alternative for construction of fused
polycyclic compounds possessing seven-membered rings 2
(Scheme 1). The palladium-catalyzed intermolecular reaction
of o-halobiaryls with alkynes was developed by Larock.5 This
approach represents a powerful approach for construction of
fused aromatic systems. The reaction is known to proceed
Scheme 2 Reaction of 2-benzoyl indole 4a with 5-decyne.
Table 1 Synthesis of heterocycles via intramolecular cyclization
reaction of o-iodobenzoyl heterocyclesa
#
Substrate
Product
Yield, %b
1
4a
4b
4c
3a
3b
3c
61
2
3
4
90c
78
Scheme 1 Intramolecular cascade annulation reaction of indole
derivatives.
4d
4e
3d
3e
81
71
Department of Chemistry, University of Illinois, 845 West Taylor Street,
Chicago, IL 60607, USA. E-mail: vlad@uic.edu;
Fax: (+1)-312 996 0431; Tel: (+1)-312-355-3579
5
w This article is part of a ChemComm ‘Catalysis in Organic Synthesis’
web-theme issue showcasing high quality research in organic
chemistry. Please see our website (http://www.rsc.org/chemcomm/
organicwebtheme2009) to access the other papers in this issue.
a
Conditions: 5 mol% Pd(OAc)2, 10 mol% Ph3P, 2 equiv. CsOAc,
b
c
1 M DMA, 110 1C, 12 h. Isolated yields. 2 h at 130 1C.
ꢀc
This journal is The Royal Society of Chemistry 2010
150 | Chem. Commun., 2010, 46, 150–152

Table 3 Synthesis of tetracycles via Pd-catalyzed cascade carbo-
palladation/annulation reaction of indole derivatives with alkynes8
Scheme 3 Relative reactivities of indole derivatives in intramolecular
arylation reaction.
#
1
Alkyne
Base
Product
Yield, %a
Table 2 Base optimization for cascade carbopalladation-annulation
of indole derivatives
Et3N
2c 90
2
3
Et3N
2d 78
2e 70
Entry
Substrate
Base
Ratiosa2a : 3f/2b : 3g
KOAc
1
2
3
4
5
1a
1a
1a
1b
1b
CsOAc
KOAc
TEA
CsOAc
KOAc
0 : 100
50 : 50
100 : 0
60 : 40
100 : 0
4
5
KOAc
KOAc
2f 76
a
The ratios were determined by GC-MS analysis of the crude reaction
b
mixtures. Compounds 2a and 2b are mixtures of regioisomers.
2g 75
of 3a (entry 1) compared to that in the presence of alkyne
(Scheme 2). It was found that unprotected indole 4b, in the
presence of 5 mol% of PdCl2(Ph3P)2 and CsOAc, produces
indeno[1,2]indole-10(5H)-one (3b) in excellent yield (entry 2).
N-Phenyl indole derivative 4c cyclized uneventfully, as well.
Analogously, carbonyl derivatives of thiophene (entry 4), and
furan (entry 5) produced tetracyclic indenones in very good yields.
To gain insight into the origins of high propensity of carbonyl
derivatives toward intramolecular arylation, we evaluated aryla-
tion of differently-tethered indole derivatives 4a, 6, and 1b
(Scheme 3). It was found that the carbonyl derivative 4a (X =
CO) underwent the fastest intramolecular arylation reaction
producing indeno[1,2]indole-10(5H)-one 3a in 100% GC yield.
Hydroxymethyl derivative 6 gave 50% yield of 7, whereas no
product formation was observed in the case of benzyl derivative
1b (X = CH2) (Scheme 3). These observations imply that the
electronic effect of a carbonyl group at the C-3 position accounts
for the efficiency of carbonyl derivatives in intramolecular cycliza-
tion over the intermolecular arylation/cyclization reaction.7 Based
on these results, we reasoned that 3-benzyl indole derivative 1b,
unreactive in intramolecular arylation, might be a suitable
substrate for intermolecular carbopalladation/annulations cascade
toward polycyclic frameworks possessing seven-membered rings.
Next, the influence of different bases on the chemoselectivity
of this reaction was examined. When 3-benzyl derivative 1a
was subjected to the reaction with methyl but-2-yanoate, in the
presence of a catalytic amount of PdCl2(Ph3P)2 and 2 equiva-
lents of CsOAc, the desired tetracycle 2a was not formed at all
(Table 2). Employment of KOAc resulted in formation of
equal amounts of 2a and 3f (entry 2). Finally, use of triethyl-
amine led to exclusive formation of the desired heterocycle 2a
possessing a seven-membered ring (entry 3).
6
7
8
KOAc
KOAc
2h 75
2i 75
KOAc
KOAc
2j 71
9
2k 75
a
Isolated yields.
Analogous annulations of NMe indole derivative 1b in the
presence of several bases have been examined, as well.
Employment of CsOAc led to formation of seven-membered
tetracycle 2b accompanied by a comparable amount of its
chemoisomer 3f. Surprisingly, switching to KOAc resulted in
excellent chemoselectivity of arylation/cyclization of 1b with
methylbut-2-yanoate (entry 5).
With the optimized conditions in hand, we examined the
scope of the cascade transformation of indoles 1a and 1b. To
our delight, a variety of alkynes, possessing electron-rich and
electron-deficient triple bonds, worked well in this annulations
reaction, leading to the formation of fused seven-membered
heterocycles in good yields (Table 3). Thus, reaction of 1a with
5-decyne led to the formation of 2c in 98% yield (entry 1).
ꢀc
This journal is The Royal Society of Chemistry 2010
Chem. Commun., 2010, 46, 150–152 | 151

cascade annulations/cyclization reaction with both electron
rich and electron deficient alkynes. Remarkably, it was found
that the base has a dramatic effect on inter- and intramollecular
cyclizations leading to seven- or five-membered fused ring
systems. In contrast, acyl-tethered substrates, regardless of
the base used, undergo intramolecular cyclization to produce
five-membered fused structures exclusively.
We are grateful to the National Institutes of Health for
funding (Grant GM-64444).
Notes and references
1 For reviews on biologically important indole derivatives, see:
(a) S. E. Lewis, Tetrahedron, 2006, 62, 8655; (b) T. Higuchi and
T. Kawasaki, Nat. Prod. Rep., 2007, 24, 843.
Scheme 4 Proposed mechanism.
2 I. A. Kashulin and I. E. Nifant’ev, J. Org. Chem., 2004, 69, 5476.
3 For radical cyclization reactions in synthesis of polycyclic indole
derivatives, see, for example: (a) S. R. Flanagan, D. C. Harrowven
and M. Bradley, Tetrahedron Lett., 2003, 44, 1795;
(b) M. L. Bennasar, T. Roca, R. Griera and J. Bosch, J. Org.
Chem., 2001, 66, 7547.
4 For Pd-catalyzed synthesis of fused nitrogen containing hetero-
cycles, see: (a) G. Zeni and R. C. Larock, Chem. Rev., 2004, 104,
2285; (b) C. Xie, Y. Zhang, Z. Huang and P. Xu, J. Org. Chem.,
2007, 72, 543; (c) T. Harayama, T. Akiyama, H. Akamutsu,
K. Kawano, H. Abe and Y. Takeuchi, Synthesis, 2001, 444;
(d) L.-C. Campeau, M. Parisien, A. Jean and K. Fagnou, J. Am.
Chem. Soc., 2006, 128, 581; (e) H. Zhang and R. C. Larock, J. Org.
Chem., 2003, 68, 5132; (f) M. A. Campo and R. C. Larock, J. Org.
Chem., 2002, 67, 5616; (g) C. Bressy, D. Alberico and
M. J. Lautens, J. Am. Chem. Soc., 2005, 127, 13148. See also ref. 9.
5 R. C. Larock, M. J. Dolty, Q. Tian and J. Zenner, M., J. Org.
Chem., 1997, 62, 7536.
6 A. P. Kozikowski and D. Ma, Tetrahedron Lett., 1991, 32, 3317.
7 For reviews discussing different mechanisms of Pd-catalyzed
arylation of heteroaromatic compounds, see: (a) I. V. Seregin
and V. Gevorgyan, Chem. Soc. Rev., 2007, 36, 1173;
(b) D. Alberico, M. E. Scott and M. Lautens, Chem. Rev., 2007,
107, 174; (c) G. Zeni and R. C. Larock, Chem. Rev., 2006, 106,
4644; See also: (d) S. Chuprakov, N. Chernyak, A. S. Dudnik and
V. Gevorgyan, Org. Lett., 2007, 9, 2333; (e) H. A. Chiong and
O. Daugulis, Org. Lett., 2007, 9, 1449; (f) N. R. Deprez,
D. Kalyani, A. Krause and M. S. Sanford, J. Am. Chem. Soc.,
2006, 128, 4972; (g) D. R. Stuart, E. Villemure and K. Fagnou,
J. Am. Chem. Soc., 2007, 129, 12072; (h) S. I. Gorelsky,
D. Lapointe and K. Fagnou, J. Am. Chem. Soc., 2008, 130,
10848; (i) D. Garcia-Cuadrado, P. de Mendoza, A. A. C. Braga,
F. Maseras and A. M. Echavarren, J. Am. Chem. Soc., 2007, 129,
6880; (j) Z. Zhao, A. Jaworski, I. Piel and V. Snieckus, Org. Lett.,
2008, 10, 2617; (k) N. Lebrasseur and I. Larrosa, J. Am. Chem.
Soc., 2008, 130, 2926; (l) X. Wang, D. V. Gribkov and D. Sames,
J. Org. Chem., 2007, 72, 1476.
8 General procedure for the palladium-catalyzed annulation-cyclization
reaction of 3(2-iodobenzyll)indole derivatives with alkynes: to a
solution of 10 mmol 3(2-iodobenzyll)indole derivative in 1 mL of
DMA was added PdCl2(Ph3P)2 (5 mol%), 20 mmol of the corres-
ponding base (see Table 3 for details) and 20 mmol of alkyne under
inert atmosphere. The reaction was stirred at 110 1C until full
consumption of starting indole derivative (8–10 h). When it was
completed the resulting solution was diluted with water (10 mL)
and extracted with EtOAc (3 Â 10 mL). The combined organic
extracts were dried over the sodium sulfate and concentrated under
reduced pressure. Resulting crude product was purified via column
chromatography on silica gel (Hexanes/EtOAc).
Annulation with diphenylacetylelene produced polyaromatic
tetracycle 2d in 78% yield (entry 2). Protected indole derivatives
1b showed somewhat lower reactivity. Thus, reaction of 1b with
5-decyne gave 2e in 70% isolated yield (Table 3, entry 3).
Reaction with MOM protected but-2-yne-1,4-diol led to the
formation of 2f in 76% yield (entry 4). Ethyl 3-(trimetylsilyl)-
prop-2-ynoate and trimetylsilylprop-2-yne smoothly reacted
with N-methyl indole derivative 1b leading to the formation
of tetracycles 2g and 2h, bearing a trimethylsilyl group at the
seven-membered ring (entries 5 and 6). On the other hand,
reaction of 1b with bistrimethylsilylacetylene produced mono-
desilylated 2i (entry 7). Analogously, reaction of 1b with
aryltrimethylsilyl alkynes resulted in formation of monodesilyl-
ated seven-membered tetracycles 2j and 2k (entries 8 and 9).9 In
all cases, formation of a single regioisomer was observed.
It is believed that the mechanism of the presented herein
intermolecular cascade arylation/cyclization reaction of the
indole derivatives follows the path proposed by Larock for
the cascade cyclization of o-haloaryls.5 It starts with the oxida-
tive addition of the Pd(0) to iodobenzylindole 1a generating the
arylpalladium complex 8 (Scheme 4). Carbopalladation of the
alkyne triple bond produces vinylpalladium intermediate 9,
which undergoes intermolecular electrophilic carbopalladation
at the C-2 position of the indole to form palladacycle 10. The
subsequent reductive elimination, produces product 2 and
regenerates the Pd(0) catalyst. On the other hand, complex 8,
in the presence of CsOAc, may undergo a direct intramolecular
cyclization at the C-2 position via a palladacycle 1110 to give 3b.
The kinetic isotope effect studies employing 1b and 1b–d
revealed the value of kH/kD = 1.1, thus supporting the
suggested above electrophilic nature of the cyclization step
(Scheme 5).7
In conclusion, we have developed an efficient methodology
for construction of fused polycyclic indole heterocycles from
easily available starting materials via the palladium-catalyzed
9 For examples on desilylation in palladium catalyzed processes, see:
(a) R. C. Larock, E. K. Yum and M. D. Refvic, J. Org. Chem.,
1998, 63, 7652; (b) M. L. Crawley, I. Goljer, D. J. Jenkin,
J. F. Mehlmann, L. Nogle, R. Dooley and P. E. Mahaney, Org.
Lett., 2006, 8, 5837.
10 It has been proposed that employment of OAc-containing
bases facilitates inter- or intramolecular deprotonation leading to
palladacycle intermediates. See ref. 4c and 7i.
Scheme 5 The kinetic isotope effect studies.
152 | Chem. Commun., 2010, 46, 150–152
ꢀc
This journal is The Royal Society of Chemistry 2010