Palladium-catalyzed cyclization/carboalkoxylation of alkenyl indoles

Article abstract of DOI:10.1021/ja046810i

Reaction of 1-methyl-2-(4-pentenyl)indole with a catalytic amount of PdCl₂(CH₃CN)₂ (5 mol %) and a stoichiometric amount of CuCl₂ (3 equiv) in methanol under CO (1 atm) at room temperature for 30 min led to cyclization/carboalkoxylation to form the corresponding tetrahydrocarbazole in 83% isolated yield as a single regioisomer. Palladium-catalyzed cyclization/carboalkoxylation of 2-(4-pentenyl)indoles tolerated substitution along the alkenyl chain and at the internal and cis-terminal olefinic positions. Palladium-catalyzed cyclization/carboalkoxylation tolerated a range of alcohols and was effective for the cyclization of 2-(3-butenyl)indoles, 3-(3-butenyl)indoles, 3-(4-pentenyl)indoles, and 2-(5-hexenyl)indoles. Copyright

Full text of DOI:10.1021/ja046810i

Published on Web 07/30/2004
Palladium-Catalyzed Cyclization/Carboalkoxylation of Alkenyl Indoles
Cong Liu and Ross A. Widenhoefer*
P. M. Gross Chemical Laboratory, Duke UniVersity, Durham, North Carolina 27708-0346
Received May 29, 2004; E-mail: rwidenho@chem.duke.edu
The transition metal-catalyzed addition of a carbonyl group to
an olefin is a transformation of considerable importance that has
Scheme 1
1
been applied to the synthesis of both complex organic molecules
2
and commodity chemicals. Industrial processes, most notably,
olefin hydroformylation, typically involve the addition of a
hydrogen atom and a carbonyl group across the CdC bond of the
olefin.2 However, the catalytic addition of a carbon or heteroatom
nucleophile and a carbonyl group across the CdC bond of an olefin
represents a more desirable transformation for the synthesis of
complex organic molecules. Indeed, effective palladium-catalyzed
,3
Scheme 2
4
protocols for the alkoxylation/carboalkoxylation and amination/
5
carboalkoxylation of unactivated olefins have been developed and
applied to the synthesis of functionalized heterocycles. In contrast,
the catalytic addition of a carbon nucleophile and a carbonyl group
across the CdC bond of an olefin has not been realized.6,7 Here
we report the palladium-catalyzed cyclization/carboalkoxylation of
alkenyl indoles, which represents the first effective protocol for
the catalytic addition of a carbon nucleophile and a carbonyl group
across the CdC bond of an olefin.
Scheme 3
We have recently reported the platinum(II)-catalyzed cyclization
of 2-alkenyl indoles to form tetrahydrocarbazoles and related
8
derivatives (Scheme 1). Although Pt(II) complexes catalyze the
9
carbonylation of vinyl arenes, all our efforts to realize the platinum-
catalyzed cyclization/carbonylation of 2-alkenyl indoles have been
unsuccessful. Because Pd(II) alkyl complexes are reactive toward
CO insertion1 and because Pd(II) complexes catalyze the oxidative
-7
10,11
cyclization of alkenyl indoles,
we considered that Pd(II)
complexes might catalyze the cyclization/carbonylation of 2-alkenyl
indoles. Indeed, in an optimized procedure,12 treatment of 1-methyl-
2
-(4-pentenyl)indole (1) with a catalytic amount of PdCl
2 3 2
(CH CN)
(
2) (5 mol %) and a stoichiometric amount of CuCl (3 equiv) in
2
methanol under CO (1 atm) at room temperature for 30 min led to
the isolation of tetrahydrocarbazole 3 in 83% yield as a single
regioisomer (Scheme 1).
a stoichiometric amount of CuCl in THF that contained methanol
(10 equiv) led to the isolation of the corresponding tetrahydrocar-
bazole in 83% yield (Scheme 2).12 By employing this procedure,
efficient palladium-catalyzed cyclization/carboalkoxylation of 2-(4-
pentenyl)indole with ethanol, n-octanol, 2-propanol, and cyclohex-
anol was achieved (Scheme 2).
2
Unprotected, electron-rich, and electron-poor 2-(4-pentenyl)-
indoles underwent efficient palladium-catalyzed cyclization/
carboalkoxylation (Table 1, entries 1-3). Palladium-catalyzed
cyclization/carboalkoxylation of 2-(4-alkenyl)indoles tolerated sub-
stitution along the alkenyl chain and at the internal and cis-terminal
olefinic positions (Table 1, entries 4-9). 2-(3-Alkenyl)indoles also
underwent efficient, regioselective, and, in the case of 2-(3-alkenyl)-
indoles that possessed terminal olefinic substitution, highly ste-
reospecific palladium-catalyzed cyclization/carboalkoxylation (Table
Because the migratory insertion of CO into an M-C bond occurs
13
with retention of stereochemistry at the metal-bound carbon atom,
the stereospecific cyclization of (E)- and (Z)-2-(3-hexenyl)indole
(Table 1, entries 11 and 12) established the anti addition of the
indole and palladium across the CdC bond of the olefin. This
stereochemical outcome directly implicates a mechanism for
palladium-catalyzed cyclization/carboalkoxylation involving attack
of the indole on the palladium-complexed olefin of II (Scheme 3);
subsequent loss of HCl would form the palladium alkyl intermediate
III. R-Migratory insertion of CO into the Pd-C bond of III would
form the palladium acyl complex IV, which could undergo
methanolysis to release the tetrahydrocarbazole and form a pal-
ladium(0) complex. Oxidation of Pd(0) with Cu(II) would then
regenerate the Pd(II) carbonyl complex I (Scheme 3).14 The 6-endo-
1, entries 10-12). In addition to 2-(4-alkenyl)- and 2-(3-alkenyl)-
indoles, 2-(5-hexenyl)-, 3-(3-butenyl)-, and 3-(4-pentenyl)indoles
also underwent palladium-catalyzed cyclization/carboalkoxylation
to form the corresponding tricyclic indole derivatives in moderate
to good yield with excellent regioselectivity (Table 1, entries 13-
15).
Effective palladium-catalyzed cyclization/carboalkoxylation of
alkenyl indoles did not require methanol as solvent. For example,
treatment of 2-(4-pentenyl)indole with a catalytic amount of 2 and
10250
9
J. AM. CHEM. SOC. 2004, 126, 10250-10251
10.1021/ja046810i CCC: $27.50 © 2004 American Chemical Society

C O MMU N I C A T I O N S
Table 1. Cyclization/Carboalkoxylation of Alkenyl Indoles
Catalyzed by PdCl2(CH3CN)2 (2) (5 mol %) in the Presence of
CuCl2 (3 equiv) in Methanol at Room Temperature
trig cyclization of 1-methyl-3-(3-butenyl)indole (Table 1, entry 14)
suggests that an analogous outer-sphere pathway is operative for
the Pd(II)-catalyzed cyclization/carboalkoxylation of 3-alkenyl
indoles.15
In summary, we have developed a mild and effective Pd(II)-
catalyzed protocol for the cyclization/carboalkoxylation of alkenyl
indoles. These transformations represent both the first examples
of the catalytic addition of a carbon nucleophile and a carbonyl
group across the CdC bond of an olefin and an efficient and
selective route to the synthesis of functionalized polycyclic indole
derivatives from simple precursors.
Acknowledgment is made to the NSF (CHE-03-04994) for
support of this research. R.W. thanks the Camille and Henry
Dreyfus Foundation and GlaxoSmithKline for additional unre-
stricted financial assistance.
Supporting Information Available: Experimental procedures and
spectroscopic data for products . This material is available free of charge
via the Internet at http://pubs.acs.org.
References
(1) Hegedus, L. S. Transition Metals in the Synthesis of Complex Organic
Molecules; University Science Books: Sausalito, CA, 1999.
(
2) Parshall, G. W.; Ittel, S. D. Homogeneous Catalysis: The Applications
and Chemistry of Catalysis by Soluble Transition Metal Complexes; John
Wiley and Sons: New York, 1992.
(
3) For application of olefin hydroformylation to the synthesis of more
complex molecules, see: (a) Cuny, G. D.; Buchwald, S. L. J. Am. Chem.
Soc. 1993, 115, 2066. (b) Burke, S. D.; Cobb, J. E.; Takeuchi K. J. Org.
Chem. 1990, 55, 2138.
(
4) (a) Semmelhack, M. F.; Bodurow, C. J. Am. Chem. Soc. 1984, 106, 1496.
(
b) Semmelhack, M. F.; Bozell, J. J.; Sato, T.; Wulff, W.; Spiess, E.;
Zask, A. J. Am. Chem. Soc. 1982, 104, 5850. (c) Boukouvalas, J.; Fortier,
G.; Radu, I.-I. J. Org. Chem. 1998, 63, 916.
(
(
(
5) (a) Harayama, H.; Abe, A.; Sakado, T.; Kimura, M.; Fugami, K.; Tanaka,
S.; Tamaru Y. J. Org. Chem. 1997, 62, 2113. (b) Tamaru, Y.; Hojo, M.;
Yoshida, Z. J. Org. Chem. 1988, 53, 5731.
6) These transformations require a stoichiometric amount of palladium under
exacting conditions: Wieber, G. M.; Hegedus, L. S.; A° kermark, B.;
Michalson, E. T. J. Org. Chem. 1989, 54, 4649.
7) The Pd-catalyzed tandem Heck cyclization/carboalkoxylation of 1-iodo-
7
a
7b
2
-alkenylbenzenes and 1-iodo dienes has been reported: (a) Negishi,
E. i.; Cop e´ ret, C.; Ma, S.; Mita, T.; Sugihara, T.; Tour, J. M. J. Am. Chem.
Soc. 1996, 118, 5904. (b) Negishi, E. i.; Ma, S.; Amanfu, J.; Cop e´ ret, C.;
Miller, J. A.; Tour, J. M. J. Am. Chem. Soc. 1996, 118, 5919.
(
8) (a) Liu, C.; Han, X.; Wang, X.; Widenhoefer, R. A. J. Am. Chem. Soc.
2
004, 126, 3700. (b) For a related transformation, see: Youn, S. W.;
Pastine, S. J. Sames, D. Org. Lett. 2004, 6, 581.
(9) Parrinello, G.; Stille, J. K. J. Am. Chem. Soc. 1987, 109, 7122.
(
10) (a) Ferreira, E. M.; Stoltz, B. M. J. Am. Chem. Soc. 2003, 125, 9578. (b)
Abbiati, G.; Beccalli, E. M.; Broggini, G.; Zoni, C. J. Org. Chem. 2003,
68, 7625.
(
11) For the Pd(II)-mediated oxidative alkylation of an alkenyl indole, see:
Baran, P. S.; Corey, E. J. J. Am. Chem. Soc. 2002, 124, 7904.
(12) See Supporting Information for details regarding optimization.
(13) Flood, T. C. In Topics in Stereochemistry; Geoffroy, G. L., Ed.; Wiley:
New York, 1981; Vol. 12, p 83.
(
14) 1H NMR analysis of 2 in CD
3
OD under CO (1 atm) revealed complete
displacement of acetonitrile by CO. Therefore, I likely exists either as a
2
dicarbonyl monomer (L ) CO) or as a chloride-bridged dimer (L ) PdCl -
CO).
(
15) Noteworthy is that the stereochemistry and mechanism of ring closure
for the palladium-catalyzed cyclization/carboalkoxylation of 2-alkenyl
indoles differs from the stereochemistry and mechanism observed for the
10a
2
Pd(OAc) -catalyzed oxidative cyclization of 3-alkenyl indoles. This latter
transformation proceeds with net syn addition of the indole and palladium
to the olefin, presumably via C-H bond activation followed by â-migra-
1
0a
tory insertion of the olefin into the resulting Pd-C bond.
a
Isolated material of >95% purity. b 10 mol % 2 employed.
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