Platinum-Catalyzed Intramolecular Alkylation of Indoles with Unactivated Olefins

Article abstract of DOI:10.1021/ja031814t

Reaction of 1-methy-2-(4-pentenyl)indole (1) with a catalytic amount of PtCl₂ (2 mol %) in dioxane that contained a trace of HCl (5 mol %) at 60 °C for 24 h led to the isolation of 4,9-dimethyl-2,3,4,9-tetrahydro-1H-carbazole (2) in 92% yield. Platinum-catalyzed cyclization of 2-(4-pentenyl)indoles tolerated substitution at each position of the 4-pentenyl chain. Furthermore, the protocol was applicable to the synthesis of tetrahydro-β-carbolinones and was effective for cyclization of unprotected indoles. 2-(3-Butenyl)indoles underwent platinum-catalyzed cyclization with exclusive 6-endo-trig regioselectivity. Mechanistic studies established a mechanism for the platinum-catalyzed cyclization of 2-alkenyl indoles involving nucleophilic attack of the indole on a platinum-complexed olefin. Copyright

Full text of DOI:10.1021/ja031814t

Published on Web 03/05/2004
Platinum-Catalyzed Intramolecular Alkylation of Indoles with Unactivated
Olefins
Cong Liu, Xiaoqing Han, Xiang Wang, and Ross A. Widenhoefer*
P. M. Gross Chemical Laboratory, Duke UniVersity, Durham, North Carolina 27708-0346
Received December 18, 2003; E-mail: rwidenho@chem.duke.edu
Fused polycyclic indoles including the carbazoles,1 carbo-
Scheme 1
lines,2 and their partially saturated counterparts represent a promi-
nent class of heterocyclic compounds with varied and often potent
biological activity.3 As a result, considerable effort has been directed
to the development of new and efficient methods for the synthe-
sis of polycyclic indoles.4 Intramolecular alkylation of an alkenyl
indole represents an attractive route to the synthesis of poly-
cyclic indoles. Unfortunately, effective alkylation of an indole
tion of an aryl C-H bond followed by olefin â-migratory
with an olefin requires either an electron-deficient Michael acceptor5
or prolonged heating under highly acidic conditions.6 For these
reasons, the development of an effective procedure for the alkyla-
tion of an indole with an unactivated olefin under mild conditions
would be significant. Here, we report a mild, platinum-catalyzed
protocol for the intramolecular alkylation of indoles with unactivated
olefins.
insertion.9a,13 Given their respective stereochemical requirements,
these inner-sphere and outer-sphere pathways can be distinguished
by cyclization of 4-d2 (Scheme 2). For example, indole C-H bond
Scheme 2
Although Pd(II) complexes catalyze the intramolecular alkylation
of alkenyl â-diketones and related substrates,7,8 this catalyst system
was ineffective for the alkylation of indoles.9 We noted with interest
a report of Maresca that documented the high reactivity of both
Pt(II) olefin complexes toward outer-sphere nucelophilic attack and
Pt(II) alkyl complexes toward protonolysis.10 Because these steps
constitute a potential catalytic cycle for the addition of a nucleophile
to an unactivated olefin, we targeted simple Pt(II) complexes as
catalysts for the alkylation of alkenyl indoles. To this end, treatment
of 1-methyl-2-(4-pentenyl)indole (1) with a catalytic amount of
[PtCl2(H2CdCH2)]2 (2.5 mol %) in dioxane at 90 °C for 12 h led
to 87% conversion to form a ∼5:1 mixture of the tetrahydrocar-
bazole 2 and carbazole 3 (Scheme 1). In an optimized procedure,11
reaction of 1 (0.50 M) with a catalytic amount of PtCl2 (2 mol %)
in dioxane that contained a trace of HCl (5 mol %) at 60 °C for 24
h led to the formation of 2 as the exclusive product (g96% by
GC) in 92% isolated yield (Table 1, entry 1).12
Platinum-catalyzed cyclization of 2-(4-pentenyl)indoles displayed
excellent generality and tolerated substitution at each position of
the 4-pentenyl chain including the internal and cis- and trans-
terminal olefinic positions (Table 1, entries 1-11). Noteworthy was
cyclization of the cyclohexenylethyl indole 4 (E ) CO2Me) to form
tetracycle 5 in 82% yield as a single (cis:trans g 50:1) diastereomer
(Table 1, entry 9). The protocol was applicable to the synthesis of
tetrahydro-â-carbolinones (Table 1, entries 12 and 13) and was
effective for cyclization of unprotected indoles (Table 1, entries 8
and 13). Somewhat surprisingly, 2-(3-butenyl)indoles underwent
platinum-catalyzed cyclization with exclusive 6-endo-trig regiose-
lectivity (Table 1, entries 14 and 15).
Although we initially envisioned a mechanism for the alkylation
of alkenyl indoles involving nucleophilic attack of the indole on a
platinum-complexed olefin, this mechanism has not been docu-
mented for transition metal-catalyzed olefin hydroarylation. Rather,
reported examples of olefin hydroarylation occur via initial activa-
activation followed by â-migratory insertion of I and protonolysis
of the Pt-C bond of syn-II-d2 with retention of stereochemistry14
would form exclusively syn-5-d2 (Scheme 2, path a). Conversely,
attack of indole on the platinum-complexed olefin of III to form
anti-II-d2 followed by stereospecific protonolysis would form
exclusively anti-5-d2 (Scheme 2, path b). Treatment of 4-d2 with a
catalytic amount of PtCl2 (2 mol %) in dioxane at 60 °C for 18 h
formed anti-5-d2 in 73% isolated yield as the exclusive product
(Scheme 2), which established a mechanism for indole alkylation
involving nucleophilic attack of the indole on a platinum-complexed
olefin (Scheme 2, path b).15
The absence of deuterium scrambling in the conversion of 4-d2
to anti-5-d2 argued against reversible â-hydride elimination/addition
prior to protonolysis. This observation suggested that the stereogenic
center generated via C-C bond formation was retained in the
product and pointed to the feasibility of asymmetric indole alkyla-
tion. In this regard, it was also significant that cationic platinum
9
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J. AM. CHEM. SOC. 2004, 126, 3700-3701
10.1021/ja031814t CCC: $27.50 © 2004 American Chemical Society

C O M M U N I C A T I O N S
Table 1. Cyclization of 2-Alkenyl Indoles Catalyzed by PtCl2 (2
mol %) in Dioxane That Contained a Trace (5 mol %) of HCl at 60
°C for 18-24 h (E ) CO2Me)
Scheme 3
In summary, we have developed a mild and effective platinum-
catalyzed procedure for the intramolecular alkylation of indoles with
unactivated olefins. We have established a mechanism for indole
alkylation involving nucleophilic attack on a platinum-complexed
olefin, and we have demonstrated the feasibility of asymmetric
carbocyclization employing this protocol.
Acknowledgment. We acknowledge the NSF (CHE-03-04994)
for support of this research. R.W. thanks the Camille and Henry
Dreyfus Foundation and GlaxoSmithKline for financial assistance.
We thank Dr. Rudolf Schmid (Hoffmann-LaRoche) for a generous
gift of BIPHEP ligands, Dr. Peter S. White for determining the
structure of 5, and Dr. Anthony Ribero for NMR spectral analysis
of 5-d2.
Supporting Information Available: Experimental procedures and
spectroscopic data for new compounds and products (PDF). This
material is available free of charge via the Internet at http://pubs.acs.org.
References
(1) Bergman, J.; Pelcman, B. Pure Appl. Chem. 1990, 62, 1967.
(2) Cox, E. D.; Cook, J. M. Chem. ReV. 1995, 95, 1797.
(3) Saxton, J. E. Nat. Prod. Rep. 1997, 559.
(4) Sundberg, R. J. Indoles; Academic Press: San Diego, 1996.
(5) Olah, G. A.; Krishnamurti, R.; Prakash, G. K. S. Friedel-Crafts
Alkylations. In ComprehensiVe Organic Synthesis; Trost, B. M., Fleming,
I., Eds.; Pergamon Press: Oxford, 1991; Vol. 3, pp 293-339.
(6) Morrison, G. C.; Waite, R. O.; Serafin, F.; Shavel, J. J. Org. Chem. 1967,
32, 2551.
(7) (a) Pei, T.; Widenhoefer, R. A. J. Am. Chem. Soc. 2001, 123, 11290. (b)
Pei, T.; Wang, X.; Widenhoefer, R. A. J. Am. Chem. Soc. 2003, 125,
648. (c) Qian, H.; Widenhoefer, R. A. J. Am. Chem. Soc. 2003, 125, 2056.
(d) Pei, T.; Widenhoefer, R. A. Chem. Commun. 2002, 650. (e) Wang,
X.; Pei, T.; Han, X.; Widenhoefer, R. A. Org. Lett. 2003, 5, 2699.
(8) (a) Franze´n, J.; Ba¨ckvall, J.-E. J. Am. Chem. Soc. 2003, 125, 6056. (b)
Dorange, I.; Lo¨fstedt, J.; Na¨rhi, K.; Franze´n, J. Ba¨ckvall, J.-E. Chem.-
Eur. J. 2003, 9, 3445.
(9) For recent reports of the palladium-catalyzed intramolecular oxidative
alkylation of indoles with unactivated olefins, see: (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.
(10) Fanizzi, F. P.; Intini, F. P.; Maresca, L.; Natile, G. J. Chem. Soc., Dalton
Trans. 1992, 309.
(11) See Supporting Information for details concerning optimization.
(12) Treatment of 1-methyl-2-(4-methyl-4-pentenyl)indole (Table 1, entry 6)
with HCl (30 mol %) in dioxane at 60 °C in the absence of platinum
formed no detectable amounts of 4,4,9-trimethyl-2,3,4,9-tetrahydro-1H-
carbazole after 24 h.
(13) (a) Tan, K. L.; Bergman, R. G.; Ellman, J. A. J. Am. Chem. Soc. 2002,
124, 3202. (b) Kakiuchi, F.; Murai, S. Acc. Chem. Res. 2002, 35, 826.
(14) (a) Merrifield, J. H.; Ferna´ndez, J. M.; Buhro, W. E.; Gladysz, J. A. Inorg.
Chem. 1984, 23, 4022. (b) De Luca, N.; Wojcicki, A. J. Organomet. Chem.
1980, 193, 359.
a Contained a small amount (∼3%) of a second isomer. b Reaction run
at 90 °C for 47 h.
bis(phosphine) complexes catalyzed the cyclization of alkenyl
indoles. In a preliminary screen of enantiomerically pure platinum
bis(phosphine) catalysts,11 the hindered platinum BIPHEP complex
(R)-6 proved effective for the asymmetric alkylation of alkenyl
indoles (Scheme 3). For example, reaction of 7 with a catalytic
1:1 mixture of (R)-6 and AgOTf at 60 °C for 24 h led to the isolation
of 8 in 84% yield with 69% ee (Scheme 3).
(15) The anti relationship between the indole carbon atom and the secondary
proton â- to the indole of anti-5-d2 was unambiguously determined by
1H NMR spectroscopy (see Supporting Information).
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