Platinum-catalyzed intramolecular asymmetric hydroarylation of unactivated alkenes with indoles

Article abstract of DOI:10.1021/ol061441b

A 1:1 mixture of the platinum bis(phosphine) complex [(S)-4]PtCl ₂ [(S)-4 = (S)-3,5-t-Bu-4-MeO-MeOBIPHEP] catalyzes the intramolecular asymmetric hydroarylation of 2-(4-pentenyl)indoles in moderate to good yield with up to 90% ee.

Full text of DOI:10.1021/ol061441b

ORGANIC
LETTERS
2006
Vol. 8, No. 17
3801-3804
Platinum-Catalyzed Intramolecular
Asymmetric Hydroarylation of
Unactivated Alkenes with Indoles
Xiaoqing Han and Ross A. Widenhoefer*
Duke UniVersity, P. M. Gross Chemical Laboratory,
Durham, North Carolina 27708-0346
rwidenho@chem.duke.edu
Received June 12, 2006
ABSTRACT
A 1:1 mixture of the platinum bis(phosphine) complex [(S)-4]PtCl2 [(S)-4
) (S)-3,5-t-Bu-4-MeO-MeOBIPHEP] catalyzes the intramolecular asymmetric
hydroarylation of 2-(4-pentenyl)indoles in moderate to good yield with up to 90% ee.
The transition metal-catalyzed addition of an aromatic C-H
bond across the CdC bond of an unactivated alkene
(hydroarylation) is an area of current interest relevant to both
organic synthesis and industrial-scale functionalization of
hydrocarbon feedstocks.1-6 A number of different catalysts
have been developed for the hydroarylation of unactivated
alkenes including Rh(I),1 Ru(II),2 Ru(III),3 Ir(III),4 and
Zr(IV)5 complexes. Lacking, however, are general and
efficient methods for the asymmetric hydroarylation of
unactivated alkenes. Examples of effective asymmetric
hydroarylation are exceedingly rare and have been restricted
to arenes that possess an imine directing group.6
Polycyclic indole derivatives such as carbazoles and their
partially saturated counterparts constitute an important class
of naturally occurring, biologically active molecules.7 For
this reason, the development of new and efficient methods
for the synthesis of polycyclic indole derivatives continues
to attract considerable attention. As part of a program directed
toward the development of new catalytic methods for the
hydrofunctionalization of unactivated alkenes with carbon,8,9
nitrogen,10 and oxygen11 nucleophiles, we have recently
reported the platinum-catalyzed intramolecular hydroarylation
of unactivated alkenes.9 As an example, reaction of 1-methyl-
(1) (a) Tan, K. L.; Park, S.; Ellman, J. A.; Bergman, R. G. J. Org. Chem.
2004, 69, 7329. (b) Thalji, R. K.; Ahrendt, K. A.; Bergman, R. G.; Ellman,
J. A. J. Org. Chem. 2005, 70, 6775. (c) Wiedemann, S. H.; Ellman, J. A.;
Bergman, R. G. J. Org. Chem. 2006, 71, 1969. (d) Wiedemann, S. H.; Lewis,
J. C.; Ellman, J. A.; Bergman, R. G. J. Am. Chem. Soc. 2006, 128, 2452.
(e) Thalji, R. K.; Ahrendt, K. A.; Bergman, R. G.; Ellman, J. A. J. Am.
Chem. Soc. 2001, 123, 9692. (f) Ahrendt, K. A.; Bergman, R. G.; Ellman,
J. A. Org. Lett. 2003, 5, 1301. (g) Tan, K. L.; Bergman, R. G.; Ellman, J.
A. J. Am. Chem. Soc. 2002, 124, 13964. (h) Tan, K. L.; Bergman, R. G.;
Ellman, J. A. J. Am. Chem. Soc. 2001, 123, 2685. (i) Lenges, C. P.;
Brookhart, M. J. Am. Chem. Soc. 1999, 121, 6616.
(2) (a) Kakiuchi, F.; Murai, S. Acc. Chem. Res. 2002, 35, 826 and
references therein. (b) Lail, M.; Arrowood, B. N.; Gunnoe, T. B. J. Am.
Chem. Soc. 2003, 125, 7506.
(7) (a) Bergman, J.; Pelcman, B. Pure Appl. Chem. 1990, 62, 1967. (b)
Cox, E. D.; Cook, J. M. Chem. ReV. 1995, 95, 1797. (c) Saxton, J. E. Nat.
Prod. Rep. 1997, 559.
(8) (a) Widenhoefer, R. A. Pure Appl. Chem. 2004, 76, 671 and
references therein. (c) Han, X.; Wang, X.; Pei, T.; Widenhoefer, R. A.
Chem.sEur. J. 2004, 10, 6333. (d) Qian, H.; Pei, T.; Widenhoefer, R. A.
Organometallics 2005, 24, 287. (e) Liu, C.; Widenhoefer, R. A. Tetrahedron
Lett. 2005, 46, 285.
(3) Youn, S. W.; Pastine, S. J.; Sames, D. Org. Lett. 2004, 6, 581.
(4) (a) Matsumoto, T.; Taube, D. J.; Periana, R. A.; Taube, H.; Yoshida,
H. J. Am. Chem. Soc. 2000, 122, 7414. (b) Matsumoto, T.; Periana, R. A.;
Taube, D. J.; Yoshida, H. J. Mol. Catal. A: Chem 2002, 180, 1.
(5) Jordan, R. F.; Taylor, D. F. J. Am. Chem. Soc. 1989, 111, 778.
(6) (a) O’Malley, S. J.; Tan, K. L.; Watzke, A.; Bergman, R. G.; Ellman,
J. A. J. Am. Chem. Soc. 2005, 127, 13496. (b) Thalji, R. K.; Ellman, J. A.;
Bergman, R. G. J. Am. Chem. Soc. 2004, 126, 7192. (c) Wilson, R. M.;
Thalji, R. K.; Bergman, R. G.; Ellman, J. A. Org. Lett. 2006, 8, 1745.
(9) Liu, C.; Han, X.; Wang, X.; Widenhoefer, R. A. J. Am. Chem. Soc.
2004, 126, 3700.
10.1021/ol061441b CCC: $33.50
© 2006 American Chemical Society
Published on Web 07/22/2006

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 isolation of tetrahydrocarbazole 2 in
92% yield (eq 1). The efficiency and stereoselectivity of
Pt(II)-catalyzed hydroarylation pointed to the potential
development of an analogous asymmetric hydroarylation
protocol. Indeed, here we report the platinum-catalyzed
asymmetric intramolecular hydroarylation of unactivated
alkenes with indoles.12
Table 1. Effect of Ligand and Solvent on the
Platinum-Catalyzed Asymmetric Hydroarylation of 3
We initially targeted the known dicationic platinum dimer
13
[(BINAP)Pt(µ-Cl)]2(OTf)2 as a catalyst for asymmetric
hydroarylation on account of the diverse range of catalytic
asymmetric transformations that employ BINAP as a sup-
porting ligand.14 Although a 1:1 mixture of [(S)-BINAP]PtCl2
and AgOTf was an active catalyst for the intramolecular
hydroarylation of alkenyl indole 3, no significant asymmetric
induction was observed (Table 1, entry 1). However,
subsequent experimentation identified (S)-3,5-t-Bu-4-MeO-
MeOBIPHEP [(S)-4] as an effective ligand for Pt-catalyzed
asymmetric hydroarylation (Table 1). In an optimized
protocol,15 treatment of 3 with a catalytic 1:1 mixture of [(S)-
4]PtCl2 and AgOTf (10 mol %) at 60 °C in methanol for 20
h led to isolation of tetrahydrocarbazole 5 in 93% yield with
90% ee (Table 1, entry 10).16
Several points regarding the optimization of the conversion
of 3 to 5 are worth noting. First, no effort was made to
exclude air or moisture in these experiments. Second, the
enantioselectivity of intramolecular hydroarylation increased
with the increasing steric bulk of the P-bound aryl groups,
in particular, the meta substituents of these aryl groups (Table
1, entries 1-6). This behavior has been observed previously
in the context of asymmetric hydrogenation,17 Heck cou-
pling,18,19 allylic alkylation,18 and allylic amination.20 Third,
a Isolated product g95% purity. b AgOTf (20 mol %) was employed.
c Enantiomeric purity not determined. d AgBF4 (10 mol %) was employed.
the enantioselectivity of the conversion of 3 to 5 increased
with the increasing donicity/polarity of the solvent (Table
1, entries 6-11), although employment of strongly donating
solvents led to a significant decrease in reaction rate (Table
1, entry 7).15 Fourth, although the nature of the silver source
had no significant effect on the reaction (Table 1, entries 10
and 11),15 the Pt/Ag ratio was important. In particular,
employment of a 1:2 ratio of Pt/Ag led to a significant
decrease in both the yield and the enantioselectivity of
hydroarylation (Table 1, entries 3 and 4). This observation
suggests that monomeric dicationic platinum complexes are
not effective catalysts for asymmetric hydroarylation.13
Asymmetric hydroarylation of 2-alkenyl indoles catalyzed
by a 1:1 mixture of [(S)-4]PtCl2 and AgOTf tolerated either
an N-benzyl or an N-allyl group and either an electron-
donating or an electron-withdrawing group on the indole
moiety (Table 2, entries 1-4). The protocol tolerated
heteroatom and alkyl substitution at the C(1) or C(2) position
of the 4-pentyl chain, although the bis(pivaloate)-substituted
indole 6 cyclized with low enantioselectivity (Table 2, entries
5-9). Similarly, 2-(1,1-dimethyl-4-pentenyl)indole cyclized
(10) (a) Han, X.; Widenhoefer, R. A. Angew. Chem., Int. Ed. 2006, 45,
1747. (b) Bender, C. F.; Widenhoefer, R. A. J. Am. Chem. Soc. 2005, 127,
1070. (c) Wang, X.; Widenhoefer, R. A. Organometallics 2004, 23, 1649.
(d) Qian, H.; Widenhoefer, R. A. Org. Lett. 2005, 7, 2635.
(11) Qian, H.; Han, X.; Widenhoefer, R. A. J. Am. Chem. Soc. 2004,
126, 9536.
(12) A preliminary result in this area has been described9 but was
unfortunately reported incorrectly. See: Liu, C.; Han, X.; Wang, X.;
Widenhoefer, R. A. J. Am. Chem. Soc. 2004, 126, 10493.
(13) Pignat, K.; Vallotto, J.; Pinna, F.; Strukul, G. Organometallics 2000,
19, 5160.
(14) (a) Noyori, R. Asymmetric Catalysis in Organic Synthesis; Wiley:
New York, 1994. (b) Catalytic Asymmetric Synthesis, 2nd ed.; Ojima, I.,
Ed.; Wiley-VCH: New York, 2000.
(15) See the Supporting Information for a more detailed description of
the optimization studies.
(17) (a) RajanBabu, T. V.; Ayers, T. A.; Casalnuovo, A. L. J. Am. Chem.
Soc. 1994, 116, 4101. (b) Schmid, R.; Broger, E. A.; Cereghetti, M.;
Crameri, Y.; Foricher, J.; Lalonde, M.; Mu¨ller, R. K.; Scalone, M.; Schoettel,
G.; Zutter, U. Pure Appl. Chem. 1996, 68, 131. (c) Blaser, H.-U.; Buser,
H.-P.; Jalett, H.-P.; Pugin, B.; Spindler, F. Synlett 1999, 867.
(18) Trabesinger, G.; Albinati, A.; Feiken, N.; Kunz, R. W.; Pregosin,
P. S.; Tschoerner, M. J. Am. Chem. Soc. 1997, 119, 6315.
(19) Tschoerner, M.; Pregosin, P. S. Organometallics 1999, 18, 670.
(20) (a) Selvakumar, K.; Valentini, M.; Pregosin, P. S. Organometallics
2000, 19, 1299. (b) Faller, J. W.; Wilt, J. C. Org. Lett. 2005, 7, 633.
(16) Two control experiments ruled out the possibility of acid- or silver-
catalyzed asymmetric hydroarylation. In one experiment, a solution of 3
that contained a catalytic mixture of (S)-4 (10 mol %), HCl (10 mol %),
and HOTf (10 mol %) in methanol was heated at 60 °C for 24 h. GC analysis
of the crude reaction mixture revealed no consumption of 3. In a second
experiment, a solution of 3 and a catalytic mixture of (S)-4 (10 mol %) and
AgOTf (5 mol %) in methanol was heated at 60 °C for 24 h. GC analysis
of the crude reaction mixture again revealed no consumption of 3.
3802
Org. Lett., Vol. 8, No. 17, 2006

Scheme 1
Table 2. Asymmetric Hydroarylation of 2-Alkenyl Indoles
Catalyzed by a Mixture of [(S)-4]PtCl2 (10 mol %) and AgOTf
(10 mol %) in Methanol at 60 °C for 20-48 h (e ) Co2Me)
mixture of [(()-BINAP]PtCl2 and AgOTf (10 mol %) formed
a 25:1 mixture of cis-8 and trans-8 in 93% yield. In contrast,
the reaction of 7 with a catalytic mixture of PtCl2 (2 mol %)
and HCl (5 mol %) formed a 1:2 mixture of cis-8 and trans-8
in 98% yield.9
Because platinum complexes of the form [(P-P)PtCl]+
are known to form stable dicationic chloride-bridged dimers,13
we probed for the potential involvement of dicationic
platinum complexes in the catalytic hydroarylation of alkenyl
indoles. To this end, the enantioselectivity of the conversion
of 3 to 5 catalyzed by a 1:1 mixture of (3,5-Xylyl-BINAP)-
PtCl2 (9) and AgOTf was determined as a function of the
enantiomeric purity of 9 over the range 0-99% ee. The linear
plot of the enantiomeric purity of 5 versus the enantiomeric
purity of 9 strongly suggests that the active catalyst is
monomeric and that dicationic diplatinum complexes are
either not formed or dissociate rapidly under reaction
conditions (Figure 1).22
a Isolated product of g95% purity.
in good yield but with low enantioselectivity (Table 2, entry
10). Platinum-catalyzed asymmetric hydroarylation was also
applied to the formation of a seven-membered ring (Table
2, entry 11).
We sought to evaluate the effect of an existing asymmetric
carbon atom on the stereoselectivity of platinum-catalyzed
hydroarylation. To this end, treatment of 7, which possessed
a single carbomethoxy group at the C(2) position of the
4-pentenyl group, with a catalytic 1:1 mixture of [(S)-4]PtCl2
and AgOTf (10 mol %) at 60 °C for 64 h led to the isolation
of 8 in 94% yield as a 9:1 mixture of cis (cis-8) and trans
(trans-8) isomers (Scheme 1).21 Whereas the major diaster-
omer cis-8 was formed with no significant enantiomeric
purity (e5% ee), trans-8 was formed with g90% ee. This
result indicates that the stereochemistry of the substrate and
not the catalyst is most responsible for determining the
stereochemistry of the product. The preferential formation
of cis-8 from the catalytic hydroarylation of 7 appears to be
a general feature of cationic platinum bis(phosphine) com-
plexes. For example, reaction of 7 with a catalytic 1:1
Figure 1. Plot of the enantiomeric purity of 5 vs the enantiomeric
purity of (3,5-xylyl-BINAP)PtCl2 (9) for the conversion of 3 to 5
catalyzed by a 1:1 mixture of 9 and AgOTf in methanol at 60 °C.
In summary, we have developed a mild and efficient Pt-
catalyzed protocol for the asymmetric hydroarylation of 2-(4-
pentenyl)indoles. We continue to work toward the identifi-
cation of more-effective catalysts for the asymmetric
(21) Compounds 8 were isolated along with ∼5% of an unidentified
impurity. Analytically pure 25:1 and 1:2 mixtures of cis-8 and trans-8 were
obtained through cyclization of 7 catalyzed by [(()-BINAP]PtCl2/AgOTf
and PtCl2,9 respectively.
(22) Girard, C.; Kagan, H. B. Angew Chem., Int. Ed. 1998, 37, 2922.
Org. Lett., Vol. 8, No. 17, 2006
3803

hydroarylation of alkenes and toward the elucidation of the
mechanism of Pt-catalyzed asymmetric hydroarylation.
Supporting Information Available: Experimental pro-
cedures and spectroscopic data for products (PDF). This
material is available free of charge via the Internet at
http://pubs.acs.org.
Acknowledgment is made to the NSF (CHE-0304994 and
CHE-0555425) for support of this research. We thank
Dr. Rudolf Schmid (Hoffmann-La Roche) for a generous
gift of (R)-3,5-i-Pr-MeOBIPHEP and (S)-4.
OL061441B
3804
Org. Lett., Vol. 8, No. 17, 2006