Palladium-catalyzed enantioselective C-3 allylation of 3-substituted-1H- indoles using trialkylboranes

Article abstract of DOI:10.1021/ja0608139

We have developed a new enantioselective C-3 allylation of 3-substituted indoles using allyl alcohol and trialkylboranes. Asymmetric syntheses of 3,3-disubstituted indolines and indolenines in enantiomeric excesses up to 90% have been achieved using the bulky borane 9-BBN-C₆H₁₃ as the promoter of the reaction. The dependence of the selectivity on the nature of the borane suggests that the boron reagent has a role beyond promoting ionization of the allyl alcohol. A protocol for oxidation of indolenines to oxindoles has also been developed and led to a formal synthesis of (-)-phenserine. Copyright

Full text of DOI:10.1021/ja0608139

Published on Web 04/15/2006
Palladium-Catalyzed Enantioselective C-3 Allylation of
3-Substituted-1H-Indoles Using Trialkylboranes
Barry M. Trost* and Jean Quancard
Department of Chemistry, Stanford UniVersity, Stanford, California 94305-5080
Received February 2, 2006; E-mail: bmtrost@stanford.edu
Table 1. Selected Optimization Studies for C-3 Allylation
The asymmetric construction of a quaternary center at C-3 of
the indole core represents a great synthetic challenge as well as a
powerful entry into the structurally diverse family of indole
alkaloids.1 While many reports describe the asymmetric synthesis
of 3,3-disubstituted oxindoles,2 there is only one example of an
enantioselective process that takes advantage of the nucleophilicity
of the C-3 of indoles to build a quaternary center directly from
3-substituted indoles.3,4 Recently, Tamaru and co-workers reported
a C-3 selective palladium-catalyzed allylation of 1H-indoles
promoted by triethylborane using allyl alcohols.5 Of particular
interest to us was the reaction of 3-methylindole which provided
the corresponding 3-methyl-3-allyl-indolenine. Since this reaction
seems to proceed via a π-allylpalladium intermediate, we envisioned
that our chiral ligands6 could be used to develop an enantioselective
version. Here we report our progress in this area, which, to the
best of our knowledge, is the first example of an enantioselective
allylic alkylation using allyl alcohol as electrophile and reveals some
insight into the mechanism of this interesting transformation.
Preliminary experiments indicated that the anthracene derived
ligand A gave the best enantioselectivities and that 1 equiv of Et3B
and 3 equiv of allyl alcohol were necessary for the reaction to
proceed in good yield. Solvent studies (Table 1) revealed that non-
coordinating solvents provided higher selectivities with CH2Cl2
giving the best result. We then envisioned that, since the high
selectivity for C-3 versus N-allylation might result from the borane
being tightly bound to the indole nitrogen during the allylation step,7
the nature of the borane should greatly influence the enantioselec-
tivity. Indeed, we were pleased to observe an increase of the
enantiomeric excess to 83% using the more bulky borane derived
from the hydroboration of 1-hexene with 9-BBN (Table 1, entry
6). Further increasing the steric bulk of the borane using the
dicyclohexylborane derivative was detrimental to the yield and
enantiomeric excess, while using disiamylborane-C6H13 completely
inhibited the reaction. Finally, optimal conditions (entry 9) were
achieved with 1.05 equiv of borane at 4 °C, providing the indolenine
in 92% yield and 85% ee. The product is then liberated from the
borane by basic hydrolysis or treatment with ethanolamine in THF.8
We then examined the effect of substitution of the indole on the
outcome of the reaction (Table 2). Surprisingly, the electronic
character of the indole seems to influence the selectivity, while
the reactivity seems hardly affected (except for 3a which failed to
react). The electron-deficient indole 3b reacts with moderate
selectivity, and the enantiomeric excess increases in correlation with
the electron-donating character of the C-5 substituent. Electron-
donating substituents in the 4- and 6-position also give high
selectivities, while the 7-substituted indole failed to react most likely
because it prevents binding of the boron to the indole nitrogen.
This electronic effect could be ascribed to the stronger boron-
nitrogen interaction in electron-rich indoles.
entry
borane
T (
°
C)
solvent
yielda (%)
eeb (%)
1
2
3
4
5
6
7
8
9
Et3B
Et3B
Et3B
Et3B
Et3B
25
25
25
25
25
25
25
25
4
DME
dioxane
THF
toluene
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
82
85
89
85
88
88
70
nr
43
33
53
61
66
83
70
9-BBN-C6H13
(Chx)2B-C6H13
Sia2B-C6H13
9-BBN-C6H13
92
85
a All reactions were performed using 2.5 mol % of Pd2(dba)3CHCl3, 7.5%
of (S,S)-A, 1 (entries 1-6) or 1.05 equiv (entries 7-9) of borane and 3
equiv of allyl alcohol. b Enantiomeric excess was determined by chiral
HPLC after reduction of the imine using NaBH3CN.
Table 2. Effect of the Substitution of the Indole Benzene Ring
entry
R
product
yielda (%)
ee (%)
1
2
3
4
5
6
7
8
9
5-NO2
5-Br
H
5-MeO
5-BnO
5-HO
5-Bn2N
4-MeO
6-MeO
7-MeO
4a
4b
4c
4d
4e
4f
4g
4h
4i
nr
89
92
95
87
88
94
92
89
nr
60
74
84
83
86
90
83
78
10
4j
a All reactions were performed on a 0.2 mmol scale for 20 h at 4 °C
using 2.5 mol % of Pd2(dba)3CHCl3, 7.5% of (S,S)-A, 1.05 equiv of 9-BBN-
(C6H13), and 3 equiv of allyl alcohol.
3-substituted indoles (Table 3). In all cases, high yields were
achieved using the previously optimized conditions, with enantio-
meric excess from 72 to 90%. Of particular interest are the
substrates with a pendant nucleophile which cyclizes onto the imine
under the reaction conditions (entries 3-11). In these cases, the
corresponding indoline is obtained with a cis-5,5- or 5,6-fused ring
system9 found in numerous natural products.1 These results also
exemplify the very high chemoselectivity of this reaction since
alcohol, phenol, carbamate,10 and malonate functional groups are
tolerated.11
With these results in hand, we examined the scope of this reaction
using mainly readily available and synthetically relevant 5-methoxy-
9
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J. AM. CHEM. SOC. 2006, 128, 6314-6315
10.1021/ja0608139 CCC: $33.50 © 2006 American Chemical Society

C O M M U N I C A T I O N S
Scheme 1 . Synthesis of (-)-Esermethole
Table 3. Scope of the Reaction
disubstituted indolenines and indolines. High enantioselectivities
could be achieved using 9-BBN-C6H13 as the promoter of the
reaction, and electron-rich indoles give higher selectivities. The
dependence of the selectivity on the nature of the borane suggests
that, in addition to promoting the ionization of allyl alcohol,14 the
boron is directly involved in the enantiodiscriminating step. Studies
to elucidate the mechanism of this reaction are underway and will
be reported shortly.
Acknowledgment. We thank the National Science Foundation
and the National Institutes of Health (GM33049) for their generous
support of our programs. J.Q. thanks the Association pour la
Recherche sur le Cancer (France) for a postdoctoral fellowship.
We thank Johnson Matthey for a generous gift of palladium salts.
Supporting Information Available: Synthesis all new indole
substrates, experimental details, and characterization data for all new
compounds (PDF). This material is available free of charge via the
Internet at http://pubs.acs.org.
References
(1) (a) Somei, M. S.; Yamada, F. Y. Nat. Prod. Rep. 2005, 22, 73. (b) Rahman,
A. U.; Basha, A. Indole Alkaloids; Hawood Academic Publishers:
Amsterdam, 1997.
(2) (a) Trost, B. M.; Frederiksen, M. U. Angew. Chem., Int. Ed. 2005, 44,
308 and references cited therein. (b) Huang, A. K.; Kodanko, J. J.;
Overman, L. E. J. Am. Chem. Soc. 2004, 126, 14043. (c) Adhikari, S.;
Caille, S.; Hanbauer, M.; Ngo, V. X.; Overman, L. E. Org. Lett. 2005, 7,
2795.
(3) Austin, J. F.; Kim, S. G.; Sinz, C. J.; Xiao, W. J.; MacMillan, D. W. C.
Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 5482.
(4) Other approaches to the formation of a quaternary center at C3 of the
indole core include the following. (a) Asymmetric Heck-iminium ion
cyclization: Dounay, A. B.; Overman, L. E.; Wrobleski, A. D. J. Am.
Chem. Soc. 2005, 127, 10186. (b) Enantioselective oxidative cyclization
of tryptophol: Hirose, T.; Sunazuka, T.; Yamamoto, D.; Kojima, N.;
Shirahata, T.; Harigaya, Y.; Kuwajima, I.; Omura, S. Tetrahedron 2005,
61, 6015 and previous work cited therein.
a All reactions were performed on a 0.2 mmol scale for 20 h using 2.5
mol % of Pd2(dba)3CHCl3, 7.5% of (S,S)-A, 1.1 equiv of 9-BBN-(C6H13),
and 3 equiv of allyl alcohol. b Cyclization to the indoline occurred after
addition of ethanolamine to the indolenine in THF (5 min stirring for 18
and 24 h stirring for 20).
(5) Kimura, M.; Futamata, M.; Mukai, R.; Tamaru, Y. J. Am. Chem. Soc.
2005, 127, 4592.
(6) (a) Trost, B. M. Chem. Pharm. Bull. 2002, 50, 1. (b) Trost, B. M.; Crawley,
M. L. Chem. ReV. 2003, 103, 2921. (c) Trost, B. M. J. Org. Chem. 2004,
69, 5813.
(7) A systematic study of base and solvent effect on the C-3 versus
N-selectivity in the palladium-catalyzed allylation of indoles using allyl
carbonates showed that the formation of a tight indolyl-metal ion favors
the C-3 allylation process. Bandini, M.; Melloni, A.; Umani-Ronchi, A.
Org. Lett. 2004, 6, 3199.
(8) Kol, M.; Bar-Haim, G. Tetrahedron Lett. 1998, 39, 2643.
(9) The relative stereochemistry was confirmed by NOE on 12a and 16.
(10) Unprotected tryptamines failed to give clean reactions and high enanti-
oselectivity.
We were also interested in the oxidation of indolenines which
could allow an easy access to the oxindole family of natural
products. After examining various oxidative conditions, we found
that treatment of 2 with tetrabutylammonium oxone12 and acetic
acid gave oxindole 23 in good yield (Scheme 1). Recrystallization
of 23 provided enantiopure material. Furthermore, after methylation
and oxidative cleavage, aldehyde 24 was converted to (-)-
esermethole by reductive amination-cyclization following Over-
man’s procedure.13 This intermediate has been previously used to
synthesize (-)-phenserine,2b which is a drug candidate for treatment
of Alzheimer’s disease.
(11) Except for 4f, which led to about 5% of allylated phenol, no allylation of
the pendant nucleophile nor of the indole nitrogen was detected.
(12) Trost, B. M.; Braslau, R. J. Org. Chem. 1988, 53, 532.
(13) 23 was used to assign the absolute configuration of 2 and, by extension,
of all indolenines and indolines. Matsuura, T.; Overman, L. E.; Poon, D.
J. J. Am. Chem. Soc. 1998, 120, 6500.
(14) Tamaru, Y. Eur. J. Org. Chem. 2005, 2647-2656.
In summary, we have developed a new enantioselective C-3
allylation of 3-substituted indoles to give the corresponding 3,3-
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