The highly enantioselective addition of indoles to N-acyl imines with use of a chiral phosphoric acid catalyst

Article abstract of DOI:10.1021/ol0703579

Equation Presented The highly enantioselective organocatalytic addition of N-benzyl indoles to N-acyl imines is reported. A total of 15 examples with product yield ranging from 89% to 99% and enantioselectivities from 90% to 97% are presented. A chiral ph

Full text of DOI:10.1021/ol0703579

ORGANIC
LETTERS
2007
Vol. 9, No. 14
2609-2611
The Highly Enantioselective Addition of
Indoles to N-Acyl Imines with Use of a
Chiral Phosphoric Acid Catalyst
Gerald B. Rowland, Emily B. Rowland, Yuxue Liang, Jason A. Perman, and
Jon C. Antilla*
Department of Chemistry, UniVersity of South Florida, 4202 East Fowler AVenue,
CHE205A, Tampa, Florida 33620
jantilla@cas.usf.edu
Received February 11, 2007
ABSTRACT
The highly enantioselective organocatalytic addition of N-benzyl indoles to N-acyl imines is reported. A total of 15 examples with product yield
ranging from 89% to 99% and enantioselectivities from 90% to 97% are presented. A chiral phosphoric acid catalyst derived from a hindered
binol derivative was employed most effectively in the reaction. Attractive features of the reaction include desirable catalyst loadings, good
reactivity, generality of substrates, and easily removable groups from both nitrogen atoms.
Over the past two decades, the development of catalytic,
enantioselective reactions has been near the forefront of
synthetic organic research.1 In recent years organocatalysis
has been demonstrated to be one of the most promising areas
for the development of environmentally friendly enantio-
selective processes.2 An important benefit of organocatalysis
is the lack of toxic metal byproducts that often accompany
metal-catalyzed enantioselective reactions.2a A recently
emerging direction for organocatalysis has been the develop-
ment of phosphoric acid catalysts derived from chiral biaryl
building blocks.3 Chiral phosphoric acids have been shown
to be remarkable catalysts for enantioselective Mannich
reactions,4 enantioselective reductions,5 cycloaddition reac-
tions,6 and the addition of other nucleophiles to imines.7
In 2004, Terada reported the first chiral phosphoric acid-
catalyzed enantioselective aza-Friedel-Crafts reaction of a
single electron-rich furan with imines.8 In a related reaction,
(4) (a) Akiyama, T.; Itoh, J.; Yokota, K.; Fuchibe, K. Angew. Chem.,
Int. Ed. 2004, 43, 1566. (b) Uraguchi, D.; Terada, M. J. Am. Chem. Soc.
2004, 126, 5356.
(5) (a) Rueping, M.; Sugiono, E.; Azap, C.; Theissmann, T.; Bolte, M.
Org. Lett. 2005, 7, 3781. (b) Hoffmann, S.; Saeyad, A. M.; List, B. Angew.
Chem., Int. Ed. 2005, 44, 7424. (c) Storer, R. I.; Carrera, D. E.; Ni, Y.;
MacMillan, D. W. C. J. Am. Chem. Soc. 2006, 128, 84. (d) Rueping, M.;
Antonchick, A. P.; Theissmann, T. Angew. Chem., Int. Ed. 2006, 45, 3683.
(e) Mayer, S.; List, B. Angew. Chem., Int. Ed. 2006, 45, 4193. (f) Rueping,
M.; Antonchick, A. P.; Theissmann, T. Angew. Chem., Int. Ed. 2006, 45,
6751.
(6) (a) Akiyama, T.; Morita, H.; Fuchibe, K. J. Am. Chem. Soc. 2006,
128, 13070. (b) Rueping, M.; Azap, C. Angew. Chem., Int. Ed. 2006, 45,
7832.
(7) (a) Rowland, G. B.; Zhang, H.; Rowland, E. B.; Chennamadhavuni,
S.; Wang, Y.; Antilla, J. C. J. Am. Chem. Soc. 2005, 127, 15696. (b)
Akiyama, T.; Morita, H.; Itoh, J.; Fuchibe, K. Org. Lett. 2005, 7, 2583. (c)
Rueping, M.; Sugiono, E.; Azap, C. Angew. Chem., Int. Ed. 2006, 118,
7832.
(1) Jacobsen, E. N.; Pfaltz, A.; Yamamoto, H. ComprehensiVe Asym-
metric Catalysis; Springer: Berlin, Germany, 1999; Vols. I-III.
(2) For reviews of enantioselective organocatalysis see: (a) Dalko, P.
I.; Moisan, L. Angew. Chem., Int. Ed. 2001, 113, 3726. (b) Dalko, P. I.;
Moisan, L. Angew. Chem., Int. Ed. 2004, 43, 5138. (c) Taylor, M. S.;
Jacobsen, E. N. Angew. Chem., Int. Ed. 2006, 45, 1520.
(3) For reviews of chiral phosphoric acid catalysis see: (a) Akiyama,
T.; Itoh, J.; Fuchibe, K. AdV. Synth. Catal. 2006, 348, 999. (b) Connon, S.
J. Angew. Chem., Int. Ed. 2006, 45, 3909.
10.1021/ol0703579 CCC: $37.00
© 2007 American Chemical Society
Published on Web 06/05/2007

Terada also reported the enantioselective addition of indole
nucleophiles to electron-rich alkenes.9 Deng and co-workers
reported the first enantioselective organocatalytic Friedel-
Crafts addition of indoles to imines by using a modified
quinine catalyst to provide chiral 3-indolyl methanamines
with excellent selectivity.10 However, the procedure required
long reaction times and harsh conditions are needed for the
removal of the tosyl group from the nitrogen products.11 Most
recently, You and co-workers reported a chiral phosphoric
acid-catalyzed Friedel-Crafts reaction of indoles with similar
N-tosyl imines.12 The reaction gave chiral methanamines in
good yield and with excellent enantioselectivity. However,
5 equiv of indole were required, and a drop in both yield
and enantioselectivity was found with substrates that were
substituted on the aromatic ring of the imine. We would like
to report an aza-Friedel-Crafts reaction between substituted
N-benzyl indoles and N-acyl imines catalyzed by chiral
phosphoric acids to provide the addition products in excellent
yield and with high enantioselectivities.
Table 1. Optimized Catalytic Asymmetric Conditions
a Enantiomeric excess (ee) determined by chiral HPLC analysis.
Inspired by our previous success7a with a chiral phosphoric
acid derived from the VAPOL (Vaulted biPhenantrOL)
ligand13 shown in Figure 1, our initial investigation involved
with no adverse affect on the yield until the reaction was
below -40 °C. However, an increase to 10 mol % catalyst
loading at -60 °C was also necessary for the formation of
the product with both high yield and selectivity (entry 6).
It was therefore determined that -30 °C was the optimal
reaction temperature for both activity (5 mol % PA2) and
selectivity (94% ee). Unprotected indole addition under these
reaction conditions provided a moderate yield but with lower
enantioselectivity (entry 7). Likewise, the use of N-methyl-
Table 2. Variation of the Imine Substrate
Figure 1. Two hindered chiral phosphoric acid catalysts.
reaction of N-Boc protected imines with indoles catalyzed
by PA1 (Table 1, entry 1). This resulted in the formation of
the product in excellent yield, but poor enantioselectivities
were found. Our first notable improvement was the use of
N-benzoyl imine substitution. This change resulted in a
drastic increase in the stereoselectivity of the reaction (entry
2). After many attempts at optimization of the reaction using
PA1 we found that chiral phosphoric acid PA2 provided for
the formation of the product in excellent yield and enantio-
selectivity (entries 3-5). The lowering of the reaction
temperature resulted in an increase in the enantioselectivity,
(8) Uraguchi, D.; Sorimachi, K.; Terada, M. J. Am. Chem. Soc. 2004,
126, 11804.
(9) Terada, M.; Sorimachi, K. J. Am. Chem. Soc. 2007, 129, 292.
(10) Wang, Y. -Q.; Song, J.; Hong, R.; Li, H.; Deng, L. J. Am. Chem.
Soc. 2006, 128, 8156.
(11) Schultz, A. G.; McClosky, P. J.; Court, J. J. J. Am. Chem. Soc.
1987, 109, 6493.
(12) During the preparation of our manuscript, a publication by S. You
appeared using similar reaction conditions but different substrates and
catalyst. This work prompted our immediate submission. Please see: Kang,
Q.; Zhao, Z. A.; You, S. -L. J. Am. Chem. Soc. 2007, 129, 1484.
(13) Bao, J.; Wulff, W. D.; Doming, J. B.; Fumo, M. J.; Grant, E. B.;
Rob, A. C.; Whitcomb, M. C.; Yeung, S.-M.; Ostrander, R. L.; Rheingold,
A. L. J. Am. Chem. Soc. 1996, 118, 3392.
a Absolute configuration of the product in entry 3 was determined to be
(R) by X-ray crystallographic analysis, with the stereochemistry of the other
products assumed by analogy (see the Supporting Information).
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Org. Lett., Vol. 9, No. 14, 2007

indole in the addition gave a lowered selectivity in com-
parison to the N-benzyl compound (entry 8).
Table 3. Variation of the Indole Substrate
With an optimal set of reaction conditions in hand the
reaction scope with regard to variation of the aryl substituent
of the imine carbon was investigated (Table 2). A variety of
substitutions proved to be very successful. For example,
m-methoxy-substituted substrate 3b allowed for excellent
yield and enantioselectivity upon addition with 4a (entry 2).
Likewise, electron-withdrawing substituents in the para
position of the imine (3c-f) were all excellent substrates
for the reaction, giving from 94% to 96% ee (entries 3-6).
Electron-donating substituents in the para position also
provided suitable substrates and their reaction gave substi-
tuted products with 94% and 95% ee (entries 7 and 8).
Sterically hindered o-methoxy substrate 3i was not prob-
lematic, providing a high yield (97%) and high selectivity
(95% ee). Likewise, a 1-naphthyl-substituted imine (entry
10) proved to be an excellent substrate for the reaction (99%
yield, 95% ee of product 5j).
Concentrating next on the variation of the indole substitu-
tion we tested six substrates (Table 3). We first examined a
series of 5-substituted indoles and were pleased to find very
good compatibility. For example, 5-methyl-, 5-bromo-,
5-carboxymethyl-, and 5-methoxyindole (entries 1-4) were
all excellent substrates for reaction with 3a, resulting in 90-
95% ee. The use of 7-methylindole was an equally fine
substrate that could provide for a product with a 98% yield
and a 96% ee. The only substrate tested that gave lowered
selectivity was the hindered 2-methylindole. In that case a
moderate enantioselectivity was observed upon reaction with
3a (64% ee). This lowering of the ee is presumably due to
detrimental steric interactions.
In summary, we have developed a general method whereby
indoles can be added in an enantioselective fashion to
N-benzoyl-activated imines utilizing chiral phosphoric acids
as efficient catalysts. The reaction proceeds with excellent
enantioselectivity and is performed with indole as the limiting
reagent. Further studies are being conducted with regard to
scope and limitations of this reaction and related Friedel-
Crafts-type additions catalyzed by chiral phosphoric acids.
Acknowledgment. This work was partially supported by
the Peteroleum Research Fund (PRF 45899-G1) and by
generous start-up funding by The University of South Florida.
We thank Ted Gauthier (HRMS) and Edwin Rivera (NMR)
of The University of South Florida for instrumentation
support.
Supporting Information Available: Experimental pro-
cedures, characterization, chiral HPLC conditions, spectra,
and X-ray crystallographic details. This material is available
free of charge via the Internet at http://pubs.acs.org.
OL0703579
Org. Lett., Vol. 9, No. 14, 2007
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