Oxazaborolidinone-Catalyzed Enantioselective Friedel-Crafts Alkylation of Furans and Indoles with α,β-Unsaturated Ketones

Article abstract of DOI:10.1021/ol9021436

Allo-Threonine-derived oxazaborolidinone (10 mol %) catalyzes the Friedel-Crafts alkylation of furans and indoles with simple acyclic α,βunsaturated ketones to give products with high yield and high enantioselectivity. The use of N,N-dimethylaniline (2.5-

Full text of DOI:10.1021/ol9021436

ORGANIC
LETTERS
2009
Vol. 11, No. 22
5206-5209
Oxazaborolidinone-Catalyzed
Enantioselective Friedel-Crafts
Alkylation of Furans and Indoles with
r,ꢀ-Unsaturated Ketones
Shinya Adachi, Fumi Tanaka, Kazuya Watanabe, and Toshiro Harada*
Department of Chemistry and Materials Technology, Kyoto Institute of Technology,
Matsugasaki, Sakyo-ku, Kyoto, Japan 606-8585
harada@chem.kit.ac.jp
Received September 17, 2009
ABSTRACT
allo-Threonine-derived oxazaborolidinone (10 mol %) catalyzes the Friedel-Crafts alkylation of furans and indoles with simple acyclic r,ꢀ-
unsaturated ketones to give products with high yield and high enantioselectivity. The use of N,N-dimethylaniline (2.5-10 mol %) as an additive
is essential for enantioselectivity.
Recently, much attention has focused on the catalytic
enantioselective Friedel-Crafts (F-C) alkylation reaction
as an atom-economical method for forming a carbon-carbon
bond between electron-rich aromatics and electron-deficient
alkenes in a stereodefined manner.1 Major efforts have been
made to develop the F-C alkylation of indoles and pyrroles
because of a wide interest in these frameworks as ubiquitous
constituents in pharmacologically important molecules. A
number of highly enantioselective metal-catalyzed reactions
have been developed for bidentate chelating substrates since
the first report of the Cu(box)(OTf)2-catalyzed reaction for
ꢀ,γ-unsaturated-R-ketoesters by Jørgensen and co-workers.2,3
More recently, efficient catalysts have been reported for a
simple nonchelating R,ꢀ-unsaturated ketone as an electron-
deficient alkene.4,5
Furans also represent an important class of electron-rich
five-membered heterocycles that are broadly found as
structural motifs of many natural products and pharmaceuti-
cally important substances.6 Moreover, they can be employed
as useful intermediates in synthetic chemistry.7 Therefore,
the synthesis and transformation of furans have attracted
significant attention.8 While furans are generally less nu-
(2) Jensen, K. B.; Thorbauge, J.; Hazell, R. G.; Jørgensen, K. A. Angew.
Chem., Int. Ed. 2001, 40, 160–163
.
(3) Recent reports: (a) Evans, D. A.; Scheidt, K. A.; Frandrick, K. R.;
Lam, H. W.; Wu, J. J. Am. Chem. Soc. 2003, 125, 10780–10781. (b)
Takenaka, N.; Abell, J. P.; Yamamoto, H. J. Am. Chem. Soc. 2007, 129,
742–743. (c) Singh, P. K.; Singh, V. K. Org. Lett. 2008, 10, 4121–4124.
(d) Zeng, M.; Kang, Q.; He, Q.-L.; You, S.-L. AdV. Synth. Catal. 2008,
350, 2169–2173. (e) Sibi, M. P.; Coulomb, J.; Stanley, L. M. Angew. Chem.,
Int. Ed. 2008, 47, 9913–9915. (f) Liu, Y.; Shang, D.; Zhou, X.; Liu, X.;
Feng, X. Chem.sEur. J. 2009, 15, 2055–2058. (g) Sheng, Y.-F.; Li, G.-
Q.; Kang, Q.; Zhang, A.-J.; You, S.-L. Chem.sEur. J. 2009, 15, 3351–
3354. (h) Hong, L.; Wang, L.; Chen, C.; Zhang, B.; Wang, R. AdV. Synth.
Catal. 2009, 351, 772–778. (i) Hong, L.; Liu, C.; Sun, W.; Wang, L.; Wong,
(1) (a) Catalytic Asymmetric Friedel-Crafts Alkylations; Bandini, M.,
Umani-Ronchi, A., Eds.; Wiley-VCH: Weinheim, 2009. (b) Poulsen, T. B.;
Jørgensen, K. A. Chem. ReV. 2008, 108, 2903–2915. (c) Sheng, Y.-F.;
Zhang, A.-J.; Zheng, X.-J.; You, S.-L. Chin. J. Org. Chem. 2008, 28, 605–
616. (d) Bandini, M.; Melloni, A.; Tommasi, S.; Umani-Ronchi, A. Synlett
2005, 1199–1222. (e) Bandini, M.; Melloni, A.; Umani-Ronchi, A. Angew.
Chem., Int. Ed. 2004, 43, 550–556. (f) Jørgensen, K. A. Synthesis 2003,
1117–1225. (g) Bolm, C.; Hildebrand, J. P.; Mun˜iz, K.; Hermanns, N.
Angew. Chem., Int. Ed. 2001, 40, 3284–3308.
K.; Wang, R. Org. Lett. 2009, 11, 2177–2180
.
10.1021/ol9021436 CCC: $40.75
Published on Web 10/26/2009
 2009 American Chemical Society

cleophilic than indoles and pyrroles,9 they do undergo the
F-C alkylation with R,ꢀ-unsaturated ketones by the catalysis
of either Brønstead acids or Lewis acids to give racemic
products.10 However, the catalytic enantioselective version
of the reaction of furans is much less developed than that of
indoles and pyrroles.
In their study on the copper-catalyzed enantioselective
F-C alkylation, Jørgensen and co-workers reported several
examples of the reaction of 2-methylfuran with ꢀ,γ-unsatur-
ated-R-ketoesters.2,11 The enantioselective reaction of highly
nucleophilic 2-methoxyfuran with R,ꢀ-unsaturated 2-acyl
imidazoles12 and nitroalkenes13 has been reported. To date,
however, the scope of the reaction with respect to both furan
derivatives and electron-deficient alkenes remains to be
expanded.
reaction between less reactive heteroaromatics and R,ꢀ-
unsaturated ketones.
Herein, we wish to report the enantioselective F-C
reactions of furans with simple R,ꢀ-unsaturated ketones
catalyzed by OXB 1a (Ar ) Ph). Also reported is an
application of the same catalyst system to the F-C alkylation
of indoles, which significantly expands the scope of alkene
partners of the reaction.
We recently reported that OXB 1a (10 mol %) catalyzes
the Diels-Alder reaction of furan with alkyl vinyl ketones
(CH2dCHCOR) at -78 °C in toluene to give the corre-
sponding endo adducts in high enantioselectivity up to
98% ee.15c During this study, the formation of F-C
product 4aa (8%) was observed in the reaction of
2-methylfuran (2a) with vinyl ketone 3a under similar
conditions (eq 1).16 The possibility of asymmetric induc-
tion at the ꢀ position was then examined in the reaction
with crotyl ketone 3b (Table 1).
We have recently developed allo-threonine derived ox-
azaborolidinones (OXB) 1 as efficient chiral Lewis acid
catalysts for the enantioselective activation of a ketone
carbonyl group.14,15 In addition to the high enantioselectivity,
OXB 1 exhibits high activity to the less reactive substrates
as demonstrated by the successful application to the Mu-
kaiyama-type aldol addition to nonactivated ketones.15d
These characteristics prompted us to employ 1 in the F-C
(4) For chiral Lewis acid catalysts, see: (a) Bandini, M.; Fagioli, M.;
Melchiorre, P.; Melloni, A.; Umani-Ronchi, A. Tetrahedron Lett. 2003, 44,
5843–5846. (b) Bandini, M.; Fagioli, M.; Garavelli, M.; Melloni, A.; Trigari,
V.; Umani-Ronchi, A. J. Org. Chem. 2004, 69, 7511–7518. (c) Blay, G.;
Fernandez, I.; Pedro, J. R.; Vila, C. Org. Lett. 2007, 9, 2601–2604. (d)
Blay, G.; Fernandez, I.; Pedro, J. R.; Vila, C. Tetrahedron Lett. 2007, 48,
6731–6734. (e) Angeli, M.; Bandini, M.; Garelli, A.; Piccinelli, F.; Tommasi,
S.; Umani-Ronchi, A. Org. Biomol. Chem. 2006, 4, 3291–3296.
(5) For organocatalysts, see: (a) Bartoli, G.; Bosco, M.; Carlone, A.;
Pesciaioli, F.; Sambri, L.; Melchiorre, P. Org. Lett. 2007, 9, 1403–1405.
(b) Chen, W.; Du, W.; Yue, L.; Li, R.; Wu, Y.; Ding, L.; Chen, Y. Org.
Biomol. Chem. 2007, 5, 816–821. See also (c) Paras, N. A.; MacMillan,
D. W. C. J. Am. Chem. Soc. 2001, 123, 4370–4371. (d) Austin, J. F.;
MacMillan, D. W. C. J. Am. Chem. Soc. 2002, 124, 1172–1173. (e) Paras,
N. A.; MacMillan, D. W. C. J. Am. Chem. Soc. 2002, 124, 7894–7895.
(6) Keay, B. A.; Dibble, P. W. In ComprehensiVe Heterocyclic Chemistry
II; Katritzky, A. R., Rees, C. W., Schriven, E. F., Bird, C. W., Eds.;
Pergamon: Oxford, U. K., 1996; Vol. 2, pp 395-436.
Table 1. Enantioselective F-C Reaction of 2-Methylfuran (2a)
with 4-Hexen-3-one (3b) Catalyzed by OXB 1aa
entry
solvent
additive (mol %)
yield (%)
ee (%)
1b c
toluene
EtCN
Et2O
toluene
EtCN
Et2O
Et2O
Et2O
Et2O
Et2O
69
48
97
97
84
96
92
23
7
1
4
2
44
55
69
80
82
22
22
,
2b
3
4
5
6
7
8
9
PhNMe2 (5)
PhNMe2 (5)
PhNMe2 (5)
PhNMe2 (10)
PhNMe2 (20)
2,6-lutidine (10)
DTBP (10)
10
12
(7) (a) Lipshutz, B. H. Chem. ReV. 1986, 86, 795–819. (b) Raczko, J.;
Jurczak, J. Stud. Nat. Prod. Chem. 1995, 16, 639–685.
a Unless otherwise noted, reactions were carried out by using 3b (1.0
mmol, 0.3 M), 2a (5.0 equiv), and OXB 1a (10 mol %) at -40 °C for
20 h. b The reaction was carried out for 2 h. c The reaction was carried out
at 0 °C.
(8) Kirsch, S. F. Org. Biomol. Chem. 2006, 4, 2076–2080.
(9) Gotta, M. F.; Mayr, H. J. Org. Chem. 1998, 63, 9769–9775.
(10) (a) Alder, K.; Schmidt, C.-H. Chem. Ber. 1943, 76, 183–205. (b)
Bulbule, V. J.; Deshpande, V. H.; Bedekar, A. V. J. Chem. Res. Synop.
2000, 5, 220–221. (c) Dyker, G.; Muth, E.; Hashmi, A. S. K.; Ding, L.
AdV. Synth. Catal. 2003, 345, 1247–1252.
(11) For a relevant, organocatalytic reaction with R,ꢀ-unsaturated
aldehydes, see: Huang, Y.; Walji, A. M.; Larsen, C. H.; MacMillan, D. W. C.
Initial examination of the reaction of 2a with 3b resulted
in the nonenantioselective formation of the corresponding
F-C product 4ab irrespective of the solvents employed
(entries 1-3). Further examination revealed the remarkable
effect of amine additives. Thus, in the presence of N,N-
dimethylaniline (5 mol %), 4ab was obtained in an enan-
J. Am. Chem. Soc. 2005, 127, 15051–15053
.
(12) Evans, D. A.; Fandrick, K. R.; Song, H. J.; Scheidt, K. A.; Xu,
R. S. J. Am. Chem. Soc. 2007, 129, 10029–10041.
(13) Liu, H.; Xu, J.; Du, D.-M. Org. Lett. 2007, 9, 4725–4728.
(14) Harada, T.; Kusukawa, T. Synlett 2007, 1823–1835
.
(15) (a) Wang, X.; Adachi, S.; Iwai, H.; Takatsuki, H.; Fujita, K.; Kubo,
M.; Oku, A.; Harada, T. J. Org. Chem. 2003, 68, 10046–10057. (b) Harada,
T.; Adachi, S.; Wang, X. Org. Lett. 2004, 6, 4877–4879. (c) Singh, R. S.;
Adachi, S.; Tanaka, F.; Yamauchi, T.; Inui, C.; Harada, T. J. Org. Chem.
2008, 73, 212–218. (d) Adachi, S.; Harada, T. Org. Lett. 2008, 10, 4999–
(16) The corresponding Diels-Alder adduct was not obtained in this
reaction.
5001
.
Org. Lett., Vol. 11, No. 22, 2009
5207

tiomerically enriched form in high yield (entries 4-6).
Increasing the amount of the additive to 10 mol % in Et2O
brought about an improved enantioselectivity of 80% ee
(entry 7), while a further increase (20 mol %) resulted in a
decrease in the product yield (entry 8). Other amine additives
also exerted a positive effect on enantioselectivity while
being inferior to N,N-dimethylaniline (entries 9 and 10).
The scope of the OXB-catalyzed F-C reaction of furans
was examined in Et2O at -40 °C in the presence of N,N-
dimethylaniline (eq 2, Table 2). In addition to methyl
of 2a and 2e gave the corresponding product 4af and 4ef in
85% ee and 89% ee, respectively, in high yield.
Catalysis by OXB was examined also for the F-C
alkylation of indoles because of the synthetic importance of
the transformation. Unlike furans 2, indole (5a) underwent
the enantioselective F-C alkylation with 3b in the absence
of N,N-dimethylaniline at lower temperature (-85 °C) to
give 6ab in 78% ee and in 90% yield (eq 3). The addition
of 2.5 mol % of the amine improved the selectivity to 87%
ee, while further increase (5 mol %) resulted in a decrease
in yield.
Table 2. OXB-Catalyzed Enantioselective Friedel-Crafts
Reaction of Furans 2 with Enones 3a
A variety of indole derivatives 5a-e underwent the F-C
alkylation with enone 3b by using OXB 1a (10 mol %) with
N,N-dimethylaniline (2.5 mol %) in Et2O at -85 °C affording
the corresponding product 6 of high ee (85-93%) (eq 4,
entries 1-5 in Table 3). As shown in entries 6-9, the
reaction was applicable to various 1-alkenyl alkyl ketones
entry
furan
enone
product
yield (%)
ee (%)b
1
2
2a
2b
2c
2d
2e
2f
2a
2a
2e
2a
2e
3b
3b
3b
3b
3b
3b
3c
3d
3e
3f
4ab
4bb
4cb
4db
4eb
4fb
4ac
4ad
4ee
4af
92
95
96
62
98
trace
79
92
87
81
99
80
77
79
85
91
3
4c
5
Table 3. OXB-Catalyzed Enantioselective Friedel-Crafts
Reaction of Indoles 5 with Enones 3a
6
7
8
81
86
85
85
89
9c
10
11d
3f
4ef
a Unless otherwise noted, reactions were carried out by using 3 (1.0
mmol), 2 (5.0 equiv), PhNMe2 (10 mol %), and OXB 1a (10 mol %) in
Et2O (3.1 mL) at -40 °C for 20 h. b Determined by chiral HPLC analysis.
The S configuration of 4ac was assigned by converting it into (S)-2-methyl-
4-oxo-heptanoic acid. See Supporting Information for details. c The reaction
was carried out with 20 mol % of OXB and PhNMe2. d The reaction was
carried out for 44 h.
entry
indole
enone
product
yield (%)
ee (%)b
1
5a
5b
5c
5d
5e
5a
5e
5a
5e
5e
3b
3b
3b
3b
3b
3d
3e
3f
6ab
6bb
6cb
6db
6eb
6ad
6ee
6af
92
85
55
93
91
81
90
96
87
52
87
89
85
93
87
92
82
94
84
37
derivative 2a, the reaction worked well with other 2-substi-
tuted furans 2b-d (entries 1-4). The reactions of the 2-ethyl,
-butyl, and -benzyl derivatives with 3b afforded the corre-
sponding F-C products of 77-84% ee in high yields. Of
these, benzyl derivative 2d was somewhat less reactive and
20 mol % of the catalyst was required. 2,3-Dimethylfuran
(2e) exhibited high enantioselectivity (91% ee) in the reaction
with 3b (entry 5). On the other hand, parent furan (2f) hardly
reacted with 3b (entry 6). Other aliphatic enones, such as
crotyl alkyl ketones 3c,d and 1-hexenyl methyl ketone (3e),
also serve as an acceptor of the F-C alkylation (entries 7
and 8), while the attempted reactions with benzalacetone (3g;
R1 ) Ph, R2 ) Me) resulted in the recovery of the enone.
Enone 3f bearing an ethoxy carbonyl group at the ꢀ-position
was also a good substrate (entries 9 and 10). The reaction
2
3c
4
5
6
7c
8c
9d
10
3g
3h
6eg
6eh
a Unless otherwise noted, reactions were carried out by using 3 (1.0
mmol), 5 (1.0 equiv), PhNMe2 (2.5 mol %), and OXB 1a (10 mol %) in
Et2O (3.1 mL) at -85 °C for 20 h. b Determined by chiral HPLC analysis
(see Supporting Information). The S configuration of 6ab,5a 6af,5a and 6ah4b
were assigned by comparison of the optical rotation signs with literature
data. c The reaction was carried out for 96 h. d The reaction was carried
out for 48 h.
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Org. Lett., Vol. 11, No. 22, 2009

3d-g. Unlike the reaction of furans, less reactive ꢀ-phenyl
substituted enone 3g afforded indole alkylation product 6eg
of 84% ee in high yield (entry 9). Catalysis by 1a was not
effective in the reaction with crotyl phenyl ketone 3g (entry
10). Pedro and co-workers reported a highly enantioselective
F-C alkylation of indoles catalyzed by a zirconium(IV)-
BINOL complex (20 mol %).4c,d Their method is specifically
effective for 1-alkenyl aryl ketones such as 3h. Therefore,
the present OXB-catalyzed reaction well complements the
zirconium-catalyzed reaction for acyclic enones.
In summary, OXB catalysis is demonstrated to be effective
in the enantioselective F-C alkylation of electron-rich
heteroaromatics. The enantioselective F-C alkylation of
furans with a monodentate R,ꢀ-unsaturated ketones is real-
ized for the first time by OXB catalysis. In addition, the
catalyst system is successfully applied to the alkylation of
indoles, expanding the scope of substrates. The use of N,N-
dimethylaniline as an additive is crucial to the enantiose-
lectivity. Studies are underway to elucidate the role of the
additive as well as to clarify the scope of the reactions.
Acknowledgment. This work was partially supported by
KAKENHI (17550101).
Supporting Information Available: Experimental pro-
cedures and characterization of products. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL9021436
Org. Lett., Vol. 11, No. 22, 2009
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