Highly enantioselective alkylation reaction of enamides by bronsted-acid catalysis

Article abstract of DOI:10.1021/ol901892s

The H₈-BINOL-derived, phosphoric acid catalyzed, highly enatioselective alkylation reaction of enamides with Indoiyl alcohols has been described. A phosphoric acid derived from H8-BINOL enabled an asymmetric α-alkylation of enamides with indoiy

Full text of DOI:10.1021/ol901892s

ORGANIC
LETTERS
2009
Vol. 11, No. 20
4620-4623
Highly Enantioselective Alkylation
Reaction of Enamides by Brønsted-Acid
Catalysis
Qi-Xiang Guo,*,† Yun-Gui Peng,† Jin-Wei Zhang,‡ Liu Song,† Zhang Feng,† and
Liu-Zhu Gong*,‡
School of Chemistry and Chemical Engineering, Southwest UniVersity,
Chongqing 400715, China, and Hefei National Laboratory for Physical Sciences at the
Microscale and Department of Chemistry, UniVersity of Science and Technology of
China, Hefei 230026, China
qxguo@swu.edu.cn; gonglz@ustc.edu.cn
Received August 15, 2009
ABSTRACT
The H8-BINOL-derived, phosphoric acid catalyzed, highly enatioselective alkylation reaction of enamides with indolyl alcohols has been
described. A phosphoric acid derived from H8-BINOL enabled an asymmetric r-alkylation of enamides with indolyl alcohols to give ꢀ-aryl
3-(3-indolyl)propanones in high yields (up to 96%) and with excellent enantioselectivity (up to 96% ee).
The catalytic enantioselective intermolecular R-alkylation of
carbonyl derivatives is a highly challenging and valuable
C-C bond-forming strategy in organic synthesis.1 This
enormously important methodology has remained a long-
standing problem in asymmetric catalysis in general until
very recently.2 In the past decades, extensive efforts have
been devoted to the development of general enantioselective
R-alkylation of carbonyl compounds.3 Most recently, Petrini
and Melchiorre and Cozzi reported their enamine-catalyzed
asymmetric alkylation of aldehydes on the basis of stable
carbocations.4 MacMillan and co-workers have introduced
a new enamine catalytic activation concept termed singly
occupied molecular orbital (SOMO) catalysis, enabling
highly enanantioselective catalytic direct R-alkylation of
aldehydes.5 Despite these elegant methods, a Brønsted acid
† Southwest University.
‡ University of Science and Technology of China.
(1) (a) Modern Carbonyl Chemistry; Otera, J., Ed.; Wiley-VCH:
Weinheim, 2000; (b) Caine, D. In ComprehensiVe Organic Synthesis; Trost,
B. M., Ed.; Pergamon Press: Mew York, 1991; Vol. 2, Chapter 1.1 and
references therein. (c) Evans, D. A. In Asymmetric Synthesis; Morrison,
J. D., Ed.; Academic Press: New York; 1983; Vol. 2, Chapter 1. (d)
Carrettin, S.; Guzman, J.; Corma, A. Angew. Chem., Int. Ed. 2005, 44, 2242.
(2) Mechiorre, P. Angew. Chem., Int. Ed. 2009, 48, 1360.
(3) For phase-transfer catalytic asymmetric R-alkylation of glycine
derivatives and special ketones, see: (a) Ooi, T.; Maruoka, K. Angew. Chem.,
Int. Ed. 2007, 46, 4222, and references cited therein. For asymmetric
alkylation of preformed lithium enolates with oligoamine catalysts, see:
(b) Imai, M.; Hagihara, A.; Kawasaki, H.; Manabe, K.; Koga, K J. Am.
Chem. Soc. 1994, 116, 8829. For metal-catalyzed alkylation of preformed
tin enolates, see: (c) Doyle, A. G.; Jacobsen, E. N J. Am. Chem. Soc. 2005,
127, 62. For a catalytic asymmetric alkylation of racemic R-bromoesters,
see: (d) Dai, X.; Strotman, N. A.; Fu, G. C J. Am. Chem. Soc. 2008, 130,
3302. For asymmetric alkylation reaction by using chiral auxiliaries, see:
(e) Job, A.; Janeck, C. F.; Bettray, W.; Peters, R.; Enders, D Tetrahedron.
2002, 58, 2253.
(4) (a) Shaikh, R. R.; Mazzanti, A.; Petrini, M.; Bartoli, G.; Melchiorre,
P. Angew. Chem., Int. Ed. 2008, 47, 8707. (b) Cozzi, P. G.; Benfatti, F.;
Zoli, L. Angew. Chem., Int. Ed. 2009, 48, 1313.
(5) (a) Beeson, T. D.; Mastracchio, A.; Hong, J.-B.; Ashton, K.;
MacMillan, D. W. C. Science 2007, 316, 582. (b) Jang, H.-Y.; Hong, J.-
B.; MacMillan, D. W. C. J. Am. Chem. Soc. 2007, 129, 7004. (c) Kim, H.;
MacMillan, D. W. C. J. Am. Chem. Soc. 2008, 130, 398. (d) D. Nicewicz,
A.; MacMillan, D. W. C. Science. 2008, 322, 77.
10.1021/ol901892s CCC: $40.75
Published on Web 09/11/2009
 2009 American Chemical Society

catalyzed asymmetric alkylation of carbonyl compounds has
not yet been reported.
successfully proceeded to afford ꢀ-indolyl ketone 3a in 84%
yield and with 51% ee (Table 1, entry 1). The preliminary
The chiral counterion strategy has successfully been used
in the fields of phase-transfer catalysis, transition-metal
catalysis, and organocatalysis.3a,6 Chiral Brønsted acids, in
particular, chiral phosphoric acids, are powerful organocata-
lysts in asymmetric organic synthesis.7,8 The chiral ion pairs
between phosphate anions and cations, including iminiums,9
metal ions,6b and carbocations,4a are well-known in the fields
of chiral phosphoric acid catalyzed organic synthesis. On
the basis of the chiral phosphate anion-iminium interaction
model, List and co-workers developed a powerful concept
of asymmetric counteranion-directed catalysis (ACDC) and
have successfully applied this strategy to several highly
enantioselective transformations.9a-c Inspired by these find-
ings, we proposed that the ACDC concept might principally
be applicable to the organocatalytic alkylation reaction, as
long as the cation generated in situ from alcohols under acidic
conditions forms a tight chiral ion pair with the phosphate
anion. (1H-Indol-3-yl)(aryl)methanols can form stable cations
in the presence of a Brønsted acid,10 thereby allowing the
formation of a chiral ion pair I with chiral phosphate.11
Enamides are important nucleophiles participating in many
C-C and C-N bond-forming reactions.12 In principle, the
Lewis basic phosphoryl oxygen in the tight ion pair I will
be able to activate the enamide by a hydrogen-bonding
interaction with the proton of the enamide,13 leading to
possible TS-I that results in an intramolecular alkylation or
a conjugated addition reaction14 in an enantioselective
manner (Scheme 1). Herein, we report a highly enantiose-
Table 1. Screening Catalysts and Optimization of Reaction
Conditionsa
entry
1
catalyst
time (h)
yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
1b
1b
4a
4b
4c
4d
4e
4f
4g
5a
5b
6
12
12
12
12
12
12
4
12
20
4
84
84
74
92
78
58
51
78
81
86
26
90
73
51
27
33
16
53
41
48d
56
9
38d
14d
79d
91e
92g
10
11
12
13
4a
4a
5af
5
34
51
a The reaction was carried out with 1 (0.2 mmol), 2 (0.1 mmol), and 5
mol % of catalyst in CH2Cl2 (2 mL) at 0 °C. b Isolated yield. c The ee
value was determined by HPLC on an AS-H column. d Using 0.12 mmol
of 1. e Using 10 mol % of 4a in CH2Cl2 (3 mL) at -20 °C. f The 5a was
acidified by 2 M HCl before use (see the Supporting Information). g Using
10 mol % of 5a in CH2Cl2 (3 mL) at -30 °C.
results encouraged us to evaluate BINOL- and H8-BINOL-
based phosphoric acids 4 and 5 as well the O-linked
bisphosphoric acid 6 (Table 1). The catalyst 5a (Figure 1)
Scheme 1
.
Genaral Strategy for the Alkylation Reaction of
Enamides
Figure 1. Catalysts used in this work.
turned out to be the catalyst of choice in terms of yield and
enantioselectivity (entry 8). A survey of solvents revealed
that dichloromethane enabled the reaction to give the best
results (Table S1, Supporting Information). The N-protecting
group of enamide has great influence on the enantioselec-
tivity. Thus, a high enantioselectivity was obtained by the
replacement of Ac (acetyl) with Bz (benzoyl) as the
lective alkylation of enamides using chiral ion pairs to control
stereochemistry.
To validate our hypothesis, a reaction of N-(1-phenylvi-
nyl)acetamide 1a with (1H-indol-3-yl)(phenyl)methanol 2a
was conducted in the presence of a BINOL-based phosphoric
acid 4a in CH2Cl2 at 0 °C. As expected, the reaction
Org. Lett., Vol. 11, No. 20, 2009
4621

protecting group (entry 11). When the reaction was conducted
with 10 mol % of 4a at -20 °C, the product 3a was isolated
in 90% yield with excellent enatioselectivity of 91% ee (entry
12). Upon conducting the reaction at an even lower tem-
perature, the catalyst 5a offered 92% ee although the reaction
comparably slowed (entry 13).
Having established the optimal reaction conditions, we
explored the substrate scope, first emphasizing the generality
for the aryl substituent of (1H-indol-3-yl)(aryl)methanols
(Table 2, entries 1-11). Both electron-rich and electron-
The (1H-indol-3-yl)(2-naphthal)methanol reacted with 1b to
afford the product 3k in 90% yield with 90% ee (entry 12).
Unfortunately, no reaction occurred when we replaced the
diaryl methanol by 1-(1H-indol-3-yl)-2-phenylethanol (Table
2, entry 13).
The next exploration of the scope with respect to the
substituent on indole ring was performed (Table 3). The
Table 3. Scope of 5-Substituted Indolyl Alcohols 2a
Table 2. Scope of (1H-Indol-3-yl)(aryl)methanols 2a
entry
3
R
time (h)
yieldb (%)
eec (%)
1
2
3
4
3m
3n
3o
Cl
Br
Me
MeO
68
68
68
68
80
79
70
69
88
85
95
94
entry
3
R
time (h)
yieldb (%)
eec (%)
3p
1
2
3
4
5
6
7
8
3a
3b
3c
3d
3e
3f
3g
3h
3i
Ph
34
57
64
51
57
56
48
57
51
57
48
48
48
90
80
74
72
80
96
78
85
74
89
90
90
0
91d
92
91
92
94
90d
90
90
91
94
90
90
a The reaction was carried out with 1b (0.2 mmol), 2 (0.1 mmol), 10
mol % of 5a in CH2Cl2 (3 mL) at -30 °C. b Isolated yield. c The ee value
was determined by HPLC on an AS-H, AD-H, or Chromasil CHI-TBB
column.
4-MePh
4-ClPh
4-BrPh
4-CNPh
4-CF3Ph
3-FPh
3-NO2Ph
3-CNPh
3,4-2FPh
3-Cl-4-FPh
2-naphthal
Bn
electron-donating substituent on the 5-position of the indole
ring had a positive influence on the enantioselectivity. Thus,
the alcohols derived from 5-methylindole and 5-methoxy-
indole underwent the alkylation with 1b to afford 3o and 3p
with 95% ee and 94% ee, respectively (entries 3 and 4). On
the contrary, the introduction of electronically withdrawing
substituents to the 5-position of the indole ring resulted in a
slight decrease in the enantioselectivity (entries 1 and 2).
The generality for the enamide component was also
examined (Table 4). The enamides bearing either an elec-
tronically poor or rich phenyl substituent were able to
smoothly undergo the alkylation reaction with various indole-
derived alcohols, giving rise to the desired products in high
yields with excellent enantioselectivities. In particular, the
4-chlorophenyl enamide offered the highest enantioselectivity
(96% ee, Table 4, entries 1-3). A much cleaner reaction
with no sacrifice of the enantioselectivity was realized by
introducing an electronically rich phenyl group to the
enamides (Table 4, entries 6-8). The enamide 1e could not
undergo this alkylation reaction with indolyl alcohol 2a under
the optimal conditions (Table 4, entry 10). It is noteworthy
that asymmetric organocatalytic Michael additions of indoles
to chalcones afforded chiral ꢀ-aryl ketones of type 3 with
only moderate enantioselectivity;15 therefore, this method
9
10
11
12
13
3j
3k
3l
e
-
a The reaction was carried out with 1b (0.2 mmol), 2 (0.1 mmol), and
10 mol % of 5a in CH2Cl2 (3 mL) at -30 °C. b Isolated yield. c The ee
value was determined by HPLC on an AS-H, AD-H, or Chromasil CHI-
TBB column. d Using 10 mol % 4a as catalyst. e No desired reaction
occurred.
deficient aryl groups were tolerable and provided high yields
and excellent enantioselectivities. Both of the (1H-indol-3-
yl)(aryl)methanols bearing a phenyl group with a para
substituent, a meta substituent, or 3,4-disubstituents were
suitable reaction partners able to participate in smooth
alkylation reactions with excellent stereochemical outcomes.
(6) (a) O’Konnell, M. J. Catalytic Asymmetric Synthesis, 2nd ed.; Ojima,
I., Ed.; Wiley-VCH: New York, 2000; Chapter 10, p 727. (b) Hamilton,
G. L.; Kang, E. J.; Mba, M.; Toste, F. D. Science 2007, 317, 496.
(7) (a) Akiyama, T.; Itoh, J.; Fuchibe, K. AdV. Synth. Catal. 2006, 348,
999. (b) Akiyama, T. Chem. ReV. 2007, 107, 5744. (c) Doyle, A. G.;
Jacobsen, E. N. Chem. ReV. 2007, 107, 5713. (d) Terada, M. Chem.
Commun. 2008, 4097.
(8) For leading literature references, see: (a) Uraguchi, D.; Terada, M.
J. Am. Chem. Soc. 2004, 126, 5356. (b) Akiyama, T.; Itoh, J.; Yokota, K.;
Fuchibe, K. Angew. Chem., Int. Ed. 2004, 43, 1566.
(11) For the chiral ion pair of phosphoramide anion and carbocation,
see: Enders, D.; Narine, A. A.; Toulgoat, F.; Bisschops, T. Angew. Chem.,
Int. Ed 2008, 47, 5661.
(9) (a) Mayer, S.; List, B. Angew. Chem., Int. Ed. 2006, 45, 4193. (b)
Wang, X.-W.; List, B. Angew. Chem., Int. Ed. 2008, 47, 1119. (c)
Mukherjee, S.; List, B. J. Am. Chem. Soc. 2007, 129, 11336. (d) Li, C.-Q.;
Barbara, V.-M.; Xiao, J.-l. J. Am. Chem. Soc. 2009, 131, 6967. (e) Li, C.-
Q.; Wang, C.; Barbara, V.-M.; Xiao, J.-l. J. Am. Chem. Soc. 2008, 130,
14450. (f) Terada, M.; Tanaka, H.; Sorimachi, K. J. Am. Chem. Soc. 2009,
131, 3430–3431.
(12) Matsubara, R.; Kobayashi, S. Acc. Chem. Res. 2008, 41, 292.
(13) For the interaction model of enamides and phosphoric acid, see:
Terada, M.; Machioka, K.; Sorimachi, K. Angew. Chem., Int. Ed. 2006,
45, 2254.
(14) In the conjugated addition manner, there may exist another
interaction model, in which the phosphoric acid activate the vinyloguos
imino intermediates and enamides by hydrogen bonding, respectively.
(10) Kogan, N. A.; Kul’bitskii, G. N. Chem. Heterocycl. Compd. 1978,
14, 46.
4622
Org. Lett., Vol. 11, No. 20, 2009

mides with indolyl alcohols. The phosphoric acid 5a enabled
the R-alkylation of enamides with indolyl alcohols to give
ꢀ-aryl 3-(3-indolyl) propanones in high yields (up to 96%)
and with excellent enantioselectivities (up to 96% ee). This
work not only represents an unprecedented protocol for the
organocatalytic R-alkylation of carbonyl compounds comple-
mentary to the protocols using aminocatalysis but is also the
first case to apply the chiral counteranion-direct catalysis to
highly enantioselective organocatalytic alkylation reactions.
In addition, this method provides a new access to ꢀ-indolyl
ketone compounds with high enantiomeric purity.
Table 4. Scope of Enamides and Several Indolyl Alcoholsa
entry
3
1
Ar
time (h) yieldb (%) eec (%)
1
2
3
4
5
6
7
8
9
3q
3r
3s
3t
3u
3v
1c 4-CNPh
1c 3-Cl-4-FPh
1c 3,4-2FPh
1c 2-naphthal
1c 4-MePh
66
66
66
66
60
66
66
66
60
48
78
83
85
75
84
91
90
87
85
0
96
96
96
93
92
93
94
92
90
Acknowledgment. We are grateful for financial support
from NSFC (20732006, 20902074), CAS, and 973 program
(2009CB825300). Q.X.G. acknowledges financial support
from Southwest University (SWUB2008056).
1d 4-CNPh
3w 1d 3,4-2FPh
3x
3y
1d 3-Cl-4-FPh
1d 4-MePh
1e Ph
Supporting Information Available: Experimental details
and characterization of new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
d
10
-
a The reaction was carried out with 1 (0.2 mmol), 2 (0.1 mmol), and 10
mol % of 5a in CH2Cl2 (3 mL) at -30 °C. b Isolated yield. c The ee value
was determined by HPLC on an AS-H, AD-H, or Chromasil CHI-TBB
column. d No desired reaction occurred.
OL901892S
(15) (a) Tang, H.-Y.; Lu, A.-D.; Zhou, Z.-H.; Zhao, G.-F.; He, L.-N.;
Tang, C.-C. Eur. J. Org. Chem. 2008, 1406. (b) Zhou, W.; Xu, L.-W.; Li,
L.; Yang, L.; Xia, C.-G. Eur. J. Org. Chem. 2006, 5225. (c) Bartoli, G.;
Bosco, M.; Carlone, A.; Pesciaioli, F.; Sambri, L.; Melchiorre, P. Org. Lett.
2007, 9, 1403. (d) Chen, W.; Du, W.; Yue, L.; Li, R.; Wu, Y.; Ding, L.-S.;
Chen, Y.-C. Org. Biomol. Chem. 2007, 5, 816.
provides a unique access to highly enantiomerically enriched
ꢀ-indolyl ketones which contain the indole framework, a type
of privileged structural motif present in a large number of
natural products and therapeutic agents.16
In summary, we have disclosed the first Brønsted acid
catalyzed highly enatioselective alkylation reaction of ena-
(16) (a) Faulkner, D. J. Nat. Prod. Rep. 2002, 19, 1–49. (b) Kleeman,
A.; Engel, J.; Kutscher, B.; Reichert, D. Pharmaceutical Substances, 4th.
ed.; Thieme: New York, 2001.
Org. Lett., Vol. 11, No. 20, 2009
4623