The direct asymmetric α alkylation of ketones by Bronsted acid catalysis

Article abstract of DOI:10.1002/anie.201106275

Being direct: A Bronsted acid catalyzed α alkylation of ketones is described. The phosphoric acid 1 promotes this reaction to afford the desired products with high yields, high diastereoselectivities, and good to excellent enantioselectivites.

Full text of DOI:10.1002/anie.201106275

Angewandte
Chemie
DOI: 10.1002/anie.201106275
Organocatalysis
The Direct Asymmetric a Alkylation of Ketones by Brønsted Acid
Catalysis**
Liu Song, Qi-Xiang Guo,* Xing-Cheng Li, Juan Tian, and Yun-Gui Peng*
The development of new catalytic asymmetric methodologies
for organic transformations is an important area of research
for organic chemists.[1] Among the numerous organic reac-
tions, a alkylation of carbonyl compounds is a highly valuable
[2]
À
C C bond-formation strategy. In the last ten years, a
number of organocatalytic methods, including asymmetric
phase-transfer catalysis[3] and asymmetric amino catalysis,[4]
have been developed for the a alkylation of carbonyl com-
pounds. Alcohols are ideal alkylation reagents for this
reaction because water is the sole by-product.[5,4a–g] Theoret-
ically, Brønsted acids are good catalysts for promoting the
a alkylation of carbonyl compounds, especially ketones and
Figure 1. Selection of the alkylation reagent in this work.
aldehydes, with alcohols. The reasons for this include the
following: 1) Brønsted acids can promote enol formation with
the ketones or aldehydes;[6] 2) Brønsted acids can activate
alcohols by protonating the hydroxy group, and then promote
formation of an active carbocation intermediate;[4a–i] and
3) whereas amino catalysts are potentially alkylated by the
alkylation reagent and then deactivated,[4o] Brønsted acids are
not. Despite their advantages, Brønsted acids have not been
decomposed quickly when it was mixed with cyclohexanone
and a Brønsted acid catalyst in an organic solvent (see the
Supporting Information). It is well known that 1a can
produce the stable carbocation or vinylogous imino inter-
mediate A under acidic conditions (Figure 1),[4b,h–i,10] and we
speculated that the weak electrophilicity of A could lead to
the poor results in the direct alkylation of ketones. According
to Mayr et al., ketones have lower nucleophilicity (N) than
enamides. Consequently, the electrophilicity (E) of the
corresponding electrophiles should be increased.[11] Because
positive charge density has a large influence on electro-
philicity, we chose to introduce an electron-withdrawing
group on 3-indolylmethanol 1a to increase the electrophilicity
of intermediate A. The isatin-derived 3-hydroxy-3-indolyox-
indole 2a could serve as a good alkylation reagent for the
direct alkylation reaction. Compound 2a can lead to the
intermediate B, which has similar stability to A, under acidic
conditions. In addition, the amide group of intermediate B
increases the positive charge density on C3, thus making it
more electrophilic than intermediate A. Therefore, the
reaction of 2a with ketones could generate chiral 3-indolyl-
oxindoles, a novel type of indole[12] and oxindole[13] that could
be potentially used in indole alkaloid synthesis.[14] Thus,
cyclohexanone (3a) and 3-hydroxy-3-indolyloxindole 2a were
chosen as reactants for the present study (see Table 1). 1,1’-
Bi-2-napthol-derived phosphoric acids 4 were chosen as
catalysts because they are powerful Brønsted acid catalysts
that have been used in many organic transformations.[15]
After the selection of the compounds for the model
reaction, 2a was reacted with 3a in toluene with 4a as the
catalyst. As expected, the reaction proceeded smoothly and
the desired alkylation product 5a was obtained in good yield
with high diastereoselectivity and enantioselectivity (Table 1,
entry 1). These promising results encouraged evaluation of
the catalytic ability of other phosphoric acids (Figure 2). All
of the catalysts were acidified before use[16] (see the Support-
À
used for asymmetric catalysis in this important C C bond-
formation reaction,[7,8] and only a few direct alkylation
reactions of carbonyl compounds with alcohols catalyzed by
achiral Brønsted acids have been described.[6c,9] Our group
reported an asymmetric Brønsted acid catalyzed a alkylation
reaction in 2009, but this involved enamides, preactivated
ketones, as donors.[10] As a continuation of this research, we
have attempted direct asymmetric a alkylation of ketones
with alcohols by Brønsted acid catalysis, and herein we report
the first example of such an alkylation of unmodified ketones
with alcohols in high yields (up to 98%) with high diastereo-
selectivities (d.r., up to 99:1), and high enantioselectivities [up
to 97% enantiomeric excess (ee)].
Recently, 3-indolylmethanols were extensively used in the
alkylation reaction of carbonyl compounds through organo-
catalysis.[4b,h–i,10] However, our initial attempt to introduce the
3-indolylmethanol 1a (Figure 1) for the direct alkylation of
unmodified ketones was unsuccessful. We found that 1a
[*] L. Song, Prof. Q.-X. Guo, X.-C. Li, J. Tian, Prof. Y.-G. Peng
Education Ministry Key Laboratory on Luminescence and Real-Time
Analysis, School of Chemistry and Chemical Engineering
Southwest University, Chongqing 400715 (China)
E-mail: qxguo@swu.edu.cn
pyg@swu.edu.cn
[**] We are grateful for financial support from NSFC (20902074) and the
financial support from the Fundamental Research Funds for the
Central Universities (XDJK2011C054).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201106275.
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.
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Communications
Table 1: Screening of catalysts and optimization of reaction conditions.[a]
indoles 2 in this alkylation reaction was investigated (Table 2).
First, subsititution of the indole ring was investigated
(Table 2, entries 1–8). The enantioselectivities greatly
depended upon the substituents on the indole ring. For
Table 2: The substrate scope of 3-hydroxy-3-indolyloxindoles.[a]
Entry
4
Solvent
t [h]
Yield [%][b]
d.r.[c]
ee [%][d]
1
2
3
4
5
6
7
8
4a
4b
4c
4d
4e
4 f
4g
4a
4a
4a
4a
4a
4a
4h
4h
toluene
toluene
toluene
toluene
toluene
toluene
toluene
CH2Cl2
CHCl3
Et2O
MTBE
m-xylene
toluene
toluene
toluene
18
18
18
18
18
18
18
18
48
48
48
18
66
48
84
71
91
97
57
98
97
89
53
trace
22
24
84
52
80
98
93:7
75:25
83:17
83:17
86:14
89:11
86:14
82:18
–
–
–
92:8
95:5
95:5
95:5
88
84
85
76
83
86
80
80
–
–
–
86
92[e]
91[e]
92[f]
Entry R1, R2, (2)
T [8C]
5
Yield [%][b] d.r.[c]
ee [%][d]
1
2
3
4
5
6
7
8
H, H (2a)
À15
À15
À15
À15
À15
À10
À10
À10
À5
5a 98
5b 65
95:5
95:5
95:5
94:6
86:14 93
88:12 84
87:13 80
99:1
90:10 92
93:7
94:6
90:10 91
89:11 90
92
91
91
93
5-MeO, H (2b)
5-Me, H (2c)
6-Me, H (2d)
7-Me, H (2e)
5-Cl, H (2 f)
5-Br, H (2g)
6-F, H (2h)
H, 5-Me (2i)
H, 7-Cl (2j)
5-MeO, 7-Cl (2k)
5-MeO, 5-Cl (2l)
5-MeO, 5-Br (2m)
6-Me, 5-F (2n)
6-Me, 6-Cl (2o)
9
5c
84
10
11
12
13
14
15
5d 86
5e 91
5 f
95
5g 90
5h 69
85
9
5i
5j
94
82
[a] The reaction was carried out with 2a (0.1 mmol), 3a (1.0 mmol), and
4 (0.01 mmol) in toluene (2 mL). [b] Yield of isolated product.
10
11
12
13
14
15
0
89
92
À15
5k 90
5l 94
5m 74
5n 66
5o 71
1
[c] Determined by H NMR spectroscopy. [d] Determined by HPLC
0
analysis using a chiral stationary phase. [e] The reaction was carried out
at À108C. [f] Using 0.5 mmol 3a and 4 mL toluene at À158C.
MTBE=methyl tert-butyl ether.
0
À5
92:8
93:7
91
92
À15
[a] The reaction was carried out with 2 (0.1 mmol), 3a (0.5 mmol), and
4h (0.01 mmol) in toluene (4 mL) for 48–159 h (see the Supporting
Information). [b] Yield of two isolated diastereomers. [c] Diastereomeric
ratio determined by 1H NMR spectroscopy on the crude reaction
mixture. [d] The enantioselectivity of the major component determined
by HPLC analysis using a chiral stationary phase.
ing Information). As shown in Table 1, 4a is the best catalyst
in terms of diastereoselectivity and enantioselectivity
(Table 1, entry 1). The introduction of para-substituted
phenyl groups on the 3,3’-position of (R)-4 increased the
example, high enantioselectivities were obtained when com-
pound 2 had an electron-rich indole ring (Table 2, entries 2–
5), whereas the enatioselectivities decreased slightly when the
indole ring was electron deficient (Table 2, entries 6–8).
Substitution on the oxindole ring was then investigated
(Table 2, entries 9–15). The desired products 5i–5o were
obtained in high yields with high diastereoselectivities and
enantioselectivities with both electron-rich and electron-
deficient oxindole rings (Table 2, entries 9–15).
Figure 2. Catalysts used in this work.
yield greatly, but the diastereoselectivity and enantioselectiv-
ity decreased slightly (entries 2 and 3, and 5–7 versus entry 1).
Evaluation of the solvent indicated that toluene was the best
solvent for this reaction. Although the diastereoselectivity
and enantioselectivity of 5a increased slightly when the
reaction was conducted at low temperature, the yield
decreased dramatically (Table 1, entry 13). The catalyst 4h,
bearing electron-rich para-substituted phenyl groups on the
3,3’-position, had better catalytic activity than 4a in this
reaction (Table 1, entry 14 versus 13). Excellent outcomes
(98% yield, 95:5 d.r., and 92% ee) were obtained when this
reaction was carried out in toluene at À158C with 4h (Table 1,
entry 15).
The substrate scope of various cyclic ketones and acyclic
ketones in this reaction was also investigated (Table 3). Six-
membered cyclic ketones, such as tetrahydropyran-4-one
(3b), tetrahydrothiopyran-4-one (3c), the N-protected piper-
idin-4-one 3d, and 1,4-dioxaspiro[4.5]decan-8-one (3e), pro-
duced the desired products 5p–5t in high yields with high
diastereoselectivities and enantioselectivities (Table 3,
entries 1–5). The best enantioselectivity in this work (97%
ee) was obtained when ketone 3c reacted with 2e in toluene
with 4h as the catalyst (Table 3, entry 3). The yields and
enantioselectivites decreased when a five- or seven-mem-
bered cyclic ketone was used as the donor (Table 3, entries 6
and 7). Notably, acyclic ketones were also suitable for this
alkylation reaction. For example, butanone reacted with 2a
smoothly and produced the desired product 5w in moderate
After the optimal reaction conditions were established,
the substrate scope of the substituted 3-hydroxy-3-indolylox-
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Table 3: The substrate scope of the ketones.[a]
Entry
3
T [8C]
t [h]
5
Yield [%][b]
d.r.[c]
ee [%][d]
Scheme 1. The alkylation reaction of cyclohexanone with 2p. Bn=ben-
zyl.
1
2
3
4
5
6
7
8
9
10
3b
3c
3c
3d
3e
3 f
3g
3h
3i
À5
À5
À5
0
91
88
60
71
66
44
93
93
91
88
5p
5q
5r
5s
5t
5u
5v
5w
5x
5y
77
91
94
84
87
49
53
53
37
27
78:22
85:15
83:17
89:11
86:14
98:2
93:7
97:3
95:5
95:5
92
92
97[e]
86
À5
88[e]
81
0
In conclusion, this is the first example of a Brønsted acid
0
0
0
0
74
catalyzed direct alkylation of unmodified ketones with an
activated alcohol. Phosphoric acid promoted this transforma-
tion to afford 3-indolyloxindoles in high yields (up to 98%)
with high diastereoselectivities (up to 99:1) and high enan-
tioselectivities (up to 97% ee). This reaction has broad
substrate scope for the substituted 3-hydroxy-3-indolyloxin-
81
97[e]
89
3j
[a] The reaction was carried out with 2a (0.1 mmol), 3 (0.5 mmol), and
4h (0.01 mmol) in toluene (4 mL). [b] Yield of two isolates diastereo-
mers. [c] Diastereomeric ratio determined by 1H NMR spectroscopy.
[d] Enantioselectivity determined by HPLC analysis using a chiral
stationary phase. [e] Using 2e as an acceptor.
yield with high diastereoselectivity and good
enantioselectivity (Table 3, entry 8). Ketones
with large steric bulk, such as 2-pentanone
(3i) and 3-pentanone (3j), did participate in
this reaction and the desired products were
obtained with high diastereoselectivities and
good enantioselectivities but in low yields
(Table 3, entries 9 and 10). These are success-
ful examples of highly enantioselective
Brønsted acid catalyzed organic reactions of
aliphatic ketones having large steric bulk.[6]
The relative and absolute configurations
of 5q (R,R) were determined by X-ray
crystallography of recrystallized 5q (see the
Supporting Information).[17] The stereochem-
istry of other alkylation products were
Scheme 2. A possible transition state (TS1) in this reaction.
assigned by comparison to 5q.
The 3-hydroxy-3-indolyoxindoles 2 can
form two possible active intermediates under
acidic conditions.[10] One is the carbocation intermediate, and
the other is the vinylogous imino intermediate. To clarify what
intermediate was involved in this alkylation reaction, the N-
benzyl-indole-derived 3-hydroxy-3-indolyloxindole 2p was
synthesized and used in this transformation. As shown in
Scheme 1, the yield and enantioselectivity of 6 decreased
greatly, thus indicating that the 3-hydroxy-3-indolyloxindole
underwent this reaction via a vinylogous imino intermediate.
Thus, the 3-hydroxy-3-indolyloxindole formed the corre-
sponding vinylogous imino intermediates C and D under
acidic conditions (Scheme 2). We believe the intermediate D
is dominant because of the unfavorable steric interactions
between the two hydrogen atoms on the isatin ring and indole
ring in C. The catalyst complexes with D and the enol form of
the ketone reacts through the transition-state TS1. The enol
attacks the vinylogous imino D at the Re face, thus giving the
alkylation adduct 5.
doles and ketones. Both cyclic and acyclic ketones afforded
the corresponding products with good outcomes.
Received: September 5, 2011
Revised: November 16, 2011
Published online: January 19, 2012
Keywords: alkylation · Brønsted acid · indole · organocatalysis ·
.
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