Asymmetric SN 1 α-Alkylation of cyclic ketones catalyzed by functionalized chiral ionic liquid (FCIL) organocatalysts

Article abstract of DOI:10.1002/chem.200902509

Ionic liquid works better: The first intermolecular asymmetric α-alkylation of cyclic ketones was realized by using functionalized chiral ionic liquids as catalysts. The reaction proceeded with good to excellent yields and high ee. Highly stereoselective desymmetrization of 4-substituted cyclohexanones with >99:1 d.r. and up to 87 % ee were achieved by using this protocol. (Chemical Equation Representation).

Full text of DOI:10.1002/chem.200902509

COMMUNICATION
DOI: 10.1002/chem.200902509
Asymmetric SN1 a-Alkylation of Cyclic Ketones Catalyzed by Functionalized
Chiral Ionic Liquid (FCIL) Organocatalysts
Long Zhang,[b] Lingyun Cui,[a] Xin Li,[a] Jiuyuan Li,[a] Sanzhong Luo,*[a] and
Jin-Pei Cheng*[b]
Echoed with the sustainable chemistry concept, the devel-
opments of highly efficient and practical asymmetric cata-
lysts have been and continue to be the fore of organic syn-
thesis. Functionalized chiral ionic liquids (FCILs), which
combine the green credential of ionic liquids[1] and the cata-
lytic principles of modern asymmetric catalysis, have recent-
ly appeared as such a type of asymmetric catalyst. Following
the initial work of Howarth[2] and Seddon;[3] the applications
of FCILs have moved beyond the use as chiral additives,
chiral reagents, or chiral inducing reaction media,[4] and now
have reached the stage of asymmetric catalysts.[5] However,
the promising potentials of FCILs as asymmetric catalysts
still remain largely underdeveloped at present and the cur-
rent successes have been primarily confined to the reactions
like Michael additions and aldol reactions. As such, in our
ACHTUNGTRENaNUNG lysis, asymmetric phase-transfer catalysis was the only suc-
cessful approach to this end and it was mostly used in the
synthesis of a-amino acids through alkylation of glycine de-
rivatives.[6] In 2004, Vignola and List reported the first cata-
lytic intramolecular nucleophilic a-alkylation of aldehydes
by means of enamine activation.[7] Later on, several cascade
reactions including an intramolecular a-alkylation of alde-
hydes as the key step were also reported.[8] However, the in-
termolecular a-alkylation of aldehydes or ketones are still a
challenging task due to the depletion of catalytic activity
through the N-alkylation of the aminocatalysts and various
competing bypaths therewith.
The past few years have witnessed notable breakthroughs
in the development of asymmetric intermolecular a-alkyla-
tions of carbonyl compounds, specifically of aldehydes. Mel-
chiorre and Cozzi have independently reported SN1 type a-
alkylation of aldehydes by enamine catalysis.[9,10] This novel
approach was based on alkyl donors endowed with suitable
leaving groups (Scheme 1, I), which can generate a stabi-
continuing efforts in exploring this type of catalACTHNUTRGNEUNG
ysis,[5d–f,n] we
have sought new reaction development by taking advantage
of the intrinsic properties of ionic liquids. Herein, we report
the first FCIL-catalyzed enantioselective SN1 type alkylation
of cyclic ketones, in which the ionic liquid moieties are
found to be critical for both the catalytic activity and stereo-
control.
The catalytic asymmetric direct a-alkylation reaction of
carbonyl compounds has long been a daunting challenge in
asymmetric catalysis and synthesis. Before the renaissance
of organocatalysis, particularly the enamine-based aminoACTHNUTRGNEcNUG at-
[a] L. Cui, Dr. X. Li, J. Li, Prof. Dr. S. Luo
Beijing National Laboratory for Molecular Sciences
CAS Key Laboratory of Molecular Recognition and Function
Institute of Chemistry, the Chinese Academy of Sciences
Beijing, 100190 (P. R. China)
Fax : (+86)10-6255-4449
E-mail: luosz@iccas.ac.cn
[b] L. Zhang, Prof. Dr. J.-P. Cheng
Department of Chemistry and
State-Key Laboratory of Elemento-organic Chemistry
Nankai University, Tianjin, 300071 (P. R. China)
E-mail: chengjp@mail.most.gov.cn
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200902509.
Scheme 1. Organocatalytic strategies for asymmetric intermolecular
alkylACTHNUGRTNEUNGation of carbonyl compounds.
Chem. Eur. J. 2010, 16, 2045 – 2049
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Table 1. Optimization studies.[a]
lized carbocation in situ and immediately intercept the en-
amine intermediate. In another notable advance, MacMillan
and co-workers developed an enamine-based photoredox
catalysis, wherein the enamine was intercepted with the pho-
togenerated stabilized alkyl radical (Scheme 1, II).[11] De-
spite these advances, organocatalytic asymmetric intermo-
lecular a-alkylation of ketones has not been achieved to
date. Only chiral transition-metal catalysts have been report-
ed to promote asymmetric direct a-alkylations of ketones,
but these reactions were limited to allylation or vinylation
reactions.[12,13] Our previous work, as well as that of others,
have shown that FCILs, such as 1, are effective enamine cat-
alysts, particularly for the reactions of cyclic ketones.[5] Bear-
ing in mind the highly polar and ionic features of ionic liq-
uids, it is envisaged that FCILs might provide a favorable
catalytic sphere for direct a-alkylation of ketones, in which
ionic intermediates/transition states, such as carbocations
(Scheme 1), are involved. Our preliminary efforts along this
line indicate that such a reaction is indeed possible with
FCIL catalysis and the first asymmetric SN1 alkylation of
cyclic ketones is realized. Notably, the FCIL catalyst has
also enabled unprecedentedly highly stereoselective desym-
metrization of para-substituted cyclic ketones by asymmetric
SN1 alkylation. These results are presented in this communi-
cation.
Cat.
t [h]
Yield
Yield
ee [%][c]
of 10 [%][b]
of 11 [%][b]
1
2
3
4
5
6
7
8
9
10
11
12
13[d]
14[e]
1a
1b
1c
2
3
4
48
48
48
48
48
48
12
20
20
7
65
64
80
48
62
51
70
–
13
–
–
19
8
27
–
77
99
–
23
–
72
54
38
69
64
79
16
–
5
6a
6b
7
8
9
–
–
83
72
88
86
80
57
66
66
82
82
40
12
20
7
4
4
–
–
The direct a-alkylation reaction of cyclohexanone with
bis(4-dimethylaminophenyl)methanol, which can form a sta-
bilized carbocation under acidic conditions,[14] was selected
as the model reaction. To our delight, our initial try with
FCIL 1a led to a smooth reactions affording the desired a-
[a] Reaction conditions: The reactions were carried out at room tempera-
ture on a 0.1 mmol scale using 3 equiv of ketones and 25 mol% catalyst
under argon. [b] Isolated as a mixture of 10 and 11, the yield was calcu-
lated based on the ratio of 10/11 determined by 1H NMR spectroscopy.
[c] Determined by chiral HPLC analysis. [d] Using 37.5% mol% phthalic
acid as acid additive. [e] The reaction was conducted in 1,2-dichloro-
ethane using 37.5 mol% phthalic acid as additive.
with a benzoimidazolium cation was found to give much im-
proved enantioselectivity (79% ee, Table 1, entry 6). With
FCIL 4 as the desired catalyst, the reaction was further opti-
mized by screening different acidic additives and solvents.
The use of phthalic acid as an additive in 1,2-dichloroethane
was found to give the optimal results (Table 1, entries 13
and 14). Under these conditions, the formation of by-prod-
uct 11 was completely inhibited and the desired alkylation
product was obtained in 80% yield with 82% ee in 7 h
(Table 1, entry 14).
For comparison, typical aminocatalysts, such as 5–7 and 9,
FCIL precursor catalyst 8, as well as some primary amine
catalysts (see Supporting Information) were also examined
in the current reaction. In all these cases, the reactions led
to either low activity, mainly by-products or lower ee
(Table 1, entries 7–12), highlighting the beneficial features
of the FCIL catalysis for this reaction.
alkylated product 10 in 65% yield with 72% ee in 48 h to-
gether with a minor by-product 11 (Table 1, entry 1). The
FCIL catalysts with different ionic liquid moieties were fur-
ther probed in order to improve both the yield and enantio-
À
selectivity. Swapping the bromide ion (1a) for BF4 (1b)
À
and PF6 (1c) gave solely the desired alkylation product,
but the enantioselectivity was seriously eroded in these
cases (Table 1, entries 2 and 3). Meanwhile, though the use
of FCILs 2 and 3, which bear more bulkier groups at the
Under the optimal conditions, the scope of the present re-
actions was examined with a series of cyclic ketones and al-
cohols. As illustrated in Table 2, the reaction worked well
with cyclohexanones. For example, the reactions of 4-oxa-
and 4-thio-cyclohexanone (D4, D5, Table 2, entries 8 and 9)
imid
ACHTUNGTRENNUNGazolium ring, did not gave results superior to that of
FCIL 1a (Table 1, entries 4 and 5), the catalysis of FCIL 4
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Chem. Eur. J. 2010, 16, 2045 – 2049

Asymmetric Catalysis
COMMUNICATION
gave the desired products in moderate to excellent yields
with high ee. 4-Aza-cyclohexanone (D3) and 1,4-cyclohex-
AHCTUNGTREGaNNUN nedione monoketal (D6) were also workable substrates
producing the desired products with reasonable yields but
low enantioselectivity (Table 2, entries 7 and 10). Notably,
cyclobutanone (D1), among many other cyclic ketones ex-
amined, worked well in the present reaction to give the de-
sired product 12 in 69% yield with moderate ee (Table 2,
entry 1). A brief survey of alcohol acceptors (the carbocat-
ion precursors A) revealed a reactivity trend in accordance
with Mayrꢁs electrophilic scale (E).[14b] The alcohols that
form more stabilized carbocations (with more negative E
value) performed relatively better with higher yield of the
desired product and higher ee (e.g., E=À7.02 for the cation
from A1a, E=À5.53 for the cation from A1c, Table 2, en-
tries 2–4). Following this trend, alcohols that form unstable
carbocations (with E values close to 0) such as A2 (E=
À2.64) and A3 (E=À0.99)[14d] are not compatible substrates
in the current reactions and demonstrate very low reactivity
(Table 2, entries 5 and 6). Similar reactivity trend has also
been reported in Cozziꢁs studies.[10a]
In the course of further extending its synthetic applicabili-
ty, we were delight to find that the reactions worked ex-
tremely well with para-substituted cyclohexanones, featuring
an unprecedented stereoselective desymmetrization process
(Table 2, entries 11–20). In most cases, the SN1 alkylation re-
actions of para-substituted cyclohexanones generally pro-
duced one single diastereoisomer (>99:1 d.r.) in excellent
yields (up to 99%) and good ee (72–87% ee), except in the
cases of D7g, D7i, and D7j, for which slightly lower dia-
Table 2. Substrate scopes.[a]
AHCTUNGTREGsNNUN tereoselectivity but good enantioselectivity were still ob-
Donor Acceptor t [h] Yield [%][b] d.r. (trans/cis)[c] ee [%][d]
tained (Table 2, entries 17, 19 and 20).[15]
1
2
3
4
D1
D2
D2
D2
A1a
A1a
A1b
A1c
A2
7
7
12
12
40
12/69
10/80
13/57
14/56
15/43
–
–
–
–
44
82
71
68
The FCIL catalyst used in this reaction could be recycled
by precipitation with diethyl ether. The recovered catalyst
could be used directly in the next run and demonstrated
similar activity, diastereoselectivity, and enantioselectivity.
Diminishing activity and selectivity were found in the fourth
recycle, but good yields and ee values still remained
(Table 2, entries 21–23).
The major isomer of 29 in the reaction of D7j and A1a
has the (2S,4S) absolute configuration as determined by X-
ray crystallographic analysis of the compound (Figure 1).[16]
Other products were therefore determined by analogy. A
5[e] D2
2:1
8 (major)
18 (minor)
6
7
8
D2
D3
D4
D5
A3
12
18
7
trace
16/60
17/93
18/82
19/66
20/94
21/82
22/89
23/90
24/89
25/99
26/99
27/99
28/98
29/86
10/90
10/86
10/74
–
–
–
–
–
–
32
80
77
57
85
80
81
87
82
80
85
72
77
78
83
80
72
A1a
A1a
A1a
A1a
A1a
A1a
A1a
A1a
A1a
A1a
A1a
A1a
A1a
A1a
A1a
A1a
A1a
9
18
18
12
12
12
12
12
18
12
12
18
24
12
12
20
10
11
12
13
14
15
16
17
18
19
20
21
22
23
D6
D7a
D7b
D7c
D7d
D7e
D7f
D7g
D7h
D7i
D7j
D7d
D7d
D7d
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
90:10
>99:1
84:16
87:13
>99:1
>99:1
>99:1
[a] Reaction conditions: The reactions were carried out at room tempera-
ture on a 0.1 mmol scale using 3 equiv of ketones under argon, 25 mol%
catalyst 4 and 37.5 mol% phthalic acid as additive were used. [b] Isolated
yield. [c] Determined by 1H NMR or chiral HPLC analysis. [d] Deter-
mined by chiral HPLC analysis. [e] 25% TFA was used as acid additive.
The absolute configuration of the major product was not determined.
Figure 1. Crystal structure of 29
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S. Luo, J.-P. Cheng et al.
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count for the observed diastereoselectivity and enantioselec-
tivity (Scheme 2). In this model, the Si-face blockage of the
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Scheme 2. Proposed transition state.
enamine by the ionic liquid moiety as well as the steric re-
pulsion between the incoming carbocation and the para-sub-
stitution group are assumed to be the key factors influencing
stereoselectivity. Besides the steric effect, the electrostatic
interaction might also play an important role in the stereo-
control. The observed inefficiency of non-ionic-liquid-type
catalysts (e.g., the FCIL precursor 8 and triazole-type orga-
nocatalyst 9) in the reactions is in line with this hypothesis.
In summary, we have developed the first asymmetric cata-
lytic direct a-alkylation of cyclic ketones catalyzed by func-
tionalized chiral ionic liquids. An unprecedented desymmet-
ric a-alkylation of para-substituted cyclohexanones was real-
ized with up to 99% yield, >99:1 diastereoselectivity and
up to 87% enantioselectivity. Further applications of FCILs
in asymmetric a-alkylation of carbonyl compounds are un-
derway in our laboratory.
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Experimental Section
Typical catalytic procedure: Catalyst 4 (8.5 mg, 25 mol%) and phthalic
acid (6.3 mg, 37.5 mol%) were dissolved in 1,2-dichloroethane (0.2 mL)
in a glass vial. To this solution, bis(4-dimethylaminophenyl)methanol
(27 mg, 0.1 mmol) and cyclohexanone (31 mL, 3 equiv) were then added.
The reaction mixture was stirred at room temperature under argon for
7 h. The solvent was removed under reduced pressure and the residue
was extracted with diethyl ether (5 mLꢂ4). The combined organic layer
were concentrated and loaded directly onto a silica gel for purification.
The desired product 10 was isolated as a white solid (28 mg, 80% yield):
82% ee (by HPLC analysis on a chiralpak AD-H column, l=254 nm,
eluent iPrOH/n-hexane (15:85), flow rate=0.7 mLminÀ1; tR =9.48 min
(minor), 10.23 min (major). The recovered catalyst was reused directly in
the next run after removal of the residue solvents.
Acknowledgements
This work was supported by the Natural Science Foundation of China
(grant nos: NSFC 20632060 and 20702052), the Ministry of Science and
Technology (2008CB617501, 2009ZX09501-018), and the Chinese Acade-
my of Sciences (CAS).
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Keywords: alkylation · asymmetric catalysis · carbocations ·
chirality · ionic liquids
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Asymmetric Catalysis
COMMUNICATION
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[15] Acyclic ketones such as hydroxyl acetone could also react smoothly
with diaryl methanol A1 (7 h, 99% yield). The alkylation occurred
exclusively at the hydroxyl side, but with only low enantioselectivity
(34% ee).
[16] CCDC-743753 contains the supplementary crystallographic data for
compound 29 in this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
Received: September 11, 2009
Published online: January 20, 2010
Chem. Eur. J. 2010, 16, 2045 – 2049
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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2049