Functionalized chiral ionic liquid catalyzed asymmetric SN1 α-alkylation of ketones and aldehydes

Article abstract of DOI:10.1002/ejoc.201000609

Pyrrolidine-derived functionalized chiral ionic liquids (FCILs) have been found to catalyze asymmetric S^N1 α-alkyl-ations of ketones and aldehydes with up to 99% yield, >99:1 dr and 87% ee. The FCIL catalysts enable S^N1 α-alkylations

Full text of DOI:10.1002/ejoc.201000609

FULL PAPER
DOI: 10.1002/ejoc.201000609
Functionalized Chiral Ionic Liquid Catalyzed Asymmetric SN1 α-Alkylation of
Ketones and Aldehydes
Long Zhang,[a] Lingyun Cui,[b] Xin Li,[b] Jiuyuan Li,[b] Sanzhong Luo,*[b] and
Jin-Pei Cheng[a]
Keywords: Ionic liquids / Asymmetric catalysis / Alkylation / Carbocations / Nucleophilic substitution
Pyrrolidine-derived functionalized chiral ionic liquids
(FCILs) have been found to catalyze asymmetric SN1 α-alkyl-
ations of ketones and aldehydes with up to 99% yield, Ͼ99:1
dr and 87% ee. The FCIL catalysts enable SN1 α-alkylations
of cyclic ketones, particularly of 3- and 4-substituted cyclo-
hexanones with excellent diastereoselectivity and good
enantioselectivity, featuring unprecedented desymmetriz-
ation and kinetic resolution processes for these types of
asymmetric reaction. Full details of this study as well as the
proposed enamine transition-state are presented.
through N-alkylation of the aminocatalysts and various
competing pathways. More recently, Melchiorre and Cozzi
have independently reported SN1-type α-alkylation of alde-
hydes through enamine catalysis by taking advantage of
stable carbocations generated in situ from alkyl donors A
and B (Scheme 1, I).[8,9] In another notable advance, Mac-
Millan and coworkers developed an enamine-based pho-
toredox catalysis, wherein the enamine was intercepted with
a photo-generated, stabilized alkyl radical (Scheme 1, II).[10]
In this context, the direct asymmetric intermolecular α-alk-
ylation of ketones remains an elusive goal. Only chiral
transition-metal catalysts have been reported to promote
asymmetric direct α-alkylation of ketones, but these reac-
tions were limited to allylation or vinylation reactions,[11]
no organocatalytic process for this transformation has been
achieved to date.
1. Introduction
Asymmetric α-alkylation of carbonyl compounds has
long been recognized as a powerful tool in modern organic
synthetic chemistry. Great efforts have been made to de-
velop chiral auxiliaries based α-alkylation reactions in the
past half century and a variety of successful examples have
been reported.[1–3] Despite these advances, catalytic asym-
metric α-alkylation reactions are still rare. Many catalytic
methodologies have been attempted for this purpose, and
most of the successes have been achieved with chiral phase-
transfer catalysis (PTC).[4] Currently, the substrates of chiral
PTC are limited to stabilized enolates such as glycine deriv-
atives, and direct nucleophilic α-alkylation of aldehydes and
ketones could not be realized through this approach. Ever
since the renaissance of organocatalysis in 2000, enamine-
based catalysis has become an attractive strategy for
α-alkylation reactions, with their origins deeply rooted in
classical enamine-alkylation chemistry.[1a,5]
However, it was not until 2004 that Vignola and List re-
ported the first catalytic intramolecular nucleophilic α-alkyl-
ation of aldehydes through enamine activation.[6] Sub-
sequently, several cascade reactions involving intramolecu-
lar α-alkylation of aldehydes as the key step were also re-
ported.[7] However, intermolecular asymmetric α-alkylation
of carbonyl compounds is still a challenging task in en-
amine catalysis due to depletion of catalytic activity
Scheme 1. Organocatalytic strategies for asymmetric intermo-
lecular alkylation of aldehydes.
[a] Department of Chemistry and State-Key Laboratory of
Element-organic Chemistry, Nankai University,
Tianjin 300071, P. R. of China
[b] 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. of China
The past decade has witnessed the burgeoning develop-
ment of functionalized chiral ionic liquids (FCILs) in or-
ganic synthesis and catalysis,[12] especially in their applica-
tion as asymmetric catalysts.[13,14] In our continuing efforts
to explore this type of catalysis,[14a–14c,14k] we have been
seeking new reactions by taking advantage of the intrinsic
properties of ionic liquids. Bearing in mind the highly polar
and ionic nature of ionic liquids, it was envisaged that
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E-mail: luosz@iccas.ac.cn
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Eur. J. Org. Chem. 2010, 4876–4885

Chiral Ionic Liquid Catalyzed α-Alkylation
Figure 1. Catalysts tested in this study.
FCILs might provide a favorable catalytic sphere for direct amount of byproduct 14 (Table 1, entry 1). Changing the
–
–
α-alkylation of ketones and aldehydes in which ionic inter- bromide anion to larger anions such as BF4 or PF6 dra-
mediates or transition-states such as carbocations are in- matically decreased the enantioselectivity, although in these
volved (Scheme 2). We found that FCILs such as 1–4 (Fig- cases the reaction gave solely the alkylation products
ure 1) could indeed catalyze α-alkylation reactions of cyclic (Table 1, entries 2 and 3). Use of FCILs bearing bulky
ketones[15] and, furthermore, this reaction could be applied groups at the imidazolium ring, such as 2 and 3, did not
to the alkylation of 3- and 4-substituted cyclohexanones give superior results compared to those obtained with FCIL
and aldehydes. Herein, we report details of our studies on 1a (Table 1, entries 4 and 6). Reducing the reaction tem-
this α-alkylation reaction.
Table 1. Screening of catalysts.[a]
Entry
Catalyst Time
[h]
Yield of 13 Yield of 14 ee of 13
Scheme 2. FCIL-catalyzed asymmetric intermolecular α-alkylation
of ketones and aldehydes (this work).
[%][b]
[%][b]
[%][c]
1
2
3
1a
1b
1c
2
48
48
48
48
12
48
12
48
12
20
20
7
40
12
10
48
20
65
64
80
48
24
62
14
51
70
–
13
–
–
19
60
8
58
27
–
77
99
–
23
–
72
54
38
69
74
64
62
79
16
–
4
5[e]
6
2
2. Results and Discussion
3
7[e]
8
3
2.1 Screening of Conditions
4
9
5
10
11
12
13
14
15
16
17
6a
6b
7
The 4,4Ј-bis(dimethylamino)diphenylmethane carbo-
cation, which has been shown to be very stable at room
temperature,[16] could be generated in situ from bis(4,4Ј-di-
methylaminophenyl)methanol under acidic conditions.
Thus, direct α-alkylation of cyclohexanone with this stable
carbocation was selected as the model reaction. Firstly,
various enamine-based organocatalysts were tested; the re-
sults are summarized in Table 1. To our delight, the second-
ary amine-based FCIL catalysts showed good catalytic ac-
tivity in this reaction. For instance, with FCIL 1a, the reac-
tion proceeded smoothly to afford the desired product with
–
–
83
72
88
51
40
40
57
66
66
16
23
40
8
9
10
11
12
–
–
n.d.[d]
[a] Reaction conditions (0.1 mmol scale): ketone (3 equiv.), catalyst
(25 mol-%), r.t., under argon. [b] Isolated as a mixture of 13 and
14, the yield was calculated based on the ratio of 13/14, determined
by 1H NMR spectroscopy. [c] Determined by chiral HPLC analysis.
[d] Combined yield of 13 and 14, the ratio was not determined. [e]
65% yield and 72% ee in 48 hours, together with a minor Reactions conducted at 4 °C.
Eur. J. Org. Chem. 2010, 4876–4885
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L. Zhang, L. Cui, X. Li, J. Li, S. Luo, J.-P. Cheng
FULL PAPER
perature led to slightly increased enantioselectivity, but at with the aim of further improving the catalytic activity and
the expense of a significant decrease in activity and an in- decreasing the amount of byproduct formation. The acidic
crease in the formation of byproduct 14 (Table 1, entries 5 additive was found to be essential because no reaction oc-
and 7). To our delight, the benzoimidazolium cation based curred without the acid (Table 2, entry 1). Both strong ac-
FCIL 4 was found to greatly improve the enantioselectivity ids, such as TfOH and HClO4, and weak acids such as
(79% ee, Table 1, entry 8). Typical secondary amine cata- HOAc, PhCOOH, led to low yields and ee (Table 2, entries
lysts such as 5–7 and 9, FCIL precursor 8, as well as some 2–5). The use of sulfonic acids such as p-toluenesulfonic
primary amine catalysts 10–12, were also examined in this acid and camphorsulfonic acid gave good enantioselectivity,
reaction. Amino acids 5 and 10 gave only very low enantio- but the isolated product contained significant amounts of
selectivities in the presence of trifluoroacetic acid (TFA) byproduct 14 (Table 2, entries 6 and 7). Improved perform-
(Table 1, entries 9 and 15). Surprisingly, catalysts 6a and ance was observed with substituted benzoic acids as addi-
6b mainly produced the byproduct 14, even though these tives (Table 2 entries 9, 10, 12, and 13). Among the benzoic
privileged skeletons have been shown to be very effective acids screened, phthalic acid was found to give optimal
in many other enamine-based reactions. Catalysts 7–9 gave yield and ee values. Encouragingly, the formation of by-
comparable results to those obtained with FCIL 1a, al- product 14 was completely inhibited when the acid loading
though with slightly lower enantioselectivity (Table 1, en- was increased to 37.5 mol-%, while the enantioselectivity
tries 12–14), whereas other primary amines gave both low was maintained (Table 2, entry 14). Further increasing the
yields and ee values (Table 1, entries 16 and 17). Overall, loading of phthalic acid slightly decreased both the yield
FCIL 4 was identified as the optimal catalyst in terms of and selectivity (Table 2, entries 15 and 16).
both activity and stereoselectivity.
The effect of solvent was next explored in order to fur-
With FCIL 4 as the optimal catalyst, the reaction was ther improve the activity of FCIL 4. Except for 1,2-di-
further optimized by screening a range of acidic additives chloroethane (Table 3, entry 8), inferior results were ob-
tained in solvents other than CH2Cl2. For example, reac-
tions in non-polar solvents such as n-hexane, Et2O and tol-
uene gave mainly the byproduct 14 (Table 3, entries 1–3),
Table 2. Screening of acid additive.[a]
and similar results were obtained in polar solvents such as
tetrahydrofuran (THF), CH3CN and tBuOH (Table 3, en-
Table 3. Solvent screening.[a]
Entry Acid
Time Yield of Yield of ee of 13
[h]
13 [%][b] 14 [%][b]
[%][c]
1
2
3
4
5
6
7
8
–
–
n. r.[d]
45
30
10
50
60
30
51
44
–
n. d.[e]
n. d.[e]
n. d.[e]
n. d.[e]
n. d.[e]
n. d.[e]
27
–
TfOH
HClO4
CH3COOH
PhCOOH
PTSA
CSA
TFA
o-OH-PhCOOH
m-NO2-PhCOOH
terephthalic acid
isophthalic acid
phthalic acid
phthalic acid
phthalic acid
phthalic acid
48
48
48
48
48
48
48
48
48
48
48
48
20
20
20
31
64
–
73
82
83
79
85
84
–
86
82
82
81
78
Entry Solvent
Yield of 13 Yield of 14
ee of 13
[%][b]
[%][b]
[%][c]
1
2
3
4
5
6
7
8
n-hexane
Et2O
toluene
THF
CH3CN
CH2Cl2
CHCl3
ClCH2CH2Cl
ClCH2CH2Cl
tBuOH
H2O
17
14
9
51
17
70
60
80
46
62
31
32
19
–
69
71
75
82
77
82
80
82
–
9
40
39
10
11
12
13
14[f]
15[g]
16[h]
45
Ͻ10
Ͻ40
80
86
77
–
n.d.[e]
3
4
–
–
–
–
9[d]
10
11
12
trace
23
n.d.[e]
38
–
80
–
74
60
n. r.[f]
66
neat
15
[a] Reaction conditions (0.1 mmol scale): ketone (3 equiv.), catalyst
(25 mol-%), r.t., under argon. [b] Isolated as a mixture of 13 and
14, the yield was calculated based on the ratio of 13/14, determined
by 1H NMR spectroscopy. [c] Determined by HPLC analysis using
a chiral OD-H column. [d] No reaction. [e] Combined yield of 13
and 14, the ratio was not determined. [f] 37.5 mol-% acid was
added. [g] 50 mol-% acid was added. [h] 100 mol-% acid was added.
[a] Reaction conditions (0.1 mmol scale): ketone (3 equiv.), catalyst
(25 mol-%), phthalic acid (37.5 mol-%), r.t., under argon. [b] Iso-
lated as a mixture of 13 and 14, the yield was calculated based
on the ratio of 13/14, determined by 1H NMR spectroscopy. [c]
Determined by HPLC analysis. [d] 4 Å molecular sieves (20 mg)
was used. [e] Not determined. [f] No reaction.
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Chiral Ionic Liquid Catalyzed α-Alkylation
tries 4, 5, 10). Interestingly, no reaction was observed in Table 4. Direct α-alkylation of cyclic ketones D1–D10 with A1a.[a]
water (Table 3, entry 11). The reaction also occurred with
no added solvent, but gave low yield and enantioselectivity
(Table 3, entry 12). To our delight, the reaction was con-
siderably accelerated in 1,2-dichloroethane without any for-
mation of byproduct 14 (Table 3, entry 8). Under these con-
ditions, the reaction was complete in seven hours with 80%
yield and 82% ee.
Entry
Donor
Time [h]
Yield [%][b]
ee [%][c]
2.2 Substrate Scope
1
2
3
4
5
6
7
8
9
10
D1
D2
D3
D4
D5
D6
D7
D8
D9
D10
7
7
7
7
7
18
7
18
18
18
69 (15)
n. r.[d]
80 (13)
n. r.[d]
n. r.[d]
60 (16)
93 (17)
82 (18)
66 (19)
dec.
44
–
82
–
Under the optimal conditions, the scope of the reaction
was next explored with various donors including: acyclic
ketones, cyclic ketones, 4-substituted cyclohexanones, 3-
substituted cyclohexanones, as well as aldehydes. Other ac-
ceptors such as A1b–A3 were also examined (Figure 2). The
results were summarized in Tables 4, 5, 6, 7, and 8.
–
32
80
77
57
–
[a] Reaction conditions (0.1 mmol scale): ketone (3 equiv.), catalyst
(25 mol-%), phthalic acid (37.5 mol-%), DCE (0.2 mL), r.t., under
argon. [b] Isolated yield. [c] Determined by HPLC analysis. [d] n. r.:
no reaction.
Table 5. Direct α-alkylation of 4-substituted cyclohexanones with
A1a.[a]
Entry
Donor
Time [h] Yield [%][b]
dr[c]
ee [%][d]
1
2
3
4
5
6
7
8
9
D11a
D11b
D11c
D11d
D11e
D11f
D11g
D11h
D11i
D11j
12
12
12
12
12
18
12
12
18
24
94 (20)
82 (21)
89 (22)
90 (23)
89 (24)
99 (25)
99 (26)
99 (27)
98 (28)
86 (29)
Ͼ99:1
Ͼ99:1
Ͼ99:1
Ͼ99:1
Ͼ99:1
Ͼ99:1
90:10
Ͼ99:1
84:16
87:13
85
80
81
87
82
80
85
72
77
78
Figure 2. Donors and acceptors tested in this study.
Firstly, direct α-alkylation of cyclic ketones with varied
ring sizes with acceptor A1a was tested; the results are listed
in Table 4. As shown, cyclic ketones reacted quite dif-
ferently. Whereas the reactions of cyclobutanone D1 and
cyclohexanone D3 worked well (Table 4, entries 1 and 3),
surprisingly, cyclic ketones with five-, seven- and eight-
membered ring sizes showed no activity in this reaction
(D2, D4, and D5; Table 4, entries 2, 4, and 5). The reason
for this inertness is still unclear. Other cyclohexanones such
10
[a] Reaction conditions (0.1 mmol scale): ketone (3 equiv.), catalyst
(25 mol-%), phthalic acid (37.5 mol-%), DCE (0.2 mL), r.t., under
argon. [b] Isolated yield. [c] Determined by 1H NMR or HPLC
analysis. [d] Determined by HPLC analysis.
as 4-oxa- and 4-thio-cyclohexanone (D7 and D8; Table 4, zation of 4-substituted cyclohexanones using the asymmet-
entries 7 and 8) gave the desired products in moderate to ric α-alkylation reaction. To our delight, the reactions
excellent yield with high ee values. 4-Azacyclohexanone worked extremely well with these substrates, and led to an
(D6) and 1,4-cyclohexanedione monoketal (D9) also pro- unprecedented desymmetrization process. Most of the sub-
duced the desired products with reasonable yields but with strates could gave the desired product in excellent yields (up
low enantioselectivity (Table 4, entries 6 and 9). Under the to 99%) with greater than 99:1 diastereoselectivity and
optimal conditions, donor D10 gave no desired product due more than 80% enantioselectivity; in the cases of D11g,
to decomposition (Table 4, entry 10).
D11i, and D11j, a slight decrease in diastereoselectivity was
Bearing in mind our previous successes with desymme- found, but good enantioselectivity was still obtained
trization reactions,[14c,17] we next explored the desymmetri- (Table 5, entries 7, 9, and 10).
Eur. J. Org. Chem. 2010, 4876–4885
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FULL PAPER
Table 6. Direct α-alkylation of 3-substituted cyclohexanones with
A1a.[a]
Table 8. Direct α-alkylation of cyclohexanone with A1a–A3.[a]
Entry
Acceptor Time [h] Yield [%][b]
dr[c]
ee [%][d]
1
2
3
4
A1a
A1b
A1c
A2
7
80 (15)
57 (45)
56 (46)
43 (47)
–
–
–
82
71
68
12
12
40
Entry Donor Time [h] Yield [%][b]
dr[c]
S.M. [%][d] ee [%][e]
2:1
8 (major),
13 (minor)
–
1
D12a
D12a
D12b
D12b
D12c
D12c
D12d
D12d
D12e
D12f
D12g
D13
72
48
72
48
72
48
72
48
72
72
72
72
80
72
72
72
72
56 (30)
80 (30)
57 (31)
66 (31)
57 (32)
51 (32)
54 (33)
67 (33)
77 (34)
67 (35)
n. r.[h]
66 (36)
77 (36)
57 (37)
50 (38)
75 (39)
n. r.[h]
Ͼ99:1
Ͼ99:1
Ͼ99:1
98:2
Ͼ99:1
Ͼ99:1
Ͼ99:1
Ͼ99:1
Ͼ99:1
Ͼ99:1 24 (26% ee)
–
91:9 40 (18% ee)
91:9
90:10
99:1
99:1
–
–
–
7
–
21
–
80
80
2[f]
3
5
A3
12
trace
–
FD[g]
FD[g]
76
4[f]
5
[a] Reaction conditions (0.1 mmol scale): ketones or aldehydes
(3 equiv.), catalyst (25 mol-%), phthalic acid (37.5 mol-%), DCE
(0.2 mL), r.t., under argon. [b] Isolated yield. [c] Determined by 1H
NMR spectroscopy. [d] Determined by HPLC analysis.
6[f]
7
74
37
–
74
75
8[f]
9
32
79
10
11
12
13[i]
14
15
16
17
76
–
–
With these results in hand, we were promoted to apply
the reaction conditions to 2- and 3-substituted cyclohexa-
nones. In these reactions, kinetic resolution of 2- or 3-sub-
stituted cyclohexanones would also occur. The results are
summarized in Table 6. Again, the reaction with 3-substi-
tuted cyclohexanones occurred readily to afford regio- and
diastereoselectively the desired α-alkylated products. Al-
though minor amounts of byproduct 14 were observed, no
unwanted regioisomers were detected and, in most cases,
the desired products were isolated with up to Ͼ99:1 dr and
84% ee. The enantioselectivity of the recovered 3-substi-
tuted cyclohexanones were also determined to examine the
ability of FCIL catalysis to facilitate kinetic resolution. Un-
fortunately, only low ee values were obtained (24% and
18%; Table 6, entries 10 and 12). Because the reaction pro-
ceeded very sluggishly with limiting loading of ketone do-
nors, the kinetic resolution properties were not pursued fur-
ther. To improve the yields, four equivalents of donor load-
ing were then tested (Table 6, entries 2, 4, 6, and 8). Under
these conditions, slightly increased isolated yields were ob-
tained in most cases, and comparable diastereo- and
enantioselectivities were observed. When a larger scale reac-
tion (0.5 mmol) was conducted using 10 mol-% catalyst and
15 mol-% acidic additive (Table 6, entry 13), the reaction
was complete in 80 hours with 77% yield and 71% ee. It
should be noted that when 3-pentylthiocyclohexanone was
used as the donor, no desired product could be isolated
(Table 6, entry 11). When 2-methylcyclohexanone was sub-
mitted to the reaction conditions no reaction occurred
(Table 6, entry 17).
69
D13
D14
D15
D16
–
22
–
71
FD[g]
59
23
–
84
–
D17
[a] Reaction conditions (0.1 mmol scale): ketone (2 equiv.), catalyst
(25 mol-%), phthalic acid (37.5 mol-%), DCE (0.2 mL), r.t., under
argon. [b] Isolated yield. [c] Determined by 1H NMR or HPLC
analysis. [d] Starting material. [e] Determined by HPLC analysis.
[f] Ketone (4 equiv.) was used. [g] Not determined. [h] No reaction.
[i] Reaction conditions (0.5 mmol scale): Ketone (2 equiv.), catalyst
(10 mol-%), phthalic acid (15 mol-%), DCE (2 mL), r.t., under ar-
gon.
Table 7. Direct α-alkylation of acyclic ketones and aldehydes with
A1a.[a]
Entry
Donor
Time [h]
Yield [%][b]
ee [%][c]
1
2
3
D18
D19
24
24
24
22
22
7
99 (40)
n. r.
34
–
–
D20
n. r.
4[d]
5[d]
6[e]
7[d]
8[d]
D21a
D21b
D21c
D21c
D21d
Ͼ99(41)
Ͼ99(42)
88 (43)
90 (43)
Ͼ99 (44)
50
33
59
66
48
Acyclic ketones and aldehydes were also examined under
the conditions described above. However, among all the
acyclic ketones tested, only hydroxyacetone gave the desired
product (34% ee; Table 7, entry 1), other ketones showed
completely no activity (Table 7, entries 2 and 3). Initial tri-
als with aldehyde D21c in this reaction gave 88% isolated
yield in seven hours, but only moderate enantioselectivity
could be obtained (59% ee; Table 7, entry 6). Screening of
other FCIL catalysts led to only a slight increase in both
7
22
[a] Reaction conditions (0.1 mmol scale): ketones or aldehydes
(3 equiv.), catalyst (25 mol-%), phthalic acid (37.5 mol-%), DCE
(0.2 mL), r.t., under argon. [b] Isolated yield. [c] Determined by
HPLC analysis. [d] FCIL 2 (25 mol-%) was used as catalyst, TFA
(25 mol-%) was used as acidic additive, CH2Cl2 (0.2 mL) was used
as solvent. [e] FCIL 4 (25 mol-%) was used as catalyst, TFA
(25 mol-%) was used as acidic additive, CH2Cl2 (0.2 mL) was used
as solvent.
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Chiral Ionic Liquid Catalyzed α-Alkylation
yield and enantioselectivity when FCIL 2 was used as a used at least four times with similar activity, diastereoselec-
catalyst with TFA as an additive (Table 7, entry 7). Other tivity, and enantioselectivity. Diminishing activity and selec-
aldehydes also gave excellent isolated yields with low to tivity were found in the fourth recycle, but good yields and
moderate enantioselectivity.
ee were maintained throughout (Figure 3).
Other accepters such as A1b–A3 were also tested in the
reaction; the results are summarized in Table 8. However,
in all cases, both the yield and enantioselectivity were de- 2.3 Proposed Mechanism
creased. According to Mayr’s electrophilic scale (E),
The relative and absolute configurations of the α-alkyl-
alcohols with more negative E values performed relatively
better and gave higher yields and ee values (e.g., E = –7.02
for the cation from A1a, E = –5.53 for the cation from A1c,
Table 8, entries 1–3).[16b] These results indicated that the
stability of the carbocation formed in situ was essential for
the reaction. Following this trend, alcohols that form un-
stable carbocations (with E values close to zero), such as
A2 (E = –2.64) and A3 (E = –0.99),[16d] are not suitable
substrates for this alkylation reaction and demonstrate very
low reactivities (Table 8, entries 4 and 5). Similar reactivity
trends have also been reported by Cozzi.[9a]
ated products were determined by X-ray crystallographic
analyses. Accordingly, the crystal structure of compound 29
Ϫ an α-alkylated product derived from 4-substituted cyclo-
hexanone Ϫ shows a 2,4-trans-disubstituted structure with
(2S,4S) configuration (Figure 4, A),[18] whereas the crystal
structure of compound 35 Ϫ an α-alkylated product derived
from 3-substituted cyclohexanone Ϫ features a 2,5-cis-di-
substituted structure with (2S,5S) configuration (Figure 4,
B).[19] These stereochemical outcomes can be rationalized
by invoking classical half-chair enamine transition-states;
the favored enamine transition-states II and VI can thus
be formulated through typical conformational analysis
for 4- and 3-substituted cyclohexanones, respectively
(Scheme 3).[20] In this transition state, the ionic liquid moi-
ety would effectively shield the Si-face of the enamine by
steric repulsion as well as by electrostatic interaction. The
reaction occurs through axial Re-face attack of the carbo-
cation to minimize the A(1,3) strain arising from the bulky
nature of the carbocation. The different relative configura-
tions of the α-alkylated products of 4- and 3-substituted
cyclohexanones can be explained by assuming late transi-
tion-states in these reactions, wherein the formation of two
axial substitutes (IǞIII, VǞVII for 4- and 3-substituted
cyclohexanones, respectively) are disfavored.
Taking the reaction of D11d and A1a as a model, the
recyclability of the FCIL catalyst was tested under the opti-
mal conditions. It was found that the catalyst could be re-
3. Conclusion
We have presented a full account of our investigations
into FCIL-catalyzed asymmetric SN1-type α-alkylation of
carbonyl compounds. Notably, the current catalytic system
enables asymmetric desymmetrization of 4-substituted cy-
clohexanones to afford 2,4-trans-substituted products with
up to 99% yield, greater than 99:1 dr and 87% ee. Similarly,
the reactions of 3-substituted cyclohexanones give 2,5-cis-
substituted products with up to 80% yield, more than 99:1
dr and 84% ee. The limitations and scope of the reaction
Figure 3. Recycling and reuse of FCIL 4.
Figure 4. Crystal structures of 29 and 35.
Eur. J. Org. Chem. 2010, 4876–4885
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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4881

L. Zhang, L. Cui, X. Li, J. Li, S. Luo, J.-P. Cheng
FULL PAPER
Scheme 3. Proposed transition states.
Products 10–29 have been previously reported.[14] Products 41–44
were further demonstrated with a range of donors, such as
acyclic ketones and aldehydes, and different carbocation ac-
ceptors. Half-chair enmaine transition-states were proposed
to account for the observed stereoselectivity.
are also known compounds.[8]
Characterization Data for New Compounds
Compound 30: Yield 29 mg, 80%; Ͼ99:1 dr; white solid. [α]2D0 = –70
1
(80% ee; c = 0.5, CHCl3). H NMR (300 MHz, CDCl3): δ = 1.02
(d, J = 6.54 Hz, 3 H, CH3), 1.60–1.78 (m, 4 H, 2ϫCH2), 1.93–2.00
(m, 1 H, CH), 2.18–2.22 (m, 2 H, CH2), 2.85 [s, 6 H, N(CH3)2], 2.88
[s, 6 H, N(CH3)2], 3.14–3.20 (m, 1 H, CH), 4.14 (d, J = 11.86 Hz,
1 H, Ph2CH), 6.60–6.67 (m, 4 H, 4ϫArH), 7.10–7.16 (m, 4 H,
4ϫArH) ppm. 13C NMR (75 MHz, CDCl3): δ = 22.0, 29.2, 35.9,
40.6, 40.7, 48.0, 49.7, 54.8, 112.8, 112.9, 128.4, 130.8, 131.4, 149.1,
Experimental Section
General Information: Commercial reagents were used as received,
unless otherwise stated. 1H and 13C NMR spectra were recorded
with a Bruker-DPX 300 spectrometer. Chemical shifts are reported
in ppm from tetramethylsilane or with the solvent resonance as the
internal standard. The following abbreviations were used to desig-
nate chemical shift mutiplicities: s = singlet, d = doublet, t = triplet,
q = quartet, h = heptet, m = multiplet, br. = broad. All first-order
splitting patterns were assigned on the basis of the appearance of
the multiplet. Splitting patterns that could not be easily interpreted
were designated as multiplet (m) or broad (br). Mass spectra were
obtained with an electron impact ionization (EI) mass spectrometer
or with an electrospray ionization (ESI) mass spectrometer. IR
spectra were obtained with a Jasco FT/IR-480 Plus instrument. Op-
tical rotations were measured using a 1 mL cell with a 1 dm path
length on a Perkin–Elmer 341 digital polarimeter and are reported
as follows: [α]2D0 (c in g per 100 mL of solvent). HPLC analysis was
performed on a Varian Prostar instrument using ChiralPak AD-H,
OD-H or AS-H columns purchased from Daicel Chemical Indus-
tries, Ltd. Alcohols A1a, A1b, A1c and A3 were obtained by re-
duction of the corresponding ketones, alcohol A2 was prepared
from commercially available aldehyde by the addition of phenyl-
magnesium bromide.
149.2, 214.1 ppm. IR (KBr): ν = 2952, 2939, 2922, 2868, 2849,
˜
2796, 1702, 1614, 1563, 1519, 1479, 1458, 1443, 1349, 803 cm–1.
HRMS (EI): calcd. for C24H32N2O [M] 364.2515; found 364.2518.
The enantiomer excess was determined by HPLC analysis with a
Chiralpak AD-H column; λ = 254 nm; eluent: iPrOH/n-hexane
(1:9, v/v); flow rate = 1.0 mL/min; tR = 10.41 min (minor),
12.20 min (major).
Compound 31: Yield 26 mg, 66%; 98:2 dr; white solid. [α]2D0 = –87
(c = 0.5, CHCl3). 1H NMR (300 MHz, CDCl3): δ = 0.89 (t, J =
6.30 Hz, 3 H, CH3), 1.26–1.39 (m, 4 H, 2ϫCH2), 1.60–1.71 (m, 3
H, CH2 + CH), 1.77–1.84 (m, 2 H, CH2), 2.22 (d, J = 7.95 Hz, 2
H, CH2), 2.86 [s, 6 H, N(CH3)2], 2.89 [s, 6 H, N(CH3)2], 3.17–3.22
(m, 1 H, CH), 4.15 (d, J = 11.95 Hz, 1 H, Ph2CH), 6.60–6.67 (m,
4 H, 4ϫArH), 7.11–7.17 (m, 4 H, 4ϫArH) ppm. 13C NMR
(75 MHz, CDCl3): δ = 14.2, 19.9, 27.1, 29.2, 38.8, 40.5, 40.6, 40.7,
46.1, 49.7, 55.2, 112.8, 112.9, 128.4, 130.9, 131.4, 149.1, 149.2,
214.2 ppm. IR (KBr): ν = 2924, 2861, 2803, 1701, 1614, 1521, 1448,
˜
1350, 806 cm–1. HRMS (EI): calcd. for C26H36N2O [M] 392.2828;
found 392.2831. We failed to determine the ee.
General Procedure for SN1 Alkylation of Ketones: 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 µL, 3 equiv.) were then added. The reaction
mixture was stirred at r.t. under argon for 7 h, then the solvent was
removed under reduced pressure and the residue was extracted with
diethyl ether (4ϫ5 mL). The combined organic layers were concen-
trated and loaded directly onto a silica gel column for purification.
The desired product 13 was isolated as a white solid (28 mg, 80%
yield) in 82% ee [HPLC analysis on a chiralpak AD-H column; λ
= 254 nm; eluent iPrOH/n-hexane (15:85, v/v); flow rate = 0.7 mL/
Compound 32: Yield 22 mg, 57%; Ͼ99:1 dr; white solid. [α]2D0 = –60
(76% ee; c = 0.125, CHCl3). 1H NMR (300 MHz, CDCl3): δ =
0.90–0.94 (m, 6 H, 2ϫCH3), 1.58–1.74 (m, 5 H, 2ϫCH2 + CH),
1.79–1.85 (m, 1 H, CH), 2.15–2.19 [m, 1 H, C(H)H], 2.26–2.33 [m,
1 H, C(H)H], 2.86 [s, 6 H, N(CH3)2], 2.89 [s, 6 H, N(CH3)2], 3.17–
3.22 (m, 1 H, CH), 4.13 (d, J = 12.06 Hz, 1 H, Ph2CH), 6.60–6.68
(m, 4 H, 4ϫArH), 7.13–7.18 (m, 4 H, 4ϫArH) ppm. 13C NMR
(75 MHz, CDCl3): δ = 19.6, 19.8, 23.7, 29.1, 32.8, 40.6, 40.7, 43.0,
47.2, 49.8, 55.1, 112.8, 113.0, 128.4, 128.5, 130.6, 131.3, 149.1,
149.2, 215.1 ppm. IR (KBr): ν = 2932, 2864, 2799, 1704, 1613,
˜
1520, 1474, 1448, 1350, 807 cm–1. HRMS (EI): calcd. for
C26H36N2O [M] 392.2828; found 392.2833. The enantiomer excess
min; tR = 9.48 min (minor), 10.23 min (major)]. The recovered cata- was determined by HPLC analysis with a Chiralpak AD-H col-
lyst was reused directly in the next run after removal of the residual
solvent.
umn; λ = 254 nm; eluent: iPrOH/n-hexane (1:9, v/v); flow rate =
0.5 mL/min; tR = 16.89 min (minor), 18.18 min (major).
4882
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© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 4876–4885

Chiral Ionic Liquid Catalyzed α-Alkylation
Compound 33: Yield 27 mg, 67%; Ͼ99:1 dr; white solid. [α]2D0 = –78
(75% ee; c = 0.5, CHCl3). H NMR (300 MHz, CDCl3): δ = 0.89 (c = 0.5, CHCl3). H NMR (300 MHz, CDCl3): δ = 1.62–1.94 (m,
Compound 37: Yield 36 mg, 57%; 90:10 dr; white solid. [α]2D0 = –33
1
1
(t, J = 6.65 Hz, 3 H, CH3), 1.27–1.40 (m, 6 H, 3ϫCH2), 1.60–1.70
4 H, 2ϫCH2), 2.22–2.25 (m, 1 H, CH), 2.51–2.66 (m, 2 H, CH2),
(m, 3 H, CH2 + CH), 1.76–1.84 (m, 2 H, CH2), 2.23 (d, J = 2.86 [s, 6 H, N(CH3)2], 2.89 [s, 6 H, N(CH3)2], 3.19–3.22 (m, 1 H,
7.95 Hz, 2 H, CH2), 2.86 [s, 6 H, N(CH3)2], 2.89 [s, 6 H, CH), 3.49 (d, J = 4.90 Hz, 1 H, CH), 4.09 (d, J = 12.04 Hz, 1 H,
N(CH3)2], 3.17–3.22 (m, 1 H, CH), 4.15 (d, J = 11.92 Hz, 1 H,
Ph2CH), 6.60–6.67 (m, 4 H, 4ϫArH), 7.11–7.17 (m, 4 H,
Ph2CH), 5.17 (s, 4 H, 2ϫPhCH2), 6.59–6.69 (m, 4 H, 4ϫArH),
7.07–7.12 (m, 4 H, 4ϫArH), 7.30–7.34 (m, 10 H, 10ϫArH) ppm.
4ϫArH) ppm. 13C NMR (75 MHz, CDCl3): δ = 14.1, 22.7, 27.2, 13C NMR (75 MHz, CDCl3): δ = 24.1, 28.3, 39.6, 40.6, 40.7, 42.9,
29.0, 29.2, 36.3, 40.6, 40.7, 40.8, 46.2, 49.7, 55.2, 112.8, 112.9,
128.5, 130.9, 131.4, 149.1, 149.2, 214.2 ppm. IR (KBr): ν = 2923,
49.6, 54.7, 56.6, 67.3, 112.8, 113.0, 128.3, 128.3, 128.4, 128.5, 128.5,
128.7, 130.4, 135.2, 149.1, 149.2, 167.6, 167.7, 211.8 ppm. IR
˜
2859, 2805, 1700, 1614, 1522, 1447, 1351, 805 cm–1. HRMS (EI): (KBr): ν = 2926, 2857, 2801, 1734, 1709, 1613, 1519, 1455, 1348,
˜
calcd. for C27H38N2O [M] 406.2984; found 406.2988. The enantio-
mer excess was determined by HPLC analysis with a Chiralpak
AD-H column; λ = 254 nm; eluent: iPrOH/n-hexane (1:9, v/v); flow
rate = 0.5 mL/min; tR = 15.40 min (minor), 17.89 min (major).
807 cm–1. HRMS (EI): calcd. for C40H44N2O5 [M] 632.3250; found
632.3256. We failed to determine the ee.
Compound 38: Yield 22.5 mg, 50%; Ͼ99:1 dr; white solid. [α]2D0
=
–47.6 (59% ee; c = 0.5, CHCl3). 1H NMR (300 MHz, CDCl3): δ =
1.62–1.67 (m, 2 H, CH2), 1.69–1.75 (m, 2 H, CH2), 2.15–2.30 (m,
2 H, CH2), 2.19 (s, 6 H, 2ϫCH3), 2.74–2.82 (m, 1 H, CH), 2.87 [s,
6 H, N(CH3)2], 2.90 [s, 6 H, N(CH3)2], 3.23–3.30 (m, 1 H, CH),
3.75 (d, J = 10.35 Hz, 1 H, CH), 4.11 (d, J = 11.83 Hz, 1 H,
Ph2CH), 6.61–6.67 (m, 4 H, 4ϫArH), 7.10–7.16 (m, 4 H,
4ϫArH) ppm. 13C NMR (75 MHz, CDCl3): δ = 25.1, 28.8, 29.6,
30.1, 40.0, 40.6, 40.7, 43.5, 49.5, 54.8, 73.9, 112.8, 112.9, 128.3,
128.4, 130.7, 130.8, 149.1, 149.2, 203.0, 203.1, 211.5 ppm. IR
Compound 34: Yield 33 mg, 77%; Ͼ99:1 dr; white solid. [α]2D0 = –42
1
(79% ee; c = 0.1, CHCl3). H NMR (300 MHz, CDCl3): δ = 1.77–
1.88 (m, 2 H, CH2), 1.93–1.98 [m, 1 H, C(H)H], 2.11–2.26
[m, 1 H, C(H)H], 2.40 [dd, J = 12.77, 3.78 Hz, 1 H, C(H)H], 2.79
[t, J = 12.80 Hz, 1 H, C(H)H], 2.88 [s, 6 H, N(CH3)2], 2.91 [s, 6 H,
N(CH3)2], 3.01–3.13 (m, 1 H, CH), 3.30–3.34 (m, 1 H, PhCH), 4.30
(d, J = 12.07 Hz, 1 H, Ph2CH), 6.64–6.71 (m, 4 H, 4ϫArH), 7.18–
7.24 (m, 4 H, 4ϫArH), 7.26–7.30 (m, 3 H, 3ϫArH), 7.35–7.40
(m, 2 H, 2ϫArH) ppm. 13C NMR (75 MHz, CDCl3): δ = 28.2,
29.1, 40.6, 40.7, 46.1, 46.3, 50.0, 54.9, 112.9, 113.0, 126.6, 126.7,
(KBr): ν = 2933, 2856, 2793, 1695, 1614, 1520, 1482, 1443, 1353,
˜
808 cm–1. HRMS (EI): calcd. for C28H36N2O3 [M] 448.2726; found
448.2730. The enantiomer excess was determined by HPLC analy-
sis with a Chiralpak AD-H column; λ = 254 nm; eluent: iPrOH/n-
hexane (1:9, v/v); flow rate = 1.0 mL/min; tR = 25.83 min (minor),
28.10 min (major).
128.4, 128.5, 128.7, 144.5, 149.2, 213.4 ppm. IR (KBr): ν = 2924,
˜
2859, 2802, 1700, 1613, 1520, 1446, 1351, 805 cm–1. HRMS (EI):
calcd. for C29H34N2O [M] 426.2671; found 426.2676. The enantio-
mer excess was determined by HPLC analysis with a Chiralpak
OD-H column; λ = 254 nm; eluent: iPrOH/n-hexane (1:9, v/v); flow
rate = 0.5 mL/min; tR = 22.98 min (major), 30.62 min (minor).
Compound 39: Yield 33 mg, 75%; Ͼ99:1 dr; white solid. [α]2D0 = –90
1
(84% ee; c = 0.2, CHCl3). H NMR (300 MHz, CDCl3): δ = 1.48–
1.53 [m, 1 H, C(H)H], 1.58 (s, 3 H, CH3), 1.60 (s, 3 H, CH3), 1.62–
1.80 (m, 2 H, CH2), 1.87–1.92 [m, 1 H, C(H)H], 2.11–2.18 (m, 1
H, CH), 2.31–2.41 (m, 2 H, CH2), 2.86 [s, 6 H, N(CH3)2], 2.88 [s,
6 H, N(CH3)2], 3.20–3.25 (m, 1 H, CH), 4.03 (d, J = 12.07 Hz,
1 H, Ph2CH), 6.60–6.66 (m, 4 H, 4ϫArH), 7.10–7.14 (m, 4 H,
4ϫArH) ppm. 13C NMR (75 MHz, CDCl3): δ = 20.9, 22.7, 24.1,
27.8, 40.1, 40.6, 40.7, 48.0, 49.9, 54.3, 90.6, 112.8, 113.0, 128.3,
Compound 35: Yield 31 mg, 67%; Ͼ99:1 dr; white solid. [α]2D0 = –37
(76% ee; c = 0.1, CHCl3). H NMR (300 MHz, CDCl3): δ = 1.74–
1
1.94 [m, 3 H, CH2 + C(H)H], 2.05–2.18 [m, 1 H, C(H)H], 2.34
[dd, J = 12.71, 3.67 Hz, 1 H, C(H)H], 2.71 [t, J = 12.71 Hz, 1 H,
C(H)H], 2.86 [s, 6 H, N(CH3)2], 2.88 [s, 6 H, N(CH3)2], 2.97–3.08
(m, 1 H, CH), 3.27–3.31 (m, 1 H, PhCH), 4.24 (d, J = 12.01 Hz, 1
H, Ph2CH), 6.60–6.67 (m, 4 H, 4ϫArH), 7.14–7.20 (m, 6 H,
6ϫArH), 7.25–7.32 (m, 2 H, 2ϫArH) ppm. 13C NMR (75 MHz,
CDCl3): δ = 28.4, 29.0, 40.7, 40.8, 45.6, 46.3, 50.1, 54.9, 112.9,
113.1, 128.1, 128.5, 128.6, 128.9, 130.3, 131.0, 132.44, 143.0, 149.4,
128.4, 129.6, 130.4, 149.3, 149.3, 211.7 ppm. IR (KBr): ν = 2985,
˜
2942, 2884, 2799, 1705, 1613, 1533, 1522, 1479, 1446, 1399, 1348,
807 cm–1. HRMS (ESI): clacd. for C26H36N3O3 [M + H+] 438.2757;
found 438.2762. The enantiomer excess was determined by HPLC
analysis on a Chiralpak AS-H column; λ = 254 nm; eluent: iPrOH/
n-hexane (1:4, v/v); flow rate = 1.0 mL/min; tR = 11.06 min (major),
12.66 min (minor).
Compound 40: Yield 32.5 mg, 99%; white solid. [α]2D0 = –9.6 (34%
ee; c = 0.5, CHCl3). 1H NMR (300 MHz, CDCl3): δ = 2.11 (s, 3
H, CH3), 2.89 [s, 6 H, N(CH3)2], 2.90 [s, 6 H, N(CH3)2], 3.3 (br., 1
H, OH), 4.27 (d, J = 4.38 Hz, 1 H, Ph2CH), 4.79 (d, J = 4.29 Hz,
1 H, CH), 6.63 (d, J = 8.70 Hz, 2 H, 2ϫArH), 6.68 (d, J = 8.70 Hz,
2 H, 2ϫArH), 7.12 (d, J = 8.67 Hz, 2ϫArH), 7.23 (d, J = 8.67 Hz,
2ϫArH) ppm. 13C NMR (75 MHz, CDCl3): δ = 26.5, 40.6, 40.7,
52.1, 80.3, 112.6, 112.8, 127.5, 129.0, 129.7, 130.0, 149.3, 149.5,
149.4, 213.0 ppm. IR (KBr): ν = 2925, 2856, 2798, 1700, 1614,
˜
1520, 1486, 1447, 1348, 808 cm–1. The enantiomer excess was deter-
mined by HPLC analysis with a Chiralpak AD-H column; λ =
254 nm; eluent: iPrOH/n-hexane (1:4, v/v); flow rate = 0.5 mL/min;
tR = 20.15 min (major), 21.87 min (minor).
Compound 36: Yield 34 mg, 66%; 91:9 dr; white solid. [α]2D0 = –51
1
(69% ee; c = 0.5, CHCl3). H NMR (300 MHz, CDCl3): δ = 1.26
(td, J = 7.19, 0.90 Hz, 6 H, 2ϫCH3), 1.64–1.90 (m, 4 H, 2ϫCH2),
2.16–2.26 (m, 1 H, CH), 2.50–2.62 (m, 2 H, CH2), 2.82 [s, 6 H,
N(CH3)2], 2.85 [s, 6 H, N(CH3)2], 3.20–3.24 (m, 1 H, CH), 3.36 (d,
J = 6.90 Hz, 1 H, CH), 4.13–4.23 (m, 5 H, 2ϫOCH2 + Ph2CH),
6.57–6.69 (m, 4 H, 4ϫArH), 7.10–7.16 (m, 4 H, 4ϫArH) ppm.
13C NMR (75 MHz, CDCl3): δ = 14.1, 24.1, 28.3, 39.5, 40.5, 40.6,
42.8, 49.6, 54.6, 56.6, 61.5, 112.7, 112.9, 128.3, 128.4, 130.3, 130.8,
209.4 ppm. IR (KBr): ν = 3462, 3381, 2951, 2914.88, 2883, 2795,
˜
1716, 1696, 1613, 1520, 1482, 1443, 1351, 794 cm–1. HRMS (ESI):
calcd. for C20H27N2O2 [M + H+] 327.2073; found 327.2077. The
enantiomer excess was determined by HPLC analysis with a Chi-
ralpak AD-H column; λ = 254 nm; eluent: iPrOH/n-hexane (1:9,
v/v); flow rate = 1.0 mL/min; tR = 26.08 min (major), 28.90 min
(minor).
149.1, 149.2, 167.8, 167.9, 211.9 ppm. IR (KBr): ν = 2980, 2935,
˜
2857, 2797, 1750, 1729, 1706, 1613, 1564, 1519, 1479, 1445, 1347,
808 cm–1. HRMS (EI): calcd. for C30H40N2O5 [M] 508.2937; found
508.2942. The enantiomer excess was determined by HPLC analy-
sis with a Chiralpak AS-H column; λ = 254 nm; eluent: iPrOH/n-
hexane (1:4, v/v); flow rate = 1.0 mL/min; tR = 17.50 min (minor),
30.07 min (major).
Supporting Information (see also the footnote on the first page of
this article): 1H and 13C NMR spectra and HPLC analyses of prod-
ucts 30–41.
Eur. J. Org. Chem. 2010, 4876–4885
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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L. Zhang, L. Cui, X. Li, J. Li, S. Luo, J.-P. Cheng
FULL PAPER
B. M. Stoltz, Chem. Asian J. 2007, 2, 1476–1491. For examples,
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Acknowledgments
This work was supported by the National Natural Science Founda-
tion of China (grant numbers NSFC 20632060 and 20702052), The
Chinese Ministry of Science and Technology (2008CB617501,
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CCDC-743753 contains the supplementary crystallographic
data for compound 29. These data can be obtained free of
4884
www.eurjoc.org
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 4876–4885

Chiral Ionic Liquid Catalyzed α-Alkylation
charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
[19] CCDC-761133 contains the supplementary crystallographic
data for compound 35. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
[20]
A. G. Cook, in: Enamines: Synthesis, Structure, and Reactions
(Ed.: A. G. Cook), 2nd ed., Marcel Dekker, Inc., New York,
Basel, 1988, chapter 1, pp. 34–60.
Received: May 3, 2010
Published Online: July 13, 2010
Eur. J. Org. Chem. 2010, 4876–4885
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4885