Asymmetric Michael addition of cyclohexanone or cyclopentanone to chalcones catalyzed by an L-proline-based organic phosphane

Article abstract of DOI:10.1002/ejoc.201201609

An organophosphane catalyst derived from L-proline was shown to be a very effective catalyst for asymmetric Michael addition reactions of various chalcones to cyclic ketones including both cyclohexanone and cyclopentanone. The corresponding adducts could

Full text of DOI:10.1002/ejoc.201201609

FULL PAPER
DOI: 10.1002/ejoc.201201609
Asymmetric Michael Addition of Cyclohexanone or Cyclopentanone to
Chalcones Catalyzed by an -Proline-Based Organic Phosphane
L
Lingyan Liu,[a] Yunna Zhu,[a] Kaimeng Huang,[a] Weixing Chang,[a] and Jing Li*[a]
Keywords: Michael addition / Asymmetric catalysis / Phosphanes
An organophosphane catalyst derived from
L
-proline was
91%) and with excellent enantioselectivities (up to 99% ee)
and diastereomeric ratios (up to Ͼ99:1). A possible catalytic
mechanism, based on 31P NMR and ESI-MS observations, for
this organophosphane-catalyzed Michael addition has been
proposed.
shown to be a very effective catalyst for asymmetric Michael
addition reactions of various chalcones to cyclic ketones in-
cluding both cyclohexanone and cyclopentanone. The corre-
sponding adducts could be obtained in high yields (up to
Introduction
and obtained the corresponding products with yields in the
The Michael addition reaction is widely considered one 45%–93% range, together with enantioselectivities of
of the most important carbon-carbon bond-forming reac- Ն80% and excellent diastereomeric ratios (Ն99:1).[5] In the
tions in organic synthesis.[1] In particular, Michael additions case of cyclopentanone, however, the Michael addition re-
of cyclic ketones to active acceptors – of cyclohexanone to action with chalcone by the same protocol gave the adduct
nitroolefins, for example – have attracted intense attention with only 73% ee. Recently, Q. S. Li et al. employed pyrrol-
over the past decade,[2] and to date there have been lots of idine-based imides to catalyze Michael addition of cyclic
successful reports.[2,3] In comparison, reported asymmetric ketones to chalcones; 30 mol-% catalyst was used and a
Michael addition reactions between cyclic ketones and less longer reaction time (7 d) was necessary.[6] The development
reactive α,β-unsaturated ketones, namely chalcones, are few of more efficient organocatalysts for Michael addition be-
and still remain a major challenge. J. Wang’s research tween less reactive chalcones and cyclic ketones is therefore
group, for example, used a chiral pyrrolidinylmethyl- a matter of urgency and great significant. Moreover, as far
sulfonamide as an organocatalyst for Michael addition of as Michael addition between cyclopentanone and chalcone
cyclohexanone to chalcones and obtained the desired is concerned, reports are very much rarer than in the case
products with moderate yields (65–85%) and good enantio- of cyclohexanone.[4–8] This might be due to the low reactiv-
selectivities (Ն90%) and diastereomeric ratios (Ͼ50:1).[4] ity and high steric hindrance of chalcone as well as to the
These reactions, however, generally required long times high ring strain of cyclopentanone.
(more than 4 d) to go to completion. Y. M. Wang and co-
In this regard, achieving a broad substrate range and
workers then reported the Michael additions of cyclohexan- higher selectivity stirred our interest. Here we report the l-
one to chalcones catalyzed by a pyrrolidine-pyridine base proline-derived organophosphane catalyst[9] shown in
Scheme 1. Asymmetric Michael addition of cyclic ketones to chalcones catalyzed by an organophosphane based on l-proline.
Scheme 1 for catalyzing asymmetric Michael addition of cy-
[a] State Key Laboratory of Elemento-Organic Chemistry, Nankai
clic ketones to chalcones.
University,
Weijin Road, Nankai District, Tianjin 300071, P. R. China
Fax: +86-22-2350-1410
E-mail: lijing@nankai.edu.cn
Results and Discussion
liulingyan@nankai.edu.cn
Homepage: http://chem.nankai.edu.cn/intro/team.php
Organic phosphane catalysts and a series of prolinamides
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201201609.
based on l-proline (Figure 1) were first prepared as de-
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Phosphane-Catalyzed Asymmetric Michael Addition
scribed in the previous reports.[10] Asymmetric Michael ad- very low yields (Table 1, Entries 4 and 5, 10% and 26%,
dition between cyclohexanone (8a) and chalcone (9a) in the respectively) and with low enantioselectivities (19% and
presence of these synthesized catalysts (20 mol-%) at room 14%, respectively) after 5 d. The trivalent organophosphane
temperature in iPrOH (0.2 mL) was then investigated. The catalyst 6, as a weak Lewis base promoter, showed no cata-
results are summarized in Table 1.
lytic activity (Entry 6) in this reaction. However, the prod-
uct could be produced in moderate yield (49%) but with
high enantioselectivity (90% ee) and diastereoselectivity
(98:2) in the presence of the organophosphane oxide 7 un-
der these reaction conditions (Table 1, Entry 7). Encour-
aged by the high enantioselectivity obtained, we defined the
catalyst 7 as the best candidate.
Subsequently, other experimental parameters in the pres-
ence of 20 mol-% catalyst 7 were examined. Benzoic acid
proved to be optimal for accelerating the reaction rate; its
use increased the reaction yield from 49% to 73% (Table 2,
Entries 1 and 2). Further fine adjustment of the acidity
(benzoic acid to p-nitrobenzoic acid) or changing to other
strong acids, such as salicylic acid and trifluoroacetic acid,
produced no obvious improvement in results even with
longer reaction times (Entries 3–5). On examination of the
Lewis base additive Et3N, although the enantioselectivity
could be retained at the 90% ee level, the yield was de-
creased (36%) (Table 2, Entry 6). Overall, benzoic acid was
considered to be the best.
Table 2. Effects of solvents and additives on the reaction between
cyclohexanone (8a) and chalcone (9a).
Figure 1. Organocatalysts derived from l-proline.
Table 1. Screening of catalysts for the Michael reaction between
cyclohexanone (8a) and chalcone (9a).
Entry Solvent
Additive
Time Yield dr
[d]
ee
[%][a] (anti/syn)[b] [%][b]
Entry Catalyst Time [d] Yield [%][a] dr (anti/syn)[b]
ee [%][b]
1
2
3
4
5
6
7
8
iPrOH
iPrOH
iPrOH
iPrOH
iPrOH
iPrOH
tBuOH
THF
–
4
3
4
4
4
4
3
3
3
3
3
5
5
49
73
46
18
trace
36
33
33
32
trace
33
98:2
98:2
90
91
95
92
–
90
92
91
93
–
1
2
3
4
5
6
7
1
2
3
4
5
6
7
5
5
3
5
5
3
4
–
–
49
10
26
–
–
–
–
–
17
19
14
–
PhCOOH
p-NO2C6H4COOH
salicylic acid
CF3COOH
Et3N
PhCOOH
PhCOOH
PhCOOH
PhCOOH
Ͼ97:3
Ͼ97:3
Ͼ97:3
Ͼ97:3
Ͼ97:3
Ͼ97:3
Ͼ97:3
Ͼ97:3
Ͼ97:3
–
Ͼ97:3
Ͼ97:3
Ͼ97:3
–
49
98:2
90
[a] Isolated yields after column chromatography. [b] Determined by
chiral-phase HPLC.
9
CH2Cl2
H2O
C6mimBF4 PhCOOH
10
11
12
95
–
93
From Table 1 it can be seen that the Michael addition
reaction between chalcone and cyclohexanone did not take
place at all, even on prolonging the time to 5 d, when cata-
lyzed by the prolinethioamide catalysts 1 or 2, regardless of
whether or not the terminal group was a hydroxy group
(Table 1, Entries 1 and 2). The reason might be that the
neat
PhCOOH
PhCOOH
trace
44
13[c] iPrOH
97:3
[a] Isolated yields after column chromatography. [b] Determined by
chiral-phase HPLC. [c] The catalyst loading was 10 mol-%.
On the other hand, solvent effects are also a key factor
strong acidity of the prolinethioamide resulted in the for- for the reaction yield and enantioselectivity. Here, changing
mation of an inactive ketal between the catalyst and the the solvent iPrOH to the analogue tBuOH led to the reac-
cyclohexanone. To our delight, however, in the presence of tion giving the product with slightly increased enantio-
the catalyst 3 this reaction afforded the product with mod- selectivity (92% ee) but in reduced yield (Entry 7). With the
erate yield (49%) in 2 d, although the enantioselectivity was other nonprotic solvents THF or CH2Cl2 the results were
low (Table 1, Entry 3). In the cases of the catalysts 4 and 5, similar to that obtained with tBuOH (Table 2, Entries 8 and
the reaction proceeded slowly and afforded the product in 9). In the hope of further improving the yield and enantio-
Eur. J. Org. Chem. 2013, 2634–2645
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L. Liu, Y. Zhu, K. Huang, W. Chang, J. Li
FULL PAPER
selectivity of this reaction and of meeting the development (up to 91%) and with excellent enantioselectivity (96% ee)
requirements of green chemistry, we selected water and the and diastereoselectivity (Ͼ99:1). In the case of Ar2 = 4-
hydrophilic ionic liquid C6mimBF4 as reaction media. BrC6H4 (Entry 7), the enantiomeric excess value from this
However, the reaction was very poor: only a trace of adduct Michael addition reaction was nearly perfect (up to 99%).
was obtained in water (Entry 10), and the yield was still low Notably, even with the bulky α-naphthyl (Ar2) this reaction
in C6mimBF4, although the enantioselectivity was excellent also proceeded smoothly, to afford the corresponding prod-
(up to 95%, Entry 11). Additionally, the reaction under uct with excellent enantioselectivity (99% ee) and high dia-
neat conditions was sluggish (Entry 12).
stereoselectivity (dr 96:4, Entry 10).
On reduction of the amount of catalyst loading from
At the same time, the asymmetric Michael addition reac-
20 mol-% to 10 mol-% the reaction became slow and the tions promoted by the catalyst 7 were also successful for
yield was only 44% even after 5 d, although the enantio- chalcones with various substituents on the Ar1 aromatic
selectivity retained the high value of 93% ee (Table 2, En- system with Ar2 kept constant (Table 3, Entries 11–16).
try 13). From the above results, it was determined that the Furthermore, a regular pattern similar to that seen with the
optimal reaction conditions were 20 mol-% catalyst and Ar2 counterparts was observed. That is, the results with
20 mol-% benzoic acid in iPrOH (0.1 mL) as solvent at electron-withdrawing substituents on Ar1 were superior to
room temperature.
those with electron-donor-substituted Ar1 groups (En-
Having established the optimized reaction conditions, we tries 11–13 vs. 14). For Ar1 = the bulky β-naphthyl group
then investigated the applicability of this protocol to vari- (Entry 15), a good yield (67%) of product 10o could be ob-
ous chalcones. As shown in Table 3, it was observed that tained, but with decreased enantioselectivity (72% ee). In
good yields, high diastereoselectivities, and excellent the case of 4-chloro substitution in both Ar1 and Ar2, the
enantioselectivities could be generated for the correspond- reaction was complete after a relatively shorter time of 2 d
ing Michael addition products in 2–4 d. When Ar1 was a and generated the adduct 10p with 88% yield and 91% ee
phenyl group, the presence of different substituents on Ar2 (Table 3, Entry 16).
in the chalcones resulted in increased enantioselectivities ex-
Because this methodology has applicability to a wide
cept in the case of the 3-chloro-substituted phenyl group range of chalcone substrates, we next attempted to substi-
(Table 3, Entries 2–9). Closer inspection of these data tute the substrate cyclohexanone (8a) with cyclopentanone
showed that the Ar2 groups with electron-withdrawing sub- (8b), which is considered a difficult Michael donor. In the
stituents gave better yields than the electron-donor-substi- presence of 10 mol-% organophosphane catalyst 7, Michael
tuted aromatic groups (Entries 2–7 vs. 8–9). Among these, addition of chalcone to cyclopentanone proceeded
the yield was worst (only 24%) in the Michael reaction of smoothly to afford the product in 69% yield, but the
the chalcone with Ar2 = 4-CH3OC6H4 (Entry 9). With a p- enantioselectivity was moderate with 63% ee (Table 4, En-
nitro-substituted Ar2 system (Table 3, Entry 2), however, try 1). To improve the enantioselectivity we used 20 mol-%
the reaction afford the corresponding product in high yield chiral catalyst loading and reduced the reaction tempera-
Table 3. Asymmetric Michael addition between cyclohexanone (8a) and chalcones 9.
Entry
Ar1, Ar2
Product
Time [d]
Yield [%][a]
dr (anti/syn)[b]
ee [%][b]
1
2
3
4
5
6
7
8
Ph, Ph
10a
10b
10c
10d
10e
10f
10g
10h
10i
10j
10k
10l
10m
10n
10o
10p
3
2
3
4
3
3
3
3
3
3
2
2
3
3
3
2
73
91
74
74
85
51
65
42
24
34
84
70
60
47
67
88
98:2
Ͼ99:1
97:3
95:5
92:8
99:1
98:2
98:2
99:1
96:4
95:5
97:3
99:1
93:7
95:5
97:3
92
96
95
94
86
92
99
96
96
99
91
99
92
89
72
91
Ph, 4-NO2C6H4
Ph, 4-CF3C6H4
Ph, 4-ClC6H4
Ph, 3-ClC6H4
Ph, 2-ClC6H4
Ph, 4-BrC6H4
Ph, 4-CH3C6H4
Ph, 4-CH3OC6H4
Ph, α-naphthyl
3-BrC6H4, Ph
4-BrC6H4, Ph
4-NO2C6H4, Ph
4-CH3C6H4, Ph
β-naphthyl, Ph
4-ClC6H4, 4-ClC6H4
9
10
11
12
13
14
15
16
[a] Isolated yields after column chromatography. [b] Determined by chiral-phase HPLC.
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Phosphane-Catalyzed Asymmetric Michael Addition
Table 4. Screening of experimental parameters for asymmetric Michael addition between cyclopentanone (8b) and chalcone (9a) catalyzed
by catalyst 7.
Entry
Solvent
Additive
T
[°C]
Time
[d]
Yield
[%][a]
dr
ee
(anti/syn)[b]
[%][b]
1[c]
2
3
iPrOH
iPrOH
tBuOH
tBuOH
iPrOH/
tBuOH
iPrOH/
tBuOH
PhCOOH
PhCOOH
PhCOOH
Et3N
r.t.
0
0
0
0
4
4
6
3
4
69
60
82
60
76
88:12
90:10
89:11
74:26
87:13
63/63
80/81
77/80
71/63
78/81
4
5[d]
PhCOOH
6[d]
PhCOOH
–10
6
42
91:9
86/80
[a] Isolated yields after column chromatography. [b] Determined by chiral-phase HPLC. [c] Catalyst loading 10 mol-%. [d] iPrOH/tBuOH
= 0.05 mL/0.05 mL.
ture to 0 °C (Entry 2). As expected, increased enantio- (60%) but the enantioselectivity was not obviously im-
selectivity (80% ee) and diastereoselectivity were achieved, proved (Table 4, Entry 5). Further lowering of the tempera-
with a similar yield and the same reaction time (4 d). The ture from 0 °C to –10 °C resulted in increased enantio-
effects of tBuOH as a solvent or of Et3N as an additive selectivity (86% ee) but the yield was decreased (42%) even
were then also studied (Table 4, Entries 3 and 4). In tBuOH with a prolonged 6 d reaction time (Entry 6). The optimal
the yield was increased to 82%, although the reaction reaction conditions were therefore as follows: 20 mol-% or-
needed a longer time (6 d). In the tBuOH/Et3N system the ganophosphane catalyst 7, 20 mol-% benzoic acid, and
results were not improved. Because tBuOH is favorable for mixed iPrOH/tBuOH solvent (0.05 mL, 0.05 mL, respec-
the reaction yield and iPrOH is beneficial for the enantio- tively) at 0 °C.
selectivity, a mixed iPrOH/tBuOH solvent system (0.05 mL,
With the optimized conditions to hand, the range of ap-
0.05 mL, respectively) was tested. The yield (76%) was in- plicability of this methodology was then investigated
deed greater than that achieved with only iPrOH as solvent (Table 5). As shown, cyclopentanone reacted with various
Table 5. Asymmetric Michael addition between cyclopentanone (8b) and chalcones 9.
Entry
Ar1, Ar2
Product
Time [d]
Yield [%][a]
dr (anti/syn)[b]
ee [%][b]
1
2
3
4
5
6
7
8
Ph, Ph
11a
11b
11c
11d
11e
11f
11g
11h
11i
4
3
3
4
4
3
3
4
4
4
3
4
4
76
95
83
77
75
87
82
52
27
72
92
81
80
87:13
88:12
84:16
88:12
89:11
90:10
86:14
89:11
93:7
67:33
79:21
74:26
76:24
78/81
90/84
85/89
82/82
76/84
78/83
79/79
90/79
79/77
63/67
78/82
79/78
85/61
Ph, 4-NO2C6H4
Ph, 4-CF3C6H4
Ph, 4-ClC6H4
Ph, 3-ClC6H4
Ph, 2-ClC6H4
Ph, 4-BrC6H4
Ph, 4-CH3C6H4
Ph, 4-CH3OC6H4
Ph, α-naphthyl
3-BrC6H4, Ph
4-BrC6H4, Ph
4-ClC6H4, 4-ClC6H4
9
10
11
12
13
11j
11k
11l
11m
[a] Isolated yields after column chromatography. [b] Determined by chiral-phase HPLC.
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L. Liu, Y. Zhu, K. Huang, W. Chang, J. Li
FULL PAPER
chalcones, providing good to excellent enantioselectivities an enamine pathway when organocatalysts based on l-prol-
and yields as well as diastereomeric ratios. When Ar1 was a ine were used. Wang also considered that the secondary
phenyl group (Table 5, Entries 1–10), the yields were signifi- chiral amine formed an enamine with cyclohexanone to
cantly influenced by the electronic nature of the substitu- produce the stereochemical adducts.[13] In Zhong’s re-
ents on Ar2. Generally, an electron-withdrawing group was port,[3f] organophosphane catalyst 7 was used for asymmet-
favorable for an increased yield. In contrast, the introduc- ric Michael addition of cyclohexanone to highly reactive
tion of an electron-donating group on Ar2 resulted in a nitroolefins. It was also mentioned in their report that the
marked decrease in yield (Table 5, Entries 2–7 vs. 8–9). The chiral pyrrolidine unit served as a catalytic site for the en-
p-nitro substituent on Ar2 gave the best reactivity with high amine transition with cyclohexanone and the phosphane
yield (up to 95%) and enantioselectivity (90% ee) in 3 d oxide moiety as a chiral induction group containing a very
(Table 5, Entry 2). Moreover, regardless of the location of polar P=O bond that might interact favorably with the nitro
electron-withdrawing substituents Ar2 (ortho-, meta-, or group through dipole interactions mediated by water to al-
para-), good results could be obtained. To our surprise, low greater control in enantio- and diastereoselectivities.
even with Ar2 = the bulky naphthyl group the reaction still Moreover, this hypothesis was verified by DFT calculations.
proceeded well and afforded the product with 72% yield
To confirm this interaction directly, we firstly monitored
(Entry 10). On maintaining Ar2 as phenyl and varying Ar1 a mixture of organophosphane catalyst 7 and chalcone (9a)
it was observed that the substituent on Ar1 has a moderate in CDCl3 by 31P NMR (Figure 2). It was found that two
influence on the diastereoselectivity of the reaction (Table 5, new peaks appeared at δ = 29.7 ppm (b) and 29.5 ppm (c),
Entries 11 and 12). When Ar1 and Ar2 are both substitued together with the peak of organocatalyst 7 (aЈ, 30.8 ppm).
phenyl groups, also good yield and good enantioselectivity This might be due to dipole ion formation between this
could be obtained (Entry 13).
strongly polar P=O bond and the carbonyl oxygen of chalc-
In summary, the diastereoselectivities of Michael ad-
dition between cyclopentanone and chalcones were lower
than those of Michael addition between cyclohexanone and
chalcones. This might be due to the different ring sizes and
reactivities of the cyclic ketones, which have different ring
strain. This effect might thus be further attributed to the
difference in the barriers for the attack of pyrrolidine on
the carbonyl groups of the different ketones to form the
enamine transition states.[11]
To determine the configurations of the Michael adducts,
we repeated the experiment in the literature.[4–6] After com-
parison of the peak time by chiral-phase HPLC analysis
with our product obtained from iPrOH, the relative config-
urations were assigned as anti and the absolute configura-
tions were confirmed to be (2R,1ЈS).
With respect to the mechanism of Michael addition be-
tween cycloketones and chalcones catalyzed by organo-
phosphane 7, we hoped to identify some direct evidence
through various measures. In previous reports, Seebach and
Golinski proposed the concept of an acyclic synclinal tran-
Figure 2. 31P NMR trace: A) catalyst 7, and B) the reaction be-
tween chalcone (9a, 0.03 mmol) and organophosphane catalyst 7
sition.[12] It was accepted that the reaction clearly involved (0.03 mmol) in CDCl3 for 12 h.
Figure 3. MS (ESI) (+) spectrum of the reaction intermediate formed from chalcone (9a, 0.03 mmol) and organophosphane catalyst 7
(0.03 mmol) in CDCl3 for 12 h.
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Phosphane-Catalyzed Asymmetric Michael Addition
one, thus leading to an upfield shift in the 31P NMR spec- static interaction between the polar phosphane and the
trum. Notably, the molecular ion peak corresponding to chalcone carbonyl oxygen atom might facilitate the discov-
this dipole ion of the organophosphane catalyst 7 and ery of more potential organocatalysts for related reactions.
chalcone (9a) – namely, 494.1 for the [M + 1] species (Fig- Further studies to extend the scope of this reaction and the
ure 3) – was also observed in the MS (ESI) spectrum.
Therefore, from the above experimental results and pre-
vious relevant reports, we have proposed the possible reac-
tion mechanism as shown in Scheme 2. Firstly, cyclic
ketones 8 would be activated and form the enamine inter-
mediates I with organocatalyst 7. Simultaneously, the chalc-
ones 9 would associate with the organocatalyst to form the
intermediates II through electrostatic interaction between
the polarized P=O bond and the chalcone carbonyl oxygen
atoms. The enamines would further attack the activated
chalcone carbon-carbon double bonds via intermediates III
to give the final products and simultaneously release the
organocatalyst 7.
design of new catalysts are now in progress.
Experimental Section
General Information: 1H NMR and 13C NMR spectra were re-
corded with Bruker AV 300 or Varian mercury Plus 400 instru-
ments with CDCl3 as solvent and TMS as internal standard unless
otherwise noted; chemical shifts are given in ppm and coupling
constants (J) in Hz. Enantiomeric excesses were determined by
HPLC with Chiralpak AS-H and AD-H columns (Daicel Chemical
Ind., Ltd.) and n-hexane and isopropanol as eluents. Acetone was
distilled from K2CO3 prior to use; all other solvents and commer-
cially available reagents were used as received without further puri-
fication unless otherwise stated. Analytical TLC was performed
with Merck 60 F254 precoated silica gel plates. Subsequent to elu-
tion, plates were visualized by UV irradiation (254 nm, Spectroline
Model ENF-24061/F 254 nm). The MS spectrum was determined
with a Thermo-Finnigan LCQ-Advantage instrument.
Typical Procedure for Michael Reaction between Cyclohexanone (8a)
and a Chalcone 9 Catalyzed by Organophosphane Catalyst 7: Or-
ganophosphane catalyst 7 (12 mg, 0.04 mmol) was added to cyclo-
hexanone (0.2 mL, 2 mmol) in iPrOH (0.1 mL). The mixture was
then stirred for 5 min, and the chalcone (0.2 mmol) and benzoic
acid (6 mg, 0.04 mmol) were added at room temperature. After the
reaction was complete (TLC monitoring), the mixture was purified
by flash silica gel chromatography (hexane/EtOAc) to afford the
desired Michael addition product.
The procedure for Michael addition between cyclopentanone and
chalcones is similar to that for cyclohexanone, except that the sol-
vent iPrOH (0.1 mL) was changed to an iPrOH/tBuOH (0.05 mL
+ 0.05 mL) mixed solvent system.
Characterization of the Michael Addition Reaction Adducts
2-(3-Oxo-1,3-diphenylpropyl)cyclohexanone (10a)[14]
Scheme 2. The proposal mechanism for Michael addition catalyzed
by organocatalyst 7 (n = 0,1).
Conclusions
In summary, we have developed a simple methodology
for Michael addition between cycloketones and various
weakly active chalcone acceptors. With the aid of the l-
proline-derived organic phosphane oxide 7, the reactions
afforded the corresponding adducts with good yields and
high or excellent enantioselectivities and diastereoselectivi-
ties. Moreover, the reaction protocol has a wide substrate
range. Both cyclohexanone and cyclopentanone reacted
smoothly with various chalcones in the presence of this or-
ganophosphane catalyst. No organocatalyst applicable for
two cycloketones has been reported previously. Addition-
ally, a possible reaction mechanism based on some direct
White solid (45 mg), yield 73%. [α]2D0 = –53.6 (c = 0.85, CHCl3).
1H NMR (400 MHz, CDCl3): δ = 1.21–1.30 (m, 1 H), 1.51–1.80
(m, 4 H), 1.95–2.00 (m, 1 H), 2.32–2.42 (m, 1 H), 2.46–2.54 (m, 1
H), 2.71 (m, 1 H), 3.21 (dd, J1 = 16.2, J2 = 9.5 Hz, 1 H), 3.47 (dd,
J1 = 16.2, J2 = 4.1 Hz, 1 H), 3.71 (m, 1 H), 7.14–7.24 (m, 5 H),
7.36–7.41 (m, 2 H), 7.46–7.51 (m, 1 H), 7.87–7.90 (m, 2 H) ppm.
MS (ESI): m/z calcd. for C21H22O2 [M + Na]+ 329.152; found
329.283; dr (anti/syn) = 98:2, enantiomeric excess: 92%, determined
by HPLC (Daicel Chiralpak AD, iPrOH/hexane 10:90), UV
254 nm, flow rate 1.0 mLmin–1. anti diastereomer: tR(major) =
evidence is proposed. The activation mode through electro- 25.12 min and tR(minor) = 32.43 min.
Eur. J. Org. Chem. 2013, 2634–2645
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2639

L. Liu, Y. Zhu, K. Huang, W. Chang, J. Li
FULL PAPER
2-[1-(4-Nitrophenyl)-3-oxo-3-phenylpropyl]cyclohexanone (10b)[4]
1.0 mLmin–1. anti diastereomer: tR(minor) = 19.82 min, tR(major)
= 23.11 min.
2-[1-(3-Chlorophenyl)-3-oxo-3-phenylpropyl]cyclohexanone (10e)[5]
1
White solid (64 mg), yield 91%. [α]2D0 = –66.2 (c = 1.1, CHCl3). H
NMR (400 MHz, CDCl3): δ = 1.19–1.29 (m, 1 H), 1.52–1.82 (m, 4
H), 1.99–2.10 (m, 1 H), 2.35–2.45 (m, 1 H), 2.45–2.54 (m, 1 H),
2.76 (m, 1 H), 3.30 (dd, J1 = 16.8, J2 = 9.9 Hz, 1 H), 3.60 (dd, J1
= 16.8, J2 = 3.7 Hz, 1 H), 3.86 (m, 1 H), 7.36–7.48 (m, 4 H), 7.54
(t, J = 7.3 Hz, 1 H), 7.90 (d, J = 7.5 Hz, 2 H), 8.2 (d, J = 8.6 Hz,
2 H) ppm. MS (ESI): m/z calcd. for C21H21NO4 [M + Na]+
374.173; found 329.226; dr (anti/syn) Ͼ 99:1, enantiomeric excess:
96%, determined by HPLC (Daicel Chiralpak AD, iPrOH/hexane
10:90), UV 254 nm, flow rate 1.0 mLmin–1. anti diastereomer:
tR(minor) = 55.83 min, tR(major) = 65.91 min.
White solid (58 mg), yield 85%. [α]2D0 = –43.5 (c = 0.85, CHCl3).
1H NMR (400 MHz, CDCl3): δ = 1.19–1.44 (m, 1 H), 1.44–1.99
(m, 4 H), 1.95–2.08 (m, 1 H), 2.00–2.18 (m, 1 H), 2.19–2.35 (m, 1
H), 2.36–2.51 (m, 1 H), 3.37 (d, J = 7.9 Hz, 1 H), 3.62–3.73 (m, 1
H), 3.89 (dd, J1 = 17.1, J2 = 5.7 Hz, 1 H), 7.12 (d, J = 8.4 Hz, 2
H), 7.08–7.25 (m, 4 H), 7.42 (t, J = 7.5 Hz, 2 H), 7.53 (t, J =
7.3 Hz, 1 H), 7.92 (t, J = 6.8 Hz, 2 H) ppm. MS (ESI): m/z calcd.
for C21H21ClO2 [M + H]+ 341.131; found 341.113; dr (anti:syn)
= 92:8, enantiomeric excess: 86%, determined by HPLC (Daicel
Chiralpak AD, iPrOH/hexane 10:90), UV 254 nm, flow rate
1.0 mLmin–1. anti diastereomer: tR(minor) = 13.10 min, tR(major)
= 23.91 min.
2-{3-Oxo-3-phenyl-1-[4-(trifluoromethyl)phenyl]propyl}cyclohexanone
(10c)
2-[1-(2-Chlorophenyl)-3-oxo-3-phenylpropyl]cyclohexanone (10f)[4]
White solid (55 mg), yield 74%. M.p. 149–150 °C. [α]2D0 = –42.8 (c
1
= 0.35, CHCl3). H NMR (400 MHz, CDCl3): δ = 1.20–1.29 (m, 1
H), 1.52–1.84 (m, 4 H), 1.97–2.07 (m, 1 H), 2.34–2.45 (m, 1 H),
2.46–2.54 (m, 1 H), 2.74 (m, 1 H), 3.27 (dd, J1 = 16.6, J2 = 9.7 Hz,
1 H), 3.54 (dd, J1 = 16.6, J2 = 3.9 Hz, 1 H), 3.81 (m, 1 H), 7.32 (d,
J = 8.1 Hz, 1 H), 7.42 (t, J = 7.6 Hz, 2 H), 7.49–7.55 (m, 3 H),
7.88–7.93 (m, 2 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 24.55,
28.56, 32.69, 40.91, 42.61, 43.78, 55.46, 125.45, 125.48, 128.18,
128.64, 128.91, 133.15, 136.85, 146.55, 198.31, 212.86 ppm. MS
(ESI): m/z calcd. for C22H21F3O2 [M + Na]+ 397.139; found
397.177; dr (anti:syn) = 97:3, enantiomeric excess: 95%, determined
by HPLC (Daicel Chiralpak AD, iPrOH/hexane 10:90), UV
254 nm, flow rate 1.0 mLmin–1. anti diastereomer: tR(minor) =
21.01 min, tR(major) = 26.31 min. C22H21F3O2: calcd. C 70.58, H
5.65; found C 70.68, H 5.73.
White solid (35 mg), yield 51%. [α]2D0 = –99.3 (c = 0.9, CHCl3). H
1
NMR (400 MHz, CDCl3): δ = 1.15–1.34 (m, 1 H), 1.40–1.80 (m, 4
H), 1.90–2.00 (m, 1 H), 2.24–2.49 (m, 2 H), 2.75–2.91 (m, 1 H),
3.31 (dd, J1 = 16.2, J2 = 9.9 Hz, 1 H), 3.43–3.57 (m, 1 H), 4.17
(dd, J1 = 22.1, J2 = 13.0 Hz, 1 H), 6.98–7.14 (m, 2 H), 7.16–7.25
(m, 2 H), 7.31–7.37 (m, 2 H), 7.40–7.47 (m, 1 H), 7.86 (d, J =
7.5 Hz,
2 H) ppm. MS (ESI): m/z calcd. for C21H21ClO2
[M + Na]+ 363.113; found 363.176; dr (anti:syn) = 99:1, enantio-
meric excess: 92%, determined by HPLC (Daicel Chiralpak AD,
iPrOH/hexane 10:90), UV 254 nm, flow rate 1.0 mLmin–1. anti dia-
stereomer: tR(minor) = 15.81 min, tR(major) = 26.32 min.
2-[1-(4-Bromophenyl)-3-oxo-3-phenylpropyl]cyclohexanone (10g)[13a]
2-[1-(4-Chlorophenyl)-3-oxo-3-phenylpropyl]cyclohexanone (10d)[4]
White solid (50 mg), yield 65%. [α]2D0 = –33.0 (c = 0.6, CHCl3). H
NMR (400 MHz, CDCl3): δ = 1.15–1.32 (m, 1 H), 1.50–1.85 (m, 4
1
White solid (50 mg), yield 74%. [α]2D0 = –51.4 (c = 0.7, CHCl3). H
1
NMR (400 MHz, CDCl3): δ = 1.18–1.29 (m, 1 H), 1.52–1.84 (m, 4
H), 1.94–2.09 (m, 1 H), 2.31–2.56 (m, 2 H), 2.69 (m, 1 H), 3.20
H), 1.95–2.08 (m, 1 H), 2.39 (m, 1 H), 2.50 (m, 1 H), 2.69 (m, 1 (dd, J1 = 16.4, J2 = 9.7 Hz, 1 H), 3.50 (dd, J1 = 16.3, J2 = 4.0 Hz,
H), 3.19 (dd, J1 = 16.3, J2 = 9.8 Hz, 1 H), 3.50 (dd, J1 = 16.3, J2
= 4.0 Hz, 1 H), 3.71 (m, 1 H), 7.12 (d, J = 8.4 Hz, 2 H), 7.22 (d, J
1 H), 3.70 (m, 1 H), 7.07 (d, J = 8.4 Hz, 2 H), 7.40 (dd, J1 = 17.0,
J2 = 8.1 Hz, 4 H), 7.49–7.55 (m, 1 H), 7.85–7.95 (m, 2 H) ppm.
= 8.4 Hz, 2 H), 7.42 (t, J = 7.6 Hz, 2 H), 7.52 (t, J = 7.3 Hz, 1 H), MS (ESI): m/z calcd. for C21H21BrO2 [M + Na]+ 407.062; found
7.91 (d, J = 7.2 Hz, 2 H) ppm. MS (ESI): m/z calcd. for 407.296; dr (anti:syn) = 98:2, enantiomeric excess: 99%, determined
C21H21ClO2 [M + Na]+ 363.113; found 363.200; dr (anti:syn) =
95:5, enantiomeric excess: 94%, determined by HPLC (Daicel
Chiralpak AD, iPrOH/hexane 10:90), UV 254 nm, flow rate
by HPLC (Daicel Chiralpak AD, iPrOH/hexane 10:90), UV
254 nm, flow rate 1.0 mLmin–1. anti diastereomer: tR(minor) =
22.31 min, tR(major) = 24.97 min.
2640
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© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 2634–2645

Phosphane-Catalyzed Asymmetric Michael Addition
2-(3-Oxo-3-phenyl-1-p-tolylpropyl)cyclohexanone (10h)[15]
2-[3-(3-Bromophenyl)-3-oxo-1-phenylpropyl]cyclohexanone (10k)
White solid (65 mg), yield 84%. M.p. 68–69 °C. [α]2D0 = –42.0 (c =
0.9, CHCl3). 1H NMR (400 MHz, CDCl3): δ = 1.16–1.24 (m, 1 H),
1.44–1.78 (m, 4 H), 1.90–2.01 (m, 1 H), 2.29–2.39 (m, 1 H), 2.42–
2.47 (m, 1 H), 2.66 (m, 1 H), 3.12 (dd, J1 = 16.2, J2 = 9.6 Hz, 1
H), 3.43 (dd, J1 = 16.2, J2 = 3.9 Hz, 1 H), 3.62 (dd, J1 = 9.9, J2 =
4.0 Hz, 1 H), 7.07–7.16 (m, 3 H), 7.17–7.25 (m, 3 H), 7.55–7.61
(m, 1 H), 7.78–7.84 (m, 1 H), 7.95–7.97 (m, 1 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 24.38, 28.66, 32.74, 41.26, 42.54, 44.52,
55.80, 122.90, 126.81, 128.36, 128.63, 130.16, 131.29, 135.73,
138.78, 141.86, 197.43, 213.65 ppm. MS (ESI): m/z calcd. for
C21H21BrO2 [M + H]+ 385.080; found 385.132; dr (anti:syn) = 95:5,
enantiomeric excess: 91%, determined by HPLC (Daicel Chi-
ralpak AD, iPrOH/hexane 5:95), UV 254 nm, flow rate
1.0 mLmin–1. anti diastereomer: tR(minor) = 39.44 min, tR(major)
= 43.52 min; C21H21BrO2: calcd. C 65.46, H 5.49; found C 65.15,
H 5.20.
White solid (27 mg), yield 42%. [α]2D0 = –64.7 (c = 0.55, CHCl3).
1H NMR (400 MHz, CDCl3): δ = 1.21–1.31 (m, 1 H), 1.53–1.85
(m, 4 H), 1.92–2.04 (m, 1 H), 2.28 (s, 3 H), 2.33–2.44 (m, 1 H),
2.47–2.57 (m, 1 H), 2.70 (m, 1 H), 3.19 (dd, J1 = 16.1, J2 = 9.6 Hz,
1 H), 3.47 (dd, J1 = 16.1, J2 = 4.1 Hz, 1 H), 3.68 (td, J1 = 9.8, J2
= 4.1 Hz, 1 H), 7.05 (s, 4 H), 7.41 (t, J = 7.6 Hz, 2 H), 7.51 (t, J =
7.3 Hz, 1 H), 7.89–7.94 (m, 2 H) ppm. MS (ESI): m/z calcd. for
C22H24O2 [M + H]+ 321.185; found 321.022; dr (anti:syn) = 98:2,
enantiomeric excess: 96%, determined by HPLC (Daicel Chi-
ralpak AD, iPrOH/hexane 10:90), UV 254 nm, flow rate
1.0 mLmin–1. anti diastereomer: tR(minor) = 14.74 min, tR(major)
= 19.95 min.
2-[1-(4-Methoxyphenyl)-3-oxo-3-phenylpropyl]cyclohexanone (10i)[16]
2-[3-(4-Bromophenyl)-3-oxo-1-phenylpropyl]cyclohexanone (10l)[5]
White solid (16 mg), yield 24%. [α]2D0 = –53.4 (c = 0.15, CHCl3).
1H NMR (400 MHz, CDCl3): δ = 1.20–1.30 (m, 1 H), 1.49–1.85
(m, 4 H), 1.92–2.04 (m, 1 H), 2.34–2.44 (m, 1 H), 2.47–2.57 (m, 1
White solid (54 mg), yield 70%. [α]2D0 = –34.6 (c = 1.3, CHCl3). H
1
NMR (400 MHz, CDCl3): δ = 1.11–1.22 (m, 1 H), 1.43–1.77 (m, 4
H), 1.88–2.00 (m, 1 H), 2.27–2.38 (m, 1 H), 2.44 (m, 1 H), 2.64 (m,
1 H), 3.06 (dd, J1 = 15.9, J2 = 9.7 Hz, 1 H), 3.42 (dd, J1 = 15.9, J2
= 4.0 Hz, 1 H), 3.62 (m, 1 H), 7.04–7.14 (m, 3 H), 7.15–7.22 (m, 2
H), 7.45–7.52 (m, 2 H), 7.68–7.75 (m, 2 H) ppm. MS (ESI): m/z
calcd. for C21H21BrO2 [M + Na]+ 407.062; found 407.096; dr
(anti:syn) = 97:3, enantiomeric excess: 99%, determined by HPLC
(Daicel Chiralpak AD, iPrOH/hexane 10:90), UV 254 nm, flow rate
1.0 mLmin–1. anti diastereomer: tR(minor) = 31.02 min, tR(major)
= 33.10 min.
H), 2.47–2.56 (m, 1 H), 2.68 (m, 1 H), 3.17 (dd, J1 = 16.0, J2
=
9.7 Hz, 1 H), 3.46 (dd, J1 = 16.0, J2 = 4.1 Hz, 1 H), 3.67 (m, 1 H),
3.75 (s, 1 H), 6.79 (d, J = 8.6 Hz, 2 H), 7.08 (d, J = 8.6 Hz, 2 H),
7.41 (t, J = 7.6 Hz, 2 H), 7.49–7.55 (m, 1 H), 7.91 (d, J = 7.4 Hz,
2 H) ppm. MS (ESI): m/z calcd. for C22H24O3 [M + Na]+ 359.162;
found 359.295; dr (anti:syn) = 99:1, enantiomeric excess: 96%, de-
termined by HPLC (Daicel Chiralpak AD, iPrOH/hexane 10:90),
UV 254 nm, flow rate 1.0 mLmin–1. anti diastereomer: tR(minor)
= 26.63 min, tR(major) = 31.33 min.
2-[1-(Naphthalen-1-yl)-3-oxo-3-phenylpropyl]cyclohexanone (10j)[5]
2-[3-(4-Nitrophenyl)-3-oxo-1-phenylpropyl]cyclohexanone (10m)[17]
White solid (24 mg), yield 34%. [α]2D0 = –120 (c = 0.5, CHCl3). H
NMR (400 MHz, CDCl3): δ = 1.15–1.25 (m, 1 H), 1.30–1.70 (m, 4
H), 1.85–1.95 (m, 1 H), 2.24–2.40 (m, 1 H), 2.45–2.57 (m, 1 H),
2.77 (m, 1 H), 3.39 (dd, J1 = 16.1, J2 = 9.9 Hz, 1 H), 3.63 (dd, J1
1
White solid (42 mg), yield 60%. [α]2D0 = –29.0 (c = 1.0, CHCl3). H
1
NMR (400 MHz, CDCl3): δ = 1.12–1.21 (m, 1 H), 1.47–1.75 (m, 4
H), 1.92–2.02 (m, 1 H), 2.22–2.40 (m, 1 H), 2.40–2.48 (m, 1 H),
= 16.1, J2 = 4.0 Hz, 1 H), 3.69 (m, 1 H), 7.25–7.40 (m, 7 H), 7.60– 2.67 (m, 1 H), 3.06–3.15 (m, 1 H), 3.49–3.60 (m, 2 H), 7.02–7.07
7.66 (m, 1 H), 7.68–7.80 (m, 3 H), 8.08–8.16 (m, 1 H) ppm. MS
(ESI): m/z calcd. for C25H24O2 [M + Na]+ 379.167; found 379.211;
dr (anti:syn) = 96:4, enantiomeric excess: 99%, determined by
HPLC (Daicel Chiralpak AD, iPrOH/hexane 5:95), UV 254 nm,
(m, 2 H), 7.09–7.15 (m, 1 H), 7.18–7.22 (m, 2 H), 7.97–8.03 (m, 2
H), 8.17–8.23 (m, 2 H) ppm. MS (ESI): m/z calcd. for C21H21NO4
[M + Na]+ 374.137; found 374.208; dr (anti:syn) = 99:1, enantio-
meric excess: 92%, determined by HPLC (Daicel Chiralpak AD,
flow rate 1.0 mLmin–1. anti diastereomer: tR(minor) = 34.59 min, iPrOH/hexane 10:90), UV 254 nm, flow rate 1.0 mLmin–1. anti dia-
tR(major) = 48.89 min.
stereomer: tR(major) = 54.73 min, tR(minor) = 63.87 min.
Eur. J. Org. Chem. 2013, 2634–2645
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2641

L. Liu, Y. Zhu, K. Huang, W. Chang, J. Li
2-(3-Oxo-1,3-diphenylpropyl)cyclopentanone (11a)[8b]
FULL PAPER
2-(3-Oxo-1-phenyl-3-p-tolylpropyl)cyclohexanone (10n)[6]
1
White solid (44 mg), yield 76%. [α]2D0 = –47.6 (c = 1.0, CHCl3). H
White solid (30 mg), yield 47%. [α]2D0 = –47.0 (c = 0.2, CHCl3). H
NMR (400 MHz, CDCl3): δ = 1.22–1.30 (m, 1 H), 1.53–1.82 (m, 4
H), 1.92–2.04 (m, 1 H), 2.37 (s, 3 H), 2.33–2.44 (m, 1 H), 2.46–2.55
(m, 1 H), 2.72 (m, 1 H), 3.21 (dd, J1 = 16.1, J2 = 9.6 Hz, 1 H),
3.42 (dd, J1 = 16.1, J2 = 4.1 Hz, 1 H), 3.73 (m, 1 H), 7.07–7.30 (m,
7 H), 7.81 (d, J1 = 8.2 Hz, 2 H) ppm. MS (ESI): m/z calcd. for
C22H24O2 [M + H]+ 321.185; found 321.104; dr (anti:syn) = 93:7,
enantiomeric excess: 89%, determined by HPLC (Daicel Chi-
ralpak AD, iPrOH/hexane 10:90), UV 254 nm, flow rate
1.0 mLmin–1. anti diastereomer: tR(major) = 41.19 min, tR(minor)
= 51.77 min.
1
NMR (400 MHz, CDCl3): δ = 1.42–1.96 (m, 4 H), 1.99–2.11 (m, 1
H), 2.16–2.31 (m, 1 H), 2.43 (dd, J1 = 17.1, J2 = 8.6 Hz, 1 H), 3.34
(dd, J1 = 16.8, J2 = 7.6 Hz, 0.87 H), 3.47 (dd, J1 = 19.3, J2
=
9.8 Hz, 0.13 H), 3.62–3.91 (m, 2 H), 7.12–7.28 (m, 5 H), 7.35–7.44
(m, 2 H), 7.46–7.54 (m, 1 H), 7.84–7.98 (m, 2 H) ppm. MS (ESI):
m/z calcd. for C20H20O2 [M + H]+ 293.154; found 293.170; dr
(anti:syn) = 87:13, enantiomeric excess (%): anti 78, syn 81, deter-
mined by HPLC (Daicel Chiralpak AD, iPrOH/hexane 10:90), UV
254 nm, flow rate 1.0 mLmin–1. syn diastereomer: tR(major) =
11.40 min and tR(minor) = 13.18 min, anti diastereomer: tR(major)
= 18.79 min and tR(minor) = 30.36 min.
2-[3-(Naphthalen-2-yl)-3-oxo-1-phenylpropyl]cyclohexanone (10o)[5]
2-[1-(4-Nitrophenyl)-3-oxo-3-phenylpropyl]cyclopentanone (11b)[7]
White solid (48 mg), yield 67%. [α]2D0 = –47.3 (c = 0.8, CHCl3). H
1
NMR (400 MHz, CDCl3): δ = 1.20–1.28 (m, 1 H), 1.44–1.79 (m, 4
H), 1.84–1.97 (m, 1 H), 2.26–2.53 (m, 2 H), 2.68 (m, 1 H), 3.27
(dd, J1 = 15.9, J2 = 9.6 Hz, 1 H), 3.56 (dd, J1 = 16.2, J2 = 4.1 Hz,
1 H), 3.71 (m, 1 H), 7.05–7.14 (m, 3 H), 7.15–7.23 (m, 3 H), 7.40–
7.54 (m, 2 H), 7.74–7.80 (m, 2 H), 7.81–7.91 (m, 2 H), 8.43 (m, 1
H) ppm. MS (ESI): m/z calcd. for C25H24O2 [M + Na]+ 357.185;
found 357.199; dr (anti:syn) = 95:5, enantiomeric excess: 72%, de-
termined by HPLC (Daicel Chiralpak AD, iPrOH/hexane 5:95),
UV 254 nm, flow rate 1.0 mLmin–1. anti diastereomer: tR(major)
= 46.98 min, tR(minor) = 68.33 min.
White solid (64 mg), yield 95%. [α]2D0 = –113.7 (c = 0.9, CHCl3).
1H NMR (400 MHz, CDCl3): δ = 1.35–1.97 (m, 4 H), 2.00–2.18
(m, 1 H), 2.23–2.37 (m, 1 H), 2.49 (dd, J1 = 18.5, J2 = 8.2 Hz, 1
H), 3.43 (dd, J1 = 17.4, J2 = 8.8 Hz, 0.88 H), 3.62 (dd, J1 = 7.7, J2
= 4.4 Hz, 0.12 H), 3.75–4.05 (m, 2 H), 7.31–7.48 (m, 4 H), 7.47–
7.58 (m, 1 H), 7.84–7.96 (m, 2 H), 8.03–8.06 (m, 2 H) ppm. MS
(ESI): m/z calcd. for C20H29NO4 [M + Na]+ 360.121; found
360.169; dr (anti:syn) = 88:12, enantiomeric excess (%): anti 90,
syn 84, determined by HPLC (Daicel Chiralpak AD, iPrOH/hexane
10:90), UV 254 nm, flow rate 1.0 mLmin–1. syn diastereomer:
tR(major) = 16.65 min and tR(minor) = 24.98 min, anti dia-
stereomer: tR(major) = 27.01 min and tR(minor) = 32.82 min.
2-[1,3-Bis(4-chlorophenyl)-3-oxopropyl]cyclohexanone (10p)
2-{3-Oxo-3-phenyl-1-[4-(trifluoromethyl)phenyl]propyl}cyclo-
pentanone (11c)[8b]
White solid (66 mg), yield 88%. M.p. 102–104 °C. [α]2D0 = –31.3 (c
1
= 0.9, CHCl3). H NMR (400 MHz, CDCl3): δ = 1.17–1.26 (m, 1
H), 1.50–1.84 (m, 4 H), 1.97–2.09 (m, 1 H), 2.33–2.44 (m, 1 H),
2.45–2.54 (m, 1 H), 2.67 (m, 1 H), 3.11 (dd, J1 = 16.1, J2 = 9.9 Hz, Colorless oil (60 mg), yield 83%. [α]2D0 = –49.6 (c = 0.5, CHCl3).
1 H), 3.50 (dd, J1 = 16.1, J2 = 3.9 Hz, 1 H), 3.64 (m, 1 H), 7.09 (d,
1H NMR (400 MHz, CDCl3): δ = 1.39–1.99 (m, 4 H), 2.00–2.14
J = 8.4 Hz, 2 H), 7.22 (d, J = 8.4 Hz, 2 H), 7.39 (d, J = 8.6 Hz, 2 (m, 1 H), 2.21–2.35 (m, 1 H), 2.47 (dd, J1 = 18.0, J2 = 8.4 Hz, 1
H), 7.86 (d, J = 8.6 Hz, 2 H) ppm. 13C NMR (100 MHz, CDCl3): H), 3.39 (dd, J1 = 17.2, J2 = 8.3 Hz, 0.84 H), 3.55 (dd, J1 = 17.3,
δ = 24.56, 28.62, 32.78, 40.80, 42.64, 44.15, 55.61, 128.73, 128.89,
129.68, 129.74, 132.41, 135.18, 139.43, 140.38, 197.40, 213.19 ppm.
MS (ESI): m/z calcd. for C21H20Cl2O2 [M + Na]+ 397.074; found
397.268; dr (anti:syn) = 97:3, enantiomeric excess: 91%, determined
by HPLC (Daicel Chiralpak AD, iPrOH/hexane 5:95), UV 254 nm,
flow rate 1.0 mLmin–1. anti diastereomer: tR(minor) = 17.3 min,
tR(major) = 19.52 min; C21H20Cl2O2: calcd. C 67.21, H 5.37; found
C 66.95, H 5.36.
J2 = 8.1 Hz, 0.16 H), 3.66–3.97 (m, 2 H), 7.31–7.46 (m, 4 H), 7.48–
7.55 (m, 3 H), 7.87–7.97 (m, 2 H) ppm. MS (ESI): m/z calcd. for
C21H19F3O2 [M + H]+ 361.142; found 361.136; dr (anti:syn) =
84:16, enantiomeric excess (%): anti 85, syn 89, determined by
HPLC (Daicel Chiralpak AD, iPrOH/hexane 10:90), UV 254 nm,
flow rate 1.0 mLmin–1. syn diastereomer: tR(major) = 9.17 min and
tR(minor) = 14.49 min, anti diastereomer: tR(major) = 13.19 min
and tR(minor) = 16.13 min.
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Phosphane-Catalyzed Asymmetric Michael Addition
2-[1-(4-Chlorophenyl)-3-oxo-3-phenylpropyl]cyclopentanone (11d)[4]
2-[1-(4-Bromophenyl)-3-oxo-3-phenylpropyl]cyclopentanone (11g)[8b]
1
White solid (50 mg), yield 77%. [α]2D0 = –71.2 (c = 1.2, CHCl3). H
NMR (400 MHz, CDCl3): δ = 1.39–1.97 (m, 4 H), 1.98–2.14 (m, 1
H), 2.19–2.33 (m, 1 H), 2.43 (dd, J1 = 17.6, J2 = 8.5 Hz, 1 H), 3.34
Colorless oil (61 mg), yield 82%. [α]2D0 = –50.5 (c = 1.9, CHCl3).
1H NMR (400 MHz, CDCl3): δ = 1.39–1.96 (m, 4 H), 1.99–2.16
(m, 1 H), 2.20–2.33 (m, 1 H), 2.43 (dd, J1 = 17.7, J2 = 8.5 Hz, 1
H), 3.34 (dd, J1 = 17.0, J2 = 8.2 Hz, 0.86 H), 3.49 (d, J1 = 19.0, J2
= 9.7 Hz, 0.14 H), 3.61–3.95 (m, 2 H), 7.03–7.17 (m, 2 H), 7.33–
7.59 (m, 5 H), 7.85–7.98 (m, 2 H) ppm. MS (ESI): m/z calcd. for
C20H19BrO2 [M + H]+ 371.065; found 371.068; dr (anti:syn) =
86:14, enantiomeric excess (%): anti 79, syn 79, determined by
HPLC (Daicel Chiralpak AD, iPrOH/hexane 10:90), UV 254 nm,
flow rate 1.0 mLmin–1. syn diastereomer: tR(major) = 12.39 min
and tR (minor) = 18.70 min, anti diastereomer: tR(major) =
20.03 min, and tR (minor) = 25.30 min.
(dd, J1 = 17.0, J2 = 8.2 Hz, 0.88 H), 3.49 (dd, J1 = 14.3, J2
=
4.9 Hz, 0.12 H), 3.62–3.92 (m, 2 H), 7.10–7.29 (m, 4 H), 7.36–
7.57 (m, 3 H), 7.86–7.97 (m, 1 H) ppm. MS (ESI): m/z calcd. for
C20H19ClO2 [M + H]+ 327.115; found 327.176; dr (anti:syn) =
88:12, enantiomeric excess (%): anti 82, syn 82, determined by
HPLC (Daicel Chiralpak AD, iPrOH/hexane 10:90), UV 254 nm,
flow rate 1.0 mLmin–1. syn diastereomer: tR(major) = 11.51 min
and tR(minor)
= 16.31 min, anti diastereomer: tR(major) =
18.47 min and tR(minor) = 22.30 min.
2-[1-(3-Chlorophenyl)-3-oxo-3-phenylpropyl]cyclopentanone (11e)[8b]
2-(3-Oxo-3-phenyl-1-p-tolylpropyl)cyclopentanone (11h)[8b]
Colorless oil (49 mg), yield 75%. [α]2D0 = –37.2 (c = 0.8, CHCl3).
1H NMR (400 MHz, CDCl3): δ = 1.39–1.99 (m, 4 H), 2.00–2.18
(m, 1 H), 2.19–2.35 (m, 1 H), 2.43 (dd, J1 = 17.5, J2 = 8.6 Hz, 1
H), 3.34 (dd, J1 = 17.1, J2 = 7.9 Hz, 0.89 H), 3.47 (dd, J1 = 15.7,
J2 = 6.2 Hz, 0.11 H), 3.61–3.97 (m, 2 H), 7.08–7.25 (m, 4 H), 7.34–
7.62 (m, 3 H), 7.82–8.00 (m, 2 H) ppm. MS (ESI): m/z calcd. for
C20H19ClO2 [M + Na]+ 349.097; found 349.238; dr (anti:syn) =
89:11, enantiomeric excess (%): anti 76, syn 84, determined by
HPLC (Daicel Chiralpak AD, iPrOH/hexane 10:90), UV 254 nm,
flow rate 1.0 mLmin–1. syn diastereomer: tR(major) = 10.85 min
White solid (32 mg), yield 52%. [α]2D0 = –73.0 (c = 0.4, CHCl3). H
1
NMR (400 MHz, CDCl3): δ = 1.48–1.99 (m, 4 H), 2.01–2.16 (m, 1
H), 2.18–2.27 (m, 1 H), 2.29 (s, 3 H), 2.44 (dd, J1 = 16.9, J2
=
8.4 Hz, 1 H), 3.34 (dd, J1 = 16.7, J2 = 7.6 Hz, 0.89 H), 3.64 (dd,
J1 = 15.5, J2 = 5.8 Hz, 0.11 H), 3.60–3.91 (m, 2 H), 7.02–7.17 (m,
4 H), 7.36–7.58 (m, 3 H), 7.86–8.02 (m, 2 H) ppm. MS (ESI): m/z
calcd. for C21H23O2 [M + H]+ 307.170; found 307.133; dr (anti:syn)
= 89:11, enantiomeric excess (%): anti 90, syn 79, determined by
HPLC (Daicel Chiralpak AD, iPrOH/hexane 5:95), UV 254 nm,
flow rate 1.0 mLmin–1. syn diastereomer: tR(major) = 15.40 min
and tR(minor)
= 11.94 min, anti diastereomer: tR(minor) =
15.80 min and tR(major) = 18.66 min.
and tR(minor)
= 20.13 min, anti diastereomer: tR(major) =
23.11 min and tR(minor) = 25.78 min.
2-[1-(2-Chlorophenyl)-3-oxo-3-phenylpropyl]cyclopentanone (11f)
2-[1-(4-Methoxyphenyl)-3-oxo-3-phenylpropyl]cyclopentanone (11i)[8b]
Colorless oil (57 mg), yield 87%. [α]2D0 = –61.4 (c = 0.7, CHCl3).
1H NMR (400 MHz, CDCl3): δ = 1.45–2.10 (m, 4 H), 2.20–2.36
(m, 2 H), 2.48–2.67 (m, 1 H), 3.47 (dd, J1 = 17.1, J2 = 8.6 Hz, 0.9 Colorless oil (17 mg), yield 27%. [α]2D0 = –58.7 (c = 0.3, CHCl3).
H), 3.64 (dd, J1 = 17.1, J2 = 6.5 Hz, 0.1 H), 3.95–4.20 (m, 2 H), 1H NMR (400 MHz, CDCl3): δ = 1.44–1.96 (m, 4 H), 1.99–2.12
7.04–7.24 (m, 2 H), 7.26–7.60 (m, 5 H), 7.85–8.03 (m, 2 H) ppm. (m, 1 H), 2.18–2.31 (m, 1 H), 2.42 (dd, J1 = 16.9, J2 = 8.5 Hz, 1
13C NMR (100 MHz, CDCl3): δ = 20.38, 29.28, 38.80, 40.07, 42.24, H), 3.33 (dd, J1 = 16.6, J2 = 7.7 Hz, 0.93 H), 3.46 (dd, J1 = 16.4,
52.56, 125.77, 127.14, 127.79, 128.16, 128.55, 130.00, 132.94,
134.16, 137.08, 140.74, 198.51, 220.22 ppm. MS (ESI): m/z calcd.
for C20H19ClO2 [M + H]+ 327.115; found 327.060; dr (anti:syn) =
90:10, enantiomeric excess (%): anti 78, syn 83, determined by
HPLC (Daicel Chiralpak AD, iPrOH/hexane 10:90), UV 254 nm,
flow rate 1.0 mLmin–1. syn diastereomer: tR (minor) = 11.41 min
and tR (major) = 12.31 min, anti diastereomer: tR(major) =
19.29 min and tR(minor) = 21.18 min; C20H19ClO2: calcd. C 73.50,
H 5.86; found C 73.28, H 5.73.
J2 = 7.1 Hz, 0.7 H), 3.63–3.74 (m, 1 H), 3.76 (s, 3 H), 3.77–3.85
(m, 1 H), 6.80 (d, J = 8.7 Hz, 2 H), 7.13 (d, J = 6.0 Hz, 2 H), 7.39–
7.57 (m, 3 H), 7.87–8.00 (m, 2 H) ppm. MS (ESI): m/z calcd. for
C21H23O3 [M + H]+ 323.165; found 323.117; dr (anti:syn) = 93:7,
enantiomeric excess (%): anti 79, syn 77, determined by HPLC
(Daicel Chiralpak AD, iPrOH/hexane 10:90), UV 254 nm, flow rate
= 15.31 min and
tR(minor) = 22.03 min, anti diastereomer: tR(major) = 25.46 min
and tR(minor) = 30.60 min.
1.0 mLmin–1. syn diastereomer: tR(major)
Eur. J. Org. Chem. 2013, 2634–2645
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2643

L. Liu, Y. Zhu, K. Huang, W. Chang, J. Li
FULL PAPER
2-[1-(Naphthalen-1-yl)-3-oxo-3-phenylpropyl]cyclopentanone (11j)
393.138; enantiomeric excess (%): anti 79, syn 78, determined by
HPLC (Daicel Chiralpak AD, iPrOH/hexane 10:90), UV 254 nm,
flow rate 1.0 mLmin–1. syn diastereomer: tR(major) = 14.61 min
and tR(minor)
= 20.07 min, anti diastereomer: tR(major) =
26.35 min and tR(minor) = 40.90 min.
2-[1,3-Bis(4-chlorophenyl)-3-oxopropyl]cyclopentanone (11m)
Light yellow oil (49 mg), yield 72%. [α]2D0 = –43.6 (c = 0.65, CHCl3).
1H NMR (400 MHz, CDCl3): δ = 1.49–1.93 (m, 4 H), 1.93–2.08
(m, 1 H), 2.10–2.25 (m, 1 H), 2.66 (m, 1 H), 3.42 (dd, J1 = 15.4,
J2 = 4.2 Hz, 0.67 H), 3.58 (dd, J1 = 16.0, J2 = 6.8 Hz, 0.33 H),
3.63–3.76 (m, 1 H), 4.02–4.20 (m, 1 H), 7.30–7.60 (m, 8 H), 7.69–
7.94 (m, 3 H), 8.17–8.34 (m, 1 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 19.58, 25.37, 37.91, 38.38, 39.06, 52.87, 122.25, 124.50,
124.72, 125.47, 126.33, 127.16, 127.31, 127.57, 127.70, 128.10,
131.94, 132.18, 136.04, 137.98, 197.96, 219.11 ppm. MS (ESI): m/z
calcd. for C24H22O2 [M + H]+ 343.170; found 343.163; dr (anti:syn)
= 67:33, enantiomeric excess (%): anti 63, syn 67, determined by
HPLC (Daicel Chiralpak AD, iPrOH/hexane 3:97), UV 254 nm,
flow rate 1.0 mLmin–1. syn diastereomer: tR(major) = 36.87 min
Colorless oil (58 mg), yield 80%. [α]2D0 = –49.3 (c = 0.6, CHCl3).
1H NMR (400 MHz, CDCl3): δ = 1.41–1.98 (m, 4 H), 1.99–2.13
(m, 1 H), 2.22–2.34 (m, 1 H), 2.40 (dd, J1 = 17.7, J2 = 8.7 Hz, 1
H), 3.30 (dd, J1 = 16.9, J2 = 8.3 Hz, 0.76 H), 3.42 (dd, J1 = 18.5,
J2 = 9.3 Hz, 0.24 H), 3.57–3.92 (m, 2 H), 7.07–7.25 (m, 4 H), 7.31–
7.45 (m, 2 H), 7.78–7.91 (m, 2 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 20.28, 28.16, 38.85, 40.44, 42.88, 52.79, 128.67, 128.95,
129.54, 129.66, 132.49, 135.27, 139.52, 140.95, 197.19, 219.64 ppm.
MS (ESI): m/z calcd. for C20H18Cl2O2 [M + H]+ 383.058; found
383.142; dr (anti:syn) = 76:24, enantiomeric excess (%): anti 85,
syn 61, determined by HPLC (Daicel Chiralpak AD, iPrOH/hexane
10:90), UV 254 nm, flow rate 1.0 mLmin–1. syn diastereomer:
tR(major) = 14.29 min and tR(minor) = 25.35 min, anti dia-
stereomer: tR(major) = 26.23 min and tR(minor) = 31.34 min;
C20H18Cl2O2: calcd. C 66.49, H 5.02; found C 65.74, H 4.90.
and tR(minor)
= 40.02 min, anti diastereomer: tR(minor) =
38.29 min and tR(major) = 43.08 min; C24H22O2: calcd. C 84.18, H
6.48; found C 83.98, H 6.27.
2-[3-(3-Bromophenyl)-3-oxo-1-phenylpropyl]cyclopentanone (11k)
Supporting Information (see footnote on the first page of this arti-
cle): NMR and mass spectra as well as chiral HPLC data of 10
and 11.
Colorless oil (68 mg), yield 92%. [α]2D0 = –24.4 (c = 0.5, CHCl3).
1H NMR (400 MHz, CDCl3): δ = 1.43–1.97 (m, 4 H), 2.01–2.17
(m, 1 H), 2.18–2.33 (m, 1 H), 2.42 (dd, J1 = 17.5, J2 = 8.8 Hz, 1
H), 3.30 (dd, J1 = 17.1, J2 = 7.7 Hz, 0.79 H), 3.42 (dd, J1 = 18.6,
J2 = 9.5 Hz, 0.21 H), 3.57–3.95 (m, 2 H), 7.13–7.39 (m, 6 H), 7.57–
7.64 (m, 1 H), 7.77–7.90 (m, 1 H), 7.97–8.11 (m, 1 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 20.37, 28.39, 38.98, 41.06, 43.24,
52.93, 123.01, 126.72, 126.88, 128.31, 128.63, 130.25, 131.25,
135.86, 138.95, 142.68, 197.37, 220.14 ppm. MS (ESI): m/z calcd.
for C40H39Br2O4 [2M + Na]+ 763.103; found 702.698; dr (anti:syn)
= 79:21, enantiomeric excess (%): anti 78, syn 82, determined by
HPLC (Daicel Chiralpak AD, iPrOH/hexane 10:90), UV 254 nm,
flow rate 1.0 mLmin–1. syn diastereomer: tR(major) = 9.15 min and
tR(minor) = 9.90 min, anti diastereomer: tR(major) = 11.81 min
and tR(minor) = 13.24 min; C20H19BrO2: calcd. C 64.70, H 5.16;
found C 65.00, H 5.31.
Acknowledgments
The authors are are grateful for the financial support from the
National Natural Science Foundation of China (NSFC) (grant
number 21142009) and Tianjin Natural Science Foundation of
China (grant number 12JCQNJC03500) for this work. The authors
also thank the Fundamental Research Funds for the Central Uni-
versities in China for support.
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Received: November 29, 2012
Published Online: March 13, 2013
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