C2-symmetric proline-derived tetraamine as highly effective catalyst for direct asymmetric Michael addition of ketones to chalcones

Article abstract of DOI:10.1039/c2ob06897d

A C₂-symmetric tetraamine catalyst was developed for the asymmetric Michael addition of ketones to chalcones. The corresponding adducts 1,5-dicarbonyl compounds were obtained in good chemical yields with high levels of diastereo- and enantioselectivities (up to >99:1 dr and 93% ee) under mild conditions. By studying the ESI-MS of the intermediates, a proposed mechanism was disclosed.

Full text of DOI:10.1039/c2ob06897d

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PAPER
C2-symmetric proline-derived tetraamine as highly effective catalyst for direct
asymmetric Michael addition of ketones to chalcones†
Shijun Ma, Lulu Wu, Ming Liu and Yongmei Wang*
Received 10th November 2011, Accepted 25th January 2012
DOI: 10.1039/c2ob06897d
A C2-symmetric tetraamine catalyst was developed for the asymmetric Michael addition of ketones to
chalcones. The corresponding adducts 1,5-dicarbonyl compounds were obtained in good chemical yields
with high levels of diastereo- and enantioselectivities (up to >99 : 1 dr and 93% ee) under mild
conditions. By studying the ESI-MS of the intermediates, a proposed mechanism was disclosed.
Introduction
The Michael addition reaction is widely recognized as a power-
ful tool for the generation of carbon–carbon bonds in organic
synthesis.1 During the past few years, a tremendous growth in
the number of organocatalyzed highly stereoselective Michael
addition reactions has been witnessed.2 However, most of orga-
nocatalyzed Michael addition reactions employed either highly
active Michael donors (e.g., 1,3-dicarbonyls,3 nitroalkanes4 and
dicyanomethane5) or highly active Michael acceptors (e.g.,
nitroalkenes6 and sulfones7). Enantioselective catalytic Michael
addition of ketones to enones has remained significantly less
developed probably due to the low reactivity and high steric
hindrance of substrates. As far as we know, only few papers have
been published on the asymmetric Michael addition of ketones
to chalcones. Wang et al. accomplished the addition of ketones
to chalcones for the first time with high enantioselectivity using
a chiral pyrrolidinylmethylsulfonamide catalyst a (Fig. 1).8 We
reported an amino acid ionic liquid b (Fig. 1)9 and a pyrrolidine–
pyridine base catalyst c (Fig. 1)10 for this type Michael addition
reaction. While these catalysts were effective in this type of
Michael addition with moderate to high enantioselectivities, they
are not without their shortcomings. Specifically, a long reaction
time (more than 4 days), high catalyst loading (200 mol%) and
low chemical yield (45–70%). And these will put up the cost
and limit their application in the pharmaceutical industry and
other fields. Therefore, design and develop more efficiency cata-
lysts aimed at overcoming these limitations in Michael addition
reactions remains a great challenge in organic synthesis
chemistry.
Fig. 1 Some organocatalysts for Michael addition of ketones to
chalcones.
Of the developed organocatalysts in asymmetric catalysis,
chiral amines derived from nature amino acid or cinchona
alkaloids, which contain primary amine,11 diamines12 and
triamines,13 have proven to be powerful and been applied for the
asymmetric catalytic Michael addition successfully. To the best
of our knowledge, there have no tetraamines as organocatalysts
for the Michael reaction. Therefore, in an effort to search for
new and high effective catalysts, in this paper, we first disclosed
such a set of tetraamines organocatalysts, which were tested in
asymmetric Michael addition of ketones to chalcones. Among
them, C2-symmetric proline-derived tetraamine 2 was proved to
be high efficiency for the reaction providing good yield with
excellent diastereo- and enantioselectivity.
Results and discussion
Our investigation began with screening the organocatalysts
shown in Table 1 for their ability to promote the asymmetric
Michael addition reaction of cyclohexanone 5a with 4-chloro-
chalcone 6a. The initial reactions were performed by using
20 mol% of the catalysts at room temperature in CHCl3. Examin-
ation of the results from this survey revealed that their catalytic
activities varied significantly. For example, catalyst 1 and 3 are
not effective catalysts for this process (entries 1 and 3). Although
catalyst 4 afforded the product in good diastereoselectivity, it
gave low yield and enantioselectivity (97 : 3 dr, 38% yield, 59%
ee, entry 4). Catalysts 2 can promote the addition smoothly with
good diastereoselectivity, higher yield and enantioselectivity
(96 : 4 dr, 51% yield, 70% ee, entry 2), and this catalyst was
Department of Chemistry, The Key Laboratory of Elemento-Organic
Chemistry, Nankai University, Tianjin 300071, China. E-mail: ymw@
nankai.edu.cn; Fax: +86 22 2350 2654; Tel: +86 22 2350 3281
†Electronic supplementary information (ESI) available. See DOI:
10.1039/c2ob06897d
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Table 1 The screen of different chiral catalysts 1–4 and solventsa
Table 2 The effect of different acid additivesa
Yield
dr [syn/
anti]c
ee
Entry Additive
T/d (%)b
(%)d
1
2
Benzoic acid
2,4-Dinitrobenzoic
acid
3
5
71
—
99 : 1
—
87
—
3
4
5
6
4-Fluorobenzoic acid
4-Chlorobenzoic acid
4-Bromobenzoic acid
2-Hydroxybenzoic
acid
3
3
3
3
59
64
61
75
>99 : 1
>99 : 1
98 : 2
79
76
80
84
95 : 5
7
8
4-Hydroxybenzoic
acid
4-Methoxybenzoic
acid
3
3
78
81
97 : 3
98 : 2
86
89
Entry Cat. Solvent
T/d Yield (%)b dr [syn/anti]c ee (%)d
1
1
2
3
4
2
2
2
2
2
2
2
CHCl3
CHCl3
CHCl3
CHCl3
CH2Cl2
i-PrOH
t-BuOH
CH3OH
THF
3
3
3
3
3
3
3
3
3
3
3
<5
51
<5
38
50
55
31
49
54
65
47
nd
96 : 4
nd
Nd
70
Nd
59
67
42
56
50
63
80
75
2
3
4
5
6
7
8
9
Phenol
3
3
3
5
74
69
85
—
98 : 2
98 : 2
96 : 4
—
80
83
86
—
10
11
12
3,5-Dimethylphenol
4-Nitrophenol
TFA
97 : 3
99 : 1
99 : 1
99 : 1
99 : 1
98 : 2
99 : 1
98 : 2
a Unless otherwise specified, all reactions were carried out using 5a
(0.4 mL, 4.0 mmol), 6a (0.2 mmol), catalysts 2 (0.04 mmol, 20 mol%)
and the additives (0.04 mmol, 20 mol%) at room temperature. b Isolated
9
10e
11
Neat
CH3CN
yield after silica gel column chromatography. c Determined by H NMR
1
spectroscopy. d Determined by HPLC analysis.
a Unless otherwise specified, all reactions were carried out using 5a
(0.2 mL, 2.0 mmol), 6a (0.2 mmol) and the catalysts (0.04 mmol,
20 mol%) in different solvents (0.5 mL) at room temperature. b Isolated
Having established the optimal reaction conditions, the scope
and the limitation of this Michael reaction with different ketones
5 and chalcones 6 were examined. As shown in Table 3, struc-
tural variation in the α,β-unsaturated ketones was found to be
tolerated in Michael addition reactions of cyclohexanone 5a to
chalcones 6 (entries 1–13). The catalyst-promoted processes
were successful with aromatic systems (Ar1) possessing electron-
withdrawing substituents (85–93% ee, entries 3–7). Although
electron-donating functionalities on Ar1 resulted in excellent dia-
stereoselectivity, a small decrease in enantioselectivity occurred
(82% ee, entry 9). Good to excellent levels of enantioselectivities
(85–92% ee) and diastereoselectivities (≥95 : 5) were obtained
for reactions of chalcones containing different aromatic substitu-
ents (Ar2) (entries 10–13). To further study the scope of catalyst
2 in Michael reaction, other cyclic ketones were also examined
as the donor (entries 14–19). Reactions with 6-membered ring
ketones such as 1,4-cyclohexanedione monoethylene acetal,
tetrahydro-4H-thiopyran-4-one and tetrahydro-4H-pyran-4-one
gave the Michael adducts in good yields (71–81%) with excel-
lent enantioselectivities (88–92% ee) and diastereoselectivities
(≥90 : 10) (entries 14, 15 and 18). Although 4-methyl cyclohex-
anone and N-methyl-4-piperidone gave high diastereoselectiv-
ities (≥95 : 5), only moderate enantioselectivities (67–75% ee)
were obtained (entries 16–17). Reaction with cyclopentanone
took place at a higher rate (1.5 d) and in high yield (90%), but
the diastereoselectivity was low (80 : 20), and the major isomer
had a comparably lower ee (60%) (entry 19).
1
yield after silica gel column chromatography. c Determined by H NMR
spectroscopy. d Determined by HPLC analysis. e 5a (0.4 mL, 4.0 mmol)
was used.
selected for further studies. Therefore, the screening of different
organic solvents with catalyst 2 was carried out (entries 5–11).
From all the conditions tested, we found that the yields and
enantioselectivities of the product differed significantly. When
the reaction performed in less polar solvents such as CH2Cl2 and
THF, no improvement was obtained in yields and enantioselec-
tivities (entries 5 and 9). When the reaction proceed in CH3OH,
i-PrOH or t-BuOH, the products were formed in much lower
enantioselectivities (entries 6–8). Higher enantioselectivity was
obtained when CH3CN was used, but the yield was low (47%
yield, 75% ee, entry 11). The reaction was also performed under
neat conditions, to our delight, it afforded the product in best
yield with highest enantioselectivity and diastereoselectivity
(65% yield, 99 : 1 dr, 80% ee, entry 10).
With the hope of improving the yield and selectivity, we next
examined the effect of various acid additives. As illustrated in
Table 2, the strong acid such as 2,4-dinitrobenzoic acid and TFA
cannot promote the reaction, probably due to the poisoning of
catalyst through salt formation (entries 2 and 12). The enantio-
selectivities are higher with benzoic acid or its derivatives
with electron-donating substituents in the para position of
the benzene ring (entries 6–8) than other weak acids such as 4-
fluorobenzoic acid, phenol or 3,5-dimethylphenol. Finally, we
found that 4-methoxybenzoic acid was the best additive in com-
bination with catalyst 2 (81% yield, 98 : 2 dr, 89% ee, entry 8),
and it was selected as the additive for further investigation.
After the above success, we sought to extend the catalytic
activity of C2-symmetric proline-derived tetraamine 2 in Michael
reaction of 4-hydroxy coumarin 8 to benzylideneacetone 9. The
results of the reaction are shown in eqn (1), it proceeded
3722 | Org. Biomol. Chem., 2012, 10, 3721–3729
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Table 3 Michael reaction of ketones to chalconesa
Entry
X
Ar1
Ar2
Product
T/d
Yield (%)b
dr [syn/anti]c
ee (%)d
1
2
3
4
5
6
7
8
CH2
CH2
CH2
CH2
CH2
CH2
CH2
CH2
CH2
CH2
CH2
CH2
CH2
C[O(CH2)2O]
S
C(CH3)
N(CH3)
O
4-ClC6H4
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
7a
7b
7c
7d
7e
7f
7g
7h
7i
7j
7k
7l
7m
7n
7o
7p
7q
7r
7s
3
3
3
3
3
3
1.5
3
4
3
5
5
3
3
3
5
3
81
77
86
84
88
90
96
73
76
91
61
67
64
76
71
46
84
81
90
98 : 2
89
89
85
90
93
90
92
86
82
90
85
87
92
92
90
75
67
88
60
>99 : 1
83 : 17
>99 : 1
>99 : 1
91 : 9
98 : 2
>99 : 1
99 : 1
99 : 1
95 : 5
98 : 2
>99 : 1
90 : 10
98 : 2
>99 : 1
95 : 5
97 : 3
80 : 20
2-ClC6H4
3-ClC6H4
4-FC6H4
4-BrC6H4
4-NO2C6H4
1-Naphthyl
4-MeC6H4
Ph
Ph
Ph
2-ClC6H4
4-ClC6H4
4-ClC6H4
Ph
9
Ph
4-ClC6H4
4-OMeC6H4
4-NH2C6H4
10
11
12
13
14e
15e
16
17
18
19
4-OMeC6H4
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
3
1.5
None
a Unless otherwise specified, all reactions were carried out using 5 (4.0 mmol), 6 (0.2 mmol), catalyst 2 (0.04 mmol, 20 mol%) and 4-methoxybenzoic
acid (0.04 mmol, 20 mol%) at room temperature. b Isolated yield after silica gel column chromatography. c Determined by 1H NMR spectroscopy.
d Determined by HPLC analysis. e CH3CN (0.5 mL) as a solvent.
efficiently to give the corresponding product 10 in high yield
(99%). However, the enantioselectivity of this reaction was low
(34% ee).
ð1Þ
The stereochemistries of the major products 7 were deter-
mined by comparison of their HPLC spectra with other previous
studies.8–10 To account for the stereochemical outcome of the
Michael reaction, a plausible mechanism is shown in Fig. 2. The
protonated catalyst 2 first forms a chiral enamine I with ketones
5, and then a Michael reaction between the enamine-activated I
and the chalcones 6 leads to the formation of the corresponding
products 7 via transition state A. The protonated catalyst 2 is
regenerated for use in the subsequent catalytic cycle. In tran-
Fig. 2 Proposed mechanism for the 2-catalyzed Michael reaction.
sition state A, the NH protons provide stabilization through
hydrogen bonding interaction with the chalcones carbonyl
group, the enamine intermediate add to the Si-face of chalcones,
thereby predicting the high enantioselectivity observed in the
reaction. The existence of the intermediates I and II in the reac-
tion mixture was confirmed by ESI-MS (Fig. 3 and 4) (reaction
of cyclohexanone 5a with 4-chlorochalcone 6a as an example).
Conclusion
In summary, we have first presented a C2-symmetric proline-
derived tetraamine 2 as highly effective catalyst for asymmetric
Michael addition reactions of ketones with chalcones. The
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Fig. 3 ESI-MS spectra of the intermediate I (before adding the chalcones).
Fig. 4 ESI-MS spectra of the intermediate II (after 3 hours of reaction).
process is carried out under mild conditions to afford syntheti-
cally useful 1,5-dicarbonyl compounds in good to high yields
with high to excellent levels of diastereoselectivities and enan-
tioselectivities. Based on the experimental results and ESI-MS
analysis of the intermediates, the mode of activity of the organo-
catalyst with the substrate was deduced. Further investigation
of synthetic applications of this valuable reaction and the use
of these organocatalysts in asymmetric catalysis are still in
progress.
shifts were calibrated to tetramethylsilane as an external refer-
ence. Coupling constants are given in hertz. The following
abbreviations are used to indicate the multiplicity: s, singlet; d,
double; t, triplet; m, multiplet. HR-MS were recorded on an
IonSpec FT-ICR mass spectrometer with ESI resource. HPLC
analysis was performed on Shimadzu CTO-10AS by using a
Chiralpak AD-H, OD-H or AS-H column purchased from Daicel
Chemical Industries. The chemicals were purchased from com-
mercial suppliers (Aldrich, USA and Shanghai Chemical
Company, China), and were used without purification prior
to use. All reactions were carried out directly under air unless
otherwise noted.
Experimental section
General information
General procedure for the synthesis of catalysts 1–4
All the solvents were purified according to standard procedures.
The 1H NMR spectra were recorded at 400 MHz, 13C NMR
Boc-protected L-proline (4.3 g, 20 mmol) and TEA (3.1 mL,
20 mmol) were dissolved in CH2Cl2 (25 mL). Isobutyl
1
spectra were recorded at 75 MHz. H and 13C NMR chemical
3724 | Org. Biomol. Chem., 2012, 10, 3721–3729
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Scheme 1 Synthesis of catalysts 1 and 2.
N,N′-Bis[(S)-prolyl]-(1R,2R)-1,2-diaminocyclohexane
(3).15
chloroformate (2.6 mL, 20 mmol) was added to the solution
dropwise at 0 °C. After the solution was stirred for 30 min,
o-phenylenediamine (1.08 g, 10 mmol) in 10 mL CH2Cl2 was
added over 15 min. The resulting solution was stirred at room
temperature for 12 h and detected by TLC. The reaction mixture
was washed with saturated aqueous NaHSO4 (30 mL), water
(30 mL), and dried over anhydrous Na2SO4, then filtered and
concentrated under reduced pressure. The crude product was dis-
solved in CH2Cl2 and TFA (6.2 mL, 80 mmol) was added drop-
wise at 0 °C. The mixture was warmed to room temperature and
stirred overnight. After removal of the organic solvents under
vacuum, the residue was dissolved in CH2Cl2 (10 mL) and
treated with saturated Na2CO3 solution (30 mL) for 1 h at room
temperature. The aqueous layer was extracted with CH2Cl2 three
times (15 mL × 3) and the combined extracts were washed with
brine (15 mL), then dried over anhydrous Na2SO4. Concentration
in vacuo after filtration, the crude product was purified by
column chromatography with CH2Cl2–MeOH (20 : 1) to afford
2.14 g (71%) of 1 as a white solid.
1
White solid, mp 159–162 °C, 81% yield; H NMR (400 MHz,
CDCl3) δ (ppm) 0.87–0.96 (m, 1H), 1.09–1.18 (m, 4H),
1.29–1.41 (m, 6H), 1.95–2.15 (m, 3H), 2.90–3.10 (m, 4H),
3.58–3.69 (m, 4H), 7.66 (s, 2H); 13C NMR (75 MHz, CDCl3) δ
(ppm) 24.73, 26.17, 30.80, 32.60, 47.12, 52.56, 60.58, 174.95;
MS m/z = 308 ([M+]).
N,N′-Bis{[(S)-pyrrolidin-2-yl]methyl}-(1R,2R)-1,2-diamino-
cyclohexane (4).15 Colorless oil, 62% yield; 1H NMR
(400 MHz, CDCl3) δ (ppm) 0.98–1.03 (m, 1H), 1.09–1.40
(m, 4H), 1.64–1.79 (m, 5H), 1.80–1.98 (m, 2H), 1.99–2.20
(m, 3H), 2.27–2.35 (m, 2H), 2.68–3.09 (m, 8H), 3.11–3.29
(m, 2H), 3.50–3.79 (m, 1H); 13C NMR (75 MHz, CDCl3) δ
(ppm) 25.03, 25.48, 29.65, 31.74, 46.34, 52.18, 52.88, 62.10;
MS m/z = 281 ([M+ + 1]).
Typical procedure for Michael reaction of ketones with
chalcones
A solution of 1 (0.86 g, 2.85 mmol) in 15 mL anhydrous THF
was added dropwise to a suspension of lithium aluminum
hydride (0.54 g, 14.2 mmol) in 25 mL anhydrous THF in an ice
bath, the mixture was stirred and heated to reflux for 10 h. The
reaction mixture was chilled and 0.5 g (28 mmol) of water was
added dropwise with vigorous stirring at 0 °C. The precipitated
mass was filtered off and washed with THF. The combined
filtrate and washings were dried over anhydrous Na2SO4, fol-
lowed by evaporation of the solvent under vacuum to give
0.53 g (67%) catalyst 2 as a dark oil.
Catalyst 2 (11 mg, 0.04 mmol) and 4-methoxybenzoic acid
(6 mg, 0.04 mmol) were added to a vial containing ketones 5
(4 mmol) and chalcones 6 (0.2 mmol) at room temperature. The
mixture was stirred vigorously and monitored by TLC. When the
reaction was finished, the mixture was purified by flash silica
gel chromatography eluting with various mixtures of petroleum
ether : EtOAc to afford the desired products 7.
(S)-2-((R)-1-(4-Chlorophenyl)-3-oxo-3-phenylpropyl)-cyclo-
hexanone (7a).10 81% yield; syn/anti = 98 : 2 (by H NMR), H
NMR (400 MHz, CDCl3) δ (ppm) 1.20–1.29 (m, 1H),
1.62–1.81 (m, 4H), 1.95–2.05 (m, 1H), 2.31–2.53 (m, 2H), 2.69
(m, 1H), 3.19 (dd, 1H, J1 = 9.9 Hz, J2 = 16.5 Hz), 3.50 (dd, 1H,
J1 = 4.2 Hz, J2 = 16.5 Hz), 3.71 (dt, 1H, J1 = 9.6 Hz, J2 = 3.9
Hz), 7.10–7.13 (m, 2H), 7.20–7.23 (m, 2H), 7.40–7.44 (m, 2H),
7.51–7.54 (m, 1H), 7.90 (d, 2H, J = 6.8 Hz); 13C NMR
(75 MHz, CDCl3) δ (ppm) 24.34, 28.51, 32.51, 40.53, 42.46,
43.94, 55.61, 128.15, 128.54, 128.63, 129.76, 132.29, 132.99,
136.89, 140.58, 198.50, 213.12. HPLC analysis: Chiralpak
1
1
Catalysts 3 and 4 are prepared according the above procedure
using (1R,2R)-1,2-diaminocyclohexane as starting material. The
catalyst 3 obtained in 81% yield as a white solid, 4 62% yield as
a colorless oil.
N,N′-Bis[(S)-prolyl]phenylenediamine (1).14 White solid, mp
1
151–152 °C, 77% yield; H NMR (400 MHz, CDCl3) δ (ppm)
1.69–1.82 (m, 4H), 1.97–2.06 (m, 2H), 2.13–2.37 (m, 2H),
2.93–2.97 (m, 2H), 2.99–3.07 (m, 2H), 3.86 (dd, 2H, J1 = 5.3
Hz, J2 = 9.2 Hz), 7.11–7.21 (m, 2H), 7.63–7.68 (m, 2H),
9.59–9.68 (s, 2H); 13C NMR (75 MHz, CDCl3) δ (ppm) 26.27,
30.85, 47.37, 61.04, 123.99, 125.60, 129.76, 174.17; MS m/z =
302 ([M+]).
AD-H column, i-PrOH–hexane 10 : 90, flow rate 1.0 mL min−1
,
λ = 254 nm, retention time: 13.4 min (minor) and 17.25 min
(major), 89% ee.
N,N′-Bis{[(S)-pyrrolidin-2-yl]methyl}-phenylenediamine
(2).14 Dark oil, 67% yield; 1H NMR (400 MHz, CDCl3) δ (ppm)
1.49–1.58 (m, 2H), 1.73–2.02 (m, 6H), 2.91–3.12 (m, 6H),
3.24–3.29 (dd, 2H, J1 = 5.6 Hz, J2 = 4.0 Hz), 3.49–3.54
(m, 2H), 6.59–6.63 (m, 2H), 6.71–6.75 (m, 2H); 13C NMR
(75 MHz, CDCl3) δ (ppm) 25.14, 29.19, 45.58, 48.03, 57.97,
111.34, 118.77, 136.87; MS m/z = 275 ([M+ + 1]).
(S)-2-((R)-3-Oxo-1,3-diphenylpropyl)-cyclohexanone
(7b).8
77% yield; syn/anti = >99 : 1 (by 1H NMR), 1H NMR
(400 MHz, CDCl3) δ (ppm) 1.23–1.30 (m, 1H), 1.59–1.81
(m, 4H), 1.95–2.03 (m, 1H), 2.36–2.49 (m, 1H), 2.52–2.58
(m, 1H), 2.75 (dt, 1H, J1 = 10.2 Hz, J2 = 4.8 Hz), 3.25 (dd, 1H,
J1 = 9.9 Hz, J2 = 16.5 Hz), 3.51 (dd, 1H, J1 = 4.2 Hz, J2 = 16.5
Hz), 3.75 (dt, 1H, J1 = 9.6 Hz, J2 = 3.9 Hz), 7.12–7.16 (m, 3H),
This journal is © The Royal Society of Chemistry 2012
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7.22–7.32 (m, 2H), 7.40–7.49 (m, 2H), 7.50–7.57 (m, 1H), 7.89
(d, 2H, J = 7.2 Hz); 13C NMR (75 MHz, CDCl3) δ (ppm) 24.11,
28.55, 32.46, 41.13, 42.33, 44.24, 55.84, 126.62, 128.18,
128.37, 128.46, 132.82, 137.07, 142.05, 198.79, 213.64. HPLC
analysis: Chiralpak AS-H column, i-PrOH–hexane 40 : 60, flow
rate 0.5 mL min−1, λ = 254 nm, retention time: 13.63 min
(minor) and 20.83 min (major), 89% ee.
(dt, 1H, J1 = 10.0 Hz, J2 = 10.0 Hz, J3 = 4.8 Hz), 3.20 (dd, 1H,
J1 = 16.37 Hz, J2 = 9.79 Hz), 3.51 (dd, 1H, J1 = 16.4 Hz, J2 =
3.9 Hz), 3.70 (dt, 1H, J1 = 9.8 Hz, J2 = 9.8 Hz, J3 = 3.9 Hz),
7.09 (d, 2H, J = 8.4 Hz), 7.39 (d, 2H J = 8.4 Hz), 7.45 (d, 2H,
J = 7.8 Hz), 7.56 (t, 1H, J = 7.3 Hz),7.92 (d, 2H, J = 7.2 Hz);
13C NMR (75 MHz, CDCl3) δ (ppm) 24.37, 28.52, 32.54,
40.57, 42.48, 43.88, 55.54, 120.38, 128.15, 128.54, 130.18,
131.57, 133.01, 136.86, 141.15, 198.45, 213.08. HPLC analysis:
Chiralpak AD-H column, i-PrOH–hexane 10 : 90, flow rate
0.9 mL min−1, λ = 254 nm, retention time: 16.26 min (minor)
and 20.31 min (major), 90% ee.
(S)-2-((R)-1-(2-Chlorophenyl)-3-oxo-3-phenylpropyl)-cyclo-
hexanone (7c).8 86% yield; syn/anti = 83 : 17 (by 1H NMR),
1H NMR (400 MHz, CDCl3) δ (ppm) 1.20–1.39 (m, 1H),
1.57–1.83 (m, 4H), 2.00–2.09 (m, 1H), 2.36–2.43 (m, 1H),
2.56–2.58 (m, 1H), 2.89 (dt, 1H, J1 = 10.0 Hz, J2 = 4.8 Hz),
3.38 (dd, 1H, J1 = 10.0 Hz, J2 = 15.6 Hz), 3.57 (dd, 1H, J1 = 4.0
Hz, J2 = 16.0 Hz), 4.22 (dt, 1H, J1 = 10.0 Hz, J2 = 4.0 Hz), 7.09
(t, 1H, J = 7.2 Hz), 7.17 (t, 1H, J = 7.2 Hz), 7.26–7.31 (m, 2H),
7.41 (t, 2H, J = 7.2 Hz), 7.51 (t, 1H, J = 7.2 Hz), 7.93 (d, 2H,
J = 7.2 Hz); 13C NMR (75 MHz, CDCl3) δ (ppm) 24.78, 28.66,
29.72, 32.62, 42.72, 42.93, 55.14, 127.02, 127.69, 128.22,
128.46, 129.89, 132.85, 134.65, 136.95, 139.61, 198.61, 213.16.
HPLC analysis: Chiralpak AS-H column, i-PrOH–hexane
40 : 60, flow rate 0.5 mL min−1, λ = 254 nm, retention time:
12.26 min (minor) and 19.34 min (major), 85% ee.
(S)-2-((R)-1-(4-Nitrophenyl)-3-oxo-3-phenylpropyl)-cyclohexa-
1
1
none (7g).8 96% yield; syn/anti = 98 : 2 (by H NMR), H NMR
(400 MHz, CDCl3) δ (ppm) 1.21–1.27 (m, 1H), 1.58–1.90
(m, 4H), 2.06–2.10 (m, 1H), 2.39–2.55 (m, 2H), 2.79 (dt, 1H,
J1 = 10.8 Hz, J2 = 5.2 Hz), 3.34 (dd, 1H, J1 = 10.0 Hz, J2 = 16.8
Hz), 3.62 (dd, 1H, J1 = 3.6 Hz, J2 = 16.8 Hz), 3.90 (dt, 1H, J1 =
9.6 Hz, J2 = 4.0 Hz), 7.41–7.47 (m, 4H), 7.56 (t, 1H, J = 7.2
Hz), 7.92 (d, 2H, J = 8.0 Hz), 8.15 (d, 2H, J = 8.8 Hz); 13C
NMR (75 MHz, CDCl3) δ (ppm) 24.70, 28.45, 32.75, 40.91,
42.67, 43.44, 55.15, 123.67, 128.09, 128.64, 129.45, 133.25,
136.59, 146.64, 150.35, 197.93, 212.25. HPLC analysis:
Chiralpak AS-H column, i-PrOH–hexane 40 : 60, flow rate
0.6 mL min−1, λ = 254 nm, retention time: 17.56 min (minor)
and 30.72 min (major), 92% ee.
(S)-2-((R)-1-(3-Chlorophenyl)-3-oxo-3-phenylpropyl)-cyclo-
1
hexanone (7d).10 84% yield; syn/anti = >99 : 1 (by H NMR),
1H NMR (400 MHz, CDCl3) δ (ppm) 1.21–1.29 (m, 1H),
1.53–1.81 (m, 4H), 1.99–2.04 (m, 1H), 2.34–2.42 (m, 1H),
2.46–2.52 (m, 1H), 2.70 (dt, 1H, J1 = 10.0 Hz, J2 = 4.8 Hz),
3.22 (dd, 1H, J1 = 9.6 Hz, J2 = 16.4 Hz), 3.49 (dd, 1H, J1 = 3.6
Hz, J2 = 16.4 Hz), 3.71 (dt, 1H, J1 = 9.6 Hz, J2 = 3.6 Hz),
7.08–7.20 (m, 4H), 7.42 (t, 2H, J = 7.6 Hz), 7.52 (t, 1H, J = 7.2
Hz), 7.90 (d, 2H, J = 7.6 Hz); 13C NMR (75 MHz, CDCl3) δ
(ppm) 24.36, 28.49, 32.55, 40.76, 42.46, 43.84, 55.51, 126.86,
128.14, 128.35, 128.53, 129.71, 132.98, 134.27, 136.90, 144.40,
198.29, 212.97. HPLC analysis: Chiralpak AD-H column,
i-PrOH–hexane 10 : 90, flow rate 1.0 mL min−1, λ = 254 nm,
retention time: 10.57 min (minor) and 20.07 min (major),
90% ee.
(S)-2-((R)-1-(Naphthalen-1-yl)-3-oxo-3-phenylpropyl)-cyclo-
1
hexanone (7h).10 73% yield; syn/anti = >99 : 1 (by H NMR),
1H NMR (400 MHz, CDCl3) δ (ppm) 1.25–1.30 (m, 1H),
1.42–1.75 (m, 4H), 1.95–2.04 (m, 1H), 2.37–2.47 (m, 1H),
2.50–2.59 (m, 1H), 2.87 (dt, 1H, J1 = 10.0 Hz, J2 = 4.8 Hz),
3.45 (dd, 1H, J1 = 10.0 Hz, J2 = 16.0 Hz), 3.69 (dd, 1H, J1 =
3.6 Hz, J2 = 16.4 Hz), 3.68 (dt, 1H, J1 = 9.6 Hz, J2 = 3.6 Hz),
7.34–7.47 (m, 7H), 7.67–7.72 (m, 1H), 7.78–7.88 (m, 3H),
8.11–8.25 (m, 1H); 13C NMR (75 MHz, CDCl3) δ (ppm) 24.67,
28.74, 32.81, 34.05, 42.68, 44.76, 57.10, 123.59, 125.48,
126.00, 127.03, 128.14, 128.41, 128.82, 132.77, 137.03, 198.83,
213.93. HPLC analysis: Chiralpak AD-H column, i-PrOH–
hexane 10 : 90, flow rate 1.0 mL min−1, λ = 254 nm, retention
time: 11.41 min (minor) and 23.32 min (major), 86% ee.
(S)-2-((R)-1-(4-Fluorophenyl)-3-oxo-3-phenylpropyl)-cyclohex-
anone (7e).8 88% yield; syn/anti = >99 : 1 (by 1H NMR), 1H
NMR (400 MHz, CDCl3) δ (ppm) 1.21–1.28 (m, 1H),
1.53–1.81 (m, 4H), 1.97–2.05 (m, 1H), 2.37–2.47 (m, 1H),
2.50–2.56 (m, 1H), 2.72 (dt, 1H, J1 = 10.0 Hz, J2 = 4.8 Hz),
3.20 (dd, 1H, J1 = 10.0 Hz, J2 = 16.0 Hz), 3.51 (dd, 1H, J1 = 4.0
Hz, J2 = 16.0 Hz), 3.74 (dt, 1H, J1 = 10.0 Hz, J2 = 4.0 Hz),
6.94–6.98 (t, 2H), 7.14–7.18 (t, 2H), 7.42–7.57
(t, 2H),7.52–7.56 (t, 1H), 7.92–7.94 (d, 2H); 13C NMR
(75 MHz, CDCl3) δ (ppm) 24.29, 28.55, 32.50, 40.40, 42.45,
44.19, 55.79, 115.20, 128.16, 128.53, 129.74, 129.81, 132.97,
136.88, 137.62, 198.68, 213.38. HPLC analysis: Chiralpak
(S)-2-((R)-3-Oxo-3-phenyl-1-p-tolylpropyl)-cyclohexanone (7i).10
1
76% yield; syn/anti = 99 : 1 (by H NMR), 1H NMR (400 MHz,
CDCl3) δ (ppm) 1.21–1.40 (m, 1H), 1.56–1.87 (m, 4H),
1.96–2.06 (m, 1H), 2.30 (s, 3H), 2.30–2.43 (m, 1H), 2.49–2.57
(m, 1H), 2.69 (dt, 1H, J1 = 10.0 Hz, J2 = 4.8 Hz), 3.19 (dd, 1H,
J1 = 9.2 Hz, J2 = 15.6 Hz), 3.47 (dd, 1H, J1 = 2.8 Hz, J2 = 16.0
Hz), 3.67 (dt, 1H, J1 = 10.0 Hz, J2 = 4.0 Hz), 7.07 (d, 4H, J =
7.2 Hz), 7.43 (t, 2H, J = 6.8 Hz), 7.52 (t, 1H, J = 6.0 Hz), 7.93
(d, 2H, J = 7.2 Hz); 13C NMR (75 MHz, CDCl3) δ (ppm) 24.08,
28.57, 32.44, 40.76, 42.31, 44.33, 50.84, 55.93, 128.18, 128.21,
128.45, 129.18, 132.81, 136.09, 137.05, 138.84, 199.01, 213.94.
HPLC analysis: Chiralpak AD-H column, i-PrOH–hexane
10 : 90, flow rate 1.0 mL min−1, λ = 254 nm, retention time:
11.23 min (minor) and 16.25 min (major), 82% ee.
OD-H column, i-PrOH–hexane 10 : 90, flow rate 1.0 mL min−1
,
λ = 254 nm, retention time: 7.48 min (minor) and 8.02 min
(major), 93% ee.
(S)-2-((R)-1-(4-Bromophenyl)-3-oxo-3-phenylpropyl)-cyclo-
1
1
hexanone (7f).9 90% yield; syn/anti = 91 : 9 (by H NMR), H
NMR (400 MHz, CDCl3) δ (ppm) 1.26–1.29 (m, 1H),
1.62–1.81 (m, 4H), 1.97–2.03 (m, 1H), 2.35–2.55 (m, 2H), 2.71
(S)-2-((R)-1-(4-Phenyl)-3-oxo-3-(4′-chlorophenyl)-propyl)-cyclo-
1
1
hexanone (7j).8 91% yield; syn/anti = 99 : 1 (by H NMR), H
NMR (400 MHz, CDCl3) δ (ppm) 1.22–1.27(m, 1H), 1.62–1.80
3726 | Org. Biomol. Chem., 2012, 10, 3721–3729
This journal is © The Royal Society of Chemistry 2012

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(R)-2-((R)-1-(4-Chlorophenyl)-3-oxo-3-phenylpropyl)-1,4-
cyclohexanedione monoethylene acetal (7n).8 76% yield;
(m, 4H), 1.97–2.05 (m, 1H), 2.35–2.55 (m, 2H), 2.73 (dt, 1H, J1
= 10.2 Hz, J2 = 10.0 Hz, J3 = 4.9 Hz), 3.15 (dd, 1H, J1 = 15.9
Hz, J2 = 9.6 Hz), 3.50 (dd, 1H, J1 = 15.9 Hz, J2 = 4.0 Hz), 3.70
(dt, 1H, J1 = 9.9 Hz, J2 = 9.9 Hz, J3 = 4.0 Hz), 7.11–7.20
(m, 3H), 7.26 (d, 2H, J = 7.5 Hz), 7.39 (d, 2H, J = 8.6 Hz), 7.86
(d, 2H, J = 8.6 Hz); 13C NMR (75 MHz, CDCl3) δ (ppm) 24.31,
28.65, 32.72, 41.41, 42.51, 44.41, 55.79, 126.74, 128.27,
128.55, 128.77, 129.68, 135.27, 139.22, 141.71, 197.70, 213.74.
HPLC analysis: Chiralpak AS-H column, i-PrOH–hexane
40 : 60, flow rate 0.5 mL min−1, λ = 254 nm, retention time:
12.86 min (minor) and 17.30 min (major), 90% ee.
1
1
syn/anti = 90 : 10 (by H NMR), H NMR (400 MHz, CDCl3) δ
(ppm) 1.54 (t, 1H, J = 12.5 Hz), 1.65–1.73 (m, 1H), 1.85–2.10
(m, 2H), 2.45–2.53 (m, 1H), 2.63–2.72 (m, 1H), 3.00–3.10
(m, 1H), 3.19 (dd, 1H, J1 = 16.0 Hz, J2 = 10.0 Hz), 3.52 (dd,
1H, J1 = 16.0 Hz, J2 = 4.0 Hz), 3.78 (dt, 1H, J1 = 13.5 Hz, J2 =
4.0 Hz), 3.75–4.01 (m, 4H), 7.12 (d, 2H, J = 8.5 Hz), 7.22
(d, 2H, J = 8.5 Hz), 7.42 (t, 2H, J = 7.5 Hz), 7.53 (t, 1H, J = 7.5
Hz), 7.91 (d, 2H, J = 8.0 Hz); 13C NMR (75 MHz, CDCl3) δ
(ppm) 35.15, 38.67, 39.12, 40.09, 43.97, 51.13, 64.52, 64.77,
107.28, 128.13, 128.55, 128.66, 129.87, 132.31, 133.01, 136.83,
140.22, 198.28, 211.35. HPLC analysis: Chiralpak AS-H
column, i-PrOH–hexane 40 : 60, flow rate 0.5 mL min−1, λ =
254 nm, retention time: 15.27 min (minor) and 30.29 min
(major), 92% ee.
(S)-2-((R)-3-(4-Methoxyphenyl)-3-oxo-1-phenylpropyl)-cyclo-
1
1
hexanone (7k).8 61% yield; syn/anti = 95 : 5 (by H NMR), H
NMR (400 MHz, CDCl3) δ (ppm) 1.25–1.30 (m, 1H),
1.58–1.88 (m, 4H), 1.97–2.04 (m, 1H), 2.38–2.45 (m, 1H),
2.49–2.55 (m, 1H), 2.75 (dt, 1H, J1 = 10.0 Hz, J2 = 5.2 Hz),
3.20 (dd, 1H, J1 = 9.6 Hz, J2 = 16.0 Hz), 3.45 (dd, 1H, J1 = 4.4
Hz, J2 = 16.0 Hz), 3.75 (dt, 1H, J1 = 9.6 Hz, J2 = 4.0 Hz), 3.88
(s, 3H), 6.90 (d, 2H, J = 8.8 Hz), 7.14–7.17 (m, 3H), 7.23–7.26
(m, 3H), 7.92 (d, 2H, J = 8.8 Hz); 13C NMR (75 MHz, CDCl3)
δ (ppm) 24.03, 28.56, 32.40, 41.32, 42.28, 43.87, 55.43, 55.89,
113.60, 126.58, 128.38, 128.46, 130.47, 142.09, 163.28, 197.33,
213.76. HPLC analysis: Chiralpak AS-H column, i-PrOH–
hexane 40 : 60, flow rate 0.5 mL min−1, λ = 254 nm, retention
time: 16.87 min (minor) and 22.85 min (major), 85% ee.
(S)-3-((R)-1-(4-Chlorophenyl)-3-oxo-3-phenylpropyl)-tetra-
hydrothiopyran-4-one (7o).8 71% yield; syn/anti = 98 : 2 (by
1
1H NMR), H NMR (400 MHz, CDCl3) δ (ppm) 2.4 (dd, 1H,
J1 = 14.0 Hz, J2 = 7.5 Hz), 2.65–2.77 (m, 2H), 2.87–3.03
(m, 4H), 3.30 (d, 2H, J = 6.5 Hz), 4.08, (dd, 1H, J1 = 13.5 Hz,
J2 = 7.0 Hz), 7.19 (d, 2H, J = 8.0 Hz), 7.25 (d, 2H, J = 8.0 Hz),
7.42 (t, 2H, J = 7.5 Hz), 7.53 (d, 1H, J = 7.5 Hz), 7.86 (d, 2H,
J = 7.5 Hz); 13C NMR (75 MHz, CDCl3) δ (ppm) 31.38, 34.63,
39.71, 43.36, 43.69, 57.72, 128.04, 128.59, 129.01, 129.72,
132.79, 133.19, 136.69, 139.59, 197.73, 210.71. HPLC analysis:
Chiralpak AS-H column, i-PrOH–hexane 40 : 60, flow rate
0.5 mL min−1, λ = 254 nm, retention time: 20.70 min (minor)
and 30.78 min (major), 90% ee.
(S)-2-((R)-1-(4-Phenyl)-3-oxo-3-(4′-aminophenyl)-propyl)-cyclo-
1
1
hexanone (7l).9 67% yield; syn/anti = 99 : 1 (by H NMR), H
NMR (400 MHz, CDCl3) δ (ppm) 1.30–1.34 (m, 1H),
1.58–1.64 (m, 3H), 1.76–1.84 (m, 2H), 1.96–2.04 (m, 1H),
2.38–2.60 (m, 2H), 2.78 (dt, 1H, J1 = 10.1 Hz, J2 = 9.8 Hz, J3 =
4.8 Hz), 3.34 (dd, 1H, J1 = 15.9 Hz, J2 = 9.6 Hz), 3.63 (dd, 1H,
J1 = 16.0 Hz, J2 = 4.0 Hz), 3.79 (dt, 1H, J1 = 9.8 Hz, J2 =
9.8 Hz, J3 = 4.0 Hz), 7.18–7.23 (m, 3H), 7.50–7.60 (m, 2H),
7.81–7.84 (m, 2H), 7.92–7.97 (m, 2H), 8.5 (s, 1H); 13C NMR
(75 MHz, CDCl3) δ (ppm) 24.16, 28.63, 32.57, 41.42, 42.41,
44.38, 55.93, 124.03, 126.62, 127.72, 128.38, 128.53, 129.67,
129.98, 132.52, 134.29, 135.49, 141.97, 198.79, 213.86. HPLC
analysis: Chiralpak AD-H column, i-PrOH–hexane 10 : 90, flow
rate 1.0 mL min−1, λ = 254 nm, retention time: 23.59 min
(major) and 28.43 min (minor), 87% ee.
(S)-2-((R)-3-Oxo-1,3-diphenylpropyl)-4-methyl-cyclohexanone
1
1
(7p).10 46% yield; syn/anti = >99 : 1 (by H NMR); H NMR
(400 MHz, CDCl3) δ (ppm) 0.88 (d, 3H, J = 6.6 Hz), 1.25–1.35
(m, 1H), 1.40–1.54 (m, 2H), 2.00–2.09 (m, 1H), 2.11–2.21 (m,
1H), 2.63–2.74 (m, 2H), 3.19 (dd, 1H, J1 = 4.5 Hz, J2 = 17.4
Hz), 3.35 (dd, 1H, J1 = 8.4 Hz, J2 = 17.4 Hz), 3.82–3.90
(m, 1H), 7.16–7.31 (m, 5H), 7.35–7.40 (m, 2H), 7.47–7.52
(m, 1H), 7.83 (d, 2H, J = 7.2 Hz); 13C NMR (75 MHz, CDCl3)
δ (ppm) 20.75, 26.22, 35.32, 37.83, 38.85, 40.78, 43.91, 54.98,
126.82, 128.02, 128.11, 128.49, 128.71, 133.01, 136.90, 142.11,
198.27, 215.32. HPLC analysis: Chiralpak AD-H column,
i-PrOH–hexane 10 : 90, flow rate 1.0 mL min−1, λ = 254 nm,
retention time: 12.19 min (major) and 12.78 min (minor),
75% ee.
(S)-2-((R)-1-(2-Chlorophenyl)-3-(4-methoxyphenyl)-3-oxopropyl)-
cyclohexanone (7m).10 64% yield; syn/anti = >99 : 1 (by 1H
NMR), 1H NMR (400 MHz, CDCl3) δ (ppm) 1.29–1.39
(m, 1H), 1.57–1.85 (m, 4H), 2.01–2.06 (m, 1H), 2.36–2.44
(m, 1H), 2.48–2.54 (m, 1H), 2.89 (dt, 1H, J1 = 10.0 Hz, J2 = 4.8
Hz), 3.32 (dd, 1H, J1 = 10.0 Hz, J2 = 16.0 Hz), 3.84 (s, 3H),
3.54 (dd, 1H, J1 = 4.0 Hz, J2 = 16.4 Hz), 4.24 (dt, 1H, J1 = 9.6
Hz, J2 = 3.6 Hz), 6.90 (d, 2H, J = 8.8 Hz), 7.09 (t, 1H, J = 6.8
Hz), 7.18 (t, 1H, J = 7.2 Hz), 7.27–7.32 (m, 2H), 7.95 (d, 2H,
J = 8.8 Hz); 13C NMR (75 MHz, CDCl3) δ (ppm) 24.73, 28.69,
32.62, 42.60, 42.70, 55.42, 113.59, 126.98, 127.64, 129.85,
130.08, 130.53, 134.65, 139.65, 163.30, 197.15, 213.29. HPLC
analysis: Chiralpak OD-H column, i-PrOH–hexane 30 : 70, flow
rate 1.0 mL min−1, λ = 254 nm, retention time: 5.89 min (minor)
and 7.57 min (major), 92% ee.
(R)-3-((R)-3-Oxo-1,3-diphenylpropyl)-1-methylpiperidin-4-one
(7q).10 84% yield; syn/anti = 95 : 5 (by 1H NMR); 1H NMR
(400 MHz, CDCl3) δ (ppm) 2.04–2.14 (m, 1H), 2.20 (s, 3H),
2.34 (s, 1H), 2.37–2.47 (m, 1H), 2.58 (d, 2H, J = 14.2 Hz),
2.71–2.88 (m, 2H), 3.28 (dd, 2H, J1 = 16.5 Hz, J1 = 9.3 Hz),
3.48 (d, 1H, J = 14.3 Hz), 3.90 (s, 1H), 7.23 (dd, 3H, J1 = 14.4
Hz, J2 = 7.3 Hz), 7.40 (d, 2H, J = 7.4 Hz), 7.88 (d, 2H, J = 7.3
Hz); 13C NMR (75 MHz, CDCl3) δ (ppm) 39.68, 41.22, 43.98,
45.27, 55.19, 56.47, 59.66, 126.80, 128.09, 128.29, 128.47,
128.59, 132.86, 137.01, 141.67, 198.29, 211.08. HPLC analysis:
Chiralpak AD-H column, i-PrOH–hexane 20 : 80, flow rate
0.6 mL min−1, λ = 254 nm, retention time: 15.71 min (minor)
and 21.32 min (major), 67% ee.
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 3721–3729 | 3727

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(R)-3-((R)-3-Oxo-1,3-diphenylpropyl)-tetrahydropyran-4-one
(7r).10 81% yield; syn/anti = 97 : 3 (by 1H NMR); 1H NMR
(400 MHz, CDCl3) δ (ppm) 2.45–2.59 (m, 1H), 2.69–2.85
(m, 2H), 3.28–3.50 (m, 3H), 3.54–3.66 (m, 1H), 3.82–4.03
(m, 3H), 7.10–7.35 (m, 4H), 7.38–7.49 (m, 2H), 7.48–7.54
(m, 1H), 7.87 (d, 2H, J = 6.4 Hz); 13C NMR (75 MHz, CDCl3)
δ (ppm) 38.77, 42.40, 43.80, 57.15, 68.89, 71.16, 125.58,
127.05, 128.06, 128.21, 128.51, 128.78, 132.99, 136.92, 141.15,
198.04, 209.05. HPLC analysis: Chiralpak AD-H column,
i-PrOH–hexane 15 : 85, flow rate 0.7 mL min−1, λ = 254 nm,
retention time: 24.58 min (minor) and 27.30 min (major),
88% ee.
Acknowledgements
This work was financially supported by the Ph.D. Programs
Foundation of Ministry and Education of China (no.
20090031110019) and National Basic Research Program of
China (973 Program) (no. 2010CB833300). We also thank the
Nankai University State Key Laboratory of Elemento-Organic
Chemistry for support.
Notes and references
1 For books, see: P. Perlmutter, Conjugate Addition Reactions in Organic
Synthesis, Pergamon, Oxford, 1992.
2 For reviews, see: (a) S. Sulzer-Mosse and A. Alexakis, Chem. Commun.,
2007, 3123; (b) E. R. Jarvo and S. J. Miller, Tetrahedron, 2002, 58,
2481; (c) D. Enders, C. Wang and J. X. Liebich, Chem.–Eur. J., 2009,
15, 11058.
(S)-2-((R)-3-Oxo-1,3-diphenylpropyl)-cyclopentanone (7s).16
90% yield; syn/anti = 80 : 20 (by 1H NMR), 1H NMR
(400 MHz, CDCl3) δ (ppm) 1.51–1.60 (m, 1H), 1.65–1.75
(m, 1H), 1.87–1.90 (m, 2H), 2.06 (dd, 1H, J1 = 9.0 Hz, J2 =
18.6 Hz), 2.21–2.27 (m, 1H), 2.46 (dd, 1H, J1 = 8.7 Hz, J2 =
17.1 Hz), 3.36 (dd, 1H, J1 = 7.5 Hz, J2 = 16.8 Hz), 3.70 (dd,
1H, J1 = 7.5 Hz, J2 = 14.4 Hz), 3.87 (dd, 1H, J1 = 6.3 Hz, J2 =
16.5 Hz), 7.17–7.29 (m, 5H), 7.42 (t, 2H, J = 7.5 Hz), 7.53
(t, 1H, J = 7.2 Hz), 7.91 (d, 2H, J = 7.2 Hz); 13C NMR
(75 MHz, CDCl3) δ (ppm) 20.30, 27.94, 38.89, 40.83, 42.92,
52.95, 126.67, 128.09, 128.32, 128.44, 128.55, 132.99, 137.05,
142.51, 198.72, 220.09. HPLC analysis: Chiralpak AD-H
column, i-PrOH–hexane 50 : 50, flow rate 1.0 mL min−1, λ =
254 nm, retention time: 7.21 min (minor) and 9.67 min (major),
60% ee.
3 For selected examples of 1,3-dicarbonyls as Michael doners, see:
(a) H. Li, J. Song, X. Liu and L. Deng, J. Am. Chem. Soc., 2005, 127,
8948; (b) J. Wang, H. Li, L. Zu, W. Duan and W. Wang, J. Am. Chem.
Soc., 2006, 128, 12652; (c) H. Li, Y. Wang, L. Tang, F. Wu, X. Liu,
C. Guo, B. M. Foxman and L. Deng, Angew. Chem., 2005, 117, 107;
(d) H. Li, Y. Wang, L. Tang and L. Deng, J. Am. Chem. Soc., 2004, 126,
9906; (e) T. Okino, Y. Hoashi, T. Furukawa, X. Xu and Y. Takemoto,
J. Am. Chem. Soc., 2005, 127, 119; (f) Y. Takemoto, Org. Biomol.
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4 For selected examples of nitroalkanes as Michael donors, see:
(a) A. Prieto, N. Halland and K. A. Jøgensen, Org. Lett., 2005, 7, 3897;
(b) B. Vakulya, S. Varga, A. Csampai and T. Soö, Org. Lett., 2005, 7,
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3520.
5 For selected examples of dicyanomethane as Michael donors, see:
(a) P. Kotrusz, S. Toma, H.-G. Schmalz and A. Adler, Eur. J. Org.
Chem., 2004, 1577; (b) T. Kakinuma, R. Chiba and T. Oriyama, Chem.
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(a) W. Wang, J. Wang and H. Li, Angew. Chem., 2005, 117, 1393;
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Typical procedure for Michael reaction of 4-hydroxy coumarin
to benzylideneacetone
To a stirring solution of catalyst 2 (11 mg, 0.04 mmol) in CHCl3
(0.5 mL), benzylideneacetone 9 (22 mg, 0.15 mmol) was added
followed by 4-hydroxy coumarin 8 (16 mg, 0.1 mmol). The
mixture was stirred vigorously and monitored by TLC. When
the reaction was finished, the solvent was evaporated and the
crude product was purified by flash silica gel chromatography
(petroleum ether–EtOAc = 2 : 1) to afford the desired product 10
as a white solid.
1
Warfarin (10).17b 99% yield; H NMR (400 MHz, CDCl3) δ
(ppm) 1.69 (s, 1.58H), 1.73 (s, 1.73H), 2.03 (dd, 0.89H, J1 =
22.3 Hz, J2 = 10.8 Hz), 2.31 (s, 0.39 H), 2.49 (dt, 1.63 H, J1 =
21.2 Hz, J2 = 14.2 Hz, J3 = 5.1 Hz), 3.34 (d, 0.61, J = 16.5 Hz),
3.88 (dd, 0.17H, J1 = 19.4 Hz, J2 = 10.1 Hz), 4.16 (m, 0.77 H),
4.31 (m, 0.52 H), 4.73 (d, 0.14 H, J = 8.0 Hz), 7.18–7.40
(m, 7H), 7.51 (t, 0.68H, J = 7.7 Hz), 7.59 (t, 0.55H, J = 7.4 Hz),
7.83 (d, 0.56H, J = 8.2 Hz), 7.92 (d, 0.46H, J = 7.8 Hz), 7.96
(d, 0.16H, J = 8.1 Hz); 13C NMR (75 MHz, CDCl3) δ (ppm)
27.72, 28.20, 30.10, 34.20, 34.85, 35.35, 40.00, 42.55, 45.17,
99.01, 100.53, 101.15, 104.19, 115.56, 115.89, 116.21, 116.52,
116.67, 122.73, 123.08, 123.64, 123.96, 126.51, 126.98, 127.05,
127.23, 127.99, 128.19, 128.64, 129.24, 131.57, 132.04, 141.45,
143.22, 152.90, 152.99, 158.82, 159.71, 161.33, 162.19. HPLC
analysis: Chiralpak AD-H column, i-PrOH–hexane 20 : 80, flow
rate 1.0 mL min−1, λ = 254 nm, retention time: 5.27 min (major)
and 13.67 min (minor), 34% ee.
3728 | Org. Biomol. Chem., 2012, 10, 3721–3729
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7 For selected examples of sulfones as Michael acceptors, see: (a) H. Li,
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Chem. Soc., 2006, 128, 4966; (e) A. Quintard, C. Bournaud and
A. Alexakis, Chem.–Eur. J., 2008, 14, 7504.
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X.-K. Chen and G. Zhao, Chem. Commun., 2010, 46, 4130;
(b) K. Ishihara and K. Nakano, J. Am. Chem. Soc., 2005, 127, 10504.
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This journal is © The Royal Society of Chemistry 2012
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