Enantioselective asymmetric michael addition of cyclic diketones to β,γ-unsaturated α-keto esters

Article abstract of DOI:10.1002/ejoc.201200179

An efficient, organocatalytic enantioselective addition of cyclic diketones with β,γ-unsaturated α-keto esters has been developed that affords products in high yields (up to 95%) and excellent enantioselectivity (up to >99ee) under mild conditions with a

Full text of DOI:10.1002/ejoc.201200179

FULL PAPER
DOI: 10.1002/ejoc.201200179
Enantioselective Asymmetric Michael Addition of Cyclic Diketones to β,γ-
Unsaturated α-Keto Esters
Yi-Feng Wang,[a] Ke Wang,[a] Wei Zhang,[a] Bin-Bin Zhang,[a] Chi-Xiao Zhang,[a] and
Dan-Qian Xu*[a]
Keywords: Asymmetric catalysis / Organocatalysis / Hydrogen bonds / Michael addition
An efficient, organocatalytic enantioselective addition of cy-
clic diketones with β,γ-unsaturated α-keto esters has been
developed that affords products in high yields (up to 95%)
and excellent enantioselectivity (up to Ͼ99%ee) under mild
conditions with a low catalyst loading (2.5 mol-%). The un-
saturated α-keto esters are effectively coordinated and acti-
vated through hydrogen bonds with the squaramides and
proved to be excellent hydrogen-bond acceptors in this
asymmetric organocatalytic reaction. This reaction provides
valuable and easy access to chiral Michael adducts, which
are important moieties in the skeletons of biological and
pharmaceutical molecules.
applications in medicinal chemistry,[8] including prospective
antihyperglycemic activity, calcium channel activity, bron-
chodilators, antiatherosclerotics, antidiabetic, and so on.
Introduction
The organocatalytic Michael reaction is often regarded
as one of the most efficient and broadly applicable carbon–
carbon bond-forming reactions, because a wide variety of
acceptors and donors can be employed and high stereose-
lectivity has been realized.[1] The organocatalytic Michael
addition of cyclic 1,3-dicarbonyl compounds to α,β-unsatu-
rated carbonyl compounds[2] has aroused great interest be-
cause of it offers an extremely effective way to synthesize a
variety of useful chiral functionalized organic molecules
that may have biological and pharmaceutical activities.[3] In
particular, Jørgensen et al., Feng et al., Calter et al., and
Yan et al. have reported high enantioselectivities for reac-
tions of β,γ-unsaturated α-keto esters as Michael acceptors
by using either chiral copper(II) complex catalysts[4] or or-
ganocatalysts,[5] but nevertheless, the development of new
efficient catalytic systems are still in demand.
Recently, we described for the first time the development
of a general and practical organocatalytic enantioselective
Michael addition of 4-hydroxycoumarins and 4-hydroxy-
pyrone with β,γ-unsaturated α-keto esters.[6] This reaction
catalyzed by easily prepared tertiary amine-squaramides[7]
provided chiral coumarins and pyrones in good yields with
excellent enantioselectivities. Additionally, we were able to
extend this procedure to the catalytic enantioselective reac-
tion of 1,3-cyclohexanedione and dimedone with β,γ-unsat-
urated α-keto esters, whose corresponding adducts can be
modified readily to hexahydroquinolines, which have wide
Results and Discussion
On the basis of our previous strategy and our interest in
the development of organocatalytic reactions, the reaction
of 1,3-cyclohexanedione (1) with β,γ-unsaturated α-keto es-
ter 2a was chosen as a model reaction to screen the catalysts
(Table 1). We found that squaramide catalysts I (Figure 1),
which were used in our previous work, also showed good
efficiency in this reaction (Table 1, Entries 1–4). Similarly,
the reaction exhibited moderate performance with thiourea
catalysts II because of the lack of the characteristic H-
bonding activation and the orientation of the α-keto esters
(Table 1, Entries 5–9). Catalyst III, which was highly effec-
tive in the reported dynamic kinetic resolution of racemic
azlactones,[7d] did not function well for the present transfor-
mation (Table 1, Entries 10 and 11). With further studies of
other chiral moieties, including (R,R)-1,2-diaminocyclohex-
ane and (R,R)-1,2-diphenylethylenediamine (Table 1, En-
tries 12–17), we were delighted to find that excellent yields
and enantioselectivities were obtained in shorter times when
catalysts possessing the (R,R)-1,2-diphenylethylenediamine
unit were employed. Evaluation of the effects of other parts
of the squaramide catalyst showed that catalyst Vc contain-
ing a bis(trifluoromethyl)phenyl group was most effective
(Table 1, Entry 17). Further exploration of the potential of
Vc revealed that no noticeable impact on the efficiency
could be observed when lowering the catalyst loading to
2.5 mol-% (Table 1, Entries 18 and 19), whereas a slightly
decreased yield and enantioselectivity were obtained when
1 mol-% of Vc was used (Table 1, Entry 20).
[a] Catalytic Hydrogenation Research Center,
Zhejiang University of Technology
Hangzhou 310014, China
Fax: +86-571-88320066
E-mail: chrc@zjut.edu.cn
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201200179.
Eur. J. Org. Chem. 2012, 3691–3696
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3691

Y.-F. Wang, K. Wang, W. Zhang, B.-B. Zhang, C.-X. Zhang, D.-Q. Xu
FULL PAPER
Figure 1. Organocatalysts tested in this study.
Table 1. Evaluation of catalysts with the model reaction.[a]
H-bonding catalytic process (Table 2, Entries 1 and 2). Gen-
erally, better results in terms of enantioselectivity were ob-
tained with similarly high yields in non-polar solvents
(Table 2, Entries 3–10). Specifically, when the process was
carried out in CHCl3, the reaction afforded the most en-
couraging results (93% yield, 98%ee; Table 2, Entry 5).
However, relatively poor results were observed with the po-
lar solvent CH3CN (Table 2, Entry 11). This is expected be-
cause non-polar, aprotic solvents can minimize the disrup-
tion of hydrogen-bonding interactions between the catalyst
and the substrates; thus, high catalytic activity and stereose-
lectivity towards the reaction are generally observed.
With the optimal reaction conditions in hand (Table 2,
Entry 5), subsequently we explored the generality of this
reaction with a spectrum of β,γ-unsaturated α-keto esters
(Table 3). It was discovered that all the reactions with β,γ-
unsaturated α-keto esters bearing an γ-aryl substituent were
complete within 12 h with good to high yields (75–93%)
and excellent enantioselectivities (93–98%ee), irrespective
of the electronic nature or position of the substituents on
the phenyl ring. Besides, the reaction also took place with
a naphthalen-2-yl or heteroaromatic substituents with excel-
lent yields and enantioselectivities (Table 3, Entries 11 and
12).
Entry
Catalyst Catalyst loading
[mol-%]
T
[h]
Yield
[%][b]
ee[c]
[%]
1
2
3
4
5
6
7
8
Ia
Ib
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
5
1
1
1
1
1
1
1
1
1
87
86
89
90
85
82
81
82
84
83
84
91
93
92
93
92
93
93
92
90
–89
–93
–95
–95
–86
–79
–78
–80
–81
–75
–61
86
88
90
92
94
96
96
95
92
Ic
Id
IIa
IIb
IIc
IId
IIe
IIIa
IIIb
IVa
IVb
IVc
Va
9
10
11
12
13
14
15
16
17
18
19
20
1
1
0.5
0.5
0.5
0.5
0.5
0.5
1
Vb
Vc
Vc
Vc
Vc
To explore further the potential of this addition process,
the reaction of dimedone (4) with various β,γ-unsaturated
α-keto esters 2 was also investigated (Table 4). The yields
and enantioselectivities of these reactions are even higher
compared with those obtained for the reaction between 1,3-
cyclohexanedione and β,γ-unsaturated α-keto esters. It is
noteworthy that substrates with an alkyl group also pro-
vided the desired products in good yields with good to high
enantioselectivities (Table 4, Entries 9–11). As shown in
2.5
1
3
12
[a] Unless otherwise specified, all reactions were carried out with
1,3-cyclohexanedione (1, 0.125 mmol), β,γ-unsaturated α-keto ester
2a (0.125 mmol) in CH2Cl2 (1.0 mL) at room temperature. [b] Iso-
lated yield. [c] Determined by chiral HPLC analysis (Daicel Chi-
ralcel AD-H, hexane/iPrOH = 70:30, 0.7 mL/min). A minus sign
before the ee value signifies the opposite enantiomer.
Subsequently, a survey of solvents showed that protic sol- Schemes 1 and 2, this catalytic system is also suitable for
vents such as CH3OH and iPrOH are not suitable for this other cyclic 1,3-diketones, such as 4-hydroxycoumarin, 4-
3692
www.eurjoc.org
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2012, 3691–3696

Michael Additions of Cyclic Diketones to β,γ-Unsaturated α-Keto Esters
Table 2. Screening of the solvents for the organocatalytic enantiose- merically enriched Michael adducts obtained by this
lective Michael reaction by using catalyst Vc.[a]
method can be easily converted into hexahydroquinoline 9
without any loss in optical activity[5a] (Scheme 3).
Table 4. Substrate scope of the enantioselective Michael addition
of dimedone with β,γ-unsaturated α-keto esters.[a]
Entry
Solvent
Yield[b] [%]
ee[c] [%]
1
2
3
4
5
6
7
8
CH3OH
iPrOH
CH2Cl2
CH2Cl/CH2Cl
CHCl3
45
55
92
88
93
84
82
80
77
85
67
18
58
95
95
98
95
94
78
89
93
85
Entry
R
T
[h]
Adduct 5 Yield[b]
ee[c]
[%]
[%]
1
2
3
4
5
6
7
8
Ph
4-MeOC6H4
4-ClC6H4
4-CF3C6H4
3-BrC6H4
2,4-Cl2C6H3
naphthalen-2-yl
thiophen-2-yl
ethyl
2
12
3
4
6
6
12
6
12
12
12
5a
5b
5c
5d
5e
5f
95
86
92
94
83
89
85
88
78
82
75
99
95
99
99
98
98
95
97
Et2O
iPr2O
THF
dioxane
toluene
CH3CN
9
10
11
5g
5h
5i
9
10
11
98[d]
[a] Unless otherwise specified, all reactions were carried out with
1,3-cyclohexanedione (1, 0.125 mmol), β,γ-unsaturated α-keto ester
2a (0.125 mmol), catalyst Vc (3.125ϫ10–3 mmol, 2.5 mol-%) in sol-
vent (1.0 mL) at room temperature for 3 h. [b] Isolated yield.
[c] Determined by chiral HPLC analysis (Daicel Chiralcel AD-H,
hexane/iPrOH = 70:30, 0.7 mL/min).
propyl
butyl
5j
5k
97[d]
79[d]
[a] Unless otherwise specified, all reactions were carried out with
dimedone (4, 0.125 mmol), β,γ-unsaturated α-keto ester
2
(0.125 mmol), catalyst Vc (3.125ϫ10–3 mmol, 2.5 mol-%) in
CH3Cl (1.0 mL) at room temperature. [b] Isolated yield. [c] Deter-
mined by chiral HPLC analysis (Daicel Chiralcel AD-H, hexane/
iPrOH = 70:30). [d] Determined by HPLC analysis of the derived
hexahydroquinoline (Daicel Chiralcel OD-H, hexane/iPrOH =
95:5).
Table 3. Substrate scope of the enantioselective Michael addition
of 1,3-cyclohexanedione with β,γ-unsaturated α-keto esters.[a]
Entry
R
T
[h]
Adduct 3 Yield[b]
ee[c]
[%]
[%]
1
2
3
4
5
6
7
8
Ph
3
12
12
6
6
6
9
9
9
9
3a
3b
3c
3d
3e
3f
3g
3h
3i
93
75
82
91
87
92
79
82
81
86
84
87
98
95
98
97
96
96
93
95
96
96
93
98
4-MeC6H4
4-MeOC6H4
4-ClC6H4
4-BrC6H4
4-CF3C6H4
4-NO2C6H4
2-ClC6H4
9
3-BrC6H4
10
11
12
2,4-Cl2C6H3
naphthalen-2-yl
thiophen-2-yl
3j
3k
3l
12
12
Scheme 1. 4-Hydroxycoumarin or 4-hydroxy-6-methyl-2-pyrone as
Michael donors.
[a] Unless otherwise specified, all reactions were carried out with
1,3-cyclohexanedione (1, 0.125 mmol), β,γ-unsaturated α-keto ester
2 (0.125 mmol), catalyst Vc (3.125ϫ10–3 mmol, 2.5 mol-%) in
CHCl3 (1.0 mL) at room temperature. [b] Isolated yield. [c] Deter-
mined by chiral HPLC analysis (Daicel Chiralcel AD-H, hexane/
iPrOH = 70:30).
hydroxypyrone, and 2-hydroxy-1,4-naphthoquinone, which
afforded the Michael adducts in high yields and enantio-
selectivities. We also tried acyclic 1,3-diketones as Michael
donors, such as acetylacetone and diethyl malonate; how-
Scheme 2. 2-Hydroxy-1,4-naphthoquinone as Michael donor.
On the basis of previous mechanistic proposals and the
ever, we did not observe a significant conversion even by experimental results described above, a possible transition-
prolonging the reaction time. Besides, the highly enantio- state model was hypothesized (Figure 2). The β,γ-unsatu-
Eur. J. Org. Chem. 2012, 3691–3696
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3693

Y.-F. Wang, K. Wang, W. Zhang, B.-B. Zhang, C.-X. Zhang, D.-Q. Xu
FULL PAPER
thesized according to reported procedures. Commercially available
cyclic diketones and solvents were used without further purification
or drying. All reactions were carried out in oven-dried glassware.
Representative Procedure for the Asymmetric Michael Addition of
Cyclic Diketones to β,γ-Unsaturated α-Keto Esters: To a solution
of catalyst Vc (0.003125 mmol, 2.5 mol-%) in CHCl3 (1.0 mL) was
added 1,3-cyclohexanedione (1, 0.125 mmol) and β,γ-unsaturated
α-keto ester 2a (0.125 mmol). The reaction mixture was then stirred
at room temperature for 3 h (monitored by TLC). The crude mix-
ture was purified by column chromatography (silica gel; petroleum
ether/EtOAc, 5:1 to 2:1) to give desired product 3a in 93% yield,
98%ee, which was found to exist in equilibrium between the cyclic
and linear anomers. This equilibration proceeded slowly enough
Scheme 3. Conversion of 5j into hexahydroquinoline 9.
rated α-keto ester is fixed and activated by the squaramide
moiety through the formation of two characteristic hydro-
gen bonds between the NH groups and the α-keto ester
group. Direct approach of the deprotonated cyclic di-
ketones from the Si face to the β,γ-unsaturated α-keto esters
would justify the observed stereochemistry of the products.
1
that they showed up as separate compounds by H and 13C NMR
spectroscopy, but quickly enough that they did not resolve by
chromatography. 1H NMR (500 MHz, CDCl3, 25 °C, TMS): δ =
1.29 (t, J = 7.13 Hz, 2.00 H), 1.33 (t, J = 7.13 Hz, 1.00 H), 1.98–
2.11 (m, 2.00 H), 2.22–2.64 (m, 6.00 H), 3.90 (t, J = 9.15 Hz, 0.66
H), 4.11 (d, J = 6.92 Hz, 0.36 H), 4.17–4.32 (m, 2.26 H), 4.56 (s,
0.59 H), 7.15–7.19 (m, 3.00 H), 7.24–7.29 (m, 2.00 H) ppm. 13C
NMR (125 MHz, CDCl3, 25 °C, TMS): δ = 13.85, 13.94, 20.12,
20.62, 28.73, 28.85, 31.82, 33.27, 35.86, 36.87, 36.92, 38.25, 62.98,
63.09, 94.69, 95.64, 113.16, 115.31, 126.05, 126.16, 126.89, 127.16,
128.19, 128.34, 142.83, 144.06, 168.81, 168.89, 168.95, 169.49,
196.44, 196.97 ppm. HPLC (Chiralcel AD-H column, hexane/
iPrOH = 70:30, flow rate = 0.7 mL/min): tR = 10.1 (major), 8.1
(minor) min.
(S)-Ethyl
2-Hydroxy-5-oxo-4-p-tolyl-3,4,5,6,7,8-hexahydro-2H-
chromene-2-carboxylate (3b): 1H NMR (500 MHz, CDCl3, 25 °C,
TMS): δ = 1.28 (t, J = 7.12 Hz, 1.90 H), 1.32 (t, J = 7.13 Hz, 1.09
H), 1.95–2.26 (m, 4.00 H), 2.28 (s, 1.10 H), 2.29 (s, 1.88 H), 2.33–
2.62 (m, 4.00 H), 3.86 (t, J = 9.24 Hz, 0.64 H), 4.07 (d, J = 7.07 Hz,
0.36 H), 4.19–4.46 (m, 3.00 H), 7.06–7.08 (m, 4.00 H) ppm. 13C
NMR (125 MHz, CDCl3, 25 °C, TMS): δ = 13.83, 13.93, 20.10,
20.61, 20.97, 28.73, 28.86, 31.42, 32.84, 35.92, 36.87, 36.89, 38.34,
Figure 2. Proposed transition-state model.
Conclusions
In summary, tertiary amine–squaramide organocatalysts
were found to promote the highly enantioselective Michael 62.95, 63.07, 94.73, 95.72, 113.32, 115.53, 126.76, 127.00, 129.01,
129.07, 135.44, 135.63, 139.70, 141.02, 168.81, 168.85, 169.02,
169.48, 196.65, 197.14 ppm. HPLC (Chiralcel AD-H column, hex-
ane/iPrOH = 85:15, flow rate = 0.7 mL/min): tR = 18.4 (major),
15.4 (minor) min.
addition of cyclic diketones to β,γ-unsaturated α-keto es-
ters. With this procedure, the desired Michael products
could be obtained in good to high yields (75–95%) with
excellent enantioselectivities (up to Ͼ99%ee) under mild
conditions with a low catalyst loading (2.5 mol-%). Com-
pared with Calter’s procedure,[5a] even higher yields and
enantioselectivities can be achieved with a reduced catalyst
loading (2.5 vs. 10 mol-%) in a shorter reaction time. Stud-
ies aimed at investigating the application of the products
and expanding the scope and applications of chiral squar-
amides in organocatalysis are underway in our laboratory.
(S)-Ethyl 2-Hydroxy-4-(4-methoxyphenyl)-5-oxo-3,4,5,6,7,8-hexahy-
1
dro-2H-chromene-2-carboxylate (3c): H NMR (500 MHz, CDCl3,
25 °C, TMS): δ = 1.29 (t, J = 7.17 Hz, 1.90 H), 1.33 (t, J = 7.13 Hz,
1.09 H), 1.97–2.11 (m, 2.00 H), 2.20–2.62 (m, 6.00 H), 3.75 (s, 1.11
H), 3.77 (s, 1.87 H), 3.86 (t, J = 9.13 Hz, 0.64 H), 4.07 (d, J =
6.92 Hz, 0.37 H), 4.18–4.32 (m, 2.38 H), 4.50 (s, 0.61 H), 6.79–
6.82 (m, 2.00 H), 7.08–7.11 (m, 2.00 H) ppm. 13C NMR (125 MHz,
CDCl3, 25 °C, TMS): δ = 13.87, 13.94, 20.14, 20.65, 28.74, 28.87,
30.93, 32.46, 35.83, 36.96, 36.99, 38.35, 55.12, 55.16, 62.95, 63.08,
94.73, 95.67, 113.40, 113.74, 113.83, 115.61, 127.85, 128.15, 134.75,
136.09, 157.83, 157.93, 168.56, 168.81, 168.99, 169.20, 196.36,
196.87 ppm. HPLC (Chiralcel AD-H column, hexane/iPrOH =
Experimental Section
1
General Methods: H and 13C NMR were recorded in CDCl3 with
70:30, flow rate
(minor) min.
= 0.7 mL/min): tR = 15.2 (major), 10.8
a Bruker Avance III (500 MHz for 1H NMR and 126 MHz for 13
C
NMR). TMS served as an internal standard (δ = 0 ppm) for 1H
NMR and CDCl3 was used as internal standard (δ = 77.0 ppm) for
13C NMR. HPLC experiments were carried out with a JASCO LC-
2000 Plus system with MD-2010 HPLC diode array detector. Flash
chromatography (FC) was carried out with silica gel (200–
300 mesh). Monitoring of reactions was performed by TLC on sil-
ica gel precoated on glass plates, and spots were visualized with
UV light at 254 nm. Catalyst II;[9] catalysts I, III, IV, and V;[7a,7h]
and γ-aryl[10] and alkyl[11] β,γ-unsaturated α-keto esters 2 were syn-
(S)-Ethyl 4-(4-Chlorophenyl)-2-hydroxy-5-oxo-3,4,5,6,7,8-hexahy-
1
dro-2H-chromene-2-carboxylate (3d): H NMR (500 MHz, CDCl3,
25 °C, TMS): δ = 1.29–1.35 (m, 3.00 H), 1.97–2.61 (m, 8.00 H),
3.85–3.88 (m, 0.66 H), 4.05 (d, J = 7.24 Hz, 0.35 H), 4.22–4.34 (m,
2.00 H), 4.34 (s, 0.29 H), 4.57 (s, 0.62 H), 7.09–7.13 (m, 2.00 H),
7.19–7.25 (m, 2.00 H) ppm. 13C NMR (125 MHz, CDCl3, 25 °C,
TMS): δ = 13.88, 13.94, 20.06, 20.61, 28.72, 28.85, 31.32, 32.83,
35.39, 36.85, 36.91, 38.05, 63.18, 63.26, 94.54, 95.35, 112.85,
3694
www.eurjoc.org
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2012, 3691–3696

Michael Additions of Cyclic Diketones to β,γ-Unsaturated α-Keto Esters
115.05, 128.15, 128.26, 128.51, 128.73, 131.62, 141.62, 142.74,
168.80, 168.84, 169.09, 169.58, 196.33, 196.90 ppm. HPLC (Chi-
ralcel AD-H column, hexane/iPrOH = 70:30, flow rate = 0.7 mL/
min): tR = 12.5 (major), 9.4 (minor) min.
(s, 1.10 H), 1.17 (s, 1.90 H), 1.20 (s, 1.10 H), 1.30 (t, J =
7.18 Hz,1.90 H), 1.34 (t, J = 7.16 Hz, 1.10 H), 2.16–2.62 (m, 6.00
H), 3.92–3.96 (m, 0.63 H), 4.12 (d, J = 6.96 Hz, 0.37 H), 4.21–4.33
(m, 2.00 H), 4.35 (s, 0.40 H), 4.56 (s, 0.60 H), 7.27–7.29 (m, 2.00
H), 7.48–7.54 (m, 2.00 H) ppm. 13C NMR (125 MHz, CDCl3,
25 °C, TMS): δ = 13.87, 13.95, 27.62, 28.23, 28.75, 29.25, 31.68,
32.02, 32.07, 33.46, 35.34, 37.92, 42.41, 42.46, 50.74, 50.76, 63.25,
63.30, 94.64, 95.39, 111.48, 113.41, 124.97, 125.00, 125.39, 125.42,
127.34, 127.83, 128.19, 128.45, 147.52, 148.56, 167.54, 168.00,
168.70, 168.78, 196.17, 196.71 ppm. HPLC (Chiralcel AD-H col-
umn, hexane/iPrOH = 70:30, flow rate = 0.7 mL/min): tR = 11.4
(major), 6.9 (minor) min.
(S)-Ethyl 4-(4-Bromophenyl)-2-hydroxy-5-oxo-3,4,5,6,7,8-hexahy-
1
dro-2H-chromene-2-carboxylate (3e): H NMR (500 MHz, CDCl3,
25 °C, TMS): δ = 1.29–1.34 (m, 3.00 H), 1.97–2.61 (m, 8.00 H),
3.83–3.87 (m, 0.66 H), 4.03 (d, J = 6.97 Hz, 0.34 H), 4.21–4.32 (m,
2.00 H), 4.37 (s, 0.37 H), 4.60 (s, 0.62 H), 7.03–7.08 (m, 2.00 H),
7.34–7.39 (m, 2.00 H) ppm. 13C NMR (125 MHz, CDCl3, 25 °C,
TMS): δ = 13.86, 13.93, 20.06, 20.58, 28.71, 28.84, 31.50, 32.90,
35.45, 36.82, 36.88, 38.01, 63.13, 63.20, 94.57, 95.40, 112.83,
114.93, 119.65, 119.71, 128.68, 129.15, 131.05, 131.42, 142.22,
143.26, 168.76, 168.80, 169.18, 169.66, 196.35, 196.90 ppm. HPLC
(Chiralcel AD-H column, hexane/iPrOH = 70:30, flow rate =
0.7 mL/min): tR = 13.2 (major), 9.8 (minor) min.
(S)-Ethyl
4-(3-Bromophenyl)-2-hydroxy-7,7-dimethyl-5-oxo-
3,4,5,6,7,8-hexahydro-2H-chromene-2-carboxylate (5e): 1H NMR
(500 MHz, CDCl3, 25 °C, TMS): δ = 1.09 (s, 1.89 H), 1.11 (s, 1.09
H), 1.17 (s, 1.91 H), 1.20 (s, 1.09 H), 1.29–1.35 (m, 3 H), 2.16–2.58
(m, 6.00 H), 3.85 (t, J = 9.07 Hz, 0.64 H), 4.04 (d, J = 7.28 Hz,
0.37 H), 4.20–4.33 (m, 2.00 H), 4.37 (s, 0.34 H), 4.58 (s, 0.57 H),
7.10–7.16 (m, 2.00 H), 7.27–7.30 (m, 2.00 H) ppm. 13C NMR
(125 MHz, CDCl3, 25 °C, TMS): δ = 13.90, 13.96, 27.66, 28.22,
28.75, 29.20, 31.70, 31.84, 32.05, 33.23, 35.51, 37.98, 42.38, 42.44,
50.75, 63.16, 63.23, 94.72, 95.49, 111.51, 113.39, 122.14, 122.40,
125.91, 126.14, 129.13, 129.18, 129.54, 129.92, 130.00, 130.68,
145.72, 146.67, 167.43, 167.91, 168.74, 168.77, 196.17, 196.66 ppm.
HPLC (Chiralcel AD-H column, hexane/iPrOH = 70:30, flow rate
= 0.7 mL/min): tR = 11.1 (major), 7.8 (minor) min.
(S)-Ethyl 2-Hydroxy-7,7-dimethyl-5-oxo-4-phenyl-3,4,5,6,7,8-hexa-
hydro-2H-chromene-2-carboxylate (5a): 1H NMR (500 MHz,
CDCl3, 25 °C, TMS): δ = 1.09 (s, 1.94 H), 1.11 (s, 1.06 H), 1.17 (s,
1.95 H), 1.20 (s, 1.05 H), 1.28 (t, J = 7.13 Hz,1.96 H), 1.33 (t, J =
7.12 Hz, 1.04 H), 2.21–2.59 (m, 6.00 H), 3.89 (t, J = 9.02 Hz, 0.65
H), 4.09 (d, J = 6.81 Hz, 0.37 H), 4.15–4.32 (m, 2.38 H), 4.53 (s,
0.57 H), 7.15–7.18 (m, 2.00 H), 7.24–7.29 (m, 2.00 H) ppm. 13C
NMR (125 MHz, CDCl3, 25 °C, TMS): δ = 13.86, 13.94, 27.61,
28.22, 28.74, 29.25, 31.67, 32.01, 32.06, 33.46, 35.33, 37.91, 42.40,
42.45, 50.73, 63.25, 63.30, 94.64, 95.39, 111.47, 113.41, 124.97,
125.00, 125.39, 127.33, 127.82, 128.19, 128.45, 147.52, 148.56,
167.54, 168.00, 168.70, 168.77, 196.17, 196.71 ppm. HPLC (Chi-
ralcel AD-H column, hexane/iPrOH = 70:30, flow rate = 0.7 mL/
min): tR = 10.2 (major), 7.5 (minor) min.
Supporting Information (see footnote on the first page of this arti-
cle): Additional characterization data and copies of the NMR spec-
tra of the Michael adducts.
(S)-Ethyl
2-Hydroxy-4-(4-methoxyphenyl)-7,7-dimethyl-5-oxo-
Acknowledgments
3,4,5,6,7,8-hexahydro-2H-chromene-2-carboxylate (5b): 1H NMR
(500 MHz, CDCl3, 25 °C, TMS): δ = 1.08 (s, 1.85 H), 1.11 (s, 1.15
H), 1.16 (s, 1.85 H), 1.19 (s, 1.15 H), 1.28 (t, J = 7.13 Hz, 1.85 H),
1.32 (t, J = 7.12 Hz,1.15 H), 2.20–2.56 (m, 6.00 H), 3.75 (s, 1.14
H), 3.76 (s, 1.85 H), 3.83–3.87 (m, 0.62 H), 4.05 (d, J = 6.73 Hz,
0.39 H), 4.16–4.32 (m, 2.39 H), 4.50 (s, 0.57 H), 6.79–6.82 (m, 2.00
H), 7.08–7.10 (m, 2.00 H) ppm. 13C NMR (125 MHz, CDCl3,
25 °C, TMS): δ = 13.85, 13.94, 27.67, 28.29, 28.70, 29.22, 31.20,
31.61, 31.98, 32.52, 36.00, 38.30, 42.40, 42.45, 50.84, 55.11, 55.14,
62.94, 63.02, 94.91, 95.80, 112.27, 113.72, 113.81, 114.12, 127.98,
128.24, 134.96, 136.06, 157.79, 157.90, 166.88, 167.48, 168.80,
168.92, 196.37, 196.78 ppm. HPLC (Chiralcel AD-H column, hex-
ane/iPrOH = 70:30, flow rate = 0.7 mL/min): tR = 15.4 (major),
9.3 (minor) min.
This work was supported by the Zhejiang Provincial Natural Sci-
ence Foundation of China (No. Y4110373) and the Foundation of
Zhejiang Education Committee (No. Y201018458).
[1] For recent reviews on asymmetric organocatalytic Michael re-
actions, see: a) S. Sulzer-Mossé, A. Alexakis, Chem. Commun.
2007, 3123–3135; b) S. B. Tsogoeva, Eur. J. Org. Chem. 2007,
1701–1716; c) J. L. Vicario, D. Badia, L. Carrillo, Synthesis
2007, 2065–2092; d) D. Almasi, D. A. Alonso, C. Nájera, Tetra-
hedron: Asymmetry 2007, 18, 299–365; e) H. Pellissier, Tetrahe-
dron 2007, 63, 9267–9331.
[2] For selected examples of the organocatalytic Michael addition
to α,β-unsaturated aldehydes and ketones, see: a) M. Rueping,
E. Sugiono, E. Merino, Angew. Chem. 2008, 120, 3089; Angew.
Chem. Int. Ed. 2008, 47, 3046–3049; b) M. Rueping, E. Su-
giono, E. Merino, Chem. Eur. J. 2008, 14, 6329–6332; c) M.
Rueping, E. Merino, E. Sugiono, Adv. Synth. Catal. 2008, 350,
2127–2131; d) N. Halland, T. Hansen, K. A. Jørgensen, Angew.
Chem. 2003, 115, 5105; Angew. Chem. Int. Ed. 2003, 42, 4955–
4957; e) J. W. Xie, L. Yue, W. Chen, W. Du, J. Zhu, J. G. Deng,
Y. C. Chen, Org. Lett. 2007, 9, 413–415; f) H. Kim, C. Yen, P.
Preston, J. Chin, Org. Lett. 2006, 8, 5239–5242; g) T. E. Kris-
tensen, K. Vestli, F. K. Hansen, T. Hansen, Eur. J. Org. Chem.
2009, 5185–5191; h) Z. H. Dong, L. J. Wang, X. H. Chen,
X. H. Liu, L. L. Lin, X. M. Feng, Eur. J. Org. Chem. 2009,
5192–5197; i) G. C. Zhang, Y. F. Wang, W. Zhang, X. S. Xu,
A. G. Zhong, D. Q. Xu, Eur. J. Org. Chem. 2011, 2142–2147.
[3] For biological and pharmaceutical activities see, for example:
a) R. D. H. Murray, J. Medez, S. A. Brown, The Natural Cou-
marins: Occurrence, Chemistry and Biochemistry, Wiley, New
York, 1982; b) K. Rehse, W. Schinkel, Arch. Pharm. 1983, 316,
pp. 988–994; c) I. Manolov, N. D. Danchev, Eur. J. Med. Chem.
1995, 30, 531–535; d) I. Manolov, N. D. Danchev, Eur. J. Med.
(S)-Ethyl
4-(4-Chlorophenyl)-2-hydroxy-7,7-dimethyl-5-oxo-
3,4,5,6,7,8-hexahydro-2H-chromene-2-carboxylate (5c): 1H NMR
(500 MHz, CDCl3, 25 °C, TMS): δ = 1.09 (s, 1.89 H), 1.11 (s, 1.10
H), 1.16 (s, 1.89 H), 1.18 (s, 1.11 H), 1.29–1.35 (m, 3 H), 2.15–2.58
(m, 6.00 H), 3.84–3.88 (m, 0.66 H), 4.04 (d, J = 6.21 Hz, 0.36 H),
4.20–4.33 (m, 2.00 H), 4.35 (s, 0.33 H), 4.55 (s, 0.59 H), 7.09–7.12
(m, 2.00 H), 7.20–7.24 (m, 2.00 H) ppm. 13C NMR (125 MHz,
CDCl3, 25 °C, TMS): δ = 13.88. 13.96, 27.68, 28.25, 28.74, 29.20,
31.67, 31.69, 32.02, 32.98, 35.68, 38.08, 42.45, 42.51, 50.85, 63.13,
63.19, 94.77, 95.55, 111.88, 113.73, 128.20, 128.43, 128.53, 128.86,
131.68, 131.70, 141.85, 142.80, 167.21, 167.72, 168.78, 168.84,
196.14, 196.60 ppm. HPLC (Chiralcel AD-H column, hexane/
iPrOH = 70:30, flow rate = 0.7 mL/min): tR = 14.1 (major), 7.7
(minor) min.
(S)-Ethyl
2-Hydroxy-7,7-dimethyl-5-oxo-4-[4-(trifluoromethyl)-
phenyl]-3,4,5,6,7,8-hexahydro-2H-chromene-2-carboxylate (5d): 1H
NMR (500 MHz, CDCl3, 25 °C, TMS): δ = 1.10 (s, 1.90 H), 1.12
Eur. J. Org. Chem. 2012, 3691–3696
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3695

Y.-F. Wang, K. Wang, W. Zhang, B.-B. Zhang, C.-X. Zhang, D.-Q. Xu
FULL PAPER
Chem. 1995, 30, 531–535; e) C. Mouli, T. Giridhar, D. M. Rao,
R. B. Reddy, J. Heterocycl. Chem. 1996, 33, 5–8.
[4] a) N. Halland, T. Velgaard, K. A. Jørgensen, J. Org. Chem.
2003, 68, 5067–5074; b) Z. H. Dong, J. H. Feng, X. A. Fu,
X. H. Liu, L. L. Lin, X. M. Feng, Chem. Eur. J. 2011, 17, 1118–
1121.
[5] a) M. A. Calter, J. Wang, Org. Lett. 2009, 11, 2205–2208; b)
J. J. Wang, J. H. Lao, Z. P. Hu, R. J. Lu, S. Z. Nie, Q. S. Du,
M. Yan, ARKIVOC 2010, 229–243.
[6] D. Q. Xu, Y. F. Wang, W. Zhang, S. P. Luo, A. G. Zhong, A. B.
Xia, Z. Y. Xu, Chem. Eur. J. 2010, 16, 4177–4180.
[7] For pioneering work in this field, see: a) J. P. Malerich, K.
Hagihara, V. H. Rawal, J. Am. Chem. Soc. 2008, 130, 14416–
14417; for recent reviews, see: b) R. I. Storer, C. Aciro, L. H.
Jones, Chem. Soc. Rev. 2011, 40, 2330–2346; c) J. Alemán, A.
Parra, H. Jiang, K. A. Jørgensen, Chem. Eur. J. 2011, 17, 6890–
6899; for recent applications of chiral squaramides in organ-
ocatalysis, see: d) J. W. Lee, T. H. Ryu, J. S. Oh, H. Y. Bae, H.
Bin Jang, C. E. Song, Chem. Commun. 2009, 7224–7226; e)
Y. F. Wang, W. Zhang, S. P. Luo, G. C. Zhang, A. B. Xia, X. S.
13, 3052–3055; m) N. Hara, S. Nakamura, Y. Funahashi, N.
Shibata, Adv. Synth. Catal. 2011, 353, 2976–2980.
[8] a) B. Loev, M. M. Goodman, K. M. Snader, R. Tedeschi, E.
Macko, J. Med. Chem. 1974, 17, 956–965; b) F. Bossert, H.
Meyer, E. Wehinger, Angew. Chem. 1981, 93, 755; Angew.
Chem. Int. Ed. Engl. 1981, 20, 762–769; c) R. Mannhold, B.
Jablonka, W. Voigdt, K. Schoenafinger, K. Schravan, Eur. J.
Med. Chem. 1992, 27, 229–235; d) V. Klusa, Drugs Future 1995,
20, 135–138; e) H. Nakayama, Y. Kasoaka, Heterocycles 1996,
42, 901–909; f) C. O. Kappe, Eur. J. Med. Chem. 2000, 35,
1043–1052; g) G. C. Rodrigo, N. B. Standen, Curr. Pharm. Des.
2005, 11, 1915–1940; h) R. Miri, K. Javidnia, H. Mirkhani,
B. Hemmateenejad, Z. Sepeher, M. Zalpour, T. Behzad, M.
Khoshneviszadeh, N. Edraki, A. R. Mehdipour, Chem. Biol.
Drug Des. 2007, 70, 329–336; i) R. S¸ims¸ek, G. S. Öztürk, I. M.
Vural, M. G. Gündüz, Y. Sarioglu, C. S¸afak, Arch. Pharm.
˘
Chem. Life Sci. 2008, 341, 55–60; j) A. Kumar, S. Sharma, V. D.
Tripathi, R. A. Maurya, S. P. Srivastava, G. Bhatia, A. K. Tam-
rakar, A. K. Srivastava, Bioorg. Med. Chem. 2010, 18, 4138–
4148.
Xu, D. Q. Xu, Eur. J. Org. Chem. 2010, 4981–4985; f) H. Jiang, [9] B. Vakulya, S. Varga, A. Csámpai, T. Soο´s, Org. Lett. 2005, 7,
M. W. Paixao, D. Monge, K. A. Jorgensen, J. Am. Chem. Soc.
2010, 132, 2775–2783; g) H. Konishi, T. Y. Lam, J. P. Malerich,
V. H. Rawal, Org. Lett. 2010, 12, 2028–2031; h) Y. Zhu, J. P.
Malerich, V. H. Rawal, Angew. Chem. 2010, 122, 157; Angew.
Chem. Int. Ed. 2010, 49, 153–156; i) W. Yang, D. M. Du, Chem.
Commun. 2011, 47, 12706–12708; j) W. Yang, D. M. Du, Adv.
Synth. Catal. 2011, 353, 1241–1246; k) S. V. Pansare, E. K.
Paul, Chem. Commun. 2011, 47, 1027–1029; l) V. Marcos, J.
Aleman, J. L. G. Ruano, F. Marini, M. Tiecco, Org. Lett. 2011,
1967–1969.
[10] T. Vaijayanthi, A. Chadha, Tetrahedron: Asymmetry 2007, 18,
1077–1084.
[11] Y. Choe, L. S. Brinen, M. S. Price, J. C. Engel, M. Lange, C.
Grisostomi, S. G. Weston, P. V. Pallai, H. Cheng, L. W. Hardy,
D. S. Hartsough, M. McMakin, R. F. Tilton, C. M. Baldino,
C. S. Craik, Bioorg. Med. Chem. 2005, 13, 2141–2156.
Received: February 15, 2012
Published Online: May 23, 2012
3696
www.eurjoc.org
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2012, 3691–3696