Tandem intramolecular oxa-Michael addition/decarboxylation reaction catalyzed by bifunctional cinchona alkaloids: Facile synthesis of chiral flavanone derivatives

Article abstract of DOI:10.1016/j.tet.2011.05.088

Bifunctional cinchona alkaloids were used to catalyze a tandem intramolecular oxa-Michael addition/decarboxylation reaction of alkylidene β-ketoesters 1, providing a series of flavanone derivatives with up to 97% yield and 93% ee.

Full text of DOI:10.1016/j.tet.2011.05.088

Tetrahedron 67 (2011) 5389e5394
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Tandem intramolecular oxa-Michael addition/decarboxylation reaction catalyzed
by bifunctional cinchona alkaloids: facile synthesis of chiral flavanone derivatives
,b,
Hai-Feng Wang a, Hua Xiao b, Xiao-Wei Wang a, Gang Zhao a
*
a Key Laboratory of Synthetic Chemistry of Natural Substances, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 LingLing Lu, Shanghai 200032, China
b Department of Chemistry, University of Science and Technology of China, Hefei, Anhui 230026, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 7 April 2011
Received in revised form 14 May 2011
Accepted 20 May 2011
Available online 27 May 2011
Bifunctional cinchona alkaloids were used to catalyze a tandem intramolecular oxa-Michael addition/
decarboxylation reaction of alkylidene
to 97% yield and 93% ee.
b
-ketoesters 1, providing a series of flavanone derivatives with up
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Oxa-Michael addition
Decarboxylation
Enantioselectivity
Bifunctional cinchona alkaloids
Flavanones
1. Introduction
this reaction. Herein, we reported the application of the catalysts 3
to a similar tandem intramolecular oxa-Michael addition/de-
Together with the rapid development of organocatalysis in re-
cent years, the organocatalytic asymmetric Michael-type reaction,
including Michael and hetero-Michael reaction, has emerged as an
efficient tool for accessing many useful molecules.1 Cinchona al-
kaloids, which are easily available and well-documented powerful
bifunctional organocatalysts in many other reactions,2 have also
found extensive applications in the asymmetric Michael reaction.3
Whereas there are numerous examples of hetero-Michael addition
with thiols4 as non-carbon nucleophiles catalyzed by cinchona
alkaloids, the aza-Michael,5 and oxa-Michael6 reactions are less
studied.
Recently, significant advances have been made in the synthesis
of biologically interesting flavanones via a catalytic asymmetric
intramolecular oxa-Michael reaction of alkylidene b-ketoesters 1.
Scheidt and co-workers pioneered the use of 1 as the advantageous
substrates for this transformation and obtained excellent results
using cinchona derived thiourea catalysts.7 Our group also de-
veloped an organocatalytic tandem intramolecular oxa-Michael
addition/electrophilic fluorination reaction of 1 to afford fluori-
nated flavanones 5 (Scheme 1, Eq. a).8 In our study, we found that
bifunctional cinchona alkaloids 3 (Fig. 1) are efficient catalysts for
carboxylation reaction of alkylidene b-ketoesters 1, which provided
flavanone derivatives 2 in excellent yields and moderate to high
enantioselectivities (Scheme 1, Eq. b).
2. Results and discussion
As a model substrate,
a,b-unsaturated ketone 1a was first
studied in the tandem reaction in the presence of various cinchona
alkaloids to afford the product 2a (Table 1). The structures of the
catalysts proved to be highly influential on both the reaction rate
and enantioselectivity. First, commercially available quinine (3a)
and quinidine (3b) were used and the desired product 2a was
obtained with low enantiomeric excesses (ee) after a long reaction
time (Table 1, entries 1 and 2). When the corresponding 6-hydroxy
catalysts 3c and 3d were used, only a little higher ee was obtained
(Table 1, entries 3 and 4). Different from the result from our pre-
viously developed tandem intramolecular oxa-Michael addition/
electrophilic fluorination reaction of 1, the quinidine-derived cat-
alyst 3i, instead of 3l, was identified as the best one in light of both
catalytic activity and enantioselectivity (Table 1, entry 9). It is also of
note that either the quinine-derived 3e (Table 1, entry 5) or other
sterically more demanding catalysts, such as 3feh, 3jem, provided
inferior results (Table 1, entries 6e8 and 10e13).
With the identified optimal catalyst 3i, other reaction conditions,
such as catalyst loading, solvents, and substrate concentration were
* Corresponding author. Tel.: þ86 21 54925182; fax: þ86 21 64166128; e-mail
address: zhaog@mail.sioc.ac.cn (G. Zhao).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.05.088

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H.-F. Wang et al. / Tetrahedron 67 (2011) 5389e5394
Scheme 1. Synthesis of fluorinated flavanone derivatives 5 and flavanone derivatives 2 using bifunctional cinchona alkaloid catalysts.
OMe
N
OMe
N
OH
N
OH
N
H
H
N
H
HO H
HO H
N
H
N
N
OH
OH
H
H
3a(QN)
3b(QD)
3c
3d
OH
OH
N
OH
N
OH
N
H
O
O
O
N
H
N
N
N
OBn
N
H
H
H
3e
3f
3g
3h
R
N
OH
N
3i: R = H
3j: R = Me
3k: R = Ph
3l: R = CF3
OH
N
O
O
N
H
H
3m
Fig. 1. Cinchona alkaloids used in this study.
next examined (Table 2). Decreasing the catalyst loading from 20 to
15,10 or 5 mol % led to a drop in both theyield and enantioselectivity,
together with significantly longer reaction times (Table 2, entries
1e4). Among the solvents screened, PhCF3 gave the highest ee value
(up to 90%), albeit with a slightly lower yield (Table 2, entries 6).
Variation of the amount of the reaction solvent PhCF3 revealed
a slight influence on the reaction results: increasing the concen-
tration from 0.1 to 0.2 M or 0.5 M, a drop in the ee value was observed
(Table 2, entries 6 and 12e13), whereas slightly higher ee value and
yield were obtained at a lower concentration of 0.05 M at the ex-
pense of a much longer reaction time (Table 2, entry 14). To sum-
marize, the present tandem reaction was best performed with
20 mol % of 3i in PhCF3 (0.1 M) at room temperature, followed by
treatment with PTSA (2 equiv) at 80 ꢀC for 2 h.
explored the scope of the reaction and the results were listed in
Table 3. Of all the substrates examined, excellent yields were gen-
erally obtained. For substrates 1aeg where R1 are differently
substituted benzene rings, relatively shorter reaction times were
needed for substrates with electron-withdrawing groups while no
consistent trend in the enantioselectivity was observed (Table 3,
entries 1e7). When R1 are bulkier naphthyl groups (1h and 1i),
longer reaction times and apparently lower ee values were ob-
served (Table 3, entries 8 and 9). Pleasingly, substrate 1j bearing an
alkyl R1 (R1¼cyclohexyl) also participated in the reaction well to
afford the desired product with high enantioselectivity (up to 90%
ee), although a long reaction time was required (Table 3, entry 10).
Changing the R2 group of substrate 1a to an electron-donating
methyl or methoxyl group resulted in somewhat diminished ee
values as well as prolonged reaction times (Table 3, entries 1 and
11e12).
With the optimal conditions for the intramolecular Michael
addition/decarboxylation cascade reaction at hand, we then

H.-F. Wang et al. / Tetrahedron 67 (2011) 5389e5394
5391
Table 1
Table 3
Evaluation of different cinchona alkaloids as catalysts in the asymmetric intra-
Examination of the reaction scopea
molecular oxa-Michael additiona
OH
O
R1
O
O
1) 3i (20 mol%)
PhCF3, RT, t
OH
O
Ph
O
O
1) Cat. (20 mol%)
Toluene, RT, t
2) p-TsOH (2.0 equiv.)
CO2t-Bu
R2
80 C, 2h
R2
R1
°
2) p-TsOH (2.0 equiv.)
CO2t-Bu
°
80 C, 2h
Ph
1
2
1a
2a
Entry
R1, R2, 1
t (h)
Product
Yieldb (%)
eec (%)
Entry
Catalyst
t
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
C6H5, H, 1a
24
16
16
24
36
18
36
48
48
120
48
48
2a
2b
2c
2d
2e
2f
2g
2h
2i
92
88
97
82
85
95
85
88
80
97
89
93
90
86
88
71
61
78
79
72
60
90
83
82
1
2
3
4
5
6
7
8
3a(QN)
3b (QD)
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
13 days
9 days
13 days
13 days
7 days
24 h
24 h
7 days
24 h
36 h
24 h
16 h
12 days
85
98
80
89
98
96
>99
89
>99
95
98
ꢁ26
16
p-BrC6H4, H, 1b
p-CNC6H4, H, 1c
p-PhC6H4, H, 1d
p-MeC6H4, H, 1e
o-ClC6H4, H, 1f
m-MeC6H4, H, 1g
1-Naphthyl, H, 1h
2-Naphthyl, H, 1i
Cyclohexyl, H, 1j
C6H5, Me, 1k
ꢁ36
24
ꢁ88
84
82
76
87
86
85
86
39
9
9
10
11
12
2j
2k
2l
10
11
12
13
C6H5, MeO, 1l
96
71
a
Unless otherwise noted, the reaction was carried out with 1 (0.1 mmol), 3i
(0.02 mmol), and PhCF3 (1.0 mL) at room temperature for 16e120 h, then p-TsOH
(0.2 mmol) was added at 80 ꢀC for 2 h.
a
Unless otherwise noted, the reaction was carried out with 1a (0.1 mmol), cat-
alyst 3 (0.02 mmol), and toluene (1.0 mL) at room temperature, then p-TsOH
(0.2 mmol) was added at 80 ꢀC for 2 h.
b
Yield of the isolated product after column chromatography on silica gel.
Determined by HPLC analysis on a chiral column. The absolute configuration of
c
b
Yield of the isolated product after column chromatography on silica gel.
Determined by HPLC analysis on a chiral column.
product 2 was determined as S by comparison of optical rotation values to literature
c
data.7,9
Table 2
As an extension of our current efforts on the utilization of 1 to
synthesize flavanones with varied functionalities, instead of the
treatment with PTSA, several electrophiles were introduced into
the system for an ensuing electrophilic cascade reaction after
intramolecular Michael addition (Scheme 2). To our delight, the use
of methyl vinyl ketone (MVK), N-bromosuccinimide (NBS), and
N-chlorosuccinimide (NCS) all smoothly led to the desired flava-
none derivatives 6e8 in high to excellent yields and 92e93% ee
values under mild conditions.
Optimization of reaction conditions with catalyst 3ia
OH
O
Ph
O
O
1) 3i (x mol%)
Solvent, RT, t
2) p-TsOH (2.0 equiv.)
CO2t-Bu
°
80 C, 2h
Ph
1a
2a
Entry
3i (mol %)
Solvent
t (h)
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
20
15
10
5
Toluene
Toluene
Toluene
Toluene
Xylene
PhCF3
ClCH2CH2Cl
CHCl3
CCl4
CH3CN
PhOMe
PhCF3
PhCF3
PhCF3
24
36
48
48
24
24
12
12
24
24
24
16
16
84
>99
98
98
92
96
92
85
96
98
85
>99
91
94
96
87
85
80
79
85
90
76
74
83
69
85
80
83
91
3. Conclusion
20
20
20
20
20
20
20
20
20
20
In summary, we have developed an intramolecular oxa-Michael
addition/decarboxylation or electrophilic cascade reaction of alky-
lidene b-ketoesters catalyzed by bifunctional cinchona alkaloids,
which provides an easy access to a series of chiral flavanone de-
rivatives. High enantioselectivities (up to 93% ee) and excellent
yields were obtained by using quinidine-derived catalyst 3i. Further
efforts toward the application of the bifunctional cinchona alkaloids
catalysts in other reactions are in progress in our laboratories.
9
10
11
12d
13e
14f
a
Unless otherwise noted, the reaction was carried out with 1a (0.1 mmol) and 3i
in solvent (1.0 mL) at room temperature for 12e84 h, then p-TsOH (0.2 mmol) was
added at 80 ꢀC for 2 h.
4. Experimental
4.1. General
b
Yield of the isolated product after column chromatography on silica gel.
Determined by HPLC analysis on a chiral column.
PhCF3 (0.2 mL) was used.
PhCF3 (0.5 mL) was used.
c
d
e
Unless otherwise indicated, chemicals and solvents were pur-
chased from commercial suppliers and purified by standard
f
PhCF3 (2.0 mL) was used.
Scheme 2. Organocatalytic intramolecular oxa-Michael addition/electrophilic halogenation cascade reaction.

5392
H.-F. Wang et al. / Tetrahedron 67 (2011) 5389e5394
techniques. Flash column chromatography was performed using
silica gel. For thin-layer chromatography (TLC), silica gel plates
(HSGF 254) were used and compounds were visualized by irradi-
ation with UV light or by treatment with a solution of phospho-
NMR (300 MHz, CDCl3)
d
2.93 (d, J¼16.2 Hz, 1H), 3.13 (dd,
J1¼12.3 Hz, J2¼16.2 Hz,1H), 5.52 (d, J¼12.3 Hz,1H), 7.07 (d, J¼6.0 Hz,
2H), 7.24e7.64 (m, 10H), 7.95 (d, J¼6.3 Hz, 1H). The ee was de-
termined by HPLC analysis using a chiralcel OD-H column, hexane/
2-propanol: 95/5, flow rate: 1.0 mL/min, tr (minor)¼18.29 min, tr
(major)¼19.72 min.
molybdic acid in ethanol followed by heating. The 1H NMR and 13
C
NMR spectra were recorded on a DPX-300 or Varian EM-360
(300 MHz) and DPX-400 (100 MHz) with TMS as the internal
standard. 19F NMR spectra were recorded at 282 MHz with CFCl3 as
4.2.5. (S)-2-p-Tolylchroman-4-one (2e)7. Colorless liquid (20.3 mg,
the external standard. All chemical shifts (d) are given in parts per
85% isolated yield, 61% ee). [a 25
]
ꢁ26.4 (c 0.19, EtOH). 1H NMR
D
million. Data are reported as follows: chemical shift, multiplicity
(s¼single, d¼doublet, t¼triplet, q¼quartet, br¼broad, and
m¼multiplet) and coupling constants (Hz), integration. Analytical
high-performance liquid chromatography (HPLC) was carried out
on WATERS equipment using a chiral column. Melting points were
determined on an SGW X-4 apparatus, and are uncorrected. Optical
rotations were measured on a JASCO P-1030 Polarimeter at
(300 MHz, CDCl3)
d
2.38 (s, 3H), 2.87 (d, J¼16.5 Hz, 1H), 3.10 (dd,
J1¼12.9 Hz, J2¼16.5 Hz,1H), 5.45 (d, J¼12.9 Hz,1H), 7.04 (d, J¼7.2 Hz,
2H), 7.24 (d, J¼6.9 Hz, 2H), 7.38 (d, J¼6.9 Hz, 2H), 7.50 (t, J¼7.2 Hz,
1H), 7.93 (d, J¼7.2 Hz, 1H). The ee was determined by HPLC analysis
using a chiralcel OD-H column, hexane/2-propanol: 90/10, flow
rate: 1.0 mL/min, tr (minor)¼7.54 min, tr (major)¼8.71 min.
l
¼589 nm. IR spectra were recorded on a PerkineElmer 983G in-
4.2.6. (S)-2-(2-Chlorophenyl)chroman-4-one (2f)7. Yellow solid
strument. Elementary analysis was taken on a Vario EL III ele-
mentary analysis instrument. Mass spectra analysis was performed
on API 200 LC/MS system (Applied Biosystems Co. Ltd).
Catalysts 3aem were prepared according to the procedure of
Zhao8 and references therein.
(24.7 mg, 95% isolated yield, 78% ee). [a 25
]
D
ꢁ135.0 (c 0.24, EtOH). 1H
NMR (300 MHz, CDCl3)
d
2.87e3.07 (m, 2H), 5.88 (d, J¼11.7 Hz, 1H),
7.06e7.11 (m, 2H), 7.30e7.43 (m, 3H), 7.53 (t, J¼7.5 Hz, 1H), 7.76 (d,
J¼7.8 Hz,1H), 7.96 (d, J¼7.5 Hz,1H). The ee was determined by HPLC
analysis using a chiralcel OD-H column, hexane/2-propanol: 90/10,
flow rate: 1.0 mL/min, tr (minor)¼6.31 min, tr (major)¼6.74 min.
Substrates 1ael were prepared according to the procedure of
Scheidt7 and Feng.9
4.2.7. (S)-2-m-Tolylchroman-4-one (2g)9. Colorless liquid (20.2 mg,
4.2. General procedure for cyclization/decarboxylation
reaction
85% isolated yield, 79% ee). [a 25
]
D
ꢁ49.0 (c 0.19, EtOH). 1H NMR
(300 MHz, CDCl3)
d
2.40 (s, 3H), 2.87 (dd, J1¼2.7 Hz, J2¼16.8 Hz, 1H),
3.10 (dd, J1¼13.8 Hz, J2¼16.8 Hz, 1H), 5.50 (dd, J1¼2.7 Hz, J2¼13.8 Hz,
1H), 7.03e7.07 (m, 2H), 7.20 (d, J2¼7.2 Hz,1H), 7.25e7.35 (m, 3H), 7.51
(t, J2¼7.5 Hz, 1H), 7.94 (d, J¼8.1 Hz, 1H). The ee was determined by
HPLC analysis usinga chiralcelOD-Hcolumn, hexane/2-propanol:90/
10, flow rate: 1.0 mL/min, tr (minor)¼7.15 min, tr (major)¼9.00 min.
A mixture of (E)-tert-butyl 2-(2-hydroxybenzoyl)-3-phenylacrylate
1 (0.1 mmol) and catalyst 3i (8 mg, 0.02 mmol) in 1.0 mL of PhCF3 was
stirred at room temperature for the appropriate times until the dis-
appearance of 1 (monitored by TLC). Then p-toluenesulfonic acid (p-
TsOH) (38 mg, 0.2 mmol) was added and the mixture was stirred at
80 ꢀC for 2 h (monitored by TLC). The reaction mixture was then
concentrated, and the residue was purified by flash column chroma-
tography on silica gel (ethyl acetate/petroleum ether¼1/20) to give
the desired products 2.
4.2.8. (S)-2-(Naphthalen-1-yl)chroman-4-one (2h)9. White solid
(24.0 mg, 88% isolated yield, 72% ee). [a 23
]
ꢁ31.5 (c 0.23, EtOH). 1H
D
NMR (300 MHz, CDCl3)
d
3.09 (d, J¼16.5 Hz, 1H), 3.26 (dd,
J1¼12.3 Hz, J2¼16.5 Hz,1H), 6.23 (d, J¼12.3 Hz,1H), 7.09 (d, J¼6.9 Hz,
2H), 7.40e7.64 (m, 4H), 7.78 (d, J¼6.9 Hz, 1H), 7.87e7.91 (m, 2H),
7.99e8.06 (m, 2H). The ee was determined by HPLC analysis using
a chiralcel OD-H column, hexane/2-propanol: 80/20, flow rate:
1.0 mL/min, tr (minor)¼11.11 min, tr (major)¼15.69 min.
4.2.1. (S)-2-Phenylchroman-4-one (2a)7. White solid (20.5 mg, 92%
isolated yield, 90% ee). [a 23
]
D
ꢁ54.9 (c 0.20, EtOH). 1H NMR
(300 MHz, CDCl3)
d
2.90 (dd, J1¼2.7 Hz, J2¼16.8 Hz, 1H), 3.11 (dd,
J1¼13.2 Hz, J2¼16.8 Hz, 1H), 5.50 (dd, J1¼2.1 Hz, J2¼13.2 Hz, 1H),
7.05e7.08 (m, 2H), 7.37e7.55 (m, 6H), 7.94 (d, J¼7.5 Hz, 1H). The ee
was determined by HPLC analysis using a chiralcel OD-H column,
hexane/2-propanol: 90/10, flow rate: 1.0 mL/min, tr (minor)¼
8.19 min, tr (major)¼10.11 min.
4.2.9. (S)-2-(Naphthalen-2-yl)chroman-4-one (2i)7. White solid
(21.9 mg, 80% isolated yield, 60% ee). [a 24
]
ꢁ45.6 (c 0.19, EtOH). 1H
D
NMR (300 MHz, CDCl3)
d
2.97 (d, J¼15.9 Hz, 1H), 3.18 (dd,
J1¼12.9 Hz, J2¼15.9 Hz, 1H), 5.64 (d, J¼12.9 Hz, 1H), 7.04e7.10 (m,
2H), 7.50e7.60 (m, 4H), 7.86e7.97 (m, 5H). The ee was determined
by HPLC analysis using a chiralcel OD-H column, hexane/2-
propanol: 80/20, flow rate: 1.0 mL/min, tr (minor)¼10.84 min, tr
(major)¼17.60 min.
4.2.2. (S)-2-(4-Bromophenyl)chroman-4-one (2b)7. White solid
(26.6 mg, 88% isolated yield, 86% ee). [a 24
]
ꢁ47.8 (c 0.26, EtOH). 1H
D
NMR (300 MHz, CDCl3)
d
2.88 (dd, J1¼2.4 Hz, J2¼16.8 Hz, 1H), 3.03
(dd, J1¼12.9 Hz, J2¼16.8 Hz,1H), 5.50 (dd, J1¼2.1 Hz, J2¼12.9 Hz, 1H),
7.04e7.09 (m, 2H), 7.37 (d, J¼8.1 Hz, 2H), 7.50e7.58 (m, 3H), 7.93 (d,
J¼8.1 Hz, 1H). The ee was determined by HPLC analysis using
a chiralcel OD-H column, hexane/2-propanol: 90/10, flow rate:
1.0 mL/min, tr (minor)¼9.58 min, tr (major)¼12.53 min.
4.2.10. (S)-2-Cyclohexylchroman-4-one
(22.3 mg, 97% isolated yield, 90% ee). [a 23
NMR (300 MHz, CDCl3) d 1.07e1.33 (m, 5H), 1.67e1.83 (m, 5H), 1.99
(d, J¼12.3 Hz, 1H), 2.61e2.78 (m, 2H), 4.16e4.24 (m, 1H), 6.96e7.01
(m, 2H), 7.46 (t, J¼7.5 Hz, 1H), 7.86 (d, J¼7.5 Hz, 1H). The ee was
determined by HPLC analysis using a chiralcel OD-H column, hex-
ane/2-propanol: 100/1, flow rate: 1.0 mL/min, tr (minor)¼7.27 min,
tr (major)¼7.73 min.
(2j)7. Colorless
liquid
]
þ58.9 (c 0.23, EtOH). 1H
D
4.2.3. (S)-4-(4-Oxochroman-2-yl)benzonitrile (2c)9. White solid
(24.2 mg, 97% isolated yield, 88% ee). [a 24
]
ꢁ75.6 (c 0.24, EtOH). 1H
D
NMR (300 MHz, CDCl3)
d
2.90e3.06 (m, 2H), 5.56 (d, J¼10.8 Hz, 1H),
7.08 (d, J¼6.6 Hz, 2H), 7.54e7.73 (m, 5H), 7.94 (d, J¼6.0 Hz, 1H). The
ee was determined by HPLC analysis using a chiralcel OD-H column,
hexane/2-propanol: 90/10, flow rate: 1.0 mL/min, tr (minor)¼
21.32 min, tr (major)¼25.52 min.
4.2.11. (S)-7-Methyl-2-phenylchroman-4-one (2k)7. White waxy
solid (21.2 mg, 89% isolated yield, 83% ee). [a 23
]
ꢁ61.6 (c 0.20, EtOH).
D
1H NMR (300 MHz, CDCl3)
d
2.37 (s, 3H), 2.86 (dd, J1¼3.0 Hz,
J2¼17.1 Hz, 1H), 3.05 (dd, J1¼13.2 Hz, J2¼16.8 Hz, 1H), 5.46 (dd,
J1¼2.7 Hz, J2¼13.2 Hz, 1H), 6.86e6.88 (m, 2H), 7.37e7.49 (m, 5H),
7.82 (d, J¼8.1 Hz, 1H). The ee was determined by HPLC analysis
4.2.4. (S)-2-(Biphenyl-4-yl)chroman-4-one
(24.7 mg, 82% isolated yield, 71% ee). [a 24
(2d)9. White
solid
]
ꢁ35.3 (c 0.24, EtOH). 1H
D

H.-F. Wang et al. / Tetrahedron 67 (2011) 5389e5394
5393
using a chiralcel OD-H column, hexane/2-propanol: 90/10, flow
rate: 1.0 mL/min, tr (minor)¼7.62 min, tr (major)¼10.55 min.
762 cmꢁ1. The ee was determined by HPLC analysis using a chiralcel
OD column, hexane/2-propanol: 98/2, flow rate: 1.0 mL/min, tr
(minor)¼8.39 min, tr (major)¼9.28 min.
4.2.12. (S)-7-Methoxy-2-phenylchroman-4-one (2l)7. Colorless liq-
uid (23.5 mg, 93% isolated yield, 82% ee). [a 23
]
D
ꢁ70.4 (c 0.23, EtOH).
Acknowledgements
1H NMR (300 MHz, CDCl3)
d
2.83 (dd, J1¼2.4 Hz, J2¼16.5 Hz, 1H),
3.05 (dd, J1¼13.2 Hz, J2¼16.5 Hz,1H), 5.47 (dd, J1¼2.4 Hz, J2¼13.2 Hz,
1H), 6.50 (d, J¼1.8 Hz, 1H), 6.62 (dd, J1¼2.1 Hz, J2¼8.7 Hz, 1H),
7.36e7.49 (m, 5H), 7.87 (d, J¼9.0 Hz, 1H). The ee was determined by
HPLC analysis using a chiralcel OD-H column, hexane/2-propanol:
90/10, flow rate: 1.0 mL/min, tr (minor)¼9.90 min, tr (major)¼
12.83 min.
Research support from National Basic Research Program of
China (973 Program, 2010CB833200), the National Natural Science
Foundation of China (Nos. 20172064, 203900502, and 21032006),
Shanghai Natural Science Council, and Excellent Young Scholars
Foundation of National Natural Science Foundation of China
(20525208).
4.3. General procedure for cyclization/electrophilic cascade
reaction to obtain products 6, 7, and 8
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tet.2011.05.088.
A mixture of (E)-tert-butyl 2-(2-hydroxybenzoyl)-3-phenylacrylate
1a (0.1 mmol) and catalyst 3i (8 mg, 0.02 mmol) in 1.0 mL of PhCF3
was stirred at room temperature for 24 h until the disappearance of 1a
(monitored by TLC). Then Na2CO3 (12.7 mg, 0.12 mmol) and electro-
phile (0.15 mmol) were added and the mixture was stirred at room
temperature for 24e48 h (monitored by TLC). The reaction mixture
was then concentrated, and the residue was purified by flash column
chromatography on silica gel (ethyl acetate/petroleum ether¼1/20 to
1/5) to give the desired products 6, 7, and 8.
References and notes
1. For reviews of catalytic asymmetric Michael addition, see: (a) Perlmutter, P.
Conjugate Addition Reactions in Organic Synthesis; Pergamon: Oxford, 1992; (b)
Sibi, M. P.; Manyem, S. Tetrahedron 2000, 56, 8033; (c) Krause, N.; Hoffmann-
€
Roder, A. Synthesis 2001, 171; (d) Berner, O. M.; Tedeschi, L.; Enders, D. Eur. J. Org.
Chem. 2002, 1877; (e) Christoffers, J.; Baro, A. Angew. Chem., Int. Ed. 2003, 42,
€
1688; (f) Christoffers, J.; Koripelly, G.; Rosiak, A.; Rossle, M. Synthesis 2007, 1279;
(g) Vicario, J. L.; Badia, D.; Carrillo, L. Synthesis 2007, 2065; (h) Tsogoeva, S. B. Eur.
ꢀ
J. Org. Chem. 2007, 1701; (i) Almasi, D.; Alonso, D. A.; Najera, C. Tetrahedron:
4.3.1. tert-Butyl 4-oxo-3-(3-oxobutyl)-2-phenylchroman-3-
Asymmetry 2007, 18, 299; (j) For reviews of catalytic asymmetric aza-Michael
addition, see: Xu, L.-W.; Xia, C.-G. Eur. J. Org. Chem. 2005, 633; (k) Enders, D.;
Wang, C.; Liebich, J. X. Chem.dEur. J. 2009, 15, 11058; (l) For reviews of catalytic
asymmetric phospha-Michael addition, see: Enders, D.; Saint-Dizier, A.; Lannou,
M.-I.; Lenzen, A. Eur. J. Org. Chem. 2006, 29; (m) For reviews of catalytic asym-
carboxylate (6). Colorless liquid (39.0 mg, 99% isolated yield, 92%
ee). [a 24
]
ꢁ50.5 (c 1.08, CHCl3). 1H NMR (300 MHz, CDCl3)
d 1.25 (s,
D
9H), 1.94e2.10 (m, 2H), 2.13 (s, 3H), 2.42e2.53 (m, 1H), 2.91e3.02
(m, 1H), 5.31 (s, 1H), 7.03 (d, J¼8.4 Hz, 1H), 7.08 (t, J¼7.8 Hz, 1H),
7.37e7.47 (m, 5H), 7.50 (t, J¼7.2 Hz, 1H), 7.95 (d, J¼7.5 Hz, 1H); 13C
€
metric sulfa-Michael addition, see: Enders, D.; Luttgen, K.; Narine, A. A. Synthesis
2007, 959; (n) For reviews of catalytic asymmetric oxa-Michael addition, see:
€
Nising, C. F.; Brase, S. Chem. Soc. Rev. 2008, 37, 1218.
2. For reviews of cinchona alkaloids, see: (a) Kacprzak, K.; Gawronski, J. Synthesis
NMR (100 MHz, CDCl3) d 24.5, 27.7, 29.9, 39.2, 60.2, 83.0, 85.1, 117.5,
ꢀ
121.5, 121.9, 127.6, 128.1, 129.2, 135.0, 135.7, 161.2, 167.1, 191.8, 207.6;
MS (EI): m/z 376 ([MꢁH2O]þ, 2%), 294 (23), 293 (100), 249 (9), 235
(17), 223 (7), 121 (12), 57 (17), 43 (9); HRMS (EI): m/z calcd for
C24H26O5 (Mþ): 394.1780; found: 394.1785; calcd for C24H25O4
2001, 961; (b) Yoon, T. P.; Jacobsen, E. N. Science 2003, 299, 1691; (c) Tian, S.-K.;
Chen, Y.; Hang, J.; Tang, L.; McDaid, P.; Deng, L. Acc. Chem. Res. 2004, 37, 621; (d)
Hoffmann, H.; Martin, R.; Frackenpohl, J. Eur. J. Org. Chem. 2004, 4293; (e) Da-
laigh, C. O. Synlett 2005, 875; (f) Marcelli, T.; van Maarseveen, J. H.; Hiemstra, H.
Angew. Chem., Int. Ed. 2006, 45, 7496; (g) Gaunt, M. J.; Johansson, C. C. C. Chem.
Rev. 2007, 107, 55960.
([MꢁOH]þ): 377.1753; found: 377.1752; IR (KBr)
n 2977, 1718, 1688,
3. (a) Hiemstra, H.; Wynberg, H. J. Am. Chem. Soc. 1981, 417; (b) Wynberg, H. Top.
Stereochem. 1986, 16, 97; (c) Bella, M.; Jørgensen, K. A. J. Am. Chem. Soc. 2004, 126,
5762; (d) Li, H.-M.; Wang, Y.; Tang, L.; Deng, L. J. Am. Chem. Soc. 2004, 126, 9906;
(e) Papageorgiou, C. D.; Cubillo de Dios, M. A.; Ley, S. V.; Gaunt, M. J. Angew.
Chem., Int. Ed. 2004, 43, 4641; (f) Li, H.-M.; Wang, Y.; Tang, L.; Wu, F.-H.; Liu, X.-F.;
Guo, C.-Y.; Foxman, B. M.; Deng, L. Angew. Chem., Int. Ed. 2005, 44, 105; (g) Li, H.-
M.; Song, J.; Liu, X.-F.; Deng, L. J. Am. Chem. Soc. 2005, 127, 8948; (h) Xue, D.;
Chen, Y.-C.; Wang, Q.-W.; Cun, L.-F.; Zhu, J.; Deng, J.-G. Org. Lett. 2005, 7, 5293; (i)
Wang, Y.; Liu, X.-F.; Deng, L. J. Am. Chem. Soc. 2006, 128, 3928; (j) Wu, F.-H.; Li, H.-
M.; Hong, R.; Deng, L. Angew. Chem., Int. Ed. 2006, 45, 947; (k) Wu, F.-H.; Hong,
R.; Khan, J.-H.; Liu, X.-F.; Deng, L. Angew. Chem., Int. Ed. 2006, 45, 4301; (l) Bartoli,
G.; Bosco, M.; Carlone, A.; Cavalli, A.; Locatelli, M.; Mazzanti, A.; Ricci, P.; Sambri,
L.; Melchiorre, P. Angew. Chem., Int. Ed. 2006, 45, 4966; (m) Wang, J.; Li, H.; Zu, L.-
S.; Liang, W.; Wang, W. Adv. Synth. Catal. 2006, 348, 2047; (n) Bell, M.; Frisch, K.;
Jørgensen, K. A. J. Org. Chem. 2006, 71, 5407; (o) Poulsen, T. B.; Bell, M.;
Jørgensen, K. A. Org. Biomol. Chem. 2006, 4, 63; (p) Shi, M.; Lei, Z.-Y.; Zhao, M.-X.;
Shi, J.-W. Tetrahedron Lett. 2007, 48, 5743; (q) Mandal, T.; Zhao, C.-G. Angew.
1608, 1583, 1464, 1150, 759 cmꢁ1. The ee was determined by HPLC
analysis using a chiralcel OD column, hexane/2-propanol: 80/20,
flow rate: 0.75 mL/min, tr (minor)¼7.82 min, tr (major)¼9.02 min.
4.3.2. tert-Butyl 3-bromo-4-oxo-2-phenylchroman-3-carboxylate
(7). Colorless liquid (33.0 mg, 82% isolated yield, 93% ee). [a 24
]
D
ꢁ142.0 (c 1.10, CHCl3). 1H NMR (300 MHz, CDCl3)
d
1.29 (s, 9H), 5.61
(s, 1H), 7.07 (d, J¼8.7 Hz, 1H), 7.15 (t, J¼7.5 Hz, 1H), 7.40e7.42 (m,
2H), 7.54e7.59 (m, 3H), 8.05 (d, J¼7.8 Hz, 1H); 13C NMR (100 MHz,
CDCl3)
d 27.5, 68.9, 85.2, 86.3, 117.7, 119.6, 122.9, 127.6, 127.8, 128.6,
128.7, 129.5, 134.2, 136.5, 160.8, 163.0, 184.3; MS (EI): m/z 402 (Mþ,
7%), 267 (88), 249 (53), 223 (88), 221 (45), 209 (39), 121 (39), 120
(100), 57 (98); HRMS (EI): m/z calcd for C20H19O4Br (Mþ): 402.0467;
ꢀ
Chem., Int. Ed. 2008, 47, 7714; (r) Aleman, J.; Jacobsen, C. B.; Frisch, K.; Overgaard,
found: 402.0470; IR (KBr) n 2978, 1752, 1698, 1606,1582, 1463, 1148,
J.; Jørgensen, K. A. Chem. Commun. 2008, 632; (s) Lu, J.; Zhou, W.-J.; Liu, F.; Loh,
T.-P. Adv. Synth. Catal. 2008, 350, 1796.
762 cmꢁ1. The ee was determined by HPLC analysis using a chiralcel
AS-H column, hexane/2-propanol: 80/20, flow rate: 0.75 mL/min, tr
(minor)¼7.49 min, tr (major)¼8.09 min.
4. (a) Pracejus, H.; Wilke, F.-W.; Hanemann, K. J. Prakt. Chem. 1977, 319, 219; (b)
Helder, R.; Arends, R.; Bolt, W.; Hiemstra, H.; Wynberg, H. Tetrahedron Lett. 1977,
18, 2181; (c) Colonna, S.; Re, A.; Wynberg, H. J. Chem. Soc., PerkinTrans. 11981, 547;
(d) Ahuja, R. R.; Natu, A. A.; Gogte, V. N. Tetrahedron Lett. 1980, 21, 4743; (e) Ko-
bayashi, N.; Iwai, K. J. Org. Chem. 1981, 46, 1823; (f) Yamashita, H.; Mukaiyama, T.
Chem. Lett.1985, 14, 363; (g) Keniya, J.; Natu, A. A.; Gogte, V. N. Chem. Ind. (London)
1986, 243; (h) Kumar, A.; Salunkhe, R. V.; Rane, R. A.; Dike, S. Y. J. Chem. Soc., Chem.
4.3.3. tert-Butyl 3-chloro-4-oxo-2-phenylchroman-3-carboxylate
(8). Colorless liquid (31.0 mg, 86% isolated yield, 93% ee). [a 25
]
D
ꢁ199.8 (c 1.03, CHCl3). 1H NMR (300 MHz, CDCl3)
d
1.28 (s, 9H), 5.49
_
ꢀ
Commun. 1991, 485; (i) Skarzewski, J.; Zielinska-Blajet, M.; Turowska-Tyrk, I.
Tetrahedron: Asymmetry 2001, 12, 1923; (j) McDaid, P.; Chen, Y.; Deng, L. Angew.
(s, 1H), 7.10 (d, J¼8.4 Hz, 1H), 7.15 (t, J¼7.5 Hz, 1H), 7.41e7.42 (m,
ꢀ
_
2H), 7.55e7.60 (m, 3H), 8.04 (d, J¼7.2 Hz, 1H); 13C NMR (100 MHz,
Chem., Int. Ed. 2002, 41, 338; (k) Zielinska-Blajet, M.; Kowalczyk, R.; Skarzewski, J.
Tetrahedron 2005, 61, 5235; (l) Dodda, R.; Goldman, J. J.; Mandal, T.; Zhao, C.-G.;
Broker, G. A.; Tiekink, E. R. T. Adv. Synth. Catal. 2008, 350, 537; (m) Liu, Y.; Sun, B.-F.;
Wang, B.-M.; Wakem, M.; Deng, L. J. Am. Chem. Soc. 2009, 131, 418.
CDCl3)
d 27.6, 73.7, 85.2, 85.7, 177.8, 119.8, 122.6, 127.9, 128.4, 128.5,
129.5, 133.8, 136.6, 161.0, 162.7, 184.8; MS (EI): m/z 358 (Mþ, 6%),
267 (37), 223 (37), 167 (21), 165 (71), 138 (32), 121 (29), 120 (100),
57 (55); HRMS (EI): m/z calcd for C20H19O4Cl (Mþ): 358.0792;
5. (a) Wang, J.; Li, H.; Zu, L.; Wang, W. Org. Lett. 2006, 8, 1391; (b) Nielsen, M.;
Zhuang, W.; Jørgensen, K. A. Tetrahedron 2007, 63, 5849; (c) Perdicchia, D.;
Jørgensen, K. A. J. Org. Chem. 2007, 72, 3565; (d) Scettri, A.; Massa, A.; Palombi, L.;
Villano, R.; Acocella, M. R. Tetrahedron: Asymmetry 2008, 19, 2149.
found: 358.0791; IR (KBr) n 2978, 1755, 1704, 1606, 1582, 1463, 1149,

5394
H.-F. Wang et al. / Tetrahedron 67 (2011) 5389e5394
6. (a) Tanaka,T.;Kumamoto,T.;Ishikawa,Y. Tetrahedron:Asymmetry2000,11, 4633;(b)
Sekino, E.; Kumamoto, T.; Tanaka, T.; Ikeda, T.; Ishikawa, T. J. Org. Chem. 2004, 69,
2760; (c) Merschaert, A.; Delbeke, P.; Daloze, D.; Dive, G. Tetrahedron Lett. 2004, 45,
4697; (d) de Figneiredo, R. M.; Frohlich, R.; Christmann, M. Angew. Chem., Int. Ed.
2007, 46, 2883;(e)Dittmer, C.;Raabe, G.;Hintermann,L.Eur. J.Org.Chem. 2007, 5886.
7. Biddle, M. M.; Lin, M.; Scheidt, K. A. J. Am. Chem. Soc. 2007, 129, 3830.
8. Wang, H.-F.; Cui, H.-F.; Chai, Z.; Li, P.; Zheng, C.-W.; Yang, Y.-Q.;
Zhao, G. Chem.dEur. J. 2009, 15, 13299.
9. Wang, L.-J.; Liu, X.-H.; Dong, Z.-H.; Fu, X.; Feng, X.-M. Angew. Chem., Int. Ed. 2008,
47, 8670.
€