Asymmetric direct michael addition of acetophenone to α,β- unsaturated aldehydes

Article abstract of DOI:10.1055/s-0030-1258459

The asymmetric direct Michael addition of ,-unsaturated aldehydes with acetophenone catalyzed by a Jorgensen-Hayashi-catalyst in methanol was developed and the corresponding Michael products of -keto aldehydes could be afforded in up to 82% yield and 98% ee. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0030-1258459

PAPER
1085
Asymmetric Direct Michael Addition of Acetophenone to a,b-Unsaturated
Aldehydes
Asymmetric
D
irect Mic
e
hael Additio
n
n of
A
cetop
j
henoneun Li, Wenbin Wu, Juanjuan Yang, Xinmiao Liang, Jinxing Ye*
Engineering Research Centre of Pharmaceutical Process Chemistry, Ministry of Education, School of Pharmacy,
East China University of Science and Technology, 130 Meilong Road, Shanghai 200237, P. R. of China
Fax +86(21)64251830; E-mail: yejx@ecust.edu.cn
Received 15 December 2010; revised 30 January 2011
malonates, we wondered whether asymmetric direct
Michael reactions of a,b-unsaturated aldehydes with ace-
tophenones could take place.
Abstract: The asymmetric direct Michael addition of a,b-unsatur-
ated aldehydes with acetophenone catalyzed by a Jørgensen–
Hayashi catalyst in methanol was developed and the corresponding
Michael products of d-keto aldehydes could be afforded in up to
82% yield and 98% ee.
In this communication, we reveal that a Jørgensen–
Hayashi catalyst provides the first enantioselective direct
Michael reactions of a,b-unsaturated aldehydes with ace-
tophenones and affords d-keto aldehydes in high yields
with excellent enantioselectivities (Scheme 1).
Key words: asymmetric catalysis, Michael additions, ketones, al-
dehydes, enals
In the model reaction between cinnamaldehyde (1a) and
acetophenone (2a) with catalyst I in a chloroalkane, the
conversions were poor (Table 1, entries 1 and 2). To our
delight, the reaction in methanol without any additive pro-
ceeded in 77% conversion with a chemoselectivity of
80:20 and with 96% enantioselectivity (entry 3). To in-
crease the conversion, we introduced lithium acetate into
the reaction system. We supposed that lithium acetate
would increase the mole fraction of the lithium enolate of
acetophenone generated in equilibrium, and could accel-
erate the nucleophilic reaction.9 A survey of different re-
action solvents revealed that methanol was the most
suitable solvent for this procedure (entry 12). Performing
the reactions in less polar or nonpolar solvents gave infe-
rior results (entries 4–11). This might be because lithium
acetate is too insoluble in other media to have an effect on
the substrates. Furthermore, an alcoholic solvent may
contribute to competitive hemiacetal formation with a,b-
unsaturated aldehyde under equilibrium, which is benefi-
cial to suppress 1,2-addition. Gratifyingly, up to 94% con-
The Mukaiyama–Michael addition reaction has been
shown to be a mild, versatile, and powerful method for
carbon–carbon bond formation.1 Considerable research
efforts have focused on the development of a catalytic
asymmetric version of this process.2 Because of the pref-
erence of a,b-unsaturated aldehydes for 1,2-addition over
1,4-addition, the development of a catalytic asymmetric
Michael addition to a,b-unsaturated aldehydes has proved
to be more challenging.3 In 2005, Wang reported a study
of an organocatalytic asymmetric Mukaiyama–Michael
addition of a,b-unsaturated aldehydes with nucleophilic
silyl enol ethers employing MacMillan’s chiral imidazoli-
dinone catalyst (Scheme 1).4 A catalytic asymmetric di-
rect Michael reaction with atom economy would be more
desirable in organic synthesis. We have recently reported
catalytic asymmetric Michael addition reactions of a,b-
unsaturated aldehydes with nitroalkanes and malonates
with a Jørgensen–Hayashi catalyst.5–8 Although the pKa
values of ketones are larger than those of nitroalkanes and
Me
O
ref. 4
N
O
N
H
OTMS
O
Ph
+
+
R
O
O
R
DNBA, 0 °C
t-BuOH–i-PrOH (5:1)
Ph
this work
R
O
O
Ph
N
OTMS
H
O
R
MeOH, LiOAc, r.t.
Scheme 1 Mukaiyama–Michael addition versus direct Michael addition; DNBA = 2,4-dinitrobenzenesulfonic acid
SYNTHESIS 2011, No. 7, pp 1085–1091
x
x
.
x
x
.2
0
1
1
Advanced online publication: 02.03.2011
DOI: 10.1055/s-0030-1258459; Art ID: F53810SS
© Georg Thieme Verlag Stuttgart · New York

1086
W. Li et al.
PAPER
version with 85:15 chemoselectivity and 96% ee were enantioselective direct Michael addition of acetophenone
obtained in the presence of lithium acetate in methanol to a,b-unsaturated aldehyde was feasible.
(entry 12). These encouraging results indicated that the
Table 1 Optimization Studiesa
O
O
O
O
catalyst (20 mol%)
solvent, additive, r.t.
Ph
+
Ph
O
+
Ph
Ph
Ph
Ph
1a
2a
catalyst:
3a
4a
R
I R = Ph
R
II R = 3,5-(F3C)2C6H3
III R = 1-naphthyl
N
OTMS
H
Entry
1
Additive base
none
Solvent
CH2Cl2
CHCl3
MeOH
CH2Cl2
CHCl3
THF
Cat.
I
Conversionb,c (%) Ratio 3a/4ac,d
eec,e (%)
nd
nd
96
nd
nd
nd
nd
nd
nd
nd
96
96
93
94
93
95
94
92
87
95
94
nd
nd
nd
nd
13
nd
2
none
I
9
77
29
28
11
20
16
20
28
62
94
92
93
96
93
95
98
96
94
97
55
11
n.r.
n.r.
nd
3
none
I
80:20
84:16
87:13
nd
4
LiOAc
I
5
LiOAc
I
6
LiOAc
I
7
LiOAc
EtOAc
benzene
toluene
MeCN
EtOH
I
nd
8
LiOAc
I
nd
9
LiOAc
I
nd
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
LiOAc
I
13:87
84:16
85:15
89:11
88:12
90:10
88:12
87:13
86:14
9:90
80:20
50:50
86:14
nd
LiOAc
I
LiOAc
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
I
NaOAc
KOAc
I
I
PhCO2Li
4-FC6H4CO2Li
4-MeOC6H4CO2Li
LiOPh
I
I
I
I
LiOH
I
Et3N
I
DBU
I
PhCO2H
AcOH
I
I
LiOAc
II
III
nd
LiOAc
nd
a Reaction conditions: cinnamaldehyde (1a; 0.1 mmol), acetophenone (2a; 0.3 mmol), catalyst (0.02 mmol), additive base (0.02 mmol), solvent
(0.1 mL), r.t., 48 h.
b Conversion was determined by GC.
c Abbreviations: nd = not determined; n.r. = no reaction.
d The 3a/4a ratio was determined by GC and NMR spectroscopy.
e The ee was determined by HPLC by using a Chiralpak® AD-H column.
Synthesis 2011, No. 7, 1085–1091 © Thieme Stuttgart · New York

PAPER
Asymmetric Direct Michael Addition of Acetophenone
1087
Subsequently, further conditions were investigated. It is triethylamine resulted in 94% conversion, 80:20
well known that an acidic environment facilitates the for- chemoselectivity, and 95% ee (entry 20). The more basic
mation of an imine from the catalyst and the enal, while a 1,8-diazabicyclo[5.4.0]undec-7-ene caused a decrease of
base aids the activation of nucleophiles. Therefore, it is chemoselectivity to 50:50 (entry 21). If the additive base
crucial to use the proper additive to promote the reaction was substituted by an acidic additive, the reaction did not
efficiently and selectively. The experiments using differ- proceed efficiently. With benzoic acid, only 55% conver-
ent additives indicated that the chemoselectivity was de- sion and a chemoselectivity of about 86:14 were obtained
pendent on the basicity of the additive base. The (entry 22). Moreover, the use of acetic acid resulted in
appropriate basicity was necessary to afford satisfying very low conversion (entry 23). More experiments also in-
chemoselectivity. For example, similar results were ob- dicated that other kinds of diarylprolinol catalysts II and
tained when other acetate additives and lithium benzoates III did not catalyze this reaction (entries 24 and 25). This
were used as additive base (entries 13–17). The more ba- might be attributed to the great steric bulk of these cata-
sic lithium phenolate caused a decrease of chemoselectiv- lysts.
ity to 86:14 (entry 18). When lithium hydroxide was used,
With the optimized reaction conditions in hand, the scope
the major product became the 1,2-addition product (entry
of the Michael reaction was investigated. The results are
19). An organic amine base was also tested. The using of
summarized in Table 2. It appears that for aromatic a,b-
Table 2 Organocatalytic Asymmetric Direct Michael Additions of Acetophenones to a,b-Unsaturated Aldehydesa
O
O
O
O
I (20 mol%)
R1
R1
R2
+
O
+
R2
R1
R2
MeOH, LiOAc, r.t.
1
2
3
4
Time (h)
48
Entry
1
R1
Ph
R2
Ph
Ph
Ph
Ph
Ratio 3/4b
85:15
90:10
91:9
Yieldc (%)
74 (3a)
75 (3b)
82 (3c)
73 (3d)
76 (3e)
73 (3f)
69 (3g)
78 (3h)
77 (3i)
eed (%)
96
2
3-MeC6H4
4-MeC6H4
4-FC6H4
48
95
3
48
98
4
48
88:12
90:10
87:13
82:18
90:10
88:12
88:12
90:10
89:11
85:15
82:18
83:17
84:16
85:15
nde
94
5
4-BrC6H4
4-ClC6H4
2-ClC6H4
4-MeOC6H4
2-MeOC6H4
2-MeOC6H4
2-MeOC6H4
2-MeOC6H4
4-ClC6H4
2-ClC6H4
2-ClC6H4
4-BrC6H4
Ph
3-BrC6H4
2-FC6H4
3-BrC6H4
Ph
24
96
6
24
97
7
24
97
8
36
96
9
Ph
24
98
10
11
12
13
14
15
16
17
18
2-HOC6H4
3-BrC6H4
4-O2NC6H4
3-BrC6H4
2-ClC6H4
2-FC6H4
2-FC6H4
2-furyl
24
76 (3j)
80 (3k)
78 (3l)
94
24
95
24
96
24
79 (3m)
71 (3n)
72 (3o)
73 (3p)
74 (3q)
mixture
96
24
98
24
97
24
96
48
94
Et
Ph
48
nde
a Reaction conditions: a,b-unsaturated aldehyde 1 (0.3 mmol), ketone 2 (0.9 mmol), I (0.06 mmol), LiOAc (0.06 mmol), MeOH (0.3 mL), r.t.,
indicated time.
b The 3/4 ratio was determined by GC and NMR spectroscopy.
c Isolated yield.
d The ee was determined by HPLC by using a Chiralpak® AD-H column and AY-H column.
e nd = not determined.
Synthesis 2011, No. 7, 1085–1091 © Thieme Stuttgart · New York

1088
W. Li et al.
PAPER
O
Ph
Ph
OTMS
Ph
Ph
OTMS
OH
N
O
AcO–
+
N
H
R
I
1
R
2
O
direct Michael addition
O
R
3
Scheme 2 Proposed working model of the Michael addition
unsaturated aldehydes, substituents on the benzene ring NMR spectra were recorded on a Varian DRX 400 spectrometer;
CDCl3 was used as the solvent with TMS as an internal reference.
had a limited effect on the reaction results. Excellent
GC analysis was carried out on an Agilent 7890N instrument. Mass
enantioselectivities and high yields were obtained regard-
spectra (EI) were measured on a Waters Micromass GCT spectrom-
less of the type of substituent on the aryl moieties (entries
eter. Optical rotations were determined on an Autopol III automatic
polarimeter. HPLC was performed on an Agilent 1200 Series chro-
1–9). Furthermore, excellent enantioselectivities and high
yields were also obtained independent of the electronic
characteristics of the aromatic ketones. All of the aromatic
ketones that have electron-withdrawing and heterocyclic
substituents gave excellent enantioselectivities (entries
10–17). Notably, in all cases, the reactions were complet-
ed with excellent levels of enantioselectivities (94–98%),
which indicated that this method has the potential to af-
ford optically pure compounds. Apart from the additive
base, the electronic properties of the cinnamaldehyde de-
rivatives also affected the chemoselectivity of the reac-
tion. The cinnamaldehyde derivatives containing
electron-donating groups such as methyl and methoxy on
the aromatic ring (entries 2, 3, and 8–12) afforded higher
chemoselectivities than those with electron-withdrawing
groups, such as chloro or bromo (entries 5–7 and 13–16).
Unfortunately, for aliphatic a,b-unsaturated aldehydes,
such as pentenal, a complex mixture was obtained, which
was caused by Robinson annulation of aliphatic a,b-un-
saturated aldehydes (entry 18).10
matograph with Chiral AD-H, AY-H (0.46 cm × 25 cm) columns,
as noted. All reagents were obtained commercially and used with-
out further purification, unless noted otherwise.
5-Oxo-3,5-diphenylpentanal (3a); General Procedure
A mixture of a,b-unsaturated aldehyde 1 (0.3 mmol), ketone 2 (0.9
mmol), catalyst I (0.06 mmol), and LiOAc (0.06 mmol) in MeOH
(0.3 mL) was stirred at r.t. for the time indicated in Table 2. Then
the solvent was removed under vacuum and the residue was purified
by column chromatography (silica gel); this gave the corresponding
product. The ee was determined by HPLC.
5-Oxo-3,5-diphenylpentanal (3a)
Purified by column chromatography (silica gel, PE–EtOAc, 10:1);
yield: 74%; yellow oil; [a]D23 –1.2 (c 0.50, CH2Cl2).
1H NMR (400 MHz, CDCl3): d = 9.73 (s, 1 H), 7.95–7.93 (m, 2 H),
7.59–7.56 (m, 1 H), 7.48–7.45 (m, 2 H), 7.35–7.22 (m, 5 H), 4.02–
3.97 (m, 1 H), 3.37 (d, J = 7.2 Hz, 2 H), 2.97–2.81 (m, 2 H).
13C NMR (100 MHz, CDCl3): d = 201.2, 198.1, 143.2, 136.7, 133.2,
128.8, 128.6, 128.0, 127.4, 127.0, 49.6, 45.0, 35.4.
HRMS (EI): m/z [M+] calcd for C17H16O2: 252.1150; found:
The absolute configuration of the Michael addition adduct
was S, which was determined by comparison of the optical
rotations to those reported in the literature.4 A proposed
working model of the Michael addition is showed in
Scheme 2. The a,b-unsaturated aldehyde is activated by
the Jørgensen–Hayashi catalyst to form an iminium cat-
ion. Enolization of acetophenone was likely promoted by
cooperative action of the lithium cation and the acetate an-
ion. Then the direct Michael addition was triggered by the
active iminium cation, which was attacked by the enol to
give the Michael product 3 in excellent enantioselectivity.
252.1149.
HPLC: 96% ee (AD-H column, 254 nm, n-hexane–i-PrOH, 9:1, 0.8
mL/min): 16.0 min (major), 22.4 min (minor).
5-Oxo-5-phenyl-3-m-tolylpentanal (3b)
Purified by column chromatography (silica gel, PE–EtOAc, 10:1);
yield: 75%; yellow oil; [a]D22 –1.8 (c 0.50, CH2Cl2).
1H NMR (400 MHz, CDCl3): d = 9.72 (t, J = 2.0 Hz, 1 H), 7.95–7.93
(m, 2 H), 7.60–7.56 (m, 1 H), 7.49–7.45 (m, 2 H), 7.24–7.20 (m, 1
H), 7.10–7.04 (m, 3 H), 4.00–3.93 (m, 1 H), 3.36 (d, J = 7.2 Hz, 2
H), 2.91–2.83 (m, 2 H), 2.35 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 201.3, 198.2, 143.2, 138.5, 136.8,
133.2, 128.7, 128.6, 128.2, 128.1, 127.7, 124.3, 49.5, 45.0, 35.4,
21.5.
In summary, the first enantioselective direct Michael reac-
tion of a,b-unsaturated aldehydes with acetophenone was
developed, and was catalyzed by the Jørgensen–Hayashi
catalyst I. This approach is a powerful tool for providing
the synthetically important d-keto aldehydes. However,
the substrate scope of this reaction is still limited. For ali-
phatic a,b-unsaturated aldehydes, no desired products
were obtained. Further research in this field is being car-
ried out and the results will be presented in the future.
HRMS (EI): m/z [M+] calcd for C18H18O2: 266.1307; found:
266.1323.
HPLC: 95% ee (AD-H column, 254 nm, n-hexane–i-PrOH, 9:1, 0.8
mL/min): 13.2 min (major), 15.6 min (minor).
Synthesis 2011, No. 7, 1085–1091 © Thieme Stuttgart · New York

PAPER
Asymmetric Direct Michael Addition of Acetophenone
1089
5-Oxo-5-phenyl-3-p-tolylpentanal (3c)
1H NMR (400 MHz, CDCl3): d = 9.74 (s, 1 H), 8.08–8.07 (m, 1 H),
7.89–7.87 (m, 1 H), 7.71–7.69 (m, 1 H), 7.41–7.30 (m, 3 H), 7.26–
7.17 (m, 2 H), 4.47–4.43 (m, 1 H), 3.43–3.37 (m, 2 H), 2.98–2.92
(m, 2 H).
13C NMR (100 MHz, CDCl3): d = 200.7, 196.5, 140.0, 138.3, 136.1,
133.5, 131.1, 130.3, 130.2, 128.3, 128.2, 127.3, 126.6, 123.0.
Purified by column chromatography (silica gel, PE–EtOAc, 10:1);
yield: 82%; yellow oil; [a]D23 –2.6 (c 0.50, CH2Cl2).
1H NMR (400 MHz, CDCl3): d = 9.73–9.72 (m, 1 H), 7.95–7.93 (m,
2 H), 7.59–7.56 (m, 1 H), 7.48–7.45 (m, 2 H), 7.20–7.13 (m, 4 H),
3.99–3.96 (m, 1 H), 3.35 (d, J = 7.2 Hz, 2 H), 2.91–2.82 (m, 2 H),
2.33 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 201.4, 198.2, 140.2, 136.8, 136.5,
133.2, 129.5, 128.6, 128.2, 127.4, 49.7, 45.1, 35.0, 21.1.
HRMS (EI): m/z [M+] calcd for C17H14O2ClBr: 363.9866; found:
363.9869.
HPLC: 97% ee (AD-H column, 254 nm, n-hexane–i-PrOH, 9:1, 0.8
mL/min): 24.1 min (major), 29.4 min (minor).
HRMS (EI): m/z [M+] calcd for C18H18O2: 266.1307; found:
266.1309.
3-(4-Methoxyphenyl)-5-oxo-5-phenylpentanal (3h)
Purified by column chromatography (silica gel, PE–EtOAc, 10:1);
yield: 78%; yellow oil; [a]D22 –3.2 (c 0.50, CH2Cl2).
HPLC: 98% ee (AD-H column, 254 nm, n-hexane–i-PrOH, 9:1, 0.8
mL/min): 15.3 min (major), 21.0 min (minor).
3-(4-Fluorophenyl)-5-oxo-5-phenylpentanal (3d)
1H NMR (400 MHz, CDCl3): d = 9.72 (s, 1 H), 7.94–7.92 (m, 2 H),
7.59–7.55 (m, 1 H), 7.48–7.45 (m, 2 H), 7.22–7.20 (m, 2 H), 6.87–
6.85 (m, 2 H), 3.98–3.94 (m, 1 H), 3.79 (s, 3 H), 3.33 (d, J = 6.8 Hz,
2 H), 2.90–2.88 (m, 1 H), 2.83–2.81 (m, 1 H).
13C NMR (100 MHz, CDCl3): d = 201.4, 198.3, 158.4, 136.8, 135.1,
133.2, 128.6, 128.3, 128.0, 114.2, 55.2, 49.7, 45.2, 34.7.
Purified by column chromatography (silica gel, PE–EtOAc, 10:1);
yield: 73%; yellow oil; [a]D23 –2.3 (c 0.50, CH2Cl2).
1H NMR (400 MHz, CDCl3): d = 9.73 (s, 1 H), 8.04–8.03 (m, 1 H),
7.85–7.83 (m, 1 H), 7.71–7.69 (m, 1 H), 7.37–7.28 (m, 4 H), 7.24–
7.21 (m, 2 H), 3.98–3.94 (m, 1 H), 3.33–3.30 (m, 2 H), 2.92–2.85
(m, 2 H).
13C NMR (100 MHz, CDCl3): d = 200.8, 197.9, 162.9, 138.9, 136.7,
133.3, 128.9, 128.7, 128.0, 115.7, 115.5, 49.7, 44.9, 34.6.
HRMS (EI): m/z [M+] calcd for C18H18O3: 282.1256; found:
282.1257.
HPLC: 96% ee (AD-H column, 254 nm, n-hexane–i-PrOH, 9:1, 0.8
mL/min): 24.3 min (major), 35.2 min (minor).
HRMS (EI): m/z [M+] calcd for C17H15O2F: 270.1056; found:
270.1057.
3-(2-Methoxyphenyl)-5-oxo-5-phenylpentanal (3i)
Purified by column chromatography (silica gel, PE–EtOAc, 10:1);
yield: 77%; yellow oil; [a]D22 –3.2 (c 0.50, CH2Cl2).
HPLC: 94% ee (AS-H column, 254 nm, n-hexane–i-PrOH, 9:1, 0.8
mL/min): 17.0 min (major), 23.8 min (minor).
5-(3-Bromophenyl)-3-(4-bromophenyl)-5-oxopentanal (3e)
Purified by column chromatography (silica gel, PE–EtOAc, 10:1);
yield: 76%; yellow oil; [a]D24 –4.2 (c 0.50, CH2Cl2).
1H NMR (400 MHz, CDCl3): d = 9.73–9.72 (m, 1 H), 8.04–8.02 (m,
1 H), 7.85–7.83 (m, 1 H), 7.72–7.69 (m, 1 H), 7.46–7.44 (m, 2 H),
7.35–7.33 (m, 1 H), 7.18–7.16 (m, 2 H), 3.97–3.93 (m, 1 H), 3.33–
3.30 (m, 2 H), 2.92–2.90 (m, 1 H), 2.87–2.85 (m, 1 H).
1H NMR (400 MHz, CDCl3): d = 9.72 (t, J = 2.0 Hz, 1 H), 7.98–7.96
(m, 2 H), 7.59–7.56 (m, 1 H), 7.49–7.45 (m, 2 H), 7.23–7.21 (m, 2
H), 6.95–6.88 (m, 2 H), 4.30–4.27 (m, 1 H), 3.85 (s, 3 H), 3.47–3.34
(m, 2 H), 2.92–2.86 (m, 2 H).
13C NMR (100 MHz, CDCl3): d = 202.1, 198.8, 157.0, 136.9, 133.1,
130.8, 128.6, 128.5, 128.4, 128.1, 120.8, 110.8, 55.3, 48.0, 43.2,
30.7.
13C NMR (100 MHz, CDCl3): d = 200.4, 196.4, 142.0, 138.3, 136.2,
131.9, 131.1, 130.3, 129.2, 126.5, 123.0, 120.8, 49.4, 44.6, 34.6.
HRMS (EI): m/z [M+] calcd for C18H18O3: 282.1256; found:
282.1263.
HRMS (EI): m/z [M+] calcd for C17H14O2Br2: 407.9361; found:
HPLC: 98% ee (AD-H column, 254 nm, n-hexane–i-PrOH, 9:1, 0.8
407.9363.
mL/min): 18.0 min (major), 21.6 min (minor).
HPLC: 96% ee (AD-H column, 254 nm, n-hexane–i-PrOH, 9:1, 0.8
mL/min): 20.9 min (major), 24.7 min (minor).
5-(2-Hydroxyphenyl)-3-(2-methoxyphenyl)-5-oxopentanal (3j)
Purified by column chromatography (silica gel, PE–EtOAc, 10:1);
yield: 76%; yellow oil; [a]D23 –4.9 (c 0.50, CH2Cl2).
1H NMR (400 MHz, CDCl3): d = 12.25 (s, 1 H) 9.74–9.73 (m, 1 H),
7.84–7.82 (m, 1 H), 7.50–7.46 (m, 1 H), 7.24–7.21 (m, 2 H), 6.99–
6.89 (m, 4 H), 4.27–4.24 (m, 1 H), 3.84 (s, 3 H), 3.43–3.39 (m, 2 H),
2.95–2.92 (m, 2 H).
13C NMR (100 MHz, CDCl3): d = 205.2, 193.9, 163.5, 162.5, 157.1,
147.9, 136.3, 130.5, 129.9, 128.0, 125.6, 120.8, 119.5, 118.8, 110.9,
55.3, 43.1, 37.4, 34.9.
3-(4-Chlorophenyl)-5-(2-fluorophenyl)-5-oxopentanal (3f)
Purified by column chromatography (silica gel, PE–EtOAc, 10:1);
yield: 73%; yellow oil; [a]D24 –3.6 (c 0.50, CH2Cl2).
1H NMR (400 MHz, CDCl3): d = 9.71–9.70 (m, 1 H), 7.81–7.77 (m,
1 H), 7.56–7.51 (m, 1 H), 7.30–7.28 (m, 2 H), 7.24–7.21 (m, 3 H),
7.16–7.12 (m, 1 H), 4.00–3.95 (m, 1 H), 3.37–3.35 (m, 2 H), 2.93–
2.78 (m, 2 H).
13C NMR (100 MHz, CDCl3): d = 200.6, 196.0, 163.1, 160.6, 141.7,
134.9, 134.8, 132.5, 130.6, 128.9, 124.6, 116.8, 116.6, 49.6, 34.5,
29.7.
HRMS (EI): m/z [M+] calcd for C18H18O4: 298.1205; found:
298.1207.
HRMS (EI): m/z [M+] calcd for C17H14O2ClF: 304.0666; found:
HPLC: 94% ee (AD-H column, 254 nm, n-hexane–i-PrOH, 9:1, 0.8
304.0670.
mL/min): 13.3 min (minor), 14.8 min (major).
HPLC: 97% ee (AD-H column, 254 nm, n-hexane–i-PrOH, 9:1, 0.8
mL/min): 14.4 min (major), 19.4 min (minor).
5-(3-Bromophenyl)-3-(2-methoxyphenyl)-5-oxopentanal (3k)
Purified by column chromatography (silica gel, PE–EtOAc, 10:1);
yield: 80%; yellow oil; [a]D23 –4.7 (c 0.50, CH2Cl2).
1H NMR (400 MHz, CDCl3): d = 9.72 (t, J = 2.0 Hz, 1 H), 8.09–8.07
(m, 1 H), 7.90–7.88 (m, 1 H), 7.70–7.68 (m, 1 H), 7.37–7.33 (m, 1
H), 7.26–7.20 (m, 2 H), 6.95–6.88 (m, 2 H), 4.28–4.21 (m, 1 H),
5-(3-Bromophenyl)-3-(2-chlorophenyl)-5-oxopentanal (3g)
Purified by column chromatography (silica gel, PE–EtOAc, 10:1);
yield: 69%; yellow oil; [a]D23 –1.9 (c 0.50, CH2Cl2).
Synthesis 2011, No. 7, 1085–1091 © Thieme Stuttgart · New York

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W. Li et al.
PAPER
3.86 (s, 3 H), 3.44–3.38 (m, 1 H), 3.32–3.26 (m, 1 H), 2.93–2.89 (m,
2 H).
13C NMR (100 MHz, CDCl3): d = 201.8, 197.5, 156.9, 138.6, 135.9,
131.2, 130.4, 130.2, 128.4, 128.2, 126.6, 122.9, 120.8, 110.9, 53.5,
47.9, 43.4, 30.8.
13C NMR (100 MHz, CDCl3): d = 200.8, 196.0, 163.2, 160.6, 140.2,
134.8, 133.6, 130.6, 130.1, 128.2, 127.2, 125.4, 124.6, 116.8, 48.4,
47.9, 31.7.
HRMS (EI): m/z [M+] calcd for C17H14O2ClF: 304.0666; found:
304.0671.
HRMS (EI): m/z [M+] calcd for C18H17O3Br: 360.0361; found:
HPLC: 97% ee (AD-H column, 254 nm, n-hexane–i-PrOH, 9:1, 0.8
360.0365.
mL/min): 12.6 min (minor), 14.3 min (major).
HPLC: 95% ee (AY-H column, 254 nm, n-hexane–EtOH, 1:1, 0.8
mL/min): 14.3 min (major), 23.1 min (minor).
3-(4-Bromophenyl)-5-(2-fluorophenyl)-5-oxopentanal (3p)
Purified by column chromatography (silica gel, PE–EtOAc, 10:1);
yield: 73%; yellow oil; [a]D24 –4.3 (c 0.50, CH2Cl2).
1H NMR (400 MHz, CDCl3): d = 9.70 (s, 1 H), 7.81–7.77 (m, 1 H),
7.54–7.51 (m, 1 H), 7.44–7.40 (m, 2 H), 7.24–7.11 (m, 4 H), 3.98–
3.95 (m, 1 H), 3.37–3.34 (m, 2 H), 2.88–2.79 (m, 2 H).
13C NMR (100 MHz, CDCl3): d = 200.5, 195.9, 142.3, 134.9, 134.8,
131.8, 130.6, 129.2, 124.6, 124.5, 120.6, 116.8, 116.5, 49.5, 49.4,
34.5.
3-(2-Methoxyphenyl)-5-(4-nitrophenyl)-5-oxopentanal (3l)
Purified by column chromatography (silica gel, PE–EtOAc, 10:1);
yield: 78%; yellow oil; [a]D23 –4.8 (c 0.50, CH2Cl2).
1H NMR (400 MHz, CDCl3): d = 9.74 (s, 1 H), 8.31–8.29 (m, 2 H),
8.11–8.09 (m, 2 H), 7.23–7.19 (m, 2 H), 6.95–6.87 (m, 2 H), 4.25–
4.24 (m, 1 H), 3.83 (s, 3 H), 3.45–3.41 (m, 2 H), 2.98–2.92 (m, 2 H).
13C NMR (100 MHz, CDCl3): d = 201.6, 197.4, 156.9, 150.3, 141.3,
130.1, 129.5, 128.4, 128.3, 123.8, 120.9, 110.9, 55.2, 47.9, 43.7,
30.9.
HRMS (EI): m/z [M+] calcd for C17H14O2FBr: 348.0161; found:
348.0159.
HRMS (EI): m/z [M+] calcd for C18H17NO5: 327.1107; found:
HPLC: 96% ee (AD-H column, 254 nm, n-hexane–i-PrOH, 9:1, 0.8
327.1110.
mL/min): 16.5 min (major), 19.0 min (minor).
HPLC: 96% ee (AD-H column, 254 nm, n-hexane–i-PrOH, 9:1, 0.8
mL/min): 13.7 min (major), 18.0 min (minor).
5-(2-Furyl)-5-oxo-3-phenylpentanal (3q)
Purified by column chromatography (silica gel, PE–EtOAc, 10:1);
yield: 74%; yellow oil; [a]D24 –5.6 (c 0.50, CH2Cl2).
5-(3-Bromophenyl)-3-(4-chlorophenyl)-5-oxopentanal (3m)
Purified by column chromatography (silica gel, PE–EtOAc, 10:1);
yield: 79%; yellow oil; [a]D24 –3.1 (c 0.50, CH2Cl2).
1H NMR (400 MHz, CDCl3): d = 9.73–9.72 (m, 1 H), 8.04–8.03 (m,
1 H), 7.85–7.83 (m, 1 H), 7.71–7.69 (m, 1 H), 7.37–7.33 (m, 1 H),
7.31–7.28 (m, 2 H), 7.24–7.21 (m, 2 H), 4.00–3.93 (m, 1 H), 3.33–
3.30 (m, 2 H), 2.97–2.80 (m, 2 H).
13C NMR (100 MHz, CDCl3): d = 200.4, 196.4, 141.5, 138.3, 136.2,
132.7, 131.1, 130.3, 129.0, 128.8, 126.5, 123.0, 49.5, 44.7, 34.6.
HRMS (EI): m/z [M+] calcd for C17H14O2ClBr: 363.9866; found:
1H NMR (400 MHz, CDCl3): d = 9.70–7.69 (m, 1 H), 7.56–7.55 (m,
1 H), 7.33–7.27 (m, 4 H), 7.23–7.16 (m, 2 H), 6.52–6.51 (m, 1 H),
3.98–3.93 (m, 1 H), 3.27–3.15 (m, 2 H), 2.95–2.81 (m, 2 H).
13C NMR (100 MHz, CDCl3): d = 201.1, 187.2, 152.6, 146.5, 142.8,
128.8, 127.3, 127.0, 117.4, 112.3,49.3, 44.6, 35.4.
HRMS (EI): m/z [M+] calcd for C15H14O3: 242.0943; found:
242.0948.
HPLC: 94% ee (AS-H column, 254 nm, n-hexane–i-PrOH, 9:1, 0.8
mL/min): 19.4 min (major), 26.9 min (minor).
363.9868.
HPLC: 96% ee (AD-H column, 254 nm, n-hexane–i-PrOH, 9:1, 0.8
mL/min): 19.3 min (major), 22.5 min (minor).
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.
3,5-Bis(2-chlorophenyl)-5-oxopentanal (3n)
Purified by column chromatography (silica gel, PE–EtOAc, 10:1);
Acknowledgment
yield: 71%; yellow oil; [a]D23 –3.3 (c 0.50, CH2Cl2).
We thank the National Natural Science Foundation of China
(20902018), Shanghai Pujiang Program (08PJ1403300), Innovation
Program of Shanghai Municipal Education Commission (11ZZ56),
and the Fundamental Research Funds for the Central Universities
for financial support of this work.
1H NMR (400 MHz, CDCl3): d = 9.74 (s, 1 H), 7.40–7.28 (m, 5 H),
7.25–7.18 (m, 3 H), 4.45–4.41 (m, 1 H), 3.44–3.41 (m, 2 H), 2.96–
2.91 (m, 2 H).
13C NMR (100 MHz, CDCl3): d = 200.6, 139.7, 138.9, 133.6, 131.9,
130.8, 130.5, 130.1, 128.9, 128.4, 128.2, 127.2, 127.0, 48.1, 47.2,
32.2.
References
HRMS (EI): m/z [M+] calcd for C17H14O2Cl2: 320.0371; found:
320.0411.
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Synthesis 2011, No. 7, 1085–1091 © Thieme Stuttgart · New York

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Synthesis 2011, No. 7, 1085–1091 © Thieme Stuttgart · New York