Efficient synthesis of a new type of baylis-hillman adducts and their stereoselective bromination

Article abstract of DOI:10.1080/00397910903262187

A new type of Baylis-Hillman adducts derived from chlorovinyl aldehydes were prepared via Vilsmeier reaction of ketones with a bis(trichloromethyl) carbonate (BTC)/DMF system to construct chlorovinyl aldehydes, followed by sonochemical Baylis-Hillman reaction under solvent-free conditions. The stereoselective bromination of these new compounds with a Br2-Ph3P system has been achieved efficiently with good to excellent yields under mild conditions. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910903262187

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Efficient Synthesis of a New Type
of Baylis–Hillman Adducts and Their
Stereoselective Bromination
Weihui Zhong a , Lingbo Jiang a , Baoming Guo a , Yaotiao Wu a ,
Lingjuan Hong a & Yanhui Chen a
a Key Laboratory of Pharmaceutical Engineering (Ministry of
Education), College of Pharmaceutical Sciences, Zhejiang University
of Technology , Hangzhou, China
Published online: 26 Jul 2010.
To cite this article: Weihui Zhong , Lingbo Jiang , Baoming Guo , Yaotiao Wu , Lingjuan Hong & Yanhui
Chen (2010) Efficient Synthesis of a New Type of Baylis–Hillman Adducts and Their Stereoselective
Bromination, Synthetic Communications: An International Journal for Rapid Communication of
Synthetic Organic Chemistry, 40:16, 2441-2456, DOI: 10.1080/00397910903262187
To link to this article: http://dx.doi.org/10.1080/00397910903262187
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Synthetic Communications1, 40: 2441–2456, 2010
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910903262187
EFFICIENT SYNTHESIS OF A NEW TYPE OF BAYLIS–
HILLMAN ADDUCTS AND THEIR STEREOSELECTIVE
BROMINATION
Weihui Zhong, Lingbo Jiang, Baoming Guo, Yaotiao Wu,
Lingjuan Hong, and Yanhui Chen
Key Laboratory of Pharmaceutical Engineering (Ministry of Education),
College of Pharmaceutical Sciences, Zhejiang University of Technology,
Hangzhou, China
A new type of Baylis–Hillman adducts derived from chlorovinyl aldehydes were prepared
via Vilsmeier reaction of ketones with a bis(trichloromethyl) carbonate (BTC)/DMF
system to construct chlorovinyl aldehydes, followed by sonochemical Baylis–Hillman
reaction under solvent-free conditions. The stereoselective bromination of these new
compounds with a Br2-Ph3P system has been achieved efficiently with good to excellent
yields under mild conditions.
Keywords: Baylis–Hillman reaction; bromination; stereoselective; ultrasonic; Vilsmeier reaction
The Baylis–Hillman reaction is a useful carbon–carbon bond-forming reaction
for the construction of important functionalized molecules,[1] and the conversion
of Baylis–Hillman adducts to the corresponding halides has also caught much atten-
tion because the halides are useful synthons for preparation of various natural and
bioactive compounds and their analogs.[2] To accelerate the Baylis–Hillman reaction
rate, various methods including novel and efficient catalysts and microwave or ultra-
sonic waves have been examined, and much success has been achieved.1b To improve
the stereoselectivity of Baylis–Hillman halides, various reagents have been used, such
as inorganic acids (HBr, HCl, HBr-H2SO4, HI-H3PO4),[3] organic acid halides
(oxalyl chloride, MsCl),[4] PBr3,[5] complex systems [NCS=N-bromosuccinimide
(NBS)-Me2S, NCS=NBS-Ph3P, I2=Br2-Ph3P, CCl4-Ph3P, I2-PMHS],[6] metallic
halides (FeCl3, NaI, LiBr, MgBr2),[7] and KSF clay under microwave irradiation.[8]
Some of them suffer from harsh reaction conditions, prolonged reaction times, and
unsatisfactory yields. Here, we describe an efficient synthesis of a new type Baylis–
Hillman adducts under ultrasonic conditions and their stereoselective bromination
using a Br2-Ph3P system (Scheme 1).
Received May 17, 2009.
Address correspondence to Weihui Zhong, Key Laboratory of Pharmaceutical Engineering
(Ministry of Education), College of Pharmaceutical Sciences, Zhejiang University of Technology,
Hangzhou 310014, China. E-mail: weihuizhong@zjut.edu.cn
2441

2442
W. ZHONG ET AL.
Scheme 1. Preparation of a new type of Baylis–Hillman adducts and their bromination.
In our previous work,[9] chlorovinyl aldehydes could be prepared by treatment
of ketones with Vilsmeier reagent derived from a bis(trichloromethyl) carbonate
(BTC)=dimethylformamide (DMF) system instead of the traditional POCl3=DMF
system. Here, we examine this reaction on a large scale, and the results are summar-
ized in Table 1.
In continuation of our research on the Baylis–Hillman reaction and its
adducts,[10] we used the chlorovinyl aldehydes 2 to construct a new type of
Baylis–Hillman adducts under ultrasonic conditions. To obtain the optimal
condition, we chose (Z)-3-chloro-3-(4-chlorophenyl)acrylaldehyde (2a) as a model
substrate of Baylis–Hillman reaction. Various factors including solvents, bases,
Table 1. Synthesis of chlorovinyl aldehydes (2) from ketones (1) by Vilsmeier reactiona
Entry
R
Time (h)
Products
Yields (%)b
1
2
3
4
5
6
7
p-ClC6H4
m-ClC6H4
p-FC6H4
8
8
8
8
7
8
8
2a
2b
2c
2d
2e
2f
82
82
81
83
80
80
81
C6H5
p-MeC6H4
p-MeOC6H4
p-NO2C6H4
2g
8
9
8
8
2h
2i
82
66
aReaction conditions: 1 (100.0 mmol), BTC (100.0 mmol), DMF (300.0 mmol), and chloroform
(100 mL) were used.
bIsolated yields based on 1.

BAYLIS–HILLMAN ADDUCTS
2443
Table 2. Reactions of 2a with methyl acrylate under different conditionsa
Entry
Solvent
Base
Temp. (ꢀC)
Time (h)
Yields of 4a (%)b
1
2
DMF
Toluene
THF
CHCl3
—
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
DMAP
50
50
50
50
50.
50
r.t.
70
50
50
14
14
14
14
3
62
56
61
57
85
72c
77
68
65
60
3
4
5
6
—
—
10
5
7
8
—
—
3
9
10
3
—
DBU
3
aReaction conditions: 2a (50.0 mmol), 3a (100.0 mmol), base (10.0 mmol), and solvent (50 mL) were
used.
bIsolated yields based on 2a.
cIn the absence of ultrasound.
and temperature were thoroughly studied, and the results are summarized in
Table 2. First, several solvents and solvent-free conditions were surveyed under
ultrasonic conditions. When 2a, methyl acrylate (3a), and 1,4-diazabicyclo[2.2.2]
octane (DABCO) were mixed in DMF, toluene, tetrahydrofuran (THF), or
chloroform for 14 h, product 4a could be obtained in moderate yield (Table 2,
entries 1–4). The greatest yield was obtained under ultrasonic and solvent-free
conditions within 3 h (Table 2, entry 5). Second, the effects of temperature and
bases on yield of 4a were considered. When DABCO was used to promote this
reaction at room temperature, 4a was formed with less yield even when the reac-
tion time was prolonged. The optimal temperature for this reaction was 50 ꢀC,
and further elevating temperature did not benefit to the reaction yield. Compared
to DABCO, the bases 4-dimethylaminopyridine (DMAP) or 1,8-diazabicyclo[5.4.0]
undec-7-ene (DBU) provided only moderate yields of the desired product 4a
(Table 2, entries 9 and 10).
To increase the scope of this strategy, various chlorovinyl aldehydes 2
were used for the Baylis–Hillman reaction under similar conditions, and the
full results are summarized in Table 3. Most of substrates 2 could produce
the corresponding products in good to excellent yields except for those derived
from cycloketones (Table 3, entries 11–13). The substituted groups on the
aromatic ring obviously influenced the rate and efficiency of the reaction.
The substrates with electron-donating groups proceeded in less time and
afforded the corresponding products in better yields than those with electron-
withdrawing groups, except for 2g (nitro group). Interestingly, treatment of
2g with methyl acrylate (3a) and DABCO under ultrasonic conditions could

2444
W. ZHONG ET AL.
Table 3. Synthesis of a new type of Baylis–Hillman adducts from chlorovinyl aldehydes with acrylate
esters or acrylonitrilea
Entry
R
EWG
Time (h)
Products and yields (%)b
1
2
p-ClC6H4
m-ClC6H4
p-FC6H4
C6H5
CO2Me
CO2Me
CO2Me
CO2Me
CO2Et
CO2Me
CO2Et
CO2Me
CO2Me
CN
3.5
3.5
4
4a (84)
4b (84)
4c (82)
4d (86)
4e (85)
4f (88)
4g (87)
4h (92)
4i (81)c
4j (88)
3
4
3.5
3.5
3
5
C6H5
6
p-MeC6H4
p-MeC6H4
p-MeOC6H4
p-NO2C6H4
C6H5
7
3
8
2.5
12
3.5
9
10
11
12
13
CO2Me
CO2Et
CO2Me
12
12
48
4k (68)
4l (66)
4m (15)
aReaction conditions: 2 (50.0 mmol), 3 (100.0 mmol), and DABCO (10.0 mmol) were used.
bIsolated yields based on 2.
cIn the absence of ultrasound.
not provide the corresponding Baylis–Hillman adduct 4i, whereas when this
reaction was stirred at 50 ꢀC for 12 h without ultrasonic radiation, 81% yield
of 4i could be obtained.
Encouraged by these results, we further investigated the bromination of these
new Baylis–Hillman adducts 4. First, preliminary experiments were carried out by
mixing compound 4a with 48% HBr in CH2Cl2 at room temperature for 4 h; the
desired product 5a and its isomer 6a were isolated with yields of 62% and 19%,
respectively (Table 4, entry 1). To improve the reaction stereoselectivity, various fac-
tors including bromination reagents, solvents, reaction temperature, and time were
screened as shown in Table 4. HBr or PBr3 produced worse stereoselectivities
(Table 4, entries 1–4). Though the NBS-Ph3P system could produce 5a with good
stereoselectivity, it needed a longer time (Table 5, entry 5). The optimal conditions
used the Br2-Ph3P system as bromination reagent in CH2Cl2 at room temperature
(Table 4, entry 6).

BAYLIS–HILLMAN ADDUCTS
2445
Table 4. Optimization of bromination reaction conditionsa
Yield (%)b
Entry
Reagent
Solvent
Temp. (ꢀC)
Time
5a
6a
1
2
48%HBr
PBr3
PBr3
CH2Cl2
CH2Cl2
CH2Cl2
CH3CN
CH2Cl2
CH2Cl2
CHCl3
THF
rt
rt
0
4 h
62
73
74
71
86
89
80
79
76
86
63
19
17
17
16
—
—
—
—
—
—
—
30 min
30 min
30 min
8 h
3
4
PBr3
rt
rt
rt
rt
rt
rt
0
5
NBS-Ph3P
Br2-Ph3P
Br2-Ph3P
Br2-Ph3P
Br2-Ph3P
Br2-Ph3P
Br2-Ph3P
6
20 min
20 min
20 min
20 min
35 min
2 h
7
8
9
CH3CN
CH2Cl2
CH2Cl2
10
11
–20
aReaction conditions: 4a (10.0 mmol), bromination reagents (10.0 mmol), and solvents (30 mL) were
used.
bIsolated yields.
Next, we determined the scope and compatibility with functional groups and
structural features. According to Table 5, all the substrates with ester moieties
could provide the desired (Z,Z)-isomers 5 with good stereoselectivities in good
to excellent yields, and in the case of nitrile moiety, (E,Z)-isomer 6j was isolated
(Scheme 2).
1
The configurations of 5 and 6 were determined by the H NMR and nuclear
Overhauser effect (NOE) data and compared with the literature values of the known
compounds.[6c,6d,6g] 1H NMR spectrum of 5l showed a chemical shift typical of Ha
(7.86), and evident NOE was observed between Hc and Hd. According to 1H
NMR and NOE spectra of 5a and 5l, the shifts of Ha and Hb in 5a were 7.86 and
7.09, respectively, whereas they were 7.33(Ha) and 8.02(Hb) in 6a (Figure 1). Then,
we considered that compounds 5 should be (Z,Z)-isomers and that compounds 6
should be (E,Z)-isomers.
In summary, we have developed a simple, efficient synthesis of a new type of
Baylis–Hillman adducts and their stereoselective bromination. Mild reaction
conditions, shorter reaction times, convenient experimental procedure, and good
stereoselectivity are the great advantages associated with this method. Applications
for the new type of Baylis–Hillman adducts and bromides have been developing in
our laboratory.

2446
W. ZHONG ET AL.
Table 5. Bromination of Baylis–Hillman adductsa
Entry
R
EWG
Substrate 4
Time (min)
Products and yields (%)b
1
2
3
4
5
6
7
8
9
p-ClC6H4
m-ClC6H4
p-FC6H4
C6H5
CO2Me
CO2Me
CO2Me
CO2Me
CO2Et
4a
4b
4c
4d
4e
4f
20
20
20
20
20
20
20
10
30
5a (89)
5b (90)
5c (87)
5d (88)
5e (88)
5f (91)
5g (91)
5h (94)
5i (87)
C6H5
p-MeC6H4
p-MeC6H4
p-MeOC6H4
p-NO2C6H4
CO2Me
CO2Et
4g
4h
4i
CO2Me
CO2Me
10
11
CO2Me
CO2Et
4k
4l
20
20
5k (89)
5l (89)
aReaction conditions: 4 (10.0 mmol), Br2 (10.0 mmol), Ph3P (10.0 mmol), and CH2Cl2 (30 mL) were
used.
bIsolated yields.
Scheme 2. Bromination of Baylis–Hillman adduct 4j.
Figure 1. NOE effect of compounds 5a, 6a, and 5l.

BAYLIS–HILLMAN ADDUCTS
2447
EXPERIMENTAL
Melting points were determined on a Buchi B-540 capillary melting-point
¨
apparatus and are uncorrected. Infrared (IR) spectra were recorded on a Thermo
1
Nicolet Avatar 370 spectrophotometer. H and 13C spectra were recorded in CDCl3
or dimethylsulfoxide (DMSO-d6) with tetramethylsilane (TMS, d ¼ 0) as an internal
standard at ambient temperature on a Varian 400-MHz spectrometer at 400 and
100 MHz or a Bruker Avance DRX 500 spectrometer at 500 and 125 MHz. Chemical
shifts (d) are expressed in parts per million, and coupling constants J are given in
hertz. Mass spectra (MS) were obtained on a Trace DSQ mass spectrometer.
High-resolution mass spectra (HRMS) were recorded using an Agilent 6210
TOF mass spectrometer. The ultrasonic reactions were taken in a Sonics VCX 750
ultrasonic processor.
Typical Procedure for (Z)-3-Chloro-3-(4-chlorophenyl)acrylaldehyde
(2a)
A mechanically stirred solution of DMF (21.90 g, 300.0 mmol) in chloroform
(30 mL) was cooled in an ice bath while a solution of bis(trichloromethyl)carbonate
(BTC) (29.70 g, 100.0 mmol) in chloroform (60 mL) was added dropwise over a
period of 30 min. The reaction mixture was stirred at room temperature for 1 h. Then
a solution of p-chloroacetophenone (15.45 g, 100.0 mmol) in chloroform (10 mL) was
added dropwise over 10 min. The mixture was then heated at 60 ꢀC for 6 h. The reac-
tion mixture was poured in saturated sodium bicarbonate solution and extracted
with chloroform (3 ꢁ 30 mL). The combined organic layer was dried over Na2SO4
and evaporated. The crude product was purified by flash-column chromatography
on silica gel (petroleum ether=ethyl acetate ¼ 8:1) to give 82% yield of 2a (16.49 g).
Typical Procedure for (Z)-Methyl-5-chloro-5-(3-chlorophenyl)-3-
hydroxy-2-methylenepent-4-enoate (4a)
A mixture of 2a (10.50 g, 50.0 mmol), methyl acrylate (8.60 g, 100.0 mmol), and
DABCO (2.20 g, 10.0 mmol) was set in a commercial ultrasonic cleaning bath (Sonics
VCX 750) for 3.5 h at around 50 ꢀC. The reaction was monitored by TLC. After
completion of the reaction, the mixture was extracted with ethyl acetate (3 ꢁ 50 mL).
The extracted solution was dried over Na2SO4 and concentrated in vacuo. The crude
product was purified by flash-column chromatography on silica gel (petroleum
ether=ethyl acetate ¼ 4:1) to give 84% yield of 4a (12.06 g).
Typical Procedure for (2Z,4Z)-Methyl-2-(bromomethyl)-5-chloro-5-
(3-chlorophenyl)penta-2,4-dienoate (5a)
Br2 (1.60 g, 10.0 mmol) was added dropwise to a stirring solution of Ph3P
(2.62 g, 10.0 mmol) in CH2Cl2 (20 mL) at 0 ꢀC, followed by dropwise addition of a
solution of 4a (2.87 g, 10.0 mmol) in CH2Cl2 (10 mL). The reaction mixture was
stirred at room temperature for 15 min. Then the reaction was quenched by 20%
Na2S2O3 solution (5 mL) and extracted with CH2Cl2 (3 ꢁ 30 mL). The combined

2448
W. ZHONG ET AL.
organic phase was dried over Na2SO4 and evaporated under reduced pressure to give
a crude product, which was purified by flash-column chromatography on silica gel
(petroleum ether=ethyl acetate ¼ 20:1) to give 89% yield of 5a (3.12 g).
Selected Data
(Z)-3-Chloro-3-(4-chlorophenyl)acrylaldehyde (2a). Yellow solid, mp
1
101.9–102.5 ꢀC (lit.[9] 102–103ꢀC). IR (KBr) nmax: 1668 cmꢂ1; H NMR (400 MHz,
CDCl3) d 10.21 (1H, d, J 6.8 Hz, CHO), 7.70 (2H, d, J 8.4 Hz, ArH), 7.44 (2H, d,
=
J 8.4 Hz, ArH), 6.65 (1H, d, J 6.8 Hz, ClC CHCHO).
(Z)-3-Chloro-3-(3-chlorophenyl)acrylaldehyde (2b). Yellow solid, mp
1
100.4 ꢂ 101.0ꢀC. IR(KBr) nmax: 1664 cmꢂ1; H NMR (500 MHz, CDCl3) d 10.21
(1H, d, J 6.5 Hz, CHO), 7.75 (1H, s, ArH), 7.62–7.64 (1H, m, ArH), 7.47–7.50
=
(1H, m, ArH), 7.39–7.42 (1H, m, ArH), 6.66 (1H, d, J 6.5 Hz, ClC CHCHO); 13C
NMR (100 MHz, CDCl3) d 190.9, 150.2, 137.3, 135.0, 131.6, 130.0, 127.2, 125.1
(2C); MS (EI) m=z 200 (Mþ, 10), 165(100), 101(46). HRMS (EI) m=z calcd. for
C9H6Cl2O: 199.9796; found: 199.9789.
(Z)-3-Chloro-3-(4-fluorophenyl)acrylaldehyde (2c). Yellow solid, mp
1
102.1–102.5ꢀC (lit.[11] oil). IR (KBr) nmax: 1664 cmꢂ1; H NMR (400 MHz, CDCl3)
d 10.20 (1H, d, J 6.8 Hz, CHO), 7.75–7.78 (2H, m, ArH), 7.13–7.17 (2H, m, ArH),
=
6.62 (1H, d, J 6.8 Hz, ClC CHCHO).
(Z)-3-Chloro-3-phenylacrylaldehyde (2d). Yellow oil (lit.[9] oil). IR (neat)
1
n
max: 1673 cmꢂ1; H NMR (500 MHz, CDCl3) d 10.18 (1H, d, J 7.0 Hz, CHO),
7.70–7.72 (2H, m, ArH), 7.40–7.46 (3H, m, ArH), 6.64 (1H, d, J 7.0 Hz,
=
ClC CHCHO).
(Z)-3-Chloro-3-p-tolylacrylaldehyde (2e). Yellow oil (lit.[9] oil). IR (neat)
1
n
max: 1670 cmꢂ1; H NMR (500 MHz, CDCl3) d 10.18 (1H, d, J 7.0 Hz, CHO),
7.63 (2H, d, J 8.0 Hz, ArH), 7.23 (2H, d, J 8.0 Hz, ArH), 6.63 (1H, d, J 7.0 Hz,
=
ClC CHCHO), 2.39 (3H, s, CH3).
(Z)-3-Chloro-3-(4-methoxyphenyl)acrylaldehyde (2f). Yellow solid, mp
57.1–57.7ꢀC (lit.[9] 57–58ꢀC). IR (KBr) nmax: 1679 cmꢂ1 1H NMR (500 MHz,
;
CDCl3) d 10.19 (1H, d, J 7.0 Hz, CHO), 7.73 (2H, d, J 9.0 Hz, ArH), 6.96 (2H, d,
=
J 9.0 Hz, ArH), 6.61 (1H, d, J 7.0 Hz, ClC CHCHO), 3.88 (3H, s, OCH3).
(Z)-3-Chloro-3-(4-nitrophenyl)acrylaldehyde (2g). Yellow solid, mp
57.1–57.7ꢀC (lit.[12] no data). IR (KBr) nmax: 1633 cmꢂ1 1H NMR (400 MHz,
;
CDCl3) d 10.25 (1H, d, J 6.8 Hz, CHO), 8.33 (2H, d, J 8.8 Hz, ArH), 7.93 (2H, d,
=
J 8.8 Hz, ArH), 6.74 (1H, d, J 6.8 Hz, ClC CHCHO).
1-Chloro-3,4-dihydronaphthalene-2-carbaldehyde (2h). Yellow solid, mp
37.1–37.6ꢀC (lit.[9] 37ꢀC). IR (KBr) nmax: 1668 cmꢂ1; 1H NMR (400 MHz, CDCl3) d
10.36 (1H, s, CHO), 7.83 (1H, d, J 7.6 Hz, ArH), 7.31–7.37 (2H, m, ArH), 7.19 (1H,
d, J 7.6 Hz, ArH), 2.81 (2H, t, J 8.0 Hz, CH2), 2.61 (2H, t, J 8.0 Hz, CH2).

BAYLIS–HILLMAN ADDUCTS
2449
2-Chlorocyclohex-1-enecarbaldehyde (2i). Yellow oil (lit.[9] oil). IR (neat)
max: 1678 cmꢂ1; 1H NMR (500 MHz, CDCl3) d 10.20 (1H, s, CHO), 2.57–2.60 (2H,
m, CH2), 2.26–2.30 (2H, m, CH2), 1.75–1.80 (2H, m, CH2), 1.65–1.68 (2H, m, CH2).
n
(Z)-Methyl-5-chloro-5-(4-chlorophenyl)-3-hydroxy-2-methylenepent-4-
1
enoate (4a). Yellow oil. IR (neat) nmax: 3463, 2953, 1723, 1507, 1237 cmꢂ1; H
NMR (400 MHz, CDCl3) d 7.51–7.53 (2H, m, ArH), 7.31–7.33 (2H, m, ArH), 6.35
=
=
=
(1H, d, J 7.6 Hz, ClC CH), 6.30 (1H, s, C CH2-a), 5.94 (1H, s, C CH2-b), 5.45
(1H, d, J 7.6 Hz, CHOH), 3.81 (3H, s, CO2CH3), 3.37 (1H, br s, OH); 13C NMR
(100 MHz, CDCl3) d 166.7, 139.3, 135.6, 135.1, 133.6, 128.5 (2C), 127.8 (2C),
127.7, 126.8, 70.4, 52.1; MS (EI) m=z 286.1 (Mþ, 1), 251.0 (84), 218.9 (100), 191.0
(28), 136.9 (42), 100.9 (40); HRMS (EI) m=z calcd. for C13H12Cl2O3: 286.0163;
found: 286.0169.
(Z)-Methyl-5-chloro-5-(3-chlorophenyl)-3-hydroxy-2-methylenepent-4-
enoate (4b). Yellow oil. IR (neat) nmax: 3435, 2952, 1720, 1440, 1335, 1156 cmꢂ1
;
1H NMR (400 MHz, CDCl3) d 7.58 (1H, s, ArH), 7.46–7.49 (1H, m, ArH),
=
=
7.29–7.31 (2H, m, ArH), 6.38 (1H, d, J 7.6 Hz, ClC CH), 6.31 (1H, s, C CH2-a),
=
5.95 (1H, s, C CH2-b), 5.44 (1H, d, J 7.6 Hz, CHOH), 3.82 (3H, s, CO2CH3); 13C
NMR (100 MHz, CDCl3) d 166.7, 139.2, 138.8, 134.4, 133.3, 129.6, 129.1, 128.4,
126.9, 126.7, 124.7, 70.4, 52.1; MS (EI) m=z 286.0 (Mþ, 3), 251.0 (100), 219.0 (90),
191.0 (48), 137.0 (50) 111.0 (25); HRMS (EI) m=z calcd. for C13H12Cl2O3:
286.0163; found: 286.0158.
(Z)-Methyl-5-chloro-5-(4-fluorophenyl)-3-hydroxy-2-methylenepent-4-
1
enoate (4c). Yellow oil. IR (neat) nmax: 3466, 2954, 1724, 1507, 1238 cmꢂ1; H
NMR (400 MHz, CDCl3) d 7.55–7.59 (2H, m, ArH), 7.02–7.06 (2H, m, ArH), 6.31
=
=
=
(1H, d, J 8.0 Hz, ClC CH), 6.30 (1H, s, C CH2-a), 5.95 (1H, s, C CH2-b), 5.45
(1H, d, J 7.6 Hz, CHOH), 3.81 (3H, s, CO2CH3), 3.38 (1H, br s, OH); 13C NMR
(100 MHz, CDCl3) 166.8, 163.1 (d, JCF 247.9 Hz), 139.5, 133.7, 133.3, 128.5,
128.4, 127.2, 126.7, 115.4, 115.2, 70.4, 52.1; MS (EI) m=z 270.0 (Mþ, 3), 235.0
(72), 203.0 (100), 121.0 (34); HRMS (EI) m=z calcd. for C13H12ClFO3: 270.0459;
found: 270.0466.
(Z)-Methyl-5-chloro-3-hydroxy-2-methylene-5-phenylpent-4-enoate
(4d). Yellow oil. IR (neat) nmax: 3466, 2954, 1724, 1507, 1238, 1161 cmꢂ1; 1H NMR
(400 MHz, CDCl3) d 7.57–7.60 (2H, m, ArH), 7.33–7.37 (3H, m, ArH), 6.35 (1H, d, J
=
=
=
7.6 Hz, ClC CH), 6.29 (1H, s, C CH2-a), 5.94 (1H, s, C CH2-b), 5.48 (1H, d, J
7.6 Hz, CHOH), 3.79 (3H, s, CO2CH3), 3.44 (1H, br s, OH); 13C NMR (100 MHz,
CDCl3) d 166.7, 139.5, 137.1, 134.7, 129.0, 128.3 (2C), 127.2, 126.5 (2C), 120.1,
70.2, 52.0; MS (EI) m=z 254.1 (Mþ þ 2, 5), 252.1 (Mþ, 3), 217.1 (81), 185.1 (100),
157.1 (45), 103.1 (68), 77.0 (46); HRMS (EI) m=z calcd. for C13H13ClO3: 252.0553;
found: 252.0558.
(Z)-Ethyl-5-chloro-3-hydroxy-2-methylene-5-phenylpent-4-enoate (4e).
Yellow oil. IR (neat) nmax: 3500, 2983, 1720, 1328, 1266 cmꢂ1
;
1H NMR
(400 MHz, CDCl3) d 7.59–7.61 (2H, m, ArH), 7.33–7.39 (3H, m, ArH), 6.35 (1H,
=
d, J 7.6 Hz, ClC CH), 6.30 (1H, s, C CH2-a), 5.93 (1H, s, C CH2-b), 5.47 (1H,
=
=
d, J 7.6 Hz, CHOH), 4.26 (2H, q, J 7.2 Hz, CO2CH2CH3), 3.34 (1H, br s, OH),

2450
W. ZHONG ET AL.
1.33 (3H, t, J 7.2 Hz, CO2CH2CH3); 13C NMR (100 MHz, CDCl3) d 166.4, 139.7,
137.2, 134.8, 129.1, 128.3 (2C), 127.3, 126.6 (2C), 126.3, 70.5, 61.1, 14.1; MS (EI)
m=z 268.1 (Mþ þ 2, 2), 266.1 (Mþ, 4), 231.1 (65), 185.1 (100), 157.1 (35), 103.1
(48), 77.0 (24); HRMS (EI) m=z calcd. for C14H15ClO3: 266.0710; found: 266.0706.
(Z)-Methyl-5-chloro-3-hydroxy-2-methylene-5-p-tolylpent-4-enoate (4f).
Yellow oil. IR (neat) nmax: 3478, 2982, 1716, 1260, 1177 cmꢂ1
;
1H NMR
(400 MHz, CDCl3) d 7.49 (2H, d, J 8.4 Hz, ArH), 7.15 (2H, d, J 8.4 Hz, ArH),
=
=
=
6.31 (1H, d, J 8.0 Hz, ClC CH), 6.29 (1H, s, C CH2-a), 5.94 (1H, s, C CH2-b),
5.47 (1H, d, J 8.0 Hz, CHOH), 3.80 (3H, s, CO2CH3), 3.36 (1H, br s, OH), 2.35
(3H, s, CH3); 13C NMR (100 MHz, CDCl3) d 166.9, 139.5, 139.2, 135.0, 134.4,
129.0 (2C), 126.6, 126.5 (2C), 126.2, 70.4, 52.1, 21.1; MS (EI) m=z 266.1 (Mþ, 1),
231.1 (51), 199.1 (100), 115.1 (39); HRMS (EI) m=z calcd. for C14H15ClO3:
266.0710; found: 266.0717.
(Z)-Ethyl-5-chloro-3-hydroxy-2-methylene-5-p-tolylpent-4-enoate (4g).
Yellow oil. IR (neat) nmax: 3501, 3127, 1703, 1400, 1300, 1188 cmꢂ1 1H NMR
;
(400 MHz, CDCl3) d 7.48 (2H, d, J 8.0 Hz, ArH), 7.15 (2H, d, J 8.0 Hz, ArH),
=
=
=
6.30 (1H, d, J 8.0 Hz, ClC CH), 6.29 (1H, s, C CH2-a), 5.92 (1H, s, C CH2-b),
5.47 (1H, d, J 7.6 Hz, CHOH), 4.25 (2H, q, J 7.2 Hz, CO2CH2CH3), 3.39 (1H, br
s, OH), 2.35 (3H, s, CH3), 1.32 (3H, t, J 7.2 Hz, CO2CH2CH3); 13C NMR
(100 MHz, CDCl3) d 166.7, 140.2, 139.4, 135.1, 134.7, 129.3 (2C), 126.7 (2C),
126.6, 126.5, 70.6, 61.4, 21.4, 14.3; MS (EI) m=z 280.1 (Mþ, 2), 245.1 (63), 199.1
(100), 171.1 (20), 115.1 (42); HRMS (EI) m=z calcd. for C15H17ClO3: 280.0866;
found: 280.0858.
(Z)-Methyl-5-chloro-3-hydroxy-5-(4-methoxyphenyl)-2-methylenepent-4-
enoate (4h). Yellow oil. IR (neat) nmax: 3479, 2953, 1715, 1509, 1255, 1178 cmꢂ1
;
1H NMR (400 MHz, CDCl3) d 7.52 (2H, d, J 8.4 Hz, ArH), 6.86 (2H, d, J 8.8 Hz,
=
ArH), 6.28 (1H, s, C CH2-a), 6.24 (1H, d, J 8.0 Hz, ClC CH), 5.94 (1H, s,
=
=
C CH2-b), 5.47 (1H, d, J 8.0 Hz, CHOH), 3.80 (6H, s, CO2CH3 and OCH3), 3.45
(1H, br s, OH); 13C NMR (100 MHz, CDCl3) d 166.8, 160.2, 139.7, 134.5, 129.6,
127.9 (2C), 126.4, 125.2, 113.6 (2C), 70.2, 55.2, 52.0; MS (EI) m=z 284.1 (Mþ þ 2,
3), 282.1 (Mþ, 9), 247.1 (66), 215.1 (100), 135.0 (60); HRMS (EI) m=z calcd. for
C14H15ClO4: 282.0659; found: 282.0652.
(Z)-Methyl-5-chloro-3-hydroxy-2-methylene-5-(4-nitrophenyl)pent-4-
1
enoate (4i). Yellow oil. IR (neat) nmax: 3480, 3106, 1703, 1518 cmꢂ1; H NMR
(400 MHz, CDCl3) d 8.21 (2H, d, J 9.2 Hz, ArH), 7.77 (2H, d, J 8.8 Hz, ArH),
=
=
=
6.56 (1H, d, J 8.0 Hz, ClC CH), 6.34 (1H, s, C CH2-a), 5.99 (1H, s, C CH2-b),
5.47 (1H, d, J 8.0 Hz, CHOH), 3.83 (3H, s, CO2CH3), 3.46 (1H, br s, OH); 13C
NMR (100 MHz, CDCl3) d 166.9, 148.2, 143.2, 139.3, 132.6, 131.5, 127.6 (2C),
127.5, 123.9 (2C), 70.8, 52.5; MS (EI) m=z 299.0 (Mþ þ 2, 4), 297.0 (Mþ, 12),
262.0 (66), 230.0 (62), 166.9 (100), 112.9 (75); HRMS (EI) m=z calcd. for
C13H12ClNO5: 297.0404; found: 297.0409.
(Z)-5-Chloro-3-hydroxy-2-methylene-5-phenylpent-4-enenitrile (4j).
Yellow oil. IR (neat) nmax: 3446, 3062, 2228, 1634, 1447, 1233, 1048 cmꢂ1 1H
;
NMR (400 MHz, CDCl3) d 7.58–7.60 (2H, m, ArH), 7.36–7.37 (3H, m, ArH), 6.20

BAYLIS–HILLMAN ADDUCTS
2451
=
=
=
(1H, d, J 8.0 Hz, ClC CH), 6.11 (1H, s, C CH2-a), 6.01 (1H, s, C CH2-b), 5.39
(1H, d, J 8.0 Hz, CHOH), 2.99 (1H, br s, OH); 13C NMR (100 MHz, CDCl3) d
137.1, 136.4, 130.8, 129.6, 128.6, 128.4, 126.9, 126.7, 124.5, 124.0, 116.7, 69.9; MS
(EI) m=z 221.0 (Mþ þ 2, 4), 219.0 (Mþ, 10), 184.1 (100), 103.1 (96), 77.0 (41); HRMS
(EI) m=z calcd. for C12H10ClNO: 219.0451; found: 219.0460.
Methyl-2-((1-chloro-3,4-dihydronaphthalen-2-yl)(hydroxy)methyl)acry-
1
late (4k). Yellow oil. IR (neat) nmax: 3478, 2952, 1727, 1438, 1270, 1146 cmꢂ1; H
NMR (400 MHz, CDCl3) d 7.64 (1H, d, J 7.6 Hz, ArH), 7.18–7.25 (2H, m, ArH),
=
=
7.12 (1H, d, J 6.8 Hz, ArH), 6.35 (1H, s, C CH2-a), 5.94 (1H, s, C CH2-b), 5.89
(1H, s, CHOH), 3.76 (3H, s, CO2CH3), 2.93 (1H, br s, OH), 2.77–2.82 (2H, m,
CH2), 2.51–2.59 (1H, m, CH2-a), 2.27–2.33 (1H, m, CH2-b); 13C NMR (100 MHz,
CDCl3) d 166.8, 139.0, 136.3, 135.0, 132.7, 128.2, 128.0, 127.0, 126.6, 126.3, 124.7,
70.2, 52.0, 27.8, 23.5; MS (EI) m=z 278.1 (Mþ, 4), 260.0 (36), 225.0 (79), 165.0
(100), 128.0 (38); HRMS (EI) m=z calcd. for C15H15ClO3: 278.0710; found: 278.0707.
Ethyl-2-((1-chloro-3,4-dihydronaphthalen-2-yl)(hydroxy)methyl)acry-
1
late (4 l). Yellow oil. IR (neat) nmax: 3466, 2939, 1720, 1481, 1270, 1144 cmꢂ1; H
NMR (400 MHz, CDCl3) d 7.64 (1H, d, J 7.2 Hz, ArH), 7.19–7.25 (2H, m, ArH),
=
7.12 (1H, d, J 7.2 Hz, ArH), 6.36 (1H, s, C CH2-a), 5.93 (1H, s, C CH2-b), 5.89
=
=
(1H, ClC CH), 4.21 (2H, q, J 7.2 Hz, CO2CH2CH3), 3.09 (1H, br s, OH),
2.75–2.82 (2H, m, CH2), 2.51–2.59 (1H, m, CH2-a), 2.24–2.31 (1H, m, CH2-b),
1.28 (3H, t, J 7.2 Hz, CO2CH2CH3); 13C NMR (100 MHz, CDCl3) d 166.4, 139.3,
136.3, 135.1, 132.8, 128.2, 128.0, 127.0, 126.6, 126.0, 124.7, 70.3, 61.0, 27.8, 23.5,
14.1; MS (EI) m=z 294.1 (Mþ þ 2, 1), 292.1 (Mþ, 3), 274.1 (48), 239.1 (100), 211.1
(98), 165.1 (82), 128.1 (66); HRMS (EI) m=z calcd. for C16H17ClO3: 292.0866; found:
292.0859.
Methyl-2-((2-chlorocyclohex-1-enyl)(hydroxy)methyl)acrylate
(4m).
1
Yellow oil. IR (neat) nmax: 3479, 2939, 1726, 1438. 1269, 1147 cmꢂ1; H NMR
=
=
(500 MHz, CDCl3) d 6.31 (1H, s, C CH2-a), 5.84 (1H, s, C CH2-b), 5.68 (1H, s,
CHOH), 3.78 (3H, s, CO2CH3), 3.09 (1H, br s, OH), 2.37–2.41 (2H, m, CH2),
2.22–2.28 (1H, m, CH2-a), 1.90–1.96 (1H, m, CH2-b), 1.60–1.75 (4H, m, 2CH2);
13C NMR (100 MHz, CDCl3) d 166.9, 139.1, 132.1, 130.0, 125.6, 69.8, 51.9, 34.0,
24.7, 23.6, 22.0; MS (EI) m=z 230.1 (Mþ, 1), 212.1 (70), 177.1 (100), 117.1 (93),
79.1 (50); HRMS (EI) m=z calcd. for C11H15ClO3: 230.0710; found: 230.0710.
(2Z,4Z)-Methyl-2-(bromomethyl)-5-chloro-5-(4-chlorophenyl)penta-2,4-
dienoate (5a). Yellow solid, mp 82.3–82.8ꢀC. IR (KBr) nmax: 3133, 1709, 1593,
1400, 1261 cmꢂ1
;
1H NMR (400 MHz, CDCl3) d 7.86 (1H, d, J 11.6 Hz,
ClC CHCH C), 7.68 (2H, d, J 8.0 Hz, ArH), 7.41 (2H, d, J 8.0 Hz, ArH), 7.09
=
=
=
=
(1H, d, J 11.6 Hz, ClC CHCH C), 4.42 (2H, s, CH2Br), 3.88 (3H, s, CO2CH3);
13C NMR (100 MHz, CDCl3) d 166.2, 141.9, 137.1, 136.8, 135.7, 130.5, 129.2
(2C), 128.5 (2C), 120.3, 52.7, 24.6; MS (EI) m=z 350 (Mþ þ 2, 3), 348 (Mþ, 2), 269
(38), 237 (100), 209.0 (72), 175.0 (30), 139.1 (30); HRMS (EI) m=z calcd. for
C13H11BrCl2O2: 347.9319; found: 347.9315.
(2E,4Z)-Methyl-2-(bromomethyl)-5-chloro-5-(4-chlorophenyl)penta-2,4-
dienoate (6a). Yellow solid, mp 81.3–82.2ꢀC. IR (KBr) nmax: 3128, 1710, 1435,

2452
W. ZHONG ET AL.
1
1263 cmꢂ1; H NMR (400 MHz, CDCl3) d 8.02 (1H, d, J 11.2 Hz, ClC CHCH C),
=
=
=
=
7.65 (2H, d, J 8.4 Hz, ArH), 7.32–7.37 (3H, m, ArH and ClC CHCH C), 4.35 (2H,
s, CH2Br), 3.86 (3H, s, CO2CH3); 13C NMR (100 MHz, CDCl3) d 165.4, 140.7,
138.4, 136.1, 135.5, 129.5, 128.8 (2C), 128.2 (2C), 121.8, 52.1, 33.3; MS (EI) m=z
349.9 (Mþ þ 2, 3), 347.9 (Mþ, 2), 269.0 (33), 236.9 (100), 208.8 (72), 174.9 (38),
139.0 (40); HRMS (EI) m=z calcd. for C13H11BrCl2O2: 347.9319; found: 347.9324.
(2Z,4Z)-Methyl-2-(bromomethyl)-5-chloro-5-(3-chlorophenyl)penta-2,4-
dienoate (5b). Yellow solid, mp 85.3–86.1ꢀC. IR (KBr) nmax: 3134, 1692, 1606,
1401, 1272 cmꢂ1
;
1H NMR (400 MHz, CDCl3) d 7.85 (1H, d, J 11.6 Hz,
ClC CHCH C), 7.71 (1H, s, ArH), 7.61 (1H, d, J 7.6 Hz, ArH), 7.34–7.41 (2H,
=
=
=
=
m, ArH), 7.09 (1H, d, J 11.6 Hz, ClC CHCH C), 4.42 (2H, s, CH2Br), 3.87 (3H,
s, CO2CH3); 13C NMR (100 MHz, CDCl3) d 165.9, 141.1, 138.7, 136.6, 134.8,
130.6, 130.2, 129.9, 127.1, 125.1, 120.6, 52.5, 24.1; MS (EI) m=z 349.9 (Mþ þ 2, 3),
347.9 (Mþ, 2), 269.0 (38), 237.0 (82), 209.0 (100), 175.0 (77), 139.1 (61); HRMS
(EI) m=z calcd. for C13H11BrCl2O2: 347.9319; found: 347.9311.
(2Z,4Z)-Methyl-2-(bromomethyl)-5-chloro-5-(4-fluorophenyl)penta-2,4-
dienoate (5c). Yellow solid, mp 84.5–85.4ꢀC. IR (KBr) nmax: 3130, 1710, 1502,
1400, 1261 cmꢂ1
;
1H NMR (400 MHz, CDCl3) d 7.86 (1H, d, J 11.6 Hz,
=
=
ClC CHCH C), 7.72–7.75 (2H, m, ArH), 7.13 (2H, m, ArH), 7.04 (1H, d, J
11.6 Hz, ClC CHCH C), 4.42 (2H, s, CH2Br), 3.87 (3H, s, CO2CH3); 13C NMR
(100 MHz, CDCl3) d 166.0, 163.9 (d, JCF 251.0 Hz), 141.8, 137.1, 133.3, 129.8,
129.2, 129.1, 119.6, 115.9, 115.7, 52.5, 24.4; MS (EI) m=z 333.8 (Mþ þ 2, 3), 331.8
(Mþ, 2), 296.9 (12), 252.9 (33), 219.0 (100), 159.0 (100), 133.0 (57); HRMS (EI)
m=z calcd. for C13H11BrClFO2: 331.9615; found: 331.9620.
=
=
(2Z,4Z)-Methyl 2-(bromomethyl)-5-chloro-5-phenylpenta-2,4-dienoate
(5d). Yellow solid, mp 83.3–83.8ꢀC. IR (KBr) nmax: 3130, 1698, 1400, 1267 cmꢂ1
;
1
=
=
H NMR (400 MHz, CDCl3) d 7.89 (1H, d, J 11.6 Hz, ClC CHCH C), 7.72–7.74
=
=
(2H, m, ArH), 7.41–7.43 (3H, m, ArH), 7.09 (1H, d, J 11.6 Hz, ClC CHCH C),
4.41 (2H, s, CH2Br), 3.85 (3H, s, CO2CH3); 13C NMR (100 MHz, CDCl3) d 166.0,
143.0, 137.1, 136.9, 130.3, 129.6, 128.6 (2C), 127.0 (2C), 119.6, 52.4, 24.4; MS (EI)
m=z 316.0 (Mþ þ 2, 3), 314.0 (Mþ, 2), 279.0 (8), 235.1 (31), 203.0 (79), 175.0 (100),
141.1 (72),115.1 (39); HRMS (EI) m=z calcd. for C13H12BrClO2: 313.9709; found:
313.9712.
(2Z,4Z)-Ethyl-2-(bromomethyl)-5-chloro-5-phenylpenta-2,4-dienoate (5e).
Yellow solid, mp 80.9–81.6ꢀC. IR (KBr) nmax: 3132, 1700, 1605, 1400, 1264 cmꢂ1
;
1
=
=
H NMR (400 MHz, CDCl3) d 7.88 (1H, d, J 11.2 Hz, ClC CHCH C),
7.73–7.76 (2H, m, ArH), 7.42–7.44 (3H, m, ArH), 7.10 (1H, d, J 11.2 Hz,
=
=
ClC CHCH C), 4.43 (2H, s, CH2Br), 4.32 (2H, q, J 7.2 Hz, COOCH2CH3), 1.38
(3H, t, J 7.2 Hz, CO2CH2CH3); 13C NMR (100 MHz, CDCl3) d 165.9, 143.2,
137.4, 137.2, 130.6, 130.3, 129.0 (2C), 127.4 (2C), 120.1, 61.8, 24.8, 14.6; MS (EI)
m=z 330.0 (Mþ þ 2, 3), 328.0 (Mþ, 2), 249.1 (25), 203.0 (83), 175.0 (100), 141.1
(92), 115.1 (50); HRMS (EI) m=z calcd. for C14H14BrClO2: 327.9866; found:
327.9875.

BAYLIS–HILLMAN ADDUCTS
2453
(2Z,4Z)-Methyl-2-(bromomethyl)-5-chloro-5-p-tolylpenta-2,4-dienoate
(5f). Yellow solid, mp 83.1–84.0ꢀC. IR (KBr) nmax: 3127, 1706, 1599, 1401, 1280;
1
cmꢂ1 H NMR (400 MHz, CDCl3) d 7.90 (1H, d, J 11.6 Hz, ClC CHCH C),
7.62–7.65 (2H, m, ArH), 7.23 (2H, d, J 8.4 Hz, ArH), 7.07 (1H, d, J 11.6 Hz,
=
=
=
=
ClC CHCH C), 4.42 (2H, s, CH2Br), 3.86 (3H, s, CO2CH3), 2.40 (3H, s, CH3);
13C NMR (100 MHz, CDCl3) d 166.2, 143.4, 140.9, 137.5, 134.3, 129.3 (2C),
129.1, 127.0 (2C), 118.8, 52.4, 24.6, 21.3; MS (EI) m=z 329.9 (Mþ þ 2, 3), 327.9
(Mþ, 2), 249.0 (51), 189.0 (100), 155.0 (62), 115.1 (20); HRMS (EI) m=z calcd. for
C14H14BrClO2: 327.9866; found: 327.9871.
(2Z,4Z)-Ethyl-2-(bromomethyl)-5-chloro-5-p-tolylpenta-2,4-dienoate (5g).
Yellow solid, mp 81.2–82.1ꢀC. IR (KBr) nmax: 3132, 1698, 1596, 1399, 1262 cmꢂ1
;
1
=
=
H NMR (400 MHz, CDCl3) d 7.89 (1H, d, J 11.6 Hz, ClC CHCH C), 7.64 (2H,
d, J 8.4 Hz, ArH), 7.23 (2H, d, J 8.0 Hz, ArH), 7.07 (1H, d, J 11.6 Hz,
=
=
ClC CHCH C), 4.43 (2H, s, CH2Br), 4.32 (2H, q, J 7.2 Hz, CO2CH2CH3), 2.40
(3H, s, CH3), 1.37 (3H, t, J 7.2 Hz, CO2CH2CH3); 13C NMR (100 MHz, CDCl3) d
165.7, 143.1, 140.9, 137.2, 134.3, 129.4 (2C), 129.1, 127.0 (2C), 118.9, 61.4, 24.7,
21.3, 14.3; MS (EI) m=z 344.0 (Mþ þ 2, 3), 342.0 (Mþ, 2), 307.0 (8), 263.1 (41),
229.1 (89), 189.0 (100), 155.1 (92), 115.1 (47); HRMS (EI) m=z calcd. for
C15H16BrClO2: 342.0022; found: 342.0027.
(2Z,4Z)-Methyl-2-(bromomethyl)-5-chloro-5-(4-methoxyphenyl)penta-
2,4- dienoate (5h). Yellow solid, mp 97.3–97.8ꢀC. IR (KBr) nmax: 3132, 1699,
1592, 1400, 1266 cmꢂ1 1H NMR (400 MHz, CDCl3) d 7.89 (1H, d, J 11.6 Hz,
;
=
ClC CHCH C), 7.70 (2H, d, J 8.8 Hz, ArH), 7.01 (1H, d, J 11.6 Hz,
=
=
=
ClC CHCH C), 6.93 (2H, d, J 8.4 Hz, ArH), 4.43 (2H, s, CH2Br), 3.86 (6H, s,
CO2CH3 and OCH3); 13C NMR (100 MHz, CDCl3) d 166.2, 161.4, 143.0, 137.7,
129.4, 128.6 (2C), 128.4, 117.8, 114.0 (2C), 55.4, 52.3, 24.8; MS (EI) m=z 346.0
(Mþ þ 2, 2), 344.0 (Mþ, 1), 265.1 (29), 231.1 (100), 171.1 (50), 128.1 (31); HRMS
(EI) m=z calcd. for C14H14BrClO3: 343.9815; found: 343.9822.
(2Z,4Z)-Methyl-2-(bromomethyl)-5-chloro-5-(4-nitrophenyl)penta-2,4-
dienoate (5i). Yellow solid, mp 127.5–128.6ꢀC. IR (KBr) nmax: 3106, 1717, 1519,
1
1347, 1264 cmꢂ1; H NMR (400 MHz, CDCl3) d 8.29 (2H, d, J 8.0 Hz, ArH), 7.92
=
=
(2H, d, J 8.0 Hz, ArH), 7.86 (1H, d, J 11.6 Hz, ClC CHCH C), 7.23 (1H, d, J
11.6 Hz, ClC CHCH C), 4.44 (2H, s, CH2Br), 3.90 (3H, s, CO2CH3); 13C NMR
(100 MHz, CDCl3) d 166.0, 148.7, 143.0, 140.1, 136.3, 132.4, 128.2 (2C), 124.2
(2C), 123.1, 53.0, 24.1; MS (EI) m=z 360.9 (Mþ þ 2, 3), 358.9 (Mþ, 2), 279.9 (32),
247.9 (100), 219.9 (38), 139.0 (54); HRMS (EI) m=z calcd. for C13H11BrClNO4:
358.9506; found: 358.9501.
=
=
(2E,4Z)-2-(Bromomethyl)-5-chloro-5-phenylpenta-2,4-dienenitrile (6j).
Yellow solid, mp 87.0–87.9ꢀC. IR (KBr) nmax: 3143, 2213, 1605, 1400, 1212 cmꢂ1
;
1H NMR (400 MHz, CDCl3) d 7.71–7.73 (2H, m, ArH), 7.47 (1H, d, J 11.2 Hz,
=
=
=
=
ClC CHCH C), 7.41–7.44 (3H, m, ArH), 7.16 (1H, d, J 11.2 Hz, ClC CHCH C),
4.18 (2H, s, CH2Br); 13C NMR (100 MHz, CDCl3) d 143.4, 142.0, 136.0, 130.8, 128.7
(2C), 127.1 (2C), 120.6, 116.0, 112.4, 30.6; MS (EI) m=z 283.0 (Mþ þ 2, 3), 281.0
(Mþ, 2), 202.0 (62), 166.1 (100), 140.1 (41), 115.1 (30); HRMS (EI) m=z calcd. for
C12H9BrClN: 280.9607; found: 280.9614.

2454
W. ZHONG ET AL.
(Z)-Methyl-2-(bromomethyl)-3-(1-chloro-3,4-dihydronaphthalen-2-yl)
acrylate (5k). Yellow solid, mp 63.9.3–64.6ꢀC. IR (KBr) nmax: 3132, 1710, 1400,
1
1288 cmꢂ1; H NMR (400 MHz, CDCl3) d 7.88 (1H, s, ClC CCH C), 7.68–7.70
(1H, m, ArH), 7.28–7.30 (2H, m, ArH), 7.18–7.20 (1H, m, ArH), 4.32 (2H, s,
CH2Br), 3.88 (3H, s, CO2CH3), 2.87–2.93 (4H, m, CH2CH2); 13C NMR
(100 MHz, CDCl3) d 166.6, 140.7, 136.8, 134.9, 132.4, 130.4, 129.5, 129.0, 127.1,
127.0, 125.7, 52.5, 27.9, 27.8, 26.3; MS (EI) m=z 342.0 (Mþ þ 2, 1), 305.0 (18),
261.1 (35), 227.1 (28), 165.1 (100), 128.1 (13); HRMS (EI) m=z calcd. for
C15H14BrClO2: 339.9866; found: 339.9857.
=
=
(Z)-Ethyl-2-(bromomethyl)-3-(1-chloro-3,4-dihydronaphthalen-2-yl)
acrylate (5l). Yellow solid, mp 61.6–62.4ꢀC. IR (KBr) nmax: 3132, 1708, 1399,
1
1287 cmꢂ1; H NMR (400 MHz, CDCl3) d 7.86 (1H, s, ClC CCH C), 7.67–7.69
(1H, m, ArH), 7.27–7.29 (2H, m, ArH), 7.16–7.18 (1H, m, ArH), 4.30–4.39 (4H, s,
CH2Br and CO2CH2CH3), 2.85–2.92 (4H, m, CH2CH2), 1.37 (3H, t, J 11.6 Hz,
CO2CH2CH3); 13C NMR (100 MHz, CDCl3) d 166.0, 140.3, 136.7, 134.6, 132.3,
130.4, 129.4, 129.2, 127.0, 126.9, 125.6, 61.4, 27.9, 27.7, 26.3, 14.2; MS (EI) m=z
356.0 (Mþ þ 2, 2), 319.0 (18), 275.1 (28), 241.1 (33), 165.1 (100), 128.1 (15); HRMS
(EI) m=z calcd. for C16H16BrClO2: 354.0022; found: 354.0017.
=
=
ACKNOWLEDGMENTS
We thank the National Key Technology Research and Development Program
(No. 2007BAI34B00) and the National Natural Science Foundation of China (No.
20676123) for financial support.
REFERENCES
1. (a) Baylis, A. B.; Hillman, M. E. D. Verfahren zur herstellung von acrylrerbindungen.
German Patent 21155113, 1972; Chem. Abstr. 1972, 77, 34174; (b) Basavaiah, D.; Rao, A. J.
Recent advances in the Baylis–Hillman reaction and applications. Chem. Rev. 2003,
103, 811–891; (c) Singh, V.; Batra, S. Advances in the Baylis–Hillman reaction–assisted
synthesis of cyclic frameworks. Tetrahedron 2008, 64, 4511–4574.
2. (a) Basavaiah, D.; Roy, S. Dimethyl sulfide–induced [3 þ 2] annulation strategy: An
efficient synthesis of functionalized dihydropyrazole derivatives using the BaylisꢂHillman
bromides. Org. Lett. 2008, 10, 1819–1822; (b) Deng, J.; Hu, X.; Huang, J.; Yu, S.; Wang,
D.; Duan, Z.; Zheng, Z. Enantioselective synthesis of b2-amino acids via Rh-catalyzed
asymmetric hydrogenation with BoPhoz-type ligands: Important influence of an N-H
proton in the ligand on the enantioselectivity. J. Org. Chem. 2008, 73, 2015–2017; (c)
Ye, L.; Sun, X.; Wang, Q.; Tang, Y. Phosphine-catalyzed intramolecular formal [3 þ 2]
cycloaddition for highly diastereoselective synthesis of bicyclo[n.3.0] compounds. Angew.
Chem., Int. Ed. Engl. 2007, 46, 5951–5954; (d) Paquette, L. A.; Rothhaar, R. R.; Isaac, M.;
Rogers, M.; Rogers, R. D. Diastereo- and enantiodifferentiation in indium-promoted ally-
lations of 2,3-azetidinediones in water: Definition of long-range stereocontrol elements on
p-facial selectivity for b-lactam synthesis. J. Org. Chem. 1998, 63, 5463–5472.
3. (a) Lee, M.; Lee, K. Y.; Kim, J. N. Synthesis of N-benzyl 3,5-disubstituted piperidines via
double Michael addition strategy. Bull. Korean Chem. Soc. 2005, 26, 477–480; (b) Marson,

BAYLIS–HILLMAN ADDUCTS
2455
C. M.; Pink, J. H.; Hall, D.; Hursthouse, M. B.; Malik, A.; Smith, C. An asymmetric
synthesis of aza analogues of the tricyclic skeleton of daphnane and the ABC ring system
of phorbol. J. Org. Chem. 2003, 68, 792–798.
4. (a) Lawrence, N. J.; Crump, J. P.; McGown, A. T.; Hadfield, J. A. Reaction of Baylis–
Hillman products with Swern and Dess–Martin oxidants. Tetrahedron Lett. 2001, 42,
3939–3941; (b) McFadden, H. G.; Harris, R. L. N.; Jenkins, C. L. D. Potential inhibitors
of phosphoenolpyruvate carboxylase, II: Phosphonic acid substrate analogs derived from
reaction of trialkyl phosphites with halomethacrylates. Aust. J. Chem. 1989, 42, 301–314;
(c) Chavan, S. P.; Ethiraj, K. S.; Kamat, S. K. Facile synthesis of 2Z-2-chloromethyl
aryl-2-enoates. Tetrahedron Lett. 1997, 38, 7415–7416.
5. (a) Liu, Y.; Zheng, H.; Xu, D.; Xu, Z.; Zhang, Y. An efficient and stereoselective synthesis
of (Z)-allyl chlorides from Baylis–Hillman adducts using Vilsmeier–Haack reagent. Org.
Prep. Proced. Int. 2007, 39, 190–194; (b) Lee, C. H.; Jung, H. J.; Kim, J. H.; Jeong, W.
J.; Cho, J. M.; Ro, S.; Hyun, Y. L.; Shin, D.; Lee, C. S. Preparation of alkylcarbamoyl
naphthalenyloxyoctenoyl hydroxyamides as histone deacetylase (HDAC) inhibitors.
WO Patent 2007052938, 2007; Chem. Abstr. 2007, 146, 500748; (c) Saxena, R.; Singh, V.;
Batra, S. Studies on the catalytic hydrogenation of Baylis–Hillman derivatives of substi-
tuted isoxazolecarbaldehydes: Unusual retention of isoxazole ring during Pd–C–promoted
hydrogenation of Baylis–Hillman adducts. Tetrahedron 2004, 60, 10311–10320.
6. (a) Ye, L.; Han, X.; Sun, X.; Tang, Y. PPh3-catalyzed ylide cyclization for the controllable
synthesis of benzobicyclo[4.3.0] compounds: Base effects and scope. Tetrahedron 2008,
64, 1487–1493; (b) Mitra, S.; Gurrala, S. R.; Coleman, R. S. Total synthesis of the
eupomatilones. J. Org. Chem. 2007, 72, 8724–8736; (c) Das, B.; Venkateswarlu, K.;
Krishnaiah, M.; Holla, H.; Majhi, A. A rapid and efficient stereoselective synthesis
of (Z)- and (E)-allyl bromides from Baylis–Hillman adducts using bromo(dimethyl)sulfo-
nium bromide. Helv. Chim. Acta 2006, 89, 1417–1421; (d) Das, B.; Majhi, A.; Banerjee, J.;
Chowdhury, N.; Venkateswarlu, K. A highly efficient stereoselective synthesis of (Z)- and
(E)-allyl iodides from Baylis–Hillman adducts. Tetrahedron Lett. 2005, 46, 7913–7915; (e)
Das, B.; Holla, H.; Srinivas, Y.; Chowdhury, N.; Bandgar, B. P. Studies on novel syn-
thetic methodologies, part 137: An expedient stereoselective synthesis of (Z)- and (E)-allyl
iodides from Baylis–Hillman adducts along with selective iodination of benzylic alcohols
using the polymethylhydrosiloxane–iodine system. Tetrahedron Lett. 2007, 48, 3201–3204;
(f) Das, B.; Kanth, B. S.; Reddy, K. R.; Satyalakshmi, G.; Kumar, R. A. A simple and
efficient protocol for chlorination of Baylis–Hillman adducts using PPh3=CCl4. Chem.
Lett. 2008, 37, 512–513; (g) Das, B.; Chowdhury, N.; Damodar, K.; Ravikanth, B. A mild
and efficient method for chlorination of Baylis–Hillman adducts using PPh3=
Cl3CCONH2. Helv. Chim. Acta 2007, 90, 2037–2040.
7. (a) Sa, M. M.; Ramos, M. D.; Fernandes, L. Fast and efficient preparation of Baylis–Hill-
man–derived (E)-allylic azides and related compounds in aqueous medium. Tetrahedron
2006, 62, 11652–11656; (b) Ying, T.; Bao, W.; Wang, Z.; Zhang, Y. Highly efficient
and stereoselective synthesis of (2Z)-2-(halomethyl)alk-2-enoates in acidic ionic liquid.
J. Chem. Res. 2005, 2, 96–98; (c) Li, J.; Wang, X.; Zhang, Y. Direct and highly efficient
synthesis of (Z)-allyl iodides from Baylis–Hillman adducts promoted by TMSCl=NaI sys-
tem. Synlett 2005, 1039–1041; (d) Das, B.; Banerjee, J.; Ravindranath, N.; Venkataiah, B.
Convenient and efficient stereoselective synthesis of (2Z)-2-(chloromethyl)alk-2-enoates
using iron(III) or indium(III) chloride. Tetrahedron Lett. 2004, 45, 2425–2426; (e) Das,
B.; Banerjee, J.; Ravindranath, N. A simple and facile stereoselective synthesis of (Z)-
and (E)-allyl halides catalyzed by silica supported sodium hydrogen sulfate: Factors
influencing the yields and stereochemistry of allyl halides. Tetrahedron 2004, 60, 8357–
8361; (f) Ravichandran, S. Facile stereoselective synthesis of (E)- and (Z)-allyl bromides
from the Baylis–Hillman adducts using MgBr2. Synth. Commun. 2001, 31, 2059–2062;

2456
W. ZHONG ET AL.
(g) Gruiec, A.; Foucaud, A.; Moinet, C. Reactivity of silica gel–supported copper(II)
bromide: Regioselective synthesis of allylic bromides. New J. Chem. 1991, 15, 943–947.
8. Yadav, J. S.; Reddy, B. V. S.; Madan, C. Montmorillonite clay–catalyzed stereoselective
syntheses of aryl-substituted (E)- and (Z)-allyl iodides and bromides. New J. Chem. 2001,
25, 1114–1117.
9. Su, W.; Zhuang, Y.; Wu, D.; Zhong, W. A convenient synthesis of b-chlorovinylaldehydes
with bis-(trichloromethyl) carbonate. Org. Prep. Proced. Int. 2007, 39, 195–199.
10. (a) Zhong, W.; Lin, F.; Chen, R.; Su, W. An efficient synthesis of 2-hydroxy-7,8-
dihydroquinolin-5(6H)-ones and 7,8-dihydroquinoline-2,5(1H,6H)-diones from Morita–
Baylis–Hillman adduct acetates. Synthesis 2008, 2561–2568; (b) Zhong, W.; Zhao, Y.;
Guo, B.; Wu, P.; Su, W. Dramatically accelerated addition under solvent-free conditions:
An efficient synthesis of (E)-1,2,4-triazole-substituted alkenes from Baylis–Hillman acet-
ates. Synth. Commun. 2008, 38, 3291–3302; (c) Zhong, W.; Zhao, Y.; Su, W. An efficient
synthesis of 3-arylmethyl-7,8-dihydro-6H-chromene-2,5-diones from Baylis–Hillman
adduct acetates under solvent-free conditions. Tetrahedron 2008, 64, 5491–5496.
11. Romagnoli, R.; Baraldi, P. G.; Carrion, M. D.; Cara, C. L.; Cruz-Lopez, O.; Preti, D.;
Tolomeo, M.; Grimaudo, S.; Di Cristina, A.; Zonta, N.; Balzarini, J.; Brancale, A.;
Sarkar, T.; Hamel, E. Design, synthesis, and biological evaluation of thiophene analogues
of chalcones. Bioorg. Med. Chem. 2008, 16, 5367–5376.
12. Rappoport, Z.; Gazit, A. Nucleophilic attacks on carbon–carbon double bonds, 33:
Approaching the retention region from the stereoconvergence region in nucleophilic
substitution of (E)- and (Z)-methyl p-substituted-a-formyl- and a-(tert-butoxycarbonyl)-
b-halocinnamates. J. Org. Chem. 1986, 51, 4112–4131.