Dimethyl sulfide-boron trihalide-mediated reactions of α,β-unsaturated ketones with aldehydes: One-pot synthesis of Baylis-Hillman adducts and α-halomethyl enones

Article abstract of DOI:10.1016/S0040-4020(01)00842-0

The reactions of aldehydes with 3-buten-2-one (2) were conducted in the presence of BBr₃·Me₂S or BCl₃·Me₂S and then worked up with aqueous NaHCO₃, affording the α-methylene aldol 3, α-halomethyl aldol 4 or 6, and α-halomethyl enones 5 or 7, respectively. In contrast, the reactions quenched with water gave the α-halomethyl enones 5 or 7 in high yields, while the work-up with an aqueous 10% trimethylamine gave the α-methylene aldol 3. The phenol 15 and half-acetal 16 were obtained from the reaction of p-nitrobenzaldehyde (1a) with cyclohexenone (10).

Full text of DOI:10.1016/S0040-4020(01)00842-0

TETRAHEDRON
Pergamon
Tetrahedron 57 ,2001) 8455±8462
Dimethyl sul®de±boron trihalide-mediated reactions of
a,b-unsaturated ketones with aldehydes: one-pot synthesis of
Baylis±Hillman adducts and a-halomethyl enones
Tatsunori Iwamura, Masaru Fujita, Tetsuya Kawakita, Sayaka Kinoshita, Shin-ichi Watanabe
and Tadashi Kataokap
Gifu Pharmaceutical University, 6-1 Mitahora-higashi 5-chome, Gifu 502-8585, Japan
Received 4 July 2001; accepted 16 August 2001
AbstractÐThe reactions of aldehydes with 3-buten-2-one ,2) were conducted in the presence of BBr3´Me2S or BCl3´Me2S and then worked
up with aqueous NaHCO3, affording the a-methylene aldol 3, a-halomethyl aldol 4 or 6, and a-halomethyl enones 5 or 7, respectively. In
contrast, the reactions quenched with water gave the a-halomethyl enones 5 or 7 in high yields, while the work-up with an aqueous 10%
trimethylamine gave the a-methylene aldol 3. The phenol 15 and half-acetal 16 were obtained from the reaction of p-nitrobenzaldehyde ,1a)
with cyclohexenone ,10). q 2001 Elsevier Science Ltd. All rights reserved.
Intense interest has recently been shown in the Baylis±Hill-
man reaction, and a great number of papers on this reaction
has been published lately.1 This reaction is quite slow;
therefore, we developed the chalcogenide±TiCl4-mediated
reactions of electron-de®cient alkenes with aldehydes in
order to overcome this drawback.2 We had deemed this
reaction to be the chalcogen version of the Baylis±Hillman
reaction because our reactions produced the Baylis±
Hillman adducts after puri®cation of the products by
preparative TLC ,PTLC) on silica gel. However, a detailed
examination of the reactions revealed that the original
products were a-chloromethyl aldols and that dehydro-
chlorination occurred during puri®cation by PTLC on silica
gel.3,4 The reactions proceed via the Michaeladdition of a
chloride ion and the successive nucleophilic attack of the
resulting carbanion to an aldehyde. The chalcogenide used
would play an important role in releasing the nucleophilic
halide ion. Recently, similar reactions using TiCl4 have
been reported,5 but the reactions of a,b-unsatureted esters
using TiCl4 only did not proceed.5c The asymmetric tandem
conjugate addition±aldol reaction of a,b-unsaturated esters
catalyzed by thiolates6 or selenolates7 has also been
extensively studied.
the bromide or chloride ion is more easily liberated in situ
from the Lewis acid by the coordination of BBr3 or BCl3
with carbonyloxygen than the ¯uoride ion. Since
BBr3´Me2S and BCl3´Me2S are commercially available,
the BBr3´Me2S- or BCl3´Me2S-mediated reactions of the
a,b-unsaturated carbonylcompounds with adl ehydes were
examined.8
On the other hand, the Baylis±Hillman adducts are multi-
functional molecules and have been used in a variety of
stereoselective transformations, e.g. from secondary allyl
alcohols to primary allyl alcohols,9 allyl ethers,10 nitro
esters,11 acetates,12 and halides.13 These compounds were
utilized as the building blocks of natural products and
biologically active compounds.1 We found that the
BBr3´Me2S- or BCl3´Me2S-mediated reactions gave the
dehydrated products, a-halomethyl enones. This paper
demonstrates that the above reactions are usefulfor the
synthesis of 2-acylallyl halides ,a-halomethyl enones).
We ®rst treated p-nitrobenzaldehyde ,1a) with 3 equiv. of
3-buten-2-one ,2) in the presence of 1 equiv. of BBr3´Me2S
in CH2Cl2 at 08C. The reaction mixture was quenched with a
saturated aqueous NaHCO3 solution, and the raw product
was separated by column chromatography on silica gel. The
products were 3-,a-hydroxy-p-nitrobenzyl)but-3-en-2-one
,3a), 3-bromomethyl-4-hydroxy-4-,p-nitrophenyl)butan-2-
one ,4a), and 3-bromomethyl-4-,p-nitrophenyl)but-3-en-2-
one ,5a) in 12, 53, and 30% yields, respectively. The
product ratio was changed upon allowing the raw product
to stand at room temperature. Therefore, the raw product
was quickly and roughly chromatographed, and the product
When we examined the various kinds of Lewis acids for the
chalcogenide-promoted tandem Michael addition±aldol
reaction, BF3 etherate was ineffective.2 We anticipated
that BBr3 or BCl3 would be reactive in this reaction because
Keywords: aldols; aldol reactions; Baylis±Hillman reactions; boron and
compounds; dehydration; Michealreactions.
p
Corresponding author. Tel.: 181-58-237-8571; fax: 181-58-237-5979;
e-mail: kataoka@gifu-pu.ac.jp
1
ratio was then determined by the H NMR spectrum. No
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020,01)00842-0

8456
T. Iwamura et al. / Tetrahedron 57 (2001) 8455±8462
Table 1. Reaction of 3-buten-2-one and aldehydes using BBr3´Me2S
Entry
RCHO
Conditions
Products ,% yield)
Puri®cation by CCa
Puri®cation by PTLCa
1
2
3
4
5
6
1a ,Rˆp-NO2C6H4)
1b ,Rˆp-ClC6H4)
1c ,Rˆp-CF3C6H4)
1d ,RˆC6H5)
08C, 30 min
08C, 30 min
08C, 15 min
08C, 1 h then rt, 11 h
08C, 1 h then rt, 11 h
08C, 1 h then rt, 12 h
3a ,12)
3b ,trace)
3c ,7)
4a ,53)
4b ,41)
4c ,65)
4d ,12)
4e ,21)
4f ,trace)
5a ,30)
5b ,59)
5c ,28)
5d ,86)
5e ,78)
5f ,78)
3a ,68)
3b ,trace)
3c ,70)
3d ,trace)
3e ,trace)
3f ,trace)
5a ,28)
5b ,59)
5c ,13)
5d ,84)
5e ,92)
5f ,46)
3d ,2)
1e ,Rˆp-CH3C6H4)
1f ,RˆC6H5CH2CH2)
3f ,trace)
7b
1a ,Rˆp-NO2C6H4)
1b ,Rˆp-ClC6H4)
08C, 30 min
08C, 30 min
3a ,trace)
3b ,trace)
4a ,69)
4b ,45)
5a ,30)
5b ,46)
8b
a
CC: column chromatography; PTLC: preparative TLC. The syn/anti isomer ratios of 4a±f were not determined because of the overlapped signals.
Me2S ,0.1 equiv.) was used.
b
change in the product ratio was observed before or after
The yields of the dehydrated products 5 were increased in
the latter cases. The long reaction time seemed to cause the
dehydration of 4, and the reactions of 1d±f were reexamined
at 08C for 1 h. However, the product ratios did not change,
but the yields of the products decreased, and the starting
materials were recovered. When 1 equiv. of BBr3 and
0.1 equiv. of Me2S were used, the product ratios of 4 were
slightly increased, and no remarkable change was observed.
puri®cation by column chromatography on silica gel.
When the raw product was separated by PTLC on silica
gel, a-bromomethyladlol 4a caused dehydrobromination
to form butenone 3a similar to the chloride 6a,2,4 and the
Baylis±Hillman adduct 3a and the a-bromomethylenone
5a were obtained in 68 and 28% yields, respectively. Other
reactions of some aldehydes with 2 were similarly
conducted; the products and their yields are shown in
Table 1. The a-bromomethyl aldols 4 were obtained as a
mixture of the syn- and anti-isomers, and the isomers were
carefully separated by recycling preparative HPLC on
polystyrene gel. The structures of syn- and anti-4a were
The reactions using a BCl3´Me2S complex were carried out,
and these results are shown in Table 2. The products were
the Baylis±Hillman adducts 3, a-chloromethyl aldols 6, and
a-chloromethyl enones 7, and the product ratios were deter-
mined by the 1H NMR spectroscopy in a similar manner as
the bromides. The reactions of the aromatic aldehydes with
an electron-withdrawing group 1a±c gave products 3 in
higher yields than the reactions using BBr3´Me2S.
1
determined by comparison of their H NMR spectra with
those of the corresponding chlorides 6a, of which the syn-6a
had been structurally well established by X-ray analysis.4
However, the isomer ratios of the syn- and anti-isomers
could not be determined from their 1H NMR spectra because
of the overlapping methylene peaks. The a-bromomethyl
The a-chloromethyl aldols 6 were obtained as a mixture of
syn- and anti-diastereomers, but the exact isomer ratios of 6
were not determined because the signals due to the allylic
methylene protons of the roughly puri®ed reaction products
had overlapped. Isomer separation of 6 and geometry deter-
mination of 5 were made in a similar manner as mentioned
above for the bromides 4 and 5, respectively.
13c
enones 5b, d-e were identicalwith authentic sampels.
The ,Z)-geometry of 5 was determined by observation of
no NOE enhancement between a vinyl proton and the allylic
methylene protons.
The reactions of aromatic aldehydes bearing an electron-
withdrawing group smoothly proceeded ,entries 1±3). The
reactions of other aromatic aldehydes and an aliphatic
aldehyde took longer but gave good yields ,entries 4±6).
Since chloromethyl aldol 6a had been transformed into the
Baylis±Hillman adduct 3a and an enone 7a upon standing in
Table 2. Reaction of 3-buten-2-one and aldehydes using BCl3´Me2S
Entry
RCHO
Conditions
08C, 30 min
08C, 30 min
Products ,% yield)a
1
2
3
4
5
6
1a ,Rˆp-NO2C6H4)
1b ,Rˆp-ClC6H4)
1c ,Rˆp-CF3C6H4)
1d ,RˆC6H5)
3a ,28)
3b ,26)
3c ,32)
3d ,2)
6a ,52)
6b ,30)
6c ,32)
6d ,12)
7b ,31)
7c ,16)
7d ,71)
7e ,74)
7f ,32)
08C, 30 min
08C, 1 h then rt, 11 h
08C, 1 h then rt, 11 h
08C, 1 h then rt, 11 h
1e ,Rˆp-CH3C6H4)
1f ,RˆC6H5CH2CH2)
a
Puri®cation by CC. The syn/anti isomer ratios of 6a±d were not determined because of the overlapped signals.

T. Iwamura et al. / Tetrahedron 57 (2001) 8455±8462
8457
Table 3. Self test and stability of 4
with an aqueous 10% trimethylamine solution ,entry 2),
while enone 5a was afforded in 88% yield by quenching
the reaction mixture with water and allowing the raw
product to stand for 12 h at room temperature ,entry 3).
Based on these ®ndings, the dehydrated products 5b±f
,entries 9±13) and methylene aldols 3b, c ,entries 4 and
5) were selectively prepared. The aliphatic enone 5f was
obtained in 25% yield after a work up with water. No
desired product was obtained by treatment of the reaction
mixtures of 1d±f with a 10% trimethylamine solution
,entries 6±8).
Entry
Storage of time
Product ratios
3a/4a/5a
3b/4b/5b
1
Just after reaction
8:66:26
4:89:7
2
3
4
1 day ,2508C)
3 days
6 days
10:64:26
8:65:27
8:65:27
4:89:7
5:89:6
4:90:6
5
6
12 h ,28C)
2 days
5:89:6
5:88:7
8:65:27
7
8
9
12 h ,208C)
1 day
2.5 days
14:40:45
15:32:53
19:19:62
11:52:37
14:41:47
12:25:63
Other electron-de®cient alkenes 8±10 reacted with the
p-nitrobenzaldehyde ,1a) to give only the Baylis±Hillman
products 11, 12, 14, and allyl bromide 13 after work up with
NaHCO3, water, or trimethylamine ,Table 5). The vinyl
sulfone and N-tosylimine did not react with 1a in the
presence of BBr3´Me2S and BCl3´Me2S.
a CDCl3 solution of 6a at room temperature for 2 days,4 we
examined the stability of the products 3±5; these results are
summarized in Table 3.
When the product, which was rapidly and roughly puri®ed
as mentioned above, was kept in a freezer or a refrigerator,
the isomer ratios did not change ,entry 1). The dehydro-
bromination and dehydration of 4 took place upon storage
at room temperature for 12 h to give 3 and 5, respectively.
These ®ndings indicated that the aldol product-boron
complex in situ formed could not be completely
decomposed by the treatment of the reaction mixture with
a saturated aqueous NaHCO3 solution and that the acid
formed by decomposition of the aldol±boron complex
caused dehydration to form 5. The enones 5 would also be
formed by the reactions of 3 with hydrogen bromide in situ
liberated because the chloro derivative 3a had reacted with
hydrogen chloride in the presence of TiCl4 to form 7a.4
The Baylis±Hillman adduct 11 was obtained in low yields
after work-up of the reaction mixture of the acrylate 8 with
1a ,Table 1, entries 1±3). Treatment of the reaction mixture
of the thioester 93 and 1a with a 10% trimethylamine solu-
tion gave a Baylis±Hillman adduct 12 in 80% yield ,entry
4), while treatment with water afforded a dehydrated
product 13 in 61% yield ,entry 5). For the cyclohexenone
,10), a Baylis±Hillman product 14 was obtained in high
yields after work-up with a saturated aqueous NaHCO3
solution or a 10% trimethylamine solution ,entries 6 and
7). However, upon a work-up of the reaction mixture with
water and then allowing the raw product to stand at room
temperature for 12 h, p-nitrobenzylphenol ,15) and a half-
acetal 16 were isolated in 33 and 38% yields, respectively
,Scheme 1).
We next examined the work-up methods of a reaction
mixture in order to selectively obtain the Baylis±Hillman
adducts 3 and enones 5 and 7. When the reaction mixture of
1a and 2 was treated with a saturated aqueous K2CO3 solu-
tion, the methylene aldols 3a and enone 5a were obtained in
32 and 22% yields, respectively ,Table 4, entry 1).
Compound 3a was quantitatively produced upon treatment
Compound 15 showed a methylene peak at d 4.08 as a
singlet and aromatic signals at d 6.76, 6.91 and 7.10±7.17
due to the o-substituted phenolin the 1H NMR spectrum.
The IR spectrum exhibited an absorption due to the phenolic
hydroxy group at 3470 cm21. The MS and elemental
analysis supported the composition formula of C13H11NO3.
Table 4. Reaction of 3-buten-2-one and p-nitrobenzaldehy quenched with different agents
Entry
RCHO
Conditions
Quenching agent
Products ,% yield)
4a ,42)a
1
2
3
1a ,Rˆp-NO2C6H4)
1a ,Rˆp-NO2C6H4)
1a ,Rˆp-NO2C6H4)
08C, 30 min
08C, 30 min
08C, 30 min
Sat. K2CO3
10% NMe3
H2O
3a ,32)a
3a ,quant)
5a ,22)a
5a ,88)
4
5
6
7
8
1b ,Rˆp-ClC6H4)
1c ,Rˆp-CF3C4H4)
1d ,RˆC6H5)
08C, 30 min
08C, 30 min
08C, 1 h±rt 11 h
08C, 1 h±rt 11 h
08C, 1 h±rt 11 h
10% NMe3
10% NMe3
10% NMe3
10% NMe3
10% NMe3
3b ,85)
3c ,52)
Complex mixture
Complex mixture
Complex mixture
1e ,Rˆp-CH3C6H4)
1f ,RˆC6H5CH2CH2)
9
1b ,Rˆp-ClC6H4)
1c ,Rˆp-CF3C6H4)
1d ,RˆC6H5)
08C, 30 min
08C, 30 min
08C, 1 h±rt 11 h
08C, 1 h±rt 11 h
08C, 1 h±rt 11 h
H2O
H2O
5b ,89)
5c ,81)
5b ,89)
5e ,85)
5f ,25)
10
11
12
13
H2O
1e ,Rˆp-CH3C6H4)
1f ,RˆC6H5CH2CH2)
H2O
H2O
a
Puri®cation by CC. Unless otherwise noted, puri®cation by PTLC.

8458
T. Iwamura et al. / Tetrahedron 57 (2001) 8455±8462
Table 5. Reaction of activated alkene and p-nitrobenzaldehyde using BBr3´Me2S
Entry
Alkene
Conditions
Quenching agent
Products ,% yield)a
11 ,28)
1
2
3
rt, 3 days
rt, 3 days
rt, 3 days
Sat. NaHCO3
10% NMe3
H2O
11 ,16)
11 ,9)
4
5
rt, 4.5 h
rt, 4.5 h
10% NMe3
H2O
12 ,80)
13 ,61)
6
7
rt, 30 min
rt, 30 min
Sat. NaHCO3
10% NMe3
14 ,70)
14 ,quant)
a
Puri®cation by PTLC.
These data are identicalwith those of p-nitrobenzyl-
phenol.14 Compound 16 showed its m/z peak at 325 ,M1/
base) in MS, and its formula was found to be C19H19NO4
from high-resolution MS, which indicated that the product
16 resulted from the addition±substitution of 15 and cyclo-
hexenone. The signals of eight aliphatic, one hydroxyl
,dˆ2.73, exchangeable), one benzylic methine ,dˆ3.19),
and three adjacent aromatic protons were observed besides
the signals of the p-nitrobenzylmoiety in the 1H NMR
spectrum. There was no absorption of the carbonylgroup
in the IR and 13C NMR spectra of 16.
For the con®rmation of the structure of 16, it was acetylated
with acetic anhydride to give the acetate 17 in 59% yield.
The structure of 17 was characterized as C21H21NO5 by
elemental analysis and MS and fully assigned by
2D NMR spectrometry ,H±H COSY, C±H COSY, long-
range C±H COSY) and NOE experiments, as shown in
Fig. 1.
In order to elucidate the mechanism for the formation of the
phenol 15 and half-acetal 16, we conducted the reactions
shown in Scheme 2.
Scheme 1.
Figure 1. 1H- and 13C NMR spectraldata of 17.

T. Iwamura et al. / Tetrahedron 57 (2001) 8455±8462
8459
Scheme 2.
Aldol 14 was treated with BBr3´Me2S, and then the reaction
mixture was decomposed with water. The 1H NMR
spectrum of the raw product did not show the presence of
the phenol 15. However, the transformation of 14 into 15
was observed after the sample was allowed to stand for 12 h
at room temperature. This indicates that a contaminated acid
would cause the conversion of the aldol 14 to the phenol 15.
The phenol 15 might be an intermediate of 16; therefore, we
conducted the reactions of o-cresoland benzyplhenol 15
with cyclohexenone ,10) in the presence of BBr3´Me2S,
but the expected products 18 and 16 were not obtained. In
contrast, the reaction of 14 with 10 in the presence of
BBr3´Me2S formed the half-acetal 16 in 28% yield together
with benzylphenol 15.
A contaminated acid dehydrates the Baylis±Hillman adduct
14 to form a cross-conjugated dienone 19, which isomerizes
into a conjugated dienone 20. Successive aromatization by
enolization forms the phenol 15. Since o-cresoldid not react
with cyclohexenone, the phenol 15 would not be an inter-
mediate of 16, and the following pathway is more feasible.
The dienol 21, an enolisomer of 14, undergoes the Michael
addition to the cyclohexenone 10 to form the diketone 22.
The 2-,a-hydroxybenzyl)cyclohexenone moiety of 22
changes into the o-benzylphenol moiety of 23 in a similar
way as 15. The phenolic hydroxy group and the keto group
of 23 intramolecularly forms the half-acetal moiety, and
compound 16 is produced.
In conclusion, reactions of 3-buten-2-one with aldehydes in
the presence of BBr3´Me2S or BCl3´Me2S proceeded in a
similar manner to the TiCl4±Me2S-mediated reactions,
Based on these ®ndings, the reaction mechanism for the
formation of 15 and 16 is proposed in Scheme 3.
Scheme 3.

8460
T. Iwamura et al. / Tetrahedron 57 (2001) 8455±8462
and the a-bromomethylene aldols were initially formed, but
the aldol±boron complexes resulting in situ were more
stable than the aldol±titanium complexes, and the boron
complex could not be completely decomposed by the treat-
ment with water or a saturated aqueous NaHCO3 solution.
The reactions treated with water or a saturated aqueous
NaHCO3 solution gave the a-halomethyl enones 5 and 7,
whereas the work-up with a 10% trimethylamine decom-
posed the boron±aldol complex and dehydrohalogenated
The residue was puri®ed by PTLC on silica gel eluted with
AcOEt±hexane ,1:3 v/v) or column chromatography on
silica gel eluted with AcOEt±hexane ,1:10 v/v).
Compounds 3a,2 3b,15 3c,16 3d±f,15 5d±e,13c 7a,4 7b±f,13c
11,2 12,3 and 14,2 were identicalto authentic sampels by
comparison of their spectraldate.
1.1.1.
0Rp,Rp)-3-Bromomethyl-4-hydroxy-4-04-nitro-
the a-bromomethyladlol
adducts 3.
4 to give the Baylis±Hillman
phenyl)butan-2-one 04a, syn). Pale yellow prisms ,ether±
hexane), mp 87±898C. Anal. Calcd for C11H12BrNO4: C,
43.73; H, 4.00; N, 4.64. Found: C, 43.78; H, 4.00; N,
1
4.65. H NMR ,CDCl3) d: 2.24 ,3H, s, CH3), 3.22 ,1H, d,
Jˆ2.4 Hz, OH), 3.46 ,1H, ddd, Jˆ3.9, 5.9, and 9.8 Hz, CH),
3.58 ,1H, dd, Jˆ3.9 and 10.3 Hz, CH2Br), 3.78 ,1H, dd,
Jˆ3.9 and 10.3 Hz, CH2Br), 5.14 ,1H, d, Jˆ5.9 Hz,
benzylic H), 7.62 ,2H, d, Jˆ8.8 Hz, ArH), 8.29 ,2H, d,
Jˆ8.3, ArH). 13C NMR ,CDCl3) d: 27.9 ,t), 32.0 ,q), 60.5
,d), 72.6 ,d), 123.8 ,d), 127.1 ,d), 147.6 ,s), 148.1 ,s), 208.8
,s). IR ,KBr) nmax/cm21: 3502 ,OH), 1703 ,CvO), 1509
and 1341 ,NO2). MS ,FAB) m/z ,rel. int. %): 304 ,M11H,
10%; 81Br), 302 ,M11H, 10%; 79Br), 154 ,base).
1. Experimental
Melting points were obtained with a Yanagimoto micro-
melting-point apparatus and were uncorrected. The IR
spectra of solids ,KBr) and liquids ,NaCl) were recorded
on a JASCO FT/IR-230 spectrophotometer. 1H NMR
spectra were recorded on a JEOL EX-400 ,400 MHz) spec-
trometer with tetramethylsilane as an internal standard. 13C
NMR spectra were obtained on a JEOL EX-400 spectro-
meter. Mass spectra ,MS) were recorded on a JEOL JMS-
SX102A spectrometer with a direct-insertion probe at
70 eV. Elemental analyses of new compounds were
performed by Yanaco CHN Corder MT-5. All chromato-
graphic isolations were accomplished with BW-350 ,Fuji
Silysia) for column chromatography ,CC) or with Kieselgel
60 PF254 with gypsum ,Merck) for preparative TLC ,PTLC).
CH2Cl2 was washed with water, dried over CaCl2, and
freshly distilled. The recycling preparative HPLC was
performed by LC-918 liquid chromatography ,Japan
Analytical Industry Co., Ltd.) equipped with JAIGEL-1H
and -2H columns ,polystyrene gels).
1.1.2.
0Rp,Sp)-3-Bromomethyl-4-hydroxy-4-04-nitro-
phenyl)butane-2-one 04a, anti). White prisms ,ether±
hexane), mp 93±978C. Anal. Calcd for C11H12BrNO4: C,
43.73; H, 4.00; N, 4.64. Found: C, 43.63; H, 3.98; N,
1
4.65. H NMR ,CDCl3) d: 2.23 ,3H, s, CH3), 3.26±3.44
,4H, m, OH, CH and CH2Br), 5.10 ,1H, t, Jˆ5.9 Hz,
benzylic H), 7.56 ,2H, d, Jˆ8.8 Hz, ArH), 8.24 ,2H, d,
Jˆ7.8 Hz, ArH). 13C NMR ,CDCl3): 28.9 ,t), 31.9 ,q),
59.7 ,d), 73.3 ,d), 123.9 ,d), 127.1 ,d), 147.8 ,s), 148.1
,s), 209.3 ,s). IR ,KBr) nmax/cm21: 3493 ,OH), 1701
,CvO), 1522 and 1342 ,NO2). MS ,FAB) m/z ,rel. int.
%): 304 ,M11H, 7%; 81Br), 302 ,M11H, 7%; 79Br), 154
,base).
1.1. General procedure
1.1.3. 03Z)-3-Bromomethyl-4-04-nitrophenyl)but-3-en-2-
one 05a). Yellow powders ,AcOEt), mp 1378C. Anal.
Calcd for C11H10BrNO3: C, 46.50; H, 3.55; N, 4.93.
To a stirred solution of p-nitrobenzaldehyde ,1a) ,76 mg,
0.5 mmol) and 3-buten-2-one ,2) ,105 mg, 1.5 mmol) in dry
CH2Cl2 ,1.5 ml) was added a boron tribromide±methyl sul-
®de complex ,160 mg, 0.5 mmol) at 08C. The mixture was
stirred at the temperature described in the tables for 0.5 h,
and the reaction mixture was worked up as follows:
1
Found: C, 46.55; H, 3.53; N, 4.92. H NMR ,CDCl3) d:
2.54 ,3H, s, CH3), 4.27 ,2H, s, CH2), 7.63 ,1H, s, CH),
7.75 ,2H, d, Jˆ8.8 Hz, ArH), 8.33 ,2H, d, Jˆ8.8 Hz,
ArH). 13C NMR ,CDCl3) d: 23.8 ,t), 26.0 ,q), 124.1 ,d),
130.1 ,d), 139.2 ,d), 140.0 ,s), 140.1 ,s), 147.9 ,s), 196.5 ,s).
IR ,KBr) nmax/cm21: 1667 ,CvO), 1511 and 1344 ,NO2).
MS ,EI) m/z ,rel. int. %): 285 ,M1, 8%; 81Br), 283 ,M1, 8%;
79Br), 158 ,base).
Method A: A saturated aqueous NaHCO3 ,3 ml) was added
to the reaction mixture, and the whole mixture was stirred
for 1 h at room temperature. The precipitates were removed
by ®ltration through Celitee, and the ®ltrate was dried
,MgSO4) and evaporated under reduced pressure.
1.1.4. 03Z)-3-Bromomethyl-4-04-chlorophenyl)but-3-en-
2-one 05b).13c White prisms ,ether±hexane), mp 99±
1008C. Anal. Calcd for C11H10ClBrO: C, 48.30; H, 3.68.
Method B: An aqueous 10% NMe3 solution ,3 ml) was
added to the reaction mixture, and the whole mixture was
stirred for 1 h at room temperature. The precipitates were
removed by ®ltration through Celitee, and the ®ltrate was
dried ,MgSO4) and evaporated under reduced pressure.
1
Found: C, 48.20; H, 3.78. H NMR ,CDCl3) d: 2.51 ,3H,
s, CH3), 4.32 ,2H, s, CH2Br), 7.47 ,2H, d, Jˆ8.8 Hz, ArH),
7.56 ,2H, d, Jˆ8.3 Hz, ArH), 7.58 ,1H, s, CH). 13C NMR
,CDCl3) d: 24.8 ,t), 25.9 ,q), 129.3 ,d), 130.9 ,d), 132.6 ,s),
135.9 ,s), 137.7 ,s), 141.3 ,d), 197.0 ,s). IR ,KBr) nmax
/
cm21: 1670 ,CvO). MS ,EI) m/z ,rel. int. %): 276 ,M1,
3%; 37Cl, 81Br), 274 ,M1, 15%), 272 ,M1, 10%; 35Cl, 79Br),
193 ,base).
Method C: Water ,3 ml) was added to the reaction mixture,
and the whole mixture was stirred for 1 h at room tempera-
ture. The precipitates were removed by ®ltration through
Celitee, and the ®ltrate was dried ,MgSO4) and evaporated
under reduced pressure. The residue was left for 12 h at
room temperature.
1.1.5. 03Z)-3-Bromomethyl-4-04-tri¯uoromethylphenyl)-
but-3-en-2-one 05c). White crystals ,ether±hexane), mp

T. Iwamura et al. / Tetrahedron 57 (2001) 8455±8462
8461
668C. Anal. Calcd for C121H10BrF3O: C, 46.93; H, 3.28.
Found: C, 46.81; H, 3.42. H NMR ,CDCl3) d: 2.53 ,3H,
s, CH3), 4.29 ,2H, s, CH2Br), 7.64 ,1H, s, CH), 7.71 ,2H,
d,Jˆ8.8 Hz, ArH), 7.75 ,2H, d, Jˆ8.3 Hz, ArH). 13C NMR
,CDCl3) d: 24.3 ,t), 26.1 ,q), 122.4 ,s), 125.1 ,s), 125.9 ,d),
129.6 ,d), 137.8 ,s), 139.1 ,s), 140.6 ,d), 196.9 ,s). IR ,KBr)
dry CH2Cl2 was added a boron tribromide±methylsu®l de
complex ,160 mg, 0.5 mmol) at 08C. The mixture was
stirred at the temperature for 0.5 h, and the reaction was
worked up by the addition of water ,3 ml). The whole
mixture was stirred for 1 h at room temperature. The
precipitates were removed by ®ltaration through Celitee,
and the ®ltrate was dried ,MgSO4) and evaporated under
reduced pressure. The residue was left for 12 h at room
temperature and then puri®ed by PTLC on silica gel, eluted
with AcOEt±hexane ,1:3 v/v) to give 2-,4-nitrobenzyl)-
phenol, 15) ,37 mg, 33%) and 10-,4-nitrobenzyl)-1,2,3,4,
5,6-hexahydro-2,6-methano-1-benzoxacine-2-ol, 16) ,61 mg,
38%).
n
max/cm21: 1673 ,CvO). MS ,EI) m/z ,rel. int. %): 308
,M112, 13%; 81Br), 306 ,M1, 13%; 79Br), 227 ,base).
1.1.6. 03Z)-3-Bromomethyl-6-phenylhex-3-en-2-one 05f).
Pale yellow oil. Anal. Calcd for C13H15BrO: C, 58.44; H,
1
5.66. Found: C, 58.30; H, 5.68. H NMR ,CDCl3) d: 2.33
,3H, s, CH3), 2.67±2.72 ,2H, m, PhCH2CH2), 2.88 ,2H, m,
PhCH2CH2), 4.13 ,2H, s, CH2Br), 6.83 ,1H, t, Jˆ7.3 Hz,
ole®nic H), 7.21±7.33 ,5H, m, ArH). 13C NMR ,CDCl3) d:
22.4 ,t), 25.5 ,q), 31.4 ,t), 34.2 ,t), 126.5 ,d), 128.3 ,d),
128.6 ,d), 138.9 ,s), 140.3 ,s), 147.0 ,d), 196.5 ,s). IR
,NaCl) nmax/cm21: 1672 ,CvO). MS ,FAB) m/z ,rel. int.
%): 269 ,M11H, 22%; 81Br), 267 ,M11H, 25%; 79Br), 187
,base).
1.2.1. 2-04-Nitrobenzyl)phenol 015). Pale yellow powders
,ether), mp 112±1138C. Anal. Calcd for C13H11NO3: C,
68.11; H, 4.84; N, 6.11. Found: C, 67.99; H, 4.99; N,
1
6.08. H NMR ,CDCl3) d: 4.08 ,2H, s, CH2), 4.83 ,1H, s,
OH), 6.76 ,1H, d, Jˆ7.8 Hz, ArH), 6.91 ,1H, t, Jˆ7.3 Hz,
ArH), 7.10±7.17 ,2H, m, ArH), 7.38 ,2H, d, Jˆ8.3 Hz,
ArH), 8.12 ,2H, d, Jˆ8.7 Hz, ArH). 13C NMR ,CDCl3) d:
36.1 ,t), 115.6 ,d), 121.2 ,d), 123.6 ,d), 125.8 ,s), 128.3 ,d),
129.5 ,d), 131.0 ,d), 146.4 ,s), 148.7 ,s), 1535 ,s). IR ,KBr)
1.1.7. 03Z)-3-Chloromethyl-4-04-tri¯uoromethylphenyl)-
but-3-en-2-one 07c). White powders ,AcOEt), mp 50±
548C. Anal. Calcd for C121H10ClF3O: C, 54.87; H, 3.84.
Found: C, 54.64; H, 3.89. H NMR ,CDCl3) d: 2.54 ,3H,
s, CH3), 4.40 ,2H, s, CH2Cl), 7.69 ,1H, s, ole®nic H), 7.69
,2H, d, Jˆ8.3 Hz, ArH), 7.75 ,2H, d, Jˆ8.3 Hz, ArH). 13C
NMR ,CDCl3) d: 26.0 ,q), 37.0 ,t), 125.8 ,s), 125.9 ,d),
129.7 ,d), 131.6 ,s), 137.6 ,s), 138.8 ,s), 141.4 ,d), 196.9
,s). IR ,KBr) nmax/cm21: 1673 ,CvO). MS ,EI) m/z ,rel.
int. %): 264 ,M1, 33%; 37Cl), 262 ,M1, 92%; 35Cl), 115
,base).
n
max/cm21: 3470 ,OH), 1505 and 1339 ,NO2). MS ,EI) m/z
,rel. int. %): 229 ,M1, base).
1.2.2.
10-04-Nitrobenzyl)-1,2,3,4,5,6-hexahydro-2,6-
methano-1-benzoxacine-2-ol 016). Pale yellow oil. 1H
NMR ,CDCl3) d: 1.19±1.30 ,1H, m, CH2), 1.53±1.78
,4H, m, CH2), 1.91 ,2H, d, Jˆ14.1 Hz, CH2), 2.03 ,1H,
dd, Jˆ2.4 and 11.7 Hz, CH2), 2.73 ,1H, brs, OH), 3.19
,1H, s, CH), 3.98 and 4.08 ,each 1H, d, Jˆ15.1 Hz benzylic
CH2), 6.79 ,1H, t, Jˆ7.3 Hz, ArH), 6.92±6.97 ,2H, m,
ArH), 7.38 ,2H, d, Jˆ8.8 Hz, ArH), 8.16 ,2H, d,
Jˆ8.3 Hz, ArH). 13C NMR ,CDCl3) d: 18.7 ,t), 32.0 ,t),
35.2 ,d), 36.1 ,t), 36.2 ,t), 39.0 ,t), 98.8 ,s), 119.9 ,d),
123.4 ,d), 125.2 ,d), 125.6 ,s), 126.8 ,d), 128.7 ,d), 129.5
,d), 146.2 ,s), 149.4 ,s), 153.2 ,s). HRMS. Calcd for
1.1.8. 03Z)-3-Chloromethyl-6-phenylhex-3-en-2-one 07f).
Pale yellow oil. Anal. Calcd for C13H15ClO: C, 70.11; H,
1
6.79. Found: C, 69.88; H, 6.90. H NMR ,CDCl3) d: 2.31
,3H, s, CH3), 2.68±2.73 ,2H, m, PhCH2CH2), 2.83±2.87
,2H, m, PhCH2CH2), 4.23 ,2H, s, CH2Cl), 6.84 ,1H, t,
Jˆ7.3 Hz, benzylic H), 7.19±7.33 ,5H, m, ArH). 13C
NMR ,CDCl3) d: 25.4 ,q), 30.9 ,t), 34.5 ,t), 35.3 ,t),
126.4 ,d), 128.4 ,d), 128.6 ,d), 138.7 ,s), 140.2 ,s), 147.4
,d), 196.7 ,s). IR ,NaCl) nmax/cm21: 1673 ,CvO). MS ,EI)
m/z ,rel. int. %): 224 ,M1, 16%; 37Cl), 222 ,M1, 47%; 35Cl),
91 ,base).
C19H19NO4: 325.1314. Found 325.1317. IR ,NaCl) nmax
/
cm21: 3437 ,OH), 1516 and 1344 ,NO2). MS ,EI) m/z
,rel. int. %): 325 ,M1, base).
1.2.3. Acetylation of 16. Compound 16 ,325 mg, 1.0 mmol)
and acetic anhydride ,133 mg, 1.3 mmol) were re¯uxed for
3 h. The reaction mixture was evaporated under reduced
pressure to remove acetic anhydride. The residue was puri-
®ed by PTLC on silica gel eluted with AcOEt±hexane
,1:4 v/v) to give 2-acetoxy-10-,4-nitrobenzyl)-1,2,3,4,5,6-
hexahydro-2,6-methano-1-benzoxacine ,17) ,217 mg, 59%).
1.1.9. S-Ethyl 0Z)-2-bromomethyl-3-04-nitrophenyl)-
thioacrylate 013). Pale yellow crystals ,ether±hexane),
mp 96±988C. Anal. Calcd for C12H12BrNO3S: C, 43.65;
1
H, 3.66; N, 4.24. Found: C, 43.57; H, 3.72; N, 4.16. H
NMR ,CDCl3) d: 1.35 ,3H, t, Jˆ7.3 Hz, CH2CH3), 3.07
,2H, q, Jˆ7.3 Hz, CH2CH3), 4.31 ,2H, s, CH2Br), 7.73
,1H, s, ole®nic H), 7.74 ,2H, d, Jˆ8.8 Hz, ArH), 8.33
,2H, d, Jˆ8.8 Hz, ArH). 13C NMR ,CDCl3) d: 14.5 ,q),
24.1 ,t), 24.5 ,t), 124.1 ,d), 130.2 ,d), 137.0 ,d), 139.4 ,s),
140.3 ,s), 147.9 ,s), 191.6 ,s). IR ,KBr) nmax/cm21: 1650
,CvO), 1521 and 1340 ,NO2). MS ,EI) m/z ,rel. int. %): 331
,M1, 47%; 81Br), 329 ,M1, 45%; 79Br), 268 ,base).
Colorless oil. Anal. Calcd for C21H21NO5: C, 68.65; H, 5.76;
N, 3.81. Found: C, 68.45; H, 5.87; N, 3.74. 1H NMR
,CDCl3) d: 1.26±1.39 ,1H, m, CH2), 1.57±1.61 ,1H, m,
CH2), 1.68±1.75 ,2H, m, CH2), 1.87±1.95 ,1H, m, CH2),
2.03 ,3H, s, CH3), 2.16 ,1H, dd, Jˆ2.9 and 12.2 Hz, CH2),
2.28±2.33 ,1H, m, CH2), 2.39±2.44 ,1H, m, CH2), 3.18 ,1H,
brs, CH), 4.02 ,2H, s, benzylic H), 6.81 ,1H, t,Jˆ7.3 Hz,
ArH), 6.92 ,1H, dd, Jˆ1.5 and 7.8 Hz, ArH), 6.98 ,1H, dd,
Jˆ1.5 and 7.8 Hz, ArH), 7.46 ,2H, d, Jˆ8.8 Hz, ArH), 8.10
,2H, d, Jˆ8.8 Hz, ArH). 13C NMR ,CDCl3) d: 18.8 ,t), 22.4
,q), 32.0 ,t), 32.9 ,t), 34.7 ,d), 36.1 ,t), 37.1 ,t), 104.0 ,s),
120.3 ,d), 123.4 ,d), 125.7 ,s), 125.9 ,s), 126.8 ,d), 128.7
,d), 129.9 ,d), 146.2 ,s), 149.3 ,s), 152.5 ,s), 168.5 ,s). IR
1.2. Reaction of p-nitrobenzaldehyde 01a) and cyclo-
hexenone 010): formation of 15 and 16
To a stirred solution of p-nitrobenzaldehyde ,1a) ,76 mg,
0.5 mmol) and cyclohexenone ,10) ,144 mg, 1.5 mmol) in

8462
T. Iwamura et al. / Tetrahedron 57 (2001) 8455±8462
,NaCl) nmax/cm21: 1748 and 1077 ,COO), 1519 and 1345
,NO2). MS ,EI) m/z ,rel. int. %): 367 ,M1, 50%), 325 ,base).
4. Kataoka, T.; Kinoshita, H.; Iwama, T.; Tsujiyama, S.;
Iwamura, T.; Watanabe, S.; Muraoka, O.; Tanabe, G.
Tetrahedron 2000, 56, 4725±4731.
5. ,a) Uehira, S.; Han, Z.; Shinokubo, H.; Oshima, K. Org. Lett.
1999, 1383±1385. ,b) Li, G.; Wei, H.-X.; Gao, J. J.; Caputo,
T. D. Tetrahedron Lett. 2000, 41, 1±5. ,c) Li, G.; Gao, J.; Wei,
H.-X.; Enright, M. Org. Lett. 2000, 617±620. ,d) Shi, M.;
Jiang, J.-K. Tetrahedron 2000, 56, 4793±4797. ,e) Shi, M.;
Jiang, J.-K.; Feng, Y.-S. Org. Lett. 2000, 2397±2400.
6. ,a) Kamimura, A.; Mitsudera, H.; Asano, S.; Kakei, A.;
Noguchi, M. Chem. Commun. 1998, 1095±1096. ,b) Ono,
M.; Nishimura, K.; Nagaoka, Y.; Tomioka, K. Tetrahedron
Lett. 1999, 40, 1509±1512 and 6979±6982. ,c) Kamimura, A.;
Mitsudera, H.; Asano, S.; Kidera, S.; Kakei, A. J. Org. Chem.
1999, 64, 6353±6360.
1.3. Reaction of 14with cyclohexenone 010)
To a stirred solution of compound 14 ,115 mg, 0.47 mmol)
and cyclohexenone ,10) ,90 mg, 0.94 mmol) in dry CH2Cl2
was added a boron tribromide±methyl sul®de complex
,150 mg, 0.47 mmol) at 08C. The mixture was stirred at
that temperature for 0.5 h, and the reaction was worked up
by the addition of water ,3 ml). The whole mixture was
stirred for 1 h at room temperature. The precipitates were
removed by ®ltaration through Celitee and the ®ltrate was
dried ,MgSO4) and evaporated under reduced pressure. The
residue was left for 12 h at room temperature and then puri-
®ed by PTLC on silica gel, eluted with AcOEt±hexane
,1:3 v/v) to give 2-,4-nitrobenzyl)phenol ,15) ,40 mg,
37%) and 10-,4-nitrobenzyl)-1,2,3,4,5,6-hexahydro-2,6-
methano-1-benzoxacine-2-ol, 16) ,43 mg, 28%).
7. ,a) Mitsudera, H.; Kakehi, A.; Kamimura, A. Tetrahedron
Lett. 1999, 40, 7389±7392. ,b) Jauch, J. Synlett 1999, 1325±
1327. ,c) Jauch, J. Angew. Chem., Int. Ed. Engl. 2000, 39,
2764±2765. ,d) Jauch, J. J. Org. Chem. 2001, 66, 609±611.
8. Very recently, Shi and his coworkers reported the reactions
using BCl3±phosphine: Shi, M.; Jiang, J.-K.; Cui, S.-C.; Feng,
Y.-S. J. Chem. Soc., Perkin Trans. 1 2001, 390±393. Indepen-
dently, we have studied the reactions using BBr3´Me2S or
BCl3´Me2S. A part of this work was presented at the Eighth
InternationalConference on New Aspects of Organic
Chemistry, July 11±15, 2000, Kyoto, Japan ,Abstract p 201)
and at the 121st AnnualMeeting of the Pharmaceutical
Society of Japan, March 28±30, 2001, Sapporo, Japan
,Abstract II p 18).
1.4. Treatment of 14 with boron tribromide±methyl
sul®de complex
To a stirred solution of compound 14 ,56 mg, 0.23 mmol) in
dry CH2Cl2 was added a boron tribromide±methylsu®l de
complex ,74 mg, 0.23 mmol) at 08C. The mixture was
stirred at that temperature for 0.5 h, and the reaction was
worked up by the addition of water ,3 ml). The whole
mixture was stirred for 1 h at room temperature. The pre-
cipitates were removed by ®ltaration through Celitee, and
the ®ltrate was dried ,MgSO4) and evaporated under
reduced pressure. The residue was left for 12 h at room
temperature and then puri®ed by PTLC on silica gel, eluted
with AcOEt±hexane ,1:2 v/v) to give 2-,4-nitrobenzyl)-
phenol, 15) ,38 mg, 73%).
9. Kim, H. S.; Kim, T. Y.; Lee, K. Y.; Chung, Y. M.; Lee, H. J.;
Kim, J. N. Tetrahedron Lett. 2000, 41, 2613±2616.
10. ,a) Basavaiah, D.; Kumaragurubaran, N.; Padmaja, K. Synlett
1999, 1630±1632. ,b) Basavaiah, D.; Hyma, R. S.;
Muthukumaran, K.; Kumaragurubaran, N. Synthesis 2000,
217±219.
11. Basavaiah, D.; Hyma, R. S.; Muthukumaran, K.; Kumaraguru-
baran, N. Tetrahedron 2000, 56, 5905±5907.
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