Titanium(IV) chloride and quaternary ammonium salt promoted Baylis-Hillman reaction

Article abstract of DOI:10.1021/jo0009853

The Baylis-Hillman reaction of aldehydes with α,β-unsaturated ketones can be drastically affected by the reaction temperature and Lewis bases. When the reaction was carried out at -78°C using catalytic amounts of quaternary ammonium salts (R₄N<

Full text of DOI:10.1021/jo0009853

4
06
J . Org. Chem. 2001, 66, 406-411
Tita n iu m (IV) Ch lor id e a n d Qu a ter n a r y Am m on iu m Sa lt P r om oted
Ba ylis-Hillm a n Rea ction
Min Shi* and Yan-Shu Feng
Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences, 354 Fenglin Lu, Shanghai 200032 China
mshi@pub.sioc.ac.cn
Received J une 29, 2000
The Baylis-Hillman reaction of aldehydes with R,â-unsaturated ketones can be drastically affected
by the reaction temperature and Lewis bases. When the reaction was carried out at -78 °C using
+
-
catalytic amounts of quaternary ammonium salts (R
4
N X , X ) Cl, Br, I) as Lewis bases, in the
presence of titanium(IV) chloride, the chlorinated aldol adduct 1 was obtained as the major product.
Quaternary ammonium bromides and iodides (R N X , X ) Br, I) have higher catalytic activity
4 4
than corresponding chlorides (R N Cl ). Quaternary ammonium fluorides (R N F ) do not have
+
-
4
+
-
+
-
activity at all. The amounts of Lewis acid and quaternary ammonium salts used affect the reaction
rate and product. A plausible reaction mechanism is proposed. If the reaction was carried out at
room temperature (about 20 °C) in the presence of titanium(IV) chloride and quaternary ammonium
+
-
salts (R
product.
4
N X , X ) Cl, Br, I), the elimination product 3, derived from 1, was formed as the major
In tr od u ction
The Baylis-Hillman reaction and related processes,
typically catalyzed by DABCO or tertiary phosphines,
have become increasingly important in organic synthesis
because the resulting adducts may have several func-
Ta ble 1. Rea ction of p-Nitr oben za ld eh yd e w ith Meth yl
Vin yl Keton e in th e P r esen ce of TiCl4 a n d Am m on iu m
Sa lt a t -78 °C
yield (%)a
ammonium salt
(equiv)
TiCl4
time
entry
(equiv) (day) 1a
2a
tional groups available for numerous further trans-
1
2
3
4
5
6
7
8
9
0
1
12
13
1.0
0.5
0.5
0.5
0.5
1.0
1.4
1.4
0.25
0.5
1.0
1.4
1.4
1.4
1.4
1.4
5
5
5
5
5
3
1
1
7
5
3
1
1
3
3
3
+
-
formations.1
-5
Bu N Br (0.0t)
82
73
71
47
82
85
91
30
86
88
90
87
65
70
0
10
16
32
trace
7
0
10
7
The major drawbacks of the Baylis-
4
+
-
Bu4N Br (0.25)
Hillman reaction are its slow reaction rate and limited
range of substrates. To overcome these shortcomings,
many efforts have been made, such as using Lewis
+
-
Bu4N Br (0.5)
+
-
Bu4N Br (1.0)
Bu N+Br- (0.25)
4
+
-
acids or various other additives to activate carbonyl
Bu4N Br (0.25)
+
-
electrophiles.6
-10
Bu N Br (0.05)
Among those Lewis acids examined,
4
+
-
Bu4N I (0.25)
TiCl
4
has been successfully utilized to promote the
+
-
1
1
Bu4N I (0.25)
Baylis-Hillman reaction in the presence of Lewis base
catalysts.11 Recently, Li and co-workers reported new Cd
C bond formation via nonstoichiometric titanium(IV)
halide mediated vicinal difunctionalization of R,â-unsat-
urated acyclic ketones in the presence of catalytic amounts
+ -
Bu4N I (0.25)
5
Bu N+I- (0.05)
4
trace
6
trace
trace
+
-
Bu4N I (0.25)
+
-
1
1
1
4
5
6
Bu4N Cl (0.25)
+
-
PhCH2Et3N Cl (0.25)
+
-
Bu4N F (0.25)
a
(1) For reviews, see: (a) Ciganek, E. Org. React. 1997, 51, 201. (b)
Isolated yields.
Basavaiah, D.; Rao, P. D.; Hyma, R. S. Tetrahedron 1996, 52, 8001.
(
c) Drewes, S. E.; Roos, G. H. P. Tetrahedron 1988, 44, 4653.
2) Brzezinski, L. J .; Rafel, S.; Leahy, J . M. J . Am. Chem. Soc. 1997,
19, 4317.
3) Marko, I. E.; Giles, P. G.; Hindley, N. J . Tetrahedron 1997, 53,
015.
+
- 12
4
of Bu N I . We have also carried out similar but
(
1
1
independent research and found different results. The
reaction temperature, the anion of the quaternary am-
monium salts, and the amount of Lewis acid or Lewis
base can drastically affect the reaction. These effects have
never been disclosed before. Herein we wish to report the
full details of titanium(IV) chloride and quaternary
ammonium salts promoted Baylis-Hillman reaction,
along with a plausible reaction mechanism based on the
previous findings and our own results.
(
(
(
4) Richter, H.; J ung, G. Tetrahedron Lett. 1998, 39, 2729.
5) Barrett, A. G. M.; Cook, A. S.; Kamimura, A. Chem. Commun.
1
999, 2533.
6) Kunidig, E. P.; Xu, L. H.; Romanens, P.; Bernardinelli, G.
Tetrahedron Lett. 1993, 34, 7049.
7) Aggarwal, V.; Mereu, A.; Tarver, G. J .; MaCague, R. J . Org.
Chem. 1998, 63, 7183.
(
(
(
(
8) Kawamura, M.; Kobayashi, S. Tetrahedron Lett. 1999, 40, 1539.
9) (a) Kataoka, T.; Iwama, T.; Tsujiyama, S.-i.; Iwamura, T.;
Watanaba, S.-i. Tetrahedron 1998, 54, 11813. (b) Kataoka, T.; Iwama,
T.; Kinoshita, S.; Tsujiyama, Y.; Iwamura, T.; Watanabe, S. Synlett
Resu lts a n d Discu ssion
1
999, 197. (c) Kataoka, T.; Iwama, T.; Tsujiyama, S.; Kanematsu, K.;
Iwamura, T.; Watanabe, S. Chem. Lett. 1999, 257. (d) Iwama, T.;
Tsujiyama, S.-I.; Kinoshita, H.; Kanamatsu, K.; Tsurukami, Y.; Iwa-
mura, T.; Watanabe, S.-I.; Kataoka, T. Chem. Pharm. Bull. 1999, 47,
We initially attempted the reaction of p-nitrobenzal-
dehyde with methyl vinyl ketone in the presence of TiCl
1.0 equiv) at -78 °C. No reactions occurred (Table 1,
4
9
56.
10) Ono, M.; Nishimura, K.; Nagaoka, Y.; Tomioka, K. Tetrahedron
Lett. 1999, 40, 1509.
11) Nagaoka, Y.; Yomioka, K. J . Org. Chem. 1998, 63, 6428.
(
(
(
(12) Li, G.; Gao, J .; Wei, H.-X.; Enright, M. Org. Lett. 2000, 2, 617.
1
0.1021/jo0009853 CCC: $20.00 © 2001 American Chemical Society
Published on Web 12/29/2000

TiCl
4
and R
4
N+ Promoted Baylis-Hillman Reaction
J . Org. Chem., Vol. 66, No. 2, 2001 407
Sch em e 1
entry 1). However, after adding 5 mol % (0.05 equiv) of
tetrabutylammonium bromide as a Lewis base, the
reaction took place smoothly to give the chlorinated
product 1a , rather than 2a and 3a (which were usually
considered as the Baylis-Hillman olefin and trisubsti-
tuted alkene) reported by Kataoka and Li,9 respectively
Ta ble 2. Ba ylis-Hillm a n Rea ction of Ald eh yd es w ith
Meth yl Vin yl Keton e in th e P r esen ce of TiCl4 (1.4 equ iv)
+
-
a n d Bu 4N Br (0.05 equ iv) a t Low Tem p er a tu r e
a
entry
R
temp/°C
time/h
yield (%) of 1
1
2
3
4
5
6
7
8
o-NO2Ph
p-CF3Ph
p-CF3Ph
p-ClPh
m-FPh
p-EtPh
Ph
CH3(CH2)8
-78
-78
-20
-20
-20
-20
-20
-20
36
72
36
36
36
36
36
36
92
40
90
52
80
52
67
29
,12
(
Scheme 1, Table 1, entry 2). By careful investigation,
we found that this reaction was very sensitive to the
amounts of both TiCl and quaternary ammonium salts
present in the reaction mixture (Table 1). With 0.05 equiv
of tetrabutylammonium bromide and 0.5 equiv of TiCl
the reaction required 5 days to provide 1a in 82% yield
Table 1, entry 2). Increasing the amount of TiCl in the
4
4
,
a
Isolated yield.
(
4
presence of catalytic amounts of quaternary ammonium
salt could significantly speed up the reaction and gave
higher yields of 1a (Table 1, entries 3, 6, and 7).
Increasing the amount of quaternary ammonium salt
reduced the selectivity of the reaction with the yield of
the Baylis-Hillman olefin 2a remarkably increased
Sch em e 2
+
-
(
Table 1, entries 3-5). The reaction using Bu
4
N Cl or
+
-
PhCH
2
Et
3
N Cl as a promoter was slower than those
N I and Bu N Br under the same reaction
4 4
conditions (Table 1, entries 14 and 15), whereas Bu
+
-
+
-
using Bu
Sch em e 3
+
-
4
N F
could not promote the reaction at all under the same
conditions (Table 1, entry 16). These results suggested
that the anion of quaternary ammonium salts played a
very important role in this reaction. The tetrabutylam-
+
-
monium bromide (Bu
4
N Br ) showed the highest cata-
lytic activity. Thus, the best reaction conditions were
+
-
shown by entry 8, with 0.05 equiv (5 mol %) of Bu
as Lewis base and 1.4 equiv of TiCl as Lewis acid at
78 °C (Table 1, entry 8). In all those cases, only
4
N Br
4
-
Sch em e 4
chlorinated compound was formed. It is interesting to
note that neither brominated nor iodinated product was
detected when using the bromide or iodide as promoter.
This means that only chloride ions from TiCl
in the reaction.
4
takes part
Next we examined other aldehydes using the optimized
reaction conditions. We found that, for aryl aldehydes
having a strong electron-withdrawing group on the
phenyl ring, the reaction proceeded quickly at -78 °C to
give 1 in high yields (Scheme 2, Table 2, entry 1).
However, other aryl aldehydes or aliphatic aldehydes
needed higher temperatures (-20 °C) to produce 1 in
moderate to high yields (Table 2, entries 3-8). Aryl
aldehydes can also react with acrylonitrile under similar
reaction conditions to give the corresponding elimination
product 2i in moderate yields (in dichloromethane at 10
formed from aldehydes in the reaction. Their relative
configurations were assigned as syn-form on the basis of
X-ray analysis of the crystal structure of 1a 13 (Figure 1,
Supporting Information). The HPLC analysis also sup-
ported our results. Compound 1 could be transformed to
compound 29d by treatment with an excess (2.0 equiv) of
triethylamine or 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU)
at room temperature (Scheme 4). Purification of 1 by
preparative TLC also caused the transformation of 1 to
2. Thus, rapid flash column chromatography was neces-
sary to obtain pure 1. However, when the reaction was
carried out at higher temperatures (0 °C), we found that
both syn and anti isomers could be formed at the same
time, along with 2 and 3. For example, in the reaction of
o-nitrobenzaldehyde with methyl vinyl ketone at 0 °C
°
C for 5 days). At -78 °C, no reaction occurred. Raising
the reaction temperature to reflux (45 °C) led to a
decrease in the yield of 2i (Scheme 3). No reactions
occurred with methyl acrylate as Michael acceptor
+
-
(
Scheme 3).
4 4
using 1.4 equiv of TiCl and 0.05 equiv of Bu N Br for
6 h, syn-1a and anti-1a were produced in a ratio of 4:1.
Thus, to obtain 1 in one isomer with high yield, the
1
The H NMR spectroscopic data and HPLC analyses
showed that only one diastereoisomer (syn/anti) was

4
08 J . Org. Chem., Vol. 66, No. 2, 2001
Shi and Feng
Sch em e 5
Sch em e 6
reaction should be strictly kept at lower temperature.
Recently Kataoka and co-workers reexamined his chal-
cogen-Baylis-Hillman reaction at 0 °C and disclosed the
plausible mechanism for the formation of syn- and anti-
1
4
1
a .
In fact, the reaction of quaternary ammonium bromide
or chloride with methyltitanium chloride had been in-
Ta ble 3. Rea ction of p-Nitr oben za ld eh yd e w ith Meth yl
Vin yl Keton e in th e P r esen ce of TiCl4 a n d 0.26 equ iv of
Am m on iu m Sa lt a t Room Tem p er a tu r e
1
5
vestigated by Clark and Coles previously. The resulting
complex was quite complicated. Two different series of
binuclear anionic complex salts could be formed depend-
a
entry ammonium salt TiCl4/equiv time/day yield (%) of 3a
Bu4N+F-
1
2
3
4
5
6
7
8
9
0.26
0.26
0.5
0.26
0.5
1.0
0.26
0.5
5
5
4
5
4
1
5
4
1
+
-
-
ing on the molar ratios of the reactants (type A, R[Me
Ti Y]; type B, [R] [MeTiX
], X ) Cl, Y ) Cl, Br).16
In our experiments, we found that mixing TiCl with
2
-
PhCH Et N Cl
20
70
71
80
92
60
73
84
2
3
+
X
6
2
3
Y
2
PhCH2Et3N Cl
2
+
-
-
-
Bu4N Br
4
+
Bu4N Br
quaternary ammonium salt gave a dark red solution,
which was very similar to that reported by Clark and
Coles in the reaction of quaternary ammonium bromide
or chloride with methyltitanium chloride. We believe that
similar binuclear anionic chemical species exist in the
reaction system involving quaternary ammonium salts
+
Bu4N Br
+
-
-
-
Bu4N I
+
Bu4N I
+
Bu4N I
1.0
a
Isolated yield.
of quaternary ammonium salt and 1.4 equiv of TiCl
produced a high yield of 1 in a short time. With 0.25 equiv
of quaternary ammonium salt and 0.5 equiv of TiCl , the
yield of 1 could reach about 80%, but the reaction
required 5 days. We tried to isolate the proposed anionic
complexes, but did not succeed so far. In fact, the
formation of chlorinated compound 1 is a major reaction
4
4
with TiCl , which are the true active catalysts for this
reaction. In Scheme 5 we propose a mechanism for the
formation of 1 on the basis of these previous findings and
the results of our own investigations (Table 1). The
4
4
quaternary ammonium salt first reacted with TiCl to
form intermediate A, which further reacted with the
quaternary ammonium salt to give intermediate B if the
reaction system contained sufficient quaternary am-
monium salt (Scheme 5). The anionic complex A acted
as the key activator by chloride ion attacking at methyl
vinyl ketone to carry out cycle 1. If the system contains
a large amount of quaternary ammonium salt, the
anionic complex B would become the major activator of
cycle 2 by carrying two chloride ions to initiate the
chlorinated aldol reaction. The reaction in cycle 1 was
fast, but cycle 2, which would give two chloride ions from
binuclear anionic titanium, was slow. Thus, 0.05 equiv
process in the TiCl and Lewis base promoted Baylis-
4
Hillman reaction. However, it is not understood yet why
the yield of Baylis-Hillman olefin 2a can be increased
by using a large amount of quaternary ammonium salt
as a Lewis base and why at low temperature only one
isomer was formed.
By carrying out this reaction at room temperature, we
confirmed that elimination product 3 was the only
product, as reported by Li and co-workers (Scheme 6).
However, we found that the yield of 3 could also be
affected drastically by the amount of TiCl . Some of our
1
2
4
results were in conflict with those reported by Li. Using
(
4
13) Crystal data for 1a : empirical formula C11H12ClNO ; formula
p-nitrobenzaldehyde as the substrate in the presence of
weight 257.67; crystal color, habit - colorless, column; crystal dimen-
+
-
0
Bu
.26 equiv of TiCl
4
4
and 0.26 equiv of Bu
4
N Br or
sions 0.28 × 0.30 × 0.18 mm; crystal system orthorhombic; lattice type
+
-
primitive; lattice parameters a ) 10.615(1) Å, b ) 14.277(1) Å, c )
N I , 3a could be obtained in 71 and 60%, respec-
3
7
D
R
.838(1) Å, V ) 1187.8(3) Å ; space group: P2
1
2
1
2
1
(No. 19); Zvalue ) 4;
tively, after 5 days (Scheme 6, Table 3, entries 4 and 7).
3
-1
clalc ) 1.441 g/cm ; F000 ) 536.00; µ(Mo KR) ) 3.23 cm ; residuals R,
The yields of 3a were slightly lower, but the reaction time
w
) 0.065, 0.052.
14) Kataoka, T.; Kinoshita, H.; Iwama, T.; Tsujiyama, S.-I.; Iwa-
mura, T.; Watanabe, S.-I.; Muraoka, O.; Tanabe, G. Tetrahedron 2000,
6, 4725.
+
-
-
(
was much longer than the 24 h reported by Li. Bu
showed no catalytic activity for this reaction. Bu
4
N F
+
4
N Cl
5
(
quaternary ammonium chloride) was less effective than
(
(
15) Clark, R. J . H.; Coles, M. Chem. Commun. 1971, 1587.
16) Clark, R. J . H.; Coles, M. J . Chem. Soc., Dalton 1972, 533.
+
-
4
either Bu N Br (quaternary ammonium bromide) or

TiCl
4
and R
4
N+ Promoted Baylis-Hillman Reaction
J . Org. Chem., Vol. 66, No. 2, 2001 409
Ta ble 4. Ba ylis-Hillm a n Rea ction of Ald eh yd es w ith
Meth yl Vin yl Keton e in th e P r esen ce of 1.0 Eq of TiCl4
4, entries 1 and 2); 70-80% yields of 3 could be achieved
for many aryl aldehydes. For aliphatic aldehydes, the
yield of 3 was only moderate (Table 4, entry 7).
+
-
a n d 0.25 Eq of Bu 4N Br a t Room Tem p er a tu r e
a
entry
R
time/h
yield (%) of 3
1
2
3
4
5
6
7
o-NO2Ph
p-CF3Ph
p-ClPh
m-FPh
p-EtPh
Ph
24
24
24
24
36
24
24
91
86
60
78
50
71
30
Con clu sion s
We have found that titanium(IV) chloride and quater-
nary ammonium salt promoted the Baylis-Hillman
reaction and that the reaction was not as simple as
previously reported. The reaction temperature, the amount
of Lewis acid, and the amount of Lewis base can drasti-
cally affect the reaction product and reaction rate. We
propose that two catalytic cycles work together at low
temperatures: cycle 1 is based on the active catalyst A
and cycle 2 is based on the active catalyst B (Scheme 5).
Me(CH2)8
a
Isolated yield.
Sch em e 7
4
In the reaction system with a large excess of TiCl (1.4
equiv) and a catalytic amount of quaternary ammonium
salt (0.05 equiv), cycle 1 plays a major role in the
formation of the chlorinated compound 1 because catalyst
A is formed predominantly and it catalyzes a fast
4
reaction. Using a smaller amount of TiCl (0.5 equiv) and
a catalytic amount of quaternary ammonium salt (0.25
equiv), cycle 2 plays a major role in the formation of the
chlorinated compound 1, because catalyst B is formed
predominantly and it catalyzes a slow reaction. Thus, the
Sch em e 8
4
ratio of TiCl to quaternary ammonium salt is crucial for
this reaction. Undoubtedly compound 3 was derived
mainly from 1. If a quaternary ammonium salt is used
as the Lewis base, the counterion is also important.
Efforts are underway to elucidate the mechanistic details
of this reaction and to define the scope and limitations
of this reaction. In addition, we are planning to synthe-
size chiral quaternary ammonium salts for use as chiral
Lewis bases to accomplish enantioselective Baylis-
Hillman reactions.
+
-
4
Bu N I (quaternary ammonium iodide) (Table 3, entries
1
-3). We also found that increasing the amount of TiCl
could enhance the reaction rate and give a higher yield
of 3a in a shorter time (Table 3, entries 5, 6, 8, and 9).
4 4
By using 1.0 equiv of TiCl and 0.26 equiv of Bu N Br ,
4
+
-
the reaction could be completed in 1 day (24 h); these
was found to be the best reaction conditions for the
preparation of 3a . The amount of quaternary ammonium
salt did not affect the reaction product or the yield of 3a
Exp er im en ta l Section
Gen er a l. Melting points are uncorrected. H and 13C NMR
spectra were recorded at 300 and 75 MHz, respectively. Mass
spectra were recorded by EI method and HRMS was measured
on a Finnigan MA+ mass spectrometer. Organic solvents used
were dried by standard methods when necessary. Com-
mercially available reagents were used without further puri-
fication. HPLC analysis was carried out by column: Kromasil
1
+
-
because, using 0.05 equiv or 0.5 equiv of Bu
the presence of 1.0 equiv of TiCl , 3a was obtained in
the 90 and 91%, respectively, very similar to the yields
4
N Br in
4
+
-
obtained using 0.26 equiv of Bu
).
Concerning the formation of 3a , we treated 1a and 2a
directly with TiCl in dichloromethane at room temper-
4
N Br (Table 4, entry
6
4
.6 × 150 mm and LUNA C18 4.6 × 150 mm, respectively. All
reactions were monitored by TLC with Huanghai GF254 silica
gel coated plates. Flash column chromatography was carried
out using 300-400 mesh silica gel.
4
ature. We found that 1a was transformed to 3a within 6
h, whereas the reaction of 2a was much slower (Scheme
Typ ica l Rea ction P r oced u r e for th e P r ep a r a tion of
syn -3-(Ch lor om eth yl)-4-h yd r oxy-4-(4′-n itr op h en yl)-2-bu -
ta n on e (1a ). To a solution of tetrabutylammonium bromide
8.06 mg, 0.025 mmol) in dichloromethane (1.3 mL) was added
.4 N titanium tetrachloride in dichloromethane (0.7 mL, 0.7
mmol) at -78 °C. After beibg stirred for 5 min, a solution of
p-nitrobenzaldehyde (76 mg, 0.5 mmol) in dichloromethane (1.0
mL) and methyl vinyl ketone (105 mg, 1.5 mmol, 123 uL) were
added. The reaction mixture was kept for 24 h at -78 °C. The
reaction was quenched by addition of a saturated aqueous
7
). These results strongly suggest that 3a is derived
directly from 1a formed first in the reaction. The Z-
configuration of 3a has been confirmed by X-ray analysis
in our previous paper (Figure 2, Supporting Informa-
tion).17
Using the optimized reaction conditions, we carried out
this reaction using various aldehydes (Scheme 8, Table
(
1
4
). Aryl aldehydes with a strongly electron-withdrawing
NaHCO
extracted with dichloromethane (5.0 mL × 2) and dried over
anhydrous MgSO . The solvent was removed under reduced
3
solution (1.0 mL). After filtration, the filtrate was
group on the phenyl ring gave higher yields of 3 (Table
4
pressure, and the residue was purified by flash silica gel
chromatography to give compound 1a (117 mg, 91%) as a
colorless solid (eluent: ethyl acetate/petroleum ether ) 1/4):
(
17) Shi, M.; J iang, J .-K. Tetrahedron, 2000, 56, 4793. The crystal
data of 3a : empirical formula C22 Cl ; formula weight 479.32;
crystal color, habit - colorless, prismatic; crystal dimensions 0.20 ×
.20 × 0.30 mm; crystal system monoclinic; lattice type: primitive;
H
20
N
2
O
6
2
0
-1
1
mp 90-91 °C; IR (KBr) ν 1720 cm (CdO); H NMR (CDCl
00 MHz) δ 2.20 (3H, s, Me), 2.93 (1H, br. s, OH), 3.22-3.38
(1H, m), 3.67 (1H, dd, J ) 11.3, 4.0 Hz), 3.89 (1H, dd, J 11.3,
.2 Hz), 5.11 (1H, d, J ) 5.6 Hz), 7.56 (2H, d, J ) 8.6 Hz, Ar),
3
,
lattice parameters: a ) 7.524(2) Å, b ) 17.541(3) Å, c ) 17.07(1) Å, â
3
3
)
D
1
98.64(4)°, V ) 2227(1) Å ; space group: P2 /n (No. 14); Z value ) 4;
3 -1
calc ) 1.429 g/cm ; F000 ) 992.00; µ(Mo KR) ) 3.33 cm ; R ) 0.066,
) 0.061. TEXSAN, Crystal Structure Analysis Package, Molecular
Structure Corporation, Houston, TX, 1985 and 1992.
9
R
w
+
8.25 (2H, d, J ) 8.6 Hz, Ar); MS (EI) m/e 258 (MH , 0.60), 208

4
10 J . Org. Chem., Vol. 66, No. 2, 2001
Shi and Feng
Cl requires
M+ - 49, 60), 71 (M - 186, 100). Found: C, 51.64; H, 4.94;
+
105, 100); HRMS (EI) m/z 212.0594 (M ), C11
M, 212.0604.
+
H
O
(
13
2
N, 5.35. C11
H
12ClNO
4
requires C, 51.27; H, 4.69; N, 5.44.
P r ep a r a tion of syn -3-(Ch lor om eth yl)-4-h yd r oxy-4-(2′-
n itr op h en yl)-2-bu ta n on e (1b). This compound was prepared
in the same manner as that described above: white solid, mp
P r ep a r a tion of syn -3-(Ch lor om eth yl)-4-h yd r oxy-4-bu -
tyl-2-bu ta n on e (1h ). This compound was prepared in the
same manner as that described above, but at -20 °C: 28 mg,
-1
1
-1
1
7
(
3
5
7
0-71 °C; 118 mg, 92%; IR (KBr) ν 1720 cm (CdO); H NMR
CDCl , 300 MHz) δ 2.44 (3H, s, Me), 3.45 (1H, br s, OH), 3.46-
.60 (2H, m, CH ), 3.95 (1H, ddd, J ) 12.1 12.1 2.1 Hz, CH),
29%; a colorless oil; IR (KBr) ν 1720 cm (CdO); H NMR
(CDCl , 300 MHz) δ 0.89 (3H, t, J ) 7.1 Hz), 1.10-1.60 (6H,
m), 2.08 (1H, s, OH), 2.34 (3H, s, Me), 3.0-3.10 (1H, m), 3.60-
3
3
2
+
+
.67 (1H, s, CH), 7.52 (1H, t, J ) 7.5 Hz, Ar), 7.71 (1H, t, J )
.5 Hz, Ar), 7.87 (1H, d, J ) 7.7 Hz, Ar), 8.10 (1H, d, J ) 8.1
3.85 (3H, m); MS (EI) m/e 192 (M , 0.80), 155 (M - 37, 30),
+
+
9 17 2
43 (M - 149, 100); HRMS (EI) m/z 192.0908 (M ), C H O -
+
+
Hz, Ar); MS (EI) m/e 257 (M , 0.60), 208 (M - 49, 60), 71
Cl requires M, 192.0917.
+
+
(M
- 186, 100); HRMS (EI) m/z 239.0353 (M - H
NCl requires M - H O, 239.0349.
P r ep a r a tion of a n ti-3-(Ch lor om eth yl)-4-h yd r oxy-4-(2′-
2
O),
Th e p h ysica l d a ta of th e k n ow n p r od u ct 3-[(4′-n itr o-
C
11
H
10
O
3
2
p h en yl)h yd r oxym eth yl]-3-bu ten -2-on e (2a ):9,16 mp 66-68
1
°C; H NMR (CDCl
3
, 300 MHz) δ 2.36 (3H, s, Me), 3.26 (1H,
n itr op h en yl)-2-bu ta n on e (1b′). This compound was pre-
br s, OH), 5.68 (1H, s), 6.05 (1H, s), 6.28 (1H, s), 7.56 (2H, d,
pared in the same manner as that described above: white
J ) 8.6 Hz, Ar), 8.19 (2H, d, J ) 8.6 Hz, Ar).
P r ep a r a t ion of 2-[(4′-Nit r op h en yl)h yd r oxym et h yl]-
-
1
solid, mp 70-71 °C; 27 mg, 23%; IR (KBr) ν 1720 cm (Cd
1
1
O); H NMR (CDCl
3
, 300 MHz) δ 2.14 (3H, s, Me), 3.48 (1H,
), 3.86 (1H, dd, J ) 9.4 9.4
a cr ylon itr ile (2i): a yellow solid; mp 60-62 °C; H NMR
br s, OH), 3.50-3.65 (2H, m, CH
2
(CDCl , 300 MHz) δ 3.26 (1H, br s, OH), 5.45 (1H, s), 6.10 (1H,
3
Hz, CH), 5.57 (1H, d, J ) 3.5 Hz, CH), 7.52 (1H, t, J ) 7.5 Hz,
Ar), 7.69 (2H, t, J ) 7.5 Hz, Ar), 8.02 (1H, d, J ) 8.1 Hz, Ar);
s), 6.19 (1H, s), 7.60 (2H, d, J ) 8.4 Hz, Ar), 8.24 (2H, d, J )
+
+
8.4 Hz, Ar); MS (EI) m/e 204 (M
, 0.80), 155 (M - 37, 30), 43
+
+
+
+
+
MS (EI) m/e 257 (M , 0.60), 208 (M - 49, 60), 71 (M - 186,
(M - 149, 100); HRMS (EI) m/z 204.0530 (M ), C H N O
1
0
8
2
3
1
00); HRMS (EI) m/z 239.0353 (M+ - H
requires M - H O, 239.0349.
2
O), C11
H
10
O
3
NCl
requires M, 204.0535.
2
Typ ica l Rea ction P r oced u r e for th e P r ep a r a tion of
3-(Ch lor om eth yl)-4-(4′-n itr op h en yl)-3-bu ten -2-on e (3a ).
To a solution of tetramethylammonium bromide (8.06 mg,
0.025 mmol) in dichloromethane (1.3 mL) was added 1.0 N
titanium tetrachloride in dichloromethane (0.5 mL, 0.5 mmol)
at room temperature. After beibg stirred for 5 min, a solution
of p-nitrobenzaldehyde (76 mg, 0.5 mmol) in dichloromethane
(1.0 mL) and methyl vinyl ketone (105 mg, 1.5 mmol, 123 uL)
were added into the reaction at room temperature. The
reaction mixture was kept for 24 h at room temperature. The
reaction was quenched by addition of a saturated aqueous
NaHCO3 solution (1.0 mL). After filtration, the filtrate was
extracted with dichloromethane (5.0 mL × 2) and dried over
P r ep a r a tion of syn -3-(Ch lor om eth yl)-4-h yd r oxy-4-(4′-
tr iflu or om eth ylp h en yl)-2-bu ta n on e (1c). This compound
was prepared in the same manner as that described above,
but at -20 °C: 126 mg, 90%; a colorless oil; IR (KBr) ν 1720
-
1
1
cm (CdO); H NMR (CDCl
2
3
3
, 300 MHz) δ 2.13 (3H, s, Me),
.65 (1H, br s, OH), 3.22-3.37 (1H, m), 3.70 (1H, dd, J ) 10.2,
.9 Hz), 3.89 (1H, dd, J ) 10.2, 10.2 Hz), 5.02 (1H, d, J ) 6.1
Hz), 7.37 (2H, d, J ) 8.0 Hz, Ar), 7.64 (2H, d, J ) 8.0 Hz, Ar);
+
+
+
MS (EI) m/e 280 (M , 0.45), 243 (M - 37, 40), 43 (M - 237,
00); HRMS (EI) m/z 262.0377 (M+ - H
O), C12 10OClF
requires M - H O, 262.0372.
1
2
H
3
2
P r ep a r a tion of syn -3-(Ch lor om eth yl)-4-h yd r oxy-4-(4′-
ch lor op h en yl)-2-bu ta n on e (1d ). This compound was pre-
pared in the same manner as that described above, but at -20
4
anhydrous MgSO . The solvent was removed under reduced
pressure, and the residue was purified by flash silica gel
chromatography to give compound 3a (110 mg, 92%) as a
colorless solid (eluent: ethyl acetate/petroleum ether ) 1/8):
-
1
°
C: 64 mg, 52%; a colorless oil; IR (KBr) ν 1720 cm (CdO);
1
H NMR (CDCl , 300 MHz) δ 2.0 (3H, s, Me), 2.50 (1H, br s,
3
-1
1
OH), 3.20-3.32 (1H, m), 3.75 (1H, dd, J ) 10.7, 3.8 Hz), 3.87
mp 134-136 °C; IR (KBr) ν 1640 cm (CdO); H NMR (CDCl
300 Hz) δ 2.55 (3H, s, Me), 4.38 (2H, s, CH ), 7.69 (1H, s),
7.75 (2H, d, J ) 8.6 Hz, Ar), 8.35 (2H, d, J ) 8.6 Hz, Ar); MS
3
,
(
7
2
1H, dd, J ) 10.7, 10.7 Hz), 4.82 (1H, d, J ) 6.7 Hz), 7.10-
2
+
+
.32 (4H, m, Ar); MS (EI) m/e 246 (M , 1.20), 121 (M - 125,
+
+
+
+
+
0), 91 (M - 155, 100); HRMS (EI) m/z 246.0210 (M ),
Cl requires M, 246.0214.
P r ep a r a tion of syn -3-(Ch lor om eth yl)-4-h yd r oxy-4-(3′-
(EI) m/e 239 (M , 0.40), 222 (M - 17, 40), 115 (M - 124,
C
11
H
12
O
2
2
100). Found: C, 54.94; H, 3.92; N, 5.87. C11
C, 55.13; H, 4.21; N, 5.84.
3
H10ClNO requires
flu or op h en yl)-2-bu ta n on e (1e). This compound was pre-
pared in the same manner as that described above, but at -20
P r ep a r a tion of 3-(Ch lor om eth yl)-4-(2′-n itr op h en yl)-3-
bu ten -2-on e (3b). This compound was prepared in the same
manner as that described above: 109 mg, 91%; a colorless
-
1
°
C: 92 mg, 80%; a colorless oil; IR (KBr) ν 1720 cm (CdO);
1
-1
1
H NMR (CDCl
3
, 300 MHz) δ 2.0 (3H, s, Me), 2.50 (1H, br s,
solid; mp 120-122 °C; IR (KBr) ν 1640 cm (CdO); H NMR
OH), 3.20-3.32 (1H, m), 3.75 (1H, dd, J ) 10.7, 3.8 Hz), 3.87
(
7
2
C
(CDCl , 300 MHz) δ 2.52 (3H, s, Me), 4.23 (2H, s, CH ), 7.64
3
2
1H, dd, J ) 10.7, 10.7 Hz), 4.82 (1H, d, J ) 6.7 Hz), 7.10-
(1H, td, J ) 6.4, 1.5 Hz, Ar), 7.72 (1H, d, J ) 6.7 Hz, Ar), 7.80
(1H, t, J ) 7.5 Hz, Ar), 8.02 (1H, s), 8.27 (1H, d, J ) 7.5 Hz,
+
+
.50 (4H, m, Ar); MS (EI) m/e 230 (M , 1.60), 105 (M - 125,
+
+
+
+
+
0), 75 (M - 155, 100); HRMS (EI) m/z 230.0512 (M ),
ClF requires M, 230.0510.
P r ep a r a tion of syn -3-(Ch lor om eth yl)-4-h yd r oxy-4-(4′-
Ar); MS (EI) m/e 239 (M , 60), 222 (M - 17, 50), 115 (M -
+
+
11
H
12
O
2
124, 50), 43 (M - 196, 100); HRMS (EI) m/z 239.0351 (M ),
10ClNO requires M, 239.0349.
P r ep a r a tion of 3-(Ch lor om eth yl)-4-(4′-tr iflu or om eth -
C
11
H
3
eth ylp h en yl)-2-bu ta n on e (1f). This compound was prepared
in the same manner as that described above, but at -20 °C:
ylp h en yl)-3-bu ten -2-on e (3c). This compound was prepared
6
3 mg, 52%; a colorless solid; mp 69-71 °C; IR (KBr) ν 1720
in the same manner as that described above: 113 mg, 86%; a
-
1
1
-1
1
cm (CdO); H NMR (CDCl
Hz), 2.02 (3H, s, Me), 2.15 (1H, br s, OH), 2.63 (2H, q, J ) 7.7
Hz), 3.22-3.37 (1H, m), 3.80 (1H, dd, J ) 10.7, 3.8 Hz), 3.90
3
, 300 MHz) δ 1.21 (3H, t, J ) 7.7
colorless solid; mp 43-45 °C; IR (KBr) ν 1640 cm (CdO); H
NMR (CDCl , 300 MHz) δ 2.54 (3H, s, Me), 4.39 (2H, s, CH ),
7.70 (1H, s), 7.60-7.76 (4H, m, Ar); MS (EI) m/e 262 (M , 100),
3
2
+
+
+
+
(
7
4
1H, dd, J ) 10.7, 10.7 Hz), 4.82 (1H, d, J ) 7.2 Hz), 7.10-
193 (M - 69, 70), 183 (M - 79, 50), 115 (M - 147, 40);
+
+
+
.32 (4H, m, Ar); MS (EI) m/e 222 (M - 18, 1.20), 191 (M
-
3
HRMS (EI) m/z 262.0381 (M ), C12H10ClF O requires M,
+
+
9, 20), 135 (M - 105, 100); HRMS (EI) m/z 240.0908 (M ),
262.0372.
C
13
H
17
O
2
Cl requires M, 240.0917.
P r ep a r a tion of 3-(Ch lor om eth yl)-4-(4′-ch lor op h en yl)-
3-bu ten -2-on e (3d ). This compound was prepared in the same
manner as that described above: 69 mg, 60%; a colorless solid;
P r epar ation of syn -3-(Ch lor om eth yl)-4-h ydr oxy-4-ph en -
yl-2-bu ta n on e (1g). This compound was prepared in the same
manner as that described above, but at -20 °C: 71 mg, 67%;
-
1
1
mp 87-89 °C; IR (KBr) ν 1640 cm (CdO); H NMR (CDCl
300 MHz) δ 2.51 (3H, s, Me), 4.42 (2H, s, CH ), 7.46 (2H, d, J
) 8.6 Hz), 7.54 (2H, d, J ) 8.6 Hz), 7.69 (1H, s); MS (EI) m/e
3
,
-
1
1
a colorless oil; IR (KBr) ν 1720 cm (CdO); H NMR (CDCl
3
,
2
3
00 MHz) δ 2.02 (3H, s, Me), 2.45 (1H, br s, OH), 3.22-3.37
1H, m), 3.78 (1H, dd, J ) 10.7, 3.8 Hz), 3.90 (1H, dd, J )
0.4, 10.4 Hz), 4.84 (1H, d, J ) 6.9 Hz), 7.10-7.32 (5H, m,
+
+
+
+
(
228 (M , 20), 193 (M - 35, 40), 149 (M - 79, 40), 115 (M
- 113, 40), 43 (M - 185, 100); HRMS (EI) m/z 228.0110 (M ),
O requires M, 228.0109.
+
+
1
+
+
+
Ar); MS (EI) m/e 212 (M , 1.05), 163 (M - 49, 60), 107 (M
-
11 2
C H10Cl

TiCl
4
and R
4
N+ Promoted Baylis-Hillman Reaction
J . Org. Chem., Vol. 66, No. 2, 2001 411
P r ep a r a tion of 3-(Ch lor om eth yl)-4-(3′-flu or op h en yl)-
-bu ten -2-on e (3e). This compound was prepared in the same
CH
s, CH
2
), 2.36 (3H, s, Me), 2.34 (2H, td, J ) 7.6, 7.6 Hz), 4.32 (2H,
+
3
2
), 6.85 (1H, t, J ) 7.6 Hz); MS (EI) m/e 244 (M , 20),
+
+
+
manner as that described above: 83 mg, 78%; a colorless solid;
209 (M - 35, 40), 109 (M - 135, 70), 43 (M - 201, 100);
HRMS (EI) m/z 244.1596 (M ), C14H25ClO requires M, 244.1594.
-
1
1
+
mp 63-64 °C; IR (KBr) ν 1640 cm (CdO); H NMR (CDCl
3
,
3
00 MHz) δ 2.51 (3H, s, Me), 4.42 (2H, s, CH ), 7.10-7.50 (4H,
2
Cr ysta llogr a p h y. A suitable single crystal was mounted
at the top of a glass capillary. Data were collected on a Rigaku
AFC7R diffractometer with graphite-monochromated Mo KR
radition, λ ) 0.71069 Å, using the ω-2θ technique at 20 °C.
The data were collected for Lorentz polarization effects. The
structure was solved by direct methods and expanded using
Fourier techniques.16 The non-hydrogen atoms were refined
anisotropically by full-matrix least squares. All hydrogen
atoms were included in calculated position. All calculations
were performed using the TEXSAN crystallographic software
package. Their crystal structures have been deposited at the
Cambridge Crystallographic Data Center and allocated the
deposition numbers CCDC 144817 for 1a and CCDC 142973
for 3a .
+
+
m, Ar), 7.69 (1H, s); MS (EI) m/e 212 (M , 15), 177 (M - 35,
+
+
4
2
0), 99 (M - 113, 40), 43 (M - 169, 100); HRMS (EI) m/z
+
12.0411 (M ), C11
H10ClFO requires M, 212.0404.
P r ep a r a tion of 3-(Ch lor om eth yl)-4-(4′-eth ylp h en yl)-3-
bu ten -2-on e (3f). This compound was prepared in the same
manner as that described above: 56 mg, 50%; a colorless oil;
-
1
1
IR (KBr) ν 1640 cm (CdO); H NMR (CDCl
3
, 300 MHz) δ
1
.28 (3H, t, J ) 7.1 Hz), 2.51 (3H, s, Me), 2.67 (2H, q, J ) 7.1
Hz), 4.48 (2H, s, CH ), 7.31 (2H, d, J ) 8.0 Hz), 7.55 (2H, d, J
2
+
+
)
8.0 Hz), 7.69 (1H, s); MS (EI) m/e 222 (M , 30), 193 (M -
+
+
2
9, 100), 128 (M - 94, 40); HRMS (EI) m/z 222.0809 (M ),
15ClO requires M, 222.0811.
P r ep a r a tion of 3-(Ch lor om eth yl)-4-p h en yl-3-bu ten -2-
13
C H
on e (3g). This compound was prepared in the same manner
as that described above: 69 mg, 71%; a colorless oil; IR (KBr)
Ack n ow led gm en t. We thank the State Key Project
of Basic Research (Project 973) (No. G2000048007) for
financial support and the Inoue Photochirogenesis
Project (ERATO, J ST) for chemical reagents.
-
1
1
ν 1640 cm (CdO); H NMR (CDCl
Me), 4.46 (2H, s, CH ), 7.31-7.50 (3H, m, Ar), 7.51-7.61 (2H,
m, Ar), 7.71 (1H, s); MS (EI) m/e 194 (M , 100), 115 (M - 79,
3
, 300 MHz) δ 2.52 (3H, s,
2
+
+
+
+
4
0), 43 (M - 151, 40); HRMS (EI) m/z 194.0498 (M ), C11
11
H -
ClO requires M, 194.0492.
1
Su p p or tin g In for m a tion Ava ila ble: The H NMR charts
P r ep a r a tion of 3-(Ch lor om eth yl)-4-n on yl-3-bu ten -2-
on e (3h ). This compound was prepared in the same manner
as that described above: 37 mg, 30%; a colorless oil; IR (KBr)
of 1a -h , 3a -h , HPLC charts of 1a and 1h , X-ray data of 1a
and 3a , and ortep drawings for 1a and 3a . This material is
available free of charge via the Internet at http://pubs.acs.org.
-
1
1
ν 1640 cm (CdO); H NMR (CDCl
3
, 300 MHz) δ 0.83 (3H, t,
J ) 7.1 Hz, Me), 1.10-1.40 (12H, m, CH
2
), 1.40-1.60 (2H, m,
J O0009853