Lewis acid mediated reactions of aldehydes with styrene derivatives: Synthesis of 1,3-Dihalo-1,3-diarylpropanes and 3-chloro-1,3-diarylpropanols

Article abstract of DOI:10.1021/jo051298k

The reactions of aryl aldehydes with styrene derivatives, mediated by various boron Lewis acids, were investigated. 1,3-Dihalo-1,3-diarylpropanes were obtained in high yields with boron trihalides, while 3-chloro-1,3- diarylpropanols were obtained in good

Full text of DOI:10.1021/jo051298k

Lewis Acid Mediated Reactions of Aldehydes with Styrene
Derivatives: Synthesis of 1,3-Dihalo-1,3-diarylpropanes and
3-Chloro-1,3-diarylpropanols
George W. Kabalka,* Zhongzhi Wu, Yuhong Ju, and Min-Liang Yao
Departments of Chemistry and Radiology, The University of Tennessee, Knoxville, Tennessee 37996-1600
kabalka@utk.edu
Received June 24, 2005
The reactions of aryl aldehydes with styrene derivatives, mediated by various boron Lewis acids,
were investigated. 1,3-Dihalo-1,3-diarylpropanes were obtained in high yields with boron trihalides,
while 3-chloro-1,3-diarylpropanols were obtained in good to excellent yields with phenylboron
dichloride. Reactions involving nonenolizable aliphatic aldehydes, trans-cinnamaldehyde, and
â-substituted styrenes were also investigated for the first time.
SCHEME 1
Introduction
The Lewis acid promoted addition of alkenes to car-
bonyl compounds is an important method for forming new
carbon-carbon bonds.1 Generally the reactions are cata-
lyzed by Lewis acids, such as BF3,2a,b,f,3 AlCl3,4 FeCl3,4b,5
(1) (a) Lewis Acids in Organic Synthesis; Yamamoto, H., Ed.; Wiley-
VCH: Weimheim, Germany, 2000. (b) Mikami, K.; Shimizhu, M. Chem.
Rev. 1992, 92, 1021. (c) Selectivities in Lewis Acid Promoted Reactions;
Schinzer, D., Ed.; Kluwer Academic Publishers: Dordrecht, The
Netherlands, 1989. (d) Reetz, M. T. Acc. Chem. Res. 1993, 26, 462. (e)
Fleming, I.; Dunoguks, J.; Smithers, R. Org. React. 1989, 37, 57. (f)
Hosomi, A. Acc. Chem. Res. 1988, 21, 200. (g) Mukaiyama, T.;
Murakami, M. Synthesis 1987, 1043. (h) Sakurai, H. Pure Appl. Chem.
1985, 57, 1759. (i) Snider, B. B. Acc. Chem. Res. 1980, 13, 426.
(2) (a) Wovkulich, P. M.; Uskokovich, M. R. J. Org. Chem. 1982,
47, 1600. (b) Wovkulick, P. M.; Barcelos, F.; Batcho, A. D.; Sereno, J.
F.; Baggiolini, E. G.; Hennessy, B. M.; Uskokovich, M. R. Tetrahedron
1984, 40, 2283. (c) Mikami, K.; Terada, M.; Nakai, T. J. Am. Chem.
Soc. 1989, 111, 1940; 1990, 112, 3949. (d) Ciufolini, M. A.; Zhu, S.;
Deaton, M. V. J. Org. Chem. 1997, 62, 7806. (e) Ciufolini, M. A.; Chen,
M.; Lovett, D. D.; Deaton, M. V. Tetrahedron Lett. 1997, 38, 4355. (f)
D’Aniello, F.; Mann, A.; Mattii, D.; Taddei, M. J. Org. Chem. 1994,
59, 3762. (g) Houston, T. A.; Tanaka, Y.; Koreeda, M. J. Org. Chem.
1993, 58, 4287.
SnCl4,6c,e,4b,7 TiCl4,6c,8 BiCl3,9 and alkylaluminum
chlorides.2g,3c,10 Interestingly, BCl3 has been reported to
be an ineffective promoter of ene reactions between
aldehydes and alkenes.4b During a study focused on boron
halide mediated reactions,11 we discovered that boron
trihalides (BX3) are very effective in promoting the
addition of aryl aldehydes with styrene derivatives. The
reactions produce diastereomeric mixtures (∼1:1) of 1,3-
dihalo-1,3-diarylpropanes (1) in excellent yields (Scheme
1).
The preliminary results have been communicated12 and
a reaction mechanism (Scheme 2) proposed based on the
isolation of 3-halo-1,3-diarylpropanols as side products.
(3) (a) Blomquist, A. T.; Himies, R. J. J. Org. Chem. 1968, 33, 1156.
(b) Blomquist, A. T.; Himies, R. J.; Meador, J. D. J. Org. Chem. 1968,
33, 2462. (c) Snider, B. B.; Rodini, D. J.; Kirk, T. C.; Cordova, R. J.
Am. Chem. Soc. 1982, 104, 555.
(6) (a) Whitesell, J. K.; Bhattacharya, A.; Buchanan, C. M.; Chen,
H. H.; Deyo, D.; James, D.; Liu, C.-L.; Minton, M. A. Tetrahedron 1986,
42, 2993. (b) Mikami, K.; Loh, T.-P.; Nakai, T. Tertahedron: Asymmetry
1990, 1, 13.
(4) (a) Gill, G. B.; Parrot, S. J.; Wallace, B. J. Chem. Soc., Chem.
Commun. 1978, 655. (b) Gill, G. B.; Wallace, B. J. Chem. Soc., Chem.
Commun. 1977, 380; 1977, 382. (c) Benner, J. P.; Gill, G. B.; Parrot,
S. J.; Wallace, B. J. Chem. Soc., Perkin Trans. 1 1984, 291; 1984, 331.
(d) Benner, J. P.; Gill, G. B.; Parrot, S. J.; Wallace, B.; Begley, M. J.
Chem. Soc., Perkin Trans. 1 1984, 315. (e) Whitesell, J. K. Acc. Chem.
Res. 1985, 18, 280.
(7) Behr, A.; Fiere, M. Eur. J. Lipid Sci. Technol. 2000, 102, 212.
(8) Vidari, G.; Boncelli, M. P.; Anastasia, L.; Zanoni, G. Tetrahedron
Lett. 2000, 41, 3471.
(9) Peidro, L.; Le Roux, C.; Laporterie, A.; Dubac, J. J. Organomet.
Chem. 1996, 521, 397.
(10) Cartaya-Marin, C. P.; Jackson, A. C.; Snider, B. B. J. Org.
Chem. 1984, 49, 2443.
(5) Snider, B. B.; van Straten, J. W. J. Org. Chem. 1979, 44, 3567.
10.1021/jo051298k CCC: $30.25 © 2005 American Chemical Society
Published on Web 11/05/2005
J. Org. Chem. 2005, 70, 10285-10291
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Kabalka et al.
SCHEME 2. Proposed Reaction Mechanism
The reaction presumably proceeds through coordination
of the carbonyl group to the boron trihalide followed by
addition of the alkene to the activated carbonyl group to
form 2. Loss of the [OBCl2-] moiety from 3 would then
generate cation 4, which could then react with a chloride
from the [OBCl2-] fragment to generate 1. A similar
intermediate has been observed in the AlCl3-catalyzed
ene reactions of aldehydes with aliphatic alkenes.3c,4a
Supporting evidence for this mechanism is the isolation
of 3-halo-1,3-diarylpropanols 6 when the reactions are
quenched with water before completion.
In fact, adding water to quench the reaction can be
utilized to prepare 3-halo-1,3-diarylpropanols 6, but the
reaction is somewhat difficult to control. We reasoned
that replacement of one or two chlorides in BCl3 with an
organic group (R) might provide an efficient route to
chloropropanol products 6. Several RBCl2 and R2BCl
derivatives were prepared and examined. We discovered
that PhBCl2 was the most effective reagent for preparing
3-chloro-1,3-diarylpropanols in excellent yields.13
The new reactions are not limited to aryl aldehydes
and simple styrenes. We have found that â-substituted
styrene derivatives work quite well and afford the
corresponding 1,3-dihalo-1,3-diaryl-2-substituted pro-
panes in good yields. The nonenolizable aliphatic alde-
hyde tribromoacetaldehyde also reacts with styrenes to
produce the corresponding chloro alcohols. We wish to
report details of these studies.
Results and Discussion
1. The BX3-Mediated Reaction of Aldehydes with
Styrene Derivatives. The reaction of benzaldehyde
with styrene was chosen as the model system to optimize
the reaction conditions with use of BCl3 as the Lewis acid.
When freshly distilled styrene was used, only polymer-
ization occurred. However, polymerization can be totally
eliminated by using commercially available styrene,
which containes 4-tert-butylcatechol as a stabilizer. When
reactions were carried out at room temperature, only
chlorination of aryl aldehydes was observed.11f,14 To avoid
the chlorination reaction, the temperature was lowered
to 0 °C. 1,3-Dichloro-1,3-diphenylpropane was isolated
in good yield using methylene chloride as solvent; the
product was found to consist of a 1:1 mixture of the syn/
anti diasteromers.
Using the optimized reaction conditions, a series of
substituted aryl aldehydes and styrenes were examined
(Table 1). The reaction tolerates a variety of functional
groups. The reactions of aldehydes containing electron-
withdrawing groups are slower but produce high yields
of the desired products.
Due to the facile bromination of aryl aldehydes by
boron tribromide,11f reactions promoted by boron tribro-
mide were carried out in methylene chloride at -40 °C.
The corresponding 1,3-dibromo-1,3-diarylpropanes were
obtained in good to excellent yields. Although reactions
with boron triiodide proceeded well, the isolated yields
of the products were low due to decomposition of the
products during chromatography on silica gel. NMR
analysis of the products revealed a nearly statistical
(11) (a) Kabalka, G. W.; Tejedor, D.; Li, N.-S.; Malladi, R. R.;
Trotman, S. J. Org. Chem. 1998, 63, 6438. (b) Kabalka, G. W.; Tejedor,
D.; Li, N.-S.; Malladi, R. R.; Trotman, S. Tetrahedron Lett. 1998, 39,
8071. (c) Kabalka, G. W.; Tejedor, D.; Li, N.-S.; Malladi, R. R.; Trotman,
S. Tetrahedron 1998, 54, 15525. (d) Kabalka, G. W.; Li, N.-S.; Tejedor,
D.; Malladi, R. R.; Gao, X.; Trotman, S. Synth. Commun. 1999, 29,
2783. (e) Malladi, R. R.; Li, N.-S.; Tejedor, D.; G. W. Synth. Commun.
2000, 30, 3613. (f) Kabalka, G. W.; Wu, Z. Tetrahedron Lett. 2000, 41,
579. (g) Kabalka, G. W.; Wu, Z.; Ju. Y. Tetrahedron Lett. 2000, 41,
5161. (h) Kabalka, G. W.; Wu, Z.; Trotman, S.; Gao, X. Org. Lett. 2000,
2, 255. (i) Kabalka, G. W.; Wu, Z.; Ju, Y. Tetrahedron 2001, 57, 1663.
(j) Kabalka, G. W.; Wu, Z.; Ju, Y. Tetrahedron 2002, 58, 3243. (k)
Kabalka, G. W.; Wu, Z.; Ju, Y. J. Organomet. Chem. 2003, 680, 12. (l)
Kabalka, G. W.; Wu, Z.; Ju, Y. Pure Appl. Chem. 2003, 75, 1231.
(12) (a) Kabalka, G. W.; Wu, Z.; Ju, Y. Tetrahedron Lett. 2001, 41,
5793. (b) Kabalka, G. W.; Wu, Z.; Ju, Y. Synthesis 2004, 2927.
(13) Kabalka, G. W.; Wu, Z.; Ju, Y. Tetrahedron Lett. 2003, 44, 1187.
1
distribution of the diastereoisomers. Generally the H
NMR resonances of the methine protons in the anti
isomers appear at lower field than the methine protons
in the syn isomers. The R,R and S,S racemate of 1,3-
dibromo-1,3-di(4-fluorophenyl)propane (1al) has been
isolated by crystallization and characterized by both
NMR and X-ray crystallography (see the Supporting
Information).
(14) Lansinger, J. M.; Ronald, R. C. Synth. Commun. 1979, 9, 341.
10286 J. Org. Chem., Vol. 70, No. 25, 2005

Reactions of Aldehydes with Styrene Derivatives
TABLE 1. BX3-Mediated Reaction of Aryl Aldehydes with Styrenes to 1,3-Dihalo-1,3-diarylpropanesa,b
yield
(%)
yield
(%)
entry
Z
R
X
product
entry
Z
R
X
product
1
2
H
H
H
H
H
H
H
H
H
H
H
H
4-F
4-F
4-F
4-F
4-F
4-F
4-F
4-F
4-F
4-Me
H
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
1a
1b
1c
1d
1e
1f
1g
1h
1i
90
98
97
89
97
92
96
99
70
74
80
99
98
98
96
99
94
96
95
96
98
80
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
4-Me
4-Me
4-Me
4-Me
4-Me
4-Me
4-Me
4-Me
H
4-Br
2-F
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
I
1w
82
85
83
80
79
80
70
75
75
98
60
76
74
70
57
96
89
76
90
35
30
4-F
1x
3
4-Cl
4-Br
2-F
2-Cl
2-Br
4-Me
2-Me
4-NO2
4-CN
H
4-F
4-Me
4-F
1y
1z
4
5
1aa
1ab
1ac
1ad
1ae
1af
1ag
1ah
1ai
1aj
1ak
1al
1am
1an
1ao
1ap
1aq
6
2-Cl
2-Br
3-Br
4-Me
2-Me
4-CN
4-NO2
4-F
4-Cl
4-Br
2-F
2-Cl
2-Br
4-Me
2-Me
4-NO2
4-Cl
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
1j
1k
1l
H
H
4-Me
4-Me
4-Me
4-Me
4-F
1m
1n
1o
1p
1q
1r
1s
1t
4-Cl
4-Br
4-Me
4-F
4-F
2-F
4-F
4-Br
3-Br
H
4-F
H
1u
1v
4-F
H
I
a Reactions carried out in dry DCM at 0 °C for BCl3, -40 °C for BBr3, and -70 °C for BI3. b Isolated yields based on starting aldehydes.
SCHEME 3
1,3-Dihalo-1,3-diarylpropanes are important interme-
diates in the preparation of arylcyclopropane,15 pyrazo-
lidine,16 and centrohexaindane.17 The bromo analogues
can also be utilized in Suzuki coupling reactions.18 1,3-
Dihalo-1,3-diarylpropanes are normally prepared by
halogenation of the corresponding cyclopropanes19 or 1,3-
propanediols20 which are not readily available. The boron
trihalide mediated method reported here provides a
simple and efficient procedure for the preparation of a
variety of 1,3-dihalo-1,3-diarylpropanes with high regio-
selectivity.
In the presence of 2 equiv of boron trichloride, tereph-
thaldicarboxaldehyde reacts with 2 equiv of a variety of
styrenes smoothly (Scheme 3).
The R,R,S,S/S,S,R,R racemate of 7a has been isolated
by recrystallization and subjected to X-ray crystal-
lographic analysis (see the Supporting Information). The
1H NMR spectrum reveals that the resonances of the
methine protons in the anti isomer appear at lower field
than those in the syn isomer.
The BCl3-mediated reaction of trans-cinnamaldehyde
with styrene was also examined (eq 1). The isolated yield
of desired product was modest.
(15) (a) Leonel, E.; Dolhem, E.; Devaud, M.; Paugam, J. P.; Nedelec,
J. Y. Electrochim. Acta 1997, 42, 23125. (b) Miranda, M. A.; Perez-
Prieto, J.; Font-Scenchis, E.; Konya, K.; Scaiao, J. C. J. Org. Chem.
1997, 62, 5713. (c) Takeda, T.; Stimane, K.; Fujiwara, T.; Tsubouchi,
A. Chem. Lett. 2002, 290.
(16) Buhle, E. L.; Moore, A. M.; Wiselogle, F. Y. J. Am. Chem. Soc.
1943, 65, 29.
(17) Kuck, D.; Schuster, A.; Paisdor, B.; Gestmann, D. J. Chem. Soc.,
Perkin Trans. 1 1995, 721.
(18) (a) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2549. (b)
Suzuki, A. J. Organomet. Chem. 1999, 576, 147. (c) Chowdhury, S.;
Georghion, P. E. Tetrahedron Lett. 1999, 40, 7599. (d) Chen, H.; Deng,
M.-Z. J. Chem. Soc., Perkin Trans. 1 2000, 1069. (e) Chowdhury, S.;
Georghion, P. E. Tetrahedron Lett. 1999, 40, 7599. (f) Chahen, L.;
Doucet, H.; Santelli, M. Synlett 2003, 1668. (g) Nobre, S. M.; Monteiro,
A. L. Tetrahedron Lett. 2004, 45, 8225.
(19) (a) Lambert, J. B.; Chelius, E. C.; Schulz, W. J., Jr.; Carpenter,
N. E. J. Am. Chem. Soc. 1990, 112, 3156. (b) Hoffman, J. M.; Graham,
K. J.; Rowell, C. F. J. Org. Chem. 1975, 40, 3005. (c) Nair, V.; Paricker,
S. B.; Mathai, S. Res. Chem. Intermed. 2003, 29, 227.
J. Org. Chem, Vol. 70, No. 25, 2005 10287

Kabalka et al.
SCHEME 4
SCHEME 5
TABLE 2. PhBCl2-Mediated Reaction of Aryl Aldehydes
with Styrenes to 3-Chloro-1,3-diarylpropanolsa
Under the same reaction conditions, the nonenolizable
aliphatic aldehyde tribromoacetaldehyde readily reacts
with substituted styrenes. However, the reactions provide
the corresponding 3-halopropanols, 9, instead of the
dihalide compounds (Scheme 4). The reaction is stereo-
selective with the anti isomer being the major product
(anti/syn > 10:1).
Reactions of aryl aldehydes with â-substituted styrenes
such as trans-â-methylstyrene and stilbene also proceed
well. The desired 1,3-dihalo-1,3-diaryl-2-methylpropanes
and 1,3-dihalo-1,3-diaryl-2-phenylpropanes were isolated
in good yields (Scheme 5). The selectivity was confirmed
by the X-ray crystallography (see the Supporting Infor-
mation). However, the reaction with R-methylstyrene and
1,1-diphenylstyrene did not afford the anticipated 1,3-
dihalides products.21 Trisubstituted and tetrasubstituted
styrenes were found to be unreactive.
2. The PhBCl2-Mediated Reaction of Aldehydes
with Styrene Derivatives. As noted earlier, 3-halopro-
pan-1-ols can be obtained in moderate yield by quenching
the BX3 mediated reactions between aryl aldehydes and
styrene with water. The resultant 3-halopropan-1-ols are
useful intermediates in organic synthesis.22 They can
undergo a number of transformations, including haloge-
nation, substitution, cyclization, and oxidation reactions,
to generate mixed 1,3-dihalogenated diarylpropanes,
cyclic ethers, and ketones. In view of the synthetic
potential of 3-halopropan-1-ols, we investigated more
efficient and practical methods for preparing the halo-
genated alcohols. We reasoned that replacement of one
or two halides in BX3 with an organic group might
stabilize interemediate 5 and prevent C-O bond cleavage
(Scheme 2). Hydrolysis of 5 would then produce the
desired 3-halopropan-1-ol. Several RBCl2 and R2BCl
reagents were prepared and used in the reaction. The
prod- yield
prod- yield
uct (%)d
entry
Z
R
uct (%)d entry
Z
R
1
H
H
H
H
H
H
H
H
H
6a
6b
6c
6d
6e
6f
76
87
79
66
57
56
79
97
9c
10
H
H
4-CN
6i
96
89
90
86
99
75
98
2
4-F
4-CHO 6j
3
4-Cl
4-Br
4-Me
2-Me
2-F
11c 4-Cl 4-NO2
6k
6l
4
12
13c 4-Me 4-NO2
14b 4-Me
15c 4-Me 4-CN
4-Cl 4-Cl
5b
6b
7
6m
6n
6o
H
6g
8c
4-NO2 6h
a Reactions carried out in dry DCM at -10 °C. b Reactions
carried out in dry DCM at -20 °C. c Reactions carried out at room
temperature. d Isolated yields based on starting aldehydes.
reaction of 4-chlorobenzaldehyde with styrene in the
presence of dicyclohexylboron chloride resulted only in
reduction of the aldehyde via a â-hydride transfer. Boron
dichloride reagents such as n-butylboron dichloride, sec-
butylboron dichloride, n-hexylboron dichloride, cyclo-
hexylboron dichloride, and cyclopentylboron dichloride
also were found to be ineffective. However, phenylboron
dichloride promoted the reaction; in CH2Cl2 at -10 °C,
3-chloro-1-(4-chlorophenyl)-3-phenylpropan-1-ol was iso-
lated in 79% yield. Solvents such as hexane, toluene, and
chloroform were examined but methylene chloride was
found to be the most effective. Diethyl ether, THF, and
dioxane simply underwent ether cleavage reactions.23
Using phenylboron dichloride, reactions of a series of
substituted aryl aldehydes with substituted styrenes
were examined (Table 2). Generally, reactions of styrenes
and aldehydes containing electron-withdrawing groups
require a higher reaction temperature (room tempera-
ture) but give higher yields of products. The reactions of
(20) (a) Gilman, H.; Thomasi, R. A.; Wittenberg, D. J. Org. Chem.
1959, 24, 821. (b) Jones, A. R. J. Labelled Comp. 1975, 11, 77. (c)
Miranda, M. A.; Pe´rez-prieto, J.; Font-Sanchˆıs, E.; Ko´nya, K.; Scaiano,
J. C. J. Org. Chem. 1997, 62, 5713.
(21) Although the reaction did not give the anticipated 1,3-dihalides
or 3-halopropanol products, a reaction did occur but the structure of
the product has not been identified.
(22) (a) Toda, F.; Tanaka, K.; Mori, K. Chem. Lett. 1983, 827. (b)
Bickley, J. F.; Gillmore, A. T.; Roberts, S. M.; Skidmore, J.; Steiner,
A. J. Chem. Soc., Perkin Trans. 1 2001, 1109. (c) Gillmore, A.; Lauret,
C.; Roberts, S. M. Tetrahedron 2003, 59, 4363.
(23) (a) Bhatt, M. V.; Kulkarni, S. U. Synthesis 1983, 249. (b)
Encyclopedia of Reactants for Organic Synthesis; Paquette, L. A., Ed.;
Wiley: Chichester, UK, 1995, 645.
10288 J. Org. Chem., Vol. 70, No. 25, 2005

Reactions of Aldehydes with Styrene Derivatives
SCHEME 6
alcohol 6. In a separate experiment, a boron complex (as
evidenced by a shift of the aldehyde proton from 9.98 δ
to 9.37 δ in the 1H NMR) was prepared by mixing
4-chlorobenzaldehyde with 1 equiv of phenylboron dichlo-
ride in CDCl3. Styrene was then added to the complex,
and the NMR spectrum revealed the formation of 5.
These observations support a mechanism involving an
electrophilic addition of a complexed aldehyde to styrene
in a concerted fashion (structure 2 in Scheme 2).
TABLE 3. PhBCl2-Mediated Reaction of Aryl Aldehydes
with trans-â-Methylstyrene to Generate
3-Chloro-1,3-diaryl-2-methylpropanolsa
Conclusion
The reactions of aryl aldehydes with styrene deriva-
tives mediated by boron Lewis acids were investigated.
The products were dependent on the boron Lewis acids
used. 1,3-Dihalo-1,3-diarylpropanes were obtained in
high yields with use of boron trihalides, while 3-chloro-
1,3-diarylpropanols were obtained with use of phenylbo-
ron dichloride.
yield
yield
entry
R
product (%)e entry
R
product (%)e
1b
2
4-F
4-Cl
4-Me
12a
12b
12c
94
65
36
4d
5d
6b
4-NO2
4-CN
2-F
12d
12e
12f
95
97
93
3c
Experimental Section
a Reactions carried out in dry DCM at -10 °C. b Reactions
carried out at 0 °C. c Reactions carried out at -20 °C. d Reactions
carried out at room temperature. e Isolated yields based on starting
aldehydes.
All glassware was dried in an oven heated to 100 °C for at
least 12 h and then cooled prior to use. All solvents were
distilled from appropriate drying agents prior to use. Reactions
were magnetically stirred and monitored by TLC. Products
were purified by flash chromatography, using silica gel (230-
400 mesh, 60 Å). Boron trichloride (1.0 M methylene chloride
solution) and phenylboron dichloride were used as received.
Boron tribromide and triiodide were diluted to use as meth-
ylene chloride solutions (1.0 M). All aldehydes and styrenes
were used as received.
All melting points are uncorrected. Nuclear Magnetic reso-
nance (NMR) spectra were measured in CDCl3 at 250 MHz
(1H) or at 62.9 MHz (13C). Chemical shifts for 1H and 13C were
referenced to TMS and CDCl3.
Synthesis of 1,3-Dichloro-1,3-diphenylpropane (1a).
Representative procedure for the synthesis of 1,3-
dichloro-1,3-diarylpropanes: Benzaldehyde (4.0 mmol, 0.42
g) and styrene (4.0 mmol, 0.42 g) were dissolved in methylene
chloride (20 mL) at room temperature in a dry flask main-
tained under a nitrogen atmosphere. The solution was cooled
to 0 °C in an ice bath, and boron trichloride (4.3 mmol, 4.3
mL of a 1.0 M CH2Cl2 solution) was added via a syringe. The
reaction was allowed to stir at 0 °C for 2 h and then at room
temperature for another 8 h, during which time the reaction
solution turned purple. Water (20 mL) was added and the
product extracted with dichloromethane (3 × 20 mL). The
combined organic layer was dried over anhydrous magnesium
sulfate and the product isolated by column chromatography
(hexanes, silica gel) to yield 0.95 g (90% yield) of the desired
product: colorless oil;20c 1H NMR δ 7.36-7.30 (m, 10H), 5.20
(dd, J ) 7.6, 7.5 Hz, 1H), 4.79 (dd, J ) 7.8, 7.1 Hz, 1H), 3.03-
2.91 (m, 0.5H), 2.74-2.63 (m, 1.5H); 13C NMR δ 140.7, 140.1,
128.8, 128.6, 127.0, 60.7, 60.1, 49.6, 49.4.
Synthesis of 1,3-Dibromo-1,3-diphenylpropane (1ae).
Representative procedure for the synthesis of 1,3-di-
bromo-1,3-diarylpropanes: Benzaldehyde (3.0 mmol, 0.32
g) and styrene (3.0 mmol, 0.31 g) were dissolved in methylene
chloride (20 mL) at room temperature in a dry flask main-
tained under a nitrogen atmosphere. The solution was cooled
to -40 °C in a dry ice-ethyl acetate bath, and boron tribromide
(3.2 mmol, 3.2 mL of a 1.0 M CH2Cl2 solution) was added via
a syringe. The reaction was first allowed to stir at -40 °C for
2 h and then at room temperature for 2 h. Water (20 mL) was
added and the product extracted with dichloromethane (3 ×
20 mL). The combined organic layer was dried over anhydrous
magnesium sulfate and the product isolated by flash column
chromatography (silica gel, hexanes) to yield 0.80 g (75% yield)
of the desired product: colorless oil;19c 1H NMR δ 7.33-7.25
styrenes and aldehydes containing electron-donating
groups are faster but produce lower yields of the desired
products.
All 3-halopropan-1-ols were characterized by elemental
analysis and NMR spectroscopy. NMR data reveal that
the reactions generate only one regioisomer with the aryl
groups at the 1,3-positions. The reactions predominantly
produce the anti-diastereoisomers (anti/syn > 10:1). The
anti isomers exhibit two sets of resonances (doublets of
doublets) for the diastereotopic benzylic protons between
5.8 and 5.0 ppm. The corresponding resonances for the
syn isomers appear upfield between 4.8 and 4.5 ppm.
Heteroaromatic aldehydes such as 3-pyridinecarbox-
aldehyde also react with styrenes to generate 3-chloro-
1-(3-pyridyl)-3-phenylpropanols in excellent yields (Scheme
6). However, the reactions are slow compared to the
reactions of aryl aldehydes. Aliphatic aldehydes and
alkenes do not undergo the desired reaction. Aliphatic
aldehydes simply enolize. The reaction of aliphatic alk-
enes with aryl aldehydes produces mixtures of 1,3-
dichloro compounds and ene-carbonyl adducts in very low
yield.
Under similar conditions, the reaction of trans-â-
methylstyrene with aryl aldehydes produces mainly
R,R,R/S,S,S isomers (Table 3). For aryl aldehydes with
electron-withdrawing groups, the reactions give excellent
yields of products. The stereoselectivity was confirmed
by NMR spectroscopy and supported by the X-ray crys-
tallography of R,R,R/S,S,S racemate of 12e (see the
Supporting Information).
To gain insight into the mechanism, the reaction of
styrene with 4-chlorobenzaldehyde was monitored by
NMR spectroscopy. Styrene and phenylboron dichloride
were placed in an NMR tube containing CDCl3. The NMR
data indicated that no haloboration occurred. 4-Chloro-
benzaldehyde was then added to the mixture; the NMR
spectrum was consistent with the formation of interme-
diate 5 (Scheme 2). Hydrolysis of 5 generated chloro
J. Org. Chem, Vol. 70, No. 25, 2005 10289

Kabalka et al.
(m, 10H), 5.18 (t, J ) 7.2 Hz, 1H), 4.79 (t, J ) 7.7 Hz, 1H),
3.26-3.14 (m, 0.5H), 2.94-2.83 (m, 1.5H); 13C NMR δ 140.9,
140.3, 128.9, 128.7, 127.4, 53.0, 51.8, 49.2, 49.1.
boron trichloride (2.2 mmol, 2.2 mL of a 1.0 M CH2Cl2 solution)
was added via a syringe. The reaction was first allowed to stir
at 0 °C for 3 h and then at room temperature for another 8 h.
Water (20 mL) was added and the product extracted with
dichloromethane (3 × 20 mL). The combined organic layer was
dried over anhydrous magnesium sulfate and the product
isolated by column chromatography (hexanes/EtOAc, silica gel)
to yield 0.78 g (93% yield) of the desired product: wax; 1H NMR
(2R,4R/2S,4S isomers) δ 7.47-7.25 (m, 5H), 5.26 (dd, J ) 11.8,
11.7 Hz, 1H), 4.49-4.43 (m, 1H), 3.03-2.88 (m, 1H), 2.27-
2.18 (m, 1H); 13C NMR (2R,4R/2S,4S isomers) δ 141.1, 128.8,
128.6, 126.7, 81.8, 60.1, 53.4, 42.6; 1H NMR (2R,4S/2S,4R
isomers) δ 7.47-7.26 (m, 5H), 5.18 (dd, J ) 11.4, 11.2 Hz, 1H),
Synthesis of 1,3-Diiodo-1,3-diphenylpropane (1ap).
Representative procedure for synthesis of 1,3-diiodo-
1,3-diarylpropanes: Benzaldehyde (4.0 mmol, 0.42 g) and
styrene (4.0 mmol, 0.42 g) were dissolved in methylene chloride
(20 mL) at room temperature in a dry flask maintained under
a nitrogen atmosphere. The solution was cooled to -70 °C in
a dry ice-acetone bath, and boron triiodide (4.3 mmol, 4.3 mL
of a 1.0 M CH2Cl2 solution) was added via a syringe. The
reaction was first allowed to stir at -70 °C for 3 h and then at
room temperature for 2 h. Water (20 mL) was added and the
product extracted with dichloromethane (3 × 20 mL). The
combined organic layer was dried over anhydrous magnesium
sulfate and the product isolated by column chromatography
(silica gel, hexanes) to yield 0.63 g (35% yield) of the desired
product: yellow oil; 1H NMR δ 7.35-7.10 (m, 10H), 5.09 (t, J
) 7.6 Hz, 1H), 4.97 (t, J ) 7.6 Hz, 1H), 3.32-3.20 (m, 0.5H),
2.99 (t, J ) 7.6 Hz, 1H), 2.29-2.68 (m, 0.5H); 13C NMR δ 142.3,
142.0, 128.9, 128.3, 127.3, 127.2, 51.7, 51.3, 31.3, 30.9; HRMS
calcd for C15H14I2 447.9185, found 447.9179.
Synthesis of 1,4-Di(1′,3′-dichloro-3′-phenylpropyl)ben-
zene (7a). Representative procedure for synthesis of di-
(1′,3′-dichloro-3′-phenylpropyl)benzene: Terephthaldicar-
boxaldehyde (2.0 mmol, 0.27 g) and styrene (4.0 mmol, 0.42
g) were dissolved in methylene chloride (20 mL) at room
temperature in a dry flask maintained under a nitrogen
atmosphere. The solution was cooled to 0 °C in an ice bath,
and boron trichloride (4.3 mmol, 4.3 mL of a 1.0 M CH2Cl2
solution) was added via a syringe. The reaction was first
allowed to stir at 0 °C for 2 h and then at room temperature
for another 10 h. Water (20 mL) was added and the product
extracted with dichloromethane (3 × 20 mL). The combined
organic layer was dried over anhydrous magnesium sulfate
and the product isolated by column chromatography (hexanes,
silica gel) to yield 0.83 g (92% yield) of the desired product:
colorless crystals; mp 135-136 °C; 1H NMR (R,R,S,S/S,S,R,R
isomers) δ 7.40-7.34 (m, 14H), 5.24-5.18 (m, 4H), 2.65 (dd, J
) 7.2, 6.7 Hz, 4H); 13C NMR (R,R,S,S/S,S,R,R isomers) δ 141.3,
140.7, 128.9, 128.7, 127.5, 127.0, 60.6, 60.1, 49.6; 1H NMR
(R,R,S,S/S,S,R,R isomers) δ 7.38-7.22 (m, 14H), 4.84-4.72
(m, 4H), 3.01-2.89 (m, 2H), 2.72-2.61 (m, 2H); 13C NMR
(R,R,S,S/S,S,R,R isomers) δ 141.4, 140.5, 139.9, 128.9, 128.8,
127.6, 127.0, 59.9, 59.5, 49.3. Anal. Calcd for C24H22Cl4: C,
63.74; H, 4.90. Found: C, 63.86; H, 4.95.
Synthesis of trans-3,5-Dichloro-1,5-diphenylpent-1-
ene (8). trans-Cinnamaldehyde (3.0 mmol, 0.40 g) and styrene
(3.0 mmol, 0.31 g) were dissolved in methylene chloride (20
mL) at room temperature in a dry flask maintained under a
nitrogen atmosphere. The solution was cooled to 0 °C in an
ice bath, and boron trichloride (3.2 mmol, 3.2 mL of a 1.0 M
CH2Cl2 solution) was added via a syringe. The reaction was
first allowed to stir at 0 °C for 3 h and then at room
temperature for 12 h. Water (20 mL) was added and the
product extracted with dichloromethane (3 × 20 mL). The
combined organic layer was dried over anhydrous magnesium
sulfate and the product isolated by flash column chromatog-
raphy (silica gel, hexanes) (0.39 g, 45%): colorless oil; 1H NMR
δ 7.36-7.12 (m, 10H), 6.13-5.90 (m, 2H), 4.74 (dd, J ) 8.9,
6.0 Hz, 0.5H), 4.56 (dd, J ) 9.3, 5.3 Hz, 0.5H), 3.64-3.47 (m,
1H), 2.58-2.29 (m, 2H); 13C NMR δ 141.5, 141.2, 141.0, 140.9,
136.1, 135.3, 128.9, 128.8, 128.7, 128.5, 127.6, 127.4, 127.2,
127.1, 126.9, 118.9, 118.5, 61.1, 60.9, 45.3, 44.9. Anal. Calcd
for C17H16Cl2: C, 70.11; H, 5.54. Found: C, 70.41; H, 5.54.
3.52-3.31 (m, 1H), 3.06-2.91 (m, 1H), 2.62-2.58 (m, 1H); 13
C
NMR (2R,4S/2S,4R isomers) δ 139.7, 129.0, 128.8, 127.3, 81.5,
59.1, 53.2, 42.2. Anal. Calcd for C10H10Br3ClO: C, 28.51; H,
2.39. Found: C, 28.70; H, 2.12.
Synthesis of 1,3-Dichloro-1,3-diphenyl-2-methylpro-
pane (10a). Representative procedure for synthesis of
1,3-dichloro-1,3-diphenyl-2-methylpropane: benzaldehyde
(4.0 mmol, 0.42 g) and â-methylstyrene (4.0 mmol, 0.47 g) were
dissolved in methylene chloride (20 mL) at room temperature
in a dry flask maintained under a nitrogen atmosphere. The
solution was cooled to 0 °C in an ice bath, and boron trichloride
(4.3 mmol, 4.3 mL of a 1.0 M CH2Cl2 solution) was added by
syringe. The reaction was first allowed to stir at 0 °C for 2 h
and then stirred at room temperature for another 5 h. Water
(20 mL) was added and the product extracted with dichlo-
romethane (3 × 20 mL). The combined organic layer was dried
over anhydrous magnesium sulfate and the product isolated
by column chromatography (hexane, silica gel) to yield 1.06 g
(95% yield) of the desired product: colorless crystals; mp 71-
72 °C. 1H NMR (1R,3R/1S,3S isomers) δ 7.37-7.28 (m, 10H),
4.75 (d, J ) 6.3 Hz, 2H), 2.63-2.50 (m, 1H), 1.22 (d, J ) 6.4
Hz, 3H); 13C NMR (1R,3R/1S,3S isomers) δ 140.0, 128.6, 128.2,
1
127.2, 66.0, 49.9, 11.0; H NMR (other two pairs of diastere-
omers) δ 7.48-7.23 (m, 10H), 5.91 (s, 0.8H), 5.01 (d, J ) 7.2
Hz, 0.4H), 4.95 (d, J ) 10.2 Hz, 0.8H), 2.89-2.81 (m, 0.2H),
2.60-2.48 (m, 0.8H), 0.74 (d, J ) 7.0 Hz, 0.6H), 0.64 (d, J )
6.7 Hz, 2.4H); 13C NMR (other two pairs of diastereomers) δ
140.0, 138.2, 128.7, 128.6, 128.5, 128.4, 128.3, 127.9, 127.7,
127.2, 66.6, 65.4, 64.8, 49.3, 49.1, 10.8. Anal. Calcd for C16H16-
Cl2: C, 68.83; H, 5.78. Found: C, 68.70; H, 5.92.
Synthesis of 3-Chloro-1,3-diphenylpropanol (6a). Rep-
resentative procedure for synthesis of 3-chloro-1,3-
diphenylpropanols: benzaldehyde (4.0 mmol, 0.42 g) and
styrene (4.0 mmol, 0.42 g) were dissolved in methylene chloride
(20 mL) at room temperature in a dry flask maintained under
a nitrogen atmosphere. The solution was cooled to -10 °C, and
phenylboron dichloride (4.3 mmol, 4.3 mL of a 1.0 M CH2Cl2
solution) was added by syringe. The reaction was first allowed
to stir at -10 °C for 4 h and then stirred at room temperature
for another 4 h. Water (20 mL) was added and the product
extracted with dichloromethane (3 × 20 mL). The combined
organic layer was dried over anhydrous magnesium sulfate
and the product isolated by column chromatography (hexane/
EtOAc, silica gel) to yield 0.75 g of the desired product:
colorless oil; 1H NMR (R,R/S,S isomers) δ 7.38-7.21 (m, 10H),
7.01-6.95 (m, 2H), 5.20 (dd, J ) 9.8, 9.7 Hz, 1H), 5.09 (dd, J
) 8.8, 8.7 Hz, 1H), 2.44 (s, 1H), 2.33-2.27 (m, 2H); 13C NMR
(R,R/S,S isomers) δ 143.8, 141.6, 128.6, 128.5, 128.3, 127.8,
126.9, 125.7, 71.2, 51.9, 60.5, 48.8. Anal. Calcd for C15H15ClO:
C, 73.02; H, 6.13. Found: C, 73.07; H, 6.24.
Synthesis of 3-Chloro-1-(3-pyridinyl)-3-phenylpro-
panol (11a). Representative procedure for synthesis of
3-chloro-1-(3-pyridinyl)-3-phenylpropanols: 3-Pyridine-
carboxaldehyde (4.0 mmol, 0.43 g) and styrene (4.0 mmol, 0.42
g) were dissolved in methylene chloride (20 mL) at room
temperature in a dry flask maintained under argon atmo-
sphere. Phenylboron dichloride (4.3 mmol, 4.3 mL of a 1.0 M
CH2Cl2 solution) was added by syringe. The reaction mixture
was stirred at room temperature for several hours, using TLC
Synthesis of 1,1,1-Tribromo-4-chloro-4-phenylbutan-
2-ol (9a). Representative procedure for synthesis of
1,1,1-tribromo-4-chloro-4-phenylbutan-2-ol: Tribromoac-
etaldehyde (2.0 mmol, 0.56 g) and styrene (2.0 mmol, 0.21 g)
were dissolved in methylene chloride (12 mL) at room tem-
perature in a dry flask maintained under a nitrogen atmo-
sphere. The solution was cooled to 0 °C in an ice bath, and
10290 J. Org. Chem., Vol. 70, No. 25, 2005

Reactions of Aldehydes with Styrene Derivatives
to monitor the reaction. Water (20 mL) was added and the
product extracted with dichloromethane (3 × 20 mL). The
combined organic layer was dried over anhydrous magnesium
sulfate and the product isolated by column chromatography
(hexane/EtoAc, silica gel) to yield 0.89 g of the desired
product: yellow wax; 1H NMR (R,R/S,S isomers) δ 9.26 (s, 1H),
8.28-8.18 (dd, J ) 15.0, 8.1 Hz, 1H), 7.75 (t, J ) 7.2 Hz, 1H),
7.38-7.24 (m, 5H), 5.35-5.25 (m, 1H), 5.01 (t, J ) 7.5 Hz, 0.5
H), 4.81 (dd, J ) 8.7, 8.5 Hz, 0.5 H), 2.89 (s, 1H), 2.74-2.62
(m, 0.5 H), 2.46-2.23 (m, 1.5H); 13C NMR (R,R/S,S isomers) δ
143.7, 143.5, 143.3, 142.7, 142.3, 142.1, 141.6, 141.4, 140.4,
139.6, 129.0, 128.8, 128.6, 127.0, 126.8, 126.0, 68.6, 68.2, 59.7,
59.3, 46.4, 46.1. Anal. Calcd for C14H14ClNO: C, 67.88; H, 5.70;
N, 5.65. Found: C, 67.98; H, 5.43; N, 5.58.
Synthesis of 3-Chloro-1-(4-fluorophenyl)-2-methyl-3-
phenylpropanol (12a). Representative procedure for
synthesis of 3-chloro-1-(4-cyanophenyl)-1-hydroxy-2-
methyl-3-phenylpropanol: 4-Cyanobenzaldehyde (4.0 mmol,
0.52 g) and trans-â-methylstyrene (4.0 mmol, 0.47 g) were
dissolved in methylene chloride (20 mL) at room temperature
in a dry flask maintained under a nitrogen atmosphere. The
solution was cooled to 0 °C in an ice bath, and boron trichloride
(4.3 mmol, 4.3 mL of a 1.0 M CH2Cl2 solution) was added via
a syringe. The reaction was first allowed to stir at 0 °C for 2
h and then at room temperature for 24 h. Water (20 mL) was
added and the product extracted with dichloromethane (3 ×
20 mL). The combined organic layer was dried over anhydrous
magnesium sulfate and the product isolated by column chro-
matography (methylene chloride, silica gel) to yield 1.11 g (97%
1
yield) of the desired product: colorless oil; H NMR (R,R,R/
S,S,S isomers) δ 7.33-7.26 (m, 7H), 7.01-6.95 (m, 2H), 5.52
(s, 1H), 5.00 (d, J ) 10.8 Hz, 1H), 2.53 (s, 1H), 2.37-2.20 (m,
1H), 0.50 (d, J ) 7.0 Hz, 3H); 13C NMR (R,R,R/S,S,S isomers)
δ 163.7, 159.1, 140.6, 139.1, 128.6, 128.1, 127.5, 127.1, 127.0,
115.1, 114.8, 71.9, 64.7, 48.1, 9.9. Anal. Calcd for C16H16-
FClO: C, 68.94; H, 5.79. Found: C, 68.85; H, 5.62.
Acknowledgment. We wish to thank the U.S.
Department of Energy and the Robert H. Cole Founda-
tion for support of this research. Acknowledgment is
made to the Donors of the Petroleum Research Fund
for support of this research.
Supporting Information Available: Experimental data
of all compounds as well as X-ray crystallographic data of
compounds 1al, 7a, 10a, and 12e. This material is available
free of charge via the Internet at http://pubs.acs.org.
JO051298K
J. Org. Chem, Vol. 70, No. 25, 2005 10291