Stereo- and regioselective synthesis of 1,3-diaryl-3-chloro-1-propanols via the reaction of aryl aldehydes with styrene and (E)-β-methylstyrene

Article abstract of DOI:10.1016/S0040-4039(02)02820-4

Reactions of aryl aldehydes with styrene and (E)-β-methylstyrene in the presence of phenylboron dichloride regioselectively generate 1,3-diaryl-3-chloro-1-propanols and 1,3-diaryl-3-chloro-2-methyl-1-propanols in good to excellent yields with high stereoselectivity.

Full text of DOI:10.1016/S0040-4039(02)02820-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 1187–1189
Stereo- and regioselective synthesis of
1,3-diaryl-3-chloro-1-propanols via the reaction of aryl aldehydes
with styrene and (E)-b-methylstyrene
George W. Kabalka,* Zhongzhi Wu and Yuhong Ju
Departments of Chemistry and Radiology, The University of Tennessee, Knoxville, TN 37996-1600, USA
Received 27 November 2002; revised 12 December 2002; accepted 12 December 2002
Abstract—Reactions of aryl aldehydes with styrene and (E)-b-methylstyrene in the presence of phenylboron dichloride regioselec-
tively generate 1,3-diaryl-3-chloro-1-propanols and 1,3-diaryl-3-chloro-2-methyl-1-propanols in good to excellent yields with high
stereoselectivity. © 2003 Elsevier Science Ltd. All rights reserved.
Boron halides are versatile reagents in organic synthe-
sis. They have been widely used for the cleavage of
ethers,1 halogenation of aryl aldehydes,2 reduction of
carbonyl compounds,3 haloboration of alkynes4 and as
enolization reagents in aldol reactions.5 We have been
investigating carbonꢀcarbon bond forming reactions
utilizing boron halide reagents. Several new reactions
have been developed including the alkylation6 and
dialkenylation of aryl aldehydes.7 Although the halobo-
ration of alkynes via boron halides4 has been well
documented, boron halides react with alkenes to give
rise to mixtures of compounds.8
Initially, styrene was allowed to react with one equiva-
lent of phenylboron dichloride in CH2Cl2 at room
temperature to form haloboration intermediates.8 Then,
one equivalent 4-chlorobenzaldehdye was introduced at
−10°C. The reaction solution turned yellow. After 1 h,
the solution was hydrolyzed and 3-chloro-1-(4-
chlorophenyl)-3-phenylpropanol was isolated in good
yield. Alternatively, the reaction could be carried out by
introducing phenylboron dichloride to a mixture of
styrene and 4-chlorobenzaldehye in CH2Cl2 at −10°C.
We noted that the freshly distilled styrene produced
only polymerization products whereas commercially
available styrene containing 4-tert-butylcatechol pro-
duced good yields of the desired product. The product
chloroalcohols can be conveniently brominated using
boron tribromide in CH2Cl2 at room temperature to
form 1-bromo-3-chloro-1,3-diarylpropanes.
We recently discovered that aryl aldehydes react with
styrenes in the presence of boron trihalides to produce
1,3-dihalo-1,3-diarylpropanes in excellent yields.9 In
these reactions we detected the formation of b-chloroal-
cohols but the yields were low. In a continuation of our
ongoing studies, we investigated the reaction of alde-
hydes with alkenes in the presence of phenylboron
dichloride and discovered that the reaction regioselec-
tively produced anti-b-chloroalcohols in good to excel-
lent yields (Tables 1–3). These b-chloroalcohols are
potentially useful intermediates in organic synthesis
because they can be subjected to a number of transfor-
mations such as halogenation, substitution, cyclization
and oxidation reactions to generate mixed 1,3-dihalo-
genated diarylpropanes, cyclic ethers and ketones.
From the data in Tables 1 and 2,10 it can be seen that
the reactions of aldehydes and styrenes containing elec-
tron-withdrawing groups require a higher reaction tem-
perature, but give higher yields of products. The
reactions of aldehydes and styrenes containing electron-
donating groups are faster but produce lower yields of
the desired products due to the facile chlorination of
the product alcohols to form 1,3-dichloro compounds.9
Heteroaromatic aldehydes such as 3-pyridinecarbox-
aldehyde also react with styrenes to generate 3-chloro-
1-(3-pyridyl)-3-phenylpropanols in excellent yields
(Table 3). However, the reactions are slow compared to
the reactions of aryl aldehydes.
Keywords: boron and compounds; aldehydes; alkenes; alcohols; alkyl
halides; aldol reaction.
Aliphatic aldehydes and alkenes do not undergo the
desired reaction. Aliphatic aldehydes simply enolize.
* Corresponding author. Tel.: +1-865-974-3260; fax: +1-865-974-2997;
e-mail: kabalka@utk.edu
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)02820-4

1188
G. W. Kabalka et al. / Tetrahedron Letters 44 (2003) 1187–1189
Table 1. Synthesis of 1,3-diaryl-3-chloro-1-propanols
Entry
X
Y
T (oC)
Time (h)
anti (%)
Yield (%)a,b (3)
1
2
3
4
5
6
7
8
H
p-F
o-F
H
H
H
H
H
H
H
p-Cl
p-Cl
p-Cl
p-Cl
p-CH3
p-CH3
p-CH3
−10
0
1
2
2
83
93
80
84
92
89
84
86
84
86
77
87
85
90
76 (3a)
87 (3b)
79 (3c)
79 (3d)
56 (3e)
45 (3f)
96 (3g)
90 (3h)
85 (3i)
86 (3j)
99 (3k)
99 (3l)
75 (3m)
98 (3n)
0
p-Cl
o-CH3
CH3O
p-CN
p-NO2
H
p-Cl
p-CN
p-NO2
H
−10
−20
−20
25
1
0.5
0.5
6
4
1
1.5
12
6
0.5
8
25
9
−10
−10
25
25
−20
25
10
11
12
13
14
p-CN
a Isolated yields based on the starting aldehydes.
b All compounds were characterized by elemental analysis and NMR spectroscopy.
Table 2. Synthesis of 1,3-diaryl-3-chloro-2-methyl-1-propanols
Entry
X
T (°C)
Time (h)
anti (%)a
Yield (%)b,c (4)
1
2
3
4
5
6
7
p-F
o-F
p-Cl
p-Br
p-Me
p-CN
p-NO2
0
0
2
2
1.5
1
0.5
48
24
94
92
89
86
90
98
95
94 (4a)
95 (4b)
65 (4c)
60 (4d)
36 (4e)
97 (4f)
95 (4g)
−10
−10
−20
25
25
a anti-3-Chloro-1-hydroxy isomer (in all cases hydoxy and methyl are syn).
b Isolated yields based on the starting aldehydes.
c All compounds were characterized by elemental analysis and NMR spectroscopy.
The reaction of aliphatic alkenes with aryl aldehydes
produces mixtures of 1,3-dichloro compounds and ene–
carbonyl adducts in low yield. Boron chlorides such as
n-butylboron dichloride, sec-butylboron dichloride, n-
hexylboron dichloride, cyclohexylboron dichloride and
cyclopentylboron dichloride were found to be ineffec-
tive. Solvents such as hexane, toluene, chloroform and
CH2Cl2 were examined as reaction solvents. CH2Cl2
was found to be the most effective. Diethyl ether, THF
and dioxane simply undergo ether cleavage reactions.1
CDCl3. The NMR data indicated that no haloboration
had occurred. 4-Chlorobenzaldehyde was then added to
the reaction mixture; the NMR spectra revealed the
rapid formation of b-chloroalkoxyborane intermediate
6 (Scheme 1). Hydrolysis of 6 generated chloroalcohol
3. In a separate experiment, a boron complex was
prepared by mixing 4-chlorobenzaldehyde with one
equivalent of phenylboron dichloride in CDCl3. Styrene
was then added to the complex, and the reaction gener-
ated intermediate 6. Based on these observations, the
reaction presumably occurs via an electrophilic addition
of the complexed aldehyde to styrene, in a concerted
mechanism (Scheme 1). A similar mechanism has been
reported for Lewis acid promoted ene–carbonyl
reactions.11
In order to gain insight regarding the mechanism, the
reaction of styrene and 4-chlorobenzaldehyde was mon-
itored by NMR spectroscopy. Styrene and phenylboron
dichloride were placed in a NMR tube containing

G. W. Kabalka et al. / Tetrahedron Letters 44 (2003) 1187–1189
1189
Table 3. Synthesis of 3-chlorlo-3-aryl-1-(3-pyridinyl)-1-
propanols
chloro-1-propanols and 3-chloro-1,3-diaryl-2-methyl-1-
propanols in excellent yields. Efforts to utilize boron
bromides and iodides, to promote new condensation
reactions are currently underway.
Acknowledgements
Entry
Y
Time (h)
anti (%)
Yield (%)a,b (5)
We wish to thank the US Department of Chemistry
and the Robert H. Cole Foundation for their support.
1
2
3
4
5
H
20
30
24
24
10
88
92
91
95
88
90 (5a)
84 (5b)
85 (5c)
91 (5d)
64 (5e)
p-F
p-Cl
o-Cl
p-Me
References
a Isolated yields based on starting aldehydes.
1. Bhatt, M. V.; Kulkarni, S. U. Synthesis 1983, 249.
2. (a) Lansinger, J. M.; Ronald, R. C. Synth. Commun.
1979, 9, 341; (b) Kabalka, G. W.; Wu, Z. Tetrahedron
Lett. 2000, 41, 579.
b All compounds were characeterized by elemental analysis and NMR
spectroscopy.
3. (a) Barret, A. G. M.; Seefeld, M. A. J. Chem. Soc., Chem.
Commun. 1994, 1053; (b) Beardsley, D. A.; Fisher, G. B.;
Goralski, C. T.; Nicholson, L. W.; Singaram, B. Tetra-
hedron Lett. 1994, 35, 1511; (c) Kabalka, G. W.; Wu, Z.;
Ju, Y. Tetrahedron Lett. 2000, 41, 5161.
4. Suzuki, A. Pure Appl. Chem. 1986, 58, 829.
5. Brown, H. C.; Ramachandran, P. V. Acc. Chem. Res.
1992, 25, 16.
6. (a) Kabalka, G. W.; Wu, Z.; Trotman, S. E.; Gao, X.
Org. Lett. 2000, 2, 255; (b) Kabalka, G. W.; Wu, Z.; Ju,
Y. Tetrahedron 2001, 57, 1663; (c) Kabalka, G. W.; Wu,
Z.; Ju, Y. Tetrahedron Lett. 2001, 42, 6239; (d) Kabalka,
G. W.; Wu, Z.; Ju, Y. Tetrahedron 2002, 58, 3243.
7. Kabalka, G. W.; Wu, Z.; Ju, Y. Org. Lett. 2002, 4, 1491.
8. Joy, F.; Lappert, M. F.; Prokai, B. J. Organomet. Chem.
1966, 5, 506.
9. Kabalka, G. W.; Wu, Z.; Ju, Y. Tetrahedron Lett. 2001,
42, 5793.
10. Representative procedure for the synthesis of 1,3-diaryl-3-
chloro-1-propanols: Benzaldehyde (4.0 mmol, 0.42 g) and
styrene (4.0 mmol, 0.42 g) were dissolved in CH2Cl2 (10
mL) at room temperature in a dry round-bottomed flask
under a nitrogen atmosphere. The solution was cooled to
−10°C in a dry-ice bath, and phenylboron dichloride (4.0
mmol, 0.64 g) was added via syringe. The solution gradu-
ally turned yellow. After stirring at −10°C for 1 h, the
solution was hydrolyzed and extracted with hexanes. The
organic layer was separated, dried over anhydrous
MgSO4, concentrated under reduced pressure, and the
product isolated by column chromatography (silica gel,
CH2Cl2) to afford 0.75 g (76%) of 3a as a colorless liquid;
1H NMR (CDCl3, 250 MHz) anti-isomers: l 7.38–7.21
(m, 10H), 5.20 (dd, 1H, J=9.7, 4.5 Hz), 4.99 (dd, 1H,
J=8.8, 4.4 Hz), 2.44 (s, 1H), 2.33–2.27 (m, 2H); 13C
NMR (CDCl3, 62.9 MHz): l 143.8, 141.6, 128.6, 128.3,
127.8, 126.9, 125.7, 71.2, 60.5, 48.8. Anal. calcd for
C15H15ClO: C, 73.02; H, 6.13. Found: C, 73.07; H,
6.24%.
Scheme 1.
All products 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. In addition, the reactions
predominantly produced the anti-diastereoisomers. For
styrenes, the R,R/S,S-isomers were the major products
whereas the (E)-b-methyl styrenes produced mainly
R,R,R/S,S,S-isomers (Table 2). The anti-isomers,
exhibit two sets of resonances (doublets of doublets) for
the diastereotopic benzylic protons in the range of
5.80–5.00 l. The corresponding resonances for the syn-
isomers appear upfield in the range of 4.80–4.50 l. A
single crystal of compound 4f was analyzed by X-ray
crystallography. The X-ray structure analysis confirmed
the NMR assignment.
In conclusion, we have discovered a new reaction of
styrenes with aryl aldehydes in the presence of
phenylboron dichlorides. The reactions stereo- and
regioselectively generate a series of useful 1,3-diaryl-3-
11. (a) Snider, B. B.; Rodini, D. J.; Kirk, T. C.; Cordova, R.
J. Am. Chem. Soc. 1982, 104, 555; (b) Mikami, K.;
Shimizhu, M. Chem. Rev. 1992, 92, 1021.