A new convenient, efficient, and regioselective synthesis of 1,3-diaryl-1,3-dihalopropanes

Article abstract of DOI:10.1055/s-2004-829191

Reactions of aryl aldehydes with styrenes in the presence of boron trihalides produce 1,3-diaryl-1,3-dihalopropanes in excellent yields.

Full text of DOI:10.1055/s-2004-829191

PRACTICAL SYNTHETIC PROCEDURES
2927
A New Convenient, Efficient, and Regioselective Synthesis of 1,3-Diaryl-
1,3-dihalopropanes
S
ynthesisof 1,3-D
e
iaryl-1,3-di
o
halopropane
r
s
ge W. Kabalka,* Zhongzhi Wu, Yuhong Ju
Departments of Chemistry and Radiology, The University of Tennessee, Knoxville,
TN 37996-1600, USA
Fax +1(865)9742997; E-mail: kabalka@utk.edu
PSP
Received 25 March 2004
No33
Abstract: Reactions of aryl aldehydes with styrenes in the presence of boron trihalides produce 1,3-diaryl-1,3-dihalopropanes in excellent
yields.
Key words: Lewis acids, propanes, aldehydes, styrenes, boron halides
Cl
Cl
O
BCl3
H
+
CH2Cl2, 0 °C
Y
X
Y
X
X = H, 4-F, 2-F, 4-Cl, 4-Br, 3-Br, 2-Br,
4-CN, 4-NO2, 4-Me
Y = H, 4-F, 4-Me
Scheme 1
usually prepared by halogenation of cyclopropanes17 or
1,3-propanediols18 but the regiochemistry of these reac-
tions can be difficult to control and there is limited avail-
Introduction
The Lewis acid promoted addition of carbonyl com- ability of starting materials. The new method provides a
pounds to alkenes is an important method for forming new simple and efficient and regioselective procedure for the
carbon–carbon bonds in synthetic organic chemistry.1 The preparation of a variety of 1,3-diaryl-1,3-dihalopropanes.
reactions are usually catalyzed by Lewis acids such as
BF3,2,3AlCl3,4 FeCl3,5 SnCl4,6 TiCl4,7 BiCl3,8 and alkyl
aluminum chlorides.1,9 Interestingly, BCl3 has been re-
ported to be an ineffective promoter for ene reactions of
Scope and Limitations
aldehydes with alkenes.4b,c During our exploration of the The reactions of aryl aldehydes with styrenes in the pres-
organic chemistry of boron halides,10,11 we discovered ence of boron trichloride were carried out in dichlo-
that BCl3 and BBr3 effectively promote the addition of romethane at 0 °C. When freshly distilled styrenes were
aryl aldehydes to styrenes. The reactions produce diaste- used, only polymerization was observed. However, the re-
reomeric mixtures of 1,3-diaryl-1,3-dihalopropanes in ex- actions produced excellent yields of 1,3-diaryl-1,3-
cellent yields (Schemes 1 and 2).
dichloropropanes when commercially available styrenes
(containing 4-tert-butylcatechol as a stabilizer) were uti-
lized. If the reactions were carried out at room tempera-
ture, chlorination of the aryl aldehydes occurred.10 The
new reactions readily tolerate functional groups but aryl
aldehydes containing electron-withdrawing groups tend
The dihalopropane products are useful intermediates in
organic synthesis.12 For example, they have been used to
prepare arylcyclopropanes,13 centrohexaindane,14 and
pyrazolidine.15 Benzylic bromides can also undergo Suzu-
ki coupling reactions.16 1,3-Diaryl-1,3-dihalopropanes are
Br Br
O
BBr3
CH2Cl2, –40 °C
H
+
Y
X
Y
X
X = H, 4-F, 4-Cl, 4-Br, 2-Br, 4-CN,
4-NO2, 4-Me
Y = H, 4-F, 4-Me
Scheme 2
SYNTHESIS 2004, No. 17, pp 2927–2929
x
x.
x
x
.
2
0
0
4
Advanced online publication: 13.08.2004
DOI: 10.1055/s-2004-829191; Art ID: Z06504SS
© Georg Thieme Verlag Stuttgart · New York

2928
G. W. Kabalka et al.
PRACTICAL SYNTHETIC PROCEDURES
syntheses of 1,3-dichloro-1-(4-fluorophenyl)-3-phenylpropane,
1,3-dibromo-1-(4-fluorophenyl)-3-phenylpropane and 1,3-dichlo-
ro-1,3-diphenyl-2-methylpropane are representative.
to react at a slower rate. They do, however, produce higher
yields of the desired products.
Due to the facile bromination of aryl aldehydes by boron
tribromide, reactions involving boron tribromide were
carried out in dichloromethane at –40 °C. The corre-
sponding 1,3-diaryl-1,3-dibromopropanes were obtained
in good to excellent yields.
All glassware was dried in an oven heated at 120 °C for at least 12
h and cooled under argon prior to use. CH2Cl2 was dried over CaH2
and distilled prior to use. Reactions were magnetically stirred and
monitored by TLC. Products were purified by flash chromatogra-
phy using silica gel (230–400 mesh, 60 D, ICN Biomedical GmbH,
Eschwege, Germany) and hexanes as eluent.
A series of aryl aldehydes containing a variety of func-
tional groups were subjected to the reactions. Essentially,
all aldehydes gave 1,3-diaryl-1,3-dichloropropanes in ex-
cellent yields and 1,3-diaryl-1,3-dibromopropanes in
good yields. Reactions involving aldehydes containing
phenoxy and methoxy groups were unsuccessful due to
the well-known ether cleavage reactions. All products
consist of a 1:1 ratio of diastereoisomers. Products con-
taining electron-donating substituents tend to decompose
on silica gel resulting in relatively low isolated yields. 1,3-
Diaryl-1,3-dibromopropanes were found to be more sus-
ceptible to decomposition on silica gel than the corre-
sponding dichlorides. Aldehydes and styrenes containing
electron-withdrawing groups reacted more slowly than
those containing electron-donating substituents. Solvents
such as ethyl ether and THF interfered with the reaction
due to cleavage of the ether linkage by the boron halides.
The use of solvents such as hexanes, benzene and toluene
enhanced competing reactions including the direct chlori-
nation of the aldehydes.10 Dichloromethane was found to
be the most effective solvent for the reaction.
BCl3 (1 M in hexane) was purchased from Aldrich Chemical Co.
and used as received. BBr3 (Aldrich Chemical Co.) was diluted to 1
M in CH2Cl2. All aldehydes and styrenes (Aldrich Chemical Co.)
were used as received.
NMR spectra were measured in CDCl3 at 250 MHz (1H) or at 62.9
MHz (13C). In cases where more than one isomer are formed, the
NMR shifts of all isomers are reported. Chemical shifts for 1H and
13C were referenced to TMS and CDCl3.
1,3-Dichloro-1-(4-fluorophenyl)-3-phenylpropane; Typical
Procedure
4-Fluorobenzaldehyde (4.0 mmol, 0.42 g) and styrene (4.0 mmol,
0.42 g) were dissolved in CH2Cl2 (20 mL) at r.t. in a dry 100 mL
round-bottomed flask equipped with a magnetic stirring bar under
N2. The reaction mixture was stirred at 0 °C in an ice bath and BCl3
(4.3 mmol, 4.3 mL of a 1.0 M hexane solution) was added via a sy-
ringe. The mixture was allowed to stir for 2 h and then for 16 h at
r.t., during which time the solution turned purple. The mixture was
hydrolyzed by adding H2O (5 mL) and extracted into hexane (3 × 20
mL). The combined organic layers were separated, dried (MgSO4),
concentrated under reduced pressure and the product was isolated
by column chromatography (hexanes, silica gel) to afford 0.95 g
(99%) of the desired product as a colorless oil.
1H NMR: d = 7.36–7.28 (m, 7 H), 7.05–6.97 (m, 2 H), 5.20 (dd, 0.5
H, J = 6.5 Hz), 5.17 (dd, 0.5 H, J = 6.4 Hz), 4.80–4.71 (m, 1 H),
2.96–2.87 (m, 0.5 H), 2.68–2.56 (m, 1.5 H).
13C NMR: d = 164.5, 160.6, 140.6, 139.9, 136.6, 135.9, 128.8,
1-[(E)-Prop-1-enyl]benzene produced excellent yields of
the corresponding 1,3-diaryl-1,3-dichloro-2-methylpro-
panes when allowed to react with aryl aldehydes in the
presence of boron trichloride (Scheme 3). NMR data re-
vealed that three pairs of diastereomers had been pro- 128.7, 128.6, 127.0, 126.9, 116.0, 115.9, 115.6, 115.5, 60.6, 59.9,
duced. Stilbene, 1,1-diphenylethylene, tetraphenylethene
59.3, 49.6, 49.5.
and triphenylethene failed to yield the desired products.
Aliphatic alkenes produced only low yields of the corre-
sponding ene products.
Anal. Calcd. for C15H13Cl2F: C, 63.62; H, 4.63. Found: C, 63.77, H,
4.73.
1,3-Bromo-1-(4-fluorophenyl)-3-phenylpropane; Typical Pro-
cedure
Cl
Cl
O
To a dry, N2 flushed, 100 mL round-bottomed flask equipped with
a magnetic stirring bar were added, 4-fluorobenzaldehyde (3.0
mmol, 0.32 g), styrene (3.0 mmol, 0.32 g) and CH2Cl2 (20 mL). The
solution was cooled to –40 °C in a dry ice-acetone bath and BBr3
(3.2 mmol, 3.2 mL of a 1.0 M CH2Cl2 solution) was added via a sy-
ringe with vigorous stirring. The reaction mixture was allowed to
stir at –40 °C for 2 h and then at r.t. for 5 h. The mixture was hydro-
lyzed by adding H2O (5 mL) and the product was extracted into hex-
anes (3 × 20 mL). The combined organic layers were dried
(MgSO4), and the product was isolated by flash column chromatog-
raphy (silica gel, hexanes) to give 0.80 g (98%) of the desired prod-
uct as a colorless oil.
1H NMR: d = 7.34–7.25 (m, 7 H), 7.03–6.96 (m, 2 H), 5.16 (t, 1 H,
J = 7.1 Hz), 4.83 (dd, 1 H, J = 14.9, 7.2 Hz), 3.24–3.11 (m, 0.5 H),
2.90–2.78 (m, 1.5 H).
13C NMR: d = 164.4, 160.5, 140.7, 140.1, 136.9, 136.2, 129.3,
129.1, 128.9, 128.7, 127.4, 116.0, 115.7, 52.8, 51.6, 50.6, 49.3,
49.1.
BCl3
H
+
Me
CH2Cl2, 0 °C
X
X
X = H, 4-F, 4-Br, 4-NO2, 4-Me
Scheme 3
In conclusion, we have discovered a new, highly efficient
method for preparing 1,3-diaryl-1,3-dihalopropanes via
reactions of aryl aldehydes with styrenes promoted by bo-
ron trihalides (BCl3 and BBr3). The product, 1,3-diaryl-
propanes are potential intermediates in a variety of
synthetic transformations including the preparation of cy-
clopropane derivatives.
Representative Procedures
Herein, we describe the typical synthetic procedures for the synthe-
sis of 1,3-diaryl-1,3-dichloropropanes, 1,3-diaryl-1,3-dibromopro-
panes, and 1,3-diaryl-1,3-dichloro-2-methylpropanes. The
Anal. Calcd for C15H13Br2F: C, 48.42; H, 3.52. Found: C, 48.48; H,
3.51.
Synthesis 2004, No. 17, 2927–2929 © Thieme Stuttgart · New York

PRACTICAL SYNTHETIC PROCEDURES
Synthesis of 1,3-Diaryl-1,3-dihalopropanes
2929
1,3-Dichloro-1,3-diphenyl-2-methylpropane; Typical Proce-
dure
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Benzaldehyde (4.0 mmol, 0.42 g) and 1-[(E)-prop-1-enyl]benzene
(4.0 mmol, 0.47 g) were dissolved in CH2Cl2 (20 mL) at r.t. in a dry
100 mL round-bottomed flask maintained under N2. The solution
was cooled to 0 °C in an ice bath and BCl3 (4.3 mmol, 4.3 mL of a
1.0 M hexane solution) was added via a syringe. The reaction mix-
ture was allowed to stir at 0 °C for 2 h and then at r.t. for 4 h during
which time the solution turned purple. The mixture was hydrolyzed
by adding H2O (5 mL) and the product was extracted into hexane.
The organic layer was separated, dried (MgSO4), and the product
isolated by column chromatography (hexane, silica gel) to give 1.12
g (95%) of the desired product; colorless crystals; mp 71–72 °C.
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1H NMR: d (1R,3R; 1S,3S-isomers) = 7.37–7.28 (m, 10 H), 4.75 (d,
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1H NMR: d (other two pairs of diastereomers) = 7.48–7.23 (m, 10
H), 5.91 (s, 0.8 H), 5.01 (d, 0.4 H, J = 7.2 Hz), 4.95 (d, 0.8 H,
J = 10.2 Hz), 2.89–2.81 (m, 0.2 H), 2.60–2.48 (m, 0.8 H), 0.74 (d,
0.6 H, J = 7.0 Hz), 0.64 (d, 2.4 H, J = 6.7 Hz).
13C NMR: d (other two pairs of diastereomers) = 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 C16H16Cl2: C, 68.83; H, 5.78. Found: C, 68.70; H,
5.92.
Acknowledgments
We wish to thank the U.S. Department of Energy and the Robert H.
Cole Foundation for support of this research.
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Synthesis 2004, No. 17, 2927–2929 © Thieme Stuttgart · New York