Boron trifluoride mediated prins reaction of methylene diacetate with styrenes. One-pot synthesis of 3-chloro-3-arylpropanols

Article abstract of DOI:10.1055/s-2006-926445

A one-pot procedure was developed for the synthesis of 3-chloro-3- arylpropanols, which are important starting materials for the synthesis of biologically active benzanilide derivatives. Styrenes were reacted with methylene diacetate in the presence of boron trifluoride to give the corresponding 3-chloro-3-arylpropanols in 36-84% yield by the Prins reaction. A strongly electron-donating methoxy substituent at either the ortho or para position of the styrene did not give the expected 3-chloro-3-arylpropanols due to polymerization. Styrene with a strongly electron-withdrawing nitro substituent gave the corresponding 3-chloro-3-arylpropanol in very low yield. Under the same reaction conditions, substituted norbornene gave a tricyclic ether. A very easy procedure for the synthesis of methylene diacetate is also reported. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-926445

PAPER
1427
Boron Trifluoride Mediated Prins Reaction of Methylene Diacetate with
Styrenes. One-Pot Synthesis of 3-Chloro-3-arylpropanols
O
ne-Pot Synthesis
l
of 3-C
p
hloro-3-aryl
e
Department of Chemistry, Middle East Technical University, 06531 Ankara, Turkey
Fax +90(312)2101280; E-mail: dogano@metu.edu.tr
Received 21 September 2005; revised 5 December 2005
tricyclic ether formation is reported in the literature,2 there
is no report on the formation of chloroalcohols in one step
via the Prins reaction starting from styrene. The only ex-
ample found in the literature for chloroalcohol formation
Abstract: A one-pot procedure was developed for the synthesis of
3-chloro-3-arylpropanols, which are important starting materials
for the synthesis of biologically active benzanilide derivatives. Sty-
renes were reacted with methylene diacetate in the presence of bo-
ron trifluoride to give the corresponding 3-chloro-3-arylpropanols is the study of Stapp et al.6 They reported that the Prins re-
in 36–84% yield by the Prins reaction. A strongly electron-donating
methoxy substituent at either the ortho or para position of the sty-
action of 2-butenes with formaldehyde and hydrogen
chloride at –65 °C gave a mixture of chloroalcohols and
rene did not give the expected 3-chloro-3-arylpropanols due to po-
their formals in 45–60% yield. However, 1-alkenes under
lymerization. Styrene with a strongly electron-withdrawing nitro
the same reaction conditions yielded 3-alkyl-4-chlorotet-
substituent gave the corresponding 3-chloro-3-arylpropanol in very
rahydropyrans, while styrene, on the other hand, gave the
simple hydrogen chloride addition product. 3-Chloro-3-
arylpropanols are important as the starting materials in the
synthesis of benzanilide derivatives which have dual a1-
adrenoceptor antagonistic action and steroid 5a-reductase
inhibitory activity.7 Therefore we were interested in syn-
thesizing 3-chloro-3-arylpropanols by our method. Here-
in, we report the full details of our work and a new method
for the one-pot synthesis of 3-chloro-3-arylpropanols via
the Prins reaction. We also report a simple procedure for
the synthesis of methylene diacetate.
low yield. Under the same reaction conditions, substituted nor-
bornene gave a tricyclic ether. A very easy procedure for the syn-
thesis of methylene diacetate is also reported.
Key words: Prins reactions, ethers, Lewis acids, arylpropanols
The Prins reaction of alkenes with formaldehyde in the
presence of Lewis and Brønsted acids has been studied
extensively.1 Depending on the reaction conditions, 1,3-
dioxanes, 1,3-diols, and allylic alcohols have been ob-
tained as the major products in varying ratios. Sauers et al.
reported that the Prins reaction of norbornene and trioxane
in the presence of acetic and sulfuric acids yielded a tricy-
clic ether in 16% yield.2a A similar result was also ob-
served by Wu and Zhang when the endo-ester-substituted
norbornene was reacted with formaldehyde in the pres-
ence of formic acid giving the corresponding tricyclic
ether in 13% yield.3 While studying the Prins reaction
with 1-phenylpropene and stilbene in the presence of
Brønsted acids, Ferrand and Huet used methylene diace-
tate as the formaldehyde equivalent and isolated 1,3-di-
acetates and 1,3-dioxanes as the products.4
Norbornene derivative 1 was reacted with tetrabutylam-
monium acetate used from a stock solution in dichlo-
romethane in the presence of boron trifluoride at –78 °C.
As mentioned in the introduction, this reaction gave the
tricyclic ether 28 in 20% yield (Scheme 1).
5
6
7
Bu4NOAc, CH2Cl2
BF3(g), –78 °C to r.t.
O
3
8
H
9
CH2CN
2
1
CH2CN
H
1
2
Scheme 1
We recently reported the results of our work on the nu-
cleophilic addition of iodide and bromide to the double
bond of endo- and exo-substituted norbornene derivatives
in the presence of boron trifluoride.5 As an extension of
this work, we wanted to study the nucleophilic addition of
an acetate ion to the double bond of endo-nitrile-substitut-
ed norbornene 1. This reaction gave a surprising result,
tricyclic ether 2 formed (Scheme 1) in low yield. When
we tried the reaction with styrene as the substrate, 3-chlo-
ro-3-phenylpropanol was obtained in good yield. This was
also a surprising result for us until we realized that these
reactions were occurring via the Prins reaction. Although
To investigate the mechanism of this unexpected cyclic
ether formation, we looked at the experimental conditions
in detail. Tetrabutylammonium acetate is highly hygro-
scopic so it was prepared as a stock solution in dichlo-
romethane and kept in the refrigerator. NMR analysis of
this stock solution showed that all the acetate was convert-
ed into methylene diacetate (MDA). Although the synthe-
sis of different methylene diesters was reported by
refluxing tetrabutylammonium salts of carboxylic acids in
dichloromethane for four days,9 there is no report on the
synthesis of MDA from tetrabutylammonium acetate in
dichloromethane at high or low temperature.10
SYNTHESIS 2006, No. 9, pp 1427–1432
x
x
.
x
x
.2
0
0
6
The mechanism we propose for the formation of tricyclic
ether 2 is outlined in Scheme 2. As reported by Ferrand
Advanced online publication: 12.04.2006
DOI: 10.1055/s-2006-926445; Art ID: T13205SS
© Georg Thieme Verlag Stuttgart · New York

1428
A. Isleyen, Ö. Dogan
PAPER
and Huet,4 we believe that MDA in the stock solution acts
as a formaldehyde equivalent and forms the formalde-
hyde–boron trifluoride complex i. This complex reacts
with norbornene derivative 1 to give intermediate ii. This
intermediate undergoes Wagner–Meerwein rearrange-
ment to give another intermediate iii which forms tricyclic
ether 2 by attack of oxygen on the positively charged car-
bon. The regioselectivity of the reaction can be attributed
to the distortion of electron density.5,11 Thus, initial attack
of norbornene 1 on complex i takes place at C-6 as shown
in Scheme 2.
Table 1 Reaction of MDA with Styrenes in the Presence of Boron
Trifluoride
Entry
1
Substrate
3a
R
Product
4a
Yield (%)
H
79
79
84
79
71
2
3b
3c
p-F
4b
4c
3
p-Cl
4
3d
3e
p-Br
p-Me
p-OMe
p-NO2
m-F
4d
4e
5
a
6
3f
4f
–
O
O
2 Bu4NOAc + CH2Cl2
2 Bu4NCl
+
7
3g
4g
5
76
62
59
63
36
45
44
47
41
O
O
MDA
8
3h
3i
4h
4i
BF3
9
m-Cl
m-Br
m-Me
m-OMe
o-F
4
10
11
12
13
14
15
16
17
3j
4j
H2CO BF3
2
1
OBF3
i
6
3k
3l
4k
4l
ii
CH2CN
CH2CN
Wagner–Meerwein
rearrangement
3m
3n
3o
4m
4n
4o
o-Cl
F3BO
2
OBF3
o-Br
o-Me
o-OMe
CH2CN
CH2CN
iii
3p
3r
4p
4r
Scheme 2
a
–
a No product isolation due to polymerization.
Under reaction conditions similar to those described for
the norbornene derivative 1, styrene resulted in the forma-
tion of 3-chloro-3-phenylpropanol 4a in 79% yield
(Scheme 3). Cyclohexene and methylcyclohexene gave
the corresponding chloroalcohols as mixtures of cis and
trans isomers in very low yield. Since 3-chloro-3-arylpro-
panols are important for the synthesis of biologically ac-
tive benzanilide derivatives we applied the reaction to
other styrenes 3b–r having a range of substituents at dif-
ferent positions of the aromatic ring (Table 1). From these
reactions we also hoped to determine if there were substit-
uent effects operating. All the styrenes except p- and m-
methoxystyrenes gave the corresponding 3-chloro-3-aryl-
propanols 4b–r.
group. For the meta-substituted styrenes, yields decrease
slightly as the electronegativity of the halide decreases. In
the case of the ortho-substituted styrenes yields were low-
er than both para- and meta-substituted styrenes but there
was not much variance with respect to the type of the sub-
stituent. Again no chloroalcohol formation was observed
for o-methoxystyrene due to polymerization. We believe
that both electronic and steric effects are involved in the
lower yields of ortho-substituted styrenes. In a similar
study where the Prins reaction was studied systematically
with substituted styrene derivatives and formaldehyde, in
the presence of aryloxyboron difluoride as a Lewis acid
catalyst, 1,3-dioxanes were formed exclusively.12 The
highest yields were reported for the methyl-substituted
styrene derivatives and no product formation was ob-
served for styrenes having strong electron-withdrawing
substituents (CN, CO2Me). In our case, methyl-substitut-
ed styrenes gave very similar results to the halogen-sub-
stituted styrenes and a very low yield was seen in the case
of p-nitrostyrene, where most of the starting material was
recovered (Table 1, entry 7). It can also be concluded
from Table 1 that the substituents with a highly negative
(like methoxy, sp = –0.28)13 or highly positive (like nitro,
sp = 0.81)14 Hammett constant do not form 3-chloro-3-
arylpropanol with ease under our experimental condi-
tions. It is also important to note that m-methoxystyrene
having as positive a Hammet constant as the halides
Cl
OH
O
O
Me
O
O
Me
Bu4NCl, CH2Cl2
BF3(g), –78 °C to r.t.
R
R
3a–r
4a–r
Scheme 3
It can be concluded from Table 1 that the highest yields
were observed for para-substituted styrenes, except p-
methoxystyrene which polymerizes under these condi-
tions. It is also true that halides at the para position of the
styrene have a very similar effect on the yield as a methyl
Synthesis 2006, No. 9, 1427–1432 © Thieme Stuttgart · New York

PAPER
One-Pot Synthesis of 3-Chloro-3-arylpropanols
1429
precoated silica gel 60 F-254. Flash chromatography was performed
using silica gel 60 (230–400 mesh). H NMR spectra were mea-
(MeO: sm = 0.10, F: sm = 0.34, Cl: sm = 0.37, Br:
sm = 0.37)14 gave the 3-chloroalcohol in a poor 36% yield
(Table 1, entry l2).
1
sured on a 400 MHz spectrometer in CCl4–CDCl3 (2:3) and reported
in ppm using TMS as an internal standard. 13C NMR spectra were
recorded at 100 MHz and are reported in ppm with the residual sol-
vent peak as internal standard (CDCl3 at 76.9 ppm). IR spectra were
recorded on a Perkin Elmer 1600 series FT-IR spectrometer in
CHCl3. HRMS were recorded on a Kratos MS25RFA mass spec-
trometer.
A reaction mechanism similar to that described in
Scheme 2 can be envisaged for the formation of 3-chloro-
3-arylpropanols (Scheme 4).
Cl–
H2CO BF3
Methylene Diacetate Stock Solution
O
BF3
i
Bu4NOAc (11.4 g, 37.8 mmol) and anhyd benzene (60 mL) were
placed in a round-bottomed flask equipped with a Dean–Stark ap-
paratus. This solution was refluxed under an argon atmosphere with
continuous removal of the azeotrope over a period of 1 h. Then the
flask was connected to a vacuum line to remove the rest of the ben-
zene. Finally, anhyd CH2Cl2 (37 mL) was added to the flask con-
taining Bu4NOAc (11.2 g, 37.1 mmol) under an argon atmosphere.
This stock solution was allowed to stand at r.t. for 3 d before use and
then kept at 4 °C.
Bu4NCl, CH2Cl2
iv
R
R
Cl
Cl
H2O
OH
O BF3
v
R
R
Tricyclic Ether and 3-Chloro-3-arylpropanols; General Proce-
dure
Scheme 4
Methylene diacetate stock solution (2.5 mL), and alkene 1/3a–r
(0.39 mmol) were added to a 10-mL flask under an argon atmo-
sphere. The flask was then cooled to –78 °C and BF3 gas was slowly
bubbled through the solution (30 min for 1 and 10 min for 3a–r) to
give a cloudy solution. At this point, the flow of BF3 was stopped,
the reaction flask was allowed to warm to r.t., and the solution was
left stirring overnight at this temperature. In the morning, H2O (5
mL) was added to the reaction flask, followed by extraction with
CH2Cl2 (3 × 10 mL). The combined organic layers were dried over
MgSO4 and concentrated. Finally, flash column chromatography
(hexanes–EtOAc, 5:1) gave the desired pure product.
As shown in Scheme 4, styrenes react with complex i to
give highly stable benzylic carbocations iv which are
trapped with chloride from TBACl produced during MDA
formation. This step leads to the intermediates v, which
give 3-chloro-3-arylpropanols 4 after hydrolysis. Com-
paring the mechanisms in Schemes 2 and 4, one can spec-
ulate that the course of these reactions depends on the fate
of the initially formed carbocation. In the case of ii, Wag-
ner–Meerwein rearrangement leads to iii, which cyclizes
to the tetrahydrofuran (Scheme 2). On the other hand, cy-
clization of carbocation iv would lead to a more strained
oxetane. In this case, the carbocation is trapped by chlo-
ride.
9-exo-(4-Oxatricyclo[4.3.0.03,7]non-9yl)acetonitrile (2)
Yield: 12.7 mg (20%); white waxy oil; Rf 0.21 (hexanes–EtOAc,
2:1).
IR: 2966, 2249, 1454, 1424, 1360, 1308, 1223, 1038, 972, 926, 894,
855, 760, 640 cm–1.
3-Chloro-3-arylpropanols 4a, 4d, 4e, and 4k have been
prepared previously by a different method starting from
methyl-3-oxo-3-arylpropionates,7 however, no spectral
1H NMR: d = 4.06 (t, J = 2.7 Hz, 1 H, H3), 3.83 (dd, J = 8.1, 3.9 Hz,
1 H, H5b), 3.64 (d, J = 8.1 Hz, 1 H, H5a), 2.36 (br s, 1 H, H7), 2.29–
2.25 (m, 3 H, H1, CH2CN), 2.19 (d, J = 6.0 Hz, 1 H, H6), 1.91 (q,
J = 7.9 Hz, 1 H, H9), 1.73 (dd, J = 14.1, 8.2 Hz, 1 H, H8endo), 1.67
(dd, J = 13.3, 6.0 Hz, 1 H, H2endo), 1.32 (dd, J = 14.1, 4.1 Hz, 1 H,
H8exo), 1.15 (d, J = 13.3 Hz, 1 H, H2exo).
1
data were reported except for the H NMR spectrum of
4a.The synthesis of compound 4a was also carried out
starting from 4-phenyl-1,3-dioxane15 and 2-phenyloxet-
ane.16
13C NMR: d = 118.8 (CN), 78.5 (C3), 66.3 (C5), 45.1 (C7), 45.0 (C1),
We have discovered a new method for the one-pot synthe- 42.5 (C6), 41.4 (C9), 35.8 (C2), 26.9 (C8), 23.1 (CH2CN).
HRMS (EI, 70 eV): m/z calcd for C10H13NO (M+): 163.0997; found:
163.0997.
sis of 3-chloro-3-arylpropanols starting from styrene and
its derivatives. Although the reactions take place via the
Prins reaction, the products are different than the products
of the classical Prins reaction. 3-Chloro-3-arylpropanols
are obtained as the major products with 2–4% of the
acetylated derivatives, and without 1,3-dioxane or 1,3-
diol formation. This can be explained by the strong com-
plexation of the intermediate alkoxide to boron trifluoride.
As a result, this alkoxide is not nucleophilic enough to re-
act with the second molecule of formaldehyde to give 1,3-
dioxanes. Also, in our case, the reactions take place under
anhydrous conditions which prevents 1,3-diol formation.
3-Chloro-3-phenylpropan-1-ol (4a)
Yield: 52.4 mg (79%); light-yellow oil; Rf 0.34 (hexanes–EtOAc,
2:1).
IR: 3629, 3465, 3016, 2955, 2885, 1495, 1453, 1233, 1042, 897,
865, 822, 699, 616 cm–1.
1H NMR: d = 7.39–7.28 (m, 5 H, Ph), 5.10 (dd, J = 9.0, 5.5 Hz, 1 H,
H3), 3.86 (m, 1 H, H1), 3.71 (m, 1 H, H1¢), 2.33–2.16 (m, 2 H, H2,
H2¢), 1.40 (br s, 1 H, OH).
13C NMR: d = 141.5 (Cq, Ph), 128.6 (2 × CH, Ph), 128.3 (CH, Ph),
126.9 (2 × CH, Ph), 60.1 (C3), 59.7 (C1), 42.3 (C2).
HRMS (EI, 70 eV): m/z calcd for C9H9Cl (M+ – H2O): 152.0393;
found: 152.0394.
All reactions were carried out in oven- or flame-dried glassware un-
der an argon atmosphere unless otherwise stated. CH2Cl2 was dis-
tilled from CaH2 under argon. Analytical TLC was performed on
Synthesis 2006, No. 9, 1427–1432 © Thieme Stuttgart · New York

1430
A. Isleyen, Ö. Dogan
PAPER
3-Chloro-3-(4-fluorophenyl)propan-1-ol (4b)
Yield: 57.9 mg (79%); colorless oil; Rf 0.30 (hexanes–EtOAc, 2:1).
HRMS (EI, 70 eV): m/z calcd for C9H8ClNO2 (M+ – H2O):
197.0244; found: 197.0246.
IR: 3621, 3423, 3013, 2955, 2891, 1894, 1606, 1512, 1473, 1422,
1296, 1228, 1160, 1044, 836, 669 cm–1.
1H NMR: d = 7.36 (dd, J = 8.6, 5.3 Hz, 2 H, Ph), 7.02 (t, J = 8.6 Hz,
2 H, Ph), 5.09 (dd, J = 9.1, 5.5 Hz, 1 H, H3), 3.85 (m, 1 H, H1), 3.69
(m, 1 H, H1¢), 2.33–2.15 (m, 2 H, H2, H2¢), 1.58 (br s, 1 H, OH).
13C NMR: d = 162.5 (d, J = 246.5 Hz, CF, Ph), 137.4 (d, J = 3.5 Hz,
Cq, Ph), 128.7 (d, J = 8.5 Hz, 2 × CH, Ph), 115.6 (d, J = 4.5 Hz,
2 × CH, Ph), 59.5 (C1), 59.2 (C3), 42.5 (C2).
3-Chloro-3-(3-fluorophenyl)propan-1-ol (4h)
Yield: 55.7 mg (76%); colorless oil; Rf 0.31 (hexanes–EtOAc, 2:1).
IR: 3627, 3448, 3015, 2954, 2882, 1614, 1593, 1489, 1446, 1263,
1235, 1138, 1038, 959, 945, 869, 669 cm–1.
1H NMR: d = 7.35 (dd, J = 4.7, 8.1 Hz, 1 H, Ph), 7.16 (dd, J = 8.1,
4.7 Hz, 2 H, Ph), 6.99 (t, J = 4.7 Hz, 1 H, Ph), 5.08 (dd, J = 9.0, 5.5
Hz, 1 H, H3), 3.87 (m, 1 H, H1), 3.70 (m, 1 H, H1¢), 2.32–2.16 (m, 2
H, H2, H2¢), 1.46 (br s, 1 H, OH).
13C NMR: d = 162.8 (d, J = 245.6 Hz, CF, Ph), 144.0 (d, J = 7.3 Hz,
Cq, Ph), 130.1 (d, J = 8.3 Hz, CH, Ph), 122.6 (d, J = 2.7 Hz, CH,
Ph), 115.2 (d, J = 20.9 Hz, CH, Ph), 114.1 (d, J = 22.1 Hz, CH, Ph),
59.4 (C1), 59.0 (C3), 42.3 (C2).
HRMS (EI, 70 eV): m/z calcd for C9H10FClO (M+): 188.0404;
found: 188.0402.
3-Chloro-3-(4-chlorophenyl)propan-1-ol (4c)
Yield: 66.8 mg (84%); colorless oil; Rf 0.31 (hexanes–EtOAc, 2:1).
HRMS (EI, 70 eV): m/z calcd for C9H10ClFO (M+): 188.0404;
found: 188.0408.
IR: 3622, 3442, 3018, 2962, 2881, 1901, 1602, 1495, 1410, 1244,
1090, 1049, 1020, 835, 669 cm–1.
1H NMR: d = 7.32 (br s, 4 H, Ph), 5.07 (dd, J = 9.1, 5.5 Hz, 1 H, H3),
3.85 (m, 1 H, H1), 3.68 (m, 1 H, H1¢), 2.31–2.14 (m, 2 H, H2, H2¢),
1.54 (br s, 1 H, OH).
3-Chloro-3-(3-chlorophenyl)propan-1-ol (4i)
Yield: 49.3 mg (62%); light-yellow oil; Rf 0.33 (hexanes–EtOAc,
2:1).
13C NMR: d = 140.0 (Cq, Ph), 134.2 (Cq, Ph), 128.9 (2 × CH, Ph),
IR: 3622, 3425, 3017, 2963, 2881, 1599, 1571, 1481, 1435, 1249,
1080, 1045, 887, 668 cm–1.
1H NMR: d = 7.40 (br s, 1 H, Ph), 7.27 (br s, 3 H, Ph), 5.07 (dd,
J = 9.0, 5.5 Hz, 1 H, H3), 3.88 (m, 1 H, H1), 3.71 (m, 1 H, H1¢), 2.33–
2.17 (m, 2 H, H2, H2¢), 1.32 (t, J = 4.8 Hz, 1 H, OH).
13C NMR: d = 143.5 (Cq, Ph), 134.6 (Cq, Ph), 129.9 (CH, Ph), 128.5
(CH, Ph), 127.3 (CH, Ph), 125.1 (CH, Ph), 59.4 (C1), 59.0 (C3), 42.3
(C2).
128.3 (2 × CH, Ph), 59.5 (C1), 59.1 (C3), 42.3 (C2).
HRMS (EI, 70 eV): m/z calcd for C9H8Cl2 (M+ – H2O): 186.0003;
found: 186.0005.
3-(4-Bromophenyl)-3-chloropropan-1-ol (4d)
Yield: 76.4 mg (79%); white wax; Rf 0.31 (hexanes–EtOAc, 2:1).
IR: 3629, 3437, 3008, 2958, 2883, 1587, 1491, 1402, 1242, 1075,
1004, 834, 809, 668 cm–1.
1H NMR: d = 7.48 (d, J = 8.4 Hz, 2 H, Ph), 7.27 (d, J = 8.4 Hz, 2 H,
Ph), 5.07 (dd, J = 9.1, 5.5 Hz, 1 H, H3), 3.86 (m, 1 H, H1), 3.70 (m,
1 H, H1¢), 2.32–2.14 (m, 2 H, H2 , H2¢), 1.34 (br s, 1 H, OH).
13C NMR: d = 140.6 (Cq, Ph), 131.8 (CH, Ph), 128.6 (CH, Ph), 122.3
(Cq, Ph), 59.4 (C1), 59.1 (C3), 42.3 (C2).
HRMS (EI, 70 eV): m/z calcd for C9H10Cl2O (M+): 204.0109;
found: 204.0111.
3-(3-Bromophenyl)-3-chloropropan-1-ol (4j)
Yield: 57.1 mg (59%); light-yellow oil; Rf 0.33 (hexanes–EtOAc,
2:1).
HRMS (EI, 70 eV): m/z calcd for C9H10BrClO (M+): 247.9604;
found: 247.9597.
IR: 3632, 3460, 3017, 2957, 2886, 1593, 1570, 1476, 1428, 1236,
1075, 884, 835, 669 cm–1.
1H NMR: d = 7.54 (s, 1 H, Ph), 7.42 (d, J = 7.9 Hz, 1 H, Ph), 7.32
(d, J = 7.8 Hz, 1 H, Ph), 7.22 (t, J = 7.8 Hz, 1 H, Ph), 5.05 (dd,
J = 9.0, 5.5 Hz, 1 H, H3), 3.87 (m, 1 H, H1), 3.70 (m, 1 H, H1¢), 2.32–
2.16 (m, 2 H, H2, H2¢), 1.31 (br s, 1 H, OH).
3-Chloro-3-p-tolylpropan-1-ol (4e)
Yield: 51.0 mg (71%); light-green oil; Rf 0.38 (hexanes–EtOAc,
2:1).
13C NMR: d = 143.8 (Cq, Ph), 131.4 (CH, Ph), 130.2 (CH, Ph), 130.1
(CH, Ph), 125.6 (CH, Ph), 122.7 (Cq, Ph), 59.4 (C1), 58.9 (C3), 42.3
(C2).
HRMS (EI, 70 eV): m/z calcd for C9H10BrClO (M+): 247.9604;
found: 247.9610.
IR: 3620, 3450, 3009, 2956, 2881, 1710, 1612, 1511, 1440, 1417,
1380, 1241, 1181, 1049, 899, 869, 817, 669, 626 cm–1.
1H NMR: d = 7.27 (d, J = 8.0 Hz, 2 H, Ph), 7.14 (d, J = 8.0 Hz, 2 H,
Ph), 5.08 (dd, J = 9.0, 5.6 Hz, 1 H, H3), 3.86 (m, 1 H, H1), 3.71 (m,
1 H, H1¢), 2.35 (s, 3 H, CH3), 2.35–2.19 (m, 2 H, H2, H2¢), 1.43 (br s,
1 H, OH).
13C NMR: d = 138.6 (Cq, Ph), 138.0 (Cq, Ph), 129.3 (2 × CH, Ph),
3-Chloro-3-m-tolylpropan-1-ol (4k)
Yield: 45.2 mg (63%); light-yellow oil; Rf 0.36 (hexanes–EtOAc,
2:1).
126.9 (2 × CH, Ph), 60.2 (C3), 59.8 (C1), 42.4 (C2), 21.2 (CH3).
HRMS (EI, 70 eV): m/z calcd for C10H13ClO (M+): 184.0655;
found: 184.0659.
IR: 3626, 3447, 3009, 2962, 2883, 1604, 1485, 1471, 1381, 1259,
1234, 1166, 1040, 878, 850, 667 cm–1.
1H NMR: d = 7.24–7.16 (m, 3 H, Ph), 7.08 (d, J = 7.1 Hz, 1 H, Ph),
5.05 (dd, J = 9.0, 5.6 Hz, 1 H, H3), 3.83 (m, 1 H, H1), 3.70 (m, 1 H,
H1¢), 2.36 (s, 3 H, CH3), 2.34–2.18 (m, 2 H, H2, H2¢), 1.51 (br s, 1 H,
OH).
3-Chloro-3-(4-nitrophenyl)propan-1-ol (4g)
Yield: 4.2 mg (5%); light-yellow oil;Rf 0.20 (hexanes–EtOAc, 2:1).
IR: 3626, 3470, 3027, 2957, 2890, 1736, 1608, 1528, 1350, 1221,
1045, 1015, 850, 667 cm–1.
13C NMR: d = 141.5 (Cq, Ph), 138.2 (Cq, Ph), 129.1 (CH, Ph), 128.5
(CH, Ph), 127.6 (CH, Ph), 124.0 (CH, Ph), 60.2 (C3), 59.8 (C1), 42.4
(C2), 21.4 (CH3).
HRMS (EI, 70 eV): m/z calcd for C10H13ClO (M+): 184.0655;
found: 184.0653.
1H NMR: d = 8.22 (d, J = 8.7 Hz, 2 H, Ph), 7.59 (d, J = 8.7 Hz, 2
H, Ph), 5.20 (dd, J = 9.1, 5.4 Hz, 1 H, H3), 3.91 (m, 1 H, H1), 3.71
(m, 1 H, H1¢), 2.31–2.17 (m, 2 H, H2, H2¢), 1.46 (br s, 1 H, OH).
13C NMR: d = 148.4 (CNO2, Ph), 147.8 (Cq, Ph), 127.9 (2 × CH,
Ph), 123.9 (2 × CH, Ph), 59.0 (C1), 58.2 (C3), 42.2 (C2).
Synthesis 2006, No. 9, 1427–1432 © Thieme Stuttgart · New York

PAPER
One-Pot Synthesis of 3-Chloro-3-arylpropanols
1431
3-Chloro-3-(3-methoxyphenyl)propan-1-ol (4l)
Yield: 28.1 mg (36%); light-yellow oil; Rf 0.26 (hexanes–EtOAc,
2:1).
HRMS (EI, 70 eV): m/z calcd for C9H10BrClO (M+): 247.9604;
found: 247.9601.
3-Chloro-3-o-tolylpropan-1-ol (4p)
Yield: 29.4 mg (41%); light-yellow oil; Rf 0.37 (hexanes–EtOAc,
2:1).
IR: 3621, 3454, 3011, 2964, 2886, 2829, 1597, 1583, 1484, 1459,
1434, 1264, 1157, 1036, 880, 841, 669 cm–1.
1H NMR: d = 7.23 (t, J = 7.9 Hz,1 H, Ph), 6.95 (d, J = 7.7 Hz, 1 H,
Ph), 6.92 (t, J = 2.0 Hz, 1 H, Ph), 6.81 (dd, J = 8.3, 2.5 Hz, 1 H, Ph),
5.05 (dd, J = 8.9, 5.6 Hz, 1 H, H3), 3.84 (m, 1 H, H1), 3.80 (s, 3 H,
OCH3), 3.70 (m, 1 H, H1¢), 2.32–2.19 (m, 2 H, H2, H2¢), 1.46 (br s, 1
H, OH).
13C NMR: d = 159.8 (Cq, Ph), 143.0 (Cq, Ph), 129.6 (CH, Ph), 119.2
(CH, Ph), 113.8 (CH, Ph), 112.7 (CH, Ph), 60.0 (C3), 59.7 (C1), 55.1
(OCH3), 42.4 (C2).
IR: 3626, 3462, 3013, 2956, 2884, 1492, 1461, 1382, 1226, 1051,
669 cm–1.
1H NMR: d = 7.45 (d, J = 8.1 Hz, 1 H, Ph), 7.23–7.12 (m, 3 H, Ph),
5.39 (dd, J = 9.4, 5.0 Hz, 1 H, H3), 3.90 (m, 1 H, H1), 3.75 (m, 1 H,
H1¢), 2.42 (s, 3 H, CH3), 2.39–2.19 (m, 2 H, H2, H2¢), 1.43 (br s, 1 H,
OH).
13C NMR: d = 139.4 (Cq, Ph), 135.2 (Cq, Ph), 130.6 (CH, Ph), 128.1
(CH, Ph), 126.6 (CH, Ph), 126.5 (CH, Ph), 59.8 (C1), 56.2 (C3), 41.3
(C2), 19.1 (CH3).
HRMS (EI, 70 eV): m/z calcd for C10H13ClO2 (M+): 200.0604;
found: 200.0602.
HRMS (EI, 70 eV): m/z calcd for C10H13ClO (M+): 184.0655;
3-Chloro-3-(2-fluorophenyl)propan-1-ol (4m)
found: 184.0652.
Yield: 33.0 mg (45%); orange oil; Rf 0.41 (hexanes–EtOAc, 2:1).
IR: 3626, 3449, 3010, 2956, 2887, 1470, 1437, 1234, 1046, 1027,
875, 824, 669 cm–1.
Acknowledgment
We thank the Scientific and Technical Research Council of Turkey
(TUBITAK, Grant No. TBAG-104T501) and the Middle East
Technical University Research Foundation for financial support.
1H NMR: d = 7.49 (td, J = 8.0, 1.6 Hz, 1 H, Ph), 7.29 (m, 1 H, Ph),
7.15 (td, J = 8.0, 1.0 Hz, 1 H, Ph), 7.04 (d, J = 1.3, 8.0 Hz, 1 H, Ph),
5.43 (dd, J = 9.2, 5.3 Hz, 1 H, H3), 3.87 (m, 1 H, H1), 3.76 (m, 1 H,
H1’), 2.37–2.21 (m, 2 H, H2, H2¢), 1.34 (t, J = 4.9 Hz, 1 H, OH).
13C NMR: d = 159.6 (d, J = 247.4 Hz, CF, Ph), 129.8 (d, J = 8.2 Hz,
CH, Ph), 128.7 (d, J = 12.7 Hz, Cq, Ph), 128.6 (d, J = 3.3 Hz, CH,
Ph), 124.4 (d, J = 3.5 Hz, CH, Ph), 115.7 (d, J = 21.9 Hz, CH, Ph),
59.6 (C1), 52.8 (d, J = 3.8 Hz, C3), 41.3 (C2).
HRMS (EI, 70 eV): m/z calcd for C9H10ClFO (M+): 188.0404;
found: 184.0406.
References
(1) Reviews: (a) Arundale, E.; Mikeska, L. A. Chem. Rev. 1952,
51, 505. (b) Adams, R. D.; Bhatnagar, S. P. Synthesis 1977,
661. (c) Snider, B. B. In Comprehensive Organic Synthesis;
Trost, B. M.; Flemming, I., Eds.; Pergamon: New York,
1991, Vol. 2, 527.
(2) (a) Sauers, R. R.; Sonnet, P. E. J. Org. Chem. 1964, 29, 754.
For the synthesis of similar structures by different methods,
see: (b) Mayr, H.; Pock, R.; Klein, H. Chem. Ber. 1986, 119,
929. (c) Nakazaki, M.; Naemura, K.; Kadowaki, H. J. Org.
Chem. 1976, 23, 3725.
(3) Wu, Y.; Zhang, J. Huaxue Xuebao 1982, 40, 157.
(4) (a) Ferrand, G.; Huet, J. Bull. Soc. Chim. Fr. 1973, 3122.
(b) Ferrand, G.; Huet, J. Bull. Soc. Chim. Fr. 1975, 351.
(c) Ferrand, G.; Huet, J. Bull. Soc. Chim. Fr. 1975, 356.
(d) Ferrand, G.; Huet, J. Bull. Soc. Chim. Fr. 1975, 1709.
(5) Isleyen, A.; Sayrac, T.; Dogan, Z. Naturforsch., B: Chem.
Sci. 2004, 59, 109.
3-Chloro-3-(2-chlorophenyl)propan-1-ol (4n)
Yield: 35.0 mg (44%); light-yellow oil; Rf 0.38 (hexanes–EtOAc,
2:1).
IR: 3615, 3433, 3017, 2955, 2886, 1593, 1572, 1472, 1443, 1246,
1129, 1035, 823, 669 cm–1.
1H NMR: d = 7.59 (dd, J = 8.0, 1.6 Hz, 1 H, Ph), 7.35 (dd, J = 7.9,
1.4 Hz, 1 H, Ph), 7.29 (td, J = 7.5, 1.4 Hz, 1 H, Ph), 7.22 (td, J =
7.7, 1.7 Hz, 1 H, Ph), 5.61 (t, J = 7.1 Hz, 1 H, H3), 3.88 (m, 1 H, H1),
3.78 (m, 1 H, H1¢), 2.25 (q, J = 6.7 Hz, 2 H, H2, H2¢), 1.49 (br s, 1 H,
OH).
13C NMR: d = 139.0 (Cq, Ph), 132.5 (Cq, Ph), 129.6 (CH, Ph), 129.2
(CH, Ph), 128.6 (CH, Ph), 127.3 (CH, Ph), 59.7 (C1), 55.8 (C3), 41.6
(C2).
(6) (a) Stapp, P. R.; Weinberg, D. S. J. Org. Chem. 1969, 34,
3592. (b) Stapp, P. R. J. Org. Chem. 1969, 34, 479.
(7) Yoshida, K.; Horikoshi, Y.; Eta, M.; Chikazawa, M. O.;
Fukuda, Y.; Sato, H. Bioorg. Med. Chem. Lett. 1998, 8,
2967.
HRMS (EI, 70 eV): m/z calcd for C9H10Cl2O (M+): 204.0109;
found: 204.0107.
(8) Structural assignment of compound 2 was based on 1H, 13
C
NMR, COSY (W coupling between H-2endo and H-6), and
HMBC spectra (correlation between C-3 and H-8endo,exo, C-3
and H-2endo, C-9 and H-2endo,exo, and C-2 and H-9).
3-(2-Bromophenyl)-3-chloropropan-1-ol (4o)
Yield: 45.5 mg (47%); light-yellow oil; Rf 0.38 (hexanes–EtOAc,
2:1).
(9) Holmberg, K.; Hansen, B. Tetrahedron Lett. 1975, 16, 2303.
(10) For the synthesis of MDA by different methods, see:
(a) Butlerow, A. Justus Liebigs Ann. Chem. 1858, 107, 111.
(b) Butlerow, A. Justus Liebigs Ann. Chem. 1859, 111, 243.
(c) Descude, M. Bull. Soc. Chim. Fr. 1902, 871.
IR: 3621, 3452, 3016, 2954, 2886, 1614, 1582, 1488, 1452, 1236,
1045, 833, 669 cm–1.
1H NMR: d = 7.62 (dd, J = 8.0, 1.6 Hz, 1 H, Ph), 7.54 (dd, J = 8.0,
1.1 Hz, 1 H, Ph), 7.35 (t, J = 7.3 Hz, 1 H, Ph), 7.15 (td, J = 7.6, 1.6
Hz, 1 H, Ph), 5.58 (dd, J = 8.6, 5.6 Hz, 1 H, H3), 3.89 (m, 1 H, H1),
3.80 (m, 1 H, H1¢), 2.31–2.18 (m, 2 H, H2, H2¢), 1.37 (t, J = 5.4 Hz,
1 H, OH).
13C NMR: d = 140.6 (Cq, Ph), 132.9 (CH, Ph), 129.5 (CH, Ph), 128.8
(CH, Ph), 128.0(CH, Ph), 122.8 (Cq, Ph), 59.7 (C1), 58.5 (C3), 41.8
(C2).
(d) Wegscheider, R. Monatsh. Chem. 1909, 30, 841.
(e) Knoevenagel, E. Justus Liebigs Ann. Chem. 1913, 402,
134. (f) Bryson, T. A. Synth. Commun. 1972, 2, 361.
(g) Bigler, P. Helv. Chim. Acta 1978, 61, 2059.
(h) Sugawara, M.; Baizer, M. M. Tetrahedron Lett. 1983, 24,
2223. (i) Griesbaum, K.; Greunig, H.-J.; Volpp, W.; Jung, I.-
C. Chem. Ber. 1991, 124, 947. (j) Sugawara, M.; Baizer, M.
Synthesis 2006, No. 9, 1427–1432 © Thieme Stuttgart · New York

1432
A. Isleyen, Ö. Dogan
PAPER
(15) (a) Shorygina, N. V. Zh. Obshch. Khim. 1956, 26, 1460.
(b) Cerveny, L.; Marhoul, A.; Ruzicka, V. Chem. Prum.
1980, 30, 127.
(16) (a) Olavi, P.; Virtanen, I.; Manninen, K. Suom. Kemistil. B
1967, 40, 341. (b) Searles, S.; Pollart, K. A.; Block, F. J. Am.
Chem. Soc. 1957, 79, 952.
M.; Monte, W. T.; Little, R. D.; Hess, U. Acta Chem. Scand.,
Ser. B 1983, 37, 509.
(11) Mayo, P.; Orlova, G.; Goddard, J. D.; Tam, W. J. Org.
Chem. 2001, 66, 5182.
(12) Bach, T.; Löbel, J. Synthesis 2002, 2521.
(13) Matsui, M.; Ko, J.; Hepler, K. Can. J. Chem. 1974, 52, 2906.
(14) Substituent constant is taken from: Exner, O. In Correlation
Analysis in Chemistry; Chapman, N. B.; Shorter, J., Eds.;
Plenum Press: New York, 1978.
Synthesis 2006, No. 9, 1427–1432 © Thieme Stuttgart · New York