Lithiation of 2-aryl-2-(chloroaryl)-1,3-dioxolanes and its application in the synthesis of new ortho-functionalized benzophenone derivatives

Article abstract of DOI:10.1002/ejoc.200400335

2-Aryl-2-(chloroaryl)-1,3-dioxolanes 4 were lithiated ortho to the ketal group of the chloroaryl ring by treatment with butyllithium in THF between -78 and 0°C. The site selectivity of some of the deprotonation reactions was rationalized by the long-range effect of the 4-chloro substituent. The lithio species thus generated were treated with various electrophiles to give ortho-functionalized benzophenone derivatives. Intramolecular competition between the aryl rings was observed in the lithiation of 2-(4-chlorophenyl)-2- (4-fluorophenyl)-1,3-dioxolane (4s). Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004.

Full text of DOI:10.1002/ejoc.200400335

FULL PAPER
Lithiation of 2-Aryl-2-(chloroaryl)-1,3-dioxolanes and Its Application in the
Synthesis of New ortho-Functionalized Benzophenone Derivatives
[a]
[a]
[a]
´
´
Gyula Lukacs, Marta Porcs-Makkay, and Gyula Simig*
´
Dedicated to Professor Karoly Lempert on the occasion of his 80th birthday
Keywords: Lithiation / Substituent effects / Benzophenones / 1,3-Dioxolanes
2-Aryl-2-(chloroaryl)-1,3-dioxolanes 4 were lithiated ortho to
the ketal group of the chloroaryl ring by treatment with
butyllithium in THF between −78 and 0 °C. The site selectiv-
ity of some of the deprotonation reactions was rationalized by
the long-range effect of the 4-chloro substituent. The lithio
trophiles to give ortho-functionalized benzophenone derivat-
ives. Intramolecular competition between the aryl rings was
observed in the lithiation of 2-(4-chlorophenyl)-2-(4-fluoro-
phenyl)-1,3-dioxolane (4s).
( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
species thus generated were treated with various elec- Germany, 2004)
Introduction
Results and Discussion
Several pharmaceutically important drugs have benzan-
nellated heterocycle structures that contain a diphenylmeth-
ane moiety, for example, diazepam[1] (and the related anxi-
olytic 1,4-benzodiazepines), tofisopam[2] (and the related
nonsedative anxiolytic 2,3-benzodiazepines), fenoldopam[3]
(antihypertensive dopamine agonist), BM 21.1298[4] (HIV-1
reverse transcriptase inhibitor). The key intermediates in
the synthesis of condensed heterocyclic compounds that
contain the diphenylmethane moiety are the corresponding
ortho-functionalized benzophenones 1. The syntheses of po-
lysubstituted benzophenones 1 described in the literature
are in most cases tedious and lengthy. The substitution pat-
tern of benzophenones 1 accessible by conventional meth-
ods is strongly limited by the regiochemistry of the aromatic
electrophilic substitution (SEAr) reactions used in the con-
struction of the benzophenones and their precursors.
The ortho-directing ability of aromatic acetals and
ketals in lithiation reactions has previously been
demonstrated.[5Ϫ7] Recently, we reported the synthesis of
ortho-functionalized acetophenone derivatives 2 by ortho-
lithiation of the corresponding ethylene ketals and sub-
sequent treatment with various electrophiles[8] (Scheme 1).
These results encouraged us to study the lithiation reactions
of readily available chloro-substituted benzophenone ketals
4 with a view to preparing new ortho-functionalized benzo-
phenone derivatives (6 and 7) suitable for use in the con-
struction of condensed heterocyclic systems.
Benzophenones 3a,[9,10] 3c,[10] 3e,[11] 3g,[12] 3h,[10] 3i,[13]
3j,[14] 3k,[15] 3l,[16] 3m,[17] 3n,[18] 3p,[19] 3q[20] and 3s[13] were
synthesized according to procedures described in the litera-
ture. The new benzophenones 3b, 3d, 3f and 3r were pre-
pared by FriedelϪCrafts acylation reactions. Ethylene ket-
als 4aϪs are new compounds,[21] which were obtained by
conventional methods (Scheme 2, Table 1).[22Ϫ24]
The lithiation of compound 4a with 1.5 equiv. of butyl-
lithium in THF at Ϫ78 °C and subsequent quenching of
the aryllithium compound 5a with electrophiles (carbon di-
oxide and sulfur dioxide, followed by treatment of the iso-
lated aryl sulfinate with sulfuryl chloride in the second
case[25]) gave products 6a and 7a in 83% and 80% yields,
respectively (Table 2). As expected, ortho-lithiation of the
monosubstituted benzene ring cannot compete with the li-
thiation of the disubstituted benzene ring at a site adjacent
to two ortho-directing groups. Although ketal 4b has two
regiochemically distinct sites between a meta-chloro and the
1,3-dioxolan-2-yl group, lithiation with 1.5 equiv. of butyl-
lithium in THF at Ϫ78 °C followed by carboxylation and
chlorosulfonation afforded products 6b (88%) and 7b (68%).
It is remarkable that the presence of a second chloro sub-
stituent in meta position with respect to the metalation site
determines the regiochemistry of the lithiation. In view of
this result, it is not surprising that the directing abilities of
the substituents of the para-disubstituted benzene moiety in
ketals 4cϪe cannot overcome the cooperative effect of the
directing groups present in the other ring as shown by the
high-yielding formation of carboxylic acids 6cϪe and sul-
fonyl chlorides 7cϪe. The regioselectivity observed in the
lithiation of ketal 4f is in agreement with the results of
[a]
Chemical Research Division, EGIS Pharmaceuticals Ltd.,
P. O. Box 100, 1475 Budapest, Hungary
Fax: (internat.) ϩ 36-1-2655613
E-mail: simig.gyula@egis.hu
4130
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DOI: 10.1002/ejoc.200400335
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Lithiation of 2-Aryl-2-(chloroaryl)-1,3-dioxolanes
FULL PAPER
Scheme 1
Schlosser and co-workers,[26,27] which indicates that the en- butyllithium in THF at Ϫ78 °C and subsequent reaction
hancement of acidity provided by the methoxy substituent with the corresponding electrophiles afforded products 6k
in its meta position is insignificant.
(64%) and 7k (54%), which demonstrates that lithiation oc-
Similarly, the lithiation of ketals 4gϪj occurred at the curs at the site ortho to the chloro moiety. The combined
doubly activated site of the meta-chlorophenyl ring as indi- ortho-directing aptitude of the chloro and the 1,3-dioxolan-
cated by the formation of the corresponding derivatives 2-yl substituents is obviously more powerful than that of
6gϪj and 7gϪj, respectively, in good yields. Ketal 4k rep- the methoxy and the 1,3-dioxolan-2-yl substituents, pre-
resents a suitable substrate for the study of the relative di- sumably due to the stronger acidifying effect of the chloro
recting abilities of meta-chloro and meta-methoxy substitu- substituent.[28,29] The lithiation and functionalization se-
ents in cooperation with the 1,3-dioxolan-2-yl group in met- quence of ketals 4lϪm provided products (6lϪm, 7lϪm) as
alation reactions. Lithiation of ketal 4k with 1.5 equiv. of expected by reason of the preceding results.
Eur. J. Org. Chem. 2004, 4130Ϫ4140
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´
Gy. Lukacs, M. Porcs-Makkay, Gy. Simig
FULL PAPER
Scheme 2
We have also studied the lithiation of benzophenone ket- conditions applied. Clearly, in contrast to the methoxy
als with a chloro substituent para to the 1,3-dioxolan-2-yl group, the chloro substituent significantly enhances the
substituent. Lithiation of 4,4Ј-dichlorobenzophenone ketal acidity at its meta position.[26,27] More strikingly, ketals 4q
4n (with 1.5 equiv. of butyllithium in THF at Ϫ10 °C) and and 4r, which have a 3-methoxyphenyl and a 3,4-dimeth-
subsequent functionalization gave products 6n (48%) and oxyphenyl group, respectively, were found to react Ϫ under
7n (76%), respectively, which demonstrates that lithiation identical conditions Ϫ also by the lithiation of the 4-chloro-
occurs ortho to the ketal substituent. A similar regiochemis- phenyl ring. The ‘‘meta-acidifying’’ effect of the chloro sub-
try was observed in our studies on the corresponding 4- stituent combined with the ability of the 1,3-dioxolan-2-yl
chloroacetophenone ketal.[8] Metalation ortho to the ketal group to coordinate the lithium ion Ϫ under the applied
substituent in the 4-chlorophenyl ring was also observed in conditions Ϫ obviously outperforms the cooperative di-
the lithiation reactions of ketal 4o (see products 6o and 7o). recting effect of the meta-methoxy and 1,3-dioxolan-2-yl
This result clearly indicates that the deprotonation site is groups.[26]
determined not only by the ortho-directing aptitude of the
Finally, lithiation of 2-(4-chlorophenyl)-2-(4-fluorophe-
ketal group (a factor present in both phenyl rings of 4o), nyl)-1,3-dioxolane (4s) with butyllithium in THF at Ϫ50 °C
but also by the long-range (meta) electron-withdrawing followed by carboxylation afforded carboxylic acid 8a in
(acidifying) effect of the chloro substituent.[27]
low yield (15%), which indicates that lithiation occurs at the
1
Regioselective lithiation occurred in the reaction of ketals position adjacent to the fluorine atom. H NMR analysis
4pϪr with butyllithium at Ϫ20 °C in THF for 2 h, however, of the product mixture obtained after a similar lithiation
with low conversion. Partial hydrolysis of the ketal group of 4s and chlorosulfonation demonstrated the formation of
was observed in the course of the acidic workup of the car- compounds 7s and 8b in a 1:2 ratio. This result indicates
boxylated reaction mixture when starting from 4p and 4r, that lithiation of 4s occurred at the site ortho to the ketal
and therefore benzophenones 9p and 9r were prepared after substituent (meta to the chloro substituent!) in the 4-chloro-
complete hydrolysis (Scheme 3). Similar lithiation of 4pϪr phenyl ring and at the site adjacent to the fluorine atom in
followed by chlorosulfonylation afforded compounds 7pϪr. a 1:2 ratio. Note that metalation meta to the fluoro sub-
The results obtained from the lithiation reaction of 4p show stituent was not observed. This result demonstrates that the
that the 4-methoxyphenyl ring cannot compete with the 4- chloro substituent exerts a stronger acidifying effect on its
chlorophenyl ring for the lithium reagent under the reaction meta site than does the fluoro substituent.[30,31]
4132
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Lithiation of 2-Aryl-2-(chloroaryl)-1,3-dioxolanes
FULL PAPER
Table 1. Experimental data for 1,3-dioxolanes 4
R1 R2
R3
R4
Yield B.p./m.p.
Empirical
formula
Elemental analysis
1H NMR: δ [ppm]
[%]
[°C]
Calcd.
Found
4a
4b
4c
Cl Cl
Cl Cl
Cl Cl
H
H
Cl
H
Cl
H
94
m.p. 65Ϫ66
C15H12Cl2O2
(295.17)
C 61.04,
H 4.10,
Cl 24.02
C 54.66,
H 3.36,
Cl 32.27
C 54.66,
H 3.36,
Cl 32.27
C 61.00,
H 4.20,
Cl 23.83
C 54.29,
H 3.43,
Cl 31.97
C 54.55,
H 3.39,
Cl 32.01
7.65Ϫ7.63 (m, 1 H), 7.51Ϫ7.25 (m, 7 H), 4.06
(s, 4 H)
(ethanol)[a]
71
92
b.p. 172Ϫ174
C15H11Cl3O2
(329.61)
7.62 (d, J ϭ 1.8 Hz, 1 H), 7.51Ϫ7.49 (m, 1 H),
7.39 (d, J ϭ 8.4 Hz, 1 H), 7.36Ϫ7.25 (m, 3 H),
7.29 (dd, J ϭ 8.4, 1.8 Hz, 1 H), 4.05 (s, 4 H)
7.60 (d, J ϭ 2.0 Hz, 1 H), 7.41 (d, J ϭ 8.8 Hz,
2 H), 7.39 (d, J ϭ 8.4 Hz, 1 H), 7.30 (d, J ϭ
8.8 Hz, 2 H), 7.60 (dd, J ϭ 8.4, 2.0 Hz, 1 H),
4.04 (s, 4 H)
(0.3 Torr)[b]
m.p. 60Ϫ61
C15H11Cl3O2
(329.61)
(ethanol)[a]
4d
4e
Cl Cl
Cl Cl
F
H
H
81
77
85
m.p. 51Ϫ53
C15H11Cl2FO2
(313.16)
C 57.53,
H 3.54,
Cl 22.64
C 57.52,
H 3.54,
Cl 22.44
7.61 (d, J ϭ 2.2 Hz, 1 H), 7.44 (ddm, J ϭ 8.8
Hz, JH,F ϭ 5.5 Hz, 2 H), 7.40 (d, J ϭ 8.4 Hz, 1
4
(ethanol)[a]
H), 7.30 (dd, J ϭ 8.4, 2.2 Hz, 1 H), 7.61 (tm, J
ϭ 8.8 Hz, 2 H), 4.05 (s, 4 H)
7.61 (d, J ϭ 1.8 Hz, 1 H), 7.39 (d, J ϭ 8.4 Hz,
1 H), 7.37 (d, J ϭ 9.2 Hz, 2 H), 7.31 (dd, J ϭ
8.4, 1.8 Hz, 1 H), 6.85 (d, J ϭ 9.2 Hz, 2 H),
4.05 (m, 4 H), 3.79 (s, 3 H)
7.64 (d, J ϭ 2.0 Hz, 1 H), 7.62 (d, J ϭ 8.4 Hz,
1 H), 7.46 (d, J ϭ 2.2 Hz, 1 H), 7.39 (dd, J ϭ
8.4, 2.0 Hz, 1 H), 7.34 (dd, J ϭ 8.6, 2.2 Hz, 1
H), 7.13 (d, J ϭ 8.6 Hz, 1 H), 4.01 (m, 4 H),
3.85 (s, 3 H)
CH3O
m.p. 74Ϫ75
C16H14Cl2O3
(325.19)
C 59.10,
H 4.34,
Cl 21.80
C 58.82,
H 4.36,
Cl 21.64
(ethanol)[a]
4f[c] Cl Cl
CH3O Cl
m.p. 59Ϫ61
C16H13Cl3O3
(359.64)
C 53.44,
H 3.64,
Cl 29.57
C 53.67,
H 3.72,
Cl 29.32
(hexane)[a]
4g
4h
4i
Cl
Cl
Cl
Cl
H
H
H
H
H
H
H
H
H
82
99
99
85
m.p. 40Ϫ41
C15H13ClO2
(260.72)
C 69.10,
H 5.03,
Cl 13.60
C 61.04,
H 4.10,
Cl 24.02
C 64.64,
H 4.34,
Cl 12.72
C 66.10,
H 5.20,
Cl 12.19
C 69.28,
H 5.24,
Cl 13.48
C 61.00,
H 4.09,
Cl 23.91
C 64.65,
H 4.45,
Cl 12.47
C 65.73,
H 5.01,
Cl 12.57
7.57Ϫ7.45 (m, 3 H), 7.42Ϫ7.21 (m, 6 H), 4.06
(s, 4 H)
(hexane)[a]
Cl
m.p. 41Ϫ43
C15H12Cl2O2
(295.17)
7.53Ϫ7.49 (m, 1 H), 7.43 (d, J ϭ 8.9 Hz, 2 H),
7.37Ϫ7.23 (m, 3 H), 7.30 (d, J ϭ 8.9 Hz, 2 H),
4.05 (s, 4 H)
7.56Ϫ7.21 (m, 6 H), 7.00 (tm, J ϭ 8.8 Hz, 2
H), 4.02 (s, 4 H)
(hexane)[a]
F
b.p. 136Ϫ138
C15H12ClFO2
(278.71)
(0.3 Torr)[b]
4j
CH3O
b.p. 174Ϫ176
C16H15ClO3
(290.75)
7.56Ϫ7.49 (m, 1 H), 7.43Ϫ7.31 (m, 1 H), 7.39
(d, J ϭ 8.9 Hz, 2 H), 7.25Ϫ7.22 (m, 2 H), 6.85
(d, J ϭ 8.9 Hz, 2 H), 4.03 (m, 4 H), 3.77 (s, 3
H)
(0.4 Torr)[b]
4k
Cl
H
H
H
CH3O 92
b.p. 157Ϫ158
C16H15ClO3
(290.75)
C 66.10,
H 5.20,
Cl 12.19
C 65.87,
H 5.33,
Cl 11.95
7.54 (m, 1 H), 7.39Ϫ7.36 (m, 1 H), 7.26Ϫ7.20
(m, 3 H), 7.09Ϫ7.04 (m, 2 H), 6.81 (ddd, J ϭ
8.3, 2.6, 0.7 Hz, 1 H), 4.03 (s, 4 H), 3.77 (s, 3
H)
7.54 (d, J ϭ 2.2 Hz, 1 H), 7.52Ϫ7.42 (m, 2 H),
7.36Ϫ7.22 (m, 4 H), 6.81 (d, J ϭ 8.6 Hz, 1 H),
3.99 (s, 4 H), 3.80 (s, 3 H)
7.51 (d, J ϭ 2.2 Hz, 1 H), 7.43 (d, J ϭ 8.8 Hz,
2 H), 7.33Ϫ7.25 (m, 3 H), 6.86 (d, J ϭ 8.8 Hz,
1 H), 4.04 (m, 4 H), 3.81 (s, 3 H)
7.42 (d, J ϭ 8.9 Hz, 4 H), 7.29 (d, J ϭ 8.9 Hz,
4 H), 4.04 (s, 4 H)
(0.4 Torr)[b]
4l
Cl CH3O
H
H
H
H
H
93
89
87
99
95
b.p. 177Ϫ179
C16H15ClO3
(290.75)
C 66.10,
H 5.20,
Cl 12.19
C 59.10,
H 4.34,
Cl 21.80
C 61.04,
H 4.10,
Cl 24.02
C 69.10,
H 5.03,
Cl 13.60
C 66.10,
H 5.20,
Cl 12.19
C 66.10,
H 5.20,
Cl 12.19
C 65.98,
H 5.13,
Cl 12.14
C 59.36,
H 4.38,
Cl 21.83
C 60.67,
H 4.30,
Cl 23.81
C 69.41,
H 5.04,
Cl 13.58
C 65.78,
H 5.18,
Cl 12.15
C 66.42,
H 5.01,
Cl 12.35
(0.3 Torr)[b]
4m
4n
4o
4p
4q
Cl CH3O Cl
m.p. 89Ϫ90
C16H14Cl2O3
(325.19)
(ethanol)[a]
H
H
H
H
Cl
Cl
Cl
Cl
Cl
m.p. 78Ϫ79
C15H12Cl2O2
(2-propanol)[a] (295.17)
H
m.p. 35Ϫ37
C15H13ClO2
(260.72)
7.44 (d, J ϭ 8.9 Hz, 2 H), 7.54Ϫ7.39 (m, 2 H),
7.32Ϫ7.22 (m, 3 H), 7.26 (d, J ϭ 8.9 Hz, 2 H),
3.97 (s, 4 H)
7.43 (d, J ϭ 8.9 Hz, 2 H), 7.38 (d, J ϭ 8.9 Hz,
2 H), 7.28 (d, J ϭ 8.9 Hz, 2 H), 6.84 (d, J ϭ
8.9 Hz, 2 H), 4.03 (m, 4 H), 3.77 (s, 3 H)
7.45 (d, J ϭ 8.8 Hz, 2 H), 7.28 (d, J ϭ 8.8 Hz,
2 H), 7.24 (t, J ϭ 8.1 Hz, 1 H), 7.10Ϫ7.02 (m,
86Ϫ6.80 (ddd, J ϭ 8.1, 2.6, 1.1 Hz, 1 H), 4.05
(s, 4 H), 3.79 (s, 3 H)
(hexane)[a]
CH3O
H
m.p. 37Ϫ38
C16H15ClO3
(290.75)
(methanol)[a]
CH3O 93
m.p. 65Ϫ67
C16H15ClO3
(290.75)
(hexane)[a]
4r
H
H
Cl
Cl
CH3O CH3O 82
m.p. 74Ϫ76
C17H17ClO4
(320.78)
C 63.65,
H 5.34,
Cl 11.05
C 63.39,
H 5.31,
Cl 11.06
7.44 (d, J ϭ 8.8 Hz, 2 H), 7.30 (d, J ϭ 8.8 Hz,
2 H), 7.03 (t, J ϭ 1.8 Hz, 1 H), 7.00 (dd, J ϭ
8.1, 1.8 Hz, 1 H), 6.81 (d, J ϭ 8.1 Hz, 1 H),
4.22Ϫ3.98 (m, 4 H), 3.85 (s, 6H)
7.45 (ddm, J ϭ 9.0, JH,F ϭ 5.5 Hz, 2 H), 7.43
(d, J ϭ 8.8 Hz, 2 H), 7.29 (d, J ϭ 8.8 Hz,
(ethanol)[a]
4
4s
F
H
96
m.p. 53Ϫ54
C15H12ClFO2
(278.71)
C 64.64,
H 4.34,
Cl 12.72
C 64.08,
H 4.43,
Cl 12.64
(ethanol)[a]
2 H), 7.00 (tm, J ϭ 9.0 Hz, 2 H), 4.04 (s, 4 H)
[a]
[b]
Colourless crystals. Colourless oil. [c] 1H NMR spectrum was measured in [D6]DMSO.
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4133

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Gy. Lukacs, M. Porcs-Makkay, Gy. Simig
FULL PAPER
Table 2. Experimental data for compounds 6 and 7 synthesized according to Scheme 2
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Lithiation of 2-Aryl-2-(chloroaryl)-1,3-dioxolanes
FULL PAPER
Table 2. (continued)
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Gy. Lukacs, M. Porcs-Makkay, Gy. Simig
FULL PAPER
Table 2. (continued)
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Lithiation of 2-Aryl-2-(chloroaryl)-1,3-dioxolanes
FULL PAPER
Table 2. (continued)
[a]
[b]
59% of the starting compound was recovered. 52% of the starting compound was recovered.
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Gy. Lukacs, M. Porcs-Makkay, Gy. Simig
FULL PAPER
Scheme 3
1H NMR spectra provided the chemical shift, multiplicity
and integration data for the assignment of the structures.
The structure of 6o was proved by its transformation to
phthalide 10 via the benzophenone derivative 9o
(Scheme 3).
calcd. C 54.68, H 2.47, Cl 37.25; found C 54.80, H 2.37, Cl 37.41.
3,4-Dichloro-4Ј-fluorobenzophenone (3d): This compound was pre-
pared analogously to 3b starting from 1,2-dichlorobenzene
(12.6 mL, 16.5 g, 0.112 mol), 4-fluorobenzoyl chloride (11.8 mL,
15.9 g, 0.1 mol) and anhydrous aluminium chloride (14.7 g, 0.11
mol) to give the title compound (17.3 g, 64%), m.p. 92Ϫ93 °C (2-
1
propanol). H NMR (500 MHz, 25 °C): δ ϭ 7.86 (d, J ϭ 1.8 Hz,
4
1 H), 7.82 (ddm, J ϭ 8.8, JH,F ϭ 5.4 Hz, 2 H), 7.60 (dd, J ϭ 8.3,
Conclusions
J ϭ 1.8 Hz, 1 H), 7.58 (d, J ϭ 8.3 Hz, 1 H), 7.19 (tm, J ϭ 8.6 Hz,
2 H) ppm. IR (KBr): ν˜ ϭ 1646 cmϪ1 (CϭO). C13H7Cl2FO (269.10):
calcd. C 58.02, H 2.62, Cl 26.35; found C 57.95, H 2.60, Cl 26.44.
The ortho-lithiation methodology described in this paper
is an efficient route to highly substituted ortho-func-
tionalized benzophenone ketals, which may be used in the
construction of condensed heterocycles by ortho cyclization.
The intramolecular competition of phenyl rings with differ-
ent substitution patterns makes benzophenone ketals inter-
esting substrates for the study of ortho-directing ability and
the long-range effects of various substituents in lithiation
reactions.
3,3Ј,4-Trichloro-4Ј-methoxybenzophenone (3f): 2-Chloroanisole
(14.0 mL, 15.7 g, 0.11 mol) was added dropwise to a mixture of
anhydrous aluminium chloride (14.6 g, 0.11 mol) and dichloro-
methane (30 mL) maintaining the temperature below 20 °C. After
stirring for 5 min, 3,4-dichlorobenzoyl chloride (21.0 g, 0.1 mol)
was added maintaining the temperature below 20 °C. After stirring
for an additional 30 min, the reaction mixture was poured onto
crushed ice (140 g). The organic layer was separated, dried and the
solvents were evaporated. The crude solid was recrystallized from
acetone (150 mL) to give the title compound (24.2 g, 77%), m.p.
145Ϫ146 °C. 1H NMR (200 MHz, [D6]DMSO, 25 °C): δ ϭ 7.90
(d, J ϭ 2.1 Hz, 1 H), 7.84 (d, J ϭ 8.2 Hz, 1 H), 7.83 (d, J ϭ 2.1 Hz,
1 H), 7.75 (dd, J ϭ 8.5, J ϭ 2.1 Hz, 1 H), 7.66 (dd, J ϭ 8.2, J ϭ
2.1 Hz, 1 H), 3.98 (s, 3 H) ppm. IR (KBr): ν˜ ϭ 1655 cmϪ1 (CϭO).
C14H9Cl3O2 (315.59): calcd. C 53.28, H 2.87, Cl 33.70; found C
53.52, H 2.75, Cl 33.53.
Experimental Section
General Remarks: All melting points were determined with a Büchi
535 capillary melting point apparatus and are uncorrected. IR spec-
tra were obtained with a Bruker IFS-113v FT spectrometer in KBr
pellets. 1H NMR spectra were recorded in CDCl3 (unless stated
otherwise) with a Varian Gemini-200 or Inova-500 spectrometer
using TMS as the internal standard. Chemical shifts (δ) and coup-
ling constants (J) are given in ppm and in Hz, respectively. Elemen-
tal analyses were performed with a PerkinϪElmer 2400 analyzer.
4Ј-Chloro-3,4-dimethoxybenzophenone (3r): This compound was
prepared analogously to 3f starting from 1,2-dimethoxybenzene
(14.0 mL, 15.2 g, 0.11 mol), 4-chlorobenzoyl chloride (12.7 mL,
17.5 g, 0.1 mol) and anhydrous aluminium chloride (20.0 g, 0.15
mol) to give the title compound (14.6 g, 53%), m.p. 111Ϫ112 °C
3,3Ј,4-Trichlorobenzophenone (3b): A mixture of 1,2-dichloroben-
zene (14.8 mL, 19.4 g, 0.132 mol), 3-chlorobenzoyl chloride
(16.9 mL, 23.1 g, 0.132 mol) and anhydrous aluminium chloride
(17.7 g, 0.132 mol) was stirred at 120 °C for 3 h. The reaction mix-
ture was poured onto crushed ice (300 g), the solid product was
filtered, washed with water and recrystallized from 2-propanol
(220 mL) to give the title compound (20.8 g, 55%), m.p. 119Ϫ120
°C. 1H NMR (500 MHz, 25 °C): δ ϭ 7.88 (d, J ϭ 1.9 Hz, 1 H),
1
(ethanol). H NMR (200 MHz, 25 °C): δ ϭ 7.71 (d, J ϭ 8.5 Hz, 2
H), 7.46 (d, J ϭ 1.8 Hz, 1 H), 7.45 (d, J ϭ 8.5 Hz, 2 H), 7.34 (dd,
J ϭ 8.2, J ϭ 1.8 Hz, 1 H), 6.90 (d, J ϭ 8.2 Hz, 1 H), 3.97 (s, 3 H),
3.95 (s, 3 H) ppm. IR (KBr): ν˜ ϭ 1644 cmϪ1 (CϭO). C15H13ClO3
(276.73): calcd. C 65.11, H 4.74, Cl 12.81; found C 65.10, H 4.77,
Cl 12.64.
7.75 (t, J ϭ 1.7 Hz, 1 H), 7.64Ϫ7.58 (m, 2 H), 7.61 (dd, J ϭ 8.3, Synthesis of 1,3-Dioxolanes 4. General Procedure: A solution of
J ϭ 1.9 Hz, 1 H), 7.58 (d, J ϭ 8.3 Hz, 1 H), 7.45 (t, J ϭ 7.9 Hz, 1 benzophenone (1.0 mol), ethylene glycol (200 mL, 222.6 g, 3.6 mol)
H) ppm. IR (KBr): ν˜ ϭ 1658 cmϪ1 (CϭO). C13H7Cl3O (285.56): and p-toluenesulfonic acid (2.0 g, 0.01 mol) in toluene (600 mL)
4138
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Eur. J. Org. Chem. 2004, 4130Ϫ4140

Lithiation of 2-Aryl-2-(chloroaryl)-1,3-dioxolanes
FULL PAPER
was refluxed in a DeanϪStark apparatus for 40 h. The reaction J ϭ 2.2 Hz, 1 H), 7.43 (d, J ϭ 8.6 Hz, 2 H), 7.34 (d, J ϭ 8.6 Hz,
mixture was washed with aqueous sodium hydrogen carbonate 2 H), 7.27 (t, J ϭ 9.1 Hz, 1 H), 4.15Ϫ4.04 (m, 4 H) ppm. IR (film):
solution (5%, 200 mL) and water (2 ϫ 200 mL), dried (MgSO4) ν˜ ϭ 1377, 1182 cmϪ1 (SϭO). C15H11Cl2FO4S (377.22): calcd. C
and the solvents were evaporated. The residue was recrystallized or
distilled in vacuo. For yields, boiling or melting points, solvents of
recrystallization, elemental analyses and 1H NMR spectroscopic
data of the ketals see Table 1.
47.76, H 2.94, Cl 18.80, S 8.50; found C 47.87, H 3.05, Cl 19.01,
S 8.40.
2-Benzoyl-5-chlorobenzoic Acid (9o): A suspension of 5-chloro-2-(2-
phenyl-1,3-dioxolan-2-yl)benzoic acid (6o) (3.05 g, 0.01 mol) in an
aqueous solution of hydrochloric acid (10%, 25 mL) was refluxed
for 4 h. The crystalline product was filtered to give 9o (2.22 g, 85%)
as colourless crystals, m.p. 174Ϫ175 °C (ethanol) (ref.[32] 172Ϫ174
°C). 1H NMR (200 MHz, 25 °C): δ ϭ 9.11 (br. s, 1 H), 8.03 (d,
J ϭ 1.8 Hz, 1 H), 7.63 (dd, J ϭ 8.3, J ϭ 1.8 Hz, 1 H), 7.32 (d, J ϭ
8.3 Hz, 1 H), 7.75Ϫ7.48 (m, 4 H), 7.48Ϫ7.37 (m, 1 H) ppm. IR
(KBr): ν˜ ϭ 1782, 1678 cmϪ1 (CϭO). C14H9ClO3 (260.66): calcd. C
64.50, H 3.48, Cl 13.60; found C 64.39, H 3.47, Cl 13.52.
Lithiation of 1,3-Dioxolanes 4. General Procedure: Butyllithium
(6 mL of a 2.5  solution in hexane, 0.015 mol) was added to a
solution of 4 (0.010 mol) in THF (10 mL) under argon and the
mixture was stirred for 2 h (for the temperature of lithiation see
Table 2). The resulting suspension of 5 was treated with the appro-
priate electrophile to give compounds 6, 7 and 8, respectively.
Carboxylation of Lithio Derivatives 5. General Procedure: A suspen-
sion of the lithio derivative 5, prepared as described above, was
poured onto a large excess of dry ice (200 g). After 3 h, water
(30 mL) was added and the layers were separated. The aqueous
layer was extracted with diethyl ether (30 mL). An aqueous solu-
tion of hydrochloric acid (10%, 20 mL) was added to the aqueous
layer. The crystalline product was filtered to give 6 as colourless
crystals. For the yields, melting points, solvents of recrystallization,
elemental analyses, IR and 1H NMR spectroscopic data see
Table 2.
3-Chloro-6-(4-methoxybenzoyl)benzoic Acid (9p): This compound
was prepared analogously to 9o starting from the crude product
obtained after the lithiation and carboxylation of 4p (see general
procedures) to give 9p (1.21 g, 36% based on 4p) as colourless crys-
1
tals, m.p. 177Ϫ178 °C (acetonitrile). H NMR (200 MHz, 25 °C):
δ ϭ 8.05 (d, J ϭ 2.2 Hz, 1 H), 7.69 (d, J ϭ 8.9 Hz, 2 H), 7.62 (dd,
J ϭ 8.1, J ϭ 2.2 Hz, 1 H), 7.31 (d, J ϭ 8.1 Hz, 1 H), 6.90 (d, J ϭ
8.9 Hz, 2 H), 3.87 (s, 3 H) ppm. IR (KBr): ν˜ ϭ 1696, 1668 cmϪ1
(CϭO). C15H11ClO4 (290.69): calcd. C 61.98, H 3.81, Cl 12.20;
found C 61.74, H 3.99, Cl 12.10.
Chlorosulfonation of Lithio Derivatives 5. General Procedure: A sus-
pension of the lithio derivative 5, prepared as described above, was
added to a stirred solution of sulfur dioxide (3.2 g, 0.05 mol) in
THF (10 mL). The mixture was stirred at ambient temperature for
12 h and the solid product (lithium sulfinate) was filtered. Sulfuryl
chloride (1.6 mL, 2.7 g, 0.02 mol) in hexane (5 mL) was added to
the suspension of the solid in hexane (30 mL) at 0 °C. After stirring
at 0 °C for 30 min, the solvent was evaporated, water (50 mL) was
added to the residue and the mixture was stirred for 30 min. The
crystalline product was filtered to give 7 as colourless crystals. For
the yields, melting points, solvents of recrystallization, elemental
3-Chloro-6-(3,4-dimethoxybenzoyl)benzoic Acid (9r): This com-
pound was prepared analogously to 9o starting from the crude
product obtained after lithiation and carboxylation of 4r (see gen-
eral procedures) to give 9r (1.35 g, 42%, based on 4r) as colourless
1
crystals, m.p. 241Ϫ242 °C (ethanol). H NMR (200 MHz, 25 °C):
δ ϭ 8.07 (d, J ϭ 2.2 Hz, 1 H), 7.62 (dd, J ϭ 8.0, J ϭ 2.2 Hz, 1 H),
7.55 (d, J ϭ 2.2 Hz, 1 H), 7.34 (d, J ϭ 8.0 Hz, 1 H), 7.07 (dd, J ϭ
8.4, J ϭ 2.2 Hz, 1 H), 6.80 (d, J ϭ 8.4 Hz, 1 H), 3.94 (s, 3 H), 3.93
(s, 3 H) ppm. IR (KBr): ν˜ ϭ 1723, 1638 cmϪ1 (CϭO). C16H13ClO5
(320.72): calcd. C 59.92, H 4.08, Cl 11.05; found C 59.69, H 4.18,
Cl 10.95.
1
analyses, IR and H NMR spectroscopic data see Table 2.
5-[2-(4-Chlorophenyl)-1,3-dioxolan-2-yl]-2-fluorobenzoic Acid (8a):
The crude product mixture, obtained after lithiation and car-
boxylation of ketal 4s according to the general procedure, was
recrystallized from EtOAc/hexane (1:3) to give 8a (0.48 g, 15%) as
colourless crystals, m.p. 159Ϫ160 °C (EtOAc/hexane, 1:3). 1H
6-Chloro-3-phenylbenzo[c]furan-1(3H)-one (10): Sodium borohyd-
ride (0.59 g, 0.0155 mol) was added to a solution of 2-benzoyl-5-
chlorobenzoic acid (9o) (0.81 g, 0.0031 mol) in ethanol (7 mL) at
ambient temperature. After stirring for 24 h, the solvent was evapo-
rated. Water (10 mL) and aqueous hydrochloric acid (10%, 10 mL)
were added to the residue. The crystalline product was collected to
give 10 (0.63 g, 63%) as colourless crystals, m.p. 95Ϫ96 °C (etha-
4
NMR (500 MHz, 25 °C): δ ϭ 8.17 (dd, JH,F ϭ 7.0, J ϭ 2.4 Hz, 1
H), 7.67 (ddd, J ϭ 8.6, 4JH,F ϭ 4.5, J ϭ 2.4 Hz, 1 H), 7.44 (d, J ϭ
8.7 Hz, 2 H), 7.32 (d, J ϭ 8.7 Hz, 2 H), 7.13 (dd, 3JH,F ϭ 10.4, J ϭ
8.6 Hz, 1 H), 4.11Ϫ3.96 (m, 4 H) ppm. IR (KBr): ν˜ ϭ 1686 cmϪ1
(CϭO). C16H12ClFO4 (322.72): calcd. C 59.55, H 3.75, Cl 10.99;
found C 59.99, H 3.88, Cl 10.60.
1
nol) (ref.[33] 88 °C). H NMR (200 MHz, 25 °C): δ ϭ 7.92 (d, J ϭ
2.0 Hz, 1 H), 7.61 (dd, J ϭ 8.2, J ϭ 2.0 Hz, 1 H), 7.44Ϫ7.34 (m, 3
H), 7.32Ϫ7.20 (m, 3 H), 6.39 (s, 1 H) ppm. IR (KBr): ν˜ ϭ 1746
cmϪ1 (CϭO). C14H9ClO2 (244.68): calcd. C 68.72, H 3.71, Cl 14.49;
found C 68.38, H 3.58, Cl 14.64.
5-[2-(4-Chlorophenyl)-1,3-dioxolan-2-yl]-2-fluorobenzenesulfonyl
Chloride (8b): Ketal 4s was lithiated and chlorosulfonated accord-
ing to the general procedure. A 1:2 mixture of sulfonyl chlorides 7s
1
and 8b was formed, as determined by H NMR measurements on
Acknowledgments
The authors are grateful to Dr. Rita Kapiller-Dezsöfi for NMR
the basis of the intensity ratio of the signals corresponding to the
aromatic proton between the chlorine and chlorosulfonyl substitu-
ent in 7s (δ ϭ 8.29 ppm) and between the ketal group and the
chlorosulfonyl substituent in 8b (δ ϭ 8.15 ppm). The crude product
mixture was recrystallized from methanol to give 7s (0.38 g, 10%);
for data see Table 2. The mother liquor was concentrated, and the
residue was triturated with a mixture of hexane (10 mL) and EtOAc
(1 mL). The resulting solution was decanted and the solvents eva-
porated to give 8b (0.3 g, 8%) as an oil, contaminated with 7s (5%,
as determined by 1H NMR). 1H NMR (500 MHz, 25 °C): δ ϭ 8.15
(dd, 4JH,F ϭ 6.6, J ϭ 2.2 Hz, 1 H), 7.80 (ddd, J ϭ 8.7, 4JH,F ϭ 4.5,
measurements and helpful discussions. We would also like to thank
´
´
Mrs. Angela Veress-Pandur and Miss Maria Vajjon for technical
assistance.
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Early View Article
Published Online September 2, 2004
4140
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Eur. J. Org. Chem. 2004, 4130Ϫ4140