Lithiation of 2-(chloroaryl)-2-methyl-1,3-dioxolanes and application in synthesis of new ortho-functionalized acetophenone derivatives

Article abstract of DOI:10.1016/S0040-4039(03)00391-5

2-(4-Chlorophenyl)-2-methyl-1,3-dioxolane 2a was lithiated ortho to the ketal group by treatment with butyllithium in THF at 0°C. Related 2-aryl-2-methyl-1,3-dioxolanes possessing a chlorine substituent at the meta position of the aryl group 2b,c were lithiated with butyllithium in THF at -78°C at the position between the two directing groups. The lithio species thus generated were treated with various electrophiles to give ortho-functionalized acetophenone derivatives.

Full text of DOI:10.1016/S0040-4039(03)00391-5

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 3211–3214
Lithiation of 2-(chloroaryl)-2-methyl-1,3-dioxolanes and
application in synthesis of new ortho-functionalized acetophenone
derivatives
Gyula Luka´cs, Ma´rta Porcs-Makkay and Gyula Simig*
Chemical Research Division, EGIS Pharmaceuticals Ltd, PO Box 100, H-1475 Budapest, Hungary
Received 17 December 2002; revised 30 January 2003; accepted 7 February 2003
Abstract—2-(4-Chlorophenyl)-2-methyl-1,3-dioxolane 2a was lithiated ortho to the ketal group by treatment with butyllithium in
THF at 0°C. Related 2-aryl-2-methyl-1,3-dioxolanes possessing a chlorine substituent at the meta position of the aryl group 2b,c
were lithiated with butyllithium in THF at −78°C at the position between the two directing groups. The lithio species thus
generated were treated with various electrophiles to give ortho-functionalized acetophenone derivatives. © 2003 Elsevier Science
Ltd. All rights reserved.
Cyclization of ortho disubstituted benzene derivatives is
an important strategy for the synthesis of benzanellated
heterocyclic compounds. A widely used route of form-
ing ortho disubstituted ring closure precursors involves
a sequence of ortho lithiation assisted by one of the
functional groups and then addition of an electrophile
to generate the required second functionality.1–4 As a
part of our work in medicinal chemistry we became
interested in an approach to chloro substituted hetero-
cycles that would rely on ortho-functionalized ace-
tophenone
precursors
(exemplified
by
the
corresponding ethylene ketals 4, Scheme 1).
Ethylene ketals 2 were prepared starting from known
acetophenones 15,6 by conventional methods.7 For
yields, bp’s and H NMR data of ketals 2 see Table 1.
The ortho directing ability of aromatic acetals and
ketals in lithiation reactions has been demonstrated.8–13
Since chlorine is also known to promote ortho lithia-
tion,14–21 the result of lithiation of para disubstituted
1
Scheme 1. Reaction conditions: (a) Ethylene glycol, PTSA/toluene; (b) butyllithium/THF; (c) electrophilic reagent.
Keywords: ortho lithiation; ortho directing group; butyllithium; 1,3-dioxolane derivatives; aryllithium derivatives.
* Corresponding author. Tel.: +36-1-2655543; fax: +36-1-2655613; e-mail: chemistry.rd@egis.hu
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)00391-5

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G. Luka´cs et al. / Tetrahedron Letters 44 (2003) 3211–3214
Table 1.
R1 R2
E
–
Yield (%)
bp or mp (°C)
Molecular
formula
1H NMR (CDCl3)
2a
H
H
H
91
91
bp: 72–74 (0.3 mmHg)a,b
bp: 112–114 (0.4 mmHg)b
C10H11ClO2
(198.65)
7.42 (2H, d, J=8.4 Hz), 7.28 (2H, d, J=8.4
Hz), 4.09–3.92 (2H, m), 3.81–3.65 (2H, m),
1.62 (3H, s).
7.59 (1H, d, J=1.8 Hz), 7.41 (1H, d, J=8.4
Hz), 7.32 (1H, dd, J=8.4 Hz, J=1.8 Hz),
4.08–4.01 (2H, m), 3.80–3.73 (2H, m), 1.63
(3H, s).
7.62 (1H, s), 7.22 (1H, s), 4.07–4.00 (2H, m),
3.76–3.69 (2H, m), 2.43 (3H, s), 1.64 (3H, s).
7.47 (1H, d, J=8.1 Hz), 7.12–7.07 (2H, m),
4.04–3.97 (2H, m), 3.72–3.66 (2H, m), 2.46
(3H, s), 1.64 (3H, s).
8.90 (1H, bs), 7.55 (1H, d, J=8.4 Hz), 7.54
(1H, d, J=2.5 Hz), 7.42 (1H, dd, J=8.4 Hz,
J=2.5 Hz), 4.10–4.03 (2H, m), 3.75–3.68 (2H,
m), 1.84 (3H, s).
8.24 (1H, d, J=2.2 Hz), 7.86 (1H, d, J=8.4
Hz), 7.66 (1H, dd, J=8.4 Hz, J=2.2 Hz),
4.16–4.09 (2H, m), 3.82–3.75 (2H, m), 1.88
(3H, s).
7.45 (1H, d, J=8.5 Hz), 7.26 (1H, d, J=8.5
Hz), 4.05–4.01 (2H, m), 3.74–3.71 (2H, m),
2.58 (3H, s), 1.67 (3H, s).
8.70 (1H, bs), 7.51 (1H, d, J=8.4 Hz), 7.43
(1H, d, J=8.4 Hz), 4.09–4.02 (2H, m),
3.80–3.73 (2H, m), 1.74 (3H, s).
7.80 (1H, d, J=8.4 Hz), 7.73 (1H, d, J=8.4
Hz), 4.10–4.03 (2H, m), 3.65–3.57 (2H, m),
1.99 (3H, s).
2b Cl
–
C10H10Cl2O2
(233.09)
2c Cl
CH3
H
–
86
95
bp: 124–126 (0.5 mmHg)b
bp: 78–80 (0.2 mmHg)b
C11H12Cl2O2
(247.12)
C11H13ClO2
(212.67)
4a
4b
H
H
CH3
H
H
COOH 91
mp: 129–130 (ethyl
acetate/hexane 1:1)c
C
11H11ClO4
(242.66)
4c
H
SO2Cl
CH3
67
69
mp: 117–118 (2-propanol)c
bp: 108–110 (0.2 mmHg)b
C
10H10Cl2O4S
(297.16)
4d Cl
4e Cl
4f Cl
H
H
H
C11H12Cl2O2
(247.12)
COOH 91
mp: 153–154 (ethyl
acetate/hexane 1:1)c
C
11H10Cl2O4
(277.10)
SO2Cl
87
71
mp: 99–100 (ethanol)c
C10H9Cl3O4S
(331.61)
4g Cl
4h Cl
4i Cl
CH3 CH3
bp: 136–138 (0.3 mmHg)b
C12H14Cl2O2
(261.14)
C12H12Cl2O4
(291.13)
C11H11Cl3O4S
(345.64)
7.09 (1H, s), 3.99–3.92 (2H, m), 3.58–3.52 (2H,
m), 2.57 (3H, s), 2.43 (3H, s), 1.72 (3H, s).
9.30 (1H, bs), 7.33 (1H, s), 4.03–3.98 (2H, m),
3.79–3.75 (2H, m), 2.49 (3H, s), 1.77 (3H, s).
7.52 (1H, s), 4.10–4.00 (1H, bs), 4.00–3.90 (1H,
bs), 3.80–3.60 (1H, bs), 3.40–3.20 (1H, bs),
2.56 (3H, s), 2.07 (3H, s).
CH3 COOH 72
CH3 SO2Cl 65
mp: 171–172 (ethyl
acetate/hexane 1:1)c
mp: 97–98 (2-propanol)c
a Lit.:30 mp 34°C; lit.:31 described 2a as an oil.
b Compounds 2a–c, 4a, 4d and 4g are colourless oils.
c Compounds 4b, 4c, 4e, 4f, 4h and 4i are colourless crystals.
compound 2a will depend on the relative directing
abilities of the two substituents which are generally
considered as poor ortho directing metallation groups.
In the case of ketal 2b lithiation at the common ortho
site is expected as a result of the cooperative effects of
the 1,3-interrelated chlorine and 2-methyl-1,3-diox-
olane-2-yl groups. Ortho and lateral metallation may
occur in the lithiation reaction of toluene derivative 2c.
Lithiation of para disubstituted derivative 2a with 1.6
equiv. of butyllithium in THF at 0°C followed by
quenching the aryllithium 3a with methyl iodide and
carbon dioxide gave products 4a and 4b, respectively, in
good yields. Lithiation conducted at 0°C is expected to
occur at the position ortho to the ketal substituent since
ortho-lithiochlorobenzenes are not stable at this tem-
perature. Nevertheless, the structure of 4b was proved
by its transformation to phthalide 625,26 via derivative
527,28 (Scheme 2). Sulfonyl chloride 4c was obtained by
trapping aryllithium 3a with sulfur dioxide and treating
the isolated lithium arylsulfinate with sulfuryl
chloride.29
Previous reports described that lithiations ortho to both
chlorine and 1,3-dioxolane groups were accompanied
with important side reactions. Benzynes are generated
from ortho-lithiochlorobenzenes when the temperature
of the reaction mixture exceeds about −60°C.14,22,23
Ketal ring cleavage of 2-aryl-1,3-dioxolanes in lithiation
reactions has also been described.10,24 In order to avoid
side reactions, the reaction conditions of metallations
involving these directing groups have to be strictly
controlled.
Lithiation of compounds 2b and 2c with 1.6 equiv of
butyllithium in THF at −78°C and subsequent reaction
with various electrophiles afforded products demon-
strating lithiation at the common site of the ortho
directing groups (3b,c). Trapping with methyl iodide

G. Luka´cs et al. / Tetrahedron Letters 44 (2003) 3211–3214
3213
Scheme 2. Reaction conditions: (a) Aq. HCl (10%); (b) 1. NaBH4, MeOH, 2. aq. HCl (10%).
Chlorosulfonation of lithio derivatives 3
and carbon dioxide gave the expected products 4d,g
and 4e,h, respectively. Sulfonyl chlorides 4f and 4i were
obtained by the sequence described above for 4c. For
At 0°C (3a) or at −78°C (3b,c), to a stirred solution of
sulfur dioxide (30 g, 0.47 mol) in THF (1000 mL) was
added a suspension of the lithio derivative 3 prepared
as described above. The mixture was stirred at ambient
temperature for 12 h and the solid product (lithium
sulfinate) was filtered. To the suspension of the solid in
hexane (1000 mL) was added sulfuryl chloride (24.3
mL, 4.5 g, 0.3 mol) in hexane (50 mL) at 0°C. After
stirring for 30 min at 0°C, the solvent was evaporated,
water (200 mL) was added to the residue and the
mixture was stirred for 30 min. The crystalline product
was filtered to give 4c, 4f, and 4i as colourless crystals.
1
yields, mp’s (bp’s) and H NMR data of compounds 4
see Table 1.
Experimental procedures
Lithiation of 2-(chloroaryl)-2-methyl-1,3-dioxolanes 2
To a solution of 2 (0.10 mol) in THF (100 mL) under
argon was added butyllithium (100 mL of a 1.6 M
solution in hexane, 0.16 mol) at 0°C (2a) or at −78°C
(2b,c) and the mixture was stirred at 0°C (2a) or at
−78°C (2b,c) for 2 h. The resulting suspension of 3 was
treated with the appropriate electrophile to give com-
pounds 4.
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for C9H7ClO2 (182.60): C, 59.19, H, 3.86, Cl, 19.42. Found:
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