Lithiation of 2-aryl-2-methyl-1,3-dioxolanes with PMDTA-complexed butyllithium

Article abstract of DOI:10.1016/j.tet.2016.11.072

The metalation of chloro- and methoxy-substituted acetophenone ketals with butyllithium (BuLi) and with N,N,N',N″,N″-pentamethyldiethylenetriamine-complexed butyllithium (BuLi/PMDTA) has been investigated. The lithio species thus generated were carboxylat

Full text of DOI:10.1016/j.tet.2016.11.072

Accepted Manuscript
Lithiation of 2-aryl-2-methyl-1,3-dioxolanes with PMDTA-complexed butyllithium
Bálint Nyulasi, András Németh, Márta Porcs-Makkay, József Kupai, Gyula Lukács,
Gyula Simig, Balázs Volk
PII:
S0040-4020(16)31252-2
10.1016/j.tet.2016.11.072
TET 28286
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 29 August 2016
Revised Date: 14 November 2016
Accepted Date: 28 November 2016
Please cite this article as: Nyulasi B, Németh A, Porcs-Makkay M, Kupai J, Lukács G, Simig G, Volk B,
Lithiation of 2-aryl-2-methyl-1,3-dioxolanes with PMDTA-complexed butyllithium, Tetrahedron (2016),
doi: 10.1016/j.tet.2016.11.072.
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ACCEPTED MANUSCRIPT
Graphical abstract
R1
R1
1. BuLi
2. CO2
R2
R2
COOH
O
O
3. H+, H2O
O
O
1. BuLi/PMDTA
2. CO2
R1, R2 = H, Cl, MeO
3. H+, H2O
R1
R1
R1
COOH
R2
HOOC
and/or
R2
and/or
COOH
O
R2
O
O
and/or
O
HOOC
O
O
O
O
Lithiation of 2-aryl-2-methyl-1,3-dioxolanes with PMDTA-complexed
butyllithium
Bálint Nyulasi,a András Németh,a Márta Porcs-Makkay,a József Kupai,b Gyula Lukács,a
Gyula Simig,a Balázs Volk*
a
Egis Pharmaceuticals Plc., Directorate of Drug Substance Development, P.O. Box 100, H-
1475 Budapest, Hungary
b Department of Organic Chemistry and Technology, Budapest University of Technology and
Economics, P.O. Box 91, H-1521 Budapest, Hungary
* To whom correspondence should be addressed. Phone: +36 1 8035874, fax: +36 1 8035613,
e-mail: volk.balazs@egis.hu.
Abstract
The metalation of chloro- and methoxy-substituted acetophenone ketals with butyllithium
(BuLi) and with N,N,N’,N”,N”-pentamethyldiethylenetriamine-complexed butyllithium
(BuLi/PMDTA) has been investigated. The lithio species thus generated were carboxylated to
benzoic acids. Lithiations with BuLi occurred regioselectively ortho to the ketal substituent.
When using BuLi/PMDTA, a regiodivergent behavior has generally been found in the
lithiations. However, in some cases a significant selectivity was observed, enabling the
1

ACCEPTED MANUSCRIPT
preparation of the main regioisomer, exhibiting a new substitution pattern, with reasonable
yield.
Keywords
Metalation; Lithiation; Regioselectivity; Acetophenone Ketals; Carboxylation
Introduction
In the course of our work in the field of medicinal chemistry we became interested in the
preparation of various heterocycles accessible from ortho-functionalized benzaldehyde,
benzophenone and acetophenone precursors. Our approach for the synthesis of these key
intermediates is based on the well-known ortho-directing ability of aromatic acetals and ketals
in lithiation reactions.1–4 We have reported in detail on the synthesis of ortho-functionalized
benzaldehyde5 and benzophenone6 derivatives by ortho-lithiation of the corresponding
ethylene ketals with butyllithium (BuLi) and subsequent treatment with electrophiles
(Scheme 1). Regioselectivities of the lithiation reaction of benzophenone ethylene ketals
exhibiting variously substituted phenyl rings with BuLi complexed with N,N,N’,N”,N”-
pentamethyldiethylenetriamine (BuLi/PMDTA) were also investigated.7
X
Y
X
Y
X
Y
EI
O
Li
electrophile
BuLi
O
O
O
O
O
R
R
R
electrophile = CO2, SO2, MeI, etc.
R = H, Ph, substituted phenyl
X, Y = various substituents
X
Y
R
heterocycle
Scheme 1. Ortho-lithiation of acetophenone or benzophenone ethylene ketals and subsequent
transformation into various heterocycles
2

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Regarding the ortho-functionalization of acetophenone ketals, some preliminary results were
previously disclosed: lithiation of 2-(4-chloroaryl)-2-methyl-1,3-dioxolanes (1) with BuLi
followed by treatment with various electrophiles gave the expected products 2 (Scheme 2).8
R1
R1
R1
R2
H
R1
H
Li
O
EI
O
Cl
Cl
Cl
BuLi
electrophile
O
Cl
Cl
H
O
O
O
Cl
R2
R2
R2
1
2
EI = Me, COOH, SO2Cl
Scheme 2. Lithiation of 2-(4-chloroaryl)-2-methyl-1,3-dioxolanes (1) reported previously
We now report the extension of this work to new substrates and to the lithiation of
acetophenone ketals with BuLi complexed with PMDTA.
Results and discussion
Ethylene ketals 3a−d and 3h are known from the literature (Scheme 3).9–12 Ketals 3f and 3g
were prepared starting from known acetophenones by conventional methods. Compound 3e
was prepared by O-methylation of the corresponding phenol, which was obtained as discussed
later.
R1
R1
Cl
1. BuLi
2. CO2
R2
R2
COOH
O
COOH
O
O
O
3. H+, H2O
O
O
5
4
3
3,4
R1
MeO
Cl
R2
H
Reaction conditions
Yield (%)
diethyl ether, 1.6 eq BuLi, 0 °C, 4 h
THF, 1.6 eq BuLi, −78 °C, 2 h
diethyl ether, 1.3 eq BuLi, 0 °C, 2 h
THF, 1.6 eq BuLi, 0 °C, 2 h
77
74
a
b
c
d
e
f
H
H
MeO
Cl
no reaction
91a
H
MeO
Cl
Cl
diethyl ether, 1.6 eq BuLi, 0 °C, 2 h
THF, 1.6 eq BuLi, −78 °C, 2 h
85
MeO
59b
3

ACCEPTED MANUSCRIPT
MeO
Cl
MeO
Cl
diethyl ether, 1.5 eq BuLi, 0 °C, 1 h
THF, 1.6 eq BuLi, −78 °C, 2 h
53c
91a
g
h
a Described in ref. 8.
b Isolated as the corresponding ketone 5 .
c Acidification with citric acid instead of HCl.
Scheme 3. Lithiation of acetophenone ethylene ketals with BuLi into the ortho position of the
ketal moiety
Lithiation of compounds 3a, 3e and 3g (exhibiting a methoxy group in the meta position to
the 1,3-dioxolan-2-yl group) with BuLi in diethyl ether at 0 °C occurred at the common ortho
position of the methoxy and ketal groups, as demonstrated by the formation of the
corresponding carboxylic acids 4 after treatment with dry ice (Scheme 3). para-Methoxyketal
3c did not react with BuLi under the applied conditions. Lithiation of the meta-chloroketals
3b and 3f with BuLi was carried out at −78 °C in order to avoid the generation of benzynes
and subsequent treatment with dry ice gave benzoic acids 4b and 4f. In certain cases the ketal
moiety (especially those exhibiting a methoxy group in the para position of the 1,3-dioxolan-
2-yl group, e.g. 4f) partially hydrolyzed, when using aqueous hydrochloric acid in the course
of the work-up process. In such cases the hydrolysis was completed and the corresponding
acetyl derivative (5) was prepared. In order to avoid hydrolysis of the ketal moiety of product
4g, aqueous citric acid solution was used for acidification of the reaction mixture.
Next, lithiation of acetophenone ketals 3 with PMDTA-complexed BuLi (a reagent frequently
used by Schlosser et al. for the lithiation of halogen-adjacent sites)13 was studied in order to
find routes to acetophenone derivatives with new substitution patterns by achieving
alternative regiochemistry of the lithiation, compared to BuLi. Lithiation of ketals 3a and 3b
with BuLi complexed to PMDTA, followed by carboxylation afforded a mixture of acids 6a,b
and 4a,b with low yield in a ratio of 68 : 32 in both cases (an accidental coincidence), as
1
indicated by the H NMR spectroscopic analysis of the product mixture (Scheme 4). The
regioselectivity is likely to be influenced by relative acidities and steric accessibilities of the
two positions. In both reactions, the starting material could be isolated indicating an
incomplete lithiation. When longer reaction times were applied, the total yield could not be
improved and the ratio of products 6 and 4 did not change significantly, while more and more
unidentified decomposition products appear.
4

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1
1
1
R
R
R
1. BuLi/PMDTA
2. CO2
COOH
O
HOOC
O
O
+
3. H+, H2O
O
O
O
3
6
4
R1
Reaction conditions
Yield (%)
6 : 4
3,4,6
MeO diethyl ether, 1.6 eq BuLi/PMDTA, 0 °C, 25 min
Cl THF, 1.6 eq BuLi/PMDTA, −78 °C, 30 min
22
47
68 : 32
68 : 32
a
b
Scheme 4. Lithiation of meta-substituted acetophenone ethylene ketals with BuLi/PMDTA
leading to mixtures of regioisomers
Lithiation of para-methoxy substituted ketal 3c with PMDTA-complexed BuLi followed by
carboxylation afforded benzoic acid 7 with poor yield (20%) after acidic work-up (Scheme 5).
Formation of the other regioisomer, indicating the occurrence of lithiation ortho to the ketal
group, could not be detected in the crude product mixture. The yield of product 7 could not be
improved by applying longer reaction times.
COOH
1. BuLi/PMDTA
diethyl ether 0 °C
40 min
,
MeO
MeO
O
2. CO2
3. H+, H2O
O
O
3c
7
Scheme 5. Regioselective lithiation of para-methoxy substituted ketal 3c with BuLi/PMDTA
Lithiation of para-chloro substituted ketal 3d with BuLi complexed to PMDTA occurred
exclusively ortho to the chloro substituent as demonstrated by the formation of benzoic acid 8
in good yield (70%, Scheme 6). Similar lithiation of ketal 3d followed by reaction with
triisopropyl borate and hydrogen peroxide gave phenol 9 with 41% yield, which served as the
precursor for the synthesis of ketal 3e. In this case, BuLi/PMDTA promotes hydrogen-lithium
exchange at the most acidic site, i.e. adjacent to the halogen atom.14
5

ACCEPTED MANUSCRIPT
OH
1. BuLi/PMDTA
COOH
,
THF -78 °C
1 h
Cl
Cl
Cl
O
O
O
2. CO2
3. H+, H2O
O
O
O
3d
9
8
Scheme 6. Regioselective lithiation of para-chloro substituted ketal 3d with BuLi/PMDTA
A high regioselectivity was also observed in the lithiation reaction of chloro-methoxy
substituted ketals 3e and 3f with BuLi/PMDTA. The metalation occurred mainly at the
uncongested site meta to the ketal group. 1H NMR spectroscopic analysis of the crude product
obtained after carboxylation indicated that only small amounts of acids 4e and 4f (4 and 8%,
respectively) were formed beside the main products 10a and 10b (Scheme 7). The result
obtained with compound 3e is in accord with that observed with derivative 3d. The influence
of the methoxy substituent on the chlorine adjacent site is negligible. The significantly more
effective lithiation at the methoxy adjacent site of compound 3f, when compared with
derivative 3c, can be explained by the meta-acidifying effect of the chloro substituent.6,15
1
1
1
R
R
R
1. BuLi/PMDTA
2. CO2
2
2
2
R
R
R
COOH
O
O
O
+
3. H+, H2O
HOOC
O
O
O
1
2
4
3
10a
10b
(R = MeO, R = Cl)
(R1 = Cl, R2 = MeO)
R1
R2
Cl
Reaction conditions
THF, 1.6 eq BuLi/PMDTA, −78 °C, 20 min
Product Yield (%)
3,4
e
MeO
Cl
60
53
10a
10b
MeO THF, 1.6 eq BuLi/PMDTA, −78 °C, 1 h
f
Scheme 7. Regioselective lithiation of chloro-methoxy substituted ketals 3e,f with
BuLi/PMDTA
3,4-Dimethoxy substituted ketal 3g dissolved in diethyl ether was lithiated with PMDTA-
1
complexed BuLi at 0 °C for 30 min. H NMR spectroscopic analysis of the product mixture
(yield 34%) obtained after carboxylation and work-up proved the presence of products 11 and
6

ACCEPTED MANUSCRIPT
4g in a 39 : 61 ratio (Scheme 8). An authentic sample of compound 11 was prepared by
transformation of acetophenone 12 to ketal 13 using ethylene glycol in the presence of
trimethyl orthoformate and para-toluenesulfonic acid (PTSA), and subsequent carboxylation
via bromine-lithium exchange. Acetophenone 12 was prepared from the natural compound
acetovanillone via a bromination-methylation sequence.16
OMe
OMe
OMe
1. BuLi/PMDTA
diethyl ether, 0 °C
30 min
MeO
COOH
O
MeO
MeO
O
O
+
2. CO2
3. H+, H2O
HOOC
O
O
O
4g
11
3g
1. BuLi
2. CO2
3. H+, H2O
1.) PhMe3N+ Br3
OMe
-
OMe
ethylene glycol
HC(OMe)3
PTSA
OMe
THF
0 °C, 15 min
HO
MeO
MeO
O
MTBE
rt, 24 h
O
O
2.) (CH3O)2SO2
K2CO3
Br
Br
O
acetone
reflux, 3 h
acetovanillone
12
13
Scheme 8. Lithiation of 3,4-dimethoxy substituted ketal 3g with BuLi/PMDTA and
alternative synthesis of minor product 11
Treatment of 3,4-dichloro substituted ketal 3h with BuLi/PMDTA at 0 °C for 30 min
followed by carboxylation resulted in a complex mixture of benzoic acids, isolated in an
overall yield of 66% (Scheme 9). The results obtained in our hands in the lithiation reactions
of ketal 3h with BuLi and BuLi/PMDTA are in agreement with the expectations based on the
analogous studies with 1,2- and 1,3-dichlorobenzene:17 lithiation of 3,4-dichloroketal 3h with
BuLi occurred at the common ortho position of the chloro and ketal groups (yield of the
carboxylated product 91%, see Scheme 3),8 while the main product 14 obtained with
BuLi/PMDTA indicated lithiation at the most acidic uncongested site. In addition to the major
and minor dichloro derivatives 14 and 4h, chlorine-lithium exchange products 6b and 8 were
1
also formed. Comparison of the H NMR spectra of the authentic samples of the products
with that of the product mixture, the ratio of the products formed proved to be 14 : 4h : 6b : 8
= 61 : 18 : 11 : 10. A similar chlorine-lithium exchange reaction was observed in the
7

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BuLi/PMDTA lithiation reaction of benzophenone ketals containing a 3,4-dichlorophenyl
ring.7
Cl
Cl
O
O
3h
1. BuLi/PMDTA
THF, -78 °C
2. CO2
3. H+, H2O
Cl
COOH
Cl
Cl
Cl
Cl
COOH
O
HOOC
Cl
O
O
O
+
+
+
HOOC
O
O
O
O
4h
14
6b
8
Scheme 9. Formation of regioisomers and chlorine-lithium exchange reactions observed
during the lithiation of 3,4-dichloro substituted ketal 3h with BuLi/PMDTA
Conclusions
Ortho-functionalized acetophenones can serve as potential precursors of various heterocycles.
In the present study, chloro- and/or methoxy-substituted acetophenone ketals were
synthesized and the regiochemistry of their lithiation with BuLi and BuLi/PMDTA was
investigated. The lithiated intermediates were converted into the corresponding benzoic acids
by trapping with carbon dioxide. Lithiations with BuLi occurred regioselectively ortho to the
ketal substituent. Lithiations with BuLi/PMDTA afforded product mixtures indicating that
metalation occurred at the meta or para position to the ketal group, in chlorine- or methoxy-
adjacent positions as well. The occurrence of chlorine-lithium exchange reactions was also
observed. Nevertheless, in some cases, the main regioisomer exhibiting a new substitution
pattern could be isolated in reasonable yield.
Experimental section
Melting points were determined on a Büchi 535 capillary melting point apparatus. IR spectra
were obtained on a Bruker IFS-113v FT spectrometer in KBr pellets or in neat. 1H NMR and
8

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1
13
13C NMR spectra were recorded on a Varian Gemini 200 (200 and 50 MHz for H and C
1
13
NMR spectra, respectively), a Bruker Avance III (400 and 100 MHz for H and C NMR
spectra, respectively) or a Varian Unity Inova 500 spectrometer (500 and 125 MHz for 1H and
13C NMR spectra, respectively). CDCl3 was used as solvent and tetramethylsilane (TMS) as
internal standard. Chemical shifts (δ) and coupling constants (J) are given in ppm and in Hz,
respectively. Elemental analyses were performed on a Perkin-Elmer 2400 analyzer. All
unspecified reagents were purchased from commercial sources. Analytical samples were
obtained by recrystallization from the solvents or solvent mixtures given in parentheses after
the melting point ranges.
2-(4-Chloro-3-methoxyphenyl)-2-methyl-1,3-dioxolane (3e). To a mixture of potassium
tert-butoxide (11.5 g, 0.103 mol) and DMF (60 mL) 2-chloro-5-(2-methyl-1,3-dioxolan-2-
yl)phenol (9, 3.50 g, 16.3 mmol) was added at 0−5 °C under argon. After stirring for 10 min,
methyl iodide (6.4 mL, 14.6 g, 0.103 mol) was added at the same temperature. The mixture
was stirred for 2 h at ambient temperature. Ethyl acetate (250 mL) and water (60 mL) were
added and the layers were separated. The organic layer was washed with aqueous sodium
hydrogencarbonate solution (5 w/w%, 80 mL) and water (2×200 mL), dried (MgSO4) and
evaporated to give product 3e (12.9 g, 88%) as a pale yellow solid, mp 61–62 °C (heptane).
IR (KBr, cm–1): 3441, 2987, 2897, 1584, 1486, 1395, 1201, 1054. 1H NMR (400 MHz,
CDCl3): δ 7.32 (1H, d, J=8.1 Hz), 7.06 (1H, d, J=1.8 Hz), 7.01 (1H, dd, J=8.1 Hz, J=1.8 Hz),
4.05–4.03 (2H, m), 3.92 (3H, s), 3.80–3.78 (2H, m), 1.64 (3H, s). 13C NMR (125 MHz,
CDCl3): δ 154.8, 143.6, 129.9, 121.8, 118.1, 109.2, 108.4, 64.5, 56.1, 27.5. Anal. Calcd for
C11H13ClO3 (228.68): C 57.78, H 5.73, Cl 15.50%. Found: C 57.91, H 5.78, Cl 15.52%.
2-(3-Chloro-4-methoxyphenyl)-2-methyl-1,3-dioxolane (3f). A solution of 1-(3-chloro-4-
methoxyphenyl)ethanone12 (54.3 g, 0.294 mol), ethylene glycol (41.0 mL, 45.6 g, 0.735 mol)
and p-toluenesulfonic acid monohydrate (1.00 g, 5.0 mmol) in toluene (440 mL) was refluxed
in a Dean-Stark apparatus for 35 h. The reaction mixture was extracted with aqueous sodium
hydrogen carbonate solution (5 w/w%, 300 mL) and water (300 mL), dried (MgSO4) and
evaporated resulting in a colorless oil, which crystallized by treating with petroleum ether to
give 3f (64.2 g, 96%) as a colorless solid, mp 42−43 °C (hexane). IR (KBr, cm–1) 3049, 2992,
2894, 1499, 1380, 1260. 1H NMR (200 MHz, CDCl3): δ 7.48 (1H, d, J=2.2 Hz), 7.33 (1H, dd,
J=8.5 Hz, J=2.2 Hz), 6.88 (1H, d, J=8.5 Hz), 4.06–3.99 (2H, m), 3.88 (3H, s), 3.81–3.74 (2H,
13
m), 1.62 (3H, s). C NMR (125 MHz, CDCl3): δ 154.5, 136.7, 127.3, 124.6, 122.1, 111.6,
108.1, 64.4, 56.1, 27.5. Anal. Calcd for C11H13ClO3 (228.68): C 57.77, H 5.73, Cl 15.50%.
Found: C 57.58, H 5.69, Cl 15.20%.
9

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2-(3,4-Dimethoxyphenyl)-2-methyl-1,3-dioxolane (3g). A solution of commercially
available 1-(3,4-dimethoxyphenyl)ethanone (57.0 g, 0.316 mol), ethylene glycol (80.0 mL,
89.1 g, 1.44 mol) and p-toluenesulfonic acid monohydrate (1.50 g, 7.5 mmol) in toluene (400
mL) was refluxed in a Dean-Stark apparatus for 35 h. The reaction mixture was washed with
aqueous sodium hydrogen carbonate solution (5 w/w%, 300 mL) and water (300 mL), dried
over MgSO4 and the solvent was evaporated resulting a brown oil, which was distilled in
vacuo (120–140 °C/0.2 Hgmm). Treatment of the resulting colorless oil with hexane (150
mL) gave 3g (44.7 g, 62%) as a colorless solid, mp 48−50 °C (hexane). IR (KBr, cm-1): 2988,
2892, 1606, 1512, 1265, 1031. 1H NMR (400 MHz, CDCl3): δ 7.04 (1H, dd, J=8.3 Hz, J=2.0
Hz), 7.01 (1H, d, J=1.8 Hz), 6.84 (1H, d, J=8.2 Hz), 4.06–3.98 (2H, m), 3.90 (3H, s), 3.87
(3H, s), 3.83–3.76 (2H, m), 1.66 (3H, s). 13C NMR (125 MHz, CDCl3): δ 160.9, 148.6, 148.4,
135.8, 117.3, 110.58, 108.6, 108.4, 64.2, 55.7, 27.5. Anal. Calcd for C12H16O4 (224.26): C
64.27, H 7.19%. Found: C 64.01, H 7.03%.
2-Methoxy-6-(2-methyl-1,3-dioxolane-2-yl)benzoic acid (4a). To a solution of 2-(3-
methoxyphenyl)-2-methyl-1,3-dioxolane9 (3a, 21.5 g, 0.111 mol) in diethyl ether (180 mL),
BuLi (71 mL of a 2.5 M solution in hexane, 0.18 mol) was added at 0 °C under argon and the
mixture was stirred for 4 h at 0 °C. It was poured onto a large excess of dry ice. After 1 h,
water (360 mL) was added, and the layers were separated. The aqueous layer was extracted
with diethyl ether (2×180 mL) and acidified with concentrated hydrochloric acid (15 mL).
The crystalline product was filtered to give 4a (20.3 g, 77%) as a colorless solid, mp 145–146
°C (hexane/ethyl acetate 1:1). IR (KBr, cm–1): 3175, 1735, 1695, 1470, 1301, 1276, 1217,
1
1027. H NMR (200 MHz, CDCl3): δ 7.36 (1H, t, J=8.1 Hz), 7.14 (1H, d, J=8.1 Hz), 6.90
(1H, d, J=8.1 Hz), 4.07–4.00 (2H, m), 3.88 (3H, s), 3.82–3.75 (2H, m), 1.77 (3H, s). 13C
NMR: (125 MHz, CDCl3): δ 173.3, 156.0, 142.2, 130.4, 121.3, 118.6, 110.5, 108.4, 64.3,
56.0, 27.5. Anal. Calcd for C12H14O5 (238.24): C 60.50, H 5.92%. Found: C 60.31, H 5.94%.
2-Chloro-6-(2-methyl-1,3-dioxolane-2-yl)benzoic acid (4b). To a solution of 2-(3-
chlorophenyl)-2-methyl-1,3-dioxolane11 (3b, 19.9 g, 0.100 mol) in THF (100 mL), BuLi (100
mL of a 1.6 M solution in hexane, 0.16 mol) was added at –78 °C, under argon and the
mixture was stirred for 2 h at –78 °C. It was poured onto a large excess of dry ice. Water (100
mL) was added, and the layers were separated. The aqueous layer was extracted with diethyl
ether (2×50 mL), acidified with an aqueous solution of hydrochloric acid (10 w/w%, 100 mL)
and extracted with diethyl ether (3×50 mL). The organic phase was dried (MgSO4) and
concentrated. Trituration of the residue with hexane (50 mL) gave 4b (18.0 g, 74%) as a
colorless solid, mp 124–126 °C (hexane/ethyl acetate 3:1). IR (KBr, cm–1): 3175, 1743, 1438,
10

ACCEPTED MANUSCRIPT
1251, 1187. 1H NMR (500 MHz, CDCl3): δ 7.48 (1H, dd, J=6.7 Hz, J=2.4 Hz), 7.39 (1H, dd,
J=7.9 Hz, J=2.4 Hz), 7.34 (1H, t, J=7.3 Hz), 4.09–3.94 (2H, m), 3.87–3.72 (2H, m), 1.76 (3H,
s). 13C NMR (125 MHz, CDCl3): δ 172.6, 143.1, 130.9, 130.8, 130.4, 129.2, 125.0, 108.2,
64.4, 27.6. Anal. Calcd for C11H11ClO4 (242.66): C 54.45, H 4.57, Cl 14.61%. Found: C
54.67, H 4.62, Cl 14.38%.
3-Chloro-2-methoxy-6-(2-methyl-1,3-dioxolane-2-yl)benzoic acid (4e). To a solution of 2-
(4-chloro-3-methyoxyphenyl)-2-methyl-1,3-dioxolane (3e, 3.57 g, 15.6 mmol) in diethyl ether
(20 mL), BuLi (10 mL of a 2.5 M solution in hexane, 25 mmol) was added at 0 °C under
argon and the mixture was stirred for 2 hs at 0 °C. It was poured onto a large excess of dry
ice. Water (80 mL) and tert-butyl methyl ether (60 mL) were added and the layers were
separated. The aqueous layer was extracted with tert-butyl methyl ether (60 mL) and acidified
with concentrated hydrochloric acid to pH = 2 to give 4e (3.62 g, 85%) as a colorless solid,
mp 133–134 °C (hexane/ethyl acetate 5:3). IR (KBr, cm–1): 3220, 1740, 1490, 1374, 1253.
1H NMR (500 MHz, CDCl3): δ 11.23 (1H, br s), 7.41 (1H, d, J=8.4 Hz), 7.26 (1H, d, J=8.4
13
Hz), 4.08–4.00 (2H, m), 3.97 (3H, s), 3.82–3.75 (2H, m), 1.75 (3H, s). C NMR (125 MHz,
CDCl3): δ 172.7, 152.7, 141.0, 131.4, 128.1, 127.5, 123.0, 108.0, 64.4, 62.2, 27.4. Anal. Calcd
for C12H13ClO5 (272.69): C 52.86, H 4.81, Cl 13.00%. Found: C 52.91, H 4.89, Cl 13.18%.
6-Acetyl-2-chloro-3-methoxybenzoic acid (5) via 2-chloro-3-methoxy-6-(2-methyl-1,3-
dioxolane-2-yl)benzoic acid (4f). To a solution of 2-(3-chloro-4-methyoxyphenyl)-2-methyl-
1,3-dioxolane (3f, 3.57 g, 15.6 mmol) in THF (25 mL), BuLi (10 mL of a 2.5 M solution in
hexane, 25 mmol) was added at –78 °C, under argon atmosphere, stirred for 2 h at –78 °C. It
was poured onto a large excess of dry ice. Water (100 mL) and tert-butyl methyl ether (60
mL) were added, stirred for 10 min, and the layers were separated. The aqueous layer was
extracted with tert-butyl methyl ether (40 mL) and acidified with aqueous solution of
hydrochloric acid (10 w/w%) to pH = 2. The aqueous layer was extracted with ethyl acetate
(2×40 mL), the organic phase was dried (MgSO4) and evaporated to afford partially
deketalized 4f. In order to complete the hydrolysis of the ketal, aqueous solution of
hydrochloric acid (10 w/w%, 75 mL) was added and suspension was boiled for 2 h. After
cooling to room temperature, the product was filtered and dried to give 5 (2.10 g, 59%) as a
colorless solid, mp 202–203 °C (diethyl ether/THF 3:1). IR (KBr, cm–1): 3045, 2951, 1744,
1650, 1562, 1279, 1240, 1041. 1H NMR (CDCl3, 200 MHz) δ 7.48 (1H, br s), 7.23 (1H, br s),
13
3.98 (3H, s), 1.91 (3H, s). C NMR (125 MHz, CDCl3): δ 165.0, 157.2, 142.8, 120.8, 117.9,
103.7, 57.0, 26.7. Anal. Calcd for C10H9ClO4 (228.63): C 52.53, H 3.97, Cl 15.51%. Found: C
52.82, H 9.96, Cl 15.29%.
11

ACCEPTED MANUSCRIPT
2,3-Dimethoxy-6-(2-methyl-1,3-dioxolane-2-yl)benzoic acid (4g). To a solution of 2-(3,4-
dimethoxyphenyl)-2-methyl-1,3-dioxolane (3g, 2.80 g, 12.5 mmol) in diethyl ether (15 mL),
BuLi (7.5 mL of a 2.5 M solution in hexane, 18.8 mmol) was added at 0 °C under argon and
stirred for 1 h at 0 °C. It was poured onto a large excess of dry ice. Water (60 mL) was added,
and the layers were separated. The aqueous layer was extracted with diethyl ether (2×40 mL),
acidified with an aqueous solution of citric acid (20 w/w%). The precipitate was collected by
filtration and recrystallized from 2-propanol (16 mL) to give 4g (1.78 g, 53%) as a colorless
solid, mp 142–144 °C (2-propanol). IR (KBr, cm–1) 3198, 2980, 1735, 1490, 1274, 1193.
1H NMR (CDCl3, 200 MHz) δ 7.23 (1H, d, J=8.5 Hz), 6.94 (1H, d, J=8.5 Hz), 4.03–3.99 (2H,
m), 3.91 (3H, s), 3.88 (3H, s), 3.81–3.77 (2H, m), 1.74 (3H, s). 13C NMR (125 MHz, CDCl3):
δ 172.5, 152.2, 145.5, 133.2, 127.1, 122.3, 113.2, 108.3, 64.3, 61.7, 56.0, 27.7. Anal. Calcd
for C13H16O5 (257.27): C 58.20, H 6.01%. Found: C 58.09, H 5.97%.
Lithiation of 2-(3-methyoxyphenyl)-2-methyl-1,3-dioxolane (3a) with BuLi/PMDTA
leading to a mixture of 2-methoxy-6-(2-methyl-1,3-dioxolane-2-yl)benzoic acid (4a) and
2-methoxy-4-(2-methyl-1,3-dioxolane-2-yl)benzoic acid (6a). To a solution of PMDTA
(4.33 g, 25.0 mmol) in diethyl ether (15 mL), BuLi (10 mL of a 2.5 M solution in hexane, 25
mmol) was added at 0 °C, under argon. After stirring for 10 min, 2-(3-methyoxyphenyl)-2-
methyl-1,3-dioxolane (3a, 3.03 g, 15.6 mmol) in diethyl ether (10 mL) was added at 0 °C. The
resulting solution was stirred for 25 min and it was poured onto a large excess of dry ice.
Water (100 mL) and tert-butyl methyl ether (50 mL) were added, and the layers were
separated. The aqueous layer was extracted with tert-butyl methyl ether (50 mL) and acidified
with aqueous solution of hydrochloric acid (10 w/w%) to pH = 3. The resulting solution was
extracted with ethyl acetate (2×50 mL), dried (MgSO4) and evaporated. The residue was
triturated with hexane to give a 32 : 68 mixture (determined by 1H NMR) of 4a and 6a (0.83
g, 22%) as a yellow solid. An analytical sample of 2-methoxy-4-(2-methyl-1,3-dioxolane-2-
yl)benzoic acid (6a) was obtained by fractional crystallization of the product mixture from
diethyl ether to give 6a as a colorless solid, mp 101–102 °C (diethyl ether). IR (KBr, cm–1):
3281, 2993, 1724, 1612, 1410, 1334, 1202, 1029. 1H NMR (500 MHz, CDCl3): δ 8.14 (1H, d,
J=8.1 Hz), 7.26 (1H, dd, J=8.1 Hz, J=1.5 Hz), 7.20 (1H, d, J=1.3 Hz), 4.10 (3H, s), 4.10–4.06
(2H, m), 3.80–3.77 (2H, m), 1.66 (3H, s). 13C NMR (125 MHz, CDCl3): δ 165.3, 158.1,
151.3, 133.8, 119.0, 117.0, 108.7, 108.2, 64.6, 56.7, 27.3. Anal. Calcd for C12H14O5 (238.24):
C 60.50, H 5.92%. Found: C 60.72, H 6.03%.
Lithiation of 2-(3-chlorophenyl)-2-methyl-1,3-dioxolane (3b) with BuLi/PMDTA leading
to a mixture of 2-chloro-6-(2-methyl-1,3-dioxolane-2-yl)benzoic acid (4b) and 2-chloro-4-
12

ACCEPTED MANUSCRIPT
(2-methyl-1,3-dioxolane-2-yl)benzoic acid (6b). To a solution of PMDTA (4.61 g, 26.6
mmol) in THF (15 mL), BuLi (10 mL of a 2.5 M solution in hexane, 25 mmol) was added at –
78 °C, under argon. After stirring for 10 min, 2-(3-chlorophenyl)-2-methyl-1,3-dioxolane (3b,
3.10 g, 15.6 mmol) in THF (15 mL) was added at –78 °C. The resulting solution was stirred
for 30 min and it was poured onto a large excess of dry ice. Water (100 mL) and tert-butyl
methyl ether (60 mL) were added and the layers were separated. The aqueous layer was
extracted with tert-butyl methyl ether (40 mL) and acidified with aqueous solution of
hydrochloric acid (10 w/w%) to pH = 3. The resulting solution was extracted with ethyl
acetate (2×40 mL) and dried (MgSO4) and evaporated. The residue was triturated with hexane
to give a 32:68 mixture (determined by 1H NMR) of 4b and 6b (1.78 g, 47%). An analytical
sample of 2-chloro-4-(2-methyl-1,3-dioxolane-2-yl)benzoic acid (6b) was obtained by
fractional crystallization from heptane to give 6b as a colorless solid, mp 112–113 °C
(heptane). IR (neat, cm–1): 2900, 1690, 1600, 1265, 1204, 1035. 1H NMR (500 MHz, CDCl3):
δ 8.66 (1H, br s), 8.00 (1H, d, J=8.1 Hz), 7.63 (1H, d, J=1.4 Hz), 7.47 (1H, dd, J=8.1 Hz,
J=1.5 Hz), 4.09–4.06 (2H, m), 3.80–3.77 (2H, m), 1.67 (3H, s). 13C NMR (125 MHz, CDCl3):
δ 170.2, 149.7, 134.8, 132.6, 128.5, 127.8, 123.8, 107.9, 64.7, 27.3. Anal. Calcd for
C11H11ClO4 (242.66): C 54.45, H 4.57, Cl 14.61%. Found: C 54.07, H 4.56, Cl 14.45%.
5-Acetyl-2-methoxybenzoic acid (7). To a solution of PMDTA (4.33 g, 25.0 mmol) in
diethyl ether (20 mL), BuLi (10 mL of a 2.5 M solution in hexane, 25 mmol) was added at 0
°C under argon. After 10 min, 2-(4-methyoxyphenyl)-2-methyl-1,3-dioxolane (3c, 3.03 g,
15.6 mmol) in diethyl ether (10 mL) was added to the solution at 0 °C, was stirred for 40 min
and was poured onto a large excess of dry ice. Water (80 mL) and tert-butyl methyl ether (60
mL) were added and the layers were separated. The aqueous layer was extracted with tert-
butyl methyl ether (40 mL), acidified with concentrated hydrochloric acid to pH = 2 and
stirred at 40 °C for 120 min. After cooling it was extracted with ethyl acetate (2×80 mL),
dried (MgSO4) and evaporated. The solid residue was recrystallized to give 7 (0.60 g, 20%) as
a yellow solid, mp 156–157 °C (hexane/ethyl acetate 2:1), lit. mp 137 °C,18 152 °C.19 IR
(KBr, cm–1): 3238, 1736, 1677, 1605, 1365, 1264. 1H NMR (500 MHz, CDCl3): δ 10.53 (1H,
br s), 8.73 (1H, d, J=2.0 Hz), 8.24 (1H, dd, J=8.8 Hz, J=2.1 Hz), 7.16 (1H, d, J=8.8 Hz), 4.16
(3H, s), 2.63 (3H, s). 13C NMR (125 MHz, CDCl3): δ 196.0, 165.7, 161.7, 134.8, 134.5, 131.0,
117.6, 112.0, 57.0, 26.4. Anal. Calcd for C10H10O4 (194.19): C 61.85, H 5.19%. Found: C
61.75, H 5.10%.
2-Chloro-5-(2-methyl-1,3-dioxolane-2-yl)benzoic acid (8). To a solution of PMDTA (4.61
g, 26.6 mmol) in THF (15 mL), BuLi (10 mL of a 2.5 M solution in hexane, 25 mmol) was
13

ACCEPTED MANUSCRIPT
added at –78 °C under argon. After stirring for 10 min, 2-(4-chlorophenyl)-2-methyl-1,3-
dioxolane (3d, 3.10 g, 15.6 mmol) in THF (5 mL) was added at –78 °C. The resulting solution
was stirred for 60 min and it was poured onto a large excess of dry ice. Water (110 mL) and
tert-butyl methyl ether (60 mL) were added and the layers were separated. The aqueous layer
was extracted with tert-butyl methyl ether (40 mL) and acidified with aqueous solution of
hydrochloric acid (10 w/w%) to pH = 3. The resulting solution was extracted with ethyl
acetate (3×40 mL), dried (MgSO4) and evaporated. The solid residue was triturated with
hexane to give 8 (2.63 g, 70%) as a yellow solid, mp 123–124 °C (heptane/ethyl acetate 2:1).
1
IR (KBr, cm–1): 2987, 2893, 1693, 1308, 1266, 1204, 1033. H NMR (500 MHz, CDCl3): δ
11.76 (1H, br s), 8.14 (1H, d, J=2.2 Hz), 7.61 (1H, dd, J=8.3 Hz, J=2.2 Hz), 7.47 (1H, d,
J=8.3 Hz), 4.09–4.07 (2H, m), 3.81–3.78 (2H, m), 1.67 (3H, s). 13C NMR (125 MHz, CDCl3):
δ 170.6, 142.5, 134.1, 131.4, 130.5, 129.3, 128.4, 108.0, 64.6, 27.4. Anal. Calcd for
C11H11ClO4 (242.66): C 54.45, H 4.57, C, 14.61%. Found: C 54.67, H 4.53, Cl 14.32%.
2-Chloro-5-(2-methyl-1,3-dioxolan-2-yl)phenol (9). To a solution of PMDTA (43.3 g, 0.250
mol) in THF (120 mL), BuLi (100 mL of a 2.5 M solution in hexane, 0.25 mol) was added at
–78 °C, under argon. After stirring for 10 min, 2-(4-chlorophenyl)-2-methyl-1,3-dioxolane
(3d, 31.0 g, 0.156 mol) in THF (30 mL) was added at –78 °C in 30 min. The resulting
solution was stirred for 30 min and triisopropyl borate (47.2 g, 0.251 mol) in THF (30 mL)
was added dropwise to the solution at –78 °C over a period of 1 h. The solution was allowed
to warm up to room temperature, stirred for 30 min and then cooled to 0 °C. At this
temperature aqueous solution of hydrogen peroxide (35 w/w%, 37.9 g, 0.390 mol) was added
dropwise to the solution. Then the solution was warmed to room temperature, stirred for 1 h,
water (350 mL) was added and stirred for further 30 min. The solution was neutralized with
concentrated hydrochloric acid. Ethyl acetate (250 mL) was added and the layers were
separated. The aqueous layer was extracted with ethyl acetate (160 mL), the organic layers
were combined and washed with water (2×300 mL), dried (MgSO4) and evaporated. Water
(115 mL) and aqueous solution of sodium hydroxide (40 w/w%, 22.5 g) was added to the oily
residue. It was stirred for 15 min and tert-butyl methyl ether (115 mL) was added. After a 10-
min stirring, the layers were separated. The aqueous phase was extracted once more with tert-
butyl methyl ether (60 mL) and the pH was adjusted to 6–7 with concentrated hydrochloric
acid. The resulting solid precipitation was filtered, washed with water and recrystallized from
heptane with activated charcoal treatment to give 9 (13.8 g, 41%) as a pale yellow solid, mp
1
77–79 °C (heptane). IR (KBr, cm–1): 3335, 2896, 1596, 1413, 1300, 1212, 1029. H NMR
(500 MHz, CDCl3): δ 7.28 (1H, d, J=8.4 Hz), 7.16 (1H, d, J=1.4 Hz), 7.00 (1H, dd, J=8.2 Hz,
14

ACCEPTED MANUSCRIPT
13
J=1.4 Hz), 5.79 (1H, s), 4.06–4.02 (2H, m), 3.80–3.76 (2H, m), 1.64 (3H, s). C NMR (125
MHz, CDCl3): δ 151.2, 144.3, 128.8, 119.3, 118.4, 113.4, 108.3, 64.5, 27.3. Anal. Calcd for
C10H11ClO3 (214.65): C 55.96, H 5.17, Cl 16.52%. Found: C 56.17, H 5.20, Cl 16.59%.
2-Chloro-3-methoxy-5-(2-methyl-1,3-dioxolane-2-yl)benzoic acid (10a). To a solution of
PMDTA (4.33 g, 25.0 mmol) in THF (20 mL), BuLi (10 mL of a 2.5 M solution in hexane, 25
mmol) was added at 0 °C under argon. After stirring for 10 min, 2-(4-chloro-3-
methoxyphenyl)-2-methyl-1,3-dioxolane (3e, 3.57 g, 15.6 mmol) in THF (20 mL) was added
dropwise to the solution at –78 °C. The resulting solution was stirred for 20 min and it was
poured onto a large excess of dry ice. Water (80 mL) and tert-butyl methyl ether (60 mL)
were added, and the layers were separated. The aqueous layer was extracted with tert-butyl
methyl ether (2×60 mL) and acidified with concentrated hydrochloric acid to pH = 2. The
resulting solution was extracted with ethyl acetate (2×40 mL), dried (MgSO4) and evaporated.
1H NMR analysis of the residue indicated the presence of compounds 10a and 4e in a 96 : 4
ratio. The solid residue was triturated with hexane to give 10a (2.53 g, 60%) as a colorless
solid, mp 150–151 °C (hexane/ethyl acetate 1:1). IR (KBr, cm–1): 3161, 1723, 1458, 1321,
1
1281, 1236, 1030. H NMR (400 MHz, CDCl3): δ 9.93 (1H, br s), 7.25 (1H, d, J=2.0 Hz),
7.26 (1H, d, J=1.9 Hz), 4.10–4.06 (2H, m), 3.96 (3H, s), 3.82–3.78 (2H, m), 1.67 (3H, s). 13C
NMR (125 MHz, CDCl3): δ 170.6, 155.9, 143.3, 130.3, 122.3, 120.2, 112.6, 108.1, 64.6, 56.7,
27.5. Anal. Calcd for C12H13ClO5 (272.69): C 52.86, H 4.81, Cl 13.00%. Found: C 52.97, H
4.87, Cl 12.75%.
3-Chloro-2-methoxy-5-(2-methyl-1,3-dioxolane-2-yl)benzoic acid (10b). To a solution of
PMDTA (4.61 g, 26.6 mmol) in THF (15 mL), BuLi (10 mL of a 2.5 M solution in hexane, 25
mmol) was added at 0 °C under argon. After stirring for 10 min, 2-(3-chloro-4-
methoxyphenyl)-2-methyl-1,3-dioxolane (3f, 3.57 g, 15.6 mmol) in THF (15 mL) was added
dropwise to the solution at –78 °C. The resulting solution was stirred for 1 h and it was
poured onto a large excess of dry ice. Water (100 mL) and tert-butyl methyl ether (60 mL)
were added, and the layers were separated. The aqueous layer was extracted with tert-butyl
methyl ether (40 mL) and acidified with aqueous solution of hydrochloric acid (10 w/w%) to
pH = 3. Ethyl acetate (50 mL) was added and the phases were separated. The aqueous layer
was extracted with ethyl acetate (2×40 mL), dried (MgSO4) and evaporated. 1H NMR analysis
of the residue indicated the presence of compounds 10b and 4f in a 92 : 8 ratio. The residue
was crystallized from a mixture of diethyl ether and hexane to give 10b (2.47 g, 58%) as an
off-white solid, mp 128–130 °C (heptane/ethyl acetate 10:1). IR (neat, cm–1): 2890, 1675,
1
1475, 1255, 1201, 1037. H NMR (500 MHz, CDCl3): δ 10.35 (1H, br s), 8.06 (1H, d, J=1.6
15

ACCEPTED MANUSCRIPT
Hz), 7.75 (1H, d, J=1.6 Hz), 4.08–4.05 (2H, m), 4.03 (3H, s), 3.82–3.79 (2H, m), 1.64 (3H, s).
13C NMR (125 MHz, CDCl3): δ 167.5, 155.3, 141.2, 132.5, 128.8, 128.0, 124.5, 107.7, 64.7,
62.3, 27.3. Anal. Calcd for C12H13ClO5 (272.69): C 52.86, H 4.81, Cl 13.00%. Found: C
52.98, H 4.85, Cl 12.88%.
Lithiation of 2-(3,4-dimethoxyhenyl)-2-methyl-1,3-dioxolane (3g) with BuLi/PMDTA
leading to a mixture of 2,3-dimethoxy-6-(2-methyl-1,3-dioxolane-2-yl)benzoic acid (4g)
and 2,3-dimethoxy-5-(2-(methyl-1,3-dioxolane-2-yl)benzoic acid (11). To a solution of
PMDTA (4.61 g, 26.6 mmol) in diethyl ether (10 mL), BuLi (10 mL of a 2.5 M solution in
hexane, 25 mmol) was added at 0 °C, under argon. After stirring for 10 min, 2-(3,4-
dimethoxyhenyl)-2-methyl-1,3-dioxolane (3g, 3.50 g, 15.6 mmol) in THF (15 mL) was added
at 0 °C. The resulting solution was stirred for 30 min and it was poured onto a large excess of
dry ice. Water (100 mL) and tert-butyl methyl ether (50 mL) were added, and the layers were
separated. The aqueous layer was extracted with tert-butyl methyl ether (40 mL) and acidified
with concentrated hydrochloric acid to pH = 3 and extracted with ethyl acetate (3×50 mL).
Combined organic phases were dried (MgSO4) and evaporated. Trituration with hexane gave
1
a pale yellow solid (1.43 g, 34%). H NMR analysis of the residue indicated the presence of
compounds 11 and 4g in a 39 : 61 ratio.
2,3-Dimethoxy-5-(2-(methyl-1,3-dioxolane-2-yl)benzoic acid (11), synthesis of an
authentic sample. Step A: 2-(3-Bromo-4,5-dimethoxyphenyl)-2-methyl-1,3-dioxolane
(13). A solution of 1-(3-bromo-4,5-dimethoxyphenyl)ethanone16 (12, 8.00 g, 30.9 mmol),
ethylene glycol (9.62 g, 0.155 mol), trimethyl orthoformate (9.84 g, 92.7 mmol) and para-
toluenesulfonic acid monohydrate (0.24 g, 1.24 mmol) in tert-butyl methyl ether (40 mL) was
stirred at room temperature for 24 h. To the reaction mixture ethyl acetate (50 mL) was added.
The organic phase was washed with aqueous sodium hydrogen carbonate solution (5 w/w%,
25 mL), water (60 mL) and brine (25 mL). The organic phase was dried over MgSO4 and the
solvent was evaporated to give 13 (9.09 g, 97%) as red-brown solid. An analytical sample
(1.00 g) was recrystallized from hexane to give 13 (0.64 g) as an off-white solid, mp 98–99
°C (hexane). IR (KBr, cm–1): 2966, 2879, 1566, 1486, 1397, 1300, 1160, 1033. 1H NMR (400
MHz, CDCl3): δ 7.26 (1H, d, J=1.9 Hz), 6.97 (1H, d, J=1.9 Hz), 4.07–4.01 (2H, m), 3.85 (3H,
s), 3.88 (3H, s), 3.82–3.77 (2H, m), 1.63 (3H, s). 13C NMR (100 MHz, CDCl3): δ 153.4,
145.8, 140.6, 121.5, 117.3, 108.8, 108.0, 64.5, 60.4, 56.1, 27.5. Anal. Calcd for C12H15BrO4
(303.15): C 47.54, H 4.99, Br 26.36%. Found: C 47.60, H 4.96, Br 25.93%. Step B: 2,3-
Dimethoxy-5-(2-(methyl-1,3-dioxolane-2-yl)benzoic acid (11). To a solution of 2-(3-bromo-
4,5-dimethoxyphenyl)-2-methyl-1,3-dioxolane (13, 1.78 g, 5.9 mmol) in THF (10 mL), BuLi
16

ACCEPTED MANUSCRIPT
(4.0 mL of a 2.5 M solution in hexane, 9.4 mmol) was added at –78 °C, under argon
atmosphere, stirred for 30 min at –78 °C, treated with dry ice and left overnight at room
temperature. Water (50 ml) and tert-butyl methyl ether (30 ml) were added, and the layers
were separated. The aqueous layer was extracted with tert-butyl methyl ether (30 mL), and
then treated with an aqueous solution of hydrochloric acid (10 w/w%) to pH = 3. The
resulting solution was extracted with ethyl acetate (2×20 ml), dried (MgSO4) and evaporated
to give 11 (1.02 g, 65%) as an orange solid. The crude product was triturated with hexane to
give 11 (0.86 g, 55%) as a yellow solid. An analytical sample (0.83 g) was recrystallized from
hexane and ethyl acetate to give 11 (0.61 g) as an off-white solid, mp 149–150 °C
1
(hexane/ethyl acetate 1:1). IR (KBr, cm–1): 2983, 1679, 1488, 1400, 1330, 1275. H NMR
(400 MHz, CDCl3): δ 7.83 (1H, d, J=2.1 Hz), 7.29 (1H, d, J=1.9 Hz), 4.09–4.03 (2H, m), 4.08
(3H, s), 3.95 (3H, s), 3.82–3.76 (2H, m), 1.65 (3H, s). 13C NMR (100 MHz, CDCl3): δ 165.6,
152.0, 147.7, 140.6, 121.9, 120.4, 114.5, 108.1, 64.6, 62.1, 56.2, 27.4. Anal. Calcd for
C13H16O6 (268.27): C 58.20, H 6.01%. Found: C 58.12, H 5.97%.
Preparation of 2,3-dichloro-5-(2-methyl-1,3-dioxolane-2-yl)benzoic acid (14) from the
product mixture obtained by the lithiation of 2-(3,4-dichlorophenyl)-2-methyl-1,3-
dioxolane (3h) with BuLi/PMDTA. To a solution of PMDTA (4.61 g, 26.6 mmol) in THF
(15 mL), BuLi (10 mL of a 2.5 M solution in hexane, 25 mmol) was added at –78 °C, under
argon. After stirring for 10 min, 2-(3,4-dichlorophenyl)-2-methyl-1,3-dioxolane (3h, 3.67 g,
15.6 mmol) in THF (15 mL) was added dropwise to the solution at –78 °C. The resulting
solution was stirred for 30 min and it was poured onto a large excess of dry ice. Water (100
mL) and tert-butyl methyl ether (60 mL) were added, and the layers were separated. The
aqueous layer was extracted with tert-butyl methyl ether (40 mL) and acidified with an
aqueous solution of hydrochloric acid (10 w/w%) to pH = 3. The resulting solution was
extracted with ethyl acetate (3×50 mL), dried (MgSO4) and evaporated to give a pale yellow
solid (2.86 g), which proved to be a mixture of compounds 14, 4h, 6b, and 8 in a
1
61 : 18 : 11 : 10 ratio as determined by H NMR. Compounds 4h, 6b, and 8 have been
isolated and characterized in the experiments described above. An analytical sample of 2,3-
dichloro-5-(2-methyl-1,3-dioxolane-2-yl)benzoic acid (14) was obtained by fractional
crystallization of the product mixture to give 14 as an off-white solid, mp 140–141 °C
1
(heptane/ethyl acetate 10:1). IR (KBr, cm–1): 2994, 2886, 1709, 1435, 1232, 1037. H NMR
(500 MHz, CDCl3): δ 7.94 (1H, d, J=2.0 Hz), 7.77 (1H, d, J=2.1 Hz), 4.09–4.06 (2H, m),
13
3.83–3.77 (2H, m), 1.64 (3H, s). C NMR (125 MHz, CDCl3): δ 170.2, 143.5, 134.9, 131.8,
17

ACCEPTED MANUSCRIPT
131.1, 127.1, 107.6, 64.8, 27.4. Anal. Calcd for C11H10Cl2O4 (277.11): C 47.68, H 3.64, Cl
25.59%. Found: C 47.74, H 3.63, Cl 25.23%.
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