Synthesis of the precursor of anti-inflammatory agents by cross-coupling using electrogenerated highly reactive zinc

Article abstract of DOI:10.1055/s-2002-35978

Highly reactive zinc metal was readily prepared by electrolysis of a DMF solution containing naphthalene and a supporting electrolyte in a one-compartment cell fitted with a platinum cathode and a zinc anode. This reactive zinc was used for efficient transformation of ethyl 2-bromoacrylate into the corresponding organozinc compound, which was reacted with various aryl iodides in the presence of palladium catalyst to give the corresponding cross-coupling products, ethyl 2-arylpropenoates, in high yields. These cross-coupling reactions were successfully applied to a synthesis of the precursors of non-steroidal anti-inflammatory agents such as ibuprofen, naproxen, ketoprofen, loxoprofen, indoprofen, suprofen, cicloprofen, and flurbiprofen.

Full text of DOI:10.1055/s-2002-35978

PAPER
2681
Synthesis of the Precursor of Anti-Inflammatory Agents by Cross-Coupling
Using Electrogenerated Highly Reactive Zinc
Electrogeneration
i
of
H
igh
s
ly Reactiv
h
e
Zinc ah A. Jalil, Nobuhito Kurono, Masao Tokuda*
Division of Molecular Chemistry, Graduate School of Engineering, Hokkaido University, Sapporo 060-8628, Japan
Fax +81(11)7066598; E-mail: tokuda@org-mc.eng.hokudai.ac.jp
Received 19 August 2002; revised 25 September 2002
with aryl iodides9 or bromides10 in the presence of a Pd(II)
catalyst. In this paper we report a successful application of
these cross-coupling reactions to an efficient synthesis of
the precursor of various anti-inflammatory agents such as
Abstract: Highly reactive zinc metal was readily prepared by elec-
trolysis of a DMF solution containing naphthalene and a supporting
electrolyte in a one-compartment cell fitted with a platinum cathode
and a zinc anode. This reactive zinc was used for efficient transfor-
mation of ethyl 2-bromoacrylate into the corresponding organozinc ibuprofen, naproxen, ketoprofen, loxoprofen, indoprofen,
compound, which was reacted with various aryl iodides in the pres-
suprofen, flurbiprofen, and cicloprofen. Similar cross-
ence of palladium catalyst to give the corresponding cross-coupling
coupling of -stannyl acrylate with aryl iodides or triflates
products, ethyl 2-arylpropenoates, in high yields. These cross-cou-
has been reported to give methyl 2-arylpropenoates in
pling reactions were successfully applied to a synthesis of the pre-
moderate yields and was found to be applicable to the syn-
cursors of non-steroidal anti-inflammatory agents such as
ibuprofen, naproxen, ketoprofen, loxoprofen, indoprofen, suprofen,
thesis of the precursor of naproxen in 71% yield.11
cicloprofen, and flurbiprofen.
We have earlier reported a new method for the preparation
Key words: anti-inflammatory agents, cross-coupling, reactive
zinc, organometallic reagents, electrolysis
of reactive zinc (EGZn) by electrolysis (Scheme 1) and its
use in facile isoprenylation12 and allylation13,14 of alde-
hydes and ketones. We have also reported a facile prepa-
ration of organozinc compounds from functionalized
alkyl iodides by using EGZn and their cross-couplings
with aryl halides.15 However, organozinc bromides were
rarely obtained or were only obtained in very low yields
from the corresponding organic bromides, even if the re-
active EGZn was used. Therefore, we developed a new
electrochemical method for preparation of more highly re-
active zinc (EGZn/Naph) by using naphthalene as a medi-
ator.9
2-Arylpropanoic acids are well-known as the lead struc-
ture of non-steroidal anti-inflammatory agents represent-
ed by ibuprofen.1 Many synthetic strategies have been
developed for the preparation of these acids, especially for
their derivatives: e.g. methylation of arylacetic acids,2 cy-
anation of 1-aryl-1-haloethanes,3 introduction of aryl
group into the -position of propanoic acids,4 rearrange-
ment of propiophenones or their derivatives,5 and others.6
However, most of these synthetic approaches give racem-
ic 2-arylpropanoic acids, whereas anti-inflammatory ac-
tive compounds are (S)-2-arylpropanoic acids. Most
useful method for the synthesis of (S)-2-arylpropanoic ac-
ids would be the preparation of 2-arylpropenoic acids fol-
lowed by enantioselective hydrogenation with Ru-(S)-
BINAP catalyst.7 Therefore, our attention has been direct-
ed to an efficient preparation of 2-arylpropenoic acids or
their derivatives.
Highly reactive zinc was readily prepared by constant-
current electrolysis of a DMF solution containing 0.1 M
Et4NClO4 in the presence of naphthalene. Electrolysis was
carried out at –10 °C in a one-compartment cell fitted with
a platinum plate cathode and a zinc plate anode.9 In this
electrolysis, a one-electron reduction of naphthalene mol-
ecule gives naphthalene radical anions, which reduce zinc
ions, generated by anodic dissolution of the zinc metal, to
give zero-valent highly reactive zinc (EGZn/Naph)
(Scheme 1).
We have already reported the preparation of 2-phenylpro-
penoic acid by electrochemical carboxylation of -bro-
mostyrene and its application to efficient synthesis of the
precursor of ibuprofen, 2-(p-isobutylphenyl)propenoic
acid.8 On the other hand, we recently examined the prep-
aration of 2-arylpropenoic acid esters by using a cross-
coupling reaction of ethyl 2-bromoacrylate with aryl ha-
lides. We developed very efficient method for the synthe-
sis of ethyl 2-arylpropenoates by cross-coupling reaction
of organozinc compound, derived from ethyl 2-bro-
moacrylate and electrogenerated highly reactive zinc,
0.1M Et4NClO4
-DMF, R.T.
"Zn" (EGZn)
electrolysis
Pt cathode - Zn anode
Naphthalene,
0.1M Et4NClO4
-DMF, -10 °C
"Zn" (EGZn/Naph)
Scheme 1
The reaction of EGZn/Naph with ethyl 2-bromoacrylate
(1) gave efficiently the corresponding organozinc bro-
mide 2 and subsequent cross-coupling reaction with vari-
ous aryl iodides 3 in the presence of palladium catalyst
proceeded efficiently to give ethyl 2-arylpropenoates 4 in
Synthesis 2002, No. 18, Print: 19 12 2002.
Art Id.1437-210X,E;2002,0,18,2681,2686,ftx,en;F06402SS.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0039-7881

2682
A. A. Jalil et al.
PAPER
almost quantitative yields (Scheme 2).9 All of the steps in-
volving the electrochemical preparation of highly reactive
EGZn/Naph, the transformation of 1 to the corresponding
organozinc 2, and the cross-coupling reaction of 2 with
aryl iodides 3 were carried out in a one-pot.
Br
COOEt
1
EGZn/Naph
BrZn
COOEt
DMF, -20 °C, 1 h
2
We applied these efficient cross-coupling reactions to a
synthesis of the precursor of anti-inflammatory agents.
Cross-coupling reaction of organozinc bromide 2 with 4-
isobutyliodobenzene (3a) gave the precursor of ibuprofen
(4a) in 93% yield. Similar one-pot reactions of 2 with aryl
iodides 3b–h afforded the precursor of ketoprofen (4b)
cicloprofen (4c), loxoprofen (4d), indoprofen (4e),
naproxen (4f), suprofen (4g), and flurbiprofen (4h) in high
yields, respectively. Results are summarized in Table 1.
Ar-I
3
Ar
COOEt
5 mol% Pd(P(o-Tol)3)2Cl2
4
DMF, 70 °C, 3h
Scheme 2
HRMS: m/z calcd for C10H13I: 260.0062. Found: 260.0066.
1
IR spectra were recorded on a Jasco IR-810 IR spectrometer. H
3-Iodobenzophenone (3b)20
NMR spectra were recorded on a Jeol JNM-EX270 FT NMR spec-
trometer operated at 270 MHz (solvent CDCl3). Proton-decoupled
13C NMR spectra were recorded at 67.5 MHz on a Jeol JNM-EX270
spectrometer. 1H and 13C chemical shifts are reported in ppm ( ) us-
ing SiMe4 as an internal standard. High and low resolution mass
spectra were determined with a Jeol JMS-AX500 or Jeol JMS-
SX102A spectrometer. TLC and column chromatography were car-
ried out on Merck silica gel (60 PF-254). Commercially available
anhyd DMF packed under N2 (Kanto Chemical) was used without
further purification. Et4NClO4 was prepared according to the previ-
ously reported method.15 Zinc plate is commercially available in
more than 99.9% purities, and they were washed with 2 N HCl be-
fore electrolysis. Commercially available naphthalene (Junsei
Chemical, 99%) was used after recrystallization from MeOH. Iodo-
benzene is commercially available and was purified by distillation
prior to use.
Ethyl 2-bromoacrylate,16 and 1-iodo-4-isobutylbenzene (3a)17 were
prepared according to the procedure reported in the literature. 3-Io-
dobenzophenone (3b), 2-iodofluorene (3c), 2-iodo-6-methoxy-
naphthalene (3f), 2-(4-iodobenzoyl)thiophene (3g),18 2-fluoro-4-
iodobiphenyl (3h) were prepared by iodination of the corresponding
aryl bromides according to the literature.19 2-(4-Iodobenzyl)cyclo-
pentanone (3d) and 2-(4-iodophenyl)-2,3-dihydroisoindol-1-one
(3e) were prepared by the following procedures described below.
IR (neat): 3058, 1663, 1447, 1270, 715, 658 cm–1.
1H NMR (270 MHz, CDCl3): = 8.13 (t, 1 H, J = 1.7 Hz), 7.92 (dd,
1 H, J = 1.0, 7.9 Hz), 7.75 (m, 3 H), 7.60 (d, 2 H, J = 7.3 Hz), 7.53
(m, 1 H), 7.23 (t, 1 H, J = 7.9 Hz).
13C NMR (67.5 MHz, CDCl3): = 194.95, 141.06, 139.41, 138.51,
136.78, 132.76, 129.94, 129.88, 129.06, 128.37, 93.99.
EIMS: m/z (%) = 308 (69), 231 (23), 203 (10), 181 (8), 105 (100),
77 (39).
HRMS: m/z calcd for C13H9IO: 307.9698. Found: 307.9699.
2-Iodofluorene (3c)21
Yield: 53%; light yellow crystals; mp 123–125 °C (Lit.21 mp 124–
126 °C).
IR (nujol): 3130, 1465, 1377, 821, 762, 729 cm–1.
1H NMR (270 MHz, CDCl3): = 7.89 (s, 1 H), 7.76 (d, 1 H, J = 7.9
Hz), 7.70 (d, 1 H, J = 7.9 Hz), 7.53 (d, 2 H, J = 7.9 Hz), 7.36 (m, 2
H), 3.87 (s, 2 H).
13C NMR (67.5 MHz, CDCl3): = 145.34, 142.55, 141.17, 140.63,
135.60, 134.02, 127.21, 126.83, 124.91, 121.38, 119.91, 91.81,
36.52.
EIMS: m/z (%) = 292 (67), 165 (100), 83 (12).
Ethyl 2-Bromoacrylate (1)16
Yield: 82%; colorless oil; bp 80 °C/69 mmHg.
HRMS: m/z calcd for C13H9I: 291.9749. Found: 291.9749.
IR (neat): 1725, 1605, 1259, 1102 cm–1.
2-(4-Iodobenzyl)cyclopentanone (3d)
To a mixture of NaH (2.0 g, 26 mmol) and anhyd DMF (170 mL) in
a 200 mL side-arm flask fitted with a reflux condenser and a N2-in-
let system, was added methyl cyclopentanone-2-carboxylate (6.2
mL, 50 mmol) via syringe and the mixture was stirred for 3 h. A
DMF (20 ml) solution of 4-bromobenzyl chloride (12.5 g, 26 mmol)
was added and the mixture was stirred for 4 d at r.t. The mixture was
extracted with Et2O (3 100 mL), and the Et2O layer was washed
with brine (4 100 mL), and dried (MgSO4). Evaporation of the sol-
vent gave methyl 1-(4-bromobenzyl)-2-oxocyclopentanecarboxy-
late as a yellow oil, which was used directly in the following
reaction. A mixture of the crude product and 48% HBr (25 mL) in
a 100 mL flask fitted with a reflux condenser and N2-inlet system
was refluxed for 22 h. The mixture was cooled and poured into ice-
water and extracted with Et2O. The combined organic solutions
were washed with sat. aq Na2CO3 (2 100 mL), brine (100 mL) and
dried (MgSO4 Evaporation of the solvent gave the crude product 2-
(4-bromobenzyl)cyclopentanone in 82% yield. Iodination of the
product according to the literature19 gave 3d as a crystalline solid in
64% yield; mp 83–84 °C.
1H NMR (270 MHz, CDCl3): = 6.96 (d, 1 H, J = 1.7 Hz), 6.27 (d,
1 H, J = 1.7 Hz), 4.29 (q, 2 H, J = 7.3 Hz), 1.34 (t, 3 H, J = 7.3 Hz).
13C NMR (67.5 MHz, CDCl3): = 161.72, 130.26, 121.47, 62.57,
13.93.
EIMS: m/z (%) = 180 (18), 178 (18), 150 (19), 133 (40), 105 (49),
99 (65), 45 (100).
HRMS: m/z calcd for C5H7BrO2: 177.9629. Found: 177.9622.
1-Iodo-4-isobutylbenzene (3a)19
Yield: 61%; bp 120–122 °C/16 mmHg.
IR (neat): 1484, 1465, 1401, 1384, 1007 cm–1.
1H NMR (270 MHz, CDCl3): = 7.58 (dd, 2 H, J = 2.0 6.6 Hz), 6.90
(dd, 2 H, J = 2.0, 6.6 Hz), 2.41 (d, 2 H, J = 7.26 Hz), 1.82 (m, 1 H),
0.88 (d, 6 H, J = 6.6 Hz).
13C NMR (67.5 MHz, CDCl3): = 141.22, 137.07, 131.20, 90.66,
44.84, 30.08, 22.25.
IR (neat): 1721, 1460, 1378, 1154, 854 cm–1.
EIMS: m/z (%) = 260 (73), 232 (68), 217 (100), 203 (18), 128 (17),
89 (27), 77 (14).
Synthesis 2002, No. 18, 2681–2686 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Electrogeneration of Highly Reactive Zinc
2683
Table 1 Synthesis of the Precursors of Anti-Inflammatory Agentsa
Entry
Aryl Iodide 3
Product 4
Yield (%)b
I
CO2Et
1
93
92
87
96
94
95
3a
4a
O
O
I
CO2Et
2
3
4
5
6
3b
4b
4c
4d
4e
I
CO2Et
3c
O
I
O
CO2Et
3d
O
O
N
N
I
CO2Et
3e
I
CO2Et
MeO
MeO
3f
4f
I
CO2Et
7
8
72
84
S
S
O
O
3g
4g
I
CO2Et
F
F
3h
4h
a Organozinc bromide 2, prepared from ethyl 2-bromoacrylate (1) (3 mmol) and EGZn/Naph (6 mmol) in DMF was reacted at 70 °C for 3 h
with aryl iodides 3 (2 mmol) in the presence of 5 mol% of Pd[P(o-Tol)3]2Cl2.
b Isolated yields based on aryl iodides.
1H NMR (270 MHz, CDCl3): = 7.60 (dd, 2 H, J = 2.0, 8.3 Hz),
6.92 (dd, 2 H, J = 2.0, 8.3 Hz), 3.07 (d, 1 H, J = 13.2 Hz), 2.55–2.47
(m, 1 H), 2.40–2.25 (m, 2 H), 2.16–1.91 (m, 4 H), 1.82–1.61 (m, 1
H).
Anal. Calcd for C12H13IO: C, 48.02; H, 4.37; I, 42.28. Found: C,
48.21; H, 4.57; I, 42.32.
2-(4-Iodophenyl)-2,3-dihydroisoindol-1-one (3e)
To a mixture of o-formylphthalic acid (3.76 g, 25 mmol) and anhyd
DMF (150 mL) in a 300 mL three-necked flask, were added MeI
(15.6 g, 250 mmol) and NaHCO3 (8.4 g, 100 mmol) and stirred for
66 h at r.t. The mixture was extracted with EtOAc (3 100 mL) and
13C NMR (67.5 MHz, CDCl3): = 219.71, 139.59, 137.43, 131.00,
91.30, 50.73, 38.10, 35.01, 29.00, 20.49.
EIMS: m/z (%) = 300 (100), 217 (80), 204 (14), 145 (9), 116 (11),
90 (14).
washed with H2O (3
100 mL), brine (100 mL), and dried
(MgSO4). Evaporation of the solvent gave a colorless oil, which was
used in the following reaction. A mixture of the crude product, 4-
iodoaniline (7.0 g, 32 mmol), AcOH (1.4 mL), and triacetoxy boro-
HRMS: m/z calcd for C12H13IO: 300.0011. Found: 300.0009.
Synthesis 2002, No. 18, 2681–2686 ISSN 0039-7881 © Thieme Stuttgart · New York

2684
A. A. Jalil et al.
PAPER
hydride (9.8 g, 46 mmol) in anhyd CH2Cl2 (250 mL) was stirred for
47 h at r.t. The mixture was extracted with CH2Cl2 (2 100 mL),
and the combined organic layers were washed with aq 2 N NaOH
(100 mL), H2O (2 100 mL), brine, and dried (MgSO4). Evapora-
tion of the solvent gave a crystalline solid, which was filtered to
give 3e in 83% yield; mp 200–203 °C.
EGZn/Naph was calculated from the weight of dissolved zinc an-
ode. A solution containing EGZn/Naph was directly used for the
preparation of organozinc compounds after the zinc anode was re-
moved from the electrolysis cell.
Cross-Coupling Reaction Using EGZn/Naph; General Proce-
dure
IR (neat): 1686, 1465, 1377, 826, 731 cm–1.
To the DMF solution containing EGZn/Naph was added ethyl 2-
bromoacrylate (1; 537 mg, 3 mmol) and the mixture was stirred at
–20 °C under N2 for 1 h. The appropriate aryl iodide 3 (2 mmol) and
Pd[P(o-Tol)3]2Cl2 (0.11 mmol) were added, and the reaction mix-
ture was stirred at 70 °C for 3 h. The resulting mixture was
quenched with aq HCl solution and filtered. The filtrate was extract-
ed with Et2O (3 50 mL) and the combined organic layers were
washed with H2O (3 100 mL), sat. aq Na2S2O3 solution (100 mL)
and brine (100 mL), and dried (MgSO4). After evaporation of Et2O,
the crude product was purified by column chromatography on silica
gel with EtOAc–hexane to give the ethyl 2-arylpropenoate 4.
1H NMR (270 MHz, CDCl3): = 7.93 (d, 1 H, J = 7.3 Hz), 7.72–
7.50 (m, 7 H), 4.84 (s, 2 H).
13C NMR (67.5 MHz, CDCl3): = 167.51, 139.80, 139.28, 138.02,
132.90, 132.33, 128.50, 124.19, 122.64, 120.88, 87.85, 50.41.
EIMS: m/z (%) = 335 (100), 307 (15), 208 (7), 179 (7), 104 (10),
90 (12), 76 (16).
HRMS: m/z calcd for C14H10INO: 334.9807. Found: 334.9798.
Anal. Calcd for C14H10INO: C, 50.17; H, 3.01; N, 4.18; I, 37.87.
Found: C, 49.91; H, 3.10; N, 4.05; I, 38.16.
Ethyl 2-(4-Isobutylphenyl)propenoate (4a)
Colorless oil.
2-Iodo-6-methoxynaphthalene (3f)19
Yield: 38%; mp 145–146 °C (Lit.19 mp 146–147 °C).
IR (neat): 1720, 1615, 1512, 1466, 1367, 1199, 1181, 1089, 850,
806 cm–1.
1H NMR (270 MHz, CDCl3): = 7.34 (d, 2 H, J = 8.3 Hz), 7.13 (d,
2 H, J = 8.3 Hz), 6.28 (d, 1 H, J = 1.3 Hz), 5.87 (d, 1 H, J = 1.3 Hz),
4.29 (q, 2 H, J = 7.3 Hz), 2.48 (d, 2 H, J = 6.9 Hz), 1.87 (m, 1 H),
1.33 (t, 3 H, J = 7.3 Hz), 0.91 (d, 6 H, J = 6.9 Hz).
1H NMR (270 MHz, CDCl3): = 8.14 (s, 1 H), 7.68–7.46 (m, 3 H),
7.25–7.07 (m, 2 H), 3.92 (s, 3 H).
13C NMR (67.5 MHz, CDCl3): = 157.93, 136.19, 134.68, 133.30,
130.55, 128.34, 128.30, 119.52, 105.63, 88.05, 55.28.
EIMS: m/z (%) = 284 (100), 269 (18), 236 (56), 223 (13), 193 (27),
114 (44).
13C NMR (67.5 MHz, CDCl3): = 163.99, 142.41, 141.37, 130.91,
128.75 125.45, 118.98, 60.90, 44.94, 30.01, 22.28, 13.95.
HRMS: m/z calcd for C11H9OI: 283.9698. Found: 283.9688.
EIMS: m/z (%) = 232 (63), 189 (100), 161 (16), 145 (15), 115 (28).
HRMS: m/z calcd for C15H20O2: 232.1463. Found: 232.1472.
2-(4-Iodobenzoyl)thiophene (3g)22
Yield: 60%; mp 107–108 °C (Lit.22 mp 106.5 °C).
IR (nujol): 1625, 1460, 1377, 849 cm–1.
Anal. Calcd for C15H20O2: C, 77.55; H, 8.68. Found: C, 77.68; H,
8.83.
1H NMR (270 MHz, CDCl3): = 7.87 (dd, 2 H, J = 2.0, 6.6 Hz),
7.75 (dd, 1 H, J = 1.0, 4.6 Hz), 7.62 (dd, 1 H, J = 1.0, 3.6 Hz), 7.59
(dd, 2 H, J = 2.0, 6.6 Hz), 7.17 (dd, 1 H, J = 3.6, 4.6 Hz).
13C NMR (67.5 MHz, CDCl3): = 187.28, 143.11, 137.68, 137.38,
134.79, 134.59, 130.60, 128.07, 99.75.
Ethyl 2-(3-Benzoylphenyl)propenoate (4b)
IR (neat): 1720, 1663, 1618, 1448, 1200, 1026, 710 cm–1.
1H NMR (270 MHz, CDCl3): = 7.86–7.76 (m, 3 H), 7.75–7.57 (m,
3 H), 7.52–7.45 (m, 3 H), 6.43 (d, 1 H, J = 1.0 Hz), 5.96 (d, 1 H,
J = 1.0 Hz), 4.30 (q, 2 H, J = 7.3 Hz), 1.33 (t, 3 H, J = 7.3 Hz).
13C NMR (67.5 MHz, CDCl3): = 196.37, 166.31, 140.67, 137.45,
137.39, 136.96, 132.51, 132.33, 130.08, 129.92, 129.72, 128.30,
128.05, 127.71, 61.28, 14.18.
EIMS: m/z (%) = 314 (82), 231 (25), 203 (14), 187 (22), 111 (100),
76 (30).
HRMS: m/z calcd for C11H7IOS: 313.9263. Found: 313.9263.
2-Fluoro-4-iodobiphenyl (3h)
Yield: 40%.
IR (neat) : 1205, 1158, 859, 764, 697 cm–1.
EIMS: m/z (%) = 280 (45), 203 (69), 105 (100), 77 (52).
HRMS: m/z calcd for C18H16O3: 280.1099. Found: 280.1094.
Anal. Calcd for C18H16O3: C, 77.12; H, 5.75. Found: C, 76.78; H,
5.85.
1H NMR (270 MHz, CDCl3): = 7.27–7.58 (m, 6 H), 7.19–7.13 (t,
2 H, J = 8.3 Hz).
13C NMR (67.5 MHz, CDCl3): = 160.97, 133.53, 131.81, 128.66,
128.45, 127.92, 125.45, 125.07, 92.08.
Ethyl 2-(2-Fluorenyl)propenoate (4c)
IR (neat): 1720, 1610, 1457, 1401, 1209, 1025, 738 cm–1.
1H NMR (270 MHz, CDCl3): = 7.80–7.62 (m, 2 H), 7.62 (d, 1 H,
J = 0.7 Hz), 7.53 (d, 1 H, J = 0.7 Hz), 7.46–7.31 (m, 3 H), 6.35 (d,
1 H, J = 1.3 Hz), 5.95 (d, 1 H, J = 1.3 Hz), 4.32 (q, 2 H, J = 7.3 Hz),
3.92 (s, 2 H), 1.35 (t, 3 H, J = 7.3 Hz).
EIMS: m/z (%) = 298 (100), 170 (97), 151 (20), 144 (7), 99 (5), 85
(23), 75 (10), 51 (8).
HRMS: m/z calcd for C12H8FI: 297.9655. Found: 297.9654.
13C NMR (67.5 MHz, CDCl3): = 167.08, 143.52, 143.31, 143.02,
141.74, 141.22, 135.20, 127.04, 126.85, 126.76, 125.89, 125.01,
124.91, 120.02, 119.43, 61.12, 36.88, 14.22.
Electrogenerated Highly Reactive Zinc (EGZn/Naph)
A normal one-compartment cell equipped with a magnetic stirrer
and a serum cap was used. Electrogenerated highly reactive zinc
(EGZn/Naph) (6 mmol) was prepared by the electrolysis of a DMF
solution (10 mL) containing 0.1 M Et4NClO4 (230 mg) and naph-
thalene (12 mmol) in a one-compartment cell fitted with a platinum
plate cathode (2 2 cm2) and a zinc plate anode (2 2 cm2). Elec-
trolysis was carried out at –10 °C at a constant current of 60 mA/cm2
under N2. The quantity of electricity passed was 0.012 Faradays,
which corresponded to 2 Faradays per mol of zinc. The amount of
EIMS: m/z (%) = 264 (85), 235 (22), 190 (100), 165 (16).
HRMS: m/z calcd for C18H16O2: 264.1150. Found: 264.1162.
Anal. Calcd for C18H16O2: C, 81.79; H, 6.10. Found: C, 81.84; H,
5.92.
Synthesis 2002, No. 18, 2681–2686 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Electrogeneration of Highly Reactive Zinc
2685
Ethyl 2-[4-(2-Oxocyclopentylmethyl)phenyl]propenoate (4d)
IR (neat): 2962, 1741, 1719, 1615, 1514, 1455, 1405, 1199, 1183,
1023, 863, 702 cm–1.
Anal. Calcd for C16H14O3S: C, 67.11; H, 4.93; S, 11.20. Found: C,
67.17; H, 4.99; 10.89.
Ethyl 2-[4-(2-Fluoro)biphenyl]propenoate (4h)
1H NMR (270 MHz, CDCl3): = 7.35 (dd, 2 H, J = 2.0, 8.3 Hz),
7.15 (dd, 2 H, J = 2.0, 8.3 Hz), 6.31 (d, 1 H, J = 1.0 Hz), 5.87 (d, 1
H, J = 1.0 Hz), 4.29 (q, 2 H, J = 7.3 Hz), 3.16 (dd, 1 H, J = 4.0, 13.5
Hz), 2.54 (dd, 1 H, J = 9.6, 13.5 Hz), 2.35 (m, 2 H), 2.05 (m, 4 H),
1.73 (m, 1 H), 1.34 (t, 3 H, J = 7.3 Hz).
IR (neat): 1721, 1616, 1486, 1413, 1220, 1171, 835, 769, 698 cm–1.
1H NMR (270 MHz, CDCl3): = 7.58–7.55 (m, 2 H), 7.48-7.37 (m,
5 H), 7.31–7.27 (m, 1 H), 6.41 (s, 1 H), 5.98 (s, 1 H), 4.33 (q, 2 H,
J = 7.3 Hz), 1.36 (t, 3 H, J = 7.3 Hz).
13C NMR (67.5 MHz, CDCl3): = 219.68, 166.52, 140.90, 139.82,
134.32, 128.34, 128.00, 125.59, 60.76, 50.57, 37.81, 34.95, 28.86,
20.24, 13.91.
13C NMR (67.5 MHz, CDCl3): = 166.33, 161.19, 140.18, 135.45,
130.37, 129.06, 129.02, 128.57, 127.30, 124.40, 116.37, 116.01,
61.39, 14.27.
EIMS: m/z (%) = 272 (83), 198 (46), 189 (100), 141 (26), 115 (48),
EIMS: m/z (%) = 270 (100), 197 (76).
91 (25).
HRMS: m/z calcd for C17H15FO2: 270.1056. Found: 270.1054.
HRMS: m/z calcd for C17H20O3: 272.1412. Found: 272.1418.
Anal. Calcd for C17H15 FO2: C, 75.54; H, 5.59; F, 7.03. Found: C,
75.71; H, 5.35; F, 6.68.
Anal. Calcd for C17H20O3: C, 74.97; H, 7.40. Found: C, 74.66; H,
7.43.
Acknowledgment
Ethyl 2-[4-(1-Oxo-1,3-dihydroisoindol-2-yl)phenyl]propenoate
(4e)
We thank the Japanese Ministry of Education, Science, Sports and
Culture for financial support under a Grant-in-Aid for Scientific Re-
search (B) (No. 11450342).
Mp 110–111 °C.
IR (nujol): 2854, 1721, 1687, 1467, 1154, 735 cm–1.
1H NMR (270 MHz, CDCl3): = 7.95–7.87 (m, 3 H), 7.61–7.58 (m,
1 H), 7.54–7.49 (m, 4 H), 6.34 (d, 1 H, J = 1.0 Hz), 5.92 (d, 1 H,
J = 1.0 Hz), 4.88 (s, 2 H), 4.31 (q, 2 H, J = 7.3 Hz), 1.35 (t, 3 H,
J = 7.3 Hz).
13C NMR (67.5 MHz, CDCl3): = 167.49, 166.76, 140.70, 140.02,
139.35, 133.08, 132.65, 132.15, 129.04, 128.39, 126.00, 124.13,
122.61, 118.74, 61.12, 50.59, 14.20.
References
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EIMS: m/z (%) = 307 (100), 234 (64), 209 (9), 103 (8), 90 (6), 77
(6).
HRMS: m/z calcd for C19H17NO3: 307.1208. Found: 307.1210.
Anal. Calcd for C19H17NO3: C, 74.25; H, 5.58; N, 4.56. Found: C,
74.09; H, 5.74; N, 4.27.
Ethyl 2-(6-Methoxynaphthalen-2-yl)propenoate (4f)
IR (neat): 1711, 1605, 1459, 1262, 1196, 1030, 859, 829, 813 cm–1.
1H NMR (270 MHz, CDCl3): = 7.84 (s, 1 H), 7.73 (t, 2 H, J = 8.3
Hz), 7.50 (dd, 1 H, J = 2.0, 8.3 Hz), 7.14 (d, 2 H, J = 8.3 Hz), 6.38
(d, 1 H, J = 1.0 Hz), 5.98 (d, 1 H, J = 1.0 Hz), 4.32 (q, 2 H, J = 7.3
Hz), 3.91 (s, 3 H), 1.35 (t, 3 H, J = 7.3 Hz).
13C NMR (67.5 MHz, CDCl3): = 166.72, 157.81, 141.22, 134.00,
131.70, 129.52, 128.27, 126.99, 126.34, 126.16, 125.61, 118.78,
105.27, 60.83, 54.92, 13.95.
EIMS: m/z (%) = 256 (100), 228 (14), 183 (71), 168 (15), 139 (19).
HRMS: m/z calcd for C16H16O3: 256.1099. Found: 256.1097.
(5) (a) Higgins, S. D.; Thomas, C. B. J. Chem. Soc., Perkin
Trans. 1 1982, 235. (b) Fujii, K.; Nakao, K.; Yamauchi, T.
Synthesis 1982, 456. (c) Tamura, Y.; Shirouchi, Y.; Haruta,
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Yamauchi, T. Synthesis 1983, 444. (e) Giordano, C.;
Castaldi, G.; Casagrande, F.; Belli, A. J. Chem. Soc., Perkin
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Giordano, C. J. Org. Chem. 1983, 48, 4658. (g)Goosen, A.;
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Anal. Calcd for C16H16O3: C, 74.98; H, 6.29. Found: C, 75.24; H,
6.39.
Ethyl 2-[4-(2-Thiophenecarbonyl)phenyl]propenoate (4g)
IR (neat): 1720, 1636, 1414, 1294, 1198, 1086, 1019, 845, 722 cm–1.
1H NMR (270 MHz, CDCl3): = 7.87 (dd, 2 H, J = 2.0, 6.6 Hz),
7.74 (dd, 1 H, J = 1.0, 5.0 Hz), 7.68 (dd, 1 H, J = 1.0, 4.0 Hz), 7.56
(dd, 2 H, J = 2.0, 6.6 Hz), 7.18 (dd, 1 H, J = 4.0, 5.0 Hz), 6.47 (d, 1
H, J = 1.0 Hz), 6.00 (d, 1 H, J = 1.0 Hz), 4.32 (q, 2 H, J = 7.3 Hz),
1.35 (t, 3 H, J = 7.3 Hz).
13C NMR (67.5 MHz, CDCl3): = 187.47, 166.02, 143.32, 140.47,
137.36, 134.72, 134.18, 128.84, 128.25, 127.94, 127.89, 61.19,
14.04.
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EIMS: m/z (%) = 286 (72), 213 (29), 203 (33), 111 (100).
HRMS: m/z calcd for C16H14O3S: 286.0663. Found: 286.0670.
Synthesis 2002, No. 18, 2681–2686 ISSN 0039-7881 © Thieme Stuttgart · New York

2686
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Synthesis 2002, No. 18, 2681–2686 ISSN 0039-7881 © Thieme Stuttgart · New York