Deprotonation of thiophenes using lithium magnesates

Article abstract of DOI:10.1016/j.tet.2005.03.024

Thiophene was regioselectively deprotonated at C2 on treatment with 1/3 equiv of Bu₃MgLi in THF at room temperature. The lithium arylmagnesate formed was either trapped with electrophiles or cross-coupled in a 'one-pot' procedure with aryl halides under palladium catalysis. 2-Chlorothiophene and 2-methoxythiophene were similarly deprotonated at C5 under the same reaction conditions. The enhancement of the reactivity of the base using TMEDA was evidenced using ¹H NMR spectroscopy.

Full text of DOI:10.1016/j.tet.2005.03.024

Tetrahedron 61 (2005) 4779–4784
Deprotonation of thiophenes using lithium magnesates
a
Omar Bayh, Ha c¸ an Awad, Florence Mongin,
a
a, ,†
a
*
Christophe Hoarau, Fran c¸ ois Tr e´ court,
a
a
a
b
b
Guy Qu e´ guiner, Francis Marsais, Fernando Blanco, Bel e´ n Abarca and Rafael Ballesteros
b
a
Laboratoire de Chimie Organique Fine et H e´ t e´ rocyclique, UMR 6014, IRCOF, CNRS, Universit e´ et INSA de Rouen, Place E. Blondel,
BP 08, 76131 Mont-Saint-Aignan Cedex, France
b
Departamento de Qu ´ı mica Org a´ nica, Facultad de Farmacia, Universidad de Valencia, Avda.Vicente Andr e´ s Estell e´ s s/n,
6100 Burjassot, Valencia, Spain
4
Received 17 January 2005; revised 4 March 2005; accepted 7 March 2005
Available online 30 March 2005
3
Abstract—Thiophene was regioselectively deprotonated at C2 on treatment with 1/3 equiv of Bu MgLi in THF at room temperature. The
lithium arylmagnesate formed was either trapped with electrophiles or cross-coupled in a ‘one-pot’ procedure with aryl halides under
palladium catalysis. 2-Chlorothiophene and 2-methoxythiophene were similarly deprotonated at C5 under the same reaction conditions. The
enhancement of the reactivity of the base using TMEDA was evidenced using H NMR spectroscopy.
1
q 2005 Elsevier Ltd. All rights reserved.
6
1
. Introduction
magnesiation of pyridine derivatives; alkylmagnesium
halides and dialkylmagnesiums rarely deprotonated such
7
substrates because of easier 1,4-addition reactions. Next,
Kondo and Sakamoto described the regioselective magne-
8
siation of N-substituted indoles, thiophenes and thiazole
using (iPr N) Mg, iPr NMgBr and iPr NMgCl. Never-
theless, because of the limited reactivity of these bases, an
excess has in general to be used to ensure good yields.
Pyrrole rings of numerous 1-phenyldipyrromethanes did not
required protection step to be deprotonated at the position
The preparation of functional heterocycles is an important
synthetic goal because of the multiple applications of these
1
molecules. Deprotonation using alkyllithiums or lithium
9
9
dialkylamides has been developed as one of the major tools
since lithiated derivatives display a high reactivity towards
2
2
2
2
2
many electrophilic functions. Nevertheless, this method-
ology often requires low temperatures, which can be
difficult to realize on an industrial scale. In addition, unlike
organoboron, organotin, organozinc and organomagnesium
compounds, organolithiums can hardly be involved in
1
0
adjacent to the nitrogen atom using EtMgBr.
3
cross-coupling reactions.
Ten years after Eaton, Kondo achieved the deprotonation of
methyl benzoate and other activated benzenes through the
formation of an arylzincate using lithium di-t-butyl(2,2,6,6-
tetramethylpiperidino) zincate as a base, a methodology
extended to the pyridine, quinoline, isoquinoline and ethyl
thiophenecarboxylates series, but with limited appli-
cations due to their moderate reactivity with electrophiles.
The arylmagnesates usually prepared by halogen–mag-
nesium exchange reacting with a wider range of electro-
philes than arylzincates, we have been interested in
deprotonation reactions using lithium magnesates. This
possibility has rarely been documented. Mulvey reported in
1999, the preparation of a mixed-metal sodium–magnesium
macrocyclic amide which behaves like a template for the
More recently, organomagnesium compounds have been
prepared by deprotonation at higher temperatures, but the
uses of such reactions have barely been explored. The
pioneering work of Marxer and Siegrist in 1974 showed
EtMgBr was capable of deprotonating 1-phenylpyrazole
at the ortho position of the phenyl ring. Eaton reported
in 1989 the deprotonation of both methyl benzoate and
N,N-diethylbenzamide with Hauser bases (iPr NMgBr or
2
1
1
4
TMPMgBr, TMPZ2,2,6,6-tetramethylpiperidino) or mag-
5
nesium diamides ((iPr N) Mg or TMP Mg). In 1995,
Schlecker extended this methodology to the regioselective
2
2
2
1
2
Keywords: Deprotonation; Ate complexes; Magnesium; Thiophene.
*
site selective dideprotonation of benzene and toluene.
Corresponding author. Tel.: C33 2 23 23 69 31; fax: C33 2 23 23 63 74;
e-mail: florence.mongin@univ-rennes1.fr
This process cannot be used as it is for synthetic purposes
because it involves a large excess of arene (5 mmol out of
the 5 mL used are consumed in the reaction). Richey
observed in 2004 that treating benzene halides with
†
Present address: Synth e` se & ElectroSynth e` se Organiques, UMR 6510,
CNRS, B aˆ timent 10A, Universit e´ de Rennes 1, Campus de Beaulieu,
Avenue du G e´ n e´ ral Leclerc, 35042 Rennes Cedex, France.
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.03.024

4780
O. Bayh et al. / Tetrahedron 61 (2005) 4779–4784
1
3
magnesates partially results in benzyne formation. Even if
the organometallic precursors have not been intercepted by
electrophiles, the results show magnesates are capable of
abstracting aromatic protons. Very recently, we studied the
deprotonation of fluoro aromatics using lithium magnesates,
the obtained arylmagnesates being either trapped with
electrophiles or involved in a palladium-catalyzed cross-
performed on 2-substituted thiophenes 2 and 3 to afford the
2,5-disubstituted compounds 5a–c and 6a,b (entries 4–8);
excellent yields were again obtained adding TMEDA to the
base (Table 1).
1
The role of TMEDA was ascertained by recording the H
NMR spectra of the reaction mixture obtained after the
deprotonation step (Fig. 1): the hydrogen–magnesium
exchange was quantitative using TMEDA whereas some
substrate was detected without. The increasing reactivity
may be accounted for by complexation of TMEDA to
the lithium ion of the triorganomagnesate to separate the
reactive magnesate ion from the intimate ion pair.
1
4
coupling.
Herein, we describe the synthesis of lithium tri(2-thienyl)
magnesates by deprotonation using lithium magnesates.
To obtain more information on the efficiency on the process,
1
the H NMR spectra of the heterocyclic magnesium ate
complexes were recorded. The reactivity of such mag-
nesium intermediates towards electrophiles or in metal-
catalyzed coupling reactions was studied.
The lithium tri(2-thienyl)magnesates were next involved in
cross-couplings with various aromatic halides under palla-
0
When lithium tri(2-thienyl)magnesate
dium catalysis using 1,1 -bis(diphenylphosphino)ferrocene
(dppf) as ligand.
1
4,18
2
. Results and discussion
was subjected to the reaction with p-deficient substrates
such as 2-bromopyridine and 3-bromoquinoline to give
compounds 4d,e, medium to good yields were obtained: the
best results were observed with the 2-bromo substrate, for
which the oxidative addition step is easier, while the other
reacts moderately (entries 1 and 2). Using iodobenzene and
4-bromoanisole surprisingly allowed the syntheses of the
phenyl derivatives 4f,g in high yields (entries 3 and 4).
Similar results were obtained starting from lithium
(5-chloro-2-thienyl)magnesate, affording the biaryl com-
pounds 5d,e (entries 5 and 6), but a lower yield of 22% was
noticed with methyl 4-iodobenzoate (entry 7), due to
competitive reactions with the ester function. 2-Substituted
5-methoxythiophenes 6c–e were obtained from lithium
(5-methoxy-2-thienyl)magnesate under the same reaction
conditions (entries 8–10, Table 2).
Lithiation of thiophene by BuLi is rapid in ethereal solvents,
a result ascribed to the strong acidifying effect of the sulfur
atom which compensates for an unlikely chelation of the
base. In addition, 2-substituted thiophenes generally give
exclusive lithiation at the 5-position, whatever the nature of
the substituent.
1
5
We attempted the deprotonation of thiophenes 1–3 using
lithium magnesates. The first experiments were conducted
1
6
on thiophene (1) using 1/3 equiv of lithium tributyl-
magnesate (Bu MgLi) in THF at room temperature.
3
Trapping the intermediate lithium magnesate with iodine
or 4-anisaldehyde afforded the iodide 4a and the alcohol 4b
in good yields (entries 1 and 2). Deprotonation of thiophene
using BuLi being favored in the presence of TMEDA, the
reaction was also carried out using Bu MgLi in the presence
1
5
3
of 1/3 equiv of this additive, and allowed the alcohol 4c
to be obtained after quenching with 3,4,5-trimethoxybenz-
aldehyde in 96% yield (entry 3). The reaction was next
3. Conclusion
Thiophene was regioselectively deprotonated at C2 using
Table 1. Deprotonation of thiophenes 1–3 and trapping with electrophiles
Entry
Substrate
Product
Yield, (%)
a
b
1
1 (RZH)
1 (RZH)
1 (RZH)
2 (RZCl)
2 (RZCl)
2 (RZCl)
3 (RZOMe)
3 (RZOMe)
4a (ElZI)
90
60
96
68
a
c
2
4b (ElZCH(OH)-4-anisyl)
d
e
e
3
4c (ElZCH(OH)-3,4,5-trimethoxyphenyl)
a
b
4
5a (ElZI)
a
c
5
5b (ElZCH(OH)-4-anisyl)
78
d
6
f
5c (ElZCH(OH)-3,4,5-trimethoxyphenyl)
93 (79)
75
87
a
b
7
6a (ElZI)
d
e
8
6b (ElZCH(OH)-3,4,5-trimethoxyphenyl)
a
The base is Bu
3
MgLi (1/3 equiv).
b
c
d
e
f
The electrophile is I
The electrophile is 4-anisaldehyde.
The base is Bu MgLi$TMEDA (1/3 equiv).
2
.
3
The electrophile is 3,4,5-trimethoxybenzaldehyde.
17
Using BuLi (1 equiv), THF, K75 8C, 2 h.

O. Bayh et al. / Tetrahedron 61 (2005) 4779–4784
4781
1
Figure 1. H NMR spectra of lithium tri(2-thienyl) magnesates.TMEDA in THF (rt) (a) from thiophene (1); (b) from 2-chlorothiophene (2) and (c) from
-methoxythiophene (3).
2
Table 2. Deprotonation of thiophenes 1–3 and cross-coupling with aromatic halides
Entry
Substrate
Product
Ar
Yield, (%)
a
1
2
3
4
5
6
7
8
9
1 (RZH)
1 (RZH)
1 (RZH)
1 (RZH)
2 (RZCl)
2 (RZCl)
2 (RZCl)
3 (RZOMe)
3 (RZOMe)
3 (RZOMe)
4d
4e
4f
4g
5d
5e
5f
6c
2-Pyridyl
3-Quinolyl
Phenyl
4-Methoxyphenyl
2-Pyridyl
4-Methoxyphenyl
4-(Methoxycarbonyl)phenyl
2-Pyridyl
Phenyl
4-(Methoxycarbonyl)phenyl
77
56
84
92
68
81
22
56
67
40
b
c
d
a
d
e
a
c
6d
6e
e
10
a
b
c
d
e
Using 2-bromopyridine.
Using 3-bromoquinoline.
Using iodobenzene.
Using 4-bromoanisole.
Using methyl 4-iodobenzoate.
1
/3 equiv of Bu MgLi in THF at room temperature; the
3
spectra were recorded with a Bruker AM 300 spectrometer
1
( H at 300 MHz and C at 75 MHz). The solvent was
13
thienylmagnesate generated was either intercepted with
electrophiles or cross-coupled in a ‘one-pot’ procedure. The
enhancement of the reactivity of the base using TMEDA
was evidenced by recording the H NMR spectra of
the reaction mixtures. Similar results were observed with
CDCl , except for the lithium magnesates for which the
3
8
spectra were recorded after addition of 20% THF-d (to
1
provide a lock signal) to the reaction mixtures. IR spectra
were taken on a Perkin–Elmer FT IR 205 spectrometer, and
K1
main IR absorptions are given in cm . Elemental analyses
were performed on a Carlo Erba 1106 apparatus.
2
-chloro and 2-methoxythiophenes.
4
. Experimental
Starting materials. THF was distilled from benzophenone/
Na. The water content of the solvents was estimated to be
lower than 45 ppm by the modified Karl Fischer method.
Metalation and cross-coupling reactions were carried out
1
9
4
.1. General
Melting points were measured on a Kofler apparatus. NMR
under dry N . Silica gel (Geduran Si 60, 0.063–0.200 mm)
2

4782
O. Bayh et al. / Tetrahedron 61 (2005) 4779–4784
was purchased from Merck. BuLi (1.6 or 2.5 M) in hexane
and PdCl (dppf) were supplied by Aldrich. MgBr was
freshly prepared in THF using a described procedure.
(p); IR (KBr) n; 3001, 2956, 2932, 2906, 2835, 1610, 1511,
1451, 1249, 1173, 1033, 996, 837, 801. Anal. Calcd for
C H ClO S (254.73): C, 56.58; H, 4.35; S, 12.59. Found:
2
2
2
0
1
2
11
2
Petrol refers to petroleum ether (bp 40–60 8C).
C, 56.69; H, 4.38; S, 12.29.
Unless otherwise noted, the reaction mixture was diluted
with CH Cl (50 mL) after the reaction. The organic layer
was dried over MgSO , the solvents were evaporated under
reduced pressure, and the crude product was chromato-
graphed on a silica gel column (eluent is given in the
product description).
4.2.5. 2-Iodo-5-methoxythiophene (6a). The general
procedure 1, starting from 3 (0.60 mL) and using a solution
of I (1.5 g) in THF (3 mL), gave 75% (1.1 g) of 6a (eluent:
2
2
4
2
1
3
petrol) as a yellow oil: C NMR d 169.9 (q), 134.4 (t), 105.7
(t), 60.3 (p), 57.2 (q); IR (KBr) n; 3009, 2960, 2934, 2822,
1547, 1466, 1421, 1234, 1199, 1058, 995, 932, 762, 573.
The other analyses are in accordance with those of the
2
3
4
5
.2. General procedure 1: substituted thiophenes 4a,b,
a,b and 6a by deprotonation of thiophenes 1–3 using
literature.
Bu MgLi and subsequent trapping with electrophiles
3
4.3. General procedure 2: substituted thiophenes 4c, 5c
and 6b by deprotonation of thiophenes 1–3 using
Bu MgLi.TMEDA and subsequent trapping with
To a solution of MgBr (2.0 mmol) in THF (3 mL) at
2
3
K10 8C were added BuLi (6.0 mmol) and, 1 h later, the
required thiophene (6.0 mmol). After 2 h at room tempera-
ture, the electrophile (6.0 mmol) was added and the mixture
was stirred for 18 h at room temperature before addition of
electrophiles
To a solution of MgBr (2.0 mmol) in THF (3 mL) at
2
K10 8C were added BuLi (6.0 mmol) and, 1 h later,
TMEDA (0.30 mL, 2 mmol). After stirring for 1 h at
K10 8C, the required thiophene (6.0 mmol) was introduced.
After 2 h at room temperature, 3,4,5-trimethoxybenzalde-
hyde (1.2 g, 6.0 mmol) was added and the mixture was
stirred for 18 h at room temperature before addition of water
water saturated with NH Cl (1 mL).
4
4.2.1. 2-Iodothiophene (4a). The general procedure 1,
starting from 1 (0.48 mL) and using a solution of I (1.5 g)
2
in THF (3 mL) (in this case, the reaction mixture was treated
with Na S O until bleaching), gave 90% (1.1 g) of 4a
saturated with NH Cl (1 mL).
4
2
2
3
(
eluent: CH Cl ) as a yellow oil. The physical and spectral
2 2
data are analogous to those obtained for a commercial
sample.
4.3.1. a-(3,4,5-Trimethoxyphenyl)-2-thiophenemethanol
(4c). The general procedure 2, starting from 1 (0.48 mL),
gave 96% (1.6 g) of 4c (eluent: cyclohexane/AcOEt 70:30):
2
1
1
4
.2.2. a-(4-Methoxyphenyl)-2-thiophenemethanol (4b).
The general procedure 1, starting from 1 (0.48 mL) and
mp 90–92 8C; H NMR d 7.25 (d, 1H, JZ4.9 Hz), 6.94 (t,
1H, JZ4.2 Hz), 6.89 (d, 1H, JZ3.0 Hz), 6.66 (s, 2H), 5.96
(d, 1H, JZ2.3 Hz), 3.82 (s, 9H), 2.74 (d, 1H, JZ3.4 Hz);
C NMR d 153.1 (q, 2C), 147.8 (q), 138.8 (q), 137.3 (q),
using 4-anisaldehyde (0.73 mL), gave 60% (0.79 g) of 4b
(
1
eluent: CH Cl /AcOEt 90:10) as a yellow oil: H NMR d
13
2
2
7
.36 (d, 2H, JZ6.8 Hz), 7.25 (dd, 1H, JZ3.8, 1.1 Hz), 6.91
126.5 (t), 125.4 (t), 124.8 (t), 103.1 (t, 2C), 72.3 (t), 60.7 (p),
56.0 (p, 2C); IR (KBr) n; 3495, 3377, 3005, 2940, 2833,
1597, 1508, 1464, 1421, 1332, 1234, 1126, 1065, 1007, 741,
719, 699. Anal. Calcd for C H O S (280.35): C, 59.98; H,
1
3
(
m, 4H), 5.97 (s, 1H), 3.80 (s, 3H), 2.61 (s, 1H); C NMR d
59.3 (q), 148.9 (q), 134.6 (q), 127.8 (t, 2C), 126.7 (t), 125.2
t), 124.8 (t), 114.1 (t, 2C), 72.0 (t), 55.4 (p); IR (KBr) n;
429, 2836, 1610, 1511, 1248, 1174, 1033, 834, 704, 579.
Anal. Calcd for C H O S (220.29): C, 65.43; H, 5.49; S,
1
(
3
1
4 16 4
5.75; S, 11.44. Found: C, 59.89; H, 5.82; S, 11.28.
1
2 12 2
1
4.56. Found: C, 65.81; H, 5.87; S, 14.26.
4.3.2. 5-Chloro-a-(3,4,5-trimethoxyphenyl)-2-thiophene-
methanol (5c). The general procedure 2, starting from 2
(0.55 mL), gave 93% (1.8 g) of 5c (eluent: cyclohexane/
2
2
.2.3. 2-Chloro-5-iodothiophene (5a). The general
4
procedure 1, starting from 2 (0.55 mL) and using a solution
of I (1.5 g) in THF (3 mL) (in this case, the reaction
2
mixture was treated with Na S O until bleaching), gave
2
6
1
AcOEt 70:30): mp 94–95 8C; H NMR d 6.70 (d, 1H, JZ
3.8 Hz), 6.59 (m, 3H), 3.80 (s, 9H), 5.77 (s, 1H), 3.38 (br s,
1
3
1H); C NMR d 153.1 (q, 2C), 146.7 (q), 138.3 (q), 137.2
(q), 129.7 (q), 125.5 (t), 123.9 (t), 103.0 (t, 2C), 72.3 (t), 60.7
(p), 55.9 (p, 2C); IR (KBr) n; 3307, 3219, 2934, 2834, 1596,
1509, 1466, 1418, 1330, 1238, 1132, 1059, 993, 750. Anal.
Calcd for C H ClO S (314.79): C, 53.42; H, 4.80; S,
2 3
1
8% (1.0 g) of 5a (eluent: petrol) as a yellow oil: H NMR d
.06 (d, 1H, JZ3.8 Hz), 6.61 (d, 1H, JZ4.1 Hz); C NMR
1
3
7
d 137.6 (t), 134.6 (q), 129.1 (t), 71.6 (q); IR (KBr) n; 3094,
923, 1515, 1408, 1204, 1062, 1003, 934, 785, 466. Anal.
Calcd for C H ClIS (241.24): C, 19.65; H, 0.82; S, 13.12.
2
1
4
15
4
10.19. Found: C, 53.59; H, 4.94; S, 10.03.
4
2
Found: C, 20.02; H, 0.85; S, 13.21.
4
.3.3. 5-Methoxy-a-(3,4,5-trimethoxyphenyl)-2-thio-
4.2.4. 5-Chloro-a-(4-methoxyphenyl)-2-thiophene-
methanol (5b). The general procedure 1, starting from 2
phenemethanol (6b). The general procedure 2, starting
from 3 (0.60 mL), gave 87% (1.6 g) of 6b (eluent:
cyclohexane/AcOEt 70:30): mp 80–82 8C; H NMR d
1
(
(
0.55 mL) and using 4-anisaldehyde (0.73 mL), gave 78%
1.2 g) of 5b (eluent: cyclohexane/AcOEt 70:30) as a yellow
6.67 (s, 2H), 6.51 (d, 1H, JZ3.8 Hz), 6.01 (d, 1H, JZ
3.8 Hz), 5.81 (d, 1H, JZ3.0 Hz), 3.85 (s, 12H), 2.43 (d, 1H,
1
oil: H NMR d 7.25 (d, 2H, JZ8.3 Hz), 6.83 (d, 2H, JZ
1
3
8
5
3
1
.3 Hz), 6.60 (d, 1H, JZ3.8 Hz), 6.45 (d, 1H, JZ3.8 Hz),
JZ3.8 Hz); C NMR d 166.8 (q), 153.2 (q, 2C), 138.4 (q),
137.3 (q), 133.5 (q), 122.8 (t), 103.1 (t, 2C), 102.8 (t), 72.8
(t), 60.8 (p), 60.2 (p), 56.1 (p, 2C); IR (KBr) n; 3362, 2936,
2835, 1595, 1558, 1509, 1462, 1422, 1329, 1238, 1209,
.75 (d, 1H, JZ3.8 Hz), 2.44 (d, 1H, JZ3.8 Hz), 3.72 (s,
H); C NMR d 159.3 (q), 147.1 (q), 134.6 (q), 129.6 (q),
27.5 (t, 2C), 125.5 (t), 123.7 (t), 113.8 (t, 2C), 71.9 (t), 55.2
1
3

O. Bayh et al. / Tetrahedron 61 (2005) 4779–4784
4783
1
129, 1036, 1005, 757. Anal. Calcd for C H O S
1
d 159.3 (q), 142.8 (q), 127.8 (q), 126.8 (t), 126.7 (t, 2C),
126.4 (q), 121.0 (t), 114.3 (t, 2C), 55.2 (p); IR (KBr) n; 2956,
2836, 1603, 1505, 1438, 1288, 1257, 1180, 1031, 827, 793.
Anal. Calcd for C H ClOS (224.71): C, 58.80; H, 4.04; S,
5
18
5
(
310.37): C, 58.05; H, 5.85; S, 10.33. Found: C, 58.26; H,
.55; S, 10.19.
5
1
1 9
4
5
.4. General procedure 3: substituted thiophenes 4d–g,
d–f and 6c–e by deprotonation of thiophenes 1–3 using
14.27. Found: C, 58.53; H, 4.11; S, 14.48.
Bu MgLi and subsequent cross-coupling with aromatic
3
halides
4.4.7. Methyl 4-(5-chloro-2-thienyl) benzoate (5f). The
general procedure 3, starting from 2 (0.55 mL) and using
methyl 4-iodobenzoate (1.6 g), gave 22% (0.33 g) of 5f
1
To a solution of MgBr (2.0 mmol) in THF (3 mL) at
2
(eluent: petrol/CH Cl 70:30): mp 146–148 8C; H NMR d
2
2
K10 8C were added BuLi (6.0 mmol) and, 1 h later, the
required thiophene (6.0 mmol). After 2 h at room tempera-
ture, the mixture thus obtained was added dropwise to a
8.03 (d, 2H, JZ8.3 Hz), 7.56 (d, 2H, JZ8.3 Hz), 7.19 (d,
13
1H, JZ4.1 Hz), 6.93 (d, 1H, JZ3.8 Hz), 3.93 (s, 3H);
C
NMR d 167.0 (q), 141.9 (q), 138.2 (q), 131.2 (q), 130.8 (t,
2C), 129.5 (q), 127.8 (t), 125.4 (t, 2C), 124.1 (t), 52.6 (p); IR
(KBr) n; 3014, 2958, 1725, 1603, 1436, 1291, 1277, 1187,
1112, 1007, 850, 801, 765, 695. Anal. Calcd for
C H ClO S (252.72): C, 57.03; H, 3.59; S, 12.69. Found:
solution of the aromatic halide (6.0 mmol) and PdCl (dppf)
2
(
1
49 mg, 60 mmol), and the mixture was heated at reflux for
8 h before addition of water saturated with NH Cl (1 mL).
4
1
2
9
2
4
3
.4.1. 2-(2-Thienyl) pyridine (4d). The general procedure
, starting from 1 (0.48 mL) and using 2-bromopyridine
C, 56.95; H, 3.41; S, 12.63.
(
0.58 mL), gave 77% (0.74 g) of 4d (eluent: CH Cl ) as a
2 2
4.4.8. 2-(5-Methoxy-2-thienyl) pyridine (6c). The general
procedure 3, starting from 3 (0.60 mL) and using 2-bromo-
pyridine (0.58 mL), gave 56% (0.64 g) of 6c (eluent: petrol/
white solid. The physical and spectral data are analogous to
those obtained for a commercial sample.
2
8
13
CH Cl 70:30): mp !50 8C (lit. 42–43.5 8C); C NMR d
2
2
4
3
.4.2. 3-(2-Thienyl) quinoline (4e). The general procedure
, starting from 1 (0.48 mL) and using 3-bromoquinoline
1
1
68.0 (q), 152.3 (q), 148.7 (t), 135.8 (t), 130.1 (q), 122.4 (t),
20.4 (t), 116.8 (t), 104.3 (t), 59.4 (p); IR (KBr) n; 3072,
(
0.83 mL), gave 56% (0.71 g) of 4e (eluent: CH Cl /Et O
2 2 2
3007, 2965, 2936, 2873, 2827, 1589, 1556, 1494, 1461,
1427, 1299, 1278, 1237, 1209, 1151, 1091, 1067, 1043, 997,
80:20) as a yellow solid. The physical and spectral data are
in accordance with those of the literature.
1
8b,24
961, 766, 744, 728, 620. The other analyses are in
accordance with those of the literature.
2
8
4
.4.3. 2-Phenylthiophene (4f). The general procedure 3,
starting from 1 (0.48 mL) and using iodobenzene (0.67 mL),
gave 84% (0.81 g) of 4f (eluent: petrol/CH Cl 80:20) as a
white solid: mp 94 8C. The physical and spectral data are
4
.4.9. 2-Methoxy-5-phenylthiophene (6d). The general
2
2
procedure 3, starting from 3 (0.60 mL) and using iodo-
benzene (0.67 mL), gave 67% (0.76 g) of 6d (eluent: petrol/
CH Cl 80:20) as a pale blue oil: H NMR d 7.48 (d, 2H, JZ
analogous to those obtained for a commercial sample.
1
2
2
7
.2 Hz), 7.33 (t, 2H, JZ7.5 Hz), 7.21 (t, 1H, JZ7.3 Hz),
.18 (d, 1H, JZ3.8 Hz), 6.18 (d, 1H, JZ3.8 Hz), 3.92
4
.4.4. 2-(4-Methoxyphenyl) thiophene (4g). The general
6
(
(
procedure 3, starting from 1 (0.48 mL) and using 4-
bromoanisole (0.75 mL), gave 92% (1.1 g) of 4g (eluent:
petrol/CH Cl 60:40) as a white solid: mp 102 8C (lit.
13
s, 3H); C NMR d 165.8 (q), 134.5 (q), 129.9 (q), 128.7
t, 2C), 126.4 (t), 124.6 (t, 2C), 120.4 (t), 104.5 (t), 59.8 (p);
2
5
2
2
IR (KBr) n; 3023, 2939, 2827, 1555, 1508, 1480, 1446,
428, 1269, 1231, 1204, 1059, 1000, 752, 690. Anal. Calcd
for C H OS (190.26): C, 69.44; H, 5.30; S, 16.85. Found:
1
06–107 8C); IR (KBr) n; 3099, 3072, 2961, 2930, 2835,
1
1604, 1500, 1293, 1274, 1261, 1104, 1031, 822, 810, 698.
The other analyses were found identical to those previously
described.
1
1 10
C, 69.23; H, 5.47; S, 16.81.
2
5
4.4.10. Methyl 4-(5-methoxy-2-thienyl) benzoate (6e).
The general procedure 3, starting from 3 (0.60 mL) and
4
.4.5. 2-(5-Chloro-2-thienyl) pyridine (5d). The general
procedure 3, starting from 2 (0.55 mL) and using 2-bromo-
pyridine (0.58 mL), gave 68% (0.80 g) of 5d (eluent:
CH Cl ): mp 69–70 8C (lit. 69–70 8C); H NMR d 8.53
using methyl 4-iodobenzoate (1.6 g), gave 40% (0.60 g) of
6
1
e (eluent: petrol/CH Cl 50:50): mp 126–127 8C; H NMR
2
6
1
2
2
2
2
d 7.99 (d, 2H, JZ8.3 Hz), 7.52 (d, 2H, JZ7.9 Hz), 7.10 (d,
H, JZ3.8 Hz), 6.22 (d, 1H, JZ4.1 Hz), 3.94 (s, 3H), 3.91
(
d, 1H, JZ4.9 Hz), 7.68 (td, 1H, JZ7.9, 1.5 Hz), 7.58 (d,
1
1
H, JZ7.1 Hz), 7.33 (d, 1H, JZ3.8 Hz), 7.15 (ddd, 1H, JZ
13
(s, 3H); C NMR d 167.3 (q), 166.8 (q), 139.0 (q), 130.1
(t, 2C), 128.6 (q), 127.6 (q), 124.1 (t, 2C), 122.5 (t), 105.0
(t), 60.2 (p), 52.0 (p); IR (KBr) n; 3084, 2942, 2831, 1709,
1
3
7
.1, 4.9, 1.1 Hz), 6.92 (d, 1H, JZ3.8 Hz); C NMR d 150.8
q), 148.7 (t), 143.0 (q), 135.9 (t), 131.4 (q), 126.7 (t), 122.9
(
(
t), 121.5 (t), 117.2 (t). Anal. Calcd for C H ClNS (195.67):
9
9
1
1
604, 1511, 1482, 1430, 1411, 1291, 1212, 1180, 1111,
065, 1014, 988, 848, 762, 696. Anal. Calcd for C H O S
C, 55.25; H, 3.09; N, 7.16; S, 16.39. Found: C, 55.16; H,
1
3 12 3
3.03; N, 7.07; S, 16.33. The other analyses were found
identical to those previously described.
(248.30): C, 62.88; H, 4.87; S, 12.91. Found: C, 62.59; H,
2
6
4.83; S, 12.81.
2
7
4.4.6. 2-Chloro-5-(4-methoxyphenyl) thiophene (5e).
The general procedure 3, starting from 2 (0.55 mL) and
using 4-bromoanisole (0.75 mL), gave 81% (1.1 g) of 5e
1
eluent: petrol/CH Cl 60:40): mp 100 8C; H NMR d 7.40
(
(
References and notes
1. Katritzky, A. R.; Rees, C. W. In Comprehensive Heterocyclic
2
2
d, 2H, JZ8.6 Hz), 6.91 (d, 1H, JZ4.1 Hz), 6.87 (d, 2H,
1
3
JZ8.7 Hz), 6.82 (d, 1H, JZ3.8 Hz), 3.74 (s, 3H); C NMR

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(
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1
7
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(
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