New and efficient access to 3-substituted 2,5-dibromothiophenes. Consecutive nickel-catalyzed electrochemical conversion to thienylzinc species

Article abstract of DOI:10.1039/b006748m

We have achieved the stepwise synthesis of 3-substituted thienylzinc reagents using both electrochemical methods and an original bromination procedure. For several compounds 3-bromothiophene was the starting substrate, which was functionalized according to recently developed electrochemical procedures. The nickel-catalyzed electrochemical reduction of the resulting 3-substituted 2,5-dibromothiophenes in the presence of zinc salts allowed the formation of monothienylzinc species in good yields. The selectivity of this reaction is discussed within the context of the electrochemical synthesis of regioregular polythiophenes.

Full text of DOI:10.1039/b006748m

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New and efficient access to 3-substituted 2,5-dibromothiophenes.
Consecutive nickel-catalyzed electrochemical conversion to
thienylzinc species
Mohamed Mellah, Eric Labbe,* Jean Yves Nedelec and Jacques Perichon
L aboratoire dÏElectrochimie, Catalyse et Synthese Organique (L ECSO, CNRS UMR 7582)
CNRS, 2È8 rue Henry Dunant, 94320 T hiais, France. E-mail: labbe=glvt-cnrs.fr
Received (in Strasbourg, France) 7th August 2000, Accepted 10th October 2000
First published as an Advance Article on the web 19th January 2001
We have achieved the stepwise synthesis of 3-substituted thienylzinc reagents using both electrochemical methods
and an original bromination procedure. For several compounds 3-bromothiophene was the starting substrate,
which was functionalized according to recently developed electrochemical procedures. The nickel-catalyzed
electrochemical reduction of the resulting 3-substituted 2,5-dibromothiophenes in the presence of zinc salts allowed
the formation of monothienylzinc species in good yields. The selectivity of this reaction is discussed within the
context of the electrochemical synthesis of regioregular polythiophenes.
3-Functionalized thiophenes have found applications as pre-
cursors in the synthesis of pharmaceutical, agrochemical and
cosmetic products,1 as well as monomers in the synthesis of
polythiophenes.2 In the latter Ðeld, the design of polymer
It appears that organometallic chemistry provides powerful
methods for the functionalization of both the a and b posi-
tions of the thiophene ring, allowing the formation of a wide
range of 3-substituted monomers together with control of the
polymer structure.
backbones bearing
a wide variety of functional groups
together with well deÐned chemical and electronic properties
requires: (i) the synthesis of 3-substituted thiophene mono-
mers, sometimes through complex and multiple step pro-
cedures,1 and (ii) a polymerization method that has good
functional group compatibility; in this context, the classical
oxidative polymerization methods cannot be extended to
monomers bearing strong electron-withdrawing or donating
groups,2 although the use of oligomeric precursors has recent-
ly allowed this obstacle to be circumvented.3 Several recent
developments in the organometallic chemistry of 3-
bromothiophene have provided its functionalization by aryl
groups in mild conditions, through the chemical4 or
electrochemical5 formation of 3-thienylzinc species. Electro-
synthetic one-step methods have also been developed in our
group in order to carry out the synthesis of thiophenes substi-
tuted by benzyl, alkenyl and activated alkyl groups in the 3
position.6
The present work deals with the electrochemical stepwise
synthesis of 3-substituted thienylzinc species under mild con-
ditions shown in Scheme 1. This work is aimed at providing
the simplest access to 3-substituted thienylzinc species with
the greatest variety of groups in the 3 position. Step 1 was
achieved for several 3-substituted thiophenes using electro-
chemical procedures recently developed in our group.5,6 The
bromination method (step 2) and the consecutive conversion
to thienylzinc species (step 3) were carried out with electro-
chemical methods that are presented in this paper.
Alternative polymerization methods have been developed,
also based on the synthesis of intermediate organometallic
reagents, providing better control of both the conjugation
length and the regioregularity of the resulting polymer.7 In
this context, zerovalent nickel complexes were found to
undergo fast oxidative addition to 2,5-dibromothiophene to
yield a monothienylnickel intermediate that underwent poly-
merization upon repeated cathodic cycling.8,9 Yamamoto et
al. used stoichiometric amounts of a Ni(0) precursor to
achieve the preparative scale polymerization of 2,5-dihalo-
thiophenes.10 The selective synthesis of 5-(bromozincio)-2-
bromothiophenes from the corresponding 3-alkyl-2,5-dibromo-
thiophenes has been carried out by Chen and Rieke and these
thienylzinc intermediates were found to undergo quantitative
polymerization with Pd or Ni catalysts.11 This procedure was
found to yield a high proportion of regioregular HTÈHT link-
ages (HT \ head-to-tail) with Ni catalysts. This method has
been extended to thiophenes bearing thioalkyl and aryl
groups.12,13 Regioregular poly-3-octylthiophene has recently
been obtained from thienylborane derivatives under Suzuki
coupling conditions.14
Scheme 1
Experimental
Reagents and methods
N,N-Dimethylformamide (DMF), used as solvent, was pur-
chased from SDS (Peypin, France; analytical grade) and used
without further puriÐcation. Dichloromethane was purchased
from SDS and distilled over calcium hydride. 3-
Methylthiophene, 2,5-dichloro-3-acetylthiophene and 2,5-dib-
romothiophene were purchased from Acros or Aldrich
Chemicals and used without further puriÐcation. 3-
Hexylthiophene was prepared by dropwise addition of 3-
bromothiophene to a solution of 1-hexylmagnesium bromide
in anhydrous diethyl ether.
318
New J. Chem., 2001, 25, 318È321
DOI: 10.1039/b006748m
This journal is ( The Royal Society of Chemistry and the Centre National de la Recherche ScientiÐque 2001

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1H-NMR (d relative to TMS) and 13C-NMR (d relative to
8.02 (d, J \ 8.2, 2H), 7.49 (d, J \ 8.34, 2H), 6.96 (s, 1H), 4.32
TMS) spectra were recorded on a Brucker AC200 NMR
(q, J \ 7.2, 2H), 1.33 (t, J \ 7.12 Hz). 13C NMR (CDCl , 200
3
spectrometer (CDCl solution); mass spectra were measured
MHz) d: 166.35, 138.04, 131.18, 129.72, 129.49, 128.21, 111.52,
3
on a Finnigan GC/MS ITD 800 spectrometer.
108.47, 60.87, 14.13. MS (EI) m/z (%): 396 [M ] 4]` (22); 394
[M ] 2]` (54); 392 [M]` (55); 390 [M [ 2]` (17); 337 (20);
335 (62); 333 (61); 331 (20); 315 (52); 313 (100); 254 (11); 234
(5); 173 (5); 94 (4).
Typical bromination procedure
The bromination of 3-substituted thiophenes was achieved
using the following procedure. To 40 cm3 of freshly distilled
dichloromethane was added 20 mmol of 3-substituted thiop-
hene, 2 mmol (10 mol%) of tetrabutylammonium bromide and
10 mmol (50 mol%) of methanol. The solution was stirred at
Electrosynthesis of thienylzinc reagents: typical procedure
The electrochemical conversion of 2,5-dibromo-3-substituted
thiophenes to the corresponding thienylzinc species has been
carried out at 263 K in an undivided cell Ðtted with a zinc
sacriÐcial anode and a nickel foam cathode. A description of
the cell is reported in ref. 15. The DMF (50 cm3) solution
contained 1.5 mmol of tetrabutylamonium tetraÑuoroborate
as supporting electrolyte, 5 mmol of 2,5-dibromo-3-substi-
room temperature and 40 mmol (2 equiv.) of Br dissolved in
2
dichloromethane (40 cm3) was added dropwise to the solution.
HBr was neutralized afterwards by adding excess tri-
ethylamine. After addition of water (100 cm3), the organic
phase was extracted and dried over anhydrous magnesium
sulfate. Dichloromethane was then removed by evaporation
and the product (2,5-dibromo-3-substituted thiophene) was
puriÐed on a silica column using either pentane or pentaneÈ
ether (95 : 5) as eluent.
tuted thiophene, 0.5 mmol of NiBr bpy (bpy \ 2,2@-bipyridine)
2
catalyst (10 mol%) and 2 mmol of ZnBr . The electrolysis was
2
carried out at a constant current density of 0.1 A (ca. 1.5È3
mA cm~2) and the potential of the cathode was monitored vs.
a calomel saturated electrode during the reaction. The electro-
lysis was stopped after total consumption of the original 2,5-
dibromo-3-substituted thiophene, that is, at a charge corre-
sponding to 2 Faradays per mol of 2,5-dibromo-3-substituted
thiophene (ca. 1000 C for 5 mmol of original substrate).
The formation of the thienylzinc species was revealed
through iodination of aliquots of the solution (0.2 mL) under
argon atmosphere, which gives the iodinated analog of the
2,5-Dibromo-3-methylthiophene.
Initial
hydrogenated
product: 20 mmol (1.96 g); isolated brominated product: 18
mmol (4.6 g, 90%). 1H NMR (CDCl , 200 MHz) d: 6.72 (s,
3
1H), 2.2 (s, 3H). 13C NMR (CDCl , 200 MHz) d: 131.65,
3
109.93, 108.16, 14.94. MS (EI) m/z (%): 258 [M ] 2]` (49);
257 [M ] 1]` (15); 256 [M]` (100); 177 (64); 96 (55); 81 (19);
69 (36).
thienylzinc species. Excess I was therefore removed by addi-
tion of 1 mL of a saturated sodium thiosulfate aqueous solu-
2,5-Dibromo-3-hexylthiophene.
Initial
hydrogenated
2
product: 20 mmol (3.36 g); isolated brominated product: 19
tion. The organic products were extracted with 2 mL Et O
mmol (6.19 g, 95%). 1H NMR (CDCl , 200 MHz) d: 6.66 (s,
2
3
and analyzed by GC-MS, calibrated using undecane as an
1H), 2.40 (t, J \ 7.54, 2H), 1.43 (m, 2H), 1.19 (m, 6H), 0.78 (t,
internal standard in the DMF solution. Products were also
identiÐed by 1H-NMR on a Brucker spectrometer (200 MHz).
J \ 6.3 Hz, 3H). 13C NMR (CDCl , 200 MHz) d: 142.74,
3
130.70, 110.08, 107.70, 31.34, 29.26, 28.56, 22.33, 13.83. MS (EI)
m/z (%): 328 [M ] 2]` (34); 327 [M ] 1]` (12); 326 [M]`
(70); 255 (72); 246 (13); 177 (100); 165 (21).
Hydrolysis and iodination products
The products arising from either hydrolysis or iodination of
the thienylzinc species reported in Table 1 have been ““fullyÏÏ
analyzed only for the three examples reported below; as gas
chromatography allowed for the fast identiÐcation and the
determination of the balance between the regioisomers (i.e.
two distinct peaks); the relative proportions reported in Table
1 were determined only through GC measurements for other
species.
(2,5-Dibromothiophen-3-yl)acetic acid ethyl ester. Initial
hydrogenated product: 20 mmol (3.4 g); isolated brominated
product: 18.6 mmol (6.1 g, 93%). 1H NMR (CDCl , 200
3
MHz) d: 6.8 (s, 1H), 4.15 (q, J \ 7, 2H), 3.55 (s, 2H), 1.13 (t,
J \ 7 Hz, 3H). MS (EI) m/z (%): 316 [M [ 15 ] 2]` (46); 314
[M [ 15 ] 1]` (81); 312 [M [ 15 [ 1]` (41); 257 (57); 255
(100); 253 (44); 235 (93); 233 (87); 205 (9) 176 (13); 154 (11); 95
(7).
2-Bromo-3-methylthiophene. 1H NMR (CDCl , 200 MHz)
2-(2,5-Dibromothiophen-3-yl)propionic acid methyl ester.
3
d: 7.05 (d, J \ 5.5, 1H), 6.67 (d, J \ 5.5 Hz, 1H), 2.09 (s, 3H).
Initial hydrogenated product: 20 mmol (3.4 g); isolated bro-
MS (EI) m/z (%): 178 [M ] 2]` (58); 177 [M ] 1]` (20); 176
[M]` (55); 97 (100); 69 (17); 53 (16).
minated product: 18.6 mmol (6.11 g, 93%). 1H NMR (CDCl ,
3
200 MHz) d: 6.84 (s, 1H), 3.78 (q, J \ 7.1, 1H), 3.60 (s, 3H),
1.32 (d, J \ 7 Hz, 3H). 13C NMR (CDCl , 200 MHz) d:
3
2-Bromo-5-iodo-3-methylthiophene. MS (EI) m/z (%): 305
[M ] 2]` (7); 304 [M ] 1]` (95); 303 [M]` (11); 302
[M [ 1]` (100); 223 (41); 96 (18).
173.06, 140.26, 135.44, 128.97, 110.99, 51.98, 39.70, 17.55. MS
(EI) m/z (%): 330 [M ] 2]` (40); 329 [M ] 1]` (14); 328
[M]` (76); 257 (54); 255 (100); 249 (52); 183; 115; 67.
2-Bromo-3-hexylthiophene. 1H NMR (CDCl , 200 MHz) d:
3-Benzyl-2,5-dibromothiophene.
Initial
hydrogenated
3
7.02 (d, J \ 5.7, 1H), 6.628 (d, J \ 5.7, 2H), 2.4 (t, J \ 7.4, 2H),
product: 20 mmol (3.48 g); isolated brominated product: 17
1.4 (m, 2H), 1È1.3 (m, 6H), 0.78 (t, J \ 7.1 Hz, 3H). MS (EI)
m/z (%): 248 [M ] 1]` (39); 246 [M [ 1]` (38); 205 (11); 178
(20); 177 (53); 176 (21); 175 (43); 167 (39); 100 (11); 98 (99); 97
(100).
mmol (5.65 g, 85%). 1H NMR (CDCl , 200 MHz) d: 7.18È
7.05 (m, 5H), 6.55 (s, 1H), 3.74 (s, 2H). MS (EI) m/z (%): 334
[M ] 2]` (28); 332 [M]` (59); 330 [M [ 2]` (27); 253 (39);
251 (35); 172 (100); 127 (85).
3
2-Bromo-5-iodo-3-hexylthiophene. MS (EI) m/z (%): 374
[M]` (100); 372 [M [ 2]` (68); 305 (16); 304 (39); 303 (63);
302 (47); 301 (38); 293 (14); 225 (35); 223 (100); 168 (15); 166
(79); 165 (17); 164 (22); 162 (18); 138 (14); 137 (32).
2,5-Dibromo-3-phenylthiophene.
Initial
hydrogenated
product: 20 mmol (3.2 g); isolated brominated product: 19
mmol (6.05 g, 95%). 1H NMR (CDCl , 200 MHz) d: 7.42È
7.38 (m, 5 H), 7.4 (s, 1H). MS (EI) m/z (%): 318 [M]` (100).
3
4-(2,5-Dibromothiophen-3-yl)benzoic acid ethyl ester. Initial
(5-Bromothiophen-3-yl)acetic acid ethyl ester + (2-bromo-
thiophen-3-yl)acetic acid ethyl ester. 5 : 2 \ 70 : 30. 1H NMR
hydrogenated product: 20 mmol (4.64 g); isolated brominated
product: 18 mmol (7 g, 90%). 1H NMR (CDCl , 200 MHz) d:
(CDCl , 200 MHz) d: [7.14 (d, J \ 5.6, 5) and 6.85 (d, J \ 5.6,
3
3
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319

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5) 1H], [6.95 (s, 2) and 6.92 (s, 2), 1H], 4.14È4.02 (m, 2H,
2 ] 5), [3.53 (s, 5) and 3.48 (s, 2), 2H], 1.18 (t, J \ 7.1 Hz, 3H,
2 ] 5). MS (EI) m/z (%): 250 [M ] 1]` (25); 248 [M [ 1]`
(29); 177 (71); 175 (65); 170 (10); 169 (100); 141 (37); 96 (13).
The resulting 2,5-dibromo-3-substituted thiophenes were
identiÐed by 1H-NMR and mass spectrometry. The yields
(85È95%) are generally excellent and this method provides a
straightforward access to dibrominated thiophenes at room
temperature. However, the method failed in brominating
thiophenes substituted either with cyano or vinyl groups. In
the former case, bromination was not achieved, whereas in the
latter case the vinyl position was also brominated.
Results and discussion
Functionalization of 3-bromothiophene
Electrochemical conversion to thienylzinc species
As mentioned in the introduction, only a few 3-substituted
thiophenes are commercially available, due to the difficulty in
activating the 3 position of the thiophene ring. For this
purpose, we have used two methods, recently developed in our
group, to carry out the preparation of some complex 3-alkyl
and 3-benzyl thiophenes6 or 3-aryl thiophenes.5 The Ðrst pro-
cedure consists of a one-step electrochemical coupling of 3-
bromothiophene with activated alkyl halides or benzyl halides
according to:
The electrochemical conversion of 2,5-dibromo-3-substituted
thiophenes to the corresponding thienylzinc species has been
carried out in DMF at 263 K in an undivided cell Ðtted with a
zinc sacriÐcial anode using catalytic amounts of NiBr bpy
2
catalyst. The overall reaction is:
The functionalization of 3-bromothiophene with aryl groups
has been carried out through a two-step procedure involving a
3-thienylzinc species:
The results are reported in Table 1. The yields are moderate
to excellent. Polymerization takes place as a side reaction
using 2,5-dibromothiophene as substrate (entry 1). As a matter
of fact, in most cases the yields are a†ected by the formation
of the corresponding oligo/polythiophenes. 2,5-Dichloro-3-
acetylthiophene (entry 9) is also converted into 2-chloro-3-
acetylthiophene (ca. 20%). For all other substrates, only traces
of hydrogenated products were detected.
A typical evolution of the the substrate and product quan-
tities as a function of electrolysis time is reported in Fig. 1 for
Table
1 Yields and regioselectivity for the conversion of 3-
substituted-2,5-dihalothiophenes into thienylzinc species
The 3-substituted thiophenes prepared by both methods are
obtained in 50È80% yields, comparable to those already
reported.5,6
Bromination of 3-substituted thiophenes in the 2 and 5 positions
We Ðrst used classical bromination methods16 reported for
thiophenes, using either molecular Br or NBS. In our hands,
2
and from our 3-substituted thiophene precursors, they led to a
mixture of the corresponding 5-bromothiophenes and 2,5-di-
bromothiophenes. We undertook to use a bromination pro-
cedure initially developed for anilines,17 based on the use of
catalytic amounts of Bu NBr and MeOH, together with stoi-
Overall
yielda
of 2 ] 5 (%)
4
chiometric amounts of Br in CH Cl as solvent. This method
Regioselectivityb
5 : 2
2
2 2
Entry
FG
allows the stepwise bromination of the 2 and 5 positions of
the thiophene ring in excellent yields. A catalytic process is
proposed (Scheme 2), similar to that reported for anilines.
1
2
3
4
5
6
7
8
9
ÈH
ÈCH
Èn-C H
30
75
76
90
80
60
65
45
45
È
100 : 0
100 : 0
70 : 30
60 : 40
80 : 20
70 : 30
72 : 28
100 : 0
3
6
13
ÈCH CO Et
2
2
ÈCH(CH )CO Me
3
2
ÈCH C H
2
ÈC H
6
6 5
5
Èp-C H CO Et
6
4
2
ÈC(O)Me
a Yields calculated from GC experiments using an internal standard.
b Evaluated from both GC and 1H NMR experiments. See text for
details.
Scheme 2
320
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tions were conÐrmed by two distinct GC signals during the
electrolysis.
The main product obtained is generally the 3-substituted
2-bromo-5-(bromozincio)thiophene. The regioisomer, 3-
substituted 5-bromo-2-(bromozincio)thiophene, is formed in
appreciable amounts for entries 4È8. For entries 4 and 5 the
zinc atom could be coordinated by the ester group if located
in the 2 position. With phenyl or benzyl groups (entries 6È8)
the proportion remains unexplained. Chen and Rieke reported
a similar proportion for the phenyl-substituted thiophene in
THF.11 This electrochemical method allows a higher regiosel-
ectivity for a thiophene ring substituted with a hexyl group
compared to the previously reported ratio of 70 : 30.11
The formation of 2,5-di(bromozincio)thiophenes is never
observed in signiÐcant yields (\5%), even if the electrolysis is
continued to a charge corresponding to 4 Faradays per mol.
This electrosynthetic process does not allow the consecutive
and quantitative insertion of zinc at the second carbonÈ
halogen bond of the thiophene ring.
Conclusion
The synthesis of 3-substituted monothienylzinc species has
been achieved using both electrochemical methods and an
original and selective bromination method. The very mild and
simple conditions used in this stepwise synthesis allow the
functionalization of thiophene with a wide variety of groups.
Such versatile and selective access to original 3-substituted
thienylzinc reagents is of great interest in the further prep-
aration of regioregular 3-substituted polythiophenes.
Fig. 1 Evolution of the quantities of 2,5-dibromo-3-hexylthiophene
(=) and 2-bromo-5-iodo-3-hexylthiophene (L) as a function of elec-
trolysis time. The solid lines are the theoretical 100% Faradaic con-
sumption (ÈÈ) and formation (É É É).
2,5-dibromo-3-hexylthiophene (entry 3). The formation of the
thienylzinc species is revealed by quantitative iodination of
aliquots of the solution according to:
Acknowledgements
The authors would like to thank Dr V. Ratovelomanana
(Universite Evry, France) for his very helpful advice concern-
ing the bromination experiments.
The consumption of 2,5-dibromo-3-hexylthiophene follows
the expected theoretical 2 Faradays per mol slope during the
major part of the electrolysis. However, the formation of the
corresponding organozinc species takes out from the ideal
100% slope, corresponding to the oligo/polymerization of the
thienylzinc species in the presence of nickel salts. Moreover, if
the electrolysis is carried out at room temperature, the yield
decreases from 76 to 60% for the same substrate (entry 3) and
a suspension of brown solid particles is observed at the end of
the electrolysis. RiekeÏs thienylzinc reagents were found to
undergo quantitative polymerization in THF in the presence
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New J. Chem., 2001, 25, 318È321
321