Selective metallation of 3-halothiophenes: Practical methods for the synthesis of 2-bromo-3-formylthiophene

Article abstract of DOI:10.1080/00397910902763904

Selective lithiation of 3-bromothiophene was accomplished under controlled conditions without formation of undesired thienyllithium compounds. A thienyl Grignard reagent derived from 2-bromo-3-iodothiophene was transformed into 2-bromo-3-formylthiophene in high selectivity by formylation with dimethylformamide (DMF) at optimal reaction temperature. Copyright Taylor & Francis Group, LLC.

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Selective Metallation of 3-
Halothiophenes: Practical
Methods for the Synthesis of 2-
Bromo-3-formylthiophene
Motohiro Sonoda a , Shoko Kinoshita a , Thanh Luu a
,
Hiroshi Fukuda a , Koji Miki a , Rui Umeda a & Yoshito
Tobe a
a Division of Frontier Materials Science, Graduate
School of Engineering Science, Osaka University ,
Toyonaka, Osaka, Japan
Published online: 12 Aug 2009.
To cite this article: Motohiro Sonoda , Shoko Kinoshita , Thanh Luu , Hiroshi
Fukuda , Koji Miki , Rui Umeda & Yoshito Tobe (2009) Selective Metallation of 3-
Halothiophenes: Practical Methods for the Synthesis of 2-Bromo-3-formylthiophene,
Synthetic Communications: An International Journal for Rapid Communication of
Synthetic Organic Chemistry, 39:18, 3315-3323, DOI: 10.1080/00397910902763904
To link to this article: http://dx.doi.org/10.1080/00397910902763904
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Synthetic Communications1, 39: 3315–3323, 2009
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910902763904
Selective Metallation of 3-Halothiophenes:
Practical Methods for the Synthesis
of 2-Bromo-3-formylthiophene
Motohiro Sonoda, Shoko Kinoshita, Thanh Luu, Hiroshi Fukuda,
Koji Miki, Rui Umeda, and Yoshito Tobe
Division of Frontier Materials Science, Graduate School of Engineering
Science, Osaka University, Toyonaka, Osaka, Japan
Abstract: Selective lithiation of 3-bromothiophene was accomplished under
controlled conditions without formation of undesired thienyllithium compounds.
A thienyl Grignard reagent derived from 2-bromo-3-iodothiophene was trans-
formed into 2-bromo-3-formylthiophene in high selectivity by formylation with
dimethylformamide (DMF) at optimal reaction temperature.
Keywords: 2-Bromo-3-formylthiophene, 2-bromo-3-iodothiophene, 3-bromo-
thiophene, thienyl Grignard reagent, thienyllithium reagent
INTRODUCTION
Thiophene-based organic materials are an important class of compounds
because they often show attractive properties that would lead to electro-
nic, magnetic, and=or photochromic functional devices.[1] From this
point of view, we recently reported the synthesis of bridged dithienyl-
ethene 1 as a key compound for photochromic or nonlinear optical
materials via palledium (Pd)–catalyzed double-cyclization reactions of
(Z,Z)-1,6-dithienyl-1,5-hexadien-3-ynes (2) (Scheme 1).[2]
Received September 30, 2008.
Address correspondence to Yoshito Tobe, Division of Frontier Materials
Science, Graduate School of Engineering Science, Osaka University, 1-3 Machika-
neyama Toyonaka, Osaka 560-8531, Japan. E-mail: tobe@chem.es.osaka-u.ac.jp
3315

3316
M. Sonoda et al.
Scheme 1.
Scheme 2.
2-Bromo-3-formylthiophene (3), one of the building blocks for the
construction of hexadienyne 2, is often employed as a useful synthetic
intermediate.[2,3] The synthesis of 3 consists of three steps; iodination of
3-lithiothiophene,[4] bromination of 3-iodothiophene (5),[5] and selective
formylation of 2-bromo-3-iodothiophene (6) via generation of
2-bromothienylmagnesium chloride[6] (Scheme 2). In the course of our
study, we observed that the iodination of 3-lithiothiophene caused
bothersome contamination with inseparable by-products generated by
migration of lithium to the 2- or 5-position of thiophene ring[5a,7] even
when we employed the method disclosed by Wu et al. that was reported
to give 5 selectively.[4] Moreover, we met with the same problem in the
preparation of 3; a considerable amount of isomeric products was formed
in the formylation of 2-bromo-3-iodothiophene (6) because of the rear-
rangement of magnesium chloride on the thiophene ring, even though
we followed the procedure reported by Christophersen et al.[6b] These
products often create unavoidable trouble in the purification step.
Christophersen also observed a small amount of by-product.[6b] There-
fore, we intended to elaborate these processes to obtain pure products
of 3 and 5 reproducibly, and we describe in detail here the successful
practical method with high selectivity.
RESULTS AND DISCUSSION
As an initial step, the synthesis of 3-iodothiophene (5) was performed
according to Wu et al.’s method.[4] A solution of n-butyllithium in hexane
was added dropwise into a solution of 3-bromothiophene in hexane at

Selective Metallation of 3-Halothiophenes
3317
Scheme 3.
ꢀ40ꢁC, and a small amount of THF was added for complete dissolution
of 3-lithiothiophene. After the supplement of additional hexane with
stirring, 1,2-diiodoethane, an electrophile, was added dropwise to the
solution at room temperature to give a mixture of products: 3-diiodothio-
phene (5), 2,3-diiodothiophene (7),[8] and 2,3,5-triiodothiophene (8)[8a,9]
(5=7=8 ¼ 67=22=11) (Scheme 3). The products were identified by 1H
NMR and GC=MS spectrometers. The product distribution was calcu-
1
lated based on the integration of the signals in H NMR spectra.
Because this result was due to the instability of 3-lithiothiophene at
such a high temperature,[7,10] we performed the reaction under the mild
conditions offered by Gronowitz.[7a,b] Thus all reagents, n-butyllithium,
THF, and 1,2-diiodoethane, were mixed at ꢀ70ꢁC without warming.
However, a mixture of 5, 7, and 8 of similar composition was produced
(5=7=8 ¼ 55=27=18). This result indicated that further improvement of the
procedure for the selective lithiation of 4 was necessary. Then we
examined the lithiation under various conditions (Scheme 4), and the
results are summarized in Table 1. The result of run 1 was obtained by
Gronowitz’s method. When addition of 1,2-diiodoethane was carried
out at 0ꢁC after short stirring at room temperature (run 2), the product
distribution remained almost unchanged (5=7=8 ¼ 61=24=15). Next, when
the addition of 1,2-diiodoethane was conducted at ꢀ30ꢁC after short stir-
ring at ꢀ30ꢁC, the yield of desired product 5 was slightly increased
(5=7=8 ¼ 85=10=5) (run 3). In the case of the reaction at ꢀ10ꢁC, the selec-
tivity became slightly worse (5=7=8 ¼ 73=18=9) (run 4). It is interesting,
however, to note that the formation of undesired product 8 completely
vanished when the addition of n-butyllithium was performed in one
portion, not dropwise, at ꢀ70ꢁC (5=7=8 ¼ 75=25=0) (run 5). Finally, the
Scheme 4.

3318
M. Sonoda et al.
Table 1. Reaction conditions of lithiation and distribution of products
Temperature (ꢁC)
Distribution (%)
(5=7=8)
Run
Addition of n-BuLi
Step 1
Step 2
Step 3
1
2
3
4
5
6
Dropwise
Dropwise
Dropwise
Dropwise
In one portion
In one portion
ꢀ70
ꢀ70
ꢀ70
ꢀ70
ꢀ70
ꢀ70
ꢀ70
Rt
ꢀ30
ꢀ10
ꢀ10
0
ꢀ70
0
ꢀ30
ꢀ10
ꢀ10
ꢀ70
55=27=18
61=24=15
85=10=5
73=18=9
75=25=0
100=0=0
selectivity was dramatically improved when n-butyllithium was added in
one portion, followed by stirring at 0ꢁC for a short period before addition
of 1,2-diiodoethane at ꢀ70ꢁC, which exhibited excellent selectivity
(5=7=8 ¼ 100=0=0) (run 6). It should be pointed out that 5 was reprodu-
cibly obtained by this procedure with good selectivity.
Next we embarked on a study of the last step, formylation of
2-bromo-3-iodothiophene (6), which was derived from 5 by bromination
with N-bromosuccinimide.[5] According to the reported synthesis of
2-bromo-3-formylthiophene (3),[6] we generated 3-(2-bromothienyl)-
magnesium chloride (11) by Grignard exchange reaction of 6 with ethyl-
magnesium chloride in THF at 0ꢁC and treated it with DMF at the same
temperature. After hydrolysis, the formylation product 3 was obtained as
the major product accompanied by 2-formyl-3-iodothiophene (9)[3d,8c,11]
and 2-formyl-3-bromothiophene (10)[12] (3=9=10 ¼72=7=21) (Scheme 5).
1
The products were identified by H NMR and GC=MS spectrometers.
The product distribution was calculated based on the integration of the
1
signals in H NMR spectra.
This result also indicated that the procedure for the formylation of
dihalothiophene 6 remained a matter of research. On lithiation of diha-
lothiophene, Gronowitz pointed out that facile migration of lithium often
occurred from the 3- to 2-position of the thiophene ring, accompanying
halogen–lithium exchange reaction.[7] This, together with the fact that a
Scheme 5.

Selective Metallation of 3-Halothiophenes
3319
Scheme 6.
3-bromothiophene derivative 10 was formed, indicated that the similar
migration occurred via halogen–magnesium exchange reaction when
using ethylmagnesium chloride. Possible pathways for the formation of
9 and 10 are shown in Scheme 6, which include an undesired reaction
of the generated Grignard reagent 11 with the starting thiophene 6
through halogen–metal exchange. The resulting 2-(3-iodothienyl)-
magnesium chloride (12) and 2,3-dibromothiophene (13) are then conver-
ted to 9 and 10, respectively, as shown.
To obtain 3 selectively, we examined the formylation of 6 under sev-
eral conditions (Scheme 7). Representative results are summarized in
Table 2. To suppress the reaction of 11 with the starting material 6, 6
was added dropwise to a solution of an equivalent or an excess amount
of ethylmagnesium chloride in THF. When 1 eq of ethylmagnesium
chloride was used, the selectivity was worse than those reported
previously[6] (3=9=10 ¼ 50=15=35) (run 1). On the other hand, when 2
eq of ethylmagnesium chloride were used, the product distribution was
considerably improved, giving 3 in high selectivity (3=9=10 ¼ 91=4=5)
(run 2). The use of a further excess amount of ethylmagnesium chloride
(3 eq), however, reduced the selectivity of the desired product (3=9=10 ¼
77=8=15) (run 3). In summary, the procedure of run 2 reproducibly pro-
vides good selectivity of 3.
Scheme 7.

3320
M. Sonoda et al.
Table 2. Formylation of 2-bromo-3-iodothiophene
Distribution (%)
(3=9=10)
Run
EtMgCl
Yield (%)
1
2
3
1 eq
2 eq
3 eq
74
62
48
50=15=35
91=4=5
77=8=15
CONCLUSIONS
In conclusion, we have accomplished the practically useful and reprodu-
cible synthesis of 2-bromo-3-formylthiophene, which included the selec-
tive halogen–metal exchange reaction of 3-bromothiophene with
butyllithium and that of 2-bromo-3-iodothiophene with a Grignard
reagent under controlled conditions. These methods provide reliable acc-
ess to the key compound for construction of various thiophene-based
functional materials.
EXPERIMENTAL
General
1H NMR (300 MHz) spectra were recorded on a Varian Mercury 300
1
spectrometer in CDCl3 at 30ꢁC. The chemical shifts of H NMR signals
are quoted relative to internal CHCl3 (d ¼ 7.26) or tetramethylsilane
(TMS). Gas liquid chromatography (GLC) analysis of the products
was performed with a Shimadzu GC-14B gas chromatograph equipped
with a CBP1 capillary column (0.25 mm ꢂ 25 m). Preparative high-
performance liquid-chromatographic (HPLC) separation was undertaken
with a Jai LC-908 chromatograph using 600 mm ꢂ 20 mm Jaigel-1H and
2H gel permeation chromatography (GPC) columns with CHCl3 as an
eluent. All reagents were obtained from commercial suppliers and used
as received. Solvents were dried (drying agent in parentheses) and dis-
tilled prior to use: THF (sodium benzophenone ketyl), DMF (CaH2),
and hexane (CaH2).
3-Iodothiophene (5)
A 1.6 M solution of n-butyllithium in hexane (12.3 mL, 19.7 mmol) was
added in one portion to a solution of 3-bromothiophene (1.74 mL,
18.4 mmol) in hexane (27.6 mL) at ꢀ70ꢁC under an argon atmosphere.

Selective Metallation of 3-Halothiophenes
3321
Successively, a small amount of THF (2.7 mL), followed by hexane
(9.3 mL), was added quickly. Then the mixture was stirred at 0ꢁC for a
short period of time and was recooled to ꢀ70ꢁC. After an addition of
1,2-diiodoethane (6.00 g, 21.3 mmol) at ꢀ70ꢁC, the reaction mixture
was warmed to room temperature and stirred there for 1 h. A sat. sodium
thiosulfate solution was poured into the reaction mixture. The organic
layer was diluted with ethyl acetate, washed with brine, and dried over
anhydrous MgSO4. After removal of the solvent in vacuo, the residue
was purified by flash chromatography (eluate: hexane) to afford 5 as a
1
yellow oil (3.32 g, 86%): H NMR (CDCl3, 30ꢁC) d 7.41 (dd, J ¼ 3.0,
1.8 Hz, 1H), 7.20 (dd, J ¼ 5.1, 3.0 Hz, 1H), 7.10 (dd, J ¼ 5.1, 1.8 Hz, 1H).
2-Bromo-3-iodothiophene (6)
A mixture of 5 (2.44 g, 11.6 mmol), N-bromosuccinimide (2.21 g,
12.4 mmol), and acetic acid (10 mL) was stirred at 100ꢁC for 1 h under
an argon atmosphere. The reaction mixture was diluted with water and
sat. NaHCO3 and was extracted with ethyl acetate. The extract was
washed with brine and dried over anhydrous MgSO4. After removal of
the solvent in vacuo, the residue was purified by flash chromatography
1
(eluate: hexane) to afford 6 as a colorless oil (2.47 g, 74%): H NMR
(CDCl3, 30ꢁC) d 7.23 (d, J ¼ 5.7 Hz, 1H), 6.96 (d, J ¼ 5.7 Hz, 1H).
2-Bromo-3-formylthiophene (3)
A solution of 6 (561 mg, 1.94 mmol) in THF (1.8 mL) was added drop-
wise into a 2.0 M solution of ethylmagnesium chloride in THF (1.9 mL,
3.8 mmol) at 0ꢁC under an argon atmosphere. The mixture was stirred
at 12ꢁC for a short period of time, and then freshly distilled DMF
(0.27 mL, 3.5 mmol) was added dropwise at 0ꢁC. After stirring at room
temperature for 1 h, the reaction mixture was diluted with sat. NH4Cl
and was extracted with ethyl acetate. Evaporation of the solvent followed
by flash chromatography (eluate: hexane=ethyl acetate ¼ 6=1) gave a mix-
ture of products containing 3 (3=9=10 ¼ 91=4=5) as a yellow oil (230 mg,
1
62%). The products were identified by H NMR and GC=MS spectro-
meters. The product distribution was calculated based on the integration
1
of the signals in H NMR spectra. The presence of by-products 9 and
10 was confirmed by comparison of the 1H NMR spectra with the
reported data.[8c,12c] Pure product 3 was obtained by subjection of the
1
mixture to a recyclable preparative HPLC: H NMR (CDCl3, 30ꢁC) d
9.94 (s, 1H), 7.36 (d, J ¼ 6.0 Hz, 1H), 7.28 (d, J ¼ 6.0 Hz, 1H).

3322
M. Sonoda et al.
ACKNOWLEDGMENT
This work was supported by a Grant-in-Aid for Scientific Research from
the Ministry of Education, Culture, Sports, Science, and Technology,
Japan. T. L. is grateful to the 21st Century Center of Excellence Program
‘‘Integrated Ecochemistry’’ for the support to his overseas internship at
Osaka University.
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