A versatile organozinc approach to the synthesis of potential organic functional building blocks: 5-substituted 3-bromo-2-methylthiophene derivatives

Full text of DOI:10.1002/bkcs.10217

Note
DOI: 10.1002/bkcs.10217
BULLETIN OF THE
J.-W. Cheon et al.
KOREAN CHEMICAL SOCIETY
A Versatile Organozinc Approach to the Synthesis of Potential
Organic Functional Building Blocks: 5-Substituted 3-Bromo-2-
Methylthiophene Derivatives
†
‡
‡,*
Jong-Woo Cheon, Hyun-Hee Cho, and Seung-Hoi Kim
†
Advanced Cosmeceutical Technology (ACT Co., Ltd.), 88, Sinwon-ro, Suwon 443-734, Korea
‡
Department of Chemistry, Dankook University, Cheonan 330-714, Korea.
*E-mail: kimsemail@dankook.ac.kr
Received September 16, 2014, Accepted December 10, 2014, Published online March 12, 2015
Keywords: Thienylzinc, Site-selective, Cross-coupling, Oxidative addition, Palladium
Photochromic compounds that undergo reversible transforma-
wide range of flexible intermediates. Therefore, it is clearly
in high demand. We herein would like to report a new route
to synthesize 5-substituted 2-methylthiphenes.
tion by appropriate stimulation have attracted much attention
in the organic material fields, especially for photoswitching
materials. A wide range of potential application for these
photosensitive materials can be attributed to their stability,
fatigue resistance, rapid response, and thermally irreversible
The present study started with readily available
2-methylthiophene, which has an economical advantage over
3-bromo-2-methylthiophene, and the overall roadmap is
depicted in Scheme 1. Bromination with N-bromosuccinimide
was easily carried out using the procedure published in the lit-
erature, giving rise to the corresponding 3,5-dibrominated
product. With the brominated thiophene, two different
approaches were attempted for the preparation of 5-arylated
thiophene derivatives: path A and path B, as shown in
Scheme 1. First, the site-selective cross-coupling reactions of
different organozinc reagents were examined (path A), and
the results are summarized in Table 1. All of the organozinc
reagents used in this study were prepared by the direct insertion
1,2
properties. Of various functional photochromic compounds,
diarylethenes are the most suitable molecules for the optoelec-
3
tronic devices such as memories and switches.
Numerous studies havebeen focused on thedevelopment of
a high performance class of photosensitive molecules. One of
the major breakthroughs was accomplished by introducing
thiophene rings on both sides of ethene, which resulted in
4
the formation of 1,2-dithienylethenes. Since then, this molec-
ular structure has been considered as the most reliable
basic platform to provide high performance in the devices5
operating based on photoresponsive functional materials.
For the construction of the 1,2-bis(thien-3-yl)ethene-based
photochromic molecules, two thiophene rings are generally
connectedbyoneofthefollowingbridgingunits:maleicanhy-
dride, maleimide, perfluorocyclopentene, cycloalkenes, or
10
of highly active zinc into the corresponding halocompounds.
To our great delight, organozinc reagents were selectively
coupled with 5-bromine on the thiophene ring in the presence
of catalytic amounts of Pd(PPh ) Cl at room temperature.
3
2
2
Organozincs from simple aryl and substituted aryl compounds
were easily coupled to give the corresponding products
(1a–1c) in moderate to good yields (entries 1–3, Table 1).
More interestingly, heterocyclic arylzinc reagents were also
effectively utilized for the selective couplings (entries 4–7,
Table 1).
With the promising results obtained from the site-selective
couplings of organozincs, more diversity of the strategy was
then explored. This was accomplished utilizing 3-bromo-2-
methylthien-5-ylzinc bromide (II). This essential organome-
tallic molecule (II) was prepared by the regioselective direct
insertion of highly active zinc into the carbon-bromine bond,
as shown in Scheme 1 above. Treatment of 3,5-dibromo-2-
methylthiophene with 1.2 equivalents of the active zinc pre-
pared by the Rieke method resulted in the formation of II.
Iodine quenching of the obtained thienylzinc bromide pro-
vided the corresponding 3-bromo-5-iodo-2-methylthiophene
with an excellent yield (>95% by GC-MS). This observation
provides evidence to rule out halogen dancing in the course of
the organozinc preparation.
1a,6
dihydrothiophene.
To date, the most popular synthetic route for constructing
the connection between the thiophene moiety and the ethene
unit is the direct coupling reaction of lithiothiophene deriva-
7
tives. More recently, Suzuki coupling has also been devel-
8
oped. To add more value into these methodologies, a larger
variety of functionalized thiophene derivatives is strongly
demanded. Among the thiophenes, 5-substituted 3-bromo-2-
methylthiophenes have been the key intermediates for the
assemble of the 1,2-bis(thien-3-yl)-system. To obtain the suc-
cessful accomplishment of this synthetic journey, as described
7
in the previous works mentioned above, the Suzuki coupling
reaction conditions were predominately used. Interestingly, a
recent work discovered another way to make the key interme-
diate, 5-arylated 3-bromo-2-methylthiophene, via the direct
9
C H activation of 3-bromo-2-methylthiohene.
Taking the strategy above into account, exploring a
more versatile synthetic approach toward 3-bromo-2-
methylthiophene derivatives can provide ready access to a
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Table 2. Coupling reaction of II with arylhalides.
Br
CH3
1.0 eq)
Br
2
% Pd(PPh ) Cl
3 2 2
+
Ar(Het)X
BrZn
THF/rt/1.0 h
(Het)Ar
CH
3
S
S
II
0.8 eq
Group A
(
a
Entry
1
Ar(Het)X
Product
Yield (%)
73
Br
2a
NC
I
Scheme 1. Schematic diagram for 5-substituted 3-bromo-2-
methylthiophenes
2
3
2b
1b
75
84
EtO C
2
I
MeO
Table 1. Site-selective cross-coupling reaction of I with organozincs.
Br
4
5
1d
2c
71
70
Br
Br
N
N
2
% Pd(PPh ) Cl
3 2 2
Br
+
Ar(Het)ZnX
Br
CH3
THF/rt/1.0 h
(Het)Ar
CH3
S
S
I (1.0 eq)
1.0 eq
Group A
6
7
Cl
Br
2d
2e
72
78
S
a
Entry
1
Ar(Het)ZnX
Product
Yield (%)
EtO
C
Br
2
S
6
1
Br
ZnBr
1a
8
2f
61
S
ZnBr
6
8
0
a
Isolated yield (based on halide).
2
3
4
5
1b
1c
1d
1e
MeO
ZnBr
7
Scheme 1, group B compounds were successfully prepared
via the coupling reaction of II with a wide range of acid chlor-
ides. Not only aryl acid chlorides (entries 1–6), but also alkyl
acid chlorides (entries 7–9) coupled with II under the normal
F3C
ZnBr
7
5
9
N
coupling conditions (10 mol% CuI/20 mol% LiBr) in THF at
ZnBr
6
ꢀ
0
C. Generally, the corresponding ketones (3a–3i, Table 3)
N
were obtained in moderate to good yields.
As previously described in this work, various organozincs
were selectively coupled with one of the bromines of 3,5-
dibromo-2-methylthiophene. The selectivity of the new orga-
nozinc reagent II was then examined. It was treated with 2-
bromo-4-iodopyridine under the same conditions used before,
and the selectively coupled product (4) was obtained in 89%
7
8
9
6
7
Br
ZnBr
ZnBr
1f
S
7
1g
O
a
Isolated yield.
(Scheme 2).
The applicability of II was first examined by the traditional
Pd(II)-catalyzed cross-coupling reaction with various aryl
and heteroaryl halocompounds. The results are summarized
in Table 2. Once again, Pd(PPh )Cl was very effective to
complete the coupling at room temperature in THF. The cor-
responding 5-substituted 3-bromo-2-methylthiohene deriva-
tives (2a–2c) were obtained in moderate to good isolated
yields (entries 1–3, Table 2). Heterocylclic compounds were
also good coupling partners to provide the corresponding
A slight change of the ratio enables expansion of the scope
of the expected utility of II. A dicoupling reaction of II was
conducted with 2,6-dibromopyridine using similar reaction
conditions, and the desired product (5) was obtained in 70%
(Scheme 3).
For the preparation of a variety of thiophene derivatives,
highly functionalized electrophiles are necessary as the
coupling partners. To fulfill the high expectations, cross-
coupling reactions of II with haloaromatic compounds con-
taining relatively acidic protons were attempted. To this
end, haloaromatic amines and phenols are reasonable candi-
dates. By utilizing this strategy, 5-(4-aminophenyl)- and
2
2
5-arylated thiophenes (2d–2h, entries 4–8, Table 2).
Utilization ofthe organozinc II wasexpanded tointroduce a
carbonyl group next to the thiophene ring. As depicted in
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BULLETIN OF THE
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Table 3. Coupling of II with acid chlorides.
Br
Br
Br
2
% Pd(PPh3)
2
Cl
2
N
+
Br
Br
H
3
C
ZnBr
H C
3
S
S
THF/rt/30 min
N
I
Br
1
0 % CuI/ 20 % LiBr
II
+
RCOCl
.8 eq
4 (89%)
H C
ZnBr
II (1.0 eq)
H
C
COR
3
S
o
3
S
THF/0 C/3 h
Scheme 2. Site-selective coupling of II
0
Group B
a
Br
Entry
1
RCOCl
COCl
Product
Yield (%)
63
2 %
3
)
2Cl2
Pd(PPh
+
S
S
N
H
C
ZnBr
II (2.2 eq)
Br
N
Br
THF/reflux/24 h
3
S
3a
3b
3c
3d
1.0 eq
Br
Br
5
(
70%)
COCl
Scheme 3. Dicoupling of 2,6-dibromopyridine with II
2
3
4
74
70
78
Br
COCl
I
Br
H C
Br
H C
2
% Pd(OAc) /4 % SPhos
2
+
3
S
NC
THF/rt/1.0 h
ZnBr
3
S
II
Y
COCl
Cl
Y
Y = NH2 (6, 61%)
OH (7, 42%)
Y = NH2
OH
N
COCl
Scheme 4. Coupling of II with aniline and phenol
5
6
3e
3f
80
62
settled down and then the supernatant was used for the subse-
quent coupling reactions.
Pd-catalyzed cross-coupling reaction: Preparation of
COCl
COCl
O
3
2
-bromo-5-(4-cyanophenyl)-2-methylthiophene (2a): Into a
7
8
3g
78
5 mL round-bottomed flask were added Pd(PPh ) Cl
3
2
2
COCl
(0.035 g, 2.0 mol%), 4-bromobenzonitrile (0.36 g, 2.0 mmol),
3h
3i
68
50
and 5.0 mL of 3-bromo-2-methylthiophen-5-ylzinc bromide
(II) (0.5 M in THF, 2.5 mmol) under an argon atmosphere
at room temperature. The resulting mixture was stirred at room
temperature for 1.0 h. Quenched with 3 M HCl solution, then
extracted with ethyl ether (10 mL × 3). Washed with saturated
NaHCO , Na S O solution, and brine, and then dried over
COCl
Isolated yield (based on RCOCl).
9
a
3
2 2 3
anhydrous MgSO . Purification by column chromatography
4
(4-hydroxyphenyl)-substituted thiophenes (6 and 7) were suc-
on silica gel (10% ethyl acetate/90% heptane) afforded 0.41
cessfully prepared under mild conditions (Scheme 4).
In conclusion, a practical synthetic procedure for the prep-
aration of 5-substituted 3-bromo-2-methylthiophene deriva-
tives, which can potentially be utilized for the synthesis of
photosensitive materials, has been demonstrated utilizing
readily accessible 3,5-dibromo-2-methylthiophene (I). Both
coupling reactions of appropriate organozinc reagents with
I, and preparation of organozinc (II) from I and its application,
turned out to be a superb approach for achieving the goal. Fur-
ther examination of applications for the new organozinc rea-
gent (II) is currently under way.
g of 2a in 73% isolated yield as a yellow solid (m.
ꢀ
1
p. 119–121 C); H NMR (CDCl , 500 MHz) δ = 7.64 (d,
3
J = 8.0 Hz, 2H), 7.58 (d, J = 8.0 Hz, 2H), 7.22 (s, 1H), 2.44
1
3
(s, 3H); C NMR (CDCl , 125 MHz) δ = 138.7, 137.6,
3
136.3, 132.8, 127.6, 125.4, 118.7, 110.8, 110.7, 15.0.
Cu-catalyzed cross-coupling reaction: Into a 25 mL
round-bottomed flask were placed CuI (0.04 g, 10 mol%)
and LiBr (0.04 g, 20 mol%). 3-Bromo-2-methylthiophen-5-
ylzinc bromide (II) (5.0 mL, 0.5 M in THF, 2.5 mmol) was
added into the flask under an argon atmosphere. Next, 4-
bromobenzoyl chloride (0.44 g, 2.0 mmol) was slowly added
ꢀ
via a syringe while being stirred at 0 C. The resulting mixture
ꢀ
Experimental
was at 0 C for 1 h. Quenched with 3.0 M HCl solution, then
extracted with ethyl ether (10 mL × 3). Washed with saturated
NaHCO , Na S O solution, and brine, and then dried over
Representative Procedures. Preparation of 3-bromo-2-
3
2 2 3
methylthiophen-5-ylzinc bromide (II): In an oven-dried
anhydrous MgSO . Purification by column chromatography
4
2
50 mL round-bottomed flask equipped with a stir bar was
on silica gel (2% ethyl acetate/98% heptane) afforded
0.53 g of (4-bromo-5-methylthiophen-2-yl)-(4-bromophenyl)
methanone (3b) in 74% isolated yield as a white solid (m.
∗
added 4.70 g of active zinc (Zn , 72.0 mmol). 3,5-Dibromo-
2-methylthiophene (15.36 g, 60.0 mmol) was cannulated neat
ꢀ
1
into the flask at room temperature. The resulting mixture was
stirred for 1.0 h at room temperature. The whole mixture was
p. 108–109 C); H NMR (CDCl , 500 MHz) δ = 7.70 (d,
3
J = 7.5 Hz, 2H), 7.64 (d, J = 7.5 Hz, 2H), 7.42 (s, 1H), 2.49
Bull. Korean Chem. Soc. 2015, Vol. 36, 1266–1269
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Note
KOREAN CHEMICAL SOCIETY
1
3
(
1
s, 3H); C NMR (CDCl , 125 MHz) δ = 185.7, 145.2, 139.4,
2000, 10, 245; (f ) U. Al-Atar, R. Fernandes, B. Johnsen, D. Bail-
lie, N. R. Branda, J. Am. Chem. Soc. 2009, 131, 15966; (g) T. C.
Pace, V. Müller, S. Li, P. Lincoln, J. Andreasson, Angew. Chem.
Int. Ed. 2013, 52, 4393; (h) D. Wilson, N. R. Branda, Angew.
Chem. Int. Ed. 2012, 51, 5431; (i) T. Kudernac, T. Kobayashi,
A. Uyama, K. Uchida, S. Nakamura, B. Feringa, J. Phys.
Chem. A 2013, 117, 8222; (j) D. Sud, T. J. Wigglesworth, D.
Branda, Angew. Chem. Int. Ed. 2007, 46, 8017; (k) S. Lee, Y.
You, K. Ohkubo, S. Fukuzumi, W. Nam, Org. Lett. 2012, 14,
3
37.1, 136.0, 131.8, 130.5, 127.5, 110.6, 15.7.
Acknowledgment. This research was financially supported in
part by the Ministry of Trade, Industry and Energy (MOTIE)
and Korea Institute for Advancement of Technology (KIAT)
through the Promoting Regional Specialized Industry.
References
2
238; (l) X. Deng, L. S. Liebeskind, J. Am. Chem. Soc. 2001,
1
2
. (a) M. Irie, Chem. Rev. 2000, 100, 1685; (b) W. Szymanski, J. M.
Beierle, H. A. V. Kistemaker, W. A. Velema, B. L. Feringa,
Chem. Rev. 2013, 113, 6114.
123, 7703.
6. Y. Chen, D. X. Zeng, M. G. Fan, Org. Lett. 2003, 5, 1435.
7. Representative recent examples: (a) S. Pu, T. Yang, J. Xu, L.
Shen, G. Li, Q. Xiao, B. Chen, Tetrahedron 2005, 61, 6623;
(b) M. Morimoto, M. Irie, Tetrahedron Lett. 2009, 50, 3404;
(c) S. Pu, T. Yang, G. Li, J. Xu, B. Chen, Tetrahedron Lett.
2006, 47, 3167; (d) S. H. Kawai, Tetrahedron Lett. 1998, 39,
4445; (e) S. Pu, T. Yang, J. Xu, B. Chen, Tetrahedron Lett.
2006, 47, 6473; (f ) H. Liu, S. Pu, G. Liu, B. Chen, Tetrahedron
Lett. 2013, 54, 646; (g) Z. Sun, H. Li, S. Pu, G. Liu, B. Chen, Tet-
rahedron Lett. 2014, 55, 2471; (h) G. Liu, S. Pu, R. Wang, Org.
Lett. 2013, 15, 980; (i) T. Yang, S. Pu, B. Chen, J. Xu, Can. J.
Chem. 2007, 85, 12; (j) T. C. Pijper, T. Kudernac, W. R. Browne,
B. L. Feringa, J. Phys. Chem. C 2013, 117, 17623.
. (a) M. Irie, T. Lifka, S. Kobakate, N. Kato, J. Am. Chem. Soc.
2
000, 121, 4872; (b) T. Yamaguchi, Y. Fujita, H. Nakazumi,
S. Kobatake, M. Irie, Tetrahedron 2004, 60, 9863; (c) S. Koba-
take, M. Irie, Tetrahedron 2003, 59, 8359; (d) N. Tamai, T.
Saika, T. Shimiduz, M. Irie, J. Phys. Chem. 1996, 100, 4689;
(
e) K. Shibata, K. Muto, S. Kobatake, M. Irie, J. Phys. Chem.
A 2002, 106, 209.
. (a) J. Saltiel, Y.-P. Sun, In Photochromism: Molecules and Sys-
tems, H. Durr, H. Bouas-Laurent Eds., Elsevier, Amsterdam,
3
1990, p. 64; (b) M. Irie, M. Mohri, J. Org. Chem. 1988, 53,
803; (c) G. M. Tsivgoulis, J.-M. Lehn, Chem. Eur. J. 1996,
2, 1399.
8. S. Hiroto, K. Suzuki, H. Kamiya, H. Shinokubo, Chem. Com-
mun. 2011, 47, 7149.
4
. R. M. Kellogg, M. B. Groen, H. Wynberg, J. Org. Chem. 1967,
2, 3093.
3
9. G. Vamvounis, D. Gendron, Tetrahedron Lett. 2013, 54, 3785.
10. For the recent applications of highly active zinc, see: (a) S. H.
Kim, R. D. Rieke, Tetrahedron Lett. 2009, 50, 5329; (b) H. H.
Cho, S. H. Kim, Bull. Korean Chem. Soc. 2014, 35, 3081; (c)
S. Y. Park, K. Lee, S. H. Kim, Bull. Korean Chem. Soc. 2014,
35, 1848; (d) H. S. Jung, S. H. Kim, Bull. Korean Chem. Soc.
2014, 35, 280; (e) H. S. Jung, H. H. Cho, S. H. Kim, Tetrahedron
Lett. 2013, 54, 960.
5
. Selected recent works for dithienylethene applications: (a) A. J.
Myles, N. R. Branda, Adv. Funct. Mater. 2002, 12, 167; (b) K.
Uchida, A. Takata, M. Saito, A. Murakami, S. Nakamura, M.
Irie, Adv. Funct. Mater. 2003, 13, 755; (c) H. Hayasaka, T. Miya-
shita, K. Tamura, K. Akagi, Adv. Funct. Mater. 2010, 20, 1243;
(
7
d) B. Gorodetsky, N. R. Branda, Adv. Funct. Mater. 2007, 17,
86; (e) A. Peters, N. R. Branda, Adv. Mater. Opt. Electron.
Bull. Korean Chem. Soc. 2015, Vol. 36, 1266–1269
© 2015 Korean Chemical Society, Seoul & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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