One-pot cross-coupling of diborylmethane for the synthesis of dithienylmethane derivatives

Article abstract of DOI:10.1055/s-0034-1378561

The one-pot palladium-catalyzed Suzuki-Miyaura cross-coupling reaction of a diborylmethane with bromothiophene derivatives realized the synthesis of various dithienylmethane derivatives. Cyclopentadithiophenes, which are promising compounds in material science, can be obtained in good yields. The in situ generation of an unstable thienylmethylboronate is a key step for the present reaction. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0034-1378561

2184▌
LETTER
letter
One-Pot Cross-Coupling of Diborylmethane for the Synthesis of Dithienyl-
methane Derivatives
One-Pot Synthesis of Dithienylmethane Derivatives
Kohei Endo,*a,b Takafumi Ishioka,c Takanori Shibata*c
a
Division of Material Sciences, Graduate School of Natural Science and Technology, Kanazawa University, Kakuma, Kanazawa 920-1192,
Japan
Fax +81(76)2645698; E-mail: kendo@se.kanazawa-u.ac.jp; E-mail: tshibata@waseda.jp
b
PRESTO, Japan Science and Technology Agency (JST), 4-1-8 Honcho Kawaguchi, Saitama 332-0012, Japan
c
Department of Chemistry and Biochemistry, School of Advanced Science and Engineering, Waseda University, Shinjuku, Tokyo 169-8555,
Japan
Received: 13.06.2014; Accepted after revision: 07.07.2014
after silica gel column chromatography. The only reported
Abstract: The one-pot palladium-catalyzed Suzuki–Miyaura
example of the synthesis of a thienylmethylboronate de-
cross-coupling reaction of a diborylmethane with bromothiophene
rivative was successful at a gram scale, but there was no
derivatives realized the synthesis of various dithienylmethane de-
rivatives. Cyclopentadithiophenes, which are promising com-
mention of its stability.4 We describe here the generation
pounds in material science, can be obtained in good yields. The in of thienylmethylboronate derivatives in situ via diboryl-
situ generation of an unstable thienylmethylboronate is a key step
for the present reaction.
methane (1) for a one-pot coupling reaction. Various
types of dithienylmethane derivatives and cyclopentadi-
Key words: boron, cross-coupling, heterocycles, organometallic
reagents, palladium
thiophenes were obtained in good to high yields.
Thiophene is an important building block for the synthesis
of pharmaceutical and organic materials (Figure 1).5
There have been numerous reports of methylene-bridged
heteroaromatic compounds, including thiophene deriva-
tives. We focused on the synthesis of dithienylmethane
derivatives via a diborylmethane in one-pot. There are
only a few conventional approaches to the synthesis of
dithienylmethane derivatives.6 The effect of the substitu-
ents of bromothiophenes was examined using diboryl-
methane (1); NMR yields are given due to the instability
of products 3 (Table 1). The use of simple 3-bromothio-
phene (2a, 1 equiv) and diborylmethane (1, 2 equiv) in the
presence of Pd[P(t-Bu)3]2 (10 mol%) and KOH (2 equiv)
The cross-coupling reaction is a powerful approach to the
synthesis of diarylmethane derivatives using aryl halides
with benzylmetal intermediates or arylmetal intermedi-
ates with benzyl halides.1,2 Typical reactions require the
use of arylmetal- or benzylmetal-type intermediates,
which sometimes degrade the reactions along with vari-
ous side products. Especially, the incorporation of het-
eroaromatic moieties into the desired coupling products
seems to be difficult, since intermediates for coupling
reactions are often unstable.
During our studies using diborylmethane derivatives in in H2O–dioxane at room temperature gave the desired
cross-coupling reactions, we found that the use of het- product 3a in 67% NMR yield; protodeboronation seems
eroaryl halides did not give the desired products.3 Exten- to be a thorny problem (Table 1, entry 1).7 We found that
sive studies have shown that 3-bromothiophene (2a) bromothiophenes bearing an electron-withdrawing group
could take part in the coupling reaction using diboryl- could give the desired products in relatively high yields.
methane (1) to give thienylmethylboronate derivative 3a The reaction of acetyl derivative 2b gave the product 3b
(Equation 1). Although the desired product 3a was ob- in high yield (Table 1, entry 2). The reaction of benzoyl
served using NMR analysis, 3a underwent decomposition derivative 2c gave the product 3c in good yield (Table 1,
S
Br
2a
Pd[P(t-Bu)3]2 (10 mol%)
KOH (2 equiv)
O
B
O
B
S
O
B
O
O
H2O–dioxane
r.t., 24 h
O
1 (2 equiv)
3a, 67% NMR yield
Equation 1
SYNLETT 2014, 25, 2184–2188
Advanced online publication: 21.08.2014
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0034-1378561; Art ID: st-2014-u0515-l
© Georg Thieme Verlag Stuttgart · New York

LETTER
One-Pot Synthesis of Dithienylmethane Derivatives
2185
entry 3). The use of carboxylate derivatives 2d, 2e, and 2f
gave the products 3d, 3e, and 3f, in good to high yields,
respectively (Table 1, entries 4–6). The nitrile derivative
2g can be compatible (Table 1, entry 7). In contrast, the re-
action of a bromothiophene bearing an electron-donating
group, even a methyl group, gave the product 3h in low
yield (Table 1, entry 8). Furthermore, regioisomers of 2b,
such as 2i and 2j, did not give the desired products at all
(Table 1, entries 9 and 10). The reaction using 2-bromo-
thiophene (2k) gave the product in low yield (Table 1, en-
try 11). Other heteroaromatic halides 2l and 2m, such as
furan and pyridine derivatives, did not give the desired
products (Table 1, entries 12 and 13).
Table 1 Substituent Effect
S
R
Br
2a–m
Pd[P(t-Bu)3]2 (10 mol%)
O
B
O
B
S
KOH (2 equiv)
O
B
O
O
R
O
H2O–dioxane
r.t., time
1 (2 equiv)
3a–m
Entry
1
2
Time (h)
NMR yield (%)a
S
24
3a 67
Br
NMe2
S
2a
S
O
S
S
NH
O
F
Br
R
N
2
3
4
5
6
2b R = Me
2c R = Ph
3
3
3
3
3
3b 91
3c 79
3d 75
3e 75
3f 90
sleep-inducing compound5a
CO2H
2d R = OEt
2e R = OPh
2f R = Ot-Bu
S
S
antagonist for
TXA2 and PGD2 receptors5b
conductive materials5c
S
S
S
R
S
Br
O
N
7
8
2g R = CN
3
4
3g 77
3h 27
H
N
N
(
)
n
2h R = Me
N
NHSO2Me
allergy inhibitors5e
O
effect on insulin exocytosis5d
S
Figure 1 Examples of thiophene derivatives
9
3
3
3i not detected
3j not detected
Br
The one-pot procedure for the synthesis of dithienylmeth-
ane derivatives and other heteroaromatic compounds is
shown in Table 2, since the thienylmethylboronate deriv-
atives 3 are not stable. An examination of the reaction
conditions gave the desired products in high yield. The re-
action required an appropriate amount of the second cou-
pling partner and an additional KOH.8 Various
heteroaromatic halides were used for the synthesis of
methylene-bridged products. The combination of 2a and
various second coupling partners showed that the second
coupling reaction of thiophene derivatives bearing an
electron-withdrawing group and/or an electron-donating
group proceeded to give 4a–f (Table 2, entries 1–6). The
use of 2-bromothiophene (2k) gave the desired product 4g
in 71% yield (Table 2, entry 7). Interestingly, the use of
2,3-dibromothiophene (2n) gave the product 4h chemose-
lectively (Table 2, entry 8).9 The benzothiophene deriva-
tive 2o could be used in the second coupling reaction to
give the product 4i in 75% yield (Table 2, entry 9). Fur-
thermore, furan and pyridine derivatives participated in
the second coupling reaction to give the products 4j and
4k in good yields (Table 2, entries 10 and 11). Other elec-
2i
Br
S
O
10
2j
S
11
12
24
24
3k, 9
Br
2k
O
3l not detected
Br
2l
N
13
3
3m not detected
Br
2m
a NMR yield is given. Products were ascertained by MS–FAB.
© Georg Thieme Verlag Stuttgart · New York
Synlett 2014, 25, 2184–2188

2186
K. Endo et al.
LETTER
tron-withdrawing groups were suitable for use under the mized reaction conditions (Scheme 1). The reaction of
conditions for the second coupling reaction and gave the diborylmethane (1) and bromothiophene derivatives 2b,
products 4l–q; however, the reaction using 2e gave the 2c, or 2f (2.2 equiv) gave the desired products 4r, 4s, or 4t
product 2n in low yield (Table 2, entries 12–17). Symmet- in moderate to good yields.
rical dithienylmethanes were synthesized under the opti-
Table 2 One-Pot Coupling Reaction
Pd[P(t-Bu)3]2
ArBr 2a–o
(10 mol%)
(3 equiv)
KOH
(2 equiv)
KOH
(3 equiv)
S
S
R
1
+
R
Ar
H2O–dioxane
r.t., 3 h
60 °C, 24 h
(2 equiv)
Br
4a–q
2b–g
(1 equiv)
Entry
1
1st ArBr
2nd ArBr
Product (%)
S
S
S
S
S
O
O
Br
Br
2b
2a
4a 84
S
S
O
O
O
Br
OR
OR
2
3
4
2b
2b
2b
2d R = Et
2e R = Ph
4b 64
4c 51
2f R = t-Bu
4d 91
S
S
S
S
S
S
O
CN
CN
5
6
7
2b
2b
2b
Br
2g
4e 50
S
O
Br
4f 63
2h
O
S
Br
S
2k
4g 71
Br
Br
S
S
O
8
9
2b
2b
S
S
Br
2n
4h 52
S
S
O
Br
2o
4i 75
S
S
O
O
O
10
11
2b
2b
Br
4j 65
2l
N
N
O
Br
4k 80
2m
Synlett 2014, 25, 2184–2188
© Georg Thieme Verlag Stuttgart · New York

LETTER
One-Pot Synthesis of Dithienylmethane Derivatives
2187
Table 2 One-Pot Coupling Reaction (continued)
Pd[P(t-Bu)3]2
(10 mol%)
KOH
ArBr 2a–o
(3 equiv)
KOH
(3 equiv)
S
S
(2 equiv)
1
R
+
R
Ar
H2O–dioxane
r.t., 3 h
60 °C, 24 h
(2 equiv)
Br
4a–q
2b–g
(1 equiv)
Entry
12
1st ArBr
2nd ArBr
Product (%)
S
S
S
S
O
O
Br
Br
Ph
Ph
2a
2c
4l 91
S
S
S
O
O
Br
RO
RO
13
14
15
2d R = Et
2e R = Ph
2f R = t-Bu
2a
2a
2a
4m 63
4n 26
4o 84
S
S
S
NC
NC
16
2a
Br
4p 74
2g
O
O
S
O
S
S
S
O
17
Br
t-BuO
Br
t-BuO
2f
2i
4q 54
Finally, the coupling reaction using diborylmethane (1)
and 3,3′-dibromo-2,2′-bithiophene (2p) was performed
for the synthesis of cyclopentadithiophene derivatives,
which are conventionally synthesized via a copper-medi-
ated intramolecular coupling or the Friedel–Crafts-type
reactions.8,10 After optimization of the reaction condi-
tions, the desired cyclopentadithiophene 5a was obtained
in moderate yield (Scheme 2). Although bithiophene de-
rivative 2q bearing an alkyl group could take part in the
reaction to give 5b, a bithiophene derivative bearing an
electron-withdrawing group, such as an acetyl group,
gave only a trace amount of the desired product. Methyl-
ation products were observed as side products after pro-
todeboronation (Scheme 3).
O
R
S
Br
2b,c,f (2.2 equiv)
Pd[P(t-Bu)3]2 (10 mol%)
S
S
KOH (2 equiv)
O
O
R
KOH (3 equiv)
1
(1 equiv)
60 °C, 24 h
H2O–dioxane
r.t., 24 h
R
4r, R = Me, 46%
4s, R = Ph, 73%
4t, R = t-BuO, 60%
Scheme 1 Synthesis of symmetrical dithienylmethanes
In conclusion, we have achieved a one-pot coupling reac-
tion for the synthesis of dithienylmethane derivatives. The
present reaction can provide unstable thienylmethylboro-
nate derivatives in situ, which were used for the sequential
coupling reactions without purification to give dithienyl
methane derivatives. The products in the present paper
should be useful for progress in pharmaceutical and mate-
rial science.
R
S
S
2p (R = H)
2q (R = Et)
(1 equiv)
Br Br
Pd[P(t-Bu)3]2 (10 mol%)
S
S
R
KOH (3 equiv)
60 °C, 24 h
KOH (1.5 equiv)
1
H2O–dioxane
r.t., 24 h
(1.5 equiv)
5a, R = H, 54%
5b, R = Et, 56%
Scheme 2 Synthesis of cyclopentadithiophene
© Georg Thieme Verlag Stuttgart · New York
Synlett 2014, 25, 2184–2188

2188
K. Endo et al.
LETTER
References
R1
S
R1
R1
S
R2
S
R2
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O
B
H
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detected by MS analyses
Scheme 3 Schematic results of protodeboronation
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Representative Procedure of One-Pot Coupling Reaction
1-{4-[(Thiophen-3-yl)methyl]thiophen-2-yl}ethanone (4a)
To a solution of diborylmethane (1, 102.8 mg, 0.38 mmol, 2 equiv),
1-(4-bromothiophen-2-yl)ethanone (2b, 39.2 mg, 0.191 mmol), and
Pd[P(t-Bu)3]2 (10.2 mg, 20 μmol, 10 mol%) in dioxane (2.0 mL)
was added 8 N KOH aq (46 μL, 0.4 mmol, 2 equiv) at r.t. The mix-
ture was stirred at r.t. for 3 h. Then, 8 N KOH aq (69 μL, 0.6 mmol,
3 equiv) and 3-bromothiophene (2a, 95.2 mg, 0.58 mmol, 3 equiv)
were added. The mixture was stirred at 60 °C for 24 h and filtered
through a pad of silica gel with Et2O. Purification by silica gel col-
umn chromatography (hexane–EtOAc = 20:1) gave the product 4a
in 84% yield (0.160 mmol, 35.6 mg/42.5 mg); yellow oil. 1H NMR
(400 MHz, CDCl3): δ = 7.51 (s, 1 H), 7.32–7.25 (m, 2 H), 6.97 (s, 1
H), 6.92 (m, 1 H), 3.98 (s, 2 H), 2.52 (s, 3 H). 13C NMR (100 MHz,
CDCl3): δ = 190.7, 144.4, 142.2, 139.9, 133.4, 129.9, 128.1, 126.1,
121.5, 31.0, 26.8. IR (neat): 2992, 2852, 1660, 1417, 1271, 777 cm–1.
ESI-HRMS (+): m/z calcd for C11H10NaOS2+ [M + Na]+: 245.0065;
found: 245.0066.
(4) Synthesis of simple thienylmethylboronate: (a) Swinnen, D.;
Morandi, F. WO 2013092979 A1, 2013.
4H-Cyclopenta[1,2-b:5,4-b′]dithiophene (5a)10c
Thienylalkylboronate: (b) Meng, F.; Jang, H.; Hoveyda,
A. H. Chem. Eur. J. 2013, 19, 3204.
To a solution of diborylmethane (1, 80.2 mg, 0.30 mmol, 1.5 equiv),
3,3′-dibromo-2,2′-bithiophene (2p, 64.7 mg, 0.200 mmol), and
Pd[P(t-Bu)3]2 (10.2 mg, 20 μmol, 10 mol%) in dioxane (2.0 mL)
was added 8 N KOH aq (36 μL, 0.3 mmol, 1.5 equiv) at r.t. The mix-
ture was stirred at r.t. for 24 h. Then, 8 N KOH aq (72 μL, 0.6 mmol,
3 equiv) was added. The mixture was stirred at 60 °C for 24 h and
filtered through a pad of silica gel with Et2O. Purification by silica
gel column chromatography (hexane) gave the product 5a in 54%
yield (0.107 mmol, 19.1 mg/35.6 mg); yellow solid; mp 74 °C. 1H
NMR (400 MHz, CDCl3): δ = 7.19 (m, 2 H), 7.08 (m, 2 H), 3.53 (s,
2 H). 13C NMR (100 MHz, CDCl3): δ = 149.6, 138.6, 124.4, 122.9,
31.8. IR (neat): 3074, 2922, 1660, 802, 685 cm–1. ESI-HRMS (+):
m/z calcd for C9H7S2+ [M + H]+: 178.9984; found: 178.9984.
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(7) The use of Ag2O as an additive did not improve the yield of
products, see ref. 3e.
(8) See Supporting Information.
(9) The halogen–lithium exchange of 4h using n-BuLi and
subsequent protonation gave 4g.
Acknowledgment
This work was supported by JST PRESTO program and a Grant-in-
Aid for Scientific Research (B).
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Supporting Information for this article is available online
at
http://www.thieme-connect.com/products/ejournals/journal/
10.1055/s-00000083.SunpfgIpi
o
o
nr
i
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