Improved synthesis of tetrakis(2-thienyl)methane

Article abstract of DOI:10.1081/SCC-200036572

An improved synthesis of tetrakis(2-thienyl)methanes, where an aromatic nucleophilic substitution is the key reaction for the introduction of the fourth 2-thienyl group, has been developed, thus, reaction of tris(2-thienyl)methyl anion with 2-fluoro-5-cya

Full text of DOI:10.1081/SCC-200036572

This article was downloaded by: [Uppsala universitetsbibliotek]
On: 04 October 2014, At: 08:25
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954
Registered office: Mortimer House, 37-41 Mortimer Street, London W1T
3JH, UK
Synthetic Communications:
An International Journal
for Rapid Communication of
Synthetic Organic Chemistry
Publication details, including instructions for
authors and subscription information:
http://www.tandfonline.com/loi/lsyc20
Improved Synthesis of
Tetrakis(2‐thienyl)methane
Kouzou Matsumoto a , Toru Tanaka a & Masaji Oda a
a Department of Chemistry, Graduate School of
Science , Osaka University , Toyonaka, Osaka, 560
0043, Japan
Published online: 10 Jan 2011.
To cite this article: Kouzou Matsumoto , Toru Tanaka & Masaji Oda (2004)
Improved Synthesis of Tetrakis(2‐thienyl)methane, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry,
34:22, 4037-4042, DOI: 10.1081/SCC-200036572
To link to this article: http://dx.doi.org/10.1081/SCC-200036572
PLEASE SCROLL DOWN FOR ARTICLE
Taylor & Francis makes every effort to ensure the accuracy of all
the information (the “Content”) contained in the publications on our
platform. However, Taylor & Francis, our agents, and our licensors
make no representations or warranties whatsoever as to the accuracy,
completeness, or suitability for any purpose of the Content. Any opinions
and views expressed in this publication are the opinions and views of
the authors, and are not the views of or endorsed by Taylor & Francis.
The accuracy of the Content should not be relied upon and should be
independently verified with primary sources of information. Taylor and
Francis shall not be liable for any losses, actions, claims, proceedings,
demands, costs, expenses, damages, and other liabilities whatsoever

or howsoever caused arising directly or indirectly in connection with, in
relation to or arising out of the use of the Content.
This article may be used for research, teaching, and private study
purposes. Any substantial or systematic reproduction, redistribution,
reselling, loan, sub-licensing, systematic supply, or distribution in any form
to anyone is expressly forbidden. Terms & Conditions of access and use
can be found at http://www.tandfonline.com/page/terms-and-conditions

SYNTHETIC COMMUNICATIONSw
Vol. 34, No. 22, pp. 4037–4042, 2004
Improved Synthesis of
Tetrakis(2-thienyl)methane
*
Kouzou Matsumoto, Toru Tanaka, and Masaji Oda
Department of Chemistry, Graduate School of Science, Osaka University,
Toyonaka, Osaka, Japan
ABSTRACT
An improved synthesis of tetrakis(2-thienyl)methanes, where an aromatic
nucleophilic substitution is the key reaction for the introduction of
the fourth 2-thienyl group, has been developed, thus, reaction of
tris(2-thienyl)methyl anion with 2-fluoro-5-cyanothiophene smoothly
proceeded to give (5-cyano-2-thienyl)-tris(2-thienyl)methane in good
yield. Alkaline hydrolysis of the cyano group to carboxylic acid followed
by decarboxylation at 1808C in quinoline in the presence of copper(I)
oxide afforded the parent tetrakis(2-thienyl)methane in 50% total yield
from the trithienylmethane.
Key Words: Tetrakis(heteroaryl)methanes; Tetrakis(2-thienyl)methane;
Aromatic nucleophilic substitution; Decyanation.
*
Correspondence: Masaji Oda, Department of Chemistry, Graduate School of Science,
Osaka University, Toyonaka, Osaka 560 0043, Japan; Fax: þ6/6850-5387; E-mail:
moda@chem.sci.osaka-u.ac.jp.
4037
DOI: 10.1081/SCC-200036572
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com
Copyright # 2004 by Marcel Dekker, Inc.

4038
Matsumoto, Tanaka, and Oda
We recently reported the first synthesis of tetrakis(2-thienyl)methane (1)
by the application of butadiyne-thiophene transformation.[1] In view of easy
functionalization of thiophene at 2-(or 5)-position either by aromatic electro-
philic substitutions or lithiation-functionalizations as well as the synthetic
equivalency of thiophene with a tetramethylene unit by Raney-nickel reduc-
tion, compound 1 would be a versatile synthon for novel three-dimensional
molecules of structural and physicochemical interest. However, the total
yield of 1 was poor, and yield improvement was needed for develop-
ment of its chemistry. More recently, we reported the synthesis of tetrakis
(2-pyridyl)methane (2)[2] by the reaction of tris(2-pyridyl)methyl anion
with 2-chloropyridine (52% yield). Later, we found that the yield can be
further improved up to 93% by use of 2-fluoropyridine in place of 2-chloro-
pyridine.[3] A key to the successful synthesis of 2 is high reactivity of
2-halopyridines toward aromatic nucleophilic substitutions. In contrast to
the electron-poor nature of pyridine, however, thiophene is one of the
electron-rich aromatic heterocyclic compounds, and therefore, aromatic
nucleophilic substitution is not practical for 2-halothiophenes. However,
2-halothiophenes having an electron-withdrawing group at 5-position
become more susceptible to aromatic nucleophilic substitutions.[4] We
now report an improved and practical synthesis of 1 based on the aromatic
nucleophilic substitution of 2-halopthiophenes.
We at first examined the reaction of tris(2-thienyl)methyl anion 3[5] with
2-chlorothiophene 4 and 2,5-dichlorothiophene 5 under several conditions.
Although 4 did not give 1 at all, 5 gave the substitution product 6 under
a drastic condition (reflux in xylene for 24 hr) in poor yield of 4%
(Scheme 1). Next examined was 2-chloro-5-nitrothiophene 7: the reaction
of 3 with 7 in THF gave the dimeric material 8 in 27% yield as only isolable
product. The formation of 8 indicates the occurrence of single electron trans-
fer (SET) from 3 to 7, generating tris(2-thienyl)methyl radical of which
dimerization has been reported (Scheme 2).[6] Thus, it turned out that the

Improved Synthesis of Tetrakis(2-thienyl)methane
4039
Scheme 1.
chloro group is too weak and the nitro group is too strong as electron-
withdrawing substituents for the present purpose.
Taking these results into account, we chose cyano group as a potentially
promising substituent. The reaction of 3 with 2-chloro-5-cyanothiophene 9a
proceeded in THF at room temperature and the desired (5-cyano-2-thienyl)-
tris(2-thienyl)methane 10 was obtained in moderate yields (Scheme 1).
However, this reaction suffered from the poor reproducibility and the yield
varied from 4% to 48% under similar conditions.
Finally, 2-fluoro-5-cyanothiophene 9b was found to be the best substrate:
the reaction of 3 with 9b smoothly proceeded in THF at 2788C to give 10 in
78% yield. Alkaline hydrolysis of the cyano group of 10 gave the correspond-
ing carboxylic acid 11 and subsequent decarboxylation by heating the crude
11 at 1808C in quinoline in the presence of copper(I) oxide afforded the
parent compound 1 in 65% yield from 10.
Thus, tetrakis(2-thienyl)methane (1) is now available in gram quantity,
and its chemistry and application to the synthesis of novel three-dimensional
molecules are in progress.
Scheme 2.

4040
Matsumoto, Tanaka, and Oda
EXPERIMENTAL
Materials
Tris(2-thienyl)methane,[5] 2-chloro-5-nitrothiophene (5),[7] 5-chlorothio-
phene-2-carbonitrile (9a),[8] and 5-fluorothiophene-2-carbonitrile (9b)[9]
were prepared according to literature. Tetrahydrofuran (THF) was distilled
over sodium benzophenone ketyl before use. Butyllithium in hexane solution,
copper(I) oxide, and quinoline were all commercially available and used
without further purification. The structure of 6 was determined by mass
1
spectral and H NMR analyses.
Procedure
(5-Chloro-2-thienyl)-tris(2-thienyl)methane (6)
To a solution of 524 mg (2.0 mmol) of tris(2-thienyl)methane in THF
(10 mL) was added dropwise a 1.4 M solution of butyllithium (1.4 mL,
2.0 mmol) over 5 min at 2708C under nitrogen atmosphere. The red suspen-
sion of anion 3 was stirred at room temperature for an hour. Dry xylene (15mL)
and 5 (1.1 mL, 10 mmol) were added, and the mixture was heated at 908C to
remove THF by distillation and then heated at refluxing temperature of xylene
for 24 hr. After cooling, the reaction mixture was added with 50 mL of water
and extracted with ethyl acetate. The combined organic layers were washed
with water and brine and dried over anhydrous sodium sulfate. After filtration
and concentration, the residue was purified by column chromatography on
silica gel eluted with hexane–ethyl acetate (10 : 1 v/v) to give 30 mg (4%)
of 8: colorless crystals; mp 92–938C (hexane); EIMS (rel intensity) m/z
1
378 (Mþ; 35Cl, 100), 380 (Mþ; 37Cl, 56), 343 ([M–Cl]þ, 58); H-NMR
(500 MHz, CDCl3) d/ppm 6.79 (d, J ¼ 4.1 Hz, 1H, Th-30H), 6.82
(d, J ¼ 4.1 Hz, 1H, Th-40H), 6.99 (dd, J ¼ 5.1, 3.5 Hz, 3H, Th-4H), 7.07
(dd, J ¼ 3.5, 1.4 Hz, 3H, Th-3H), 7.25 (dd, J ¼ 5.1, 1.4 Hz, 3H, Th-5H);
13C-NMR (125 MHz, CDCl3) d/ppm 53.34 (central-C), 125.48 (Th-5C),
125.57 (Th-30C), 126.50 (Th-4C), 126.89 (Th-40C), 127.89 (Th-3C), 129.94
(Th-50C), 151.05 (Th-20C), 151.81 (Th-2C); UV-vis (CH2Cl2) lmax (log 1)
228sh (4.33), 241 (4.43); Anal. Calcd for C17H11ClS4: C, 53.88; H, 2.93.
Found: C, 53.83; H, 3.14.
(5-Cyano-2-thienyl)-tris(2-thienyl)methane (10)
A solution of 3, generated by the treatment of tris(2-thienyl)methane
(1.05 g, 4.0 mmol) in THF (20 mL) with 1.4 M solution of butyllithium in

Improved Synthesis of Tetrakis(2-thienyl)methane
4041
hexane (2.8 mL, 4.0 mmol) at 2788C then rt for an hour, was added dropwise
to a solution of 9b (0.51 g, 4.0 mmol) in THF (20 mL) at 2788C. After stirring
for 2 hr, 50 mL of water was added to the reaction mixture, and the mixture
was extracted with ethyl acetate. The combined organic layers were washed
with water and brine and dried over anhydrous sodium sulfate. After filtration
and concentration, the residue was purified by column chromatography on
silica gel eluted with hexane–ethyl acetate (15 : 1 v/v) to give 1.14 g (78%)
of 10: colorless needles; mp 131–1328C (hexane–ethyl acetate); EIMS (rel
1
intensity) m/z 369 (Mþ, 100), 286 ([M–Th]þ, 20); H NMR (500 MHz,
CDCl3) d/ppm 7.01 (dd, J ¼ 5.2, 3.7 Hz, 3H, Th-4H), 7.06 (dd, J ¼ 3.7,
1.2 Hz, 3H, Th-3H), 7.11 (d, J ¼ 4.0 Hz, 1H, Th-30H), 7.28 (dd, J ¼ 5.2,
1.2 Hz, 3H, Th-5H), 7.51 (d, J ¼ 4.0 Hz, 1H, Th-40H); 13C NMR (125 MHz,
CDCl3) d/ppm 53.39 (central-C), 109.36 (Th-50C), 114.08 (CN), 125.89
(Th-5C), 126.69 (Th-4C), 128.03 (Th-30C), 128.14 (Th-3C), 136.96
(Th-40C), 150.95 (Th-2C), 160.97 (Th-20C); IR (KBr disk) n/cm21 2220
(CN); UV-vis (CH2Cl2) lmax (log 1) 240 (4.44), 272 (4.14); Anal. Calcd for
C18H11NS4: C, 58.50; H, 3.00; N, 3.79. Found: C, 58.35; H, 2.86; N, 3.82.
Tetrakis(2-thienyl)methane (1)
A mixture of 10 (1.71 g, 4.6 mmol), ethanol (75 mL), and 10% NaOHaq
(60 mL) was heated at reflux for 3 hr. After cooling, the reaction mixture
was neutralized with 2M HClaq and extracted with ethyl acetate. The
combined organic layers were washed with water and brine and dried over
anhydrous sodium sulfate. Filtration and concentration gave the crude
5-(tris(2-thienyl)methyl)-2-thiophenecarboxylic acid (12) (1.73 g, 96%) that
was used for further reaction without purification. A suspension of the
crude 12 (0.50 g, 1.3 mmol), Quinoline (5 mL), and copper(I) oxide (46 mg,
0.32 mmol) was heated at 1808C for 2 hr. After cooling, solids were
removed by filtration through a pad of celite and washed with ethyl acetate
thoroughly. The filtrate and washings were combined and washed with
water, 2M HCl aq, water, and brine and then dried over anhydrous sodium
sulfate. After filtration and concentration, the residue was purified by
column chromatography on silica gel eluted with hexane–ethyl acetate
(10 : 1 v/v) to give 290 mg (65%) of 1: colorless crystals; mp 171–1728C
(hexane–ethyl acetate); EIMS (rel intensity) m/z 344 (Mþ, 41), 261
1
([M–Th]þ, 27), 178 ([M–2Th]þ, 37); H-NMR (500 MHz, CDCl3) d/ppm
6.98 (dd, J ¼ 5.2, 3.7 Hz, 4H, Th-4H), 7.07 (dd, J ¼ 3.7, 1.2 Hz, 4H,
Th-3H), 7.23 (dd, J ¼ 5.2, 1.2 Hz, 4H, Th-5H); 13C-NMR (125 MHz,
CDCl3) d/ppm 53.19 (central-C), 125.22 (Th-5C), 126.37 (Th-4C), 127.79
(Th-3C), 152.67 (Th-2C); UV-vis (CH2Cl2) lmax (log 1) 228sh (4.36), 240
(4.46); Anal. Calcd for C17H12S4: C, 59.26; H, 3.51. Found: C, 59.11; H, 3.52.

4042
Matsumoto, Tanaka, and Oda
ACKNOWLEDGMENT
This work was supported in part by the 21st Century COE Program,
Japanese Government (Creation of Integrated EcoChemistry).
REFERENCES
1. Matsumoto, K.; Nakaminami, H.; Sogabe, M.; Kurata, H.; Oda, M. Syn-
thesis of tetrakis(2-thienyl)methane. Tetrahedron Lett. 2002, 43, 3049.
2. Matsumoto, K.; Kannami, M.; Oda, M. Synthesis of tetrakis(2-pyridyl)-
methane: the first tetrapyridylmethane. Tetrahedron Lett. 2003, 44, 2861.
3. Unpublished result in our laboratory.
4. For a review on aromatic nucleophilic substitution of thiophene deriva-
tives: Consiglio, G.; Spinelli, D.; Dell’Erba, C.; Marino, N.; Petrillo, G.
Nucleophilic substitution on thiophene derivatives: a multi-lane speedway.
Gazz. Chim. Ital. 1997, 127, 753, and references therein.
5. Nakayama, J.; Sugino, M.; Ishii, A.; Hoshino, M. Reaction of tri-2-thienyl-
methyllithium with alkyl halides. Substitution on carbanion center vs.
thiophene ring. Chem. Lett. 1992, 703.
6. Nakayama, J.; Ishii, A.; Yamada, Y.; Suhino, M.; Hoshino, M. Dimeriza-
tion of tri-2-thienylmethyl radical. Tetrahedron Lett. 1990, 31, 2627.
7. Hurd, C.D.; Kreuz, K.L. Nitrothienols and halogenated nitrothiophenes.
J. Am. Chem. Soc. 1952, 74, 2965.
8. Suzuki, H.; Iwao, T.; Sugiyama, T. A convenient laboratory method for the
preparation of thiophenecarbonitriles. Bull. Inst. Chem. Res., Kyoto Univ.
1974, 52, 561.
9. Chambers, R.J.; Marfat, A. An improved synthesis of 5-fluorothiophene-2-
carboxylic acid. Synth. Commun. 2000, 30, 3629.
Received in Japan May 10, 2004