Synthesis of 2-Bromo-2′-phenyl-5,5′-thiophene: Suzuki reaction versus Negishi reaction

Article abstract of DOI:10.1081/SCC-120021039

2-Bromo-2′-phenyl-5,5′-thiophene was synthesized by cross-coupling reaction of phenylboric acid and 2,2′-dibromo-5,5′-bithiophene with a Suzuki reaction; we found the Suzuki reaction to give a higher yield when compared to the Negishi reaction.

Full text of DOI:10.1081/SCC-120021039

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Synthesis of 2-Bromo-2′-phenyl-5,5′-thiophene: Suzuki
Reaction Versus Negishi Reaction
Nai-Xing Wang a
a Institute of Photographic Chemistry , Chinese Academy of Sciences , Beijing, P.R. China
Published online: 17 Aug 2006.
To cite this article: Nai-Xing Wang (2003) Synthesis of 2-Bromo-2′-phenyl-5,5′-thiophene: Suzuki Reaction Versus Negishi
Reaction, Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry,
33:12, 2119-2124, DOI: 10.1081/SCC-120021039
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SYNTHETIC COMMUNICATIONSÕ
Vol. 33, No. 12, pp. 2119–2124, 2003
Synthesis of 2-Bromo-20-phenyl-5,50-thiophene:
Suzuki Reaction Versus Negishi Reaction
*
Nai-Xing Wang
Institute of Photographic Chemistry, Chinese Academy
of Sciences, Beijing, P.R. China
ABSTRACT
2-Bromo-20-phenyl-5,50-thiophene was synthesized by cross- coupling
reaction of phenylboric acid and 2,20-dibromo-5,50-bithiophene with
a Suzuki reaction; we found the Suzuki reaction to give a higher yield
when compared to the Negishi reaction.
INTRODUCTION
The cross-coupling reaction of organoboranes with a number of
organic halides in presence of a catalytic amount of palladium complexes
and bases was reported as a versatile and useful method for conjugated
*Correspondence: Nai-Xing Wang, Institute of Photographic Chemistry,
Chinese Academy of Sciences, Beijing 100101, P.R. China; E-mail:
naixingwang@hotmail.com.
2119
DOI: 10.1081/SCC-120021039
Copyright & 2003 by Marcel Dekker, Inc.
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com

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2120
Wang
alkadiene, arylated alkenes, 1,4-alkadienes, allylic benzene, a,b-unsatu-
rated carboxylic acid and 2,4-alkadienoates.[1–4]
Thecross-coupling raection of organoboron compounds, which
involves the transmetallation to palladium(II) halides as a key step, was
found to proceed smoothly when these were activated with suitable bases
and technique for a wide range of selective carbon-carbon bond forma-
tion.[5–9] Many organometallic reagents undergo similar cross-coupling
reactions, however, recently much attention has been focused on the
use of organoboronic acids in laboratories and industry since they
are convenient reagents, which are generally thermally stable and
inert to water and oxygen, thus allowing their handling without special
precautions.
RESULTS AND DISCUSSION
Using thecross-coupling of organoboranes with an organic halidein
the presence of a catalytic amount of palladium complexes and bases, the
conjugated coupled thiophene derivative 2-bromo-2-phenyl-5,50-thio-
phene was synthesized. Our experiments found that the Suzuki reaction
gave a higher yield when compared to the Negishi reaction.
The title compound was synthesized by Suzuki reaction (Sch. 1):
Scheme 1.
Synthesis of 2-bromo-20-phenyl-5,50-thiophene via palladium-
catalyzed cross-coupling reactions (Suzuki reaction) related to an inter-
esting mechanism, which might be described as three steps: 1) oxidative
addition 2) transmetallation 3) reductive elimination sequence.

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Suzuki Reaction Versus Negishi Reaction
2121
1. Oxidativeaddition:
Ar-X ———— [Arþ XÀ
]
Pd(PPh3)4 ———— [Pdo þ PPh3]
[Arþ XÀ ] þ Pd0 ———— [ArÀ Pd2þ XÀ
]
2. Transmetallation:
[ArÀ Pd2þ XÀ ] þ Ar0B(OH)2 ———— Ar-Pd-Ar0 þ X-B(OH)2
3. Reductive elimination:
Ar-Pd-Ar0 ———— Ar-Ar0 þ Pd0
Oxidativeaddition of 1-alkneyl, 1-alkynyl, allyl, bnezyl, and aryl
halides to a palladium(0) complex affords a stable palladium(II) com-
plex.[10–13] The reaction proceeds with complete retention of configura-
tion for alkenyl halides and with inversion for allylic and benzylic halides.
Oxidative addition was the rate-determining step in the catalytic cycle.
The reaction activity decreased with the order of I> Br ꢀ Cl.[10–13] Aryl
and 1-alkenyl halides were activated by the proximity effect of electron-
withdrawing groups, which were more reactive to the oxidative addition
than those with donating group, thus, chlorides were allowed for the
cross-coupling reaction. A very wide range of palladium(0) catalysts or
precursors were used for cross-coupling reaction, reagent Pa(PPh3)4 was
most commonly used.
The cross-coupling reaction was accelerated exceptionally by weak
bases, the stronger bases such as potassium carbonate gave byproduct
arising from further coupling of the product with aryl halides, here
barium hydroxide was used as a base to achieve the selected cross
coupling. Sincethehalogne ligand on organopalladium(II) in the
oxidative addition mechanism, halide was readily displaced by alkoxy
anion to provide Ar-Pd-OR complexes, which had been postulated as
reaction intermediates[14–16] or isolated[17,18] from theraection of
organopalladium(II) halides with methoxide, therefore, methanol was
used as a solvent here.
[RÀ Pd2þ XÀ] þ MeOÀ ———— R-Pd-OMe þ XÀ
R-Pd-OMe þ Ar-B(OH)2 ———— R-Pd-Ar þ MeO-B(OH)2
R-Pd-Ar ———— R-Ar þ Pd0
The formation of alkoxy palladium intermediate should be
considered to be one of the crucial transmetallation processes in the
base-palladium induced cross-coupling reactions.

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2122
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Scheme 2.
To research on the synthesis of 2-bromo-20-phenyl-5,50-thiophene,
we also set up the Negishi reaction by using n-butyl lithium and
zinc chloride reagents. However, our experiments found that the
Suzuki reaction gave a much more higher yield when compared to the
Negishi reaction.
The title compound also could be synthesized by Negishi reaction
(Sch. 2).
EXPERIMENTAL SECTION
Synthesis of 2,20-Dibromo-5,50-bithiophene
To a cooled (À78ꢁC) solution of dry ether (20 mL), 2, 5-dibromothio-
phene (3.5 mmol, 0.4 mL) and n-BuLi (1.56 mL, 3.9 mmol, 1.1 eq)
under N2 were added. The mixture was stirred at À78ꢁC for 2 h, dry
CuBr2 (2.69 g) then was added into the mixture under N2 at À78ꢁC,
cooling bath was removed and the reaction mixture was stirred at r.t.
overnight. The mixture was poured into 40 mL of ice water, extracted
with CHCl3 (50 mL Â 3), theCHCl 3 layer was washed with 25 mL of 15%
HCl, the organic layer was washed with NaHCO3 (aq., 50 mL), then
water (50 mL), and dried with anhydrous MgSO4 for 30 min. Solvent
was evaporated to get slightly gray solid 543.5 mg (yield 94%). TLC
(hexane, Rf ¼ 0.45). Recrystallization with hexane, plate crystal was
got, melting point: 81ꢁC. H NMR (CDCl3, TMS, 500 MHz), ꢀ 6.96 (d,
1
J ¼ 3.6, 2H), 6.85 (d, J ¼ 3.6, 2H). 13C NMR (CDCl3, TMS, 500 MHz), ꢀ
112.047 (2C), 124.667 (2C), 131.168 (2C), 138.302 (2C). GC-MS (EI): 324
[Mþ] (100%).

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Suzuki Reaction Versus Negishi Reaction
2123
Synthesis of 2-Bromo-20-phenyl-5,50-thiophene
by Suzuki Reaction
Phenylboric acid (225.8 mg, 1.8 mmol) and barium hydroxide
octahydrate (583 mg, 1.8 mmol) were put into a reaction flask and
vacuumed for 40 min, then N2 was filled. Pd(PPh3)4 (48.16 mg,
0.0417 mmol) was dissolved in 10 mL toluene and methanol (1:1),
bubbled with N2, then it was transfer into the reaction flask under N2.
2,20-dibromo-5,50-bithiophene (546 mg, 1.68 mmol) was vacuumed for
30 min, and filled with N2, then it was dissolved in 15 mL chloroform
(bubbled with N2) and then was transferred into the reaction flask under
N2. The result reaction mixture was stirred at 100ꢁC under N2 for 48 h.
The reaction mixture was allowed to add into 80 mL CHCl3, washed with
15% HCl (aq.) (80 mL), then 80 mL NaHCO3 solution (aq.), finally
washed with water, dried with anhydrous MgSO4, crudeproduct
(0.82 g) was got, separation by chromatograph on silica gel column,
hexane and toluene (98:2) was used as eluent, pure compound
275.03 mg was obtained (yield 51%). TLC (hexane, Rf ¼ 0.314).
Recrystallization with hexane, melting point: 145ꢁC. H NMR (CDCl3,
1
TMS, 500 MHz), ꢀ 7.58 (m, 2H), 7.37 (m, 2H), 7.29 (m, 1H), 7.21 (d,
J ¼ 3.61Hz, 1H), 7.08 (d, J ¼ 3.61, 1H), 6.98 (d, 1H, J ¼ 3.62, 1H), 6.94
(d, J ¼ 3.62, 1H). GC-MS (EI): 322 [Mþ], 240 [M-Br]þ.
Synthesis of 2-Bromo-20-phenyl-5,50-thiophene
by Negishi Reaction
Bromobenzene (1.14 g, 7.26 mmol) was dissolved in 45 mL dry THF
in a schlenk’s vessel at À35ꢁC, n-BuLi (2.5 eq., 1.16268 g) was added
dropwise to the reaction vessel at À35ꢁC, and the brightly yellow-green
solution was stirred at À35ꢁC for 2 h, the reaction mixture was cooled to
À78ꢁC for 15 min, ZnCl2 (18.876 mmol, 19.30 mL, 0.978 M/ether) was
added at À78ꢁC for 3 min, then the stirring was continued at ambient
temperature for 2 h, 2,20-dibromo-5,50-thiophene (3 eq. 21.78 mmol,
7.056 g) and Pd(PPh3)4 (251 mg) was dissolved in 30 mL of dry THF
under nitrogen and then was added to reaction vessel at ambient tem-
perature, stirring was continued at ambient temperature for 2 h in the
dark, then the reaction mixture was stirred at 110ꢁC for 60 h in thedark.
The brown mixture was cooled to ambient temperature, 150 mL of water
was added, extracted with CHCl3 (3 Â 100 mL) and washed with 100 mL
of 15% hydrochloric acid, 150 mL of saturated NaHCO3 solution and
100 mL of H2O, organic phase was dried over anhydrous MgSO4, the

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2124
Wang
solvent was removed to give a brown solid, which was chromatographed
(silica gel, hexane). Recrystallization with hexane, 636.2 mg product was
obtained (yield 27.3%). melting point: 145ꢁC. H NMR (CDCl3, TMS,
1
500 MHz), ꢀ 7.58 (m, 2H), 7.36 (m, 2H), 7.28 (m, 1H), 7.21 (d, J ¼ 3.61Hz,
1H), 7.08 (d, J ¼ 3.61, 1H), 6.98 (d, 1H, J ¼ 3.62, 1H), 6.93 (d, J ¼ 3.62,
1H). GC-MS (EI): 322 [Mþ], 240 [M-Br]þ.
REFERENCES
1. Suzuki, A. Pure& Appl. Chem. 1985, 57, 1749.
2. Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457.
3. Suzuki, A. Pure& Appl. Chem. 1994, 66, 213.
4. Maddaford, S.P.; Keay, B.A. J. Org. Chem. 1994, 59, 6501.
5. Negishi, E. Aspects of Mechanism and Organometallic Chemistry;
Brewster, J.H., Ed.; Plenum Press: New York, 1978; 285.
6. Suzuki, A. Acc. Chem. Res. 1982, 15, 178.
7. Miyaura, N.; Suzuki, A. J. Synth. Org. Chem. Jpn. 1988, 46, 848.
8. Miyaura, N.; Suzuki, A. J. Synth. Org. Chem. Jpn. 1993, 51, 1043.
9. Suzuki, A. Pure& Appl. Chem. 1991, 63, 419.
10. Tamao, K. Comprehensive Organic Synthesis; Trost, B.M., Fleming,
I., Pattenden, G., Eds.; Pergamon: New York, 1991; Vol. 3, 435.
11. Hegedus, L.S. Organometallics in Organic Synthesis; Schlosser Ed.;
Wiley: New York, 1994, 383.
12. Aliprantis, A.O.; Canary, J.W. J. Am. Chem. Soc. 1994, 116, 6985.
13. Stille, J.K.; Lau, K.S.Y. Acc. Chem. Res. 1977, 10, 434.
14. Anderson, C.B.; Burreson, B.J.; Michalowski, T.J. J. Org. Chem.
1976, 41, 1990.
15. Blackburn, T.F.; Schwartz, J. J. Chem. Soc., Chem. Commun.
1977, 157.
16. Zask, A.; Helquist, P. J. Org. Chem. 1978, 43, 1619.
17. Yoshida, T.; Okano, T.; Otsuka, S. J. Chem. Soc., Dalton Trans.
1976, 993.
18. Grushin, V.V.; Alper, H. Organometallics 1993, 12, 1890.
Received in the USA September 16, 2002