Dual electrophilic trapping-negishi coupling with dilithiothiophenes in a three-component, one-pot process

Article abstract of DOI:10.1055/s-0029-1219203

Based upon a twofold bromine-lithium exchange with 2,5-dibromo thiophene and sequential trapping of the dilithio intermediate, organo zinc halides were generated in situ and subsequently transformed by Negishi cross-coupling to unsymmetrically substituted thiophenes in a one-pot fashion. Application of this novel sequence to diiodo(hetero)arenes quickly furnishes highly interesting building blocks for materials science applications. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0029-1219203

LETTER
415
Dual Electrophilic Trapping–Negishi Coupling with Dilithiothiophenes in a
Three-Component, One-Pot Process
Sequential
Dual
E
h
lectrophilic
r
Trappin
i
g–Negi
s
shi
C
oupl
t
ing wit
i
h
D
ilith
a
iothiophe
n
n
es Muschelknautz, Catherine Dostert, Thomas J. J. Müller*
Institut für Organische Chemie und Makromolekulare Chemie, Lehrstuhl für Organische Chemie, Heinrich Heine Universität Düsseldorf,
Universitätsstr. 1, 40225 Düsseldorf, Germany
Fax +49(211)8114324; E-mail: ThomasJJ.Mueller@uni-duesseldorf.de
Received 26 November 2009
Dedicated to Prof. Dr. Karl Kleinermanns on the occasion of his 60th birthday.
n-BuLi
Abstract: Based upon a twofold bromine–lithium exchange with
2,5-dibromo thiophene and sequential trapping of the dilithio inter-
mediate, organo zinc halides were generated in situ and subsequent-
ly transformed by Negishi cross-coupling to unsymmetrically
substituted thiophenes in a one-pot fashion. Application of this nov-
el sequence to diiodo(hetero)arenes quickly furnishes highly inter-
esting building blocks for materials science applications.
Br (hetero)arene Br
Li (hetero)arene Li
electrophile E1
THF, –78 °C
electrophile E2
E1 (hetero)arene Li
E1 (hetero)arene E2
Key words: arenes, C–C coupling, heterocycles, lithiation, multi-
component reactions
Scheme 1 General scheme for the one-pot desymmetrization of di-
bromo(hetero)arenes by sequential addition of different electrophiles
generating dilithio intermediates
Halogen–metal exchange offers a versatile transformation
of organic halides into carbon nucleophiles which can be
subsequently trapped by addition of a broad variety of
electrophiles in a one-pot fashion.1 In case of dihalogenat-
ed aryl compounds, dual halogen–metal exchange and
dual electrophilic trapping furnishes symmetrical prod-
ucts. However, desymmetrizing symmetrical dilithio(het-
ero)arenes to unsymmetrical target molecules represents
an attractive synthetic manipulation. Usually, this trans-
formation has been carried out by repetitive bromine–
lithium exchange followed by electrophilic trapping in a
stepwise fashion with intermediate workup and purifica-
tion after each bromine–lithium exchange–trapping se-
quence.2 However, direct sequential electrophilic trapping
of dilithio species in a one-pot fashion appears to be more
efficient and economical. Just recently, we reported first
examples of this type of one-pot methodology disclosing
a straightforward and effective way to desymmetrized
products. Upon variation of the electrophilic species, the
sequential trapping methodology has become an entry to
new consecutive multicomponent processes in a one-pot
fashion (Scheme 1).3
Negishi coupling sequence that rapidly leads to unsym-
metrically substituted thiophenes.
Upon double bromo–lithium exchange of 2,5-dibro-
mothiophene (1) with n-butyllithium in the presence of
TMEDA at low temperatures, the corresponding dilithio
species is generated in situ.3 To ensure quantitative con-
version, reverse addition was chosen, that is, 2,5-dibro-
mothiophene was added dropwise to a precooled solution
of n-butyllithium.5 Then, sequential transmetalation with
trimethylsilylchloride and anhydrous zinc bromide fur-
nishes an in situ generated organozinc derivative that is
immediately submitted to Negishi coupling in the same
pot, simply by addition of catalytic amounts of
tetrakis(triphenylphosphine)palladium(0) and a slight
excess of various iodo(hetero)arenes 2, to give unsymmet-
rically substituted thiophenes 3 in moderate to good yields
(Scheme 2, Table 1).6 The structures of all new com-
pounds have been unambiguously assigned by spectro-
scopic (NMR, IR, MS) and elemental analysis.
As expected for Negishi coupling a broad range of aryl
and heteroaryl substituents with variable electronic sub-
stitution are well tolerated. Considering four elementary
processes with five-bond transformations being per-
formed in a one-pot fashion, the overall yields ranging
from 52–67% correspond to yields of 85–90% per step.
Likewise symmetric 2,5-diiodothiophene and 1,4-diiodo-
benzene can be successfully applied as terminal coupling
partners for the formation of symmetrical tri(hetero)are-
nes 4 with a,w-bis(trimethylsilyl) substitution in good
yields (Scheme 3).7
Interestingly, the order of electrophile addition can even
open access to highly reactive organometallic species set-
ting the stage for a subsequent cross-coupling reaction in
a consecutive one-pot fashion. Therefore, we set out to in-
troduce zinc bromide as a second electrophile for generat-
ing unsymmetrical organozinc halides, suitable
nucleophiles for envisioned Negishi coupling.4 Here we
communicate a facile one-pot, three-component bromine–
lithium exchange–sequential electrophilic trapping–
The straightforward one-pot synthesis of 5,5¢¢-bis(trime-
thylsilyl)-2,2¢,5¢2¢¢-terthiophene (4a) by this methodology
nicely illustrates the rapid access to a building block in the
synthesis of oligothiophenes and corresponding oligo-
mers which have turned out to be promising materials for
SYNLETT 2010, No. 3, pp 0415–0418
Advanced online publication: 15.01.2010
DOI: 10.1055/s-0029-1219203; Art ID: G39809ST
© Georg Thieme Verlag Stuttgart · New York
1
2.
0
2.
2
0
1
0

416
C. Muschelknautz et al.
LETTER
n-BuLi (TMEDA) (2 equiv)
THF, –78 °C, 30 min
TMS
(hetero)arene
Br
S
Br
S
then: TMSCl, –78 °C, 3 h
then: ZnBr2, –78 °C to r.t., 35 min
then: iodo(hetero)arene 2,
Pd(PPh3)4 (5 mol%), r.t., 16 h
3
1
54–78%, 8 examples
Scheme 2 One-pot three-component bromine–lithium exchange–sequential electrophilic trapping–Negishi coupling sequence starting from
2,5-dibromothiophene (1)
Table 1 One-Pot, Three-Component Synthesis of Unsymmetrically Substituted Thiophenes 3 from 2,5-Dibromothiophene (1)
Entry
Iodo(hetero)arene 2
Product
Yield (%)a
1
4-iodotoluene (2a)
3a 64
TMS
S
S
Me
Me
TMS
2
1-iodo-3,5-di-methylbenzene (2b)
3b 54
Me
3
4
5
4-iodoanisole (2c)
3c 78
3d 57
3e 56
TMS
TMS
TMS
S
S
S
OMe
Cl
1-chloro-4-iodobenzene (2d)
1-fluoro-4-iodobenzene (2e)
F
6
7
8
methyl 4-iodobenzoate (2f)
4-iodobenzonitrile (2g)
3-iodopyridine (2h)
3f 59
3g 52
3h 67
TMS
TMS
TMS
S
S
S
CO2Me
CN
N
a Yields of isolated products after chromatography.
electronic devices.8 According to the literature, the con- underlines its superior efficacy. Furthermore, the trimeth-
ventional synthesis of 4a is achieved via a three-step pro- ylsilyl groups can be easily transformed into bromo10 or
cess with an overall yield of 37%.9 Using our novel one- iodo substituents,11 respectively, for further reactions.
pot methodology the identical terthiophene is accessed in Therefore, the initially introduced TMS substituent oper-
67% yield. Besides more than 100% increase in yield of ates as protecting group and dormant functionality for
the isolated product, the conciseness of the one-pot meth- subsequent chemo- and regioselective transformations.
odology and only one terminal workup procedure clearly
Since 2,5-dilithiothiophene can be alternatively accessed
by double deprotonation of thiophene with n-butyllithium
and TMEDA, we also scouted the direct comparison of se-
n-BuLi (TMEDA) (2 equiv)
THF, –78 °C
1
TMS
TMS
(hetero)arene
quences based upon the different generation of the key in-
termediate 2,5-dilithiothiophene as shown for the
synthesis of thiophene 3b (Scheme 4).12 Although, the
yield of 3b for the sequence based upon dilithiation of
thiophene 5 is lower than for the sequence based upon di-
rect generation of 2,5-dilithiothiophene from 2,5-dibro-
mothiophene (1, Table 1, entry 2), the ease of the five-
S
S
then: TMSCl, –78 °C
then: ZnBr2, –78 °C
then: diiodo(hetero)arene,
4a (hetero)arene = 2,5-thienylene, 67%
4b (hetero)arene = 1,4-phenylene, 60%
Pd(PPh3)4 (5 mol%),
r.t., 16 h
Scheme 3 One-pot, three-component synthesis of (hetero)arene-
bridged dithiophenes 4 by sequential electrophilic trapping and termi-
nating Negishi cross-coupling
Synlett 2010, No. 3, 415–418 © Thieme Stuttgart · New York

LETTER
Sequential Dual Electrophilic Trapping–Negishi Coupling with Dilithiothiophenes
417
Sapountzis, I.; Vu, V. A. Angew. Chem. Int. Ed. 2003, 42,
4302. (d) El Sheikh, S.; Schmalz, H.-G. Curr. Opin. Drug
Discovery Dev. 2004, 7, 882. (e) Leroux, F.; Schlosser, M.;
Zohar, E.; Marek, I. In Chemistry of Organolithium
Compounds, Vol. 1; Rappoport, Z.; Marek, I., Eds.; Wiley-
VCH: Weinheim, 2004, 435–493.
n-BuLi (TMEDA) (2 equiv)
n-hexane, reflux
Me
TMS
S
S
5
then: adding THF
then: TMSCl, –78 °C
then: ZnBr2, –78 °C,
to r.t., 35 min
then: 2b, Pd(PPh3)4 (5 mol%),
r.t., 16 h
Me
3b (39%)
(2) See, for example: (a) Liu, Y.; Gribble, G. W. Tetrahedron
Lett. 2002, 43, 7135. (b) Wang, X.; Rabbat, P.; O’Shea, P.;
Tillyer, R.; Grabowski, E. J. J.; Reider, P. J. Tetrahedron
Lett. 2000, 41, 4335. (c) Hegedus, L. S.; Odle, R. R.;
Winton, P. M.; Weider, P. R. J. Org. Chem. 1982, 47, 2607.
(d) Parham, W. E.; Piccirilli, R. M. J. Org. Chem. 1977, 42,
257.
Scheme 4 One-pot, three-component lithiation–sequential electro-
philic trapping–Negishi coupling sequence starting from thiophene
(5)
bond transformation in a consecutive one-pot process is
still appealing and a facile alternative.
(3) Muschelknautz, C.; Sailer, M.; Müller, T. J. J. Synlett 2008,
6, 845.
Finally, we also scouted the in situ generation of bor-
onates and their sequential transformation in the sense of
a trapping BLEBS (bromine–lithium exchange–boryla-
tion–Suzuki) sequence13 giving rise to the formation of
thiophene derivative 3c in good yields (Scheme 5).
Hence, both the Negishi and the Suzuki as terminating
cross-coupling permit concise, versatile one-pot, three-
component accesses to unsymmetrically substituted
thiophenes.
(4) For recent reviews, see: (a) Knochel, P.; Calaza, M. I.;
Hupe, E.; Negishi, E.-I.; Liu, F. In Metal-Catalyzed Cross-
Coupling Reactions; de Meijere, A.; Diederich, F., Eds.;
Wiley-VCH: Weinheim, 2004, 619–670. (b) Negishi, E.-I.;
Zeng, X.; Tan, Z.; Qian, M.; Hu, Q.; Huang, Z. In Metal-
Catalyzed Cross-Coupling Reactions; de Meijere, A.;
Diederich, F., Eds.; Wiley-VCH: Weinheim, 2004, 815–
889.
(5) Cai, D.; Hughes, D. L.; Verhoeven, T. R. Tetrahedron Lett.
1996, 37, 2537.
(6) Representive Procedure: Synthesis of 3b (Table 1, Entry
2)
n-BuLi (TMEDA) (2 equiv)
THF, –78 °C, 30 min
In a flame-dried Schlenk flask under argon atmosphere n-
BuLi (1.6 M in n-hexane, 2.5 mL, 4.0 mmol) and TMEDA
(0.6 mL, 4.0 mmol) were dissolved in anhyd THF (80 mL)
at –78 °C. 2,5-Dibromothiophene (1, 484 mg, 2.0 mmol)
was added slowly to the solution, and the mixture was stirred
for 30 min. Then, TMSCl (217 mg, 2.0 mmol) in anhyd THF
(20 mL) was added dropwise to the stirred solution over a
period of 3 h. The reaction mixture was stirred for another 30
min, and ZnBr2 (496 mg, 2.2 mmol) in anhyd THF (10 mL)
was added. After stirring for 15 min the reaction mixture was
allowed to warm to r.t. and stirred for another 20 min. 1-
Iodo-3,5-dimethylbenzene (510 mg, 2.2 mmol) in anhyd
THF (5 mL) and Pd(PPh3)4 (5 mol%) were added. The
solution was stirred at r.t. for 16 h. The solvent was removed
under reduced pressure and the residue purified by flash
chromatography on silica gel (n-hexane) yielding 280 mg
(54%) of 3b as a colorless oil. 1H NMR (500 MHz, CDCl3):
d = 0.32 (s, 9 H), 2.33 (s, 6 H), 6.90 (s, 1 H), 7.18 (d, 3J = 3.3
Hz, 1 H), 7.23 (s, 2 H), 7.31 (d, 3J = 3.3 Hz, 1 H). 13C NMR
(125 MHz, CDCl3): d = 0.1 (CH3), 21.5 (CH3), 124.2 (CH),
129.4 (CH), 134.5 (Cq), 135.1 (Cq), 138.5 (CH), 139.8 (Cq),
150.2 (Cq). MS (EI, 70 eV): m/z (%) = 260 (44) [M]+, 245
(100) [C14H17SSi]+, 215 (5) [C12H11SSi]+, 123 (9), 115 (43).
IR (KBr): n = 544 (w), 561 (w), 608 (w), 623 (w), 652 (w),
692 (m), 756 (m), 802 (s), 842 (s), 947 (w), 990 (s), 1055
(m), 1182 (w), 1212 (m), 1250 (s), 1323 (w), 1377 (w), 1438
(m), 1526 (w), 1601 (m), 1760 (w), 2858 (m), 2925 (m),
2956 (m) cm–1. UV/Vis (CH2Cl2): lmax (e) = 294 (12700),
314 (21800) nm. Anal. Calcd for C15H20SSi (260.5): C,
69.17; H, 7.74. Found: C, 69.34; H, 7.60.
1
3c (63%)
then: TMSCl, –78 °C, 3 h
then: B(OMe)3, –78 °C to r.t., 35 min
then: 2c, Pd(PPh3)4 (5 mol%),
KOt-Bu, 60 °C, 16 h
Scheme 5 One-pot, three-component bromine–lithium exchange–
sequential electrophilic trapping–Suzuki coupling sequence
In summary, based upon the generation of 2,5-dilithio-
thiophenes and their consecutive trapping with two orga-
nometallic electrophiles, we have developed a one-pot
three-component sequence that terminates with a Negishi
coupling to give unsymmetrically substituted thiophenes
in good yields. In addition, this diversity-oriented meth-
odology paves the way to concise syntheses of oligo-
thiophene and the corresponding oligomer building-
blocks for electronic devices. Studies directed towards the
synthesis of electro-active molecular materials based
upon this one-pot methodology are currently under inves-
tigation.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
Acknowledgment
(7) Representive Procedure: Synthesis of Terthiophene 4a
In a flame-dried Schlenk flask under argon atmosphere n-
BuLi (1.6 M in n-hexane, 2.5 mL, 4.0 mmol) and TMEDA
(0.6 mL, 4.0 mmol) were dissolved in anhyd THF (80 mL)
at –78 °C. 2,5-Dibromothiophene (1, 484 mg, 2.0 mmol)
was added slowly to the solution, and the mixture was stirred
for 30 min. Then, TMSCl (217 mg, 2.0 mmol) in anhyd THF
(20 mL) was added dropwise to the stirred solution over a
period of 3 h. The reaction mixture was stirred for another 30
min, and ZnBr2 (496 mg, 2.2 mmol) in anhyd THF (10 mL)
The support of this work by the Deutsche Forschungsgemeinschaft
is gratefully acknowledged.
References and Notes
(1) For selected reviews on halogen–metal exchange, see, e.g.:
(a) Parham, W. E. C.; Bradsher, K. Acc. Chem. Res. 1982,
15, 300. (b) Bailey, W. F.; Patricia, J. J. J. Organomet.
Chem. 1988, 352, 1. (c) Knochel, P.; Dohle, W.;
Gommermann, N.; Kneisel, F.; Kopp, F.; Korn, T.;
Synlett 2010, No. 3, 415–418 © Thieme Stuttgart · New York

418
C. Muschelknautz et al.
LETTER
was added. After stirring for 15 min the reaction mixture was
allowed to warm to r.t. and stirred for another 20 min.
Finally, 2,5-diiodothiophene (269 mg, 0.8 mmol) and
Pd(PPh3)4 (5 mol%) were added. The solution was stirred at
r.t. for 16 h and afterwards the solvent removed under
reduced pressure and the residue purified by flash
chromatography on silica gel (n-hexane) yielding 200 mg
(67%) of 3a as a light yellow solid. 1H NMR (500 MHz,
CDCl3): d = 0.32 (s, 18 H), 7.06 (s, 2 H), 7.12 (d, 3J = 3.4 Hz,
2 H), 7.20 (d, 3J = 3.4 Hz, 2 H). 13C NMR (125 MHz,
CDCl3): d = 0.1 (CH3), 124.6 (CH), 125.1 (CH), 135.0 (CH),
136.5 (Cq), 140.2 (Cq), 142.4 (Cq). MS (EI, 70 eV): m/z (%)
= 393 (2.5) [M]+, 320 (47), 305 (46), 261 (47), 215 (49), 203
(12), 184 (12), 171 (36), 137 (17), 115 (100), 109 (10).
(11) See, for example: (a) Ebata, H.; Miyazaki, E.; Yamamoto,
T.; Takimiya, K. Org. Lett. 2007, 9, 4499. (b) Bossi, A.;
Maiorana, S.; Graiff, C.; Tiripicchio, A.; Licandro, E. Eur. J.
Org. Chem. 2007, 4499.
(12) Synthesis of 3b Starting from Thiophene
In a flame-dried, three-neck flask under argon atmosphere
n-BuLi (1.6 M in n-hexane, 6 mL, 8.8 mmol), TMEDA (1.2
mL, 8.0 mmol), and thiophene (340 mg, 4.0 mmol) were
dissolved in n-hexane (20 mL). The reaction mixture was
heated to reflux for 1.5 h. After complete deprotonation, the
mixture was allowed to cool to r.t. and was then cooled to
–78 °C. THF (130 mL) was given to the content of the flask.
Then TMSCl (430 mg, 4.0 mmol) in anhyd THF (20 mL)
was added dropwise to the stirred solution over a period of 3
h. The reaction mixture was stirred for another 30 min, and
ZnBr2 (496 mg, 2.2 mmol) in anhyd THF (10 mL) was
added. After stirring for 15 min the reaction mixture was
allowed to warm to r.t. and stirred for another 20 min.
Finally, 1-iodo-3,5-dimethylbenzene (1029 mg, 4.4 mmol)
in anhyd THF (10 mL) and Pd(PPh3)4 (5 mol%) were added.
The solution was stirred at r.t. for 16 h and afterwards the
solvent removed under reduced pressure and the residue
purified by flash chromatography on silica gel (n-hexane)
yielding 406 mg (39%) of 3b as a colorless oil.
(8) (a) Handbook of Oligo- and Polythiophenes; Fichou, D.,
Ed.; Wiley-VCH: Weinheim, 1998. (b) Bäuerle, P. In
Electronic Materials: The Oligomer Approach; Müllen, K.;
Wegner, G., Eds.; Wiley-VCH: Weinheim, 1998, 105–197.
(c) Handbook of Conducting Polymers, 2nd ed.; Skotheim,
T. A.; Elsenbaumer, R. L.; Reynolds, J. R., Eds.; Marcel
Dekker: New York, 1998. (d) Mishra, A.; Ma, C.-Q.;
Bäuerle, P. Chem. Rev. 2009, 109, 1141. (e) Roncali, J.
Chem. Rev. 1997, 97, 173.
(9) Tour, J. M.; Wu, R. Macromolecules 1992, 25, 1901.
(10) See, for example: (a) Hou, J.; Chen, H.-Y.; Zhang, S.; Li, G.;
Yang, Y. J. Am. Chem. Soc. 2008, 130, 16144. (b) Li, C.;
Shi, J.; Xu, L.; Wang, Y.; Cheng, Y.; Wang, H. J. Org.
Chem. 2009, 74, 408.
(13) Franz, A. W.; Müller, T. J. J. Synthesis 2008, 1121.
Synlett 2010, No. 3, 415–418 © Thieme Stuttgart · New York

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