Pd- and Cu-catalyzed one-pot multicomponent synthesis of hetero α,α′-dimers of heterocycles

Article abstract of DOI:10.1021/ol300718x

A novel palladium- and copper-catalyzed one-pot multicomponent synthesis of hetero α,α′-dimers of heterocycles via Sonogashira coupling and double cyclization cascade involving imine formation has been developed. This reaction cascade proceeded under mild conditions, providing a powerful synthetic tool for the assembly of π-conjugated systems with a combination of palladium-catalyzed post-direct C-H bond arylations.

Full text of DOI:10.1021/ol300718x

ORGANIC
LETTERS
2012
Vol. 14, No. 9
2296–2299
Pd- and Cu-Catalyzed One-Pot
Multicomponent Synthesis of Hetero
r,r0-Dimers of Heterocycles
Takahiko Murata, Masahito Murai, Yuji Ikeda, Koji Miki, and Kouichi Ohe*
Department of Energy and Hydrocarbon Chemistry, Graduate School of Engineering,
Kyoto University, Katsura, Nishikyo-ku, Kyoto 615-8510, Japan
ohe@scl.kyoto-u.ac.jp
Received March 21, 2012
ABSTRACT
A novel palladium- and copper-catalyzed one-pot multicomponent synthesis of hetero R,R0-dimers of heterocycles via Sonogashira coupling and
double cyclization cascade involving imine formation has been developed. This reaction cascade proceeded under mild conditions, providing a
powerful synthetic tool for the assembly of π-conjugated systems with a combination of palladium-catalyzed post-direct CꢀH bond arylations.
The efficient synthesis of novel functional organic mole-
cules has become an important challenge at the cutting edge
between organic chemistry and materials sciences.1 In parti-
cular, the design of the multicatalytic cascade processes, in
which two or more distinct chemical transformations are
promoted sequentially by one or more catalysts, is highly
desirable because they achieve high molecular complexity,
forming several bonds from readily accessible starting
materials, and they make isolation of intermediates
unnecessary.2 Molecules containing conjugated heterocycles
based on pyrroles, furans, and thiophenes are attractive
targets for these transformations because they are promising
materials for organic field-effect transistors (OFETs), or-
ganic light-emitting diodes (OLEDs), dye-sensitized organic
solar cells (DSSCs), and many other potential applications.3
While conjugated heterocycles based on R,R0-linked oligo-
heterocycles are promising in the area of organic electronics,4
much attention has recently been paid to mixed-heterocyclic
oligomers with pyrroles, furans, and thiophenes.5 Precisely
controlled chemical structures exhibit improved light ab-
sorption, electronic compatibility with fullerene acceptors
such as PCBM, charge transport characteristics, thin-film
morphology, and molecular packing.6 In order to acquire a
better understanding of the structureꢀproperty relation-
ships that govern material performance, the development
of facile and flexible access to new tailor-made functional
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Germany, 2009. (b) Mishra, A.; Ma, C.-Q.; Ba€uerle, P. Chem. Rev. 2009,
109, 1141. For R-oligofurans, see: (c) Gidron, O.; Diskin-Posner, Y.;
Bendikov, M. J. Am. Chem. Soc. 2010, 132, 2148. (d) Bunz, U. H. F.
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r
10.1021/ol300718x
Published on Web 04/25/2012
2012 American Chemical Society

mixed-heterocyclic oligomers has the potential to give ready
access to a wide variety of novel materials. Despite the
significant interest, however, these approaches have been
limited to stepwise cross-coupling reactions of stannyl or
boryl heterocycles with heteroaryl halides or conventional
PaalꢀKnorr-type dehydrative cyclization of the 1,4-diheter-
oaroylethane derivatives.5 Although these methods are
highly useful, there are some drawbacks such as low stability
of some heteroaryl halides and poor tolerance of functional
groups under acidic conditions. Herein we report a new
approach toward hetero dimers of heterocycles through
palladium- and copper-catalyzed Sonogashira coupling
and double-cyclization cascade involving imine formation.7
Recently, we have reported a preliminary study of a
ruthenium-catalyzed cycloisomerization of 1,2-di(carbonyl-
ene)yne compounds 1 leading to 2,20-bifurans (Scheme 1).8,9
The reaction mechanism involves the generation of (2-furyl)-
carbene complexes A via the nucleophilic attack of carbonyl
oxygen atoms to alkyne moieties, in which carbene complex
A undergoes nucleophilic attack of the neighboring carbonyl
oxygen atom to furnish 2,20-bifurans (double cyclization).
These successful results prompted us to investigate the
transition-metal-catalyzed cycloisomerization of nitrogen
and sulfur analogues 2, prepared by Sonogashira coupling
of two coupling partners, which leads to 2-(20-furyl)pyrrole
and 2-(50-thienyl)furan (Scheme 2).
Scheme 2. Transition-Metal-Catalyzed Synthesis of Hetero
Dimers of Heterocycles
To synthesize the precursor 2, we first examined the
Sonogashira coupling of formyl-ene-yne compound 3
with 2-bromocyclohexenal 4 in the presence of Pd(PPh3)4
(3 mol %), CuI (9 mol %), and various amines. When tert-
butylamine was used as a base, we unexpectedly observed
the formation of 2-(20-furyl)pyrrole 6 and 2,20-bipyrrole 7,
each in 23% yield, together with the expected 1,2-di-
(formyl-ene)yne compound 5 in 40% yield, respectively
(Scheme 3). This result indicates that the Sonogashira
coupling, imine formation, and double cyclization succes-
sively took place under the present reaction conditions.
Scheme 1. Ru-Catalyzed Double Cyclization of 1
(5) For recent examples, see: (a) Fujii, M.; Nishinaga, T.; Iyoda, M.
Tetrahedron Lett. 2009, 50, 555. (b) Woo, C. H.; Beaujuge, P. M.;
ꢀ
Holcombe, T. W.; Lee, O. P.; Frechet, J. M. J. J. Am. Chem. Soc.
2010, 132, 15547. (c) Nishinaga, T.; Tateno, M.; Fujii, M.; Fujita, W.;
Takase, M.; Iyoda, M. Org. Lett. 2010, 12, 5374. (d) Oliva, M. M.;
Pappenfus, T. M.; Melby, J. H.; Schwaderer, K. M.; Johnson, J. C.;
Scheme 3. Pd- and Cu-Catalyzed Reaction of 3 with 4
ꢀ
McGee, K. A.; da Silva Filho, D. A.; Bredas, J.-L.; Casado, J.;
Navarrete, J. T. L. Chem.;Eur. J. 2010, 16, 6866. (e) Bijleveld, J. C.;
Karsten, B. P.; Simon, G. J. M.; Wienk, M. M.; de Leeuw, D. M.;
Janssen, R. A. J. J. Mater. Chem. 2011, 21, 1600. (f) Li, Y.; Sonar, P.;
Singh, S. P.; Zeng, W.; Soh, M. S. J. Mater. Chem. 2011, 21, 10829. (g)
Nishinaga, T.; Miyata, T.; Tateno, M.; Koizumi, M.; Takase, M.; Iyoda,
M.; Kobayashi, N.; Kunugi, Y. J. Mater. Chem. 2011, 21, 14959.
(6) For recent examples, see: (a) Beaujuge, P. M.; Pisula, W.; Tsao,
€
H. N.; Ellinger, S.; Mullen, K.; Reynolds, J. R. J. Am. Chem. Soc. 2009,
131, 7514. (b) Peet, J.; Heeger, A. J.; Bazan, G. C. Acc. Chem. Res. 2009,
42, 1700. (c) Piliego, C.; Holcombe, T. W.; Douglas, J. D.; Woo, C. H.;
ꢀ
Beaujuge, P. M.; Frechet, J. M. J. J. Am. Chem. Soc. 2010, 132, 7595. (d)
€
ꢀ
To our delight, 2-(20-furyl)pyrrole 9a was obtained
selectively in70% yield withoutforming the corresponding
2,20-bipyrrole when keto-ene-yne compound 8a was used
instead of formyl-ene-yne compound 3 (Scheme 4).
Furthermore, studies revealedthat the yield of 9aincreased
up to 92% when the combination of Pd2(dba)3, PPh3, and
CuI was employed as catalysts.
These interesting results stimulated us to investigate the
generality of the present three-component coupling reac-
tions. The results are summarized in Table 1. Not only
keto-ene-yne compounds 8b and 8c, which possess elec-
tron-donating substituents such as N,N-diphenylamino
and methoxy groups, but also 8d and 8e having electron-
withdrawing substituents such as trifluoromethyl and
cyano groups at the para position of the benzene ring
Johns, J. E.; Muller, E. A.; Frechet, J. M. J.; Harris, C. B. J. Am. Chem.
Soc. 2010, 132, 15720. (e) Zhou, H.; Yang, L.; Price, S. C.; Knight, K. J.;
You, W. Angew. Chem., Int. Ed. 2010, 49, 7992. (f) Varotto, A.; Treat,
N. D.; Jo, J.; Shuttle, C. G.; Batara, N. A.; Brunetti, F. G.; Seo, J. H.;
Chabinyc, M. L.; Hawker, C. J.; Heeger, A. J.; Wudl, F. Angew. Chem.,
Int. Ed. 2011, 50, 5166.
(7) The present method is defined as a time- and space-integrated
process, because it can construct molecular diversity and structural
complexity by successive reactions in a one-shot reaction without
separation and purification of intermediates. The time and space inte-
gration in synthetic organic reactions refers to (a) Suga, S.; Yamada, D.;
Yoshida, J. Chem. Lett. 2010, 39, 404. (b) Yoshida, J.; Saito, K.;
Nokami, T.; Nagaki, A. Synlett 2011, 9, 1189.
(8) (a) Abo, T.; Ohe, K. J. Phys.: Conf. Ser. 2008, 106, 012004.
(b) Ohe, K.; Miki, K. J. Synth. Org. Chem., Jpn. 2009, 67, 1161.
(9) The similar double cyclization of 1,2-di(carbonyl-ene)ynes lead-
ing to bifurans proceeded under the photoirradiated conditions. See: (a)
Nakatani, K.; Adachi, K.; Tanabe, K.; Saito, I. J. Am. Chem. Soc. 1999,
121, 8221. (b) Zhang, H.; Wakamiya, A.; Yamaguchi, S. Org. Lett. 2008,
10, 3591. In the present study, all Sonogashira coupling reactions were
carried out in the dark.
Org. Lett., Vol. 14, No. 9, 2012
2297

Scheme 4. One-Pot Three-Component Synthesis of 9a
Scheme 5. Pd- and Cu-Catalyzed Reaction of 8a with 10
produced the corresponding 2-(20-furyl)pyrroles 9bꢀe
in good to high yields, respectively (entries 1ꢀ4). It is
worth mentioning that the reaction of 8f afforded pyrrole-,
furan-, and thiophene-conjugated heterocycle 9f in 68%
yield (entry 5). Furthermore, benzylamine and allylamine
instead of tert-butylamine were applicable to the present
three-component coupling reaction to afford 1-benzyl-
2-(20-furyl)pyrrole 9g and 1-allyl-2-(20-furyl)pyrrole 9h10
in 71% and 54% yields, respectively (entries 6 and 7).
To shed light on the reaction mechanism, the reaction of
8a with imine 10 as a coupling partner was carried out
under identical reaction conditions. However, neither
2-(20-furyl)pyrrole 9a nor 1-(imino-ene)-2-(keto-ene)yne
compound 11 was observed, 2-bromocyclohexenal 4 that
was formed via the hydration of 10 being obtained in 95%
yield (Scheme 5). This result clearly indicates that Sonoga-
shira coupling of 8 with 4 proceeds faster than the con-
densation with amines, and resulting 11 undergoes double
cyclization to afford the 2-(20-furyl)pyrrole 9.
Figure 1. Plausible reaction mechanism leading to 9.
We next examined the reaction of 1-formyl-6-benzoyl-
1,5-dien-3-yne 12, which was prepared by Sonogashira
coupling of 8a and 4, with tert-butylamine at room
temperature in C6D6, and the time course of the reaction
1
was monitored by H NMR spectroscopy. The reaction
without palladium and copper catalysts reached equilibrium
between 9a and 12, and 53% of 12 was still observed even
after 24 h (Figure S1a in Supporting Information). In con-
trast, with 9 mol % of CuI was added, the reaction proceeded
rapidly, and 9a was obtained in 96% yield in 24 h (Figure
S1b). These observation indicate that CuI, which is known to
possess both oxophilic and carbophilic characters,11 seems to
effectively activate both the carbonyl group and the CꢀC
triple bond to promote the condensation between tert-buty-
lamine and the formyl group of 12 to form imine 11 and the
following double cyclization leading to 9a (Figure 1).12
When thiocarbamoyl-ene-yne compound 1313 was used
instead of 8 in the presence of Pd2(dba)3, PPh3, and CuI as
catalysts and triethylamine asa base, 2-(50-thienyl)furan 15
was obtained in 90% yield (Scheme 6, X = O). The re-
action may proceed via the formation of 1-formyl-6-thiocar-
bamoyldienyne 14 (X = O) followed by double cyclization.
Table 1. Synthesis of 2-(20-Furyl)pyrroles via Three-Component
Coupling Reactionsa
entry
Ar
R
product
yield of 9 (%)b
1
2
3
4
5
6
7
4-MeOC6H4
4-Ph2NC6H4
4-CF3C6H4
4-CNC6H5
2-thienyl
Ph
8b
8c
8d
8e
8f
tBu
tBu
tBu
tBu
tBu
Bn
9b
9c
9d
9e
9f
53
87
71
86
68
71
54
8a
8a
9g
9h
(11) Shirtcliff, L. D.; McClintock, S. P.; Haley, M. M. Chem. Soc.
Rev. 2008, 37, 343.
Ph
allyl
(12) For the reaction of 12 with tert-butylamine in the presence of
CuI, see Supporting Information. We suppose that double cyclization
might proceed via copper-carbenoide, as depicted in Scheme 1, although
the alternate pathway via direct Michael addition of an amine to a CꢀC
triple bond cannot be ruled out.
a Reaction conditions: 8 (0.30 mmol), 4 (0.30 mmol), amine
(1.5 mmol), Pd2(dba)3 (0.0090 mmol), PPh3 (0.054 mmol), and Cul
(0.027 mmol) in toluene (1 mL). b Isolated yields based on 4.
(13) For rhodium-catalyzed carbene transfer reaction using 13 via a
(2-thienyl)carbene complex, see: Tsuneishi, A.; Okamoto, K.; Ikeda, Y.;
Murai, M.; Miki, K.; Ohe, K. Synlett 2011, 9, 455.
(10) An allyl group of pyrrole 9h could be deprotected by the
treatment with DIBAL in the presence of NiCl2(dppp).
2298
Org. Lett., Vol. 14, No. 9, 2012

Scheme 6. Synthesis of 2-(50-Thienyl)furan and 2-(50-Thienyl)-
pyrrole via Tandem Coupling Reactions
Scheme 7. Pd-Catalyzed Direct CꢀH Bond Arylations of
Hetero Dimers of Heterocycles
Interestingly, when benzylamine was used in place of triethy-
lamine under the same reaction conditions, 2-(50-thienyl)-
pyrrole 16 was obtained selectively in 84% yield without
forming 15 (Scheme 6, X = NBn). These results prove that
the present one-pot Sonogashira coupling, imine formation,
and double cyclization cascades are suitable for flexible access
to tailor-made functional hetero dimers of heterocycles.
Combined further with the cross-coupling reaction, the
present one-pot multicomponent synthesis for hetero di-
mers of heterocycles would allow rapid access to various
π-conjugated heterocyclic oligomers. Over the past decades,
extensive efforts have been directed toward the transition-
metal-catalyzed direct CꢀH bond arylations of
aromatics.14 In comparison to furans and thiophenes,
however, intermolecular direct CꢀH bond arylations of
pyrroles have been limited.15 The reported examples need
to employ aryl iodides15g and electronically activated
pyrroles15b,d or commercially unavailable hypervalent-
iodine reagents15a as coupling partners. Taking these
facts into consideration, first we examined palladium-
catalyzed direct CꢀH bond arylations of 1-benzyl-2-(20-
furyl)pyrrole 9g with bromobenzene. To our delight, the
expected coupling product 17 was obtained in 73% yield,
using the catalyst composed of Pd(OAc)2, PCy3, K2CO3,
and pivalic acid in DMF15c (Scheme 7). Under the identical
conditions, 2-(50-thienyl)pyrrole 16 reacted with 4-bromo-
benzonitrile to give the corresponding donorꢀacceptor
conjugate 18 in 69% yield. It is noteworthy that the
coupling reaction with 2,5-dibromothiophene also took
place to afford the pyrrole-, furan-, and thiophene-con-
jugated oligomer 19 in 53% yield.
In conclusion, we have developed a one-pot synthesis of
hetero dimers of heterocycles via Sonogashira coupling
and double cyclization cascade involving imination. The
reaction proceeds under mild conditions forming several
CꢀC and CꢀN bonds to afford a variety of 2-(20-furyl)-
pyrroles, 2-(50-thienyl)furans, and 2-(50-thienyl)pyrroles in
good to excellent yields by simple alternation of the
combination of reagents employed. Moreover, combined
with a palladium-catalyzed post-direct CꢀH bond aryla-
tion, the present method provides a simple and powerful
synthetic tool that permits the assembly of a π-conjugated
system in a programmed and diversity-oriented format.
The present strategy should find many uses for combina-
torial lead structure identification and optimization in the
development of functional organic materials where the
structureꢀpropertyrelationships areoftennot predictable.
Further investigations of the reaction scope as well as
measurement of optical properties of the obtained mixed-
heterocyclic oligomers are currently in progress in our
laboratory.
(14) For recent reviews, see: (a) Ackermann, L.; Vicente, R.; Kapdi,
A. Angew. Chem., Int. Ed. 2009, 48, 9792. (b) Fagnou, K. Top. Curr.
Chem. 2010, 292, 35. (c) Colby, D. A.; Bergman, R. G.; Ellman, J. A.
Chem. Rev. 2010, 110, 624. (d) Yeung, C. S.; Dong, V. M. Chem. Rev.
2011, 111, 1215.
Acknowledgment. This work was financially supported
by a Grant-in-Aid for Scientific Research on Innovative
Areas (no. 2105) (Grant no. 22106518) from the MEXT
and (B) (Grant no. 22350087) from the JSPS.
(15) For palladium- or rhodium-catalyzed intermolecular direct
CꢀH bond arylations of N-alkylpyrroles, see: (a) Deprez, N. R.;
Kalyani, D.; Krause, A.; Sanford, M. S. J. Am. Chem. Soc. 2006, 128,
Supporting Information Available. General procedures
and characterization of new compounds. This material is
available free of charge via the Internet at http://pubs.acs.
org.
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Liegault, B.; Lapointe, D.; Caron, L.; Vlassova, A.; Fagnou, K. J. Org.
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Rostaing, S.; Lemaire, M. J. Org. Chem. 2009, 74, 3160. (e) Gryko, D. T.;
Vakuliuk, O.; Gryko, D.; Koszarna, B. J. Org. Chem. 2009, 74, 9517. (f)
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The authors declare no competing financial interest.
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