Direct synthesis of bipyrroles using phenyliodine bis(trifluoroacetate) with bromotrimethylsilane

Article abstract of DOI:10.1021/ol060333m

The hypervalent iodine(III) reagent, phenyliodine bis(trifluoroacetate) (PIFA), mediates the unprecedented, oxidative coupling reaction of pyrroles to give α-linked bipyrroles selectively in the presence of bromotrimethylsilane. This straightforward synthesis could provide 2,3′-bipyrrole by the choice of a N-substituent of pyrrole. Mechanistic consideration of the present reaction is also described.

Full text of DOI:10.1021/ol060333m

ORGANIC
LETTERS
2006
Vol. 8, No. 10
2007-2010
Direct Synthesis of Bipyrroles Using
Phenyliodine Bis(trifluoroacetate) with
Bromotrimethylsilane
Toshifumi Dohi, Koji Morimoto, Akinobu Maruyama, and Yasuyuki Kita*
Graduate School of Pharmaceutical Sciences, Osaka UniVersity, 1-6 Yamada-oka,
Suita, Osaka, 565-0871 Japan
kita@phs.osaka-u.ac.jp
Received February 8, 2006
ABSTRACT
The hypervalent iodine(III) reagent, phenyliodine bis(trifluoroacetate) (PIFA), mediates the unprecedented, oxidative coupling reaction of pyrroles
to give -linked bipyrroles selectively in the presence of bromotrimethylsilane. This straightforward synthesis could provide 2,3 -bipyrrole by
the choice of a N-substituent of pyrrole. Mechanistic consideration of the present reaction is also described.
r
′
Bipyrrole structures occur in natural products, pigments, and
porphyrin mimics and are known as common components
in molecular recognition and self-assembly systems.1 Re-
cently, some electron-rich bipyrroles have been applied as a
precursor of oligo- or polypyrroles,2 which are valuable
compounds in the field of material sciences due to their
beneficial physical properties such as high conductivity.3
Under these circumstances, bipyrroles are increasing in
importance in a wide range of modern science research
studies. However, their practical synthetic methods are quite
limited, especially for bipyrroles not having electron-
withdrawing groups.4-6 A classical stepwise approach starting
from pyrrolinones and pyrroles is a promising way to
synthesize the electron-rich 2,2′-bipyrroles, in which forma-
tion of dihydrobipyrroles 1 followed by the dehydrogenation
of 1 produced the 2,2′-bipyrroles (Scheme 1).7 In contrast,
little attention has been paid to the oxidative coupling
reaction of pyrroles for the preparation of bipyrroles, though
the direct oxidative coupling reaction of pyrroles using
palladium(II) salts has been reported.8
However, even in this case, substoichiometric amounts of
palladium(II) salts are required to obtain the 2,2′-bipyrroles
in good yields, and sometimes an undesired mixture of
byproducts were produced. Consequently, indirect ap-
(4) The oxidative couplings: (a) Ceacareanu, D. M.; Gerstenberger, M.
R. C.; Haas, A. J. Heterocycl. Chem. 1985, 22, 281. (b) Oda, K.; Sakai,
M.; Ohno, K.; Machida, M. Heterocycles 1999, 40, 277. (c)Wasserman, H.
H.; Petersen, A. K.; Xia, M.; Wang, J. Tetrahedron Lett. 1999, 40, 7567.
(5) Ullman-type couplings: (a) Vogel, E.; Balci, M.; Kakumanu, P.;
Kogh, P.; Lex, J.; Ermer, O. Angew. Chem. Int. Ed. 1987, 26, 928. (b)
Sessler, J. L.; Cyr, M. J.; Lynch, V.; McGhee, E.; Ibers, J. A. J. Am. Chem.
Soc. 1990, 112, 2810. (c) Shevchuk, S. V.; Davis, J. M.; Sessler, J. L.
Tetrahedron Lett. 2001, 42, 2447. (d) Skowronek, P.; Lightner, D. A.
Monatsh. Chem. 2003, 134, 889. For recent reports, see: (e) D’Alesssion,
R.; Rossi, A. Synlett 1996, 513. (f) Shevchuk, V. S.; Davis, J. M.; Sessler,
J. L. Tetrahedron Lett. 2001, 42, 2447. (g) Merz, A.; Anikin, S.; Lieser,
B.; Heinze, J.; John, H. Chem.-Eur. J. 2003, 9, 449. (h) Fu¨rstner, A.;
Radkowski, K.; Peters, H. Angew. Chem. Int. Ed. 2005, 44, 2777.
(6) Using donor-acceptor cyclopropanes: Yu, M.; Pantos, G. D.; Sessler,
J. L.; Pagenkopf, B. L. Org. Lett. 2004, 6, 1057.
(1) (a) Mervyn, H. Chem. ReV. 1996, 5, 19. (b) Korostova, S. E.;
Mikhaleva, A. I.; Trofimov, B. A. Russ. Chem. ReV. 1999, 68, 459. (c)
Sessler, J. L.; Camiolo, S.; Gale, P. A. Coord. Chem. ReV. 2003, 240, 17.
(d) Gale, P. A.; Anzenbacher, P., Jr.; Sessler, J. L. Coord. Chem. ReV. 2001,
222, 57. (e) Kleemann, A.; Engel, J.; Kutscher, B.; Reichert, D. Phar-
maceutical Substance: Synthesis, Patents, Applications, 4th ed.; Georg
Thieme: Stuttgart, 2001.
(2) Mu¨llen, K., Wegner, G., Eds. Electronic Materials: The Oligomer
Approach; Wiley-VCH: Verlag GmbH, 1998.
(3) (a) Kanazawa, K.; Diaz, A. F.; Geiss, R. H.; Gill, W. D.; Kwak, J.
F.; Logan, J. A.; Rabolt, J. F.; Street, G. B. J. Chem. Soc., Chem. Commun.
1979, 854. (b) Ogasawara, M.; Funahashi, K.; Demura, T.; Hagiwara, T.;
Iwata, K. Synth. Met. 1986, 14, 62. (c) Baughman, R. H. Science 2005,
308, 63.
(7) Rapoport, H.; Castagnoli, N., Jr. J. Am. Chem. Soc. 1962, 84, 2178.
(b) Bordner, J.; Rapoport, H. J. Org. Chem. 1965, 30, 3824. (c) Brown,
D.; Griffiths, D.; Rider, M. E.; Smith, R. C. J. Chem. Soc., Perkin Trans.
1 1986, 455.
10.1021/ol060333m CCC: $33.50
© 2006 American Chemical Society
Published on Web 04/13/2006

the corresponding biaryl products. Recently, we discovered
that the Lewis acids play an important role not only in the
activation of the hypervalent iodine(III) reagents but also in
determining the course of the reaction.10c During our
investigation on the hypervalent iodine(III) chemistry, we
have found that bipyrroles could be formed in the reaction
of pyrroles depending on the Lewis acids used. Herein, we
report a novel straightforward synthetic method using PIFA
with bromotrimethylsilane (TMSBr), which provides the
facile and selective construction of 2,2′-bipyrroles and even
2,3′-bipyrrole.
Scheme 1
The influences of Lewis acids on the oxidative coupling
reaction of 3,4-diethylpyrrole 3a leading to 2,2′-bipyrrole
4a,5c are summarized in Table 1. BF3‚Et2O, the most common
proaches involving decarboxylation steps were required in
many cases.5,6 Therefore, development of new methods for
the synthesis of various types of bipyrroles remains an
important issue.
Hypervalent iodine(III) reagents, such as phenyliodine
diacetate (PIDA) and phenyliodine bis(trifluoroacetate) (PIFA),
hydroxy(tosyloxy)iodobenzene (HTIB), and iodosobenzene,
have been widely recognized as safe and useful oxidants
having reactivities similar to those of the highly toxic heavy
metal oxidizers.9 We have previously developed the PIFA-
induced mild and efficient direct oxidative coupling reaction
of phenyl ethers and alkylarenes in (CF3)2CHOH or using
BF3‚Et2O in CH2Cl2 (Scheme 2).10 The reaction would
Table 1. Survey of Oxidants for the Oxidative Coupling
Reaction of 3a
entrya
oxidant
additive
yield of 4a (%)b
1
2
3
4
5
6
7
8
9
PIFA
//
//
BF3‚OEt2
TMSOTf
TMSCl
TMSBr
n.d.
17
22
75 (69)c
31
trace
n.d.e
n.d.
n.d.
Scheme 2
//
(PhIO)n
DMPd
Tl(OCOCF3)3
CANf
//
//
//
//
//
DDQg
a Reaction conditions: 3 equiv of 3a, 1 equiv of oxidant, 2 equiv of
additive. b Isolated yields based on oxidant. c Isolated yields based on
consumed 3a. d DMP ) Dess-Martin periodinane. e n.d. ) not detected.
f CAN ) ceric ammonium nitrate. g DDQ ) 2,3-dichloro-5,6-dicyano-1,4-
benzoquinone
proceed via the cation radical intermediates A,11 and the
carbon-carbon bond formation could oxidatively occur by
the reaction of A with neutral molecules of substrates to give
Lewis acid for the oxidative coupling reaction of phenyl
ethers and alkylarenes, did not give a good result; although
almost all of 3a was consumed, insoluble oligomeric products
were mainly obtained in this case (entry 1). After an
extensive number of unfavorable results using the boron-
based Lewis acids, we found that 4a was produced when
using silicon-based Lewis acids (entries 2-5). Of all the
Lewis acids treated, TMSBr gave the best result, and thus
4a was obtained in 75% yield (69% yield based on consumed
3a) at -40 °C (entry 4). Using the pentavalent iodine reagent,
other heavy metal and organic oxidants (entries 6-9), and
Brønsted acids, such as CF3CO2H and HNO3, instead of
TMSBr, we did not obtain 4a, but oligomeric products were
formed.
(8) (a) Itahara, T. J. Chem. Soc., Chem. Commun. 1980, 49. (b) Itahara,
T. J. Org. Chem. 1985, 50, 5272. (c) Boger, D. L.; Patel, M. Tetrahedron
Lett. 1987, 28, 2499. Oxidative homocoupling of 2-substituted thiophenes:
(d) Masui, K.; Ikegami, H.; Mori, A. J. Am. Chem. Soc. 2004, 126, 5074.
(9) For recent reviews, see: (a) Stang, P. J.; Zhdankin, V. V. Chem.
ReV. 1996, 96, 1123. (b) Kita, Y.; Takada, T.; Tohma, H. Pure. Appl. Chem.
1996, 68, 627. (c) Varvoglis, A. HyperValent Iodine in Organic Synthesis;
Academic Press: San Diego, 1997. (d) Kirschning, A. Eur. J. Org. Chem.
1998, 2267. (e) Ochiai, M. In Chemistry in HyperValent Compounds; Akiba,
K., Ed.; Wiley-VCH: New York, 1999; Chapter 12. (f) Zhdankin, V. V.;
Stang, P. J. Chem. ReV. 2002, 102, 2523. (g) HyperValent Iodine Chemistry;
Wirth, T., Ed.; Springer-Verlag: Berlin, Heidelberg, 2003. (h) Moriarty,
R. M. J. Org. Chem. 2005, 70, 2893. (i) Wirth, T. Angew. Chem. Int. Ed.
2005, 44, 3656.
(10) (a) Tohma, H.; Morioka, H.; Takizawa, S.; Arisawa, M.; Kita, Y.;
Tetrahedron 2001, 57, 345. (b) Tohma, H.; Iwata, M.; Maegawa, T.; Kita,
Y. Tetrahedron Lett. 2002, 43, 9241. (c) Dohi, T.; Morimoto, K.; Kiyono,
Y.; Maruyama, A.; Tohma, H.; Kita, Y. Chem. Commun. 2005, 2930 and
references therein.
(11) Kita, Y.; Tohma, H.; Hatanaka, K.; Takada, T.; Fujita, S.; Mitoh,
S.; Sakurai, H.; Oka, S. J. Am. Chem. Soc. 1994, 116, 3684.
The present reaction proceeded with a wide range of
electron-rich pyrroles having various substitutions (Table 2).12
It should be noted that N-nonprotected pyrroles were usable,
and the reaction was rapid enough to finish in 1 h. Although
there was concern of forming the regioisomers of bipyrroles
2008
Org. Lett., Vol. 8, No. 10, 2006

results were obtained with sterically hindered 3c and 4,5,6,7-
tetrahydro-2H-isoindole 3d (entries 3 and 4).
Table 2. PIFA-Induced Selective Synthesis of R-Linked
Bipyrroles 4 from 1-H Pyrroles 3
In the case of the 3-substituted pyrroles, useful head to
tail dimers 4′13 were obtained in preference to head to head
dimers 4′′ (entries 5-10).10c The regiochemistry of the
products was determined by measurement of their 1H NMR
or by comparing them to authentic samples.13c Some
functional groups (ester, ether, halogen, etc.) are tolerable
under the reaction conditions, but electron-deficient pyrroles,
such as 1-tosylpyrrole, did not react at all.
The reaction was applicable to the indole 5,14 though the
addition product 715 was formed (29% yield based on PIFA)
together with the desired bisindole 6 (74% yield based on
PIFA) (Figure 1).
Figure 1. Oxidative coupling reaction of 3-methylindole 5.
Next, we tried to apply the present reaction to the synthesis
of other types of bipyrroles because no facile methods have
appeared. We found that it was made possible by choosing
the phenyl group as the suitable N-substituent of pyrrole.
Thus, the 2,3′-bipyrrole 916 was obtained in 56% yield using
N-phenyl pyrrole 8 under the reaction conditions (Scheme
3).17
Scheme 3
a Reaction conditions: 3 equiv of 3, 1 equiv of PIFA, 2 equiv of TMSBr.
b Isolated yields based on PIFA. c Isolated yield based on consumed 3a.
A possible reaction mechanism of the present oxidative
coupling reaction of the pyrroles and indole is illustrated in
in the case of pyrrole 3b itself, 2,2′-bipyrrole 4b6a was
obtained in 78% yield in high selectivity (entry 2). Similar
(13) For utility of the head to tail dimers of heteroaromatic compounds,
see: (a) Roncali, J. Chem. ReV. 1992, 92, 711. (b) McCullough, R. D. AdV.
Mater. 1998, 10, 93. (c) Benincori, T.; Brenna, E.; Sannicolo`, F.; Zotti, G.;
Zecchin, S.; Schiavon, G.; Gatti, C.; Frigerio, G. Chem. Mater. 2000, 12,
1480. (d) Gatti, C.; Frigerio, G.; Benincori, T.; Brenna, E.; Sannicolo`, F.;
Zotti, G.; Zecchin, S.; Schiavon, F. Chem. Mater. 2000, 12, 1490.
(14) The intramolecular oxidative coupling reaction of the N-free
bisindolylmaleimide hardly occurs using PIFA with BF3‚Et2O: Faul, M.
M.; Sullivan, K. A. Tetrahedron Lett. 2001, 42, 3271.
(15) We have observed the slow formation of the addition product 7 in
the absence of PIFA. For the related studies on the Lewis acid-catalyzed
reaction, see: (a) Smith, G. F.; Walters, A. E. J. Chem. Soc. 1961, 940. (b)
Hinman, R. L.; Shull, E. R. J. Org. Chem. 1961, 26, 2339.
(12) Typical Experimental Procedure: To a stirred solution of 1H-
pyrrole 3a (111 mg, 0.9 mmol) in CH2Cl2 (15 mL) were quickly added
PIFA (0.3 mmol) and TMSBr (0.6 mmol) at -78 °C. The reaction mixture
was then stirred for 1 h, while the reaction temperature was maintained
below -40 °C. After the reaction completion, saturated aqueous NaHCO3
(ca. 20 mL) was added to the mixture and then stirred for an additional 10
min at ambient temperature. The organic layer was separated, and the
aqueous phase was extracted with CH2Cl2. The combined extract was dried
with Na2SO4 and evaporated to dryness. The residue was purified by column
chromatography (SiO2 (neutral)/n-hexane-AcOEt) to give the pure 2,2′-
bipyrrole 4a (56 mg, 75%) as a colorless oil. The less polar fractions gave
unreacted 3a as a pure form (31 mg).
(16) Farnier, M.; Soth, S.; Fournari, P. Can. J. Chem. 1976, 54, 1083.
(17) A certain degree of the 2,2′-bipyrrole formed, but it decomposed
under the reaction conditions.
Org. Lett., Vol. 8, No. 10, 2006
2009

to activate PIFA but also to suppress the oligomerization
process of the pyrroles during the coupling reaction. How-
ever, the precise intermediate of the coupling reaction is yet
unclear, and we consider the following two alternative
reaction intermediates generated in situ: (a) a bromonium
ion in the form of a hypobromite or the bromate(I) complex
by PIFA-induced oxidation of the bromide ion20 and (b)
activated I(III) species containing an I-Br bond.21,22 Exten-
sive studies on the mechanism and real intermediate of the
coupling reaction will be done and described elsewhere.
In conclusion, we have developed the hypervalent iodine-
(III)-induced effective oxidative coupling reactions of electron-
rich pyrroles and indoles using TMSBr as an appropriate
Lewis acid. This is the first straightforward synthesis of a
variety of bipyrroles in good yields, and therefore, it might
accelerate further applications of these compounds in the
research fields already mentioned. Applications of these
useful bipyrrole compounds are also underway in our
laboratory.
Scheme 4
Scheme 4. As presumed from our previous reports,11
electrolytic3 or some chemical oxidations18 yielding pyrrole
cation radicals, i.e., cation radical A′, appear to be generated
from the pyrroles 3 through a one-electron oxidation by the
action of PIFA-TMSBr. A then reacts with 3 to give the
bipyrroles 4 after the further one-electron oxidation followed
by deprotonation. Although an alternative stepwise mecha-
nism involving B19 is conceivable, the former explanation
is more reasonable based on the following experimental
result; thus, the isolated dihydroindole 7, which was slowly
formed during the oxidative coupling reaction condition of
5, did not produce bisindole 6 in the presence of PIFA and
TMSBr. Our persistent attempts to detect the dihydropyrroles
B also suggested the absence of B during the reaction, and
effective inhibition of the reaction by the radical scavenger,
galvinoxyl, supports the former cation radical pathway.
Because pyrroles cause acid-catalyzed oligomerization or
polymerization by treatment with strong acids even at low
temperature, TMSBr acts as a suitable Lewis acid not only
Acknowledgment. This work was financially supported
by a Grant-in-Aid for Scientific Research (S) (No. 13853010)
from the Ministry of Education, Culture, Sports, Science,
and Technology, Japan.
Supporting Information Available: Experimental details
and detailed spectroscopic data of all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL060333M
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2010
Org. Lett., Vol. 8, No. 10, 2006