4-Alkoxy- and 4-Amino-2,2′-bipyrrole Synthesis

Article abstract of DOI:10.1021/ol0625583

(Chemical Equation Presented) 4-Alkoxy-2,2′-bipyrroles and the first examples of 4-amino-2,2′-bipyrroles have been synthesized by a diversity-oriented strategy from 4-hydroxyproline. The bipyrrole products offer interesting potential as building blocks fo

Full text of DOI:10.1021/ol0625583

ORGANIC
LETTERS
2006
Vol. 8, No. 26
6107-6110
4-Alkoxy- and 4-Amino-2,2
Synthesis
′-bipyrrole
Benoit Jolicoeur and William D. Lubell*
De´partement de chimie, UniVersite´ de Montre´al, C.P. 6128, Succ. Centre-Ville,
Montre´al, Que´bec H3C 3J7, Canada
lubell@chimie.umontreal.ca
Received October 17, 2006
ABSTRACT
4-Alkoxy-2,2′-bipyrroles and the first examples of 4-amino-2,2′-bipyrroles have been synthesized by a diversity-oriented strategy from
4-hydroxyproline. The bipyrrole products offer interesting potential as building blocks for making pyrrole products, as demonstrated by the
first synthesis of an amino prodigiosin analogue.
2,2′-Bipyrrole structures are components of natural products
such as the prodigiosins,1,2 streptorubin B and the tamb-
jamines (Figure 1). Encompassed in expanded porphyrins3,4
Among the synthetic routes that have been reported for
making bipyrrole, few strategies have been diversity-
oriented.7-17 For example, toward achieving the first prodi-
giosin synthesis,7 Rapoport introduced the construction of a
series of bipyrroles by condensation of substituted pyrrole
and ∆1-pyrroline precursors, followed by dehydrogenation.
Focused on the synthesis of the key 4-methoxy-2,2′-
bipyrrole-5-carboxaldehyde intermediate employed in this
(6) Krondak, M.; Broncova, G.; Anikin, S.; Merz, A.; Mirsky, V. M. J.
Solid State Electr. 2006, 10, 185-191.
(7) (a) Rapoport, H.; Holden, K. G. J. Am. Chem. Soc. 1962, 84, 635-
642. (b) Rapoport, H.; Castagnoli, N. J. Am. Chem. Soc. 1962, 84, 2178-
2181. (c) Rapoport, H.; Castagnoli, N.; Holden, K. G. J. Org. Chem. 1964,
29, 883-885. (d) Rapoport, H.; Bordner, J. J. Org. Chem. 1964, 29, 2727-
2731. (e) Bordner, J.; Rapoport, H. J. Org. Chem. 1965, 30, 3824-3828.
(8) Hinz, W.; Jones, R. A.; Patel, S. U.; Karatza, M.-H. Tetrahedron
1986, 42, 3753-3758.
Figure 1. Representative natural products containing 2,2′-bipyrrole.
(9) Boger, D. L.; Patel, M. J. Org. Chem. 1988, 53, 1405-1415.
(10) Wasserman, H. H.; Lombardo, L. J. Tetrahedron Lett. 1989, 30,
1725-1728.
and conductive materials,5,6 bipyrroles have served in a wide
range of applications.
(11) Nonell, S.; Bou, N.; Borrell, J. I.; Teixido, J.; Villanueva, A.;
Juarranz, A.; Canete, M. Tetrahedron Lett. 1995, 36, 3405-3408.
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J. 2003, 9, 449-455.
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899.
(15) Wasserman, H. H.; Xia, M. D.; Wang, J. J.; Petersen, A. K.;
Jorgensen, M.; Power, P.; Parr, J. Tetrahedron 2004, 60, 7419-7425.
(16) Dohi, T.; Morimoto, K.; Maruyama, A.; Kita, Y. Org. Lett. 2006,
8, 2007-2010.
(17) Dairi, K.; Tripathy, S.; Attardo, G.; Lavalle´e, J. F. Tetrahedron Lett.
2006, 47, 2605-2606.
* Corresponding author. Tel: +1-514-343-7339. Fax: +1-514-343-7586.
(1) Fu¨rstner, A. Angew. Chem., Int. Ed. 2003, 42, 3582-3603.
(2) Bennett, J. W.; Bentley, R. AdV. App. Microbiol. 2000, 47, 1-32.
(3) (a) Sessler, J. L.; Camiolo, S.; Gale, P. A. Coord. Chem. ReV. 2003,
240, 17-55. (b) Sessler, J. L.; Aguilar, A.; Sanchez-Garcia, D.; Seidel, D.;
Ko¨hler, T.; Arp, F.; Lynch, V. M. Org. Lett. 2005, 7, 1887-1890.
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10.1021/ol0625583 CCC: $33.50
© 2006 American Chemical Society
Published on Web 12/02/2006

prodigiosin synthesis, four strategies were later achieved
featuring intramolecular Pd(II)-promoted 2,2′-diary1 cou-
pling,9 amination of a vicinal tricarbonyl intermediate,10
intermolecular oxidative coupling of pyrrole and pyrrole-2-
carboxylate precursors with singlet oxygen,15 and Pd-
catalyzed cross-coupling of bromopyrrole and pyrrole boro-
nate starting materials.17 In addition, symmetrical 2,2′-
bipyrroles have recently been prepared using hypervalent
iodine(III)-induced oxidative couplings of 3-alkyl- and
3-arylpyrroles.16
from 4-hydroxy-N-(PhF)prolinate 7 by the addition of freshly
prepared vinylmagnesium bromide in THF (Scheme 2).20
Scheme 2. Synthesis of 2-Acyl-4-aminopyrroles 10
Methology for enhancing the diversity of bipyrrole units
is desired to further structure-activity relationship studies
of interesting pyrrole products. For example, elaborating the
B-ring methoxy group to provide other ethers has improved
the therapeutic potential of certain prodigiosin analogues.18
Moreover, to the best of our knowledge, the chemistry of
4-amino-2,2′-bipyrroles has yet to be explored.
In our earlier explorations of new methodology for pyrrole
synthesis, 4-aminopyrrole-2-carboxylates 2 were found to be
effectively prepared by reacting 4-oxo-N-(PhF)prolinate 1
with an amine and catalytic acid at 50 °C in a polar solvent
[PhF ) 9-(9-phenylfluorenyl)].19 4-Hydroxypyrrole-2-car-
boxylate 3 was similarly made on treatment of 4-oxoprolinate
1 with aqueous ammonium hydroxide and p-TsOH in THF
(Scheme 1).19 In addition, 1,2,5-trisubstituted pyrroles 6 were
Oxidation of alcohol 8 was performed using oxalyl chloride
and dimethyl sulfoxide to furnish 4-oxopyrrolidine 9 in 95%
yield after purification by column chromatography.23 2-Acyl-
4-aminopyrroles 10b-e were prepared under similar condi-
tions previously used to make amino pyrrole-2-carboxylates
2. Treatment of 4-oxopyrrolidine 9 with a primary or
secondary amine in the presence of a catalytic amount of
p-toluenesulfonic acid in warm THF caused elimination of
9-phenylfluorene (PhFH) and formation of the desired
pyrroles 10b-e in 51-78% yields. In the case of 4-di-
methylaminopyrrole 10a, Et3N (110 mol %) was used to
partially neutralize dimethylamine hydrochloride (300 mol
%) in acetonitrile prior to reaction with ketone 9.
Scheme 1. Prior Methodology for Pyrrole Synthesis
Alternatively, 2-acyl-4-hydroxypyrrole 11 was prepared
in 89% yield by exposure of ketone 9 with a catalytic amount
of sodium bis(trimethylsilyl)amide (10 mol %) in THF for
15 min (Scheme 3). O-Alkylation of 4-hydroxypyrrole 11
prepared by a practical three-step protocol featuring the
synthesis of homoallylic ketone 5 by exposure of methyl ester
4 to excess of vinylmagnesium bromide in the presence of
a catalytic amount of a copper salt (Scheme 1),20 followed
by olefin oxidation and Paal-Knorr condensation.21 Novel
syntheses of 4-alkoxy- and 4-amino-2,2′-bipyrroles have now
been developed using strategies that combine elements of
these past methods for substituted pyrrole synthesis.
Scheme 3. Synthesis of 2-Acyl-4-alkoxypyrroles 12
4-Alkoxy- and 4-amino-2,2′-bipyrroles were synthesized
from 4-hydroxyproline as an inexpensive starting material.22
As reported, homoallylic ketone 8 was prepared in 78% yield
(18) D’Alessio, R.; Bargiotti, A.; Carlini, O.; Colotta, F.; Ferrari, M.;
Gnocchi, P.; Isetta, A.; Mongelli, N.; Motta, P.; Rossi, A.; Rossi, M.; Tibolla,
M.; Vanotti, E. J. Med. Chem. 2000, 43, 2557-2565.
(19) Marcotte, F. A.; Lubell, W. D. Org. Lett. 2002, 4, 2601-2603.
(20) Hansford, K. A.; Dettwiler, J. E.; Lubell, W. D. Org. Lett. 2003, 5,
4887-4890.
was accomplished by deprotonation with potassium tert-
butoxide followed by the addition of methyliodide or
(21) Hansford, K. A.; Zanzarova, V.; Dorr, A.; Lubell, W. D. J. Comb.
Chem. 2004, 6, 893-898.
(23) Mancuso, A. J.; Huang, S. L.; Swern, D. J. Org. Chem. 1978, 43,
2480-2482.
(22) Gill, P.; Lubell, W. D. J. Org. Chem. 1995, 60, 2658-2659.
6108
Org. Lett., Vol. 8, No. 26, 2006

benzylbromide in, respectively, 65% and 58% yield. Under
these conditions, some N- and O-bisalkylated side product
13 was also obtained together with starting material (Scheme
3).
presumably due to the influence of the relatively electron-
deficient aromatic ring on the neighboring carbonyl group.8
By employing a modification of the Paal-Knorr condensa-
tion that had been used to make sterically crowded 1,2,5-
trisubstituted pyrroles,8,27 annulation was achieved by ex-
posing 1,4-diketones 16b-c and 17a to primary amines in
the presence of stoichiometric TiCl4 (Scheme 4). Ammonia
failed to react with 1,4-diketone 16b under similar conditions;
however, aniline reacted with 17a to give bipyrrole 19a in
94% yield. Using the same conditions, 2-(p-nitrophenyl)-
ethylamine and 2-(phenylthio)ethylamine gave incomplete
conversion to bipyrroles 18c and 19b, respectively, and
significant amounts (>50%) of starting material were
recovered. Using this Paal-Knorr condensation protocol, six
examples of 4-amino-2,2′-bipyrroles 18a-f and two different
4-methoxy-2,2′-bipyrroles 19a,b were prepared in 33-94%
yields after purification by chromatography over silica gel
(Figure 2).
Attempts to oxidize olefins 10a-e using the Tsuji-
Wacker protocol (O2, PdCl2, CuCl),24 ozonolysis, and OsO4/
NaIO4 conditions25 all led to decomposition of the electron-
rich pyrrole ring. The protection of pyrroles 10 and 12 with
an electron-withdrawing group was pursued to reduce
nucleophilicity;26 however, moderate electron-withdrawing
groups, such as Boc at the 1-position and a carboxylate at
the 2-position, failed to prevent pyrrole decomposition during
Tsuji-Wacker oxidation. Protection of the nitrogen of
pyrroles 10a-c and 12a as the corresponding phenyl-
sulfonamides 14a-c and 15a was achieved by reacting the
pyrrolyl anion, formed with potassium tert-butoxide, with
phenylsulfonyl chloride in THF. The influence of the
sulfonamide on the electron density of the aromatic ring was
indicated by comparison of the 1H NMR spectra of pyrroles
10b and 14b in which the chemical shifts of the ring protons
at 6.60 and 6.55 ppm were deshielded, respectively, on
sulfonylation to 7.20 and 6.75 ppm.
In the case of 4-dimethylaminopyrrole 10a, besides the
desired sulfonamide 14a (60% yield), the corresponding
2-phenylsulfonylpyrrole was isolated as a side product in
8% yield. With sulfonamide protected pyrroles 14a-c and
15a in hand, the Tsuji-Wacker oxidation protocol performed
effectively to convert the homoallylic ketones into 1,4-diones
16a-c and 17a in yields of 25-81% after purification by
column chromatography (Scheme 4).
Scheme 4. Synthesis of 2,2′-Bipyrroles 18 and 19
Figure 2. 4-Amino- and 4-methoxy-2,2′-bipyrroles 18 and 19.
In the Paal-Knorr annulation, 1,4-diones 16a-c and 17a
failed to react under a variety of condensation conditions,
Finally, to demonstrate the utility of the bipyrrole products,
4-morpholino-2,2′-bipyrrole 18a was employed in the first
synthesis of a 4-aminoprodigiosin analogue (Scheme 5).
Removal of the sulfonamide from aminobipyrrole 18a was
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Org. Lett., Vol. 8, No. 26, 2006
6109

achieved using magnesium turnings in a methanol/chloroform
(99:1) mixture under ultrasonic irradiation for 5 min to
provide bipyrrole 20.26 2-Undecylpyrrole-5-carboxaldehyde
21 was prepared by formylation39 of 2-undecylpyrrole.40 The
condensation of pyrrole aldehyde 21 with bipyrrole 20 was
performed in EtOH on addition of a catalytic quantity of
48% aq HBr. The red pigment 4-morpholinoprodigiosin 22
was separated from unreacted formylpyrrole 21 by prepara-
tive HPLC and isolated as its TFA salt in 36% yield.
Saturation of the upfield signals for the morpholine meth-
ylene protons (Ha) caused NOE enhancement of the di-
pyrrolomethene proton signal (Hb) indicative of their close
proximity in the â-conformer in CDCl3 (Scheme 5).
4-Hydroxyproline was used as precursor for making a set
of 1,1′-disubstituted 4-alkoxy- and 4-amino-2,2′-bipyrroles.
Among these first examples of 4-amino-2,2′-bipyrroles,
morpholino adduct 18a was also used to prepare the first
4-aminoprodigiosin 22. Considering the power of this method
for providing bipyrroles with varying ring substituents and
the growing use of such intermediates for the synthesis of
natural products and pyrrole analogues exhibiting interesting
activity, this approach should be of general interest and utility
for the community engaged in medicinal chemistry and
material science.
Scheme 5. Synthesis and Conformational Analysis of
4-Morpholinoprodigiosin 22 (double tipped arrows indicate
characteristic observed NOE)
more difficult than anticipated, and many previously reported
conditions for desulfonylation were unsuccessful.28-38 Depro-
tection of sulfonamido bipyrrole 18a was successfully
Acknowledgment. We acknowledge Dalbir Sekhon from
the Regional Laboratory of Mass Spectrometry at the
Universite´ de Montre´al for his helpful assistance as well as
the Natural Sciences and Engineering Research Council of
Canada (NSERC) and Fonds Que´be´cois de la Recherche sur
la Nature et les Technologies (FQRNT) for financial support.
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Supporting Information Available: Experimental details
and spectroscopic characterization for all compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
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OL0625583
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