Synthesis of a new class of C2-symmetrical biheteroaryls by ammonium cerium(IV) nitrate mediated dimerization of 2-(furan-3-yl)pyrroles

Article abstract of DOI:10.1002/ejoc.200901314

Polyfunctionalized 2-(furan-2-yl)pyrroles and 2-(furan-3-yl)pyrroles derived from 2-azetidinone-tethered alienes by two independent cerium(IV)-mediated single-electron oxidations provided a (4-oxopent-2-enoyl) pyrrole and 3,3′-bis(pyrrol-2-yl)-2, 2′-bifurans, respectively. Access to the oxidation precursors was achieved by regiocontrolled cyclization of β-allenamine intermediates derived from selective β-lactam nucleus breakage of 2-azetidinone-tethered allenols.

Full text of DOI:10.1002/ejoc.200901314

SHORT COMMUNICATION
DOI: 10.1002/ejoc.200901314
Synthesis of a New Class of C2-Symmetrical Biheteroaryls by Ammonium
Cerium(IV) Nitrate Mediated Dimerization of 2-(Furan-3-yl)pyrroles
Benito Alcaide,*[a] Pedro Almendros,*[b] Rocío Carrascosa,[a] and M. Rosario Torres[c]
Keywords: Allenes / Cerium / Chemoselectivity / Dimerization / Heterocycles
Polyfunctionalized 2-(furan-2-yl)pyrroles and 2-(furan-3-yl)-
pyrroles derived from 2-azetidinone-tethered allenes by two
independent cerium(IV)-mediated single-electron oxidations
provided a (4-oxopent-2-enoyl)pyrrole and 3,3Ј-bis(pyrrol-2-
yl)-2,2Ј-bifurans, respectively. Access to the oxidation pre-
cursors was achieved by regiocontrolled cyclization of β-al-
lenamine intermediates derived from selective β-lactam nu-
cleus breakage of 2-azetidinone-tethered allenols.
Introduction
Cerium is a member of the lanthanides, whose electronic
configuration facilitates that it can exist in both tri- and
tetrapositive states. The strong oxidising power of the ce-
rium(IV) ion has been recognised for many years, being of
valuable synthetic utility for organic chemists.[1] We wish to
report herein the use of CAN as an efficient and selective
reagent for generating molecular diversity from furanylpyr-
roles.
Results and Discussion
We have recently reported a novel regiocontrolled prepa-
ration of functionalized N-substituted pyrroles 2 from 2-
azetidinone-tethered allenes 1 (Scheme 1).[2] To strengthen
the synthetic utility of this methodology, procedures for the
effective removal of the N-protecting groups in the pyrrole
core were then surveyed. In an attempt to perform the
CAN-promoted oxidative cleavage of the N-(4-meth-
oxyphenyl) substituent in 2-(5-methylfuran-2-yl)pyrrole
(2a), surprisingly, we found that the pyrrole-based 1,4-di-
carbonyl compound 3 was isolated as the sole product
(Scheme 2).[3]
Scheme 1. Preparation of pyrroles 2 from allenic β-lactams 1. PMP
= 4-MeOC6H4.
[a] Departamento de Química Orgánica I, Facultad de Química,
Universidad Complutense de Madrid
28040 Madrid, Spain
Fax: +34-91-3944103
E-mail: alcaideb@quim.ucm.es
[b] Instituto de Química Orgánica General, Consejo Superior de
Investigaciones Científicas, CSIC,
Scheme 2. CAN-mediated reaction of (furan-2-yl)pyrrole 2a. Syn-
thesis of α,β-unsaturated 1,4-diketone 3. E = CO2Me; PMP = 4-
MeOC6H4; CAN = ammonium cerium(IV) nitrate.
Juan de la Cierva 3, 28006 Madrid, Spain
Fax: +34-91-5644853
E-mail: Palmendros@iqog.csic.es
[c] CAI Difracción de Rayos X, Facultad de Química, Universidad
Complutense de Madrid,
To our delight, in contrast to the 2-(furan-2-yl)pyrrole
2a, the 2-(furan-3-yl)pyrrole 2b does not undergo oxidative
cleavage of the furan ring under CAN exposure, but the
28040 Madrid, Spain
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.200901314.
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B. Alcaide, P. Almendros, R. Carrascosa, M. R. Torres
SHORT COMMUNICATION
product obtained was the C2-symmetrical 3,3Ј-bis(pyrrol-2-
yl)-2,2Ј-bifuran 4a (Scheme 3), probably through the forma-
tion of a C–C bond by the coupling of two aromatic
units.[4,5] The structure of biheteroaryl 4a was established by
X-ray crystallography (Figure 1).[6] Similar behaviour was
observed for phenyl derivative 2c, which is readily amenable
for the CAN-promoted conversion to 3,3Ј-bis(pyrrol-2-yl)-
2,2Ј-bifuran 4b, as depicted in Scheme 3. Although no pre-
cedent could be found for this reactivity in the literature,
further investigation of its potential scope was of interest.
As a result, N-allyl- and N-benzyl-substituted pyrroles 2d
and 2e were treated with CAN under the same conditions
as N-PMP-substituted pyrroles. Again, the reaction yielded
only one product, namely, the homodimers 4c and 4d
(Scheme 3). Thus, for the first time the controlled dimeriza-
tion reaction of furanylpyrrole derivatives can be achieved,
eliminating the need to prepare halogen or metal derivatives
of the aryl fragments prior to their actual union.
Figure 1. X-ray diffraction analysis of bis(pyrrol-2-yl)-2,2Ј-bifuran
4a.
by rearrangement of intermediate 8 into 1,4-dicarbonyl
compound 3a complete the proposal. Arguably, formation
of the stable allyl-like carbocation is the major driving force
for this oxidative cleavage.
A possible pathway for the oxidative dimerization of 2-
(furan-3-yl)pyrroles may initially involve the CAN-medi-
ated formation of the radical cation 9. Next, addition of
water followed by proton elimination should afford radical
Scheme 3. CAN-mediated reactions of (furan-3-yl)pyrroles 2b–e.
Synthesis of 3,3Ј-bis(pyrrol-2-yl)-2,2Ј-bifurans 4a–d. E = CO2Me;
PMP = 4-MeOC6H4; CAN = ammonium cerium(IV) nitrate.
The following mechanism for the formation of pyrrole- 10, which dimerizes to intermediate 11. Double dehydration
based α,β-unsaturated γ-ketone 3a was considered of bis(dihydrofuran) 11 may be the final step for the
(Scheme 4). The reaction begins with the electron transfer achievement
of
3,3Ј-bis(pyrrol-2-yl)-2,2Ј-bifurans
4
from 2-(5-methylfuran-2-yl)pyrrole 2a to CeIV to generate (Scheme 5).[7] The success of the reaction rests on the di-
the radical cation 5. The cationic center of 5 is trapped by merization of radical 10 in opposition to abstraction of hy-
water to afford species 6, which after proton elimination drogen, probably due to the higher stability of the radical
gave radical 7. One-electron oxidation of radical 7 followed because of the proximal oxygen atom. The presence of the
Scheme 4. Mechanistic explanation for the CAN-mediated preparation of pyrrole-based α,β-unsaturated 1,4-diketone 3a. E = CO2Me.
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New Class of C2-Symmetrical Biheteroaryls
grant. We thank Alexandra Martinsson for her help in the prepara-
tion of some materials.
methoxycarbonyl group is probably necessary; otherwise
the radical cation should have charge and spin mainly local-
ized on the pyrrole ring.
[1] The most extensively used cerium(IV) reagent in organic chem-
istry is ammonium cerium(IV) nitrate (CAN). For reviews on
the use of CAN as a versatile single-electron oxidant, see: a) V.
Nair, A. Deepthi, Tetrahedron 2009, 65, 10745; b) V. Nair, A.
Deepthi, Chem. Rev. 2007, 107, 1862; for selected examples on
CAN-promoted oxidative dimerization and oxidative arylation,
see: c) C. Xi, Y. Jiang, X. Yang, Tetrahedron Lett. 2005, 46,
3909; d) J. C. Conrad, J. Kong, B. N. Laforteza, D. W. C. Mac-
Millan, J. Am. Chem. Soc. 2009, 131, 11640.
[2] a) B. Alcaide, P. Almendros, R. Carrascosa, M. C. Redondo,
Chem. Eur. J. 2008, 14, 637; b) B. Alcaide, P. Almendros, M. C.
Redondo, Chem. Commun. 2006, 2616.
[3] For a report available in the literature on the DDQ-mediated
oxidative cleavage of 3-alkoxy-2,5-dihydrofurans to afford α,β-
unsaturated γ-oxo aldehydes, see: a) M. Brasholz, H.-U. Reis-
sig, Angew. Chem. Int. Ed. 2007, 46, 1634; Angew. Chem. 2007,
119, 1659; for a report available in the literature on the CAN-
mediated oxidative cleavage of a 3-ethoxycarbonyl-2-methylfu-
ran to afford an oct-2-enoate, see: b) A. J. Moreno-Vargas, I.
Robina, J. Fernández-Bolaños, J. Fuentes, Tetrahedron Lett.
1998, 39, 9271.
Scheme 5. Mechanistic explanation for the CAN-mediated prepa-
ration of 3,3Ј-bis(pyrrol-2-yl)-2,2Ј-bifurans 4. E = CO2Me.
[4] Furans and pyrroles constitute an important structural compo-
nent in pharmaceuticals and natural products, being some of
the best-selling drug heterocycles of these types. For atorvasta-
tin (a pyrrole used to control high cholesterol), see: a) M. E. M.
Noble, J. A. Endicott, L. N. Johnson, Science 2004, 303, 1800;
b) J. C. Reed, M. Pellecchia, Blood 2005, 106, 408; c) A. P. Lea,
D. Mctavish, Drugs 1997, 53, 828; for ranitidine (a furan used
to treat stomach ulcers), see: d) J. A. Joule, K. Mills, Heterocy-
clic Chemistry, 4th ed., Blackwell Science Ltd., Malden, MA,
2000; in particular, bipyrroles are natural products belonging
to the prodigiosins, and they are also capable of inducing
apoptosis in human cancer cells, see: e) H. Rapoport, K. G.
Holden, J. Am. Chem. Soc. 1962, 84, 635; f) B. Montaner, R.
Pérez-Tomás, Life Sci. 2001, 68, 2025; on the other hand, bifu-
rans are key motifs in natural products, such as licorice, present
in foods and beverages, see: g) C. Frattini, C. Bicchi, C. Baret-
tini, G. M. Nano, J. Agric. Food Chem. 1977, 25, 1238.
Conclusions
Using
a simple reagent we have successfully ac-
complished two mild cerium(IV)-mediated single-electron
oxidations of polyfunctionalized 2-(furan-2-yl)pyrroles and
2-(furan-3-yl)pyrroles to form a pyrrole-based 1,4-dicar-
bonyl compound and a new class of C2-symmetrical bihet-
eroaryls, namely 3,3Ј-bis(pyrrol-2-yl)-2,2Ј-bifurans, respec-
tively.
[5] Biaryls, important constituents of natural products and of
pharmaceutical agents, have been recently recognized as a core
functional group in organic molecular materials, and have re-
ceived attention due to the use of axially chiral biaryls as li-
gands in asymmetric reactions; for selected reviews, see: a) J.-P.
Corbet, G. Mignani, Chem. Rev. 2006, 106, 2651; b) J. Hagen,
Industrial Catalysis, Wiley-VCH, Weinheim, 2nd ed., 2006, pp.
59–80; c) A. O. King, N. Yasuda, in Organometallics in Process
Chemistry (Ed.: R. D. Larsen), Springer-Verlag, Berlin, Heidel-
berg, 2004, pp. 205–245; d) R. Noyori, Chem. Soc. Rev. 1989,
18, 187; e) K. Narasaka, Synthesis 1991, 1.
[6] X-ray data of 4a: crystallized from ethyl acetate/n-hexane at
20 °C. C38H36N2O8 (Mr = 648.69); monoclinic; space group
P21/c; a = 17.0807(9), b = 10.4055(5); c = 19.0427(9) Å; β =
100.6450(10)°; V = 3326.3(3) Å3; Z = 4; dcalcd. = 1.295 mgm–3;
µ = 0.091 mm–1; F(000) = 1368. A transparent crystal of
0.45ϫ0.14ϫ0.08 mm was used. 5630 [R(int) = 0.0550] inde-
pendent reflections were collected with a Bruker Smart CCD
difractomer using graphite-monochromated Mo-Kα radiation
(λ = 0.71073 Å) operating at 50 kV and 30 mA. Data were
collected over a hemisphere of the reciprocal space by combi-
nation of three exposure sets. Each exposure of 20 s covered
0.3° in ω. The cell parameters were determined and refined by
a least-squares fit of all reflections. The first 100 frames were
recollected at the end of the data collection to monitor crystal
decay, and no appreciable decay was observed. The structure
was solved by direct methods and Fourier synthesis. It was re-
fined by full-matrix least-squares procedures on F2 (SHELXL-
97). All non-hydrogen atoms were refined anisotropically. All
Experimental Section
General Procedure for the CAN-Mediated Homodimerization of
(Furan-3-yl)pyrroles 2b–e. Preparation of 3,3Ј-Bis(pyrrol-2-yl)-2,2Ј-
bifurans 4a–d: A solution of CAN (171 mg, 0.313 mmol) in water
(2 mL) was slowly added to a stirred solution of the appropriate
(furan-3-yl)pyrrole 2 (0.136 mmol) in acetonitrile (2 mL) at –20 °C.
The reaction mixture was stirred at –20 °C for 0.5 h. Aqueous
(10%) sodium sulfite (1.0 mL) was added, and the mixture was
extracted with ethyl acetate. The organic extract was washed with
brine, water, dried (MgSO4), and concentrated under reduced pres-
sure. Chromatography of the residue using ethyl acetate/hexanes
mixtures gave analytically pure compounds 4.
Supporting Information (see also the footnote on the first page of
this article): Compound characterization data and experimental
procedures as well as copies of NMR spectra for all new com-
pounds.
Acknowledgments
Support for this work by the Dirección General de Investigación,
Ministerio de Educación
CTQ2006-10292) and Universidad Complutense de Madrid/Banco
Santander Central Hispano UCM-BSCH (Grant GR58/08) are
gratefully acknowledged. R. C. thanks MEC for a predoctoral
y
Ciencia (DGI-MEC) (Project
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B. Alcaide, P. Almendros, R. Carrascosa, M. R. Torres
SHORT COMMUNICATION
hydrogen atoms were included in calculated positions and re-
fined riding on the respective carbon atoms. Final R(Rw) val-
ues were R1 = 0.0394 and wR2 = 0.0941. CCDC-675795 con-
tains the supplementary crystallographic data for this paper.
These data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_
request/cif.
into the furan moiety could be envisaged and would explain
the selectivity observed and the difference of behavior between
2-furan (2a) and 3-furan (2b–e) compounds under such condi-
tions. However, we think that both the presence of the ester
group as well as the relatively low ionization potentials of the
furan ring will undergo electron transfer particularly easily into
the oxygenated heterocycle.
[7] A referee suggested an analogous mechanistic pathway involv-
ing the oxidation of the pyrrole segment first. Thus, an oxi-
dation of the pyrrole nucleus and a delocalization of the charge
Received: November 17, 2009
Published Online: December 22, 2009
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