Domino metal-free allene-β-lactam-based access to functionalized pyrroles

Article abstract of DOI:10.1039/b601238h

A novel transition metal-free domino reaction sequence in allene-β-lactams, leading to the biologically relevant pyrrole frame has been developed using a sodium methoxide-methanol system. The Royal Society of Chemistry 2006.

Full text of DOI:10.1039/b601238h

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Domino metal-free allene-b-lactam-based access to functionalized
pyrroles{
Benito Alcaide,*a Pedro Almendros*b and Mar´ıa C. Redondoa
Received (in Cambridge, UK) 26th January 2006, Accepted 25th April 2006
First published as an Advance Article on the web 19th May 2006
DOI: 10.1039/b601238h
A novel transition metal-free domino reaction sequence in
allene-b-lactams, leading to the biologically relevant pyrrole
frame has been developed using a sodium methoxide–methanol
system.
Of the various synthetic and naturally occurring heterocyclic
Scheme 1 One-pot synthesis of pyrrole (2)-5a through domino b-lactam
ring opening–allene cyclization. Reagents and conditions: (i) Me2SO4,
NaOH, TBAI, DCM–H2O, RT; (ii) MeONa, MeOH, RT. PMP =
4-MeOC6H4.
structures, pyrrole derivatives are among the most prevalent,
because of their remarkable pharmacological activities.1
Furthermore, pyrroles are useful intermediates in the synthesis of
natural products as well as in heterocyclic chemistry,2 and they are
widely used in materials science.3 Recently, organometallic
transformations have been pursued with renewed interest to
approach the elusive addition reaction of the N–H bond across
allenes.4 On the other hand, in addition to the key role that
b-lactams have played in the fight against pathogenic bacteria, the
use of 2-azetidinones as chiral building blocks in organic synthesis
is now well established.5 Although many efforts have been made in
these fields, the direct preparation of the pyrrole ring from
b-lactams has not been reported yet. Furthermore, the use of the
allenamine building block for the synthesis of pyrroles has
remained seldom explored.6 We recently reported that the
2-azetidinone nucleus is the precursor of different types of
nitrogen-containing molecules.7 As a cleaner alternative to the
use of metal-containing reagents and catalysts, herein, we present a
powerful methodology for the preparation of functionalized
pyrroles, which relies on a base-promoted domino reaction in
allene-b-lactams.
above reaction gave as the only product the 1,2,3,5-tetrasubstituted
pyrrole (2)-5a in reasonable yield (77%) and total regioselectivity.
Compound (2)-5a can be considered as a hybrid scaffold as
combination of the biological and synthetically relevant pyrrole
and a-hydroxy acid cores.9 The susceptibility of the reaction to
stereochemically different b-lactam allenic ethers was examined by
exploring the possibility of employing 2-azetidinone-tethered allene
anti-(+)-3a. Gratifyingly, pyrrole (2)-5a was obtained in similar
selectivity and yield (Scheme 1). When the reaction was performed
on unprotected a-allenol (+)-1a, the domino sequence provided the
desired product (2)-5a but in low yield (10%).
Reactions of a variety of b-lactam allenic ethers with sodium
methoxide gave the expected functionalized pyrroles in reasonable
isolated yields without the need for a transition metal catalyst.10
No other regioisomers were observed in all cases. Typical results
are shown in Scheme 2. Although complete conversion was
1
observed by TLC and H NMR analysis of the crude reaction
Precursors for the pyrrole formation, a-allenols 1 and 2, were
made starting from the appropriate 4-oxoazetidine-2-carbaldehyde
or azetidine-2,3-dione via indium-mediated Barbier-type carbonyl–
allenylation reaction in aqueous media using our previously
described methodologies.8 a-Allenols 1 and 2 were protected as the
corresponding methyl ethers 3 and 4 by treatment with dimethyl
sulfate under phase transfer conditions. During the search for a
suitable protocol for the preparation of enantiopure b-allenamines,
we detected an unexpected and interesting formation of highly
functionalized enantiopure pyrrole derivatives. In an initial
experiment, a-allenyl methyl ether (+)-3a and sodium methoxide
were mixed in methanol at room temperature. To our delight, the
mixtures, some decomposition was observed on sensitive pyrroles
5a–e during purification by flash chromatography, which may be
responsible for the moderate isolated yields.
The influence of the position of the allene moiety at the b-lactam
ring for the one-pot synthesis of the pyrrole nucleus, was
aDepartamento de Qu´ımica Orga´nica, Facultad de Qu´ımica, Universidad
Complutense de Madrid, 28040 Madrid, Spain.
Scheme 2 One-pot synthesis of pyrroles 5b–e through domino ring
opening–cyclization reaction of b-lactam allenic ethers 3b–e. Reagents and
conditions: (i) Me2SO4, NaOH, TBAI, DCM–H2O, RT; (ii) MeONa,
MeOH, RT. PMP = 4-MeOC6H4; (+)-1b, (+)-3b, and (2)-5b (R1 = PMP,
R2 = PhO, R3 = H); (+)-1c, (2)-3c, and (2)-5c (R1 = allyl, R2 = MeO,
R3 = H); (¡)-1d, (¡)-3d, and (¡)-5d (R1 = PMP, R2 = Me, R3 = H);
(+)-1e, (+)-3e, and (2)-5e (R1 = PMP, R2 = MeO, R3 = allyl).
E-mail: alcaideb@quim.ucm.es; Fax: +34 91-3944103
bInstituto de Qu´ımica Orga´nica General, CSIC, Juan de la Cierva 3,
28006 Madrid, Spain. E-mail: iqoa392@iqog.csic.es;
Fax: +34 91-5644853
{ Electronic supplementary information (ESI) available: Compound
characterization data and experimental procedures for all new compounds.
See DOI: 10.1039/b601238h
2616 | Chem. Commun., 2006, 2616–2618
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Notes and references
{ Representative experimental procedure for the synthesis of pyrroles 5:
Sodium methoxide (0.6 mmol) was added in portions at 0 uC to a solution
of the appropriate allene-b-lactam 3 (0.15 mmol) in methanol (3 mL). The
reaction was stirred at room temperature under argon atmosphere until
complete disappearance of the starting material (TLC) and then water was
added (0.5 mL). The methanol was concentrated under reduced pressure,
the aqueous residue was extracted with ethyl acetate (5 6 3 mL), the
organic layer was dried over MgSO4, and the solvent was removed under
reduced pressure. Chromatography of the residue on deactivated silica gel
eluting with ethyl acetate–hexanes mixtures gave analytically pure
compounds 5a–e.
Scheme 3 One-pot synthesis of pyrroles 6a–b through domino ring
opening–cyclization reaction of b-lactam allenic ethers 4a–b. Reagents and
conditions: (i) Me2SO4, NaOH, TBAI, DCM–H2O, RT; (ii) MeONa,
MeOH, reflux. PMP = 4-MeOC6H4.
1 A. Fu¨rstner, Angew. Chem., Int. Ed., 2003, 42, 3528; P. A. Jacobi,
L. D. Coults, J. S. Guo and S. I. Leung, J. Org. Chem., 2000, 65, 205;
A. Fu¨rstner, Synlett, 1999, 1523; S. Higgins, Chem. Soc. Rev., 1997, 26,
247; G. W. Gribble, in Comprehensive Heterocyclic Chemistry II, ed.
A. R. Katritzky, C. W. Rees and E. F. Scriven, Pergamon Press,
Oxford, UK, 1996, vol. 2, p. 207; A. Gossauer, Die Chemie der Pyrrole,
Springer-Verlag, Berlin, 1974.
2 D. L. Boger, C. W. Boyce, M. A. Labrili, C. A. Sehon and Q. Jin, J. Am.
Chem. Soc., 1999, 121, 54.
3 V. M. Domingo, C. Alema´n, E. Brillas and L. Julia, J. Org. Chem.,
2001, 66, 4058; L. Groenendaal, E.-W. Meijer and J. A. J. M. Vekemans,
in Electronic Materials: The Oligomer Approach, ed. K. Mu¨llen and
G. Wegner, Wiley-VCH, Weinheim, 1997.
4 For a comprehensive review, see: Modern Allene Chemistry, ed.
N. Krause and A. S. K. Hashmi, Wiley-VCH, Weinheim, 2004. For
a selection of recent examples, see for instance: P. H. Lee, H. Kim,
K. Lee, M. Kim, K. Noh, H. Kim and D. Seomoon, Angew. Chem., Int.
Ed., 2005, 44, 1840; R. K. Dieter, N. Chen, H. Yu, L. E. Nice and
V. K. Gore, J. Org. Chem., 2005, 70, 2109; N. Morita and N. Krause,
Org. Lett., 2004, 6, 4121; S. Ma, F. Yu and W. Gao, J. Org. Chem.,
2003, 68, 5943; L. Ackermann, R. G. Bergman and R. N. Loy, J. Am.
Chem. Soc., 2003, 125, 11956.
5 For selected reviews, see: b-Lactams: Synthesis, Stereochemistry,
Synthons and Biological Evaluation, Curr. Med. Chem., guest ed.
B. K. Banik 2004, vol. 11, issue 14; B. Alcaide and P. Almendros,
Synlett, 2002, 381; C. Palomo, J. M. Aizpurua, I. Ganboa and
M. Oiarbide, Synlett, 2001, 1813; B. Alcaide and P. Almendros, Chem.
Soc. Rev., 2001, 30, 226; I. Ojima and F. Delaloge, Chem. Soc. Rev.,
1997, 26, 377; M. S. Manhas, D. R. Wagle, J. Chiang and A. K. Bose,
Heterocycles, 1988, 27, 1755.
6 To the best of our knowledge, only two reports are available:
R. K. Dieter and H. Yu, Org. Lett., 2001, 3, 3855; M. O. Amombo,
A. Hausherr and H.-U. Reissig, Synlett, 1999, 1871. The preparation of
pyrroles from allenimines is somewhat more developed: O. Flo¨gel,
J. Dash, I. Bru¨dgam, H. Hartl and H.-U. Reißig, Chem. Eur. J., 2004,
10, 4283; A. V. Kel’in, A. W. Sromek and V. Gevorgyan, J. Am. Chem.
Soc., 2001, 123, 2074; L. Brandsma, N. A. Nedolya and B. A. Trofimov,
Eur. J. Org. Chem., 1999, 2663; N. A. Nedolya, L. Brandsma,
O. A. Tarasova, H. D. Verkruijsse and B. A. Trofimov, Tetrahedron
Lett., 1998, 39, 2409.
investigated by stirring protected quaternary a-allenols 2 for 48 h
in a mixture of MeONa in MeOH at room temperature. After
workup, the starting materials were recovered. Only after heating
at reflux temperature did the b-lactam a-allenic ethers 4 react to
form the corresponding heterocycles.10 New pentasubstituted
pyrroles 6 were obtained in fair yields by means of our metal-
free procedure, without the concomitant formation of any
regioisomer (Scheme 3).11
From a mechanistic point of view, our domino sequence could
be explained through a bond breakage process on the four-
membered lactam followed by allene cyclization, with concomitant
aromatization. The selective N1–C2 bond cleavage of the b-lactam
nucleus in 2-azetidinone-tethered allenes 1, 3 gave the non-isolable
allenic-b-amino esters 7, which after a totally regioselective
cyclization onto the central carbon atom of the neighbouring
allene under the reaction conditions followed by aromatization of
the pyrrolines 8 yielded the pyrroles 5 (Scheme 4).12 The pyrrole
formation must be driven by relief of the strain associated with the
four-membered ring, on forming a more stable five-membered
ring.
In conclusion, using a simple reagent we have successfully
accomplished an unprecedented domino lactam ring opening–
allene cyclization reaction for the construction of the biologically
relevant pyrrole frame. Studies concerning the scope and generality
of this methodology, as well as mechanistic implications are
underway in our laboratory, and further details will be reported in
due course.{
Support for this work by the DGI-MEC (Project BQU2003-
07793-C02-01) is gratefully acknowledged. M. C. R. thanks the
MEC for a predoctoral grant.
7 B. Alcaide, P. Almendros and R. Rodr´ıguez-Acebes, Chem. Eur. J.,
2005, 11, 5708; B. Alcaide, P. Almendros, M. C. Redondo and
M. P. Ruiz, J. Org. Chem., 2005, 70, 8890; B. Alcaide, P. Almendros,
G. Cabrero and M. P. Ruiz, Org. Lett., 2005, 7, 3981; B. Alcaide,
P. Almendros and R. Rodr´ıguez-Acebes, J. Org. Chem., 2005, 70, 3198.
8 B. Alcaide, P. Almendros, C. Aragoncillo, M. C. Redondo and
M. R. Torres, Chem. Eur. J., 2006, 12, 1539; B. Alcaide, P. Almendros
and C. Aragoncillo, Chem. Eur. J., 2002, 8, 1719; B. Alcaide,
P. Almendros, C. Aragoncillo and R. Rodr´ıguez-Acebes, J. Org.
Chem., 2001, 66, 5208; B. Alcaide, P. Almendros and C. Aragoncillo,
Org. Lett., 2000, 2, 1411.
9 For a review on natural product hybrids, see: L. F. Tietze, H. P. Bell
and S. Chandrasekhar, Angew. Chem., Int. Ed., 2003, 42, 3996. For a
preparation of 1,2,3,5-tetrasubstituted pyrroles bearing the bioactive
pyrroleacetic acid scaffold, see: P. S. Baran, J. M. Richter and D. W. Lin,
Angew. Chem., Int. Ed., 2005, 44, 609.
10 No loss of enantiomeric purity was evident by the 1H NMR spectra in
the presence of a chiral shift reagent of europium(III). Typically, after the
addition of the chiral shift reagent the signals for enantiopure pyrroles
moved about ca. 0.3 ppm downfield. For racemates, after the addition
of the chiral shift reagent, the signals for both enantiomers in the
Scheme 4 Possible reaction course for the domino ring opening–allene
cyclization sequence.
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1
1H NMR spectra can be differentiated ca. 0.4 ppm. Besides, in the H
A. D. Abell, Org. Biomol. Chem., 2003, 1, 2103; A. D. Abell and
B. K. Nabbs, Bioorg. Med. Chem., 2001, 9, 621; D. Della Bella,
A. Carenzi, M. Cibin and N. Gentile, Eur. Pat. Appl., 1992, EP 480458
A2 19920415; Chem. Abstr. 1992, 117, 14434; in addition 2-
(hydroxymethyl)pyrroles are versatile intermediates in the synthesis of
natural products, especially porphyrins and related pyrrole oligomers.
See: A. R. Katritzky and J. Li, J. Org. Chem., 1996, 61, 1624.
NMR spectra of the racemates after the addition of the chiral shift
reagent, the hydrogens of the enantiomers not prepared in this work
were upfield of the analogous hydrogens of our enantiopure pyrrole
derivatives.
11 Another structural feature which is often associated with pronounced
physiological activities of pyrroles, is the presence of hydroxymethyl
functionalities at the 2-position. Recently, 2-(hydroxymethyl)pyrroles
were discovered as a new class of inhibitors of a-chymotrypsin, as well
as central analgesics. See: D. C. Martin, A. J. Vernall, B. M. Clark and
12 One of the referees has suggested that compounds 5 might also arise
from a 5-endo process, leading either to an intermediate stabilized
benzylic anion, or directly to SN29 displacement of methoxide.
2618 | Chem. Commun., 2006, 2616–2618
This journal is ß The Royal Society of Chemistry 2006