Two-step synthesis of 2,3-dihydropyrroles via a formal 5-endo cycloisomerization of Ugi 4-CR/propargyl adducts

Article abstract of DOI:10.1021/ol3024727

A practical two-step synthesis of 2,3-dihydropyrroles from Ugi 4-CR/propargyl adducts is presented. The protocol includes a base-mediated formation of an allenamide functional group and an in situ metal-free formal 5-endo cycloisomerization that occurs in a highly regioselective manner at the allenamide C-γ.

Full text of DOI:10.1021/ol3024727

ORGANIC
LETTERS
2012
Vol. 14, No. 21
5408–5411
Two-Step Synthesis of
2,3-Dihydropyrroles via a Formal
5-endo Cycloisomerization of Ugi
4‑CR/Propargyl Adducts
´
Luis A. Polindara-Garcıa and Luis D. Miranda*
´
Instituto de Quımica, Universidad Nacional Autonoma de Mexico, Circuito Exterior,
Ciudad Universitaria, Coyoacan, Mexico D.F. 04510, Mexico
ꢀ
ꢀ
ꢀ
ꢀ
lmiranda@unam.mx
Received September 7, 2012
ABSTRACT
A practical two-step synthesis of 2,3-dihydropyrroles from Ugi 4-CR/propargyl adducts is presented. The protocol includes a base-mediated
formation of an allenamide functional group and an in situ metal-free formal 5-endo cycloisomerization that occurs in a highly regioselective
manner at the allenamide C-γ.
The 2,3-dihydropyrrole (2-pyrroline) core is an important
motif present in numerous natural products with important
biological activities. Two examples are sibiromycin (1) and
anthramycin (2), two compounds isolated from actinomy-
cetes which show significant antitumor properties, e.g.,
sequence-selective DNA alkylation (Figure 1).1 The main
synthetic approaches to this heterocyclic system have been
based on metal-catalyzed reactions,2 cycloadditions,3 and
tandem Michael/cyclization sequences.4 Additionally, 2,3-
dihydropyrroles derivatives have been used as a key building
block in various total syntheses5 as well as in the construc-
tion of other complex molecules.6
(1) (a) Hurley, L. H. J. Antibiot. 1977, 30, 349. (b) Hurley, L. H.;
Thurston, D. E. Pharm. Res. 1984, 52. (c) Leber, J. D.; Hoover, J. R. E.;
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Figure 1. Natural products bearing the 2,3-dihydropyrrole core.
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r
10.1021/ol3024727
Published on Web 10/25/2012
2012 American Chemical Society

Heteroannulation of allenes and allenamides has at-
tracted considerable attention for the elegant construction
of miscellaneous heterocyclic scaffolds in recent years.7
Among the most frequently used protocols are those which
involve metal-catalyzed methods.8 The unique contiguous
nitrogen/two π-bonds array of allenamides makes their
rich chemistry noteworthy. The interesting electronic ar-
rangement provides them with the ability to participate in
either electrophilic or nucleophilic processes, generally in a
highly regioselective fashion.9 Indeed, it has been reported
that suitably substituted allenamides undergo nucleophilic
addition (most of them in a metal-catalyzed protocol) at all
three of their carbon atoms, R,10 β,11 and γ12 (see Scheme 1,
B). Several other allenamide transformations, including
radical additions,13 cycloadditions,14 and oxidations,15 are
now well documented in the literature. On the other hand,
the Ugi four-component reaction (Ugi 4-CR) is undoubt-
edly one of the most powerful methodologies to easily
build up molecular complexity, generally from simple raw
materials. Furthermore, when this reaction is sequentially
combined with one or more meticulously selected process,
the resultant synthetic sequence provides products with
amplified molecular complexity and, in several cases, also
with augmented molecular diversity.16 Recently as part
of our ongoing interest in the development of practical
protocols to construct heterocyclic scaffolds using a pro-
grammed combination of a Ugi-4CR,17 we envisaged that
a Ugi-allenamide adduct such as B (Scheme 1) might be a
useful template to easily construct heterocyclic scaffolds
via a consecutive heteroannulation process. Preliminary
observations on this endeavor are described in the present
communication.
A under typical base-induced isomerization conditions
(catalytic potassium tert-butoxide).18 In principle, the pro-
pargyl Ugi adduct might be prepared in a straightforward
manner by simply using propargylamine as the amine input
in the component set of an Ugi 4-CR. We recognized that
under certain basic conditions the anion C might be formed
by deprotonation of the Ugi moiety17b,19 and undergo
cyclization into the allenamide moiety in a base-induced
cycloisomerization (Scheme 1). However, our question was,
“At which carbon atom would the cyclization take place, if it
did indeed occur?”
Scheme 1. Synthetic Strategy toward 2,3-Dihydropyrroles from
Ugi Adducts
This querywas rapidly addressed in our first experiment.
We observed that the 2,3-dihydropyrrole 4a was directly
formed when the Ugi adduct 3awas treated witha catalytic
amount (0.2 equiv) of t-BuOK in THF, although in rather
low yield, after 12h at room temperature (Table 1, entry 1).
Nevertheless, this promising result demonstrated that
under the basic conditions, both processes, i.e., formation
of the allenamide, and formal 5-endo20 cycloisomerization
at C-γ did occur. The starting material 3a for this process
was easily prepared (77% yield) by the reaction of 4-chlor-
obenzaldehyde, propargylamine 5, 2-bromobenzoic acid,
and tert-butyl isocyanide [catalytic indium(III) chloride in
methanol (0.3 M) under microwave heating conditions
(50 °C, 100 W, 2 h)]. Encouraged by the highly regioselec-
tive, uncommon, metal-free cycloisomerization18 of the
Ugi-allenamide adduct, we performed a short survey
of reaction conditions to optimize the yield of the 2,3-
dihydropyrrole using the Ugi adduct 3a as the model
compound. The use 1.0 equiv of t-BuOK once again gave
At the outset, we envisioned that the Ugi-allenamide
adducts B might be obtained from the propargyl Ugi-adduct
(7) (a) Bongers, N.; Krause, N. Angew. Chem., Int. Ed. 2008, 47, 2178.
(b) Gandon, V.; Lemiere, G.; Hours, A.; Fensterbank, L.; Malacria, M.
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2010, 75, 5406. (b) Kimber, M. C. Org. Lett. 2010, 12, 1128.
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Org. Lett., Vol. 14, No. 21, 2012
5409

only traces of the product (entry 2); however, the use of
2.5 equiv of t-BuOK afforded 4a in improved 51% yield
after 30 min (entry 3). The optimal conditions were
ultimately fixed when the reaction time was extended to
2.5 h using 2.5 equiv of the base, affording 4a in 71% yield
(entry 4). Neither longer reaction times (entries 5 and 6)
nor the use of 3 equiv of t-BuOK (entry 7) improved the
yields.
separable isomeric mixture of 2,3 (4n) and 2,5-dihydropyr-
roles (4n0) in 71% yield (1:1.2). When Ugi adduct deriva-
tives bearing 3-indoleacetic or 3,4-dimethoxyphenylacetic
acids were submitted to the same cycloisomerization
conditions, we observed similar results: a mixture of the
isomeric dihydropyrroles 4o and 4o0, as well as 4p and
4p0, were obtained after purification by flash column
chromatography.
Table 1. Optimization of the Reaction Conditions
Scheme 2. Synthesis of 2,3-Dihydropyrroles
entry
t-BuOK (equiv)
time (h)
yield 4aa (%)
1
2
3
4
5
6
7
0.2
1.0
2.5
2.5
2.5
2.5
3.0
12
trace
trace
51
12
0.5
2.5
3.5
6.5
2.5
71
57
39
53
a Yields given are those of the isolated pure products.
With the optimal conditions in hand, we evaluated the
scope of the methodology on a wide variety of Ugi adducts
obtained similarly to 3a (See Supporting Information).
The use of different substituted benzoic acids 8 (R2) were
surveyed (Scheme 2). o-Iodo and o-bromo substituents
both gave good yields of the N-acylated 2,3-dihydropyr-
roles (4a,b). Polyoxygenated systems (4d,e), an unsubsti-
tuted variant 4c, as well as a methyl group 4g were well
tolerated in the reaction. The use of an aliphatic acid, such
as acetic acid, in the Ugi reaction resulted in a modest yield
of the expected product 4f. We then conducted a prelimin-
ary investigation of the scope of substituted benzaldehydes
(R1) and observed a strong influence of electron-with-
drawing groups on the yield of the product. While
p-bromo- 4h and p-fluoro-substituted 4i products were
obtained in moderate yields, the presence of the trifluor-
omethyl group considerably reduced the yield (4j, 20%),
and a p-nitro group completely hampered the reaction
(3q, 0%). Apparently, the putative anion intermediate
(Scheme 1) is rapidly generated as a result of the effect of
the electron-withdrawing group, obstructing the allena-
mide formation.21 The best results were observed when
electron-donating groups were present on the aromatic
ring (2kꢀm). The use of cyclohexyl isocyanide instead
of tert-butyl isocyanide resulted in the formation of an
a Yields of Ugi-4CR adducts.
Although we currently have no logic explanation for this
putative isomerization, the data in Scheme 2 nevertheless
demonstrates that a variety of diversely substituted 2,3-
dihydropyrroles could be prepared using the two-step
protocol described herein. The structures of compounds
4a, 4h, and 4l were confirmed by an X-ray analysis.22
Interestingly, allenamide intermediate B was not ob-
served in all of the experiments described under catalytic
conditions or in the stoichiometric reactions. However,
when the 6-bromopiperonal propargyl-Ugi adduct 3r was
(22) CCDC895604 (4a), CCDC895647 (4h), CCDC895648 (4l), and
CCDC895649 (11) contain the supplementary crystallography data for
this paper. Copies of these data can be obtained, free of charge, from the
Cambridge Crystallographic Data Center via www.ccdc.cam.ac.uk/
data_request/cif.
(21) Moutiers, G.; El Fahid, B.; Goumont, R.; Chatrousse, A. P.;
Terrier, F. J. Org. Chem. 1996, 61, 1978.
5410
Org. Lett., Vol. 14, No. 21, 2012

submitted to the same base-induced cycloisomerization,
the major product observed was the corresponding allena-
mide 9, supporting its intermediacy in the process. Appar-
ently, the presence of the o-bromo substituent exerts a
strong steric hindrance in the vicinity of the intermediate
anion, preventing its cyclization onto the allenamide dou-
ble bond (Scheme 3).
Scheme 4
Scheme 3
The 2,3-dihydropyrroles obtained using this modular
approach might be useful as building blocks for the con-
struction of more complex molecules if the starting materi-
als are suitably functionalized for further transformations
prior to introduction into theUgi process. Forinstance, the
pyrrolo[2,1-a]isoindolone23 10 was obtained in good yield
when 4b was subjected to typical Heck conditions24 (three-
step synthetic sequence from a commercial Ugi four-
component set). Furthermore, the dihydropyrrole 4a was
transformed into the N-acyl-2-aryl prolinamide 1119 by
simply reducing the double bond using triethylsilane hy-
dride as the reductant (Scheme 4). It is important to note
that this three-step protocol constitutes an easy entry to the
pharmacologically important 2-arylproline derivatives25
In conclusion, a two-step synthesis of 2,3-dihydropyr-
roles via a formal 5-endo cycloisomerization of Ugi 4-CR/
propargyl adducts is described. The convergent character,
atom economy, operational simplicity, and the structural
diversity of the resulting dihydropyrroles make this proto-
col attractive for both the construction of libraries of
molecules of this kind in the search for diverse biological
properties, and also for their use as building blocks in the
construction of more complex molecules. In this two-step
sequential protocol, simple starting materials are trans-
formed into not-easily anticipated, more complex molecules
by creating several bonds. It is worth noting that the atom
economy of this protocol is almost perfect; only one H2O
molecule (in the imine formation) is lost from the starting
Ugi four-component set to the final dihydropyrrole.
Acknowledgment. Financial support from CONACYT
(167092) is gratefully acknowledged. We also thank R.
~
~
~
Patino, A. Pena, E. Huerta, I. Chavez, R. Gabino, H.
ꢀ
´
a-Rios, L. Velasco, and J. Perez for technical support
Garcı
and A. Toscano and S. Hernandez-Ortega for X-ray
crystallography (Instituto de Quımica UNAM). L.A.P.G
(23) Deok-Chan, H.; Chang-Soo, Y.; Eusun, Y. Tetrahedron Lett.
1996, 37, 2577.
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(b) Wada, Y.; Nishida, N.; Kurono, N.; Ohkuma, T.; Orito, K. Eur. J.
Org. Chem. 2007, 4320. (c) Sato, Y.; Nukui, S.; Sodeoka, M.; Shibasaki,
M. Tetrahedron 1994, 50, 371. (d) Nukui, S.; Sodeoka, M.; Shibasaki, M.
Tetrahedron Lett. 1993, 34, 4965. (e) Kiewel, K.; Tallent, M.; Sullikowski,
G. A. Tetrahedron Lett. 2001, 42, 6621. (f) Onozaki, Y.; Kurono, N.;
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is a CONACYT (223857) graduate scholarship holder.
Supporting Information Available. Experimental pro-
cedures, NMR spectra, and characterization for all new
materials. This material is available free of charge via the
Internet at http://pubs.acs.org.
~
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The authors declare no competing financial interest.
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