A diversity-oriented strategy for the construction of tetrasubstituted pyrroles via coupled domino processes

Article abstract of DOI:10.1021/ja047396p

A new microwave-assisted rearrangement of 1,3-oxazolidines scaffolds is the basis for a new, metal-free, direct, and modular construction of tetrasubstituted pyrroles from terminal-conjugated alkynes, aldehydes, and primary amines. This new reaction manif

Full text of DOI:10.1021/ja047396p

Published on Web 06/19/2004
A Diversity-Oriented Strategy for the Construction of Tetrasubstituted
Pyrroles via Coupled Domino Processes
David Tejedor,†,‡ David Gonza´lez-Cruz,† Fernando Garc´ıa-Tellado,*,†
Jose´ Juan Marrero-Tellado,‡,§ and Mat´ıas Lo´pez Rodr´ıguez§
Instituto de Productos Naturales y Agrobiolog´ıa, Consejo Superior de InVestigaciones Cient´ıficas, AVenida
Astrof´ısico Francisco Sa´nchez 3, 38206 La Laguna, Tenerife, Canary Islands, Spain, Instituto Canario de
InVestigacio´n del Ca´ncer, and Instituto UniVersitario de Bioorga´nica Antonio Gonza´lez, UniVersidad de La Laguna,
AVenida Astrof´ısico Francisco Sa´nchez 2, 38206 La Laguna, Tenerife, Canary Islands, Spain
Received May 4, 2004; E-mail: fgarcia@ipna.csic.es
Domino processes have received great attention from the
chemical community because they address fundamental principles
of synthetic efficiency and reaction processing.1 Over the last four
years, we have been involved in a research program aimed at
developing metal-free and diversity-oriented domino-based syn-
theses of biologically relevant heterocyclic scaffolds.2 Our design
principle is based on the expected multiplicative effect on molecular
complexity achieved by a chain of two or more coupled domino
processes in the same reaction vessel. This approach requires a
careful design of each of the participant domino processes. To be
coupled in a chain manner, each domino process must generate a
suitably functionalized molecule able to be simultaneously engaged
in the subsequent complexity-generating domino process and so
on. Additionally, the whole process would be performed in a format
amenable for application in combinatorial chemistry. Experimen-
tally, the transformation of this concept in a one synthetic step
strategy is not a simple task because of the unattainable kinetic
tuning of each of the numerous chemical reactions involved. A more
feasible approach should consist in the transformation of this
concept in a one-pot synthetic strategy. In this new scenario, the
consecutive coupled domino processes should be performed one
at a time and linked in a one-pot operation. In a first experimental
approach, we chose the simple model shown in eq 1, addressing
the synthesis of polysubstituted pyrroles. The protocol combines
two coupled domino processes: the trialkylamine-catalyzed syn-
thesis of enol-protected propargylic alcohols 12 (domino I) and their
sequential transformation into pyrroles 3 (domino II). The key for
this transformation came from a serendipitously discovered spon-
taneous rearrangement of 1,3-oxazolidines 2 to pyrroles 3.
syntheses of these heterocycles. Among the plethora of methods
available for pyrrole construction,3 metal-based strategies5 and 1,3-
dipolar cycloadditions6 have received the most attention. In contrast,
the number of examples reported in the literature dealing with metal-
free, modular, and direct syntheses of these heterocycles is scarce.7
Therefore, there is a clear demand for new metal-free, modular,
and direct synthetic protocols with atom economy, easy reaction
processing, general applicability, and environmental care perfor-
mance.
1,3-Oxazolidines 2 are readily obtained in a one-pot manner by
the ytterbium-catalyzed reaction8 of the conjugated alkynoates 1
and primary amines (eq 2). Pure 1,3-oxazolidines 2 rearrange to
pyrroles 3 when they are stored on the bench without solvent (eq
2). This rearrangement is very slow at room temperature and needs
months to be completed.9 While heating speeds up this process from
months to hours (see Supporting Information for full details),
microwaVe (µυ)-irradiation assists this rearrangement, reducing
the reaction time from hours to minutes. As an example, µυ-
irradiation (900 W) of a sample of 2i absorbed on silica gel (1 g
silica gel/mmol) (neat 2 is transparent to µυ-irradiation) for 5 min
in a domestic µυ-oven cleanly afforded the 1,2,3,4-tetrasubstituted
pyrrole 3i in 78% yield with traces of the decarboxylated derivative
4. This result proved to be general for all of the oxazolidines
assayed. After some experimentation, we found that tetrasubstituted
pyrroles 3 could be directly synthesized from scaffolds 1 and the
primary amines by µυ-irradiation of a silica gel absorbed mixture
of both components (eq 2; Table 1). Overall, this transformation
constitutes a solVent-free domino process inVolVing a 1,3-oxazo-
lidine synthesis and its subsequent skeletal rearrangement. The
process is general for the amine (entries 1-7) and tolerates a range
of functionalities in the aldehyde (entries 8-16). Even aniline, a
bad nucleophile, transforms alkynoate 1a into oxazolidine 3b (entry
2). R-Oxygenated aldehydes afford conjugated alkynoates 1p and
pyrroles 3p with moderate efficiency (entry 16).
Polysubstituted pyrroles are common pharmacophores of numer-
ous natural antibiotics and alkaloids,3 and they have also found
applications in the field of material chemistry.4 These properties
are of considerable interest in the development of new efficient
The complete synthetic protocol was performed by linking the
two coupled domino processes involved (domino I and domino II)
in a one-pot manner (Figure 1; Table 1). Overall, these two linked
and coupled domino processes build up two carbon-carbon bonds,
† Consejo Superior de Investigaciones Cient´ıficas.
‡ Instituto Canario de Investigacio´n del Ca´ncer (www.icic.es).
§ Universidad de La Laguna.
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8390
J. AM. CHEM. SOC. 2004, 126, 8390-8391
10.1021/ja047396p CCC: $27.50 © 2004 American Chemical Society

C O M M U N I C A T I O N S
Table 1. Synthesis of Pyrroles 3 from Conjugated Alkynoates 1
Finally, selective hydrolysis of the aliphatic ester generates an
additional point for functional diversity on the pyrrole molecule
(see Supporting Information for full details).
(Domino)a and from Alkyl Propiolate and Aldehydes (One-Pot)b
1
c
entry
Z
R
R
1 (%)
domino
one-potc
In summary, we have developed a metal-free, modular, and direct
synthesis of 1,2,3,4-tetrasubstituted pyrroles from simple and
commercially available components. The synthetic protocol embod-
ies two coupled domino processes and is neatly accomplished in a
one-pot manner according to the new chemical efficiency para-
digm.10 We believe that this method will have a significant
application in the fields of combinatorial chemistry, diversity-
oriented synthesis, and drug research.
1
2
3
4
5
6
7
8
9
CO2Me Et
CO2Me Et
CO2Me Et
Bn
Ph
pOMe-Ph
pOMe-Ph
Bn
(S)PhCHMe
amino acide
Bn
1a (87) 3a (74)
3b (38)d
(44)
3c (56)d
CO2Et
CO2Et
Et
Et
3dd
(53)
(51)
(47)
(42)
1e (88)
3e (77)
3f (72)
3g (69)
CO2Me Et
CO2Me Et
CO2Et
Me
1h (73) 3h (76)
CO2Me Hex
Bn
Bn
1i (76)
3i (61)
10 CO2Et
11 CO2Et
12 CO2Et
13 CO2Et
14 CO2Me iPr
15 CO2Et
16 CO2Et
Hex
3j
(47)
(41)
(49)
(46)
3-butenyl Bn
1k (79) 3k (60)
1l (68) 3l (65)
1m (85) 3m (63)
1n (81) 3n (58)
1o (72) 3o (70)
1p (41) 3p (55)
Acknowledgment. Dedicated to Professor AÄ ngel Gutie´rrez
Ravelo on the occasion of his 62nd birthday. This research was
supported by the Spanish MEC (PPQ2002-04361-C04-03). F.G.T.
and D.T. thank the Instituto Canario de Investigacio´n del Ca´ncer
for financial support (ISCiii, RTICCC C03/10). D.G.C. thanks the
Spanish MEC for an FPI grant. F.G.T. thanks Dr. P. de Armas and
Prof. V. S. Mart´ın for helpful comments on this work.
cit.f
Bn
Bn
Bn
Bn
iPr
cPr
(46)
BnOCH2 Bn
a
Conjugated alkynoate 1 (1 mmol) and the amine (1.3 mmol) were
b
absorbed on 1 g of silica gel and irradiated at 900 W for 8 min;
(1)
Aldehyde (1 mmol), alkyl propiolate (2 mmol), Et3N (0.5 mmol), 0 °C, 30
min. (2) silica gel (1 g), amine (1.3 mmol). (3) µυ-irradiation (900 W), 8
Supporting Information Available: Crystallographic data of 3n
(CIF) and experimental preparations for 1a-p, 3a-p, 5, and 6 (PDF).
This material is available free of charge via the Internet at http://
pubs.acs.org.
c
d
min. Yields of isolated pyrroles, in percent. Silica gel (2g) was used.
e
f
Amino acid is ethyl 3-aminobutyrate. Cit. from (S)-(-)-citronellal.
Scheme 1. Proposed Mechanism for the µυ-Assisted
Rearrangement of 1,3-Oxazolidines 2 to Pyrroles 3.
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