Three-component access to pyrroles promoted by the CAN-silver nitrate system under high-speed vibration milling conditions: A generalization of the Hantzsch pyrrole synthesis

Article abstract of DOI:10.1039/c2cc38099d

A sequential multicomponent process involving the high-speed vibration milling of ketones with N-iodosuccinimide and p-toluenesulfonic acid, followed by addition of a mixture of primary amines, β-dicarbonyl compounds, cerium(iv) ammonium nitrate and silver nitrate afforded polysubstituted, functionalized pyrroles. This one-pot, solid-state process can be considered as the coupling of an α-iodoketone preparation with a general version of the classical Hantzsch pyrrole synthesis.

Full text of DOI:10.1039/c2cc38099d

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Three-component access to pyrroles promoted by the
CAN–silver nitrate system under high-speed vibration
milling conditions: a generalization of the Hantzsch
pyrrole synthesis†‡
Cite this: Chem. Commun., 2013,
49, 591
Received 8th November 2012,
Accepted 26th November 2012
DOI: 10.1039/c2cc38099d
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Veronica Estevez, Mercedes Villacampa and J. Carlos Menendez*
www.rsc.org/chemcomm
A sequential multicomponent process involving the high-speed In spite of the existence of a variety of approaches to substituted
vibration milling of ketones with N-iodosuccinimide and p-toluene- pyrroles, including the classical Knorr, Paal–Knorr and Hantzsch
sulfonic acid, followed by addition of a mixture of primary amines, reactions, their synthesis remains challenging because it often
b-dicarbonyl compounds, cerium(IV) ammonium nitrate and silver poses difficult problems of regioselectivity and is often complicated
nitrate afforded polysubstituted, functionalized pyrroles. This by the low chemical stability of many pyrrole derivatives, which
one-pot, solid-state process can be considered as the coupling of leads to their degradation unless the reaction conditions are
an a-iodoketone preparation with a general version of the classical very mild. Therefore, the efficient synthesis of highly substituted
Hantzsch pyrrole synthesis.
pyrroles remains far from trivial.
In view of its named reaction status, it is surprising that the
Multibond forming reactions are one of the primary strategies Hantzsch pyrrole synthesis has received little attention in the
to be considered in the search for synthetic efficiency. Further- literature. In a study published in 1970, Roomi and MacDonald
more, they are also particularly important in the current effort mentioned that, in spite of the 80 year period elapsed since
for the development of environmentally sustainable synthetic Hantzsch’s original publication, which describes a single
processes, since they avoid the generation of waste from solvents experiment,9 they had located only eight additional examples
and chromatographic stationary phases in the purification of in the literature, proceeding in yields below 45% and allowing
synthetic intermediates.1 Multicomponent reactions (MCRs)2,3 very little structural variation, which was limited to alkyl
are one of the best studied types of multibond forming processes, substituents at C-4 and C-5. These authors extended slightly
but the combination of MCRs and other methodologies aimed at the scope of the reaction and prepared compounds with substitu-
reducing reaction waste is not so common. More specifically, we ents different from methyl at C-2 and esters different from ethyl at
are aware of a single reference that describes a multicomponent C-3, and they also obtained pyrroles with R5 = H. Nevertheless,
reaction under solvent-free, mechanochemical conditions,4 and it yields remained below 50% and the preparation of N-substituted
has the limitation of requiring special equipment with fittings for pyrroles was not possible.10 More recent examples of the
circulating boiling water. The term ‘‘mechanochemistry’’ refers to Hantzsch pyrrole synthesis under traditional conditions still
reactions induced by mechanical energy, including grinding and suffer from these limitations. Recently, three-component varia-
ball milling, and it constitutes an emerging field of synthetic tions of the Hantzsch pyrrole synthesis have been reported
methodology that is particularly relevant because the reactions under non-conventional conditions, but they lack generality. In
are normally performed in the solid state, avoiding or minimizing 1998, Jung et al. reported a solid phase version of the reaction,11
the use of solvents and offering many opportunities for the which allowed the preparation of N-substituted pyrroles (but
development of cleaner synthetic methods.5
not of their unsubstituted counterparts) and was restricted to a
Pyrrole is one of the most important simple heterocycles; it methyl group at C-2 and a carbamoyl at C-3. On the other hand,
can be found as a structural fragment of many natural products6 it allowed the introduction of aryl substituents at C-4 and, in
and drugs such as the top-selling cholesterol-lowering drug one case, at C-5. However, the authors failed to report any
atorvastatin,7 and it is also very important in materials science.8 yields. The latest significant advancement in this area was due
to Herath and Cosford and involved the use of flow conditions,
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Departamento de Quımica Organica y Farmaceutica, Facultad de Farmacia,
Universidad Complutense, 28040 Madrid, Spain. E-mail: josecm@farm.ucm.es;
Fax: +34 913941822; Tel: +34 913941840
which were focused on the preparation of carboxylic acids and
their subsequent transformation into amides, although they
also examined the synthesis of some esters during preparatory
studies. Very high temperatures (200 1C) were required,
although reaction times were short (8 min).12
† This article is part of the ChemComm ‘Mechanochemistry’ web themed issue.
‡ Electronic supplementary information (ESI) available: Experimental
procedures and copies of spectra of all compounds. See DOI: 10.1039/c2cc38099d
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This journal is The Royal Society of Chemistry 2013
Chem. Commun., 2013, 49, 591--593 591

Communication
ChemComm
In the context of our current research into MCRs based on the alkyl (compounds 4b, 4d and 4f–p) secondary alkyl (4c) and
use of b-dicarbonyl building blocks for the synthesis of hetero- dialkylamino (4e). Unsubstituted pyrroles (compounds 4q, r)
cycles, we became interested in realizing the full synthetic were also accessible by employing commercially available ethyl
potential of the Hantzsch synthesis of pyrroles by development 2-aminocrotonate as starting material. The possibility of having
of a new multicomponent protocol13 that overcame its short- R2 substituents different from methyl, including a side chain
comings and allowed it to be regarded as a truly general pyrrole ending in an ester function, was also verified (compounds 4f–h).
synthesis. We also wished this method to proceed under solvent- Regarding the carbonyl function at the pyrrole C-3 position, we
free conditions and, to this end, we decided to use high-speed normally prepared compounds having an ester (4a–h and 4k–r),
vibration milling (HSVM), a ball-milling technique that can be but also demonstrated the possibility of introducing ketone (4i)
performed with very simple and affordable instruments but that and amide (4j) groups. Our method also accommodated the
has found little application in synthesis, especially in terms of preparation of 4,5-disubstituted pyrroles (compounds 4o and
the generation of carbon–heteroatom bonds.14
4p), which is not possible via previous Hantzsch-like strategies.
As shown in Scheme 1, the desired transformation was Finally, a variety of aromatic substituents were introduced at
initiated by the milling-promoted reaction between ketones 1 the pyrrole C-5 position, including phenyl and its derivatives
and N-iodosuccinimide in the presence of p-toluenesulfonic (compounds 4a–j and 4o–r), 2-naphthyl (4k), 3-indolyl (4l) and
acid. After 60 min of operation at a frequency of 20 Hz, a 2-thienyl (4m). It was also possible to have alkyl substituents at
mixture of primary amines 2, b-dicarbonyl compounds 3, 5% of
cerium(IV) ammonium nitrate (CAN)15 and silver nitrate (1 eq.
with respect to 1) was added and milling was continued for an
additional hour under the same conditions, leading to the
formation of desired pyrroles 4. The mechanism of this process
can be rationalized as a sequence of reactions starting from the
initial a-iodination of the starting ketone 1, which was verified
by interrupting one of the reactions at this stage and identifying
the corresponding intermediate I. The CAN-catalyzed reaction
between the primary amine 2 and the b-dicarbonyl compound 3
affords the corresponding b-enaminone II,16 which then reacts
with I to give III and a molecule of HI, which is trapped by silver
nitrate. In the absence of silver nitrate, the liberated HI reacts
with intermediate I, leading to its reductive dehalogenation to
the starting compound 1 and lowering the yield of pyrrole.17
A
final cyclocondensation, with loss of a molecule of water, affords
the pyrrole products 4. The intermediacy of II was proved by the
fact that an experiment starting from an isolated b-enaminone
led to the same result as the multicomponent reaction.
The scope of the pyrrole synthesis was much broader than
the one described in the literature for previous variations of the
Hantzsch reaction. As shown in Fig. 1, our method could be
adapted to the preparation of pyrroles bearing the following
types of substituents at nitrogen: aryl (compound 4a), primary
Fig. 1 Scope of the pyrrole synthesis. aThe a-iodoketone derivatives were isolated
from 1 and I2 in the presence of CuO (4l and 4m)18 or by a-bromination of 1 with
19
Scheme 1 Sequential three-component pyrrole synthesis.
592 Chem. Commun., 2013, 49, 591--593
HBr/H2O2 followed by exchange with NaI (4p).
c
This journal is The Royal Society of Chemistry 2013

ChemComm
Communication
grant GR35/10-A-920234) and CAM (fellowship to VE) is grate-
fully acknowledged.
Notes and references
1 For a review of multibond forming reactions as a pathway towards
eco-compatible chemistry, see: Y. Coquerel, T. Boddaert, M. Presset,
D. Mailhol and J. Rodriguez, Ideas in Chemistry and Molecular
Sciences, in Advances in synthetic chemistry, ed. B. Pignataro, Wiley-
VCH, Weinheim, vol. 1, ch. 9, 2010.
2 For a recent monograph, see: E. Ruijter and R. V. A. Orru, Synthesis
of heterocycles via multicomponent reactions, vol. 1 and 2, Springer
Verlag, 2010 (Topics in Heterocyclic Chemistry series, volumes
23 and 25).
¨
3 For selected recent reviews, see: (a) A. Domling, Chem. Rev., 2006,
Fig. 2 Compounds obtained in pseudo five-component double Hantzsch-like reactions.
´
106, 17; (b) B. B. Toure and D. G. Hall, Chem. Rev., 2009, 109, 4439;
(c) E. Ruijter, R. Scheffelaar and R. V. A. Orru, Angew. Chem., Int. Ed.,
2011, 50, 6234; (d) H. Eckert, Molecules, 2012, 17, 1074;
(e) C. de Graaff, E. Ruijter and R. V. A. Orru, Chem. Soc. Rev.,
2012, 41, 3969.
4 S. Mashkouri and M. R. Naimi, Molecules, 2009, 14, 474.
5 For a review, see: S. L. James, C. J. Adams, C. Bolm, D. Braga,
C-5, as shown by the preparation of compound 4n. In all cases,
the reactions were complete after 2 h at room temperature and
normally proceeded in good to excellent yields.
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In order to further prove the flexibility of the method for the
generation of molecular complexity, we examined two types of
pseudo five-component reactions leading to the generation of
two pyrrole rings. In the first example, use of 1,10-(biphenyl-
4,40-diyl)diethanone (1 eq.), ethyl acetoacetate (3 eq.) and butyl-
amine (3 eq.) as the starting materials afforded the quater-aryl
derivative 4s in an excellent 94% yield. Double Hantzsch-like
reactions based on the use of diamines as starting materials
were also possible. Thus, the reaction involving ethylenediamine
P. Collier, T. Friscic, F. Grepioni, K. D. M. Harris, G. Hyett, W. Jones,
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10 M. W. Roomi and S. F. MacDonald, Can. J. Chem., 1970, 48, 1689.
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13 For a review of the synthesis of pyrroles by multicomponent
compound 4t in 60% yield (Fig. 2).
´
´
strategies, see: V. Estevez, M. Villacampa and J. C. Menendez, Chem.
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In conclusion, we have developed a sequential multicomponent
synthesis of polysubstituted, functionalized pyrroles under solvent- 14 For the use of HSVM in the formation of C–C bonds, see:
´
(a) B. Rodrıguez, A. Bruckmann, T. Rantanen and C. Bolm, Adv.
free mechanochemical conditions and using ketones, primary
amines and b-dicarbonyl compounds as building blocks. This
one-pot process proceeds entirely in the solid-state and can be
viewed as the coupling of a-iodoketone preparation with a general
version of the classical Hantzsch pyrrole synthesis. Furthermore, it
Synth. Catal., 2007, 349, 2213; (b) for a general review of the use of
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15 For a review of the use of CAN as a catalyst in organic synthesis, see:
´
V. Sridharan and J. C. Menendez, Chem. Rev., 2010, 110, 3805.
is the first multicomponent reaction carried out under high-speed 16 CAN catalysis allows the very fast generation of b-enaminones from
˜
amines and b-dicarbonyl compounds: V. Sridharan, C. Avendano
vibration milling conditions using a simple instrument without
temperature control and with the sole input of mechanical energy.
Our protocol proceeded in a 77% average yield for the 20 examples
studied, generating one cycle, one C–C and two C–N bonds.
Financial support from MICINN (grants CTQ2009-12320-
´
and J. C. Menendez, Synlett, 2007, 2133.
17 For precedent of a related reductive dehalogenation of a phenacyl
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BQU and CTQ2012-33272), UCM (Grupos de Investigacion,
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c
This journal is The Royal Society of Chemistry 2013
Chem. Commun., 2013, 49, 591--593 593