Synthesis of functionalized pyrroles via catalyst- and solvent-free sequential three-component enamine-azoene annulation

Article abstract of DOI:10.1021/jo200287k

A new and efficient synthesis of polysubstituted pyrroles by a sequential one-pot three-component reaction between primary aliphatic amines, active methylene compounds, and 1,2-diaza-1,3-dienes (DDs) is reported. The reactions were performed without catalyst and under solvent-free conditions with complete control of pathway selectivity. Notably, the ready availability of the starting materials and the high level of practicability of the reaction and work up make this approach an attractive complementary method for access to unknown polysubstituted pyrroles.

Full text of DOI:10.1021/jo200287k

ARTICLE
pubs.acs.org/joc
Synthesis of Functionalized Pyrroles via Catalyst- and Solvent-Free
Sequential Three-Component EnamineꢀAzoene Annulation
Orazio A. Attanasi, Gianfranco Favi,* Fabio Mantellini, Giada Moscatelli, and Stefania Santeusanio
Istituto di Chimica Organica, Universitꢀa degli Studi di Urbino “Carlo Bo”, Via I Maggetti 24, 61029 Urbino, Italy
S Supporting Information
b
ABSTRACT: A new and efficient synthesis of polysubstituted
pyrroles by a sequential one-pot three-component reaction
between primary aliphatic amines, active methylene compounds,
and 1,2-diaza-1,3-dienes (DDs) is reported. The reactions were
performed without catalyst and under solvent-free conditions
with complete control of pathway selectivity. Notably, the ready
availability of the starting materials and the high level of practic-
ability of the reaction and work up make this approach an
attractive complementary method for access to unknown poly-
substituted pyrroles.
’ INTRODUCTION
natural products, and precursors of chiral amines upon asym-
metric transformations. Among them, β-enaminones and related
compounds represent versatile and useful building blocks for the
construction of heterocyclic scaffolds, such as pyrrole, pyrazole,
piperidine, 1,4-dihydropyridine, pyridinone, pyrimidine, isoxa-
zole, indole, 1,5-benzodiazepine, quinoline derivatives, etc.12,13
On the other hand, the potential value of the 1,2-diaza-1,3-
dienes (DDs)14 in synthetic chemistry is derived mainly from
their ready availability and unique reactivity. The chemistry of
DDs, especially their behavior with various secondary enamines
(used as enolate equivalents), has been a well-investigated area of
research over the years. Earlier works reported by Sommer
account for [3 þ 2] and [4 þ 2] cycloaddition reactions of
several 4-alkoxycarbonyl-DDs with cyclopentanone-derived en-
amines and 9-vinylcarbazole, giving rise, in low to moderate
yields, to octahydro-cyclopenta[b]indole and 9-pyridazin-3-yl-
9H-carbazole.15 South et al. reported the synthesis and reactions
of 4-chloro- or 4,4-dichloro-DDs as a new and general method
for access to 1,2,5,6-tetrahydropyridazines.16 In addition, regio-
and stereoselective one-pot protocols for the synthesis of highly
functionalized 1-aminopyrrolines and oxazoline-fused 1-amino-
pyrrolines or oxazoline-fused pyridazines have been reported
starting from 4-alkoxycarbonyl- or 4-chloro-DDs and 3-dimeth-
ylaminopropenoates.17 Finally, a solvent-dependent, divergent
synthesis of various functionalized pyrroles and pyridazines
starting from 4-alkoxycarbonyl-DDs with enamines β-, β,β-,
and R,β-substituted with simple alkyl and/or aryl groups was
also described.18
The rapid assembly of complex molecules from simple pre-
cursors in a one-pot procedure has attracted the interest of the
organic chemistry community over recent decades. In this regard,
sequential processes1ꢀ3 that incorporate “green chemistry”
values such as atom, time, and labor economies, resource
management, and minimal chemical waste generation maintain
a privileged status. Because of the importance of heterocycle-
based compounds including biologically active agents, compo-
nents in polymers, and intermediates, pyrroles4 are considered
one of the most important classes. Accordingly, substantial
attention has been paid to developing efficient methods for their
synthesis. The most frequently used methods include the classi-
cal Hantzch procedure,5 the cyclocondensation of R-aminoke-
tones with β-ketoester or β-diketones (Knorr synthesis),6 the
cyclocondensation of primary amines with 1,4-dicarbonyl com-
pounds (PaalꢀKnorr synthesis),7 and various cycloaddition and
transition-metal-catalyzed cyclization strategies.8,9 Many of these
procedures, however, have certain restrictions in terms of the
scope and placement of the substitution pattern around the
heterocycle core. We were surprised to discover that relatively
few methods for the synthesis of the 3,4-EWG-substituted
pyrrole system exist in the literature considering the importance,
for example, of pyrrole-3,4-dicarboxylic acid derivatives in med-
icinal and material/surface attachment chemistry.9,10 In addition,
many of these reaction conditions require the use of high
temperature or the presence of strong bases/acids and metal
catalysts or produce non-negligible byproducts.
Enamines are valuable structures in organic synthesis.11ꢀ13
They are extensively employed as nucleophiles in Michael-type
additions, intermediates in the synthesis of heterocycles and
Received: February 7, 2011
Published: March 11, 2011
r
2011 American Chemical Society
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Scheme 1. Formation of Pyrroles by Different Aza-annulation
Table 1. Amine Scope in the Synthesis of Pyrroles 4a
Reactions of Primary and Secondary Enamines
A stepwise mechanism that explains the results obtained in
[3 þ 2] cycloaddition reactions of simple secondary enamines with
DDs was reported to involve a transient zwitterionic hydrazone
intermediate generated by C-nucleophilic attack of the enamines at
the terminal carbon of the azoꢀene system.15a,17b,18 Starting from
all these results, we hypothesized that a chemo- and regioselective
reaction of the N-alkylenamine-derived zwitterionic intermediate
could provide a new synthetic pathway for N-alkylaminopyrrole
derivatives.
Thus, we were intrigued by the possible use of the N-
substituted enamines (β-stabilized with electron-withdrawing
groups (EWG1) (e.g., CO2R, CONR2, COSR, SO2R, PO(OR)2)
instead of N,N-disubstituted enamines as a bidentate nucleophile
for aza-annulation reaction with DDs (Scheme 1).
As part of our ongoing research program aimed at developing
metal-free, multicomponent, and diversity-oriented domino-
based syntheses of biologically relevant heterocycles, we report
here a novel, multistep, three-component reaction of primary
aliphatic amines, active methylene compounds, and DDs for the
synthesis of highly functionalized pyrroles.19 In this one-pot
assembly, two independent reactions should occur sequentially: a
condensation of 1,3-dicarbonyl compounds with amines to
produce N-alkylenamine compounds, and an aza-annulation
process to generate pyrrole derivatives through stepwise C-alky-
lation (Michael addition) and N-condensation of the enamine
functionality with DDs.
a For experimental details, see Supporting Information. b Yield of pure
isolated products.
obtained in 65% yield without appreciable formation of dectable
byproduct (Table 1, entry 1). With optimized reaction conditions
in hand, we next examined the scope and limitation of this reaction.
At first, various primary aliphatic amines such as (4-methoxyben-
zyl)amine 1b, n-propylamine 1c, n-butylamine 1d, allylamine 1e,
1-amino-2-propanol 1f, 1-amino 2-acetaldehyde diethyl acetal 1g,
and cyclohexylamine 1h were used and effectively converted into
the corresponding substituted pyrroles 4(bꢀh)aa. Substantially,
the nature of the used amines had little influence on the reaction
efficiency, and generally excellent yields were obtained (Table 1,
entries 1ꢀ8).
’ RESULTS AND DISCUSSION
To realize a single-pot process by subsequent addition of
reactants, we first developed the preparation of enamino inter-
mediates. Although this transformation has been reported to
proceed in the presence of various Brønsted or Lewis acids,20 we
found that it occurred well also in the absence of catalyst by using
solvent-free conditions. In fact, treatment of benzylamine 1a with
ethyl acetoacetate 2a under neat conditions at room temperature
produced the corresponding enamino ester AI in exclusively Z
form21 (see Supporting Information). The 1H NMR spectra of the
crude reaction mixture were very clean, indicating that the reaction
took place quantitatively. As the next step, we attempted to
combine the enamino ester formation with the subsequent aza-
annulation process. After formation of the corresponding enam-
inone compound from benzylamine 1a and ethyl acetoacetate 2a,
1.0 equiv of DD 3a was added directly to the reaction mixture under
the same reaction conditions. To our delight, after the mixture was
stirred 10 min at room temperature, the desired pyrrole 4aaa was
Because the activity of aromatic amines was lower than that of
aliphatic amines in the aza-heterocyclization, unfortunately, the
reactions with both electron-deficient/electron-rich substituent-
containing anilines (R = Ph, p-Me(C6H5), p-OMe(C6H5),
p-Br(C6H5)) did not provide the pertinent pyrroles.
Moreover, to expand the scope of this reaction with respect to
active methylene substrates, a range of active methylene com-
pounds 2bꢀl containing ketone groups were surveyed for this
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Table 2. Active Methylene Compounds Scope in the Synthesis of Pyrroles 4a
a For experimental details, see Supporting Information. b Yield of pure isolated products.
reaction (Table 2, entries 1ꢀ10). The methyl acetoacetate 2b,
ethyl 3-oxopentanoate 2c, and allyl acetoacetate 2d also worked
well to give analogous pyrroles 4aba, 4eca, and 4cda (entries 1ꢀ3).
N,N-Diethyl-3-oxobutanamide 2e, 4-morpholin-4-yl-4-oxobutan-
2-one 2f, N-(4-methoxyphenyl)-3-oxobutanamide 2g, and N-(4-
chlorophenyl)-3-oxobutanamide 2h furnished the corresponding
pyrroles 4dea, 4dfa, 4aga, and 4aha in good yields (entries 4ꢀ7).
Interestingly, β-ketothioester 2j also provides the corresponding
pyrrole 4aja (entry 8). Additionally, pyrroles 4dka and 4dla were
also obtained with both β-ketosulfone, namely 1-[(4-chlorophe-
nyl)sulfonyl]acetone 2k, and β-ketophosphones, namely dimethyl
acetylmethylphosphonate 2l (entries 9 and 10), albeit in moderate
yields. For these reactions, an appreciable amount of side-products
in both enamino compound formation and the aza-heterocyclization
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Table 3. DDs Scope in the Synthesis of Pyrroles 4a
a For experimental details, see Supporting Information. b Yield of pure isolated products.
process were detected. Besides, use of both aliphatic and aromatic
1,3-diketones was unsuccessful, leading to a complicated mixture of
products.22
The structures all of the substituted pyrroles were unambigu-
ously characterized by 1H and 13CNMR, IR, and MS and
unequivocally confirmed by comparison of pyrrole-3,4-dicarb-
oxylate 4abe with the same compound previously reported by
Yu et al.23
Variations in all three components were accommodated very
comfortably in this sequential three-component reaction, gen-
erating good to high yields of the functionalized pyrroles. Thus,
pyrroles substituted with EWG-containing functional groups at
the C-3 and C-4 positions of the heterocyclic ring such as
Lastly, the scope of this methodology was further broadened
by using several azoene partners. Additional DDs 3bꢀh differ-
ently substituted (Table 3, EWG2 = COX; X = OMe, OEt, NEt2,
morpholinyl, NHPh; PO(OMe)2; R2 = Me, Ph, CH2CO2Me;
R3 = CO2Y; Y = Me, t-Bu) were compatible with this protocol. A
series of 3,4-EWG-substituted pyrroles were so obtained in
satisfactory yields (Table 3, entries 1ꢀ8).
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Scheme 2. Mechanistic Rationale for the Synthesis of Pyrrole Derivatives
carboxylic acid derivatives (both symmetrical and unsymmetrical
dicarboxylate scaffold) (ester, amide, and/or thioester), sulfone,
and phosphonate moiety can be directly obtained. Among them,
phosphonylpyrroles could be very interesting compounds be-
cause C-phosphorylated heterocycles are known to regulate
important biological functions and increase the biological activ-
ity, in similar way to that reported for other pharmaceuticals.24 In
addition, it should be noted that the presence of multiple points
of derivatization onto the pyrrole skeleton provides opportunity
for further synthetic manipulations, for example, to their fused
aza-heterocycles.
Although the behavior of DDs with various enamines has been
extensively investigated so far, no example of N-alkylpyrrole 4 using
N-monosubstituted enamines/enaminones are known. In fact,
even if a large number of modifications of the enamine reagent
have been explored, the studies were restricted to the use of
secondary amine-derived enamine.15a,17b,18 For these reactions,
the accepted mechanism of generation of aminopyrrole derivative 5
has been hypothesized to involve as a key step the formation of the
zwitterionic transient species of type B (Scheme 2).
Based on these results, a plausible mechanism for the sequen-
tial three-component reaction was proposed (Scheme 2). In the
first step, the formation of enamino ester A occurs through
condensation of amine 1 with active methylene compound 2.
Next, 1,4-nucleophilic addition of A to the azo-ene system of DD
3 produces the nonisolable zwitterionic adduct intermediate B,
that promptly afforded 5-alkylhydrazino-pyrroline-3-carboxylic
acid derivatives C by an intramolecular azacyclization via tauto-
merization CH/NH or 1,3-hydrogen shift. In turn, C aromatizes
into the N-alkylpyrrole 4 by loss of the hydrazine residue (path a,
Scheme 2).
The exclusive formation of N-alkylpyrrole 4 rather than
1-aminopyrrole 5 may be explained by the light of the nature
of the enamine component. In fact, as expected, the use of A by
introduction of a primary amine has a strong influence on the
position of iminium/enamine equilibrium in B favoring the intra-
molecular nucleophilic attack of the NH bond of enamine (derived
from 1,3-H5 shift) across the unsaturated CdN bond of a hydrazone
function (path a) to give stable aromatic compound 4. This
occurrence would be assisted from the presence of EWG1 group
in the R-position to the iminium functionality (intermediate B).
Alternatively, the tautomerization of intermediate B via pro-
totropism CH/NH idrazono/hydrazino form (derived from 1,3-
H4 shift) before cyclization process (path b, Scheme 2) remains
the generally accepted mechanism when simple N,N-disubsti-
tuted enamine and DD 3 are used.15a,17b,18
Generally, the solvent-free reaction is experimentally simple,
proceeds well without any catalyst, and generates virtually no
byproducts. In all cases, N-alkylpyrrole 4 was obtained as a single
product without concurrent formation of N-aminopyrrole 5
issued from the alternative pathway. From our study we have
revealed that the nature of the amine (hence enamine) compo-
nent plays a crucial role in aza-annulation reaction. This approach
differs from previously reported strategies, as primary enamines
were preformed as nucleophiles for heterocycle formation in-
stead of secondary enamines. More precisely, when the N,N-
disubstituted enamines were replaced with N-substituted enam-
ines, the desired N-alkylpyrroles were obtained with complete
reversal of the aza-annulation process. Thus, the chemoselec-
tivity outcome can be modulated simply by tuning the nature of
the enaminic components, and EWG substituents at C-3 and C-4
of the pyrrole synthesized can be introduced as well by starting
from the appropriately materials 2 and 3. It is important to note
that in the formation of N-alkylpyrrole 4, the nitrogen atom of
the heterocycle ring is derived from amine component 1, and two
carbons come from active methylene compound 2, while the
remaining two carbons come from C-3 and C-4 of the DD 3.
Particularly, with respect to the use of secondary enamines, the
methodology here described permits an additional, easy diversi-
fication of the nitrogen substituents by choosing suitable primary
amines.
’ CONCLUSION
In summary, we have reported a novel, efficient, and practical
one-pot procedure for the preparation of functionalized pyrroles
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through a sequential three-component reaction of primary
aliphatic amines, active methylene compounds, and DDs. This
method circumvents some of the problems and limitations
associated with frequently used procedures, is advantageous in
terms of simplicity and mildness, and hopefully could find wide
application in the synthesis of complex pyrrole-containing com-
pounds. Notably, this environmentally friendly single flask
approach avoids transition-metal catalysts, employs readily avail-
able materials, and occurs with complete control of pathway
selectivity. Current studies to extend this methodology, including
the use of other nucleophilic partners, are actively underway.
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’ EXPERIMENTAL SECTION
General Methods. Reagent and solvent purification, work up
procedures, and analyses were performed in general as described in
Supporting Information.
General Procedure for the Catalyst- and Solvent-free Sequential
Three-Component Reaction of Primary Amines 1, 1,3-Dicarbonyl
Compounds 2, and DDs 3. Synthesis of N-Alkylpyrroles 4. A mixture
of amine 1 (1 mmol) and active methylene compound 2 (1 mmol) was
stirred under solvent-free conditions at room temperature for 15 min to
1
48 h (TLC and H NMR monitoring). Then, DD 325 (1 mmol) was
added, and the reaction was stirred until the disappearance of the starting
materials (over 5ꢀ10 min, monitored by TLC). The crude mixture was
purified by column chromatography on silica gel to afford the product 4.
Spectroscopic data for representative alkylpyrroles are given below.
Ethyl 1-Benzyl-4-[(dimethylamino)carbonyl]-2,5-dimethyl-1H-pyr-
role-3-carboxylate (4aaa). N-Alkylpyrrole 4aaa was isolated by column
1
chromatography (ethyl acetate) in 65% yield. White waxy; H NMR
(400 MHz, DMSO-d6, 25 °C): δ = 1.17 (t, J = 7.2 Hz, 3H), 1.94 (s, 3H),
2.37 (s, 3H), 2.76 (s, 3H), 2.91 (s, 3H), 4.01ꢀ4.15 (m, 2H), 5.15 (s,
2H), 6.91 (d, J = 7.2 Hz, 2H), 7.25 (t, J = 7.2 Hz, 1H), 7.34 (t, J = 7.2 Hz,
2H); 13C NMR (100 MHz, DMSO-d6, 25 °C): δ = 10.0 (q), 10.9 (q),
14.1 (q), 34.0 (q), 37.7 (q), 46.2 (t), 58.8 (t), 108.4 (s), 117.5 (s), 125.6
(d), 127.2 (d), 128.9 (d), 134.9 (s), 137.1 (s), 163.8 (s), 167.1 (s); IR
(nujol): νmax = 1701, 1632, 1545, 1262, 1162, 1084 cmꢀ1; MS m/z (%):
328 (Mþ) (55), 313 (5), 284 (100), 268 (4), 256 (43), 240 (22), 237
(17), 211 (11). Anal. Calcd for C19H24N2O3 (328.41): C 69.49, H 7.37,
N 8.53. Found: C 69.61, H 7.26, N 8.42.
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’ ASSOCIATED CONTENT
S
Supporting Information. Experimental and characteriza-
b
tion details. This material is available free of charge via the
Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
*E-mail: gianfranco.favi@uniurb.it.
’ ACKNOWLEDGMENT
This work was supported by the financial assistance from the
Ministero dell’Universitꢀa, dell’Istruzione e della Ricerca (MIUR)ꢀ
Roma and the Universitꢀa degli Studi di Urbino “Carlo Bo”.
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(20) A variety of catalysts such as HCl, H2SO4, PTSA, AcOH,
HClO4, TMSOTf, montmorillonite K10, I2, BF3 Et2O, InBr3, Yb-
3
(OTf)3, Bi(TFA)3, Al2O3, silica gel, Zn(ClO4)2 6H2O, CeCl3 7H2O,
3
3
FeCl3 6H2O, NaAuCl4, CAN, and natural clays have been employed for
3
enamination of β-dicarbonyl compounds. See, for example: Zhang,
Z.-H.; Yin, L.; Wang, Y.-M. Adv. Synth. Catal. 2006, 348, 184ꢀ190
and references cited herein.
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