A novel assembly of substituted pyrroles by acid-catalyzed sequential three-component reaction of amines, alkynoates, and 1,2-diaza-1,3-dienes

Article abstract of DOI:10.1002/adsc.201100094

A novel protocol for the assembly of polysubstituted pyrroles has been developed through the acid-catalyzed, sequential three-component reaction of primary aliphatic amines, alkynoates and 1,2-diaza-1,3-dienes (DDs). This methodology proceeds with complet

Full text of DOI:10.1002/adsc.201100094

FULL PAPERS
DOI: 10.1002/adsc.201100094
A Novel Assembly of Substituted Pyrroles by Acid-Catalyzed
Sequential Three-Component Reaction of Amines, Alkynoates,
and 1,2-Diaza-1,3-dienes
Orazio A. Attanasi,a Gianfranco Favi,a,* Fabio Mantellini,a Giada Moscatelli,a
and Stefania Santeusanioa
a
Istituto di Chimica Organica, Universitꢀ degli Studi di Urbino “Carlo Bo”, Via I Maggetti 24, 61029 Urbino (PU), Italy
Fax : (+39)-0722-303-441; e-mail: gianfranco.favi@uniurb.it
Received: February 7, 2011; Revised: March 22, 2011; Published online: June 16, 2011
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adcs.201100094.
Abstract: A novel protocol for the assembly of poly- formation of an enamino ester intermediate, in situ
substituted pyrroles has been developed through the Michael addition with azo-ene compounds and sub-
acid-catalyzed, sequential three-component reaction sequent intramolecular ring closure.
of primary aliphatic amines, alkynoates and 1,2-
diaza-1,3-dienes (DDs). This methodology proceeds Keywords: 1,2-diaza-1,3-dienes; Michael addition;
with complete chemo-/regioselectivity involving first pyrroles; regioselectivity; sequential reactions
Introduction
Knorr,[12] and Hantzsch[13] protocols. Pursuing our
long-standing interest in the chemistry of heterocy-
By virtue of their productivity, specificity, facile exe- cles, we have recently reported a novel synthetic
cution and high yields of products avoiding laborious route to highly functionalized pyrroles.[14] Specifically,
purification techniques, sequential reactions offer sig- the process was realized by a preliminary addition of
nificant advantages over classical step-by-step ap- a primary amine to a 1,2-diaza-1,3-diene (DD),[15]
a
proaches allowing the direct synthesis of complex hydroamination reaction with an activated alkyne
molecules from simple precursors in a one-pot opera- producing an a-(N-enamino)-hydrazone and a subse-
tion.[1–3] Consequently, over the past decades, numer- quent Lewis acid-catalyzed ring closure by means of
ous reports on sequential transformations have been intramolecular C-nucleophilic attack to give the pyr-
published.[4] In this context, the concept of combining role heterocycle (El1 +Nu!I1 +El2!4’; Scheme 1,
one set of substrates/reagents for a diverse assembly A).
of functionalized target structures is very attractive,
In connection with these findings, and considering
but largely unexplored. Although substantial effort the mutual reactivity of the reagents, we envisage that
has been directed at the development of diversity-ori- an intriguing modified three-component process in-
ented synthesis (DOS)[5] platforms to construct volving first the combination of an amine with an
heteroACHTUNGTRENNUNGcyclic compounds, a “rational” approach able alkyne and then the reaction with an azo-ene com-
to unite three or more different and independent com- pound could also be worthy of interest. Thus, we pos-
ponents in such a way to divert the regioselectivity in tulate that the amine-alkyne adduct (enamino
the heterocycle formation is still lacking.
ester)[16] I2 could be suitable for a sequential Michael
Among compounds containing nitrogen heterocy- addition and ring closure, directly providing the re-
clic frameworks, regioselectively substituted pyrroles[6] gioisomerically substituted pyrrole. The key step
represent an indispensable structural motif of a large would involve a reactive zwitterionic intermediate
number of natural products,[7] synthetic pharmaceuti- that could cyclize through N-nucleophilic attack upon
cals,[8] and electrically conducting materials.[9] As a 1,3-hydrogen shift (in essence a tautomerization) fur-
consequence, many new synthetic approaches[10] have nishing the corresponding pyrrole derivative
been devised and developed as alternatives to the (El2+Nu!I2 +El1!4; Scheme 1, B).
classical methods represented by the Knorr,[11] Paal–
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Orazio A. Attanasi et al.
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Scheme 1. Divergent regioselective synthesis of pyrroles from amines, alkynoates and DDs.
Importantly, it is noteworthy that, with this se- EtOAc, etc.[16] Since these conditions cannot be com-
quence, it is possible to divert the regioselective be- bined with the subsequent Michael addition/hetero-
haviour of the reaction from the formation of pyrroles cyclization step in a single flask because of the natural
towards that of their regioisomers simply by changing incompatibility of the starting DD with these solvents
the addition order of the two electrophilic compo- (scarce solubility and/or degradability) we found that
nents (4’ vs. 4; Scheme 1). Here, we describe a novel the synthesis of the desired enamino compound also
and flexible one-pot strategy towards pyrroles by way proceeds at room temperature under solvent-free con-
of a sequential enamino ester formation/Michael ad- ditions[19] and in the absence of a Brønsted or Lewis
dition reaction/azaheterocyclization process starting acid.
from primary amines, alkynoates[17] and DDs.
To the best of our knowledge, the use of one set of tions was conducted using benzylamine (1a)
substrates/reagents in sequential reactions to produce (1 mmol), diethyl acetylenedicarboxylate (2a)
Thus, a preliminary study of the sequential reac-
regioisomers, specifically heterocyclic isomers, has not (1 mmol), followed by addition of 1,2-diaza-1,3-diene
been reported previously. Recently, Zhuꢂs group has (3a) (1 mmol) under the above-mentioned conditions.
reported a palladium-catalyzed three-component syn-
A careful examination of the reaction progress over
thesis of 3-(diarylmethylene)oxindoles in a stereocon- time revealed that even when the reaction was
trolled manner.[18] Both E- and Z-isomers of the oxo- stopped after consumption of the starting DD at
ACHTUNGTRENNUNGindoles can be prepared through identical domino So- room temperature or heating up to 808C no transfor-
ꢀ
ꢀ
nogashira/carbopalladation/C H activation/C C bond mation to a pyrrole compound was observed. To our
forming sequences from the same starting materials delight, the formation of pyrrole was detected (34%)
simply by changing the addition order of the two aryl when the reaction was performed in refluxing toluene
halides.
after addition of the azo-ene compound. Gratifically,
increasing the DD from 1 equivalent to 1.5 equiva-
lents and adding a catalytic amount of triflouroacetic
acid (TFAA) after the disappearance of the starting
3a enhanced the product yield (83%) (Table 1,
Results and Discussion
With this hypothesis in mind, we planned to explore entry 1). Other catalysts (Lewis/Brønsted acids), such
the feasibility of this strategy. In order to realize a as AcOH, PTSA, ZnCl2, Zn(TfO)2, InCl3, InBr3, In-
one-pot process by subsequent addition of reagents, (TfO)3 and Cu(TfO)2 also promoted the transforma-
AHCTUNGTRENNUNG
A
ACHTUNGTRENNUNG
we first developed the desired formation of the enam- tion albeit in lower yields. Furthermore, a change of
ino ester by reaction of primary aliphatic amines and the solvent (CH3CN) did not improve the yields
alkynoates. This aza-Michael reaction has been re- (35%).
ported under the following conditions: in EtOH,
Based on the success of the model system, a series
MeOH, AcOH, DMF, THF, H2O MeOH/AcOH, of products 4a–r was constructed in order to evaluate
DMF/MeOH, DMF/AcOH, DMF/H2O, DMSO/H2O, the applicability of this reaction sequence (Table 1).
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A Novel Assembly of Substituted Pyrroles by Acid-Catalyzed Sequential Three-Component Reaction
Table 1. Acid-catalyzed sequential three-component reaction of primary amines 1a–e, alkynoates 2a–d and DDs 3a–f; syn-
thesis of N-alkylpyrroles 4a–r.[a]
1
(R)
2
A
3
4
Entry
(R1; R2)
(R3; R4; EWG)
[%][b]
1
2
3
4
5
6
7
8
1a (Bn)
1a (Bn)
1a (Bn)
1a (Bn)
1a (Bn)
1a (Bn)
1a (Bn)
1a (Bn)
2a (CO2Et; Et)
2b (CO2Me; Me)
2b (CO2Me; Me)
2d (Ph; Et)
2b (CO2Me; Me)
2a (CO2Et; Et)
2c (H; Et)
3a (Me; Me; CO2Me)
3a (Me; Me; CO2Me)
3e (Et; Pr; CO2Et)
3a (Me; Me; CO2Me)
3b (Et; Me; Ts)
4a (83)
4b (68)
4c (59)
4d (37)
4e (66)
4f (61)
4g (42)
4h (47)
4i (56)
4j (57)
4k (55)
4l (67)
4m (59)
4n (65)
4o (47)
4p (73)
4q (54)
4r (49)
3c (Bn; Me; CO2-t-Bu)
3d (Me; Et; CO2Me)
3f (All; Me; CO2Me)
3a (Me; Me; CO2Me)
3c (Bn; Me; CO2-t-Bu)
3f (All; Me; CO2Me)
3a (Me; Me; CO2Me)
3a (Me; Me; CO2Me)
3d (Me; Et; CO2Me)
3a (Me; Me; CO2Me)
3a (Me; Me; CO2Me)
3d (Me; Et; CO2Me)
3a (Me; Me; CO2Me)
2d (Ph; Et)
2c (H; Et)
9
1a (Bn)
10
11
12
13
14
15
16
17
18
1b (n-Pr)
1b (n-Pr)
1b (n-Pr)
1c (n-Bu)
1c (n-Bu)
1d (sec-Bu)
1e (c-Hex)
1e (c-Hex)
1e (c-Hex)
2a (CO2Et; Et)
2a (CO2Et; Et)
2b (CO2Me; Me)
2a (CO2Et; Et)
2b (CO2Me; Me)
2a (CO2Et; Et)
2b (CO2Me; Me)
2b (CO2Me; Me)
2c (H; Et)
[a]
Reaction conditions: all the reactions were run by mixing amine 1 (1 mmol), and alkynoate 2 (1.1 mmol) under solvent-
free conditions at room temperature. After 5–10 min (12 h when 2d was used), DD 3 (1.5 mmol) in toluene (10 mL) was
added and the reaction was refluxed for 2-4 h. A catalytic amount of TFAA was added once the DD had been consumed
completely (TLC check) and the reaction was refluxed for additional 2-4 h.
[b]
Yield of pure product 4 after column chromatography.
Various amines 1a–e, alkynoates 2a–d, and DDs[20] CO2R3, R4, and EWG groups (R3 =Me, Et, Bn, All;
3a–f were explored and the results are summarized in R4 =Me, Et, Pr, Ph, CO2Et; EWG=Ts, CO2Me,
Table 1. In general, primary aliphatic amines such as CO2Et, CO2-t-Bu).
benzylamine, n-propylamine, n-butylamine, sec-butyl-
The structures of the N-alkylpyrrole-3-carboxylic
amine, and cyclohexylamine (R=Bn, n-Pr, n-Bu, sec- acid derivatives 4a–r were supported by spectroscopic
Bu, c-Hex) worked well to give the substituted pyr- evidence and unequivocally confirmed by comparison
roles. Although aromatic primary amines (R=Ph, p- of the 4,5-dimethoxycarbonyl-2-methylpyrrole deriva-
Me-C6H5, p-MeO-C6H5, p-Br-C6H5) were well tolerat- tive 4e with the same pyrrole previously reported by
ed in the coupling with alkynoates, unfortunately the Chuang and Wu.[21]
subsequent acid-promoted enamine-azoene annula-
tion failed, probably because of the reduced nucleo- ines has been extensively investigated so far, no ex-
philicity of the amine nitrogen atom. amples of alkylpyrroles 4 using N-monosubstituted
Although the behaviour of DDs with various enam-
Moderate to excellent yields were achieved with enamines/enaminones are known. In fact, even if a
several types of activated alkynes such as dimethyl large number of modifications of the enamine reagent
acetylenedicarboxylate, diethyl acetylenedicarboxy- have been explored, the studies were restricted to the
late, ethyl propiolate and ethyl 3-phenylprop-2-ynoate use of secondary amine-derived enamines.[22] For
(R1 =H, Ph, CO2Et, CO2Me). If R2 was changed from these reactions, the accepted mechanism of genera-
ethyl to methyl, the yields were almost the same even tion of aminopyrrole derivative 5 has been hypothe-
when different amine/DD partners were used. Addi- sized to involve as a key step the formation of a zwit-
tionally, these reactions were compatible with a varie- terionic transient species of type B (Scheme 2).
ty of DD compounds possessing different functional
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Orazio A. Attanasi et al.
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cepted mechanism when a simple N,N-disubstituted
enamine and DD 3 are used.[22]
Taken together, the previous and present results, in-
cluding the impact of the nature of the substitutents
of the enamine moiety, suggest that the ability to re-
verse the regiochemistry in the N-alkylpyrrole forma-
tion using the one and the same set of substrates/re-
agents (amines, alkynoates and DDs) simply depends
on the addition order of the two electrophilic compo-
nents. Notably, the present synthetic protocol was per-
formed by combining two steps in the same reaction
vessel; overall, this sequential methodology builds up
two carbon-nitrogen bonds, one carbon-carbon bond,
and an aromatic heterocycle ring in a chemo-, regio-
selective and efficient manner.
Experiments to perform a one-pot three-compo-
nent reaction by putting all the substrates in one flask
showed that both the competitive Michael additions
(Nu=amine on El1 =DD[14b] and Nu=amine on El2 =
alkynoate) proceed to give complex reaction mixtures
of both pyrrole heterocycle derivatives.
Scheme 2. Plausible mechanism for the formation of pyrrole
derivatives.
Conclusions
In conclusion, we have discovered a novel, simple
(metal-free), two-step, three-component process for
On the basis of all these results, a plausible mecha- the union of readily available primary amines, alkyn-
nism for the sequential three component reaction is oates and DDs. The synthetic route itself is complete-
AHCTUNGTRENNUNG
described in Scheme 2. In the first step, the formation ly different from the previous one and provides an or-
of enamino ester A occurs through addition of amine thogonal approach for easy access of regioselectively
1 with alkynoate 2. Next, 1,4-nucleophilic addition of polysubstituted pyrroles (that are regioisomers at C-4
A to the azo-ene system of DD 3 produces the zwit- and C-5). Thus, a formal reversal of regioselectivity in
terionic hydrazone adduct intermediate B, which is the pyrrole ring formation can be obtained through
not isolable, that promptly afforded 5-alkylhydrazino- sequential non-identical reactions with respect to
pyrroline-3-carboxylic acid derivatives C by an intra- those previously published simply by changing the ad-
molecular azacyclization (promoted by TFAA) via dition order of the two electrophilic components (4’
CH/NH tautomerization or 1,3-hydrogen shift. In vs. 4; Scheme 1).
turn, C aromatizes into the N-alkylpyrrole 4 by loss of
the hydrazine residue (path a, Scheme 2).
Compared with the related enamine-DD [3+2]cy-
cloaddition,[22] the complete control of pathway selec-
The exclusive formation of 1-alkylpyrrole 4 rather tivity of these reactions is strictly dictated by the use
than 1-aminopyrrole 5 may be explained by the of the primary amine-derived enamino ester as nucle-
nature of the enamine component. In fact, as expect- ophilic partner for heterocycle annulation. Further
ed, the use of A by introduction of a primary amine, work to expand and apply these findings is ongoing,
has a strong influence on the position of the iminium/ and the results will be reported in due course.
enamine equilibrium in B favouring the intramolecu-
lar nucleophilic attack of the NH bond of the enam-
ine (derived from a 1,3-hydrogen shift of H-5) across
Experimental Section
the unsaturated C=N bond of the hydrazone function
(path a) to give the stable aromatic compound 4. This
occurrence would be assisted by the presence of the
CO2R2 group in the a-position to the iminium func-
tionality (intermediate B).
Alternatively, the tautomerization of intermediate
B via CH/NH prototropism of the hydrazono/hydrazi-
no form (derived from H4) before the cyclization pro-
General Procedure for the Acid-Catalyzed Sequential
Three-Component Reaction of Primary Amines 1a–e,
Alkynoates 2a–d and DDs 3a–f; Synthesis of N-
Alkylpyrroles 4a–r
A mixture of amine 1a–e (1 mmol), and alkynoate 2a–d
(1.1 mmol) was stirred under solvent-free conditions at
cess (path b, Scheme 2) still remains the generally ac- room temperature. After 5–10 min (12 h when 2d was used),
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A Novel Assembly of Substituted Pyrroles by Acid-Catalyzed Sequential Three-Component Reaction
DD 3a–f[20] (1.5 mmol) in toluene (10 mL) was added and
the reaction mixture was refluxed for 2–4 h. A catalytic
amount of TFAA (2 drops) was added once the DD had
been consumed completely (TLC check) and the reaction
was refluxed for additional 2–4 h. After removal of the sol-
vent, the crude mixture was purified by column chromatog-
raphy on silica gel (elution mixture: ethyl acetate/cyclohex-
ane) to afford products 4a–r.
2,3-Diethyl 4-methyl 1-benzyl-5-methyl-1H-pyrrole-2,3,4-
tricarboxylate (4a): N-Alkylpyrrole 4a was isolated by
column chromatography (ethyl acetate/cyclohexane=15:85)
as a yellow oil; yield: 83%. 1H NMR (400 MHz, CDCl3,
258C): d=1.24 (t, J=7.2 Hz, 3H), 1.38 (t, J=7.2 Hz, 3H),
2.46 (s, 3H), 3.78 (s, 3H), 4.19 (q, J=7.2 Hz, 2H), 4.36 (q,
J=7.2 Hz, 2H), 5.61 (s, 2H), 6.94 (d, J=7.6 Hz, 2H), 7.20–
7.29 (m, 3H); 13C NMR (100 MHz, CDCl3, 258C): d=11.3
(q), 13.8 (q), 14.1 (q), 48.3 (t), 60.6 (t), 61.3 (t), 110.9 (s),
119.0 (s), 125.7 (d), 126.3 (s), 127.3 (d), 128.7 (d), 136.2 (s),
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141.4 (s), 159.5 (s), 163.6 (s), 166.2 (s); IR (nujol): nmax
=
;
1722, 1516, 1452, 1267, 1217, 1146, 1097, 1033, 876 cmꢀ1
MS: m/z (%)=373 (M+) (16), 341 (10), 327 (77), 281 (100),
267 (19), 192 (24); anal. calcd. for C20H23NO6 (373.40): C
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Supporting Information
Experimental details, spectroscopic characterization of all
compounds and copies of NMR spectra are given in the
Supporting Information.
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Acknowledgements
The authors thank the Ministero dell’Universitꢀ, dell’Istru-
zione e della Ricerca (MIUR)-Roma and the Universitꢀ degli
Studi di Urbino “Carlo Bo” for support of this work.
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FULL PAPERS
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[16] b-Enamino esters are widely used as versatile inter-
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[17] For examples of pyrrole synthesis from alkynoates, see:
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[19] Treatment of benzylamine 1a with diethyl acetylenedi-
carboxylate 2a at room temperature under solvent-free
conditions produced the corresponding enamino ester
1
A in exclusively the Z form (determined by H NMR
spectroscopy of the crude reaction using CDCl3 as sol-
vent).
[20] DDs 3a–f were synthesized from the corresponding
chlorohydrazones by treatment with base (see Support-
ing Information).
[21] C.-P. Chuang, Y.-L. Wu, Tetrahedron 2004, 60, 1841–
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Adv. Synth. Catal. 2011, 353, 1519 – 1524