Zinc(II) triflate-catalyzed divergent synthesis of polyfunctionalized pyrroles

Article abstract of DOI:10.1002/adsc.201000796

The zinc(II) triflate-catalyzed synthesis of highly functionalized pyrroles is described. The sequence involves the preliminary preparation of α-aminohydrazones by Michael addition of primary amines to 1,2-diaza-1,3-dienes. The treatment of these intermed

Full text of DOI:10.1002/adsc.201000796

FULL PAPERS
DOI: 10.1002/adsc.201000796
Zinc(II) Triflate-Catalyzed Divergent Synthesis of
Polyfunctionalized Pyrroles
Orazio A. Attanasi,a Stefano Berretta,a Lucia De Crescentini,a Gianfranco Favi,a
Gianluca Giorgi,b Fabio Mantellini,a,* and Simona Nicolinia
a
Istituto di Chimica Organica, Universitꢀ degli Studi di Urbino “Carlo Bo”, Via I Maggetti 24, 61029 Urbino (PU), Italy
Fax : (+39)-0722-303441; e-mail: fabio.mantellini@uniurb.it
Dipartimento di Chimica, Universitꢀ degli Studi di Siena, Via Aldo Moro, 53100 Siena, Italy
b
Received: October 21, 2010; Revised: December 20, 2010; Published online: March 4, 2011
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.201000796.
Abstract: The zinc(II) triflate-catalyzed synthesis of several Lewis/Brønsted acid catalysts is performed.
highly functionalized pyrroles is described. The se- Zinc(II) triflate is the most efficient catalyst. Under
quence involves the preliminary preparation of a- similar reaction conditions, employing 4-alkoxycar-
aminohydrazones by Michael addition of primary bonyl-1,2-diaza-1,3-dienes, only 4-hydroxy-1H-pyr-
amines to 1,2-diaza-1,3-dienes. The treatment of role-2,3-dicarboxylates are synthesized. These latter
these intermediates with dialkyl acetylenedicarboxy- reactions can be accomplished regioselectively also
lates produces a-(N-enamino)-hydrazones that are in one pot. Using 4-aminocarbonyl-1,2-diaza-1,3-
converted into the corresponding pyrroles. The sub- dienes, diamines and dialkyl acetylenedicarboxylates
stituents on the carbon in position four of 1,2-diaza- the sequence provides the corresponding a,w-di(N-
1,3-dienes drive the regioselectivity of the ring clo- pyrrolyl)alkanes.
sure process. Starting from 4-aminocarbonyl-1,2-
diaza-1,3-dienes only dialkyl 1-substituted 5-amino-
carbonyl-1H-pyrrole-2,3-dicarboxylates are achieved Keywords: alkynes; 1,2-diaza-1,3-dienes; Lewis
by Lewis acid-catalyzed ring closure. A screening of acids; Michael addition; pyrroles
Introduction
significant limitations in terms of substituents that can
be introduced, the substitution pattern, or regioselec-
Pyrroles continue to draw a lot of attention from the tivity. Several recent variations in the formation of
scientific community due to their prevalence in natu- pyrrole rings are based on metal-catalyzed reac-
ral products and wide range of biological and materi- tions[13] and catalytic multicomponent coupling meth-
als science applications.[1,2] Pyrroles can be found in odologies[14] which can improve usefully the classical
immunosuppressants,[3a] antitumor agents,[3b] and anti- synthetic approaches.
inflammatory agents.[3c] Within these large classes of
We have demonstrated that the reactions between
relevant products, tetrasubstituted pyrroles are ex- 1,2-diaza-1,3-dienes (DDs) and carbonyl com-
tremely important, displaying antibacterial, antiviral, pounds[15] or enol silyl derivatives[16] represent useful
anticonvulsant and antioxidant activities as well as in- and convenient entries to 1-aminopyrroles. More re-
hibiting cytokine-mediated diseases.[4] 3-Hydroxypyr- cently, we have introduced a new and flexible Knorr-
roles are employed as synthetic ligands in the shape- related strategy for the construction of amply func-
selective recognition of base pairs in the DNA se- tionalized pyrroles A (Scheme 1).[17] The typical
quence.[5] Similarly, polypyrroles are of growing rele- Knorr approach utilizes a-amino ketones and carbon-
vance in material science, non-linear optics, and yl derivatives containing an activated methylene
supramolecular chemistry as molecular sensors and group as starting materials.[10] A variation of this syn-
devices.[6–9] As a consequence, much attention has thesis implicates the use of alkynes as reagents rather
been paid to their preparation by classical methods than carbonyl compounds.[18] In our methodology, the
such as the Knorr,[10] Hantzsch,[11] and Paal–Knorr[12] a-amino ketones are replaced with a-aminohydra-
syntheses. However, these approaches usually present zones. The advantages of this technique are, first of
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595

Orazio A. Attanasi et al.
FULL PAPERS
ature in the case of 1a–c, e, or under reflux for 1d
producing the desired a-aminocarbonyl a-aminohy-
drazones 3a–i in high yields. The reaction takes place
by means of the nitrogen-nucleophilic attack of 2a–d
to the terminal carbon atom of the azo-ene system of
the DDs 1a–e (Scheme 2, Table 1).[15b,19]
By reacting the a-aminocarbonyl a-aminohydra-
zones 3a–g with dialkyl acetylenedicarboxylates 4a–c
in ethanol under reflux, the same nitrogen gives a fur-
ther nucleophilic attack onto the sp-carbon of 4, pro-
ducing a-aminocarbonyl a-(N-enamino)-hydrazones
5a–j as E/Z mixtures in 2–4 h in good yields
(Scheme 2, Table 1). The a-aminocarbonyl a-amino-
hydrazones 3h, i derived from p-toluidine 2c, and p-
anisidine 2d do not furnish the corresponding a-ami-
nocarbonyl a-(N-enamino)-hydrazones 5.
Although generally weaker than aliphatic ones, aro-
matic amines are able to give the 1,4-hydroamination
of the azo-ene system of DDs.[20] However, the nucle-
ophilicity of the nitrogen atom in the resulting amino-
hydrazones 3 could be reduced by the presence of
electron withdrawing groups on the a-carbon atom.
For this reason, the subsequent nucleophilic attack by
this nitrogen atom at the triple bond of alkynes failed.
Scheme 1. Different pyrroles obtained from DDs, amines
and dialkyl acetylenedicarboxylates.
all, the easiness of the preparation of a wide range of
different a-aminohydrazones. Moreover, the latter
substrates are solids that are appreciably more stable
to storage and handling than a-amino ketones. In
fact, no self-condensation of a-aminohydrazones has
been observed. Furthermore, since with this method-
ology the “construction” of the heterocyclic structure
requires the assembly of three building blocks, it is
possible to widely plan ab initio the substituents of
the pyrroles by changing one or more starting materi-
als.
Herein, we report full details of these studies. With
regard to our preliminary communication, the scope
considerably extends the applicability of this protocol,
involving both diamines and different substituted
DDs. In this way it was possible to obtain new bis-
pyrroles B through a double process, or different and
interesting hydroxypyrroles C by means of distinct
and complete chemoselectivity in the heterocycliza-
tion process (Scheme 1).
As regards to the synthesis of the hydroxypyrroles
C, a novel tandem reaction sequence was also devel-
oped whereby sequential transformations can be per-
formed without isolation or purification of intermedi-
ates in a single-pot with minimal work-up.
Scheme 2. Synthesis of a-aminocarbonyl-a-aminohydrazones
3a–i, a-aminocarbonyl-a-(N-enamino)-hydrazones 5a–j and
dialkyl 1-substituted-5-aminocarbonyl-1H-pyrrole-2,3-dicar-
boxylates 8a–g. Reaction conditions: i: THF, room tempera-
ture for 1a–c, e; THF, reflux for 1d; ii: EtOH, reflux. iii:
Results and Discussion
4-Aminocarbonyl DDs 1a–e readily react with pri-
mary amines 2a–d in tetrahydrofuran at room temper- CH2Cl2, reflux, ZnACHTNUTRGNEUNG(OTf)2.
596
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Adv. Synth. Catal. 2011, 353, 595 – 605

Zinc(II) Triflate-Catalyzed Divergent Synthesis of Polyfunctionalized Pyrroles
Table 1. Yields of the a-aminocarbonyl-a-aminohydrazones 3a–i, bis-a-aminocarbonyl-a-aminohydrazones 3j–n, a-aminocar-
bonyl-a-(N-enamino)-hydrazones 5a–j, bis-a-aminocarbonyl-a-(N-enamino)-hydrazones 5k–p, dialkyl 1-substituted-5-amino-
carbonyl-1H-pyrrole-2,3-dicarboxylates 8a–g and a,w-di(N-pyrrolyl)alkanes 8h–k.
1
R1
R2
2
R3
3
Yield
[%][a]
4
R4
5
E-isomer,
Z-isomer,
8
Yield
[%][d]
yield [%][b,c] yield [%][b,c]
1a Me NH2
1b Me NHPh
1b Me NHPh
1b Me NHPh
2a Cy
2a Cy
2a Cy
2a Cy
3a[e]
3b[e]
3b[e]
3b[e]
3c[e]
3d
83
97
97
97
74
83
91
81
81
69
96
92
74
74
53
85
4a Et
4a Et
4b Me
5a[e]
5b[e]
5c[e]
75
76
74
66
56
68
55
68
80
57
/
/
/
/
/
/
19
25
14
28
8a[e] 87
8a[e] 91
8b[e] 86
8c[e] 88
8b[e] 91
4c t-Bu 5d[e]
1c Me 3F-NHPh 2a Cy
4b Me
4b Me
4a Et
4b Me
4a Et
4b Me
5e[e]
5f
1d Et
NH2
2a Cy
2b Bn
2b Bn
2b Bn
2b Bn
2c 4-Me-NHPh
2d 3-MeO-NHPh 3i
8d
86
1a Me NH2
1b Me NHPh
1b Me NHPh
3e[e]
3f[e]
3f[e]
3g[e]
3h
5g[e]
5h[e]
5i[e]
5j[e]
8e[e] 88
8f[e] 93
8e[e] 89
8g[e] 92
1d Et
NH2
1e Me O-t-Bu
1e Me O-t-Bu
1e Me O-t-Bu
1e Me O-t-Bu
1f Me OMe
1b Me NHPh
1f Me OMe
1e Me O-t-Bu
2e
2e
2e
2f
2f
2f
N
3j
3j
4b Me
4a Et
4a Et
4b Me
4a Et
4a Et
5k
5l
5m
46
54
51
/
/
/
/
/
/
8h
8i
8i
8j
8k
8k
54
69
76
98
52
56
3k
3l[f,g]
5n[f,g] 70
5o[g,h] 75
5p[g,i] 76
3m[g,h] 98
3n[g,i]
99
[a]
Yield of the isolated purified compounds 3a–n based on the DDs 1a–f.
Yield of the isolated purified compounds (E/Z) 5a–p based on the hydrazones 3a–n.
[b]
[c]
The E and Z geometry was assigned on the basis of the vicinal heteronuclear coupling constant between the esteric
1
carbon and the vinylic H nucleus.
[d]
[e]
[f]
Yield of the isolated purified compounds 8a–k based on 5a–p.
Compound reported in a preliminary paper.[17]
Mixture of diastereoisomers in ratio 96:4.
The diastereoisomers ratios were determined considering the integral values in the H NMR spectra.
Mixture of diastereoisomers in ratio 99:1.
Mixture of diastereoisomers in ratio 98:2.
[g]
[h]
[i]
1
The C=C bond geometry of compounds 5 is deter-
mined by NMR measurements, considering the value
of vicinal heteronuclear coupling constant between
the esteric carbon and the vinylic proton (3JC,H of E
3
isomers 9.3–12.0 Hz, JC,H of Z isomers 3.4–3.6 Hz).[17]
We have observed that the N-cyclohexyl a-(N-enami-
no)-hydrazono compounds 5a–f are only in the E
forms, while the N-benzyl a-(N-enamino)-hydrazones
5g–j are obtained as a mixture of E/Z isomers (E 55–
80%, Z 14–28%).[17] The X-ray diffraction study of
(E)-5h (Figure 1) unambiguously supports the as-
signed structure.[21]
We have then explored the conversion of the a-
aminocarbonyl-a-(N-enamino)-hydrazones 5a–j into
the corresponding pyrroles 8a–g by acid-catalyzed in-
tramolecular ring closure. Among the different types
of the tested Lewis/Brønsted acids,[17] only the Lewis
ones exhibit remarkable catalytic activity, and this oc-
currence is probably due to the chelation effect of the
N-carbonylhydrazones towards metal catalysts
(Scheme 2).[22] The discovered optimized conditions
for this conversion require a catalytic amount (20%)
Figure 1. X-ray structure of compound (E)-5h. Ellipsoids for
non-hydrogen atoms enclose 50% probability.
of Zn
G
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597

Orazio A. Attanasi et al.
FULL PAPERS
values of the vicinal heteronuclear coupling constant
between the esteric carbon and the vinylic proton
(9.1–10.8 Hz) indicate that compounds 5k–p are
achieved exclusively as E isomer. Their final acid-cat-
alyzed ring closure process produces new and amply
functionalized
a,w-di(N-pyrrolyl)alkanes
8h–k
(Scheme 3, Table 1). Such compounds can find appli-
cation in the recognition of the minor groove of
DNA,[23] in the construction of conducting poly-
mers,[24] or as chelate ligands in organoplatinum com-
plexes.[25]
Thus, we have extended our investigations to the
employ of different DDs 1g–l in which the amido
moiety in position four of the azo-ene system is re-
placed with an ester group. Also in this case, the 4-
alkACTHNUTRGNEUoGN xycarbonyl DDs 1g–l easily react with primary
amines 2a–d, g in THF, at room temperature afford-
ing the corresponding a-alkoxycarbonyl-a-aminohy-
drazones 3o–ab in high yields (Scheme 4, Table 2). By
reacting these latter alkoxycarbonyl 1,4-adducts 3o–
ab with the same dialkyl acetylenedicarboxylates 4a,
b under the same conditions previously employed for
their analogous aminocarbonyl ones 3a–n (EtOH
under reflux) only a complicated reaction mixture is
obtained. The hydrazone 3z and the dimethyl acetyle-
nedicarboxylate 4b are then chosen to test different
solvent and temperature conditions for this reaction.
Surprisingly, we have observed that using dichlorome-
thane or chloroform, directly new dimethyl 5-[N-(an-
ilinocarbonyl)ethanehydrazonoyl]-1-butyl-4-hydroxy-
Scheme 3. Synthesis of bis-a-aminocarbonyl-a-aminohydra-
zones 3j–n, bis-a-aminocarbonyl-a-(N-enamino)-hydrazones
5k–p and a,w-di(N-pyrrolyl)alkanes 8h–k. Reaction condi-
tions: i: THF, room temperature; ii: EtOH, reflux; iii:
1H-pyrrole-2,3-dicarboxylate
13g
is
achieved
(Scheme 4).
CH2Cl2, reflux, ZnACHTUNGTRENNUNG(OTf)2.
The structure of 13g was confirmed by X-ray crystal
structure analysis (Figure 2).[26]
The reaction proceeds by means of the intramolec-
The presence of a catalytic amount of Lewis acids
ular nucleophilic attack of the ene-amino carbon to does not improve the progress of the reaction, and
the hydrazono moiety of the intermediate 6, activated the best results in terms of yields and reaction times
by coordination with the Lewis acid. This process pro- are obtained in chloroform under reflux (see Support-
duces the pyrrolium intermediates 7 that provide the ing Information). Having found the optimal condi-
final aromatic dialkyl 1-substituted 5-aminocarbonyl- tions, we next examined their extension to other sub-
1H-pyrrole-2,3-dicarboxylates 8, by elimination of the strates by using the a-alkoxycarbonyl a-aminohydra-
hydrazino moiety (Scheme 2, Table 1).
zones 3o–ab with diethyl or dimethyl acetylenedicar-
It is noteworthy that the Knorr equivalent starting boxylates 4a, b to test the efficiency of the protocol.
a-amino a-amido ketones are not commercially avail- In general, the a-alkoxycarbonyl a-aminohydrazones
able products and also difficult to prepare by other 3q–v, y–ab derived from benzyl 2b, or n-butylamine
methods.
2g give the corresponding dialkyl 5-N-(ethanehydra-
To improve the usefulness of our synthetic protocol zonoyl)-1-substituted-4-hydroxy-1H-pyrrole-2,3-dicar-
and with the aim to prepare new molecules containing boxylates 13a–i in 4–14 h without the isolation of the
two differently spaced pyrrole rings, we have next ap- corresponding a-alkoxycarbonyl-a-(N-enamino)-hy-
plied our procedure to diamines 2e, f. The double nu- drazone intermediates 10. Instead, compounds 3o, p,
cleophilic attack of the 1,4-diaminopropane 2e, or 1,6- w, x derived from relatively hindered primary amines
diaminohexane 2f, to two equivalents of 4-aminocar- such as the cyclohexylamine 2a, or from aromatic
bonyl DDs 1b, e, f furnishes the bis-a-aminocarbonyl- amines such as p-toluidine 2c, or p-anisidine 2d, do
a-aminohydrazones 3j–n, that in turn, are converted not furnish the pertinent heterocycles (Table 2).
in to the corresponding bis-a-aminocarbonyl-a-(N-en-
On the basis of these findings, a plausible mecha-
amino)-hydrazones 5k–p by reaction with two equiva- nism for the formation of 4-hydroxy-1H-pyrrole-2,3-
lents of dialkyl acetylenedicarboxylates 4a, b. The dicarboxylates 13 involves a double nucleophilic
598
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Adv. Synth. Catal. 2011, 353, 595 – 605

Zinc(II) Triflate-Catalyzed Divergent Synthesis of Polyfunctionalized Pyrroles
Scheme 4. Regioselective synthesis of a-alkoxycarbonyl-a-aminohydrazones 3o–ab, and 4-hydroxy-1H-pyrrole-2,3-dicarboxy-
lates 13a–i. Multistep procedure: i: THF, room temperature; ii: CHCl3, reflux. One pot procedure: i: CHCl3, room tempera-
ture; ii: CHCl3, reflux.
attack of the amino-nitrogen, initially to the terminal
The absence of catalytic activity by the Lewis acids
carbon atom of the azo-ene system producing the hy- observed in the synthesis of 13a–i can be accounted
drazones 3o–ab and then to the sp carbon of the di- for by considering that the chelation effect of the N-
ACHTUNGTRENNUNGalkyl acetylenedicarboxylate 4 furnishing the non isol- carbonylhydrazones towards metal catalysts does not
able intermediates a-alkoxycarbonyl-a-(N-enamino)- involve the ester group responsible as electrophilic
hydrazones 10. The subsequent spontaneous cycliza- site of the ring closure. The aromaticy and the pres-
tion process occurs by means of intramolecular nucle- ence of strong hydrogen bonds, as evidenced from the
ophilic attack of the ene-amino carbon to the ester X-ray analysis of compound 13g (Figure 2), justifies
function affording the intermediate 3,4-dihydro-2H- the exclusively presence of the hydroxy-tautomeric
pyrrolium-3-olates 11. The loss of an alcohol molecule form of the pyrrole derivatives 13a–i.
produces the pyrrol-3-ones 12 that tautomerize to the
The synthesis of 13a–i is also performed in one pot
final 4-hydroxy-1H-pyrrole-2,3-dicarboxylates 13a–i. without the isolation of the hydrazono intermediates
It is noteworthy that the replacement of an amide 3. In this case, the reaction between 4-alkoxycarbonyl
with a better electrophile such as an ester group in DDs 1g–l and primary amines 2b, g is carried out in
position four of the starting DD determines a differ- chloroform, at room temperature until the disappear-
ent regioselectivity during the ring closure process. In ance of DDs 1g–l, as evidenced by the vanishing of
fact, the nucleophilic attack of the ene-amino carbon the typical red colour and by TLC analysis. To the
happens exclusively onto the hydrazonic functions in mixture 1.2 equivalents of dialkyl acetylenedicarboxy-
the case of a-aminocarbonyl-a-(N-enamino)-hydra- lates 4a, b are then added and the crude is refluxed
zones 5a–p producing 5-aminocarbonyl-1H-pyrrole- for 4–11 h obtaining directly the desired the 4-hy-
2,3-dicarboxylates 8a–k (Scheme 3, Scheme 4), or droxy-1H-pyrrole-2,3-dicarboxylates 13a–i (Scheme 4,
onto the ester function in the case of the a-alkoxycar- Table 2).
bonyl-a-(N-enamino)-hydrazono intermediates 10
Some differences in the construction of the pyrrole
achieving the 4-hydroxy-1H-pyrrole-2,3-dicarboxy- skeleton can be observed with respect to our previous
lates 13a–i (Scheme 4).
syntheses.
Adv. Synth. Catal. 2011, 353, 595 – 605
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Orazio A. Attanasi et al.
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Table 2. Yields of a-alkoxycarbonyl-a-aminohydrazones 3o–ab and dialkyl 5-N-(ethanehydrazonoyl)-1-substituted-4-hy-
droxy-1H-pyrrole-2,3-dicarboxylates 13a–i.
1
R1
R2
2
R3
3
Yield [%][a]
4
R4
13
Yield [%][b]
Yield [%][c]
1g
1g
1h
1i
Et
Et
Et
Me
Me
Et
Et
Me
Et
Me
Me
Et
Et
Et
NH2
NH2
O-t-Bu
NH2
NH2
2a
2a
2a
2b
2b
2b
2b
2b
2b
2b
2b
2b
2b
2c
2d
2g
2g
2g
2g
2g
2g
2g
2g
Cy
Cy
Cy
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
3o
3o
3p
3q
3q
3r
3r
3s
3t
3u
3u
3v
3v
3w
3x
3y
3y
3z
98
98
89
97
97
97
97
86
85
78
78
98
98
96
93
73
73
98
98
84
84
96
96
4a
4b
4b
4a
4b
4a
4b
4b
4b
4a
4b
4a
4b
Et
Me
Me
Et
Me
Et
Me
Me
Me
Et
Me
Et
13a
13b
13a
13b
13c
13c
13d
13e
13d
13e
61
48
52
47
52
53
50
46
50
50
34
37
31
37
38
33
34
32
36
32
1i
1g
1g
1j
1k
1l
NH2
NH2
NHPh
NHPh
O-t-Bu
O-t-Bu
O-t-Bu
O-t-Bu
NH2
1l
1h
1h
1g
1g
1j
Bn
Me
4-Me-NHPh
3-MeO-NHPh
n-Bu
n-Bu
n-Bu
n-Bu
n-Bu
n-Bu
n-Bu
n-Bu
Et
NH2
Me
Me
Et
NHPh
NHPh
NHPh
NHPh
O-t-Bu
O-t-Bu
O-t-Bu
O-t-Bu
4a
4b
4a
4b
4a
4b
4a
4b
Et
Me
Et
Me
Et
Me
Et
13f
13g
13f
13g
13h
13i
54
48
55
51
51
47
61
63
31
34
38
36
33
35
39
42
1j
1k
1k
1l
1l
1h
Et
3z
Me
Me
Et
3aa
3aa
3ab
3ab
13h
13i
1h
Et
Me
[a]
[b]
[c]
Yield of the isolated purified compounds 3o–ab based on the DDs 1g–l.
Yield of the isolated purified compounds 13a–i based on the hydrazones 3o–ab.
Yield of the isolated purified compounds 13a–i obtained in a one-pot procedure based on the DDs 1g–l.
Conclusions
In conclusion, this paper describes a smooth proce-
dure for the preparation of a-aminocarbonyl-a-(N-en-
amino)-hydrazones and amply functionalized pyrroles
by reaction between DDs, primary amines and dialkyl
acetylenedicarboxylates.
The present investigation has evidenced that the
substituents on the carbon in position four of the
starting DD drive the regioselectivity of the ring clo-
sure process: by using 4-aminocarbonyl DDs, only di-
alkyl 1-substituted 5-aminocarbonyl-1H-pyrrole-2,3-
dicarboxylates 8a–g are achieved, while, starting from
4-alkoxycarbonyl DDs, only dialkyl 5-N-(ethanehy-
drazonoyl)-1-substituted-4-hydroxy-1H-pyrrole-2,3-di-
carboxylates 13a–i are produced. The preparation of
Figure 2. X-ray structure of compound 13g.
In fact, starting from DDs and carbonyl com- a,w-di(N-pyrrolyl)alkanes 8h–k proves that this easy
pounds[15] (Route B, Scheme 5) or enol silyl deriva- procedure can be successfully employed for further
tives[16] (Route C, Scheme 5), we obtained N-substi- synthetic applications in the construction of more
tuted-aminopyrroles in which the pyrrole nitrogen is complex systems which are not easily obtainable by
originally situated in the position two of the azo-ene other methods.
system, while using DDs, primary amines and dialkyl
The advantage of the use of DDs as building blocks
acetylenedicarboxylates, the pyrrole nitrogen derives in the modelling of pyrroles is the stability and the
from the substituted amino reagents 2 (Route A, easy accessibility both of the starting materials as well
Scheme 5). This fact permits an additional diversifica- as of the intermediates. These reactions proceed
tion site that can be easily introduced using a variety under mild conditions furnishing interesting new
of amines.
products without complicated work-up procedures. In
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Zinc(II) Triflate-Catalyzed Divergent Synthesis of Polyfunctionalized Pyrroles
Scheme 5. Different approaches for the construction of pyrroles starting from DDs: Route A with primary amines and acety-
lenedicarboxylates; Route B with carbonyl compounds; Route C with enol silyl derivatives.
particular, the synthesis of the 4-hydroxy-1H-pyrrole- carbon (middle peak) in DMSO-d6 and d=7.26 ppm for
proton and d=77.00 ppm for carbon (middle peak) in
CDCl3. Coupling constants (J) are given in Hz; the multi-
plicities were obtained using 1358 and 908 DEPT experi-
ments to aid in assignment. The abbreviations used are as
follows: s, singlet; d, doublet; t, triplet; q, quartet, m, mul-
tiplet; br, broad. All the NH, OH and NH2 exchanged with
D2O. Precoated silica gel plates 0.25 mm were employed for
analytical thin layer chromatography and silica gel 35–70 m
for column chromatography. Precoated silica gel plates
0.25 mm were employed for analytical thin-layer chromatog-
raphy and silica gel 60 ꢂ (35–70 mm) for column chromatog-
raphy. All new compounds shown satisfactory elemental
analysis (CÆ0.35; HÆ0.30; NÆ0.30). The chemical name
abbreviations of the substituents used are as follows: Me,
methyl; Et, ethyl; t-Bu, tert-butyl; Bn, benzyl; Cy, cyclohex-
yl; Ph, phenyl; n-Bu, normal-butyl. The nomenclature was
generated using ACD/IUPAC Name (version 3.50, 5 Apr.
1998), Advanced Chemistry Development Inc., Toronto,
ON (Canada).
2,3-dicarboxylates 13a–i can be conducted also in a
one pot mode, avoiding the isolation of the a-amino-
hydrazone intermediates. Furthermore, all pyrroles
here obtained present a large multifunctionality that
is difficult to obtain by successive reactions of an un-
functionalized starting skeleton.
Experimental Section
General Remarks
All of the commercially available reagents and solvents
were used without further purification. 1,2-Diaza-1,3-dienes
1a–l were synthesized as a mixture of E/Z isomers as previ-
ously reported.[27] Solvents were purchased and used without
further purification with the exception of THF which was
distilled over sodium hydroxide. Melting points were deter-
mined on open capillary tubes. Mass spectra EI were made
1
at an ionizing voltage of 70 eV. H NMR and 13C NMR spec-
General Procedure for the Synthesis of a-Amino-
carbonyl-a-aminohydrazones 3a–i, Bis-a-amino-
carbonyl-a-aminohydrazones 3j–n and a-Alkoxy-
carbonyl-a-aminohydrazones 3o–ab
tra were recorded at 400 and 100.32 MHz, respectively. All
NMR spectra were recorded in CDCl3 or in DMSO-d6, as
specified below. Chemical shifts (dH) are reported in parts
per million (ppm). Proton and carbon spectra were refer-
enced internally to solvent signals, using values of d=
2.49 ppm for proton (middle peak) and d=39.50 ppm for
For the preparation of a-aminocarbonyl-a-aminohydrazones
3a–i and a-alkoxycarbonyl-a-aminohydrazones 3o–ab: to a
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FULL PAPERS
solution of the 4-aminocarbonyl DDs 1a–e or 4-alkoxycar-
bonyl DDs 1g–l as a mixture of E/Z isomers[27] (1.0 mmol)
in tetrahydrofuran (10 mL), the cyclohexylamine 2a, the
benzylamine 2b, the p-toluidine 2c, the p-anisidine 2d, or
the n-butylamine 2g, (1.0 mmol) was added. The reaction
was allowed to proceed under magnetic stirring at room
temperature for 2–4 h in the case of 1a–c, e, g–l or under
reflux for 4 h in the case of 1d, until the disappearance of
the reagents (monitored by TLC). The solvent was then
evaporated under reduced pressure. The products 3a–i, o–ab
were purified by silica gel chromatography (elution mixture:
ethyl acetate/cyclohexane) and they were crystallized from
ethyl acetate (see Supporting Information). With regard to
the synthesis of the bis-a-aminocarbonyl-a-aminohydra-
zones 3j–n, to a solution of the 4-aminocarbonyl DDs 1b, e,
f as a mixture of E/Z isomers[27] (2.0 mmol) in tetrahydrofur-
an (15 mL), the 1,4-diaminopropane 2e, or 1,6-diaminohex-
ane 2f (1.0 mmol) was added dropwise. The reaction was al-
lowed to proceed under magnetic stirring at room tempera-
ture for 2–4 h, until the disappearance of the reagents
(monitored by TLC). The solvent was then evaporated
under reduced pressure. The products 3j–n were purified by
silica gel chromatography (elution mixture: ethyl acetate/cy-
clohexane) and they were crystallized from ethyl acetate
(see Supporting Information).
C13H24N4O3 (284.35): C 54.91, H 8.51, N 19.70; found C
54.80, H 8.54, N 19.58.
General Procedure for the Synthesis a-Amino-
carbonyl-a-(N-enamino)-hydrazones 5a–j and Bis-a-
aminocarbonyl-a-(N-enamino)-hydrazones 5k–p
To a solution of the a-aminocarbonyl a-aminohydrazones
3a–i (1.0 mmol) in ethanol (20 mL) a stoichiometric amount
of the dialkyl acetylenedicarboxylates 4a–c (1.0 mmol) was
added. The reaction mixture was refluxed for 2–4 h until the
complete disappearance of the reagents (monitored by
TLC). Starting from compounds 3h, i, no reactions were re-
vealed. In the other cases, the solvent was then evaporated
under reduced pressure. The products 5a–j were purified by
silica gel chromatography (elution mixture: ethyl acetate/cy-
clohexane) and they were crystallized from ethyl acetate. In
the case of the a-(N-enamino)-hydrazones 5g–j derived
from the benzylamine 2b, it was possible to separate the E,
Z isomers, while for 5a–f, derived from the cyclohexylamine
2a, we have observed the exclusive formation of the E
isomer (see Supporting Information). With regard to the
synthesis of bis-a-aminocarbonyl-a-(N-enamino)-hydrazones
5k–p, to a solution of the bis-a-aminocarbonyl-a-aminohy-
drazones 3j–n (1.0 mmol) in ethanol (20 mL) two equiva-
lents of the dialkyl acetylenedicarboxylates 4a, b (2.0 mmol)
were added. The reaction mixture was refluxed for 4–7 h
until the complete disappearance of the reagents (monitored
by TLC). The solvent was then evaporated under reduced
pressure. The products 5k–p are purified by silica gel chro-
matography (elution mixture: ethyl acetate) and they were
crystallized from ethyl acetate (see Supporting Informa-
tion).
Diethyl (2E)-2-({2-[(aminocarbonyl)hydrazono]-1-[(dime-
thylamino)carbonyl]propyl}(cyclohexyl)amino)but-2-enedi-
oate (5a): mp: 161–1638C; 1H NMR (400 MHz, CDCl3,
258C): d=0.97–1.23 (m, 9H), 1.28 (t, J=7.2 Hz, 3H), 1.47–
1.54 (m, 2H), 1.71–1.81 (m, 2H), 1.90 (s, 3H), 2.98 (s, 3H),
2.93 (s, 3H), 3.23–3.29 (m, 1H), 3.89–4.06 (m, 2H), 4.18–
4.32 (m, 2H), 4.77 (s, 1H), 5.13 (s, 1H), 5.58 and 5.86 (2 brs,
2H), 9.18 (s, 1H); 13C NMR (100 MHz, CDCl3, 258C): d=
13.8 (q), 14.2 (q), 25.4 (t), 25.8 (t), 26.0 (t), 30.9 (t), 31.1 (t),
35.9 (t), 37.0 (t), 59.1 (t), 61.4 (d), 61.8 (t), 64.0 (d), 91.2 (d),
144.0 (s), 153.1 (s), 157.8 (s), 166.0 (s), 167.4 (s), 167.8 (s);
IR (nujol): nmax =3424, 3200, 1741, 1727, 1704, 1685,
1658 cmÀ1; MS: m/z (%)=453 (M+ +1) (1), 408 (3), 378
(48), 349 (11), 334 (41), 306 (8), 262 (100), 239 (22), 193
(53); anal. calcd. for C21H35N5O6 (453.53): C 55.61, H 7.78, N
15.44; found C 55.72, H 7.91, N 15.51.
3-[(Aminocarbonyl)hydrazono]-2-(cyclohexylamino)-N,N-
dimethylbutanamide (3a): mp: 124–1268C; 1H NMR
(400 MHz, CDCl3, 258C): d=0.77–0.94 (m, 6H), 1.23–1.29
(m, 1H), 1.35–1.41 (m, 2H), 1.46–1.52 (m, 1H), 1.54 (s, 3H),
1.93–1.99 (m, 1H), 2.65 (s, 3H), 2.72 (s, 3H), 2.83 (brs, 1H),
3.99 (s, 1H), 5.86 and 6.21 (2 brs, 2H), 9.13 (s, 1H);
13C NMR (100 MHz, CDCl3, 258C): d=12.4 (q), 24.7 (t),
24.8 (t), 26.0 (t), 33.1 (t), 33.4 (t), 36.0 (q), 36.9 (q), 54.7 (d),
61.8 (d), 147.9 (s), 159.0 (s), 170.6 (s) ppm; IR (nujol): nmax
=
3422, 3374, 3265, 3204, 1776, 1732, 1676 cmÀ1; MS: m/z
(%)=283 (M+) (16), 238 (74), 211 (100), 167 (31), 152 (11);
anal. calcd. for C13H25N5O2 (283.37): C 55.10, H 8.89, N
24.71; found: C 55.21, H 8.94, N 24.59.
1,18-Dianilino-N,N,N’,N’,4,15-hexamethyl-1,18-dioxo-
2,3,6,13,16,17-hexaazaoctadeca-3,15-diene-5,14-dicarboxam-
ide (3l): mp: 165–1668C; 1H NMR (400 MHz, DMSO-d6,
258C): d=1.23–1.29 (m, 4H), 1.32–1.42 (m, 4H), 1.76 (s,
6H), 2.35–2.43 (m, 4H), 2.85 (s, 6H), 2.98 (brs, 2H), 3.07 (s,
6H), 4.27 (s, 2H), 6.99 (t, J=7.6 Hz, 2H), 7.29 (t, J=7.6 Hz,
4H), 7.55 (d, J=8.4 Hz, 4H), 8.73 (s, 2H), 9.56 (brs, 2H);
13C NMR (100 MHz, DMSO-d6, 258C): d=12.1 (q), 26.2 (t),
29.2 (t), 34.8 (q), 36.0 (q), 46.8 (t), 63.8 (d), 118.6 (d), 121.8
(d), 128.1 (d), 138.5 (s), 147.8 (s), 152.9 (s), 169.5 (s); IR
(nujol): nmax =3422, 3374, 3265, 3204, 1776, 1732, 1676 cmÀ1
;
MS: m/z (%)=283 (M+) (16), 238 (74), 211 (100), 167 (31),
152 (11); anal. calcd. for C32H48N10O4 (283.37): C 60.36, H
7.60, N 22.00; found C 60.48, H 7.54, N 21.89.
Tetramethyl (2E,2E’)-2,2’-[hexane-1,6-diylbis({2-[(anilino-
carbonyl)hydrazono]-1-[(dimethylamino)carbonyl]propyl}-
imino)]bisbut-2-enedioate (5n): mp: 164–1658C; 1H NMR
(400 MHz, DMSO-d6, 258C): d=1.15–1.30 (m, 8H), 2.03 (s,
6H), 2.96 (s, 6H), 3.00 (s, 6H), 3.17–3.30 (m, 4H), 3.65 (s,
6H), 3.90 (s, 6H), 4.75–4.83 (m, 4H), 7.01–7.30 (m, 4H),
7.44 (d, J=7.2 Hz, 4H), 8.12 (s, 2H), 9.72 and 9.75 (2brs,
2H); 13C NMR (100 MHz, DMSO-d6, 258C): d=14.0 (q),
15.2 (q), 26.5 (t), 35.9 (q), 37.0 (q), 48.7 (t), 50.9 (q), 53.1
(q), 65.9 (d), 87.5 (d), 119.0 (d), 123.1 (d), 128.8 (d), 137.9
(s),143.0 (s), 153.8 (s), 154.2 (s), 166.0 (s), 166.4 (s), 167.6
(s); IR (nujol): nmax =3365, 3276, 1773, 1735, 1712,
1687 cmÀ1; MS: m/z (%)=666 (13), 594 (7), 522 (35), 463
Ethyl
3-[(aminocarbonyl)hydrazono]-2-(cyclohexylami-
no)butanoate (3o): mp: 128–1298C; 1H NMR (400 MHz,
CDCl3, 258C): d=1.02–1.14 (m, 8H), 1.52–1.75 (m, 5H),
1.83 (s, 3H), 2.26–2.33 (m, 1H), 2.60 (brs, 1H), 4.01 (s, 1H),
4.13 (q, J=7.2 Hz, 2H), 5.98 (brs, 2H), 9.09 (s, 1H);
13C NMR (100 MHz, CDCl3, 258C): d=13.1 (q), 14.0 (q),
24.5 (t), 25.7 (t), 33.0 (t), 54.7 (d), 61.2 (t), 64.6 (d), 147.0
(s), 158.4 (s), 171.5 (s); IR (nujol): nmax =3431, 3389, 3226,
1782, 1751, 1703 cmÀ1; MS: m/z (%)=284 (M+) (3), 239
(13), 211 (29), 167 (100), 151 (75); anal. calcd. for
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Adv. Synth. Catal. 2011, 353, 595 – 605

Zinc(II) Triflate-Catalyzed Divergent Synthesis of Polyfunctionalized Pyrroles
(67), 404 (52), 379 (82), 320 (100), 261 (34); calcd. for
C44H60N10O12 (921.01): C 57.38, H 6.57, N 15.21; found C
57.32, H 6.64, N 15.16.
for 5.0–7.0 h until the complete disappearance of the re-
agents (monitored by TLC). Starting from compounds 3o, p,
w, x no reactions were revealed. In the other cases, the sol-
vent was then evaporated under reduced pressure. The
products 13a–i were purified by silica gel chromatography
(elution mixture: ethyl acetate/cyclohexane) and they were
crystallized from diethyl ether (see Supporting Information).
General Procedure for the Synthesis of Dialkyl 1-
Substituted-5-aminocarbonyl-1H-pyrrole-2,3-di-
carboxylates 8a–g and a,w-Di(N-pyrrolyl)alkanes 8h–
k
General Procedure for the One-Pot Synthesis 4-
Hydroxy-1H-pyrrole-2,3-dicarboxylates 13a–i
To a solution of the a-aminocarbonyl-a-(N-enamino)-hydra-
zones 5a–j (1.0 mmol) in dichloromethane (15 mL), a cata-
To a solution of 4-alkoxycarbonyl DDs 1g–l as a mixture of
E/Z isomers[27] (1.0 mmol) in chloroform (10 mL), the ben-
zylamine 2b (1.0 mmol) or the n-butylamine 2g was added.
The reaction was allowed to proceed under magnetic stirring
at room temperature for 2–4 h, until the disappearance of
the reagents (monitored by TLC). To the mixture 1.2 equiv-
alents of dialkyl acetylenedicarboxylates 4a, b were then
added and the crude solution was refluxed for 4–11 h until
the complete disappearance of the reagents (monitored by
TLC). The solvent was then evaporated under reduced pres-
sure. The products 13a–i were purified by silica gel chroma-
tography (elution mixture: ethyl acetate/cyclohexane) and
they were crystallized from diethyl ether (See Supporting
Information).
lytic amount of ZnACHTUNGTRENNUNG(OTf)2 (0.2 mmol) was added. The reac-
tion mixture was refluxed for 0.5–0.6 h, until the disappear-
ance of the starting materials (monitored by TLC). The sol-
vent was then evaporated under reduced pressure. The
products 8a–g were purified by silica gel chromatography
(elution mixture: ethyl acetate/cyclohexane) and they were
crystallized from ethyl acetate (see Supporting Information).
To a solution of the bis-a-aminocarbonyl-a-(N-enamino)-hy-
drazones 5k–p (1.0 mmol) in dichloromethane (20 mL), a
catalytic amount of ZnACHTUNTRGNEUNG(OTf)2 (0.4 mmol) was added. The re-
action is refluxed for 2–3 h, until the disappearance of the
starting materials (monitored by TLC). The solvent was
then evaporated under reduced pressure. The products 8h–k
were purified by silica gel chromatography (elution mixture:
ethyl acetate/cyclohexane) and they were crystallized from
ethyl acetate (see Supporting Information).
Diethyl
5-[N-(aminocarbonyl)ethanehydrazonoyl]-1-
benzyl-4-hydroxy-1H-pyrrole-2,3-dicarboxylate (13a): mp:
1
141–1438C; H NMR (400 MHz, CDCl3, 258C): d=1.13 (t,
Diethyl
1-cyclohexyl-5-[(dimethylamino)carbonyl]-4-
J=7.2 Hz, 3H), 1.32 (t, J=7.2 Hz, 3H), 2.19 (s, 3H), 4.18
(q, J=7.2 Hz, 2H), 4.31 (q, J=7.2 Hz, 2H), 4.83 (brs, 2H),
5.48 (s, 2H), 6.95 (d, J=8.4 Hz, 2H), 7.20–7.30 (m, 3H),
8.42 (s, 1H), 8.51 (brs, 1H); 13C NMR (100 MHz, CDCl3,
258C): d=13.8 (q), 14.2 (q), 14.6 (q), 50.0 (t), 60.8 (t), 61.8
(t), 102.9 (s), 115.9 (s), 125.6 (s), 127.2 (d), 128.6 (s), 128.8
(s), 138.0 (s), 139.7 (s), 147.7 (s), 157.3 (s), 161.4 (s), 166.1
(s); IR (nujol): nmax =3381, 3278, 3167, 1737, 1669 cmÀ1; MS:
m/z (%)=416 (M+) (4), 370 (40), 343 (57), 325 (62), 252
(100), 207 (32), 179 (41), 134 (16), 106 (83); anal. calcd. for
C20H24N4O6 (416.43): C 57.68, H 5.81, N 13.45; found C
57.76, H 5.75, N 13.49.
methyl-1H-pyrrole-2,3-dicarboxylate (8a): mp: 143–1458C;
1H NMR (400 MHz, CDCl3, 258C): d=1.12–1.26 (m, 4H),
1.29 (t, J=7.2 Hz, 3H), 1.35 (t, J=7.2 Hz, 3H), 1.58–1.65
(m, 1H), 1.73–1.82 (m, 3H), 1.89–1.96 (m, 2H), 2.07 (s, 3H),
2.94 (s, 3H), 3.10 (s, 3H), 4.06–4.15 (m, 1H), 4.23 (q, J=
7.2 Hz, 2H), 4.32 (q, J=7.2 Hz, 2H); 13C NMR (100 MHz,
CDCl3, 258C): d=10.2 (q), 13.9 (q), 14.2 (q), 24.9 (t), 26.0
(t), 26.3 (t), 31.3 (t), 33.2 (t), 34.7 (q), 38.1 (q), 59.8 (d), 60.1
(t), 61.6 (t), 116.1 (s), 118.8 (s), 126.7 (s), 127.7 (s), 162.9 (s),
164.4 (s), 164.5 (s); IR (nujol): nmax =1745, 1730, 1640 cmÀ1
;
MS: m/z (%)=378 (M+) (45), 306 (100), 260 (71), 233 (100),
188 (67), 159 (100): anal. calcd. for C20H30N2O5 (378.46): C
63.47, H 7.99, N 7.40; found C 63.29, H 8.04, N 7.51.
Supporting Information
Tetramethyl 1,1’-hexane-1,6-diylbis{5-[(dimethylamino)-
carbonyl]-4-methyl-1H-pyrrole-2,3-dicarboxylate} (8j): mp:
Experimental details and spectroscopic characterization of
all compounds are given in the Supporting Information.
1
142–1448C; H NMR (400 MHz, DMSO-d6, 258C): d=1.02–
1.26 (m, 4H), 1.41–1.56 (m, 4H), 2.04 (s, 6H), 2.84 (s, 6H),
2.95 (s, 6H), 3.75 (s, 6H), 3.83–3.92 (m, 2H), 3.96 (s, 6H),
4.04–4.13 (m, 2H); 13C NMR (100 MHz, DMSO-d6, 258C):
d=9.8 (q), 24.6 (t), 27.6 (t), 33.8 (q), 37.3 (q), 45.5 (t), 51.4
(q), 53.2 (q), 116.5 (s), 117.5 (s), 125.2 (s), 128.5 (s), 160.4
(s), 161.1 (s), 163.7 (s); IR (nujol): nmax =3393, 3243, 1782,
1721, 1702, 1674 cmÀ1; MS: m/z (%)=618 (M+) (6), 559
(12), 486 (38), 456 (67), 428 (52), 355 (100), 297 (43), 238
(53); anal. calcd. for C30H42N4O10 (618.68): C 58.24, H 6.84,
N 9.06; found C 58.42, H 6.78, N 8.95.
Acknowledgements
The authors thank the Ministero dell’Istruzione, dell’Universi-
tꢀ e della Ricerca (MIUR) – Roma and the Universitꢀ degli
Studi di Urbino “Carlo Bo”.
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Adv. Synth. Catal. 2011, 353, 595 – 605
ꢁ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
603

Orazio A. Attanasi et al.
FULL PAPERS
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