One-pot three-component synthesis of tetrasubstituted N - H pyrroles from secondary propargylic alcohols, 1,3-dicarbonyl compounds and tert-butyl carbamate

Article abstract of DOI:10.1002/jhet.301

(Chemical Equation Presented) Several tetrasubstituted N - H pyrroles, functionalized with ester or ketone groups at C-3 position, were prepared by one-pot coupling of secondary propargylic alcohols with 1,3-dicarbonyl compounds and tert-butyl carbamate,

Full text of DOI:10.1002/jhet.301

January 2010
One-Pot Three-Component Synthesis of Tetrasubstituted NAH
Pyrroles from Secondary Propargylic Alcohols, 1,3-Dicarbonyl
Compounds and tert-Butyl Carbamate
233
´
Victorio Cadierno,* Jose Gimeno,* and Noel Nebra
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Departamento de Quımica Organica e Inorganica. IUQOEM (Unidad Asociada al CSIC),
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Universidad de Oviedo, Julian Claverıa 8, 33006 Oviedo, Spain
*E-mail: vcm@uniovi.es or jgh@uniovi.es
Received August 17, 2009
DOI 10.1002/jhet.301
Published online 8 January 2010 in Wiley InterScience (www.interscience.wiley.com).
Several tetrasubstituted NAH pyrroles, functionalized with ester or ketone groups at C-3 position,
were prepared by one-pot coupling of secondary propargylic alcohols with 1,3-dicarbonyl compounds
and tert-butyl carbamate, via in situ deprotection of the corresponding pentasubstituted N-Boc pyrroles.
The three-component coupling process was promoted by the combined use of the 16-electron rutheniu-
m(II) catalyst [Ru(g3-2-C3H4Me)(CO)(dppf)][SbF6] (dppf ¼ 1,10-bis(diphenylphosphino)ferrocene) and
trifluoroacetic acid (TFA).
J. Heterocyclic Chem., 47, 233 (2010).
INTRODUCTION
In this context, we have recently described an effi-
cient one-pot three-component coupling reaction for the
synthesis of fully substituted pyrroles from secondary
propargylic alcohols, 1,3-dicarbonyl compounds (b-dike-
tones or b-keto esters), and primary amines (Scheme 1)
[8]. The process, which is catalyzed by the 16-electron
allyl-ruthenium(II) complex [Ru(g3-2-C3H4Me)(CO)
(dppf)][SbF6] (1; dppf ¼ 1,10-bis(diphenylphosphino)fer-
rocene) and trifluoroacetic acid (TFA), involves the ini-
tial propargylation of the 1,3-dicarbonyl compound pro-
moted by TFA, subsequent condensation between the
resulting c-keto alkyne A and the primary amine to
afford a b-enamino ester or ketone B, which undergoes
a ruthenium-catalyzed 5-exo-dig annulation to give the
final pyrrole (indium(III) chloride is also able to pro-
mote efficiently these propargylation/condensation/cyclo-
isomerization tandem reactions [9]; we note that
involvement of propargylic alcohols in multicomponent
syntheses of pyrroles is scarcely documented [10]).
Pyrroles are one of the most prominent heterocyclic
compounds, being present as key structural motifs in
several natural products (for reviews, see [1]), conduct-
ing organic materials (for reviews, see [2]), and bioac-
tive molecules (for reviews, see [3]). Consequently, a
large number of general methods have been developed
to construct these five-membered heterocycles, including
the well-known Knorr, Paal-Knorr, and Hantzch synthe-
ses, 1,3-dipolar cycloaddition reactions, reductive cou-
plings, and aza-Wittig reactions (see, for example, [4]).
However, it is still challenging to prepare polysubsti-
tuted pyrroles directly from inexpensive and readily
available starting materials. In this sense, important
efforts have been made during the last years in the
design of multicomponent strategies (for reviews and
highlights on pyrrole syntheses through multicomponent
reactions, see [5] and for recent examples of multicom-
ponent syntheses of pyrroles, see [6]). Multicomponent
reactions (MCR), in which multiple reactants are com-
bined into a single product, offer significant advantages
over classical linear syntheses since molecular diversity
can be reached from simple precursors in an efficient,
economic, and environmentally friendly manner (see,
for example, [7]).
Following this route, which allows the direct introduc-
tion of carbonyl functionalities onto the pyrrolic skele-
ton and tolerates the presence of a wide variety of func-
tional groups in the starting materials, a large number of
pentasubstituted pyrroles could be synthesized in good
to excellent yields [8]. As an extension of these studies,
herein, we report on the applicability of this one-pot
C
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234
V. Cadierno, J. Gimeno, and N. Nebra
Vol 47
Scheme 1
three-component reaction for the synthesis of tetrasubsti-
tuted NAH pyrroles.
in Scheme 2, treatment of THF solutions of propargylic
alcohols 2a–e with ethyl acetoacetate and tert-butyl car-
bamate (1:1:1 molar ratio) in the presence of 50 mol %
of TFA and 5 mol % of complex 1 led, after 24 h of
heating (75ꢀC), to the selective formation of pyrroles
3a–e, which were isolated in 60–82% yield after appro-
priate chromatographic workup.
RESULTS AND DISCUSSION
In our first report, we already attempted the prepara-
tion of NAH pyrroles by coupling secondary propargylic
alcohols with 1,3-dicarbonyl compounds in the presence
of simple ammonia sources such as NH4OH or NH4Cl.
Unfortunately, the desired products were not formed
using these inexpensive reagents, the reactions leading
instead to the major formation of tetrasubtituted furans
as the result of the known 5-exo-dig annulation of c-
keto alkyne intermediates A [11]. Only the use of prop-
argylamine allowed us the preparation of this type of
molecules (one example), via TFA-promoted scission of
the CAN bond on the initially formed pentasubstituted
N-propargyl pyrrole [8]. However, an extremely long
reaction time (4 days) was required reducing consider-
ably the synthetic interest of the process. This fact
prompted us to search for a more appropriate NH source
compatible with the propargylation/condensation/cycloi-
somerization sequence outlined in Scheme 1. Thus, our
attention turned firstly to ammonium carbamate since it
was successfully employed by Zhan and coworkers in
related reactions using InCl3 as promoter [9]. However,
the reactions, which were performed in the presence of
variable amounts of this reagent (1–10 equiv.), led again
to the major formation of furans with only traces of the
desired NH pyrroles being detected by GC/MS in the
crude reaction mixtures. Neither the use of primary
silylamines, such as NH2SiPh3, gave to the desired
results. Finally, we were pleased to find that commer-
cially available tert-butyl carbamate is compatible with
our one-pot three-component reaction. Thus, as shown
Characterization of 3a–e was straightforward by fol-
lowing their analytical and spectroscopic data. In partic-
ular, the presence of the NAH unit was unambiguously
confirmed by the appearance of: (i) an intense absorp-
tion band at about 3300 cmꢁ1 in their IR spectra, and
(ii) a singlet signal at about 8 ppm in their 1H-NMR
spectra. Pyrroles 3a–e result from the TFA-mediated hy-
drolysis of the tert-butyl ester (Boc) group in the ini-
tially formed pentasubstituted pyrroles C (detected mon-
itoring the reactions by GC/MS) and subsequent decar-
boxylation of the resulting intermediates D (The Boc
group is a versatile and commonly used protecting
group for the pyrrole nitrogen atom, being easily remov-
able in acidic media. See, for example, [12]).
Following the same approach, NH-pyrroles 4a–d and
5a–b (Fig. 1) could also be synthesized in 64–79% yield
employing methyl acetoacetate and 2,4-pentanedione as
the 1,3-dicarbonyl compound, respectively, thus con-
firming the generality of this transformation.
In summary, an efficient MCR reaction for the prepa-
ration of tetrasubstituted NAH pyrroles, functionalized
with carbonyl groups at C-3 position, has been devel-
oped using the catalytic system [Ru(g3-2-C3H4Me)(-
CO)(dppf)][SbF6]/TFA. The results reported herein rep-
resent a new example of the utility of the allyl-rutheniu-
m(II) complex 1 in synthetic organic chemistry (for an
account on the applications of complex 1 in synthesis,
see [13]).
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

January 2010
One-Pot Three-Component Synthesis of Tetrasubstituted NAH Pyrroles from
Secondary Propargylic Alcohols, 1,3-Dicarbonyl Compounds and tert-Butyl Carbamate
235
Scheme 2
EXPERIMENTAL
(300 MHz, CDCl3): d 1.08 (t, J ¼ 7.1 Hz, 3H), 2.10, 2.49, and
3.80 (s, 3H each), 4.09 (q, J ¼ 7.1 Hz, 2H), 6.78–6.86 (m,
3H), 7.24 (m, 1H), 8.21 (s, 1H) ppm; 13C{1H} NMR (75
MHz, CDCl3): d 11.1, 13.5, 14.0, 55.1, 59.0, 110.5, 111.3,
116.0, 122.1, 123.0, 123.5, 128.1, 133.5, 137.6, 158.7, 165.7
ppm; GC-MS (EI, 70 eV): m/z 273 (100%, Mþ), 244 (60), 227
(55), 198 (18), 184 (25), 168 (20), 156 (15), 115 (15); Anal.
Calcd. for C16H19O3N: C, 70.31; H, 7.01; N, 5.12. Found: C,
70.44; H, 7.19; N, 5.06.
Infrared spectra were recorded on a Perkin-Elmer 1720-XFT
spectrometer. NMR spectra were recorded on a Bruker DPX-
300 instrument at 300 MHz (1H) or 75 MHz (13C). The chemi-
cal shift values (d) are given in parts per million and are
referred to the residual peak of the deuterated solvent used
(CDCl3). DEPT experiments have been carried out for all the
compounds reported. GC/MS measurements were performed
on a Agilent 6890N equipment coupled to a 5973 mass detec-
tor (70 eV electron impact ionization) using a HP-1MS col-
umn. Elemental analyses were acquired with a Perkin-Elmer
2400 microanalyzer. Flash chromatography was performed
using Merck silica gel 60 (230–400 mesh). All reagents were
obtained from commercial suppliers and used without any fur-
ther purification, with the exception of complex 1 [14] and
propargylic alcohols 2b–e [15] which were prepared by fol-
lowing the methods reported in the literature.
General procedure for the catalytic reactions. The appro-
priate propargylic alcohol 2a–e (1 mmol), 1,3-dicarbonyl com-
pound (1 mmol), and tert-butyl carbamate (1 mmol) were
introduced into a sealed tube under a nitrogen atmosphere.
THF (0.5 mL), complex 1 (0.049 g, 0.05 mmol), and TFA (37
lL, 0.5 mmol) were then added at room temperature, and the
resulting solution was heated at 75ꢀC for 24 h. After elimina-
tion of the solvent under reduced pressure, the crude reaction
mixture was purified by column chromatography over silica
gel using an ethyl acetate/hexane mixture (1:10 v/v) as eluent.
1H and 13C{1H} NMR spectra, as well as melting points,
obtained for compounds 3a [9], 3b [16], 3d [8], 3e [9], 4a
[16], 4c [16], 5a [17], and 5b [18] were in complete accord
with those described in the literature. Characterization data for
the novel pyrroles 3c and 4b,d are as follows:
4-(2-Methoxyphenyl)-2,5-dimethyl-1H-pyrrole-3-carboxylic
acid methyl ester (4b) Orange solid; Yield: 0.205 g (79%);
1
mp: 138ꢀC; IR (Nujol): 3314 (NAH), 1683 (C¼¼O) cmꢁ1; H-
NMR (300 MHz, CDCl3): d 2.05, 2.47, 3.59, and 3.75 (s, 3H
each), 6.90–6.99 (m, 2H), 7.15 (dd, J ¼ 7.4 and 1.7 Hz, 1H),
7.26 (td, J ¼ 8.0 and 1.7 Hz, 1H), 8.31 (s, 1H) ppm; 13C{1H}
NMR (75 MHz, CDCl3): d 11.1, 13.4, 50.3, 55.3, 110.3,
111.1, 117.7, 119.9, 123.8, 125.2, 127.6, 131.5, 133.6, 157.4,
166.4 ppm; GC-MS (EI, 70 eV): m/z 259 (85%, Mþ), 228
(15), 212 (100), 200 (50), 184 (60), 168 (18), 154 (15), 128
(35), 115 (45), 15 (90); Anal. Calcd. for C15H17O3N: C, 69.48;
H, 6.61; N, 5.40. Found: C, 69.55; H, 6.74; N, 5.52.
4-(4-Methoxyphenyl)-2,5-dimethyl-1H-pyrrole-3-carboxylic
acid methyl ester (4d) Orange solid; Yield: 0.199 g (77%);
4-(3-Methoxyphenyl)-2,5-dimethyl-1H-pyrrole-3-carboxylic
acid ethyl ester (3c) Orange solid; Yield: 0.169 g (62%); mp:
1
144ꢀC; IR (Nujol): 3311 (NAH), 1683 (C¼¼O) cmꢁ1; H-NMR
Figure 1. Structures of the NH-pyrroles 4a–d and 5a–b.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

236
V. Cadierno, J. Gimeno, and N. Nebra
Vol 47
mp: 140ꢀC; IR (Nujol): 3295 (NAH), 1687 (C¼¼O) cmꢁ1; H-
NMR (300 MHz, CDCl3): d 2.08, 2.48, 3.64, and 3.82 (s, 3H
each), 6.89 and 7.18 (d, J ¼ 8.6 Hz, 2H each), 8.15 (s, 1H)
ppm; 13C{1H} NMR (75 MHz, CDCl3): d 11.1, 13.7, 50.3,
55.1, 110.1, 112.8, 122.0, 123.4, 128.4, 131.2, 133.9, 157.7,
166.3 ppm; GC-MS (EI, 70 eV): m/z 259 (100%, Mþ), 244
(20), 228 (20), 198 (18), 184 (23), 168 (24), 156 (30), 115
(40), 42 (60), 15 (80); Anal. Calcd. for C15H17O3N: C, 69.48;
H, 6.61; N, 5.40. Found: C, 69.31; H, 6.78; N, 5.59.
1
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet