Iron-catalyzed synthesis of polysubstituted pyrroles via [4C+1N] cyclization of 4-acetylenic ketones with primary amines

Article abstract of DOI:10.1039/c0cc03802d

A highly efficient iron-catalyzed approach to polysubstituted pyrroles has been developed through the [4C+1N] cyclization of 4-acetylenic ketones with primary amines, leading to the synthesis of a variety of tetra- and fully-substituted pyrroles as well a

Full text of DOI:10.1039/c0cc03802d

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Iron-catalyzed synthesis of polysubstituted pyrroles via [4C+1N]
cyclization of 4-acetylenic ketones with primary amineswz
Yeming Wang, Xihe Bi,* Dehua Li, Peiqiu Liao, Yidong Wang, Jin Yang, Qian Zhang* and
Qun Liu
Received 11th September 2010, Accepted 14th October 2010
DOI: 10.1039/c0cc03802d
A highly efficient iron-catalyzed approach to polysubstituted
pyrroles has been developed through the [4C+1N] cyclization
of 4-acetylenic ketones with primary amines, leading to the
synthesis of a variety of tetra- and fully-substituted pyrroles as
well as fused pyrrole derivatives in good to excellent yields.
been used to catalyze relevant reactions but were unsuccessful.
For example, when Zhan and co-workers employed FeCl3
instead of InCl3 in an indium-catalyzed multicomponent
reaction of propargyl alcohols, b-dicarbonyl compounds and
primary amine for the synthesis of pyrroles, the reaction was
stuck at the step of 4-acetylenic ketone without further
cyclization with amines.12 Considering the many reactive
species in the reaction mixture, which possibly deactivated
the iron catalyst, we hypothesized that the cyclization of
4-acetylenic ketones with primary amines directly catalyzed by
iron salts might be feasible. Further studies realized this idea. In
this context, we wish to report results on the iron-catalyzed
synthesis of polysubstituted pyrrole derivatives, including the
achievement of a previously unexploited synthesis of fully-
substituted pyrroles via this [4C+1N] cyclization reaction. A
mechanistic study disclosed an iron-catalyzed intramolecular
hydroamination of the alkyne in the ring-closing step. To our
knowledge, this is the first procedure for the synthesis of
pyrroles using non-toxic iron salts as catalysts with high
reaction efficiency, good to excellent yields, and a wide
variation of substituents.
Pyrroles are among the most representative heteroaromatic
compounds and are common structural motifs in many
biologically active molecules and pharmaceutical substances,
they are also widely employed as versatile building blocks in
synthetic organic chemistry.1,2 The interest in the pyrrole unit
is exemplified by the great variety of procedures known for its
synthesis.3 Among them, the metal-catalyzed cyclization
reactions have taken a dominant position, and a variety of
metal species have been utilized in the synthesis of pyrroles,
including Au, Ag, Pd, Pt, Rh, Ru, Cu, In, Mg, Zr, Co, Zn, Bi,
Ni, Sc, and Yb.4 Iron is one of the most abundant metals on
Earth, and the study of iron-catalyzed reactions has received
great attention in recent years,5 however, reports on the iron-
catalyzed reaction for the synthesis of pyrroles are still rare.6
Moreover, the reported methods exhibit significant
deficiencies, for example, using stoichiometric amounts of
highly toxic carbonyl irons7 and lacking the variation of
substituents on the pyrrole ring due to the unity of starting
materials.8 More recently, Maiti et al. reported an iron(III)-
catalyzed, operationally simple four-component coupling
reaction of 1,3-dicarbonyl compounds, amines, aromatic
aldehydes, and nitroalkanes, however, it generally required
long reaction times and afforded pyrroles in low yields in most
cases.9 Therefore, the development of an efficient iron-
catalyzed synthesis of pyrroles is highly desirable.
In the initial attempts to screen the iron catalysts for the
[4C+1N] cyclization of 4-acetylenic ketones with primary
amines, the reaction of 4-acetylenic ketone 1a1 and
4-chlorobenzenamine was selected as a model. A toluene
solution of 4-acetylenic ketone 1a1 was allowed to react with
4-chlorobenzenamine (1.2 equivalents) at 60 1C in the presence
of a catalytic amount of the iron salt (10 mol%). The
representative data were summarized in Table 1. To our
delight, on using iron halide salts such as FeCl3 or FeBr3 as
catalysts, excellent yields of pyrrole 2a1 were obtained in 89
and 91% yields, respectively (entries 1 and 2). The structure of
2a1 was established by X-ray analysis (CCDC 792079w).
Fe(OTf)3 gave a similarly high yield of 2a1 in a short time,
whereas 10 mol% CF3SO3H produced 2a1 in 78% yield in 18 h
but with 10% substrate 1a1 recovered (entries 3 and 4), which
confirmed that the iron salt is the active catalyst. Fe(acac)3
afforded a mixture of pyrrole 2a1 and unreacted substrate 1a1
with the ratio of 43% to 57% determined by 1H-NMR analysis
of reaction mixture (entry 5). Interestingly, the oxidation state
of iron appears to have no influence on the catalysis, because
the FeCl2 afforded a similar yield of 2a1 to that under a
nitrogen atmosphere which could to a large extent protect
FeCl2 from oxidizing to FeCl3 (entries 6, 7). Other iron sources
such as Fe2O3 and Fe powder all gave poor yields of pyrrole
2a1, and most of the substrate 1a1 was recovered (entries 8, 9).
Furthermore, upon decreasing the amount of FeCl3 catalyst to
0.1 mol%, the reaction still proceeded smoothly, affording 2a1
During our continued interest in the development of iron-
catalyzed reactions for the synthesis of heterocycles,10 we have
noted the [4C+1N] cyclization of 4-acetylenic ketones with
primary amines acting as a straightforward approach to
polysubstituted pyrrole derivatives. This route is attractive
because both substrates are easily available. Until now, only a
few catalysts have been utilized to catalyze this transformation,
including gold, silver, palladium, and copper.11 Iron salts have
Department of Chemistry, Northeast Normal University,
5268 Renmin Street, 130024 Changchun, China.
E-mail: bixh507@nenu.edu.cn, zhangq651@nenu.edu.cn
w Electronic supplementary information (ESI) available: Experimental
procedure, 1H and 13C NMR spectra for all compounds. CCDC
792079. For ESI and crystallographic data in CIF or other electronic
format see DOI: 10.1039/c0cc03802d
z Dedicated to Professor Michael Famulok on the occasion of his 50th
birthday.
c
This journal is The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 809–811 809

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Table 1 Screening the iron catalysta
keto, ester, and aryl groups all furnished the desired products
2a1–2a7 in high to excellent yields within short times (entries
1–7). The R1 group appears to be tolerant to bulky aromatic
groups, thus product 2b1 was formed in nearly the same
efficiency as 2b2 (entries 8, 9). The internal alkyne was also
applicable to this iron-catalyzed procedure, yielding 84% 2c
(entry 10). Treatment of 4-acetylenic ketones 1a1 with various
primary amines furnished the corresponding tetrasubstituted
pyrroles 2d in good to excellent isolated yields (entries 11–21).
Aromatic amines whether with electron-withdrawing groups
or with electron-donating groups are all suitable for this
protocol (2d1–2d5). Additionally, the sterically hindered 2,6-
diisopropylaniline as well as the fused aromatic naphthalen-2-
amine proved to be suitable partners (2d6 and 2d7). All of the
tested aliphatic amines resulted in excellent yields of pyrroles
2d8–2d11 (82%–91%). Noticeably, most of the pyrroles 2
contain a characteristic 3-carboxamide group. The pyrrole-3-
carboxamide was found to be a key subunit in therapeutically
active compounds,13 for example, the well-known cholesterol-
reducing drug Lipitors. Thus, we have provided an efficient
access to such kinds of compounds.
Entry
Fe source
Time (h)
2a1 Yield (%)b
1
2
3
4
5
6
7
8
9
10
FeCl3
FeBr3
1.5
1.5
1.8
18
89
91
86
Fe(OTf)3
CF3SO3H
Fe(acac)3
FeCl2
78 (10)b
43 (57)c
83
24
2.0
3.0
24
24
10
d
FeCl2
80
Fe2O3
Fe
FeCl3
40 (60)c
33 (67)c
81
e
a
Reactions were performed with 4-acetylenic ketone 1a1 (1.0 mmol),
4-chlorobenzenamine (1.2 mmol), and [Fe] catalyst (10 mol%) in
b
c
toluene (1 mL) at 60 1C. Isolated yields. Ratio of the product 2a
to the recovered reactant 1a1 in parentheses was determined by
1H-NMR analysis of crude reaction mixture. Under nitrogen
d
e
protection. 0.1 mol% FeCl3 was used.
Catalytic approaches to fully-substituted pyrroles remains
scarce;14 on the other hand, the [4C+1N] strategy of
4-acetylenic ketones with primary amines has yet to be
exploited for the synthesis of fully-substituted pyrroles, so we
decided to achieve this aim by using the iron-catalyzed
procedure. As shown in Table 3, all the 4-acetylenic ketones
1b with representative variation of substituents reacted
smoothly with aromatic or alkyl primary amines, affording
the corresponding fully-substituted 3a–3f in high yields.
in 81% yield, albeit within a much longer reaction time (entry 10).
Considering the reaction efficiency, we thus chose the condition
of 10 mol% FeCl3 as a catalyst for the following study.
Under the optimal conditions (Table 1, entry 1), we started
to explore the scope of the iron-catalyzed cyclization. A range
of tetrasubstituted pyrroles were firstly prepared starting from
the 4-acetylenic ketones 1a, and the results are summarized in
Table 2. The variation of R2 groups on 1a including amide,
Table 2 Iron-catalyzed synthesis of tetrasubstituted pyrrolesa
Entry
R1
R2
R3
R4
Time (h)
2
Yield (%)b
1
2
3
4
5
6
7
8
Me
Me
Me
Me
Me
Me
Me
4-MeOPh
Et
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
CONHPh
CONH(4-MePh)
CONH(4-ClPh)
COPh
COMe
COOEt
4-MeOPh
CONH(4-MePh)
CONH(4-MePh)
CONHPh
CONHPh
CONHPh
CONHPh
CONHPh
CONHPh
CONHPh
CONHPh
CONHPh
CONHPh
CONHPh
CONHPh
H
H
H
H
H
H
H
H
H
Et
H
H
H
H
H
H
H
H
H
H
H
4-ClPh
4-ClPh
4-ClPh
4-ClPh
4-ClPh
4-ClPh
4-ClPh
4-ClPh
4-ClPh
4-ClPh
Ph
4-MePh
2,4-diMeOPh
2-ClPh
1.5
1.5
1.5
1.5
1.0
1.0
1.5
2
1.5
1.5
1.5
2
2a1
2a2
2a3
2a4
2a5
2a6
2a7
2b1
2b2
2c
2d1
2d2
2d3
2d4
2d5
2d6
2d7
2d8
2d9
2d10
2d11
89
87
78
89
91
90
78
81
84
84
86
83
82
90
92
79
79
87
82
83
91
9
10
11
12
13
14
15
16
17
18
19
20
21
5
1.5
1.5
4
4
1.5
2
3-ClPh
2,6-di(i-Pr)Ph
2-Naphthyl
Bn
Cyclohexyl
n-Bu
(MeO)2CHCH2
2.5
2
a
b
Reactions were performed with 4-acetylenic ketones 1a (1.0 mmol), amines (1.2 mmol), and FeCl3 (10 mol%) in Toluene (1 mL) at 60 1C. Isolated
yields.
c
This journal is The Royal Society of Chemistry 2011
810 Chem. Commun., 2011, 47, 809–811

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Table 3 Iron-catalyzed synthesis of fully-substituted pyrrolesa
Scheme 1 A plausible reaction mechanism.
Based on the above result as well as other annulation
processes involving the metal-catalyzed intramolecular
hydroamination of alkynes,16 a mechanistic proposal for this
iron-catalyzed process is depicted in Scheme 1. The enamine
was first formed by the condensation of carbonyl group and
primary amine with the release of one H2O. Subsequently, the
regioselective 5-exo-dig annulation took place through an iron-
catalyzed intramolecular hydroamination of alkynes followed
by isomerization to give pyrroles.
a
Reactions were performed with 4-acetylenic ketones 1b (1.0 mmol),
amines (1.2 mmol), and FeCl3 (10 mol%) in toluene (1 mL) at reflux.
Compared with the conditions for the synthesis of
tetrasubstituted pyrroles, this reaction needed to be heated at
reflux to reach a fast transformation, otherwise, the substrates
can not disappear, which indicated that the presence of aromatic
R5 group heavily affected the cyclization efficiency. Overall,
the iron-catalyzed procedure constitutes a straightforward
alternative to the limited catalytic approaches to the synthesis
of fully-substituted pyrroles that are presently available.
Cyclic ketone 1c was applied to the iron-catalyzed
cyclization with representative amines under the above
conditions (10 mol% FeCl3, toluene, reflux), to our delight,
the corresponding fused pyrrole 6,7-dihydro-4-indolones 4
were also produced in good yields within short times
(Table 4, entries 1–4).
We gratefully acknowledge NSFC (20902010) and NCET
(08-0756) for financial support.
Notes and references
1 F. Bellina and R. Rossi, Tetrahedron, 2006, 62, 7213.
2 Pyrroles, The Synthesis, Reactivity, and Physical Properties of
Substituted Pyrroles, Part II, ed. R. A. Jones, Wiley, New York, 1992.
3 D. St. C. Black, in Science of Synthesis, ed. G. Maas, Georg Thieme
Verlag, Stuttgart, New York, vol. 9, 2001, pp. 441–552.
4 For representative examples for the metal-catalyzed synthesis of
pyrroles please see the ESI.
5 C. Bolm, J. Legros, J. Le Paih and L. Zani, Chem. Rev., 2004, 104, 6217.
6 For a summary of the iron-catalyzed reactions for the synthesis of
pyrroles please see the ESI.
7 (a) S. Nakanishi, Y. Otsuji, K. Itoh and N. Hayashi, Bull. Chem.
Soc. Jpn., 1990, 63, 3595; (b) M. Nitta, H. Miyano and
T. Kobayashi, Heterocycles, 1986, 24, 77; (c) M. Nitta and
T. Kobayashi, Chem. Lett., 1985, 877; (d) S. Nakanishi, Y. Shirai,
K. Takahashi and Y. Otsuji, Chem. Lett., 1981, 869; (e) F. Bellamy,
J. L. Schuppiser and J. Streith, Heterocycles, 1978, 11, 461.
8 (a) P. Nesvadba and J. Kuthan, Coll. Czech. Chem. Commun., 1982,
47, 1494; (b) N. Azizi, A. Khajeh-Amiri, H. Ghafuri,
M. Bolourtchian and M. R. Saidi, Synlett, 2009, 2245.
ð1Þ
To investigate the reaction mechanism, the reaction of
compound 1c with 4-chlorobenzenamine was quenched at
half way. In addition to the pyrrole 4a (60%), an enaminone
4a–i was isolated in 10% yield (eq. (1)). In an independent
experiment, the enaminone 4a–i was quickly converted into 4a
in the presence of 10 mol% FeCl3 in refluxing toluene, which
indicated that 4a–i is the precursor for pyrrole 4a and the ring
closure proceeded through an iron-catalyzed intramolecular
hydroamination of alkynes.15
9 S. Maiti, S. Biswas and U. Jana, J. Org. Chem., 2010, 75, 1674.
10 Y. Wang, W.-Q. Li, G. Che, X. Bi, P. Liao, Q. Zhang and Q. Liu,
Chem. Commun., 2010, 46, 6843.
11 (a) T. J. Harrison, J. A. Kozak, M. Corbella-Pane and G. R. Dake,
´
J. Org. Chem., 2006, 71, 4525; (b) A. Arcadi, S. Di Giuseppe,
F. Marinelli and E. Rossi, Adv. Synth. Catal., 2001, 343, 443;
(c) A. Arcadi and E. Rossi, Tetrahedron, 1998, 54, 15253;
(d) A. Arcadi and E. Rossi, Synlett, 1997, 667J. Barluenga,
´ ´
M. Tomas, V. Kouznetsov, A. Suarez-Sobrino and E. Rubio,
J. Org. Chem., 1996, 61, 2185.
Table 4 Iron-catalyzed synthesis of fused pyrrolesa
12 X. Liu, L. Huang, F. Zheng and Z. Zhan, Adv. Synth. Catal., 2008,
350, 2778.
13 (a) B. D. Roth, Prog. Med. Chem., 2002, 40, 1; (b) D. Lindsay and
P. Jackson, PCT Int. Pat. Appl., WO 2010/103319 A1, 2010;
(c) J. Nuss, M. Williams, R. Mohan, R. Martin, T.-L. Wang,
K. Aoki, H. Tsuruoka, N. Hayashi and T. Homma, PCT Int. Pat.
Appl., WO 2010/042622 A1, 2010; (d) M. A. Seefeld and
M. B. Rouse, PCT Int. Pat. Appl., WO 2008/098105 A1, 2008.
14 Selected examples, see: (a) D. J. St. Cyr, N. Martin and
B. A. Arndtsen, Org. Lett., 2007, 9, 449; (b) J. T. Binder and
S. F. Kirsch, Org. Lett., 2006, 8, 2151; (c) J. Wang, X. Wang, Z. Yu
and W. Yu, Adv. Synth. Catal., 2009, 351, 2063.
Entry
R4
Time (h)
4
Yield (%)b
1
2
3
4
Ph
0.5
0.5
0.6
0.6
4a
4b
4c
4d
71
75
70
75
4-ClC6H4
4-MeC6H4
Bn
a
Reactions were performed with 4-acetylenic ketones 1c (1.0 mmol),
amines (1.2 mmol), and FeCl3 (10 mol%) in toluene (1 mL) at
15 V. Terrason, J. Michaux, A. Gaucher, J. Wehbe, S. Marque,
D. Prim and J.-M. Campagne, Eur. J. Org. Chem., 2007, 5332.
16 R. Severin and S. Doye, Chem. Soc. Rev., 2007, 36, 1407.
b
reflux. Isolated yields.
c
This journal is The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 809–811 811