Tetrahedron 71 (2015) 2595e2602
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Tetrahedron report number 1077
Unique chemoselective Paal-Knorr reaction catalyzed by MgI2
etherate under solvent-free conditions
Xingxian Zhang *, Guodong Weng, Yongdong Zhang, Pengcheng Li
College of Pharmaceutical Sciences, Zhejiang University of Technology, Hangzhou, Zhejiang 310032, PR China
a r t i c l e i n f o
Article history:
Received 3 January 2015
Received in revised form 3 March 2015
Accepted 7 March 2015
Available online 12 March 2015
Keywords:
Chemoselective
Paal-Knorr reaction
Primary amine
1,4-Diketone
MgI2 etherate
Contents
1.
2.
3.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2596
Results and discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2596
Experimental section . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2600
3.1.
General procedure for the synthesis of N-substituted pyrroles 3ae3t . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2600
3.1.1. 1-Phenyl-2,5-dimethyl-1H-pyrrole (3a)29 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2600
3.1.2. 1-o-Tolyl-2,5-dimethyl-1H-pyrrole (3b)30 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2600
3.1.3. 1-(4-Methoxyphenyl)-2,5-dimethyl-1H-pyrrole31 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2600
3.1.4. 1-(3-Methoxyphenyl)-2,5-dimethyl-1H-pyrrole (3d)30 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2600
3.1.5. 1-(2,6-Diisopropylphenyl)-2,5-dimethyl-1H-pyrrole (3e)32 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2600
3.1.6. 1-(4-Bromophenyl)-2,5-dimethyl-1H-pyrrole (3f)27 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2600
3.1.7. 1-(3,5-Difluorophenyl)-2,5-dimethyl-1H-pyrrole (3g)33 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2600
3.1.8. 1-(4-Nitrophenyl)-2,5-dimethyl-1H-pyrrole (3h)29 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2600
3.1.9.
2,5-Dimethyl-1-(4-amino-3-nitrophenyl)-1H-pyrrole (3i) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2600
3.1.10.
2-(2,5-Dimethyl-1H-pyrrol-1-yl)pyridine (3j)15 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2600
3.1.11.
2-(2,5-Dimethyl-1H-pyrrol-1-yl)pyrimidine (3k)34 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2600
3.1.12. 1-Benzyl-2,5-dimethyl-1H-pyrrole (3l)27 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2600
3.1.13. 1-(4-Fluorobenzyl)-2,5-dimethyl-1H-pyrrole (3m)30 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2600
3.1.14. 1-Isobutyl-2,5-dimethyl-1H-pyrrole (3n)35 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2600
3.1.15.
2,5-Dimethyl-1-(prop-2-ynyl)-1H-pyrrole(3o)36 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2600
3.1.16.
(R)-1-(1-(Naphthalen-1-yl)ethyl)-2,5-dimethyl-1H-pyrrole (3p) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2600
3.1.17. 1-((1R,2S)-2-(3,4-Difluorophenyl)cyclopropyl)-2,5-dimethyl-1H-pyrrole (3q) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2600
3.1.18.
(S)-Methyl 2-(2,5-dimethyl-1H-pyrrol-1-yl)-3-phenylpropanoate (3r)37 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2601
3.1.19.
(R)-Methyl 2-(2,5-dimethyl-1H-pyrrol-1-yl)propanoate (3s) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2601
3.1.20.
(S)-2-(2,5-Dimethyl-1H-pyrrol-1-yl)-2-phenylacetamide (3t) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2601
3.1.21. 1-(4-Methoxyphenyl)-2-methyl-5-phenyl-1H-pyrrole (4a)30 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2601
3.1.22. 1-(4-Methoxybenzyl)-2-methyl-5-phenyl-1H-pyrrole (4b) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2601
* Corresponding author. Tel.: þ86 571 88320320; fax: þ86 571 88320913; e-mail address: [email protected] (X. Zhang).
http://dx.doi.org/10.1016/j.tet.2015.03.035
0040-4020/Ó 2015 Elsevier Ltd. All rights reserved.
2596
4.
X. Zhang et al. / Tetrahedron 71 (2015) 2595e2602
3.1.23. 1-(1-(4-Methoxyphenyl)-2-methyl-5-phenyl-1H-pyrrol-3-yl) ethanone (4c)38 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2601
3.1.24. 1-(1-(4-Methoxybenzyl)-2-methyl-5-phenyl-1H-pyrrol-3-yl)ethanone (4d) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2601
3.1.25. 1-(2-Methyl-1-phenethyl-5-phenyl-1H-pyrrol-3-yl)ethanone (4e)38 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2601
3.1.26.
Ethyl 2-methyl-1-phenethyl-5-phenyl-1H-pyrrole-3-carboxylate (4f) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2601
3.1.27.
Ethyl 1-(4-methoxyphenyl)-2-methyl-5-phenyl-1H-pyrrole-3-carboxylate (4g)39 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2601
3.1.28.
Diethyl 1-(4-methoxyphenyl)-2,5-dimethyl-1H-pyrrole-3,4-dicarboxylate (4h)39 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2601
3.1.29.
Diethyl 1-4-chlorophenyl-2,5-dimethyl-1H-pyrrole-3,4-dicarboxylate (4i)39 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2601
3.1.30. 1,3-Bis(2,5-dimethyl-1H-pyrrol-1-yl)propane (5)35 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2601
3.1.31. 1,4-Bis(2,5-dimethyl-1H-pyrrol-1-yl)benzene (6)15 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2601
3.1.32.
2,5-Dimethyl-1-(4-aminophenyl)-1H-pyrrole (7)40 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2601
3.1.33.
4,40 -Bis(2,5-dimethyl-1H-pyrrol-1-yl)biphenyl (8)41 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2601
3.1.34.
2,5-Dimethyl-1-(2-aminophenyl)-1H-pyrrole (9)15 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2601
3.2.
General procedure for crossover reaction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2601
Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2602
Supplementary data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2602
References and notes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2602
1. Introduction
Pyrrole derivatives are important species with remarkable biological activities1 and useful intermediates in the synthesis of
natural products and heterocycles.2 Many methods for the synthesis of pyrrole derivatives have been developed, which involve
conjugate addition,3 Hantzsch procedure,4 1,3-dipolar cycloaddition reaction,5 transition metal-mediated cyclization,6 aza-Wittig
reaction,7 titanium catalyzed hydroamination of diynes,8 multicomponents reactions9 and other operations.10 Among them, the
Paal-Knorr reaction remains one of the most significant and simple
methods, which consists of the cyclocondensation of primary
amines with 1,4-diketones to produce N-substituted pyrroles.
Recently, many methods for the synthesis of pyrroles by PaalKnorr cyclization of primary amines with 1,4-diketones have been
developed in the presence of various Lewis acid catalysts, such as,
Ti(OiPr)4,13 ZrOCl2$8H2O,14 Sc(OTf)3,15 Bi(NO3)3$5H2O,16 ZrCl4,17
BiCl3/SiO2,18 InCl3,19 and FeCl3.20 Although, pyrroles can be obtained by the aforementioned strategies, it is highly desirable to
develop methods that will overcome the inherent limitations, such
as harsh reaction conditions, poor substrate generality, and can
introduce a diverse substitution pattern into the heterocyclic core.
Therefore, the development of less expensive, environmentally
benign, and easily handled promoters for the synthesis of
N-substituted pyrroles by Paal-Knorr condensation under neutral,
mild, and convenient condition is still highly desirable. Magnesium,
a practically ideal main group metal, which abundantly exists in
nature, has been actively investigated as a catalyst in the field of
CeC bond formation and functional group transformation.21
In our previous papers,22 we have demonstrated that MgI2
etherate could efficiently catalyze the Mukaiyama aldol reaction
of aldehydes with trimethylsilyl enolates, allylation of aldehydes
with allylstannane, cycloaddition of isocyanates with oxiranes
and Clauson-Kass reaction of primary amines with 2,5dimethoxytetrahydrofuran. In continuation of our ongoing
research field, we wish to report a mild, efficient, and highly
chemoselective Paal-Knorr condensation of various primary
amines with 1,4-diketones catalyzed by 3 mol % MgI2 etherate
under solvent-free conditions.
2. Results and discussion
Initially, we have chosen aniline and 2,5-hexadione 1a (acetonylacetone) as the model substrates for surveying the reaction
parameters in the model reaction. The results are summarized in
Table 1. By screening various solvents we have found that CH2Cl2 is
the best solvent for this reaction (Table 1, entry 1). Moderate yields
were given in THF, MeCN, acetone and methanol (Table 1, entries
2e5). Very low yield was given in DMF (Table 1, entries 6). It is
worthy to be noted that this Paal-Knorr reaction was carried out
very efficiently under solvent-free conditions in a short time. Under
solvent-free condition, temperature has a remarkable effect on the
yield of compound 3a. The results showed that the yields were
improved by increasing the reaction temperature. The excellent
yield was given at 70 C (Table 1, entry 9). However, the higher
temperature could not cause the obvious increase for the yield of
product (Table 1, entries 10e11). In addition, the reaction was carried out sluggishly without catalyst under solvent-free condition
(Table 1, entry 12). To examine the halide anion effect, halogen
analogs of MgI2 etherate, MgBr2 etherate, MgCl2, Mg(ClO4)2 and
Mg(OTf)2 were compared under parallel reaction conditions, respectively. The best result has been observed with MgI2 etherate as
the catalyst (Table 1, entry 9). Good yield was given by using 3 mol %
of MgClO4 (Table 1, entry 13). MgCl2 and MgBr2 etherate are also
effective to this reaction and produced the moderate yields (Table 1,
Table 1
Optimization of reaction conditions for MgX2-catalyzed Paal-Knorr reactiona
O
Me
Me
Me
+ Ph NH2
3 mol% MgX2
2a
N Ph
O
Me
1a
3a
Entry
Solvent
Catalyst
Temp ( C)
Time (h)
Yields (%)b
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
DCM
MeCN
THF
MeOH
Acetone
DMF
None
None
None
None
None
None
None
None
None
None
MgI2(OEt2)n
MgI2(OEt2)n
MgI2(OEt2)n
MgI2(OEt2)n
MgI2(OEt2)n
MgI2(OEt2)n
MgI2(OEt2)n
MgI2(OEt2)n
MgI2(OEt2)n
MgI2(OEt2)n
MgI2(OEt2)n
None
Mg(ClO4)2
MgCl2
MgBr2(OEt2)n
Mg(OTf)2
40
70
70
65
55
70
30
50
70
90
110
70
70
70
70
70
5
5
5
5
5
5
1
1
1
1
1
5
2
2
2
2
94
75
70
78
60
20
70
76
96
89
89
48
85
75
78
50
a
The reaction was carried out by the condensation of aniline(5.0 mmol) and 2,5hexadione (6.0 mmol) in the presence of MgX2 under the above reaction conditions.
b
Isolated yield by silica gel flash chromatography.
X. Zhang et al. / Tetrahedron 71 (2015) 2595e2602
entries 14e15). However, Mg(OTf)2 is less effective in terms of
substrate conversion (Table 1, entry 16).
With these optimal conditions in hand, we further explored the
scope and limitation of this simple process by reaction of electronically, sterically and functionally diverse amines with 2,5-hexadione
under the same conditions. The results are listed in Table 2. As
shown in Table 2, the reaction proceeded smoothly under solventfree conditions at 70 C and provided 2,5-dimethyl-N-substituted
pyrroles in good to excellent yields. Furthermore, we have observed
the following delicate electronic effects: (1) anilines bearing an
electron-donating group (i.e., OMe, Me) reacted much faster than
aniline and provided the corresponding products in excellent yields
(Table 2 entries 2e4). (2) anilines bearing electron-withdrawing
group (i.e., Br, F, NO2) deactivated aryl amine remarkably and afforded the corresponding pyrrole derivatives in moderate yields
(Table 2 entries 6e9). It is worthy to be noted that p-methoxy aniline
is much more reactive than m-methoxy aniline, due to its delicate
electronic effect. Seemingly, this reactivity of aromatic amine is
principally dependent on the electron density of the amino group,
which is further suggested by the exclusively regioselective condensation of 2-nitro-benzene-1,4-diamine 2i. It is worthy to be noted
that Paal-Knorr reaction of 2-nitro-1,4-benzenediamine 2i with two
equivalents of 2,5-hexadione exclusively afforded the mono-pyrrole
compound 1-(3-nitro-4-aminophenyl)-2,5-dimethyl -1H-pyrrole 3i
in 95% yield (Table 2, entry 9). In addition, the reaction of less sterically hindred 2-methylaniline with 2,5-hexadione could give a good
yield (Table 2 entry 2). However, the more sterically hindered 2,6diisopropylaniline gave a moderate yield (Table 2, entry 5). Morever, we examined the reactivity of heterocyclic amines with 2,5hexadione in the presence of 3 mol % of MgI2 etherate under
solvent-free conditions. The Paal-Knorr reaction of heterocyclic
amine such as 2-aminopyridine 2j affords 2-(2,5-dimethyl-1H-pyrrol-1-yl)pyridine 3j in 90% yield (Table 2, entry 10). 2-amino-pyrimidine 2k gave 2-(2,5-dimethyl-1H-pyrrol-1-yl)pyrimidine 3k in
80% yield (Table 2, entry 11). Therefore, heterocyclic amines exhibited analogous behavior to that of aromatic amines. Furthermore, we
have examined the Paal-Knorr reaction of aliphatic amines with 2, 5hexadione (Table 2, entries 12e15). As well, the corresponding
products were obtained with good yields. Unfortunately, no reaction
of tert-butylamine with 2, 5-hexadione was observed under the same
conditions, due to its higher steric hindrance.
Under further observation, the pyrrole derivatives containing
a chiral substituent at the nitrogen atom are encountered, which
are potential building blocks for the synthesis of biologically active
compounds with an optimal combination of activity and safety.23
The alkylation of pyrrolyl anion with esters of chiral a-hydroxy
acids by tosylates in polar aprotic solvents by the action of bases is
involved to provide pyrrole derivatives containing a chiral substituent at the nitrogen atom by complete conversion.24 However,
this method clearly unsuitable to pyrroles with a chiral substituent
at the nitrogen atom since the use of basic media may lead to racemization due to the CH acidity of the chiral site. Thus, it is necessary to develop another method for the synthesis of pyrroles with
a chiral substituent at the nitrogen atom, which involved PaalKnorr cyclization using chiral amines since the chiral site in this
case is not affected in the reaction. It is observed that the reaction of
chiral amine with 2,5-hexadione catalyzed by 3 mol % of MgI2
etherate under solvent-free conditions provided the optically pyrrole derivative in good yields without racemization (Table 2 entries
16e20). We used this method for the synthesis of chiral derivatives
of N-aryl-2,5-dimethylpyrroles employing 2,5-hexadione with (R)(þ)-1-(1-naphthyl)ethylamine 2p in 85% yield. As well, the chiral
N-alkyl-2,5-dimethylpyrroles derivatives are prepared by Paal-Korr
reaction of optically active a-amino acids as the amine component.
Interestingly, the condensation of (R)-2-amino-2-phenylacetamide
2t, which has two amino groups, exclusively gave (R)-2-(2,5-
2597
Table 2
Paal-Knorr condensation of 2,5-hexadione with various amines catalyzed by MgI2
etheratea
O
Me
Me
+
Me
3 mol% MgI2 (OEt2)n
R NH2
solvent free
70 oC
2a-2t
O
1a
N R
Me
3a-3t
Entry
Amine
t (h)
Product
Yield (%)b
1
2
3
4
5
6
7
8
C6H5NH2
2-CH3C6H4NH2
4-MeOC6H4NH2
3-MeOC6H4NH2
2,6-(iPr)2C6H3NH2
4-BrC6H4NH2
3,5-F2C6H3NH2
4-NO2C6H4NH2
2
2
0.5
4
8
2
4
10
3a
3b
3d
3c
3e
3f
3g
3h
93
93
98
80
76
85
73
78
1
3i
95
10
2
3j
90
11
8
3k
80
2
2
2
3l
3m
3n
90
95
80
2
3o
83
2
3p
85
NH2
3
3q
78
OMe
4
3r
84
3
3s
94
5
3t
75
O2N
9
12
13
14
H2N
NH2
C6H5CH2NH2
4-FC6H4CH2NH2
(CH3)2CHCH2NH2
NH2
15
NH2
16
F
17
F
NH2
18
O
NH2
19
OMe
NH2
NH2
20
O
a
The reaction was carried out by the condensation of amine (5.0 mmol) and 2,5hexadione (6.0 mmol) in the presence of 3 mol % MgI2(OEt2)n under solvent-free
conditions at 70 C.
b
Isolated yield by silica gel flash chromatography.
2598
X. Zhang et al. / Tetrahedron 71 (2015) 2595e2602
Table 3
Paal-Knorr condensation of various 1,4-diketones with amines catalyzed by MgI2
etheratea
O
R1
Me
R3
R2
3 mol% MgI2 (OEt2)n
+ R NH2
solvent free
70 oC
O
Me
R1
N R
R2
1b, R1 = R2 = H, R3 = Ph
1c, R1 = COMe, R2 = H, R3 = Ph
1d, R1 = CO2Et, R2 = H, R3 = Ph
1e, R1 = R2 = CO2Et, R3 = Me
R3
4a-4i
Entry
Amine
R1
R2
R3
t (h)
Product
Yield (%)b
1
2
3
4
5
6
7
8
9
4-MeOC6H4NH2
4-CH3OC6H4CH2NH2
4-MeOC6H4NH2
4-CH3OC6H4CH2NH2
C6H5(CH2)2NH2
C6H5(CH2)2NH2
4-MeOC6H4NH2
4-MeOC6H4NH2
4-ClC6H4NH2
H
H
COCH3
COCH3
COCH3
COOEt
COOEt
COOEt
COOEt
H
H
H
H
H
H
H
COOEt
COOEt
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Me
Me
0.5
1.0
2
3
1.5
1.0
0.5
2.0
2.0
4a
4b
4c
4d
4e
4f
4g
4h
4i
80
86
88
78
89
82
87
90
86
a
The reaction was carried out by the condensation of amines (5.0 mmol) and 1,4diketones (6.0 mmol) in the presence of 3 mol % MgI2(OEt2)n under solvent-free
conditions at 70 C.
b
Isolated yield by silica gel flash chromatography.
dimethyl-1H-pyrrol-1-yl)-2-phenylacetamide 3t with the retention
of absolute configuration. This procedure permitted to obtain pyrroles with a chiral substituent at the nitrogen atom in high synthetic and enantiomeric yields.
The synthesis of functionalized N-substituted pyrroles under
mild reaction conditions from readily available precursors has
remained problematic. Furthermore, an efficient synthesis for
accessing fully substituted pyrrole is rare. Consequently, various
procedures have been devised for the synthesis of functionalized
pyrroles.25 Among them, the multicomponent coupling reactions
(MCRs) are an efficient alternative approach.26 However, the harsh
reaction conditions, strict avoidance from moisture and poor substrate generality limited this method. To the best of our knowledge,
the reported procedures for the synthesis of functionalized Nsubstituted pyrroles via Paal-Knorr condensation are few. Herein, we
attempted to examined the scope and generality of our protocol
using different substituted 1,4-diketone with primary amines. The
results are summarized in Table 3. As shown in Table 3, the results
showed that various substituted 1,4-diketones are also good substrates in this catalytic system, and the desired functionalized
N-substituted pyrroles are formed in good yields. For example, The
condensation of 1-phenylpentane-1,4-dione with p-methoxyaniline
or p-methoxy-benzyl amine gave the desired products in good yields,
respectively (Table 3, entries 1 and 2). 3-Acetyl-1-phenylpentane
1,4-dione and ethyl 2-acetyl-4-oxo-4-phenylbutanoate underwent efficientyl Paal-Knorr cyclization with p-methoxyaniline
or p-methoxybenzyl amine (Table 3, entries 3e7) to give N-protected
trisubstituted pyrroles. Interestingly, the fully substituted
pyrroles are afforded using diethyl 2,3-diacetylsuccinate as substrate
in good yield (Table 3, entries 8 and 9). Unfortunately, no reaction of
1, 4-diphenylbutane-1,4-dione with 4-methoxyaniline was occurred.
The observed interesting chemoselectivity was further evaluated
by crossover experiments of various aniline with 2,5-hexadione,
respectively. The MgI2 etherate catalysis shows high levels of aromatic amines discrimination in the competitive reactions with 2,5hexadione (Table 4). Firstly, the catalyst can differentiate the steric
difference in aromatic amines to much higher extents (Table 4 entries
1 and 2). Secondly, the MgI2 etherate catalyst can uniquely recognize
the delicate difference in electronic effect involved in aniline.
Apparently, 4-nitroaniline is much less reactive than aniline and
4-methoxyaniline in the MgI2 etherate-catalyzed process. Only the
Paal-Knorr condensation product of aniline and 4-methoxyaniline
was obtained, respectively (Table 4, entries 3 and 4). As well, the
crossover-reaction between aniline and 4-bromoaniline provided
1-phenyl-2,5-dimethyl-1H-pyrrole in high chemoselectivity. In
crossover-reaction of 4-nitroaniline with 4-bromoaniline, the former
is also less reactive than the latter (Table 4, entry 6) and the reaction
exclusively gave the 1-(4-bromophenyl)-2,5-dimethyl-1H-pyrrole.
Furthermore, MgI2 etherate catalyst shows the remarkable preference for 4-methoxyaniline over aniline, 4-bromoaniline (Table 4,
entries 7 and 8). More significantly, the reactivity of 4methoxyaniline is much better than that of 3-methoxyaniline in
this catalysis process(Table 4, entry 9). It is worthy to be noted that
the highly selective conversion of aniline was observed versus benzyl
amine, which is just different from the silimar reaction catalyzed by
PEG-SO3H reported by Jafari.27 These results suggest that the relative
Table 4
Crossover condensation of 2,5-hexadione with aromatic aminesa
.
O
Me
Me
ArNH2 + Ar'NH2 +
3 mol% MgI2 (OEt2)n
solvent-free
O
3 + 3'
70 oC
Entry
Ar
Ar0
Ratio (3/30 )b
Yield (%)c
1
2
3
4
5
6
7
8
9
10
C6H5
4-MeOC6H4
C6H5
4-MeOC6H4
C6H5
4-BrC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
C6H5
2,6-(CH3)2CHC6H3
2,6-(CH3)2CHC6H3
4-NO2C6H4
4-NO2C6H4
4-BrC6H4
4-NO2C6H4
C6H5
4-BrC6H4
3-MeOC6H4
C6H5CH2
>99/<1
>99/<1
>99/<1
>99/<1
96/4
>99/<1
97/3
>99/<1
93/7
>99/<1
90
97
91
96
91
85
97
97
97
92
a
Reactions were run with a mixture of 5.0 mmol of each amine, 5.0 mmol of 2,5-hexadione 1a in the presence of 3 mol % of MgI2 etherate under solvent-free conditions at
70 C.
b
The ratio was determined by flash column chromatography.
c
Isolated overall yield.
X. Zhang et al. / Tetrahedron 71 (2015) 2595e2602
2599
O
H2N
+
NH2
O
Me
Me
NH2 +
3 mol% MgI2 etherate
Me
N
solvent-free, 0.5h
95% yield
O
H2N
Me
3 mol% MgI2 etherate
Me
Me
N
Me
Me
Me
N
N
Me
5
Me
+
N
NH2
solvent-free, 1h
Me
98% yield
O
Me
6
Me
7
(6 : 7 = 95 : 5)
O
H2N
NH2
3 mol% MgI2 etherate
Me
Me
+
solvent-free, 1h
98% yield
O
Me
Me
N
N
Me
O
NH2
NH2
NH2 Me
3 mol% MgI2 etherate
Me
Me
+
Me
8
N
solvent-free, 1h
93% yield
O
9
Me
Scheme 1. Paal-Knorr condensation of 2,5-hexadione with diamines.
was studied, the reaction gave only the mono-pyrrole product (9)
in the presence of two equivalents of 2,5-hexadione in excellent
yield.
Apparently, the reactivity of aromatic amine is subject to its
inherent electron density of the amino group, which implies the
coordination of MgI2 etherate with electron-rich amino group and
exhibits the unique chemoselectivity in this catalytic process. To
the best of our knowledge, commonly used strong Lewis acids, i.e.
Ti(OiPr)4,13 Sc(OTf)315 and Bi(NO3)3$5H2O16 are usually non- or
poor-chemoselective. Thus, MgI2 etherate represents a novel type
of main group Lewis acid catalyst, which selectively activates the
electron-rich functionality aromatic amines. A possible mechanism
for the formation of N-substitution pyrroles in the presence of MgI2
etherate as a catalyst is shown in Scheme 2. The uniqueness of MgI2
etherate is attributed to the dissociative character of iodide counterion, which is cooperating with the coordination of Lewis basic
reactivity of aromatic amines in the MgI2 etherate-catalyzed process
is determined almost solely by nucleophilicity of nitrogen lone pair
upon the aromatic amines themselves.
The reaction using MgI2 etherate as catalyst has shown an important feature that is the ability to tolerate various amines including
aliphatic, aromatic, and heterocyclic amines. Next, we investigated
the reaction of diamines with 2,5-hexadione (Scheme 1). In this
reaction, two equivalents of 2,5-hexadione were required in order to
have a complete conversion of diamines. When aliphatic diamine
such as 1,3-propanediamine was examined, the corresponding bispyrrole product 5 was obtained in 95% yield. However, aromatic
diamine such as 1,4-benzenediamine was examined, the reaction
mainly produced bis-pyrrole product 6. As well, the sole bis-pyrrole
product 8 was afforded by the condensation of benzidine with two
equivalents of 2,5-hexadione in excellent yield. Furthermore, sterically more hindered aromatic diamine such as 1, 2-benzenediamine
Me
O O
Me
R-NH2
1
I
MgI2 (OEt2)n
N
MgI (OEt2)n
3
R
Me
O O
Me
R
+ H2O
H H
O MgI (OEt2)n
HO
Me
2
NH O
Me
Me
H
MgI2 (OEt2)n
H2O
Me
N
Me
R
5
MgI (OEt2)n
O
I
N Me
R
4
Scheme 2. The proposed mechanism of MgI2 etherate-catalyzed Paal-Knorr reaction.
I
2600
X. Zhang et al. / Tetrahedron 71 (2015) 2595e2602
oxygen atom of carbonyl group with Mg (II) leading to a more Lewis
acidic cationic Mgecoordinate as a result of Lewis base activation of
Lewis acid.28 The reactive intermediate 3 on reaction with amine 1
can lead to intermediate 4 following a nucleophilic addition and
subsequent expulsion of H2O. Then a similar process was followed
to attack another activated carbon atom of carbonyl group with
imine as described in the intermediate 4, which further converted
into pyrrole 2 by dehydration and aromatization steps as shown in
the intermediate 5. This reaction suggests the capability of MgI2
etherate to serve as Lewis acid activator.
In conclusion, we have developed a mild, convenient and
environmentally friendly procedure for efficient synthesis of
N-substituted pyrroles and multifunctional-substituted pyrroles by
the condensation of amines with 1,4-diketones in the presence of
3 mol % of MgI2 etherate under solvent-free conditions Furthermore, we have demonstrated that the MgI2 etherate catalysis system has unique chemoselectivity to the substrates. An approach to
the preparation of optically active pure pyrrole derivatives with
a chiral substituent at the nitrogen atom based on MgI2 etheratecatalyzed Paal-Knorr reaction is developed. Exploitation of this
protocol for generation of novel multicyclic stuctures is actively
pursued in our lab.
3. Experimental section
3.1. General procedure for the synthesis of N-substituted
pyrroles 3ae3t
A Schlenk reaction tube was charged with primary aromatic
amine (5.0 mmol), 2,5-hexadione (6.0 mmol), MgI2 etherate
(0.15 mmol, 3 mol %). The reaction mixture was stirred at 70 C for
several hours and then concentrated in vacuo. The residue was
purified by flash column chromatography on a silica gel to give the
desired product.
The physical and spectra data of the compounds 3ae3t are
shown as follows.
3.1.1. 1-Phenyl-2,5-dimethyl-1H-pyrrole (3a).29 Pale yellow solid; Rf
0.67 (100% PE); mp 49e50 C (lit. 48e50 C); 1H NMR (500 MHz,
CDCl3): d¼2.11 (s, 6H), 5.98 (s, 2H), 7.27e7.29 (m, 2H), 7.44e7.47 (m,
1H), 7.50e7.54 (m, 2H) ppm.
3.1.2. 1-o-Tolyl-2,5-dimethyl-1H-pyrrole (3b).30 Pale yellow liquid;
Rf 0.42 (100% PE); 1H NMR (500 MHz, CDCl3): d¼1.96 (s, 6H), 1.98
(s, 3H), 5.96 (s, 2H), 7.20 (d, J¼7.5 Hz, 1H), 7.29e7.35 (m, 1H),
7.36e7.37 (m, 2H) ppm.
3.1.3. 1-(4-Methoxyphenyl)-2,5-dimethyl-1H-pyrrole.31 White
solid; Rf 0.57 (PE:EA¼10:1); mp 54.8e55.5 C (lit. 57e59 C); 1H
NMR (500 MHz, CDCl3): d¼2.15 (s, 6H), 3.96 (s, 3H), 6.01 (s, 2H), 7.08
(d, J¼8.8 Hz, 2H), 7.24 (d, J¼8.8 Hz, 2H) ppm.
3.1.4. 1-(3-Methoxyphenyl)-2,5-dimethyl-1H-pyrrole
(3d).30 Pale
1
yellow liquid; Rf 0.42 (100%PE); H NMR (500 MHz, CDCl3): d¼2.18
(s, 6H), 3.92 (s, 3H), 6.01 (s, 2H), 6.88 (d, J¼2.2 Hz, 1H), 6.89e6.94
(m, 1H), 7.05e7.7.07 (m, 1H), 7.46 (t, J¼8.0 Hz, 1H) ppm.
3.1.5 . 1 -(2, 6-D iiso pro pylp henyl) -2, 5 -dim ethyl -1H -pyrrole
(3e).32 White solid; Rf 0.73 (PE:EA¼10:1); mp 56e57 C (lit.
56e58 C). 1H NMR (500 MHz, CDCl3) d 1.16 (d, J¼6.9 Hz, 12H), 1.95
(s, 6H), 2.0e2.1 (m, 2H), 5.98 (s, 2H), 7.28 (d, J¼7.7 Hz, 2H), 7.44
(t, J¼7.7 Hz, 1H) ppm.
3.1.6. 1-(4-Bromophenyl)-2,5-dimethyl-1H-pyrrole
(3f).27 Yellow
solid; Rf 0.64 (PE:EA¼10:1); mp 69e71 C (lit. 70e72 C); 1H NMR
(500 MHz, CDCl3): d¼2.08 (s, 6H), 5.95 (s, 2H), 7.12e7.15 (m, 2H),
7.62e7.65 (m, 2H) ppm.
3.1.7. 1-(3,5-Difluorophenyl)-2,5-dimethyl-1H-pyrrole (3g).33 White
solid; Rf 0.68 (PE:EA¼10:1); mp 54.8e55.3 C; 1H NMR (500 MHz,
CDCl3): d¼2.09 (s, 6H), 5.93 (s, 2H), 6.81 (dd, J¼2.2, 7.4 Hz, 2H),
6.88e6.92 (m, 1H) ppm.
3.1.8. 1-(4-Nitrophenyl)-2,5-dimethyl-1H-pyrrole
(3h).29 Yellow
solid; Rf 0.35 (PE:EA¼10:1); mp 141.7e143.2 C (lit. 143e144 C); 1H
NMR (500 MHz, CDCl3): d¼2.10 (s, 6H), 5.98 (s, 2H), 7.39e7.43
(m, 2H), 8.35e8.38 (m, 2H) ppm.
3.1.9. 2,5-Dimethyl-1-(4-amino-3-nitrophenyl)-1H-pyrrole
(3i). Yellow solid; Rf 0.6 (PE:EA¼1:1); mp 142.0e143.1 C; 1H NMR
(500 MHz, CDCl3): d¼2.07 (s, 6H), 5.92 (s, 2H), 6.30 (br s, 2H), 6.94
(d, J¼8.8 Hz, 1H), 7.25e7.28 (m, 1H), 8.04 (d, J¼2.4 Hz, 1H) ppm; 13C
NMR (125 MHz，CDCl3): d¼13.0, 106.0, 119.4, 125.4, 128.1, 128.9,
131.5, 135.7, 144.1 ppm; HRMS (EI) calcd for C12H13N3O2: 231.2505,
found for [M]þ: 231.2494.
3.1.10. 2-(2,5-Dimethyl-1H-pyrrol-1-yl)pyridine (3j).15 Yellow liquid; Rf 0.54 (PE:EA¼5:1); 1H NMR (500 MHz, CDCl3): d¼2.15 (s, 6H),
5.93 (s, 2H), 7.23e7.28 (m, 1H), 7.30e7.33 (m, 1H), 7.82e7.86 (m,
1H), 8.62e8.64 (m, 1H) ppm.
3.1.11. 2-(2,5-Dimethyl-1H-pyrrol-1-yl)pyrimidine
(3k).34 Yellow
liquid; Rf 0.32 (PE:EA¼10:1); 1H NMR (500 MHz, CDCl3): d¼2.38 (s,
6H), 5.94 (s, 2H), 7.17 (t, J¼4.9 Hz, 1H), 8.77 (d, J¼4.8 Hz, 2H) ppm.
3.1.12. 1-Benzyl-2,5-dimethyl-1H-pyrrole (3l).27 White solid; Rf 0.42
(100%PE); mp 41.0e42.0 C (lit. 42e43 C); 1H NMR (500 MHz,
CDCl3): d¼2.32 (s, 6H), 5.17 (s, 2H), 6.05 (s, 2H), 7.06 (d, J¼7.4 Hz,
2H), 7.39 (t, J¼7.3 Hz, 1H), 7.45 (t, J¼7.3 Hz, 2H) ppm.
3.1.13. 1-(4-Fluorobenzyl)-2,5-dimethyl-1H-pyrrole
(3m).30 Pale
yellow solid; Rf 0.39 (100% PE); mp 55e56 C (lit. 56e57 C); 1H
NMR (500 MHz, CDCl3): d¼2.22 (s, 6H), 5.05 (s, 2H), 5.95 (s, 2H),
6.92 (dd, J¼3.4, 5.4 Hz, 2H), 7.03e7.07 (m, 2H) ppm.
3.1.14. 1-Isobutyl-2,5-dimethyl-1H-pyrrole (3n).35 Pale yellow liquid;
Rf 0.46 (100% PE); 1H NMR (500 MHz, CDCl3): d¼0.96 (d, J¼6.7 Hz, 6H),
2.01e2.07 (m, 1H), 2.26 (s, 6H), 3.58 (d, J¼7.6 Hz, 2H), 5.83 (s, 2H) ppm.
3.1.15. 2,5-Dimethyl-1-(prop-2-ynyl)-1H-pyrrole(3o).36 White
solid; Rf 0.52 (PE:EA¼20:1); mp 60.5e62.1 C; lH NMR (500 MHz,
CDC13): d¼2.32 (s, 7H), 4.54 (d, J¼2.5 Hz, 2H), 5.83 (s, 2H) ppm.
3.1.16. (R)-1-(1-(Naphthalen-1-yl)ethyl)-2,5-dimethyl-1H-pyrrole
(3p). Yellow liquid; Rf 0.31 (PE:EA¼10:1); [a]25
D þ95 (c¼1.0, CHCl3);
FTIR (KBr) y (cm1): 2978, 1566, 1516, 1448, 1420, 1245, 1212, 1060,
760; lH NMR (500 MHz, CDC13): d¼2.05 (d, J¼7.1 Hz, 3H), 2.19 (s,
6H), 5.91 (s, 2H), 6.10 (q, J¼7.1 Hz, 1H), 7.53e7.57 (m, 3H), 7.77e7.79
(m, 1H), 7.90e7.95 (m, 1H), 7.95e7.96 (m, 1H) ppm; l3C NMR
(125 MHz, CDC13): d¼14.2, 20.5, 51.7, 106.5, 123.2, 123.4, 124.4,
126.7, 128.0, 128.4, 128.8, 129.4, 132.3, 135.3, 137.0 ppm; EIMS:
249.1(10), 155.2(100), 149.2(31), 95.2(43), 81.2(23); HRMS (EI) calcd
for C18H19N: 249.1517, found for [M]þ: 249.1522.
3.1.17. 1-((1R,2S)-2-(3,4-Difluorophenyl)cyclopropyl)-2,5-dimethyl1H-pyrrole (3q). Yellow liquid; Rf 0.63 (PE:EA¼10:1); [a]25
D 291
(c¼1.0, CHCl3); 1H NMR (500 MHz, CDCl3): d¼1.47e1.51 (m, 1H),
1.63e1.67 (m, 1H), 2.30 (s, 6H), 2.33e2.37 (m, 1H), 3.06e3.09 (m,
1H), 5.79 (s, 2H), 6.91e6.99 (m, 2H), 7.11e7.17 (m, 1H) ppm; 13C
NMR (125 MHz，CDCl3): d¼13.6, 17.9, 24.4, 29.8, 36.0, 105.9, 114.7,
117.4, 121.9, 130.0, 137.5, 148.8, 150.7 ppm; EIMS: 246.9 (100), 232.0
X. Zhang et al. / Tetrahedron 71 (2015) 2595e2602
(49), 151.0 (17), 133.0 (34), 96.1 (9), 77.1 (6); HRMS (EI) calcd for
C15H15NF2: 247.1173, found for [M]þ: 247.1175.
3 .1.18 . ( S ) - M e t h y l 2 - ( 2 , 5 - d i m e t h y l - 1 H - p y r r o l - 1 - y l ) - 3 phenylpropanoate (3r).37 Yellow liquid; Rf 0.38 (PE:EA¼10:1).
l
[a]30
D 155 (c¼1.0, CHCl3); H NMR (500 MHz, CDC13): d¼1.99 (s,
6H), 3.20 (dd, J¼10.0, 14.0 Hz, 1H), 3.57 (dd, J¼4.8, 10.0 Hz, 1H), 3.78
(s, 3H), 4.79 (dd, J¼4.8, 10.0 Hz, 1H), 5.76 (s, 2H), 6.91e6.93 (m, 2H),
7.21e7.23 (m, 3H) ppm.
3.1.19. (R)-Methyl
2-(2,5-dimethyl-1H-pyrrol-1-yl)propanoate
(3s). Yellow solid; Rf 0.38 (PE:EA¼10:1); mp 35.5e37.0 C; [a]30
D
þ133 (c¼1.0, CHCl3); FTIR (KBr) y (cm1): 2950, 1744, 1579, 1522,
1401, 1223, 1114, 754; lH NMR (500 MHz, CDC13): d¼1.70 (d,
J¼7.3 Hz, 3H), 2.25 (s, 6H), 3.80 (s, 3H), 4.91 (q, J¼7.3 Hz, 1H), 5.85 (s,
2H) ppm; 13C NMR (125 MHz, CDC13): d¼13.0, 17.3, 52.3, 106.2,
127.4, 171.4 ppm; EIMS: 181.1 (18), 167.0 (23), 151.1 (13), 149.0 (100),
134.1 (21), 123.1 (18), 95.1 (37), 77.1 (28). HRMS (EI) calcd for
C10H15NO2: 181.1103, found for [M]þ: 181.1108.
3.1.20. (S)-2-(2,5-Dimethyl-1H-pyrrol-1-yl)-2-phenylacetamide
(3t). Yellow solid; Rf 0.4 (PE:EA¼3:1); mp 102.7e105.2 C; FTIR
(KBr) y (cm1): 2983, 1693, 1564, 1513, 1444, 1230, 1074, 840, 765;
l
H NMR (500 MHz, CDC13): d¼2.07 (s, 6H), 5.70 (s, 1H), 5.89 (s, 2H),
5.98 (s, 1H), 6.85 (s, 1H), 7.25e7.28 (m, 2H), 7.30 (s, 1H), 7.31e7.36
(m, 2H) ppm; l3C NMR (125 MHz, CDC13): d¼13.6, 61.1, 107.7, 127.8,
128.1, 128.4, 128.8, 135.4, 171.6 ppm; EIMS: 228.1(7), 185.4(11), 184.3
(43), 94.7 (100), 106.4 (10); HRMS (EI) calcd for C14H16N2O:
228.1263, found for [M]þ: 228.1260.
3.1.21. 1-(4-Methoxyphenyl)-2-methyl-5-phenyl-1H-pyrrole
(4a).30 Yellow solid; Rf 0.49 (PE:EA¼10:1); mp 104.5e106.0 C; lH
NMR (500 MHz, CDC13): d¼2.19 (s, 3H), 3.86 (s, 3H), 6.15 (d,
J¼3.0 Hz, 1H), 6.42 (d, J¼3.4 Hz, 1H), 6.94 (d, J¼8.8 Hz, 2H),
7.12e7.16 (m, 5H), 7.20 (t, J¼7.6 Hz, 2H) ppm.
3.1.22. 1-(4-Methoxybenzyl)-2-methyl-5-phenyl-1H-pyrrole
(4b). Yellow solid; Rf 0.68 (PE:EA¼10:1); mp 91.0e92.0 C; FTIR
(KBr) y (cm1): 2930, 1550, 1510, 1444, 1403, 1240, 1170, 1033, 820;
l
H NMR (500 MHz, CDC13): d¼2.28 (s, 3H), 3.87 (s, 3H), 5.20 (s, 2H),
6.18 (d, J¼3.0 Hz, 1H), 6.37 (d, J¼3.3 Hz, 1H), 6.97 (dd, J¼5.2, 8.9 Hz,
4H), 7.27e7.36 (m, 1H), 7.40e7.46 (m, 4H) ppm 13C NMR (125 MHz,
CDC13): d¼12.5, 47.0, 55.1, 107.2, 107.9, 114.0, 126.5, 126.7, 128.3,
128.5, 130.3, 130.9, 133.8, 134.5, 158.1 ppm EIMS: 277.1 (8), 156.2 (2),
121.2 (100), 91.4 (11), 77.3 (13); HRMS (EI) calcd for C19H19NO:
277.1467, found for [M]þ: 277.1461.
3.1.23. 1-(1-(4-Methoxyphenyl)-2-methyl-5-phenyl-1H-pyrrol-3-yl)
ethanone (4c).38 Yellow solid; Rf 0.36 (PE:EA¼5:1); mp
116.5e118.0 C; lH NMR (500 MHz, CDC13): d¼2.43 (s, 3H), 2.51 (s,
3H), 3.83 (s, 3H), 6.73 (s, 1H), 6.91 (dd, J¼2.2, 4.6 Hz, 2H), 7.05e7.10
(m, 4H), 7.15e7.20 (m, 3H) ppm.
3.1.24. 1-(1-(4-Methoxybenzyl)-2-methyl-5-phenyl-1H-pyrrol-3-yl)
ethanone (4d). Yellow liquid; Rf 0.33 (PE:EA¼5:1); FTIR (KBr) y
(cm1): 2934, 1643, 1607, 1514, 1445, 1416, 1248, 1180, 1031, 821; lH
NMR (500 MHz, CDC13): d¼2.45 (s, 3H), 2.51 (s, 3H), 3.72 (s, 3H),
5.05 (s, 2H), 6.62 (s, 1H), 6.82 (s, 4H), 7.27e7.30 (m, 5H) ppm; l3C
NMR (125 MHz, CDC13): d¼12.1, 28.6, 47.0, 55.3, 110.4, 114.3, 121.4,
126.8, 127.7, 128.6, 129.1, 129.3, 132.5, 134.0, 136.6, 158.9, 195.1 ppm;
EIMS: 319.1 (5), 183.3 (1), 121.3 (100), 91.1 (6), 77.1 (7); HRMS (EI)
calcd for C21H21NO2: 319.1572, found for [M]þ: 319.1565.
3.1.25. 1-(2-Methyl-1-phenethyl-5-phenyl-1H-pyrrol-3-yl)ethanone
(4e).38 Yellow liquid; Rf 0.49 (PE:EA¼5:1); lH NMR (500 MHz,
2601
CDC13): d¼2.46 (s, 3H), 2.59 (s, 3H), 2.77 (t, J¼7.8 Hz, 2H), 4.12 (t,
J¼7.7 Hz, 2H), 6.52 (s, 1H), 6.89e6.91 (m, 2H), 7.22e7.28 (m, 3H),
7.34e7.36 (m, 2H), 7.41e7.46 (m, 3H) ppm.
3.1.26. Ethyl 2-methyl-1-phenethyl-5-phenyl-1H-pyrrole-3carboxylate
(4f). Yellow
solid;
Rf
0.69
(PE:EA¼5:1);
mp102.5e103.5 C; FTIR (KBr) y (cm1): 2979, 1679, 1564, 1526,
1418, 1209, 1062, 767, 703; lH NMR (500 MHz, CDC13): d¼1.40 (t,
J¼7.1 Hz, 3H), 2.57 (s, 3H), 2.77 (t, J¼7.8 Hz, 2H), 4.13 (t, J¼7.7 Hz,
2H), 4.33 (q, J¼7.1 Hz, 2H), 6.62 (s, 1H), 6.90e6.92 (m, 2H), 7.24 (d,
J¼7.0 Hz, 3H), 7.37 (t, J¼1.7 Hz, 2H), 7.40e7.44 (m, 3H) ppm; l3C
NMR (125 MHz, CDC13): d¼11.5, 14.6, 37.1, 45.7, 59.3, 110.1, 112.1,
126.8, 127.7, 128.5, 128.7, 129.5, 133.2, 133.4, 136.5, 137.7, 165.7 ppm;
EIMS: 333.0 (100), 304.0 (5), 288.1 (7), 260.1 (12), 242.2 (43), 196.2
(59), 170.6 (91), 169.0 (69), 105.2 (17), 77.4 (10); HRMS (EI) calcd for
C22H23NO2: 333.1729, found for [M]þ: 333.1735.
3.1.27. Ethyl 1-(4-methoxyphenyl)-2-methyl-5-phenyl-1H-pyrrole3-carboxylate (4g).39 White solid; Rf 0.51 (PE:EA¼5:1); mp
120.0e122.5 C; FTIR (KBr) y (cm1): 2983, 2833, 1693, 1603, 1564,
1443, 1414,1074.1,1030, 840, 704; 1H NMR (500 MHz, CDCl3): d¼1.39
(t, J¼7.2 Hz, 3H), 2.40 (s, 3H), 3.84 (s, 3H), 4.34 (q, J¼7.1 Hz, 2H), 6.80
(s, 1H), 6.89e6.92 (m, 2H), 7.05e7.09 (m, 4H), 7.12e7.19 (m, 3H).
3.1.28. Diethyl 1-(4-methoxyphenyl)-2,5-dimethyl-1H-pyrrole-3,4dicarboxylate (4h).39 White solid; Rf 0.35 (PE:EA¼5:1);
mp 71.0e73.0 C；FTIR (KBr) y (cm1): 2980, 1720, 1554, 1506,
1440, 1070, 840, 705; 1H NMR (500 MHz, CDC13): d¼1.34 (t,
J¼7.0 Hz, 6H), 2.13 (s, 6H), 3.87 (s, 3H), 4.29 (q, J¼7.0 Hz, 4H), 6.99
(d, J¼8.6 Hz, 2H), 7.08 (d, J¼8.6 Hz, 2H) ppm.
3.1.29. Diethyl 1-4-chlorophenyl-2,5-dimethyl-1H-pyrrole-3,4dicarboxylate (4i).39 White solid; Rf 0.41 (PE:EA¼5:1); mp
96.0e98.0 C；FTIR (KBr) y (cm1): 3030, 1700, 1544, 1506, 1445,
1071, 840, 700; H NMR (500 MHz, CDCl3) d 1.34 (t, J¼7.1 Hz, 6H),
2.14 (s, 6H), 4.30 (q, J¼7.1 Hz, 4H), 7.12 (d, J¼8.7 Hz, 2H), 7.49 (d,
J¼8.7 Hz, 2H) ppm.
3.1.30. 1,3-Bis(2,5-dimethyl-1H-pyrrol-1-yl)propane
(5).35 White
1
solid; Rf 0.87 (PE:EA¼1:1); mp 138.0e140.0 C; H NMR (500 MHz,
CDCl3): d¼2.06e2.08 (m, 2H), 2.30 (s, 12H), 3.87 (t, J¼7.7 Hz, 4H),
5.90 (s, 4H) ppm.
3.1.31. 1,4-Bis(2,5-dimethyl-1H-pyrrol-1-yl)benzene
(6).15 White
solid; Rf 0.57 (PE:EA¼10:1); mp 239.0e242.0 C; 1H NMR
(500 MHz, CDCl3): d¼2.11 (s, 12H), 5.96 (s, 4H), 7.32 (s, 4H) ppm.
3.1.32. 2,5-Dimethyl-1-(4-aminophenyl)-1H-pyrrole (7).40 Yellow
liquid; Rf 0.13 (PE:EA¼10:1); 1H NMR (500 MHz, CDCl3) d 2.03 (s,
6H), 5.88 (s, 2H), 6.74 (d, J¼8.6 Hz, 2H), 6.97e7.00 (m, 2H) ppm.
3.1.33. 4,40 -Bis(2,5-dimethyl-1H-pyrrol-1-yl)biphenyl (8).41 White
solid; Rf 0.75 (PE:EA¼5:1); mp 278.0e279.5 C (lit. 279e280 C); lH
NMR (500 MHz, CDC13): d¼2.12 (s, 12H), 5.97 (s, 4H), 7.28e7.36
(m, 4H), 7.74e7.77 (m, 4H) ppm.
3.1.34. 2,5-Dimethyl-1-(2-aminophenyl)-1H-pyrrole
(9).15 Yellow
1
liquid; Rf 0.38 (PE:EA¼10:1); H NMR (500 MHz, CDCl3): d¼2.01
(s, 6H), 3.47 (br s, 2H), 5.96 (s, 2H), 6.81e6.84 (m, 2H), 7.07e7.09
(dd, J¼1.4, 6.9 Hz, 1H), 7.22e7.28 (m, 1H) ppm.
3.2. General procedure for crossover reaction
A schlenk reaction tube was charged with each amine
(5.0 mmol), 2,5-hexadione (5.0 mmol), MgI2 etherate (3 mol %). The
2602
X. Zhang et al. / Tetrahedron 71 (2015) 2595e2602
reaction mixture was stirred at 70 C for several hours. Flash
column chromatography afforded the desired products. The ratio
of each product was determined by column chromatography
isolation.
Acknowledgements
We are grateful to the National Natural Science Foundation of
China (No. 21372203 and 21272076), National university student
innovation test plan (201310337007) and Zhejiang Xinmiao talent
projects (2014R403021) for financial support.
Supplementary data
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.tet.2015.03.035.
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