An efficient heterogeneous catalytic method for the N-arylation of pyrrole and other N-heterocycles

Article abstract of DOI:10.1007/s10562-015-1523-6

Abstract 4 ? molecular sieve modified with copper(0) or copper(II) is an efficient heterogeneous catalyst for the arylation of pyrrole and some other heterocycles with iodo- or bromoarenes, Cs₂CO₃ base and pyrrole (or DMF) solvent. The catalysts can be easily prepared and are reusable.

Full text of DOI:10.1007/s10562-015-1523-6

Catal Lett
DOI 10.1007/s10562-015-1523-6
An efficient heterogeneous catalytic method for the N-arylation
of pyrrole and other N-heterocycles
1
Janos Nemeth Nora Debreczeni Ivan Gresits Maria Balint
2
3
4
•
•
•
•
´
´
Zoltan Hell
´
´
´
´
2
´
Received: 19 December 2014 / Accepted: 22 March 2015
ꢀ Springer Science+Business Media New York 2015
˚
Abstract 4 A molecular sieve modified with copper(0) or
1 Introduction
copper(II) is an efficient heterogeneous catalyst for the
arylation of pyrrole and some other heterocycles with iodo-
or bromoarenes, Cs2CO3 base and pyrrole (or DMF) sol-
vent. The catalysts can be easily prepared and are reusable.
Graphical Abstract
The N-substituted heterocycles (e.g. pyrrole) are important
and common targets e.g. in the pharmaceutical industry [1].
A possible way for the synthesis of these compounds is the
direct N-arylation of the unsubstituted heterocycle with
aryl halides. There are numerous publications [2–14] about
heterogeneous catalytic methods for this N-arylation using
different copper catalysts e.g. Cu2O [9], CuI [3, 12],
CuFAP [5], or Cu powder [10], and the desired arylated
N-heterocycles are generally obtained with good
(80–95 %) yields. But most of the publications report the
examination of the arylation of imidazole, the solvents
most commonly used in the reactions are DMF and DMSO,
the reaction time is often 18–24 h, sometimes even with
aryl iodides as arylating agent. Often, the best results were
obtained using Cs2CO3 as base. The main disadvantages of
these processes are that the preparation of the catalyst is
tedious [2, 4, 5, 7, 8], PTC is required [2, 6], sensitive
Cu(I) salt is used [3, 9, 12], the reaction time is long [12],
inert atmosphere is necessary [4, 8, 12], or there are
problems with the reusability of the catalyst [9, 10, 13, 14].
Our research group works on the elaboration of new
heterogeneous catalytic methods for the preparation of
organic compounds using supported metal catalysts. Dur-
ing this work palladium(0) on Mg:La 3:1 mixed oxide was
successfully used in the Heck [15], Sonogashira [16] and
Suzuki [17] reactions, nickel(II) on the same support in the
X
Cu0/4A
N
+
R
N
H
Cs2CO3
pyrrole
R
1a
2
3a
Keywords Heterogeneous catalysis ꢀ Heterocycles ꢀ
Copper ꢀ Molecular sieve
´
& Zoltan Hell
zhell@mail.bme.hu
1
MTA-BME Organic Chemical Technology Research Group,
Hungarian Academy of Sciences, Budapest 1111, Hungary
2
Department of Organic Chemistry and Technology, Budapest
University of Technology and Economics, M}uegyetemrkp. 3,
Budapest 1111, Hungary
˚
Kumada-coupling [18], while copper(II) on 4 A molecular
sieve (Cu2?/4A) in the A3-coupling [19], as well as in the
selective transformation of oximes into nitriles [20] or ni-
triles into amides [21].
3
Department of Chemical and Environmental Process
Engineering, Budapest University of Technology and
Economics, Budapest 1521, Hungary
Continuing this work we examined the applicability of
the supported copper catalysts in the arylation of pyrrole
and other heterocycles. The support used was a commercial
4
´
Balint Analitika Kft, Fehervari ut, 144, Budapest 1116,
Hungary
´
´
´
123

´ ´
Janos Nemeth et al.
˚
4 A molecular sieve, a crystalline, synthetic zeolite having
(entries 1–4). DMF and DMSO, the solvents often used in
the published methods, gave poor or moderate yields (en-
tries 10 and 11). We found, that the best solvent was the
pyrrole itself. In case of Cu2?/4A, after 15 h complete
conversion was observed (entry 7), but an excellent con-
version (86 %) could be reached already after 4 h (entry 9).
Using Cu0/4A the GC–MS spectra showed no starting ma-
terials in the reaction mixture after only 4 h (entry 8). This
time is slightly shorter than the shortest found in literature
(6 h) [5]. Without base or catalyst no reaction was observed.
The arylation of different aryl halides (Fig. 3.) were
examined under the above mentioned conditions (Table 2).
The required products were generally obtained with good
to excellent conversion and yield. In the reaction of
3-iodonitrobenzene (1g) instead of the desired (3-nitro-
phenyl)pyrrole (3g) (3-aminophenyl)pyrrole (3g0) was the
main product (entry 8). After changing the reaction time to
15 h, the amount of the amino compound accrued (entry 9).
(3-Aminophenyl)pyrrole can be formed via the reduction of
either the starting 3-iodonitrobenzene, or the product (3-
nitrophenyl)pyrrole. However, when the reaction tem-
perature was decreased to 115 ꢁC, the desired nitro com-
pound became the main product (81 %, entry 10).The
reduced product was also obtained when 4-iodonitroben-
zene (1f) was the arylating agent, but in much lower amount
(3f0, 8 %, entry 7). Recently we observed a reduction of
nitrobenzene derivatives via transfer hydrogenation in the
presence of Pd/4A catalysts in ethanol [25], where ethanol
sodalite structure. Its crystal grating is similar to a cage
with numerous hollow spaces with volume 0.3 cm3/g. The
cavities are accessible from all sides by pores of exactly
defined dimensions, 0.4 nm in diameter. This material is a
very good adsorbent for molecules small enough to pass
through the pores. The BET surface of 4A is 800 m2/g [22].
Copper(II) on 4 A molecular sieve (Cu2?/4A) was pre-
˚
pared by impregnation of finely ground molecular sieve
with copper(II) chloride in deionized water. The targeted
copper content of this catalyst was 6.3 wt%, the ex-
perimental value was 5.8 wt% (determined by ICP-OES).
The surface analysis by scanning electron microscope
(SEM) showed cubic zeolite (sodalite) crystals, most of the
particles were in the 2.5–5 lm range (Fig. 1). EDS showed
that copper covered the support’s surface evenly. The
surface area of the original molecular sieve (800 m2/g)
dropped to 360 m2/g after the impregnation. Cu2?/4A was
reduced with hydrazine hydrate using the proven method
described for the preparation of the supported Pd0 catalysts
earlier [15, 23]. Copper content of Cu0/4A catalyst dropped
to 5.5 wt%. There were no remarkable changes in the
surface area, the particle size distribution remained prac-
tically the same. Copper distribution on the surface was not
modified during the reduction. The finely distributed cop-
per made the catalyst slightly sensitive to the atmospheric
oxygen [24].
2 Results and discussion
I
First the optimal reaction conditions were determined in
the reaction of iodobenzene and pyrrole (Fig. 2). The effect
of the solvent, the reaction time and the base added were
examined. The results are summarized in Table 1.
N
catalyst
+
N
H
base
solvent
Based on the GC–MS analysis of the filtered reaction
mixture, good results were only obtained with cesium car-
bonate base. Potassium acetate, potassium carbonate and
potassium hydroxide gave moderate or no conversion
1a
2
3a
Fig. 2 Model reaction for the determination of the best reaction
conditions
Fig. 1 SEM image of the Cu2?/4A catalyst (left 91000 magnification, right 920,000 magnification)
123

An efficient heterogeneous catalytic method for the N-arylation…
Table 1 Determination of the
best reaction conditions
Entry
Catalyst
Base
Solvent
Reaction time
Yield (%)a
1
Cu0/4A
Cu0/4A
Cu0/4A
Cu0/4A
Cu0/4A
Cu0/4A
Cu2?/4A
Cu0/4A
Cu2?/4A
Cu0/4A
Cu0/4A
Cu0/4A
–
KOAc
K2CO3
K2CO3
KOH
DMF
24
20
24
24
24
15
15
4
–
2
DMF
38
3
Pyrrole
Pyrrole
Pyrrole
Pyrrole
Pyrrole
Pyrrole
Pyrrole
DMF
25
4
40
5
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
–
100
100
100
100 (86b)
86
6
7
8
9
4
10
11
12
13
14
4
19
DMSO
Acetonitrile
Pyrrole
Pyrrole
4
56
12
24
10
9
0
Cu0/4A
\1
3 mmol 1a, 0.3 g catalyst, 6 mmol base, 3 ml solvent, 135 ꢁC (or 80 ꢁC in acetonitrile)
a
Based on GC–MS examination of the reaction mixture
b
Preparative yield
mixture of compounds was obtained, probably the products
of a reaction between the carbonyl group and pyrrole. The
desired aldehyde was not observed (entries 17, 18). With
4-bromoacetophenone (1l) the desired arylpyrrole derivative
was the main product, but a significant amount of other
byproducts appeared, too (entry 16). From the GC–MS
analysis of this mixture a similar reaction between the car-
bonyl group and pyrrole can be assumed as it was observed in
the reaction of aldehydes. This means that our method is not
suitable for the preparation of carbonyl derivatives from aryl
bromides. 4-(1H-Pyrrol-1-yl)-benzoic acid (3o) was isolated
when 4-bromobenzonitrile (1o) was the arylating agent (en-
try 19). This can be formed via the hydrolysis of the starting
material under basic conditions. It is known that hydrocar-
bonates can disproportionate at higher temperature yielding
carbonates and carbonic acid, the decomposition of which
yield the water required for this hydrolytic side reaction.
4-Bromoanisole in the presence of Cu2?/4A gave poor
result even after 24 h (entry 13). Chlorobenzene (1p) failed
to react even after 36 h (entry 20).
X
Cu0/4A
N
+
R
N
H
Cs2CO3
pyrrole
R
1a
2
3a
Fig. 3 N-Arylation of pyrrol with different aryl halides in the
presence of copper on 4A
served as hydrogen donor. In the N-arylation reaction the
mixture did not contain any obvious hydrogen donor. Per-
haps, pyrrole itself induced this hydrogen transfer reaction.
In the cases of 2-iodophenol (1e), 3- and 4-iodonitroben-
zene (1g, 1f) the reaction mixtures contained occasionally a
little amount of phenol (2 %) or nitrobenzene, too, which
can be formed via the dehalogenation of the starting ma-
terials (entries 6–8, 10).
Cu2?/4A gave just slightly less conversion than Cu0/4A in
the reaction of iodobenzene (see Table 1). With iodoanisole
(1c), after 4 h full conversion was observed (entry 3). Thus,
in this case the electron donating group on the phenyl ring
might have an activating effect. Therefore Cu2?/4A (whose
preparation is slightly shorter and simpler than Cu0/4A) can
give a good alternative of Cu0/4A for this reaction.
The recycling of the pyrrole is simple; after the workup
it can be distilled from the mixture. In the small scale we
applied, about 50 % of pyrrole could be recovered.
The reusability of both catalysts were examined in the
reaction of iodobenzene and pyrrole (reaction time 4 h).
After the reaction, the catalysts were filtered and washed
with dichloromethane and water, and then preheated at ca.
150 ꢁC for 1 h. In the first 3 use with Cu0/4A full con-
version was reached, while in the 4th use the catalytic
performance decreased, after 4 h ca. 75 % GC yield was
obtained.
With bromoarenes, using Cu0/4A, an increase in the re-
action time was necessary for reaching good to excellent GC
yields (entries 8, 9, 12–18). Better results were obtained
when methoxy (1i) or ethyl group (1j) was attached to the
aryl compound. In the reaction of aldehydes (1m, 1n) a
123

´ ´
Janos Nemeth et al.
Table 2 Reaction of pyrrole with aryl halides
Reaction
Entry
1
Aryl halide
Yield (%)a
time (h)
I
N
4
3a100 (86b)
1a
I
N
2
3
4
4
4
4
3b 100 (79b)
3c 100 (73c)
3c 100d
1b
O
O
I
I
O
O
N
N
1c
1c
I
5
6
4
4
N
3d 100 (86b)
1d
1e
OH
OH
I
N
3e 77, phenol 2
N
N
O2N
I
7
4
1f
3f 90 (74c),
3fಿಿ 8,
NO2
NH2
nitrobenzene 2
N
N
I
8
9
4
15
4d
O2N
1g
NO2
NH2
3g 42,
3gಿ 46
N
N
I
O2N
1g
NO2
NH2
3g 25,
3g 81,
3gಿ 69
N
N
I
10
O2N
1g
1h
NO2
NH2
3gಿ 10,
nitrobenzene 9
Br
N
11
12
13
24
24
24
3a 71
O
O
Br
O
O
N
N
3c 100 (95c)
3c 4e
1i
1i
Br
123

An efficient heterogeneous catalytic method for the N-arylation…
Table 2 continued
Reaction
Entry
14
Aryl halide
Yield (%)a
time (h)
O
O
24
Br
N
1j
3j 100
Br
N
15
16
24
24
1k
1l
3k 90
Br
N
O
O
3l 36
OHC
f
17
18
24
24
–
–
Br
1m
OHC
Br
f
1n
NC
Br
HOOC
N
19
20
24
36
1o
3o 100
Cl
n.r.
1p
3 mmol 1, 0.3 g catalyst, 6 mmol Cs2CO3, 3 ml pyrrole, 135 ꢁC
a
Based on GC–MS examination of the reaction mixture
b
Isolated yield
c
Isolated yield after recrystallization from methanol
d
At 115 ꢁC
Using Cu2?/4A
e
f
See text below
Contrarily, Cu2?/4A gave significantly worse results
after the first use. In the 2nd use moderate yield (67 %) was
obtained, and in the 3rd use the yield dropped further
(35 %). In the 4th use the conversion remained the same
(36 %).
pyrrole. The preparation of the catalysts is very simple and
cheap. The best solvent was pyrrole itself. The nature of the
halogen in the aryl halide had a crucial role to the con-
version; iodobenzenes gave excellent yield after only 4 h,
while aryl bromides required longer reaction time (24 h),
chlorobenzene failed to react. Carbonyl and nitrile groups
as substituents were not tolerated in the reaction. In case of
aryl iodides Cu2?/4A was also efficient, thus, as its
preparation is simpler, it might give a good alternative.
Cu0/4A is reusable 3 times with full conversion of the aryl
halide. The catalytic efficiency of Cu2?/4A decreased
significantly even after the first use, but still gave moderate
yield in the second use. Imidazole, pyrazole and indole can
also be arylated efficiently with both catalysts.
XRF examination showed that while in the products of
the Cu0/4A experiments there was negligible amount of
copper, in the case of Cu2?/4A high copper content (sev-
eral %) of the products were observed. Thus, dissolution of
Cu2? into the reaction mixture may explain the difference
between the reusabilities of the two catalysts.
The arylation of other heterocycles with iodobenzene in
the presence of our copper catalysts was also examined. As
the applied N-heterocycles are solid at room temperature,
DMF was used as a solvent. Both Cu0/4A and Cu2?/4A
were efficient in the reactions. Although in case of pyrrole
Cu0/4A was more efficient, in case of indole (6) Cu2?/4A
gave slightly better result (Table 3).
Comparing with the published methods [2–14] the main
advantages of our procedure are the simple preparation of
the catalyst from commercially available, cheap starting
materials, its reusability, no inert atmosphere is required,
the workup is simple and easy, no chromatographic pu-
rification is required. The conversion is generally 100 %,
˚
In summary, copper(0) and copper(II) on 4 A molecular
sieve proved to be an efficient catalyst for the arylation of
123

´ ´
Janos Nemeth et al.
Table 3 Reaction of N-heterocycles with iodobenzene
Entry
1
Catalyst
Cu2+/4A
Compound
Product
Yield (%)a
~100
N
N
N
NH
4
7
N
N
N
Cu2+/4A
Cu2+/4A
~100
96
NH
2
3
8
5
N
N
H
6
9
N
4
Cu0/4A
90
N
H
6
9
6 mmol compound, 3 mmol iodobenzene, 0.3 g catalyst, 6 mmol Cs2CO3, 5 mL DMF, 150 ꢁC, 24 h
a
Based on GC–MS examination of the reaction mixture
the lower preparative yield can be originated from the loss
during the workup. If pyrrole was used as solvent, too, it
could be recovered and reused easily.
filtered and washed thoroughly with 500 mL of deionized
water yielding Cu2?/4A.
Cu0/4A was prepared by the reduction of Cu2?/4A.
Cu2?/4A (5 g) was reduced with hydrazine hydrate
(6.13 mL of 80 % aqueous solution) in ethanol (50 mL) for
3 h at room temperature, filtered, and washed with ethanol.
A mixture of pyrrole (3 ml), Cs2CO3 (1.96 g, 6 m-
mol), Cu0/4A or Cu2?/4A (0.3 g) and the appropriate
aryl halide (3 mmol) were stirred at 135 ꢁC (bath tem-
perature) for 4–36 h. Before adding to the mixture,
Cu2?/4A was preheated at ca. 150 ꢁC for 1 h. The
mixture was filtered, the solid was washed with
dichloromethane. The filtrate was extracted with deio-
nised water (2 9 40 ml). The organic phase was dried
over Na2SO4 and concentrated in vacuum. The residue
was distilled and clarified. Certain products (3c, 3f) were
purified by recrystallization from MeOH.
3 Experimental
GC–MS was carried out on an Agilent 6890 N-GC-5973
N-MSD chromatograph, using a 30 m 9 0.25 mm Restek,
Rtx-5SILMS column with a film layer of 0.25 lm. The
initial temperature of column was 45 ꢁC for 1 min, fol-
lowed by programming at 10 ꢁC/min up to 310 ꢁC and a
final period at 310 ꢁC (isothermal) for 17 min. The tem-
perature of the injector was 250 ꢁC. The carrier gas was He
and the operation mode was splitless.
1H NMR spectra were obtained in CDCl3 solution on a
Bruker AV-300 spectrometer operating at 300 or
500 MHz.
A mixture of the appropriate heterocycle (6 mmol),
Cs2CO3 (1.96 g, 6 mmol), Cu0/4A or Cu2?/4A (0.3 g),
iodobenzene (334 ll, 3 mmol) and DMF (5 mL) were
stirred at 150 ꢁC (bath temperature) for 24 h. The mixture
was filtered, the solid was washed with dichloromethane,
and the filtrate was analyzed with GC–MS.
All chemicals are commercially available products, and
were purchased from Meck Hungary Ltd.
3.1 Preparation of the catalysts
Finely ground 4A (5 g) was suspended in 500 mL of
aqueous copper(II) chloride (0.6725 g, 5 mmol) solution
and stirred at 25 ꢁC for 12 h. The solid material was
All products have satisfactory spectral data (1H NMR,
MS). The spectral data of the known compounds were
identical with those reported in the literature.
123

An efficient heterogeneous catalytic method for the N-arylation…
3.2 Representative spectroscopic data of compounds
3.2.1 1-Phenylpyrrole, 3a
2. Yang Q, Wang Y, Lin D, Zhang M (2013) Tetrahedron Lett
54:1994
3. Sreedhar B, Arundhathi R, Reddy PL, Kantam ML (2009) J Org
Chem 74:7951
4. Panda N, Jena AK, Mohapatra S, Rout SR (2011) Tetrahedron
Lett 52:1924
5. Kantam ML, Venkanna GT, Sridhar Ch, Kumar KBS (2006)
Tetrahedron Lett 47:3897
6. Yong FF, Teo YC, Tay SH, Tan BYH, Lim KH (2011) Tetra-
hedron Lett 52:1161–1164
1H NMR (300 MHz, CDCl3) d (ppm): 6.34 (s, 2H), 7.08 (s,
2H), 7.22 (m, 1H), 7.37 (m, 4H).
GC: Rt: 9.86 min; MS (m/z): M?: 143 (100), 115 (70),
104 (6), 89 (6), 77 (18).
7. Kim AY, Lee HJ, Park JC, Kang H, Yang H, Song H, Park KH
(2009) Molecules 14:5169
3.2.2 1-(4-Methylphenyl)pyrrole, 3b
8. Islam M, Mondal S, Mondal P, Roy AS, Tuhina K, Mobarok M,
Paul S, Salam N, Hossain D (2011) Catal Lett 141:1171
9. Correa A, Bolm C (2007) Adv Synth Catal 349:2673
10. Zhu R, Xing L, Wang X, Cheng C, Su D, Hua Y (2008) Adv
Synth Catal 350:1253
11. Rout L, Jammi S, Punniyamurthy T (2007) Org Lett 9:3397–3399
12. Zhu L, Guo P, Li G, Lan J, Xie R, You J (2007) J Org Chem
72:8535
1H NMR (300 MHz, CDCl3) d (ppm): 2.37 (s, 3H), 6.33 (s,
2H), 7.05 (s, 2H), 7.2 (d, 2H), 7.28 (d, 2H).
GC: Rt: 12.37 min; MS (m/z): M?: 157 (100), 142 (6),
129 (20), 115 (19), 91 (7), 77 (6).
13. Kantam ML, Yadav J, Laha S, Sreedhar B, Jha S (2007) Adv
Synth Catal 349:1938
3.2.3 1-(4-Nitrophenyl)pyrrole, 3f
14. Taillefer M, Xia N, Ouali A (2007) Angew Chem Int Ed 46:934
15. Cwik A, Hell Z, Figueras F (2006) Adv Synth Catal 348:523
16. Cwik A, Hell Z, Figueras F (2006) Tetrahedron Lett 47:3023
17. Cwik A, Hell Z, Figueras F (2005) Org Biomol Chem 3:4307
18. Kiss A, Hell Z, Balint M (2010) Org Biomol Chem 8:331
19. Fodor A, Kiss A, Debreczeni N, Hell Z, Gresits I (2010) Org
Biomol Chem 8:4575
1H NMR (300 MHz, CDCl3) d (ppm): 6.43 (m, 2H), 7.17
(m, 2H), 7.51 (d, 2H), 8.31 (d, 2H).
GC: Rt: 16.77 min; MS (m/z): M?: 188 (100), 158 (8),
141 (31), 115 (30), 103 (4), 89 (7), 76 (7).
3.2.4 1-(3-Aminophenyl)pyrrole, 3 h
20. Kiss A, Hell Z (2013) Synth Commun 43:1778
21. Kiss A, Hell Z (2011) Tetrahedron Lett 52:6021
22. Drying Agents Brochure, Merck KGaA, Germany. http://www.
merckmillipore.com/reagents-chemicals-labware/literature-inorg
anics
GC: Rt: 14.99 min; MS (m/z): M?: 158 (100), 142 (2), 130
(44), 118 (4), 103 (5), 91 (3), 76 (4).
23. Choudary BM, Madhi S, Chowdari NS, Kantam ML, Sreedhar B
(2002) J Am Chem Soc 124:14127
24. Debreczeni N, Fodor A, Hell Z (2014) Catal Lett 144:1547–1551
´
25. Nemeth J, Hell Z (2013) React Kinet Mech Catal 111:115–121
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