A green, homogeneous and reusable surfactant/copper based ionic liquid for the N-arylation of indoles, pyrazoles and imidazoles

Article abstract of DOI:10.1016/j.tetlet.2015.09.128

An efficient surfactant/copper based ionic liquid promoter was examined as a reusable system for the N-arylation of indole, pyrazole and imidazole by a variety of aryl halides. The products were obtained in good to excellent yields by a convenient one-pot procedure. The reaction could be carried out in water under air and did not require the use of arylboronic acids as the active aryl source, palladium as the catalyst or a strong base.

Full text of DOI:10.1016/j.tetlet.2015.09.128

Accepted Manuscript
A green, homogeneous and reusable surfactant/copper based ionic liquid for the
N-arylation of indoles, pyrazoles and imidazoles
Fariba Heidarizadeh, Afrooz Majdi-nasab
PII:
S0040-4039(15)30170-2
DOI:
http://dx.doi.org/10.1016/j.tetlet.2015.09.128
TETL 46800
Reference:
Tetrahedron Letters
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18 September 2015
26 September 2015
Please cite this article as: Heidarizadeh, F., Majdi-nasab, A., A green, homogeneous and reusable surfactant/copper
based ionic liquid for the N-arylation of indoles, pyrazoles and imidazoles, Tetrahedron Letters (2015), doi: http://
dx.doi.org/10.1016/j.tetlet.2015.09.128
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Tetrahedron Letters
A green, homogeneous and reusable surfactant/copper based ionic liquid for the N-
arylation of indoles, pyrazoles and imidazoles
Fariba Heidarizadeh*, a, Afrooz Majdi-nasaba
a Department of Chemistry, Shahid Chamran University, Ahvaz 6135743169, Iran
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
An efficient surfactant/copper based ionic liquid promoter was examined as a reusable system
for the N-arylation of indole, pyrazole and imidazole by a variety of aryl halides. The products
were obtained in good to excellent yields by a convenient one-pot procedure. The reaction could
be carried out in water under air and did not require the use of arylboronic acids as the active
aryl source, palladium as the catalyst or a strong base.
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
Copper(I) promoter ionic liquid
N-Arylation reaction
Tetrabutylammonium bromide
One-pot synthesis
Surfactant/ionic liquid
1. Introduction
that can form micelles which solubilize organic substances in
water.9
N-aryl heterocycles form the core of numerous natural and
biologically active products.1 Thus, much effort has been directed
at improving the formation of the C-N bond. The Ullmann type
reaction of aryl halides with nitrogen heterocycles is a simple and
efficient approach to the synthesis of N-arylated heterocycles.2
The palladium-catalyzed N-arylation of heterocycles is an
alternative method which proceeds under mild reaction
conditions,3 however, the high cost of palladium limits the
possible industrial applications of the method. Modified copper-
catalyzed Ullmann reactions have become more attractive and the
efficiency has been improved by changing the ligands, bases, and
other additives.4
As part of our efforts to develop new environmentally friendly
reaction conditions which overcome some of the drawbacks of
homogeneous catalysis, such as the difficulty of catalyst-reaction
mixture separation, we decided to explore the use of bis(1-
dodecylimidazole)cupronium dichlorocuprate, Cu(Im12)2]CuCl2,10
as a Lewis acid-surfactant ionic liquid promoter for the Ullmann-
type coupling of N-aryl heterocycles with aryl halides. Ionic
liquids containing chlorometallate ions, first developed by Hurley
and Rice,11 have been applied to several catalytic reactions.12, 13
2. Results/Discussion
Initially, we examined the reaction of iodobenzene (1 mmol)
and indole (1 mmol) in the presence of the promoter (0.5 mmol)
at 80 ºC in order to optimize the reaction. The N-arylation
reaction did not occur in the absence of base, thus, various bases
were examined with K2CO3 giving the highest yield (Table 1).
TBAB (tetrabutylammonium bromide) was included as a phase
transfer reagent, and we believe that the reaction rate
enhancement afforded by TBAB could be attributed to an
increase of solubilization as well as a decrease in both surface
tension and critical micelle concentration (CMC).14 The amount
of TBAB was investigated and 1 equivalent was found to be
optimal.
Although many copper(I) catalyst have been reported to be
suitable for N-arylation,4 many have deficiencies, including
instability, high tendency towards oxidation leading to catalytic
inactivity, and low solubility. An example of progress towards
overcoming these drawbacks are the coordination complexes
5
Cu(P(OMe)3)3 and Cu(PPh3)3Br6,7 which are often utilized in
organic solvents where cuprous salts have limited solubility.
The use of water as a solvent for organic synthesis has
recently attracted considerable attention due to advantages such
as low cost, wide availability, non-toxicity, and nonflammability,
thus providing more economic and sustainable synthetic routes.8
However, one of the major disadvantages of using water as a
solvent is the low solubility of most organic substrates. This
problem can be overcome by the use of a surfactant which
consists of both hydrophilic head and hydrophobic tail groups
Table 1

2
Tetrahedron Letters
Several solvents, including ethanol, methanol, acetonitrile,
Acknowledgments
dimethylformamide and water were investigated with the best
results based on yields and reaction times achieved using water
as the solvent. The reaction was examined at different
temperatures. No reaction occurred after 24 h stirring at room
temperature. Increasing the temperature to a maximum of 100 ºC,
showed that the reaction rate was greatest at 80 ºC and that
further increases in temperature did not show further
enhancement of the yield. Further optimization of the reaction
conditions was carried out using different amounts of
[Cu(Im12)2]CuCl2 showing that 0.5 mmol of promoter was
effective for the coupling reaction.
The authors gratefully acknowledge financial support of this
research by Shahid Chamran (Ahvaz) University.
References and notes
1. (a) Corbert, J. P.; Mignani, G. Chem. Rev. 2006, 106, 2651-2710; (b)
Beccalli, E. M.; Broggini, G.; Martinelli, M.; Sottocornola, S. Chem. Rev.
2007, 107, 5318-5365; (c) Evano, G.; Blanchard, N.; Toumi, M. Chem. Rev.
2008, 108, 3054-3131; (d) Grauer, A.; Spät , a, ni , B. Chem.-
Asian J. 2009, 4, 1134-1140.
2. (a) Ullmann, F. Ber. Dtsch. Chem. Ges. 1903, 36, 2382-2384; (b) Ullmann,
F. Ber. Dtsch. Chem. Ges. 1904, 37, 853-854; (c) Lindly, J. Tetrahedron
1984, 40, 1433-1456; (d) Unangst, P. C.; Connor, D. T.; Stabler, S. R.;
Weikert, R. J. J. Hetrocycle. Chem. 1987, 24, 811-816.
3. (a) Mann, G.; Hartwig, J. F.; Driver, M. S.; Fernandez-Rivas, C. J. Am.
Chem. Soc. 1998, 120, 827-828; (b) Watanable, M.; Nishiyama, M.;
Yamamoto, T.; Koie, Y. Tetrahedron Lett. 2000, 41, 481-483; (c) Grasa, G.
A.; Viciu, M. S.; Huang, J.; Nolan, S. P. J. Org. Chem. 2001, 66, 7729-7737.
4. (a) Kunaz, K.; Scholz, U.; Ganzer, D. Synlett 2003, 15, 2428-2439; (b)
Beletskaya, I. P.; Cheprakov, A. V. Coord. Chem. Rev. 2004, 248, 2337-
2364; (c) Corbet, J. P.; Mignani, G. Chem. Rev. 2006, 106, 2651-2710; (d)
Ley, S. V.; Thomas, A. W. Angew. Chem., Int. Ed. 2003, 42, 5400-5449; (e)
Swapana, K.; Murthy, S. N.; Nageswar, Y. V. D. Eur. J. Org. Chem. 2010,
34, 6678- 6684.
Finally, under the optimized reaction conditions, the
generality and scope of this new protocol were explored. A range
of functionalized aryl halides were reacted with indole to give the
corresponding N-arylindoles (Table 2). Additionally, the
reactions of pyrazole and imidazole were investigated. It was
found that the reaction generally proceeded smoothly to give the
corresponding N-arylated products in high yields. The reactivity
of aryl iodides containing electron-withdrawing groups was
higher than that of aryl iodides containing electron-donating
groups. Sterically hindered aryl iodides, such as N-(2-
methoxyphenyl)
indole,
reacted
slower than
N-(4-
5. Balderas, P. F.; Munoz, O. M.; Sanfrutos, M. J.; Mateo, H. F.; Flores, F.
G.; Asin, J. A.; Garcia, I. J. Org. Lett. 2003, 5, 1951-1954.
methoxyphenyl)indole. A proposed mechanistic pathway for the
[Cu(Im12)2]CuCl2 promoted N-arylation of indole is depicted in
Figure 1.
6. Malkoch, M.; Schleicher, K.; Drockenmuller, E.; Hawker, C. J.; Russell, T.
P.; Wu, P.; Fokin, V. V. Macromolecules 2005, 38, 3663-3678.
7. Wu, P.; Feldman, A. K.; Nugent, A. K.; Hawker, C. J.; Scheel, A.; Voit,
B.; Pyun, J.; Frechet, J. M. J.; Sharpless, K. B.; Fokin, V. V. Angew. Chem.
Int. Ed. 2004, 43, 3928-3932.
Table 2
8. (a) Lindstorm, U. M., Ed.; Wiley-Blackwell: New York, NY, 2007; (b)
Simon, M. O.; Li, C. J. Chem. Soc. Rev. 2012, 41, 1415-1427.
9. (a) Dwars, T.; Paetzold, E.; Oehme, G. Angew. Chem., Int. Ed. 2005, 44,
7174-7199; (b) Lipshutz, B. H.; Ghorai, S. Aldrichimica Acta. 2008, 41, 59-
72.
10. (a) Stricker, M.; Linder, T.; Oelkers, B.; Sundemeyer, J. Green Chem.,
2010, 12, 1589–1598; (b) Zarei Ahmady, A.; Heidarizadeh, F.; Keshavarz. M.
Synthetic Communications, 2013, 43, 2100-2109; (c) Keshavarz, M.; Karami,
B; Zarei Ahmady, A.; Ghaedi, A. M.; Vafaei, H. C. R. Chimie, 2013, 17 ,
570-576.
Figure 1
The reusability of the promoter was examined with the
reaction of indole with iodobenzene. After reaction completion,
the product was extracted from the ionic liquid mixture using
EtOAc. The recovered ionic liquid mixture was used directly in
the next run and the results are summarized in Table 3.
Table 3
11. Hurley, F. H.; US Pat., 2 446 331, 1948.
The efficiency of this method was compared to recently
reported methods for the N-arylation of imidazole15-16, 18-20 (Table
4). The reported procedure involves the use of a recoverable
promoter, avoidance of organic solvents, mild reaction
conditions, high yield, short reaction time and low temperature.21
12. Sun, H.; Harm, K.; Sundemeyer, J. J. Am. Chem. Soc. 2004, 126, 9550–
9551.
13. Chauvin, Y.; Muβmann, L.; Olivier, H. Angew. Chem., 1995, 107, 2941–2943
14. (a) Mata, J.; Varade, D.; Ghosh, G.; Bahadur, P. Colloids Surf., A 2004,
245, 69-73 (b) Jain, R.; Sharma, K.; Kumar, D. Tetrahedron Lett. 2012, 53,
6236- 6240 (c) Kumar, B. A.; Satyanarayana, G.; Parthasarathy, T.; Uma, V.
J. Indian Chem. Soc. 2005, 82, 558-560 (d) Buxaderas, E.; Alonso, D. A.;
Nájera, C. RSC Adv. 2014, 4, 46508-46512.
Table 4
We postulate that the [Cu(Im12)2]CuCl2 had a synergistic
effect where the Lewis acid part of the promoter activates the
substrates and the surfactant part helps solubilize the substrates in
water. Thus, the combination of these two effects enhance the
rate and the yield of the reaction.
15. Chen, H. H.; Huang, H. M.; Chen, S.C.; Chen, Y. G. J. Chin. Chem. Soc,
2010, 57, 14-18.
16. Yang, Q.; Wang, Y.; Yang L.; Zhang M. Tetrahedron 2013, 69, 6230-
6233.
17. Wang, H.; Li, Y.; Sun, F.; Feng, Y.; Jin, K.; Wang, X. J. Org. Chem.
2008, 73, 8639-8642.
18. Kim, A.Y.; Lee H. J.; Park J. C.; Kang H.; Yang H.; Song H.; Park K. H.
Molecules 2009, 14, 5169-5178.
19. Antilla, J. C.; M. Baskin J.; E. Barder, T.; L. Buchwald, S. J. Org. Chem.
2004, 69, 5578-5587.
20. Khalil, A.; Fihri, A.; Jouiad, M.; Hashaikeh, R. Tetrahedron Lett. 2014,
55, 5973-5975.
3. Conclusion
The current research reports a simple, one-pot synthesis of N-
arylindoles, N-arylpyrazoles and N-arylimidazoles using a
reusable surfactant type copper based ionic liquid and base. It is
postulated that the surfactant properties increased the
concentration of organic reactants to form micelle particles in
water. The advantages of this methodology include the use of
water as solvent, using an aryl halide instead of boronic acid
derivatives, ease of product isolation and the capacity for
promoter recycling. Accordingly, the methodology can be
regarded as a useful and attractive process for the synthesis of N-
arylated heterocycles. We believe that this procedure may have
industrial and scale-up applications.
21. Preparation of [Cu(Im12)2]CuCl2: A solution of 1-dodecylimidazole
(Im12) (3.06 g, 12.95 mmol) in CH3CN (5 mL) was added to a Schlenk flask
filled with CuCl (1.21 g, 12.22 mmol). The reaction was placed in an
ultrasonic bath at ambient temperature for approximately 30 min. The solvent
was removed in vacuo and the precipitate washed with Et2O and dried under
vacuum to give [Cu(Im12)2]CuCl2 as a fine crystalline colorless solid (4.6 g,
99 %). General procedure for the synthesis of N-arylated heterocycles in
Ullman-type coupling: At first [Cu(Im12)2]CuCl2 (0.5 mmol, 0.305 g) was
added to a 25 ml round bottom flask containing water (4 mL), indole (0.117
g, 1 mmol) and iodobenzene (0.203 g, 1 mmol). K2CO3 (0.276 g, 2 mmol)
and TBAB (0.322 g, 1 mmol) was added and the reaction stirred at 80 ºC for
12 hours. The reaction progress was monitored by TLC (EtOAc/n-hexane;
1:3 v/v) and after completion, the organic phase was extracted from the ionic
liquid with EtOAc (2×8 mL) and concentrated in vacuo. The promoter was

Tetrahedron Letters
used directly for the next run. The product was purified by silica gel column
chromatography (EtOAc/n-hexane; 1:3 v/v). The isolated product was dried
under vacuum overnight to give a yield of 92%. All products are known in
1
the literature and were identified by comparison of their FT-IR, H, and 13C
NMR spectra with the literature data. Selected characterization data are given
1
below. N-Phenylindole (1): H NMR (400 MHz, CDCl3): δ (ppm): 7 68 (d,
J=8.0 Hz, 1H), 7.55 (d, J=8.0 Hz, 1H), 7.50-7.47 (m, 4H), 7.35-7.31 (m, 2H),
7.21 (t, J=7.2 Hz, 1H), 7.16 (t, J=7.2 Hz, 1H), 6.67 (d, J=2.8 Hz, 1H). 13C
NMR (100 MHz, CDCl3) δ (ppm): 139 8, 135 8, 129 6, 129 3, 127 9, 126 4,
124.3, 122.3, 121.1, 120.3, 1105, 103.5, IR (film, cm-1): 2924, 1596, 1502,
1138, 745, 688. N-Phenylimidazole (12): 1H NMR (400 MHz, CDCl3) δ
(ppm): 7.22 (br s, 1H), 7.30 (br s, 1H), 7.35-7.41 (m, 3H), 7.46-7.51 (m, 2H),
7.87 (br s,1H); 13CNMR (100 MHz, CDCl3) δ (ppm): 118 2, 121 4, 127 4,
129.8, 130.4, 135.6, 137.3; IR (film, cm-1): 3407, 3116, 1718, 1600, 1507,
1303, 1056, 963, 757, 685.

4
Tetrahedron Letters
Table 1. Effects of base on the N-arylation reaction.
Table 2. Reactions of arylhalides with indole, pyrazole and
imidazole to form the corresponding N-arylindoles, N-
arylpyrazoles and N-arylimidazoles.
Table 3. Reusability of the promoter in the N-arylation of
iodobenzene and indole.
Table 4. Comparison of this method with recently reported
protocols for the N-arylation of imidazole with iodobenzene.
Figure 1. Proposed mechanistic pathway for the
[Cu(Im12)2]CuCl2 promoted N-arylation of indole.

Tetrahedron Letters
Figure 1. Proposed mechanistic pathway for the
[Cu(Im12)2]CuCl2 promoted N-arylation of indole

*Tables
Table 1. Effects of base on the N-arylation reactiona
Entry
1
base
Time (h)a Yield (%)
K2CO3 (1 mmol)
12
12
12
12
12
92
92
50
76
89
2
3
4
5
K2CO3 (2 mmol)
Bu3N (2 mmol)
K3PO4 (2 mmol)
Na2CO3 (2 mmol)
6
7
NH3 (2 mmol)
Et3N (2 mmol)
12
12
70
75
(a) Reaction conditions: iodobenzene (1 mmol), indole (1
mmol), [Cu(Im12)2]CuCl2 (0.5 mmol), TBAB (1 mmol), H2O,
80 °C.

Table 2. Reactions of aryl halides with indole, pyrazole and imidazole to form the corresponding N-arylindoles, N-
arylpyrazoles and N-arylimidazolesa
Entry
Substrates
Product
Time (h) Yield (%)b Ref
1
I
N
12
8
92
98
85
15
4e
4e
N
H
O2N
I
O2N
N
2
N
H
H3CO
I
H3CO
N
12
3
4
N
H
I
N
14
75
4e
N
H
OCH3
OCH3
5
6
Br
Cl
N
N
12
24
75
0
15
N
H
-
N
H
12
10
12
85
95
75
16
16
16
N
7
8
I
I
I
N
HN
HN
HN
HN
N
N
O2N
O2N
N
N
N
N
N
9
H3CO
H3CO
N
N
10
I
N
15
12
68
65
16
16
OCH3
OCH3
N
N
11
12
Br
I
HN
HN
N
N
N
N
12
12
85
90
17
16

N
N
(a)
13
14
O2N
I
HN
HN
N
H3CO
I
H3CO
N
12
67
17
N
N
N
15
16
I
N
15
12
60
52
17
17
HN
OCH3
OCH3
N
Br
N
HN
Reaction conditions: aryl halide (1 mmol), N-heterocycle (1 mmol), [Cu(Im12)2]CuCl2 (0.5 mmol), K2CO3 (2 mmol),
TBAB (1 mmol), H2O, 80 °C
(b) Isolated yield

Table 3. Reusability of the promoter in the N-arylation of iodobenzene and indole.
Entry Cycle Time (h) Yield (%)
1
2
3
4
1
2
3
4
12
12
12
12
92
90
83
80
(a) Reaction conditions: iodobenzene (1 mmol), indole (1
mmol), [Cu(Im12)2]CuCl2 (0.5 mmol), K2CO3 (2 mmol), TBAB
(1 mmol), H2O, 80 °C.
Table 4. Comparison of this method with recently reported protocols for the N-arylation of imidazole with
iodobenzene
Entry
1
System
Time (h)
12
Yield (%)
[Cu(Im12)2]CuCl2/ K2CO3/ TBAB/ H2O/ 80 ºC
85 (This work)
2
3
4
5
CuI/ tripod-liganda/ Cs2CO3/ DMF/ 110 ºC
CuI/ TEPAb/ TBAB/ H2O/ 125 ºC
24
24
18
24
9515
8616
CuO/ ABc/ toluene/ KOtBu/ 180 ºC
10018
7419
CuI/ diamine ligands/ DMF or dioxane/ Cs2CO3/ Reflux
(a) tripod-ligand: 1,1,1-tris(hydroxymethyl)ethane
(b) TEPA: teraethylenepentaamine
(c) AB: acetylene black

Graphical Abstract (for review)
Leave this area blank for abstract info.
A green, homogeneous and reusable
surfactant/ copper based ionic liquid for the
N-arylation of indoles, pyrazoles, and
imidazoles
Fariba Heidarizadeh, Afrooz Majdi-nasab