N-Arylation of heterocycles promoted by tetraethylenepentamine in water

Article abstract of DOI:10.1016/j.tet.2013.05.027

Tetraethylenepentamine and triethylenetetramine are found to be efficient organic bases for the N-arylation of pyrazole and imidazole with aryl and heteroaryl-iodides and -bromides catalyzed by CuI in water at moderate temperature. The cross-couplings proceed smoothly with good to excellent yields and a variety of functional groups are tolerated under this condition.

Full text of DOI:10.1016/j.tet.2013.05.027

Accepted Manuscript
N-Arylation of heterocycles promoted by tetraethylenepentamine in water
Qichao Yang, Yufang Wang, Li Yang, Mingjie Zhang
PII:
S0040-4020(13)00762-X
10.1016/j.tet.2013.05.027
TET 24365
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 21 February 2013
Revised Date: 27 April 2013
Accepted Date: 10 May 2013
Please cite this article as: Yang Q, Wang Y, Yang L, Zhang M, N-Arylation of heterocycles promoted by
tetraethylenepentamine in water, Tetrahedron (2013), doi: 10.1016/j.tet.2013.05.027.
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to
our customers we are providing this early version of the manuscript. The manuscript will undergo
copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please
note that during the production process errors may be discovered which could affect the content, and all
legal disclaimers that apply to the journal pertain.

ACCEPTED MANUSCRIPT
Graphical Abstract
N-Arylation of heterocycles promoted by
tetraethylenepentamine in water
Leave this area blank for abstract info.
Qichao Yang, Yufang Wang, Li Yang and Mingjie Zhang
a Chemistry Department, School of Science,Tianjin University, Tianjin 300072, China.
b Chemistry and Pharmaceutical Engineering College, Nanyang Normal University, Nanyang 473061, China.

ACCEPTED MANUSCRIPT
1
Tetrahedron
journal homepage: www.elsevier.com
N-Arylation of heterocycles promoted by tetraethylenepentamine in water
Qichao Yanga, b , Yufang Wanga, , Li Yanga , and Mingjie Zhang a,
a Chemistry Department, School of Science, Tianjin University, Tianjin 300072, China.
b Chemistry and Pharmaceutical Engineering College, Nanyang Normal University, Nanyang 473061, China.
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Tetraethylenepentamine and triethylenetetramine are found to be efficient organic bases for the
N-arylation of pyrazole and imidazole with aryl and heteroaryl -iodides and -bromides
catalyzed by CuI in water at moderate temperature. The cross-couplings proceed smoothly with
good to excellent yields and a variety of functional groups are tolerated under this condition.
Available online
2013 Elsevier Ltd. All rights reserved.
Keywords:
N-arylation
Aqueous medium
Cross-coupling
Organic base
Heterocycle
1. Introduction
1,8-diazabicyclo(5,4,0)undec-7-ene,6 tetraalkylammonium salts,7
and alkoxide8 have been reported. In addition, these catalytic
N-Arylheterocycles are common and important motifs in
pharmaceutical and material fields, 1 thus many efforts have been
devoted to the improvement in the formation of C—N bond
catalyzed by transition metals by now. Among these various
progressive strategies of direct N-arylation of heterocycles with
aromatic halogen compounds, Pd-catalyst systems possess
inevitable drawbacks of high cost and toxicity, which limited
their massive applications for industrial scales,2 so the modified
copper-catalyzed Ullmann reactions have become an attractive
alternative. However, in the most of these successful examples,
ligands must be applied.3 In recent years, with the development
of the nanotechnology, some ligand-free copper-catalyzed N-
arylation reactions have been reported, but they showed high
substrate limitation.4 Meanwhile, it's worth mentioning that the
arylation methods of N-heterocycles with aryl boronic acids have
been discovered. Unfortunately, they are often trapped by the
high cost and less availability of the functionalized boronic
acids.5
systems possess disadvantages, for example, requirement of
additional ligands,7a-d,8a,8b,8d stoichiometric [Cu] as catalyst,6 and
protection of inert gas.7,8b-d Therefore, it is necessary to explore
more efficient organic bases to simplify the process.
In view of the importance of industrial exploitation, it is
becoming urgent to develop the sustainable methods. The media
of water has many merits, such as low cost, safety and
environmentally benign nature, so reactions in aqueous media
have attracted more interests of researchers for large scale
industrial processes,9 and we prefer to perform the cross-coupling
reactions in water. To the best of our knowledge, only a few
methods about the N-arylation of heterocycles have been
reported in aqueous media so far, and most of them need the
organic ligands.10 Herein, as a part of our ongoing research about
environmentally friendly catalyst system for the C—N coupling
reactions,4n we introduce a novel protocol to form C—N bond
catalyzed by CuI and using TEPA (tetraethylenepentamine) as
base and ligand in water. The transformation of pyrazole and
imidazole with aryl iodides or bromides proceeds smoothly at
moderate temperature with good to excellent yields. We believe
As far as Ullmann-type cross coupling, inorganic bases (KOH,
K2CO3, Cs2CO3, K3PO4 etc.) are commonly used in most reported
methods,2,3,4 which make the transformation suffer heterogeneous
reaction in organic solvents. Only a few organic bases such as
———
Corresponding author. Tel.: +0-086-022-27403475; e-mail: mjzhangtju@163.com

ACCEPTED MANUSCRIPT
2
Tetrahedron
that this catalyst system will enrich the methods of the
expected, no product is observed in the absence of copper source
Ullmann-type reaction.
(table 1, entry 17). The temperature proved to be crucial, the
yields are 54% and 92% at lower temperature (100℃) and at
higher temperature (125℃) respectively (table 1, entries 1 and
18). In the absence of TBAB, the yield only is 37% (table 1,
entry 1). When 0.2 mmol TEPA was added in the reaction in
which N(C2H5)3 or NH(C2H5)2 is used as base, the yields change
small (table 1, entries 3 and 4); moreover, we observed that the
CuI can dissolve in water in the presence of TEPA. Therefore,
we could speculate that the main contribution of TEPA in this
reaction is as base, and followed by as ligand which can promote
the dissolution of CuI in water. In addition the yields would not
dramatically increase with the prolonging of the reaction time
and 12 h is the proper time (table 1, entries1 and 19).
2. Results and discussion
In our initial experiment, pyrazole (1.5 equiv) is treated with
iodobenzene (1 equiv), CuI (0.1 equiv), TBAB (0.3 equiv) and
TEPA in water at 125℃ for 12 h. To our delight, 1-phenyl-1H-
pyrazole is formed in excellent yield. Encouraged by this result,
different amines are tested under the same conditions. In
addition, we investigate the effects of the amount of base and the
precursor catalyst on the yields. The results are shown in Table 1.
Table 1
Screening reaction conditions for N-arylation of pyrazole with iodobenzenea
Therefore, the optimal results have been obtained when amine
(1.5 equiv) and aryl halide (1.0 equiv) are allowed to react with
tetraethylenepentamine (2.0 equiv), CuI (0.1 equiv) and TBAB
(0.3 equiv) in water at 125℃.
Entry [Cu]
Baseb
TEPA (2mmol)
TETA (2mmol)
N(C2H5)3 (2mmol)
Time (h) Yieldc (%)
1
2
3
4
5
6
7
8
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuCl2
CuBr
CuO
Cu
12
12
12
92, 37g
89
Table 2
N-arylation of heterocycles with aryl halides in watera
0, 0h
51, 54h
45
NH(C2H5)2 (2mmol) 12
TMEDA (2mmol)
Thiourea (2mmol)
NH3(2mmol)
12
12
20
12
12
12
12
18
16
16
20
12
12
12
---
0
0,71d
94
Entry Aryl halide
1
products
Time(h) Yield(%)b
TEPA (5mmol)
TEPA (3mmol)
TEPA (1mmol)
TEPA (0.5mmol)
TEPA (2mmol)
TEPA (2mmol)
TEPA (2mmol)
TEPA (2mmol)
9
91
84
67
87
88
72
74
12
12
92(88)
86(87)
10
11
12
13
14
15
16
17
18
19 i
2a
2b
2
3
12
73
Cu(OAc)2 TEPA(2mmol)
—
CuI
CuI
85
TEPA(2mmol)
TEPA(2mmol)
TEPA (2mmol)
0e
2c
54f
4
5
12
12
64
93
60, 93
2d
2e
a reaction conditions䟛iodobenzene (1 mmol), pyrazole (1.5 mmol), [Cu] (0.1
mmol) and TBAB (tetrabutyl ammonium bromide (0.3mmol) in 2 mL water
b
at 125℃ for 12 h; TEPA (tetraethylenepentamine), TETA (triethylene-
tetramine), TMEDA (tetramethyl-ethylenediamine), c GC yield determined
6
7
8
9
12
12
12
12
89
d
by using methoxybenzene as internal standard; in the present of KOH (2
mmol) and ammonia(2 mmol); e in the absence of CuI ; f at 100℃ for 12 h; g
in the absence of TBAB; 0.2 mmol TEPA was added; at 125℃ for 6h and
24 h respectively.
2f
h
i
57(62)
64
2g
2h
According to the results in table 1, it is observed clearly that
the base plays a very important role in the transformation. There
is no coupling product when only using ammonia. However, the
reaction proceeds smoothly with the addition of KOH. The
speculated reason is that only the basicity of the ammonia is not
enough for the reaction (table 1, entry 7). Therefore, with the
76
2i
10
11
12
12
12
12
81(84)
77
2j
increasing basicity, thiourea, triethylamine,
TMEDA,
2k
diethylamine, triethylenetetramine and tetraethylenepentamine
lead coupling efficiency to ascend sharply (table 1, entries 1~6).
In addition, the amount of the base is screened and obviously, the
2 equiv. base is appropriate (table 1, entries 1, 8, 9). The copper
source has been studied in the reactions, and the readily available
copper salts such as CuI, CuBr, CuCl2, CuO, Cu and Cu(OAc)2
all can afford satisfactory results in the arylation of pyrazole.
These results are in agreement with the previously reported
conclusions that copper catalyst precursors in different oxidation
states presumably could be transformed into the same active
catalyst firstly under the reaction conditions.10k Here, CuI turns
out to give the best results (table 1, entries 1, 12~16), so CuI is
chosen as the catalyst precursor for subsequent experiments. As
80(76)
2l
13
12
65
2m
2a
14
15
22
24
63(67)
58
2b
16
36
45
2c

ACCEPTED MANUSCRIPT
3
a Reaction conditions: pyrazole (1.5 mmol), iodobenzene (1 mmol), TEPA
(2 mmol), CuI (10 mol%) and TATB (0.3 mmol) at 125℃ for 12 h in water
(2 mL). b GC yield determined by using methoxybenzene as internal
standard.
17
18
19
36
36
12
67(62)
60
2n
2o
3. Conclusion
N
N
N
88(87)
In summary, to our knowledge, it is the first time that the
tetraethylenepentamine and triethylenetetramine have been found
to be efficient organic bases for the CuI-catalyzed N-arylation of
N-containing heterocycles with aryl iodides or aryl bromides. A
variety of arylation products have been obtained with good yields
by this method. The simple reaction conditions, the easy
separation of the products and the broad scope of substrate render
this method particularly attractive. Even so, to develop an
effective catalytic system for the arylation of amines in water is
still far from being satisfied, our further work is to enlarge the
applications of this catalytic system.
2e
20
21
22
23
12
48
48
24
84
2f
2j
51(53)
44
2k
78
2p
24
25
26
24
24
24
80
4. Experimental
2q
2r
General procedure: iodobenzene (1.0mmol), imidazole (1.5
mmol), TEPA (2.0 mmol), TBAB (0.3 mmol), CuI (0.1 mmol)
and 3 mL H2O were added to a 10 mL flask which was
subsequently capped with a rubber balloon. The mixture was
stirred in a preheated oil bath at 125 ℃ for 12 h. After cooling
the mixture to the room temperature, 5 mL water was added and
the product was extracted by ethyl acetate (10 mL×3). The
combined organic layer was washed by brine (15 mL) , dried
over anhydrous MgSO4 and evaporated under the reduced
pressure. Further purification by silica gel column
chromatography (6:1 petroleum ether/ethyl acetate) give the 1-
phenyl-1H-imidazole.
75(78)
83
2s
27
36
66
2t
a
reaction conditions䟛iodide (1 mmol), nucleophile (1.5 mmol), TEPA(2
b
mmol), CuI (0.1 mmol) and TBAB (0.3mmol) in 2 mL water at 125℃;
isolated yields; the yields in brackets is catalyzed by TETA.
With the optimized conditions in hand, then, we examined the
scope of the substrates for this catalyst system. As shown in table
2, firstly, both aryl iodides and bromides give the coupling
products under the optimized conditions, but the aryl iodides
react more quickly than aryl bromides with the same
nucleophiles and afford higher yields. However, it is regretful
that the N-arylations of N-heterocycles with aryl chlorides are
not observed under this condition. Secondly, aryl halides with
electron-donating substituents proceed with nucleophile more
smoothly than those with electron-withdrawing ones (table 2,
entries 17~25). Thirdly, it is remarkable that aryl heterocycle
halides such as 4-bromopyridine, 4-iodopyridine and 2-
bromothiophene can couple with pyrazole or imidazole in higher
yields in this catalytical system (table 2, entries 5, 6, 19, 20, 26).
Fourthly, the obviously reduced yields of 2-methylimidazole and
2-iodotoluene suggest that the adverse impact of steric hindrance
exists in the current system (table 2, entries 4, 13). Finally, it is
notable that there are no obvious byproducts in this
transformation, and the operation procedure is simplified.
Acknowledgement
The financial support from National Natural Science
Foundation of China (No. 20802049 and No. 31201426) is
greatly acknowledged.
Supplementary data
Supplementary data associated with this article can be found
in the online version, at doi:
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.; Späth, A.; Ma, D.;
König, B. Chem. Asian J. 2009, 4, 1134–1140.
2. For recent reviews palladium catalyzed C–N bond formation, see: (a)
Buchwald, S. L.; Mauger, C.; Mignani, G.; Scholz, U. Adv. Synth. Catal.
2006, 348, 23–39; (b) Kienle, M.; Dubbaka, S. R.; Brade, K.; Knochel,
P. Eur. J. Org. Chem. 2007, 4166–4176; (c) Hartwig, J. F. Acc. Chem.
Res. 2008, 41, 1534–1544; (d) Surry, D. S.; Buchwald, S. L. Angew.
Chem. Int. Ed. 2008, 47, 6338–6361.
Catalyst recycle experiments have been carried out and the
results were presented in Table 3. The catalyst system in aqueous
phase was reused after the extraction with ethyl acetate. 1mmol
TEPA and 0.1 mmol TBAB should have been complemented to
the reaction system before the next test. According to the yields,
the catalytic activity of CuI was gradually declining in the
coupling reaction.
3. For recent reviews copper catalyzed C–N bond formation, see: (a) Ley,
S. V.; Thomas, A. W. Angew. Chem. Int. Ed. 2003, 42, 5400–5449; (b)
Beletskaya, I. P.; Cheprakov, A. V. Coord. Chem. Rev. 2004, 248, 2337–
2364; (c) Yang, M.; Liu, F. J. Org. Chem. 2007, 72, 8969–8971; (d) Ma,
D.; Cai, Q.; Acc. Chem. Res. 2008, 41, 1450–1460; (e) Monnier, F.;
Taillefer, M. Angew. Chem. Int. Ed. 2008, 47, 3096–3099; (f) Chen, Y.;
Li, H. X.; Liu, D.; Liu, L. L.; Li, N. Y.; Ye, H. Y.; Zhang, Y.; Lang, J. P.
Cryst. Growth Des. 2008, 8, 3810-3816; (g) Monnier, F.; Taillefer, M.
Angew. Chem. Int. Ed. 2009, 48, 6954–6971.
4.(a) Chang, J. W.; Xu X. Chan, P. W. H. Tetrahedron Lett. 2007, 48, 245–
248; (b) Correa, A., Bolm, C. Adv. Synth. Catal. 2007, 349, 2673–2676;
(c) Kantam M. L., Yadav J., Laha S., Sreedhar B.; Jha S. Adv. Synth.
Catal. 2007, 349, 1938–1942; (d) Taillefer, M.; Xia, N.; Oualli, A.
Angew. Chem. Int. Ed. 2007, 46, 934–936; (e) Rout, L.; Jammi, S.;
Punniyamurthy, T. Org. Lett. 2007, 9, 3397–3399; (f) Zhu, L.; Guo, P.;
Li, G.; Lan, J.; Xie, R. and You, J. J. Org. Chem. 2007, 72, 8535–8538;
(g) Sperotto, E.; de Vries, J. G.; van Klink, G. P. M. and van Koten, G.
Tetrahedron Lett. 2007, 48, 7366–7370; (h) Zhu, R.; Xing, L.; Wang, X.;
Table 3.
Recycle studies of catalyst for N-aryllation of pyrazole with iodobenzenea
Run
1
90
2
84
3
62
4
37
Yield [%]b

ACCEPTED MANUSCRIPT
4
Tetrahedron
Cheng, C.; Su, D.; Hu, Y. Adv. Synth. Catal. 2008, 350, 1253–1257; (i)
Kubo, T.; Katoh, C.; Yamada, K.; Okano, K.; Tokuyama, H. Fukuyama,
T. Tetrahedron 2008, 64, 11230–11236; (j) Sreedhar, B., Arundhathi, R.,
Linga Reddy, P., Kantam, L. M. J. Org. Chem. 2009, 74, 7951–7954; (k)
Zhu, L. B.; Li, G. C.; Luo, L.; Guo, P.; Lan, J. B.; You, J. S. J. Org.
Chem. 2009, 74, 2200–2202; (l) Kim, A. Y.; Lee, H. J.; Park, J. C.;
Kang, H.; Yang, H.; Song, H.; Park, K. H. Molecules 2009, 14, 5169–
5178. (m) Panda, N.; Jena, A. K.; Mohapatra, S.; Rout, S. R. Tetrahedron
Lett. 2011, 52, 1924–1927; (n) Xu Z. L, Li H. X, Ren Z. G, Du W. Y, Xu
W. C, Lang J. P. Tetrahedron 2011, 67, 5282–5288. (m) Yang, Q. C.;
Wang Y. F.; Zhang, B. J.; Zhang, M. J. Chin. J. Chem. 2012, 30, 2389–
2393.
5. (a) Chan, D. M. T.; Monaco, K. L.; Wang, R. P.; Winters, M. P.
Tetrahedron Lett. 1998, 39, 2933–2936; (b) Evans, D. A.; Katz, J. L.;
West, T. R. Tetrahedron Lett. 1998, 39, 2937–2940; (c) Lam, P. Y. S.;
Deudon, S.; Hauptman, E.; Clark, C. G. Tetrahedron Lett. 2001, 42,
2427–2429; (d) 3a; (e) Denton, T. T.; Zhang, X.; and Cashman, J. R. J.
Med. Chem. 2005, 48, 224–239.
6. Huang, H.; Yan, X. H.; Zhu, W. L.; Liu, H.; Jiang, H. L. and Chen. K. X.
J. Comb. Chem. 2008, 10, 617–619.
7. (a) Liu, L.; Frohn, M.; Xi, N.; Dominguez, C.; Hungate, R.; Reider, P. J.
J. Org. Chem. 2005, 70, 10135–10138; (b) Feng, Y. S.; Man, Q. S.; Pan,
P.; Pan, Z. Q.; Xu, H. J. Tetrahedron Lett. 2009, 50, 2585–2588; (c)
Yang, C. T.; Fu, Y.; Huang, Y. B.; Yi, J.; Guo, Q. X.; Liu, L. Angew.
Chem. Int. Ed. 2009, 48, 7398–7401; (d) Xie, Y. X.; Pi, S. F.; Wang, J.;
Yin, D. L.; Li, J. H. J. Org. Chem. 2006, 71, 8324–8327; (e) Lee, H. G.;
Won, J. E.; Kim, M. J.; Park, S. E.; Jung, K. J.; Kim, B. R.; Lee, S. G.;
Yoon, Y. J. J. Org. Chem. 2009, 74, 5675–5678; (f) Xu, H. J.; Zheng, F.
Y.; Liang, Y. F.; Cai, Z. Y.; Feng, Y. S.; Che, D. Q. Tetrahedron Lett.
2010, 51, 669–671.
8. (a) Ma, H. C.; Jiang, X. Z. J. Org. Chem. 2007, 72, 8943-8946 (b) Xue,
F.; Cai, C. Y.; Sun, H. M.; Shen, Q.; Rui. J. Tetrahedron Lett. 2008, 49,
4386–4389; (c) Panda, N.; Jena, A. K.; Mohapatra, S.; Rout, S. R.
Tetrahedron Lett. 2011, 52, 1924–1927,
9. (a) Siskin, M.; Katritzky, A. R. Chem. Rev. 2001, 101, 825–836; (b)
Lindström, U. M. Chem. Rev. 2002, 102, 2751–2772; (c) Kobayahi, S.;
Manabe, K. Acc. Chem. Res. 2002, 35, 209–217; (d) Akiya, N.; Savage,
P. E. Chem. Rev. 2002, 102, 2725–2750; (e) Li, C. J. Chem. Rev. 2005,
105, 3095-3166; (f) Li, C. J.; Chen, L. Chem. Soc. ReV. 2006, 35, 68–82.
(g) Chen, L.; Li, C. J. AdV. Synth. Catal. 2006, 348, 1459–1484. (h)
Blackmond, D. G.; Armstrong, A.; Coombe, V.; Wells, A. Angew.
Chem., Int. Ed. 2007, 46, 3798–3800; (i) Herrerıás, C. I.; Yao, X.; Li, Z.;
Li, C. J. Chem. Rev. 2007, 107, 2546–2562. (j) Minakata, S.; Komatsu,
M. Chem. Rev. 2009, 109, 711–724; (k) Carril, M.; SanMartin, R.;
Dominguez, E. Chem. Soc. Rev. 2008, 37, 639–647.
10. (a) Oshovsky, G. V.; Ouali, A.; Xia, N.; Zablocka, M.; Boeré, R. T.;
Duhayon, C.; Taillefer, M.; Majoral, J. P. Organometallics 2008, 27,
5733–5736. (b) Teo, Y. C. Adv. Synth. Catal. 2009, 351, 720–724. (c)
Lee, H. W.; Chan, A. S. C.; Kwong, F. Y. Tetrahedron Lett. 2009, 50,
5868–5871; (d) Liang, L.; Li, Z.; Zhou, X. Org. Lett. 2009, 11(15),
3294–3297; (e) Xie, J.; Zhu, X.; Huang, M.; Meng, F.; Chen, W.; Wan,
Y. Eur. J. Org. Chem. 2010, 3219–3223; (f) Swapna, K.; Murthy, S. N.;
Nageswar, Y. V. D. Eur. J. Org. Chem. 2010, 6678–6684; (g) Yong, F.
F.; Teo, Y. C.; Tay, S. H.; Tab, B. Y. H.; Lim, K. H. Tetrahedron Lett.
2011, 52, 1161–1164.