KOH/adogen 464/proline system for highly effective Cu-catalyzed "on-water" N-H arylation of heteroaromatic compounds

Full text of DOI:10.1007/s10593-013-1389-8

Chemistry of Heterocyclic Compounds, Vol. 49, No. 9, December, 2013 (Russian Original Vol. 49, No. 9, September, 2013)
LETTERS TO THE EDITOR
KOH / ADOGEN 464 / PROLINE SYSTEM FOR HIGHLY
EFFECTIVE Cu-CATALYZED "ON-WATER" N–H
ARYLATION OF HETEROAROMATIC COMPOUNDS
1
1
*
E. Abele and R. Abele
Keywords: aryl iodides, imidazoles, indoles, pyrazoles, water, copper catalysis.
Copper catalyst systems have been widely applied in the synthesis of heterocyclic compounds [1],
natural products [2], and biologically active compounds [3]. Recently, excellent reviews on the "on-water"
synthesis [4] and copper-catalyzed coupling reactions were published [5]. Some articles were dedicated to
Cu-catalyzed "on-water" N-arylation of heterocyclic and heteroaromatic compounds with aryl halides [6-11].
However, in most cases selectivity of arylation and yields of obtained products were modest. In some cases it is
also necessary to use expensive and complicated ligand/additive systems or co-solvent.
We have found that the catalytic system CuI / KOH / Adogen 464 / proline can be used for the N–H
arylation of heterocycles 1-4 in water. The products were isolated in good to excellent yields. Adogen 464 as
phase transfer agent or cationic surfactant is widely used in organic synthesis. However, the use of Adogen 464
as an additive in the Cu-catalyzed reactions in water was recently demonstrated for the first time in the synthesis
of imidazothiazole derivatives [12]. Workup of reaction mixture in these cases is very simple – the product was
isolated by extraction followed by flash column chromatography.
Thus, a highly efficient Cu-catalyzed method of N-arylation of heteroaromatic compounds using
Adogen 464 as an additive and proline as ligand was reported.
1H and 13С NMR spectra were recorded on a Varian Mercury BB instrument (400 and 100 MHz,
respectively) in CDCl3. The residual proton signal of the solvent (δ 7.26 ppm) was used as the reference.
Electron impact ionization mass spectra were recorded on an Agilent Technologies 5975C MSD detector at
70 eV. Melting points were determined on a Boetius apparatus equipped with visual detector PHMH 05. The
progress of the reactions was monitored by TLC silica gel 60 F254 aluminum sheets using hexane–EtOAc in
different ratios as eluent. Сompounds 1-4, iodobenzene, m-chloroiodobenzene (all Acros), copper(I) iodide,
proline (Reakhim), and Adogen 464 (Sigma-Aldrich) were used without purification.
"On-water" Arylation (General Method). Solid KOH (0.220 g, 4.0 mmol) was added to a solution of
the heterocycles 1-4 (1.0 mmol) and iodobenzene or m-chloroiodobenzene (1.2 mmol), CuI (0.038 g, 0.2 mmol),
_______
*To whom correspondence should be addressed, e-mail: abele@osi.lv.
1Latvian Institute of Organic Synthesis, 21 Аizkraukles St., Riga LV-1006, Latvia.
_________________________________________________________________________________________
Published in Khimiya Geterotsiklicheskikh Soedinenii, No. 9, pp. 1486-1487, September, 2013.
Original article submitted July 23, 2013.
1384
0009-3122/13/4909-1384©2013 Springer Science+Business Media New York

Me
N
Me
N
H
R
1
5 a (63%), b (74%)
R
N
N
N
N
I
H
6a (91%)
2
CuI, KOH
R
N
Adogen 464, proline
H2O
N
N
N
H
150°C
7 a (99%), b (66%)
3
N
N
N
N
R
H
4
8 a (89%), b (85%)
a R = H, b R = Cl
proline (0.020 g, 0.2 mmol) and Adogen 464 (0.100 mg) in water (2 ml) in a glass reactor (50 ml). The reaction
mixture was stirred at 150°C (TLC control) for 18 h. The products were extracted with EtOAc (2×20 ml) and
purified by flash column chromatography (EtOAc–hexane in different mixtures). Spectroscopic and physical
data of 2-methyl-1-phenylindole (5a) [13], 1-phenylpyrazole (6a) [14], 1-phenylimidazole (7a) [15], 1-(3-
chloro-phenyl)imidazole (7b) [16], 1-phenylbenzimidazole (8a) [17], and 1-(3-chlorophenyl)benzimidazole
(8b) [18] are identical with those described in the literature.
1
1-(3-Chlorophenyl)-2-methylindole (5b). Yield 74%. Yellow oil. H NMR spectrum, ppm2.23
(3H, s, CH3); 6.32 (1H, s, H-3 indole); 6.91-7.20 (4H, m, H-5,6 indole, H-4,6 Ar); 7.32 (1H, s, H-2 Ar);
13
7.34-7.50 (3H, m, H-4,7 indole, H-5 Ar). C NMR spectrum, ppm13.3; 101.9; 109.8; 119.7; 120.3; 121.3;
126.2; 127.9; 128.2; 130.4; 130.9; 134.9; 136.6; 138.0; 139.2. Mass spectrum, m/z (Irel, %): 243 [M (37Cl)]+ (33),
241 [M (35Cl)] (100), 204 (35), 165 (9), 102 (14).
REFERENCES
1.
2.
C. Fisher and B. Koenig, Beilstein J. Org. Chem., 7, 59 (2011).
J. Juen, Y.-Q. Fang, and M. Lautens, Org. Lett., 8, 653 (2006).
3.
G. I. Elliott and J. P. Konopelski, Org. Lett., 2, 3055 (2000).
4.
A. Chanda and V. V. Fokin, Chem. Rev., 109, 725 (2009).
5.
H. Rao and H. Fu, Synlett, 745 (2011).
6.
7.
8.
9.
10.
11.
C. Mukhopadhyay, P. K. Tapaswi, and R. J. Butcher, Org. Biomol. Chem., 8, 4720 (2010).
X. Li, D. Yang, Y. Jiang, and H. Fu, Green Chem., 12, 1097 (2010).
K. Swapna, S. N. Murthy, and Y. V. D. Nageswar, Eur. J. Org. Chem., 6678 (2010).
Q. Yang, Y. Wang, L. Yang, and M. Zhang, Tetrahedron, 69, 6230 (2013).
D. Wang, F. Zhang, D. Kuang, J. Yu, and J. Li, Green Chem., 14, 1268 (2012).
Q. Yang, Y. Wang, D. Lin, and M. Zhang, Tetrahedron Lett., 54, 1994 (2013).
1385

12.
T. Beresneva, J. Popelis, and E. Abele, Khim. Geterotsikl. Soedin., 370 (2013). [Chem. Heterocycl.
Compd., 49, 345 (2013).]
13.
14.
15.
16.
17.
18.
L. Zhu, P. Guo, G. Li, J. Lan, R. Xie, and J. You, J. Org. Chem., 72, 8535 (2007).
Z.-L. Xu, H.-X. Li, Z.-G. Ren, W-Y. Du, W-C. Xu, and J.-P. Lang, Tetrahedron, 67, 5282 (2011).
F. Xue, C. Cai, H. Sun, Q. Shen, and J. Rui, Tetrahedron Lett., 49, 4386 (2008).
P. Franchetti, M. Grifantini, S. Martinelli, and M. L. Stein, J. Med. Chem., 17, 18 (1974).
T. Mino, Y. Harada, H. Shindo, M. Sakamoto, and T. Fujita, Synlett, 614 (2008).
F. Diness and D. P. Fairlie, Angew. Chem., Int. Ed., 51, 8012 (2012).
1386