N-Arylation of azaindoles in LiCl-mediated catalytic CuI reactions

Article abstract of DOI:10.1016/j.tetlet.2007.05.062

N-Arylation of 5- and 7-azaindoles was achieved in LiCl-mediated catalytic CuI reactions at 120 °C with moderate to high yields. N-Arylation can be performed with various arylhalides, such as phenyl, pyridine, quinoline, thiophen, and thiazole moieties.

Full text of DOI:10.1016/j.tetlet.2007.05.062

Tetrahedron Letters 48 (2007) 4831–4833
N-Arylation of azaindoles in LiCl-mediated catalytic CuI reactions
Chang Sung Hong, Jae Young Seo and Eul Kgun Yum*
Department of Chemistry, Chungnam National University, Yusung Daejon 305-764, South Korea
Received 24 March 2007; revised 10 May 2007; accepted 11 May 2007
Available online 17 May 2007
Abstract—N-Arylation of 5- and 7-azaindoles was achieved in LiCl-mediated catalytic CuI reactions at 120 °C with moderate to
high yields. N-Arylation can be performed with various arylhalides, such as phenyl, pyridine, quinoline, thiophen, and thiazole
moieties.
Ó 2007 Published by Elsevier Ltd.
Azaindoles have attracted considerable attention as
analogs of the indole nucleus with interesting biological,
pharmaceutical, and material properties.1 Since azain-
doles are present in only a few natural products,2 most
azaindole derivatives for study are prepared syntheti-
cally.1 Recently, organometallic complexes of azaindoles
have been reported as potential luminescent materials in
organic light-emitting devices (OLEDs).3 One major
modification was the replacement of the proton in the
azaindole nitrogen atom by an aromatic group to
improve the stability and performance of organometallic
complexes in OLEDs. Although N-arylated azaindoles
are very useful intermediates in material and pharma-
ceutical sciences, the preparation of arylated azaindoles
requires high temperatures and stoichiometric amounts
of copper reagents in the classical Ullmann reaction.4
Recently, copper-catalyzed N-arylation has been
applied to many heterocycles with various organic
ligands.5 Only a few examples of N-arylated azaindoles
using catalytic CuI and trans-1,2-cyclohexanediamine
ligand have been reported.6 However, when we applied
the reported N-arylation reaction conditions to vari-
ous arylhalides to obtain N-arylated azaindoles, the
reactions provided variable yields with aryl halide
substrates. Therefore, we explored the N-arylation of
5- and 7-azaindoles using copper-catalyzed reactions.
shown to be quite sensitive to the copper source, bases,
ligands, and other additives.5a Initially, 7-azaindoles
with iodobenzene were chosen as a model study with
various additives, copper sources, bases, and solvents.
The results are summarized in Table 1.
The reaction with added LiCl gave higher yields of the
desired product compared to the reactions using
n-BuN4Cl, KCl, CsCl, or no chloride source (entries
1–5). In addition, the reactions using less than
10 mol % CuI needed longer time for completion. From
the above results, different cationic species of chloride
influenced catalytic activity in this reaction. We also
examined the effect of several copper species that are
frequently used for Cu coupling reactions (entries 1, 6,
and 7). The N-arylation of 7-azaindole using CuI gave
higher yields of the desired product than the reactions
using other copper sources. The reactions using
K2CO3 or Cs2CO3 as the base gave the desired product
in good yields (entries 1 and 8), while the reactions using
Na2CO3, K3PO4, or Li2CO3 as the base had poor yields
of the desired product (entries 10–12). We also investi-
gated the effect of different solvents at the same reaction
temperature (entries 1 and 13–15). Only the reaction
using DMF gave good yields of the desired product.
The results showed that the optimum conditions for
the N-arylation of azaindoles consisted of 1 equiv of
LiCl, 3 equiv of K2CO3, 10 mol % CuI, and DMF at
120 °C.10 N-Arylation was examined using various aryl
iodides or bromides under the optimum reaction condi-
tions to diversify the N-arylated azaindoles. The results
are summarized in Table 2.
Continuing our research into the diversification of
indoles,7 azaindoles,8 and quinolines,9 we applied our
palladium-catalyzed reaction conditions7–9 to the
copper-catalyzed reaction. In recently reported catalytic
copper reactions, the N-arylation of heterocycles was
The reactions using halo-substituted iodobenzene gave
good to excellent yields of N-aryl-7-azainoles (entries
1–4). Another reaction using o-ethyl ester instead of
*
Corresponding author. Tel.: +82 42 821 5474; fax: +82 42 821
8896; e-mail: ekyum@cnu.ac.kr
0040-4039/$ - see front matter Ó 2007 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2007.05.062

4832
C. S. Hong et al. / Tetrahedron Letters 48 (2007) 4831–4833
Table 1. Optimization of Cu-catalyzed N-arylation of 7-azaindole
10 mol % Cu cat.
1 eq Additive, 3 eq Base
I
+
Solvent, 120 oC
N
Ph
N
H
N
N
Entrya
Additive
Cu source
Base
Solvent
Reaction time (h)
Isolated yield (%)
1b
2
3
4
5
6
7
8
LiCl
None
n-Bu4NCl
KCl
CuI
CuI
CuI
CuI
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Cs2CO3
KOAc
Na2CO3
K3PO4
Li2CO3
K2CO3
K2CO3
K2CO3
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMAc
NMP
24
48
48
48
48
36
36
36
48
48
48
48
36
36
36
70
10<
55
60
57
60
25
60
45
CsCl
LiCl
LiCl
LiCl
LiCl
LiCl
LiCl
LiCl
LiCl
LiCl
LiCl
CuI
Cu(OAc)2
CuSO4
CuI
CuI
CuI
CuI
CuI
CuI
CuI
9
10
11
12
13
14
15c
30
5<
10<
30
30
—
CuI
1,4-Dioxane
a All of the reactions were run on a 1.0-mmol scale with 10 mL of dimethyl formamide (DMF).
b The reactions using less than 10% CuI needed longer times for completion.
c The reaction did not proceed at refluxing temperature.
Table 2 (continued)
iodobenzene also gave excellent yields of the desired
product (entry 5). In addition, the reactions using a het-
eroaryl bromide, such as pyridine, quinoline, thiophen,
Entrya
Azaindole
Aryl halide
Reaction
Isolated
time (h)
yield (%)
N
I
I
Cl
10
12
24
85
65
N
H
Table 2. Diverse N-arylation to 5- and 7-azaindoles
10 mol % CuI
24
OCH3
1 eq LiCl , 3 eq K2CO3
N
+
Arylhalide
N
N
H
CO2Et
DMF, 120 oC
Aryl halide
N
I
13
14
15
24
36
36
88
75
80
Ar
Entrya
Azaindole
Reaction
time (h)
Isolated
yield (%)
Br
Br
N
1
2
3
24
24
24
60
85
75
I
I
I
Br
Cl
F
N
N
H
N
a All reactions were run on a 1.0-mmol scale in 10 ml DMF.
or thiazole, gave N-heteroarylated 7-azaindoles in good
to reasonable yields (entries 6–9). The results showed
that reactions using nitrogen-containing heterocycles
had the same reactivity with the benzene ring, while
the reactions using sulfur-containing heterocycles gave
low yields of the desired product after a long reaction
time. Finally, the reaction conditions were applied to
the diversification of 5-azaindole with halo-substituted
iodobenzene and heterocyclic bromides (entries 10–15).
The results showed that N-arylation of 5-azaindole with
high yields was also possible under our optimized reac-
tion conditions.
F
F
4
5
24
36
78
92
I
I
CO2Et
Br
Br
6
7
36
48
85
50
N
N
In conclusion, simple, efficient N-arylation to 5- and 7-
azaindole was achieved in a LiCl-mediated catalytic
CuI reaction without any organic ligand. Various N-
arylated azaindoles were synthesized at low reaction
temperatures with high yields. We will further explore
S
Br
Br
8
9
48
48
40
40
S
N

C. S. Hong et al. / Tetrahedron Letters 48 (2007) 4831–4833
4833
Chem. Soc. 2006, 128, 15990; (g) Kuil, M. K.; Bekedam, E.
K.; Visser, G. M.; Hoogenband, A.; Rerpstra, J. W.;
Kamer, P. C. J.; Leeuwen, P. W. N. M.; Strijdonck, G. P.
F. Tetrahedron Lett. 2005, 46, 2405; (h) Chang, J. W. W.;
Xu, X.; Chan, P. W. H. Tetrahedron Lett. 2007, 48, 245; (i)
Job, G. E.; Buchwald, S. L. Org. Lett. 2002, 4, 3703; (j)
Jiang, D.; Fu, H.; Jiang, Y.; Zhao, Y. J. Org. Chem. 2007,
72, 672.
the possible synthetic applications to biologically active
azaheterocycles.
Acknowledgment
The authors thank Chungnam National University for
financial support.
6. (a) Enguehard, C.; Allouchi, H.; Gueiffer, A.; Buchwald,
S. L. J. Org. Chem. 2003, 68, 5614; (b) Klapars, A.;
Antilla, J. C.; Huang, X.; Buchwald, S. L. J. Am. Chem.
Soc. 2001, 123, 7727.
References and notes
7. (a) Larock, R. C.; Yum, E. K. J. Am. Chem. Soc. 1991,
113, 6689; (b) Larock, R. C.; Yum, E. K.; Refvik, M. D.
J. Org. Chem. 1998, 63, 7652; (c) Hong, K. B.; Lee, C. W.;
Yum, E. K. Tetrahedron Lett. 2004, 45, 693.
1. (a) Popowycz, F.; Routier, S.; Joseph, B.; Merour, J.-Y.
Tetrahedron 2007, 63, 1031; (b) Merour, J.-Y. Curr. Org.
Chem. 2001, 5, 471.
8. (a) Park, S. S.; Choi, J.-K.; Yum, E. K.; Ha, D.-C.
Tetrahedron Lett. 1998, 39, 627; (b) Chi, S. M.; Choi,
J.-K.; Yum, E. K.; Chi, D. Y. Tetrahedron Lett. 2000, 41,
919; (c) Lee, M. S.; Yum, E. K. Bull. Korean Chem. Soc.
2002, 23, 535; (d) Kang, S. S.; Yum, E. K.; Sung, N. D.
Heterocycles 2003, 60, 2727; (e) Hong, C. S.; Seo, J. Y.;
Yum, E. K.; Sung, N.-D. Heterocycles 2004, 63, 631.
9. (a) Kang, S. K.; Park, S. S.; Kim, S. S.; Choi, J.-K.; Yum,
E. K. Tetrahedron Lett. 1999, 40, 4379; (b) Yum, E. K.;
Kang, S. K.; Kim, S. S.; Choi, J.-K.; Cheon, H. G. Bioorg.
Med. Chem. Lett. 1999, 9, 1819; (c) Lee, W. J.; Gee, M. B.;
Yum, E. K. Hueterocycles 2003, 60, 1821.
2. (a) Perry, N. B.; Ettouati, L.; Litaudon, M.; Blunt, J. W.;
Munro, M. H. G.; Parkin, S.; Hope, H. Tetrahedron 1994,
50, 3967; (b) Trimurtulu, G.; Faulkner, D. J.; Perry, N. B.;
Ettouati, L.; Litaudon, M.; Blunt, J. W.; Munro, M. H.
G.; Jameson, G. B. Tetrahedron 1994, 50, 3993; (c)
Katritzky, A. R.; Rees, C. W.; Scriven, E. F. V. Compre-
hen. Heterocycl. Chem. II 1996, 7, 168.
3. (a) Wu, Q.; Lavigne, J. A.; Tao, Y.; D’Iorio, M.; Wang, S.
Chem. Mater. 2001, 13, 71; (b) Wu, Q.; Hook, A.; Wang,
S. Angew. Chem., Int. Ed. 2000, 39, 3933; (c) Jia, W.-L.;
Bai, D.-R.; McCormick, T.; Liu, Q.-D.; Motala, M.;
Seward, C.; Tao, Y.; Wang, S. Chem. Eur. J. 2004, 10, 994;
(d) Kang, Y.; Song, D.; Schmilder, H.; Wang, S. Organo-
metallics 2002, 21, 2413; (e) Tani, K.; Sakurai, H.; Fuji,
H.; Hirao, T. J. Organomet. Chem. 2004, 689, 1665; (f)
Ma, Y.; Chao, H.-Y.; Lee, S. T.; Yu, W.-Y.; Che, C.-M.
Chem. Commun. 1998, 2491.
4. (a) Kang, Y.; Wang, S. Tetrahedron Lett. 2002, 43, 3711;
(b) Ullmann, F. Ber. Disch. Chem. Ges. 1903, 36, 2382; (c)
Bacon, R. C. R.; Hill, H. A. O. J. Chem. Soc. 1964, 1097;
(d) Fanta, P. E. Synthesis 1974, 9; (e) Sainsbury, M.
Tetrahedron 1980, 36, 3327; (f) Lindley, J. Tetrahedron
1984, 40, 1433.
5. (a) Ley, S. V.; Thomas, A. W. Angew. Chem., Int. Ed.
2003, 42, 5400, and references cited therein; (b) Cristau,
H.-J.; Cellier, P. P.; Spindler, J.-F.; Taillefer, M. Chem.
Eur. J. 2004, 10, 5607; (c) Kantam, M. L.; Venkanna, G.
T.; Sridhar, C.; Sreedhar, B.; Choudary, B. M. J. Org.
Chem. 2006, 71, 9522; (d) Kantam, M. L.; Venkanna, G.
T.; Sridhar, C.; Kumar, K. B. S. Tetrahedron Lett. 2006,
47, 3897; (e) Liu, Y.-H.; Chen, C.; Yang, L.-M. Tetra-
hedron Lett. 2006, 47, 9275; (f) Ouali, A.; Laurent, R.;
Caminade, A.-M.; Majoral, J.-P.; Tailefer, M. J. Am.
10. Typical reaction procedures. 7-Azaindole (1.0 mmol), LiCl
(1.0 mmol), K2CO3 (3.0 mmol), iodobenzene (1.1 mmol),
CuI (0.1 mmol), and DMF (10 mL) were added to a screw-
capped pressure tube. The reaction mixture was stirred for
24 h at 120 °C, and then diluted with saturated aqueous
ammonium chloride. The product was isolated with ethyl
acetate, the organic layer was dried over anhydrous
magnesium sulfate, and the reaction mixture was filtered
and concentrated. The product was purified by silica gel
column chromatography using hexane:ethyl acetate (3:1)
solvent. N-Phenyl-7-azaindole was obtained in 70% yield
1
as a brown oil. H NMR (CDCl3, 400 MHz) d 8.36 (dd,
1H, J = 3.2, 1.6 Hz, ArH), 7.54 (dd, 1H, J = 6.4, 1.2 Hz,
ArH), 7.72 (m, 2H, ArH), 7.64 (m, 3H, ArH), 7.30 (m, 1H,
ArH), 7.10 (dd, 1H, J = 5.0, 2.8 Hz, ArH), 6.59 (d, 1H,
J = 4.0 Hz, ArH); 13C NMR (CDCl3, 100 MHz) d 147.3,
134.4, 138.3, 129.2, 128.9, 127.7, 126.1, 123.8, 121.4, 116.5,
101.5; MS (m/z) 194 (M+, 100), 193 (MÀ1, 82), 167 (14),
139 (10), 97 (25), 77 (18). Anal. Calcd for C13H10N2: C,
80.38; H, 5.19, N, 214.42. Found: C, 80.40; H, 5.17, N,
7.65.