Highly regioselective C-N bond formation through C-H azolation of indoles promoted by iodine in aqueous media

Article abstract of DOI:10.1021/ol302609m

An efficient and metal-free method for the direct C-N coupling of indoles with azoles to produce 2-(azol-1-yl)indoles in aqueous solution has been developed. This reaction proceeded highly regioselectively to provide a variety of indole derivatives with good to excellent yields.

Full text of DOI:10.1021/ol302609m

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Highly Regioselective CꢀN Bond
Formation through CꢀH Azolation
of Indoles Promoted by Iodine
in Aqueous Media
Wen-Bin Wu and Jing-Mei Huang*
School of Chemistry and Chemical Engineering, South China University of Technology,
Guangzhou, Guangdong, 510640, China
chehjm@scut.edu.cn
Received September 22, 2012
ABSTRACT
An efficient and metal-free method for the direct CꢀN coupling of indoles with azoles to produce 2-(azol-1-yl)indoles in aqueous solution has been
developed. This reaction proceeded highly regioselectively to provide a variety of indole derivatives with good to excellent yields.
The substituted indole core, which is present in numerous
biologically active products,1 has attracted the extensive
attention of synthetic chemists to explore methods for
indole CꢀC and CꢀN functionalization.2 Compared with
a large number of reports on CꢀC functionalization, the
general method of CꢀN derivatization of indoles is still
limited, especially for the direct CꢀN bond formation at
the C2 position. It is rare due to the poor control of both the
chemo- and regioselectivities. Recently, Li and co-workers
reported a copper-catalyzed regioselective amidation of
1-methylindole at the C2 position with acetanilide.3 Liu
and co-workers reported a Pd/Cu-catalyzed C2 regioselec-
tive amination of N-protected indole derivatives with
chlorosulfonamides.4 Liang and co-workers described
the reactions of N-protected indoles with morpholine and
N-tosylbenzenamines in the presence of iodine.5,6
2-(Azol-1-yl)indoles, which represent another group of
N-linked indoles at the C2 position, were found in some
biologically active compounds, such as 11H-1,5,11,11b-
tetraaza-benzo[a]trindene-4,6-dione (I),7 indolo[3,2-e]-
[1,2,3]triazolo[1,5-a]pyrimidine (II),8 and the celogentin
and moroidin family of compounds9 (Figure 1). Some
groups had reported the synthesis of the 2-(azol-1-yl)indoles
(5) Li, Y.-X.; Ji, K.-G.; Wang, H.-X.; Ali, S.; Liang, Y.-M. J. Org.
Chem. 2011, 76, 744.
(6) Li, Y.-X.; Wang, H.-X.; Ali, S.; Xia, X.-F.; Liang, Y.-M. Chem.
Commun. 2012, 48, 2343.
(1) (a) Sundberg, R. J. Indoles; Academic Press: San Diego, 1996. (b)
Sundberg, R. J. In Comprehensive Heterocyclic Chemistry II; Katritzky,
A. R., Rees, C. W., Scriven, E. F. V., Eds.; Pergamon: Oxford, 1996; Vol. 2,
p 119. (c) Gribble, G. W. In Comprehensive Heterocyclic Chemistry II;
Katritzky, A. R., Rees, C. W., Scriven, E. F. V., Eds.; Pergamon: Oxford,
1996; Vol. 2, p 207. (d) Joule, J. A. In Science of Synthesis ꢀ Houben-
Weyl Methods of Molecular Transformations; Thomas, E. J., Ed.; Thieme:
Stuttgart, 2000; Vol. 10, p 361. (e) Gribble, G. W. J. Chem. Soc., Perkin
Trans. 1 2000, 1045.
(2) (a) Cacchi, S.; Fabrizi, G. Chem. Rev. 2005, 105, 2873. (b) Seregin,
I. V.; Gevorgyan, V. Chem. Soc. Rev. 2007, 36, 1173. (c) Bandini, M.;
Eichholzer, A. Angew. Chem., Int. Ed. 2009, 48, 9608.
(3) Shuai, Q.; Deng, G.; Chua, Z.; Bohle, D. S.; Li, C.-J. Adv. Synth.
Catal. 2010, 352, 632.
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2010, 51, 5640. (b) Deslandes, S.; Lamoral-Theys, D.; Frongia, C.;
ꢀ
Chassaing, S.; Bruyere, C.; Lozach, O.; Meijer, L.; Ducommun, B.;
Kiss, R.; Delfourne, E. Eur. J. Med. Chem. 2012, 54, 626.
(8) (a) Lauria, A.; Patella, C.; Diana, P.; Barraja, P.; Montalbano, A.;
Cirrincione, G.; Dattolo, G.; Almerico, A. M. Heterocycles 2003, 60,
2669. (b) Lauria, A.; Patella, C.; Diana, P.; Barraja, P.; Montalbano, A.;
Cirrincione, G.; Dattolo, G.; Almerico, A. M. Tetrahedron Lett. 2006,
47, 2187. (c) Lauria, A.; Patella, C.; Dattolo, G.; Almerico, A. M.
J. Med. Chem. 2008, 51, 2037.
(9) For examples, see: (a) Morita, H.; Shimbo, K.; Shigemori, H.;
Kobayashi, J. Bioorg. Med. Chem. Lett. 2000, 10, 469. (b) Kobayashi, J.;
Suzuki, H.; Shimbo, K.; Takeya, K.; Morita, H. J. Org. Chem. 2001, 66,
6626. (c) Suzuki, H.; Morita, H.; Iwasaki, S.; Kobayashi, J. Tetrahedron
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Tetrahedron 2004, 60, 2489.
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r
10.1021/ol302609m
XXXX American Chemical Society

Table 1. Optimization of the I2-Promoted CꢀN Bond Formation
of 1-Methylindole with Pyrazolea
entry
solvent
H2O/dioxane (1:1)
yield (3a/5/6/1a, %)b
1c
2
3
4
5
6
30/32/0/0
96/2/1/0
sat. aq NH4OOCH/dioxane (1:1)
sat. aq NaOOCH/dioxane (1:1)
sat. aq NH4Cl/dioxane (1:1)
sat. aq NH4OAc/dioxane (1:1)
NaOAcꢀHOAc buffer (pH 5.5)d/
dioxane (1:1)
90/2/5/0
Figure 1. Structure of compounds I, II, celogentin C (X = Pro,
Y = bond) and moroidin (X = bond, Y = Gly).
45/50/0/0
15/0/65/15
47/0/50/0
from indole derivatives with an electron-withdrawing group
at the C3 position.10 And recently, Poirier and Beaulieu
reported a general method of a thermal or microwave-
mediated reaction of haloindoles with azoles to afford novel
2-(azol-1-yl)indoles.11 Since some of the haloindoles are not
readily accessible and some are not stable, exploring new
methods of direct CꢀH amination of nonactivated indoles
with azoles is highly desirable, even though an intramo-
lecular oxidative coupling method has been applied in the
total synthesis to build up the 2-(imidazole-1-yl)indole
core.12
7
sat. aq NH4OOCH/CH3CN (1:1)
sat. aq NH4OOCH/THF (1:1)
sat. aq NH4OOCH/DMF (1:1)
sat. aq NH4OOCH/DMSO (1:1)
sat. aq NH4OOCH/CH3OH (1:1)
sat. aq NH4OOCH/sulfolane (1:1)
sat. aq NH4OOCH/dioxane (1:1)
95/2/2/0
8
72/2/1/24
74/2/2/20
76/2/10/10
62/2/10/25
52/0/23/23
80/1/1/16
9
10
11
12
13e
a Reaction conditions: 1a (0.5 mmol), 2a (1.25 mmol), I2 (1.0 mmol),
solvent (sat. aq NH4OOCH/dioxane (1:1), 0.6 mL), rt, 24 h. b Yield
based on 1H NMR using CH3NO2 as an internal standard. c With some
other unidentified compounds. d Prepared from saturated aqueous
NaOAc solution (250 μL) and HOAc (50 μL). e I2 (0.75 mmol, 1.5 equiv).
In recent years, organic reactions in aqueous media have
attracted a great deal of attention, because of environ-
mental concerns and the unique reactivity and selectivity
observed in aqueous reactions.13 In connection with our
interests inaqueousmedium reactions,14 herein wereport a
metal-free selective CꢀN bond formation of inactive
indoles with azoles in aqueous media.
presence of 2.0 equiv of iodine (I2) in H2O/dioxane (1:1) at
room temperature. After 24 h, the desired product 3a was
obtained in 30% yield, and a 32% yield of 1-methyl-1,3-
dihydro-indol-2-one (5) was observed (Table 1, entry 1).
Optimization studies were then performed to improve the
yield of the desired product. When water was replaced with
a saturated NH4OOCH solution, the yield was signifi-
cantly increased to 96% (Table 1, entry 2), and a saturated
NaOOCH solution gave a slightly lower yield of 90%
(Table 1, entry 3). However, a saturated NH4Cl and a
saturated NH4OAc solution led to drastic reductions in
yields (Table 1, entries 4 and 5). Studies on the influence of
different organic cosolvents showed that CH3CN gave an
almost identical yield with dioxane (Table 1, entry 7), but
other solvents such as THF, DMF, DMSO, CH3OH, and
sulfolane were inferior to dioxane (Table 1, entries 8ꢀ12).
Furthermore, an attempt to reduce the iodine loading
showed that lowering the amount of I2 to 1.5 equiv
decreased the yield sharply (Table 1, entry 13). Hence,
our optimized reaction conditions are illustrated in entry 2,
Table 1.
Initial studies were performed with the reaction of
1-methylindole (1a) with 2.5 equiv of pyrazole (2a) in the
(10) For examples, see: (a) Somei, M.; Tanimoto, A.; Orita, H.;
Yamada, F.; Ohta, T. Heterocycles 2001, 54, 425. (b) Yamada, K.;
Yamada, F.; Shiraishi, T.; Tomioka, S.; Somei, M. Heterocycles 2009,
77, 971. (c) Benkli, K.; Demirayak, S.; Gundogdu-Karaburun, N.;
Kiraz, N.; Iscan, G.; Ucucu, U. Indian J. Chem. 2004, 43B, 174. (d)
Comber, M. F.; Moody, C. J. Synthesis 1992, 731. (e) Harrison, J. R.;
Moody, C. J. Tetrahedron Lett. 2003, 44, 5189.
(11) Poirier, M.; Goudreau, S.; Poulin, J.; Savoie, J.; Beaulieu, P. L.
Org. Lett. 2010, 12, 2334.
(12) (a) He, L.; Yang, L.; Castle, S. L. Org. Lett. 2006, 8, 1165. (b)
Ma, B.; Litvinov, D. N.; He, L.; Banerjee, B.; Castle, S. L. Angew. Chem.,
Int. Ed. 2009, 48, 6104. (c) Ma, B.; Banerjee, B.; Litvinov, D. N.; He, L.;
Castle, S. L. J. Am. Chem. Soc. 2010, 132, 1159. (d) Feng, Y.; Chen, G.
Angew. Chem., Int. Ed. 2010, 49, 958. (e) Hu, W.; Zhang, F.; Xu, Z.; Liu,
Q.; Cui, Y.; Jia, Y. Org. Lett. 2010, 12, 956.
(13) For reviews, see: (a) Li, C.-J. Chem. Rev. 2005, 105, 3095. (b)
Loh, T. P. In Science of Synthesis; Yamamoto, H., Ed.; Georg Thieme
€
Verlag: New York, 2004; p 413. (c) Lindstrom, U. M. Chem. Rev. 2002,
102, 2751. (d) Li, C.-J. Acc. Chem. Res. 2002, 35, 533. (e) Li, C.-J. Chem.
Rev. 1993, 93, 2023.
Next, a wide variety of indole derivatives were examined
to react with pyrazole under the optimized conditions, and
the results are summarized in Scheme 1. It showed that free
indoles afforded comparable yields with 1-methylindoles.
The new method revealed a tolerance toward functional
groups for both 1-methylindole derivatives and indole
(14) (a) Huang, J.; Zhou, L.; Jiang, H. Angew. Chem., Int. Ed. 2006,
45, 1945. (b) Huang, J.-M.; Dong, Y. Chem. Commun. 2009, 3943. (c)
Huang, J.-M.; Ren, H.-R. Chem. Commun. 2010, 46, 2286. (d) Huang,
J.-M.; Dong, Y.; Wang, X.-X.; Luo, H.-C. Chem. Commun. 2010, 46, 1035.
(e) Huang, J.-M.; Wang, X.-X.; Dong, Y. Angew. Chem., Int. Ed. 2011, 50,
924. (f) Huang, J.-M.; Lin, Z.-Q.; Chen, D.-S. Org. Lett. 2012, 14, 22.
B
Org. Lett., Vol. XX, No. XX, XXXX

Table 2. Reaction of Azoles with 1-Methylindole and Indolea
Scheme 1. Reaction of 1-Methylindoles and Indoles with
Pyrazolea
I2
time
(h)
yield
(%)b
entry
azole
R1
(equiv)
4
1
2
3
4
5
6
7
1,2,3-triazole
1,2,4-triazole
imidazole
Me
Me
Me
3
3
2
4
3
3
4
30
30
48
48
30
30
48
4a
4b
4c
4d
4e
4f
81c
81
64
61
93e
80
90
2-methylimidazoled Me
1,2,3-triazole
1,2,4-triazole
imidazolef
H
H
H
4g
a Standard conditions: 1a or 1b (0.5 mmol), 2 (1.25 mmol), sat. aq
NH4OOCH/dioxane (1:1, 0.6 mL), rt. b Isolated yield. c Only the 1-triazolyl
isomer observed. d 2-Methylimidazole (4.0 mmol). e Only the 1-triazolyl
isomer observed. f Imidazole (4.0 mmol), HOAc (0.5 mmol).
for 7-azaindole, and the desired product was obtained in
92% yield (3o). Thestructureof 3bwas confirmed by X-ray
diffraction analysis.15
Encouraged by the above results, we applied this reaction
system to other azoles to synthesize various 2-(azol-1-yl)-
indole derivatives (4aꢀg) in aqueous solution (Table 2).
The reactions of 1-methylindole and indole with different
azoles proceeded smoothly with good to excellent yields.
It was found that, for the 1,2,3-triazole, only the 2-(1-
triazolyl)indole isomer 4a was observed in 81% yield
(Table 2, entry 1) when it was treated with 1-methylindole.
And only 2-(1-triazolyl)indole isomer 4e was collected in
93% yield in the case of free indole (Table 2, entry 5). The
structure of 4a, 4b, and 4e (Figure 2) had been determined
by X-ray diffraction analysis.15
a Unless otherwise specified, all reactions were carried out using 1
(0.5 mmol), 2a (1.25 mmol), and I2 (1.0 mmol) in sat. aq NH4OOCH/
dioxane (1:1, 0.6 mL), rt, 24 h. Isolatedyield. b I2 (1.5 mmol), 30 h. c n.r. =
no reaction.
To investigate further the effect of the salts in the solvent
mixtures, the pH values of some of the reaction mixtures
(Table 1, entries 1ꢀ6) were carefully monitored during the
process of the reaction. The results obtained were shown in
Figure 3. Itwas found that, under the optimized conditions
(Table 1, entry 2), the pH value dropped rapidly from
7.0 to 4.7 within 30 min after the I2 was added, and a slow
decline from 4.7 to 3.8 was observed during the remaining
reaction time. A control study showed that the pH varia-
tion of the solvent was mainly caused by I2. Similar
processes were seen when the solute was changed to pure
water, NaOOCH, NH4Cl, and NH4OAc, while the pH
values weredifferent (Table 1, entries 1 and 3ꢀ5). When the
reactions proceeded in a saturated NH4Cl solution or pure
water, both pH values were maintained near 1.0 during
the reaction, and an oxidation product 5 was observed
(Table 1, entries 1 and 4). When the reaction proceeded in
saturated NaOOCH and NH4OAc solutions, after 30 min,
the pH values slowly changed from 4.3 to 3.5, and 6.1to 5.2,
respectively, and an iodination product 6 was detected
in both conditions (Table 1, entries 3 and 5). These results
Figure 2. ORTEP drawing of compound 4e.
derivatives (3aꢀl), and in most cases, excellent yields were
obtained. It is noteworthy that the functional group of
carboxylic acid can be utilized in this method (3k and 3l),
whereas 5-nitro-indoles (3m and 3n) and 1-acetylindole
(3p) were not active in this procedure. The 1,3-dimethyl-
indole and 3-methylindole, which are more sterically
hindered with a methyl group at the C3 position, led to
excellent yields too (3c and 3d). This method also worked
(15) Crystallographic data for the structures of 3b, 4a, 4d, and 4e have
been deposited with the Cambridge Crystallographic Data Centre as
supplementary publication numbers CCDC 891118 (3b), CCDC 900318
(4a), CCDC 891119 (4b), and CCDC 900319 (4e). Data can be obtained,
free of charge, on application to CCDC, 12 Union Road, Cambridge
CB2 1EZ, U.K. [fax: þ44 (0) 1223-336033; e-mail: deposit@ccdc.cam.
ac.uk].
Org. Lett., Vol. XX, No. XX, XXXX
C

Scheme 2. Proposed Mechanism
Iodination on C3 produces reactive iminium intermediate
7. Then the intermediate 7 was trapped by azoles, and the
subsequent elimination generated the product 3.11,12a
In conclusion, an efficient and metal-free method for a
direct CꢀN bond formation from indoles and azoles to
produce 2-(azol-1-yl)indoles in aqueous solution was de-
veloped. The reaction worked on free and alkyl-protected
indoles, and a series of novel indole derivatives were
prepared by this method. The reaction is highly selective,
mild, and environmentally friendly. Application of this
method to the synthesis of more complex indole com-
pounds is currently under investigation.
Figure 3. Monitoring the pH values of the reaction mixtures in
different solutions for the first 3 h. For a full display over 24 h,
see the Supporting Information.
suggested that the direct coupling reaction of indoles with
azoles was sensitive to the pH of the reaction mixture. Also,
the NH4OOCH solution might work as a buffer system,
which provided an appropriate pH environment for this
reaction. A lower or higher pH value accounted for the
lower yields. Although buffer NaOAcꢀHOAc (pH 5.5)
gave a similar pH curve with the NH4OOCH solution
during the reaction time from 10 min to 24 h, only a 47%
yield of desired product was observed (Table 1, entry 6).
This result showed that the two ions, NH4þ and HCOOꢀ,
were also important for this reaction.
Acknowledgment. We are grateful to the National Nat-
ural Science Foundation of China (Grant 21172080) and
the Fundamental Research Funds for the Central Univer-
sities (Grant 2011ZZ0005) for financial support.
Supporting Information Available. Experimental pro-
cedures, characterization data, NMR spectra for all
compounds, and crystallographic data for 3b, 4a, 4b,
and 4e in CIF format. This material is available free of
charge via the Internet at http://pubs.acs.org.
A mechanism for the reaction was proposed (Scheme 2).
The reaction was promoted by the Hþ which was pro-
duced from a slow reaction between iodine and water.16
(16) For example, see: Lengyel, I.; Epstein, I. R.; Kustin, K. Inorg.
Chem. 1993, 32, 5880 and references cited therein.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX