The direct C-H halogenations of indoles

Article abstract of DOI:10.1016/j.tetlet.2014.02.071

A novel and efficient transition metal-free C-H bond halogenation of indole derivatives has been developed. 3-Halogenated (3-Br, 3-I) indoles are highly regioselectively produced by this protocol. Simple and readily available halide salts (TBAB, KI) are employed as the halogen source. The transition metal-free and the mild conditions make this protocol very easy to handle and practical.

Full text of DOI:10.1016/j.tetlet.2014.02.071

Tetrahedron Letters 55 (2014) 2243–2245
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Tetrahedron Letters
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The direct C–H halogenations of indoles
b,
Leilei Shi a,b, Dongmei Zhang c, Riyuan Lin b, Chun Zhang b, Xun Li a, , Ning Jiao
⇑
⇑
a Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, Ji’nan 250012, China
b State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Xue Yuan Rd. 38, Beijing 100191, China
c Shandong Institute for Food and Drug Control, Ji’nan 250101, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel and efficient transition metal-free C–H bond halogenation of indole derivatives has been devel-
oped. 3-Halogenated (3-Br, 3-I) indoles are highly regioselectively produced by this protocol. Simple and
readily available halide salts (TBAB, KI) are employed as the halogen source. The transition metal-free and
the mild conditions make this protocol very easy to handle and practical.
Received 20 December 2013
Revised 11 February 2014
Accepted 20 February 2014
Available online 28 February 2014
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
C–H funtionalization
Transition-metal free
Halogenation
Indoles
Organic halides are important building blocks for pharmaceuti-
cals and fine chemicals.1 The sp2 C–X units are also significant
structure fragments in many pharmaceuticals and natural prod-
ucts.2 In order to prepare aryl halides, electrophilic halogenation
of aromatic compounds through Friedel–Crafts reaction with elec-
trophilic reagents such as NIS, NBS, NCS, Br2 and I2, as the halogen
source has been realized several decades ago (a, Scheme 1).3
Though this transformation exhibited good reactivity, it suffered
some drawbacks in the functional group tolerance and regioselec-
tivity. In recent decades, C–H functionalization has attracted con-
siderable attentions.4 More recently, transition-metal mediated
oxidative C–H halogenation has been developed employing readily
available halide salts as the halogen source (b, Scheme 1).5 Despite
the significance of these protocols with high atom economy and
high efficiency, the relatively high price and considerable toxicity
of transition metals may limit their further applications and
improvements. Therefore, the development of a transition metal-
free approach via C–H halogenation would be more meaningful
and attractive.6
X
H
[M] or without [M]
a)
R
R
X+ = NIS, NBS, NCS, Br2, I2.....
X
H
[M]
R
R
R
b)
c)
X-/[O]
X-
= CuCl2, CuBr2, KI, NH4I.....
H
X
[M]
R
N
R'
X-
X-/[O] or without [O]
N
R'
= CuBr2, CuCl2, CuBr, NCS.....
transition-metal free
this work
H
X
d)
R
R
Selectflour
N
R'
N
R'
TBAB, KI
(
)
Due to the ubiquitous existence of indole skeleton in pharma-
ceuticals and bioactive natural products, indole skeleton based
modification has attracted enormous interest of medicinal chem-
ists.7,8 3-Halogenation of indoles has also been reported by using
transition-metal salts catalysis.9 Our group has been interested in
designing and modifying indole derivatives (c, Scheme 1).10 Herein,
we describe an efficient transition-metal free approach for the
Scheme 1. Direct halogenation reactions.
synthesis of 3-halogenated (3-Br, 3-I) indoles using simple and
readily available TBAB and KI as the halogen source, respectively,
(d, Scheme 1). To the best of our knowledge, the direct halogena-
tion of indoles under transition metal-free conditions with halide
⇑
Corresponding authors. Tel./fax: +86 010 8280 5297.
E-mail addresses: tjulx2004@sdu.edu.cn (X. Li), jiaoning@bjmu.edu.cn (N. Jiao).
http://dx.doi.org/10.1016/j.tetlet.2014.02.071
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.

2244
L. Shi et al. / Tetrahedron Letters 55 (2014) 2243–2245
Table 2
Table 1
Halogenation of indoles with different halidesa,b
Optimization of reaction conditionsa
H
X
X
H
oxidants (2.0 eq)
R3
R3
NaHCO3 (1.0 eq)
standard conditions
R2
R2
N
R1
X = Br, I
halides (1.1 eq)
solvent, r.t., air
N
R1
1
N
N
Me
Me
1a
2a (X = Br)
3a (X = I)
Br
Br
Br
Yieldb (%)
iPr
Entry
Oxidants
Solvents
Halides
Product
F
N
Me
N
N
1
2
3
4
5
6
7
8
Selectfluor
BQ
Air
Ag2CO3
TBHP
Selectfluor
Selectfluor
Selectfluor
Selectfluor
NFSI
Selectfluor
Selectfluor
Selectfluor
Selectfluor
Selectfluor
Selectfluor
DCE
DCE
DCE
DCE
DCE
DCE
DCE
TBAB
TBAB
TBAB
TBAB
TBAB
NaBr
KBr
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
3a
3a
85
0
0
0
0
71
67
74
96
75
72
Trace
0
Me
Me
90% (2c)
96% (2a)
(2b)
Br
85%
Br
Br
Me
Me
N
N
N
Me
(2d)
Cl
64%
81% (2e)
85% (2f)
DCE
NBS
9
Toluene
Toluene
DCM
DMF
DMSO
THF
TBAB
TBAB
TBAB
TBAB
TBAB
TBAB
KI
Br
Br
Br
Br
10
11
12
13
14
15
16
N
N
N
Me
55% (2g)
Cl
(2h)
75%
94%
75% (2i)
Cl
iPr
77
96
76
I
I
I
Toluene
Toluene
TBAI
F
N
Me
N
Me
(3a)
I
N
Me
(3b)
a
Unless otherwise noted, the reaction was carried out at room temperature using
1a (0.2 mmol), oxidant (0.4 mmol), base (0.2 mmol), halides (0.22 mmol), solvents
(2 mL) for 2 h under air atmosphere.
Isolated yield. NFSI: N-Fluorodibenzenesulfonimide, Selectfluor: 1-Chloro-
methyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane, TBAB: tetrabutylammonium
bromide, TBAI: tetrabutylammonium iodide, NBS: 1-bromopyrrolidine-2,5-dione.
96%
67%
(3c)
96%
I
I
b
Me
N
N
N
Me
(3d)
I
96% (3e)
Cl
(3f)
90%
I
salts has rarely been realized.11 The present approach achieves
high regioselectivity with good substrate compatibility.
I
Br
Me
Me
N
N
N
Initially, the halogenation of 1-methyl-2-phenyl-1H-indole (1a)
with TBAB as a source of bromide ions was chosen as a model reac-
tion. Interestingly, when Selectfluor12 was used as an oxidant, the
reaction in DCE in the presence of NaHCO3 as a base produced the
desired 3-halogenation product 2a in 85% isolated yield at room
temperature (Table 1, entry 1). Then, different oxidants were
screened. However, no product was detected when Selectfluor
was replaced by other oxidants such as BQ, dioxygen, Ag2CO3
and TBHP (Table 1, entries 2–5). These results indicate that Select-
fluor was the most suitable oxidant for this halogenation transfor-
mation. Although the reactions with other bromide salts such as
NaBr and KBr as the halogen source proceeded well, the reaction
with TBAB showed the highest efficiency (Table 1, entries 7 and
8). Furthermore, when toluene was utilized as solvent, the product
2a was obtained in 96% isolated yield (Table 1, entry 9). Similarly,
NFSI was also suitable for our reaction giving the desired bromin-
ation product 2a in moderate yields (Table 1, entry 10). Other sol-
vents were not favourable for this bromination transformation,
especially for those non-proton polar solvents (Table 1, entries
11–14). Moreover, various bases were screened. The results dem-
onstrate that NaHCO3 is most suitable for our reaction (see ESI).
Based on the above screening results, the optimal conditions can
be determined (Table 1, entry 9).
We next investigated whether iodination works under the opti-
mized conditions. Gratifyingly, iodination of 1a proceeded
smoothly under the standard conditions with KI and TBAI as the
iodinating reagents leading to the iodination product 3a in 96%
and 76% yields, respectively (Table 1, entries 15 and 16).
With the optimized conditions in hand, the substrate scope was
studied as shown in Table 2. All substrates examined under opti-
mized conditions afforded the corresponding products in moderate
to excellent yields. The halogenation appears to be invariant to the
electronic properties of the substrates as the reaction with both
electron-efficient and electron-deficient substituents on the
62% (3g)
Cl
(3i)
87%
36% (3j)
Cl
a
Standard reaction conditions: see (Table 1, entry 9) for bromination of indoles
and (Table 1, entry 15) for iodination of indoles.
Isolated yield.
b
H
Br
R3
R3
R2
standard conditions
R2
N
N
R1
R1
1
2
selectfluor
[Br+]
TBAB
-H+
Br
H
Br
R3
R3
H
R2
R2
N
R1
N
R1
B
A
Scheme 2. The proposed mechanism for this transformation.
2-phenyl group proceeded efficiently to give the halogenating
products with moderate to excellent yields (Table 2, 2a–2c,
3a–3c). When the 2-phenyl was replaced by 2-methyl, both
bromination and iodination completed smoothly to give the prod-
uct with good isolated yields (Table 2, 2d, 2g, 3d, 3j, 3g). When
N-methyl was replaced by N-benzyl or 4-substituted benzyl, all
of the substrates performed well to afford the desired products

L. Shi et al. / Tetrahedron Letters 55 (2014) 2243–2245
2245
4. For some reviews on C–H functionalization, see: (a) Song, G.; Wang, F.; Li, X.
Chem. Soc. Rev. 2012, 41, 3651; (b) Wencel-Delord, J.; Dröge, T.; Liu, F.; Glorius,
F. Chem. Soc. Rev. 2011, 40, 4740; (c) Lu, H.; Zhang, X. P. Chem. Soc. Rev. 1899,
2011, 40; (d) Yeung, C. S.; Dong, V. M. Chem. Rev. 2011, 111, 1215; (e) Lyons, T.
W.; Sanford, M. S. Chem. Rev. 2010, 110, 1147; (f) Daugulis, O. Top. Curr. Chem.
2010, 292, 57; (g) Satoh, T.; Miura, M. Chem. Eur. J. 2010, 16, 11212; (h) Colby,
D. A.; Bergman, R. G.; Ellman, J. A. Chem. Rev. 2010, 110, 624; (i) Mkhalid, I. A. I.;
Barnard, J. H.; Marder, T. B.; Murphy, J. M.; Hartwig, J. F. Chem. Rev. 2010, 110,
890; (j) Chen, X.; Engle, K. M.; Wang, D.-H.; Yu, J.-Q. Angew. Chem., Int. Ed. 2009,
48, 5094; (k) Ackermann, L.; Vicente, R.; Kapdi, A. R. Angew. Chem., Int. Ed. 2009,
48, 9792; (l) Sun, C.-L.; Li, B.-J.; Shi, Z.-J. Chem. Rev. 2011, 111, 1293.
5. (a) Dick, A. R.; Hull, K. L.; Sanford, M. S. J. Am. Chem. Soc. 2004, 126, 2300; (b)
Wan, X.; Ma, Z.; Li, B.; Zhang, K.; Cao, S.; Zhang, S.; Shi, Z. J. Am. Chem. Soc. 2006,
128, 7416; (c) Bedford, R. B.; Haddow, M. F.; Mitchell, C. J.; Webster, R. L. Angew.
Chem., Int. Ed. 2011, 50, 5524; (d) Powers, D. C.; Benitez, D.; Tkatchouk, E.;
Goddard, W. A., III; Ritter, T. J. Am. Chem. Soc. 2010, 132, 14092; (e) Chen, X.;
Hao, X.-S.; Goodhue, C. E.; Yu, J.-Q. J. Am. Chem. Soc. 2006, 128, 6790; (f)
Schröder, N.; Wencel-Delord, J.; Glorius, F. J. Am. Chem. Soc. 2012, 134, 8298; (g)
Mo, F.; Yan, J. M.; Qiu, D.; Li, F.; Zhang, Y.; Wang, J. Angew. Chem., Int. Ed. 2010,
49, 2028; (h) Sun, X.; Shan, G.; Sun, Y.; Rao, Y. Angew. Chem., Int. Ed. 2013, 52,
4440.
6. For some examples of transition-metal free of C–H activation, see: (a) Sun, C.-
L.; Li, H.; Yu, D.-G.; Yu, M.; Zhou, X.; Lu, X.-Y.; Huang, K.; Zheng, S.-F.; Li, B.-J.;
Shi, Z.-J. Nat. Chem. 2010, 2, 1044; (b) Zhang, H.; Shi, R.; Ding, A.; Lu, L.; Chen, B.;
Lei, A. Angew. Chem., Int. Ed. 2012, 51, 12524; (c) Liu, W.; Cao, H.; Zhang, H.;
Zhang, H.; Chung, K. H.; He, C.; Wang, H.; Kwong, F. Y.; Lei, A. J. Am. Chem. Soc.
2010, 132, 16737; (d) Shirakawa, E.; Itoh, K.; Higashino, T.; Hayashi, T. J. Am.
Chem. Soc. 2010, 132, 15537; (e) Yanagisawa, S.; Ueda, K.; Taniguchi, T.; Itami,
K. Org. Lett. 2008, 10, 4674.
7. The Chemistry of Heterocyclic Compounds; Taylor, E. C., Saxton, J. E., Eds.; Wiley-
Interscience: New York, 1983; Vol. 25, p 1994; (b) Sundberg, R. J. Indoles;
Academic: New York, 1996; (c) Kawasaki, T.; Higuchi, K. Nat. Prod. Rep. 2005,
22, 761; (d) Saracoglu, N. Top. Heterocycl. Chem. 2007, 11, 145.
with satisfactory isolated yields (Table 2, 2e, 3e, 2f, 3f). Substrates
without any substituents on the 2-position of indole proceeded
efficiently and halogenations occurred highly selectively at the
3-position of indoles with good isolated yields (Table 2, 2h, 3i).
Halosubstituted indole also can be tolerated in this transformation
(Table 2, 2i, 3i). Unfortunately, 2-phenyl-1H-indole did not work
under the standard conditions, mainly because the unprotected
indoles can be destructed by Selectfluor.
The proposed mechanism is illustrated in Scheme 2. As reported
in literatures, some additional electrophilic reactions can be per-
formed in the presence of Selectfluor.13 The corresponding Br+
and I+ are generated in situ from TBAB and KI, respectively, upon
oxidation with Selectfluor.14 Then the bromide (iodine) cation is
attacked by the electron-rich indoles highly regioselectively at C-
3 position to form intermediate A or its resonance B. At last the
proton was abstracted by the base (NaHCO3) to give the product.
In summary, a novel and efficient protocol of transition metal-
free C–H bond halogenation of indoles has been developed. 3-Hal-
ogenated (3-Br, 3-I) indoles are highly regioselectively produced by
this protocol. Simple and readily available halide salts (TBAB, KI)
are employed as the halogen source. The transition metal-free
and the mild conditions make this protocol very easy to handle
and practical. Further investigations on the reaction scope and
the synthetic applications are ongoing in our group.
Acknowledgments
8. For some reviews, see: (a) Cacchi, S.; Fabrizi, G. Chem. Rev. 2011, 111, 215; (b)
Palmisano, G.; Penoni, A.; Sisti, M.; Tibiletti, F.; Tollarim, S.; Nicholas, K. M. Curr.
Org. Chem. 2010, 14, 2409; (c) Bartoli, G.; Bencivenni, G.; Dalpozzo, R. Chem. Soc.
Rev. 2010, 39, 4449; (d) Zeng, M.; You, S.-L. Synlett 2010, 1289; (e) Bandini, M.;
Eichholzer, A. Angew. Chem., Int. Ed. 2009, 48, 9608; (f) Driver, T. G. Angew.
Chem., Int. Ed. 2009, 48, 7974; (g) Joucla, L.; Djakovitch, L. Adv. Synth. Catal.
2009, 351, 673; (h) Zhou, Y.-G. Acc. Chem. Res. 2007, 40, 1357.
9. (a) Singh, P. P.; Thatikonda, T.; Kumar, K. A. A.; Sawant, S. D.; Sharma, A. K.;
Sharma, P. R.; Singh, D.; Vishwakarma, R. A. J. Org. Chem. 2012, 77, 5823; (b)
Yang, L.; Lu, Z.; Stahl, S. Chem. Commun. 2009, 6460; (c) John, A.; Nicholas, K. M.
Organometallics 2012, 31, 7914.
Financial support from the National Science Foundation of Chi-
na (Nos. 21325206, 21172006), National Young Top-notch Talent
Support Program and the Ph.D. Programs Foundation of the Minis-
try of Education of China (No. 20120001110013) are greatly appre-
ciated. We thank Yuepeng Yan in this group for reproducing the
results of 2f and 3d.
10. (a) Shi, Z.; Zhang, C.; Li, S.; Pan, D.; Ding, S.; Cui, Y.; Jiao, N. Angew. Chem., Int. Ed.
2009, 48, 4752; (b) Shi, Z.; Zhang, C.; Li, S.; Pan, D.; Ding, S.; Cui, Y.; Jiao, N.
Angew. Chem., Int. Ed. 2009, 48, 7895; (c) Ding, S.; Shi, Z.; Jiao, N. Org. Lett. 2010,
12, 1540; (d) Shi, Z.; Zhang, B.; Cui, Y.; Jiao, N. Angew. Chem., Int. Ed. 2009, 49,
4036; (e) Shi, Z.; Cui, Y.; Jiao, N. Org. Lett. 2010, 12, 2908; (f) Xiang, S.-K.; Zhang,
B.; Zhang, L.-H.; Cui, Y.; Jiao, N. Chem. Commun. 2011, 47, 8097; (g) Xiang, S.-K.;
Wu, G.-L.; Zhang, B.; Cui, Y.; Jiao, N. Tetrahedron Lett. 2012, 53, 3802; (h) Ding,
S.; Jiao, N. J. Am. Chem. Soc. 2011, 133, 12374; (i) Lin, R.-Y.; Ding, S.; Shi, Z.; Jiao,
N. Org. Lett. 2011, 13, 4498.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2014.02.
071.
References and notes
11. (a) Zolfigol, M. A.; Khazaei, A.; Kolvari, E.; Koukabi, N.; Soltani, H.; Behjunia, M.
Hel. Chim. Acta 2010, 93, 587; (b) Khazaei, A.; Zolfigol, M. A.; Kolvari, E.;
Koukabi, N.; Soltani, H.; Komaki, F. Synthesis 2009, 3672.
1. (a)Metal-Catalyzed Cross Coupling Reactions; Meijere, A., Diederich, F., Eds., 2nd
ed.; Wiley-VCH: Weinheim, 2004; (b) Beller, M.; Bolm, C. Transition Metals for
Organic Synthesis; Wiley-ACH: Weinheim, 2004; (c) Suzuki, A.; Brown, H. C.
Organic Synthesis via Boranes; Aldrich: Milwaukee, WI, 2003; (d) Oestreich, M.
The Mizoroki-Heck Reaction; Wiley: Weinheim, 2009; (e) Martin, R.; Buchwald,
S. L. Acc. Chem. Res. 2008, 41, 1461.
2. For some reviews see: (a) Anbarasan, P.; Schareina, T.; Beller, M. Chem. Soc. Rev.
2011, 40, 5049; (b) Hartwig, J. F. Acc. Chem. Res. 2008, 41, 1534; (c) Buchwald, S.
L. Acc. Chem. Res. 2008, 41, 1439; (d) Negishi, E.; Anastasia, L. Chem. Rev. 1979,
2003, 103; (e) Negishi, E.; Copéret, C.; Ma, S.; Liou, S.-Y.; Liu, F. Chem. Rev. 1996,
96, 365; (f) Stille, J. K.; Lau, K. S. Y. Acc. Chem. Res. 1977, 10, 434; (g) Miyaura, N.;
Suzuki, A. Chem. Rev. 1995, 95, 2457.
3. (a) Comins, D. L.; Killpack, M. O. Tetrahedron Lett. 1989, 30, 4337; (b) Duan, X.-
H.; Mayr, H. Org. Lett. 2010, 12, 2238; (c) Roper, K. A.; Lange, H.; Polyzos, A.;
Berry, M. B.; Baxendale, I. R.; Ley, S. V. Beilstein J. Org. Chem. 2011, 7, 1648; (d)
Joseph, R.; Pallan, P.; Sudalai, A.; Ravindranathan, T. Tetrahedron Lett. 1995, 36,
609; (e) Branytska, O. V.; Neumann, R. J. Org. Chem. 2003, 68, 9510.
12. (a) Banks, R. E. J. Fluorine Chem. 1998, 87, 1; (b) Singh, R.; Shreeve, J. M. Acc.
Chem. Res. 2004, 37, 31; (c) Shibata, N.; Ishimaru, T.; Nakamura, S.; Toru, T. J.
Fluorine Chem. 2007, 128, 469; (d) Yin, F.; Wan, Z.; Li, Z.; Li, C. J. Am. Chem. Soc.
2012, 134, 10401; (e) Li, Z.; Song, L.; Li, C. J. Am. Chem. Soc. 2013, 135, 4640.
13. (a) Zupan, M.; Iskra, J.; Stavber, S. Tetrahedron Lett. 1997, 38, 6305; (b) Stavber,
S.; Kralj, P.; Zupan, M. Synlett 2002, 598; (c) Stavber, S.; Kralj, P.; Zupan, M.
Synthesis 2002, 1513; (d) Stavber, S.; Jereb, M.; Zupan, M. Chem. Commun. 2002,
488; (e) Podgorešk, A.; Zupan, M.; Iskra, J. Angew. Chem., Int. Ed. 2009, 48, 8424;
(f) Stavber, S. Molecules 2011, 16, 6432.
14. Selectfluor as an oxidant, see some examples: (a) Ye, C.; Shreeve, M. J. Org.
Chem. 2004, 69, 8561; (b) Engle, K. M.; Mei, T.-S.; Wang, X.; Yu, J.-Q. Angew.
Chem., Int. Ed. 2011, 50, 1478; (c) Peng, Y.; Cui, L.; Zhang, G.; Zhang, L. J. Am.
Chem. Soc. 2009, 131, 5062; (d) Zhang, G.; Peng, Y.; Cui, L.; Zhang, L. Angew.
Chem., Int. Ed. 2009, 48, 3112; (e) Zhang, G.; Cui, L.; Wang, Y.; Zhang, L. J. Am.
Chem. Soc. 2010, 132, 1474.