Transition metal-free regioselective C-3 amidation of indoles with N-fluorobenzenesulfonimide

Article abstract of DOI:10.1002/adsc.201300767

A direct transition metal-free regioselective C-3 amidation of indoles has been developed with the commercially available N-fluorobenzenesulfonimide (NFSI) as the amino source under external oxidant-free conditions. This amidation requires only a catalytic amount of base and exhibits excellent functional group tolerance and regioselectivity. The C-3 regioselectivity was proposed to realize by a free radical mechanism. Copyright

Full text of DOI:10.1002/adsc.201300767

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DOI: 10.1002/adsc.201300767
Transition Metal-Free Regioselective C-3 Amidation of Indoles
with N-Fluorobenzenesulfonimide
+
a
+a
a
a,
Hai-Hong Liu, Yi Wang, Guojun Deng, and Luo Yang *
a
Key Laboratory for Environmentally Friendly Chemistry and Application, Department of Chemistry, Xiangtan
University, Hunan 411105, Peopleꢀs Republic of China
Fax : (+86)-731-5829-2251; phone: (+86)-731-5829-8351; e-mail: yangluo@xtu.edu.cn
+
H.-H. Liu and Y. Wang contributed equally to this work.
Received: August 24, 2013; Published online: November 13, 2013
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201300767.
[
7e]
Abstract: A direct transition metal-free regioselec-
tive C-3 amidation of indoles has been developed
with the commercially available N-fluorobenzene-
sulfonimide (NFSI) as the amino source under ex-
ternal oxidant-free conditions. This amidation re-
quires only a catalytic amount of base and exhibits
excellent functional group tolerance and regioselec-
tivity. The C-3 regioselectivity was proposed to real-
ize by a free radical mechanism.
of
indole
with
N-arylbenzenesulfonamide
(Scheme 1d). However, all these methods could only
deliver C-2 amidation products of indole. Herein, we
report an unprecedented transition metal-free regio-
selective C-3 amidation of indoles with N-fluoroben-
zenesulfonimide requiring only a catalytic amount of
base (Scheme 1e). As far as we know, this should be
the first direct regioselective C-3 amidation of indole.
N-Fluorobenzenesulfonimide (NFSI) is a well-
known fluorination reagent and oxidant in CÀH trans-
[
9]
Keywords: amidation; indole; N-fluorobenzenesul-
fonimide; transition metal-free reaction
formation reactions. Actually, the electrophilic fluo-
rination of N-alkylindoles to afford 3,3-difluoro-2-ox-
indoles using N-fluorobenzenesulfonimide was report-
ed by Lim et al. and an organocatalytic asymmetric
fluorocyclization of C-3 substituted indoles with Se-
lectfluor or NFSI was discovered by Gouverneur
[
9c]
[
9g]
Indoles and their derivatives are ubiquitous in natural et al. Recently, NFSI was also found to be an effi-
2
3
products, biologically active compounds and pharma- cient amino source in both sp and sp CÀH amida-
[1]
[10a–c]
[10d]
ceuticals. Therefore, continuous efforts have been tions catalyzed by Pd or Cu. As part of our
paid to the direct functionalization of indole scaffold continuing interest in developing facile and efficient
since more than a century. While the direct CÀC nucleophilic reactions, we recently reported the
[
2]
[3]
2
bonds formations through alkylation, acylation, ar- Rh ACHUTGTNRENNUG( III)-catalyzed C ACTHUNGTRENNNUG
[4]
[5]
[6]
[11]
ylation, alkenylation and alkynylation have been philic amidation with NFSI. In this communication,
studied extensively, the corresponding direct CÀN a new transition metal-free and regioselective C-3
[
7,8]
bonds formation is rare.
Recently, C. J. Li et al. amidation of indoles with N-fluorobenzenesulfoni-
demonstrated the first C-2 amidation of indole cata- mide is described.
lyzed by CuBr employing tert-butyl peroxide (TBP) Based on our recent research results on Rh ACHTUNGTRENNUNG( III)-
[
11]
[
7a]
2
as oxidant
(Scheme 1a) and Liang reported a Pd/ catalyzed C
A
H
U
G
R
N
U
G
Cu-catalyzed amidation of indole with N-chloroben- tions, we first examined the reaction of 1-acetylindole
zenesulfonamide in the presence of a stoichiometric (1a) and NFSI in the presence of a rhodium catalyst.
amount of base
[7b]
(Scheme 1b). Later, Chang devel- To our delight, the desired C-3 amidation product 2a
oped a wonderful Rh-catalyzed directed amination/ was obtained in 65% yield when the reaction was run
amidation using aryl or sulfonyl azides as amino sour- in 1,2-dichloroethane (DCE) at 608C for 24 h
[7c]
ces, which was subsequently exemplified to be a reli- (Table 1, entry 1). To assign the regiochemistry of
able procedure for the C-2 amidation of indoles by Y. products beyond doubt, the structure of the C-3 ami-
[
7d]
Li and co-workers
(Scheme 1c). While the above dation product (2f) of 1-acetyl-7-chloroindole (1f)
methods relied on transition metal catalysts, Liang was determined unambiguously by X-ray crystallogra-
[
12]
further discovered an iodine-promoted amidation phy (Figure 1).
Adv. Synth. Catal. 2013, 355, 3369 – 3374
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Hai-Hong Liu et al.
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Scheme 1. Various routes for CÀH amidation of indoles.
Table 1. Optimization of the regioselective C-3 amidation.
[a]
[b]
Entry
Catalyst (mol%)
Additive (mol%)
Cs CO (10)
Temp. [8C]
Solvent
Yield [%]
[c]
1
2
3
4
5
6
7
8
Rh* (2.5)
60
60
60
60
60
60
60
60
60
40
80
60
60
60
60
60
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
THF
65
69
60
37
95
74
71
85
59
4
90
65
66
57
15
<5
2
3
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
Cs CO (10)
2 3
Cs CO (0)
2
3
Cs CO (50)
2
3
K CO (10)
2
3
Na CO (10)
2
3
t-BuOLi (10)
Et N (10)
3
[
d]
9
1
1
1
1
1
1
1
K CO (10)
2
3
0
1
2
3
4
5
6
K CO (10)
2 3
K CO (10)
2
3
Cs CO (10)
2
3
Cs CO (10)
toluene
ethanol
DMF
DMSO
2
3
Cs CO (10)
2
3
Cs CO (10)
2
3
Cs CO (10)
2
3
[
a]
Conditions: 1a (0.2 mmol), NFSI (0.4 mmol), additive, solvent (0.6 mL), reacted for 24 h under argon unless otherwise
noted.
Isolated yields.
Rh*=(CH CN) Cp*Rh ACHTUNGTRNENUG( SbF ) , Bs=benzenesulfonyl.
NFSI (1.5 equiv., 0.3 mmol) was added.
[
[
[
b]
c]
3
3
6 2
d]
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Adv. Synth. Catal. 2013, 355, 3369 – 3374

Transition Metal-Free Regioselective C-3 Amidation of Indoles with N-Fluorobenzenesulfonimide
ly in yields up to 95%. Use of other common N-pro-
tecting groups like tert-butoxycarboynyl (Boc) result-
ed in low yield and benzyloxycarbonyl (Cbz) led to
no product due to the instability of these two groups
[
13]
under the optimized conditions. Next, other N-pro-
tected indoles with substituents on C-4 to C-7 were
investigated. We were pleased to observe that func-
tional groups such as alkyl (1e), halo (1f, 1g, 1i and
1k), phenyl (1h, 1j) and methoxycarbonyl (1l) were
all tolerated. It is worthy of note that for some of
these substrates, a higher temperature (100–1108C)
was necessary to promote full consumption of the
starting materials.
Figure 1. X-ray structure of 2f.
Encouraged by the exciting results obtained be-
tween the reaction of different indoles with NFSI, the
During the following optimization study, we soon application of this reaction to N-protected pyrroles
realized that the rhodium catalyst was unnecessary was investigated next (Scheme 2). Unexpectedly,
and the control reaction proceeded equally well with- under the optimized conditions, 1-benzoylpyrrole
out adding it (entry 2). On the other hand, a catalytic (1m) and 1-tosylpyrrole (1n) did react with NFSI, but
amount of base did prove to be essential for this C-3 the amidation turned out to take place selectively on
[
14]
amidation. In the absence of the base or increasing the C-2 of pyrrole in 97% and 50% yields, respec-
the quantity of Cs CO to 50 mol% both led to inferi- tively.
2
3
or yields (entries 2–4) and subsequently screening of
Since the more electron-deficient indole substrates
the common weak bases such as K CO , Na CO , t- generally led to higher yields in this transition metal-
2
3
2
3
BuOLi and Et N revealed that the cheap and abun- free C-3 amidation (Table 1), this implies that the
3
dant inorganic base K CO was the best choice (en- mechanism is different from that of the previously re-
2
3
[
9]
tries 5–8). The best result was obtained (95% yield) ported electrophilic fluorination of N-alkylindoles
when the reaction mixture was heated at 608C for by NFSI. To gain insights into the mechanism of this
24 h (entry 5). An excess of NFSI (2 equiv.) was re- transition metal-free C-3 amidation of indoles, the re-
quired to promote the complete consumption of 1- action of 1-acetyl-3-methylindole (1o) with NFSI was
acetylindole (1a), thus the yield diminished considera- carried out (Scheme 3). Unexpectedly, neither a C-2
bly when 1.5 equiv. of NFSI were added (entry 9). amidation nor an electrophilic fluorination product
While decreasing the reaction temperature gave can be isolated and the main product was character-
a much inferior yield with most of the starting materi- ized to be the benzylic amidation product 2o, which
al remaining unreacted (entry 10), increasing the reac- might imply that the reaction is realized by a free rad-
tion temperature had little influence (entry 11). Next, ical mechanism.
the effect of solvents on this reaction was also investi-
In summary, we have developed an efficient transi-
gated and the most satisfactory yield was obtained in tion metal-free regioselective amidation of indoles
low polarity DCE. Other common solvents such as and pyrroles with NFSI as the commercially available
THF, toluene and ethanol were also applicable; how- amino source. Different from the previous reports,
ever they displayed lower yields (entries 12–14). More the amidation takes place selectively on C-3 of in-
polar DMF and DMSO were almost ineffective (en- doles and C-2 of pyrroles. This procedure does not re-
tries 15 and 16). It is worthy of note that no C-2 ami- quire any external oxidant and only a catalytic
dation product was detected by in situ GC-MS and amount of base was required. The amidation can tol-
1
H NMR under all these conditions.
erate a wide range of functional groups such as alkyl,
Under the optimized conditions (Table 1, entry 5), halides and methoxycarbonyl. The detailed reaction
the substrate scope of this novel transition metal-free mechanism and applications of this novel amidation
regioselective C-3 amidation of indoles with NFSI are under investigation.
was explored (Table 2). First, the influence of the N-
protecting groups on the indole was studied. When
the indole was N-substituted by methyl, benzyl and
Experimental Section
phenyl groups, which increased the electron density of
the indole, the main product of the reaction was 3,3-
[
9c]
General Experimental Procedure
difluoro-2-oxindole as reported by Lim. When the
indole was N-substituted by the electron-withdrawing
groups such as acetyl, benzoyl, pyrimidyl and tosyl dole (1a) (31.8 mg, 0.2 mmol), DCE (0.6 mL), K CO3
An oven-dried reaction vessel was charged with 1-acetylin-
2
groups (1a–1d), the C-3 amidation proceeded smooth- (2.8 mg, 0.02 mmol, 10 mol%), and NFSI (126 mg,
Adv. Synth. Catal. 2013, 355, 3369 – 3374
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Hai-Hong Liu et al.
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[a]
Table 2. The substrate scope of regioselective C3-amidation of indoles with NFSI.
[a]
Conditions: 1a–1l (0.2 mmol), NFSI (0.4 mmol), K CO (10 mol%, 0.02 mmol), DCE
2
3
(
0.6 mL), reacted for 24 h under argon unless otherwise noted. Isolated yields. Bs=ben-
zenesulfonyl.
Scheme 3. Mechanism investigation of the transition metal-
free C-3 amidation.
Scheme 2. Transition metal-free regioselective C-2 amida-
tion of pyrroles with NFSI.
Acknowledgements
0
6
.4 mmol) under argon. The vessel was sealed and heated at
08C (oil bath temperature) for 24 h. The resulting mixture
This work was supported by the National Natural Science
Foundation of China (21202138), Xiangtan University “Aca-
demic Leader Program” (11QDZ20), New Teachersꢀ Fund
was cooled to room temperature, transferred to a silica gel
column directly and eluted with hexanes and ethyl acetate
(
6:1) to give product 2a; yield: 86.4 mg (95%).
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Transition Metal-Free Regioselective C-3 Amidation of Indoles with N-Fluorobenzenesulfonimide
for
20124301120007), University Student Innovation Program,
Ministry of Education (201210530008) and Project of Hunan
Provincial Natural Science Foundation (13JJ4047,
2JJ7002), as well as Excellent Young Scientist Foundation
Doctor
Stations,
Ministry
of
Education
124, 10042; Angew. Chem. Int. Ed. 2012, 51, 9904; d) J.
Shi, B. Zhou, Y. Yang, Y. Li, Org. Biomol. Chem. 2012,
10, 8953; e) Y.-X. Li, H.-X. Wang, S. Ali, X.-F. Xia, Y.-
M. Liang, Chem. Commun. 2012, 48, 2343; f) L. He,
P. W. H. Chan, W.-M. Tsui, W.-Y. Yu, C.-M. Che, Org.
Lett. 2004, 6, 2405; g) J. A. Souto, C. Martinez, I. Velil-
la, K. Muniz, Angew. Chem. 2013, 125, 1363; Angew.
Chem. Int. Ed. 2013, 52, 1324.
(
1
of Hunan Provincial Education Department (13B114). The
authors declare no competing financial interest.
[
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see: a) V. S. Thirunavukkarasu, K. Raghuvanshi, L. Ac-
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Adv. Synth. Catal. 2013, 355, 3369 – 3374
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Hai-Hong Liu et al.
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Cambridge
www.ccdc.cam.ac.uk/data_request/cif.
Crystallographic Data
Centre via
MS confirmed that the starting material was de-protect-
ed.
[
13] When the indole was N-protected by a tert-butoxycar-
bonyl (Boc) group, the desired amidation product (N-
Boc-3-dibenzenesulfonylaminoindole) was obtained in
[14] The C-2 selectivity was determined by the chemical
shifts and coupling constants of the protons on C-3 to
[7f]
C-5, which were all most the same as in ref. and the
following literature reports: a) M. Nitta, T. Kobayashi,
Chem. Lett. 1985, 877; b) T. Itahara, J. Org. Chem.
1985, 50, 5272; c) M. D. Rosa, V. R. Marwaha, Hetero-
cycles 1994, 37, 979.
1
8% yield together with the de-protected product (3-di-
benzenesulfonylaminoindole) in 22% yield. When the
indole was N-protected by benzyloxycarbonyl (Cbz),
the reaction led to no amidation product and the GC-
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