Selective sulfonylation and diazotization of indoles

Article abstract of DOI:10.1039/c4cc06795a

A metal-free synthesis of bifunctionalized indole derivatives was developed through a novel TBHP/TBAI-mediated oxidative coupling of C2,C3-unsubstituted indoles with arylsulfonyl hydrazide. Under the same conditions C3-methyl substituted indoles underwent a diazotization process, affording 2-sulfonyldiazenyl-1H-indoles. The former reaction simultaneously established C-S and C-N bonds through selective sulfonylation and diazotization of the indole framework, enabling a mild and practical access to polyfunctionalized indoles with good to excellent yields. This journal is

Full text of DOI:10.1039/c4cc06795a

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Selective sulfonylation and diazotization of
indoles†
Cite this:DOI: 10.1039/c4cc06795a
Jiang-Kai Qiu,ab Wen-Juan Hao,b De-Cai Wang,a Ping Wei,*a Jun Sun,a Bo Jiang*b
and Shu-Jiang Tu*b
Received 28th August 2014,
Accepted 1st October 2014
DOI: 10.1039/c4cc06795a
www.rsc.org/chemcomm
A metal-free synthesis of bifunctionalized indole derivatives was toward 3-arylsulfonyl-1H-indole derivatives. A survey of the litera-
developed through a novel TBHP/TBAI-mediated oxidative coupling ture shows that three general strategies have been developed,
of C2,C3-unsubstituted indoles with arylsulfonyl hydrazide. Under including the direct C3-arylsulfonylation of indoles,5 indole annu-
the same conditions C3-methyl substituted indoles underwent a lation of suitable acyclic precursors,6 and the oxidation of the
diazotization process, affording 2-sulfonyldiazenyl-1H-indoles. The corresponding sulfide with diverse oxidants such as m-CPBA,7
former reaction simultaneously established C–S and C–N bonds oxone,8 and KMnO4/MnO2.9 However, the majority of these meth-
through selective sulfonylation and diazotization of the indole ods involve either multistep sequences,6c,g,7b metal catalysts,5a–e,6a–f
framework, enabling a mild and practical access to polyfunctionalized drastic conditions,5d,6a–c lengthy reaction times6c,d or laborious
indoles with good to excellent yields.
workup.6a–c,7–9 Therefore, the development of a versatile, efficient
and selective access to 3-arylsulfonyl-1H-indoles from simple and
The indole skeleton is widespread in a myriad of natural readily available starting materials is highly valuable.
products,1 and has been considered as a ‘‘privileged structure’’
Recently, Tian and co-workers have reported an iodine-
in a large family of medicinally relevant compounds due to its catalyzed reaction between indoles and sulfonyl hydrazides
special chemical and biological properties.2 Of particular interest, affording structurally diverse indole thioethers though sulfenyl-
synthetic 3-arylsulfonyl-1H-indoles have served as valid HIV-1 ation (Scheme 1, eqn (1)).10 Enlightened by this interesting reac-
Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)3 tion and our recent findings on oxidative coupling reactions,11,12
(Fig. 1, type I) and 5-HT6 receptor ligands (Fig. 1, type II) useful we assumed that the reaction of indoles with sulfonyl hydrazides
in the treatment of CNS disorders (schizophrenia, depression, would proceed in another direction to form 3-arylsulfonyl-1H-
and Alzheimer’s disease).4 In view of their biological significance, indole derivatives using tetrabutylammonium iodide (TBAI)
many efforts have been devoted to efficient synthetic approaches and tert-butyl hydroperoxide (TBHP),13 based on the fact that
TBAI/TBHP-mediated sulfonylation via sulfonyl radicals generated
in situ from sulfonyl hydrazides is well established.14 Unexpectedly,
in this reaction sulfonyl hydrazides play a dual role as both a
sulfonyl precursor and a sulfonyl azo source, allowing regio-
selective formation of a series of novel 3-sulfonyl-2-sulfonyldiazenyl-
1H-indoles in one step without isolating or purifying any
Fig. 1 Biologically active sulfonylated indoles.
a Biotechnology and Pharmaceutical Engineering, Nanjing Tech University, Nanjing,
210009, Jiangsu, P. R. China. E-mail: weiping@njtech.edu.cn
b Jiangsu Key Laboratory of Green Synthetic Chemistry for Functional Materials,
Jiangsu Normal University, Xuzhou, 211116, P. R. China.
E-mail: jiangchem@jsnu.edu.cn, laotu@jsnu.edu.cn; Fax: +86 51683500065;
Tel: +86 51683500065
† Electronic supplementary information (ESI) available. CCDC 1021404 (3a) and
1021405 (4b). For ESI and crystallographic data in CIF or other electronic format
see DOI: 10.1039/c4cc06795a
Scheme 1 Coupling reaction of indoles with sulfonyl hydrazides.
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intermediates (Scheme 1, eqn (2)). Herein, we report this
interesting and challenging discovery.
We started our investigation with the optimization of the oxida-
tive coupling reaction using indole (1a) with p-toluenesulfonyl
hydrazide (2a) in 1/2.2 mol ratio as model substrates. The above
model reaction was conducted to investigate the impact of various
reaction conditions on the reaction outcome, including solvents,
temperatures, catalysts and oxidants. The results are listed in
Table S1, ESI.† Initially, the reaction of 1a with 2a was performed in
CH3CN at room temperature utilizing TBHP (70% in water) as the
oxidant and 30 mol% of TBAI as the catalyst. An unexpected
product, 3a, was obtained in 81% yield (Table S1, entry 1, see ESI).†
Next, different solvents, such as DMSO, EtOH, MeOH, 1,2-
dichloroethane (DCE) and toluene, were examined under iden-
tical conditions (Table S1, entries 2–6, ESI†). It was found that the
reaction did not proceed at all and the starting materials remained
completely unconsumed in DMSO (Table S1, entry 2, ESI†).
Attempts to employ other solvents including EtOH, MeOH, DCE,
and toluene were less effective (Table S1, entries 3–6, ESI†). An
increase in reaction temperature to 40 1C delivered a higher yield of
3a (Table S1, entry 7, ESI†); however, a higher reaction temperature
(60 1C) decreased the chemical yield (Table S1, entry 8, ESI†). The
effect of different amounts of TBAI was then evaluated. With
substrates 1a and 2a, the reaction gave a lower yield of 3a in the
presence of 10 mol% of TBAI (Table S1, entry 7, ESI†). Using
50 mol% of TBAI did not improve the yield of 3a (Table S1,
entry 10, ESI†). After this, we tuned other reaction parameters such
as the catalyst and the oxidant. Replacing TBAI with iodine resulted
in a slightly lower yield of 3a whereas Cu-catalysts did not promote
the reaction process. Without TBAI, no product 3a was observed.
Finally, various oxidants were screened, such as benzoyl peroxide
(BPO), tert-butyl peroxybenzoate (TBPB), H2O2, di-tert-butyl per-
oxide (DTBP) and m-chloroperoxybenzoic acid (m-CPBA). The
Scheme 2 Substrate scope for synthesis of 3.
use of H2O2 resulted in an 80% yield. Other oxidants gave an effective substrate, resulting in a good yield of the product.
unsatisfactory results (42–67% yield). However, when the more strongly electron-withdrawing nitro group
Once the feasibility of the proposed pathway had been was installed, the reaction became slightly sluggish and provided 3q
validated, we subsequently examined its scope by using various in 42% yield. Unfortunately, ortho-substituted arylsulfonylhydrazides
readily available indoles and arylsulfonyl hydrazides through such as 2-bromobenzenesulfonohydrazide did not work in the
selective C3-sulfonylation and C2-diazotization of the indole reaction. In general, these domino coupling reactions provide new
ring. As shown in Scheme 2, substituents on different positions examples for synthesizing richly decorated indoles, which are wide-
of the indole ring did not hamper the reaction process. A broad spread structural cores in a large number of bioactive compounds.
spectrum of substituted indoles containing both electron-donating
After successfully synthesizing 3-sulfonyl-2-sulfonyldiazenyl-
and electron-withdrawing groups were successfully transformed 1H-indoles 3, we attempted to further evaluate the reaction
into the corresponding 3-sulfonyl-2-sulfonyldiazenyl-1H-indoles scope using 3-methyl-1H-indole (1l) as an indole component
3a–k in good to excellent yields. Notably, halogen-containing under the same conditions (Scheme 3). The reaction proceeded
indoles could be employed and were tolerated well under the smoothly, affording 2-sulfonyldiazenyl-1H-indoles in moderate
optimal reaction conditions, furnishing the desired products in yields. The sulfonylated products were not generated in these
excellent yields, which offers possibilities for further function- reactions, which suggested that the sulfonylation reaction did
alizations by modern coupling methods. After the successful not take place as the C3 position of the indole ring was occupied
utilization of different substituted indoles, we next extended our by a methyl group. A set of arylsulfonyl hydrazides with diverse
study to a variety of arylsulfonyl hydrazides with different func- substituents, such as methyl, chloro and bromo groups, were
tional groups such as chloro, bromo, tert-butyl and methoxy on the well tolerated in this oxidative reaction.
phenyl ring. Arylsulfonyl hydrazides bearing electron-donating,
After the formation of polyfunctionalized indoles 3 and 4,
electron-neutral and electron-withdrawing groups showed high we made efforts to explore the potential applications of 3. The
reactivity and gave high yields (Scheme 2). As per our expectation, reaction between 3-tosyl-2-(tosyldiazenyl)-1H-indole (3a) and
the extended 2-naphthylsulfonyl hydrazide was also shown to be diethyl acetylenedicarboxylate was carried out in the presence
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Scheme 3 Substrate scope for synthesis of 4.
of Et3N in EtOH at room temperature, affording tricyclic imidazo-
[1,2-a]indole-2,3-dicarboxylate 5 in 47% yield (Scheme S4, see ESI†).
The 3-sulfonyl-2-sulfonyldiazenyl-1H-indole 3a was converted into
4-methyl-N0-(3-tosyl-1H-indol-2-yl)benzenesulfonohydrazide 6 in
93% yield by hydrogenation using active zinc powder and
ammonium (Scheme S4, see ESI†).16
Although functionalized indoles 3 and 4 were fully charac-
terized by NMR spectroscopy and HRMS, their structures were
determined by X-ray diffraction of compounds 3a and 4b (see
ESI†).
To explore the reaction mechanism for this transformation,
some control experiments were conducted (Scheme 4). When
the reaction mixture of 1a with 2.2 equivalents of 2a and TBHP
(4.0 equiv.) was treated using the radical scavenger TEMPO
(4 equiv.), the reaction did not give the product 3a, indicating
the possibility of a radical mechanism (eqn (1)). To provide
further support for the radical pathway, the reaction was carried
Scheme 5 Proposed mechanism for formation of products 3.
out without the use of aq. TBHP. The desired product 3a was not
observed (eqn (2)). This suggested that TBAI is insufficient to
form the radical and the radical initiator TBHP plays a pivotal
role in this transformation. To further confirm the effect of
N-substituents of indole on the reaction process, 1-methylindole
was subjected to the reaction with 2a, transforming readily into
the corresponding functional indole 3u (eqn (3)), which indicated
that both free and N-substituted indoles were suitable for this
protocol. However, 2-methylindole did not undergo this reaction
(eqn (4)). Finally, to further probe the sulfonylation sequence,
the reaction of 3-((4-bromophenyl)sulfonyl)-1H-indole15 and 2a
generated a trace amount of 3-sulfonyl-2-sulfonyldiazenyl-1H-
indoles 3w (eqn (5)). We therefore reasoned that the diazotiza-
tion occurred prior to the sulfonylation step.
On the basis of literature reports and taking our experi-
mental outcomes into consideration, a tentative mechanism for
the formation of products 3 is outlined in Scheme 5. Initially,
tert-butoxyl and tert-butylperoxy radicals are generated from the
decomposition of TBHP in an Iꢀ catalytic system.17 Then,
sequential H-abstraction of sulfonylhydrazides by the resultant
radicals yields arylsulfonyldiazene radicals B, followed by reac-
tion with indoles to afford indole radicals D.18 The intermediates
D are trapped by sulfonyl radical C generated in situ from B under
the oxidative conditions with the release of molecular nitrogen,19
producing substituted indolines E. The final 3-sulfonyl-2-
sulfonyldiazenyl-1H-indoles are obtained through H-abstraction
by tert-butoxyl radical or tert-butylperoxy radical.
In conclusion, we have developed a facile, selective sulfonyl-
ation and diazotization of C2,C3-unsubstituted indoles, providing
a straightforward and metal-free protocol for the unprecedented
synthesis of bifunctionalized indole derivatives through TBAI/
TBHP-mediated oxidative reactions. Moreover, under the same
conditions 3-methylindole underwent a diazotization process,
affording 2-sulfonyldiazenyl-1H-indoles. This convergent and
versatile approach presents broad substrate scope, reliable
scalability and excellent functionality tolerance, allowing the
rapid construction of highly functionalized indoles with the use
Scheme 4 Control experiments.
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