Nitrosonium ion catalysis: aerobic, metal-free cross-dehydrogenative carbon-heteroatom bond formation

Article abstract of DOI:10.1039/C8CC08328B

Catalytic cross-dehydrogenative coupling of heteroarenes with thiophenols and phenothiazines has been developed under mild and environmentally benign reaction conditions. For the first time, NO_x⁺ was applied for catalytic C-S and C-N bond formation. A comprehensive scope for the C-H/S-H and C-H/N-H cross-dehydrogenative coupling was demonstrated with >60 examples. The sustainable cross-coupling conditions utilize ambient oxygen as the terminal oxidant, while water is the sole by-product.

Full text of DOI:10.1039/C8CC08328B

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Nitrosonium ion catalysis: aerobic, metal-free
cross-dehydrogenative carbon–heteroatom
bond formation†
Cite this: Chem. Commun., 2018,
54, 13022
Received 17th October 2018,
Accepted 31st October 2018
ab
Luis Bering,
Laura D’Ottavio,ac Giedre Sirvinskaitea and
ab
Andrey P. Antonchick
*
DOI: 10.1039/c8cc08328b
rsc.li/chemcomm
Catalytic cross-dehydrogenative coupling of heteroarenes with
thiophenols and phenothiazines has been developed under mild
and environmentally benign reaction conditions. For the first time,
+
NOx was applied for catalytic C–S and C–N bond formation.
A comprehensive scope for the C–H/S–H and C–H/N–H cross-
dehydrogenative coupling was demonstrated with 460 examples.
The sustainable cross-coupling conditions utilize ambient oxygen
as the terminal oxidant, while water is the sole by-product.
The formation of carbon–heteroatom bonds is fundamental for
the synthesis of natural products, pharmaceuticals and materials
science.1 To overcome the requirement for pre-functionalized
starting materials, cross-dehydrogenative coupling (CDC) has
emerged as a highly efficient strategy.2 Transition-metal-catalyzed
C–S and C–N bond formation has been widely reported.3 Cost,
toxicity and oxygen sensitivity of catalysts limit the general
applicability.4 Consequently, metal-free synthesis has gained
increasing interest.5 Different metal-free approaches for the
C–H/S–H CDC have been reported.6 Additionally, the unique
dehydrogenative amination with phenothiazines has received
Fig. 1 Prior work on the oxidative carbon–carbon bond formation via
C–H bond functionalization and newly developed transformation
+
catalyzed by NOx
.
significant attention.7 High temperatures, excess of oxidants reported the NO+ catalyzed coupling for the construction of C–C
and harmful solvents are common limitations.
bonds.13 Despite the impact of NO+ as catalyst for oxidative C–C
Nitronium and nitrosonium salts are inexpensive, stable and bond formation, the application in carbon–heteroatom bond
non-toxic single-electron oxidants.8 Radner’s group reported the formation via C–H bond functionalization is unprecedented.
synthesis of biaryls using NOBF4 as catalyst (Fig. 1a).9 Ambient Herein, we demonstrate the first NOx catalyzed C–H/S–H and
+
oxygen was identified as the terminal oxidant and water as the C–H/N–H CDC under mild and environmentally benign reaction
by-product.10 Later, Wang’s group reported the catalytic intra- conditions (Fig. 1d).
molecular C–C bond formation (Fig. 1b).11 Under acidic reaction
Nitrosonium salts are capable to convert thiols to disulfides.14
conditions, NO+ is generated in situ from NaNO2. The oxidative Oxidation of thiols proceeds via transient S-nitrosation and recom-
coupling of phenols is well studied.12 Recently, our group bination of S-centred radicals. Due to the low bond dissociation
energy (BDE) of phenols and thiophenols, the possibility for
a Department of Chemical Biology, Max-Planck-Institute of Molecular Physiology,
a radical–radical recombination reaction of phenoxy and sulfur
radicals was hypothesized.15 A multi parameter optimization for
the cross-coupling of p-cresol (1a) and 4-chlorothiophenol (2a) was
performed (Table S1, ESI†). To our delight, 3a was isolated in
excellent yield, by using NO2BF4 as the catalyst. Hexafluoroiso-
propanol (HFIP) was identified as the best solvent, due to its acidic
Otto-Hahn-Straße 11, 44227 Dortmund, Germany.
E-mail: Andrey.Antonchick@mpi-dortmund.mpg.de
b Faculty of Chemistry and Chemical Biology, TU Dortmund University,
Otto-Hahn-Straße 4a, 44227 Dortmund, Germany
c University of Bologna, Department of Pharmacy and Biotechnology,
Via Belmeloro 6, 40126 Bologna, Italy
† Electronic supplementary information (ESI) available. See DOI: 10.1039/c8cc08328b character and the unique ability to stabilize radical intermediates.16
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products either. To stress the utility of the obtained products,
3a was transformed into benzothiophene 3z by applying a dual
C–H bond activation strategy.17
Next, the thioarylation of indoles was studied (Scheme 2).
Unprotected indoles gave better results than N-protected
analogues. This result makes the reaction conditions more
attractive for other applications. The cross-coupling of indole
4a and thiophenol 2a yielded 5a in 77% yield. Scaling the
reaction to 1 mmol gave 5a unaffectedly. Functional groups
with different electronic properties at the indole skeleton were
well tolerated (5b–f). Further, thiophenols were decorated with
functional groups at the para (5h–j), ortho (5k–l) and meta (5m)
position. Product 5n was isolated in 51% yield bearing a
napthyl moiety. Polysubstituted products 5o–5s were synthe-
sized in good yields, covering combinations of electron-rich
and electron-deficient functional groups. Next, substituted
pyrroles were tested. Product 5t was isolated in 64% yield.
2-Substituted pyrrol yielded the double functionalized product
5v in good yield. To further stress the applicability, 5l was
transformed into the indol-fused benzothiophenes 5v.18
Next, the time course of the cross-coupling reactions was
analysed by GC-MS-FID (Fig. 2). Interestingly, thiophenol 2a
was fully converted to disulfide 6a, prior to the coupling step
with phenol 1a (Fig. 2A). In contrast, indole 4a and thiophenol
2a underwent synchronous cross-coupling without initial
Scheme 1 Scope with respect to phenols (1) and thiophenols (2). Reac-
tion conditions: 1 (0.1 mmol, 1 equiv.), 2 (2 equiv.), HFIP (0.05 M), at room
temperature under air atmosphere. Yields are given for isolated products
after column chromatography. a Reaction carried out with 1 mmol of
phenol 1a. b 1. 3a (0.3 mmol, 1 equiv.), MeI (1.5 equiv.), NaH (1.2 equiv.) in
DMF (0.1 M) at room temperature; 2. (CF3CO2)2Pd (20 mol%), AgOAc
(5 equiv.), K2CO3 (1.5 equiv.) in PivOH (0.3 M) at 130 1C for 2 d.
Initially, the scope for the cross-coupling of phenols and
thiophenols was studied (Scheme 1). The reaction was scaled
to 1 mmol, which did not alter the outcome of the reaction.
Functional groups at the para-position of phenols were well
tolerated (3b–3d). 2,4-Substituted phenols yielded products 3e–3h
in good to excellent yields, covering electron-rich and sterically
demanding functional groups. Product 3g was isolated in quanti-
tative yield and product 3l was synthesized with high para-
selectivity. Electron-rich product 3j revealed selectivity for the
meta-position of phenol. The same outcome was observed for
product 3k by blocking the ortho- and para-positions. Dearomatiza-
tion and subsequent 1,4-addition appeared to be an alternative
pathway. 3l was isolated in moderate yield, using a 3,5-subsituted
phenol. Polysubstituted phenols allowed the isolation of products
3m–o in 76–98% yields. Naphthol derivatives were compatible,
affording products 3p, 3q. Next, substituted thiophenols were
tested. Different functional groups on the para-position were
well tolerated (3s–v). Alkyl or chloro substituents at the ortho-
and meta-position afforded products 3w–3y in good yields.
Double thioarylation was not observed under the developed
conditions. Alkyl and benzyl thiols did not yield the desired
Scheme 2 Scope with respect to indoles (4) and thiophenols (2).
Reaction conditions: 4 (0.1 mmol, 1 equiv.), 2 (2 equiv.), HFIP (0.05 M), at
room temperature under air atmosphere. Yields are given for isolated
products after column chromatography. a Reaction carried out with 1 mmol
of indol 4a. b 5l (0.08 mmol, 1 equiv.), Pd(PPh3)2Cl2 (5 mol%), CsPiv (2 equiv.)
in N,N-dimethylacetamide (0.1 M).
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starting materials to form NO2. NO2 dimerizes to form N2O4,
which undergoes disproportionation to NONO3.11a Water is
released upon protonation by HBF4 and nitrosonium and
nitronium tetrafluoroborate are regenerated. NOBF4 is capable
of oxidizing the substrates in the same way as the nitronium
salt. Oxidation of substrates results in the formation of nitrogen
monoxide, which has to be oxidized by ambient oxygen, in order
to maintain the catalytic cycle.
Based on the revealed radical mechanism, we hypothesized
that phenothiazines represent suitable substrates for the
radical recombination with phenols, due to the low N–H BDE
and the unique ability to stabilize radical intermediates.19
Multi parameter optimization was performed (Table S2, ESI†).
Sustainable C–H bond amination of phenols with phenothiazines
was achieved using NaNO2 as catalyst, omitting halogenated
reagents and solvents. The developed conditions overcome
environmental issues of known methods.7
Next, the scope of the catalytic C–H/N–H cross-dehydrogenative
coupling was studied (Scheme 3). Initially, the cross-coupling
of 4-methoxyphenol (7a) and different phenothiazines was
performed. Products 9a–d were isolated in good yields. Different
4-substituted phenols yielded the desired cross-coupling
products in moderate to excellent yields (9e–j). Cross-coupling
with differently substituted phenothiazines was achieved for
several phenols. Product 9k was isolated in good yield as single
regioisomer. Polyfunctionalized products 9l–q were isolated in
Fig. 2 Reaction profiles and proposed mechanism. (A) Reaction profiles for
the thioarylation of phenol 1a with thiophenol 2a. (B) Reaction profiles for
the thioarylation of indole 4a with thiophenol 2a. (C) Reaction mechanism.
formation of 6a (Fig. 2B). Conducting the coupling reaction with moderate to good yields. Phenoxazine proved to be compatible
disulfide 6a confirmed the discrete recombination selectivities
(Schemes S2 and S5, ESI†). Consequently, disulfide 6a is an
intermediate for the coupling with phenol, but indoles undergo
direct recombination with thiophenols. Further control experi-
ments were conducted (ESI† for the details). No product was
formed in the presence of radical trap butylated hydroxytoluene
(BHT) and the product formation was inhibited under inert
gas atmosphere (Schemes S2 and S4, ESI†). Ambient oxygen
was crucial to maintain the catalytic activity. Initiation of
the coupling reaction through oxidation of weak heteroatom–
hydrogen bonds was studied by methylating the starting materials.
Drastically reduced conversion was observed, which excludes
a direct single-electron-transfer (Schemes S2 and S4, ESI†).
Thiophenol 2a was quantitatively oxidized to disulfide 6a in the
presence of NOBF4 (Scheme S3, ESI†). Conversion to disulfide 6a
was tied to the presence of air and did not take place in the
presence of BHT (Scheme S3, ESI†).
Based on the control experiments, a mechanism for the
cross-coupling of phenol 1a and indole 4a with thiophenol 2a
was proposed (Fig. 2C). Initially, intermediate A is formed by
S-nitrosylation of 2a. Homolytic cleavage releases radical B,
which forms disulfide 6a by recombination with itself. Phenol
1a is oxidized to form a phenoxy radical. Delocalization of the
phenoxy radical (C) and attack at the disulfide bond leads to
release of radical B. Rearomatization furnishes product 3a.
Oxidation of indole 4a gives intermediate D, which undergoes
recombination with B. Oxidation of indole 4a and thiophenol
2a occurs synchronously, leading to the formation of 5a before
disulfide 6a begins to form. Further, NO2BF4 oxidizes the
Scheme 3 Scope for the cross-dehydrogenative C–H bond amination.
Reaction conditions: 8 (0.2 mmol, 1 equiv.), 9 (3 equiv.), 4 : 1 toluene/PivOH
(0.05 M), 0 1C to rt under air atmosphere. Yields are given for isolated
products after column chromatography. a NOBF4 (0.02 mmol, 10 mol%)
was used as catalyst.
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+
In summary, we have reported the first application of NOx
as efficient and environmentally friendly catalyst for carbon–
heteroatom bond formation. The operationally simple and
sustainable protocol enables the C–H/S–H and C–H/N–H CDC.
Ambient oxygen serves as stoichiometric oxidant and water is
generated as by-product. A broad scope was demonstrated in
good yields and regioselectivities. The reported methodology
offers mild reaction conditions and does not require an excess
of reagents or any specialized equipment.
A. P. A. acknowledges the support of the DFG (AN 1064/4-1)
and the Boehringer Ingelheim Foundation (Plus 3). L. B. is
supported by the Verband der Chemischen Industrie e.V.
We gratefully acknowledge Ms R. Perinbarajah for assistance.
Open Access funding provided by the Max Planck Society.
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Conflicts of interest
There are no conflicts to declare.
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