Transition-Metal-Free Synthesis of N-Arylphenothiazines through an N- And S-Arylation Sequence

Article abstract of DOI:10.1021/acs.orglett.1c00515

An efficient synthetic method of N-arylphenothiazines from o-sulfanylanilines under transition-metal-free conditions is disclosed. An N- and S-arylation sequence of o-sulfanylanilines enabled us to synthesize a wide variety of N-arylphenothiazines. In par

Full text of DOI:10.1021/acs.orglett.1c00515

pubs.acs.org/OrgLett
Letter
Transition-Metal-Free Synthesis of N-Arylphenothiazines through an
N- and S‑Arylation Sequence
Tsubasa Matsuzawa, Takamitsu Hosoya, and Suguru Yoshida*
Cite This: Org. Lett. 2021, 23, 2347−2352
Read Online
sı
*
Metrics & More
Article Recommendations
Supporting Information
ACCESS
ABSTRACT: An efficient synthetic method of N-arylphenothiazines
from o-sulfanylanilines under transition-metal-free conditions is
disclosed. An N- and S-arylation sequence of o-sulfanylanilines enabled
us to synthesize a wide variety of N-arylphenothiazines. In particular,
one-pot synthesis of N-arylphenothiazines was accomplished from easily
available modules through preparation of o-sulfanylanilines by
thioamination of aryne intermediates and following N- and S-arylation
sequence.
ucleophilic aromatic substitution (SNAr) reactions are of
ortho arylthio group plays as a masked thiolate and an aryl
donor moiety for N-arylation.4
N
great significance in organic chemistry for synthesizing a
wide variety of aromatic molecules.1 Diverse aromatic
compounds bearing strongly electron-withdrawing groups
have been prepared by traditional SNAr reactions under simple
transition-metal-free conditions (Figure 1A).1 Accessible
Phenothiazine derivatives have served in broad disciplines
including medicinal chemistry and materials science.5 In
particular, various N-aryl-substituted phenothiazines have
gained attention as photoredox catalysts, organic semi-
conductor compounds, and fluorescent compounds from a
wide range of researchers (Figure 2A).6 Because of their
significance, a number of N-arylphenothiazines have been
synthesized from N-H phenothiazines by cross-coupling
reactions with haloarenes (Figure 2B, top).7 Recently,
Jørgensen and co-workers reported an elegant synthetic
protocol of N-arylphenothiazines via palladium-catalyzed
three-component coupling of 2-bromothiophenols, anilines,
and 1-bromo-2-iodobenzene (Figure 2B, middle).8 An N-
arylphenothiazine synthesis from anilines, cyclohexanones, and
elemental sulfur was accomplished by Xiao, Deng, and co-
workers (Figure 2B, bottom).9 Although a number of efficient
methods have recently been reported, synthesizable N-
arylphenothiazines are still limited due to the unavailability
of starting materials.10 Therefore, a novel approach that can
expand the scope of available compounds is eagerly awaited.
Sequential reactions through migratory N-tolylation and
following ring closure by C−S bond formation of N-(2-
bromophenyl)-2-(4-tolylthio)aniline (1a) was realized under
simple basic conditions (Figure 2C). Indeed, we found that
treatment of o-sulfanylaniline 1a with potassium t-butoxide in
N,N-dimethylacetamide (DMA) at 140 °C provided 10-(4-
Figure 1. (A) Traditional SNAr reaction. (B) Concerted SNAr
reaction. (C) This work.
arenes were significantly expanded using a variety of substrates
without the activation by electron-withdrawing groups in
recent remarkable achievements on concerted SNAr reactions
(Figure 1B).2 We herein present an N- and S-arylation
sequence not requiring electron-withdrawing groups to form
N-arylphenothiazine scaffold from easily available o-sulfanylani-
lines (Figure 1C).3 A key point for the facile N-
arylphenothiazine synthesis is that the easily introducible
Received: February 11, 2021
Published: March 5, 2021
https://dx.doi.org/10.1021/acs.orglett.1c00515
© 2021 American Chemical Society
Org. Lett. 2021, 23, 2347−2352
2347

Organic Letters
pubs.acs.org/OrgLett
Letter
Figure 2. (A) Significant N-arylphenothiazines. (B) Conventional
a
b
synthetic methods. (C) Our method. 50 μmol scale. 4 mmol scale.
tolyl)phenothiazine (2a) in excellent yield.11 To our surprise,
the activation of aromatic rings was not mandatory in the
efficient N- and S-arylation sequence without transition metal
catalysis. Good scalability was demonstrated by a gram-scale
synthesis of phenothiazine 2a from o-sulfanylaniline 1a. The
phenothiazine synthesis was also accomplished from chloro- or
fluoro-substituted o-sulfanylaniline 1a′ or 1a′′ suggesting that
the cyclization took place in an SNAr manner.
A broad range of N-arylphenothiazines 2 were prepared
from the corresponding o-sulfanylanilines 1 under the
transition-metal-free conditions (Figures 3A and 3B). For
example, N-arylphenothiazines 2b−d were prepared efficiently
from methyl-, chloro-, and methylthio-substituted o-sulfanyla-
nilines. The N- and S-arylation sequence proceeded smoothly
when using o-sulfanylanilines having not only tolyl but also
electron-rich 4- or 2-methoxyphenyl or electron-deficient 4-
chloro- or 4-amidophenyl group to afford N-arylphenothia-
zines 2e−h without damaging these functional groups. Also, N-
arylphenothiazines 2i and 2j were efficiently synthesized
through migratory benzofurylation and naphthylation, respec-
tively, followed by the construction of the phenothiazine
skeleton. The synthesis of phenothiazines 2k−m was realized
via N-tolylation and subsequent S-arylation without affecting
the electron-donating methyl and methoxy groups on the 2-
bromoaryl group. In particular, the smooth phenothiazine ring
formation from N-(2-bromo-3-methylphenyl)-2-(4-tolylthio)-
aniline (1k) clearly excluded aryne intermediates in the S-
arylation.12 Notably, we accomplished the efficient synthesis of
phenothiazine S-oxide 2n and dioxide 2o from o-sulfinyl- and
o-sulfonylanyline 1n and 1o, respectively, through N-tolylation
and following ring closures at the sulfur atom (Figure 3C).
To gain insight into the reaction mechanism, we conducted
several mechanistic studies (Figure 4). The initial migratory N-
arylation was clearly demonstrated by heating N-phenyl-o-
(phenylthio)aniline (1p) in the presence of potassium t-
butoxide (Figure 4A). Conducting the reaction of o-
Figure 3. Synthesis of N-arylphenothiazines 2 from o-sulfanylanilines
1. See the Supporting Information for the structures of 1. (A) General
scheme for the phenothiazine synthesis from 1. (B) Scope of N-
arylphenothiazines 2. Experiments were performed on 50 μmol scale.
(C) Reactions of S-oxidized o-sulfanylanilines 1n and 1o.
sulfanylaniline 1a in the presence of 2,2,6,6-tetramethylpiper-
idine 1-oxyl free radical (TEMPO) or 2,6-di-t-butyl-4-
hydroxytoluene (BHT) as a radical scavenger uneventfully
afforded N-arylphenothiazine 2a, which suggests that the
involvement of radical intermediates is ruled out (Figure
4B).13 In addition, no reaction occurred when N-(2-
bromophenyl)-N-methyl-2-(tolylthio)aniline (1q) was treated
with potassium t-butoxide (Figure 4C). On the basis of these
results, we postulated a reaction mechanism shown in Figure
4D. First, the deprotonation of o-sulfanylanilines 1 by
potassium t-butoxide proceeds. Then, Smiles rearrangement
of the resulting potassium amide I, involving a C−S bond
cleavage and migratory N-arylation, leads to thiolate
intermediate II.14 Third, the phenothiazine ring formation is
realized by dehalogenative intramolecular SNAr reaction of the
resulting highly nucleophilic thiolate intermediate II to furnish
2348
https://dx.doi.org/10.1021/acs.orglett.1c00515
Org. Lett. 2021, 23, 2347−2352

Organic Letters
pubs.acs.org/OrgLett
Letter
Figure 4. Mechanistic studies. (A) Reactions of halogen-unsub-
stituted-o-sulfanylaniline 1p. (B) Radical scavenger experiments. (C)
Reactions of N-methyl-o-sulfanylaniline 1q. (D) Plausible reaction
pathway.
N-arylphenothiazines 2.15 Since the activation by electron-
withdrawing group was not mandatory in the efficient N- and
S-arylation sequence, both Smiles rearrangement and cycliza-
tion would proceed in concerted SNAr reaction mechanisms.2
The utility of this N-arylphenothiazine synthesis was
showcased by the combination with thioamination of aryne
intermediates (Figure 5).16 Indeed, highly functionalized N-
arylphenothiazines 2r−w were successfully prepared from
aryne precursors 4 and S-aryl-S-(o-bromoaryl)sulfilimines 5
through o-sulfanylanilines 1r−w by the aryne reaction
triggered by potassium fluoride in the presence of 18-crown-
6 and subsequent N- and S-arylation sequence leaving
methoxy, morpholino, chloro, bromo, naphthalene, and
triphenylene moieties untouched (Figure 5A).16a It is worthy
to note that 2-bromophenyl group for the phenothiazine
skeleton was selectively migrated to the amino group to
provide 1r−w. In the facile synthesis of N-arylphenothiazines
2r−u having electron-donating methoxy- and morpholino- and
electron-withdrawing chloro and bromo groups, selective C−N
and C−S bond formations of aryne intermediates took place
without regioisomers due to the inductive substituents of the
aryne rings. Ring-fused N-arylphenothiazines 2v and 2w were
also synthesized through 2,3-naphthalyne and 2,3-didehydro-
triphenylene. Furthermore, a one-pot synthesis of N-
arylphenothiazine 2r was accomplished from 3-methoxyben-
zyne precursor 4a, and S-(2-bromophenyl)-S-(4-tolyl)-
sulfilimine (5a) in THF by the fluoride-triggered aryne
reaction followed by the addition of potassium t-butoxide
and DMA to the reaction mixture (Figure 5B). These results
clearly showed that the aryne reaction/N- and S-arylation
sequence allowed us to synthesize diverse functionalized N-
arylphenothiazines involving π-extended skeletons by virtue of
the good availability of aryne precursors.
Figure 5. Synthesis of N-arylphenothiazines 2 through the direct
thioamination of aryne. (A) Scope of various o-sulfanylanilines 1 and
N-arylphenothiazines 2 via aryne intermediates. Experiments were
performed on 50 μmol scale. (B) One-pot synthesis of N-
arylphenothiazine 2r from o-silylaryl triflate 4a and sulfilimine 5a.
We achieved a modular synthesis of multisubstituted N-
arylphenothiazine 10 from o-silylaryl triflate 4b, thiosulfonate
7, and arylboronic acids 6, 8a, and 8b (Figure 6). First, o-
sulfanylanilines 1x was prepared by the reaction between 3-
chlorobenzyne precursor 4b with N-H diarylsulfilimine 5b
prepared through copper-catalyzed deborylthiolation of 6 with
thiosulfonate 7.17 Second, the N- and S-arylation sequence
using o-sulfanylanilines 1x proceeded smoothly to provide 2x
in good yield keeping bromo and chloro groups intact. Third,
consecutive Suzuki−Miyaura cross-couplings of N-arylpheno-
thiazine 2x with arylboronic acids 8a and 8b catalyzed by
palladium complexes to provide highly arylated phenothiazine
10. Since halogeno groups tolerated in the transition-metal-free
N-arylphenothiazine synthesis by the aryne reaction/N- and S-
arylation sequence, this modular synthetic route will realize the
preparation of diverse multisubstituted N-arylphenothiazines
2349
https://dx.doi.org/10.1021/acs.orglett.1c00515
Org. Lett. 2021, 23, 2347−2352

Organic Letters
pubs.acs.org/OrgLett
Letter
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c00515
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors thank Dr. Yuki Sakata at Tokyo Medical and
Dental University for HRMS analyses. This work was
supported by JSPS KAKENHI Grant Numbers JP19K05451
(C; S.Y.) and 19J14128 (JSPS Research Fellow; T.M.); the
Naito Foundation (S.Y.); the Japan Agency for Medical
Research and Development (AMED) under Grant Number
JP20am0101098 (Platform Project for Supporting Drug
Discovery and Life Science Research, BINDS); and the
Cooperative Research Project of Research Center for
Biomedical Engineering.
REFERENCES
■
(1) (a) Bunnett, J. F.; Zahler, R. E. Aromatic Nucleophilic
Substitution Reactions. Chem. Rev. 1951, 49, 273. (b) Terrier, F.
Modern Nucleophilic Aromatic Substitution; Wiley-VCH: Weinheim,
2013.
Figure 6. Modular synthesis of multisubstituted phenothiazine 10.
(2) (a) Neumann, C. N.; Hooker, J. M.; Ritter, T. Concerted
nucleophilic aromatic substitution with 19F− and 18F−. Nature 2016,
534, 369. (b) Neumann, C. N.; Ritter, T. Facile C−F Bond Formation
through a Concerted Nucleophilic Aromatic Substitution Mediated by
the PhenoFluor Reagent. Acc. Chem. Res. 2017, 50, 2822. (c) Kaga, A.;
Hayashi, H.; Hakamata, H.; Oi, M.; Uchiyama, M.; Takita, R.; Chiba,
S. Nucleophilic Amination of Methoxy Arenes Promoted by a Sodium
Hydride/Iodide Composite. Angew. Chem., Int. Ed. 2017, 56, 11807.
(d) Kwan, E. E.; Zeng, Y.; Besser, H. A.; Jacobsen, E. N. Concerted
nucleophilic aromatic substitutions. Nat. Chem. 2018, 10, 917.
(e) Lennox, A. J. J. Meisenheimer Complexes in SNAr Reactions:
Intermediates or Transition States? Angew. Chem., Int. Ed. 2018, 57,
14686. (f) Masuya, Y.; Kawashima, Y.; Kodama, T.; Chatani, N.;
Tobisu, M. Thiolate-Initiated Synthesis of Dibenzothiophenes from
2,2’-Bis(methylthio)-1,1’-Biaryl Derivatives through Cleavage of Two
Carbon-Sulfur Bonds. Synlett 2019, 30, 1995. (g) Rohrbach, S.; Smith,
A. J.; Pang, J. H.; Poole, D. L.; Tuttle, T.; Chiba, S.; Murphy, J. A.
Concerted Nucleophilic Aromatic Substitution Reactions. Angew.
Chem., Int. Ed. 2019, 58, 16368.
(3) (a) Zhao, Y.; Wu, Y.; Jia, J.; Zhang, D.; Ma, C. One-Pot
Synthesis of Benzo[1,4]thiazin-3(4H)-ones and a Theoretical Study
of the S−N Type Smiles Rearrangement Mechanism. J. Org. Chem.
2012, 77, 8501. (b) Zhao, Y.; Dai, Q.; Chen, Z.; Zhang, Q.; Bai, Y.;
Ma, C. Global Analysis of Peptide Cyclization Efficiency. ACS Comb.
Sci. 2013, 15, 130. (c) Yang, B.; Tan, X.; Guo, R.; Chen, S.; Zhang, Z.;
Chu, X.; Xie, C.; Zhang, D.; Ma, C. Transition Metal-Free One-Pot
Synthesis of Fused 1,4-Thiazepin-5(4H)-ones and Theoretical Study
of the S−N Type Smiles Rearrangement Process. J. Org. Chem. 2014,
79, 8040. (d) Starosotnikov, A. M.; Nikol’skiy, V. V.; Bastrakov, M.
A.; Kachala, V. V.; Pavlov, A. A.; Ugrak, B. I.; Shevelev, S. A. Synthesis
of Pyrido[2, 3-a]phenoxazines and Pyrido[2, 3-a]phenothiazines via
Successive SNAr Processes. ChemistrySelect 2018, 3, 1230.
from easily available modules such as various o-silylaryl
triflates, thiosulfonates, and arylboronic acids.
In summary, we have developed a novel method to prepare
N-arylphenothiazine derivatives from o-sulfanylanilines via an
N- and S-arylation sequence by virtue of easily introducible
arylthio groups as a masked thiolate and an aryl donor
moiety.18 The synthetic utility of this method was clearly
shown by the N-arylphenothiazine synthesis on the basis of the
direct thioamination of arynes with N-H diarylsulfilimines and
the consecutive cross-coupling approach. Further studies are
underway to clarify the detailed reaction mechanism by
theoretical calculations and synthesize multisubstituted and
highly π-extended compounds.
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c00515.
Experimental procedures, characterization for new
compounds, including NMR spectra (PDF)
AUTHOR INFORMATION
Corresponding Author
■
Suguru Yoshida − Laboratory of Chemical Bioscience,
Institute of Biomaterials and Bioengineering, Tokyo Medical
and Dental University (TMDU), Tokyo 101-0062, Japan;
orcid.org/0000-0001-5888-9330; Email: s-yoshida.cb@
tmd.ac.jp
(4) (a) Zong, C.; Liu, J.; Chen, S.; Zeng, R.; Zou, J. Efficient C−S
Cross-Coupling of Thiols with Aryl Iodides Catalyzed by Cu(OAc)2·
H2O and 2,2’-Biimidazole. Chin. J. Chem. 2014, 32, 212. (b) Yang, D.;
Yan, K.; Wei, W.; Zhao, J.; Zhang, M.; Sheng, X.; Li, G.; Lu, S.; Wang,
H. Metal-Free Iodine-Catalyzed Direct Arylthiation of Substituted
Anilines with Thiols. J. Org. Chem. 2015, 80, 6083. (c) Xiao, F.; Chen,
S.; Li, C.; Huang, H.; Deng, G.-J. Copper-Catalyzed Three-
Component One-Pot Synthesis of Aryl Sulfides with Sulfur Powder
under Aqueous Conditions. Adv. Synth. Catal. 2016, 358, 3881.
(d) Liu, B.; Lim, C.-H.; Miyake, G. M. Visible-Light-Promoted C−S
Cross-Coupling via Intermolecular Charge Transfer. J. Am. Chem. Soc.
2017, 139, 13616. (e) Liu, C.; Szostak, M. Decarbonylative
Authors
Tsubasa Matsuzawa − Laboratory of Chemical Bioscience,
Institute of Biomaterials and Bioengineering, Tokyo Medical
and Dental University (TMDU), Tokyo 101-0062, Japan
Takamitsu Hosoya − Laboratory of Chemical Bioscience,
Institute of Biomaterials and Bioengineering, Tokyo Medical
and Dental University (TMDU), Tokyo 101-0062, Japan;
orcid.org/0000-0002-7270-351X
2350
https://dx.doi.org/10.1021/acs.orglett.1c00515
Org. Lett. 2021, 23, 2347−2352

Organic Letters
pubs.acs.org/OrgLett
Letter
thioetherification by nickel catalysis using air- and moisture-stable
nickel precatalyst. Chem. Commun. 2018, 54, 2130. (f) Zhao, F.; Tan,
Q.; Wang, D.; Deng, G.-J. Metal- and solvent-free direct C−H
thiolation of aromatic compounds with sulfonyl chlorides. Green
Chem. 2020, 22, 427.
phenothiazine and carbazole adducts. Dyes Pigm. 2008, 79, 40.
(b) Seo, Y.-H.; Lee, W.-H.; Park, J.-H.; Bae, C.; Hong, Y.; Park, J.-W.;
Kang, I.-N. Side-chain effects on phenothiazine-based donor-acceptor
copolymer properties in organic photovoltaic devices. J. Polym. Sci.,
Part A: Polym. Chem. 2012, 50, 649. (c) Sharghi, H.; Sepehri, S.;
Aberi, M. Cu(II) complex of pyridine-based polydentate as a novel,
efficient, and highly reusable catalyst in C−N bond-forming reaction.
Mol. Diversity 2017, 21, 855. (d) Choy, P. Y.; Chung, K. H.; Yang, Q.;
So, C. M.; Sun, R. W.-Y.; Kwong, F. Y. A General Palladium−
Phosphine Complex To Explore Aryl Tosylates in the N-Arylation of
Amines: Scope and Limitations. Chem. - Asian J. 2018, 13, 2465.
(e) Chen, Z.; Chen, X.; So, C. M. Palladium-Catalyzed C(sp2)-N
Bond Cross-Coupling with Triaryl Phosphates. J. Org. Chem. 2019,
84, 6366.
(8) Dahl, T.; Tornøe, C.; Bang-Andersen, B.; Nielsen, P.; Jørgensen,
M. Palladium-Catalyzed Three-Component Approach to Promazine
with Formation of One Carbon-Sulfur and Two Carbon-Nitrogen
Bonds. Angew. Chem., Int. Ed. 2008, 47, 1726.
(9) Chen, J.; Li, G.; Xie, Y.; Liao, Y.; Xiao, F.; Deng, G.-J. Four-
Component Approach to N-Substituted Phenothiazines under
Transition-Metal-Free Conditions. Org. Lett. 2015, 17, 5870.
(10) (a) Bordwell, F. G.; Hughes, D. L. Nucleophilic Aromatic
Substitution Reactions with Carbanions and Nitranions in Dimethyl
Sulfoxide Solution. J. Am. Chem. Soc. 1986, 108, 5991. (b) Lamanna,
G.; Faggi, C.; Gasparrini, F.; Ciogli, A.; Villani, C.; Stephens, P. J.;
Devlin, F. J.; Menichetti, S. Efficient Thia-Bridged Triarylamine
Heterohelicenes: Synthesis, Resolution, and Absolute Configuration
Determination. Chem. - Eur. J. 2008, 14, 5747. (c) Zhang, X.-F.;
Zheng, H. Tetra(β-phenothiazinyl) zinc phthalocyanine: An easily
prepared D4−A system for efficient photoinduced electron transfer.
Inorg. Chim. Acta 2010, 363, 2259. (d) Chen, C.; Liao, J.-Y.; Chi, Z.;
Xu, B.; Zhang, X.; Kuang, D.-B.; Zhang, Y.; Liu, S.; Xu, J. Metal-free
organic dyes derived from triphenylethylene for dye-sensitized solar
cells: tuning of the performance by phenothiazine and carbazole. J.
Mater. Chem. 2012, 22, 8994. (e) Louillat-Habermeyer, M.-L.; Jin, R.;
Patureau, F. W. O2-mediated dehydrogenative amination of phenols.
Angew. Chem., Int. Ed. 2015, 54, 4102. (f) Jin, R.; Patureau, F. W.
Mild, Periodate-Mediated, Dehydrogenative C−N Bond Formation
with Phenothiazines and Phenols. Org. Lett. 2016, 18, 4491. (g) Zhao,
Y.; Huang, B.; Yang, C.; Xia, W. Visible-Light-Promoted Direct
Amination of Phenols via Oxidative Cross-Dehydrogenative Coupling
Reaction. Org. Lett. 2016, 18, 3326. (h) Zhang, L.; Huang, X.; Zhen,
S.; Zhao, J.; Li, H.; Yuan, B.; Yang, G. Pd-Catalyzed double N-
arylation of primary amines to synthesize phenoxazines and
phenothiazines. Org. Biomol. Chem. 2017, 15, 6306. (i) Tang, S.;
Wang, S.; Liu, Y.; Cong, H.; Lei, A. Electrochemical Oxidative C−H
Amination of Phenols: Access to Triarylamine Derivatives. Angew.
Chem., Int. Ed. 2018, 57, 4737. (j) Tian, Z.-Y.; Ming, X.-X.; Teng, H.-
B.; Hu, Y.-T.; Zhang, C.-P. Transition-Metal-Free N-Arylation of
Amines by Triarylsulfonium Triflates. Chem. - Eur. J. 2018, 24, 13744.
(k) Bering, L.; D’Ottavio, L.; Sirvinskaite, G.; Antonchick, A. P.
Nitrosonium ion catalysis: aerobic, metal-free cross-dehydrogenative
carbon−heteroatom bond formation. Chem. Commun. 2018, 54,
13022. (l) Jin, R.; Bub, C. L.; Patureau, F. W. Phenothiazinimides:
Atom-Efficient Electrophilic Amination Reagents. Org. Lett. 2018, 20,
2884. (m) Liu, K.; Tang, S.; Wu, T.; Wang, S.; Zou, M.; Cong, H.;
Lei, A. Electrooxidative para-selective C−H/N−H cross-coupling
with hydrogen evolution to synthesize triarylamine derivatives. Nat.
Commun. 2019, 10, 639. (n) Vemuri, P. Y.; Wang, Y.; Patureau, F. W.
Para-Selective Dehydrogenative Phenothiazination of Hydroquino-
lines and Indolines. Org. Lett. 2019, 21, 9856. (o) Wu, Y.-C.; Jiang, S.-
S.; Song, R.-J.; Li, J.-H. A metal- and oxidizing-reagent-free anodic
para-selective amination of anilines with phenothiazines. Chem.
Commun. 2019, 55, 4371. (p) Kumar, M.; Sharma, R.; Raziullah;
Khan, A. A.; Ahmad, A.; Dutta, H. S.; Koley, D. Cu(II)-Catalyzed
Ortho C(sp2)−H Diarylamination of Arylamines To Synthesize
Triarylamines. Org. Lett. 2020, 22, 2152. (q) Chen, Q.; Xie, R.; Jia,
H.; Sun, J.; Lu, G.; Jiang, H.; Zhang, M. Access to Phenothiazine
(5) (a) Lai, R.; Kong, X.; Jenekhe, S.; Bard, A. Synthesis, Cyclic
Voltammetric Studies, and Electrogenerated Chemiluminescence of a
New Phenylquinoline-Biphenothiazine Donor−Acceptor Molecule. J.
Am. Chem. Soc. 2003, 125, 12631. (b) Weiss, E.; Tauber, M.; Kelley,
R.; Ahrens, M.; Ratner, M.; Wasielewski, M. Conformationally Gated
Switching between Superexchange and Hopping within Oligo-p-
phenylene-Based Molecular Wires. J. Am. Chem. Soc. 2005, 127,
11842. (c) Pluta, K.; Morak-Mlodawska, B.; Jelen, M. Recent progress
in biological activities of synthesized phenothiazines. Eur. J. Med.
́
Chem. 2011, 46, 3179. (d) Jaszczyszyn, A.; Gąsiorowski, K.; Swiątek,
́
P.; Malinka, W.; Cieslik-Boczula, K.; Petrus, J.; Czarnik-Matusewicz,
B. Chemical structure of phenothiazines and their biological activity.
Pharmacol. Rep. 2012, 64, 16. (e) Zhao, W.; Liu, X.; Lv, H.; Fu, H.;
Yang, Y.; Huang, Z.; Han, A. A phenothiazine−rhodamine ratiometric
fluorescent probe for Hg2+ based on FRET and ICT. Tetrahedron Lett.
2015, 56, 4293. (f) Hsieh, T.-S.; Wu, J.-Y.; Chang, C.-C. Multiple
fluorescent behaviors of phenothiazine-based organic molecules. Dyes
Pigm. 2015, 112, 34. (g) Dai, X.; Feng, H.; Huang, Z.; Wang, M.;
Wang, L.; Kuang, D.; Meier, H.; Cao, D. Synthesis of phenothiazine-
based di-anchoring dyes containing fluorene linker and their
photovoltaic performance. Dyes Pigm. 2015, 114, 47. (h) Dao, P.;
Ye, F.; Liu, Y.; Du, Z. Y.; Zhang, K.; Dong, C. Z.; Meunier, B.; Chen,
H. Development of Phenothiazine-Based Theranostic Compounds
That Act Both as Inhibitors of β-Amyloid Aggregation and as Imaging
Probes for Amyloid Plaques in Alzheimer’s Disease. ACS Chem.
Neurosci. 2017, 8, 798. (i) Krishna, N. V.; Krishna, J. V. S.; Singh, S.
P.; Giribabu, L.; Han, L.; Bedja, I.; Gupta, R. K.; Islam, A. Donor-π−
Acceptor Based Stable Porphyrin Sensitizers for Dye-Sensitized Solar
Cells: Effect of π-Conjugated Spacers. J. Phys. Chem. C 2017, 121,
6464.
(6) (a) Treat, N. J.; Sprafke, H.; Kramer, J. W.; Clark, P. G.; Barton,
B. E.; de Alaniz, J. R.; Fors, B. P.; Hawker, C. J. Metal-Free Atom
Transfer Radical Polymerization. J. Am. Chem. Soc. 2014, 136, 16096.
(b) Tanaka, H.; Shizu, K.; Nakanotani, H.; Adachi, C. Dual
Intramolecular Charge-Transfer Fluorescence Derived from a
Phenothiazine-Triphenyltriazine Derivative. J. Phys. Chem. C 2014,
118, 15985. (c) Discekici, E. H.; Treat, N. J.; Poelma, S. O.; Mattson,
K. M.; Hudson, Z. M.; Luo, Y.; Hawker, C. J.; de Alaniz, J. R. A highly
reducing metal-free photoredox catalyst: design and application in
radical dehalogenations. Chem. Commun. 2015, 51, 11705. (d) Shinde,
D. B.; Salunke, J. K.; Candeias, N. R.; Tinti, F.; Gazzano, M.;
Wadgaonkar, P. P.; Priimagi, A.; Camaioni, N.; Vivo, P. Crystal-
lisation-enhanced bulk hole mobility in phenothiazine-based organic
semiconductors. Sci. Rep. 2017, 7, 46268. (e) Wang, H.; Jui, N. T.
Catalytic Defluoroalkylation of Trifluoromethylaromatics with Un-
activated Alkenes. J. Am. Chem. Soc. 2018, 140, 163. (f) Liao, X.;
Zhang, H.; Huang, J.; Wu, G.; Yin, X.; Hong, Y. (D-π-A)3-Type
metal-free organic dye for dye-sensitized solar cells application. Dyes
Pigm. 2018, 158, 240. (g) He, Z.; Song, F.; Sun, H.; Huang, Y.
Transition-Metal-Free Suzuki-Type Cross-Coupling Reaction of
Benzyl Halides and Boronic Acids via 1,2-Metalate Shift. J. Am.
Chem. Soc. 2018, 140, 2693. (h) Corbin, D. A.; Lim, C.-H.; Miyake,
G. M. Aldrichimica Acta 2019, 52, 7. (i) Garrido-Castro, A. F.;
Salaverri, N.; Maestro, M. C.; Alemán, J. Photoinduced Transition-
Metal-Free Cross-Coupling of Aryl Halides with H-Phosphonates.
Org. Lett. 2019, 21, 5295. (j) Shibutani, S.; Kodo, T.; Takeda, M.;
Nagao, K.; Tokunaga, N.; Sasaki, Y.; Ohmiya, H. Organophotoredox-
Catalyzed Decarboxylative C(sp3)−O Bond Formation. J. Am. Chem.
̌
̌
Soc. 2020, 142, 1211. (k) Aukland, M. H.; Siauciulis, M.; West, A.;
Perry, G. J. P.; Procter, D. J. Metal-free photoredox-catalysed formal
C−H/C−H coupling of arenes enabled by interrupted Pummerer
activation. Nat. Catal. 2020, 3, 163.
(7) (a) Simokaitiene, J.; Grazulevicius, J. V.; Jankauskas, V.;
Rutkaite, R.; Sidaravicius, J. Synthesis and properties of glass-forming
2351
https://dx.doi.org/10.1021/acs.orglett.1c00515
Org. Lett. 2021, 23, 2347−2352

Organic Letters
pubs.acs.org/OrgLett
Letter
Derivatives via Iodide-Mediated Oxidative Three-Component Annu-
lation Reaction. J. Org. Chem. 2020, 85, 5629.
(11) See the Supporting Information for details.
to Aminoarenes: Synthesis of 3-Aminoaryne Precursors via
Regioselective Silylamination of 3-(Triflyloxy)arynes. Org. Lett.
2016, 18, 6212. (c) Yoshida, S.; Nakajima, H.; Uchida, K.; Yano,
T.; Kondo, M.; Matsushita, T.; Hosoya, T. Reactions of Arynes with
Sulfoximines: Formal Sulfinylamination vs. N-Arylation. Chem. Lett.
2017, 46, 77. (d) Matsuzawa, T.; Uchida, K.; Yoshida, S.; Hosoya, T.
Synthesis of Diverse Phenothiazines by Direct Thioamination of
Arynes with S-(o-Bromoaryl)-S-methylsulfilimines and Subsequent
Intramolecular Buchwald−Hartwig Amination. Chem. Lett. 2018, 47,
825. (e) Yoshida, S.; Kuribara, T.; Morita, T.; Matsuzawa, T.;
Morimoto, K.; Kobayashi, T.; Hosoya, T. Expanding the synthesizable
multisubstituted benzo[b]thiophenes via 6,7-thienobenzynes gener-
ated from o-silylaryl triflate-type precursors. RCS Adv. 2018, 8, 21754.
(f) Nakamura, Y.; Miyata, Y.; Uchida, K.; Yoshida, S.; Hosoya, T. 3-
Thioaryne Intermediates for the Synthesis of Diverse Thioarenes. Org.
Lett. 2019, 21, 5252. (g) Uchida, K.; Minami, Y.; Yoshida, S.; Hosoya,
T. Synthesis of Diverse γ-Aryl-β-ketoesters via Aryne Intermediates
Generated by C−C Bond Cleavage. Org. Lett. 2019, 21, 9019.
(h) Kobayashi, T.; Hosoya, T.; Yoshida, S. Consecutive Aryne
Generation Strategy for the Synthesis of 1,3-Diarylpyrazoles. J. Org.
Chem. 2020, 85, 4448.
(17) (a) Yoshida, S.; Sugimura, Y.; Hazama, Y.; Nishiyama, Y.; Yano,
T.; Shimizu, S.; Hosoya, T. A mild and facile synthesis of aryl and
alkenyl sulfides via copper-catalyzed deborylthiolation of organo-
borons with thiosulfonates. Chem. Commun. 2015, 51, 16613.
(b) Kanemoto, K.; Sugimura, Y.; Shimizu, S.; Yoshida, S.; Hosoya,
T. Rhodium-catalyzed odorless synthesis of diaryl sulfides from
borylarenes and S-aryl thiosulfonates. Chem. Commun. 2017, 53,
10640. (c) Kanemoto, K.; Yoshida, S.; Hosoya, T. Modified
Conditions for Copper-catalyzed ipso-Thiolation of Arylboronic
Acid Esters with Thiosulfonates. Chem. Lett. 2018, 47, 85.
(12) (a) Kessar, S. V. A Novel Route to Condensed Polynuclear
Systems; Reality and Illusion of Benzyne Intermediacy. Acc. Chem.
Res. 1978, 11, 283. (b) Noji, T.; Fujiwara, H.; Okano, K.; Tokuyama,
H. Synthesis of Substituted Indoline and Carbazole by Benzyne-
Mediated Cyclization−Functionalization. Org. Lett. 2013, 15, 1946.
(13) (a) Roman, D. S.; Takahashi, Y.; Charette, A. B. Potassium tert-
Butoxide Promoted Intramolecular Arylation via a Radical Pathway.
Org. Lett. 2011, 13, 3242. (b) Mehta, V. P.; Punji, B. Recent advances
in transition-metal-free direct C−C and C−heteroatom bond forming
reactions. RSC Adv. 2013, 3, 11957. (c) Liu, W.; Hou, F. Transition-
metal-free dehalogenation of aryl halides promoted by phenanthro-
line/potassium tert-butoxide. Tetrahedron 2017, 73, 931.
(14) (a) Levy, A.; Rains, H. C.; Smiles, S. CCCCLII.−The
rearrangement of hydroxy-sulphones. Part I. J. Chem. Soc. 1931, 0,
3264. (b) Mizuno, M.; Yamano, M. A New Practical One-Pot
Conversion of Phenols to Anilines. Org. Lett. 2005, 7, 3629.
(c) Plesniak, K.; Zarecki, A.; Wicha, J. The Smiles Rearrangement
and the Julia-Kocienski Olefination Reaction. Top. Curr. Chem. 2006,
275, 163. (d) Snape, T. J. A truce on the Smiles rearrangement:
revisiting an old reaction−the Truce−Smiles rearrangement. Chem.
Soc. Rev. 2008, 37, 2452. (e) Liu, S.; Zhu, S.; Wu, Y.; Gao, J.; Qian, P.;
Hu, Y.; Shi, L.; Chen, S.; Zhang, S.; Zhang, Y. One-Pot Synthesis of
N-Aryl-Nicotinamides and Diarylamines Based on a Tunable Smiles
Rearrangement. Eur. J. Org. Chem. 2015, 2015, 3048. (f) Holden, C.
M.; Greaney, M. F. Modern Aspects of the Smiles Rearrangement.
Chem. - Eur. J. 2017, 23, 8992. (g) Costil, R.; Dale, H. J. A.; Fey, N.;
Whitcombe, G.; Matlock, J. V.; Clayden, J. Heavily Substituted
Atropisomeric Diarylamines by Unactivated Smiles Rearrangement of
N-Aryl Anthranilamides. Angew. Chem., Int. Ed. 2017, 56, 12533.
(15) (a) Bose, D. S.; Idrees, M. Intramolecular Cascade C-S Bond
Formation: Regioselective Synthesis of Substituted Benzothiazoles.
Synthesis 2010, 12, 1983. (b) Wang, F.; Cai, S.; Wang, Z.; Xi, C.
Synthesis of 2-Mercaptobenzothiazoles via DBU-Promoted Tandem
Reaction of o-Haloanilines and Carbon Disulfide. Org. Lett. 2011, 13,
3202. (c) Zhao, J.; Zhao, Y.; Fu, H. Transition-Metal-Free
Intramolecular Ullmann-Type O-Arylation: Synthesis of Chromone
Derivatives. Angew. Chem., Int. Ed. 2011, 50, 3769. (d) Rodriguez-
Aristegui, S.; Clapham, K. M.; Barrett, L.; Cano, C.; Murr, M. D.-E.;
Griffin, R. J.; Hardcastle, I. R.; Payne, S. L.; Rennison, T.; Richardson,
C.; Golding, B. T. Versatile synthesis of functionalised dibenzothio-
phenes via Suzuki coupling and microwave-assisted ring closure. Org.
Biomol. Chem. 2011, 9, 6066. (e) Thomé, I.; Bolm, C. Transition-
Metal-Free Intramolecular N-Arylations. Org. Lett. 2012, 14, 1892.
(f) Majumdar, K. C.; Ganai, S.; Nandi, R. K.; Ray, K. Catalyst-free
synthesis of coumarin-, quinolone- and pyridine-annulated oxazole
derivatives. Tetrahedron Lett. 2012, 53, 1553. (g) Choi, Y. L.; Lim, H.
S.; Lim, H. J.; Heo, J.-N. One-Pot Transition-Metal-Free Synthesis of
Dibenzo[b,f ]oxepins from 2-Halobenzaldehydes. Org. Lett. 2012, 14,
5102. (h) Tu, X.; Zhou, L.; Li, Z.; Lei, N.; Zeng, Q. Transition-metal-
free synthesis of imidazobenzothiazines via domino C-S/C-N bond
formation. Monatsh. Chem. 2014, 145, 1925. (i) Vijay, T. A. J.;
Sandhya, N. C.; Pavankumar, C. S.; Rangappa, K. S.; Mantelingu, K.
Ligand- and catalyst-free intramolecular C-S bond formation: direct
access to indalothiochromen- 4-ones. Heterocycl. Commun. 2015, 21,
159. (j) Ouyang, L.; Qi, C.; He, H.; Peng, Y.; Xiong, W.; Ren, Y.;
Jiang, H. Base-Promoted Formal [4 + 3] Annulation between 2-
Fluorophenylacetylenes and Ketones: A Route to Benzoxepines. J.
Org. Chem. 2016, 81, 912. (k) Mao, J.; Wang, Z.; Xu, X.; Liu, G.;
Jiang, R.; Guan, H.; Zheng, Z.; Walsh, P. J. Synthesis of Indoles
through Domino Reactions of 2-Fluorotoluenes and Nitriles. Angew.
Chem., Int. Ed. 2019, 58, 11033.
(18) Among three aromatic rings of o-sulfanylanilines 1, substituents
on the aromatic rings for migratory N-arylation significantly affected
the efficiency of the N-arylphenothiazine synthesis.
(16) (a) Yoshida, S.; Yano, T.; Misawa, Y.; Sugimura, Y.; Igawa, K.;
Shimizu, S.; Tomooka, K.; Hosoya, T. Direct Thioamination of
Arynes via Reaction with Sulfilimines and Migratory N-Arylation. J.
Am. Chem. Soc. 2015, 137, 14071. (b) Yoshida, S.; Nakamura, Y.;
Uchida, K.; Hazama, Y.; Hosoya, T. Aryne Relay Chemistry en Route
2352
https://dx.doi.org/10.1021/acs.orglett.1c00515
Org. Lett. 2021, 23, 2347−2352