Phenothiazinimides: Atom-Efficient Electrophilic Amination Reagents

Article abstract of DOI:10.1021/acs.orglett.8b00914

Phenothiazinimides, a fairly unknown class of imines, were prepared and found to be very reactive as ultrasimple atom-efficient electrophilic amination reagents for phenols and indoles under metal-free conditions.

Full text of DOI:10.1021/acs.orglett.8b00914

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Phenothiazinimides: Atom-Efficient Electrophilic Amination
Reagents
Rongwei Jin,‡ Christina L. Bub,‡ and Frederic W. Patureau*
Fachbereich Chemie, Technische Universitat Kaiserslautern, Erwin-Schrodinger Strasse Geb. 52, 67663 Kaiserslautern, Germany
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* Supporting Information
ABSTRACT: Phenothiazinimides, a fairly unknown class of imines, were prepared and found to be very reactive as ultrasimple
atom-efficient electrophilic amination reagents for phenols and indoles under metal-free conditions.
“Linkages of the type C−X−C are much easier to make than
direct C−C linkages. So why not focus on them?”1
Scheme 1. Sulfimides and Phenothiazinimides
Chloramines are arguably underappreciated as convenient and
relatively sustainable nitrene sources (NaCl as sole byproduct),
in particular, for metal-free synthetic methods. The action of
chloramine T and related trivial chloramines on thioethers has
been known to deliver sulfimides since the pioneering work of
Nicolet and Willard in 1921.2 Their protocol is very general
sulfur is quite sensitive to nitrene oxidationand is still utilized
nowadays to prepare sulfimides in a single step.3 In 1977, Shah
utilized this method to prepare what he thought to be sulfimide−
phenothiazines.4 Shah’s claim lies solely on an IR band at 920
cm−1, which he attributes to the sulfimide SN double bond. In
1979, however, Gontar claimed that Shah’s structure could not
be correct because of the absence of NH band in the IR
spectrum.5 Gontar proposed, instead, a carbon-based pheno-
thiazinimide interpretation (Scheme 1). In any case, these
compounds are generally very insoluble, and the broadness of the
NMR lines forbids a decisive interpretation as to the one
structure or the other, or possibly a mixture thereof. In this paper,
the reactivity of phenothiazinimides is described for the first time
and thus lifts this structural ambiguity, surprisingly, in favor of
Gontar’s interpretation (Schemes 1−4).
In the frame of our research interests for the development of
ultrasimple direct C−H amination methods,6 we decided to
investigate the unexplored reactivity of those phenothiazini-
mides, in particular, as electrophilic amination reagents.7 In this
context, the intermolecular direct amination of C−H bonds
remains a considerable challenge. Indeed, the vast majority of
intermolecular C−N bond-forming coupling reactions still
operate via prior preactivation of the substrates and usually
through precious metal catalysis (Ullmann condensation,
Buchwald−Hartwig amination).8 To this end, we first prepared
a series of phenothiazinimides according to Shah’s protocol
(Scheme 2). As expected, in the case of unsymmetrical
phenothiazines (PTZs), the imide is formed preferentially on
the more electron-rich side. In most cases, the regioselectivity is
excellent (Scheme 2).
We then devised an intrinsically sustainable, ultrasimple,
metal-free, atom-efficient condensation method with phenol-
coupling partners. The phenothiazinimide (1 mmol) is typically
placed in a 180 mL reactor with 3 mmol of phenol-coupling
Received: March 20, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b00914
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
a
Scheme 2. Phenothiazinimides Synthesis, All Compounds Are
Isolated by Precipitation as Deep Purple Poorly Soluble
Substances
Scheme 3. Phenol Substrate Scope
a
Ratios of [6]/[6′] and [7]/[7′] were determined a posteriori from
the more soluble coupling products [29]/[29′] and [30]/[30′].
partner. Cumene (2.5 mL) and acetic acid (0.5 mL) are then
added, the reactor is flushed with O2, and the reaction is then
stirred at 110 °C for 16 h. During the first hours of the reaction,
the deep purple suspension typically and progressively turns to a
clear light blue or light pink solution.
A new coupling product is thereby obtained that is fortunately
more soluble and that we solved by a combination of COSY,
NOESY, and natural abundance 1H−15N HMBC NMR
characterization techniques (crystallization attempts have been
unsuccessful so far, Figure 1).9 Importantly, control experiments
a
b
c
d
Isolated yields. 0.5 mmol scale. 90 °C reaction temperature. Very
minor para isomer lost during purification; see also entry [27] for
ortho/para relative reactivity/selectivity.
typically obtained ([9], [11]). It should be noted that in the case
of competing ortho and para C−H positions very poor
regioselectivity is typically observed. For example, 3,5-
dimethylphenol affords the ortho-aminated product [27]
(64%) and the para-aminated product [27′] (34%) in a close
to statistical ratio. Strong steric repulsion, however, such as in 3-
tBu-phenol, afforded a single regioisomeric amination product
[28] in 67% yield. In order to explore the applicability of this new
electrophilic amination reagent, we then investigated other
nucleophilic substrate classes. Gratifyingly, it was found that
unprotected indoles are often competent substrates in this
reaction, affording typically C3-aminated coupling products in
moderate to good yields (Scheme 4). In general, C2-function-
alized indoles performed best (for example, [31], 90%).
Moreover, even unprotected sensitive indoles afforded the C3-
aminated coupling product in encouraging 45−52% yields ([36],
[37]). No coupling product occurred, however, with structurally
related benzofuran or benzothiophene. The reaction is thus
highly specific to phenols and indoles.
Figure 1. COSY, NOESY, and 1H−15N HMBC NMR structural
resolution of coupling product [8].9
showed that the O2 atmosphere is not necessarythe reaction is
formally redox neutralhowever, it affords higher yields of
product compared to inert N2 atmospheric conditions (see
mechanistic discussion).
We next explored the substrate scope of the reaction.
Gratifyingly, as long as phenols and phenothiazinimides are
involved, a good number of functional groups are tolerated
(methoxy, halide, ketone, nitrile, CF3, naphthol, and more, see
Scheme 3). We also verified that the N-tosyl group of the
phenothiazinimide could be replaced by an N-benzenesulfonyl
group. This is indeed the case, although lower yields are then
We then performed a number of essential mechanistic
experiments. We first prepared phenothiazone [38], a
B
DOI: 10.1021/acs.orglett.8b00914
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a,b
Scheme 4. Indole Substrate Scope
Scheme 5. Control/Mechanistic Experiments
a
b
c
Isolated yields. 0.5 mmol scale. 1 mmol scale.
compound found in the literature.10 The corresponding
condensation product [39] could not be detected. Indeed, no
conversion occurred at 110 °C. Increasing the reaction
temperature to 150 °C did not yield any expected product
either (eq 5, Scheme 5). In contrast, a second control experiment
starting with the parent S-oxide phenothiazine substrate [40],
also a well-known material,11 led to the formation of the known
C−N coupling product12 [41] in which the oxygen atom is not
retained (H2O as leaving group, internal oxidant concept,13 eq
6). Some further control experiments (eq 7) show that the
reaction also works under strict N2 atmosphere, albeit with lower
yields, thereby proving the internal oxidant character of
phenothiazinimides.9 Thus, in spite of the formal redox-neutral
character of this new C−N bond-forming reaction, utilizing a
mild oxidative atmosphere in combination with cumene is useful
for maintaining the phenothiazinimide in its oxidized electro-
philic active form. Indeed, the cumene/acetic acid/O2 (re)-
oxidizing system has been exemplified by us in a previous method
wherein the cumene and its oxidized forms (i.e., cumyl
hydroperoxide) may play an active role in radical oxidation
processes.12a Moreover, the acetic acid cosolvent may increase
the electrophilic character of the phenothiazinimide through H-
bonding and/or partial protonation. It should in addition be
noted that the reduced phenothiazinimide, i.e., [(1)H2], is
sometimes observed as an undesired byproduct when the oxygen
atmosphere is omitted and/or when the arene-coupling partner
is not sufficiently nucleophilic (i.e., very electron-poor/acidic
phenols).
Finally, a cross-over control experiment between substrates
[2] and [3], based on two different PTZ backbones and two
different chloramines, was attempted (eq 8). Out of the four
potential products, only the two noncrossed products [9] and
[22] were obtained. Thus, no imine crossover event occurs in
this reaction, which arguably constitutes another argument
against Shah’s structure and in favor of Gontar’s. Indeed, Shah’s
substrate would have involved a 1,4 nitrene sulfur-to-carbon
migration, a relatively long distance migration, which might
therefore have been susceptible to crossover scrambling. In order
to better understand and further confirm the Gontar
phenothiazinimide structural interpretation, we then envisioned
a different synthetic route. We started from Bernthsen’s PTZ,
known since 1885 and prepared by nitration of ordinary PTZ.14
Conversely, we were so far unsuccessful at utilizing Bernthsen’s
PTZ as an electrophilic coupling partner of any kind. Further
reduction with Fe0 in acetic acid affords the corresponding bis-
acetamidophenothiazine [42] (Scheme 6). The latter compound
is then oxidized with chloramine T to the corresponding
acetylated phenothiazinimide [43].9 It should be noted that, in
this case, the tosylonitrene moiety does not insert into the
substrate and functions solely as an external oxidant. Acetylated
phenothiazinimide [43] was found to be a competent electro-
philic amination reagent, albeit with moderate yield ([44], 38%
yield). Gratifyingly, conducting the reaction in a single step from
the bis-acetamidophenothiazine [42] in combination with a
strong oxidant such as NaIO4 (route B, Scheme 6)15 afforded
[44] in 70% yield.
In summary, we solved the 40-year-old disputed structural
assignment of phenothiazinimides and validated Gontar’s
proposal as the dominant species, in which the sulfur atom
remains surprisingly unoxidized.16 We moreover demonstrated
the strong electrophilic amination reactivity of those compounds
toward phenols and indoles. We expect these new electrophilic
amination reagents to impact first the field of phenothiazine
centered material synthesis.17 Moreover, we expect this method
to consolidate the intermolecular metal-free C−H oxidative
phenothiazination toolbox.6
C
DOI: 10.1021/acs.orglett.8b00914
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
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Scheme 6. Alternative Route to the Phenothiazinimide9
(3) Selected references: (a) Campbell, M. M.; Johnson, G. Chem. Rev.
1978, 78, 65. (b) Minakata, S. Acc. Chem. Res. 2009, 42, 1172.
(4) Shah, J. J. J. Tennessee Acad. Sci. 1977, 52, 19.
(5) Gontar, S. S.; Karpishchenko, L. S.; Kremlev, M. M.; Markov, V. I.
Russ. J. Org. Chem. 1978, 14, 2626.
(6) Selected reviews on oxidative C−H aminations: (a) Kim, H.;
Chang, S. ACS Catal. 2016, 6, 2341. (b) Jiao, J.; Murakami, K.; Itami, K.
ACS Catal. 2016, 6, 610. (c) Louillat, M.-L.; Patureau, F. W. Chem. Soc.
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Soc. Rev. 2011, 40, 5068. (e) Dick, A. R.; Sanford, M. S. Tetrahedron
2006, 62, 2439. See also electrochemical C−H aminations, for example:
(f) Waldvogel, S. R.; Mohle, S. Angew. Chem., Int. Ed. 2015, 54, 6398.
̈
(g) Morofuji, T.; Shimizu, A.; Yoshida, J.-I. J. Am. Chem. Soc. 2015, 137,
9816.
(7) For a recent illustration of imino-quinone derived N-electrophile,
see: Raju, S.; Annamalai, P.; Chen, P.-L.; Liu, Y.-H.; Chuang, S.-C. Org.
Lett. 2017, 19, 4134.
(8) (a) Surry, D. S.; Buchwald, S. L. Angew. Chem., Int. Ed. 2008, 47,
6338. (b) Hartwig, J. F. Acc. Chem. Res. 2008, 41, 1534 and references
cited therein.
(9) See the SI for details.
(10) Phenothiazone synthesis. See, for example: Barret, R.; Daudon,
M. Monatsh. Chem. 1991, 122, 323.
(11) Sulfoxide−phenothiazine synthesis. See, for example: Kano, H.;
Fujimoto, M. Pharm. Bull. 1957, 5, 389.
(12) (a) Louillat-Habermeyer, M.-L.; Jin, R.; Patureau, F. W. Angew.
Chem., Int. Ed. 2015, 54, 4102. (b) Zhao, Y.; Huang, B.; Yang, C.; Xia, W.
Org. Lett. 2016, 18, 3326.
(13) Internal oxidant concept. See, for example: Patureau, F. W.;
Glorius, F. Angew. Chem., Int. Ed. 2011, 50, 1977.
(14) Bernthsen, A. Annalen der Chemie 1885, 230, 73.
(15) Jin, R.; Patureau, F. W. Org. Lett. 2016, 18, 4491.
(16) However, when the nitrogen atom is protected, Shah’s proposed
structure remains valid (see the SI):
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.8b00914.
■
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Experimental procedures and characterization of new
compounds (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: patureau@chemie.uni-kl.de.
ORCID
(17) N-Functionalized PTZs are of crucial importance for material
sciences, notably as photocatalysts, as electroluminescent organic
semiconductors for OLED devices, or as hole-transporting compounds
for solar cells. Their efficient synthesis is thus of strategic importance.
See, for example: (a) Pan, X.; Lamson, M.; Yan, J.; Matyjaszewski, K.
ACS Macro Lett. 2015, 4, 192. (b) Pan, X.; Fang, C.; Fantin, M.;
Malhotra, N.; So, W. Y.; Peteanu, L. A.; Isse, A. A.; Gennaro, A.; Liu, P.;
Matyjaszewski, K. J. Am. Chem. Soc. 2016, 138, 2411. (c) Treat, N. J.;
Sprafke, H.; Kramer, J. W.; Clark, P. G.; Barton, B. E.; Read de Alaniz, J.;
Fors, B. P.; Hawker, C. J. J. Am. Chem. Soc. 2014, 136, 16096.
(d) Salunke, J. K.; Wong, F. L.; Feron, K.; Manzhos, S.; Lo, M. F.;
Shinde, D.; Patil, A.; Lee, C. S.; Roy, V. A. L.; Sonar, P.; Wadgaonkar, P.
P. J. Mater. Chem. C 2016, 4, 1009. (e) Kumar, S.; Singh, M.; Jou, J.-H.;
Ghosh, S. J. Mater. Chem. C 2016, 4, 6769. (f) Grisorio, R.; Roose, B.;
Colella, S.; Listorti, A.; Suranna, G. P.; Abate, A. ACS Energy Lett. 2017,
2, 1029. (g) Shinde, D. B.; Salunke, J. K.; Candeias, N. R.; Tinti, F.;
Gazzano, M.; Wadgaonkar, P. P.; Priimagi, A.; Camaioni, N.; Vivo, P. Sci.
Rep. 2017, 7, 46268.
Frederic W. Patureau: 0000-0002-4693-7240
Author Contributions
‡R.J. and C.L.B. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the DFG-funded Transregional
Collaborative Research Center SFB/TRR 88 “Cooperative
effects in homo and heterometallic complexes” (http://3MET.
de), DFG-funded project PA 2395/2-1, COST Action CA15106
(CHAOS), and since March 2017: by ERC project 716136:
“2O2ACTIVATION”. We are also thankful to Dr. Alaleh
Malekafzali (TU Kaiserslautern) for occasional control experi-
ments in parallel to her research project. Tobias Jost, Patrick Gaß,
Benedict Wyrwol, and Ben Teichmann (all from TU
Kaiserslautern) are acknowledged for short internships in the
group.
REFERENCES
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D
DOI: 10.1021/acs.orglett.8b00914
Org. Lett. XXXX, XXX, XXX−XXX