The Smiles rearrangement in the syntheses of azaphenothiazines. Part I

Journal Pre-proof The Smiles rearrangement in the syntheses of azaphenothiazines. Part I.

Krystian Pluta, Małgorzata Jeleń, Beata Morak-Młodawska PII:

S0022-2860(19)31610-2

DOI:

https://doi.org/10.1016/j.molstruc.2019.127501

Reference:

MOLSTR 127501

To appear in:

Journal of Molecular Structure

Received Date:

24 October 2019

Accepted Date:

29 November 2019

Please cite this article as: Krystian Pluta, Małgorzata Jeleń, Beata Morak-Młodawska, The Smiles rearrangement in the syntheses of azaphenothiazines. Part I., Journal of Molecular Structure (2019), https://doi.org/10.1016/j.molstruc.2019.127501

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Journal Pre-proof

X

NH2 A

+

N X *

SH

C

B H N A

NH2 X N

S * P1

direct cyclization

A

A

A

N S

S * S S

S

A

* NH2

N

H N *

Smiles rearr.

H2N

D

N

N SH

A

=

cyclization

A S

X A

or

H N *

N (azine)

N

P2

P1, P2 = azaphenothiazines (azinobenzothiazines and diazinothiazines)

Journal Pre-proof The Smiles rearrangement in the syntheses of azaphenothiazines. Part I. Krystian Pluta*, Małgorzata Jeleń, Beata Morak-Młodawska The Medical University of Silesia, Faculty of Pharmaceutical Sciences, Department of Organic Chemistry, Jagiellońska 4, 41-200 Sosnowiec, Poland Abstract The Smiles rearrangement, an intramolecular nucleophilic aromatic substitution proving to be a synthetically useful tool to obtain various types compounds of diverse applications, has undergone a potent revival in recent years. Phenothiazines and azaphenothiazines, one of the most bioactive heterocyclic scaffolds in medicinal chemistry providing recognized drugs and recently drug candidates, have been synthesized in multistep processes through the Smiles rearrangement of S-N type. The Smiles rearrangement during the syntheses of azaphenothiazines occurs more frequently than one can expect and observe. This review discusses cascades of C-S coupling/S-N Smiles rearrangement/C-S cyclization and S-N Smiles rearrangement/C-S cyclization steps, competition of the rearrangement with the Ullmann type cyclization (C-N cyclization), an influence of the azine nature, steric hindrance and reaction conditions (neutral, basic, weakly acidic, strongly acidic and thermal) on the reaction pathways and efficiency, occurrence of a very rare double Smiles rearrangement, importance of proper structural analysis and confusing chemical literature on azaphenothiazines. 1. Introduction Molecular rearrangements as an important class of organic reactions accompanied the

organic synthesis from the beginning and one of them, known as the Woehler reaction – a rearrangement of ammonium cyanate to urea, laid the foundations of organic chemistry. The rearrangements result in changes of the connectivity between atoms in a molecule, the position of multiple bonds and their multiplicity. Most of rearrangements are accomplished with conservation of the atom composition of the molecule [1]. The rearrangements are very interesting for the chemists to study their mechanisms but they can be also a real challenge for them. As a rearranged product is isomeric to an expected product, it is possible to miss the fact that the rearrangement has occurred. The Smiles rearrangement is one of the most known intramolecular nucleophilic aromatic ipso-substitution reactions, discovered by Samuel Smiles and coworkers in the thirties of 20th century which published over a dozen papers on the rearrangement of ethers, sulfides, sulfoxides and sulfones [2]. In this rearrangement, a nucleophilic group -YH dissociates in compound I to form anionic group -Y- (II) which substitutes a heteroatom X via the formation of the Meisenheimer spiro adduct (III) to form an anionic group -X- (IV, Scheme 1).

YH X * I

Z

Z -H

Y X * II

Z

Y *

Y X

Y

X III

Scheme 1 1

*

X IV

Z

Journal Pre-proof For the migration of the aromatic ring from a heteroatom X to a heteroatom Y, the rearrangement is considered as of the X→Y type. As the nucleophilic groups –YH, the most often the amino, hydroxyl, amido and sulfonamido were used. Almost 90 years of widespread using in organic synthesis this rearrangement has described in hundreds papers and it has gained even its variants as the Truce-Smiles, Ugi-Smiles, radical Smiles rearrangement, and it is a key step of the Julia-Kocienski olefination [3-10]. The classical Smiles rearrangement was reviewed in papers and chapters in the past [11-14] and new examples of the rearrangement were described recently in distinguished reviews [10,15-19]. One of the most proliferative applications of the Smiles rearrangement is the synthesis of phenothiazines (dibenzo-1,4-thiazines), which have been well recognized as antipsychotic and antihistaminic drugs for years [20]. Nowadays, these classical phenothiazines have been used as good targets for drug repurposing as they exhibit significant properties for multidrugresistant tuberculosis, methicillin-resistant Staphylococcus aureus, vancomycin-resistant enterococci and lung cancer therapy through targeting lung cancer stem cells [21-25]. The synthesis of azaphenothiazines is more complex than that of phenothiazines as azaphenothiazines represent the variety of azinobenzothiazine and diazinothiazine structures (where azine = pyridine, pyridazine, pyrimidine, pyrazine, 1,2,4-triazine, qunoline and quinoxaline) [26]. As a lot of new azaphenothiazine compounds have been synthesized recently and some of them exhibited promising biological activities such as anticancer, anti-inflammatory, antibacterial, antimycobacterial, antifungal, antiviral, analgesic, 15-lipoxygenase inhibitory, trypanothione reductase inhibitory, antiasthmatic, cardiovascular, antiarrhythmic, hypotensive, antiswelling, anti-obesity [26], there is a need to review the syntheses based on the Smiles rearrangement and to discuss the structural evidences for obtained products. The structure – activity relationship is one of basic features in rational drug design and a wrong structure of a drug candidate leads to false conclusions. Recent review papers argue that the Smiles rearrangement gained more attention nowadays describing syntheses of various types of aromatic and heteroaromatic compounds. The Smiles rearrangement during phenothiazines syntheses was observed in basic conditions and these facts were discussed in chapters [20,27]. Unlike to the phenothiazine syntheses, this rearrangement in the azaphenothiazine syntheses was observed also in acidic, neutral and thermal conditions, and was found as two consecutive processes known as the double Smiles rearrangement. The Smiles rearrangement in the azaphenothiazine syntheses has not been comprehensively reviewed, it was only partially discussed when the syntheses of selected azaphenothiazines were reviewed in seventies of 20th century [28,29] and recently in 2009 [30]. What is more, the Smiles rearrangement during the syntheses of azaphenothiazines (and phenothiazines) occurs more frequently than one can expect and observe. The aim of this review is to present comprehensively a phenomenon of the Smiles rearrangement during the syntheses of different azaphenothiazines. In Part I, we discuss the single and the double rearrangement, the reaction conditions (some azinyl sulfides underwent the Smiles rearrangement in basic, weakly and strongly acidic conditions and some sulfides underwent the Ullmann reaction in weakly acidic conditions), mechanisms and the product 2

Journal Pre-proof structure elucidation. It is worth noting that a variety of azaphenothiazines (there are known over 50 types of azaphenothiazines belonging to different heterocyclic ring systems) and 3 types of the azaphenothiazine nomenclature systems (two of them confusing, generating misunderstandings in names and numbering of the ring atoms) did not facilitate to follow this rearrangement in literature. In forthcoming Part II, we will overview the Smiles rearrangement in details in the synthesis of monoaza-, diaza-, triaza-, tetraazaphenothiazines and their benzo- and dibenzo derivatives. 2. The Smiles rearrangement in the synthesis of phenothiazines Theoretically, ortho-aminodiphenyl sulfide S with a leaving group X and an additional group Z (obtained in C-S coupling reaction of disubstituted benzenes B and C) can undergo direct C-N cyclization to form the 1,4-thiazine ring and thereby phenothiazine P1 (the Ullmann reaction in the presence of copper powder or copper compounds, and dehydrative cyclization) or undergo in some conditions the Smiles rearrangement of the S→N type to amine A and further C-S cyclization to 1,4-thiazine ring and phenothiazine P2 (Scheme 2). The possible phenothiazines P1 and P2 differ in the location of the substituent Z: in positions 1 or 4, and 2 or 3. As the laboratory practice shows, the Smiles rearrangement takes place in basic conditions and phenothiazine P2 is the final product. The scope, limitations and mechanism of the Smiles rearrangement during the phenothiazine synthesis was discussed in chapters [20,27]. The direct syntheses of phenothiazines P2 from pairs of o-disubstituted benzenes B and C proceed very often through the step of formation of appropriate sulfide (which is not isolated) which readily undergo cyclization to the thiazine ring. These syntheses are regarded as tandem processes: C-S coupling/S-N Smiles rearrangement/C-S cyclization and S-N Smiles rearrangement/C-S cyclization starting from compounds B and C or S. Sometimes in milder conditions (at lower temperature), the resulting sulfide is isolated. In some cases, the Ullmann type and the Smiles (followed by cyclization) products are the same (for example when Z = H in Scheme 2 or when the same substituents are in positions 1 and 4 or 2 and 3) and the rearrangement can be missed. Z

X

NH2 +

X *

SH

C

B H N S *

NH2 X

Z direct cyclization

P1

S *

Z Smiles rearr. S

N

S

H N * SH

X

cyclization Z

A

H N * S

Z

P2

Scheme 2 3. The Smiles rearrangement in the synthesis of azaphenothiazines 3.1. General remarks Whereas the reaction of the o-aminodiphenyl sulfide leads to only one cyclic product, dibenzo1,4-thiazine (because of two phenyl moieties), differing in only the location of the substituents, the reaction of o-aminophenyl azinyl sulfide or o-aminodiazinyl sulfide (azinyl = pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl and so on) can lead to two types of azaphenothiazines belonging to different classes of heterocycles. The chemistry of azaphenothiazine is plentiful as these compounds represent a variety of ring systems. Up to 3

Journal Pre-proof now, there are known over 50 types of azaphenothiazines: 4 monozaphenothiazines, 12 diazaphenothiazines, 6 triazaphenothiazines, 10 tetraazaphenothiazines, and their monobenzo, dibenzo and naphtho derivatives [26]. Not all the authors of the azaphenothiazine synthesis were aware of the Smiles rearrangement and were able to unequivocally identify the azaphenothiazine structure. Similarly to the phenothiazine synthesis, analogous azaphenothiazine synthesis can be considered the tandem processes with forming C-S/breaking C-S/forming C-N/forming C-S single bonds. The structures and transformations of o-aminophenyl azinyl sulfides and oaminodiazinyl sulfides (S1 and S2) in reaction conditions are essential for direction of the azaphenothiazine formations (Scheme 3). Those sulfides can undergo direct cyclization (the Ullmann type reaction) or can rearrange to appropriate phenyl azinyl amines A1 or diazinyl amines A2, depending on the reaction conditions, followed by cyclization, and two types of azaphenothiazines (P3 and P5 or P4 and P6) can be produced. As the Smiles rearrangement of those sulfides can proceed in basic, acidic and neutral conditions, one can approach the final product identification with care. H N

NH2 X

A

N S *

direct cyclization

A

S

N

SH

S1

H N

X N

A * S P5

direct cyclization

cyclization

N

A

N S *

P3

H N *

Smiles rearr.

H N * N

A S

X

P4

A1

NH2 N

A

H * N

Smiles rearr. A S

* S S2

N

cyclization

N X

A

H * N

P6

A2

A

or

=

N

N

S

SH

= (azine)

Scheme 3 As was mentioned, the synthesis of azaphenothiazines is very often realized via reactions of pairs of compounds: o-disubstituted benzenes with o-disubstituted azines or two odisubstituted azines (B and C, Scheme 4). Those reactions run through formation of oaminoazinyl sulfides (S) or o-mercaptoazinyl amines (A, most often different from the amines obtained after the rearrangement), but these compounds were not isolated, and the structures of final azaphenothiazines are the results of direct cyclization or the Smiles rearrangement. NH2 A

NH2 X A

N S * S1

B1

X *

NH2

X +

X

NH2

A

N

A B3

* S S2

* X

B4

* SH A3

C3

N X

N * X

H2N +

H N

A

N HS

X * SX

H N

C2

H 2N +

A

C1 N

HS *

X X

N

SH

A B2

X +

C4

4

A

N * SH

* X A4

Journal Pre-proof Scheme 4 The first synthesis of azaphenothiazine dates back to 1945 when Petrow and Rewald published the obtainment of 1-nitro-3-azaphenothiazine 6 in the reaction of hydrochloride of oaminobenzenethiol 1 or its zinc salt 2 with 4-chloro-3,5-dinitropyridine 3 in basic conditions (Scheme 5) [31]. The product was identified on the chemical way on the basis of a location of the nitro group. 1-Nitroazaphenothiazine 6 was reduced to 1-amino derivative 7 followed by diazotization and coupling to triazole derivative 8. The last reaction was found to be typical for o-aminodiphenylamine residue which excluded possible the Ullmann type product (4-nitro-2azaphenothiazine 9). Although the authors did not mention the Smiles rearrangement, the synthesis proceeded through formation of sulfide 4, the rearrangement to amine 5 and cyclization to 3-azaphenothiazine 6 (a tandem process: coupling/Smiles rearrangement/cyclization). Sulfide 4 was not observed, probably because of the rapid cyclization step, but the final product structure is evidence for the step of the Smiles rearrangement. NH3Cl SH

Cl NO2

1. AcONa, EtOH O N 2 2. NaOH, H2O N 3

1

N N

S

AcONa

NH2

4

benzene

NO2

H N

NH2 NO2

NO2

NO2

H N

N

N

S

SNa NO2

6

5

red.

S 1/2 Zn 2

N H N

N

H N N

S 8

S 9

N

N

NO2

S 7

NH2

N

Scheme 5 On the other hand, there are some syntheses of azaphenothiazines P which are impossible to state whether the Smiles rearrangement occurred or not, for example when the migrated azine moiety in sulfide S is symmetrical (pyridazine-4,5-diyl, pyrazine-2,3-diyl, quinoxaline-2,3-diyl and benzoquinoxaline-2,3-diyl, Scheme 6). In common basic conditions (a base and a solvent) used in the Smiles rearrangement, one can expect the rearrangement to amine A followed by cyclization, but the final product P has structure supporting both the rearrangement and the direct cyclization. NH2 A SH

+

N

A

N S

B

A

direct

X

cyclization

H N

or

N

A

N SH

X A

N N

= N

N ,

N ,

N

N N

A

cyclization

S

C

=

H N

NH2 X

X

,

N

Scheme 6

5

N S P

Journal Pre-proof Contrary to classical phenothiazines which belong to the dibenzothiazine ring system, azaphenothiazines represent different heterocyclic ring systems and were named in the chemical literature in three different ways, using more popular and present-day British and American system A (as x-azaphenothiazine where x is the location of an azine nitrogen atom in the system), less known German system B used in the past mainly in German language journals and Beillstein’s Handbook of Organic Chemistry (also as x-azaphenothiazine but with different atom numbering), and the fused ring system C used in Chemical Abstracts (as azino[x,y-b][1,4]benzothiazine and diazino[x,y-b;z,q-e][1,4]benzothiazine, where x, y, z and q are the numbers of azine carbon atoms fused with the thiazine ring bonds b and e). The existence of these nomenclature systems generated misunderstandings in names and numbering of atoms in rings. One of the early synthesized azaphenothiazines (in 1958) [32] were described as 1aza-, 3-aza- and 4-azaphenothiaznes (under system B) whereas in fact they are 4-aza-, 2-azaand 4-azaphenothiazines according to contemporary system A. The authors were not aware of the Smiles rearrangement as sulfides 10 in the presence of NaOH did not give 1azaphenothiazines 11 but underwent the rearrangement to amines 12 and cyclization to give 4azaphenothiazine 13a and 8-chloro-4-azaphenothiazine 13b (Scheme 7). H N

X X

NH2 Cl

X a. H b. Cl

S

N

S

N

11 NaOH

H N

X

X

H N

10 SNa Cl 12

N

S

N

13

Scheme 7 All those facts prompted us to revise the azaphenothiazine syntheses in the terms of the Smiles rearrangement and to discuss the proper structures of the final products. 3.2. The mechanistic study 3.2.1. In basic conditions The syntheses of azaphenothiazines most often were carried in basic conditions using following bases in various solvents: KOH or NaOH in ethanol, methanol, aqueous ethanol, water, acetone, dioxane, DMSO, DMF, ethyl acetate, and 1,3-propanediol; K2CO3 in DMF; Na2S in DMF; NEt3 in benzene, DMF; NaNH2 in acetonitrile; Na2CO3 in o-dichlorobenzene. The mechanistic study of the azaphenothiazines synthesis includes the steps of the sulfide formation, direct cyclization or possible rearrangement and subsequent cyclization. Some observations of the Smiles rearrangement found during the phenothiazine synthesis are valid in the azaphenothiazine synthesis. An electron accepting group in the ortho and para positions to the carbon atom (*) as a nitro group activates the rearrangement through the resonance and inductive effects increasing the electrophilic character of this atom. The lone nitro group in ortho position is a stronger activating group than that in para position. Such an activating character has the azine nitrogen atom due to its electron accepting property. A halogen atom interferes the rearrangement decreasing probably through the resonance effect (but not via inductive action). Formylation and acetylation of the amino group to form the Nformyl (-NHCHO) and N-acetyl (-NHAc) groups increase the acidity of those groups facilitating the ionization to anionic nucleophilic group but decrease their nucleophilic strength. 6

Journal Pre-proof The net influence of the acyl group on the rearrangement is the result of these two counterbalancing effects. The most valuable mechanistic study was carried out by Rodig and coworkers [33] in 1964 on substituted 3-amino-2,2’-dipyridinyl sulfides in methanol and ethanol at room temperature and in boiling alcohols. Sulfides 14a-c readily rearranged in boiling alcohols in the presence of KOH to sodium salt of 3-mercapto-2’,3-dipyridinylamines 15a-c, and after cooling methyl iodide was added to the obtained red solution giving 3-methylthio-2’,3dipyridinylamines 16a-c (Scheme 8). As the rearranged products containing free thiol and thione groups were found to be isolated with undue difficulty, methylation to a S-methyl group facilitates their isolation and identification. The N-acetyl sulfides 17b-d rearranged more smoothly than sulfides 14 as even in methanol (with KOH) at room temperature to give sodium salt of 3-mercapto-N-acetyl-2’,3-dipyridinylamines 18b-d, and after methylation 3-methylthioN-acetyl-2’,3-dipyridinylamines 19b-d. The acidification of the rearrangement product 18d with hydrochloric acid led to amine 20d containing the N-acetyl and thione functions. The Nacetyl function was removed by hydrolysis in ethanol with NaOH yielding amines 16b-d. NH2 X

N

S

X1

KOH

N

H N

ROH N

14a-c

H N

MeI X1

X

N

15a-c

N X1

SMe X 16a-d EtOH NaOH

Ac NH

N

SK

N

Ac

X

S

X1

ROH KOH

N

Ac

N N

17a-d

SK

N

X

X1

18a-d a. b. c. d.

X H CH3 NO2 NO2

X1 CH3 NO2 CH3 H

N

MeI N

N H

X1

19a-d

Ac N

SMe X

N

N

S NO 2 20d

Scheme 8 The authors postulated that the initial step of the rearrangement in basic conditions involves a removal of the proton from the amino group –NH2 to form anionic amino group – NH- (an amide anion) which as the strong nucleophilic group attacks the carbon atom breaking the C-S bond. 3.2.2. In acidic conditions It is well known that protonation of the ring nitrogen atom in azines increases the ease of nucleophilic aromatic substitution and this fact was exploited in the Smiles rearrangement in acidic conditions. In fact, sulfides 14a-e rearranged smoothly when heated in 5% hydrochloric acid on a steam bath (most often for 1 h) to give amines 21a-d with a thione group (Scheme 9). Only sulfide 14e gave in the same conditions hydrochloride of amine 21e. The rearrangement occurs even more easily in concentrated hydrochloric acid. Sulfides 14a and 14d rearranged in high yield even within a few minutes when treated with the acid at room temperature. Two selected amines 21a-b methylated with methyl iodide gave amines 16a-b, obtained earlier in 7

Journal Pre-proof basic conditions. The N-acetyl sulfides 17a-d rearranged at a slower rate than sulfides 14a-d in boiling 5% hydrochloric acid but with additional deacetylation process yielding amines 21a-d. H N N

N

SMe X 16a-b

X1

MeI 8a-b NH2 X

N

S

H N

X1 N

5% HCl

N H

14a-e

Ac NH

N

S X 21a-e

X1

5% HCl

N

X

S

X1 N

17a-d

e X = X1 = H

Scheme 9 To answer the question when the acetyl group is removed, before or after the rearrangement, amine 20d was heated in ethanol. After a few minutes rapid loss of the acetyl group was observed which suggests the deacetylation process after rearrangement (Scheme 10). When the thione group was transformed into the S-methyl group as in 19d, the heating of this compound in ethanol within 24 h gave no deacetylation process. Ac N N H

N

H N

EtOH N H

S NO 2 20d

Ac N

N N

S NO 2

N

SMe NO2 19d

21d

H N

EtOH N

N

SMe NO2 16d

Scheme 10 The catalyzing effect of acid in the Smiles rearrangement is explained by protonation of either of the ring nitrogen atoms (Fig. 1). If the nitrogen atom is protonated in the migrating ring (SH1), it would increase the susceptibility of the carbon atom in position 2’ to nucleophilic attack of the amino group by increasing its electrophilic character through the inductive and resonance effect of ammonium type of the nitrogen atom followed by breaking the C-S bond. Alternatively, if the protonated is the nitrogen atom in the other ring (SH2), it would increase the electrophilic character of the carbon atom in position 2 enhancing the ability of the sulfur atom to accommodate a negative charge after breaking the C-S bond. NH

N

X

X1

NH

S * N H SH1

N H

X

X1

S * N SH2

Fig. 1 Unfortunately, there are several examples of the azaphenothiazine synthesis which were carried out in acidic conditions giving only direct products or both the direct and rearranged products depending on the reaction conditions and the substrate structure. These examples will be discussed individually in respect of the type of sulfides. 3.2.3. In neutral and thermal conditions

8

Journal Pre-proof The first examples of the Smiles rearrangement of azinyl sulfides in neutral and thermal conditions were reported by Takahashi and Maki [34] as early as in 1958 when substituted phenyl pyridinyl sulfide 22 and dipyridinyl sulfides 24 (Schemes 12 and 13) underwent the rearrangement in methanol in the presence of methyl iodide in a sealed tube in a water bath for 5 h. NO2

NH2

O2N

MeOH S NO2

N

MeI

Cl

H N

O 2N 23

22

N SMe

Cl

Scheme 12 In the case of N-acetyl derivative 24 the deacetylation process was observed. R NH

Cl

N

X

X1

S

H N

MeOH MeI

N

Cl

N

24 R X a. H NO2 b. Ac NO2 c. H H

N X1

SMe X 25

X1 Cl Cl NO2

Scheme 13 Rodig and coworkers [33] observed the rearrangement and deacetylation during crystallization of sulfide 17b from gentle heated absolute ethanol on a water bath (without boiling) to give amine 21b (Scheme 14). The yellow solution turned orange during heating. This sulfide heated in benzene for 68 h gave no rearranged product. Ac NH

N

CH3

S

NO2

H N

N

EtOH N H

N

S CH 3

NO2

21b

17b

Scheme 14 Sulfide 17d also underwent the rearrangement when heated in absolute ethanol (for 8 h) and water (for 45 h), but not in DMSO (for 11 h, Scheme 15). Nonacetylated sulfide 14d rearranged only to some extent (10%) in ethanol during the 21 h heating, but practically completely in boiling water for 8.5 h despite that the sulfide was only partially soluble in water [33]. Ac NH

H N

NO2 EtOH

N

S 17d

N

or H2O

N H

N

S NO 2 21d

NH2 NO2 H2O N

S

N

14d

Scheme 15 The findings that N-acetyl sulfides rearranged easily than nonacetyl sulfides and the rearrangement took place in ethanol and water but not in benzene, strongly suggest that the 9

Journal Pre-proof reaction involves solvent participation. The solvent can initiate the rearrangement through the attack at the acetyl group with simultaneous release a lone electron pair at the nitrogen atom enabling attack at the carbon atom (*) in sulfide 17d (Scheme 16). On the other hand, the solvent can initiate ionization of relatively acidic amide proton and the anionic amide group in sulfide 17dA could attack the carbon atom (*) followed by rapid solvolysis of the acetyl group in resulting amine. The observations that the rate of the rearrangement is considerably slower in water (possessing greater ionizing power) than in ethanol and lack of the rearrangement in high ionizing DMSO rule out latter mechanism and favors the former concerted process. Me

Et

NH

H

N

Ac

Ac

O

O

H N * N

NO2 N H

S * N

N

NO2

-H N

S NO 2 15d

17d

NH

NO2 DMSO

S * N

N

S * N 17d

17dA

Scheme 16 Not only homogenity of solution but even a solvent is not necessary for the thermal rearrangement. It was found that sulfides 14a-b and 14d rearranged in a solid state when heated in a drying oven at 110 oC for 9 days (Scheme 17). NH2 X

N

S

X1 N

H N

drying oven without solvent

N H

14a-b, 14d

N X1

S X 21a-b, 21d

Scheme 17 3.3. Steric requirements Steric requirements in the sulfides can promote the rearrangement, but also can prevent from it. In certain circumstances, the reaction between disubstituted benzenes or heteroarenes with disubstituted heteroarenes (the coupling step) can produce not a compound with single sulfide function but with the disulfide or bis-sulfide groups. Already in 1957 Maki [35] observed that 3-amino-6-chloro-3’-nitro-2,2’-dipyridinyl sulfide 24 in basic conditions (boiling ethanol with KOH) did not lead to 10H-7-chloro-1,6diazaphenothiazine 27, contrary to the reaction of N-acetyl sulfide 28. Both reactions proceeded through the rearrangement to amines 26 and 29 but the nonacetyl amine is thought to form the hydrogen bonding between the amino and nitro groups preventing from the rotation around the C-N bond to achieve an appropriate conformation enabling the cyclization to diazaphenothiazine 27 (Scheme 18). O NH2

Cl

N

H

NO2

S

N

Cl

N

N

N

Ac

N

N Cl

N

SK

28

10

N

NO2

29

N

S

27

26 NO2

S

Cl

SK

Ac

Cl

H N

N

24 NH

O N

N

Journal Pre-proof Scheme 18 Later Maki with coworkers [36] followed certain chemical behavior which suggested that the rearrangement is activated by the effect of bulky substituents. Whereas sulfide 32a was obtained in the reaction of aminobenzenethiol 30 with 4-chloro-3-nitropyridine 31a in basic conditions (ethanol with EtONa) at 20 oC, the similar reaction with 5-substituted 4-chloro-3nitropyridines 31b-d did not lead to the similar sulfides but to the rearrangement products, amines 33a-c with the disulfide function (Scheme 19). When pyridines 31b-c were used, additionally the rearrangement and cyclization product, 1-nitro-3-azaphenothiazine 34, was isolated. NH2 NO2 N

R= H S 32a NH2 O2N + SH 30

N

H N

20o

Cl 31

EtOH

X

X

S NO 2 S NO2

X aH b NO2 c Br d CH3

N

N

+

H N S 34

NO2

N

N H

X 33a-c

Scheme 19 It is evident that both electron donating (CH3) and electron accepting (NO2, Br) groups in position 5 activate the rearrangement due to steric factor in comparison with the isolated sulfide 32. The observed rearrangement was followed by autooxidation to disulfide or the cyclization. The authors postulated that the substituents in position 5 gave rise to a restricted rotation around the C-S bond and this steric effect resulted in the favorable conformation enabling the nucleophilic substitution in the pyridine ring 32 (Fig. 2). NH2 R N S 32

NO2

Fig. 2 When a compound has two sulfide functions (two o-aminophenylthio substituents), there are several reaction routes. Yoneda and coworkers [37] observed that the reaction of 2aminobenzenethiols 35 with 3,4,5-trichloropyridazine 36 in alcoholic solution of KOH at 3060 oC led unexpectedly to 4-(2-aminophenylthio)-1,2-diazaphenothiazines 38 (Scheme 20). As this product could not be obtained in the substitution reaction of 4-chloro-10H-1,2diazaphenothiazine (obtained in other reaction conditions), the authors postulated bis-sulfide 37 to be an intermediate in this reaction. The product structures indicate that the direct cyclization proceeded via substitution of the chlorine atom by the amino group. The lack of the Smiles rearrangement can be explained by the steric hindrance in the molecules. When this reaction was carried out at lower temperature (15-20 oC), two isomeric products were isolated, 10H-4-chloro-1,2-diazaphenothiazine 39 (a main product) and 10H-1-chloro-2,3diazaphenothiazine 40. However, there is some doubts about the proper structure elucidation. 11

Journal Pre-proof H N

N

N

N

+

N

S

S 39

Cl

H N

40

Cl EtOH, R=H

KOH 15-20 oC Cl

NH

Cl

SH

S

MeOH

+ N 36

35 R = H, Me

R

NHR Cl

Cl

R

N

KOH, 30-60 oC

N

N

N S

N

S

N NHR

S

38

NHR

37

Scheme 20 Such a bis-sulfide 43 was found as the only product by Okafor and coworkers [38] in the reaction of 4,6-diaminopyrimidine-5-thiol 41 with 2,3,5-trichloropyrazine 42 in boiling DMA in the presence of KOH. Bis-sulfide 43 neither underwent the rearrangement nor cyclization to 1,3,6,9-tetraazaphenothiazines 44 and 45 (Scheme 21). N

N

H2N N

NH2

Cl

N

Cl

N

+

N

SH NH2

41

Cl

DMA

Cl

NH2

N

S

N

KOH

Cl

S

H2N

42

N

H N

N

S

NH2 N

N N

Cl

NH2

44

N

H N

N

S

+

45

N N NH2

N 43

Scheme 21 The same authors [38,39] studied reactions of 2-amino-6-methylpyridine-3-thiol 46 with trichloropyrazine 42 and 2,3-dichloroquinoxalines 47 in basic conditions (DMA, DMF or DMSO with NaOH). The reactions ended up at the formation of bis-sulfides 48 and 49 without subsequent rearrangement or cyclization (Scheme 22). Me N H2N Cl

N

Cl

N

Cl

Cl

42

Me

N H 46

NH2

Cl

N

S

Me

47

N

Me

X

N

48

N

S N

S

H2N

DMA, NaOH

Cl

N

H2N X

N

S

N

S

49

DMSO or DMF, NaOH X = H, Cl

H2N N Me

Scheme 22 12

Journal Pre-proof On the other hand, Scapini and coworkers [40] studied a heating of bis-sulfide 50 in basic conditions (MeOH, KOH). The reaction proceeded as direct cyclization to 2,3diazaphenothiazine 51 without the Smiles rearrangement (Scheme 23). The authors considered an attack of the amino group (that closer to the carbonyl group, route a) at the carbon atom (*) to be the most probable as this atom is activated by the carbonyl group for nucleophilic substitution. The attack of the second amino group at the carbon atom (*) (route b) giving rise to the Smiles rearrangement is rather impossible (but not completely excluded) as the resulting a thiolate anion in compound 52 should substitute the second sulfur atom to give azaphenothiazine 51. Only deep insight into mechanism could answer if this reaction runs with or without the rearrangement H N

N

a

N

S AcHN a b

O

O S

N

Me

MeOH KOH

N

S *

AcHN

Me 51

50

b

AcHN

O S

N

Me

N

HN KS

52

Scheme 23 Similarly, bis-sulfide 53 heated in the same basic conditions gave 2,3diazaphenothiazine 54 (Scheme 24) [41]. Such a product can be formed with or without the rearrangement. AcHN

O S

N N

S AcHN

Me

MeOH KOH

Me

O

H N

O N N

S 54

Me Me

O

53

Scheme 24 3.4. Limitations of the Smiles rearrangement 3.4.1. The direct cyclization through the Ullmann type reaction The Ullmann reaction is a name reaction referred to the synthesis of symmetrical biaryls via copper-catalyzed coupling of aryl halides. This name was expanded to the "Ullmann-type" reaction which includes nucleophilic aromatic substitution in aryl halides catalyzed by first of all copper powder and copper compounds, but also by other metal compounds. The cyclizations of diphenyl sulfides containing the amino and halogen substituents to phenothiazines in the presence of a copper catalyst proceeded as the direct thiazine ring closure through the Ullmann type reaction [27]. The same reactions conditions were used in the azaphenothiazine synthesis. The mentioned syntheses of monoazaphenothiazines in section 3.1 13

Journal Pre-proof were carried out in DMF under nitrogen in the presence of copper powder and K2CO3 proceeded as the Ullmann type reaction [32]. In those conditions, o-bromophenyl 3-amino-2-pyridinyl sulfide 56 gave 4-azaphenothiazine 13a (Scheme 25). It is worth noting that possible rearranged product has the same structure. NH2

Br

H N

DMF, N2 S

K2CO3, Cu

N

S

N

13a

56

Scheme 25 Bromophenyl 3-amino-4-pyridinyl sulfide 57 in the same conditions cyclized, according to the authors, directly to 2-azaphenothiazine 58 (Scheme 26), but the rearrangement cannot be ruled out. This product was formed also without a solvent or when cuprous iodide (instead of copper powder) was used [42]. When chloro-substituted sulfide 57 (X = Cl) was used, the product structure 58 excluded the rearrangement, but the structural evidence was not added. X

NH2

Br

N

H N

X

DMF, N2 K2CO3, Cu

S

N

S

57

58

X = H, Cl

Scheme 26 Contrary to it, in the same reaction conditions (but without nitrogen), aminophenyl 4pyrimidinyl sulfides 59 underwent unexpectedly the rearrangement to amine 60 (not isolated, Scheme 27) and cyclized to 1,3-diazaphenothiazines 61 [43]. The evidence for the product structure came from independent synthesis – cyclization of amine 62 in DMF with K2CO3. X3

NH2 Br

X2 N

S

N

59

DMF X1 K2CO3, Cu

X3

H N

N

X1

X3

H N

N SK

Br 60

N N

S

X2

X2

61

X1 = H, Me, Ph X2 = H, Me X3 = H, Cl

K2CO3

DMF X3

X1

H N

N

X1 N

SH

Br 62

X2

X1, X2 = H, Me

Scheme 27 In the same reaction conditions as above, isomeric bromophenyl 4-amino-5-pyrimidinyl sulfides 63 also underwent the rearrangement and subsequent cyclization to an isomeric product of the postulated structure of 2,4-diazaphenothiazines 65 (Scheme 28) [43]. However, for sulfide 63 with a chlorine atom (X = Cl), the rearrangement to amine 64 with further cyclization should have given 7-chlororo-2,4-diazaphenothiazine 66 (instead of the 8-chloro isomer 65).

14

Journal Pre-proof

Br H2N

X

N

Me N

S

K2CO3, Cu

X

Me 63 X = H, Cl

S

N N SK

Br

N

Me

H N

DMF

Me

H N

X

N Me 65 Me

H N

Me

64

X

N

S

N

66 Me

Scheme 28 When aminophenyl 4-pyrimidinyl sulfide 67 was heated in the same reaction conditions but under nitrogen both products, direct 68 and rearranged 69 (Scheme 29), were obtained in very low yield of 12.7% and 7.7%, respectively [43]. NH2 Br

S

H N

DMF, N2

N

K2CO3, Cu

N

S

N

H N + 69

68

67

N

S

N

N

Scheme 29 The discussed above reactions proceeded in DMF in the presence of copper powder and K2CO3, and gave either non-rearranged or rearranged or both products. One can see that copper powder in some cases does not prevent the rearrangement. Recently, several excellent papers [44-51] were published on the syntheses of phenothiazines and azaphenothiazines using the Ullmann type reactions. These syntheses (regarded as the domino, cascade or tandem C-S and C-N coupling) were based on the reactions of pairs o-aminobenzenethiols with o-dihalogenobenzenes or azines, or rearranged dipyridinyl disulfides with anilines in the presence of palladium, copper or iron catalysts and sometime some ligands. The reactions proceeded as complex multistep mechanism with the sulfide formation but sulfides underwent the cyclization without the rearrangement. Zeng and coworkers [46] carried out the reaction aminobenzenethiols 70 with 2-bromo3,5-dichloropyridine 71 in DMSO at 120 oC in the presence of CuI and K2CO3 to give 4azaphenothiazines 73 (Scheme 30). Other used bases as NaOH, Cs2CO3, t-BuOK and K3PO4 gave lower yield. The reaction ran through the formation of sulfide 72 (not isolated) which further underwent direct cyclization. X

NH2

Cl

Cl

+ SH 70

Br

N

NH2 Cl

X

DMSO K2CO3, CuI

S 72

71

Cl N

X

H N S 73

Cl N

X = H, Cl

Scheme 30 Zhang and Hu [48] used other reaction conditions. The reactions of acetylaminobenzenethiols 74 with 2,3-dibromopyridines 75 or 2,3-dibromoquinoxaline 76 were carried out in DMF at 135 oC under nitrogen in the presence of FeSO4, t-BuOK and phenanthroline to yield 4-azaphenothiazines 78 and quinoxalinobenzothiazines (benzo-1,4diazaphenothiazines) 80 via the formation of sulfide 77 and 79 (Scheme 31). A deacetylation process was also observed. 15

Journal Pre-proof Br

X1

Br

X

NHAc SH

DMF, N2, FeSO4

Br

N

Ac

S 77

N

X1

H N

X

X1

S 78

N

N

Ac

phenanthroline, t-BuOK Br

74 X = H, Cl

Br

NH

X 75

N

Br

NH

X

76

S 79

H N

X

N

S 80

N

N

Scheme 31 Tang and coworkers [49] studied the hydrogen aromatic substitution in the reactions of substituted N-methyl- and N-ethylanilines 81 with substituted 2,2’-dipyridinyl disulfides 82 in nitromethane at 60-120 oC in the presence of iodine and FeF3 giving substituted 4azaphenothiazines 84 (Scheme 32). The reactions in DMSO, DMF, acetonitrile and dioxane, and with FeCl3, FeBr3 and Fe2O3 gave lower yields. The presence of iodine or Niodosuccinimide was necessary as the reaction did not work without them. Me H N

NH

X2 +

X1

X1 N

NHR

S

81

S

82

N

I2 / FeF3

X1

X1

MeNO2 60-120 oC

X2

S 83

X2

N

S

N

84

R = Me, Et

X1 = H, 2-Cl, 3-Me

X2 = Me, OMe, F, Cl, Br Ph, CO2Me

Scheme 32 3.4.2. Cyclization when the hydroxyl, oxo and amino substituents are leaving groups There are several examples of direct cyclization of amino-substituted sulfides with the hydroxyl, oxo and amino substituents instead of good leaving groups (halogen atoms and a nitro group). Such reactions proceeded without the Smiles rearrangement as the condensation process with formation of water or ammonia as by-products. Those aminophenyl azinyl sulfides contained the diazine and triazine rings possessing one, two or even three oxo groups. When there was only one oxo group sometimes authors drew their tautomeric structures with an enolic hydroxyl group. Various substituted aminophenyl pyrimidinonyl sulfides 85 underwent the cyclization in acidic conditions (hydrochloric acid in ethanol or in acetic acid) to give substituted 1,3-diazaphenothiazines 86 (Scheme 33) [52-54]. R NH O X3

X1 N

S 85

R

H N

HCl, EtOH (AcOH)

N

N

X3

N

S

X2

86

X1

X2

R = H, Me, Bu X1 = H, OH, OR, Cl, SR, NH2, NR2, cyclic amino X2 = H, alkyl, NH2 X3 = H,Me, Cl

Scheme 33 Similarly, substituted aminophenyl pyrimidinetrionyl sulfides 87 gave 1,3diazaphenothiazin-2,4-diones 88 in acidic conditions (acetic acid or hydrochloric acid in ethanol, Scheme 34) [55,56]. 16

Journal Pre-proof R

R1

NH O

N

O N R 2

S 87

AcOH or HCl, EtOH

R

R1

N

N

N R 2

S

O

O

O

88

R = H, Me, CH2Ph R1, R2 = H, Me

Scheme 34 Contrary to above sulfide 87, N-methylaminophenyl pyridazinonyl sulfide 89 underwent cyclization in boiling 1% acetic acid to a product which treated with 70% perchloric acid gave a precipitate of ammonium salt, 3,10-dimethyl-2,3-diazaphenothiazinium perchlorate 90 (Scheme 35 [57]. Me

Me

NH O

N N Me

S 89

N

1. aq. AcOH 2. HClO4

S 90

N

ClO4 N Me

Scheme 35 In Japanese patents [58,59], substituted aminophenyl 1,2,4-triazinedionyl sulfides 91 cyclized in acetic acid to different 1,3,4-triazaphenothiazin-2-ones 92 and 93 depending on the substituent at the amino group – the hydrogen atom or a benzyl group (Scheme 36). R

R1 N

N

S N 92 R = H, Me, CH2Ph R1, R2 = H, CH2Ph

O

AcOH R=H

N R 2

R

R1

NH O

N

S 91

N

O

AcOH R = CH2Ph R1 = H

N R 2

N

N

S 93

N

O N R 2

R2 = H, CH2Ph

Scheme 36 Substituted aminophenyl aminopyrimidinyl sulfides 94 in acidic conditions (hydrochloric acid in ethanol or in acetic acid) underwent cyclization to 1,3diazaphenothiazines 86. When sulfide had an N-methyl group, this group was in the product, but in the case of an N-benzyl group the debenzylation process was observed (Scheme 37) [54,60]. R X3

R

NH2 N

NH

S 94

X1

HCl, EtOH (AcOH)

N

N S 86

X2

R = H, Me, CH2Ph X1 = NH2, OH X2 = H, NH2, NMe2, N

X3

X X = CH2, NMe, O

X3 = H, Cl

Scheme 37 3.4.3. Cyclization of 3,3’-diquinolinyl sulfides

17

N

X1 N

X2

Journal Pre-proof Unlike to 2,2’-, 2,4’- and 4,4’-dipyridinyl sulfides, reaction of 3,3’-diquinolinyl sulfide 95 containing an amino substituent (an anilino group) in position 4 in boiling methyl ether of diethylene glycol (MEDG) led directly to angularly condensed diquinothiazine 96 (Scheme 38). The Smiles rearrangement to diquinolinyl amine 97 and further cyclization to diquinothiazine 98 was not observed probably due to low susceptibility of a carbon atom in position 3’ for a nucleophilic attack of the amino group. The amino group attacked a carbon atom in position 4’ [61].

N NH

N

SMe S

N

95

N

S

96

MEDG N N

X N

N

N

N

S SH MeS

N

98

97

Scheme 38 Annulation reactions of 4,4’-dichloro-3,3’-diquinolinyl sulfide 99 with ammonia, acetamide and primary aliphatic, aromatic and heteroaromatic amines in boiling phenol or MEDG led directly to various angularly condensed 14-substituted diquinothiazines 101. The reactions are thought to run through formation of sulfide 100 which undergoes cyclization to diquinothiazines 101, but not the rearrangement to diquinolinyl amine 102 and further cyclization to diquinothiazine 103 (Scheme 39) [62,63]. R N

R Cl

NH

Cl S +

N

N 99

RNH2

a,b

a. phenol b. MEDG

N

Cl

N

100

N

S

S

101 N

R N

N

X N

R = H, Me, i-Bu, Ph, C6H4X, C6H4CH2, (CH2)nNR2, naphthyl, 2-pyridinyl, 2-thiazolyl

Cl 102

SH

R N

N S

N

103

Scheme 39 Similarly, annulation reactions of 2,2’-dichloro-3,3’-diquinolinyl sulfide 104 with ammonia, acetamide and primary aliphatic, aromatic and heteroaromatic amines in boiling phenol, MEDG, and DMF led directly to cyclization products - varied linearly condensed 6substituted diquinothiazines 106 (Scheme 40) [64,65].

18

Journal Pre-proof S N S + N

Cl

Cl 104

N

RNH2

S

a-c

a. phenol b. MEDG c. DMF/NaOH

N

NH R

Cl

N

N

R

106

N

R

105

X

N

R = H, Me, Bu, Ph, C6H4X, C6H4CH2, (CH2)nNR2, 2-pyridinyl

N

SH

Cl

N 107

N

S N

N

R

108

Scheme 40 In those annulation reactions the amine group (despite its basicity) substituted the chlorine atom at the carbon atoms in positions 2 and 4 which were more susceptible than the carbon in position 3 for nucleophilic substitution. 3.5. The double Smiles rearrangement Sometimes aminophenyl azinyl bis-sulfides and aminodiazinyl sulfides (with appropriate leaving groups) underwent rare kind of the rearrangement, a double Smiles rearrangement of two types. Bis(N-acetylaminophenylthio)pyrimidines 109 (the bis-sulfide compound) in ethanolic KOH at 20 oC in the presence of methyl iodide underwent smoothly the double Smiles rearrangement (of the symmetrical sort – two identical single processes) to bis(N-acetyl-Nphenylamino)pyrimidines 111 instead of the formation of 1,3-diazaphenothiazines 110. To avoid an argument against too low reaction temperature for the cyclization process, the reactions were repeated at 150 oC for 2 h (without initial addition of methyl iodide). This last reagent was added after 2 h to the reaction mixture, but once again the rearranged products 111 were obtained (in 60-75% yield, Scheme 41) [66]. H N

N N

S

X

NH

110 NHAc

NO2 S N R

SMe

NHAc S

N

R

1. KOH, MeI DMF, 150oC Ac

NO2 Ac

N

109

N N

R = CH3, C6H5, N(CH3)2 SMe

111

N R

SMe

Scheme 41 There are known several double Smiles rearrangements which proceeded consecutively. Rodig and co-workers [67] carried out the reaction of 3-amino-3’-nitro-2,2’-dipyridinyl sulfide 14d in basic conditions (KOH in ethanol, Scheme 42). This compound rearranged to 2,3’19

Journal Pre-proof dipyridinyl amine 15d which with 2-chloro-3-aminopyridine 112 gave 3(nitropyridinylamino)-3’-nitro-2,2’-dipyridinyl sulfide 113. Next, sulfide 113 rearranged to tripyridinylamine 114 (not isolated) which cyclized to 10-(3’-nitro-2’-pyridinyl)-1,6diazaphenothiazine 115. N

NH2 H N

NH2 NO2 KOH N

EtOH

S N 14d

N

NO2 NH

N

N

112

Cl N

SK NO2 15d

N

NO2

S

NO2 N

N

N

113

N

NO2

SK

114

N

NO2 N

N

N

S 115

Scheme 42 Later Morak and coworkers [68] found unexpectedly the single and double Smiles rearrangement during reaction of 4-chloro-3-nitropyridine 31a with sodium sulfide in refluxing DMF. The reaction led to new type of azaphenothiazines, 10H-2,7-diazaphenothiazine 116 and 10-(3’-nitro-4’-pyridinyl)-2,7-diazaphenothiazine 117 (Scheme 43). The reaction started as a reductive action of DMF/Na2S to form 3-amino-3’-nitro-4,4’-dipyridinyl sulfide 118 which underwent the rearrangement to dipyridinylamine 119 and further the cyclization to 10H-2,7diazaphenothiazine 116. On the other hand, dipyridinylamine 119 reacted with the substrate 31a giving sulfide 120 which underwent the rearrangement to tripyridinylamine 121 and further the cyclization to 10-nitropyridinyl-2,7-diazaphenothiazine 117. N Cl NO2

Na2S DMF

N 31a

H N N

NO2 N

S 116

Na2S DMF

N +

N

N

S 117 N

N

Cl NO2

NO2 NH2 NO2 N

N S 118

N

H N

31a

N N

NH N

N S 120

SNa NO2 119

NO2

NO2 N

N N SNa NO2 121

Scheme 43 Quite recently this group [69] studied the double Smiles rearrangement in the reaction of 3’-amino-3-nitro-2,4’-dipyridinyl sulfide 122 with 4-chloro-3-nitropyridine 31a in refluxing DMF (without a base). The first rearrangement led to sulfide 123 which did not cyclize to 10(3’-nitro-2’-pyridinyl)-2,8-diazaphenothiazine 124 (route a, Scheme 44) but underwent the second rearrangement (route b) to tripyridinylamine 125. This compound did not cyclize to 1020

Journal Pre-proof (3’-nitro-2’-pyridinyl)-2,7-diazaphenothiazine 126 (route c) but to 10-(3’-nitro-4’-pyridinyl)1,8-diazaphenothiazine 127 (route d). N N

N

N

NO2 N N

S 124

N

NO2 N

c

31a

N

NO2

NO2

NH a NO2 N

N

b

DMF

S N 122

X

N

Cl

N

N

S 126

X a

NH2 NO2

NO2 N

N N c d SH NO2 125

N

b

S 123

NO2 N

N

d

N

S 127

Scheme 44 Similarly, 3’-amino-3-nitro-2,2’-dipyridinyl sulfide 14d in the presence of 4-chloro-3nitropyridine 31a in refluxing DMF rearranged firstly to sulfide 128 which did not cyclize to 10-(3’-nitro-2’-pyridinyl)-2,6-diazaphenothiazine 129 (route a, Scheme 45), but underwent the second rearrangement to tripyridinylamine 130 (route b). The subsequent thiazine ring formation did not proceed through route c to 10-(3’-nitro-2’-pyridinyl)-3,6-diazaphenothiazine 131, but through route d to 10-(3’-nitro-4’-pyridinyl)-1,6-diazaphenothiazine 132 [70]. N N N

N

NO2 N

S 129

N

S 131

X a

NO2 N N

S N 14d

DMF

X

N

c N

Cl NH2 NO2

NO2 N

N

N

NO2 NH a NO2

31a

b N

N

NO2

N d N c N SH NO2 130

b

S 128

NO2 N

d N

N

S 132

Scheme 45 3.6. Identification of azaphenothiazines as the products of the Smiles rearrangement As was mentioned in section 3.1, the Smiles rearrangement of phenyl azinyl and diazinyl sulfides to amines is the key step in cascade processes (coupling/rearrangement/cyclization or rearrangement/cyclization) leading to azaphenothiazines from disubstituted benzenes and azines or phenyl azinyl and diazinyl sulfides. Whereas the basic reaction conditions favor the Smiles rearrangement (however, not in all cases), the reactions in the acidic conditions lead to both types of isomeric azaphenothiazines as the products of the Smiles rearrangement and the

21

Journal Pre-proof Ullmann type cyclization. There are only a few examples of isolation of the direct rearrangement products, dipyridinyl [33-36,67] or pyridazinyl phenyl [40,71] amines. In most cases, the identification of the Smiles rearrangement was based on the structure elucidation of resulted azaphenothiazines. The structural analysis of azaphenothiazines includes the localization of the azine nitrogen atoms in the ring system, localization of substituents at the carbon atoms, determination of tautomeric forms (for example hydroxypyrimidine or pyrimidinone fragments), and the analysis should be performed unequivocally and unmistakable. Several decades ago, the authors identified obtained azaphenothiazines on the basis of chemical ways, such as independent syntheses [43,72-74] or transformations of substituents via substitution [75-78], eliminations of some substituents [76,77,79,80], formations or not of 1,2,3-triazole derivatives upon diazotizations and hydrazine group condensations [75,80-84], and nitration to analyze the directive influence of substituents [8487]. Since of the middle of seventies the identification has been based on spectroscopic methods, mainly on the NMR spectra. The authors analyzed a chemical shift of the H-1 proton signal in 2,3-diazaphenothiazines [88], a broad NH proton signal resulting in the NH-O hydrogen bonding in 2,3,6-triazaphenothiazines [39], long range of the NH and H-4 proton coupling in 2,3-diazaphenothiazines [88] and the 13C_1H coupling in 1,4-diazaphenothiazines [89]. In last two decades, advanced NMR techniques were used such as NOE and later twodimensional COSY, NOESY, ROESY, HSQC and HMBC for the structure solutions of various dipyridothiazines and diquinothiazines obtained from appropriate sulfides [61,64,69,70,90-93]. Other spectroscopic methods were used occasionally, the UV spectra to identify 1,2and 2,3-diazaphenothiazines [79], and the IR spectra to observe strong hydrogen bonding between the NH and NO2 groups in 3,6-diazaphenothiazines [94]. Although the structure analysis with the X-ray method enables for direct structure elucidation without any doubts, however, only 15 types of azaphenothiazines out of over 50 known were X-ray analyzed confirming the assumed structures and showed the spatial arrangement of the molecules. Only a part of this analysis concerns the azaphenothiazines obtained through the sulfide cyclization giving the evidence of the Smiles rearrangement or not. The most X-ray analyzed azaphenothiazines is 1-azaphenothiazine with different substituents at the thiazine nitrogen atom, but these analyses were focused only on the spatial arrangement, however, they, by the way, supported the rearrangement [95-101]. The rearrangement was confirmed during syntheses of 1,3-diazaphenothiazine [102], 1,4-diazaphenothiazine [89], 2,3diazaphenothiazine [103-105], 1,6-diazaphenothiazines [70,91], 1,8-diazaphenothiazines [69,93], 2,4-diazaphenothiazine [102], 2,7-diazaphenothiazine [68] and 3,6-diazaphenothiazine [92]. Unexpectedly, the annulation reactions of dichlorodiquinolinyl sulfides with ammonia, acetamide and amines led to linear and angular diquinothiazines without the rearrangement [65,106-109]. As many the azaphenothiazines structures were assigned arbitrarily, the X-ray analysis would be more useful in the structure elucidation. 4. Summary The Smiles rearrangement, being known for almost 90 years, has been extensively studied in recent two decades proving to be a synthetically useful tool for organic and medicinal chemists to obtain various types of aromatic and heteroaromatic compounds of diverse 22

Journal Pre-proof applications. Phenothiazines and azaphenothiazines are one of the most bioactive heterocyclic scaffolds in medicinal chemistry providing recognized drugs and recently drug candidates of multitarget activities. Syntheses of azaphenothiazines are multistep processes containing coupling/Smiles rearrangement/cyclization or Smiles rearrangement/cyclization depending on starting materials (pairs of appropriate disubstituted benzenes and azines or sulfides with substituted azine moieties). The key step is the Smiles rearrangement of the S-N type of the resulted oaminophenyl azinyl sulfide or o-aminodiazinyl sulfide - the phenyl or azinyl moiety migrates from the sulfur atom to the nitrogen one (the formation of C-N bond) - followed by cyclization to form the thiazine ring (formation of C-S bond). The syntheses of azaphenothiazines without the Smiles rearrangement (with direct cyclization via the Ullmann reaction type) are observed less commonly. The rearrangement during azaphenothiazines proceeds not only in basic conditions (as in the phenothiazine synthesis) but also in weak or strong acidic and even in neutral and thermal conditions. The scope investigations showed the importance of the nature of azinyl sulfides (azines did not require additional activating groups) and steric effects of ring substituents on the rearrangement efficiency. As these syntheses are complex processes leading to azaphenothiazines of various types (mono-, diaza-, triaza- and tetraazaazaphenothiazines, and their benzo and dibenzo derivatives) and in some cases the direct cyclizations are observed, the proper structural analysis of resulting products need to be performed unequivocally and unmistakable. Unlike to examples of the Smiles rearrangement in other branches of organic chemistry, this rearrangement in the azaphenothiazine chemistry was found not only as a single kind, but also as very rare double kind of the rearrangement of two variants. The Smiles rearrangement during the syntheses of azaphenothiazines (as well as phenothiazines) occurs more frequently than one can expect and observe. There are quite a number of examples when the obtained products, especially in basic conditions, have the structures which can be attributed to both direct cyclization and the rearrangement/cyclization pathways. In these cases, only further investigations with labelled compounds will prove the reaction pathway. The azaphenothiazine literature does not facilitate searching the Smiles rearrangement due to three types of the azaphenothiazine nomenclature which two of them are confusing leading to misunderstandings in chemical names and numberings of the ring atoms. Some researchers in past and nowadays have not been aware of the rearrangement possibility and their obtained azaphenothiazines were wrongly identified. Not all azaphenothiazine structures were undoubtedly proved in past. We are convinced that this review on the Smiles rearrangement involved in the azaphenothiazine synthesis will meet with the interest of current researchers who are engaged in the synthesis and structural analysis of this type of heterocyclic compounds and pay attention to this rearrangement as a tremendously versatile reaction which has found widespread synthetic applications. 5. References 1. V. A. Mamedov, Rearrangement in the chemistry of heterocycles, Chem. Heterocycl. Compd. 53 (2017) 935. 2. A rearrangement of ortho-aminodiphenyl sulfides: a) V. J. Evans, S. Smiles, A rearrangement of o-acetamido-sulfones and –sulfides, J. Chem. Soc. 1935, 181-188, b) C. F. Wight, S. Smiles, A rearrangement of o-benzamido-sulfides, ibid, 1935, 340-343. 3. W. E. Truce, Forty years in organic chemistry, Sulfur Rep. 9 (1990) 351-357. 23

Journal Pre-proof 4. T. J. Snape, A truce on the Smiles rearrangement: revisiting an old reaction – the TruceSmiles rearrangement, Chem. Soc. Rev. 37 (2008) 2452-2458. 5. A. R. P. Henderson, J. R. Kosowan, T. E. Wood, The Truce-Smiles rearrangement and related reactions: a review, Can. J. Chem. 95 (2017) 483-504. 6. L. El Kaïm, L. Grimaud, Ugi-Smiles and Passerini_Smiles coupling, in: J. Zhu, Q. Wang, M.-X. Wang (eds), Multicomponent reactions in organic synthesis, Wiley-VCH Verlag GmbH, KGaA, Weinheim, 2015, pp 73-107. 7. L. El Kaïm, L. Grimaud, The Ugi-Smiles and Passerini-Smiles couplings: a story about phenols in isocyanides-based multicomponent reactions, Eur. J. Org. Chem. 2014, 7749-7762. 8. L. El Kaïm, L. Grimaud, Ugi-Smiles couplings: new entries to N-acyl carboxamide derivatives, Mol. Divers, 14 (2010) 855-867. 9. I. Allart-Simon, S Gerard, J. Sapi, Radical Smiles rearrangement: an update, Molecules, 21 (2016) 878. 10. K. Plesniak, A. Zarecki, J. Wicha, The Smiles rearrangement and the Julia-Kocieński olefination reaction, Top Curr. Chem. Springer-Verlag, Berlin, 2007, 275, pp 163-250. 11. J. F. Bunnet, R. E. Zahler, Aromatic nucleophilic substitution reactions, Chem. Revs. 49 (1951) 273-412. 12. H. J. Shine, Aromatic rearrangements, Elsevier, Amsterdam, 1967 pp 307-316. 13. W. E. Truce, E. M. Kreider, W. W. Brand, The Smiles and related rearrangements of aromatic systems, Org. React. 18 (1970) 99-215. 14. T. S. Stevens, W. E. Watts, Selected molecular rearrangements, van Nostrand-Reinchold, London 1973, pp 120-124. 15. R. R. Kumar, S. Perumal, Smiles rearrangement, Name reactions for homologations, part 2, in: J. J. Li (ed.) Wiley, Hoboken, New Jersey, 2009, pp 489-515. 16. S. Xia, L.-Y. Wang, H. Zuo, Z.-B. Li, Smiles rerrangement in synthetic chemistry, Curr. Org. Synthesis, 10 (2013) 935-946. 17. L. El Kaïm, L. Grimaud, Smiles rearrangements, in: C. Rojas (ed.), Molecular rearrangements in organic synthesis, 2016, Wiley, Hoboken, New Jersey, pp 629-660. 18. C. M. Holden, M. F. Greaney, Modern aspects of the Smiles rearrangement, Chem. Eur. J. 23 (2017) 8992-9008. 19. A. Ramazani, F. Moradnia, H. Aghahosseini, I Abdolmaleki, Several species of nucleophiles in the Smiles rearrangement, Curr. Org. Chem. 21 (2017) 1612-1625. 20. R. R. Gupta; M. Kumar, Synthesis, properties and reactions of phenothiazines, in: R. R. Gupta (ed.), Phenothiazine and 1,4-Benzothiazines – Chemical and Biological Aspect; Elsevier, Amsterdam, 1988, pp 1-161. 21. J. Huang, D. Zhao, Z. Liu, F. Liu, Repurposing psychiatric drugs as anti-cancer agents, Cancer Lett. 419 (2018) 257-265. 22. J. E. Kristiansen, S. G. Dastidar, S. Palchoudhuri, D. S. Roy, S. Das, O. Hendricks, J. B. Christensen, Phenothiazines as a solution for multidrug resistant tuberculosis: from the origin to present, Int. Microb. 18 (2015) 1-12. 23. L. Amaral, M. Viveiros, Thioridazine: a non-antibiotic drug highly effective, in combination with first line anti-tuberculosis drugs, against any form of antibiotic resistance of mycobacterium tuberculosis due to its multi-mechanisms of action, Antibiotics, 6, (2017) 3. 24. G. Sudeshna, K. Parimal, Multiple non-psychiatric effects of phenothiazines: a review, Eur. J. Pharmacol. 648 (2010) 6-14. 25. H. Yue, D. Huang, L. Qin, Z. Zheng, L. Hua, G. Wang, J. Huang, H. Huang, Targeting lung cancer stem cells with antipsychological, drug thioridazine, BioMed. Res. Int. 2016, 6709828. 24

Journal Pre-proof 26. K. Pluta, M. Jeleń, B. Morak-Młodawska, M. Zimecki, J. Artym, M. Kocięba, E. Zaczyńska, Azaphenothiazines - promising phenothiazine derivatives. An insight into nomenclature, synthesis, structure elucidation and biological properties, Eur. J. Med. Chem. 138 (2017) 774806. 27. I. A. Silberg, G. Cormos, D. C. Oniciu, Retrosynthetic approach to the synthesis of phenothiazines, in: A. R. Katritzky (ed.), Advances in Heterocyclic Chemistry; Elsevier, 90 (2006) 205-237. 28. C. O. Okafor, Studies in the heterocyclic series. III. The chemistry of azaphenothiazine compounds, Int. J. Sulfur Chem. B 6 (1971) 239-265. 29. C. O. Okafor, Studies in heterocyclic series. XIV, Phosphorus Sulfur Silicon Relat. Elem. 4 (1978) 79-99. 30. K. Pluta, B. Morak-Młodawska, M. Jeleń, Synthesis and properties of diaza-, triaza- and tetraazaphenothiazines, J. Heterocycl. Chem. 46 (2009) 355-391. 31. V. A. Petrow, E. L. Rewald, New synthesis of heterocyclic compounds. Part IV. 3Azaphenothiazines, J. Chem. Soc. 1945, 591-593. 32. Rhône-Poulenc, Azaphenothiazines and intermediates, British Patent 791190 (1958). 33. O. Rodig, R. Collier, R. Schlatzer, Pyridine chemistry. I. The Smiles rearrangement of the 3-amino-2,2‘-dipyridyl sulfide system, J. Org. Chem. 29 (1964) 2652-2658. 34. T. Takahashi, Y. Maki, Sulfur-containing pyridine derivatives .LVI. Smiles rearrangement of pyridine derivatives and synthesis of benzopyrido- and dipyrido-1,4-thiazine derivatives, Chem. Pharm. Bull. 6 (1958) 369-373. 35. Y. Maki, Sulfur-containing pyridine derivatives. LIII. Smiles rearrangement in pyridine derivatives and syntheses of azaphenothiazine derivatives. Yakugaku Zasshi 77 (1957) 485490. 36. Y. Maki, M. Suzuki, T. Masugi, Steric effect on the Smiles rearrangement, Chem. Pharm. Bull. 16 (1968) 559-560. 37. F. Yoneda, T. Ohtaka, Y. Nitta, Pyridazine derivatives. VII. Syntheses of 1,2- and 2,3diazaphenothiazines, Chem. Pharm. Bull. 13 (1965) 580-585. 38. C. O. Okafor, R. Castle, D. Wise, Unequivocal synthesis of 2,3,6-triazaphenothiazine and two new tetraazaphenothiazine heterocycles, J. Heterocycl. Chem. 20 (1983) 1047-1051. 39. C. O. Okafor, R. Castle, Synthesis of analogues of the 2,3,6-triazaphenothiazine ring system, J. Heterocycl. Chem. 20 (1983) 199-203. 40. G. Scapini, F. Duro, G. Pappalardo, Syntesi di 2,3-diazafenotiazine. IV. 3,10-diidro-3Hpiridazino[4,5-b][1,4]benzotiazin-4-one e derivati, Ann. Chim. 58 (1968) 718-724. 41. P. Condorelli, G. Pappalardo, M. Raspagliesi, Syntesi di 2,3-diazafenotiazine. II. N-metil derivati di 1,4-diossi-1,2,3,4-tetraidro-2,3-diazafenotiazine, Boll. Sedute. Accad. Gioenia Sci. Natur. Catania 9 (1967) 242-251. 42. A. J. Saggiomo, P. N. Craig, M. Gordon, Synthesis of 2-aza- and 8-chloro-3-azaphenothiazine, J. Org. Chem. 23 (1958) 1906-1909. 43. A. Westermann, O. Bub, L. Suranyi, Verfahren zur Herstellung von Diaza-phenthiazinen, German. Patent 1,110,651 (1961). 44. T. Dahl, C. W. Tornøe, B. Bang-Andersen, P. Nielsen, M. Jørgensen, Palladium-catalyzed three-component approach to promazine with formation of one carbon–sulfur and two carbon– nitrogen bonds, Angew. Chem. Int. Ed. 47 (2008) 1726-1728. 45. D. Ma, Q. Geng, H. Zhang, Y. Jiang, Assembly of substituted phenothiazines by a sequentially controlled CuI/L-proline-catalyzed cascade C_S and C_N bond formation, Angew. Chem. Int. Ed. 49 (2010) 1291-1294. 25

Journal Pre-proof 46. C. Dai, X. Sun, X. Tu, L. Wu, D. Zhan, Q. Zeng, Synthesis of phenothiazinesvialigand-free CuI-catalyzed cascade C–S and C–N coupling of aryl ortho-dihalides and orthoaminobenzenethiols, Chem. Commun. 48 (2012) 5367-5369. 47. M. Huang, J. Hou, R. Yang, L. Zhang, X. Zhu, Y. Wan, A catalyst system, copper/Nmethoxy-1H-pyrrole-2-carboxamide, for the synthesis of phenothiazines in poly(ethylene glycol), Synthesis 46 (2014), 46, 3356-3364. 48. W. Hu, S. Zhang, Method for the synthesis of phenothiazines via a domino iron-catalyzed C–S/C–N cross-coupling reaction, J. Org. Chem. 80 (2015) 6128-6132. 49. L. Wei, L. Xub, R.-Y. Tang, Iodine-mediated synthesis of benzopyridothiazines via tandem C–H thiolation and amination, RSC Adv. 15 (2015) 107927-107930. 50. M. Huang, D. Huang, X. Zhu, Y. Wan, Copper-catalyzed domino reactions for the synthesis of phenothiazines, Eur. J. Org. Chem. 2015, 4835-4839. 51. S. Wu, W.-Y. Hu, S.-L. Zhang, Potassium carbonate-mediated tandem C–S and C–N coupling reaction for the synthesis of phenothiazines under transition-metal-free and ligand-free conditions, RSC Adv. 6 (2016) 24257-24260. 52. B. Roth, L. Schloemer, 5-Arylthiopyrimidines.III. Cyclization of 4-hydroxy derivatives to 10H-pyrimido[5,4-b]benzothiazines (1,3-diazaphenothiazines), J. Org. Chem. 28 (1963) 26592672. 53. B. Roth, J. Bunnett, 5-Arylthiopyrimidines. V. Kinetics of the cylization of 4-oxoderivatives to 10H- and 10-alkylpyrimido[5,4-b][1,4]benzothiazines (1,3-diazaphenothiazines), J. Am. Chem. Soc. 87 (1965) 340-349. 54. The Wellcome Foundation Ltd, 10-Substituted 1,3-diazaphenothiazines, British Patent 1,015784 (1966). 55. H. Fenner, Dioxopyrimido-benzothiazin-Derivative – möglische Flavin-Antimetaboliten, Arzneim-Forsch. (Drug Res.) 20 (1970) 1815-1818. 56. H. Fenner, R. Grauert, Synthese und Reaktivitatät von 1,5-Dihydro-5-thiaflavinen, Liebigs Ann. Chem. 1978, 193-213. 57. G. Pappalardo, F. Vittorio, G. Ronsisvalle, F. Duro, Investigation on 2,3diazaphenothiazine. VII. Quaternization reactions, Ann. Chim. 63 (1973) 255-267. 58. K. Kaji, H. Nagashima, Y. Masaki, M. Yoshida, K. Kamija, 4-HBenzo[b][1,2,4]triazino[5,6-e][1,4]thiazin-3(2H)-ones, Japan. Kokai 74 48,697 (1974); Chem. Abstr. 82 (1975) 43470p. 59. K. Kaji, H. Nagashima, Y. Masaki, M. Yoshida, K. Kamija, 5-HBenzo[b][1,2,4]triazino[5,6-e][1,4]thiazin-3(2H)-ones, Japan. Kokai 74 48,698 (1974); Chem. Abstr. 82 (1975) 43471q. 60. The Wellcome Foundation Ltd, 1,3-Diazaphenothiazines and method, British Patent 1,014,881 (1965). 61. K. Pluta, Synthesis and NMR properties of pentacyclic heterocycles containing sulfur, nitrogen and oxygen or selenium, Phosphorus, Sulfur, Silicon 92 (1994) 149-154. 62. K. Pluta, Synthesis and properties of 14-substituted 1,4-thiazinodiquinolines, Phosphorus, Sulfur, Silicon 126 (1997) 145-156. 63. K. Pluta, A. Maślankiewicz, M. Szmielew, N,N-Dialkylaminoalkyl substituted quinobenzo[1,4]thiazines and diquino[1,4]thiazines, Phosphorus, Sulfur, Silicon 159 (2000) 79-86. 64. M. Nowak, K. Pluta, Synthesis of novel heteropentacenes containing nitro-gen, sulfur and oxygen or selenium, New J. Chem. 26 (2002) 1216-1220.

26

Journal Pre-proof 65. M. Nowak, K. Pluta, K. Suwińska, L. Straver, Synthesis of new pentacyclic diquinothiazines, J. Heterocycl. Chem. 44 (2007) 543-550. 66. Y. Maki, M. Suzuki, The double Smiles rearrangement, Chem. Pharm. Bull. 20 (1972) 607609. 67. O. Rodig, R. Collier, R. Schlatzer, Pyridine chemistry. II. Further studies on the Smiles rearrangement of the 3-amino-2,2‘-dipyridyl sulfide system. The synthesis of some 1,6diazaphenothiazines, J. Med. Chem. 9 (1965) 116-120. 68. B. Morak, K. Pluta, K. Suwińska, Unexpected simple route to novel dipyrido-1,4-thiazines Heterocycl. Commun. 4 (2002) 331-334. 69. B. Morak-Młodawska, K. Suwińska, K. Pluta, M. Jeleń, 10-(3’-Nitro-4’-pyridyl)-1,8diazaphenothiazine as the double Smiles rearrangement, J. Mol. Struct. 1015 (2012) 94-98. 70. B. Morak-Młodawska, K. Pluta, K. Suwińska, M. Jeleń, The double Smiles rearrangement in neutral conditions leading to one of 10-(nitropyridinyl)dipyridothiazine isomers, J. Mol. Struct. 1133 (2017) 398-404. 71. Y. Maki, M. Suzuki, O. Toyota, M. Takaya, Studies on the Smiles rearrangement. XII. Synthesis and structural assignment of two isomeric N-phenyl-2,3-diazaphenothiazinones, Chem. Pharm. Bull. 21 (1973) 241-247. 72. A. Phillips, N. Mehta, J. Z. Strelitz, Syntheses of 1,3-Diazaphenothiazines, J. Org. Chem. 28 (1963) 1488-1490. 73. Y. Maki, T.; Hiramitsu, M. Suzuki, Studies on the Smiles r5arrangement. XIV. Novel reactions of 1,3-dimethyl-5-nitro-6-chlorouracil with 2-aminothiophenol, Chem. Pharm. Bull. 22 (1974) 1265-1268. 74. D. Wise, R. Castle, The synthesis of novel dipyridazinothiazine ring systems, J. Heterocyclic Chem. 11 (1974) 1001-1009. 75. G. Pappalardo, F. duro, G. Scapini, Sintezi di 2,3-diazafenotiazine. V. 10H-piridazino[4,5b][1,4]benzotiazina e derivati clorurati ed idrazinici, ,Ann. Chim. 61 (1971) 280-289. 76. G. Pappalardo, E. Bousquet, F. Duro, Sintezi di 2,3-diazafenotiazine. VIII. 3-Arilderivati del 2,3-diidropiridazino[4,5-b][1,4]benzotiazin-(10H)-1,4-dione, Farmaco 28 (1973) 681-690. 77. F. Duro, P. Condorelli, G. Pappalardo, Sintezi di 2,3-diazafenotiazine. XI. 2- e 3-arilderivati del 10-metil-2,3-diidropiridazino[4,5-b][1,4]benzotiazin-1,4(10H)-dione, Farmaco 32 (1977) 173-179. 78. P. Condorelli, G. Pappalardo, F. Duro, Sintezi di 2,3-diazafenotiazine. XII. Derivati dialchilaminoalchilici del 2-fenile 3-fenil-10-metil-2,3-diidropiridazino[4,5b][1,4]benzotiazin-(10H)-dione, Farmaco 32 (1977) 531-538. 79. F. Yoneda, T. Ohtaka, Y. Nitta, Pyridazine derivatives. VII. Syntheses of 1,2- and 2,3diazaphenothiazines, Chem. Pharm. Bull. 13 (1965) 580-585. 80. G. Pappalardo, F. Duro, G. Scapini, F. Vittorio, Sintezi di 2,3-diazafenotiazine. VI. Derivati idrazinici della 2,3-diazafenotiazina, Farmaco 27 (1972) 643-655. 81. C. O. Okafor, Studies in the heterocyclic series. VIII. The first synthesis of a triazaphenothiazine ring, J. Org. Chem.38 (1973) 4387-4390. 82. C. O. Okafor, M. L. Steenberg, J. P. Buckley, Studies in the heterocyclic series. XIII. New CNS-depresants derived from 1,9-diazaphenoxazine and two isomeric triazaphenothiazine ring systems, Eur. J. Med. Chem. - Chem. Ther. 12 (1977) 249-256. 83. C.O. Okafor, 1,3,9-Triazaphenothiazine ring system, a new phenothiazine ring, J. Org. Chem. 40 (1975) 2753-2755. 84. C.O. Okafor, I. Uche, L. Akpanisi, Studies in the heterocyclic series. XXI. A novel tetraazaanalog of phenothiazines, J. Heterocycl. Chem. 18 (1981) 1589-1593. 27

Journal Pre-proof 85. C.O. Okafor, A new type of triazaphenothiazine heterocycle, J. Heterocycl. Chem. 17 (1980) 149-153. 86. C.O. Okafor, Studies in the heterocyclic series. XVIII. Utilization of 4-aminopyrimidine chemistry in 1,4,7,9-tetraazabenzo[b]phenothiazine synthesis, J. Heterocycl. Chem. 17 (1980) 1587-1592. 87. C.O. Okafor, Studies in heterocyclic series. XIX. Synthesis of 1,4-diazaphenothiazine and its benzo derivatives, J. Heterocycl. Chem. 18 (1981) 405-409. 88. F. Duro, G. Scapini, F. Vittorio, Sintezi di 2,3-diazafenotiazine. IX. Derivati 1- e 4alchilaminoci, triazolici ed N-10-dialchilaminoalchilici della 2,3-diazafenotiazina, Farmaco 30 (1975) 208-222. 89. W. Saari, D. Cochran, Y. Lee, E. Cresson, J. Springer, M. Williams, J. Totaro, G. Yarbrough, Preparation of some 10-[3-(dimethylamino)propyl]-10H-pyrazino[2,3b][1,4]benzothiazines as potential neuroleptics, J. Med. Chem.26 (1983) 564-569. 90. B. Morak, K. Pluta, Synthesis of novel dipyrido-1,4-thiazines, Heterocycles 71 (2007) 1347-1361. 91. B. Morak-Młodawska, K. Pluta, M. Zimecki, M. Jeleń, J. Artym, M. Kocięba, Synthesis and selected immunological properties of 10-substituted 1,8-diazaphenothiazines, Med. Chem. Res. 24 (2015) 1408-1418. 92. B. Morak-Młodawska, K. Pluta, M. Latocha, K. Suwińska, M. Jeleń, D. Kuśmierz, 3,6Diazaphenothiazines as potential lead molecules - synthesis, characterization and anticancer activity, J. Enzyme Inhib. Med. Chem. 31 (2016) 1512-1519. 93. B. Morak-Młodawska, K. Pluta, M. Latocha, M. Jeleń, Synthesis, spectroscopic characterization and anticancer activity of new 10-substituted 1,6-diazaphenothiazines, Med. Chem. Res.25 (2016) 2425-2433. 94. C.O. Okafor, A novel diazaphenothiazine system, J. Org. Chem. 32 (1967) 2006-2007. 95. S. S. C. Chu, P. de Meester, R. D. Rosenstein, Conformation of 10heteroarylphenothiazines, Acta Crystallogr. A 40 (1984) (Suppl), C277. 96. P. de Meester, S. S. C. Chu, 10-(2-Methoxypenyl)pyrido[3,2-b][1,4]benzothiazine, C18H14N2OS, Acta Crystallogr. C 40 (1984) 1753-1756. 97. M. V. Jovanovic, E. R. Biehl, P. de Meester, S. S. C. Chu, Radical cation formation and crystal structure determination of 4’-dimethylamino-10-phenylpyrido[3,2-b]benzothiazine, J. Heterocycl. Chem. 21 (1984) 1425-1429. 98. M. V. Jovanovic, E. R. Biehl, P. de Meester, S. S. C. Chu, Molecular structure and 13C chemical shift assignments of 10-(2’-pyridyl)pyrido[3,2-b][1,4]benzothiazine using 10phenylpyrido[3,2-b][1,4]benzothiazine as the model compound, J. Heterocycl. Chem. 22 (1985) 777-783. 99. P. de Meester, S. S. C. Chu, Structure of 10-(4-methoxypenyl)pyrido[3,2-b] [1,4]benzothiazine, C18H14N2OS, Acta Crystallogr. C 41 (1985) 1246-1249. 100. P. de Meester, S. S. C. Chu, 10-(4-Nitrophenyl)pyrido[3,2-b][1,4]benzothiazine, Acta Crystallogr. C 42 (1986) 877-879. 101. M. V. Jovanovic, E. R. Biehl, P. de Meester, R. D. Rosenstein, S. S. C. Chu, Synthesis, 13C NMR spectrum and crystal structure of 10-phenylpyrido[3,2-b][1,4]benzothiazine 5-oxide, J. Heterocycl. Chem. 23 (1986) 797-800. 102. E. A. Haidasz, D. A. Pratt, Diazaphenoxazines and diazaphenothiazines: synthesis of the “correct” isomers reveals they are highly reactive radical‑trapping antioxidants, Org. Lett. 19 (2017) 1854−1857. 103. G. D. Andretti, G. Bocelli, P. Sgarabotto, 1-Oxo-1,2-dihydro-2,3-diazaphenothiazine. C10H7N3OS·H2O, Cryst. Struct. Commun. 3 (1974) 519-522. 28

Journal Pre-proof 104. G. D. Andretti, G. Bocelli, P. Sgarabotto, 10-Methyl-2,3-diazaphenothiazine. C11H9N3S, Cryst. Struct. Commun. 3 (1974) 547-549. 105. G. D. Andretti, G. Bocelli, P. Sgarabotto, The structures of 1-oxo-1,2-dihydro-2,3diazaphenothiazine and 1-chloro-10-methyl-2,3-diazaphenothiazine, Acta Crystallogr. B 36 (1980) 1839-1846. 106. K. Pluta, M. Nowak, K. Suwińska, X-ray structure of 6-phenyldiquino[3,2b;5,6-b’][1,4]thiazine, J. Chem. Crystallogr. 30 (2000) 479-482. 107. K. Pluta, K. Suwińska, 14-Methyl-1,4-thiazino[2,3-c;6,5-c’]diquinoline, Acta Crystallogr. C 56 (2000) 374-375. 108. C. Besnard, C. Kloc, T. Siegrist, K. Pluta, X-ray structure of 14-phenyldiquino [3,4-b;4’,3’-e][1,4]thiazine, J. Chem. Cryst. 35 (2005) 731-736. 109. M. Jeleń, A. Shkurenko, K. Suwińska, K. Pluta, B. Morak-Młodawska, 6-[3-(pTolylsulfonylamino)propyl]diquinothiazine, Acta Crystallogr. E 69 (2013) o972-o973.

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Declaration of interests ☒ The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. ☐The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:

Journal Pre-proof Highlights Azaphenothiazines are obtained via the Smiles rearrangement or direct cyclization. The rearrangement of phenyl azinyl sulfides and diazinyl sulfides was reviewed. The rearrangement proceeds in basic, neutral, weakly and strongly acidic conditions. The review discusses nature of sulfides, steric hindrance and structural analysis. The review contains 44 reaction schemes and 108 references.