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Substituted 1,3l4d2,2,4-Benzodithiadiazines, a Formally Antiaromatic 12p-Electron Heterocycles: Synthesis and Some Properties

Alexander Yu. Makarova, Irina Yu. Bagryanskayaa, Victor A. Bagryanskyb, Yuri V. Gatilova, Makhmut M. Shakirova

and Andrey V. Zibareva*

a Institute of Organic Chemistry, Russian Academy of Sciences, 630090 Novosibirsk, Russia
b Institute of Chemical Kinetics and Combustion, Russian Academy of Sciences, 630090 Novosibirsk, Russia


Abstract

The preparation, X-ray structural and 15N NMR characterization of the title compounds is described along with their some properties such as transformation into Herz salts (1,2,3-arenodithiazolium chlorides) under the action of SCl2, into persistent radicals of benzo[c]-1,2-thiazet-yl type under mild thermolysis, and into substituted 2,2'-diaminodiphenyl disulfides via corresponding 2-aminobenzenethiols under mild acid hydrolysis.

Graphical Abstract


Introduction

Recently, the synthesis of 1,3l4d2,2,4-benzodithiadiazine (1)1 and its 5,6,7,8-tetrafluoro derivative (2)2 (Scheme 1) was described. These are 12p-electron, formally antiaromatic3, but thermodinamically quite stable compounds4-6. Their chemistry has been investigated only to a slight degree1,2,7, while possible antiaromaticity (although obviously reduced5,6 ) should lead to high and varied, essentially unpredictable7, reactivity.
Scheme 1
 
 
The present article deals with the synthesis of novel substituted 1,3l4d2,2,4-benzodithiadiazines for further investigation of their  heteroatom reactivity.

Results and Discussion

Cyclization. The 1:1 condensation of C6H5-N=S=N-SiMe3 with SCl2, followed by intramolecular electrophilic ortho-cyclization of [C6H5-N=S=N-S-Cl] intermediate, had previously been used to prepare 11. Despite some limitations, the same approach also makes it possible to obtain various carbocyclic substituted derivatives of 1 in moderate to good yields (Scheme 2, Table 1).
Scheme 2
 
 
 
n/R
CH3
OCH3
F
CF3
Cl
NO2
5
3
7
11
15
19
 
6
4
8
12
(16)
20
 
7
5
(9)
(13)
(17)
21
(23)
8
6
(10)
(14)
(18)
22
 
Brackets indicate that corresponding heterocycle was not either synthesized by this way (9, 13, 16-18, 23), or detected as minor isomer (10, 14).

Thus, the target heterocycle formation proceeds smoothly with all the 2-RC6H4-N=S=N-SiMe (R=CH3, OCH3 , F, Cl, CF3) compounds tried to give corresponding 5-R-substituted derivatives of 1. In the case of 4-RC6H4-N=S=N-SiMe the cyclization readily occurs with R=CH3, Cl, while with R=OCH3 , F, CF3 and NO2 the expected 7-R-substituted derivatives of 1 are not found in the reaction mixtures. This is somewhat unexpected because the site of ring closure meta to R is the same for both 2-R-  and 4-RC6H4-N=S=N-SiMe3.

With 3-RC6H4-N=S=N-SiMe3 (R=CH3, OCH3 , F, Cl) the cyclization is highly regioselective leading exclusively (R=OCH3,  F ) or predominantly (R=CH3, Cl ) to 6-R-substituted derivatives of 1; the ratio of the major 6-R isomer to the minor 8-R one is 78:22 (R = Cl) and 72:28 (R=CH3) as shown by 1H NMR spectroscopy (the structure of the 6-CH3 isomer 4 and of the 6-F isomer 12 has been confirmed by X-ray crystallography, see Figure 1). In the case of R=CFthe cyclization fails, probably due to an unfavorable situation for electrophilic ring closure involving distribution of effective charges, qi, around the carbocycle perimeter.

The preferred direction of cyclization of 3-RC6H4-N=S=N-SiMe3 is consistent with the thermodynamics of corresponding Wheland type s-complexes (modeling a late transition state of the electrophilic aromatic substitution), as well as factors of kinetic control for orbital-controlled El-Nu interaction 8. Thus, according to the DHfo (PM3) data, the 6-R isomer of a s-complex is more stable than the 8-R one by ~ 3 ( R=CH3, Cl; 8-R isomer of a final product being observable) or by ~ 6 (R=OCH3 , F; 8-R isomer of a final heterocycle not being detectable) kcal mol -1. Under the orbital control the site of the cyclization is determined by ci2 distribution for the Nu's HOMO (taken as aromatic ring part of the HOMO (PM3) of the [3-RC6H4-N=S=N-S-Cl] intermediate with El's LUMO being an S-Cl s*-antibonding MO) with the c62 value exceeding that of c22 by a factor of 2.3 - 3.1.

According to the  DHfo (PM3) data there is no specific destabilization of the corresponding s-complexes nor of the desired heterocycles in the case of the unsuccessful cyclizations as compared with the successful ones. It seems that a complex  balance of different parameters of a molecular electronic structure (ci2 and qi distribution, ei values of Nu's HOMO and El's LUMO) is responsible for the cyclization failures observed.

Cyclization By-Products. In some cases of both successful and unsuccessful cyclizations, the Herz salts (1,2,3-arenodithiazolium chlorides)9 have been isolated from the reaction mixtures (for selected examples, see Table 2) along with sulfur nitride (SN)4. Special experiments confirmed that it is possible to explain formation of the salts via interaction of the title compounds with SCl2 according to Scheme 3. The Scheme 3 is also substantiated by 14N NMR identification of thiazyl  chloride NSCl (d14N 730 in CCl4) in the reaction mixtures. The identification was based on previously reported data19 as well as measurements on authentic sample prepared19 by heating a solution of (NSCl)320 in CCl4. At the same time, (NSCl)3 is not found in the reaction mixtures which corresponds to the conclusion that trimerization of NSCl is very kinetically hindered19.

Comparison of data presented above on the one hand, and data7 on the interaction of 2 with Ph3P (Scheme 3) on the other hand, makes it possible to speculate that reaction of the title compounds with formal both electrophile (SCl2) and nucleophile (Ph3P) proceeds in a similar way, namely, as neutralization of Lewis acid (the title compounds: low-lying vacant MOs; cf. Table 1) by Lewis base (SCl2 and Ph3P: electron lone-pair).
 

Scheme 3
 
 

Molecular Structure. According to the X-ray diffraction data, the parent molecule 1 is planar 1, whereas heterocycle  2 is twisted along the S1 ... N4 line by 5.5o 2.

In the present work both types of molecular geometry were observed (Figure 1).  In the case of derivatives of 1 possessing moderate or strong p-donor R substituents, 4 (R = 6-CH3) and 7 (R = 5-OCH3), the heterocycles were found to be bent along the S1 ... N4 line by ~ 7o (4)  or ~ 11o (7). Contrary to 4 and 7, the heterocycles of derivatives of 1 with a weak p-donor and/or a strong s-acceptor substituent R, 12 (R = 6-F) and 15 (R = 5-CF3), are planar.

Figure 1. Molecular structure of compounds 4, 7, 12 and 15 (atomic coordinates, thermal parameters, bond lengths, and bond angles have been deposited at the Cambridge Crystallographic Data Centre). The bond lengths are typical1,2,18

The structural dichotomy found for the title compounds is reminiscent of the result previously observed for related 3,7-R2-1,5-dithia-2,4,6,8-tetrazocines: according to the X-ray diffraction data, with R = C6H5 the molecules are planar while with R = (CH3)2N they are folded along an S1 ... N5 axis10. The distortion was rationalized as being driven by a pseudo-Jahn-Teller instability in the p-system, namely, by p-donor-induced mixing of the high-lying p-HOMO with a low-lying virtual s-MO11. It seems, that the same explanation is also valid in the case of the title compounds too. For verification, quantum chemical calculations are planned for the future.

Heteroatom Reactivity.  The extensive investigation of the title compounds' heteroatom reactivity is in progress. Only few results obtained are presented below just to provide the examples.

Thus, mild thermolysis of the title compounds (~ 150oC in squalane) leads to persistent radicals of benzo[c]-1,2-thiazet-yl type12 (Scheme 4) identified by ESR spectroscopy. Previously, only parent benzo[c]-1,2-thyazet-yl and its naphtho-analog, prepared in a different way, were known12. The thermolysis of the title compounds suggested here provides an easy access to the whole family of ring substituted benzo[c]-1,2-thyazet-yls.

On mild acid hydrolysis the title compounds afford 2-aminobenzenethiols, identified for technical reasons in the form of corresponding disulfides (Scheme 4), which is useful adjunct to known methods. In particular, some previously unknown derivatives become available (for selected examples, see Table 3).

Scheme 4
 

As the starting materials for the preparation of the title compounds are ArNH2 (à ArN=S=O à ArN=S=NSiMe3 à heterocycle) in hydrocarbon series (1 and this work), and ArFSH (à ArFSCl à ArFSN=S=NSiMe3 à heterocycle) in fluorocarbon series2, the formation of dithiadiazine followed by hydrolysis of the heterocycle can be considered to be a useful method for both ortho-thiolation  of aromatic amines and ortho-amination of polyfluoroaromatic thiols (cf. also the related approach to ortho-amination of polyfluoroaromatic amines via polyfluorinated 2,1,3-benzothiadiazoles13).

For the reaction of the title compounds with SCl2 leading to the Herz salts, see Cyclization By-products (Scheme 3).

Acknowledgments

The authors are grateful to the Russian Foundation for Basic Research for financial support of this work (Project 96-03-33276), and for providing both multinuclear NMR facilities at the Collective Analytical Center of the Siberian Division of the Russian Academy of Sciences (Project 96-03-40001) and an access to the Cambridge Crystallographic Data Centre (Project 96-07-89187).
 

Experimental

The 1H, 13C, 14N and 15N NMR spectra were recorded with a Bruker DRX-500 spectrometer at frequencies of 500.13, 125.76, 36.13, and 50.68 MHz, respectively, with TMS and NH3 (liq.) as standards; the 19F NMR spectra were measured on a Bruker AC-200 spectrometer at a frequency of 188.28 MHz with C6F6 as standard; the mass spectra were taken on a Finnigan MAT MS-8200 instrument (EI, 70 eV); and the UV/Vis spectra were collected on a Beckman DU-8 spectrophotometer.
The ESR spectra were recorded by using a Bruker EMX spectrometer (microwave power was 2 mW, modulation frequency 100 KHz, and modulation amplitude 0.1 G). The spectra simulation was performed with Simphonia-Bruker program.

The X-ray structure determinations (Figure 1) were carried out on a Syntex P21 diffractometer using Cu-Ka radiation with a graphite monochromator. Corrections for both a systematic intensity drop and absorption were made. The structures were solved by direct methods using the SHELX-86 program and refined by the least-squares method in the full-matrix anisotropic (isotropic for H atoms) approximation using the SHELXL-93 and SHELXL-97 programs to R (wR2) 0.0475 (0.1252), 0.0501 (0.1381), 0.0633 (0.1593) and 0.0693 (0.1939) for 4, 7, 12 and 15, respectively. The PM3 calculations were performed with full geometry optimization.

The syntheses described subsequently were carried out, except for hydrolysis, in an argon atmosphere in absolute solvents with stirring.

Substituted 1,3l4d2,2,4-Benzodithiadiazines 3-8, 11, 12, 15, 19-22 (Table 1)

a) Solutions of 1.03 g (0.01 mol) of SCl2 and 0.01 mol of corresponding Ar-N=S=N-SiMe314, each in 30 ml of CH2Cl2, were slowly mixed by adding them dropwise to 300 ml of CH2Cl2 at 20oC, over a period of 1 h. After a further 1 h, the reaction solution was filtered, the solvent distilled off under reduced pressure, the residue sublimed in vacuo and the product recrystallized from hexane. Compounds 3-5, 7, 8, 11, 12, 15, 19-21 were isolated as black crystals. The precipitate was recrystallized from SOCl2:CCl4 (3:1) to obtain Herz salts.

In the case of Ar = 3-RC6H4, the filtrate was concentrated to an appropriate volume and the 1H NMR spectrum was measured to estimate the ratio of 6-R and 8-R isomers (enchanced shielding of H5,8 as compared with H6,7 makes it possible to assign unambiguously the signals of both isomers). After the same as above work-up of the solution, the major 6-R isomer was obtained by recrystallization while the minor 8-R isomer (6 and 22) was characterized only spectroscopically without eventual isolation.

b) In all other cases under the same conditions only (SN) and/or Herz salts were obtained along with some unidentified products.

Interaction of the title compounds with SCl2. Herz salts.

At 20oC, a solution of 0.31 g (0.003 mol) of SCl2 in 20 ml of CH2Cl2, was added during 45 min to a solution of 0.03 mol of one of the title compounds in 50 ml of the same solvent. After 15 min, the precipitate was filtered off, dried in vacuo, and recrystallized from SOCl2:CCl4 (3:1). Corresponding Herz salts9 were obtained as crystalline solids in nearly quantitative yields and characterized by high-resolution MS and multinuclear (1H, 13C and 14N) NMR (selected examples are given in Table 2).

To detect NSCl, the interaction was performed in CCl4 with more concentrated (~ 0.6 M) reactant solutions, and the 14N NMR spectrum of the reaction mixture was measured periodically during the reaction time.

Acid hydrolysis of the title compounds. 2,2'-Diaminodiaryl disulfides via 2-aminoarenethiols

At 0oC, to a solution of 0.02 mol of one of the title compounds in 10 ml of THF, was added a solution of 0.36 g of 1:10 diluted hydrochloric acid in 5 ml of THF. After 30 min, 15 ml of Et2O and then aqueous Na2CO3 were added. Organic layer was separated, dried over CaCl2, the solvent distilled off, and the residue recrystallized from hexane or heptane. 2,2'-Diaminodiaryl disulfides were obtained as (pale) yellow crystals (selected examples are given in Table 3).

Thermolysis of the title compounds. Ring substituted benzo[c]-1,2-thyazet-yls.

A 10-3 M solution of the title compound in squalane, degassed by a series of three freeze-pump-thaw cycles,  was gradually heated in a ESR velve-equipped quartz capillary until ESR spectrum of a persistent radical appeared (at ~ 150oC). After 1 h, the sample was cooled to 20oC, diluted with hexane (1:3), and ESR spectrum was measured. The ESR parameters of selected radicals are given in Table 4. The simulated and experimental spectra are in very good agreement.
 

Table 1. Substituted 1,3l4d2,2,4-Benzodithiadiazinesa
 
Compound
M.p. (oC)
Yield (%)
15N NMRb 
d (ppm) (J, Hz)
UV-Visc, lmax(nm) 
(log e)
3
46 - 47
15
268.4 (s),
261.3 (s)
629 (2.60)
4
70 -71
30
269.4 (s),
263.0 (d, 2.7)
632 (2.61)
5
67 - 68
19
263.1 (d, 3.0),
262.6 (s)
621 (2.69)
6
 
 
261.7 (s),
260.0 (d, 3.0)
 
7
73 - 74
41
263.6 (s),
251.0 (s)
637 (2.63)
8
31 - 32
25
274.9 (s),
261.2 (d, 2.7)
636 (2.49)
11
73 - 74
42
268d
620 (2.66)
12
63 - 64
56
275.7 (d, 2.2)
259.6 (s)
631 (2.56)
15
85 - 86
38
270.7 (s),
253.2 (s)
634 (2.64)
19
97 - 98
31
275.0 (s),
252.0 (s)
636 (2.74)
20
77 - 78
30
272.8 (s),
259.0 (d, 2.5)
629 (2.60)
21
111 - 113
18
264.5 (s),
260.2 (d, 2.4)
629 (2.71)
22
261.6 (s),
251.2 (d, 2.0)
 
 
a Except for 6, 22, the compounds are also characterized by high-resolution MS and by 1H and 13C (and 19F for  11, 12, 15) NMR
b In CDCl3; standard: NH3 (liq.)
c In CHCl3
d Both N2 and N4 gave the same signal

Table 2. Multinuclear NMR Data for the Herz Saltsa 24, 25 and their isomeric 1,3,2-Benzodithiazolium Chloride 2615,16
 
 Salts
d NMR (ppm)b
 
1H
13C
 14
24
9.09, 9.00,
8.65, 8.46c
164.0, 156.2,
139.1, 133.9,
128.1, 123.4
406
25
8.60, 8.39,
7.62, 4.42
 
159.8, 158.1,
157.8, 145.6, 
115.7, 111.8,
58.1
378
26d
9.09,
8.22
163.3, 132.6,
122.8
378

 
a 24 and 25 are also characterized by high-resolution MS
b In CF3COOH; standards: TMS (1H, 13C), NH3 (liq.) (14N)
c Cf. ref. 17
d It is interesting to note that according to PM3 data symmetric 1,3,2-benzodithiazolium cation (DHfo 233.5 kcal mol -1) is prominently more stable than asymmetric 1,2,3-benzodithiazolium cation (DHfo 249.1 kcal mol -1).

Table 3. Novel Substituted 2,2'-Diaminodiphenyl Disulfidesa Prepared from the Title Compounds
 
Compound
M.p. (oC)
Yield (%)
d NMR (ppm)b
 
1H
19F
27
134 - 135
85
4.47
29.6, 10.3
2.0, -9.9
28
71 - 73
 
80
7.03, 6.39
6.27, 4.45
56.6
 
a Compounds 27 and 28 are also characterized by high-resolution MS.
b In CDCl3; standards: TMS (1H), C6F6 (19F).

 Table 4. ESR Parameters of Radicals 29 and 30a, b
 
 
 
aN
aH
aC
aF
g
29
8.24
2.94 (H3), 0.95 (H4)
3.70 (H5), 0.85 (H6)
(2x) 4.1,
5.15, 9.0
2.0078
30
5.58
9.94, 3.54,
10.76, 2.55
2.0078
a Parent benzo[c]-1,2-thiazet-yl (29) and its 3,4,5,6-tetrafluoro derivative (30).
b aX, in G.

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