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

Alexander Yu. Makarov^a, Irina Yu. Bagryanskaya^a, Victor A. Bagryansky^b, Yuri V. Gatilov^a, Makhmut M. Shakirov^a

and Andrey V. Zibarev^a*

Abstract

Graphical Abstract

Introduction

Results and Discussion

Thus, the target heterocycle formation proceeds smoothly with all the 2-RC₆H₄-N=S=N-SiMe₃  (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-SiMe₃  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=CF₃  the cyclization fails, probably due to an unfavorable situation for electrophilic ring closure involving distribution of effective charges, q_i, 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 DH_f^o (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 c_i² 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  DH_f^o (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 (c_i² and q_i distribution, e_i 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).
 

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 5.5^{o 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 ~ 7^o (4)  or ~ 11^o (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 typical^1,2,18

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 (~ 150^oC 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).

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 Ar_FSH (à Ar_FSCl à Ar_FSN=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

Experimental

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 20^oC, 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 H^5,8 as compared with H^6,7 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)₄  and/or Herz salts were obtained along with some unidentified products.

Interaction of the title compounds with SCl₂. Herz salts.

At 20^oC, 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 0^oC, 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 ~ 150^oC). After 1 h, the sample was cooled to 20^oC, 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-Benzodithiadiazines^a
 

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 Salts^a 24, 25 and their isomeric 1,3,2-Benzodithiazolium Chloride 26^15,16
 

Salts		d NMR (ppm)b
		1H	13C	14N
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

Table 3. Novel Substituted 2,2'-Diaminodiphenyl Disulfides^a 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 30^{a, 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 a_X, in G.

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