A new synthesis of spiro-fused 1,4-benzothiazines

Article abstract of DOI:10.1023/A:1014019209635

A new preparative procedure was developed for the synthesis of spiro-fused 1,4-benzothiazines by thermal heterocyclization of S-benzyl and S-phenacyl derivatives of o-indothiophenol.

Full text of DOI:10.1023/A:1014019209635

1264
Russian Chemical Bulletin, International Edition, Vol. 50, No. 7, pp. 1264—1267, July, 2001
A new synthesis of spiro-fused 1,4-benzothiazines
A. V. Lesin,a O. Ya. Borbulevych,b« S. V. Kurbatov,a A. E. Ruzhnikov,a M. Yu. Antipin,b and L. P. Olekhnovicha
aRostov State University, Chemical Department,
7 ul. Zorge, 344090 Rostov-on-Don, Russian Federation.
Fax: +7 (863 2) 64 5255. E-mail: lesin@chimfak.rsu.ru
bA. N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences,
28 ul. Vavilova, 119991 Moscow, Russian Federation.
Fax: +7 (095) 135 5085. E-mail: oleg@xrlab.ineos.ac.ru
A new preparative procedure was developed for the synthesis of spiro-fused 1,4-benzo-
thiazines by thermal heterocyclization of S-benzyl and S-phenacyl derivatives of o-indo-
thiophenol.
Key words: o-indothiophenol, benzothiazine.
ortho-Substituted quinone N-arylimines1,2 are prom-
ising chelating ligands3 and starting compounds for the
preparation of previously unknown spiro-fused benzo-
azines.4 However, mercapto-substituted quinone N-aryl-
imines have been previously inaccessible because of the
formation of S—S dimers under the standard conditions
of condensation of o-aminothiophenol with quinones
acting as oxidants.
2,6-di-tert-butyl-1,4-benzoquinone (2) in MeOH to ob-
tain the target compound 1 in 58% yield (Scheme 1).
The present study was aimed at employing intramo-
lecular heterocyclization of S-methylene derivatives of
o-indothiophenol for the synthesis of previously inac-
cessible spiro-fused benzothiazines. The starting quinone
N-(o-benzylthio)phenylimines (3) were prepared (see
Scheme 1) by either condensation of o-aminophenyl
benzyl sulfides (4) with benzoquinone 2 (method A) or
alkylation of o-indothiophenol (1) with benzyl halides
(method B). The method A is advantageous because of
its simplicity, higher yields of the target products, and
the possibility of performing the one-pot synthesis.
However, the corresponding phenacyl sulfides can-
not be prepared according to the method A because the
reaction of o-aminobenzenethiol with p-bromophenacyl
Results and Discussion
We succeeded in preparing o-indothiophenol (1)
from o-aminobenzenethiol with the use of diethyl mal-
onate as the SH-protective group, which has previously
been unknown in the traditional chemistry of thiols.5
The resulting sulfide was treated without isolation with
Scheme 1
O
O
6´
O
NH2
SH
NH2
BrCH(COOEt)2
2
N
2´
SCH(COOEt)2
SH
5
4
2
3
O
1
NH2
SH
NH2
ArCH2X
ArCH2Br
2
N
SCH2Ar
SCH2Ar
4a,b
3a,b
Ar = Ph (a), 4-NO2C6H4 (b); X = Cl, Br
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 7, pp. 1206—1209, July, 2001.
1066-5285/01/5007-1264 $25.00 ©ꢀ2001 Plenum Publishing Corporation

Russ.Chem.Bull., Int.Ed., Vol. 50, No. 7, July, 2001
1265
Spiro-fused 1,4-benzothiazines
bromide (5) is known6 to afford directly 3-p-bromo-
phenyl-2H-1,4-benzothiazine (Scheme 2).
C(23)
C(22)
C(20)
C(26)
O(1)
C(25)
Scheme 2
C(4)
C(21)
C(24)
C(3)
C(2)
Br
COCH2Br
NH2
SH
C(5)
C(27)
5
C(6)
C(18)
C(19)
C(14)
C(1)
S
O(3)
C(7)
N(2)
N(1)
C(9)
C(15)
C(17)
N
S(1)
C(8)
C(16)
O(2)
Br
O
C(10)
5´
3´
C(13)
4´
C(11)
6´
2´
1´
3
∆
C(12)
3a,b
Ar
HN4
2
S
Fig. 1. Structure of molecule 6b.
1
5
6
8
Table 1. Principal bond lengths (d) in molecule 6b
7
6a,b
Bond
d/Å
Bond
d/Å
Ar = Ph (a), 4-NO2C6H4 (b)
S(1)—C(8)
S(1)—C(7)
N(1)—C(9)
N(1)—C(1)
N(2)—O(3)
N(2)—O(2)
N(2)—C(17)
O(1)—C(4)
C(1)—C(2)
C(1)—C(6)
C(1)—C(7)
C(2)—C(3)
1.762(2)
1.821(2)
1.392(3)
1.458(3)
1.215(3)
1.231(3)
1.458(3)
1.229(2)
1.493(3)
1.509(3)
1.565(3)
1.338(3)
C(3)—C(4)
C(3)—C(20)
C(4)—C(5)
C(5)—C(6)
C(5)—C(24)
C(7)—C(14)
C(8)—C(13)
C(8)—C(9)
C(9)—C(10)
C(10)—C(11)
C(11)—C(12)
C(12)—C(13)
1.496(3)
1.532(3)
1.485(3)
1.334(3)
1.548(3)
1.502(3)
1.396(3)
1.407(3)
1.398(3)
1.372(4)
1.389(4)
1.382(4)
O
O
1´
3
5
1
HN
Br
2
1S
7
Like analogous o-indophenol derivatives,4 sulfides 3
are converted into spirobenzothiazines 6 upon heating
(see Scheme 2). However, intramolecular cyclization of
the thio analogs proceeds much more rapidly. Benzyl
sulfide 3a undergoes cyclization on refluxing in toluene,
whereas cyclization of 4-nitrobenzyl sulfide 3b proceeds
even on refluxing in benzene. The formation of
spirobenzothiazines 6 from sulfides 3 is evidenced by the
appearance of two one-proton signals of the CH and
NH groups instead of the two-proton signal of the
methylene group. The reaction of o-indothiophenol (1)
with phenacyl bromide 5 gave rise directly to spiro-
benzothiazine 7 (see Scheme 2). Its structure was con-
firmed by the fact that the signals for two tert-butyl
groups and two protons of the cyclohexadiene ring are
isochronous and also by the presence of one-proton
singlet signals for the protons of the CH and NH groups.
The spirane structure of benzothiazine 6b was unam-
biguously established by X-ray diffraction analysis (Fig. 1,
Tables 1 and 2).
Table 2. Principal bond angles (ω) in molecule 6b
Angle
ω/deg
Angle
ω/deg
C(8)—S(1)—C(7) 101.0(1)
C(9)—N(1)—C(1) 123.8(2)
O(3)—N(2)—O(2) 122.8(2)
O(3)—N(2)—C(17) 119.1(2)
O(2)—N(2)—C(17) 118.0(2)
N(1)—C(1)—C(2) 107.0(2)
N(1)—C(1)—C(6) 111.9(2)
C(2)—C(1)—C(6) 111.8(2)
N(1)—C(1)—C(7) 109.0(2)
C(2)—C(1)—C(7) 107.3(2)
C(6)—C(1)—C(7) 109.7(2)
C(3)—C(2)—C(1) 125.2(2)
C(2)—C(3)—C(4) 117.1(2)
C(2)—C(3)—C(20) 123.0(2)
C(4)—C(3)—C(20) 119.9(2)
O(1)—C(4)—C(5) 121.2(2)
O(1)—C(4)—C(3)
C(5)—C(4)—C(3)
C(6)—C(5)—C(4)
C(6)—C(5)—C(24) 123.2(2)
C(4)—C(5)—C(24) 118.3(2)
120.4(2)
118.4(2)
118.4(2)
C(5)—C(6)—C(1)
C(14)—C(7)—C(1) 114.3(2)
123.9(2)
C(14)—C(7)—S(1)
C(1)—C(7)—S(1)
C(13)—C(8)—S(1)
C(9)—C(8)—S(1)
N(1)—C(9)—C(10) 119.1(2)
N(1)—C(9)—C(8) 122.3(2)
113.1(2)
111.9(2)
117.6(2)
123.1(2)
C(19)—C(14)—C(7) 118.5(2)
C(15)—C(14)—C(7) 123.1(2)

1266
Russ.Chem.Bull., Int.Ed., Vol. 50, No. 7, July, 2001
Lesin et al.
o-Indothiophenol (1). A solution of o-aminobenzenethiol
(0.02 mol) in MeOH (15 mL) was added to a solution of KOH
(0.02 mol) in MeOH (15 mL) and the reaction mixture was
stirred for 0.5 h. Then a solution of diethyl bromomalonate
(0.02 mol) in MeOH (15 mL) was added. The reaction mixture
was brought to boiling and kept at ∼20 °C for 1 h. Then
benzoquinone 2 (0.02 mol) was added. The mixture was re-
fluxed for 15 h and cooled. The precipitate that formed was
filtered off, purified by column chromatography (Al2O3, ben-
zene—light petroleum, 1 : 2), and recrystallized from MeOH.
The yield was 58%, m.p. 58 °C. Found (%): C, 73.35; H, 7.69;
N, 4.28. C20H25NOS. Calculated (%): C, 73.48, H, 7.55,
The six-membered C(1)...C(6) ring in the molecule
6b adopts a boat conformation with the C(1) and C(4)
atoms deviating from the plane through the remaining
atoms of the ring by –0.205(4) and –0.216(4) Å, re-
spectively. The presence of the bulky tert-butyl substitu-
ents causes noticeable steric strain in this fragment of
the molecule, which is manifested in the following
shortened intramolecular contacts: C(2)...H(21A),
2.77(3) Å (the sum of the van der Waals radii7 of the C
and H atoms is 2.87 Å); C(2)...H(21B), 2.80(3) Å;
H(2)...C(14), 2.73(2) Å; H(2)...C(21), 2.45(2) Å;
H(2)...H(21A), 2.28(3) Å (the sum of the van der Waals
radii7 of the H atoms is 2.32 Å); H(2)...H(21B),
2.23(3) Å; C(4)...H(23A), 2.74(3) Å; C(4)...H(26C),
2.77(4) Å; C(6)...H(27B), 2.85(4) Å; H(6)...C(27),
2.47(2) Å; and H(6)...H(27A), 2.31(3) Å. In addition,
the C(3)—C(20) and C(5)—C(24) bonds are elongated
to 1.532(3) and 1.548(3) Å, respectively, compared to
the average C(sp2)—C(sp3) bond length (1.507 Å).8
The O(1) atom of the carbonyl group forms two
intermolecular C—H...O hydrogen bonds with the H
atoms of the aryl rings: H(12)...O(1´) (0.5 – y, x,
0.5 – z), 2.66(3) Å; C(12)...O(1´), 3.522(4) Å; the
C(12)—H(12)...O(1´) angle is 151(2)°, and H(16)...O(1″)
(x, y, z – 1), 2.41(2) Å; C(16)...O(1″), 3.304(3) Å; the
C(16)—H(16)...O(1″) angle is 153(2)°.
The six-membered heterocycle adopts a half-chair
conformation with the C(1) and C(7) atoms deviating
from the plane through the remaining atoms of the ring
by –0.337(4) and 0.418(3) Å, respectively. The aryl
substituent at the C(7) atom is in the axial position (the
C(8)—S(1)—C(7)—C(14) torsion angle is –86.7(2)°)
and is substantially rotated with respect to the C(7)—S(1)
bond (the S(1)—C(7)—C(14)—C(15) torsion angle is
65.2(3)°). Such position of the substituent gives rise to
the shortened intramolecular contacts: H(7)...H(19),
2.26(3) Å; N(1)...C(15), 3.097(3) Å (the sum of the van
der Waals radii7 of the C and N atoms is 3.21 Å);
C(8)...H(15), 2.80(2) Å; and C(9)...H(15), 2.71(2) Å.
The nitro group in the molecule 6b is rotated
with respect to the plane of the benzene ring (the
O(2)—N(2)—C(17)—C(16) torsion angle is 22.9(4)°).
The H(1) atom forms a bifurcated intermolecular hydro-
gen bond with the O atoms of the nitro group:
H(1)...O(2″′) (y – 0.5, 1 – x, 0.5 + z), 2.22(3) Å;
N(1)...O(2″′), 3.077(3) Å; the N(1)—H(1)...O(2″′) angle
is 173(2)°; and H(1)...O(3″′), 2.64(2) Å; N(1)...O(3″′),
3.224(3) Å; the N(1)—H(1)...O(3″′) angle is 127(2)°. In
addition, the O(3) atom is involved in the formation of the
intermolecular C—H...O hydrogen bond: H(18)...O(3″″)
(–x + 1, –y + 1, –z), 2.55(3) Å; C(18)...O(3″″), 3.187(4)
Å; the C(18)—H(18)...O(3″″) angle is 127(2)°.
1
N, 4.39. H NMR, δ: 1.20 and 1.33 (both s, 9 H each, But);
6.65 (d, 1 H, H(2), J = 7.4 Hz); 6.77 and 7.09 (both d,
1 H each, H(2´), H(6´), J = 2.4 Hz); 7.10—7.22 (m, 2 H,
H(3), H(4)); 7.34 (s, 1 H, SH); 7.67 (d, 1 H, H(5), J = 7.4 Hz).
3,5-Di-tert-butyl-p-benzoquinone N-(o-benzylthio)phenyl-
imine (3a). A. A solution of o-aminobenzenethiol (0.02 mol) in
MeOH (15 mL) was added to a solution of KOH (0.02 mol) in
MeOH (15 mL). The reaction mixture was stirred for 0.5 h and
a solution of benzyl chloride (0.02 mol) in MeOH (15 mL) was
added. The reaction mixture was brought to boiling and kept at
∼20 °C for 1 h. Then benzoquinone 2 (0.02 mol) was added and
the mixture was refluxed for 5 h. The solvent was evaporated,
the residue was purified by column chromatography (Al2O3,
benzene—light petroleum, 1 : 2), and compound 3a was ob-
tained in 80% yield, m.p. 98—100 °C (from MeOH).
B. o-Indothiophenol 1 (0.02 mol) was added to a solution
of KOH (0.02 mol) in MeOH (35 mL) and the reaction
mixture was stirred with gentle heating until the precipitate
completely dissolved. Then benzyl chloride (0.02 mol) was
added and the reaction mixture was refluxed for 5 h. The
product was isolated as described above, the yield was 35%.
Found (%): C, 77.75; H, 7.39; N, 3.45. C27H31NOS.
Calculated (%): C, 77.65; H, 7.48; N, 3.35. 1H NMR, δ: 1.18
and 1.31 (both s, 9 H each, But); 4.10 (s, 2 H, CH2); 6.63 (d,
1 H, H(2), J = 7.4 Hz); 6.70 and 7.08 (both d, 1 H each,
H(2´), H(6´), J = 2.5 Hz); 7.10—7.35 (m, 8 H, H(3),
H(4), H(5), Ph).
3,5-Di-tert-butyl-p-benzoquinone N-[o-(4-nitrobenzyl-
thio)]phenylimine (3b). A. o-Aminobenzenethiol (0.02 mol)
was alkylated with p-nitrobenzyl bromide in MeOH in the
presence of KOH analogously to the synthesis of 3a. The
reaction with benzoquinone 2 lasted for 4 h. After column
chromatography (Al2O3, benzene—light petroleum, 1 : 2), com-
pound 3b was obtained in 76% yield, m.p. 153 °C.
B. Alkylation of o-indothiophenol 1 (0.02 mol) with
p-nitrobenzyl bromide in MeOH in the presence of KOH was
carried out as described for 3a. The yield was 30%. Found (%):
C, 70.31; H, 6.43; N, 6.18. C27H30N2O3S. Calculated (%):
C, 70.10; H, 6.54; N, 6.06. 1H NMR, δ: 1.17 and 1.32 (both s,
9 H each, But); 4.13 (s, 2 H, CH2); 6.65 and 7.06 (both d,
1 H each, H(2´), H(6´), J = 2.4 Hz); 6.66 (d, 1 H, H(2),
J = 6.8 Hz); 7.08—7.26 (m, 3 H, H(3), H(4), H(5)); 7.44 and
8.11 (both d, 2 H each, H(2″), H(6″), H(3″), H(5″), J = 8.7 Hz).
3´,5´-Di-tert-butyl-4´-oxo-2-phenyl-2,3-dihydrospi-
ro(4H-1,4-benzothiazine-3,1´-cyclohexa-2´,5´-diene) (6a). A so-
lution of sulfide 3a (0.005 mol) in toluene (15 mL) was refluxed
for 5 h and concentrated. Then the residue was purified by
column chromatography (Al2O3, benzene). The product was
dried and triturated with light petroleum until the crystalline
precipitate formed. The yield was 78%, m.p. 175 °C. Found (%):
C, 77.81; H, 7.44; N, 3.39. C27H31NOS. Calculated (%):
C, 77.65; H, 7.48; N, 3.35. 1H NMR, δ: 1.02 and 1.14 (both s,
9 H each, But); 4.17 (s, 1 H, NH); 4.39 (s, 1 H, H(2)); 6.39
and 6.89 (both d, 1 H each, H(2´), H(6´), J = 3.0 Hz); 6.62 (d,
Experimental
The 1H NMR spectra were recorded on a Bruker DPX-250
spectrometer (250 MHz) at 25 °C (CDCl3) with Me4Si as the
internal standard.

Russ.Chem.Bull., Int.Ed., Vol. 50, No. 7, July, 2001
1267
Spiro-fused 1,4-benzothiazines
1 H, H(8), J = 8.0 Hz); 6.72 (dd, 1 H, H(7), J = 7.3 and
8.0 Hz); 6.99 (dd, 1 H, H(6), J = 7.3 and 7.9 Hz); 7.10—7.22
(m, 6 H, H(5), Ph).
by the full-matrix least-squares method (418 parameters) based
on F 2 using 5600 reflections converged to R1 = 0.044 (for
2515 reflections with F > 4σ(F)), wR2 = 0.116, S = 0.82. The
atomic coordinates for the structure of 6b and the complete
tables of the bond lengths and bond angles were deposited with
the Cambridge Structural Database. The principal bond lengths
and bond angles are listed in Tables 1 and 2, respectively.
3´,5´-Di-tert-butyl-4´-oxo-2-(p-nitrophenyl)-2,3-dihydro-
spiro(4H-1,4-benzothiazine-3,1´-cyclohexa-2´,5´-diene) (6b).
A solution of sulfide 3b (0.005 mol) in benzene (15 mL) was
refluxed for 0.5 h. The solvent was evaporated and the residue
was purified by column chromatography (Al2O3, benzene). The
yield was 88%, m.p. 202 °C (from benzene). Found (%):
C, 70.26; H, 6.45; N, 6.14. C27H30N2O3S. Calculated (%):
C, 70.10; H, 6.54; N, 6.06. 1H NMR, δ: 1.04 and 1.13 (both s,
9 H each, But); 4.21 (s, 1 H, NH); 4.38 (s, 1 H, H(2)); 6.48
and 6.67 (both d, 1 H each, H(2´), H(6´), J = 3.0 Hz); 6.65 (d,
1 H, H(8), J = 7.5 Hz); 6.79 (dd, 1 H, H(7), J = 7.5 and
8.7 Hz); 7.03 (dd, 1 H, H(6), J = 8.7 and 7.8 Hz); 7.12 (d,
1 H, H(5), J = 7.8 Hz); 7.32 and 8.08 (both d, 2 H each,
H(2″), H(6″), H(3″), H(5″), J = 8.8 Hz).
This work was financially supported by the Russian
Foundation for Basic Research (Project Nos. 00-15-
97359, 00-03-32807a, 98-03-32903a, and 99-03-33496a).
References
1. L. P. Olekhnovich, S. N. Lyubchenko, I. N. Shcherbakov,
S. V. Kurbatov, and V. A. Kogan, Ros. Khim. Zh., 1996, 40,
139 [Mendeleev Chem. J., 1996, 40 (Engl. Transl.)].
2. L. P. Olekhnovich, S. N. Lyubchenko, V. I. Simakov, A. I.
Shif, S. V. Kurbatov, A. V. Lesin, G. S. Borodkin, E. P.
Ivakhnenko, and Yu. A. Zhdanov, Dokl. Akad. Nauk, 1999,
369, 632 [Dokl. Chem., 1999 (Engl. Transl.)].
3. S. N. Lyubchenko, V. V. Litvinov, T. A. Ryskina, E. P.
Ivakhnenko, V. A. Kogan, and L. P. Olekhnovich, Zh. Obshch.
Khim., 1990, 60, 1618 [J. Gen. Chem. USSR, 1990, 60 (Engl.
Transl.)].
4. L. P. Olekhnovich, V. I. Simakov, N. G. Furmanova, E. P.
Ivakhnenko, O. Yu. Rekhlova, and T. A. Ryskina, Yu. A.
Zhdanov, Zh. Obshch. Khim., 1992, 62, 885 [Russ. J. Gen.
Chem., 1992, 62 (Engl. Transl.)].
5. Protective Groups in Organic Chemistry, Ed. J. F. W. McOmie,
Plenum Press, London—New York, 1973.
6. M. Wilhelm and P. Schmidt, J. Heterocycl. Chem.,
1969, 6, 635.
7. Yu. V. Zefirov and P. M. Zorkii, Usp. Khim., 1989, 58, 713
[Russ. Chem. Rev., 1989, 58 (Engl. Transl.)].
8. F. H. Allen, O. Kennard, D. G. Watson, L. Brammer, A. J.
Orpen, and R. Taylor, J. Chem. Soc., Perkin Trans. 2,
1987, 1.
9. G. M. Sheldrick, SHELXTL PLUS. PC Version., A System of
Computer Programs for the Determination of Crystal Structure
from X-Ray Diffraction Data, Rev. 5.02, Seimens Analytical
X-ray Instruments Inc., Germany, 1994.
2-p-Bromobenzoyl-3´,5´-di-tert-butyl-4´-oxo-2,3-dihydro-
spiro(4H-1,4-benzothiazine-3,1´-cyclohexa-2´,5´-diene) (7).
o-Indothiophenol 1 (0.02 mol) was added to a solution of KOH
(0.02 mol) in MeOH (35 mL) and the reaction mixture was
stirred with gentle heating until thiophenol 1 completely dis-
solved. Then a solution of p-bromophenacyl bromide 5
(0.02 mol) in MeOH (20 mL) was added and the mixture was
refluxed for 3 h. The solvent was evaporated and the residue
was purified by column chromatography (Al2O3, benzene—light
petroleum, 1 : 1). The yield was 28%, m.p. 200 °C. Found (%):
C, 75.38; H, 7.13; N, 3.28. C28H31NO2S. Calculated (%):
1
C, 75.47; H, 7.01; N, 3.14. H NMR, δ: 1.40 (s, 18 H, But);
5.37 (s, 1 H, NH); 6.00 (d, 1 H, H(8), J = 7.8 Hz); 6.70—6.88
(m, 3 H, H(5), H(6), H(7)); 6.89 (s, 1 H, H(2)); 7.01 (s, 2 H,
H(2´), H(6´)); 7.42 and 7.49 (both d, 2 H each, H(3″), H(5″),
H(2″), H(6″), J = 8.6 Hz).
X-ray diffraction study of compound 6b. Crystals of
C27H30O3N2S are tetragonal, at 138(2) K, a = 22.015(8) Å,
c = 10.697(6) Å, V = 5184(4) Å3, crystal dimensions
are 0.5½0.3½0.2 mm, space group P42/n, Z = 8, dcalc
=
–1
1.185 g cm–3, F(000) = 1968, µ = 0.154 mm
.
The intensities of 5953 reflections (of which 5657 reflec-
tions were independent, Rint = 0.068) were measured on an
automated four-circle Siemens P3/PC diffractometer (graphite
monochromator, Mo-Kα radiation, ω/2θ scanning technique,
2θmax = 54°).
The structure was solved by the direct method using the
SHELXTL PLUS program package.9 The positions of all H
atoms were revealed from the difference electron density syn-
thesis. The anisotropic (isotropic for the H atoms) refinement
Received August 24, 2000;
in revised form March 6, 2001