Aryl ring migration reaction in the synthesis of 2,4-diaryl-4H-3,1- benzothiazines

Article abstract of DOI:10.1055/s-0029-1217399

A new rearrangement of 1-(diarylmethyl)-2-isothiocyanatobenzenes into 2,4-diaryl-4H-3,1-benzothiazine derivatives is described. Treatment of the starting compounds with aluminum trichloride under Friedel-Crafts conditions leads to migration of an aryl sub

Full text of DOI:10.1055/s-0029-1217399

2616
PAPER
Aryl Ring Migration Reaction in the Synthesis of
2,4-Diaryl-4H-3,1-benzothiazines
2
, 4-Diaryl-4
H
-3,1-
l
benzot
e
hiazines xander V. Butin,*a Fatima A. Tsiunchik,a Vladimir T. Abaev,b Andrey V. Gutnov,c Dmitry A. Cheshkovd
a
Research Institute of Heterocyclic Compounds Chemistry, Kuban State Technological University,
Moskovskaya St. 2, Krasnodar 350072, Russian Federation
Fax +7(861)2596592.; E-mail: alexander_butin@mail.ru; E-mail: av_butin@yahoo.com.
North-Ossetian State University, Vatutina St. 46, Vladikavkaz 362025, Russian Federation
ChiroBlock GmbH, Andresenstr. 1a, 06766 Wolfen, Germany
State Scientific Research Institute of Chemistry and Technology of Organoelement Compounds,
Entuziastov Shosse 38, Moscow 111123, Russian Federation
Received 2 April 2009; revised 9 April 2009
b
c
d
heterocyclic system involves a combination of sulfur
atom alkylation with an electrophilic carbon compound
followed by 3,1-benzothiazine ring closure. 2-Aminoben-
zyl alcohols are the substrates that are most frequently
Abstract: A new rearrangement of 1-(diarylmethyl)-2-isothiocy-
anatobenzenes into 2,4-diaryl-4H-3,1-benzothiazine derivatives is
described. Treatment of the starting compounds with aluminum
trichloride under Friedel–Crafts conditions leads to migration of an
aryl substituent by an electrophilic ipso-substitution mechanism, used for the synthesis of 3,1-benzothiazines. 2-Amino-4-
followed by cyclization to form a 3,1-benzothiazine ring. The ex-
aryl-4H-3,1-benzothiazines can be obtained easily in high
pected intramolecular thiocarbamoylation reaction also takes place,
yields by refluxing 2-aminobenzhydrols with thiourea in
and 5,11-dihydro-6H-dibenzo[b,e]azepine-5-thiones are isolated as
ethanol in the presence of concentrated hydrobromic
byproducts. Factors influencing the mechanism and selectivity of
acid.4,14 In this reaction, the generated benzhydryl bro-
the reaction are discussed. The corresponding 1-(arylmethyl)-2-
mide alkylates thiourea, and the resulting isothiuronium
salt cyclizes with elimination of ammonia. 2-Aminoben-
zyl alcohol reacts in the same way.15 The reaction can be
also carried out with preformed benzyl halides, as in the
case of 2-aminobenzyl chloride hydrochloride, which
gives 2-aryl-substituted 4H-3,1-benzothiazines and ben-
zoic acid thioamides.16
isothiocyanatobenzene derivatives were also synthesized, and their
behavior under Friedel–Crafts reaction conditions was investigated
to confirm the crucial role of the stability of the intermediate ben-
zhydryl/benzyl cations in determining the course of the reaction.
Key words: 1-(diarylmethyl)-2-isothiocyanatobenzenes, Friedel–
Crafts, rearrangement, aryl migration, 3,1-benzothiazines
The formation of a nucleophilic sulfur-containing func-
tion can precede the cyclization stage. By this route, un-
like the cyclization of 2-aminobenzhydrols in acidic
media, the reaction with carbon disulfide in the presence
of an aqueous alkali gives 4H-3,1-benzothiazines in
which the amino group is attacked before cyclization oc-
curs.10b,17a,b The same approach can be implemented in a
solid-phase synthesis of amino-3,1-benzothiazine through
treatment of 2-aminocinnamic acid with aryl isothiocyan-
ates, followed by an intramolecular Michael addition.18 A
similar method involves the intramolecular cyclization of
carbodiimides and isothiocyanates having an a,b-unsatur-
ated ketone function in the ortho-position through treat-
ment with carbon disulfide and fluoride anion.19 An
interesting bifunctional synthon, 1-(bromomethyl)-2-
isothiocyanatobenzene20 or the quaternary salt generated
by its reaction with pyridine,21 gives substituted 4H-3,1-
benzothiazines on treatment with amines or phenols.
Lawesson’s reagent is widely used for introduction of a
thioamide function. On treatment with this reagent, 2-
(acylamino)benzyl alcohols can be transformed into 2-
aryl-, 4-aryl-, or 2,4-diaryl-4H-3,1-benzothiazines,22 al-
though the method is not, in general, selective and often
gives 3,1-benzoxazines and thiazolines as byproducts.
Xanthates can be also used as sulfur donors.1,5 Interaction
of 2-aminobenzyl alcohols with 4,5-dichloro-1,2,3-dithia-
zolium chloride (Appel’s salt) gives the corresponding
Among 3,1-benzothiazine derivatives, many are biologi-
cally active as cardiac stimulants,1 antiischemic agents,2
inotropic drugs,3 medications for treatment of anaphylac-
tic reactions and allergies,4 cAMP phosphodiesterase in-
hibitors,5 antibacterial agents,6 plant-disease-controlling
agents,7 and medicines for treating bone-deficit condi-
tions.8 3,1-Benzothiazin-4-ones have shown activity in
chymotrypsin inactivation,9 and are candidates as anthel-
mintic drugs.10 3,1-Thiazine derivatives have also been
patented for use as color formers in a wide range of copy-
ing systems.11
In contrast to the isomeric 1,3-benzothiazines, little re-
search has been devoted to the chemistry of 3,1-benzothi-
azines, largely because the synthetic precursors of these
compounds are less accessible. There are few general ap-
proaches among the known methods for the synthesis of
3,1-benzothiazines. Besides some special methods, such
as the synthesis of 4-aryl- or 4,4-diaryl-4H-3,1-benzothi-
azines through cycloaddition reactions of keteneimines
and thiones,12 or by oxygen–sulfur exchange in aryl-sub-
stituted 4H-3,1-benzoxazines using phosphorus pentasul-
fide,13 the most general route to the 3,1-benzothiazine
SYNTHESIS 2009, No. 15, pp 2616–2626
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x.
x
x
.
2
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Advanced online publication: 22.06.2009
DOI: 10.1055/s-0029-1217399; Art ID: Z05309SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
Synthesis of 2,4-Diaryl-4H-3,1-benzothiazines
2617
R
imines, which can be transformed into benzothiazine de-
rivatives by treatment with sodium cyanoborohydride,23
sodium hydride,24 or triphenylphosphine.25 An original
method for the synthesis of 2-aryl(hetaryl)-4H-3,1-ben-
zothiazine-4-ones involves the acid-catalyzed acylation of
aromatic/heteroaromatic substrates with 2-isothiocyano-
benzoate, followed by intramolecular cyclization of the
intermediate amides.26
O
4-RC6H4MgBr
OMe
NH2
Zn
HO
AcOH
R
NH2
1
2a R = H (66%)
2b R = Me (70%)
2c R = OMe (61%)
This analysis of the available synthetic approaches to 4H-
3,1-benzothiazine derivatives shows that almost all re-
quire sequential generation of a sulfur nucleophile and a
carbon electrophile as reactive centers. This leads to a re-
duced yields and the formation of various isomeric
byproducts. Benzyl or benzhydryl halides prepared from
the corresponding alcohols, as well as activated double
bonds or carboxyl functions, have been used as electro-
philes. However, we have previously discovered a rear-
rangement of 1-(difurylmethyl)-2-isothiocyanatoben-
zenes into 3,1-benzothiazine derivatives27 that overcomes
this limitation, as the electrophilic benzhydryl cation and
the thioamide function are generated simultaneously un-
der the reaction conditions; the generation of a benzhydryl
cation by transfer of a hetaryl group from the sterically
overloaded triaryl(hetaryl)methyl center was used for the
first time in the synthesis of 3,1-benzothiazine deriva-
tives.
R
R
KOH
(CH2OH)2
R
R
NH2
NHAc
3a R = H (83%)
3b R = Me (82%)
3c R = OMe (79%)
4a R = H (83%)
4b R = Me (86%)
4c R = OMe (75%)
Scheme 1 Synthesis of carbinols 2a–c, acetamides 3a–c, and
amines 4a–c
R3
R4
R1
R2
CHO
AlCl3
+
NO2
R3
6
5
R3
We initially supposed that this reaction might be specific
to aryl(difuryl)methyl derivatives, because the furan ring
is prone to react with electrophiles at its a-position, a re-
action that is well documented in the literature.28 Howev-
er, some preliminary studies with 1-(diarylmethyl)-2-
isothiocyanatobenzenes showed, to our surprise, that
these compounds also reacted to form 3,1-benzothiazine
derivatives as the main products.29 In contrast, seven-
membered azepinethiones, which might be expected to
form as a result of an intramolecular cyclization reaction
that is typical of many aromatic or heteroaromatic isocy-
anates,30 were observed only as minor byproducts in a few
cases.29 Here, we describe our detailed investigations of
synthesis of 2,4-diaryl-4H-3,1-benzothiazines and the
scope of this reaction.
R4
R4
Raney–Ni
N2H4
R3
R3
R4
R1
R2
R1
R4
NO2
R2
NH2
4d–g
7d–g
Scheme 2 Synthesis of starting amines 4d–g
Table 1 Yields of Nitro Compounds 7d–g and Amines 4d–g
R1
R2
R3
R4
Yield (%)
7
4
d
e
f
H
H
OMe
OMe
OEt
OMe
OMe
OEt
57
27
50
76
84
91
78
75
The 2-(diarylmethyl)aniline derivatives used as starting
compounds in this work were prepared in two ways.
Treatment of methyl 2-aminobenzoate (1) with arylmag-
nesium bromides31 gave the corresponding triaryl-
carbinols 2a–c. These products were reduced by zinc in
acetic acid to give the corresponding N-[2-(diarylmeth-
OMe
OMe
H
OMe
OMe
H
g
OCH2CH2O
yl)phenyl]acetamides 3a–c, which were subsequently hy- The 1-(diarylmethyl)-2-isothiocyanatobenzenes 8a–g
drolyzed with alkali to give the free amines 4a–c were synthesized by treatment of the corresponding
(Scheme 1).
amines 4 with thiophosgene and aqueous sodium bicar-
bonate (Scheme 3, Table 2).
Alternatively, condensation of 2-nitrobenzaldehydes 5
with 1,2-dialkoxybenzenes 6 in the presence of anhydrous Treatment of isothiocyanates 8 with aluminum trichloride
aluminum trichloride gave the 1-(diarylmethyl)-2-ni- in 1,2-dichloroethane gave the corresponding benzothiaz-
trobenzenes 7d–g, which were reduced with hydrazine ines 9a–g in moderate yields (Scheme 4, Table 3). Forma-
and Raney nickel to give the corresponding amino deriv- tion of azepinethiones 10 as byproducts was observed in
all cases except for isothiocyanate 8b, which gave the
benzothiazine 9b as the sole product. The side products
atives 4d–g (Scheme 2, Table 1).
Synthesis 2009, No. 15, 2616–2626 © Thieme Stuttgart · New York

2618
A. V. Butin et al.
PAPER
R3
R3
R3
R4
R4
R4
CSCl2
NaHCO3
R4
R4
R3
R4
R3
R1
R2
R1
R2
R1
R2
R3
NCS
NCS
NH2
8a–g
4a–g
8a–g
AlCl3
DCE
Scheme 3 Synthesis of isothiocyanates 8a–g
R3
R3
Table 2 Yields of Isothiocyanates 8a–g
R4
R4
R1
R2
R3
R4
Yield of 8
R4
(%)
97
87
50
77
78
65
89
R1
R2
R1
R2
R3
a
b
c
d
e
f
H
H
H
H
H
H
+
S
R4
R3
H
H
Me
N
N
H
S
H
H
OMe
OMe
OMe
OEt
9a–g
10a,d,f
H
H
OMe
OMe
OEt
Scheme 4 Synthesis of 2,4-diaryl-4H-3,1-benzothiazines 9a–g and
azepinethiones 10a, 10d, and 10f
OMe
OMe
H
OMe
OMe
H
Table 3 Yields of 2,4-Diaryl-4H-3,1-Benzothiazines 9a–g and
Azepinethiones 10a, 10d, and 10f
g
OCH2CH2O
R1
R2
R3
R4
Yield (%)
10
10a, 10d, and 10f were isolated chromatographically and
fully characterized by spectral methods. X-ray analysis of
a single crystal of 10d gave unambiguous proof of its
structure (Figure 1). Note that benzothiazine derivatives 9
prevail over the azepinethiones 10 as the main reaction
products in all cases except for isothiocyanate 8a, which
gave azepinethione 10a in 25% yield and the correspond-
ing benzothiazine 9a in 9% yield (Scheme 4, Table 3).
9
a
b
c
d
e
f
H
H
H
H
H
9
25
–
H
H
Me
60
19
37
30
26
61
H
H
OMe
OMe
OMe
OEt
H
–
H
H
OMe
7
OMe
OMe
H
OMe
OMe
H
OMe
–
A plausible mechanism for the reaction is shown in the
Scheme 5. In the case of the products 10 (path B), a classic
intramolecular electrophilic substitution with the alumi-
num trichloride-activated isothiocyanate group takes
place at the C2 position of the aromatic ring; this is a well-
documented intramolecular cyclization reaction under
OEt
5
g
OCH2CH2O
–
Friedel–Crafts conditions.30 In the case of the products 9,
however, the activated isothiocyanate group attacks the
aromatic ring at the position connected to the meso-carbon
to form a s-complex (path A). Interestingly, the second
route predominates even when the ipso-attack is strongly
disfavored sterically, because the formation of the six-
membered thiazine ring is energetically more favored
than formation of an azepinethione.
In the case of isothiocyanate 8c, along with the expected
rearrangement product 9c, the product of demethylation at
the methoxy group 11 was also isolated in 15% yield
(Scheme 6); the structure of this compound was con-
firmed by single-crystal X-ray crystallography (Figure 2).
It appeared that the methoxy group at the 2-position of the
aromatic ring the benzothiazine cycle had been demeth-
ylated. Although aluminum chloride is a common reagent
for demethylation, it usually requires refluxing of the re-
action mixture for several hours to achieve complete con-
Figure 1 X-ray crystallographic structure of azepinethione 10d
Synthesis 2009, No. 15, 2616–2626 © Thieme Stuttgart · New York

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Synthesis of 2,4-Diaryl-4H-3,1-benzothiazines
2619
R3
R3
8c
R4
R4
R3
R4
OMe
OMe
+
R1
R2
–
R1
R2
+
AlCl3
S
Me
O+
R4
R3
– MeCl
O
S
N
N
Cl–-
–
AlCl3
A
– AlCl3
Path A
S
S
N
N
R3
–
–
AlCl3
AlCl3
9
R4
– AlCl3
– AlCl3
OMe
OMe
R4
R3
R1
R2
N
C
10
S
8
AlCl3
S
S
– AlCl3
R4
N
N
R3
R3
Path B
R4
OMe
OH
11
9c
R4
R4
Scheme 6 Probable mechanism of the demethylation reaction
R1
R2
R1
R2
R3
R3
+
H
N
N
–
–
S
AlCl3
S
AlCl3
H+
Scheme 5 Probable mechanism of formation of 2,4-diaryl-4H-3,1-
benzothiazines 9 and azepinethiones 10
version. Surprisingly in this case, however, the reaction
was easily accomplished at room temperature.32 This
ready elimination of a methyl group from the 2-position of
the aryl ring of the ring strongly supports the assumption
that demethylation occurred at the stage of the spiro com-
plex (Scheme 6). The absence of demethylation products
in the cases of compounds 9d–f can be rationalized in
terms of steric hindrance from the second alkoxy group
retarding attack by the nucleophile.
Obviously, the driving force of the reaction is the genera-
tion of the stable carbocation A (Scheme 5) as an interme-
diate. Its stability is a prerequisite for aromatic ring
migration to form the benzothiazine heterocycle. This ex-
plains, in particular, why intramolecular cyclization dom-
inates in the case of isothiocyanate 8a, which is much less
prone to formation of carbocation A because of the ab-
sence of stabilizing electron-donor substituents on the
aromatic rings of the benzhydryl cation, in contrast to the
other substrates. We therefore believed that migration of
an aryl would be less favored in the case of the corre-
sponding diarylmethane derivatives and that the same re-
action would lead to intramolecular cyclization to give
corresponding azepinethiones.
Figure 2 X-ray crystallographic structure of the demethylated deri-
vative 11
dimethoxybenzene (veratrole) by benzoyl chlorides to
give the corresponding benzophenones 12a–c, which,
without additional purification, were nitrated with con-
centrated nitric acid in acetic acid to give the 2-nitro com-
pounds 13a–c. These were reduced with iron and acetic
acid to give the corresponding 2-aminobenzophenones
14a–c.33 Further, reduction of 2-aminobenzophenones
14a–c with sodium borohydride and aluminum chloride in
boiling tetrahydrofuran gave the 2-benzylanilines 15a–c,
which, without purification or characterization, were con-
verted directly into isothiocyanates 16a–c through treat-
ment with thiophosgene using the standard procedure.
Intrigued by this possibility, we focused our efforts on the
synthesis of isothiocyanates 16a–c (Scheme 7). The se-
quence begins with Friedel–Crafts acylation of 1,2-
Synthesis 2009, No. 15, 2616–2626 © Thieme Stuttgart · New York

2620
A. V. Butin et al.
PAPER
O
MeO
MeO
R
12a–c
HNO3
AcOH
O
O
MeO
MeO
MeO
MeO
Fe, AcOH
R
R
NH2
NO2
13a–c
14a–c
NaBH4
AlCl3
MeO
MeO
MeO
MeO
CSCl2
NaHCO3
R
NCS
R
NH2
16a R = H (72%)
16b R = Cl (84%)
16c R = Me (85%)
15a R = H (60%)
15b R = Cl (60%)
15c R = Me (76%)
Scheme 7 Synthesis of isothiocyanates 16a–c
Surprisingly, treatment of compound 16a or 16b with alu-
minum trichloride in 1,2-dichloroethane gave a mixture of
unstable products that could not be separated chromato-
graphically. Only in the case of isothiocyanate 16c was
the azepinethione 17 isolated from the reaction mixture in
38% yield (Scheme 8). Unfortunately we failed in our at-
tempts to grow a single crystal of azepinethione 17 that
was suitable for X-ray analysis, and instead we used a
two-dimensional NMR technique ([D6]-DMSO, 323K) to
confirm its structure.
Figure 3 Key NOESY correlations of azepinethione 17
1
correlations are shown in Figure 4. Results of the assign-
ments are listed in Table 4.
The H NMR spectrum of azepinethione 17 contains the
ten expected signals; three signals corresponding to pro-
tons H12 (7.76 ppm), H14 (7.22 ppm), and H15 (7.14
ppm) are in the aromatic region, and clearly arise from the
trisubstituted (m, p) benzene ring. It was easy to assign the
NH proton signal H1 of the thioamide group at 12.25 ppm.
The signal of the methylene group H5 (3.67 ppm) was as-
signed on the basis of the integral intensities of the corre-
sponding peaks. The remaining 1H signals in the spectrum
were assigned by means of 1H–1H nuclear Overhauser ef-
fect spectroscopy (NOESY), and the critical NOE con-
tacts are shown in Figure 3.
We observed a dynamic effect in the 1H NMR spectrum of
azepinethione 17 in deuteriochloroform (Figure 5). Sig-
nals from the methylene group C5, which usually form a
broad singlet at room temperature, appeared as a singlet
upon heating to 45 °C, and split into two doublets at –10 °C.
At the same time we did not observe any significant
The assignments of the NMR signals of the carbon atoms
were made by means of two-dimensional 1H–13C hetero-
nuclear single quantum coherence (HSQC) experiments,
and 1H–13C heteronuclear multiple bond correlation (HM-
BC) spectroscopy for the quaternary carbons. The main
Figure 4 Key HMBC (H → C) correlations for azepinethione 17
MeO
MeO
AlCl3
DCE
MeO
NCS
16c
MeO
N
H
S
17
Scheme 8 Synthesis of azepinethione 17
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Synthesis of 2,4-Diaryl-4H-3,1-benzothiazines
2621
Table 4 1H and 13C Chemical Shifts (ppm) for Azepinethione 17
13C (ppm)
1H (ppm)
12.25
13C (ppm)
147.2
111.1
132.4
135.1
132.2
126.1
55.7
1H (ppm)
N1-H
C2
C10
198.0
137.2
137.0
36.3
C11-H
C12-H
C13
6.95
C3
7.76 (d, J = 1.6 Hz)
C4
C5-H
C6
3.67 (2 H)
C14-H
C15-H
C18-H
C20-H
C21-H
7.22 (dd, J = 1.6, 7.7 Hz)
7.14 (d, J = 7.7 Hz)
3.70 (3 H)
128.2
130.2
106.4
147.2
C7
C8-H
C9
6.89
55.7
3.75 (3 H)
20.2
2.27 (3 H)
Figure 5 Temperature effects on the 1H NMR spectrum of azepinethione 17 in CDCl3
changes in the other signals. Because the molecule has a
butterfly conformation (Figure 6), we believe that the
temperature dependence of the spectrum is probably asso-
ciated with a rapid conformational change (like the flap-
ping of a butterfly’s wings).
In conclusion, we investigated a novel rearrangement of
1-(diarylmethyl)-2-isothiocyanatobenzenes into 3,1-ben-
zothiazines. The key step in the mechanism of this reac-
tion is a nontrivial electrophilic C–C bond breakage with
formation of a benzhydryl cation and migration of an aryl
Figure 6 Conformation of azepinethione 17 optimized by MM2
calculations (ChemOffice Chem3D view)
group. In the case of corresponding diarylmethane deriv-
atives, rearrangement does not take place because of the
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2622
A. V. Butin et al.
PAPER
6.49 (dd, J = 1.7, 8.2 Hz, 2 H, HAr), 6.09 (s, 1 H, CH), 3.99 (q, J =
7.0 Hz, 4 H, OCH2CH3), 3.91 (q, J = 7.0 Hz, 4 H, OCH2CH3), 3.85
(s, 3 H, OCH3), 3.61 (s, 3 H, OCH3), 1.31 (t, J = 7.0 Hz, 6 H,
OCH2CH3), 1.25 (t, J = 7.0 Hz, 6 H, OCH2CH3).
much lower stability of the benzyl carbocation intermedi-
ates, even when electron-donor stabilizing groups are
present.
Anal. Calcd for C29H35NO8: C, 66.27; H, 6.71; N, 2.66. Found: C,
66.15; H, 6.58; N, 2.75.
The microanalyses were carried out at the Laboratory of Physico-
Chemical Methods of Research, Department of Chemistry, M.V.
Lomonosov Moscow State University. Melting points are uncor-
rected. 1H NMR and 13C NMR spectra were recorded in CDCl3 and
DMSO-d6 on Bruker AC 200, WM 250, DPX 300, and Avance 600
spectrometers. Chemical shifts are reported in ppm relative to TMS
as an internal standard; coupling constants (J) are quoted in Hz.
Two-dimensional spectra of azepinethione 17 were recorded on a
Bruker Avance 600 spectrometer using standard Bruker software,
and the XWINNMR 3.5 program (Bruker) was used to acquire and
store the NMR data. A mixing time of 800 ms was used in the
gNOESY experiment. The gHMBC experiment was optimized for
the coupling constant nJH–C = 8 Hz. Mass spectra were recorded on
a Kratos MS-30 instrument with 70-eV electron-impact ionization
at 200 °C. IR spectra were recorded on InfraLUM FT-02 and FT-
801 instruments. Column chromatography was carried out using sil-
ica gel KSK (50–160 mm; Sorbpolymer, Russia).
2-(Diarylmethyl)anilines 4d–g; General Procedure
A mixture of the nitro compound 7 (4.6 mmol), N2H4 H2O (2 mL),
and Raney Ni (1.5 g) in EtOH (40 mL) was stirred under reflux until
the reaction was complete (TLC). The catalyst was filtered off and
the soln was treated with active charcoal, filtered, and concentrated.
Compounds 4e–g were obtained as yellow oils and used in the next
step as prepared.
2-[Bis(3,4-dimethoxyphenyl)methyl]aniline (4d)
White solid; yield: 84%; mp 163–164 °C (EtOH).
IR (KBr): 3468, 3384, 1516, 1464, 1448, 1416, 1264, 1232, 1136,
1028, 760 cm–1.
1H NMR (300 MHz, DMSO-d6): d = 6.97–6.91 (m, 1 H, HAr), 6.87
(d, J = 8.2 Hz, 2 H, HAr), 6.72 (d, J = 1.6 Hz, 2 H, HAr), 6.66–6.63
(m, 1 H, HAr), 6.53 (dd, J = 1.6, 8.2 Hz, 2 H, HAr), 6.58–6.47 (m, 2
H, HAr), 5.38 (s, 1 H, CH), 4.56 (s, 2 H, NH2), 3.73 (s, 6 H, OCH3),
3.64 (s, 6 H, OCH3).
Crystallographic data for compound 11 and 10d have been deposit-
ed at the Cambridge Crystallographic Data Centre with the acces-
sion numbers CCDC-693283 and CCDC-693284, respectively. The
data can be obtained free of charge from www.ccdc.cam.ac.uk/
data_request/cif.
Anilines 4a–c were obtained according to the literature procedure31
as yellow oils, and used in the next step as prepared. Compounds 14
were prepared according to the literature procedure.33
Anal. Calcd for C23H25NO4: C, 72.80; H, 6.64; N, 3.69. Found: C,
73.01; H, 6.66; N, 3.76.
1-(Diarylmethyl)-2-isothiocyanatobenzenes 8; General Proce-
dure
A soln of CSCl2 (0.3 mL, 3.9 mmol) in CH2Cl2 (4 mL) and a soln of
NaHCO3 (0.84 g, 10 mmol) in H2O (30 mL) were added simulta-
neously to a stirred soln of amine 4 (3.2 mmol) in CH2Cl2 (10 mL)
at r.t. When the reaction was complete (TLC), the mixture was
poured into H2O (150 mL) and the mixture was stirred for 6 h. The
organic layer was extracted with CH2Cl2 (2 × 40 mL), separated,
and dried (Na2SO4). The solvent was evaporated, and the oily resi-
due was dissolved in hot PE and filtered through a pad of silica gel.
The soln was concentrated and the residue was crystallized (PE–
CH2Cl2).
1-(Diarylmethyl)-2-nitrobenzenes 7d–g; General Procedure
AlCl3 (1.9 g, 14.2 mmol) was added in small portions to a stirred
soln of 2-nitrobenzaldehyde 5 (9.5 mmol) and 1,2-dialkoxybenzene
6 (19.9 mmol) in CH2Cl2 (80 mL) at 5 °C, and the mixture was
stirred at 5 °C for 2.5 h. The cooling bath was then removed, and
stirring was continued at r.t. until full conversion was achieved
(TLC). The mixture was poured into H2O (300 mL) and extracted
with CH2Cl2 (3 × 70 mL). The organic layer was separated, dried
(Na2SO4), and concentrated in vacuo. The residue was dissolved in
PE and the soln was filtered through the pad of silica gel and then
concentrated under reduced pressure.
Compound 8g was isolated as a yellow oil and used at the next step
as prepared.
Compounds 7d and 7f were recrystallized, whereas compounds 7e
and 7g were used at the next step as prepared.
1-(Diphenylmethyl)-2-isothiocyanatobenzene (8a)
Colorless plates; yield: 97%; mp 97–98 °C (PE–CH2Cl2).
1-[Bis(3,4-dimethoxyphenyl)methyl]-2-nitrobenzene (7d)
Pale yellow solid; yield: 57%; mp 95–96 °C (PE–CH2Cl2).
IR (KBr): 2139, 1593, 1446, 1076, 1027, 930, 760, 700 cm–1.
1H NMR (300 MHz, DMSO-d6): d = 7.48–7.44 (m, 1 H, HAr), 7.37–
7.23 (m, 8 H, HAr), 7.11–7.08 (m, 4 H, HAr), 6.93–6.90 (m, 1 H,
HAr), 5.81 (s, 1 H, CH).
IR (KBr): 1528, 1508, 1464, 1440, 1360, 1272, 1244, 1236, 1140,
1028, 860, 816, 760, 728 cm–1.
1H NMR (300 MHz, DMSO-d6): d = 7.91–7.88 (m, 1 H, HAr), 7.64–
7.60 (m, 1 H, HAr), 7.52–7.48 (m, 1 H, HAr), 7.12–7.10 (m, 1 H,
HAr), 6.88 (d, 2 H, J = 8.2 Hz, HAr), 6.68 (d, J = 1.6 Hz, 2 H, HAr),
6.48 (dd, J = 1.6, 8.2 Hz, 2 H, HAr), 6.00 (s, 1 H, CH), 3.73 (s, 6 H,
OCH3), 3.64 (s, 6 H, OCH3).
Anal. Calcd for C20H15NS: C, 79.70; H, 5.02; N, 4.65; S, 10.64.
Found: C, 79.83; H, 5.06; N, 4.53; S, 10.76.
1-[Bis(4-methylphenyl)methyl]-2-isothiocyanatobenzene (8b)
Pale beige solid; yield: 87%; mp 63–65 °C (PE–CH2Cl2).
Anal. Calcd for C23H23NO6: C, 67.47; H, 5.66; N, 3.42. Found: C,
67.19; H, 5.45; N, 3.37.
IR (KBr): 2100, 1512, 1476, 1448, 932, 808, 800, 724 cm–1.
1H NMR (300 MHz, DMSO-d6): d = 7.24–7.18 (m, 3 H, HAr), 7.11
(d, J = 7.8 Hz, 4 H, HAr), 6.98 (d, J = 7.8 Hz, 4 H, HAr), 7.00–6.97
(m, 1 H, HAr), 5.73 (s, 1 H, CH), 2.34 (s, 6 H, CH3).
1-[Bis(3,4-diethoxyphenyl)methyl]-4,5-dimethoxy-2-nitroben-
zene (7f)
Yellow solid; yield: 50%; mp 103–104 °C (MeOH).
Anal. Calcd for C22H19NS: C, 80.20; H, 5.81; N, 4.25; S, 9.73.
Found: C, 80.59; H, 5.92; N, 4.16; S, 9.74.
IR (KBr): 1524, 1516, 1472, 1440, 1396, 1336, 1276, 1248, 1212,
1140, 1060, 1048, 992, 796, 756 cm–1.
1H NMR (250 MHz, DMSO-d6): d = 7.60 (s, 1 H, HAr), 6.87 (d, J =
8.2 Hz, 2 H, HAr), 6.67 (d, J = 1.7 Hz, 2 H, HAr), 6.53 (s, 1 H, HAr),
1-[Bis(4-methoxyphenyl)methyl]-2-isothiocyanatobenzene (8c)
Beige solid; yield: 50%; mp 65–67 °C (PE–CH2Cl2).
Synthesis 2009, No. 15, 2616–2626 © Thieme Stuttgart · New York

PAPER
Synthesis of 2,4-Diaryl-4H-3,1-benzothiazines
2623
IR (KBr): 2140, 1588, 1480, 1468, 1448, 1248, 1184, 1108, 1032,
936, 816, 804, 756 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.26–7.18 (m, 3 H, HAr), 7.01 (d,
J = 8.6 Hz, 4 H, HAr), 6.97–6.94 (m, 1 H, HAr), 6.85 (d, J = 8.6 Hz,
4 H, HAr), 5.70 (s, 1 H, CH), 3.81 (s, 6 H, OCH3).
1H NMR (300 MHz, DMSO-d6): d = 8.06–8.03 (m, 2 H, HAr), 7.57–
7.44 (m, 5 H, HAr), 7.37–7.33 (m, 1 H, HAr,), 7.29–7.17 (m, 6 H,
HAr), 5.79 (s, 1 H, CH).
13C NMR (50 MHz, DMSO-d6): d = 157.7, 143.2, 142.1, 137.3,
131.7, 128.7 (2C), 128.6 (3C), 128.1, 127.6, 127.4 (2C), 127.3 (2C),
126.9 (2C), 122.5, 43.4.
Anal. Calcd for C22H19NO2S: C, 73.10; H, 5.30; N, 3.87; S, 8.87.
Found: C, 72.82; H, 5.37; N, 3.82; S, 8.50.
MS (EI, 70 eV): m/z (%) = 301 (100) [M+], 300 (53), 299 (12), 224
(28), 197 (14), 165 (52), 121 (31), 76 (18).
1-[Bis(3,4-dimethoxyphenyl)methyl]-2-isothiocyanatobenzene
(8d)
Pale beige solid; yield: 77%; mp 89–90 °C (PE–CH2Cl2).
Anal. Calcd for C20H15NS: C, 79.70; H, 5.02; N, 4.65; S, 10.64.
Found: C, 80.04; H, 5.19; N, 4.49; S, 10.68.
IR (KBr): 2120, 1592, 1480, 1464, 1264, 1244, 1140, 1028, 756 cm–1.
2,4-Bis(4-methylphenyl)-4H-3,1-benzothiazine (9b)
Pale yellow solid; yield: 60%; mp 111 °C (PE–CH2Cl2).
1H NMR (300 MHz, CDCl3): d = 7.24–7.15 (m, 3 H, HAr), 6.97–
6.92 (m, 1 H, HAr), 6.80 (d, J = 8.3 Hz, 2 H, HAr), 6.69 (d, J = 1.5
Hz, 2 H, HAr), 6.55 (dd, J = 1.5, 8.3 Hz, 2 H, HAr), 5.66 (s, 1 H, CH),
3.87 (s, 6 H, OCH3), 3.80 (s, 6 H, OCH3).
IR (KBr): 1604, 1534, 1507, 1450, 1195, 1174, 1107, 940, 822, 763,
729 cm–1.
1H NMR (300 MHz, DMSO-d6): d = 7.93 (d, J = 8.0 Hz, 2 H, HAr),
7.52–7.42 (m, 2 H, HAr), 7.31 (d, J = 8.0 Hz, 2 H, HAr), 7.34–7.30
(m, 1 H, HAr), 7.22–7.20 (m, 1 H, HAr), 7.05 (s, 4 H, HAr), 5.72 (s, 1
H, CH), 2.37 (s, 3 H, CH3), 2.22 (s, 3 H, CH3).
Anal. Calcd for C24H23NO4S: C, 68.39; H, 5.50; N, 3.32; S, 7.61.
Found: C, 68.05; H, 5.49; N, 3.09; S, 7.55.
1-[Bis(3,4-dimethoxyphenyl)methyl]-2-isothiocyanato-3,4-
dimethoxybenzene (8e)
Pale green cubes; yield: 78%; mp 128–129 °C (PE–CH2Cl2).
13C NMR (50 MHz, DMSO-d6): d = 157.7, 143.4, 141.9, 139.1,
136.8, 134.8, 129.3 (2C), 129.1 (2C), 128.4, 127.8, 127.5 (3C),
127.2, 126.9 (2C), 122.9, 43.4, 21.0, 20.5.
IR (KBr): 2127, 1589, 1511, 1462, 1344, 1236, 1137, 1109, 1026,
793, 747 cm–1.
1H NMR (250 MHz, CDCl3): d = 6.79 (d, J = 8.2 Hz, 2 H, HAr), 6.74
(s, 1 H, HAr), 6.69 (d, J = 1.8 Hz, 2 H, HAr), 6.56 (dd, 2 H, J = 1.8,
8.2, HAr), 6.43 (s, 1 H, HAr), 5.61 (s, 1 H, CH), 3.90 (s, 6 H, OCH3),
3.86 (s, 3 H, OCH3), 3.80 (s, 6 H, OCH3), 3.67 (s, 3 H, OCH3).
MS (EI, 70 eV): m/z (%) = 329 (100) [M+], 297 (11), 238 (16), 197
(12), 193 (11), 180 (12), 179 (56), 178 (30), 165 (26), 135 (12).
Anal. Calcd for C22H19NS: C, 80.20; H, 5.81; N, 4.25; S, 9.73.
Found: C, 80.53; H, 6.03; N, 4.11; S, 10.09.
2,4-Bis(4-methoxyphenyl)-4H-3,1-benzothiazine (9c)
Pale yellow solid; yield: 19%; mp 149 °C.
Anal. Calcd for C26H27NO6S: C, 64.85; H, 5.65; N, 2.91; S, 6.66.
Found: C, 65.07; H, 5.89; N, 2.95; S, 6.59.
IR (KBr): 1608, 1540, 1508, 1268, 1260, 1252, 1168, 1028, 844,
832, 772 cm–1.
1-[Bis(3,4-diethoxyphenyl)methyl]-2-isothiocyanato-3,4-
dimethoxybenzene (8f)
Beige solid; yield: 65%; mp 117 °C (PE–CH2Cl2).
1H NMR (300 MHz, DMSO-d6): d = 8.01 (d, J = 8.3 Hz, 2 H, HAr),
7.51–7.49 (m, 1 H, HAr), 7.44–7.40 (m, 1 H, HAr), 7.32–7.28 (m, 1
H, HAr), 7.20–7.18 (m, 1 H, HAr), 7.08 (d, J = 8.2 Hz, 2 H, HAr), 7.03
(d, J = 8.3 Hz, 2 H, HAr), 6.82 (d, J = 8.2 Hz, 2 H, HAr), 5.68 (s, 1 H,
CH), 3.81 (s, 3 H, OCH3), 3.68 (s, 3 H, OCH3).
IR (KBr): 2152, 1512, 1476, 1464, 1456, 1436, 1424, 1304, 1256,
1244, 1224, 1204, 1136, 1044, 864 cm–1.
1H NMR (250 MHz, CDCl3): d = 6.79 (d, J = 8.2 Hz, 2 H, HAr), 6.73
(s, 1 H, HAr), 6.66 (d, J = 1.8 Hz, 2 H, HAr), 6.53 (dd, J = 1.8, 8.2
Hz, 2 H, HAr), 6.40 (s, 1 H, HAr), 5.57 (s, 1 H, CH), 4.07 (q, J = 7.0
Hz, 4 H, OCH2CH3), 3.99 (q, J = 7.0 Hz, 4 H, OCH2CH3), 3.85 (s,
3 H, OCH3), 3.65 (s, 3 H, OCH3), 1.44 (t, J = 7.0 Hz, 6 H,
OCH2CH3), 1.39 (t, J = 7.0 Hz, 6 H, OCH2CH3).
13C NMR (50 MHz, DMSO-d6): d = 162.2, 158.5, 157.2, 143.5,
134.0, 130.0, 129.2 (2C), 128.5, 128.2 (2C), 127.5, 127.3, 127.0,
123.1, 114.0 (2C), 113.9 (2C), 55.4, 54.9, 43.2.
MS (EI, 70 eV): m/z (%) = 361 (100) [M+], 360 (19), 347 (14), 346
(38), 329 (16), 254 (15), 210 (10), 195 (12), 59 (16), 57 (19).
Anal. Calcd for C22H19NO2S: C, 73.10; H, 5.30; N, 3.87; S, 8.87.
Found: C, 73.18; H, 5.16; N, 3.66; S, 8.52.
Anal. Calcd for C30H35NO6S: C, 67.02; H, 6.56; N, 2.61; S, 5.96.
Found: C, 67.29; H, 6.74; N, 2.63; S, 6.08.
2,4-Bis(3,4-dimethoxyphenyl)-4H-3,1-benzothiazine (9d)
Pale yellow cubes; yield; 37%; mp 121 °C.
Compounds 9–11; General Procedure
AlCl3 (0.3 g, 2.25 mmol) was added to a soln of isocyanate 8 (1.66
mmol) in DCE (5 mL). The mixture was stirred for 24 h at r.t. (TLC
monitoring), then poured into H2O (100 mL) and extracted with
CH2Cl2 (3 × 40 mL). The organic layer was separated, dried
(Na2SO4), and concentrated in vacuo. The oily residue was purified
by chromatography (silica gel; EtOAc–benzene–PE, 6:5:13 for 9a
and 10a; acetone–CH2Cl2–PE, 3:2:12 for 9c and 11; EtOAc–PE, 1:3
for 9d and 10d; acetone–CH2Cl2–PE, 4:5:14 for 9e; EtOAc–PE, 1:4
for 9f and 10f; acetone–CH2Cl2–PE, 3:2:12 for 9g).
IR (KBr): 1596, 1536, 1512, 1464, 1448, 1444, 1416, 1348, 1264,
1236, 1224, 1156, 1140, 1024, 804, 764 cm–1.
1H NMR (300 MHz, DMSO-d6): d = 7.71 (d, J = 1.8, Hz, 1 H, HAr),
7.62 (dd, J = 1.8, 8.5 Hz, 1 H, HAr), 7.53–7.51 (m, 1 H, HAr), 7.45–
7.40 (m, 1 H, HAr), 7.33–7.28 (m, 1 H, HAr), 7.21–7.19 (m, 1 H,
HAr), 7.05 (d, J = 8.5 Hz, 1 H, HAr), 6.94 (d, J = 1.6 Hz, 1 H, HAr),
6.80 (d, J = 8.3 Hz, 1 H, HAr), 6.56 (dd, J = 1.6, 8.3 Hz, 1 H, HAr),
5.56 (s, 1 H, CH), 3.85 (s, 3 H, OCH3), 3.82 (s, 3 H, OCH3), 3.67 (s,
6 H, OCH3).
Benzothiazine 9b was recrystallized from PE–CH2Cl2.
13C NMR (50 MHz, DMSO-d6): d = 152.1, 148.8, 148.6 (2C),
148.3, 143.5, 134.1, 130.1, 128.3, 127.5, 127.3, 127.0, 123.3, 121.7,
119.4, 111.7, 111.2 (2C), 109.7, 55.6, 55.5, 55.4 (2C), 43.7.
2,4-Diphenyl-4H-3,1-benzothiazine (9a)
Pale beige solid; yield: 9%; mp 91 °C.
IR (KBr): 1536, 1492, 1448, 1196, 1180, 948, 768, 720 cm–1.
MS (EI, 70 eV): m/z (%) = 421 (100) [M+], 407 (13), 406 (47), 59
(16).
Synthesis 2009, No. 15, 2616–2626 © Thieme Stuttgart · New York

2624
A. V. Butin et al.
PAPER
Anal. Calcd for C24H23NO4S: C, 68.39; H, 5.50; N, 3.32; S, 7.61.
Found: C, 68.68; H, 5.63; N, 3.15; S, 7.78.
11-Phenyl-5,11-dihydro-6H-dibenzo[b,e]azepine-6-thione (10a)
Yellow solid; yield: 25%; mp 216 °C.
IR (KBr): 1604, 1528, 1492, 1448, 1388, 1240, 1184, 1160, 1008,
772, 760, 740, 708, 696 cm–1.
1H NMR (300 MHz, DMSO-d6): d = 12.23 (s, 1 H, NH), 8.10–8.08
(m, 1 H, HAr), 7.61–7.48 (m, 3 H, HAr), 7.39–7.14 (m, 7 H, HAr),
6.78–6.76 (m, 2 H, HAr), 5.47 (s, 1 H, CH).
13C NMR (50 MHz, DMSO-d6): d = 198.0, 141.4, 140.0, 137.5,
137.0, 136.6, 133.7, 132.1, 130.0, 128.5, 128.0 (2C), 127.8, 127.1,
126.5 (2C), 126.3 (2C), 122.6, 53.7.
MS (EI, 70 eV): m/z (%) = 301 (100) [M+], 269 (20), 267 (47), 239
(16), 224 (19), 191 (12), 190 (25), 180 (19), 165 (32), 152 (11), 79
(12), 59 (13).
2,4-Bis(3,4-dimethoxyphenyl)-6,7-dimethoxy-4H-3,1-benzothi-
azine (9e)
Pale yellow solid; yield: 30%; mp 194 °C.
IR (KBr): 1595, 1504, 1460, 1415, 1265, 1242, 1141, 1019, 876,
812, 759 cm–1.
1H NMR (300 MHz, DMSO-d6): d = 7.67 (d, J = 1.8 Hz, 1 H, HAr),
7.55 (dd, J = 1.8, 8.5 Hz, 1 H, HAr), 7.10 (s, 1 H, HAr), 7.04 (d, J =
8.5 Hz, 1 H, HAr), 6.91 (d, J = 1.6 Hz, 1 H, HAr), 6.83 (s, 1 H, HAr),
6.78 (d, J = 8.3 Hz, 1 H, HAr), 6.50 (dd, J = 1.6, 8.3 Hz, 1 H, HAr),
5.56 (s, 1 H, CH), 3.86 (s, 3 H, OCH3), 3.85 (s, 3 H, OCH3), 3.82 (s,
3 H, OCH3), 3.75 (s, 3 H, OCH3), 3.67 (s, 6 H, OCH3).
13C NMR (50 MHz, DMSO-d6): d = 154.4, 151.8, 148.8, 148.6,
148.5, 148.2 (2C), 137.3, 135.1, 130.4, 121.3, 119.2, 114.6, 111.6,
111.1, 111.0, 110.7, 110.3, 109.5, 55.7, 55.6 (3C), 55.5 (2C), 43.4.
MS (EI, 70 eV): m/z (%) = 481 (97) [M+], 466 (38), 451 (22), 450
(100), 434 (11), 420 (13), 344 (35), 328 (12), 299 (59), 284 (12),
225 (15), 181 (23), 151 (26).
Anal. Calcd for C20H15NS: C, 79.70; H, 5.02; N, 4.65; S, 10.64.
Found: C, 79.53; H, 5.06; N, 4.61; S, 10.55.
11-(3,4-Dimethoxyphenyl)-8,9-dimethoxy-5,11-dihydro-6H-
dibenzo[b,e]azepine-6-thione (10d)
Yellow solid; yield: 7%; mp 100–101 °C.
IR (KBr): 1602, 1512, 1412, 1265, 1235, 1128, 1025, 949, 872, 757
cm–1.
Anal. Calcd for C26H27NO6S: C, 64.85; H, 5.65; N, 2.91; S, 6.66.
Found: C, 64.72; H, 5.51; N, 2.70; S, 6.75.
1H NMR (300 MHz, DMSO-d6): d = 12.06 (s, 1 H, NH), 7.72 (s, 1
H, HAr), 7.56–7.53 (m, 1 H, HAr), 7.32–7.28 (m, 2 H, HAr), 7.22–
7.19 (m, 1 H, HAr), 7.09 (s, 1 H, HAr), 6.77 (d, J = 8.0 Hz, 1 H, HAr),
6.32 (d, J = 1.6 Hz, 1 H, HAr), 6.31 (dd, J = 1.6, 8.0 Hz, 1 H, HAr),
5.32 (s, 1 H, CH), 3.87 (s, 3 H, OCH3), 3.78 (s, 3 H, OCH3), 3.67 (s,
3 H, OCH3), 3.54 (s, 3 H, OCH3).
13C NMR (50 MHz, DMSO-d6): d = 197.0, 152.1, 148.0, 147.3,
147.0, 137.9, 136.5, 134.9, 132.7, 129.6, 129.2, 127.5, 126.1, 122.5,
119.1, 117.0, 111.6, 111.4, 111.0, 55.8, 55.6, 55.5, 55.3, 53.0.
2,4-Bis(3,4-Diethoxyphenyl)-6,7-dimethoxy-4H-3,1-benzothiaz-
ine (9f)
Pale yellow solid; yield: 26%; mp 124–125 °C.
IR (KBr): 1605, 1503, 1473, 1422, 1262, 1236, 1140, 1040, 1002,
865, 775 cm–1.
1H NMR (300 MHz, DMSO-d6): d = 7.64 (d, J = 1.9 Hz, 1 H, HAr),
7.52 (dd, J = 1.9, 8.6 Hz, 1 H, HAr), 7.08 (s, 1 H, HAr), 7.02 (d, J =
8.6 Hz, 1 H, HAr), 6.86 (d, J = 2.0 Hz, 1 H, HAr), 6.82 (s, 1 H, HAr),
6.77 (d, J = 8.3 Hz, 1 H, HAr), 6.49 (dd, J = 2.0, 8.3 Hz, 1 H, HAr),
5.53 (s, 1 H, CH), 4.13–4.06 (m, 4 H, OCH2CH3), 3.96–3.88 (m, 4
H, OCH2CH3), 3.86 (s, 3 H, OCH3), 3.75 (s, 3 H, OCH3), 1.33–1.38
(m, 6 H, OCH2CH3), 1.28–1.23 (m, 6 H, OCH2CH3).
13C NMR (50 MHz, DMSO-d6): d = 154.3, 151.3, 148.5, 148.1,
148.0, 147.8, 147.6, 137.4, 135.1, 130.3, 121.4, 119.3, 114.6, 113.1,
112.6, 112.3, 111.2, 110.7, 110.3, 64.0, 63.8 (2C), 63.7, 55.7, 55.6,
43.3, 14.7 (4C).
MS (EI, 70 eV): m/z (%) = 421 (100) [M+], 406 (23), 390 (27), 388
(17), 329 (27), 328 (16), 301 (30), 267 (14), 238 (12), 179 (29), 178
(15), 151 (36), 59 (12).
Anal. Calcd for C24H23NO4S: C, 68.39; H, 5.50; N, 3.32; S, 7.61.
Found: C, 68.50; H, 5.48; N, 3.25; S, 7.50.
Crystal data: C24H23NO4S, orthorhombic, space group Pbca;
a = 10.108(2) Å, b = 16.238(3) Å, c = 25.960(5) Å, V = 4260.9(14)
Å3, Z = 8, Dcalcd = 1.314 Mg/m3, F(000) = 1776; 3703 reflections
collected, 3602 unique (Rint = 0.0252); final R indices (1307 ob-
served collections I > 2sI): R1 = 0.0350, wR2 = 0.0875; final R indi-
ces (all data): R1 = 0.1700, wR2 = 0.0980.
MS (EI, 70 eV): m/z (%) = 537 (100) [M+], 508 (11), 507 (45), 506
(98), 328 (14), 327 (21).
Anal. Calcd for C30H35NO6S: C, 67.02; H, 6.56; N, 2.61; S, 5.96.
Found: C, 67.45; H, 6.71; N, 2.59; S, 6.12.
11-(3,4-Diethoxyphenyl)-8,9-diethoxy-2,3-dimethoxy-5,11-di-
hydro-6H-dibenzo[b,e]azepine-6-thione (10f)
Yellow solid; yield: 5%; mp 186–187 °C.
2,4-Bis(2,3-dihydro-1,4-benzodioxin-6-yl)-4H-3,1-benzothiaz-
ine (9g)
IR (KBr): 1600, 1508, 1476, 1444, 1420, 1396, 1356, 1264, 1244,
1224, 1140, 1104, 1040, 996, 864, 796, 756 cm–1.
Yellow oil; yield: 61%. This compound was obtained with 90% pu-
rity, and characterized by spectral methods only.
1H NMR (300 MHz, DMSO-d6): d = 11.85 (s, 1 H, NH), 7.70 (s, 1
H, HAr), 7.12 (s, 1 H, HAr), 7.01 (s, 1 H, HAr), 6.85 (s, 1 H, HAr), 6.74
(d, J = 8.4 Hz, 1 H, HAr), 6.31 (d, J = 1.6 Hz, 1 H, HAr), 6.29 (dd,
J = 1.6, 8.4 Hz, 1 H, HAr), 5.18 (s, 1 H, CH), 4.17–4.09 (m, 2 H,
OCH2CH3), 4.06–3.97 (m, 2 H, OCH2CH3), 3.95–3.87 (m, 2 H,
OCH2CH3), 3.82 (s, 3 H, OCH3), 3.83–3.73 (m, 2 H, OCH2CH3),
3.71 (s, 3 H, OCH3), 1.37 (t, J = 7.0 Hz, 3 H, OCH2CH3), 1.32 (t,
J = 7.0 Hz, 3 H, OCH2CH3), 1.26 (t, J = 7.0 Hz, 3 H, OCH2CH3),
1.20 (t, J = 7.0 Hz, 3 H, OCH2CH3).
13C NMR (50 MHz, DMSO-d6): d = 195.7, 151.5, 147.4, 147.3,
146.8, 146.7, 146.0, 135.4, 133.2, 130.1, 129.7, 129.1, 119.4, 118.6,
113.2, 112.9, 112.7, 112.3, 106.7, 64.0 (2C), 63.8, 63.7, 55.8, 55.6,
52.4, 14.7 (3C), 14.6.
IR (Nujol): 1612, 1584, 1540, 1500, 1480, 1460, 1428, 1320, 1288,
1260, 1248, 1204, 1164, 1128, 1068, 1052, 920, 888, 820, 768 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.68 (d, J = 2.0 Hz, 1 H, HAr), 7.65
(dd, J = 2.0, 8.4 Hz, 1 H, HAr), 7.56–7.54 (m, 1 H, HAr), 7.42–7.37
(m, 1 H, HAr), 7.27–7.22 (m, 1 H, HAr), 7.08–7.06 (m, 1 H, HAr),
6.92 (d, J = 8.4 Hz, 1 H, HAr), 6.77–6.67 (m, 3 H, HAr), 5.30 (s, 1 H,
CH), 4.29–4.26 (m, 4 H, CH2CH2), 4.19 (s, 4 H, CH2CH2).
13C NMR (50 MHz, DMSO-d6): d = 158.7, 147.0, 144.0, 143.5
(2C), 143.3, 134.5, 131.5, 128.6, 127.7, 127.5, 127.3, 123.0, 121.9,
120.7, 117.5 (2C), 117.3, 116.6, 64.7, 64.3 (3C), 45.2.
MS (EI, 70 eV): m/z (%) = 417 (100) [M+], 361 (10), 333 (26), 250
(10), 238 (17), 237 (14), 223 (26), 179 (25), 171 (20), 163 (17), 87
(29), 85 (38), 59 (29), 57 (14).
Synthesis 2009, No. 15, 2616–2626 © Thieme Stuttgart · New York

PAPER
Synthesis of 2,4-Diaryl-4H-3,1-benzothiazines
2625
MS (EI, 70 eV): m/z (%) = 537 (100) [M+], 522 (71), 509 (24), 506
(43), 478 (15), 462 (13), 328 (18), 193 (14), 179 (36), 151 (30), 123
(31), 59 (27), 57 (27).
1H NMR (200 MHz, CDCl3): d = 7.10 (s, 4 H, HAr), 6.66 (s, 1 H,
HAr), 6.31 (s, 1 H, HAr), 3.84 (s, 3 H, OCH3), 3.83 (s, 2 H, CH2), 3.81
(s, 3 H, OCH3), 3.30 (s, 2 H, NH2), 2.33 (s, 3 H, CH3).
Anal. Calcd for C30H35NO6S: C, 67.02; H, 6.56; N, 2.61; S, 5.96.
Found: C, 67.11; H, 6.86; N, 2.65; S, 5.80.
Anal. Calcd for C16H19NO2: C, 74.68; H, 7.44; N, 5.44. Found: C,
74.47; H, 7.48; N, 5.55.
4-[4-(4-Methoxyphenyl)-4H-3,1-benzothiazin-2-yl]phenol (11)
Pale yellow solid; yield: 15%; mp 226 °C.
1-Benzyl-2-isothiocyanatobenzenes 16; General Procedure
The procedure used for the synthesis of compounds 8 was also used
for the synthesis of compounds 16.
IR (KBr): 3459, 1608, 1584, 1540, 1508, 1436, 1292, 1256, 1236,
1188, 1164, 1032, 964, 836, 768 cm–1.
1-Benzyl-2-isothiocyanato-4,5-dimethoxybenzene (16a)
Pale beige needles; yield: 72%; mp 83–84 °C (CH2Cl2–PE).
1H NMR (300 MHz, DMSO-d6): d = 10.09 (s, 1 H, OH), 7.91 (d,
J = 8.6 Hz, 2 H, HAr), 7.48–7.39 (m, 2 H, HAr), 7.31–7.26 (m, 1 H,
HAr), 7.19–7.17 (m, 1 H, HAr), 7.07 (d, J = 8.6 Hz, 2 H, HAr), 6.88
(d, J = 8.6 Hz, 2 H, HAr), 6.82 (d, J = 8.6 Hz, 2 H, HAr), 5.66 (s, 1 H,
CH), 3.68 (s, 3 H, OCH3).
13C NMR (50 MHz, DMSO-d6): d = 160.9, 158.5, 157.3, 143.6,
134.1, 129.4 (2C), 128.5, 128.2 (2C), 127.3 (2C), 127.2, 126.9,
123.1, 115.4 (2C), 113.9 (2C), 55.0, 43.1.
IR (KBr): 2136, 1612, 1516, 1496, 1464, 1452, 1404, 1348, 1296,
1268, 1228, 1208, 1168, 1124, 1004, 788, 728 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.34–7.18 (m, 5 H, HAr), 6.76 (s,
1 H, HAr), 6.63 (s, 1 H, HAr), 4.00 (s, 2 H, CH2), 3.86 (s, 3 H, OCH3),
3.81 (s, 3 H, OCH3).
Anal. Calcd for C16H15NO2S: C, 67.34; H, 5.30; N, 4.91; S, 11.24.
Found: C, 67.39; H, 5.33; N, 4.93; S, 11.01.
MS (EI, 70 eV): m/z (%) = 347 (100) [M+], 332 (29).
Anal. Calcd for C21H17NO2S: C, 72.60; H, 4.93; N, 4.03; S, 9.23.
Found: C, 72.73; H, 5.13; N, 3.93; S, 9.02.
1-(4-Chlorobenzyl)-2-isothiocyanato-4,5-dimethoxybenzene
(16b)
Pale beige needles; yield: 84%; mp 118–119 °C (CH2Cl2–PE).
Crystal data: C21H17NO2S, monoclinic, space group P2(1)/n;
a = 13.795(3) Å, b = 8.128(2) Å, c = 15.622(3) Å, b = 96.06(3)°,
V = 1741.8(7) Å3, Z = 4, Dcalcd = 1.325 Mg/m3, F(000) = 728; 3459
reflections collected, 3335 unique (Rint = 0.0181); final R indices
(2105 observed collections I > 2sI): R1 = 0.0288, wR2 = 0.0827; fi-
nal R indices (all data): R1 = 0.0622, wR2 = 0.0877.
IR (KBr): 2156, 1604, 1516, 1492, 1460, 1404, 1352, 1288, 1268,
1232, 1208, 1172, 1124, 1008, 864, 844, 788 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.28 (d, J = 8.3 Hz, 2 H, HAr), 7.11
(d, J = 8.3 Hz, 2 H, HAr), 6.75 (s, 1 H, HAr), 6.60 (s, 1 H, HAr), 3.96
(s, 2 H, CH2), 3.86 (s, 3 H, OCH3), 3.83 (s, 3 H, OCH3).
2-Benzyl-4,5-dimethoxyanilines 15; General Procedure
Anhydrous AlCl3 (4.5 g, 34 mmol) and NaBH4 (1.3 g, 34 mmol)
were added portionwise to a stirred soln of compound 14 (17 mmol)
in THF (120 mL) cooled to 0–5 °C. The resulting suspension was
stirred at 0–5 °C for 20 min and then refluxed for 1–2 h until the
starting compound was consumed (TLC). The mixture was then
cooled and poured into H2O (400 mL). The organic layer was sepa-
rated and the H2O layer was extracted with EtOAc (3 × 50 mL). The
combined organic layers were dried (Na2SO4), treated with activat-
ed charcoal, and concentrated under reduced pressure. The residue
was dissolved in CH2Cl2–PE (1:2) and the soln was filtered through
the pad of silica gel. The residue was crystallized from CH2Cl2–PE
(1:4).
Anal. Calcd for C16H14ClNO2S: C, 60.09; H, 4.41; N, 4.38; S, 10.03.
Found: C, 60.19; H, 4.46; N, 4.36; S, 9.90.
1-Isothiocyanato-4,5-dimethoxy-2-(4-methylbenzyl)benzene
(16c)
White solid; yield: 85%; mp 106–107 °C (CH2Cl2–PE).
IR (KBr): 2152, 1608, 1520, 1464, 1448, 1404, 1348, 1292, 1268,
1232, 1168, 1124, 1008, 868, 840, 788 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.12 (d, J = 8.1 Hz, 2 H, HAr), 7.08
(d, J = 8.1 Hz, 2 H, HAr), 6.75 (s, 1 H, HAr), 6.63 (s, 1 H, HAr), 3.96
(s, 2 H, CH2), 3.86 (s, 3 H, OCH3), 3.82 (s, 3 H, OCH3), 2.33 (s, 3
H, CH3).
Anal. Calcd for C17H17NO2S: C, 68.20; H, 5.72; N, 4.68; S, 10.71.
Found: C, 68.03; H, 5.68, N, 4.71; S, 10.50.
Compound 15a was obtained as a yellow oil and used at the next
step as prepared.
2,3-Dimethoxy-8-methyl-5,11-dihydro-6H-dibenzo[b,e]azepine-
6-thione (17)
Compound 17 was obtained analogously to compounds 9 and 10,
except that the reaction mixture was kept at r.t. for 48 h. See Table 4
for NMR data.
2-(4-Chlorobenzyl)-4,5-dimethoxyaniline (15b)
Pale beige plates; yield: 60%; mp 98–99 °C.
IR (KBr): 3420, 3346, 1609, 1522, 1485, 1465, 1414, 1295, 1234,
1127, 1085, 1005, 840, 795, 751 cm–1.
1H NMR (200 MHz, CDCl3): d = 7.26 (d, J = 8.2 Hz, 2 H, HAr), 7.11
(d, J = 8.2 Hz, 2 H, HAr), 6.62 (s, 1 H, HAr), 6.32 (s, 1 H, HAr), 3.84
(s, 3 H, OCH3), 3.82 (s, 2 H, CH2), 3.80 (s, 3 H, OCH3), 3.28 (s, 2
H, NH2).
Yellow solid; yield: 38%; mp 186–187 °C (EtOAc–PE).
IR (KBr): 1520, 1508, 1440, 1348, 1280, 1264, 1248, 1124, 1112,
1020, 860 cm–1.
MS (EI, 70 eV): m/z (%) = 299 (81) [M+], 284 (28), 266 (26), 256
Anal. Calcd for C15H16ClNO2: C, 64.87; H, 5.81; N, 5.04. Found: C,
64.65; H, 5.95; N, 5.12.
(17), 165 (20), 104 (19), 101 (100), 82 (58), 58 (78), 57 (37).
Anal. Calcd for C17H17NO2S: C, 68.20; H, 5.72; N, 4.68; S, 10.71.
Found: C, 67.01; H, 5.71; N, 4.69; S, 10.48.
4,5-Dimethoxy-2-(4-methylbenzyl)aniline (15c)
Pale beige needles; yield: 76%; mp 104–105 °C.
IR (KBr): 3420, 3347, 1610, 1521, 1461, 1296, 1234, 1210, 1168,
1127, 1005, 840, 803, 758 cm–1.
Acknowledgment
Financial support was provided by the Russian Foundation of Basic
Research (grant 07-03-00352) and Bayer HealthCare AG (Germa-
ny).
Synthesis 2009, No. 15, 2616–2626 © Thieme Stuttgart · New York

2626
A. V. Butin et al.
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Synthesis 2009, No. 15, 2616–2626 © Thieme Stuttgart · New York