Regioselective synthesis of pyrimido[5,4-c][2,1]benzothiazines by reactions of β-chloroaldehydes with N-C-N binucleophiles

Article abstract of DOI:10.1002/jhet.271

(Chemical Equation Presented) The method of pyrimidine ring fusion at the [c] side of benzothiazines based on the reaction of their chloroaldehyde derivatives with amidines is described. Formation of the structural isomers of reaction products was investigated, and regioselectivity of heterocyclization reactions was shown. A number of novel pyrimidobenzothiazines were synthesized.

Full text of DOI:10.1002/jhet.271

January 2010
Regioselective Synthesis of Pyrimido[5,4-c][2,1]benzothiazines by
Reactions of b-Chloroaldehydes with N-C-N Binucleophiles
Kirill Popov,* Tatyana Volovnenko, Alexander Turov, and Yulian Volovenko
85
Organic Synthesis Laboratory, Kyiv National University, Kyiv 01033, Ukraine
*E-mail: popovkirill@bk.ru
Received May 25, 2009
DOI 10.1002/jhet.271
Published online 29 December 2009 in Wiley InterScience (www.interscience.wiley.com).
The method of pyrimidine ring fusion at the [c] side of benzothiazines based on the reaction of their
chloroaldehyde derivatives with amidines is described. Formation of the structural isomers of reaction
products was investigated, and regioselectivity of heterocyclization reactions was shown. A number of
novel pyrimidobenzothiazines were synthesized.
J. Heterocyclic Chem., 47, 85 (2010).
INTRODUCTION
dobenzothiazines as only products is expected. In case
of asymmetric bis-nucleophiles 4d–i, structural isomers
of the reaction product can be formed. Depending on
which electrophilic center is attacked by nucleophile at
the first stage of heterocyclization process, linear- or
angular-type fused compound is obtained.
Among benzothiazine derivatives, there are a number
of compounds known to show biological activity [1]. In
particular, heterocyclic ring fusion on a side [c] of ben-
zothiazine leads to the condensed systems some repre-
sentatives of which are known as drugs. Thus, 5-methyl-
3-(2-pyridyl)-2H,5H-1,3-oxazino[5,6c][1,2]benzo thiazin-2,
4-(3H)-dione-6,6-dioxide 1 [2] is a well-known anti-
inflammatory agent (trade name ‘‘Droxicam’’), and (4-
methoxy-3,5-dimethyl-phenyl)-(9-methyl-9H-10-thia-2,4,9-
triaza-phenantren-3-yl)-amine 2 is a protein tyrosine ki-
nase inhibitor [3] (Fig. 1). However, condensed benzothia-
zines currently used in medicine have a number of
adverse effects [4].
Pyrazoles 4d–f and benzoimidazole 4h both contain
two N-nucleophilic centers, thus in reactions with chlor-
oaldehydes 3 two different isomeric pyrazolobenzothia-
zine products are possible (Scheme 1). Triazole 4g and
quinazalone 4i contain three N-nucleophilic centers
each, which causes four possible isomeric products in
reaction with 3 (Scheme 2). One of current research
goals was to establish exactly which isomer is formed in
every case.
The interaction of chloroaldehydes 3a,b with ami-
dines 4a–c (Scheme 3) led to pyrimidobenzothiazines
5a–f. Reactions proceeded under mild conditions, and
no first-stage intermediates were observed in the reac-
tion mixtures.
RESULTS AND DISCUSSION
In our previous paper [5], we have reported the syn-
thesis of some novel benzo[e][2,1]thiazine derivatives—
chloroaldehydes 3a–e (Fig. 2), and their chemistry was
shown to be quite diverse. Compounds 3 contain labile
chlorine atom at C-4 and carbonyl group at C-3 position
of the ring. We assumed that the studies of chloroalde-
hyde fragment reactivity could provide a way to obtain
new condensed benzothiazines devoid of side effects or
less toxic.
The next step of this work was to investigate the reac-
tions of compounds 3 with aminopyrazoles 4d–f. The
heating of 3 with 4d–f resulted in crystalline products 6
(Scheme 4). We have expected the formation of angular
1
products, and H NMR spectra of compounds 6a–l did
not contradict angular structures, as H-1 phenylene proton
doublet was observed to undergo low-field shift. How-
ever, X-ray analysis proved the structure of compounds
6a–l to be linear (Fig. 3). It seems that the signal of
phenylene proton in compound 6 can shift to 8.5 ppm
due to the effect of nitrogen atom of pyrimidine ring.
We have not found in the literature any example of
the reaction of b-halogenvinylcarbonyl compounds with
In this article, we describe the method of pyrimidine
ring fusion at the [c] side of benzothiazines. The route
developed by our group involves the interaction of
chloroaldehydes 3a–e with bis-nucleophilic agents 4a–i
containing N-C-N fragment (Table 1). When amidines
4a–c are used as nucleophiles, the formation of pyrimi-
C
V
2009 HeteroCorporation

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K. Popov, T. Volovnenko, A. Turov, and Y. Volovenko
Vol 47
Figure 2. 4-Chloro-benzo[c][1,2]thiazine-3-carbaldehydes 3a–e.
Figure 1. Examples of biologically active condensed benzothiazines.
the conclusion that compounds 9 most probably adopt
helical-type structure.
amidine nucleophiles proceeding via nucleophilic substi-
tution of halogen atom at the first stage of the reaction
followed by nucleophilic addition to carbonyl group
resulting in the products of linear type. All reactions of
analogous nature described until now proceed by Schiff
base formation at first stage, then displacement of chlo-
rine. What we observe is opposite to that route. Alde-
hyde group in compounds 3 is more sterically available
than C-4 carbon atom; therefore, its reactions have to
proceed under kinetic control, whereas the substitution
of chlorine is rather thermodynamically controlled pro-
cess. We assume the nucleophilic substitution of chlo-
rine atom to be the ‘‘push–pull’’ process, with addition
of exocyclic amino function of 4d–f to C-4 carbon fol-
lowed by halogen cleavage with C3–C4 double bond
restoration.
When 3-aminotriazole 4g was used as a nucleophile,
the reaction with 3a–c proceeded in more common man-
ner: the initial condensation of exocyclic amino function
with carbonyl group is followed by the displacement of
chlorine atom (Scheme 6). Depending on which nitrogen
atom (N-2 or N-4) attacks the C-4 position at the second
stage of the heterocyclization, formation of structural
isomers of the reaction products 7 can occur. 1D-
NOESY experiment revealed strong interaction between
the protons with chemical shifts 8.82 and 9.58 ppm
(Scheme 6) that proved N-4 (but not N-2) nitrogen atom
of 3-aminotriazole to participate in the ring formation.
The reactions of chloroaldehydes 3 with 2-aminoquina-
zolin-4-one 4i give angular compounds 10a–c (Scheme 7).
To determine the structure of the product isolated
1
from the reaction mixture, H and 13C NMR spectros-
The interaction of 3b,c with 2-aminobenzoimidazole
4h proceeds in a similar way (Scheme 5). Upon mild
heating (30–35ꢀC) of the reaction solution in DMF, the
mixture of the Schiff base 8a,b and the heterocycliza-
tion product 9a,b is formed in the equimolar ratio (1H
NMR data). Subsequent temperature increase (50–70ꢀC)
acts in favor of the cyclic derivative 9a,b (1:2 ratio).
Heating the mixture to 100ꢀC results in the formation of
9a,b only. The interaction between the protons with
chemical shifts 7.51 and 8.45 ppm (Scheme 5) observed
during 1D-NOESY experiment proved angular structure
of products 9. Analysis of 3D molecular models led to
copy was used. The investigation of 3D models of the
product showed that in the structure 10 the doublet of
H-1 proton should be shifted to low field due to the
neighboring carbonyl oxygen effect.
In experimental NMR spectrum, we observe a pro-
nounced shift of the doublet that due to homonuclear
(COSY) and heteronuclear (1H-13C HMBC, HMQC)
correlation experiments originated from the H-5 proton
of starting benzothiazine 3. Thus, the reaction proceeds
regioselectively; the ‘‘amide’’ nitrogen of the starting
quinazoline 4i participates in cyclization.
Table 1
Structures of bis-nucleophilic reagents.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

January 2010
Regioselective Synthesis of Pyrimido[5,4-c][2,1]benzothiazines by Reactions of
b-Chloroaldehydes with N-C-N Binucleophiles
87
Scheme 1
EXPERIMENTAL
The NMR spectra were measured on a Varian 400 spec-
trometer at 25ꢀC using DMSO-d6. All chemical shifts are
reported in ppm relative to TMS.
Starting materials used were obtained from Makrochim and
used without further purification. Dry solvents were prepared
according to the standard methods.
6-Alkyl-6H-pyrimido[5,4-c][2,1]benzothiazine-5,5-dioxides
(5a–f); general procedure. The mixture of b-chloroaldehyde
3 (1 mmol) with the corresponding amidine 4a–c (1.2 mmol)
was dissolved in 2 mL of dry DMF. Triethylamine (2 mL)
was added and the reaction mixture was heated for 6 h at
80ꢀC. The mixture was cooled to room temperature, quenched
with water (20 mL), solid product was filtered off, and then
washed with ethanol. The pure product was obtained by crys-
tallization from DMF (64–86%).
Product 5a (77%, R Me, R1 i-Pr). m.p.: 103–104ꢀC; 1H
NMR (400 MHz, DMSO): d ¼ 1.42 (d, J ¼ 7.8 Hz, 6H), 3.48
(quin. J ¼ 7.7 Hz, 1H), 3.58 (s, 3H), 7.48(t, J ¼ 7.8, 1H),
7.63(d, J ¼ 7.8 Hz, 1H), 7.75(t, J ¼ 7.8 Hz, 1H), 8.68(d, J ¼
7.75 Hz, 1H), 9.11 (s, 1H). 13C NMR (100 MHz, DMSO): d
¼ 14.55 (ꢂ2), 43.78, 49.13, 122.63, 125.36, 128.65, 129.47,
135.34, 141.17, 143.19, 153.17, 156.22, 164.62; MS (CI):
290(MþH)þ; Anal. calcd. C, 58.11; H, 5.23; N, 14.52; found
C, 58.14; H, 5.25; N, 14.54.
Product 5b (79%, R Me, R1 Ph). m.p.: 202–203ꢀC; 1H
NMR (400 MHz, DMSO): d ¼ 3.59 (s, 3H) 7.45–7.63 (m,
5H), 7.82 (t, J ¼ 7.8 Hz, 1H), 8.57(d, J ¼ 8 Hz, 2H), 8.83 (d,
J ¼ 7.8 Hz, 1H) 9.30 (s, 1H). 13C NMR (100 MHz, DMSO):
d ¼ 38.22, 120.51, 123.34, 126.72, 126.97, 127.62, 129.38,
129.68, 133.29, 135.07, 136.54, 140.07, 141.04, 142.57,
152.88, 156.23, 166.91; MS (CI): 324(MþH)þ; Anal. calcd. C,
63.14; H, 4.05; N, 12.99; found C, 63.17; H, 4.07; N, 13.02.
Product 5c (64%, R Me, R1 Thienyl). m.p.: 194–195ꢀC;
1H NMR (400 MHz, DMSO): d ¼ 3.59 (s, 3H) 7.26 (t, J ¼ 8
Hz, 1H), 7.48 (t, J ¼ 7.8 Hz, 1H), 7.61 (d, J ¼ 8 Hz, 1H),
7.74–7.81 (m, 2H), 8.16 (d, J ¼ 7.8 Hz, 1H), 8.69 (d, J ¼ 7.8
Hz, 1H), 9.15 (s, 1H). 13C NMR (100 MHz, DMSO): d ¼
37.74, 120.44, 123.75, 125.37, 126.74, 128.68, 129.15, 129.94,
133.45, 135.89, 136.35, 141.94, 152.56, 156.84, 164.89; MS
Structures of all aforementioned compounds were
established on the basis of their 1H NMR, 13C NMR,
Mass spectrometry data, and elemental microanalyses.
In summary, we disclose the synthesis of novel benzo
[e][2,1]thiazine derivatives, in particular substituted pyr-
imidobenzothiazines and pyrazolo-, imidazo-, triazolo-
pyrimidobenzothiazines. These compounds were ob-
tained in high yields (ꢁ70–80%) via convenient proto-
cols involving heterocyclization reactions of chloroalde-
hydes 3a–e with N-C-N bisnucleophiles 4a–i.
Scheme 2
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K. Popov, T. Volovnenko, A. Turov, and Y. Volovenko
Vol 47
Scheme 3
Scheme 4
¼ 7.8 Hz, 1H), 8.46 (d, J ¼ 7.8 Hz, 1H), 9.83 (s, 1H); MS
(CI): 315 (MþH)þ; Anal. calcd. C, 57.31; H, 4.49; N, 17.82;
found C, 57.32; H, 4.51; N, 17.81.
Product 6c (86%, R Pr, R2 Me, R3 H). m.p.: >250ꢀC
(CI): 330(MþH)þ; Anal. calcd. C, 54.69; H, 3.37; N, 12.76;
found C, 54.72; H, 3.40 N, 12.77.
1
(decomp.); H NMR (400 MHz, DMSO): d ¼ 0.80 (t, J ¼ 6.8
Hz,3H), 1.54 (m, 2H), 2.50 (s, 3H), 3.83 (t, J ¼ 6.8 Hz,2H),
6.67 (s, 1H), 7.46 (t, J ¼ 7.8 Hz, 1H), 7.53 (d, J ¼ 8 Hz, 1H),
7.67 (t, J ¼ 7.8 Hz, 1H), 8.49 (d, J ¼ 7.8 Hz, 1H), 9.61 (s,
1H); MS (CI): 329(MþH)þ; Anal. calcd. C, 58.52; H, 4.91; N,
17.06; found C, 58.53; H, 4.93; N, 17.07.
Product 5d (82%, R Et, R1 i-Pr). m.p.: 114–115ꢀC; 1H
NMR (400 MHz, DMSO): d ¼ 1.22 (t, J ¼ 8 Hz, 3H), 1.42
(d, J ¼ 7.8 Hz, 6H), 3.48 (quin. J ¼ 7.8 Hz, 1H), 4.08 (q, J ¼
8 Hz, 2H), 7.46(t, J ¼ 7.8, 1H), 7.60(d, J ¼ 7.8 Hz, 1H),
7.78(t, J ¼ 7.8 Hz, 1H), 8.63(d, J ¼ 7.8 Hz, 1H), 9.16 (s, 1H).
13C NMR (100 MHz, DMSO): d ¼ 14.64 (ꢂ2), 44.25, 49.02,
121.60, 123.37, 125.76, 127.65, 129.78, 132.15, 135.33,
141.09, 142.18, 152.77, 156.20, 162.82; MS (CI):
304(MþH)þ; Anal. calcd. C, 59.38; H, 5.65; N, 13.85; found
C, 59.40; H, 5.66; N, 13.85.
Product 6d (75%, R Bu, R2 Me, R3 H). m.p.: >250ꢀC
1
(decomp.); H NMR (400 MHz, DMSO): d ¼ 0.83 (t, J ¼ 6.8
Hz,3H), 1.22 (m, 2H), 1.50 (m, 2H), 2.54 (s, 3H), 3.86 (t, J ¼
6.8 Hz, 2H), 6.67 (s, 1H), 7.46 (t, J ¼ 7.8 Hz, 1H), 7.52 (d, J
¼ 7.8 Hz, 1H), 7.67 (t, J ¼ 7.8 Hz, 1H), 8.49 (d, J ¼ 7.8 Hz,
1H), 9.61 (s, 1H); MS (CI): 343(MþH)þ; Anal. calcd. C,
59.63; H, 5.30; N, 16.36; found C, 59.64; H, 5.33; N, 16.36.
Product 6e (78%, R Bn, R2 Me, R3 H). m.p.: >250ꢀC
(decomp.); 1H NMR (400 MHz, DMSO): d ¼ 2.55 (s, 3H),
5.08 (s, 2H), 6.65 (s, 1H), 7.12–7.15 (m, 5H), 7.41–7.45 (m,
2H), 7.59 (t, J ¼ 7.8 Hz, 1H), 8.43 (d, J ¼ 7.8 Hz, 1H), 9.63
(s, 1H); MS (CI): 377(MþH)þ; Anal. calcd. C, 63.81; H, 4.28;
N, 14.88; found C, 63.83; H, 4.29; N, 14.90.
Product 5e (86%, R Et, R1 Ph). m.p.: 214–215ꢀC; 1H
NMR (400 MHz, DMSO): d ¼ 1.23 (t, J ¼ 7.6 Hz, 3H), 4.08
(q, J ¼ 7.6 Hz, 2H), 7.49–7.67 (m, 5H), 7.80 (t, J ¼ 7.8 Hz,
1H), 8.61(d, J ¼ 8 Hz, 2H), 8.80 (d, J ¼ 7.8 Hz, 1H) 9.32 (s,
1H). 13C NMR (100 MHz, DMSO): d ¼ 14.71, 44.22, 121.52,
123.64, 125.76, 126.59, 127.82, 129.35, 129.62, 132.89,
135.27, 136.59, 141.02, 152.60, 156.12, 165.93; MS (CI):
338(MþH)þ; Anal. calcd. C, 64.08; H, 4.48; N, 12.45; found
C, 64.09; H, 4.47; N, 12.47.
Product 6f (63%, R Me, R2 Me, R3 m-Cl-Ph). m.p.:
219–220ꢀC; 1H NMR (400 MHz, DMSO): d ¼ 2.68 (s, 3H),
3.41 (s, 3H), 7.34 (d, J ¼ 7.8 Hz, 1H), 7.44–7.52 (m, 3H),
7.68–7.74 (m, 2H), 7.83 (s, 1H), 8.48 (d, J ¼ 8 Hz, 1H), 9.75
(s, 1H). 13C NMR (100 MHz, DMSO): d ¼ 13.99, 15.16,
19.84, 30.18, 49.53, 108.72, 119.39, 123.53, 125.62, 126.74,
127.44, 127.72, 128.62, 131.18, 133.18, 140.62, 145.83,
147.95, 156.77; MS (CI): 411(MþH)þ; Anal. calcd. C, 58.46;
H, 3.68; N, 13.64; found C, 58.48; H, 3.70; N, 13.65.
1
Product 5f (71%, R Et, R1 Thienyl). m.p.: 205–206ꢀC; H
NMR (400 MHz, DMSO): d ¼ 1.21 (t, J ¼ 8 Hz, 3H), 4.07
(q, J ¼ 8 Hz, 2H), 7.24 (t, J ¼ 7.8 Hz, 1H), 7.49 (t, J ¼ 7.8
Hz, 1H), 7.60 (d, J ¼ 7.8 Hz, 1H), 7.75–7.82 (m, 2H), 8.17
(d, J ¼ 8 Hz, 1H), 8.67 (d, J ¼ 7.8 Hz, 1H), 9.18 (s, 1H). 13C
NMR (100 MHz, DMSO): d ¼ 14.73, 22.05, 43.96, 121.43,
123.50, 125.68, 126.37, 135.16, 140.88, 152. 07, 155.60,
178.09; MS (CI): 344(MþH)þ; Anal. calcd. C, 55.96; H, 3.82;
N, 12.24; found C, 55.96; H, 3.83; N, 12.27.
5-Alkyl-5H-pyrazolo[10,50:1,2]pyrimido[5,4-c][2,1]benzo
thiazin-6,6-dioxides (6a–l); general procedure. The mix-
ture of b-chloroaldehyde 3 (1 mmol) with the corresponding
aminopyrazole 4d–f (1.2 mmol) was dissolved in 2 mL of dry
DMF. The reaction mixture was heated for 10 h at 90ꢀC. The
mixture was cooled to room temperature; solid product was fil-
tered off and washed with ethanol. The pure product was
obtained by crystallization from DMF (59–86%).
Product 6g (59%, R Et, R2 Me, R3 m-Cl-Ph). m.p.: 232–
1
233ꢀC; H NMR (400 MHz, DMSO): d ¼ 1.28 (t, J ¼ 6.7 Hz,
3H), 2.62 (s, 3H), 3.93 (q, J ¼ 6.7 Hz, 2H), 7.36 (d, J ¼ 7.8
Hz, 1H), 7.42–7.53 (m, 3H), 7.68–7.75 (m, 2H), 7.82 (s, 1H),
Product 6a (68%, R Me, R2 Me, R3 H). m.p.: 178–
179ꢀC; 1H NMR (400 MHz, DMSO): d ¼ 3.35 (s, 3H), 3.37
(s, 3H), 6.81 (s, 1H), 7.49 (t, J ¼ 7.8 Hz, 1H), 7.56 (d, J ¼ 8
Hz, 1H), 7.73 (t, J ¼ 7.8 Hz, 1H), 8.47 (d, J ¼ 8 Hz, 1H),
9.86 (s, 1H); MS (CI): 301(MþH)þ; Anal. calcd. C, 55.99; H,
4.03; N, 18.65; found C, 56.02; H, 4.03; N, 18.68.
Product 6b (70%, R Et, R2 Me, R3 H). m.p.: >250ꢀC
1
(decomp.); H NMR (400 MHz, DMSO): d ¼ 1.03 (t, J ¼ 6.8
Hz, 3H), 3.35 (s, 3H), 3.91 (q, J ¼ 6.8 Hz, 2H), 6.80 (s, 1H),
7.51 (t, J ¼ 7.8 Hz, 1H), 7.63 (d, J ¼ 7.8 Hz, 1H), 7.70 (t, J
Figure 3. X-ray structure of compound 6a.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

January 2010
Regioselective Synthesis of Pyrimido[5,4-c][2,1]benzothiazines by Reactions of
b-Chloroaldehydes with N-C-N Binucleophiles
89
Scheme 5
8.51 (d, J ¼ 7.8 Hz, 1H), 9.73 (s, 1H). 13C NMR (100 MHz,
DMSO): d ¼ 15.04, 30.24, 53.22, 118.86, 123.72, 126.07,
126.88, 127.36, 128.49, 129.67, 132.96, 133.86, 136.63,
140.36, 147.37, 149.14, 159.63; MS (CI): 425(MþH)þ; Anal.
calcd. C, 59.36; H, 4.03; N, 13.19; found C, 59.36; H, 4.05;
N, 13.23.
Product 6h (67%, R Pr, R2 Me, R3 m-Cl-Ph). m.p.:
>250ꢀC; 1H NMR (400 MHz, DMSO): d ¼ 0.86 (t, J ¼ 6.8
Hz, 3H), 1.65 (m, J ¼ 6.8 Hz, 2H), 2.72 (s, 3H), 4.03 (t, J ¼
6.8 Hz, 2H), 7.35 (d, J ¼ 7.8 Hz, 1H), 7.49 (t, J ¼ 7.8 Hz,
1H), 7.59 (t, J ¼ 7.8 Hz, 1H), 7.66 (d, J ¼ 8 Hz, 1H), 7.74 (d,
J ¼ 7.8 Hz, 1H), 7.77 (s, 1H), 7.86 (t, J ¼ 7.8 Hz, 1H), 8.92
(s, 1H), 9.74 (d, J ¼ 8 Hz, 1H); MS (CI): 439.5(MþH)þ;
Anal. calcd. C, 60.20; H, 4.36; N, 12.76; found C, 60.23; H,
4.39; N, 12.77.
Hz, 3H), 1.46 (t, J ¼ 6.8 Hz, 3H), 3.67 (q, J ¼ 6.8 Hz,2H),
3.89 (q, J ¼ 6.8 Hz, 2H), 7.35 (t, J ¼ 7.8 Hz, 1H), 7.86 (d, J
¼ 7.8 Hz, 1H), 7.77 (t, J ¼ 7.8 Hz, 1H), 7.89 (s, 1H), 8.43 (d,
J ¼ 7.8 Hz, 1H), 9.78 (s, 1H). 13C NMR (100 MHz, DMSO):
d ¼ 14.28, 15.02, 34.78, 60.44, 108.55, 118.29, 122.04,
124.36, 127.15, 128.55, 131.16, 133.69, 134.27, 141.98,
145.86, 147.87, 156.98; MS (CI): 373(MþH)þ; Anal. calcd. C,
54.83; H, 4.33; N, 15.04; found C, 54.85; H, 4.36; N, 15.05.
7-Alkyl-7H-[1,2,4]triazolo[30,40:2,3]pyrimido[5,4-c][2,1]
benzothiazine-6,6-dioxides (7a–c); general procedure. The
mixture of the b-chloroaldehyde 3 (1 mmol) with the amino-
triazole 4g (0.1 g, 1.2 mmol) was dissolved in 2 mL of dry
DMF. The reaction mixture was heated for 2.5 h at 80ꢀC. The
mixture was cooled to room temperature; solid product was fil-
tered off and washed with ethanol. The pure product was
obtained by crystallization from DMF (52–57%).
Product 6i (61%, R Bu, R2 Me, R3 m-Cl-Ph). m.p.:
>250ꢀC; 1H NMR (400 MHz, DMSO): d ¼ 0.84 (t, J ¼ 6.8
Hz, 3H), 1.23 (m, 2H), 1.50 (m, 2H), 2.68 (t, J ¼ 7.8 Hz, 2H),
3.89 (s, 3H), 7.35–7.85 (m, 7H), 8.48 (d, J ¼ 7.8 Hz, 1H),
9.71 (s, 1H); MS (CI): 453.5(MþH)þ; Anal. calcd. C, 60.99;
H, 4.67; N, 12.37; found C, 61.04; H, 4.69; N, 12.36.
Product 6j (60%, R Bn, R2 Me, R3 m-Cl-Ph). m.p.:
1
Product 7a (54%, R Me). H NMR (400 MHz, DMSO): d
¼ 3.51 (s, 3H), 7.62 (t, J ¼ 7.8 Hz, 1H), 7.73 (d, J ¼ 7.8 Hz,
1H), 7.90 (t, J ¼ 7.8 Hz, 1H), 8.60 (d, J ¼ 7.8 Hz, 1H), 9.06
(s, 1H), 10.04 (s, 1H); MS (CI): 288(MþH)þ; Anal. calcd. C,
50.17; H, 3.16; N, 24.38; found C, 50.19; H, 3.16; N, 24.39.
1
Product 7b (52%, R Et). H NMR (400 MHz, DMSO): d
1
>250ꢀC; H NMR (400 MHz, DMSO): d ¼ 2.69 (s, 3H), 5.09
¼ 1.28 (t, J ¼ 6.8 Hz, 3H), 4.09 (q, J ¼ 6.8 Hz, 2H), 7.61 (t,
J ¼ 7.8 Hz, 1H), 7.79 (d, J ¼ 7.8 Hz, 1H), 7.88 (t, J ¼ 8 Hz,
1H), 8.60 (d, J ¼ 8 Hz, 1H), 9.04 (s, 1H), 10.02 (s, 1H); MS
(CI): 302(MþH)þ; Anal. calcd. C, 51.82; H, 3.68; N, 23.24;
found C, 51.82; H, 3.67; N, 23.27.
(s, 2H), 7.16 (s, 5H), 7.34 (d, J ¼ 7.8 Hz, 1H), 7.41–7.46 (m,
2H), 7.50 (t, J ¼ 7.8 Hz, 1H), 7.59 (t, J ¼ 8 Hz, 1H), 7.72 (d,
J ¼ 7.8 Hz, 1H), 7.82 (s, 1H), 8.42 (d, J ¼ 8 Hz, 1H), 9.72 (s,
1H); MS (CI): 487.5(MþH)þ; Anal.calcd. C, 64.13; H, 3.93;
N, 11.51; found C, 64.15; H, 3.97; N, 11.54.
1
Product 7c (57%, R Pr). H NMR (400 MHz, DMSO): d
Product 6k (79%, R Me, R2 H, R3 CO2Et). m.p.:
1
¼ 0.86 (t, J ¼ 6.8 Hz, 3H), 1.67 (m, 2H), 4.04 (t, J ¼ 6.8 Hz,
2H), 7.60 (t, J ¼ 7.8 Hz, 1H), 7.77 (d, J ¼ 7.8 Hz, 1H), 7.89
(t, J ¼ 7.8 Hz, 1H), 8.89 (d, J ¼ 7.8 Hz, 1H), 9.07 (s, 1H),
10.04 (s, 1H); MS (CI): 317(MþH)þ; Anal. calcd. C, 53.32;
H, 4.16; N, 22.21; found C, 53.33; H, 4.13; N, 22.22.
>250ꢀC (decomp.); H NMR (400 MHz, DMSO): d ¼ 1.23 (t,
J ¼ 6.8 Hz, 3H), 3.46 (s, 3H), 3.89 (q, J ¼ 6.7 Hz, 2H), 7.37
(t, J ¼ 7.8 Hz, 1H), 7.56 (d, J ¼ 7.8 Hz, 1H), 7.74 (t, J ¼ 7.8
Hz, 1H), 7.86 (s, 1H), 8.49 (d, J ¼ 7.8 Hz, 1H), 9.75 (s, 1H);
13C NMR (100 MHz, DMSO): d ¼ 15.03, 34.80, 61.02,
117.69, 122.04, 124.47, 126.27, 133.34, 134.08, 141.87,
147.31, 149.32, 159.68; MS (CI): 359(MþH)þ; Anal. calcd. C,
53.62; H, 3.94; N, 15.63; found C, 53.64; H, 3.94; N, 15.62.
Product 6l (82%, R Et, R2 H, R3 CO2Et). m.p.: >250ꢀC
5-Alkyl-5H-benzimidazo[20,10:2,3]pyrimido[5,4-c][2,1] benzo-
thiazin-6,6-dioxides (9a,b); general procedure. The mixture of
the chloroaldehyde 3 (1 mmol) with the aminobenzoimidazole
4h (0.16 g, 1.2 mmol) was dissolved in 3 mL of dry DMF.
The reaction mixture was heated for 2 h at 50ꢀC, 2 h at 70ꢀC,
1
(decomp.); H NMR (400 MHz, DMSO): d ¼ 1.27 (t, J ¼ 6.8
and
1
h
at 100ꢀC. The mixture was cooled to room
Scheme 6
Scheme 7
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

90
K. Popov, T. Volovnenko, A. Turov, and Y. Volovenko
Vol 47
temperature; solid product was filtered off and washed with
ethanol. The pure product was obtained by crystallization from
DMF (61–63%).
13C NMR (100 MHz, TFA): d ¼ 50.01, 108.65, 118.86,
119.47, 123.58, 125.89, 126.87, 127.35, 129.08, 130.43,
131.24, 133.41, 135.64, 140.46, 145.79, 147.97, 156.92,
159.61; MS (CI): 365(MþH)þ; Anal. calcd. C, 59.33; H, 3.32;
N, 15.38; found C, 59.35; H, 3.36; N, 15.41.
Product 10b (59%, R Et). m.p.: 234ꢀC; 1H NMR (400
MHz, TFA): d ¼ 1.37 (t, J ¼ 6.8 Hz, 3H), 4.24 (q, J ¼ 6.8 Hz,
2H), 7.63 (m, 2H), 7.78 (m, 2H), 7.87 (t, J ¼ 7.8 Hz, 1H), 8.11
(t, J ¼ 7.8 Hz, 1H), 8.48 (d, J ¼ 7.8 Hz, 1H), 8.67 (t, J ¼ 7.8
Hz, 1H), 9.38 (s, 1H). 13C NMR (100 MHz, TFA): d ¼ 15.09,
54.02, 118.67, 124.01, 126.12, 126.87, 127.43, 128.66, 129.54,
133.04, 135.61, 137.76, 140.72, 142.85, 144.50, 146.08, 147.76,
149.34, 159.76; MS (CI): 379(MþH)þ; Anal. calcd. C, 60.31;
H, 3.73; N, 14.81; found C, 60.34; H, 3.75; N, 14.81.
Product 10c (56%, R Pr). m.p.: >250ꢀC (decomp); 1H
NMR (400 MHz, TFA): d ¼ 0.91 (t, J ¼ 6.8 Hz, 3H), 1.77
(m, 2H), 4.14 (q, J ¼ 6.8 Hz, 2H), 7.13 (m, 2H), 7.77 (m,
2H), 7.85 (t, J ¼ 7.8 Hz, 1H), 8.10 (t, J ¼ 7.8 Hz, 1H), 8.48
(d, J ¼ 7.8 Hz, 1H), 8.66 (t, J ¼ 7.8 Hz, 1H), 9.37 (s, 1H).
13C NMR (100 MHz, TFA): d ¼ 15.04, 38.44, 53.22, 118.86,
123.69, 126.06, 126.85, 127.37, 128.49, 132.94, 135.63,
137.76, 140.37, 142.58, 144.51, 146.03, 147.36, 149.14,
150.05, 159.62; MS (CI): 393(MþH)þ; Anal. calcd. C, 61.21;
H, 4.11; N, 14.28; found C, 61.22; H, 4.14; N, 14.31.
Product 9a (61%, R Et). m.p.: >250ꢀC (decomp.); 1H
NMR (400 MHz, TFA): d ¼ 1.49 (t, J ¼ 6.8 Hz, 3H), 4.29 (q,
J ¼ 6.8 Hz, 2H), 7.70–7.75 (m, 2H), 7.89 (d, J ¼ 7.8 Hz, 1H),
8.02 (t, J ¼ 7.8 Hz, 1H), 8.12 (m, 2H), 8.24 (d, J ¼ 8 Hz,
1H), 8.53 (d, J ¼ 8 Hz, 1H), 9.57 (s, 1H). 13C NMR (100
MHz, DMSO): d ¼ 14.63, 49.34, 115.62, 117.19, 120.01,
121.16, 122.76, 123.67, 125.28, 128.48, 128.79, 135.64,
139.95, 143.84, 145.89, 148.43, 151.79; MS (CI):
351(MþH)þ; Anal. calcd. C, 61.70; H, 4.03; N, 15.99; found
C, 61.72; H, 4.04; N, 15.99.
Product 9b (63%, R Pr). m.p.: >250ꢀC (decomp.); 1H
NMR (400 MHz, TFA): d ¼ 0.98 (t, J ¼ 6.8 Hz, 3H), 1.90
(m, 2H), 4.16 (q, J ¼ 6.8 Hz, 2H), 7.71–7.77 (m, 2H), 7.86 (d,
J ¼ 7.8 Hz, 1H), 8.10 (t, J ¼ 7.8 Hz, 1H), 8.15 (m, 2H), 8.27
(d, J ¼ 8 Hz, 1H), 8.50 (d, J ¼ 7.8 Hz, 1H), 9.58 (s, 1H). 13C
NMR (100 MHz, DMSO): d ¼ 11.62, 21.93, 49.74, 116.63,
118.18, 120.21, 121.15, 122.34, 123.92, 125.20, 128.50,
128.76, 135.61, 139.89, 143.87, 145.88, 148.20, 151.78; MS
(CI): 365(MþH)þ; Anal. calcd. C, 62.62; H, 4.43; N, 15.37;
found C, 62.65; H, 4.45; N, 15.39.
5-Alkyl-14-oxo-5,14-dihydroquinazolino[20,30:2,3]pyrimid-
o[5,4-c][2,1]benzothiazin-6,6-dioxides
(10a–c);
general
procedure. The mixture of 2-amino-quinazolin-4-one 4i (0.21
g, 1.3 mmol) and a catalytic amount of triethylamine in 2 mL
of dry DMF was heated to 100ꢀC. To the resulting solution
chloroaldehyde 3 (1 mmol) was added in portions at 80ꢀC.
The reaction mixture was heated for 10 h at reflux and then
cooled to room temperature. Solid product was filtered off and
washed with ethanol. The pure product was obtained by crys-
tallization from DMF (56–59%).
Product 10a (58%, R Me). m.p.: 206–207ꢀC; 1H NMR
(400 MHz, TFA): d ¼ 3.98 (s, 3H), 7.12 (m, 2H), 7.78 (m,
2H), 7.89 (t, J ¼ 8 Hz, 1H), 8.08 (t, J ¼ 8 Hz, 1H), 8.46 (d, J
¼ 8 Hz, 1H), 8.65 (t, J ¼ 7.8 Hz, 1H), 9.35 (s, 1H)
REFERENCES AND NOTES
[1] Catsoulacos, P.; Camoutsis, C. J Heterocycl Chem 1979,
16, 1503.
[2] Olkkola, K. T.; Brunetto, A. V.; Mattila, M. J. Clin Phar-
macokinet 1994, 26, 107.
[3] Davis, J. M.; Davis, P. D.; Moffat, D. C.; Batchelor, M. J.
WO 9,828,281, (1998).
[4] Rossi, S. Australian Medicines Handbook 2006; Adelaide:
Australian Medicines Handbook, 2006. ISBN 0-9757919-2-3.
[5] Popov, K. S.; Volovnenko, T. A.; Volovenko, Yu. M.
J Heterocycl Chem 2007, 44, 1413.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet