A study of the reactions of 2-aryl-4-hydroxy-6H-1,3-thiazin-6-ones with chromone-3-carboxaldehydes

Article abstract of DOI:10.1016/j.tetlet.2010.11.023

Reaction of 3-formylchromones with 2-aryl-4-hydroxy-6H-1,3-thiazin-6-ones in the presence of pyridine leads to formation of a mixture of novel N-thioaroyl-5-hydroxy-2H,5H-pyrano[3,2-]chromen-2-one-3-carboxamides and 2-aryl-5-(4′-oxochromen-3′-yl)-6,7-dihy

Full text of DOI:10.1016/j.tetlet.2010.11.023

Tetrahedron Letters 52 (2011) 266–269
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Tetrahedron Letters
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A study of the reactions of 2-aryl-4-hydroxy-6H-1,3-thiazin-6-ones
with chromone-3-carboxaldehydes
⇑
Roman V. Shutov , Elizaveta V. Kuklina, Boris A. Ivin
Department of Organic Chemistry, Saint-Petersburg State Chemical & Pharmaceutical Academy, Professor Popov St. 14, Saint-Petersburg 197376, Russia
a r t i c l e i n f o
a b s t r a c t
Article history:
Reaction of 3-formylchromones with 2-aryl-4-hydroxy-6H-1,3-thiazin-6-ones in the presence of pyridine
leads to formation of a mixture of novel N-thioaroyl-5-hydroxy-2H,5H-pyrano[3,2-c]chromen-2-one-3-
carboxamides and 2-aryl-5-(40-oxochromen-30-yl)-6,7-dihydro-4H,5H-pyrano[2,3-d][1,3]thiazine-4,7-
diones. The yields of these compounds clearly depend on the nature of the substituent on the 3-formyl-
chromone and on the reaction conditions.
Received 16 August 2010
Revised 23 October 2010
Accepted 5 November 2010
Available online 11 November 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
3-Formylchromone
1,3-Thiazine
Active methylene compounds
Pyridine
1. Introduction
ric acids.1 The products formed are predominantly 40-oxochro-
men-30-ylmethylene compounds 2,2 3-diheteroarylmethyl-4H-
According to the literature, chromone-3-carboxaldehydes react
with active methylene compounds (Scheme 1), including barbitu-
chromen-4-ones 3,3 substituted aryl heteroaryl ketones 6,4 and,
less commonly, tricyclic pyridochromenes 4 or 5.5 No data were
CH3
O
O
H
O
COOR
N
O
NH
NH
O
N
H
X
H3C
OH
COOR
O
O
N
H
X
H
2; X = O, S
NH2
4; R = Me, Et
O
O
H
2
R
R2
1
R
N
N
O
R1
O
H
N
N
N
2
N
1
CONH2
O
R
N
N
O
O
R
R
R
O
OH
H
N
NH
5;
H
OH
O
O
R
6; R = CONH2, CN, COCH3
3; R = H, Me
Scheme 1.
⇑
Corresponding author. Tel.: +7 (812) 234 1172; fax: +7 (812) 434 3070.
E-mail address: H4O2@yandex.ru (R.V. Shutov).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.11.023

R. V. Shutov et al. / Tetrahedron Letters 52 (2011) 266–269
267
found describing the reaction of 3-formylchromones with pyrimi-
dine thia-analogues, for example, 4-hydroxy-6H-1,3-thiazin-6-
ones, as active methylene compounds.
The yields of 11 and 12 depend on the nature of the substituent
on the chromone 1 and on the reaction conditions. Chromones
with electron-withdrawing substituents (Br, Cl, NO2) form pre-
dominantly pyranochromenes 11, while chromones with a strong
electron-donating substituent (MeO) react with thiazines forming
pyranothiazines 12. Unsubstituted and alkylchromones produce a
mixture of 11 and 12 in approximately equal yields.
The other important factor influencing the yield of pyrano-
chromenes 11 was the solvent used. As mentioned above, com-
pounds 11 are formed in the presence of pyridine. The use of
THF or MeCN resulted in decreased yields of 11 and longer reaction
times. Moreover, when thiazines 7 were reacted with 6-bromo- or
6-chlorochromones 1f,g in glacial acetic acid, the corresponding
pyranothiazines 12f,g were obtained in ꢀ60% yield. Alcohols could
not be used as solvents due to the unstable nature of the thiazine
under such conditions.
It has previously been shown that 2-aryl-4-hydroxy-6H-1,3-thi-
azin-6-ones 7 react with aromatic aldehydes in a way that differs
from the respective pyrimidines. The products are methyl 2,6-dia-
ryl-4-oxo-5,6-dihydro-4H-1,3-thiazine-5-carboxylates 8, in abso-
lute MeOH (Scheme 2),6 and pyranothiazines 9 in the presence of
pyridine.7 When compound 7 was reacted with salicylaldehydes,
N-thioacylcoumarin-3-carboxamides 10 were formed.8 The reac-
tion of 1 and 7 has been reported previously,9 but after a more de-
tailed study, new results were obtained supporting an alternative
reaction mechanism and a different structure for the final product.
Herein, we report the formation of a mixture of novel N-thioa-
royl-5-hydroxy-2H,5H-pyrano[3,2-c]-chromen-2-one-3-carbox-
amides 11a–h and 2-aryl-5-(40-oxochromen-30-yl)-6,7-dihydro-
4H,5H-pyrano[2,3-d][1,3]thiazine-4,7-diones 12a–h via reaction
of 3-formylchromones 1a–h10 with 1,3-thiazines 7a,b11 in the
presence of pyridine (Scheme 3). Common by-products are (2E)-
3-(4-oxo-4H-chromen-3-yl)prop-2-enoic acids 13a–g. The com-
bined yields of 11, 12 and 13 are 55–75%. All three groups of com-
pounds could be easily isolated from the product mixture.
The formation of several types of products results from the
presence of two electrophilic sites on the chromone: these are C-
2 and CH@O. A possible mechanism for the reaction is shown in
Scheme 4. Attack of the thiazine at C-2 of the chromone is followed
by pyran ring-opening (1,4-addition, intermediate A1) with further
ring closure by way of the free formyl group to produce A2. Addi-
O
O
MeOH
N
OMe
CHO
O
O
S
OH
S
Ar1
S
Ar2
H
Ar2CHO
NH
Ar1
8
OH
N
O
Ar1
O
O
10
O
H
py
7
N
Ar2
H
Ar1
S
O
9
Scheme 2.
O
O
O
S
H
O
S
O
O
OH
O
H
R
R
H
NH
Ar
O
H
R
THF, py, 60 oC
N
N
O
+
+
O
OH
O
Ar
S
Ar
O
1a-h
O
H
11a-h
12a-h
7a,b
O
H
O
R
OH
+
H
O
13a-g
Thiazine
Ar
Ph
Chromone
R
7-Me
6-OMe
6-OH
6-Me
H
6-Cl
6-Br
6-NO2
6-Me
6-Br
Product (yield, %)
1a
1b
1c
1d
1e
1f
1g
1h
1d
1g
11a (33)
-
-
11b (35)
11c (40)
11d (60)
11e (65)
11f (52)
11g (38)
11h (66)
12a (32)
12b (52)
12c (48)
12d (31)
12e (29)
12f (5)
12g (5)
-
13a (16)
13b (18)
13c (18)
13d (17)
13e (14)
13f (17)
13g (14)
-
7a
12h (35)
-
13d (13)
13g (14)
7b
4-MeOC6H4
Scheme 3.

268
R. V. Shutov et al. / Tetrahedron Letters 52 (2011) 266–269
O
H
R
O
H
OH
S
O
O
H
O
O
S
R
R
O
S
OH
N
O
O
N
N
-H2O
+
OH
O
Ar
Ar
A1
O
Ar
N
1a-h
B1
7a,b
2a,b
-ArCSNH2
2H2O
H
Ar
Ar
Ar
-CO2
O
O
R
S
S
N
N
S
H2O
O
O
HO
O
OH
R
OH
O
OH
OH
OH
O
R
R
H
H
O
OH
N
OH
OH
13a-g
O
O
O
O
S
Ar
H
H
B2
-ArCSNH2
H2O
A2
-H2O
A3
-CO2
O
O
O
S
H
H
O
O
S
O
O
NH
Ar
R
R
H
N
OH
O
O
Ar
H
12a-h
11a-h
Scheme 4.
tion of a water molecule allows enolization of the C-4 keto group to
give A3 and subsequent cleavage of the thiazine ring form products
11. Alternatively, attack at the aldehyde group follows a Knoevena-
gel type reaction leading to ylidenothiazines (intermediate B1),
which combine with a second molecule of 7 to form bis(thiazine-
5-yl)methanes B2. Subsequent intramolecular cyclization and
hydrolysis leads to pyranothiazines 12. The third reaction route
is the direct hydrolysis of B1 to form acids 13.
the substituent on the chromone and the solvent used. Correct
choice of these parameters meant that pyranochromenes and
5-(4-oxochromen-3-yl)pyranothiazines could be obtained in mod-
erate yields. In addition, the reaction appears to be important for
further understanding the reactivity of 3-formylchromones and
2-aryl-4-hydroxy-6H-1,3-thiazin-6-ones.
The starting compounds 1 and 7 were prepared according to de-
scribed procedures.10
The structures of the synthesized compounds were established
by their elemental and spectral (1H and 13C NMR, APT, IR and mass
spectral) analyses.
2. General procedure for pyranochromene-3-carboxamides
11a–h, pyranothiazine-4,7-diones 12a–h and (2E)-3-(4-oxo-4H-
chromen-3-yl)prop-2-enoic acids 13a–g
Pyranochromenes 11a–h are characterized by 1H NMR (DMSO-
d6) singlets for NH (12.5–12.9 ppm), CH-4 (8.6–8.9 ppm) and dou-
blets for CH-5 (7.1–7.3 ppm, J = 6 Hz) and COH-5 (6.5–6.6 ppm,
J = 6 Hz). The 13C NMR spectra (DMSO-d6) of 11a–h revealed sig-
nals for the carbon atoms of the carbonyl and thiocarbonyl groups
(159–161 and 198–202 ppm, respectively), and the pyran ring: C-2
(160–162 ppm), C-3 (110–115 ppm), C-4 (147–149 ppm) and C-5
(91–98 ppm).
2-Aryl-4-hydroxy-6H-1,3-thiazin-6-one 7 (0.01 mol) was dis-
solved in 20 ml of THF, then 1 ml of pyridine was added. The solu-
tion was heated to 50 °C and the respective 3-formylchromone 1
was added (0.011 mol). Heating was continued at 50–60 °C for
2 h with intermittent stirring. The solvent was removed in vacuo
(20 mmHg), EtOH (10 ml) was added to the residue, and the
formed precipitate filtered, washed with EtOH (3 ꢂ 10 ml), and
recrystallized from THF to give pyranochromenes 11 as brown-
ish-orange powder. The ethanolic rinses were evaporated under a
current of air to a volume of 5 ml. CH2Cl2 (20 ml) was added, the
formed precipitate filtered, washed with CH2Cl2 (3 ꢂ 10 ml), and
recrystallized from EtOH to give propenoic acids 13 as yellowish
powders. The CH2Cl2 rinses were evaporated under a current of
air to a volume of 5 ml and n-hexane (20 ml) was added. The
formed precipitate was filtered, washed with n-hexane
(3 ꢂ 10 ml), and recrystallized from CH2Cl2–C6H14 (1:1) to give
pyranothiazines 12 as yellow powders.
Pyranothiazines 12a–h are characterized by 1H NMR (DMSO-
d6) signals due to the CH-5–CH2-6 structural fragment of the
dihydropyran ring that form the ABX spin system: doublet C-5–
H[ (4.6–4.8 ppm, Jax ꢁ 8.4–9.5 Hz), doublet of doublets C-6–Hb
(3.2–3.5 ppm, Jab ꢁ 15–17 Hz and Jbx ꢁ 8.7–9.5 Hz), doublet C-6–
Ha (2.4–2.7 ppm, Jab ꢁ 15–17 Hz). The 13C NMR spectra (DMSO-
d6) of 12a-h revealed signals for the two sp3-hybridized carbon
atoms of the pyran ring: C-6 (35–41 ppm) and C-5 (32–37 ppm),
which were not present in the spectra of the original compounds.
Propenoic acids 13a–g are characterized by 1H NMR (DMSO-d6)
doublets for the olefinic protons CH-2–CH-3 with coupling
constants of 15–16 Hz, which is indicative of the trans-configura-
tion of this structural fragment. Additionally, a broad singlet for
the carboxyl group was present at 12.3–12.5 ppm.
2.1. 5-Hydroxy-9-bromo-2-oxo-N-thiobenzoyl-2H,5H-
pyrano[3,2-c]chromene-3-carboxamide (11e)
In conclusion, we have shown, that 2-aryl-4-hydroxy-6H-1,3-
thiazin-6-ones react with 3-formylchromones to give mixtures of
easily isolated products. The yields depended on the nature of
Yield 65%, Mp 235–237 °C; 1H NMR (500 MHz, DMSO-d6) d 6.59
(d, 1H, CH-5, J = 5.8 Hz), 7.14 (d, 1H, CH-7, J = 8.7 Hz), 7.45–7.81 (m,

R. V. Shutov et al. / Tetrahedron Letters 52 (2011) 266–269
269
5H, Ph), 7.71 (dd, 1H, CH-8, J = 7.6 Hz, 1.8 Hz), 7.83 (d, 1H, CH-10,
2.4. General procedure for 60-chloro- or 60-bromopyran-
othiazine-4,7-diones 12f,g in glacial acetic acid
J = 1.9 Hz), 8.06 (d, 1H, C-5OH, J = 6.0 Hz), 8.53 (s, 1H, CH-4),
12.75 (s, 1H, NH); 13C NMR (125 MHz, DMSO-d6) d 91.4 (C-5),
110.8 (C-4A), 115.6 (C-9), 117.4 (C-3), 120.6 (C-7), 125.3 (C-10A),
127.4 (C–Ph), 128.6 (C–Ph), 132.4 (C–Ph), 135.4 (C-10), 136.9 (C-
8), 142.3 (C–Ph), 148.5 (C-4), 153.3 (C-10B), 153.7 (C-6A), 160.3
(C-2), 160.8 (C@O), 202.3 (C@S); MS (70 eV): m/z 459 (M+, 81Br,
8%), 457 (M+, 79Br, 8%), 441 (12), 439 (12), 415 (13), 413 (13),
279 (80), 277 (78), 251 (100), 249 (100); IR (KBr) 1169, 1540,
1688, 1720, 3400 cmꢃ1; Anal. Calcd for C20H12BrNO5S: C, 52.42;
H, 2.64; N, 3.06. Found: C, 52.62; H, 2.47; N 3.16.
2-Phenyl-4-hydroxy-6H-1,3-thiazin-6-one (7a) (0.01 mol) was
dissolved in 20 ml of glacial AcOH with heating at 50 °C, and the
respective 6-chloro- or 6-bromo-3-formylchromone 1 was added
(0.011 mol). Heating was continued at 50–60 °C for 2 h with inter-
mittent stirring. The solvent was removed in vacuo (20 mmHg),
EtOH (10 ml) was added to the residue, and the formed precipitate
filtered, washed with EtOH (3 ꢂ 10 ml), and recrystallized from
CH2Cl2–C6H14 (1:1) to give pyranothiazines 12f,g as yellow pow-
ders. Their physical and spectral properties were identical to those
obtained by the previous method.
2.2. 5-(60-Bromo-40-oxo-4H-chromen-30-yl)-2-phenyl-5,6-
dihydro-4H,7H-pyrano[2,3-d][1,3]thiazine-4,7-dione (12g)
Supplementary data
Yield 5%, Mp 246–249 °C; 1H NMR (500 MHz, DMSO-d6) d 2.82
(d, 1H, CH-6B, J = 16.0 Hz), 3.30 (dd, 1H, CH-6A, J = 16.1 Hz,
9.0 Hz), 4.28 (d, 1H, CH-5X, J = 9.0 Hz), 7.45–7.81 (m, 5H, Ph),
7.53 (d, 1H, CH-80, J = 8.1 Hz), 7.78 (d, 1H, CH-70, J = 8.2 Hz), 8.10
(d, 1H, CH-50, J = 1.9 Hz), 8.45 (s, 1H, CH-20); 13C NMR (125 MHz,
DMSO-d6) d 28.1 (C-6), 32.9 (C-5), 103.0 (C-4A), 113.4 (C-30),
118.8 (C-80), 123.3 (C-60), 126.2 (C-4A0), 127.3 (C-Ph), 129.8 (C-
Ph), 130.3 (C-70), 135.4 (C-50), 134.3 (C-Ph), 142.4 (C-Ph), 146.1
(C-20), 156.5 (C-8A0), 164.2 (C-40), 165.6 (C-7), 173.3 (C-8A), 176.8
(C-4), 180.8 (C-2); MS (70 eV): m/z 483 (M+, 81Br, 100%), 481 (M+,
79Br, 90%), 455 (9), 453 (8), 427 (40), 425 (37), 324 (21), 322
(18), 172 (13), 158 (22), 121 (44); IR (KBr) 1190, 1680,
1745 cmꢃ1; Anal. Calcd for C22H12BrNO5S: C, 54.79; H, 2.51; N,
2.90. Found: C, 55.21; H, 2.10; N 3.25.
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2010.11.023.
References and notes
1. Gašparová, R.; Lácová, M. Molecules 2005, 10, 937–960.
2. Haas, G.; Stanton, L.; Von Sprecher, A.; Wenk, P. J. Heterocycl. Chem. 1981, 18,
607–612.
3. Sosnovskikh, V. Ya.; Irgashev, R. A. Tetrahedron Lett. 2007, 48, 7436–7439.
4. (a) Nohara, A.; Ishiguto, T.; Sanno, Y. Tetrahedron Lett. 1974, 15, 1183–1186; (b)
Ghosh, C. K.; Khan, S. Synthesis 1981, 903; (c) Jones, W. D.; Albrecht, W. L. J. Org.
Chem. 1976, 41, 706; (d) Bandyophadhyay, C.; Sur, K. R.; Patra, R. J. Chem. Res.
(S) 1998, 12, 802; (e) Ryabukhin, S. V.; Plaskon, A. S.; Volochnyuk, D. M.;
Tolmachev, A. A. Synlett 2004, 2287–2290; (f) Abdel-Rahman, A. H.;
Hammouda, M. A. A.; El-Desoky, S. I. Heteroat. Chem. 2005, 16, 20–27; (g)
Coutinho, D. L. M.; Fernandes, P. S. Indian J. Chem. 1992, 31B, 573–577.
5. (a) Heber, D. Synthesis 1978, 691–692; (b) Ghosh, C. K.; Ray, A.; Patra, A. J.
Heterocycl. Chem. 2001, 38, 1459–1463; (c) Quiroga, J.; Rengifo, A.; Insuasty, B.;
Abonia, R.; Nogueras, M.; Sanchez, A. Tetrahedron Lett. 2002, 43, 9061–9063.
6. (a) Sopova, M. V.; Mikhailov, L. E.; Krylov, A. V.; Ivin, B. A. Russ. J. Gen. Chem.
2007, 77, 155–157; (b) Krylov, A. V.; Sopova, M. V.; Mikhailov, L. E.; Ivin, B. A.
Collection of Abstracts, First International Conference ‘Chemistry and Biological
Activity of Nitrogen Heterocycles and Alkaloids’, Moscow, Oct 9–12, 2001;
Moscow State University: Moscow, 2001; Vol. 2, p 170.
7. Shutov, R.V.; Kaluzhskikh, A. N.; Krylov, A. V.; Sopova, M. V.; Mikhailov, L. E.;
Ivin, B. A. Collection of Papers, International Conference, dedicated to the 85th
anniversary of SPCPA, Saint-Petersburg, Apr 24–28, 2004; Saint-Petersburg
State Chemical Pharmaceutical Academy: Saint-Petersburg, 2001; pp 118–122.
8. Shutov, R. V.; Kaluzhskikh, A. N.; Moskvin, A. V.; Ivin, B. A. Russ. J. Gen. Chem.
2006, 76, 814–821.
9. Shutov, R. V.; Kuklina, E. V.; Ivin, B. A. Russ. J. Gen. Chem. 2009, 79, 1049–1051.
10. Nohara, A.; Umetani, T.; Sanno, Y. Tetrahedron Lett. 1973, 14, 1995–1998.
11. Mironova, G. A.; Kirillova, E. N.; Kuklin, V. N.; Smorygo, N. A.; Ivin, B. A. Chem.
Heterocycl. Compd. (Engl. Transl.) 1984, 20, 1088–1094.
2.3. (2E)-3-(6-Bromo-4-oxo-4H-chromen-3-yl)prop-2-enoic acid
(13g)
Yield 14%, Mp 247–249 °C; 1H NMR (500 MHz, DMSO-d6) d 7.03
(d, 1H, CH-2, J = 16.2 Hz), 7.61 (d, 1H, CH-80, J = 8.2 Hz), 7.73 (d, 1H,
CH-70, J = 8.1 Hz), 7.42 (d, 1H, CH-3, J = 16.0 Hz), 8.03 (d, 1H, CH-50,
J = 1.8 Hz), 8.92 (s, 1H, CH-20), 12.5 (s, 1H, COOH); 13C NMR
(125 MHz, DMSO-d6) d 118.2 (C-2), 121.0 (C-30), 121.7 (C-4A0),
124.0 (C-60), 125.0 (C-70), 131.1 (C-80), 135.1 (C-8A0), 148.1 (C-50),
154.1 (C-20), 159.8 (C-3), 163.5 (C-40), 175.0 (C-1); IR (KBr) 1180,
1680, 2650 cmꢃ1; Anal. Calcd for C12H7BrO4: C, 48.84; H, 2.39.
Found: C, 49.11; H, 2.47.