Three-component condensation of 4-aminoisothiazole derivatives with aldehydes and Meldrums acid. Synthesis of 6,7-dihydro-4H-isothiazolo[4,5-b] pyridin-5-ones

Article abstract of DOI:10.1007/s11172-009-0211-3

A convenient method was developed for the synthesis of previously unknown substituted 6,7-dmydro-4H-isothiazolo[4,5-b]pyridin-5-ones based on the three-component condensation of 4-aminoisothiazole hydrochlorides, Meldrum's acid, and aromatic aldehydes.

Full text of DOI:10.1007/s11172-009-0211-3

Russian Chemical Bulletin, International Edition, Vol. 58, No. 7, pp. 1538—1541, July, 2009
1538
Threeꢀcomponent condensation of 4ꢀaminoisothiazole derivatives
with aldehydes and Meldrum´s acid.
Synthesis of 6,7ꢀdihydroꢀ4Hꢀisothiazolo[4,5ꢀb]pyridinꢀ5ꢀones
B. V. Lichitsky, A. N. Komogortsev, R. M. Belyi, A. A. Dudinov, and M. M. Krayushkin
N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences,
47 Leninsky prosp., 119991 Moscow, Russian Federation.
Eꢀmail: mkray@ioc.ac.ru
A convenient method was developed for the synthesis of previously unknown substituted
6,7ꢀdihydroꢀ4Hꢀisothiazolo[4,5ꢀb]pyridinꢀ5ꢀones based on the threeꢀcomponent condensation
of 4ꢀaminoisothiazole hydrochlorides, Meldrum's acid, and aromatic aldehydes.
Key words: 4ꢀaminoisothiazoles, threeꢀcomponent condensation, Meldrum's acid, decarꢀ
boxylation, 6,7ꢀdihydroꢀ4Hꢀisothiazolo[4,5ꢀb]pyridinꢀ5ꢀones.
Scheme 1
Aminoisothiazole derivatives have bactericidal propꢀ
erties,1 inhibit cyclinꢀdependent kinases (CDK) and glyꢀ
cogen synthase kinase 3 (GSKꢀ3),2 and are used for the
synthesis of antibiotics.3,4 Hence, the synthesis of new
fused heterocyclic systems containing the 4ꢀaminoisothiꢀ
azole moiety is an important problem.
Previously, we have developed a general approach to
the synthesis of 4,7ꢀdihydroꢀ5Hꢀthieno[2,3ꢀb]pyridinꢀ6ꢀ
ones 1a,5 6,7ꢀdihydroꢀ4Hꢀthiazolo[4,5ꢀb]pyridinꢀ5ꢀones
1b,6,7 6,7ꢀdihydroꢀ4Hꢀthieno[3,2ꢀb]pyridinꢀ5ꢀones 1c,8
and 6,7ꢀdihydroꢀ4Hꢀselenazolo[4,5ꢀb]pyridinꢀ5ꢀones 1d9
based on the threeꢀcomponent condensation of labile hetꢀ
erocyclic amines 2 with aldehydes 3 and Meldrum's acid 4
(Scheme 1).
In this method, the generation of aminoheterocycles 2
directly in the reaction mixture plays a key role. The genꢀ
eration is performed by either the in situ decarboxylation
of vicinal aminocarboxylic acids 5, which are formed by
the alkaline hydrolysis of readily available esters,5,6,8 or by
the neutralization of stable hydrochlorides 6 with anhyꢀ
drous sodium acetate.7,9
In the present study, we extended the previously develꢀ
oped approach based on the threeꢀcomponent condensaꢀ
tion of 4ꢀaminoisothiazole derivatives 7, which are formed
in situ from the corresponding hydrochlorides 8, with aroꢀ
matic aldehydes 3 and Meldrum's acid 4 to the synthesis
of 6,7ꢀdihydroꢀ4Hꢀisothiazolo[4,5ꢀb]pyridinꢀ5ꢀones 9
(Scheme 2, Table 1).
Labile amines 7 can be generated in situ with the use
of either hydrochlorides 8, which are prepared by the
acid hydrolysis of ethyl 4ꢀaminoisothiazoleꢀ5ꢀcarboxyꢀ
lates 10 (see Ref. 10) followed by the decarboxylation, or
potassium 4ꢀaminoisothiazoleꢀ5ꢀcarboxylates 11,11 which
are formed by the alkali treatment of esters 10 (Scheme 3).
1
a
b
c
d
X
S
N
CR1
N
Y
Z
CR2
S
S
Se
CR1
CR1
CR2
CR1
Our studies showed that 4ꢀaminoisothiazole hydroꢀ
chlorides 8 are the reagents of choice for the synthesis
of the target 6,7ꢀdihydroꢀ4Hꢀisothiazolo[4,5ꢀb]pyridinꢀ
5ꢀones 9.
Fused pyridinones 9 were synthesized in acetic acid in
the presence of anhydrous sodium acetate, which served
as the base for the generation of free 4ꢀaminoisothiazole 7.
It should be noted that the reaction with the use of amino
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 7, pp. 1493—1496, July, 2009.
1066ꢀ5285/09/5807ꢀ1538 © 2009 Springer Science+Business Media, Inc.

6,7ꢀDihydroꢀ4Hꢀisothiazolo[4,5ꢀb]pyridinꢀ5ꢀones
Russ.Chem.Bull., Int.Ed., Vol. 58, No. 7, July, 2009
1539
Table 1. Yields, melting points, and elemental analysis data for compounds 9a—m
Comꢀ
pound
Substituents
Ar
M.p./°C
Yield
(%)
Found
Molecular formula
(%)
Calculated
R
C
H
N
9a
9b
9c
9d
9e
9f
4ꢀClꢀC6H4
4ꢀClꢀC6H4
4ꢀClꢀC6H4
4ꢀClꢀC6H4
Ph
4ꢀClꢀC6H4
3ꢀMeOꢀC6H4
2ꢀFꢀC6H4
267—269
169—171
186—188
222—224
177—179
164—166
45
37
29
34
43
41
33
30
43
46
42
51
35
57.43
57.61
61.33
61.54
60.53
60.25
63.64
63.43
67.61
67.84
65.77
65.56
63.57
63.31
66.38
66.65
57.16
56.92
50.79
50.57
53.69
53.42
50.77
50.57
55.51
55.26
3.13
3.22
4.21
4.08
3.49
3.37
3.72
3.84
4.92
4.79
5.09
4.95
4.65
4.52
4.16
4.04
3.80
3.67
3.05
2.94
3.00
3.10
3.82
2.94
4.11
3.97
7.30
7.46
7.38
7.55
7.99
7.81
8.07
8.22
8.15
8.33
7.79
7.64
10.93
11.07
8.81
8.64
10.04
10.21
9.25
9.07
9.74
9.58
9.23
9.07
9.40
9.21
C18H12Cl2N2OS
C19H15ClN2O2S
C18H12ClFN2OS
C18H13ClN2OS
C19H16N2O2S
C20H18N2O3S
C20H17N3O3S
C18H13FN2OS
C13H10N2O3S
C13H9ClN2O3S
C13H9FN2O3S
C13H9ClN2O3S
C14H12N2O4S
Ph
4ꢀMeOꢀC6H4
2,3ꢀ(MeO)2C6H3
Ph
9g
9h
9i
Ph 4ꢀ(NH2C(O)CH2O)ꢀC6H4 190—192
Ph
2ꢀFꢀC6H4
Ph
144—146
226—228
156—159
179—181
123—124
118—120
COOH
COOH
COOH
COOH
COOH
9j
4ꢀClꢀC6H4
4ꢀFꢀC6H4
3ꢀClꢀC6H4
3ꢀMeOꢀC6H4
9k
9l
9m
Scheme 2
Scheme 3
8—10: R = 4ꢀClꢀC6H4 (a), Ph (b), CO2H (8c), CO2Et (10c),
CO2K (11c)
7: R = 4ꢀClꢀC6H4 (a); Ph (b); CO2H (c)
acid 8c was performed in the presence of a twofold excess
of the starting compound 8c and sodium acetate because
of instability of amino acid 8c. The proposed scheme of
the synthesis of 6,7ꢀdihydroꢀ4Hꢀisothiazolo[4,5ꢀb]pyꢀ
ridinꢀ5ꢀones 9 involves the Michael addition of 4ꢀaminoꢀ
isothiazole 7 to arylmethylidene derivative 12, which is
formed in situ from aldehydes and Meldrum´s acid,
followed by the intramolecular cyclization accompaꢀ
nied by the elimination of CO2 and acetone molecules
(Scheme 4).
The newly synthesized compounds are crystalline solꢀ
ids, whose structures were confirmed by elemental analyꢀ

1540
Russ.Chem.Bull., Int.Ed., Vol. 58, No. 7, July, 2009
Lichitsky et al.
Scheme 4
1
sis and H NMR spectroscopy (see Tables 1 and 2). The
1H NMR spectra of reaction products 9 show characteristic
signals for the methine protons at δ 4.67—5.00 and for the
nonequivalent protons of the methylene unit at δ 2.81—3.02,
which agree well with the data published in the literature
for related compounds.5—9
threeꢀcomponent condensation of 4ꢀaminoisothiazole
hydrochlorides, Meldrum's acid, and aromatic aldehydes.
Experimental
1
The H NMR spectra were recorded on a Bruker Avance II
To sum up, we developed a new general method for the
synthesis of the previously unknown substituted 6,7ꢀdiꢀ
hydroꢀ4Hꢀisothiazolo[4,5ꢀb]pyridinꢀ5ꢀones based on the
300 instrument (300 MHz) in DMSOꢀd6. The melting points
were measured on a Boetius hotꢀstage apparatus and are uncorꢀ
rected. The course of the reactions was monitored and the purity
Table 2. 1H NMR spectra (DMSOꢀd6, δ, J/Hz) of compounds 9a—m
Comꢀ
pound
R
H—C—H
(dd, 1 H)
H—C—H
(dd, 1 H)
CH
(dd, 1 H)
Ar
NH
(br.s, 1 H)
9a
9b
7.56 (d, 2 H, С6Н4, J = 8);
7.74 (d, 2 H, С6Н4, J = 8)
7.56 (d, 2 H, С6Н4, J = 8);
7.74 (d, 2 H, С6Н4, J = 8)
2.90
(J = 0, 7)
2.86
2.90
(J = 0, 7)
2.94
4.79
(J = 7, 7)
4.72
7.36 (d, 2 H, С6Н4, J = 8);
7.45 (d, 2 H, С6Н4, J = 8)
7.3 (t, 1 H, С6Н4, J = 8);
6.8—7 (m, 3 H, С6Н4);
3.74 (s, 3 H, MeO)
10.23
10.19
(J = 16, 7)
(J = 16, 7)
(J = 7, 7)
9c
9d
9e
7.56 (d, 2 H, С6Н4, J = 8);
7.74 (d, 2 H, С6Н4, J = 8)
7.56 (d, 2 H, С6Н4, J = 8);
7.74 (d, 2 H, С6Н4, J = 8)
7.43—7.56 (m, 3 H, Ph);
7.68—7.78 (m, 2 H, Ph)
2.83
(J = 16, 8)
2.90
(J = 0, 7)
2.81
3.02
(J = 16, 7)
2.90
(J = 0, 7)
2.91
5.00
(J = 7, 8)
4.75
(J = 7, 7)
4.67
7.1—7.45 (m, 4 H, С6Н4)
10.25
10.20
10.11
7.23—7.45 (m, 4 H, С6Н5)
6.94 (d, 2 H, С6Н4, J = 9);
7.28 (d, 2 H, С6Н4, J = 9);
3.75 (s, 3 H, MeO)
(J = 16, 6)
(J = 16, 9)
(J = 6, 9)
9f
7.41—7.58 (m, 3 H, Ph);
7.65—7.79 (m, 2 H, Ph)
2.81
(J = 16, 8)
2.93
(J = 16, 7)
4.92
(J = 7, 8)
6.70—6.80 (m, 1 H, С6Н3);
6.98—7.11 (m, 2 H, С6Н3);
3.81 (s, 3 H, MeO);
10.11
10.13
3.82 (s, 3 H, MeO)
9g
7.45—7.60 (m, 3 H, Ph);
7.68—7.81 (m, 2 H, Ph)
2.86
(J = 16, 8)
2.93
(J = 16, 7)
4.72
(J = 7, 8)
6.85—7.02 (m, 1 H, С6Н4);
7.26—7.44 (m, 3 H, С6Н4);
6.85—7.02 (m, 2 H, NH2);
4.41 (s, 2 H, CH2)
9h
9i
7.45—7.57 (m, 3 H, Ph);
7.67—7.81(m, 2 H, Ph)
13.20—14.25 (br.s, 1 H)
2.84
(J = 16, 7)
2.86
(J = 16, 8)
2.86
(J = 16, 8)
2.86
(J = 16, 8)
2.89
3.02
(J = 16, 7)
2.98
(J = 16, 7)
2.96
(J = 16, 7)
2.95
(J = 16, 7)
2.99
5.00
(J = 7, 7)
4.81
(J = 7, 8)
4.83
(J = 7, 8)
4.82
(J = 7, 8)
4.84
7.15—7.44 (m, 4 H, С6Н4)
10.19
9.17
9.17
9.16
9.19
9.15
7.22—7.41 (m, 5 H, Ph)
9j
12.40—13.01 (br.s, 1 H)
13.20—14.68 (br.s, 1 H)
13.20—14.68 (br.s, 1 H)
13.20—14.68 (br.s, 1 H)
7.34 (d, 2 H, С6Н4, J = 8);
7.44 (d, 2 H, С6Н4, J = 8)
7.14—7.27 (m, 2 H, С6Н4);
7.31—7.45 (m, 2 H, С6Н4)
7.24—7.49 (m, 4 H, С6Н4)
9k
9l
(J = 16, 8)
2.91
(J = 0, 8)
(J = 16, 7)
2.91
(J = 0, 8)
(J = 7, 8)
4.76
(J = 8, 8)
9m
6.80—6.97 (m, 1 H, С6Н4);
7.23—7.35 (m, 3 H, С6Н4);
3.74 (s, 3 H, MeO)

6,7ꢀDihydroꢀ4Hꢀisothiazolo[4,5ꢀb]pyridinꢀ5ꢀones
Russ.Chem.Bull., Int.Ed., Vol. 58, No. 7, July, 2009
1541
of the reaction products was checked by TLC on Merck Silica gel
60 F254 plates using an ethyl acetate—hexane mixture as the eluent.
Esters 10 and aminoisothiazole hydrochlorides 8a—c were
synthesized according to methods described in the literature.10
3,7ꢀDiarylꢀ6,7ꢀdihydroꢀ4Hꢀisothiazolo[4,5ꢀb]pyridinꢀ5ꢀones
9a—h (general procedure). A mixture of 4ꢀaminoisothiazole hyꢀ
drochloride 8a,b (2 mmol), anhydrous sodium acetate (0.16 g,
2 mmol), Meldrum's acid (0.32 g, 2.3 mmol), and the correꢀ
sponding aldehyde (2.15 mmol) in acetic acid (7 mL) was reꢀ
fluxed for 2 h and concentrated in vacuo. The residue was recrysꢀ
tallized from aqueous ethanol, filtered off, and washed on a filter
with aqueous ethanol and water.
7ꢀArylꢀ5ꢀoxoꢀ6,7ꢀdihydroꢀ4Hꢀisothiazolo[4,5ꢀb]pyridineꢀ3ꢀ
carboxylic acids 9i—m (general procedure). A mixture of hydroꢀ
chloride 8c (0.72 g, 4 mmol), anhydrous sodium acetate (0.33 g,
4 mmol), Meldrum's acid (0.32 g, 2.2 mmol), and the correꢀ
sponding aldehyde (2 mmol) in acetic acid (7 mL) was refluxed
for 2 h and concentrated in vacuo. The residue was dissolved in
aqueous ethanol, and then concentrated hydrochloric acid (0.5 mL)
was added to the solution. The precipitate that formed was
filtered off and dissolved in a 0.6 M NaOH solution (10 mL). The
alkaline solution was filtered from insoluble impurities and
neutralized with concentrated hydrochloric acid. The precipiꢀ
tate that formed was filtered off and washed on a filter with water.
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Received February 11, 2009