Michael additions on 2H-1,4-benzothiazin-3-ones

Article abstract of DOI:10.1023/B:COHC.0000003531.28525.85

Michael addition on 2H-1,4-benzothiazin-3-ones is studied in this communication. An approach towards the regioselective synthesis of Michael adducts is shown.

Full text of DOI:10.1023/B:COHC.0000003531.28525.85

Chemistry of Heterocyclic Compounds, Vol. 39, No. 8, 2003
MICHAEL ADDITIONS ON
2H-1,4-BENZOTHIAZIN-3-ONES
M. S Chande and V. Suryanarayan
Michael addition on 2H-1,4-benzothiazin-3-ones is studied in this communication. An approach
towards the regioselective synthesis of Michael adducts is shown.
Keywords: Michael addition, 2H-1,4-benzothiazin-3-ones, regioselectivity.
Michael addition [1-3] is a very well-known reaction which involves the addition of an active methylene
group across an α,β-unsaturated compound. This reaction has found extensive use in the synthesis of
carbocyclic and heterocyclic ring systems.
Literature survey indicated that Michael additions of compounds having active methylene groups often
lead to a mono adduct [4, 5] or a mixture of mono and diadducts [6, 7], especially when the β-carbon of the
acceptor is unsubstituted. The formation of the adduct depends on the type of base catalyst and the acceptors
used in the reaction.
Recently we explored the scope of Michael additions on various heterocyclic ring systems containing
active methylene/methine groups for the synthesis of spiro compounds. The present paper is an account of our
studies on the Michael addition of 2H-1,4-benzothiazin-3-one 1 [8] with acceptors, viz. methyl acrylate 2 and
acrylonitrile 5.
It was expected that under ideal conditions methyl acrylate 2 would add at position 2 of 1, yielding
either a mono-adduct or mixtures of mono- and di-adducts. When the reaction was carried out in the presence of
sodamide in DMF at ambient temperature, a yellow colored semisolid was obtained. It readily decolorized the
pink coloration due to phenolphthalein in a dilute alkali. This confirmed the presence of an ester linkage. Hence,
it was hydrolyzed to its carboxylic acid derivative by refluxing in alcoholic potassium hydroxide. The spectral
data indicated that it was the corresponding N-alkylated acid derivative 3. The reaction was highly
regioselective without the formation of any kind of side products. The N-carboxyethyl derivative 3 was further
cyclized in PPA at 140°C to afford compound 4 in near quantitative yields (Scheme 1).
Based on this observation it was thought that similar results would be obtained with a different β-
unsubstituted Michael acceptor. Hence, 2H-1,4-benzothiazin-3-one 1 was reacted with acrylonitrile (5) without
any alteration in the conditions. Interestingly, two different products were obtained from the reaction. The
corresponding N-alkylated nitrile derivative 6 was obtained in 28% yield. Its structure was confirmed by
spectral studies and was further supported by its independent hydrolysis in acid, which furnished the
N-alkylated acid derivative 3. The other compound obtained in 64% yield was identified as Michael bisadduct 7,
with the addition taking place at position 2 of the benzothiazine ring (Scheme 1).
__________________________________________________________________________________________
Department of Chemistry, The Institute of Science, 15, M Cama Road, Mumbai 400 032, India; e-mail:
chandems@vsnl.com, kgsurya@vsnl.com. Published in Khimiya Geterotsiklicheskikh Soedinenii, No. 8,
pp. 1250-1254, August, 2003. Original article submitted November 26, 2001.
1094
0009-3122/03/3908-1094$25.00©2003 Plenum Publishing Corporation

Scheme 1
O
O
O
H
N
O
DMF
O
N
S
+
NaNH2
30 oC, 45 min
O
2
S
+
N
1
C2H5OH
KOH
reflux
10 min
5
DMF
NaNH2
N
30 oC, 45 min
O
O
H
H
N
O
N
S
O
N
O
conc. HCl
+
N
reflux
3 hr
S
S
7
6
3
PPA
140 oC, 2 hr
N
O
O
N
S
4
A conclusion that could be drawn based on the above reactions is that the formation of the Michael
adduct depends much more on the acceptors used in the reaction than on the donors under similar reaction
conditions.
Regioselective addition of Michael acceptors at position 2 of compound 1 could be achieved by
blocking the amido group. It would also determine whether a mono-, di-, or mixtures of Michael adduct is
obtained from the reaction. Hence, the amido proton was blocked with a benzyl group by reacting 1 with benzyl
chloride 8 in DMF/K2CO3. The Michael addition of N-benzyl derivative 9 with equimolar proportions of methyl
acrylate 2 afforded a diadduct 10 and unreacted 9 in the presence of sodamide in DMF. When the reaction was
repeated with 2 moles of methyl acrylate 2, the reaction went to completion and 10 was obtained in an
extremely pure form. The formation of the mono adduct was not observed in the reaction The diadduct was
obtained as a semisolid. On refluxing the diadduct with sodium ethoxide in absolute ethanol, it underwent
Dieckmann condensation [8] and furnished the spirocyclohexanone derivative 11. Similarly, 9 with acrylonitrile
5 afforded only the diadduct in excellent yields (Scheme 2).
Thus, Michael addition on 2H-1,4-benzothiazin-3-one 1 afforded selectively only the diadduct in the
presence of sodamide in DMF when the amido group is blocked. These reactions have also been extended to
2H-1,4-benzoxazin-3-one [10], which gave identical results as 1,4-benzothiazin-3-one under identical reaction
1095

Scheme 2
H
N
O
O
N
S
O
DMF
K2CO3
30 oC, 5 hrs
Cl
+
S
9
1
8
+
+
O
N
O
2
5
N
S
O
O
30 oC
2 hr
DMF
NaNH2
DMF
NaNH2
30 oC
3 hr
O
11
N
O
N
S
O
O
NaOMe / MeOH
4 hr, reflux
N
S
O
12
O
10
N
conditions. It seems that sodamide in DMF is a special combination which leads to the formation of a diadduct
only. We have used this combination successfully on other heterocyclic systems containing active methylene
group which are currently under communication.
EXPERIMENTAL
The elemental analysis of all the reported compounds had values in the range of ±0.05% of the desired
calculated values.
N-(Carboxyethyl)-2H-benzothiazine-3-one (3). To sodamide (0.01 mol, 0.4 g) in DMF (15 ml) was
added 2H-1,4-benzothiazin-3-one 1 at room temperature (28-30°C). This was followed by the addition of methyl
acrylate 2 (0.01 mol, 0.86 g). The reaction mixture was then stirred for 45 min at the same temperature. It was
then poured onto crushed ice containing a few drops of conc. HCl when a pale yellow colored semisolid
separated out. It was then extracted with diethyl ether (50 ml) twice. The organic layer was then dried over
anhydrous sodium sulfate. Removal of ether afforded the ester as a pale yellow colored semisolid (76%). This
semisolid was then refluxed in alcoholic KOH (0.01 mol, 0.56 g in 25 ml of ethanol) for 10 min. The reaction
mixture was concentrated and poured onto crushed ice containing a few drops of conc. HCl. Compound 3
separated as a colorless amorphous powder in a pure state. It was filtered off and dried. Yield 83%; mp 158°C.
IR spectrum, ν, cm-1: 3017 (br, OH and C–H str. merged), 1710 (C=O; carboxylic acid), 1667 (C=O;
benzothiazine). 1H NMR spectrum (CDCl3), , ppm (J, Hz): 2.77 (t, 2H, J = 8, CH2COOH); 3.40 (s, 2H, CH2 of
δ
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benzothiazine ring); 4.31 (t, 2H, J = 8, NCH2); 7.03-7.39 (2t and 2d, 4H, aromatic protons). Interestingly, the
peak due to the OH of carboxylic acid was not observed. 13C NMR spectrum (CDCl3), , ppm: 31.48 (CH2
δ
attached to carboxylic group); 32.10 (CH2 of benzothiazine ring); 40.79 (NCH2); 117.53, 123.85, 124.27,
127.41, 128.65, 138.88 (6 aromatic carbons); 165.52 (C=O; benzothiazine ring); 176.19 (C=O, carboxylic acid).
Found, %: C 55.64; H 4.64; N 5.88; S 13.48. C11H11NO3S. Calculated, %: C 55.68; H 4.67; N 5.90; S 13.51.
c
A mixture of o-phosphoric acid
3,7-Dioxo-2H,5H,6H-(3',2':5,6'-benz)pyrido[2',1'- ]thiazine (4).
(12.5 ml) and phosphorus pentoxide (25 g) was heated at 110°C for half an hour. Compound 3 (0.01 mol) was
added and the reaction mixture was heated at 140°C for 2 h more. It was then cooled and poured onto crushed
ice. Dione 4 which separated out was filtered off and purified by washing well with dilute solution of sodium
1
bicarbonate to remove the unreacted carboxylic acid derivative. Yield 82%; mp 172°C. H NMR spectrum
(CDCl3), , ppm (J, Hz): 2.81 (t, 2H, J = 6.5, CH2CO); 3.51 (s, 2H, CH2 of benzothiazine ring); 4.38 (t, 2H,
δ
J = 6.5, N–CH2); 7.11 (t, 1H, Ar–H); 7.55 (t, 1H, Ar–H); 7.92 (d, 1H, Ar–H). MS, m/z: 219 [M]+ , 190, 177, 162,
149, 135, 121, 108, 95, 81, 69, 63, 45, 31. Found, %: C 60.22; H 4.08; N 6.34; S 14.60. C11H9NO2S.
Calculated, %: C 60.26; H 4.10; N 6.39; S 14.62.
N-Cyanoethyl-1,4-benzothiazin-3-one (6) and 2-di(cyanoethyl)-1,4-benzothiazin-3-one (7).
Compound 1 (0.01 mol, 1.65 g) was added to sodamide (0.01 mol, 0.4 g) in DMF (15 ml). This was followed by
the addition of acrylonitrile (5) (0.01 mol, 0.53 g). The reaction mixture was stirred at room temperature
(28-30°C) for 45 min. On pouring onto crushed ice an off-white compound separated which was filtered off and
dried. This compound was washed thoroughly with diethyl ether. The insoluble product was identified as
2-di(cyanoethyl)-1,4-benzothiazin-3-one 7. Removal of ether afforded N-(cyanoethyl)-1,4-benzothiazin-3-one 6.
1
Compound 6. Yield 28%; mp 120°C. H NMR spectrum (CDCl3), , ppm (J, Hz): 2.80 (t, 2H, J = 10,
δ
CH2CN); 3.41 (s, 2H, CH2 of benzothiazine); 4.28 (t, 2H, J = 10, NCH2); 7.05-7.46 (m, 4H, Ar–H). Found, %:
C 60.52; H 4.60; N 12.83; S 14.66. C11H10N2OS. Calculated, %: C 60.53; H 4.62; N 12.83; S 14.69.
1
Compound 7. Yield 64%; mp >250°C (shrinks at 180°C). H NMR spectrum (CDCl3), , ppm:
δ
2.04-2.63 (m, 8H, 4 × CH2); 6.85-7.34 (m, 4H, Ar–H); 8.01 (s, 1H, NHCO; D2O exchangeable). 13C NMR
spectrum (CDCl3), , ppm: 12.69 (2 × CH2CN); 30.54 (2 × CH2); 49.03 (tetrahedral carbon); 116.93 (2 × C≡N);
δ
117.24, 118.47, 125.98, 128.12, 128,47, 136.45 (6 aromatic carbons); 167.84 (C=O). Found, %: C 61.93;
H 4.82; N 15.45; S 11.81. C14H13N3OS. Calculated, %: C 61.97; H 4.83; N 15.49; S 11.82.
N-Benzyl-1,4-benzothiazin-3-one (9). Benzylchloride (0.012 mol, 1.26 g) was added to a mixture of 1
(0.01 mol) and potassium carbonate (0.01 mol, 1.38 g) in DMF (15 ml). The reaction mixture was stirred at
room temperature (28-30°C) for 5 h. The contents were poured onto crushed ice containing a few drops of conc.
HCl. The product which separated was filtered, dried, and recrystallized from 50% ethanol. Yield 90%;
1
mp 110°C. H NMR spectrum (CDCl3), , ppm: 3.54 (s, 2H, CH2 of benzothiazine ring); 5.24 (s, 2H, N–CH2–
δ
Ph); 6.84-7.31 (m, 9H, Ar–H). Found, %: C 70.55; H 5.08; N 5.47; S 12.53. C15H13NOS. Calculated, %:
C 70.58; H 5.09; N 5.49; S 12.54.
N-Benzyl-2-(dicarbomethoxyethyl)-1,4-benzothiazin-3-one (10). N-Benzyl-1,4-benzothiazin-3-one
(9) (0.01 mol) was stirred in DMF in the presence of sodamide (0.02 mol, 0.8 g) at room temperature (28-30°C).
Methyl acrylate (2) (0.02 mol, 1.72 g) was added dropwise to this mixture. The reaction mixture was stirred for
3 h more. It was then poured onto crushed ice containing a few drops of conc. HCl. A yellow colored semisolid
separated out which was extracted with diethyl ether (25 ml, 2 times). The ethereal layer was dried over
anhydrous sodium sulfate. Removal of ether under reduced pressure afforded a pale yellow semisolid which was
used directly for further reactions. Yield 82%. IR spectrum (CHCl3), ν, cm-1: 3066, 3017 (C–H str.), 1728 (C=O,
1
ester), 1667 (C=O, benzothiazine). H NMR spectrum (CDCl3), , ppm: 2.69-3.39 (m, 8H, 4 × CH2); 3.55 (s,
δ13
6H, 2 × OCH3); 5.24 (s, 2H, NCH2); 6.96-7.35 (m, 9H, Ar–H). C NMR spectrum (CDCl3), , ppm: 31.55
(2 × CH2–CH2); 36.72 (2 × CH2–CO); 40.92 (N–CH2); 48.50 (tetrahedral carbon); 51.89 (2 × OCH3);
117.60-136.61 (12 aromatic carbons); 163.00 (C=O, benzothiazine); 171.69, 174.87 (2 × C=O, ester carbonyl).
δ
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4-Aza-1-thia-2,3-benz-5,9-dioxo-8-carbomethoxy-4-phenylspiro[5,5]undecane (11). Compound 10
(0.01 mol) was refluxed in freshly prepared sodium methoxide (0.01 mol) in methanol (30 ml) for 4 h. The
excess methanol was removed under reduced pressure. The residue was poured onto crushed ice containing a
few drops of conc. HCl. Compound 11 separated as a yellow solid which was filtered off, washed well with
1
water and hexane, and recrystallized from 50% methanol. Yield 78%; mp 92°C. H NMR spectrum (CDCl3),
, ppm: 1.92-2.25 (br. m, 6H, 3 × CH2); 3.54 (s, 3H, OCH3); 4.31-4.35 (m, 1H, CH); 5.24 (s, 2H, CH2);
δ
6.98-7.32 (m, 9H, Ar–H). Found, %: C 67.10; H 6.12; N 3.37; S 7.78. C22H21NO4S. Calculated, %: C 66.81;
H 5.35; N 3.55; S 8.11.
N-Benzyl-2-(dicyanoethyl)-1,4-benzothiazin-3-one (12). Compound 9 (0.01 mol) was stirred with
sodamide (0.02 mol, 0.8 g) in DMF (15 ml) at room temperature (28-30°C). Acrylonitrile 5 (0.02 mol) was
added and the reaction mixture was stirred at the same temperature for 2 h. The reaction mixture was then
poured onto crushed ice containing a few drops of HCl. The product 12 separated as a brown colored
1
amorphous solid in its pure form. Yield 91%; mp >250°C. H NMR spectrum (CDCl3), , ppm: 2.05-2.68 (m,
δ
8H, 4 × CH2); 5.24 (s, 2H, NCH2); 6.92-7.42 (m, 9H, Ar–H). Found, %: C 69.77; H 5.27; N 11.61; S 8.83.
C21H19N3OS. Calculated, %: C 69.78; H 5.30; N 11.62; S 8.87.
ACKNOWLEDGMENTS
The authors are extremely thankful to TIFR (Mumbai) and RSIC (IIT, Mumbai) for scanning the spectra
of the compounds.
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