Efficient and convenient synthesis of 1,4-benzoxazines, 1,4-benzothiazines, spiro-1,4-benzoxazines, and spiro-1,4-benzothiazines

Article abstract of DOI:10.1080/00397911.2012.714829

An efficient, convenient synthesis of 1,4-benzoxazines, 1,4-benzothiazines, spiro-1,4-benzoxazines, and spiro-1,4-benzothiazines derivatives was accomplished in good yields via the novel intramolecular cyclization mediated by mild base K₂CO₃ in ethanol solvent. A variety of substrates can participate in the process with good yields, making this methodology have broad applicability. All the structures of synthesized compound have been confirmed by spectral analysis. Copyright

Full text of DOI:10.1080/00397911.2012.714829

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An Efficient and Convenient Synthesis of 1, 4-
benzoxazines, 1, 4-benzothiazines, Spiro-1, 4-
benzoxazines, and Spiro-1, 4-benzothiazines
Samundeeswari L. Shastri a , Bahubali M. Chougala a , Manohar V. Kulkarni a & Lokesh A.
Shastri a
a Department of Chemistry, Karnatak University, Dharwad, India
Accepted author version posted online: 26 Mar 2013.
To cite this article: Samundeeswari L. Shastri , Bahubali M. Chougala , Manohar V. Kulkarni & Lokesh A. Shastri (2013):
An Efficient and Convenient Synthesis of 1, 4-benzoxazines, 1, 4-benzothiazines, Spiro-1, 4-benzoxazines, and Spiro-1, 4-
benzothiazines, Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry,
DOI:10.1080/00397911.2012.714829
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AN EFFICIENT AND CONVENIENT SYNTHESIS OF 1, 4-BENZOXAZINES, 1,
4-BENZOTHIAZINES, SPIRO-1, 4-BENZOXAZINES, AND SPIRO-1, 4-
BENZOTHIAZINES
Samundeeswari L. Shastri1, Bahubali M. Chougala1, Manohar V. Kulkarni1, Lokesh A.
Shastri1
1Department of Chemistry, Karnatak University, Dharwad, India
Corresponding author. Tel.: +91 836 2215286; fax: +91 836 2747884; E-mail:
chemilok@yahoo.co.in
Abstract
An efficient, convenient, synthesis of 1, 4-benzoxazines, 1,4-benzothiazines, spiro-1, 4-
benzoxazines and spiro-1, 4-benzothiazines derivatives were accomplished in good
yields via the novel intramolecular cyclisation mediated by mild base K2CO3 in ethanol
solvent. A variety of substrates can participate in the process with good yields, making
this methodology have broad applicability. All the structures of synthesised compound
have been confirmed by spectral analysis.
Supplemental materials are available for this article. Go to the publisher’s online edition
of Synthetic Communications® to view the free supplemental file.
KEYWORDS: 4-bromomethylcoumarin, Schiff base, 1, 4-benzoxazines, 1,4-
benzothiazines, spiro-1, 4-benzoxazines, spiro-1, 4-benzothiazines and intramolecular.
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1. INTRODUCTION
Recently,organic chemistry receives increasing attention because they address
diversity,in development of pharmaceutical industries and is main interest to discover the
new drug entities.Therefore, the organic chemists have developeda new synthetic
methods and technologies,according to the need of industries,to obtain expected
compounds in a pure and efficient. Hence, among these the multicomponent
reactions(MCRs)are offer the favourable condition for constructing a complex molecules
with exceptional synthetic efficiency and high stereo selectivity, from easily available
starting materials.[1–4]Therefore, MCRs is now well established technique organic
chemistry for the synthesis of vastnumber of compounds at short time[5–7]and also
straightforward approach.[8]The intrinsic cytotoxicity study was done from a series of
newly synthesised 8-amino (Figure 1) and 2-amino-1,4-benzoxazine (Figure 1a)
derivatives, which areable to inhibit oxidative stress-mediated neuronal degeneration in
neuronal cell cultures. Thus, the 1,4-benzoxazines were showing more potent
neuroprotective activity, without affecting the intrinsic cytotoxicity.[9,10]The structural
activity relationship studies of 1,4-benzoxazines (Figure 2) and combined results of both
intrinsic cytotoxicity and neuro protection results confirms 1,4-benzoxazines derivatives
are more potential and effective in protecting against the lesions induced by S-bromo-
willardiine injected into the cortex of 5-day old mice-pups,[11] and exhibited diverse
biological activity.[12–16]
A verity of electrochemical multistep one-pot synthesis of 2-alkylamino-1,4-benzoxazine
and 2-hydroxy -1,4-benzoxazine (Figure 3) derivatives werereported[17,18]via inverse-
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electron-demand Diels-Alder reaction of an o-iminoquinone diene and a secondary
alkylenamine dienophile. 2-Aminophenols and 2-nitrophenols have been widely used as
the starting materials for thesynthesis of 1,4-benzoxazines. In the case of 2-nitrophenols,
the initial O-alkylation was followed by nitro reduction and subsequent intramolecular N-
substitution,[19]and with 2-haloalkanoyl chlorides or bromide in the first place to form the
2-aminophenols, which then underwent an intramolecular O- alkylation on heating in the
presence of base.[20–22]
Similarly several substituted 1,4-benzothiazine derivatives are currently of interest due to
their therapeutic role as smooth muscle relaxants [23] potassium channel-opening
agents,[24]urokinase inhibitors[25] and calcium antagonists.[26–28]Therefore, thenew chiral
benzothiazines(Figure 5)wereascribed and this classof benzothiazines derivatives, opens
the way to development of newinhibitors for carbohydrate processing enzymes of
therapeutic importance.[29]The synthetic chemotherapeuticantibioticlevofloxacin drug has
been reported by short route synthesis through palladium mediated amination to 1,4-
benzoxazines and 1,4-benzothiazines[30] via tele nucleophilic aromatic substitution.[31]
Thebiosynthesis of pheomelanins is the typical epidermal pigment of red haired, Celtic-
type Caucasians, arise from oxidative cyclisation of cysteinyldopas, mainly the 5-S-
isomer, via 1,4-benzothiazines (Figure 6).[32–34] The structural modification of 1,4-
benzothiazines, attracts the greater pharmacological activity and some of the methods
used for the synthesis of these compounds on condensation of 2-aminothiophenols,
with α,β- unsaturated acids or halo acetic acid /esters. Hence only few synthesis of
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intramolecular hetero cyclisation of S-methylene derivatives of spiro-fused
benzothiazines has been prepared (Figure 7).[35–37]
In view of these observations and our ongoing interest in the chemistry of 1,4-
benzothiazines[38] and 1,4-benzoxazines, the complexity of the existing methods, it is sure
that a simpler method isnecessary for the synthesis of aryl substituted title compounds.
2. RESULTS AND DISCUSSION
We have considered worthwhile to explore the reactions depicted in the following
schemes 1 to 6 and considered the possibility of synthesizing desired compounds in a
single synthetic operation from arylalkylhalides and aldehydes/cyclic ketoneswith 2-
aminophenol/2-aminothiophenol. Thus, we hypothesized that, an intramolecular
carbanion addition across the imine carbon, by an appropriate reagent, in a three
component systemthrough simple approach. Taking into consideration all the above-
mentioned points we thought that the combination of all the three substrates under mild
experimental condition by single synthetic approach using L-proline as catalyst. The L-
proline favours the desired product10 with very pooryield.
Hence, we initiated our studies with the reactions of 4-bromomethylcoumarins (7), 2-
aminophenol/2-aminothiophenol (8)with aromatic aldehydes (9)and L-proline in presence
of dichlomethane (DCM) as a solvent, at room temperature for 18 hrs under stirring
(Scheme 1), these reactions led to the formation of the 1,4-benzoxazines(10 = O)/ 1,4-
benzothiazine (10 = S)at low yield (10-15%) along with other isolated intermediate
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productsare (10 (i) 50% and 10 (ii)30%). The same reaction at refluxing temperature we
observed 10(i)is the major product (70 %). Therefore, our initial efforts were directed to
finding the appropriate reagent and reaction conditions to perform the proposed sequence
in Scheme 2 starting from 4-bromomethylcoumarins (7)[35] with Schiff base (11) which is
derived from 2-aminophenol and substituted aldehydes. Regarding the reagent for the
intramolecular carbanion addition across the imine carbon for two component
systems(Scheme 2), we considered anhydrous potassium carbonate asmild base, of their
ability to activate the functionalityof hydroxyl group under mild condition at room
temperature followed by in situ formation of carbanion, on methylene carbon and add to
imine carbon to lead compound 10.Thus, this approach led as single product 10 without
any other side products and the obtained product showed a characteristic NH stretching
band in IR around 3300-3400 cm-1 and 1H NMR showed two doublet around 4.56and
5.59δppm (J= 6.6 Hz)is due to C2-H and C3-H respectively. The NH is D2O exchanges
around 6.71δppm andthe results of physical analysis data are summarised in Table 1.
The scope of the reaction was surveyed by probing changes to the benzyl bromide (12),
and the Schiff base (13) substrates. The flexibility of the method allows the desired
product (14&15) in low yield (Scheme 3). The isolated compounds showed characteristic
IR NH stretching band and two doublets around 4.41 and 5.07 δppm (J=7.0 Hz) in 1H
NMR.The yield drop wasobserved, which is compared with coumarin system, it may be
due to the generation of carbanion is difficult and less favourable in this system by
anhydrous potassium carbonate condition. In the case of coumarin system, formation of
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carbanion is more feasible due to the stabilisation via enolate form (Scheme 2) and the
results are summarised in Table 2.
Many of the synthetic spiro-benzothiazines derivatives display important structural
features, but very limited number of synthetic methods for this kind of compounds was
reported. However, these methods suffer from tedious synthetic routes, long reaction
timeand drastic reaction conditions. The developments of new protocols for the synthesis
of complex spiro-cyclic compounds are still remains a great challenge to synthetic
chemists due to their associated reactivity patterns. In particular, the spiro-1,4-
benzothiazines and spiro-1,4-benzoxazines framework. On the basis of our progressive
endeavors in exploring new methodologies toward spiro-1,4-benzothiazines, and spiro-
1,4-benzoxazines, we report herein, a two component reaction involving 7 and 16
inethanol to provide spiro- 1,4-benzoxazines (17) /1,4-benzothiazines (18)found by
serendipity with good yield (Scheme4). The results are summarised in Table 3. In other
hand the reaction between benzyl bromide (12) and imine (16),the isolated products (19)
and (20) shows less yield (Scheme 5)compared with(17) and (18) (scheme 4).The
isolated products showed characteristic NH stretching band in IR around 3318 cm-1 and
singlet around 4.24 δppm in 1H NMR. All synthesised compounds structure has been
confirmed by IR, 1H NMR,13C NMR and mass spectra (see supplementary file). The
results are summarised in Table 4.
3. CONCLUTION
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In summary, we have demonstrated a simple and facile two component reaction for the
synthesis of 1,4-benzoxazines, 1,4-benzothiazine, spiro-1,4-benzoxazines and spiro-1,4-
benzothiazine derivativesfrom4-bromomethylcoumarins and benzyl bromiderespectively,
by using potassium carbonate which played the role of base. The simplicity of approach
makes this strategy useful for the synthesis of spiro-frameworks. Further studies to
delineate the scope and limitations of the present methodology are underway.
4. EXPERIMENTAL
General Procedures
Melting points were recorded from sheetal scientific instrument and presented in degree
centigrade. IR spectra were recorded on a Nicolet-impact – 410 FT infrared spectrometer.
The NMR was recorded on a Bruker 300 and 400 MHz FT NMR spectrometer. 1H and
13C Chemical shift were represented as δppm values relative to the internal standard,
trimethylsilane. 4-bromomethylcoumarin 135 was prepared according to our earlier report
and substituted aromatic aldehydes and cyclic ketones were used commercially.
Generalexperimental Procedure For Synthesis Of 10, 17 And 18
The substituted 4-bromomethyl coumarins (7) (1.0equiv.) was refluxed with Schiff base
(11/16) (1.0 equiv.) and potassium carbonate (2.0 equiv.) in 20mL of dry ethanol on a
water bath for 8-10 hrs. The reaction mixture was cooled and filtered to remove
potassium carbonate. The filtrate was concentrated and added into crushed ice. The solid
separated was filtered and the residue was washed with dilute hydrochloric acid (1N) 20
mL followed by water wash and recrystallized from ethanol solvent.
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4-(3-(4-Chlropheny)-3,4-Dihydro-2H-Benzo[B][1,4]Oxazin-2-Yl)-6-Methoxy-2H-
Chromon-2-One (10o)
Light brown solid, Yield 82%, mp: 153 oC. IR (KBr) ν 1705, 3315 cm-1; 1H NMR (300
MHz, DMSO-d6): δH 3.71(s, 3H, OCH3), 4.56(d, 1H, C-H, J = 6.6 Hz), 5.59 (d, 1H, C-H,
J = 6.6 Hz), 6.53(s, 1H, C3-H of coum), 6.60 (m, 1H, Ar-H), 6.88(s, 1H, NH and D2O
exchanges), 6.60-6.84(m, 3H, Ar-H), 7.00 (d, 1H, Ar-H, J= 2.69 Hz), 7.09 (dd 1H, Ar-H,
J = 9.00 Hz), 7.25 (dd, 3H, Ar-H, J = 8.4 Hz), 7.39 (d, 2H, Ar-H, J = 8.4 Hz) ; 13C NMR
(400 MHz, DMSO-d6): 52.56, 58.23, 67.30, 113,12, 116.16, 116.91, 117.11, 117.96,
119.04, 121.26, 123.63, 124.23, 125.51, 125.85, 129.82, 130.43, 134.78, 144.56, 145.31,
148.46, 152.51, 153.90, 161.88: Mol.F.C24H18ClNO4 mass: 419.09; LC-MS found: m/z
419.8 (98.8%).
General Experimental Procedure For Synthesis Of 14, 15, 19 And 20
The benzyl bromide (12) (1.0equiv.) was refluxed with Schiff base (13/16) (1.0 equiv.)
and potassium carbonate (2.0 equiv.) in 20 mL of dry ethanol on a water bath for 8-10
hrs. The reaction mixture was cooled and filtered to remove potassium carbonate. The
filtrate was concentrated and added into crushed ice. The solid separated was filtered and
the residue was washed with dilute hydrochloric acid (1N) 20 mL followed by water
wash. The isolated compound was purified by column chromatography by using ethyl
acetate : hexane (3:7).
3,4-Dihydro-2,3-Diphenyl-2H-Benzo[B][1,4]Oxazine (14a)
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Light yellow solid, Yield 30%, mp: 128 oC. IR (KBr) ν 1619, 3360 cm-1; 1H NMR (300
MHz CDCl3): δH 4.41(d, 1H, C-H, J = 7.0 Hz), 5.07(d, 1H, C-H, J = 7.0 Hz), 6.64-
7.09(m, 15H, Ar-H and NH and NH D2O exchanges); 13C NMR (400 MHz, DMSO-d6):
56.42, 67.88, 123.52, 125.38, 125.65, 126.48, 127.02, 128.10, 128.58, 128.96, 129.09,
129.88, 132.02, 141.26, 141.86, 143.01: Mol.F.C20H17NO mass: 287.13; GC-MS found:
m/z 287.0 (95.7%)
ACKNOWLEDGEMENTS
We acknowledge the University Grant Commission, New Delhi (UGC) and Department
of Science and Technology, New Delhi (DST) for the financial support.
REFERENCES
1. Tietze, L. F.; Brasche, G.; Gericke, K. Domino Reactions in Organic Synthesis; Wiley-
VCH, Weinheim, 2006.
2. DJmling, A.; Ugi, I. Multicomponent Reactions with Isocyanides, Angew. Chem.
2000, 112, 3300 - 3344; Angew. Chem. Int. Ed. 2000, 39, 3168 -3210.
3. Tietze, L. F. Reactions in Organic Synthesis. Chem. Rev. 1996, 96, 115-136.
4. Tietze, L. F.; Beifuss, U. Sequentielle Transformationen in der Organischen Chemie
eine Synthesestrategie mit Zukunft. Angew. Chem. 1993, 105, 137-170.
5. Ugi, I. IsonitrileChemistry; Academic Press: New York, 1971.
6.Ugi, I. Multicomponent Reactions in Total Synthesis. J. Prakt. Chem. 1997, 339, 499-
516.
ACCEPTED MANUSCRIPT
9

ACCEPTED MANUSCRIPT
7. Umesh, R. P.; Dhanaji, V. J.; Balaji, S. L.; Ramrao, A. M.Baker's yeast catalyzed
synthesis of 1,4-benzothiazines, performed under ultrasonication. J. Molecul.Catal.B.
2011, 68, 94-97.
8.Uli, K.; Andrea, P. A straightforward approach towards 5-substituted thiazolylpeptides
via the thio-Ugi –reaction. Org. Biomol. Chem. 2010, 8, 5442-5447.
9. Martine, L.; Brian, L.; Bruno, P.; Fleury, M. B. Synthesis and in Vitro Evaluation of
New 8-Amino-1,4-benzoxazine Derivatives as Neuroprotective Antioxidants, J. Med.
Chem. 1999, 42, 5043-5052.
10. Estelle, B.; Brian, L.; Pierre, L.; Leslie, S.; Pierre, G.;Fleury, M. B.; Martine, L.Novel
2-Alkylamino-1,4-benzoxazine Derivatives as Potent Neuroprotective Agents:
Structure−Activity Relationship Studies. J. Med. Chem. 2005, 48, 1282-1286.
11. Largeron, M.; Mesples, B.; Gressens, P.; Cechelli, R.; Spedding, M.; Le Ridant, A.;
Fleury, M. B. Eur. J. Pharmacol. 2001, 424, 189-194.
12. Kuroita, T.; Marubayashi, N.; Sano, M.; Kanzoki, K.; Inoba, K.; Kawakita, T. Chem.
Pharm. Bull. 1996, 44, 2051-2060.
13.Caliendo, G.; Griew, P.; Perssutti, E.; Santagada, V.; Santini, A.; Alberizio, S.;
Fattorusso, C.; Pinto, A.; Sorrentino, R. Synthesis, biological activity and conformational
study of 1,4-benzoxazine derivatives as potassium channel modulators. Eur. J. Med.
Chem. 1998, 33, 957-967.
14.
Caliendo, G.; Perssutti, E.; Santagada, V.; Fiorino, F.; Severino, B. d’Emmanuele
diVilla Bionca, R.; Lippolis, L.; Pinto, A.; Sorrentino, R. Synthesis and vasorelaxant
activity of new 1,4-benzoxazine derivatives potassium channel openers. Bioorg.
Med.Chem. 2002, 10, 2663-2669.
ACCEPTED MANUSCRIPT
10

ACCEPTED MANUSCRIPT
15. Sebille, S.; deTullio, P.; Boverie, S.; Antoine, M. H.; Lebrun, P.; Pirotte, B.Recent
developments in the chemistry of potassium channel activators: the cromakalim analogs.
Curr. Med.Chem. 2004, 11, 1213-1222.
16. Matsuoka, H.; Ohi, N.; Mihara,M.; Suzuki, H.; Miyamota, K.; Maruyama, N.; Tsuji,
K.; Kato, N.; Akimoto, T.; Tekeda, Y.; Yano, K.; Kuroki, T.Antirheumatic Agents:
Novel Methotrexate Derivatives Bearing a Benzoxazine or Benzothiazine Moiety. J.
Med. Chem. 1997, 40, 105- 111.
17.
Estelle, B.; Fleury, M. B.; Martine, L. Simultaneously Electrogenerated
Cycloaddition Partners for Regiospecific Inverse-Electron-Demand Diels−Alder
Reactions: A Route for Polyfunctionalized 1,4-Benzoxazine Derivatives. J. Org. Chem.
2004, 69, 882-890.
18.
Daiwang, X.; Angele, C.; Fleury, M. B.; Martine, L. Electrochemically Induced
Cascade Reaction for the Assembly of Libraries of Biologically Relevant 1,4-
Benzoxazine Derivatives. J. Org. Chem. 2006, 71, 6374-6381.
19.
Touzeau, F.; Arrault, A.; Guillaumet, G.; Scalbert, E.; Pfeiffer, B.; Rettori, M.;
Renard, P.; Merour, J-Y. Synthesis and Biological Evaluation of New 2-(4,5-Dihydro-
1H-imidazol-2-yl)-3,4-dihydro-2H-1,4-benzoxazine Derivatives. J. Med. Chem. 2003, 46,
1962-1979.
20. Arrault, A.; Touzeau, F.; Guillaumet, G.; Leger, J.-M.; Jarry, C.; Merour, J.-Y.
Synthesis of functionalised pyrido[4,3-b][1,4]oxazine and imidazo[1,2-a]pyridine
derivatives. Tetrahedron 2002, 58, 8145-8152.
ACCEPTED MANUSCRIPT
11

ACCEPTED MANUSCRIPT
21. Lee, C. L.; Chan, K. P.; Lam, Y.; Lee, S. Y. Solid-phase combinatorial synthesis of
1,4-benzoxazin-3(4H)-one and 1,4-benzothiazin-3(4H)-one derivatives. Tetrahedron Lett.
2001, 42, 1167-1169.
22. Atkinson, J.; Morand, P.; Amason, J. T.; Niemeyer, H. M.; Bravo, H. R. Analogs of
the cyclic hydroxamic acid 2,4-dihydroxy-7-methoxy-2H-1,4-benzoxazin-3-one
(DIMBOA): decomposition to benzoxazolinones and reaction with .beta.-
mercaptoethanol. J. Org. Chem. 1991, 56, 1788-1800.
23. Schreder, M. E.; Erker, T. Studies on the chemistry of thienoannelated O,N- and S,N-
containing heterocycles. 17. Preparation of 1H-thieno[2,3-b][1,4]thiazine-1-
carboxarnides as smooth muscle relaxants. J. Heterocycl. Chem. 2000, 37, 349-354.
24.
Erker, T.; Schreder, M. E.; Studenik, C. Studies on the chemistry of
thienoannelated O,N- and S,N-containing heterocycles. Part 19: thieno[2,3-
b][1,4]thiazines with calcium antagonistic and potassium opening activities. Arch.
Pharm. 2000, 333, 58-62.
25.
Derivatives and Their Use as Urokinase Inhibitors. PCT. Int. Appl. 1998, WO 9811089.
26. Watanabe, Y.; Osanai, K.; Nishi, T.Synthesis of azido derivatives of semotiadil, a
Tanaka, A.; Mizuno, H.; Sakurai, M. Preparation of Novel Benzothiophene
novel 1,4-benzothiazine calcium antagonist, for photoaffinity probes of calcium channels.
Bioorg. Med. Chem. Lett. 1996, 6, 1923-1926.
27.
Schou, C. S.; Hansen, C. H.; Tagmose, M. T. Synthesis and pharmacological
evaluation of 4H-1,4-benzothiazine-2-carbonitrile 1,1-dioxide and N-(2-
cyanomethylsulfonylphenyl)acylamide derivatives as potential activators of ATP
sensitive potassium channelsBioorg. Med. Chem. 2005, 13, 141-155.
ACCEPTED MANUSCRIPT
12

ACCEPTED MANUSCRIPT
28.
Omprakash, Ajay, K.; Anil, S. Study of the reaction of chalcone analogs of
dehydroacetic acid and o-aminothiophenol: synthesis and structure of 1,5-
benzothiazepines and 1,4-benzothiazines. Tetrahedron 2005, 61, 6642-6651.
29.
Gao, L.; Rawle, I. H. Analogs of the cyclic hydroxamic acid 2,4-dihydroxy-7-
methoxy-2H-1,4-benzoxazin-3-one (DIMBOA): decomposition to benzoxazolinones and
reaction with .beta.-mercaptoethanol. J. Org. Chem. 2005, 70, 9013-9016.
30. John, F. B.; Peter, S.; Timothy, G. Enantiopure 1,4-Benzoxazines via 1,2-Cyclic
Sulfamidates. Synthesis of Levofloxacin, Org. Lett. 2007, 9, 3283-3286.
31.
Thomas, G.; John, R. F.; Basil, J. W.; George, V. Tele Nucleophilic Aromatic
Substitutions in 1-Nitro-3- and 1,3-Dinitro-5-trichloromethylbenzene, and 3-
Trichloromethylbenzonitrile. A New Synthesis of the 1,4-Benzothiazine-3(4H)-one Ring
System from 3-Nitrobenzoic Acid. Tetrahedron 2000, 56, 447-453.
32. Alessandra, N.; Sofia, M.; Giuseppe, P. A New Insight in the Biosynthesis of
Pheomelanins: Characterization of a Labile 1,4-Benzothiazine Intermediate. J. Org.
Chem. 1999, 64, 3009-3011.
33. Alessandra, N.; Paola, D. D.; Giuseppe, P. Characterisation of 1,4-benzothiazine
intermediates in the oxidative conversion of 5-S-cysteinyldopa to pheomelanins.
Tetrahedron Lett. 1994, 35, 6365-6368.
34. Renata, F.; Fausto, S.; Pilar, U. N. M.; Lara, M.; Cristina, S.; Michela,, R.; Cristina,
M.; Carlo, R.4-Benzothiazine analogues and apoptosis: structure–activity relationship.
Bioorg.Med. Chem. 2003, 11, 3245-3254.
ACCEPTED MANUSCRIPT
13

ACCEPTED MANUSCRIPT
35. Nazarenko, K. G.; Shtil, N. A.; Chernega, A. N.; Lozinskii, M. O.; Tolmachev, A.
A.2-Hetaryl Derivatives of 3-Oxo-3,4-dihydro-2H-1,4-benzothiazine. Synthesis 2004,
1195-1202.
36. (a) Fokas, D.; Ryan, W.; Casebier, D.; Coffen, D. Solution phase synthesis of a
spiro[pyrrolidine-2,3′-oxindole] library via a three component 1,3-dipolar cycloaddition
reaction. Tetrahedron Lett. 1998, 39, 2235–2238; (b) Suchy, M.; Kutschy, P.; Monde,
K.; Goto, H.; Harada, N.; Takasugi, M.; Dzurilla, M.; Balentova, E.Synthesis, Absolute
Configuration, and Enantiomeric Enrichment of a Cruciferous Oxindole Phytoalexin, (S)-
(−)-Spirobrassinin, and Its Oxazoline Analog. J. Org. Chem. 2001, 66, 3940-3947; (c)
Risitano, F.; Grasii, G.; Foti, F.; Nicolo, F.; Condello, M. Tetrahedron 2002, 58, 191-
195; (d) Nair, V.; Biju, A.; Vinod, A.; Suresh, E.Reaction of Huisgen Zwitterion with
1,2-Benzoquinones and Isatins: Expeditious Synthesis of Dihydro-1,2,3-
benzoxadiazoles and Spirooxadiazolines. Org. Lett. 2005, 7, 5139-5142.
37.Nazarenko, K. G.; Shtil, N. A.;Lozinskii, M. O.;Tolmachev, A. A. New 2-
functionalized 2H-3,4-dihydro-1,4-benzothiazin-3-ones and their application in the
synthesis of spiro heterocycles, Tetrahedron 2007, 63, 7727-7732.
38. Shastri, L. A.; Shivashankar, K.; Kulkarni, M. V. Facile synthesis of some novel 4-
{3-aryl-3,4-dihydro-2H-benzo[b][1,4] thiazin-2-yl}-2H-chromen-2-one derivatives, J.
Sulfur Chem. 2007, 28, 625-630.
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Table 1. Synthesis of 1,4-benzoxazinylcoumarins 10a-10o
Entry
R
R1
M.P (oC) Yield
(%)
10a
10b
10c
10d
10e
10f
6-CH3
6-CH3
6-CH3
6-CH3
6-CH3
6-CH3
7-CH3
7-CH3
7-CH3
7-CH3
7-CH3
7-CH3
6-OCH3
H
193
139
253
223
202
154
178
149
215
233
261
177
188
226
153
88
86
82
85
89
84
86
85
84
87
85
86
82
80
82
2-Cl
4-Cl
2-NO2
4-NO2
4-OCH3
H
10g
10h
10i
2-Cl
4-Cl
10j
2-NO2
4-NO2
4-OCH3
H
10k
10l
10m
10n
10o
6-OCH3 2-Cl
6-OCH3 4-Cl
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Table 2. Physical data of synthesized compounds 14a-14b and 15a-15b
Entry
X
R
%
M.P. oC
Yield
30
14a
14b
15a
15b
O
O
S
H
128
137
132
124
4-Cl
H
30
35
S
4-Cl
36
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Table 3. Physical and Analytical data of compounds (17a-17c and 18a-18c)
Comp. R
X
Y
M.P (ºC) Yield
(%)
17a
17b
17c
18a
18b
18c
6-CH3
O
O
O
S
-CH2
-CH2
165
152
73
66
58
75
68
65
6-OCH3
6-CH3
-NCH2Ph 164
6-CH3
-CH2
-CH2
135
162
6-OCH3
6-CH3
S
S
-NCH2Ph 158
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Table 4. Physical data of compounds (19a-19b and 20a-20b)
Entry
X
Y
%
M.P. oC
Yield
30
19a
19b
20a
20b
O
O
S
-CH2
148
153
132
142
-NCH2Ph 32
-CH2 35
-NCH2Ph 40
S
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Figure 1. R1=H, R2=-CH2OH, R3=H; R4=NH-R; a. R1=H, R2=-CH2OH, R3=NRR; R4=H
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Figure 2
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Figure 3. R=OH, NH-R1
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Figure 5
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Figure 6
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Figure 7
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Scheme 1. R=6-CH3; R1=H; X=O,S
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Scheme 2. R=6-CH3, 7-CH3, 6-OCH3; R1=H, 2-Cl. 4-Cl, 4-OCH3, 2-NO2, 4-NO2
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Scheme 3. R=H,4-Cl, X=O and S
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Scheme 4. R=6-CH3, 6-OCH3; Y=CH2, N-CH2Ph
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Scheme 5. Y=CH2, N-CH2Ph
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