Synthesis of fused heterocycles derived from 2H-1,4-benzoxazin-3(4H)-ones
-
Gowravaram Jagath Reddy
and
Khandavalli Srinivasa Rao
Abstract
The synthesis of 1,4-benzoxazine fused heterocycles has been reviewed.
Introduction
The past few decades have seen the emergence of a number of 1,4-benzoxazin-3(4H)-one 1 derivatives including a cardiotonic agent 2 [1], antihypertensive agent 3 [2], antidiabetic agent 4 [3], anticancer agent 5 [4], laxative 6 [5], aldose reductase inhibitor 7 [6], antianxiety agent 8 [7], antiemetic agent 9 [8] and antiparasitic agent 10 [9]. A number of these simple benzofused 1,4-oxazines are a part of natural products with antituberculosis 11 [10] and anticancer 12 [11] activities. 2,4-Dihydroxy-7-methoxy-1,4-benzoxazinone 13 [12] isolated from corn seedling is an active compound in the resistance of maize to the European corn borer. Blepharin 14 is a biologically significant 1,4-benzoxazinone glycoside [13]. Ofloxacin 15, a 1,4-benzoxazine fused heterocycle, is an active antibacterial agent and presently in clinical use [14] (Figure 1). In view of these findings, an attempt was made to review the synthesis of various 1,4-benzoxazine fused heterocycles in the present article. To the best of our knowledge, no review has appeared on 1,4-benzoxazine fused systems and the literature available is very limited.
1,4-Benzoxazin-3(4H)-one (1) and its biologically active derivatives.
Synthetic methods of 2,3-dihydro-1,4-benzoxazin-3(4H)-ones
The most convenient and commonly used method for the synthesis of 1,4-benzoxazinones 1 has been reported by Shridhar et al. [15] by reaction of 2-aminophenol with chloroacetyl chloride in refluxing methylisobutylketone (MIBK) in the presence of aqueous sodium bicarbonate in a single step (Scheme 1).
Another strategy involves reduction of nitro ethers 16 with Fe/AcOH [16] and Zn/NH4Cl [17], which gives the desired benzoxazinones in moderate yields. The nitro ethers can be prepared by the alkylation of potassium nitrophenoxides with a 2-bromoester (Scheme 2).
1,4-Benzoxazinones 17 with acetic acid substitution in 2-position have been prepared in a single step by the reaction of 2-aminophenols with maleic anhydride [18] (Scheme 3).
In another method, 2-hydroxyethyl-2,3-dihydro(2H)-1,4-benzoxazinones 18 [19] have been prepared by the reaction of 2-aminophenols with α-bromo-γ-butyrolactone in N,N-dimethylformamide in the presence of potassium carbonate or sodium hydride at room temperature followed by reduction [14] (Scheme 4).
Reactions and classification of 1,4-benzoxazine fused heterocyclic systems
In the present review, the heterocycles are classified according to the site of the reaction, as shown below, followed by cyclocondensation to form the fused heterocycle. This classification is purely based on convenience and is not general.
Reaction at C-3 followed by cyclocondensation at 4 (3–4 fused system).
Reaction at ring nitrogen (4) followed by cyclocondensation at C-3 (4–3 fused system).
Reaction at ring nitrogen (4) followed by cyclocondensation at C-5 (4–5 fused system).
Reaction at C-2 and C-3 (2–3 fused system).
Benzofused system (6–7 fused system).
3–4 Fused systems
1,2,4-Triazolo[3,4-c][1,4]benzoxazines
A wide range of medicinal properties such as anti-inflammatory [20], central muscle relaxant [21] and diuretic activities [22] have been reported for these systems. Compounds have been prepared by thiation of 1 with Lawesson’s reagent to give 19 followed by reaction with alkyl/aryl hydrazones to give 20. Thermal cyclization of 20 has furnished the triazolo-1,4-benzoxazines 21 as crystalline solids (Scheme 5).
Hydrazones 20 have also been prepared conveniently via iminochloride 22 obtained by reaction of 1 with phosphorous oxychloride in the presence of CH3CN/Et3N [23]. Hydrazones obtained in situ undergo cyclocondensation under PTC conditions to give 1-oxo-triazolobenzoxazines 23 in good yields (Scheme 5).
The isomeric triazolobenzoxazines 25 and 27 have been prepared as outlined in Scheme 6. Thus, compounds 25 have been prepared by an intramolecular cyclocondensation of the azido group [24] to the acetylenic function of O-azido-acetylenic derivative 24, whereas the other isomer 27 was obtained by refluxing O-phenoxyacetonitrile-nitrile imide 26 in benzene in the presence of triethylamine [25].
Chowdary et al. [26] have reported a palladium-copper catalyzed synthesis of 1,2,3-triazolo[5,1-c]benzoxazines through C-C bond formation followed by intramolecular cycloaddition of aromatic azide with internal alkyne generated in situ (Scheme 7).
4H-[1,2,3,5]–Thiatriazolo[4,5-c][1,4]benzoxazine
Hydrazones 20 undergo reaction with thionyl chloride forming sulfur containing C-annulated benzoxazines 28 via intermolecular ring formation [27] (Scheme 8)
4H-[1,2,4]–Oxadiazolo[3,4-c][1,4]benzoxazine
Bartsch et al. [28] have synthesized another interesting system starting from thioxobenzoxazine 19. Thus, reaction of 19 with hydroxylamine hydrochloride in the presence of triethylamine gives the oxime 29. Cyclocondensation of 29 with carbonyl di-imidazole yields oxadiazolo[1,4]benzoxazine 30 in approximately 45% yield (Scheme 9).
Thiazolo[2,3-c][1,4]benzoxazine
The reaction of 2-ethoxycarbonyl-3-thioxobenzoxazine 31 with ethyl bromoacetate in the presence of sodium hydride gives thiazolo[2,3-c][1,4]benzoxazine 32 ring system [29] in approximately 50% yield (Scheme 10).
4H-Tetrazolo[5,1-c][1,4]benzoxazines
The synthetic utility of iminochloride 22 derived from 1 is further exemplified in the synthesis of tetrazolobenzoxazine system 33. The treatment of iminochloride 22 in situ with sodium azide gives the tetrazolobenzoxazine 33 in 40–60% yield [30] (Scheme 11).
An alternative synthetic route to this system involves a 1, 3-dipolar addition of O-azidophenoxyacetonitrle [24].
Pyrimido[2,3-c][1,4]benzoxazines
A number of pyrimidobenzoxazines have been synthesized utilizing the reactivity of iminochloride 22. It undergoes reaction with anthranilic acid in refluxing acetonitrile to give quinazolino[2,3-c][1,4]benzoxazine 34 in a single step [31]. A multistep synthesis of this system has been reported by Kulkarni and Abdi [32]. Similarly, 22 undergoes cyclocondensation with 5-aminopyrazole-4-carboxylic-acids 35 and 3-amino-thiophene-2-carboxylates 36 to give pyrazolo [3′,4′:4,5] pyrimido [2,3-c] [1,4] benzoxazines [33] 37 and thieno[3′,2′:4,5] pyrimido[2,1-c][1,4]benzoxazines [34] 38, respectively (Scheme 12).
4–3 Fused systems
4H–Imidazo[2,1-c][1,4]benzoxazines
A number of substituted imidazobenzoxazines have been reported to exhibit antiallergic and bronchodilator activities [35]. Sundara Murthy et al. [36] have reported a two-step synthesis of imidazobenzoxazines. Alkylation of 1 with phenacyl bromide in refluxing acetone in the presence of potassium carbonate gives N-substituted benzoxazine 39, which was cyclocondensed in glacial acetic acid in the presence of ammonium acetate to give imidazobenzoxazine 40 in good yield. In another strategy, propynyl-substituted benzoxazines 41 have been cyclocondensed in the presence of mercuric acetate and ammonium acetate (Scheme 13).
Shridhar et al. [37] have reported the synthesis of antiparasitic imidazobenzoxazinyl carbamates 43 starting from 3-aminobenzoxazine 42 (Scheme 14). Substrate 42 has been prepared by amination of thioxobenzoxazine 19.
Rowlands et al. [38] have reported the synthesis of antiallergic imidazo[2,1-c][1,4] benzoxazines 46 by a different method. Thus, the reaction of benzoxazine derivative 44 with chloroacetyl chloride gives acetamido intermediate 45. This compound in refluxing methanol in the presence of triethylamine undergoes an interesting rearrangement giving 46 in approximately 80% yield. The mechanism is depicted in Scheme 15.
Bartch et al. [27] have reported the synthesis of isomeric imidazo[5,1-c][1,4] benzoxazines 47 from 1 after activation with diethyl chlorophosphate and subsequent treatment with ethyl isocyanoactate (Scheme 16).
4H–[1,2,4]Triazino[3,4-c][1,4]benzoxazines
N-Acylbenzoxazinones 48 undergo cyclocondensation with hydrazine hydrate in the presence of catalytic amount of sulfuric acid to give triazino benzoxazines 49 in good yields [39]. These compounds have been found to exhibit significant anti-inflammatory activities (Scheme 17).
Pyrrolo[2,1-c][1,4]benzoxazines
Sanohez and Pujol [40] have synthesized this interesting system starting from N-(2-fluorophenyl) pyrrole 50. Vilsmeyer formylation of 50 with phosphorous oxychloride/dimethyl formamide gives the formylpyrrole derivative 51, which on sodium borohydride reduction has been transformed into the alcohol 52. In the presence of NaH, this compound has been cyclized to pyrrolo[2,1][1,4]benzoxazine ring system 53 (Scheme 18).
Azaindolo[2,1-c][1,4]benzoxazines
Bhuniya et al. [41] have reported a two-step one-pot synthesis of an azaindolo[2,1-c][1,4]benzoxazine ring system. Thus, reaction of dilithiated reagent 54 with Weinreb amide derivative 55 followed by treatment with trifluoroacetic acid (TFA) gave the new tetracyclic ring system 56 (Scheme 19).
2–3 Fused systems
Pyrazolo[4,3-b] and pyrazolopyrimido[4,5-b][1,4]benzoxazines
Reaction of 1 with phosphorous oxychloride in the presence of N,N-dimethylformamide under Vilsmeyer-Hack conditions [42] results in the formation of 2-dimethylamino-formylidene-3-chloro[1,4]benzoxazine 57 with reactive centers at positions 2 and 3. Bifunctional nucleophiles undergo reaction with 57 leading to the formation of fused 1,4-benzoxazines (Scheme 20).
Combs [43] has reported the synthesis of pyrazolobenzoxazine analog 58 (Scheme 21) of cardiotonic agent Bemoradon 2 (Figure 1).
Jagath Reddy et al. [44] have reported the cyclocondensation of 57 with a variety of 5(3)-aminopyrazoles to give a new tetracyclic ring system pyrazolo[5,′1′:2,3]pyrimido[4,5-b][1,4] benzoxazine 59.
Thieno[3,2-b][1,4]benzoxazines and thiazolo[2,3-b][1,4]benzoxazines
N-substituted benzoxazinones undergo reaction with phosphorous oxychloride in N,N-dimethylformamide to give 3-chloro 1,4-benzoxazin-2-yl-carboxaldehydes 60. Compounds 60 undergo cyclocondensation with ethyl mercaptoacetate and thiourea to give thieno- and thiazolo-fused benzoxazines 61 and 62, respectively, in approximately 58% yields [45] (Scheme 22). Reaction of 62 with phenacyl bromide results in the formation of benzoxazine fused imidazothiazole system [46].
1H,9H–Pyrrolo[3,2-b][1,4]benzoxazines
Okafor and Akpuaka [47] have reported the construction of this ring system starting from benzoxazin-2-yl-acetic acid 63. The acid chloride 64 was obtained by reaction of 63 with thionyl chloride. The corresponding amide 65 then undergoes cyclization when treated with polyphosphoric acid at 120–130°C to give 67 in good yields (Scheme 23).
Benzopyranobenzoxazines and quinolinobenzoxazines
Bartsch et al. [48] have reported the synthesis of these systems utilizing the reactivity of an active methylene group at position 2 of benzoxazinone ring system. N-Substituted benzoxazinones undergo electrophilic substitution with salicylaldehyde, methyl salicylate and methyl anthranilates giving the corresponding benzylidene derivatives 68, which then undergo cyclocondensation to form fused benzoxazine systems 69 and 70 (Scheme 24).
Moustafa [49] has reported the synthesis of new thieno- and pyrano-fused 1,4-benzoxazines starting from 4-methylbenzoxazin-3-ones. A series of coumarino[3,4-b][1,4]benzoxazines 75 has been reported by Ruzhang et al. [50] via domino [5+1] annulation of 2-halo-1,3-dicarbonyl compounds 73 with imines 74 under mild conditions (Scheme 25).
Pyrano-bis-benzoxazine
A novel pentacyclic compound 72 has been reported by Kikelji et al. [51]. Thus, the attempted sodium borohydride reduction of a mixed anhydride of 2,4-dimethyl-7-nitro-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-ylcarboxylic acid 71 resulted in the formation of a novel pyranobis-benzoxazine ring system 72 (Scheme 26).
4–5 Fused systems
Oxazino[2,3,4-ij]quinoline
Katekar [52] has reported the synthesis of oxajulolidene, which is 3,7-dioxo-2,3,6,7-tetrahydro-5H-[1,4]oxazino[2,3,4,ij]quinoline 77, via polyphosphoric acid cyclization of benzoxazin-4-yl-propionic acid 76 (Scheme 27) in approximately 67% yield.
Ofloxacin 15 is a 4,5-fused 1,4-benzoxazine derivative discovered and developed as a broad-spectrum antibacterial agent that is currently in clinical use. The synthesis of 15 is depicted in Scheme 28.
The asymmetric synthesis of levofloxacin, which is less toxic than the racemic drug ofloxacin, has also been developed [53].
Pyrrolo[1,2,3,-de][1,4]benzoxazines
A series of pyrrolobenzoxazines 78 has been reported as anti- inflammatory and antiallergic agents [54]. The synthesis of this ring system starts from the substrate 17 as shown in Scheme 29.
6–7 Benzo-fused systems
Cyclopenta[g]-2,3-dihydro[1,4]benzoxazines
Depreux et al. [55] have synthesized these derivatives for evaluation as antiparasitic agents. 7-Acetyl–3-oxo–2,2,4-trimethyl[1,4]benzoxazine 79 has been transformed into product 80 in 55% yield. On heating with sulfuric acid at 40°C this compound undergoes cyclization to cyclopenta[g][1,4]benzoxazine 81 in approximately 50% yield (Scheme 30).
Pyridobenzoxazines
Carboxylic acid 83 and a number of its analogs have been synthesized starting from 6-aminobenzoxazin-3-one 82 and evaluated as antibacterial agents [56] (Scheme 31).
Imidazo and pyrazinobenzoxazines
The systems 85 and 86 have been prepared starting from 6,7-diaminobenzoxazin-3-one 84. Product 85 and its derivatives have been evaluated for their anthelmintic activity [57, 58] (Scheme 32).
Conclusion
During the past decade, a number of substituted benzoxazinones have been synthesized and evaluated for their medicinal properties. The present article reviews some of the known fused 1,4-benzoxazine systems.
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Articles in the same Issue
- Masthead
- Masthead
- Reviews
- Polyoxin and nikkomycin analogs: recent design and synthesis of novel peptidyl nucleosides
- Synthesis of fused heterocycles derived from 2H-1,4-benzoxazin-3(4H)-ones
- Research Articles
- Green synthesis of 1-monosubstituted 1,2,3-triazoles via ‘click chemistry’ in water
- Synthesis of a novel fused tricyclic heterocycle, pyrimido[5,4-e][1,4]thiazepine, and its derivatives
- Synthesis of 2-[(quinolin-8-yloxy)methyl]quinoline-3-carboxylic acid derivatives
- Pyrimidine-5-carbonitriles – part III: synthesis and antimicrobial activity of novel 6-(2-substituted propyl)-2,4-disubstituted pyrimidine-5-carbonitriles
- Tungstic acid-catalyzed synthesis of 3,3-bis (1H-indol-3-yl)indolin-2-one derivatives
- One-pot synthesis of dihydropyrano[c]chromene derivatives by using BF3•SiO2 as catalyst
