Microwave-assisted one-pot regioselective synthesis of 2-alkyl-3,4-dihydro-3-oxo-2H-1,4-benzoxazines

A protocol for regioselective one-pot synthesis of 2-alkyl-3,4-dihydro-3-oxo-2H-1,4-benzoxazines under controlled microwave heating has been developed. Starting from commercially available 2-aminophenols, a base-mediated regioselective O-alkylation took place with 2-bromoalkanoates to give the acyclic intermediates, which underwent spontaneously an intramolecular amidation reaction to furnish 2-alkyl-3,4-dihydro-3-oxo-2H-1,4-benzoxazines in 44-82% yields. For the acyclic intermediate possessing an electron-withdrawing group, microwave heating was necessary for the annulation reaction.     

Efficient and Convenient Synthesis of 1,4-Benzoxazines, 1,4-Benzothiazines,Spiro-1,4-benzoxazines,and Spiro-1,4-benzothiazines

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.

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Synthesis of substituted 4-(3-alkyl-1,2,4-oxadiazol-5-ylmethyl)-3,4-dihydro-2H-1,4-benzoxazines and 4-(1H-benzimidazol-2-ylmethyl)-3,4-dihydro-2H-1,4-benzoxazines

Substituted 2H-1,4-benzoxazines were synthesized from substituted 2-amino phenols and 1,2-dibromoethane using K₂CO₃ in good to excellent yields. The cyclized products were further reacted with alkyl bromides to obtain the desired N-substituted 3,4-dihydro-2H-1,4-benzoxazines.     

Palladium-catalyzed regiospecific tandem allylation of 2-aminophenols using 2-butene-1,4-diol

The direct activation of C-O bonds in 2-butene-1,4-diol by palladium complexes has been accelerated by carrying out the reactions in the presence of a titanium reagent. Palladium-catalyzed regiospecific tandem allylation of 2-aminophenols with 2-butene-1,4-diol leads to 3,4-dihydro-2-vinyl-2H-1,4-benzoxazines.     

Efficient synthesis of 2,3-dihydro-1,4-benzoxazines via intramolecular copper-catalyzed O-arylation

A highly efficient synthetic approach to 2,3-dihydro-1,4-benzoxazines is described. The method involves a mild intramolecular copper-catalyzed O-arylation of β aminoalcohol, which works well without N-protection.     

Synthesis of unsaturated 1,4-heteroatom-containing benzo-fused heterocycles using a sequential isomerization-ring-closing metathesis strategy

A small library of 1,4-benzodioxins and 4H-1,4-benzoxazines was synthesized from the corresponding bis-allyloxy precursors by way of an initial isomerization to the bis-vinyloxy compounds, followed by a ring-closing metathesis using the second generation Grubbs' catalyst (G2). A related strategy, starting from benzene-1,2-dithiol and 2-mercaptophenol, afforded benzodithiin and 1,4-benzoxathiin, respectively.     

One-pot synthesis of tricyclo-1,4-benzoxazines via visible-light photoredox catalysis in continuous flow

A facile one-pot synthesis of tricyclo-1,4-benzoxazines has been developed via metal-free intramolecular cyclization of indole derivates. These reactions were efficiently achieved at ambient temperature by using visible-light photoredox catalysis in continuous flow. This directed intramolecular cyclization could be easily handled and scaled up in an open flask, enabling construction of a focused compound library for further pharmacological evaluation.     

Oxidation and photochemical reactions of 3-phenyl-2H-1,4-benzoxazines

3-Phenyl-2H-1, 4-benzoxazines 4-oxides are light sensitive compounds, irradiation leads to 3-phenyl-2H-1,4-benoxazines and to their 3-oxidized derivatives, whenever possible. Intermediate oxaziridines are formed during the photolysis and transformed into stable nitroxide radicals. The structure of these radicals was confirmed through peracid oxidation of 3-phenyl-2H-1,4-benzoxazines and 3-phenyl-3, 4-dihydro-2H-1,4-benzoxazines. A reaction mechanism is proposed on the basis of experimental observations.     

Efficient stereoselective synthesis of benzoxazines via copper-catalyzed three-component coupling reactions

A convenient one-pot synthesis of 1,4-benzoxazines via three-component coupling and subsequent O-cyclization is reported. The present reaction provides an efficient protocol to functionalized 1,4-benzoxazine derivatives in good to high yields from aldehydes, amines and alkynes. Furthermore, the O-annulation process is completely regio- and stereoselective, only the six-membered rings and its Z-isomers were obtained.     

A palladium-catalyzed facile and general method for the stereoselective synthesis of (E)-3-arylidene-3,4-dihydro-2H-1,4-benzoxazines and their naphthoxazine analogues

Palladium-catalyzed cyclocondensation of an aryl iodide with N-tosyl-2-(prop-2′-ynyloxy)aniline at room temperature is shown to constitute a convenient general method for the synthesis of (E)-3-arylidene-3,4-dihydro-2H-1,4-benzoxazines in moderate to very good yields. The method could also be extended to the synthesis of (E)-3-arylidene-2H-naphth[1,2-b][1,4]oxazines. The regio- and stereo-selectivity of the process, short reaction time, operational simplicity, and use of inexpensive starting materials represent its attractive features.     

Construction of functionalized 2,3-dihydro-1,4-benzoxazines via [5 + 1] annulations of 2-halo-1,3-dicarbonyl compounds with imines

A series of functionalized 2,3-dihydro-1,4-benzoxazines were obtained in moderate to excellent yields via domino [5 + 1] annulations of 2-halo-1,3-dicarbonyl compounds 2 with imines 1 under mild conditions and the application of this method in the synthesis of bioactive analogues, such as functionalized tetracyclic-1,4-benzoxazines which contain two new heterocyclic rings and one quaternary carbon center has also been developed.     

DMAP-catalyzed cyclization of Schiff bases with α-halo ketones: Synthesis of 1,4-benzoxazines

We demonstrate that 1,4-benzoxazines can be efficiently synthesized using 4-dimethylaminopyridine (DMAP) as a catalyst. We found that the DMAP catalyst can successfully promote the incorporation of the activated carbon atoms of α-halo ketones into the Schiff bases. The 1,4-benzoxazines can be synthesized through the formation of C–O and C–C bonds in high yield, using DMAP as the catalyst, α-halo ketones and phenolic Schiff bases as the reactants. Furthermore, a possible mechanism is proposed. This work provides a simple and efficient route to prepare the 1,4-benzoxazines.     

Palladium-catalyzed heteroannulation leading to heterocyclic structures with two heteroatoms: a highly regio- and stereoselective synthesis of (Z)-4-alkyl-2-alkyl(aryl)idene-3,4-dihydro-2H-1,4-benzoxazines and (Z)-3-alkyl(aryl)idene-4-tosyl-3,4-dihydro-2H-1,4-benzoxazines.

A highly convenient method has been developed for the synthesis of (Z)-4-alkyl-2-alkyl(aryl)idene-3,4-dihydro-2H-1,4-benzoxazines 9 and (Z)-3-alkyl(aryl)idene-4-tosyl-3,4-dihydro-2H-1,4-benzoxazines 34-38 through palladium-copper-catalyzed reactions. Aryl halides 7 reacted with 2-[N-alkyl(benzyl)-N-prop-2'-ynyl]aminophenyl tosylate 6 in the presence of (PPh3)2PdCl2 (3 mol %), CuI(5 mol %) in triethylamine at room temperature to yield 2-[N-alkyl(benzyl)-N-(3-aryl-prop-2'-ynyl)]-aminophenyl tosylates 8 in extremely good yields (72-96%). The latter could then be cyclized with KOH in ethanol-water to Z-9 in a highly regio- and stereoselective manner. Similarly, palladium-copper-catalyzed reaction of 2-(prop-2'-ynyloxy)aniline (21) with aryl iodides 7 led to 22-26 which after tosylation and cyclization with cuprous iodide in CH3CN in the presence of K2CO3 and Bu4-NBr led to the (Z)-3-alkyl(aryl)idene-4-tosyl 3,4-dihydro-2H-1,4-benzoxazines 34-38 in good overall yields. The Z-stereochemistry of the products was established from 1H NMR spectra, 3JCH values (between vinylic proton and methylenic carbon of the heterocyclic ring), NOE experiments, and X-ray analysis. The method was also found to be suitable for the synthesis of bis(benzoxazinylated) derivatives 17, 39, and 2-alkyl-3,4-dihydro-2H-1,4-benzoxazines 18. Our method for the synthesis of 3,4-dihydro-2H-1,4-benzoxazines is highly efficacious, using easily available starting materials under very mild conditions. Also the synthesis of some novel 5-substituted uracil derivatives 40 and 41 containing the benzoxazinyl moiety and of potential biological interest is being reported.     

Totally regio- and stereoselective synthesis of (E)-3-arylidene-3,4-dihydro-2H-1,4-benzoxazines under palladium catalyst

A new, one-pot palladium catalyzed reaction has been developed for the general synthesis of (E)-3-arylidene-3,4-dihydro-2H-1,4-benzoxazines at room temperature. The reaction procedure tolerates various functional groups. The method is characterized by regio- and stereoselectivity, operational simplicity, mild reaction conditions, and short reaction time.     

One-pot regioselective annulation toward 3,4-dihydro-3-oxo-2H-1,4-benzoxazine scaffolds under controlled microwave heating

An efficient and general synthesis of 2-alkyl-3,4-dihydro-3-oxo-2H-1,4-benzoxazines under controlled microwave heating has been established. It consists of a microwave-assisted reductive N-arylmethylation of substituted 2-aminophenols with aromatic aldehydes followed by a one-pot base-mediated regioselective O-alkylation of the N-arylmethyl-2-aminophenols with 2-bromoalkanoates to give the acyclic intermediates, which cyclize spontaneously to furnish the benzoxazine scaffolds in good to excellent yields. It was found that microwave heating over 180 °C was necessary for ring closure of the acyclic intermediates possessing an electron-withdrawing group.     

New efficient synthesis of 4-aminocarbonyl substituted 4H-3,1-benzoxazines by a Passerini 3CC/Staudinger/aza-Wittig sequence

α-Acyloxy-carboxamide azides 1, obtained from Passerini reaction of easily accessible o-azidobenzaldehyde with isocyanides and carboxylic acids, reacted with triphenylphosphine to give various 4-aminocarbonyl substituted 4H-1,3-benzoxazines 3 in moderate to high yields via sequential Staudinger and intramolecular aza-Wittig reaction. However, α-hydroxy carboxamide azides 5 were obtained in moderate yields when pyruvic acid was used in the Passerini reaction. Further sequential reaction of azides 5 with triphenylphosphine and isocyanates produced 2-amino-4-aminocarbonyl substituted 4H-1,3-benzoxazines 8 via a tandem Staudinger/aza-Wittig/heterocumulene-mediated annulation.     

Concise synthesis of 3,4-dihydro-1,4-benzoxazines by three-component reactions of acyl chlorides, o-aminophenols and 1,2-dichloroethane

The Cu(OAc)₂-catalyzed three-component reactions of o-aminophenols, acyl chlorides and 1,2-dichloroethane (DCE) have been established for the efficient synthesis of 3,4-dihydro-2H-benzo[b][1,4]oxazines (3,4-dihydro-1,4-benzoxazines). This method features advantages of the one-pot operation enabling N-acylation, CCl bond amidation and etherification, as well as the structural divergence of the synthesized products.     

Synthesis of Tetra-Substituted Trifluoromethyl-3,1-Benzoxazines by Transition-Metal-Catalyzed Decarboxylative Cyclization of N-Benzoyl Benzoxazinones

Efficient synthesis of N,O-heterocyclic tetra-substituted trifluoromethyl-3,1-benzoxazines via a transition-metal-catalyzed decarboxylative intramolecular cyclization was achieved. The decarboxylation of N-benzoyl trifluoromethyl-benzoxazinones generated the amide oxygen nucleophile, allowing a selective internal C₁-attack on Pd- or Cu-coordinated zwitterions, affording medicinally attractive tetra-substituted vinyl- or ethynyl-trifluoromethyl-3,1-benzoxazines. This protocol can be applied to the synthesis of perfluoroalkyl- and non-fluorinated 3,1-benzoxazines.     

Isomerization and ring-closing metathesis for the synthesis of 6-, 7- and 8-membered benzo- and pyrido-fused N,N-, N,O- and N,S-heterocycles

An isomerization-ring-closing metathesis (RCM) strategy afforded N-substituted 4H-1,4-benzoxazines from the protected N-allyl-2-(allyloxy)anilines. In addition, RCM was used to synthesize the N-substituted, 8-membered benzo-fused heterocycles from the respective diallyl compounds: 1,2,5,6-tetrahydro-1,6-benzodiazocine, 5,6-dihydro-2H-1,6-benzoxazocine, 5,6,9,10-tetrahydropyrido[2,3-b][1,4]diazocine and 5,6-dihydro-2H-1,6-benzothiazocine 1,1-dioxide. The isomerization-RCM approach also afforded the 7-membered ring system, 2,5-dihydro-1,5-benzothiazepine 1,1-dioxide, from the protected N-allyl-2-(allylsulfonyl)aniline. Furthermore, the structure of 1,6-bis[(4-methylphenyl)sulfonyl]-1,2,5,6-tetrahydro-1,6-benzodiazocine was confirmed by a single crystal X-ray determination.     

Enantiopure 1,4-benzoxazines via 1,2-cyclic sulfamidates. Synthesis of levofloxacin

1,2-Cyclic sulfamidates undergo efficient and regiospecific nucleophilic cleavage with 2-bromophenols (and related anilines and thiophenols), followed by Pd(0)-mediated amination to provide an entry to substituted and enantiomerically pure 1,4-benzoxazines (and quinoxalines and 1,4-benzothiazines). This chemistry provides a short and efficient entry to (3S)-3-methyl-1,4-benzoxazine 19, a late stage intermediate in the synthesis of levofloxacin.