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ABSTRACT. 6-Methoxy-3-[2-[1-(phenylmethyl)-4-piperidinyl]ethyl]-1,2-benzisoxazole is a high affinity (Ki = 8.2 nM) reversible inhibitor of acetylcholinesterase (AChE). The carbon-11 labeled form was prepared in high (>97%) radiochemical purity and with specific activities of 37 ± 20 GBq/μmol at end of synthesis, by the alkylation of the desmethyl precursor with [11C]methyl trifluoromethanesulfonate in N,N-dimethylformamide at room temperature. In vivo studies in mice demonstrated good blood brain permeability but essentially uniform regional brain distribution. Thus, despite in vitro and in vivo activity as an AChE inhibitor, 6-[11C]methoxy-3-[2-[1-(phenylmethyl)-4-piperidinyl]ethyl]-1,2-benzisoxazole does not appear to be a good candidate for in vivo imaging studies of AChE in the mammalian brain.

In the title compound, C21H21FN2O3, the piperidine ring is in a chair conformation with the substituted benzisoxazole ring system in an equatorial position. An inter­molecular C—H⋯O inter­action is present in the crystal structure.

Zonisamide (1,2-benzisoxazole-3-methanesulphonamide), a new anticonvulsant, is mainly metabolized to 2-sulphamoylacetylphenol by reduction of the benzisoxazole ring. Recent studies have shown that mammalian liver enzymes are responsible for the reduction of zonisamide. Because intestinal bacteria can also mediate the reduction of xenobiotics, this study was designed to evaluate the role of intestinal bacteria in in-vivo reductive metabolism of zonisamide. Treatment of rats with antibiotics significantly reduced the urinary and faecal excretion of 2-sulphamoylacetylphenol after oral administration of zonisamide. Re-contamination of the antibiotic-treated rats with microflora restored the excretion of the metabolite. The caecal contents of the control rats had significant zonisamide reductase activity, whereas little or no zonisamide reductase activity was observed with the caecal contents of the antibiotic-treated rats. Eight pure strains of intestinal bacteria were tested for zonisamide reductase activity and the highest was observed in Clostridium sporogenes. We concluded that intestinal bacteria play a major role in the reductive metabolism of zonisamide to 2-sulphamoylacetylphenol in-vivo.

Synthesis of 1,2-benzisoxazole-3-carboxaldehyde is achieved from 3-methyl 1,2-benzisoxazole via 3-ethoxymethyl-1,2-benzisoxazole (4).

Benzoxazole, 1,2-benzisoxazole and 2,1-benzisoxazole are biologically active molecules with potential applications in drug design. Their interaction with aqueous medium in biological systems may be simulated by considering their interaction with explicit water molecules. Such studies provide information on the structures, energies and type of interactions stabilizing the resulting geometric systems. The objective of the current study was to utilize theoretical approaches to investigate the structures, stabilization energy and binding energy of benzoxazole–water, 1,2-benzisoxazole–water and 2,1-benzisoxazole–water complexes. The calculations were performed utilizing the density functional theory (DFT)/M06-2X/6-311 ++ G(d,p) method and the DFT/ωB97XD method with both the 6-311 ++ G(d,p) and the aug-cc-pVDZ basis sets. The results suggest that the stability of the different clusters depends on interrelated factors including the rings formed by intermolecular hydrogen bonds and the proton affinity (PA) or acidity of the atoms forming the intermolecular hydrogen bonds with the water molecules. A comparison across methods indicates that the results follow similar trends with different methods.

MIMICKING the efficiency of enzyme catalysis is a daunting challenge. An enzyme selectively binds and stabilizes the transition state(s) for a particular reaction1,2. Artificial host systems can bind ground states just as efficiently3, and rate enhancements comparable to those in enzymatic reactions can be achieved by bringing catalytic and substrate groups together in intramolecular reactions. But the combination of selective binding and efficient catalysis remains elusive. The best enzyme mimics currently known are catalytic antibodies5,6. They bind transition-state analogues with high affinity, but their catalytic efficiency generally falls far short of that of enzymes4,8. Thorn et al.9 recently described an antibody that catalyses the eliminative ring-opening of a benzisoxazole "exceptionally efficiently" using car-boxylate as the general base, raising the intriguing possibility that this high efficiency derives from precise positioning of catalytic and substrate groups10. Here we show that familiar 'off-the-shelf proteins—serum albumins—catalyse the same reaction at similar rates, using a lysine side-chain amino group as the catalytic general base. Comparisons suggest that formal general base catalysis is of only modest efficiency in both systems, and that the antibody catalysis is boosted by a non-specific medium effect.

1,2-Benz-isoxazol-3-acetic acid is slightly toxic to unorganized growing carrot cells and completely prevents somatic embryogenesis beyond the globular stage. Its action is time dependent: if added early, it affects the determination of the early stages; if added later, after determination has occurred, it has practically no effect. The blocked forms can evolve, in the presence of the compound, creating secondary embryos that, in turn, are arrested at the globular stage. Since the secondary embryos adhere to the primary ones, irregular polyembryonic masses of typical appearance are created. The internal structures of the blocked globular embryos were examined and were shown to be enlarged, vacuolized and detached from the central cells. The protoderm also displayed an altered appearance. These data, when considered together with the effects of the compound on rooting and callus formation, suggest that benz-isoxazol acetic acid acts as a weak auxin.

In the title compound, C15H13NO2, the isoxazole unit and the attached benzene ring are almost coplanar, making a dihedral angle of 1.42 (8)°. The benzyl ring is inclined to the isoxazole ring by 74.19 (8)° and is in a +sc conformation with respect to the benzisoxazole unit. In the crystal, C—H...O hydrogen bonds link the molecules, forming zigzag chains propagating along the b axis. There are also π–π interactions present involving the isoxazole and benzyl rings [centroid–centroid distance = 3.5209 (10) Å], and C—H...π interactions involving the benzene ring of the benzoisoxazole unit and the methylene bridging group.

A series of N-benzylpiperidine benzisoxazoles has been developed as potent and selective inhibitors of the enzyme acetylcholinesterase (AChE). The benzisoxazole heterocycle was found to be an appropriate bioisosteric replacement for the benzoyl functionality present in the N-benzylpiperidine class of inhibitors. The title compounds were synthesized by alkylating 3-methyl-1,2-benzisoxazoles with an iodo piperidine derivatives as the key step. Benzisoxazoles 1b-j,o displayed potent inhibition of AChE in vitro with IC50's = 0.8-14 nM. Particularly interesting were N-acetyl and morpholino derivatives 1g (IC50 = 3 nM) and 1j (IC50 = 0.8 nM), respectively, which displayed outstanding selectivity for acetyl-over butyrylcholinesterase, in excess of 3 orders of magnitude. N-Acetyl 1g also displayed a favorable profile in vivo. This analog showed a dose-dependent elevation of total acetylcholine in mouse forebrain after oral administration with an ED50 = 2.4 mg/kg. In addition, 1g was able to reverse amnesia in a mouse passive avoidance model at doses of 3.2 and 5.6 mg/kg with an average reversal of 89.7%. Molecular dynamics simulations were used to study the possible binding modes of N-benzylpiperidine benzisoxazoles to AChE from Torpedo californica. Key structural insights were obtained regarding the potency of this class of inhibitors. Specifically, Asp-72, Trp-84, Trp-279, Phe-288, and Phe-330 are implicated in the binding of these inhibitors. The N-benzylpiperidine benzisoxazoles may be suitable compounds for the palliative treatment of Alzheimer's Disease.

A series of 5,6,7,8,9,10-hexahydro-7,10-iminocyclohept[b]indoles and 6,7,8,9,10,11-hexahydro-7,11-imino-5H-cyclooct[b]indoles was prepared. Structural modifications of the lead compound, 11-[4-(4-fluorobenzoyl)propyl]-5,6,7,8,9,10-hexahydro-7,10- iminocyclohept[b]indole (5, Ki = 0.82 nM vs [3H]ketanserin) enabled the identification of the functionality necessary for high affinity at serotonin 5-HT2 and dopamine D2 receptors in ligand binding studies. The indole ring, as well as the benzoyl or isosteric benzisoxazole moiety, were essential for high affinity. Variations of the length of the side chains resulted in ligands having either selective affinity for the 5-HT2 receptor or a combination of 5-HT2 and D2 affinity. In vivo binding studies were performed on selected members in this series. The most potent member, 2-fluoro-11-[4-(4-fluorobenzoyl)butyl]-5,6,7,8,9,10-hexahydro-7,10- iminocyclohept[b]indole (36) had an ED50 of < 1 mg/kg at the 5-HT2 and D2 receptors following oral administration.

Zonisamide, a benzisoxazole derivative, is an antiepileptic drug with a long half-life. Three nationwide, double-blind, placebo-controlled studies carried out in Japan prompted the approval of zonisamide as an antiparkinsonian agent in early 2009. The addition of zonisamide at 25-50 mg/day to currently used antiparkinsonian drugs significantly improved cardinal symptoms in patients with advanced Parkinson's disease. The effects were maintained over more than 1 year even in patients with advanced disease. Zonisamide has multiple modes of action, and its effects on Parkinson's disease include activation of dopamine synthesis, inhibition of monoamine oxidase, inhibition of T-type calcium channels and inhibition of an indirect pathway in the basal ganglia through the δ opioid receptor. Furthermore, zonisamide exhibits neuroprotective effects in animal models of Parkinson's disease. It strongly inhibits quinoprotein formation and markedly increases glutathione S-transferase levels in the striatum by enhancing the astroglial cysteine transport system and/or astroglial proliferation via S100beta production and secretion.

A series of substituted 1, 3-dioxolo[4, 5-f]-1, 2-benzisoxazole-6-carboxylic acids 13 and 1, 3-dioxolo[4, 5-g]-1, 2-benzisozazole-7-carboxylic acids 14 were synthesized and evaluated for diuretic and uricosuric activities in rats. Most of the benzisoxazole derivatives 13 and 14 showed potent diuretic activities. Moderate uricosuric activities were also found in 14a, 14b, and 14f.

1. The metabolism of zonisamide in vitro was characterized through aerobic and anaerobic incubations with rat liver subcellular fractions and cultured gastrointestinal microflora. 2. Zonisamide reacted with rat hepatic microsomal cytochrome P-450 and exhibited a Type I binding spectrum. 3. Metabolism of zonisamide in vitro by hepatic subcellular fractions and cultured gastrointestinal flora produced a single metabolite, 2-(sulphamoylacetyl)-phenol (2-SMAP), by reductive cleavage of the 1,2-benzisoxazole ring. 4. The reductive metabolism of zonisamide was primarily mediated by microsomal cytochrome P-450. The soluble fraction enhanced reduction when combined with the microsomal fraction but itself possessed only weak reductive activity. 5. Reduction of zonisamide by the most enzymically active liver fractions required NADPH, was stimulated by FMN and SKF-525A, and was inhibited by CO or air, as well as by n-octylamine. 6. Unlike their involvement in the reduction of numerous nitro, azo, and N-oxide compounds, cultured aerobic and anaerobic intestinal flora were not principally involved in the reduction of zonisamide.

Risperidone is a new benzisoxazole derivative displaying a very potent serotonin antagonism and a potent dopamine antagonism in pharmacological studies. These properties suggest the hypothesis that risperidone may exert antipsychotic effects and be superior to classic neuroleptics in its beneficial effects on negative and affective symptoms and its low extrapyramidal side-effect propensity. In an open pilot study 13 patients suffering from acute schizophrenic psychosis were treated with risperidone within an individually adapted dose range from 1 to 10 mg per day. A good antipsychotic efficacy could be demonstrated in 6 of the 8 patients who completed the trial. Risperidone was very well tolerated. The substance possesses a low EPS-inducing profile. Future research has to test the suggested advantage of risperidone over other neuroleptic drugs and its performance in the treatment of chronic schizophrenic patients.

A series of 3,5-disubstituted-2,1-benzisoxazole-4,7-diones was synthesized and evaluated as radiosensitizers both in vitro and in vivo. These compounds were designed as non-nitro electron-affinic agents in an effort to alleviate some of the toxicities seen with the 2-nitroimidazole radiosensitizers evaluated in the clinic. Several compounds in this series were potent radiosensitizers in vitro, with sensitizer enhancement ratios of 2.0-2.3 at concentrations less than 0.5 mM. Compounds with potent in vitro activity were also evaluated in vivo. However, none of these compounds showed radiosensitizing activity in vivo. The reduction potentials of these compounds were determined by cyclic voltammetry and compared to other electron-affinic radiosensitizers. In general, the reduction potentials of this series of compounds was slightly more positive than the 2-nitroimidazoles, but they fell within the range postulated as acceptable to yield in vivo activity. The results suggest that factors other than reduction potential may be responsible for the lack of in vivo radiosensitizing activity observed for this class of radiosensitizers.

A series of substituted 7,8-dihydrofuro[2,3-g]-1,2-benzisoxazole-7-carboxylic acids 9 and 7,8-dihydrofuro[2,3-g]benzoxazole-7-carboxylic acids 12 were synthesized and evaluated for uricosuric and diuretic activities in rats. Many of the benzisoxazole derivatives 9 showed uricosuric and only weak diuretic activities, whereas the benzoxazoles 12 exhibited potent diuretic activities with little affecting urate excretion. Among these compounds, 5-chloro-7,8-dihydro-3-phenylfuro[2,3-g]-1,2-benzisoxazole-7-carbo xylic acid (9b, AA-193) was found to be a potent uricosuric agent without diuretic activity and was selected for further development.

We tested the morphogenetic and cell elongating activity of 1,2-benzisoxazole-3-one, a compound similar to 1,2-benzisoxazole-3-acetic acid but lacking the lateral carbon chain. For comparison, we tested also the activity of indole 2,3-dione, having the same indolic ring as indole 3-acetic acid but no lateral carbon chain. The tests were made on the regeneration of tomato (Lycopersicon esculentum Miller var. Alice) from cotyledons and on pea (Pisum sativum L. var. Alaska) stem elongation. We found that 1,2 benzisoxazole-3-one retains part of the high shoot inducing activity of 1,2-benzisoxazole-3-aceticacid, while indole-2,3-dione is inactive. Both compounds have no effect on root induction or cell elongation. It seems therefore that the activity of 1,2 benzisoxazole-3-acetic acid is partly related to the structure of its ring, and that also in this respect 1,2 benzisoxazole-3-acetic acid differs from other auxinlike compounds.

It is well known that both isoxazole ring as well as pyrazole ring possess various biological activities and they both show interesting antimicrobial activity [1,2,3].[...]

The first example of a [4+2] cycloaddition reaction of 4-(l-ethenylsubstituted)isoxazoles with acetylenedicarboxylates is reported, while the corresponding 5-substituted isomers do not react with the same dienophile; density functional theory (DFT) calculation indicate the electronic origin of the different behaviour.

Enzyme catalysis depends on subtle combinations of effects that are difficult to separate and quantify.1 Medium effects are a crucial part of this package, but the assignment of a local dielectric constant to the structured microenvironment of an active site and its effect on ground state destabilization2 or transition state stabilization by electrostatic interactions3 is experimentally impossible. We aim to mimic and thus begin to quantify such active site medium effects experimentally. As a test reaction, we use the eliminative cleavage of benzisoxazole (1 f 2, the Kemp elimination), known to be particularly sensitive to the effects of the medium.4,5 We report that a subset

The effect of liver enzymes (S9) on the mutagenic response of nitroimidazoles and nitrofurans in the Ames test was evaluated with strain TA100. A diminished response was observed with a 5-nitroimidazole and 5-nitrofurans when the S9 preparation was incorporated in the agar layer. Preincubation with S9 under anaerobic conditions prior to adding the bacteria resulted in a greater and sometimes complete loss of the mutagenic effect. The loss of mutagenic potency was dependent on both incubation time and quantity of the S9 preparation. These results suggest that metabolites formed after reductive metabolism are neither mutagenic (presumably due to the loss of the nitro group) nor capable of activation to mutagenic metabilites. One 5-nitroimidazole, 3a,4,5,6,7,7a-hexahydro-3-(1-methyl-5-nitro-1 H -imidazol-2-yl)-1,2-benzisoxazole (MK-0436), gave an increased response in the presence of S9 in both the plate test and when preincubated under aerobic conditions. 7 metabolties were produced by the incubation. 4 monooxygenated metabolites were isolated and found to possess significant mutagenic activity. 2 synthetic dihydroxy analogs were more mutagenic than MK-0436. Similar results were obtained with S9 preparations from human liver and the livers of control, phenobarbital and Aroclor-1254 pretreated rats.

The base catalyzed ring expansion of 2-substituted 2H-1, 2-benzisoxazolin-3-one (3) to 2-substituted 2H-1, 3-benzoxazin-4-one (4) was observed during the alkylation of 3-hydroxy-1, 2-benzisoxazole (1).

New active diesters and diamides derived from 3-hydroxy-1,2-benzisoxazole were prepared for use in polyamide synthesis. The active esters and amides reacted readily with amines to give quantitative yields of amides. The high reactivity to these active esters and amides was discussed in relation to the electon-withdrawing effect of the leaving group and intramolecular general-base catalysis. Solution polycondensation of new active diesters and diamides with aliphatic and aromatic diamines proceeded slowly under mild conditions to produce polyamides with inherent viscosities up to 1.5.

3-Amidinomethyl- (8), 3-imidazolinylmethyl- (9) and 3-tetrahydropyrimidinylmethyl-1, 2-benzisoxazole (10) were synthesized from 1, 2-benzisoxazole-3-acetonitrile (4) via iminoether (7). 3-Tetrazolylmethyl-1, 2-benzisoxazole (5) and 1, 2-benzisoxazole-3-acetamide oxime (11) were also prepared from 4. 3-Aminoethyl-1, 2-benzisoxazole (25), a tryptamine analogue of 1, 2-benzisoxazole, was synthesized from 3-chloroethyl-1, 2-benzisoxazole (20). The bromination of 1, 2-benzisoxazole-3-acetic acid (1) with one molar equivalent of bromine afforded α-bromo-1, 2-benzisoxazole-3-acetic acid (27), which was decarboxylated to give 3-bromomethyl-1, 2-benzisoxazole (30). The amination of 30 afforded 3-amino-methyl-1, 2-benzisoxazole (31). The bromination of 1 with excess of bromine gave 3-tribromomethyl-1, 2-benzisoxazole (28). N-Substituted 1, 2-benzisoxazolylglycine ester (32) was synthesized from methyl α-bromo-1, 2-benzisoxazole-3-acetate (29) which was obtained by the bromination of methyl 1, 2-benzisoxazole-3-acetate (2).

13C and 15N chemical shift assignments of a number of 1,2-benzisoxazole 2-oxides and their deoxygenated analogues are reported and discussed. Similarly, assignments for some of the precursors to the N-oxides, o-hydroxyaryl ketoximes, are reported. In the N-oxides the “push-pull” effect of the NO dipole is largely localized on the isoxazole unit. A large (ca 39 ppm) upfield shift of the C-3 resonance is caused by the exocyclic oxygen whereas C-7a and, to a lesser extent, C-6 are the most heavily deshielded nuclei. The substituents do not have a significant effect on the C-3 resonance, whereas their effect on the carbocyclic carbons is more pronounced, the most markedly affected being the C-4 and C-6 nuclei. N-Oxidation of 1,2-benzisoxazole causes a large (50.5 ppm) shielding of the 15N nucleus.

The synthesis of a series of 3-(1-substituted-4-piperidinyl)-1,2-benzisoxazoles is described. The neuroleptic activity of the series was evaluated by utilizing the climbing mice assay and inhibition of [3H]spiroperidol binding. Structure-activity relationships were studied by variation of the substituent on the benzisoxazole ring with concomitant variation of four different 1-piperidinyl substituents. Maximum neuroleptic activity was realized when there was a 6-fluoro substituent on the benzisoxazole ring. The 1-piperidinyl substituent appeared less significant, although in most cases, the (1,3-dihydro-2-oxo-2H-benzimidazol-1-yl)propyl group imparted maximum potency. The most potent compound in both assays was 6-fluoro-3-[1-[3-(1,3-dihydro-2-oxo-2H-benzimidazol-1-yl) propyl]-4-piperidinyl]-1,2-benzisoxazole (11b).

A new anticonvulsant compound, zonisamide (1,2 benzisoxazole-methanesulfonamide), was studied in 10 adults with medically refractory partial seizures. Following a single oral dose of 400 mg, peak plasma levels occurred an average of 2.8 h after dosing, and the mean clearance from plasma was 2.34 L/h. Whole blood concentrations were higher than plasma concentrations because of red blood cell binding. Steady-state plasma concentrations were higher than predicted from a linear kinetic model. In most patients, seizure frequency was reduced after zonisamide was substituted for a standard antiepileptic drug. Dose-related reversible side effects in the central nervous and gastrointestinal systems were observed. Most patients tolerated doses between 5.2 and 12.5 mg/kg/day.

A combined use of deuterium labelling and recently developed scanning thinlayer chromatography/matrix-assisted-secondary-ion mass spectrometry(TLC/SIMS) was applied for identification of metabolites of zonisamide in rat urine. Zonisamide with deuterium distribution of d2/d3/d4=1/2/1 were prepared and orally given to rats at the dose of 40 mg/kg. Metabolites were extracted from 48 hr-urine and subjected to TLC/SIMS. The specific distribution of deuterium made easy the identification of the urinary metabolites by simple inspection of the spectrum for the presence of triplet ion clusters.In rat urine unchanged drug and three metabolites, N-acetyl-3-sulfamoylmethyl-1, 2-benzisoxazole, 1, 2-benzisoxazoel-3-carboxylic acid, and the sulfate of (2-hydroxybenzoyl)methanesulfonamide, were identified, and the presence of a polar conjugate of unchanged drug was suggested. Cleavage of N-O bond in benzisoxazole ring was demonstrated.

Metabolite fractions from the urine of a dog dosed with 3a,4,5,6,7,7a-hexahydro-3-(1-methyl-5-nitro-1H-imidazol-2-yl)-1,2-benzisoxazole (MK-0436) were obtained by the use of high-performance liquid chromatography. These fractions were of suitable purity for structural elucidation. Data obtained by mass spectrometry and NMR spectroscopy allowed the identification of seven major metabolites of this drug. Biotransformation in each case involved hydroxylation (mono or di) of the hexahydrobenzisoxazole ring.

A number of 2,1-benzisoxazole and 2,1-benzisothiazole compounds containing alkoxy or amino substituents in the 3-position and carboxy substituents in the 7-position, and potentially capable of valency tautomerism have been synthesized by reduction or oxidation, respectively, of suitable 2-nitro- or 2-aminoisophthalic acid derivatives. Thionation of 2-aminoisophthalic esters gave benzothiazaphosphorine derivatives. A temperature dependent n.m.r. study of the benzisoxazole and benzisothiazole derivatives indicates that in only one case, for methyl 3-methoxy-2,1-benzisothiazole-7-thionocarboxylate is there evidence for tautomerism at 200°.

Methyl 5-chloro- and 5,7-dichloro-2,1-benzisoxazole-3-carboxylates have been synthesized by treatment of o-nitromandelic and 5-chloro-2-nitroamandelic methyl esters, respectively, with thionyl chloride under appropriate reaction conditions. The structural assignments of both heterocyclic products were based on elemental and spectral analyses, and their conversion to the corresponding 5-chloro- and 5,7-dichloro substituted 2,1-benzisoxazole-3-carboxylic acids and isatins. Methyl α-chloro-o-nitrophenylacetate and o-nitrophenylcarbomethoxymethinyl sulfite were also obtained from reactions of methyl o-nitromandelate and thionyl chloride. A possible reaction mechanism involving two consecutive nucleophilic substitutions of methyl o-nitromandelate with thionyl chloride was proposed to account for the formation of methyl 5-chloro-2,1-benzisoxazole-3-carboxylate.

The reactions of the 3-methoxy-isoxazole quinones 1 and 9 in a highly polar solution of dimethyl sulfoxide have been studied. Quinones of type 2, 4/11, 5/12, 6 and 7/13 have been isolated; nmr measurements give a detailed insight into the reaction mechanism.

The site of the electrophilic substitution of 1, 2-benzisoxazole-3-acetic acid (1) altered depending on species of electrophiles and reaction conditions. In halogenation, only the α-methylene group of 1 was substituted. In the chlorosulfonation, the α-methylene group was substituted at first and then the 5-position of the nucleus was substituted. On the other hand, in the nitration, the 5-position was substituted at first and the α-methylene group was substituted secondly.

The mass spectra of a new class of heterocyclic N-oxides are reported. It is proposed that the fragmentation processes proceed either by an initial deoxygenation, and or an impact-induced isomerisation, prior to fragmentation. Substituents on the carbocyclic ring normally confer stability on the m olecular ions, whereas those on the heterocyclic ring open up additional fragmentation modes. A phenyl group at the 3-position allows an intramolecular oxygen transfer prior to fragmentation.

The reaction between methyl or ethyl esters of 1, 2-benzisoxazole-3-acetic acid and iso-amyl nitrite is reported. The main product is identified as 4-(2′-hydroxyphenyl)furazan-3-carboxylic acid (4) by chemical and X-ray crystal structure analyses. The synthesis of esters of E- and Z-α-(hydroxyimino)-1, 2-benzisoxazole-3-acetic acid is also reported.

Many 1,2-benzisoxazole-3-acetamides were synthesized and their herbicidal activities in the paddy field were studied. Of the compounds tested, N-α,α-dimethylbenzyl-2-bromo-(1,2-benzisoxazol-3-yl)acetamide 10a was the most effective. Details of the synthesis and the results of herbicidal evaluations are given.

4,2′-Iodonio-3-phenyl-l,2-benzisoxazole tetrafluoroboride monohydrate (IV) was synthesized and an x-ray diffraction structural study showed that the cation (IV) is a tetracyclic system and the crystal structure is insular with I...F and I...OH22 ionic and ion-dipole interactions.

A series of imidazo[4,5-e]-2,1-benzisoxazole derivatives was synthesized by reacting benzyl cyanide with 1,2-disubstituted 5-nitrobenzimidazoles; their reduction gave 1,2-disubstituted 4-benzoyl-5-aminobenzimidazoles. Acylation, oximation, and diazotization reactions with subsequent replacement of the diazo group by iodine were investigated. In the reaction with DMFA diethyl acetal, amidines were obtained, whose cyclization by the action of ammonia leads to imidazo[4,5-f]quinazoline derivatives.

The pyrolysis of 3-(2-pyridyl)-2,1-benzisoxazoles 5A, 5B, and 5C (A: unsubstituted; B: 5-bromo; C: 5,7-dibromo) at about 215° afforded 5,11-dihydro-11-oxopyrido [1,2-b] cinnolin-6-ium hydroxide inner salt 6A, the 2-bromo (6B) and the 2,4-dibromo (6C) compounds respectively in high yields. X-ray crystallographic analysis of 6B unambiguously confirmed the structure. The benzisoxazoles 5A-5C were obtained from the pyrolysis of the corresponding 2-(2-azidobenzoyl) pyridines 2A-2C at about 112°. While 2A and 2B afforded the corresponding benzisoxazoles 5a and 5B in 82% and 51% yields respectively, 2-(2-azido-3,5-dibromobenzoyl)pyridine (2C) afforded a mixture of the benzisoxazole 5C and the tricyclic compound 6C, isolated 43% and 41% yields respectively. The properties of the novel mesoionic compounds of type 6, their oxidative and reductive ring cleavage products together with alkylation and catalytic hydrogenation products are described. Electrophilic substitutions, substitutions in position 11 via the 11-thiones 11 and other miscellaneous trans of 6 are also presented.

The hydrogenation of 1, 2-benzisoxazole-3-acetamide oxime (1) proceeded as follows. At first 1 absorbed one molar hydrogen to give 2-hydroxybenzimidoylacetamide oxime (2) and then 2 was cyclized to 3-amino-5-(2-hydroxyphenyl) isoxazole (4) which absorbed one more molar hydrogen to give 2-hydroxybenzoylacetamidine (3). The alkaline treatment of 2-hydroxybenzoylacetonitrile (11), which was obtained from 1, 2-benzisoxazole-3-acetnitrile (9) by the catalytic reduction and successive hydrolysis, gave 2-coumarinimine (12). The acidic treatment of 2-hydroxybenzimidoylacetamide (13), which was the product of the catalytic reduction of 1, 2-benzisoxazole-3-acetamide (8), afforded 4-aminocoumarin (15), an isomer of 12.

A CNDO/2 study was carried out to elucidate features of the electronic structure of substituted 1,2-benzisoxazole 2-oxides and to explain their reactivity. Charge densities fail to account for the observed reactivity and both electrophilic and nucleophilic substituion reactions appear to be orbital controlled. An attempt is made to explain the cleavage of the ring N-O bond that invariably accompanies nucleophilic attack.

In order to ascertain to what extent benzisoxazole and benzisothiazole can substitute the indole nucleus in auxin, several benzisoxazole and benzisothiazole analogs of indole-3-acetic acid were synthesized and their activity as plant hormones tested. The results of the slit-pea-stem curvature test are reported; among other compounds, 5-chloro-1, 2-benzisothiazole-3-acetic acid was the most active, showing about 330 per cent of the activity of indole-3-acetic acid.