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C-Unsubstituted 1,2-diazetidines, a rarely studied type of four-membered heterocyclic compounds, were synthesized through an operationally simple intermolecular vicinal disubstitution reaction. 1,2-Diazetidine derivatives bearing various N-arylsulfonyl groups were readily accessed and studied by experimental and computed Raman spectra. The ring-opening reaction of the diazetidine was explored and resulted in the identification of a selective N-N bond cleavage with thiols as nucleophiles, which stereoselectively produced a new class of N-sulfenylimine derivatives with C-aminomethyl groups.

Though the Cadogan-Sundberg approach has been employed to synthesize a variety of indole and carbazole derivatives from nitroarenes, surprisingly, very little is reported for making pyrroles using the same approach from non-arene nitrodienes. Herein, we report a general method to synthesize substituted pyrroles, in one step with modest yields, from nitrodienes using triphenylphosphine in the presence of an Mo catalyst, bis(acetylaceto)dioxomolybdenum (VI). To shed light on the mechanism of this reaction, we performed DFT calculations using uB3LYP/6-31+G(d) basis set and observed that the reaction favors a path through a nitrene intermediate.

Quantitative HPLC and colorimetry are used to study color variations in dyeings with indigo, 6-bromoindigo, and 6,6′-dibromoindigo, the main components of the historic dye Tyrian purple. For the first time, visible light is identified conclusively as a cause of debromination of the leuco form of 6-bromoindigo. A dyeing run using 6-bromoindigo alone is found to yield a dyed fabric containing large amounts of indigo, when the vat is exposed to visible light. The extent of debromination is dependent upon the pH of the dye bath and also the source of the visible light. This information allowed development of a dyeing procedure which is demonstrated to give consistent colors through two passes. Quantitative HPLC analysis of extracts from the dyed fabrics indicates that the leuco form of 6-bromoindigo vs. the leuco forms of indigo and 6,6′-dibromoindigo has the strongest affinity for wool fabric. This is postulated to be due to attractive electrostatic interactions between the leuco form of 6-bromoindigo and wool.

When treated with SeO2, 2,4-diphenyl-3H-1-benzazepine (1) is oxidized equally at C3 and C5, giving either products of rearrangement or fragmentation; in both cases quinoline derivatives are the primary products. When C3 is oxidized, electrocyclization followed by ring-opening with phenyl migration gives the major product phenyl(3-phenylquinolin-2-yl)methanone (6), whereas C5 oxidation produces 2,4-diphenylquinoline (2) and 1,2-bis(2,4-diphenylquinolin-3-yl)diselane (8). Oxidation of C5 in 1 also results in formation of 2-(3,5-diphenylfuran-2-yl)aniline (7). On the other hand, 3-methyl-2,4-diphenyl-3H-1-benzazepine (9) upon treatment with SeO2 gives primarily a product of oxidation of C3, 2,3-diphenylquinoline (5). Oxidation of C5 in (9) is a minor pathway, and gives both 3-methyl-2,4-diphenylquinoline (10) and (3-methyl-2-phenylquinolin-4-yl)(phenyl)methanone (11). CO was detected as a byproduct in both reactions. Although the ring-contraction reaction using SeO2 has been previously noted, no mechanistic proofs have been firmly established. In this Letter, we provide evidence for the ring-contraction of benzazepines to quinolines through a fragmentation path (loss of CO and acetic acid) or through rearrangement.

Thirteen fabrics are each dyed with either indigo, or 6-bromoindigo, or 6,6′-dibromoindigo. When the dyed fabrics, which had not undergone any finishing procedures, are boiled in water for 10 min, color changes are observed: many indigo- and 6-bromoindigo-dyed fabrics turn more blue, while many 6,6′-dibromoindigo-dyed fabrics turn more red. These color changes are characterized by reflectance spectra and colorimetry data. Evidence is presented that the color changes are related to particle sizes of the dyes: 6,6′-dibromoindigo-dyed carbon nanotubes, used as a fabric surrogate, show an increase in dye-particle size upon heating, as judged by electron microscopy. Because we have shown previously that 6-bromoindigo-dyed carbon nanotubes give decreased dye-particle size when heated, we infer that, no matter the indigoid or fabric, smaller particles tend to cause a bluer fabric shade, while larger particles cause a redder shade.

2,4-Diphenyl-3H-1-benzazepine is deprotonated with either LDA or KHMDS. The resulting anion is alkylated with alkyl halides or MeOTs, giving either products of alkylation at C3, or at N, or a mixture of both. The regioselectivity depends on the base, presence of the complexing agent HMPA, and the leaving group of the alkylating agent. Using MeI as alkylating agent gives exclusively the C3-methylated product, while using MeOTs gives exclusively the N-methylated product. The N-alkylated products show evidence of stereodynamic behavior in their NMR spectra.

Fundamental dyeing properties of three dyes of historical importance – indigo, 6-bromoindigo, and 6,6′-dibromoindigo – on 13 fabrics are examined. The hues of the dyed fabrics vary from blue-green to blue for indigo, blue to violet for 6-bromoindigo, and violet–blue to purple for 6,6′-dibromoindigo, as determined by reflectance measurements. Many of the dyed fabrics change color markedly with application of gentle heat. For indigo and 6-bromoindigo, the color changes are predominantly towards absorption of longer wavelengths (giving a bluer fabric color), while for 6,6′-dibromoindigo, the color changes are towards absorption of shorter wavelengths (giving a redder fabric color). The greatest thermochromic effects are seen for dyed wool: with 6-bromoindigo, the color changes from violet to blue, while with 6,6′-dibromoindigo, the color changes from violet to red–purple upon brief boiling in water. Transmission electron microscopy analysis of 6-bromoindigo-dyed carbon nanotubes, used as surrogates for dyed fabric fibers, suggests that the basis of the thermochromic effect is a change in the size distribution of dye aggregates.

Attempted free-radical bromination of 2,4-diphenyl-3H-1-benzazepine (3) with NBS led to an unusual ring-contraction reaction, giving rise to 2,4-diphenylquinoline (5) in high yield. This is a convenient path for the synthesis of a quinoline in one step from the easily accessible 1-benzazepine. We have elucidated the mechanism of ring-contraction reaction using 13C-labeled and deuterated benzazepines, and DFT calculations. There is strong experimental evidence that the departing carbon atom is initially part of a reactive intermediate dibromomethyl cation, which leads to methyl formate upon reaction with methanol. In the absence of methanol, water can complete the ring-contraction. In this case, the departing carbon atom is in the form of carbon monoxide.

A series of 2,4-disubstituted 1H-1-benzazepines, 2a-d, 4, and 6, were studied, varying both the substituents at C2 and C4 and at the nitrogen atom. The conformational inversion (ring-flip) and nitrogen-atom inversion (N-inversion) energetics were studied by variable-temperature NMR spectroscopy and computations. The steric bulk of the nitrogen-atom substituent was found to affect both the conformation of the azepine ring and the geometry around the nitrogen atom. Also affected were the Gibbs free energy barriers for the ring-flip and the N-inversion. When the nitrogen-atom substituent was alkyl, as in 2a-c, the geometry of the nitrogen atom was nearly planar and the azepine ring was highly puckered; the result was a relatively high-energy barrier to ring-flip and a low barrier to N-inversion. Conversely, when the nitrogen-atom substituent was a hydrogen atom, as in 2d, 4, and 6, the nitrogen atom was significantly pyramidalized and the azepine ring was less puckered; the result here was a relatively high energy barrier to N-inversion and a low barrier to ring-flip. In these N-unsubstituted compounds, it was found computationally that the lowest-energy stereodynamic process was ring-flip coupled with N-inversion, as N-inversion alone had a much higher energy barrier.

The absolute configuration of the title acid 2 has been determined to be S by X-ray crystallography. Thus, decarboxylation of 2 produces ( S )-(+)-halothane with 99% retention of configuration. This behavior is compared to other stereoselective decarboxylation reactions of α-haloacids from the literature that also gave high degrees of retention of configuration when in the form of their quaternary ammonium salts, which contain one proton. The proton of the ammonium salt is necessary in order to protonate the anionic intermediate formed from decarboxylation. In the absence of this relatively acidic proton, we had previously found that using triethylene glycol (TEG) as both the solvent and proton source for the decarboxylation reaction of acid 2 caused poor stereoselectivity. This was in contrast to 1,2,2,2-tetrafluoro-1-methoxypropionic acid 6 , which showed a high degree of retention of configuration in TEG. In order to rationalize this differing behavior, we report DFT studies at PCM-B3LYP/6-31++G ∗∗ level of theory (the results were additionally confirmed with 6-311++G ∗∗ and aug-cc-pVDZ basis sets). The energy barrier to inversion of configuration of the anionic reaction intermediate 11 of acid 2 is 10.23 kcal/mol. However, we find that the anionic intermediate 10 from acid 6 would rather undergo β-elimination instead of inversion of configuration. Thus the planar transition state required for inversion of configuration is never reached, regardless of the rate of proton transfer to the anion.

3H-1-Benzazepines are prepared in one step from the reaction of 2-fluoro- or 2-chloroaniline and several aryl vinyl ketones. Enones 9a-c gave benzazepines 11a-c as expected, showing that alkyl substitution at C4 and C5 in the benzazepines is possible. However, enone 9d underwent decomposition due to conjugate addition of the 2-fluoroaniline, while enone 10 gave unsaturated imine 12 as the only product able to be isolated. The failure of unsaturated imine 12 to undergo cyclization may indicate that placement of an alkyl group at C3 of the benzazepines may not be possible. Isolation of by-products buttressed by a computational study verifies a postulated multi-step process for benzazepine formation: a [1,5] sigmatropic shift in fluoroimine 3, addition elimination to give carbocation 15, formation of the unstable 5H-1-benzazepine 7, and acid-catalyzed isomerization to give the stable 3H-1-benzazepine 2. The calculations also indicate why unsaturated imine 12 fails to cyclize. NMR spectroscopic experiments show that the 3H-benzazepines undergo fast conformational exchange on the NMR time scale at room temperature except when there is an alkyl substituent at C5.

Deprotonation of benzazepine (I) followed by reaction with alkyl halides or tosylates give either products of alkylation at C3 or at the nitrogen as well as mixtures of both types of products.

New and recent work by the author and colleagues will be presented. Six methods for functionalizing halogenated ethers will be presented: (1) a new regent for halogen-exchange fluorination of chloromethyl ethers, (2) a selective photochemical or thermal reduction of poly-chlorinated substrates, (3) new organic sources of fluoride for antimony-pentachloride-catalyzed halogen-exchange fluorination, (4) a chemoselective methanolysis reaction of the trifluoromethyl group, (5) a stereoselective decarboxylation reaction, and (6) the use of bromine trifluoride for fluorination with inversion of configuration. The reactions are applied to the synthesis of individual enantiomers of fluoroether anesthetics.

Diisopropylethylamine mono(hydrogen fluoride) ( 8 ), which can be prepared by addition of two equivalents of diisopropylethylamine to the complex diisopropylethylamine tris(hydrogen fluoride) ( 7 ), is shown to be an effective and selective nucleophilic fluorinating reagent when applied to halogen-exchange reactions of chloromethyl ethers, in particular the conversion of 1,1,1,3,3,3-hexafluoroisopropyl chloromethyl ether ( 3 ) to the volatile anesthetic sevoflurane (1,1,1,3,3,3-hexafluoroisopropyl fluoromethyl ether). The amine portion of the reagent does not react with the starting material to give a troublesome quaternary ammonium salt, as is the case for the species formed by addition of two equivalents of triethylamine to triethylamine tris(hydrogen fluoride). These particular chloromethyl ether substrates require a 1:1 stoichiometry of diisopropylethylamine to hydrogen fluoride to give useful rates of reaction and yields when solventless conditions are desired. Two other complexes, diisopropylethylamine bis(hydrogen fluoride) and 7 , are ineffective for conversion of 3 to sevoflurane.

Allysine ethylene acetal [(S)-2-amino-5-(1,3-dioxolan-2-yl)-pentanoic acid (2)] was prepared from the corresponding keto acid by reductive amination using phenylalanine dehydrogenase (PDH) from Thermoactinomyces intermedius ATCC 33205. Glutamate, alanine, and leucine dehydrogenases, and PDH from Sporosarcina species (listed in order of increasing effectiveness) also gave the desired amino acid but were less effective. The reaction requires ammonia and NADH. NAD produced during the reaction was recyled to NADH by the oxidation of formate to CO(2) using formate dehydrogenase (FDH). PDH was produced by growth of T. intermedius ATCC 33205 or by growth of recombinant Escherichia coli or Pichia pastoris expressing the Thermoactinomyces enzyme. Using heat-dried T. intermedius as a source of PDH and heat-dried Candida boidinii SC13822 as a source of FDH,98%, but production of T. intermedius could not be scaled up. Using heat-dried recombinant E. coli as a source of PDH and heat-dried Candida boidinii 98%. In a third generation process, heat-dried methanol-grown P. pastoris expressing endogenous FDH and recombinant Thermoactinomyces98% ee.

Vibrational absorption and circular dichroism spectra of (−)-1,2,2,2-tetrafluoroethyl methyl ether have been measured in CCl4 solution in the 2000–900 cm−1 region. These spectra are compared with the ab initio predictions of absorption and VCD spectra obtained with density functional theory using B3LYP/6-31G* and B3PW91/6-311G(2d) basis sets for different conformers of (R)-1,2,2,2-tetrafluoroethyl methyl ether. The results suggest that the trans-conformer of 1,2,2,2-tetrafluoroethyl methyl ether is predominant in the solution phase and that the (−)-enantiomer has the R-configuration.

Treatment of 2-fluoroaniline and some derivatives with aryl methyl ketones under acid catalysis gives the title compounds.

Fluoromethyl 2,2,2-trifluoro-1-(trifluoromethyl)ethyl ether (sevoflurane), fluoromethyl 1,1,2,3,3,3-hexafluoropropyl ether, and fluoromethyl 1,2,2,2-tetrafluoroethyl ether are found to be selective fluoride donors in some halogen-exchange reactions. For example, treatment of a mixture of a polychlorinated substrate and one equivalent of sevoflurane with a catalytic amount of antimony pentachloride gives a monofluorinated product and one equivalent of chloromethyl 2,2,2-trifluoro-1-(trifluoromethyl)ethyl ether as by-product.

Certain 2-aryl-3H-1-benzazepines are conformationally mobile on the NMR time scale. Variable-temperature NMR experiments bolstered by calculations indicate that alkylation of the azepine ring will slow the interconversion of conformational enantiomers markedly. DFT studies show that, while the substitution patterns of the aryl groups at C2 and C4 do not exert large effects on the rate of enantiomerization, alkylation at C5 slows it appreciably. Alkylation at C3 slows enantiomerization even more, possibly to the extent that isolation of atropisomers might be attempted.

Treatment of 1,1-dichloro-2,2,2-trifluoroethyl difluoromethyl ether (3) with 2-propanol followed by either irradiation with UV light or heating with radical initiators gives the inhalational anesthetic isoflurane. Unlike most other common dechlorination methods, monoreduction is the exclusive process and the by-products acetone and HCl are relatively benign. Some comments about the mechanism of the reduction will be presented, along with solutions to problems encountered during scale-up.

Eighteen chiral analogues of the chiral fluoroether anesthetics desflurane, isoflurane, and enflurane are synthesized and studied by capillary GC on four cyclodextrin-derived stationary phases. Trends in separability and elution order of enantiomers are related to structure and absolute configuration. In particular, a very large separation factor is found for the commercial anesthetic desflurane using Lipodex® E stationary phase, suggesting that a preparative enantiomer separation is possible. One of the stationary phases, Cyclodex® G-TA, is found to be a chiral shift reagent for several of the fluoroethers. A rough correspondence is found relating the enantiomeric separation factor of a fluoroether and the chemical shift differences between its 1 H and 19 F nuclei in the NMR spectrum. Based on this data, it is proposed that a simple NMR experiment can screen chiral stationary phases prior to a desired gas chromatographic enantiomer separation of a given chiral compound.

Acyl-substituted succinates are useful starting materials for the synthesis of cyclobutyl ketones. The key step, reductive cyclization of the intermediate dihalide, afforded yields of 32–60% of cyclobutyl-containing products.

1-Methoxytetrafluoropropionic acid (2) is resolved by diastereomeric amide formation with (S)-(-)-1-phenethylamine/chromatography/hydrolysis. Both enantiomers are obtained in ≥99% ee. Conversion of each enantiomeric acid to its potassium salt followed by thermolysis in triethylene glycol/1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU) gives the enantiomers of 1,2,2,2-tetrafluoroethyl methyl ether (1) with a very high degree of stereospecificity. The use of DMPU as co-solvent results in a significant yield improvement.

1-Methoxytetrafluoropropionic acid (2) is resolved by diastereomeric amide formation with (S)-(-)-1-phenethylamine/chromatography/hydrolysis. Both enantiomers are obtained in ≥99% ee. Conversion of each enantiomeric acid to its potassium salt followed by thermolysis in triethylene glycol/1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU) gives the enantiomers of 1,2,2,2-tetrafluoroethyl methyl ether (1) with a very high degree of stereospecificity. The use of DMPU as co-solvent results in a significant yield improvement.

Fluoromethyl 2,2,2-trifluoro-1-(trifluoromethyl)ethyl ether (sevoflurane), fluoromethyl 1,1,2,3,3,3-hexafluoropropyl ether, and fluoromethyl 1,2,2,2-tetrafluoroethyl ether are found to be selective fluoride donors in some halogen-exchange reactions. For example, treatment of a mixture of a polychlorinated substrate and one equivalent of sevoflurane with a catalytic amount of antimony pentachloride gives a monofluorinated product and one equivalent of chloromethyl 2,2,2-trifluoro-1-(trifluoromethyl)ethyl ether as by-product.

1,1-Difluoroethyl methyl ethers such as the commercial veterinary anesthetic methoxyflurane (2,2-dichoro-1,1-difluoroethyl methyl ether, 6 ) decompose in the presence of a catalytic amount of antimony pentachloride. The rate of decomposition is dependent upon the number and position of halogen atoms in the ether: a high degree of halogenation at the methyl group or at the 2-position of the ethyl group makes the ether less prone to decomposition. The decomposition products are acid fluorides and halogenated methanes. The fate of the antimony pentachloride is conversion to a fluorochloroantimony species which can be used in situ to selectively fluorinate a polychlorinated substrate. Thus, 1,2,2,2-tetrachloro-1-fluoroethyl methyl ether ( 1 ) is converted cleanly to the anesthetic compound 2,2,2-trichloro-1,1-difluoroethyl methyl ether ( 2 ) using 6 as the fluoride source, exploiting the difference in stability of 2 and 6 to the pentavalent antimony species. It is also demonstrated that the acid fluorides obtained from decomposition of the 1,1-difluoroethyl methyl ethers are fluoride sources for halex reactions.

Diisopropylethylamine mono(hydrogen fluoride) ( 8 ), which can be prepared by addition of two equivalents of diisopropylethylamine to the complex diisopropylethylamine tris(hydrogen fluoride) ( 7 ), is shown to be an effective and selective nucleophilic fluorinating reagent when applied to halogen-exchange reactions of chloromethyl ethers, in particular the conversion of 1,1,1,3,3,3-hexafluoroisopropyl chloromethyl ether ( 3 ) to the volatile anesthetic sevoflurane (1,1,1,3,3,3-hexafluoroisopropyl fluoromethyl ether). The amine portion of the reagent does not react with the starting material to give a troublesome quaternary ammonium salt, as is the case for the species formed by addition of two equivalents of triethylamine to triethylamine tris(hydrogen fluoride). These particular chloromethyl ether substrates require a 1:1 stoichiometry of diisopropylethylamine to hydrogen fluoride to give useful rates of reaction and yields when solventless conditions are desired. Two other complexes, diisopropylethylamine bis(hydrogen fluoride) and 7 , are ineffective for conversion of 3 to sevoflurane.

Treatment of 2-fluoroaniline and some derivatives with aryl methyl ketones under acid catalysis gives the title compounds.

(+/−)-[151-67-7] C2HF3BrCl (MW 197.37) InChI = 1S/C2HBrClF3/c3-1(4)2(5,6)7/h1H InChIKey = BCQZXOMGPXTTIC-UHFFFAOYSA-N (R)-[51230-17-2] InChI = 1S/C2HBrClF3/c3-1(4)2(5,6)7/h1H/t1-/m0/s1 InChIKey = BCQZXOMGPXTTIC-SFOWXEAESA-N (S)-[51239-18-3] InChI = 1S/C2HBrClF3/c3-1(4)2(5,6)7/h1H/t1-/m1/s1 InChIKey = BCQZXOMGPXTTIC-PVQJCKRUSA-N Physical Data: bp 50 °C, d 1.872 g cm−3. Solubility: slightly soluble in water, soluble in most organic solvents. Form Supplied in: colorless liquid. Preparative Methods: (+/−)-halothane is commercially available; preparation of its enantiomers has been described.1, 2 Handling, Storage, and Precautions: severe eye irritant. May act as a carcinogen or mutagen. May cause reproductive damage. Experimental teratogen. Harmful if inhaled. May be harmful in contact with the skin or if swallowed. Narcotic. Ceiling limit 2 ppm. Stable, but may be light sensitive. Incompatible with rubber, plastics, strong oxidizing agents. Noncombustible. May be stabilized with 0.01% thymol.

The first enantioselective synthesis of the commercial volatile anesthetic desflurane is reported. Treatment of ( R )-(−)-isoflurane with BrF 3 gives ( S )-(+)-desflurane with >96% inversion of configuration. This constitutes a correction of previously reported results.

A new synthesis of non-racemic halothane (1-bromo-1-chloro-2,2,2-trifluoroethane) is reported. The stereospecificity of the key reaction, decarboxylation of a salt of optically enriched 1-bromo-1-chloro-2,2,2-trifluoropropionic acid to give halothane, is shown to be highly dependent on the nature of the cation. When the cation is trialkylammonium, a high level of stereospecificity is observed. © 1996 Wiley-Liss, Inc.

The trifluoromethyl group of certain compounds containing one or two trifluoromethyl groups can be converted to the carbomethoxy group by treatment with sodium methoxide followed by aqueous acidic work-up. α-Trifluoromethyl esters can be obtained by selective methanolysis of the 1,1,1,3,3,3-hexafluoroisopropyl group in some cases. The structural requirements for the transformation are delineated, and a mechanistic study confirms the proposed mechanism, a dehydrofluorination–addition–elimination process.

A brief synthesis of (±)-hirsutene demonstrates the novel use of tris(phenylthio)methane as a dilithiomethane equivalent capable of consecutive conjugate additions to different enones to form a dienolate which can be oxidized to a cyclopentane