Bortrifluorid-katalysierte Umsetzungen von 3-Amino-2H-azirinen mit Aminosäure-estern und Aminen

Boron-Trifluoride-Catalyzed Reactions of 3-Amino-2H-azirines with Amino-acid Esters and Amines After activation by protonation or complexation with BF₃, 3-amino-2H-azirines 1 react with the amino group of α-amino-acid esters 3 to give 3,6-dihydro-5-aminopyrazin-2(1H)-ones 4 by ring enlargement (Scheme 2, Table 1). The configuration of 3 is retained in the products 4 . With unsymmetrically substituted 1 (R¹ ≠ R²), two diastereoisomers of 4 (cis and trans) are formed in a ratio of 1:1 to 2:1. With β-amino-acid esters 5 and 7 , only openchain α-amino-imidamides 6 and 8 , respectively, are formed, but none of the seven-membered heterocycle (Scheme 3). Primary amines also react with BF₃-complexed 1 to yield α-amino-imidamides of type 9 (Scheme 4, Table 2). Compound 9b is characterized chemically by its transformation into crystalline derivatives 10 and 12 with 4-nitrobenzoyl chloride and phenyl isothiocyanate, respectively (Scheme 5). The structure of 12 is established by X-ray crystallography. Mechanisms for the reaction of activated 1 with amino groups are proposed in Schemes 6 and 7.     

Umsetzung von 3-Amino-2H-azirinen mit Salicylohydrazid

Reaction of 3-Amino-2H-azirines with Salicylohydrazide 3-Amino-2H-azirines 1a–g react with salicylohydrazide ( 7 ) in MeCN at 80° to give 2H, 5H-1,2,4-triazines 10 , 1,3,4-oxadiazoles 12 and, in the case of 1d , 1,2,4-triazin-6-one 11a (Scheme 3). The precursor of these heterocycles, the amidrazone of type 9 , except for 9c and 9g , which could not be isolated, has been found as the main product after reaction of 1 and 7 in MeCN at room temperature. 3-(N-Methyl-N-phenylamino)-2-phenyl-2H-azirin ( 1g ) reacts with 7 to give mainly the aromatic triazines 15b₁ and 15b₂ . In this case, two unexpected by-products, 16 and salicylamide ( 17 ), occurred, probably by disproportionation of a 1:1 adduct from 1g and 7 (Scheme 8). Oxidation of 10f with DDQ leads to the triazine 15a . The structure of 10c, 11a, 12c, 13 (by-product in the reaction of 1b and 7 ), the N′-phenylureido derivative 14 of 9d (Scheme 4) as well as 15b₂ has been established by X-ray crystallography. The ratio of 10/12 as a function of substitution pattern in 1 and solvent has been investigated (Tables 1, 3, 4, and 7). A mechanism for the formation of 10 and 12 is proposed in Scheme 7.     

4,4-Disubstituierte Imidazol-Derivate aus der Umsetzung von 3-Amino-2H-azirinen mit Salicylamid

4,4-Disubstituted Imidazole Derivatives from the Reaction of 3-Amino-2H-azirines with Salicylamide Reaction of 3-amino-2H-azirines 1a–c with salicylamide ( 7 ) in MeCN leads to imidazoles 10 and 11 in different rates, depending on the conditions. In the case of 1a and 1b, 11a and 11b , respectively, have been obtained as the main product at 50°; in reactions at 80°, 10a and 10b are the favored products (Tables 1 and 2). 2,2-Dimethyl-3-(N-methyl-N-phenylamino)-2H-azirine ( 1c ) reacts with 7 in MeCN mainly to 2-(2-hydroxyphenyl)-5,5-dimethyl-3,5-dihydroimidazol-4-one ( 10a ); in boiling toluene, 11c is formed with low preference (Table 3). The structure of the products has been established by spectroscopic means, and in the case of 10b and 11c , by X-ray crystallography. Two different reaction mechanisms for the formation of the products are discussed (Scheme 2).     

Reaktion von 3-Amino-2H-azirinen mit Diphenylcyclopropenthion. Vorläufige Mitteilung

Reaction of 3-Amino-2H-azirines with Diphenylcyclopropenethione 3-Dimethylamino-2H-azirines ( 4a , 4b ) react with diphenylcyclopropenethione ( 8 ) to give 4(3 H)-pyridinethione derivatives of type 10 (Scheme 3). The reaction mechanism for the formation of 10 is given in Scheme 3 by analogy with a previous reported one [4] [5]. Hydrolysis of the 4(3 H)-pyridinethione 10a yields 2-oxo-2, 3-dihydro-4(1 H)-pyridinethione ( 11 ) and reduction of 10a with sodium borohydride leads to the 2, 3-dihydro-4 (1 H)-pyridinethione 12 (Scheme 4). The results of the reaction of 4a , 4b and the thione 8 demonstrate the similarity to the reaction of 4a , 4b and 2 [5] (cf. Scheme 1). In contrast, the reactions of imines of type 7a with 2 and 8 , respectively, lead to different products (cf. [1] [6]).     

Umsetzungen von 3-(Dimethylamino)-2,2-dimethyl-2H-azirin mit Barbitursäure-Derivaten

Reactions of 3-(Dimethylamino)-2,2-dimethyl-2H-azirines with Barbituric-Acid Derivatives The reaction of 3-(dimethylamino)-2,2-dimethyl-2H-azirine ( 1 ) and 5,5-disubstituted barbituric acids 5 in i-PrOH at ca. 70° gives 2-[5-(dimethylamino)-4,4-dimethyl-4H-imidazol-2-yl]alkanamides of type 6 in good yields (Scheme 1). The formation of 6 proceeds with loss of CO₂; various reaction mechanisms with a zwitterionic 1:1 adduct B as common intermediate are discussed (Schemes 2 and 5). Thermolysis of product 6 leads to 2-alkyl-5-(dimethylamino)-4,4-dimethyl-4H-imidazoles 8 or the tautomeric 2-alkylidene derivatives 8 ′ via elimination of HNCO (Scheme 3). The latter undergoes trimerization to give 1,3,5-triazine-2,4,6-trione. No reaction is observed with 1,5,5-trisubstituted barbiturates and 1 in refluxing i-PrOH, but an N-alkylation of the barbiturate occurs in the presence of morpholine (Scheme 4). This astonishing reaction is explained by a mechanism via formation of the 2-alkoxy-2-(dimethylamino )aziridinium ion H which undergoes ring opening to give the O-alkylated 2-amino-N¹,N¹-dimethylisobutyramide I as alkylating reagent (Scheme 4).     

Bortrifluorid-katalysierte Umsetzung von 3-Amino-2H-azirinen mit Amiden: Bildung von 4,4-disubstituierten 4H-Imidazolen

Boron Trifluoride Catalyzed Reaction of 3-Amino-2H-azirines and Amides: Formation of 4,4-Disubstituted 4H-Imidazoles Reaction of trifluoroacetamide and 3-amino-2H-azirines 1 in refluxing MeCN affords 4-amino-2-(trifluoromethyl)-4H-imidazoles 5 in fair yields (Scheme 3). Less acidic amides do not react with 1 under similar conditions. Therefore, a procedure involving BF₃-catalysis has been elaborated: the aminoazirine 1 in CH₂Cl₂ at ?78° is treated with BF₃ · Et₂O and then with a solution of the sodium salt of an amide in THF, prepared by addition of sodium hexamethyldisilazane at ?78°. The 4H-imidazoles of type 5 are formed in ca. 50% yield (Scheme 4). Reaction mechanisms for this ring enlargement of 1 are proposed in Schemes 5 and 6.     

Photoinduzierte Reaktionen von 3-Phenyl-2H-azirinen mit Carbonsäureestern 40. Mitteilung über Photoreaktionen

Irradiation (280–350 nm light) of a benzene solution of 3-phenyl-2H-azirines 1a – e in the presence of carboxylate esters, whose carbonyl groups are activated by electron withdrawing groups situated in the acyl or alkyl moiety, produces 5-alkoxy-3-oxazolines (Tab. 1 and 4, Scheme 2) isolated in 18–82% yield. These heterocycles undoubtedly originate by regiospecific addition of the ester carbonyl group to the azirine-derived benzonitrile-methylide ‘dipole’ (Scheme 1). The 5-(2,′ 2′, 2′-trifluoroethoxy)-3-oxazolines, derived from 2′, 2′, 2′-trifluoroethyl carboxylic esters, on treatment with methanolic hydrogen chloride at low concentration, are smoothly transformed into the corresponding 5-methoxy-3-oxazolines (e.g. 16 → 17 , Tab. 5). Utilizing this process, various hitherto relatively unknown 9. 5-alkoxy-3-oxazolines become accessible. The constitution of the adducts is based essentially on spectral data. The structure of trans-5-methoxy-2,4-diphenyl-5-trifluoromethyl-3-oxazoline (trans- 14 ), the addition product of methyl trifluoroacetate and the benzonitrile-benzylide from 2,3-diphenyl-2H-azirine ( 1d ), was determined by X-ray crystallography (Section 5). Benzonitrile-isopropylide ( 22 ), resulting from the photochemical transformation of 2,2-dimethyl-3-phenyl-2H-azirine ( 1a ), also reacts with S-methyl thiobenzoate to give 2,2-dimethyl-5-methylthio-4,5-diphenyl-3-oxazoline ( 26 ). Ethyl cyanoacetate protonates predominantly the dipolar species derived from 1a at the nitrile C-atom and yields after work-up ethyl α-cyano-cinnamate ( 29 ) and ethyl isopropylidene-cyanoacetate ( 30 ) (Scheme 4). The relative rate of addition (k_rel) of benzonitrile-isopropylide ( 22 ) to methyl α-haloacetates and dimethyl oxalate was determined by competition experiments (Section 6). Log k_rel correlated satisfactorily (r = 0.97) with the pK_a of the acide derived from the ester reactant: log k_rel = ? 1.72 pK_a + 2.58 or with Taft's substituent constants σ*: log k_rel = 2.06 σ* ? 4.11 [k_rel(methyl dichloroacetate) = 1; Section 7.1]. On the basis of the results obtained, the mode of reaction of the so-called benzonitrile-methylide ‘dipole’ is discussed and a model for the transition state of addition of ester-carbonyl groups is proposed that accounts for the observed regiospecifity and steroselectivity.     

Photochemisch induzierte Reaktionen von 3-Amino-2H-azirinen

Photochemically Induced Reactions of 3-Amino-2H-azirines Irradiation of 3-(N-methylanilino)-2H-azirines with a mercury low pressure lamp induces the cleavage of the C(2), C(3)-ring bond thus affording nitrilio-methanide dipols, substituted by an amino group at C(1). Depending on the substitution pattern at C(3), these intermediates can be trapped by dipolarophiles to yield five-membered heterocycles with high regioselectivity, or they undergo a 1,4-H-shift forming 2-azabutadiene derivatives. Further, the dipol is protonated at C(1) even by weak CH–acids.     

5,6,7,8-Tetrahydro-4H-1,2,5-oxadiazocin-6-one durch Ringerweiterung nach Addition eines 3-Isoxazolidinons mit 3-Amino-2H-azirinen

5,6,7,8-Tetrahydro-4H-1,2,5-oxadiazocin-6-ones, Ring Enlargement Products from a 3-Isoxazolidinone and 3-Amino-2H-azirines 3-Dimethylamino-2H-azirines 1 and 4,4-dimethyl-3-isoxazolidinone ( 7 ) undergo already at room temperature a ring enlargement reaction to yield 5,6,7,8-tetrahydro-4H-1,2,5-oxadiazocines of type 8 . The structure of 8a has been confirmed by X-ray crystallography. The conformation of the eight-membered ring with a trans-amide group is of particular interest (Fig. 1 and 2).     

Uncatalyzed synthesis of 3-amino-1,5-dihydro-2H-pyrrol-2-ones

Uncatalyzed one-pot pseudo-four-component reaction of ethyl pyruvate, anilines, and aldehydes in n-hexane as solvent, under reflux, affords a variety of 3-amino-1,5-dihydro-2H-pyrrol-2-ones in high yield. n-Hexane is an excellent driving force in preparation of the desired products. These compounds have biological and pharmacological properties and are also used in medicinal chemistry. Use of a non-toxic and inexpensive solvent, simple and efficient synthesis, clean work-up, and high yields of the products are the advantages of this method. We report the first catalyst-free method for synthesis this class of compounds.     

Amination of 5-Spiro-Substituted 3-Hydroxy-1,5-dihydro-2H-pyrrol-2-ones

The 3-hydroxy-1,5-dihydro-2H-pyrrol-2-one motif is a valuable scaffold in drug discovery. The replacement of the 3-oxy fragment in 3-hydroxy-1,5-dihydro-2H-pyrrol-2-ones-based compounds with a 3-amino one (3-amino analogs of 3-hydroxy-1,5-dihydro-2H-pyrrol-2-ones, 3-amino-1,5-dihydro-2H-pyrrol-2-ones) can play a crucial role in their biological effect. Thus, approaches to 3-amino-1,5-dihydro-2H-pyrrol-2-ones are of significant interest. We developed an approach to 5-spiro-substituted 3-amino-1,5-dihydro-2H-pyrrol-2-ones that could not be obtained using previously reported approaches (reactions of 3-hydroxy-1,5-dihydro-2H-pyrrol-2-ones with amines). The developed approach is based on the thermal decomposition of 1,3-disubstituted urea derivatives of 5-spiro-substituted 3-hydroxy-1,5-dihydro-2H-pyrrol-2-ones, which were prepared via their reaction with carbodiimides.     

Photochemische Cycloadditionen von 3-Phenyl-2H-azirinen an Carbonsäurechloride. 35. Mitteilung über Photoreaktionen

Irradiation of 2, 3-diphenyl-2H-azirine ( 1a ) and 1-azido-1-phenyl-propene, the precursor of 2-methyl-3-phenyl-2H-azirine ( 1b ), in benzene, with a high pressure mercury lamp (pyrex filter) in the presence of acid chlorides yields the oxazoles 5a–d (Scheme 2). Photolysis of 2, 2-dimethyl-3-phenyl-2H-azirine ( 1c ) under the same conditions gives after methanolysis the 5-methoxy-2, 2-dimethyl-4-phenyl-3-oxazolines 7a, b, d , while hydrolysis of the reaction mixture leads to the formation of the 1, 2-diketones 8a, c, d (Scheme 4). The suggested reaction path for all these reactions is a 1, 3-dipolar cycloaddition of the photochemically generated benzonitrilemethylides 2 to the carbonyl double bond of the acid chlorides to give the intermediates 4 , followed by either elimination of hydrogen chloride or solvolysis (Schemes 2 and 4). Irradiation of 1c in the presence of acetic acid anhydride leads via the intermediate 9 to the 5-hydroxy-3-oxazoline 10 and the 5-methylidene-3-oxazoline 11 (Scheme 5).     

Synthese de 4-Amino-3-dialkylaminomethyl-2,3-dihydro-1,5-benzothiazepines

Reaction of 2-aminothiophenol with 2-dialkylaminomethylpropenenitriles leads to the corresponding benzothiazepines with a good yield. Mechanism is discussed and determined by isolating some intermediates.     

Photochemische Cycloadditionen von 3-Phenyl-2H-azirinen mit aktivierten Doppelbindungen. Vorläufige Mitteilung

Irradiation of 2-methyl- ( 1a ), 2,2-dimethyl- ( 1b ) and 2,3-diphenyl-2H-azirine ( 1c ) in the presence of diethyl mesoxalate yields the corresponding 4-phenyl-5,5-diethoxycarbonyl-3- oxazolines 3a–c . Similar cycloadducts are observed (cf. 6 ) by irradiation of 1b and 1c in the presence of trifluoroacetophenone. When ethyl cyanoformate is used as trapping agent photolysis of 1b or 1c leads to cycloadducts with the carbonyl and nitrile group, respectively which are present in the cyanoformate.     

Dipolare (1:1)-Addukte aus der Reaktion von 3-Amino-2H-azirinen mit 1,3,4-Oxadiazol- und 1,3,4-Thiadiazol-2(3H)-onen

Dipolar 1:1 Adducts from the Reaction of 3-Amino-2H-azirines with 1,3,4-Oxadiazol- and 1,3,4-Thiadiazol-2(3H)-ones 3-Amino-2H-azirines 1 react with 5-(trifluoromethyl)-1,3,4-oxadiazol-2(3H)-one ( 2 ) as well as with different 5-substituted 1,3,4-thiadiazol-2(3H)-ones ( 5a–e ) in 2-propanol at room temperature to give dipolar 1:1 adducts of type 3 and 6 , respectively, in reasonable-to-good yields (Schemes 3 and 6, Tab. 1 and 2). The structure of two of these dipolar adducts, 6a and 6e , which are formally donor-acceptor-stabilized azomethin imines, have been elucidated by X-ray crystallography (Figs. 1-4). In the reaction of 2 and sterically crowded 3-amino-2H-azirines 1c–e with a 2-propyl and 2-propenyl substituent, respectively, at C(2), a 4,5-dihydro-1,2,4-triazin-3(2H)-one of type 4 is formed as minor product (Scheme 3 and Table 1). Independent syntheses of these products proved the structure of 4 . Several reaction mechanisms for the formation of compounds 3 and 4 are discussed, the most likely ones are described in Scheme 4: reaction of 2 as an NH-acidic compound leads, via a bicyclic zwitterion of type A , to 3 as well as to 4 . In the latter reaction, a ring-expanded intermediate B is most probable.     

Photochemische Cycloadditionen von 3-Phenyl-2H-azirinen mit kumulierten Doppelbindungen. Vorläufige Mitteilung

Irradiation of 2-methyl- ( 1c ) and 2,2-dimethyl-3-phenyl-2H-azirine ( 1d ) in benzene solution in the presence of carbon dioxide yields 2-methyl-4-phenyl- ( 3c ) and 2,2-dimethyl-4-phenyl-3-oxazolin-5-one ( 3d ), respectively. Similar cycloadducts are observed (see table) when 2,3-diphenyl-2H-azirine ( 1b ) and 1d are irradiated in the presence of phenylisocyanate, o-tolylisocyanate, phenylisothiocyanate or di-o-tolyl-carbodiimide.     

Ringerweiterungen und Ringverengungen bei der Umsetzung von 1, 3-Oxazolidin-2, 4-dionen und 1, 3-Thiazoiidin-2, 4-dion mit 3-Amino-2H-azirinen

Ring Enlargements and Ring Contractions in the Reaction of 1, 3-Oxazolidine-2, 4-diones and l, 3-Thiazolidine-2, 4-dione with 3-Amino-2H-azirines The reaction of 3-amino-2H-azirines 1 and 1, 3-oxazolidine-2, 4-diones 2 in MeCN at room temperature leads to 3, 4-dihydro-3-(2-hydroxyacetyl)-2H-imidazol-2-ones 3 in good yield (Scheme 2, Table 1). A reaction mechanism proceeding via ring enlargement of the bicyclic zwitterion A to give B, followed by transannular ring contraction to C, is proposed for the formation of 3 . This mechanism is in accordance with the result of the reaction of 2a and the ¹⁵N-labelled 1a *: in the isolated product 3a *, only N(3) is labelled (Scheme 1). The analogous reaction of 1 and 1, 3-thiazolidine-2, 4-dione ( 5 ) is more complex (Schemes 4 and 5, Table 2). Besides the expected 3, 4-dihydro-3-(2-mercaptoacetyl)-2H-imidazol-2-ones 7, 5-amino-3, 4-dihydro-2H-imidazol-2-ones of type 8 and/or N-(1, 4-thiazin-2-ylidene)ureas 9 are formed. In the case of 2-(dimethylamino)-1-azaspiro[2. 3]hex-1-ene ( 1d ), the postulated eight-membered intermediate 6d could be isolated. Its structure as well as that of 9f has been determined by X-ray structure analysis. A reaction mechanism for the formation of the 1, 4-thiazine derivatives of type 9 is proposed in Scheme 6.     

Darstellung von 3-Amino-4-nitro-5-methylisoxazol aus 3-Amino-5-methylisoxazol

Zusammenfassung 3-Amino-5-methylisoxazol wird mit Bernsteinsäureanhydrid in 3-Succinimido-5-methylisoxazol übergeführt, welches sich mit Oleum und rauch. HNO₃ nitrieren läßt. Die Abnahme der Schutzgruppe zu 3-Amino-4-nitro-5-methylisoxazol erfolgt mit alkohol. HCl.

---

Preparation of 3-amino-4-nitro-5-methylisoxazole from 3-amino-5-methylisoxazole

3-Amino-5-methylisoxazole is converted to 3-succinimido-5-methylisoxazole with succinic anhydride. The product can be nitrated with oleum and fuming HNO₃. Removal of the protective group yielding 3-amino-4-nitro-5-methylisoxazole is effected with alcoholic HCl.