Die «Zip»-Reaktion: Eine neue Ringerweiterungsreaktion. Synthese von 17-, 21- und 25-gliedrigen Polyaminolactamen. 4. Mitteilung über Umamidierungsreaktionen

The Zip-reaction: A New Method for the Synthesis of Macrocyclic Polyaminolactams The 21- and 25-membered aminolactams 11 and 25 were synthesized from the 13-membered lactam 4 . To introduce the ring enlargement unit (a propylamino group) 4 was N-alkylated using acrylonitrile and the resulting product hydrogenated. Repetition of this reaction sequence gave 3 , which was converted in the presence of base in 90% yield to the ring-enlarged macrocyclic base 11 (Scheme 2). In a similar but stepwise synthesis consisting of two separate ring-enlargement reactions 4 was transformed to 11 via 13 (Scheme 4). Introducing three ringenlargement units into 4 the 25-membered aminolactam 25 was synthesized in 84% yield (Scheme 5). The mechanism of the ring-enlargement reaction is given in Scheme 3. In comparison to a zip-fastener or zipper this reaction is called “zipreaction”.     

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]).     

4-Amino-1,5-dihydro-2H-pyrrol-2-one aus Bortrifluorid-katalysierten Umsetzungen von 3-Amino-2H-azirinen mit Carbonsäure-Derivaten

4-Amino-1,5-dihydro-2H-pyrrol-2-ones from Boron Trifluoride Catalyzed Reactions of 3-Amino-2H-azirines with Carboxylic Acid Derivatives Reaction of 3-amino-2H-azirines 1 with ethyl 2-nitroacetate ( 6a ) in refluxing MeCN affords 4-amino-1,5-dihydro-2H-pyrrol-2-ones 7 and 3,6-diamino-2,5-dihydropyrazines 8 , the dimerization product of 1 (Scheme 2). Thus, 6a reacts with 1 as a CH-acidic compound by C? C bond formation via C-nucleophilic attack of deprotonated 6a onto the amidinium-C-atom of protonated 1 (Scheme 5). The scope of this reaction seems to be rather limited as 1 and 2-substituted 2-nitroacetates do not give any products besides the azirine dimer 8 (see Table 1). Sodium enolates of carboxylic esters and carboxamides 11 react with 1 under BF₃ catalysis to give 4-amino-1,5-dihydro-2H-pyrrol-2-ones 12 in 50–80% yield (Scheme 3, Table 2). In an analogous reaction, 3-amino-2H-pyrrole 13 is formed from 1c and the Li-enolate of acetophenone (Scheme 4). A reaction mechanism for the ring enlargement of 1 involving BF₃ catalysis is proposed in Scheme 6.     

Synthesen des Analgetikums 2-[1-(m-Methoxyphenyl)-2-cyclohexen-1-yl]-N,N -dimethyl-äthylamin

Syntheses of the Analgesic 2-[1-(m-Methoxyphenyl)-2-cyclohexen-1-yl] -N,N-dimethyl-ethylamine Three principal routes to 2-[1-(m-methoxyphenyl)-2-cyclohexen-1-yl]- N,N-dimethyl-ethylamine (13) , a compound with interesting analgesic properties, are described. In the first, derivatives of [1-(m-methoxyphenyl)-2-cyclohexen-1-yl]acetic acid (10) (alternatively the ethyl ester 29 , the dimethylamide 32 or the nitrile 34 ) serve as crucial intermediates. All three can be synthesized from 2-(m-methoxyphenyl)cyclohexanone (1) by sequences comprising successively C-alkylation ( 1→2,4,5; Scheme 1), reduction of the ketone carbonyl group ( 2→6;4→18;5→19; Scheme 1 and 2) and elimination ( 16→29; 18→32; 19→34; Scheme 2). The relative configuration of the cyclohexanols 16, 18, 19 and of a series of related compounds is established by chemical correlation with the lactone 30 the structure of which follows from ¹H-NMR. data (Scheme 2). The second route creates the intermediates 29 and 32 by ester- or amide-enolate-Claisen-type-rearrangement reactions starting from 3-(m-methoxyphenyl)-2-cyclohexen-1-ol ( 39; Scheme 3). Compounds 29, 32 and 34 are transformed into the target molecule 13 by standard reactions. A Hofmann elimination of the quaternary ammonium fluoride 50 (X=F), derived from the known cis-perhydroindoline 48 , is the essential step in the third approach to 13 (Scheme 4).     

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.     

3-(Dimethylamino)-2,2-dimethyl-2H-azirin als α-Aminoisobuttersäure(Aib)-Äquivalent: Cyclische Depsipeptide durch direkte Amid-Cyclisierung

3-(Dimethylamino)-2,2-dimethyl-2H,-azirine as an α-Aminoisobutyric-Acid (Aib) Equivalent: Cyclic Depsipeptides via Direct Amid Cyclization In MeCN at room temperature, 3-(dimethylamino)-2,2-dimethyl-2H-azirine ( 1 ) and α-hydroxycarboxylic acids react to give diamides of type 8 (Scheme 3). Selective cleavage of the terminal N,N-dimethylcarboxamide group in MeCN/H₂O leads to the corresponding carboxylic acids 13 (Scheme 4). In toluene/Ph SH , phenyl thioesters of type 11 are formed (see also Scheme 5). Starting with diamides 8 , the formation of morpholin-2,5- diones 10 has been achieved either by direct amide cyclization via intermediate 1,3-oxazol-5(4H)-ones 9 or via base-catalyzed cyclization of the phenyl thioesters 11 (Scheme 3). Reaction of carboxylic acids with 1 , followed by selective amide hydrolysis, has been used for the construction of peptides from α-hydroxy carboxylic acids and repetitive α-aminoisobutyric-acid (Aib) units (Scheme 4). Cyclization of 14a, 17a , and 20a with HCI in toluene at 100° gave the 9-, 12-, and 15-membered cyclic depsipeptides 15, 18 , and 21 , respectively.     

Umamidierungsreaktionen an cyclischen Amino-amid-Systemen. 3. Mitteilung über Umamidierungsreaktionen

Transamidation Reactions with Cyclic Amino-amides Lactames which are substituted at the nitrogen atom by a 3-aminopropyl residue are transformed under base catalysis to cyclic amino-amides enlarged by 4 ring atoms. The formed ring must be at minimum 12-membered. Scheme 2 illustrates this result: the 8-membered 7 is transamidated in 96% yield to the 12-membered ring 8 (in the presence of potassium 3-aminopropylamid in 1, 3-propanediamine), the 9-membered 10 to the 13-membered ring 11 (97%) and the 11-membered 14 to the 15-membered ring 15 . Furthermore, the 13-membered ring 27 (Scheme 5) is transformed to the 17-membered 28 . In the case of the 15-membered lactame 15 it is demonstrated that 14 is not formed back under the conditions of the transamidation. Large ring lactames which are substituted at the nitrogen atom by a 3-(alkylamino) propyl group lead under base catalysis to an equilibrium mixture, e.g. the 17-membered 26 is in equilibrium with the 21-membered 29 . This result is similar to the behavior of the corresponding open-chain amino-amides [2]. Because of transannular interactions, the 11-membered ring 2 is not stable: transamidation of the 7-membered 1 (Scheme 1) doesn't give the expected 2 , but its water elimination product 3 in small yield. The N-tosyl derivative of 2 , namely 20 , is synthesized by an independent route (Scheme 3). Detosylation of 20 yields the 7-membered 1 instead of 2 . Concerning the mechanism of this interesting reaction see Scheme 4.     

Struktur des Hydrazinolyseproduktes von N-(3-Oxo-1-isoindolinyliden)-alanin-äthylester

Hydrazinolysis of N-(3-Oxo-1-isoindolinyliden)alanin Ethyl Ester, Structure of the Product Treatment of N-(3-oxo-1-isoindolinyliden)alanin ethyl ester (6) with hydrazine hydrate leads to 4-methyl-2,3,4,6-tetrahydro[1,2,4]triazino[3,4-a]isoindole-3, 6-dione ( 8 , Scheme 3) and not to the previously postulated 6-hydroxy-2-methyl-2,3-dihydro-imidazo [2,1-a]phthalazin-3-one ( 7 , cf. [2]). The structure of 8 has been established by an independent synthesis as well as by the X-ray analysis of the reaction product 11 from 8 and 3-dimethylamino-2,2-dimethyl-2 H-azirine ( 1 , Scheme 4). A reaction mechanism for the formation of 8 from 6 is suggested in Scheme 5.     

The Synthesis of Bicyclic N4-Amino-2′-deoxycytidine Derivatives

Nucleosides which have ambivalent tautomeric properties have value in a variety of nucleic acid hybridization applications, and as mutagenic agents. We describe here synthetic studies directed to stable derivatives of this kind of nucleoside based on N⁴-aminocytosine. Treatment of the 4-(1H-1,2,4-triazol-1-yl)-5-(chloroethyl)pyrimidinone nucleoside derivative 5 with hydrazine leads to formation of the 6,6-bicyclic pyrimido-pyridazin-7-one 3 , and with methylhydrazine to the corresponding fixed tautomeric 1-methyl derivative 7 (Scheme 1). If these cyclization reactions are carried out in the presence of a base, the 6-ring bicyclic derivatives undergo rearrangement to their corresponding 5-ring pyrrolo-pyrimidin-2-one analogues 8 (Scheme 2). In the reaction of the triazolyl derivative 5 with 1-[(benzyloxy)carbonyl]-1-methylhydrazine, spontaneous cyclization gives the 5-ring derivative 13 related to 8 rather than the open-chain product 12 (Scheme 4). Reaction of an acetylated analogue of triazolyl derivative 5 with 1,1-dimethylhydrazine gives rise to some of the open-chain product 9 , but it too cyclizes to a product that we have assigned the structure of the 6,6-ring quaternary ammonium salt 11 (Scheme 3).     

Synthetische Verwendung von Epoxynitronen. I. N-(2,3-Epoxypropyliden)-cyclohexylamin-oxid,ein neues Reagens zur Synthese von α-Methyliden-γ-lactonen aus Olefinen

Synthetic Application of Epoxynitrones I. Nitrone, a New α-Methylidene-γ-lactone Annelating Reagent The N-(2, 3-epoxypropyliden)-cyclohexylamine-N-oxide/CF₃SO₃SiR₃ reagent descried in this communication opens a new and interesting entry to the versatile N-substituted N-propenylnitrosonium ions of type b (Scheme 6). One of the uses of this reagent is shown to be the synthesis of α-methylidene-γ-lactones from olefins. This new method shows similar features as the method based on 2, 3-dichloropropylidenamine-oxide/AgBF₄ originally developed for the same purpose by Petrzilka, Felix and Eschenmoser. Epoxynitrone 18 can be transformed to the positively charged heterodiene of type b (Scheme 5) using the highly electrophilic reagents CF₃SO₃SiMe₃ ( 23 ) and CF₃SO₃Si (t-Bu)Me₂ ( 24 ), respectively. Low temperature ¹H- and ¹³C-NMR. spectroscopy at ?78° showed the sole formation of the nitrone-O-silyl-ethers a (Scheme 5). Epoxid opening leading to the diene b and subsequent reactions are observed only at about ?30°. The diene b prepared in situ, adds to isolated double bonds by way of an inverse Diels-Alder reaction to afford cycloadducts of type 27 (Scheme 7). Their stable cyanoderivatives, e.g. 28 (Scheme 7), can be isolated and transformed via 31 , 44 and 54 into cis annelated α-methylidene-γ-lactones of type 55 (Scheme 11). Using trisubstituted olefins, substitution at the lower substituted olefinic C-atom competes efficiently with the cycloaddition (e.g. 34 , Scheme 8).     

On the formation and reactivity of N(2),N(2′)-tetrasubstituted 2,4-diamino-5-(2-amino-4-thiazolyl)thiazoles

By the reaction of weak bases with N(2)-disubstituted 2-amino-4-thiazoliniminium chlorides 3, easily available by the reaction of thioureas 1 with α-chloroacetonitrile 2, N(2),N(2′)-persubstituted 2,4-diamino-5-(2-amino-4-thiazolyl)thiazoles 8 are formed. These new bis-thiazoles react, as exemplified with the dimorpholino derivative 8a, with different electrophilic reagent, such as phenyl isothiocyanate 9, 4-nitro-phenyldiazonium salt 11, or 4-dialkylaminobenzaldehydes 13 at their 5H-substituted thiazole moieties to give the corresponding thioanilides 10, azo compounds 12, and methine dyes 14, respectively. With sodium nitrite and the Vilsmeier reagent the thiazole 8a is transformed, via unstable intermediates, into the tricyclic 2,7-dimorpholinothiazolo[4,5-c]thiazolo[4,5-e]pyridazine 16 and 2,7-dimorpholinothiazolo[4,5-b]thiazolo[4,5-d]pyridine 19, respectively.     

3-(Dimethylamino)-2,2-dimethyl-2H-azirin als Aib-Äquivalent: Synthese von Aib-Oligopeptiden

3-(Dimethylamino)-2,2-dimethyl-2H-azirine as an Aib Equivalent; Synthesis of Aib Oligopeptides 3-(Dimethylamino)-2,2-dimethyl-2H-azirine ( 1 ) reacts with carboxylic acids at 0–25° to give 2-acylamino-N,N,2-trimethylpropionamides ( = 2-acylamino-N,N-dimethylisobutyramide, acyl-Aib-NMe₂) in excellent yields (Scheme 2 and 3). Examples of α-amino-, α-hydroxy-, and α-mercapto-carboxylic acids are given. On treatment with HCl in toluene, the terminal dimethylamide group is selectively converted to the corresponding carboxylic acid (→acyl-Aib) via an amide cleavage (Scheme 4 and 5); 1,3-oxazol-5(4H)-ones are intermediates of this amide hydrolysis. This reaction sequence has been used for the extension of peptide chains (Scheme 6). The synthesis of Aib-oligopeptides using this methodology is described (Scheme 8).     

From 1-(Silyloxy)Butadiene to 4-Amino-4-Deoxy-DL-Erythrose and to 1-Amino-1-Deoxy-DL-Erythritol Derivatives via Hetero-Diels-Alder Reactions with Acylnitroso Dienophiles

Acylnitroso dienophiles 4 reacted instantly with 1-(silyloxy)butadiene 5α and led in good yield to the regioisomeric cycloadducts 6 (major) and 7 (minor; Scheme 2, Table 1). cis-Hydroxylation of these primary cycloadducts with OsO₄ (catalyst) occurred stereospecifically and in high yield (→ 8 and 9 , resp.; Scheme 2). It was followed by reductive ring cleavage to give either 1-amino-1-deoxy-DL -erythritol or 4-amino-4-deoxy-DL -erythrose derivatives 10 and 14 , respectively, depending on the nature of the reducing agent (Schemes 3 and 4).     

Über die Stereoselektivität der α-Alkylierung von (1R, 2S) (+)-cis-2-hydroxy-cyclohexancarbonsäureäthylester

The Stereoselectivity of the α-Alkylation of (+)-(1R, 2S)-cis-Ethyl-2-hydroxy-cyclohexanecarboxylate In continuation of our work on the stereoselectivity of the α-alkylation of β-hydroxyesters [1] [2], we studied this reaction with the title compound (+)- 2 . The latter was prepared through reduction of 1 with baker's yeast. Alkylation of the dianion of (+)- 2 furnished (?)- 4 in 72% chemical yield (Scheme 1) and with a stereoselectivity of 95%. Analogously, (?)- 7 was prepared with similar yields. Oxidation of (?)- 4 and (?)- 7 respectively furnished the ketones (?)- 6 (Scheme 3) and (?)- 8 (Scheme 4) respectively, each with about 76% enantiomeric excess (NMR.). It is noteworthy that yeast reduction of rac- 6 (Scheme 3) is completely enantioselective with respect to substrate and product and gives optically pure (?)- 4 in 10% yield, which was converted into optically pure (?)- 6 (Scheme 3). The alkylation of the dianionic intermediate shows a higher stereoselectivity (95%) from the pseudoequatorial side than that of 1-acetyl- or 1-cyano-4-t-butyl-cyclohexane (71% and 85%) [9] or that of ethyl 2-methyl-cyclohexanecarboxylate (82%). The stereochemical outcome of the above alkylation is comparable with that found in open chain examples [1] [2]. Finally (+)-(1R, 2S)- 2 was also alkylated with Wichterle's reagent to give (?)-(1S, 2S)- 9 in 64% yield. The latter was transformed into (?)-(S)- 10 and further into (?)-(S)- 11 (Scheme 5). (?)-(S)- 10 and (?)-(S)- 11 showed an e.e. of 76–78% (see also [11]). Comparison of these results with those in [11] confirmed our former stereochemical assignment concerning the alkylation step.     

Von der basenkatalysierten Ringöffnung von 2H-Azirinen zu einer α-Alkylierungsmethode von primären Aminen

From a Base Catalyzed Ring Opening of 2H-Azirines to an α-Alkylation Method of Primary Amines It is shown that fluorene-9′-spiro-2-(3-phenyl-2H-azirine) ( 1 ) on treatment with various alcohols in the presence of the corresponding alkoxide ions yields N-(9′-fluorenyl)benzimidates 2a-d (Scheme 1). 2,2,3-Triphenyl-2H-azirine ( 3 ) reacts with methanol in a similar manner (Scheme 2). Benzimidates 2a (Scheme 3), 8 (Scheme 4) and and 10 (Scheme 5) can easily be deprotonated by butyllithium (BuLi) or lithium diisopropylamide (LDA) in tetrahydrofuran (THF) to 1-methoxy-2-aza-allylanions, that can be alkylated, at C(3), exclusively, by various electrophiles (e.g. R-X(X = I, Br), RCHO or methyl acrylate (see also Scheme 6)). As the acidic hydrolyses (1N HCl) of benzimidates 9 and 11 leads to the corresponding α-alkylated free amines 15 and 18 (Scheme 7 and 8), benzoyl derivatives 16 and 19 are obtained from the hydrolysis under basic conditions. On the other hand, it is observed that a catalyzed Chapman rearrangement of 9 and 11 results in the formation of N-benzoyl-N-methyl derivatives 17 and 20 (Scheme 7 and 8). The described reactions offer a simple method for the α-alkylation of activated primary amines.     

Ringerweiterung von 1,2-Thiazol-3(2H)-on-1,1-dioxiden und 3-Amino-2H-azirinen zu 4H-1,2,5-Thiadiazocin-6-on-1,1-dioxiden

Ring Enlargement of 1,2-Thiazol-3(2H)-one-1,1-dioxides and 3-Amino-2H-azirines to 4H-1,2,5-Thiadiazocin-6-one-1,1-dioxides Reaction of 3-amino-2H-azirines 2 with the 1,1-dioxides 4 and 7 of 1,2-thiazol-3(2H)-ones and 1,2-thiazoli-din-3-ones, respectively, in i-PrOH at room temperature leads to 4H-1,2,5-thiadiazocin-6(5H)-one-1,1-dioxides 5 (Scheme 2, Table) and the corresponding 7,8-dihydro derivatives 8 (Scheme 4), respectively. The structure of some of the new 8-membered heterocycles as well as the structure of the minor by-product 6 (Scheme 3) have been established by X-ray crystallography (Chapt. 4). The proposed reaction mechanism for the ring expansion to 5 and 8 (Scheme 2) is in accordance with previously published results of reactions of 2 and NH-acidic heterocycles and is further supported by the results of the reaction of 4a and the (1-¹⁵N)-labelled aminoazirine 2a *.     

Methylierung von 4-Hydroxy-4-(2-piperidyl)-4H-pyrazolo [1,5-a]indol mit Formaldehyd und Ameisensäure. 11. Mitteilung über metallorganische Reaktionen und Folgeprodukte

In the 10^th communication of this series [1] the synthesis of 4-hydroxy-4-(2-piperidyl)-4H-pyrazolo[1,5-a]indole ( 4 ) was described (Scheme). Surprisingly enough, methylation of this compound with formaldehyde and formic acid led via ring closure and a subsequent rearrangement to a pentacyclic ketone. By means of ¹³C-NMR.-spectroscopy and mass spectroscopy, this ketone could be identified as a indolizino-pyrazolo-indole ( 9 ). Its structure and configuration were determined by X-ray structure analysis.     

Synthese der Phoracantholide K,O und M

Synthesis of Phoracantholide K, O and M Two 14membered ring lactones 3 and 4 and a 12membered ring lactone 5 isolated from the metasternal secretion of the eucalypt longicorn Phoracantha synonyma have been synthesized as racemic mixtures by the following method. Reaction of the dilithium derivative of 5-hexynoic acid (6) with threo-8-bromo-2,4-isopropylidenedioxyoctane (7) , followed by removal of the protecting group and esterification with diazomethane gave methyl-threo-11, 13-dihydroxy-5-tetradecy-noate (8) (s. Scheme 2). Partial hydrogenation of the triple bond in 8 with Lindlar Pd-catalyst, followed by saponification lead to (threo, Z)-11, 13-dihydroxy-5-tetra-decenoic acid (10) . The dihydroxy acid 10 was converted into the S-(2-pyridyl) thioate and cyclized in diluted benzene solution under the influence of silver ions to yield the corresponding 12- and 14-membered lactones in approximately equal amounts. Isomerization of the mixture with p-toluenesulfonic acid in methylene chloride yielded the 14-membered lactone (cis-11, 13–5Z)-11-hydroxy-5-tetradecen-13-olide almost exclusively. It proved to be identical in its properties with natural phoracantholide K (3). With 5-hexynoic acid and 7-tetrahydropyranyloxy-octyl bromide or 5-tetrahydropyranyloxy-hexyl bromide as starting materials (±)-phoracantholide O (4) and M (5) have been synthesized in an analogous manner.     

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).     

Reaction of 3-Amino-2H-azirines with 2-Amino-4,6-dinitrophenol (Picramic Acid): Synthesis of Quinazoline- and 1,3-Benzoxazole Derivatives

The reaction of 3-(dimethylamino)-2H-azirines 1a–c and 2-amino-4,6-dinitrophenol (picramic acid, 2 ) in MeCN at 0° to room temperature leads to a mixture of the corresponding 1,2,3,4-tetrahydroquinazoline-2-one 5 , 3-(dimethylamino)-1,2-dihydroquinazoline 6 , 2-(1-aminoalkyl)-1,3-benzoxazole 7 , and N-[2-(dimethylamino)phenyl]-α-aminocarboxamide 8 (Scheme 3). Under the same conditions, 3-(N-methyl-N-phenyl-amino)-2H-azirines 1d and 1e react with 2 to give exclusively the 1,3-benzoxazole derivative 7 . The structure of the products has been established by X-ray crystallography. Two different reaction mechanisms for the formation of 7 are discussed in Scheme 6. Treatment of 7 with phenyl isocyanate, 4-nitrobenzoyl chloride, tosyl chloride, and HCl leads to a derivatization of the NH₂-group of 7 (Scheme 4). With NaOH or NaOMe as well as with morpholine, 7 is transformed into quinazoline derivatives 5 , 14 , and 15 , respectively, via ring expansion (Scheme 5). In case of the reaction with morpholine, a second product 16 , corresponding to structure 8 , is isolated. With these results, the reaction of 1 and 2 is interpreted as the primary formation of 7 , which, under the reaction conditions, reacts with Me₂NH to yield the secondary products 5 , 6 , and 8 (Scheme 7).