Heterocyclole als Zwischenprodukte einer neuen, überraschenden Umlagerung bei der Reaktion von 3-(Dimethylamino)-2,2-dimethyl-2H-azirin mit monosubstituierten Parabansäuren. Vorläufige Mitteilung

Cyclols as Intermediates in the Reaction of 3-(Dimethylamino)-2,2-dimethyl-2H-azirine with Monosubstituted Parabanic Acids; a New and Unexpected Rearrangement The reaction of 3-(dimethylamino)-2,2-dimethyl-2H-azirine ( 1 ) with N-methylparabanic acid ( 4 ) in 2-propanol at room temperature gives the cyclol 5 in 97% yield. In acetonitrile solution 5 rearranges to the imidazoline derivative 6 (Scheme 2). The structures of the unexpected products 5 and 6 have been established by X-ray crystallography.     

Additionsreaktion von 3-Dimethylamino-2,2-dimethyl-2H-azirin mit Phenylisothiocyanat

Reaction of 3-Dimethylamino-2,2-dimethyl-2H-azirine with Phenyl Isothiocyanate In contrast to the reactions of 3-dimethylamino-2,2-dimethyl-2H-azirine ( 1a ) with various isothiocyanates, leading to thiazoline derivatives, the reaction of 1a with phenyl isothiocyanate at room temperature gives 5,5-dimethyl-3-phenyl-Δ¹-imidazolin-4-dimethyliminium-2-thiolate ( 9 , Scheme 2). The structure of 9 is deduced from spectral data and reactions of this zwitterionic compound (Schemes 2 and 4).     

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.     

Herstellung und Reaktionen der valenzpolaromeren Verbindung (4,4-Dimethyl-2-thiazolin-5-dimethyliminium)-2-thiolat ⇌ (1-Dimethylthiocarbamoyl-1-methyl-äthyl)-isothiocyanat aus 3-Dimethyl-amino-2,2-dimethyl-2H-azirin und Schwefelkohlenstoff

Synthesis and reactions of the valence polaromeric compound (4,4-dimethyl-2-thiazoline-5-dimethyliminium)-2-thiolate ? 1-dimethylthiocarbamoyl-1-methyl-ethyl isothiocyanate from 3-dimethylamino-2,2-dimethyl-2H-azirine and carbon disulfide. 3-Dimethylamino-2,2-dimethyl-2H-azirine ( 1 ) reacts with carbon disulfide to give crystals which have the dipolar structure 3a [(4,4-dimethyl-2-thiazoline-5-dimethyliminium)-2-thiolate, Scheme 1]. In solution, the non-dipolar (charge-free) isomeric form 3b (1-Dimethyl-thiocarbamoyl-1-methyl-ethyl isothiocyanate) is almost exclusively populated. Reaction products are derived from both forms: Derivatives of 3a are the hydrolysis product 6 , the sodium borohydride reduction product 7 and the methylation products 9 and 10 , respectively (Scheme 2). The isothiocyanate form 3b is responsible for the various reaction products with amines (Scheme 3). One of the reaction products with ammonia, namely 20 , is also obtained by the reaction of 1 with thiocyanic acid. Thermolysis of the azirine/carbon disulfide adduct 3 leads to 2-dimethylamino-4,4-dimethyl-2-thiazoline-5-thione ( 17 ) in high yield. A possible mechanism is outlined in Scheme 4. The same compound is also formed by rearrangement of 3 under the catalytic influence of dimethylamine. Its structure has been established by X-ray crystallography (section 4). Again a rearrangement is involved in the reductive (NaBH₄) conversion of 17 to 7 , the direct reduction product of the dipolar species 3a (Scheme 5). The isothiocyanate form 3b is able to react with a second molecule of 3-dimethylamino-2,2-dimethyl-2H-azirine ( 1 ) to yield compound 25 , which in the crystalline or dissolved state appears to be almost entirely populated by the carbodiimide form with structure 25b (Scheme 7), though all reaction products of 25 (reduction with sodium borohydride, addition of water or hydrogen sulfide, Schemes 7 and 8) are derived from the dipolar form 25a , not detectable as such; here again therefore there is a dynamic equilibrium 25a ? 25b . The two forms of adduct 3 , namely 3a and 3b , are obviously very easily interconverted at room temperature and therefore can be considered as valence polaromeric forms (section 5). A classification of the dipolar (zwitterionic) form is given, which allows a comparison of various dipolar species and gives as indication of charge stabilization by delocalization. The versatile reactivity of the 3-dimethylamino-2,2-dimethyl-2H-azirine/carbon disulfide adduct is demonstrated by the fact that with simple reagents approximately 25 derivatives have been obtained, most of them being new heterocyclic compounds.     

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).     

Reaktion von 3-Dimethylamino-2,2-dimethyl-2H-azirin mit 6-Methyluracil; Kristallstruktur der Reaktionsprodukte

Reaction of 3-Dimethylamino-2,2-dimethyl-2H-azirine with 6-Methyluracil; Crystal Structure of the Products The reaction of 3-dimethylamino-2,2-dimethyl-2H-azirine ( 1 ) with 6-methyl-uracil ( 4 ) in 2-propanol at 80° yields the 4H-imidazoje derivative 5 as the main product. This reaction is similar to the previously reported ones with heterocyclic compounds containing the sequence NH? CO? NH? CO. In the presence of water, 5 is easily hydrolyzed to 6 . The structures of 5 and 6 have been established by X-ray crystallography.     

Ringerweiterung von sechs- zu neungliedrigen Heterocyclen: Umsetzung von 3-(Dimethylamino)-2,2-dimethyl-2H-azirin mit 3,4-Dihydro-2H-1,2,4-benzothiadiazin-3-on-1,1-dioxiden

Ring Enlargement of Six- to Nine-Membered Heterocycles: Reaction of 3-(Dimethylamino)-2,2-dimethyl-2H-azirine with 3,4-Dihydro-2H-1,2,4-benzothiadiazin-3-one 1,1-Dioxides Reaction of 3-(dimethylamino)-2,2-dimethyl-2H-azirine ( 1 ) and N-substituted 3,4-dihydro-2H-1,2,4-benzothiadiazin-3-one 1,1-dioxides ( 4 ) in CHCl₃ yields 3-(dimethylamino)-4,5,6,7-tetrahydro-1,2,5,7-benzothiatriazonin-6-one 1,1-dioxides 5 , a novel nine-membered heterocyclic system, by ring enlargement (Schemes 2 and 4). In refluxing MeOH, the heterocycle 5a rearranges to give the N-[1-methyl-1-(1,1-dioxo-4H-1,2,4-benzothiadiazin-3-yl)ethyl]-N′, N′-dimethylurea 10 . The three isomeric 2-(methylamino)benzenesufonamides 8,9 , and 11 (Scheme 3) are obtained by naBH₄ reduction of 5a and 10 , respectively. Mechanisms for the thermal isomerization 5a → 10 and the NaBH₄ reduction of 5a are proposed in Schemes 5 and 6.     

Die Struktur einer stabilen dipolaren Verbindung aus 2,2-Dimethyl-3-dimethylamino-2H-azirin und Benzoylisothiocyanat. Vorläufige Mitteilung

Structure of a Stable Dipolar Compound from 2,2-Dimethyl-3-dimethylamino-2H-azirine and Benzoylisothiocyanate. Benzoylisothiocyanate and 2,2-dimethyl-3-dimethylamino-2H-azirine ( 1 ) react to given the dipolar compound 4,4-dimethyl-2-thiazolin-5-dimethylimminium-2-benzcarboxamidate ( 2 ), whose structure has been proved by X-ray analysis. Compound 2 , upon addition of water, yields the thiourea derivative 3 , whereas by acid catalyzed hydrolysis the thiazolinone derivative 4 is formed. The dipolar structure 2 is also existent in organic solvents like dimethylsulfoxide or chloroform.     

Eine überraschende Ringerweiterung von 3-(Dimethylamino)-2,2-dimethyl-2H-azirin zu 4,5-Dihydropyridin-2(3H)-on-Derivaten

An Unexpected Ring Enlargement of 3-(Dimethylamino)-2,2-dimethyl-2H-azirine to 4,5-Dihydropyridin-2(3H)-one Derivatives The reaction of 3-(dimethylamino)-2,2-dimethyl-2H-azirine ( 1a ) and 4,4-disubstituted 2-(trifluoromethyl)-1,3-oxazol-5(4H)-ones 7 in MeCN at 70° afforded 5-(dimethylamino)-3,6-dihydropyrazin-2(1H)-ones 10 (Scheme 4), whereas no reaction could be observed between 1a and 2-allyl-4-phenyl-2-(trifluoromethyl)-1,3-oxazol-5(2H)-one ( 8a ) or 4,4-dibenzyl-2-phenyl-1,3-oxazol-5(4H)-one ( 9 ). The formation of 10 is rationalized by a mechanism via nucleophilic attack of 1a onto 7 . The failure of a reaction with 9 shows that only activated 1,3-oxazol-5(4H)-ones bearing electron-withdrawing substituents do react as electrophiles with 1a . The amino-azirine 1a and 2,4-disubstituted 1,3-oxazol-5(4H)-ones 2b – e in refluxing MeCN undergo a novel ring enlargement to 4,5-dihydropyridin-2(3H)-ones 11 (Scheme 5). Several side products were observed in these reactions. Two different reaction mechanisms for the formation of 11 are proposed: either 1a undergoes a nucleophilic addition onto the open-chain ketene tautomer of 2 (Scheme 6), or 2 reacts as CH-acidic compound (Scheme 7).     

Ring-Transformationen bei der Umsetzung von 3-(Dimethylamino)-2,2-dimethyl-2H-azirin mit 1-substituierten Imidazolidin-2,4,5-trionen

Ring-Transformations in the Reaction of 3-(Dimethylamino)-2,2-dimethyl-2H-azirines with 1-Substituted Imidazolidine-2,4,5-triones Reaction of 1-substituted imidazolidine-2,4,5-triones ( = N-substituted parabanic acids; 2 ) and 3-(dimethylamino)-2,2-dimethyl-2H-azirine ( 1 ) in i-PrOH or MeCN at room temperature yields 5,6,7,7a-tetrahydro-3H-imidazo[3,4-a]imidazole-5,7-diones 3 (Scheme 1). By ¹⁵N-NMR studies, using (3-¹⁵N)- 2a , it has been shown that only N( 1 ) in (¹⁵N)- 3a is labelled and, hence, N(4) stems from 1 , e.g. the azirine reacts via cleavage of the N(1)=C(3) bond. In MeCN at room temperature, the azacyclols 3 rearrange slowly to give monocyclic 2H, 5H-imidazol-2-ones 4 (Scheme 3); the ¹⁵N-label in (¹⁵N)- 4a is in position 1. Both reactions proceed via deep-seated skeletal rearrangements, most probably via ring-expansion/ring-contraction processes.     

Die Struktur des Adduktes aus 3-Dimethylamino-2,2-dimethyl-2H-azirin und 3-Methyl-2,4-diphenyl-1,3-oxazolium-5-olat. Vorläufige Mitteilung

Structure of the adduct from 3-dimethylamino-2,2-dimethyl-2H-azirine and 3-methyl-2,4-diphenyl-1,3-oxazolium-5-olate 3-Dimethylamino-2,2-dimethyl-2H-azirine ( 1 ) reacts with 3-methyl-2,4-diphenyl-1,3-oxazolium-5-olate ( 5a ) to give a 1:1 adduct ( 7 ) in a 88% yield. Its crystal structure has been determined by X-ray analysis (direct methods) and refined with 1056 structure amplitudes to R = 0,032. The crystal system is monoclinic, space group P2₁/c, with unit cell dimensions a = 10.663, b = 9,828, c = 18,592 Å, and β = 90,63°. It is obvious that 4-dimethylamino-5,5-dimethyl-2-[α-(N-methyl-benzamido)benzyliden]-Δ³-1,3-oxazoline ( 7 ) arises from an addition of 1 to the valence-polaromeric ketene form 5b of the mesoionic oxazolone 5a (Scheme 3).     

15N-Markiertes 3-(Dimethylamino)-2,2-dimethyl-2H-azirin zur mechanistischen Untersuchung von Reaktionen mit NH-aciden Heterocyclen

₁₅N-Labelled 3-(Dimethylamino)-2,2-dimethyl-2H-azirine for Mechanistic Studies of Reactions with NH-Acidic Heterocycles The synthesis of 3-(dimethylamino)-2,2-dimethyl(1-¹⁵N)-2H-azirine ( 1 *) was accomplished via reaction of 1-chloro-N,N,2-trimethyl-1-propenylamine ( 9 ) and sodium (1-¹⁵N) azide (Scheme 3). The earlier reported reactions of 1 with saccharin ( 10 , Scheme 4), phthalimide ( 12 , Scheme 5), and 2H-1,3-benzoxazin-2,4(3H)-dione ( 16 , Scheme 6) were repeated with 1 *, and the position of the ¹⁵N-label in the products was determined by ¹⁵N-NMR spectroscopy. Whereas the postulated reaction mechanisms for 10 and 12 were confirmed by these experiments, the mechanism for the reaction of 16 had to be revised. With respect to the position of ¹⁵N in the products 17 and 18 , a new mechanism is formulated in Scheme 7. Treatment of 5,5-dimethyl-1,3-oxazolidine-2,4-dione ( 19 ) with 1 * led to 3,4-dihydro-2H-imidazol-2-on 20 in which only N(3) was labelled. The mechanism of a ring expansion and transannular ring contraction as shown in Scheme 8 is in agreement with this finding.     

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.     

Ring-Transformation von Imidazolidin–2,4-dionen ( = Hydantoinen) zu 4H-Imidazolen bei der Umsetzung mit 3-(Dimethylamino)-2,2-dimethyl-2H -azirin

Ring Transformation of Imidazolidine-2,4-diones ( = Hydantoins) to 4H-Imidazoles in the Reaction with 3-(Dimethylamino)-2,2-dimethyl-2H-azirines At ca. 70°, 3-(dimethylamino)-2,2-dimethyl-2H -azirine ( 1 ) and 5,5-disubstituted hydantoins 4 in MeCN or i-PrOH give 2-(1-aminoalkyl)-5-(dimethylamino)-4,4-dimethyl-4H -imidazoles 5 in good yield (Scheme 2). These products are decarboxylated 1:1 adducts of 1 and 4 . A reaction mechanism is suggested in analogy to the previously reported reactions of 1 and NH-acidic heterocycles containing the CO? NH? CO? NH moiety (Scheme 5). The formation of ureas 6 and 7 can be rationalized by trapping the intermediate isocyanate F by an amine. No reaction is observed between 1 and 1,5,5- or 3,5,5-trisubstituted hydantoins in refluxing MeCN or i-PrOH, but an N-isopropylation of 1,5,5-trimethylhydantoin ( 8b ) occurs in the presence of morpholine (Scheme 3). The reaction of the bis(azirine)dibromozink complex 11 and hydantoines 4 in refluxing MeCN yields zink complexes 12 of the corresponding 2-(1-aminoalkyl)-4H -imidazoles 5 (Scheme 4).     

1,3-Dipolare Cycloadditionen von 2-(Benzonitrilio)-2-propanid mit 4,4-Dimethyl-2-phenyl-2-thiazolin-5-thion und Schwefelkohlenstoff

1,3-Dipolar Cycloadditions of 2-(Benzonitrilio)-2-propanide with 4,4-Dimethyl-2-phenyl-2-thiazolin-5-thione and Carbon Disulfide Irradiation of 2,2-dimethyl-3-phenyl-2H-azirine ( 11 ) in the presence of 4,4-dimethyl-2-phenyl-2-thiazolin-5-thione ( 7 ) yields a mixture of the three (1:1)-ad-ducts 8 , 12 and 13 (Schemes 3 and 6). The formation of 8 and 12 can be explained by 1,3-dipolar cycloaddition of 2-(benzonitrilio)-2-propanide ( 1b ) to the C, S-double bond of 7. Photochemical isomerization of 12 leads to the third isomer 13 (Schemes 3 and 7). Photolysis of the azirine 11 in the presence of carbon disulfide gives a mixture of two (2:l)-adducts, namely 12 and 13 (Scheme 4). A reaction mechanism via the intermediate formation of the 3-thiazolin-5-thione b is postulated. The structure of the heterocyclic spiro compound 13 has been established by single-crystal X-ray structure determination (cf. Fig. 1 and 2).     

Reaktion von 3-Dimethylamino-2,2-dimethyl-2H-azirin mit Barbitursäure

Reaction of 3-Dimethylamino-2,2-dimethyl-2H-azirine with Barbituric Acid The reaction of 3-dimethylamino-2,2-dimethyl-2H-azirine (1) with barbituric acid (4) in dimethyl formamide at room temperature yields a mixture of several compounds. The two main products 5 and 6 have been isolated in 40 and 10% yield, respectively, and their structures established by X-ray analysis. In Schemes 4–6 reaction mechanisms for the formation of 5 and 6 are postulated, the first step beeing either a C- or an N-alkylation of barbituric acid. Reduction of 5 and 6 with NaBH₄ in ethanol at room temperature yields 6,6-dimethyl-1,5,6,7-tetrahydro-pyrrolo[2,3-d]pyrimidin-2,4(3H)-dione (7) and 3,3-dimethyl-2,3-dihydro-imidazo[1,2-c]pyrimidin-5,7(1H, 6H)-dione (8) in 38 and 48% yield, respectively. Treatment of 6 with 3N aqueous NaOH at room temperature gives 3,3-dimethyl-imidazo[1,2-c]pyrimidin-2,5,7 (1H, 3H, 6H)-trione (9) in 51% yield (Scheme 3).     

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).     

Synthese von 1, 3, 4-Oxadiazolen und 4, 5-Dihydro-1, 2, 4-triazinen aus 3-Dimethylamino-2, 2-dimethyl-2 H-azirin und Carbohydraziden

Synthesis of 1,3,4-Oxadiazoles and 4,5-Dihydro-l,2,4-triazines from 3-Dimethylamino-2,2-dimethyl-2 Hazirine and Carbohydrazides 3-Dimethylamino-2, 2-dimethyl-2 H-azirine ( 1 ) reacts with aromatic carbohydrazides to give 2-(1-amino-1-methylethyl)-5-aryl-1, 3, 4-oxadiazoles ( 7 , 10 , 11 ). With ethyl carbazate the azirine 1 forms the aminoester 15 , which is easily cyclized to the 4, 5-dihydro-1, 2, 4-triazin-3 (2H)-one 16 . From the reaction of 1 with oxamohydrazide ( 17 ) and oxalodihydrazide 19 the 4, 5-dihydro-1, 2, 4-triazin-3-carboxamide 18 and the symmetric compound 20 , respectively, have been isolated. Reactions supporting the structures of the new compounds are described.     

A Ring Enlargement from Seven- to Ten-Membered-Ring sulfonamide derivatives

The reaction of 3-(dimethylamino)-2,2-dimethyl-2H-azirine ( 1a ) with 4,5-dihydro-7,8-dimethoxy-1,2-benzothiazepin-3-one 1,1-dioxide ( 4 ) in dioxane at room temperature gave the correspondingly substituted 4H-1,2,5-benzothiadiazecin-6-one 1,1-dioxide 5a in 64% yield (Scheme 2). The structure of this novel ten-membered ring-enlargement product was established by X-ray crystallography (Fig.). Under more vigorous conditions (refluxing dichloroethane), 5a was formed together with the isomeric 6a , both in low yield. The 3-(dimethylamino)-2H-azirines 1b and 1c reacted sluggishly to give the two isomeric ring-enlargement products of type 5 and 6 in yields of 24–29% and 2–4%, respectively (Table 1). Even less reactive is 2,2-dimethyl-3-(N-methyl-N-phenylamino)-2H-azirine ( 1d ), which reacted with 4 in MeCN only at 65°. Under these conditions, besides numerous decomposition products, only traces of 5d and 6d were formed. No ring enlargement was observed with the sterically crowded 1e , which bears an isopropyl group at C(2).     

Ein neues 3-Amino-2H-azirin als Aib-Pro-Baustein: Synthese des C-terminalen Nonapeptids von Trichovirin I 1B

A New 3-Amino-2H-azirine as an Aib-Pro Synthon: Synthesis of the C-Terminal Nonapeptide of Trichovirin I 1B The synthesis of methyl N-(2,2-dimethyl-2H-azirin-3-yl)-L -prolinate ( 3 ), a novel 3-amino-2H-azirine, is described (Scheme 2). It is shown that the reaction of COCl₂ with thioamide 5 is remarkably faster than with the corresponding amide 4 , and the yield of 3 is much better in the synthesis starting with 5 . The 3-amino-2H-azirine 3 has been used as a building block of the dipeptide moieties Aib-Pro in the synthesis of nonapeptide 17 (Schemes 4 and 5), the C-terminal 6–14 segment of the peptaibole trichovirin I 1B. The structure of 17 was established by single-crystal X-ray crystallography (Figs.1 and 2).