5-Chloroisoxazoles: A Versatile Starting Material for the Preparation of Amides, Anhydrides, Esters, and Thioesters of 2H-Azirine-2-carboxylic Acids

Amides, anhydrides, esters, and thioesters of 2H-azirine-2-carboxylic acids were prepared by a rapid procedure at room temperature involving FeCl2-catalyzed isomerization of 5-chloroisoxazoles to 2H-azirine-2-carbonyl chlorides, followed by reaction with N-, O-, or S-nucleophiles mediated by an ortho-substituted pyridine. With readily available chloroisoxazoles and a nucleophile, 2-picoline can be used as an inexpensive base. When a high yield of the acylation product is important, the reagent 2-(trimethylsilyl)pyridine/ethyl chloroformate is more suitable for the acylation with 2H-azirine-2-carbonyl chlorides.


Results and Discussion
Since the reaction of 2H-azirine-2-carbonyl chloride 1a with 3 equiv. of morpholine 6a, gives within 3 min a complex mixture of products, without any amide 7a among them, the amount of used morpholine was varied. It resulted in the presence of 2 equiv of morpholine, amide 7a was formed at 70% yield. Moreover, it was found that when 1 equiv. of morpholine was added to the amide 7a, its complete destruction occurred within 10 min. This means that the absence of amide 7a among products of the reaction o 2H-azirine-2-carbonyl chloride 1a with 3 equiv. of morpholine 6a is due to the destruction of the azirine core of amide 7a and possibly the azirine core of the starting chloride 1a Then, the effect of adding other bases to trap HCl on the yield of amide 7a was investi gated ( Table 1). The best yield of amide 7a (89-90%) was obtained with 2,6-lutidine and 2-picoline (Table 1, entries 4,5). The use of pyridines without an ortho-substituent gave a significantly lower yield of amide 7a (Table 1, entries 2, 6). Tertiary amines also turned out to be less effective in the reaction (Table 1,

Results and Discussion
Since the reaction of 2H-azirine-2-carbonyl chloride 1a with 3 equiv. of morpholine, 6a, gives within 3 min a complex mixture of products, without any amide 7a among them, the amount of used morpholine was varied. It resulted in the presence of 2 equiv. of morpholine, amide 7a was formed at 70% yield. Moreover, it was found that when 1 equiv. of morpholine was added to the amide 7a, its complete destruction occurred within 10 min. This means that the absence of amide 7a among products of the reaction of 2H-azirine-2carbonyl chloride 1a with 3 equiv. of morpholine 6a is due to the destruction of the azirine core of amide 7a and possibly the azirine core of the starting chloride 1a. Then, the effect of adding other bases to trap HCl on the yield of amide 7a was investigated ( Table 1). The best yield of amide 7a (89-90%) was obtained with 2,6-lutidine and 2-picoline (Table 1, entries 4,5). The use of pyridines without an ortho-substituent gave a significantly lower yield of amide 7a (Table 1, entries 2, 6). Tertiary amines also turned out to be less effective in the reaction (Table 1, entries 7, 8).
We also tested some other approaches to amide 7a. Thus, heating 5-chloroisoxazole 2a with morpholine 6a to form 5-morpholinoisoxazole 8a, followed by its isomerization catalyzed by Fe(II), gave amide 7a only with an isolated yield of 60% (Scheme 2). Hydrolysis of carbonyl chloride 1a to azirine-2-carboxylic acid 9a, followed by amide coupling using HATU/DIPEA reagents, gave amide 7a in a 77% yield (Scheme 2). These results indicated that using 1 equiv. of morpholine in a reaction with chloride 1a in the presence of 1 equiv. of the ortho-substituted pyridine is the most efficient approach in converting chloroisoxazole 2a to amide 7a. We also tested some other approaches to amide 7a. Thus, heating 5-chloroisoxazole 65 2a with morpholine 6а to form 5-morpholinoisoxazole 8a, followed by its isomerization 66 catalyzed by Fe(II), gave amide 7а only with an isolated yield of 60% (Scheme 2). Hy-67 drolysis of carbonyl chloride 1a to azirine-2-carboxylic acid 9a, followed by amide cou-68 pling using HATU/DIPEA reagents, gave amide 7a in a 77% yield (Scheme 2). These re-69 sults indicated that using 1 equiv. of morpholine in a reaction with chloride 1a in the 70 presence of 1 equiv. of the ortho-substituted pyridine is the most efficient approach in 71 converting chloroisoxazole 2a to amide 7а. We also tested some other approaches to amide 7a. Thus, heating 5-chloroisoxa 2a with morpholine 6а to form 5-morpholinoisoxazole 8a, followed by its isomeriza catalyzed by Fe(II), gave amide 7а only with an isolated yield of 60% (Scheme 2). drolysis of carbonyl chloride 1a to azirine-2-carboxylic acid 9a, followed by amide pling using HATU/DIPEA reagents, gave amide 7a in a 77% yield (Scheme 2). Thes sults indicated that using 1 equiv. of morpholine in a reaction with chloride 1a in presence of 1 equiv. of the ortho-substituted pyridine is the most efficient approac converting chloroisoxazole 2a to amide 7а. Scheme 2. Other approaches to morpholide 7.
It resulted that the yields of amides 7b-h obtained from amines 6b-h were significantly lower than the yield of morpholide 7a. This may be due to the complex effect of amine nucleophilicity on the competition of amine attack on the carbonyl of the acid chloride group and on the C=N azirine bond, which affects the ratio of the processes of amide formation and azirine ring destruction. In addition, the difference in the basicity of amines affected the formation and ratio of hydrochlorides of amine 6 and 2-picoline, which complicated the protonation of the azirine nitrogen of compounds 1 and 7. In turn, this catalyzed the reaction of the amine with the azirine core, and this catalysis accelerated the decomposition of azirines. Surprisingly when chloride 1a was treated with 2-picoline without the subsequent addition of any amine, anhydride 10a was obtained in a 40% yield (Scheme 4). Compound 10a was obtained as a mixture of two diastereomers (~1:1.1). (RS,SR)-isomer crystallized from the mixture, and its amazing π-stacked structure was confirmed by X-ray analysis ( Figure 1) (See the Supplementary Materials). It was found that chloride 1a does not react with acid 9a to give anhydride 10a in the absence of 2-picoline. A plausible mechanism of the formation of anhydride 10 includes the reaction of salt 11 with acid 9 promoted by 2-picoline. Acid 9 was formed by the hydrolysis of chloride 1 with water adsorbed on the wall of the glassware (the glassware was not specially dried) and traces of water entering the reaction mixture during the isolation of chloride 1 from the mixture obtained after the isomerization of chloroisoxazole 2 (extraction with ether, filtration through celite). Since the scale of the reaction of chloroisoxazole 2a was 1 mmol, only 3.6 mg of water was required to obtain a 40% yield of anhydride 10a. When chloroisoxazole 2b was used in the reaction, anhydride 10b was obtained at 66% (Scheme 4). The addition of 0.2 equiv. of water, together with 2-picoline, increased the yield of anhydride 10b to 78%. Both the excess and deficiency of water in the reaction mixture will reduce the yield of anhydride, but it is difficult to control the exact amount of water required for the reaction on a 1 mmol scale without technically complicating the reaction procedure. It resulted that the yields of amides 7b-h obtained from amines 6b-h were signifi cantly lower than the yield of morpholide 7a. This may be due to the complex effect o amine nucleophilicity on the competition of amine attack on the carbonyl of the acid chloride group and on the С=N azirine bond, which affects the ratio of the processes o amide formation and azirine ring destruction. In addition, the difference in the basicity o amines affected the formation and ratio of hydrochlorides of amine 6 and 2-picoline which complicated the protonation of the azirine nitrogen of compounds 1 and 7. In turn this catalyzed the reaction of the amine with the azirine core, and this catalysis acceler  Table 2 (vide infra); b 35% with 2 equiv. of amine 6h.
The formation of anhydride 10 due to the presence of traces water suggests an additional route for the formation of amides through the reaction of an amine with an anhydride. Thus, the formation of amides 7 can proceed via several mechanisms that can operate simultaneously: (1) direct interaction of chloride 1a with amines 6 (Scheme 5, route a); (2) pathways mediated by a pyridine via salt A (Scheme 5, route b); and (3) formation of anhydride 10, initiated by traces of water, followed by reaction of this anhydride with amines 6 (Scheme 5, route c). ( Table 2). The best results in terms of the yield of amide 7a and the economical use of 140 reagents correspond to experiment 3. It was also seen that the use of acetyl chloride (Ta-141 ble 2, entry 6) for the above purposes was much less efficient than ethyl chloroformate, 142 which may be due to the fact that salt F, with AcOinstead of EtO2CO -, can better catalyze 143 the decomposition of azirines, being a salt of a stronger acid. 144 High yields of amides 7 using pyridines with bulky ortho-substituents (Table 2) may 145 be because, on the one hand, the C(O)-N bond in salt A (Scheme 5) in such compounds is 146 weaker, making the respective pyridinium a better leaving group, and on the other hand, 147 the pyridinium chloride with such ortho-substituents has a lower protonation capacity for 148 azirines.

Entry
Reagent 1 (Equiv.) Reagent 2 (Equiv.) Isolated Yield (%) of 7a 1 ( Table 2). The best results in terms of the yield of amide 7a and the economical use of 140 reagents correspond to experiment 3. It was also seen that the use of acetyl chloride (Ta-141 ble 2, entry 6) for the above purposes was much less efficient than ethyl chloroformate, 142 which may be due to the fact that salt F, with AcOinstead of EtO2CO -, can better catalyze 143 the decomposition of azirines, being a salt of a stronger acid. 144 High yields of amides 7 using pyridines with bulky ortho-substituents (Table 2) may 145 be because, on the one hand, the C(O)-N bond in salt A (Scheme 5) in such compounds is 146 weaker, making the respective pyridinium a better leaving group, and on the other hand, 147 the pyridinium chloride with such ortho-substituents has a lower protonation capacity for 148 azirines.
149 Table 2. Optimization of the reaction conditions for the synthesis of morpholide 7. Then, experiments were carried out with various amines, 6a-h, under optimal con-151 ditions (entry 3 of Table 2). The use of these reaction conditions allowed for the prepara-152 tion of amides 7 in higher yields (excluding 7c): 7a (90%), 7b (62%), 7c (35%), 7d (75%), 7e 153 (53%), 7f (86%), 7g (72%), and 7h (91%) (Scheme 3, footnote a). A dramatic increase in 154 yield was significant in the case of tert-butylamine (6h). We noted that the yield of amide 155 7h was only 42% in the direct reaction of chloride 1a with 2 equiv. of 6h. Importantly, the 156 reaction with aniline gave anilide 7f, which was not available by other approaches [10-157 17], in an 86% yield. 158 The scope of the reaction with various 2H-azirine-2-carbonyl chlorides 1 was evalu-159 ated using tert-butyl amine (6h) as the N-nucleophile. Amides 7h-q were obtained in 60-160 ( Table 2). The best results in terms of the yield of amide 7a and the economical use of 140 reagents correspond to experiment 3. It was also seen that the use of acetyl chloride (Ta-141 ble 2, entry 6) for the above purposes was much less efficient than ethyl chloroformate, 142 which may be due to the fact that salt F, with AcOinstead of EtO2CO -, can better catalyze 143 the decomposition of azirines, being a salt of a stronger acid. 144 High yields of amides 7 using pyridines with bulky ortho-substituents (Table 2) may 145 be because, on the one hand, the C(O)-N bond in salt A (Scheme 5) in such compounds is 146 weaker, making the respective pyridinium a better leaving group, and on the other hand, 147 the pyridinium chloride with such ortho-substituents has a lower protonation capacity for 148 azirines.
149 Table 2. Optimization of the reaction conditions for the synthesis of morpholide 7. Then, experiments were carried out with various amines, 6a-h, under optimal con-151 ditions (entry 3 of Table 2). The use of these reaction conditions allowed for the prepara-152 tion of amides 7 in higher yields (excluding 7c): 7a (90%), 7b (62%), 7c (35%), 7d (75%), 7e 153 (53%), 7f (86%), 7g (72%), and 7h (91%) (Scheme 3, footnote a). A dramatic increase in 154 yield was significant in the case of tert-butylamine (6h). We noted that the yield of amide 155 7h was only 42% in the direct reaction of chloride 1a with 2 equiv. of 6h. Importantly, the 156 reaction with aniline gave anilide 7f, which was not available by other approaches [10-157 17], in an 86% yield. 158 The scope of the reaction with various 2H-azirine-2-carbonyl chlorides 1 was evalu-159 ated using tert-butyl amine (6h) as the N-nucleophile. Amides 7h-q were obtained in 60-160 76 2 ( Table 2). The best results in terms of the yield of amide 7a and the economical use of 140 reagents correspond to experiment 3. It was also seen that the use of acetyl chloride (Ta-141 ble 2, entry 6) for the above purposes was much less efficient than ethyl chloroformate, 142 which may be due to the fact that salt F, with AcOinstead of EtO2CO -, can better catalyze 143 the decomposition of azirines, being a salt of a stronger acid. 144 High yields of amides 7 using pyridines with bulky ortho-substituents (Table 2) may 145 be because, on the one hand, the C(O)-N bond in salt A (Scheme 5) in such compounds is 146 weaker, making the respective pyridinium a better leaving group, and on the other hand, 147 the pyridinium chloride with such ortho-substituents has a lower protonation capacity for 148 azirines.
149 Table 2. Optimization of the reaction conditions for the synthesis of morpholide 7. Then, experiments were carried out with various amines, 6a-h, under optimal con-151 ditions (entry 3 of Table 2). The use of these reaction conditions allowed for the prepara-152 tion of amides 7 in higher yields (excluding 7c): 7a (90%), 7b (62%), 7c (35%), 7d (75%), 7e 153 (53%), 7f (86%), 7g (72%), and 7h (91%) (Scheme 3, footnote a). A dramatic increase in 154 yield was significant in the case of tert-butylamine (6h). We noted that the yield of amide 155 7h was only 42% in the direct reaction of chloride 1a with 2 equiv. of 6h. Importantly, the 156 reaction with aniline gave anilide 7f, which was not available by other approaches [10-157 17], in an 86% yield. 158 The scope of the reaction with various 2H-azirine-2-carbonyl chlorides 1 was evalu-159 ated using tert-butyl amine (6h) as the N-nucleophile. Amides 7h-q were obtained in 60-160 ( Table 2). The best results in terms of the yield of amide 7a and the economical use of 140 reagents correspond to experiment 3. It was also seen that the use of acetyl chloride (Ta-141 ble 2, entry 6) for the above purposes was much less efficient than ethyl chloroformate, 142 which may be due to the fact that salt F, with AcOinstead of EtO2CO -, can better catalyze 143 the decomposition of azirines, being a salt of a stronger acid. 144 High yields of amides 7 using pyridines with bulky ortho-substituents (Table 2) may 145 be because, on the one hand, the C(O)-N bond in salt A (Scheme 5) in such compounds is 146 weaker, making the respective pyridinium a better leaving group, and on the other hand, 147 the pyridinium chloride with such ortho-substituents has a lower protonation capacity for 148 azirines.
149 Table 2. Optimization of the reaction conditions for the synthesis of morpholide 7. Then, experiments were carried out with various amines, 6a-h, under optimal con-151 ditions (entry 3 of Table 2). The use of these reaction conditions allowed for the prepara-152 tion of amides 7 in higher yields (excluding 7c): 7a (90%), 7b (62%), 7c (35%), 7d (75%), 7e 153 (53%), 7f (86%), 7g (72%), and 7h (91%) (Scheme 3, footnote a). A dramatic increase in 154 yield was significant in the case of tert-butylamine (6h). We noted that the yield of amide 155 7h was only 42% in the direct reaction of chloride 1a with 2 equiv. of 6h. Importantly, the 156 reaction with aniline gave anilide 7f, which was not available by other approaches [10-157 17], in an 86% yield. 158 The scope of the reaction with various 2H-azirine-2-carbonyl chlorides 1 was evalu-159 ated using tert-butyl amine (6h) as the N-nucleophile. Amides 7h-q were obtained in 60-160  Table 2). The best results in terms of the yield of amide 7a and the economical use of 140 reagents correspond to experiment 3. It was also seen that the use of acetyl chloride (Ta-141 ble 2, entry 6) for the above purposes was much less efficient than ethyl chloroformate, 142 which may be due to the fact that salt F, with AcOinstead of EtO2CO -, can better catalyze 143 the decomposition of azirines, being a salt of a stronger acid. 144 High yields of amides 7 using pyridines with bulky ortho-substituents (Table 2) may 145 be because, on the one hand, the C(O)-N bond in salt A (Scheme 5) in such compounds is 146 weaker, making the respective pyridinium a better leaving group, and on the other hand, 147 the pyridinium chloride with such ortho-substituents has a lower protonation capacity for 148 azirines.
149 Table 2. Optimization of the reaction conditions for the synthesis of morpholide 7. Then, experiments were carried out with various amines, 6a-h, under optimal con-151 ditions (entry 3 of Table 2). The use of these reaction conditions allowed for the prepara-152 tion of amides 7 in higher yields (excluding 7c): 7a (90%), 7b (62%), 7c (35%), 7d (75%), 7e 153 (53%), 7f (86%), 7g (72%), and 7h (91%) (Scheme 3, footnote a). A dramatic increase in 154 yield was significant in the case of tert-butylamine (6h). We noted that the yield of amide 155 7h was only 42% in the direct reaction of chloride 1a with 2 equiv. of 6h. Importantly, the 156 reaction with aniline gave anilide 7f, which was not available by other approaches [10-157 17], in an 86% yield. 158 The scope of the reaction with various 2H-azirine-2-carbonyl chlorides 1 was evalu-159 ated using tert-butyl amine (6h) as the N-nucleophile. Amides 7h-q were obtained in 60-160 ( Table 2). The best results in terms of the yield of amide 7a and the economical use of 140 reagents correspond to experiment 3. It was also seen that the use of acetyl chloride (Ta-141 ble 2, entry 6) for the above purposes was much less efficient than ethyl chloroformate, 142 which may be due to the fact that salt F, with AcOinstead of EtO2CO -, can better catalyze 143 the decomposition of azirines, being a salt of a stronger acid. 144 High yields of amides 7 using pyridines with bulky ortho-substituents (Table 2) may 145 be because, on the one hand, the C(O)-N bond in salt A (Scheme 5) in such compounds is 146 weaker, making the respective pyridinium a better leaving group, and on the other hand, 147 the pyridinium chloride with such ortho-substituents has a lower protonation capacity for 148 azirines.
149 Table 2. Optimization of the reaction conditions for the synthesis of morpholide 7. Then, experiments were carried out with various amines, 6a-h, under optimal con-151 ditions (entry 3 of Table 2). The use of these reaction conditions allowed for the prepara-152 tion of amides 7 in higher yields (excluding 7c): 7a (90%), 7b (62%), 7c (35%), 7d (75%), 7e 153 (53%), 7f (86%), 7g (72%), and 7h (91%) (Scheme 3, footnote a). A dramatic increase in 154 yield was significant in the case of tert-butylamine (6h). We noted that the yield of amide 155 7h was only 42% in the direct reaction of chloride 1a with 2 equiv. of 6h. Importantly, the 156 reaction with aniline gave anilide 7f, which was not available by other approaches [10-157 17], in an 86% yield. 158 The scope of the reaction with various 2H-azirine-2-carbonyl chlorides 1 was evalu-159 ated using tert-butyl amine (6h) as the N-nucleophile. Amides 7h-q were obtained in 60-160 90 4 ( Table 2). The best results in terms of the yield of amide 7a and the economical use of 140 reagents correspond to experiment 3. It was also seen that the use of acetyl chloride (Ta-141 ble 2, entry 6) for the above purposes was much less efficient than ethyl chloroformate, 142 which may be due to the fact that salt F, with AcOinstead of EtO2CO -, can better catalyze 143 the decomposition of azirines, being a salt of a stronger acid. 144 High yields of amides 7 using pyridines with bulky ortho-substituents (Table 2) may 145 be because, on the one hand, the C(O)-N bond in salt A (Scheme 5) in such compounds is 146 weaker, making the respective pyridinium a better leaving group, and on the other hand, 147 the pyridinium chloride with such ortho-substituents has a lower protonation capacity for 148 azirines.
149 Table 2. Optimization of the reaction conditions for the synthesis of morpholide 7. Then, experiments were carried out with various amines, 6a-h, under optimal con-151 ditions (entry 3 of Table 2). The use of these reaction conditions allowed for the prepara-152 tion of amides 7 in higher yields (excluding 7c): 7a (90%), 7b (62%), 7c (35%), 7d (75%), 7e 153 (53%), 7f (86%), 7g (72%), and 7h (91%) (Scheme 3, footnote a). A dramatic increase in 154 yield was significant in the case of tert-butylamine (6h). We noted that the yield of amide 155 7h was only 42% in the direct reaction of chloride 1a with 2 equiv. of 6h. Importantly, the 156 reaction with aniline gave anilide 7f, which was not available by other approaches [10-157 17], in an 86% yield. 158 The scope of the reaction with various 2H-azirine-2-carbonyl chlorides 1 was evalu-159 ated using tert-butyl amine (6h) as the N-nucleophile. Amides 7h-q were obtained in 60-160 ( Table 2). The best results in terms of the yield of amide 7a and the economical use of 140 reagents correspond to experiment 3. It was also seen that the use of acetyl chloride (Ta-141 ble 2, entry 6) for the above purposes was much less efficient than ethyl chloroformate, 142 which may be due to the fact that salt F, with AcOinstead of EtO2CO -, can better catalyze 143 the decomposition of azirines, being a salt of a stronger acid. 144 High yields of amides 7 using pyridines with bulky ortho-substituents (Table 2) may 145 be because, on the one hand, the C(O)-N bond in salt A (Scheme 5) in such compounds is 146 weaker, making the respective pyridinium a better leaving group, and on the other hand, 147 the pyridinium chloride with such ortho-substituents has a lower protonation capacity for 148 azirines.
149 Table 2. Optimization of the reaction conditions for the synthesis of morpholide 7. Then, experiments were carried out with various amines, 6a-h, under optimal con-151 ditions (entry 3 of Table 2). The use of these reaction conditions allowed for the prepara-152 tion of amides 7 in higher yields (excluding 7c): 7a (90%), 7b (62%), 7c (35%), 7d (75%), 7e 153 (53%), 7f (86%), 7g (72%), and 7h (91%) (Scheme 3, footnote a). A dramatic increase in 154 yield was significant in the case of tert-butylamine (6h). We noted that the yield of amide 155 7h was only 42% in the direct reaction of chloride 1a with 2 equiv. of 6h. Importantly, the 156 reaction with aniline gave anilide 7f, which was not available by other approaches [10-157 17], in an 86% yield. 158 The scope of the reaction with various 2H-azirine-2-carbonyl chlorides 1 was evalu-159 ated using tert-butyl amine (6h) as the N-nucleophile. Amides 7h-q were obtained in 60-160 ( Table 2). The best results in terms of the yield of amide 7a and the economical use of 140 reagents correspond to experiment 3. It was also seen that the use of acetyl chloride ( Ta-141 ble 2, entry 6) for the above purposes was much less efficient than ethyl chloroformate, 142 which may be due to the fact that salt F, with AcOinstead of EtO2CO -, can better catalyze 143 the decomposition of azirines, being a salt of a stronger acid. 144 High yields of amides 7 using pyridines with bulky ortho-substituents (Table 2) may 145 be because, on the one hand, the C(O)-N bond in salt A (Scheme 5) in such compounds is 146 weaker, making the respective pyridinium a better leaving group, and on the other hand, 147 the pyridinium chloride with such ortho-substituents has a lower protonation capacity for 148 azirines.
149 Table 2. Optimization of the reaction conditions for the synthesis of morpholide 7. Then, experiments were carried out with various amines, 6a-h, under optimal con-151 ditions (entry 3 of Table 2). The use of these reaction conditions allowed for the prepara-152 tion of amides 7 in higher yields (excluding 7c): 7a (90%), 7b (62%), 7c (35%), 7d (75%), 7e 153 (53%), 7f (86%), 7g (72%), and 7h (91%) (Scheme 3, footnote a). A dramatic increase in 154 yield was significant in the case of tert-butylamine (6h). We noted that the yield of amide 155 7h was only 42% in the direct reaction of chloride 1a with 2 equiv. of 6h. Importantly, the 156 reaction with aniline gave anilide 7f, which was not available by other approaches [10-157 17], in an 86% yield. 158 The scope of the reaction with various 2H-azirine-2-carbonyl chlorides 1 was evalu-159 ated using tert-butyl amine (6h) as the N-nucleophile. Amides 7h-q were obtained in 60-160 0 6 ( Table 2). The best results in terms of the yield of amide 7a and the economical use of 140 reagents correspond to experiment 3. It was also seen that the use of acetyl chloride (Ta-141 ble 2, entry 6) for the above purposes was much less efficient than ethyl chloroformate, 142 which may be due to the fact that salt F, with AcOinstead of EtO2CO -, can better catalyze 143 the decomposition of azirines, being a salt of a stronger acid. 144 High yields of amides 7 using pyridines with bulky ortho-substituents (Table 2) may 145 be because, on the one hand, the C(O)-N bond in salt A (Scheme 5) in such compounds is 146 weaker, making the respective pyridinium a better leaving group, and on the other hand, 147 the pyridinium chloride with such ortho-substituents has a lower protonation capacity for 148 azirines.
149 Table 2. Optimization of the reaction conditions for the synthesis of morpholide 7. Then, experiments were carried out with various amines, 6a-h, under optimal con-151 ditions (entry 3 of Table 2). The use of these reaction conditions allowed for the prepara-152 tion of amides 7 in higher yields (excluding 7c): 7a (90%), 7b (62%), 7c (35%), 7d (75%), 7e 153 (53%), 7f (86%), 7g (72%), and 7h (91%) (Scheme 3, footnote a). A dramatic increase in 154 yield was significant in the case of tert-butylamine (6h). We noted that the yield of amide 155 7h was only 42% in the direct reaction of chloride 1a with 2 equiv. of 6h. Importantly, the 156 reaction with aniline gave anilide 7f, which was not available by other approaches [10-157 17], in an 86% yield. 158 The scope of the reaction with various 2H-azirine-2-carbonyl chlorides 1 was evalu-159 ated using tert-butyl amine (6h) as the N-nucleophile. Amides 7h-q were obtained in 60-160 Molecules 2022, 27, x FOR PEER REVIEW 7 of 18 ( Table 2). The best results in terms of the yield of amide 7a and the economical use of 140 reagents correspond to experiment 3. It was also seen that the use of acetyl chloride (Ta-141 ble 2, entry 6) for the above purposes was much less efficient than ethyl chloroformate, 142 which may be due to the fact that salt F, with AcOinstead of EtO2CO -, can better catalyze 143 the decomposition of azirines, being a salt of a stronger acid. 144 High yields of amides 7 using pyridines with bulky ortho-substituents (Table 2) may 145 be because, on the one hand, the C(O)-N bond in salt A (Scheme 5) in such compounds is 146 weaker, making the respective pyridinium a better leaving group, and on the other hand, 147 the pyridinium chloride with such ortho-substituents has a lower protonation capacity for 148 azirines.
149 Table 2. Optimization of the reaction conditions for the synthesis of morpholide 7. 12 -0 Then, experiments were carried out with various amines, 6a-h, under optimal con-151 ditions (entry 3 of Table 2). The use of these reaction conditions allowed for the prepara-152 tion of amides 7 in higher yields (excluding 7c): 7a (90%), 7b (62%), 7c (35%), 7d (75%), 7e 153 (53%), 7f (86%), 7g (72%), and 7h (91%) (Scheme 3, footnote a). A dramatic increase in 154 yield was significant in the case of tert-butylamine (6h). We noted that the yield of amide 155 7h was only 42% in the direct reaction of chloride 1a with 2 equiv. of 6h. Importantly, the 156 reaction with aniline gave anilide 7f, which was not available by other approaches [10-157 17], in an 86% yield. 158 The scope of the reaction with various 2H-azirine-2-carbonyl chlorides 1 was evalu-159 ated using tert-butyl amine (6h) as the N-nucleophile. Amides 7h-q were obtained in 60-160  Table 2). The best results in terms of the yield of amide 7a and the economical use of 140 reagents correspond to experiment 3. It was also seen that the use of acetyl chloride (Ta-141 ble 2, entry 6) for the above purposes was much less efficient than ethyl chloroformate, 142 which may be due to the fact that salt F, with AcOinstead of EtO2CO -, can better catalyze 143 the decomposition of azirines, being a salt of a stronger acid. 144 High yields of amides 7 using pyridines with bulky ortho-substituents (Table 2) may 145 be because, on the one hand, the C(O)-N bond in salt A (Scheme 5) in such compounds is 146 weaker, making the respective pyridinium a better leaving group, and on the other hand, 147 the pyridinium chloride with such ortho-substituents has a lower protonation capacity for 148 azirines. 149 Table 2. Optimization of the reaction conditions for the synthesis of morpholide 7. Then, experiments were carried out with various amines, 6a-h, under optimal con-151 ditions (entry 3 of Table 2). The use of these reaction conditions allowed for the prepara-152 tion of amides 7 in higher yields (excluding 7c): 7a (90%), 7b (62%), 7c (35%), 7d (75%), 7e 153 (53%), 7f (86%), 7g (72%), and 7h (91%) (Scheme 3, footnote a). A dramatic increase in 154 yield was significant in the case of tert-butylamine (6h). We noted that the yield of amide 155 7h was only 42% in the direct reaction of chloride 1a with 2 equiv. of 6h. Importantly, the 156 reaction with aniline gave anilide 7f, which was not available by other approaches [10-157 17], in an 86% yield. 158 The scope of the reaction with various 2H-azirine-2-carbonyl chlorides 1 was evalu-159 ated using tert-butyl amine (6h) as the N-nucleophile. Amides 7h-q were obtained in 60-160 ( Table 2). The best results in terms of the yield of amide 7a and the economical use of 140 reagents correspond to experiment 3. It was also seen that the use of acetyl chloride (Ta-141 ble 2, entry 6) for the above purposes was much less efficient than ethyl chloroformate, 142 which may be due to the fact that salt F, with AcOinstead of EtO2CO -, can better catalyze 143 the decomposition of azirines, being a salt of a stronger acid. 144 High yields of amides 7 using pyridines with bulky ortho-substituents (Table 2) may 145 be because, on the one hand, the C(O)-N bond in salt A (Scheme 5) in such compounds is 146 weaker, making the respective pyridinium a better leaving group, and on the other hand, 147 the pyridinium chloride with such ortho-substituents has a lower protonation capacity for 148 azirines.
149 Table 2. Optimization of the reaction conditions for the synthesis of morpholide 7.

-0
Then, experiments were carried out with various amines, 6a-h, under optimal con-151 ditions (entry 3 of Table 2). The use of these reaction conditions allowed for the prepara-152 tion of amides 7 in higher yields (excluding 7c): 7a (90%), 7b (62%), 7c (35%), 7d (75%), 7e 153 (53%), 7f (86%), 7g (72%), and 7h (91%) (Scheme 3, footnote a). A dramatic increase in 154 yield was significant in the case of tert-butylamine (6h). We noted that the yield of amide 155 7h was only 42% in the direct reaction of chloride 1a with 2 equiv. of 6h. Importantly, the 156 reaction with aniline gave anilide 7f, which was not available by other approaches [10-157 17], in an 86% yield. 158 The scope of the reaction with various 2H-azirine-2-carbonyl chlorides 1 was evalu-159 ated using tert-butyl amine (6h) as the N-nucleophile. Amides 7h-q were obtained in 60-160  Table 2). The best results in terms of the yield of amide 7a and the economical use of 140 reagents correspond to experiment 3. It was also seen that the use of acetyl chloride (Ta-141 ble 2, entry 6) for the above purposes was much less efficient than ethyl chloroformate, 142 which may be due to the fact that salt F, with AcOinstead of EtO2CO -, can better catalyze 143 the decomposition of azirines, being a salt of a stronger acid. 144 High yields of amides 7 using pyridines with bulky ortho-substituents (Table 2) may 145 be because, on the one hand, the C(O)-N bond in salt A (Scheme 5) in such compounds is 146 weaker, making the respective pyridinium a better leaving group, and on the other hand, 147 the pyridinium chloride with such ortho-substituents has a lower protonation capacity for 148 azirines.
149 Table 2. Optimization of the reaction conditions for the synthesis of morpholide 7. Then, experiments were carried out with various amines, 6a-h, under optimal con-151 ditions (entry 3 of Table 2). The use of these reaction conditions allowed for the prepara-152 tion of amides 7 in higher yields (excluding 7c): 7a (90%), 7b (62%), 7c (35%), 7d (75%), 7e 153 (53%), 7f (86%), 7g (72%), and 7h (91%) (Scheme 3, footnote a). A dramatic increase in 154 yield was significant in the case of tert-butylamine (6h). We noted that the yield of amide 155 7h was only 42% in the direct reaction of chloride 1a with 2 equiv. of 6h. Importantly, the 156 ( Table 2). The best results in terms of the yield of amide 7a and the economical use of 140 reagents correspond to experiment 3. It was also seen that the use of acetyl chloride (Ta-141 ble 2, entry 6) for the above purposes was much less efficient than ethyl chloroformate, 142 which may be due to the fact that salt F, with AcOinstead of EtO2CO -, can better catalyze 143 the decomposition of azirines, being a salt of a stronger acid. 144 High yields of amides 7 using pyridines with bulky ortho-substituents (Table 2) may 145 be because, on the one hand, the C(O)-N bond in salt A (Scheme 5) in such compounds is 146 weaker, making the respective pyridinium a better leaving group, and on the other hand, 147 the pyridinium chloride with such ortho-substituents has a lower protonation capacity for 148 azirines.
149 Table 2. Optimization of the reaction conditions for the synthesis of morpholide 7.

-0
Then, experiments were carried out with various amines, 6a-h, under optimal con-151 ditions (entry 3 of Table 2). The use of these reaction conditions allowed for the prepara-152 tion of amides 7 in higher yields (excluding 7c): 7a (90%), 7b (62%), 7c (35%), 7d (75%), 7e 153 (53%), 7f (86%), 7g (72%), and 7h (91%) (Scheme 3, footnote a). A dramatic increase in 154 yield was significant in the case of tert-butylamine (6h). We noted that the yield of amide 155 7h was only 42% in the direct reaction of chloride 1a with 2 equiv. of 6h. Importantly, the 156 reaction with aniline gave anilide 7f, which was not available by other approaches [10-157 17], in an 86% yield. 158 The scope of the reaction with various 2H-azirine-2-carbonyl chlorides 1 was evalu-159 ated using tert-butyl amine (6h) as the N-nucleophile. Amides 7h-q were obtained in 60-160  Table 2). The best results in terms of the yield of amide 7a and the economical use of 140 reagents correspond to experiment 3. It was also seen that the use of acetyl chloride (Ta-141 ble 2, entry 6) for the above purposes was much less efficient than ethyl chloroformate, 142 which may be due to the fact that salt F, with AcOinstead of EtO2CO -, can better catalyze 143 the decomposition of azirines, being a salt of a stronger acid. 144 High yields of amides 7 using pyridines with bulky ortho-substituents (Table 2) may 145 be because, on the one hand, the C(O)-N bond in salt A (Scheme 5) in such compounds is 146 weaker, making the respective pyridinium a better leaving group, and on the other hand, 147 the pyridinium chloride with such ortho-substituents has a lower protonation capacity for 148 azirines.
149 Table 2. Optimization of the reaction conditions for the synthesis of morpholide 7. Then, experiments were carried out with various amines, 6a-h, under optimal con-151 ditions (entry 3 of Table 2). The use of these reaction conditions allowed for the prepara-152 tion of amides 7 in higher yields (excluding 7c): 7a (90%), 7b (62%), 7c (35%), 7d (75%), 7e 153  Table 2). The best results in terms of the yield of amide 7a and the economical use of 140 reagents correspond to experiment 3. It was also seen that the use of acetyl chloride (Ta-141 ble 2, entry 6) for the above purposes was much less efficient than ethyl chloroformate, 142 which may be due to the fact that salt F, with AcOinstead of EtO2CO -, can better catalyze 143 the decomposition of azirines, being a salt of a stronger acid. 144 High yields of amides 7 using pyridines with bulky ortho-substituents (Table 2) may 145 be because, on the one hand, the C(O)-N bond in salt A (Scheme 5) in such compounds is 146 weaker, making the respective pyridinium a better leaving group, and on the other hand, 147 the pyridinium chloride with such ortho-substituents has a lower protonation capacity for 148 azirines.
149 Table 2. Optimization of the reaction conditions for the synthesis of morpholide 7. Then, experiments were carried out with various amines, 6a-h, under optimal con-151 ditions (entry 3 of Table 2). The use of these reaction conditions allowed for the prepara-152 tion of amides 7 in higher yields (excluding 7c): 7a (90%), 7b (62%), 7c (35%), 7d (75%), 7e 153 (53%), 7f (86%), 7g (72%), and 7h (91%) (Scheme 3, footnote a). A dramatic increase in 154 yield was significant in the case of tert-butylamine (6h). We noted that the yield of amide 155 7h was only 42% in the direct reaction of chloride 1a with 2 equiv. of 6h. Importantly, the 156 reaction with aniline gave anilide 7f, which was not available by other approaches [10-157 17], in an 86% yield. 158 The scope of the reaction with various 2H-azirine-2-carbonyl chlorides 1 was evalu-159 ated using tert-butyl amine (6h) as the N-nucleophile. Amides 7h-q were obtained in 60-160  Table 2). The best results in terms of the yield of amide 7a and the economical use of 140 reagents correspond to experiment 3. It was also seen that the use of acetyl chloride (Ta-141 ble 2, entry 6) for the above purposes was much less efficient than ethyl chloroformate, 142 which may be due to the fact that salt F, with AcOinstead of EtO2CO -, can better catalyze 143 the decomposition of azirines, being a salt of a stronger acid. 144 High yields of amides 7 using pyridines with bulky ortho-substituents (Table 2) may 145 be because, on the one hand, the C(O)-N bond in salt A (Scheme 5) in such compounds is 146 weaker, making the respective pyridinium a better leaving group, and on the other hand, 147 the pyridinium chloride with such ortho-substituents has a lower protonation capacity for 148 azirines.
149 Table 2. Optimization of the reaction conditions for the synthesis of morpholide 7.  Table 2). The best results in terms of the yield of amide 7a and the economical use of 140 reagents correspond to experiment 3. It was also seen that the use of acetyl chloride (Ta-141 ble 2, entry 6) for the above purposes was much less efficient than ethyl chloroformate, 142 which may be due to the fact that salt F, with AcOinstead of EtO2CO -, can better catalyze 143 the decomposition of azirines, being a salt of a stronger acid. 144 High yields of amides 7 using pyridines with bulky ortho-substituents (Table 2) may 145 be because, on the one hand, the C(O)-N bond in salt A (Scheme 5) in such compounds is 146 weaker, making the respective pyridinium a better leaving group, and on the other hand, 147 the pyridinium chloride with such ortho-substituents has a lower protonation capacity for 148 azirines.
149 Table 2. Optimization of the reaction conditions for the synthesis of morpholide 7. Then, experiments were carried out with various amines, 6a-h, under optimal con-151 ditions (entry 3 of Table 2). The use of these reaction conditions allowed for the prepara-152 tion of amides 7 in higher yields (excluding 7c): 7a (90%), 7b (62%), 7c (35%), 7d (75%), 7e 153 (53%), 7f (86%), 7g (72%), and 7h (91%) (Scheme 3, footnote a). A dramatic increase in 154 yield was significant in the case of tert-butylamine (6h). We noted that the yield of amide 155 7h was only 42% in the direct reaction of chloride 1a with 2 equiv. of 6h. Importantly, the 156 reaction with aniline gave anilide 7f, which was not available by other approaches [10-157 17], in an 86% yield. 158 The scope of the reaction with various 2H-azirine-2-carbonyl chlorides 1 was evalu-159 ated using tert-butyl amine (6h) as the N-nucleophile. Amides 7h-q were obtained in 60-160  Table 2). The best results in terms of the yield of amide 7a and the economical use of 140 reagents correspond to experiment 3. It was also seen that the use of acetyl chloride (Ta-141 ble 2, entry 6) for the above purposes was much less efficient than ethyl chloroformate, 142 which may be due to the fact that salt F, with AcOinstead of EtO2CO -, can better catalyze 143 the decomposition of azirines, being a salt of a stronger acid. 144 High yields of amides 7 using pyridines with bulky ortho-substituents (Table 2) may 145 be because, on the one hand, the C(O)-N bond in salt A (Scheme 5) in such compounds is 146 weaker, making the respective pyridinium a better leaving group, and on the other hand, 147 the pyridinium chloride with such ortho-substituents has a lower protonation capacity for 148 azirines.
149 Table 2. Optimization of the reaction conditions for the synthesis of morpholide 7.  Table 2). The best results in terms of the yield of amide 7a and the economical use of 140 reagents correspond to experiment 3. It was also seen that the use of acetyl chloride (Ta-141 ble 2, entry 6) for the above purposes was much less efficient than ethyl chloroformate, 142 which may be due to the fact that salt F, with AcOinstead of EtO2CO -, can better catalyze 143 the decomposition of azirines, being a salt of a stronger acid. 144 High yields of amides 7 using pyridines with bulky ortho-substituents (Table 2) may 145 be because, on the one hand, the C(O)-N bond in salt A (Scheme 5) in such compounds is 146 weaker, making the respective pyridinium a better leaving group, and on the other hand, 147 the pyridinium chloride with such ortho-substituents has a lower protonation capacity for 148 azirines.
149 Table 2. Optimization of the reaction conditions for the synthesis of morpholide 7. Then, experiments were carried out with various amines, 6a-h, under optimal con-151 ditions (entry 3 of Table 2). The use of these reaction conditions allowed for the prepara-152 tion of amides 7 in higher yields (excluding 7c): 7a (90%), 7b (62%), 7c (35%), 7d (75%), 7e 153 (53%), 7f (86%), 7g (72%), and 7h (91%) (Scheme 3, footnote a). A dramatic increase in 154 yield was significant in the case of tert-butylamine (6h). We noted that the yield of amide 155 7h was only 42% in the direct reaction of chloride 1a with 2 equiv. of 6h. Importantly, the 156 reaction with aniline gave anilide 7f, which was not available by other approaches [10-157 17], in an 86% yield. 158 The scope of the reaction with various 2H-azirine-2-carbonyl chlorides 1 was evalu-159 ated using tert-butyl amine (6h) as the N-nucleophile. Amides 7h-q were obtained in 60-160  Table 2). The best results in terms of the yield of amide 7a and the economical use of 140 reagents correspond to experiment 3. It was also seen that the use of acetyl chloride (Ta-141 ble 2, entry 6) for the above purposes was much less efficient than ethyl chloroformate, 142 which may be due to the fact that salt F, with AcOinstead of EtO2CO -, can better catalyze 143 the decomposition of azirines, being a salt of a stronger acid. 144 High yields of amides 7 using pyridines with bulky ortho-substituents (Table 2) may 145 be because, on the one hand, the C(O)-N bond in salt A (Scheme 5) in such compounds is 146 weaker, making the respective pyridinium a better leaving group, and on the other hand, 147 the pyridinium chloride with such ortho-substituents has a lower protonation capacity for 148 azirines.
149 Table 2. Optimization of the reaction conditions for the synthesis of morpholide 7. Then, experiments were carried out with various amines, 6a-h, under optimal con-151 ditions (entry 3 of Table 2). The use of these reaction conditions allowed for the prepara-152 tion of amides 7 in higher yields (excluding 7c): 7a (90%), 7b (62%), 7c (35%), 7d (75%), 7e 153 (53%), 7f (86%), 7g (72%), and 7h (91%) (Scheme 3, footnote a). A dramatic increase in 154 yield was significant in the case of tert-butylamine (6h). We noted that the yield of amide 155 7h was only 42% in the direct reaction of chloride 1a with 2 equiv. of 6h. Importantly, the 156 reaction with aniline gave anilide 7f, which was not available by other approaches [10-157 17], in an 86% yield. 158 The scope of the reaction with various 2H-azirine-2-carbonyl chlorides 1 was evalu-159 ated using tert-butyl amine (6h) as the N-nucleophile. Amides 7h-q were obtained in 60-160 0 Amines 6 differ considerably in nucleophilicity [22] and basicity [23], which affects the rate of their acylation with azirinecarbonyl chlorides 1 and the relative rate of decomposition of the starting azirines 1 and products 7 (vide supra). For instance, the difference in the relative rate of decomposition of azirine 7h in the presence of different amines was demonstrated by 1 H NMR analysis of equimolar mixtures of azirine 7h with tert-butylamine and azirine 7h with morpholine in C 6 D 6 . In the first mixture, primarily starting substances were detected after 1 h, and there was 85% decomposition of azirine 7h with the formation of a complex mixture of products after 10 h, while in the second mixture, complete decomposition of azirine 7h was recorded after 1 h. of anhydride, but it is difficult to control the exact amount of water required for the re-106 action on a 1 mmol scale without technically complicating the reaction procedure. The formation of anhydride 10 due to the presence of traces water suggests an ad-113 ditional route for the formation of amides through the reaction of an amine with an an-114 hydride. Thus, the formation of amides 7 can proceed via several mechanisms that can 115 operate simultaneously: (1) direct interaction of chloride 1a with amines 6 (Scheme 5, 116 route a); (2) pathways mediated by a pyridine via salt A (Scheme 5, route b); and (3) 117 formation of anhydride 10, initiated by traces of water, followed by reaction of this an-118 hydride with amines 6 (Scheme 5, route c).  The formation of anhydride 10 due to the presence of traces ditional route for the formation of amides through the reaction of hydride. Thus, the formation of amides 7 can proceed via several operate simultaneously: (1) direct interaction of chloride 1a with route a); (2) pathways mediated by a pyridine via salt A (Schem formation of anhydride 10, initiated by traces of water, followed b hydride with amines 6 (Scheme 5, route c). In order to partially smooth out the differences in the nucleophilicity and basicity of the amines, we decided to increase the excess of amine to 3 equiv. to accelerate the rate of amide formation and reduce the effect of this excess on the decomposition of azirines and add ethyl chloroformate. We assumed that such an additive could, on the one hand, create an additional pathway for the formation of amide 7 and, on the other hand, neutralize the unfavorable effect of an excess of amine by converting it into amide E and a salt of weak acid F. The latter, in contrast to the corresponding hydrochloride salt, should not protonate azirines and thus initiate their decomposition by amines (Scheme 5, route d). To check this hypothesis, additional experiments were carried out to prepare amide 7a ( Table 2). The best results in terms of the yield of amide 7a and the economical use of reagents correspond to experiment 3. It was also seen that the use of acetyl chloride (Table 2, entry 6) for the above purposes was much less efficient than ethyl chloroformate, which may be due to the fact that salt F, with AcO − instead of EtO 2 CO − , can better catalyze the decomposition of azirines, being a salt of a stronger acid.

121
Amines 6 differ considerably in nucleophilicity [22] and basicity [23], which affects 122 the rate of their acylation with azirinecarbonyl chlorides 1 and the relative rate of de-123 composition of the starting azirines 1 and products 7 (vide supra). For instance, the dif-124 ference in the relative rate of decomposition of azirine 7h in the presence of different 125 amines was demonstrated by 1 H NMR analysis of equimolar mixtures of azirine 7h with 126 tert-butylamine and azirine 7h with morpholine in C6D6. In the first mixture, primarily 127 starting substances were detected after 1 h, and there was 85% decomposition of azirine 128 7h with the formation of a complex mixture of products after 10 h, while in the second 129 mixture, complete decomposition of azirine 7h was recorded after 1 h. 130 In order to partially smooth out the differences in the nucleophilicity and basicity of 131 the amines, we decided to increase the excess of amine to 3 equiv. to accelerate the rate of 132 amide formation and reduce the effect of this excess on the decomposition of azirines and 133 add ethyl chloroformate. We assumed that such an additive could, on the one hand, cre-134 ate an additional pathway for the formation of amide 7 and, on the other hand, neutralize 135 the unfavorable effect of an excess of amine by converting it into amide E and a salt of 136 weak acid F. The latter, in contrast to the corresponding hydrochloride salt, should not 137 protonate azirines and thus initiate their decomposition by amines (Scheme 5, route d). 138 To check this hypothesis, additional experiments were carried out to prepare amide 7a 139 Scheme 5. Plausible mechanisms for the formation of amides 7.
High yields of amides 7 using pyridines with bulky ortho-substituents (Table 2) may be because, on the one hand, the C(O)-N bond in salt A (Scheme 5) in such compounds is weaker, making the respective pyridinium a better leaving group, and on the other hand, the pyridinium chloride with such ortho-substituents has a lower protonation capacity for azirines.

General Instrumentation
Melting points were determined on a melting point apparatus SMP30. 1 H-NMR (400 MHz) and 13 C-NMR (100 MHz) spectra were recorded on a Bruker AVANCE 400 spectrometer in CDCl3 or C6D6. Chemical shifts (δ) were reported in parts per million downfield from tetramethylsilane (TMS, δ = 0.00). 1 H-NMR spectra were calibrated according to the residual peak of CDCl3 (7.28 ppm) and C6D6 (7.16 ppm). For all new compounds, 13 C{ 1 H} spectra were recorded and calibrated according to the peak of CDCl (77.00 ppm) and C6D6 (128.00 ppm). Electrospray ionization (ESI), positive mode, and mass spectra were measured on a Bruker MaXis mass spectrometer, HRMS-ESI-QTOF using MeOH for the dilution of samples. Single-crystal X-ray data were collected by means of "XtaLAB Synergy" and "SuperNova" diffractometers. The crystals of 7n and 10a were measured at a temperature of 99.9(8) K. Crystallographic data for the structure 7n (CCDC 2214535) and 10a (CCDC 2215155) have been deposited with the Cambridge Crystallographic Data Centre. Thin-layer chromatography (TLC) was conducted on aluminum sheets precoated with SiO2 ALUGRAM SIL G/UV254. Column chromatography was performed on Macherey-Nagel silica gel 60M (0.04-0.063 mm). Al solvents were distilled and dried prior to use. Toluene and diethyl ether were distilled and stored over sodium metal. MeCN was distilled from P2O5 and redistilled from K2CO3. 5-Chloroisoxazoles 2a [18], 2b [24], 2f,g,i [19], 2h [20], and 2j [25] are known compounds and were prepared by the reported procedures.

General Instrumentation
Melting points were determined on a melting point apparatus SMP30. 1 H-NMR (400 MHz) and 13 C-NMR (100 MHz) spectra were recorded on a Bruker AVANCE 400 spectrometer in CDCl 3 or C 6 D 6 . Chemical shifts (δ) were reported in parts per million downfield from tetramethylsilane (TMS, δ = 0.00). 1 H-NMR spectra were calibrated according to the residual peak of CDCl 3 (7.28 ppm) and C 6 D 6 (7.16 ppm). For all new compounds, 13 C{ 1 H} spectra were recorded and calibrated according to the peak of CDCl 3 (77.00 ppm) and C 6 D 6 (128.00 ppm). Electrospray ionization (ESI), positive mode, and mass spectra were measured on a Bruker MaXis mass spectrometer, HRMS-ESI-QTOF, using MeOH for the dilution of samples. Single-crystal X-ray data were collected by means of "XtaLAB Synergy" and "SuperNova" diffractometers. The crystals of 7n and 10a were measured at a temperature of 99.9(8) K. Crystallographic data for the structures 7n (CCDC 2214535) and 10a (CCDC 2215155) have been deposited with the Cambridge Crystallographic Data Centre. Thin-layer chromatography (TLC) was conducted on aluminum sheets precoated with SiO 2 ALUGRAM SIL G/UV254. Column chromatography was performed on Macherey-Nagel silica gel 60M (0.04-0.063 mm). All solvents were distilled and dried prior to use. Toluene and diethyl ether were distilled and stored over sodium metal. MeCN was distilled from P 2 O 5 and redistilled from K 2 CO 3 . 5-Chloroisoxazoles 2a [18], 2b [24], 2f,g,i [19], 2h [20], and 2j [25] are known compounds and were prepared by the reported procedures. (2) Triethylamine (253 mg, 2.5 mmol, 0.35 mL) was added dropwise at 0 • C to a stirring suspension of isoxazol-5(4H)-one (3 mmol) in POCl 3 (4 mL). The mixture was stirred at 75 • C for 12 h, poured into ice (300 g), and extracted with EtOAc (3 × 30 mL). The organic layer was washed with brine and dried over Na 2 SO 4 . The solvent was evaporated under reduced pressure, and the product was purified by column chromatography (petroleum ether-EtOAc, 10:1) to give chloroisoxazole 2. (7) Anhydrous FeCl 2 (51 mg, 0.4 mmol, 0.2 equiv.) was added to a solution of 5-chloroisoxazole 2 (2 mmol) in dry acetonitrile (4 mL) under an Ar atmosphere. The mixture was stirred at room temperature for 2 h until 5-chloroisoxazole 2 was consumed (monitored by TLC). The solvent was evaporated, the residue was diluted with dry diethyl ether (100 mL), and the precipitated iron chloride was filtered off through celite. The ether was evaporated under reduced pressure, and the formed 2H-azirine-2-carbonyl chloride 1 was dissolved in anhydrous toluene (4 mL). Then amine 6 (4 mmol, 2 equiv.) was added, and the reaction mixture was stirred at room temperature for 3 min. The solvent was evaporated, and the residue was purified by column chromatography (petroleum ether-EtOAc). (7) Anhydrous FeCl 2 (51 mg, 0.4 mmol, 0.2 equiv.) was added to a solution of 5-chloroisoxazole 2 (2 mmol) in dry acetonitrile (4 mL) under an Ar atmosphere. The mixture was stirred at room temperature for 2 h until 5-chloroisoxazole 2 was consumed (monitored by TLC). The solvent was evaporated, the residue was diluted with dry diethyl ether (100 mL), and the precipitated iron chloride was filtered off through celite. The ether was evaporated under reduced pressure, and the formed 2H-azirine-2-carbonyl chloride 1 was dissolved in anhydrous toluene (4 mL). Then 2-methylpyridine (186 mg, 2 mmol, 1 equiv.) and amine 6 (2 mmol, 1 equiv.) were added successively. The reaction mixture was stirred for 10 min at room temperature, the solvent was evaporated, and the residue was purified by column chromatography (petroleum ether-EtOAc). (7) Anhydrous FeCl 2 (51 mg, 0.4 mmol, 0.2 equiv.) was added to a solution of 5-chloroisoxazole 2 (2 mmol) in dry acetonitrile (4 mL) under an Ar atmosphere. The mixture was stirred at room temperature for 2 h until 5-chloroisoxazole 2 was consumed (monitored by TLC). The solvent was evaporated, the residue was diluted with dry diethyl ether (100 mL), and the precipitated iron chloride was filtered off through celite. The ether was evaporated under reduced pressure, and the formed 2H-azirine-2-carbonyl chloride 1 was dissolved in anhydrous toluene (2 mL). The resulting solution was added to a stirred mixture of 2-(trimethylsilyl)pyridine (151 mg, 1 mmol, 0.5 equiv.) and ethyl chloroformate (109 mg, 1 mmol, 0.5 equiv.) at room temperature. Then amine 6 (6 mmol, 3 equiv.) was added, and the reaction mixture was stirred for 5 min. The solvent was evaporated, and the residue was purified by column chromatography (petroleum ether-EtOAc).
3.2.6. General Procedure F (GP-F) for the Synthesis of Amides (7) Anhydrous FeCl 2 (51 mg, 0.4 mmol, 0.2 equiv.) was added to a solution of 5-chloroisoxazole 2 (2 mmol) in dry acetonitrile (25 mL) under an Ar atmosphere. The mixture was stirred at room temperature for 2 h until 5-chloroisoxazole 2 was consumed (monitored by TLC). Water (25 mL) was added, and the mixture was stirred at room temperature for 15 min. The 2H-azirine-2carboxylic acid was extracted with EtOAc (325 mL), washed with water (25 mL) and brine (10 mL), and dried over Na 2 SO 4 . The solvent was evaporated, and the residue was diluted with DMF (5 mL) and cooled to 0 • C. Then HATU (1.52 g, 4 mmol, 2 equiv.) and DIPEA (774 mg, 6 mmol, 3 equiv.) were added, and the reaction mixture was stirred at 0 • C for 10 min. After that, amine 6 (2.4 mmol, 1.2 equiv) was added, and the reaction mixture was stirred at room temperature for 10 min. The reaction mixture was then diluted with water (75 mL), extracted with EtOAc (3 × 25 mL), washed with brine (30 mL), and dried over Na 2 SO 4 . The solvent was evaporated, and the residue was purified by column chromatography (petroleum ether-EtOAc).