Metal-Catalyzed Isomerization of 5-Heteroatom-Substituted Isoxazoles as a New Route to 2-Halo-2 H -azirines

SYNTHESIS

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en

N. V. Rostovskii et al.

Paper

Synthesis

Metal-Catalyzed Isomerization of 5-Heteroatom-Substituted

Isoxazoles as a New Route to 2-Halo-2H-azirines

Nikolai V. Rostovskii

Anastasiya V. Agafonova

Ilia A. Smetanin

Mikhail S. Novikov*

Alexander F. Khlebnikov

Julia O. Ruvinskaya

Galina L. Starova

Saint Petersburg State University, Institute of Chemistry,

7/9 Universitetskaya nab., St. Petersburg, 199034,

Russian Federation

m.novikov@spbu.ru

Received: 17.05.2017

Accepted after revision: 03.06.2017

Published online: 03.08.2017

were synthesized via a one-, two-, or three-atom ring ex-

pansion of 2-haloazirines. Further development of these

methodologies requires a wide range of 2-haloazirines, the

synthesis of which is often a serious problem. Currently, the

Neber approach via dehydration of ketoximes¹³and the

‘non-classical Wittig reaction–vinyl azide thermal decom-

position’ sequence¹⁴are used for the preparation of 2-het-

eroatom-substituted 2H-azirines including 2-haloazirine-2-

carboxylates (Scheme 1).^14aThe vinyl azides are prepared

by acylation of α-oxophosphonium ylides with acyl chlo-

rides followed by azidohalogenation using the azido-

trimethylsilane/N-halosuccinimide system.

DOI: 10.1055/s-0036-1590822; Art ID: ss-2017-t0340-op

Abstract A convenient gram-scale method for the preparation of

2-halo-2H-azirine-2-carboxylic acid esters, thioesters and amides via

metal-catalyzed isomerization of 5-heteroatom-substituted 4-haloisox-

azoles is developed. The formation of the esters and amides is efficient-

ly catalyzed by Rh₂(Piv)₄, while FeCl₂·4H₂O is the catalyst of choice for

the synthesis of the thioesters. In addition, rhodium catalysis is success-

fully applied in the synthesis of azirine-2-carboxylates from non-haloge-

nated 5-alkoxyisoxazoles.

Key words azirines, isoxazoles, haloheterocycles, rhodium(II) carbox-

ylates, iron(II) chloride, catalysis, isomerization

Previous work

2H-Azirine-2-carboxylic acid derivatives have attracted

increased attention in recent years due to their unique bio-

logical and chemical properties.¹In particular, molecules

containing this structural element, viz. azirinomycin, dysi-

dazirine and antazirine, are found in nature and exhibit a

broad range of biological activity.²A number of novel meth-

ods to access useful nitrogen-containing heterocycles, such

as pyrroles,³imidazoles,^3c,4pyridines,⁵and pyrazines,⁶have

been recently developed employing azirine-2-carboxylates

and their isosteres as building blocks. Azirines containing a

good leaving group, such as Cl, Br or I, at the C2 position are

of special interest due to their ability to undergo various

transformations both with retention of the azirine system

and ring expansion.⁷For example, 2-bromoazirine-2-car-

boxylates have been recently used as starting materials for

the synthesis of functionalized azirines.⁸The presence of a

halogen atom at the C2 position of the azirine ring can also

substantially expand the range of the heterocycles that can

be synthesized via azirine ring expansion. Thus, 2,3-dihy-

droazetes,⁹oxazolines,^8a,9boxazoles,¹⁰isoxazoles,¹¹quinox-

alines,^8a2H-1,4-oxazines,^8aand 5H-1,4-benzodiazepines,¹²

O

N

N₃

Hal

COR²

PPh₃

R¹

Δ

Hal

COR²

Hal

R¹

TMSN₃

N

This work

Hal

COR²

R¹

R²

halogenation

cat.

R¹

R²

N

O

N

O

R¹= Alk, Ar; Hal = Cl, Br, I; R²= OAlk, NR₂, SR

Scheme 1 Synthesis of 2-halo-2H-azirine-2-carboxylates

The reaction is applicable for a variety of substituents

and usually gives high product yields. However, this meth-

od, as we have found out, does not apply in the case of the

synthesis of 2-halo-2H-azirine-2-carboxylates with elec-

tron-poor aryl substituents.^9bHere, chromatographic puri-

fication of the products is required, due to non-quantitative

yields in the last step, that leads to further diminishing of

the yields in the case of acid-sensitive azirines.

B

N. V. Rostovskii et al.

Paper

Synthesis

In a search for a concise and reliable method for the

preparation of a wide range of 2-haloazirine-2-carboxylic

acid derivatives in sizeable quantities, devoid of the above

disadvantages, we turned our attention to the isoxazole–

azirine rearrangement.¹⁵There are several reports describ-

ing catalytic variants of this reaction.¹⁶In 1997, Auricchio et

al. reported that 5-alkoxy- and 5-aminoisoxazoles isomeri-

ze smoothly into the corresponding 2H-azirine-2-carboxyl-

ates/carboxamides under iron(II) chloride (FeCl₂) cataly-

sis.^16cWe assumed that the use of readily available 4-ha-

loisoxazoles in such a reaction might provide a concise

approach to 2-halo-2H-azirine-2-carboxylic acid deriva-

tives (Scheme 1). Herein, we report a general method for

the synthesis of 2-halo-2H-azirines with 2-alkoxycarbonyl,

2-carbamoyl or 2-sulfanylcarbonyl substituents via catalyt-

ic N–O bond cleavage of 4-haloisoxazoles under Rh(II) or

Fe(II) catalysis.

A variety of methods for the synthesis of isoxazoles have

been developed to date.¹⁷In the current study, 4-bromo-, 4-

chloro-, and 4-iodoisoxazoles were synthesized starting

from the same precursors, isoxazolones 1, according to the

reaction sequence depicted in Scheme 2. 5-Methoxyisoxaz-

oles 3 were readily prepared from the corresponding isox-

azolones 1 in two steps via 5-chloro-3-phenylisoxazole

(2),¹⁸or in one step using diazomethane.^9cOther 5-alkoxy-

isoxazoles 4,¹⁸5-aminoisoxazoles 5¹⁹and 5-sulfanylisoxaz-

oles 6^18,19were synthesized via replacement of chlorine in

5-chloro-3-phenylisoxazole (2). 4-Bromo- and 4-chloro-

substituted isoxazoles 8 and 9 were obtained from the cor-

responding 4-unsubstituted isoxazoles 3–6 by treatment

with N-bromosuccinimide^9cor sulfuryl chloride,¹⁹respec-

tively. 4-Iodoisoxazole 7 was prepared via the known reac-

tion of the corresponding 4-lithioisoxazole derivative with

iodine.¹⁸

Our first experiments showed that the isomerization of

4-bromo-5-methoxy-3-phenylisoxazole (8a) proceeded

smoothly under FeCl₂·4H₂O (30 mol%) catalysis in acetoni-

trile at ambient temperature within 24 hours, affording the

corresponding 2-bromo-2H-azirine 10a in good yield (Table

1, entry 1). A decrease in the catalyst loading led to incom-

plete conversion of the 5-methoxyisoxazole. Despite the

high efficiency of the reaction, chromatographic purifica-

tion for removal of iron-containing compounds cannot be

avoided. This fact prompted us to perform an additional

screening of catalysts for the isomerization. It is known that

Rh₂(OAc)₄isomerizes 2H-azirine-2-carbaldehydes into the

more thermodynamically stable 3-aryl/3,4-diaryl isoxaz-

oles, probably via formation of a rhodium(II)–nitrene com-

plex.²⁰In contrast, according to quantum chemical calcula-

tions, azirine-2-carboxylic acid derivatives are more ther-

modynamically stable than their isoxazole isomers.¹⁵We

speculated, based on these facts, that Rh₂(OAc)₄can induce

the isomerization of 4-haloisoxazoles into azirines. When

isoxazole 8a was treated with Rh₂(OAc)₄(0.5 mol%) in tolu-

ene under reflux, azirine 10a was formed quantitatively

within 1 hour (entry 2). Dirhodium tetrapivalate [Rh₂(Piv)₄]

proved to be a much more effective catalyst, enabling the

completion of the reaction in 0.5 hours at 0.1 mol% catalyst

loading (entry 3). Since most 2-haloazirines are solids, sim-

ple washing of the crude residue, obtained by concentration

of the reaction mixture in vacuo, with hexane–diethyl ether

mixture, was sufficient to remove Rh₂(Piv)₄traces from the

product. To our delight, the use of Rh₂(Piv)₄led to a smooth

isomerization of 4-iodoisoxazole 7 to afford 2-iodoazirine

10b in 92% yield (entry 4). Further isomerization reactions

were carried out in refluxing toluene using Rh₂(Piv)₄as the

catalyst.

By using this procedure, 2-bromoazirines 10c–g with

electron-donating and electron-withdrawing substituents

on the phenyl ring were obtained in excellent yields (Table

1, entries 5–9). In addition, various 2-chloro-substituted

azirines 10h–q were efficiently synthesized by using the

above procedure (entries 10–19). It should be noted that

azirines 10f,g,j are unstable on silica, so their synthesis can

only be performed by a chromatography-free procedure

(entries 8, 9 and 12). 5-Aminoisoxazoles 9f–i proved to be

less reactive than 5-alkoxyisoxazoles and underwent isom-

erization into the corresponding 2-haloazirines 10m–p

within 8–44 hours with higher catalyst loadings (entries

15–18). An exception to this was the isomerization of N-(1-

adamantylmethyl)isoxazole (9j) which, surprisingly, dis-

played a reactivity comparable with that of 5-alkoxyisoxaz-

oles (entry 19).

I

R¹

O

1) n-BuLi; 2) I₂

Ph

OMe

R¹= Ph

N

O

N

O

1

7

CH₂N₂

R¹= Ph

Ph

POCl₃

Cl

Br

R¹

OMe

R²

NBS

MeONa

N

O

N

O

N O

SO₂Cl₂

8a–g

3a–i

2

NaOAlk

NBS

or HNR₂

or HSR³

Cl

R¹

R²

SO₂Cl₂

Ph

R²

N

O

N

O

4a,b,5a–e,6a,b

9a–n

1, 3: R¹= Ph (a), 4-MeC₆H₄(b), 4-MeOC₆H₄(c), 3,4-[O(CH₂)₂O]C₆H₃(d),

4-ClC₆H₄(e), 4-O₂NC₆H₄(f), 2,5-(Me)₂C₆H₃(g), Me (h), cyclopropyl (i)

4: R²= OHex (a), OBn (b)

To test the ability to scale up the synthesis, a gram-scale

reaction of 4-bromoisoxazole 8a (3.56 g, 14 mmol) in the

presence of Rh₂(Piv)₄(8.5 mg, 0.1 mol%) was carried out

giving 2-bromoazirine 10a in 96% yield. This is the same

yield as that observed in the small-scale reaction (entry 3).

5: R²= pyrrolidin-1-yl (a), morpholin-4-yl (b), N(Me)Bn (c), NEt₂(d), NHCH₂Ad (e)

6: R²= SCH₂CF₃(a), SPh (b)

Scheme 2 Synthesis of 4-haloisoxazoles

C

N. V. Rostovskii et al.

Paper

Synthesis

Table 1 Isomerization of 4-Haloisoxazoles into 2-Halo-2H-azirines^a

Hal

R¹

catalyst

R²

R¹

conditions

N

O

N

O

7–9

10

Entry

Isoxazole

R¹

Ph

Halide

R²

Catalyst (mol%)

Time

Yield of 10 (%)^b

1

2

8a

7

Br

I

MeO

FeCl₂·4H₂O (30)

Rh₂(OAc)₄(0.5)

Rh₂(Piv)₄(0.1)

Rh₂(Piv)₄(0.2)

Rh₂(Piv)₄(0.1)

Rh₂(Piv)₄(0.2)

Rh₂(Piv)₄(1.0)

Rh₂(Piv)₄(0.5)

Rh₂(Piv)₄(0.6)

Rh₂(Piv)₄(1.0)

Rh₂(Piv)₄(0.1)

Rh₂(Piv)₄(1.5)

FeCl₂·4H₂O (60)

FeCl₂·4H₂O (30)

24 h

1 h

95 (10a)

96^c(10a)

92 (10b)

95 (10c)

97 (10d)

95 (10e)

94 (10f)

97 (10g)

96 (10h)

97 (10i)

95 (10j)

97 (10k)

85 (10l)

92 (10m)

90 (10n)

58 (10o)

60 (10p)

77 (10q)

20^d(10r)

66 (10r)

67 (10s)

90 (10t)

85 (10u)

Ph

MeO

3

Ph

MeO

0.5 h

1 h

4

Ph

MeO

5

8b

8c

8d

8e

8f

4-MeC₆H₄

Br

Cl

Br

Cl

MeO

0.5 h

0.75 h

0.5 h

2.5 h

1 h

6

4-MeOC₆H₄

MeO

7

3,4-[O(CH₂)₂O]C₆H₃

MeO

8

4-ClC₆H₄

MeO

9

4-O₂NC₆H₄

MeO

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

9a

9b

9c

9d

9e

9f

Ph

MeO

2,5-(Me)₂C₆H₃

MeO

4-ClC₆H₄

Ph

MeO

HexO

Ph

BnO

Ph

pyrrolidin-1-yl

morpholin-4-yl

Bn(Me)N

Et₂N

8 h

9g

9h

9i

Ph

28 h

44 h

0.5 h

18 h

7 d

Ph

9j

Ph

1-AdCH₂NH

CF₃CH₂S

PhS

9k

9l

Ph

36 h

6 d

8g

9m

Ph

PhS

Me

MeO

^aReaction conditions: isoxazole (1 mmol), Rh₂(Piv)₄, toluene (3 mL), 110 °C, or FeCl₂·4H₂O, MeCN (3 mL), r.t.; Piv = pivalate, Ad = 1-adamantyl.

^bYield of isolated product.

^cAzirine 10a (3.4 g, 96%) was obtained in a gram-scale reaction.

^dIsoxazole 9k (70%) was recovered.

Attempts to convert chlorinated 5-sulfanylisoxazole 9k

into thioester 10r under Rh(II) catalysis failed (Table 1, en-

try 20). Only a low conversion of the starting material was

observed, due to a strong complexation of the catalyst with

the sulfur atom. However, the replacement of Rh₂(Piv)₄by

FeCl₂·4H₂O permits the preparation of thioesters 10r–t in

good yields from isoxazoles 9k,l and 8g (entries 21–23). It

should be noted that the synthesis of thioesters 10r–t is the

first example of catalytic isomerization of 5-sulfanylisoxaz-

oles.²¹Rh(II)-catalyzed isomerization at 110 °C was also

found to be unsuitable for the synthesis of 3-methyl-2-

chloroazirine 10u, probably due to its thermal instability. In

contrast, a mild isomerization in the presence of FeCl₂·4H₂O

provided the desired azirine 10u in good yield (entry 24).

Unfortunately, all attempts to transform 4-chloro-3-cyclo-

propyl-5-methoxyisoxazole (9n) into its corresponding

azirine failed, regardless of the catalyst and conditions used.

1

All compounds 10 were characterized by H, ¹³C NMR

and HRMS data. The structures of azirines 10a (Figure 1)

and 10b (Figure 2) were additionally confirmed by X-ray

crystallography.²²All the synthesized 2-haloazirines 10 are

quite stable compounds and can be stored at 4 °C for

months without decomposition.

D

N. V. Rostovskii et al.

Paper

Synthesis

In summary, we have developed a simple, atom-eco-

nomic synthesis of 2H-azirine-2-carboxylic acid derivatives

via metal-catalyzed N–O bond cleavage of readily available

5-heteroatom-substituted isoxazoles including 4-haloge-

nated isoxazoles. The latter, in turn, can be easily obtained

in two or three steps from the corresponding isoxazolones.

The isomerization of 4-haloisoxazoles into 2-haloazirines

was found to be efficiently catalyzed by Rh(II) carboxylates

at very low catalyst loading. 2-Halo-2H-azirines can be pre-

pared on gram scale by this method, and in some cases, in a

chromatography-free manner. 3-Methyl- and 5-sulfanyl-

substituted 4-haloisoxazoles can be transformed into the

corresponding 2-haloazirines only under FeCl₂catalysis.

The ability of Rh₂(Piv)₄to catalyze the transformation of

non-halogenated 5-alkoxyisoxazoles into azirine-2-carbox-

ylates is also demonstrated for the first time. These synthe-

ses can be performed with practically complete regenera-

tion of the rhodium catalyst.

Figure 1 X-ray crystal structure of azirine 10a

Figure 2 X-ray crystal structure of azirine 10b

The Rh(II)-catalyzed isomerization can also be applied

to a range of non-halogenated 5-alkoxyisoxazoles (Table 2).

Alkyl, aryl, and methoxycarbonyl substituents at the C-4

position of the isoxazole are well tolerated in the reaction

(entries 3–5). The isomerization of 5-tert-butoxyisoxazole

4c requires a higher catalyst loading and a prolonged reac-

tion time, resulting in a lower product yield (entry 6). For-

tunately, Rh₂(Piv)₄can be fully recovered from the reactions

of non-halogenated isoxazoles if pure chloroform is used as

the eluent for chromatography.

All solvents were distilled and dried prior to use. Toluene was distilled

and stored over sodium metal. Chloroform was washed with concen-

trated H₂SO₄and water, then distilled from P₂O₅and stored refrigerat-

ed in the dark over anhydrous K₂CO₃. Acetonitrile was distilled from

P₂O₅and redistilled from K₂CO₃. The catalyst Rh₂(Piv)₄was prepared

by the reported procedure.²³Thin-layer chromatography (TLC) was

conducted on aluminum sheets precoated with SiO₂ALUGRAM SIL

G/UV254. Column chromatography was performed on Macherey-

Nagel silica gel 60 M (0.04–0.063 mm). Melting points were deter-

mined on an SMP30 melting point apparatus. ¹H (400 MHz) and ¹³C

(100 MHz) NMR spectra were recorded on a Bruker AVANCE 400

spectrometer in CDCl₃. Chemical shifts (δ) are reported in ppm down-

field from tetramethylsilane. Electrospray ionization (ESI), positive

mode, mass spectra were measured on a Bruker MaXis mass spec-

trometer using acetonitrile for dilution of samples. Elemental analysis

was performed using a Euro EA3028-HT analyzer. Single-crystal X-ray

data were collected using an Agilent Technologies ‘Xcalibur’ diffrac-

tometer.

Table 2 Isomerization of Non-Halogenated 5-Alkoxyisoxazoles into

Azirine-2-carboxylates^a

R²

R¹

Rh₂(Piv)₄

OR³

R¹

toluene, reflux

N

O

N

O

5-Alkoxyisoxazoles 3a,4a–c; General Procedure A

3 or 4c

11

To a stirred suspension of NaH (60% in mineral oil, 440 mg, 11 mmol,

prewashed with hexane) in anhydrous THF (20 mL) was added the

appropriate alcohol (15 mmol) at r.t. and the reaction mixture was

stirred for 0.5 h. Next, 5-chloro-3-phenylisoxazole (2)²¹(1.0 g, 5.6

mmol) was introduced as a solid and the mixture was refluxed for 1 h.

After cooling to r.t., the mixture was quenched with H₂O (20 mL). For

4a and 4b, the resulting precipitate was collected, washed with H₂O

and recrystallized from hexane–Et₂O mixture. For 3a, the reaction

mixture was extracted with CH₂Cl₂(3 × 20 mL). The combined organ-

ic layers were dried (Na₂SO₄) and concentrated in vacuo to give isox-

azole 3a. 5-tert-Butoxy-3-phenylisoxazole (4c)^3k,18was synthesized

analogously using commercially available potassium tert-butoxide.

Entry Isoxazole R¹

R²

R³

Rh₂(Piv)₄Time Yield of 11

(mol%) (h) (%)^b

1

2

3

4

5

6

3a

3j

Ph

H

Me

5.0

1.0

2.0

1.0

0.3

3.0

3

96 (11a)

90 (11b)

92 (11c)

90 (11d)

92 (11e)

81 (11f)

4-NCC₆H₄

H

Me

t-Bu

3k

3l

Ph

Me

Ph

9

3

3m

4c

CO₂Me

H

5

20

^aReaction conditions: isoxazole (1 mmol), Rh₂(Piv)₄, toluene (3 mL), 110 °C.

^bYield of isolated product.

5-Alkoxyisoxazoles 3a–m; General Procedure B

To a stirred suspension/solution of isoxazolone²⁴(5.6 mmol) in anhy-

drous Et₂O (50 mL) was added dropwise at 0 °C a solution of diazo-

methane (11.2 mmol) in Et₂O, prepared from N-nitroso-N-methylurea

Unlike other eluents, such as hexane–ethyl acetate or

hexane–diethyl ether mixtures, chloroform destroys the

azirine–Rh₂(Piv)₄complex and, therefore, allows successful

separation of the catalyst.

E

N. V. Rostovskii et al.

Paper

Synthesis

and KOH. The resulting mixture was stirred at r.t. for 2 h and then

concentrated in vacuo. The residue was purified by column chroma-

tography on silica gel (PE–EtOAc, 3:1).

Alkoxyisoxazoles 3a–e,j^9cand 3f,h^3kare known compounds and have

5-Hexyloxy-3-phenylisoxazole (4a)

Yield: 1.26 g (92%); colorless solid; mp 54–55 °C.

¹H NMR (400 MHz, CDCl₃): δ = 7.82–7.73 (m, 2 Н), 7.51–7.41 (m, 3 Н),

5.52 (s, 1 H), 4.25 (t, J = 6.5 Hz, 2 H), 1.92–1.80 (m, 2 Н), 1.55–1.44 (m,

2 Н), 1.43–1.31 (m, 4 Н), 1.00–0.88 (m, 3 Н).

full characterization data.

¹³С NMR (100 MHz, CDCl₃): δ = 173.9, 164.1, 129.9, 129.7, 128.7,

126.4, 75.6, 72.5, 31.3, 28.8, 25.3, 22.5, 13.9.

5-Methoxy-3-phenylisoxazole (3a)^9c

Yield according to general procedure A: 877 mg (89%); yield according

to general procedure B: 745 mg (76%); colorless solid.

¹H NMR (400 MHz, CDCl₃): δ = 7.82–7.72 (m, 2 Н), 7.51–7.41 (m, 3 Н),

5.55 (s, 1 H), 4.06 (s, 3 Н).

HRMS (ESI): m/z [M + Na]⁺calcd for С₁₅Н₁₉NO₂Na: 268.1308; found:

268.1309.

5-Benzyloxy-3-phenylisoxazole (4b)²⁶

Yield: 1.28 g (91%); colorless solid; mp 136–137 °C.

¹H NMR (400 MHz, CDCl₃): δ = 7.82–7.73 (m, 2 Н), 7.53–7.37 (m, 8 Н),

5.58 (s, 1 H), 5.32 (s, 2 H).

¹³С NMR (100 MHz, CDCl₃): δ = 173.4, 164.2, 134.3, 130.0, 129.5,

129.0, 128.78, 128.76, 128.0, 126.4, 76.6, 73.8.

HRMS (ESI): m/z [M + Na]⁺calcd for С₁₆Н₁₃NO₂Na: 274.0838; found:

274.0841.

3-(2,5-Dimethylphenyl)-5-methoxyisoxazole (3g)

Yield: 706 mg (62%); pale yellow oil.

¹H NMR (400 MHz, CDCl₃): δ = 7.32 (s, 1 H), 7.22–7.13 (m, 2 Н), 5.41

(s, 1 H), 4.06 (s, 3 H), 2.45 (s, 3 H), 2.37 (s, 3 H).

¹³С NMR (100 MHz, CDCl₃): δ = 173.8, 165.2, 135.4, 133.5, 130.9,

130.2, 129.8, 129.1, 78.1, 58.7, 20.8, 20.4.

HRMS (ESI): m/z [M + H]⁺calcd for C₁₂H₁₄NO₂: 204.1019; found:

204.1025.

5-Aminoisoxazoles 5a–e; General Procedure

A mixture of 5-chloro-3-phenylisoxazole (2)²¹(5 mmol), amine (10

mmol) and K₂CO₃(15 mmol) in DMF (25 mL) was refluxed under stir-

ring for 1.5 h. The reaction mixture was cooled and diluted with cold

H₂O (40 mL). For 5a and 5b, the resulting precipitate was collected,

washed with H₂O and recrystallized from hexane–Et₂O. For 5c–e, the

reaction mixture was extracted with CH₂Cl₂(3 × 20 mL). The com-

bined organic layers were dried (Na₂SO₄) and concentrated in vacuo.

The residue was purified by column chromatography on silica gel

(hexane–EtOAc, 5:1).

3-Cyclopropyl-5-methoxyisoxazole (3i)

Yield: 226 mg (29%); colorless oil.

¹H NMR (400 MHz, CDCl₃): δ = 4.68 (s, 1 H), 3.42 (s, 3 H), 1.56 (tt, J =

8.3, 5.0 Hz, 1 H), 1.17–1.10 (m, 2 H), 0.85–0.78 (m, 2 H).

¹³С NMR (100 MHz, CDCl₃): δ = 171.9, 171.1, 84.2, 37.8, 8.6, 7.1.

HRMS (ESI): m/z [M + H]⁺calcd for С₇Н₁₀NO₂: 140.0706; found:

140.0710.

5-Aminoisoxazoles 5a²⁷and 5b^19,28are known compounds and have

full characterization data.

5-Methoxy-4-methyl-3-phenylisoxazole (3k)²⁵

Yield: 636 mg (60%); colorless oil.

¹H NMR (400 MHz, CDCl₃): δ = 7.72–7.62 (m, 2 H), 7.53–7.42 (m, 3 H),

N-Benzyl-N-methyl-3-phenylisoxazol-5-amine (5c)

4.15 (s, 3 H), 1.98 (s, 3 H).

¹³С NMR (100 MHz, CDCl₃): δ = 169.6, 164.7, 130.3, 129.4, 128.7,

127.7, 86.5, 57.8, 6.5.

HRMS (ESI): m/z [M + H]⁺calcd for С₁₁Н₁₂NO₂: 190.0863; found:

Yield: 1.02 g (77%); colorless solid; mp 65–66 °C.

¹H NMR (400 MHz, CDCl₃): δ = 7.83–7.74 (m, 2 H), 7.49–7.29 (m, 8 H),

5.29 (s, 1 H), 4.57 (s, 2 H), 3.01 (s, 3 H).

¹³С NMR (100 MHz, CDCl₃): δ = 171.1, 163.8, 136.5, 130.1, 129.5,

190.0868.

128.7, 128.6, 127.7, 127.6, 126.6, 75.2, 55.0, 36.3.

HRMS (ESI): m/z [M + H]⁺calcd for С₁₇Н₁₇N₂O: 265.1335; found:

265.1338.

5-Methoxy-3,4-diphenylisoxazole (3l)

Yield: 886 mg (63%); colorless oil.

¹H NMR (400 MHz, CDCl₃): δ = 7.53–7.22 (m, 10 H), 4.21 (s, 3 H).

N,N-Diethyl-3-phenylisoxazol-5-amine (5d)

¹³С NMR (100 MHz, CDCl₃): δ = 168.9, 163.6, 129.62, 129.57, 129.1,

Yield: 896 mg (83%); colorless oil.

¹H NMR (400 MHz, CDCl₃): δ = 7.81–7.75 (m, 2 H), 7.47–7.39 (m, 3 H),

5.19 (s, 1 H), 3.41 (q, J = 7.1 Hz, 4 H), 1.26 (t, J = 7.1 Hz, 6 H).

129.0, 128.5, 128.44, 128.37, 126.9, 93.5, 58.0.

HRMS (ESI): m/z [M + H]⁺calcd for C₁₆H₁₄NO₂: 252.1019; found:

¹³С NMR (100 MHz, CDCl₃): δ = 170.2, 163.6, 130.3, 129.4, 128.5,

252.1026.

126.5, 74.0, 43.8, 13.1.

Methyl 5-Methoxy-3-phenylisoxazole-4-carboxylate (3m)

HRMS (ESI): m/z [M + H]⁺calcd for С₁₃Н₁₇N₂O: 217.1335; found:

Yield: 450 mg (85%); colorless solid; mp 105–106 °C.

217.1335.

¹H NMR (400 MHz, CDCl₃): δ = 7.71–7.60 (m, 2 H), 7.54–7.41 (m, 3 H),

4.31 (s, 3 H), 3.76 (s, 3 H).

N-(1-Adamantylmethyl)-3-phenylisoxazol-5-amine (5e)

¹³С NMR (100 MHz, CDCl₃): δ = 173.5, 165.2, 161.5, 130.0, 129.2,

Yield: 893 mg (58%); colorless solid; mp 121–123 °C.

¹H NMR (400 MHz, CDCl₃): δ = 7.82–7.72 (m, 2 H), 7.48–7.38 (m, 3 H),

5.27 (s, 1 H), 4.64 (br t, J = 6.2 Hz, 1 H), 2.92 (d, J = 6.6 Hz, 2 H), 2.04 (br

s, 3 H), 1.81–1.63 (m, 6 H), 1.58 (br d, J = 2.4 Hz, 6 H).

128.5, 128.0, 87.2, 58.5, 51.3.

HRMS (ESI): m/z [M + Na]⁺calcd for С₁₂Н₁₁NO₄Na: 256.0580; found:

256.0587.

F

N. V. Rostovskii et al.

Paper

Synthesis

¹³С NMR (100 MHz, CDCl₃): δ = 171.1, 163.5, 130.1, 129.5, 128.6,

4-Bromoisoxazoles 8a–g; General Procedure

126.6, 74.7, 57.1, 40.2, 36.9, 34.2, 28.2.

HRMS (ESI): m/z [M + H]⁺calcd for C₂₀H₂₅N₂O: 309.1961; found:

309.1958.

A solution of isoxazole 3a–f,6b (2 mmol) and N-bromosuccinimide

(2.2 mmol) in AcOH (20 mL) was heated at 75 °C under stirring for 40

min. The reaction mixture was cooled and diluted with cold H₂O (60

mL). The resulting precipitate was collected, washed with H₂O and re-

crystallized from hexane–Et₂O to give the desired compound.

4-Bromoisoxazoles 8a–e are known compounds.^9c4-Bromoisoxazole

8g, without purification (not characterized spectroscopically), was

converted into 2-bromoazirine 10t.

5-Sulfanylisoxazoles 6a,b; General Procedure

A mixture of 5-chloro-3-phenylisoxazole (2)²¹(5 mmol), thiol (10

mmol) and K₂CO₃(15 mmol) in DMF (25 mL) was stirred for 36 h at

r.t. The reaction mixture was diluted with H₂O (40 mL) and extracted

with CH₂Cl₂(3 × 20 mL). The combined organic layers were dried over

Na₂SO₄and concentrated in vacuo. The residue was purified by col-

umn chromatography on silica gel using hexane–EtOAc as the eluent

to give the desired compound.

4-Bromo-5-methoxy-3-(4-nitrophenyl)isoxazole (8f)

Yield: 532 mg (89%); colorless solid; mp 63–66 °C (Et₂O–hexane).

¹H NMR (400 MHz, CDCl₃): δ = 8.40–8.29 (m, 2 H), 8.13–8.00 (m, 2 H),

4.27 (s, 3 H).

3-Phenyl-5-[(2,2,2-trifluoroethyl)sulfanyl]isoxazole (6a)

¹³С NMR (100 MHz, CDCl₃): δ = 169.9, 160.6, 148.9, 134.4, 128.9,

123.8, 66.7, 58.7.

HRMS (ESI): m/z [M + Na]⁺calcd for С₁₀Н₇⁷⁹BrN₂O₄Na: 320.9481;

found: 320.9483.

Yield: 1.28 g (99%); colorless oil.

¹H NMR (400 MHz, CDCl₃): δ = 7.85–7.75 (m, 2 H), 7.54–7.44 (m, 3 H),

6.69 (s, 1 H), 3.66 (q, J = 9.3 Hz, 2 H).

¹³С NMR (100 MHz, CDCl₃): δ = 163.5, 162.3, 130.4, 129.0, 128.3,

126.8, 124.5 (q, J = 277 Hz), 105.0, 35.3 (q, J = 34.4 Hz).

HRMS (ESI): m/z [M + H]⁺calcd for C₁₁H₉F₃NOS: 260.0351; found:

4-Chloroisoxazoles 9a–n; General Procedure

To a stirred solution of isoxazole 3a,e,g–i,4a,b,5a–e,6a,b (4 mmol) in

CH₂Cl₂(20 mL) at 0 °C was added dropwise SO₂Cl₂(4 mmol). The mix-

ture was allowed to warm to r.t. and then refluxed for 20 min. The

reaction mixture was cooled and washed with NaHCO₃solution (20

mL). The aqueous layer was extracted with CH₂Cl₂(2 × 15 mL). The

combined organic layers were dried (Na₂SO₄) and concentrated in

vacuo. The residue was purified by column chromatography on silica

gel using hexane–EtOAc as the eluent to give the desired compound.

260.0355.

3-Phenyl-5-(phenylsulfanyl)isoxazole (6b)

Yield: 1.18 g (93%); colorless solid; mp 55–56 °C.

¹H NMR (400 MHz, CDCl₃): δ = 7.83–7.74 (m, 2 H), 7.61–7.53 (m, 2 H),

7.51–7.44 (m, 3 H), 7.43–7.37 (m, 3 H), 6.51 (s, 1 H).

¹³С NMR (100 MHz, CDCl₃): δ = 166.0, 163.0, 132.1, 130.6, 130.2,

129.6, 128.9, 128.8, 128.6, 126.7, 104.5.

HRMS (ESI): m/z [M + Ag]⁺calcd for С₁₅Н₁₁NOS¹⁰⁷Ag: 359.9607;

found: 359.9591.

4-Chloro-5-methoxy-3-phenylisoxazole (9a)

Yield: 821 mg (98%); colorless oil.

¹H NMR (400 MHz, CDCl₃): δ = 7.95–7.80 (m, 2 Н), 7.56–7.45 (m, 3 Н),

4.24 (s, 3 H).

4-Iodo-5-methoxy-3-phenylisoxazole (7)¹⁸

¹³С NMR (100 MHz, CDCl₃): δ = 167.9, 161.5, 130.3, 128.7, 127.9,

To a stirred solution of isoxazole 3а (525 mg, 3 mmol) in anhydrous

THF (8 mL) at –78 °C under argon was added dropwise n-BuLi (1.33

mL, 2.5 M in hexane, 3.3 mmol). The reaction mixture was stirred at

the same temperature for 30 min, and then a solution of iodine (838

mg, 3.3 mmol) in anhydrous THF (10 mL) was introduced in one por-

tion. The mixture was allowed to warm to r.t. and stirred for an addi-

tional 20 min at r.t. The solvent was removed in vacuo, and the resi-

due was treated with H₂O (50 mL) and extracted with EtOAc (3 × 15

mL). The organic layer was washed with sat. Na₂S₂O₃(2 × 20 mL),

dried (Na₂SO₄), and concentrated in vacuo. The product was purified

by flash chromatography on silica gel using hexane–EtOAc (10:1) as

the eluent.

127.7, 83.0, 58.5.

HRMS (ESI): m/z [M + H]⁺calcd for С₁₀Н₉³⁵ClNO₂: 210.0316; found:

210.0311.

4-Chloro-3-(2,5-dimethylphenyl)-5-methoxyisoxazole (9b)

Yield: 931 mg (98%); colorless solid; mp 52–53 °C.

¹H NMR (400 MHz, CDCl₃): δ = 7.26–7.16 (m, 3 Н), 4.25 (s, 3 H), 2.38

(s, 3 H), 2.34 (s, 3 H).

¹³С NMR (100 MHz, CDCl₃): δ = 167.3, 163.9, 135.3, 134.2, 130.8,

130.4, 130.3, 126.8, 84.2, 58.4, 20.8, 19.3.

HRMS (ESI): m/z [M + H]⁺calcd for C₁₂H₁₃³⁵ClNO₂: 238.0629; found:

238.0633.

Yield: 541 mg (81%); colorless solid; mp 89–90 °C (Et₂O–hexane)

(Lit.¹⁸89–91 °C).

¹H NMR (400 MHz, CDCl₃): δ = 7.88–7.75 (m, 2 Н), 7.58–7.44 (m, 3 Н),

4.23 (s, 3 H).

4-Chloro-3-(4-chlorophenyl)-5-methoxyisoxazole (9c)

Yield: 781 mg (80%); colorless solid; mp 69–71 °C.

¹H NMR (400 MHz, CDCl₃): δ = 7.88–7.77 (m, 2 Н), 7.53–7.42 (m, 2 Н),

¹³С NMR (100 MHz, CDCl₃): δ = 172.2, 164.6, 130.2, 129.0, 128.5,

128.2, 58.5, 30.7.

4.24 (s, 3 H).

HRMS (ESI): m/z [M + H]⁺calcd for С₁₀Н₉INO₂: 301.9672; found:

¹³С NMR (100 MHz, CDCl₃): δ = 168.0, 160.5, 136.6, 129.0, 128.9,

301.9665.

126.4, 83.0, 58.5.

HRMS (ESI): m/z [M + K]⁺calcd for С₁₀Н₇³⁵Cl₂KNO₂: 281.9485; found:

281.9489.

G

N. V. Rostovskii et al.

Paper

Synthesis

4-Chloro-5-hexyloxy-3-phenylisoxazole (9d)

N-(1-Adamantylmethyl)-4-chloro-3-phenylisoxazol-5-amine (9j)

Yield: 1.08 g (97%); colorless oil.

Yield: 879 mg (64%); colorless solid; mp 139–141 °C.

¹H NMR (400 MHz, CDCl₃): δ = 7.92–7.82 (m, 2 Н), 7.56–7.45 (m, 3 Н),

4.51 (t, J = 6.6 Hz, 2 H), 1.95–1.81 (m, 2 Н), 1.58–1.45 (m, 2 Н), 1.43–

1.32 (m, 4 Н), 1.00–0.85 (m, 3 Н).

¹H NMR (400 MHz, CDCl₃): δ = 7.92–7.82 (m, 2 H), 7.52–7.44 (m, 3 H),

4.62 (br t, J = 6.4 Hz, 1 H), 3.15 (d, J = 6.8 Hz, 2 H), 2.04 (br s, 3 H),

1.81–1.65 (m, 6 H), 1.58 (br d, J = 2.4 Hz, 6 H).

¹³С NMR (100 MHz, CDCl₃): δ = 167.9, 161.3, 130.2, 128.7, 128.1,

¹³С NMR (100 MHz, CDCl₃): δ = 165.6, 159.5, 129.9, 128.5, 128.3,

127.7, 83.5, 72.5, 31.3, 29.2, 25.1, 22.5, 13.9.

127.7, 79.4, 54.8, 39.9, 36.9, 34.0, 28.2.

HRMS (ESI): m/z [M + K]⁺calcd for С₁₅Н₁₈³⁵ClKNO₂: 318.0658; found:

HRMS (ESI): m/z [M + Na]⁺calcd for С₂₀Н₂₃³⁵ClN₂NaO: 365.1391;

318.0673.

found: 365.1387.

5-Benzyloxy-4-chloro-3-phenylisoxazole (9e)

4-Chloro-3-phenyl-5-[(2,2,2-trifluoroethyl)sulfanyl]isoxazole

(9k)

Yield: 434 mg (38%); colorless solid; mp 58–59 °C.

Yield: 1.07 g (91%); colorless oil.

¹H NMR (400 MHz, CDCl₃): δ = 7.94–7.81 (m, 2 Н), 7.56–7.40 (m, 8 Н),

5.52 (s, 2 H).

¹H NMR (400 MHz, CDCl₃): δ = 7.93–7.85 (m, 2 H), 7.58–7.48 (m, 3 H),

3.68 (q, J = 9.2 Hz, 2 H).

¹³С NMR (100 MHz, CDCl₃): δ = 160.4, 159.1, 130.7, 128.9, 127.9,

126.8, 124.2 (q, J = 277 Hz), 111.4, 34.6 (q, J = 34.7 Hz).

¹³С NMR (100 MHz, CDCl₃): δ = 167.5, 161.3, 134.3, 130.3, 129.2,

128.8, 128.7, 128.5, 128.0, 127.7, 84.3, 73.7.

HRMS (ESI): m/z [M + Ag]⁺calcd for С₁₆Н₁₂¹⁰⁷Ag³⁵ClNO₂: 391.9602;

found: 391.9588.

HRMS (ESI): m/z [M + Na]⁺calcd for С₁₁Н₇³⁵ClF₃NNaOS: 315.9781;

found: 315.9787.

4-Chloro-3-phenyl-5-(pyrrolidin-1-yl)isoxazole (9f)

4-Chloro-3-phenyl-5-(phenylsulfanyl)isoxazole (9l)

Yield: 776 mg (78%); colorless solid; mp 68–70 °C.

Yield: 1.14 g (99%); colorless oil.

¹H NMR (400 MHz, CDCl₃): δ = 7.96–7.85 (m, 2 H), 7.59–7.47 (m, 5 H),

¹H NMR (400 MHz, CDCl₃): δ = 7.86–7.77 (m, 2 H), 7.52–7.43 (m, 3 H),

3.81–3.69 (m, 4 H), 2.06–1.94 (m, 4 H).

7.44–7.33 (m, 3 H).

¹³С NMR (100 MHz, CDCl₃): δ = 163.7, 161.1, 129.7, 128.6, 128.4,

128.1, 79.4, 47.7, 25.3.

¹³С NMR (100 MHz, CDCl₃): δ = 161.5, 160.2, 132.0, 130.5, 129.6,

129.5, 128.83, 128.78, 127.9, 127.2, 112.0.

HRMS (ESI): m/z [M + H]⁺calcd for C₁₅H₁₁³⁵ClNOS: 288.0244; found:

HRMS (ESI): m/z [M + H]⁺calcd for C₁₃H₁₄³⁵ClN₂O: 249.0789; found:

249.0790.

288.0256.

4-(4-Chloro-3-phenylisoxazol-5-yl)morpholine (9g)

4-Chloro-5-methoxy-3-methylisoxazole (9m)

Yield: 383 mg (65%); colorless oil.

¹H NMR (400 MHz, CDCl₃): δ = 4.15 (s, 3 H), 2.22 (s, 3 H).

¹³С NMR (100 MHz, CDCl₃): δ = 166.9, 161.0, 83.9, 58.3, 10.5.

Yield: 995 mg (94%); colorless solid; mp 96–97 °C.

¹H NMR (400 MHz, CDCl₃): δ = 7.84–7.76 (m, 2 H), 7.54–7.45 (m, 3 H),

3.91–3.80 (m, 4 H), 3.71–3.60 (m, 4 H).

¹³С NMR (100 MHz, CDCl₃): δ = 164.7, 161.6, 130.0, 128.5, 128.1 (2 C),

83.9, 66.3, 46.6.

HRMS (ESI): m/z [M + H]⁺calcd for C₅H₇³⁵ClNO₂: 148.0167; found:

148.0160.

HRMS (ESI): m/z [M + H]⁺calcd for C₁₃H₁₄³⁵ClN₂O₂: 265.0738; found:

265.0748.

4-Chloro-3-cyclopropyl-5-methoxyisoxazole (9n)

N-Benzyl-4-chloro-N-methyl-3-phenylisoxazol-5-amine (9h)

Yield: 438 mg (63%); colorless solid; mp 51–52 °C.

Yield: 812 mg (68%); colorless solid; mp 45–47 °C.

¹H NMR (400 MHz, CDCl₃): δ = 7.89–7.78 (m, 2 H), 7.54–7.46 (m, 3 H),

¹H NMR (400 MHz, CDCl₃): δ = 3.42 (s, 3 H), 1.62 (tt, J = 8.5, 5.4 Hz, 1

H), 1.30–1.10 (m, 4 H).

7.45–7.31 (m, 5 H), 4.75 (s, 2 H), 3.14 (s, 3 H).

¹³С NMR (100 MHz, CDCl₃): δ = 165.0, 161.7, 136.6, 129.8, 128.7,

128.5, 128.4, 128.1, 127.8 (2 C), 81.3, 54.5, 36.0.

HRMS (ESI): m/z [M + Ag]⁺calcd for С₁₇Н₁₅¹⁰⁷Ag³⁵ClN₂O⁺: 404.9918;

¹³С NMR (100 MHz, CDCl₃): δ = 166.6, 164.0, 94.6, 39.2, 7.2, 5.9.

HRMS (ESI): m/z [M + K]⁺calcd for С₇Н₈³⁵ClKNO₂: 211.9875; found:

211.9869.

found: 404.9903.

Rh(II)-Catalyzed Synthesis of 2-Halo-2H-azirines 10a–r; General

Procedure

4-Сhloro-N,N-diethyl-3-phenylisoxazol-5-amine (9i)

A solution of 4-haloisoxazole 7,8a–f,9a–k (1 mmol) and Rh₂(Piv)₄

(0.1–1.5 mol%) in toluene (3 mL) was refluxed for 0.5–44 h (see Table

1). The solvent was removed in vacuo and the residue was purified by

flash chromatography on silica gel (hexane–EtOAc) to give the desired

product. If the azirine is a solid, it can be washed with hexane–Et₂O

instead of chromatography.

Yield: 782 mg (78%); colorless oil.

¹H NMR (400 MHz, CDCl₃): δ = 7.85–7.77 (m, 2 H), 7.52–7.45 (m, 3 H),

3.58 (q, J = 7.1 Hz, 4 H), 1.30 (t, J = 7.1 Hz, 6 H).

¹³С NMR (100 MHz, CDCl₃): δ = 164.2, 161.5, 129.7, 128.6, 128.4,

128.2, 79.9, 43.5, 14.2.

HRMS (ESI): m/z [M + Na]⁺calcd for С₁₃Н₁₅³⁵ClN₂NaO: 273.0765;

found: 273.0770.

H

N. V. Rostovskii et al.

Paper

Synthesis

Fe(II)-Catalyzed Synthesis of 2-Halo-2H-azirines 10a,r–u; General

Methyl 2-Bromo-3-(4-chlorophenyl)-2H-azirine-2-carboxylate

Procedure

(10f)

A solution of 4-haloisoxazole 8a,g,9k–m (1 mmol) and FeCl₂·4H₂O

(30–60 mol%) in MeCN (3 mL) was stirred at ambient temperature for

a period of 24 h to 7 d (see Table 1). The insoluble inorganic material

was filtered off and the filtrate concentrated in vacuo. The residue

was purified by flash chromatography on silica gel (hexane–EtOAc) to

give the desired product.

Yield: 271 mg (94%); colorless solid; mp 69–70 °C.

¹H NMR (400 MHz, CDCl₃): δ = 7.96–7.88 (m, 2 H), 7.68–7.60 (m, 2 H),

3.84 (s, 3 H).

¹³С NMR (100 MHz, CDCl₃): δ = 167.0, 163.9, 141.9, 132.0, 130.2,

118.2, 54.2, 43.5.

HRMS (ESI): m/z [M + Na]⁺calcd for С₁₀Н₇⁷⁹Br³⁵ClNNaO₂: 309.9241;

found: 309.9251.

Methyl 2-Bromo-3-phenyl-2H-azirine-2-carboxylate (10a)^14a

Yield: 241 mg (95%) [catalyst: Rh₂(OAc)₄(0.5 mol%)]; 3.4 g (96%) in a

gram-scale reaction [catalyst: Rh₂(Piv)₄(0.1 mol%)]; 242 mg (95%)

[catalyst: FeCl₂·4H₂O (30 mol%)]; colorless solid; mp 74–76 °C.

¹H NMR (400 MHz, CDCl₃): δ = 8.00–7.96 (m, 2 H), 7.79–7.73 (m, 1 H),

Methyl 2-Bromo-3-(4-nitrophenyl)-2H-azirine-2-carboxylate

(10g)

Yield: 290 mg (97%); colorless solid; mp 116–119 °C.

¹H NMR (400 MHz, CDCl₃): δ = 8.54–8.47 (m, 2 H), 8.23–8.15 (m, 2 H),

7.68–7.63 (m, 2 H), 3.84 (s, 3 H).

3.86 (s, 3 H).

¹³С NMR (100 MHz, CDCl₃): δ = 167.1, 164.3, 135.1, 130.8, 129.6,

¹³С NMR (100 MHz, CDCl₃): δ = 166.5, 164.5, 151.4, 131.7, 125.4,

119.6, 54.1, 43.7.

124.8, 54.4, 43.0.

Methyl 2-Iodo-3-phenyl-2H-azirine-2-carboxylate (10b)^14a

Anal. Calcd for C₁₀H₇BrN₂O₄: C, 40.16; H, 2.36; N, 9.37. Found: C,

40.77; Н, 2.60; N, 9.10.

Yield: 277 mg (92%); colorless solid; mp 87–88 °C.

¹H NMR (400 MHz, CDCl₃): δ = 8.00–7.92 (m, 2 Н), 7.79–7.73 (m, 1 Н),

7.69–7.62 (m, 2 Н), 3.81 (s, 3 H).

¹³С NMR (100 MHz, CDCl₃): δ = 166.3, 165.3, 135.0, 130.8, 129.7,

Methyl 2-Chloro-3-phenyl-2H-azirine-2-carboxylate (10h)

Yield: 201 mg (96%); colorless solid; mp 62–63 °C.

¹H NMR (400 MHz, CDCl₃): δ = 8.01–7.90 (m, 2 Н), 7.79–7.70 (m, 1 Н),

7.68–7.58 (m, 2 Н), 3.82 (s, 3 H).

120.0, 54.3, 13.6.

HRMS (ESI): m/z [M + K]⁺calcd for С₁₀Н₈IKNO₂: 339.9231; found:

339.9229.

¹³С NMR (100 MHz, CDCl₃): δ = 167.8, 163.5, 135.1, 130.8, 129.6,

119.6, 53.9, 53.8.

Methyl 2-Bromo-3-(4-methylphenyl)-2H-azirine-2-carboxylate

HRMS (ESI): m/z [M + Na]⁺calcd for С₁₀Н₈³⁵ClNO₂Na: 232.0136;

(10c)

found: 232.0147.

Yield: 255 mg (95%); colorless solid; mp 61–63 °C.

Methyl 2-Chloro-3-(2,5-dimethylphenyl)-2H-azirine-2-carboxyl-

ate (10i)

¹H NMR (400 MHz, CDCl₃): δ = 7.95–7.78 (m, 2 H), 7.54–7.39 (m, 2 H),

3.82 (s, 3 H), 2.51 (s, 3 H).

Yield: 231 mg (97%); colorless solid; mp 68–70 °C.

¹H NMR (400 MHz, CDCl₃): δ = 7.61 (br s, 1 H), 7.45–7.39 (m, 1 Н),

7.36–7.30 (m, 1 Н), 3.84 (s, 3 H), 2.65 (s, 3 H), 2.43 (s, 3 H).

¹³С NMR (100 MHz, CDCl₃): δ = 167.4, 163.9, 146.6, 131.0, 130.4,

116.8, 54.1, 43.9, 22.1.

HRMS (ESI): m/z [M + Na]⁺calcd for С₁₁Н₁₀⁷⁹BrNNaO₂: 289.9787;

found: 289.9794.

¹³С NMR (100 MHz, CDCl₃): δ = 168.2, 162.5, 139.4, 136.6, 135.7,

132.6, 131.3, 118.3, 53.9, 53.1, 20.6, 19.3.

Methyl 2-Bromo-3-(4-methoxyphenyl)-2H-azirine-2-carboxylate

HRMS (ESI): m/z [M + Na]⁺calcd for С₁₂Н₁₂³⁵ClNNaO₂: 260.0449;

found: 260.0453.

(10d)^9b

Yield: 275 mg (97%); colorless solid; mp 67–69 °C (Lit.^9b59–63 °C).

Methyl 2-Chloro-3-(4-chlorophenyl)-2H-azirine-2-carboxylate

(10j)

¹H NMR (400 MHz, CDCl₃): δ = 7.94–7.88 (m, 2 H), 7.15–7.09 (m, 2 H),

3.94 (s, 3 H), 3.82 (s, 3 H).

Yield: 232 mg (95%); colorless solid; mp 76–78 °C.

¹H NMR (400 MHz, CDCl₃): δ = 8.00–7.82 (m, 2 Н), 7.72–7.56 (m, 2 Н),

¹³С NMR (100 MHz, CDCl₃): δ = 167.5, 165.1, 162.9, 133.2, 115.3,

111.6, 55.7, 54.0, 44.3.

3.84 (s, 3 H).

Methyl 2-Bromo-3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2H-azir-

¹³С NMR (100 MHz, CDCl₃): δ = 167.6, 163.1, 141.8, 132.0, 130.2,

ine-2-carboxylate (10e)

118.2, 54.0, 53.8.

HRMS (ESI): m/z [M + K]⁺calcd for С₁₀Н₇³⁵Cl₂KNO₂: 281.9485; found:

Yield: 296 mg (95%); colorless solid; mp 122–124 °C.

¹H NMR (400 MHz, CDCl₃): δ = 7.56–7.40 (m, 2 H), 7.14–7.04 (m, 1 H),

281.9488.

4.46–4.28 (m, 4 H), 3.82 (s, 3 H).

Hexyl 2-Chloro-3-phenyl-2H-azirine-2-carboxylate (10k)

¹³С NMR (100 MHz, CDCl₃): δ = 167.4, 163.2, 149.8, 144.4, 125.2,

Yield: 271 mg (97%); colorless oil.

120.0, 118.8, 112.3, 64.8, 64.0, 54.1, 44.4.

¹H NMR (400 MHz, CDCl₃): δ = 8.01–7.93 (m, 2 Н), 7.79–7.71 (m, 1 Н),

7.69–7.60 (m, 2 Н), 4.29–4.16 (m, 2 H), 1.72–1.58 (m, 2 Н), 1.38–1.19

(m, 6 Н), 0.94–0.78 (m, 3 Н).

HRMS (ESI): m/z [M + Na]⁺calcd for С₁₂Н₁₀⁷⁹BrNNaO₄: 333.9685;

found: 333.9691.

I

N. V. Rostovskii et al.

Paper

Synthesis

¹³С NMR (100 MHz, CDCl₃): δ = 167.4, 163.8, 135.0, 130.8, 129.6,

¹³С NMR (100 MHz, CDCl₃): δ = 171.7, 164.4, 134.8, 131.1, 129.4,

119.9, 67.4, 54.1, 31.2, 28.3, 25.3, 22.4, 13.8.

120.9, 57.3, 42.3, 39.6, 14.0, 12.2.

HRMS (ESI): m/z [M + Na]⁺calcd for С₁₅Н₁₈³⁵ClNNaO₂: 302.0918;

HRMS (ESI): m/z [M + Na]⁺calcd for С₁₃Н₁₅³⁵ClN₂NaO: 273.0765;

found: 302.0933.

found: 273.0767.

Benzyl 2-Chloro-3-phenyl-2H-azirine-2-carboxylate (10l)

N-(1-Adamantylmethyl)-2-chloro-3-phenyl-2H-azirine-2-carbox-

amide (10q)

Yield: 243 mg (85%); colorless oil.

Yield: 264 mg (77%); colorless solid; mp 111–113 °C.

¹H NMR (400 MHz, CDCl₃): δ = 7.98–7.91 (m, 2 Н), 7.78–7.71 (m, 1 Н),

7.69–7.59 (m, 2 Н), 7.40–7.30 (m, 5 Н), 5.37–5.19 (m, 2 H).

¹³С NMR (100 MHz, CDCl₃): δ = 167.3, 163.6, 135.0, 134.9, 130.9,

129.6, 128.6, 128.4, 128.0, 119.7, 68.6, 54.0.

HRMS (ESI): m/z [M + Na]⁺calcd for С₁₆Н₁₂³⁵ClNNaO₂: 308.0449;

¹H NMR (400 MHz, CDCl₃): δ = 8.05–7.91 (m, 2 H), 7.78–7.68 (m, 1 H),

7.67–7.57 (m, 2 H), 6.90 (br s, 1 H), 3.09 (qd, J = 13.5, 6.3 Hz, 2 H), 2.03

(br s, 3 H), 1.81–1.62 (m, 6 H), 1.56 (br d, J = 2.1 Hz, 6 H).

¹³С NMR (100 MHz, CDCl₃): δ = 166.2, 165.0, 134.8, 130.9, 129.5,

120.2, 58.1, 52.2, 40.1, 36.8, 33.8, 28.1.

found: 308.0451.

HRMS (ESI): m/z [M + Na]⁺calcd for С₂₀Н₂₃³⁵ClN₂NaO: 365.1391;

found: 365.1395.

(2-Chloro-3-phenyl-2H-azirin-2-yl)(pyrrolidin-1-yl)methanone

(10m)

S-(2,2,2-Trifluoroethyl) 2-Chloro-3-phenyl-2H-azirine-2-carboth-

ioate (10r)

Yield: 229 mg (92%); colorless solid; mp 72–73 °C.

¹H NMR (400 MHz, CDCl₃): δ = 8.15–8.06 (m, 2 H), 7.74–7.67 (m, 1 H),

7.66–7.58 (m, 2 H), 4.19–3.99 (m, 2 H), 3.60–3.41 (m, 2 H), 2.15–1.87

(m, 4 H).

¹³С NMR (100 MHz, CDCl₃): δ = 170.9, 163.3, 134.8, 131.0, 129.4,

120.9, 57.3, 46.9, 46.2, 26.2, 23.9.

Yield: 59 mg (20%) [catalyst: Rh₂(Piv)₄(1.5 mol%)]; 194 mg (66%) [cat-

alyst: FeCl₂·4H₂O (60 mol%)]; colorless oil.

¹H NMR (400 MHz, CDCl₃): δ = 7.99–7.93 (m, 2 H), 7.81–7.75 (m, 1 H),

7.70–7.63 (m, 2 H), 3.67 (qd, J = 9.7, 1.2 Hz, 2 H).

¹³С NMR (100 MHz, CDCl₃): δ = 191.4, 163.2, 135.7, 131.2, 129.8,

124.4 (q, J = 276 Hz), 118.7, 60.1, 32.2 (q, J = 34.3 Hz).

HRMS (ESI): m/z [M + Na]⁺calcd for С₁₁Н₇³⁵ClF₃NNaOS: 315.9781;

HRMS (ESI): m/z [M + Na]⁺calcd for С₁₃Н₁₃³⁵ClN₂NaO: 271.0609;

found: 271.0616.

found: 315.9792.

(2-Chloro-3-phenyl-2H-azirin-2-yl)(morpholin-4-yl)methanone

(10n)

S-Phenyl 2-Chloro-3-phenyl-2H-azirine-2-carbothioate (10s)

Yield: 238 mg (90%); colorless solid; mp 78–79 °C.

Yield: 192 mg (67%); colorless oil.

¹H NMR (400 MHz, CDCl₃): δ = 8.06–7.99 (m, 2 H), 7.82–7.75 (m, 1 H),

¹H NMR (400 MHz, CDCl₃): δ = 8.23–8.04 (m, 2 H), 7.80–7.69 (m, 1 H),

7.68–7.57 (m, 2 H), 4.31–4.09 (m, 2 H), 3.98–3.54 (m, 6 H).

7.72–7.65 (m, 2 H), 7.47–7.41 (m, 5 H).

¹³С NMR (100 MHz, CDCl₃): δ = 192.5, 163.6, 135.4, 134.6, 131.1,

¹³С NMR (100 MHz, CDCl₃): δ = 171.0, 163.6, 135.0, 131.1, 129.5,

120.7, 66.8, 66.5, 56.3, 46.7, 42.3.

129.84, 129.77, 129.3, 126.9, 119.2, 60.6.

HRMS (ESI): m/z [M + K]⁺calcd for С₁₅Н₁₀³⁵ClKNOS: 325.9803; found:

HRMS (ESI): m/z [M + Na]⁺calcd for С₁₃Н₁₃³⁵ClN₂NaO₂: 287.0558;

found: 287.0567.

325.9800.

N-Benzyl-2-chloro-N-methyl-3-phenyl-2H-azirine-2-carboxam-

ide (10o)

S-Phenyl 2-Bromo-3-phenyl-2H-azirine-2-carbothioate (10t)

Yield: 173 mg (58%); colorless oil.

Obtained from isoxazole 6b (1 mmol) in two stages without purifica-

tion of 4-bromoisoxazole 8g. Yield: 299 mg (90% calculated based on

6b); colorless solid; mp 50–52 °C.

¹H NMR (400 MHz, CDCl₃): δ = 8.11–8.00 (m, 2 H), 7.84–7.77 (m, 1 H),

¹H NMR (400 MHz, CDCl₃): δ (rotameric mixture) = 8.24–8.10 (m, 2

H), 7.75–7.67 (m, 1 H), 7.66–7.57 (m, 2 H), 7.44–7.24 (m, 5 H), 5.34

and 5.13 (AB-q, J = 15.5 Hz, 0.8 H), 4.68 and 4.56 (AB-q, J = 14.7 Hz, 1.3

H), 3.50 (s, 1.9 H), 2.85 (s, 1.2 H).

7.75–7.66 (m, 2 H), 7.51–7.38 (m, 5 H).

¹³С NMR (100 MHz, CDCl₃): δ (rotameric mixture) = 171.3, 171.1,

165.2, 165.0, 136.0, 135.6, 134.8, 131.0, 129.3, 128.60, 128.58, 127.8,

127.7, 127.5, 120.65, 120.62, 57.0, 56.6, 53.6, 50.8, 35.0, 32.3.

¹³С NMR (100 MHz, CDCl₃): δ = 191.5, 164.5, 135.5, 134.6, 131.2,

129.8 (2 C), 129.3, 127.0, 119.2, 51.2.

HRMS (ESI): m/z [M + K]⁺calcd for С₁₅Н₁₀⁷⁹BrKNOS: 369.9298; found:

369.9298.

HRMS (ESI): m/z [M + K]⁺calcd for С₁₇Н₁₅³⁵ClKN₂O: 337.0504; found:

337.0509.

Methyl 2-Chloro-3-methyl-2H-azirine-2-carboxylate (10u)

Yield: 125 mg (85%); unstable colorless oil.

2-Сhloro-N,N-diethyl-3-phenyl-2H-azirine-2-carboxamide (10p)

Yield: 150 mg (60%); colorless oil.

¹H NMR (400 MHz, CDCl₃): δ = 3.82 (s, 3 H), 2.62 (s, 3 H).

¹³С NMR (100 MHz, CDCl₃): δ = 168.0, 165.6, 53.8, 53.3, 10.8.

¹H NMR (400 MHz, CDCl₃): δ = 8.19–8.10 (m, 2 H), 7.74–7.67 (m, 1 H),

7.65–7.58 (m, 2 H), 4.02 (q, J = 7.1 Hz, 2 H), 3.50–3.30 (m, 2 H), 1.39 (t,

J = 7.1 Hz, 3 H), 1.18 (t, J = 7.1 Hz, 3 H).

J

N. V. Rostovskii et al.

Paper

Synthesis

Rh(II)-Catalyzed Synthesis of Non-Halogenated 2H-Azirine-2-car-

¹³С NMR (100 MHz, CDCl₃): δ = 170.8, 158.9, 133.6, 130.3, 129.3,

boxylates 11a–f; General Procedure

122.7, 81.6, 30.5, 28.0.

A solution of 5-alkoxyisoxazole 3a,j–m,4c (1 mmol) and Rh₂(Piv)₄

(0.3–5 mol%) in toluene (3 mL) was refluxed for 3–20 h (see Table 2).

The solvent was removed in vacuo and the residue was purified by

flash chromatography on silica gel (CHCl₃) to give the desired com-

pound and recovered Rh₂(Piv)₄.

Funding Information

We gratefully acknowledge the financial support of the Russian Sci-

ence Foundation (Grant No. 17-13-01078). This research used re-

sources of the ‘Magnetic Resonance Research Centre’, the ‘Chemical

Analysis and Materials Research Centre’, the ‘Centre for X-ray Diffrac-

tion Studies’ and the ‘Chemistry Educational Centre’ of the Research

Methyl 3-Phenyl-2H-azirine-2-carboxylate (11a)²⁹

Yield: 168 mg (96%); pale yellow solid; mp 44–46 °C.

¹H NMR (400 MHz, CDCl₃): δ = 7.95–7.87 (m, 2 H), 7.71–7.56 (m, 3 H),

3.77 (s, 3 H), 2.89 (s, 1 H).

Park of St. Petersburg State University.

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¹³С NMR (100 MHz, CDCl₃): δ = 172.1, 158.5, 133.9, 130.5, 129.3,

122.2, 52.3, 29.5.

Supporting Information

HRMS (ESI): m/z [M + Na]⁺calcd for C₁₀H₉O₂NNa: 198.0525; found:

198.0528.

Supporting information for this article is available online at

https://doi.org/10.1055/s-0036-1590822.

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Methyl 3-(4-Cyanophenyl)-2H-azirine-2-carboxylate (11b)

References

Yield: 180 mg (90%); colorless solid; mp 86–87 °C.

¹H NMR (400 MHz, CDCl₃): δ = 8.03 (d, J = 8.4 Hz, 2 H), 7.90 (d, J = 8.4

Hz, 2 H), 3.78 (s, 3 H), 2.97 (s, 1 H).

¹³С NMR (100 MHz, CDCl₃): δ = 171.2, 158.6, 133.0, 130.7, 126.2,

117.4, 117.3, 52.5, 30.1.

(1) For recent reviews on 2H-azirine chemistry, see: (a) Khlebnikov,

A. F.; Novikov, M. S. Tetrahedron 2013, 69, 3363. (b) Huang, C.-

Y.; Doyle, A. G. Chem. Rev. 2014, 114, 8153. (c) Khlebnikov, A. F.;

Novikov, M. S. Top. Heterocycl. Chem. 2016, 41, 143.

HRMS (ESI): m/z [M + Na]⁺calcd for С₁₁Н₈N₂O₂Na: 223.0478; found:

223.0482.

(2) (a) Miller, T. W.; Tristram, E. W.; Wolf, F. J. J. Antibiot. 1971, 24,

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Methyl 2-Methyl-3-phenyl-2H-azirine-2-carboxylate (11c)²⁹

Yield: 174 mg (92%); colorless oil.

¹H NMR (400 MHz, CDCl₃): δ = 7.91–7.80 (m, 2 H), 7.69–7.54 (m, 3 H),

3.70 (s, 3 H), 1.65 (s, 3 H).

¹³С NMR (100 MHz, CDCl₃): δ = 173.5, 163.5, 133.6, 130.1, 129.3,

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Tomashenko, O. A.; Khlebnikov, A. F.; Novikov, M. S.; Ivanov, A.

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122.5, 52.4, 35.4, 17.7.

Methyl 2,3-Diphenyl-2H-azirine-2-carboxylate (11d)²⁹

Yield: 226 mg (90%); colorless solid; mp 75–77 °C (Et₂O–hexane)

(Lit.²⁹70–71 °C).

¹H NMR (400 MHz, CDCl₃): δ = 8.01–7.91 (m, 2 H), 7.70–7.64 (m, 1 H),

7.63–7.57 (m, 2 H), 7.56–7.50 (m, 2 H), 7.39–7.29 (m, 3 H), 3.78 (s, 3

H).

¹³С NMR (100 MHz, CDCl₃): δ = 171.6, 160.7, 136.2, 133.9, 130.4,

129.4, 128.22, 128.15, 127.8, 122.0, 52.7, 41.1.

Dimethyl 3-Phenyl-2H-azirine-2,2-dicarboxylate (11e)

(4) Cardoso, A. L.; Lemos, A.; Pinho e Melo, T. M. V. D. Eur. J. Org.

Chem. 2014, 5159.

Yield: 214 mg (92%); colorless solid; mp 87–90 °C.

¹H NMR (400 MHz, CDCl₃): δ = 7.97–7.90 (m, 2 H), 7.74–7.67 (m, 1 H),

7.65–7.58 (m, 2 H), 3.79 (s, 6 H).

¹³С NMR (100 MHz, CDCl₃): δ = 167.5, 155.2, 134.6, 131.0, 129.5,

(5) (a) Shimada, N.; Ashburn, B. O.; Basak, A. K.; Bow, W. F.; Vicic, D.

A.; Tius, M. A. Chem. Commun. 2010, 46, 3774. (b) Loy, N. S. Y.;

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120.2, 52.9, 38.6.

HRMS (ESI): m/z [M + Na]⁺calcd for С₁₂Н₁₁NNaO₄: 256.0580; found:

256.0574.

(6) Ryu, T.; Baek, Y.; Lee, P. H. J. Org. Chem. 2015, 80, 2376.

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tert-Butyl 3-Phenyl-2H-azirine-2-carboxylate (11f)³⁰

Yield: 176 mg (81%); colorless solid; mp 56–58 °C (Lit.³⁰71–72 °C).

¹H NMR (400 MHz, CDCl₃): δ = 7.94–7.86 (m, 2 H), 7.69–7.55 (m, 3 H),

2.78 (s, 1 H), 1.49 (s, 9 H).

K

N. V. Rostovskii et al.

Paper

Synthesis

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Article Doi

Metal-Catalyzed Isomerization of 5-Heteroatom-Substituted Isoxazoles as a New Route to 2-Halo-2 H -azirines

DOI: 10.1055/s-0036-1590822

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Article abstract of DOI:10.1055/s-0036-1590822

Full text of DOI:10.1055/s-0036-1590822

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