Unexpected heterocyclization of electrophilic alkenes by

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Unexpected heterocyclization of electrophilic alkenes by tetranitromethane in the presence of triethylamine. Synthesis of 5-nitroisoxazoles Yulia Alexeevna Volkova, Elena Borisovna Averina, Dmitry A. Vasilenko, Kseniya N. Sedenkova, Yuri K. Grishin, Per Bruheim, Tamara S. Kuznetsova, and Nikolay S. Zefirov J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b03086 • Publication Date (Web): 06 Feb 2019 Downloaded from http://pubs.acs.org on February 7, 2019

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The Journal of Organic Chemistry

Unexpected heterocyclization of electrophilic alkenes by tetranitromethane in the presence of triethylamine. Synthesis of 5-nitroisoxazoles

Yulia A. Volkova,† Elena B. Averina,*† Dmitry A. Vasilenko,† Kseniya N. Sedenkova,† Yuri K. Grishin,† Per Bruheim,‡ Tamara S. Kuznetsova,† Nikolai S. Zefirov† Lomonosov Moscow State University, Department of Chemistry, Leninskie Gory, 1-3, Moscow

†

119992, Russia ‡

Department of Biotechnology, Norwegian University of Science and Technology, Sem Selands vei 6/8, N-7431 Trondheim, Norway

[email protected]

R2

R1

O N

O

R2

R1

C(NO2)4 Et3N

O

NO2

18-64%, R1, R2 = NHAlk, NHAr, NAlk2, NHAr2 45-86%, R1, R2 = H, Alk, Ar

RO2S N

NO2

O 2N N

SO2R

40-49%, R = H, Alk 46-75%, R1, R2 = OAlk, OAr

R

PO(OEt)2

R O

NO2

38-63% R = H, Alk

(EtO)2OP

NO2 O 25-28% R = Ph, OPh

N

O

NO2

76%

Novel reaction of tetranitromethane with electrophilic alkenes in the presence of triethylamine affording substituted 5-nitroisoxazoles is described. Triethylamine reacts with tetranitromethane to generate

N-nitrotriethylammonium

and

trinitromethanide.

This

process

provides

the

heterocyclization of electrophilic alkenes. A variety of α,β-unsaturated aldehydes, ketones, esters, amides, phosphonates, nitro- and sulfur compounds was involved in the heterocyclization reaction and a wide range of functionalized 5-nitroisoxazoles was obtained in good to high yields. The scope and limitations of the reaction and the mechanistic proposal are discussed.

ACS Paragon Plus Environment

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Introduction Polynitromethanes have been found to be versatile reagents for heterocyclization reactions of alkenes.1 These reactions discovered in the 1960s2,3 result in five-membered N,O-heterocyclic compounds, mainly dinitroisoxazolidines. It was mentioned that only nucleophilic alkenes were used in the heterocyclization with tetranitromethane, moreover “electron-withdrawing groups at double bond dramatically reduce the nucleophilicity of alkene and exclude its reaction…with tetranitromethane”. 4 Studying the reactions of polynitromethanes with alkenes containing small ring, we have developed one-pot three component heterocyclization reaction with a variety of alkenes and proposed a preparative approach to highly functionalized nitro-substituted heterocycles, such as isoxazolidines, as well as piperidones, aziridines, and isoxazolines.5 Moreover, we have found that the combination of tetranitromethane (TNM) with triethylamine (TEA) may be regarded as a specific reagent, which was used for the ring opening reaction of oxiranes and N-tosylaziridines giving β-hydroxy nitrate6 and -tosylamino nitrates,7 respectively. It should be noted that TNM itself does not cleave the epoxides and the aziridines directly without activation with a basic reagent (TEA). In this paper we report a novel reaction of TNM in the presence of TEA with conjugated functionalized alkenes containing electron-withdrawing group at the double bond, which may be considered as a general method for the synthesis of substituted 5-nitroisoxazoles. It is well-known that isoxazoles constitute a class of heterocyclic compounds possessing a remarkable variety of applications and being versatile building blocks in organic synthesis.8 A wide range of isoxazoles’ biological activity includes antibacterial, antiviral, antifungal properties; they can act as various glutamate and GABA receptors ligands, and also display herbicide activity.8d,9 The construction of the isoxazole ring can be achieved by two basic synthetic approaches, including ACS Paragon Plus Environment

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the condensations of 1,3-dielectrophiles under the treatment with hydroxylamine and 1,3-dipolar cycloaddition of nitrile oxides to acetylenes or the reactions of their synthetic equivalents.8 However, both these methods have limited application for the synthesis of 5-nitroisoxazoles. The only one synthetic approach to 5-nitroisoxazoles has been known until recently, and it involved 1,3-dipolar cycloaddition of nitrile oxides to nitroethylenes followed by the oxidation of 5nitroisoxazoline intermediates into the corresponding 5-nitroisoxazoles.10 An approach based on the heterocyclization reaction of polynitrocompounds, was also reported,11 but this reaction was studied on a limited number of substrates and not extended to general procedures. Results and Discussion We have started our studies by examining the reaction of TNM-base complex with α,βunsaturated compounds containing carbonyl group. Methyl vinyl ketone (MVK) was chosen as a model substrate for the optimization of the reaction conditions. Full data concerning the optimization of the type of base and solvent used and the amounts of the reagents are presented in Supporting Information. Several tertiary amines (TEA, Bu3N, Py, TMEDA, DBU, DABCO) and triphenyl phosphine were tested as the bases for heterocyclization in either catalytic or equimolar amounts. In all cases we have observed the formation of 5-nitroizoxazole 1 as shown in Scheme 1: SCHEME 1. Heterocyclization of MVK under the treatment of TNM in the presence of base. Me Me O

+ C(NO2)4

base 20 oC

O N

O

NO2

1

However, in some cases side product, 5,5,5-trinitropentan-2-one, was isolated in 6-10% yields. TEA was found to be the most effective base to promote the heterocyclization (yield of 1, 80%). The use of other bases such as Bu3N, Py, TMEDA, DBU resulted in moderate yields of isoxazole 1 (30-40%), and low yields were obtained when employing DABCO and Ph3P (20 and



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6%). Variation of the mole ratio of the reagents in the case of TEA showed that the highest yield of isoxazole 1 was achieved using MVK, TNM and TEA in 1:2.5:2 ratio. After screening the solvents we have found that the heterocyclization proceeded smoothly in dioxane at room temperature and complete conversion of the starting olefin was achieved within 12 h. It should be noted that if the reaction was carried out in methanol, the trinitropentanone was isolated exclusively. The reaction protocol involved a slow addition of alkene at 5 oC to a previously prepared complex of TNM with TEA. The reaction was scaled up using 10 mmol of MVK, 25 mmol of TNM and 20 mmol of TEA under standard conditions to produce 80% yield of isoxazole 1. Having this general optimized protocol in hand, we examined the heterocyclization of series of α,β-unsaturated ketones and aldehydes. The results are presented in Scheme 2. SCHEME 2. Heterocyclization of α,β-unsaturated ketones and aldehydes under the treatment with TNM-TEA (alkene:TNM:TEA in 1:2.5:2 ratio). R2

R1 R2

+

O

Me

C(NO2)4

1, 80%

O

N

O NO2 4, 77%

O Me

H

H

O NO2 5, 52%

N

O NO2 3, 85%

O

O N

NO2

2, 86%

O O

O

O N

NO2

O

NO2

O 1-7

Ph

O N

N

1,4-dioxane 20 oC, 12 h

Et

O

R1

O

Et3N

N

NO2 O 6, 40%

N

O

NO2

7, 49%

α,β-Unsaturated ketones smoothly reacted with the TNM-TEA complex at room temperature forming 3-acyl-5-nitroisoxazoles 1-7 in high yields. We also succeeded to involve in the heterocyclization with TNM-TEA levoglucosenone, a highly functionalized chiral synthon, which is ACS Paragon Plus Environment

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an excellent starting material and building block for the synthesis of natural compounds.12 A new chiral 5-nitroisoxazole 5 was obtained in a good yield. It was found that acrolein and (E)crotonaldehyde also reacted with TNM under the same conditions producing 5-carbaldehyde-3nitroisoxazoles 6 and 7 in 40 and 49% yields, correspondingly. The lower yields of compounds 6 and 7 can be explained by partial polymerization of starting aldehydes under reaction conditions. Next, α,β-unsaturated esters were involved in the heterocyclization reaction with TNM-TEA complex. We have found that methyl acrylate scarcely reacted with TNM-TEA at room temperature for 12 h giving corresponding 5-nitroisoxazole 8 in a poor yield (10%).13 However, further investigation revealed that this reaction proceeded smoothly at 70 oC for 2 h affording 8 in 62% yield. These conditions were found to be optimal for α,β-unsaturated esters and a series of 5nitroisoxazole-3-carboxylates 8-16 was obtained in moderate to good yields (Table 1). TABLE 1. Synthesis of 5-nitroisoxazole-3-carboxylates.a OR2 R

1

OR

2

+

O

C(NO2)4

R1

O

Et3N

N


O

NO2

8-16

Entry

5-nitroisoxazole

R1

R2

Yieldb, %

1

8

H

Me

62

2

9

H

Et

75

3

10

H

Bu

60

4

11

H

t-Bu

72

5

12

H

CH2Ph

60

6

13

Me

Et

50

7

14

Et

Et

40



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8

15

(CH2)3Cl

Et

46

9

16

CH2Ph

Et

21

aalkene:TNM:TEA

in 1:2.5:2 ratio; bisolated

yield.

It is worth noting that increasing the volume of substituents R1 or R2 led to a moderate decrease of isoxazole yields. For instance, if R1 in the starting ester was changed from proton (table 1, entry 2) to ethyl group (table 1, entry 7) and then to benzyl group (table 1, entry 9) the yields of corresponding isoxazoles 9, 14 and 16 decreased from 75 to 40 and 20%, respectively. Moreover, it was found that sterically hindered cumarin and (E)-ethyl 4-methylpent-2-enoate do not react with complex TNM-TEA under the optimal conditions. The results of the heterocyclization of N-substituted acryl amides upon the action of TNMTEA are summarized in Table 2. We have found that acryl amide in the reaction with the complex TNM-TEA at room temperature forms 5-nitroisoxazole-3-carboxamide 17a as a sole product in 64% yield. However the heterocyclization of N-substituted acryl amides led to the mixtures of the desired nitroisoxazoles 17b-g and the products of trinitromethane Michael addition to the starting amides – N-substituted 4,4,4-trinitrobutanamides 18b-g. The attempt to optimize the reaction conditions for hemoselective preparation of 5-nitroisoxazole carbamides was unsuccessful. The mixtures of compounds 17c and 18c in nearly equal ratio were obtained in the reaction of N-benzyl acryl amide as a model compound with TNM-TEA complex at room temperature for 48 h or upon heating at 70 oC

in dioxane for 2 h. The use of methylene chloride as a solvent in reaction of N-benzyl acryl

amide with TNM-TEA complex at room temperature for 72 h led to trinitroamide 18c as the sole product in 54% yield. The products 17 and 18 were isolated by column chromatography (Table 2). TABLE 2. Reaction of acrylamides with TNM-TEA.a


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NR1R2 NR1R2 O

+ C(NO2)4

O

Et3N

N


O

NO2

NR1R2

+ (O2N)3C O

17a-f

18b-f

compounds 17, 18

R1

R2

Yieldb 17, %

Yieldb 18, %

a

H

H

64

-

b

H

Bu

29

21

c

H

CH2Ph

20

23

d

H

cy-hexyl

41

38

e

H

Ph

24

19

f

C3H7

C3H7

23

25

18

25

g aalkene:TNM:TEA

-(CH2)5in 1:2.5:2 ratio; bisolated yield.

A similar result was observed in the reaction of α,β-unsaturated sulfone and sulfonate in the reaction with TNM–TEA complex. It was found that phenyl vinyl sulfone reacted with TNM in the presence of TEA at 70 oC in dioxane for 5 h to give the target 5-nitro-3-(phenylsulfonyl)isoxazole 19 along with phenyl trinitropropyl sulfone 20 (Scheme 3). When the reaction was conducted at room temperature in dioxane for 14 days, only compound 20 was obtained in 38% yield. The increase of the reaction temperature up to 100 oC (in chlorobenzene as a solvent) afforded 19 and 20 in 2% and 3% yields, respectively, along with a number of unidentified by-products. SCHEME 3. Reaction of phenyl vinyl sulfone with TNM-TEA complex (alkene:TNM:TEA in 1:2.5:2 ratio).



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PhO2S 70 oC, 5 h

N

+

(O2N)3C

NO2

O

19, 25% SO2Ph + C(NO2)4

SO2Ph

20, 20%

Et3N 1,4-dioxane 20 oC, 14 d

(O2N)3C

SO2Ph

20, 38%

We have found that the reaction of phenyl ethylenesulfonate with TNM-TEA in boiling dioxane proceed with the formation of trinitromethyl derivative 21 in a 66% yield (Scheme 4), however, the same reaction in boiling chlorobenzene afford the isoxazole 22 in moderate yield. SCHEME 4. Reaction of phenyl ethylenesulfonate with complex TNM-TEA (alkene:TNM:TEA in 1:2.5:2 ratio).

1,4-dioxane

(O2N)3C

70 oC, 2 h

SO3Ph

21, 66% SO3Ph + C(NO2)4

Et3N PhO3S C6H5Cl 110 oC, 1.5 h

N

O

NO2

22, 28%

It was found that phenyl vinyl sulfoxide in the reaction with TNM-TEA did not afford expected isoxazole, and only benzenesulfonic acid was formed as a result of the oxidation of starting alkene by TNM. This result was the same at room temperature and at 70 oC in dioxane. We were encouraged to find that vinyl phosphonate ester smoothly reacted with TNM-TEA complex in dioxane upon heating at 70 oC to form desired 5-nitroisoxazole-3-phosphonate 23 in high yield (Scheme 5). SCHEME 5. Synthesis of 5-nitro-3-phosphonate isoxazole (alkene:TNM:TEA in 1:2.5:2 ratio).


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(EtO)2OP PO(OEt)2 +

Et3N

C(NO2)4

N


NO2

O

23, 76%

Finally, a series of α,β-unsaturated nitroalkenes were investigated in the reaction with TNMTEA complex. We have found that heterocyclization proceeds smoothly at 70 oC in dioxane affording 3,5-dinitroisoxazoles 24-28 in good yields (Table 3). The yield of 24 was substantially reduced due to a partial polymerization of starting nitroethylene under the reaction conditions. The bulky substituents at the double bond have dilatory effect on reactivity of starting olefins. E.g., the yield

of

cyclopropylmethyl

substitued

isoxazole

28

did

not

exceed

50%,

isopropylnitroethylene was totally inert in the reaction with TNM in optimized conditions. TABLE 3. Synthesis of 3,5-dinitroisoxazolesa

O2N R

NO2 +

C(NO2)4

Et3N 1,4-dioxane 70 oC, 2 h

R

N

O

NO2

24-28

3,5-dinitro-

R

Yieldb, %

24

H

38

25

Me

63

26

Et

53

27

(CH2)3Cl

51

28

H2 C

50

isoxazole

aalkene:TNM:TEA

in 1:2.5:2 ratio; bisolated

yield.


while


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Structures of the obtained products were confirmed by NMR spectroscopy.14,15 A proposed mechanism for the formation of 5-nitroisoxazoles is outlined on Scheme 6 using α,β-unsaturated ketone as a model.16 SCHEME 6. Proposed mechanism for the heterocyclization affording 5-nitroisoxazoles. R (NO2)3C

R

+H

Path A (O2N)3C

I

R O

O VII

C(NO2)3

Et3N NO2 I

Path B (O2N)3C

CTC

C(NO2)4 + Et3N

O

(O2N)3C

H

C(NO2)3

Et3N

II

O III

R

O VI

NO2

-HNO3

O

N

NO2

(O2N)3C -NEt3H IV

R

O

R(O)C

R(O)C

R(O)C N

NO2

O

NO2 NO2

-NO2

O

N O

NO2 C NO 2 NO2

V

At the first step, the molecule of TNM is polarized upon the reaction with TEA to give charge-transfer complex (CTC) and then complex I with trinitromethyl group possessing anionic character, while [Et3N-NO2]+ cation can be considered as a reagent for the electrophilic nitration. Such reactivity of TNM with electron donor molecules has been reviewed.1a,f It should be emphasized that TNM does not react with electrophilic alkenes in the absence of the amine. Subsequent process of heterocyclization involves Michael addition of [C(NO2)3]- as the nucleophile to give anionic species II. Further nitration of this intermediate (Path A) leads to ketone III which transforms into IV in the result of deprotonation under the action of TEA. Next, intramolecular cyclization of IV proceeds accompanied by the elimination of nitrite anion and HNO3 resulting in 5-nitroisoxazole VI. The indirect proof of the elimination of HNO3 and HNO2 molecules is the successful isolation of Et3N·HNO3 salt and N-nitroso diethylamine from the reaction mixture. Proceeding the transformation through intermediate V is not proved, but the


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cyclization of substituted 1,1,1,3-tetranitropropanes leading to the formation of the corresponding 5nitroisoxazoles is known.11a Trinitrosubstituted adducts of type VII could be formed via the protonation of the intermediate II by a free proton from the solvent or substrate (path B). This is in a good agreement with the fact that 5,5,5-trinitropentan-2-one was the only product in the reaction of methyl vinyl ketone with TNM-TEA in methanol. Acrylic acid reacted with TNM-TEA complex at room temperature in 1,4-dioxane affording the sole product 4,4,4-trinitro-butyric acid in 49% yield. Although the cyclization of trinitromethyl substituted compounds leading to the formation of the corresponding 5-nitroisoxazoles is described in the literature,11 our attempts to cyclize the products of the Michael addition VII were unsuccessful.

Conclusion In conclusion, it is has been demonstrated that TNM activated by triethylamine possesses unusual properties and may be used as an efficient and readily available reagent for numerous synthetic purposes. The present investigation describes the employment of TNM-TEA complex for heterocyclization of electrophilic alkenes under mild conditions affording hardly accessible 5nitroisoxazoles in good isolated yields. The reaction tolerates a variety of substituents in alkenes. We have developed a simple general and preparative method for the synthesis of functionalized 5nitroisoxazoles which are convenient precursors of pharmacologically active compounds.

Experimental Section Measurements NMR spectra were recorded on 400.1, 162.0, 100.6 and 28.9 MHz for 1H,

31P, 13C

and

14N,

respectively at room temperature; the chemical shifts  were measured in ppm with respect to the solvent (1Н: CDCl3,  = 7.26 ppm, DMSO-d6,  = 2.49 ppm, CD3OD,  = 3.31 ppm; 13C: CDCl3,  = ACS Paragon Plus Environment


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77.1 ppm, DMSO-d6,  = 39.5 ppm, CD3OD,  = 49.0 ppm). Data are reported as follows: chemical shift, multiplicity (s=singlet, d=doublet, t=triplet, q=quartet, m=multiplet, app=apparent, and br=broad), coupling constant in Hertz (Hz), and integration. Accurate mass determination (ESI) was performed on instrument equipped with a dual electrospray ion source. Samples were injected into the MS using methanol as carrier solvent and analysis was performed as a flow injection analysis without any chromatographic step. Both negative and positive electrospray and chemical ionization were conducted. Two reference compounds were continuously injected enabling post-analyses correction of mass axis. Samples for Infrared spectroscopy were recorded as indicated on film, KBr pellet or nujol. Melting points (mp) are uncorrected. Analytical thin layer chromatography (TLC) was carried out with “Silufol” silica gel plates (supported on aluminum); the revelation was done by UV lamp (254 and 365 nm) and chemical staining (iodine vapor and potassium permanganate solution in water). Column chromatography was performed on silica gel 60 (230-400 mesh, Merck).

Materials All solvents were dried and distillated. 1,4-dioxane and chlorobenzene were stored over molecular sieves. All bases (triethylamine, tributylamine, pyridine, tetramethylethylenediamine, 1,8diazabicyclo[5.4.0]undecene,

1,4-diazabicyclo[2.2.2]octane,

triphenylphosphine)

and

tetranitromethane, methyl vinyl ketone, ethyl vinyl ketone, cyclohex-2-enone, levoglucosenone, acrolein, crotone aldehyde, methyl acrylate, ethyl acrylate, butyl acrylate, tert-butyl acrylate, benzyl acrylate, acrylamide, vinylsulfinylbenzene, vinylsulfonylbenzene, phenyl ethenesulfonate, acrylic acid were commercially available. Tertiary amines (triethylamine, tributylamine, pyridine, tetramethylethylenediamine) were dried and distillated. Other materials obtained from commercial suppliers were used without further purification. All reactions with tetranitromethane were carried out under an atmosphere of argon. 1-Phenylprop-2-en-1-one was obtained in two steps, i.e. paraformaldehyde Mannich reaction and thermal elimination17. (E)-Methyl but-2-enoate, (E)-methyl ACS Paragon Plus Environment

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pent-2-enoate, (E)-methyl 6-chlorohex-2-enoate, (E)-methyl 4-phenylbut-2-enoate were synthesized by general procedure based on Wittig reaction18. N-Butylacrylamide, N-benzylacrylamide, Nphenylacrylamide, N-cyclohexylacrylamide were obtained by known procedure19 and N,Ndipropylacrylamide, 1-(piperidin-1-yl)prop-2-en-1-one by procedure20, both were included reaction of acryloyl chloride with corresponding amine in the presents of triethylamine. Diethyl vinylphosphonate was obtained in two steps, i.e. Arbuzov reaction of 1,2-dibromoethane with triethyl phosphate and dehydrohalogenation of Arbuzov’s product21. Nitroethene was prepared from 2-nitroethanol by treatment of phthalic anhydride22. (E)-1-Nitroprop-1-ene, (E)-1-nitrobut-1-ene, (E)-5-chloro-1-nitropent-1-ene, (E)-(3-nitroallyl)cyclopropane were synthesized by condensation aldehydes with nitroethane23. General Procedure for the Synthesis of 5-nitroisoxazoles 1-17, 19, 23-28. Triethylamine (0.28 mL, 2 mmol) was added dropwise to a solution of tetranitromethane (0.3 mL, 2.5 mmol) in 1,4dioxane (2 mL) at 0 oC (ice bath). The reaction mixture was stirred for 5 min and alkene (1 mmol) was added in one portion. Then the cooling was taken off and the mixture was stirred either at room temperature for 12-48 h (for isoxazoles 1-7, 17) or at 70 oC for 2-5 h (for isoxazoles 8-16, 19, 2328), the reaction time is indicated in Scheme 2-5 and Table 1-3. The solvent was removed under reduced pressure and the product was isolated by column chromatography. Caution: Although we did not experience any problem in handling tetranitromethane, full safety precautions should be taken due to its toxicity and explosive nature. 1-(5-Nitroisoxazol-3-yl)ethanone (1)24,11b Yield 120 mg (80%), colorless solid, mp 70-72 C, Rf 0.62 (petroleum ether - EtOAc, 4:1). 1H NMR (CDCl3) δ 2.69 (s, 3H, CH3), 7.33 (s, 1H, CH); 13C{1H}

NMR (CDCl3) δ 26.9 (q, J = 130 Hz, CH3), 100.2 (d, J = 197 Hz, CH), 163.3 (C), 165.7 (br

s, CNO2) , 189.6 (q, JCH = 6 Hz, CO); IR (KBr) 1718 (s), 1544 (s), 1364 (s) cm-1.



Page 14 of 30

1-(5-Nitroisoxazol-3-yl)propan-1-one (2). Yield 150 mg (86%), pale yellow solid, mp 53-54 C, Rf 0.67 (CHCl3). 1H NMR (CDCl3) δ 1.20 (t, J = 7.3 Hz, 3H, CH3), 3.08 (q, J = 7.3 Hz, 2H, CH2), 7.34 (s, 1H, CH); 13C{1H} NMR (CDCl3) δ 7.0, 33.1, 100.4, 162.9, 165.7 (br s, CNO2), 192.7; IR (KBr) 1710 (s), 1546 (s), 1359 (s) cm-1; Anal. Calcd for C6H6N2O4: C, 42.36; H, 3.55; N, 16.47. Found: C, 42.45; H, 3.54; N, 16.32. (5-Nitroisoxazol-3-yl)(phenyl)methanone (3). Yield 190 mg (85%), colorless solid, mp 82-83 C, Rf 0.66 (CHCl3). 1H NMR (CDCl3) δ 7.53 (s, 1H, CH), 7.56-7.60 (m, 2H, Ph), 7.71-7.75 (m, 1H, Ph), 8.31-8.33 (m, 2H, Ph); 13C{1H} NMR (CDCl3) δ 102.9, 129.0 (2C), 130.8 (2C), 134.3, 135.1, 163.5, 165.5 (br s, CNO2), 182.9; IR (KBr) 1715 (s), 1542 (s), 1325 (s) cm-1; Anal. Calcd for C10H6N2O4: C, 55.05; H, 2.77; N, 12.84. Found: C, 55.27; H, 2.63; N, 12.88. 3-Nitro-5,6-dihydrobenzo[d]isoxazol-7(4H)-one (4). Yield 140 mg (77%), pale yellow solid, mp 114-115 C, Rf 0.25 (CHCl3). 1H NMR (CDCl3) δ 2.22-2.29 (m, 2H, CH2), 2.73-2.79 (m, 2H, CH2), 3.11-3.17 (m, 2H, CH2);

13C{1H}

NMR (CDCl3) δ 20.3, 22.3, 39.8 (CH2), 118.9 (C), 158.9 (C),

160.9 (br s, CNO2), 188.9 (CO); IR (KBr) 1716 (s), 1540 (s), 1357 (s) cm-1; Anal. Calcd for C7H6N2O4: C, 46.16; H, 3.32; N, 15.38. Found: C, 46.21; H, 3.50; N, 15.19. (4R,7S)-3-Nitro-4,5-dihydro-4,7-epoxyoxepino[4,5-d]isoxazol-8-one (5). Yield 110 mg (53%), colorless solid, mp 110-112 C, Rf 0.25 (petroleum ether - EtOAc, 2:1). 1H NMR (CDCl3) δ 4.09 (d, J = 7.8 Hz, 1H, CH2), 4.20 (dd, J = 4.3, 7.8 Hz, 1H, CH2), 5.65 (s, 1H, CH), 6.02 (d, J = 4.3 Hz, 1H, CH); 13C{1H} NMR (CDCl3) δ 68.6 (JCH = 156 Hz, CH2), 69.9 (J = 165 Hz, CH), 99.9 (J = 185 Hz, CH), 117.1 (С), 156.4 (C), 158.4 (br s, CNO2), 179.0 (CO); IR (nujol) 1730 (s), 1535 (s), 1340 (s) cm-1; Anal. Calcd for C7H4N2O6: C, 39.64; H, 1.90; N, 13.21. Found: C, 39.81; H, 2.07; N, 13.29. 5-Nitroisoxazole-3-carbaldehyde (6).25 Yield 80 mg (60%), pale yellow liquid, Rf 0.75 (petroleum ether - EtOAc, 2:1). 1H NMR (CDCl3) δ 7.32 (s, 1H, CH), 9.96 (s, 1H, CH); 13C{1H} NMR (CDCl3) δ 99.7, 163.0, 166.7 (br s, CNO2), 182.5.


Page 15 of 30 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


4-Methyl-5-nitroisoxazole-3-carbaldehyde (7). Yield 70 mg (49%), pale yellow liquid, Rf 0.76 (petroleum ether - EtOAc, 2:1). 1H NMR (CDCl3) δ 2.58 (s, 3H, CH3), 10.14 (s, 1H, CH); 13C{1H} NMR (CDCl3) δ 8.0, 114.1, 161.2, 162.3 (br s, CNO2), 184.4; IR (KBr) 1718 (s), 1542 (s), 1359 (s) cm-1; Anal. Calcd for C5H4N2O4: C, 38.47; H, 2.58; N, 17.95. Found: C, 38.31; H, 2.60; N, 17.86. Methyl 5-nitroisoxazole-3-carboxylate (8). Yield 110 mg (62%), colorless solid, mp 71-72 C, Rf 0.46 (CHCl3). 1H NMR (CDCl3) δ 4.01 (s, 3H, CH3), 7.40 (s, 1H, CH);

13C{1H}

NMR (CDCl3) δ

53.7 (q, J = 148 Hz, CH3), 102.3 (d, J = 197 Hz, CH), 157.96 (C), 158.04 (C), 165.6 (br s, CNO2); IR (KBr) 1741 (s), 1550 (s), 1359 (s) cm-1; Anal. Calcd for C5H4N2O5: C, 34.90; H, 2.34; N, 16.28. Found: C, 34.91; H, 2.19; N, 16.40. Ethyl 5-nitroisoxazole-3-carboxylate (9). Yield 140 mg (75%), pale yellow liquid, Rf 0.49 (CHCl3). 1H NMR (CDCl3) δ 1.46 (t, J = 7.2 Hz, 3H, CH3), 4.52 (q, J = 7.2 Hz, 2H, CH2), 7.41 (s, 1H, CH); 13C{1H} NMR (CDCl3) δ 14.0, 63.4, 102.3, 157.6, 158.3, 165.6 (br s, CNO2); IR (KBr) 1740 (s), 1552 (s), 1357 (s) cm-1; Anal. Calcd for C6H6N2O5: C, 38.72; H, 3.25; N, 15.05. Found: C, 38.65; H, 3.24; N, 15.25. Butyl 5-nitroisoxazole-3-carboxylate (10). Yield 130 mg (60%), pale yellow liquid, Rf 0.55 (CHCl3). 1H NMR (CDCl3) δ 0.99 (t, J = 7.3 Hz, 3H, CH3), 1.45-1.51 (m, 2H, CH2), 1.77-1.84 (m, 2H, CH2), 4.46 (t, J = 6.7 Hz, 2H, CH2), 7.41 (s, 1H, CH);

13C{1H}

NMR (CDCl3) δ 13.6, 19.0,

30.4, 67.1, 102.3, 157.7, 158.3, 165.6 (br s, CNO2); IR (KBr) 1739 (s), 1550 (s), 1357 (s) cm-1; Anal. Calcd for C8H10N2O5: C, 44.86; H, 4.71; N, 13.08. Found: C, 44.70; H, 4.57; N, 13.19. tert-Butyl 5-nitroisoxazole-3-carboxylate (11). Yield 155 mg (72%), colorless solid, mp 57-58 C, Rf 0.60 (CHCl3). 1H NMR (CDCl3) δ 1.57 (s, 9H, 3×CH3), 7.30 (s, 1H, CH);

13C{1H}

NMR

(CDCl3) δ 27.8 (q, J = 127 Hz, 3CH3), 85.5 (C), 102.3 (d, J = 197 Hz, CH), 156.5 (C), 159.3 (d, J = 3 Hz, C), 165.3 (br s, CNO2); IR (KBr) 1736 (s), 1548 (s), 1375 (s) cm-1; Anal. Calcd for C8H10N2O5: C, 44.86; H, 4.71; N, 13.08. Found: C, 44.98; H, 4.49; N, 13.11.



Page 16 of 30

Benzyl 5-nitroisoxazole-3-carboxylate (12). Yield 150 mg (60%), colorless solid, mp 61-62 C, Rf 0.57 (CHCl3). 1H NMR (CDCl3) δ 5.47 (s, 2H, CH2), 7.37-7.48 (m, 5H, Ph), 7.41 (s, 1H, CH); 13C{1H}

NMR (CDCl3) δ 68.8 (CH2), 102.3 (CH), 128.9 (4СН, Рh), 129.1 (СН, Рh), 134.0 (С, Ph),

157.5(C), 158.1 (C), 165.7 (br s, CNO2); IR (KBr) 1749 (s), 1540 (s), 1355 (s) cm-1; Anal. Calcd for C11H8N2O5: C, 53.23; H, 3.25; N, 11.29. Found: C, 53.29; H, 3.33; N, 11.24. Ethyl 4-methyl-5-nitroisoxazole-3-carboxylate (13). Yield 100 mg (50%), pale yellow liquid, Rf 0.54 (CHCl3). 1H NMR (CDCl3) δ 1.45 (t, J = 7.2 Hz, 3H, CH3), 2.61 (s, 3H, CH3), 4.50 (q, J = 7.2 Hz, 2H, CH2); 13C{1H} NMR (CDCl3) δ 8.6, 14.0, 63.0, 115.6, 157.3, 158.6, 162.1 (br s, CNO2); IR (KBr) 1736 (s), 1543 (s), 1354 (s) cm-1; Anal. Calcd for C7H8N2O5: C, 42.01; H, 4.03; N, 14.00. Found: C, 42.30; H, 4.22; N, 14.15. Ethyl 4-ethyl-5-nitroisoxazole-3-carboxylate (14). Yield 80 mg (40%), pale yellow liquid, Rf 0.47 (CHCl3). 1H NMR (CDCl3) δ 1.27 (t, J = 7.5 Hz, 3H, CH3), 1.47 (t, J = 7.1 Hz, 3H, CH3), 3.08 (q, J = 7.5 Hz, 2H, CH2), 4.51 (q, J = 7.1 Hz, 2H, CH2); 13C{1H} NMR (CDCl3) δ 13.4 (q, J = 128 Hz, CH3), 14.0 (q, J = 127 Hz, CH3), 16.3 (t, J = 133 Hz,CH2), 63.0 (t, J = 127 Hz, CH2), 121.3 (C), 157.0 (C), 158.5 (C), 161.8 (br s, CNO2); IR (KBr) 1734 (s), 1539 (s), 1348 (s) cm-1; Anal. Calcd for C8H10N2O5: C, 44.86; H, 4.71; N, 13.08. Found: C, 44.70; H, 4.75; N, 13.20. Ethyl 4-(3-chloropropyl)-5-nitroisoxazole-3-carboxylate (15). Yield 120 mg (46%), pale yellow liquid, Rf 0.36 (petroleum ether - EtOAc, 5:1). 1H NMR (CDCl3) δ 1.48 (t, J = 7.1 Hz, 3H, CH3), 2.11-2.18 (m, 2H, CH2), 3.21-3.25 (m, 2H, CH2), 3.65 (app t, J = 6.3 Hz, 2H, CH2), 4.53 (q, J = 7.1 Hz, 2H, CH2); 13C{1H} NMR (CDCl3) δ 14.0, 20.6, 31.5, 44.0, 63.2, 118.5, 157.1, 158.4, 162.1 (br s, CNO2); IR (film) 1730 (s), 1540 (s), 1335 (s) cm-1; Anal. Calcd for C9H11ClN2O5: C, 41.16; H, 4.22; N, 10.67. Found: C, 41.21; H, 4.13; N, 10.75. Ethyl 4-benzyl-3-nitroisoxazole-5-carboxylate (16). Yield 60 mg (21%), pale yellow liquid, Rf 0.55 (CHCl3). 1H NMR (CDCl3) δ 1.41 (t, J = 7.2 Hz, 3H, CH3), 4.45-4.50 (m, 4H, 2×CH2), 7.237.32 (m, 5H, Ph); 13C{1H} NMR (CDCl3) δ 14.0, 27.8, 63.1, 118.1, 127.3, 128.6 (2C), 128.8 (2C), ACS Paragon Plus Environment

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133.3, 157.0, 158.5, 162.0 (br s, CNO2); IR (KBr) 1739 (s), 1544 (s), 1348 (s) cm-1; HRMS (ESITOF) m/z: [M-H]- Calcd. for C13H11N2O5 275.0674; Found: 275.0676. 5-Nitroisoxazole-3-carboxamide (17a). Yield 100 mg (64%), colorless solid, mp 159-163 C, Rf 0.21 (CHCl3). 1H NMR (CD3OD) δ 7.60 (с, 1H, CH);

13C{1H}

NMR (CD3OD) δ 101.0, 159.4,

160.8, 165.9 (br s, CNO2); IR (KBr) 3369 (s), 1678 (s), 1545 (s), 1344 (s) cm-1; Anal. Calcd for C4H3N3O4: C, 30.58; H, 1.92; N, 26.75. Found: C, 30.70; H, 2.09; N, 26.85. N-Butyl-5-nitroisoxazole-3-carboxamide (17b). Yield 70 mg (29%), colorless solid, mp 72-74 C, Rf 0.40 (petroleum ether - EtOAc, 5:1). 1H NMR (CDCl3) δ 0.97 (t, J = 7.3 Hz, 3H, CH3), 1.39-1.47 (m, 2H, CH2), 1.60-1.67 (m, 2H, CH2), 3.45-3.51 (m, 2H, CH2), 6.88 (br. m, 1H, NH), 7.44 (s, 1H, CH);

13C{1H}

NMR (CDCl3) δ 13.6, 20.0, 31.3, 39.6, 101.7, 156.3, 160.6, 165.6 (br s, CNO2); IR

(nujol) 3315 (w), 1672 (s), 1548 (s), 1320 (s) cm-1; Anal. Calcd for C8H11N3O4: C, 45.07; H, 5.20; N, 19.71. Found: C, 45.32; H, 5.08; N, 19.92. N-butyl-4,4,4-trinitrobutanamide (18b). Yield 60 mg (21%), colorless solid, mp 73-75 C, Rf 0.32 (CНCl3). 1H NMR (CDCl3) δ 0.93 (t, J = 7.2 Hz, 3H, CH3), 1.30-1.39 (m, 2H, CH2), 1.45-1.52 (m, 2H, CH2), 2.58-2.62 (m, 2H, CH2), 3.22-3.29 (m, 2H, CH2), 3.42-3.45 (m, 2H, CH2), 5.81 (br. m, 1H, NH);

13C{1H}

NMR (CDCl3) δ 13.5, 20.0, 29.6, 30.0, 31.3, 39.8, 129.5 [C(NO2)3], 168.0; IR

(nujol) 3290 (w), 1620 (s), 1470 (s), 1280 (s) cm-1; Anal. Calcd for C8H14N4O7: C, 34.54; H, 5.07; N, 20.14. Found: C, 34.49; H, 5.13; N, 19.95. N-benzyl-5-nitroisoxazole-3-carboxamide (17c). Yield 50 mg (20%), colorless solid, mp 101-105 C, Rf 0.47 (petroleum ether - EtOAc, 5:1). 1H NMR (CDCl3) δ 4.67 (d, J = 6.0 Hz, 2H, CH2), 7.14 (br. m, 1H, NH), 7.34-7.39 (m, 5H, Ph), 7.47 (s, 1H, CH);

13C{1H}

NMR (CDCl3) δ 43.9, 101.8,

128.0 (2C), 128.1, 129.0 (2C), 136.6, 156.3, 160.4, 165.6 (br s, CNO2); IR (KBr) 3356 (w), 1668 (s), 1537 (s), 1338 (s) cm-1; Anal. Calcd for C11H9N3O4: C, 53.44; H, 3.67; N, 17.00. Found: C, 53.55; H, 3.65; N, 16.95.



Page 18 of 30

N-benzyl-4,4,4-trinitrobutanamide (18c). Yield 70 mg (23%), yellow liquid, Rf 0.39 (petroleum ether - EtOAc, 5:1). 1H NMR (CDCl3) δ 3.67 (s, 4H, 2×CH2), 4.94 (s, 2H, CH2), 7.19-7.33 (m, 5H, Ph);

13C{1H}

NMR (CDCl3) δ26: 29.1, 29.6, 42.7, 128.3, 128.7 (2C), 128.8 (2C), 133.8, 172.9; IR

(KBr) 3345 (w), 1739 (s), 1597 (s), 1303 (s) cm-1; Anal. Calcd for C11H12N4O7: C, 42.31; H, 3.87; N, 17.94. Found: C, 42.47; H, 3.71; N, 18.07. N-cyclohexyl-5-nitroisoxazole-3-carboxamide (17d). Yield 100 mg (41%), colorless solid, mp 142-144 C, Rf 0.44 (petroleum ether - EtOAc, 5:1). 1H NMR (CDCl3) δ 1.19-1.48 (m, 5H, CH2), 1.67-1.71 (m, 1H, CH2), 1.78-1.81 (m, 2H, CH2), 2.02-2.05 (m, 2H, CH2), 3.92-4.01 (m, 1H, CH), 6.96 (br s, 1H, NH), 7.45 (s, 1H, CH);

13C{1H}

NMR (CDCl3) δ 24.7 (2C), 25.3, 32.8 (2C), 49.0,

101.8, 155.3, 160.8, 165.6 (br s, CNO2); IR (KBr) 3320 (w), 1670 (s), 1550 (s), 1320 (s) cm-1; Anal. Calcd for C10H13N3O4: C, 50.21; H, 5.48; N, 17.56. Found: C, 50.39; H, 5.44; N, 17.50. N-cyclohexyl-4,4,4-trinitrobutanamide (18d). Yield 110 mg (38%), colorless solid, mp 150-152 C, Rf 0.52 (CНCl3). 1H NMR (CDCl3) δ 1.09-1.22 (m, 3H, CH2), 1.33-1.43 (m, 2H, CH2), 1.631.66 (m, 1H, CH2), 1.72-1.75 (m, 2H, CH2), 1.92-1.95 (m, 2H, CH2), 2.57-2.60 (m, 2H, CH2), 3.443.47 (m, 2H, CH2), 3.74-3.81 (m, 1H, CH), 5.42 (br s, 1H, NH); 13C{1H} NMR (DMSO-d6) δ2624.8 (2C), 25.6, 29.2 (2C), 32.7 (2C), 48.2, 167.4; IR (KBr) 3288 (w), 1643 (s), 1594 (s), 1299 (s) cm-1; Anal. Calcd for C10H16N4O7: C, 39.48; H, 5.30; N, 18.41. Found: C, 39.55; H, 5.19; N, 18.35. 5-Nitro-N-phenylisoxazole-3-carboxamide (17e). Yield 60 mg (24%), colorless solid, mp 105-107 C, Rf 0.21 (petroleum ether - EtOAc, 5:1). 1H NMR (CDCl3) δ 7.24-7.28 (m, 1H, Ph), 7.41-45 (m, 2H, Ph), 7.55 (s, 1H, CH), 7.66-7.68 (m, 2H, Ph), 8.48 (br s, 1H, NH);

13C{1H}

NMR (CDCl3) δ

101.8, 120.2 (2C), 125.9, 129.4 (2C), 136.1, 154.0, 160.7, 165.8 (br s, CNO2); MS (ESI) 234 [(М+Н)] +; IR (KBr) 3338 (w), 1680 (s), 1551 (s), 1348 (s) cm-1; Anal. Calcd for C10H7N3O4: C, 51.51; H, 3.03; N, 18.02. Found: C, 51.77; H, 3.14; N, 17.95.


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4,4,4-Trinitro-N-phenylbutanamide (18e). Yield 60 mg (19%), yellow liquid, Rf 0.18 (petroleum ether - EtOAc, 5:1). 1H NMR (CD3OD) δ 2.81-2.85 (m, 2H, CH2), 3.56-3.60 (m, 2H, CH2), 7.067.09 (m, 1H, Ph), 7.26-7.30 (m, 2H, Ph), 7.47-7.49 (m, 2H, Ph); 13C{1H} NMR (CD3OD) δ26 31.6, 32.3, 122.5 (2C), 126.8, 131.1 (2C), 140.3, 170.5; MS (ESI) 299 [(М+Н)] +; IR (KBr) 3262 (w), 1670 (s), 1602 (s), 1324 (s) cm-1; HRMS (ESI-TOF) m/z: [M+H]+

Calcd. for C10H11N4O7+

299.0622; Found: 299.0627. 5-Nitro-N,N-dipropylisoxazole-3-carboxamide (17f). Yield 50 mg (23%), yellow oil, Rf 0.23 (petroleum ether - EtOAc, 5:1). 1H NMR (CDCl3) δ 0.90 (t, J = 7.4 Hz, 3H, CH3), 0.95 (t, J = 7.4 Hz, 3H, CH3), 1.64-1.73 (m, 4H, 2×СН2), 3.46-3.51 (m, 4H, СН2, 2×CH2), 7.34 (s, 1H, CH); 13C{1H}

NMR (CDCl3) δ 11.1, 11.3, 20.7, 21.9, 48.0, 49.3, 103.6, 157.8, 162.4, 165.8 (br s, CNO2);

IR (KBr) 2964 (w), 1648 (s), 1596 (s), 1305 (s) cm-1; HRMS (ESI-TOF) m/z: [M+H]+ Calcd. for C10H16N3O4+ 242.1135; Found: 242.1132. 4,4,4-Trinitro-N,N-dipropylbutanamide (18f). Yield 80 mg (25%), yellow liquid, Rf 0.18 (petroleum ether - EtOAc, 5:1). 1H NMR (CDCl3) δ 0.90 (t, J = 7.4 Hz, 3H, CH3), 0.94 (t, J = 7.4 Hz, 3H, CH3), 1.51-1.64 (m, 4H, 2×СН2), 2.71-2.74 (m, 2H, CH2), 3.15-3.19 (m, 2H, CH2), 3.273.31 (m, 2H, CH2), 3.48-3.51 (m, 2H, CH2); 13C{1H} NMR (CDCl3) δ 11.1, 11.3, 20.7, 21.9, 27.4, 30.3, 48.0, 49.3, 129.9, 167.1; MS (ESI) 307 [(М+Н)] +; IR (KBr) 2967 (w), 1646 (s), 1596 (s), 1305 (s) cm-1; HRMS (ESI-TOF) m/z: [M+H]+ Calcd. for C10H19N4O7+ 307.1248; Found: 307.1251; Anal. Calcd for C10H18N4O7: C, 39.22; H, 5.92; N, 18.29. Found: C, 39.40; H, 5.85; N, 18.29. (5-Nitroisoxazol-3-yl)(piperidin-1-yl)methanone (17g). Yield 40 mg (18%), yellow oil, Rf 0.18 (petroleum ether - EtOAc, 5:1). 1H NMR (CDCl3) δ 1.52-1.74 (m, 6H, 3×СН2), 3.71-3.76 (m, 4H, 2×CH2), 7.30 (s, 1H, CH);

13C{1H}

NMR (CDCl3) δ 24.3, 25.4, 26.2, 43.3, 46.3, 103.4, 156.5,

161.0, 165.8 (br s, CNO2); IR (KBr) 2954 (w), 1635 (s), 1581 (s), 1307 (s) cm-1; HRMS (ESI-TOF) m/z: [M+H]+ Calcd. for C9H12N3O4+ 226.0822; Found: 226.0823.



Page 20 of 30

4,4,4-Trinitro-1-(piperidin-1-yl)butan-1-one (18g). Yield 70 mg (25%), yellow liquid, Rf 0.35 (CHCl3). 1H NMR (CD3OD) δ 1.54-1.69 (m, 6H, 3×CH2), 2.84-2.88 (m, 2H, CH2), 3.43-3.45 (m, 2H, CH2), 3.52-3.56 (m, 2H, CH2), 3.58-3.64 (m, 2H, CH2); 13C{1H} NMR (CD3OD) δ 24.0, 25.2, 25.9, 26.9, 29.4, 43.0, 46.1, 130.6, 167.2; IR (KBr) 2950 (w), 1635 (s), 1581 (s), 1305 (s) cm-1; HRMS (ESI-TOF) m/z: [M+H]+ Calcd. for C9H15N4O7+ 291.0935; Found: 291.0939; Anal. Calcd for C9H14N4O7: C, 37.25; H, 4.86; N, 19.30. Found: C, 37.47; H, 4.73; N, 19.14. 5-Nitro-3-(phenylsulfonyl)isoxazole (19). Yield 60 mg (25%), colorless solid, mp 75-76 C; Rf = 0.42 (petroleum ether - EtOAc, 10:1). 1H NMR (CDCl3) δ 7.42 (s, 1H, CH), 7.68-7.70 (m, 2H, Ph), 7.71-7.83 (m, 1H, CH), 8.10-8.12 (m, 2H, Ph); 13C{1H} NMR (CDCl3) δ 100.7, 128.2 (2C), 129.1 (2C), 135.8 (C), 137.4 (C), 165.4 (br s, CNO2), 168.0; IR (KBr) 1594 (s), 1334 (s), 1294 (s), 1157 (s) cm-1; Anal. Calcd for C9H6N2O5S: C, 42.52; H, 2.38; N, 11.02. Found: C, 42.90; H, 2.60; N, 10.85. (3,3,3-Trinitropropylsulfonyl)benzene (20). Yield 60 mg (19%), colorless solid, mp 163-165 C; Rf = 0.39 (petroleum ether - EtOAc, 10:1). 1H NMR (CDCl3) δ 3.44-3.51 (m, 4Н, 2×CH2), 7.66-7.70 (m, 2H, Ph), 7.78-7.85 (m, 1H, Ph), 7.97-7.98 (m, 2H, Ph); 13C{1H} NMR (CDCl3) δ26 28.4, 50.1, 130.0 (4C), 135.0, 137.1; IR (KBr) 1596 (s), 1332 (s), 1294 (s), 1160 (s) cm-1; Anal. Calcd for C9H9N3O8S: C, 33.86; H, 2.84; N, 13.16. Found: C, 33.83; H, 2.73; N, 13.27. Phenyl 3,3,3-trinitropropane-1-sulfonate 21. To a solution of tetranitromethane (0.3 ml, 2.5 mmol) in 2 ml 1,4-dioxane at 0 oC (ice bath) triethylamine (0.28 ml, 2 mmol) dropwise was added. The mixture was stirred over cooling 5 min, and phenyl ethenesulfonate (0.18 g, 1 mmol) was added in one portion. The cooling was taken off and the mixture was stirred at 70 C for 2 hours. Solvent was removed under reduced pressure and 220 mg (yield 66%) of 21 was isolated by column chromatography with petroleum ether - EtOAc, 5:1. Colorless solid, mp 89-91 C, Rf 0.68 (petroleum ether - EtOAc, 5:1). 1H NMR (DMSO-d6) 4.06-4.09 (m, 2H, CH2), 4.15-4.18 (m, 2H,


Page 21 of 30 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


CH2), 7.40-7.45 (m, 3H, Ph), 7.49-7.55 (m, 2H, Ph); 13C{1H} NMR (DMSO-d6) δ: 28.2, 45.0, 123.1 (2C), 128.6, 129.8, 131.1(2C), 149.5; IR (nujol) 1490 (s), 1385 (s), 1305 (s), 1200 (s) cm-1; Anal. Calcd for C9H9N3O9S: C, 32.24; H, 2.71; N, 12.53. Found: C, 32.48; H, 2.73; N, 12.27. Phenyl 5-nitroisoxazole-3-sulfonate 22. To a solution of tetranitromethane (0.3 ml, 2.5 mmol) in 2 ml chlorobenzene at 0 oC (ice bath) triethylamine (0.28 ml, 2 mmol) dropwise was added. The mixture was stirred over cooling 5 min, and phenyl ethenesulfonate (0.18 g, 1 mmol) was added in one portion. The cooling was taken off and the mixture was stirred at 110 C for 1.5 hours. Solvent was removed under reduced pressure and 80 mg (yield 28%) of 22 was isolated by column chromatography with petroleum ether - EtOAc, 5:1. Colorless solid, mp 93-94 C, Rf 0.38 (petroleum ether - EtOAc, 5:1). 1H NMR (CDCl3) δ 7.23-7.24 (m, 2H, Ph), 7.36 (s, 1H, CH), 7.387.48 (m, 3H, Ph);

13C{1H}

NMR (CDCl3) δ 101.6, 121.8 (2C), 128.5, 130.4 (2C), 149.1, 162.7,

165.6 (br s, CNO2); IR (nujol) 1596 (s), 1310 (s), 1350 (s), 1200 (s) cm-1; Anal. Calcd for C9H6N2O6S: C, 40.00; H, 2.24; N, 10.37. Found: C, 40.12; H, 2.30; N, 10.25. Diethyl 5-nitroisoxazol-3-ylphosphonate (23). Colorless liquid, Rf 0.67 (CHCl3-МеОН, 20:1). 1H NMR (CDCl3) δ 1.41 (t, J = 7.1 Hz, 6H, 2×CH3), 4.29-4.34 (m, 4H, 2×CH2), 7.27 (s, 1H, CH); 13C{1H}

NMR (CDCl3) δ 16.2 (d, JCP = 6 Hz, 2×CH3), 64.6 (d, JCP = 6 Hz, 2×CH2), 104.2 (d, JCP =

19 Hz, CH), 159.5 (d, JCP = 211 Hz, C), 165.5 (br s, CNO2);

31Р{1H}

NMR (CDCl3) δ -0.12; IR

(KBr) 2987 (s), 1554 (s), 1355 (s), 1220 (s) cm-1; Anal. Calcd for C7H11N2O6Р: C, 33.61; H, 4.43; N, 11.20. Found: C, 33.35; H, 4.30; N, 11.15. 3,5-Dinitroisoxazole (24).11a,27 Yield 60 mg (38%), colorless solid, mp 51-53 C, Rf = 0.76 (petroleum ether - EtOAc, 5:1). 1H NMR (CDCl3) δ 7.65 (s, 1H, CH); 13C{1H} NMR (CDCl3) δ 97.7 (CH), 165.7 (br. t, JCN = 18 Hz, CNO2), 167.1 (br. t, J CN = 16 Hz, CNO2); 14N{1H} NMR (CDCl3) δ -38.4, -33.7 (NO2).



Page 22 of 30

4-Methyl-3,5-dinitroisoxazole (25). Yield 110 mg (63%), pale yellow solid, mp 24-28 C, Rf 0.81 (CHCl3). 1H NMR (CDCl3) δ 2.71 (s, 3H, CH3); 13C{1H} NMR (CDCl3) δ 8.5, 110.7, 165.3 (br s, CNO2), 166.4 (br s, CNO2); IR (nujol) 1560 (s), 1315 (s) cm-1; Anal. Calcd for C4H3N3O5: C, 27.76; H, 1.75; N, 24.28. Found: C, 27.90; H, 1.67; N, 24.10. 4-Ethyl-3,5-dinitroisoxazole (26). Yield 100 mg (53%), pale yellow liquid, Rf 0.75 (petroleum ether - EtOAc, 10:1). 1H NMR (CDCl3) δ 1.35 (t, J = 7.4 Hz, 3H, CH3), 3.14 (q, J = 7.4 Hz, 2H, 13C{1H}

CH2);

NMR (CDCl3) δ 13.0, 16.3, 116.0, 162.2, 166.1 (br s, CNO2); IR (KBr) 1558 (s),

1334 (s) cm-1; Anal. Calcd for C5H5N3O5: C, 32.10; H, 2.69; N, 22.46. Found: C, 32.12; H, 2.71; N, 22.41. 4-(3-Chloropropyl)-3,5-dinitroisoxazole (27). Yield 120 mg (51%), pale yellow liquid, Rf 0.42 (petroleum ether - EtOAc, 10:1). 1H NMR (CDCl3) δ 2.16-2.23 (m, 2H, CH2), 3.27-3.31 (m, 2H, CH2), 3.69 (app t, J = 6.1 Hz, 2H, CH2); 13C{1H} NMR (CDCl3) δ 20.4, 31.0, 43.8, 113.5, 162.3 (br s, CNO2), 166.2 (br s, CNO2); IR (film) 1540 (s), 1345 (s) cm-1; Anal. Calcd for C6H6ClN3O5: C, 30.59; H, 2.57; N, 17.84. Found: C, 30.77; H, 2.56; N, 17.69. 4-(Cyclopropylmethyl)-3,5-dinitroisoxazole (28). Yield 100 mg (50%), pale yellow liquid, Rf 0.75 (petroleum ether - EtOAc, 10:1). 1H NMR (CDCl3) δ 0.34-0.40 (m, 2H, CH2), 0.55-0.61 (m, 2H, CH2), 1.07-1.14 (m, 1H, CH), 3.07-3.11 (m, 2H, CH2);

13C{1H}

NMR (CDCl3) δ 4.7 (2C), 10.3,

26.5, 114.3, 161.9 (br s, CNO2), 166.3 (br s, CNO2); IR (KBr) 1621 (s), 1558 (s), 1140 (s), 1334 (s) cm-1; Anal. Calcd for C7H7N3O5: C, 39.44; H, 3.31; N, 19.71. Found: C, 39.45; H, 3.39; N, 19.52. Experimental data concerning studies of heterocyclization reaction mechanism. Triethylammonium nitrate was isolated by column chromatography from the reaction of methyl vinyl ketone and TNM-TEA in dioxane. Pale yellow solid,28 Rf 0.35 (petroleum ether - EtOAc, 1:1). 1H

NMR (CD3OD) δ 1.33 (t, J = 7.3 Hz, 3H, CH3), 3.25 (q, J = 7.3 Hz, 2H, CH2). 4.77 (br.s 1H,

NH);

13C{1H}

NMR (CD3OD) δ 7.9, 46.6; IR (nujol) 1463 (s), 1376 (s) cm-1; Anal. Calcd for

C6H16N2O3: C, 43.89; H, 9.82; N, 17.06. Found: C, 44.06; H, 10.03; N, 17.08. ACS Paragon Plus Environment

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5,5,5-Trinitropentan-2-one29 To a solution of tetranitromethane (0.3 ml, 2.5 mmol) in 2 ml MeOH at 0 oC (ice bath) triethylamine (0.28 ml, 2 mmol) dropwise was added. The mixture was stirred over cooling 5 min, and methyl vinyl ketone (0.08 ml, 1 mmol) was added in one portion. The cooling was taken off and the mixture was stirred at rt for 12 h. Solvent was removed under reduced pressure and 140 mg (63%) of product was isolated by column chromatography with petroleum ether - EtOAc, 5:1. Pale yellow solid, mp 44 C, Rf 0.35 (CHCl3). 1H NMR (CDCl3) δ 2.21 (s, 3H, CH3), 2.86-2.90 (m, 2H, CH2), 3.31-3.34 (m, 2H, CH2C(NO2)3);

13C{1H}

NMR (CDCl3) δ 28.4,

29.5, 37.0, 129.6, 202.5. 4,4,4-Trinitrobutanoic acid. To a solution of tetranitromethane (0.3 ml, 2.5 mmol) in 2 ml 1,4dioxane at 0 oC (ice bath) triethylamine (0.28 ml, 2 mmol) dropwise was added. The mixture was stirred over cooling 5 min, and acryl acid (0.07 ml, 1 mmol) was added in one portion. The cooling was taken off and the mixture was stirred at rt for 3 days. Solvent was removed under reduced pressure and 110 mg (49%) of product was isolated by column chromatography with petroleum ether - EtOAc, 4:1. Colorless solid, mp 55-57 C, Rf 0.19 (petroleum ether - EtOAc, 2:1). 1H NMR (CDCl3) δ 2.86-2.89 (m, 2H, CH2), 3.40-3.43 (m, 2H, CH2), 9.21 (br s, 1H, OH);

13C{1H}

NMR

(CDCl3) δ 28.2, 29.4, 128.6, 175.2; IR (nujol) 2900 (s), 1598 (s), 1310 (s), 1245 (s) cm-1; Anal. Calcd for C4H5N3O8: C, 21.53; H, 2.26; N, 18.83. Found: C, 21.67; H, 2.38; N, 18.71.

Acknowledgment. This work was supported by the Russian Science Foundation, grant no. 17-1501455. This study was fulfilled using a STOE STADI VARI PILATUS-100K diffractometer and NMR spectrometer Agilent 400-MR purchased by MSU Development Program. We are indebted to Dr. L. D. Konyushkin for а sample of levoglucosenone.



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Supporting Information Available: Copies of NMR spectra for all reaction products, tables with the information on the optimization of reaction conditions. This material is available free of charge via the Internet at http://pubs.acs.org.

1. (a) Altukhov, K. V.; Perekalin, V. V. Chemistry of tetranitromethane. Uspekhi Khimii 1976, 45, 2050–2076; Chem. Abstr. 1977, 86, 71774s. (b) Fridman, A. L.; Surkov, V. D.; Novikov, S. S. Chemistry of α-halonitroalkanes. Uspekhi Khimii 1980, 49, 2159–2187; Chem. Abstr. 1981, 94, 156194t. (c) Shvekhgeymer, G. A.; Zvolinskii, V. I.; Kobrakov, K. I. Synthesis of heterocycles from aliphatic nitro compounds. Khim. Heterotsikl. Soed. 1986, 435–452; Chem. Abstr. 1987, 106, 50078j. (d) Nielsen, A. T. in Nitronic acids and esters, Feuer, H., Ed.; Wiley-VCH: New York, 1981, 349. (e) Torssell, K. B. G. in Nitrile oxides, nitrones and nitronates in organic synthesis, Feuer, H., Ed.; Wiley-VCH: New York, 1988, 95. (f) Nielsen, A. T. in Nitrocarbons, Feuer, H., Ed.; Wiley-VCH: New York, 1995, 1. (g) Padwa, A.; Pearson, W. H. in Synthetic applications of 1,3dipolar cycloaddition chemistry toward heterocycles and natural products, Feuer, H., Ed.; WileyVCH: New Jersey, 2002, 83. (h) Ioffe, S. L. in Nitrile oxide, nitrones and nitronates on organic synthesis, Feuer, H., Ed.; Wiley-VCH: New Jersey, 2008, 435. (i) Averina, E.B.; Ivanova, O.A.; Budynina, E.M.; Volkova, Y.A.; Kuznetsova, T.S.; Zefirov, N.S. Acyclic Nitronic Esters: Generation and Utilization in the Synthesis of N- and O-Heterocycles. Moscow University Chem. Bull. 2008, 63, 131–149. 2. Tartakovskii, V. A.; Chlenov, I. E.; Smagin, S. S.; Novikov, S. S. Nitro compounds in reactions of 1,3-dipolar addition. Izv. Akad. Nauk SSSR, Ser. Khim. 1964, 583–584; Chem. Abstr. 1964, 61, 4335e. 3. Altukhov, K. V.; Perekalin, V. V. Reaction of nitro-trinitromethylation of ethylene by tetranitromethane. Zh. Org. Khim. 1966, 2, 1902–1902; Chem. Abstr. 1967, 66, 46354j.


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4. Ratsino, E. V.; Altukhov, K. V. Reaction of tetranitromethane with substituted ethylenes containing electron-donor and electron-acceptor substituents. Zh. Org. Khim. 1972, 8, 2281–2283; Chem. Abstr. 1972, 73, 58289. 5. For account, see: Averina, E. B.; Kuznetsova, T. S.; Zefirov, N. S. Polynitromethanes - Unique Reagents in the Synthesis of Nitro-Substituted Heterocycles. Synlett 2009, 1543–1557. 6. Volkova, Y. A.; Ivanova, O. A.; Budynina, E. M.; Averina, E. B.; Kuznetsova, T. S.; Zefirov, N. S. Tetranitromethane as an efficient reagent for the conversion of epoxides into β-hydroxy nitrates. Tetrahedron Lett. 2008, 49, 3935–3938. 7. Volkova, Y. A.; Averina, E. B.; Kuznetsova, T. S.; Zefirov, N. S. Ring opening of aziridines with tetranitromethane in the presence of triethylamine. Efficient synthesis of β-tosylamino nitrates. Tetrahedron Lett. 2010, 51, 2254–2257. 8. For reviews, see: (a) Lang, S. A.; Lin, Y.-I. In Comprehensive Heterocyclic Chemistry; Katritzky, A. R.; Rees, C. W., Eds.; Pergamon: Oxford, 1984; Vol. 6, p.1. (b) Grünanger, P.; VitaFinzi, P. Isoxazoles, Part I, The Chemistry of Heterocyclic Compounds; Taylor E. C.; Weissberger, A., Eds.; Willey: New York, 1991; Vol.49, p.1. (c) Teresa, M. V. D.; Pinho e Melo. Recent Advances on the Synthesis and Reactivity of Isoxazoles. Curr. Org. Chem. 2005, 9, 925–958. (d) Giomi, D.; Cordero, F. M.; Machetti, F. Isoxazoles. In Comprehensive Heterocyclic Chemistry; Katritzky, A. R.; Ramsden, C. A.; Scriven, E. F. V.; Taylor, R. J. K, Eds.; Elsevier: Oxford, 2008; Vol. 4, p.365. 9. For selected examples on bioactivity: (a) Stein, P. D.; Floyd, D. M.; Bisaha, S.; Dickey, J.; Girotra, R. N.; Gougoutas, J. Z.; Kozlowski, M. L.; Lee, V. G.; Liu, E.C.-K.; Malley, M. F.; McMullen, D.; Mitchell, C.; Moreland, S.; Murugesan, N.; Serafino, R.; Webb, M.L.; Zhang, R.; Hunt, J. T. Discovery and Structure-Activity Relationships of Sulfonamide ETA-Selective Antagonists. J. Med. Chem. 1995, 38, 1344–1354. (b) Madsen, U.; Bang-Andersen, B.; Brehm, L.; Christensen, I. T.; Ebert, B.; Kristoffersen, I. T. S.; Lang, Y.; Krogsgaard-Larsen, P. Synthesis and ACS Paragon Plus Environment


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Pharmacology of Highly Selective Carboxy and Phosphono Isoxazole Amino Acid AMPA Receptor Antagonists. J. Med. Chem. 1996, 39, 1682–1691. (c) Solankee, A.; Solankee, S.; Patel, G. Synthesis and antibacterial evaluation of some novel isoxazole and pyrazoline derivatives. Rasayan J. Chem. 2008, 1, 581–585. (d) Srinivas, A.; Nagaraj, A.; Reddy, Ch. S. Synthesis and in vitro study of a new class of methylene‐bis‐4,6‐diarylbenzo[d]isoxazoles as potential antifungal agents. J. Het. Chem. 2009, 46, 497–502. (e) Kuz’min, V. E.; Artemenko, A. G.; Muratov, E. N.; Volineckaya, I. L.; Makarov, V. A.; Riabova, O. B.; Wutzler, P.; Schmidtke, M. Quantitative Structure−Activity Relationship Studies of [(Biphenyloxy)propyl]isoxazole Derivatives. Inhibitors of Human Rhinovirus 2 Replication. J. Med. Chem. 2007, 50, 4205–4213. (f) Pieroni, M.; Lilienkampf, A.; Wan, B.; Wang, Y.; Franzblau, S. G.; Kozikowski, A. P. Synthesis, Biological Evaluation, and Structure−Activity Relationships for 5-[(E)-2-Arylethenyl]-3-isoxazolecarboxylic Acid Alkyl Ester Derivatives as Valuable Antitubercular Chemotypes. J. Med. Chem. 2009, 52, 6287–6296. (g) Dayan, F. E.; Duke, S. O.; Reddy, K. N.; Hamper, B. C.; Leschinsky, K. L. Effects of Isoxazole Herbicides on Protoporphyrinogen Oxidase and Porphyrin Physiology. J. Agric. Food Chem. 1997, 45, 967–975. (h) Zimecki, M.; Maczynski, M.; Ryng, S. Closely related isoxazoles may exhibit opposite immunological activities. Acta Polon. Pharm.- Drug Res. 2008, 65, 793–794. (i) Simoni, D.; Rondanin, R.; Baruchello, R.; Rizzi, M.; Grisolia, G.; Eleopra, M.; Grimaudo, S.; Di Cristina, A.; Pipitone, M. R.; Bongiorno, M. R.; Arico, M.; Invidiata, F. P.; Tolomeo, M. Novel Terphenyls and 3,5-Diaryl Isoxazole Derivatives Endowed with Growth Supporting and Antiapoptotic Properties. J. Med. Chem. 2008, 51, 4796–4803. 10. (a) Barański, A.; Kuba, J.; Cholewka, E. Synthesis and properties of azols and their derivatives. Part XXI. Regio- and stereoselectivity of the the [2+3]cycloaddition of trans-β-nitroethylenes to 4nitrobenzonitrile-N-oxide. Pol. J. Chem. 1990, 64, 753–763. (b) Diamantini, G.; Duranti, E.; Tontini, A. Nitroisoxazoles by Manganese (IV) Oxide Oxidation of Nitro-4,5-dihydroisoxazoles. Synthesis, 1993, 1104–1108. (c) Barański, A. Synthesis and properties of azols and their derivatives. ACS Paragon Plus Environment

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Part VIII. Regiochemistry in cycloaddition reaction of benzonitrile N-oxide with gem-substituted nitroethylenes. Pol. J. Chem. 1982, 56, 1585–1589. 11. (a) Golod, E. L.; Novatskiy, G. N., Bagal, L. I. Reaction of 1,1,1,3-tetranitroalkanes with inorganic acids. Zh. Org. Khim. 1973, 9, 1111–1116; Chem. Abstr. 1973, 79, 78662. (b) Khisamutdinov, G. K.; Lyapin, N. M.; Nikitin, V. G.; Slovetskii, V. I.; Fainzil’berg, A. A. Synthesis of 3-acyl-5-nitroisoxazoles on the base of geminal trinitro- and chlorodinitro-substituted pentan-2one or 2-oximino-1-phenylbutan-1-one. Izv. Akad. Nauk. Ser. Khim. 2009, 2113–2116; Russ. Chem. Bull. 2009, 58, 2178–2181. 12. (a) Miftakhov, M. S.; Valeev, F. A.; Gaisina, I. N. Levoglucosenone: chemical properties and use in fine organic synthesis. Uspekhi Khimii 1994, 63, 543–555; Russ. Chem. Rev. 1994, 63, 869– 882. (b) Witczak, Z. J. In Chemicals and Materials from Renewable Resources; Bozell, J. J., Ed.; ACS publication: Washington DC, 2001, No 784, Ch. 7, p. 81. 13. If the mixture of 1,4-dioxane-CH3CN was used as a solvent only methyl 4,4,4-trinitrobutanoate in yield 36% was evolved as a reaction product. 14. The isoxazole fragments of the compounds present characteristic spectral patterns with small variations of the 1H and 13C chemical shift values. The C(4)H protons of heterocycles give singlets at  7.3-7.6 ppm. The signals of the corresponding carbon atoms (C4) are observed in the typical region at  100 to 104 ppm that reveals weak dependence on substituent at C3. Introduction of the substituent at C4 causes expected downfield shift (Δ 14-20 ppm). Relatively narrow ranges of 13C chemical shifts in a series of compounds are found for carbon atoms C3 (at 162 to 167 ppm) and C5 (at 154 to 164 ppm). It is interesting to note the peculiarity of the signals of quaternary carbon atoms C5 bonded to nitro group due to scalar relaxation mechanism [E.D. Becker. High Resolution NMR. Theory and Chemical Applications. Sec. Ed., London, 1980, Academic Press, p. 192]. Relaxation of 14N

nuclei causes appreciable resonance line broadening for these carbon atoms. In contrast, in the



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case of 3,5-dinitroisoxazole 24 resolved 13C-14N splitting was observed for both CNO2 groups with JCN equal to 18 and 16 Hz. Nitro groups of this compound give rather narrow resonance signals in 14N

NMR spectrum at -33.7 and -38.4 ppm with respect to CH3NO2. The 13C resonance of C(NO2)3

group (at ca 130 ppm) in trinitrosubstituted adducts 18, 21 is upfield shifted compared to C-NO2 group of 5-nitroisoxazoles. Weak 13C signal of this group was not found for compounds 18c-e and 20. 15. For conclusive proof of 5-nitroisoxazoles structure we have done X-ray for compounds 2, 4, 5, 8, 12 and confirmed the 13C NMR chemical shifts assignments for the isoxazole ring carbon atoms (3- vs. 5-nitroisoxazoles) by empirical and DFT computations. For details see: (a) Averina, E. B.; Volkova, Y. A.; Samoilichenko, Y. V.; Grishin, Y. K.; Rybakov, V. B.; Kutateladze, A. G.; Elyashberg, M. E.; Kuznetsova, T. S.; Zefirov, N. S. Heterocyclization of electrophilic alkenes with tetranitromethane revisited: regiochemistry and the mechanism of nitroisoxazole formation Tetrahedron Lett. 2012, 53, 1472–1475. We also obtained X-ray data for some products of reduction of 5-nitroisoxazoles: (b) Averina, E. B.; Vasilenko, D. A.; Samoilichenko, Y. V.; Grishin, Y. K.; Rybakov, V. B.; Kuznetsova, T. S.; Zefirov, N. S. Chemoselective Reduction of Functionalized 5Nitroisoxazoles: Synthesis of 5-Amino- and 5-[Hydroxy(tetrahydrofuran-2-yl)amino]isoxazoles. Synthesis 2014, 46, 1107–1113; (c) Vasilenko, D. A.; Averina, E. B.; Zefirov, N. A.; Wobith, B.; Grishin, Y. K.; Rybakov, V. B.; Zefirova, O. N.; Kuznetsova, T. S.; Kuznetsov, S. A.; Zefirov, N. S. Synthesis and antimitotic activity of novel 5-aminoisoxazoles bearing alkoxyaryl moieties Mendeleev Commun. 2017, 27, 228–230. 16. In more details the revised the mechanism for the heterocyclization of electrophilic alkenes using TNM-Et3N see in ref 15a. 17.

Young, W. G.; Roberts, J. D. Allylic Rearrangements. XX. Some Addition Reactions of

Butenylmagnesium Bromide. J. Am. Chem. Soc. 1946, 68, 649–652.


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18.

(a) Wei, X.; Taylor, R. J. K. In Situ Manganese Dioxide Alcohol Oxidation−Wittig

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Unexpected heterocyclization of electrophilic alkenes by

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