ISSN 1070-3632, Russian Journal of General Chemistry, 2018, Vol. 88, No. 3, pp. 439–451. © Pleiades Publishing, Ltd., 2018. Original Russian Text © L.M. Pevzner, V.S. Zavgorodnii, 2018, published in Zhurnal Obshchei Khimii, 2018, Vol. 88, No. 3, pp. 411–424.

Aminophosphonocarboxylates of the Furan Series L. M. Pevzner* and V. S. Zavgorodnii St. Petersburg State Institute of Technology (Technical University), Moskovskii pr. 26, St. Petersburg, 190031 Russia *e-mail: [email protected] Received December 21, 2017

Abstract—Halomethyl derivatives of (diethoxyphosphorylmethyl)furan-2(3)-carboxylates containing blocking methyl group in the position 5 of the furan ring were synthesized. In the course of constructing of carbon skeleton of these compounds it was found that alkyl 3-methoxymethyl-, 3-chloromethyl-, and 3-(diethoxyphosphorylmethyl)-5-methyl-2-furoates are halomethylated at elevated temperature in the position 4 of the furan ring. No ring destructure or transformation of the side chain of substituents was observed. The obtained halomethylfurans and their tert-butyl analogs by treating with sodium azide in acetonitrile were converted to corresponding azides. The reduction of latter with triphenylphosphine in ethanol led to formerly unavailable aminophosphonocarboxylates of the furan series. Keywords: furans, halomethylation of furans, chloromethylfuroic acids, reduction with triphenylphosphine, aminophosphonocarboxylic acids

DOI: 10.1134/S1070363218030106 at 20–40°C in dichloroethane in the presence of zinc chloride it was converted to bromide 3 (Scheme 1). The reaction proceeded regioselectively according to the orientation rules in the furan ring. Despite of the large excess of hydrogen bromide no substitution of chlorine with bromine was observed. Yield of the target product 3 was 78%.

Recently it was shown that aminophosphoncarboxylates of the furan series were prepared via the twostage synthesis from the corresponding haloromethyl compounds by substitution of halogen with azido group and its reduction to amine with triphenylphosphine [1]. Using this protocol seven of twelve possible isomers of (aminomethyl)(phosphonomethyl)furoic acids were synthesized. Many of them can be regarded as isostere of naturally occurring amino acids carrying additional phosphorus-containing group. Actuality of this theme is confirmed by the fact that investigation of chemistry of structurally similar amino acids of the furan series is related to the total synthesis of proximycines A, B, and C, new furan-containing antibiotics isolated from marine actinomycetes Verrucosispora [2].

Phosphonate group was introduced via the Arbuzov reaction. The phosphorylation was carried out with the excess of triethyl phosphite at 90–135°C. Liberating ethyl bromide was removed from the reaction mixture by distillation. Phosphonate 4 was isolated in 87% yield (Scheme 1). In the temperature range used the reaction proceeded selectively without involving chloromethyl group. Substitution of chlorine with azido group was carried out as described in [1] in acetonitrile in the presence of 10 mol % of potassium iodide. Azide 5 was isolated in 60% yield (Scheme 1). The signal of protons of the azidomethyl group in the 1H NMR spectrum of this substance was located at 4.49 ppm, and that of corresponding carbon atom, at 43.88 ppm. The chemical shift of phosphorus in this compound was 21.49 ppm.

Continuing this work we turned to the synthesis of remaining five isomers. Recent studies showed that largest obstacles in the course of synthesis are created not by the introduction proper of amino group, but by constructing the required carbon skeleton of the furan derivative. First step of this work was the synthesis of isomeric derivatives of 3-furoic acid. Starting compound for preparing 4-aminomethyl-5-(diethoxyphosphorylmethyl)3-furoate 1 was chloride 2 [3]. By bromomethylation

The reduction of azide 5 to aminoester 1 with triphenylphosphine was carried out similarly to [1]. The 439

440

PEVZNER, ZAVGORODNII Scheme 1.

ClCH2

ClCH2

COOEt CH2O, HBr

BrCH2 N3CH2

(EtO)2OPCH2

O 3 COOEt

NaN3

4

COOEt

P(OEt)3

ZnCl2

O 2

ClCH2

COOEt

H2NCH2

O 4 COOEt

PPh3

(EtO)2OPCH2

KI

EtOH

O 5

liberation of nitrogen was observed at 38–40°C, and after refluxing in ethanol for 12 h the target product was isolated in 52% yield (Scheme 1). A broad signal of the amino group protons was observed in the 1H NMR spectrum of this substance at 2.05 ppm, the signal of the aminomethyl group protons was located at 3.70 ppm, and of the corresponding carbon atom, at 35.73 ppm. The latter signal was split from coupling with phosphorus with the coupling constant 4JPC = 1.2 Hz. The chemical shift of phosphorus was 22.24 ppm.

The substitition of chlorine with azido group was carried out as described in [1]. Yield of azide 10 was 76% (Scheme 3). The signal of phosphorus nucleus was located at 26.36 ppm, the signal of azidomethyl group protons at 4.50 ppm, and the signal of the corresponding carbon atom was revealed at 45.97 ppm. When treated with triphenylphosphine in ethanol this azide liberated nitrogen at 50°C for several minutes. After refluxing the reaction mixture for 12 h amine 11 was obtained in 62% yield (Scheme 3). The broad signal of amino group protons was observed in the 1H NMR spectrum of this substance at 1.98 ppm, the signal of methylene protons at nitrogen was located at 3.94 ppm, and that of the corresponding carbon atom, at 39.06 ppm.

COOEt

O 6

O 1

Phosphonate 8 was chloromethylated in the position 2 of the furan ring in dichloroethane at 20–28°C by treating with paraformaldehyde and hydrogen chloride in the presence of zinc chloride for 2 h. The yield of chloromethyl derivative 9 was 96%. The chemical shift of phosphorus in this compound was 26.42 ppm, the signal of chloromethyl group protons was located at 4.83 ppm and that of the corresponding carbon atom, at 36.29 ppm.

We failed to construct the carbon skeleton of aminoester 6. More available were compounds having blocking methyl group in the position 5 of the furan ring. (EtO)2OPCH2

(EtO)2OPCH2

CH2NH2

In this case starting substance was chloromethylphosphonate 7 [3]. It was found that it can be reduced with zinc in 90% acetic acid to methyl derivative 8 analogously to chloromethylfurans having no phosphonate group (Scheme 2). It is the first example of applying this reaction to phosphorylated furans. Dechlorination proceeds at 100°C for 7 h. No dealkylation of diethoxyphosphoryl group as well as the formation of phosphonites was observed. Phosphonate 8 was isolated by vacuum distillation in 65% yield.

Starting substance in synthesis of amine 12 was phosphonate 13 [4]. Its chloromethylation at 20–25°C in dichloroethane for 3 h led to chloromethyl derivative 14 in 73% yield (Scheme 4). No dealkylation of phosphonate was observed. The chemical shift

Scheme 2. (EtO)2OPCH2

(EtO)2OPCH2

COOEt

O 7

CH3COOH

COOEt

CH2O, HCl

Zn

ClCH2

(EtO)2OPCH2

COOEt

O 8

ZnCl2

O 9

CH2Cl

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AMINOPHOSPHONOCARBOXYLATES OF THE FURAN SERIES

441

Scheme 3. (EtO)2OPCH2 9

(EtO)2OPCH2

COOEt

NaN3

COOEt

Ph3P

KI

O 10

CH2N3

EtOH

O 11

CH2NH2

Scheme 4.

COOEt

ClCH2

COOEt

CH2O, HCl

CH2PO(EtO)2

O 13

ZnCl2

O 14

NaN3

COOEt

H2NCH2

COOEt

N3CH2

CH2PO(EtO)2

PPh3

KI

O 15

CH2PO(EtO)2

of phosphorus in the obtained compound was 21.60, the signal of chloromethyl group protons was located at 4.67 ppm, and that of the corresponding carbon atom at 36.43 ppm. The substitution of chlorine with azide group was performed as described above (Scheme 4). Phosphorylated azide 15 was isolated in 94% yield. Below 80°C this compound is stable. The signal of azidomethyl group protons was revealed at 4.34 ppm, and the signal of the corresponding carbon atom, at 44.28 ppm. Reaction of azide 15 with triphenylphosphine in ethanol began at 30°C. At 40°C the liberation of nitrogen completed. The alcoholysis of iminophosphorane to amine required refluxing for 12 h. Aminoester 12 was isolated in 32% yield (Scheme 4). The broad signal of the amino group protons was observed in the NMR spectrum at 1.83 ppm, the signal of the methylene group protons at nitrogen was located at 3.64 ppm, and the signal of the corresponding carbon atom, at 36.23 ppm. The synthesis of aminoester 16 was carried out using several approaches. (EtO)2OPCH2

CH2NH2 O 16

COOEt

Recently obtained methoxymethyl derivative 17 [1] was chloromethylated with paraformaldehyde in the

EtOH

O 12

CH2PO(EtO)2

presence of zinc chloride in dichloroethane at 60–65°C for 2 h. Chloromethyl derivative 18 was isolated by vacuum distillation in 68% yield. The signal of chloromethyl group in the NMR spectrum of this compound was located at 4.54 ppm, and the signal of the corresponding carbon atom was revealed at 35.60 ppm. Finkelstein reaction of this compound gave iodide 19 in 90% yield. The signal of iodomethyl group protons in the NMR spectrum of this compound was found at 4.29 ppm, and the signal of corresponding carbon atom was revealed at –6.65 ppm. Phosphorylation of this substance via the Arbuzov reaction with triethyl phosphite at 120–160°C for 10 min led to phosphonate 20 in 84% yield (Scheme 5). The signal of phosphorus in this compound was observed at 26.45 ppm, the doublet of methylene protons at phosphorus was located at 2.91 ppm (JPH = 20.4 Hz), and the doublet of corresponding carbon atom was found at 21.60 ppm (1JPC = 143.0 Hz). Methoxymethyl group of the phosphonate obtained occurred to be very stable to the action of dichloromethyl methyl ether. At boiling compound 20 with the excess of this reagent in chloroform in the presence of zinc chloride for 9 h no reaction occurred. Performing this process with the same reagent ratio at 85°C in dichloroethane led to decomposition of the substrate. In connection with that we decided to start from chloromethyl derivative 22 [1]. It was found that this compound when treated with paraformaldehyde and hydrogen bromide in dichloroethane in the

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442

PEVZNER, ZAVGORODNII Scheme 5.

ClCH2 O

CH2O + HCl

COOEt

O 17

ICH2 O

ZnCl2

O

NaI

COOEt

O 18

O 19 (EtO)2OPCH2

(EtO)2OPCH2 O

P(OEt)3

O 20

CH2Cl

Cl2CHOCH3

COOEt

COOEt

COOEt

O 21

ZnCl2

Scheme 6. Cl O 22

COOEt

CH2O, HBr ZnCl2

(EtO)2OPCH2

Br

Cl O 23

presence of zinc chloride at 65–70°C forms bromomethyl derivative 23 in 52% yield (Scheme 6). The bromide obtained was unusually thermostabile. It can be distilled in a vacuum at 163°C (1 mmHg) without noticeable decomposition. In the 1H NMR spectrum of this derivative the broad signal of bromomethyl group protons was observed at 4.80 ppm, the protons of chloromethyl group gave a singlet at 4.93 ppm. Methyl group of the furan ring forms two signals of equal intensity at 2.37 and 2.38 ppm. The doubling of signals was observed also for protons of the ester ethyl group. In the 13C NMR spectrum the signal of the chloromethyl group carbon atom was located at 34.33 ppm. Carbon atoms of bromomethyl and methyl groups gave two pairs of signals of close intensity at 20.94, 21.16, and 12.14, 12.17 ppm respectively. Signals of C2, C3 and C4 nuclei of the furan ring were also doubled. This effect is evidently caused by steric hindrances appearing in molecular structure because of close location of halomethyl and carbonyl groups. Negatively charged atoms of bromine, chlorine, and oxygen repulse one another and try to occupy the most remote positions. It may lead to the formation of stable conformations which occur to be spectroscopically distinguishable. Analogous effect we observed in 5phosphorylated derivatives of 3-chloromethyl-2furoate [1]. The phosphorylation of bromide 23 with triethyl phosphite was carried out under the conditions of the Arbuzov reaction at 130–145°C with the continuous distillation of ethyl bromide from the reaction mixture

COOEt

Cl

P(OEt)3

O 24

COOEt

(Scheme 6). Total reaction time was 9 min. Phosphonate 24 was obtained in 68% yield. In its 1H NMR spectrum the broad signal of chloromethyl group protons was observed at 4.91 ppm, and the signal of the corresponding carbon atom was revealed at 34.92 ppm. In the 31P NMR spectrum three signals of the approximately equal intensity were located at 24.58, 25.48, and 25.70 ppm. In the 1H NMR spectrum signals of the methylene group protons at phosphorus were three doublets at 2.94 (JPH = 20.0 Hz), 3.10 (JPH = 20.0 Hz), and 3.54 ppm (JPH = 22.0 Hz). The signals of the corresponding carbon atoms were revealed at 21.59 ppm (1JPC = 142.6 Hz), 21.71 ppm (1JPC = 143.6 Hz), and 22.65 ppm (1JPC = 137.8 Hz). The signals of all carbon atoms of the furan ring and carbonyl group were tripled, and protons of the methyl group at the furan ring as well as the corresponding carbon nucleus gave two signals. Probably so complicated spectral pattern reflects extremely hindered steric situation in this tetra-substituted furan. Around the furan ring three considerably bulky substituents were located. Their negatively charged chlorine and oxygen atoms repulse one another. Unlike that, the phosphorus atom carries an effective positive charge. As a result of these interactions spectroscopically distinguishable stable conformers are probably formed. Azide 25 was synthesized according to the abovedescribed protocol. It was isolated in 83% yield (Scheme 7). It is stable at room temperature. The signal of protons of azidomethyl group in the NMR spectrum of this substance was observed at 4.62 ppm.

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443

AMINOPHOSPHONOCARBOXYLATES OF THE FURAN SERIES Scheme 7.

(EtO)2OPCH2 24

CH2N3 Ph3P + EtOH

NaN3 KI

COOEt

O 25

_Ph

3P=O

16

The carbon atom of azidomethyl group was revealed by two signals at 43.46 and 43.97 ppm. In the 31P NMR spectrum three signals at 24.55, 25.53, and 25.62 ppm were present. Protons of the methylene group at phosphorus resonated by three doublets at 2.90 (JPH = 20.4 Hz), 3.18 (JPH = 20.0 Hz), and 3.64 ppm (JPH = 22.4 Hz). Signals of carbon atom at phosphorus were three doublets at 21.63 ppm (1JPC = 142.3 Hz), 21.77 ppm (1JPC = 143.7 Hz), and 22.86 ppm (1JPC = 137.8 Hz). Similarly to phosphonate 24 the ratio of intensities of signals of protons and phosphorus nuclei was about 1 : 1 : 1. Carbon atoms C2 and C3 of the furan ring are revealed by the doubled signals, while signals of C4, C5, and C=O atoms are tripled. A good agreement in spectral characteristics of structural fragments of compounds 24 and 25 permits a conclusion permits to conclude that at such location of substituents in the furan ring there really exist three stable conformations which negligibly alter at the transfer from chloride to azide. Reduction of azide 25 to amine 16 was performed as described above with triphenylphosphine in ethanol. The liberation of nitrogen was observed immediately after addition of triphenylphosphine to the ethanol solution of azide at room temperature. The alcoholysis of obtained iminophosphorane to amine required refluxing for 10 h. Amine 16 was isolated in 26% yield (Scheme 7). In its 1H NMR spectrum the broad signal of the amino group protons was observed at 1.86 ppm. The signal of the methylene group protons at nitrogen was found at 3.67 ppm, and the signal of the cor-

responding carbon atom was located at 35.65 ppm. The doublet of protons of the methylene group at phosphorus was revealed at 2.89 ppm (JPH = 20.0 Hz). Signals of protons of aminomethyl and phosphonomethyl groups were significantly broadened indicating that these fragments take part in exchange processes. In the 31P NMR spectrum three signals of practically equal intensity were located at 25.55, 25.96, and 26.84 ppm. Three doublets of the corresponding carbon atoms were revealed at 21.64 ppm (1JPC = 142.3 Hz), 21.72 ppm (1JPC = 143.9 Hz), and 22.69 ppm (1JPC = 137.8 Hz). Nuclei of C2, C3, and C5 carbon atoms of the furan ring gave tripled signals while signals of C3 and C=O carbon atom nuclei were doubled. Evidently the nature of the atom in the methylene group occupying position 3 of the furan ring slightly influences the conformational equilibrium. Amino ester 26 with the position 5 blocked with tert-butyl group was significantly more available. The starting substance for its synthesis was bromomethylphosphonate 27 [5]. Azide 28 was prepared by the above-mentioned typical procedure in 60% yield (Scheme 8). The signal of the azidomethyl group protons in this compound was observed at 4.72 ppm, and the signal of the corresponding carbon atom was located at 43.52 ppm. The reduction of this compound with triphenylphosphine in ethanol led to aminoester 26 obtained in 20% yield. The formation of primary amine was confirmed by a broad signal of the amino group protons at 1.99 ppm, by a singlet of protons of the aminomethyl fragment at 3.82 ppm, and by a signal of corresponding carbon atom at 35.44 ppm. Unlike compounds 16 and 23–25 in the 1H, 13C, and 31P NMR spectra of substances 26–28 each structural fragment was characterized only by one signal though sterical situation in this case is even more hindered. It evidently arises from the fact that subsituents in the

Scheme 8.

(EtO)2OPCH2

(EtO)2OPCH2

CH2Br

CH2N3

(EtO)2OPCH2 Ph3P

NaN3

O 27

COOEt

CH2NH2

COOEt

KI

O 28 CH2PO(OEt)2

H2NCH2 O 29

COOEt

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_

Ph3P=O

O 26

COOEt

444

PEVZNER, ZAVGORODNII Scheme 9.

Scheme 10. ClCH2

ClCH2 18

CH2Br 30

Ph3PBr2

O

CH2O, HCl ZnCl2

COOEt

furan ring are rigidly fixed in definite positions and no different conformers can be formed. The synthesis of aminoester 29 with the last possible version of mutual location of the aminomethyl, phosphonomethyl, and ester group we started from chloride 18 (Scheme 9). By treating it with triphenyldibromophosphorane we tried to convert methoxymethyl group to bromomethyl one, but no reaction was observed. Then we tried to halomethylate previously synthesized phosphonate 30 [1]. It was found that this reaction proceeds successfully in dichloroethane saturated with hydrogen chloride at the phosphonate : paraformaldehyde : zinc chloride molar ratio 1 : 3 : 0.5 at 65–70°C for 6 h. Chloride 31 was isolated in 76% yield (Scheme 10). The signal of phosphorus nucleus in this compound was observed at 24.45 ppm, but in the 1H and 13C NMR spectra the doubling of signals of protons of the methyl group in the furan ring, of chloromethyl group and of the phosphorylmethyl one, and also of the corresponding carbon atoms as well as carbon atoms of the furan ring and of the carbonyl group was observed. It permits stating that chloride 31 in chloroform exists as a mixture of spectroscopically distinguishable conformers in 1 : 0.7 ratio basing on the ratio of integral intensities of the signals of protons of chloromethyl and phosphorylmethyl groups. Signals of the methyl group protons were not considered because of their strong overlapping. Detailed spectral characteristics are presented in the Experimental. Hence, sterical situation on chloride 31 also occurred to be rather hindered, though conformational differences are revealed only in the proton and carbon spectra. While performing the reaction with sodium azide it was found that compound 31 reacts much slower that

CH2PO(OEt)2 O 31

COOEt

previously studied substances. Only after refluxing in acetonitrile for 20 h at the phosphonate : sodiun azide : potassium iodide molar ratio 1 : 3.5 : 0.16 the target product 32 was prepared in 68% yield (Scheme 11). The signal of the azidomethyl group protons in NMR spectrum of this substance was found at 4.39 ppm, and of the corresponding carbon atom at 44.02 ppm. Unlike chloride 31, azide 32 was characterized by a single set of signals in the 1H, 13C, and 31P NMR spectra. The reduction of azide 32 with triphenylphosphine was carried out as described above. Liberation of nitrogen was observed at 50°C for 2 min, and the alcoholysis of the intermediate iminophosphorane required boiling in ethanol for 11 h. Amine 29 was isolated in 46% yield. In the 1H NMR spectrum of this substance the broad signal of the amino group protons was observed at 1.66 ppm. Aminomethyl group protons were characterized by two signals at 3.61 and 3.68 ppm with the intensity ratio 0.4 : 1. Protons of phosphonomethyl group also gave two doublets at at 3.47 (JPH = 22.4 Hz) and 3.51 (JPH = 22.8 Hz) ppm with the same intensity ratio. In the 31P NMR spectrum two signals with the intensity ratio 1 : 0.4 were located at 25.08 and 25.15 ppm respectively. The doubling of signals was observed also in the carbon spectrum of compound 29. Hence, this amonoester forms two spectroscopically different conformers. Analog of aminoester 29 with the position 5 of the furan ring blocked with tert-butyl group also occurred to be more available than methyl derivative. Its synthesis was started from the previously obtained chloromethylphosphonate 33 [5]. The reaction of this compound with sodium iodide was carried out according to the general procedure at phosphonate : sodium azide : potassium iodide ratio = 1 : 2 : 0.1. No

Scheme 11.

N3CH2 31

CH2PO(OEt)2

NaN3 KI

Ph3P, EtOH

O 32

COOEt

_N

2,

_Ph

3P=O

29

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AMINOPHOSPHONOCARBOXYLATES OF THE FURAN SERIES Scheme 12.

ClCH2

N3CH2

CH2PO(OEt)2 NaN3

O 33

COOEt

KI

H2NCH2

CH2PO(OEt)2

CH2PO(OEt)2

Ph3P, EtOH

O 34

COOEt

deceleration of the process was observed that occurred with compound 31. Azide 34 was isolated in 72% yield (Scheme 12). The signal of the azidomethyl group proton was located at 4.49 ppm, and of the corresponding carbon atom, at 43.62 ppm. By the reduction of this compound with triphenylphosphine in ethanol amine 35 was obtained in 55% yield. The broad signal of the amino group proton in the NMR spectrum of this compound was observed at 1.72 ppm, the singlet of aminomethyl group protons was located at 3.74 ppm, and the signal of the corresponding carbon atom, at 34.45 ppm. Azide 34 and amine 35 were characterized only by one set of signals in NMR spectra. Evidently, as in the case of compounds 26 and 28 bulky substituents provide sufficiently rigid fixing of the structure. Hence, blocking of position 5 of the furan ring with methyl or tert-butyl group permits to obtain aminomethyl derivatives of phosphonocarboxylates of the furan series with mutual location of substituents which is nowadays not available without using this trick. At the same time the substitution of halogen with azido group and subsequent reduction of the latter to amine is the universal protocol for preparing any isomer of target substances. Previously remarked tendency of the increase in the yield of azide as well as of amine at the decrease in the sum of the electronacceptor action of substituents in the furan ring on halomethyl or azidomethyl group respectively [1] appears in the cases under investigation in this work as well. At the same time, no significant influence of steric factors on the yield of target products was marked. In the course of constructing the carbon skeleton of halomethylfurans it was for the first time found that methoxymethyl, chloromethyl, and (diethoxyphosphorylmethyl)furoates are halomethylated in deactivated α- and β-positions of the furan ring without transformation of substituents. It was shown also that chloromethyl group in (diethoxyphosphorylmethyl)furoates can be reduced with zinc in aqueous acetic acid to methyl one. At the same time no transformations of phosphonate group take place.

_N

2,

_Ph

3P=O

O 35

COOEt

These facts sufficiently broaden methods of synthesis of polysubstituted furans. EXPERIMENTAL 1

H, 13C, and 31P NMR spectra were taken on a Bruker ASCENDTM-400 spectrometer [400.13 (1H), 161.97 (31P), 100.16 (13C) MHz respectively] in CDCl3. Ethyl 4-chloromethyl-5-bromomethyl-3-furoate (3). To the solution of 4.70 g of ethyl 4-chloromethyl-3furoate 2 in 50 mL of dichloroethane 1.2 g of paraformaldehyde and 0.8 g of freshly pulverized zinc chloride were added. Through this mixture dry hydrogen bromide was passed for 4 h under intense stirring. Hydrogen bromide was prepared by bromination of excess of tetraline with 20 mL of bromine in the presence of 0.5 g of aluminum chloride. During first 30 min spontaneous heating of reaction mixture to 40°C was observed. Then it gradually decreased to 20°C. The reaction mixture was washed with water (2× 20 mL), with 20 mL of brine, and dried over calcium chloride. After removing the solvent and keeping in a vacuum (1 mmHg) for 1 h 5.47 g (78%) of bromide 3 was obtained as light yellow oil. While heating in a vacuum the product decomposes below its boiling point. 1H NMR spectrum (CDCl3), δ, ppm: 1.35 t (3Н, СН3-ethyl, JHH = 7.2 Hz), 4.32 q (2Н, СН2О-ethyl, JHH = 7.2 Hz), 4.53 s (2Н, СН2Br), 4.76 s (2Н, СН2Cl), 7.97 s (1Н, Н2-furan). 13С NMR spectrum (CDCl3), δС, ppm: 14.24 (СН3-ethyl), 20.11 (СН2Br), 34.09 (СН2Cl), 60.76 (СН2О-ethyl), 118.60 (С3-furan), 120.27 (С4furan), 148.46 (С2-furan), 150.60 (С5-furan), 162.21 (С=О). Ethyl 4-chloromethyl-5-(diethoxyphosphorylmethyl)-3-furoate (4). The mixture of 7.50 g of bromide 3 and 6 mL of triethyl phosphite was heated with stirring. The distillation of ethyl bromide began at 90°C and completed at 135°C. Low boiling products (40–70°C at 1 mmHg) were distilled off from the reaction mixture to give 7.85 g (87%) of phosphonate 4 as yellow syrup. 1H NMR spectrum (CDCl3), δ, ppm: 1.23 t (6Н, СН3-phosphonate, JHH = 7.0 Hz), 1.38 t

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PEVZNER, ZAVGORODNII

(3Н, СН3-ethyl, JHH = 7.2 Hz), 3.27 d (2Н, СН2Р, JРH = 20.8 Hz), 4.07 d.q (4Н, СН2О-phosphonate, JHH = 7.0 Hz, JРH = 15.2 Hz), 4.35 q (2Н, СН2О-ethyl, JHH = 7.2 Hz), 4.71 s (2Н, СН2Cl), 7.86 s (1Н, Н2-furan). 13С NMR spectrum (CDCl3), δС, ppm: 14.14 (СН3-ethyl), 16.29 d (СН3-phosphonate, 3JРС = 5.8 Hz), 25.38 d (СН2Р, 1JРС = 142.5 Hz), 34.76 (СН2Cl), 60.46 (СН2Оethyl), 62.58 d (СН2О-phosphonate, 2JРС = 6.6 Hz), 118.39 d (С3-furan, 4JРС = 3.0 Hz), 118.86 d (С4-furan, 3 JРС = 8.7 Hz), 146.88 d (С5-furan, 2JРС = 12.3 Hz), 147.58 d (С2-furan, 4JРС = 2.7 Hz), 162.46 (С=О). 31Р NMR spectrum (CDCl3), δР, ppm: 21.36. Ethyl 4-(diethoxyphosphorylmethyl)-5-methyl-3furoate (8). To the solution of 6.13 g of ethyl 4-(diethoxyphosphorylmethyl)-5-chloromethyl-3-furoate in 25 mL of glacial acetic acid 2.8 mL of water and then 4.7 g of zinc powder were added under intense stirring. The reaction mixture heated spontaneously to 43°C. After completion of heat evolution the mixture formed was stirred intensely for 7 h at 90–100°C and then poured in 120 mL of water. The solution obtained was saturated with sodium chloride, extracted with carbon tetrachloride (4×20 mL), washed with 30 mL of brine, and dried over sodium sulfate. After removing the solvent 3.60 g (65%) of phosphonate 8 was isolated by vacuum distillation. Colorless oil with bp 159–161°C (1 mmHg). 1H NMR spectrum (CDCl3), δ, ppm: 1.13 t (6Н, СН3-phosphonate, JHH = 7.0 Hz), 1.21 t (3Н, СН3-ethyl, JHH = 7.0 Hz), 2.17 br.s (3Н, СН3-furan), 3.16 d (2Н, СН2Р, JРH = 21.2 Hz), 3.89– 3.98 m (4Н, СН2О-phosphonate), 4.15 q (2Н, СН2Оethyl, JHH = 7.0 Hz), 7.72 s (1Н, Н2-furan). 13С NMR spectrum (CDCl3), δС, ppm: 11.70 d (СН3-furan, 4JРС = 2.1 Hz), 14.14 (СН3-ethyl), 16.20 d (СН3-phosphonate, 3 JРС = 6.2 Hz), 21.19 d (СН2Р, 1JРС = 142.0 Hz), 60.11 (СН2О-ethyl), 61.72 d (СН2О-phosphonate, 2JРС = 6.7 Hz), 61.90 d (СН2О-phosphonate, 2JРС = 6.6 Hz), 109.26 d (С4-furan, 2JРС = 11.0 Hz), 118.55 d (С3furan, 3JРС = 2.8 Hz), 146.50 (С2-furan), 151.65 d (С5furan, 3JРС = 9.1 Hz), 163.32 (С=О). 31Р NMR spectrum (CDCl3), δР, ppm: 26.51. Ethyl 2-chloromethyl-4-(diethoxyphosphorylmethyl)-5-methyl-3-furoate (9). To the solution of 2.46 g of phosphonate 8 in 40 mL of dichloroethane 0.40 g of paraformaldehyde and 0.30 g of freshly pulverized zinc chloride was added under intense stirring. Hydrogen chloride was passed through the reaction mixture for 2 h. During first 20 min a spontaneous heating of reaction mixture took place. Its temperature rose to 28°C and then gradually decreased

to 20°C. The mixture formed was washed with water (2×20 mL) and then with 20 mL of brine and dried over sodium sulfate. After removing the solvent and keeping the residue in a vacuum (1 mmHg) for 1 h at room temperature 2.75 g (96%) of phosphonate 9 was obtained as light brown syrup gradually darkening while storage. 1H NMR spectrum (CDCl3), δ, ppm: 1.24 t (6Н, СН3-phosphonate, JHH = 7.2 Hz), 1.37 t (3Н, СН3-ethyl, JHH = 7.2 Hz), 2.29 d (3Н, СН3-furan, JРH = 4.4 Hz ), 3.24 d (2Н, СН2Р, JРH = 21.2 Hz), 4.02 d.q (4Н, СН2О-phosphonate, JHH = 7.2 Hz, JРH = 14.8 Hz), 4.32 q (2Н, СН2О-ethyl, JHH = 7.2 Hz), 4.82 s (2Н, СН2Сl). 13С NMR spectrum (CDCl3), δС, ppm: 11.80 d (СН3-furan, 4JРС = 2.1 Hz), 14.14 (СН3-ethyl), 16.36 d (СН3-phosphonate, 3JРС = 7.0 Hz), 21.94 d (СН2Р, 1JРС = 143.9 Hz), 36.29 (СН2Сl), 60.59 (СН2Оethyl), 61.91 d (СН2О-phosphonate, 2JРС = 7.0 Hz), 110.77 d (С4-furan, 2JРС = 10.9 Hz), 116.17 d (С3furan, 3JРС = 2.8 Hz), 151.65 d (С5-furan, 3JРС = 9.3 Hz), 153.16 (С2-furan), 163.09 (С=О). 31Р NMR spectrum (CDCl3), δР, ppm: 26.42. Ethyl 2-(diethoxyphosphorylmethyl)-4-chloromethyl-5-methyl-3-furoate (14). This compound was prepared analogously from 2.54 g of ethyl (2-diethoxyphosphrylmethyl)-5-methyl-3-furoate 13, 0.40 g of paraformaldehyde, and 0.30 g of freshly pulverized zinc chloride. Yield 2.18 g (73%), light brown syrup. 1 H NMR spectrum (CDCl3), δ, ppm: 1.30 t (6Н, СН3phosphonate, JHH = 7.0 Hz), 1.39 t (3Н, СН3-ethyl, JHH = 7.0 Hz), 2.32 d (3Н, СН3-furan, JРH = 2.0 Hz), 3.68 d (2Н, СН2Р, JРH = 22.0 Hz), 4.11 d.q (4Н, СН2Оphosphonate, JHH = 7.0 Hz, JРH = 14.8 Hz), 4.40 q (2Н, СН2О-ethyl, JHH = 7.0 Hz), 4.67 s (2Н, СН2Сl). 13С NMR spectrum (CDCl3), δС, ppm: 11.44 (СН3-furan), 14.16 (СН3-ethyl), 16.31 d (СН3-phosphonate, 3JРС = 6.1 Hz), 26.62 d (СН2Р, 1JРС = 139.2 Hz), 36.43 (СН2Сl), 60.50 (СН2О-ethyl), 62.40 d (СН2О-phosphonate, 2JРС = 6.4 Hz), 114.17 d (С3-furan, 3JРС = 8.4 Hz), 116.90 d (С4-furan, 4JРС = 2.4 Hz), 151.23 d (С5-furan, 4JРС = 2.3 Hz), 151.53 d (С2-furan, 2JРС = 13.7 Hz), 163.27 d (С=О, 4JРС = 1.6 Hz). 31Р NMR spectrum (CDCl3), δР, ppm: 21.60. Ethyl 3-(methoxymethyl-4-chloromethyl-5-methyl2-furoate (18). To the solution of 3.94 g of ethyl 3-methoxymethyl-5-methyl-2-furoate 17 in 30 mL of dichloroethane 0.90 g of paraformaldehyde and 0.70 g of freshly pulverized zinc chloride were added under intense stirring. The mixture formed was saturated at room temperature with hydrogen chloride, then heated to 60–65°C and hydrogen chloride was passed at this

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temperature under intense stirring. After that the reaction mixture was triturated with 50 mL of water, 30 mL of dichloroethane was added, and the mixture formed was filtered in a vacuum through the sodium chloride layer. The filtrate was placed in the separating funnel, the organic layer was removed, and water layer was washed with 15 mL of dichloroethane. Joined organic phases were washed with water (2×20 mL), with 20 mL of brine, and dried over calcium chloride. After removing the solvent the residue was distilled in a vacuum to give 3.34 g (68%) of the target product 18 as colorless oil with bp 130°C (1 mmHg). 1H NMR spectrum (CDCl3), δ, ppm: 1.37 t (3Н, СН3-ethyl, JHH = 7.0 Hz), 2.37 s (3Н, СН3-furan), 3.37 s (3Н, СН3О), 4.36 q (2Н, СН2О-ethyl, JHH = 7.0 Hz), 4.54 s (2Н, СН2Сl), 4.77 s (2Н, ОСН2-furan). 13С NMR spectrum (CDCl3), δС, ppm: 11.98 (СН3-furan), 14.32 (СН3ethyl), 35.60 (СН2Сl), 58.26 (СН3О), 60.89 (СН2Оethyl), 64.20 (ОСН2-furan), 119.71 (С4-furan), 130.31 (С3-furan), 139.36 (С2-furan), 154.86 (С5-furan), 158.94 (С=О).

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in a vacuum. The residue was the target product 20, yield 3.44 g (84%), light yellow viscous syrup. 1H NMR spectrum (CDCl3), δ, ppm: 1.14 t (6Н, СН3phosphonate, JHH = 7.0 Hz), 1.24 t (3Н, СН3-ethyl, JHH = 7.0 Hz), 2.21 br.s (3Н, СН3-furan), 2.91 d (2Н, СН2Р, JРH = 20.4 Hz), 3.21 s (3Н, СН3О), 3.90–3.92 m (4Н, СН2О-phosphonate), 4.21 q (2Н, СН2О-ethyl, JHH = 7.0 Hz), 4.65 s (2Н, ОСН2-furan). 13С NMR spectrum (CDCl3), δС, ppm: 12.13 d (СН3-furan, 4JРС = 1.3 Hz), 14.22 (СН3-ethyl), 16.30 d (СН3-phosphonate, 3 JРС = 5.9 Hz), 21.60 d (СН2Р, 1JРС = 143.0 Hz), 57.85 (СН3О), 60.60 (СН2О-ethyl), 61.87 d (СН2Оphosphonate, 2JРС = 6.9 Hz), 113.12 d (С4-furan, 2JРС = 10.0 Hz), 130.96 d (С4-furan, 3JРС = 3.1 Hz), 139.10 (С2-furan), 153.86 d (С5-furan, 3JРС = 8.2 Hz), 158.91 d (С=О). 31Р NMR spectrum (CDCl3), δР, ppm: 26.45.

Ethyl 3-methoxymethyl-4-iodomethyl-5-methyl2-furoate (19). To the solution of 5 g of sodium iodide dihydrate in 30 mL of acetone the solution of 3.18 g of chloride 17 in 10 mL of acetone was added. The reaction mixture was left overnight in the dark, then poured in 100 mL of water, treated with sodium sulfite solution, and extracted with chloroform (3×20 mL). The extract was washed with 20 mL of brine and dried over calcium chloride in the dark. After removing acetone 3.92 g (90%) of iodide 19 was obtained as light yellow oil. In the scattered light at room temperature coloration of iodide does not change for 2–3 h. 1H NMR spectrum (CDCl3), δ, ppm: 1.34 t (3Н, СН3-ethyl, JHH = 7.2 Hz), 2.23 s (3Н, СН3-furan), 3.35 s (3Н, СН3О), 4.29 s (2Н, СН2I), 4.32 q (2Н, СН2Оethyl, JHH = 7.2 Hz), 4.72 s (2Н, ОСН2-furan). 13С NMR spectrum (CDCl3), δС, ppm: –6.65 (СН2I), 12.24 (СН3-furan), 14.34 (СН3-ethyl), 58.26 (СН3О), 60.85 (СН2О-ethyl), 64.19 (ОСН2-furan), 120.88 (С4-furan), 129.90 (С3-furan), 139.30 (С2-furan), 153.84 (С5furan), 158.85 (С=О).

Ethyl 3-chloromethyl-4-bromomethyl-5-methyl2-furoate (23). To a solution of 3.13 g of ethyl 3-chloromethyl-5-methyl-2-furoate in 50 mL of dichloroethane 0.70 g of paraformaldehyde and 0.50 g of freshly pulverized zinc chloride were added. Through the mixture formed hydrogen bromide was passed at 65–70°C for 3 h. HBr was obtained by bromination of 150 mL of teraline with 15 mL of bromine in the presence of 0.5 g of aluminum chloride. Then the reaction mixture was washed with water (2×20 mL), with 20 mL of brine, and dried over calcium chloride. After removing the solvent the residue was distilled in a vacuum. Yield 2.37 g (52%), colorless oil with bp 163°C (1 mmHg). 1H NMR spectrum (CDCl3), δ, ppm: 1.40 t (3Н, СН3-ethyl, JHH = 7.2 Hz), 1.41 t (3Н, СН3-ethyl, JHH = 7.2 Hz), 2.37 s (3Н, СН3-furan), 2.38 s (3Н, СН3-furan), 4.40 q (2Н, СН2О-ethyl, JHH = 7.0 Hz), 4.41 q (2Н, СН2Оethyl, JHH = 7.0 Hz), 4.80 s (2Н, СН2Br), 4.93 s (2Н, CH2Cl). 13С NMR spectrum (CDCl3), δС, ppm: 12.14 (СН3-furan), 12.17 (СН3-furan), 14.32 (СН3-ethyl), 20.94 (СН2Br), 21.16 (СН2Br), 34.33 (CH2Cl), 61.25 (СН2О-ethyl), 119.03 (С4-furan), 119.16 (С4-furan), 128.79 (С3-furan), 129.03 (С3-furan), 139.37 (С2furan), 139.54 (С2-furan), 154.92 (С5-furan), 158.51 (С=О).

Ethyl 3-methoxymethyl-4-(diethoxyphosphorylmethyl)-5-methyl-2-furoate (20). The mixture of 3.92 g of iodide 19 and 4 mL of triethyl phosphite was heated with stirring. At 120°C the distillation of ethyl iodide began. The temperature of the reaction mixture was gradually risen to 160°C when liberation of ethyl iodide completed. The reaction time was 10 min. Then the fraction of bp 30–65°C (1 mmHg) was distilled off

Ethyl 3-chloromethyl-4-(diethoxyphosphorylmethyl)-2-methyl-2-furoate (24). The mixture of 2.85 g of bromide 23 and 3 mL of triethyl phosphite was heated with stirring. At 130°C the distillation of ethyl bromide began which continued until 145°C in the reaction mixture. The reaction time was 9 min. After removing in a vacuum the fraction of bp 30–55°C (1 mmHg) 2.36 g (68%) of phosphonate 24 was

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obtained as light yellow very viscous syrup. 1H NMR spectrum (CDCl3), δ, ppm: 1.16–1.23 m (6Н, СН3phosphonate) 1.29–1.31 m (3Н, СН3-ester), 2.25 d (3Н, СН3-furan, JРH = 3.6 Hz), 2.27 d (3Н, СН3-furan, JРH = 3.6 Hz), 2.94 d (2Н, СН2Р, JРH = 20.0 Hz), 3.10 d (2Н, СН2Р, JРH = 20.0 Hz), 3.54 d (2Н, СН2Р, JРH = 22.0 Hz), 3.94–4.03 m (4Н, СН2О-phosphonate), 4.25– 4.33 m (2Н, СН2О-ester), 4.91 br.s (2Н, CH2Cl). 13С NMR spectrum (CDCl3), δС, ppm: 12.15 d (СН3-furan, 4 JPC = 1.9 Hz), 12.27 d (СН3-furan, 4JPC = 1.9 Hz ), 14.23 (СН3-ethyl), 14.33 (СН3-ethyl), 16.24 d (СН3phosphonate, 3JРС = 6.2 Hz), 16.34 d (СН3phosphonate, 3JРС = 5.9 Hz), 21.59 d (СН2Р, 1JРС = 142.6 Hz), 21.71 d (СН2Р, 1JРС = 143.6 Hz, 22.65 d (СН2Р, 1JРС = 137.8 Hz), 34.92 (CH2Cl), 60.51 (СН2Оethyl), 60.92 (СН2О-ethyl), 61.99 d (СН2О-phosphonate, 2JРС = 7.8 Hz), 62.06 d (СН2О-phosphonate, 2 JРС = 7.0 Hz), 62.17 d (СН2О-phosphonate, 2JРС = 6.8 Hz), 112.66 d (С4-furan, 2JРС = 9.9 Hz), 113.63 d (С4-furan, 2JРС = 9.8 Hz), 113.67 d (С4-furan, 2JРС = 9.7 Hz), 126.33 d (С3-furan, 3JРС = 2.9 Hz), 126.44 d (С3-furan, 3JРС = 2.7 Hz), 128.41 d (С3-furan, 3JРС = 2.9 Hz), 139.02 (С2-furan), 139.12 (С2-furan), 139.39 (С2-furan), 153.81 d (С5-furan, 3JРС = 8.7 Hz), 153.84 d (С5-furan, 3JРС = 8.6 Hz), 154.12 d (С5-furan, 3JРС = 8.6 Hz), 158.59 (С=О), 158.84 d (С=О, 5JРС = 2.9 Hz), 159.00 d (С=О, 5JРС = 2.8 Hz). 31Р NMR spectrum (CDCl3), δР, ppm: 24.58, 25.48, 25.70. Ethyl 3-(diethoxyphosphorylmethyl)-4-chloromethyl-5-methyl-2-furoate (31). To the solution of 3.11 g of 3-(diethoxyphosphorylmethyl)-5-methyl-2furoate 30 in 35 mL of dichloroethane 1.00 g of paraformaldehyde and 0.80 g of zinc chloride was added under intense stirring. The mixture formed was saturated with hydrogen chloride at room temperature and heated for 6 h while intense stirring at 65–70°C and passing hydrogen chloride for maintaining the saturation. After that the reaction mixture was washed with water (2×20 mL), then with 20 mL of brine, and dried over sodium sulfate. After removing dichloroethane and keeping the residue in a vacuum (1 mmHg) for 1 h at room temperature 2.78 g (76%) of chloride 31 was obtained as light yellow very viscous oil. 1H NMR spectrum (CDCl3), δ, ppm: common signals: 1.24–1.37 m (9Н, СН3-ester, СН3-phosphonate), 4.10 br.s (4Н, СН2О-phosphonate), 4.33–4.40 m (2Н, СН2О-ester); main conformer: 2.35 s (3Н, СН3-furan), 3.58 d (2Н, СН2Р), 4.63 s (2Н, СН2Сl); minor conformer: 2.33 s (3Н, СН3-furan), 3.51 d (2Н, СН2Р), 4.60 s (2Н, СН2Сl); conformer ratio 1 : 0.7. 13С NMR

spectrum (CDCl3), δС, ppm: common signals: 16.25 d (СН3-phosphonate, 3JPC = 6.7 Hz), 16.39 d (СН3phosphonate, 3JPC = 6.3 Hz), 62.24 d (СН2О-phosphoinate, 2JPC = 6.3 Hz), 62.86 d (СН2О-phosphonate, 2 JPC = 6.5 Hz), 125.39 d (С3-furan, 2JPC = 10.6 Hz); main conformer: 12.32 (СН3-furan), 14.39 (СН3-ester), 22.84 d (СН2Р, 1JPC = 139.8 Hz), 35.84 (СН2Сl), 61.03 (СН2О-ester), 120.03 d (С4-furan, 3JPC = 3.0 Hz), 139.46 d (С2-furan, 3JPC = 9.0 Hz), 154.75 d (С5-furan, 4 JPC = 2.0 Hz), 159.04 d (С=О, 4JPC = 2.8 Гц); minor conformer: 12.14 (СН3-furan), 14.34 (СН3-ester), 23.28 d (СН2Р, 1JPC = 142.1 Hz), 35.56 (СН2Сl), 60.51 (СН2О-ester), 120.07 d (С4-furan, 3JPC = 2.8 Hz), 139.34 d (С2-furan, 3JPC = 8.5 Hz), 154.87 d (С5-furan, 4 JPC = 2.4 Hz), 159.58 br.s (С=О). 31Р NMR spectrum (CDCl3), δР, ppm: 24.45. Synthesis of azidomethyl derivatives of (diethoxyphosphorylmethyl)furoates (general procedure). To a solution of 10 mmol of halomethyl derivative of (diethoxyphosphorylmethyl)furoate in 15 mL of acetonitrile 20 mmol of sodium azide and 1 mmol of potassium iodide was added. The mixture formed was refluxed with stirring for 7 h in the case of αhalomethylfurans and 12 h for β-derivatives. After that the mixture formed was poured in 40 mL of water, the mixture obtained was saturated with sodium chloride, extracted with chloroform (3×15 mL), and dried over sodium sulfate. After removing the solvent the residue was kept in a vacuum (1 mmHg) at room temperature for 1 h. Azides were light yellow or light brown viscous oils stable under moderate heating. Ethyl 4-azidomethyl-5-(diethoxyphosphorylmethyl)-3-furoate (5). Yield 60%, light brown oil. 1H NMR spectrum (CDCl3), δ, ppm: 1.28 t (6Н, СН3phosphonate, JHH = 7.0 Hz), 1.34 t (3Н, СН3-ethyl, JHH = 7.2 Hz), 3.27 d (2Н, СН2Р, JРH = 20.8 Hz), 4.08 d.q (4Н, СН2О-phosphonate, JHH = 7.0 Hz, JРH = 15.2 Hz), 4.31 q (2Н, СН2О-ethyl, JHH = Hz), 4.49 s (2Н, СН2N3), 7.95 s (1Н, Н2-furan). 13С NMR spectrum (CDCl3), δС, ppm: 14.23 (СН3-ethyl ), 16.34 d (СН3phosphonate, 3JРС = 5.8 Hz), 25.42 d (СН2Р, 1JРС = 142.8 Hz), 43.88 (СН2N3), 60.62 (СН2О-ethyl), 62.56 d (СН2О-phosphonate, 2JРС = 6.6 Hz), 116.31 d (С4furan, 3JРС = 8.7 Hz), 118.94 d (С3-furan, 4JРС = 3.1 Hz), 146.84 d (С5-furan, 2JРС = 12.3 Hz), 147.96 d (С2-furan, 4JРС = 2.8 Hz), 162.74 (С=О). 31Р NMR spectrum (CDCl3), δР, ppm: 21.49. Ethyl 2-azidomethyl-4-(diethoxyphosphorylmethyl)5-methyl-3-furoate (10). Yield 76%, light brown oil.

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H NMR spectrum (CDCl3), δ, ppm: 1.21 t (6Н, СН3phosphonate, JHH = 7.0 Hz), 1.33 t (3Н, СН3-ethyl, JHH = 7.2 Hz), 2.26 d (3Н, СН3-furan, JРH = 3.2 Hz), 3.21 d (2Н, СН2Р, JРH = 20.8 Hz), 3.96–4.02 m (4Н, СН2О-phosphonate), 4.28 q (2Н, СН2О-ethyl, JHH = 7.2 Hz), 4.50 s (2Н, СН2N3). 13С NMR spectrum (CDCl3), δС, ppm: 11.74 d (СН3-furan, 4JРС = 2.2 Hz), 14.12 (СН3-ethyl), 16.25 d (СН3-phosphonate, 3JРС = 6.1 Hz), 16.31 d (СН3-phosphonate, 3JРС = 6.2 Hz), 21.89 d (СН2Р, 1JРС = 142.4 Hz), 45.97 (СН2N3), 60.55 (СН2О-ethyl), 61.85 d (СН2О-phosphonate, 2JРС = 6.7 Hz), 62.14 d (СН2О-phosphonate, 2JРС = 6.6 Hz), 110.46 d (С4-furan, 2JРС = 11.0 Hz), 116.40 d (С3furan, 3JРС = 2.7 Hz ), 151.04 d (С5-furan, 3JРС = 9.4 Hz), 152.35 (С2-furan), 163.19 (С=О). 31Р NMR spectrum (CDCl3), δР, ppm: 26.36. Ethyl 2-(diethoxyphosphorylmethyl)-4-azidomethyl-5-methyl-3-furoate (15). Yield 94%, light brown oil. 1H NMR spectrum (CDCl3), δ, ppm: 1.28 t (6Н, СН3-phosphonate, JHH = 7.0 Hz), 1.37 t (3Н, СН3ethyl, JHH = 7.2 Hz), 2.30 d (3Н, СН3-furan, JРH = 1.6 Hz), 3.68 d (2Н, СН2Р, JРH = 22.0 Hz), 4.09 d.q (4Н, СН2О-phosphonate, JHH = 7.0 Hz, JРH = 14.8 Hz), 4.33 q (2Н, СН2О-ethyl, JHH = 7.2 Hz), 4.34 s (2Н, СН2N3). 13С NMR spectrum (CDCl3), δС, ppm: 11.48 (СН3-furan), 14.20 (СН3-ethyl), 16.28 d (СН3phosphonate, 3JРС = 6.2 Hz), 26.71 d (СН2Р, 1JРС = 139.0 Hz), 44.28 (СН2N3), 60.53 (СН2О-ethyl), 62.38 d (СН2О-phosphonate, 2JРС = 6.6 Hz), 114.01 d (С4furan, 4JРС = 2.5 Hz), 114.66 d (С3-furan, 3JРС = 8.2 Hz), 151.25 d (С5-furan, 4JРС = 3.7 Hz), 151.61 d (С2furan, 2JРС = 13.7 Hz), 163.34 d (С=О, 4JРС = 2.7 Hz). 31 Р NMR spectrum (CDCl3), δР, ppm: 21.50. Ethyl 3-azidomethyl-4-(diethoxyphosphorylmethyl)-5-methyl-2-furoate (25). Yield 83%, light brown oil. 1H NMR spectrum (CDCl3), δ, ppm: 1.20– 1.26 m (6Н, СН3-phosphonate) 1.34 t (3Н, СН3-ethyl, JHH = 7.0 Hz), 1.35 t (3Н, СН3-ethyl, JHH = 7.0 Hz), 2.29 d (3Н, СН3-furan, JРH = 3.6 Hz), 2.33 d (3Н, СН3furan, JРH = 3.2 Hz), 2.90 d (2Н, СН2Р, JРH = 20.4 Hz), 3.18 d (2Н, СН2Р, JРH = 20.0 Hz), 3.64 d (2Н, СН2Р, JРH = 22.4 Hz), 3.98–4.08 m (4Н, СН2О-phosphonate), 4.29–4.37 m (2Н, СН2О-ester), 4.63 br.s (2Н, СН2N3). 13 С NMR spectrum (CDCl3), δС, ppm: 12.30 (СН3furan), 14.28 (СН3-ethyl), 14.35 (СН3-ethyl), 16.28 d (СН3-phosphonate, 3JРС = 6.3 Hz), 16.39 d (СН3phosphonate, 3JРС = 5.9 Hz), 21.63 d (СН2Р, 1JРС = 142.3 Hz), 21.77 d (СН2Р, 1JРС = 143.7 Hz), 22.86 d (СН2Р, 1JРС = 137.8 Hz), 43.46 (СН2N3), 43.97 (СН2N3), 60.57 (СН2О-ethyl), 61.01 (СН2О-ethyl),

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62.04 d (СН2О-phosphonate, 2JРС = 8.3 Hz), 62.11 d (СН2О-phosphonate, 2JРС = 7.1 Hz), 62.19 d (СН2Оphosphonate, 2JРС = 7.9 Hz), 112.72 d (С4-furan, 2JРС = 9.8 Hz), 113.67 d (С4-furan, 2JРС = 9.7 Hz), 113.69 d (С4-furan, 2JРС = 9.6 Hz), 128.30 d (С3-furan, 3JРС = 3.0 Hz), 128.46 d (С3-furan, 3JРС = 2.7 Hz), 139.15 (С2furan), 139.76 (С2-furan), 153.86 d (С5-furan, 3JРС = 8.4 Hz), 153.89 d (С5-furan, 3JРС = 8.7 Hz), 154.33 d (С5-furan, 3JРС = 8.5 Hz), 158.73 (С=О), 158.91 d (С=О, 5JРС = 2.6 Hz), 159.05 d (С=О, 5JРС = 2.8 Hz). 31 Р NMR spectrum (CDCl3), δР, ppm: 24.55, 25.53, 25.62. Ethyl 3-azidomethyl-4-(diethoxyphosphorylmethyl)-5-tert-butyl-2-furoate (28). Yield 60%, brown oil. 1H NMR spectrum (CDCl3), δ, ppm: 1.28 t (6Н, СН3-phosphonate, JHH = 7.2 Hz), 1.37 t (3Н, СН3ethyl, JHH = 7.0 Hz), 1.42 s (9Н, СН3-tert-butyl), 3.15 d (2Н, СН2Р, JРH = 21.2 Hz), 4.02–4.10 m (4Н, СН2Оphosphonate), 4.36 q (2Н, СН2О-ethyl, JHH = 7.0 Hz), 4.72 s (2Н, СН2N3). 13С NMR spectrum (CDCl3), δС, ppm: 14.29 (СН3-ethyl), 16.38 d (СН3-phosphonate, 3 JРС = 5.9 Hz), 22.42 d (СН2Р, 1JРС = 142.9 Hz), 29.27 (СН3-tert-butyl), 35.01 (С-tert-butyl), 43.52 (СН2N3), 60.87 (СН2О-ethyl), 62.19 d (СН2О-phosphonate, 2 JРС = 6.7 Hz), 110.33 d (С4-furan, 2JРС = 9.5 Hz), 128.74 d (С3-furan, 3JРС = 2.7 Hz), 139.11 d (С2-furan, 4 JРС = 0.9 Hz), 158.86 (С=О), 162.86 d (С5-furan, 2 JРС = 9.1 Hz). 31Р NMR spectrum (CDCl3), δР, ppm: 25.66. Ethyl 3-(diethoxyphosphorylmethyl)-4-azidomethyl-5-tert-butyl-2-furoate (34). Yield 72%, light brown oil. 1H NMR spectrum (CDCl3), δ, ppm: 1.22 t (6Н, СН3-phosphonate, JHH = 7.2 Hz), 1.35 t (3Н, СН3ethyl, JHH = 7.0 Hz), 1.38 s (9Н, СН3-tert-butyl), 3.47 d (2Н, СН2Р, JРH = 22.4 Hz), 4.03 d.q (4Н, СН2Оphosphonate, JHH = 7.2 Hz, JРH = 14.8 Hz), 4.32 q (2Н, СН2О-ethyl, JHH = 7.0 Hz), 4.49 s (2Н, СН2N3). 13С NMR spectrum (CDCl3), δС, ppm: 14.30 (СН3-ethyl), 16.26 d (СН3-phosphonate, 3JРС = 6.2 Hz), 22.73 d (СН2Р, 1JРС = 139.1 Hz), 29.57 (СН3-tert-butyl), 34.68 (С-tert-butyl), 43.62 (СН2N3), 60.61 (СН2О-ethyl), 62.22 d (СН2О-phosphonate, 2JРС = 6.8 Hz), 115.13 d (С4-furan, 3JРС = 3.2 Hz), 128.03 d (С3-furan, 2JРС = 10.2 Hz), 138.56 d (С2-furan, 3JРС = 8.7 Hz), 159.01 d (С=О, 4JРС = 2.9 Hz), 164.29 d (С5-furan, 4JРС = 2.4 Hz). 31Р NMR spectrum (CDCl3), δР, ppm: 24.53. Ethyl 3-(diethoxyphosphorylmethyl)-4-azidomethyl-5-methyl-2-furoate (32). To a solution of 1.56 g of chloride 31 in 25 mL of acetonitrile 1.00 g of sodium azide and 0.12 g of potassium iodide was

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added. The mixture formed was refluxed under intense stirring for 20 h, then poured in 50 mL of water, and the solution formed was saturated with sodium chloride. It was extracted with chloroform (3×25 mL). Joined organic extracts were washed with 30 mL of brine and dried over sodium sulfate. After removing chloroform the residue was kept in a vacuum (1 mmHg) at room temperature for 1 h. Yield 1.11 g (68%), light brown oil. 1H NMR spectrum (CDCl3), δ, ppm: 1.27 t (6Н, СН3-phosphonate, JHH = 7.0 Hz), 1.40 t (3Н, СН3-ethyl, JHH = 7.0 Hz), 2.40 s (3Н, СН3furan), 3.52 d (2Н, СН2Р, JРH = 22.4 Hz), 4.07 d.q (4Н, СН2О-phosphonate, JHH = 7.0 Hz, JРH = 14.4 Hz), 4.37 q (2Н, СН2О-ethyl, JHH = 7.0 Hz), 4.39 s (2Н, СН2N3). 13 С NMR spectrum (CDCl3), δС, ppm: 12.29 (СН3furan), 14.37 (СН3-ethyl), 16.33 d (СН3-phosphonate, 3 JРС = 6.3 Hz), 22.91 d (СН2Р, 1JРС = 138.9 Hz), 44.02 (СН2N3), 60.83 (СН2О-ethyl), 62.29 d (СН2Оphosphonate, 2JРС = 6.7 Hz), 117.54 d (С4-furan, 3JРС = 3.2 Hz ), 125.57 d (С3-furan, 2JРС = 10.3 Hz), 139.55 d (С2-furan, 3JРС = 9.2 Hz), 154.75 d (С5-furan, 4JРС = 2.3 Hz), 158.96 d (С=О, 4JРС = 2.9 Hz). 31Р NMR spectrum (CDCl3), δР, ppm: 24.59. Reduction of azides with triphenylphosphine (general procedure). A mixture of 10 mmol of azide, 30 mL of ethanol, and 15 mmol of triphenylphosphine was heated with stirring. In the temperature range 30– 45°C the liberation of nitrogen proceeded during several minutes. The reaction mixture was refluxed with stirring for 12 h, and then ethanol was distilled off. The residue was triturated with 50 mL of ethyl acetate–light petroleum ether mixture (1 : 4), and triphenylphosphine oxide was filtered off. The filtrate was extracted with 5% hydrochloric acid (2×15 mL), and the extract was treated with sodium carbonate to pH 9–10. The amine was extracted with methylene choride (4×15 mL). The extract was dried over sodium sulfate, the solvent was removed, and the residue was kept in a vacuum (1 mmHg) for 1 h at room temperature. The amines were yellow or light brown oils, stable on handling and having to tend to hydrolysis. Ethyl 4-aminomethyl-5-(diethoxyphosphorylmethyl)-3-furoate (1). Yield 60%, light brown oil. 1H NMR spectrum (CDCl3), δ, ppm: 1.17–1.31 m (9Н, СН3-phosphonate, СН3-ethyl), 2.05 br.s (2Н, NH2), 3.20 d (2Н, СН2Р, JРH = 20.4 Hz), 3.71 d (2Н, СН2N), 3.97–4.06 m (4Н, СН2О-phosphonate), 4.24 q (2Н, СН2О-ethyl, JHH = 7.02 Hz), 7.85 s (1Н, Н2-furan). 13С NMR spectrum (CDCl3), δС, ppm: 14.23 (СН3-ethyl), 16.32 d (СН3-phosphonate, 3JРС = 5.9 Hz), 25.12 d

(СН2Р, 1JРС = 142.9 Hz), 35.73 d (СН2N, 4JРС = 1.2 Hz), 60.35 (СН2О-ethyl), 62.39 d (СН2Оphosphonate, 2JРС = 6.7 Hz), 118.82 d (С3-furan, 4JРС = 3.4 Hz), 123.71 d (С4-furan, 3JРС = 8.8 Hz), 143.75 d (С5-furan, 2JРС = 12.5 Hz), 147.65 d (С2-furan, 4JРС = 3.1 Hz), 163.32 (С=О). 31Р NMR spectrum (CDCl3), δР, ppm: 22.24. Ethyl 2-aminomethyl-4-(diethoxyphosphorylmethyl)-5-methyl-3-furoate (11). Yield 62%, yellowish brown oil. 1H NMR spectrum (CDCl3), δ, ppm: 1.20 t (6Н, СН3-phosphonate, JHH = 7.2 Hz), 1.31 t (3Н, СН3-ethyl, JHH = 7.2 Hz), 1.98 br.s (2H, NH2), 2.21 d (3Н, СН3-furan, JРH = 4.0 Hz), 3.19 d (2Н, СН2Р, JРH = 20.8 Hz), 3.94 s (2Н, СН2N), 3.99 d.q (4Н, СН2О-phosphonate, JHH = 7.2 Hz, JРH = 14.4 Hz), 4.25 q (2Н, СН2О-ethyl, JHH = 7.2 Hz). 13С NMR spectrum (CDCl3), δС, ppm: 11.61 d (СН3-furan, 4JРС = 2.5 Hz), 14.22 (СН3-ethyl), 16.35 d (СН3-phosphonate, 3 JРС = 6.1 Hz), 21.91 d (СН2Р, 1JРС = 142.2 Hz), 39.06 (СН2N), 60.17 (СН2О-ethyl), 61.75 d (СН2Оphosphonate, 2JРС = 6.7 Hz), 109.85 d (С4-furan, 2JРС = 11.1 Hz), 113.04 d (С3-furan, 3JРС = 2.5 Hz), 148.87 d (С5-furan, 3JРС = 9.4 Hz), 160.79 (С2-furan), 163.96 (С=О). 31Р NMR spectrum (CDCl3), δР, ppm: 26.78. Ethyl 2-(diethoxyphosphorylmethyl)-4-aminomethyl-5-methyl-3-furoate (12). Yield 32%, dark yellow syrup. 1H NMR spectrum (CDCl3), δ, ppm: 1.25 t (6Н, СН3-phosphonate, JHH = 7.2 Hz), 1.34 t (3Н, СН3-ethyl, JHH = 7.2 Hz), 1.83 br.s (2H, NH2), 2.22 d (3Н, СН3-furan, JРH = 2.0 Hz), 3.62 d (2Н, СН2Р, JРH = 22.0 Hz), 3.64 s (2Н, СН2N), 4.06 d.q (4Н, СН2О-phosphonate, JHH = 7.2 Hz, JРH = 14.8 Hz), 4.29 q (2Н, СН2О-ethyl, JHH = 7.2 Hz). 13С NMR spectrum (CDCl3), δС, ppm: 11.20 (СН3-furan), 14.22 (СН3-ethyl), 16.28 d (СН3-phosphonate, 3JРС = 6.2 Hz), 26.78 d (СН2Р, 1JРС = 139.1 Hz), 36.23 (СН2N), 60.37 (СН2О-ethyl), 62.60 d (СН2О-phosphonate, 2JРС = 6.4 Hz), 114.67 d (С3-furan, 3JРС = 8.2 Hz), 121.56 (С4furan), 148.08 d (С5-furan, 4JРС = 2.6 Hz), 151.08 d (С2furan, 2JРС = 13.7 Hz), 163.90 d (С=О, 4JРС = 2.7 Hz). 31 Р NMR spectrum (CDCl3), δР, ppm: 21.88. Ethyl 3-aminomethyl-4-(diethoxyphosphorylmethyl)-5-methyl-2-furoate (16). Yield 26%, light brown oil. 1H NMR spectrum (CDCl3), δ, ppm: 1.21– 1.27 m (6Н, СН3-phosphonate) 1.33–1.37 m (3Н, СН3ethyl), 1.35 t (3Н, СН3-ethyl, JHH = 7.0 Hz), 1.86 br.s (2H, NH2), 2.30 br.s (3Н, СН3-furan), 2.89 d (2Н, СН2Р, JРH = 20.0 Hz), 3.83 s (2Н, СН2N), 3.98–4.07 m (4Н, СН2О-phosphonate), 4.31–4.37 m (2Н, СН2Оester). 13С NMR spectrum (CDCl3), δС, ppm: 12.31

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AMINOPHOSPHONOCARBOXYLATES OF THE FURAN SERIES

(СН3-furan), 14.36 (СН3-ethyl), 14.38 (СН3-ethyl), 16.28 d (СН3-phosphonate, 3JРС = 6.3 Hz), 16.40 d (СН3-phosphonate, 3JРС = 6.0 Hz), 16.42 d (СН3phosphonate, 3JРС = 5.8 Hz), 21.64 d (СН2Р, 1JРС = 142.3 Hz), 21.72 d (СН2Р, 1JРС = 143.9 Hz), 22.64 d (СН2Р, 1JРС = 137.8 Hz), 35.65 (СН2N), 60.58 (СН2Оethyl), 60.69 (СН2О-ethyl), 62.03 d (СН2О-phosphonate, 2JРС = 7.3 Hz), 62.12 d (СН2О-phosphonate, 2 JРС = 8.0 Hz), 62.20 d (СН2О-phosphonate, 2JРС = 7.2 Hz), 112.11 d (С4-furan, 2JРС = 9.9 Hz), 113.67 d (С4-furan, 2JРС = 9.7 Hz), 113.71 d (С4-furan, 2JРС = 9.6 Hz), 126.39 d (С3-furan, 3JРС = 3.0 Hz), 126.49 d (С3-furan, 3JРС = 2.7 Hz), 138.71 (С2-furan), 139.07 (С2-furan), 139.16 (С2-furan), 153.86 d (С5-furan, 2JРС = 8.4 Hz), 153.61 d (С5-furan, 3JРС = 8.2 Hz), 153.87 d (С5-furan, 3JРС = 8.5 Hz), 153.90 d (С5-furan, 3JРС = 8.5 Hz), 158.06 d (С=О, 5JРС = 2.9 Hz), 159.13 (С=О). 31 Р NMR spectrum (CDCl3), δР, ppm: 25.55, 25.96, 26.84. Ethyl 3-aminomethyl-4-(diethoxyphosphorylmethyl)-5-tert-butyl-2-furoate (26). Yield 20%, yellow oil. 1H NMR spectrum (CDCl3), δ, ppm: 1.26 t (6Н, СН3-phosphonate, JHH = 7.0 Hz), 1.34 t (3Н, СН3ethyl, JHH = 7.0 Hz), 1.37 s (9Н, СН3-tert-butyl), 1.99 br.s (2H, NH2), 3.12 d (2Н, СН2Р, JРH = 21.2 Hz), 3.82 s (2Н, СН2N), 4.00–4.08 m (4Н, СН2О-phosphonate), 4.31 q (2Н, СН2О-ethyl, JHH = 7.0 Hz). 13С NMR spectrum (CDCl3), δС, ppm: 14.37 (СН3-ethyl), 16.38 d (СН3-phosphonate, 3JРС = 5.8 Hz), 22.36 d (СН2Р, 1 JРС = 143.3 Hz), 29.34 (СН3-tert-butyl), 34.92 (С-tertbutyl), 35.43 (СН2N3), 60.51 (СН2О-ethyl), 62.13 d (СН2О-phosphonate, 2JРС = 6.8 Hz), 109.74 d (С4furan, 2JРС = 9.6 Hz ), 131.89 d (С3-furan, 3JРС = 2.6 Hz), 138.13 d (С2-furan, 4JРС = 1.1 Hz), 159.21 (С=О), 162.03 d (С5-furan, 2JРС = 9.0 Hz). 31Р NMR spectrum (CDCl3), δР, ppm: 25.90. Ethyl 3-(diethoxyphosphorylmethyl)-4-aminomethyl-5-methyl-2-furoate (29). Yield 46%, yellow syrup. 1H NMR spectrum (CDCl3), δ, ppm: common signals: 1.22–1.27 m (6Н, СН3-phosphonate), 1.33– 1.39 m (3Н, СН3-ethyl), 1.66 br.s (2H, NH2), 2.35 br.s (3Н, СН3-furan), 4.01–4.11 m (4Н, СН2О-phosphonate), 4.31–4.39 m (2Н, СН2О-ethyl); main conformer: 3.51 d (2Н, СН2Р, JРH = 22.8 Hz), 3.68 s (2Н, СН2N); minor conformer: 3.47 d (2Н, СН2Р, JРH = 22.4 Hz), 3.61 s (2Н, СН2N). 13С NMR spectrum (CDCl3), δС, ppm: common signals: 16.33 d (СН3phosphonate, 3JРС = 6.2 Hz); main conformer: 12.19 (СН3-furan), 14.39 (СН3-ethyl), 22.99 d (СН2Р, 1JРС = 139.3 Hz), 35.06 (СН2N), 60.56 (СН2О-ethyl), 62.25 d

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(СН2О-phosphonate, 2JРС = 6.7 Hz), 116.65 (С4-furan), 125.65 d (С3-furan, 2JРС = 10.4 Hz), 138.87 d (С2furan, 3JРС = 8.7 Hz), 153.30 d (С5-furan, 4JРС = 2.5 Hz), 159.18 d (С=О, 4JРС = 2.8 Hz); minor conformer: 12.48 (СН3-furan), 14.45 (СН3-ethyl), 23.10 d (СН2Р, 1 JРС = 138.9 Hz), 35.14 (СН2N), 60.29 (СН2О-ethyl), 62.10 d (СН2О-phosphonate, 2JРС = 6.7 Hz), 119.27 (С4-furan), 126.36 d (С3-furan, 2JРС = 10.7 Hz), 139.11 d (С2-furan, 3JРС = 8.6 Hz), 153.93 d (С5-furan, 4JРС = 2.5 Hz), 159.71 (С=О) . 31Р NMR spectrum (CDCl3), δР, ppm: 25.08 (main conformer), 25.15 (minor conformer), conformer ratio 1 : 0.4. Ethyl 3-(diethoxyphosphorylmethyl)-4-aminomethyl-5-tert-butyl-2-furoate (35). Yield 55%, light brown oil. 1H NMR spectrum (CDCl3), δ, ppm: 1.20 t (6Н, СН3-phosphonate, JHH = 7.2 Hz), 1.32 t (3Н, СН3ethyl, JHH = 7.2 Hz), 1.35 s (9Н, СН3-tert-butyl), 1.72 br.s (2H, NH2), 3.45 d (2Н, СН2Р, JРH = 22.4 Hz), 3.74 s (2Н, СН2N), 4.00 d.q (4Н, СН2О-phosphonate, JHH = 7.2 Hz, JРH = 14.8 Hz), 4.28 q (2Н, СН2О-ethyl, JHH = 7.2 Hz). 13С NMR spectrum (CDCl3), δС, ppm: 14.31 (СН3-ethyl), 16.26 d (СН3-phosphonate, 3JРС = 6.1 Hz), 22.75 d (СН2Р, 1JРС = 139.6 Hz), 29.41 (СН3-tertbutyl), 34.45 (СН2N), 34.85 (С-tert-butyl), 60.33 (СН2О-ethyl), 62.18 d (СН2О-phosphonate, 2JРС = 6.8 Hz), 122.55 d (С4-furan, 3JРС = 3.3 Hz), 126.01 d (С3-furan, 2JРС = 10.2 Hz), 137.92 d (С2-furan, 3JРС = 8.4 Hz), 159.23 d (С=О, 4JРС = 2.9 Hz), 162.40 d (С5furan, 4JРС = 2.4 Hz). 31Р NMR spectrum (CDCl3), δР, ppm: 25.16. ACKNOWLEDGMENTS The work was carried out within the framework of the basic part of State project of Ministry of education and science of Russia, project no 4.5554.2017/8.9. REFERENCES 1. Pevzner, L.M., Russ. J. Gen. Chem., 2017, vol. 87, no. 11, p. 2563. doi 10.1134/S1070363217110093 2. Brucoli, A., Notoli, A., Marimuthu, P., Botello, M.T., Stapleton, P., Gibbons, S., and Schatzlein, A., Bioorg. Med. Chem., 2012, vol. 20, p. 2019. doi 10.1016/ jbmc2012.01.043 3. Pevzner, L.M., Russ. J. Gen. Chem., 2012, vol. 82, no. 3, p. 404. doi 10.1134/S1070363212030073 4. Pevzner, L.M., Ignat’ev, V.M., and Ionin, B.I., Russ. J. Gen. Chem., 1994, vol. 84, no. 12, p. 1754. 5. Pevzner, L.M., Russ. J. Gen. Chem., 2003, vol. 73, no. 12, p. 1877. doi 10.1123/B:RUGC.0000025146.10575.79

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