ISSN 1070-3632, Russian Journal of General Chemistry, 2017, Vol. 87, No. 3, pp. 447–455. © Pleiades Publishing, Ltd., 2017. Original Russian Text © E.P. Doronina, L.M. Pevzner, V.A. Polukeev, M.L. Petrov, 2017, published in Zhurnal Obshchei Khimii, 2017, Vol. 87, No. 3, pp. 441–449.
Synthesis of Trifluoromethyl Derivatives of Alkyl 2-Nitromethylphosphonopropionates and -Phosphonobutyrates E. P. Doroninaa, L. M. Pevznera*, V. A. Polukeevb, and M. L. Petrova a
St. Petersburg State Institute of Technology (Technical University), Moskovskii pr. 26, St. Petersburg, 190013 Russia *e-mail:
[email protected] b
Institute of Experimental Medicine, St. Petersburg, Russia Received October 31, 2016
Abstract—By adding diethyl hydrogen phosphite to 5-trifluoromethyl-2-furaldehyde (5-trifluoromethylfur-2yl)(diethoxyphosphoryl)methanol was synthesized. It was oxidized with DMSO-acetic anhydride mixture to diethyl 5-trifluoromethyl-2-furoyl phosphonate. The reaction of the latter with ethoxymethylenetriphenylphosphorane gives ethyl (2E)-3-(diethoxyphosphoryl)-3-(5-trifluoromethylfur-2-yl)propenoate. Analogous reaction of (diethoxyphosphoryl)(5-trifluoromethylfur-2-yl)acetic aldehyde yields ethyl (4E)-4-(diethoxyphosphoryl)-4-(5-trifluoromethylfur-2-yl)-but-3-enoate. The addition of nitromethane to these esters of unsaturated acids in the presence of potassium fluoride gives a mixture of diastereomers of phosphorylated esters of 2nitromethyl-3-(5-trifluoromethylfur-2-yl)propanoic and 3-nitromethyl-4-(5-trifluoromethylfur-2-yl)butanoic acids respectively. By the reduction of ethyl nitropropanoate with zinc and formic acid in dioxane ethyl 2aminomethyl-3-(diethoxyphosphoryl)-3-(5-trifluoromethylfur-2-yl)propanoate was prepared in a low yield. It may be considered as the derivative of β-alanine containing additional pharmacophore fragments. Keywords: trifluoromethylfurans, furoyl phosphonate, furylacetic aldehyde, Wittig reaction, ethoxy-carbonylmethylenetriphenylphosphorane, nucleophilic addition, nitromethane, potassium fluoride
DOI: 10.1134/S1070363217030136 Recently we have developed preparative methods for trifluoromethylfuryl derivatives of phosphonopropionic and phosphonobutyric acids [1], but the derivatives of these acids containing pharmacophore substituents in the aliphatic part of the molecule are much more interesting for biologic applications. Studies on mice showed that glutamatergic system involving the (±)-2amino-3-phosphonopropionic acid plays a role in the motivational component of withdrawal from acute morphine dependence [2]. Phosphonopeptides containing in their structure 2-amino-3-methyl-4-phosphonobutanoic acid may serve as compatible antagonists of related protein-protein interactions. They are used as antitumor therapeutic means [3]. Therefore the search for methods of introduction of amino group in trifluoromethyl derivatives of phosphonopropanoic and phosphonobutyric acids is of interest for obtaining new medicinal preparations. One of most available pathways to introduction of the amino group in the aliphatic part of a molecular 447
structure may be the reduction of a nitro group. In its turn nitroalkyl fragment may be formed by means of nucleophilic addition of nitroalkane to the activated double bond. Consequently we have chosen the following approach to synthesis of derivatives of 3-(5trifluoromethylfur-2-yl)-3-(diethoxyphosphoryl)propanoate and 4-(5-trifluoromethylfur-2-yl)-4-(diethoxyphosphoryl)butyrate containing amino group in the side chain. In the case of phosphonopropanoate in the first stage it was suggested to prepare 5-trifluoromethyl-2-furoyl phosphonate 1, then by using Wittig reaction with ethoxycarbonylmethylenetriphenyl-hosphorane to prepare 3-(5-trifluoromethylfur-2-yl)-3(diethoxyphosphoryl)acrylate, to add to it nitromethane, and then to reduce the ester of nitrophosphonocarboxylic acid to the amino acid derivative. In the case of phosphonobutyric acid we aimed to use previously synthesized (5-trifluoromethylfur-2-yl)(diethoxyphosphoryl)acetaldehyde [4] in the Wittig reaction and then to follow the above-presented scheme.
448
DORONINA et al. Scheme 1. P(OEt)3
F3C
O
F3C
COCl
PO(OEt)2
O
P(OEt)3
F3C
PO(OEt)2 O
O 1
OR PO(OEt)2
Scheme 2. HPO(OEt)2
F3C
O
CHO
EtONa
F3C
O
PO(OEt)2
Ac2O DMSO
1
OH 3
2
The first step on this way was the synthesis of furoyl phosphonate 1. 5-Trifluoromethyl-2-furoyl chloride was used as starting substance. Its phosphorylation was carried out with a small excess of triethyl phosphite (1 : 1.4 mol/mol) in benzene at 65°C analogously to the procedure [5]. It was found that no furoyl phosphonate can be obtained under these conditions. While distillation of the reaction mixture in a vacuum after removing a small amount of volatile products (40–45°C, 1 mmHg) the main fraction with bp 170°C (1 mmHg) was isolated. In its 1H NMR spectrum no characteristic signals of the furan ring protons were found. In the 31P NMR spectrum besides the main signal at –1.19 ppm signals of the phosphonate phosphorus at 14.27 and 13.72 ppm, the signal at –13.27 ppm, and some minor signals were present. In the 19F NMR spectrum 9 signals between –64.17 and –64.74 ppm were observed. Then we decided to carry out the reaction of triethyl phosphite with acid chloride at the same molar ratio, but at room temperature. The reaction progress was monitored by the 31P NMR spectroscopy. It turned out that several hours after mixing of reagents the signal of phosphorus nucleus appeared at –1.00 ppm and two doublets were observed at 8.71 ppm and –5.72 ppm with the coupling constant JPP 35.1 Hz. One more pair of doublets with JPP = 31.9 Hz was observed at 13.26 and –1.42 ppm. The intensity ratio of these three groups of signals was 1 : 0.6 : 0.3. In the 19F NMR spectrum taken at the same time two intense fluorine signals at –64.38 and –64.74 with the intensity ratio 1 : 0.8 were observed. In the course of the reaction the intensity of the singlet phosphorus signal increased, and those of the doublet signals decreased. Spectral changes came to an end after keeping the reaction mixture for 14 days. Resulting ratio of phosphorus
signals become equal to 1 : 0.3 : 0.3. In the 19F NMR spectrum taken at this time two intense signals at –64.37 and –64.73 ppm were present. In the 1H NMR spectrum of this mixture three doublets of the furan ring protons H3 at 6.79, 7.05, and 7.35 ppm with the characteristic coupling constant 3JHH = 3.6 Hz were marked. Their relative intensity was approximately the same. Two signals of protons H4 were observed at 6.69 and 6.85 ppm with the intensity ratio 1 : 2. Because of the additional interaction with CF3 group they were broadened. Besides, at 5.62 ppm there was a doublet of doublets with the coupling constants 10.4 and 15.6 Hz and the intensity corresponding to one proton. As is seen from the presented data, the furan ring was retained in the course of the reaction, but the electronacceptor properties of the substituent that appeared instead of the carbonyl group were significantly weaker. It results in the upfield shift of all signals of the furan ring protons as compared with that in the starting acid chloride. One of the compounds formed contains the fragment PCH(furan)OP as proved by the coupling constant value. Hence, it must be stated that furoyl phosphonate is formed in this process. But its carbonyl group immediately reacts with triethyl phosphite or diethyl hydrogen phosphite formed by dealkylation of triethyl phosphite with hydrogen chloride (Scheme 1). Then, evidently, the cascade of phosphonate-phosphate transformations described by Griffiths et al. [6] for the reaction of 2-furoyl phosphonates with trimethyl phosphite is started. Another approach to the synthesis of furoyl phosphonate 1 included addition of diethyl hydrogen phosphite to 5-trifluoromethyl-2-furaldehyde 2 with the subsequent oxidation of alcohol 3 to acyl phosphonate (Scheme 2). Phosphonate 3 was prepared according to the described typical protocol by addition
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 87 No. 3 2017
SYNTHESIS OF TRIFLUOROMETHYL DERIVATIVES
of diethyl hydrogen phosphite to the carbonyl group of aldehyde 2 using freshly prepared sodium ethylate. The reaction was carried out at room temperature. The product was obtained in 70% yield as viscous oil. In the 1H NMR spectrum of this compound the doublet at 5.03 ppm with the coupling constant 1JPH = 14.0 Hz belonging to the proton of CH group directly bound with phosphorus was observed. The signal of the corresponding carbon atom was located at 64.52 ppm (1JPC = 166.8 Hz). Note that in this compound C3 carbon atom resonated with a doublet signal at 109.45 ppm (3JPC = 5.8 Hz), while the signal of C2 carbon atom at 152.82 ppm was not split. The broadened proton signal at 5.28 ppm belongs to OH group. The signal of phosphorus in the 31P NMR spectrum was located at 18.16 ppm, and that of fluorine in the 19F NMR spectrum, at –64.19 ppm. The oxidation of hydroxyphosphonate 3 to acyl phosphonate 1 was carried out according to [8] with a mixture of DMSO and acetic anhydride for 4 days at room temperature. The reaction progress was monitored by 31P HMR spectroscopy. The target product was isolated as viscous oil in 62% yield. The signal of phosphorus atom in the 31P HMR spectrum of this substance was located at –3.94 ppm. In its 1H NMR spectrum the characteristic signal of the proton of the CHP fragment was absent, and the signal of the furan ring proton H3 was shifted downfield. In the 13C NMR spectrum the doublet of carbonyl group carbon atom was located at 186.27 ppm (1JPC = 192.5 Hz). The signal of C2 carbon atom of the furan ring was a doublet at 152.51 ppm with the coupling constant 2 JPC = 88.3 Hz characteristic of 2-furoyl phosphonates [5]. The signal of fluorine nucleus in the 19F NMR spectrum was observed at –64.65 ppm. Acyl phosphonate 1 was involved in the Wittig reaction with ethoxymethylenetriphenylphosphorane. The reaction was carried out in benzene at 70°C according to [9]. The composition of reaction mixture was monitored by 31P HMR spectroscopy (Scheme 3). After the disappearance of the acyl phosphonate signal at –3.94 ppm and the appearance of the product signal at 12.82 ppm the reaction mixture was diluted with light petroleum ether for removing triphenylphosphine oxide, and ethyl phosphonacrylate 4 was isolated from filtrate in 89% yield as viscous syrup. In the 1H NMR spectrum of this product a doublet at 6.88 ppm (3JPH = 23.6 Hz) was observed belonging to the proton of CHgroup at the double bond which was cis-located with respect to the phosphoryl group. The signal of Cβ
449
Scheme 3. O 1
Ph3P=CHCOOEt _
Ph3P=O
F3C
OEt
O O P EtO 4
OEt
carbon atom of the side chain was located at 126.67 ppm (1JPC = 179.9 Hz), and of Cα atom, at 133.18 ppm (2JPC = 6.3 Hz). The doublet of the carbonyl group carbon atom was observed at 165.35 ppm (3JPC = 25.3 Hz). Hence, Wittig reaction in this case proceeds stereoselectively. The carbonyl group of compound 4 is trans-located with respect to the phosphoryl group in fair agreement with the reported data [10]. Note also that the signal of Cα carbon atom is located downfield as compared to Cβ one. The signal of C2 carbon atom of the furan ring at 149.29 ppm has the coupling constant 2JPC as large as 19.1 Hz. This set of spectral data is characteristic of all esters of 5-substituted 3-(2-furyl)-3-(dietoxyphosphoryl)acrylic acids regardless of the nature of substituent. It occurs that in the presence of such strong σ-acceptor as trifluoromethyl group this effect remains. The signal of fluorine nucleus in the 19F NMR spectrum of compound 4 was revealed at –64.65 ppm. For the preparation of derivatives of (trifluoromethyl)phosphonobutyric acid it was necessary to synthesize the unsaturated compound whose side chain is longer by one carbon atom. Recently we have synthesized and investigated (5-trifluoromethylfur-2yl)(diethoxyphosphoryl)acetic aldehyde 5 [4]. Despite of its almost complete enolization in solutions we decided to involve it in Wittig reaction with ethoxymethylenetriphenylphosphorane. The process was carried out in benzene at 75°C. Its progress was monitored by the 31P HMR spectroscopy [9]. It occurred that instead of the expected signal at 20.0 ppm characteristic of 2-phosphonoalkyl derivatives the signal at 14.71 ppm increased in the course of the reaction. After completion of the synthesis and the work up of the reaction mixture the product was isolated as yellow very viscous oil. In its 1H NMR spectrum besides the signals of protons of the ester groups and the furan ring two doublets of doublets at 3.62 ppm (JHH = 7.0 Hz, JPH = 3.8 Hz) and 3.88 ppm (JHH = 7.2 Hz, JPH = 3.2 Hz) were observed. Their intensity ratio was 6 : 1, and their total intensity
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 87 No. 3 2017
450
DORONINA et al. Scheme 4. H F3C
OH O (EtO)2OP 5 F3C
Ph3P=CHCOOEt
F3C
H
_
O +
O (EtO)2OP H
P(Ph)3 COOEt
_
O (EtO)2OP H
O
P(Ph)3
H+
_
F3C
Ph3P=O
COOEt
corresponded to two protons. Besides, at 6.88 ppm a doublet of triplets was located with the coupling constants JHH = 7.0 Hz and JPH = 23.2 Hz. The intensity of this signal corresponded to one proton. In the 13C NMR spectrum the signal of Cγ carbon atom was revealed at 122.19 ppm (1JPC = 184.0 Hz), the signal of Cβ was found at 140.77 ppm (2JPC = 7.4 Hz), and the signal of Cα carbon atom was located at 35.74 ppm (3JPC = 18.3 Hz). From these data it follows that the double bond is located between Cβ and Cγ carbon atoms. The phosphoryl and ethoxycarbonylmethyl groups are trans-located with respect to the double bond. The signal of the olefin proton is split due to coupling with the phosphorus and with the protons of adjacent methylene group. Evidently because of steric hindrances at the double bond the formation of two conformers is possible. These conformers have different shifts of signals of the methylene group protons, but the coupling constants are of close values. In the 19F and 31P NMR spectra two signals at δF –64.08 (0.18), –64.31 (1.00), and δP 14.71 (1.00), 12.61 (0.17) ppm were found. As their ratio of intensities agrees with those observed in the 1H NMR spectrum for the methylene group protons, they must characterize the same conformers. Among the other spectral peculiarities note that signals of carbon atoms at the double bond are located at the same chemical shifts as in 5-substituted 3-(2-furyl)acrylates. The constant of spin-spin coupling between the carbon atom C2 of the furan ring and the phosphorus atom 2JPC increases from the usually observed value (~19.0 Hz) to 21.8 Hz. The product formed should be characterized by structure 6. As no formation of usual product of the Wittig reaction was observed in the course of the process, it can be presumed that the phosphorane reacted with the enol form of aldehyde 5. In this case the pathway of
COOEt O (EtO)2OP 6
H
the reaction can be described by Scheme 4 beginning with the addition of the bipolar form of phosphorane to the vinyl fragment. Then scheme of transformation agrees with that usually accepted for the mechanism of the Wittig reaction [11]. In the last stage the elimination of triphenylphosphine oxide may result in the formation of an anionic center either on Cα or on Cγ carbon atom. First case occurs to be preferable because the double bond and the furan ring form longer conjugated system, and the basicity of both anions is at least comparable. Therefore the formation of structure 6 resulting from the protonation of Cα carbon atom is more energetically favorable. The addition of nitromethane to unsaturated esters 4 and 6 was carried out analogously to [10] (Scheme 5). Nitromethane was used as the reaction medium, and freshly calcined potassium chloride was used as catalyst. For both esters the reaction was carried out at 100°C under vigorous stirring. The reaction progress was monitored by 31P NMR spectroscopy. As the process went on, the signal of the phosphorus nucleus in the range typical of unsaturated phosphonates gradually decreased, and the signals at 20–21 ppm characteristic of α-phosphonalkylfurans [10] appeared. Total reaction time in both cases was 40 h. Compound 7, the product of nitromethane addition to ethyl phosphonoacrylate 4 was isolated in 47% yield. In its 1H NMR spectrum two doublets of Scheme 5. 4
COOEt
CH3NO2 KF
F3C
O (EtO)2OP 7
NO2
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 87 No. 3 2017
SYNTHESIS OF TRIFLUOROMETHYL DERIVATIVES Scheme 6. COOEt 6
CH3NO2 KF
F3C
O (EtO)2OP 8
NO2
doublets of different intensity at 3.74 ppm (JHH = 9.2, JPH = 22.0 Hz) and 3.94 ppm (JHH = 6.2, JPH = 24.6 Hz) were observed. They belonged to PCH fragment of two different structures. In each of them the signal of proton was split due to coupling with phosphorus and with one more proton on the adjacent carbon atom. Hence in the course of the reaction the nitromethyl group adds to Cα and a proton to Cβ carbon atom of the acrylic fragment. Due to that in the molecule of nitroester 7 two asymmetric carbon atoms appear, and a diastereomer pair of compounds having different spectral characterisrics is formed. Most exact evaluation of diastereomer ratio may be done from the 31 P and 19F NMR spectra where two signals with δP 20.88 and 21.05 ppm in 0.75 : 1.00 ratio and two signals at δF –64.18 and –64.27 ppm in 1.00 : 0.81 ratio were observed. The signals of protons of the HC– C=O fragment and of nitromethyl group are poorly resolved multiplets at 3.16–3.39 ppm and 4.41– 4.60 ppm. Due to strong overlapping we failed to evaluate their spectral parameters. 13C NMR spectral data are more informative. Signals of carbon atom Cβ directly bound to phosphorus are located at 42.53 ppm (1JPC = 143.8 Hz) for major diasereomer and at 39.87 ppm (1JPC = 143.7 Hz) for minor one. Signals of Cα carbon atom are revealed at 26.30 ppm (2JPC = 6.1 Hz) for the major and at 27.29 ppm for the minor diastereomer. Signals of carbon nuclei of nitromethyl group are singlets at 73.13 and 71.67 ppm. Signals of the carbonyl group carbon atom appear as doublets at 171.44 ppm (3JPC = 15.0 Hz) and at 171.63 ppm (3JPC = 12.2 Hz). The product of addition of nitromethane to the ester 6 was isolated in 95% yield (Scheme 6). In its 1H NMR spectrum two doublets of doublets of equal intensity at 3.75 ppm [1H, Hγ, JH(γ)H(β) = 6.4, 1JPH(γ) = 24.4 Hz] and 3.94 ppm [1H, Hγ, JH(γ)H(β) = 5.6, 1JPH(γ) = 25.7 Hz] were observed. These are characteristic signals of PCH fragment. Hence, in this case the addition of a proton also occurss to the carbon atom bound with phosphorus, and of nitromethyl group to the neighboring carbon atom of the double bond. The
451
product may be described by the structure 8 with two asymmetric carbon atoms. It exists as spectroscopically distinguishable pair of diastereomers. Spectral characteristics of the greater part of proton-containing fragments in this case could be approximately evaluated by means of subspectrum method. Protons of CαH2 fragment in each of diastereomers interact with one another with the same coupling constant 2JHH = 17.2 Hz forming an AB-system. It turned out that in one of diastereomers chemical shifts of protons differ notably stronger than in the other one. Due to that distribution of intensities between the components of signals of AB-system strongly differs, and attribution can be made unambiguously. One of AB-systems is formed by the signals of protons with chemical shifts 2.28 (2JHH = 17.2, 3JHH = 9.2 Hz) and 2.85 ppm (2JHH = 17.2, 3JHH = 4.0 Hz). Each of these protons interacts with the proton CβH with individual 3 JHH constant. No interaction with phosphorus is revealed in this case. Second AB-systems is formed by the signals of protons at 2.50 (2JHH = 17.2, 3JHH = 7.8 Hz) and 2.64 ppm (2JHH = 17.2, 3JHH = 5.4, 4JPH = 2.4 Hz). Each of protons of this system interacts with the proton CβH, and one of them also with phosphorus nucleus. Signals of protons of nitromethyl group in each of diastereomers form an AB system with the constants 2 JHH = 13.6 and 13.8 Hz. Due to close values of constants the attribution of signals also was carried out considering the difference in the intensity distribution between spectral components. As well as for the fragment CαH2 it strongly differed because of the difference in chemical shifts of protons. One of the systems included the signals at 4.33 (2JHH = 13.6, 3 JHH = 9.6 Hz) and 5.03 ppm (2JHH = 13.6, 3JHH = 4.0 Hz). Each of the protons forming this system interacts with CβH proton with individual 3JHH constant. Second system includes the signals at 4.64 (2JHH = 13.8, 3JHH = 6.4 Hz) and 4.77 ppm (2JHH = 13.8, 3JHH = 5.8, 4JPH = 1.6 Hz). In this case one of protons also interacts with phosphorus nucleus. Signal of CβH proton forms poorly resolved multiplet that cannot be used in calculations. In the 13C NMR spectrum signal of Cα carbon atom was located at 34.05 ppm, doublets of Cβ carbon atom were revealed at 33.44 (2JPC = 6.1 Hz) and 34.50 ppm (2JPC = 9.7 Hz), and doublets of Cγ at 38.57 (1JPC = 141.6 Hz) and 38.96 ppm (1JPC = 141.4 Hz). Doublets of carbon atoms of nitromethyl group were located at
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 87 No. 3 2017
452
DORONINA et al. Scheme 7. 7
COOEt
Zn + HCOOH Dioxane
F3C
O (EtO)2OP 9
NH2
76.05 (3JPC = 8.1 Hz) and 76.34 (3JPC = 5.5 Hz). The signal of phosphorus is common for both diastereomers (δP = 21.31), and fluorine nuclei give two signals of equal intensity at –63.23 and –64.28 ppm. Hence, the direction of addition of nitromethane to the double bond in the ethyl esters of 3-(5-trifluoromethylfur-2-yl)-3-phosphoacrylic 4 and 4-(5-trifluoromethylfur-2-yl)-4-phosphono-3-butenoic acid 6 remains the same as in 3-(5-methylfur-2-yl)-3-phosphonoacrylate [10]. Consequently the direction of the double bond dipole while introduction of σ-acceptor substituent instead of the σ-donor one remains the same. For the reduction of nitro group we have chosen the protocol [12] which was used previously for reduction of 4-nitrobutyrate. According to this procedure the reducing agent was the mixture of zinc and formic acid in methanol. Due to low solubility of phosphonate 7 in methanol we have used dioxane instead (Scheme 7). It was found that at room temperature recommended by [12] no reduction takes place, but when heated to 100°C this system reduces nitro group to amine. In the 31P NMR spectrum of the isolated product two signals of equal intensity at 21.81 and 21.84 ppm were present. Evidently they belong to the diastereomer pair. The signal of trifluoromethyl group was common for both diastereomers. It was found at δF –64.19 ppm. In the 1H NMR spectrum a broad signal of the amino group protons was observed at 1.24 ppm. Signals of the aminomethyl protons of one of diastereomers form weakly bound ABC-system which could be approximately calculated using the subspectrum method. It includes two doublets of doublets at 2.12 (2JHH = 16.8, 3JHH = 8.8 Hz) and 2.60 ppm (2JHH = 16.8, 3JHH = 8.4 Hz). The signal of the CαH proton appears as a multiplet at 3.07–3.32 ppm. Signals of proton of the aminomethyl group belonging to the second diastereomer form a multiplet at 2.27– 2.37 ppm. We failed to calculate it because of strong overlapping. The signal of the PCH proton fragment of one of diastereomers was revealed as a doublet of doublets at 3.41 ppm (2JPH = 22.8, 3JHH = 9.0 Hz). The signal of this proton from the second diastereomer is
also located in the range 3.30–3.38 ppm, but the spectral lines strongly overlap, and we have not been able to isolate them. In the 13C NMR spectrum aminoalkyl fragment is reliably characterized by the presence of signals of CH2NH2 carbon atom at 46.34 (3JPC = 13.5 Hz) and 46.87 ppm (3JPC = 5.5 Hz), of CαH carbon atom at 35.28 (2JPC = 11.1 Hz) and 35.81 ppm (2JPC = 11.1 Hz), and of PCH carbon atom at 41.86 (1JPC = 141.2 Hz) and 41.98 ppm (1JPC = 141.8 Hz). Signals of the carbonyl group carbon atom are located at 176.58 and 176.98 ppm. Hence, spectral data permit to characterize the product synthesized by the structure 9. This compound was isolated in 17% yield. Summarizing the above-discussed data it was shown that starting from 5-phosphorylated carbonyl compounds of 5-trifluoromethylfuran via the Wittig reaction with the resonance-stabilized phosphoranes and subsequent addition of nitromethane esters of nitrophosphonocarboxylic acids were obtained. They can be regarded on the one hand as precursors of derivatives of β-alanine and γ-aminobutyric acid, and on the other hand, as precursors of γ-aminopropanephosphonic acid containing heterocyclic fragment on the periphery of the molecule. At the same time, the reducing system chosen for obtaining esters of the corresponding amino acids occurred to be unsatisfactory. EXPERIMENTAL 1
H, 13C, 19F and 31P NMR spectra were registered on a Bruker DPX-400 spectrometer (400.13 MHz 1H, 376.43 MHz 19F, 161.97 MHz 31P, 100.16 MHz 13C respectively) in CDCl3. 5-Trifluoromethyl-2-furaldehyde 2 was obtained according to [13], (5-trifluoromethylfur-2-yl)(diethoxyphosphoryl)acetic aldehyde 4, according to [5]. (5-Trifluoromethylfur-2-yl)(diethoxyphosphoryl)methanol (3). To a mixture of 1.4 g (8.53 mmol) of 5-trifluoromethyl-2-furaldehyde and 1.1 mL of diethyl hydrogen phosphite 3 drops of freshly prepared saturated solution of sodium ethylate in anhydrous ethanol were added. The reaction mixture spontaneously heated to 70°C. It was stirred without cooling for 8 h and left overnight. On the next day the mixture formed was neutralized with acetic acid, dissolved in 20 mL of chloroform, washed with 5 mL of saturated solution of sodium chloride and dried over sodium sulfate. The solvent was removed on a rotary
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 87 No. 3 2017
SYNTHESIS OF TRIFLUOROMETHYL DERIVATIVES
453
evaporator, the residue was kept in a vacuum (1 mmHg) at room temperature. Yield 1.8 g (70%), yellow syrup. 1H NMR spectrum (CDCl3), δ, ppm (J, Hz): 1.24 t (3H, CH3-phosphonate, JHH = 7.0), 1.28 t (3H, CH3-phosphonate, JHH = 7.2), 4.06–4.19 m (4H, OCH2-phosphonate), 5.03 d (1H, PCH, 1JPH = 14.0), 5.28 br.s (OH), 6.57 d.d (1H, H3-furan, JHH = 3.0, JРH = 2.8), 6.74 d (1H, H4-furan, JHH = 3.0). 13C NMR spectrum (CDCl3), δС, ppm (J, Hz): 16.14 d (СH3phosphonate, 3JPC = 5.0), 16.19 d (СH3-phosphonate, 3 JPC = 4.2), 61.84 d (CH2OP, 2JPC = 5.5), 64.52 d (CP, 1 JPC = 166.8), 109.45 d (С3-furan, 3JPC = 5.8), 112.52 br.s (С4-furan), 118.95 q (CF3, JCF = 265.2), 141.45 q (С5-furan, 2JCF = 42.3), 153.82 (C2-furan). 19F NMR spectrum (CDCl3), δF, ppm: –64.19 (СF3). 31P NMR spectrum (CDCl3), δР, ppm: 18.16.
was kept in a vacuum (1 mmHg) at room temperature for 1 h. Yield 1.2 g (89%), yellow syrup. 1H NMR spectrum (CDCl3), δ, ppm (J, Hz): 1.26 t (3H, CH3ester, JHH = 7.2), 1.31 t (6H, CH3-phosphonate, JHH = 6.8), 4.06–4.20 m (4H, OCH2-phosphonate), 4.24 q (2H, OCH2-ester, JHH = 7.2), 6.81 br.d (1H, H3-furan, JHH = 3.6), 6.86 br.s (1H, H4-furan), 6.88 d (=СH, 2JPH = 23.6). 13C NMR spectrum (CDCl3), δС, ppm (J, Hz): 13.82 (СH3-ester), 16.16 d (СH3-phosphonate, 3JPC = 6.0), 61.58 (CH2О-ester), 63.12 d (CH2OP, 2JPC = 5.6), 112.99 (С3-furan), 113.71 (С4-furan), 118.72 q (CF3, JCF = 265.8), 126.67 d (=CP, 1JPC = 179.9), 133.18 (=СН, 2JPC = 6.3), 142.33 q (С5-furan, 2JCF = 42.8), 149.29 d (С2-furan, 2JPC = 19.1), 165.35 d (C=O, 3JPC = 25.3). 19F NMR spectrum (CDCl3), δF, ppm: –64.25 (CF3), 31P NMR spectrum (CDCl3), δР, ppm: 12.82.
Diethyl 5-trifluoromethyl-2-furoylphosphonate (1). To a solution of 1.8 g (6.0 mmol) of alcohol 3 in 18 mL of DMSO 12 mL of acetic anhydride was added. Small heat evolution was observed while mixing of reagents. The reaction mixture was left for 4 days at room temperature. After that DMSO and acetic anhydride were distilled off at a reduced pressure, the residue was poured in 20 mL of water, and the mixture formed was extracted with chloroform (2×15 mL). The extract was dried overnight over sodium sulfate. On the next day the solvent was removed at a reduced pressure, and the residue was kept in a vacuum (1 mmHg) at room temperature for 1 h. Yield 1.1 g (62%), yellow syrup. 1H NMR spectrum (CDCl3), δ, ppm (J, Hz): 1.41 t (6H, CH3, JHH = 7.0), 4.30 d.q (4H, OCH2, JHH = 7.4, JРH = 14.8), 6.98 d (1H, H3-furan, JHH = 3.6), 7.86 d (1H, H4-furan, JHH = 3.6). 13C NMR spectrum (CDCl3), δС, ppm (J, Hz): 16.30 (СH3, 3JPC = 5.7), 64.63 (CH2OP, 2JPC = 7.0), 113.34 (С4-furan), 118.20 q (CF3, JCF = 267.5), 123.64 (С3-furan), 146.58 q (С5-furan, 2JCF = 43.2), 152.51 d (С2-furan, 2JPC = 88.6), 186.40 d (C=O, 1JPC = 192.5). 19 F NMR spectrum (CDCl3), δF, ppm: –64.65 (CF3), 31 P NMR spectrum (CDCl3), δР, ppm: –3.94.
Ethyl (E)-4-(diethoxyphosphoryl)-4-(5-trifluoromethylfur-2-yl)but-3-enoate (6). The mixture of 1.8 g (5.17 mmol) of ethoxycarbonylmethylenetriphenylphosphorane and 1.5 g (4.77 mmol) of aldehyde 5 in 18 mL of benzene was heated for 8 h at 75°C under vigorous stirring. After that half of benzene was evaporated, and the residual solution was diluted with 45 mL of hexane. The reaction mixture was left for 45 min for crystallization of triphenylphosphine oxide and filtered. The filtrate was treated with 3 g of silica gel (Chemapol L 40/100) and stirred with a magnetic stirrer for 1 h. The solution formed was filtered, and the solvent was removed from the filtrate at a reduced pressure. The residue was kept in a vacuum (1 mmHg) at room temperature for 1 h. Yield 1.2 g (65%), viscous yellow oil. 1H NMR spectrum (CDCl3), δ, ppm (J, Hz): 1.25–1.33 m (9H, СH3-ester, СH3-phosphonate), 3.62 d.d (1.7H, CР=CHCH2, 3JHH = 7.0, 4JPH = 3.8), 3.88 d.d (0.3H, PC=CHCH2, 3JHH = 7.2, 4JPH = 3.2), 6.74 br.d (1H, H3–furan, JPH = 2.0), 6.81 br.s (1H, H4-furan), 6.88 d.t (1H, PC=CH, 3JPH = 23.2, 3JHH = 7.0). 13C NMR spectrum (CDCl3), δС, ppm (J, Hz): 14.06 (СH3-ester), 16.17 d (СH3-phosphonate, 3JPC = 6.2), 35.74 d (PC=CHCαH2, 3JPC = 18.3), 61.19 (CH2Оester), 62.31 d (CH2OP, 2JPC = 4.9), 62.62 d (CH2OP, 2 JPC = 5.4), 112.34 (С3-furan), 112.79 br.s (С4-furan), 118.91 q (CF3, JCF = 265.6), 122.19 d (=CP, 1JPC = 184.0), 140.77 d (=СН, 2JPC = 7.4), 141.63 q (С5-furan, 2 JCF = 43.1), 151.20 d (C2-furan, 2JPC = 21.8), 169.88 (C=O). 19F NMR spectrum (CDCl3), δF, ppm: –64.05 (CF3, 0.18), –64.31 (CF3, 1.00). 31P NMR spectrum (CDCl3), δР, ppm: 12.61 (0.17), 14.71 (1.00).
Ethyl (E)-3-(diethoxyphosphoryl)-3-(5-trifluoromethylfur-2-yl)prop-2-enoate (4). The mixture of 1.53 g (4.4 mmol) of ethoxycarbonylmethylenetriphenylphosphorane and 1.1 g (3.7 mmol) of acyl phosphonate 1 in 15 mL of benzene was stirred for 8 h at 70°C. After that the reaction mixture was diluted with 40 mL of light petroleum ether and kept overnight for crystallization of triphenylphosphine oxide. Obtained precipitate was filtered off, and solvent was removed from filtrate at reduced pressure. The residue
Ethyl 2-nitromethyl-3-(5-trifluoromethylfur-2-yl)3-(diethoxyphosphoryl)propionate (7). To the
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 87 No. 3 2017
454
DORONINA et al.
solution of 1.4 g (3.78 mmol) of phosphonate 4 in 11 mL of nitromethane 1.15 g (19.82 mmol) of freshly calcined finely pulverized potassium fluoride was added under vigorous stirring. The reaction mixture was stirred for 40 h at 100°C. Then 50 mL of chloroform was added, and potassium fluoride was filtered off. The filtrate was washed with 5% acetic acid (2×5 mL), with 10 mL of saturated sodium chloride solution, and the filtrate was dried over sodium sulfate. The solvent was removed from the filtrate at a reduced pressure. The residue was kept in a vacuum (1 mmHg) at room temperature for 1 h. Yield 0.8 g (47%), brown oil. 1H NMR spectrum (CDCl3), δ, ppm (J, Hz): 1.20–1.36 m (9H, CH3), 3.16–3.29 m (1H, CH-С=О), 4.03–4.23 m (6H, ОСН2-ester, ОСН2phosphonate), 4.41–4.60 m (2H, CH2 NO2); main diastereomer: 3.94 d.d (1H, PCH, JPH = 24.6, JHH = 6.2), 6.53 br.s (1H, H4-furan), 6.78 (1H, H3-furan); minor diastereomer: 3.74 d.d (1Н, PCH, JPH = 22.0, JHH = 9.2), 6.42 (1H, H4-furan), 6.75 (1H, H3-furan). 13 C NMR spectrum (CDCl3), δС, ppm (J, Hz): common signals: 118.79 q (CF3, JCF = 265.5), 144.26 q (С5furan, 2JCF = 42.8); main diastereomer: 13.96 (СH3ester) 16.26 (СH3-phosphonate, 3JPC = 6.6), 26.30 d (О=С-CH, 2JPC = 6.1), 42.53 d (CНP, 1JPC = 143.0), 61.52 (CH2О-ester), 62.92 d (CH2OP, 2JPC = 7.9), 62.99 d (CH2OP, 2JPC = 7.9), 73.13 ( CH2NO2), 111.28 d (С3-furan, 3JPC = 5.0), 112.36 br.s (С4-furan), 150.10 br.s (С2-furan), 171.44 d (C=O, 3JPC = 15.0); minor diastereomer: 14.08 (СH3-ester), 16.19 (СH3-phosphonate, 3JPC = 5.9), 27.29 (О=С–CH), 39.87 d (CP, 1 JPC = 143.7), 61.78 (CH2О-ester), 63.26 d (CH2OP, 2 JPC = 7.4), 63.34 d (CH2OP, 2JPC = 7.4), 71.67 (CH2NO2), 109.83 d (С3-furan, 3JPC = 5.9), 112.69 br.s (С4–furan), 151.62 d (С2-furan, 2JPC = 6.1), 171.63 d (C=O, 3JPC = 12.2). 19F NMR spectrum (CDCl3), δF, ppm: –64.18 (CF3, 1.00), –64.27 (CF3, 0.85). 31P NMR spectrum (CDCl3), δР, ppm: 20.88 (0.75), 21.05 (1). Ethyl 3-nitromethyl-4-(5-trifluoromethylfur-2yl)-4-(diethoxyphosphoryl)butyrate (8). This compound was prepared analogously from 1 g (2.6 mmol) of the ester 6, 13 mL of nitromethane, and 1 g (17.24 mmol) of potassium fluoride. Yield 1.1 g (95%), brown oil. 1H NMR spectrum (CDCl3), δ, ppm (J, Hz): 1.21–1.38 m (9H, СH3-ester, СH3-phosphonate); 2.28 d.d (0.5H, СαHА, 2JНН = 17.2, 3JНН = 9.2), 2.85 d.d (0.5H, СαHВ, 2JНН = 17.2, 3JНН = 4.0); 2.50 d.d (0.5H, СαHА, 2JНН = 17.2, 3JНН = 7.8), 2.64 d.d.d (0.5H, СαHВ, 2JНН = 17.2, 3JНН = 5.4, 4JHP = 2.4); 3.32–3.44 m (1H, СβН); 3.75 d.d (0.5H, РСH, 1JHP =
24.4, 2JНН = 6.4), 3.87 d.d (0.5H, РСH, 1JHP = 25.7, 2 JНН = 5.6); 3.96–4.04 m (4H, CH2О-phosphonate), 4.05–4.23 m (2H, CH2О-ester); 4.33 d.d (0.5H, NСHА, 2 JНН = 13.6, 3JНН = 9.6), 5.03 d.d (0.5H, NСHВ, 2JНН = 13.6, 3JНН = 4.0); 4.64 d.d (0.5H, NСHА, 2JНН = 13.8, 3 JНН = 6.4), 4.77 d.d.d 0.5H, NСHВ, 2JНН = 13.8, 3JНН = 5.8, 4JHP = 1.6); 6.49 br.d (1H, H3-furan, JPH = 2.4) 6.79 br.s (1H, H4-furan). 13C NMR spectrum (CDCl3), δС, ppm (J, Hz): 14.01 (СH3-ester), 16.14 d (СH3-phosphonate, 3JPC = 6.1), 16.20 d (СH3-phosphonate, 3JPC = 6.0), 34.05 (Сα), 33.44 d (Сβ, 2JPC = 6.1), 34.50 d (Сβ, 2 JPC = 9.7), 38.57 d (PCγ, 1JPC = 141.6), 38.96 d (PCγ, 1 JPC = 141.4), 61.04 (CH2О-ester), 63.09 d (CH2OP, 2 JPC = 4.7), 63.15 d (CH2OP, 2JPC = 6.0), 63.42 d (CH2OP, 2JPC = 6.8), 76.05 d (CH2NO2, 3JPC = 8.1), 76.34 d (CH2NO2, 3JPC = 5.5), 111.40 d (С3-furan, 3JPC = 5.0), 111.45 d (С3-furan, 3JPC = 5.1), 112.748 br.s (С4furan), 118.71 q (CF3, JCF = 267.7), 142.09 q (С5-furan, 2 JCF = 43.8), 142.19 q (С5-furan, 2JCF = 42.9), 150.66 d (C2-furan, 2JPC = 9.8), 150.33 d (C2-furan, 2JPC = 4.5), 170.75(C=O), 170.89(C=O). 19F NMR spectrum (CDCl3), δF, ppm: –64.23 (CF3, 1.00), –64.28 (CF3, 1.00). 31P NMR spectrum (CDCl3), δР, ppm: 21.31. Ethyl 2-aminomethyl-3-(5-trifluoromethylfur-2-yl)3-(diethoxyphosphoryl)propionate (9). To a solution of 0.8 g (1.79 mmol) of nitroester 7 in 12 mL of dioxane 1.8 g (27.69 mmol) of zinc powder was added under vigorous stirring. Then 2.6 mL of 85% formic acid was added, and the reaction mixture spontaneously heated to 31°C. After complete heat evolution the reaction mixture was refluxed with stirring for 8 h. On the next day the precipitate was filtered off, treated with 20% solution of potassium hydroxide until the dissolution of zinc hydroxide, and the water phase formed was extracted with chloroform (3×25 mL). Joined dioxane and chloroform solutions were evaporated to dryness on the rotary evaporator, the residue was dissolved in 30 mL of ethyl acetate and washed with 10% solution of hydrochloric acid (3×10 mL). Water layer was treated with sodium carbonate to pH 10 and extracted with chloroform (3×15 mL). The extract was dried with sodium sulfate, chloroform was distilled off at a reduced pressure, and the residue was kept in a vacuum (1 mmHg) at room temperature for 1 h. Yield 0.13 g (17%), yellow oil. 1H NMR spectrum (CDCl3), δ, ppm (J, Hz): 1.20–1.32 m (9H, CH3), 1.24 br.s (2Н, NН2), 2.12 d.d (0.5Н, СН2NН2, 2JНH = 16.8, 3 JHH = 8.4), 2.27–2.37 m (1Н, СН2NН2), 2.60 d.d (0.5Н, СН2NН2, 2JНH = 16.8, 3JHH = 8.8), 3.30–3.38 m (0.5Н, РСН), 3.34 d.d (0.5Н, РСН, 2JPH = 22.8, 3JHH =
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 87 No. 3 2017
SYNTHESIS OF TRIFLUOROMETHYL DERIVATIVES
9.0), 3.07–3.32 m (1H, CH-С=О), 3.93–4.13 m (6H, ОСН2-ester, ОСН2-phosphonate), 6.40 d (1H, H3furan, 3JHH = 3.6), 6.76 br.s (1H, H4-furan). 13C NMR spectrum (CDCl3), δС, ppm (J, Hz): 14.07 (СH3-ester), 16.26 br.s (СH3-phosphonate), 35.29 d (О=С–CH, 2JPC = 11.1), 35.81 d (О=С-CH, 2JPC = 4.1), 41.87 d (CНP, 1 JPC = 141.2), 41.98 d (CНP, 1JPC = 141.8), 46.34 d (СН2NН2, 3JPC = 13.5), 46.87 d (СН2NН2, 3JPC = 5.5), 62.64 d (CH2OP, 2JPC = 6.4), 62.67 (CH2О-ester), 62.70 d (CH2OP, 2JPC = 5.7), 63.03 d (CH2OP, 2JPC = 6.5), 110.02 d (С3-furan, 3JPC = 7.0), 110.09 d (С3furan, 3JPC = 7.0), 112.74 br.s (С4-furan), 118.79 q (CF3, JCF = 265.5), 141.55 q (С5-furan, 2JCF = 44.6), 141.61 q (С5-furan, 2JCF = 44.1), 151.66 d (С2-furan, 2 JPC = 16.4), 151.73 d (С2-furan, 2JPC = 16.5), 176.58 (C=O), 176.98 (C=O). 19F NMR spectrum (CDCl3), δF, ppm: –64.19 (CF3). 31P NMR spectrum (CDCl3), δР, ppm: 21.81 (1.00), 21.90 (1.00). ACKNOWLEDGMENTS The work was carried out within the frames of basic part of state contract with the Ministry of science and education of Russia. REFERENCES 1. Doronina, E.P., Pevzner, L.M., Polukeev, V.A., and Petrov, M.L., Russ. J. Gen. Chem., 2016, vol. 86, no. 12, p. 2616. doi 10.1134/S1070363216120082
455
2. Kawasaki, Y., Jin, C., Suematu, K., Kawasaki, H., Shibata, K., Choshi, T., Hibino, S., Gomita, Y., and Araki, H., British J. Pharm., 2005, vol. 145, no. 6, p. 751. doi 10.1038/sj.bjp.0706228 3. Stanton, P., Chattarji, S., and Sejnowski, T.-J., Neurosci. Lett., 1991, vol. 127, no. 1, p. 61. doi 10.1016/0304-3940(91)90815-z 4. Pevzner, L.M. and Polukeev, V.A., Russ. J. Gen. Chem., 2015, vol. 85, no. 9, p. 2120. doi 10.1134/ S1070363215090169 5. Pevzner, L.M., Russ. J. Gen. Chem., 2016, vol. 86, no. 5, p. 1046. doi 10.1134/S107036321605011X 6. Griffiths, D.V., Al-Jeboori, M.J., Cheong, Y-K., Duncanson, P., and Harris, J.E., Org. Bioorg. Chem., 2008, vol. 6, p. 577. doi 10.1039/b717130g 7. Ramirez, F., Bhatia, B., and Smith, P., Tetrahedron, 1967, vol. 23, no. 5, p. 2067. doi 10.1016/0040-4020 (67)80040-1 8. Albright, J.D. and Goldman, L., J. Amer. Chem. Soc., 1967, vol. 89, no. 10, p. 2416. doi 10.1021/ja00986a031 9. Pevzner, L.M., Russ. J. Gen. Chem., 2016, vol. 86, no. 7, p. 1624. doi 10.1134/S107036321607015X 10. Pevzner, L.M., Russ. J. Gen. Chem., 2016, vol. 86, no. 8, p. 1864. doi 10.1134/S1070363216080156 11. Keough, P.T. and Grayson, M., J. Org. Chem., 1962, vol. 27, no. 5, p. 1817. doi 10.1021/jo01052a082 12. Gowda, D.C., Mohesh, B., and Gowda, S., Indian J. Chem B, 2001, vol. 40, no. 1, p. 75. 13. Grigorash, R.V., Lyalin, V.V., Alekseeva, L.A., and Yagupol’skii, L.M., Chem. Heterocycl. Compd., 1977, vol. 13, no. 12, p. 1280. doi 10.1007/BF00469881
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 87 No. 3 2017
