Difluoromethylation of parent azoles

Accepted Manuscript Title: Difluoromethylation of parent azoles Author: Kirill I. Petko. PII: DOI: Reference:

S0022-1139(17)30409-8 https://doi.org/10.1016/j.jfluchem.2017.11.003 FLUOR 9069

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Received date: Revised date: Accepted date:

20-9-2017 11-11-2017 12-11-2017

Please cite this article as: Kirill I.Petko., Difluoromethylation of parent azoles, Journal of Fluorine Chemistry https://doi.org/10.1016/j.jfluchem.2017.11.003 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Difluoromethylation of parent azoles Kirill I. Petko. Institute of Organic Chemistry, National Academy of Sciences of Ukraine, 5 Murmans’ka Str., Kyiv, Ukraine, 02094. E-mail: [email protected]. Tel +380505949797

N N

N H

sulfolane

aq. KOH (70%), CF2ClH 18-crown-6, ether

N N 1 CHF2

N H

yield 35%

N N + N N CHF N 2 N CHF2 2 8:1 3 overall yield 80%

N N N N H

ClCF2COONa, K2CO3

N

ClCF2COONa, K2CO3 sulfolane

N N 4 N CHF2

"neat"

yield 45%

F2 HC

N N N N

5

yield 17%

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N H

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1) NaH 2) CF2ClH

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Graphical abstract

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Highlights

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 The methods of N-difluoromethylation of parent azoles were developed  The original methodologies would be useful in the cases of low-nucleophilic substrates or highly volatile final products  The difluoromethylation of all parent azoles (from 1 to 4 N atoms) is described now

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Abstract: The method for difluoromethylation of parent azoles, namely pyrrole, 1,2,3triazole, 1,2,4-triazole and tetrazole was developed. Difluorometylation of pyrrole and 1,2,3-

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triazole was performed by action of chlorodifluoromethane. Sodium chlorodifluoroacetate was used as a difluoromethylation agent for 1,2,4-triazole and tetrazole. N-Difluoromethyl derivatives of pyrrole, 1,2,3- and 1,2,4- triazoles were synthesized in moderate to good yields in

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a multigram scale. N-difluoromethyltetrazole was obtained in a low yield.

Keywords: pyrrole, 1,2,3-triazole, 1,2,4-triazole, tetrazole, difluoromethylation _____________________________________________________________________________ 1. Introduction Difluoromethylation of organic compounds attracts considerable attention in modern fluoroorganic chemistry [1]. The introduction of CF2H group can affect membrane permeability,

binding affinity and lipophilicity [2]. Heterocycles with fluorinated substituents are representatives of major structures in medicinal and agricultural chemistry [3]. For example, known herbicide Sulfentrazone and drug candidate Neuropeptide Y antagonist [4] have N-CHF2 moiety in the heterocycle ring. Numerous reagents were used in the difluoromethylation reactions [5]. Among them, chlorodifluorometane (Freon-22) is very cheap and readily available reagent, which was widely used for difluoromethylation of phenols, thiols and azoles in a multikilogram scale. The ozone

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depletion potential of Freon-22 is low (0.05), and it’s using is not banned in many countries. A lot of research was devoted to the introduction of CHF2 group to N-atom of azoles [3]. However, the difluoromethylation of parent azoles was studied insufficiently till now. Although

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these simple compounds could be the key building blocks for the construction of more complex molecules. Difluoromethylation of unsubstituted imidazole and benzimidazole with Freon-22 was first described by Poludnenko et al. in 1984 [6]; Levterov et al. improved this method [7]. Difluoromethylation of pyrazole was performed in our laboratory [8]. 1-Difluoromethyl-1,2,4-

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triazole was also obtained for the first time in our laboratory, albeit in a low yield as a by-product

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in the synthesis of 1-trifluoromethyl-1,2,4-triazole from the correspondent bromodifluoromethyl

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derivative [9]. N-Difluoromethyl derinatives of pyrrole, 1,2,3-triazole and tetrazole were not yet synthesized.

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The goal of the present work was to develop the preparative method for difluoromethylation

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of parent azoles, namely pyrrole, 1,2,3-triazole, 1,2,4-triazole and tetrazole.

2. Results and discussion

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Difluoromethylation of azoles by Freon-22 are usually carried out in aqueous alkali medium where N-anions of azoles are formed. Pyrrole almost does not have acidic properties (pKa = 23)

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so it almost does not form the salt under these conditions. Only negligible amounts of Ndifluoromethylpyrrole were detected by GC when the interaction of pyrrole with Freon-22 in 50% aq. alkali was studied [10]. The N-difluoromethylation of pyrrole derivatives with electron-

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withdrawing substituents in the similar conditions have been described [11]. Pyrrole in anhydrous medium reacts with NaH to form highly reactive sodium pyrrolide. To

prevent side reactions under the interaction of sodium pyrrolide with Freon-22, considerable dilution of the reaction mixture is necessary. We performed the difluoromethylation of pyrrole using the high-boiling sulfolane as a solvent to isolate the volatile product – Ndifluoromethylpyrrole (1) by distillation off. Yield 50% was detected judging by 19F NMR spectra in the reaction mixture. Pure target product was isolated in 35% yield (Scheme 1). Ndifluoromethylpyrrole (1) is hydrolytically stable liquid with b.p. 89-90 °C, very sensitive to

traces of acids. It should be noted, that compound 1 has to be stored in the cold and the presence of triethylamine as a stabilizer. Unlike pyrrole, 1,2,3-triazole readily forms triazolide in an alkali medium, but the reactivity of this salt is very low. The 19F NMR monitoring of difluoromethylation of 1,2,3-triazole with Freon-22 in 50% aq. KOH-dioxane mixture showed very low reaction rate. We carried out this reaction in aqueous-ether alkali medium using phase-transfer catalysis. Diethyl ether was used as a solvent to facilitate the isolation of the volatile target products 2 and 3. The reaction rate was

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unsatisfactory when 30% and even 50% aqueous solution of KOH was used. The reaction proceeded at a satisfactory rate with an exothermic effect when we used a 70% suspension of powdered KOH with water as alkali agent. The reaction mixture was slurry that required

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vigorous stirring. The mixture of 1-difluoromethyl-1,2,3-triazole (2) and 2-difluoromethyl-1,2,3triazole (3) in the ratio of 8:1 (on the evidence of 19F NMR spectra) was obtained in 80% overall yield. The isomers 2 and 3 were separated by fractional distillation to give the low boiling

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triazole 3 (b.p. 92-93 °C) and the high-boiling one 2 (b.p. = 145-147 °C).

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sulfolane

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aq. KOH (70%), CF2ClH 18-crown-6, ether

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N N N H

ClCF2COONa, K2CO3

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N N

A

N H

A

N H

N

1) NaH 2) CF2ClH

N N N N H

"neat"

ClCF2COONa, K2CO3 sulfolane

Scheme 1 Difluoromethylation of parent azoles

N 1 CHF2

yield 35%

N N + N N CHF N 2 N CHF2 2 8:1 3 overall yield 80% N N 4 N CHF2

N N N F2 HC N

5

yield 45%

yield 17%

Further we carried out difluoromethylation of 1,2,4-triazole with Freon-22 in an aqueousalkali medium. 19F NMR analysis of obtaining reaction mixture showed the formation of Ndifluoromethyl derivative of this triazole, but we failed to isolate it after water workup. It turned out that triazole 4 gave stable hydrate, azeotropically distilled with water. We were also not successful to isolate desired compound 4 by extraction with any organic solvents from concentrated water solutions. Difluoromethylation in anhydrous sulfolane using NaH as an alkali

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agent was unsuccessful too because low reactive sodium 1,2,4-triazolide did not interact with Freon-22 without excess of alkali.

To overcome these difficulties we worked out the method of “neat” difluoromethylation

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using sodium chlorodifluoroacetate instead of Freon-22 as a difluoromethylating agent and

potassium carbonate as a base. Thus, thoroughly powdered mixture of three solid reagents was gradually heated to 220 ˚C with simultaneous distillation of formed volatile products. Fractionation of obtained distillate gave monohydrate of 1-difluoromethyl-1,2,4-triazole (4) (bp

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95-98 ˚C) and anhydrous 4 (bp 127-129 ˚C) in the overall yield ~45%. Monohydrate can be dried

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by azeotropic distillation with benzene to give anhydrous triazole 4 although this is accompanied

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by a significant loss of the product. This approach allowed getting exactly only one isomer (4) from two possible.

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This methodology can be used for difluoromethylation of other azoles if their Ndifluoromethyl derivatives are volatile enough compounds. For example, imidazole was

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difluoromethylated in such a way in 48% yield, although Freon-22 approach gave Ndifluoromethylimidazole in 75% yield [7].

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We faced the problems when tried to synthesize difluoromethyl derivative of the last parent azole – tetrazole. Extremely low reactive sodium tetrazolide was absolutely inert to the

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action of Freon-22 both in the water-alkali medium and in anhydrous sulfolane. The application of the above described “neat” methodology with chlorodifluoroacetate led to the explosion at 150 ˚C in a bath. We succeeded to obtain one of two possible isomers - 2difluoromethyltetrazole (5) when parent tetrazole was reacted with sodium chlorodifluoroacetate

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in the presence of potassium carbonate in sulfolane containing 0.5-1% of water at 120-130 ˚C. We obtained moist compound 5 in a low yield after distillation from the reaction mixture under vacuum. It can be dried by common drying agents like MgSO4. Anhydrous 5 is a stable at r.t. liquid with boiling point near 110-115 °C, but it is very undesirable to distill it, as this can lead to an explosion. The structure of the compound 5 was unambiguously determined by 1H-13C and 1

H-15N HMBC NMR spectroscopy.

3. Conclusion As a conclusion of the work carried out, it can be stated that N-difluoromethyl derivatives of all parent azoles are described and fully characterized. We developed the original methodologies that can be useful in difluoromethylation reactions, especially in the cases of formation of volatile or water-soluble products.

4. Experimental

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Melting points were measured in open capillary and are given uncorrected. 1H NMRspectra (400 MHz) and 19F NMR-spectra (376,5 MHz) were recorded on a Varian-Mercury-400 spectrometer using TMS and CCl3F as internal standards. 13C NMR-spectra and two-dimensional H-13C and 1H-15N HMBC NMR spectra were recorded on a Bruker Avance DXR-500

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spectrometer (125 MHz for 13C and 40.5 MHz for 15N). Mass spectra were recorded on an Agilent 1100 LS/MSD SL instrument with Rapid Resolution HT Cartrige 4.6×30 mm, 1.8

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4.1. 1-Difluoromethylpyrrole (1)

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micron Zorbax SB-C18 column.

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To a suspension of NaH (5g of 60% suspension in mineral oil, 0.125 mol) in sulfolane (100 mL) the solution of pyrrole (6.7g, 0.1 mol) in sulfolane (100 mL) was added dropwise at

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30-35 ○C, and volume precipitate was formed. The reaction mixture was stirred vigorously for 30 min at this temperature. Then the reactor was placed in an ice-cooled bath, and the intensive stream of CF2ClH was bubbled throw the reaction mixture with vigorous stirring for 20 min. An

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exothermic reaction occurred, the temperature rose to 50-55 °C; the precipitate disappeared and the reaction mixture turned dark. The crude desired product (1) was distilled off under reduced

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pressure (150 Torr), gradually heating the reaction mixture up to 120-130 ˚C and collecting the product (1) in an ice-cooled receiver. Repeated distillation at atmospheric pressure gave 1difluoromethylpyrrole (1) as a colorless liquid. Yield 4.13 g (35%), bp 89-90 ºC (760 Torr). 1H NMR (400 MHz, CDCl3) δ: 6.32-6.34

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(m, 2H), 6.92 (t, 1H, CHF2, J = 60 Hz), 6.95-6.97 (m, 2H). 19F NMR (376 MHz, CDCl3) δ: –88.8 (d, 2F, J = 60 Hz). {1H}13C NMR (125 MHz, CDCl3) δ: 110.0 (t. J = 246 Hz), 111.3, 117.4, MS (Electrospray) ES+ m/z (%): 118 (100%) [M + H]+. Anal. Calcd for C5H5F2N: C, 51.29; H, 4.30; N, 11.96; Found: C, 51.55; H, 4.42; N, 11.77.

4.2. 1-Difluoromethyl-1,2,3-triazole (2) and 2-difluoromethyl-1,2,3-triazole (3)

To a stirred solution of 1,2,3-triazole (69 g, 1 mol) in diethyl ether (300 mL) 50 % aq KOH (180 g, 3 mol KOH and 180 mL water) and 2 g of 18-crown-6 were added. To obtained solution solid powdered KOH (240 g, 4 mol) was added to form a suspension. An excess of CF2ClH was bubbled throw the reaction mixture with vigorous stirring for 4h until gas absorption was observed. The presence of an effective reflux condenser is desirable to prevent the ether and product evaporation with a gas flow. Water (200 mL) was added to a mixture, organic layer was separated, aqueous layer was extracted with ether (100 mL), and combined

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ether extracts were dried over MgSO4. The ether extracts were separated by distillation with an efficient fractionating column. After ether was distilled off, two fractions were collected. The first fraction with bp = 92-93 ˚C (8.3 g, 7% yield) was 2-difluoromethyl-1,2,3-triazole (3), 4-5 g

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of mixture of isomers, and the second fraction with bp = 145-147 °C (80.0 g, 68% yield) was 1difluoromethyl-1,2,3-triazole (2).

1-Difluoromethyl-1,2,3-triazole (2) was obtained as a colourless liquid. Yield 80.0 g (68%), bp 145-147 ºC (760 Torr). 1H NMR (400 MHz, CDCl3) δ: 7.57 (t, 1H, CHF2, J = 60 Hz),

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7.79 (s, 1H), 7.96 (s, 1H). 19F NMR (376 MHz, CDCl3) δ: –95.8 (d, 2F, J = 60 Hz). {1H}13C

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NMR (125 MHz, CDCl3) δ: 109.7 (t. J = 246 Hz), 120.3, 134.8, MS (Electrospray) ES+ m/z (%):

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120 (100%) [M + H]+. Anal. Calcd for C3H3F2N3: C, 30.26; H, 2.54; N, 35.29; Found: C, 30.45; H, 2.42; N, 35.55.

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2-Difluoromethyl-1,2,3-triazole (3) was obtained as a colourless liquid. Yield 8.3 g (7%), bp 92-93 ºC (760 Torr). 1H NMR (400 MHz, CDCl3) δ: 7.37 (t, 1H, CHF2, J = 60 Hz), 7.83 (s,

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2H). 19F NMR (376 MHz, CDCl3) δ: –96.9 (d, 2F, J = 60 Hz). {1H}13C NMR (125 MHz, CDCl3) δ: 109.8 (t. J = 246 Hz), 136.4. MS (Electrospray) ES+ m/z (%): 120 (100%) [M + H]+. Anal.

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Calcd for C3H3F2N3: C, 30.26; H, 2.54; N, 35.29; Found: C, 30.33; H, 2.44; N, 35.42.

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4.3. 1-Difluoromethyl-1,2,4-triazole (4) 1,2,4-Triazole (76 g, 1.1 mol), ClCF2COONa (154 g, 1 mol) and calcined K2CO3 (140 g,

1 mol) were carefully mixed and powdered. This mass was placed in a round-bottomed flask, equipped with an effective condenser and an ice-cooled receiver. The reaction mixture was

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gradually heated up to 200-220 °C. Intensive evolution of gas (CO2) observed. All volatiles products were collected in an ice-cooled receiver. After gas evolution stopped, additional quantity of products was distilled from the residue under vacuum 100 Torr. The crude condensate was distilled to give three fractions. The first fraction (bp 97-98 °C; yield 15.0 g, 11%) was monohydrate of triazole 4; the second fraction, boiled at 100-125 ˚C (7-10 g) was a mixture of 4 with a little water; the last fraction (bp = 127-128 °C; yield 35.7 g, 30%) was anhydrous 1-difluoromethyl-1,2,4-triazole (4). Azeotropic dehydration of containing water

fractions with benzene (30 mL) gave additionally ~8 g of anhydrous 4. All spectral data for triazole 4 corresponded with those described in [9].

4.4. 2-Difluoromethyltetrazole (5) Tetrazole (7g, 0.1 mol), ClCF2COONa (15.4 g, 0.1 mol), calcined K2CO3 (14.0 g, 0.1 mol) and sulfolane (70 mL) were heated with stirring at 120-130 ˚C until gas (CO2) evolution stopped. All volatiles products were distilled off under reduced pressure (70 Torr) and at 100-

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120 ˚C in a bath and collected in an ice-cooled receiver to give the moist product 5 as a turbid liquid. This liquid was dried with MgSO4, and after filtration 2-difluoromethyltetrazole (5) of ~97% purity was obtained as a colourless liquid.

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Yield 1.83 g (17%), bp about 115 ºC, decomp. (760 Torr). 1H NMR (400 MHz, CDCl3) δ: 7.69 (t, 1H, CHF2, J = 60 Hz), 8.71 (s, 1H). 19F NMR (376 MHz, CDCl3) δ: –98.5 (d, 2F, J = 60 Hz). {1H}13C NMR (125 MHz, CDCl3) δ: 108.8 (t. J = 246 Hz), 153.4. MS (Electrospray) ES+ m/z (%): 120 (100%) [M + H]+. Anal. Calcd for C2H2F2N4: N, 46.66; Found: N, 46.48.

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CAUTION! Our attempts to distill anhydrous tetrazole 5 led to an explosion.

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5. Acknowledgment

We are grateful to ENAMINE Ltd. for financial support and the provision of necessary

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6. References

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reagents and special gratitude to Vitaliy V. Polovinko for the registration of the 1H-13C and 1H-

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