Communication pubs.acs.org/OPRD
Short and Safe Synthesis of Ethyl 3‑(Trifluoromethyl)pyrazine-2carboxylate Florencio Zaragoza* and Annabelle Gantenbein Lonza AG, Rottenstrasse 6, CH-3930 Visp, Switzerland S Supporting Information *
amines. For this reason, 2-hydroxyimino-4,4,4-trifluoro-3oxobutanoates do not readily undergo condensation with primary aliphatic amines. After testing numerous reaction conditions for the cyclocondensation of ethyl 2-hydroxyimino-4,4,4-trifluoro-3-oxobutanoate (3) with ethylenediamine, we found that this reaction is mediated by trialkyl phosphites (Scheme 3).5 The best way to prevent detrifluoroacetylation was the protonation of ethylenediamine with an excess of a carboxylic acid in pyridine or picoline as solvent. Although acetic acid could also be used (30−40% yield), for unknown reasons the highest yields were attained with benzoic acid. Byproducts of this synthesis were trimethyl phosphate (bp 197 °C) and a small amount of methyl benzoate (bp 200 °C). Bulb-to-bulb distillation of the crude product did not separate these byproducts from pyrazine 2 (bp 140 °C, 10 mbar), but a more careful fractional distillation on a larger scale should. In small-scale laboratory preparations, most trimethyl phosphate could be removed by washing with brine, and methyl benzoate was removed by chromatography on silica gel. When attempting to prepare oxime 3 as reported,6 a roughly equimolar mixture of oxime 3 and its hydrate 4a was obtained (Scheme 4). The hydrate could be dehydrated by treatment with CaCl2 in CH2Cl2, but this did not significantly improve the yield of pyrazine 2. Oxime 3 could also be prepared by treating ketoester 1 with an excess of neat butyl nitrite in the presence of catalytic amounts of an acid. Thereby, a mixture of 3 and a hemiacetal 4b was obtained. This mixture could be used directly for the pyrazine synthesis, after evaporating the excess of alkyl nitrite (to prevent the consumption of ethylenediamine by reaction with the excess alkyl nitrite). When tert-butyl nitrite was used as nitrosating reagent, mostly the oxime 3 and almost no acetal was formed. Pure oxime 3, however, gave similar yields of pyrazine as the mixture 3 + 4b. A tentative proposal for the mechanism of this new pyrazine synthesis is sketched in Scheme 5. When trialkyl phosphites are added to oxime 3 in pyridine, an exothermic reaction occurs. One plausible product of this reaction could be a highly electrophilic oxazaphosphole 5.7 This intermediate may undergo amine-mediated detrifluoroacetylation less readily than openchain derivatives of trifluoroketone 1 and rather yield enamine 6 upon reaction with ethylenediamine. Cyclization and bromine-mediated dehydrogenation would account for the formation of pyrazine 2.
ABSTRACT: The treatment of ethyl 2-hydroxyimino4,4,4-trifluoro-3-oxobutanoate (3) with trialkyl phosphites, ethylenediamine, and an excess of a carboxylic acid in pyridine or picoline leads to the formation of an intermediate, which can be aromatized to a pyrazine by treatment with bromine or other oxidants. This synthesis can be performed either with the isolated oxime 3 or from ethyl 4,4,4-trifluoro-3-oxobutanoate (1) in a one-pot fashion, without any solvent change and without having to isolate any intermediates. KEYWORDS: pyrazines, organofluorine compounds, dehydrogenation, oximes, fungicides, acetoacetates
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yraziflumid (Scheme 1) is a new succinate dehydrogenase inhibiting fungicide developed by Nihon Nohyaku Ltd. in 2007.1 The substituted pyrazine required for its manufacture can be prepared in a number of ways, the most practical being those in Scheme 1. One reported synthesis of 3-(trifluoromethyl)pyrazine-2carboxylates starts from ethyl trifluoropyruvate, includes a palladium-catalyzed carbonylation, and requires the isolation of at least two intermediates.2 A shorter synthesis, also patented by Nihon Nohyaku Ltd.,3 consists in chlorinating ethyl 4,4,4trifluoro-3-oxobutanoate (1), and in treating the resulting chloride with sodium azide and ethylenediamine in the presence of palladium on charcoal. Sodium azide is difficult to handle safely on a large scale, and azide-based syntheses cannot be conducted in industrial multipurpose plants without expensive safety precautions. The main difficulty of condensing amines with alkyl 4,4,4trifluoro-3-oxobutanoates is the sensitivity of the latter toward bases. Treatment of 2-monohalogenated 4,4,4-trifluoro-3oxobutanoates with amines does not lead to alkylation of the amine or to imine formation, but to base-induced disproportionation into nonhalogenated ketoesters and 2,2-dihaloketoesters (Scheme 2). The latter are cleaved by amines to trifluoroacetamides and dihaloacetates.4 Moreover, 2-halogenated 4,4,4trifluoro-3-oxobutanoates often act as halogenating reagents (transfer of Hal+). For these reasons, 2-monohalogenated 4,4,4trifluoro-3-oxobutanoates only alkylate weakly basic nucleophiles (thiols, thioamides, amides, ureas, azide), and yields of these reactions are often low. 3-Ketoesters can be readily nitrosated to oximes by treatment with sodium nitrite or alkyl nitrites in the presence of acids. 2-Hydroxyimino-4,4,4-trifluoro-3-oxobutanoates, however, are strongly acidic and form salts when treated with aliphatic © XXXX American Chemical Society
Received: December 20, 2016
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DOI: 10.1021/acs.oprd.6b00429 Org. Process Res. Dev. XXXX, XXX, XXX−XXX
Organic Process Research & Development
Communication
Scheme 1. Published Syntheses of 3-(Trifluoromethyl)pyrazine-2-carboxylates2,3
Scheme 2. Main Products of the Reaction of Ethyl 2-Chloro4,4,4-trifluoro-3-oxobutanoate with Ethylenediamine
Scheme 4. Preparation of Oxime 3
After cooling to 0 °C, trimethyl phosphite (3.31 mL, 28.0 mmol, 1.4 equiv) was added, followed by the dropwise addition of the crude oxime. The oxime container was rinsed with 3-picoline (3.0 mL, 31 mmol, 1.5 equiv), and this solution was also added to the reaction mixture. After stirring at 0 °C for 0.5 h and at room temperature for 3.5 h, the mixture was heated to 70 °C for 0.5 h and then cooled to 0 °C. Bromine (2.56 mL, 50.0 mmol, 2.5 equiv) was then added dropwise within 5 min. The mixture was stirred at 0 °C for 0.5 h and then at room temperature for 1.5 h. The mixture was cooled to 0 °C and added to an ice-cold mixture of concentrated aqueous hydrochloric acid (67 mL, 0.70 mol, 35 equiv) and water (200 mL). After adding sodium bisulfite (3.12 g, 30.0 mmol, 1.5 equiv), the product was extracted with butyl acetate (3 × 50 mL), and the combined extracts were washed with brine (100 mL), with a solution of potassium carbonate (15 g, 0.11 mol) in water (100 mL), with brine (100 mL), dried (MgSO4), and concentrated under reduced pressure. The residue was purified by chromatography over silica gel (30 g; gradient elution with heptane/ethyl acetate). Pyrazine 2 was obtained as an oil (1.81 g, 40% yield, 99% pure by 1H NMR content determination with triisobutyl phosphate as internal standard). 1H NMR (CDCl3, 400 MHz) δ 8.85 (m, 1H), 8.81 (m, 1H), 4.52 (q, J = 7 Hz, 2H),
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EXPERIMENTAL SECTION Chemical shifts (δ) in NMR spectra are reported in ppm relative to Me4Si (δ = 0.00 ppm) or 1,4-difluorobenzene (19F; δ = −120.9 ppm). All reagents and starting materials were commercially available and used without further purification. Product 2 is a known compound and was identified by GC-MS and by comparison of its NMR spectra with those reported.3 One-Pot Procedure. Ethyl 3-(Trifluoromethyl)pyrazine-2carboxylate (2, CAS Registry 1253196-13-2). To ethyl 4,4,4trifluoro-3-oxobutanoate (1, 3.70 g, 20.1 mmol, 1.0 equiv) at 0 °C were added butyl nitrite (2.81 mL, 24.0 mmol, 1.2 equiv) and benzoic acid (366 mg, 3.00 mmol, 0.15 equiv), and the mixture was stirred at 0 °C for 2 h and then at room temperature for 24 h. Vacuum (10 mbar, 40 °C) was applied for 0.5 h, to remove the excess butyl nitrite. In a separate flask a mixture of benzoic acid (8.18 g, 67.0 mmol, 3.3 equiv), 3-picoline (38 mL, 0.39 mol, 19 equiv), and ethylenediamine (1.74 mL, 26.1 mmol, 1.3 equiv) was prepared. Upon addition of the amine, a precipitate formed (probably the salt of ethylenediamine and benzoic acid). This mixture could still be thoroughly stirred with a magnetic stirrer. Scheme 3
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DOI: 10.1021/acs.oprd.6b00429 Org. Process Res. Dev. XXXX, XXX, XXX−XXX
Organic Process Research & Development
Communication
Scheme 5. Possible Mechanism of the Formation of Pyrazine 2
1.44 (t, J = 7 Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ 163.7, 146.3, 145.3, 144.7, 141.6 (q, J = 37 Hz), 120.6 (q, J = 274 Hz), 63.2, 13.9; 19F NMR (CDCl3, 377 MHz) δ −66.2; DSC (4 K/min) dec onset 173 °C, dec energy −11 J/g. Ethyl 4,4,4-Trifluoro-2-(hydroxyimino)-3-oxobutanoate (3) and Ethyl 4,4,4-Trifluoro-3,3-dihydroxy-2-(hydroxyimino)butanoate (4a). To a solution of ethyl 4,4,4-trifluoro-3oxobutanoate (9.21 g, 50.0 mmol, 1.0 equiv) in acetic acid (30 mL, 0.5 mol, 10 equiv), cooled to 10−15 °C, a solution of sodium nitrite (4.52 g, 65.5 mmol, 1.3 equiv) in water (7.0 mL) was added dropwise within 10 min. After stirring at room temperature for 1.5 h, the mixture was diluted with ethyl acetate (100 mL), and while stirring and cooling, a cold solution of sodium hydroxide (16 g, 0.4 mol, 8 equiv) in water (200 mL) was added. Phases were separated, and NaHCO3 (1.0 g) was added to the aqueous phase. The aqueous phase was then extracted with ethyl acetate (2 × 50 mL), and the combined organic phases were dried (MgSO4) and concentrated under reduced pressure. Ethyl 4,4,4-trifluoro-2-(hydroxyimino)-3-oxobutanoate was obtained as an oil (9.60 g, 91% pure by 1H NMR with triisobutyl phosphate as internal standard; remainder: ethyl acetate; 82% yield), which slowly and partially solidified. According to the NMR spectra this oil consisted of an equimolar mixture of a hydrated (4a) and a nonhydrated oxime (3). 1H NMR (DMSO, 400 MHz) δ 14.66 (s, br, 0.4H), 12.04 (s, 0.4H), 7.82 (s, 0.76H), 4.34 (q, J = 7 Hz, 1H), 4.20 (q, J = 7 Hz, 1H), 1.25 (m, 3H); 13C NMR (DMSO, 100 MHz) δ 174.9 (q, J = 36 Hz), 161.7, 159.5, 149.6, 146.7, 122.4 (q, J = 288 Hz), 115.6 (q, J = 288 Hz), 91.0 (q, J = 36 Hz), 62.1, 13.7; 19F NMR (DMSO, 376.5 MHz) δ = −71.5 (s), −82.0 (s); DSC (4 K/min) dec onset 109 °C, dec energy −529 J/g.
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Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS Inspiring discussions with Christoph Sklorz, Erick M. Carreira, and Christoph Täschler are gratefully acknowledged. We also thank Eberhard Irle and Damian Venetz for the DSC measurements.
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(1) Oda, M.; Furuya, T.; Hasebe, M.; Kuroki, N. (Nihon Nohyaku Co., Ltd., Japan) PCT Int. Pat. Appl. WO 2007/072999 A1, 2007; Chem. Abstr. 2007, 705796. (2) Oda, M.; Matsuzaki, Y.; Morishita, Y. (Nihon Nohyaku Co., Ltd., Japan) PCT Int. Pat. Appl. WO 2010/055884 A1, 2010; Chem. Abstr. 2010, 628463. (3) Oda, M.; Morishita, Y. (Nihon Nohyaku Co., Ltd., Japan) PCT Int. Pat. Appl. WO 2010/122794 A1, 2010; Chem. Abstr. 2010, 1344136. (4) (a) Skryabina, Z. E.; Saloutin, V. I.; Pashkevich, K. I. Izv. Akad. Nauk SSSR, Ser. Khim. 1987, 7, 1560−1564; Chem. Abstr. 1988, 19, 472998. (b) Didenko, A. V.; Vorobiev, M. V.; Sevenard, D. V.; Sosnovskikh, V. Y. Chem. Heterocycl. Compd. (N. Y., NY, U. S.) 2015, 51, 259−268. (5) No reaction occurred using PPh3 instead of P(OR)3, and no pyrazine formation was observed using nonfluorinated methyl 2-hydroxyimino-3-oxobutanoate as a starting material. (6) Poss, M. A. (E. R. Squibb and Sons, Inc., USA) Eur. Pat. Appl. 488532 A1, 1992. (7) (a) Ganoub, N. A.; Abdou, W. M.; Shaddy, A. A. Phosphorus, Sulfur Silicon Relat. Elem. 1998, 132, 109−122. (b) Sidky, M. M.; Zayed, M. F.; El-Kateb, A. A.; Hennawy, I. T. Phosphorus Sulfur Relat. Elem. 1981, 9, 343−345. (c) Arbuzov, B. A.; Polezhaeva, N. A. Izv. Akad. Nauk, Ser. Khim. 1979, 445−447 A freshly prepared solution of oxime 3/4a (1.0 equiv) in pyridine-d5 to which trimethyl phosphite (1.2 equiv) had been added was analyzed by NMR. In addition to signals resulting from trimethyl phosphate, a new 31P resonance at −48.5 ppm was observed, which lies within the range of chemical shifts of phosphorus in oxazaphospholes such as 5 (−32 ppm to −55 ppm).
ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.oprd.6b00429. Copies of 1H, 13C, and 19F NMR spectra and a DSC of ethyl 3-(trifluoromethyl)pyrazine-2-carboxylate (2) (PDF)
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REFERENCES
AUTHOR INFORMATION
Corresponding Author
*E-mail: fl
[email protected]. ORCID
Florencio Zaragoza: 0000-0003-0969-2712 C
DOI: 10.1021/acs.oprd.6b00429 Org. Process Res. Dev. XXXX, XXX, XXX−XXX
