Solvent-free synthesis of quaternary alpha-hydroxy alpha-trifluoromethyl diazenes: the key step of a nucleophilic formylation strategy

Green Chemistry PAPER Cite this: Green Chem., 2016, 18, 4042 Received 11th February 2016, Accepted 18th April 2016 DOI: 10.1039/c6gc00408c www.rsc.org/greenchem Solvent-free synthesis of quaternary α-hydroxy α-trifluoromethyl diazenes: the key step of a nucleophilic formylation strategy† Esteban Matador, a David Monge,* a Rosario Fernández* a and José M. Lassaletta* b An efficient, scalable and operationally simple one-pot, 2-step strategy for the nucleophilic formylation of trifluoromethyl ketones is presented. The key step is an unprecedented diaza-carbonyl-ene reaction of formaldehyde tert-butyl hydrazone and trifluoromethyl ketones under solvent-free conditions. This reaction proved to be very fast, clean and high-yielding, affording densely functionalised α-hydroxy α-trifluoromethyl diazenes. The ensuing diazene-to-aldehyde transformation, avoiding protection/deprotection reactions and chromatographic purifications, and subsequent derivatizations in a one-pot fashion provide a direct entry to a variety of useful trifluoromethylated building blocks. Introduction Organofluorine compounds have attracted the interest of academia and industry from the viewpoint of their fruitful applications in pharmaceutical (approximately 20% of the market, including some of the most selling drugs) 1 and materials sciences. 2 Therefore, the development of synthetic methods for accessing new fluorinated compounds is an increasingly important issue in modern organic chemistry. 3 In recent years, trifluoromethylated compounds have received considerable attention due to their unique chemical, physical and biological properties. 4 In particular, trifluoromethyl carbinols and derivatives are present in a plethora of biologically active compounds. The selected examples shown in Scheme 1 include aminoalcohols I 5 and II, 6 α-hydroxy amides III and IV, 7 the marketed anti-HIV agent efavirenz V, 8 matrix metalloproteinase (MMP) peptidomimetic inhibitors such as VI, 9 and the neurokinin 1 receptor antagonist CJ-17493 VII. 10 Accordingly, two general approaches to the synthesis of such compounds have been developed. The first one is the nucleophilic trifluoromethylation of carbonyl compounds, 11 and the second strategy is based on the addition of carbon nucleophiles to trifluoromethyl ketones. 12 The retrosynthetic analysis of the selected targets suggests the use of α-hydroxy Scheme 1 Retrosynthetic analysis of biologically relevant functionalized trifluoromethyl carbinols and derivatives. †Electronic supplementary information (ESI) available: Detailed experimental procedures, characterization data and copies of NMR spectra. See DOI: 10.1039/ c6gc00408c a Departamento de Química Orgánica, Universidad de Sevilla and Centro de Innovación en Química Avanzada (ORFEO-CINQA), C/ Prof. García González, 1, 41012 Sevilla, Spain. E-mail: [email protected], ff[email protected] b Instituto de Investigaciones Químicas (CSIC-US) and Centro de Innovación en Química Avanzada (ORFEO-CINQA), Avda. Américo Vespucio, 49, 41092 Sevilla, Spain. E-mail: [email protected] 4042 |Green Chem.,2016,18,4042–4050 This journal is © The Royal Society of Chemistry 2016 Open Access Article. Published on 18 April 2016. Downloaded on 6/1/2022 1:10:33 PM. This article is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported Licence. View Article Online View Journal | View Issue α-trifluoromethyl aldehydes as common building blocks by virtue of the versatility of the formyl group. 13 These intermediates might be conveniently built by employing trifluoromethyl ketones as electrophiles for the attack of d 1 reagents (Scheme 1). This approach, however, has been scarcely investigated. 14 Our research team has intensively explored the nucleophilic reactivity of formaldehyde N,N-dialkylhydrazones (FDAHs), 15 which behave as formyl anion equivalents (d 1 synthons) in their reactions with a variety of electrophiles, including carbonyl compounds. 16 In particular, pyrrolidine derivatives spontaneously add to trifluoromethyl ketones affording α-hydroxy α-trifluoromethyl hydrazones (Scheme 2, top). 16a,b This reaction, combined with hydroxyl protection and hydrazone cleavage by ozone, constitutes a convenient entry (3-steps) to both racemic or enantiomerically enriched α-alkoxy-α-trifluoromethyl aldehydes and derivatives thereof. More recently, we have exploited the superior reactivity of formaldehyde tert-butyl hydrazone (FTBH) with carbonyl compounds (α-keto esters, 17 isatins 18 and α-keto phosphonates) 19 as the key step of a formylation strategy. In the seeking of greener methodologies, herein we present a more concise one-pot, 2-step approach to α-hydroxy α-trifluoromethyl aldehydes employing FTBH (Scheme 2, bottom) based on the positive effect that solvent-free conditions have on the reaction rate of the first step, allowing subsequent transformations in a one-pot fashion. Results and discussion Preliminary experiments were performed with commercially available 2,2,2-trifluoroacetophenone (1a) as the model substrate. For comparative purposes, the reactivity of different simple formaldehyde hydrazones was analysed (Scheme 3). The simplest formaldehyde dimethylhydrazone 2was very slowly added to the carbonyl compound (employed in a 2-fold excess) to afford the corresponding α-hydroxy α-trifluoromethyl-hydrazone 5a in a modest 55% yield (after 20 days in CH 2 Cl 2 at room temperature) along with small amounts of the hydrazo transfer by-product 6a. It was observed that the reaction rates are highly dependent on the reaction media (32% after 3 days (neat); 10 and 40% yields after 5 days in CH 3 CN and H 2 O, respectively). The anisyl-substituted derivative 3 showed no reactivity, while formaldehyde N-tert-butyl hydrazone 4, employed in a 1.5-fold excess, readily added to 1a in CH 2 Cl 2 with complete C-selectivity, affording the desired α-hydroxy α-trifluoromethyl diazene 7a in 83% yield after 9 hours (entry 1, Table 1). Further optimization experiments were conducted in different solvents and the E-factor‡ 20 was Scheme 2 Nucleophilic formylations of trifluoromethyl ketones employing formaldehyde hydrazones as d 1 reagents. Scheme 3 Preliminary reactivity experiments. Table 1 Optimization of the reaction of 1a and 4 a Entry Solvent T7a :8a b Yield c (%) E-factor d (g g −1 ) 1CH 2 Cl 2 9 h 10 : 0 83 12.08 2 CHCl 3 7 h 8 : 2 70 16.31 3n-Hexane 31 h 10 : 0 80 6.49 4 Toluene 31 h 10 : 0 81 8.27 5Et 2 O 31 h 10 : 0 74 7.63 6CH 3 CN 6 h 10 : 0 90 6.69 7H 2 O 45 min 10 : 0 90 1.31 8—20 min 10 : 0 >99 0.18 9 e —10 min 10 : 0 >99 0.18 10 e,f —20 min 10 : 0 >99 0.0004 a Reactions performed on a 0.5 mmol scale (0.5 M) using 1a (0.5 mmol) and 4(0.75 mmol). b Determined by 1 H NMR. c Isolated yield after column chromatography (entries 1–6), after L–L extraction (entry 7), after removing the excess of hydrazone 4under reduced pressure (entries 8 and 9). d E-factor = Waste (g)/7a (g); without considering potential recycling of 4and solvents. e Reactions performed on a 6 mmol scale. f 1:11a/4molar ratio. ‡The E-factor is defined as the mass ratio of the waste to the desired product. For E-factors including solvents after chromatographic purifications or L–L extractions see the ESI.† Green Chemistry Paper This journal is © The Royal Society of Chemistry 2016 Green Chem.,2016,18,4042–4050 | 4043 Open Access Article. Published on 18 April 2016. Downloaded on 6/1/2022 1:10:33 PM. This article is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported Licence. View Article Online used as a descriptor of the environmental impact. Using CHCl 3 instead of CH 2 Cl 2 provided full conversions in shorter reaction times, albeit yielding an 8 : 2 mixture of azocompound 7a and its tautomeric hydrazone form 8a, presumably induced by acid traces in the reaction media (entry 2). In general, lower reactivities were observed in hydrocarbons and ethereal solvents (entries 3–5), while conducting the reaction in a polar aprotic solvent such as CH 3 CN had a positive effect, affording 7a in a higher yield (E-factor = 6.68, entry 6) and shorter reaction time (6 hours). Next, we decided to explore the possibility of performing the reaction “on water”, exploiting the rate acceleration previously observed for FDAHs in reactions with α-keto esters. 16e When pure water was used as the reaction medium, full conversion was observed in only 45 minutes, giving 7a in 90% isolated yield after simple L–L extraction with Et 2 O, with an E-factor of 1.31§(entry 7). Finally, we were delighted that the reaction carried out in the absence of a solvent¶ 21,22 proceeded cleanly and at a high rate, reaching completion in only 20 minutes. These conditions efficiently afforded analytically pure 7a in quantitative yield after removing the excess of hydrazone 4under reduced pressure and without the need for chromatographic purification (E-factor = 0.18, entry 8). Finally, scaling-up from 0.5 to 6 mmol made the reaction proceed even faster, reaching completion in 10 minutes (entry 9). Under these optimal conditions, the reaction was performed with a 1 : 1 ratio of ketone 1a and reagent 4to afford 7a without any further elaboration and, therefore, in a very high overall efficiency, quantified by an E-factor close to zero (entry 10). The scope of the reaction was then explored with a range of trifluoromethyl ketones 1, including aromatic (1a–1d), heteroaromatic (1e), aliphatic derivatives (1f–1i) and the densely functionalized ethyl 3,3,3-trifluoropyruvate (1j), as outlined in Scheme 4. The collected data indicate that the reaction is highly efficient (5–300 minutes of reaction time) for all types of substrates, proceeding at room temperature to afford α-hydroxy α-trifluoromethyl diazenes 7in quantitative yields (>99%) and high purity (>95% by NMR), without the need for chromatographic purification. The reaction rates correlate with stereoelectronic properties of the substituents, with the more reactive 1d (R = 4-F-C 6 H 4 ), 1h (R = Me), and 1j (R = CO 2 Et) reaching completion in less than 10 minutes. The solid ketone 1c, bearing an electron-rich aryl group, appeared as the most challenging substrate but, although requiring extra time for complete solubilisation, also afforded a satisfactory result. The mild and simple reaction conditions (room temperature, no need of oxygen and/or moisture exclusion) offer a practical way to scale-up the production (see pictures in the ESI†), as illustrated by a 10 gram (36 mmol) synthesis of 7a. Moreover, the simplicity of the solvent-free methodology allowed the development of some transformations of diazenes 7into useful building blocks in a one-pot fashion. For example, applying an acidcatalysed isomerization reaction, α-hydroxy α-trifluoromethyl hydrazones 8 23 were obtained in high yields (Scheme 5). To validate the announced formylation strategy, the subsequent one-pot diazene-to-aldehyde transformation from 7 Scheme 4 Synthesis of diazenes 7. Scheme 5 Synthesis of α-hydroxy α-trifluoromethyl hydrazones. §Water amounts are normally not included in the E-factor; even though additional amounts of organic solvents are required in the subsequent L–L extractions. ¶Solvent-free methodologies (ref. 21) are among the most promising strategies towards waste prevention and environmental protection, which also lead to milder conditions, very high volumetric productivity, increased safety and cost reduction (ref. 22). Paper Green Chemistry 4044 |Green Chem.,2016,18,4042–4050 This journal is © The Royal Society of Chemistry 2016 Open Access Article. Published on 18 April 2016. Downloaded on 6/1/2022 1:10:33 PM. This article is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported Licence. View Article Online was easily performed (Scheme 6). Thus, upon completion of the addition step, a simple treatment with HCl in a biphasic H 2 O/Et 2 OorH 2 O/MTBE medium∥afforded the desired α-hydroxy α-trifluoromethyl aldehydes 9in good yields with a high degree of purity (>95% estimated by 1 H NMR, see the ESI†). Remarkably, the tert-butyl hydrazine was recovered (92–96%) as its hydrochloride salt and reused for the synthesis of 4, thus minimizing waste production in the formylation procedure. 20c Sensitive aldehydes 9were directly used in subsequent reductive aminations or condensations with hydroxylamine to yield valuable trifluoromethylated β-aminoalcohols 10 and α-hydroxy aldoximes 11 in satisfactory overall yields for the three-step transformations. To again demonstrate the preparative utility of this methodology, the synthesis of 10a and 11a was performed on an 18 mmol scale without compromising the chemical yield. Finally, the efficiency and simplicity of the present methodology are highlighted with 3-step protocols outlined in Scheme 7 for the synthesis of representative trifluoromethylated β-aminoalcohol hydrochloride 10a-HCl and α-hydroxy acids 12a and 12g in good overall yields, without the need for further chromatographic purifications of these products. These α-hydroxy α-trifluoromethyl carboxylic acids 12 are valuable building blocks for target oriented synthesis, as illustrated with their transformation into amide III, 7a,b and the formal synthesis of several biologically active α-hydroxy α-trifluoromethyl amides (Scheme 8). 24 Experimental Spectra were recorded at 300 or 500 MHz ( 1 H NMR); 75.5 or 125 MHz ( 13 C NMR); and 470.6 MHz ( 19 F NMR) with the solvent peak used as the internal reference (7.26 and 77.0 ppm for 1 H and 13 C respectively). Column chromatography was performed on silica gel (Merck Kieselgel 60). Analytical TLC was performed on aluminum backed plates (1.5 × 5 cm) pre-coated (0.25 mm) with silica gel (Merck, Silica Gel 60 F254). Compounds were visualized by exposure to UV light or by dipping the plates in solutions of KMnO 4 , vanillin or phosphomolybdic acid stains followed by heating. Melting points were recorded in a metal block and are uncorrected. Unless otherwise noted, analytical grade solvents and commercially available reagents were used without further purification. Formaldehyde hydraScheme 7 Chromatography-free synthesis of β-aminoalcohol hydrochloride 10a-HCl and α-hydroxy acids 12a and 12g. Scheme 8 Synthesis of amide III and the formal synthesis of rac-VIII and ZM156854. Scheme 6 Synthesis of β-aminoalcohols 10 and α-hydroxy aldoximes 11. Overall yield for the three-step sequence. ∥For products 9of relatively low volatility, Et 2 O can be replaced by less hazardous MTBE, as illustrated for 9c (see crude 1 H-NMR in the ESI†). Green Chemistry Paper This journal is © The Royal Society of Chemistry 2016 Green Chem.,2016,18,4042–4050 | 4045 Open Access Article. Published on 18 April 2016. Downloaded on 6/1/2022 1:10:33 PM. This article is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported Licence. View Article Online zones 2–4 25 and not commercially available trifluoromethyl ketones 1 26 were synthesized according to literature procedures. General procedure for the synthesis of α-hydroxy α-trifluoromethyl diazenes 7 Freshly distilled formaldehyde tert-butylhydrazone 4(0.75 mL, 6 mmol) was added to trifluoromethyl ketone 1(6 mmol) at room temperature. The mixture was stirred for the time specified (Scheme 4, TLC monitoring) to afford pure diazene 7. 3-(tert-Butyldiazenyl)-1,1,1-trifluoro-2-phenylpropan-2-ol (7a). Following the general procedure starting from 1a (0.84 mL, 6 mmol), diazene 7a was obtained as a pale yellow oil (1.64 g, 99%). 1 H NMR (300 MHz, CDCl 3 ): δ7.63–7.54 (m, 2H), 7.46–7.30 (m, 3H), 4.52 (s, 1H), 4.43 (d, 1H, J= 14.2 Hz), 4.36 (dd, 1H, J= 0.4, 14.2 Hz), 1.12 (s, 9H). 13 C NMR (75.5 MHz, CDCl 3 ): δ136.3, 128.6, 128.3, 126.4, 124.8 (q, J C,F = 285.6 Hz), 76.6 (q, J C,F = 28.7 Hz), 69.9, 68.7, 26.4. 19 F NMR (470.6 MHz, CDCl 3 ): δ−78.01 (s, CF 3 ). HRMS (ESI): m/zcalcd for C 13 H 18 F 3 N 2 O[M+H] + 275.1366, found 275.1356. 3-(tert-Butyldiazenyl)-1,1,1-trifluoro-2-(p-tolyl)propan-2-ol (7b). Following the general procedure starting from 1b (0.91 mL, 6 mmol), diazene 7b was obtained as a pale yellow oil (1.73 g, 99%). 1 H NMR (300 MHz, CDCl 3 ): δ7.46 (d, 2H, J= 8.2 Hz), 7.19 (d, 2H, J= 8.2 Hz), 4.52 (s, 1H), 4.41 (d, 1H, J= 14.2 Hz), 4.32 (d, 1H, J= 14.2 Hz), 2.35 (s, 3H), 1.13 (s, 9H). 13 C NMR (75.5 MHz, CDCl 3 ): δ138.5, 133.3, 129.0, 126.3, 124.8 (q, J C,F = 285.6 Hz), 76.5 (q, J C,F = 28.8 Hz), 70.0, 68.8, 26.5, 21.1. 19 F NMR (470.6 MHz, CDCl 3 ): δ−78.07 (s, CF 3 ). HRMS (ESI): m/zcalcd for C 14 H 20 F 3 N 2 O[M+H] + 289.1522, found 289.1521. 3-(tert-Butyldiazenyl)-2-(2,4-dimethoxyphenyl)-1,1,1-trifluoropropan-2-ol (7c). Following the general procedure starting from 1c (1.47 g, 6 mmol), diazene 7c was obtained as a pale yellow oil (2.01 g, 99%). 1 H NMR (300 MHz, CDCl 3 ): δ7.43 (d, 1H, J= 8.6 Hz), 6.53–6.48 (m, 2H), 5.68 (d, 1H), 4.51 (d, 1H, J= 14.3 Hz), 4.38 (d, 1H, J= 14.3 Hz), 3.85 (s, 3H), 3.81 (s, 3H), 1.11 (s, 9H). 13 C NMR (75.5 MHz, CDCl 3 ): δ161.1, 158.7, 131.2, 125.3 (q, J C,F = 287.3), 115.8, 104.8, 99.4, 77.5 (q, J C,F = 28.3 Hz), 70.0, 68.1, 55.8, 55.3, 26.5. 19 F NMR (470.6 MHz, CDCl 3 ): δ−79.29 (s, CF 3 ). HRMS (ESI): m/zcalcd for C 15 H 21 F 3 N 2 O 3 Na [M + Na] + 357.1396, found 357.1388. 3-(tert-Butyldiazenyl)-1,1,1-trifluoro-2-(4-fluorophenyl)propan2-ol (7d). Following the general procedure starting from 1d (0.85 mL, 6 mmol), diazene 7d was obtained as a pale yellow oil (1.75 g, 99%). 1 H NMR (300 MHz, CDCl 3 ): δ7.62–7.51 (m, 2H), 7.13–7.02 (m, 2H), 4.41 (d, 1H, J= 14.1 Hz), 4.35 (d, 1H, J= 14.1 Hz), 1.12 (s, 9H). 13 C NMR (75.5 MHz, CDCl 3 ): δ162.8 (d, J C,F = 247.7 Hz), 132.1 (d, J C,F = 3.1 Hz), 128.5 (dd, J C,F = 8.2, 1.1 Hz), 124.6 (q, J C,F = 286.0 Hz), 115.2 (d, J= 21.5 Hz), 76.3 (q, J C,F = 28.6 Hz), 69.7, 68.9, 26.4. 19 F NMR (470.6 MHz, CDCl 3 ): δ−78.32 (s, CF 3 ), [(−113.35)–(−113.44) m, 1F]. HRMS (ESI): m/zcalcd for C 13 H 17 F 4 N 2 O[M+H] + 293.1272, found 293.1261. 3-(tert-Butyldiazenyl)-1,1,1-trifluoro-2-(thiophen-2-yl)propan2-ol (7e). Following the general procedure starting from 1e (0.76 mL, 6 mmol), diazene 7e was obtained as a pale yellow oil (1.68 g, 99%). 1 H NMR (300 MHz, CDCl 3 ): δ7.33 (dd, 1H, J= 1.17, 5.13 Hz), 7.13–7.07 (m, 1H), 7.01 (dd, 1H, J= 3.82, 5.09 Hz), 4.82 (s, 1H), 4.40 (d, 1H, J= 14.3 Hz), 4.35 (d, 1H, J= 14.3 Hz), 1.13 (s, 9H). 13 C NMR (75.5 MHz, CDCl 3 ): δ140.2, 127.1, 126.3, 125.8, 124.1 (q, J C,F = 285.8 Hz), 70.0 (q, J C,F = 28.5 Hz), 68.9, 26.4. 19 F NMR (470.6 MHz, CDCl 3 ): δ−79.25 (s, CF 3 ). HRMS (ESI): m/zcalcd for C 11 H 16 F 3 N 2 OS [M + H] + 281.0930, found 281.0920. 2-Benzyl-3-(tert-butyldiazenyl)-1,1,1-trifluoropropan-2-ol (7f). Following the general procedure starting from 1f (0.91 mL, 6 mmol), diazene 7f was obtained as a pale yellow oil (1.73 g, 99%). 1 H NMR (300 MHz, CDCl 3 ): δ7.38–7.27 (m, 5H), 3.92 (d, 1H, J= 14.4 Hz), 3.71 (dd, 1H, J= 0.4, 14.4 Hz), 3.29 (d, 1H, J= 14.2 Hz), 3.00 (d, 1H, J= 14.2 Hz), 1.17 (s, 9H). 13 C NMR (75.5 MHz, CDCl 3 ): δ134.1, 131.2, 128.3, 127.3, 125.9 (q, J C,F = 297.2 Hz), 75.4 (q, J C,F = 27.0 Hz), 68.5, 68.3, 38.5, 26.4. 19 F NMR (470.6 MHz, CDCl 3 ): δ−78.64 (s, CF 3 ). HRMS (ESI): m/z calcd for C 14 H 20 F 3 N 2 O[M+H] + 289.1522, found 289.1512. 2-[(tert-Butyldiazenyl)methyl]-1,1,1-trifluoro-4-phenylbutan2-ol (7g). Following the general procedure starting from 1g (1.01 mL, 6 mmol), diazene 7g was obtained as a pale yellow oil (1.81 g, 99%). 1 H NMR (300 MHz, CDCl 3 ): δ7.35–7.17 (m, 5H), 4.03 (d, 1H, J= 14.4 Hz), 3.97 (d, 1H, J= 14.4 Hz), 2.97–2.73 (m, 2H), 2.25–1.99 (m, 2H), 1.23 (s, 9H). 13 C NMR (75.5 MHz, CDCl 3 ): δ141.2, 128.7, 128.3, 126.2, 126.0 (q, J C,F = 286.8), 77.2, 75.1 (q, J C,F = 27.8 Hz), 68.7, 35.3, 28.9, 26.6. 19 F NMR (470.6 MHz, CDCl 3 ): δ−78.95 (s, CF 3 ). HRMS (ESI): m/zcalcd for C 15 H 22 F 3 N 2 O[M+H] + 303.1679, found 303.1679. 3-(tert-Butyldiazenyl)-1,1,1-trifluoro-2-methylpropan-2-ol (7h). Following the general procedure starting from 1h (0.52 mL, 6 mmol), diazene 7h was obtained as a pale yellow oil (1.27 g, 99%). 1 H NMR (300 MHz, CD 2 Cl 2 ): δ3.93 (d, 1H, J= 13.7 Hz), 3.81 (d, 1H, J= 13.7 Hz), 1.44 (s, 3H), 1.18 (s, 9H). 13 C NMR (125 MHz, CD 2 Cl 2 ): δ125.9 (q, J C,F = 284.3 Hz), 73.4 (q, J C,F = 28.5 Hz), 70.7, 68.3, 26.3, 20.0 (d, J C,F = 1.0 Hz). 19 F NMR (470.6 MHz, CDCl 3 ): δ−81.14 (s, CF 3 ). HRMS (ESI): m/zcalcd for C 8 H 15 F 3 N 2 O[M+H] + 213.1209, found 213.1206. 2-[(tert-Butyldiazenyl)methyl]-1,1,1-trifluorononan-2-ol (7i). Following the general procedure starting from 1i (1.14 mL, 6 mmol), diazene 7i was obtained as a pale yellow oil (1.78 g, 99%). 1 H NMR (300 MHz, CDCl 3 ): δ3.95 (d, 1H, J= 14.2 Hz), 3.89 (d, 1H, J= 14.2 Hz), 3.69 (s, 1H), 1.89–1.68 (m, 2H), 1.63–1.38 (m, 2H), 1.37–1.23 (m, 8H), 1.21 (s, 9H), 0.88 (t, 3H, J= 7.0 Hz). 13 C NMR (75.5 MHz, CDCl 3 ): δ126.0 (q, J C,F = 286.7 Hz), 75.3 (q, J C,F = 27.7 Hz), 68.7, 68.5, 33.3, 31.7, 29.9, 29.0, 26.5, 22.6, 22.4, 14.0. 19 F NMR (470.6 MHz, CDCl 3 ): δ−78.98 (s, CF 3 ). HRMS (ESI): m/zcalcd for C 14 H 28 F 3 N 2 O[M+H] + 297.2148, found 297.2145. Ethyl 2-[(tert-butyldiazenyl)methyl]-3,3,3-trifluoro-2-hydroxypropanoate (7j). Following the general procedure starting from 1j (0.77 mL, 6 mmol), diazene 7j was obtained as a colorless oil (1.62 g, 99%). 1 H NMR (300 MHz, CDCl 3 ): δ4.40 (d, 1H, J= 13.9 Hz), 4.38 (q, 1H, J= 7.1 Hz), 4.37 (q, 1H, J= 7.1 Hz), 4.03 (d, 1H, J= 13.9 Hz), 1.34 (t, 3H, J= 7.15 Hz), 1.17 (s, 9H). 13 C NMR (75.5 MHz, CDCl 3 ): δ168.6, 122.9 (q, J C,F = 286.2 Hz), 76.7 (q, J C,F = 29.2 Hz), 68.5, 68.0, 63.8, 26.7, 14.0. 19 F NMR Paper Green Chemistry 4046 |Green Chem.,2016,18,4042–4050 This journal is © The Royal Society of Chemistry 2016 Open Access Article. Published on 18 April 2016. Downloaded on 6/1/2022 1:10:33 PM. This article is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported Licence. View Article Online (470.6 MHz, CDCl 3 ): δ−77.49 (s, CF 3 ). HRMS (ESI): m/zcalcd for C 10 H 17 F 3 N 2 O 3 Na [M + Na] + 293.1083, found 293.1081. General procedure for the ‘one-pot’synthesis of α-hydroxy α-trifluoromethyl hydrazones 8 Freshly distilled formaldehyde tert-butylhydrazone 4(0.13 mL, 1 mmol) was added to trifluoromethyl ketone 1(1 mmol) at room temperature. The mixture was stirred for the time specified (Scheme 4, TLC monitoring) to afford pure diazene 7. Subsequently, a solution of TFA (0.1 mmol) in CH 2 Cl 2 (10 mL) was added to a solution of diazene 7(1 mmol) in CH 2 Cl 2 (0.5 mL) at 0 °C. The mixture was allowed to warm to room temperature and stirred for 12 h. A saturated NaHCO 3 solution (15 mL) was added and the organic phase was separated. The remaining aqueous phase was extracted with Et 2 O (3 × 10 mL), and the combined organic layer was dried over anhydrous MgSO 4 , filtered and concentrated to afford pure α-hydroxy hydrazone 8. 3-[2-(tert-Butyl)hydrazono]-1,1,1-trifluoro-2-phenylpropan-2-ol (8a). Following the general procedure, α-hydroxy hydrazone 8a was obtained as a white solid (0.26 g, 95%); mp: 72–75 °C. 1 H NMR (300 MHz, CDCl 3 ): δ7.66–7.58 (m, 2H), 7.45–7.35 (m, 3H), 7.34 (s, 1H), 5.04 (s, 1H), 1.20 (s, 9H). 13 C NMR (75.5 MHz, CDCl 3 ): δ136.3, 132.7 (d, J C,F = 1.7 Hz), 128.6, 128.4 (d, J C,F = 0.6 Hz), 126.2 (d, J C,F = 1.7 Hz), 124.4 (q, J C,F = 286.2 Hz), 75.2 (q, J C,F = 29.2 Hz), 54.1, 28.3. 19 F NMR (470.6 MHz, CDCl 3 ): δ−78.18 (s, CF 3 ). HRMS (CI): m/zcalcd for C 13 H 17 F 3 N 2 O [M] + 274.1293, found 274.1289. 3-[2-(tert-Butyl)hydrazono]-1,1,1-trifluoro-2-(thiophen-2-yl)- propan-2-ol (8e). Following the general procedure, α-hydroxy hydrazone 8e was obtained as a yellow oil (0.27 g, 96%). 1 H NMR (300 MHz, CDCl 3 ): δ7.34 (dd, J= 0.8, 5.1 Hz, 1H), 7.20 (s, 1H), 7.18 (d, J= 3.6 Hz, 1H), 7.04 (dd, J= 3.9, 5.1 Hz, 1H), 5.23 (s, 1H), 1.20 (s, 9H). 13 C NMR (75.5 MHz, CDCl 3 ): δ140.2, 131.5 (d, J C,F = 1.1 Hz), 127.2, 126.0, 125.3 (d, J C,F = 1.7 Hz), 123.9 (q, J C,F = 286.1 Hz), 74.8 (q, J C,F = 30.8 Hz), 54.2, 28.3. 19 F NMR (470.6 MHz, CDCl 3 ): δ−79.30 (s, CF 3 ). HRMS (ESI): m/zcalcd for C 11 H 16 F 3 N 2 OS [M + H] + 281.0930, found 281.0920. 2-Benzyl-3-[2-(tert-butyl)hydrazono]-1,1,1-trifluoropropan-2-ol (8f). Following the general procedure, α-hydroxy hydrazone 8f was obtained as a white solid (0.28 g, 96%); mp: 62–64 °C. 1 H NMR (300 MHz, CDCl 3 ): δ7.25–7.16 (m, 5H), 6.88 (s, 1H), 4.30 (s, 1H), 3.21 (d, 1H, J= 14.2 Hz), 3.02 (d, 1H, J= 14.2 Hz), 0.96 (s, 9H). 13 C NMR (75.5 MHz, CDCl 3 ): δ134.0, 132.4 (d, J C,F = 0.7 Hz), 130.7, 128.0, 126.9, 77.2, 75.2 (q, J C,F = 28.0 Hz), 53.9, 38.7, 28.0. 19 F NMR (470.6 MHz, CDCl 3 ): δ−78.95 (s, CF 3 ). HRMS (ESI): m/zcalcd for C 14 H 20 F 3 N 2 O[M+H] + 289.1522, found 289.1511. General procedure for the one-pot synthesis of α-hydroxy α-trifluoromethyl aldehydes 9 Freshly distilled formaldehyde tert-butylhydrazone 4(0.75 mL, 6 mmol) was added to trifluoromethyl ketone 1(6 mmol) at room temperature. The mixture was stirred for the time specified (Scheme 4, TLC monitoring) to afford pure diazene 7. Subsequently, aq. HCl (30 mL, 6 M) was added to a solution of diazene 7(6 mmol) in Et 2 O (55 mL) at 0 °C. The mixture was allowed to warm to room temperature and stirred until consumption of the starting material (TLC monitoring, approx. 6 h). The organic phase was separated and the aqueous phase was extracted with Et 2 O (2 × 30 mL). The combined organic layers were dried over anhydrous MgSO 4 , filtered and the solvent was removed under reduced pressure (35 mmHg, 5 °C) to afford α-hydroxy aldehyde 9(purity > 95% estimated by 1 H-NMR). This material was used in subsequent transformations without further purification. 9c was synthesized employing MTBE as the solvent, which was removed under reduced pressure (15 mmHg, 15 °C). General procedure for the synthesis of β-aminoalcohols 10 p-Methoxyphenylaniline (0.73 g, 6 mmol) was added to a solution of crude aldehyde 9(6 mmol) in TFE (15 mL). The mixture was stirred at 30 °C for 20 minutes. NaBH 4 (0.28 g, 7.2 mmol) was then added and the reaction was stirred vigorously until hydrogen evolution ceased (approx. 30 min). The mixture was filtered through a Celite pad, concentrated and the residue was purified by flash chromatography (pentane/ CH 2 Cl 2 )toafford products 10. 1,1,1-Trifluoro-3-[(4-methoxyphenyl)amino]-2-phenylpropan2-ol (10a). Following the general procedure, β-aminoalcohol 10a was obtained as a brown solid (1.31 g, 70%); mp: 53–55 °C. 1 H NMR (300 MHz, CDCl 3 ): δ7.69–7.59 (m, 2H), 7.50–7.39 (m, 3H), 6.83–6.74 (m, 2H), 6.72–6.64 (m, 2H), 4.25 (s, 1H), 3.94 (d, 1H, J= 13.8 Hz), 3.75 (s, 3H), 3.61 (dd, 1H, J= 13.8, 0.4 Hz), 3.10 (s, 1H). 13 C NMR (75.5 MHz, CDCl 3 ): δ153.9, 141.2, 136.5, 128.9, 128.5, 126.3, 125.4 (q, J C,F = 285.4 Hz), 116.6, 114.8, 74.8 (q, J C,F = 27.6 Hz), 55.6, 51.5. 19 F NMR (470.6 MHz, CDCl 3 ): δ−78.28 (s, CF 3 ). HRMS (ESI): m/zcalcd for C 16 H 17 F 3 NO 2 [M + H] + 312.1206, found 312.1195. 2-(2,4-Dimethoxyphenyl)-1,1,1-trifluoro-3-[(4-methoxyphenyl)- amino]propan-2-ol (10c). Following the general procedure, β-aminoalcohol 10c was obtained as a brown oil (1.22 g, 55%). 1 H NMR (300 MHz, CDCl 3 ): δ7.43–7.34 (m, 1H), 6.83–6.72 (m, 2H), 6.71–6.60 (m, 2H), 6.59–6.50 (m, 2H), 5.88 (s, 1H), 3.89 (s, 3H), 3.83 (d, 1H, J= 13.4 Hz), 3.82 (s, 3H), 3.77 (d, 1H, J= 13.4 Hz), 3.75 (s, 3H). 13 C NMR (75.5 MHz, CDCl 3 ): δ161.3, 159.4, 152.7, 142.1, 130.8, 125.5 (q, J C,F = 287.8 Hz), 115.1, 114.7, 105.3, 99.8, 77.3 (q, J C,F = 28.2 Hz), 55.9, 55.6, 55.2, 48.4 (d, J C,F = 1.3 Hz). 19 F NMR (470.6 MHz, CDCl 3 ): δ−79.84 (s, CF 3 ). HRMS (ESI): m/zcalcd for C 18 H 21 F 3 NO 4 [M + H] + 302.1417, found 372.1408. 1,1,1-Trifluoro-3-[(4-methoxyphenyl)amino]-2-(thiophen-2-yl)- propan-2-ol (10e). Following the general procedure, β-aminoalcohol 10e was obtained as a brown solid (1.24 g, 65%); mp: 41–43 °C. 1 H NMR (500 MHz, CDCl 3 ): δ7.38 (dd, 1H, J= 5.1, 1.2 Hz), 7.18 (d, 1H, J= 3.3 Hz), 7.07 (dd, 1H, J= 5.1, 3.6 Hz), 6.81–6.72 (m, 2H), 6.72–6.64 (m, 2H), 3.87 (d, 1H, J= 13.5 Hz), 3.75 (s, 3H), 3.60 (d, 1H, J= 13.5 Hz). 13 C NMR (75.5 MHz, CDCl 3 ): δ154.0, 140.9, 140.7, 127.4, 126.6, 125.6, 124.7 (q, J C,F = 1.3 Hz), 123.8 (q, J C,F = 285.7 Hz), 116.7, 114.9, 74.8 (q, J C,F = 29.9 Hz), 55.7, 52.2. 19 F NMR (470.6 MHz, CDCl 3 ): Green Chemistry Paper This journal is © The Royal Society of Chemistry 2016 Green Chem.,2016,18,4042–4050 | 4047 Open Access Article. Published on 18 April 2016. Downloaded on 6/1/2022 1:10:33 PM. This article is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported Licence. View Article Online δ−79.39 (s, CF 3 ). HRMS (ESI): m/zcalcd for C 14 H 15 F 3 NO 2 S [M + H] + 318.0770, found 318.0759. 2-Benzyl-1,1,1-trifluoro-3-[(4-methoxyphenyl)amino]propan2-ol (10f). Following the general procedure, β-aminoalcohol 10f was obtained as a brown oil (1.17 g, 60%). 1 H NMR (500 MHz, CDCl 3 ): δ7.39–7.30 (m, 5H), 6.70–6.63 (m, 2H), 6.37–6.30 (m, 2H), 3.71 (s, 3H), 3.44 (d, 1H, J= 14.1 Hz), 3.27 (d, 1H, J= 13.9 Hz), 3.18 (dd, 1H, J= 14.1, 0.6 Hz), 2.87 (d, 1H, J= 13.9 Hz). 13 C NMR (75.5 MHz, CDCl 3 ): δ153.5, 141.6, 134.2, 132.1, 128.0, 127.3, 126.5 (q, J C,F = 287.2 Hz), 116.0, 114.7, 73.2 (q, J C,F = 26.3 Hz), 55.6, 48.2, 38.0 (d, J= 1.4 Hz). 19 F NMR (470.6 MHz, CDCl 3 ): δ−80.21 (s, CF 3 ). HRMS (ESI): m/zcalcd for C 15 H 20 F 3 NO 2 [M + H] + 326.1338, found 326.1350. Ethyl 3,3,3-trifluoro-2-hydroxy-2-{[(4-methoxyphenyl)amino]- methyl}propanoate (10j). Following the general procedure, β-aminoalcohol 10j was obtained as a brown oil (1.23 g, 67%). 1 H NMR (300 MHz, CDCl 3 ): δ6.81–6.74 (m, 2H), 6.70–6.63 (m, 2H), 4.33 (dq, 1H, J= 10.7, 7.2 Hz), 4.21 (dq, 1H, J= 10.7, 7.2 Hz), 3.84 (d, 1H, J= 13.2 Hz), 3.75 (s, 3H), 3.46 (d, 1H, J= 13.2 Hz), 1.27 (t, 3H, J= 7.2 Hz). 13 C NMR (75.5 MHz, CDCl 3 ): δ168.8 (d, J C,F = 1.1 Hz), 153.1, 141.1, 122.9 (q, J C,F = 288.3 Hz), 115.8, 114.7, 77.8 (q, J C,F = 28.6 Hz), 64.0, 55.7, 46.5 (d, J C,F = 1.2 Hz), 13.8. 19 F NMR (470.6 MHz, CDCl 3 ): δ−77.26 (s, CF 3 ). HRMS (ESI): m/zcalcd for C 13 H 17 F 3 NO 4 [M + H] + 308.1104, found 308.1102. General procedure for the synthesis of α-hydroxy aldoximes 11 Hydroxylamine hydrochloride (0.50 g, 7.2 mmol) and sodium hydroxide (0.29 g, 7.2 mmol) were sequentially added to a solution of crude aldehyde 9(6 mmol) in MeOH (45 mL). The mixture was stirred at room temperature overnight. The mixture was then diluted with water (15 mL) and the organic phase was extracted with CH 2 Cl 2 (2 × 30 mL) and Et 2 O(2× 30 mL). The combined organic layer was dried (MgSO 4 ), filtered and concentrated. The product was purified by flash chromatography (3 : 1 cyclohexane/AcOEt) to afford α-hydroxy aldoximes 11. 3,3,3-Trifluoro-2-hydroxy-2-phenylpropanal oxime (11a). Following the general procedure, α-hydroxy aldoxime 11a was obtained as a white solid (0.76 g, 58%); mp: 62–64 °C. 1 H NMR (300 MHz, CDCl 3 ): δ7.97 (d, J= 0.3 Hz, 1H), 7.66–7.56 (m, 3H), 7.47–7.36 (m, 3H), 4.21 (s, 1H). 13 C NMR (75.5 MHz, CDCl 3 ): δ147.3, 134.7, 129.3, 128.7, 126.3 (d, J C,F = 0.6 Hz), 123.9 (q, J C,F = 288.0 Hz), 75.4 (q, J C,F = 29.6 Hz). 19 F NMR (470.6 MHz, CDCl 3 ): δ−78.24 (s, CF 3 ). HRMS (ESI): m/zcalcd for C 9 H 8 F 3 NO 2 Na [M + Na] + 242.0399, found 242.0390. 3,3,3-Trifluoro-2-hydroxy-2-(p-tolyl)propanal oxime (11b). Following the general procedure, α-hydroxy aldoxime 11b was obtained as a white solid (1.08 g, 77%); mp: 66–68 °C. 1 H NMR (500 MHz, CDCl 3 ): δ7.95 (s, 1H), 7.85 (s, 1H), 7.48 (d, 2H, J= 8.2 Hz), 7.24 (d, 2H, J= 8.2 Hz), 4.23 (s, 1H), 2.38 (s, 3H). 13 C NMR (75.5 MHz, CDCl 3 ): δ147.5, 139.3, 131.7, 129.2, 126.2, 124.1 (q, J C,F = 285.2 Hz), 75.5 (q, J C,F = 29.9 Hz), 21.0. 19 F NMR (470.6 MHz, CDCl 3 ): δ−79.27 (s, CF 3 ). HRMS (ESI): m/zcalcd for C 10 H 10 F 3 NO 2 Na [M + Na] + 256.0556, found 256.0548. 2-(2,4-Dimethoxyphenyl)-3,3,3-trifluoro-2-hydroxypropanal oxime (11c). Following the general procedure, α-hydroxy aldoxime 11c was obtained as a white solid (1.46 g, 87%); mp = 150–152 °C. 1 H NMR (300 MHz, CDCl 3 ): δ10.55 (s, 1H), 8.12 (s, 1H), 7.63 (d, 1H, J= 8.5 Hz), 6.66–6.56 (m, 2H), 3.88 (s, 3H), 3.82 (s, 3H), 3.81 (s, 1H). 13 C NMR (75.5 MHz, CDCl 3 ): δ162.0, 158.5, 147.6, 130.1, 124.9 (q, J C,F = 286.3), 116.6, 105.2, 99.3, 75.4 (q, J C,F = 30.3 Hz), 55.5, 54.9. 19 F NMR (470.6 MHz, CDCl 3 ): δ−78.59 (s, CF 3 ). HRMS (ESI): m/zcalcd for C 11 H 13 F 3 NO 4 [M + H] + 280.0791, found 280.0785. 3,3,3-Trifluoro-2-hydroxy-2-(thiophen-2-yl)propanal oxime (11e). Following the general procedure, α-hydroxy aldoxime 11e was obtained as a colorless oil (1.01 g, 75%). 1 H NMR (500 MHz, CDCl 3 ): δ7.84 (s, 1H), 7.71 (s, 1H), 7.39 (dd, 1H, J= 5.1, 1.2 Hz), 7.21–7.18 (m, 1H), 7.07 (dd, 1H, J= 5.1, 3.7 Hz), 4.47 (s, 1H). 13 C NMR (75.5 MHz, CDCl 3 ): δ146.2, 137.9, 127.4, 127.0, 126.3 (d, J C,F = 0.5 Hz), 123.4 (q, J C,F = 286.1 Hz), 75.0 (q, J C,F = 31.6 Hz). 19 F NMR (470.6 MHz, CDCl 3 ): δ−78.30 (s, CF 3 ). HRMS (ESI): m/zcalcd for C 7 H 6 F 3 NO 2 Na [M + Na] + 247.9964, found 247.9959. 2-Benzyl-3,3,3-trifluoro-2-hydroxypropanal oxime (11f). Following the general procedure, α-hydroxy aldoxime 11f was obtained as a colorless oil (0.84 g, 60%). 1 H NMR (500 MHz, CDCl 3 ): δ7.50 (s, 1H), 7.43 (s, 1H), 7.33–7.23 (m, 3H), 7.22–7.16 (m, 2H), 3.55 (s, 1H), 3.22 (d, 1H, J= 14.0 Hz), 3.09 (d, 1H, J= 14.0 Hz). 13 C NMR (75.5 MHz, CDCl 3 ): δ146.4, 132.8, 130.8, 128.3, 127.4, 124.4 (q, J C,F = 286.4 Hz), 75.3 (q, J C,F = 28.5 Hz), 38.6. 19 F NMR (470.6 MHz, CDCl 3 ): δ−79.85 (s, CF 3 ). HRMS (ESI): m/zcalcd for C 10 H 10 F 3 NO 2 Na [M + Na] + 256.0056, found 256.0552. Synthesis of β-aminoalcohol hydrochloride 10a-HCl p-Methoxyphenylaniline (0.37 g, 3 mmol) was added to a solution of crude aldehyde 9a (3 mmol) in TFE (7.5 mL). The mixture was stirred at 30 °C for 20 minutes. After this time, NaBH 4 (0.14 g, 3.6 mmol) was added and the reaction was stirred vigorously until the end of hydrogen evolution (approximately 30 minutes). The solvent was removed under reduced pressure and the crude was dissolved in CH 2 Cl 2 (5 mL). The mixture was filtered through silica and Celite pad (height: 1 cm), and washed with a mixture of pentane/CH 2 Cl 2 (2/1, 10 mL). Solvents were removed under reduced pressure and the product was dissolved in dry Et 2 O (15 mL). HCl (1 M in dioxane, 3.8 mL) was added and the mixture was stirred at room temperature until the appearance of a white solid (approximately 1 h). The solid was filtered and washed with Et 2 O (2 mL) to afford the pure amine hydrochloride 10a-HCl (0.72 g, 83%). 1 H NMR (300 MHz, DMSO-d 6 ): δ7.69–7.60 (m, 2H), 7.44–7.33 (m, 3H), 7.02 (d, 2H, J= 8.8 Hz), 6.81 (d, 2H, J= 8.8 Hz), 6.70 (br s, 2H), 4.01 (d, 1H, J= 13.4 Hz), 3.77 (d, 1H, J= 13.4 Hz), 3.68 (s, 3H). 13 C NMR (75.5 MHz, CDCl 3 ): δ156.9, 134.9, 133.4, 128.9, 128.2, 127.1, 125.0 (q, J C,F = 285.3 Hz), 121.8, 114.5, 75.2 (q, J C,F = 27.8 Hz), 55.5, 53.0. 19 F NMR (470.6 MHz, CDCl 3 ): δ−77.07 (s, CF 3 ). HRMS (ESI): m/zcalcd for C 16 H 17 F 3 NO 2+ [M + ] 312.1206, found 312.1198. Paper Green Chemistry 4048 |Green Chem.,2016,18,4042–4050 This journal is © The Royal Society of Chemistry 2016 Open Access Article. Published on 18 April 2016. Downloaded on 6/1/2022 1:10:33 PM. This article is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported Licence. View Article Online General procedure for the synthesis of α-hydroxy acids 12 A solution of NaClO 2 (20 mmol) and KH 2 PO 4 (18 mmol) in H 2 O (70 mL) was added dropwise to a solution of crude aldehyde 9(6 mmol) in t BuOH (70 mL) and 2-methyl-but-2-ene (60 mL) at 0 °C. The mixture was allowed to warm to room temperature and stirred for 16 h. The solvents were removed under reduced pressure and the residue was treated with 2 M NaOH and extracted with Et 2 O. The aqueous layer was acidified to pH 1 (2 M HCl) and extracted with EtOAc. The combined organic layer was dried (MgSO 4 ), filtered and the solvent was removed under reduced pressure to afford pure α-hydroxy acid. 3,3,3-Trifluoro-2-hydroxy-2-phenylpropanoic acid (12a). Following the general procedure, 12a was obtained as a white solid (0.98 g, 74%). Characterization data are in agreement with those reported in the literature. 27 2-Hydroxy-4-phenyl-2-(trifluoromethyl)butanoic acid (12g). Following the general procedure, α-hydroxy acid 12g was obtained as a white solid (0.89 g, 60%); mp = 83–85 °C. 1 H NMR (500 MHz, acetone-d 6 ): δ8.57 (s, 1H), 7.35–7.07 (m, 5H), 2.89 (dt, J= 4.6, 12.8 Hz, 1H), 2.54 (dt, J= 4.6, 12.8 Hz, 1H), 2.34 (dt, J= 4.6, 12.8 Hz, 1H), 2.15 (dt, J= 4.6, 12.8 Hz). 13 C NMR (125 MHz, acetone-d 6 ): δ169.6, 140.8, 128.5, 128.3, 126.1, 124.4 (c,J C,F = 286.7 Hz), 77.3 (c,J C,F = 28.2 Hz), 34.2. 19 F NMR (470.6 MHz, acetone-d 6 ): δ−78.80 (s, CF 3 ). HRMS (ESI): m/zcalcd for C 11 H 11 F 3 O 3 [M + Na] + 271.0845, found 271.0849. Synthesis of α-hydroxy αtrifluoromethyl amide III Oxalyl chloride (0.2 mL, 2.16 mmol) and a drop of DMF were subsequently added to a stirred solution of the acid 12a (264 mg, 1.2 mmol) in dichloromethane (10 mL) at 0 °C. The reaction mixture was stirred for 3 h, slowly warming to rt, then NH 3 (28% in water, 40 mL) was added. The resulting solution was stirred at rt for 6 h, diluted with water (40 mL), and extracted with ethyl acetate (3 × 100 mL). The combined organic phase was washed with brine (100 mL), dried over MgSO 4 , filtered and concentrated under reduced pressure. The product was purified by flash chromatography (1 : 1 cyclohexane/AcOEt) to afford α-hydroxy amide III as a white solid (0.2 g, 76%). Characterization data are in agreement with those reported in the literature. 27 Conclusions In summary, the high diaza–ene reactivity of formaldehyde tert-butyl hydrazone (FTBH) with trifluoromethyl ketones under solvent-free conditions afforded analytically pure α-hydroxy α-trifluoromethyl diazenes in a quantitative way. From these products, operationally simple diazene-to-aldehyde transformations and subsequent derivatizations in a ‘one-pot’ fashion provide a simple and environmentally friendly entry to trifluoromethylated β-aminoalcohols, α-hydroxy aldoximes and α-hydroxy acids. Acknowledgements This work was supported by the Ministerio de Economía y Competitividad of Spain (CTQ2013-48164-C2-1-P, CTQ201348164-C2-2-P, and predoctoral fellowship to E. M.), European FEDER funds and the Junta de Andalucía (Grant 2012/FQM 1078). D. M. acknowledges Universidad de Sevilla for a postdoctoral contract. Notes and references 1 A. M. Thayer, Chem. Eng. News, 2006, 84, 15. 2(a) T. 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