SYNLETT0936-52141437-2096 © Georg Thieme Verlag Stuttgart · New York 2015, 26, 1911–1912 1911 spotlight Syn lett S. Kyasa Spotlight Fluoroform (CHF3) ShivaKumar Kyasa ShivaKumar Kyasa was born in Telangana state, India, in 1978. After completing a B.Sc. (chemis- try, biology) and a M.Sc. (medicinal chemistry) Department of Chemistry, University of Nebraska-Lincoln, Lincoln, NE 68588-0304, USA from Osmania University, he worked at Dr. Red- [email protected] dy’s Laboratories, Ltd., Hyderabad, India. He is currently pursuing a Ph.D. in chemistry at the Published online: 11.06.2015 University of Nebraska–Lincoln, USA under the DOI: 10.1055/s-0034-1380924; Art ID: st-2015-v0519-v supervision of Prof. Patrick H. Dussault. His re- search focuses on C–O bond formation and syn- thesis of functionalized ethers using peroxide oxygen as an electrophile. Introduction with Lewis bases (most commonly catalytic fluoride) to af- ford pentavalent silicon species as nucleophiles has enabled Fluoroform, which is generated in ~20 kilotons/year trifluoromethylation of a number of electrophiles.4 The tri- as a side product of Teflon manufacture,1,2 is a low-boiling fluoromethyl group has great importance in medicinal, ag- (-82 °C), non-toxic and non-ozone-depleting gas.1,3 Howev- rochemical and materials science.5 This spotlight describes er, fluoroform is a potent greenhouse agent and there is recently reported methods for tri- and difluoromethylation great interest in methods for use of the gas as a synthetic based upon fluoroform. reagent. The direct use of trifluoromethyl anion as a nucleo- phile has been challenging due to facile α-elimination to CF3 CF2 + F fluoride and difluorocarbene (Scheme 1). The activation of Scheme 1 α-Elimination of trifluoromethyl anion to difluorocarbene Me3SiCF3 (often described as the Ruppert–Prakash reagent) and fluoride. Table 1 Use of Fluoroform (CHF3) KHMDS; PhMe or Et O (A) Prakash and co-workers have demonstrated successful depro- 2 R Si-CF CF3H + R3Si-Cl 3 3 Eq 1 tonation of CHF3 in ethereal solvents using KHMDS; the method was –78 °C to r.t. 42–80% applied to the synthesis of trialkyl trifluoromethyl silane, trifluoro- methyl fluoroborate and trifluoromethane sulfonic acid (Eq 1–3). CF3H KHMDS; THF 48% aq HF F3CBF3 K Eq 2 Nucleophilic trifluoromethylation was also demonstrated for 1,2- + F3C B(OR)3 K B(OR) –5 °C to r.t. R = Me, 53%; R = n-Bu, 66% additions to non-enolizable ketones and esters, chalcones, formate 3 esters, and displacement of benzyl bromide and methyl benzoate 30% H O ; H SO CF H KHMDS; THF [ ] 2 2 2 4 CF SO H was also demonstrated to proceed in moderate yields (illustrated for 3 CF3Sn 3 3 Eq 3 + 100% by 19F NMR –78 °C to r.t. 18% by non-enolizable carbonyl compounds, Eq 4). Attempts to apply sodi- S8 19 based on CF3Sn ated and lithiated bases were unsuccessful, revealing that potassium F NMR 1 O is essential for stable :CF3 generation. F3C OH CHF ; KHMDS; ether 3 Eq 4 –78 °C to r.t. This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. R 53–81% R OH SCF H (B) Dolbier and co-workers utilized CHF3 as a difluorocarbene OCF2H 2 source, preparing difluoromethyl ethers and thioethers from the Method A or B Method A or B corresponding phenols and thiophenols in the presence of KOH.6 62–90% The method, which involves biphasic conditions and can be con- 40–88% R R R ducted at atmospheric pressure, furnishes moderate to good yields Method-A: CHF3 (8 equiv); KOH (10 equiv); H2O–dioxane, 50 °C, 4 h of ethers. Method-B: CHF3 (14.2 equiv); KOH (15 equiv); H2O–MeCN, r.t., 2 h (C) Mikami and co-workers discovered that lithium enolates react B with CF H to achieve α-difluoromethylation via displacement of a Li Li 3 O LHMDS O O C–F bond; the method has been applied thus far only to lactone and 1 (2 equiv) 1 CF H (5 equiv) R R 3 CF H 7 X X 2 lactam enolates. THF X 2 1 R 0 °C, 30 min R2 R2R X = N-Ts or O B = N(SiMe3)2 © Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 1911–1912 1912 Syn lett S. Kyasa Spotlight (D) The Shibata group explored activation of fluoroform with organ- P4-t-Bu (1.5 equiv) P4-t-Bu ic super bases and demonstrated that P4-t-Bu can be used to gener- O CF3H, THF –30 °C, 2 h HO CF3 ate a stable CF anion at –30 °C in THF solvent; under these t-Bu 3 R1 R2 R1 R2 conditions, the anion was stable at up to –10 °C. The anion was ap- N N N R1 = aryl; R2 = H or alkenyl or aryl 52–92% plied to the trifluoromethylation of aromatic carbonyl compounds.5 N P N P N P N P4-t-Bu (1.5 equiv) N N N CF3H, THF N P N –10 °C, 2 h Ar SSAr Cl SCF3 N Ar = 4-ClC6H4 74% OH (E) Nucleophilic trifluoromethylation using CHF3 in the presence of O + P4-t-Bu has also been applied to reactions with acid chlorides, es- PhCOCl Eq 1 8 Ph CF3 Ph CF3 ters, carbon dioxide, and epoxides. Acid chlorides react to provide CF3 mixtures of trifluoromethyl ketones and 3° alcohols (Eq 1). In con- 0–81% trace – 90% trast, methyl benzoate reacted to give only phenyl trifluoromethyl Product ratio depends on acid chloride CF3H + P4-t-Bu equivalents and reaction time ketone (Eq 2). The trifluoromethyl anion reacts with carbon dioxide O to produce trifluoroacetic acid (Eq 3). Curiously, reaction with ter- PhCO2Me Eq 2 minal epoxides occurs at the more hindered carbon to give a 3° alco- 58% Ph CF3 hol (Eq 4). CO2 CF3 + P4-t-Bu CF3CO2H Eq 3 78% O OH Bn H3C Bn Eq 4 53% CF3 CuCl (F) Grushin and co-workers synthesized CuCF3 by cupration of fluo- DMF 1. CF H used for the 3a 3 CuCF roform using CuCl and t-BuOK in DMF. The reagent was applied to + [K(DMF)] [Cu(Ot-Bu)2] 3 trifluoromethylation – KCl ⋅ trifluoromethylation of aryl and heteroaryl halides,3b aryl boro- 2. Et3N 3HF >90% of various substrates 2 t-BuOK stabilizer nates,9 and α-halo ketones.10 (G) Potash and Rozen demonstrated the formation of trifluorometh- CuCF3, DMF R-SeCN R-SeCF3 yl thioethers through reaction of CuCF with alkyl, aryl, and het- 80–95% 3 R = Alk, Ar 2 eroaryl thiocyanates. Similarly, fluoroform-derived CuCF3 was applied to the synthesis of trifluoromethyl selenides from selenocy- anates.11 CHF3, t-BuOK, CuCl; DMF CuCF3, DMF R-SCN R-SCF3 50 to >95% R = Alk, Ar References (1) Prakash, G. K. S.; Jog, P. V.; Batamack, P. T. D.; Olah, G. A. Science (6) Thomson, C. S.; Dolbier, W. R. Jr J. Org. Chem. 2013, 78, 8904. 2012, 338, 1324. (7) Iida, T.; Hashimoto, R.; Aikawa, K.; Ito, S.; Mikami, K. Angew. This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. (2) Potash, S.; Rozen, S. J. Fluorine Chem. 2014, 168, 173. Chem. Int. Ed. 2012, 51, 9535. (3) (a) Zanardi, A.; Novikov, M. A.; Martin, E.; Benet-Buchholz, J.; (8) Zhang, Y.; Fujiu, M.; Serizawa, H.; Mikami, K. J. Fluorine Chem. Grushin, V. V. J. Am. Chem. Soc. 2011, 133, 20901. 2013, 156, 367. (b) Lishchynskyi, A.; Novikov, M. A.; Escudero-Adan, E. C.; (9) Novak, P.; Lishchynskyi, A.; Grushin, V. V. Angew. Chem. Int. Ed. Novak, P.; Grushin, V. V. J. Org. Chem. 2013, 78, 11126. 2012, 51, 7767. (4) (a) Surya Prakash, G. K.; Yudin, A. K. Chem. Rev. 1997, 97, 757. (10) Novak, P.; Lishchynskyi, A.; Grushin, V. V. J. Am. Chem. Soc. 2012, (b) Ma, J.-A.; Cahard, D. Chem. Rev. 2008, 108, PR1. 134, 16167. (5) Kawai, H.; Yuan, Z.; Tokunaga, E.; Shibata, N. Org. Biomol. Chem. (11) Potash, S.; Rozen, S. J. Org. Chem. 2014, 79, 11205. 2013, 11, 1446. © Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 1911–1912.