2-Substituted 4-(Trifluoromethyl)phenols by Directed ortho-Lithiation

Abstract

A broad variety of 2-substituted 4-(trifluoromethyl)phenols can be prepared in a large scale by o-lithiation and reaction with electrophiles in good to excellent yields. The key for the selectivity is the superior ortho-directing effect of the THP-protected hydroxy group (OTHP) as compared to the CF 3 -group.In the course of the development of new methods for the synthesis of intermediates for pharmaceuticals we became interested in 2-substituted 4-(trifluoromethyl)phenols. Although usually rather low, the reactivity of the trifluoromethyl group is greatly enhanced in p-trifluoromethylsubstituted phenols. 1 Traces of hydrogen fluoride or basic conditions induce polymerization. 2 Reaction with aqueous ammonia furnishes the corresponding nitrile. 3 When 4-(trifluoromethyl)phenol is heated, decomposition is observed at 130°C. 4 Due to conjugation, 1,6-elimination of hydrogen fluoride and formation of 4-(difluoromethylene)-2,5-cyclohexadiene-1-one seems to be the most prominent reaction. 5 In most cases this elimination is the reason why yields of substitution of 4-(trifluoromethyl)phenols are poor (< 50%). 6,7a,b,8a,b In other cases very toxic reagents (e.g. anhydrous hydrogen fluoride, 7c,d chloromethyl methyl ether 8g ) are used or the syntheses are tedious. [8][9][10] We became interested in the directed ortho-lithiation, a general method which offers the possibility of synthesising all of these derivatives of 4-(trifluoromethyl)phenol selectively, in good yields, short reaction times and convenience of handling. O-Tetrahydropyranyl (OTHP) is a very efficient ortho-directing group. 11 Due to the stabilising effect, the lithium complexes are stable enough to avoid very low reaction temperatures. 12For the preparation of the THP ether 1b we used a modified procedure. 13 By addition of 4-(trifluoromethyl)phenol (1a) to a solution of 3,4-dihyro-2H-pyran (DHP) and a catalytic amount of HCl/dioxane in dichloromethane the ether 1b was obtained in 90% yield (Scheme). Due to its distinct sensitivity to acid, the inverse sequence of addition of DHP to phenol 1a produced a considerable amount of insoluble solid. SchemeCompound 1b was lithiated with butyllithium at -70°C or with butyllithium/TMEDA at -10°C or -20°C and subsequently quenched with an electrophile ElX (Table). Although CF 3 is a strongly electron-withdrawing group, it has the least ortho-directing aptitude because of its bulkiness. Therefore, the deprotonation occurs at the ortho-position relative to the O-containing function. 8h,14 The protective group can be removed during workup by addition of HCl/dioxane (entry 1 and 5), an advantage as compared to the methoxymethyl group, which requires a supplementary deprotection step. 8h,15 Moreover, the methoxymethyl group has to be introduced using a highly toxic chloro compound. A very efficient and convenient method for the chlorination of 1b was the addition of hexachloroethane (entry 6). 16 For the synthesis of the boronic ester 2g an excess of triisopropyl borate and an inverse sequence of addition was important...

Tuning the Fluorescence Emission and HOMO‐LUMO Band Gap in Homoleptic Zinc(II) Complexes with N,O‐Bidentate (Imidazo[1,5‐a]pyrid‐3‐yl)phenols

“…as source of the sp 2 nitrogen of the desired heterocycle (Scheme ). 2‐Hydroxy‐5‐(trifluoromethyl)benzaldehyde is not commercially available and was prepared following literature methods. All (imidazo[1,5‐ a ]pyrid‐3‐yl)phenols were obtained in moderate to good yields and their purity was assessed by 1 H NMR, 13 C NMR and elemental analysis.…”

“…diameter). 2‐Hydroxy‐5‐(trifluoromethyl)benzaldehyde was prepared following literature methods; all other chemicals were of reagent grade quality, were purchased commercially (AlfaAesar, Acros, TCI Chemicals) and used as received.…”

Synthesis and properties of anionic ruthenium thionitrosyl and selenonitrosyl complexes that contain tetraanionic 2-hydroxybenzamidobenzene ligands

“…To prepare these compounds, we treated THP-protected 4-(trifluoromethyl)phenol with BuLi and ethyl chloroformate to afford ester 2 (Scheme 2). 17 Subsequently, 2 was treated with 1,2-phenylenediamine derivatives in the presence of sodium bis(trimethylsilyl)amide (NaHMDS) 18 to furnish the corresponding THP-protected H 4 hybeb R 1 ,CF3 . Finally, the THP group was removed under acidic conditions to generate 1d and 1e in good yield.…”

“…Bond angles dmap-Ru-N -176.57 (8) 173. 53(19) 173.79 (16) 176.82 (8) 173.78(19) 172.78 (17) Ru-N-E -174.9(2) 171.0 3171.2(3) 177. 27(19) 172.2 3169.9(3) Bond lengths RuN-E -1.144 31.511(4) 1.670(4) 1.149 31.516(4) 1.671(4) Ru-NE 1.6040 15 CD 32 SO with 0.03% v/v TMS ( 1 H: δ 2.50; 13 C{ 1 H}: δ 39.52) or to the external 19 F signal of C 6 F 6 (δ −164.9) or 31 P{ 1 H} signal of H 3 PO 4 (δ 0.00).…”

Syntheses of symmetric and unsymmetric 2,6‐bis(phosphino)phenols

“…Since phenols protected by the THP group readily undergo ortho-lithiations via deprotonation by organolithium bases [2,6,20,25], compounds containing the structural motif of 2,6-bis(phosphino)phenol can also be constructed via a different synthetic approach, avoiding 2,6-dibromophenol derivatives as starting materials. We have successfully implemented this feature for the syntheses of symmetric and unsymmetric 2,6-bis(phosphino)phenols 4a,b (Eq.…”