Synthesis of Fluorinated Alkyl Aryl Ethers by Palladium-Catalyzed C-O Cross-Coupling.

Herein, we report a highly effective protocol for the cross-coupling of (hetero)aryl bromides with fluorinated alcohols using the commercially available precatalyst tBuBrettPhos Pd G3 and Cs2CO3 in toluene. This Pd-catalyzed coupling features a short reaction time, excellent functional group tolerance, and compatibility with electron-rich and -poor (hetero)arenes. The method provides access to 18F-labeled trifluoroethyl ethers by cross-coupling with [18F]trifluoroethanol.

Fluorinated alkyl aryl ethers are encountered in medicinal chemistry and agrochemistry, due to the ability of fluorine to modulate molecular properties including lipophilicity and metabolic stability.[1] Prominent molecules featuring these motifs include the multibillion-dollar proton pump inhibitor lansoprazole, the antiarrhythmic flecainide, and idalopirdine (Figure ). Approaches for fluoroalkyl aryl ether preparation include Chan–Lam coupling of aryl boronic acids,[2,3] Williamson ether synthesis,[4] and transition metal mediated cross-coupling of aryl halides with fluorinated alcohols.[5−8] Copper mediated approaches include coupling of fluorinated alcohols with aryl iodides under copper catalysis reported by Bonnet-Delpon and co-workers[5] and reaction of aryl bromides with a copper(I) fluoroalkoxide complex reported by the Weng group.[8] The Singh group has reported palladium-catalyzed coupling of fluorinated alcohols with aryl bromides bearing para-electron-withdrawing groups.[6,7] Limitations of these protocols include the use of stoichiometric transitions metals (Cu(I) fluoroalkoxide procedure),[8] limited substrate scope (Pd-catalyzed procedure), long reaction times, and/or the requirement of neat fluorinated alcohols (Cu-catalyzed procedure).[5]

Figure 1

Drugs containing fluorinated alkyl aryl ethers.

Shekhar and co-workers reported novel biaryl phosphorinane ligands for Pd-catalyzed C–O cross-coupling with electron-rich and heteroaryl halides, but these ligands are currently not commercially available.[9] In this field of research, the contribution of Buchwald and co-workers stands out by providing an excellent procedure for C–O cross-coupling of alcohols and aryl halides in the presence of NaOtBu in dioxane and using commercially available precatalysts BuBrettPhos Pd G3 and AdCyBrettPhos Pd G3.[10] For alcohols of reduced nucleophilicity including 2,2,2-trifluoroethanol and 2,2,3,3,3-pentafluoropropanol, superior yields were obtained using AdCyBrettPhos Pd G3.

Given our interest in narrowing the gap between 19F- and 18F-chemistry,[11−14] we considered applying this C–O cross-coupling as a radiosynthetic route to install 18F-labeled fluorinated alkyl aryl ethers motifs. For this purpose, it was necessary to adapt the protocol to accommodate short reaction times (18F half-life = 109.7). In addition, it is important that no large excess of fluorinated alcohol is required for effective coupling considering that cyclotron-produced 18F-fluoride is available in the picomolar range. Herein, we report the Pd-catalyzed C–O coupling of fluorinated alcohols using BuBrettPhos Pd G3 with the mild base Cs2CO3 in toluene. This protocol accommodates an extensive range of (hetero)aryl bromide and fluorinated alcohols and was adapted for cross-coupling with [18F]trifluoroethanol.

We investigated the Pd-catalyzed cross-coupling reaction between trifluoroethanol and 1a, a demanding aryl bromide considering the lack of an activating electron-withdrawing group attached directly to the aromatic ring, and the presence of mildly acidic protons α to the ketone (Table ). We screened short reaction durations with the foresight of applying the coupling for introducing 18F-labeled motifs. Under conditions similar to those reported by Singh, using BrettPhos, Pd2(dba)3, and Cs2CO3 in toluene, no coupled product was formed after 1 h (entry 1).[6] Switching the ligand to either XPhos or BuXPhos also resulted in no product formation (entries 2 and 3).[15,16] Using BuBrettPhos as ligand, the coupled product was observed in 51% yield (entry 4). An increase to 70% yield was observed using Buchwald’s BuBrettPhos Pd G3 precatalyst (entry 5). Buchwald’s precatalysts are air and moisture stable Pd(II)-palladacycles, which allow for quantitative formation of the catalytically active LPd(0) species in situ following base induced C–N reductive elimination.[17] Cs2CO3 gave superior results compared to both sodium and potassium carbonate (entries 6 and 7). K3PO4 was an effective base, affording the product in 70% yield (entry 8). While Cs2CO3 was used for this study, use of K3PO4 may be advantageous on a larger scale, as it is significantly cheaper than Cs2CO3. The use of NaOBu as base with 1,4-dioxane as solvent[10] resulted in a reduced yield (entry 9). While stronger bases such as NaOBu can promote C–O cross-couplings at lower temperatures than weaker inorganic bases such as Cs2CO3, they can also lead to reduced yields for base-sensitive substrates.[18,19] Toluene afforded a higher yield than 1,4-dioxane (entry 10) and tert-amyl alcohol (entry 11). Reducing the reaction duration to 30 min or the temperature to 80 °C resulted in lower yields (entries 12 and 13).

Table 1

Reaction Optimization

Entry	Catalyst	Solvent	Base	Yield (%)a
1	BrettPhos, Pd2(dba)3	toluene	Cs2CO3	0
2	XPhos, Pd2(dba)3	toluene	Cs2CO3	0
3	tBuXPhos, Pd2(dba)3	toluene	Cs2CO3	0
4	tBuBrettPhos, Pd2(dba)3	toluene	Cs2CO3	51
5	tBuBrettPhos Pd G3*	toluene	Cs2CO3	70
6	tBuBrettPhos Pd G3*	toluene	Na2CO3	0
7	tBuBrettPhos Pd G3*	toluene	K2CO3	8
8	tBuBrettPhos Pd G3*	toluene	K3PO4	70
9	tBuBrettPhos Pd G3*	1,4-dioxane (80 °C, 16 h)	NaOtBu	48
10	tBuBrettPhos Pd G3*	1,4-dioxane	Cs2CO3	61
11	tBuBrettPhos Pd G3*	tert-amyl alcohol	Cs2CO3	33
12	tBuBrettPhos Pd G3*	toluene (80 °C)	Cs2CO3	34
13	tBuBrettPhos Pd G3*	toluene (30 mins)	Cs2CO3	48

Yields determined by 19F qNMR with PhCF3 as internal standard. For entries 1–4, 0.5 mol % of Pd2(dba)3 and 1.25 mol % of ligand were used. For entries 6–13, 1 mol % of the precatalyst was used.

The scope of the reaction with respect to the aryl bromide was explored next (Scheme ). Various electron-rich aryl bromides underwent coupling with trifluoroethanol in high yield after 0.5 to 2 h, with morpholinyl and methoxy substitution well tolerated (2b to 2d). Product 2c was isolated in 89% yield, while it has been reported to form in 69% NMR yield using NaOBu and 1,4-dioxane.[10] The reaction conditions were applied to the double C–O cross-coupling of 1,4-dibromobenzene to yield 2f in a single step. Electron-deficient aryl bromides also underwent coupling in excellent yields (substrates 2h to 2k). A wide range of functional groups were well tolerated including sulfone, ester, ketone, aldehyde, and nitro groups, some bearing acidic α-protons. For many substrates, the reaction temperature could be decreased to 80 °C without detrimental impact on reactivity. In contrast, when electron-rich aryl bromides such as 1d were reacted with trifluoroethanol at 80 °C, starting material was recovered almost quantitatively. Heteroaryl bromides also underwent coupling (2n–2r), with 80 °C being adequate for some substrates. Pyridines, pyrimidine, quinoline, and quinoxaline substrates all coupled effectively. This cross-coupling method was applied to prepare the drug precursor N-Boc-flecainide (2t).

Scheme 1

Pd-Catalyzed C–O Cross-Coupling of Fluorinated Alcohols with Aryl Bromides (Yields of Isolated Products Are Quoted)

2 mol % BuBrettPhos Pd G3, 3 equiv of Cs2CO3 and trifluoroethanol used.

Yield determined by 19F qNMR.

Reaction duration of 4 h. NMRY = NMR yield under the conditions reported herein. NMRY* = NMR yield using NaOBu in 1,4-dioxane at 40 to 80 °C.

Aryl chlorides were also investigated as substrates. The activated aryl chloride fenofibrate 1v underwent C–O cross-coupling in excellent yield. A control experiment excluding BuBrettPhos Pd G3 afforded no product, ruling out a nucleophilic aromatic substitution mechanism. Contrarily, electron-rich aryl chloride 1b(Cl) afforded only traces of the coupled product. For preparing compounds 2a, 2u, and 2w, the conditions reported herein were compared directly to use of NaOBu with 1,4-dioxane (NMRY for conditions herein vs NMRY* for NaOBu conditions, Scheme ).[10] In these cases, higher yields were observed using Cs2CO3 and toluene.

Various other fluorinated alcohols were successfully coupled to aryl bromides under our optimized conditions. Notably, in contrast to 2,2,2-trifluoroethanol, coupling reactions of electron-rich aryl bromides with 2,2-difluoroethanol could be carried out at 80 °C. Furthermore, electron-poor aryl bromides and heteroaryl bromides successfully coupled with 2,2-difluoroethanol. 2-Fluoroethanol also reacted in high yield (4d). In a competition experiment in which equimolar quantities of 2,2,2-trifluorethanol, 2,2-difluoroethanol, and 2-fluoroethanol were reacted with substrate 1d at 100 °C for 2 h under the conditions reported herein, the trifluoroethyl, difluoroethyl, and fluoroethyl ethers were formed in an ∼1:3:2 ratio, respectively. This supports decreased reactivity of 2,2,2-trifluoroethanol relative to 2,2-difluoroethanol and 2-fluoroethanol.

The scalability of the C–O cross-coupling reaction was demonstrated by the gram-scale coupling of 2,2,3,3-tetrafluoropropanol and 3-bromobenzaldehyde for the preparation of 2u, an intermediate in the synthesis of the drug idalopirdine (Figure ).[20] For this scale-up, the catalyst loading was reduced to 0.5 mol % without impacting the yield of isolated product. On a larger scale, use of Pd2(dba)3 with tBuBrettPhos rather than BuBrettPhos Pd G3, and K3PO4 rather than Cs2CO3, may be preferable to reduce costs.

The short reaction time and high efficiency of incorporation of the fluorinated alcohol encouraged the use of this cross-coupling reaction for the introduction of 18F-labeled motifs, specifically [18F]trifluoroethanol (Scheme A). Preparation of an 18F-trifluoroethyl ether has been reported by the Riss group via alkylation of the corresponding phenol with [18F]trifluoroethyl tosylate (Scheme A).[21−24] Here, we propose a complementary approach that utilizes a C–O cross-coupling event to prepare 18F-trifluoroethyl ethers [18F]2 from aryl bromides and [18F]trifluoroethanol. [18F]Trifluoroethanol has previously been synthesized by nucleophilic radiofluorination of ethyl bromodifluoroacetate 5 with [18F]KF/K2.2.2, followed by reduction with AlH3 prepared in situ from LiAlH4 and H2SO4 (Scheme B).[25] The [18F]trifluoroethanol was not used directly and required an additional step to generate [18F]trifluoroethyl triflate, which was then applied for amine alkylation. Multiple distillations were used to purify ethyl [18F]trifluoroacetate 7 and [18F]trifluoroethanol.

Scheme 2

(A) Approaches to [18F]Trifluoroethyl Ethers; (B) Previously Reported Synthesis of [18F]Trifluoroethanol Requiring Multiple Distillations and AlH3; (C) Our Approach for the Synthesis of [18F]Trifluoroethanol; (D) Coupling of Aryl Bromides with [18F]Trifluoroethanol

RCY = radiochemical yield, determined by integration of the radio-HPLC trace (prior to HPLC for compound 9).

We sought to develop an [18F]trifluoroethanol synthesis without distillation, using instead HPLC purification. We also aimed to replace AlH3 with NaBH4, a reducing agent readily available and easy to handle. Our initial experiments showed that ethyl trifluoroacetate [18F]6 is unstable under reversed-phase HPLC conditions. Therefore, we targeted menthol [18F]trifluoroacetate [18F]9, an ester which is more resistant to hydrolysis and therefore amenable to purification by reversed-phase HPLC (Scheme C). Under conditions slightly modified from those previously reported by Szabó and Schou,[26] synthesis of [18F]9 was achieved in 27 ± 10% radiochemical yield (RCY) using [18F]TBAF and DBU in 1,3-dimethyl-2-imidazolidinone (DMI).[27] After HPLC purification and reformulation into 1,4-dioxane, reduction using NaBH4 afforded [18F]trifluoroethanol in 98 ± 1% RCY. Menthol, formed during the reduction step, was found to be unreactive under the conditions applied for C–O cross-coupling, and therefore a purification step by filtration to remove salts was sufficient. 1,4-Dioxane was used as the reaction solvent, as it afforded high yields for the reduction (toluene performed poorly) and proved highly suitable for the subsequent C–O cross-coupling (Table , entry 10). This modification was advantageous by avoiding a second reformulation step.

Under slightly modified coupling conditions, [18F]trifluoroethanol was coupled with aryl bromide 1a and naphthyl bromide 1l to afford the desired cross-coupled [18F]trifluoroethyl ethers (Scheme D). Radio-HPLC showed clean reaction profiles, with mainly the 18F-labeled product and unreacted [18F]trifluoroethanol. Extending the reaction duration beyond 20 minutes did not increase the RCY. Our study showed that the coupling was sensitive to the water content in the [18F]trifluoroethanol solution; drying of menthol [18F]trifluoroacetate [18F]9 under a flow of nitrogen was essential prior to reformulation in 1,4-dioxane.[27] While Pd-mediated C–N and C–C cross-coupling has been used for introduction of 18F-labeled motifs,[28] this work supports the feasibility of 18F-radiolabeling by Pd-mediated C–O cross-coupling.

In conclusion, we have developed a protocol for Pd-catalyzed cross-coupling between fluorinated alcohols and (hetero)aryl bromides using the mild base Cs2CO3; the reaction tolerates various electronic patterns on the arene ring, a wide range of functional groups including those with mildly acidic α-protons, and proceeds over a short duration. An activated aryl chloride has also been shown to couple effectively. In addition, K3PO4 was found to be a cheaper alternative base to Cs2CO3. The utility of the coupling has been further demonstrated with a new disconnection approach to 18F-labeled trifluoroethyl ethers consisting of C–O cross-coupling of aryl bromides with [18F]trifluoroethanol.