Pd-catalyzed fluoro-carbonylation of aryl, vinyl, and heteroaryl iodides using 2-(difluoromethoxy)-5-nitropyridine

Acyl fluorides have recently gained a lot of attention as robust and versatile synthetic tools in synthetic chemistry. While several synthetic routes to acyl fluorides have been reported, a procedure involving direct insertion of the “fluoro-carbonyl” moiety using a single reagent has not yet been realized. Here we report the preparation of acyl fluorides by palladium-catalyzed fluoro-carbonylation of aryl, vinyl, and heteroaryl iodides using 2-(difluoromethoxy)-5-nitropyridine under CO-free conditions. 2-(difluoromethoxy)-5-nitropyridine is a stable, colorless solid that can be used as an alternative to the toxic gaseous formyl fluoride, which is commonly used under fluoride catalysis conditions. A wide variety of acyl fluorides are efficiently and safely obtained in high yield (up to 99%). A broad range of functional groups is tolerated under the optimized reaction conditions and the method can be applied to the late-stage fluoro-carbonylation of structurally complex Csp2-iodides, including bioactive derivatives, such as Fenofibrate, Isoxepac, and Tocopherol. Furthermore, the one-pot transformation of aryl-iodides, including drug-like molecules, into the corresponding amides by successive fluoro-carbonylation/amidation reactions, demonstrates the potential synthetic utility of this strategy.

The first group, which involves the fluorination of carboxylic acids or their derivatives, including aldehydes via deoxyfluorinations, halogen-exchange reactions, or C-H activation reactions, is the central area of the traditional research (type I, cleavage 1 in Fig. 1b) [38][39][40][41][42][43][44][45][46][47][48][49] . The other group includes step-wise fluoro-carbonylation reactions of organic halides using a combination of toxic gaseous carbon monoxide (CO) [50][51][52] or more stable alternative sources of CO, and fluorinating reagents 53 (type II, cleavages 1 and 2 in Fig. 1b). While methods of type I and type II are usually useful, the development of simpler protocols for the generation of R-COFs remains pertinent, especially if one can avoid the use of toxic and or unstable reagents. However, methods for the direct insertion of the "fluoro-carbonyl" moiety. i.e., "F-C=O" using a single reagent has not yet been realized (type III, cleavage 2 in Fig. 1b). Although gaseous formyl fluoride (F-C(=O)H), a potential precursor for a "F-C=O" moiety, has been reported [54][55][56] , formyl fluoride is fundamentally impractical due to its instability, potential toxicity, and the difficulties associated with its handling 54    research [54][55][56] . We thus designed a type III strategy that is based on the fluoride-catalyzed in-situ generation of formyl fluoride, followed by a cross-coupling reaction with aryl halides in the presence of a Pd-catalyst. Initially, the difluoromethoxy anion (-OCF 2 H), should be generated from difluoromethoxy ether under fluoride catalysis, and the resulting difluoromethoxy anion can be expected, given its instability, to spontaneously decompose into formyl fluoride by releasing a fluoride anion (F − ), which is responsible for the negative fluorine effect 57,58 . Subsequently, the generated formyl fluoride can be used in cross-coupling reactions with aryl halides under Pd-catalysis (Fig. 1c).
The treatment of 1 with 2 in the presence of CsF furnishes the corresponding aroyl fluorides (Ar-COFs, 3) in good to high yield. The reactions also proceed well using only a catalytic amount of CsF, provided a stoichiometric amount of a base is added. This cross-coupling reaction using 2 works not only for aryl iodides but can also be extended to alkenyl and heteroaryl iodides, which furnishes the corresponding acyl fluorides in good to high yield. R-COFs of pharmaceutical derivatives can also be synthesized under these conditions, despite their often functionalized and complex three-dimensional structures. The key for this fluoro-carbonylation reaction is an in-situ generation of formyl fluoride by decomposition of the unstable -OCF 2 H, which is delivered from 2 upon a nucleophilic attack of a fluoride-releasing 5-nitropyridine (4). Furthermore, we examine the application of this method to the one-pot transformation of aryl iodides into aryl amides, and we investigate the diversification of the resulting aryl fluorides. Moreover, the reaction mechanism is discussed based on the results of control experiments, nuclear magnetic resonance (NMR) spectroscopy, and liquid chromatography-mass spectrometry (LC-MS). As 2 is a stable solid that can be easily synthesized and stored, the method represents a powerful addition to the toolkit of fluorocarbonylation reactions.
Substrate scope. With the optimal reaction conditions in hand, we investigated the substrate scope of the reaction with respect to aryl iodides (Fig. 3). Iodobenzene (1b) provided the corresponding product (3b) in 92% yield. Both electron-rich and -poor aryl substituents are compatible with the reaction conditions, providing the desired products (3c-3n) in generally good to excellent yield. Meta-substituted aryl iodides (1j-1k) afforded the desired products (3j-3k) in high yield. Sterically hindered orthosubstituted 1l provided 3l in good yield without hampering the reactivity. It should be noted here that the procedure was also efficient for alkenyl iodides (1o, 1p), which provided 3o and 3p in excellent yield. Heterocyclic aryl iodides (1q-1t) can also be used and generate the desired products (3q-3t) in good to excellent yield; the results of other heterocyclic aryl substituents are discussed later (vide infra; cf. "Synthetic application"). Reactions of α-iodostyrene (1u) and the aliphatic olefin substrate 1v also proceeded smoothly and afforded the desired products (3u, 3 v) in acceptable yield. Due to the hydrolysis of the products during purification and the volatility of some products, the isolated product yields are usually lower than the 19 F NMR yields, albeit that isolation is possible via column chromatography on silica gel. Interestingly, the reaction can also be scaled up; when the reaction was carried out on a 4.5-mmol scale, 3a was isolated in 90% yield (Fig. 2b).
To highlight the synthetic utility of this procedure, we used 2 for the late-stage fluoro-carbonylation of natural products and bioactive molecules derivatives. As shown in Fig. 2c, menthol was functionalized to afford 3w in 35% yield (84% 19 F NMR yield). Fenofibrate, a synthetic phenoxy-isobutyric acid derivate and prodrug with antihyperlipidemic activity, the fluorocarbonylation of a fenofibrate derivative 1x furnished 3x in 40% yield (88% 19 F NMR yield). Estrone, arguably one of the most important mammalian estrogens, was transformed into 3y and 3z in good yield. Isoxepac, an anti-inflammatory with analgesic and antipyretic activity, afforded 3za in 63% (87% 19 F NMR yield). Tocopherol, which exhibits antioxidant activity, could also be fluoro-carbonylated to generate 3zb in 75% (93% 19 F NMR yield). The fluoro-carbonylation of a testosterone derivative furnished the desired fluoroacylated product (3zc) in 15% (61% 19 F NMR yield). Synthetic application I. As mentioned in "Introduction", acyl fluorides 3 represent a potent platform for a variety of chemical transformations. To demonstrate the broad synthetic utility of 3, we carried out eight chemical transformations using 3a (Fig. 4). Specifically, 3a was successfully transformed into amide 7a (95%), ester 8a (85%), and thioester 9a (76%) by reaction with the heteroatom nucleophiles aniline, phenol, and p-tolyl-thiol, respectively, in the presence of triethylamine in DMF at rt. A Pdcatalyzed cross-coupling reaction of 3a with PhB(OH) 2 using Pd (OAc) 2 (2.5 mol%) and PCy 3 (10.0 mol%) in the presence of KF in toluene at 120°C furnished phenyl-coupling product 10a in 47% yield 22 . A reduction of 3a with NaBH 4 afforded alcohol 11a in 93% yield, while carboxylic acid 12a was obtained in 63% from the hydrolysis in water under reflux. The Pd-catalyzed transformation of Ar-COF 3a with HSiEt 3 in toluene at 100°C in the presence of different phosphine ligands such as PCy 3 23 or 1,2ethanediylbis(dicyclohexylphosphine) (DCPE) 23 resulted in the formation of Ar-CHO 13a and Ar-H 14a, respectively, in good to high yield.
After stirring overnight at rt, the desired aryl and heteroaryl amides (7zd-7zh) were obtained in moderate to good yield. The low yield of 7zh can be rationalized in terms of the low stability of 1zh. The aforementioned natural product and bioactive molecule (1zi, 1zj) can also be used in this one-pot fluoro-carbonylation/amidation procedure to furnish the corresponding amides (7zi, 7zj) in good yield.
Proposed reaction mechanism. To shed light on the underlying reaction mechanism, we examined a series of experiments under reaction conditions that are slightly different from the optimal conditions (entry 1, Table 2). Initially, we carried out the reaction under the optimized conditions: 2 (1.2 equiv), CsF (1.5 equiv), Pd (TFA) 2 (1.0 mol%), and Xantphos (1.5 mol%) in DMF, but using a catalytic amount of CsF (10 mol%). This dramatically decreased the yield of 3a to 10% (entries 1 and 2), albeit that the yield was recovered to 70% (entry 3) in the presence of a stoichiometric amount of Cs 2 CO 3 . Stoichiometric amounts of organic bases such as Et 3 N or N,N-dimethyl-4-aminopyridine (DMAP) are also effective for this transformation in the presence of a catalytic amount of CsF to furnish 3a in 51 and 79% yield, respectively (entries 4 and 5). These results suggest that the fluoride in 3a stems from 2, not from CsF. Subsequently, we changed the order of addition of the reagents (entries 6 and 7). When 1a was first treated with Pd(TFA) 2 (1.0 mol%) and Xantphos (1.5 mol%) at 70°C for 5 h in DMF, and then with 2 (1.2 equiv) and CsF (1.5 equiv) at 70°C for another 5 h in DMF, 3a was obtained in 97% yield (entry 6). However, only 6% of 3a was detected when the order of addition was reversed, i.e., when 2 was treated with CsF, Pd(TFA) 2 , and Xantphos in DMF at 70°C for 5 h, followed by the addition of 1a (entry 7). Since the optimized reaction conditions (entry 1, Table 2) refer to a reaction where all reagents are mixed from the beginning, it can be concluded that the reaction of 1a with the Pd-catalyst is much faster than the reaction of formyl fluoride with the Pd-catalyst. Based on these experiments, additional 19 F NMR experiments, and mass spectroscopy analyses (for details, see Supplementary Figs. [26][27][28] as well as information from the literature 60 , we would like to propose a plausible reaction mechanism (Fig. 6). Reaction mechanism starts with the generation of a phosphine-ligated Pd(0) species (LnPd 0 ), which undergoes an oxidative addition into the C-I bond of Ar-I (1a), resulting in the formation of aryl Pd(II) species I. An LC-MS analysis supported the generation of I by confirming the presence of Pd-Xantphos species I′ (m/z = 837) and I″ (m/z = 731). The process from LnPd 0 to I under concomitant detection of I′ and I″ is in good agreement with the report by Lee and Morandi 61 . The resulting complex I can then coordinate to the formyl fluoride, generated from 2 via a fluoride-catalyzed selfdecomposition of the difluoromethoxy anion, to furnish I-Pd-Ar species II. Then, the insertion of the aryl group across the C=O moiety in Pd-complex II providing intermediate III, followed by a base-induced β-hydride elimination would directly afford 3a under regeneration of the Pd(0) catalyst. Related pathways, involving β-hydride elimination steps for cross-coupling reactions, have been reported by Martin (Pd-catalysis) 62 , Newman (Ni-catalysis) 63 , and Lee  64 . However, the details of the reaction mechanism remain to be determined. In summary, we have developed an efficient strategy for the Pd-catalyzed fluoro-carbonylation of aryl, vinyl, and heteroaryl iodides using formyl fluoride that is generated spontaneously from 2-(difluoromethoxy)-5-nitropyridine (2). The high reactivity and broad applicability of this synthetic methodology suggest that this protocol may become a compelling alternative synthetic route to acyl fluorides, which represent essential intermediates in the process of pharmaceutical integration. So far, four methods for the Pd-catalyzed (or mediated) fluorocarbonylation have been reported using toxic CO (Tanaka 50 , Kiji 51 , Hiyama 52 ) or a stable CO-equivalent (Manabe 53 ) with different combinations of fluoride sources; in comparison, our method exhibits a substantially broader substrate scope and uses 2 as a combined source of CO and fluoride. Further investigations into the extension of this fluoro-carbonylation strategy to generate more complex substrates, as well as establishing the details of the reaction mechanism, are currently in progress in our laboratory.

Methods
General procedure for the generation of acyl fluorides 3a using a stoichiometric amount of CsF. An oven-dried vessel containing a magnetic stirrer bar was charged with Pd(TFA) 2 (1.0 mg, 0.003 mmol, 1.0 mol%), Xantphos (2.6 mg, 0.0045 mmol, 1.5 mol%), CsF (68.4 mg, 0.45 mmol, 1.5 equiv), and anhydrous N,Ndimethylformamide (DMF, 2.0 mL, 0.15 M) in a nitrogen-filled glovebox. After stirring the reaction mixture for 10 min at room temperature, 2 (0.36 mmol, 1.2 equiv) and aryl iodide 1a (0.3 mmol, 1.0 equiv) were added. The vessel was capped with a rubber septum, removed from the glovebox, and stirred for 15 h at 70°C. Then, the mixture was cooled to room temperature and the yield (>99%) was determined by 19 F NMR analysis of the crude reaction mixture using C 6 H 5 F (28.5 μL, 0.3 mmol, 1.0 equiv) as an internal standard. The crude mixture was directly purified by flash chromatography on silica gel (thickness: 10 cm; diameter: 2 cm) to afford 3a (55.3 mg, 92% yield) as a white solid.

Data availability
The data supporting the findings of this study are available within the paper and its Supplementary Information. All relevant data are also available from the authors.