Ring-opening fluorination of bicyclic azaarenes

We have discovered a ring-opening fluorination of bicyclic azaarenes. Upon treatment of bicyclic azaarenes such as pyrazolo[1,5-a]pyridines with electrophilic fluorinating agents, fluorination of the aromatic ring is followed by a ring-opening reaction. Although this overall transformation can be classified as an electrophilic fluorination of an aromatic ring, it is a novel type of fluorination that results in construction of tertiary carbon–fluorine bonds. The present protocol can be applied to a range of bicyclic azaarenes, tolerating azines and a variety of functional groups. Additionally, mechanistic studies and enantioselective fluorination have been examined.


Introduction
Fluorine is one of the most important elements that could be installed onto hydrocarbon frameworks in pharmaceuticals, agrochemicals, and materials science. 1 Particularly, in medicinal chemistry, uorine has been incorporated into drug molecules to improve their liposolubility and metabolic stability. 2 The effect of uorine atoms in molecules has been well-studied, 3 and in turn, uorination methodology has ourished as well. 4 One of the most conventional ways to achieve uorination is electrophilic uorination. Nucleophiles used in electrophilic uorinations can be broadly classied into carbanions (e.g., 1,3-dicarbonyls), electron-rich unsaturated bonds (e.g., alkenes and alkynes), and aromatics. 5 However, in these existing methods, uorination proceeds while retaining the carbon skeleton of the starting material, and uorinations involving skeletal transformations are rare.
Ring-opening uorination, in which a uorine atom is introduced onto a cyclic compound with concomitant ring cleavage, has recently attracted attention as a useful method for efficiently constructing complex uorine-containing skeletons (Fig. 1A). Although ring-opening uorinations have recently been reported, most are limited to three-or four-membered ring starting materials such as epoxides, cyclopropanes/butanes, and aziridines, which have strained chemical bonds. 6 Fluorinations involving bond cleavage in a ring size $5 are rare. The Lectka, Leonori, and Ma group reported ring-opening uorinations via C-C bond cleavage of carbocycles (Fig. 1B). 7,8 Very recently, the Lim group disclosed acyl uoride synthesis through C-C bond cleavage of carbocycles and cyclic amides. 9 In 2018, the Sarpong group reported an elegant ring-opening uorination of cyclic amines (Fig. 1B). 9,10 In the heteroatom-heteroatom (X-Y) bond paradigm, the Yao group reported a ring-opening uorination using isoxazoline N-oxides via O-N bond cleavage (Fig. 1C). 11 However, all these methods require the use of highly specic substrates, and uorinations involving the ring opening of aromatic rings or asymmetric uorination have not yet been reported. In contrast to existing methods, we planned to develop a ring-opening uorination of bicyclic azaarenes such as pyrazolo [1,5-a]pyridines. We hypothesized that treating bicyclic azaarenes with an electrophilic uorinating agent would result in uorination at the C3 position, followed by deprotonation at the C2 position and pyrazole ring opening via N-N bond cleavage. Although this can be considered as a simple electrophilic uorination using an electron-rich heteroaromatic system as a nucleophile, the resulting compound is an sp 3 -uorinated compound (C(sp 3 )-F bond) instead of a uorine-substituted heteroarene (C(sp 2 )-F bond). In other words, we thought that this would be a novel type of uorination reaction with accompanying skeletal transformation.

Results and discussion
First, we selected 3-phenylpyrazolo [1,5-a]pyridine (1A) as the model substrate (which was readily prepared in three steps from a commercially available compound) to examine electrophilic uorinating agents and reaction conditions (Table 1). When N-uoropyridinium salts (F1-F3) were used in MeCN at 80 C, ring-opening uorinated product 2A was successfully obtained, albeit in low yields (entries 1-3). 12 The use of other nonpyridinium based electrophilic uorinating agents such as NFSI and Selectuor® gave uorinated products in high yields (entries 4 and 5). 13 As for the reaction temperature, the yield of 2A was 68% even at 50 C. The yield increased as the temperature was increased, and the uorinated product was obtained quantitatively at 80 C (entries 6-8 vs. entry 5). The reaction proceeded in polar solvents such as acetone and DMF (which is able to dissolve Selectuor®), and gave the uorinated product 2A (entries 9-11). Finally, we conformed the optimal conditions: Selectuor® (1.0 equiv.) at 80 C in MeCN for 24 h. With the optimal conditions in hand, the substrate scope was investigated (Scheme 1). Various 3-arylpyrazolo [1,5-a]pyridines were examined: Methyl (1B), tert-butyl (1C), and phenyl (1D) at the paraposition on the aryl group gave the ring-opening uorinated products 2B-2D in moderate yields. It should be noted that uorination of these aryl groups was detected. When using trimethylphenyl (1E) and naphthyl (1F) starting materials, the corresponding products 2E and 2F were obtained in moderate yields, and occurred decomposition of 1E or uorinated the aryl group of 1F (less than 10% yields). The reaction showed good functional group tolerance in the presence of formyl (1G), acetyl (1H), cyano (1I), triuoromethyl (1J), nitro (1K), and chloro (1L) groups, as the reaction worked to give the corresponding products 2G-2L in excellent yields. Next, 3-alkylpyrazolo [1,5-a] pyridines were investigated. The uorination using bicyclic azaarenes bearing alkyl groups (1M and 1N) or acetal (1O) proceeded smoothly to give the corresponding uorinated products 2M-2O in moderate to excellent yields. Pyrazolo [1,5-a] pyridines with alkyl acetate (1P), cyano (1Q), and ethylcarboxylate (1R) afforded the corresponding products (2P-2R) in good yields. Pyrazolo [1,5-a]pyridine carboxylates were also examined. Substrates with alkyl groups including alkene (1U) and alkyne (1W) remained intact to give products 2S-2X in high yields. Carboxylic acid 1Y also reacted well, but the product was difficult to purify, resulting in a low yield of 2Y. In the case of compounds with amides such as 1Z, deamidation occurred to give 3-uoropyrazolo [1,5-a]pyridine as a byproduct. Therefore, the uorinated product 2Z was obtained in moderate yield (39%) by reacting at a lower temperature (À30 C). Furthermore, azaarenes 1AA and 1AB derived from probenecid and estrone also gave uorinated compounds 2AA and 2AB in high yields. Of note, in the case of an unsaturated ester or iodine at the C3 position, the desired uorinated product could not be obtained, giving a complex mixture.
Substituted bicyclic arenes gave uorination products 2AC-2AF, however, for some substrates such as 1AC and 1AE, the uorination reactions were more difficult. Aer extensive screening of additives, we found that NaClO 4 (1.0 equiv.) was effective for increasing yields (see the ESI † for details). For example, without this additive, 1AC gave 2AC in only 51% yield, but with the additive, the yield improved to 87%. The role of the additive remains unclear, but we hypothesize that the counter anion exchange in the intermediate might affect the acidity of the proton at the C3 position. 14 This uorination was also applicable to other azaarenes: pyrazolo [1,5-a]pyrimidine with a phenyl group at the C3 position gave uorinated compounds 2AG-2AI in high yields. 6-Bromopyrazolo [1,5-a]pyrimidine with various aryl groups at the C3 position gave uorinated compounds 2AJ-2AL as well. The ring-opening uorination proceeded well even when using zaleplon, a hypnotic agent, for which the desired product 2AM was obtained. The reaction was also applicable to pyrazolopyrazine, triazine, quinoline, and quinazoline, giving uorinated products 2AN-2AQ in moderate yields.
In order to elucidate the reaction mechanism, we performed reaction tracking by 1 H NMR analysis using 1M (Fig. 2A). When Selectuor® was added to 1M in an NMR tube without stirring, 1M was immediately consumed at room temperature to produce tetrauoroborate 3 as the intermediate, which is thought to be the result of electrophilic uorination at the C3 position. Aer 2 to 4 hours of reaction time at 80 C, 1M almost entirely disappeared, and NMR peaks showed a mixture of 2M and 3; nally, practically only 2M resulted in the 1 H NMR spectrum. This experiment indicated that the uorination and the cleavage of the N-N bond proceeds in a stepwise fashion. When the reaction was stirred in a ask, 1M disappeared aer 10 min at room temperature, giving intermediate 3 and the residue 4 of Selectuor® (Fig. 2B). Upon removal of 4 from the resulting mixture, further reaction did not procced by heating at 80 C for 24 h (see the ESI † for experimental details). Therefore, triethylamine (1.0 equiv.) was added, and the reaction proceeded quickly to give the desired 2M quantitatively. This supports the role of Selectuor® as the uorinating agent in the reaction and the conjugate base of 4 as the base that promotes the N-N bond cleavage. These results also suggested that the basicity of the conjugate base of the uorinating agent was crucial for this ring-opening uorination. In the case of F1-F3, the consumption of 1A was increased as the electrophilicity of the uorinating agents was higher (F3 > F2 z F1), but the yield of 2A was proportional to the basicity of the conjugate base (F1 > F2 > F3). Furthermore, the reaction proceeded efficiently with the use of base with higher pK a such as triethylamine and 4. Next, the uorination reaction was carried out with 5, where the C2 position was substituted (Fig. 2C). As a result, only tri-uoroborate salt 6 was obtained in a good yield, with no ringopened product was obtained upon heating. When the uorination reaction was attempted using 7, which is unsubstituted at the C3 position, one equivalent of Selectuor® gave the uorinated compound 8 as the main product (50%) and the ring-opened compound 9 as a byproduct, demonstrating further uorination. When the amount of Selectuor® was increased to two equivalents, 9 became the main product (58%). These results indicated that a substituent is required at the C3 position because deprotonation of an acidic C-H (adjacent to F) to regain aromaticity occurs preferentially over deprotonation/ ring-opening.
We then studied the enantioselective version of this uorination reaction (Fig. 2D). 15 We attempted asymmetric uorinations using chiral uorinating agents. Shibata reported that a chiral uorinating agent, NF-(DHQD) 2 PHAL, can be prepared by mixing (DHQD) 2 PHAL and Selectuor® at room temperature. 16 A reaction using stoichiometric amounts of these agents with 3-phenyl-6-bromopyrazolo [1,5-a]pyrimidine 1AJ in MeCN at 50 C gave the corresponding product in 68 : 32 e. r., albeit in a low yield. However, when (DHQD) 2 PHAL was reduced to catalytic amount, enantioselectivity was dropped whereas the yield was increased. The substrate without a bromo atom at the C6 position (1AG) gave the uorinated product in moderate yield (44%) and 65 : 35 e. r. By lowering the temperature, changing the uorinating agent, and changing the solvent, we nally succeeded in obtaining the uorinated compound 2AJ with an enantioselectivity of 84 : 16 e. r. The absolute stereochemical conguration was determined by derivatization to give optically pure amide 10, recrystallization, and then X-ray structural analysis. In the crystal structure, the C]O bond of amide 10 is align antiparallel to the C-F bond, a conformation in which the amide dipole opposes the C-F dipole due to a dipole minimization effect. The enantioselectivity of this asymmetric uorination could be explained using the proposed transition state model. Although the direction in which the substrate reacts with the chiral uorinating agent determines the enantioselectivity, we believe that the transition state of the desired compound has a p-p interaction between the substrate and the methoxyquinoline moiety of (DHQD) 2 PHAL, which xes the conformation. 16c,17 Finally, the obtained uorinated compounds were derivatized into various compounds (Scheme 2). The ring-opened uorinated products of pyrazolo [1,5-a]pyridine 2U (R ¼ CO 2 allyl) were condense with amines to give amide 11 in 41% yield. Palladium-catalyzed decarboxylative allylation and removal of allyl esters proceeded to give derivatives 12 and 13 in high yields. Furthermore, we attempted to convert the cyano group of the product of the uorination reaction. Fluorinated product 2A (R ¼ Ph) was converted to methyl ester 14 by methanolysis. 2A was also converted to amides 15 and 16 by hydrolysis and Ritter reaction. 18 Furthermore, borane reduction gave amine 17. In this way, we have succeeded in synthesizing a variety of uorinecontaining compounds by orthogonal functional group transformations following ring-opening uorination.

Conclusions
In summary, we developed a ring-opening uorination of bicyclic azaarenes leading to sp 3 -uorinated compounds via N-N bond cleavage. Studies revealed that the electrophilic uorinating reagent functioned not only as the uorine source, but also as the base required for ring opening. Expanding the range of substrates and other electrophiles for this type of transformation is currently underway in our laboratory. 19

Data availability
All experimental data is available in the ESI. †

Author contributions
B. S. and J. Y. conceived and designed the study. M. K., A. S. and H. K. performed the chemical experiments and analyzed the data. K. K. performed the X-ray crystallography experiments and analyzed the obtained data. H. T. performed the preliminary experimental studies. J. Y. wrote the manuscript and all authors discussed the results and commented on the nal manuscript.

Conflicts of interest
There are no conicts to declare.