Light-Induced Metal-Free Transformations of Unactivated Pyridotriazoles

Transition metal-catalyzed denitrogenative transformations of pyridotriazoles have been recently evolving as a powerful tool for synthesis of diverse molecules possessing N-hetero-Scheme 1. Thermal and light-induced generation of carbenes from pyridotriazoles. cyclic fragments. [1][2] These protocols take advantage of the well-known ring-chain tautomerism of the pyridotriazole core in solution into the corresponding diazo tautomer A, which then can be trapped by a transition metal catalyst to form the reactive pyridyl metal carbene intermediate B (Scheme 1 a). Since the first report on the transannulation reaction of pyridotriazoles in 2007, [3] numerous effective catalytic methods including transannulation, [4] X-H insertions, [5] and cyclopropanation [6] reactions have been developed. [7] However, all these methods are not without shortcomings. The reactions proceeding at room temperature require Cl, Br, or OMe activating groups (AG) at C7, [3a,b] otherwise high temperatures [3c,d,e] are necessary for achieving sufficient amounts of the open form of pyridotriazole A, which would lead to the reaction products. In either case, the employment of transition metal catalysts is required. Herein, we report room temperature efficient and operationally simple lightinduced metal-free arylation, X-H insertion, and cyclopropanation reactions of pyridotriazoles giving access to various pyridyl-containing synthons, which can be used for convenient synthesis of bioactive molecules. In continuation of our studies on application of pyridotriazoles in the synthesis of nitrogen-containing heterocycles, [3a-e] we hypothesized a metal-free strategy which can be accessed by utilizing light irradiation. [8] Compared with numerous methods reported for thermal processes, photochemical studies of pyridiotriazoles are relatively scarce. [9] Aiming at the development of milder reaction conditions, we started our investigation by analysing the UVvis absorption spectra of pyridotriazoles 1a-d (Figure 1, see SI for more details). Among them, only pyridotriazoles 1a and 1b bearing aryl substituents at the C3 position showed appreciable absorption around 390 nm region, which is attributed to the extended conjugation in these systems. Thus, we hypothesized that upon irradiation, the excited pyridotriazole 1a could undergo a ring-chain tautomerism to deliver its diazo tautomer C (Scheme 1b), which upon denitrogenation [10] would deliver reactive carbene species D. Table 1. Optimization of arylation reaction parameters. [a] Entry Deviation from standard conditions Yield [b] , % To test this hypothesis, we examined a metal-free arylation reaction of 3-phenyl [1,2,3]triazolo [1,5-a]pyridine 1a with boronic acid 2 (Table 1). The optimization studies indicated that performing this reaction under 390 nm irradiation in 0.1 M benzene solution with 1.5 equiv. of boronic acid in the presence of 3 equiv. K2CO3 at room temperature allows to produce diphenyl-2-pyridylmethane 3aa in 89% yield (entry 1). Employment of other additives (entries 2-4) or solvents (entries 5-7) led to diminished yields. Only 25% of the product was formed without K2CO3 (entry 8), which points on the importance of the base for formation of the reactive triphenylboronxine arylating reagent [7a] . The control experiments indicated no reaction under 455 nm or 427 nm LED irradiating (entries 9 and 10) or under thermal conditions in the absence of light (entry 11). [11] Expectedly, the attempts on employment of pyridotriazoles 1c and 1d, which are transparent in 390 nm region under these reaction conditions failed. Although the pyridotriazole 1d showed notable absorbtion in 370 nm region, the attempts of its arylation under irradiation with 370 nm LED lamp failed probably due to competing side reactions of the formed unstable carbene.

Intrigued by the uncovered novel reactivity of pyridotriazoles under photo-induced conditions and inspired by the importance of triarylmethanes, [12] we further explored the scope of this arylation reaction. Markedly, this C-C coupling reaction showed wide scope and high functional-group tolerance on both reaction partners (Table 2 a). Thus, diversely Table 2. Arylation reactions of pyridotriazoles. [a,b] [a] Reaction conditions: pyridotriazole 1 (0.2 mmol), boronic acids 2 (1.5 equiv), K2CO3

(3 equiv), benzene (0.1 M), 40 W 390 nm LED at room temperature. [b] Yield of isolated product. [c] Reaction was performed in 1 mmol scale. [d] Toluene (0.1 M) used as a solvent.

3ap [d] , 70% Please do not adjust margins Please do not adjust margins Table 3. X-H insertion reactions. [a,b] [a] Reaction conditions: pyridotriazole 1 (0. functionalized boronic acids 2 bearing electron-rich (2b-2d), electron-deficient (2h-2j), electron-neutral (2n), halogencontaining (2e-2g and 2k-2m), and sterically encumbered (2o) substituents at the ortho-, meta-and para-positions smoothly reacted with 3-phenyl [1,2,3]triazolo [1,5-a]pyridine 1a to produce diphenyl-2-pyridylmethanes 3aa-3an in good to excellent yields. In addition, the reaction of phenylboronic acid with the para-siloxy substituent worked well to give 3ab in good yield, which upon desilylation offered access to the phenol product. Notably, the reaction also efficiently proceeded with the alkenyl boronic acid 2p providing cyclohexen-1-yl product 3ap in 70% yield. Studies on the scope of pyridotriazoles showed that pyridotriazoles 1 bearing different 4-substitued phenyl or heteroaryl groups at C3 position furnished the corresponding triarylmethane products 3ea-3ia in moderate to high yields. In addition, 5-chloro pyridotriazole, 6-bromo pyridotriazole and N-fused heterocyclic pyrazinotriazole successfully underwent arylation with different arylboronic acids to give 3ja, 3ka, 2-(diphenylmethyl) pyrazine (3la, 3le and 3lf) in good yields.

Next, we turned our attention to carbene X-H insertion reactions [10a] (Table 3). To this end, pyridotriazoles 1, under standard reaction conditions, were examined in reactions with phenols, alcohols, sulfonamides, and carboxylic acids (Table 3 a). All Table 4. Cyclopropanation reactions.

[a]

[a] Reaction conditions: pyridotriazole 1 (0.2 mmol), styrene 10 (3 equiv), benzene (0.1 M), 40 W 390 nm LED at room temperature. This journal is © The Royal Society of Chemistry 20xx

Please do not adjust margins Please do not adjust margins substituted phenols tested provided the O-H insertion products 7aa-7af in moderate yields, albeit with trace to substantial amounts of the C-H insertion regioisomers. [13] These reaction conditions appeared to be very general for reactions with alcohols 4g-4n. Thus, alcohols possessing various alkyl, alkenyl, thiomethyl, and even sterically hindered bicyclo groups all reacted well, providing ethers 7ag-7fm in good to high yields. Moreover, this reaction chemoselectively gave O-H insertion products with alkenols (7al and 7am), double bond moiety of which was not compromised. Likewise, aliphatic chlorine substituent was tolerated in 4n, which constitutes an additional handle for further derivatizations. In contrast to a facile O-H insertion reaction with phenols, the insertion into the N-H bond of aniline 5a was sluggish (Table 3 b), which can probably be attributed to its higher pKa value. [5d] However, more acidic primary and secondary sulfonamides 5bg reacted smoothly to produce the N-H insertions products 8ab-8ag in reasonable to high yields. Phthalimide 5h provided the insertion product 8ah in reasonable yield. Furthermore, both aliphatic and aromatic carboxylic acids 6a-6c were also found to be the competent substrates for the COO-H insertion reactions producing the corresponding esters 9aa-9cc in good yields (Table 3 c).

In addition, it was also found that upon photoirradtion, the pyridotriazoles underwent efficient cyclopropanation with alkenes 10 (Table 4). The scope of pyridotriazoles was studied first. Pyridotriazoles 1 bearing different 4-substitued phenyl or heteroaryl groups at C3 position gave the corresponding cyclopropanes 11aa-11ia in moderate to high yields. [14] 3-Naphthalenyl pyridotriazole furnished product 11na in high yield. Furthermore, N-fused heterocyclic quinolinotriazole and 7-chloro pyridotriazole successfully underwent cyclopropanation with styrene to give 11ma, 11oa. The scope of the process with respect to the alkene components was examined next. Cyclopropanes 11ab-11ae were obtained from a diverse array of ortho-, meta-, para-and disubstituted styrenes in high yields. 2-Vinylpyridine, vinyl ether, acrylonitrile, vinyl ketone and ethyl acrylate efficiently participated in the reaction to give the products 11ag-11ak. Notably, a double bond of indole also participated in this reaction, providing fused product 11al in moderate yield.

Synthetic usefulness of this methodology was illustrated on the facile syntheses of selected bioactive molecules. Thus, desacetyl bisacodyl (DAB) 12 [15] and Bisacodyl 13, [16] which are used as stimulant laxative drugs, were efficiently obtained via the one-pot procedures from the pyridotriazole 1b with arylboronic acid 2b (Scheme 2 a). Furthermore, piperidine derivative 14, [17] the synthetic precursor of antihistamine agent Bepotastine, was easily accessed by the O-H insertion reaction of 7n with pyridotriazole 1f (Scheme 2 b).