Anomeric stereoauxiliary strategy enables ecient synthesis of wide-ranging imidazo[1,5-α]pyridines

Imidazo[1,5-α]pyridines are one of the most important groups of N-heterocyclic compounds, with wide applications in pharmaceutics, chemical science and material science. Despite tremendous progress in their synthesis over the past decade, a number of important imidazo[1,5-α]pyridines as intermediate products remain inaccessible, such as 1-alkylimidazo[1,5-α]pyridines. Herein, we report a novel anomeric stereoauxiliary approach for the preparation of this important class of compounds. It strongly expands the scope of readily accessible imidazo[1,5-α]pyridines well beyond the existing state-of-the-art methods. More than 80 products with a substantial number of deemed unattainable ones were synthesized. With the rst time accessibility to alkyl(pyridine-2-yl)methanone substrates, a group of important deuterated imidazo[1,5-α]pyridines derivatives were also eciently achieved. The mechanism containing a key seven-membered ring transition state via α-anomeric stereoauxiliary for this new synthetic pathway is provided in great detail and supported by electronic structure calculations. In total, this novel synthetic approach for a broad range of imidazo[1,5-α]pyridines involving the native stereochemistry will open a new window for research endeavors in diverse elds, encompassing organic synthesis, biomass conversion via cleavage of C-N bonds and medicinal chemistry.

Carbohydrates as chiral auxiliaries in stereoselective synthesis 16,17 and stereochemistry of transition metal complexes controlled by the metallo-anomeric effect 18 have drawn much attention until today.
Depending on the suitable pKa aqueous solution, the α/β-anomers of D-glucosamine exist with adjustable ratios. 19,20 Inspired by these different stereochemical structures of α/β-anomers, we report herein an novel anomeric stereoauxiliary approach for the preparation of these important class of imidazo [1,5-α]pyridines which expands the scope of readily accessible products (more than 80) relative to existing state-of-the-art methods (Fig. 1b).
Reaction development. We commenced our study by probing various reaction conditions for imidazo [1,5α]pyridines by using 2-acetylpyridine (1a), 2-methylbenzaldehyde (2a) and diverse nitrogen sources (Supplementary Table 1 and Fig. 2a). After extensive experimentation, we got the optimal condition for the e cient synthesis of imidazo [1,5-α]pyridines of 74% yield with D-glucosamine as nitrogen source in the solvent mixtures (v AcOH :v H2O of 9:1) at 120 ˚C under Ar gas atmosphere (Fig. 2a). Then, the commercial acetylated amine sugars as stabilized α-anomer (3b) and β-anomer (3c) were used for the reactions under the optimal conditions (Fig. 2a). The α-anomer of acetylated D-glucosamine led to 30% yield, while only trace of the product was detected using the β-anomer. Therefore, the α-anomer of Dglucosamine with the hydroxyl group at the neighbor C1 position should play an important role for imidazo [1,5-α]pyridines. Besides, the scope with D-mannosamine under the same conditions led to a yield of 41% in the presence of a major β-anomer distribution (α/β = 0.79/1). This result further veri ed that the con guration of amine and hydroxyl group should be on the same side to cooperatively cleave C-N bonds for imidazo [1,5-α]pyridines. Various amines 3e to 3i were also scoped. As a result, only 3e ful lling these con guration requirements generated the highest yield of 16%.
To explore the correlation between the yield of imidazo[1,5-α]pyridines 4 and the anomer of Dglucosamine in solvents with diverse pKa, solvent mixtures with various pKa (0.9 mL) and H 2 O (0.1 mL) were investigated under the optimal conditions (Fig. 2b). It should be noted that the ratio between αand β-anomer of D-glucosamine (refers as α/β) highly depends on the pKa of solvents. Solvents with higher pKa, such as HFIP (pKa: 9. stabilize the methyl group of alkyl(pyridine-2-yl)methanone, and to hinder the deprotonation of the methyl group. 28 Substrate scope. With the optimized reaction conditions in hand, we rst probed the scope of various aldehydes amenable to this process using 2-acetypyridine as a representative heteroaryl ketones (Fig. 3).
An array of aromatic aldehydes, including those with electron-donating or -withdrawing groups at different positions (ortho, meta or para), was used for the e cient transformation into corresponding products 4-23. A variety of common functional groups at diverse positions, such as methoxyl (11 and 12), halogens (14-18), tri uoromethyl (19), nitro (20), nitrile (21) and ester (22), were well compatible with these conditions. It is noteworthy that free para-dialdehyde (23) and ortho-phenolic hydroxyl (13) were also tolerated in this protocol. The structure of 20 was determined by X-ray crystallographic analysis, and those of other products in Fig. 3 and 4 were assigned by analogy. Moreover, 2-phenylacetaldehyde (product 24), cinnamaldehyde (product 25), 1-naphthaldehyde (product 26) and heterocyclic aldehydes (product 27-28) were also well compatible with this reaction approach. Furthermore, a series of aliphatic aldehydes, including cyclic aldehydes (product 29-30) and aliphatic chain aldehydes (product 31-34), could also be transformed into corresponding products.
Synthetic applications. Certain imidazo [1,5-α]pyridines with multiple substitutions have interesting optical properties and ligand effects due to the conjugation and the presence of lone pair electrons in nitrogen and oxygen atoms. Because of the di culty for the regioselective functionalization and the interference of potential side reactions, there is still no e cient method to synthesize such compounds so far. In our method, bi-functionalization of dialdehyde (product 61) substantially took place after 3 days (Fig. 5a).
Isotope labeling, such as deuterated ne chemicals, has a broad range of applications, for instance for drug absorption, distribution, metabolism and excretion, for the investigation of reaction processes and for imaging. [29][30][31][32] The rst deuterated drug, deutetrabenazine, was approved by FDA in 2017. 33 Because of the versatile functionalities of imidazo [1,5-α]pyridines that are interesting for diverse elds ranging from material science to pharmaceutics, e cient synthetic methods for deuterated building blocks of imidazo [1,5-α]pyridines derivatives are highly desired.
The protons at the α-position of pyridine ketone and aliphatic aldehydes could reversibly exchange protons with acidic aqueous surroundings ( Supplementary Fig. 18-19). Therefore, in our work, deuterated imidazo[1,5-α]pyridines were readily synthesized via one-pot process with the simultaneous cleavage of C-N bond of D-glucosamine. The aromatic aldehydes with electro-withdrawing and electro-donating groups at diverse positions were transformed into deuterated products with high yields for 66-81 (Fig. 6). Moreover, 1-naphthaldehyde, pyridine aldehyde and cyclopentyl(pyridin-2-yl)methanone were also compatible with the reaction condition (products 82, 83 and 86). In addition, the products 84 and 85 even achieved the e cient deuteration at multiple positions.
Mechanistic considerations. To gain insight into the mechanism, four groups of control experiments were conducted ( Fig. 7 and 8). First, intermediates 3j and 3k were used to verify the reaction order (Group 1 in Fig. 7a-7b). 34,35 As a result, product 13 was detected via 1 H-NMR spectra and con rmed via HR-ESI-MS spectra (Group 1 in Fig. 7a), while product 4 was not detectable (Group 1 in Fig. 7b). Therefore, Dglucosamine should have reacted with aldehyde at rst to form the imine intermediate.  Fig. 7f). 36 In further control groups, 1,3,4,6-tetra-O-acetyl-2-amino-2-deoxy-β-D-glucopyranose hydrochloride (3b) and 1,3,4,6-tetra-O-acetyl-2-amino-2-deoxy-α-D-glucopyranose hydrochloride (3c) were tested under the same conditions (Group 3 in Fig. 8a-8b). As a result, the product 4 with 30% yield was obtained using 3c (αanomer), while 3b (β-anomer) could only achieve 8% yield of product 4. Based on the results shown in Fig. 7, plausible reaction pathways for TS α and TS β are proposed in Fig. 8 to explain the distinct reaction activities between 3c (α-anomer) and 3b (β-anomer). First, in comparison to 3b (β-anomer), 3c (α-anomer) should favor the formation of the E isomer of imine due to the steric hinderance (Fig. 8a). Moreover, the αanomer promotes the formation of a seven-membered ring transition state with the acetate anion in solutions via hydrogen bonds. This ring of the α-anomer transition state (TS α ) not only could help to stabilize the intermediate during the cleavage of the C-N bond, but also shows a favourable alignment with the aromatic ring. With the 3b (β-anomer) (Fig. 8b), a seven-membered ring transition state under βanomer forms via a hydrogen bond between the acetyl group of the β-anomer and the acetate anion. The E isomer of imine is easier to form, 35 especially the stronger steric shielding from seven-membered ring transition state. The ring of the β-anomer transition state (TS β ) shows a disfavourable alignment with aromatic ring. The energy states of both TS α and TS β were calculated by electronic structure calculations (Fig. 9b).
Proposed mechanism. Hence, based on the results shown in Fig. 2, 7 and 8, a seven-membered ring of αanomer transition state (TS α ) should be formed via hydrogen bonds, which favors the following cleavage of the C-N bond. [37][38][39] Combining all results, a plausible mechanism is proposed (Fig. 9a) Based on the proposed mechanism and control experiments, theoretical calculations were performed for the reaction step of the C-N bond cleavage (D→E+H) with the consideration of the stereoselectivity to further support the proposed mechanism. The calculated nal Gibbs free energy of the transition state of the α-anomer (TS α in Fig. 9b) was 0.9 kcal/mol lower than that of the β-anomer (TS β ). Since the reactant connected to TS α (D α ) was 0.7 kcal/mol higher than that connected to TS β (D β ), the reaction barrier of the α-anomer is thus 1.6 kcal/mol lower than that of the β-anomer (22.2 vs. 23.8 kcal/mol). Given that the two anomers do not stand in kinetic competition (they are utilized in separate reactions), the latter value should be taken as the actual barrier difference. The acetate molecule stabilizes the transition state via the hydrogen bond as depicted in Fig. 5a, which is ultimately transferred. The ring system, as schematically shown in Fig. 5b, aligns with the carboxylic group, with dispersion forces reducing the barrier. This stands as a further example for the importance of London forces in stereoselectivity. 41 The α/β-ratio for the mixture of D-glucosamine and HCl was determined using the same theoretical method. Three conformers (Fig. 9c) were taken into consideration for each anomer, where the chloride might interact with each of the hydrogen atom of the protonated amine group. The Gibbs free energy of the α-v1-conformer was taken as reference for all the energy terms listed in Fig. 9c. For each anomer the Gibbs free energy was obtained by averaging the Gibbs free energies of the three conformers with their Boltzmann-factors and applying conformational entropy corrections. The resulting nal Gibbs free energy was -0.1 kcal/mol for the α-anomer and 0.8 kcal/mol for the β-anomer, respectively. The energy difference of 0.9 kcal/mol corresponds to an α/β-ratio of 3.1 at the reaction temperature of 393.15 K. This difference would be reduced to 0.55 kcal/mol if one excludes the chloride anion. Such energy difference corresponding to an α/β-ratio of 2.0 gives us a range, which comfortably accommodates the experimental observations.
In summary, we have developed a novel α-anomeric stereoauxiliary strategy to e ciently access to diverse imidazo [1,5-α]pyridines products (more than 80). This includes important with/withoutdeuterated 1-alkylimidazo [1,5-α]pyridines. Control experiments and DFT calculations revealed that a seven-membered ring in the α-anomer transition state (TSα) formed in site facilitates the cleavage of C-N bonds and was stabilized by dispersion interactions to a neighboring aromatic ring. We believe that this approach for the synthesis of imidazo [1,5-α]pyridines by using native stereochemistry of D-glucosamine will be of signi cant and general interest for chemical synthesis. Workup: The reactions were conducted in a sealed Schlenk tube and heated by an IKA magnetic heating agitator with oil bath. The reaction temperature was directly read from temperature detector of IKA apparatus and was calibrated by thermometer. After cooling to room temperature, the reaction mixture was basi ed up to pH 7 using Na 2 CO 3 aqueous solution, extracted by diether (3×3 mL) and dried over anhydrous Na 2 SO 4 . After ltration and concentration on rotary evaporator, the crude product was puri ed with ash chromatography on silica gel (ethyl acetate : n-hexane : Et 3 N) to give products 4-62. The deuterated products 66-86 were synthesized through the same procedure B in AcOH-d 4 : D 2 O (0.9 mL : 0.1 mL) solvent.

Declarations Data availability
The data that support the ndings of this study are available in the Supplementary Information (experimental procedures and characterization data). Crystallographic data have been deposited at the Cambridge Crystallographic Data Centre (CCDC) as CCDC 2068036 (20) and 2068037 (51) and can be obtained free of charge from the CCDC via www.ccdc.cam.ac.uk/structures. Diverse methods for imidazo [1,5-α]pyridines. a The representative example of previous strategies for the preparation of imidazo [1,5-α]pyridines. b Our strategy through anomeric stereoauxiliary cleavage of C-N bond for imidazo [1,5-α]pyridines.     One-pot synthetic applications for diverse deuterated imidazo [1,5-α]pyridines. All yields are isolated products and the D incorporation was measured by 1H-NMR analysis.  Mechanistic studies of anomeric stereoauxiliary control experiments. a A favourable alignment shows when using α-acetyl-glucosamine (3c). b A disfavourable alignment shows when using β-acetylglucosamine (3b). Figure 9 a Proposed mechanism. b Density functional theory calculations for the step reaction of D intermediate of Fig. 5a to intermediates E and H. c Simpli ed scheme of the computed DFT conformers for the mixture of D-glucosamine and HCl, discriminated according to the respective anomers. The relative energies (in kcal/mol) in respect to the most stable conformer are provided.