Direct nitrogen interception from chitin/chitosan for imidazo[1,5- a ]pyridines †

A catalyst-free one-pot methodology that enables direct nitrogen interception of chitosan/chitin for imidazo[1,5- a ]pyridines was developed. This strategy features direct synthesis of important deuterated imidazo[1,5- a ]pyridines and tridentate ligands. In particular, a broad group of previously inaccessible products including saturated 1-alkylimidazo[1,5- a ]pyridines are unprecedently synthesized by this protocol.

Chitin and chitosan are abundant native linear polymers composed of randomly distributed units, namely, N-acetyl-Dglucosamine (GlcNAc) and D-glucosamine (GlcN) linked by b-1,4-linkages. 1 The quantities of GlcNAc units are generally more than 50% in chitin, while chitosan contains less than 50% GlcNAc and has thus a degree of deacetylation (DD) of more than 50%. [2][3][4] Human processing of sustainable chitincontaining raw materials represents only a very minor fraction of all the chitin produced annually in nature, 5-10 while the major fraction remains intact. 11 On the other hand, low molecular weight nitrogen-containing chemicals (NCCs) play a pivotal role in modern life, from pharmaceutical, agriculture and food fields to material fields. [12][13][14][15][16] The nitrogen source of prevailing industrial processes for NCCs is mainly from NH 3 , NO 3 À and NO 2 À etc., which are obtained from N 2 fixation. [17][18][19][20][21][22][23][24][25] The quantities of nitrogen element fixed annually in chitin via the biochemical process are much more than the N 2 fixed in the Haber-Bosch process. 26 Therefore, the transformation of renewable chitin containing fixed nitrogen into value-added NCCs has drawn much attention. 14 Four types of strategies are currently known for the activation of amines in chitin/chitosan (Scheme 1a). The first strategy (i) is referred to as the direct modification of amines on the chitosan/chitin backbone without the cleavage of C-N bonds. 5 The second strategy (ii) involves the cleavage of C-N bonds via strong oxidants or acidic conditions with the simultaneous release of N 2 , acetamide and ammonium salts. [27][28][29] Recently, the third strategy (iii) has emerged in biorefineries by converting chitin/chitosan into a preliminary C6 backbone via a depolymerization and by further conversion of the C6 backbone into diversified products. 14,26,30 Although various protocols have been established through enzymatic, catalytic and/or hydrothermal treatments, only more than 10 NCC examples (including sugar derivatives, amino alcohols and furanic amides) have been obtained with complicated conditions and a low efficiency. The fourth strategy (iv) involves the cleavage of C-N bonds of chitin for the assembly of pyrrole with a low yield of 4%, which was realized in alkali aqueous solution at 300 1C in 2016. 31 In particular, it should be stressed that the synthesis of N-heterocycles from chitin/chitosan biomass is challenging and introducing an unsustainable nitrogen source such as NH 3 is the main pathway for the construction of N-heterocycles from biomass. [32][33][34] The C-N bond of chitin/chitosan that offers a potential reactive site for various versatile chemical diversifications generally remains intact. Therefore, a one-pot protocol enabling the targeted efficient incorporation of nitrogen from chitin/chitosan into diverse valuable NCCs like N-heterocycles is highly attractive, which will advance the existing methodologies while expanding the library of NCCs derived from renewable sources.
We initiated our studies by using 2-acetylpyridine (1a) and 2-methylbenzaldehyde (2a) as substrates to evaluate the envisioned nitrogen interception from chitosan for desired imidazo[1,5-a]pyridine 3 employing metal-free conditions. At the outset, product 3 was detected by 1 H NMR analysis under conditions with a solvent mixture of AcOH/H 2 O (0.9/0.1 mL) (Table S1, entries 1 and 2, †). After that, several silver salt additives were investigated. Interestingly, the yield of 3 was increased obviously from 3% to 13% when silver trifluoroacetate (AgTFA) was exploited, while silver acetate (AgOAc) was not beneficial for the efficacy (Table S1, entries 3 and 4, †). These results indicated that the anion À OCOCF 3 in AgTFA might facilitate the transformation. Therefore, a solvent mixture of CF 3 COOH/H 2 O (0.9/0.1 mL) was employed as a substitute of the previous solvent AcOH/H 2 O (0.9/0.1 mL). To our delight, the yield was improved to 29% when CF 3 COOH/H 2 O was used as reaction media (Table S1, entry 5, †). Then, a higher yield (61%) was achieved with CF 3 COOH (1.0 mL) as the solvent (Table S1, entry 6, †). Besides, diverse reaction temperatures, ranging from 90 1C to 140 1C, were examined (Table S1, entries 7 and 8, †). Thus, the optimal temperature was determined to be 140 1C and a 78% yield was obtained. Moreover, the reaction was conducted at 12 h, 24 h and 36 h with a yield of 31%, 59% and 78%, respectively. The lower equivalent of chitosan leads to inferior yield. Combining all factors regarding the equivalent of chitosan, reaction temperature and time, the optimal reaction conditions were identified as shown in entry 8: 140 1C for 36 h (Table S1, †).
With the optimized reaction conditions in hand, we next explored the versatility of metal-free nitrogen interception from chitosan with various aldehydes for NCCs (Scheme 2). A series of aromatic aldehydes, including those bearing electrondonating or electron-withdrawing groups at different positions (ortho, meta or para) were subjected to the optimized conditions. As a result, these aldehydes could be efficiently transformed into the corresponding products 3-23. Aldehydes with electron-donating groups, such as methyl, isopropyl and methoxy groups (3)(4)(5)(6)(7)(8)(9)(10)(11), are well compatible with the transformations, while lower yields were obtained for substrates with a hydroxyl group and dimethylamino group (12 and 13). The reason could be that the dimethylamino and hydroxyl groups with high nucleophilicity are much more sensitive to carbonyl groups. Surprisingly, a larger scale (1a, 0.5 mmol) with a lower load of chitosan (2.0 equiv.) in a smaller volume of TFA (0.5 M) was also well compatible for the desired product 4 (Fig. S4,  †). In addition, electron-withdrawing substituents, including halogen and trifluoromethyl groups, were well accommodated (14)(15)(16)(17)(18)(19). Moderate yields were achieved for aldehydes with nitro and nitrile groups (20 and 21). It is noteworthy that the challenging para-dialdehyde also delivered the corresponding products with diverse conditions (22 and 23). With the controllable reaction conditions, products 22 and 23 can be obtained separately, but it is not excluded that there is a tiny amount of 23 in 22, and a small amount of 22 in 23 (the amount can be ignored). Furthermore, 1-naphthaldehyde (24), thiophene-2-carbaldehyde (25) and nicotinaldehyde (26) were also amenable in our protocol. In addition to aromatic aldehydes, those aliphatic aldehydes (27)(28)(29)(30) were well compatible with the protocol.
Isotope labeling showed important applications in drug absorption, distribution, metabolism and excretion. [35][36][37] Inspired by the H-D exchange between a-C-H of the pyridine ketone and CF 3 COOD solvent, a variety of C(sp 3 )-H deuterated imidazo[1,5-a]pyridines derivatives were synthesized in a onepot procedure (Scheme 3). Those aromatic aldehydes, pyridine aldehyde and cyclic aliphatic aldehyde were synthesized with deuterated incorporation of products (46-55). In addition, it is worth noting that the proton of the aromatic aldehyde with a hydroxy group and methoxy group could also be deuterated under this condition (47-49).
Moreover, 11% of ammonium was trapped via 1 H-NMR analysis, which could provide support for the major release of nitrogen after condensation into an intermediate, such as imidazo[1,5a]pyridine-2,4-diium or imidazo[1,5-a]pyridin-4-ium (Fig. S2,  †). Besides, an imidazo[1,5-a]pyridin-4-ium 3 0 was confirmed by ESI-HRMS analysis (calc. for C 15 . S3,  †), which reveals a pathway for imidazo[1,5-a]pyridine 3 via deprotonation of 3 0 . Based on the control experiment ( Fig. S2 and  S3, †), a plausible reaction pathway was proposed. First, deacetylation takes place which enables the transformation of chitin to chitosan. 38  In summary, we have developed a new strategy for the rapid assembly of NCCs with ample scope through the direct use of native nitrogen sources from biomass. This strategy is achieved through a one-pot conversion approach of chitin/chitosan by cleaving the C-N bonds and simultaneously integrating the nitrogen in the synthesis of a broad range of imidazo[1,5-a]pyridines (52 examples) that show diverse potential applications. A broad group of previously inaccessible products including saturated 1-alkylimidazo[1,5-a]pyridines is unprecedently synthesized by this protocol. The amine groups of the chitin/chitosan backbone are intercepted via aldehyde and pyridine ketone assisted with CF 3 COOH under metal-free conditions. We believe that this approach will initiate research endeavors for the targeted efficient incorporation of nitrogen from biomass for high-value NCCs.
Kai Zhang thanks German Research Foundation (DFG) for the financial support for the project with the grant number ZH546/3-1 and University of Göttingen for the Department Start-up funding. Kui Zeng thanks China Scholarship Council for the PhD grant.