Application of Silica-Supported Alkylating Reagents in a One-Pot, Sequential Protocol to Diverse Benzoxathiazepine 1,1-Dioxides.

Applications of silica-ROMP reagents in a one-pot, sequential protocol have been developed for the synthesis of a variety of diverse benzoxathiazepine 1,1-dioxides. This protocol includes sulfonylation, intramolecular SNAr, alkylation with silica-supported oligomeric benzyl (Si-OBPn) and triazole (Si-OTPn) phosphates, and intermolecular SNAr addition with a number of secondary amines in one-pot to afford a variety of unique benzoxathiazepine 1,1-dioxides sultams in good to excellent yields.

Multicomponent reactions in one-pot processes are efficient pathways to synthesize complex heterocyclic scaffolds from simple building blocks.[1] One-pot strategies enable the formation of multiple bonds and stereocenters in one synthetic step, as well as reducing purification resources, time and waste. This process minimizes the need of workup and procedures for chromatographic separations of intermediary reactions. Among several literature reports, elegant efficient efforts by Hayashi[2] have demonstrated the power of consecutive one-pot, sequential procedures to complete multistep syntheses.

The utilization of immobilized reagents in one-pot protocols can further integrate synthesis, diversification, and purification into one parallel process to rapidly expand efforts in early stage drug discovery.[3] A number of technologies for immobilization of reagents and catalysts have been developed, including those based on polystyrene resins,[4] Janda-gels and microporous resins,[5] soluble polyethylene glycol (PEG) polymers,[6] monolith,[7] fluorous-tagging,[8] and silica.[9] In particular, silica-supported reagents and scavengers have shown a number of advantages that can exploited in synthesis, including (i) elimination of the precipitation step, (ii) avoidance of polymeric swelling, and (iii) providing a free-flowing solid support for ease of handling. These features have inspired the recent development of a number of silica-supported reagents and catalysts.[10] A critical part of developing successful silica-supported reagents and scavengers is finding a suitable technology to install functional groups on the surface of silica. The use of ring-opening metathesis polymerization (ROMP) to attach functional groups on Nb-tagged silica core, has proven to be an efficient method for high-load functionality on cost-effective and environmentally benign silica particles.[11] A number of ROMP-derived Si-supported reagents have been developed in our group.[12] To expand the applicability of our recently developed silica-immobilized benzyl phosphate Si-OBP and triazole phosphate Si-OTP reagents,[13,14] we herein report studies aimed at the use of Si-OBP and Si-OTP in one-pot, sequential protocols for the facile synthesis of diverse benzothiaoxazepine-1,1-dioxides.

Benzothiaoxazepine-1,1-dioxides are unique scaffolds,[15] that have shown a broad range of bioactivities, including inhibition against a variety of enzymes.[16] Substituted benzothiaoxazepine-1,1-dioxides have shown activity as antipsychotic agents,[17] modulators of histamine H3-recceptor,[18] glucokinase activators,[19] and modulators of AMPA receptors (Figure ).[20] The current demand is to develop step-economical methods, which can facilitate the synthesis of these biologically inspired sultams in a desirable fashion. In light of our recent approaches for the synthesis of scaffolds containing benzothiaoxazepine-1,1-dioxides,[21] herein, we further elaborate the importance of 2,4-difluoroarylsulfonyl chloride (4) as an attractive building block for the generation of these scaffolds.

Figure 1

Biologically active benzothiaoxazepine-1,1-dioxide-containing sultams.

The titled silica phosphate reagents, Si-OBP and Si-OTP, were synthesized from norbornenyl-functionalized silica (Si–Nb) 1 and Nb-tagged phosphate monomers 2a–2e using a similar protocol reported in our previous work.[12] Surface-initiated polymerization of these monomers onto the surface of silica was achieved using the Grubbs second-generation catalyst (G-II) in toluene-CH2Cl2.[22] Following the reported procedure, the desired Si-ROMP benzylating Si-OBP3a–3c (n ≈ 50) and triazolating Si-OTP3d–3e (n ≈ 50) reagents were furnished as free-flowing solids on gram-scale.

With Si-OBP reagents 3a–3c and (triazolyl)methylating reagents Si-OTP3d–3e in hand, we directed our attention for their utilization in the titled one-pot sequential process. Thus, we planned to achieve sulfonylation, intramolecular nucleophilic aromatic substitution (IM-SNAr), alkylation (Si-OBP and Si-OTP) and intermolecular SNAr reactions using the same solvent (DMF) in an overall one-pot protocol. The synthesis started with commercially available 2,4-difluorobenzenesulfonyl chloride (4), and a simple chiral amino alcohol 5 to achieve sulfonylation at room temperature using Et3N in DMF. The resulting sulfonamide 6 next underwent facile IM-SNAr cyclization using microwave conditions at 140 °C in the same pot to furnish benzothiaoxazepine-1,1-dioxide 7 (Scheme ). Further diversification of 7 was achieved through use of Si-OBPn and Si-OTPn for benzylation and (triazolyl)methylation, respectively. Successful benzylations using Si-OBPn3a of the corresponding cyclic sulfonamides were achieved in the same pot by heating the reaction mixture to 80 °C for 10–12 h. The final intermolecular SNAr reaction (150 °C under microwave irradiation) with a variety of cyclic five- or six-membered secondary/aromatic amines afforded diverse benzofused sulfonamides 10a–10e in the same pot (Table , entry 1–5).

Scheme 2

Synthesis of Benzothiaoxazepine-1,1-dioxides in a One-Pot, Sequential Protocol

Table 1

One-Pot Synthesis of Benzothiaoxazepine-1,1-dioxides Utilizing Various Si-OBP Reagents

In the next stage, different variants of silica-immobilized benzylating reagents 3b–3c were employed in similar one-pot procedures, and the desired N-benyzlated benzoxathiazepine 1,1-dioxides 10f–10j were achieved after the final intermolecular SNAr reactions (DMF, 150 °C under microwave irradiation), again using a variety of cyclic five-membered secondary/aromatic amines (Table , entry 6–10).

We next studied diversifications via sulfonamide N-(triazolyl)methylation utilizing Si–OTP reagents 3d–3e as summarized in Table . These efforts were driven by the biological importance of 1,2,3-triazole-containing scaffolds,[23] as well as their effective mimicry of trans-amide bonds due to similarity in size, planarity, dipole and H-bonding capabilities.[24] To consider the biological importance of benzoxathiazepine 1,1-dioxides, we planned to design a small library of diverse N-(triazolyl)methylated benzoxathiazepine 1,1-dioxides derivatives using a similar one-pot protocol as described above.[25] Subsequent intermolecular SNAr reaction in the same pot using various cyclic amines afforded the desired N-(triazolyl)methylated benzoxathiazepine 1,1-dioxides 11a–11e in high yield, 70–92% over four sequential steps, representing average yields of 91.5–98% per reaction (av/rxn) (Table ).

Table 2

One-Pot Synthesis of Benzofused Sultams Utilizing Variable Si-OTP Reagents

The one-pot, sequential protocol employing Si-alkylating reagents 3a–3e highlights the importance of our recently developed silica-immobilized reagents, which allow for facile direct N-benzylation or N-(triazolyl)methylation. Overall, grafting of Nb-tagged silica particles with functionalized Nb-tagged phosphate monomers using ROM polymerization efficiently yields high-load, hybrid Si-immobilized oligomeric benzyl (Si-OBP) and triazole phosphates (Si-OTP). We have now demonstrated applications of these Si-ROMP reagents in the diversification of core scaffolds to achieve the synthesis of a variety of unique benzoxathiazepine 1,1-dioxides in a one-pot, sequential protocol. Efforts to expand the scope of these reagents to various drug-related molecules, and improvement in synthesis and scale-up are continued for application in diversity-oriented synthesis.