Synthesis of High-Load, Hybrid Silica-Immobilized Heterocyclic Benzyl Phosphate (Si–OHBP) and Triazolyl Phosphate (Si–OHTP) Alkylating Reagents

Abstract

The development of new ROMP-derived silica-immobilized heterocyclic phosphate reagents and their application in purification-free protocols is reported. Grafting of norbornenyl norbornenyl-functionalized (Nb-tagged) silica particles with functionalized Nb-tagged heterocyclic phosphate monomers efficiently yield high-load, hybrid silica-immobilized oligomeric heterobenzyl phosphates (Si–OHBP) and heterotriazolyl phosphates (Si–OHTP) as efficient alkylation agents. Applications of these reagents for the diversification of N-, O-, and S-nucleophilic species, for efficient heterobenzylation and hetero(triazolyl)methylation have been validated.

Heterocycles are prevalent in small molecule drugs and natural compounds¹ and often they are used to manipulate structural and electronic properties of small molecules that are key to regulating molecular lipophilicity, polarity, and hydrogen bonding capacity.² Despite these attributes, introduction of N-heterocyclic functionality into core structures can be problematic in subsequent purification stages due to increased polarity and basicity in combinatorial synthesis. Immobilized reagents offer many advantages that can potentially circumvent these issues. Compared to traditional solution-phase synthesis, solid-phase techniques³ have shown advantages in simplifying the purification process, especially in flow-through chemistry and automated synthesis.⁴ As part of our program aimed at the development of immobilized reagents to facilitate synthetic pathways, we herein report the development of hybrid silica-immobilized oligomeric heterobenzyl phosphates (Si–OHBP_n) and heterotriazolyl phosphate (Si–OHTP_n) as efficient alkylating reagents. We envision that, these high load ring-opening metathesis polymerization (ROMP)-derived reagents are highly applicable in purification-free protocols to install heterocycles, namely pyridines and pyridine-substituted triazoles in N-, O-, and S-nucleophilic species, in the synthesis of complex molecules. In addition to these benefits, the titled Si–OHBP_n and Si–OHTP_n reagents are bench stable, environmental friendly, and have ease of purification via simple filtration through Celite. Furthermore, the low cost, commercial availability of the starting pyridine methanol derivatives, as compared to their corresponding bromomethylpyridines, is another advantage that inspired us to produce the titled silica-supported phosphate analogs.

When compared to their polymeric counterparts, silica-supported reagents and scavengers have shown a number of advantages, including (i) elimination of the precipitation step and (ii) elimination of polymeric swelling. These features have inspired the recent development of a number of silica-supported reagents/catalysts, include an isocyanide reagent⁵ developed by Diver and co-workers for the removal of ruthenium, a chiral dirhodium(II) catalyst⁶ developed by Davies and co-workers for enantioselective carbenoid reactions, an iron BPMEN-inspired catalysts⁷ for C–H bond functionalization and hybrid sulfonic acid catalysts⁸ demonstrated by Jones and co-workers, a tungsten oxo alkylidene⁹ as a highly active metathesis catalyst developed by Copéret–Schrock and co-workers, and a peracid¹⁰ developed by González-Núñez and co-workers for the epoxidation of olefins.

A critical part in developing successful silica-supported reagents and scavengers is to find a suitable technology to install functional groups on the surface of silica. There have been, a number of grafting methods reported for immobilized compounds, such as immobilized polystyrene resins,¹¹ silicas,¹² soluble polyethylene glycol (PEG) polymers,¹³ monolith,¹⁴ and fluorous-tagged compounds.¹⁵ In particular, using ring-opening metathesis polymerization (ROMP) to attach functional groups on Nb-tagged silica core, have been proven to be an efficient method to bring high-loading functionality on cost-effective and environmentally benign silica particles.¹⁶ A number of ROMP-derived Si-supported reagents have been developed, including oligomeric bis-acid chloride Si-OBAC₅₀ as scavenger,¹⁷ dichlorotriazine Si-ODCT₅₀ as a coupling reagent,^17a and triphenylphosphine Si-OTPP₅₀.^17a Recently, our group has reported silica-immobilized benzyl phosphate Si-OBP_n and triazole phosphate Si-OTP_n as efficient alkylating reagents.¹⁸ Taken collectively, these examples have showcased the synthesis of high-load, ROMP-derived silica-immobilized reagents and their utilization in a variety of organic reactions.

The route to the titled phosphates began with reduction of exo-norbornenyl carbic anhydride (readily derived from commercially available endo-norbornenyl carbic anhydride)¹⁹ to the corresponding diol using LiAlH₄, followed by phosphorylation of the norbornenyl (Nb) exo-diol 1 using freshly distilled POCl₃ and Et₃N, to afford the Nb-phosphorochloridate 2 as a white solid in 73% yield (Scheme 1). This reagent was conveniently stored up to several months as a solid over argon in a desiccator for use in preparing various phosphate monomer analogs. Addition of 2 into a solution containing heterobenzyl alcohol, NMI, and CH₂Cl₂ at room temperature cleanly afforded heterobenzylic phosphates 3a–3b in good yields (65–70%). Similarly, phosphorylation of Nb-tagged phosphorochloridate 2 with propargyl alcohol, followed by a “click”-capture event of an azidomethylpyridine, afforded the corresponding heterobenzylic triazole phosphate monomers 4a–4b in good yields (63–65% over two steps).

Scheme 1. Synthesis of Hetero-benzyl and Hetero-triazole Phosphate Monomers.

Utilizing a similar protocol reported in our previous work,^17a we tagged activated silica (60 Å, 20 μm particle size) with (MeO)₃Si-(CH₂)₂–(Nb) 5, and the unreacted hydroxyl groups were capped with trimethoxymethylsilane and dimethoxydimethylsilane (Scheme 2). Using this method, we obtained Nb-tagged silica particles (Si–Nb) 6 in gram-scale quantities with 0.3–0.4 mmol/g loading (determined using a bromine titration method).²⁰ It should be noted that we observed an increased norbornene loading of Si–Nb when (MeO)₃Si–(CH₂)₂–(Nb) [(2-(bicyclo[2.2.1]hept-5-en-2-yl)ethyl)trimethoxysilane] was utilized, as compared to using bicyclo[2.2.1]hept-5-en-2-yltriethoxysilane.

Scheme 2. Synthesis of Silica-Supported Oligomeric Hetero-benzyl (Si–OHBP_n) and Hetero-triazole (Si–OHTP_n) Phosphates.

With these Nb-tagged silica particles in hand, surface-initiated polymerization of Nb-tagged phosphate monomers 3a–3b and 4a–4b onto the silica surface was achieved using the Grubbs second-generation catalyst (G-II), followed by washing with CH₂Cl₂, to furnish the desired silica-tagged heterocyclic phosphates as free-flowing solids possessing experiment loads of 1.1–1.7 mmol/g (Scheme 2).¹⁷ Gram-scale syntheses were next carried out for both Si-ROMP heterobenzylating (Si–OHBP_n) and hetero(triazolyl)methylating (Si–OHTP_n) reagents, 7a–7b and 7c–7d, respectively. The SEM images of Si–OHBP_n and Si–OHTP_n are shown in Figure 1 and depict grafting of the corresponding monomer onto the silica surface and the inherent morphology of the new hybrid Si-ROMP materials.

Figure 1.

SEM images of Si–OHBP_n (left) and Si–OHTP_n (right).

With the hybrid Si-ROMP materials in hand, efforts were focused on utilization of Si–OHBP_n7a–7b as heterobenzylating reagents. After investigating various reagent stoichiometry an optimized condition was established by using nucleophiles (1 equiv), Si–OHBP_n (1.5 equiv), Cs₂CO₃ (3.0 equiv), and NaI (0.2 equiv) in 0.1 M THF at 80 °C (oil bath temperature) in a sealed pressure tube. With these optimized conditions, the heterobenzylation of a variety of N-, O-, and S- nucleophiles was achieved using two silica oligomeric heterobenzyl phosphates (Si–OHBP_n, 7a–7b) (Table 1). Various phenols and thiophenols, as well as more complex sulfonamides were successfully alkylated to afford the corresponding heterobenzylated products 8a–8i (Table 1). In all cases, simple filtration through a Celite SPE allowed the products to be isolated in good to excellent yields (70–99%) and desired crude purity (>90%, calculated by UV area percent from HPLC analysis).

Table 1. Hetero-benzylation of N-, O-, and S-Nucleophiles Utilizing Si–OHBP_n.

With these results in hand, silica-immobilized triazole phosphate derivatives 7c–7d were synthesized on gram scale having load of 1.1–1.3 mmol/g as free-flowing powders. Utilization of these reagents in nucleophilic substitution reactions with N-, O-, and S-nucleophiles afforded (triazolyl)methylated products 9a–9f in excellent yield (81–93%) and purities (>90%, calculated by UV area percent from HPLC analysis) using simple filtration through a Celite SPE (Table 2).

Table 2. Hetero-(triazolyl)methylation of N-, O-, and S-Nucleophiles Utilizing Si–OHTP_n.

Efforts to expand the scope of these reagents in multicomponent reactions (one-pot processes) toward drug-related heterocycles, and improvement in scale-up are continued for further applications in diversity-oriented synthesis. These efforts and corresponding results will be reported in due course.

Grafting of Nb-tagged silica particles with functionalized Nb-tagged heterocyclic phosphate monomers using ROM polymerization efficiently yields high-load, hybrid Si-immobilized oligomeric heterobenzyl (Si–OHBP_n) and triazolyl phosphates (Si–OHTP_n). Further application of these ROMP-derived oligomeric heterocyclic phosphate reagents have been demonstrated for diversification of various N-, O-, and S-nucleophilic species, for efficient heterobenzylation and (triazolyl)methylation in purification-free protocols. Further applications of these Si-ROMP reagents in one-pot protocols and in diversification of core scaffolds for the synthesis of drug-like molecules is underway and will be reported in due time.

Supporting Information Available

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acscombsci.6b00042.

• Experimental details and NMR spectral data for new compounds (PDF)

The authors declare the following competing financial interest(s): P.R.H. is on the Scientific Advisory Board of Materia, Inc.