Synthesis of Novel C-Pivot Lariat 18-Crown-6 Ethers and their Efficient Purification

Abstract

The syntheses of various lariat ethers including several not previously reported and their efficient purification are presented. The synthesis route brings together reactions from a variety of previous works leading to a robust and generalized approach to these C-pivot lariats. The main steps are condensation of functionalized diols with pentaethylene glycol ditosylate in the presence of potassium as a templating cation. Purification of the final products was achieved without chromatography by extracting from an aqueous potassium hydroxide solution.

Crown ethers have long been exploited as phase transfer agents in organic chemistry¹ and thus their efficient preparation has attracted the attention of numerous researchers.² An exciting variation of crown ethers involves the inclusion of a side arm on the macrocyclic which often contains metal coordinating heteroatoms. These lariat ethers, first studied by Gokel and co-workers,³ were found to confer unique cation binding properties.⁴ Carbon-pivot lariat ethers are a subclass of these compounds in which the side arm (podand) extend from a carbon atom in the macrocycle. These compounds often exhibit increased guest specificity.^5,6

We have recently used lariat ethers as metal chelating leaving groups to expedite nucleophilic substitution reactions⁷ with emphasis on the expedited radiofluorination of small molecules.⁸ Following a similar strategy, we have appended chelating leaving groups to silicon for ultrafast silicon radiofluorination using K¹⁸F.⁹ In an attempt to further improve the efficiency of silicon fluorination, we have begun to use lariat ethers as nucleophilic catalysis. For this project, we required access to gram quantities of 18-crown-6 (18-C-6) containing side-arms possessing an hydroxyl group including some derivatives not previously reported. A careful review of the literature revealed a variety of lariat ether synthesis strategies and purification methods. These reports used either vacuum distillation or column chromatography as the purification method.^10,11 In this letter, we report our development of an optimized route that takes advantage of various elements of previous reports to efficiently prepare a series of C-pivot 18-C-6 compounds.

We began with the synthesis of lariats 1d – 3d (Scheme 1). Intermediate epoxides 1a - 3a were synthesized from reaction of the appropriate alcohol¹² with epichlorohydrin in aqueous sodium hydroxide in the presence of catalytic TBAB.¹³ The resulting epoxides 1a – 3a were converted¹⁴ to functionalized diols 1b – 3b that were then reacted with pentaethylene glycol ditosylate and KO^tBu in THF under reflux conditions to afford benzyl protected lariats 1c – 3c. These intermediates were debenzylated under hydrogenation conditions^2c (H₂/Pd-C) to afford 18-C-6 lariat ethers 1d – 3d in 55% to 65% two-step yields after purification.

Scheme 1.

Synthesis of Lariats 1d – 3d

Reagents and conditions: (a) 40% aq. NaOH, TBAB, 0 °C for 1 h and then r.t. for 24 h; (b) 2% H₂SO₄, r.t., 5 h; (c) KO^tBu, pentaethyleneglycol ditosylate, THF, r.t. for 1h and then reflux for 48 h; (d) Pd-C, H₂, EtOH, r.t., 48 h.

The overall yields for our lariat products were between 40% and 53%, a substantial improvement over previously reported methods. For example, for compound 1d, synthesized by a number of groups, our overall yield was 53% in four steps. Fukunishi and coworkers reported overall yields of 32% and 24% respectively for 1d using two different pathways with product isolation accomplished by chromatography on alumina.^2c Others have reported overall yields of 31% and 35% of 1d using a distillation technique to purify the final compound.^2d-2f

The only synthesis of 5d, reported in literature, uses a radical process to functionalize the 18-C-6 with allyl alcohol in 8% yield.^2h Colera and coworkers report the synthesis of 7d in an overall yield of 11% in six steps^2l compared to the 41% overall yield in 4 steps in this work. In this letter, we also report for the first time the synthesis of lariats 2d, 3d, 4d, and 6d.

The above route to obtain functionalized diols worked well for 1d – 3d since the starting materials, benzyl alcohol and its mono- and diethylene glycol derivatives, had reasonable aqueous solubility. This was not the case for the analogous reactions required to give lariats 4d – 7d containing alkanol side-arms. The analogous epichlorohydrin addition reactions (not shown) led to low yields (~10%) even after significant attempts at optimization. Therefore, an alternative approach was required. Our synthesis began with a benzylation step using NaH and BnBr to obtain alkene 4a - 7a.¹⁵ Diols 4b-7b were then prepared using OsO₄/NMO following a literature procedure.¹⁶ Cyclization reactions between various diols and pentaethyleneglycol ditosylate followed by debenzylation afforded the desired crown ethers in reasonable overall yields (30 – 40%).

As mentioned, benzyl lariat ethers 1c - 7c were formed by condensation with pentaethylene glycol ditosylate in the presence of potassium tert-butoxide using the well-known template effect.¹⁷ These reactions usually required more than 48 hours for all starting material to be consumed. Upon completion, the reaction mixture contained byproducts that could not be conveniently separated using flash chromatography. A variety of traditional eluent systems and both silica gel and alumina stationary phases were evaluated to no avail. We carried forward these product mixtures to the hydrogenolysis step. The resulting mixture of debenzylated compounds was then separated on neutral alumina using a gradient elution of 1 – 10% 2-propanol/dichloromethane or 1–10% MeOH/EtOAc eluent system. However, this gradient method is a lengthy process requiring copious amounts of solvent (> 3 L for 3 g of crude).

In an attempt to isolate the final lariat products more efficiently, we sought to take advantage of their metal chelating properties to bring about a selective precipitation of the desired compound from the product mixture. A few reports demonstrate that complexation followed by precipitation using KBF₄ is a feasible approach.¹⁸ Along these lines, we also found KNO₃ to be effective in purifying lariat ether products by precipitation. However, these methods were problematic and unreliable on the multi-gram scale.

As an alternative, we developed a simplified extraction technique using aqueous potassium hydroxide. Thus crude debenzylated reaction mixtures (~5 g) were stirred with 50 mL of KOH_aq (1 M) for 5 mins. After this time, the impurities were removed by extraction using ethyl acetate until TLC showed the absence of any impurity (usually three extractions). The water layer was then extracted with dichloromethane (3 times) (monitored by alumina TLC; 4% ⁱPrOH/DCM eluent). The organic layer was collected; the solvent was removed in vacuo; and the resulting material was passed through a small plug of neutral alumina (10% MeOH/EtOAc as eluent) to furnish non-complexed lariat products. This process was significantly less tedious and offered nearly identical isolated yields as those based on flash chromatography.

In summary, bringing together reactions from a variety of previous works, we have developed a robust approach to a series C-pivot lariat ether compounds. This process involves the condensation of functionalized diols with pentaethylene glycol ditosylate in the presence of templating cations. Purification of the final products was achieved by a simple extraction method that obviated the need for tedious chromatography. We believe that this convenient synthesis of lariat ethers will facilitate their use as novel bifunctional catalysts.

Scheme 2.

Synthesis of Lariats 4d – 7d

Reagents and Conditions: (a) NaH, BnBr, THF, 0 °C to r.t. over 6 h; (b) OsO₄, NMO, acetone/H₂O, r.t., 12 h; (c) KO^tBu, pentaethyleneglycol ditosylate, THF, r.t. for 1 h then reflux for 48 h (d) Pd-C, H₂, EtOH, r.t., 48 h.