Thiocarbonyl imidazolide

A relevant reductive process, which has found wide application in organic synthesis, is the deoxygenation of alcohols introduced in 1975 by Barton and McCombie [58]. Reaction (4.28) shows that the thiocarbonyl derivatives, easily obtained from the corresponding alcohol, can be reduced in the presence of BusSnH under free radical conditions. The reactivity of xanthates and thiocarbonyl imidazolides [58] was successfully extended to 0-arylthiocarbonates [59] and (9-thioxocarbamates [60]. Several reviews have appeared on this subject, thus providing an exhaustive view of this methodology and its application in natural product synthesis [61-64]. 

Deoxygenation and Cyclization of the Carbohydrate-Derived Thiocarbonyl-imidazolide 55 with TBTH and AIBN [52]... 

A solution of 6.13 g (12.8 mmol) of the thiocarbonyl-imidazolide 55 [Eq. (23)]. 5.15 mL (19.1 mmol) of tributyltin hydride (TBTH), and 0.12 g of AIBN in 120 itiL of dry toluene was refluxed for 1 h. Additional TBTH (0.5 Eq) and AIBN (60 mg) were added and the refluxing was continued for 1 h. The reaction mixture was added to 400 mL of ether, and washed with 80 mL each of saturated KF, 1 M HCl, and saturated NaHCOj. The organic layer was wa.shed with three more 50-mL portions of saturated KF solution and dried over anhydrous MgS04. Concentration and chromatography of the crude mixture yielded 3.59 g (58% for the two steps) of the cyclopentane derivative 56 [a) —23.8 0.8°. 

Thus secondary or tertiary alcohols ROH can be reduced to RH via their thiocarboxy-lates R C(S)OR, or dithiocarbonates [xanthates, R S(CS)OR the Barton McCombie reaction] 147-149 for example cholesteryl thiobenzoate or S-methyl dithiocarbonate gives cholest-5-ene in 90% and 78% yield respectively (equation 15-47, R = Ph or MeS). The reaction works best for secondary alcohols the 0-t-alkyl xanthates are often rather unstable at room temperature, though the reactions can be carried out at low temperature with initiation by Et3B/02. The primary alkyl xanthates undergo C-O fission only at higher temperatures, when other reactions may compete. The thiocarbonyl imidazolides provide a variant on this theme, and the cholesterol derivative (15-5, R = /V-imidazolc) reacts with tributyltin hydride to give an 18% yield of cholestene.147... 

The starting xanthate 1 is easily obtained by treatment of the requisite alcohol with base (e.g. NaOH, KOH, NaH, KH, or BuLi), carbon disulfide, and methyl iodide, normally in this order, but variations have been reported where all the ingredients are mixed in the presence of a phase transfer catalyst [4]. Thus, the overall transformation is a deoxygenation of the initial alcohol ROH into the corresponding alkane RH. Other thiocarbonyl derivatives are also suitable as substrates for the deoxygenation thiocarbonyl imidazolides [1], O-aryldithiocarbonates [5], or even certain thiocarbamates [6]. These derivatives are often easier to introduce than a xanthate, but are more expensive. 

Alcohols are ubiquitous in natural products or as intermediates in organic synthesis, and the Barton-McCombie deoxygenation has been applied hundreds of times on all kinds of molecules, and several reviews have already appeared [1]. Three examples, illustrating its tremendous synthetic potential, are set out in Scheme 3 they represent a deoxygenation of secondary thiocarbonyl imidazolide... 

The radical-induced epoxide ring-opening of a,/3-epoxy-0-thiocarbonyl-imidazolides (23) [equation (3)] has been reported to be a convenient alternative to the Wharton rearrangement (action of hydrazine on epoxides of a,/3-unsaturated ketones) for production of allylic alcohols. /3,y-Disubstituted allylic alcohols with Z-conhguration are the major products formed on addition of alkyl-lithiums to the vinyl epoxide (24) [equation (4)]. ... 

Deoxygenation of sec-alcohols.1 2 -Deoxynucleosides (1) can be deoxygen-ated efficiently to 2 3 -dideoxynucleosides (3) by reaction with N,N -thiocarbonyl-diimidazole in DMF (80°) to form imidazolides, which on reaction with methanol are converted into methylthionocarbonates (2). These crystalline derivatives are reduced by Bu3SnH to 3. 

A mixture of the (l-hydroxymethyl ester (10.0 g, 25 mmol) and 1,1 -thiocarbonyl-imidazole (9.0 g, 50 mmol) in anhydrous THE (130 mL) was heated at reflux for 16 h. The solvent was removed under reduced pressure. The residue was dissolved in EtOAc (100 inL), and the resulting solution was washed with 0.5 N HCl (3 x 100 mL). The organic layer was dried, filtered, and concentrated. The residue was recrystallized from EtOAc/hexane to give 7.6 g (60%) of imidazolide thioester. The filtrate was concentrated, and the residue was purified by flash column chromatography using EtOAc/hexane as the eluent to give an additional 1.4 g (11%) of product. 

Radical Chemistry. Treatment of secondary alcohols with 1 equiv of TCDI affords an imidazole-1-thiocarbonyl derivative (imidazolide), which can be reduced to a CH2 unit under Tri-n-butylstannane (TBTH) radical chain reaction conditions. - The deoxygenation of secondary alcohols by way of an imidazolide or other thiocarbonyl derivative is called the Barton-McCombie reaction (eq 4). Since imidazolide formation (TCDI, reflux, 65 °C) and the subsequent radical chemistry are done under neutral or near-neutral conditions, the overall reduction is tolerant of the presence of many sorts of functional groups. Furthermore, the low solvation requirements of radical species permits deoxygenation in sterically congested environments (eq 5). ... 

Thiocarbonyl Transfer. While virtually all uses of TCDI involve a thiocarbonyl transfer reaction, this section covers those uses of the thiocarbonyl transfer that do not lead to radical chemistry or alkene syntheses. TCDI has been used for the simple placement of a thiocarbonyl group between two nucleophilic atoms of one or two molecules. An alcohol which has been converted to an imidazolide is a reactive functionality for coupling reactions, for sigmatropic rearrangements, and for elimination (eq 8). The TCDI alternative l,r-thiocarbonyl-2,2 -pyridone seems to be an excellent thiocarbonyl transfer agent. 

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