PS-BEMP

PS-BEMP Polymer-supported 2- tert-butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2-diazaphosphorine... 

Schemes Synthesis of 1,3,4-oxadiazoles using PS-BEMP and tosyl chloride...

An alternative reported in the same publication involves the in situ conversion of the carboxylic acids to the corresponding acyl chlorides using PS-PPh3 and CCI3CN (THE, 10 °C, 5 min) before treatment with the amidoxime in the presence of DIEA (THE, 150 °C, 15 min). The resin-bound phosphine not interfering with the second step, and THF being the best solvent for both steps, the two-steps sequence could be performed one-pot with yields comparable to those obtained using the HBTU/PS-BEMP combination (Scheme 12). 

Fig. 7.8 Polystyrene-bound dehydrating agent (left) and polymer-supported phosphazene base PS-BEMP (right) utilized for oxadiazole synthesis.

BnOC6H4, 3-NO2C6H4, 3-CF3C6H4, PS-BEMP/HBTU/ 45-97 20050L925... 

PS-BEMP = polymer-supported 2-ferf-butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2-diazophosphorine EDAC = 1 -[3-(dimethylamino)propyl]-3-ethylcarbodiimide PS-PPh3 = polystyrene-supported PPh3 TBTU = 2(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate. 

Schwesingefs phosphazene base 2-tert-butylamino-2-diethylamino-l,3-dimethyl-perhydro-l,3,2-diazaphosphorine (PS-BEMP has a pKb = 27.5 in MeCN) has been immobilized and shown to have immense utility in the N- and O-alkylation of many weakly acidic heterocycles. Kim et al. has made extensive use of this reagent in the multi-step synthesis of a small collection of guanines possessing potential antiviral activity [90]. The generic procedure involved the direct alkylation of the purine moiety (20) (Scheme 2.64), promoted by PS-BEMP, resulting in a mixture... 

Scheme 2.66 PS-BEMP as a versatile base in organic synthesis.

In a representative example alkylation of 4-phenyl-2H-phthalazin-l-one (Scheme 2.67) was achieved using PS-BEMP at ambient temperature in acetonitrile. Purification of the reaction mixture was realized by removal of the excess alkylating agent using an aminomethylpolystyrene scavenger. 

PS-BEMP). The reaction gave 4,5-disubsituted isothiazole in 58% yield. What was interesting was that an additional washing of the immobilized base with an electrophile (in a typical setup, 2,4 -dibromoacetophenone) gave the corresponding 1,4,5-trisubstimted imidazole in 38% yield and >95% purity. Additional efforts were done to produce only the imidazole structure by using the premixed electrophile and ethyl isothiocyanate, however, without success. 

In the same publication, it was reported that this cyclo-dehydration could also be affected by using tosyl chloride and the polymer-supported phosphazene base PS-BEMP, and again, microwave heating was found to be advantageous (Scheme 6.25). In utilising this protocol, no scavenger purification strategy was deemed necessary and the authors note that this is the most efficient 1,3,4-oxadiazole synthesis of the three polymer-supported methods described. 

As Scheme 73 illustrates to attain the target compound 255, the authors reacted 4-bromophenyl isothiocyanate 256 with ethyl isocyanoacetate 257 in the presence of PS-BEMP124 to afford the thiazole 258 in 58% yield and introduction of a-bromoamide 259 through the PS-BEMP 124 cartridge subsequently afforded the target compound 255 in 30% yield. 

Two complementary methodologies were designed for rapid generation of libraries of 3,5-disubstituted 1,2,4-oxadiazoles from widely available carboxylic acids and amidoximes [93]. Both methods employed solid-phase reagents to simplify the purification process. Carboxylic acids were directly condensed with amidoximes in the presence of HBTU and an excess of PS-BEMP in acetonitrile (150 °C, 15 min). Alternatively, carboxylic acids were in situ converted to acid chlorides (with PS - PPI13/CCI3CN in THF) and subsequently reacted with amidoximes to furnish disubstituted oxadiazoles in good to excellent yields (Scheme 33). 

A single pot synthetic protocol for the synthesis of 2-sulphonamide-l,3,4-oxadiazoles from 1,2-diacylhydrazine (xxix) under microwave irradiation using PS-BEMP (xxxi) and corresponding sulfonyl chloride (xxx) is reported by Baxendale et al. [33]. 

The commercially available polystyrene-supported iminophosphorane (PS-BEMP) 55 (Figure 3.1) has been utilized to promote the Michael addition of acyclic- and cyclic-1,3-dicarbonyl compounds, including those substituted at the active methylene, to electron-poor olefins. 

An interesting comparison between the catalytic activity of commercially available PS-BEMP and silica- and polystyrene-supported-TBD in the production of substituted aza-heterocycles 93 and 96 was reported (Scheme 3.26) ... 

PS-BEMP was able to promote the first step (the alkylation process) in higher yield but failed in the Knoevenagel condensation (very long reaction times, 48-72 h, were needed) the best results were obtained by employing the supported TBD catalysts. No significant differences between SiO2-TBD and PS-TBD were observed, probably because the latter catalyst can swell sufficiently in THF. Consequently, the less expensive PS-TBD was employed for the preparation of a library of substituted aza-heterocycles Table 3.7 gives some examples. 

When the p-ketoamide 133, containing an acidic methine group and pendant nucleophilic pyrrole substituent, was dissolved with methyl vinyl ketone (53) in dichloromethane and treated at room temperature with PS-BEMP (10%), the Michael adduct 134 was formed as the sole reaction product in 100% yield. 

Conversely, when the reaction was carried out by using Amberlyst A15 (200%) in the presence or absence of liquid BEMP (10%), the only observed reaction product was substituted pyrrole 135, which was isolated in 68% yield product 134 was not present at all in the reaction mixture. However, when the reaction was repeated by using a combination of PS-BEMP (10%) and Amberlyst A15 (200%), the sole reaction product was the desired tetracyclic product 136 -obtained in 83% yield as a 1 1 mixture of diastereoisomers. By using sub-stoichiometric quantities of PS-BEMP (10%) and Amberlyst A15 (50%), an 85% conversion into 136 after 5 days was produced. These results demonstrate that PS-BEMP and Amberlyst A15 can operate as mutually compatible strongly basic and strongly acidic reagents, respectively, in the same vessel to facilitate the Michael-initiated N-acyl iminium ion cyclization cascade. 

Table 3.12 Polycyclic products obtained by Michael-initiated A-acyl iminium ion cyclization cascade between p-ketoamides and a,p-unsaturated carbonyl compounds catalysed by PS-BEMP and Amberlyst A-15 mixture.

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