Phosphorus-based reagents

Dialkyl- and diaiylcarbodiimides bearing qrdohexyl, phenyl, p-chlorophenyl, and p-ethoxyphenyl residues have been synthesized from the corresponding ureas with phosphorus pentoxide in pyridine, charged with sand, under reflux [1255]. DCC has been prepared this way within 2.25 h in 76% yield (see also Section 4.5.3.5, Table 4.48). 

Typical procedure. Dicyclohexylcarbodiimide DCC [1255] A stirred mixture of N,N -dicyclohexylurea (19.7 g), phosphorus pentoxide (100 g), sand (175 g), and pyridine (700 mL) was refluxed for 2.25 h. Stirring was no longer possible after about 30 min. The mixture was filtered and the residue was extracted with pyridine (100 mL). Pyridine was removed from the combined solutions on a flash evaporator, and the residual oil was extracted with boiling petroleum ether (bp 60-80 °C) (2 X 100 mL), and then with diethyl ether (100 mL). The combined extracts were washed with iced water (3 x 80 mL), dried over calcium chloride, and Altered. The solvents were removed from the filtrate under reduced pressure to give 17.4 g of an oil, which on distillation yielded 13.7 g (76%) of a dear liquid bp 143 °C (3.5 mmHg), which solidified in the receiver mp 34-35 °C. 

Another method for producing DCC from dicyclohexylurea is a two-step process using phosphoryl chloride in dichloromethane at 40 °C for 4 h under non-basic conditions followed by removal of acidic components with aq. sodium hydroxide. This method, which gives an 89% yield of DCC, has been presented in a patent application [1256] (see Section 4.5.3.5, Table 4.48). 

A general method for the synthesis of carbodiimides, isonitriles, ketimines, and aldehydes using triphenylphosphine dibromide has been developed. Diphenyl and dicyclohexyl carbodiimides are formed from N,N -disubstituted ureas in the presence of triethylamine at 80 °C in 90 min in yields of 66-75% [1257]. 

As already mentioned in Section 4.3.4.1, bis-4-(2,2-dimethyl-l,3-dioxolyl)methyl carbodiimide (BDDC) 1034, a useful reagent for residue-free esterifications, race-mization-free peptide couplings, and dehydrations, has been prepared in 89% yield from the symmetrical urea 1033 by dehydration with triphenylphosphine dibromide at room temperature [758]. 

Selective replacement of primary hydroxyl groups in carbohydrates by iodine atoms has been achieved by using the Rydon reagent, namely, methyltriphenoxyphosphonium iodide.368 Treatment of methyl 3,4-O-isopropylidene-jS-D-galactopyranoside with the phosphonium salt in benzene for 48 hours at room temperature yielded 60% of the 6-deoxy-6-iodo derivative,369 and reaction of thymidine, uridine, and 2,2 -anhydrouridine in N,N-dimethylformamide afforded 5 -deoxy-5 -iodo derivatives in yields of 63, 65, and 31%, respectively.370 

Reagents derived from triphenylphosphine may show similar, selective reactivity towards primary hydroxyl groups. Thus, after 

The selective activation of the primary hydroxyl group in methyl a-D-glucopyranoside by reaction with carbon tetrachloride and tris(dimethylamino)phosphine in A/.N-dimethylformamide at —40° has been reported.381 An alkoxytris(dimethylamino)phosphonium 

The interesting observation has been made that 3 -amino-3 -deoxy-adenosine as a suspension in phosphoryl chloride-triethyl phosphate at 4° is converted into the 5 -chloro-5 -deoxy derivative in 80% yield, but that predissolution of the nucleoside in triethyl phosphate, followed by treatment with phosphoryl chloride at 0°, yields the 5 -phosphate in 62% yield.382 

In nearly all of the reactions described in this subsection, it appears that steric factors are the cause of the selectivities observed. 

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Scheme 9 Reductive processes with phosphorus based reagents...

The reaction of 6-methylpteridines with A -chlorosuccinimide has been shown to be a mild and efficient route to 6-trichloromethylpteridines and other similarly substituted heterocycles in yields in excess of 70% avoiding the experimental problems associated with phosphorus-based reagents <2007CL552>. 

The P-H bond is also weak enough to serve in thione-based radical chemistry. The first success was achieved with dialkyl phosphites [40a]. However, hypophosphorous acid and its salts proved to be even better [40b]. In a final paper [40c], the various phosphorus-based reagents were compared. The crystalline salt N-ethylpiperidine hypophosphite was very convenient and has been commercialized 140c]. The use of hypophosphorous acid has the advantages of nontoxicity, cheapness, and ease of removal from the organic reduction products. It already has several industrial applications. 

Aliphatic alcohols do not undergo solvolysis as readily as benzylic alcohols, and are generally converted into halides under basic reaction conditions via an intermediate sulfonate. Because of the hydrophobicity of polystyrene, however, nucleophilic substitutions with halides on this support do not always proceed as readily as in solution (Table 6.3). Alternatively, phosphorus-based reagents can also be used to convert aliphatic alcohols into halides. 

Masamune et al. [53] and Corey et al. [54] explored phosphorus-based reagents such as diphenylchlorophosphate 38 [55], Palomo s reagent 39 [56], PyBroP 40 [57], and PyBOP 41 [58] in macrolactonization (Figure 6.14). Peptide coup-Hng agents of carbodiimide class, such as 42a,b, also were explored by Boden and Keck [59] as activators for macrolactonization with DMAP as a base (Figure 6.14). 

Two phosphorus-based reagents for amide formation have appeared this year the first is (230) and has the advantage that when used in peptide synthesis in the presence of N-hydroxysuccinimide racemization is suppressed to < 0.1 %. The second is (231), which has also been used to prepare symmetrical anhydrides. The use of the acid-stable Peoc group (232) for hydroxyl protection has been described. ... 

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