Phosphonium-based reagents

Phosphonium-based reagents PyBOP and PyBroP were found to be very effective in this transformation, affording oxytripyrrolidino-phosphonium intermediates in high yields, with PyBroP being slightly superior to PyBOP. Weak nucleophiles such as iV-methyl benzenesulfonamide, imidazole, indole, diethyl malonate, and phenol were coupled smoothly with oxytripyrrolidino-phosphonium in high yields. Sodium terr-butoxide was found to be an excellent base to ensure a clean and complete reaction. 

PYRROLIDINO INSTEAD OF DIMETHYLAMINO SUBSTITUENTS FOR THE ENVIRONMENTAL ACCEPTABILITY OF PHOSPHONIUM AND CARBENIUM SALT-BASED REAGENTS... 

FIGURE 2.19 Pyrrolidino instead of dimethylamino substitutents for the environmental acceptability of phosphonium and carbenium salt-based reagents.56 Tetramethylurea from O-benzotriazol- l -yl/V./V./V./V -tetramethyluronium hexafluorophosphate and tetrafluoroborate is more volatile and is cytotoxic. The product released from PyBOP is not environmentally objectionable. PyBOP = benzotriazol-l-yl-oxytripyrrolidinophosphonium hexafluorophosphate. 

HYDROXYBENZOTRIAZOLE AS ADDITIVE IN COUPLINGS OF N-ALKOXYCARBONYLAMINO ACIDS EFFECTED BY PHOSPHONIUM AND URONIUM SALT-BASED REAGENTS... 

Phosphonium and uronium salt-based reagents effect couplings by first reacting with the anion of the starting acid (Figure 2.22, path A). The benzotriazolyl ester is then one of the two possible precursors of the peptide. Operating in a research climate in which HOBt was commonly used as additive, Hudson rationalized that if the ester is the precursor of the peptide, additional HOBt in the form of the anion would be beneficial because it would by mass action promote formation of the ester. A favorable effect from adding HOBt was reported, so one variant of the use of... 

FIGURE 2.22 Couplings using phosphonium and uronium salt-based reagents with 1-hydroxybenzotriazole as additive.60 The additional HOBt promotes formation of the benzotriazolyl ester, which is the precursor of the peptide. 

When HOBt and HOAt are used with phosphonium and uronium salt-based reagents, they are present as anions, and they suppress epimerization by trapping the O-acyloxyphosphonium, O-acy I uronium, and oxazolone intermediates as the activated esters (see Section 2.21). 

Other oxazine-based reagents, such as the phosphonium salt (741) prepared from 2-chloromethyl-4,4,6-trimethyldihydro-l,3-oxazine (740), have been used in Wittig reactions to synthesize a,/3-unsaturated aldehydes or acids (Scheme 170) (74JOC623). 

The reactivity of uronium- (and phosphonium-) based coupling reagents is mainly determined by the type of activated acid derivative formed during activation (see Figure 13.2). Unlike phosphonium salts, uronium salts can react with amines to yield guanidines [84]. This side reaction can interfere with amide formation if more uronium salt than carboxylic acid is used. Illustrative examples of the use of uronium salts are listed in Table 13.6. 

Figure 5 Structures and examples of nomenclature for phosphonium and carbonium salt-based reagents. Rules of nomenclature dictate that the latter be named as modified ureas see text for revised structures "ino" indicates a ring linked at the nitrogen atom.

Independent work of Kenner [57], Castro [58], Hmby [59], and Yamada [60] has shown the potential of applying derivatives of trisdimethylaminophos-phonium salts for the activation of carboxylic acids and subsequent preparation of amides and peptides (Fig. 7). The first phosphonium salt-based reagents commercially available were pi-oxo-bis-[tris(dimethylamino)-phos-phonium]-bis-tetrafluoroborate (22) ( Bates reagent ) [61] and benzotria-zol-1 -yl-iV-oxy-tris(dimethylamino)phosphonium hexafluorophosphate (23) (BOB) [62]. Later, Coste et al. [63] described the pyrrolidino derivative of BOP, benzotriazol-1 -yl-7V-oxy-tris(pyrrolidino)phosphonium hexafluorophosphate (24) (PyBOP), which does not form carcinogenic hexamethylphosphoric triamide (HMPA) as a by-product [64]. Furthermore, phosphonium salts derived from HOAt, such as (7-azabenzotriazol-l-yloxy)-tris(dimethylamino)-phosphonium hexafluorophosphate (25) (AOP) and (7-azabenzotriazol-l-yloxy)-tris(pyrrolidino)phosphonium hexafluorophosphate (26) (PyAOP), have also been prepared and are generally more efficient than BOP and PyBOP [31,65,66]. 

In spite of this diversity, most of ILs are synthesized using similar procedures. The nature of the reagents, as well as the conditions, are changed from one product to the other but the principle remains the same. As a consequence, this contribution will be limited to the synthesis of imidazolium ILs, because they are the most widely used ILs. Phosphonium-based ILs are reviewed in Section 5.3.3.2. 

In recent years, aminium- (until recently referred to as uronium) and phosphonium-based derivatives have become the preferred tools for in situ carboxyl activation. The most popular reagents PyBOP 15 (23), TBTU 16 (24), and HBTU 21 (24, 33) smoothly convert Fmoc-amino acids, in the presence of a tertiary base, to their corresponding OBt esters Figure 6). Recently, analogous derivatives HATU 17 (25) and PyAOP 22 (34) which generate OAt esters have become commercially available. These are used in an identical manner but have been shown to give superior results in terms of both coupling efficiency and suppression of enantiomerization (34-37). 

The reactivities of analogous aminium and phosphonium derivatives are essentially equivalent. However, aminium-based reagents can, if used inappropriately, cause capping of resin-bound amino groups through formation of N-terminally guanidinated peptides 23 (38). This side-reaction occurs most... 

Acidic ILs [116] that are quite not stable can be replaced by the Bronsted acidic IL (BAIL). Imidazolium-based ILs are unsuitable for reactions involving either active metals like Na or K or solutions that involve strong bases, since these reagents react with the imidazolium salts for this pnrpose, phosphonium-based ILs have been de-... 

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