Mitsunobu amides

Scheme 3) [30]. The pY + 3 diversity alcohols (Ri)-OI I (Fig. 15) were attached to the template through a Mitsunobu coupling to provide ether derivatives of 16. Palladium-mediated Alloc deprotection followed by amide formation using the phosphate-ester-containing diversity acids (R2)-C02H provided the fully coupled resin-bound products of 17. Cleavage from the resin with 95% TFA/H20, which also afforded benzyl phosphate deprotection, followed by reversed-phase (RP) semipreparative... 

For the synthesis of perfectly dendronized sohd-phase polymers (Fig. 7.4) various dendritic structures were prepared based on amide connections [6]. For example, the naturally occurring amino acid lysine was used as a building block in creating a dendritic scaffold [33]. The synthesis of symmetrical tri-branching den-drimers on aminomethyl polystyrene macrobeads was also described in literature [34]. Recently, aryl ether dendrimers were prepared on hydroxymethyl polystyrene using a Mitsunobu reaction with 3,5-bis(acetoxymethyl)phenol [35]. 

The Mitsunobu reaction has also been applied successfully for the preparation of oxazolines from p-hydroxy amides. This method provides an alternative to the Burgess reagent. Some recent examples are listed in Table... 

Oxazoline formation under Mitsunobu conditions is very facile. As shown in the last example in Table 8.10, as much as 30% of the oxazoline is formed in addition to the desired vinylaziridine that is obtained in 64% yield. Only amide groups participate in this cyclization since the oxazoline is not formed when the nitrogen is protected as a benzyloxycarbonyl (Cbz) or ferf-butyloxycarbonyl (Boc) derivative. 

TABLE 8.10. OXAZOLINES VIA THE MITSUNOBU REACTION OF P-HYDROXY AMIDES... 

Oxazoline formation under Mitsunobu conditions requires that the amide substituent be in an antipepriplanar orientation to the activated hydroxyl substituent. With flWo-threonines 77, these groups are predisposed in such an orientation in the most stable conformation (transition state 78b). As a result, frani-oxazolines 79 are easily formed. With threonines, the formation of c/i-oxazoline 76 is disfavored because of destabilizing gauche interactions between the ot-carboxyl... 

N-Alkyl amides or imides can also be prepared starting from alcohols by treatment of the latter with equimolar amounts of the amide or imide, Ph3P, and diethyl azodicarboxylate (EtOOCN=NCOOEt) at room temperature (the Mitsunobu reaction, see p. 396).925... 

Addition of the lithium acetylide of tetrahydropyranyl-protected but-3-yn-l-ol 156 provided the racemic alcohol 157 (Scheme 34). The nitrogen was introduced through a Mitsunobu reaction, followed by oxidation of the primary alcohol to the carboxylic acid and a change of the phthaloyl protecting group to Boc protection. The latter reaction was necessary because hydrazinolysis of the C-terminal amide analogue of 159 did result in deeply red-colored mixtures, indicating that phthaloyl removal by this method should occur prior to peptide synthesis. 131 ... 

As illustrated by the examples in Table 3.9, resin-bound 4-alkoxybenzylamides often require higher concentrations of TFA and longer reaction times than carboxylic acids esterified to Wang resin. For this reason, the more acid-sensitive di- or (trialkoxy-benzyl)amines [208] are generally preferred as backbone amide linkers. The required resin-bound, secondary benzylamines can readily be prepared by reductive amination of resin-bound benzaldehydes (Section 10.1.4 and Figure 3.17 [209]) or by A-alkyla-tion of primary amines with resin-bound benzyl halides or sulfonates (Section 10.1.1.1). Sufficiently acidic amides can also be A-alkylated by resin-bound benzyl alcohols under Mitsunobu conditions (see, e.g., [210] attachment to Sasrin of Fmoc cycloserine, an O-alkyl hydroxamic acid). 

Oxazolines.1 Hydroxy amides, prepared from p-hydroxy amines and acid chlorides, are converted into 2-oxazolines with the Mitsunobu reagent at 0 — 25° (equation I). 

The p-sulfanyl amides 28 are synthesized from N-protected amino acids 24 via amino alcohols 25, which are converted into (5-acetylsulfanyl amides 26 by a Mitsunobu reaction. The (5-amine disulfide 27 is subsequently coupled with a variety of carboxylic acids, followed by reduction with tributylphosphine in aqueous THF in the presence of pyridine to produce the free thiol 28 (Scheme 5).1211 Detailed experimental procedures for these compounds have not been reported. 

Mitsunobu reaction. The Mitsunobu reaction is an intramolecular cyclization of suitable amides (Scheme 4). 

HSAB is particularly useful for assessing the reactivity of ambident nucleophiles or electrophiles, and numerous examples of chemoselective reactions given throughout this book can be explained with the HSAB principle. Hard electrophiles, for example alkyl triflates, alkyl sulfates, trialkyloxonium salts, electron-poor car-benes, or the intermediate alkoxyphosphonium salts formed from alcohols during the Mitsunobu reaction, tend to alkylate ambident nucleophiles at the hardest atom. Amides, enolates, or phenolates, for example, will often be alkylated at oxygen by hard electrophiles whereas softer electrophiles, such as alkyl iodides or electron-poor alkenes, will preferentially attack amides at nitrogen and enolates at carbon. 

Pyridone is O-alkylated more readily than normal amides, because the resulting products are aromatic. With soft electrophiles, however, clean N-alkylations can be performed (Scheme 1.7). The Mitsunobu reaction, on the other hand, leads either to mixtures of N- and O-alkylated products or to O-alkylation exclusively, probably because of the hard, carbocation-like character of the intermediate alkoxyphosphonium cations. Electrophilic rhodium carbene complexes also preferentially alkylate the oxygen atom of 2-pyridone or other lactams [20] (Scheme 1.7). 

Imides are sufficiently acidic to enable N-alkylation via the Mitsunobu reaction. As with amides, only cyclic imides are readily N-alkylated whereas acyclic imides tend to yield mixtures of N- and O-alkylated products or O-alkylated products exclusively when treated with an alkylating agent (Scheme 6.25). 

N-Acyl or N-alkoxycarbonyl amidines or guanidines can be deprotonated and then alkylated [120]. The scope and limitations of these reactions are similar to those of the N-alkylation of amides or carbamates. N,N -Bis(tert-butyloxycarbonyl)guan-idine is sufficiently acidic to undergo clean N-alkylation under the conditions of the Mitsunobu reaction [121]. 

In 1991, Duncia et al. reported on the synthesis of 1,5-disubstituted tetrazoles from secondary amides and azidotrimethylsilane under the conditions of the Mitsunobu reaction <1996CHEC-II(4)621>. The Mitsunobu protocol was successfully applied to the conversion of AT(cyanoethyl)amide into tetrazole 510. The tetrazole ring in this event forms by the cyclization of an imidoyl azide (not shown in the scheme) whose precursor is the phosphonium imidate 509 (Scheme 67) <2000JME488>. 

At the same time, Yang et al. <2004TL111> noted that the conversion of amides into tetrazoles under the conditions of the Mitsunobu reaction is disfavored by the presence of bulky substituents on the starting amides. 

There are two problems. Enolates of primary amides are not very practical as the NH protons are more acidic than the CH protons. The solution is to use the nitrile and hydrolyse it later to the amide. A more serious problem is that the Sn2 reaction we want to use to couple the two together will go with inversion and that will give the biologically inactive enantiomer of darifenacin. The solution is a double inversion. Protection of the amine by tosylation 67 is followed by tosylation of the alcohol with inversion using a Mitsunobu-style reaction. This unusual esterification goes reliably with inversion.20... 

The amides derived from /3-hydroxy-a-amino acids, obtained from the reaction of the latter with resin-bound hydroxylamine, have been cyclized under the Mitsunobu conditions to afford 3-aminoazetidin-2-ones. The free azetidin-2-ones were cleaved from the resin by reduction with samarium iodide <20010L337>. 

---