Mitsunobu reaction, alkylation

In the olivanic acid series of carbapenems the ( )-acetamidoethenyl grouping can be isomerised to the (Z)-isomer (19) (22) and reaction with hypobromous acid provides a bromohydrin that fragments to give a thiol of type (20) when R = H, SO H, or COCH. The thiol is not isolated but can react to provide new alkyl or alkenyl C-2 substituents (28). In the case of the nonsulfated olivanic acids, inversion of the stereochemistry at the 8(3)-hydroxyl group by way of a Mitsunobu reaction affords an entry to the 8(R)-thienamycin series (29). An alternative method for introducing new sulfur substituents makes use of a displacement reaction of a carbapenem (3)-oxide with a thiol (30). Microbial deacylation of the acylamino group in PS-5 (5) has... 

A further extension to this concept was (dimethylsilyl)propionic acid linker 75 used for the solid-phase synthesis of aryl-containing organic compounds [86], The linker was cleaved smoothly with TFA and has been used for the synthesis of compounds which involved alkylation, acylation, and Mitsunobu reactions. 

N-Alkylation of 2//-pyrido[l,2- ][ 1,3,5 tria/inc-2,4(3//)-dionc 81 was carried out with the alcohol 82 to obtain 83 under standard Mitsunobu reaction conditions (Equation 3) <2003JME3840>. 

Phenylamino-l,3-thiazolines have been synthesized from /V-(2-hydroxy-ethyl)-/V -alkyl thioureas by a one-pot intramolecular Mitsunobu reaction. 

For X=OH and R=EWG group or alkyl, the Mitsunobu reaction (10) is evidently the most convenient procedure for the synthesis of the corresponding nitronates (35a) (Scheme 3.34). 

Intermolecular reactions of hydroxylamines with secondary alkyl halides and mesylates proceed slower than with alkyl triflates and may not provide sufficiently good yield and/or stereoselectivity. A nseful alternative for these reactions is application of more reactive anions of 0-alkylhydroxamic acids or 0-alkoxysulfonamides ° like 12 (equation 8) as nucleophiles. The resulting Af,0-disubstituted hydroxamic acids or their sulfamide analogs of type 13 can be readily hydrolyzed to the corresponding hydroxylamines. The same strategy is also helpful for synthesis of hydroxylamines from sterically hindered triflates and from chiral alcohols (e.g. 14) through a Mitsunobu reaction (equation 9). 

Sulfahydantoins 87 and 88 are analogues of hydantoins and provide heterocyclic scaffolds with a great potential for the construction of bioactive compounds. A total of 28 derivatives, with crude purity generally higher than 85%, were prepared by parallel synthesis using an oxime resin as a solid support (Scheme 46) . The results constitute the first report of successful Mitsunobu reactions and reductive alkylations on the oxime resin. 

In the case of the thiazolidinedioxides (38), the increased acidity of the cyclic sulfamide determines the reactivity. Metallation (NaH) occurs at N—H producing an anion which is readily alkylated <93TL4705>. Treatment with triphenylphosphine produces a stable betaine which can be used to couple alcohols and acids in a variant of the Mitsunobu reaction <94JOC2289>. 

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... 

Relatively electron-deficient indoles such as (39) can be alkylated on nitrogen using Mitsunobu reaction conditions (Equation 1) (94TL1847). 

The first synthesis of optically pure N-methylated derivatives of Ala, Leu, Phe, and Tyr was published by Fischer and Lipschitz in 1915 73 using the sulfonamide method. Two main developments have ensured that this method remains useful for the preparation of TV-alkyl amino acids both in solution and solid phase (1) the introduction of the Mitsunobu reaction for the alkylation step and (2) the introduction of replacements for Tos (such as the Fukuyama Nbs) that allow easy removal of the sulfonamide protecting group after the alkylation step. Sulfonamide-protected amino acid derivatives can be alkylated in two different ways. Because of the acidity of the sulfonamide hydrogen it is possible to introduce the N-substituent either by direct alkylation (e.g., alkyl halides) or by the Mitsunobu reaction 74 (Scheme 4). 

Weinreb and co-workers 79 were the first to use the Mitsunobu reaction, which offered an efficient route for the synthesis of A-alkyl amino adds. One of the great advantages of the Mitsunobu method is that it uses mild conditions thus allowing its application to SPPS. jV°-Boc-and 7V -Z-protected amino acids are not N -alkylated under these mild reaction conditions. 

The pK.d values of TV-methyltrifluoromethanesulfonamide (TfNHMe = 7.5) and TV-meth-yltoluenesulfonamide (TosNHMe= 11.7) have been examined and it was found that these sulfonamides are applicable to the Mitsunobu reaction conditions. 80 A modified Mitsunobu reaction has been used for the synthesis of A7"-alkyl amino acid esters 81,82 this method is only applicable to amino acid esters and not to the free acids. Thus, TV-Tos amino acid esters are condensed with MeOH, EtOH, or iPrOH in the presence of TPP and DEAD. The Tos group is deprotected by sodium in liquid ammonia or with sodium amalgam. 83 The deprotection of the Tos group has also been achieved electrochemically under mild conditions and in good yields. 84 ... 

Alternatively, alkyl aryl ethers can be prepared from support-bound aliphatic alcohols by Mitsunobu etherification with phenols (Table 7.13). In this variant of the Mit-sunobu reaction, the presence of residual methanol or ethanol is less critical than in the etherification of support-bound phenols, because no dialkyl ethers can be generated by the Mitsunobu reaction. For this reason, good results will also be obtained if the reaction mixture is allowed to warm upon mixing DEAD and the phosphine. Both triphenyl- and tributylphosphine can be used as the phosphine component. Tributyl-phosphine is a liquid and generally does not give rise to insoluble precipitates. This reagent must, however, be handled with care because it readily ignites in air when absorbed on paper. 

Sulfonamides of primary amines are readily deprotonated (pAia 9-11) and can thus be N-alkylated or N-arylated. Because of their high nucleophilicity and low basicity, deprotonated sulfonamides also react smoothly with less reactive electrophiles, such as n-alkyl bromides [136] (Table 8.9). Sulfonamides can also be N-alkylated with aliphatic alcohols under Mitsunobu conditions. Suitable solvents for the N-alkylation of sulfonamides on polystyrene by Mitsunobu reaction are DCM, toluene, and THF. 

Sulfonamides can also be alkylated by support-bound electrophiles (Table 8.10). Polystyrene-bound allylic alcohols have been used to N-alkylate sulfonamides under the conditions of the Mitsunobu reaction. Oxidative iodosulfonylamidation of support-bound enol ethers (e.g. glycals Entry 3, Table 8.10) has been used to prepare /V-sulfonyl aminals. Jung and co-workers have reported an interesting variant of the Baylis-Hillman reaction, in which tosylamide and an aromatic aldehyde were condensed with polystyrene-bound acrylic acid to yield 2-(sulfonamidomethyl)acrylates (Entry 4, Table 8.10). 

The Mitsunobu reaction is usually only suitable for the alkylation of negatively charged nucleophiles rather than for the alkylation of amines, and only a few examples of such reactions (mainly intramolecular N-alkylations or N-benzylations) have been reported (Entry 15, Table 10.2). Halides, however, are very efficiently alkylated under Mitsunobu conditions, and it has been found that the treatment of resin-bound ammonium iodides with benzylic alcohols, a phosphine, and an azodicarboxylate leads to clean benzylation of the amine (Entry 9, Table 10.3). Unfortunately, alkylations with aliphatic alcohols do not proceed under these conditions. The latter can, however, also be used to alkylate resin-bound aliphatic amines when (cyanomethyl)-phosphonium iodides [R3P-CH2CN+][r] are used as coupling reagents [62]. These reagents convert aliphatic alcohols into alkyl iodides, which then alkylate the amine (Entry 10, Table 10.3). 

Transesterification under strongly basic reaction conditions has been used to acy-late support-bound alcohols with alkyl esters (Entry 10, Table 13.12). For sensitive acids, the Mitsunobu reaction is a particularly mild method of esterification. This reaction gives high yields with support-bound primary aliphatic alcohols and proceeds under essentially neutral reaction conditions (Experimental Procedure 13.4). Mitsunobu esterification of PEG with /V-Fmoc amino acids has also been reported [172]. 

Isothioureas can be prepared on insoluble supports by S-alkylation or S-arylation of thioureas (Entry 7, Table 14.6). Further methods for the preparation of isothioureas on insoluble supports include the N-alkylation of polystyrene-bound, A/,/V -di(alkoxy-carbonyl)isothioureas with aliphatic alcohols by Mitsunobu reaction (Entry 7, Table 14.6) and the addition of thiols to resin-bound carbodiimides [7]. Resin-bound dithio-carbamates, which can easily be prepared from Merrifield resin, carbon disulfide, and amines [76], react with phosgene to yield chlorothioformamidines, which can be converted into isothioureas by treatment with amines (Entry 8, Table 14.6). The conversion of support-bound a-amino acids into thioureas can be accompanied by the release of thiohydantoins into solution (see Section 15.9). The rate of this cyclization depends, however, on the type of linker used and on the nucleophilicity of the intermediate thiourea. 

Support-bound quinazolin-2,4-diones can be N-alkylated, either with alkyl halides under basic conditions or with aliphatic alcohols by means of the Mitsunobu reaction (Entries 12-14, Table 15.29). The methyl group of a 2-methylquinazolin-4-one is sufficiently acidic to undergo aldol condensations with aldehydes [343]. Aminations of chloroquinazolines are discussed in Section 10.1.2. 

Enantioselective Birch reduction-alkylation The chiral benzoic acid derivative 1, prepared by condensation of o-hydroxybenzoic acid with L-prolinol followed by cyclization (Mitsunobu reaction), undergoes Birch reduction (K, NH3, THF, t-butyl alcohol) followed by alkylation with C2H5I to give essentially only 2. Acid hydrolysis returns the chiral auxiliary and provides the 2-alkylated cyclo-hexenone 3. 

Schultz and co-workers31 also described the preparation of a 2,6,9-trisubstituted purine library. A preformed 2-fluoro-6-(4-aminobenzylamino) purine was reductively aminated onto the BAL linker 12. Mitsunobu chemistry was employed to alkylate the C9 position on the support-bound intermediate (Scheme 4). Subsequently, SNAr chemistry was used to incorporate amines at C6. The newly introduced primary and secondary amines bear diverse functional groups and the Mitsunobu reaction allows for incorporation of primary and secondary alcohols lacking acidic hydrogens. The support-bound product 13 was cleaved with 90% TFA/10% H20 to give a library with HPLC purities ranging between 51 and 85%. 

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