Mitsunobu reaction amines

The major application of the Mitsunobu reaction is the conversion of a chiral secondary alcohol 1 into an ester 3 with concomitant inversion of configuration at the secondary carbon center. In a second step the ester can be hydrolyzed to yield the inverted alcohol 4, which is enantiomeric to 1. By using appropriate nucleophiles, alcohols can be converted to other classes of compounds—e.g. azides, amines or ethers. 

An oxidizing agent. Useful for the dealkylation of amines and the conversion of pyrimidines to purines. It is most often associated with triphenylphosphine (TPP) in the Mitsunobu reaction. Examples ... 

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). 

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. 

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. 

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%. 

Novel nor-seco baccatin 99 was synthesized in 92% yield through oxidative cleavage of the A ring of 14-OH-DAB (75) with periodic acid via the hydroxy ketone intermediate 100 (Scheme 19). Protection of the 7-hydroxyl of 99 as TES ether followed by reduction of the aldehyde with sodium borohydride yielded nor-seco baccatin alcohol 101 in 80% yield. Nor-seco 13-amino-baccatins 102 and 103 were synthesized from 101 and 99a via the Mitsunobu reaction and reductive amination, respectively, in high yields (Scheme 20). 

Another approach to the preparation of iV-alkyl derivatives 26 is the Mitsunobu reaction. The Mitsunobu procedure is now a well-known method for preparing amines from alcohols using acidic imide derivatives as a nitrogen nucleophile < 198IS 1, 19960PP127>. The remarkably high acidity of l,2,4-dithiazolidine-3,5-dione 12 (pA), 2.8) <2000SL1622>... 

It has been found that the results of this new variant of the Mitsunobu procedure are generally comparable with the results of the traditional Mitsunobu reaction both with respect to the yields and enantiomeric excess (ee) of chiral compounds 26. Thus, products prepared from alcohol 86e using both methods had ee 70% and 72%, and from (Tl-methyl lactate 86i 92% and 99%, respectively. However the new variant of the Mitsunobu procedure has a significant synthetic advantage over the traditional procedure imides 26 can be transformed into primary amines under milder conditions in comparison with the deprotection of /V-alkylphthalimides (see Section 6.03.6.1.3). 

A very interesting variant of the polymer-supported Mitsunobu reaction was recently disclosed by Gelb and Aronov (Scheme 14) [40]. Polymer-bound phthalimide 34 was designed which is able to trap alcohols such as nucleosides under Mitsunobu conditions. After purification by washing the loaded resin the corresponding amine was subsequently released into solution in high yield by hydrazinolysis. 

It was converted to the phthalimide via a Mitsunobu reaction, reduced to the amine, and the amine was coupled with />-nitrophenylacetic acid to give the precursor to the macrocycle. Macrocylization was done via Troger s base formation using Johnson s method, which resulted in two isomers of the amide macrocycle. These were separated and reduced to give the cyclophane host. This was the first time two diastereomers were observed in these syntheses and the separation of these diastereomers was very difficult. 

Note that alkyl azides are potentially explosive. This and the simpler reaction conditions involved is one reason why the reaction described above is mainly carried out as a Mitsunobu reaction. In this method the alkanol is reacted with diethyl diazenedicarboxylate, triphenylphosphane and hydra-zoic acid in a one-pot reaction. The reaction also proceeds with inversion and affords the amine directly because the intermediate azide is reduced by excess triphenylphosphane in situ. 

Several examples of reactions of allyl alcohols under Mitsunobu reaction conditions using diethyl azodicarboxylate (DEAD) and triphenyl phosphine giving allyl amines are known. An example is the reaction of the steroid 5 with azide nucleophiles under Mitsunobu reaction conditions, giving the corresponding azide 6 in 63 % yield (Eq. (3)) [5]. The reaction is regioselective with inversion of the configuration and no SN2/ substitution is observed. 

Next, triphenylphosphine in water was used for reduction to the primary amine. This process might remind you of the Mitsunobu reaction earlier in this chapter. 

The 14-membered ring phosphonate 208 was synthesized via cyclization of the acyclic precursor 207 using the Mitsunobu reaction. Macrocycle 208 was obtained in 82% yield as a mixture of two diastereomers (5 1). The phenyl moiety in 208 was substituted with iV-Cbz-protected aminopentanol, followed by hydrogenolysis in EtOH with hydrogen and 10% Pd/C to afford amine 209 in 50% yield <20010L643, 2002CJC1643>. 

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