Intramolecular Mitsunobu reaction

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

Scheme 21 shows the synthesis of a dihydrofuran derivative 86. Synthesis of this compound was described by Nam et al. [68] utilizing a furanone compound 87 synthesized by Kim et al. [61] via a similar synthetic approach as described in Scheme 17. The lactone was reduced using lithium aluminum hydride to give the diol 88 and intramolecular etherification using the Mitsunobu reaction afforded the dihydrofuran 86 in moderate yield (47%).

Synthesis of acid 129 starts from the commercially available 6-heptenoic acid (122), which upon reaction with (4S)-benzyloxazolidin-2-one (123) as the chiral auxiliary group yields the intermediate 124, hydroxymethylation of which affords compound 125. Hydrolysis of compound 125 followed by condensation with O-benzylhydroxylamine gives rise to the hydroxamate (126), which is then converted into (Claclam 127 via an intramolecular Mitsunobu reaction. Hydrolysis of the (Claclam 127 affords acid 128, which is subsequently formylated at the benzyloxyamine moiety to give the required intermediate acid (129) in quantitative yield, as depicted in Scheme 26. 

A Mitsunobu reaction then inverts the C-4 configuration to provide compound 151, and subsequent isomerization provides compound 152, which is ready for Lewis acid-mediated cyclization to construct the eight-membered firing. Using MeiAlOTf as a catalyst, intramolecular cyclization occurs, giving product 153 in which A, B, and C rings have been introduced with the desired stereochemistry (Scheme 7-45). 

In another approach, 2-(alkylamino)alcohol is employed as starting material for aziridine syntheses with the aid of dihalogenophosphoranes (70BCJ1185). Intramolecular transformation of 3-azidopropyloxirane 73 results in a simultaneous formation of a condensed aziridino[l,2-a]pyrrol-idine system (Scheme 39). The azide group is first transformed into imino-phosphorane 74, the nucleophilic N atom cleaves the oxirane to form betaine 75 [as in the Mitsunobu reaction (81S1)], and the phosphorus is shifted from N to O and then eliminated as phosphane oxide under simultaneous cyclization to bicyclic 76 (89JA7500). 

A new method for the preparation of pyrrolo[2,l-c][l,4]benzothiazepine 292 starting from aldehyde 291 with an intramolecular Mitsunobu cyclization in the last step has been reported (Scheme 63 (1999T1479)). A disadvantage of this procedure is the redox nature of the Mitsunobu reaction, which is responsible for a side oxidation of the thiol group and poor isolated yields of the product. 

Benzisoxazoles and isoxazoles are also accessible in excellent yields by intramolecular Mitsunobu reaction or related reactions of o-hydroxy- or a-hydroxyoximes ° . Thus, treatment of oxime 208 in the presence of diethyl azodicarboxylate (DEAD) and PPhs in THE leads to benzisoxazoles 209 (equation 91). ... 

Schkeryantz and Pearson (59) reported a total synthesis of ( )-crinane (298) using an intramolecular azide-alkene cycloaddition (Scheme 9.59). The allylic acetate 294 was first subjected to an Ireland-Claisen rearrangement followed by reduction to give alcohol 295, which was then converted into the azide 296 using Mitsunobu conditions. Intramolecular cycloaddition of the azide 296 in refluxing toluene followed by extrusion of nitrogen gave the imine 297 in quantitative yield. On reduction with sodium cyanoborohydride and subsequent reaction with... 

Intermolecular and intramolecular nucleophilic substitution of an alcoholic hydroxy group by the triphenylphosphine/dialkyl azodicarboxylate redox system is widely used in the synthesis and transformation of natural products and is known in organic chemistry as the Mitsunobu reaction.1951 This reaction starts with formation of the zwitterionic phosphonium adduct 19 (Scheme 9) from triphenylphosphine and diethyl (or diisopropyl) azodicarbox-... 

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). 

Diazepanones have been prepared on insoluble supports by intramolecular nucleophilic cleavage, by intramolecular Mitsunobu reaction of sulfonamides with alcohols, and by intramolecular acylations (Table 15.36). As in the case of azepines, these reactions do not always proceed smoothly, and care must be taken to prevent potential side reactions from occurring. For instance, intramolecular acylations in peptides containing aspartic acid (Entry 2, Table 15.36) will generally lead to the formation of suc-cinimides (see Table 13.20) unless A-alkylamino acids are used. 

Treatment of y-nitro alcohols with diethyl azodicarboxylate DEAD and triphenylphos-phine affords nitrocyclopropanes with inversion of configuration at the a-carbon via the intramolecular Mitsunobu reaction involving carbon nucleophiles stabilized by the nitro group (equation 16)28. The reaction works best with nitro compounds (pA"a < 17) and is not applicable to the sulfonyl derivatives (pATa 25). 

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

The final ring closure was attempted via several methods (O-activation, N-deprotection and intramolecular nucleophilic replacement, O-mesylation and subsequent hydrogenation, intramolecular Mitsunobu reaction), but all attempts were unsuccessful. The method implemented involved an intramolecular reductive animation. Compound 69 was oxidised with Dess-Martin periodinane to afford ketone 75, which was then hydrogenated in the presence of Pd/C, to give the desired ring-closed product (-)-indolizidine 167B. 

Isomerization of the enantiopure hydroxylated azepane 42, after hydroxyl group activation, afforded either the ring-contracted piperidine derivative 45 (on O-mesylation to 43 followed by internal displacement to the aziridinium ion intermediate 44 and subsequent chloride ion induced ring opening) or the chiral ethylene-bridged morpholines 48 via 47 and an intramolecular Mitsunobu reaction of 46 (Scheme 4) <1996TL1613>. 

An intramolecular Mitsunobu reaction has been used to prepare a range of substituted 1-benzazepines 104 from 103 in generally very good yields (Equation 11) <2005H(66)481>. 

A stereochemical study of the synthesis of unsaturated 1,4-aminoalcohols via the reaction of unsaturated 1,4-alkoxyalcohols with chorosulfonyl isocyanate revealed a competition between an retentive mechanism and an SnI racemization mechanism, with the latter having a greater proportion with systems where the carbocation intermediate is more stable.254 An interrupted Nazarov reaction was observed, in which a nonconjugated alkene held near the dienone nucleus undergoes intramolecular trapping of the Nazarov cyclopentenyl cation intermediate.255 Cholesterol couples to 6-chloropurine under the conditions of the Mitsunobu reaction the stereochemistry and structural diversity of the products indicate that a homoallylic carbocation derived from cholesterol is the key intermediate.256 l-Siloxy-l,5-diynes undergo a Brpnsted acid-promoted 5-endo-dig cyclization with a ketenium ion and a vinyl cation proposed as intermediates.257... 

Resin-based chemistry has been used to construct 480 from 481 by use of boron trifluoride to mediate both the cyclization and cleavage steps <1999AGE1121 >. When the monosaccharide was bound to the polystyrene resin (Merrifield and MPP type) by an alkylsulfonyl linker 482 and cyclization was mediated by 2- r/-butylimino-2-diethylamino-l,3-dimethylperhydro-l,3,2-diazaphosphorine, the reaction had low stereoselectivity and the products included tricyclic oxetanes and oxiranes <2004EJ04177>. The Mitsunobu reaction was used to obtain intramolecular N-alkylation of 483 and formation of 484 <2005AGE3732>. 

The Mitsunobu reaction has been successfully applied to the synthesis of carbohydrate epoxides directly from diols (Scheme 3.15c).84 The more accessible and nucleophilic hydroxyl is converted into an alkoxyphos-phonium ion, which in turn is intramolecularly displaced by a hydroxyl to give an epoxide. Again it is of critical importance that a coplanar SN2 transition state be attained. 

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