Phthalimides, Mitsunobu reaction

MacDougall and Cashman et al. prepared a number of analogs of morphine-6-glucuronide. As such, the amine intermediate 111 was prepared using a phthalimide Mitsunobu reaction. The free phenol was protected as the acetate ester prior to the Mitsimobu reaction since the phenol is more reactive than the vinyl alcohol under the reaction conditions. Other diverse examples employing phthalimide are listed below as well (112-115). - ... 

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. 

For the preparation of Gly- j/-[CF=CH]-Pro in relation to the study of cyclophilin A inhibitors, Welch and co-workers employed the Peterson reaction of a-fluoro-a-trimethylsilyl acetate (15a,b) with ketone 10. E/Z selectivity was found to be influenced by the ester part of the acetate (see Scheme 10.4) [15]. The reaction of tert-butyl ester 15a gave almost an equal amount of the isomers (lib, E Z= 1 1.1), while moderate E selectivity was observed when trimethylphenyl ester 15b was used (11c, E Z= 6 1). Conversion of ester Z-llb to amino derivative 16 was achieved via the Mitsunobu reaction of phthalimide with the alcohol formed by the DIBAL-H reduction of Z-llb. 

Treatment of 75 with lithium acetylide ethylenediamine complex afforded the acetylene derivative 78 (85%), which was transformed into the vinyl alcohol 79 by partial hydrogenation using Lindlar catalyst. Employing the Mitsunobu reaction, compound 79 was transformed into the phthalimide 80, which was converted into the benzamide 82 (64%) via the primary amine 81 by sequential deacylation and benzoylation. When the... 

Another application of 50 is the synthesis of /3,y-unsaturated amino acids such as 102 (Scheme 17). To this end, 50 was debenzylated with sodium in ammonia and then submitted to a Mitsunobu reaction. Clean SN2 -reaction with crnf/ -stereochemistry occurred to furnish phthalimide 100 which was converted into the acid 102 by standard modifications (13). 

Theil et al. developed a method for chemoenzymatic synthesis of both enantiomers of cispentacin [89]. frans-2-Hydroxymethylcyclopentanol, obtained by the sodium borohydride reduction of ethyl 2-oxocyclopentanecarboxylate, was monosilylated with tert-butyldimethylsilyl (TBDMS) chloride to afford 55. Lipase PS-catalysed transesterification with vinyl acetate in /erf-butyl methyl ether furnished the ester 56 and the alcohol 57. The deacetylated 58 was obtained by the Mitsunobu reaction with phthalimide, triphenylphosphine and diethyl azodicarboxylate (DEAD) to furnish the cis oriented 59 with inversion of configuration (not retention as mentioned in the original article) (Scheme 9). Desilylation, Jones oxidation and subsequent deprotection with aqueous methylamine gave the ( R,2S) enantiomer 5 [89]. The (15, 2/f) enantiomer was prepared by the same route from the silyl alcohol 57. 

Allylic amines. With phthalimide as nucleophile in the modified Mitsunobu reaction, high yields of the A -allylated phthalimides are prepared. The phthaloyl group can be removed with methylamine in methanol. 

Lastly, phthaloyl-protected (R)-alanine 112 is formed in high yield by reaction of 2 with phthalimide [40]. Recently, polystyrene-supported methyl azodicarboxylate has been used as a replacement for the soluble dialkyl azodicarboxylates in the Mitsunobu reaction [41]. Yields generally are not as high as in the classical reaction (e.g., 2 112, 45% yield), but, purification can be expedited simply by filtration of the nonexplosive resin. 

N 0 Me 0 From hydroxymethyl polystyrene by treatment with COClj, HjNNHCOjMe and NBS or Cl,.2i Mitsunobu reactions esters from carboxylic acids and alcohols lactones from hydroxy acids A/-aUcylation of phthalimides, a-alkylation of cyanoacetate carbodiimides from thioureas. ... 

Isomannide (80) was the core for a hexahydrofurofuran library." Primary amines were loaded onto solid-support by reductive amination and acylated with bromoacetic acid to give bromides 79 (Scheme 7.16). Alkylation of bromides 79 on solid-support with isomannide (80) gave the solid-supported alcohols 81. A Mitsunobu reaction with phthalimide (82) proceeded to furnish amines 83 in excellent yield and purity after removal of the protecting group." " Support-bound primary amines 83 were converted to secondary amines by stepwise imine formation with aldehydes 84 and reduction with sodium borohydride." The hindered secondary amines 85 were acylated with acid chlorides, sulfonyl chlorides, isocyanates, and isothiocyanates to yield 87 after cleavage from solid-support. 

Two different N-protected hydroxylamines have been used to accomplish the synthesis of these novel hydroxylamine-functionalized resins. fV-Hydroxy-phthalimide has been employed in two ways first, as a nucleophile to splace either a resin-bound chloride ion (30) or a resin-bound mesylate ion (31) Figure 8a) and second, to generate the active phosphonium species required to perform a Mitsunobu reaction on a hydroxyl-functionalized resin (32) (Figure 8b). In both cases, the resin-bound iV-hydroxyphthalimide ester that is generated is subsequently treated with hydrazine to afford resin-bound hydroxylamine. 

Yields are largely comparable with standard Mitsunobu reactions between alcohols and phthalimide, with enantiomeric excesses varying from 69 to 97%, depending on the alcohol substrate. For example, using 5-metbyl lactate (8), 6a was obtained in a 52% yield, the product 6a exhibiting an ee of 92% (eq8). 

In comparison, a standard Mitsunobu reaction between 5-ethyl lactate and phthalimide gave a 45% yield of the expected protected D-alanine derivative with an ee greater than 99%, while Barrett s modified method using potassium phthalimide and an imidate ester gave a 25% yield with racemization. (Note Less than complete inversion of configuration has been noted with the use of 7 as a Mitsunobu-type reagent. )... 

More typically, activated amines in the form of amides or sulfonamides are employed as coupling partners in the Mitsunobu reaction. Amides, sulfonamides, lactams, imides, azides, and more esoteric acidic amine derivatives work well in this context. The figures below list a significant number of amine derivatives that have been used in the Mitsunobu reaction. Phthalimide, originally employed by Mitsunobu s group many years ago, remains one of the most important amine surrogates for use... 

In analogy to the phthalimide Mitsimobu reaction above, a number of other imides also participate in the Mitsunobu reaction. For example, various imides (116 to 123) were examined by Alcarez et al. in their search for novel... 

A new route to bromopyrroles was developed. It depends on addition of HBr to A-protected y-aminoynones. When applied to alkynyl ketones, 2-aryl or 2-alkyl 4-bromopyrroles are formed. 2-Alkyl or 2-aryl 3-bromopyrroles can be obtained from acetals of V-aminoynals. The ketones are made from A -protected propargylamines by ( -acylation. The acetals are made from 3,3-diethoxypropyne by addition to an aldehyde followed by introduction of the amino group by reaction with phthalimide under Mitsunobu conditions. <95S276>... 

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