Unsaturated imides

A series of cross-linkable copoly(amide—imides) is known to be possible from aromatic diamines and substituted isophthaloyl chlorides containing unsaturated imide rings as a pendent function (13). 

Aldehyde 170 is to serve as the electrophile in an intermolecular Homer-Wadsworth-Emmons (HWE) reaction70 with enantiomeri-cally pure phosphonate 169. Compounds 169 and 170 can in fact be joined efficiently under the mild reaction conditions shown in Scheme 50 to give a,/ -unsaturated imide 206 (96 % yield). The use... 

Asymmetric Diels-Alder reactions. Unlike methyl crotonate, which is a weak dienophile, chiral (E)-crotonyl oxazolidinones when activated by a dialkylaluminum chloride (1 equiv.) are highly reactive and diastereoselective dienophiles. For this purpose, the unsaturated imides formed from oxazolidinones (Xp) derived from (S)-phenylalanol show consistently higher diastereoselectivity than those derived from (S)-valinol or (IS, 2R)-norephedrine. The effect of the phenyl group is attributed in part at least to an electronic interaction of the aromatic ring. The reactions of the unsaturated imide 1 shown in equation (I) are typical of reactions of unsaturated N-acyloxazolidinones with cyclic and acyclic dienes. All the Diels-Alder reactions show almost complete endo-selectivity and high diastereoselectivity. Oxazolidinones are useful chiral auxiliaries for intramolecular Diels-Alder... 

Addition of an alkene to a compound containing a metal-H bond usually results in insertion, and it does in this case, too, to give the stabler 1° alkylmetal. Addition of CuBr to this complex might result in transmetallation, to give a C2-Cu bond. Addition of the copper compound to the unsaturated imide gives conjugate addition, perhaps by coordination of the C3=C4 tz bond and insertion into the C2-Cu bond. Workup gives the observed product. 

The stereochemistry of the addition can be controlled through the attachment of a chiral auxiliary or using asymmetric catalysis. Addition of 0-benzylhydroxylamine to unsaturated imide 51 (equation 33) bearing a chiral auxiliary was found to proceed with high diastereoselectivity at the a-position". ... 

The Chen group early in 2005 constituted the novel class of thiourea-function-ahzed cinchona alkaloids with the first reported synthesis and application of thioureas 116 (8R, 9S) and 117 (8R, 9R) prepared from cinchonidine and cinchonine in over 60% yield, respectively (Scheme 6.112) [273]. In the Michael addition of thiophenol to an a,(5-unsaturated imide, the thioureas 116 and 117 displayed only poor stereoinduction (at rt 116 7% ee 117 17% ee), but high catalytic activity (99% yield/2h) (Scheme 6.112). 

Scheme 6.112 Michael addition of thiophenol to an a,p-unsaturated imide catalyzed by cinchonidine-derived thiourea 116 and cinchonine-derived thiourea 117, the first representatives of this class of bifunctional hydrogen-bonding cinchona alkaloid-thioureas.

Many of the synthetic routes derived for pregabalin (2) before 2003 have relied on classical chiral resolution of either an intermediate or the final racemic 3-isobutyl GABA (43). In 2003, Jacobsen and co-workers published their work on a novel enantio-selective synthesis of pregabalin (2) (Sammis and Jacobsen, 2003). The Harvard group was able to promote conjugate addition of hydrogen cyanide into the unsaturated imide... 

Although the transformation is not an oxidation, Eric N. Jacobsen of Harvard University has developed (J. Am. Chem. Soc. 2004,126, 14724) an elegant route to enantiomerically-pure alcohols, based on the conjugate addition of an oxime such as 13 to an a.fi-unsaturated imide such as 14. 

Jacobsen et al. have shown that cyanoacetate derivatives undergo conjugate addition to ,/i-unsaturated imides in the presence of a chiral Al-oxo salen complex 32 to afford the corresponding product in up to 98% ee (Scheme 16) [19]. When an a-amino cyanoacetate was used, a highly functionalized lactam 33 was obtained in one step. Another example of Lewis acid-catalyzed conjugate addition of cyclic 1,3-dicarbonyl compounds to 2-oxobutenoate employed the chiral Cu-bisoxazoline complex 34 (Scheme 17) [20]. 

Table 6.3 Thiourea-catalyzed additions of malononitrile to a,/ -unsaturated imides.

Thiourea-Amine-Catalyzed Malononitrile Enolate Additions to a,/ -Unsaturated Imide [30] (pp. 196-197)... 

Very recently, the conjugate addition of phthalimide salts to chiral a,/ -unsaturated imides has been reported. After further transformations, optically active /J-amino acid derivatives were obtainedl37. 

Diels-Alder Reactions. Chiral a,p-unsaturated imides participate in Lewis acid-promoted Diels-Alder cycloaddition reactions to afford products in uniformly excellent endo/exo and endo diastereoselectivities (eq 50 and 51). Unfortunately, this reaction does not extend to certain dienophiles, including methacryloyl imides, p,3-dimethylacryloyl imides, or alkynic imides. Cycloadditions also occur with less reactive acyclic dienes with high diastereoselectivity (eq 52). Of the auxiliaries surveyed, the phenylalanine-derived oxazolidinones provided the highest diastereoselectivities. This methodology has been recently extended to complex intramolecular processes (eq 53). In this case, use of the unsubstituted achiral oxazolidinone favored the undesired diastereomer. 

Coixjugate Addition Reactions. a,3-Unsaturated N-acyloxazolidinones have been implemented as Michael acceptors, inducing chirality in the same sense as in enolate alkylation reactions. Chiral a,3-unsaturated imides undergo 1,4-addition when treated with diethylaluminum chloride (eq 55). Photochemical initiation is required for the analogous reaction with Dimethylaluminum Chloride. ... 

Organocuprates also undergo conjugate addition with chiral a,p-unsaturated imides. Treatment of the imides derived from... 

Dimethylaluminum chloride also catalyzes the ene reactions of chiral a,p-unsaturated imides with 1,1-disubstituted alkenes in moderate yields and selectivities. ... 

Hoashi Y, Okino T, Takemoto Y (2005) Enantioselective michael addition to alpha, beta-unsaturated imides catalyzed by a bifunctional organocatalyst. Angew Chem Int Ed Engl 44 4032... 

In 2005, Chen and coworkers found that the epi-cinchonidine/cinchonine-derived thiourea catalysts, 79a,b, can serve as highly active promoters of the Michael addition ofthiophenol to the a,P-unsaturated imide 80 however, the reaction proceeded with low enantioselectivity (up to 17% ee) (Scheme 9.28) [22]. 

Tetraaryl-l,3-dioxolane-4,5-dimethanol (TADDOL) ligands synthesized from tartaric acid have been extensively employed by Narasaka as the chiral control element in selective Diels-Alder reactions. Initial experiments were conducted with simple dienes and a,P-unsaturated imides using complex 44 (Scheme 36) [104,105]. Several rather subtle features have contributed to the success of these endeavors 1) the use of the acetophenone-derived dioxolane rather than the ac-etonide resulted in an increase of 20% ee 2) the use of alkyl-substituted benzenes as solvent augmented enantioselectivities relative to more common organic solvents e.g., CH2CI2, THF) [106] 3) use of 4 A molecular sieves was typically required to achieve maximum enantioselectivity. 

Kobayashi and coworkers have reported that a chiral complex derived from scandium(III)triflate, i -(-i-)-BINOL ((i )-59), and 1,2,6-trimethylpiperidine in the presence of 4 A molecular sieves catalyzes the reaction of unsaturated imides with cyclopentadiene in 96-97% ee (Scheme 49) [130]. 

Cycloadditions. It was found recently that N-tosyl imines of a variety of aldehydes react with alkynyl sulfides in the presence of a Lewis acid catalyst to afford a, /J- unsaturated thioimidates [100]. Thus alkynyl sulfide 291 combines with an N-sulfonyl imine in the presence of a catalyst such as BF3 etherate, Yb(OTf)3, Sc(OTf)3 or Ln(OTf)3to give an imidate 293 [Eq. (70)]. It is believed that this transformation occurs through an initial [2 + 2]-cycloaddition of the reactants to form an azetine 292. Other types of N-substituted imines were found to react with alkynyl sulfides under these conditions to provide different sorts of products and not a, /3-unsaturated imidates like 293. 

Titanium alcoholates of diols 2.50 generated by exchange with (/-PrO TiC are also potent catalysts, and the most efficient catalyst is derived from 2.50 (R = Me, R = Ar=Ph). These catalysts promote the diastereo- and enantioselective cycloaddition of cyclopentadiene or acyclic dienes with some a,P-unsaturated imides 7.68 (R = H, Rg=Me, MeOOC) [45, 778] or of acyclic dienes with substituted benzoquinones at -78°C [1572, 1573] (Figure 9.20). Reactions occur at 0°C in the presence of molecular sieves, and only catalytic amounts of these alcoholates are used. Intramolecular cycloadditions also give useful sdectivities under these conditions [1574]. However, the process for preparation of the catalyst varies according to the reaction [778, 1573], and this is veiy important to the observation of high selectivities. 

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