Inverse electron demand aza-Diels-Alder

Azacanthines, 374, like their deaza analogues (cf. Equation 128), can be prepared by inverse electron demand aza-Diels-Alder reactions of the appropriately tethered amidoalkyl-l,2,4-triazinylindoles 373 (Equation 135) <1995TL6591>. The sulfonyl-substituted derivatives 375 can be prepared similarly in high yield, although the conditions for each individual reaction are important, since an appreciable amount of the desulfonated product 376 may also be formed (Equation 136) <1998TL2487>. 

Scheme 38 Inverse-electron-demand aza-Diels-Alder reaction...

The decrease of electron density necessary for inverse electron demand aza Diels-Alder reactions can also be effected by appropiate substituents attached to C-2, especially by a cyano moiety. Several l-aza-2-cyano-1,3-butadienes have been investigated by Fowler and his coworkers in this context [243-245]. Strikingly, the easily accessable 1-aza-l,3-butadiene 3-29 undergoes cycloaddition not only with electron-rich dienophiles, it reacts as well with neutral and even with electron-deficient dienophiles (Fig. 3-10) [246,247],... 

Activation of 2-aza-l,3-butadienes for inverse electron demand aza Diels-Alder reactions can also be achieved by introducing electron-withdrawing substituents. Thus, Barluenga s group has developed 3,4-bismethoxycarbonyl-2-aza-1,3-butadienes which undergo smooth intramolecular cycloadditions upon heating [278]. 

Akiyama T, Morita H, Itoh J, Fuchibe K (2005 a) Chiral Brpnsted acid catalyzed enantioselective hydrophosphonylation of imines asymmetric synthesis of alpha-amino phosphonates. Org Lett 7 2583-2585 Akiyama T, Morita H, Fuchibe K (2006b) Chiral Brpnsted acid-catalyzed inverse electron-demand aza Diels-Alder reaction. J Am Chem Soc 128 13070-13071... 

Inverse Electron-Demand Aza-Diels Alder Reaction (Povarov Reaction)... 

Electron-deficient dienophiles will not work under the conditions, because the present reactions are based on inverse electron-demand aza-Diels-Alder reactions... 

Inverse Electron Demand aza-Diels-Alder Reactions of 1,2,4-Triazines 85... 

INVERSE ELECTRON DEMAND AZA-DIELS-ALDER REACTIONS OF 1,2,4-TRIAZINES... 

The Povarov reaction is the inverse electron-demand aza-Diels-Alder reaction, a [4 + 2] cycloaddition between an A -aiylimine (as the diene) and an electron-rich olefin (as the dienophile), which gives tetiahydroquinolines or substituted quinolines as the product. 

A highly enantioselective inverse-electron-demand aza-Diels-Alder reaction of A-sulfonyl-l-aza-1,3-butadienes 88 and aldehydes 71 was reported by Chen and his co-workers. Scheme 3.31 [46]. Few chiral piperidine derivatives 89 were prepared via this methodology. The addition of water in the reaction media led to a dramatic acceleration of the reaction. Presumably, water is helpful for the hydrolysis of the catalyst-incorporated intermediate to release the catalyst and thus enable the catalytic turnover. Noteworthy, replacement of acetic acid to stronger acid, e.g. p-tolue-nesulfonic acid, resulted in no reaction. 

Scheme 3.31 Organocatalytic asymmetric inverse-electron-demand aza-Diels-Alder reaction of A-Sulfonyl-l-aza-1,3-butadienes and aldehydes...

More recently, Chen and co-workers reported an organocatalytic regio- and stereoselective inverse-electron-demand aza-Diels-Alder reaction of a,p-unsaturated aldehydes 28 and iV-tosyl-l-aza-1,3-butadienes 88, providing the enantiomerically pure piperidine derivatives 89, Scheme 3.33 [48]. 

The Povarov reaction is the inverse electron-demand aza-Diels-Alder reaction, a [4 + 2] cycloaddition between an A-arylimine (as the diene) and an electron-rich olefin (as the dienophile), which gives tetrahydroquinolines 3 or substituted quinolines 4 as the product. This reaction also called as imino-Diels-Alder reaction, usually catalyzed by Lewis or Bronsted acids. Since the jV-arylimine can be prepared in situ from aniline and aldehyde, thus the Povarov reaction can be performed in a one-pot fashion. ... 

M. Xie, X. Chen, Y. Zhu, B. Gao, L. Lin, X. Liu, X. Feng, Angew. Chem. Int Ed. 2010,49,3799-3802. Asymmetric three-component inverse electron-demand aza-Diels-Alder reaction efficient synthesis of ring-fused tetrahydroquinolines. 

The same catalyst (93) was applied with success to the first organocatalytic multi component asymmetric Biginelli reaction providing medicinally relevant chiral 3,4-dihydropyrimidini-2-(l//)-ones (94) (Scheme 29)7 Chiral acid-catalyzed inverse electron-demanding aza Diels-Alder reaction of aldimines (95) with electron-rich alkenes (Scheme 30). A new catalyst salt (96) that consist of an achiral ammonium ion and chiral phosphate anion has been developed that catalyzes highly... 

The catalytic asymmetric /-selective Diels-Alder annulation of a, -unsaturated /-butyrolactams with enones provided a synthesis of, y-functionalized bridged bi-or tri-cyclic dihydropyranopyrrolidin-2-ones in one step (up to 98% yield, >20 1 dr, and 99% ee) The inverse-electron-demand aza-Diels-Alder cycloaddition 0 of A-aryl-a,/0-unsaturated ketimines with enecarbamates in the presence of chiral bifunctional phosphoric acids produced 4,5,6-trisubstituted 1,4,5,6-tetrahydropyridines having three contiguous stereogenic centres in up to 84% yield, 95 5 dr, and 95% 5-Alkenylthiazoles react as in-out dienes with e-poor dienophiles in polar 44-2- 0 cycloaddition reactions. The cycloadditions are site selective. The mechanism is thought to lie between a concerted but highly asynchronous process and a stepwise process. 

The Povarov reaction, an inverse electron-demand aza-Diels-Alder reaction of 2-azadienes with electron-rich olefins, allows a rapid construction of polysubstituted tetrahydroquinolines. It must be noted that enantiose-lective versions of the Povarov reaction remain rare. Actually, the first highly enantioselective example of this type of reaction was developed by Zhu et al., in 2009. Later, Jacobsen et al. reported another enantioselective Povarov reaction catalysed by a combination of a strong Bronsted acid, such as o-nitrobenzene sulfonic acid, with a chiral urea. As shown in Scheme 2.8, the reaction of electron-rich alkenes with imines provided the corresponding tricyclic products in good yields, moderate diastereoselectivities of up to 62% de, and generally high enantioselectivities ranging from 90 to 98% ee. 

Recently, Wang and co-workers reported the first asynunetric inverse-electron-demand aza-Diels-Alder reactirai of indoles with in situ formed azoalkenes catalyzed by a Cu(I)/Bu-Phosfeirox complex (Scheme 35) [60]. The current methodology provides an expedient access to highly functionalized [2,3]-fused indoline... 

Akiyama, T, Morita, H., Fuchibe, K. (2006). Chiral Brpnsted acid-catalyzed inverse electron-demand aza Diels—Alder reaction. Journal of the American Chemical Society, 128, 13070-13071. 

Haider N, Holzer W (2004) In Yamamoto Y, Shinkai I (eds) Science of synthesis Houben-Weyl method of molecular transformation, vol 26. Thieme, Stuttgart, p 251 Hamer J, Macaluso A (1964) Nitrones. Chem Rev 64 473-495. doi 10.1021/cr60230a006 Han B, Li J-L, Ma C, Zhang S-J, Chen Y-C (2008) Organocatalytic as5rmmetric inverse-electron-demand aza-Diels-Alder reaction of A-sulfonyl-l-aza-1,3-butadienes and aldehydes. Angew Chem 47(51) 9971-9974. doi 10.1002/anie.200804183 Hanefeld W, Wurtz S (2000) Synthese potentieller pflanzenschutzwirkstoffe auf... 

In 2009, Masson, Zhu and coworkers reported a sequential inverse-electron-demand aza-Diels-Alder reaction (Povarov reaction) [105]. They prepared imines in situ from the corresponding aldehydes 211 and anilines 210 and reacted them with enecarbamates 212 as electron-rich dienophiles with excellent enantioselectivity using phosphoric acid 99c (Scheme 42.49). The practicality of their approach was highlighted by its application in an efficient synthesis of the drug torcetrapib [106]. 

The asymmetric inverse-electron-demand aza-Diels-Alder reaction of Af-Ts-1-aza-l,3-butadienes derived from 3-argiocarbonylcoumarins and acetaldehyde has also been developed using chiral aminocatalysis, giving tricyclic chroman-2-one derivatives in high enantioselectivities (up to 95% ee) [35]. 

After Akiyama et al. reported the first organocatalzyed inverse electron-demand aza-Diels-Alder reaction (Povarov reaction) between o-hydroxyaniline-derived imines and alkyl vinyl ethers [6], Liu et al. developed a three-component Povarov reaction of aldehydes 3, anilines 7, and benzyl A-vinylcarbamates 8a that efficiently afforded enantioenriched (2,4-c )-4-amino-l,2,3,4-terahydroquinoline 35 with a wild substrate scope (Scheme 2.9) [15a], Subsequently, a full study of the mechanism, substrate scope, and catalyst loading of this transformation was made, which revealed that this type of three-component Povarov reaction underwent a stepwise mechanism [15b]. Very recently, He, Shi, and others proved independently that the hydroxystyrenes 8b or 8c can also act as good dienophiles in asymmetric three-component Povarov reactions, thus providing efficient methods to access structurally diverse multisubstituted tetrahydroquinolines 35a or 35b in high stereoselectivities [16]. 

Three component inverse electron demand aza-Diels-Alder reaction was reported recently by Feng et al., where aldehyde 335, aromatic amino alcohol 336, and cyclopenta-diene 337 afforded tetrahydroquinoline derivatives 338 with high yield and excellent stereoselectivity. L-Ramipril-acid-derived A,A -dioxide L was found to be the best ligand and Sc(OTf)3 as the best LA for the reaction (Scheme 40.74). 

An extensive review of the one-pot inverse-electron-demand aza-Diels-Alder reaction between A-arylimine and -rich olefins (Povarov reaction) has been presented. " A chiral phosphoric acid-catalysed inverse-electron-demand aza-Diels-Alder reaction... 

Highly enantioselective, three-component, inverse electron-demand aza-Diels-Alder reaction of aldehydes, anilines, and isoeugenol derivatives (129) catalysed by a phosphoric acid (119) has been reported by Masson and co-workers. A wide variety of 2,3,4-trisubstituted tetra-hydroquinolines (130) containing an aryl group at the 4-position were obtained in a one-pot process with good to high yields and excellent enantioselectivities (up to >99% ee) (Scheme 45). ... 

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