Tetrahydroquinolines Povarov reaction

Sridharan V, Avendano C, Menendez JC (2008) New findings on the cerium(IV) ammonium nitrate catalyzed Povarov reaction stereoselective synthesis of 4-alkoxy-2-aryl-l,2,3,4-tetrahydroquinoline derivatives. Synthesis 1039-1044... 

An inverse electron demand aza D A reaction of electron rich alkenes with N aryl imines as 2 azadiene (Povarov reaction) provides tetrahydroquinolines. Reactions catalyzed by chiral phosphoric acids yielded different absolute ste reochemical outcomes when ethyl vinyl efher and enecarbamate are employed as electron rich alkenes, although chiral phosphoric acids have the same axial chirality in both cases (see Scheme 3.26). 

Zhu and co-workers [77] have successfully developed the first organocatalytic enantioselective three-component Povarov reaction for the efficient synthesis of enantiomerically enriched (2,4-cis)-4-amino-2-aryl(alkyl)-tetrahydroquinolines. To illustrate the power of this novel catalytic enantioselective three-component Povarov reaction, they applied this methodology to the short and efficient synthesis of torcetrapib (188), a potent cholesteryl ester transfer protein (CETP) inhibitor (Scheme 17.31). Reaction of 4-trifluoromethylaniline 184, propionaldehyde 18, and enecarbamate 185 using phosphoric acid catalyst 186 afforded tetrahydroquino-line 187 in 57% yield with 93% ee. Ethoxycarbonylation, deprotection/acylation, and benzylation provided torcetrapib (188) in four steps with 32% overall yield. 

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. ... 

Normally, the A-arylimine is obtained by reaction of aldehyde and aniline in acidic condition. Either tetrahydroquinoline or its corresponding substituted quinoline can be generated in the Povarov reaction, depending on the reaction conditions. For instance, DDQ-promoted dehydrogenation, vacuum distillation under acidic condition, oxidation by air or Mn(OAc)3, and Pd/C-catalyzed aromatization of tetrahydroquinoline, provides the corresponding substituted quinolines in good to excellent yield. Since some tetrahydroquinolines are unstable under the reaction conditions, the corresponding substituted quinolines could be isolated as the sole products. Electron-rich olefin, such as vinyl enol ethers, vinyl sulfides, and silyl enol ethers, are widely used as dienophiles in the cycloaddition of A-aryl aldimines to obtain substituted tetrahydroquinolines. To access natural... 

The mechanism of tetrahydroquinoline formation by the Povarov reaction has been debated. A stepwise mechanism involves ionic intermediate 13, followed by an intramolecular electrophilic substitution. A concerted hetero Diels-Alder reaction was proposed where a concerted asynchronous transition state 14 was suggested. 

Using Ln(OTf)3 catalyst, Batey demonstrated that the three-component Povarov reaction generated highly functionalized C-2 aliphatic-substituted tetrahydroquinolines 45, which were inaccessible previously using the traditional Povarov reaction, due to the instability of the aliphatic iV-arylaldimine. It is interesting that cyclopentadiene was used as the dienophile in this new process. ... 

A practical approach using chiral Br0nsted acids for the enantioselective three-component Povarov reaction has been successfully developed by Zhu and co-workers recently/ When 10 mol% chiral acid 91 was used as catalyst, a reaction of aniline, aldehyde and enecarbamate 88 in one-pot gave tetrahydroquinoline derivatives in good yield and excellent enantioselectivities (up to > 99% ee). To illustrate the power of this novel catalytic enantioselective three-component Povarov reaction, toprcetrapib was prepared in only 4 steps, so far the most effective approach to this target. 

Recently, Jacobsen developed a new strategy for inducing enantioselectivity in reactions of protio-iminium ions, wherein a chiral urea 95 interacts with the highly reactive intermediate through a network of noncovalent interactions. This interaction leads to an attenuation of the reactivity of the iminium ion and allows high enantioselectivity in the Povarov reaction, giving lactam-substituted tetrahydroquinoline derivatives 98 in excellent enantioselectivities and diastereoselectivities. ... 

Substituted 1,2,3,4-tetrahydroquinolines are present in several natural products, and the synthesis of some of those have been achieved starting with a Povarov reaction [197], For example, luotonin A 502, with a rather simple structure but promising cytotoxicity against leukemia cells, was the target of a four-step total synthesis, which involves a Povarov reaction combined with an oxidation to build the quinoline intermediate 501 (Scheme 13.106) [197c],... 

A slightly more complex application of a Povarov reaction in total synthesis is the preparation of martinellic acid 504, reported by Batey in 2002 (Scheme 13.107) [197b]. Using the Povarov reaction, it was possible to bnild the highly snbstituted 1,2,3,4-tetrahydroquinoline core 503 in only two steps with good diastereoselectivity. 

The obtained 1,2,3,4-tetrahydroquinolines V are rather stable, but the 1,2-dihydroquinolines VI are highly reactive and usually oxidized to the corresponding quinolines Vn (Scheme 13.110) on exposure to air [200, 202, 211, 212] or by a hydrogen transfer reaction [207b] in a domino one-pot process with the elimination [202, 212] or the Povarov reaction itself [202, 207a, b, 209a, 211], Also direct oxidation of the 1,2,3,4-tetrahydroquinolines can be accomplished stoi-chiometrically with 2,3-dichloro-5,6-dicyano-l,4-benzoqui-none (DDQ) [201] or catalytically with palladium combined with air [212],... 

The simplest access to 2,4-a 5 1,2,3,4-tetrahydroquinolines 506 via Povarov reaction is the use of vinyl ethers or vinyl amides 67 under Lewis acid catalysis (Scheme 13.111) [203b, 204, 205]. 

By introducing chiral information into the substrate, a diastereo- and enantioselective preparation of 1,2,3,4-tetrahydroquinolines is possible. Jprgensen therefore combined an organocatalytic Michael addition (not shown) with a Povarov reaction in a one-pot process to achieve good selectivities in the synthesis of octahydroacridines 527 (Scheme 13.119) [199]. 

The Povarov reaction is related to the previous examples in that it can be defined as the formal imino Diels-Alder reaction between aromatic imines and electron-rich olefins. It is one of the most popular methods for the synthesis of tetrahydro-quinolines [40], and two examples of Povarov reactions in water are summarized in Scheme 1.27. In an eaily example of the use of ceric ammonium nitrate as a catalyst in synthesis [41], Perumal reported a few examples of a CAN-catalyzed Povarov reaction of aldehydes, amines and N-viitylpyrroUdin-2-ones as the olefin component in water for the synthesis of heteroaiyl-substituted tetrahydroquinolines 54 [42]. Using a different approach, Vaultier later described an onium salt-supported Povarov three-component reaction in water at room temperature affording tricyclic compounds 55. In this study, either the aldehyde or the amine components were linked to a side chain containing an onium salt, which confers solubility to the reactant [43]. 

Shashikanth et al. [61] reported iodine-catalyzed aza-Diels-Alder (Povarov) reaction of 3,4-diltydro-2/f-pyran with in situ-generated A -aiylimines containing enohzable protons using acetonitrile as a solvent. It is an easy way to introduce C-2 aliphatic substitution in tetrahydroquinolines 37 and 38 (Scheme 10.27). A mixture of cis and trans products was obtained, but in the case of cyclopropane-substituted compound, the trans product is formed selectively in a good amount. 

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. 

The synthesis of tetrahydroquinolines has received a great deal of attention owing to their presence in many natural frameworks and also to their pharmacological importance [59], Enantioselective [4 -1- 2] cycloadditions constitute one of the most widely employed tools for the preparation of six-membered nitrogen heterocycles [60], Among them, the Povarov reaction is one of the main approaches to... 

Jacobsen investigated cooperative catalysis for the Povarov reaction by combining a chiral urea catalyst (84) with a Brpnsted acid (o-nitrobenzenesulfonic acid) to induce highly enantioselective syntheses of tetrahydroquinolines and their fused derivatives [66]. Unusually for a Povarov reaction, the final product 85 is trans, with the absolute configuration shown in Scheme 3.25. This strategy was applied to the generation of compound libraries for drug discovery [67]. 

Interesting approach to the synthesis of tetrahydroquinolines 31 using three-component Povarov reaction (Scheme 19) was reported by Kouznetsov et al. [36]. These compoxmds (31) were prepared directly from the anise seeds (main component anethole) upon treatment with anilines and benzaldehyde in supercritical CO2 in Ihe presence of BF3-OEt2-... 

Scheme 42.49 Chiral phosphoric acid-catalyzed Povarov reaction between aromatic aldimines and enecarbamates, affording tetrahydroquinolines 213.

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]. 

In 2010, Wang et al. applied the gold(I)/chiral Brpnsted acid relay catalysis to a novel three-component cascade reaction, providing direct access to structurally diverse julolidine derivatives 374 in high optical purity (Scheme 2.99). The phosphoric acid (Se)-catalyzed asymmetric Povarov reaction of 2-(2-propynyl)anihnes 365, (V-vinylcarbamate 8, and aldehydes 3 provided enantioenriched tetrahydroquinoline intermediates 372, which then underwent a hydroamination reaction under the catalysis of a gold complex to give julolidine derivatives with up to >99% ee [133]. 

A three-component Povarov reaction involving substituted benzalde-hydes and anilines as well as 2-hydro)ystyrenes in the presence of the chiral phosphoric acid (144) provided structurally diverse cis-disubstituted tetrahydroquinolines (143) in high stereoselectivities of up to >99 1 dr and 97% ee (Scheme 49). ... 

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