The Intramolecular Povarov Tool in the Construction of Fused Nitrogen-Containing Heterocycles

Nitrogen heterocycles are part of the structure of natural products and agents with important biological activity, such as antiviral, antibiotic, and antitumor drugs. For this reason, heterocyclic compounds are one of today’s most desirable synthetic targets and the Povarov reaction is a powerful synthetic tool for the construction of highly functionalized heterocyclic systems. This process involves an aromatic amine, a carbonyl compound, and an olefin or acetylene to give rise to the formation of a nitrogen-containing heterocycle. This review illustrates advances in the synthetic aspects of the intramolecular Povarov reaction for the construction of intricate nitrogen-containing polyheterocyclic compounds. This original review presents research done in this field, with references to important works by internationally relevant research groups on this current topic, covering the literature from 1992 to 2022. The intramolecular Povarov reactions are described here according to the key processes involved, using different combinations of aromatic or heteroaromatic amines, and aliphatic, aromatic, or heteroaromatic aldehydes. Some catalytic reactions promoted by transition metals are detailed, as well as the oxidative Povarov reaction and some asymmetric intramolecular Povarov processes.


Introduction
Nitrogen-containing heterocycles are present in many natural products and agents with important biological activity, such as antiviral, antibiotic, and antitumor drugs [1][2][3][4][5]. For this reason, the synthesis of N-heterocycles and their derivatives has always been an attractive topic in organic synthesis. Food and Drug Administration (FDA) databases reveal the structural importance of nitrogen-based heterocycles in drug design, considering that a large amount of small-molecule drugs contain a nitrogen heterocycle [6,7]. In addition, N-heterocyclic skeletons are used as building blocks for a number of new drug candidates, due to the ability of the nitrogen atom to readily form hydrogen bonds with biological targets [8]. Hence, in the drug discovery process, the development of practical synthetic routes to access these structural motifs in the simplest possible way is an important goal for synthetic and medicinal chemists. One of the most straightforward and versatile processes for the preparation of heterocyclic nitrogen compounds is the Povarov reaction. Especially this reaction allows the preparation of tetrahydroquinolines (THQs) and their more aromatized analogs, the quinolines (QUINs), one of the most relevant nitrogen-containing heterocycles ( Fig. 1) [9][10][11][12].
This process was first reported in the 1960s, when Povarov et al. described the formation of two new C-C bonds from N-arylimines 3 with vinyl enolethers 4 under medium-strength Lewis acid catalysis (BF 3 ·OEt 2 ), thus obtaining substituted THQs 5 that were oxidized to the corresponding QUIN 6 (Scheme 1) [13].
Since Povarov's first reaction, several reports indicated the versatility of this tool for the synthesis of nitrogen heterocycles [14,15]. In general, in this process an aromatic amine 1, a carbonyl compound 2, and an olefin participate to give rise explained as a formal intramolecular [4 + 2] cycloaddition reaction of aldimines 9, obtained by condensation between aromatic or heteroaromatic amines 7 and aldehydes 8 functionalized with double or triple bonds (Scheme 2). The initial adduct 10 obtained by the intramolecular cycloaddition of aldimine 9, followed by a doublebond tautomerization would generate the heteroaromatic compound 11 whose subsequent aromatization would give rise to derivatives 12.
Therefore, the intramolecular version of the Povarov reaction allows the generation of fused rings of high molecular complexity for the preparation of a wide variety of heterocyclic compounds. Skeletons of different sizes and with various condensed cycles can be obtained depending on the different combinations of aromatic or heteroaromatic amines with aliphatic, aromatic or heteroaromatic aldehydes (Scheme 3).
The aim of this review is to illustrate the advances in the synthetic aspects of the intramolecular Povarov reaction for the construction of intricate nitrogen-fused polyheterocyclic compounds. The revision is intended to be a comprehensive, authoritative, critical, and accessible review of general interest to the chemical community, as it contains a broad overview of published data on the intramolecular Povarov reaction covering the literature from 1992 to 2022, described according to the key processes involved, combining different aromatic/heteroaromatic amines and aliphatic/aromatic/heteroaromatic aldehydes. Some catalytic reactions promoted by transition metals are detailed, as well as the oxidative Povarov reaction and some asymmetric intramolecular Povarov processes. In addition, the effect of catalysts and solvents on the preparation of the final products will be examined, reflecting the synthetic potential of this strategy. This process has been extended to chromium complexes. When starting from chromiun tricarbonylamine 22, the highly trans-selective preparation of (octahydroacridine)chromium complexes 24 was accomplished through the intramolecular [4 + 2]-cycloaddition of the (imino-arene)chromium complexes 23 (Scheme 6) [24]. Different conditions were used. For example, the reaction of the imino complexes 23 with catalytic amounts of SnCl 4 (10 mol%) gave (1,2,3,4,4a,9,9a,l0octahydroacridine)chromium tricarbonyl complexes 24 in high yields and stereoselectivity toward the trans-products, which seems to agree with a concerted hetero-Diels-Alder type mechanism. These (octahydrocridine)chromium complexes 24 could be also prepared by direct complexation of octahydroacridines 26 with chromium tricarbonyl 25 [25].
A major drawback in cyclization and cycloaddition reactions of imines is the necessary activation; therefore, Laschat et al. [26] studied the reaction of anilines with para-and ortho-electron-withdrawing substituents with 3-methylcitronellal 14 in the presence of molecular sieves. The authors observed that the reaction proceeded differently depending largely on the type of molecular sieves used (Scheme 7). When powdered molecular sieves were used, anilines 18 gave very pure imines 27 in almost quantitative yield after 15 min. However, while the 4-nitroaniline 18 (R 1 = 4-NO 2 ) could not be converted to the imine 27 with powdered molecular sieves, when molecular sieve beads were used the formation of a mixture of the trans-cyclization products 28 and 29 was observed with other anilines.
In previous works, a variety of Lewis or Brønsted strong acids has been used for the preparation of octahydroacridine derivatives. Sabitha et al. [27] studied the intramolecular hetero-Diels-Alder reaction of (R)-citronellal 30 and anilines 18 when bismuth (III) chloride was used (Scheme 8). As authors stated, the temperature of the reaction medium seems to play a key role in determining the cis/trans ratio formation, and in this case, the reaction with a catalytic amount of BiCl 3 at 0 °C in acetonitrile proceeds in a highly stereoselective fashion giving trans-products 31 diastereoselectively. These trans-adducts 31 were obtained exclusively when non-substituted amines 18 (R 1 = H) were used.
A solid-supported catalyst (SiO 2 /ZnCl 2 ), under MW irradiation and without any solvent, has also been used for the synthesis of octahydroacridines (Scheme 9) [28]. Thus, an environmentally friendly and efficient method consisting on a facile imino-Diels-Alder reaction from N-aryl amines 18 and (R)-citronellal 30 has been developed and corresponding octahydroacridine derivatives 32 have been obtained in good yields.
Six years later, the same group reported the synthesis of several acridine derivatives with sulfur substituents by using the same catalyst, (R)-citronellal 30 and thio-functionalized anilines 33. In this case, octahydroacridines 34 were obtained in moderate yields and poor diastereoselectivity, obtaining almost stoichiometric mixtures of cis-and trans-diastereoisomers (Scheme 10) [29].
The synthesis of octahydroacridines 39 has been performed through intramolecular imino-Diels-Alder reaction starting from aniline 37 and citronellal 38 catalyzed by solid acid catalyst (Scheme 12) [30]. Several catalytic materials were studied, firstly, in the presence of pre-reduced Cu catalyst with molecular hydrogen, giving the corresponding octahydroacridines 39 as the only product in high yield. The use of the unreduced CuO/SiO 2 (CuO/Si) catalyst at room temperature in the presence of air Scheme 10 Synthesis of octahydroacridine derivatives 34 using a solid-supported catalyst and thio-functionalized anilines Scheme 11 Synthesis of octahydroacridine derivatives 36 with a solid-supported catalyst and thio-functionalized aldehydes gave comparable results. Other solid acids can be used in the synthesis of 39, such as silica-alumina cracking catalysts with a 13% content of Al 2 O 3 (SiAl 13) and a 0.6% alumina on silica (SiAl 0.6). Furthermore, two commercial acid-treated clays were also tested, namely Montmorillonite K10 and KSF. However moving from aniline 37 (R 1 = H) to electron-rich amines 37 (R 1 ≠ H), the selectivity of heterocycles 39 increased. In addition, differences in stereochemistry are evident. Pure Lewis solids (both CuO/silica and SiAl 0.6) promote 40/60 mixtures with a slight excess of transisomers. Conversely, the use of Brønsted acids, as Montmorillonite KSF, favor selectively the formation of the cis-isomer.
Based on the activation with molecular sieves, Laschat et al. studied the biscyclization of N-aryl diimines for the preparation of polycyclic ring systems [26]. In diamines with "separated" aromatic systems the reaction proceeded with molecular sieve beads. In this sense, when aryldiamines 40-42 were treated with 3-methylcitronellal 14 in the presence of 4 Å molecular sieve beads (Scheme 13), the biscyclization was complete after 24 h as determined by nuclear magnetic resonance (NMR) spectroscopy and corresponding compounds 46-48 were isolated. However, Scheme 12 Synthesis of octahydroacridines 39 catalyzed by different solid acid catalysts Scheme 13 Synthesis of bis-octahydroacridines 46-48 treatment of compound 40 (X = CH 2 ) with aldehyde 14 in the presence of powdered molecular sieves gave, as expected, complete formation of the diimine 43 (X = CH 2 ) after 15 min with no further cyclization. On the other hand, treatment of the isolated imine 43 with MeAlCl 2 yielded the biscyclization product 46 (X = CH 2 ). When the aromatic diamine has both functionalities in the same aromatic system (diamines 49-52, Scheme 13), the biscyclization reaction was not possible neither with powered molecular sieves nor with 4 Å MS beads. This means that the presence of a second imino function in the same aromatic ring decreases the reactivity of the first one, so that a stronger activation, e.g., by Lewis acids, is required to obtain the biscyclization products. Moreover, only when diamines 49 and 52 are used are the corresponding biscycloadducts obtained, probably because the two amino functions should be separated from each other, avoiding unfavorable steric interactions. Therefore, after formation of corresponding bisimines from amines 49 and 52, the treatment with 2.5 equivalents of MeAlC1 2 gave the corresponding biscyclization products.
Exploiting the advantages of the solid-phase synthesis methodology, the preparation of octahydroacridines by concomitant formation of the imine and subsequent intramolecular capture of the alkene has been reported [31]. For example, when aniline resin 53 was reacted with (R)-citronellal 30 in the presence of Yb(OTf) 3 , the only product isolated after cleavage of the resin with TFA was octahydroacridine 55 in excellent yield as a single diastereoisomer (Scheme 14).
Fluorous phase synthesis was also applied for the preparation of octahydroacridines [32]. Intramolecular aza-Diels-Alder reaction of functionalized N-aryl imines 56, produced in situ from aryl amines 18 and citronellal 38, was carried out at room temperature in the presence of trifluoroethanol (TFE), without any additional catalyst. In parallel, same reactions were studied in the presence of 10 mol% TiCl 3 (Scheme 15). Regarding the yields of the reactions, a greater amount of product 57 was obtained with the use of the fluorinated solvent; however, worse results were obtained in terms of the stereochemistry of the reaction, while TiCl 3 afforded a diastereomeric excess of trans-derivatives 57 the use of TFE gave to equimolecular mixtures of cis-and trans-derivatives.
The use of Lewis acids for the preparation of octahydroacridines presents some drawbacks, such as long reaction times, the use of low temperatures (−78 °C), and organic solvents. As previously reported, molecular sieves and BiCl 3 have been introduced, among other variations, as alternatives for cyclization promoters solving some of these limitations. Moreover, with the use of ionic liquids (IL), easily recoverable after the reaction, no polluting solvents or complementary catalysts are needed, as the ionic liquids perform this function. In this regard, selenium-and tellurium-based ionic liquids have been used as solvents and/or catalysts in the synthesis of octahydroacridines via the hetero-Diels-Alder reaction involving (R)-citronellal 30 and aryl amines 37 (Scheme 16) [33]. When using 5 mol% of ionic liquid 61 or 62 the expected products 63 are obtained in good yield. Moreover, to reduce the reaction times, microwave irradiation was used, the consumption of the starting products was observed in 6 min and the expected products 63 were also obtained in good yields. A cis/trans-mixture of diastereoisomers was obtained as determined by NMR spectroscopy.  [34]. The cycloaddition of aryl imines 20, formed in situ from a wide range of anilines 18 and (R)-citronellal 19 (R 2 = Me, R 3 = H) or 3-methyl citronellal 19 (R 2 = R 3 = Me), exhibited improved reactivity in the ionic liquid, thus reducing reaction time and significantly improving the yield. For example, the treatment of aniline 18 (R 1 = H) with (R)-citronellal 19 (R 2 = Me, R 3 = H) at room temperature, without the need for any additional catalyst, resulted in the formation of 3,9,9-trimethyl-1,2,3,4,4a,9,9a,10octahydroacridine 21 in 95% yield as a mixture of cis-and trans-isomers.
Not only citronellal was used as a suitable aldehyde for intramolecular Povarov reaction with anilines. The synthesis of cyclopenta[b]quinoline 70 and 71, as a part of isoschizozygane alkaloids, was accomplished by an intramolecular formal hetero-Diels-Alder Brønsted acid-catalyzed reaction from imine 66 obtained from unsaturated aldehyde 65 and aniline 64 (Scheme 18) [35]. In this case, the acidcatalyzed condensation of aromatic amine 64 with conjugated unsaturated aldehyde 65, followed by the cycloaddition reaction is described as a good route for the preparation of cyclopenta[b]quinoline derivative 70 and 71. The optimized conditions involved catalysis with 5 mol% of TsOH and provided 89% yield of an 86:14 mixture of 70 and 71 that could be readily separated by crystallization or column chromatography. The reaction is highly diastereoselective and produces adducts 70 and 71 with four contiguous stereocenters. The authors suggest in this case that the diastereoselectivity in adduct formation is determined by the nucleophilic attack of the diene on the iminium ion and directed by the C-3 stereocenter. Semiempirical calculations suggest that the closure of the cyclopentane ring would occur via a more stable intermediate 68 and give rise to 69 with a trans arrangement of the allylic cation and an amine. An alternative intermediate 67 is destabilized by the torsional interaction of the dienyl and imino moieties. The electrophilic aromatic substitution reaction between the allylic cation and the aniline in 69 will give rise to the more stable 1,2,4-trisubstituted arenes of structure 70 and 71.
Fused acridines have been prepared also by intramolecular Povarov reaction. 1,2,4-Trisubstituted cyclohexadienal 72, obtained by self-condensation of citral in the presence of NaH, is a suitable carbonyl substrate in the Povarov reaction providing molecular complexity and structural diversity. In this way, octahydrobenzo[c] acridines 73 have been prepared by intramolecular Povarov reaction of substituted anilines 18 and aldehyde 72 catalyzed by InCl 3 (Scheme 19) [36]. Methylene chloride was selected as the best solvent for this transformation, since ethyl ether, THF, or hexanes were found to be less efficient. The scope of substituted anilines 18 with a varied array of functional groups was studied, showing a strong reaction efficiency effect by steric and electronic factors. For instance, electron-withdrawing groups and sterically crowded anilines lead to acridine derivatives 73 in very low yield.
Condensation of aldehyde 74 with o-toluidine 13 afforded compound 75 whose subsequent intramolecular hetero-Diels-Alder reaction catalyzed by a Lewis or Brønsted acid produced diastereoselectively the cyclopenta[c]acridine derivatives 76 (Scheme 20) [37]. The formation of the cis-or trans-isomers was modulated depending on the Lewis or Brønsted acid used.
See Table 1

Steroid-and Carbohydrate-Derived Aldehydes
The intramolecular Povarov reaction with aliphatic aldehydes has been applied to the preparation of hybrid derivatives of tetrahydroquinolines condensed to a steroid skeleton by using Lewis or Brønsted acids. For this purpose, the reaction of the estrone derivative 77, with an allyl and a formyl group in suitable positions, with different anilines 18 was studied (Scheme 21) [38,39]. After the reaction of aldehyde 77 and anilines 18 and subsequent treatment with BF 3 ·OEt 2 , two different cyclic products 80 and 82 were obtained. Although compound 80 is the formal Diels-Alder adduct, the authors indicated that this compound may be obtained in a two-step mechanism from the initially formed iminium ion 78, which led to the carbocation 79 and then an electrophilic aromatic substitution to give 80. However, the iminium ion in 78 might also react with the alkene moiety to afford the cation 81 which could be further transformed by the addition of a nucleophile into compound 82.
In a similar manner, other aryl imino steroids 84 were prepared from the aldehyde steroid fragment 83 and various anilines 37 (Scheme 22) [40]. Afterwards, their intramolecular cyclization was studied via a Lewis acid-catalyzed reaction in the presence of BF 3 ·OEt 2 . The nature of the substituent on the aniline influenced the reactivity since different tetrahydroquinoline derivatives 85 were formed from unsubstituted (R 1 = H) or substituted (R 1 = Br, OMe) anilines 37 followed by treatment with acetic acid anhydride/potassium acetate. However, when 4-nitroaniline (R 1 = NO 2 ) was used, a fluoro-d-homosteroid derivative was isolated, apparently through an intramolecular Prins reaction.
Not only steroid-derived aldehydes have been used in intramolecular Povarov type cycloaddition reactions, as previously indicated, but also carbohydrate-derived aldehydes. Because natural carbohydrates, readily available and affordable, present a certain absolute stereochemistry, they are interesting substrates as chiral auxiliaries or chiral building blocks. Intramolecular hetero-Diels-Alder reactions of carbohydrate-derived aldehydes have been performed by Sabitha et al. [41]. In this work, pyrano [4,3-b] it can be used in substoichiometric amount (10 mol%), while other Lewis acids such as ZnCl 2 , FeCl 3 , ZrCl 4 , AlCl 3 , and BF 3 ·OEt 2 are needed in at least stoichiometric amounts. Cycloadducts 88 were obtained with high selectivity and good to excellent yields. In general, the reactions led to the formation of trans-isomers as major products, although small amounts of cis-isomers were observed. However, when a bulky group, such as tert-butyl (R 1 = t Bu), was present in the ortho position of the amine 18, only the trans-adduct 88 was exclusively obtained. On the basis of this protocol, the same group has performed the preparation of tetra-or pentacyclic furo [3,2-h] [1,6]naphthyridine derivatives from anilines or 1-naphthylamine and a simple sugar derivative [42]. In this case, an N-prenylated sugar aldehyde 89 and different aromatic amines 18 were used in the condensation reaction to give the imines 90 (Scheme 24). Afterwards, intramolecular hetero-Diels-Alder reaction in the presence of bismuth(III) chloride as catalyst, under very mild conditions, was completed within 30 min to give the corresponding trans-fused products 91 stereoselectively and in good to excellent yields.

Nitrogen-or Oxygen-Containing Aliphatic Alkene or Alkyne-Tethered Aldehydes
Some functionalized aldehydes with side chains possessing alkene or alkyne linked to a heteroatom such as oxygen or nitrogen have been described, allowing the preparation of fused heterocycles. For example, aldimines 93 derived from condensation of aromatic amines 37 with glyoxylic acid-derived O-allyl ester 92 in toluene and in the presence of molecular sieves were subjected to Lewis acid-catalyzed  [43]. Using 1 equivalent of BF 3 ·OEt 2 in CH 2 Cl 2 at room temperature, a mixture of quinoline-fused lactones 94 and amines derived from the reduction of aldimines 93 was observed, instead of expected tetrahydroquinoline-fused lactone (Scheme 25). This result suggests that the imine 93 reacts as an oxidant to convert the expected tetrahydroquinoline into quinoline 94, confirming that this oxidation proceeds faster or at the same rate as the intramolecular Povarov cycloaddition. However, the presence of an oxidant such as 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ) afforded quinoline 94 in low to moderate yields. Two equivalents of DDQ were necessary to convert aldimines 93 into quinoline-fused-lactone 94 with better yields without any traces of amines derived from the reduction of aldimines 93.
In a similar way, the glyoxylic acid-derived aldehydes 95 (X = O) react with anilines 18 in the presence of TFA to afford the tetrahydroquinoline lactones 97. A stepwise process in the [4 + 2]-cyclization would provide the trans-diastereoisomer (Scheme 26) [44]. When the reaction was performed with the N-benzylglyoxamides 96 (X = NBn) the corresponding derivatives 98 were obtained. In these cyclizations, the trans-configuration of the major isomer was obtained (Scheme 26).
Cyclization of the imine formed from cinnamoylaminoaldehyde 102 derived from different amino acids with aniline derivatives 37 using the mild Lewis acid ytterbium triflate yielded the thermodynamically more stable trans-products 103 (Scheme 28). The stereoselectivity was explained by a stepwise mechanism involving the transition states TSI and TSII (Scheme 28). In the electrophilic attack of the ytterbium-imine complex, fewer steric interactions would occur between the R 3 substituent and the aromatic ring of the aniline in TSII, maintaining the equatorial orientation of the aryl substituent in the subsequent closure of the second ring. The strategy of the cyclization from aminoaldehydes 102 was also transferred from solution to solid phase [44].
Likewise, aldimines 105 prepared from N-(prenylaminomethyl)cinnamaldehydes 104 derived from Morita-Baylis-Hillman adducts of acrylates, and aromatic amines 37, were subjected to an intramolecular cycloaddition reaction to furnish Scheme 28 Ytterbium triflate-catalyzed Povarov reaction with N-cinnamoyl-α-aminoaldehydes benzonaphthyridine derivatives 106 (Scheme 29) [48]. Several Lewis acids, for instance, Yb(OTf) 3 , InCl 3 , Sc(OTf) 3 , or BiCl 3 , or even Brønsted acids such as TFA, were used for this transformation; however, only in the presence of BiCl 3 did the reaction proceed efficiently to afford azaheterocycles 106 in good to excellent yields, but as a diastereomeric mixture of cis-and trans-adducts. ]. This cycloaddition reaction, where a second nitrogen atom has been introduced, displayed a remarkable Lewis acid-dependent reversal of the diastereoselectivity. The formation of the cis-or trans-isomers was modulated depending on the Lewis or Brønsted acid used. When using FeCl 3 , SnCl 4 , BF 3 ·OEt 2 , p-TsOH, TFA, AlCl 3 , and Et 2 AlCl trans-stereoselectivity was observed, whereas when using EtAlCl 2 , MeAlCl 2 and Me 2 AlCl 2 the diastereoselectivity is favored to the formation of the cis-isomers.

Scheme 33 Synthesis of fused benzo[g]quinolino[2,3-a]quinolidines 122
treated with various aryl amines 18 in the presence of molecular sieves, giving rise to the corresponding imines 121, which were immediately cyclized in the presence of EtAlC1 2 to the benzo[g]quinolino[2,3-a]quinolidines 122. The formal hetero-Diels-Alder reaction of 121 proceeded with high diastereoselectivity in favor of the cis configured product. The amino-substituent into a rigid pentacyclic system like 122 resulted in a good cytotoxic activity against human brain tumor cell lines.
On the one hand, the corresponding imine intermediate, obtained by condensation of aldehyde 120 with ethyl 4-aminobenzoate 123 in the presence of molecular sieves, directly treated with EtAlCl 2 , afforded the pentacyclic benzo[b]isoquino[2,3h] [1,7]naphthyridine 125 with high cis-diastereoselectivity (Scheme 34). Whereas, when the same imine was treated with SnCl 4 the pentacyclic trans-diastereoisomer 126 was obtained in a dr 0.5/99.5 [54]. The authors highlight the interest of preparing polycyclic all-trans-derivatives because of their more planar shape, which could induce a different interaction mode with DNA.
More aromatized fused heterocyclic compounds can be prepared directly by intramolecular Povarov reaction with triple-bond-functionalized aldehydes. When aldimines 129 derived from condensation of aromatic amines 127 with glyoxalderived alkynes 128 are used, only one equivalent of DDQ is required to carry out the oxidation of dihydroquinoline-fused lactones 130, obtained by intramolecular Povarov cycloaddition using 1 equivalent of BF 3 ·OEt 2 in CH 2 Cl 2 at room temperature, affording the corresponding quinoline-fused lactones 131 (Scheme 35) [43].
Pyrrolo [3,4-b]quinolines 133 can also be synthesized by using propargyl aldehydes derived from α-amino acids 132 and various substituted anilines 18. The intramolecular Povarov reaction requires a strategically positioned aldehyde moiety tethered to an alkynyl group. Hence, the reaction of N-propargyl aldehyde 132 and aromatic amines 18 was carried out in the presence of BF 3 ·OEt 2 in dry CH 2 Cl 2 . Using these reaction conditions, a series of pyrrolo [3,4-b]quinolines 133 were obtained in excellent yields (Scheme 36) [55].
A small library of A-and D-ring modified luotonin-inspired heterocyclic systems was synthesized in moderate to good yields following a six-step route that starts from phenylalanine. The key step of this total synthesis consists in an intramolecular Povarov reaction of imines obtained from a tetrahydroquinoline-derived alkynyl aldehyde 138 and various aryl amines 18 (Scheme 38 imines 139 were formed in situ from aldehyde 138 and substituted aryl amines 18 in the presence of 4 Å molecular sieves. Without isolation, subsequent treatment of N-aryl imines 139 with 1.5 equivalents of BF 3 ·OEt 2 afforded the target pentacyclic heterocycles 140 in yields that were approximately in the 40-50% range [56]. When longer side chain with a triple bond is used in aldehyde 141, benzo[b] isoquinolino [2,3-h] [1,7]naphthyridine 142 is obtained (Scheme 39) [54]. In this case, aldehyde 141 was treated with ethyl 4-aminobenzoate 123 and the formation of the corresponding imine was observed and used further without purification. Subsequent addition of BF 3 ·OEt 2 and aqueous workup resulted in the formation

Scheme 39 Synthesis of fused benzo[b]isoquinolino[2,3-h][1,7]naphthyridines 142
of the quinoline ester 142 in 38% yield. When BF 3 ·OEt 2 was replaced by EtAlCl 2 , a chloro compound was isolated in 7% yield as a minor by-product. The isolation of this latter compound, further supports a cationic cyclization mechanism where in the presence of EtAlCl 2 the cyclization of imine should afford carbenium ion 143, which can undergo Friedel-Crafts-type electrophilic aromatic substitution, followed by tautomerization to give 142 after oxidation.

Aromatic Amines and Aromatic Aldehydes
In this section, we disclose the intramolecular Povarov reaction using aromatic amines and aromatic aldehydes which allows the preparation of a diversity of polycyclic nitrogen containing heterocycles. Reactions have been classified considering the structure of the ortho-formylarenes and the way that the dienophile is tethered to the benzene ring.

C-Alkenyl(Alkynyl) Ortho-Formylarenes
Hexahydrobenzoacridine derivatives can be synthesized by intramolecular Povarov reaction of aldimines 145 derived from aromatic amines 18 and 2-prenylated benzaldehyde 144 (Scheme 40) [57]. The use of amines bearing electron-withdrawing or electron-donating groups in this approach, which was promoted by catalytic amount of bismuth(III) chloride, seems to have no effect on the reaction time or the yield. cis-Annulated hexahydrobenzo[c]acridines 146 were achieved in all cases with selectivities up to 97:3.
Through a tandem allylation/intramolecular Povarov reaction, polycyclic compounds 150 were synthesized by a [4 + 2] cycloaddition process (Scheme 41). The imine group in compound 147 acts as a directing group to enable the introduction of a pendant alkene, thereby enabling a Lewis acid-catalyzed intramolecular Povarov reaction. Specifically, a manganese (I) complex catalyzed the directed C-H allylation with allene 148, producing compound 149 ready for an in situ Povarov cyclization catalyzed by silver (I). Other Lewis acid, including BiCl 3 , Sc(OTf) 2 and Zn(OTf) 2 , led to significant decomposition of the ketimine 149. The reaction proceeds with high bond-forming efficiency (three C-C bonds), broad substrate scope, high regioand trans-stereoselectivity, and 100% atom economy (Scheme 41). The polycyclic A modified Povarov reaction involving 2′-alkynylbiaryl-2-carbaldehydes 156 and aryl amines 18 with tandem oxidation was performed using catalytic FeCl 3 . The outcome was an efficient general synthesis of dibenzo[a,c]acridines 157 with moderate to high yields (Scheme 43). This method offers simplicity in the preparation of substrates, diverse substrate scope, and high atom economy. The optimum reactions conditions for the general synthesis of dibenzo[a,c]acridine derivatives 157 were obtained with a 10 mol% FeCl 3 in toluene at 100 °C in open air. The synthesized compounds 157 had significant absorption and emission properties [60].
Alternatively, condensation of 2-allyloxynaphthalene-1-carbaldehyde 160 with substituted anilines 37 and subsequent intramolecular cyclization in the presence of  [68]. When the reaction was carried out with TFA, the obtained products were not those expected but their dehydrogenated derivatives 162. In a similar manner, cis-compounds 161 could also be obtained performing the intramolecular aza-Diels-Alder reaction in [bmim]BF 4 ionic medium [67], being the last one a green protocol that offers significant advantages over reported methods.
Substituted chromeno [4,3-b]quinolines 166 were achieved, under mild conditions, by tandem intramolecular aza-Diels-Alder reaction/photooxidation using a strategy of combination of visible-light photoredox and Lewis-acid catalysis. This intramolecular aza-Diels-Alder cycloaddition took place between the in situ generated benzylidene imine 164, derived from aryl amines 18 and salicylaldehydes 163 bearing an alkene-tethered partner, followed by oxidative aromatization to give the products 166 (Scheme 46). The reaction takes place using BF 3 ·OEt 2 as Lewis acid and Ru(bpy) 3 (PF 6 ) 2 as photosensitizer in acetonitrile under aerobic condition with the irradiation of visible light [69].

Scheme 47 Synthesis of trans-fused tetrahydrochromeno[4,3-b]quinolines from nitrobenzenes 167
The reaction between nitrobenzenes 167 and ω-unsaturated aldehydes, that is, 2-(cinnamyloxy)benzaldehydes 168, in the presence of iron as reductant and catalytic amounts of montmorillonite K10 in aqueous citric acid at 80 °C produced trans-fused tetrahydrochromeno [4,3-b]quinolines 170 exclusively with yields ranging from 69% to 87% (Scheme 47) [70]. It is assumed that the sequence of reactions starts with an iron-mediated reduction of the nitrobenzene 167. The resulting aniline reacts with the ω-unsaturated aldehyde 168 to give the corresponding imine 169, which in turn undergoes an intramolecular aza-Diels-Alder reaction. This Povarovtype reaction is catalyzed by montmorillonite K10, proceeds via an exo-transition state structure, and delivers the trans-fused tetrahydrochromeno [4,3-b]quinolines 170 in diastereomerically pure form. The method enables the replacement of anilines with nitrobenzenes as substrates for intramolecular aza-Diels-Alder reactions. The domino reaction can be performed with numerous functionalized nitrobenzenes and a number of 2-(cinnamyloxy)benzaldehydes.
Other configurational and functionally diverse heterocyclic compounds have also been prepared through an intramolecular formal aza-Diels-Alder cyclization. The substrates included substituted functionalized salicylaldehydes with a variety of anilines to yield different tetrahydroquinoline products [44]. Thus, cyclization of cinnamyl salicylaldehyde ethers 171 with substituted anilines 18 and treatment with trifluoroacetic acid in acetonitrile at 55 °C for 30 min afford the tetrahydroquinoline cycloadducts 173 in good yield (Scheme 48). Modest variations are well tolerated on the aniline ring, and the process can be extended to an electron-rich cinnamate ester 172 as well, although products 174 were obtained in modest yield. The major products isolated as single isomers after chromatographic or crystallographic purification possess the thermodynamically favored trans-configuration.
This methodology has also been extended to solid-phase synthesis with acidsensitive methoxy benzaldehyde polystyrene (AMEBA) resin 177 (Scheme 49). The reaction of immobilized anilines 175 with salicylic aldehyde derivatives 176 containing an electron-rich olefin substituent, catalyzed by both TFA and Yb(OTf) 3 yielded polysubstituted tetrahydrochromeno [4,3-b]quinolines 178 as 50:50 mixtures of diastereoisomers, which were subsequently separated by preparative HPLC [71]. Very recently, Kouznetsov et al. [72] have described the synthesis of chromeno [4,3-b]quinolines 186 promoted by I 2 and DMSO from easily available aryl amines 18 and O-cynnamyl salicyladehydes 183. Iodine acts as a Lewis acid to catalyze the formation and cyclization of the imines 184, using DMSO as the solvent, to generate the respective tetrahydrochromenoquinolines 185 as intermediates (Scheme 51). Finally, the I 2 /DMSO catalytic system could mediate the aromatization of 185 to the corresponding chromeno[4,3-b]quinolines 186. The scope and general applicability of the reaction has been widely studied, considering both anilines and 2-(cinnamyloxy)benzaldehydes. The reaction proceeds under mild conditions, tolerates a great range of functional groups and features high step economy, since it constitutes a tandem process.
Other strategies have been used for the synthesis of chromenoquinoline derivatives involving the use of O-propargyl-substituted salicylaldehyde ethers. In this context, activation of a terminal alkyne C-H bond by transition-metal catalysts is one of the major interests in synthetic organic chemistry. Several reports describe this activation by transition metal catalyst such as Ag, Au(I), Au(III), Cu(I), Ru, and Ir [73][74][75][76]. In this way, Nagarajan's group [77] described a straightforward approach to chromenoquinolines using a mixture of copper(I) iodide and lanthanum triflate as an efficient catalyst. Moreover, copper compounds are readily available, non-air-sensitive, nontoxic catalysts and inexpensive, compared with other transition metal catalysts. 6H-Chromeno [4,3-b]quinolines 189 can be attained in  [78]. A plausible mechanism assumes the formation of a copper-acetylide imine intermediates 191 that after the sequential intramolecular [4 + 2] cycloaddition, protonation, and oxidation generate the product 192. The best yield was only obtained using highly Complementarily, a new method was developed to synthesize 7-halogenated chromenoquinolines 195 and 7-halogenated thiochromenoquinolines 196. The products can be directly obtained through Cu-catalyzed cascade reaction, that is, aza-Diels-Alder reaction of Schiff base 193 or 194, followed by halogenation (chlorination or bromination), using chloranil or bromanil as halogen sources. Cu 2 O worked as both a Lewis acid and transition-metal catalyst in the aza-Diels-Alder reaction and halogenation reaction, respectively. Chloranil and bromanil also performed dual functions, that is, as a halogen source and oxidant. Although the halogenated products were obtained in moderate yields (Scheme 54), the present method is highly useful in organic synthesis because of mild reaction conditions and experimental simplicity [79].
See Table 2 for the most representative examples of Sect. 3.2.

N-Alkenyl(Alkynyl) Ortho-Formylarenes
As in the case of O-allyl derivatives of salicylaldehydes, BiCl 3 was used as Lewis acid to catalyze the intramolecular [4 + 2] cycloaddition reaction of in situ generated aldimines derived from aromatic amines and o-aminobenzaldehyde [81]. Therefore Alternatively, 1,6-naphthyridines 209 were achieved by tandem intramolecular aza-Diels-Alder reaction/oxidative aromatization using a strategy of combination of visible-light photoredox and Lewis acid catalysis. This intramolecular aza-Diels-Alder cycloaddition of the in situ generated benzylidene imines 207, derived from aryl amines 18 and 2-aminoaryl aldehydes 206 bearing an alkenetethered partner, took place followed by oxidative aromatization to give products 209 (Scheme 57). The reaction proceeds using BF 3 ·OEt 2 as Lewis acid and Ru(bpy) 3 (PF 6 ) 2 as photosensitizer in acetonitrile under aerobic condition with the irradiation of visible light. This method provided a new access to the synthesis of important heterocycles under mild conditions [69].
Another highly efficient synthesis of 5,6-dihydrodibenzo[b,h][1,6]naphthyridines 212 was achieved by reaction between 2-(N-propargylamino)benzaldehydes 210 and aryl amines 18 in the presence of CuBr 2 (Scheme 58). First, other copper halides were tested, such as CuCl, CuBr, and CuBr 2 , with the last one being the most efficient in terms of yield. Meanwhile, CuI and Cu(OAc) 2 resulted to be inefficient. The proposed route involves that the in situ generated electron-deficient heterodienes 211 underwent an intramolecular inverse electron-demand hetero-Diels-Alder reaction
N-alkenyl pyrrolopyrimidine-6-carbaldehydes 218 have also been used as carbonyl component for the preparation of intermediate imines, which readily cyclized in an intramolecular Povarov reaction to afford uracil-annulated quinoline derivatives 223 in good yields and good to excellent stereoselectivities (Scheme 61) [83,86]. Different Lewis acid catalysts were studied in this transformation, namely BF 3 ·OEt 2 , Yb(OTf) 3 , Sc(OTf) 3 , and InCl 3 . Indium trichloride proved to be the most efficient with overall yields higher compared with other tested Lewis acid catalysts [86]. These results indicate that the cyclization pathway proceeds by a stepwise mechanism as outlined in Scheme 61. Tetrahydroquinoline-annulated heterocycles 223 (R 1 = Cl) were evaluated for their antibacterial activity against six different bacterial strains, being as active as the antibiotic ciprofloxacin and presenting a MIC value of 2.5 mg/mL against Escherichia coli [83].

Six-Membered Nitrogen-or Oxygen-Containing Heterocyclic Alkene-Tethered Aldehydes
Recently, Zhang's group [89]  A synthetic strategy developed in 2010 by Bai's group [90] affords an efficient access to a series of libraries of the tetracyclic pyrimidine-fused heterocycles. The key step in this synthetic methodology entails the intramolecular Povarov reaction of imine intermediate formed in situ from the reaction of aromatic amines 18 and allylaminopyrimidine-5-carbaldehydes 234. Trifluoroacetic acid was selected as Brønsted acid catalyst to accomplish this transformation, affording exclusively cis-benzopyrimido [4,5-h] [1,6]naphthyridines 235 in good to excellent yields (Scheme 65). Although the use of 10 mol% TFA in acetonitrile yielded the desired product in good yields, increasing the catalyst loading to 2 equivalents led to shorter reaction rates and higher yields.
In 2010 Subba Reddy et al. [91] described the first synthesis of pentacyclic polyaromatic chromenoacridine derivatives in a single-pot operation. This protocol involves the formation of the intermediate imine between para-and orthosubstituted aromatic amines 18 and alkene-tethered chromene-3-carbaldehyde 239, followed by the BF 3 ·OEt 2 -induced intramolecular Povarov reaction. Under these reaction conditions a set of 18 chromeno[2,3-c]acridines 240 were obtained in 66-88% yield with high trans-steroselectivity (Scheme 67). Other Lewis acids such as AlCl 3 , FeCl 3 , ZnCl 2 , SnCl 4 , Sc(OTf) 3 , InCl 3 , InBr 3 , In(OTf) 3 , LiClO 4 , and Brønsted acid TFA, were ineffective for this transformation in terms of both yield and selectivity. All attempts to extend this protocol to diamines such as 1,5-diaminonaphthalene did not furnish the desired product. . As a further extension of this work, the same reaction was carried out using InCl 3 impregnated in silica gel as Lewis acid catalyst under microwave irradiation. These reaction conditions dramatically increase the overall yields from 55-82% to 75-97%, retaining nearly the same diastereoselectivity ratios. This ecofriendly protocol avoids the use of organic solvents, has general applicability, and notably enhances reaction rates and chemical yields. In 2008, Zhang's group developed a new intramolecular Povarov reaction for the preparation of luotonin A analogs [95]. This approach entails the in situ formation of imidates through activation of corresponding chemically stable amides. Thus, bis(triphenyl)oxodiphosphonium trifluoromethanesulfonate, formed in situ from Ph 3 PO and Tf 2 O used for the total synthesis of camptothecin [96] and luotonin A [97], works as an amide-activating reagent to convert the amide moiety to its corresponding imidate under mild reaction conditions, and also to promote the subsequent intramolecular Povarov reaction in the desired direction. Using these catalytic conditions, cyclization of N-allyl naphthyridones 247 to afford luotonin A analogs 249 through the corresponding imidates 248 was attained in 64-78% yield (Scheme 70). The formation of compound 249 may be rationalized by the stability of aromatic system, driven by the catalytic system acidity.
Nagaiah et al. [98] reported the diastereoselective synthesis of tetrahydropyranochromeno [4,3-b]quinolines 251 by intramolecular Povarov reaction of formal 2-azadienes obtained in situ from aromatic amines 37 and O-prenyladed compounds 250 derived from 8-formyl chromenones (Scheme 71). Several Lewis and Brønsted acid catalysts were tested in this reaction and, among them, Yb(OTf) 3 and Sc(OTf) 3 were found to be almost equally efficient according to reaction yields, times, and See Table 4

Oxygen-or Nitrogen-Containing Heterocyclic Alkyne-Tethered Aldehydes
O-Propargylated compounds derived from 8-formyl chromenones 255 have been used as carbonyl compounds in the preparation of pyranochromeno [4,3-b]quinolines 256 [100]. Authors analyze the activity of several copper catalyst for the activation of the terminal alkyne C-H bond in 255 by the use of CuFe 2 O 4 nanoparticles, CuI, Cu(OTf) 2 , CuCl, and CuBr. CuFe 2 O 4 nanoparticles were found to be the best catalyst for this transformation, which due to their magnetic properties can be easily separated from the reaction mixture and reused without loss of activity. In addition, Similarly, this methodology allowed the synthesis of luotonin A 264 in 51% yield from the intramolecular Povarov reaction of N-propargylic-substituted aldehyde derived from quinazoline 263 and aniline 1 in the presence of 10 mol% Dy(OTf) 3 in acetonitrile (Scheme 76) [102].

Scheme 75 Intramolecular Povarov reaction in the formal synthesis of camptothecin
Luotonin A analogs [95] have also been prepared by intramolecular Povarov reaction through in situ formation of imidates by activation of corresponding chemically stable amides. Bis(triphenyl)oxodiphosphonium trifluoromethanesulfonate, an amide-activating reagent, catalyzes the cyclization of N-propargyl naphthyridones 265 yielding luotonin A analogs 266 in moderate yield (Scheme 77).

Heteroaromatic Amines and Aliphatic Aldehydes
Amino-heterocycles have scarcely been exploited as building blocks for either interor intramolecular imino-Diels-Alder reaction, even though they can condense with aldehydes to form imine derivatives. As far as we know, only two examples have been reported in the intramolecular Povarov reaction of imines generated from heteroaromatic amines and aliphatic alkene-tethered aldehydes. For instance, a catalyst-free intramolecular imino-Diels-Alder protocol for the synthesis of annulated tetrahydropyridines has been developed by Vilches-Herrera et al. [103]. The corresponding octahydro-1H-pyrrolo[2,3-b]quinoline 269 was obtained in 65% yield via cycloaddition of aldimine 268 obtained by condensation reaction between 2-aminopyrrole 267 and a non-aromatic aldehyde such as citronellal 38 (Scheme 78). The reaction is carried out in water under microwave irradiation at 200 °C and with no catalyst, which fulfills all the requirements for sustainable chemistry.
The Nagarajan's group [104] 3 . Although the diastereoselectivity is highly temperature dependent, the trans-isomer is the major product isolated in this reaction, and better diastereoselectivities (10:90) were attained at low reaction temperatures.

Heteroaromatic Amines and Aromatic Aldehydes
The first example was reported by Tietze et. al. in 1992. They worked out the intramolecular Diels-Alder reaction between benzaldehydes 273 and aminoisoxazole 272 under thermal conditions (Scheme 80) [105]. In this case, the condensation of both reagents generated the corresponding imines 274, which can be isolated, and selectively cyclized to form the cis-or trans-fused tetrahydropyridines 275 (Scheme 80). The selectivity of these reactions could be explained by electronic effects. In the reaction of 273 (R 1 = R 2 = R 3 = R 4 = H) with 272 only the trans-annulated tetrahydropyridine 275 was obtained. In addition, during the reaction of 272 with 273 (R 1 = R 2 = R 3 = H, R 4 = CO 2 Me) two diastereoisomers could be formed, but only the trans-annulated tetrahydropyridine 275 was observed. Surprisingly, the reaction of 273 (R 1 = R 2 = Cl, R 3 = R 4 = Me) with 272 yielded only the cis-fused compound 275.  [4 + 2] cycloaddition reaction was conducted in water under microwave irradiation and with no catalyst (Scheme 81). Moreover, in most of the cases the products precipitate in the reaction media, avoiding the use of solvents for extraction and column chromatography for purification. The reaction is solvent dependent with regard to its stereoselectivity. Only the trans-isomer is obtained if the reaction is performed in water, whereas in a nonpolar solvent such as p-xylene the cis-isomer can also be isolated.
A BF 3 ·OEt 2 -catalyzed intramolecular Povarov reaction, followed by oxidation with DDQ, was used to synthesize chromenopyridine-fused thiazolino-2-pyridone peptidomimetics with the ability to bind α-synuclein and amyloid-β fibrils in vitro [108]. The reaction works with several O-alkylated salicylaldehydes 295 and amino functionalized thiazolino-2-pyridones 294, to generate polyheterocycles 296 with diverse substitution in moderate to excellent yields (Scheme 84). On the contrary, attempts to synthesize C-7 unsubstituted molecules 296 (R 2 = H) through intramolecular Povarov reaction, using O-allylsalicylaldehyde 295 (R 2 = H) took place in very low yields, but the use of a vinyl ester moiety as electron-donating auxiliary 296 (R 2 = OCOPh), allowed the obtainment of the C-7 unsubstituted compounds 297 in reasonable reaction times and moderate yields after removal of benzoate functionality during the oxidation process.
Nagarajan et al. [111] have reported the synthesis of isomeric isoellipticine derivatives through a straightforward CuI/La(OTf) 3  After careful analysis, authors identified the intramolecular Povarov occurred through C-4 of the carbazole ring.
The synthesis of hybrid substituted quinolino [1,5]naphthyridines 330 and quinolino [1,8]naphthyridines 331 may also be obtained in good yields by BF 3 ·OEt 2 -catalyzed intramolecular cycloaddition of aldimines 326 or 327, derived from N-propargyl substituted aldehyde 325 and the corresponding aminopyridines 298 or 324 (Scheme 90) [107,109]. The deprotection of the tosyl group at the nitrogen atom was carried out with Mg under acidic conditions. See Table 5 for the most representative examples of Sect. 6.

Heteroaromatic Amines and Heteroaromatic Aldehydes
Only one report has disclosed in the intramolecular Povarov reaction of imine intermediates derived from heteroaromatic aldehydes and heteroaromatic amines. In this way, Nagarajan et al. [104] demonstrated the utility of imines, resulting from the condensation of N-prenylated indole-2-carbaldehydes 333 with aminocarbazoles 332, in the intramolecular Povarov reaction. This protocol efficiently proceeds in the presence of Lewis or Brønsted acids, but diastereoselectivity is influenced by the nature of the catalyst. The best catalytic conditions were found for La(OTf) 3

Scheme 91 Synthesis of isomeric ellipticine derivatives by means of intramolecular Povarov reaction of heteroaromatic aldehydes and heteroaromatic amines
Scheme 92 Intramolecular Povarov reaction of iminium ions for the synthesis of octahydroacridines (10 mol%) in 1,4-dioxane at 150-160 °C, yielding isomeric ellipticine ring system derivatives 335 (R 3 = R 4 = H) in good yields and excellent diastereoselectivities (Scheme 91). The intramolecular Povarov reaction occurred through C-4 of the carbazole ring, and the six-membered piperidine and five-membered pyrrolidine rings were cis-fused. When amine 332 with substitution at C-1 and C-4 (R 3 = R 4 = Me) reacted with aldehyde 333, the intramolecular cyclization occurred through the C-2 position of the carbazole ring, affording the corresponding product 337 in only 51% yield (Scheme 91).

Intramolecular Povarov Reaction with Secondary Amines
In 1996 Beifuss's group [112] developed the first intramolecular cationic Povarov cyclization. The condensation of N-substituted anilines 338 and chiral ω-unsaturated aldehydes 339 in situ affords cationic iminium ions 340 (Scheme 92). Subsequent intramolecular [4 + 2]-cycloaddition of 340 leads to the highly trans-diastereoselective formation of octahydroacridines 341 with five stereogenic centers. The best yields were obtained when the transformation was performed with BF 3 ·OEt 2 (30 mol%) as the Lewis acid in CH 2 Cl 2 . A one-pot diastereoselective synthesis of new N-substituted octahydroacridines was successfully achieved by Kouznetsov et al. [113,114] via BiCl 3 -catalyzed intramolecular cationic imino-Diels-Alder reaction. The intermediate iminium ions were prepared in situ through condensation of N-protected anilines 342 and (±)-citronellal 38 under mild reaction conditions (Scheme 93). It was observed that bulky N-substituent groups play a key role in the cis/trans ratio of the corresponding octahydroacridines 344. For instance, when R 1 = Me, a mixture of 50:50 cis/trans-octahydroacridine derivatives 344 were observed. However, increasing bulkiness (R 1 = allyl, propargyl, and benzyl substituents) allows preferential formation of the trans-fused heterocycles in ratios ranging from 22:78 to 3:97 cis/trans-isomers. It was found that use of the N-benzyl group resulted in a highly diastereoselective process that gives easily separable trans-fused N-substituted octahydroacridines 344. The developed protocol was extended to involve the use of citronella essential oil from Cymbopogon nardus as a renewable source of these biologically important heterocyclic molecules. The results obtained from C. nardus essential oil are comparable to those observed from pure (±)-citronellal 38, without changes in the diastereoselectivity. Furthermore, this methodology can be extended to other N-substituted anilines with reactive groups as starting materials to prepare different trans-N-substituted hybrid octahydroacridines 344 as potential bioassay substrates.
Spaller et al. [115] described the application of the intramolecular aza-Diels-Alder transformation to generate a diverse range of quinoline-fused structures with multiple stereogenic centers, many of which resemble lignan and arylnaphthalene-type natural products. In this work, they combined several secondary (N-alkylated) anilines 342 and aldehyde-alkene bridge 345, with various Brønsted and Lewis acid catalysts (Scheme 94). For instances, several Brønsted acids such as TFA,  [90] trifluoromethanesulfonic acid (TFMSA), acetic acid, p-TsOH, or l-tartaric acid and Lewis acids such as Yb(OTf) 3 or BiCl 3 were used for this transformation. The results demonstrated that both Brønsted and Lewis acids have a slight effect on both selectivity and overall yields. The use of 3 equivalents of TFA in acetonitrile at room temperature afforded hexahydropyrrolo [3,4-b]quinolin-1-ones 346 in moderate to excellent yields, and diastereoselectivities ranging from 34:66 to 6:94 (Scheme 94). N-alkyl substitution in the N-aromatic amine component was rigidified by incorporating a saturated ring system. Thus, trifluoroacetic acid-catalyzed intramolecular Povarov reaction of the corresponding iminium ion intermediate, generated in the condensation between 1,2,3,4-tetrahydroquinoline 347 and aldehyde 348, bearing an alkene-tethered partner, produced cycloadduct 349 in 93% yield and 15:85 in favor of trans-selectivity (Scheme 95) [115].
See Table 6 for the most representative examples of Sect. 8.

Oxidative Intramolecular Povarov Reaction
In 2011, Mancheño's group described the oxidative Povarov reaction between glycine derivatives with olefins [116]. In this method, a crucial oxidant was required for both the in situ generation of the iminium intermediate (by a C sp3 -H bond oxidation of N-aryl amine) and the final dehydrogenation of the tetrahydroquinoline to form the corresponding heteroaromatic compound. The strategy represents a milestone in organic synthesis and specifically in the Povarov reaction as no prefunctionalization is required in the reaction partners and CH bonds are ubiquitous in organic Scheme 97 Catalytic radical cation salt induced C sp3 -H oxidation for the construction of quinoline-fused lactones molecules. Since then, the oxidative Povarov reaction to form quinoline derivatives, also in its intramolecular version, has been extensively studied as the process involves the use of simpler starting materials and less waste generation. C sp3 -H bond oxidation of N-aryl glycine esters and amides can be carried out under catalytic radical cation salt-induced conditions. The peroxyl radical cation, which is generated in the coupling between tris(4-bromophenyl)ammoniumyl hexachloroantimonate (TBPA + ·) and oxygen, might be involved to initiate the catalytic oxidation. In this way, Jia's group [117,118] reported a direct construction of quinoline-fused lactones accomplished by C sp3 -H bond oxidation under catalytic radical salt-induced conditions of starting N-aryl glycine esters. Radical cation salt TBPA + , stable in the solid state but decomposed after 3 h in MeCN in the presence of oxygen, promotes the cyclization of glycine derivatives 353 to yield Povarov adducts. Both electron-withdrawing and electron-donating substituted N-aryl glycine cinnamyl esters 353 were converted to quinoline-fused lactones 358 in moderate to excellent yields (Scheme 97). The lack of substituents or the presence of a substituent at the ortho position of the aniline dramatically diminished the reaction yield; for instance, when R 1 = H compound 358 was obtained in 49% and only 20% yield of 358 was observed when R 1 = 2-Me. The key step in this transformation comprises the formation of a glycine imine (or iminium ion) that can efficiently add to the styrene moiety to afford Povarov adducts. In this way, authors suggest a plausible mechanism where the sp 3 C-H bond adjacent to the aniline group is oxidized by TBPA + · in the presence of oxygen, giving radical intermediate 354, which can be further oxidized to the corresponding glycine imine 355 (Scheme 97, route a). The formation of quinoline-fused lactones 358 may arise from a radical cation salt-induced Povarov reaction. Nevertheless, radical intermediate 354 may also add to the double bond of styrene, and subsequent radical addition to the phenyl group would yield 357. Further oxidation and aromatization would afford 358 (Scheme 97, route b) [118].
The generality of this protocol was determined by the use of glycine amides toward the construction of quinoline-fused lactams 360 under the same catalytic radical salt-induced conditions [118]. All of the tested N-aryl glycine cinnamyl amides 359 displayed good reactivity, yielding the corresponding quinoline-fused lactams 360 in good to excellent yields (Scheme 98). Bulky amide N-protecting groups gave better results, probably due to the closeness of the cinnamyl group to the reactive radical in those derivatives, which favors the intramolecular annulation. In addition, the effect of the substituents on the cinnamyl group was studied, showing that electron-donating groups increase the annulation yields.
More recently, Muthukrishnan's group [119] reported an intramolecular dehydrogenation promoted by oxone followed by imino-Diels-Alder reaction (Povarov cyclization) of alkyne-tethered N-aryl glycine esters and amides for the preparation of quinoline-fused lactones and lactams. Hence, the dehydrogenative Povarov reaction of N-aryl glycine ester 361 (X = O) was proved by using 5 mol% BF 3 ·OEt 2 as a Lewis acid in the presence of 2-iodoxybenzoic acid (IBX) as an oxidant at room temperature. Under these conditions, quinoline fused lactones 363 were obtained in 58% yield (Scheme 99). Other Lewis acids, such as Cu(OTf) 2 or Sn(OTf) 3 , and different peroxide-based oxidants such as PhI(OAc) 2 , PhI(IOCOCF 3 ) 2 , Na 2 S 2 O 8 , benzoyl peroxide (BPO) or Oxone (2KHSO 5 -KHSO 4 -K 2 SO 4 ) were screened. The combination of Cu(OTf) 2 as Lewis acid and Oxone as oxidant works well, affording cycloadducts 363 in good yields, except for methyl-substituted alkyne 361 (R 2 = Me), which was obtained in 17% yield (Scheme 99). Remarkably, Oxone would be a favorable oxidant as it is easy to handle, cheap, and nontoxic. The scope and generality of this approach indicated that different electron-donating and electron-withdrawing groups on the aniline ring as well as the aryl alkyne moiety were well tolerated (Scheme 99). This method was further extended to the preparation of quinoline-fused lactams 364 (X = NR 3 ) (Scheme 99). The intramolecular dehydrogenative Povarov cyclization of N-aryl glycine amide 362 (X = NR 3 ) using the optimized reaction conditions, yielded the cycloadducts 364 in moderate to good yield, although higher temperatures were required for reaction completion [119]. This protocol is very general since electron-donating and electron-withdrawing groups on the aniline ring as well as the aryl alkyne moiety of NR 3 protected glycine amide furnished the corresponding products 364 (Scheme 99). The method was further Scheme 99 Oxone promoted intramolecular dehydrogenation followed by Povarov cyclization for the construction of quinoline-fused lactones and lactams

Asymmetric Intramolecular Povarov Reaction
Masson's group first described the asymmetric version of the intramolecular Povarov reaction in 2017 [120]. They developed an efficient asymmetric organocatalytic intramolecular Povarov reaction for the preparation of optically active chromenofused quinoline derivatives as well as dibenzo-fused naphthyridine derivatives. A chiral phosphoric acid, (R)-3,3′-bis(2,4,6-triisopropylphenyl)-1,1′-binaphthyl-2,2′diyl hydrogen phosphate (369, TRIP) catalyzes the enantioselective intramolecular Povarov-type reaction of alkene-tethered aldehydes 366-368 and primary 2-hydroxy anilines 365. The corresponding tetrahydrochromeno [4,3-b]quinolin-6-ones 370 (X = O) as well as tetrahydrodibenzo [1,6]naphthyridin-6-ones 371 (X = NH) were obtained in excellent yields, with high diastereo-and enantioselectivities ranging  [4,3-b]quinolin-6-one derivative 370 when the dienophile possesses a benzene ring with a hydroxy group at para-position, while ortho-and metaanalogs were completely unreactive in this cycloaddition. It appears to be reasonable that hydrogen bonding of the phosphoric acid 369 to p-phenol seems to be critical for effective cycloaddition, but not for enantioselectivity, since 35% ee has been observed for 370 when 4-methoxy aniline was used. The use of 2-aminophenol 365 (R 1 = H) as starting material might form an additional hydrogen bond with the chiral phosphoric acid 369 to increase facial discrimination of the N-2-hydroxy aldimine in the Povarov cycloaddition. This is observed by a dramatic increase in enantioselectivity. Furthermore, the catalyst loading could be lowered to 1 mol%, and the obtained azacycles were formed in high yield and high purity, after precipitation in the reaction vessel and isolation by filtration without purification by column chromatography. As an extension of a previous paper, Masson et al. [121] reported the enantioselective intramolecular Povarov synthesis of tetrahydrothiochromeno [4,3-b] quinolin-6-ones 372 (X = S, Scheme 100). These new fused nitrogen-containing tetraheterocycles were attained in excellent diastereo-and enantioselectivity (93-96% ee), although the reaction conversion is not completed. However, a slight increase in the catalyst loading to 2 mol% gave the corresponding cycloadducts in excellent yields (91-97%). If the intermediate imine coordinates in a bidentate manner to the chiral phosphoric acid (R)-369 through a nine-membered cyclic transition state, the cyclization pathway may proceed by a stepwise mechanism (Scheme 100).
To further demonstrate the efficiency and scope of the present method, it was next applied to linear precursors with ether (374, X = O) or amine groups (375-377, X = NR 2 ) as the linker between the aromatic aldehyde ring and the styrene group [121]. Precursors with an ether group as a linker were smoothly converted into the corresponding tetrahydro-6H-chromeno [4,3-b]quinolines 378 in excellent yields, enantioselectivities up to 99% ee, and trans,trans-diastereoselectivities (Scheme 101). In the same way, linear precursors with amine linker provided access to hexahydrodibenzo[b,h] [1,6]naphthyridines 379-381, which were obtained with Scheme 102 Enantioselective intramolecular Povarov reaction with secondary anilines Scheme 103 Enantioselective intramolecular Povarov reaction with indoline derivatives excellent yields, diastereo-and enantioselectivities ranging from 87% to 98% ee (Scheme 101). Diversely substituted 2-aminophenols were suitable partners to afford the corresponding cycloadducts in high yields and enantioselectivities. Modification of the protecting group on nitrogen afforded the desired products with similar yields although with slightly lower enantioselectivity.
Catalytic enantioselective reactions with secondary amine substrates that involve intermediate iminium ions remain far less studied than the corresponding transformations with primary amines or preformed imines. Seidel et al. [122], for the purpose of developing the such transformation, synthesized polycyclic amines containing three contiguous stereogenic centers with excellent stereocontrol in a single step from N-methyl aryl amines 382 and aldehyde 383 possessing a pendant dienophile. Thus, N-methyl aryl amines 382 and O-allylsalicylaldehyde derivative 383 reacted using chiral Brønsted acid catalyst 384, afforded tetrahydrochromeno [4,3b]pyrrolo [3,2,1-ij]quinolines 385 in moderate to excellent yields and high levels of diastereo-and enantioselectivity (Scheme 102). Catalyst 384, which involves a carboxylic acid group and a thiourea moiety as a covalently connected anion-recognition site, was previously applied to a catalytic enantioselective three-component Povarov reaction [123].
As an extension of Seidel's methodology, the same group introduced a new approach for the rapid synthesis of polycyclic amines through aza-Diels-Alder (Povarov) reaction, applying the kinetic resolution of two-substituted indolines to enhance the stereochemical complexity of the products [124]. Under control of a chiral Brønsted acid catalyst, racemic 2-phenylindoline 392 (R 1 = Ph) undergoes intramolecular Povarov reaction with achiral aromatic aldehydes 387 bearing a pendant dienophile. One enantiomer of the indoline reacts preferentially, resulting in the highly enantio-and diastereoselective formation of polycyclic Scheme 104 Enantioselective intramolecular Povarov reaction with two-substituted indoline derivatives heterocycles, tetrahydrochromeno [4,3-b]pyrrolo[3,2,1-ij]quinolines 393 with four stereogenic centers (Scheme 104). This kinetic resolution approach exploits the differential formation/reactivity of diastereomeric ion pairs. The use of (S)-TRIP 369 provided good results, which were increased lowering the temperature to -10 ºC, improving de enantioselectivity process. The scope of this transformation was evaluated with a range of O-allylsalicylaldehyde derivatives 387. A range of substituents on the aldehyde phenyl ring and the styrene component were readily tolerated in reactions with 2-phenylindoline 392 (R 1 = Ph), producing polycyclic heterocycles in excellent yields (82-99%), diastereo-(up to 20:1) and enantioselectivities (80-96% ee). Variation of the indoline cycloaddition partner was evaluated next. A number of two-substituted indolines 392 with diverse substituents (R 1 = Ar, Alk) performed well. Even ethyl ester substituent or tert-butyldimethylsilyl (TBS)-protected alcohol were accommodated (Scheme 104).
Jørgensen's group [125] developed an efficient asymmetric organocatalytic one-pot domino Michael addition/intramolecular Povarov reaction for the synthesis of optically active octahydroacridines having four stereocenters. Thus, malononitriles 394 react with a series of aliphatic α,β-unsaturated aldehydes 395 and p-substituted anilines 37, in the presence of diarylprolinol 396 and benzoic Scheme 105 Enantioselective organocatalytic one-pot domino Michael/intramolecular Povarov reaction with malononitriles acid as additive, to produce octahydroacridines 398 with high yields and excellent enantio-and diastereomeric control (Scheme 105). The conjugate addition of malononitriles 394 to α,β-unsaturated aldehydes 395 using aminocatalysis leads to the formation of proper intermediates 397, which could be trapped in an amine condensation/intramolecular Povarov cascade to afford products 398. This asymmetric organocatalytic one-pot domino protocol displays great tolerance toward different aliphatic α,β-unsaturated aldehydes, malononitriles, and p-substituted anilines.

Scheme 106
Enantioselective organocatalytic one-pot domino Michael/intramolecular Povarov reaction with indolinones Next, authors examined the addition of additives, reveling that the combination of diarylprolinol 400 with chiral Brønsted acid 401 gave products 402 in higher yield and excellent stereoselectivities. Under optimal conditions, the scope to probe the generality of this procedure was examined, exhibiting an excellent acceptance toward a variety of different substrates furnishing enantiomerically enriched spirooctahydroacridine-3,3′-oxindole 402 in good yields, diastereoselectivities up to 20:1, and enantioselectivities ranging from 84% to > 99% (Scheme 106).

Conclusions
The Povarov reaction allowed the preparation of heterocyclic compounds, tetrahydroquinoline skeleton, in a chemo-, regio-and stereoselective way by [4 + 2] cycloaddition between aromatic aldimines and dienophiles, in the presence of Lewis or Brønsted acids and under mild reaction conditions. A particular type of Povarov reaction is its intramolecular version when both, the aromatic imine (diene) and the dienophile system, are present in the same initial chemical structure, so that in the presence of Lewis or Brønsted acids this strategy allows the synthesis of a wide variety of fused heterocyclic compounds. These present important applications in medicinal, biological, and materials chemistry.
The intramolecular Povarov reaction provides a simple way to modulate the structural variety of the heterocyclic compounds to be prepared. Thus, the review began with a description of the heterocycles formed from aromatic amines with aliphatic, aromatic, and heteroaromatic aldehydes, followed by an analysis of the heterocycles obtained from heteroaromatic amines with different aldehydes. Likewise, special sections have been devoted to the intramolecular Povarov reaction with secondary amines and to the oxidative Povarov reaction demonstrating the applicability of this tool. Finally, the enantioselective preparation of fused heterocycles has been also addressed. As an improvement of the methods described so far, further exploration remains to be done in this field to discover new synthetic strategies for the preparation of new molecules and the development of new efficient asymmetric catalytic protocols to obtain compounds in an enantioselective way. you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http:// creat iveco mmons. org/ licen ses/ by/4. 0/.