Mannich base-connected syntheses mediated by ortho-quinone methides

This article provides an overview about specifically modified Mannich reactions where the process involves an ortho-quinone methide (o-QM) intermediate. The reactions are classified on the basis of the o-QM source followed by the reactant, e.g., the dienophile partner in cycloaddition reactions (C=C or C=N dienophiles) or by the formation of multicomponent Mannich adducts. Due to the important pharmacological activities of these reactive o-QM intermediates, special attention is paid to the biological activity of these compounds.


Introduction
The Mannich reaction is an important, one-pot, multicomponent, C-C bond forming reaction that is widely used in the syntheses of many biologically active and natural compounds [1][2][3][4][5]. Originally, the Mannich product is formed through a three-component reaction containing a C-H acid, formaldehyde and a secondary amine. Recently, one of its special variations called modified Mannich reaction, has gained ground, in which the C-H acid is replaced by electron-rich aromatic compounds such as 1-and 2-naphthols as active hydrogen sources [6]. At the beginning of the 20th century, Mario Betti reported the synthesis of 1-aminobenzyl-2-naphthol starting from ammonia, benzaldehyde and 2-naphthol. This protocol is known as Betti reaction and the compound formed as Betti base [7][8][9]. Several examples have been published to extend the reaction and to synthesize varied substituted aminonaphthol derivatives [10]. Their relatively easy accessibility and promising biological properties have led to the resurgence of their chemistry coming again into the focus of pharmacological research.
The formation of aminonaphthols can be explained by two mechanisms. According to one possibility, first the reaction of the amine and the aldehyde yields a Schiff base and then the latter reacts with 2-naphthol in the second nucleophilic addition step. The other theory assumes the formation of an orthoquinone methide (o-QM) intermediate by the reaction of 2-naphthol and benzaldehyde. Re-aromatization, the driving force of the transformation, takes place in the second step by the nucleophilic addition of the amine component.
The class of o-QMs has recently been investigated from many aspects. They are known as short-lived species playing an important role as key intermediates in numerous synthetic pathways. Reviews have recently been published about o-QM generation, applicability in organic syntheses and biological properties [11][12][13][14][15][16][17]. However, in this review we would like to focus on their role in syntheses connected to Mannich base chemistry as well as their wider applicability and properties.

Formation of Mannich bases via o-QM intermediates Synthesis of amidoalkylnaphthols
The preparation of amidoalkylnaphthols has recently been discussed from many points of view [18]. This indicates the importance of this reaction because 1-amidoalkyl-2-naphthols can be easily converted to important biologically active 1-aminoalkyl-2-naphthol derivatives by a simple amide hydrolysis.
The mechanism of the Mannich reaction is depicted in Scheme 1. First, the reaction between the aldehyde and 2-naphthol, induced by the catalyst, leads to the generation of o-QM intermediate 3 that reacts further with the amide component to form the desired 1-amidoalkyl-2-naphthol derivatives. This second step can also be considered as a nucleophilic addition of the amide to the o-QM component.
Various catalysts and conditions were used to optimize reaction conditions considering economical and environmental aspects. These include microwave-assisted reactions, solvent-free conditions and the reusability of the catalyst (Table 1). Procedures are carried out as one-pot multicomponent transformations without the isolation of the intermediates formed. Therefore, with the application of nontoxic, readily available and inexpensive reagents, both time and energy are saved.
Recently the applicability of nanocatalysts in these reactions has been of interest since nanocatalysts, in general, are stable and recyclable and they exhibit higher activity than conventional catalysts. A few notable examples are worth mentioning here. Aluminatesulfonic acid nanoparticles (ASA NPs) proved to be efficient under neat conditions for the synthesis of 1-amidoalkyl-2-naphthols [19]. Zali  nanoparticle-supported sulfuric acid (MNPs-SO 3 H) [22]. As shown in Table 1 3 } as the first nanostructured molten salt [23]. As depicted in Table 1, entry 5, the catalyst gave remarkable results at room temperature in short reactions (5-30 minutes) in 90-96% yields. Comparing these results with those achieved by the application of tin dioxide nanoparticles (nano SnO 2 , Table 1, entry 6), molten salt catalysis affording higher yields in shorter reactions is definitely more advantageous.
Safari et al. combined the benefits of using magnetic nanoparticles and ionic liquids by the application of magnetic Fe 3 O 4 nanoparticles functionalized with 1-methyl-3-(3-trimethoxysilylpropyl)-1H-imidazol-3-ium acetate (MNP-IL-OAc) as catalyst [28]. As shown in Table 1, entries 11 and 12, syntheses carried out by conventional heating at 100 °C required long reaction times affording yields of 82-97%. In contrast,    [42] or wet cyanuric acid (wet-TCT) [43] was also tested. These methods suffer from a number of drawbacks, such as strong acidic media, high temperature, and prolonged reactions. Furthermore, the yields are often not satisfactory.
To eliminate the disadvantages of previous strategies, Samant et al. reported an ultrasound-promoted condensation catalysed by sulfamic acid [44]. As shown in Table 1, entries 39 and 40, both dichloroethane (DCE) and solvent-free conditions were tested. The catalyst worked at low temperature (28-30 °C) and the products were formed in short reaction times in up to 94% yields. Shinde et al. also published iodine catalysis carried out at room temperature in DCE [45]. Whereas long reaction times were needed in the latter process, good yields could be achieved under mild conditions.
In additional publications listed in  [60], polyphosphate ester [61] and amberlite IR-120 [62] were used as catalysts. These latest strategies provide efficient syntheses under mild conditions without using harsh chemicals. Furthermore, the application of  [66] microwave irradiation or sonication is also preferred to conventional heating methods to accelerate the reactions.

Synthesis of aminoalkylphenols
The mechanism of the formation of phenolic Mannich bases is similar to that discussed above for the synthesis of amidoalkylnaphthols.  [64]. Later, the same research group published a similar reaction extended by various lactams carried out in trifluoroacetic acid in water [65]. As reported in both papers, Mannich bases formed 9a-t were isolated in good yields. Plausible reaction pathways were described and the energetic values of the transition states were calculated.
In one of the latest publications with respect to this topic, Priya et al. disclosed the synthesis of a wide range of novel 2-[(benzo[d]thiazol-2-ylamino(phenyl)methyl]phenols 10a-m [66]. In their study, 2-amino-1,3-benzothiazoles, various aldehydes and substituted phenols were reacted in the presence of ZnCl 2 as catalyst.
The synthetic protocol was then extended to isolate benzo[a]xanthen-11-ones or chromeno[3,2-g]β-carboline-8,13dione starting from 2-naphthol and 1H-β-carboline-1-one Mannich bases [71]. Although a high temperature was needed (reflux at 153 °C for 4 hours), the desired products were isolated in good (53-91%) yields. The authors reported better results with the use of polyheterocyclic initial compounds. This can be explained by a dearomatisation step taking place in the transformation of phenolic Mannich bases, leading to the disappearance of the only aromatic ring. In a recent publication by same research group [72], they elaborated a simple route to 1,2-dihydronaphtho[2,1-b]furan and 2,3-dihydrobenzofurans via baseinduced desamination. They also reported the development of a simple, general route to 2,3-dihydrobenzofurans 21 starting from phenolic Mannich bases. The syntheses were also extended to 2-naphthol Mannich bases as initial compounds affording C-2- Bray et al. reacted ortho-hydroxybenzylamines with 2,3dihydrofuran and γ-methylene-γ-butyrolactone in DMF at 130 °C [73]. This method could successfully be applied in the synthesis of the spiroketal core of rubromycins 22 and 23.
One of the latest publications around the topic is published by Hayashi et al. in 2015 [74]. Starting from diarylmethylamines 24 and arylboroxines, they successfully developed a rhodiumcatalyzed asymmetric arylation process leading to triarylmethanes 25. With the application of mild reaction conditions (40 °C, 15 h), a high enantioselectivity (≥90% ee) was reached with good to excellent yields. (Scheme 2).
Watt et al. achieved the regioselective condensation of bis(N,Ndimethylamino)methane with various hydroxyisoflavonoids to synthesize C-6-and C-8-substituted isoflavonoids 33 and 34 in a Mannich-type reaction [76]. These o-QM precursors by a thermal elimination of dimethylamine were then reacted with differ-ent cyclic dienophiles to give various inverse electron-demand Diels-Alder adducts 35-37. In case of 36, the cis-fused ring system found to be similar to bioactive xyloketals isolated from fungi (Scheme 4) o-QMs are also known to undergo oligomerization in the absence of dienophiles and nucleophiles via an oxo-Diels-Alder protocol (Table 4). During the syntheses of 1,4,9,10anthradiquinones with potential antitumor activity, Kucklaender et al. isolated new spiro derivatives 38 [77]. These latter spirocyclic dimers formed in a Diels-Alder dimerization process by heating the corresponding Mannich bases under reflux in dichloromethane for 2 hours.   mal desamination of the initial compounds [78]. However, some of the publications report this phenomenon as an advantageous reaction rather than the formation of unexpected side products. As mentioned above [71],

Reactions with C=N dienophiles
The preparation of novel o-QM-condensed poliheterocycles is a relatively new area of Mannich base chemistry. Our research group has also been interested in cycloaddition reactions of o-QMs generated from Mannich adducts 42, when a serendipitous reaction occurred. Namely, the formation of new naphthoxazino-isoquinoline derivatives 43 under neat conditions staring from 1-aminoalkyl-2-naphthols and 6,7-dimethoxy-3,4-dihydroisoquinoline was observed [79]. At the same time, Osyanin et al. reported the same reaction extended by various substituted aminonaphthols [80]. Achieving the syntheses in ethanol at 78 °C, [4 + 2] cycloaddition took place between the o-QM generated from the corresponding aminonaphthol as diene component and cyclic imines playing the role of heterodienophiles (Scheme 5).
Fülöp and co-workers then extended their studies by applying both 2-aminoalkyl-1-naphthols and 1-aminoalkyl-2-naphthols [81]. These bifunctional compounds were reacted with various cyclic imines such as 4,5-dihydrobenzo[c]azepine or 6,7-dihydrothieno [3,2-c]pyridine to have new naphthoxazinobenzazepine 44 and -thienopyridine 45 derivatives [82]. Transformations at 80 °C in 1,4-dioxane as solvent were performed in a microwave reactor to utilize the advantages of this method. As expected, reaction times shortened, while the products were isolated in higher yields in comparison with those found by conventional heating.
The application of (4aS,8aS)-hexahydroquinoxalin-2-one served as the first example with respect to the use of an enantiomeric cyclic imine in this type of reaction [83]. The formation of the possible naphthoxazino-quinoxalinone diastereomers 46 was investigated and studied by theoretical calculations (Scheme 5).
In this and all previous cases, the conformational behaviour of the polyheterocycles formed was also described.

Reactions with electron rich aromatic compounds
The formation of aza-o-QMs is also possible, if the initial phenolic Mannich base bears an aromatic moiety on its benzylic carbon atom. Rueping et al. recently performed reactions between aza-o-QMs in situ generated from α-substituted orthoamino benzyl alcohols 48 and substituted indoles catalysed by N-triflylphosphoramides (NTPAs) [85]. (Scheme 6) The process provided new C-2 and C-3-functionalized indole polyheterocycles 49 and 50 in good yields with 90-99% ee.

Miscellaneous reactions
It is also known that o-QMs could cross-link two biologically important molecules such as peptides, proteins or nucleic bases. several N-, O-and S-nucleophiles [88]. They examined both thermal and photochemical generations of such intermediates. By selecting the appropriate reaction conditions (various pH and temperatures), they were able to alkylate free amino acids, e.g., glycine (Gly), L-serine (Ser), L-cysteine (Cys), L-lysine (Lys), L-tyrosine (Tyr) and glutathione (Glu) in aqueous solution to isolate 55 (Scheme 8).
Rokita et al. focused on generating o-QMs and used them as cross-linking and DNA alkylating agents. Starting from Mannich base 56 and transforming it by a number of synthetic steps, they were managed to elaborate a process that provides easy access to o-QM precursors containing a broad array of linkers 57, which were used to connect with site-directing ligands [89] (Scheme 9).
As reactive intermediates, o-QMs can also play the role of monomers in polymerization reactions. Ishida et al. reported the ring-opening polymerization of monofunctional alkyl-substituted aromatic amine-based benzoxazines [90]. It was shown that the methylene bridges can be formed by o-QMs that are resulted by the cleavage of phenolic Mannich bridge structure 56 (Scheme 9).

Biological properties
As discussed earlier, o-QMs are known as short-lived, highly reactive intermediates. Therefore, their biological activity is mostly examined from the point of view of their application as DNA alkylating agents. One of the first examples was reported by Kearney et al. in 1996 about preformulation studies of the antitumor agent topotecan [91]. The antitumor activity of the compound could be explained by its degradation to highly active zwitterionic species via an o-QM intermediate. Dimmock et al. subsequently examined the cytotoxic activity of phenolic azobenzene Mannich bases [92]. Correlations were found between structures and activities against murine P388DI and L1210 cells, human T-lymphocyte cell lines and, in some cases, mutagenous properties were also shown.
Freccero et al. examined the photogeneration by laser flash photolysis and reactivity of naphthoquinone methides as well as their activity as purine selective DNA alkylating agents [93]. Farrell et al. studied the mechanism of the cytotoxic action of naphthoquinone-platinum(II) complexes [94]. Both DNA binding and topoisomerase I inhibition studies proved that the coordination and stabilization of the quinone methide structure can effect marked changes in DNA reactivity. In a recent publication, 3-(aminomethyl)naphthoquinones were investigated from the point of view of cytotoxicity, structure-activity relationships and electrochemical behaviour [95]. Derivatives that contain an aromatic amine and salicylaldehyde or 2-pyridinecarboxaldehyde moieties were found to be the most active against the HL-60 (promyelocytic leukaemia) cell line. Zhou et al. obtained phenolic Mannich bases bearing functional groups that are suitable for cross-linking DNA; therefore, their antitumor effects could also be confirmed [96].
The formation of o-QMs and their biological properties were also illustrated by kinetic studies. Rokita et al. using laser flash photolysis showed that formation and reactivity of these intermediates strongly depended on the presence of electron-donating or electron-withdrawing functional groups of the o-QM precursors [97].

Conclusion
The high number of publications that has recently appeared on the o-QM-mediated Mannich-type transformations is a clear in-dication that the application of this highly-reactive intermediate has made the modified Mannich reaction to be a hot topic again in organic chemistry. This review presents a wide range of applications including cycloadditions and the synthesis of bifunctional amino-or amidonaphthols that can later be transferred as building blocks into several natural or biologically active compounds. Thanks to the immense number of possibilities for Mannich reaction through the use of various amines, aldehydes and electron-rich aromatic compounds, the continued evolution of the literature on these reactions appears to be guaranteed. By the application of various cyclic imines and subsequently extended by the use of nonracemic derivatives, a wide range of enantiomeric polyheterocyclic compounds could be isolated and might be tested as potential anticancer drug candidates.