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Review

Synthesis of Bioactive Aminomethylated 8-Hydroxyquinolines via the Modified Mannich Reaction

by
Oszkár Csuvik
1 and
István Szatmári
1,2,*
1
Institute of Pharmaceutical Chemistry, University of Szeged, Eötvös u. 6, H-6720 Szeged, Hungary
2
Stereochemistry Research Group, Eötvös Loránd Research Network, University of Szeged, Eötvös u. 6, H-6720 Szeged, Hungary
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2023, 24(9), 7915; https://doi.org/10.3390/ijms24097915
Submission received: 1 April 2023 / Revised: 19 April 2023 / Accepted: 23 April 2023 / Published: 26 April 2023
(This article belongs to the Collection Feature Paper Collection in Biochemistry)
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Abstract

:
8-hydroxyquinoline (oxine) is a widely known and frequently used chelating agent, and the pharmacological effects of the core molecule and its derivatives have been studied since the 19th century. There are several synthetic methods to modify this core. The Mannich reaction is one of the most easily implementable examples, which requires mild reaction conditions and simple chemical reagents. The three components of the Mannich reaction are a primary or secondary amine, an aldehyde and a compound having a hydrogen with pronounced activity. In the modified Mannich reaction, naphthol or a nitrogen-containing naphthol analogue (e.g., 8-hydroxyquinoline) is utilised as the active hydrogen provider compound, thus affording the formation of aminoalkylated products. The amine component can be ammonia and primary or secondary amines. The aldehyde component is highly variable, including aliphatic and aromatic aldehydes. Based on the pharmacological relevance of aminomethylated 8-hydroxyquinolines, this review summarises their syntheses via the modified Mannich reaction starting from 8-hydroxyquinoline, formaldehyde and various amines.

1. Introduction

The Mannich reaction allows the formation of a C–C single bond with the involvement of an aldehyde, an amine and a compound possessing a particularly active hydrogen. The essence of the Mannich reaction is that the active H is replaced with an aminomethylene group—if formaldehyde (CH2O) is the aldehyde component—or substituted aminoalkyl moiety—if any other aldehyde is applied. During the reaction, a 1-molar equivalent of the H2O by-product is formed. The procedure is named after Carl Mannich [1], whose systematic research in this particular field started in 1912 [2]. However, similar condensation reactions were already performed before him, including German patents from 1896 (DE89979) [3] and 1897 (DE90907, DE92309) [4,5] by Bayer & Co. Ltd. (Hong Kong). In the first patent, the procedure included the reaction of dimethylamine, formaldehyde with phenol and naphthol derivatives, as well as the transformation of piperidine, formaldehyde and 1-naphthol. It was suggested that the hydrogen of the phenolic OH group reacts with the aldehyde and amine, resulting in alkylaminomethoxy derivatives. The structures in patent DE92309 were corrected, which thus corresponded to the structures known today as Mannich products. Franz Sachs published his work on the condensation of piperidine, formaldehyde and phthalimide in 1898 [6], and so did Herm Hildebrandt, reporting the condensation of piperidine, formaldehyde, various phenols, and 2-naphthol in 1900 [7]. Mario Betti’s research was launched in 1900 [8,9], in which ammonia, benzaldehyde, and 2-naphthol were reacted. In recognition of his extensive efforts, when a naphthol or phenolic compound is the provider of the active hydrogen, the reaction is referred to as the Betti reaction and the condensation product as the Betti base [10]. Further researchers who also studied this type of condensation before Mannich, are van Marle and Tollens [11], Schäfer and Tollens [12], Auwers and Dombrowski [13], and Petrenko-Kritschenko and his co-workers [14,15,16,17]. In recent times, the procedure has garnered notable consideration due to the versatile nature of its constituents, the use of gentle reaction conditions, and the potential pharmacological activity of the final products [18,19,20,21].
One possible extension of the Mannich reaction is the application of nitrogen-containing naphthol analogues, i.e., hydroxyquinolines (HQ). One of the first bioactive HQs discovered is 8-hydroxyquinoline (8HQ), which itself is a well-known antipathogenic and chelating agent [22]. It has many derivatives with more or less similar properties, including clioquinol, chlorquinaldol, chloroxine, broxyquinoline, iodoquinol, nitroxoline, and tilbroquinol [23,24,25,26,27,28,29]. In contrast, procaterol is a β2-adrenoreceptor agonist used in the treatment of asthma [30]. The Mannich derivatives of 8HQs have a prominent place in medicinal chemistry [31] and have been reviewed from many angles [1,18,19,20,22]. In this framework—covering more than one century of Mannich chemistry—derivatives in which the 8HQ and amine functions are linked by a methylene bridge will be included because aminoalkylation of 8HQs has not been reviewed from this particular chemical perspective. These compounds are synthesised by treating the 8HQ core with formaldehyde (paraformaldehyde or formalin, its aqueous solution) and an amine. These derivatives also possess diverse pharmacological activities. The antipathogenic effect is one of the most studied areas, including different mechanisms of action: increasing cell membrane permeability [32], inhibition of MetAP1 [33,34], ubiquinone synthesis [35], or type III secretion [36,37]. Antifungal activity of these 8HQs has been assessed among humans [34,38,39] and phyto-pathogens [40,41]. Furthermore, a potential antiprion compound has also been identified [42]. Clamoxyquine is an effective drug for treating whirling disease in rainbow trout [43]. Recently, a large group of aminomethylated 8HQs has been designed to combat cancer. There are derivatives that act by inhibiting DNA biosynthesis [32,44], MetAP2 [45], JMJD2C [46], and Rcel [47]. MDR-targeting agents have been studied as well [48,49], while in some derivatives, the metal-binding property has been utilised to enhance the antiproliferative activity [50,51,52,53]. The effects on the MAPK pathway [54], the caspase-dependent apoptotic pathway [55,56] and survivin [57,58] have also been examined, while some 5-nitro compounds were associated with inhibition of cathepsin B [59,60,61,62]. In the last few years, potential neuroprotective agents have been identified to treat Alzheimer’s disease by influencing multiple intramolecular targets [63,64,65,66]. Concerning the central nervous system, dopamine D2 receptor [67,68] and inward rectifier potassium channels [69] have also been targeted with 8HQ Mannich products.

2. Syntheses of Aminomethylated 8-Hydroxyquinolines

The next sections are divided considering two aspects: first, the ratios of the incorporated reagents in the Mannich product (CH2O, amine and 8HQ) and second, the structure of the applied amine and 8HQ.

2.1. Syntheses of Mannich Bases Furnishing 1:1:1 (CH2O:Amine:8HQ) Ratio in the Product

This subsection will be organised with regard to the order of amines and their structure (primary, acyclic and cyclic secondary).

2.1.1. Syntheses by Using Primary Amines

Various primary amines were reacted with 8HQ (1) and formaldehyde (CH2O), resulting in the formation of Mannich bases 2–13 (Table 1). Compound 2 was synthesised by Zaoui et al. by treating 1 with an aqueous solution of CH2O (37%; hereinafter formalin) and octylamine in EtOH [70]. Fields carried out the synthesis of 3a,b in two steps: first, an azomethine was obtained from CH2O and the corresponding amine, and subsequently, it was stirred with 1 in benzene (3a) or without solvent (3b) [71]. Burckhalter et al. used N1,N1-dimethylethane-1,2-diamine and paraformaldehyde to transform 1. After stirring the components in EtOH and then removing the solvent, the mixture was treated with hydrogen chloride gas in excess, isolating 4 with excellent yield [72]. Xie and Ding reacted 3-methylbutan-1-amine or 2-morpholinoethylamine with 1 and paraformaldehyde for 4 h under reflux conditions, resulting in 5a,b [46]. The synthesis of 6a–c was performed by Manetti et al. by applying 1, paraformaldehyde and the appropriate amine [73]. The synthesis of various Mannich products was published by Mohammed et al., including 7-((phenylamino)methyl)quinolin-8-ol (7), applying paraformaldehyde as the source of CH2O (for conditions, see Table 1) [47]. The synthesis of thiourea derivative 8 was carried out by Abuthir et al. [74]. Benzensulfonamide derivative 9 was furnished by Shaw et al. by dissolving 1, paraformaldehyde and the amine in dry EtOH at room temperature (r.t.) and then treating the mixture under reflux conditions [55]. 10a–c were synthesised by Banerjee et al. by stirring CH2O with the appropriate amine in EtOH. After the addition of 1, the mixture was cooled on ice, followed by a pH adjustment to 5–6 [75]. 11a–g were prepared by Tripathy et al. (11a), Sahoo et al. (11b,c,g) and Bhargava and Sharma (11d–f) by means of stirring 1, 4-substituted-2-aminothiazole and paraformaldehyde in the presence of HCl in EtOH [76,77,78]. Novel triheterocyclic systems (12a–m) were described by Mallur et al., applying reaction conditions similar to those of Sahoo et al., Tripathy et al. and Bhargava and Sharma [79]. Fernández-Bachiller et al. reported tacrine−8HQ hybrids (13a–g), synthesised via heating paraformaldehyde and the corresponding diamine at 90 °C in EtOH. The mixture was then cooled, and 8HQ, dissolved in EtOH, was added dropwise, followed by stirring at r.t. [64].
The 7-aminomethylation of nitroxoline (5-nitro-8HQ, 14) is achieved by using different primary amine sources: aliphatic amines, amino acids and substituted benzylamines (Scheme 1). Sosič et al. synthesised various derivatives, including 15a, 15h, 16m and 17a, by heating 14 in pyridine and then adding formalin (≥36.5%) and the desired amine [60]. Yin et al. carried out the synthesis of 15b–g in dry EtOH under reflux conditions [40]. One of the first to deal with the Mannich bases of 14 was Movrin et al., who synthesised 15i and 15j, reacting 14, paraformaldehyde and the corresponding amine in pyridine [80]. Morvin and Marok also tested various amino acids in the Mannich reaction, providing 16a–l [81]. Szakács et al. furnished 17b–e by heating the mixture of 14, formalin (37%) and substituted benzylamines in pyridine at reflux temperature (50 °C) [48].
Primary amines applied in 5-chloro-8HQ (18) transformations include aliphatic amines, diamines and benzylamines (Table 2). Burckhalter et al. did not only synthesise 4, but they also prepared its 5-Cl derivative 19a and also 20a in a similar way [71]. In addition, Burckhalter also provided further compounds (19b, 20b, 21, 22, 23c, 24a, 24b, 25, 27b, 31, 32) by treating 18 with paraformaldehyde and appropriate amines in EtOH under reflux conditions for 90 min, followed by a treatment with hydrogen chloride [82]. One exception is 27a. In this case, the mixture was heated until a thick, oily material remained. Later, 20b proved to be an efficient antiamoebic and antidiarrheal agent and became known as clamoxyquine [43,83,84]. Burckhalter et al. prepared 20c–e, 23a, 23b, 26, 34–36, using the appropriate amine and CH2O in the form of paraformaldehyde [85]. Bolognesi et al. synthesised compound 28 by carrying out the reaction in toluene and using paraformaldehyde [42]. Fernández-Bachiller et al. applied not only 1 as the starting scaffold for tacrine–8HQ hybrid but also 18, yielding 29a–e [64]. 33a,b was furnished by stirring 18, the corresponding amine and 1.1 equivalents of paraformaldehyde in absolute EtOH at 60 °C for 16 h by Ahn et al. [63]. If 2 molar equivalents of CH2O were applied in the synthesis of 33a, the concomitant formation of benzoxazine 30a was also observed. Note that the synthesis of other benzoxazines will be discussed in Section 2.2 [63]. Kenyon et al. published the preparation of 37 using other Mannich bases. The starting compounds were stirred without solvent at 120–150 °C; therefore, the mixture melted, forming the desired products [86]. Szakács et al. described the synthesis of 38 and 39b–d from 17b–e but applied different conditions. To obtain 38 and 39c,d, the EtOH solution of 18 mixed with cyclohexylamine and formalin solution was stirred under different conditions: 4 days at r.t. (38), 14 days at r.t. (39c), and 120 h at 50 °C (39d) [48]. 39b was prepared from benzoxazine 30b under acidic conditions (HCl/EtOH 22%) in 1 h at r.t. [48]. Compound 39a was synthesised by Combes and Mesnier via sulfuric acid treatment of 30c, which was previously prepared [87,88]. Gianni et al. reported the formation of 39e, after treating 18 with formalin and phenethylamine in MeOH at r.t. for 12 h [89].
Scheme 2 shows the aminomethylation of additional 5-substituted 8HQs (40–44). Szakács et al. transformed 5-bromo-8HQ (40) to 45a–d upon stirring 40 with formalin (37%) and the corresponding amine for 1 h [48]. Mannich reaction of 41 was performed by Yanni, testing methylamine, p-anisidine and 3-aminopyridine, thus acquiring 46a–c [90]. The substitution of 8-hydroxyquinoline-5-sulfonic acid (37) at C-7 with various alkyl- and arylamines was reported by Yanni and Timawy (47a–r) [91]. 48 was also delivered by Szakács et al. by stirring 2,4-dimethoxybenzylamine dissolved in EtOH, formalin (37%) and 43 at 60 °C for 48 h [48]. Yanni et al. accomplished the concomitant formation of the 7-aminomethyl- and 5-sulfonamide functional groups starting from 44, paraformaldehyde and the corresponding amine. The reaction mixture was treated under reflux conditions in EtOH, yielding 49a–d. Subsequently, they carried out sulfonamidation and then aminomethylation of 39, giving 50a,b [92].
The Mannich transformation of various 8HQs (51–59) listed in Table 3 was performed under rather similar conditions, despite the fact that they were carried out by different research groups. Fernández-Bachiller et al. prepared 60a–e utilising exactly the same conditions used in the fabrication of 13a–g and 29a–e [64]. 61a–c were synthesised by Bourquin et al., applying 1-methylpiperidine as an amine [93]. The transformation of 4-chloro-2-methylquinoline-8-ol (54) and 4-chloro-3-(2-chloroethyl)-2-methylquinoline-8-ol (55) was performed by Ozawa and Shibuya, resulting in 62a,b [94]. In addition to 6a–c, Manetti et al. also synthesised 63a,b from 4-butoxy (57) and 4-benzyloxy (58) derivatives [73]. The preparation of 64a,b was reported by Shoeb et al. using paraformaldehyde under the conditions indicated [95]. Yanni and Mohharam reacted the 7-sulphonic acid derivative of 8HQ with various aromatic and aliphatic amines and paraformaldehyde in the Mannich reaction, which afforded the formation of compounds 65a–k [96].
The transformation of pyridazine-annulated 8HQ was implemented by Abdelmohsen, who treated the solution of 66a or 66b in abs. EtOH with formalin (40%) and then added the aromatic amine in EtOH. Subsequently, the mixture was stirred for 3 h at r.t. and left overnight with the result of 67a–c and 68a–c. An interesting feature is that the Mannich reaction occurred on the side chain rather than on the 8HQ core at position 7 (Scheme 3) [97].

2.1.2. Syntheses by Using Acyclic Secondary Amines

The results of aminomethylation of 8HQ and 5-nitro- and 5-halogeno-8HQs with symmetric and asymmetric acyclic secondary amines are listed in Table 4. One of the earliest utilisations of the Mannich reaction to transform 8HQ (1) was performed by Burckhalder et al. when equimolar amounts of dimethylamine, paraformaldehyde and 1 were dissolved in EtOH and treated under reflux for 2 h (70a, yield: 74%) [98]. Philips and Fernando prepared 70b by mixing paraformaldehyde and diethylamine, then adding 1 dissolved in EtOH and, after a one-hour standing, the mixture was treated under reflux for 5 h [99]. Motaleb et al. used DMF as a solvent and paraformaldehyde as the aldehyde source to synthesise dicarboxylic acid derivative 70c [100]. The n-propyl derivative 70d was prepared by Faydy et al. in two steps: first, the Mannich reagent was synthesised by mixing dipropylamine and paraformaldehyde in EtOH, and in the second step, 8HQ in EtOH was added. Subsequently, after 1 h at r.t., the mixture was treated at reflux for 3 h [101]. The synthetic process of 70e–q was performed by Ishida and Watanabe. Formalin (35%) was added dropwise to the mixture of 1 followed by the addition of the ethanol solution of different amines. Then, the reaction mixture was stirred for 1 h at r.t. and kept under reflux for 3 h [102]. Szakács et al. also used formalin (37%) to furnish 70r [48]. 71a was the product of the reaction of 14 with dimethylamine and paraformaldehyde in pyridine/EtOH under reflux conditions, performed by Shterev et al. [103]. 71b was obtained by Burckhalder et al. by dissolving the components (14, paraformaldehyde and diethylamine) in EtOH and heating at reflux for 90 min [104]. Yin et al. reported dipropyl homologue derivative 71c, while Movrin et al. described the iPr and (CH2)2OH derivatives (61d,e) [40,80]. Liu et al. performed the synthesis of 71f by dissolving 14 and CH2O in EtOH, then adding dicyclohexylamine and treating the mixture under reflux for 24 h [41]. The synthesis of compound 71g was disclosed by Elofsson, and acetonitriles 71h,i were prepared by Sosič et al. [36,60]. Helin and Vanderwerf synthesised 72 by adding paraformaldehyde and diethylamine in EtOH to the 1:1 ether:EtOH solution of 5-fluoro-8HQ (69) and leaving it to stand for 30 min [105]. The aminomethylation of 18 and 40 leading to the formation of 73 and 74 was studied by Burckhalter et al. [71,85,106,107].
Table 5 shows further 5-substituted 8HQ derivatives. The synthesis of 96a,b was performed by Edgerton and Burckhalter by adding 75 in EtOH to the heated EtOH solution of the appropriate amine and paraformaldehyde and exposing it to 1–2 h of reflux [108]. 97 was furnished by mixing 76, paraformaldehyde and dibenzylamine in abs. EtOH, and treating it under reflux for 4 h by Himmi et al. [109]. Venkataramani applied paraformaldehyde as a CH2O source in the reaction of 77 and 79 with ethanolamine, which yielded 98 and 100 [110]. 99 was synthesised by Burckhalter and Leib by treating the EtOH solution of the components (78, paraformaldehyde and diethylamine) at reflux for 3 h [111]. Schraufstätter and Bock extended the reaction to several 5-acyl derivatives, delivering 101a, 102a–e and 103–109 by stirring the mixture of 80–93 each with formalin (30%) and the appropriate amine in EtOH at reflux [112]. 101b was synthesised by Mangeney and Pechmèze by reacting 80, formalin (30%) and the amine at reflux for 10 h [113]. 102f was obtained by Gopalchari and Dhar by stirring the starting compounds (83, paraformaldehyde and diethylamine) in EtOH at reflux [114]. Möhrle and Schaltenbrand gained epoxy ketone 94 from 87, and subsequently 110a,b from 94 [115]. 111 was synthesised by Burckhalter et al. from 95 with a yield of 74% [104]. Sen and Kulkarni carried out the transformation of 42, applying paraformaldehyde and several dialkyl amines, which gave products 112a–f [116]. Yanni et al. treated 44 with diethylamine and paraformaldehyde, leading to the formation of 113 [92].
Scheme 4 includes further aminomethylated 8HQs. In addition to the preparation of 64a,b, the synthesis of 115 was also carried out by Shoeb et al. [95]. The dimethyl and diethyl derivatives of quinaldine (116a,b) were first reported by Bourquin et al., and then the synthesis of 116d was shown to be efficient from both 52 via the Mannich reaction and 116b via chlorination [93]. 116c was furnished using diethanolamine and CH2O by Ozawa and Shibuya, with the finding that the reaction occurred at position 7, not involving the 2-Me group [117]. The transformation of 6-chloro-8-hydroxyquinoline (114) to 117a,b was performed by Burckhalter et al. Their interest was motivated by the biological importance of these isomeric structures (73a,b) [71,107]. The synthesis of 117a was performed in EtOH, but the synthesis of 117b could be carried out efficiently in both MeOH and EtOH using paraformaldehyde as the CH2O source. Yanni and Mohharam prepared 118, similar to the method applied in the synthesis of primary amine derivatives 65a–k [96].

2.1.3. Syntheses by Using Cyclic Secondary Amines

This subsection covers Mannich reactions carried out with the use of cyclic amines. Scheme 5 depicts the transformation of 8HQ derivatives by pyrrolidine and CH2O. 119a, the simplest core, was reported by Goyal and Chaturvedi [118]. The synthesis of 119b–g is an extension of methods described previously by Movrin et al. (119b) [80], Burckhalter et al. (119c) [71], Himmi et al. (119d,e) [109], Schraufstätter and Bock (119f) [112] and Möhrle and Schaltenbrand (119g) [115]. Numerous 5-substituted 7-pyrrolidinylmethyl derivatives (120a, 120c–x) were obtained by Xiao et al. on the basis of 120b (UC-112) by reacting the appropriate functionalised 8HQs with paraformaldehyde and pyrrolidine in EtOH [57]. Note that this approach was previously studied by Wang and Li [56]. Based on these findings, the synthesis of further UC-112 analogues (121–123) was carried out under the same conditions by Wang et al. [58].
Scheme 6 shows the application of functionalised/condensed nitrogen-containing five-membered ring systems. The utilisation of L- and D-proline in the Mannich reaction was described by Mészáros et al. and the Pivarcsik group. Compounds 124a,b and 125 were synthesised by stirring L- or D-proline with formalin (38%) and the appropriate 8HQ (14 or 18) in MeOH at 75 °C [51,52,53]. Further derivatives were described by Mohamed et al. and Elofsson et al., including phthalimide, isatin and 5-halogenoisatins, succinimide and 3-phenylpyrrolidine affording 126a–e and 127 [36,119].
Piperidine, a secondary amine, has been frequently utilised in the Mannich reaction (see Table 6), which is probably due to its stability and reactivity. Note that it was the first amine to be applied for the aminomethylation of 8HQ, described in a German patent in 1897 [5]. Briefly, 14 kg of 8HQ (1) was dissolved in EtOH, then 8 kg of formalin (40%) and 8.5 kg of piperidine were added, and the mixture was stirred for 6 h under reflux. After distillation, the free base (137) was crystallised. Its hydrochloride salt was prepared by Burckhalter et al. [97]. The reaction conditions for the compounds in Table 6 are almost identical. EtOH was used as a solvent, except for compound 144, which was performed in a solventless process by Burckhalter and Leib (for 146a,b, 148d and 150, details were not available) [109,111,115]. Reaction mixtures were treated primarily at reflux or at an unspecified heated temperature, with the exception of 145, synthesised at r.t. [48]. Additional examples are 138, 139, 151, 152 (Burckhalter et al.) [71,104]; 140, 147 (Burckhalter and Leib) [111]; 141 (Yanni) [90]; 142a–c, 148a–c (Edgerton and Burckhalter) [108]; 143a,b (Himmi et al.) [109]; 146c (Xiao et al.) [57]; 149 (Schraufstätter and Bock) [112]; 153 (Sen and Kulkarni) [116] and 154 (Yanni) [92]. In the case of 154, reactions started from 44, and not only aminomethylation but also concomitant sulfodamidation was achieved.
The transformations of 2-, 4-, 7- or 8-substituted 8HQs are depicted in Scheme 7. Quinaldine 155a was obtained by reacting equimolar amounts of 8-hydroxyquinaldine, paraformaldehyde and piperidine in EtOH for 3 h under reflux conditions by Rose et al. [120]. Szakács et al. transformed some 2-functionalised 8HQs by stirring the mixture of piperidine and formalin (35%) in EtOH for 1 h, then, after adding the appropriate 8HQ, stirring was continued at r.t. for 2 days (155d), 3 days (155e–h) or 4 days (155b,c) [48]. 4-(4-Chloroanilino)-8-hydroxyquinoline was added to the heated ethanolic solution of piperidine and paraformaldehyde and heated to boiling for 25 min to obtain 156 by Burckhalter and Edgerton, who also synthesised 157 in 72% [106]. To provide 158a, 7-chloro-8-hydroxyquinoline, piperidine and paraformaldehyde were dissolved in MeOH and heated at reflux for 90 min [71]. Among the 8-hydroxyquinoline-7-sulfonic acids previously described, 158b was reported by Yanni and Mohharam [96].
Additional piperidylmethylene-substituted 8HQs are included in Scheme 8. Compounds 159a–f were synthesised by Meenakshi et al. [121], and derivatives 160a,b were published by Chhajed and Padwal [122]. 161a–f and 162a–f were prepared by Madhu et al. The starting 8HQ, piperidine and water were mixed, and after adding H2O and DMF to this clear solution, stirring was continued in an ice bath for 2 h, followed by leaving at r.t. overnight [123,124]. Similar to 67a–c and 68a–c, these are exceptional cases, since piperidine and formaldehyde did not appear to react with the 8HQ nuclei but resulted in N-functionalisation of the isatin core.
Scheme 9 depicts the Mannich reaction of 8HQs with various functionalised/condensed piperidine derivatives. 163a was synthesised by dissolving 14 in pyridine at 60 °C, adding formalin (36.5%) and (R)-2-methyl-piperidine, and then stirring until the reaction was complete [60]. The synthesis of compound 163b was disclosed by Mirković et al. [59]. 163c–e were prepared by Shterev et al. by treating 14 with piperazine derivatives and paraformaldehyde in a 1:1 mixture of pyridine and EtOH [103]. In addition to prolines, Pivarcsik et al. also applied (R)-piperidine-2-carboxylic acid (L-pipecolic acid), resulting in 164a under the same conditions used for 124a,b and 125 [52]. Only a few examples were reported on the utilisation of microwave irradiation (MW) in the Mannich reaction of 8HQ. In one of them, demonstrated by Swale et al., 20–30 min of MW irradiation at 140 °C and EtOH as solvent were applied to gain 164c–d [69]. Compounds 164e–g were obtained by Chough in the reaction of 18, paraformaldehyde and the appropriate 4-(2-cyclic-aminoethyl)-piperidine [125]. The incorporation of 1,2,3,4-tetrahydroisoquinoline (165a–c) was achieved by Chakravorti et al. by adding paraformaldehyde and 1,2,3,4-tetrahydroisoquinoline to the solution of 8HQ (1, 18 or 40) in EtOH and treating the mixture under reflux for 5 h [126].
In addition to piperidine, morpholine, too, was applied rather frequently in the Mannich reaction (Scheme 10). The simplest core in this framework is 166, which was disclosed by Grzycka and Miłkowska [127]. Similar to 155a, 8-hydroxyquinaldine 167 was also described by Rose et al. [120]. Petrow and Sturgeon prepared 168a by treating 5-NO2-8HQ in EtOH under reflux with formalin (36%) and morpholine [128]. The synthesis of 168b in a yield of 78% was reported by Burckhalter et al.; however, its synthesis later appeared in several publications [71]. The 5-bromo analogue 168c was disclosed by Kim et al. [129]. The preparation of 168d–l and 169–172 is an extension of synthetic procedures described previously by Edgerton and Burckhalter (168d) [108], Himmi et al. (168e,f) [109], Venkataramani (168g,h) [109], Xiao et al. (168i) [57], Gopalchari and Dhar (168j) [114], Möhrle and Schaltenbrand (168k) [115], Sen and Kulkarni (168l) [116], Abdelmohsen (169a,b) [97], Madhu et al. (170a,b) [123,124], Chhajed and Padwal (171) [122] and Yanni and Mohharam (172) [96].
Morpholine analogues and derivatives, such as thiomorpholine and 2,6-dimethylmorpholine, were also applied in the Mannich reaction. The synthesis of the latter (173) was disclosed by Elofsson (Scheme 11) [36]. 174a was prepared by stirring the components in EtOH (1, thiomorpholine, and formalin) for 12 h at r.t. by Zaoui et al. [70]. The synthesis of 174b and 174c was carried out by Wangtrakuldee et al. by treating the appropriate 8HQ, CH2O and thiomorpholine in dry EtOH at 80 °C for 24 h and isolating the products in yields of 90.6% and 73.7% [33].
In the following, the application of piperazine and N-substituted piperazines as secondary amines is demonstrated in the Mannich reaction of 8HQ (1) and 5-NO2-8HQ (14) (Table 7). Another example of the use of MW to carry out aminomethylation of 8HQ is the study by Prati et al. to synthesise 175, by adding 1 and paraformaldehyde to the dry EtOH solution of piperazine and stirring it at r.t. for 10 min, then treating the mixture at 130 °C for 45 min under MW irradiation [65]. The research group used 175 to synthesise further derivatives, including 178a, via classical SN2 nucleophilic substitution with the appropriate benzyl chloride. Shaw et al., in turn, synthesised 178a directly from 1, N-benzylpiperazine and paraformaldehyde by stirring the components in dry EtOH at reflux [55]. Shaw et al. used this method successfully for compounds 178b, 181b–o, 182a,b and 189a,b [55]. Derivatives 176, 177a,c and 179 were prepared by Faydy et al. by adding the EtOH solution of 1 to the EtOH solution of paraformaldehyde and the amine kept under reflux, then stirring at reflux for 3 h [130,131]. The preparation of 177b and 185b was reported by Enquist et al. by reacting CH2O and 4-fluorophenylpiperazine under cooling on ice, then adding the resulting precipitation portionwise to 1 or 14 in pyridine at 50 °C [37]. 180 was synthesised by Free et al. [67]. Chen et al. carried out the synthesis of 181a and 189c by dissolving the components in dry EtOH and then treating the mixture at reflux for 18–22 h [54]. 183 and 186a–c were obtained by Shterev et al. utilising the same method as applied for 71a and 163c–e [103]. 184a and 185a were prepared by Movrin et al. upon reacting the components in pyridine at 50–60 °C [80]. Yin et al. accomplished the transformation of 14 in pyridine with the appropriate amine at 50 °C for 30–40 min, resulting in 184b, 185c–n and 187a–c [40]. Sosič et al. also applied pyridine as a solvent to acquire 184c and 188a,b [60]. Elofsson et al. disclosed the fabrication of 185m [36].
The results of aminoalkylation of 5-halogeno, 5-alkyl and 5-alkoxy 8HQs by piperazine and N-substituted piperazines are included in Scheme 12. Prati et al. synthesised 192a similar to that used for 175 [65]. 192b–e, 192g,h and 193a were prepared by Burckhalter et al. They also made 192a, not via Mannich reaction, but by treating 192h with cc. HCl and then NH4OH [71]. Moreover, they prepared 193a both by the Mannich route and, alternatively, by treating 192a with ethanesulfonyl chloride. 192f and 192i were made by Thinnes et al. by stirring 18, paraformaldehyde and 1-acyl/Boc-piperazine in the presence of triethylamine in EtOH for 16 h under reflux [132]. Compound 193b was described by Shaw et al. [55]. The synthesis of 194a,b,e was carried out by Enquist et al. using the same method used for 177b and 185b [37]. The treatment of 18 in abs. EtOH solution, paraformaldehyde and 1-(4-methoxyphenyl)piperazine in the presence of triethylamine delivered 194c (Bhat et al.) [45]. 194d, 194f and 195b were disclosed by Elofsson [36]. Among the compounds mentioned previously, 194g was reported by Edgerton and Burckhalter as well [108]. The syntheses of 195a and 195d from 69/40, 1-(pyridin-2-yl)piperazine and formalin (37%) were achieved by Chan et al., stirring the mixture of components at 80 °C for 12 h under a nitrogen atmosphere [68]. The synthesis of compound 195c was reported by Free et al. [67]. In a rather remarkable study by Fu et al., an 8HQ–ciprofloxacin hybrid was synthesised. The treatment of the dry EtOH solution of 18 with paraformaldehyde and ciprofloxacin as secondary amines for 8 h under reflux gave the desired 196 [133]. Burckhalter and Leib extended their research on 197a–c, whereby the EtOH solution of N-methylpiperazine and paraformaldehyde was added to the EtOH solution of 5-alkoxy-8HQ (75, 190 or 191) followed by heating under reflux for 2.5 h [111]. In addition to previous acyl derivatives, 5-cinnamoyl 198 was also described by Schraufstätter and Bock using formalin (30%) as the CH2O provider [112].
Scheme 13 depicts the application of seven-membered ring systems. Rivera et al. reported a modification of the Mannich reaction. Instead of using the reactants CH2O and an amine, 1,3,6,8-tetraazatricyclo-[4.4.1.1]dodecane (TATD) was added to 1 and isolated from 199. The process was described as a solvent-free Mannich-type reaction [134]. Shterev et al. extended their investigation to the synthesis of 200a as well [103]. Möhrle and Schaltenbrand applied azepine similar to Shterev et al., and the synthesis of 200b was accomplished starting from 94 [115]. Magarian and Nobles used formalin (37%), 3-azabicyclo[3.2.2]nonane and 8HQ (1 or 14) in EtOH at reflux to acquire 201a,b [135]. Disubstituted products are not usual in the Mannich reaction, but Magarian and Nobles could achieve the synthesis of 202; however, it could be synthesised only from 201a rather than from 1.
An extension of the Mannich reaction is the application of the aza-crown ethers included in Scheme 14. The synthesis of 203–205a was carried out by Aragoni et al., stirring the appropriate aza-crown ether, 18 and paraformaldehyde in benzene under reflux conditions [136,137]. Zhang et al. and Bordunov et al. synthesised 205b,c and 206 via a modified Mannich reaction in two steps. First, the aza-crown ether and paraformaldehyde were stirred in MeOH, followed by evaporation. Subsequently, the formed N-methoxymethyl aza-crown ether, as an electrophilic reagent, was stirred with 18 in benzene at reflux temperature, delivering the desired products [138,139,140]. Sharghi and Ebrahimpourmoghaddam treated 18 with paraformaldehyde and macrocyclic ether in the presence of CaCl2, and it was found to be efficiently promoting the Mannich reaction. Stirring the mixture without a solvent for 30–60 min at 110 °C, followed by extraction with acetone, gave 207 [141]. In an upcoming study, Sharghi et al. applied an aza-crown ether in the Mannich reaction but perceived a low yield. Therefore, they switched to another, more efficient approach. Specifically, the aza-crown ether was converted to an N-methoxymethyl derivative (similar to that by Zhang et al. [138] and Bordunov et al. [139,140]) and then it was stirred with 8HQ (1 or 18) and graphite at 100 °C for 10–20 min without solvent, delivering 208a,b [142]. Compound 209 was synthesised by treating azathia-crown ether, 14 and paraformaldehyde in benzene under reflux for 15 h by Song et al. [143]. 210 was furnished from 1, 4-aza-dibenzo 18-crown-6 ether and paraformaldehyde upon stirring in THF at r.t. for 75 h by Mehta et al. [144].

2.2. Syntheses of Mannich Bases Furnishing 2:1:1 Moiety Ratio in the Product (CH2O:Amine:8HQ)

2.2.1. Syntheses by Using Primary Amines Delivering Dihidro-1,3-Oxazinoquinolines

Table 8 depicts the reactions of 1 molar equivalent 8HQ derivatives with 1 equivalent alkyl amines and 2 equivalents of formaldehyde. The reasons to acquire an oxazine scaffold are the following: The aim of the synthesis was the benzoxazine core itself, but sometimes it was considered an intermediary product or a side-product—during the synthesis of furnishing open-chain Mannich derivatives (see Table 2, 30a–c). The formation of 212a was achieved from 1, aniline and paraformaldehyde by Ma et al. [145]. In order to prepare 212b and 214a–f, March et al. stirred the appropriate 8HQ (1 or 2-trifluoromethyl-8HQ—210), paraformaldehyde and several amines in 50% benzene–EtOH at reflux for 2 h [146]. Page et al. synthesised 212b as well as 212c,d as starting compounds for their further transformation via reductive cleavage to obtain asymmetric acyclic aminomethyled 8HQs. Compounds 7-ethylmethyl and 7-benzylmethyl aminomethylquinolin-8-ols (similar derivatives are listed in Table 4) were efficiently prepared from 212b and 212c [147]. In addition to 39e with the 7-aminomethyl side chain, 213a,c,e,g–k and 215a,b were also synthesised by Gianni et al. They, however, applied different conditions by treating the corresponding amine and paraformaldehyde under reflux in EtOH for 6 h, followed by cooling to r.t., adding 1 or 211 and stirring at r.t. for 12 h [89]. Manetti et al. used identical conditions as used by Gianni et al., delivering 213b,d,f [73]. Si et al. treated paraformaldehyde and the appropriate amine in 1,4-dioxane at 75 °C for 30 min, and then 58 was added and stirred at 75 °C overnight, producing 216a–g [148].
Many attempts were made to transform 5-Cl- and 5-Br-8HQ into oxazine derivates (Scheme 15). Fu et al. efficiently applied the same method and conditions used in the synthesis of the 8HQ–ciprofloxacin hybrid (196) and carried out the synthesis of 217a–c, 217e–k and 217v–x [133]. Other N-alkyl derivatives were described by Kim et al. (217d) [129], Fiorentino et al. (217l, 219h) [149], Olaleye et al. (217m) [150], Gianni et al. (217n–p) [89], March et al. (217q) [146] and Ratan et al. (217r–u) [151]. Bowlin and co-workers carried out the synthesis of 217y in a solvent mixture of benzene and EtOH [152]. 30a was synthesised by Ahn et al. applying 18, 4-amino-1-benzylpiperidine and 2 molar equivalents of paraformaldehyde. Note that the formation of 33a (Table 2) was also observed [63]. 218a, 218c–e and 219i were studied by Mordarski and Chylińska [153]. 218b, 219j, 220b–k and 221a,b were synthesised via the method used for 216a–g by Si et al. [148]. March et al. carried out the synthesis of 30b and 219b–e in 50% benzene–EtOH, similarly to how 212b and 214a–f were prepared (Table 8) [146]. Identical and resembling derivatives (30b, and 219a,f,g) were furnished by treating the components (14, appropriate benzylamine and paraformaldehyde in a molar ratio of 1:1:2) in EtOH in the presence of KOH at reflux for 1 h by Combes and Mesnier [88]. 30c was described by Szakács et al., and its open-chain product 39b was transformed by means of HCl/EtOH (22%) (Table 2) [48]. 220a was included in the study by De La Fuente et al. [154].

2.2.2. Syntheses by Using Primary Amines Furnishing Azabicyclo Derivatives

Scheme 16 depicts an intriguing extension of the Mannich reaction, whereas the incorporated CH2O and the amine form a bridge between positions 5 and 7. The transformation of 5,7-dinitro-8HQ (222) and its 2-Me derivative (223) was carried out by Yakunina et al. and Medvedeva et al., resulting in several structural analogues of cytisine [155,156,157]. 228a–g were obtained by treating 222 or 223 with NaBH4 in a DMF–EtOH mixture for 10 min under cooling, resulting in the intermediary hydride σH-adducts (224 and 225). Subsequently, formalin (32%) and the appropriate amine in water were added to the reaction mixture and then it was acidified with 20% phosphoric acid. From the reaction of 222 with acetone and sodium ethoxide, the Janovszky σ-adduct 226 was isolated, which was transformed to 228h–l with formalin (32%) and the appropriate amine. 228m was synthesised in a similar manner; the only modification was that acetophenone was applied instead of acetone, and the intermediary σ-adduct was compound 227.

2.3. Syntheses of Mannich Bases Furnishing 2:1:2 Moiety Ratio in the Product (CH2O:Amine:8HQ)

2.3.1. Syntheses by Using Primary and Cyclic Secondary Amines

Some unusual Mannich bases are included in Scheme 17. Fu et al. applied the method described previously (Scheme 11) to form 229a,b as well [133]. 229c was furnished by treating 42 with formalin (37%) in 7% aqueous ammonia at 90 °C for 40 min by Matsumura et al. [158]. When the synthesis of 62b from 55 was performed by Ozawa and Shibuya, the formation of side-product 230 was observed. By reducing the molar equivalent of ethanolamine, 230 became the main isolable product [94]. Shebab et al. applied 1,3-di(piperidine-4-yl)propane and formalin (37%) to treat 1 in EtOH at r.t., which led to the formation of 231 [39]. 232 was obtained from the reaction of 1, N,N’-dimethylethylenediamine and formalin (37%) in EtOH at 50 °C by Zaoui et al. [70]. 233a was furnished via stirring 1, paraformaldehyde and piperazine in EtOH at reflux in the presence of HCl by Raj et al. [159] The preparation of 233b was performed in a mixture of pyridine and DMF by Movrin et al. [80]. 233c and 233f were synthesised via stirring the starting components (14, paraformaldehyde and piperazine or trans-2,5-dimethylpiperazine) in EtOH at reflux by Burckhalter et al. [71]. 233d and 233e were obtained by Gopalchari and Dhar by applying paraformaldehyde as the CH2O source and treating the reaction in EtOH at reflux for 3–4 h [114].

2.3.2. Syntheses by Using Diaza-Crown Ethers

When two secondary aliphatic amines are included in a crown ether (for instance, diazadithia-15-crown-5, diazatrithia-15-crown-5, etc.), their application leads to compounds depicted on Scheme 18. Shamsipur et al. stirred 18, paraformaldehyde and a macrocyclic amine in benzene at reflux, resulting in 234 [160]. Identical conditions were applied to synthesise 235a–d (Bradshaw et al. [161]) and 235e–h (Song et al. [162]). Bronson et al. prepared 236 and 237 by stirring diaza-crown ethers and paraformaldehyde in MeOH overnight, followed by the removal of MeOH. Subsequently, benzene and 18 were added, and the mixture was treated at reflux for 24 h [163].
Diaza-18-crown-6, diazadithia-18-crown-6 and other S-containing diaza-crown ethers were also used in Mannich reactions (Scheme 19). Su et al. prepared 243a–c and 243m by means of the reaction of the 8HQ derivative, paraformaldehyde and an appropriate crown ether in anhydrous toluene under reflux conditions [164]. 243d was synthesised by Bordunov et al. under the same conditions as 205c (Scheme 14) [139]. Farruggia et al. used microwave irradiation (600 W for 2–4 h) to optimise the preparation of 243e–l and efficiently carried out the syntheses in both toluene and 1,4-dioxane [165]. In addition to compounds described previously, 244a–d, 245a–c, and 245e–i were furnished by Bradshaw et al. [161], 244e–g and 245d by Song et al. [143,162] and 245j by Bronson et al. [163].
Further extensions to diaza-21-crown-7, its sulphur analogues and diaza-24-crown-8 ether were performed by Song et al. and Bordunov et al. as depicted in Scheme 20, including 246a (Song et al.) [166], 246b–d (Song et al.) [143], 246e, 247a,b (Song et al.) [162] as well as 246f and 248 (Bordunov et al.) [139].

2.4. Syntheses of Mannich Bases Furnishing Products in Miscellaneous Ratios

Syntheses by Furnishing (Methylene)bisproducts with 2:2:1 Ratio in the Product (CH2O:Amine:8HQ)

In general, diaminomethylation in the Mannich reaction is not a common occurrence, although compound 202 is a noteworthy exception (Scheme 13). On the other hand, it is relatively simple to obtain disubstitution when the starting compound is a bis or methylenebis compound (Scheme 21). Gopalchari and Dhar first synthesised 249 and 250, and from these derivatives, 251a–c and 252a–d were prepared by means of different secondary amines and paraformaldehyde [167]. 252e was furnished by Xie et al. by treating 250 with formalin (37%) and dibutylamine in DMF under reflux for 4 h [168]. Abdelhameed et al. reacted 250 with formalin (37%) and N-benzylpiperazine in MeOH at r.t. for 24 h, resulting in the formation of 252f [169].
Scheme 22 depicts bis- and trisproducts starting from “mono” compounds. 253a,b were obtained under conventional Mannich conditions by Möhrle and Schaltenbrand. The interesting fact is that the side chains were involved in the reaction; therefore, methylenebis compounds were isolated rather than the 7-aminomethylated product, in contrast to compound 104 (Table 5) [170]. In the reaction of 254, formalin (37%), ethylenediamine and 1, with ratios of 4:1:2, were dissolved in 1,4-dioxane under stirring at r.t. for 4 h by Rivera et al. [134]. Bencini et al. carried out the transformation of 255 with 1,4,7-triazacyclononane and paraformaldehyde in toluene at 90 °C with a yield of 62% [171].

3. Conclusions

The past milestones and current trends in the Mannich reaction of 8HQ have been reviewed. Transformations were performed utilising various amines and formalin or paraformaldehyde as the CH2O source. In some cases, the Mannich reaction was carried out without a solvent; however, it is a general trend to perform these reactions in a solvent or a mixture of solvents, primarily in EtOH. Pyridine, benzene (mainly in the case of aza-crown ethers), MeOH, DMF, toluene, 1,4-dioxane, and their mixtures were also utilised. Both the order of the applied amine and the molar equivalents of the reactants were crucial. The reactions took place at position 7 of the 8HQ core, except when the 7-position was substituted and when the structure had a more reactive position (1,3-dicarbonyl side chain or (thio)amide-containing ring).
The aminomethylated 8HQ derivatives possess several biological properties and can affect pharmacological targets, including pathogenic microorganisms, cancer cells and central nervous system targets.
Research on aminomethylation via the Mannich reaction over more than a century has generated a series of versatile compounds with broad structural diversity. The ongoing advancement of the area undoubtedly draws the attention of researchers and demonstrates that there is much more to discover in the Mannich chemistry of 8HQs.

Author Contributions

Conceptualization, I.S.; investigation, O.C.; writing—original draft preparation, O.C.; writing—review and editing, I.S. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Acknowledgments

The authors’ thanks are due to the Hungarian Research Foundation (OTKA No. K-138871), the Ministry of Human Capacities, Hungary grant, TKP-2021-EGA-32, and the Gedeon Richter Plc. Centenarial Foundation.

Conflicts of Interest

The authors declare no conflict of interest.

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Ijms 24 07915 sch001 550
Scheme 1. Reaction of 5-NO2-8HQ (14), CH2O and primary amines including primary alkyl amines, substituted benzyl amines and amino acids.
Scheme 1. Reaction of 5-NO2-8HQ (14), CH2O and primary amines including primary alkyl amines, substituted benzyl amines and amino acids.
Ijms 24 07915 sch001
Ijms 24 07915 sch002 550
Scheme 2. Reaction of 5-substituted 8HQs, CH2O, and primary amines.
Scheme 2. Reaction of 5-substituted 8HQs, CH2O, and primary amines.
Ijms 24 07915 sch002
Ijms 24 07915 sch003 550
Scheme 3. Reaction of 5-substituted 8HQs, CH2O, and primary amines.
Scheme 3. Reaction of 5-substituted 8HQs, CH2O, and primary amines.
Ijms 24 07915 sch003
Ijms 24 07915 sch004 550
Scheme 4. Reaction of 8HQ derivatives, CH2O, and acyclic secondary amines.
Scheme 4. Reaction of 8HQ derivatives, CH2O, and acyclic secondary amines.
Ijms 24 07915 sch004
Ijms 24 07915 sch005 550
Scheme 5. Reaction of 8HQ and substituted 8HQs, CH2O and pyrrolidine.
Scheme 5. Reaction of 8HQ and substituted 8HQs, CH2O and pyrrolidine.
Ijms 24 07915 sch005
Ijms 24 07915 sch006 550
Scheme 6. Reaction of 8HQ and substituted 8HQs, CH2O and pyrrolidine derivatives.
Scheme 6. Reaction of 8HQ and substituted 8HQs, CH2O and pyrrolidine derivatives.
Ijms 24 07915 sch006
Ijms 24 07915 sch007 550
Scheme 7. Reaction of 2-, 4-, 7- or 8-substituted 8HQs, CH2O and piperidine.
Scheme 7. Reaction of 2-, 4-, 7- or 8-substituted 8HQs, CH2O and piperidine.
Ijms 24 07915 sch007
Ijms 24 07915 sch008 550
Scheme 8. Reaction of substituted 8HQs, CH2O and piperidine.
Scheme 8. Reaction of substituted 8HQs, CH2O and piperidine.
Ijms 24 07915 sch008
Ijms 24 07915 sch009 550
Scheme 9. Reaction of 8HQ and 5-substituted 8HQs, CH2O and piperidine derivatives.
Scheme 9. Reaction of 8HQ and 5-substituted 8HQs, CH2O and piperidine derivatives.
Ijms 24 07915 sch009
Ijms 24 07915 sch010 550
Scheme 10. Reaction of 8HQ and substituted 8HQs, CH2O, and morpholine.
Scheme 10. Reaction of 8HQ and substituted 8HQs, CH2O, and morpholine.
Ijms 24 07915 sch010
Ijms 24 07915 sch011 550
Scheme 11. Reaction of 8HQ and 5-substituted 8HQs, CH2O and morpholine derivatives.
Scheme 11. Reaction of 8HQ and 5-substituted 8HQs, CH2O and morpholine derivatives.
Ijms 24 07915 sch011
Ijms 24 07915 sch012 550
Scheme 12. Reactions of 5-Hlg-8HQs, CH2O, and piperazine derivatives.
Scheme 12. Reactions of 5-Hlg-8HQs, CH2O, and piperazine derivatives.
Ijms 24 07915 sch012
Ijms 24 07915 sch013 550
Scheme 13. Reaction of 8HQ and 5-substituted 8HQs, CH2O and 7-membered cyclic amines.
Scheme 13. Reaction of 8HQ and 5-substituted 8HQs, CH2O and 7-membered cyclic amines.
Ijms 24 07915 sch013
Ijms 24 07915 sch014 550
Scheme 14. Reaction of 8HQ and 5-Cl-8HQ, CH2O, and aza-crown ethers.
Scheme 14. Reaction of 8HQ and 5-Cl-8HQ, CH2O, and aza-crown ethers.
Ijms 24 07915 sch014
Ijms 24 07915 sch015 550
Scheme 15. Reaction of 5-Hlg-8HQs, CH2O, and primary amines.
Scheme 15. Reaction of 5-Hlg-8HQs, CH2O, and primary amines.
Ijms 24 07915 sch015
Ijms 24 07915 sch016 550
Scheme 16. Reaction of 5,7-dinitro-8HQs, CH2O and primary amines.
Scheme 16. Reaction of 5,7-dinitro-8HQs, CH2O and primary amines.
Ijms 24 07915 sch016
Ijms 24 07915 sch017 550
Scheme 17. Reaction of 8HQs, CH2O and primary amines.
Scheme 17. Reaction of 8HQs, CH2O and primary amines.
Ijms 24 07915 sch017
Ijms 24 07915 sch018 550
Scheme 18. Reaction of 8HQ and substituted 8HQs, CH2O and diaza-crown ethers.
Scheme 18. Reaction of 8HQ and substituted 8HQs, CH2O and diaza-crown ethers.
Ijms 24 07915 sch018
Ijms 24 07915 sch019 550
Scheme 19. Reaction of 8HQ and substituted 8HQs, CH2O and diaza-crown ethers.
Scheme 19. Reaction of 8HQ and substituted 8HQs, CH2O and diaza-crown ethers.
Ijms 24 07915 sch019
Ijms 24 07915 sch020 550
Scheme 20. Reaction of 5-substituted 8HQs, CH2O and diaza-crown ethers.
Scheme 20. Reaction of 5-substituted 8HQs, CH2O and diaza-crown ethers.
Ijms 24 07915 sch020
Ijms 24 07915 sch021 550
Scheme 21. Reaction of bis and methylenebis 8HQs, CH2O and secondary amines.
Scheme 21. Reaction of bis and methylenebis 8HQs, CH2O and secondary amines.
Ijms 24 07915 sch021
Ijms 24 07915 sch022 550
Scheme 22. Reaction of 8HQ and 5-Cl-8HQ, CH2O, and different amines.
Scheme 22. Reaction of 8HQ and 5-Cl-8HQ, CH2O, and different amines.
Ijms 24 07915 sch022
Table
Table 1. Reaction of 8HQ, CH2O, and primary amines.
Table 1. Reaction of 8HQ, CH2O, and primary amines.
Ijms 24 07915 i001
Compound–RConditionsRefs.
2Ijms 24 07915 i002EtOH, reflux (78 °C), 1 h; Yield: 98%[70]
3a,bIjms 24 07915 i003a: Benzene, reflux, 30 min; Yield: n.d.
b: Neat, 104 °C, 1 h; Yield: n.d.		[71]
4Ijms 24 07915 i004EtOH, reflux, 90 min; Yield: 90%[72]
5a,bIjms 24 07915 i005EtOH, reflux, 4 h; Yield: n.d.[46]
6a–cIjms 24 07915 i006MeOH, reflux, 12 h;
Yield: a: 13%; b: 3%; c: 31%		[73]
7Ijms 24 07915 i007EtOH, r.t. 5 min → 120 °C, 12 h;
Yield: 52%		[47]
8Ijms 24 07915 i008DMF, 60 °C, 6 h; Yield: 92.75%[74]
9Ijms 24 07915 i009EtOH, r.t.→reflux, 18–22 h;
Yield: n.d.		[55]
10a–cIjms 24 07915 i010EtOH, r.t. → 0 °C; Yield: n.d.[75]
11a–dIjms 24 07915 i011EtOH, reflux, HCl;
Yield: a: 65%; b: 65%; c: 68%;
d: 46%; e: 52%; f: 54%; g: 70%		[76,77,78]
12a–mIjms 24 07915 i012EtOH, reflux, 8 h, HCl;
Yield: a: 85%; b: 85%;
c: 80%; d: 85%; e: 75%; f: 75%;
g: 65%; h: 75%; i: 82%; j: 65%;
k: 65%; l: 70%; m: 70%		[79]
13a–gIjms 24 07915 i013EtOH, 90 °C, 6 h → r.t. 18 h;
Yield: a: 45%;
b: 38%; c: 23%; d: 38%;
e: 20%; f: 22%; g: 25%		[64]
Table
Table 2. Reaction of 5-Cl-8HQ, CH2O and primary amines.
Table 2. Reaction of 5-Cl-8HQ, CH2O and primary amines.
Ijms 24 07915 i014
Compoundn–R1Refs.Compound–R2Refs.
19a,b2: a, 3: bIjms 24 07915 i015[71,82]31Ijms 24 07915 i016[82]
20a–e2: a, 3: b;
4: c; 5: d; 6: e		Ijms 24 07915 i017[71,82,85]
213Ijms 24 07915 i018[82]32Ijms 24 07915 i019[82]
223Ijms 24 07915 i020[82]33a,bIjms 24 07915 i021[63]
23a–c3: a; 4: b; 5: cIjms 24 07915 i022[82,85]
24a,b3: a; 5: bIjms 24 07915 i023[82]
253Ijms 24 07915 i024[82]34Ijms 24 07915 i025[85]
263Ijms 24 07915 i026[85]35a,bIjms 24 07915 i027[85]
36Ijms 24 07915 i028[85]
27a,b3Ijms 24 07915 i029[82]37Ijms 24 07915 i030[86]
283Ijms 24 07915 i031[42]38Ijms 24 07915 i032[48]
29a–e1Ijms 24 07915 i033[64]39a–eIjms 24 07915 i034[48,87,89]
Table
Table 3. Reaction of 8HQ derivatives, CH2O and primary amines.
Table 3. Reaction of 8HQ derivatives, CH2O and primary amines.
Ijms 24 07915 i035
CompoundX and Y–RConditionsRefs.
60a–e2-MeIjms 24 07915 i036EtOH, 90 °C, 6 h →
r.t. 18 h;
Yield: a: 33%;
b: 35%; c: 35%;
d: 35%; e: 27%		[64]
61a–c2-Me: a;
5-Cl-2-Me: b;
5-Br-2-Me: c		Ijms 24 07915 i037EtOH, reflux;
Yield: n.d.		[93]
62a,b4-Cl-2-Me: a;
4-Cl-3-(2-chloroethyl)-2-Me: b		Ijms 24 07915 i038EtOH, reflux;
Yield: a: 87%; b: 40%		[94]
63a,b4-OBu: a;
4-OBn: b		Ijms 24 07915 i039EtOH, reflux, 12 h;
Yield: a: 8%; b: 53%		[73]
64a,b2-OH-4-MeIjms 24 07915 i040EtOH, reflux, 9 h;
Yield: a: 58%; b: 50%		[95]
65a–k7-SO3HIjms 24 07915 i041EtOH, reflux,
30–50 h;
Yield: 60–70%		[96]
Table
Table 4. Reaction of 8HQ and 5-substituted 8HQs, CH2O and secondary acyclic amines.
Table 4. Reaction of 8HQ and 5-substituted 8HQs, CH2O and secondary acyclic amines.
Ijms 24 07915 i042
CompoundX–R1, –R2ConditionsRefs.
70a–fHR1 = R2 = Me: a; Et: b; CH2CO2H: c; nPr: d;
nBu: e; n-hexyl: f; cyclohexyl: g; 2-ethylhexyl: h;
n-octyl: i; n-dodecyl: j; n-octadecyl: k;
iso-dodecenyl: l; Ph: m; octylphenyl: n; Bn: o;
3-(octyloxy)propoxy: p; R1 = n-octyl, R2 = Ph: q;
Ijms 24 07915 i043: r		a: EtOH, reflux, 2 h; Yield: 74%
b: EtOH, r.t., 1 h → reflux, 5 h; Yield: 55%
c: DMF, reflux, 24 h; Yield: 27%
d: EtOH, r.t., 1 h → reflux, 3 h; Yield: 65%
e–q: MeOH, 20 °C, 1 h→reflux, 3 h; Yield: n.d.
r: EtOH, reflux 60 °C, 48 h; Yield: 51%		[48,98,99,100,101,102]
71a–iNO2R1 = R2 = Me: a;
Et: b; nPr: c;
iPr: d; (CH2)2OH: e;
cyclohexyl: f;
R1 = Me, R2 = cyclohexyl: g;
R1 = Me, R2 = CH2CN: h;
R1 = Bn, R2 = CH2CN: i		a: pyridine:EtOH 1:1, reflux; Yield: n.d.
b: EtOH, reflux, 90 min; Yield: 83%
c: EtOH, reflux 80 °C, 24 h; Yield: 14%
d, e: pyridine, 50–60 °C; Yield: 74–84%
f: EtOH, reflux 80 °C, 24 h; Yield: 19%
g: n.d.
h, i: pyridine, 60 °C; Yield: 70%/74%		[36,40,41,60,80,103,104]
72FR1 = R2 = EtEtOH, r.t., 30 min; Yield: 42%[105]
73a–lClR1 = R2 = Me: a; Et: b;
nPr: c; nBu: d; (CH2)2OH: e;
CH2CO2Et: f; CH2CN: g;
R1 = Me, R2 = (CH2)2NEt2: h;
R1 = Me, R2 = (CH2)3NEt2: i;
R1 = Et, R2 = (CH2)2NEt2: j;
R1 = Et, R2 = (CH2)3NEt2: k;
R1 = Et, R2 = (CH2)2OH: l;		a: EtOH, reflux, 90 min; Yield: 75%
b: EtOH, reflux, 90 min; Yield: 74%
c, d: EtOH, reflux, 2 h/30 min; Yield: n.d.
e: EtOH, reflux, 90 min; Yield: 70%
f: EtOH, reflux, 2 h; Yield: 79%
g: EtOH, reflux, 3 h; Yield: 42%
h–k: EtOH, reflux, 90 min; Yield: n.d.
l: EtOH, reflux, 90 min; Yield: 80%		[71,82,85,106,107]
74a,bBrR1 = R2 = Et: a;
R1 = Me, R2 = Et: b		a: EtOH, reflux, 90 min; Yield: 51%
b: EtOH, reflux, 1 h; Yield: n.d.		[106,107]
Table
Table 5. Reaction of 5-substituted 8HQs, CH2O and secondary acyclic amines.
Table 5. Reaction of 5-substituted 8HQs, CH2O and secondary acyclic amines.
Ijms 24 07915 i044
CompoundX–R4, –R5Refs.CompoundX–R4, –R5Refs.
96a,bIjms 24 07915 i045R4 = R5 = Et: a; R4 = Et,
R5 = (CH2)2OH: b		[108]106a,bIjms 24 07915 i046R2 = 4-Cl,
R4 = R5 = Me: a;
R2 = 3,4-(OMe)2,
R4 = R5 = Me: b		[112]
97Ijms 24 07915 i047R4 = R5 = Bn[109]
98Ijms 24 07915 i048R4 = R5 = (CH2)2OH[109]
99Ijms 24 07915 i049R4 = R5= Et[111]107Ijms 24 07915 i050R4 = R5 = Me[112]
100Ijms 24 07915 i051R4 = R5 = (CH2)2OH[109]108a,bIjms 24 07915 i052R3 = H,
R4 = R5 = Me: a;
R3 = NO2,
R4 = R5 = Me: b		[112]
101a,bIjms 24 07915 i053R4 = R5 = Me: a;
R4 = (CH2)2CN, R5 = C12H25: b		[112,113]109Ijms 24 07915 i054R4 = R5 = Me[112]
102a–fIjms 24 07915 i055R1 = H, R4 = R5 = Me: a;
R1 = H, R4 = Et, R5 = (CH2)2NEt2: b;
R1 = 2-Cl, R4 = R5 = Me: c;
R1 = 4-Cl, R4 = R5 = Me: d;
R1 = 2,4-Cl2, R4 = R5 = Me: e;
R1 = 4-Cl, R4 = R5 = Et: f		[112,114]
103Ijms 24 07915 i056R1 = R2 = Me[112]110a,bIjms 24 07915 i057R4 = R5 = Me: a; Et: b[115]
104Ijms 24 07915 i058R1 = R2 = Me[112]111Ijms 24 07915 i059R4 = R5 = Et[104]
105a–hIjms 24 07915 i060R4 = R5 = Me: a; Et: b; nBu: c;
(CH2)2OH: d; (CH2)2NEt2: e;
R4 = Me, R5 = Bn: f;
R4 = Me, R5 = C12H25: g;
R4 = Et, R5 = (CH2)2NEt2: h		[112]112a–fIjms 24 07915 i061R4 = R5 = Me: a; Et: b; nPr: c; nBu: d; iBu: e; (CH2)2OH: f[116]
113Ijms 24 07915 i062R4 = R5 = Et[92]
Table
Table 6. Reaction of 8HQ and 5-substituted 8HQs, CH2O and piperidine.
Table 6. Reaction of 8HQ and 5-substituted 8HQs, CH2O and piperidine.
Ijms 24 07915 i063
CompoundXConditionsRefs.CompoundXConditionsRefs.
137Ijms 24 07915 i064EtOH, reflux, 6 h;
Yield: n. d.		[5]148a–dIjms 24 07915 i065EtOH, reflux,
1–4 h;
Yield: a: 67%; b: 81%; c: 54%
d: n.d.		[108,112]
138Ijms 24 07915 i066EtOH, heat; Yield: 83%[104]
139Ijms 24 07915 i067EtOH, reflux, 1.5 h;
Yield: 80%		[71]
140Ijms 24 07915 i068EtOH, reflux, 1 h;
Yield: 65%		[111]149Ijms 24 07915 i069EtOH, reflux,
8 h;
Yield: n. d.		[112]
141Ijms 24 07915 i070EtOH, reflux; Yield: 60%[90]
142a–cIjms 24 07915 i071EtOH, reflux, 1–2 h;
Yield: a: 97%;
b: 95%; c: 56%		[108]150Ijms 24 07915 i072n. d.;
Yield: 67–90%		[115]
143a,bIjms 24 07915 i073EtOH, reflux, 4 h;
Yield: a: 78%; b: 81%		[109]
144Ijms 24 07915 i074Neat conditions,
heat, 3 h;
Yield: 90%		[111]151Ijms 24 07915 i075EtOH, reflux,
1 h;
Yield: 92%		[104]
145Ijms 24 07915 i076EtOH, r. t.,
3 days;
Yield: 68%		[48]152Ijms 24 07915 i077EtOH, reflux,
2 h;
Yield: 93%		[104]
146a–cIjms 24 07915 i078a, b: n. d.
c: EtOH, reflux, 4 h;
Yield: n. d. 		[57,109]153Ijms 24 07915 i079EtOH, reflux,
6 h;
Yield: 80%		[116]
147Ijms 24 07915 i080EtOH, reflux, 3 h;
Yield: 88%		[111]154Ijms 24 07915 i081EtOH, reflux, 30–40 h;
Yield: 70%		[92]
Table
Table 7. Reaction of 8HQ and 5-NO2-8HQ, CH2O and piperazine derivatives.
Table 7. Reaction of 8HQ and 5-NO2-8HQ, CH2O and piperazine derivatives.
Ijms 24 07915 i082
Compound–R1Refs.Compound–R2Refs.
175Ijms 24 07915 i083[65]183Ijms 24 07915 i084[103]
176Ijms 24 07915 i085[130]184a–cIjms 24 07915 i086[40,60,80]
177a–cIjms 24 07915 i087[37,130,131]185a–mIjms 24 07915 i088[36,37,40,80]
178a,bIjms 24 07915 i089[55]
179Ijms 24 07915 i090[131]186a–cIjms 24 07915 i091[103]
180Ijms 24 07915 i092[67]
181a–oIjms 24 07915 i093[54,55]187a–cIjms 24 07915 i094[40]
188a,bIjms 24 07915 i095[60]
182a,bIjms 24 07915 i096[55]189a–cIjms 24 07915 i097[54,55]
Table
Table 8. Reaction of 8HQ and substituted 8HQs, CH2O and primary amines.
Table 8. Reaction of 8HQ and substituted 8HQs, CH2O and primary amines.
Ijms 24 07915 i098
CompoundX/Y/Z–RConditionsRefs.
212a–dX = H
Y = H
Z = H		Ijms 24 07915 i099a: n.d.
b: Benzene:EtOH 1:1,
reflux 2 h; Yield: 18%
c, d: n.d.		[145,146,147]
213a–hX = H
Y = H
Z = H		Ijms 24 07915 i100EtOH, reflux 6 h → r.t. 12 h;
Yield: a: 35%;
b: 18%; c: 51%;
d: 15%; e: 48%;
f: 51%; g: 87%;
h: 48%; i: 30%;
j: 21%; k: 10%		[73,89]
214a–fX = CF3
Y = H
Z = H		Ijms 24 07915 i101Benzene:EtOH 1:1,
reflux 2 h;
Yield: a: 44%; b: 47%; c: 50%;
d: 22%; e: 24%; f: 15%		[146]
215a,bX = H
Y = F
Z = H		Ijms 24 07915 i102EtOH, reflux 6 h →
r.t. 12 h;
Yield: a: 50%; b: 55%		[89]
216a–gX = H
Y = H
Z = F		Ijms 24 07915 i1031,4-dioxane, 75 °C;
Yield: a: 35.0%; b: 52.6%;
c: 68.7%; d: 62.9%; e: 34.3%;
f: 67.6%; g: 81.6%		[148]
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Csuvik, O.; Szatmári, I. Synthesis of Bioactive Aminomethylated 8-Hydroxyquinolines via the Modified Mannich Reaction. Int. J. Mol. Sci. 2023, 24, 7915. https://doi.org/10.3390/ijms24097915

AMA Style

Csuvik O, Szatmári I. Synthesis of Bioactive Aminomethylated 8-Hydroxyquinolines via the Modified Mannich Reaction. International Journal of Molecular Sciences. 2023; 24(9):7915. https://doi.org/10.3390/ijms24097915

Chicago/Turabian Style

Csuvik, Oszkár, and István Szatmári. 2023. "Synthesis of Bioactive Aminomethylated 8-Hydroxyquinolines via the Modified Mannich Reaction" International Journal of Molecular Sciences 24, no. 9: 7915. https://doi.org/10.3390/ijms24097915

APA Style

Csuvik, O., & Szatmári, I. (2023). Synthesis of Bioactive Aminomethylated 8-Hydroxyquinolines via the Modified Mannich Reaction. International Journal of Molecular Sciences, 24(9), 7915. https://doi.org/10.3390/ijms24097915

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