Recent advances in the synthesis and synthetic applications of Betti base (aminoalkylnaphthol) and bis-Betti base derivatives

The multicomponent reaction between 2-naphthol, arylaldehydes and ammonia yields aminobenzylnaphthols in a process known as the Betti reaction, which was first uncovered at the beginning of the 20th century. Various methods have been reported for the synthesis of aminobenzylnaphthol (Betti base) and bis-Betti base derivatives using various types of naphthols, aromatic amines, heteroaromatic amines, and aliphatic and cyclic amines instead of ammonia or diamines and aliphatic and aromatic aldehydes or dialdehyde compounds under various conditions in recent years. The Betti reaction produces racemic and non-racemic aminobenzylnaphthol ligands. It is also clear that the most important area of application of the non-racemic aminonaphthols prepared in this manner is their use in asymmetric synthesis, either as chiral ligands or as chiral auxiliaries. The functional groups in these Mannich products offer many ring closure possibilities. Some of these products or the starting bifunctional compounds possess biological activity. Herein, we present a selection of the relevant studies on this topic.


Introduction
Senator Mario Betti (1875Betti ( -1942 (Fig. 1) was a distinguished Italian chemist, 1,2 very active at the beginning of the 20th century. In 1892 Betti registered as a student at the chemistry school of the University of Pisa. In 1897, Betti obtained his degree with a thesis on the reaction of methylisoxazolones with aldehydes and co-authored with Roberto Schiff the rst two papers of his career. 3,4 In 1898, Betti moved to the University of Florence as an assistant of Ugo Schiff, who was founder and director of the Institute of Chemistry. In the Florence laboratories, Betti

The Betti reaction
This synthetic strategy originated between the end of the 19th and the beginning of the 20th century when research in several laboratories was performed on reactions between ammonia, or amines, formaldehyde and enolisable carbonyl compounds. 10 The rst two components yield an imine that reacts with the carbonyl compound. These procedures are commonly classied as Mannich aminoalkylations, aer the systematic work of the latter author, which began in 1912, thus subsequent to Betti's research. 7,9,11 Eventually, Betti also reported 7 that the product 2 (Scheme 1) could be obtained from a three-component condensation of 2-naphthol, an ethanolic solution of ammonia and 2 equiv. of benzaldehyde (91% yield). Actually, the product of the reaction is represented by the forms 2a and 2b in equilibrium. 12 The intermediate 2 was treated with hydrochloric acid to obtain the salt of the Betti base 1a HCl (91% yield, Scheme 1). Addition of a solution of sodium hydroxide to chloride yielded Betti base 1 (75% yield). 7,13

Synthesis and synthetic applications of Betti base derivatives
In 1930, aer a long period of silence, work was performed by Littman and Brode, who used different secondary amines such as dimethylamine and piperidine instead of ammonia in a onepot multicomponent process. 14 In this reaction, dimethylamino derivative of the Betti base 3 and 1-(1-piperidylbenzyl)-2naphthol (4) were obtained (Scheme 2). 14 According to Littman and Brode, secondary amines should react with benzaldehyde via the formation of a benzylidinediamine. This intermediate attacks 2-naphthol and yields aminobenzylnaphthol, aer the elimination of an amine molecule.  Two decades ago, Cardellicchio et al. 15 reported a protocol for the resolution of the Betti base and the absolute conguration of the Betti base hydrobromide was established by means of X-ray diffractometry. Also, a series of optically active derivatives such as the N,N-dimethyl and the N,N,O-trimethyl derivatives were prepared in racemic form by means of the Betti reaction and were resolved into two enantiomers with an extremely easy and efficient procedure. The conguration of each base was determined by correlation with the conguration of the Betti amine. In their work, the N-benzyl derivative 6 was easily obtained by reducing (S)-(+)-5 with hydrogen in the presence of Pd/C, or with NaBH 4 (Scheme 3).
The Mannich reaction on acidic alumina assisted by microwave irradiation was reported for the aminoalkylation of 2naphthol with aromatic aldehydes and secondary amines such as piperidine, pyrrolidine and morpholine for 5 min under solvent-free condition, resulting in the desired products 17 in 67-91% yields (Scheme 9). 20 A procedure for selective direct N,N-alkylation of the chiral Betti base was developed, and a family of chiral ligands, (S)-1-(acycloaminobenzyl)-2-naphthols 18, were prepared. Initially, oxazine derivatives 19 were achieved by the condensation of (S)-1-(a-aminobenzyl)-2-naphthol and bis-aldehydes in the presence of NaBH 3 CN in a buffer solution (aqueous EtOH solution of Na 2 HPO 4 -KH 2 PO 4 ) at 0 C in 1.5 h. Subsequently, compounds 19 were treated with LiAlH 4 , the C-O bond being cleaved selectively to yield the desired products 18 in 94-98% yields at À10 C in 1.5 h without any loss of enantiomeric excess (Scheme 10). 21 A practical procedure for the stereoselective synthesis of a group of functionalized secondary and tertiary aminoalkylnaphthols (20, 21 and 22) was employed by Palmieri et al. 22 A series of secondary aminoalkylnaphthols were prepared by heating a mixture of 2-naphthol, (R)-amines and aldehydes at 60 C in 8-30 h, under solvent-free conditions with yields from 45 to 95% (Scheme 11). Then, selective N-alkylation was carried out by cyclization of compounds 23 with formaldehyde, followed by reduction or alkylation with organometallic reagents (R 4 M), resulting in the corresponding chiral tertiary aminonaphthols 21 and 22 (Scheme 12). The catalytic activity of this class of compounds was used in the addition of diethylzinc to benzaldehyde in toluene at room temperature, resulting in moderate to good enantioselectivities (12-89% ee) and 26-97% yields.
A practical procedure for the stereoselective synthesis of a group of functionalized aminoalkylnaphthols (24) in 45-95% yields was reported, involving heating a mixture of 2-naphthol, secondary amines (R) and aldehydes at 60 C within 8-30 h under solvent-free conditions (Scheme 13). It is noteworthy that the aminonaphthols obtained as the major diastereomer (dr: 71-84%) in the solvent-free synthesis have the best asymmetric induction properties in the alkylation reaction. 22 Condensation of 2-naphthol and substituted benzaldehydes in the presence of 25% methanolic ammonia, and subsequent acidic hydrolysis afforded the aminoalkylnaphthols 25 in 45-71% yields. The crystalline product 26 separated out aer 2 days, which was suspended in 20% HCl and the mixture was stirred and reuxed for 3 h (Scheme 14). 23 The Mannich reaction of 2-naphthol and 1-naphthol with in situ prepared imines from (R)-1-phenylethylamine and aromatic aldehydes in 5 M ethereal lithium perchlorate at room temperature in the presence of TMSCl under an argon atmosphere within 6 h afforded the corresponding aminoalkylated products 27 and 28 in moderate to good yields (35-78%) with moderate to very high diastereoselectivities (75-99%) (Scheme 15). 24 Chan et al. 25 reported a one-step procedure for the synthesis of optically active tertiary aminonaphthol 29 via benzaldehyde, (S)-(À)-N,R-dimethylbenzylamine and 2-naphthol at 95 C for 30 h in 78% yield (Scheme 16). Optically active tertiary aminonaphthol 29 (15 mol%) was found to catalyze the enantioselective alkenylation of various aldehydes in toluene at À30 C for 15 h with high ee values (up to >99%), which provides a practical method for the synthesis of chiral (E)-allyl alcohols in 77-95% yields.
Saidi et al. 26 reported a one-pot, three-component Mannich reaction of 2-naphthol or 1-naphthol with (R)-1-phenylethylamine and an aromatic aldehyde in concentrated ethereal lithium perchlorate solution at room temperature, which afforded highly diastereoselective access to the requisite 2-aminoalkylated products 30 and 31 in high to low yields, respectively (Scheme 17).
In 2004, a one-pot preparation of chiral N-methyl-N-alkyl Betti bases 32 was reported involving a highly regioselective Nalkylation of (S)-(+)-Betti base. The strategy involved formation  The aminonaphthols 39a-c were obtained in high yields (89-94%) from the reaction of oxazines 40a-c with LiAlH 4 within half hour at À5 to 0 C. Also, by using compound 40b as a model, the arylation at its a-position was carried out by treating it with ArMgBr at À5 to 0 C to give a series of diastereopure compounds 41 aer 2-3 h in 73-85% yields. Reductions of 41 via LiAlH 4 at 0 C within 0.5 h yielded a group of highly hindered 1,3-aminophenols (42) in 84-92% yields, which could serve as potential chiral ligands in catalytic asymmetric reactions (Scheme 20). 29 Wu et al. 30 introduced a uorescent chemosensor (43) containing aminonaphthol, which selectively recognizes uoride anions with high sensitivity. A uoride anion can strongly interact with a hydrogen-donating group such as hydroxyl or amide through hydrogen bonding interaction to form HF. Aminonaphthol 43 was synthesized from the reaction of 2naphthol and 4-aminoantipyrine in ethanol at reux for 4 h. Then reduction with NaBH 4 in EtOH afforded the desired product aer 4 h in 80% yield (Scheme 21). Chiral tertiary aminonaphthol ligand 44 was synthesized via the condensation of 1-naphthaldehyde, (S)-(À)-N,R-dimethylbenzylamine and 2-naphthol in the absence of solvent at 85 C for 72 h in 51% yield. It served as a highly efficient ligand for the asymmetric catalytic phenyl transfer to aromatic aldehydes and a variety of chiral diarylmethanols was prepared in toluene at À15 C for 15 h with high ee values (ee up to 99%) and in 87-95% yields (Scheme 22). 31 Total syntheses of enantiopure alkaloidal natural products (2S,6R)-dihydropinidine (as hydrochloride) and (2S,6R)-isosolenopsins (as hydrochlorides) (45) were achieved in four steps and in 80-82% total yields by using a synthetic strategy involving the formation and cleavage of 1,3-oxazinane. (S)-Betti base proved to be an excellent chiral auxiliary and a novel Pd/C- catalyzed N-debenzylation straightforwardly to amine hydrochloride in the presence of CH 2 Cl 2 was developed (Scheme 23). 32 Optically active aminonaphthol derivatives 46 were obtained by condensation of 2-naphthol, substituted benzaldehyde, and (S)-methylbenzylamine in THF at 73 C for 17-18 h under an argon atmosphere in 48-81% yields. The addition of diethylzinc to aromatic aldehydes was considerably accelerated by the presence of a catalytic amount of crystalline 46 in toluene at room temperature for 24 h to give, aer hydrolysis, the corresponding 1-phenylpropanol in good enantiomeric purity (up to >99% ee) and 80-92% yields (Scheme 24). 33 Solvent-free synthesis of 1-(a-or b-hydroxynaphthyl)-1,2,3,4-tetrahydroisoquinolines 47 and 48 has been described by Fulop et al. 34 via nucleophilic addition of 1-or 2naphthol to 3,4-dihydroisoquinolines in MeCN at room temperature for 10-14 days under solvent-free conditions or using microwave irradiation at 70-90 C within 40-60 min. The reactions yielded the corresponding products in 35-85% yields (Scheme 25).
Palmieri et al. 38 introduced a short and stereoselective synthesis of vicinal aminodiols, diamines and diaminols in good yields, through a three-component aromatic Mannichtype reaction. Initially, the reaction of 2-naphthol, enantiopure aldehydes containing stereogenic centres and amines at room temperature in solventless conditions for 12-36 h  Palmieri et al. 43 demonstrated that 1-(aminoalkyl)naphthols 65 can be used as ligands in the nickel-catalyzed enantioselective addition of organozinc to chalcones in CH 3 CN at À30 C to room temperature for 4 h and afforded the corresponding products 66 in 15-99% yields and 14-64% ee (Scheme 34).
Kumar et al. 44 succeeded in the preparation of Betti bases 67 from secondary amine, aromatic aldehydes and 2-naphthol using a non-ionic surfactant (Triton X-100, 5 mol%) at room temperature. All the aromatic aldehydes reacted almost equally well to afford Betti bases aer 2-4.5 h in excellent yields (80-94%) (Scheme 35). Hui et al. 49 have reported an asymmetric aza-Friedel-Cras reaction of 2-naphthol with tosylimines catalyzed by a dinuclear zinc complex. The expected products 73 were obtained in 76-95% yields and good to excellent enantioselectivities of 74-98% ee in toluene at 30 C aer 48 h (Scheme 40).
Addition of (R)-3-phenyl-3,4-dihydroisoquinoline to 2naphthols in water at 80 C overnight led to the formation of (S)-(R)-1,3-disubstituted tetrahydroisoquinolines 74 as chiral ligands in 40-69% yields (Scheme 41). 50 These chiral ligands were then used to catalyze asymmetric addition of diethylzinc to aldehydes in toluene at 0 C for 72 h and the desired Triton X-100 as a non-ionic surfactant catalyst was used for the synthesis of Betti bases 76 from secondary amine, aromatic aldehydes, and 2-naphthol using Mannich-type reaction in water at room temperature. The catalyst gave the best results and the reaction proceeds through imine formation, which is stabilized by colloidal dispersion and undergoes nucleophilic addition to afford the corresponding N,N-dialkylated Betti bases in excellent yields (80-94%) aer 2-4 h (Scheme 43). 52 Olyaei et al. 53 demonstrated a convenient and efficient method for the synthesis of N-heteroarylaminonaphthols 77 by using heteroarylamines such as 2-aminopyrimidine, 2-aminopyrazine, 2-aminopyridine and 3-aminopyridine under solventfree conditions at 125 C. The reactions completed in 4-25 min with products obtained in 87-94% yields (Scheme 44).
Jha et al. 54 have devoted considerable attention to an efficient synthesis of 1-((2-hydroxynaphthalen-1-yl)arylmethyl)piperidin-4-ol prototypes 78 as racemic mixtures via the Mannich reaction protocol from 2-naphthol, 4-piperidinol, and different aromatic aldehydes. The reaction proceeded in the presence of p-TSA as catalyst in ethanol at reux and was complete within 72 h to produce the corresponding products in 6.5-85% yields (Scheme 45). These chiral Mannich bases were then resolved utilizing an enzyme-assisted chemo-, regio-, and enantioselective (Novozyme 435®) acetylation process in CHCl 3 . An eco-friendly method for the synthesis of the Betti bases 1-(a-aminoalkyl)naphthols 83 has been carried out over a basic nanocrystalline MgO catalyst in aqueous condition at room temperature. The reactions worked well with almost all the aldehydes and aliphatic amines within 2-6 h and gave the corresponding products in 78-92% yields (Scheme 48).
Surprisingly, the reaction was not successful with aromatic amines which might be due to their reduced nucleophilicity. 57 Nitro derivative 84 was achieved from treatment of 2-naphthol, 2-nitrobenzaldehyde and tert-butyl carbamate under solvent-free conditions for 47 h at 80 C in 53% yield. In the following experiment, the Boc group was removed with tri-uoroacetic acid, resulting in 85 in 90% yield. This step was followed by reduction of the nitro group by means of catalytic (Pd/C) hydrogenation, yielding 1-(amino(2-aminophenyl) methyl)-2-naphthol (86) (68%). Also, using the reaction of 2naphthol, 2-nitrobenzaldehyde and benzyl carbamate under solvent-free conditions, 87 was synthesized at 80 C aer 32 h in 76% yield. Removal of the protecting group and reduction of the nitro group were accomplished in one step by catalytic (Pd/C) hydrogenation, yielding 86 (69%) (Scheme 49). 58 A synthesis of useful enantiomerically pure arylglycinates 88 via spontaneous reaction between phenol or naphthol derivatives and enantiopure a-imino glyoxylate in toluene at À15 C within 3-10 h in the absence of an acid catalyst was reported. A library of enantiopure substituted phenol or naphthol glycinates was obtained in 58-79% yields and high diastereoselectivities (62-87%) (Scheme 50). Diastereomerically pure aryl glycinates were obtained via ash chromatographic separation of the crude reaction mixture. 59 The cupreine-derived bifunctional organocatalyst BzCPN efficiently catalyzes the formation of aza-Friedel-Cras products 89 in toluene and 4Å MS as the additives from naphthols and N-sulfonylimines within 48 h in good to excellent yields (up to 99%) with high enantioselectivities (up to 99.5 : 0.5 er) under mild reaction conditions, with a low catalyst loading (5 mol%), and in an aerobic environment (Scheme 51). 60 A large library of aminocycloalkylnaphthols 90 is obtained by the Betti reaction between activated naphthols (1-naphthol, 2-naphthol and 4methoxy-1-naphthol) and veand six-membered cyclic imines in CH 2 Cl 2 within 3-7 h at room temperature in 49-81% yields. Betti base derivatives 90 were methylated at the nitrogen atom by cyclization with formaldehyde to the corresponding oxazolidines, followed by reduction with sodium triacetoxyborohydride in THF, to form the corresponding products 91 in yields of 79 and 85% (Scheme 52). 61 Aminoalkylnaphthol derivatives 92 were obtained in 38-47% yields by performing a Mannich reaction between 2-naphthol, 4piperidinol and appropriate 4-(2-(dialkylamino)ethoxy)benzaldehydes in the presence of catalytic amounts of p-toluenesulfonic acid in a microwave reactor aer 7-10 min (Scheme 53). 62 (S)-Betti base 1 was converted into sulfonamide organocatalysts 93 by the reaction with corresponding sulfonyl chlorides in the presence of pyridine in CH 2 Cl 2 at room temperature for 24 h in 12-56% yields. Next, the hetero-Diels-Alder reaction of ethyl glyoxylate with Danishefsky's diene was carried out in a catalytic manner using the chiral sulfonamide 93 (30 mol%) in CH 2 Cl 2 at À20 C for 24 h, followed by treatment with TFA at room temperature for 1 h to obtain corresponding 2-substituted 2,3-dihydropyran-4-ones 94 in 20-86% yields (Scheme 54). 63 Bedekar and Chaudhary 64 achieved 1-(a-aminobenzyl)-2naphthols 95 by the reaction of 2-naphthol, benzaldehyde and primary or secondary amines in absolute alcohol at room temperature for 48 h or under solvent-free condition at 60 C for 24 h in 30-81% yield. Compounds 95 were used as ligands in palladium-catalyzed Mizoroki-Heck reaction in dimethylacetamide in the presence of K 2 CO 3 at 140 C for 40 h with a variety of substrates and afforded trans-stilbene in 60-96% yields. High turnover numbers are observed for the reactions with both aryl bromides and iodides, while aryl chlorides are inert (Scheme 55).
(S,S)-Aminobenzylnaphthols 96 were obtained by a Betti reaction of 2-naphthol, benzaldehyde or p-halobenzaldehyde with (R)-or (S)-1-arylethylamine for two days at 60 C without any solvent in 51-68% yields (Scheme 56). The crystal structures of (S,S)-aminobenzylnaphthols, easily produced by a chromatography-free highly stereoselective Betti reaction, were investigated by means of single-crystal X-ray diffraction analysis, and the main intra-and intermolecular interactions were described. 65 An efficient catalyst-free synthesis of Betti base derivatives via Mannich-type one-pot three-component condensation reaction of 2-aminopyrimidine derivatives, salicylaldehyde and naphthols (2-naphthol, 1-naphthol, 2,7-naphthalenediol and 2,3-naphthalenediol) under solvent-free conditions has been described. The reactions were carried out at 80 C within 25-30 min, affording the desired aminonaphthols 97 in 85-93% yields (Scheme 57). 66 Hosseinian et al. 67 have reported that 1-(benzothiazolylamino)methyl-2-naphthol derivatives 98 are achieved from one-pot, three-component condensation of aldehydes, 2-naphthol, and 2-aminobenzothiazole in the presence of sodium hydrogen sulfate as an effective catalyst at 80 C aer 4-30 min. The reactions worked well with a variety of heterocyclic aldehydes, aliphatic aldehydes, and aryl aldehydes including those bearing electron-withdrawing and electrondonating groups, and the desired compounds were obtained in 52-93% yields (Scheme 58).
A methodology has been developed for the multicomponent one-pot synthesis of aminoalkylnaphthols 99 in 74-95% yields in dichloromethane under catalyst-free conditions at room temperature within 2-3 h. Secondary amines such as piperidine, pyrrolidine, morpholine, N-methylpiperazine, and dimethylamine were used in the reaction and the yields of the desired products were moderate to excellent (Scheme 59). 68 Nanocrystalline TiO 2 -HClO 4 -catalyzed three-component preparation of 1-(a-aminoalkyl)-2-naphthols 100 in 90-93% yields under solvent-free condition at room temperature within 22-30 min has been reported by Shaterian et al. This white acidic heterogeneous catalyst is very stable under the reaction conditions and was reused several times without signicant loss of activity (Scheme 60). 69 Jeong et al. 70 described Cu(OTf) 2 $SiO 2 (10 mol%)-catalyzed three-component coupling of aldehyde, 2-naphthol, and alicyclic amine to generate Betti bases 101 in 72-95% yields under neat conditions at room temperature to 40 C aer 0.5-3 h without additional co-catalyst or additive in air (Scheme 61).
Betti bases 102 were obtained in 76-94% yields via the condensation reaction of aromatic aldehydes, secondary amines and 2-naphthol in PEG-400 as solvent in the absence of catalyst at room temperature aer 2-4 h. In this reaction, aromatic aldehydes and heteroaromatic carbaldehydes worked satisfactorily, but the reaction with aromatic amines was not successful (Scheme 62). 71 Song et al. 72 developed a new method for the synthesis of enantiomerically pure Betti bases 103. By using triuoroacetic acid to replace the more traditionally used hydrochloric acid, the hydrolysis procedure used in the classical synthesis of racemic Betti base was carried out at 50 C in CH 2 Cl 2 /H 2 O with an improved yield (up to 96%), which was followed by a new and efficient resolution using recyclable (R)-1,1 0 -binaphthalene-2,2 0diyl sodium phosphate to provide enantiomerically pure (S)-Betti base 103a in 95% yield with up to 99% ee and (R)-Betti base 103b in 93% yield with 90% ee in one resolution step (Scheme 63).
A series of chiral aminonaphthols 104 has been synthesized diastereoselectively in 33-82% yields by applying a solvent-free 'Betti-type' condensation using 2,6-and 2,3-dihydroxynaphthalenes, 2-naphthol, (S)-phenylethylamine as a chiral auxiliary, and aldehydes at 80 C aer 24 and 72 h (Scheme 64). The major diastereomers (90-96%) formed could be isolated in pure form. 73 These chiral aminonaphthols have been used as precatalysts for the addition of diethylzinc and alkynylzinc reagents to aldehydes in toluene at room temperature with enantioselectivities of up to 98% and 50% ee, respectively. Ganesan et al. 74  Sulfanilic acid-functionalized silica-coated nano-Fe 3 O 4 particles (MNPs-PhSO 3 H) as an efficient, reusable and magnetically separable catalyst has been studied for the solventfree synthesis of 1-aminoalkyl-2-naphthols 108 at 120 C. Treatment of a variety of aldehydes and 2-naphthol with heterocyclic amines afforded the corresponding 1-aminoalky-2naphthol derivatives in 81-92% yields aer 10-20 min (Scheme 67). The reaction with the usual aromatic amines such as aniline and p-toluidine afforded Schiff bases instead of the corresponding aminoalkylnaphthols. 76 A reaction of triethyl phosphite with 3-alkyl-1phenylnaphthoxazines in the presence of halotrimethylsilanes in toluene with subsequent removal of the trimethylsilyl group by hydrolysis furnished diastereomeric a-aminoalkylphosphonic derivatives of Betti base 109. The highest diastereomeric excess was observed in the reaction with bromotrimethylsilane at low temperature (Scheme 68). 77 Aminobenzylnaphthols 110 and 111 were synthesized in 36 and 37% yields via the reaction of 2-naphthol, arylaldehyde and (S)-or (R)-prolinol at 60 C under solvent-free conditions for two days (Scheme 69). These aminobenzylnaphthols, synthesized from different components and thus having different structural features, were tested as anti-yeast agents inhibiting Candida albicans. The activity towards C. albicans of these prolinol derivatives was interesting and could represent a promising alternative to overcome the problem of strains resistant to the traditional antifungals. 78 A reaction of triethyl phosphite with 3-alkyl-1phenylnaphthoxazines in the presence of halotrimethylsilanes in toluene at À30 C for 6 h with subsequent removal of the trimethylsilyl group by hydrolysis furnished diastereomeric aaminoalkylphosphonic derivatives of Betti base 112 with high diastereoselectivity (de up to 75%) (Scheme 70). 79 4-Aminoantipyrine derivatives 113 were achieved in 92-95% yields by the condensation of aromatic aldehyde, 4-aminoantipyrine, and 8-hydroxyquinoline in the presence of uorite as catalyst in ethanol at room temperature for 10-15 min (Scheme 71). All derivatives showed in vivo and in vitro anti-inammatory and anthelmintic activities against reference drugs diclofenac and albendazole. 80 Jana et al. 81 reported the reaction of 2-hydroxynaphthaldehyde with two equivalents of pyrrolidine in xylene under microwave irradiation at 170 C within 20 min, giving 2hydroxy-1-naphthylmethylamine (114) as the major product. Similarly, various aldehydes and ketones were reacted with different cyclic saturated amines producing structurally diverse mono-or di-arylmethylamines 114 in 60-74% yields (Scheme 72).
Shahrisa et al. 86 have obtained arylaminonaphthols 119 from the condensation of 2-naphthol, aldehydes, and arylamines in the presence of N,N-dimethylethanolamine (7.5 mol%) as an organocatalyst at 50 C under solvent-free conditions. The reaction of aromatic and heteroaromatic aldehydes with piperidine, morpholine, aromatic amines and heteroarylamines in the presence of catalytic amounts of DMEA also afforded desired products aer 30-45 min in 83-95% yields (Scheme 77).
The rst example of incorporating the oxindole moiety into Betti bases has been reported by Yan et al. 87 The new type of Betti bases 120 were conveniently synthesized in 42-88% yields from the three-component reaction of 2-naphthol, isatins and cyclic amines, such as piperidine or morpholine, in CH 2 Cl 2 at reux within 24 h without any other catalyst (Scheme 78). Other secondary amines, such as pyrrolidine, dimethylamine, diethylamine, and di(n-propyl)amine, and a-naphthol, resorcinol, and pyrogallol did not afford the expected products under similar reaction conditions.
An efficient method has been described for the synthesis of 2-aminobenzothiazolomethylnaphthol derivatives 123 by onepot three-component reaction of aldehydes, 2-naphthol, and 2-aminobenzothiazole using Triton X-100 as a catalyst in water at 60-65 C within 1.0-1.8 h in 75-95% yields (Scheme 81). It was shown that the synthesized derivatives demonstrated good antimicrobial activity against Gram-positive and Gram-negative bacteria and antifungal activity against fungal strains such as Aspergillus niger, Aspergillus fumigatus, and Aspergillus avus. 90 Wu et al. 91 demonstrated for the rst time a straightforward and one-pot strategy to synthesize the bifunctional phosphorus Betti bases 124 in 52-95% yields under solvent-free conditions at 180 C within 0.5-2 h via the condensation of 2-naphthol, arylaldehydes and diphenylphosphine oxide in the presence of p-toluenesulfonic acid (Scheme 82). The procedure worked well with almost all the aldehydes.
Abdel Hameed et al. 92 reported an efficient multicomponent, one-pot synthesis of Betti bases 125 catalyzed by cerium(IV) ammonium nitrate (CAN) (10 mol%) in MeOH as solvent at ambient temperature. The reaction worked well for representative anilines, morpholine, piperidine and aromatic aldehydes, and led to the formation of the desired products aer 10-50 min in 80-92% yields (Scheme 83).
The work of Nasr-Esfahani et al. 93 demonstrated that various Betti bases 126 could be synthesized in one-pot threecomponent condensation of aldehydes, 2-naphthol, and cyclic and acyclic amines in the presence of aluminatesulfonic acid nanoparticles (ASA NPs) (10 mol%) as recoverable catalyst at 80 C under solvent-free conditions. Aromatic aldehydes containing either electron-donating or electron-withdrawing groups reacted successfully and gave the products within 10-24 min in 88-94% yields (Scheme 84).
Meshram et al. 95 synthesized a series of sulfonamides fused with Betti bases 128 in 63-80% yields by the reaction of substituted 1-(amino(phenyl)methyl)naphthalen-2-ol and acetamidobenzenesulfonyl chloride in DMF and triethylamine at 150 C for 10-12 hours (Scheme 86). On the basis of the results obtained from docking studies, some of the synthesized sulfonamide derivatives 128 might show signicant anticancer activity by inhibiting DNA topoisomerase II.
Novel Betti bases 135 based on kojic acid derivatives have been synthesized by coupling 2-naphthol, aniline derivatives and kojic aldehyde in the presence of Fe 3 O 4 @SiO 2 -boric acid nanocatalyst at 40 C min under solvent-free condition (Scheme 92). The reactions were carried out efficiently within 55-60 min and the desired products obtained in 87-90% yields. 101 Georgieva et al. 102 synthesized several Betti bases 136 by a modied Betti reaction via the condensation reaction of primary heterocyclic amine, aromatic aldehydes, 8-quinolinol and halogeno-substituted aromatic aldehydes. The reaction mixtures were allowed to stand for 21 days in absolute ethanol at room temperature in a closed ask affording the corresponding products in yields of 80-98% (Scheme 93).
Subsequently they were evaluated for cytotoxicity against breast cancer (MCF-7) and colon cancer (HCT116) cell lines. Regarding the cytotoxicity, the relative inhibition activity was notably found to be moderate to high in MCF-7 cell line. Also, they were docked into the active site of phosphoinositide 3kinase (PI3K) (PDB ID: 4JPS) which is a crucial regulator of apoptosis or programmed cell death. Results showed that the hydrophobic interactions in the binding pockets of PI3K exploited the affinity of the most favorable binding ligands.
Cost-effective green chemical methods are reported for the one-pot multicomponent solventless synthesis of 1-aminoalkyl-2-naphthol 139 in 52-90% yields by the reaction of vanillin, 2naphthol and 4-nitroaniline in the presence of tannic acid as a Lewis acid catalyst. A mixture was stirred by following various green protocols such as oil bath at 120-125 C for 10-15 min, microwave irradiation at 100 W for 1-4 min, hot plate with magnetic stirrer at about 120-125 C for 20-25 min, grindstone method for 10-15 min and nally conventional heating method with a few drops of methanol at reux for 60-90 min (Scheme 96). Antibacterial activity of the synthesized compound against Bacillus subtilis was tested by zone inhibition method, showing negligible inhibition against the growth of this bacterium. 105 Cardellicchio and Capozzi 106 succeeded in the preparation of aminobenzylnaphthol 140 bearing two stereogenic centers from the condensation of 2-naphthol, arylaldehydes and valine methyl ester at 60 C under solvent-free condition for two days or in Et 2 O at 35 C for two days in 35-68% yields (Scheme 97).
The Betti bases 141 in 52 and 62% yields were obtained from the reaction of (S)-5-{[(tert-butyldimethylsilyl)oxy]methyl} pyrrolidin-2-one or (S)-5-(azidomethyl)pyrrolidin-2-one and 2naphthol in dry CHCl 3 under microwave irradiation at 120 C for 2 h (Scheme 98). 107 Bosica et al. 108 reported that the reaction of 2-naphthol, aromatic aldehydes and amines in the presence of montmorillonite K30 as a heterogeneous catalyst at 60 C under neat conditions yielded aminocycloalkylnaphthols 142 aer 2-12 h. The catalyst is fully recoverable and recyclable for up to 5 runs. Furthermore, it could catalyze reactions involving both secondary and primary aliphatic amines to give products usually in 37-92% yields (Scheme 99).
Synthesis of Betti base derivatives 144 catalyzed by nano-CuO-ionic liquid has been reported from the reaction of 2naphthols, aromatic aldehydes and cyclic amines in [BMIM] [OH] at 60 C. The desired products were obtained in a short period of time (40-60 min) in good yields (81-90%) (Scheme 101). All of the synthesized aminonaphthol derivatives 144 exhibit good inhibitory effects toward mild steel corrosion with inhibition efficiencies in the range of 84-95%. Therefore, these compounds can be practically used as effective corrosion inhibitors for acid pickling applications. 110 Janati 111 introduced a nanocomposite of Fe 3 O 4 /cellulose/ vitamin C as a new biopolymer catalyst for synthesis of pharmacologically active 1-(a-aminoalkyl)naphthols 145 via a onepot condensation of 2-naphthol, alkylamines and aldehydes at room temperature within 20-55 h under solvent-free conditions in 80-95% yields (Scheme 102).
g-Aminobutyric acid (GABA) and isinglass, a collagen peptide, have been utilized as highly efficient bifunctional biocatalysts for the efficient and convenient synthesis of 2aminobenzothiazolomethyl-2-naphthols through a one-pot three-component Mannich reaction between diverse aldehydes, 2-naphthol and 2-aminobenzothiazole under solventfree condition in high yields. The reaction in the presence of GABA (10 mol%) was carried out under a microwave irradiation power of 900 W for 3-5 min and with isinglass at 110 C for 85-125 min to afford the desired products 147 in 87-97% and 80-95% yields, respectively (Scheme 104). 113 Application of novel 1,2,3-triazolylferrocene-containing ionic liquid supported on Fe 3 O 4 nanocatalyst in the synthesis of new pyran-substituted Betti bases 148 has been reported by Safa et al. 114 The catalytic activity of the magnetic nanoparticles was evaluated in the one-pot three-component synthesis of a wide variety of Betti bases 148 in 85-96% yields from kojic aldehyde, 2-naphthol or 6-bromo-2-naphthol and aniline derivatives in EtOH-H 2 O at room temperature for 40-50 min (Scheme 105).
Synthesis of 1-(a-aminoalkyl)-2-naphthol derivatives 149 employing combined ultrasonic/Mo Schiff base complex immobilized on Fe 3 O 4 nanoparticles (Fe 3 O 4 @SiO 2 @MoSB) as a heterogeneous acid catalyst has been reported via the reaction of 2-naphthol, aromatic aldehydes and 2-, 3-or 4-aminopyridine under ultrasound irradiation without solvent at room temperature. All the reactions proceeded equally smoothly and afforded the desired products in 85-97% yields and short reaction time within 10-40 min irrespective of the nature of the substituents (Scheme 106). Additionally, binding interactions of 1-(phenyl(pyridin-2-ylamino)methyl)naphthalen-2-ol with various types of rigid DNA and HSA have been investigated by molecular modeling study. In vitro studies under physiological conditions showed that the desired derivative interacts with calf-thymus DNA via an intercalative binding mode. 115 Fathalipour et al. 116 studied aqueous suspension of biocompatible reduced graphene oxide-AuNPs composite (rMGO-AuNPs) as an effective recyclable catalyst in a Betti reaction. In this process, 1-(a-aminoalkyl)naphthols 150 were obtained at 50 C under solvent-free conditions aer 20-60 min in 80-95% yields (Scheme 107).

Synthesis of bis-Betti base derivatives and synthetic applications
Among Betti bases, the bis derivatives are less studied. Zhang et al. 117 reported new kinds of chiral alkylaminobenzylnaphthols (bis-Betti bases) 151 and 152 enantioselectively synthesized for the rst time via the reaction of methylbenzylamine, dialdehydes and 2-naphthol in THF at 80 C for 24 h in 32 and 45% yields, respectively. Subsequently, treatment of bis-Betti bases 151 and 152 with formaldehyde in the presence of TFA in THF at room temperature for 4 h followed by reduction with LiAlH 4 within 5 h in THF at 80 C afforded bis-Betti bases 153 and 154 in 60 and 69% yields, respectively (Scheme 108).
Xiong 118 described a short and facile synthesis of bis-Betti bases 155 with two chiral carbon centers via the reaction of 2,6-dihydroxynaphthalene, piperidine or morpholine and cyanobenzaldehyde at 100 C under reux condition, affording the anticipated products in 81-86% yields (Scheme 109). This reaction has two steps. Firstly, the reaction of 2,6-dihydroxynaphthalene with cyanobenzaldehyde and piperidine or morpholine affords mono-Betti base products. And then, mono-Betti base product is used as 2naphthalene continuously to react with excess cyanobenzaldehyde and piperidine or morpholine to give the nal bis-Betti base products.
Microwave-assisted synthesis of bis-Mannich bases 156 and 157 of 2-naphthols derived from aromatic aldehydes and diamines namely piperazine and N,N 0 -dialkylethylenediamines was studied under two conditions, as follows: (A) solvent-free microwave irradiation using a CEM Discover S Class microwave oven at 125 C for ve minutes in the absence of any catalyst; (B) reux in ethanol for 72 h in the presence of catalytic amount of pTSA (Scheme 110). 119 Weng and Li 120 disclosed that bis-Betti base-derived tetradentate ligand 158 could be synthesized by the reaction of Betti base with glyoxal in MeOH at room temperature for 6 h. The combination of CuI, Cs 2 CO 3 , DMF-MeCN and the proper amount of 158 was a more efficient system to catalyze the N-arylation of imidazoles at 120 C within 24 h. To explore the scope of this catalytic system, a variety of aryl bromides and aryl chlorides were examined, and the corresponding products in 40-91% yields were obtained (Scheme 111).
An efficient, expeditious, and diastereoselective one-pot pseudo-ve-component reaction for the synthesis of bis-Betti bases 159 and 160 has been reported. The reaction of 2,3-dihydroxynaphthalene or 2,6-dihydroxynaphthalene, two equivalents of arylaldehydes, and two equivalents of 3-amino-5methylisoxazole was carried out at 80 C under solvent-free conditions within 0.5-6 h, affording the corresponding products in 70-95% yields (Scheme 112). 121 Bis-Betti bases 161 and 162 have been synthesized diastereoselectively by applying a solvent-free 'Betti-type' condensation using 2,6-dihydroxynaphthalene, (S)-phenylethylamine, and mmethylbenzaldehyde or 1-naphthaldehyde at 80 C for 48 h. The major diastereomers formed could be isolated in pure form (Scheme 113). 73 A mild, efficient and straightforward method has been developed for the synthesis of bis-Betti bases 163 via a pseudo-vecomponent, one-pot condensation reaction of heteroarylamines, terephthaldehyde and naphthols in the presence of formic acid as catalyst at 80 C within 5-20 min under solvent-free conditions (Scheme 114). A wide range of heteroarylamines with electrondonating and electron-withdrawing groups and naphthols were well tolerated under the reaction conditions and afforded products in 85-92% yields. 122 A simple and efficient procedure for the synthesis of bis-Betti bases 164 via a one-pot pseudo-ve-component reaction of one equivalent of 2,3-dihydroxynaphthalene, two equivalents of arylaldehydes, and two equivalents of heteroarylamines in the presence of formic acid catalyst at 80 C for 50-115 min under solventfree conditions has been described. This reaction worked well with heteroaromatic amines such as 2-aminopyrimidines and 2-aminopyridine derivatives and afforded desired products in 81-91% yields (Scheme 115). 123 Abdul and Hussain 124 have exploited an efficient method for the synthesis of N,N 0 -bis-[(2-hydroxynapthalene-1-yl)(substituted phenyl)methyl]-2,6-diaminopyridine derivatives 165 by one-pot three-component reaction of 2-naphthol, 2,6-diaminopyridine and substituted aromatic aldehydes in ethanol at 80 C within 24-120 h and under microwave irradiation within 2-6 min at high power (400-900 W) without any catalyst. The isolated yields in ethanol condition (up to 98%) are higher than in microwaveassisted solvent-free condition (up to 42%) (Scheme 116).

Conclusions
The high number of publications in the literature that have recently appeared on the syntheses of Betti bases and bis-Betti base derivatives with different methods using various types of naphthols, amines and aldehydes in various conditions indicates the importance of these compounds. These procedures are commonly classied as Mannich aminoalkylations. The non-racemic nature of the Betti base and derivatives could be of special interest for organic chemists working in the eld of ligand-metal catalyzed reactions. It is also clear that the most important area of application of the non-racemic aminonaphthols is their use in asymmetric transformations, either as chiral ligands or as chiral auxiliaries. Investigation of Betti base structures indicated that some of these products possess biological activity. However, in spite of the number of structures reported, it is possible to synthesize and investigate applications of the various structures of these compounds due to their importance.

Conflicts of interest
There are no conicts to declare.