Design of Two Alternative Routes for the Synthesis of Naftifine and Analogues as Potential Antifungal Agents.

Two practical and efficient approaches have been implemented as alternative procedures for the synthesis of naftifine and novel diversely substituted analogues 16 and 20 in good to excellent yields, mediated by Mannich-type reactions as the key step of the processes. In these approaches, the γ-aminoalcohols 15 and 19 were obtained as the key intermediates and their subsequent dehydration catalyzed either by Brønsted acids like H₂SO₄ and HCl or Lewis acid like AlCl₃, respectively, led to naftifine, along with the target allylamines 16 and 20. The antifungal assay results showed that intermediates 18 (bearing both a β-aminoketo- and N-methyl functionalities in their structures) and products 20 were the most active. Particularly, structures 18b, 18c, and the allylamine 20c showed the lowest MIC values, in the 0.5-7.8 µg/mL range, against the dermatophytes Trichophyton rubrum and Trichophyton mentagrophytes. Interesting enough, compound 18b bearing a 4-Br as the substituent of the phenyl ring, also displayed high activity against Candida albicans and Cryptococcus neoformans with MIC80 = 7.8 µg/mL, being fungicide rather than fungistatic with a relevant MFC value = 15.6 µg/mL against C. neoformans.

1. Introduction

Allylamines represent one of the most important primary units in organic chemistry [1]. They are important synthetic precursors for β-aminoacids [2], alkaloids [3] and carbohydrate derivatives [4]. Among the synthetic allylamines of biological importance, it is worth mentioning cinnarizine (1), used for the treatment of vertigo and related cerebral disorders [5], abamine (2), an important tool to elucidate the mechanisms that regulate the levels of abscisic acid (ABA) in plants and animals [6], terbinafine (brand name Lamisil) and naftifine (brand name Naftin) that are effective antifungal agents. Naftifine is a topical allylamine that is effective against a broad spectrum of dermatophyte fungi of the Trichophyton and Microsporum spp., and has also shown good activity against Candida and Aspergillus spp. Terbinafine represents the most effective of this chemical class of antimycotic compounds. Terbinafine proved to be highly active against dermatophytes and Sporothrix schenckii and also exerts good activity against several yeasts [7,8,9] (Figure 1).

Figure 1

Some allylamines with important biological activities.

Since naftifine was discovered, different synthetic routes have been developed to obtain it and some of its analogues. Among them, Stütz et al. obtained naftifine in 94% yield via a cinnamyl Schiff´s base (Scheme 1, entry 1) [10], Petasis et al. obtained it in 82% yield via a trans-2-phenylvinylboronic acid coupling reaction (Scheme 1, entry 2) [11], and Correia et al. synthesized it in 68% yield via a Heck-type reaction (Scheme 1, entry 3) [12].

Scheme 1

Some previous synthetic approaches for the synthesis of naftifine.

Despite the good performance of the allylamines as antifungal agents, there have been some cases in which they have failed in the treatment of patients who have shown antifungal resistance toward some of these drugs [13,14]. These findings suggest the need of looking for new methods and synthesis of new potential antifungal agents inspired in naftifine that can be used as alternatives to the existing ones.

As part of our current program on the synthetic utilization of benzylamine derivatives [15,16,17], herein we wish to report our results on the synthesis of naftifine and analogues through two alternative synthetic strategies mediated in both cases by Mannich-type reactions.

2. Results and Discussion

2.1. Chemistry

In view of the above, we envisioned that our previous results on the synthesis of γ-aminoalcohols type 15 and 19 [18,19], could be exploited as alternative approaches for the synthesis of naftifine and analogues mediated by Mannich-type reactions. In this direction, two straightforward strategies, shown in Scheme 2 and Scheme 3, were proposed. Strategy 1 consisted on the synthesis of γ-aminoalcohols 15 via a three-component Mannich-type reaction between secondary amines 13, (see Figure 2), formaldehyde and activated alkenes 14. Subsequently, a dehydration of 15 should afford the expected allylamines 16, as shown in Scheme 2. It is remarkable that from Strategy 1, products 16 could be formed by a combination of both Mannich- and aza-Prins-type reactions in a one pot sequence if acid is used as catalyst since Step 1. It is worth mentioning that, the N-vinylpyrrolidin-2-one 14a and 2,3-dihydrofuran 14b were chosen in this strategy along with styrene 14c as activated alkenes, due to the fact that these two heterocyclic rings can be found forming part of the structures of synthetic compounds with outstanding antifungal activities [20,21,22,23]. For that reason we supposed that the presence of these heterocycles instead of the phenyl ring in the naftifine analogues (i.e., X = heterocycle in 16), along with the allylamine moiety in the same structure could produce enhanced effects in the antifungal assays.

Scheme 2

Designed alternative route for the synthesis of naftifine-analogues 16 by combination of a three-component Mannich- and aza-Prins-reactions.

Scheme 3

Designed alternative route for the synthesis of naftifine and analogues 20 from a reduction/dehydration strategy.

Figure 2

Set of secondary amines 13 used for the synthesis of the intermediate γ-aminoalcohols 15.

The proposed Strategy 2 consisted in the synthesis of γ-aminoalcohols 19 via reduction of their corresponding β-aminoketones 18. The subsequent dehydration of 19 should also afford a second family of allylamines 20, as shown in Scheme 3.

Prior to starting, it is worth mentioning that the non-commercial secondary amines 13a–f (Figure 2), were synthesized from their corresponding primary amines and different aryl aldehydes via a reductive amination reaction [15,16,17].

Initially, with the aim of obtaining the allylamines 16, described in Scheme 2, an acid-catalyzed one-pot approach was planned in order to obtain products 16 directly in a one-step sequence (involving an in situ dehydration), without isolation of their corresponding γ-aminoalcohol intermediates 15 (i.e., from a combination of both Mannich- and aza-Prins-type reactions). Thus, as a model reaction, a mixture of amine 13a (1.0 mmol), formaldehyde (1.5 mmol) and alkene 14a (1.0 mmol) in acetonitrile (ACN) was treated with a catalytic amount of conc. H2SO4 at room temperature for 24 h. The thin-layer chromatography (TLC) analysis showed the formation of a complex mixture of products. Then, the reaction mixture was neutralized with NaOH and their components were separated by column chromatography affording the expected allylamine 16a in only 11% yield along with unreacted starting amine 13a and pyrrolidin-2-one (the acid-catalyzed degradation product from 14a) [24] (Scheme 4).

Scheme 4

Attempts for acid-catalyzed synthesis of allylamine 16a via a one-step sequence.

In an attempt to improve the yield of product 16a the reaction was repeated with other both stronger (HCl) and milder protic acids (i.e., oxalic, acetic and formic), but unfortunately, with the same behavior and low product yield (Scheme 4). Similar results were obtained when 14a was replaced by 2,3-dihydrofuran as activated alkene. In a further experiment, the same model reaction depicted in Scheme 4 was performed, but using styrene instead of alkene 14a in the presence of H2SO4. After purification and characterization of the product, we were delighted to confirm that naftifine was obtained in an acceptable 65% yield. The higher stability of styrene in acidic medium in comparison with alkene 14a and 2,3-dihydrofuran (both structures decomposes in such conditions), permitted the selective formation of naftifine in a one-pot procedure (by combination of both Mannich- and aza-Prins-type reactions), as initially was planned in Strategy 1 (Scheme 2).

Due to the above drawbacks of the acid-catalyzed one-step reaction, when 14a and 2,3-dihydrofuran were used as activated alkenes, we decided to move the process to a two-step sequence involving the isolation of the γ-aminoalcohol intermediates 15 (Scheme 2). Starting with Step 1 of Strategy 1 depicted in Scheme 2, a set of γ-aminoalcohols 15a–k (Figure 3), was obtained by following our previously established catalyst-free three-component methodology [19]. Thus, a mixture of secondary amines 13 (1.0 mmol, Figure 2), polyformaldehyde (1.5 mmol) and the corresponding activated alkene 14 (1.0 mmol) was stirred at room temperature in ACN to afford the corresponding γ-aminoalcohols 15 in good yields (Figure 3).

Figure 3

Set of γ-aminoalcohols 15 obtained via a three-component Mannich-type reaction.

Subsequently, after several failed attempts to optimize the dehydration reaction mediated by different Brønsted-Lowry acids (Scheme 2, Step 2), the expected allylamines 16 were obtained by subjecting the corresponding γ-aminoalcohols 15 (1.0 mmol) to reflux in 1,4-dioxane as the solvent in the presence of AlCl3 (1.0 mmol) as Lewis acid catalyst. After neutralization with triethylamine (TEA) and purification, the expected compounds 16 were obtained in in acceptable to excellent yields (Scheme 2, Step 2). Scheme 5 depicts the structures of the new allylamines 16 obtained from Strategy 1 (Scheme 2), in a two-step sequence.

Scheme 5

New allylamines 16 obtained by dehydration of the γ-aminoalcohols 15 catalyzed by AlCl3. a Naftifine was obtained from Strategy 1 in a one-pot fashion starting from styrene and catalyzed by sulfuric acid.

Regarding Strategy 2, depicted in Scheme 3, we could optimize steps 1 and 2 to obtain satisfactory yields of the expected γ-aminoalcohols 19–20 (Figure 4) in a one-pot reaction by treating amines 13 (1.0 mmol) with propiophenone salts 17a–f (1.0 mmol) in a mixture of 1,4-dioxane/TEA at reflux. Compounds 17 were obtained from a Mannich reaction between the corresponding acetophenones, dimethylamine hydrochloride and polyformaldehyde in ethanol at reflux [25]. After removing the solvent, the obtained crude products (corresponding to the β-aminoketones 18), were reduced by treatment with NaBH4 in MeOH affording the expected γ-aminoalcohols 19–20 in good to excellent yields (Figure 4).

Figure 4

Set of γ-aminoalcohols 19–20 obtained via a one-pot SN/reduction sequence from amines 13f and 13h and propiophenone salts 17a–f.

Once we obtained the set of aminoalcohols 19–20 (Figure 4), we attempted a couple of trials leading to the expected naftifine and its analogues 21–22. Thus, the expected naftifine and analogues 21–22 were obtained in good to excellent yields by refluxing 19–20 in 5N HCl (Step 3), followed by neutralization with NaOH and purification. Scheme 6 depicts the structures of the new allylamines 21–22. It is remarkable that naftifine was obtained using Strategy 2 in a very good yield (90%). This value is comparable with the 94% yield obtained previously by Stütz et al., and higher than those obtained through either Petasis or Correia´s methodologies, as shown in Scheme 1. A further advantage of our Strategy 2 is the easy availability of the starting materials used, the simplicity of the processes involved and a major structural diversity in comparison with previous reports.

Scheme 6

Naftifine and analogues 21–22 obtained by dehydration of the γ-aminoalcohols 19–20 catalyzed by 5N HCl.

Finally, structures for all the new compounds obtained from strategies 1 and 2 were fully assigned by IR, NMR, elemental analysis and mass spectra, (see also Supplementary Materials).

2.2. Antifungal Activity Studies

Minimum inhibitory concentrations (MIC) of compounds 15–22 were determined with the Clinical and Laboratory Standards Institute (CLSI) microbroth dilution methods M27-A3 for yeasts and M38-A2 for filamentous fungi [26,27], against a panel of eight fungal clinically relevant species comprising two yeasts (Candida albicans and Cryptococcus neoformans), three Aspergillus spp. (A. niger, A. fumigatus, and A. flavus) and three dermatophytes (Trichophyton rubrum, T. mentagrophytes and Microsporum gypseum). Compounds were tested at serial two-fold dilutions from 250 to 0.5 μg/mL. Compounds with MICs > 250 μg/mL were considered inactive; between 250–125 μg/mL low active, and in the range 62.5–20 μg/mL, moderately active. MICs below 20 μg/mL was considered as indicative of high activity. From the obtained MIC values of compounds 15–22, some conclusions can be drawn:

In general, the series of precursors 15 and products 16 were significantly less active than the series of precursors 18–20 and products 21–22.

Almost all compounds 15–22 showed either very low to moderate activities or were inactive against A. flavus, A. niger and M. gypseum (data not shown).

Compounds 15–22 identified with the letters a and d–k showed moderate to low (31.2–250 µg/mL) activities against the rest of the fungal panel (data not shown).

Among compounds 18–22, the structures 18b, 18c and 21c displayed outstanding activities against one or more dermatophytes (0.5–7.8 µg/mL), (Table 1), while 19b was moderately active (MICs = 31.2–62.5 µg/mL) against four of the fungi tested (i.e., C. neoformans, M. gypseum, T. rubrum and T. mentagrophytes), being the only compound of the series showing activity against M. gypseum. It is worth to take into account that the most active compounds within 18–22 possess a CH3 group as R substituent although with variations in the substituent R1 of the phenyl ring. This finding is in accordance with the required features found by Stütz et al. for the allylamines to display antifungal activity [10].

Table 1

MIC values (µg/mL) of allylamine derivatives 18, 19 and 21 acting against human opportunistic pathogenic fungi. MIC/MFC values are recorded in µg/mL.

Compound		R	R1	Ca	Sc	Cn	Afu	Afl	An	Mg	Tr	Tm
18	b	CH3	4-Br	15.6/62.5	15.6/31.3	7.8/15.6	7.8/15.6	250/250	250/>250	>250/>250	3.9/3.9	2.0/2.0
	c	CH3	3,4-OCH2O	125/125	125/125	31.25/62.5	31.3/62.5	250/250	250/>250	>250/>250	7.8/15.6	7.8/15.6
19	b	CH3	4-Br	125/250	125/250	62.5/125	250/>250	250/>250	250/>250	62.5/125	31.2/62.5	31.2/62.5
	c	CH3	3,4-OCH2O	>250	>250	>250	>250	>250	>250	250/250	250/250	250/250
21	b	CH3	4-Br	250	>250	>250	>250	>250	>250	125/>250	125/>250	125/>250
	c	CH3	3,4-OCH2O	125/>250	250/250	125/250	250/>250	250/>250	250/>250	125/>250	1.0/1.8	0.5/1.0
Amphotericin B				1.0/1.0	1.0/1.0	1.0/2.0	2.0/2.0	2.0/2.0	2.0/2.0	0.5/0.5	0.5/0.5	0.5/0.5
Terbinafine				-	-	-	-	-	-	0.008/0.015	0.004/0.008	0.004/0.015

Ca: Candida albicans ATCC 10231, Sc: Saccharomyces cerevisiae ATCC 9763, Cn: Cryptococcus neoformans ATCC 32264, An: Aspergillus niger ATCC 9029, Afl: Aspergillus flavus ATCC 9170, Afu: Aspergillus fumigatus ATCC 26934, Mg: Microsporum gypseum CCC 115, Tr: Trichophyton rubrum CCC 113, Tm: Trichophyton mentagrophytes ATCC 9972.

Compound 18b was the most active of the whole series, showing activity not only against dermatophytes but also against Candida spp., S. cerevisiae, C. neoformans and A. flavus (MICs between 7.8 to 15.6 µg/mL). From these results it is clear that within the compounds bearing 4-Br and 3,4-methylenedioxy R1 substituents, the β-aminoketones 18 displayed the best activities, suggesting that the ketone group play an important role in the antifungal activity of these structures. Instead, among the γ-aminoalcohols 19–20, only 19b showed moderate activity against dermatophytes and C. neoformans, while its corresponding allylamine 21b displayed very low activities (MICs = 125–250 µg/mL) against the whole fungal panel. It is remarkable that allylamine 21c displayed the most outstanding activities against T. rubrum and T. mentagrophytes (MICs = 0.5–1.0 µg/mL) constituting this datum a finding that deserves great attention for future research.

It is worth taking into account that compound 18b displayed high activity against all yeasts as well as A. fumigatus. This finding constitutes an interesting result, since previous studies of naftifine-analogues reported no activity against this fungal species [10,28].

In order to have a look into the potential usefulness of 18b against clinically relevant yeasts, we investigated the fungal inhibition percentages displayed by 18b against C. albicans and C. neoformans at concentrations obtained by two fold-dilutions from 250 to 3.9 µg/mL. In addition, the inhibition percentages of 19b and 21b were also determined for comparative purposes against the two clinically important fungal species. With these data, two graphs showing inhibition % (Y axis) vs. concentration (X axis), were constructed (Figure 5). The selection of these two fungal species for deepening the studies of the antifungal behavior of 18b, was due to their clinical relevance. C. neoformans is the main cause of cryptococcal meningoencephalitis among HIV patients with impaired defenses that many times led to disease relapse and death [29,30]. In turn, C. albicans is the fourth leading cause of nosocomial bloodstream infection (BSI) in intensive care units, causing fatal invasive candidiasis in a high percentage of patients [31]. For these reasons, new compounds that show new potential anticandidal or anti-cryptococcal drugs are highly welcome.

Figure 5

Comparative antifungal activities of compounds 18b, 19b, 21b possessing the same R1 substituent but differing in their functional groups (i.e., 18b is a β-ketoamine; 19b a γ-aminoalcohol and 21b an allylamine). (A) against C. albicans; (B) against C. neoformans. Amphotericin B (Amp B) inhibits 100% growth at 1.0 µg/mL against C. albicans and at 0.5 µg/mL against C. neoformans. Curves of Amp B are not included.

In Figure 5A,B the higher percentage of inhibition of C. albicans and C. neoformans by 18b in comparison with 19b and 21b can be clearly observed, suggesting that the β-aminoketo structure plays an important role in the anti-yeast activity of this naftifine-analogue. As an example, while 18b showed 80% inhibition of C. albicans at 7.8 µg/mL, 19b and 21b inhibited less than 10% and similar results can be observed against C. neoformans. Table 2 shows the inhibition percentages values displayed by the above three compounds used to construct Figure 5.

Table 2

The inhibition percentages values and Minimum Inhibitory Concentrations (MIC100, MIC80 and MIC50) and Minimum Fungicidal Concentration (MFC) of the naftifine-analogues 18b, 19b and 21b against C. albicans (Ca) and C. neoformans (Cn).

Compound		Fungus	Concentrations of the Compounds (µg/mL)							MIC (µg/mL)			MFC (µg/mL)
			250	125	62.5	31.2	15.6	7.8	3.9	MIC100	MIC80	MIC50	MFC
18b		Ca	100	100	100	100	100	87.4 ± 1.7	28.8 ± 2.6	15.6	7.8	7.8	62.5
		Cn	100	100	100	100	100	98.9 ± 3.6	39.3 ± 3.7	7.8	7.8	7.8	15.6
19b		Ca	100	100	86.8 ± 1.3	54.3 ± 2.2	20.7 ± 3.2	7.7 ± 1.6	4.5 ± 0.7	125	62.5	31.2	250
		Cn	100	100	100	87.3 ± 1.6	20.2 ± 1.3	8.37 ± 1.3	0	62.5	31.2	31.2	125
21b		Ca	95.4 ± 8.3	83.2 ± 10.2	74.9 ± 5.7	52.4 ± 2.1	14.9 ± 1.6	5.6 ± 1.2	1.9 ± 1.5	250	62.5	31.2	>250
		Cn	58.1 ± 2.7	52.5 ± 4.2	49.4 ± 2.3	48.8 ± 1.8	35.1 ± 0.0	19.3 ± 1.2	0	>250	>250	31.2	>250
Amphotericin B		Ca	100	100	100	100	100	100	100	1.0	0.5	0.2	1.0
		Cn	100	100	100	100	100	100	100	1.2	0.5	0.2	1.2

From Table 2 and Figure 5, it is clear that compound 18b is the most active, being fungicidal rather than fungistatic with a MFC = 15.6 µg/mL against C. neoformans and 62.5 µg/mL against C. albicans. Instead, 19b is fungicide at high concentrations (125 and 250 µg/mL, respectively) and 21b was no fungicide up to 250 µg/mL. In addition, the MIC80 of 18b against both fungi is 7.8 µg/mL (Table 2), a relevant low value that positions 18b as a good candidate for future research. As it is clearly stated in the CLSI document M27A2 for yeasts, application of a less stringent endpoint such as MIC80 (allowing some turbidity above the MIC), has improved inter-laboratory agreement and also discriminates between putatively susceptible and resistant isolates [32].

3. Materials and Methods

3.1. General Information

Melting points were determined on a Büchi melting point B-450 apparatus (Instrumart, South Burlington, VT, USA) and are uncorrected. FTIR spectra were recorded on a Shimadzu FTIR 8400 spectrophotometer (Scientific Instruments Inc., Seattle, WA, USA) in KBr disks and films. 1H- and 13C-NMR spectra were recorded on a Bruker Avance 400 spectrophotometer (Bruker BioSpin GmbH, Rheinstetten, Germany) operating at 400 MHz and 100 MHz, respectively, and using CDCl3 as solvent and tetramethylsilane as internal standard. DEPT spectra were used for the assignment of carbon signals. Mass spectra were run on a Shimadzu-GCMS 2010-DI-2010 spectrometer (Scientific Instruments Inc., Columbia, SC, USA) (equipped with a direct inlet probe) operating at 70 eV. Microanalyses were performed on a Thermo-Finnigan Flash EA1112 CHN elemental analyzer (Thermo Fischer Scientific Inc., Madison, WI, USA), and the values are within ±0.4% of the theoretical values. Silica gel aluminum plates (Merck 60 F254) were used for analytical TLC. The starting chemicals were purchased from (Sigma-Aldrich, San Luis, MO, USA) and Merck Millipore (Billerica, MA, USA) analytical or reagent grade and were used without further purification, unless otherwise noted. All starting materials were weighed and handled in air at room temperature. The reactions were monitored by TLC visualized by a (254/365 nm) UVGL-25 compact UV Lamp (UVP, Upland, CA, USA) and/or with vanillin-H2SO4 in EtOH. Column chromatography was performed on silica gel (230–400 mesh, Merck). Non-commercially available secondary amines 13a, 13b, 13c, 13d, 13e and 13f were prepared using known procedures [15,16,17,19,33,34].

3.2. Synthesis

3.2.1. General Procedure for the Synthesis of Secondary Amines 13a–e

A mixture of primary amine (1.0 mmol) and the appropriate aldehyde (1.0 mmol) was heated in an oil bath at 120 °C for 20–45 min. After a complete disappearance of the starting materials, as monitored by TLC, the mixture was allowed to cool to ambient temperature and dissolved in methanol (4–5 mL). Then, solid NaBH4 (2.0 mmol) was added portionwise with stirring over a period of 5 min. The stirring was continued at ambient temperature for 30 min further. After the reaction was complete (monitored by TLC), the volume of the reaction mixture was reduced to 1 mL under reduced pressure, and water (5 mL) was added. The aqueous solution was extracted with EtOAc (2 × 5 mL), and the combined organic layers were dried with anhydrous Na2SO4. The mixture was filtered and the solvent was removed under reduced pressure. All amines 13 were used without further purification.

3.2.2. General Procedure for the Synthesis of γ-Aminoalcohols 15

A mixture of secondary amine 13 (~200 mg, 1.0 mmol), polyformaldehyde (1.5 mmol) and the activated alkene 14 (1.1 mmol) was dissolved in ACN (2 mL). The solution was stirred at room temperature for 3 days until the starting secondary amine 13 was no longer detected by TLC (revealed with an ethanolic solution of vanillin-sulfuric acid or iodine). After the excess of solvent was removed under reduced pressure, the oily material obtained was purified by column chromatography on silica gel, using EtOAc:hexane (2:1 v/v) as eluent. When the same reaction was performed starting from N-methyl-1-(naphthalen-1-yl)methanamine 13a, polyformaldehyde and styrene in the presence of conc. H2SO4 (1 drop) as catalyst, during 24 h, afforded directly naftifine as the main reaction product.

3.2.3. General Procedure for the Synthesis of Allylamines 16

A mixture of the γ-aminoalcohol 15 (200 mg, 1.0 mmol), AlCl3 (1.0 mmol) and ACN (4 mL) was stirred at reflux during 2–3 h. After reaction finished (TLC control), TEA (0.5 mL) was added at room temperature. The solvent was removed under reduced pressure, water (5 mL) was added and the aqueous solution was extracted with EtOAc (3 × 5 mL). The combined organic layers were dried with anhydrous Na2SO4, the mixture was filtered and the solvent was removed under reduced pressure. Finally, the crudes were purified by column chromatography on silica gel using CHCl3:MeOH (40:1 v/v) as eluent.

(E)-1-(3-(Benzyl(naphthalen-1-ylmethyl)amino)prop-1-en-1-yl)pyrrolidin-2-one (16a). Following the strategy 1 for the formation of allylamines, the reaction of γ-aminoalcohol 15a (200 mg, 0.52 mmol) and AlCl3 (69 mg, 0.52 mmol) in 4.0 mL of ACN afforded product 16a as a yellow oil. Yield: 92% (177 mg). FT-IR (film): 3058, 3030, 2925, 2798, 1702, 1660, 1408, 1364, 1334, 1119 cm−1. 1H-NMR δ (ppm): 8.28–8.21 (m, 1H), 7.89–7.82 (m, 1H), 7.77 (d, J = 8.0 Hz, 1H), 7.56 (d, J = 6.8 Hz 1H), 7.53–7.46 (m, 2H), 7.46–7.41 (m, 1H), 7.37–7.28 (m, 4H), 7.27–7.21 (m, 1H), 7.02 (d, J = 14.4 Hz, 1H), 5.00 (dt, J = 7.2, 14.4 Hz, 1H), 4.04 (s, 2H), 3.66 (s, 2H), 3.41 (t, J = 7.2 Hz, 2H), 3.19 (d, J = 6.8 Hz, 2H), 2.46 (t, J = 8.2 Hz, 2H), 2.06 (tt, J = 7.6, 7.6 Hz, 2H). 13C-NMR δ (ppm): 173.0 (C=O), 139.7 (Cq), 135.2 (Cq), 133.8 (Cq), 132.4 (Cq), 129.0, 128.3, 128.1, 127.7, 127.3, 126.8, 126.2, 125.5, 125.5, 125.2, 124.8, 108.8, 58.4, 56.6, 54.1, 45.2, 31.2, 17.3. Anal. Calcd. for C25H26N2O: C, 81.05; H, 7.07; N, 7.56. Found: C, 80.82; H, 7.25; N, 7.32.

(E)-1-(3-((4-Chlorobenzyl)(naphthalen-1-ylmethyl)amino)prop-1-en-1-yl)pyrrolidin-2-one (16b). Following the strategy 1 for the formation of allylamines, the reaction of γ-aminoalcohol 15b (215 mg, 0.51 mmol) and AlCl3 (68 mg, 0.51 mmol) in 4.0 mL of ACN afforded product 16b as a yellow oil. Yield: 85% (176 mg). FT-IR (film): 3046, 2925, 2882, 2803, 1702, 1660, 1488, 1408, 1298, 1089 cm−1. 1H-NMR δ (ppm): 8.25–8.20 (m, 1H), 7.87–7.83 (m, 1H), 7.77 (d, J = 8.4 Hz, 1H), 7.54–7.46 (m, 3H), 7.44–7.39 (m, 1H), 7.24 (s, 4H), 7.01 (d, J = 14.4 Hz, 1H), 4.96 (dt, J = 7.2, 14.4 Hz, 1H), 4.00 (s, 2H), 3.58 (s, 2H), 3.43 (t, J = 7.2 Hz, 2H), 3.15 (d, J = 6.8 Hz, 2H), 2.48 (t, J = 8.4 Hz, 2H), 2.09 (tt, J = 8.0, 8.0 Hz, 2H). 13C-NMR δ (ppm): 173.0 (C=O), 138.3 (Cq), 134.9 (Cq), 133.8 (Cq), 132.4 (Cq), 132.3 (Cq), 130.2, 128.4, 128.2, 127.8, 127.3, 126.3, 125.5, 125.5, 125.2, 124.7, 108.4, 57.6, 56.8, 54.3, 45.2, 31.2, 17.4. Anal. Calcd. for C25H25ClN2O: C, 74.15; H, 6.22; N, 6.92. Found: C, 74.02; H, 6.50; N, 7.05.

(E)-1-(3-((Benzo[d][1,3]dioxol-5-ylmethyl)(naphthalen-1-ylmethyl)amino)prop-1-en-1-yl)pyrrolidin-2-one (16c). Following the strategy 1 for the formation of allylamines, the reaction of γ-aminoalcohol 15c (216 mg, 0.50 mmol) and AlCl3 (68 mg, 0.51 mmol) in 4.0 mL of ACN afforded product 16c as a yellow oil. Yield: 77% (159 mg). FT-IR (film): 3045, 2977, 2922, 2884, 2802, 1701, 1660, 1487, 1441, 1409, 1364, 1298, 1243, 1113, 1038 cm−1. 1H-NMR δ (ppm): 8.30–8.24 (m, 1H), 7.88–7.82 (m, 1H), 7.77 (d, J = 8.4 Hz, 1H), 7.57–7.46 (m, 3H), 7.43 (t, J = 7.6 Hz, 1H), 7.03 (d, J = 14.4 Hz, 1H), 6.86 (s, 1H), 6.80–6.71 (m, 2H), 5.92 (s, 2H, OCH2O), 5.00 (dt, J = 7.2, 14.4 Hz, 1H), 4.00 (s, 2H), 3.53 (s, 2H), 3.42 (t, J = 7.2 Hz, 2H), 3.16 (d, J = 6.8 Hz, 2H), 2.46 (t, J = 8.0 Hz, 2H), 2.05 (tt, J = 7.6, 7.6 Hz, 2H). 13C-NMR δ (ppm): 172.9 (C=O), 147.4 (Cq), 146.3 (Cq), 135.1 (Cq), 133.7 (Cq), 133.5 (Cq), 132.3 (Cq), 128.2, 127.6, 127.2, 126.1, 125.4 (2 × CH), 125.1, 124.7, 121.9, 109.2, 108.5, 107.7, 100.7, 57.9, 56.4, 53.8, 45.1, 31.1, 17.2. Anal. Calcd. for C26H26N2O3: C, 75.34; H, 6.32; N, 6.76. Found: C, 75.48; H, 6.21; N, 6.83.

(E)-1-(3-((Naphthalen-1-ylmethyl)(napthalen-2-ylmethyl)amino)prop-1-en-1-yl)pyrrolidin-2-one (16d). Following the strategy 1 for the formation of allylamines, the reaction of γ-aminoalcohol 15d (237 mg, 0.54 mmol) and AlCl3 (73 mg, 0.55 mmol) in 4.0 mL of ACN afforded product 16d as a yellow oil. Yield: 68% (154 mg). FT-IR (film): 3045, 2927, 2882, 2800, 1701, 1660, 1509, 1409, 1363, 1299, 1261, 1224, 1115 cm−1. 1H-NMR δ (ppm): 8.02 (d, J = 8.4 Hz, 2H), 7.83 (d, J = 8.0 Hz, 2H), 7.77 (d, J = 8.4 Hz, 2H), 7.51 (d, J = 6.8 Hz, 2H), 7.47–7.38 (m, 4H), 7.28–7.22 (m, 2H), 7.06 (d, J = 14.4 Hz, 1H), 5.04 (dt, J = 7.2, 14.4 Hz, 1H), 4.04 (s, 4H), 3.42 (t, J = 7.2 Hz, 2H), 3.22 (d, J = 7.2 Hz, 2H), 2.47 (t, J = 8.0 Hz, 2H), 2.07 (tt, J = 7.6, 7.6 Hz, 2H). 13C-NMR δ (ppm): 172.9 (C=O), 135.1 (Cq), 133.8 (Cq), 132.5 (Cq), 128.2, 127.9 (2 × CH), 126.4, 125.4, 125.3, 125.2, 125.1, 108.4, 57.2, 54.6, 45.2, 31.1, 17.4. Anal. Calcd. For C29H28N2O: C, 82.82; H, 6.71; N, 6.66. Found: C, 82.90; H, 6.85; N, 6.48.

(E)-1-(3-((Naphthalen-1-ylmethyl)(3,4,5-trimethoxybenzyl)amino)prop-1-en-1-yl)pyrrolidin-2-one (16e). Following the strategy 1 for the formation of allylamines, the reaction of γ-aminoalcohol 15e (239 mg, 0.50 mmol) and AlCl3 (68 mg, 0.51 mmol) in 4.0 mL of ACN afforded product 16e as a yellow oil. Yield: 69% (159 mg). FT-IR (film): 3042, 2298, 2936, 2831, 1700, 1660, 1591, 1505, 1461, 1414, 1230, 1125, 1009 cm−1. 1H-NMR δ (ppm): 8.36–8.31 (m, 1H), 7.87–7.81 (m, 1H), 7.76 (d, J = 8.4 Hz, 1H), 7.52–7.37 (m, 4H), 7.05 (d, J = 14.4 Hz, 1H), 6.49 (s, 2H), 4.99 (dt, J = 7.2, 14.4 Hz, 1H), 4.03 (s, 2H), 3.80 (s, 3H), 3.76 (s, 6H), 3.54 (s, 2H), 3.43 (t, J = 7.2 Hz, 2H), 3.22 (d, J = 6.8 Hz, 2H), 2.47 (t, J = 8.2 Hz, 2H), 2.08 (tt, J = 8.0, 8.0 Hz, 2H). 13C-NMR δ (ppm): 173.0 (C=O), 152.9 (Cq), 136.5 (Cq), 135.8 (Cq), 135.2 (Cq), 133.9 (Cq), 132.4 (Cq), 128.4, 127.9, 127.5, 126.3, 125.4, 125.3, 125.1, 125.0, 108.3, 105.5, 60.7, 58.1, 57.1, 55.9, 54.5, 45.1, 31.1, 17.3. Anal. Calcd. For C28H32N2O4: C, 73.02; H, 7.00; N, 6.08. Found: C, 73.15; H, 6.89; N, 6.23.

(E)-1-(3-Benzyl(3,4,5-trimethoxybenzyl)amino)prop-1-en-1-yl)pyrrolidin-2-one (16f). Following the strategy 1 for the formation of allylamines, the reaction of γ-aminoalcohol 15f (236 mg, 0.55 mmol) and AlCl3 (77 mg, 0.58 mmol) in 4.0 mL of ACN afforded product 16f as a yellow oil. Yield: 66% (149 mg). FT-IR (film): 2942, 2838, 1704, 1659, 1594, 1166, 1124, 1034, 1009 cm–1. 1H-NMR δ (ppm): 7.37 (d, J = 6.8 Hz, 2H), 7.32 (t, J = 7.5 Hz, 2H), 7.24 (td, J = 1.9, 7.2 Hz, 1H), 7.04 (d, J = 14.5 Hz, 1H), 6.62 (s, 2H), 4.95 (dt, J = 7.0, 14.3 Hz, 1H), 3.87 (s, 6H), 3.83 (s, 3H), 3.59 (s, 2H), 3.53 (s, 2H), 3.46 (t, J = 7.2 Hz, 2H), 3.14 (dd, J = 1.8, 6.8 Hz, 2H), 2.48 (t, J = 8.2 Hz, 2H), 2.13–2.05 (m, 2H). 13C-NMR δ (ppm): 173.0 (C=O), 153.1 (Cq), 139.6 (Cq), 136.7 (Cq), 135.5 (Cq), 128.7, 128.2, 126.8, 126.2, 108.6, 105.4, 60.8, 58.1, 57.9, 56.1, 53.9, 45.2, 31.2, 17.4. MS (70 eV, EI): m/z (%) 409 [M-1]+ (5), 300 (12), 124 (100), 181 (39), 91 (45) [PhCH2]+. Anal. Calcd. For C24H30N2O4: C, 70.22; H, 7.37; N, 6.82. Found: C, 70.35; H, 7.23; N, 6.93.

(E)-1-(3-Methyl(naphthalen-1-ylmethyl)amino)prop-1-en-1-yl)pyrrolidin-2-one (16g). Following the strategy 1 for the formation of allylamines, the reaction of γ-aminoalcohol 15g (178 mg, 0.57 mmol) and AlCl3 (80 mg, 0.60 mmol) in 4.0 mL of ACN afforded product 16g as a yellow oil. Yield: 89% (149 mg). FT-IR (film): 3045, 2976, 2942, 2878, 2785, 1701, 1660, 1406, 1337 cm−1. 1H-NMR δ (ppm): 8.28 (d, J = 8.3 Hz, 1H), 7.86 (d, J = 8.0 Hz, 1H), 7.79 (dd, J = 1.4, 7.7 Hz, 1H), 7.57–7.51 (m, 1H), 7.51–7.46 (m, 1H), 7.46–7.39 (m, 2H), 7.08 (d, J = 14.4 Hz, 1H), 5.06 (dt, J = 7.2, 14.4 Hz, 1H), 3.91 (s, 2H), 3.50 (t, J = 7.2 Hz, 2H), 3.18 (d, J = 7.3 Hz, 2H), 2.49 (t, J = 8.4 Hz, 2H), 2.25 (s, 3H), 2.08 (tt, J = 7.6, 7.6 Hz, 2H). 13C-NMR δ (ppm): 173.0 (C=O), 134.8 (Cq), 133.8 (Cq), 132.3 (Cq), 128.3, 127.8, 127.3, 126.1, 125.7, 125.4, 125.0, 124.4, 108.7, 59.8, 58.0, 45.1, 42.2, 31.1, 17.3. Anal. Calcd. For C19H22N2O: C, 77.52; H, 7.53; N, 9.52. Found: C, 77.67; H, 7.64; N, 9.41.

(E)-1-(3-(Dibenzylamino)prop-1-enyl)pyrrolidin-2-one (16h). Following the strategy 1 for the formation of allylamines, the reaction of γ-aminoalcohol 15h (172 mg, 0.51 mmol) and AlCl3 (69 mg, 0.52 mmol) in 4.0 mL of ACN afforded product 16h as a yellow oil. Yield: 94% (154 mg) (lit. [19], yellow oil).

(E)-1-(3-(Benzyl(methyl)amino)prop-1-enyl)pyrrolidin-2-one (16i). Following the strategy 1 for the formation of allylamines, the reaction of γ-aminoalcohol 15i (134 mg, 0.51 mmol) and AlCl3 (69 mg, 0.52 mmol) in 4.0 mL of ACN afforded product 16i as a yellow oil. Yield: 64% (80 mg). FT-IR (film): 2927, 2885, 1701, 1665, 1589 cm−1. 1H-NMR δ (ppm): 7.31–7.22 (m, 5H), 7.01 (d, J = 14.6 Hz, 1H), 5.01 (dt, J = 7.2, 14.8 Hz, 1H), 3.51 (t, J = 7.8 Hz, 2H), 3.49 (s, 2H), 3.06 (d, J = 7.3 Hz, 2H), 2.48 (t, J = 8.2 Hz, 2H), 2.18 (s, 3H), 2.15–2.07 (m, 2H). 13C-NMR δ (ppm): 173.1 (C=O), 138.9 (Cq), 129.1, 128.2, 127.0, 126.3, 108.7, 61.7, 57.5, 45.2, 41.9, 31.2, 17.4. MS (70 eV, EI): m/z (%) 243 [M-1]+ (7), 153 (63), 124 (100), 120 (26), 91 (56) [PhCH2]+, 69 (21). Anal. Calcd. For C15H20N2O: C, 73.74; H, 8.25; N, 11.47. Found: C, 73.85; H, 8.12; N, 11.62.

N-(4-Chlorobenzyl)-1-(4,5-dihydrofuran-3-yl)-N-(naphthalen-1-ylmethyl)methanamine (16k). Following the strategy 1 for the formation of allylamines, the reaction of γ-aminoalcohol 15k (217 mg, 0.57 mmol) and AlCl3 (80 mg, 0.60 mmol) in 4.0 mL of ACN afforded product 16k as a yellow oil. Yield: 62% (128 mg). FT-IR (film): 3045, 2921, 2888, 2853, 2799, 1663, 1489, 1090 cm-1. 1H-NMR δ (ppm): 8.26–8.21 (m, 1H), 7.90–7.85 (m, 1H), 7.79 (d, J = 8.0 Hz, 1H), 7.57 (d, J = 6.8 Hz, 1H), 7.53–7.48 (m, 2H), 7.47–7.42 (m, 1H), 7.28–7.26 (m, 4H), 6.29 (s, 1H), 4.35 (t, J = 9.4, Hz, 2H), 4.02 (s, 2H), 3.59 (s, 2H), 3.12 (s, 2H), 2.62 (t, J = 9.0 Hz, 2H). 13C-NMR δ (ppm): 143.0, 138.2 (Cq), 135.0 (Cq), 133.8 (Cq), 132.4 (Cq), 132.3 (Cq), 130.1, 128.4, 128.2, 127.7, 126.9, 125.5, 125.4, 125.2, 124.4, 112.3 (Cq), 70.3, 57.6, 56.7, 50.2, 31.8. Anal. Calcd. For C23H22ClNO: C, 75.92; H, 6.09; N, 3.85. Found: C, 76.05; H, 5.99; N, 4.01.

3.2.4. General Procedure for the Synthesis of the γ-Aminoalcohols 19 and 20

(i) Synthesis of the β-aminoketones 18. A mixture of amine 13 (500 mg, 1.0 mmol) and the suitable 3-(N,N-dimethylamino)propiophenone hydrochloride 17 (1.0 mmol) was dissolved in a mixture of 1,4-dioxane (5 mL) and TEA (1 mL). The solution was stirred at reflux for 0.5–2 h until the starting materials were not further detected by TLC. After cooling, the solvent was removed under reduced pressure and the crude was extracted from an aqueous solution with EtOAc (2 × 5 mL). The combined organic layers were dried with anhydrous Na2SO4 and the solvent was removed under reduced pressure. Ketones 18 were used without further purification for the reduction step.

(ii) Synthesis of the γ-aminoalcohols 19 and 20. Residue of the β-aminoketone 18 was re-dissolved in methanol (5 mL) and subjected to reduction by following a similar procedure than the above described for the synthesis of the starting secondary amines 13. After reaction was completed (TLC control), the crude was purified by column chromatography on silica gel, using a mixture of CH2Cl2:MeOH (20:1) as eluent.

3-(Methyl(naphthalen-1-ylmethyl)amino)propan-1-one (18a). Following the general procedure for the formation of β-aminoketones, the reaction of N-methyl-1-(naphthalen-1-yl)methanamine (13g, 453 mg, 3.01 mmol) and 1-(phenyl)-3-(N,N-dimethylamino)propan-1-one hydrochloride (17a, 750 mg, 3.51 mmol) in a mixture of 1,4-dioxane (5.0 mL) and TEA (1.0 mL) afforded compound 18a as an orange solid (168 mg, 21% yield). M.p. = 88–90 °C (amorphous) (lit. [10], 55%).

1-(4-Bromophenyl)-3-(methyl(naphthalen-1-ylmethyl)amino)propan-1-one (18b). Following the general procedure for the formation of β-aminoketones, the reaction of N-methyl-1-(naphthalen-1-yl)methanamine 13g (515 mg, 3.01 mmol) and 1-(4-bromophenyl)-3-(N,N-dimethylamino)propan-1-one hydrochloride (17b, 875 mg, 2.99 mmol) in a mixture of 1,4-dioxane (5.0 mL) and TEA (1.0 mL) afforded compound 18b as a yellow solid (518 mg, 45% yield). M.p. = 55–57 °C (amorphous). FTIR (KBr): 3060, 2947, 2840, 2794, 1685 (C=O), 1584, 1069 cm−1. 1H-NMR δ (ppm): 8.23–8.19 (m, 1H), 7.87–7.83 (m, 1H), 7.80–7.75 (m, 1H), 7.68–7.64 (m, 2H), 7.51–7.45 (m, 4H), 7.41–7.37 (m, 2H), 3.94 (s, 2H), 3.11 (t, J = 7.2 Hz, 2H), 2.96 (t, J = 7.2 Hz, 2H), 2.33 (s, 3H). 13C-NMR δ (ppm): 198.4 (C=O), 135.4 (Cq), 134.4 (Cq), 133.8 (Cq), 132.3 (Cq), 131.6, 129.4, 128.3, 128.0, 127.9 (Cq), 127.3, 125.7, 125.5, 124.9, 124.6, 61.0, 52.7, 42.3, 37.0. Anal. Calcd. For C21H20BrNO: C, 65.98; H, 5.27; N, 3.66. Found: C, 66.12; H, 5.35; N, 3.73.

1-(Benzo[d][1,3]dioxol-5-yl)-3-(methyl(naphthalen-1-ylmethyl)amino)propan-1-one (18c). Following the general procedure for the formation of β-aminoketones, the reaction of N-methyl-1-(naphthalen-1-yl)methanamine (13g, 527 mg, 3.08 mmol) and 1-(benzo[d][1,3]dioxol-5-yl)-3-(N,N-dimethylamino)- propan-1-one hydrochloride (17c, 799 mg, 3.10 mmol) in a mixture of 1,4-dioxane (5.0 mL) and TEA (1.0 mL) afforded compound 18c as a yellow solid (567 mg, 53% yield). M.p. = 91–92 °C (amorphous). FTIR (KBr): 3045, 2981, 2950, 2904, 2795, 2764, 1669 (C=O), 1601, 1503, 1256, 1036 cm−1. 1H-NMR δ (ppm): 8.27–8.22 (m, 1H), 7.86–7.82 (m, 1H), 7.77 (d, J = 6.8 Hz, 1H), 7.51–7.36 (m, 6H), 6.77 (d, J = 8.0 Hz, 1H), 6.03 (s, 2H, OCH2O), 3.95 (s, 2H), 3.11 (t, J = 7.2 Hz, 2H), 2.96 (t, J = 7.2 Hz, 2H), 2.30 (s, 3H). 13C-NMR δ (ppm): 197.6 (C=O), 151.5 (Cq), 148.0 (Cq), 134.6 (C), 133.8 (Cq), 132.4 (Cq), 131.8 (Cq), 128.3, 127.9, 127.4, 125.7, 125.5, 125.0, 124.7, 124.2, 107.8, 107.7, 101.7 (OCH2O), 61.0, 53.2, 42.2, 36.7. Anal. Calcd. For C22H21NO3: C, 76.06; H, 6.09; N, 4.03. Found: C, 76.21; H, 6.25; N, 3.86.

3-(Methyl(naphthalen-1-ylmethyl)amino)-1-(3,4,5-trimethoxyphenyl)propan-1-one (18d). Following the general procedure for the formation of β-aminoketones, the reaction of N-methyl-1-(naphthalen-1-yl)methanamine (13g, 498 mg, 2.91 mmol) and 3-(N,N-dimethylamino)-1-(3,4,5-trimethoxy- phenyl)propan-1-one hydrochloride (17d, 896 mg, 2.95 mmol) in a mixture of 1,4-dioxane (5.0 mL) and TEA (1.0 mL) afforded compound 18d as a yellow solid (572 mg, 50% yield). M.p. = 94 °C (amorphous). FTIR (KBr): 3045, 2940, 2835, 2794, 1676 (C=O), 1584, 1504, 1459, 1412, 1336, 1126, 1003 cm−1. 1H NMR δ (ppm): 8.25–8.20 (m, 1H), 7.85–7.80 (m, 1H), 7.76 (d, J = 7.6 Hz, 1H), 7.76 (d, J = 7.6 Hz, 1H), 7.49–7.35 (m, 4H), 7.12 (s, 2H), 3.96 (s, 2H), 3.91 (s, 3H), 3.84 (s, 6H), 3.13 (t, J = 7.2 Hz, 2H), 2.98 (t, J = 7.2 Hz, 2H), 2.34 (s, 3H). 13C-NMR δ (ppm): 198.2 (C=O), 152.9 (Cq), 142.4 (Cq), 134.5 (Cq), 133.8 (Cq), 132.3 (Cq), 132.1 (Cq), 128.3, 127.9, 127.3, 125.7, 125.5, 125.0, 124.6, 105.4, 61.1, 60.8 (OCH3), 56.1 (OCH3), 53.2, 42.4, 36.9. Anal. Calcd. For C24H27NO4: C, 73.26; H, 6.92; N, 3.56. Found: C, 73.41; H, 6.87; N, 3.67.

(±)-3-(N-Methyl-N-((naphthalen-5-yl)methyl)amino)-1-phenylpropan-1-ol (19a). Following the general procedure for the formation of γ-aminoalcohols, the reaction of β-aminoketone 18a (394 mg, 1.30 mmol) and NaBH4 (98 mg, 2.60 mmol) in 5.0 mL of MeOH afforded compound 19a as a yellow solid. Yield: 93% (369 mg). M.p. = 75–76 °C (lit. [18], 76–77 °C).

(±)-1-(4-Bromophenyl)-3-(methyl(naphthalen-1-ylmethyl)amino)propan-1-ol (19b). Following the general procedure for the formation of γ-aminoalcohols, the reaction of β-aminoketone 18b (510 mg, 1.34 mmol) and NaBH4 (101 mg, 2.68 mmol) in 5.0 mL of MeOH afforded compound 19b as a yellow oil. Yield: 83% (427 mg). FTIR (film): 3374, 3046, 2948, 2801, 1593, 1509, 1485, 1463, 1072, 1048, 1009 cm−1. 1H-NMR δ (ppm): 8.18 (d, J = 8.8 Hz, 1H), 7.91 (d, J = 8.0 Hz, 1H), 7.85 (d, J = 8.0 Hz, 1H), 7.63–7.58 (m, 1H), 7.56–7.51 (m, 1H), 7.46–7.38 (m, 2H), 7.31 (d, J = 8.4 Hz, 2H), 6.95 (d, J = 8.4 Hz, 2H), 6.19 (br s, 1H, OH), 4.74 (dd, J = 3.2, 7.6 Hz, 1H), 4.03 (d, J = 12.8 Hz, 1H), 3.86 (d, J = 12.8 Hz, 1H), 2.80–2.72 (m, 1H), 2.69–2.62 (m, 1H), 2.40 (s, 3H), 1.96–1.88 (m, 1H), 1.86–1.75 (m, 1H). 13C-NMR δ (ppm): 143.8 (Cq), 133.9 (Cq), 133.3 (Cq), 132.3 (Cq), 131.0, 128.6, 128.4, 128.1, 127.2, 126.3, 125.9, 125.1, 123.9, 120.3 (Cq), 74.5, 61.2, 55.6, 42.2, 34.3. Anal. Calcd. For C21H22BrNO: C, 65.63; H, 5.77; N, 3.64. Found: C, 65.70; H, 5.86; N, 3.58.

(±)-1-(Benzo[d][1,3]dioxol-5-yl)-3-(methyl(naphthalen-1-ylmethyl)amino)propan-1-ol (19c). Following the general procedure for the formation of γ-aminoalcohols, the reaction of β-aminoketone 18c (495 mg, 1.42 mmol) and NaBH4 (108 mg, 2.85 mmol) in 5.0 mL of MeOH afforded compound 19c as a white solid. Yield: 93% (461 mg). M.p. = 96–98 °C. FT-IR (KBr): 3373, 3045, 2948, 2886, 2841, 2800, 1599, 1503, 1486, 1441, 1241, 1039 cm−1. 1H-NMR δ (ppm): 8.21 (d, J = 8.4 Hz, 1H), 7.90 (d, J = 8.0 Hz, 1H), 7.86–7.81 (m, 1H), 7.64–7.58 (m, 1H), 7.55–7.50 (m, 1H), 7.47–7.41 (m, 2H), 6.74 (d, J = 1.2 Hz, 1H), 6.68 (d, J = 8.0 Hz, 1H), 6.61 (dd, J = 1.2, 7.8 Hz, 1H), 5.98 (br s, 1H, OH), 5.91 (s, 2H), 4.72 (dd, J = 5.6, 5.6 Hz, 1H), 3.99 (d, J = 12.8 Hz, 1H), 3.93 (d, J = 12.8 Hz, 1H), 2.86–2.78 (m, 1H), 2.70–2.63 (m, 1H), 2.37 (s, 3H), 1.90–1.84 (m, 2H). 13C-NMR δ (ppm): 147.4 (Cq), 147.4 (Cq), 146.2 (Cq), 139.0 (Cq), 133.9 (Cq), 133.4 (Cq), 132.3 (Cq), 128.6, 128.4, 127.9, 126.3, 125.8, 125.1, 123.9, 118.6, 107.8, 106.2, 100.7, 75.1, 61.1, 56.2, 42.1, 34.8. Anal. Calcd. For C22H23NO3: C, 75.62; H, 6.63; N, 4.01. Found: C, 75.70; H, 6.75; N, 4.15.

(±)-3-(Methyl(naphthalen-1-ylmethyl)amino)-1-(3,4,5-trimethoxyphenyl)propan-1-ol (19d). Following the general procedure for the formation of γ-aminoalcohols, the reaction of β-aminoketone 18d (520 mg, 1.32 mmol) and NaBH4 (100 mg, 2.64 mmol) in 5.0 mL of MeOH afforded compound 19d as a yellow oil. Yield: 90% (470 mg). FT-IR (film): 3414, 3050, 2940, 2834, 1592, 1506, 1461, 1417, 1232, 1182, 1126, 1009 cm−1. 1H-NMR δ (ppm): 8.22 (d, J = 8.4 Hz, 1H), 7.88 (d, J = 8.0 Hz, 1H), 7.82 (dd, J = 1.8, 7.0 Hz, 1H), 7.61–7.56 (m, 1H), 7.54–7.42 (m, 3H), 6.56 (s, 2H), 6.07 (br s, 1H, OH), 4.72 (dd, J = 2.4, 9.0 Hz, 1H), 4.01 (d, J = 13.0 Hz, 1H), 3.96 (d, J = 13.0 Hz, 1H), 3.83 (s, 9H), 2.99–2.90 (m, 1H), 2.74–2.65 (m, 1H), 2.36 (s, 3H), 2.01–1.88 (m, 1H), 1.87–1.79 (m, 1H). 13C-NMR δ (ppm): 153.0 (Cq), 140.7 (Cq), 136.7 (Cq), 133.8 (Cq), 133.4 (Cq), 132.2 (Cq), 128.6, 128.30, 127.8, 126.2, 125.7, 125.1, 123.8, 102.4, 75.5, 61.0, 60.7, 56.9, 56.0, 43.0, 35.0. Anal. Calcd. For C24H29NO4: C, 72.89; H, 7.39; N, 3.54. Found: C, 72.95; H, 7.50; N, 3.42.

(±)-1,1′-(1,4-Phenylene)bis(3-(methyl(naphthalen-1-ylmethyl)amino)propan-1-ol (19e). Following the general procedure for the formation of γ-aminoalcohols, the reaction of β-aminoketone 18e (481 mg, 0.91 mmol) and NaBH4 (69 mg, 1.82 mmol) in 5.0 mL of MeOH afforded compound 19e as a yellow oil. Yield: 80% (388 mg). FT-IR (film): 3363, 3048, 2948, 2841, 2800, 1463, 1129, 1076, 1049, 1021 cm−1. 1H-NMR δ (ppm): 8.21 (d, J = 8.0 Hz, 2H), 7.88 (d, J = 8.0 Hz, 2H), 7.85–7.79 (m, 2H), 7.63–7.56 (m, 2H), 7.54–7.48 (m, 2H), 7.46–7.39 (m, 4H), 7.06 (s, 2H), 7.05 (s, 2H), 5.89 (br s, 2H, OH), 4.80–4.74 (m, 2H), 3.99 (d, J = 13.1 Hz, 1H), 3.99 (d, J = 12.8 Hz, 1H), 3.92 (d, J = 13.1 Hz, 1H), 3.92 (d, J = 12.8 Hz, 1H), 2.85–2.76 (m, 2H), 2.69–2.61 (m, 2H), 2.36 (s, 6H), 1.93–1.85 (m, 4H). 13C-NMR δ (ppm): 143.3 (Cq), 133.9 (Cq), 133.5 (Cq), 132.3 (Cq), 128.6, 128.3, 127.9, 126.3, 125.8, 125.2, 125.1, 124.0, 75.0, 61.1, 56.3, 42.1, 34.7. Anal. Calcd. For C36H40N2O2: C, 81.17; H, 7.57; N, 5.26. Found: C, 81.26; H, 7.65; N, 5.01.

(±)-3-Benzyl(2-hydroxyethyl)amino)-1-phenylpropan-1-ol (20a). Following the general procedure for the formation of γ-aminoalcohols, the reaction of β-aminoketone 23a (521 mg, 1.84 mmol) and NaBH4 (139 mg, 3.68 mmol) in 5.0 mL of MeOH afforded compound 20a as a yellow oil. Yield: 94% (494 mg). FT-IR (film): 3396, 2943, 2827, 1603, 1129, 1059, 1031 cm−1. 1H-NMR δ (ppm): 7.39–7.22 (m, 10H), 4.84 (dd, J = 3.5, 8.8 Hz, 1H), 3.81 (d, J = 13.3 Hz, 1H), 3.75–3.64 (m, 2H), 3.55 (d, J = 13.1 Hz, 1H), 2.86 (ddd, J = 4.5, 8.8, 13.2 Hz, 1H), 2.79–2.69 (m, 3H), 2.61 (ddd, J = 4.4, 5.7, 13.3 Hz, 1H), 1.89–1.82 (m, 2H), OH is absent. 13C-NMR δ (ppm): 144.6 (Cq), 137.9 (Cq), 129.3, 128.6, 128.3, 127.5, 127.2, 125.6, 74.9, 59.9, 59.6, 56.2, 52.8, 35.3. Anal. Calcd. For C18H23NO2: C, 72.76; H, 8.12; N, 4.91. Found: C, 72.85; H, 8.01; N, 5.06.

(±)-2-Benzyl(2-hydroxyethyl)amino)-1-(4-methoxyphenyl)propan-1-ol (20f). Following the general procedure for the formation of γ-aminoalcohols, the reaction of β-aminoketone 23f (530 mg, 1.69 mmol) and NaBH4 (128 mg, 3.38 mmol) in 5.0 mL of MeOH afforded compound 20f as a yellow solid. Yield: 87% (464 mg). M.p. = 68–69 °C. FT-IR (KBr): 3375, 2949, 2835, 1611, 1176, 1130, 1034 cm−1. 1H-NMR δ (ppm): 7.37–7.29 (m, 5H), 7.23 (d, J = 8.8 Hz, 2H), 6.85 (d, J = 8.5 Hz, 2H), 5.52 (br s, 1H, OH), 4.78 (dd, J = 3.3, 8.6 Hz, 1H), 3.80 (s, 3H), 3.80 (d, J = 13.1 Hz, 1H), 3.73–3.63 (m, 2H), 3.54 (d, J = 13.1 Hz, 1H), 2.87–2.67 (m, 4H), 2.59 (ddd, J = 5.1, 5.1, 13.1 Hz, 1H), 1.98–1.88 (m, 1H), 1.77–1.85 (m, 1H). 13C-NMR δ (ppm): 158.7 (Cq), 137.9 (Cq), 136.8 (Cq), 129.2, 128.5, 127.4, 126.7, 113.6, 74.4, 59.8, 59.5, 56.1, 55.2, 52.7, 35.2. Anal. Calcd. For C19H25NO3: C, 72.35; H, 7.99; N, 4.44. Found: C, 72.51; H, 8.10; N, 4.60.

3.2.5. General Procedure for the Synthesis of Allylamines 21 and 22

A mixture of the γ-aminoalcohol 19 and 20 (300 mg) and 5N HCl solution (5 mL) was stirred at reflux during 2–3 h. After reaction finished (TLC control), the mixture was neutralized with 5N NaOH until pH = 8. Then, solution was extracted with EtOAc (3 × 5 mL), the combined organic layers were dried with anhydrous Na2SO4 and the solvent was removed under reduced pressure. Crudes were purified by column chromatography on silica gel, using a mixture of CHCl3:MeOH (40:1) as eluent.

(E)-N-Methyl-N-(naphthalen-1-ylmethyl)-3-phenylprop-2-en-1-amine (21a), naftifine. Following the strategy 2 for the formation of allylamines, the reaction of γ-aminoalcohol 19a (310 mg, 1.01 mmol) and 5N HCl solution (5.0 mL) afforded compound 21a as a yellow oil (lit. [10] 94%, lit. [11] 82%, lit. [12], 68%). Yield: 90% (310 mg). FT-IR (film): 3028, 2943, 2835, 2786, 1596, 1509, 1451, 1362, 1127, 1013 cm−1. 1H-NMR δ (ppm): 8.36 (d, J = 8.4 Hz, 1H), 7.90 (d, J = 7.6 Hz, 1H), 7.83 (d, J = 8.0 Hz, 1H), 7.62–7.43 (m, 6H), 7.37 (t, J = 7.2 Hz, 2H), 7.32–7.25 (m, 1H), 6.63 (d, J = 15.6 Hz, 1H), 6.43 (td, J = 6.4, 15.6 Hz, 1H), 4.01 (s, 2H), 3.34 (d, J = 6.0 Hz, 2H), 2.34 (s, 3H). 13C-NMR δ (ppm): 137.1 (Cq), 134.8 (Cq), 133.9 (Cq), 132.7, 132.5 (Cq), 128.5, 128.4, 127.9, 127.5, 127.4, 127.3, 126.3, 125.8, 125.5, 125.1, 124.6, 60.3, 60.1, 42.4. Anal. Calcd. For C21H21N: C, 87.76; H, 7.37; N, 4.87. Found: C, 87.83; H, 7.45; N, 4.95.

(E)-3-(4-Bromophenyl)-N-methyl-N-(naphthalen-1-ylmethyl)prop-2-en-1-amine (21b). Following the strategy 2 for the formation of allylamines, the reaction of γ-aminoalcohol 19b (301 mg, 0.78 mmol) and 5N HCl solution (5.0 mL) afforded compound 21b as a yellow solid. Yield: 81% (231 mg). M.p. = 55–57 °C (lit. [35], 84%).

(E)-3-(Benzo[d][1,3]dioxol-5-yl)-N-methyl-N-(naphthalen-1-ylmethyl)prop-2-en-1-amine (21c). Following the strategy 2 for the formation of allylamines, the reaction of γ-aminoalcohol 19c (325 mg, 0.93 mmol) and 5N HCl solution (5.0 mL) afforded compound 21c as a yellow oil. Yield: 90% (277 mg). FT-IR (film): 3040, 2979, 2943, 2885, 2835, 2783, 1600, 1487, 1443, 1249, 1039 cm−1. 1H-NMR δ (ppm): 8.33 (d, J = 8.0 Hz, 1H), 7.88 (d, J = 7.6 Hz, 1H), 7.80 (d, J = 7.6 Hz, 1H), 7.58–7.41 (m, 4H), 6.98 (d, J = 1.2 Hz, 1H), 6.84 (dd, J = 1.2, 8.0 Hz, 1H), 6.78 (d, J = 8.0 Hz, 1H), 6.51 (d, J = 16.0 Hz, 1H), 6.22 (td, J = 6.8, 15.6 Hz, 1H), 5.98 (s, 2H, OCH2O), 3.96 (s, 2H), 3.28 (d, J = 6.0 Hz, 2H), 2.30 (s, 3H). 13C-NMR δ (ppm): 148.0 (Cq), 147.0 (Cq), 134.9 (Cq), 133.9 (Cq), 132.5 (Cq), 132.2, 131.6 (Cq), 128.4, 127.9, 127.4, 125.8, 125.7, 125.5, 125.1, 124.6, 120.8, 108.2, 105.7, 101.0, 60.3, 60.0, 42.4. Anal. Calcd. For C22H21NO2: C, 79.73; H, 6.39; N, 4.23. Found: C, 79.90; H, 6.45; N, 4.05.

(E)-N-Methyl-N-(naphthalen-1-ylmethyl)-3-(3,4,5-trimethoxyphenyl)prop-2-en-1-amine (21d). Following the strategy 2 for the formation of allylamines, the reaction of γ-aminoalcohol 19d (314 mg, 0.79 mmol) and 5N HCl solution (5.0 mL) afforded compound 21d as a yellow oil. Yield: 70% (209 mg). FT-IR (film): 3041, 2938, 2834, 2786, 1581, 1505, 1457, 1416, 1331, 1239, 1126, 1011 cm−1. 1H-NMR δ (ppm): 8.33 (d, J = 8.4 Hz, 1H), 7.88 (d, J = 7.6 Hz, 1H), 7.80 (d, J = 7.6 Hz, 1H), 7.59–7.41 (m, 4H), 6.64 (s, 2H), 6.52 (d, J = 15.6 Hz, 1H), 6.29 (td, J = 6.8, 15.6 Hz, 1H), 3.98 (s, 2H), 3.89 (s, 6H), 3.87 (s, 3H), 3.30 (d, J = 6.4 Hz, 2H), 2.32 (s, 3H). 13C-NMR δ (ppm): 153.2 (Cq), 137.6 (Cq), 134.7 (Cq), 133.8 (Cq), 132.8 (Cq), 132.4 (Cq), 132.4, 128.4, 127.9, 127.4, 127.2, 125.8, 125.5, 125.1, 124.5, 103.3, 60.8, 60.3, 60.2, 56.0, 42.5. Anal. Calcd. For C24H27NO3: C, 76.36; H, 7.21; N, 3.71. Found: C, 76.45; H, 7.10; N, 3.86.

(E)-N-Methyl-3-(4-((E)-3-(methyl(naphthalen-1-ylmethyl)amino)prop-1-en-1-yl)phenyl)-N-(naphthalen-2-ylmethyl)prop-2-en-1-amine (21e). Following the strategy 2 for the formation of allylamines, the reaction of γ-aminoalcohol 19e (295 mg, 0.55 mmol) and 5N HCl solution (5.0 mL) afforded compound 21e as a yellow oil. Yield: 78% (213 mg). FT-IR (film): 3042, 2943, 2834, 2785, 1596, 1509, 1456, 1013 cm−1. 1H-NMR δ (ppm): 8.36 (d, J = 8.4 Hz, 2H), 7.90 (d, J = 8.4 Hz, 2H), 7.83 (d, J = 8.0 Hz, 2H), 7.61–7.44 (m, 8H), 7.39 (s, 4H), 6.61 (d, J = 16.0 Hz, 2H), 6.42 (td, J = 6.8, 16.0 Hz, 2H), 3.33 (d, J = 6.8 Hz, 4H), 4.00 (s, 4H), 2.33 (s, 6H). 13C-NMR δ (ppm): 136.2 (Cq), 134.8 (Cq), 133.9 (Cq), 132.5 (Cq), 132.3, 128.4, 127.9, 127.4 (× 2C), 126.5, 125.8, 125.5, 125.1, 124.6, 60.4, 60.1, 42.4. Anal. Calcd. For C36H36N2: C, 87.05; H, 7.31; N, 5.64. Found: C, 87.22; H, 7.44; N, 5.45.

(E)-2-(Benzyl(cinnamyl)amino)ethan-1-ol (22a). Following the strategy 2 for the formation of allylamines, the reaction of γ-aminoalcohol 20a (331 mg, 1.16 mmol) and 5N HCl solution (5.0 mL) afforded compound 22a as a yellow oil. Yield: 70% (217 mg). FT-IR (film): 3424, 2944, 2880, 1599, 1580, 1127, 1053, 1028 cm−1. 1H-NMR δ (ppm): 7.42–7.25 (m, 10H), 6.55 (d, J = 16.0 Hz, 1H), 6.29 (td, J = 6.8, 16.0 Hz, 1H), 3.73 (s, 2H), 3.65 (t, J = 5.4 Hz, 2H), 3.34 (dd, J = 1.0, 6.8 Hz, 2H), 2.76 (t, J = 5.4 Hz, 2H), 2.43 (br s, 1H, OH). 13C-NMR δ (ppm): 138.7 (Cq), 136.8 (Cq), 133.2, 129.0, 128.5, 128.4, 127.5, 127.2, 126.5, 126.3, 58.6, 58.2, 56.0, 54.8. Anal. Calcd. For C18H21NO: C, 80.86; H, 7.92; N, 5.24. Found: C, 80.97; H, 8.04; N, 5.33.

(E)-2-(Benzyl(3-(4-methoxyphenyl)allyl)amino)ethan-1-ol (22f). Following the strategy 2 for the formation of allylamines, the reaction of γ-aminoalcohol 20f (319 mg, 1.01 mmol) and 5N HCl solution (5.0 mL) afforded compound 22f as a colorless oil. Yield: 68% (204 mg) (lit. [36], yellow oil).

3.3. Antifungal Evaluation

3.3.1. Microorganisms and Media

For the antifungal evaluation, standardized strains from the American Type Culture Collection (ATCC), Rockville, MD, USA, and CEREMIC (CCC), Centro de Referencia en Micología, Facultad de Ciencias Bioquímicas y Farmacéuticas, Suipacha 531-(2000)-Rosario, Argentina, were used: C. albicans ATCC 10231, S. cerevisiae ATCC 9763, C. neoformans ATCC 32264, Aspergillus flavus ATCC 9170, Aspergillus fumigatus ATTC 26934, Aspergillus niger ATCC 9029, Trichophyton rubrum CCC 113, Trichophyton mentagrophytes ATCC 9972, and Microsporum gypseum CCC 115. Strains were grown on Sabouraud-chloramphenicol agar slants for 48 h at 30 °C, maintained on slopes of Sabouraud-dextrose agar (SDA, Oxoid, Cambridge, UK), and subcultured every 15 days to prevent pleomorphic transformations. Inocula of cell or spore suspensions were obtained according to reported procedures [26,27] and adjusted to 1–5 × 103 cells/spores with colony forming units (CFU)/mL.

3.3.2. Antifungal Susceptibility Testing

Minimum inhibitory concentration (MIC) of each compound was determined by using broth microdilution techniques according to the guidelines of the Clinical and Laboratory Standards Institute for yeasts (M27-A3) [26] and for filamentous fungi (including dermatophytes) (M38-A2) [27]. MIC values were determined in RPMI-1640 (Sigma-Aldrich) buffered to pH 7.0 with MOPS. Microtiter trays were incubated at 35 °C for yeasts and Aspergillus spp. and at 28–30 °C for dermatophyte strains in a moist, dark chamber, and MICs were visually recorded at 48 h for yeasts, and at a time according to the control fungus growth, for the rest of fungi. For the assay, stock solutions of pure compounds were two-fold diluted with RPMI from 250 to 1.0 µg/mL (=250, 125, 62.5, 31.3, 15.6, 7.8, 3.9, 2.0, 1.0 and 0.5 µg/mL) (final volume = 100 µL) and a final DMSO concentration ≤1%. A volume of 100 µL of inoculum suspension was added to each well with the exception of the sterility control where sterile water was added to the well instead. Terbinafine (obtained from the commercial drug Lamisil from Novartis Co., Basel, Switzerland) and amphotericin B were used as positive controls. Endpoints were defined as the lowest concentration of drug resulting in total inhibition (MIC100) of visual growth compared to the growth in the control wells containing no antifungal drug. In addition to MIC determinations, the evaluation of Minimum Fungicide Concentration (MFC) of each compound against the fungal panel was accomplished by subculturing a sample of media from MIC tubes showing no growth, onto drug-free agar plates.

3.3.3. Fungal Growth Inhibition Percentage Determination

Yeasts broth microdilution technique M27-A3 of CLSI [26] was performed in 96-well microplates. For the assay, compound test wells (CTWs) were prepared with stock solutions of each compound in DMSO (maximum concentration ≤1%), diluted with RPMI-1640, to final concentrations of 250–3.9 μg/mL−1. An inoculum suspension (100 μL) was added to each well (final volume in the well = 200 μL). A growth control well (GCW) (containing medium, inoculum, and the same amount of DMSO used in a CTW, but compound-free) and sterility control well (SCW) (sample, medium, and sterile water instead of inoculum) were included for each fungus tested. Microtiter trays were incubated in a moist, dark chamber at 30 °C for 48 h for both yeasts. Microplates were read in a VERSA Max microplate reader (Molecular Devices, Sunnyvale, CA, USA). Amphotericin B was used as positive control. Tests were performed in triplicate. Reduction of growth for each compound concentration was calculated as follows: % of inhibition = 100 − (OD405 CTW − OD405 SCW)/(OD405 GCW − OD405 SCW). The means ± SD (standard deviations) were used for constructing the dose-response curves representing % inhibition vs. concentration of each compound. Dose-response curves were constructed with SigmaPlot 11.0 software.

3.3.4. MIC100, MIC80 and MIC50 Determinations

Three endpoints were defined from the dose-response curves. Minimum Inhibitory concentration (MIC) resulting in total fungal growth inhibition was named MIC100, while MIC80 and MIC50 were defined as the minimum concentration that inhibits 80% or 50% of the fungal growth, respectively.

4. Conclusions

In summary, we have developed two efficient and straightforward approaches for the synthesis of naftifine and diversely substituted analogues 16 and 20 mediated by a Mannich-type reaction in at least one step of each approach. Strategy 1 involved a two-step (both Mannich- and aza-Prins- combined reactions) sequence, mediated by an uncatalyzed three-component Mannich-type reaction leading to γ-aminoalcohols 15 as the key intermediates for allylamines 16. Particularly, we were able to obtain naftifine in a one-pot fashion through Strategy 1 starting from styrene. Although naftifine was isolated in a relatively lower yield than in previous approaches, remarkably, this strategy represents the first direct method for the synthesis of this antifungal compound. Strategy 2 consisted in a three-step sequence involving a one-pot synthesis of the γ-aminoalcohols 19 and 20 as the key intermediates for allylamines 21 and 22. In general, naftifine and the target products 16, 21 and 22 were obtained in good to excellent yields after their corresponding dehydration processes catalyzed whether by Brønsted or Lewis acids like H2SO4, HCl and AlCl3, respectively. The synthesized compounds were tested for antifungal properties against a panel of clinically important fungi. Most compounds were inactive against Aspergillus spp., while showed relevant activities against the dermatophytes T. rubrum and T. mentagrophytes. The most active compounds 18b and 18c possessed a β-aminoketo structure, and among them, compounds 18b, 18c and 21c were 4-Br (18b) or 3,4-methylenedioxy (18c and 21c) substituted in their R1 groups. Interesting enough, 18b displayed high activities also against yeasts, with a MIC80 against C. neoformans and C. albicans of 7.8 µg/mL. This is a relevant low value that positions 18b as a good hit candidate for future research. In addition, 18b is fungicide rather than fungistatic with MFC value of 15.6 µg/mL against C. neoformans.