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Current Organic Synthesis, 2018, 15, 370-379

RESEARCH ARTICLE ISSN: 1570-1794 eISSN: 1875-6271

Current Organic Synthesis

A Straightforward Synthesis of 4,7-Disubstituted 1,4-Oxazepanes via a Brønsted Acid-Catalyzed Intramolecular Etherification Reaction

Impact Factor: 1.91

BENTHAM SCIENCE

Juan-Carlos Castilloa,b, Jaime Portillab, Braulio Insuastya, Jairo Quirogaa and Rodrigo Aboniaa,* a b

Research Group of Heterocyclic Compounds, Department of Chemistry, Universidad del Valle, A. A. 25360, Cali, Colombia; Bioorganic Compounds Research Group, Department of Chemistry, Universidad de los Andes, Bogotá 111711, Colombia Abstract: Aim and Objective: Although many synthetic methods are known for seven-membered N,Oheterocycles, most of them focus on fused benzoxazepines. In fact, an exhaustive searching of the literature revealed that very few synthetic approaches for non-fused 1,4-oxazepanes have been reported. Thus, straightforward and efficient synthetic strategies for the construction of diversely substituted 1,4-oxazepanes would be a welcome access to a relatively underexplored chemical space. Two of these strategies were undertaken in this study.

Pe N rs ot on fo al rD U is se tri O bu n tio ly n

Current Organic Synthesis

370

ARTICLE HISTORY Received: February 22, 2017 Revised: May 12, 2017 Accepted: August 21, 2017

DOI: 10.2174/1570179414666171011160917

Materials and Methods: One of our reactions proceeded by the treatment of ethanolamines with polyformaldehyde and N-vinylpyrrolidin-2-one in ACN as solvent at room temperature in order to obtain the title 1,4oxazepane derivatives. Alternatively, through a careful temperature control, analog structures were selectively obtained from a H2 SO4 catalyzed intramolecular etherification reaction of diversely substituted N-tethered bisalcohols in p-dioxane as solvent.

Results: Based on intramolecular etherifications, two strategies (i.e. a three-component Mannich-type approach and cyclization of N-tethered bis-alcohols), were implemented for the synthesis of novel and diversely 4,7disubstituted 1,4-oxazepanes in moderate to good yields. Structures of the new obtained compounds were confirmed by 1- and 2D NMR techniques as well as MS spectra. Conclusion: According to the results, the above intramolecular etherification reactions proceeded with the formation of benzylic carbocations as the key intermediates for the generation of the title compounds. Temperature and the nature of the R1 substituent in the N-tethered bis-alcohols were critical variables for the selective formation of the desired products from this kind of precursors.

Keywords: Etherification reactions, N-tethered bis-alcohols, Mannich-type reactions, three-component reactions, 1,4-oxazepanes, intramolecular cyclization. 1. INTRODUCTION

The development of innovative synthetic methodologies that allow rapid access to drug-like small N-heterocyclic molecules are of critical importance in the medicinal chemistry and pharmaceutical industry because it provides the ability to expand the available drug-like chemical space and accelerate the drug development process [1-3]. Recently, well-recognized limitations in the solubility, pharmacokinetics and bioavailability of heteroaromatic compounds have led many scientists to favor saturated N-heterocycles for novel drug development [4-6]. However, synthetic methodologies toward saturated N-heterocycles involving direct ring closure are often slow and hampered by unfavorable entropies and enthalpies of the reaction [7]. In particular, the 1,4-oxazepane ring is a seven-membered heterocycle containing nitrogen and oxygen in 1,4-positions, which is endowed with a wide range of biological activities [8], and is found in important natural products such as the neurotoxin batrachotoxin 1 (Fig. 1) [9]. Recently, Yukawa and

*Address correspondence to this author at the Research Group of Heterocyclic Compounds, Department of Chemistry, Universidad del Valle, A. A. 25360, Cali, Colombia; Tel: + 57 (2) 3393248; Fax: + 57 (2) 3392440; E-mail: [email protected]

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co-workers reported the synthesis and biological evaluation of 1,4oxazepane derivatives 2 and 3 as peripheral-selective noradrenaline reuptake inhibitors [10]. The sordarin analog 4 showed a potent antifungal activity against Candida albicans [11], whereas the 1,4oxazepan-3-imine 5 has been studied for their ability to inhibit the nitric oxide synthases [12]. Furthermore, Audouze and co-workers reported the synthesis and biological study of 2,4-disubstituted 1,4oxazepanes as selective dopamine D4 receptor ligands [8c].

Although many synthetic methods are known for this N,Oheterocycle, most of these reports focus on fused benzoxazepines [13]. In fact, an exhaustive searching of the literature revealed that very few synthetic approaches for non-fused 1,4-oxazepanes have been reported. Most notable examples include (a) base-promoted intramolecular hydroalkoxylation of alkynyl alcohols [14a], (b) intramolecular hydroalkoxylation of N-tethered alkenols mediated by boron trifluoride etherate [14b], (c) Lewis acid-mediated intramolecular reductive etherification of N-tethered ketoalcohols [14c], (d) phosphine-triggered tandem annulation reaction between Morita-Baylis-Hillman carbonates and -amino alcohols [14d], (e) intramolecular haloetherification of N-tethered alkenols [14e], (f) tandem aziridine/epoxide ring opening sequences [14f], and (g) aminotributylstannane-mediated cross-coupling with aldehydes [14g].

© 2018 Bentham Science Publishers

A Straightforward Synthesis of 4,7-Disubstituted 1,4-Oxazepanes

Current Organic Synthesis, 2018, Vol. 15, No. 3

371

O O

O

O HO

N

NH

N H

H N

HO

N

H N

O O

O HO

O O

Cl F

H Cl

1

2

Cl

3

R N HO H

O

H N

O

NH


O H

O

O

OH

4, R = p-CH3OC6H4CH2

5

Fig. (1). Some representative examples of biologically active 1,4-oxazepanes.

Thus, a straightforward and efficient synthetic strategy for the construction of diversely substituted 1,4-oxazepanes would be a welcome access to a relatively underexplored chemical space. As part of our current program on the synthetic utilization of benzylamine derivatives mediated by Mannich-type reactions [15], herein, we wish to report both a metal-free three component Mannich-type reaction and a Brønsted acid-catalyzed approach for the synthesis of novel 4,7-disubstituted 1,4-oxazepanes via an intramolecular etherification reaction of N-tethered bis-alcohols as the key intermediates for these processes. 2. EXPERIMENTAL

2.1. General Information

All reagents were purchased from commercial sources and 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 UV lamp (254 nm or 365 nm) and/or with p-anisaldehyde and H2SO4 in EtOH. Column chromatography was performed on silica gel. NMR spectra were recorded on a Bruker Avance 400 (400.13 MHz for 1H; 100.61 MHz for 13C) at 298 K using tetramethylsilane (0 ppm) as the internal reference. NMR spectroscopic data were recorded in CDCl3 using as internal standards the residual non-deuterated signal for 1H NMR and the deuterated solvent signal for 13C NMR spectroscopy. Chemical shifts () are given in ppm and coupling constants (J) are given in Hz. The following abbreviations are used for multiplicities: s = singlet, d = doublet, t = triplet, q = quartet, dd = doublet of doublets, and m = multiplet. Melting points were determined in capillary tubes on a Stuart SMP10 melting point apparatus and are uncorrected. IR data (max) are reported in reciprocal centimeters and were collected on a Shimadzu FT-IR 8400 spectrophotometer in KBr disks and films. Mass spectra were recorded with a Shimadzu GC-MS 2010-DI-2010 spectrometer (with a direct inlet probe) operating at 70 eV. Microanalyses were performed on an Agilent CHNS elemental analyzer and the values are within ± 0.4% of the theoretical values. The 3-(N,N-dimethylamino)propiophenone hydrochlorides 14 were synthesized from their respective acetophenones by following a procedure similar to that described in the literature [15b].

2.2. General Procedure for the Synthesis of 1,4-oxazepanes 9

A mixture of ethanolamine 6 (1.0 mmol), polyformaldehyde (1.5 mmol) and N-vinyl-2-pyrrolidone 8 (1.1 mmol) in acetonitrile (2.0 mL) was stirred at room temperature for 48 h until the starting secondary amine 6 was not detected by TLC (revealed with an ethanolic solution of vanillin-sulfuric acid or iodine). After removal of the solvent, the oily material was purified by column chromatography on silica gel using a mixture of CH2Cl2:MeOH as eluent to afford the pure 4,7-disubstituted 1,4-oxazepanes 9. 2.2.1. General Procedure for the Synthesis of N-tethered bisalcohols 16

A mixture of N-benzylethanolamine 6a (2.0 mmol) and 3-(N,Ndimethylamino)propiophenone hydrochloride 14 (2.0 mmol) was dissolved in a 5:1 v/v mixture of p-dioxane:TEA. The reaction mixture was stirred at reflux for 2 h until the starting materials were not further detected by TLC. After removing the solvent under reduced pressure, the -aminoketone 15 formed was dissolved in MeOH (5.0 mL) and NaBH4 (3.0 mmol) was added portionwise, and the reaction was stirred for 1 h at room temperature. Then, the volume of the reaction mixture was reduced to 1.0 mL under reduced pressure, and water (5.0 mL) was added. The aqueous solution was extracted with EtOAc (2 x 5.0 mL), and the combined organic extracts were dried with anhydrous Na2SO4. The oily material was purified by column chromatography on silica gel using a mixture of CH2Cl2:MeOH as eluent to afford the pure N-tethered bis-alcohols 16. 2.2.2. General Procedure for the Synthesis of 1,4-oxazepanes 17 Concentrated sulfuric acid (0.5 mmol, 2 equiv) was slowly added to a solution of N-tethered bis-alcohol 16 (0.5 mmol) in pdioxane (2.0 mL) at room temperature. The reaction mixture was stirred at the corresponding temperature described in the Table 3 for 12 h until the starting material 16 was no longer detected by TLC. The reaction mixture was neutralized with aqueous 20% NaOH, diluted with 5.0 mL of water and extracted with ethyl acetate (2 x 5.0 mL). The combined organic extracts were dried with anhydrous Na2SO4. After removal the solvent, the residue was purified by column chromatography on silica gel using a mixture of

372 Current Organic Synthesis, 2018, Vol. 15, No. 3

CH2Cl2/MeOH or CH2Cl2/EtOAc as eluent to afford the pure 4,7disubstituted 1,4-oxazepanes 17. 2.3. Characterization Data of Products 2.3.1. (±)-1-(4-Benzyl-1,4-oxazepan-7-yl)pyrrolidin-2-one, 9a

Hz, 2H), 7.29–7.36 (m, 5H) ppm; 13C NMR (100 MHz, CDCl3): 35.3 (CH2), 52.8 (CH2), 55.3 (CH3), 56.2 (CH2), 59.6 (CH2), 59.9 (CH2), 74.5 (CH–O), 113.7 (CH), 126.8 (CH), 127.5 (CH), 128.6 (CH), 129.3 (CH), 136.9 (C), 138.1 (C), 158.8 (C) ppm; MS (70 eV, EI): m/z (%) = 284 (20) [M–31]+ (20), 164 (6), 150 (19), 134 (33), 120 (4), 91 (100) [PhCH2]+, 42 (26); Anal. Calcd for C19H25NO3: C, 72.35; H, 7.99; N, 4.44. Found: C, 72.41; H, 8.12; N, 4.55. 2.3.4. (±)-1-(Benzo[d][1,3]dioxol-5-yl)-3-(benzyl(2-hydroxyethyl) amino)propan-1-ol, 16b Following the general procedure, the reaction between 2(benzylamino)ethanol 6a (340 mg, 2.25 mmol), 1-(benzo[d][1,3]dioxol-5-yl)-3-(N,N-dimethylamino)propan-1-one hydrochloride 14b (593 mg, 2.30 mmol) and NaHB4 (128 mg, 3.38 mmol) in 5.0 mL of MeOH afforded compound 16b as a yellow oil. Purification: CH2Cl2/MeOH (20:1). Yield: 78% (578 mg); FTIR (film): 3454 (O–H), 2932, 2830, 1606, 1129, 1073, 1040 (C–O) cm–1; 1H NMR (400 MHz, CDCl3): 1.75–1.82 (m, 1H), 1.85–1.95 (m, 1H), 2.59 (ddd, J = 4.3, 5.8, 13.4 Hz, 1H), 2.67–2.87 (m, 3H), 3.53 (d, J = 13.1 Hz, 1H), 3.63–3.74 (m, 2H), 3.81 (d, J = 13.3 Hz, 1H), 4.74 (dd, J = 3.4, 9.2 Hz, 1H, CH–O), 5.93 (s, 2H), 6.74 (s, 2H), 6.83 (s, 1H), 7.29–7.36 (m, 5H) ppm, OH is absent; 13C NMR (100 MHz, CDCl3): 35.4 (CH2), 52.8 (CH2), 56.2 (CH2), 59.6 (CH2), 60.0 (CH2), 74.8 (CH–O), 100.9 (CH2), 106.3 (CH), 108.1 (CH), 118.9 (CH), 127.6 (CH), 128.7 (CH), 129.3 (CH), 138.0 (C), 138.9 (C), 146.6 (C), 147.7 (C) ppm; MS (70 eV, EI): m/z (%) = 329 (2) [M]+, 298 (20), 164 (6), 150 (13), 134 (30), 120 (4), 91 (100) [PhCH2]+, 42 (35); Anal. Calcd for C19H23NO4: C, 69.28; H, 7.04; N, 4.25. Found: C, 69.13; H, 7.21; N, 4.33.


Following the general procedure, the reaction between Nbenzylethanolamine 6a (149 L, 1.05 mmol), polyformaldehyde (48 mg, 1.60 mmol) and N-vinyl-2-pyrrolidone 8 (125 L, 1.17 mmol) in 2.0 mL of acetonitrile afforded a mixture of 1,4oxazepane 9a (150 mg, 52%), 3-benzyloxazolidine 11a (48 mg, 28%) and N-tethered bis-alcohol 13a (40 mg, 13%). Colorless oil. FTIR (film): 2945, 2874, 1693 (C=O), 1607, 1139, 1100, 1068 (C– O) cm-1; 1H NMR (400 MHz, CDCl3): 1.89–2.07 (m, 3H), 2.12– 2.22 (m, 1H), 2.38 (t, J = 8.5 Hz, 2H), 2.59–2.64 (m, 2H), 2.71– 2.77 (m, 1H), 2.78–2.85 (m, 1H), 3.40–3.46 (m, 1H), 3.52–3.58 (m, 1H), 3.61 (d, J = 13.3 Hz, 1H), 3.65 (d, J = 13.3 Hz, 1H), 3.76 (ddd, J = 2.3, 7.1, 13.1 Hz, 1H), 3.94 (ddd, J = 2.3, 6.7, 13.0 Hz, 1H), 5.69 (dd, J = 4.4, 9.6 Hz, 1H, CH–O), 7.23–7.36 (m, 5H) ppm; 13C NMR (100 MHz, CDCl3): 18.1 (CH2), 31.4 (CH2), 32.6 (CH2), 42.6 (CH2), 52.1 (CH2), 58.2 (CH2), 62.7 (CH2), 67.4 (CH2), 80.8 (CH–O), 127.1 (CH), 128.3 (CH), 128.9 (CH), 138.8 (C), 174.9 (C=O) ppm; MS (70 eV, EI): m/z (%) = 273 (4) [M–1]+, 164 (19), 134 (15), 124 (70), 91 (100) [PhCH2]+; Anal. Calcd for C16H22N2O2: C, 70.04; H, 8.08; N, 10.21. Found: C, 70.35; H, 7.96; N, 10.42. 3-Benzyloxazolidine, 11a. Colorless oil (lit. Colorless oil) [17]; FTIR (film): 2941, 2878, 1602, 1156, 1057, 1006 (C–O) cm-1; 1H NMR (400 MHz, CDCl3): 2.99 (t, J = 6.8 Hz, 2H), 3.73 (s, 2H), 3.83 (t, J = 6.8 Hz, 2H), 4.33 (s, 2H), 7.28–7.39 (m, 5H) ppm; 13C NMR (100 MHz, CDCl3): 52.0 (CH2), 58.1 (CH2), 63.3 (CH2), 86.6 (CH2), 127.3 (CH), 128.4 (CH), 128.8 (CH), 138.9 (C) ppm; MS (70 eV, EI): m/z (%) = 162 (10) [M–1]+, 120 (12), 91 (100) [PhCH2]+, 72 (24), 65 (19). The NMR data matches with the previously reported data [16].

Castillo et al.

2.3.2. (±)-1-(4-(2-Hydroxyethyl)-1,4-oxazepan-7-yl)pyrrolidin-2one, 9b

Following the general procedure, the reaction between diethanolamine 6b (108 mg, 1.03 mmol), polyformaldehyde (47 mg, 1.56 mmol) and N-vinyl-2-pyrrolidone 8 (125 L, 1.17 mmol) in 2.0 mL of acetonitrile afforded compound 9b as a colorless oil. Purification: CH2Cl2/MeOH (30:1). Yield: 46% (108 mg); FTIR (film): 3461 (O–H), 2949, 2856, 1671 (C=O), 1145, 1105, 1071 (C–O) cm 1 1 ; H NMR (400 MHz, CDCl3): 1.87–2.04 (m, 3H), 2.09–2.18 (m, 1H), 2.35 (t, J = 8.5 Hz, 2H), 2.60–2.86 (m, 7H), 3.37–3.43 (m, 1H), 3.47–3.52 (m, 1H), 3.56 (t, J = 5.3 Hz, 2H), 3.74 (ddd, J = 2.5, 7.1, 13.1 Hz, 1H), 3.92 (ddd, J = 2.5, 7.0, 13.2 Hz, 1H), 5.59 (dd, J = 4.4, 9.6 Hz, 1H, CH–O) ppm; 13C NMR (100 MHz, CDCl3): 18.2 (CH2), 31.4 (CH2), 32.6 (CH2), 42.7 (CH2), 52.2 (CH2), 57.9 (CH2), 58.4 (CH2), 58.9 (CH2), 67.1 (CH2), 80.8 (CH–O), 175.1 (C=O) ppm; MS (70 eV, EI): m/z (%) = 228 (9) [M]+, 197 (100), 183 (13); Anal. Calcd for C11H20N2O3: C, 57.87; H, 8.83; N, 12.27. Found: C, 57.98; H, 8.72; N, 12.10. 2.3.3. (±)-3-(N-Benzyl-N-(2-hydroxyethyl)amino)-1-(4-methoxyphenyl)propan-1-ol, 16a Following the general procedure, the reaction between 2(benzylamino)ethanol 6a (319 mg, 2.11 mmol), 3-(N,N-dimethylamino)-1-(4-methoxyphenyl)propan-1-one hydrochloride 14a (512 mg, 2.10 mmol) and NaBH4 (119 mg, 3.15 mmol) in 5.0 mL of MeOH afforded compound 16a as a yellow solid. Purification: CH2Cl2/MeOH (20:1). Yield: 88% (583 mg); m.p. 68-69ºC (amorphous); FTIR (KBr): 3375 (O–H), 2949, 2835, 1611, 1176, 1130, 1034 (C–O) cm-1; 1H NMR (400 MHz, CDCl3): 1.77–1.84 (m, 1H), 1.88–1.98 (m, 1H), 2.59 (ddd, J = 5.1, 5.1, 13.1 Hz, 1H), 2.67– 2.86 (m, 4H), 3.54 (d, J = 13.1 Hz, 1H), 3.63–3.73 (m, 2H), 3.80 (d, J = 13.1 Hz, 1H), 3.80 (s, 3H), 4.78 (dd, J = 3.3, 8.6 Hz, 1H, CH– O), 5.52 (br s, 1H, OH), 6.85 (d, J = 8.5 Hz, 2H), 7.23 (d, J = 8.8

2.3.5. (±)-3-(Benzyl(2-hydroxyethyl)amino)-1-(3,4,5-trimethoxyphenyl)propan-1-ol, 16c

Following the general procedure, the reaction between 2(benzylamino)ethanol 6a (287 mg, 1.90 mmol), 3-(N,N-dimethylamino)-1-(3,4,5-trimethoxyphenyl)propan-1-one hydrochloride 14c (586 mg, 1.93 mmol) and NaBH4 (108 mg, 2.85 mmol) in 5.0 mL of MeOH afforded compound 16c as a yellow oil. Purification: CH2Cl2/MeOH (15:1). Yield: 97% (692 mg); FTIR (film): 3365 (O–H), 2954, 2839, 1606, 1162, 1130, 1036 (C–O) cm–1; 1H NMR (400 MHz, CDCl3): 1.79–1.94 (m, 2H), 2.59 (ddd, J = 5.0, 5.0, 13.6 Hz, 1H), 2.70–2.80 (m, 2H), 2.87 (ddd, J = 4.3, 8.8, 13.2 Hz, 1H), 3.55 (d, J = 13.3 Hz, 1H), 3.64–3.75 (m, 2H), 3.80–3.85 (m, 10H), 4.75 (dd, J = 2.9, 9.0 Hz, 1H, CH–O), 6.57 (s, 2H), 7.28–7.36 (m, 5H) ppm, OH is absent; 13C NMR (100 MHz, CDCl3): 35.4 (CH2), 53.1 (CH2), 56.2 (CH3), 56.3 (CH2), 59.6 (CH2), 59.9 (CH2), 60.9 (CH3), 75.1 (CH–O), 102.5 (CH), 127.6 (CH), 128.6 (CH), 129.3 (CH), 137.0 (C), 137.9 (C), 140.5 (C), 153.2 (C) ppm; Anal. Calcd for C21H29NO5: C, 67.18; H, 7.79; N, 3.73. Found: C, 67.07; H, 7.91; N, 3.52. 2.3.6. (±)-3-(N-Benzyl-N-(2-hydroxyethyl)amino)-1-p-tolylpropan1-ol, 16d Following the general procedure, the reaction between 2(benzylamino)ethanol 6a (295 mg, 1.95 mmol), 3-(N,Ndimethylamino)-1-(p-tolyl)propan-1-one hydrochloride 14d (460 mg, 2.02 mmol) and NaBH4 (114 mg, 3.01 mmol) in 5.0 mL of MeOH afforded compound 16d as a yellow oil. Purification: CH2Cl2/MeOH (30:1). Yield: 67% (391 mg); FTIR (film): 3364 (O–H), 2946, 2831, 1602, 1128, 1054 (C–O) cm–1; 1H NMR (400 MHz, CDCl3): 1.79–1.86 (m, 1H), 1.88–1.97 (m, 1H), 2.33 (s, 3H), 2.60 (ddd, J = 4.4, 5.8, 13.4 Hz, 1H), 2.67–2.77 (m, 2H), 2.84 (ddd, J = 4.4, 8.7, 13.1 Hz, 1H), 3.53 (d, J = 13.3 Hz, 1H), 3.62– 3.72 (m, 2H), 3.78 (d, J = 13.3 Hz, 1H), 4.79 (dd, J = 3.4, 8.8 Hz, 1H, CH–O), 7.12 (d, J = 8.0 Hz, 2H), 7.19 (d, J = 8.0 Hz, 2H), 7.28–7.35 (m, 5H) ppm, OH is absent; 13C NMR (100 MHz, CDCl3): 21.2 (CH3), 35.3 (CH2), 52.8 (CH2), 56.2 (CH2), 59.6 (CH2), 59.9 (CH2), 74.7 (CH–O), 125.6 (CH), 127.5 (CH), 128.6 (CH),


129.0 (CH), 129.3 (CH), 136.8 (C), 138.0 (C), 141.7 (C) ppm; Anal. Calcd for C19H25NO2: C, 76.22; H, 8.42; N, 4.68. Found: C, 76.01; H, 8.46; N, 4.83. 2.3.7. (±)-3-(N-Benzyl-N-(2-hydroxyethyl)amino)-1-phenylpropan-1-ol, 16e

373

3-(N,N-dimethylamino)propan-1-one hydrochloride 14h (533 mg, 2.15 mmol) and NaBH4 (121 mg, 3.20 mmol) in 5.0 mL of MeOH afforded compound 16h as a yellow oil. Purification: CH2Cl2/ MeOH (20:1). Yield: 89% (603 mg); FTIR (film): 3388 (O–H), 2948, 2828, 1598, 1130, 1086, 1014 (C–O) cm-1; 1H NMR (400 MHz, CDCl3): 1.79–1.90 (m, 2H), 2.61 (ddd, J = 5.1, 5.2, 13.4 Hz, 1H), 2.69–2.80 (m, 2H), 2.85 (ddd, J = 4.6, 8.6, 13.0 Hz, 1H), 3.54 (d, J = 13.3 Hz, 1H), 3.65–3.76 (m, 2H), 3.81 (d, J = 13.3 Hz, 1H), 4.81 (dd, J = 3.5, 8.2 Hz, 1H, CH–O), 7.23 (d, J = 8.5 Hz, 2H), 7.28 (d, J = 8.3 Hz, 2H), 7.31–7.41 (m, 5H) ppm, OH is absent; 13C NMR (100 MHz, CDCl3): 35.0 (CH2), 52.6 (CH2), 56.0 (CH2), 59.4 (CH2), 59.8 (CH2), 74.1 (CH–O), 126.9 (CH), 127.4 (CH), 128.3 (CH), 128.5 (CH), 129.2 (CH), 132.5 (C), 137.7 (C), 143.1 (C) ppm; Anal. Calcd for C18H22ClNO2: C, 67.60; H, 6.93; N, 4.38. Found: C, 67.82; H, 6.85; N, 4.52. 2.3.11. (±)-(Benzyl(2-hydroxyethyl)amino)-1-(2-chlorophenyl)propan-1-ol, 16i Following the general procedure, the reaction between 2(benzylamino)ethanol 6a (310 mg, 2.05 mmol), 1-(2-chlorophenyl)3-(N,N-dimethylamino)propan-1-one hydrochloride 14i (509 mg, 2.05 mmol) and NaBH4 (117 mg, 3.10 mmol) in 5.0 mL of MeOH afforded compound 16i as a yellow oil. Purification: CH2Cl2/MeOH (30:1). Yield: 82% (538 mg); FTIR (film): 3380 (O–H), 2945, 2830, 1599, 1129, 1083, 1018 (C–O) cm-1; 1H NMR (400 MHz, CDCl3): 1.70–1.79 (m, 1H), 1.97–2.04 (m, 1H), 2.62 (ddd, J = 5.0, 5.0, 13.4 Hz, 1H), 2.72–2.78 (m, 2H), 2.88 (ddd, J = 4.5, 9.5, 12.7 Hz, 1H), 3.58 (d, J = 13.2 Hz, 1H), 3.68–3.75 (m, 2H), 3.78 (d, J = 13.2 Hz, 1H), 5.20 (dd, J = 2.0, 9.0 Hz, 1H, CH–O), 7.15 (t, J = 7.5 Hz, 1H), 7.21–7.37 (m, 7H), 7.53 (d, J = 7.7 Hz, 1H) ppm, OH is absent; 13C NMR (100 MHz, CDCl3): 33.1 (CH2), 52.9 (CH2), 56.1 (CH2), 59.6 (CH2), 60.0 (CH2), 71.8 (CH–O), 127.1 (CH), 127.2 (CH), 127.6 (CH), 128.1 (CH), 128.7 (CH), 129.3 (CH), 129.4 (CH), 131.3 (C), 137.8 (C), 142.0 (C) ppm; Anal. Calcd for C18H22ClNO2: C, 67.60; H, 6.93; N, 4.38. Found: C, 67.74; H, 6.85; N, 4.47.


Following the general procedure, the reaction between 2(benzylamino)ethanol 6a (322 mg, 2.13 mmol), 3-(N,N-dimethylamino)-1-phenylpropan-1-one hydrochloride 14e (449 mg, 2.10 mmol) and NaBH4 (115 mg, 3.05 mmol) in 5.0 mL of MeOH afforded compound 16e as a yellow oil. Purification: CH2Cl2/MeOH (30:1). Yield: 94% (563 mg); FTIR (film): 3396 (O–H), 2943, 2827, 1603, 1129, 1059, 1031 (C–O) cm-1; 1H NMR (400 MHz, CDCl3): 1.86–1.97 (m, 2H), 2.60 (ddd, J = 4.4, 5.7, 13.3 Hz, 1H), 2.68–2.78 (m, 2H), 2.85 (ddd, J = 4.5, 8.8, 13.2 Hz, 1H), 3.54 (d, J = 13.0 Hz, 1H), 3.63–3.73 (m, 2H), 3.79 (d, J = 13.0 Hz, 1H), 4.83 (dd, J = 3.5, 8.8 Hz, 1H, CH–O), 7.22–7.37 (m, 10H) ppm, OH is absent; 13C NMR (100 MHz, CDCl3): 35.3 (CH2), 52.9 (CH2), 56.2 (CH2), 59.6 (CH2), 60.0 (CH2), 74.9 (CH–O), 125.6 (CH), 127.2 (CH), 127.6 (CH), 128.4 (CH), 128.7 (CH), 129.4 (CH), 138.0 (C), 144.7 (C) ppm; MS (70 eV, EI): m/z (%) = 254 (11) [M– 31]+, 164 (5), 150 (2), 134 (44), 120 (3), 91 (86) [PhCH2]+, 42 (100); Anal. Calcd for C18H23NO2: C, 75.76; H, 8.12; N, 4.91. Found: C, 75.91; H, 8.24; N 5.01.


2.3.8. (±)-3,3'-((1,4-Phenylenebis(methylene))bis((2-hydroxyethyl) azanediyl))bis(1-phenylpropan-1-ol), 16f

Following the general procedure, the reaction between 2(benzylamino)ethanol 6a (331 mg, 2.19 mmol), 1,1'-(1,4-phenylene)bis(3-(N,N-dimethylamino)propan-1-one) dihydrochloride 14f (367 mg, 1.05 mmol) and NaBH4 (119 mg, 3.15 mmol) in 5.0 mL of MeOH afforded compound 16f as a yellow oil in a 1:1 mixture of diastereomers. Purification: CH2Cl2/MeOH (15:1). Yield: 87% (450 mg); FTIR (film): 3494 (O–H), 2935, 2833, 1603, 1130, 1071 (C– O) cm–1; 1H NMR (400 MHz, CDCl3): 1.79–1.94 (m, 4H), 2.59 (ddd, J = 5.0, 5.0, 13.6 Hz, 2H), 2.67–2.76 (m, 4H), 2.79–2.86 (m, 2H), 3.54 (d, J = 13.3 Hz, 2H), 3.62–3.70 (m, 4H), 3.78 (d, J = 13.2 Hz, 2H), 4.80 (dd, J = 3.5, 8.4 Hz, 2H, CH–O), 7.24–7.36 (m, 14H) ppm, OH is absent; 13C NMR (100 MHz, CDCl3): 35.2 (CH2), 52.8 (CH2), 56.2 (CH2), 59.6 (CH2), 59.9 (CH2), 74.7 (CH–O), 125.6 (CH), 127.5 (CH), 128.7 (CH), 129.4 (CH), 138.0 (C), 143.6 (C) ppm; Anal. Calcd for C30H40N2O4: C, 73.14; H, 8.18; N, 5.69. Found: C, 73.25; H, 8.02; N, 5.73. 2.3.9. (±)-3-(N-Benzyl-N-(2-hydroxyethyl)amino)-1-(4-bromophenyl)propan-1-ol, 16g

Following the general procedure, the reaction between 2(benzylamino)ethanol 6a (304 mg, 2.01 mmol), 1-(4-bromophenyl)3-(N,N-dimethylamino)propan-1-one hydrochloride 14g (600 mg, 2.05 mmol) and NaBH4 (116 mg, 3.08 mmol) in 5.0 mL of MeOH afforded compound 16g as a yellow solid. Purification: CH2Cl2/MeOH (30:1). Yield: 91% (666 mg); m.p. 73-74ºC (amorphous); FTIR (KBr): 3354 (O–H), 2938, 2823, 1590, 1112, 1069, 1057, 1009 (C–O) cm -1; 1H NMR (400 MHz, CDCl3): 1.79–1.86 (m, 2H), 2.58–2.85 (m, 5H), 3.52 (d, J = 13.3 Hz, 1H), 3.65–3.72 (m, 2H), 3.78 (d, J = 13.3 Hz, 1H), 4.78 (dd, J = 3.4, 7.8 Hz, 1H, CH–O), 5.95 (br s, 1H, OH), 7.15 (d, J = 8.3 Hz, 2H), 7.28–7.37 (m, 5H), 7.41 (d, J = 8.3 Hz, 2H) ppm; 13C NMR (100 MHz, CDCl3): 35.1 (CH2), 52.8 (CH2), 56.2 (CH2), 59.7 (CH2), 60.0 (CH2), 74.4 (CH–O), 120.8 (C), 127.4 (CH), 127.6 (CH), 128.7 (CH), 129.4 (CH), 131.4 (CH), 137.8 (C), 143.8 (C) ppm; Anal. Calcd for C18H22BrNO2: C, 59.35; H, 6.09; N, 3.85. Found: C, 59.28; H, 5.93; N, 4.01. 2.3.10. (±)-3-(Benzyl(2-hydroxyethyl)amino)-1-(4-chlorophenyl) propan-1-ol, 16h Following the general procedure, the reaction between 2(benzylamino)ethanol 6a (320 mg, 2.12 mmol), 1-(4-chlorophenyl)-

2.3.12. (±)-3-(Benzyl(2-hydroxyethyl)amino)-1-(thiophen-2-yl) pro-pan-1-ol, 16j

Following the general procedure, the reaction between 2(benzylamino)ethanol 6a (295 mg, 1.95 mmol), N,N-dimethyl-3oxo-3-(thiophen-2-yl)propan-1-aminium chloride 14j (442 mg, 2.01 mmol) and NaBH4 (114 mg, 3.01 mmol) in 5.0 mL of MeOH afforded compound 16j as a yellow oil. Purification: CH2Cl2/MeOH (30:1). Yield: 93% (528 mg); FTIR (film): 3381 (O–H), 2941, 2829, 1601, 1130, 1079, 1009 (C–O) cm-1; 1H NMR (400 MHz, CDCl3): 1.95–2.09 (m, 2H), 2.59 (ddd, J = 5.2, 5.2, 13.4 Hz, 1H), 2.48 (br s, 1H, OH), 2.56–2.87 (m, 3H), 3.56 (d, J = 13.2 Hz, 1H), 3.60–3.70 (m, 2H), 3.77 (d, J = 13.2 Hz, 1H), 5.09 (dd, J = 4.0, 8.0 Hz, 1H, CH–O), 5.96 (br s, 1H, OH), 6.88 (d, J = 3.3 Hz, 1H), 6.93 (t, J = 4.2 Hz, 1H), 7.20 (d, J = 5.0 Hz, 1H), 7.25–7.36 (m, 5H) ppm; 13C NMR (100 MHz, CDCl3): 35.2 (CH2), 52.5 (CH2), 56.1 (CH2), 59.5 (CH2), 60.0 (CH2), 71.1 (CH–O), 122.8 (CH), 124.1 (CH), 126.7 (CH), 127.6 (CH), 128.7 (CH), 129.3 (CH), 137.8 (C), 149.0 (C) ppm; Anal. Calcd for C16H21NO2S: C, 65.95; H, 7.26; N, 4.81. Found: C, 66.10; H, 7.40; N, 4.98. 2.3.13. (±)-3-(N-Benzyl-N-(2-hydroxyethyl)amino)-1-(4-nitrophenyl)propan-1-ol, 16k Following the general procedure, the reaction between 2(benzylamino)ethanol 6a (319 mg, 2.11 mmol), 3-(N,Ndimethylamino)-1-(4-nitrophenyl)propan-1-one hydrochloride 14k (543 mg, 2.10 mmol) and NaBH4 (121 mg, 3.20 mmol) in 5.0 mL of MeOH afforded compound 16k as a yellow oil. Purification: CH2Cl2/MeOH (30:1). Yield: 63% (437 mg); FTIR (film): 3386 (O–H), 2946, 2836, 1602, 1519 (NO2), 1346 (NO2), 1109, 1076, 1054 (C–O) cm–1; 1H NMR (400 MHz, CDCl3): 1.81–1.88 (m, 2H), 2.63 (ddd, J = 4.8, 5.0, 12.0 Hz, 1H), 2.70–2.80 (m, 2H), 2.87


Castillo et al.

3.82 (s, 3H), 3.86 (s, 6H), 4.01 (ddd, J = 3.5, 5.1, 12.7 Hz, 1H), 4.78 (dd, J = 4.8, 8.8 Hz, 1H, CH–O), 6.58 (s, 2H), 7.25 (t, J = 7.0 Hz, 1H), 7.30–7.38 (m, 4H) ppm; 13C NMR (100 MHz, CDCl3): 37.3 (CH2), 53.0 (CH2), 56.2 (CH3), 58.2 (CH2), 60.9 (CH3), 62.8 (CH2), 68.5 (CH2), 80.2 (CH–O), 102.9 (CH), 127.1 (CH), 128.3 (CH), 128.9 (CH), 137.0 (C), 139.2 (C), 140.1 (C), 153.2 (C) ppm; MS (70 eV, EI): m/z (%) = 357 (10) [M]+, 279 (40), 266 (68), 238 (15), 222 (54), 195 (86), 167 (48), 149 (88), 106 (12), 91 (29) [PhCH2]+, 83 (100); Anal. Calcd for C21H27NO4: C, 70.56; H, 7.61; N, 3.92. Found: C, 70.67; H, 7.43; N, 4.05.

2.3.14. (±)-4-Benzyl-7-(4-methoxyphenyl)-1,4-oxazepane, 17a

2.3.17. (±)-4-Benzyl-7-p-tolyl-1,4-oxazepane, 17d

According to the general procedure, the reaction of bis-alcohol 16a (158 mg, 0.50 mmol) and concentrated sulfuric acid (28 L, 0.53 mmol) in 2.0 mL of p-dioxane at 30ºC afforded first 1,4oxazepane 17a (132 mg, 89%) and then allylamine 18a (9 mg, 6%). Yellow oil; FTIR (film): 2936, 2832, 1611, 1176, 1140, 1034 (C– O) cm-1; 1H NMR (400 MHz, CDCl3): 2.16–2.28 (m, 2H), 2.77– 2.94 (m, 4H), 3.75 (s, 2H), 3.79–3.86 (m, 4H), 4.02 (ddd, J = 3.8, 4.7, 13.1 Hz, 1H), 4.86 (dd, J = 5.1, 8.4 Hz, 1H, CH–O), 6.91 (d, J = 8.8 Hz, 2H), 7.29–7.42 (m, 7H) ppm; 13C NMR (100 MHz, CDCl3): 36.7 (CH2), 52.7 (CH2), 55.4 (CH3), 58.3 (CH2), 62.7 (CH2), 67.6 (CH2), 79.6 (CH–O), 113.8 (CH), 127.0 (CH), 127.3 (CH), 128.4 (CH), 129.1 (CH), 136.4 (C), 138.6 (C), 158.8 (C) ppm; MS (70 eV, EI): m/z (%) = 297 (7) [M]+, 206 (100), 190 (6), 178 (52), 162 (15), 135 (82), 119 (46), 106 (23), 91 (50) [PhCH2]+, 42 (22); Anal. Calcd for C19H23NO2: C, 76.73; H, 7.80; N, 4.71. Found: C, 76.85; H, 7.96; N, 4.85. (E)-2-(Benzyl(3-(4-methoxyphenyl)allyl) amino)ethanol, 18a. Yellow oil (lit. Yellow oil) [18]; FTIR (film): 3460 (O–H), 2934, 2834, 1607, 1577, 1176, 1033 (C–O) cm–1; 1 H NMR (400 MHz, CDCl3): 2.49 (br s, 1H, OH), 2.65 (t, J = 5.5 Hz, 2H), 3.22 (d, J = 6.8 Hz, 2H), 3.54 (t, J = 5.4 Hz, 2H), 3.62 (s, 2H), 3.74 (s, 3H), 6.05 (dt, J = 6.8, 16.0 Hz, 1H), 6.39 (d, J = 16.1 Hz, 1H), 6.79 (d, J = 8.8 Hz, 2H), 7.18–7.30 (m, 7H) ppm; 13C NMR (100 MHz, CDCl3): 54.8 (CH2), 55.4 (CH3), 56.1 (CH2), 58.1 (CH2), 58.6 (CH2), 114.1 (CH), 124.3 (CH), 127.3 (CH), 127.5 (CH), 128.5 (CH), 129.1 (CH), 129.8 (C), 132.8 (CH), 138.9 (C), 159.3 (C) ppm; MS (70 eV, EI): m/z (%) = 297 (4) [M]+, 266 (29), 147 (100), 115 (9), 91 (68) [PhCH2]+. The NMR data matches with the previously reported data [18].

Following the general procedure, the reaction of bis-alcohol 16d (144 mg, 0.48 mmol) and concentrated sulfuric acid (28 L, 0.53 mmol) in 2.0 mL of p-dioxane at 60ºC afforded compound 17d as a colorless oil. Yield: 85% (115 mg); FTIR (film): 2931, 2858, 1603, 1143, 1108, 1086 (C–O) cm-1; 1H NMR (400 MHz, CDCl3): 2.11–2.25 (m, 2H), 2.35 (s, 3H), 2.72–2.87 (m, 4H), 3.70 (s, 2H), 3.81 (ddd, J = 3.2, 6.4, 12.8 Hz, 1H), 4.01 (ddd, J = 3.1, 5.5, 12.9 Hz, 1H), 4.86 (dd, J = 4.9, 8.6 Hz, 1H, CH–O), 7.16 (d, J = 8.0 Hz, 2H), 7.26–7.30 (m, 3H), 7.32–7.40 (m, 4H) ppm; 13C NMR (100 MHz, CDCl3): 21.1 (CH3), 37.1 (CH2), 52.9 (CH2), 58.4 (CH2), 62.8 (CH2), 68.0 (CH2), 79.9 (CH–O), 125.8 (CH), 127.1 (CH), 128.3 (CH), 129.0 (CH), 129.1 (CH), 136.6 (C), 139.3 (C), 141.4 (C) ppm; MS (70 eV, EI): m/z (%) = 250 (3) [M–31]+, 190 (25), 162 (41), 119 (41), 106 (14), 91 (62) [PhCH2]+, 42 (100); Anal. Calcd for C19H23NO: C, 81.10; H, 8.24; N, 4.98. Found: C, 81.25; H, 8.15; N, 5.10.

2.3.15. 17b


(ddd, J = 4.7, 8.0, 12.3 Hz, 1H), 3.53 (d, J = 13.3 Hz, 1H), 3.68– 3.76 (m, 2H), 3.78 (d, J = 13.3 Hz, 1H), 4.92 (dd, J = 4.1, 7.9 Hz, 1H, CH–O), 7.29–7.37 (m, 5H), 7.40 (d, J = 8.8 Hz, 2H), 8.11 (d, J = 8.8 Hz, 2H) ppm, OH is absent; 13C NMR (100 MHz, CDCl3): 34.8 (CH2), 52.8 (CH2), 56.2 (CH2), 59.7 (CH2), 60.0 (CH2), 74.3 (CH–O), 123.6 (CH), 126.3 (CH), 127.7 (CH), 128.7 (CH), 129.4 (CH), 137.6 (C), 147.0 (C), 152.2 (C) ppm; MS (70 eV, EI): m/z (%) = 299 (45) [M–31]+, 164 (18), 150 (3), 134 (60), 120 (6), 91 (100) [PhCH2]+, 42 (15); Anal. Calcd for C18H22N2O4: C, 65.44; H, 6.71; N, 8.48. Found: C, 65.58; H, 6.66; N, 8.54.

(±)-7-(Benzo[d][1,3]dioxol-5-yl)-4-benzyl-1,4-oxazepane,

Following the general procedure, the reaction of bis-alcohol 16b (161 mg, 0.49 mmol) and concentrated sulfuric acid (28 L, 0.53 mmol) in 2.0 mL of p-dioxane at 40ºC afforded compound 17b as a colorless oil. Yield: 81% (124 mg); FTIR (film): 2936, 2815, 1607, 1243, 1144, 1103, 1039 (C–O) cm-1; 1H NMR (400 MHz, CDCl3): 2.07–2.24 (m, 2H), 2.71–2.89 (m, 4H), 3.70 (s, 2H), 3.81 (ddd, J = 3.3, 6.4, 12.8 Hz, 1H), 4.00 (ddd, J = 3.3, 5.3, 12.9 Hz, 1H), 4.81 (dd, J = 5.0, 8.4 Hz, 1H, CH–O), 5.96 (s, 2H), 6.79 (d, J = 8.0 Hz, 1H), 6.84 (dd, J = 1.1, 8.0 Hz, 1H), 6.92 (d, J = 1.2 Hz, 1H), 7.26–7.41 (m, 5H) ppm; 13C NMR (100 MHz, CDCl3): 37.2 (CH2), 52.8 (CH2), 58.3 (CH2), 62.8 (CH2), 68.1 (CH2), 79.9 (CH– O), 100.9 (CH2), 106.7 (CH), 108.1 (CH), 119.0 (CH), 127.1 (CH), 128.3 (CH), 129.0 (CH), 138.5 (C), 139.2 (C), 146.5 (C), 147.7 (C) ppm; MS (70 eV, EI): m/z (%) = 220 (1) [M–91]+, 119 (5), 106 (4), 91 (19) [PhCH2]+, 42 (100); Anal. Calcd for C19H21NO3: C, 73.29; H, 6.80; N, 4.50. Found: C, 73.45; H, 6.97; N, 4.36. 2.3.16. 17c

(±)-4-Benzyl-7-(3,4,5-trimethoxyphenyl)-1,4-oxazepane,

Following the general procedure, the reaction of bis-alcohol 16c (210 mg, 0.56 mmol) and concentrated sulfuric acid (28 L, 0.53 mmol) in 2.0 mL of p-dioxane at 40ºC afforded compound 17c as a colorless oil. Yield: 88% (176 mg); FTIR (film): 2936, 2831, 1591, 1236, 1128, 1010 (C–O) cm-1; 1H NMR (400 MHz, CDCl3): 2.06– 2.23 (m, 2H), 2.71–2.86 (m, 4H), 3.68 (s, 2H), 3.76–3.83 (m, 1H),

2.3.18. (±)-4-Benzyl-7-phenyl-1,4-oxazepane, 17e

According to the general procedure, the reaction of bis-alcohol 16e (150 mg, 0.53 mmol) and concentrated sulfuric acid (28 L, 0.53 mmol) in 2.0 mL of p-dioxane at 60ºC afforded first 1,4oxazepane 17e (116 mg, 82%) and then allylamine 18e (10 mg, 7%). Yellow oil; FTIR (film): 2936, 2865, 1602, 1143, 1109, 1070 (C–O) cm–1; 1H NMR (400 MHz, CDCl3): 2.10–2.19 (m, 1H), 2.22–2.29 (m, 1H), 2.73–2.90 (m, 4H), 3.70 (s, 2H), 3.83 (ddd, J = 3.5, 6.6, 12.8 Hz, 1H), 4.03 (ddd, J = 3.3, 5.4, 12.8 Hz, 1H), 4.89 (dd, J = 5.0, 8.8 Hz, 1H, CH–O), 7.28 (t, J = 6.9 Hz, 2H), 7.33–7.41 (m, 8H) ppm; 13C NMR (100 MHz, CDCl3): 37.2 (CH2), 52.9 (CH2), 58.4 (CH2), 62.8 (CH2), 68.2 (CH2), 80.1 (CH–O), 125.8 (CH), 127.1 (CH x 2), 128.4 (CH x 2), 129.0 (CH), 139.2 (C), 144.4 (C) ppm; MS (70 eV, EI): m/z (%) = 176 (2) [M–91]+ (2), 148 (5), 119 (7), 106 (5), 91 (43) [PhCH2]+, 42 (100); Anal. Calcd for C18H21NO: C, 80.86; H, 7.92; N, 5.24. Found: C, 81.01; H, 8.06; N, 5.09. (E)-2-(Benzyl(cinnamyl)amino)ethanol, 18e. Yellow oil; FTIR (film): 3424 (O–H), 2944, 2880, 1599, 1580, 1127, 1053, 1028 (C–O) cm–1; 1H NMR (400 MHz, CDCl3): 2.43 (br s, 1H, OH), 2.76 (t, J = 5.4 Hz, 2H), 3.34 (dd, J = 1.0, 6.8 Hz, 2H), 3.65 (t, J = 5.4 Hz, 2H), 3.73 (s, 2H), 6.29 (dt, J = 6.8, 16.0 Hz, 1H), 6.55 (d, J = 16.0 Hz, 1H), 7.25–7.42 (m, 10H) ppm; 13C NMR (100 MHz, CDCl3): 54.7 (CH2), 55.9 (CH2), 58.1 (CH2), 58.5 (CH2), 126.3 (CH), 126.5 (CH), 127.2 (CH), 127.5 (CH), 128.4 (CH), 128.5 (CH), 129.0 (CH), 133.2 (CH), 136.8 (C), 138.7 (C) ppm; Anal. Calcd for C18H21NO: C, 80.86; H, 7.92; N, 5.24. Found: C, 80.92; H, 7.78; N, 5.36. 2.3.19. (±)-1,4-bis(4-Benzyl-1,4-oxazepan-7-yl)benzene, 17f Following the general procedure, the reaction of N-tethered alcohol 16f (251 mg, 0.51 mmol) and concentrated sulfuric acid (54 L, 1.01 mmol) in p-dioxane (2.0 mL) at 60ºC afforded compound 17f as a colorless oil in a 1:1 mixture of diastereomers. Yield: 68% (158 mg); FTIR (film): 2934, 2855, 1603, 1142, 1107, 1084, 1070, 1024 (C–O) cm-1; 1H NMR (400 MHz, CDCl3): 2.07–2.15 (m, 2H), 2.17–2.25 (m, 2H), 2.70–2.87 (m, 8H), 3.68 (s, 4H), 3.80 (ddd, J = 3.4, 6.6, 13.0 Hz, 2H), 3.99 (ddd, J = 3.1, 5.6, 12.9 Hz, 2H), 4.86 (dd, J = 5.0, 8.6 Hz, 2H, CH–O), 7.25–7.38 (m, 14H) ppm; 13C



R1

R1 N

H +

CH2O

N

+

O

OH 6a,b

ACN

O N

N

rt, 48 h

O 9a, R1 = Ph (52%) 9b, R1 = CH2OH (46%)

8

7

375

Pathway (a)

R1

R1 N

R1 N

CH2

O

11 (R1 = Ph)

8

R1

O N

OH 10

N OH

OH or H2O

OH N

Pathway (b)

O N

OH 13 (R1 = Ph)

12


Scheme 1. Synthesis of novel 1,4-oxazepanes 9 through a three-component Mannich-type reaction.

NMR (100 MHz, CDCl3): 37.1 (CH2), 52.9 (CH2), 58.4 (CH2), 62.8 (CH2), 68.1 (CH2), 79.9 (CH–O), 125.8 (CH), 127.1 (CH), 128.3 (CH), 129.0 (CH), 139.3 (C), 143.1 (C) ppm; MS (70 eV, EI): m/z (%) = 456 (13) [M]+, 425 (34), 397 (20), 365 (100), 337 (24), 306 (28), 294 (30), 280 (18), 264 (19), 190 (5), 91 (5) [PhCH2]+; Anal. Calcd for C30H36N2O2: C, 78.91; H, 7.95; N, 6.13. Found: C, 78.79; H, 7.84; N, 6.32.

2H), 3.64 (t, J = 5.4 Hz, 2H), 3.70 (s, 2H), 6.24 (dt, J = 6.6, 15.8 Hz, 1H), 6.48 (d, J = 15.8 Hz, 1H), 7.27–7.38 (m, 9H) ppm; 13C NMR (100 MHz, CDCl3): 55.0 (CH2), 56.0 (CH2), 58.3 (CH2), 58.6 (CH2), 127.4 (CH), 127.5 (CH), 127.6 (CH), 128.6 (CH), 128.8 (CH), 129.1 (CH), 132.0 (CH), 133.2 (C), 136.5 (C), 138.7 (C) ppm; MS (70 eV, EI): m/z (%) = 153/151 (31/100) [M–150]+, 115 (51), 91 (93) [PhCH2]+, 42 (28); Anal. Calcd for C18H20ClNO: C, 71.63; H, 6.68; N, 4.64. Found: C, 71.52; H, 6.74; N, 4.51.

2.3.20. (±)-4-Benzyl-7-(4-bromophenyl)-1,4-oxazepane, 17g

2.3.22. (±)-4-Benzyl-7-(2-chlorophenyl)-1,4-oxazepane, 17i

According to the general procedure, the reaction of bis-alcohol 16g (189 mg, 0.52 mmol) and concentrated sulfuric acid (28 L, 0.53 mmol) in 2.0 mL of p-dioxane at 80ºC afforded compound 17g as a yellow oil. Yield: 51% (92 mg); FTIR (film): 2938, 2864, 1591, 1144, 1108, 1071 (C–O) cm–1; 1H NMR (400 MHz, CDCl3): 2.03–2.12 (m, 1H), 2.21–2.28 (m, 1H), 2.72–2.87 (m, 4H), 3.70 (s, 2H), 3.82 (ddd, J = 4.5, 5.5, 12.7 Hz, 1H), 4.01 (ddd, J = 4.4, 5.3, 12.8 Hz, 1H), 4.86 (dd, J = 4.8, 8.4 Hz, 1H, CH–O), 7.25–7.31 (m, 3H), 7.34–7.40 (m, 4H), 7.48 (d, J = 8.3 Hz, 2H) ppm; 13C NMR (100 MHz, CDCl3): 37.2 (CH2), 52.7 (CH2), 58.4 (CH2), 62.8 (CH2), 68.3 (CH2), 79.3 (CH–O), 120.8 (C), 127.1 (CH), 127.6 (CH), 128.4 (CH), 128.9 (CH), 131.4 (CH), 139.2 (C), 143.5 (C) ppm; MS (70 eV, EI): m/z (%) = 347/345 (18/17) [M]+, 256/254 (59/53), 228/226 (69/73), 119 (31), 91 (100) [PhCH2]+, 42 (13); Anal. Calcd for C18H20BrNO: C, 62.44; H, 5.82; N, 4.05. Found: C, 62.66; H, 5.71; N, 4.30.

According to the general procedure, the reaction of bis-alcohol 16i (156 mg, 0.49 mmol) and concentrated sulfuric acid (28 L, 0.53 mmol) in 2.0 mL of p-dioxane at 80ºC afforded compound 17i as a yellow oil. Yield: 42% (62 mg); FTIR (film): 2937, 2862, 1597, 1140, 1103, 1085 (C–O) cm–1; 1H NMR (400 MHz, CDCl3): 1.92–2.00 (m, 1H), 2.22–2.30 (m, 1H), 2.69–2.83 (m, 4H), 3.67 (d, J = 13.5 Hz, 1H), 3.71 (d, J = 13.5 Hz, 1H), 3.85 (ddd, J = 3.3, 7.1, 12.7 Hz, 1H), 4.03 (ddd, J = 3.3, 5.0, 12.8 Hz, 1H), 5.20 (dd, J = 4.4, 7.6 Hz, 1H, CH–O), 7.16 (td, J = 1.5, 7.6 Hz, 1H), 7.23–7.38 (m, 7H), 7.60 (d, J = 7.6 Hz, 1H) ppm; 13C NMR (100 MHz, CDCl3): 35.7 (CH2), 52.8 (CH2), 58.0 (CH2), 62.6 (CH2), 68.9 (CH2), 76.7 (CH–O), 126.9 (CH), 127.1 (CH), 127.3 (CH), 128.1 (CH), 128.4 (CH), 129.0 (CH), 129.3 (CH), 131.4 (C), 139.2 (C), 142.0 (C) ppm; Anal. Calcd for C18H20ClNO: C, 71.63; H, 6.68; N, 4.64. Found: C, 71.85; H, 6.79; N, 4.48.

2.3.21. (±)-4-Benzyl-7-(4-chlorophenyl)-1,4-oxazepane, 17h

According to the general procedure, the reaction of bis-alcohol 16h (156 mg, 0.49 mmol) and concentrated sulfuric acid (28 L, 0.53 mmol) in 2.0 mL of p-dioxane at 80ºC afforded first 1,4oxazepane 17h (68 mg, 46%) and then allylamine 18h (28 mg, 19%). Yellow oil; FTIR (film): 2938, 2865, 1595, 1143, 1108, 1088 (C–O) cm–1; 1H NMR (400 MHz, CDCl3): 1.98–2.06 (m, 1H), 2.14–2.21 (m, 1H), 2.65–2.80 (m, 4H), 3.64 (s, 2H), 3.76 (ddd, J = 4.4, 5.6, 12.6 Hz, 1H), 3.95 (ddd, J = 3.9, 4.8, 12.8 Hz, 1H), 4.81 (dd, J = 5.0, 8.4 Hz, 1H, CH–O), 7.20–7.34 (m, 9H) ppm; 13C NMR (100 MHz, CDCl3): 37.2 (CH2), 52.7 (CH2), 58.4 (CH2), 62.8 (CH2), 68.3 (CH2), 79.3 (CH–O), 127.1 (CH), 127.2 (CH), 128.4 (CH), 128.5 (CH), 128.9 (CH), 132.7 (C), 139.2 (C), 142.9 (C) ppm; MS (70 eV, EI): m/z (%) = 212/210 (25/72) [M–91]+, 184/182 (35/100), 162 (16), 119 (40), 91 (53) [PhCH2]+, 42 (28); Anal. Calcd for C18H20ClNO: C, 71.63; H, 6.68; N, 4.64. Found: C, 71.84; H, 6.53; N, 4.72. (E)-2-(Benzyl(3-(4-chlorophenyl)allyl) amino)ethanol, 18h. Yellow oil; FTIR (film): 3406 (O–H), 2928, 2816, 1596, 1091, 1052 (C–O) cm–1; 1H NMR (400 MHz, CDCl3): 1.71 (br s, 1H, OH), 2.74 (t, J = 5.4 Hz, 2H), 3.32 (d, J = 6.5 Hz,

2.3.23. (±)-4-Benzyl-7-(thiophen-2-yl)-1,4-oxazepane, 17j

According to the general procedure, the reaction of bis-alcohol 16j (137 mg, 0.50 mmol) and concentrated sulfuric acid (28 L, 0.53 mmol) in 2.0 mL of p-dioxane at 30ºC afforded compound 17j as a colorless oil. Yield: 90% (123 mg); 1H NMR (400 MHz, CDCl3): 2.20–2.36 (m, 2H), 2.66–2.88 (m, 4H), 3.65 (s, 2H), 3.73 (ddd, J = 2.2, 6.8, 13.0 Hz, 1H), 3.96 (ddd, J = 2.2, 6.8, 13.0 Hz, 1H), 5.09 (dd, J = 5.4, 8.8 Hz, 1H, CH–O), 6.91–6.97 (m, 2H), 7.21–7.36 (m, 6H) ppm; 13C NMR (100 MHz, CDCl3): 37.0 (CH2), 52.4 (CH2), 58.5 (CH2), 62.8 (CH2), 67.2 (CH2), 76.0 (CH– O), 123.2 (CH), 124.4 (CH), 126.7 (CH), 127.1 (CH), 128.4 (CH), 129.0 (CH), 139.2 (C), 148.1 (C) ppm; Anal. Calcd for C16H19NOS: C, 70.29; H, 7.00; N, 5.12. Found: C, 70.41; H, 6.86; N, 5.31. 3. RESULTS AND DISCUSSION In an attempt to obtain the non-fused 1,4-oxazepane core 9 under very mild reaction conditions, we envisioned that 1,4oxazepane skeleton could be assembled by the three-component Mannich-type reaction/intramolecular etherification sequence under catalyst-free conditions (Scheme 1). To test the feasibility of this


Ph

Castillo et al.

Ph

OH

Ph

Ph

O

NH OH

N

R1

N

R1 O 17

R1

N

OH

OH

16

15

6a O

+

R1

NHMe2Cl 14

Scheme 2. Retrosynthetic approach for the synthesis of the 4,7-disubstituted 1,4-oxazepanes 17. Synthesis of the N-tethered bis-alcohols 16 from a one-pot N-alkylation/reduction processa.

Table 1.

OH Ph

N

O

H

1 2 3 4 5

R1

NHMe2Cl

R1

N

2) MeOH, NaBH4, rt, 1 h (yields from two-step)

OH 16

14


Entry

Ph

+ OH

6a

1) p-dioxane:TEA, reflux, 2 h

14 (R1)

Product

Yield (%)b

4-MeOC6H4

16a

88

3,4-(OCH2O)C6H3

16b

78

3,4,5-(MeO)3C6H2

16c

97

4-MeC6H4

16d

67

Ph

16e

94

16f

87

4-BrC6H4

16g

91

4-ClC6H4

16h

89

ClMeHN

6

c

O

7 8 9 10 11 a

2-ClC6H4

16i

82

2-Thienyl

16j

93

4-O2NC6H4

16k

63

Reaction conditions: N-benzylethanolamine 6a (2.0 mmol, 1.0 equiv) and 3-(N,N-dimethylamino)propiophenone hydrochloride 14 (2.0 mmol, 1.0 equiv) using a 5:1 v/v mixture of p-dioxane:TEA under reflux for 2 h; after removing solvent under reduced pressure, addition of NaBH4 (3.0 mmol, 1.5 equiv) and MeOH (5.0 mL) at room temperature for 1 h; see experimental section for details. bIsolated yields are shown. c2.0 equiv of N-benzylethanolamine 6a was used.

strategy, a mixture of N-benzylethanolamine 6a (1.0 equiv), polyformaldehyde 7 (1.5 equiv), N-vinyl-2-pyrrolidone 8 (1.1 equiv) and acetonitrile (ACN) (2.0 mL) was stirred at room temperature for 48 h. After complete consumption of the starting amine 6a, we noticed the formation of several spots by TLC control. Then, the solvent was removed under reduced pressure, and the dense oily material so obtained was purified by column chromatography on silica gel using a mixture CH2Cl2/MeOH (40:1) as eluent. Notably, three new compounds were isolated and characterized by spectroscopic techniques corresponding to the expected 1,4-oxazepane 9a in 52% yield along with the 3-benzyloxazolidine 11a (28% yield) and the N-tethered bis-alcohol 13a in 13% yield (Scheme 1) [16]. Furthermore, subjecting diethanolamine 6b to the above established reaction conditions afforded the 1,4-oxazepane derivative 9b in 46% yield as the main component. Attempts to improve the yielding of the 1,4-oxazepanes 9a,b or reducing the number of sideproducts by modifying the reaction conditions (such as adding catalytic amount of Brønsted acids like PTSA or H2SO4, replacing ACN by polar aprotic solvents like THF or DMF and adding drying agents like Na2SO4 at room temperature or under heating) was unfruitful.

According to these results, the formation of 1,4-oxazepane 9 could occur via an intramolecular attack of the hydroxyl functionality as shown in the stabilized N-acyliminium species 12 (see pathway (a), Scheme 1), while the attack of a hydroxyl ion or a water molecule over 12 should lead to the N-tethered bis-alcohol 13 (see pathway (b), Scheme 1). Similarly, formation of the 3-benzyloxazolidine 11 should proceed by an intramolecular attack of the hydroxyl functionality as shown in the iminium ion type 10. It is worth mentioning that to date, a similar catalyst-free threecomponent approach for the synthesis of 1,4-oxazepane derivatives type 9 has not been documented elsewhere. The fact that three new bonds were formed in only one-step, gives to this approach an outstanding bond-forming efficiency and atom economy. However, this approach had some drawbacks such as long reaction times, limited substrate scope, and moderate yields of the desired product due to the formation of competing side-products.

Therefore, we visualized an alternative strategy for the synthesis of the novel 4,7-disubstituted 1,4-oxazepanes 17 (structurally analogous to 9), but this time, through the intramolecular etherification of previously formed N-tethered bis-alcohols type 16 (Scheme 2).


Table 2.

Solvent

Brønsted Acid

T (°C)b

t (h)

Ratio 17ac

Ratio 18ac

Ratio 19ac

Ratio 20ac

Ratio 21ac

1

ACN

PTSA

50

12

--

--

--

--

--

2

--

PTSA

110

3

14

80

--

--

--

d

377

Optimization of the reaction conditions for the synthesis of 1,4-oxazepanes 17a.

Entry

AcOH

AcOH

50

12

--

10

85

--

--

4e

ACN

H2SO4

50

12

24

3

--

49

--

5

PhMe

H2SO4

50

12

--

7

--

--

89

6

p-dioxane

H2SO4

90

12

9

91

--

--

--

7

p-dioxane

H2SO4

60

12

45

55

--

--

--

8

p-dioxane

--

--


3

a


H2SO4

30

12

95

5

--

Reaction conditions: mixture of N-tethered bis-alcohol 16a (0.30 mmol, 1.0 equiv) and Brønsted acid (2.0 equiv) in anhydrous solvent (2.0 mL). bConventional heating in an oil bath. cDetermined by 1H NMR from the crude reaction mixtures and confirmed by isolation from column chromatography. dOnly AcOH (2.0 mL) was used. eIncomplete reaction.

In turn, the key bis-alcohols 16 could be synthesized by reduction of their corresponding -aminoketones 15. Compounds 15 could be obtained from N-benzylethanolamine 6a and 3-(N,Ndimethylamino)propiophenone hydrochlorides 14 via two possible processes, either by a SN2 type reaction (of 6a over 14) or alternatively through a Michael type addition of 6a over the corresponding enones proceeding from a 1,2 (NHMe2/HCl)-elimination process of compounds 14 [15b]. These latter compounds 14 could be synthesized from their respective acetophenones by following a Mannich type procedure similar to that described in the literature [15b].

Thus, the N-tethered bis-alcohols 16 were obtained in a one-pot approach, using a single reaction vessel, as shown in Table 1. The treatment of N-benzylethanolamine 6a with 3-(N,N-dimethylamino)propiophenone hydrochlorides 14 [15b] in a 5:1 v/v mixture of p-dioxane:TEA under reflux for 2 h, afforded the -aminoketone intermediates 15 in nearly quantitative yields (TLC control). Then, after removing the initial solvents under reduced pressure, the crudes containing ketones 15 were re-dissolved in methanol and reduced with sodium borohydride at room temperature affording the expected N-tethered bis-alcohols 16 in combined yields up to 97% (Table 1). With this set of substrates 16 in hand, their subsequent key cyclization reactions toward the title compounds 17 were assayed (involving different solvents such as ACN, toluene, p-dioxane and solvent-free conditions or various Brønsted acids such as AcOH, PTSA and H2SO4 under heating conditions), Table 2. Throughout the course of the cyclization reaction described in Table 2, one can expect the formation of the desired 1,4-oxazepane 17a via the Brønsted acid-catalyzed intramolecular etherification reaction or alternatively the competing allylamines 18a which could be formed as side-products via a water elimination reaction. However, undesired side-products like 19a, 20a and 21a also were observed due to the trapping of the carbocationic species (formed during the course of the reaction) by the solvent used. Thus, 19a was formed via an esterification reaction involving the AcOH used as solvent (entry 3, Table 2), 20a was formed from a Ritter type reaction involving the ACN solvent [17], (entry 4, Table 2), while, 21a proceeds from an alkylation reaction of the toluene solvent (entry 5, Table 2).

Meanwhile, the couple sulfuric acid as catalyst and p-dioxane as the solvent afforded the most promising results in terms of selectivity and product yields (entries 6-8, Table 2). Thus, in a first assay, a mixture of the bis-alcohol 16a (1.0 equiv), sulfuric acid (2.0 equiv) and p-dioxane (2.0 mL) was stirred at 90°C for 12 h. After completion (TLC control), the undesired allylic amine 18a was formed as the major product (91%), while the expected 1,4oxazepane 17a was formed in just 9% (entry 6, Table 2). Due to the above undesired result, we decided to evaluate the effect of lowering the temperature over the regioselectivity of this reaction. Thus, the following assay was performed at 60°C during the same 12 h. This time, formation of both regioisomers was almost in similar yields (i.e. 45% of 17a and 55% of 18a, entry 7, Table 2). Finally, we were pleased to find that lowering the reaction temperature at 30°C the 1,4-oxazepane 17a was formed in 95%, while the allylic amine 18a was formed just in 5% (entry 8, Table 2). The above results allowed us to infer that the use of high temperatures favored the E1 mechanism leading to the formation of the undesired allylic amine 18a, while low temperatures favored the SN1 mechanism affording the desired 1,4-oxazepane 17a. Although the temperature plays a remarkable role in the prevailing mechanism (SN1 vs E1) of this intramolecular etherification reaction, we noticed that the nature of the R1 substituent in bisalcohols 16 resulted also critical. For that, in order to evaluate the general character of this methodology, it was also necessary to optimize the cyclization conditions for each of the remaining Ntethered bis-alcohols 16 depicted in Table 1. Table 3 outlines the scope of this Brønsted acid-catalyzed intramolecular etherification reaction for the synthesis of novel and diverse 4,7-disubstituted 1,4oxazepanes 17. According to the above results depicted in Table 3, the nature of the (hetero)aromatic ring (i.e. R1) attached to the secondary carbon atom holding the hydroxyl group in 16 turned out to be critical, perhaps as a result of the substituent effects on the stability of the benzylic carbocation species 22 formed in situ under the acidic reaction conditions established. Thus, the N-tethered bis-alcohols 16a–j having aromatic and heteroaromatic groups as R1 substituents, gave the desired 4,7disubstituted 1,4-oxazepanes 17a–j in moderate to good yields (entries 1-10, Table 3). Remarkably, the undesired competing allylamines 18 were formed in minority ratio or were not isolated. Par-


Castillo et al.

Synthesis of novel 4,7-disubstitued 1,4-oxazepanes 17 through a Brønsted acid-catalyzed intramolecular etherification reactiona,b.

Table 3.

Ph

OH R1

N

Ph

Ph p-dioxane H2SO4

R1

N

T (°C), 12 h

OH

Ph N

OH

16

R1

N

R1

+

OH

O

22

17

18

Entry

16; R1

T (°C)

Yield 17 (%)c

Yield 18 (%)c

1

16a; 4-MeOC6H4

30

17a (89)

18a (6)

2

16b; 3,4-(OCH2O)C6H3

40

17b (81)

-- d

3

16c; 3,4,5-(MeO)3C6H2

40

17c (88)

-- d

4

16d; 4-MeC6H4

60

17d (85)

-- d

5

16e; Ph

60

17e (82)

18e (7)

OH HO

60

17f (68)

-- d

16g; 4-BrC6H4

80

17g (51)

-- d

16h; 4-ClC6H4

80

17h (46)

18h (19)

16i; 2-ClC6H4

80

17i (42)

18i (20)

30

17j (90)

--d

--

--

--


6

e

N

Ph

16f;

7 8f 9

f

10 11g a

16j;

S

16k; 4-O2NC6H4

Reaction conditions: a mixture of N-tethered bis-alcohol 16 (0.50 mmol, 1.0 equiv) and concentrated H2SO4 (0.5 mmol, 2.0 equiv) in p-dioxane (2.0 mL) was stirred for 12 h; see experimental section for details. bConventional heating in an oil bath. cIsolated yields are shown. dAllylic amine was not isolated by column chromatography. eConcentrated H2SO4 (1.0 mmol, 4.0 equiv) was required. fUnreacted starting material 16 was recovered. gNo reaction at 70–90 °C or using higher amounts of H2SO4, the starting material 16k was recovered in 95%.

Cl

O

4 N

7

4 N

7

N

2 O 1

2 O 1

H

H

9a

17i

Fig. (2). H-2,C-7 three-bonds correlations observed in the HMBC spectra of products 9a and 17i.

ticularly, substrates 16 having H- or electron-donating groups (like MeO, OCH2O, Me, Ar) in their R1 substituents gave good yields (i.e. entries 1-6), whereas moderate electron-withdrawing groups (like Br-, Cl-) in their R1 substituents afforded acceptable yields (i.e. entries 7-9). Introducing a heteroaromatic activated ring like thiophene in 16 facilitated the cyclization and its corresponding product 17j was isolated in very good yield (entry 10). Interestingly, substrate 16k having a 4-nitrophenyl moiety as R1 substituent was unreactive under the established reaction conditions and it was recovered in 95% (entry 11). Moreover, efforts made increasing the equivalents of H2SO4 and temperature were unfruitful. At this stage, the effect of the substituent attached to R1 in 16 correlated quite well with the stability of the benzylic carbocation species 22 suggested as the key intermediate of this synthetic approach. So that, activated R1 substituents in 16 stabilized species 22 and hence increased the yield of products 17. Conversely, deactivated R1 substituents decreased it. Indeed, the presence of the strong deactivating group -NO2 did not afford any product 17 or 18 even at higher temperatures or higher amounts of H2SO4 (entry 11). This finding is

in agreement with a very low stability of its corresponding species 22 which is the common intermediate for both products 17 or 18 under the established reaction conditions. Furthermore, the temperature also correlated with the effect of the substituents in R1. Strong electron-donating substituents required lower temperatures (i.e. entries 1-3), than the deactivating ones (i.e. entries 7-9). All structures of the new obtained compounds were confirmed by 1H NMR, 13C NMR, 2D NMR and MS spectra. Particularly, formation of the 1,4-oxazepane ring in products 9 and 17 was unequivocally confirmed by the three-bonds H-2,C-7 correlations observed in their HMBC spectra, as depicted for the representative structures 9a and 17i (Fig. 2) (See Supporting Information for details). CONCLUSION In summary, as a consequence of our finely planned intramolecular etherification reaction we implemented a catalyst-free


three-component Mannich-type approach for the synthesis of the novel 4,7-disubstituted 1,4-oxazepanes 9a,b in moderate yields. Although the scope of this first strategy was limited, three new bonds were formed in only one-step, giving to this approach an outstanding bond-forming efficiency. Alternatively, we developed also a straightforward, efficient and regioselective procedure for the synthesis of novel 4,7-disubstituted 1,4-oxazepanes 17 (from Ntethered bis-alcohols 16) in moderate to good yields through a Nalkylation/Reduction/Brønsted acid-catalyzed intramolecular etherification sequence, starting from N-benzylethanolamine 6a and 3(N,N-dimethylamino)propiophenone hydrochlorides 14 as easily accessible precursors. This process accepted a broad substrate scope of electronically diverse aryl and heteroaryl substituents on the Ntethered bis-alcohols 16. An extension of this approach toward the synthesis of 1,4-thiazepane analogues starting from N-alkylethanethiols instead of N-alkylethanolamines 6 is currently under study. CONSENT FOR PUBLICATION

Current Organic Synthesis, 2018, Vol. 15, No. 3 [9] [10]

[11]

[12]

[13]

Not applicable.

The authors declare no conflict of interest, financial or otherwise.

[14]

ACKNOWLEDGEMENTS

Authors are grateful to COLCIENCIAS, Universidad del ValleProject No CI-7812 and Universidad de los Andes for the financial support. SUPPLEMENTARY MATERIAL

Supplementary material is available on the publisher’s website along with the published article. REFERENCES [1]

[2]

[3] [4]

[5]

[6]

[7]

[8]

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