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Straightforward Synthetic Approach to Aminoalcohols with 9-Oxabicyclo[3.3.1]nonane or Cyclooctane Core via Nucleophilic Ring-Opening of Spirocyclic Bis(oxiranes)

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17 December 2025

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18 December 2025

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Abstract
Nucleophilic ring-opening of bis(oxiranes), containing several reactive centers, can be used to elaborate straightforward atom-economy and stereoselective approaches to polyfunctionalized compounds. In the present work ring-opening of cis- and trans-diastereomers of a spirocyclic bis(oxirane), containing a cyclooctane core (namely, 1,8-dioxadispiro[2.3.2.3]dodecane), upon the treatment with various amines was studied. Trans-isomer afforded aminoalcohols with 9-oxabicyclo[3.3.1]nonane moiety, formed via domino-process, including opening of an oxirane ring followed by intramolecular cyclization. Ring-opening of cis-isomer gave aminosubstituted cis-cyclooctane-1,5-diols, derived from independent reaction of two oxirane moieties. Activation of oxirane rings by the addition of LiClO4, acting as a Lewis acid, allowed involving a number of primary and secondary aliphatic amines as well as aniline derivatives into the reaction. Scope and limitations of the reaction were studied and a series of aminoalcohols with 9-oxabicyclo[3.3.1]nonane core and symmetric diaminodiols with cyclooctane core were obtained.
Keywords: 
oxiranes
;  
amines
;  
9-oxabicyclo[3.3.1]nonanes
;  
cyclooctanes
;  
aminodiols
;  
ring-opening
;  
domino reaction
;  
intramolecular cyclization
Subject: 
Chemistry and Materials Science  -   Organic Chemistry

1. Introduction

Oxiranes represent versatile intermediates finding application in synthesis of medicinal drugs, natural compounds, polymers and other products with practicable properties [1,2,3,4,5]. Synthetically useful transformations of these strained rings are characterized with predictability, regio- and stereoselectivity, mild conditions and broad reaction scope [6,7,8,9,10]. Bis(oxiranes), containing several reactive centers, are the structures of particular interest. Generally they are used to elaborate straightforward approaches to polyfunctionalized compounds [11,12,13], though examples of formation of saturated O-heterocycles via intramolecular cyclization are reported as well [14,15]. An eight-membered ring present in the molecule opens additional synthetic opportunities due to transannular transformations leading to polycyclic structures [16,17].
Previously we have reported the first example of transannular reactions of spirocyclic bis(oxirane) 1a as a nucleophile (Scheme 1) [18], which was later expanded for a tetrakis(oxirane) [19]. The reactivity of two diastereomers of bis(oxirane) 1a and 1b towards NaN3 was investigated and it was shown to be determined by the configuration of oxirane moieties: while trans-isomer 1a afforded 9-oxabicyclo[3.3.1]nonane 2, formed via domino-process, including opening of one oxirane ring followed by intramolecular cyclization, cis-diastereomer 1b gave the sole isomer of diazidodiol 3, derived from independent ring-opening of two oxirane moieties.
It should be mentioned that molecules containing cleft-shaped frameworks such as bicyclo[3.3.1]nonanes and their aza-derivatives have found application as conformationally restricted molecules for the purposes of medicinal chemistry, metal complex catalysis, and detection of metal ions and small molecules [20]. Natural and synthetic derivatives of aza- and diazabicyclo[3.3.1]nonanes (granisetron, pentazocine, cytisine) are used as medicinal drugs (Figure 1) [21,22,23]. Numerous natural compounds containing fragments of bicyclo[3.3.1]nonane (for example, polycyclic polyprenylated acylphloroglucinols (PPAPs) [24,25]), 2-azabicyclo[3.3.1]nonane (morphine alkaloids [26]), 9-azabicyclo[3.3.1]nonane (granate [27] and bis(indole) alkaloids [28]), 3,7-diazabicyclo[3.3.1]nonane (bispidine-based alkaloids [29]), as well as synthetic bicyclo[3.3.1]nonanes, reveal a broad spectrum of biological activity, including anticancer properties [30,31,32,33].
9-Oxabicyclo[3.3.1]nonane moiety, as well as similar frameworks, represents a conformationally restricted 3D-scaffold attractive for the drug-design and occurring in bioactive compound. For example, diterpenoid I (Figure 1) exhibits antiproliferative activity towards cancer cells with good selectivity comparing to normal cell lines [34]. At the same time, in contrast to above-mentioned bicyclononane derivatives, 9-oxabicyclo[3.3.1]nonanes are rather hard to synthesize and much less examples of them are described, that makes the search for straightforward approaches to these compounds a challenging task.
As for diazidodiol 3, it represented an attractive structure to be used as a linker moiety for construction of conjugates for biomedical applications using azide-alkyne cycloaddition strategies [35,36]. It was successfully used to obtain bis(triazoles) [37] and bis(steroid) derivatives with anticancer activity [38].
In the present work we aimed to elaborate preparative approaches to other types of products of nucleophilic ring-opening of bis(oxiranes) 1a and 2b. Amines were chosen as nucleophiles because the expected products of ring-opening – aminoalcohols and diaminodiols – are of interest as scaffolds occurring in a number of bioactive and natural compounds. For instance, adrenalin represents a β-aminoalcohol, as well as a number of adrenergic drugs, such as a short-acting bronchodilator albuterol [39]; 2-deoxystreptamine (2-DOS) is the aminocyclitol core of clinically important aminoglycoside antibiotics (gentamicin, neomycin, etc.) [40]; linear aminodi- or polyol moieties are present in natural antibiotics such as amicoumacin A [41] and zwittermicin A [42] (Figure 2).

2. Results and Discussion

A diastereomeric mixture of bis(oxiranes) 1a,b was studied upon the treatment with n-butylamine, morpholine, azepane and aniline (Scheme 2). The reactions were performed under reflux in the medium of an amine without a solvent. In the case of n-butylamine 9-oxabicyclo[3.3.1]nonane 5a, derived from transannular reaction of trans-isomer 1a, was the only product. Cis-bis(oxirane) 1b did not interact with butylamine. Reaction of 1a,b with more nucleophilic morpholine and azepane besides oxabicyclononane derivatives 5c,d afforded symmetric diaminodiols 6c,d, the products of independent ring-opening. Diaminodiols 6b,c were obtained as diastereomeric mixtures where cis-isomers prevailed. The configuration of isomers 6b,c was established basing on different symmetry of molecules as it has been previously done for the starting bis(oxiranes) [18]. Aniline, containing less nucleophilic amino group, did not interact with bis(oxiranes) 1a,b in this conditions.
In order to involve a broader scope of amines into the reaction and to improve its yield and selectivity, the conditions of nucleophilic opening were optimized on the examples of morpholine and butylamine. The solvent, temperature, time and reagents ratios were varied, but the reaction proceeded slowly until the additive of LiClO4 was used (see Table S1). LiClO4 was chosen because of its ability to promote oxiranes ring-opening by acting as Lewis acid with non-nucleophilic anion [43]. Optimal conditions were found to be reflux in acetonitrile for 5 h in the presence of LiClO4. Various quantities of LiClO4 were required, depending on the structure of amine: reactions with butylamine required 10-fold excess per oxirane ring, while for more nucleophilic morpholine 1.2-fold excess per oxirane ring was enough for complete conversion of starting bis(oxiranes). It should be mentioned that in optimized conditions only cis-isomers of diaminodiols 6 were formed, i.e., only transannular reaction proceeded for trans-bis(oxirane) 1a.
Bis(oxiranes) 1a and 1b were treated with various amines in optimized conditions (Table 1). In most cases diastereomeric mixture of starting bis(oxiranes) was involved into reaction, ratio of starting diastereomers 1a:1b varying from 1:0.8 to 1:0.9; in some cases when the products were hard to separate, individual diastereomers 1a or 1b were used as starting material. Bis(oxirane) 1a smoothly reacted with primary and secondary amines, affording aminoalcohols 5a-k of 9-oxabicyclo[3.3.1]nonane series. Aniline, as well as EDG-substituted p-toluidine and p-anisidine, afforded the products of transannular reaction 5l-n after reflux for 5–10 h, while the reaction with p-bromoaniline gave the product 5o only after reflux for 30 h. Bis(oxirane) 1b also interacted with the abovementioned amines, yet, unfortunately, resulting diaminodiols 6 were hard to isolate due to low chromatographic mobility and tendency to form salts. Nevertheless, diaminodiols 6a-f could be isolated via column chromatography in moderate to high yields. Reaction of 1b with p-bromoaniline even after 40 h afforded an equimolar mixture of diaminodiol 6o and 7-{[(4-bromophenyl)amino]methyl}-1-oxaspiro[2.7]decan-7-ol (7o), the product of ring-opening of one oxirane moiety. Amines with stronger electron-acceptor substituents, namely, p-nitroaniline, sulfanilamide and methanesulfonamide did not act as nucleophiles towards bis(oxiranes) 1a,b in the described conditions.
To summarize, a preparative method of ring-opening of spirocyclic bis(oxiranes) 1a,b upon the treatment with various amines in presence of LiClO4 was elaborated to yield a series of aminoalcohols with 9-oxabicyclo[3.3.1]nonane core and substituted cis-cyclooctane-1,5-diols, containing two fragments of amine. The products of the ring-opening of trans-bis(oxirane) 1a, functionalized 9-oxabicyclo[3.3.1]nonanes, represent a valuable conformationally restricted scaffold for drug-design, while the ring-opening of cis-bis(oxirane) 1b with bioactive amines may be used as a stereoselective approach to bivalent ligands with a hydrophobic linker.

3. Materials and Methods

3.1. General

1H and 13C NMR spectra were recorded on a 400 MHz spectrometer Agilent 400-MR (Agilent Technologies, Santa Clara, CA, USA; 400.0, 100.6 or 376.3 MHz for 1H, 13C or 19F, respectively) at r.t. in CDCl3, if not stated otherwise; chemical shifts δ were measured with reference to CDCl3 (δH = 7.26 ppm, δC = 77.16 ppm) or to CFCl3. When necessary, assignments of signals in NMR spectra were made using 2D techniques. Accurate mass measurements (HRMS) were obtained on Bruker micrOTOF II (Bruker Daltonik GmbH, Bremen, Germany) or G3 QTof quadrupole-time-of-flight (Waters, Milford MA, USA) with electrospray ionization (ESI). Analytical thin layer chromatography was carried out with silica gel plates supported on aluminum (ALUGRAM® Xtra SIL G/UV254, Macherey-Nagel, Duren, Germany); the detection was done by UV lamp (254 nm). Column chromatography was performed on silica gel (Silica 60, 0.015–0.04 mm, Macherey-Nagel, Duren, Germany). Bis(oxiranes) 1a,b[18] were obtained via described method. All other starting materials were commercially available. All reagents except commercial products of satisfactory quality were purified according to literature procedures prior to use.

3.2. Reaction of Bis(oxiranes) 1a,b with Amines (General Method)

To a solution of bis(oxirane) (0.1 mmol, 17 mg) in dry CH3CN (3 mL) LiClO4 (0.5–2 mmol) and corresponding amine (0.22 mmol) were added. The mixture was stirred at 80˚C for 5–40 h. The solvent was evaporated under reduced pressure. The product was isolated via preparative column chromatography (SiO2).
{5-[(Butylamino)methyl]-9-oxabicyclo[3.3.1]nonan-1-yl}methanol (5a). Reaction time – 5 h. Reagents ratio (bis(oxirane) : amine : LiClO4) – 1:2.2:20. Yield 81% (20 mg), yellow oil, Rf 0.20 (light petrol : EtOAc : MeOH 3:1:0.1). 1H NMR (δ, ppm, J, Hz): 0.91 (t, 3H, 3J =7.3, CH3), 1.27-1.39 (m, 4H, 2CH2, cy-Oct + CH2, Bu), 1.39-1.57 (m, 4H, 2CH2, cy-Oct + CH2, Bu), 1.58-1.75 (m, 6H, 6CH2, cy-Oct), 1.91-2.08 (m, 2H, 2CH2, cy-Oct), 2.54 (s, 2H, CH2N), 2.61-2.69 (m, 2H, CH2N, Bu), 3.11 (br.s, 2H, OH + NH), 3.31 (s, 2H, CH2OH). 13C NMR (δ, ppm): 14.1 (CH3), 18.5 (2CH2, cy-Oct), 20.6 (CH2, Bu), 29.8 (2CH2, cy-Oct), 31.4 (CH2, Bu), 31.8 (2CH2, cy-Oct), 50.2 (CH2N, Bu), 61.2 (CH2N), 71.4 (CH2OH), 71.7 (C-CH2N), 72.5 (C-CH2O). HRMS (ESI+, m/z): calculated for C14H27NO2 [M+H]+ : 242.2115, found: 242.2122.
[5-(Morpholin-4-ylmethyl)-9-oxabicyclo[3.3.1]nonan-1-yl]methanol (5b). Reaction time – 5 h. Reagents ratio (bis(oxirane) : amine : LiClO4) – 1:2.2:5. Yield 88% (22 mg), orange oil, Rf 0.20 (light petrol : EtOAc : MeOH 3:1:0.1). 1H NMR (δ, ppm): 1.28-1.46 (m, 4H, 4CH2, cy-Oct), 1.57-1.78 (m, 6H, 6CH2, cy-Oct), 1.94-2.11 (m, 2H, 2CH2, cy-Oct), 2.23 (s, 2H, CH2N), 2.37 (br.s, 1H, OH), 2.51-2.62 (m, 4H, 2CH2N, morpholine), 3.28 (s, 2H, CH2OН), 3.64-3.73 (m, 4H, 2CH2O, morpholine). 13C NMR (δ, ppm): 18.8 (2CH2, cy-Oct), 29.8 (2CH2, cy-Oct), 31.9 (2CH2, cy-Oct), 55.7 (2CH2N, morpholine), 67.2 (2CH2O, morpholine), 70.0 (CH2N), 71.6 (CH2OH), 72.1 (C-CH2O), 73.7 (C-CH2N). HRMS (ESI+, m/z): calculated for C14H25NO3 [M+H]+: 256.1907, found: 256.1906.
[5-(Azepan-1-ylmethyl)-9-oxabicyclo[3.3.1]nonan-1-yl]methanol (5c). Reaction time – 5 h. Reagents ratio (bis(oxirane) : amine : LiClO4) – 1:2.2:5. Yield 54% (15 mg), yellow oil, Rf 0.26 (light petrol : DCM : МeOH 1:3:1). 1H NMR (δ, ppm): 1.31-1.47 (m, 4H, 4CH2, cy-Oct), 1.51-1.73 (m, 14H, 6CH2, cy-Oct + 4CH2, azepane), 1.93-2.09 (m, 2H, 2CH2, cy-Oct), 2.41 (s, 2H, CH2N), 2.73-2.83 (m, 4H, 2CH2N, azepane), 3.29 (s, 2H, CH2OH), 4.62 (br.s, 1H, OH). 13C NMR (δ, ppm): 18.9 (2СH2, cy-Oct), 27.5 (2СH2, azepane), 29.1 (2СH2, azepane), 30.0 (2СH2, cy-Oct), 31.7 (2СН2, cy-Oct), 57.9 (2СН2N, azepane), 69.2 (CH2N), 71.79 (CH2OH), 71.83 (C-CH2OH), 74.4 (C-CH2N). HRMS (ESI+, m/z): calculated for C16H29NO2 [M+H]+: 268.2271, found: 268.2272.
[5-(Piperidin-1-ylmethyl)-9-oxabicyclo[3.3.1]nonan-1-yl]methanol (5d). Reaction time – 5 h. Reagents ratio (bis(oxirane) : amine : LiClO4) – 1:2.2:5. Yield 78% (13 mg), yellow oil, Rf 0.14 (light petrol: DCM : МeOH 1:3:0.5). 1H NMR (δ, ppm): 1.29-1.48 (m, 4H, 4CH2, cy-Oct + 2H, CH2, piperidine), 1.49-1.81 (m, 6H, 6CH2, cy-Oct + 4H, 2CH2, piperidine), 1.95-2.11 (m, 2H, 2CH2, cy-Oct), 2.14-2.34 (m, 2H, CH2N), 2.54 (br.s, 4H, 2CH2N, piperidine), 3.29 (s, 2H, CH2O). 13C NMR (δ, ppm): 18.9 (2CH2, cy-Oct), 24.1 (CH2, piperidine), 26.1 (2CH2, piperidine), 29.9 (2CH2, cy-Oct), 32.0 (2CH2, cy-Oct), 56.8 (2CH2N, piperidine), 70.2 (CH2N), 71.7 (CH2OH), 72.0 (C-CH2OH), 73.6 (C-CH2N). HRMS (ESI+, m/z): calculated for C15H27NO2 [M+H]+: 254.2115, found: 254.2119.
[5-(Pyrrolidin-1-ylmethyl)-9-oxabicyclo[3.3.1]nonan-1-yl]methanol (5e). Reaction time – 5 h. Reagents ratio (bis(oxirane) : amine : LiClO4) – 1:2.2:5. Yield 83% (20 mg), yellow oil, Rf 0.24 (light petrol : DCM : МeOH 1:4:1). 1H NMR (δ, ppm): 1.32-1.40 (m, 2H, 2CH2, cy-Oct), 1.44 -1.52 (m, 2H, 2CH2, cy-Oct), 1.58-1.76 (m, 6H, 6CH2, cy-Oct), 1.78-1.92 (m, 4H, 2CH2, pyrrolidine), 1.96-2.13 (m, 2H, 2CH2, cy-Oct), 2.56 (br.s, 2H, CH2N), 2.82 (br.s, 4H, 2CH2N, pyrrolidine), 3.32 (br.s, 2H, 2CH2OH, pyrrolidine). 13C NMR (δ, ppm): 18.8 (2CH2, cy-Oct), 23.8 (2CH2, pyrrolidine), 29.6 (2CH2, cy-Oct), 32.1 (2CH2, cy-Oct), 56.5 (2CH2, pyrrolidine), 68.1 (CH2N), 71.5 (CH2OH), 72.3 (C-CH2N), 72.8 (C-CH2OH). HRMS (ESI+, m/z): calculated for C14H25NO2 [M+H]+ : 240.1958, found: 240.1961.
1,5-Bis[(dibutylamino)methyl]cyclooctane-1,5-diol (5f). Reaction time – 5 h. Reagents ratio (bis(oxirane) : amine : LiClO4) – 1:2.2:5. Yield 83% (25 mg), yellow oil, Rf 0.16 (EtOAc). 1H NMR (δ, ppm, J, Hz): 0.89 (t, 3J = 7.2, 6H, 2CH3, Bu), 1.20-1.31 (m, 4H, 2CH2, Bu), 1.31-1.45 (m, 8H, 4CH2, cy-Oct + 2CH2, Bu), 1.56-1.77 (m, 6H, 6CH2, cy-Oct), 1.95-2.08 (m, 2H, 2CH2, cy-Oct), 2.30 (s, 2H, CH2N), 2.44-2.57 (m, 4H, 2CH2N, Bu), 3.28 (s, 2H, CH2O). 13C NMR (δ, ppm): 14.3 (2CH3, Bu), 18.9 (2CH2, cy-Oct), 20.8 (2CH2, Bu), 29.5 (2CH2, Bu), 29.8 (2CH2, cy-Oct), 31.8 (2CH2, cy-Oct), 56.1 (2CH2N, Bu), 66.3 (CH2N), 71.7 (CH2O), 72.1 (C-CH2O), 73.8 (C-CH2N). HRMS (ESI+, m/z): calculated for C18H35NO2 [M+H]+: 298.2741, found: 298.2725.
{5-[(Propargylamino)methyl]-9-oxabicyclo[3.3.1]nonan-1-yl}methanol (5g). Reaction time – 5 h. Reagents ratio (bis(oxirane) : amine : LiClO4) – 1:2.2:20. Yield 70% (16 mg), yellow oil, Rf 0.32 (light petrol : EtOAc : MeOH 1:1:1). 1H NMR (δ, ppm, J, Hz): 1.30-1.40 (m, 2H, 2CH2, cy-Oct), 1.41-1.52 (m, 2H, 2CH2, cy-Oct), 1.57-1.74 (m, 6H, 6CH2, cy-Oct), 1.95-2.10 (m, 2H, 2CH2, cy-Oct), 2.28 (t, 4J = 2.4, 1H, CH, propargyl), 2.67 (s, 2H, CH2N), 3.06 (br.s, 2H, NH, OH), 3.35 (s, 2H, CH2O), 3.54 (d, 4J = 2.4 Hz, CH2, propargyl). 13C NMR (δ, ppm): 18.4 (2CH2, cy-Oct), 29.7 (2CH2, cy-Oct), 31.6 (2CH2, cy-Oct), 38.5 (CH2, propargyl), 59.8 (CH2N), 71.3 (CH2OH), 71.7 (C-CH2N), 72.6 (C-CH2O), 72.8 (CH, propargyl), 80.9 (C, propargyl). HRMS (ESI+, m/z): calculated for C13H21NO2 [M+H]+: 224.1645, found: 224.1649.
{5-[(Benzylamino)methyl]-9-oxabicyclo[3.3.1]nonan-1-yl}methanol (5h). Reaction time – 5 h. Reagents ratio (bis(oxirane) : amine : LiClO4) – 1:2.2:20. Yield 80% (22 mg), yellow oil, Rf 0.39 (light petrol : EtOAc : MeOH 1:1:0.5). 1H NMR (δ, ppm): 1.27–1.36 (m, 2H, 2CH2, cy-Oct), 1.37–1.50 (m, 2H, 2CH2, cy-Oct), 1.54–1.71 (m, 6H, 4CH2, cy-Oct), 1.89–2.03 (m, 2H, 2CH2, cy-Oct), 2.57 (s, 2H, CH2N), 3.31 (s, 2H, CH2O), 4.00 (s, 2H, PhCH2N), 4.10 (br.s, 2H, NH+OH), 7.28–7.41 (m, 5H, 5CH, Ph). 13C NMR (δ, ppm): 18.5 (2CH2, cy-Oct), 29.7 (2CH2, cy-Oct), 31.7 (2CH2, cy-Oct), 53.7 (PhCH2N), 60.0 (CH2N), 71.5 (CH2OH), 71.8 (C), 72.6 (C), 127.5 (CH, Ph), 128.7 (4CH, Ph), 138.7 (C, Ph). HRMS (ESI+, m/z): calculated for C17H25NO2 [M+H]+: 276.1958, found: 276.1965.
(5-{[(4-Ethylbenzyl)amino]methyl}-9-oxabicyclo[3.3.1]nonan-1-yl)methanol (5i). Reaction time –5 h. Reagents ratio (bis(oxirane) : amine : LiClO4) – 1:2.2:20. Yield 65% (20 mg), yellow oil, Rf 0.78 (light petrol : DCM : МeOH 1:1:0.5). 1H NMR (δ, ppm, J, Hz): 1.23 (t, 3H, 3J 7.6, CH3), 1.25–1.34 (m, 2H, 2CH2, cy-Oct), 1.38–1.49 (m, 2H, 2CH2, cy-Oct), 1.56–1.74 (m, 6H, 6CH2, cy-Oct), 1.91–2.06 (m, 2H, 2CH2, cy-Oct), 2.55 (s, 2H, CH2N), 2.64 (q, 2H, 3J 7.6, CH2, Et), 3.26 (s, 2H, CH2O), 3.77 (br.s, 2H, NH+OH), 3.93 (s, 2H, ArCH2N), 7.15–7.20 (m, 2H, 2CH, Ar), 7.30–7.36 (m, 2H, 2CH, Ar). 13C NMR (δ, ppm): 15.7 (СH3), 18.4 (2CH2, cy-Oct), 28.7 (CH2, Et), 29.6 (2CH2, cy-Oct), 31.7 (2CH2, cy-Oct), 53.3 (ArCH2N), 59.5 (CH2N), 71.2 (СH2OH), 71.3 (C-CH2N), 72.8 (C-CH2OH), 128.3 (2CH, Ar), 129.0 (2CH, Ar), 134.4 (C, Ar), 143.9 (C, Ar). HRMS (ESI+, m/z): calculated for C19H29NO2 [M+H]+ : 304.2271, found: 304.2272.
[5-({[4-(Trifluoromethyl)benzyl])amino}methyl)-9-oxabicyclo[3.3.1]nonan-1-yl]methanol (5j). Reaction time – 10 h. Reagents ratio (bis(oxirane) : amine : LiClO4) – 1:2.2:20. Yield 40% (13 mg), yellow oil, Rf 0.24 (light petrol : EtOAc 1:1). 1H NMR (δ, ppm, J, Hz): 1.31–1.46 (m, 4H, 4CH2, cy-Oct), 1.55–1.78 (m, 6H, 6CH2, cy-Oct), 1.93–2.09 (m, 2H, 2CH2, cy-Oct), 2.47 (s, 2H, CH2N), 3.31 (s, 2H, CH2O), 3.87 (s, 2H, ArCH2N), 7.41–7.50 (m, 2H, 2CH, Ar), 7.54–7.60 (m, 2H, 2CH, Ar). 13C NMR (δ, ppm, J, Hz): 18.6 (2CH2, cy-Oct), 29.9 (2CH2, cy-Oct), 31.8 (2CH2, cy-Oct), 53.7 (ArCH2N), 61.0 (CH2N), 71.6 (СH2OH), 72.3 (C), 72.4 (C), 124.5 (q, 1JCF 272), 125.4 (q, 3JCF 4, 2CH, Ar), 128.3 (2CH, Ar), 129.3 (q, 2JCF 32, C, Ar), 145.0 (С, Ar). 19F NMR (δ, ppm): -62.37 (s, 3F). HRMS (ESI+, m/z): calculated for C18H24F3NO2 [M+H]+: 344.1832, found: 344.1836.
[5-({[4-(3-Methylpiperidin-1-yl)benzyl]amino}methyl)-9-oxabicyclo[3.3.1]non-1-yl]methanol (5k). Reaction time – 5 h. Reagents ratio (bis(oxirane) : amine : LiClO4) – 1:2.2:20. Yield 16% (6 mg), yellow oil, Rf 0.78 (light petrol : DCM : МeOH 1:1:0.5). 1H NMR (δ, ppm, J, Hz): 0.94 (d, 3H, 3J 6.6, CH3), 0.99-1.13 (m, 1H, CH2, piperidine), 1.19–1.35 (m, 2H, cy-Oct), 1.40–1.51 (m, 2H, 2СH2, cy-Oct), 1.50–1.87 (m, 10H, 6CH2, cy-Oct + 2CH2 piperidine + СH, piperidine), 1.88–2.09 (m, 2Н, 2CH2, cy-Oct), 2.31– 2.41 (m, 1H, CH2N, piperidine), 2.60–2.73 (m, 1H, CH2N, piperidine), 2.76 (s, 2H, CH2N), 3.34 (s, 2H, CH2O), 3.54–3.69 (m, 2H, 2CH2N, piperidine), 4.26 (s, 2H, ArCH2N), 6.86–6.96 (m, 2H, 2CH, Ar), 7.36–7.38 (d, 2H, 2CH, Ar), 7.89 (br.s, 2H, NH+OH). 13C NMR (δ, ppm): 18.1 (2CH2, cy-Oct), 19.6 (CH3), 25.2 (CH2, piperidine), 28.9 (2CH2, cy-Oct), 30.9 (CH, piperidine), 31.3 (2CH2, cy-Oct), 33.0 (CH2, piperidine), 49.2 (CH2, piperidine), 51.7 (ArCH2N), 55.7 (CH2N), 56.9 (CH2, piperidine), 69.4 (С-CH2N), 70.7 (CH2OH), 73.8 (C-CH2OH), 116.1 (2CH, Ar), 118.9 (C, Ar), 131.6 (2CH, Ar), 152.5 (C, Ar). HRMS (ESI+, m/z): calculated for C23H36N2O2 [M+H]+: 373.2850, found: 373.2852.
{5-[(Phenylamino)methyl]-9-oxabicyclo[3.3.1]nonan-1-yl}methanol (5l). Reaction time – 5 h. Reagents ratio (bis(oxirane) : amine : LiClO4) – 1:2.2:20. Yield 36% (9 mg), yellow oil, Rf 0.77 (light petrol : EtOAc 1:2). 1H NMR (δ, ppm): 1.35–1.43 (m, 2H, 2CH2, cy-Oct), 1.44–1.53 (m, 2H, 2CH2, cy-Oct), 1.59–1.79 (m, 6H, 4CH2, cy-Oct), 1.97–2.11 (m, 2H, 2CH2, cy-Oct), 3.03 (s, 2H, CH2N), 3.35 (s, 2H, CH2O), 6.58-6.73 (m, 3H, 3CH, Ph), 7.12–7.19 (m, 2H, 2CH, Ph). 13C NMR (101 MHz, CDCl3) δ, ppm: 18.5 (2СH2, cy-Oct), 29.8 (2CH2, cy-Oct), 31.6 (2CH2, cy-Oct), 55.4 (CH2N), 71.5 (CH2OH), 72.4 (C), 72.5 (C), 113.0 (2CH, Ph), 117.3 (CH, Ph), 129.3 (2CH, Ph), 148.9 (C, Ph). HRMS (ESI+, m/z): calculated for C16H23NO2 [M+H]+: 262.1802, found: 262.1806.
{5-[(4-Methoxyphenylamino)methyl]-9-oxabicyclo[3.3.1]nonan-1-yl}methanol (5m). Reaction time – 5 h. Reagents ratio (bis(oxirane) : amine : LiClO4) – 1:2.2:20. Yield 95% (27 mg), yellow oil, Rf 0.32 (EtOAc : DCM 1:5). 1H NMR (δ, ppm): 1.34-1.42 (m, 2H, 2CH2, cy-Oct), 1.43-1.53 (m, 2H, 2CH2, cy-Oct), 1.59-1.81 (m, 6H, 6CH2, cy-Oct), 1.96-2.10 (m, 2H, 2CH2, cy-Oct), 2.97 (s, 2H, CH2N), 3.35 (s, 2H, CH2O), 3.74 (s, 3H, OMe), 6.56-6.64 (m, 2H, 2CH, Ar), 6.74-6.80 (m, 2H, 2CH, Ar). 13C NMR (δ, ppm): 18.5 (2CH2, cy-Oct), 29.9 (2CH2, cy-Oct), 31.7 (2CH2, cy-Oct), 56.0 (OMe), 56.5 (CH2N), 71.6 (CH2O), 72.4 (C-CH2NH), 72.5 (C-CH2OH), 114.3 (2CH, Ar), 115.1 (2CH, Ar), 143.3 (C-NH, Ar), 152.1 (C-O, Ar). HRMS (ESI+, m/z): calculated for C17H25NO3 [M+H]+ : 292.1907, found: 292.1911.
{5-[(4-Methylphenylamino)methyl]-9-oxabicyclo[3.3.1]nonan-1-yl}methanol (5n). Reaction time – 10 h. Reagents ratio (bis(oxirane) : amine : LiClO4) – 1:2.2:20. Yield 26% (7 mg), yellow oil, Rf 0.67 (light petrol : EtOAc 1:1). 1H NMR (δ, ppm): 1.32–1.42 (m, 2H, 2CH2, cy-Oct), 1.43–1.53 (m, 2H, 2CH2, cy-Oct), 1.57–1.82 (m, 6H, 4CH2, cy-Oct), 1.95–2.11 (m, 2H, 2CH2, cy-Oct), 2.23 (s, 3H, CH3), 3.00 (s, 2H, CH2N), 3.35 (s, 2H, CH2O), 6.52-6.58 (m, 2H, 2CH, Ar), 6.93–7.01 (m, 2H, 2CH, Ar). 13C NMR (δ, ppm): 18.5 (2СH2, cy-Oct), 20.5 (CH3), 29.8 (2CH2, cy-Oct), 31.6 (2CH2, cy-Oct), 55.7 (CH2N), 71.6 (CH2OH), 72.4 (C), 72.5 (C), 113.1 (2CH, Ar), 126.4 (C, Ar), 129.8 (2CH, Ar), 146.7 (C, Ar). HRMS (ESI+, m/z): calculated for C17H25NO2 [M+H]+: 276.1958, found: 276.1966.
{5-[(4-Bromophenylamino)methyl]-9-oxabicyclo[3.3.1]nonan-1-yl}methanol (5o). Reaction time – 30 h. Reagents ratio (bis(oxirane) : amine : LiClO4) – 1:2.2:20. Yield 17% (6 mg), yellow oil, Rf 0.58 (light petrol : EtOAc 1:1). 1H NMR (δ, ppm): 1.34–1.43 (m, 2H, 2CH2, cy-Oct), 1.43–1.52 (m, 2H, 2CH2, cy-Oct), 1.58–1.75 (m, 6H, 4CH2, cy-Oct), 1.97–2.12 (m, 2H, 2CH2, cy-Oct), 2.98 (s, 2H, CH2N), 3.35 (s, 2H, CH2O), 6.45-6.54 (m, 2H, 2CH, Ar), 7.19–7.26 (m, 2H, 2CH, Ar). 13C NMR (δ, ppm): 18.5 (2СH2, cy-Oct), 29.8 (2CH2, cy-Oct), 31.6 (2CH2, cy-Oct), 55.3 (CH2N), 71.6 (CH2OH), 72.4 (C), 72.6 (C), 108.7 (C, Ar), 114.5 (2CH, Ar), 132.0 (2CH, Ar), 148.0 (C, Ar). HRMS (ESI+, m/z): calculated for C16H22BrNO2 [M+H]+: 340.0907, found: 340.0916.
1,5-Bis[(butylamino)methyl]cyclooctane-1,5-diol (6a). Reaction time – 5 h. Reagents ratio (bis(oxirane) : amine : LiClO4) – 1:2.2:20. Yield 56% (19 mg), yellow oil, Rf 0.05 (CH3CN). 1H NMR (δ, ppm, J, Hz): 0.90 (t, 6H, 3J 7.2, 2CH3), 1.29-1.38 (m, 4H, 2CH2, Bu), 1.39-1.50 (m, 10H, 6CH2, cy-Oct + 2CH2, Bu), 1.77-1.90 (m, 6H, 6CH2, cy-Oct), 2.46 (s, 4H, 2CH2N), 2.62 (t, 4H, 3J 7.1, 2CH2N, Bu). 13C NMR (δ, ppm): 14.1 (2CH3, Bu), 18.8 (2CH2, cy-Oct), 20.5 (2CH2, Bu), 32.6 (2CH2, Bu), 37.5 (4CH2, cy-Oct), 50.5 (2CH2N, Bu), 60.5 (2CH2N), 72.8 (2C). HRMS (ESI+, m/z): calculated for C18H38N2O2 [M+H]+: 315.3006, found: 315.3015.
1,5-Bis(morpholin-4-ylmethyl)cyclooctane-1,5-diol (6b). Reaction time – 5 h. Reagents ratio (bis(oxirane) : amine : LiClO4) – 1:2.2:5. Yield 97% (33 mg), yellow oil, Rf= 0.61 (light petrol : EtOAc : MeOH 3:1:1). 1H NMR (δ, ppm): 1.37-1.54 (m, 6H, 6CH2, cy-Oct), 1.79-1.95 (m, 6H, 6CH2, cy-Oct), 2.26 (s, 4H, 2CH2N), 2.60-2.63 (m, 8H, 4CH2N, morpholine), 2.99 (br.s, 2H, 2OH), 3.68-3.71 (m, 8H, 4CH2O, morpholine). 13C NMR (δ, ppm): 18.4 (2CH2, cy-Oct), 37.9 (4CH2, cy-Oct), 56.3 (4CH2N, morpholine), 67.5 (4CH2O, morpholine), 69.0 (2CH2N), 74.0 (2C). HRMS (ESI+, m/z): calculated for C18H34N2O4 [M+H]+: 343.2591, found: 343.2596
1,5-Bis(azepan-4-ylmethyl)cyclooctane-1,5-diol (6c). Reaction time – 5 h. Reagents ratio (bis(oxirane) : amine : LiClO4) – 1:2.2:5. Yield 19% (7 mg), yellow oil, Rf 0.08 (light petrol : DCM : МeOH 1:3:1). 1H NMR (δ, ppm): 1.38-1.52 (m, 6H, 6CH2, cy-Oct), 1.53-1.71 (m, 16H, 8CH2, azepane), 1.78-1.96 (m, 6H, 6CH2, cy-Oct), 2.43 (s, 4H, 2CH2N), 2.74-2.86 (m, 8H, 4CH2N, azepane). 13C NMR (δ, ppm): 18.7 (2CH2, cy-Oct), 27.1 (4CH2, azepane), 29.1 (4CH2, azepane), 37.8 (4CH2, cy-Oct), 59.2 (4CH2N, azepane), 68.8 (2CH2N), 73.7 (2C). HRMS (ESI+, m/z): calculated for C22H42N2O2 [M+H]+: 367.3319, found: 367.3319.
1,5-Bis(piperidin-4-ylmethyl)cyclooctane-1,5-diol (6d). Reaction time – 5 h. Reagents ratio (bis(oxirane) : amine : LiClO4) – 1:2.2:5. Yield 97% (30 mg), yellow oil, Rf 0.09 (light petrol : DCM : МeOH 1:3:2). 1H NMR (δ, ppm): 1.35-1.53 (m, 6H, 6CH2, cy-Oct + 4H, 2CH2, piperidine), 1.53-1.65 (m, 8H, 4CH2, piperidine), 1.79-1.95 (m, 6H, 6CH2, cy-Oct), 2.29 (s, 4H, 2CH2N), 2.61 (br.s, 8H, 4CH2N, piperidine). 13C NMR (δ, ppm): 18.5 (2CH2, cy-Oct), 23.9 (2CH2, piperidine), 26.3 (4CH2, piperidine), 38.0 (4CH2, cy-Oct), 57.4 (4CH2N, piperidine), 68.6 (2CH2N), 73.3 (2С). HRMS (ESI+, m/z): calculated for C20H38N2O2 [M+H]+: 339.3006, found 339.3003.
1,5-Bis(pyrrolidin-4-ylmethyl)cyclooctane-1,5-diol (6e). Reaction time – 5 h. Reagents ratio (bis(oxirane) : amine : LiClO4) – 1:2.2:5. Yield 61% (23 mg), yellow oil, Rf 0.1 (light petrol : DCM : МeOH 1:1:1). 1H NMR (δ, ppm): 1.40-1.57 (m, 6H, 6CH2, cy-Oct), 1.68-1.79 (m, 8H, 4CH2, pyrrolidine), 1.80-1.94 (m, 6H, 6CH2, cy-Oct), 2.45 (s, 4H, 2CH2N), 2.62-2.74 (m, 8H, 4CH2N, pyrrolidine). 13C NMR (δ, ppm): 18.6 (2CH2, cy-Oct), 24.3 (4CH2, pyrrolidine), 38.0 (4CH2, cy-Oct), 57.0 (4CH2, pyrrolidine), 67.2 (2CH2N), 73.4 (2С). HRMS (ESI+, m/z): calculated forc
1,5-Bis[(dibutylamino)methyl]cyclooctane-1,5-diol (6f). Reaction time – 20 h. Reagents ratio (bis(oxirane) : amine : LiClO4) – 1:2.2:5. Yield 65% (28 mg), yellow oil, Rf 0.24 (light petrol : DCM : МeOH 1:4:1). 1H NMR (CD3OD; δ, ppm, J, Hz): 0.96 (t, 3J = 7.3, 12H, 4CH3, Bu), 1.25-1.42 (m, 8H, 4CH2, Bu), 1.46-1.64 (m, 14H, 6CH2, cy-Oct + 4CH2, Bu), 1.85-1.98 (m, 6H, 6CH2, cy-Oct), 2.64 (br.s, 4H, 2CH2N), 2.79 (br.s, 8H, 4CH2N, Bu). 13C NMR (CD3OD; δ, ppm): 14.3 (4CH3, Bu), 18.8 (2CH2, cy-Oct), 21.4 (4CH2, Bu), 29.0 (4CH2, Bu), 38.4 (4CH2, cy-Oct), 57.2 (4CH2N, Bu), 66.5 (2CH2N), 74.6 (2C). HRMS (ESI+, m/z): calculated for C26H54N2O2 [M+H]+: 427.4258, found: 427.4282.
1,5-Bis[(phenylamino)methyl]cyclooctane-1,5-diol (6l). Reaction time – 5 h. Reagents ratio (bis(oxirane) : amine : LiClO4) – 1:2.2:20. Yield 6% (2 mg), yellow oil, Rf 0.58 (light petrol : EtOAc 2:1). 1H NMR (δ, ppm): 1.56–1.71 (m, 6H, 6CH2, cy-Oct), 1.83–1.93 (m, 2H, 2CH2, cy-Oct), 1.93–2.04 (m, 4H, 4CH2, cy-Oct), 3.05 (s, 4H, 2CH2N), 6.59-6.77 (m, 6H, 6CH, Ph), 7.12–7.20 (m, 4H, 4CH, Ph). 13C NMR (δ, ppm): 18.5 (2СH2, cy-Oct), 37.3 (4CH2, cy-Oct), 55.9 (2CH2, CH2N), 74.2 (2C), 113.4 (4CH, Ar), 118.0 (2CH, Ar), 129.4 (4CH, Ar), 148.9 (2C, Ar). HRMS (ESI+, m/z): calculated for C22H30N2O2 [M+H]+: 355.2380, found: 355.2388.
1,5-Bis[(4-bromophenylamino)methyl]cyclooctane-1,5-diol (6o). Reaction time – 40 h. Reagents ratio (bis(oxirane) : amine : LiClO4) – 1:2.2:20. Yield 4% (2 mg), yellow oil, Rf 0.32 (light petrol : EtOAc 1:2). 1H NMR (δ, ppm): 1.50–1.69 (m, 6H, 6CH2, cy-Oct), 1.79–1.91 (m, 2H, 2CH2, cy-Oct), 1.91–2.02 (m, 4H, 4CH2, cy-Oct), 3.00 (s, 4H, 2CH2N), 6.49-6.59 (m, 4H, 4CH, Ar), 7.20–7.29 (m, 4H, 4CH, Ph). 13C NMR (δ, ppm): 18.4 (2СH2, cy-Oct), 37.3 (4CH2, cy-Oct), 55.8 (2CH2, CH2N), 74.2 (2C), 109.4 (2C, Ar), 114.9 (4CH, Ar), 132.1 (4CH, Ar), 147.9 (C, Ar). HRMS (ESI+, m/z): calculated for C22H28Br2N2O2 [M+H]+: 511.0590, found: 511.0587.
Preprints 190239 i012
7-({[(4-Trifluoromethyl)benzyl]amino}methyl)-1-oxaspiro[2.7]decan-7-ol (7j). Reaction time – 10 h. Reagents ratio (bis(oxirane) : amine : LiClO4) – 1:2.2:20. Yield 7% (2 mg), yellow oil, Rf 0.16 (EtOAc). 1H NMR (δ, ppm): 1.38-1.49 (m, 4H, 2CH2, cy-Oct), 1.56-1.87 (m, 8H, 6CH2, cy-Oct), 2.55 (s, 2H, CH2O), 2.60 (s, 2H, CH2N), 3.90 (s, 2H, ArCH2N), 7.37–7.48 (m, 2H, 2CH, Ar), 7.54–7.64 (m, 2H, 2CH, Ar). 13C NMR (δ, ppm): 19.3 (2CH2, cy-Oct), 34.9 (2CH2, cy-Oct), 35.9 (2CH2, cy-Oct), 54.1 (CH2N), 55.3 (CH2O), 58.1 (ArCH2N), 59.1 (C, epoxy), 73.8 (C-OH), 125.5 (q, 3JCF 4, 2CH, Ar), 128.4 (2CH, Ar). Signals of CF3-group and quaternary carbon atoms were not observed due to low concentration of the compound. 19F NMR (δ, ppm): -62.44 (с, 3F). HRMS (ESI+, m/z): calculated for C18H24F3NO2 [M+H]+: 344.1832, found: 344.1827.
Preprints 190239 i013
7-{[(4-Bromophenyl)amino]methyl}-1-oxaspiro[2.7]decan-7-ol (7o). Reaction time – 40 h. Reagents ratio (bis(oxirane) : amine : LiClO4) – 1:2.2:20. Yield 6% (2 mg), yellow oil, Rf 0.39 (light petrol : EtOAc 1:1). 1H NMR (δ, ppm): 1.47-1.92 (m, 12H, 6CH2, cy-Oct), 2.63 (s, 2H, CH2O), 3.04 (s, 2H, CH2N), 7.48–7.58 (m, 2H, 2CH, Ar), 7.19–7.26 (m, 2H, 2CH, Ar). 13C NMR (δ, ppm): 19.4 (2CH2, cy-Oct), 34.9 (2CH2, cy-Oct), 35.8 (2CH2, cy-Oct), 53.5 (CH2N), 55.5 (CH2O), 59.0 (C, epoxy), 75.1 (C-OH), 109.2 (C, Ar), 114.8 (2CH, Ar), 132.1 (2CH, Ar), 147.9 (C, Ar). HRMS (ESI+, m/z): calculated for C16H22BrNO2 [M+H]+: 340.0907, found: 340.0915.

Supplementary Materials

The following supporting information can be downloaded at the website of this paper posted on Preprints.org, Table S1: Optimization of ring-opening conditions; copies of NMR spectra of the obtained compounds.

Author Contributions

Conceptualization, E.B.A. and K.N.S.; methodology, E.B.A. and K.N.S.; validation, K.N.S. and Y.K.G.; investigation, O.V.R., D.V.S., S.V.K., Y.K.G. and O.A.M.; data curation, K.N.S.; writing—original draft preparation, K.N.S.; writing—review and editing, E.B.A.; visualization, K.N.S. and Y.K.G.; supervision, E.B.A.; project administration, E.B.A. All authors have read and agreed to the published version of the manuscript.

Funding

This study was performed within the framework of the State Assignment (No. 121021000105-7, Molecular design, synthesis, and study of physiologically active compounds, advancing the methodology of medicinal chemistry, chemoinformatics, and targeted chemical synthesis).

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Data is contained within the article or Supplementary Material.

Acknowledgments

The research was carried out using the NMR spectrometer Agilent 400-MR and mass-spectrometer G3 QTof quadrupole-time-of-flight purchased under the program of M.V. Lomonosov Moscow State University development.

Conflicts of Interest

The authors declare no conflicts of interest.

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Preprints 190239 sch001
Scheme 1. Ring-opening of bis(oxiranes) 1a,b with sodium azide [18].
Scheme 1. Ring-opening of bis(oxiranes) 1a,b with sodium azide [18].
Preprints 190239 sch001
Preprints 190239 g001
Figure 1. Examples of medicinal drugs and bioactive natural compounds containing bicyclo[3.3.1]nonane and related scaffolds.
Figure 1. Examples of medicinal drugs and bioactive natural compounds containing bicyclo[3.3.1]nonane and related scaffolds.
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Preprints 190239 g002
Figure 2. Examples of bioactive and natural compounds containing aminoalcohol scaffolds.
Figure 2. Examples of bioactive and natural compounds containing aminoalcohol scaffolds.
Preprints 190239 g002
Preprints 190239 sch002
Scheme 2. Ring-opening of bis(oxiranes) 1a,b with n-butylamine, morpholine and azepane; amines used as solvent.
Scheme 2. Ring-opening of bis(oxiranes) 1a,b with n-butylamine, morpholine and azepane; amines used as solvent.
Preprints 190239 sch002
Table 1. Ring-opening of bis(oxiranes) 1a,b with various amines.
Table 1. Ring-opening of bis(oxiranes) 1a,b with various amines.
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NHR1R2 product Yield,%1 product Yield,%1
NH2Bu 5a 81 6a 652
Preprints 190239 i002 5b 88 6b 97
Preprints 190239 i003 5c 54 6c 19
Preprints 190239 i004 5d 83 6d 972
Preprints 190239 i005 5e 83 6e 612
NHBu2 5f 832 6f 652
NH2CH2C≡CH 5g 70 6g –
NH2CH2Ph 5h 80 6h –
Preprints 190239 i006 5i 65 6i –
Preprints 190239 i007 5j 402 6j –3
Preprints 190239 i008 5k 16 6k –
NH2Ph 5l 36 6l 6
Preprints 190239 i009 5m 95 6m –
Preprints 190239 i010 5n 26 6n –
Preprints 190239 i011 5o 17 6o 22,3
1 Isolated yields, taking in account ratio of starting diastereomers 1a,b. 2Obtained from individual diastereomer 1a or 1b. 3The products of opening of one oxirane ring 7j,o (see section 3.2) were obtained.
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Copyright: This open access article is published under a Creative Commons CC BY 4.0 license, which permit the free download, distribution, and reuse, provided that the author and preprint are cited in any reuse.
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