Mechanistic Evaluation of the Stability of Arylvinyl-1,2,4-trioxanes under Acidic Conditions for Their Oral Administration as an Antimalarial Drug.

A mechanistic approach to understand the course of metabolism for synthetic 1,2,4-trioxanes, potent antimalarial compounds, to evaluate their bioavailability for antimalarial action has been studied in the present work. It is an important parameter to study the course of metabolism of a drug candidate molecule when administered via oral route during its journey from oral intake to its target site. From the pharmacokinetics point of view, it determines the bioavailability of an active drug or a prodrug at the target point. In this work, synthetic arylvinyl-1,2,4-trioxanes 1a-u have been evaluated under various acidic conditions to mimic the milieu of the stomach (pH between 1.5 and 3.5) through which they have to pass when administered orally. The effect of acid on trioxanes led to their degradation into corresponding ketones and glyoxal. Under such acidic conditions glyoxal polymerized to form a nonisolable condensate product. The study indicates that the actual bioavailability of the drug is far less than the administered dose.

Introduction

Malaria still remains an unbeatable disease due to the development of resistance against commonly available antimalarials and accounts for 241 million clinical cases around the world mostly in low-income areas.[1] Artemisinin,[2−7] a sesquiterpene lactone endoperoxide isolated from Chinese traditional medicinal herb Artemisia annua, and its semisynthetic derivatives (e.g., arteether and artemether) are presently the drugs of choice for the treatment of multidrug resistant malaria (Figure ).

Figure 1

Artemisinin and its semisynthetic derivatives.

These compounds are fast acting and are currently the drugs of choice for the treatment of cerebral malaria caused by multidrug-resistant Plasmodium falciparum. While these drugs show excellent activity by the parenteral route, the extra acetal–lactone or acetal–acetal linkages are linked with their poor hydrolytic stability under the acidic environment of the stomach and therefore poor absorption by the oral route.[8]

The discovery of peroxide present in the form of 1,2,4-trioxanes in artemisinin as an active pharmacophore for its antimalarial activity has encouraged scientists to develop simple, economical, and effective substitutes having a 1,2,4-trioxane unit. Since then, numerous simple molecules containing 1,2,4-trioxanes (Scheme ) have been synthesized and evaluated for antimalarial activity by different groups including us.[9−29]

Scheme 1

Preparation of 6-Arylvinyl-1,2,4-trioxanes

For a drug to be effective via oral or intramuscular administration, it should reach the target site in the form of an active species that can interact with pathogens in infected cells. For trioxanes, the active species is 1,2,4-trioxane, which interacts with the hemoglobin present in infected red blood cells and creates peroxy free radicals resulting in an oxidative atmosphere, which kills the malarial parasite present in cells.[30−37] During the course of its journey to the affected cells, the drug has to survive both acidic and basic environments in the body. If administered orally, it has to survive the strongly acidic environment of the stomach (pH 1.5–3.5), then the basic environment of bile juices (pH 7.5–8.5), and then in cells the basic environment of amino acids. Singh and Malik reported earlier the effect of basic conditions on 1,2,4-trioxanes (Scheme ), which resulted in the generation of the corresponding ketones.[38,39] In continuation of that study, herein, we report the effect of acidic conditions on the stability of synthetic aryl vinyl-1,2,4-trioxanes thus mimicking the conditions that can prevail in the body. In the present study, the temperature has also been examined along with acidic conditions as certain activation energy is required to initiate the reaction, which is accomplished by various enzymes in the body in actual conditions thus bringing down the activation energy required to initiate the reaction.[40]

Scheme 2

Stability of 1,2,4-Trioxanes under Basic Conditions

Chemistry

Naphthyloxy phenyl vinyl trioxane 1a was used as a model to explore the scope of the reaction. Initially, we investigated the effect of different acids on the stability of trioxane; among them TMSOTf emerged as the most effective for the generation of the corresponding ketones from the trioxane (Table , entry 8). p-TSA and BF3·Et2O required a little longer time, 2.5 h, for the transformation of trioxane 1a into ketone 2a (Table , entries 1 and 3).[41−43] Amberlyst-15 took 3 h for the transformation to ketone 2a (Table , entry 4). Concentrated HCl showed slow conversion of trioxane 1a into 2a, even after 16 h, only a trace of ketone 2a was observed (Table , entry 2). Other acids, HClO4, TiCl4, and AlCl3, showed decent conversion into ketones with longer duration of reaction (Table , entries 5, 6, and 7). We have screened different solvents for feasibility of the reaction with the TMSOTf and found that THF is the most appropriate solvent for catalysis, giving 52% of ketone 2a and 88% of ketone 3a (Table , entry 8). Use of other common solvents such as MeCN, DCM, EtOAc, toluene, and DMF allowed transformation to the corresponding ketones with longer reaction duration (Table , entries 9–13). Then, we optimized different equivalents of TMSOTf for catalytic activity and found that 0.1 equiv of TMSOTf required 1 h for completion of reaction while 0.01 equiv of TMSOTf required a longer reaction time with comparatively low yield. The 0.2 equiv amount was found to be the optimal conditions with excellent yield. We have monitored the stability of trioxane at room temperature for 48 h under TMSOTf condition and found no remarkable changes to the trioxane (Scheme ). Moreover, the transformation of trioxane 1a to ketones 2a and 3a did not take place in the absence of acid, which showed that the presence of some acid is essential to move the reaction in a forward direction (Table , entry 17).[44]

Table 1

Screening of Different Reaction Conditions for the Exploration of Acid Effects on Arylvinyl-1,2,4-trioxanesa

				product yieldb (%)
entry	acid	solvent	time	2a	3a
1	p-TSA	THF	2 h	32	69
2	concn HCl	THF	16 h	4	7
3	BF3·Et2O	THF	2.5 h	38	72
4	Amberlyst-15	THF	3 h	32	78
5	HClO4	THF	6 h	36	70
6	TiCl4	THF	4 h	40	77
7	AlCl3	THF	7 h	42	79
8f	TMSOTf	THF	15 min	52	88
9	TMSOTf	MeCN	12 h	10	69
10	TMSOTf	DCM	8 h	15	60
11	TMSOTf	EtOAc	5 h	5	72
12	TMSOTf	toluene	7 h	10	59
13	TMSOTf	DMF	6 h	10	69
14c	TMSOTf	THF	1 h	49	77
15d	TMSOTf	THF	3 h	45	75
16e	TMSOTf	THF	48 h	g	g
17		THF	48 h	g	g

Reaction conditions: trioxane (1 equiv), solvent (1.0 mL), and TMSOTf (0.2 equiv) at 80 °C.

Isolated yield.

0.1 equiv of TMSOTf.

0.01 equiv of TMSOTf.

0.2 equiv of TMSOTf at room temperature.

Bold indicates the optimal reaction condition.

No reaction.

Scheme 3

Stability of 1,2,4-Trioxanes under Acidic Conditions

We have also explored the scope of reaction on different trioxanes to gain insight on the effect of acid on transformation to corresponding ketones. To our delight, we found that most of the trioxanes in the presence of TMSOTf gave the corresponding aromatic and aliphatic ketones in good to excellent yield with shorter reaction time (Table , entries 1–21). We have explored the effect of TMSOTf on different ether derivatives of mono-1,2,4-trioxanes 1a–l, which resulted in the corresponding ether ketones 2a–d and aliphatic ketones 3a–c in good to excellent yield in shorter reaction time (Scheme , Table , entries 1–12). We have also screened the outcome of bis-trioxanes 1m–u in the presence of TMSOTf, which resulted in the corresponding bis-ketones 2e–g and aliphatic ketones 3a–c in good yield with a little longer duration (Table , entries 13–21).

Table 2

Exploration of Different Arylvinyl-1,2,4-trioxanes with TMSOTf

Results and Discussion

A general plausible mechanism for this acid-catalyzed rearrangement of substituted arylvinyl-1,2,4-trioxanes is shown in Scheme taking arylvinyl-trioxane 1a as a representative compound, which involves protonation of peroxy oxygen followed by ring opening to furnish aliphatic ketone 3a, coupled with migration of the phenylvinyl group to electropositive oxygen with subsequent cyclization to furnish an unstable epoxy product, which gets hydrolyzed to furnish the corresponding ketone 2a.

Scheme 4

Plausible Mechanism for Acid-Catalyzed Rearrangement of Substituted Arylvinyl-1,2,4-trioxanes

This study suggests that during oral administration of an active drug or prodrug, it has to first of all survive the strongly acidic conditions of the stomach (pH 1.5–3.5), during its journey to the target site. The mechanism shown suggests how 1,2,4-trioxanes behave under such acidic conditions.

By virtue of this study, we have tried to show the effect of acidic conditions on the stability of synthetic arylvinyl-1,2,4-trioxanes by mimicking the conditions that can prevail in the alimentary canal. In this study, elevated temperature has also been provided along with acidic conditions as a minimum amount of activation energy is required to initiate the reaction, which in actual in vivo conditions is affected by various enzymes in the body, which catalyze the reaction, thus bringing down the activation energy required to initiate the degradation process.

Thus, the study indicates that the actual bioavailability of active drug at the target site is far less than orally administered dose.[45]

Conclusion

In the present study, we have reported the effect of acidic conditions on the stability of arylvinyl-1,2,4-trioxanes, potent antimalarial agents, by reacting them with various acids. The main idea of this study was actually to mimic the acidic conditions prevailing in the stomach (pH 1.5–3.5) by artificially creating such conditions to evaluate the effect of such conditions on orally administered arylvinyl-1,2,4-trioxanes.We also analyzed the mechanistic behavior of these trioxanes under such conditions, which resulted in the generation of corresponding parent ketones from which the trioxanes were synthesized. The study revealed that actual bioavailability of the active drug, arylvinyl-1,2,4-trioxane, at the target site is far less than the orally administered dose. This study can pave the way to evaluate other synthetic peroxides under acidic conditions. We believe the outcome from the exploration of trioxanes under acidic conditions assists scientists in finding a better oral bioavailability profile of trioxane for malaria chemotherapy.

Experimental Section

All glass apparatus were oven-dried prior to use. Melting points were taken in open capillaries on Complab melting point apparatus and have been presented uncorrected. Infrared spectra were recorded on a PerkinElmer FT-IR RXI spectrophotometer. 1H NMR and 13C NMR spectra were recorded using Bruker Supercon Magnet DPX-200, DRX-300, or AVANCE-III-HD 400 spectrometers (operating at 200, 300, and 400 MHz, respectively, for 1H; 50, 75, and 100 MHz, respectively, for 13C) using CDCl3 as solvent. Tetramethylsilane (δ 0.00 ppm) and CDCl3 (δ 77.0 ppm) served as an internal standard in 1H NMR and 13C NMR, respectively. Chemical shifts have been reported in parts per million. Splitting patterns are described as singlet (s), doublet (d), triplet (t), quintet (quin), multiplet (m), and broad (br). Electrospray mass spectra (ES-MS) were recorded on a Micro mass Quattro II triple quadruple mass spectrometer. High-resolution electron impact mass spectra (ESI-HRMS) were obtained on Bruker Compass and TOF MS. Elemental analyses were performed on Vario EL-III C H N S analyzer (Germany), and values were within range (0.4% of the calculated values). Column chromatography was performed over Merck silica gel (particle size 60–120 mesh) procured from Qualigens (India) or flash silica gel (particle size 230–400 mesh). All chemicals and reagents were obtained from Aldrich (Milwaukee, WI), Lancaster (England), or Spectrochem (India) and were used without further purification. Nomenclature and log p values of the compounds were assigned using ChemDraw Professional 15.1.

General Procedure for Exploration of TMSOTf Effect on Arylvinyl-1,2,4-trioxanes

TMSOTf (9 μL, 0.2 equiv) was added to a stirred solution of trioxane 1a (100 mg, 0.257 mmol) in THF (2 mL). The reaction mixture was stirred at 80 °C, and progress of the reaction was monitored by TLC. After completion of the reaction, it was cooled to room temperature; reaction mixture was quenched with water (2 mL), extracted with EtOAc, dried over anhydrous Na2SO4, and concentrated. Column chromatography was done to obtain pure corresponding ketone products.

All the 1,2,4-trioxanes, 1a–u, were prepared by the reported procedure. The obtained analytical data for compounds 1a–i, 1k–u, and 2a–g are in agreement with the reported literature.[10,16]

8-{1-[4-(Naphthalen-2-yloxy)-phenyl]-vinyl}-6,7,10-trioxa-spiro[4.5]decane (1a)

White solid was obtained in 27% yield; mp 87–90 °C; IR (KBr, cm–1) 1591; 1H NMR (400 MHz, CDCl3) δ1.68–1.96 (m, 7H), 2.51–2.57 (m, 1H), 3.86 (d, 2H, J = 5.8 Hz), 5.30–5.33 (m, 2H), 5.51 (s, 1H), 7.05 (d, 2H, Ar, J = 8.8 Hz), 7.27–7.29 (m, 1H, Ar), 7.37–7.51 (m, 5H, Ar), 7.75 (d, 1H, Ar, J = 8 Hz), 7.86 (t, 2H, Ar, J = 8.6 Hz); 13C NMR (100 MHz, CDCl3) δ 23.58 (CH2), 24.99 (CH2), 33.00 (CH2), 37.24 (CH2), 66.25 (CH2), 80.48 (CH), 114.81 (C), 116.12 (CH2), 118.99 (CH), 120.25 (CH), 125.08 (CH), 126.80 (CH), 127.37 (CH), 127.97 (CH), 128.11 (CH), 130.19 (CH), 130.51 (C), 133.79 (C), 134.49 (C), 142.66 (C), 154.75 (C), 157.58 (C); FAB-MS (m/z) 389 [M + H]+; HRMS calcd for C25H24O4 388.1675, found 388.1674. Anal. Calcd for C25H24O4: C, 77.30; H, 6.23%. Found: C, 77.35; H, 6.28.

8-{1-[4-(Naphthalen-1-yloxy)-phenyl]-vinyl}-6,7,10-trioxa-spiro[4.5]decane (1b)

Compound 1b was obtained in 49% yield as oil; IR (neat, cm–1) 1599; 1H NMR (400 MHz, CDCl3) δ 1.67–1.93 (m, 7H), 2.48–2.55 (m, 1H), 3.86 (d, 2H, J = 5.8 Hz), 5.27–5.30 (m, 2H), 5.46 (s, 1H), 6.98–7.02 (m, 3H, Ar), 7.36–7.45 (m, 3H, Ar), 7.47–7.55 (m, 2H, Ar), 7.65 (d, 1H, Ar, J = 8.2 Hz), 7.88 (d, 1H, Ar, J = 7.4 Hz), 8.15 (d, 1H, Ar, J = 8.6 Hz); 13C NMR (100 MHz, CDCl3) δ 23.57 (CH2), 24.99 (CH2), 32.99 (CH2), 37.24 (CH2), 65.26 (CH2), 80.47 (CH), 114.31 (CH), 114.79 (C), 115.97 (CH2), 118.37 (CH), 122.22 (CH), 124.00 (CH), 126.00 (CH), 126.27 (CH), 126.86 (CH), 127.09 (C), 128.02 (CH), 128.08 (CH), 133.48 (C), 135.15 (C), 142.67 (C), 152.69 (C), 158.32 (C); FAB-MS (m/z) 389 [M + H]+; HRMS calcd for C25H24O4 388.1674, found 388.1672. Anal. Calcd for C25H24O4: C, 77.30; H, 6.23. Found: C, 77.36; H, 6.28.

8-{1-[4-(Biphenyl-4-yloxy)-phenyl]-vinyl}-6,7,10-trioxa-spiro[4.5]decane (1c)

Compound 1c was obtained in 29% yield as oil; IR (KBr, cm–1) 1598; 1H NMR (400 MHz, CDCl3) δ 1.67–1.95 (m, 7H), 2.51–2.58 (m, 1H), 3.88 (d, 2H, J = 6.1 Hz), 5.30–5.33 (m, 2H), 5.49 (s, 1H), 7.04 (d, 2H, Ar, J = 8.6 Hz), 7.11 (d, 2H, Ar, J = 8.6 Hz), 7.33–7.47 (m, 5H, Ar), 7.57–7.61 (m, 4H, Ar); 13C NMR (100 MHz, CDCl3) δ 23.56 (CH2), 24.97 (CH2), 32.97 (CH2), 37.21 (CH2), 65.21 (CH2), 80.43 (CH), 114.77 (C), 116.05 (CH2), 118.87 (CH), 119.51 (CH), 127.09 (CH), 127.28 (CH), 128.06 (CH), 128.67 (CH), 128.98 (CH), 133.70 (C), 136.80 (C), 140.60 (C), 142.62 (C), 156.50 (C), 157.50 (C); ESI (m/z) 415 [M + H]+; HRMS calcd for C27H26O4 414.1831, found 414.1834. Anal. Calcd for C27H26O4: C, 78.24; H, 6.32. Found: C, 78.29; H, 6.37.

8-[1-(4-Phenoxy-phenyl)-vinyl]-6,7,10-trioxa-spiro[4.5]decane (1d)

White solid was obtained in 27% yield; mp 51–52 °C; IR (KBr, cm–1) 1590; 1H NMR (400 MHz, CDCl3) δ 1.66–1.93 (m, 7H), 2.48–2.55 (m, 1H), 3.85 (d, 2H, J = 6.0 Hz), 5.27–5.30 (m, 2H), 5.46 (s, 1H), 6.96 (d, 2H, Ar, J = 8.6 Hz), 7.02 (d, 2H, Ar, J = 7.6 Hz), 7.12 (t, 1H, Ar, J = 7.4 Hz), 7.33–7.38 (m, 4H, Ar); 13C NMR (100 MHz, CDCl3) δ 23.57 (CH2), 24.98 (CH2), 32.99 (CH2), 37.23 (CH2), 65.25 (CH2), 80.48 (CH), 114.80 (C), 116.00 (CH2), 118.75 (CH), 119.38 (CH), 123.80 (CH), 128.03 (CH), 130.02 (CH), 133.57 (C), 142.67 (C), 156.95 (C), 157.64 (C); FAB-MS (m/z) 339 [M + H]+; HRMS calcd for C21H22O4 338.1518; found 338.1529. Anal. Calcd for C21H22O4: C, 74.54; H, 6.55. Found: C, 74.61; H, 6.58.

3-{1-[4-(Naphthalen-2-yloxy)-phenyl]-vinyl}-1,2,5-trioxa-spiro[5.5]undecane (1e)

White solid was obtained in 43% yield; mp 108–110 °C; IR (KBr, cm–1) 1596; 1H NMR (400 MHz, CDCl3) δ 1.40–1.66 (m, 8H), 1.96–2.02 (m, 1H), 2.21–2.26 (m, 1H), 3.77 (dd, 1H, J = 11.9 and 2.9 Hz), 3.98 (dd, 1H, J = 11.8 and 10.6 Hz), 5.22 (dd, 1H, J = 10.3 and 2.7 Hz), 5.28 (s, 1H), 5.47 (s, 1H), 7.01 (d, 2H, Ar, J = 8.7 Hz), 7.22–7.25 (m, 1H, Ar), 7.32–7.46 (m, 5H, Ar), 7.70 (d, 1H, Ar, J = 8 Hz), 7.81 (t, 2H, Ar, J = 8.7 Hz); 13C NMR (100 MHz, CDCl3) δ 22.49 (CH2), 22.54 (CH2), 25.73 (CH2), 29.20 (CH2), 34.85 (CH2), 62.86 (CH2), 80.46 (CH), 102.85 (C), 114.73 (CH), 116.03 (CH2), 119.03 (CH), 120.23 (CH),125.07 (CH), 126.80 (CH), 127.37 (CH), 127.97 (CH),128.10 (CH), 130.18 (CH), 130.50 (C), 133.92 (C), 134.49 (C), 142.88 (C), 154.79 (C), 157.54 (C); FAB-MS (m/z) 403 [M + H]+; HRMS calcd for C26H26O4 402.1831; found 402.1828. Anal. Calcd for C26H26O4: C, 77.59; H, 6.51. Found: C, 77.65; H, 6.56.

3-{1-[4-(Naphthalen-1-yloxy)-phenyl]-vinyl}-1,2,5-trioxa-spiro[5.5]undecane (1f)

This was obtained in 50% yield as oil; IR (Neat, cm–1) 1598; 1H NMR (400 MHz, CDCl3) δ 1.44–1.65 (m, 8H), 2.01–2.05 (m, 1H), 2.21–2.26 (m, 1H), 3.79 (dd, 1H, J = 11.8 and 2.9 Hz), 4.01 (dd, 1H, J = 11.8 and 10.6 Hz), 5.25 (dd, 1H, J = 10.3 and 2.8 Hz), 5.30 and 5.49 (2 × s, 2H), 7.01 (d, 3H, Ar, J = 8.6 Hz), 7.37–7.43 (m, 3H, Ar), 7.48–7.56 (m, 2H, Ar), 7.66 (d, 1H, Ar, J = 8.2 Hz), 7.90 (d, 1H, Ar, J = 7.4 Hz), 8.18 (d, 1H, Ar, J = 8 Hz); 13C NMR (100 MHz, CDCl3) δ 22.46 (CH2), 22.50 (CH2), 25.71 (CH2), 29.16 (CH2), 34.82 (CH2), 62.84 (CH2), 80.41 (CH), 102.79 (C), 114.22 (CH), 115.82 (CH2), 118.38 (CH), 122.19 (CH), 123.95 (CH), 125.97 (CH), 126.24 (CH), 126.83 (CH), 127.05 (C), 128.01 (CH), 128.03 (CH), 133.57 (C), 135.13 (C), 142.84 (C), 152.69 (C), 158.26 (C); FAB-MS (m/z) 403 [M + H]+; HRMS calcd for C26H26O4 402.1831; found 402.1830. Anal. Calcd for C26H26O4: C, 77.95; H, 6.51. Found: C, 77.99; H, 6.55.

3-{1-[4-(Biphenyl-4-yloxy)-phenyl]-vinyl}-1,2,5-trioxa-spiro[5.5]undecane (1g)

White solid was obtained in 50% yield; mp 54–56 °C; IR (KBr, cm–1) 1594; 1H NMR (400 MHz, CDCl3) δ 1.43–1.64 (m, 8H), 1.99–2.05 (m, 1H), 2.20–2.25 (m, 1H), 3.79 (dd, 1H, J = 11.8 and 2.8 Hz), 4.02 (t, 1H, J = 11.7 Hz), 5.24 (dd, 1H, J = 10.3 and 2.6 Hz), 5.30 (s, 1H), 5.49 (s, 1H), 7.02 (d, 2H, Ar, J = 8.6 Hz), 7.09 (d, 2H, Ar, J = 8.6 Hz), 7.32–7.46 (m, 5H, Ar), 7.56–7.58 (m, 4H, Ar); 13C NMR (100 MHz, CDCl3) δ 22.48 (CH2), 22.52 (CH2), 25.73 (CH2), 29.19 (CH2), 34.84 (CH2), 62.84 (CH2), 80.45 (CH), 102.83 (C), 115.98 (CH2), 118.92 (CH), 119.50 (CH), 127.12 (CH), 127.30 (CH), 128.07 (CH), 128.69 (CH), 128.99 (CH), 133.86 (C), 136.82 (C), 140.65 (C), 142.87 (C), 156.56 (C), 157.49 (C); ESI (m/z) 428 [M + H]+; HRMS calcd for C28H28O4 428.1988; found 428.1990. Anal. Calcd for C28H28O4: C, 78.48; H, 6.59; Found: C, 78.58; H, 6.77.

3-[1-(4-Phenoxy-phenyl)-vinyl]-1,2,5-trioxa-spiro[5.5]undecane (1h)

White solid was obtained in 46% yield; mp 54–55 °C; IR (KBr, cm–1) 1590; 1H NMR (400 MHz, CDCl3) δ 1.40–1.67 (m, 8H), 1.97–2.05 (m, 1H), 2.19–2.24 (m, 1H), 3.76 (dd, 1H, J = 11.9 and 2.9 Hz), 3.98 (dd, 1H, J = 11.8 and 10.4 Hz), 5.22 (dd, 1H, J = 10.4 and 2.8 Hz), 5.28 and 5.47 (2 × s, 2H), 6.96 (d, 2H, Ar, J = 8.8 Hz), 7.02 (dd, 2H, Ar, J = 8.6 and 1.1 Hz), 7.10–7.15 (m, 1H, Ar), 7.32–7.38 (m, 4H, Ar); 13C NMR (100 MHz, CDCl3) δ 22.48 (CH2), 22.52 (CH2), 25.72 (CH2), 29.16 (CH2), 34.85 (CH2), 62.86 (CH2), 80.45 (CH), 102.83 (C), 115.92 (CH2), 118.78 (CH), 119.35 (CH), 123.78 (CH), 128.00 (CH), 130.03 (CH), 133.67 (CH), 142.84 (C), 156.95 (C), 157.60 (C); FAB-MS (m/z) 353 [M + H]+; HRMS calcd for C22H24O4 352.1675; found 352.1677. Anal. Calcd for C22H24O4: C, 74.98; H, 6.86. Found: C, 74.99; H, 6.87.

(1R,3R,5R,7R)-6′-(1-(4-(Naphthalen-2-yloxy)phenyl)vinyl)spiro[adamantane-2,3′-[1,2,4]trioxane] (1i)

White solid was obtained in 57% yield; mp 103–105 °C; IR (KBr, cm–1) 1593; 1H NMR (400 MHz, CDCl3) δ1.62–2.08 (m, 13H), 2.97 (s, 1H), 3.77 (dd, 1H, J = 11.8 and 2.9 Hz), 3.98 (dd, 1H, J = 11.8 and 10.6 Hz), 5.26 (dd, 1H, J = 10.4 and 2.8 Hz), 5.29 (s, 1H), 5.49 (s, 1H), 7.02 (d, 2H, Ar, J = 8.7 Hz), 7.24–7.27 (m, 1H, Ar), 7.34 (d, 1H, Ar, J = 2.8 Hz) 7.37–7.49 (m, 4H, Ar), 7.72 (d, 1H, Ar, J = 7.9 Hz), 7.83 (t, 2H, Ar, J = 8.7 Hz); 13C NMR (100 MHz, CDCl3) δ 27.33 (2 × CH), 29.56 (CH), 33.19 (CH2), 33.43 (CH2), 33.66 (CH2), 33.77 (CH2), 36.42 (CH), 37.38 (CH2), 62.34 (CH2), 80.29 (CH), 104.91 (C), 114.71 (CH), 115.97 (CH2), 119.04 (CH), 120.23 (CH), 125.06 (CH), 126.80 (CH), 127.37 (CH), 127.97 (CH), 128.07 (CH), 130.18 (CH), 130.49 (C), 134.00 (C), 134.49 (C), 142.89 (C), 154.80 (C), 157.52 (C); FAB-MS (m/z) 455 [M + H]+; HRMS calcd for C30H30O4 454.2144; found 454.2156. Anal. Calcd for C30H30O4: C, 79.27; H, 6.65. Found: C, 79.35; H, 6.68.

(1R,3R,5R,7R)-6′-(1-(4-(Naphthalen-1-yloxy)phenyl)vinyl)spiro[adamantane-2,3′-[1,2,4]trioxane] (1j)

See ref (16).

(1R,3R,5R,7R)-6′-(1-(4-([1,1′-Biphenyl]-4-yloxy)phenyl)vinyl)spiro[adamantane-2,3′-[1,2,4]trioxane] (1k)

White solid was obtained in 50% yield; mp 122–125 °C; IR (KBr, cm–1) 1592; 1H NMR (400 MHz, CDCl3) δ 1.60–2.10 (m, 13H), 2.96 (s, 1H), 3.79 (dd, 1H, J = 11.8 and 2.8 Hz), 3.98 (t, 1H, J = 11.6 Hz), 5.25 (dd, 1H, J = 10.4 and 2.6 Hz), 5.29 (s, 1H), 5.48 (s, 1H), 7.02 (d, 2H, Ar, J = 8.6 Hz), 7.09 (d, 2H, Ar, J = 8.6 Hz), 7.32–7.46 (m, 5H, Ar), 7.55–7.58 (m, 4H, Ar); 13C NMR (100 MHz, CDCl3) δ 27.33 (2 × CH), 29.58 (CH), 33.19 (CH2), 33.43 (CH2), 33.67 (CH2), 33.77 (CH2), 36.43 (CH), 37.38 (CH2), 62.34 (CH2), 80.30 (CH), 104.89 (C), 115.93 (CH2), 118.93 (CH), 119.49 (CH), 127.13 (CH), 127.30 (CH), 128.05 (CH), 128.70 (CH), 129.01 (CH), 133.96 (C), 136.81 (C), 140.67 (C), 142.91 (C), 156.59 (C), 157.48 (C); FAB-MS (m/z) 481 [M + H]+; HRMS calcd for C32H32O4 480.2301; found 480.2250. Anal. Calcd for C32H32O4: C, 79.97; H, 6.71. Found: C, 79.99; H, 6.78.

(1R,3R,5R,7R)-6′-(1-(4-Phenoxyphenyl)vinyl)spiro[adamantane-2,3′-[1,2,4]trioxane] (1l)

White solid was obtained in 49% yield; mp 53–56 °C; IR (KBr, cm–1) 1591; 1H NMR (400 MHz, CDCl3) δ 1.58–2.07 (m, 13H), 2.95 (s, 1H), 3.77 (dd, 1H, J = 11.8 and 2.9 Hz), 3.96 (dd, 1H, J = 11.8 and 10.4 Hz), 5.24 (dd, 1H, J = 10.4 and 2.8 Hz), 5.27 (s, 1H), 5.47 (s, 1H), 6.96 (d, 2H, Ar), 7.02 (dd, 2H, Ar, J = 8.7 and 1.1 Hz), 7.10–7.15 (m, 1H, Ar), 7.33–7.38 (m, 4H, Ar); 13C NMR (100 MHz, CDCl3) δ 27.31 (2 × CH), 29.53 (CH), 33.16 (CH2), 33.42 (CH2), 33.64 (CH2), 33.75 (CH2), 36.42 (CH), 37.36 (CH2), 62.34 (CH2), 80.28 (CH), 104.88 (C), 115.85 (CH2), 118.79 (CH), 119.33 (CH), 123.77 (CH), 127.97 (CH), 130.02 (CH), 133.75 (C), 142.86 (C), 156.98 (C), 157.58 (C); FAB-MS (m/z) 405 [M + H]+; HRMS calcd for C26H28O4 404.1988, found 404.1967. Anal. Calcd for C26H28O4: C, 77.20; H, 6.98. Found: C, 77.24; H, 6.99.

8,8′-((Oxybis(4,1-phenylene))bis(ethene-1,1-diyl))bis(6,7,10-trioxaspiro[4.5]decane) (1m)

Compound 1m was obtained in 43% yield as white solid; mp 78–80 °C; IR (KBr, cm–1) 1596; 1H NMR (400 MHz, CDCl3) δ 1.64–1.91 (m, 14H, 7 × CH2), 2.46–2.52 (m, 2H), 3.84 (d, 4H, 2 × CH2, J = 6.2 Hz), 5.24–5.27 (m, 3H), 5.45 (s, 2H), 6.96 (d, 4H, Ar, J = 8.7 Hz), 7.35 (d, 4H, Ar, J = 8.7 Hz); 13C NMR (100 MHz, CDCl3) δ 23.57 (2 × CH2), 24.99 (2 × CH2), 32.99 (2 × CH2), 37.23 (2 × CH2), 65.22 (2 × CH2), 80.45 (2 × CH), 114.81 (2 × C), 116.22 (2 × CH2), 119.06 (4 × CH), 128.10 (4 × CH), 133.95 (2 × C), 142.60 (2 × C), 157.14 (2 × C); FAB-MS (m/z) 507 [M + H]+; HRMS calcd for C30H34O7 506.2305; found 506.2317. Anal. Calcd for C30H34O7: C, 71.13; H, 6.77. Found: C, 71.25; H, 6.82.

2,7-Bis(4-(1-(6,7,10-trioxaspiro[4.5]decan-8-yl)vinyl)phenoxy)naphthalene (1n)

Compound 1n was obtained in 35% yield as oil; IR (neat, cm–1) 1600; 1H NMR (400 MHz, CDCl3) δ 1.67–1.93 (m, 14H, 7 × CH2), 2.50–2.56 (m, 2H), 3.89 (d, 4H, 2 × CH2, J = 5.9 Hz), 5.28–5.32 (m, 4H), 5.51 (s, 2H), 7.02 (d, 4H, Ar, J = 8.7 Hz), 7.16–7.19 (m, 4H), 7.39 (d, 4H, Ar, J = 8.7 Hz), 7.81 (d, 2H, Ar, J = 9.5 Hz); 13C NMR (100 MHz, CDCl3) δ 23.57 (2 × CH2), 24.98 (2 × CH2), 32.99 (2 × CH2), 37.22 (2 × CH2), 65.22 (2 × CH2), 80.42 (2 × CH), 113.72 (2 × CH), 114.80 (2 × C), 116.20 (2 × CH2), 118.96 (2 × CH), 119.26 (4 × CH), 127.16 (C), 128.11 (4 × CH), 130.02 (2 × CH), 133.99 (2 × C), 135.58 (C), 142.58 (2 × C), 155.72 (2 × C), 157.22 (2 × C); FAB-MS (m/z) 649 [M + H]+. Anal. Calcd for C40H40O8: C, 74.06; H, 6.22. Found: C, 74.20; H, 6.35.

1,5-Bis(4-(1-(6,7,10-trioxaspiro[4.5]decan-8-yl)vinyl)phenoxy)naphthalene (1o)

Compound 1o was obtained in 30% yield as white solid; mp 148–150 °C; IR (KBr, cm–1) 1596; 1H NMR (400 MHz, CDCl3) δ 1.67–1.93 (m, 14H, 7 × CH2), 2.48–2.54 (m, 2H), 3.86 (d, 4H, J = 6 Hz), 5.27–5.32 (m, 4H), 5.47 (s, 2H), 7.01–7.04 (m, 6H), 7.37–7.42 (m, 6H), 7.95 (d, 2H, Ar, J = 8.5 Hz); 13C NMR (100 MHz, CDCl3) δ 23.58 (2 × CH2), 24.99 (2 × CH2), 33.01 (2 × CH2), 37.24 (2 × CH2), 65.25 (2 × CH), 80.50 (2 × C), 114.82 (2 × CH2), 114.88 (2 × CH), 116.09 (4 × CH), 118.01 (2 × CH), 118.58 (4 × CH), 126.21 (2 × C), 128.16 (2 × C), 128.68 (2 × C), 133.75 (2 × C), 142.69 (2 × C), 152.91 (2 × C) 158.09 (2 × C); FAB-MS (m/z) 649 [M + H]+. Anal. Calcd for C40H40O8: C, 74.06; H, 6.22. Found: C, 74.17; H, 6.38.

3,3′-((Oxybis(4,1-phenylene))bis(ethene-1,1-diyl))bis(1,2,5-trioxaspiro[5.5]undecane) (1p)

Compound 1p was obtained in 51% yield as white solid; mp 98–100 °C; IR (KBr, cm–1) 1596; 1H NMR (400 MHz, CDCl3) δ 1.40–1.60 (m, 16H, 8 × CH2), 1.95–2.01 (m, 2H), 2.16–2.21 (m, 2H), 3.37 (dd, 2H, J = 11.8 and 2.8 Hz), 3.96 (dd, 2H, J = 11.8 and 10.5 Hz), 5.20 (dd, 2H, J = 10.4 and 2.3 Hz), 5.27 (s, 2H), 5.46 (s, 2H), 6.96 (d, 4H, Ar, J = 8.7 Hz), 7.35 (d, 4H, Ar, J = 8.7 Hz); 13C NMR (100 MHz, CDCl3) δ 22.49 (2 × CH2), 22.53 (2 × CH2), 25.73 (2 × CH2), 29.18 (2 × CH2), 34.84 (2 × CH2), 62.83 (2 × CH2), 80.45 (2 × CH), 102.85 (2 × C), 116.12 (2 × CH2), 119.07 (4 × CH), 128.09 (4 × CH), 134.06 (2 × C), 142.82 (2 × C), 157.14 (2 × C); FAB-MS(m/z) 535 [M + H]+. Anal. Calcd for C32H38O7: C, 71.89; H,7.16. Found: C, 71.98; H, 7.22. HRMS calcd for C32H38O7 534.2618; found 534.2614.

2,7-Bis(4-(1-(1,2,5-trioxaspiro[5.5]undecan-3-yl)vinyl)phenoxy)naphthalene (1q)

Compound 1q was obtained in 34% yield as oil; IR (neat, cm–1) 1603; 1H NMR (400 MHz, CDCl3) δ 1.40–1.65 (m, 16H, 8 × CH2), 1.97–2.04 (m, 2H), 2.18–2.23 (m, 2H), 3.78 (dd, 2H, J = 11.8 and 2.8 Hz), 3.99 (dd, 2H, J = 11.9 and 10.5 Hz), 5.23 (dd, 2H, J = 10.5 and 2.2 Hz), 5.29 and 5.49 (2 × s, 4H), 7.02 (d, 4H, Ar, J = 8.8 Hz), 7.17–7.18 (m, 4H, Ar), 7.39 (d, 4H, Ar, J = 8.8 Hz), 7.81 (d, 2H, Ar, J = 9.5 Hz); 13C NMR (100 MHz, CDCl3) δ 22.48 (2 × CH2), 22.52 (2 × CH2), 25.72 (2 × CH2), 29.17 (2 × CH2), 34.83 (2 × CH2), 62.83 (2 × CH2), 80.41 (2 × CH2), 102.84 (2 × C), 113.67 (2 × CH), 116.11 (2 × CH), 118.94 (2 × CH), 119.29 (4 × CH), 127.14 (C), 128.10 (4 × CH), 130.01 (2 × C), 134.11 (2 × C), 135.58 (C), 142.79 (2 × C), 155.75 (2 × C), 157.19 (2 × C); FAB-MS (m/z) 677 [M + H]+. Anal. Calcd for C42H44O8: C, 74.54; H, 6.55. Found: C, 74.66; H, 6.68.

1,5-Bis(4-(1-(1,2,5-trioxaspiro[5.5]undecan-3-yl)vinyl)phenoxy)naphthalene (1r)

Compound 1r was obtained in 32% yield as white solid; mp 158–160 °C; IR (KBr, cm–1) 1596; 1H NMR (400 MHz, CDCl3) δ 1.30–1.63 (m, 16H, 8 × CH2), 1.96–2.02 (m, 2H), 2.17–2.21 (m, 2H), 3.76 (dd, 2H, J = 11.9 and 2.9 Hz), 3.97 (dd, 2H, J = 11.9 and 10.4 Hz), 5.21 (dd, 2H, J = 10.3 and 2.7 Hz), 5.27 and 5.46 (2 × s, 4H), 6.99–7.01 (m, 6H, Ar), 7.34–7.40 (m, 6H, Ar), 7.93 (d, 2H, Ar, J = 8.5 Hz); 13C NMR (100 MHz, CDCl3) δ 22.49 (2 × CH2), 22.53 (2 × CH2), 25.73 (2 × CH2), 29.20 (2 × CH2), 34.84 (2 × CH2), 62.86 (2 × CH2), 80.46 (2 × CH), 102.85 (2 × C), 114.84 (2 × CH), 115.99 (2 × CH2), 118.00 (2 × CH), 118.59 (4 × CH), 126.20 (2 × CH), 128.13 (4 × CH), 128.66 (2 × C), 133.84 (2 × C), 142.87 (2 × C), 152.91 (2 × C), 158.07 (2 × C); FAB-MS (m/z) 677 [M + H]+. Anal. Calcd for C42H44O8: C, 74.54; H, 6.55. Found: C, 74.82; H, 6.78.

(1R,1″R,3R,3″R,5R,5″R,7R,7″R)-6′,6‴-((Oxybis(4,1-phenylene))bis(ethene-1,1-diyl))dispiro[adamantane-2,3′-[1,2,4]trioxane (1s)

Compound 1s was obtained in 19% yield as white solid; mp 60–63 °C; IR (KBr, cm–1) 1596; 1H NMR (300 MHz, CDCl3) δ 1.60–2.11 (m, 26H), 2.96 (s, 2H), 3.79 (dd, 2H, J = 11.8 and 2.9 Hz), 3.99 (dd, 2H, J = 11.7 and 10.5 Hz), 5.25 (dd, 2H, J = 10.3 and 2.7 Hz), 5.31 and 5.49 (2 × s, 4H), 6.99 (d, 4H, Ar, J = 8.6 Hz), 7.4 (d, 4H, Ar, J = 8.6 Hz); 13C NMR (75 MHz, CDCl3) δ 27.38 (4 × CH), 29.64 (2 × CH), 33.22 (2 × CH2), 33.46 (2 × CH2), 33.69 (2 × CH2), 33.79 (2 × CH2), 36.44 (2 × CH), 37.42 (2 × CH2), 62.33 (2 × CH2), 80.33 (2 × CH), 104.89 (2 × C), 116.02 (2 × CH2), 119.07 (4 × CH), 128.09 (4 × CH), 134.20 (2 × C), 142.97 (2 × C), 157.18 (2 × C); FAB-MS (m/z) 639 [M + H]+. Anal. Calcd for C40H46O7: C, 75.21; H, 7.26. Found: C, 75.10; H, 7.30.

2,7-Bis(4-(1-(spiro[adamantane-2,3′-[1,2,4]trioxan]-6′-yl)vinyl)phenoxy)naphthalene (1t)

Compound 1t was obtained in 33% yield as oil; IR (neat, cm–1) 1598; 1H NMR (400 MHz, CDCl3) δ 1.55–2.05 (m, 26 H), 2.92 (s, 2H), 3.76 (dd, 2H, J = 11.8 and 2.8 Hz), 3.95 (t, 2H, J = 11.7 Hz), 5.22 (dd, 2H, J = 10.5 and 2.3 Hz), 5.26 (s, 2H), 5.47 (s, 2H), 7.01 (d, 4H, Ar, J = 8.6 Hz), 7.15–7.17 (m, 4H, Ar), 7.37 (d, 4H, Ar, J = 8.6 Hz), 7.79 (d, 2H, Ar, J = 9.5 Hz); 13C NMR (100 MHz, CDCl3) δ 27.34 (4 × CH), 29.58 (2 × CH), 33.19 (2 × CH2), 33.43 (2 × CH2), 33.66 (2 × CH2), 33.77 (2 × CH2), 36.42 (2 × CH), 37.38 (2 × CH2), 62.32 (2 × CH2), 80.27 (2 × CH), 104.89 (2 × C), 113.68 (2 × CH), 116.04 (2 × CH2), 118.94 (2 × CH), 119.31 (4 × CH), 127.16 (C), 128.09 (4 × CH), 130.01 (2 × CH), 134.22 (2 × CH), 135.61 (C), 142.87 (2 × C), 155.79 (2 × C), 157.19 (2 × C); FAB-MS (m/z) 781 [M + H]+. Anal. Calcd for C50H52O8: C, 76.90; H, 6.71. Found: C, 76.97; H, 6.98.

1,5-Bis(4-(1-(spiro[adamantane-2,3′-[1,2,4]trioxan]-6′-yl)vinyl)phenoxy)naphthalene (1u)

Compound 1u was obtained in 29% yield as white solid; mp 155–157 °C; IR (KBr, cm–1) 1598; 1H NMR (400 MHz, CDCl3) δ 1.56–2.03 (m, 26H), 2.92 (s, 2H), 3.76 (dd, 2H, 2 × CH, J = 11.8 and 2.9 Hz), 3.96 (dd, 2H, J = 11.8 and 10.9 Hz), 5.22 (dd, 2H, J = 10.9 and 2.9 Hz), 5.26 (s, 2H), 5.46 (s, 2H), 6.99–7.01 (m, 6H, Ar), 7.36–7.40 (6H, Ar), 7.93 (d, 2H, Ar, J = 8.5 Hz); 13C NMR (75 MHz, CDCl3) δ 27.40 (4 × CH), 29.67 (2 × CH), 33.24 (2 × CH2), 33.48 (2 × CH2), 33.71 (2 × CH2), 38.81 (2 × CH2), 36.46 (2 × CH), 37.44 (2 × CH2), 62.37 (2 × CH2), 80.34 (2 × CH), 104.90 (2 × C), 114.84 (2 × CH), 115.89 (2 × CH2), 118.03 (2 × CH), 118.62 (4 × CH), 126.20 (2 × CH), 128.14 (4 × CH), 128.72 (2 × C), 134 (2 × C), 143.01 (2 × C), 152.99 (2 × C), 158.10 (2 × C); FAB-MS (m/z) 781 [M + H]+. Anal. Calcd for C50H52O8: C, 76.90; H, 6.71. Found: C, 76.87; H, 6.95.

1-[4-(Naphthalen-2-yloxy)-phenyl]-ethanone (2a)

White solid was obtained in 52% yield; mp 75–85 °C; 1H NMR (400 MHz, CDCl3) δ 2.58 (s, CH3), 7.06 (d, 2H, Ar, J = 8.8 Hz), 7.25 (dd, 1H, Ar, J = 8.8 and 2.4 Hz), 7.44–7.52 (m, 3H, Ar), 7.76 (d, 1H, Ar, J = 8.5 Hz), 7.87 (t, 2H, Ar, J = 9.1 Hz), 7.96 (d, 2H, Ar, J = 8.8 Hz); 13C NMR (100 MHz, CDCl3) δ 26.67 (CH3), 116.40 (CH), 117.73 (CH), 120.53 (CH), 125.56 (CH), 126.97 (CH), 127.50 (CH), 128.03 (CH), 130.45 (CH), 130.83 (CH), 130.98 (C), 132.27 (C), 134.45 (C), 153.40 (C), 162.13 (C), 196.93 (C); FAB-MS (m/z) 263 [M + H]+; HRMS calcd for C18H14O2 262.0994, found 262.0991. Anal. Calcd for C18H14O2: C, 82.42; H, 5.38. Found: C, 82.48; H, 5.41.

1-[4-(Naphthalen-1-yloxy)-phenyl]-ethanone (2b)

White solid was obtained in 45% yield; mp 52–55 °C; 1H NMR (400 MHz, CDCl3) δ 2.56 (s, CH3), 7.01 (d, 2H, Ar,), 7.01 (d, 2H, Ar, J = 8.9 Hz), 7.12 (dd, 1H, Ar, J = 7.5 and 0.9 Hz), 7.90–7.56 (m, 3H, Ar), 7.73 (d, 1H, Ar, J = 8.2 Hz), 7.90–7.96 (m, 3H, Ar), 8.02 (d, 1H, Ar, J = 8.7 Hz); 13C NMR (100 MHz, CDCl3) δ 26.65 (CH3), 116.10 (CH), 117.03 (CH), 122.04 (CH), 125.17 (CH), 126.03 (CH), 126.59 (CH), 126.98 (CH), 127.23 (CH), 128.21 (CH), 130.90 (CH), 132.02 (C), 135.30 (C), 151.32 (C), 162.87 (C), 196.96 (C); FAB-MS (m/z) 263 [M + H]+; HRMS calcd for C18H14O2 262.3080, found 262.3081. Anal. Calcd for C18H14O2: C, 82.42; H, 5.38. Found: C, 82.48; H, 5.41.

1-[4-(Biphenyl-4-yloxy)-phenyl]-ethanone (2c)

White solid was obtained in 48% yield; mp 113–118 °C; 1H NMR (400 MHz, CDCl3) δ 2.58 (s, CH3), 7.05 (d, 2H, Ar, J = 8.9 Hz), 7.13 (d, 2H, Ar, J = 8.7 Hz), 7.33–7.38 (m, 1H, Ar), 7.43–7.48 (m, 2H, Ar), 7.57–7.64 (m, 4H, Ar), 7.95–7.98 (m, 2H, Ar); 13C NMR (100 MHz, CDCl3) δ 26.71 (CH3), 117.60 (CH), 120.58 (CH), 127.19 (CH), 127.53 (CH), 128.94 (CH), 129.07 (CH), 130.85 (CH), 132.19 (CH), 137.91 (C), 140.46 (C), 155.18 (C), 162.11 (C), 197.02 (C); FAB-MS (m/z) 289 [M + H]+; HRMS calcd for C20HO4 288.1150, found 288.1155. Anal. Calcd for C20H16O2: C, 83.31; H, 5.59. Found: C, 83.36; H, 5.62.

1-(4-Phenoxy-phenyl)-ethanone (2d)

White crystalline solid was obtained in 49% yield; mp 47–49 °C; 1H NMR (400 MHz, CDCl3) δ 2.57 (s, CH3), 6.99 (d, 2H, Ar, J = 8.9 Hz), 7.07 (dd, 2H, Ar, J = 8.7 and 1.1 Hz), 7.18–7.22 (m, 1H, Ar), 7.37–7.41 (m, 2H, Ar), 7.93 (d, 2H, Ar, J = 8.9 Hz); 13C NMR (100 MHz, CDCl3) δ 26.69 (CH3), 117.48 (CH), 120.39 (CH), 124.84 (CH), 130.27 (CH), 130.81 (CH), 132.07 (CH), 155.67 (CH), 162.20 (CH), 197.01 (C); FAB-MS (m/z) 213 [M + H]+; HRMS calcd for C14H12O2 212.0837, found 212.0857. Anal. Calcd for C14H12O2: C, 79.23; H, 5.70. Found: C, 79.28; H, 5.75.

1-[4-(4-Acetyl-phenoxy)-phenyl]-ethanone (2e)

Compound 2e was obtained in 42% yield as white solid; mp 98–100 °C; IR (KBr, cm–1) 1678; 1H NMR (400 MHz, CDCl3) δ 2.58 (s, 6H, 2 × CH3), 7.06 (d, 4H, Ar, J = 8.8 Hz), 7.97 (d, 4H, Ar, J = 8.8 Hz); 13C NMR (100 MHz, CDCl3) δ 26.76 (2 × CH3), 118.96 (4 × CH), 130.94 (4 × CH), 133.24 (2 × C), 160.39 (2 × C), 196.92 (2 × C); FAB-MS (m/z) 255 [M + H]+.

1-{4-[7-(4-Acetyl-phenoxy)-naphthalen-2-yloxy]-phenyl}-ethanone (2f)

Compound 2f was obtained in 38% yield as reddish brown solid; mp 135–137 °C; IR (KBr, cm–1) 1673; 1H NMR (400 MHz, CDCl3) δ 2.56 (s, 6H, 2 × CH3), 7.04 (d, 4H, Ar, J = 8.8 Hz), 7.19 (dd, 2H, J = 8.9 and 2.3 Hz), 7.29 (d, 2H, Ar, J = 2.3 Hz), 7.86 (d, 2H, Ar, J = 8.9 Hz), 7.94 (dd, 4H, Ar, J = 8.9 and 2.0 Hz); 13C NMR (100 MHz, CDCl3) δ 26.71 (2 × CH3), 115.44 (2 × CH), 118.03 (4 × CH), 119.75 (2 × CH), 128.07 (C), 130.36 (2 × CH), 130.86 (4 × CH), 132.45 (C), 135.52 (2 × C), 154.48 (2 × C), 161.70 (2 × C), 197.02 (2 × C); FAB-MS (m/z) 397 [M + H]+.

1-{4-[5-(4-Acetyl-phenoxy)-naphthalen-1-yloxy]-phenyl}-ethanone (2g)

Compound 2g was obtained in 40% yield as gray solid; mp 180–183 °C; IR (KBr, cm–1) 1680; 1H NMR (400 MHz, CDCl3) δ 2.58 (s, 6H, 2 × CH3), 7.05 (d, 4H, Ar, J = 8.6 Hz), 7.15 (d, 2H, Ar, J = 7.4 Hz), 7.44 (t, 2H, J = 7.6 Hz), 7.91 (d, 2H, Ar, J = 8.5 Hz), 7.96 (d, 4H, Ar, J = 8.8 Hz); 13C NMR (100 MHz, CDCl3) δ 26.65 (2 × CH3), 116.60 (2 × CH), 117.39 (2 × CH), 118.94 (2 × CH), 126.55 (4 × CH), 128.95 (2 × C), 130.94 (4 × CH), 132.29 (2 × C), 151.78 (2 × C), 162.47 (2 × C), 196.83 (2 × C); FAB-MS (m/z) 397 [M + H]+.

Cyclopentanone (3a)

Compound 3a was obtained in 88% yield as oil; 1H NMR (400 MHz, CDCl3) δ 1.87–1–91(m, 4H), 2.09 (t, 4H, J = 3.7 Hz); 13C NMR (100 MHz, CDCl3) δ 23.32 (2 × CH2), 38.45(2 × CH2), 220.90 (C).

Cyclohexanone (3b)

Compound 3b was obtained in 70% yield as oil; 1H NMR (400 MHz, CDCl3) δ 1.61–1.66 (m, 2H), 1.74–1.81 (m, 4H), 2.25 (t, 4H, J = 6.6 Hz); 13C NMR (100 MHz, CDCl3) δ 25.03 (CH2), 27.09 (2 × CH2), 42.03(2 × CH2), 212.45 (C).

2-Adamantanone (3c)

Compound 3c was obtained in 81% yield as a white powder; mp 256–258 °C; 1H NMR (400 MHz, CDCl3) δ 1.89–2.06 (m, 12H), 2.51 (s, 2H); 13C NMR (100 MHz, CDCl3) δ 27.61 (2 × CH), 36.46 (CH2), 39.43 (4 × CH2), 47.14 (2 × CH), 218.81 (C).