Synthesis of 4-substituted ethers of benzophenone and their antileishmanial activities.

Leishmaniasis is a vector-borne protozoan disease; it mainly originates from the bite of sandfly and initiated when parasite is transmitted to human at metacyclic flagellated promastigote form. In the current study, a synthesis of a series of 4-substituted benzophenone ethers 1-20 was carried out in good yields and their in vitro antileishmanial activities were also screened. Among synthetic derivatives, 15 compounds 1, 3, 5-12, 15 and 17-20 showed antileishmanial activities against promastigotes of Leishmania major with IC50 values in the range of 1.19-82.30 µg ml-1, and the values were compared with those of the standard pentamidine (IC50 = 5.09 ± 0.09 µg ml-1). Our study identified a series of new antileishmanial molecules as potential leads. Structures of these synthetic compounds were deduced by different spectroscopic techniques, such as 1H and 13C nuclear magnetic resonance, electron impact and high-resolution electron impact mass spectrometry and IR.

Introduction

Naturally, benzophenone nucleus is found in the aerial part of Gentiana verna L [1] and Garcinia cochinchinensis [2]. Benzophenone-containing molecules are extensively used in medicinal and agriculture fields. Numerous pharmacological properties are associated with this nucleus, such as non-nucleoside reverse transcriptase inhibition [3], antineoplastic, cytotoxic [4], anti-inflammatory [5], antibacterial [6], antimicrotuble [7], antifungal [8], and urease inhibitory activities [9], inhibitory effects at low-density lipoproteins [10], tolemerase inhibitor [11], anti-cancer agent [12], signal transducer and activator of transcription protein inhibitor [13]. In addition to various biological activities, benzophenone skeleton is also known to have a wide range of luminescence properties [14,15]. Benzophenone derivatives have significant use in dyes. This nucleus also exhibits good photo-initiator properties [16,17].

Leishmaniasis is among the neglected diseases and according to the surveys of the World Health Organization, 350 million people are suffering from this. Leishmaniasis is also responsible for a high mortality rate worldwide [18,19]. It is a vector-borne protozoan disease, mainly originated from the bite of sandfly. Leishmaniasis is initiated when parasite is transmitted to human at metacyclic-flagellated promastigote form. The main site of action involves reticulo-endothelial system of the host. Based on symptoms, leishmaniasis appears in diffused, cutaneous, mucosal and visceral (Kala Azar) forms [20,21].

Currently, antileishmanial remedies include antimonial drugs, such as tartaremetic (antimony potassium tartrate), urea stibamine, amphotericin B and pentamidines bisamidine [22]. However, adverse side effects of these chemotherapeutic agents have made their use limited [23].

In the light of a previous report on antileishmanial activities of benzophenone ethers [24], structure of pentamidine which possesses ether functionality (figure 1), and in continuation of our search for antileishmanial agents [25-27], we have synthesized a library of functionalized benzophenone ethers and evaluated their antileishmanial activities in vitro. To the best of our knowledge, compounds 1 and 2 were previously reported, while remaining compounds are new [28,29].

Figure 1.

Rationale for the current study.

Results and discussion

Chemistry

4-Hydroxybenzophenone (2 mmol), varyingly substituted aryl halide or phenacyl halide (2 mmol), and potassium carbonate (2 mmol) in the presence of catalytic amount of tetrabutylammonium bromide (TBAB) in dichloromethane (15 ml) were refluxed for 6 h. Progression of reaction was studied by thin layer chromatography (TLC). Reaction mixture was cooled to room temperature and a solid material was obtained. The solid was filtered and washed with hexane followed by drying resulting in the desired compounds in good yields (scheme 1). The characterization of synthetic compounds was carried out by 1H and 13C nuclear magnetic resonance (NMR), electron impact mass spectrometry (EI-MS), high-resolution EI-MS (HREI-MS) and IR spectroscopy.

Scheme 1.

Synthesis of benzophenone ethers.

Spectroscopic studies on representative (most active) compound, 2-(4-benzoylphenoxy)-1-(3,4-dichlorophenyl)ethanone (18)

The structure of most active compound (2-(4-benzoylphenoxy)-1-(3,4-dichlorophenyl)ethanone, 18) was deduced by 1H- and 13C-NMR spectroscopy which was performed in deuterated dimethylsulfoxide (DMSO-d6) with a Bruker Avance AM 300 MHz instrument. In 1H-NMR spectrum doublet for H-2 and H-6 protons was obtained at δH 7.73 (J2,3/6,5 = 8.7 Hz). However, one more doublet with integration of two protons at δH 7.64 (J2′,3′/6′,5′ = 7.2 Hz) was assigned to H-2′ and H-6′. Another proton doublet for H-4 was obtained at δH 7.70 (J4(3,5) = 8.7 Hz). A triplet for two protons H-3 and H-5 was obtained at δH 7.56 (J3(2,4)/5(4,6) = 8.5 Hz). A doublet at δH 7.88 (J6′′,5′′ = 8.4 Hz) was assigned to H-6‴. However, singlet at δH 5.74 for CH2 group confirmed the existence of ether linkage. In addition, other aromatic protons justified their resonance frequency along with their respective J values (figure 2).

Figure 2.

1H-NMR chemical shift values for most active compound 18.

In broadband decoupled 13C-NMR spectra, 16 signals appeared: eight signals are for methines, and seven signals for quaternary carbons. Carbon at δC 70.3 appeared also in spectra: it was for one methylene present in the structure. The most deshielded signals at δC 194.4 and 193.1 were due to carbonylic carbons. Signal at δC 161.6 was due to aromatic cabon directly attached to ether oxygen C-4′. Adjacent to carbonyl groups, three carbons, i.e. (C-1), (C-1′), and (C-1‴), resonated at δC 133.5, 133.8 and 130.8, respectively. Rest of the carbons in the structure resonated in the normal aromatic range of δC 132.2–114.6 (figure 3).

Figure 3.

13C-NMR chemical shift values for compound 18.

High-resolution mass spectrum of compound 18 displayed the M+ at m/z 384.0321 with a composition of C21H14Cl2O3 (calcd 384.0320). The per cent abundance of isotopic [M + 4]+ 10%, [M + 2]+ 49% and molecular ion peak M+ 76% at m/z 388, 386 and 384, respectively, confirmed the presence of two chlorine atoms in a molecule. Cleavage of carbon–carbon bond from α-carbonyl group of ether resulted in respective methylene benzophenone ether which appeared at m/z 211, and remaining acylium ion appeared as base peak at m/z 173. Fragment at m/z 198 was due to benzophenone fragment. It was further fragmented into respective acylium ion at m/z 121. Fragments at m/z 105 and 77 were due to benzyl acylium ion and benzene radical cation, respectively (figure 4).

Figure 4.

EI-MS fragmentation pattern of compound 18.

In the Fourier transform IR (FT-IR) spectrum, vibrational frequencies at 1710 and 1628 cm−1 correspond to the carbonyl (C=O) functionality. However, vibrational frequencies of aromatic (C=C) bond and ether (C–O) appeared at 1557 and 1309 cm−1 (figure 5), respectively. These are spectroscopic observations of proposed structure for compound 18. Structures of all other compounds were deduced in a similar manner.

Figure 5.

FT-IR absorptions of compound 18.

Antileishmanial studies

Twenty 4-substituted ether derivatives of benzophenone (1–20) were synthesized. Among these, nine were α-substituted carbonyl ether derivatives, while 11 were simple ether derivatives of benzophenone. All the synthetic compounds were screened for antileishmanial activities. Results indicated that aryl or alkyl parts of ether analogues having different substituents are responsible for antileishmanial activities (figure 6; table 1).

Figure 6.

General structures of 4-substituted ether derivatives of benzophenone.

Table 1.

Antileishmanicidal activity of benzophenone ethers 1–20 (s.e.m. is the standard error of the mean and n.a. means not active).

4-Substituted α-carbonyl ether analogues of benzophenone

Among 4-substituted α-carbonyl ethers, compound 18 containing chloro groups at meta and para positions of aryl part was found to be the most active member of series having IC50 value of 1.94 ± 0.70 µg ml−1. However, the introduction of chloro group at para position of aryl part, as in compound 17, exhibited a decreased inhibitory activity (IC50 = 82.3 ± 2.30 µg ml−1). Nevertheless, the presence of a bromo functionality at para position of aryl part, as in compound 12, exhibited a weak inhibitory effect (IC50 = 53.3 ± 2.6 µg ml−1) (figure 7).

Figure 7.

Structure–activity relationship of halide-substituted aryl part for 12, 17 and 18.

When compounds 19, 20 and 15 were screened for their antileishmanial activities, compound 19 having an unsubstituted aryl part and compound 20 having a methyl group at para position of aryl part showed moderate inhibitory effect with IC50 value of 27.63 ± 0.38 µg ml−1 and 22.78 ± 0.31 μg ml−1, respectively. However, increase of carbon load at aryl part such as placing a para phenyl as in analogue 15 resulted in a decreased activity (IC50 = 67.2 ± 2.20 µg ml−1) (figure 8).

Figure 8.

Structure–activity relationship in unsubstituted, methyl and phenyl compounds 15, 19 and 20.

4-Substituted ether derivatives of benzophenone

In 4-substituted ether derivatives, compound 8 having chloro group at meta position of aryl part was found to be the second most active member of the series with IC50 = 13.11 ± 0.42 µg ml−1. Nevertheless, the introduction of chloro substituent to para position, as in 9 (IC50 = 17.02 ± 0.70 µg ml−1), showed a slight decreased activity. When a dichloro substituent was present at meta and para positions of aryl part, as in compound 5, a sharp decline (IC50 = 63.3 ± 3.30 µg ml−1) in activity was observed (figure 9).

Figure 9.

Structure–activity relationship of chloro-substituted compounds 5, 8 and 9.

However, the presence of a chloro group at ortho and a fluoro group at para as in compound 6 demonstrated a weak inhibitory activity having an IC50 value of 65.0 ± 5.00 µg ml−1. Moreover, a bromo substituent at ortho position, as in compound 3, made it weakly active with an IC50 value of 68.75 ± 6.20 µg ml−1 (figure 10).

Figure 10.

Structure–activity relationship of chloro-, fluoro- and bromo-substituted compounds 3 and 6.

The presence of methoxy group at meta position as in molecule 11 made it fairly active (IC50 = 30.43 ± 0.50 µg ml−1). Replacement of methoxy substituent with a methyl substituent at meta position of aryl part as in derivative 10 displayed a good activity (IC50 = 13.59 ± 0.28 µg ml−1). However, when switching the methyl group to para position of aryl part as in analogue 7 (IC50 = 77.5 ± 2.50 µg ml−1), a weak inhibitory activity was observed (figure 11).

Figure 11.

Structure–activity relationship of alkoxy- and alkyl-substituted compounds 7, 10 and 11.

To study the effect of carbon load, compound 1 having a propyl group at ether part was screened and found to have a weak activity with an IC50 value of 70.6 ± 2.3 μg ml−1. But, remaining derivatives were found to be inactive (figure 12).

Figure 12.

Structure–activity relationship of 4-ether-substituted compound 1.

Conclusion

This study deals with the synthesis of 20 4-substituted ethers of benzophenone derivatives and their antileishmanial activities were screened. Fifteen compounds displayed antileishmanial activity having IC50 values within the range of 1.94–82.30 μg ml−1. Compound 18 was found to be the most active compound (IC50 = 1.94 µg ml−1) of this series. These compounds seemingly have potential to develop powerful antileishmanial agents.

Experimental procedure

Material and methods

TBAB, 4-hydroxybenzophenone, potassium carbonate, different phenacyl halide and aryl halides were acquired from TCI (Japan). RPMI 1640 Liquid 20 mM HEPES (4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid), with l-glutamine without NaHCO3 was purchased from Sigma-Aldrich (USA). Neubauer counting chamber (2.5 × 10−3 mm2) was obtained from Marienfeld, Germany. Leishmania major was obtained from DESTO. Fetal bovine serum (Cat No. S181H-100 and Lot No. S11302S181H) was acquired from Biowest (The Serum Specialist), and standard drug pentamidine was obtained from Merck. 2-Amino-5-benzonitrile, N,N-dimethylformamide 1,1-dimethoxyethane and acetic acid-substituted anilines were purchased from TCI (Japan). All chemicals were used as received without purification. TLC analysis was performed on pre-coated silica gel aluminium cards (Kieselgel 60, 254, E. Merck, Germany). UV lamp at 254 and 365 nm was employed for the visualization of TLC chromatograms.

Mass spectra were recorded with a Finnigan MAT-311A (Germany) mass spectrometer. 1H- and 13C-NMR spectra were recorded with Bruker Avance AM 300 and 400 MHz spectrometers. Melting points of the compounds were determined using a Stuart® SMP10 melting point apparatus, and are uncorrected. IR spectra (KBr discs) were recorded with a FTS 3000 MX, Bio-RAD Merlin (Excalibur Model) spectrophotometer.

Antileishmanial assay protocol

Leishmania major (MHOM/Pk/88/DESTO) was performed in bulk in modified N,N,N-biphasic medium by means of normal physiological saline. Leishmania major (MHOM/Pk/88/DESTO) promastigotes were grown in the RPMI 1640 medium (Sigma, St Louis, USA), supplemented with 10% heat-inactivated fetal calf serum (PAA Laboratories GmbH, Austria). Parasites at log phase were centrifuged at 2000 r.p.m. for 10 min and at the same speed and washed time three times with saline. Parasites were diluted to a final density of 1 × 106 cells ml−1 with a fresh culture medium.

The assay was carried out in a 96-well micro-titre plate; the medium was added in different wells. The test compound (20 µl) was added in the medium and serially diluted. Parasite culture (100 µl) was added in all wells. Two rows were left for positive and negative controls. In positive controls, different quantities of standard antileishmanial drug pentamidine (ICN Biomedical Inc, USA) were present, while negative controls contained only medium. The plate was incubated for 72 h at 22–25°C. The culture was microscopically examined on Neubauer counting chamber. IC50 values were calculated by software Ezfit 5.03 (Perella Scientific, USA). All tests were carried out three times [30].

General procedure for the synthesis of compounds 1–20

Differently substituted benzophenone ethers were synthesized by refluxing a mixture of 4-hydroxybenzophenone, potassium carbonate, TBAB, differently substituted phenacyl halide and aryl/alkyl halide in dichloromethane as solvent. The reaction was examined by TLC. Subsequently, the reaction mixture was filtered, and cooled until precipitates became visible. These precipitates were sieved and rinsed with hexane. Yield of all the synthetic compounds was moderate to high.

Spectral data of synthetic compounds 1–20

Phenyl(4-propoxyphenyl)methanone (1)

Yield: 81%; m.p. 91–93°C; R: 0.51 (ethyl acetate/hexanes, 2:8); IR (KBr, cm−1): 3272 (=C–H), 1645 (C=O), 1599 (C=C), 1257 (C–O); 1H-NMR (300 MHz, DMSO-d): δH 7.79 (d, 2H, J2,3/6,5 = 8.7 Hz, H-2, H-6), 7.71 (d, 2H, J2′,3′/6′,5′ = 6.9 Hz, H-2′, H-6′), 7.63 (t, 1H, J4(3,5) = 8.1 Hz, H-4), 7.53 (t, 2H, J3(2,4)/5(6,4) = 7.8 Hz, H-3, H-5), 7.03 (d, 2H, J3′,2′/5′,6′ = 8.7 Hz, H-3′, H-5′), 4.05 (t, 2H, J(CH2,CH2) = 6.6 Hz, CH2), 1.88 (m, 2H, CH2), 1.081 (t, 3H, J(CH3,CH2) = 7.5 Hz, CH3); EI-MS: m/z (rel. abund.%), 240 [M]+ (51.0), 198 (20.0), 163 (9.6), 121 (100.0), 105 (14.5), 77 (7.7); HREI-MS: m/z calcd for C16H16O2 [M]+ 240.1150, found 240.1151.

(4-(Benzyloxy)phenyl)(phenyl)methanone (2)

Yield: 82%; m.p. 90–92°C; R: 0.50 (ethyl acetate/hexanes, 2:8); IR (KBr, cm−1): 3273 (=C–H), 1641 (C=O), 1597 (C=C), 1242 (C–O); 1H-NMR (300 MHz, DMSO-d): δH 7.75 (d, 2H, J2,3/6,5 = 8.7 Hz, H-2, H-6), 7.69 (m, 3H, H-2′′, H-4′′, H-6′′), 7.56 (t, 2H, J3(2,4)/5(4,6) = 7.8 Hz, H-3, H-5), 7.48 (d, 2H, J2′,3′/6′,5′ = 6.9 Hz, H-2′, H-6′), 7.42 (m, 3H, H-4, H-3′′, H-5′′), 7.18 (d, 2H, J3′,2′/5′,6′ = 8.7 Hz, H-3′, H-5′), 5.21 (s, 2H, CH2); 13C-NMR (125.0 MHz, DMSO-d6): δC 194.3 (C=O), 162.0 (C-4′), 137.7 (C-4), 136.4 (C-1), 132.1 (C-1′′), 132.0 (C-1′), 129.5 (C-2′, C-6′), 129.2 (C-2, C-6), 128.5 (C-2′′, H-6′′), 128.4 (C-3, C-5), 128.0 (C-3′′, C-5′′), 127.7 (C-4′′), 114.6 (C-3′, C-5′), 69.5 (CH2); EI-MS: m/z (rel. abund.%), 288 [M]+ (46.9), 211 (1.4), 198 (4.1), 181 (1.3), 141 (7.0), 121 (8.3), 115 (6.6), 105 (19.7), 91 (100.0), 77 (28.2); HREI-MS: m/z calcd for C20H16O2 [M]+ 288.1150, found 288.1140.

(4-(2-Bromobenzyloxy)phenyl)(phenyl)methanone (3)

Yield: 84%; m.p. 96–98°C; R: 0.47 (ethyl acetate/hexanes, 2:8); IR (KBr, cm−1): 3261 (=C–H), 1703 (C=O), 1637 (C=C), 1265 (C–O), 704 (=C–Br); 1H-NMR (300 MHz, DMSO-d): δH 7.77 (d, 2H, J2,3/6,5 = 8.7 Hz, H-2, H-6), 7.70 (d, 2H, J2′,3′/6′,5′/3′′,4′′ = 8.1 Hz, H-2′, H-6′, H-3′′), 7.65 (t, 2H, J3(2,4)/5(4,6) = 6.9 Hz, H-3, H-5), 7.56 (m, 2H, H-4, H-6′′), 7.47 (t, 1H, J5′′ (4′′,6′′) = 7.2 Hz, H-5′′), 7.36 (t, 1H, J4′′ (3′′,5′′) = 7.5 Hz, H-4′′), 7.20 (d, 2H, J3′,2′/5′,6′ = 8.7 Hz, H-3′, H-5′), 5.23 (s, 2H, CH2); 13C-NMR (125.0 MHz, DMSO-d6): δC 194.4 (C=O), 161.8 (C-4′), 137.6 (C-4), 135.2 (C-1), 132.7 (C-1′′), 132.2 (C-1′), 132.1 (C-2′, C-6′), 130.5 (C-2, C-6), 130.4 (C-3, C-5), 129.8 (C-3′, C-5′), 129.3 (C-2′′), 128.4 (C-6′′), 128.0 (C-3′′), 123.0 (C-5′′), 114.6 (C-4′′), 69.4 (CH2); EI-MS: m/z (rel. abund.%), 368 [M + 2]+ (8.7), 366 [M]+ (8.7), 287 (1.7), 197 (1.0), 181 (0.2), 167 (95.0), 169 (100.0), 152 (1.3), 105 (9.4), 90 (21.7), 77 (11.9); HREI-MS: m/z calcd for C20H15BrO2 [M]+ 366.0255, found 366.0252.

(4-(4-Nitrobenzyloxy)phenyl)(phenyl)methanone (4)

Yield: 85%; m.p. 135–137°C; R: 0.46 (ethyl acetate/hexanes, 2 : 8); IR (KBr, cm–1): 3072 (=C–H), 1641 (C=O), 1602 (C=C), 1515 (N=O), 1255 (C–O); 1H-NMR (300 MHz, DMSO-d): δH 8.28 (d, 2H, J3′′,2′′/5′′,6′′ = 8.4 Hz, H-3′′, H-5′′), 7.77 (m, 4H, H-2′, H-3′, H-5′, H-6′), 7.69 (m, 3H, H-2, H-4, H-6), 7.56 (t, 2H, J3(2,4)/5(4,6) = 7.5 Hz, H-3, H-5), 7.20 (d, 2H, J3′,2′/5′,6′ = 8.7 Hz, H-3′, H-5′), 5.40 (s, 2H, CH2); 13C-NMR (125.0 MHz, DMSO-d6): δC 194.4 (C=O), 161.5 (C-4′), 147.1 (C-4′′), 144.3 (C-4), 137.6 (C-1′′), 132.2 (C-1′), 129.8 (C-1), 129.2 (C-2′, C-6′), 128.4 (C-2, C-6), 128.3 (C-3, C-5), 123.4 (C-2′′, C-6′′), 123.6 (C-3′, C-5′), 114.7 (C-3′′, C-5′′), 69.4 (CH2); EI-MS: m/z (rel. abund.%), 333 [M]+ (43.2), 287 (1.0), 256 (4.1), 197 (30.5), 169 (10.6), 136 (89.7), 106 (74.4), 77 (100.0); HREI-MS: m/z calcd for C20H15NO4 [M]+ 333.1001, found 333.1014.

(4-(3,4-Dichlorobenzyloxy)phenyl)(phenyl)methanone (5)

Yield: 83%; m.p. 142–145°C; R: 0.47 (ethyl acetate/hexanes, 2:8); IR (KBr, cm−1): 3255 (=C–H), 1641 (C=O), 1600 (C=C), 1257 (C–O), 810 (=C–Cl); 1H-NMR (300 MHz, DMSO-d): δH 8.28 (d, 3H, J2,3/6,5/6′′,5′′ = 8.4 Hz, H-3′′, H-5′′), 7.69 (t, 2H, J3(2,4)/4(3,5)/5(4,6) = 7.5 Hz, H-3, H-4, H-5), 7.56 (m, 3H, H-2′, H-6′, H-2′′), 7.18 (d, 2H, J3′,2′/5′,6′ = 8.7 Hz, H-3′, H-5′), 5.23 (s, 2H, CH2); 13C-NMR (75.0 MHz, DMSO-d6): δC 194.3 (C=O), 161.6 (C-4′), 137.7 (C-4′′), 137.6 (C-1′′), 132.1 (C-1′), 131.1 (C-1), 130.7 (C-3′′), 130.5 (C-4), 129.8 (C-2, C-6), 129.6 (C-2′, C-6′), 129.2 (C-2′′), 128.4 (C-5′′), 127.9 (C-6′′), 127.5 (C-3, C-5), 114.7 (C-3′, C-5′), 67.9 (CH2); EI-MS: m/z (rel. abund.%), 356 [M]+ (2.3), 198 (0.2), 159 (100.0), 141 (6.5), 123 (15.3), 105 (11.5), 91 (1.6), 77 (39.7); HREI-MS: m/z calcd for C20H14Cl2O2 [M]+ 356.0371, found 356.0370.

(4-(2-Chloro-4-fluorobenzyloxy)phenyl)(phenyl)methanone (6)

Yield: 82%; m.p. 88–90°C; R: 0.45 (ethyl acetate/hexanes, 2:8); IR (KBr, cm−1): 3255 (=C–H), 1641 (C=O), 1600 (C=C), 1257 (C–O), 810 (=C–Cl); 1H-NMR (300 MHz, DMSO-d): δH 8.28 (d, 2H, J2,3/6,5 = 8.4 Hz, H-2, H-6), 8.26 (s, 1H, H-3′′), 7.69 (t, 3H, J3(2,4)/4(3,5)/5(4,6) = 7.5 Hz, H-3, H-4, H-5), 7.56 (m, 4H, H-2′, H-6′, H-5′′, H-6′′), 7.18 (d, 2H, J3′,2′/5′,6′ = 8.7 Hz, H-3′, H-5′), 5.23 (s, 2H, CH2); 13C-NMR (75.0 MHz, DMSO-d6): δC 194.3 (C=O), 161.6 (C-4′), 137.7 (C-4′′), 137.6 (C-1′′), 132.1 (C-1′), 131.1 (C-1), 130.7 (C-3′′), 130.5 (C-4), 129.8 (C-2, C-6), 129.6 (C-2′, C-6′), 129.2 (C-2′′), 128.4 (C-5′′), 127.9 (C-6′′), 127.5 (C-3, C-5), 114.7 (C-3′, C-5′), 67.9 (CH2); EI-MS: m/z (rel. abund.%), 342 [M + 2]+ (2.0) 340 [M]+ (5.4), 145 (53.6), 143 (100.0), 141 (6.5), 108 (9.0), 107 (20.8), 105 (9.8) 91 (1.6), 77 (28.4); HREI-MS: m/z calcd for C20H14ClFO2 [M]+ 340.0666, found 340.0667.

(4-(4-Methylbenzyloxy)phenyl)(phenyl)methanone (7)

Yield: 85%; m.p. 102–104°C; R: 0.48 (ethyl acetate/hexanes, 2:8); IR (KBr, cm−1): 3091 (=C–H), 1654 (C=O), 1593 (C=C), 1147 (C–O); 1H-NMR (300 MHz, DMSO-d): δH7.74 (d, 2H, J2,3/6,5 = 8.7 Hz, H-2, H-6), 7.68 (d, 2H, J2′,3′/6′,5′ = 7.2 Hz, H-2′, H-6′), 7.64 (d, 1H, J4(3,5) = 6.3 Hz, H-4), 7.56 (t, 2H, J3(2,4)/5(4,6) = 7.5 Hz, H-3, H-5), 7.36 (d, 2H, J3′,2′/5′,6′ = 8.1 Hz, H-3′, H-5′), 7.21 (d, 2H, J3′′,2′′/5′′,6′′ = 7.8 Hz, H-3′′, H-5′′), 7.16 (d, 2H, J2′′,3′′/6′′,5′′ = 8.7 Hz, H-2′′, H-6′′), 5.16 (s, 2H, CH2), 2.30 (s, 3H, 4′′-CH3); 13C-NMR (75.0 MHz, DMSO-d6): δC 194.5 (C=O), 162.0 (C-4′), 137.7 (C-4′′), 137.3 (C-1′′), 133.3 (C-1′), 132.1 (C-1), 132.0 (C-4), 129.4 (C-2, C-6), 129.2 (C-2′, C-6′), 129.0 (C-2′′, C-6′′), 128.4 (C-3, C-5), 127.9 (C-3′′, C-5′′), 114.6 (C-3′, C-5′), 69.4 (CH2), 20.7 (4′′-CH3); EI-MS: m/z (rel. abund.%), 302 [M]+ (11.5), 209 (35.1), 198 (22.5), 179 (5.8), 141 (6.1), 121 (36.6), 105 (100.0), 91 (7.7), 77 (16.8); HREI-MS: m/z calcd for C21H18O2 [M]+ 302.1307, found 302.1305.

(4-(3-Chlorobenzyloxy)phenyl)(phenyl)methanone (8)

Yield: 81%; m.p. 128–130°C; R: 0.46 (ethyl acetate/hexanes, 2:8); IR (KBr, cm−1): 3100 (=C–H), 1660 (C=O), 1598 (C=C), 1197 (C–O); 1H-NMR (400 MHz, DMSO-d): δH7.76 (d, 2H, J2,3/6,5 = 10.0 Hz, H-2, H-6), 7.69 (m, 3H, H-3, H-4, H-5), 7.56 (m, 3H, H-2′, H-6′, H-2′′), 7.45 (m, 3H, H-4′′, H-5′′, H-6′′), 7.18 (d, 2H, J3′,2′/5′,6′ = 11.6 Hz, H-3′, H-5′), 5.23 (s, 2H, CH2); EI-MS: m/z (rel. abund. %), 322 [M]+ (11.8), 169 (10.6), 141 (18.2), 125 (100.0), 89 (23.9), 77 (25.9); HREI-MS: m/z calcd for C20H15ClO2 [M]+ 322.0761, found 322.0762.

(4-(4-Chlorobenzyloxy)phenyl)(phenyl)methanone (9)

Yield: 81%; m.p. 130–132°C; R: 0.47 (ethyl acetate/hexanes, 2:8); IR (KBr, cm−1): 3125 (=C–H), 1670 (C=O), 1634 (C=C), 1278 (C–O), 878 (=C–Cl); 1H-NMR (400 MHz, DMSO-d): δH 7.75 (d, 2H, J2,3/6,5 = 8.8 Hz, H-2, H-6), 7.68 (d, 2H, J2′,3′/6′,5′ = 7.2 Hz, H-2′, H-6′), 7.64 (d, 1H, J4(3,5) = 7.2 Hz, H-4), 7.55 (d, 2H, J3′′,2′′/5′′,6′′ = 7.6 Hz, H-3′′, H-5′′), 7.51 (t, 2H, J3 (2,4)/5 (4,6) = 7.6 Hz, H-3, H-5) 7.48 (d, 2H, J2′′,3′′/6′′,5′′ = 7.2 Hz, H-2′′, H-6′′), 7.52 (d, 2H, J3′,2′/5′,6′ = 8.8 Hz, H-3′, H-5′), 5.14 (s, 2H, CH2); 13C-NMR (100 MHz, DMSO-d6): δC 194.4 (C=O), 161.8 (C-4′), 137.7 (C-1), 135.5 (C-1′), 132.6 (C-1′′), 132.2 (C-2, C-6), 132.1 (C-2′′, C-6′′), 129.7 (C-3, C-5), 129.6 (C-3′′, C-5′′), 129.2 (C-4), 128.5 (C-4′′), 128.4 (C-2′, C-6′), 114.7 (C-3′, C-5′), 68.7 (CH2); EI-MS: m/z (rel. abund. %), 324 [M + 2]+ (1.9), 322 [M]+ (6.1), 125 (100.0), 105 (3.2), 89 (6.7), 78 (8.6); HREI-MS: m/z calcd for C20H15ClO2 [M]+ 322.0761, found 322.0760.

(4-(4-Methylbenzyloxy)phenyl)(phenyl)methanone (10)

Yield: 86%; m.p. 106–108°C; R: 0.49 (ethyl acetate/hexanes, 2:8); IR (KBr, cm−1): 3090 (=C–H), 1665 (C=O), 1578 (C=C), 1167 (C–O); 1H-NMR (400 MHz, DMSO-d): δH 7.75 (d, 2H, J2,3/6,5 = 8.4 Hz, H-2, H-6), 7.68 (d, 2H, J2′,3′/6′,5′ = 7.2 Hz, H-2′, H-6′), 7.64 (d, 1H, J4(3,5) = 7.2 Hz, H-4), 7.55 (t, 2H, J3 (2,4)/5 (4,6) = 7.6 Hz, H-3, H-5), 7.28 (m, 2H, H-3′, H-5′), 7.17 (d, 3H, J4′′(5′′,6′′)/5′′,4′′/6′′,5′′ = 8.8 Hz, H-4′′, H-5′′, H-6′′), 5.17 (s, 2H, CH2), 2.31 (s, 3H, 3′′-CH3); EI-MS: m/z (rel. abund.%), 302 [M]+ (0.9), 141 (3.9), 121 (5.4), 115 (3.2), 105 (100.0), 77 (34.1), 63 (9.2), 51 (4.8); HREI-MS: m/z calcd for C21H18O2 [M]+ 302.1307, found 302.1305.

(4-(3-Methoxybenzyloxy)phenyl)(phenyl)methanone (11)

Yield: 83%; m.p. 120–122°C; R: 0.44 (ethyl acetate/hexanes, 2:8); IR (KBr, cm−1): 3150 (=C–H), 1689 (C=O), 1550 (C=C), 1157 (C–O); 1H-NMR (300 MHz, DMSO-d): δH 7.74 (d, 2H, J2,3/6,5 = 8.8 Hz, H-2, H-6), 7.68 (d, 2H, J2′,3′/6′,5′ = 8.4 Hz, H-2′, H-6′), 7.64 (d, 1H, J6′′,5′′ = 7.2 Hz, H-6′′) 7.55 (t, 2H, J3 (2,4)/5 (4,6) = 7.6 Hz, H-3, H-5), 7.33 (t, 1H, J4(3,5) = 7.2 Hz, H-4), 7.17 (d, 2H, J3′,2′/5′,6′ = 8.4 Hz, H-3′, H-5′), 7.03 (m, 2H, H-2′′, H-5′′), 6.91 (dd, 1H, J4′′,5′′ = 6.4 Hz, J4′′,2′′ = 1.6 Hz, H-4′′); EI-MS: m/z (rel. abund. %), 318 [M]+ (74.4), 211 (4.2), 198 (6.4), 169 (2.3), 141 (4.2), 121 (100.0), 105 (16.0), 91 (38.8), 77 (28.1); HREI-MS: m/z calcd for C21H18O3 [M]+ 318.1256, found 318.1255.

2-(4-Benzoylphenoxy)-1-(4-bromophenyl)ethanone (12)

Yield: 82%; m.p. 126–128°C; R: 0.47 (ethyl acetate/hexanes, 2:8); IR (KBr, cm−1): 3390 (=C–H) 1703 (C=O), 1637 (C=O), 1593 (C=C), 1315 (C–O), 560 (=C–Br); 1H-NMR (300 MHz, DMSO-d): δH 7.79 (d, 2H, J2′′,3′′/6′′,5′′ = 8.4 Hz, H-2′′, H-6′′), 7.81 (d, 2H, J3′′,2′′/5′′,6′′ = 8.4 Hz, H-3′′, H-5′′), 7.73 (m, 5H, H-2, H-4, H-6, H-2′, H-6′), 7.56 (t, 2H, J3(2,4)/5(4,6) = 7.2 Hz, H-3, H-5), 7.71 (d, 2H, J3′,2′/5′,6′ = 8.7 Hz, H-3′, H-5′), 5.71 (s, 2H, CH2); 13C-NMR (100 MHz, DMSO-d6): δC 194.4 (C=O), 193.2 (C=O), 161.6 (C-4′), 137.6 (C-1), 133.2 (C-1′), 132.1 (C-1′′), 132.0 (C-2, C-6), 131.9 (C-2′′, C-6′′), 129.9 (C-3, C-5), 129.7 (C-3′′, C-5′′), 129.2 (C-4), 128.4 (C-4′′), 128.0 (C-2′, C-6′), 114.6 (C-3′, C-5′), 70.2 (CH2); EI-MS: m/z (rel. abund.%), 396 [M++2] (3.8), 394 [M]+ (3.9), 376 (4.7), 332 (7.7), 239 (7.5), 180 (100.0), 166 (95.3), 155 (3.5), 77 (44.9); HREI-MS: m/z calcd for C21H15BrO3 [M]+ 394.0205, found 394.0203.

2-(4-Benzoylphenoxy)-1-(4-nitrophenyl)ethanone (13)

Yield: 84%; m.p. 113–115°C; R 0.49 (Ethyl acetate/hexane, 3 : 7); IR (KBr, cm−1): 3393 (=C–H) 1709 (C=O), 1620 (C=O), 1598 (C=C), 1311 (C–O), 760 (N–O); 1H-NMR (300 MHz, DMSO-d): δ 8.40 (d, 2H, J3′′,2′′/5′′,6′′= 7.5 Hz, H-3′′,H-5′′), 8.27 (d, 2H, J2′′,3′′/6′′,5′′= 7.5 Hz, H-2′′,H-6′′), 7.74 (d, 2H, J3′,2′/5′,6′ = 7.5 Hz, H-3′,H-5′), 7.70 (m, 2H, H-3, H-5), 7.64 (m, 1H, H-4), 7.56 (m, 2H, H-2,H-6), 7.17 (d, 2H, J2′,3′/6′,5′= 7.5 Hz, H-2′, H-6′), 5.80 (s, 2H, CH2); EI-MS: m/z (rel. abund.%), 361.1 [M]+ (41.0), 345 (1.6), 284 (16.6), 211 (17.8), 198 (39.9), 181 (11.2), 150 (100.0), 121 (77.7), 105 (65.9), 77 (42.3); HREI-MS: m/z calcd for C21H15NO5 [M]+ 361.0950, found 361.0952.

2-(4-Benzoylphenoxy)-1-(3-methoxyphenyl)ethanone (14)

Yield: 84%; m.p. 153–156°C; R: 0.46 (ethyl acetate/hexanes, 2:8); IR (KBr, cm−1): 3377 (=C–H), 1697 (C=O), 1635 (C=O), 1598 (C=C), 1313 (C–O); 1H-NMR (300 MHz, DMSO-d): δH 7.73 (m, 4H, H-2, H-3, H-5, H-6), 7.64 (d, 2H, J2′,3′/6′,5′ = 8.4 Hz, H-2′, H-6′), 7.56 (m, 4H, H-2′′, H-4′′, H-5′′, H-6′′), 7.28 (d, 1H, J4(3,5) = 6.6 Hz, H-4), 7.13 (t, 2H, J3′(2′,4′)/5′(4′,6′) = 8.7 Hz, H-3′, H-5′), 5.73 (s, 2H, CH2), 3.83 (s, 3H, 3′′-OCH3); 13C-NMR (100 MHz, DMSO-d6): δC 194.4 (C=O), 193.8 (C=O), 161.7 (C-4′), 159.5 (C-3′′), 137.7 (C-1), 135.5 (C-1′′), 132.1 (C-1′), 132.0 (C-2, C-6), 130.0 (C-4), 129.7 (C-3, C-5), 129.2 (C-2′, H-6′), 128.4 (C-2′′), 120.3 (C-5′′), 119.8 (C-2′′), 114.4 (C-6′′), 112.3 (C-4′′), 70.3 (CH2), 55.4 (3′′-OCH3); EI-MS: m/z (rel. abund.%), 346 [M]+ (18.5), 209 (2.6), 198 (7.8), 150 (2.7), 135 (100.0), 121 (15.8), 107 (19.1), 92 (4.1), 77 (12.0); HREI-MS: m/z calcd for C22H18O4 [M]+ 346.1205, found 346.1224.

2-(4-Benzoylphenoxy)-1-(biphenyl-4-yl)ethanone (15)

Yield: 88%; m.p. 100–102°C; R: 0.50 (ethyl acetate/hexanes, 2:8); IR (KBr, cm−1): 3376 (=C–H), 1692 (C=O), 1636 (C=O), 1589 (C=C), 1310 (C–O); 1H-NMR (300 MHz, DMSO-d): δH 8.13 (d, 2H, J2′′,3′′/6′′,5′′ = 8.4 Hz, H-2′′, H-6′′), 7.89 (d, 2H, J2,3/6,5 = 8.4 Hz, H-2, H-6), 7.78 (m, 7H, H-3, H-4, H-5, H-2′, H-6′, H-3′′, H-5′′), 7.56 (m, 4H, H-3′, H-5′, H-3‴, H-5‴), 7.46 (d, 1H, J4‴(3‴,5‴) = 8.7 Hz, H-4‴), 7.15 (d, 2H, J2‴,3‴/6‴,5‴ = 9.0 Hz, H-2‴, H-6‴), 5.77 (s, 2H, CH2); 13C-NMR (75.0 MHz, DMSO-d6): δC 194.4 (C=O), 193.5 (C=O), 161.7 (C-4′), 145.2 (C-1‴), 138.7 (C-1), 137.7 (C-1′), 133.0 (C-4), 132.1 (C-2, C-6), 132.0 (C-2′, C-6′), 129.7 (C-2′′, C-6′′), 129.2 (C-3′′, H-5′′), 129.1 (C-2‴, C-6‴), 128.6 (C-3‴, C-5‴), 128.5 (C-1′), 128.4 (C-4‴), 127.3 (C-3, C-5), 127.0 (C-3′, C-5′), 114.6 (C-4′′), 70.3 (CH2); EI-MS: m/z (rel. abund.%), 392 [M]+ (11.6), 315 (0.8), 287 (0.2), 211 (0.2), 181 (100.0), 152 (63.4), 115 (0.9), 105 (39.8), 77 (55.9); HREI-MS: m/z calcd for C27H20O3 [M]+ 394.1412, found 392.1413.

2-(4-Benzoylphenoxy)-1-(4-methoxyphenyl)ethanone (16)

Yield: 84%; m.p. 145–147°C; R: 0.47 (ethyl acetate/hexanes, 2:8); IR (KBr, cm−1): 3372 (=C–H), 1690 (C=O), 1636 (C=O), 1158 (C=C), 1310 (C–O); 1H-NMR (300 MHz, DMSO-d): δH 8.02 (d, 2H, J2,3/6,5 = 8.7 Hz, H-2, H-6), 7.73 (m, 4H, H-2′, H-3′, H-5′, H-6′), 7.64 (d, 1H, J4(3,5) = 8.7 Hz, H-4), 7.56 (t, 2H, J3′(2′,4′)/5′(4′,6′) = 8.7 Hz, H-3′, H-5′), 7.10 (d, 4H, J2′′,3′′/3′′,2′′/6′′,5′′/5′′,6′′) = 8.7 Hz, H-2′′, H-3′′, H-5′′, H-6′′), 5.77 (s, 2H, CH2), 3.85 (4′′-OCH3); 13C-NMR (75.0 MHz, DMSO-d6): δC 194.3 (C=O), 192.2 (C=O), 163.6 (C-4′), 161.7 (C-4′′), 137.6 (C-1), 132.0 (C-1′), 131.9 (C-1′′), 130.2 (C-4), 129.6 (C-2, C-6), 129.2 (C-3, C-5), 128.4 (C-2′, H-6′), 127.1 (C-2′′, C-6′′), 114.5 (C-3′, C-5′), 114. (C-3′′, C-5′′), 69.9 (CH2), 55.6 (4′′-OCH3); EI-MS: m/z (rel. abund.%), 346 [M]+ (19.9), 198 (5.9), 181 (2.1), 169 (2.1), 152 (3.4), 135 (100.0), 121 (25.0), 107 (18.5), 92 (15.9), 77 (45.7); HREI-MS: m/z calcd for C22H18O4 [M]+ 346.1205, found 346.1183.

2-(4-Benzoylphenoxy)-1-(4-chlorophenyl)ethanone (17)

Yield: 83%; m.p. 150–152°C; R: 0.45 (ethyl acetate/hexanes, 2:8); IR (KBr, cm−1): 3390 (=C–H), 1703 (C=O), 1637 (C=O), 1596 (C=C), 1315 (C–O), 1192 (=C–Cl); 1H-NMR (300 MHz, DMSO-d): δH 8.05 (d, 2H, J2,3/6,5 = 8.7 Hz, H-2, H-6), 7.73 (m, 7H, H-4, H-2′, H-3′, H-5′, H-6′, H-3′′, H-5′′), 7.56 (t, 2H, J3(2,4)/5(4,6) = 7.8 Hz, H-3, H-5), 7.14 (d, 2H, J2′,3′/6′,5′ = 8.4 Hz, H-2′, H-6′), 5.72 (s, 2H, CH2); 13C-NMR (75.0 MHz, DMSO-d6): δC 194.3 (C=O), 193.1 (C=O), 161.6 (C-4′), 138.7 (C-4′′), 137.6 (C-1), 132.9 (C-1′), 132.1 (C-1′′), 132.0 (C-4), 129.8 (C-2, C-6), 129.7 (C-3, C-5), 129.2 (C-2′, H-6′), 128.9 (C-2′′, C-6′′), 128.4 (C-3′′, C-5′′), 114.6 (C-3′, C-5′), 70.2 (CH2); EI-MS: m/z (rel. abund.%), 352 [M + 2]+ (11.7), 350 [M]+ (36.0), 211 (2.7), 198 (4.8), 181 (100.0), 151 (1.2), 105 (19.0), 77 (20.9); HREI-MS: m/z calcd for C21H15ClO3 [M]+ 350.0710, found 350.0691.

2-(4-Benzoylphenoxy)-1-(3,4-dichlorophenyl)ethanone (18)

Yield: 81%; m.p. 142–145°C; R: 0.45 (ethyl acetate/hexanes, 2:8); IR (KBr, cm−1): 3383 (=C–H), 1710 (C=O), 1628 (C=O), 1557 (C=C), 1309 (C–O); 1H-NMR (300 MHz, DMSO-d): δH 8.26 (d, 1H, J2′′,5′′ = 1.5 Hz, H-2′′), 7.98 (dd, 1H, J5′′,6′′ = 6.6 Hz, J5′′,2′′ = 1.8 Hz, H-5′′), 7.88 (d, 1H, J6′′,5′′ = 8.4 Hz, H-6′′), 7.73 (d, 2H, J2,3 = J6,5 = 8.7 Hz, H-2, H-6), 7.70 (t, 1H, J4(3,5) = 8.7 Hz, H-4), 7.64 (d, 2H, J(2′,3′)/(6′,5′) = 7.2 Hz, H-2′, H-6′), 7.56 (t, 2H, J3(2,4)/5(4,6) = 8.5 Hz, H-3, H-5), 7.16 (d, 2H, J3′,2′/5′,6′ = 7.3 Hz, H-3′, H-5′), 5.74 (s, 2H, CH2); 13C-NMR (75.0 MHz, DMSO-d6): δC 194.4 (C=O), 193.1 (C=O), 161.6 (C-4′), 137.7 (C-3‴), 136.0 (C-4‴), 133.8 (C-1′), 133.5 (C-1), 132.1 (C-2, C-6), 132.0 (C-2′, C-6′), 130.8 (C-1‴), 129.8 (C-2‴), 129.3 (H-5′′), 128.4 (C-6‴), 127.7 (C-3, C-5), 126.5 (C-3′, C-5′), 114.6 (C-4), 70.3 (CH2); EI-MS: m/z (rel. abund. %), 388 [M + 4]+ (10), 386 [M + 2]+ (49), 384 [M]+ (76.2), 349 (1.9), 211 (9.2), 198 (19.1), 173 (100.0), 121 (29.9), 105 (33.6), 77 (24.0); HREI-MS: m/z calcd for C21H14Cl2O3 [M]+ 384.0320, found 384.0321.

2-(4-Benzoylphenoxy)-1-phenylethanone (19)

Yield: 82%; m.p. 150–152°C; R: 0.47 (ethyl acetate/hexanes, 2:8); 1H-NMR (400 MHz, DMSO-d): δH 8.03 (d, 2H, J2,3/6,5 = 7.2 Hz, H-2, H-6), 7.73 (d, 2H, J2′,3′/6′,5′ = 9.2 Hz, H-2′, H-6′), 7.70 (m, 4H, H-4, H-2′′, H-4′′, H-6′′), 7.64 (d, 1H, J4(3,5) = 7.2 Hz, H-4), 7.59 (m, 4H, H-3, H-5, H-3′′, H-5′′), 7.13 (d, 2H, J3′,2′/5′,6′ = 8.8 Hz, H-3′, H-5′), 5.74 (s, 2H, CH2); EI-MS: m/z (rel. abund. %), 316 [M]+ (41.7), 239 (1.4), 211 (1.9), 198 (4.9), 121 (5.8), 105 (100.0), 77 (20.4); HREI-MS: m/z calcd for C21H16O3 [M]+ 316.1099, found 316.1098.

2-(4-Benzoylphenoxy)-1-p-tolylethanone (20)

Yield: 85%; m.p. 220–222°C; R: 0.49 (ethyl acetate/hexanes, 2:8); 1H-NMR (400 MHz, DMSO-d): δH 7.93 (d, 2H, J2,3/6,5 = 8.4 Hz, H-2, H-6), 7.73 (d, 2H, J2′,3′/6′,5′ = 8.8 Hz, H-2′, H-6′), 7.69 (d, 2H, J3′,2′/5′,6′ = 8.0 Hz, H-3′, H-5′), 7.64 (d, 1H, J4(3,5) = 7.2 Hz, H-4), 7.55 (t, 2H, J3(2,4)/5(4,6) = 7.6 Hz, H-3, H-5), 7.39 (d, 2H, J3′′,2′′/5′′,6′′ = 8.0 Hz, H-3′′, H-5′′), 7.11 (d, 2H, J2′′,3′′/6′′,5′′ = 8.8 Hz, H-2′′, H-6′′), 5.73 (s, 2H, CH2), 2.39 (s, 3H, CH3); EI-MS: m/z (rel. abund.%), 330 [M]+ (48.0), 253 (1.2), 198 (2.8), 181 (4.1), 152 (10.2), 119 (100.0), 105 (41.2), 91 (60.4), 77 (37.4); HREI-MS: m/z calcd for C22H18O3 [M]+ 330.1256, found 330.1255.