Solvent-free synthesis of stable oxaphosphaphenanthrene derivatives using multicomponent reaction of naphthols

Multi-component reactions (MCRs), due to their productivity, simple procedures, convergence, and facile execution, are one of the best tools in combinatorial chemistry [1]. Therefore, the design of novel MCRs has attracted great attention from research groups working in areas such as drug discovery, organic synthesis and materials science. As a result, the number of new MCRs has grown rapidly [2]. Green chemistry approaches hold out significant potential not only for reduction of byproducts, a reduction in the waste produced, and lowering of energy costs but also in the development of new methodologies toward previously unobtainable materials, using existing technologies [3-5]. Organophosphorus compounds, i.e. those bearing a carbon atom directly bound to a phosphorus atom, are synthetic targets of interest, not least because of their value for a variety of industrial, biological, and chemical synthetic uses [6-8]. As a result, a large number of methods have appeared describing novel syntheses of organophosphorus compounds. There are many studies on the reaction between trivalent phosphorus nucleophiles and α,β-unsaturated carbonyl compounds in the presence of a proton source such as alcohol or phenol [9-11]. We describe herein the reaction of dimethyl acetylenedicarboxylate with triphenyl, triethyl and trimethylphosphit as the P-nucleophile in the presence of OH-acid such as 1-naphthol or 2-naphthol under solvent-free conditions at 70 ^oC in excellent yield (Scheme 1).

 

Scheme 1 Click here to View Scheme

 

Melting points were measured on an Electrothermal 9100 aparatus. Elemental analyses for the C, H, and N were performed using a Heraeus CHN-O-Rapid analyzer. Mass spectra were recorded on a FINNIGAN-MATT 8430 spectrometer operating at an ionization potential of 70 eV. IR spectra were measured on a Shimadzu IR-460 spectrometer. ¹H , ¹³C, and ³¹P NMR spectra were measured with a BRUKER DRX-500 AVANCE spectrometer at 500.1, 125.8, and 202.4 MHz, respectively. ¹H, ¹³C, and 31P spectra were obtained for solutions in CDCl₃ using TMS as internal standard or 85% H₃PO₄ as external standard. All the chemicals used in this work were purchased from Fluka (Buchs, Switzerland) and are used without further purification. 

General procedure for preparation of compounds 4a-b and 9, 17.

Dimethyl2,2-diphenoxy-4H-1-oxa-2l⁵-phosphaphenanthrene-3,4-dicarboxylate (4a).

To a magnetically stirred of 0.28 g dimethyl  acethylenedicarboxylate 2 (2 mmol) and 0.29 g 2-naphthol 3 (2 mmol) was added 0.62 g triphenyl phosphite 1a (2 mmol) at 70^oC. The reaction mixture was then stirred for 2 h. The reaction mixture was crystallized from diethyl ether. The product 4a was obtained as colorless crystals, m.p. 178-180 °C, 0.90 g, yield 90%. IR (KBr) (νmax/cm^-1): 1667, and 1722 (2 C=O). Anal. Calcd for C₂₈H₂₃O₇P (502.4): C, 66.93; H, 4.61. Found: C, 66.9; H, 4.7%. ¹H NMR (500 MHz, CDCl₃): δ 3.21 and 3.72 (6 H, 2 s, 2 Me), 5.55 (1 H, d ³JHP 33 Hz, CH), 6.98-9.20 (16 H, m, 16 CH). ¹³C NMR (125.7 MHz, CDCl₃): δ 41.10 (d, ¹JCP 225 Hz, C), 41.37 (d, ²JCP 9 Hz, CH), 50.32 and 52.06 (2 OMe), 118.22 (d, ³JPC 6 Hz, CH of C₁₀H₆), 120.54 (d, ³JCP 4 Hz, 2 CHortho of Ph), 120.83 (d, ³JPC 9 Hz, C of C₁₀H₆), 121.50 (d, ³JPC 4 Hz, 2 CHortho of Ph), 124.10, and 125.56 (2 CH of C₁₀H₆), 125.92 and 126.14 (2 CHpara of Ph), 127.49 and 128.43 (2 CH of C₁₀H₆), 129.71 (m, 4 CHmeta of Ph groups), 129.79 (CH of C₁₀H₆), 131.13 and 131.33 (2 C of C₁₀H₆), 148.13 (d 2JPC 8 Hz, C-O of C₁₀H₆), 149.96 (m, 2 Cipso of Ph groups), 168.40 (d 2JPC 17.3 Hz, C=O), 173.32 (C=O). ³¹P NMR (202 MHz, CDCl₃): δ 41.54.

Dimethyl 2,2-dimethoxy-4H-1-oxa-2l⁵-phospha-phenanthrene-3,4-dicarboxylate (4b).

The procedure for preparation of 4b was similar to that for 4a. Colorless crystals, m.p. 128-130 °C, 0.64 g, yield 85%. IR (KBr) (νmax/cm-1): 1652, and 1722 (2 C=O). Anal. Calcd for C₁₈H₁₉O₇P (378.3): C, 57.15; H, 5.06. Found: C, 57.2; H, 5.1%. ¹H NMR (500 MHz, CDCl₃): δ 3.61 and 3.70 (6 H, 2 s, 2 Me), 3.65 (3 H, d ³JPH 13 Hz, OMe), 4.07 (3 H, d ³JPH 13 Hz, OMe), 5.65 (1 H, d ³JHP 31 Hz, CH), 7.26 (d, 3JHH 9 Hz, CH), 7.45 (1 H, t, ³JHH 9 Hz, CH), 7.59 (1 H, t, ³JHH 9 Hz), 7.73 (1 H, d ³JHH 9 Hz, CH), 7.79 (1 H, d 3JHH 9 Hz, CH), 8.39 (1 H, d ³JHH 9 Hz, CH). ¹³C NMR (125.7 MHz, CDCl₃): δ 39.20 (d, 1JCP 222 Hz, C), 41.37 (d, ²JCP 9 Hz, CH), 50.37 and 52.21 (2 OMe), 55.33 (d, ²JPC 6 Hz, P-OMe), 55.65 (d, ²JPC 5 Hz, P-OMe), 118.35 (d, ³JPC 6 Hz, CH), 121.29 (d, ³JPC 9.1 Hz, C), 124.40, 125.43, 127.38, 128.40 and 129.79 (5 CH), 131.13 and 131.31 (2 C), 148.58 (d ²JPC 8 Hz, C-O), 169.20 (d ²JPC 18 Hz, C=O), 174.92 (C=O). ³¹P NMR (202 MHz, CDCl₃): δ 42.53.

Methyl 3-oxo-2,3-dihydro-1H-benzo[f]chromene-1-carboxylate (9).

To a magnetically stirred of 0.28 g dimethyl acethylenedicarboxylate 2 (2 mmol) and 0.29 g 2-naphthol 3 (2 mmol) was added 0.33 g triethyl phosphite 1c (2 mmol) at 70 ^oC. The reaction mixture was then stirred for 5 h. The reaction mixture was crystallized from diethyl ether. (0.49 g, yield 96%). m.p. 151-152 °C, IR (KBr) (νmax/cm-1): 1711, and 1752 (2 C=O). Anal. Calcd for C₁₅H₁₂O₄ (256.3): C, 70.31; H, 4.72. Found: C, 70.1; H, 4.7%. ¹H NMR (500 MHz, CDCl₃): δ 2.82 (1 H, dd ²JHH 16 Hz ³JHH 6 Hz, HCH), 3.25 (1 H, d ²JHH 16 Hz, HCH), 3.65 (3 H, s, OMe), 4.60 (1 H, d ³JHH 6 Hz, CH), 7.26 (d, ³JHH 9 Hz, CH), 7.49 (1 H, t, ³JHH 8 Hz, CH), 7.59 (1 H, t, ³JHH 8 Hz), 7.73 (1 H, d ³JHH 8 Hz, CH), 7.79 (1 H, d ³JHH 8 Hz, CH), 8.32 (1 H, ³JHH 9 Hz, CH). ¹³C NMR (125.7 MHz, CDCl₃): δ 31.37 (CH₂), 37.87 (CH), 52.84 (OMe), 112.73 (C), 117.70, 123.27, 125.42, 127.75, 128.76, and 130.65 (6 CH), 130.90, 131.00, and 149.96 (3 C), 166.16 and 171.22 (2 C=O). MS, m/z (%): 256 (M+^., 15), 196 (100), 168 (41).

Dimethyl2-(dimethoxy-phosphoryl)-3-(1-hydroxy-naphthalene-2-yl)-succinate (17).

To a magnetically stirred of 0.28 g dimethyl acethylenedicarboxylate 2 (2 mmol) and 0.29 g 1-naphthol 16 (2 mmol) was added 0.25 g trimethyl phosphite 1b (2 mmol) at 70 ^oC. The reaction mixture was then stirred for 4 h. The reaction mixture was crystallized from diethyl ether. The product 17 was obtained as colorless crystals, m.p. 173-185 °C, 0.76 g, yield 96%. IR (KBr) (νmax/cm-1): 3230 (OH), 1724 (C=O). Anal. Calcd for C₁₈H₂₁O₈P (396.3): C, 54.55; H, 5.34. Found: C, 54.4; H, 5.3%. ¹H NMR (500 MHz, CDCl₃): δ 2.85 (3 H, d ³JHP 11 Hz, OMe), 3.60 (3 H, s, OMe), 3.67 (3 H, d ³JHP 11 Hz, OMe), 3.82 (3 H, s, OMe), 3.88 (1 H, dd ²JHP 21 Hz ³JHH 12 Hz, CH), 4.99 (1 H, dd ³JHH 12 Hz ³JHP 9 Hz, CH), 7.10-8.42 (6 H, m, 6 CH), 8.47 (1 H, s, OH). ¹³C NMR (125.7 MHz, CDCl₃): δ 44.04 (CH), 48.51 (d ¹JPC 135 Hz, CH), 52.79 (OMe), 52.86 (d 2JPC 7 Hz, OMe), 53.05 (OMe), 53.97 (d ²JPC 7 Hz, OMe), 116.92 (C), 121.78 and 123.42 (2 CH), 124.60 (C), 125.74, 126.82 and 127.20 (3 CH), 127.67 (C), 134.20 (CH), 150.50 (C), 168.24 (d ²JPC 5 Hz, C=O), 173.01 (d ³JPC 22 Hz, C=O). ³¹P NMR (202 MHz, CDCl₃): δ 18.56. MS, m/z (%): 396 (M+^., 42), 305 (82), 273 (100), 168 (87),139(72).

Result and discussion 

The reaction of dimethyl acetylene dicarboxylate 2 and 2-naphthol 3 in the presence of trimethyl or triphenyl phosphite 1 leads to oxaphosphaphenanthrene-3,4-dicarboxylate derivatives 4 in good yields (Scheme 2). The structures of 4 were determined on the basis of their ¹H, ¹³C, and ³¹P NMR spectra, IR spectra, elemental analyses, and mass spectrometric data. The ¹H NMR spectrum of 4a in CDCl₃ shows two singlets at δ = 3.21 and 3.72 ppm for the methoxy protons and one doublet at δ = 5.48 (³JPH = 34 Hz) for the methine proton, along with multiplets at δ = 6.98-9.20 for the aromatic protons. Characteristic carbonyl resonances appear clearly at δ = 168.40 (d, ²JPC = 17 Hz), 173.32 ppm, whereas the ylide carbon atom exhibits resonances at δ = 41.10 (d, ¹JPC = 225 Hz) ppm. The observed ¹JCP values are typical of an α-ylide ester [12]. The double bond character of the C-P bond and the presence of three electronegative oxo substituent on the phosphorus atom increases the ¹JCP value.11 Evidence for the presence of an oxaphosphaphenantrene skeleton in 4a was shown by the ¹³C signals at δ = 118.22 (d, ³JCP = 6 Hz) for CH of naphthalene moiety and at δ = 148.13 (d, ²JCP = 8 Hz) for the C-O carbon of naphthalene. ³¹P NMR signals was found at δ = 41.54 ppm. The ¹H and ¹³C NMR spectra of 4b were similar to those for 4a except for the phosphoranyl moiety. Although we have not yet established the mechanism of the reaction between dimethylacetylene dicarboxylate and phosphites in the presence of 2-naphthol in an experimental manner, a possible explanation is proposed in (Scheme 2). On the basis of the well established chemistry of phosphorus nucleophiles2,3 it is reasonable to assume that ylide 4 results from initial addition of the phosphite to DMAD and subsequent protonation of the reactive 1:1 adduct, followed by attack of carbon atom of the anion of 2-naphthol 6 to cation 5 to generate ylide 7 which isomerises under the reaction conditions employed to produce the oxaphosphorane 8. Elimination of ROH from 8 leads to product 4. The reaction between triethyl phosphite 1, dimethylacetylene dicarboxylate 2, and 2-naphthol 3 quantitatively gave product 9 (Scheme3).

 

Scheme 2 Click here to View Scheme

 

Scheme 3  Click here to View Scheme

 

The IR spectrum of 9 exhibited the ester and lactone carbonyl groups at 1711 and 1752 cm^-1, respectively. The ¹H NMR spectrum of 9 showed a double doublet at δ = 2.82 (²JHH = 16 Hz, ³JHH = 6 Hz) for one of the methylene protons. The other methylene proton displayed a doublet (²JHH = 16 Hz) at δ = 3.25 ppm. The methine proton showed a doublet (³JHH = 6 Hz) at δ = 4.60 ppm. The coupling constants observed for this AMX system are consistent with a conformation in which theH-C-C-H dihedral angles for the CH-CH₂ moiety are expected to be about 90º and 30º [12]. The ¹³C NMR spectrum of 9 displayed 15 distinct resonance in agreement with the proposed structure. A possible mechanism for the formation of compound 9 is shown in Scheme 4. The oxaphosphorane 12 is formed in similar steps shown for oxaphosphorane 8 in Scheme 2. However, since the ethoxide anion is a weaker living group, cleavage of the phosphorus-oxygen bond of the naphthol residue become favorable, giving dimethyl succinate 15. Lactonization of this hydroxy-ester gave product 9.

 

Scheme 4  Click here to View Scheme

 

Under similar conditions, the reaction of dimethylacetylene dicarboxylate 2 and trimethyl phosphite 1 in the presence of 1-naphthol 16 gave succinate 17 in good yield (Scheme 5).

 

Scheme 5  Click here to View Scheme

 

The ¹H NMR spectrum of 17 displayed signals for vicinal methine protons at δ = 3.88 and 4.99, which appeared as two set of double doublets with ²JHP and ³JHP values of 21 and 9 Hz, respectively. The methoxy groups of the phosphoranyl moiety are diastereotopic and show two separate doublets at δ = 2.85 and 3.67. The hydroxy proton was observed as a broad singlet at δ = 8.47 which disappeared with addition of D₂O. Observation of ³JHH = 12 Hz for the vicinal methine protons in 17 indicates the dominance of anti arrangement. A proposed mechanism for the formation of compound 17 is shown in Scheme 4.

 

Scheme 6  Click here to View Scheme

 

In conclusion, we found that the reaction of dimethylacetylene dicarboxylate with trimethyl phosphite or triphenyl phosphite in the presence of 2-naphthol leads to functionalizedoxaphosphaphenanthrenes. The reaction of 1-naphthol with dimethylacetylene dicarboxylate and trimethyl phosphite produces, stereoselectively benzochromene derivative in high yield. The addition reaction of triethyl phosphite, dimethylacetylene dicarboxylate, and 1-naphthol or 2-naphthol leads quantitatively to benzochromene derivatives. The present method carries the advantage that, not only is the reaction performed under solvent-free conditions, but also the substances can be mixed without any activation or modification.

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