A Convenient Entry to 3-Methylidenechroman-2-ones and 2-Methylidenedihydrobenzochromen-3-ones

Abstract

A simple and versatile synthesis of 3-methylidenechroman-2-ones and 2-methylidenedihydrobenzochromen-3-ones has been developed. The reaction of phenols or naphthols with 3-methoxy-2-diethoxyphosphorylacrylate gave intermediate 3-diethoxyphosphorylchromen-2-ones or 2-diethoxyphosphorylbenzo-chromen-3-ones, respectively. These compounds were employed as Michael acceptors in the reaction with Grignard reagents to yield 4-substituted 3-diethoxyphosphorylchroman-2-ones or 1-substituted 2-diethoxyphosphoryldihydrobenzochromen-3-ones. The obtained adducts were next used as Horner-Wadsworth-Emmons reagents for the olefination of formaldehyde to give the final products.

Key words

Friedel-Crafts electrophilic aromatic substitution - Michael addition - Horner-Wadsworth-Emmons olefination - 3-methylidenechroman-2-ones - 2-methylidenedihydrobenzochromen-3-ones

References and Notes

• 1a Borges F. Roleira F. Milhazes N. Santana L. Uriarte E. Curr. Med. Chem.  2005,  12:  887 
• 1b Kostova I. Curr. Med. Chem.: Anti-Cancer Agents  2005,  5:  29 
• 1c Kulkarni MV. Kulkarni GM. Lin C.-H. Sun C.-M. Curr. Med. Chem.  2006,  13:  2795 
• 1d Semeniuchenko V. Groth U. Khilya V. Synthesis  2009,  3533 
• 1e Riveiro ME. De Kimpe N. Moglioni A. Vazquez R. Monczor F. Shayo C. Davio C. Curr. Med. Chem.  2010,  17:  1325 
• 2a Rajanarendar E. Ramu K. Ramesh P. Indian J. Chem., Sect. B: Org. Chem. Incl. Med. Chem.  2004,  43:  1790 
• 2b Reddy NS. Gumireddy K. Mallireddigari MR. Cosenza S. Venkatapuram P. Bell SC. Reddy EP. Ramana Reddy MVR. Bioorg. Med. Chem.  2005,  13:  3141 
• 3 Zaha AA. Hazem A. New Microbiol.  2002,  25:  213 
• 4 Finn GJ. Creaven B. Egan DA. Melanoma Res.  2001,  11:  461 
• 5 Budzisz E. Brzezinska E. Krajewska U. Różalski M. Eur. J. Med. Chem.  2003,  38:  597 
• 6 Reddy NS. Mallireddigari MR. Cosenza S. Gumireddy K. Bell SC. Reddy EP. Reddy MVR. Bioorg. Med. Chem. Lett.  2004,  14:  4093 
• 7 Donnelly DMX. Boland GM. Nat. Prod. Rep.  1995,  12:  321 
• 8a Petragnani N. Ferraz HMC. Silva GVJ. Synthesis  1986,  157 
• 8b Kitson RRA. Millemaggi A. Taylor RJK. Angew. Chem. Int. Ed.  2009,  48:  9426 
• 8c Albrecht Ł. Wojciechowski J. Albrecht A. Wolf WM. Janecka A. Studzian K. Krajewska U. Różalski M. Janecki T. Krawczyk H. Eur. J. Med. Chem.  2010,  45:  710 
• 9 Harmon AD. Hutchinson CR. J. Org. Chem.  1975,  40:  3474 
• 10 Groutas WC. Felker D. Magnin D. Synth. Commun.  1980,  10:  355 
• 11a Sunitha K. Balasubramanian KK. Rajagopalan K. Tetrahedron Lett.  1984,  25:  3125 
• 11b Sunitha K. Balasubramanian KK. Rajagopalan K. J. Org. Chem.  1985,  50:  1530 
• 11c Krishnamoorthy TV. Rajagopalan K. Balasubramanian KK. Tetrahedron Lett.  1985,  26:  1747 
• 11d Sunitha K. Balasubramanian KK. Rajagopalan K. Tetrahedron Lett.  1985,  26:  4393 
• 11e Drewes SE. Emslie ND. Karodia N. Loizou G. Synth. Commun.  1990,  20:  1437 
• 11f Foucaud A. Brine N. Synth. Commun.  1994,  24:  2851 
• 11g Liu Y. Qian J. Lou S. Xu Z. Synlett  2009,  2971 
• 12 Bestmann HJ. Lehnen H. Tetrahedron Lett.  1991,  32:  4279 
• 13a Falsone G. Cateni F. De Nardo MM. Darai MM. Z. Naturforsch., B  1993,  48:  1391 
• 13b Krawczyk H. Albrecht Ł. Wojciechowski J. Wolf WM. Tetrahedron  2007,  63:  12583 
• 14 Janecki T. Wąsek T. Tetrahedron  2004,  60:  1049 
• 15 Janecki T. Albrecht A. Koszuk JF. Modranka J. Sowak D. Tetrahedron Lett.  2010,  51:  2274 

16

General Procedure for the Synthesis of 3-Diethoxy-phosphorylchromen-2-ones 6a-c and 2-Diethoxy-phosphoryldihydrobenzochromen-3-ones 8a,b: To a solution of the corresponding phenol 5a-c (11 mmol) or naphthol 7a,b (11 mmol) in CH₂Cl₂ (50 mL), trifluoro-methanesulfonic acid (3.00 g, 20 mmol) or methanesulfonic acid (1.92 g, 20 mmol) and acrylate 4 (2.66 g, 10 mmol) were added and the resulting mixture was stirred at r.t. for the period of time given in Table  [¹] . Next, sat. aq NaHCO₃ solution was added (100 mL). Extraction with CH₂Cl₂ (3 × 30 mL), drying (MgSO₄) and evaporation of the solvent gave the crude product, which was purified by crystallization from Et₂O.
Diethyl (7-Methoxy-2-oxo-2 H -chromen-3-yl)-phosphonate (6a): orange solid; mp 64-65 ˚C. IR (film): 1726, 1601, 1228, 1134, 1016 cm^-¹. ^¹H NMR (250 MHz, CDCl₃): δ = 1.35 [t, ^³ J _HP = 7.1 Hz, 6 H, (CH ₃CH₂O)₂P(O)], 3.88 (s, 3 H, MeO), 4.14-4.31 [m, 4 H, (CH₃CH ₂O)₂P(O)], 6.69 (d, ⁴ J _HH = 2.4 Hz, 1 H, CH-Ar), 6.87 (dd, ^³ J _HH = 8.7 Hz, ⁴ J _HH = 2.4 Hz, 1 H, CH-Ar), 7.46 (d, ^³ J _HH = 8.7 Hz, 1 H, CH-Ar), 8.43 (d, ^³ J _HP = 17.4 Hz, 1 H, H-4). ^¹³C NMR (62.9 MHz, CDCl₃): δ = 16.18 [d, ^³ J _PC = 6.4 Hz, (CH₃CH₂O)₂P(O)], 55.81 (s, MeO), 62.97 [d, ^² J _PC = 5.8 Hz, (CH₃ CH₂O)₂P(O)], 100.38 (s, C-Ar), 111.49 (d, ^³ J _PC = 14.3 Hz, C-Ar), 112.84 (d, ^¹ J _PC = 198.9 Hz, C-3), 113.16 (s, C-Ar), 130.33 (s, C-Ar), 153.19 (d, ^² J _PC = 7.0 Hz, C-4), 157.31 (s, C-Ar), 158.37 (d, ^² J _PC = 15.0 Hz, C-2), 164.72 (s, C-Ar). ^³¹P NMR (101 MHz, CDCl₃): δ = 12.47. Anal. Calcd for C₁₄H₁₇O₆P: C, 53.85; H, 5.49. Found: C, 53.64; H, 5.52.
Diethyl (3-Oxo-3 H -benzo[ f ]chromen-2-yl) phosphonate (8a): orange solid; mp 136-137 ˚C. IR (film): 1732, 1604, 1256, 1136, 1024 cm^-¹. ^¹H NMR (250 MHz, CDCl₃): δ = 1.38-1.44 [m, 6 H, (CH ₃CH₂O)₂P(O)], 4.15-4.39 [m, 4 H, (CH₃CH ₂O)₂P(O)], 7.48 (d, ^³ J _HH = 9.0 Hz, 1 H, CH-Ar), 7.61 (t, ^³ J _HH = 9.0 Hz, 1 H, CH-Ar), 7.75 (t, ^³ J _HH = 9.0 Hz, 1 H, CH-Ar), 7.93 (d, ^³ J _HH = 7.2 Hz, 1 H, CH-Ar), 8.10 (d, ^³ J _HH = 7.2 Hz, 1 H, CH-Ar), 8.37 (d, ^³ J _HH = 9.0 Hz, 1 H, CH-Ar), 9.30 (d, ^³ J _HP = 17.6 Hz, 1 H, H-1). ^¹³C NMR (62.9 MHz, CDCl₃): δ = 16.27 [d, ^³ J _PC = 6.3 Hz, (CH₃CH₂O)₂P(O)], 63.30 [d, ^² J _PC = 5.9 Hz, (CH₃ CH₂O)₂P(O)], 112.20 (s, C-Ar), 115.70 (d, ^¹ J _PC = 197.0 Hz, C-2), 116.52 (s, C-Ar), 121.45 (s, C-Ar), 126.43 (s, C-Ar), 128.97 (s, C-Ar), 129.12 (s, 2 × C-Ar), 130.08 (s, C-Ar), 135.82 (s, C-Ar), 148.99 (d, ^² J _PC = 7.4 Hz, C-1), 155.79 (s, C-Ar), 158.23 (d, ^² J _PC = 14.5 Hz, C-3). ^³¹P NMR (101 MHz, CDCl₃): δ = 12.38. Anal. Calcd for C₁₇H₁₇O₅P: C, 61.45; H, 5.16. Found: C, 61.67; H, 4.89.

17

General Procedure for the Synthesis of 3-Diethoxy-phosphorylchroman-2-ones 12a-l and 3-Diethoxy-phosphoryldihydrobenzochromen-2-ones 14a-h: To a solution of the corresponding chromenones 6a-c (1 mmol) or benzochromenones 8a,b (1 mmol) and a catalytic amount of CuI (19 mg, 0.1 mmol) in THF (10 mL) a solution of Grignard reagent 11a-d (5 mmol) was added dropwise, under an argon atmosphere at r.t. (Me, n-Bu and i-Pr magnesium iodides were prepared from the corresponding alkyl halides and magnesium in Et₂O; vinylmagnesium bromide was purchased from ALDRICH^®). The solution was stirred for 48 h. After this time the reaction mixture was quenched with H₂O (2 mL), acidified to pH ca. 1.5 with 10% aq HCl solution and extracted with CHCl₃ (4 × 10 mL). The organic extracts were washed with brine (10 mL) and dried over MgSO₄. Evaporation of the solvent gave the crude product which was purified by column chromatography (eluent: EtOAc-hexane, 3:1).
Diethyl trans -(7-Methoxy-4-methyl-2-oxochroman-3-yl)phosphonate (12a): colorless oil. IR (film): 1762, 1625, 1257, 1229, 1147, 1015 cm^-¹. ^¹H NMR (250 MHz, CDCl₃): δ = 0.94 [t, ^³ J _HH = 7.1 Hz, 3 H, CH ₃CH₂OP(O)], 1.29 (dd, ^³ J _HH = 7.2 Hz, ^³ J _HH = 1.8 Hz, 3 H, Me), 1.31 [t, ^³ J _HH = 7.1 Hz, 3 H, CH ₃CH₂OP(O)], 3.28 (dd, ^² J _HP = 25.0 Hz, ^³ J _HH = 1.1 Hz, 1 H, CH-3), 3.42-3.58 [m, 2 H, CH₃CH ₂OP(O)], 3.71-3.85 (m, 4 H, MeO, CH-4), 4.05-4.17 [m, 2 H, CH₃CH ₂OP(O)], 6.59 (d, ⁴ J _HH = 2.5 Hz, 1 H, CH-Ar), 6.70 (dd, ^³ J _HH = 8.4 Hz, ⁴ J _HH = 2.5 Hz, 1 H, CH-Ar), 7.12 (d, ^³ J _HH = 8.4 Hz, 1 H, CH-Ar). ^¹³C NMR (62.9 MHz, CDCl₃): δ = 15.74 [d, ^³ J _PC = 6.1 Hz, CH₃CH₂OP(O)], 15.96 [d, ^³ J _PC = 6.3 Hz, CH₃CH₂OP(O)], 23.64 (d, ^³ J _PC = 18.6 Hz, Me), 31.56 (d, ^² J _PC = 4.3 Hz, C-4), 47.19 (d, ^¹ J _PC = 127.7 Hz, C-3), 55.32 (s, MeO), 61.75 [d, ^² J _PC = 7.0 Hz, CH₃ CH₂OP(O)], 62.92 [d, ^² J _PC = 6.8 Hz, CH₃ CH₂OP(O)], 91.80 (s, C-Ar), 102.05 (s,
C-Ar), 110.64 (s, C-Ar), 117.26 (s, C-Ar), 128.10 (s, C-Ar), 151.37 (s, C-Ar), 159.65 (s, C-Ar), 163.50 (d, ^² J _PC = 6.0 Hz, C-2). ^³¹P NMR (101 MHz, CDCl₃): δ = 19.20. Anal. Calcd for C₁₅H₂₁O₆P: C, 54.88; H, 6.45. Found: C, 54.97; H, 6.61.

Diethyl trans -(1-Methyl-3-oxo-2,3-dihydro-1 H -benzo[ f ]chromen-2-yl)phosphonate (14a): yellow oil. IR (film): 1764, 1440, 1392, 1260, 1232, 1224, 1160, 1024 cm^-¹. ^¹H NMR (250 MHz, CDCl₃): δ = 0.73 [t, ^³ J _HH = 7.1 Hz, 3 H, CH ₃CH₂OP(O)], 1.27 [t, ^³ J _HH = 7.1 Hz, 3 H, CH ₃CH₂OP(O)], 1.44 (dd, ^³ J _HH = 7.2 Hz, ^³ J _HH = 1.8 Hz, 3 H, Me), 3.28-3.38 (m, 1 H, CH-1), 3.47 (dd, ^² J _HP = 25.3 Hz, ^³ J _HH = 1.2 Hz, 1 H, CH-2), 3.59-3.69 [m, 1 H, CH₃CH ₂OP(O)], 4.04-4.16 [m, 2 H, CH₃CH ₂OP(O)], 4.24-4.39 [m, 1 H, CH₃CH ₂OP(O)], 7.21-7.26 (m, 1 H, CH-Ar), 7.44-7.50 (m, 1 H, CH-Ar), 7.56-7.63 (m, 1 H, CH-Ar), 7.76-7.87 (m, 2 H, 2 × CH-Ar), 7.96-8.00 (m, 1 H, CH-Ar). ^¹³C NMR (62.9 MHz, CDCl₃): δ = 15.64 [d, ^³ J _PC = 6.1 Hz, CH₃CH₂OP(O)], 16.07 [d, ^³ J _PC = 6.2 Hz, CH₃CH₂OP(O)], 21.72 (d, ^³ J _PC = 18.4 Hz, Me), 28.48 (d, ^² J _PC = 4.2 Hz, C-1), 47.01 (d, ^¹ J _PC = 127.6 Hz,
C-2), 62.84 [d, ^² J _PC = 6.9 Hz, CH₃ CH₂OP(O)], 63.15 [d, ^² J _PC = 6.7 Hz, CH₃ CH₂OP(O)], 116.95 (s, C-Ar), 118.49 (s,
C-Ar), 122.35 (s, C-Ar), 125.16 (s, C-Ar), 127.48 (s, C-Ar), 128.71 (s, C-Ar), 129.13 (s, C-Ar), 130.25 (s, C-Ar), 131.04 (s, C-Ar), 148.29 (s, C-Ar), 163.74 (d, ^² J _PC = 5.8 Hz, C-3). ^³¹P NMR (101 MHz, CDCl₃): δ = 18.72. Anal. Calcd for C₁₈H₂₁O₅P: C, 62.07; H, 6.08. Found: C, 62.37; H, 6.23.

18

General Procedure for the Synthesis of 3-Methylidene-chroman-2-ones 13a-l and 2-Methylidenedihydro-benzochromen-3-ones 15a-h: To a solution of the corresponding chromanones 12a-l (0.5 mmol) or benzochromenones 14a-h (0.5 mmol) in THF (5 mL), t-BuOK (67 mg, 0.6 mmol) or NaH (14 mg, 0.6 mmol) was added and the resulting mixture was stirred at r.t. for 30 min. Then paraformaldehyde (75 mg, 2.5 mmol) was added in one portion. After 1.5 h, the reaction mixture was quenched with brine (5 mL), THF was removed under reduced pressure and the aqueous layer was extracted with CH₂Cl₂ (3 × 10 mL). The organic layer was dried over MgSO₄ and the solvent was evaporated. The crude product was purified by column chromatography (eluent: CH₂Cl₂).
7-Methoxy-4-methyl-3-methylidenechroman-2-one (13a): colorless oil. IR (film): 1755, 1441, 1258, 1192, 1014 cm^-¹. ^¹H NMR (250 MHz, CDCl₃): δ = 1.39 (d, ^³ J _HH = 7.1 Hz, 3 H, CH ₃CH), 3.78 (s, 3 H, MeO), 3.74 (q, ^³ J _HH = 7.1 Hz, 1 H, CH-4), 5.73 (dd, ⁴ J _HH = 0.9 Hz, ^² J _HH = 1.3 Hz, 1 H, CH₂=C), 6.33 (dd, ⁴ J _HH = 0.9 Hz, ^² J _HH = 0.9 Hz, 1 H, CH ₂=C), 6.61 (d, ⁴ J _HH = 2.5 Hz, 1 H, CH-Ar), 6.69 (dd, ^³ J _HH = 8.4 Hz, ⁴ J _HH = 2.5 Hz, 1 H, CH-Ar), 7.08 (d, ^³ J _HH = 8.4 Hz, 1 H, CH-Ar). ^¹³C NMR (62.9 MHz, CDCl₃): δ = 22.81 (s, Me), 36.59 (s, C-4), 55.50 (s, MeO), 102.54 (s,
C-Ar), 110.94 (s, C-Ar), 118.85 (s, C-5), 126.99 (s, CH₂=C), 127.33 (s, C-Ar), 138.20 (s, CH₂=C), 150.76 (s, C-6), 159.64 (s, C-Ar), 163.49 (s, C-2). Anal. Calcd for C₁₂H₁₂O₃: C, 70.57; H, 5.92. Found: 70.30; H, 5.81.
1-Methyl-2-methylidene-1,2-dihydrobenzo[ f ]chromen-3-one (15a): pale-yellow oil. IR (film): 1756, 1440, 1224, 1160, 1024 cm^-¹. ^¹H NMR (250 MHz, CDCl₃): δ = 1.51 (d, ^³ J _HH = 7.2 Hz, 3 H, CH ₃CH), 4.47 (q, ^³ J _HH = 7.2 Hz, 1 H, CH-1), 5.88 (s, 1 H, CH₂=C), 6.44 (s, 1 H, CH₂=C), 7.25-7.28 (m, 1 H, CH-Ar), 7.46-7.52 (m, 1 H, CH-Ar), 7.58-7.65 (m, 1 H, CH-Ar), 7.76-7.97 (m, 3 H, 3 × CH-Ar). ^¹³C NMR (69.2 MHz, CDCl₃): δ = 21.76 (s, Me), 33.11 (s, C-1), 115.83 (s, C-Ar), 118.23 (s, C-Ar), 120.44 (s, C-Ar), 123.38 (s,
C-Ar), 125.53 (s, CH₂=C), 126.37 (s, C-Ar), 127.22 (s,
C-Ar), 127.29 (s, C-Ar), 128.37 (s, C-Ar), 129.38 (s, C-Ar), 136.18 (s, CH₂=C), 145.60 (s, C-Ar), 161.48 (s, C-3). Anal. Calcd for C₁₅H₁₂O₂: C, 80.34; H, 5.39. Found: 80.01; H, 5.23.