One-Pot, Three-Component Synthesis of 4-Aryl-5,6-dihydropyran via Prins-Friedel-Crafts Reaction

Abstract

An efficient method for the synthesis of 4-aryldihydropyrans has been developed from the reaction of aldehydes or epoxides with homopropargylic alcohols in the presence of arenes promoted by boron trifluoride etherate

Key words

Lewis acid - multicomponent - Prins cyclization - Friedel-Crafts reaction - dihydropyran

References and Notes

• 1a Tieze LF. Chem. Rev.  1996,  96:  115 
• 1b Yus DJ. Ramon M. Angew. Chem. Int. Ed.  2005,  44:  1602 
• 1c Dömling A. Ugi I. Angew. Chem. Int. Ed.  2000,  39:  3168 
• 1d Multicomponent Reaction   Zhu J. Bienaymé H. Wiley-VCH; Weinheim: 2005. 
• 2a Strubing D. Neumann H. Hubner S. Klaus S. Beller M. Tetrahedron  2005,  61:  11345 
• 2b Nair V. Sreekumar V. Bindu S. Suresh E. Org. Lett.  2005,  7:  2297 
• 3a Clarke PA. Santos S. Eur. J. Org. Chem.  2006,  2045 
• 3b Class YJ. DeShong P. Chem. Rev.  1995,  95:  1843 
• 3c Kopecky DJ. Rychnovsky SD. J. Am. Chem. Soc.  2001,  123:  8420 
• 3d Wang Y. Janjic J. Kozmin SA. J. Am. Chem. Soc.  2002,  124:  13670 
• 3e Aubele DL. Wan S. Floreancig PE. Angew. Chem. Int. Ed.  2005,  44:  3485 
• 3f Bahnck KB. Rychnovsky SD. Chem. Commun.  2006,  2388 
• 3g Tian XT. Jaber JJ. Rychnovsky SD. J. Org. Chem.  2006,  7:  3176 
• 4a Yet L. Chem. Rev.  2000,  100:  2963 
• 4b Boivin TLB. Tetrahedron  1987,  43:  3309 
• 4c Coppi L. Ricci A. Taddei M. J. Org. Chem.  1988,  53:  911 
• 4d Li C.-J. Zhang W.-C. Tetrahedron  2000,  56:  2403 
• 4e Schmidt B. Westhus M. Tetrahedron  2000,  56:  2421 
• 5 Vinals JF, Kiwala J, Hruza DE, Hall JB, and Vock MHA. inventors; US  4070491. 
• 6a Markó IE. Bayston DJ. Tetrahedron  1994,  50:  7141 
• 6b Su Q. Panek JS. J. Am. Chem. Soc.  2004,  126:  2425 
• 6c Miranda PO. Carballo RM. Martín VS. Padrón JI. Org. Lett.  2009,  11:  357 
• 6d Lian Y. Hinkle RJ. J. Org. Chem.  2006,  71:  7071 
• 6e Dobbs AP. Martinović S. Tetrahedron Lett.  2002,  43:  7055 
• 6f Viswanathan GS. Yang J. Li C.-J. Org. Lett.  1999,  1:  993 
• 6g Miranda PO. Díaz DD. Padrón JI. Bermejo J. Martín VS. Org. Lett.  2003,  5:  1979 
• 6h Miranda PO. Ramírez MA. Martín VS. Padrón JI. Org. Lett.  2006,  8:  1633 
• 6i Liu F. Loh T.-P. Org. Lett.  2007,  9:  2063 
• 6j Dobbs AP. Parker RJ. Skidmore J. Tetrahedron Lett.  2008,  49:  827 
• 6k Hu X.-H. Liu F. Loh T.-P. Org. Lett.  2009,  11:  1741 
• 7a Yadav VK. Kumar NV. J. Am. Chem. Soc.  2004,  126:  8652 
• 7b Romanov NA. Kantor EA. Brudnik IM. Musavirov RS. Kiladze TK. Rakhmankulov DL. Zh. Prikl. Khim.  1982,  55:  2778 
• 7c Romanov NA. Kantor EA. Karakhanov RA. Rakhmankulov DL. Zh. Org. Khim.  1982,  18:  403 
• 7d Romanov NA. Kantor EA. Musavirov RS. Karakhanov RA. Rakhmankulov DL. Zh. Prikl. Khim.  1982,  55:  157 
• 7e Balaban T.-S. Balaban AT. Tetrahedron Lett.  1987,  28:  1341 
• 8a Reddy UC. Bondalapati S. Saikia AK. Eur. J. Org. Chem.  2009,  1625 
• 8b Reddy UC. Bondalapati S. Saikia AK. J. Org. Chem.  2009,  74:  2605 
• 10 Podder S. Choudhury J. Roy UK. Roy S. J. Org. Chem.  2007,  72:  3100 
• 12a Ranu BC. Jana U. J. Org. Chem.  1998,  63:  8212 
• 12b Li J. Li C.-J. Tetrahedron Lett.  2001,  42:  793 

9

Synthesis of 2,4-Diphenyl-5,6-dihydro-2 H -pyran (1b)
To a mixture of benzaldehyde (0.10 mL, 1.0 mmol) and homopropagyl alcohol (140 mg, 2.0 mmol) in dry benzene (2.0 mL) was added freshly distilled BF₃˙OEt₂ (0.15 mL, 1.2 mmol) under nitrogen atmosphere. The reaction mixture was stirred at 40 ˚C for 8 h. The progress of the reaction was monitored by TLC with EtOAc and hexane as eluents. After completion of the reaction, the reaction mixture was treated with aq NaHCO₃, the mixture was extracted with Et₂O, and the combined organic extracts washed with brine and water. The organic layer was dried (Na₂SO₄) and evaporated to leave the crude product, which was purified by short column chromatography over silica gel to give 2,4-diphenyl-5,6-dihydro-2H-pyran 1b (106 mg, 45% yield) as a liquid. ^¹H NMR (400 MHz, CDCl₃): δ = 2.45-2.52 (m, 1 H), 2.70-2.80 (m, 1 H), 3.92 (ddd, J = 11.6, 8.8, 4.0 Hz, 1 H), 4.18 (ddd, J = 11.6, 5.2, 3.6 Hz, 1 H), 5.30 (d, J = 2.4 Hz, 1 H), 6.22 (d, J = 1.2 Hz, 1 H), 7.23-7.45 (m, 10 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 27.3, 63.6, 72.4, 124.3, 124.4, 125.1, 127.9, 128.6 (2 C), 129.6, 133.4, 135.5, 136.9, 139.9, 148.5. IR: 3029, 2923, 2854, 1600, 1493, 1453, 1273, 1119, 1075, 1029, 886, 749, 698 cm^-¹. HRMS (APCI): m/z calcd for C₁₇H₁₆O [M + H]⁺: 237.1279; found: 237.1258.
6-Isopropyl-4-phenyl-5,6-dihydro-2 H -pyran (22)
To a mixture of 1,2-epoxy-2-methylpropane (0.09 mL, 1.0 mmol) and homopropagyl alcohol (140 mg, 2.0 mmol) in dry benzene (3.0 mL) was added freshly distilled BF₃˙OEt₂ (0.15 mL, 1.2 mmol) under nitrogen atmosphere. The reaction mixture was stirred at r.t. for 5 h. The progress of the reaction was monitored by TLC with EtOAc and hexane as eluents. After completion of reaction, the reaction mixture was treated with aq NaHCO₃, and the product was extracted with Et₂O, and then the combined organic extracts washed with brine and H₂O. The organic layer was dried (Na₂SO₄) and evaporated to leave the crude product, which was purified by short column chromatography over silica gel to give 6-isopropyl-4-phenyl-5,6-dihydro-2H-pyran 25 (90 mg, 45% yield) as a liquid. ^¹H NMR (400 MHz, CDCl₃): δ = 0.99 (t, J = 6.8 Hz, 6 H), 1.82-1.93 (m, 1 H), 2.27-2.40 (m, 1 H), 2.60-2.71 (m, 1 H), 3.73 (dt, J = 10.4, 3.2 Hz, 1 H), 4.00-4.06 (m, 1 H), 4.16 (ddd, J = 10.8, 5.6, 1.6 Hz, 1 H), 6.10 (m, 1 H), 7.24-7.28 (m, 1 H), 7.30-7.36 (m, 2 H), 7.38-7.42 (m, 2 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 18.1, 18.6, 27.7, 33.3, 64.2, 79.4, 125.0 (2C), 127.5, 127.7, 135.6, 140.8. IR: 2960, 2853, 1645, 1494, 1363, 1115, 1089, 880, 751, 699 cm^-¹. HRMS (APCI): m/z calcd for C₁₄H₁₈O [M + H]⁺: 203.1436; found: 203.1431.

11

The product 26 was sensitive to silica gel. While purifying the compound by column chromatography, it was decomposed. Therefore, the silica gel of the column chromatography was impregnated with 3% Et₃N in hexane during the purification