Microwave Irradiation as an Efficient Tool for the Generation of N-Heterocyclic o-Quinodimethanes: Synthesis of Polyheterocyclic Compounds by Diels-Alder Reactions

Abstract

Microwave irradiation provides a general methodology for the generation of o-quinodimethanes derived from 1,2,4-tri­azine, pyrazole and 1,2,3-triazole. The cycloaddition reactions of such compounds with electron-deficient dienophiles allow the ­corresponding heteropolycyclic adducts to be obtained within 15 minutes in 51-87% yield.

Diels-Alder reactions - microwaves - heterocycles - o-quinodimethanes

References and Notes

<A NAME="RG38205ST-1">1</A> Segura JL. Martín N. Chem. Rev.  1999,  99:  3199 

<A NAME="RG38205ST-2A">2a</A> Chou T.-S. Rev. Heteroat. Chem.  1993,  8:  65 

<A NAME="RG38205ST-2B">2b</A> Collier SJ. Storr RC. Prog. Heterocycl. Chem.  1999,  10:  25 

<A NAME="RG38205ST-2C">2c</A> Wojciechowski K. Eur. J. Org. Chem.  2001,  3587 

<A NAME="RG38205ST-2D">2d</A> Ando K. Takayama H. Heterocycles  1994,  37:  1417 

<A NAME="RG38205ST-2E">2e</A> Van de Water RW. Pettus TRR. Tetrahedron  2002,  58:  5367 

For instance:

<A NAME="RG38205ST-3A">3a</A> Nicolaou KC. Gray DLF. J. Am. Chem. Soc.  2004,  126:  607 

<A NAME="RG38205ST-3B">3b</A> Nicolaou KC. Gray DLF. Tae JS. J. Am. Chem. Soc.  2004,  126:  613 

<A NAME="RG38205ST-4A">4a</A> Strauss CR. Trainor RW. Aust. J. Chem.  1995,  48:  1665 

<A NAME="RG38205ST-4B">4b</A> Loupy A. Petit A. Hamelin J. Texier-Boullet F. Jacquault P. Mathé D. Synthesis  1998,  1213 

<A NAME="RG38205ST-4C">4c</A> Microwaves in Organic Synthesis   Loupy A. Wiley-VCH; Weinheim: 2002. 

<A NAME="RG38205ST-4D">4d</A> Varma RS. Microwave Technology - Chemical Synthesis Applications, In Kirk-Othmer Encyclopedia of Chemical Technology   John Wiley and Sons Inc.; New York: 2003. 

<A NAME="RG38205ST-4E">4e</A> Kappe CO. Angew. Chem. Int. Ed.  2004,  43:  6250 

<A NAME="RG38205ST-4F">4f</A> De la Hoz A. Díaz-Ortiz A. Moreno A. In Advances in Organic Synthesis   Vol. 1:  . Bentham Science Publishers Ltd.; Hilversum: 2005.  p.119 

<A NAME="RG38205ST-5">5</A> Díaz-Ortiz A. de la Hoz A. Moreno A. Prieto P. León R. Herrero MA. Synlett  2002,  2037 

<A NAME="RG38205ST-6A">6a</A> Hurst DT. Prog. Heterocycl. Chem.  1995,  7:  244 

<A NAME="RG38205ST-6B">6b</A> Groger H. Sans J. Gunther T. Chim. Oggi  2000,  18:  12 

<A NAME="RG38205ST-6C">6c</A> Neunhoffer H. In Comprehensive Heterocyclic Chemistry   Vol. 3:  Katrizky AR. Rees CW. Boulton AJ. McKilop A. Pergamon; Oxford: 1984. 

<A NAME="RG38205ST-7A">7a</A> Hirata K. Nakagami H. Takashina J. Miyamoto K. Heterocycles  1996,  43:  1513 

<A NAME="RG38205ST-7B">7b</A> Abdel-Rahman RM. Seada M. Fawly M. El-Baz I. Farmaco  1993,  48:  397 

<A NAME="RG38205ST-8A">8a</A> Häufel J. Breitmaier E. Angew. Chem., Int. Ed. Engl.  1974,  13:  604 

<A NAME="RG38205ST-8B">8b</A> Wustrow DJ. Capiris T. Rubin R. Knobelsdorf JA. Akunne H. Davis MD. MacKenzie R. Pugsley TA. Zoski KT. Heffner TG. Wise DL. Bioorg. Med. Chem. Lett.  1998,  8:  2067 

<A NAME="RG38205ST-9A">9a</A> Menozzi G. Mestri L. Fossa P. Mattioli F. Ghia M. J. Heterocycl. Chem.  1997,  34:  963 

<A NAME="RG38205ST-9B">9b</A> Penning TD. Talley JJ. Bertenshaw SR. Carter JS. Collins PW. Docter S. Graneto MJ. Lee LF. Malecha JW. Miyashiro JM. Rogers RS. Rogier DJ. Yu SS. Anderson GD. Burton GD. Cogburn JN. Gregory SA. Kobodt CM. Perkins WE. Seibert K. Veenhuizen AW. Zhang YY. Isakson PC. J. Med. Chem.  1997,  40:  1347 

<A NAME="RG38205ST-10A">10a</A> Habib NS. Tawil GG. Sci. Pharm.  1981,  49:  42 

<A NAME="RG38205ST-10B">10b</A> Devi S. Mitro P. Mishra SB. Mittra AS. J. Indian Chem. Soc.  1983,  60:  679 

<A NAME="RG38205ST-10C">10c</A> Daidone G. Maggio B. Plescia S. Raffa D. Musiu C. Milia C. Perra G. Marongiu ME. Eur. J. Med. Chem.  1998,  33:  375 

<A NAME="RG38205ST-10D">10d</A> El-Emary TI. Bakhite EA. Pharmazie  1999,  54:  106 

<A NAME="RG38205ST-11A">11a</A> Alvarez R. Velazquez S. San-Felix A. Aquaro S. De Clercq E. Perno C.-F. Karlsson A. Balzarini J. Camarasa MJ. J. Med. Chem.  1994,  37:  4185 

<A NAME="RG38205ST-11B">11b</A> Ölgen S. Chung KC. Z. Naturforsch., B: Chem. Sci.  2001,  56:  804 

<A NAME="RG38205ST-12">12</A> Genin MJ. Alwine DA. Anderson DJ. Barbachyn MR. Emmert DE. Garmon SA. Graber DR. G rega KC. Hester JB. Hutchison DK. Morris J. Reischer RJ. Ford CW. Zurenko GE. Hamel JC. Schaadt RD. Stapert D. Yagi BH. J. Med. Chem.  2000,  43:  953 

<A NAME="RG38205ST-13">13</A> Brockunier LL. Parmee ER. Ok HO. Candelore MR. Cascieri MA. Colwell LF. Deng L. Feeney WP. Forrest MJ. Hom GJ. MacIntyre DE. Tota L. Wyvratt MJ. Fisher MH. Weber AE. Bioorg. Med. Chem. Lett.  2000,  10:  2111 

<A NAME="RG38205ST-14A">14a</A> Mitkidou S. Stephanidou-Stephanatou J. Tetrahedron Lett.  1990,  31:  5197 

<A NAME="RG38205ST-14B">14b</A> Mertzanos GE. Stephanidou-Stephanatou J. Tsoleridis CA. Alexandrou NE. Tetrahedron Lett.  1992,  33:  4499 

<A NAME="RG38205ST-15">15</A>

Experimental Procedure.
A mixture of bromoderivative (1 equiv), NaI (5 equiv if 1 is employed or 3 equiv in the case of 2 and 3), DMF (0.1 mL) and the corresponding dienophile (2 equiv) was placed in an open vessel and irradiated at 10 W in a focused microwave reactor (Discover^®, CEM) for 15 min. The crude product was purified by flash column chromatography (silica gel, Merck type 60, 230-400 mesh) using hexane-EtOAc as the eluent to obtain the adduct.
Data for 8: mp 204-205 °C. ¹H NMR (500 MHz, CDCl₃): δ = 3.35 (s, 3 H, CH₃), 8.60 (s, 1 H, H-5), 9.05 (s, 1 H, H-9), 10.14 (s, 1 H, H-3) ppm. ¹³C NMR (125 MHz, CDCl₃):
δ = 25.0 (CH₃), 126.0 (C-5), 126.3 (C-9), 132.2, 135.7 (C-9a and -4a), 143.9, 149.6 (C-8a and -5a), 165.6 (C=O). MS (EI): m/z = 214 [M⁺].
Data for 10: mp 165.5-166.5 °C. ¹H NMR (500 MHz, CDCl₃): δ = 2.86 (dd, 1 H, J = 7.3, 15.4 Hz, H-4), 2.90 (s, 3 H, CH₃), 2.93 (dd, 1 H, J = 7.3, 16.1 Hz, H-10), 3.23 (dd, 1 H, J = 1.6, 15.4 Hz, H-4), 3.34 (dd, 1 H, J = 1.6, 7.3 Hz, H-5), 3.36 (dd, 1 H, J = 1.8, 7.3 Hz, H-9), 3.55 (dd, 1 H, J = 1.8, 16.1 Hz, H-10), 7.37 (t, 1 H, J = 6.3 Hz, p-H Ph), 7.44 (t, 2 H, J = 6.3 Hz, m-H Ph), 7.46 (t, 2 H, J = 6.3 Hz, o-H Ph), 7.47 (s, 1 H, H-3) ppm. ¹³C NMR (125 MHz, CDCl₃): δ = 21.1 (C-4), 21.7 (C-10), 25.3 (CH₃), 39.6, 39.9 (C-5 and -9), 123.5 (m-C), 127.5 (p-C), 129.3 (o-C), 137.7 (C-3), 179.0, 179.4 (C=O), 115.2, 135.9, 139.1 ppm. MS (EI): m/z 281 [M⁺].
Data for 16: yellow oil. ¹H NMR (500 MHz, CDCl₃): δ = 1.26 (m, 6 H, 2 × CH₃), 4.21 (m, 4 H, 2 × CH₂), 4.51 (br s, 2 H, H-4a and -7a), 5.30 (br s, 2 H, H-4b and -7b), 7.54 (m, 5 H, Ph) ppm. ¹³C NMR (125 MHz, CDCl₃): δ = 14.4 (CH₃), 42.0, 44.3 (C-4 and -7), 63.2 (COOCH₂), 122.3 (p-C), 129.3 (m-C), 129.9 (o-C), 140.7 (ipso-C), 155.3, 155.6 (COO), 136.3 ppm. MS (EI): m/z = 345 [M⁺].

<A NAME="RG38205ST-16">16</A> Shepherd MK. J. Chem. Soc., Perkin Trans. 1  1986,  1495 

<A NAME="RG38205ST-17">17</A> Leadbeater NE. Torenius HM. Tye H. Tetrahedron  2003,  59:  2253 

<A NAME="RG38205ST-18">18</A>

Experimental Procedure.
A mixture of hydroxyderivative 17 or 18 (1 equiv), ionic liquid 19 (2.8 equiv), PTSA (2 equiv) and xylene (1 mL) was placed in an closed vessel and irradiated at 15 W in a focused microwave reactor (Discover®, CEM) for 3.5 min (final temperature 150 °C). The organic layer was separated from this two-phase system. The ionic liquid was washed with xylene (2 × 1 mL). The combined organic layers were dried with MgSO₄ and the solvent removed at reduced pressure. The resulting bromoderivatives, 2 or 3, can be directly employed or purified by flash column chromatography (silica gel, Merck type 60, 230-400 mesh) using hexane-EtOAc 2:1 as the eluent.