Regio- and Stereoselective One-Pot Synthesis of Unknown Oxazoline-Fused Pyridazines by ‘Michael Addition-Pyridazine Cyclization-Oxazoline Cyclization’ Cascade Reactions of 4-Chloro-1,2-diaza-1,3-butadienes with 3-Dimethylaminopropenoates

Abstract

A one-pot, three-step regio- and stereoselective synthesis of unknown functionalized oxazoline-fused pyridazines is reported. The approach involves base-assisted ‘Michael addition-pyridazine cyclization-oxazoline cyclization’ cascade reactions of 4-chloro-1,2-diaza-1,3-butadienes with 3-dimethylaminopropenoates.

1,2-diaza-1,3-butadienes - 3-dimethylaminopropenoates - Michael additions - cyclizations - oxazoline-fused pyr­idazines

References and Notes

<A NAME="RD27707ST-1A">1a</A> Sperry JB. Wright DL. Curr. Opin. Drug Discovery Dev.  2005,  8:  723 

<A NAME="RD27707ST-1B">1b</A> Ziegert RE. Toraeng J. Knepper K. Braese S. J. Comb. Chem.  2005,  7:  147 

<A NAME="RD27707ST-2">2</A> Loughlin WA. Tyndall JDA. Glenn MP. Fairlie DP. Chem. Rev.  2004,  104:  6085 

For recent reviews on general cascade reactions, see:

<A NAME="RD27707ST-3A">3a</A> Cane DE. Chem. Rev.  1990,  90:  1089 

<A NAME="RD27707ST-3B">3b</A> Tietze LF. Chem. Rev.  1996,  96:  115 

<A NAME="RD27707ST-3C">3c</A> Tietze LF. Modi A. Med. Res. Rev.  2000,  20:  304 

<A NAME="RD27707ST-3D">3d</A> Tietze LF. Haunert F. Stimulating Concepts in Chemistry   Vögtle F. Stoddart JF. Shibasaki M. Wiley-VCH; Weinheim: 2000.  p.39-64  

<A NAME="RD27707ST-3E">3e</A> Mayer SF. Kroutil W. Faber K. Chem. Soc. Rev.  2001,  30:  332 

<A NAME="RD27707ST-3F">3f</A> Nicolaou KC. Montagnon T. Snyder SA. Chem. Commun.  2003,  551 

<A NAME="RD27707ST-3G">3g</A> Ramon DJ. Yus M. Angew. Chem. Int. Ed.  2005,  44:  1602 

<A NAME="RD27707ST-3H">3h</A> Wasille J.-C. Obrey SJ. Baker RT. Bazan GC. Chem. Rev.  2005,  105:  1001 

<A NAME="RD27707ST-3I">3i</A> Nicolaou KC. Edmonds DJ. Bulger PG. Angew. Chem. Int. Ed.  2006,  45:  7134 

<A NAME="RD27707ST-3J">3j</A> Albert M. Fensterbank L. Lacôte E. Malacria M. Top. Curr. Chem.  2006,  264:  1 

<A NAME="RD27707ST-3K">3k</A> Enders D. Grondal C. Hüttl MRM. Angew. Chem. Int. Ed.  2007,  46:  1570 

<A NAME="RD27707ST-3L">3l</A> Tietze LF. Brasche G. Gerike K. Domino Reactions in Organic Synthesis   Wiley-VCH; Weinheim: 2006. 

<A NAME="RD27707ST-3M">3m</A> Chapman CJ. Frost CG. Synthesis  2007,  1 

<A NAME="RD27707ST-4">4</A> Attanasi OA. Favi G. Filippone P. Golobič A. Stanovnik B. Svete J. J. Org. Chem.  2005,  70:  4307 

For the synthesis and application of this and related compounds, see:

<A NAME="RD27707ST-5A">5a</A> Sommer S. Tetrahedron Lett.  1977,  18:  117 

<A NAME="RD27707ST-5B">5b</A> Attanasi OA. Filippone P. Mei A. Santeusanio S. Synthesis  1984,  671 

<A NAME="RD27707ST-5C">5c</A> Attanasi OA. Filippone P. Mei A. Santeusanio S. Synthesis  1984,  873 

<A NAME="RD27707ST-5D">5d</A> Attanasi OA. De Crescentini L. Filippone P. Mantellini F. Santeusanio S. ARKIVOC  2002,  (xi):  274 

<A NAME="RD27707ST-5E">5e</A> Attanasi OA. De Crescentini L. Favi G. Filippone P. Giorgi G. Mantellini F. Santeusanio S. J. Org. Chem.  2003,  68:  1947 

<A NAME="RD27707ST-5F">5f</A> Attanasi OA. De Crescentini L. Favi G. Filippone P. Mantellini F. Santeusanio S. J. Org. Chem.  2004,  69:  2686 

<A NAME="RD27707ST-5G">5g</A> Attanasi OA. Baccolini G. Boga C. De Crescentini L. Filippone P. Mantellini F. J. Org. Chem.  2005,  70:  4033 

<A NAME="RD27707ST-5H">5h</A> Attanasi OA. De Crescentini L. Favi G. Filippone P. Lillini S. Mantellini F. Santeusanio S. Org. Lett.  2005,  7:  2469 

<A NAME="RD27707ST-5I">5i</A> Aparicio D. Attanasi OA. Filippone P. Ignacio R. Lillini S. Mantellini F. Palacios F. de los Santos JM. J. Org. Chem.  2006,  71:  5897 

<A NAME="RD27707ST-5J">5j</A> Attanasi OA. Favi G. Filippone P. Lillini S. Mantellini F. Spinelli D. Stenta M. Adv. Synth. Catal.  2007,  349:  207 

<A NAME="RD27707ST-5K">5k</A> Attanasi OA. Davoli P. Favi G. Filippone P. Forni A. Moscatelli G. Prati F. Org. Lett.  2007,  9:  3461 

<A NAME="RD27707ST-6A">6a</A> Boger DL. Tetrahedron  1983,  39:  2869 

<A NAME="RD27707ST-6B">6b</A> Gilchrist TL. Stevens JA. J. Chem. Soc., Perkin Trans. 1  1985,  1741 

<A NAME="RD27707ST-6C">6c</A> Attanasi OA. Caglioti L. Org. Prep. Proced. Int.  1986,  18:  299 

<A NAME="RD27707ST-6D">6d</A> Boger DL. Chem. Rev.  1986,  86:  781 

<A NAME="RD27707ST-6E">6e</A> Boger DL. Weinreb SM. Hetero Diels-Alder Methodology in Organic Synthesis   Academic; San Diego: 1987. 

<A NAME="RD27707ST-6F">6f</A> Fringuelli F. Taticchi A. Dienes in the Diels-Alder Reaction   Wiley-Interscience; New York: 1990. 

<A NAME="RD27707ST-6G">6g</A> Attanasi OA. De Crescentini L. Filippone P. Fringuelli F. Mantellini F. Matteucci M. Piermatti O. Pizzo F. Helv. Chim. Acta  2001,  84:  513 

<A NAME="RD27707ST-6H">6h</A> Fringuelli F. Taticchi A. The Diels-Alder Reaction: Selected Practical Methods   John Wiley and Sons; New York: 2002. 

<A NAME="RD27707ST-7A">7a</A> Sommer S. Chem. Lett.  1977,  583 

<A NAME="RD27707ST-7B">7b</A> Sommer S. Angew. Chem.  1979,  91:  756 

<A NAME="RD27707ST-7C">7c</A> South MS. Jakuboski TL. Tetrahedron Lett.  1995,  36:  5703 

<A NAME="RD27707ST-7D">7d</A> South MS. Jakuboski TL. Westmeyer MD. Dukesherer DR. Tetrahedron Lett.  1996,  37:  1351 

<A NAME="RD27707ST-7E">7e</A> South MS. Jakuboski TL. Westmeyer MD. Dukesherer DR. J. Org. Chem.  1996,  61:  8921 

<A NAME="RD27707ST-7F">7f</A> Attanasi OA. Favi G. Filippone P. Forzato C. Giorgi G. Morganti S. Nitti P. Pitacco G. Rizzato E. Spinelli D. Valentin E. Tetrahedron  2006,  62:  6420 

<A NAME="RD27707ST-7G">7g</A> Rossi E. Abbiati G. Attanasi OA. Rizzato S. Santeusanio S. Tetrahedron  2007,  63:  11055 

For the synthesis and application of this and related compounds, see:

<A NAME="RD27707ST-8A">8a</A> Hvala A. Simonic I. Stanovnik B. Svete J. Tisler M. Zorz L. Heterocycles  1988,  27:  903 

<A NAME="RD27707ST-8B">8b</A> Čade˛ Z. Stanovnik B. Svete J. Tiler M. Synthesis  1990,  70 

<A NAME="RD27707ST-8C">8c</A> Smodiš J. Stanovnik B. Tetrahedron  1998,  54:  9799 

<A NAME="RD27707ST-8D">8d</A> Stanovnik B. J. Heterocycl. Chem.  1999,  36:  1581 

<A NAME="RD27707ST-8E">8e</A> Stanovnik B. Svete J. Synlett  2000,  1077 

<A NAME="RD27707ST-8F">8f</A> Stanovnik B. Svete J. Synthesis, Reactions and Properties, In Targets in Heterocyclic Systems   Vol. 4:  Attanasi OA. Spinelli D. Italian Society of Chemistry; Rome: 2000.  p.105 

<A NAME="RD27707ST-8G">8g</A> Stanovnik B. Svete J. Chem. Rev.  2004,  104:  2433 

<A NAME="RD27707ST-8H">8h</A> Svete J. J. Heterocycl. Chem.  2005,  42:  361 

<A NAME="RD27707ST-8I">8i</A> Pirc S. Bevk D. Jakše R. Rečnik S. Golič L. Golobič A. Meden A. Stanovnik B. Svete J. Synthesis  2005,  2969 

<A NAME="RD27707ST-8J">8j</A> Bevk D. Grošelj U. Meden A. Svete J. Stanovnik B. Tetrahedron  2006,  62:  8126 

<A NAME="RD27707ST-8K">8k</A> Pirc S. Bevk D. Golobič A. Stanovnik B. Svete J. Helv. Chim. Acta  2006,  89:  30 

<A NAME="RD27707ST-8L">8l</A> Wagger J. Bevk D. Meden A. Svete J. Stanovnik B. Helv. Chim. Acta  2006,  89:  240 

<A NAME="RD27707ST-8M">8m</A> Wagger J. Golič L. Grdadolnik S. Grošelj U. Meden A. Stanovnik B. Svete J. Tetrahedron: Asymmetry  2007,  18:  464 

<A NAME="RD27707ST-8N">8n</A> Malavašič Č. Brulc B. Čebašek P. Dahmann G. Heine N. Bevk D. Grošelj U. Meden A. Stanovnik B. Svete J. J. Comb. Chem.  2007,  9:  219 

<A NAME="RD27707ST-9">9</A>

General Procedure for the Synthesis of II and 3a-k 4-Chloro-1,2-diaza-1,3-butadiene 1a-g and 3-dimethyl-aminopropenoate 2a-d were synthesized by known procedures and were isolated as an E/Z isomeric mixture^5,7e and Z-isomer,⁸ respectively. To a CHCl₃ solution (5 mL) of 4-chloro-1,2-diaza-1,3-butadiene 1a-g (1 mmol) was added 3-dimethylaminopropenoate 2a-d (2 mmol) and DIPEA (1 mmol) and the reaction mixture was refluxed for the appropriate time (see Table [1] ). In order to obtain the intermediate II the reaction between 1a and 2a was heated to reflux for 5 h. The solvent was removed under reduced pressure and the residue was purified by silica gel chromatography (eluent cyclohexane-EtOAc mixtures).

<A NAME="RD27707ST-10">10</A>

Data for Methyl (3a S *,4 R *,7a S* )-5-(Aminocarbonyl)-4-(dimethylamino)-7-methyl-2-phenyl-3a,4,5,7a-tetra-hydropyridazino[4,5- d ][1,3]oxazole-3a-carboxylate (3a)
Colorless crystals from cyclohexane-EtOAc, mp 187-191 °C (dec.). IR (mull): ν_max = 3403, 3304, 3252, 3159, 1740, 1703, 1681, 1634, 1591 cm^-1. ¹H NMR (400 MHz, DMSO-d ₆): δ = 2.11 [s, 9 H, CH₃ and N(CH₃)₂], 3.73 (s, 3 H, OCH₃), 5.70 (s, 1 H, CH), 5.72 (s, 1 H, CH), 6.61 (br s, 2 H, CONH₂, D₂O exch.), 7.49 (t, 2 H, J = 8.0 Hz, Ar), 7.61 (t, 1 H, J = 8.0 Hz, Ar), 7.85 (d, 2 H, J = 8.0 Hz, Ar). ¹³C NMR (100 MHz, DMSO-d ₆): δ = 19.70 (q), 42.42 (q), 52.54 (q), 67.20 (d), 71.00 (d), 77.15 (s), 125.45 (s), 128.26 (d), 128.86 (d), 132.76 (d), 142.72 (s), 156.68 (s), 164.05 (s), 168.93 (s). MS: m/z (%) = 359 [M⁺] (13), 316 (16), 257 (49), 211 (29), 168 (42), 149 (56), 125 (53), 111 (100). Anal. Calcd for C₁₇H₂₁N₅O₄: C, 56.82; H, 5.89; N, 19.49. Found: C, 56.97; H, 5.68; N, 19.62.

<A NAME="RD27707ST-11">11</A>

Crystallographic data for compound 3a have been deposited with the Cambridge Crystallographic Data Centre as supplementary publication number CCDC 657267. Copies of the data can be obtained, free of charge, on application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK [fax: [phone] or e-mail: [e-mail]].

<A NAME="RD27707ST-12">12</A> Clerici F. Gelmi ML. Gambini A. J. Org. Chem.  1999,  64:  5764 

<A NAME="RD27707ST-13">13</A>

Data for Methyl (3 R *,4 R *,5 R* )-2-(Aminocarbonyl)-4-(benzoylamino)-5-chloro-3-(dimethylamino)-6-methyl-2,3,4,5-tetrahydro-4-pyridazinecarboxylate (II)
White powder from Et₂O, mp 133-134 °C (dec.). IR (mull): ν_max = 3465, 3342, 3280, 3205, 1735, 1698, 1658, 1581 cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 2.21 (s, 3 H, CH₃), 2.49 [br s, 6 H, N(CH₃)₂], 3.73 (s, 3 H, OCH₃), 4.94 (br s, 1 H, CONH₂, D₂O exch.), 5.25 (s, 1 H, CH), 5.34 (s, 1 H, CH), 6.47 (br s, 1 H, CONH₂), 7.40-7.52 (m, 2 H, Ar), 7.53-7.60 (m, 1 H, Ar), 7.80-7.88 (m, 3 H, Ar and NH, D₂O exch.). ¹³C NMR (100 MHz, CDCl₃): δ = 22.26 (q), 43.96 (q), 49.88 (d), 53.97 (q), 59.88 (s), 69.34 (d), 127.80 (d), 129.22 (d), 132.70 (d), 133.38 (s), 144.61 (s), 157.23 (s), 167.60 (s), 170.58 (s). MS: m/z (%) = 360 [M⁺ - HCl] (65), 317 (100), 257 (10), 214 (14), 196 (23), 187 (30), 111 (69). Anal. Calcd for C₁₇H₂₂N₅O₄Cl: C, 51.58; H, 5.60; N, 17.69. Found: C, 51.72; H, 5.81; N, 17.48.