Synlett 2009(12): 2002-2004  
DOI: 10.1055/s-0029-1217526
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Synthesis of Substituted Pyranopyrazoles under Neat Conditions via a Multicomponent Reaction

Arasampattu S. Nagarajan, Boreddy S. R. Reddy*
Industrial Chemistry Laboratory, Central Leather Research Institute, Adyar, Chennai 600020, India
Fax: +91(44)24911589; e-Mail: induchem2000@yahoo.com;
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Publikationsverlauf

Received 23 April 2009
Publikationsdatum:
01. Juli 2009 (online)

Abstract

A simple and efficient synthesis of pyranopyrazoles in good yields via a four-component reaction between an aromatic aldehyde, hydrazine hydrate, ethyl acetoacetate and malononitrile under neat conditions is described.

    References and Notes

  • 1a Zhu J. Bienayme H. In Multicomponent Reactions   Zhu J. Bienayme H. Wiley-VCH; Weinheim: 2005.  and references cited therein
  • 1b Tejedor D. Garcia-Tellado F. Chem. Soc. Rev.  2007,  36:  484 
  • 1c Ugi I. Pure Appl. Chem.  2001,  73:  187 
  • For MCR-based heterocyclic libraries see:
  • 1d Lie’by-Muller F. Simon C. Constantieux T. Rodriguez J. QSAR Comb. Sci.  2006,  25:  432 
  • 1e Simon C. Constantieux T. Rodriguez J. Eur. J. Org. Chem.  2004,  4957 
  • 1f Evdokimov NM. Kireev AS. Yakovenko AA. Antipin MY. Magedov IV. Kornienko A. J. Org. Chem.  2007,  72:  3443 
  • For drug discovery see:
  • 1g Weber L. Drug Discovery Today  2002,  7:  143 
  • 1h Hulme C. Gore V. Curr. Med. Chem.  2001,  10:  51 
  • 2a Herrerias CI. Yao X. Li Z. Li C. Chem. Rev.  2007,  107:  2546 
  • 2b Comprehensive Organic Reactions in Aqueous Media   Li CJ. Chan TH. John Wiley & Sons; New York: 2007. 
  • 2c Grieco PA. Organic Reactions in Water   Thomson Science; Glasgow: 1998. 
  • 2d For recent examples, see: Varma RS. Clean Chemical Synthesis in Water, In Org. Chem. Highlights (Online)   U. S. Environmental Protection Agency; Washington D.C.: 2007.  http://www.organic-chemistry.org/Highlights/2007/01February.shtm
  • 2e Bonifacio VDB. Organic Reactions in Water, In Org. Chem. Highlights (Online)   U. S. Environmental Protection Agency; Washington D.C.: 2005.  http://www.organic-chemistry.org/Highlights/2005/25July.shtm
  • 3a Yu D. Suzuki M. Xie L. Morris-Natschke SL. Lee K.-H. Med. Res. Rev.  2003,  23:  322 
  • 3b Khan KM. Saify ZS. Khan MZ. . Choudhary MI. ; Atta-rr-Rahman; Perveen S. Chohan ZH. Supuran CT. J. Enzym. Inhib. Med. Chem.  2004,  19:  373 
  • 3c Abd El-Aziz AS. El-Agrody AM. Bedair AH. Corkery TC. Ata A. Heterocycles  2004,  63:  1793 
  • 4a Borges F. Roleira F. Milhazes N. Santana L. Uriarte E. Curr. Med. Chem.  2005,  12:  887 
  • 4b Chimenti F. Bizzarri B. Bolasco A. Secci D. Chimenti P. Carradori S. Granese A. Rivanera D. Lilli D. Scaltrito MM. Brenciaglia MI. Eur. J. Med. Chem.  2006,  41:  208 
  • 4c Kulkarni MV. Kulkarni GM. Lin CH. Sun CM. Curr. Med. Chem.  2006,  13:  2795 
  • 5a Kitamura ROS. Romoff P. Young MCM. Kato MJ. Lago JHG. Phytochemistry  2006,  67:  2398 
  • 5b Iqbal MCM. Jayasinghe ULB. Herath HMTB. Wijesekara KB. Fujimoto Y. Phytoparasitica  2004,  32:  119 
  • 5c Kraus GA. Kim I.
    J. Org. Chem.  2003,  68:  4517 
  • 5d Sardari S. Nishibe S. Daneshtalab M. Stud. Nat. Prod. Chem.  2000,  23:  335 
  • 5e El-Agrody AM. El-Latif MSA. El-Hady NA. Fakary AH. Bedair AH. Molecules  2001,  6:  519 
  • 6 Junek H. Aigner H. Chem. Ber.  1973,  106:  914 
  • 7a Wamhoff H. Kroth E. Strauch K. Synthesis  1993,  1129 
  • 7b Sharanina LG. Marshtupa VP. Sharanin YuA. Khim. Geterosikl. Soedin.  1980,  10:  1420 
  • 8 Sharanin YuA. Sharanina LG. Puzanova VV.
    Zh. Org. Khim.  1983,  19:  2609 
  • 9a Shestopalov AM. Emeliyanova YM. Shestopalov AA. Rodinovskaya LA. Niazimbetova ZI. Evans DH. Tetrahedron  2003,  59:  7491 
  • 9b Shestopalov AM. Emeliyanova YM. Shestopalov AA. Rodinovskaya LA. Niazimbetova ZI. Evans DH. Org. Lett.  2002,  4:  423 
  • 10 Peng Y. Song G. Dou R. Green Chem.  2006,  8:  573 
  • 11a Kljin JE. Engberts JBN. Nature (London)  2005,  435:  746 
  • 11b Narayan S. Fokin MG. Kolb HC. Sharpless KB. Angew. Chem. Int. Ed.  2005,  44:  3275 
  • 11c Kanizsai I. Gyónfalvi S. Szadonyi Z. Sillanpää R. Fülöp F. Green Chem.  2007,  9:  357 
  • 12a Pirrung MC. Sarma KD. Tetrahedron  2005,  61:  11456 
  • 12b Pirrung MC. Sarma KD. J. Am. Chem. Soc.  2004,  126:  444 
  • 12c Hailes HC. Org. Process Res. Dev.  2007,  11:  114 
  • 13 Vasuki G. Kumaravel K. Tetrahedron Lett.  2008,  49:  5636 
14

General Procedure for Pyranopyrazoles: To a stirred mixture of hydrazine hydrate 1 (2 mmol) and ethyl acetoacetate 3 (2 mmol), aldehyde 2 (2 mmol) and malononitrile 4 (2 mmol) were added successively at r.t. with vigorous stirring for 3-11 min. The precipitated solid was filtered, and washed with a mixture of EtOAc-hexane (20:80). The product obtained was pure as found in TLC and ¹H NMR and ¹³C NMR spectroscopy. However, the products were further purified by recrystallization from EtOAc. Table  [¹] , entry 4: yellow solid; mp 158-161 ˚C. ¹H NMR (500 MHz, DMSO-d 6): δ = 1.75 (s, 3 H), 2.16 (s, 3 H), 2.46 (s, 2 H), 4.53 (s, 1 H), 6.85 (s, 1 H), 7.01 (d, 1 H, J = 12.0 Hz), 7.03 (d, 1 H, J = 8.4 Hz), 12.09 (br s, 1 H). ¹³C NMR (125 MHz, DMSO-d 6): δ = 10.3, 14.8, 39.8, 57.7, 98.1, 115.2, 121.3, 127.2, 130.9, 136.2, 140.9, 155.2, 159.0, 161.3. IR (KBr): 3484.5, 3239.7, 2195.3, 1638.0, 1597.6, 1493.4, 1399.4, 1116.5, 1057.3, 822.1, 749.0, 549.6 cm. LCQ-MS (ESI): m/z calcd for C15H13FN4O: 284.0; found: 284.3. Anal. Calcd for C15H13FN4O: C, 63.37; H, 4.61; N, 19.71. Found: C, 6 3.29; H, 4.52; N, 19.63.

15

Table  [¹] , entry 10: yellow solid; mp 145-147 ˚C. ¹H NMR (500 MHz, DMSO-d 6): δ = 1.76 (s, 3 H), 2.47 (s, 2 H), 4.58 (s, 1 H), 7.10 (d, 2 H, J = 10.0 Hz), 7.47 (d, 2 H, J = 10.0 Hz), 12.05 (br s, 1 H). ¹³C NMR (125 MHz, DMSO-d 6): δ = 10.3, 39.8, 57.2, 97.6, 120.3, 121.2, 130.2, 131.9, 136.2, 144.4, 155.2, 161.4. IR (KBr): 3476.7, 3232.8, 3100.4, 2193.4, 1648.6, 1600.0, 1490.9, 1401.1, 1069.1, 794.8, 749.3, 541.9 cm. LCQ-MS (ESI): m/z calcd for C14H11FN4O: 270.0; found: 270.1. Anal. Calcd for C14H11FN4O: C, 62.22; H, 4.10; N, 20.73. Found: C, 62.16; H, 4.22; N, 20.65.

16

Table  [¹] , entry 19: yellow solid; mp 168-170 ˚C. ¹H NMR (500 MHz, DMSO-d 6): δ = 1.75 (s, 3 H), 2.47 (s, 2 H), 3.69 (s, 3 H), 4.50 (s, 1 H), 6.83 (d, 2 H, J = 8.4 Hz), 7.04 (d, 2 H, J = 8.4 Hz), 12.05 (br s, 1 H). ¹³C NMR (125 MHz, DMSO-d 6): δ = 10.3, 35.9, 55.5, 58.1, 98.4, 114.3, 121.4, 129.0, 136.1, 136.9, 155.3, 158.5, 161.2. IR (KBr): 3481.4, 3253.2, 2925.3, 2191.1, 1642.5, 1600.8, 1492.0, 1392.8, 1258.4, 1172.1, 1031.2, 870.0, 804.4, 565.9 cm. LCQ-MS (ESI): m/z calcd for C15H14N4O2: 282.0; found: 282.0. Anal. Calcd for C15H14N4O2: C, 63.82; H, 5.00; N, 19.85. Found: C, 63.71; H, 5.15; N, 19.94.