Tandem CH-Activation-Imine-Formation Reaction: A New Route to Imidazo[2,1-a]phthalazines

Abstract

A general and efficient synthesis of imidazo[2,1-a]phthalazines by palladium- and copper-mediated coupling of N-aminoimidazoles with 2-haloaryl aldehydes with concurrent imine formation is described. This new synthesis of the imidazo[2,1-a]phthalazine ring system allows for facile introduction of different substituents around the entire core.

imidazo[2,1-a]phthalazine - imine formation - CH activation - N-aminoimidazoles - 2-bromoaryl aldehydes

References

1a Hardtmann GE. inventors; US Patent 3 711  481.  Chem. Abstr. 1973, 78, 84430

1b Razvi M. Ramalingam T. Indian J. Chem., Sect. B: Org. Chem. Incl. Med. Chem.  1992,  31:  788 

1c Catarzi D. Cecchi L. Colotta V. Conti G. Melani F. Filacchioni G. Martini C. Giusti L. Lucacchini A. Farmaco  1993,  48:  447 

2a Castle RN. Takano S. J. Heterocycl. Chem.  1966,  3:  381 

2b Barlin GB. Aust. J. Chem.  1986,  39:  1803 

2c Mavel S. Thery I. Gueiffier A. Arch. Pharm. Pharm. Med. Chem.  2002,  335:  7 

2d Solyom S. Hamori T. Borosy AP. Tarnawa I. Berzsenyi P. Pallagi I. Med. Chem. Res.  2002,  11:  39 

2e Shubin KM. Kuznetsov VA. Galishev VA. Tetrahedron Lett.  2004,  45:  1407 

2f Kuznetsov VA. Shubin KM. Schipalkin AA. Petrov ML. Tetrahedron  2006,  62:  10018 

2g Parenty ADC. Song Y.-F. Richmond CJ. Cronin L. Org. Lett.  2007,  9:  2253 

3a Heim-Riether A. Healy J. J. Org. Chem.  2005,  70:  7331 

3b

N-Amination of imidazoles leads to separable regioisomers.

4a For a review, see: Miura M. Nomura M. Top. Curr. Chem.  2002,  219:  211 

For most recent examples of direct intermolecular Pd-catalyzed arylation of azoles, see:

4b Yokooji A. Okazawa T. Satoh T. Miura M. Nomura M. Tetrahedron  2003,  59:  5685 

4c Mori A. Sekiguchi A. Masui K. Shimada T. Horie M. Osakada K. Kawamoto M. Ikeda T. J. Am. Chem. Soc.  2003,  125:  1700 

4d Li W. Nelson DP. Jensen MS. Hoerrner RS. Javadi GJ. Cai D. Larsen RD. Org. Lett.  2003,  5:  4835 

4e Zificsak CA. Hlasta DJ. Tetrahedron  2004,  60:  8991 

4f Park C.-H. Ryabova V. Seregin IV. Sromek AW. Gevorgyan V. Org. Lett.  2004,  6:  1159 

4g Alagille D. Baldwin RM. Tamagnan GD. Tetrahedron Lett.  2005,  46:  1349 

4h Bellina F. Cauteruccio S. Mannina L. Rossi R. Veil S. J. Org. Chem.  2005,  70:  3997 

4i Gracias V. Gasiecki AF. Pagano TG. Djuric SW. Tetrahedron Lett.  2006,  47:  8873 

4j Bellina F. Cauteruccio S. Mannina L. Rossi R. Viel S. Eur. J. Org. Chem.  2006,  693 

4k Cerna I. Pohl R. Klepetarova B. Hocek M. Org. Lett.  2006,  8:  5389 

4l Bellina F. Cauteruccio S. Rossi R. J. Org. Chem.  2007,  72:  8543 

4m Hien-Quang D. Daugulis O. J. Am. Chem. Soc.  2007,  129:  12404 

4n Yoshizumi T. Tsurugi H. Satoh T. Miura M. Tetrahedron Lett.  2008,  49:  1598 

5 Caron S. Massett SS. Bogle DE. Castaldi MJ. Braish TF. Org. Process Res. Dev.  2001,  5:  254 

6

No imine formation was observed under standard coupling conditions without one of the two metals (Pd, Cu) present.

7a Ohff M. Ohff A. Milstein D. Chem. Commun.  1999,  357 

7b For a review on palladacyles, see: Ghedini M. Aiello I. Crispini A. Golemme A. La Deda M. Pucci D. Coord. Chem. Rev.  2006,  250:  1373 

8 MeP(t-Bu)₂˙HBF₄ has been reported to significantly increase yield in CH activation reaction: Wang JX. McCubbin A. Meizhong J. Laufer RS. Mao Y. Crew AP. Mulvihill MJ. Snieckus V. Org. Lett.  2008,  10:  2923 

9 Direct arylations of azoles were performed under ligandless conditions; see reference 4j and: Bellina F. Cauteruccio S. Rossi R. Eur. J. Org. Chem.  2006,  1379 

10

Starting 1-aminoimidazoles, except commercially available benzimidazol-1-ylamine, were prepared according to reference 3.