Novel Synthesis of Pyrido[2,1-a]isoindoles via a Three-Component Assembly Involving Benzynes

Abstract

A novel three-component assembly involving benzynes has been developed for the synthesis of pyrido[2,1-a]isoindoles in moderate yields. Reaction conditions have been optimized and the scope of the reaction has been studied. A plausible mechanism has been proposed to account for the three-component reaction.

three component - benzyne - aryne - pyrido[2,1-a]iso­indole

References and Notes

1a Diana P. Martorana A. Barraja P. Montalbano A. Dattolo G. Cirrincione G. Dall’Acqua F. Salvador A. Vedaldi D. Basso G. Viola G. J. Med. Chem.  2008,  51:  2387 

1b Luebbers T. Angehrn P. Gmuender H. Herzig S. Bioorg. Med. Chem. Lett.  2007,  17:  4708 

1c Peese KM. Gin DY. J. Am. Chem. Soc.  2006,  128:  8734 

1d Wang SZ. Cao LY. Shi HJ. Dong YM. Sun JW. Hu YF. Chem. Pharm. Bull.  2005,  53:  67 

2a Mitsumori T. Bendikov M. Dautel O. Wudl F. Shioya T. Sato H. Sato Y. J. Am. Chem. Soc.  2004,  126:  16793 

2b Voitenko ZV. Pocholenko OA. Chkarov OO. Shishkin OV. Shishkina SV. Dall’Ava A. Vedrenne M. Sanchez M. Wolf J.-G. Eur. J. Org. Chem.  2001,  7:  1401 

3a Dix I. Doll C. Hopf H. Jones PG. Eur. J. Org. Chem.  2002,  15:  2547 

3b Burner S. Canesso R. Widmer U. Heterocycles  1994,  37:  239 

3c Fozard A. Bradsher CK. J. Org. Chem.  1967,  32:  2966 

3d Fozard A. Bradsher CK. Tetrahedron Lett.  1966,  28:  3341 

For reviews on multicomponent reactions see:

4a Tetrahedron  2005,  61: Special issue for ‘Multicomponent Reactions’

4b Domling A. Chem. Rev.  2006,  106:  17 

4c D’Souza DM. Mueller TJJ. Chem. Soc. Rev.  2007,  36:  1095 

4d Eckert H. Heterocycles  2007,  73:  149 

4e Guillena G. Ramon DJ. Yus M. Tetrahedron: Asymmetry  2007,  18:  693 

5a Nair V. Rajesh C. Vinod AU. Bindu S. Sreekanth AR. Mathen JS. Balagopal L. Acc. Chem. Res.  2003,  36:  899 

5b Dondoni A. Massi A. Acc. Chem. Res.  2006,  39:  451 

5c Balme G. Bouyssi D. Monteiro N. Heterocycles  2007,  73:  87 

5d Orru R. de Greef M. Synthesis  2003,  1471 

6a Xiao YJ. Zhang JL. Angew. Chem. Int. Ed.  2008,  47:  1903 

6b Dahl T. Tornoee CW. Bang-Andersen B. Nielsen P. Joergensen M. Angew. Chem. Int. Ed.  2008,  47:  1726 

6c Reddy UC. Raju BR. Kumar EKP. Saikia AK. J. Org. Chem.  2008,  73:  1628 

6d Zhao YL. Zhang W. Wang SH. Liu Q. J. Org. Chem.  2007,  72:  4985 

6e St. Cyr DJ. Martin N. Arndtsen BA. Org. Lett.  2007,  9:  449 

6f Pearson WH. Stoy P. Mi Y. J. Org. Chem.  2004,  69:  1919 

6g Wamhoff H. Bamberg C. Herrmann S. Nieger M. J. Org. Chem.  1994,  59:  3985 

7a Gein VL. Mihalev VA. Kasimova NN. Voronina EV. Vakhrin MI. Babushkina EB. Pharm. Chem. J.  2007,  41:  208 

7b Glushkov VA. Arapov KA. Minova ON. Ismailova NG. Syropyatov BY. Shklyaev YV. Pharm. Chem. J.  2006,  40:  363 

7c Gein VL. Yushkov VV. Kasimova NN. Rakshina NS. Gubanova MV. Voronina EV. Pharm. Chem. J.  2006,  40:  248 

7d Bräse S. Gil C. Knepper K. Bioorg. Med. Chem.  2002,  10:  2415 

For reviews on aryne chemistry, see:

8a Heaney H. Chem. Rev.  1962,  62:  81 

8b Kessar SV. Acc. Chem. Res.  1978,  11:  283 

8c Bryce MR. Vernon JM. Adv. Heterocycl. Chem.  1981,  28:  183 

8d Buchwald SL. Nielsen RB. Chem. Rev.  1988,  88:  1047 

8e Snieckus V. Chem. Rev.  1990,  90:  879 

8f Majoral JP. Igau1 A. Cadierno V. Zablocka M. Top. Curr. Chem.  2002,  220:  54 

8g Pellissier H. Santelli M. Tetrahedron  2003,  59:  701 

8h Jia GC. Acc. Chem. Res.  2004,  37:  479 

8i Guitian E. Perez D. Pena D. Top. Organomet. Chem.  2005,  14:  109 

9a Yoshida H. Fukushima H. Ohshita J. Angew. Chem. Int. Ed.  2004,  43:  3935 

9b Jayanth TT. Jeganmohan M. Cheng CH. Org. Lett.  2005,  7:  2921 

9c Henderson JL. Edwards AS. Greaney MF. J. Am. Chem. Soc.  2006,  128:  7426 

9d Liu ZJ. Larock RC. Angew. Chem. Int. Ed.  2007,  46:  2535 

9e Jayanth TT. Cheng CH. Angew. Chem. Int. Ed.  2007,  46:  5921 

9f Henderson JL. Edwards AS. Greaney MF. Org. Lett.  2007,  9:  5589 

9g Huang X. Xue J. J. Org. Chem.  2007,  72:  3965 

10a Yoshikawa E. Yamamoto Y. Angew. Chem. Int. Ed.  2000,  39:  173 

10b Yoshikawa E. Radhakrishnan KV. Yamamoto Y. J. Am. Chem. Soc.  2000,  122:  7280 

11 Shou WG. Yang YY. Wang YG. J. Org. Chem.  2006,  71:  9241 

12a Xie CS. Zhang YH. Org. Lett.  2007,  9:  781 

12b Xie CS. Zhang YH. Huang ZD. Xu PX. J. Org. Chem.  2007,  72:  5431 

12c Xie CS. Liu LF. Zhang YH. Xu PX. Org. Lett.  2008,  10:  2393 

13

The CCDC number of the X-ray structure is 701719.

14a All the reactions were carried out under the nitrogen atmosphere in oven-dried flasks. MeCN was distilled from CaH₂ using benzophenone as the indicator. 2-Bromo-1-(4-methoxyphenyl)ethanone, 2-bromo-1-(4-ethylphenyl)-ethanone, 2-bromo-1-(4-nitrophenyl)ethanone, 2-bromo-1-(4-chlorophenyl)ethanone were prepared according to the method described in: Ismail MA. Brun R. Wenzler T. Tanious FA. Wilson WD. Boykin DW. J. Med. Chem.  2004,  47:  3658 

14b Benzyne precursors were prepared according to the method of: Himeshima Y. Sonoda T. Kobayashi H. Chem. Lett.  1983,  12:  1211 

14c

Other materials were purchased from common commercial sources and used without additional purification. ^¹H NMR spectra were recorded at 400 MHz using TMS as internal standard. ^¹³C NMR spectra were recorded at 100 MHz using TMS as internal standard. Mass spectroscopy data of the reaction product were collected on an HRMS (EI) instrument.

15

General Procedure of the Three-Component Reaction: An oven-dried flask was charged with 2-bromo-1-phenyl-ethanone (0.6 mmol), pyridine (1.0 mmol), CsF (1.5 mmol) and MeCN (3 mL). Benzyne precursor (0.5 mmol) in MeCN (2 mL) was added dropwise under the protection of N₂. The reaction mixture was then allowed to react at 80 ˚C for 2 h. After the completion of the reaction, the mixture was cooled to r.t. and filtered through a pad of celite. The solvent was then removed in vacuum, and the final product was obtained by flash chromatography on a silica gel column as a yellow powder.