Efficient Synthesis of 6-Amino-Substituted Pyridin-2(1H)-ones Using in situ Generated Propiolic Acid Chloride

Abstract

A regioselective and highly efficient synthesis of 6-amino-substituted pyridin-2(1H)-ones is presented. In situ generated propiolic acid chloride was used for the cyclization of acyclic β-keto N,S-acetals to afford the heterocyclic core. Substitution by amines led to a flexible access of the target compounds.

pyridin-2(1H)-ones - cyclizations - thioacetals - N,S-acetals - ring closure

References

1a Knölker H.-J. Boese R. Hitzemann R. Heterocycles  1989,  29:  1551 

1b Huang Z.-T. Wang M.-X. J. Chem. Soc., Perkin Trans. 1  1993,  1085 

1c Zhao M.-X. Wang M.-X. Huang Z.-T. Tetrahedron  2002,  58:  1309 

For reviews see:

1d Huang Z.-T. Wang M. Heterocycles  1994,  37:  1233 

1e Wang M. Huang Z.-T. Prog. Nat. Sci.  2002,  12:  249 

2

From the cyclization of the ketene aminal comprising 1-cyclohexylmethanamine and cyclopropylamine (1, R = CH₂-cHex R′ = cPr) with propiolic acid methyl ester we isolated the regioisomeric compounds 3 and 3′ in 21% and 27% yield.

3 Hehemann DG. Winnik W. J. Heterocycl. Chem.  1994,  31:  393 

4a Huang Z.-T. Shi X. Synthesis  1990,  162 

4b Huang Z.-T. Shi X. Chem. Ber.  1990,  123:  541 

During the revision of our manuscript the aza-annulation of acyclic ketene-N,S-acetals 4 with itaconic anhydride yielding tetrahydro-2-pyridones was reported:

4c Chakrabarti S. Panda K. Misra NC. Ila H. Junjappa H. Synlett  2005,  1437 

See for example:

5a Thuillier A. Vialle J. Bull. Soc. Chim. Fr.  1959,  1398 

5b Rudorf W.-D. Schierhorn A. Augustin M. Tetrahedron  1979,  35:  551 

5c Potts KT. Cipullo MJ. Ralli P. Theodoridis G. J. Org. Chem.  1982,  47:  3027 

5d Huang Z.-T. Liu Z.-R. Synth. Commun.  1989,  19:  945 

5e Perjessy A. Rudorf W.-D. Loos D. Sustekova Z. Monatsh. Chem.  1994,  125:  1389 

6a Hojo M. Masuda R. Okada E. Yamamoto H. Morimoto K. Okada K. Synthesis  1990,  195 

6b Barun O. Ila H. Junjappa H. J. Org. Chem.  2000,  65:  1583 

6c Mahata PK. Venkatesh C. Syam Kumar UK. Kumar Ila H. Junjappa H. J. Org. Chem.  2003,  68:  3966 

6d Karim E. Kishore K. Vishwakarma JN. J. Heterocycl. Chem.  2003,  40:  901 

7 Kumar A. Aggarwal V. Ila H. Junjappa H. Synthesis  1980,  748 ; the thioamide may be isolated or alkylated in situ

8 The methylation of 3-keto thioamides after their generation applying Lawesson’s reagent has also been described: Nishio T. Helv. Chim. Acta  1998,  81:  1207 

9 Similar results from the reaction with dimethyl but-2-ynedioate were reported: Aggarwal V. Ila H. Junjappa H. Synthesis  1983,  147 

10 Savarin CG. Murry JA. Dormer PG. Org. Lett.  2002,  4:  2071 

11a Jones RCF. Smallridge MJ. Tetrahedron Lett.  1988,  29:  5005 

11b Jones RCF. Patel P. Hirst SC. Smallridge MJ. Tetrahedron  1998,  54:  6191 

12a Capps NK. Davies GM. Loakes D. McCabe RW. Young DW. J. Chem. Soc., Perkin Trans. 1  1991,  3077 

12b Capps NK. Davies GM. Loakes D. Young DW. Tetrahedron  1992,  48:  10149 

13a Purkayastha ML. Chandrasekharam M. Ila H. Junjappa H. Indian J. Chem., Sect. B: Org. Chem. Incl. Med. Chem.  1991,  30:  646 

13b Davies GM. Hitchcock PB. Loakes D. Young DW. Tetrahedron Lett.  1996,  37:  5601 

13c Bhattia SH. Davies GM. Hitchcock PB. Loakes D. Young DW. J. Chem. Soc., Perkin Trans. 1  1999,  2449 

14 Chakrasali RT. Ila H. Junjappa H. Synthesis  1988,  87 

15 Chakrabarti S. Srivastava MC. Ila H. Junjappa H. Synlett  2003,  2369 

16a Dietz G. Fiedler W. Faust G. Chem. Ber.  1969,  102:  522 

16b Berry JM. Doyle PM. Young DW. Tetrahedron Lett.  2002,  49:  8963 

Stille explored the application of several acrylic acid derivatives in the aza-annulation of β-enamino esters and ketones:

17a Barta NC. Brode A. Stille JR. J. Am. Chem. Soc.  1994,  116:  6201 

17b Benovsky P. Stille JR. Tetrahedron Lett.  1997,  38:  8475 

For a review on this topic see:

17c Stille JR. Barta NS. In Studies in Natural Products Chemistry: Stereoselective Synthesis   Vol. 18:  . Elsevier; New York: 1996.  p.315-389  

18 Takayama H. Yamamoto R. Kurihara M. Kitajima M. Aimi N. Mao L. Sakai S.-i. Tetrahedron Lett.  1994,  35:  8813 

19 The spontaneous inflammation during the isolation of propiolic acid chloride was attributed to trace amounts of monochloroacetylene formed during destillation: Balfour WJ. Greig CC. Visaisouk S. J. Org. Chem.  1974,  39:  725 

20a Tominaga M. Tone H. Nakagawa K. Takada K. Hoshino Y. Watanabe K. Chem. Pharm. Bull.  1981,  29:  2166 

20b Beholz LG. Benovsky P. Ward DL. Barta NS. Stille JR. J. Org. Chem.  1997,  62:  1033 

21a Eilingsfeld H. Seefelder M. Weidinger H. Angew. Chem.  1960,  72:  836 

22b Sayre LM. Larson DL. Takemori AE. Portoghese PS. J. Med. Chem.  1984,  27:  1325 

22 Devos A. Remion J. Frisque-Hesbain A.-M. Colens A. Ghosez L. J. Chem. Soc., Chem. Commun.  1979,  1180