A New Multicomponent Domino Transformation of 1,3-Dicarbonyl Compounds: One-Pot Regio-, Chemo- and Stereoselective Access to Valuable α,γ-Difunctionalized α-Ketoesters and Amides

Abstract

A new multi-component transformation between 1,3-dicarbonyls 1, aldehydes 2, and allylic, propargylic or benzylic halides 3 is described. It provides a regio-, chemo- and stereoselective one-pot access to α,γ-difunctionalized α-ketoesters and amides 4, bearing a quaternary center valuable for further synthetic transformations via ring-closing metathesis to give azaspiro systems found in bioactive natural products.

multi-component reaction - β-ketoesters - β-ketoamides - α,γ-difunctionalization - azaspiro derivatives

References

1 Strecker A. Liebigs Ann. Chem.  1850,  75:  27 

For reviews on M-CRs, see:

2a Posner GH. Chem. Rev.  1986,  86:  831 

2b Armstrong RW. Combs AP. Tempest PA. Brown SD. Keating TA. Acc. Chem. Res.  1996,  29:  123 

2c Tietze LF. Lieb M. Curr. Opin. Chem. Biol.  1998,  2:  363 

2d Dax SL. McNally JJ. Youngman MA. Curr. Med. Chem.  1999,  6:  255 

2e Tietze LF. Modi A. Med. Res. Rev.  2000,  20:  304 

2f Bienaymé H. Hulme C. Oddon G. Schmitt P. Chem.-Eur. J.  2000,  6:  3321 

2g Dömling A. Ugi I. Angew. Chem. Int. Ed.  2000,  39:  3168 

3 Nefzi A. Ostresh JM. Houghten RA. Chem. Rev.  1997,  97:  449 

4 Weber L. Illgen K. Almstetter M. Synlett  1999,  366 

5 Simon C. Peyronel JF. Rodriguez J. Org. Lett.  2001,  3:  2145 

6a Hantzsch A. Liebigs Ann. Chem.  1882,  215:  1 

6b Hantzsch A. Ber. Dtsch. Chem. Ges.  1890,  23:  1474 

6c For a recent example of pyrroles synthesis using M-CRs, see: Ranu BC. Hajra A. Jana U. Synlett  2000,  75 

6d Biginelli P. Ber. Dtsch. Chem. Ges.  1891,  24:  2962 

6e For a recent account, see: Kappe CO. Acc. Chem. Res.  2000,  33:  879 

6f Robinson R. J. Chem. Soc.  1917,  111:  762 

6g Schöpf C. Angew. Chem.  1937,  50:  779 

6h Schöpf C. Angew. Chem.  1937,  50:  797 

6i For a more recent utilization, see: List B. J. Am. Chem. Soc.  2000,  122:  9336 

6j Tietze LF. Hippe T. Steinmetz A. Synlett  1996,  1043 

6k Tietze LF. Chem. Rev.  1996,  96:  115 

6l Tietze LF. Evers H. Töpken E. Angew. Chem. Int. Ed.  2001,  40:  903 

7a Hauser CR. Hudson BE. Org. React.  1942,  1:  266 

7b Hauser CR. Harris TM. J. Am. Chem. Soc.  1958,  80:  6360 

8a Thompson CM. Green DLC. Tetrahedron  1991,  47:  4223 

8b Thompson CM. Dianion Chemistry in Organic Synthesis   CRC Press Inc.; Boca Raton: 1994. 

8c Moreno-Mañas M. Marquet J. Vallribera A. Tetrahedron  1996,  52:  3377 

9 For a comprehensive review on synthetic utilizations of β-ketoesters, see: Benetti S. Romagnoli R. De Risi C. Spalluto G. Zanirato V. Chem. Rev.  1995,  95:  1065 

For a recent account, see:

10a Rodriguez J. Synlett  1999,  505 

10b Lavoisier-Gallo T. Charonnet E. Pons JM. Rajzman M. Faure R. Rodriguez J. Chem.-Eur. J.  2001,  7:  1056 

11 Charonnet E. Filippini MH. Rodriguez J. Synthesis  2001,  788 

For some important bioactive azaspiro compounds, see:

12a Commins DL. Zhang YM. Zheng X. Chem. Commun.  1998,  2509 

12b François D. Lallemand MC. Selkti M. Tomas A. Kunesh M. Husson HP. Angew. Chem. Int. Ed.  1998,  37:  104 

12c Williams GM. Roughley SD. Davies JE. Holmes AB. J. Am. Chem. Soc.  1999,  121:  4900 

12d Tsujimoto T. Ishihara J. Horie M. Murai A. Synlett  2002,  399 

12e Ishihara J. Horie M. Shimada Y. Tojo S. Murai A. Synlett  2002,  403 

For selected references, see:

13a Abdulla RF. Fuhr KF. J. Org. Chem.  1978,  43:  4248 

13b Corey EJ. Mehrotra MM. J. Am. Chem. Soc.  1984,  106:  3384 

13c Sasai H. Shibasaki M. Tetrahedron Lett.  1987,  28:  333 

13d Jung ME. Pan YC. Hart MW. Nat. Prod. Rep.  1988,  1 

13e Iwasaki G. Sano M. Sodeoka M. Yoshida K. Shibasaki M. J. Org. Chem.  1988,  53:  4864 

14 Deli J. Lorand T. Szabo D. Földesi A. Pharmazie  1984,  39:  539 

15a Tyndall DV. Al Nakib T. Meegan MJ. Tetrahedron Lett.  1988,  29:  2703 

15b Huang C.-Y. Cabell LA. Anslyn EV. J. Am. Chem. Soc.  1994,  116:  2778 

16 Sayed HH. Indian J. Chem., Sect. B  1998,  37:  1054 

17 Popkov SV. Kovalenko LV. Tashchi VP. Bogel’fer LY. Russ. Chem. Bull.  1994,  43:  1363 ; Izv. Akad. Nauk., Ser. Khim.; 1994, 8, 1439

18 Koch K. Smitrovich JH. Tetrahedron Lett.  1994,  35:  1137 

19 Varma RS. Kumar D. Synthesis  1999,  1288 

20

General Experimental Procedure: To a solution of 1,3-dicarbonyl 1 (1 mmol) and DBU (3 mmol) in dry THF (8 mL) containing 10% dry MeOH in the case of β-ketoesters and MeOH alone (8 mL) in the case of β-ketoamides was added the corresponding aldehyde 2 (1 mmol) and halide 3 (2 mmol). The resulting solution was stirred under nitrogen at r.t. or under reflux for the indicated time (Table [1] ). After completion and evaporation of most of the solvent under reduced pressure, water (50 mL) was added to the oily residue. Extraction with Et₂O (3 × 40 mL) followed by successive washing with distilled water (2 × 20 mL) and brine (20 mL) gave, after drying (MgSO₄) and evaporation of the solvent, the crude compounds which were purified by flash chromatography on silica gel.

21 Filippini MH. Rodriguez J. Synth. Commun.  1995,  25:  245 

22a Crandall JK. Arrington JP. Hen J. J. Am. Chem. Soc.  1967,  89:  6208 

22b Nakano T. Irifune S. Umano S. Inada A. Ishii Y. Ogawa M. J. Org. Chem.  1987,  52:  2239 

23

All new compounds showed correct mass spectra or elemental analyses (C, H, N); for example, 4d: yellow crystals, mp 52-54 °C, R_f = 0.55 (Et₂O/pentane, 30/70). IR(neat): ν = 2923, 1734, 1706, 1617, 1430, 1265 cm^-1. ¹H NMR (200 MHz, CDCl₃): δ = 2.01 (m, 1 H), 2.54 (dd, broad, J = 13.6, 7.1 Hz, 1 H), 2.64 (m, 1 H), 2.86 (dd, broad, J = 13.6, 7.2 Hz, 1 H), 3.03 (m, 2 H), 3.74 (s, 3 H), 5.15 (m, 2 H), 5.73 (m, 1 H), 6.56 (dd, J = 3.4, 1.8 Hz, 1 H), 6.74 (d, J = 3.4 Hz, 1 H), 7.28 (t, J = 3.2 Hz, 1 H), 7.62 (d, J = 1.4 Hz, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 26.7, 29.5, 39.0, 53.0, 60.9, 113.1, 117.3, 119.3, 121.5, 132.8, 133.6, 145.8, 152.5, 171.9, 172.2, 202.8. Anal. Calcd for C₁₅H₁₆O₄: C, 69.22; H, 6.20. Found: C, 68.98; H, 6.21.

For efficient preparations from the corresponding ketoesters, see:

24a Cossy J. Thellend A. Synthesis  1989,  753 

24b Mottet C. Hamelin O. Garavel G. Deprés JP. Greene AE. J. Org. Chem.  1999,  64:  1380 

24c Ponde DE. Deshpande VH. Bulbule VJ. Sudalai A. Gajare AS. J. Org. Chem.  1998,  63:  1058 

25a Pearson RG. Dillon RL. J. Am. Chem. Soc.  1953,  75:  2439 

25b Evans DA. Ennis MD. Le T. J. Am. Chem. Soc.  1984,  106:  1154 

25c Hoffman RV. Huizenga DJ. J. Org. Chem.  1991,  56:  6435 

See inter alia:

26a Cossy J. Bouzide A. Tetrahedron  1997,  53:  5775 

26b Moya P. Cantin A. Castillo M.-A. Primo J. Miranda MA. Primo-Yufera E. J. Org. Chem.  1998,  63:  8530 

26c Nair V. Sheeba V. J. Org. Chem.  1999,  64:  6898 

27 Babudri F. Ciminale F. Di Nunno L. Florio S. Tetrahedron  1982,  38:  557 

28a Snider BB. Zhang Q. Tetrahedron Lett.  1992,  33:  5921 

28b

For our own recent contribution with cyclic ketoamides, see: ref. [11]

28c For related γ-functionalization of chiral β-ketoimides and their important synthetic applications, see inter alia: Evans DA. Kim AS. Metternich R. Novack VJ. J. Am. Chem. Soc.  1998,  120:  5921 ; and references cited therein

29 Takada N. Umemura N. Suenaga K. Chou T. Nagatsu A. Haino T. Yamada K. Uemura D. Tetrahedron Lett.  2001,  42:  3491 

30 Takada N. Umemura N. Suenaga K. Uemura D. Tetrahedron Lett.  2001,  42:  3495 

For other recent related RCM approaches to azaspiro compounds, see inter alia:

31a Faure S. Piva-Leblanc S. Piva O. Tetrahedron Lett.  1999,  40:  6001 

31b Wallace DJ. Goodman JM. Kennedy DJ. Davies AJ. Cowden CJ. Ashwood MS. Cottrell IF. Dolling UH. Reider P. Org. Lett.  2001,  3:  671 

31c Hughes RC. Dvorak CA. Meyers AI. J. Org. Chem.  2001,  66:  5545