Catalytic Direct Asymmetric Michael Reactions: Addition of Unmodified Ketone and Aldehyde Donors to Alkylidene Malonates and Nitro Olefins

Abstract

The Michael additions of a number of ketones and aldehydes to alkylidene malonates and nitro olefins were studied. The reactions employ small organic molecules as catalyst under mild reaction conditions and do not require preactivation of the carbonyl donors. These reactions afforded a variety of highly functionalized products in good yields with moderate to good enantioselectivity.

Key words

asymmetric catalysis - Michael additions - organocatalysis - ketones - enamines

References

• 1a Comprehensive Asymmetric Catalysis   Vol. I-III:  Jacobsen EN. Pfaltz A. Yamamoto H. Springer; Berlin: 1999. 
• 1b Noyori R. Asymmetric Catalysis in Organic Synthesis   Wiley; New York: 1994. 
• 1c Ojima I. Catalytic Asymmetric Synthesis   Wiley-VCH; Weinheim: 1993. 
• 2a For an excellent review, see: Dalko PI. Moisan L. Angew. Chem. Int. Ed.  2001,  40:  3726 
• 2b See also: Jarvo ER. Miller SJ. Tetrahedron  2002,  58:  2481 
• 3 Perlmutter P. Conjugate Addition Reactions in Organic Synthesis   Pergamon Press; Oxford: 1992. 
• For recent reviews on catalytic asymmetric 1,4-addition, see:
• 4a Krause N. Hoffmann-Roder A. Synthesis  2001,  171 
• 4b Sibi MP. Manyem S. Tetrahedron  2000,  56:  8033 
• 4c Tomioka K. Nagaoka Y. In Comprehensive Asymmetric Catalysis   Vol. III:  Jacobsen EN. Pfaltz A. Yamamoto H. Springer; Berlin: 1999.  p.1105-1120  
• 4d Yamaguchi M. In Comprehensive Asymmetric Catalysis   Vol. III:  Jacobsen EN. Pfaltz A. Yamamoto H. Springer; Berlin: 1999.  p.1121-1139  
• 4e Kanai M. Shibasaki M. In Catalytic Asymmetric Synthesis   2nd ed.:  Ojima I. Wiley; New York: 2000.  p.569 
• 4f Berner OE. Tedeschi L. Enders D. Eur. J. Org. Chem.  2002,  1788 
• 5a Kim YS. Matsunaga S. Das J. Sekine A. Ohshima T. Shibasaki M. J. Am. Chem. Soc.  2000,  122:  6506 
• 5b Arai T. Sasai H. Aoe K. Okamura K. Date T. Shibasaki M. Angew. Chem., Int. Ed. Engl.  1996,  35:  104 
• 5c Hanessian S. Pham V. Org. Lett.  2000,  2:  2975 
• 5d Yamaguchi M. Shiraishi T. Hirama M. J. Org. Chem.  1996,  61:  3520 
• 5e Ji J. Barnes DM. Zhang J. King SA. Wittenberger SJ. Morton HE. J. Am. Chem. Soc.  1999,  121:  10215 
• 6a Yasuda K. Shindo M. Koga K. Tetrahedron Lett.  1996,  37:  6343 
• 6b Enders D. Demir AS. Rendenbach BEM. Chem. Ber.  1987,  120:  1731 
• 6c Martens J. Lubben S. Tetrahedron  1991,  47:  1205 
• 6d Blarer SJ. Seebach D. Chem. Ber.  1983,  116:  2250 
• 7 For a seminal reference, see: Stork G. Brizzolara A. Landesman H. Szmuszkovicz J. Terrell R. J. Am. Chem. Soc.  1963,  85:  207 
• For a general discussion of atom economy in organic synthesis, see:
• 8a Trost BM. Science  1991,  254:  1471 
• 8b Trost BM. Angew. Chem., Int. Ed. Engl.  1995,  34:  259 
• For previous work on Aldol reaction, see the following:
• 9a Mase N. Tanaka F. Barbas CF. Angew. Chem. Int. Ed.  2004,  43:  2420 
• 9b Cordova A. Notz W. Barbas CF. J. Org. Chem.  2002,  67:  301 
• 9c Sakthivel K. Notz W. Bui T. Barbas CF. J. Am. Chem. Soc.  2001,  123:  5260 
• 9d List B. Lerner R. Barbas CF. J. Am. Chem. Soc.  2000,  122:  2395 
• For previous work on Mannich reactions, see the following:
• 10a Chowdari NS. Ramachary DB. Barbas CF. Synlett  2003,  12:  1906 
• 10b Cordova A. Barbas CF. Tetrahedron Lett.  2003,  44:  1923 
• 10c Notz W. Tanaka F. Watanabe S.-I. Chowdari NS. Turner JM. Thayumanavan R. Barbas CF. J. Org. Chem.  2003,  68:  9624 
• 10d Watanabe S. Cordova A. Tanaka F. Barbas CF. Org. Lett.  2002,  4:  4519 
• 10e Cordova A. Barbas CF. Tetrahedron Lett.  2002,  43:  7749 
• 10f Cordova A. Notz W. Zhong G. Betancort JM. Barbas CF. J. Am. Chem. Soc.  2002,  124:  1866 
• 10g Cordova A. Watanabe S. Tanaka F. Notz W. Barbas CF. J. Am. Chem. Soc.  2002,  124:  1866 
• 10h Notz W. Sakthivel K. Bui T. Zhong G. Barbas CF. Tetrahedron Lett.  2001,  42:  199 
• 11 For previous work on Robinson annulations, see: Bui T. Barbas CF. Tetrahedron Lett.  2000,  41:  6951 
• For previous work on Diels-Alder reactions, see the following:
• 12a Thayumanavan R. Dhevalapally B. Sakthivel K. Tanaka F. Barbas CF. Tetrahedron Lett.  2002,  43:  3817 
• 12b Ramachary DB. Chowdari NS. Barbas CF. Tetrahedron Lett.  2002,  43:  6743 
• For previous work on multicomponent reactions, see the following:
• 13a Ramachary DB. Chowdari NS. Barbas CF. Synlett  2003,  12:  1910 
• 13b Chowdari NS. Ramachary DB. Barbas CF. Org. Lett.  2003,  5:  1685 
• 13c Chowdari NS. Ramachary DB. Cordova A. Barbas CF. Tetrahedron Lett.  2002,  43:  9591 
• For leading references on Aldol reactions, see the following:
• 14a Bogevig A. Kumaragurubaran N. Jorgensen KA. Chem. Commun.  2002,  620 
• 14b Northrup AB. MacMillan DWC. J. Am. Chem. Soc.  2002,  124:  6798 
• 15 For leading references on Mannich reactions, see: List B. Pojarliev P. Biller WT. Martin HJ. J. Am. Chem. Soc.  2002,  124:  827 
• For leading references on Michael reactions, see the following:
• 16a Halland N. Hansen T. Jørgensen KA. Angew. Chem. Int. Ed.  2003,  42:  4955 
• 16b Enders D. Seki A. Synlett  2002,  26 
• 16c Halland N. Hazell RG. Jorgensen KA. J. Org. Chem.  2002,  67:  8331 
• 16d Horstmann TE. Guerin DJ. Miller SJ. Angew. Chem. Int. Ed.  2000,  39:  3635 
• For leading references on Diels-Alder reactions, see the following:
• 17a Northrup AB. MacMillan DWC. J. Am. Chem. Soc.  2002,  124:  2458 
• 17b Ahrendt KA. Borths CJ. MacMillan DWC. J. Am. Chem. Soc.  2000,  122:  4243 
• For leading references on α-aminations, see the following:
• 18a Bogevig A. Juhl K. Kumaragurubaran N. Zhuang W. Jorgensen KA. Angew. Chem. Int. Ed.  2002,  41:  1790 
• 18b List B. J. Am. Chem. Soc.  2002,  124:  5656 
• For leading references on α-oxidation reactions, see the following:
• 19a Zhong G. Angew. Chem. Int. Ed.  2003,  42:  4247 
• 19b Brown SP. Brochu MP. Sinz CJ. MacMillan DWC. J. Am. Chem. Soc.  2003,  125:  10808 
• For leading references on α-chlorination reactions, see the following:
• 20a Halland N. Braunton A. Bachmann S. Marigo M. Jorgensen KA. J. Am. Chem. Soc.  2004,  126:  4790 
• 20b Brochu MP. Brown SP. MacMillan DWC. J. Am. Chem. Soc.  2004,  126:  4108 
• 21 For leading references on 1,3-dipolar cycloadditions, see: Jan WS. Wiener JJM. MacMillan DWC. J. Am. Chem. Soc.  2000,  122:  9874 
• Portions of this work have been communicated:
• 22a Betancort JM. Sakthivel K. Thayumanavan R. Barbas CF. Tetrahedron Lett.  2001,  42:  4441 
• 22b Betancort JM. Barbas CF. Org. Lett.  2001,  3:  3737 
• 23a Herrman K. Wynberg H. J. Org. Chem.  1979,  44:  2238 
• 23b Latvala A. Stanchev S. Linden A. Hesse M. Tetrahedron: Asymmetry  1993,  4:  173 
• 24 Diamines were prepared according to the method of Asami: Asami M. Bull. Chem. Soc. Jpn.  1990,  63:  721 
• 25 The use of amines as catalysts for the asymmetric aldol reaction see refs 9c, 11 and: Saito S. Nakadai M. Yamamoto H. Synlett  2001,  8:  1245 
• 26a Andrey O. Alexakis A. Bernardinelli G. Org. Lett.  2003,  5:  2559 
• 26b Andrey O. Vidonne A. Alexakis A. Tetrahedron Lett.  2003,  44:  7901 
• 26c Alexakis A. Andrey O. Org. Lett.  2002,  4:  3611 
• 27 In this case we opted for the preparation of the dibenzyl derivatives since the aryl group provided a better chromophore for chiral-phase HPLC determination of the enantiomeric excess
• 28 For a non-stereoselective version employing l-proline as catalyst, see: List B. Castello C. Synlett  2001,  11:  1687 
• 29a Krapcho AP. Synthesis  1982,  805 
• 29b Tomioka K. Yasuda K. Koga K. Tetrahedron Lett.  1986,  27:  4611 
• 30 For a review on stereoselective additions to nitroalkenes, see: Pyne SG. In Stereoselective Synthesis, Methods of Organic Chemistry (Houben-Weyl)   E21 ed., Vol. IV:  Helmchen G. Hoffmann RW. Mulzer J. Schaumann E. Thieme; Stuttgart: 1996.  p.2161-2176  
• 31 See, for example: Ono N. The Nitro Group in Organic Synthesis   Wiley-VCH; New York: 2001. 
• For Alexakis’s later studies employing chiral diamines, see ref. 26c. For a recent example of addition of naked aldehydes to electron-deficient olefins in a non-enantioselective manner, see:
• 32a Hagiwara H. Okabe T. Hakoda K. Hoshi T. Ono H. Kamat VP. Suzuki T. Ando M. Tetrahedron Lett.  2001,  42:  2705 
• 32b Hagiwara H. Komatsubara N. Ono H. Okabe T. Hoshi T. Suzuki T. Ando M. Kato M. J. Chem. Soc., Perkin Trans. 1  2001,  316 
• 33a O’Hagan D. Nat. Prod. Rep.  2000,  17:  435 
• 33b Numata A. Ibuka T. In The Alkaloids   Vol. 31:  Brossi A. Academic Press; New York: 1987.  Chap. 6.
• 33c Massiot G. Delaude C. In The Alkaloids   Vol. 27:  Brossi A. Academic Press; New York: 1986.  Chap. 3.
• 34a Ling R. Ekhato IV. Rubin JR. Wustrow DJ. Tetrahedron  2001,  57:  6579 
• 34b Karlsson S. Han F. Hogberg H.-E. Caldirola P. Tetrahedron: Asymmetry  1999,  10:  2605 
• 34c Denmark SE. Marcin LR. J. Org. Chem.  1995,  60:  3221 ; and references cited therein
• 36a Seebach D. Golinski J. Helv. Chim. Acta  1981,  64:  1413 
• 36b Blarer SJ. Schweizer WB. Seebach D. Helv. Chim. Acta  1982,  65:  1637 
• 36c Blarer SJ. Seebach D. Chem. Ber.  1983,  116:  3086 
• 36d Haner R. Laube T. Seebach D. Chimia  1984,  38:  255 
• 36e Seebach D. Beck AK. Golinski J. Hay JN. Laube T. Helv. Chim. Acta  1985,  68:  162 
• 36f Seebach D. Brook MA. Helv. Chim. Acta  1985,  68:  319 
• For theoretical studies of the reaction of chiral enamines to electrophilic olefins, see:
• 37a Sevin A. Masure D. Giessner-Prettre C. Pfau M. Helv. Chim. Acta  1990,  73:  552 
• 37b Lucero MJ. Houk KN. J. Am. Chem. Soc.  1997,  119:  826 ; and references cited therein
• 38 Enders D. Demir AS. Rendenbach BEM. Chem. Ber.  1987,  120:  1731 
• 39 Yamaguchi M. Shiraishi T. Hirama M. J. Org. Chem.  1996,  61:  3520 
• 40 Blarer SJ. Seebach D. Chem Ber.  1983,  116:  2250 
• 41 Schionato A. Paganelli S. Botteghi C. Chelucci G. J. Mol. Catal.  1989,  50:  11 
• 42 Yamamoto Y. Nishii S. J. Org. Chem.  1988,  53:  3597 
• 43 Blarer SJ. Schweizer WB. Seebach D. Helv. Chim. Acta  1982,  65:  1637 

35

When (S)-1-(2-pyrrolidinylmethyl)pyrrolidine and 2,4-pentanedione are mixed in equimolar amounts in DMSO, enamine formation is detected through UV spectroscopy. Furthermore, while pyrrolidine itself promotes the Michael reaction, the N-methyl derivative, which lacks the secondary amine is ineffective as catalyst. Alexakis et al. have also reported detection of enamine intermediates by GC-MS. See ref. 26c.