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DOI: 10.1055/s-2001-12762
Novel DBU-MeOH-Promoted One-Pot Stereoselective γ-Functionalization of 1,3-Dicarbonyls: An Easy Access to γ-Arylidene, γ-Alkylidene and γ-Allylidene α-Ketoesters and -amides
Publikationsverlauf
Publikationsdatum:
28. September 2004 (online)
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Abstract
Cyclic β-ketoesters and β-ketoamides undergo, in a one-pot process, an unprecedented DBU-MeOH-promoted regio- and stereoselective γ-functionalization with aldehydes, by a directed γ-aldol reaction and dehydration sequence, to afford synthetically valuable alkylidene (or arylidene) cycloalkanones in good yields. While β-ketoesters give good results only with aromatic aldehydes, β-ketoamides react smoothly either with aromatic, aliphatic, or α,β-unsaturated aldehydes following a totally regioselective 1,2-addition. The overall sequence, probably initiated by a reversible α-aldol reaction, allows the formation of hitherto unknown and stereodefined γ-functionalized cycloalkanones having three reactive centers, such as two electrophilic and one nucleophilic site.
Key words
β-ketoesters - β-ketoamides - γ-functionalization - aldol reaction - alkylidene (or arylidene) cycloalkanones
-
1a
Hauser CR.Hudson BE. Jr. Org. React. 1942, 1: 266 -
1b
Hauser CR.Harris TM. J. Am. Chem. Soc. 1958, 80: 6360 -
2a
Thompson CM.Green DLC. Tetrahedron 1991, 47: 4223 -
2b
Thompson CM. Dianion Chemistry in Organic Synthesis CRC Press Inc.; Boca Raton: 1994. -
2c
Moreno-Mañas M.Marquet J.Vallribera A. Tetrahedron 1996, 52: 3377 - 3 For a recent review on the chemistry of β-ketoesters, see:
Benetti S.Romagnoli R.DeRisi C.Spalluto G.Zanirato V. Chem. Rev. 1995, 95: 1065 -
4a
Filippini M.-H.Faure R.Rodriguez J. J. Org. Chem. 1995, 60: 6872 -
4b
Filippini M.-H.Rodriguez J. J. Org. Chem. 1997, 62: 3034 -
4c For a recent account, see:
Rodriguez J. Synlett 1999, 505 - For recent α,γ-difunctionalizations of 1,3-dicarbonyl derivatives leading to cyclic compounds, see:
-
5a
Edafiogho IO.Hinko CN.Chang H.Moore JA.Mulzac D.Nicholson JM.Scott KR. J. Med. Chem. 1992, 35: 2798 -
5b
Chong B.-D.Ji Y.-I.Oh S.-S.Yang J.-D.Baik W.Koo S. J. Org. Chem. 1997, 62: 9323 -
5c
Yang J.-D.Kim M.-S.Baik W.Koo S. Synthesis 2000, 801 -
5d
Dyker G.Thöne A. Tetrahedron 2000, 56: 8669 - For γ-alkylation of β-ketoesters via their enamine derivatives, see:
-
6a
Gravel D.Labelle M. Can. J. Chem. 1985, 63: 1874 -
6b For γ-acylation of 1,3-diacarbonyls via their bis(trimethylsiloxy)-1,3-diene derivatives, see:
Langer P.Schneider T. Synlett 2000, 497 -
7a
Harris TM.Harris CM. Org. React. 1969, 17: 155 -
7b
Kaiser EM.Petty JD.Knutson PLA. Synthesis 1977, 509 -
7c
Thompson CM.Green DLC. Tetrahedron 1991, 47: 4223 -
7d
Thompson CM. Dianion Chemistry in Organic Synthesis CRC Press Inc.; Boca Raton: 1994. -
7e For recent synthetic application of the selective γ-alkylation, see:
Lygo B. Synlett 1993, 764 -
7f
Nakada M.Iwata Y.Takano M. Tetrahedron Lett. 1999, 40: 9077 -
7g
Langer P.Freifeld I.Holtz E. Synlett 2000, 501 -
7h
Langer P.Karimé I. Synlett 2000, 743 -
8a
Huckin SN.Weiler L. J. Am. Chem. Soc. 1974, 96: 1082 -
8b
Caine D. Comprehensive Organic SynthesisTrost BM.Fleming I. Pergamon Press; Oxford: 1991. Vol. 3: Chap. 1.1. - Computer-assisted structural search on REACS or Beilstein databases gave no answer. See also:
-
9a
Trost BM. Comprehensive Organic SynthesisTrost BM.Fleming I. Pergamon Press; Oxford: 1991. Vol. 3: Chap 1.1. -
9b
Trost BM. Comprehensive Organic SynthesisTrost BM.Fleming I. Pergamon Press; Oxford: 1991. Vol. 3: Chap. 1.6 and 3.6. - For a comprehensive review on the directed aldol reaction, see:
-
10a
Mukaiyama T. Org. React. 1982, 28: 203 -
10b For general references on the Knoevenagel reaction, which can be regarded as an α-aldol-dehydration sequence, see:
Jones G. Org. React. 1967, 15: 204 -
10c
Tietze LF.Beifuss U. In Comprehensive Organic SynthesisTrost BM.Fleming I. Pergamon Press; Oxford: 1991. 341. -
10d See also:
Sqbal J.Srivastava RR. Tetrahedron Lett. 1991, 32: 1663 -
11a
Bonini C.Racioppi R.Righi G.Viggiani L. J. Org. Chem. 1993, 58: 802 -
11b For a recent synthetic application of a similar γ-aldolization/dehydration sequence, using acetyl acetone, see:
Haddad N.Rukhman I.Abramovich Z. J. Org. Chem. 1997, 62: 7629 -
12a
Huckin SN.Weiler L. Can. J. Chem. 1974, 52: 2157 -
12b
Spino C.Tu N. Tetrahedron Lett. 1994, 35: 3683 - 13
Trost BM.Kunz RA. J. Org. Chem. 1974, 39: 2648 -
14a
Bodalski R.Pietrusiewicz KM.Monkiewicz J.Koszuk J. Tetrahedron Lett. 1980, 21: 2287 -
14b
van der Goorbergh JAM.van der Gen A. Tetrahedron Lett. 1980, 21: 3621 -
14c
Ley SV.Woodward PR. Tetrahedron Lett. 1987, 28: 345 -
15a
Zibuck R. In Encyclopedia of Reagents for Organic SynthesisPaquette LA. John Wiley; New York: 1995. 3558. -
15b For some selected synthetic transformations, see:
Cooke MP. Jr.Jaw J.-Y. Synth. Commun. 1992, 22: 2213 -
15c
Dodd DS.Oehlschlager AC.Georgopapadakou NH.Polak A.-M.Hartman PG. J. Org. Chem. 1992, 57: 7226 -
15d
Banwell MG.Cameron JM. Tetrahedron Lett. 1996, 37: 525 - 16
Moorhoff CM.Schneider DF. Tetrahedron Lett. 1987, 28: 559 -
17a For preliminary results with cyclic β-ketoesters, see:
Filippini MH.Rodriguez J. Chem. Commun. 1995, 33 -
17b It has been shown that formaldehyde and other substituted aldehydes reacted selectively at the α-position of cyclic and acyclic 1,3-dicarbonyls to give, after a deacylative condensation, α,β-unsaturated compounds:
Ksander GM.McMurry JE.Johnson M. J. Org. Chem. 1977, 42: 1180 -
17c
Tsuboi S.Uno T.Takeda A. Chem. Lett. 1978, 1325 -
17d
Ueno Y.Setoi H.Okawara M. Tetrahedron Lett. 1978, 3753 -
17e
Queignec R.Kirschleger B.Lambert F.Aboutaj M. Synth. Commun. 1988, 18: 1213 -
17f
Ben Ayed T.Amri H. Synth. Commun. 1995, 25: 3813 - For selected references, see:
-
18a
Abdulla RF.Fuhr KF. J. Org. Chem. 1978, 43: 4248 -
18b
Corey EJ.Mehrotra MM. J. Am. Chem. Soc. 1984, 106: 3384 -
18c
Sasai H.Shibasaki M. Tetrahedron Lett. 1987, 28: 333 -
18d
Jung ME.Pan YC.Hart MW. Nat. Prod. Rep. 1988, 1 -
18e
Iwasaki G.Sano M.Sodeoka M.Yoshida K.Shibasaki M. J. Org. Chem. 1988, 53: 4864 - 19
Deli J.Lorand T.Szabo D.Földesi A. Pharmazie 1984, 39: 539 -
20a
Tyndall DV.Al Nakib T.Meegan MJ. Tetrahedron Lett. 1988, 29: 2703 -
20b
Huang C.-Y.Cabell LA.Anslyn EV. J. Am. Chem. Soc. 1994, 116: 2778 - 21
Sayed HH. Indian J. Chem., Sect. B 1998, 37: 1054 - 22
Popkov SV.Kovalenko LV.Tashchi VP.Bogel’fer LY. Russ. Chem. Bull. 1994, 43: 1363 - 23
Koch K.Smitrovich JH. Tetrahedron Lett. 1994, 35: 1137 - 24
Varma RS.Kumar D. Synthesis 1999, 1288 -
25a
Pearson RG.Dillon RL. J. Am. Chem. Soc. 1953, 75: 2439 -
25b
See also ref. 27a and 32b for discussions on pKa.
- 26
Moya P.Cantin A.Castillo MA.Primo J.Miranda MA.Primo-Yufera E. J. Org. Chem. 1998, 63: 8530 -
27a
Hoffman RV.Huizenga DJ. J. Org. Chem. 1991, 56: 6435 -
27b
Schultz AG.Holoboski MA. Tetrahedron Lett. 1993, 34: 5885 -
27c
Nair V.Sheeba V. J. Org. Chem. 1999, 64: 6898 -
28a
DeShong P.Lowmaster NE.Baralt O. J. Org. Chem. 1983, 48: 1149 -
28b
Schlessinger RH.Bebernitz GR.Lin P.Poss AJ. J. Am. Chem. Soc. 1985, 107: 1777 -
29a
Cossy J.Leblanc C. Tetrahedron Lett. 1989, 31: 4531 -
29b
Cossy J.Thellend A. Tetrahedron Lett. 1990, 31: 1427 -
29c
Meyer C.Piva O.Pete J.-P. Tetrahedron Lett. 1996, 37: 5885 -
29d
Cossy J.Bouzide A. Tetrahedron 1997, 53: 5775 - 30
Snider BB.Zhang Q. Tetrahedron Lett. 1992, 33: 5921 - 31
Babudri F.Ciminale F.DiNunno L.Florio S. Tetrahedron 1982, 38: 557 - For our preliminary results with cyclic β-ketoamides, see:
-
32a
Charonnet E.Filippini M.-H.Rodriguez J. Synlett 1999, 1951 -
32b For related γ-functionalization of chiral β-ketoimides and their important synthetic applications, see:
Evans DA.Ennis MD.Le T. J. Am. Chem. Soc. 1984, 106: 1154 -
32c
Evans DA.DiMare M. J. Am. Chem. Soc. 1986, 108: 2476 -
32d
Evans DA.Sheppard GS. J. Org. Chem. 1990, 55: 5192 -
32e
Evans DA.Ratz AM.Huff BE.Sheppard GS. J. Am. Chem. Soc. 1995, 117: 3448 -
32f
Evans DA.Kim AS.Metternich R.Novack VJ. J. Am. Chem. Soc. 1998, 120: 5921 -
33a
Fillipini M.-H.Rodriguez J. Synth. Commun. 1995, 25: 245 -
33b
We have also shown that treating 1d with 1 equiv DBU in refluxing MeOH for 48 h or stirring at r. t. for 3 d gave the open chain ketoamide 11 (Figure 2).
-
34a
Crandall JK.Arrington JP.Hen J. J. Am. Chem. Soc. 1967, 89: 6208 -
34b
Nakano T.Irifune S.Umano S.Inada A.Ishii Y.Ogawa M. J. Org. Chem. 1987, 52: 2239 - For efficient preparations from the corresponding ketoesters, see:
-
37a
Cossy J.Thellend A. Synthesis 1989, 753 -
37b
Mottet C.Hamelin O.Garavel G.Deprés JP.Greene AE. J. Org. Chem. 1999, 64: 1380 -
37c
Ponde DE.Deshpande VH.Bulbule VJ.Sudalai A.Gajare AS. J. Org. Chem. 1998, 63: 1058 -
38a
Cossy J.Bouzide A.Pfau M. J. Org. Chem. 1997, 62: 7106 and references cited therein -
38b
Cossy J.Bouzide A.Leblanc C. J. Org. Chem. 2000, 65: 7257 - 39
Carey FA.Sundberg RJ. Advanced Organic Chemistry, Part B Plenum Press; 1977. 3. An alternative mechanism involving the formation of the corresponding dianion, which is known to react selectively at the γ-position with various electrophiles,7,8,11,12 cannot be ruled out totally, although it can hardly be accommodated with the protic medium and with the fact that a substoichiometric amount of DBU is sufficient for the transformation to occur (vide supra) - For regioselective aldolization at the less hindered site in alkyl substituted unsymmetrical ketones via equilibration of their potassium enolates, see:
-
40a
Quesnel Y.Bidois-Sery L.Poirier J.-M.Duhamel L. J. Org. Chem. 1998, 63: 3793 -
40b
Duhamel P.Cahard D.Quesnel Y.Poirier J.-M. J. Org. Chem. 1996, 61: 2232 - 41
Habi H.Gravel D. Tetrahedron Lett. 1994, 35: 4315 - 42
Heilbron I.Jones ERH.Richardson RW.Sondheimer F. J. Am. Chem. Soc. 1949, 71: 737 - 43
Black GP.Dinon F.Fratucello S.Murphy PJ.Nielsen M.Williams HL.Walshe NDA. Tetrahedron Lett. 1997, 38: 8561 - 45
Still WC.Hahn M.Mitra A. J. Org. Chem. 1978, 43: 2923 - 46
Marx JN.Norman LR. J. Org. Chem. 1975, 40: 1602
References
While 1c was totally unreactive, 1a gave methyl adipate resulting from a retro-Dieckmann ring cleavage, see ref. 33.
36The dimethoxy acetal function resulted from a trans-acetalization of the ethoxy enol ether under the reaction conditions. Methyl adipate (35 %) resulting from a retro-Dieckmann ring cleavage of 1a was also formed.
44Attempts to extend the Robinson annulation using various experimental conditions including the use of MeONa+-MeOH, K2CO3-MeOH or acetone, and pyrrolidine in refluxing benzene or toluene, were unsuccessful due to the retro-Michael reaction.