Subscribe to RSS
DOI: 10.1055/s-2006-926259
Michael-Induced Ring Closure to 2-Azidocyclopropane-1,1-dicarboxylates and their Staudinger Reduction to 5-Alkoxy-3-(alkoxycarbonyl)pyrrolidin-2-ones
Publication History
Publication Date:
06 February 2006 (online)
![](https://www.thieme-connect.de/media/synlett/200603/lookinside/thumbnails/10.1055-s-2006-926259-1.jpg)
Abstract
An easy and short synthesis of new β-azidocyclopropanedicarboxylates, a rather unexplored class of conformationally constrained N-protected β-aminocyclopropanecarboxylic acid derivatives, is described. Michael-induced ring closure (MIRC) of sodium azide to 2-bromoalkylidenemalonates in alcoholic solvents leads to 3,3-dialkyl-2-azidocyclopropane-1,1-dicarboxylates, whereas other polar solvents give increasing amounts of competitive 2-azidoalkylidenemalonates. The reactivity of the azidocyclopropanes was investigated under reducing conditions, giving an easy access to diastereomeric mixtures of 5-alkoxy-3-(alkoxycarbonyl)pyrrolidin-2-ones.
Key words
Michael-induced ring closure - cyclopropanes - β-azido acids - Staudinger reduction - ring expansion
- 1
Gnad F.Reiser O. Chem. Rev. 2003, 103: 1603 -
2a
Reissig HU.Zimmer R. Chem. Rev. 2003, 103: 1151 -
2b
Reissig HU. Top. Curr. Chem. 1988, 144: 73 -
2c
Yu M.Pagenkopf BL. Tetrahedron 2005, 61: 321 -
3a
Horikawa H.Nishitani T.Iwasaki T.Inoue I. Tetrahedron Lett. 1983, 24: 2193 -
3b
El Abdioui K.Martinez J.Viallefont P.Vidal Y. Bull. Soc. Chim. Belg. 1997, 106: 425 -
3c
Papageorgiou CD.Cubillo de Dios MA.Ley SV.Gaunt MJ. Angew. Chem. Int. Ed. 2004, 43: 4641 -
3d
Adams LA.Charmant JPH.Cox RJ.Walter M.Whittingham WG. Org. Biomol. Chem. 2004, 2: 542 -
3e
Adams LA.Cox RJ.Gibson JS.Mayo-Martín MB.Walter M.Whittingham W. Chem. Commun. 2002, 2004 -
3f
Jiménez JM.Rifé J.Ortuño RM. Tetrahedron: Asymmetry 1995, 6: 1849 -
3g
Jiménez JM.Rifé J.Ortuño RM. Tetrahedron: Asymmetry 1996, 7: 537 -
3h
Yamazaki S.Inoue T.Hamada T.Takada T.Yamamoto K. J. Org. Chem. 1999, 64: 282 -
3i
Wick L.Tamm C.Boller T. Helv. Chim. Acta 1995, 78: 403 -
4a
Bubert C.Voigt J.Biasetton S.Reiser O. Synlett 1994, 675 -
4b
Bubert C.Cabrele C.Reiser O. Synlett 1997, 827 -
4c
Maas G.Müller A. J. Prakt. Chem. 1998, 340: 315 -
5a
Geen GR.Kincey PM.Choudary BM. Tetrahedron Lett. 1992, 33: 4609 -
5b
Geen GR.Harnden MR.Parratt MJ. Bioorg. Med. Chem. Lett. 1991, 1: 347 -
5c
Geen GR,Grinter TJ, andMoore S. inventors; Eur. Pat. Appl. EP 420559. ; Chem. Abstr. 1991, 115, 28993 -
5d
Hayashi T,Yasuoka J, andNishikawa J. inventors; Jpn. Kokai Tokkyo Koho JP 2000327593. ; Chem. Abstr. 2000, 133, 362933 -
5e
Hayashi T,Yasuoka J, andNishiura A. inventors; Eur. Pat. Appl. EP 916674. ; Chem. Abstr. 1999, 131, 5268 -
5f
Kim HS.Barak D.Harden TK.Boyer JL.Jacobson KA. J. Med. Chem. 2001, 44: 3092 - 6
Su Q.Wood JL. Synth. Commun. 2000, 30: 3383 -
7a
Trukhin EV.Makarenko SV.Berestovitskaya VM. Russ. J. Org. Chem. 1998, 34: 59 ; Chem. Abstr. 1998, 130, 3661 -
7b
Villemin D.Thibault-Starzyk F.Hachemi M. Synth. Commun. 1994, 24: 1425 -
7c
Le Menn JC.Tallec A.Sarrazin J. Can. J. Chem. 1991, 69: 761 -
7d
Sopova AS.Bakova OV.Metelkina EL.Perekalin VV. Zh. Org. Khim. 1975, 11: 68 ; Chem. Abstr. 1975, 83, 9406 -
7e
Sopova AS.Yurchenko OI.Perekalin VV. Zh. Obshch. Khim. 1965, 1: 1707 ; Chem. Abstr. 1966, 64, 3726 -
7f
Kohler EP.Darling SF. J. Am. Chem. Soc. 1930, 52: 424 -
8a
Smirnov VO.Tishkov AA.Lyapkalo IM.Ioffe SL.Kachala VV.Strelenko YA.Tartakovsky VA. Russ. Chem. Bull. 2001, 50: 2433 ; Chem. Abstr. 2002, 137, 279247 -
8b
Danilenko VM.Tishkov AA.Ioffe SL.Lyapkalo IM.Strelenko YA.Tartakovsky VA. Synthesis 2002, 635 -
8c
Tishkov AA.Kozintsev AV.Lyapkalo IM.Ioffe SL.Kachala VV.Strelenko YA.Tartakovsky VA. Tetrahedron Lett. 1999, 40: 5075 - 9
Mangelinckx S.De Kimpe N. Synlett 2005, 1521 - 10
Harnisch J.Szeimies G. Chem. Ber. 1979, 112: 3914 - 11
Su J.Qiu G.Liang S.Hu X. Synth. Commun. 2005, 35: 1427 - 13
Verhé R.De Kimpe N.De Buyck L.Courtheyn D.Schamp N. Bull. Soc. Chim. Belg. 1978, 87: 215 -
14a
Murahashi SI.Taniguchi Y.Imada Y.Tanigawa Y. J. Org. Chem. 1989, 54: 3292 -
14b
Hoffman RV.Severns BS. J. Org. Chem. 1996, 61: 5567 - 16
Sunitha K.Balasubramanian KK. Tetrahedron 1987, 43: 3269 - 17
Graziano ML.Scarpati R. J. Chem. Soc., Perkin Trans. 1 1985, 289 -
18a
Doyle MP.van Leusen D. J. Org. Chem. 1982, 47: 5326 -
18b
Reissig HU. Tetrahedron Lett. 1985, 26: 3943 -
19a
Saito S.Nakajima H.Inaba M.Moriwake T. Tetrahedron Lett. 1989, 30: 837 -
19b
Woltering TJ.Weitz-Schmidt G.Wong C.-H. Tetrahedron Lett. 1996, 37: 9033 - 20
von Angerer S. Carbocyclic Three-Membered Ring Compounds, In Houben-Weyl Vol. E 17c:de Meijere A. Thieme; Stuttgart: 1997. p.2121-2123 - 21
Rosen T.Lico JM.Chu DTW. J. Org. Chem. 1988, 53: 1580 - 22
Barua A.Bez G.Barua NC. Synlett 1999, 553 -
23a
Afonso CAM. Tetrahedron Lett. 1995, 36: 8857 -
23b
Ariza X.Urpi F.Viladomat C.Vilarrasa J. Tetrahedron Lett. 1998, 39: 9101 - 24
Nyffeler PT.Liang C.-H.Koeller KM.Wong C.-H. J. Am. Chem. Soc. 2002, 124: 10773 - 25
Hemming K.Bevan MJ.Loukou C.Patel SD.Renaudeau D. Synlett 2000, 1565 - 27 For a recent review on the intramolecular reaction of iminophosphoranes with esters see:
Fresneda PM.Molina P. Synlett 2004, 1 - 28
Quin LDA. A Guide to Organophosphorus Chemistry Wiley; New York: 2000. -
29a
Lin FL.Hoyt HM.van Halbeek H.Bergman RG.Bertozzi CR. J. Am. Chem. Soc. 2005, 127: 2686 -
29b
Shalev DE.Chiacchiera SM.Radkowsky AE.Kosower EM. J. Org. Chem. 1996, 61: 1689 -
30a
Barluenga J.Ferrero M.Palacios F. J. Chem. Soc., Perkin Trans. 1 1990, 2193 -
30b
Palacios F.Ochoa de Retana AM.Pagalday J. Eur. J. Org. Chem. 2003, 913 -
32a
Leguern D.Le Moing MA.Morel G.Foucaud A. Tetrahedron 1977, 33: 27 -
32b
Leguern D.Morel G.Foucaud A. Tetrahedron Lett. 1974, 15: 955 - 33
Neidlein R.Shatzmiller S.Sinnreich D. Liebigs Ann. Chem. 1983, 8 - 34
Graziano ML.Iesce MR. J. Chem. Res., Synop. 1987, 362 - 35
Kolsaker P.Jensen AK. Acta Chem. Scand., Ser. B 1988, 42: 345 - 36
Takeda A.Tsuboi S.Oota Y. J. Org. Chem. 1973, 38: 4148
References and Notes
General Procedure for the Synthesis of 3-Azido-2,2-dialkyl-1,1-dicarboxylates 9.
To a solution of 2-bromoalkylidenemalonate 8
13 (5 mmol) in MeOH (5 mL) (or EtOH for 9b) was added NaN3 (6 mmol). The reaction mixture was stirred at reflux for 14-16 h. The reaction mixture was then evaporated, diluted with dry Et2O, filtered and concentrated. The pure cyclopropanes 9a-c, γ-azido-α,β-unsaturated diesters 10a,b and olefin 11
13 were obtained by column chromatography (silica gel, PE-EtOAc, 4:1) for 9a and 10a; (silica gel, PE-Et2O, 9:1) for 9b and 10b; (silica gel, hexane-Et2O, 95:5) for 9c and 11.
Cyclopropanes 9a,b and γ-azido-α,β-unsaturated diesters 10a,b are reported as representative examples.
Dimethyl 3-Azido-2,2-dimethylcyclopropane-1,1-dicarboxylate (9a): colourless oil. R
f
= 0.47 (PE-EtOAc, 4:1). 1H NMR (270 MHz, CDCl3): δ = 1.24 (s, 3 H), 1.26 (s, 3 H), 3.70 (s, 1 H), 3.75 (s, 3 H), 3.79 (s, 3 H). 13C NMR (68 MHz, CDCl3): δ = 17.9, 19.6, 31.1, 42.3, 51.9, 52.5, 52.9, 165.8, 167.7. IR (NaCl): ν = 2113, 1732 cm-1. MS (ES, pos. mode): m/z (%) = 200(19) [M - N2 + H+], 173 (100) [M - CHN3 + H+]. Anal. Calcd for C9H13N3O4: C, 47.57; H, 5.77; N, 18.49. Found: C, 47.32; H, 5.69; N, 18.65.
Dimethyl (2-Azido-2-methylpropylidene)malonate (10a): colourless oil. R
f
= 0.32 (PE-EtOAc, 4:1). 1H NMR (270 MHz, CDCl3): δ = 1.49 (s, 6 H), 3.80 (s, 3 H), 3.87 (s, 3 H), 6.80 (s, 1 H). 13C NMR (68 MHz, CDCl3): δ = 26.5, 52.6, 52.8, 60.7, 127.2, 148.0, 164.0, 166.2. IR (NaCl): ν = 2110, 1737, 1654 cm-1. MS (EI, 70 eV): m/z (%) = no [M+], 196 (2), 185 (59), 184 (10), 168 (3), 154 (5), 153 (53), 125 (10), 124 (11), 88 (11), 86 (73), 84 (100), 59 (10). Anal. Calcd for C9H13N3O4: N, 18.49. Found: N, 18.21.
Diethyl 3-Azido-2,2-dimethylcyclopropane-1,1-dicarboxylate (9b): colourless oil. R
f
= 0.39 (PE-Et2O, 4:1). The 1H NMR and 13C NMR data are in good agreement with reported data, with the exception that in the 1H NMR the signals at δ = 1.23 and 1.27 ppm are two times a singlet and not doublet of doublet, and in the 13C NMR, the signals for CHN3 (δ = 51.6 ppm) and CMe2 (δ = 30.7 ppm) were mistakenly attributed.11 1H NMR (300 MHz, CDCl3): δ = 1.23 (s, 3 H), 1.27 (s, 3 H), 1.27 (t, J = 7.15 Hz, 3 H), 1.31 (t, J = 7.15 Hz, 3 H), 3.68 (s, 1 H), 4.11-4.31 (m, 4 H). 13C NMR (75 MHz, CDCl3): δ = 14.1, 17.9, 19.6, 30.7, 42.8, 51.6, 61.4, 61.9, 165.2, 167.4. IR (NaCl): ν = 2112, 1729 cm-1. MS (ES, pos. mode): m/z (%) = 228 (17) [M - N2 + H+], 201 (100) [M - CHN3 + H+]. Anal. Calcd for C11H17N3O4: C, 51.76; H, 6.71; N, 16.46. Found C, 51.46; H, 6.65; N, 16.33.
Diethyl (2-Azido-2-methylpropylidene)malonate (10b): colourless oil. R
f
= 0.20 (PE-Et2O, 4:1). 1H NMR (300 MHz, CDCl3): δ = 1.30 (t, J = 7.15 Hz, 3 H), 1.36 (t, J = 7.15 Hz, 3 H), 1.49 (s, 6 H), 4.25 (q, J = 7.15 Hz, 2 H), 4.34 (q, J = 7.15 Hz, 2 H), 6.76 (s, 1 H). 13C NMR (75 MHz, CDCl3): δ = 13.97, 14.05, 26.6, 60.7, 61.7, 61.9, 128.0, 147.2, 163.6, 165.7. IR (NaCl): ν = 2111, 1735, 1655 cm-1. MS (ES, pos. mode): m/z (%) = 228 (52) [M - N2 + H+], 213 (100). Anal. Calcd for C11H17N3O4: C, 51.76; H, 6.71; N, 16.46. Found: C, 51.53; H, 6.63; N, 16.38.
Methyl 4-Azidobut-3-enoate (13): colourless oil. R
f
= 0.37 (PE-EtOAc, 4:1). 1H NMR (300 MHz, CDCl3): δ
(Z-isomer) = 3.14 (dd, J = 7.15 Hz, J = 1.65 Hz, 2 H), 3.70 (s, 3 H), 5.06 (dt, J = 7.43 Hz, J = 7.15 Hz, 1 H), 6.32 (dt, J = 7.43 Hz, J = 1.65 Hz, 1 H); δ (E-isomer) = 3.07 (dd, J = 7.43 Hz, J = 1.38 Hz, 2 H), 3.70 (s, 3 H), 5.45 (dt, J = 13.76 Hz, J = 7.43 Hz, 1 H), 6.03 (dt, J = 13.76 Hz, J = 1.38 Hz, 1 H). 13C NMR (75 MHz, CDCl3): δ
(Z-isomer) = 31.0, 52.0, 111.4, 128.3, 171.6; δ (E-isomer) = 34.5, 52.1, 111.8, 129.9, 171.6. IR (NaCl): ν = 2111, 1739, 1648 cm-1. MS (ES, pos. mode): m/z (%) = 283 (100)
[2 M + H+]. Anal. Calcd for C5H7N3O2: C, 42.55; H, 5.00; N, 29.77. Found: C, 42.35; H, 5.15; N, 29.63.
General Procedure for the Synthesis of Alkyl 5-Alkoxy-4,4-dialkyl-2-oxopyrrolidine-3-carboxylates (15).
To a solution of azidocyclopropane 9 (1 mmol) in dry THF (4 mL) under nitrogen atmosphere was added Ph3P (0.275 g, 1.05 mmol). The reaction mixture was stirred for 3 h at r.t. The reaction mixture was poured into H2O (10 mL) and extracted with CH2Cl2. After drying of the organic layer (MgSO4), filtration and evaporation, the pure pyrrolidin-2-ones 15 were obtained as diastereomeric mixtures after column chromatography (silica gel, PE-EtOAc).
Pyrrolidinone 15a is reported as a representative example.
Methyl 5-Methoxy-4,4-dimethyl-2-oxopyrrolidine-3-carboxylate (15a): amorphous white solid. R
f
= 0.29 and 0.22 (PE-EtOAc, 1:3). Mp 73.8-74.7 °C. Spectral data obtained from the mixture of two isomers (ratio 4:1). 1H NMR (300 MHz, CDCl3): δ = 1.09 (s, 3 H), 1.25 (s, 3 H), 2.98 (s, 1/5 H), 3.34 (s, 12/5 H), 3.36 (s, 3/5 H), 3.37 (s, 4/5 H), 3.73 (s, 3/5 H), 3.76 (s, 12/5 H), 4.31 (d, J = 1.24 Hz, 4/5 H), 4.33 (d, J = 1.10 Hz, 1/5 H), 8.62 (br s, 4/5 H), 8.67 (br s, 1/5 H). 13C NMR (75 MHz, CDCl3): δ (for the major isomer) = 22.1, 23.5, 44.2, 52.1, 55.9, 56.7, 93.2, 168.8, 174.4; δ (for the minor isomer) = 19.1, 29.5, 43.3, 52.2, 56.1, 59.0, 94.0, 169.1, 174.7. IR (KBr): ν = 3218, 3116, 1733, 1698 cm-1. LCMS (ES, pos. mode): m/z (for the major isomer, %) = 425 (7) [2 M + Na+], 202 (100) [M + H+]; m/z (for the minor isomer, %) = 425 (7) [2 M + Na+], 170 (100) [M - MeOH + H+]. Anal. Calcd for C9H15NO4: C, 53.72; H, 7.51; N, 6.96. Found: C, 53.47; H, 7.58; N, 6.88.
5-Methoxy-3-(methoxycarbonyl)-4,4-dimethyl-1-(triphenylphosphonio)-4,5-dihydro-1 H -pyrrol-2-olate (20a): hygroscopic white crystals; mp 76.5-78.0 °C. 1H NMR (300 MHz, CDCl3): δ = 1.32 (s, 3 H), 1.46 (s, 3 H), 2.65 (s, 3 H), 3.63 (s, 3 H), 3.87 (s, 1 H), 7.50-7.80 (m, 15 H). 13C NMR (75 MHz, CDCl3): δ = 20.4, 28.5, 46.5 (d, 3 J P,C = 9.2 Hz), 49.4, 56.5, 79.9 (d, 3 J P,C = 8.1 Hz), 97.0 (d, 2 J P,C = 3.5 Hz), 122.3 (d, 1 J P,C = 105.0 Hz), 129.4 (d, 3 J P,C = 13.9 Hz), 133.9 (d, 4 J P,C = 2.3 Hz), 134.1 (d, 2 J P,C = 11.5 Hz), 165.5, 167.6. 31P NMR (121 MHz, CDCl3): δ = 34.8. IR (KBr): ν = 1667, 1615 cm-1. MS (ES, pos. mode): m/z (%) = 462 (100) [M + H+].