Michael-Induced Ring Closure to 2-Azidocyclopropane-1,1-dicarboxylates and their Staudinger Reduction to 5-Alkoxy-3-(alkoxycarbonyl)pyrrolidin-2-ones

Sven Mangelinckx; Norbert De Kimpe

doi:10.1055/s-2006-926259

LETTER

Michael-Induced Ring Closure to 2-Azidocyclopropane-1,1-dicarboxylates and their Staudinger Reduction to 5-Alkoxy-3-(alkoxycarbonyl)pyrrolidin-2-ones

Sven Mangelinckx, Norbert De Kimpe*
Department of Organic Chemistry, Faculty of Bioscience Engineering, Ghent University, Coupure links 653, 9000 Ghent, Belgium
Fax: +32(9)2646243; e-Mail: norbert.dekimpe@UGent.be;

Abstract

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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

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References

References and Notes

<A NAME="RG36205ST-1">1</A> Gnad F. Reiser O. Chem. Rev. 2003, 103: 1603

<A NAME="RG36205ST-2A">2a</A> Reissig HU. Zimmer R. Chem. Rev. 2003, 103: 1151

<A NAME="RG36205ST-2B">2b</A> Reissig HU. Top. Curr. Chem. 1988, 144: 73

<A NAME="RG36205ST-2C">2c</A> Yu M. Pagenkopf BL. Tetrahedron 2005, 61: 321

<A NAME="RG36205ST-3A">3a</A> Horikawa H. Nishitani T. Iwasaki T. Inoue I. Tetrahedron Lett. 1983, 24: 2193

<A NAME="RG36205ST-3B">3b</A> El Abdioui K. Martinez J. Viallefont P. Vidal Y. Bull. Soc. Chim. Belg. 1997, 106: 425

<A NAME="RG36205ST-3C">3c</A> Papageorgiou CD. Cubillo de Dios MA. Ley SV. Gaunt MJ. Angew. Chem. Int. Ed. 2004, 43: 4641

<A NAME="RG36205ST-3D">3d</A> Adams LA. Charmant JPH. Cox RJ. Walter M. Whittingham WG. Org. Biomol. Chem. 2004, 2: 542

<A NAME="RG36205ST-3E">3e</A> Adams LA. Cox RJ. Gibson JS. Mayo-Martín MB. Walter M. Whittingham W. Chem. Commun. 2002, 2004

<A NAME="RG36205ST-3F">3f</A> Jiménez JM. Rifé J. Ortuño RM. Tetrahedron: Asymmetry 1995, 6: 1849

<A NAME="RG36205ST-3G">3g</A> Jiménez JM. Rifé J. Ortuño RM. Tetrahedron: Asymmetry 1996, 7: 537

<A NAME="RG36205ST-3H">3h</A> Yamazaki S. Inoue T. Hamada T. Takada T. Yamamoto K. J. Org. Chem. 1999, 64: 282

<A NAME="RG36205ST-3I">3i</A> Wick L. Tamm C. Boller T. Helv. Chim. Acta 1995, 78: 403

<A NAME="RG36205ST-4A">4a</A> Bubert C. Voigt J. Biasetton S. Reiser O. Synlett 1994, 675

<A NAME="RG36205ST-4B">4b</A> Bubert C. Cabrele C. Reiser O. Synlett 1997, 827

<A NAME="RG36205ST-4C">4c</A> Maas G. Müller A. J. Prakt. Chem. 1998, 340: 315

<A NAME="RG36205ST-5A">5a</A> Geen GR. Kincey PM. Choudary BM. Tetrahedron Lett. 1992, 33: 4609

<A NAME="RG36205ST-5B">5b</A> Geen GR. Harnden MR. Parratt MJ. Bioorg. Med. Chem. Lett. 1991, 1: 347

<A NAME="RG36205ST-5C">5c</A> Geen GR, Grinter TJ, and Moore S. inventors; Eur. Pat. Appl. EP 420559. ; Chem. Abstr. 1991, 115, 28993

<A NAME="RG36205ST-5D">5d</A> Hayashi T, Yasuoka J, and Nishikawa J. inventors; Jpn. Kokai Tokkyo Koho JP 2000327593. ; Chem. Abstr. 2000, 133, 362933

<A NAME="RG36205ST-5E">5e</A> Hayashi T, Yasuoka J, and Nishiura A. inventors; Eur. Pat. Appl. EP 916674. ; Chem. Abstr. 1999, 131, 5268

<A NAME="RG36205ST-5F">5f</A> Kim HS. Barak D. Harden TK. Boyer JL. Jacobson KA. J. Med. Chem. 2001, 44: 3092

<A NAME="RG36205ST-6">6</A> Su Q. Wood JL. Synth. Commun. 2000, 30: 3383

<A NAME="RG36205ST-7A">7a</A> Trukhin EV. Makarenko SV. Berestovitskaya VM. Russ. J. Org. Chem. 1998, 34: 59 ; Chem. Abstr. 1998, 130, 3661

<A NAME="RG36205ST-7B">7b</A> Villemin D. Thibault-Starzyk F. Hachemi M. Synth. Commun. 1994, 24: 1425

<A NAME="RG36205ST-7C">7c</A> Le Menn JC. Tallec A. Sarrazin J. Can. J. Chem. 1991, 69: 761

<A NAME="RG36205ST-7D">7d</A> Sopova AS. Bakova OV. Metelkina EL. Perekalin VV. Zh. Org. Khim. 1975, 11: 68 ; Chem. Abstr. 1975, 83, 9406

<A NAME="RG36205ST-7E">7e</A> Sopova AS. Yurchenko OI. Perekalin VV. Zh. Obshch. Khim. 1965, 1: 1707 ; Chem. Abstr. 1966, 64, 3726

<A NAME="RG36205ST-7F">7f</A> Kohler EP. Darling SF. J. Am. Chem. Soc. 1930, 52: 424

<A NAME="RG36205ST-8A">8a</A> 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

<A NAME="RG36205ST-8B">8b</A> Danilenko VM. Tishkov AA. Ioffe SL. Lyapkalo IM. Strelenko YA. Tartakovsky VA. Synthesis 2002, 635

<A NAME="RG36205ST-8C">8c</A> Tishkov AA. Kozintsev AV. Lyapkalo IM. Ioffe SL. Kachala VV. Strelenko YA. Tartakovsky VA. Tetrahedron Lett. 1999, 40: 5075

<A NAME="RG36205ST-9">9</A> Mangelinckx S. De Kimpe N. Synlett 2005, 1521

<A NAME="RG36205ST-10">10</A> Harnisch J. Szeimies G. Chem. Ber. 1979, 112: 3914

<A NAME="RG36205ST-11">11</A> Su J. Qiu G. Liang S. Hu X. Synth. Commun. 2005, 35: 1427

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.

<A NAME="RG36205ST-13">13</A> Verhé R. De Kimpe N. De Buyck L. Courtheyn D. Schamp N. Bull. Soc. Chim. Belg. 1978, 87: 215

<A NAME="RG36205ST-14A">14a</A> Murahashi SI. Taniguchi Y. Imada Y. Tanigawa Y. J. Org. Chem. 1989, 54: 3292

<A NAME="RG36205ST-14B">14b</A> Hoffman RV. Severns BS. J. Org. Chem. 1996, 61: 5567

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.

<A NAME="RG36205ST-16">16</A> Sunitha K. Balasubramanian KK. Tetrahedron 1987, 43: 3269

<A NAME="RG36205ST-17">17</A> Graziano ML. Scarpati R. J. Chem. Soc., Perkin Trans. 1 1985, 289

<A NAME="RG36205ST-18A">18a</A> Doyle MP. van Leusen D. J. Org. Chem. 1982, 47: 5326

<A NAME="RG36205ST-18B">18b</A> Reissig HU. Tetrahedron Lett. 1985, 26: 3943

<A NAME="RG36205ST-19A">19a</A> Saito S. Nakajima H. Inaba M. Moriwake T. Tetrahedron Lett. 1989, 30: 837

<A NAME="RG36205ST-19B">19b</A> Woltering TJ. Weitz-Schmidt G. Wong C.-H. Tetrahedron Lett. 1996, 37: 9033

<A NAME="RG36205ST-20">20</A> von Angerer S. Carbocyclic Three-Membered Ring Compounds, In Houben-Weyl Vol. E 17c: de Meijere A. Thieme; Stuttgart: 1997. p.2121-2123

<A NAME="RG36205ST-21">21</A> Rosen T. Lico JM. Chu DTW. J. Org. Chem. 1988, 53: 1580

<A NAME="RG36205ST-22">22</A> Barua A. Bez G. Barua NC. Synlett 1999, 553

<A NAME="RG36205ST-23A">23a</A> Afonso CAM. Tetrahedron Lett. 1995, 36: 8857

<A NAME="RG36205ST-23B">23b</A> Ariza X. Urpi F. Viladomat C. Vilarrasa J. Tetrahedron Lett. 1998, 39: 9101

<A NAME="RG36205ST-24">24</A> Nyffeler PT. Liang C.-H. Koeller KM. Wong C.-H. J. Am. Chem. Soc. 2002, 124: 10773

<A NAME="RG36205ST-25">25</A> Hemming K. Bevan MJ. Loukou C. Patel SD. Renaudeau D. Synlett 2000, 1565

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.

<A NAME="RG36205ST-27">27</A> For a recent review on the intramolecular reaction of iminophosphoranes with esters see: Fresneda PM. Molina P. Synlett 2004, 1

<A NAME="RG36205ST-28">28</A> Quin LDA. A Guide to Organophosphorus Chemistry Wiley; New York: 2000.

<A NAME="RG36205ST-29A">29a</A> Lin FL. Hoyt HM. van Halbeek H. Bergman RG. Bertozzi CR. J. Am. Chem. Soc. 2005, 127: 2686

<A NAME="RG36205ST-29B">29b</A> Shalev DE. Chiacchiera SM. Radkowsky AE. Kosower EM. J. Org. Chem. 1996, 61: 1689

<A NAME="RG36205ST-30A">30a</A> Barluenga J. Ferrero M. Palacios F. J. Chem. Soc., Perkin Trans. 1 1990, 2193

<A NAME="RG36205ST-30B">30b</A> Palacios F. Ochoa de Retana AM. Pagalday J. Eur. J. Org. Chem. 2003, 913

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⁺].

<A NAME="RG36205ST-32A">32a</A> Leguern D. Le Moing MA. Morel G. Foucaud A. Tetrahedron 1977, 33: 27

<A NAME="RG36205ST-32B">32b</A> Leguern D. Morel G. Foucaud A. Tetrahedron Lett. 1974, 15: 955

<A NAME="RG36205ST-33">33</A> Neidlein R. Shatzmiller S. Sinnreich D. Liebigs Ann. Chem. 1983, 8

<A NAME="RG36205ST-34">34</A> Graziano ML. Iesce MR. J. Chem. Res., Synop. 1987, 362

<A NAME="RG36205ST-35">35</A> Kolsaker P. Jensen AK. Acta Chem. Scand., Ser. B 1988, 42: 345

<A NAME="RG36205ST-36">36</A> Takeda A. Tsuboi S. Oota Y. J. Org. Chem. 1973, 38: 4148