Synlett 2005(13): 2072-2076  
DOI: 10.1055/s-2005-871957
LETTER
© Georg Thieme Verlag Stuttgart · New York

A Straightforward and Convenient Synthesis of Cbz-Protected 2-(1-Aminoalkyl)oxazole-5-carboxylates

Dmitry V. Trukhin, Irina Yu. Bagryanskaya, Yuri V. Gatilov, Tatiana V. Mikhalina, Olga Yu. Rogozhnikova, Tatiana I. Troitskaya, Victor M. Tormyshev*
Novosibirsk Institute of Organic Chemistry, 9 Acad. Lavrentjev Ave., 630090 Novosibirsk, Russia
Fax: +7(3833)309752; e-Mail: torm@nioch.nsc.ru;
Further Information

Publication History

Received 20 April 2005
Publication Date:
12 July 2005 (online)

Abstract

Cbz-protected 2-(1-aminoalkyl)oxazole-5-carboxylates are readily obtainable by a two-step enantioselective sequence involving reaction of benzyloxycarbonyl protected amino acids with α-chloro-β-ketoesters and subsequent cyclization of the resulting acyloxyketones to required oxazoles upon treatment with neat ammonium trifluoacetate.

    References

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8

Typical Synthesis of Ketoesters 7 - Preparation of 7c.
Cbz-protected glycine (0.052 g, 0.25 mmol), 2-chloro-3-oxo-butyric acid ethyl ester (0.042 g, 0.25 mmol), Et3N (0.075 g, 0.75 mmol) and EtOAc (1 mL) were shaken in a screw-top 2-mL vial at 65 °C for 48 h. The mixture was cooled to ambient temperature and passed through a short column of silica gel. All the volatiles were removed under a steam of nitrogen to give 7c (0.082 g, 97%) in form of pale yellow oil, which was used without further purification. 1H NMR (200 MHz, CDCl3): δ = 1.40 (t, 3 H, J = 7.2 Hz, CH 3CH2O), 2.37 (s, 3 H, COCH 3), 3.87 (app. d, 2 H, NHCH 2CO), 4.31 (q, 2 H, J = 7.2 Hz, CH3CH 2O), 5.09 (s, 2 H, PhCH 2O), 5.11 (s, 1 H, COCHCO), 5.53 (br s, 1 H, NH), 7.44 (br s, 5 H, C6 H 5).

9

It is not advisable to carry out the reaction for shorter reaction time or at decreased temperature (<150 °C); these conditions lead to incomplete conversion of the precursor. Alternatively, prolongation of reaction or increasing the temperature result in notable decomposition of the product. Substitution of ammonium trifluoroacetate with ammonium acetate led to partial destruction of starting materials. This is in line with earlier observations of Claiborne and co-workers (ref. 7).

10

Typical Conditions for Heterocyclization - Synthesis of 8c.
A mixture of 7c (0.084 g, 0.25 mmol) and ammonium trifluorocetate (0.327 g, 2.50 mmol) was stirred magnetically in a screw-top 2-mL Wheaton V-vial placed in an air bath heated to 150 °C. After the contents had completely liquefied (1.5-2 min), the mixture was stirred for another 5 min at the same temperature. The heat was removed, after which H2O (0.050 mL) and EtOAc (1 mL) were added at r.t. to the solidified material. The mixture was stirred for 20 min and filtered through a short column of silica gel. Removal of solvent under a steam of nitrogen afforded 0.078 g of the crude product. Column chromatography (CH2Cl2) on silica gave the title compound 8c (0.037 g, 46%) as a pale yellow oil. HRMS: m/z calcd for C16H18N2O5: 318.1216; found: [M+] 318.1254. 1H NMR (200 MHz, CDCl3): δ = 1.35 (t, 3 H, J = 7.2 Hz, CH 3CH2O), 2.41 (s, 3 H, CH 3), 4.34 (q, 2 H, J = 7.2 Hz, CH3CH 2O), 4.48 (br d, 2 H, J = 5.8, CH 2NH), 5.11 (s, 2 H, PhCH 2O), 5.51 (br t, 1 H, J = 5.8 Hz, NH), 7.31 (br s, 5 H, C6 H 5). Here and below the unambiguous assignment of signals in 13C NMR spectra was deduced from INADEQUATE, short-range (HMQC) and long-range (HMBC COLOC) 2D NMR experiments. 13C NMR (400 MHz, CDCl3): δ = 12.97 (q, CH3C=C), 14.08 (q, CH3CH2O), 38.44 (t, CH2NH), 60.97 (t, CH3 CH2O), 67.05 (t, PhCH2), 127.91 (d, phenyl), 127.98 (d, phenyl), 128.30 (d, phenyl), 135.99 (s, phenyl), 137.84 (s, OC=C), 145.59 (s, CH3 C=C), 156.03 (s, OCONH), 158.30 (s, COOEt), 161.92 (s, OC=N).
Oxazoles 8d-g have been prepared analogously.
Compound 8d: white powder; mp 102-103 (from hexane- CH2Cl2, 5:1). [α]D 25 +13.4 (c 3.33, CHCl3). HRMS: m/z calcd for C23H24N2O5: 408.1686; found: [M+] 408.1709. 1H NMR (200 MHz, CDCl3): δ = 1.37 (t, 3 H, J = 7.2 Hz, CH 3CH2O), 2.40 (s, 3 H, CH 3C=C), 3.22 (br m, 2 H, PhCH 2CH), 4.35 (q, 2 H, J = 7.2 Hz, CH3CH 2O), 5.07 (s, 2 H, PhCH 2O), 5.25 (br m, 1 H, PhCH2CH), 5.45 (br d, 1 H, J = 8.0 Hz, NH), 7.02-7.22 (m, 5 H, C6 H 5CH2CH), 7.30 (br s, 5 H, C6 H 5CH2O). 13C NMR (400 MHz, CDCl3): δ = 13.17 (q, CH3C=C), 14.25 (q, CH3CH2O), 39.76 (t, PhCH2CH), 50.65 (d, PhCH2 CH), 61.07 (t, CH3 CH2O), 67.01 (t, PhCH2O), 127.09 (d, phenyl), 127.96 (d, phenyl), 128.07 (d, phenyl), 128.40 (d, phenyl), 128.55 (d, phenyl), 129.20 (d, phenyl), 135.27 (s, phenyl), 136.30 (s, phenyl), 137.89 (s, OC=C), 145.62 (s, CH3 C=C), 156.00 (s, OCONH), 158.47 (s, COOEt), 164.19 (s, OC=N).
Compound 8e: white powder; mp 81-82 °C (from hexane-CH2Cl2, 5:1). [α]D 25 +24.1 (c 3.33, CHCl3). HRMS: m/z calcd for C28H26N2O5: 470.1842; found: [M+] 470.1856. 1H NMR (200 MHz, CDCl3): δ = 1.34 (t, 3 H, J = 7.2 Hz, CH 3CH2O), 3.23 (br m, 2 H, PhCH 2CH), 4.34 (q, 2 H, J = 7.2 Hz, CH3CH 2O), 5.09 (s, 2 H, PhCH 2O), 5.27 (br m, 1 H, PhCH2CH), 5.44 (br d, 1 H, J = 8.0 Hz, NH), 7.07-7.21 (m, 5 H, C6 H 5CH2CH), 7.31 (br s, 5 H, C6 H 5CH2O), 7.40-7.96 (m, 5 H, C6 H 5C=C). 13C NMR (400 MHz, CDCl3): δ = 14.03 (q, CH3CH2O), 39.76 (t, PhCH2CH), 50.56 (d, PhCH2 CH), 61.38 (t, CH3 CH2O), 66.96 (t, PhCH2O), 127.06 (d, phenyl), 127.93 (d, phenyl), 128.05 (d, phenyl), 128.37 (d, phenyl), 128.43 (d, phenyl), 129.21 (d, phenyl), 129.56 (d, phenyl), 129.76 (s, phenyl), 135.12 (s, phenyl), 136.00 (s, phenyl), 136.55 (s, OC=C), 146.39 (s, PhC=C), 155.38 (s, OCONH), 158.18 (s, COOEt), 163.98 (s, OC=N).
Compound 8f: pale yellow oil. [α]D 25 +16.6 (c 6.99, CHCl3). HRMS: m/z calcd for C19H24N2O5: 360.1685; found: [M+] 360.1690. 1H NMR (200 MHz, CDCl3): δ = 0.90 [d, 6 H, J = 6.8 Hz, (CH 3)2CH], 1.32 (t, 3 H, J = 7.2 Hz, CH 3CH2O), 2.29 [m, 1 H, (CH3)2CH], 2.39 (s, 3 H, CH 3C=C), 4.31 (q, 2 H, J = 7.2 Hz, CH3CH 2O), 4.75 (br m, 1 H, CHNH), 5.07 (s, 2 H, PhCH 2), 5.59 (br d, 1 H, J = 8.0 Hz, NH), 7.28 (br s, 5 H, C6 H 5). 13C NMR (400 MHz, CDCl3): δ = 12.64 (q, CH3C=C), 13.72 (q, CH3CH2O), 17.44 (q, CH3CH), 18.41 (q, CH3CH), 32.04 [d, (CH3)2 CH], 54.64 [d, (CH3)2CHCH], 60.45 (t, CH3 CH2O), 66.39 (t, PhCH2O), 127.87 (d, phenyl), 127.90 (d, phenyl), 128.36 (d, phenyl), 135.90 (s, phenyl), 137.11 (s, OC=C), 144.99 (s, CH3 C=C), 155.70 (s, OCONH), 157.94 (s, COOEt), 164.49 (s, OC=N).
Compound 8g: white powder; mp 88-90 °C (from hexane-CH2Cl2, 5:1). [α]D 25 +48.0 (c 4.45, CHCl3). HRMS: m/z calcd for C24H26N2O5: 422.1842; found: [M+] 422.1844. 1H NMR (200 MHz, CDCl3): δ = 0.98 [d, 6 H, J = 6.8 Hz, (CH 3)2CH], 1.35 (t, 3 H, J = 7.2 Hz, CH 3 CH2O), 2.30 [m, 1 H, (CH3)2CH], 4.36 (q, 2 H, J = 7.2 Hz, CH3CH 2 O), 4.93 (br m, 1 H, CHNH), 5.13 (s, 2 H, PhCH 2 ), 5.48 (br d, 1 H, J = 8.0 Hz, NH), 7.33 (br s, 5 H, C6 H 5CH2), 7.40-8.02 (m, 5 H, C6 H 5 C=C). 13C NMR (400 MHz, CDCl3): δ = 13.99 (q, CH3CH2O), 17.66 (q, CH3CH), 18.61 (q, CH3CH), 32.62 [d, (CH3)2 CH], 54.86 [d, (CH3)2CHCH], 61.26 (t, CH3 CH2O), 67.01 (t, PhCH2O), 127.88 (d, phenyl), 127.94 (d, phenyl), 128.01 (d, phenyl), 128.35 (d, phenyl), 129.24 (d, phenyl), 129.47 (d, phenyl), 129.93 (s, phenyl), 136.06 (s, phenyl), 136.50 (s, OC=C), 146.31 (s, PhC=C), 155.89 (s, OCONH), 158.22 (s, COOEt), 164.45 (s, OC=N).

11

Typically 2-(1-aminoalkyl)oxazole-5-carboxylates crystallize as aggregates of ultra-fine plates unsuitable for X-ray analysis. Oxazole 8d was the only product for which we obtained suitable crystals using mixed solvent (hexane-CH2Cl2, 1:1) and very slow evaporation of solvent inside a desiccator in the presence of a solvent absorber (p-xylene placed in a separate vial).
X-ray data were measured on a BRUKER P4 diffractometer with graphite monochromated MoKα radiation using θ/2θ scans (θ<25.99°). A correction for absorption was made according to the crystal faces (transmission 0.95-0.99). The structure was solved by direct methods and refined by a full matrix least-squares anisotropic procedure using SHELXL97 program. The parameters of the hydrogen atoms were given geometrically. The final indexes are wR 2 = 0.1340, S = 0.996 for all 2442 F 2 and R 1 = 0.0535 for 1366 Fo>4σ (300 parameters, 6 restraints). Atomic coordinates, thermal parameters, bond lengths and bond angles have been deposited with the Cambridge Crystallographic Data Centre. Data can be retrieved in CIF format by quoting the deposition no. 274488 in an e-mail request to deposit@ccdc.cam.ac.uk.
Crystallographic data for 8d: C23H24N2O5, MW = 408.44, crystal class orthorhombic, space group P212121, a = 8.0298 (8), b = 9.853 (1), c = 27.308 (3) Å, V = 2160.5 (4) Å3, Z = 4, d c = 1.256 mg m-3, µ(MoKα) = 0.089 mm-1, crystal size 0.6 × 0.4 × 0.08 mm.

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In preliminary experiments, it was found that both methyl and phenyl resonances in the spectra of racemic forms of oxazoles 8d-g are shifted downfield, and are each resolved into signals of individual enantiomers (ratio 1:1) upon addition of Eu(tfc)3.