Coupling of 1-Alkyl-2-(bromomethyl)aziridines with Lithium Dialkylcuprates towards 1,2-Dialkylaziridines

Abstract

The reactivity of 1-alkyl-2-(bromomethyl)aziridines with respect to lithium dialkylcuprates (Gilman reagents) has been evaluated for the first time, pointing to the conclusion that these substrates can be applied successfully as synthetic equivalents for the aziridinylmethyl cation synthon towards, e.g. 2-ethyl-, 2-pentyl- and 2-(phenylmethyl)aziridines in good yields.

2-(bromomethyl)aziridines - organometallics - nucleophilic substitution - 1,2-dialkylaziridines

References

<A NAME="RG45704ST-1A">1a</A> Hu XE. Tetrahedron  2004,  60:  2701 

<A NAME="RG45704ST-1B">1b</A> Sweeney JB. Chem. Soc. Rev.  2002,  31:  247 

<A NAME="RG45704ST-1C">1c</A> Zwanenburg B. ten Holte P. Top. Curr. Chem.  2001,  216:  93 

<A NAME="RG45704ST-1D">1d</A> McCoull W. Davis FA. Synthesis  2000,  1347 

<A NAME="RG45704ST-1E">1e</A> Lindström UM. Somfai P. Synthesis  1998,  109 

<A NAME="RG45704ST-1F">1f</A> Somfai P. Ahman J. Targets in Heterocyclic Systems   Vol. 3:  Italian Chemical Society; Rome, Italy: 1999.  p.341 

<A NAME="RG45704ST-2">2</A> D’hooghe M. Kerkaert I. Rottiers M. De Kimpe N. Tetrahedron  2004,  60:  3637 

<A NAME="RG45704ST-3">3</A> Sweeney JB. Cantrill AA. Tetrahedron  2003,  59:  3677 

<A NAME="RG45704ST-4A">4a</A> Sekar G. Vinod KS. J. Org. Chem.  1999,  64:  2537 

<A NAME="RG45704ST-4B">4b</A> Kelly JW. Anderson NL. Evans SA. J. Org. Chem.  1986,  51:  95 

<A NAME="RG45704ST-5">5</A> Brown HC. Midland MM. Levy AB. Suzuki A. Sono S. Itoh M. Tetrahedron  1987,  43:  4079 

<A NAME="RG45704ST-6A">6a</A> Bäckvall J.-E. J. Chem. Soc., Chem. Commun.  1977,  12:  413 

<A NAME="RG45704ST-6B">6b</A> Barelle M. Apparu M. Tetrahedron  1977,  33:  1309 

<A NAME="RG45704ST-7A">7a</A> De Kimpe N. Verhé R. De Buyck L. Schamp N. Synth. Commun.  1975,  5:  269 

<A NAME="RG45704ST-7B">7b</A> Duhamel L. Valnot JY. Tetrahedron Lett.  1974,  36:  3167 

<A NAME="RG45704ST-7C">7c</A> De Kimpe N. Moens L. Tetrahedron  1990,  46:  2965 

<A NAME="RG45704ST-7D">7d</A> De Kimpe N. Schamp N. Verhé R. Synth. Commun.  1975,  5:  403 

<A NAME="RG45704ST-7E">7e</A> De Kimpe N. Verhé R. De Buyck L. Dejonghe W. Schamp N. Bull. Soc. Chim. Belg.  1976,  85:  763 

<A NAME="RG45704ST-8A">8a</A> Hancock MT. Pinhas AR. Tetrahedron Lett.  2003,  44:  7125 

<A NAME="RG45704ST-8B">8b</A> Hancock MT. Pinhas AR. Organometallics  2002,  21:  5155 

<A NAME="RG45704ST-8C">8c</A> Chandrasekhar M. Sekar G. Singh VK. Tetrahedron Lett.  2000,  41:  10079 

<A NAME="RG45704ST-9">9</A> Chamchaang W. Pinhas AR. J. Org. Chem.  1990,  55:  2943 

<A NAME="RG45704ST-10A">10a</A> Hancock MT. Pinhas AR. Tetrahedron Lett.  2003,  44:  5457 

<A NAME="RG45704ST-10B">10b</A> Nomura R. Nakano T. Nishio Y. Ogawa S. Ninagawa A. Matsuda H. Chem. Ber.  1989,  122:  2407 

<A NAME="RG45704ST-11A">11a</A> De Kimpe N. Jolie R. De Smaele D. J. Chem. Soc., Chem. Commun.  1994,  1221 

<A NAME="RG45704ST-11B">11b</A> Abbaspour Tehrani K. Van Nguyen T. Karikomi M. Rottiers M. De Kimpe N. Tetrahedron  2002,  58:  7145 

<A NAME="RG45704ST-11C">11c</A> De Kimpe N. De Smaele D. Szakonyi Z. J. Org. Chem.  1997,  62:  2448 

<A NAME="RG45704ST-12A">12a</A> Davoli P. Caselli E. Bucciarelli M. Forni A. Torre G. Prati F. J. Chem. Soc., Perkin Trans. 1  2002,  1948 

<A NAME="RG45704ST-12B">12b</A> Jahnisch K. Liebigs Ann. Recl.  1997,  757 

<A NAME="RG45704ST-12C">12c</A> Lohray BB. Gao Y. Sharpless KB. Tetrahedron Lett.  1989,  30:  2623 

<A NAME="RG45704ST-13">13</A>

Synthesis of 2-(Bromomethyl)-1-isobutylaziridine ( 3c).
To a solution of isobutanal (5c, 0.14 g, 2 mmol) in CH₂Cl₂ (10 mL) was added 2,3-dibromo-1-propylammonium bromide (0.60 g, 2 mmol, 1 equiv), MgSO₄ (0.5 g) and Et₃N (0.20 g, 2 mmol, 1 equiv) at 0 °C, and the mixture was heated under reflux for 2 h. After evaporation of the solvent, dry Et₂O (20 mL) was added, the resulting precipitate was filtered and the solvent evaporated, affording the corresponding dibromoimine in 94% yield. This imine was used as such in the next step due to its lability. To a solution of N-(isobutylidene)-2,3-dibromopropylamine (0.54 g, 2 mmol) in MeOH (2 mL) was added NaBH₄ (0.15 g, 4 mmol, 2 equiv) in small portions at 0 °C, and the mixture was heated under reflux for 3 h. Extraction with CH₂Cl₂ (2 × 10 mL), drying (MgSO₄) and filtration afforded 2-(bromo-methyl)-1-isobutylaziridine (3c, 0.33 g, 87%), which was purified by distillation (65-69 °C/11-12 mmHg); colorless liquid, bp 65-69 °C/11-12 mmHg. ¹H NMR (300 MHz, CDCl₃): δ = 0.92 and 1.01 [6 H, 2 d, J = 6.6 Hz, (CH₃)₂], 1.47 [1 H, d, J = 6.1 Hz, (H _cis CH)N], 1.68-1.76 (1 H, m, CHMe₂), 1.75 [1 H, d, J = 3.0 Hz, (HCH _trans )N], 1.80-1.93 (1 H, m, CHN), 2.05 and 2.17 [2 H, 2 dd, J = 5.8, 8.1, 11.6 Hz, N(HCH)CHMe₂], 3.27 and 3.36 [2 H, 2 dd, J = 5.4, 7.3, 10.3 Hz, (HCH)Br]. ¹³C NMR (75 MHz, CDCl₃): δ = 20.80 and 20.92 [(CH₃)₂], 28.99 (CHMe₂), 35.77 and 36.00 (NCH₂CH and CH₂Br), 40.03 (NCH₂ CH), 69.18 (NCH₂ i-Pr). IR (NaCl): ν = 3040, 1469, 1383, 1364, 1238, 1220 cm^-1. MS (70 eV): m/z (%) = 191/193 (1) [M⁺], 148/150 (20), 119/121 (18), 112 (100), 70 (7), 68 (5), 57 (41), 56 (77), 42 (73), 41 (45). Anal. Calcd for C₇H₁₄BrN (%): C, 43.77; H, 7.35; N, 7.29. Found: C, 43.94; H, 7.55; N, 7.17.

<A NAME="RG45704ST-14">14</A>

As a representative example, the synthesis of 2-ethyl-1-(phenylmethyl)aziridine (6a) is described. To a suspension of CuI (1.52 g, 8 mmol, 2 equiv) in dry Et₂O (40 mL) was added slowly MeLi (10 mL, 4 equiv, 1.6 M in Et₂O) via a syringe at -78 °C under nitrogen atmosphere. After stirring for 30 min at -78 °C, a solution of 1-benzyl-2-(bromo-methyl)aziridine (3a, 0.90g, 4 mmol) in Et₂O (10 mL) was added at -78 °C, and the resulting suspension was further stirred for 6 h at r.t. The reaction mixture was quenched with a sat. solution of NH₄Cl (20 mL), filtered over Celite^® and washed with Et₂O (2 × 20 mL). The filtrate was poured into H₂O (100 mL), extracted with Et₂O (2 × 75 mL), and the combined organic extracts were washed with sat. NH₄Cl (50 mL) and brine (50 mL). Drying (MgSO₄), filtration and evaporation of the solvent afforded 2-ethyl-1-(phenyl-methyl)aziridine (6a), which was purified by means of column chromatography on silica gel (EtOAc-hexane, 1:4).
Spectroscopic data of, e.g. 1-(phenylmethyl)-2-pentyl-aziridine (6b): yield 54%, colorless liquid. Flash chromato-graphy on silica gel: EtOAc-hexane, 1:4, R _f = 0.32. ¹H NMR (270 MHz, CDCl₃): δ = 0.84 (3 H, t, J = 6.2 Hz, CH₃), 1.22-1.47 [10 H, m, (H _cis CH)N, CHN and (CH ₂)₄CH₃], 1.60 [1 H, d, J = 2.9 Hz, (HCH _trans )N], 3.30 and 3.49 [2 H, 2 d, J = 13.2 Hz, (HCH)C₆H₄], 7.22-7.35 (5 H, m, C₆H₅). ¹³C NMR (68 MHz, CDCl₃): δ = 14.00 (CH₃), 22.62, 27.12, 31.57 and 32.96 [(CH₂)₄CH₃], 34.07 (NCH₂CH), 39.82 (NCH₂ CH), 65.00 (CH₂C₆H₄), 126.95 (HC_para), 128.17 and 128.26 (2 HC_ortho and 2 HC_meta), 139.40 (C_arom,quat). IR (NaCl): ν = 1607, 1496, 1454 cm^-1. MS (70 eV): m/z (%) = 203 (6) [M⁺], 202 (9), 174 (11), 173 (20), 161 (26), 160 (51), 147 (19), 146 (39), 121 (23), 112 (22), 92 (56), 91 (100), 65 (13). Anal. Calcd for C₁₄H₂₁N (%): C, 82.70; H, 10.41; N, 6.89. Found: C, 82.84; H, 10.55; N, 6.74.
Spectroscopic data of aziridines 6a,c-f,j,k are available upon request.