A Low-Temperature Ammonium Ylid Rearrangement: Enhanced Reactivity Engendered by Rigidity

Abstract

Sigmatropic rearrangement of tetrahydropyridine-­derived ammonium is a valuable method for the preparation of substituted prolines. These reaction normally require elevated temperatures to proceed, but bicyclic tetrahydropyridine-like ylid 1 undergoes rearrangement at -15 ˚C; the extra rigidity of the azabicyclo[3.3.0]octene system preorganizes the transition state and lowers the activation energy for rearrangement.

Key words

catalytic - rearrangement - activation - H₃ - HT_2C

References and Notes

• 1 Hashimoto K. Ohfune Y. Shirahama H. Tetrahedron Lett.  1995,  36:  6235 
• 2 Jao E. Bogen S. Saksena AK. Girijavallabhan V. Tetrahedron Lett.  2003,  44:  5033 
• 3 Jiang B. Xu M. Angew. Chem. Int. Ed.  2004,  43:  2543 
• 4a Cossy J. Cases M. Pardo DG. Synlett  1998,  507 
• 4b Collado I. Ezquerra J. Mateo AI. Rubio A. J. Org. Chem.  1998,  63:  1995 
• 4c Collado I. Ezquerra J. Mateo AI. Pedregal C. Rubio A. J. Org. Chem.  1999,  64:  4304 
• 5 Huck BR. Llamas L. Robarge MJ. Dent TC. Song J. Hodnick WF. Crumrine C. Stricker-Krongrad A. Harrington J. Brunden KR. Bennani YL. Bioorg. Med. Chem. Lett.  2006,  16:  4130 
• 6 Santora VJ. Covel JA. Hayashi R. Hofilena BJ. Ibarra JB. Pulley MD. Weinhouse MI. Sengupta D. Duffield JJ. Semple G. Webb RR. Sage C. Ren A. Pereira G. Knudsen J. Edwards JE. Suarez M. Frazer J. Thomsen W. Hauser E. Whelan K. Grottick AJ. Bioorg. Med. Chem. Lett.  2008,  18:  1490 
• 7 Heath P. Roberts E. Wessel HP. Workman JA. Sweeney JB. J. Org. Chem.  2003,  68:  4083 
• 8 Related aza-Claisen rearrangements: Chao S. Kunng F.-A. Gu J.-M. Ammon HL. Mariano PS. J. Org. Chem.  1984,  49:  2708 
• 9a Larson SD. Grieco PA. J. Am. Chem. Soc.  1985,  107:  1768 
• 9b Fray AH. Augeri DJ. Kleinman EF. J. Org. Chem.  1988,  53:  896 
• 10 Roberts E. Sançon J. Workman JA. Sweeney JB. Org. Lett.  2003,  5:  4775 
• 13 Mageswaran S. Ollis WD. Sutherland IO. J. Chem. Soc., Perkin Trans. 1  1981,  1953 

11

Key Data for 4
^¹H NMR (400 MHz, CDCl₃): δ = 1.24-1.31 (6 H, m), 2.33-2.38 (1 H, br m), 2.41 (3 H, s), 2.67-2.74 (1 H, m), 2.82 (1 H, dd, J = 8.5, 9.0 Hz), 2.90-2.97 (2 H, m), 3.80-3.88 (1 H, m), 4.18-4.31 (4 H, m), 5.31-5.34 (1 H, m), 5.83-5.86 (1 H, m). ^¹³C NMR (100 MHz, CDCl₃): δ = 14.3, 14.4, 37.2, 37.4, 41.7, 58.3, 60.8, 61.0, 63.0, 78.0, 128.1, 134.8, 168.0 (C=O), 169.4. MS (ES⁺): m/z calcd for C₁₄H₂₁NO₄: 268.1543; found: 268.1539.

12

Key Data for 5
^¹H NMR (250 MHz, CDCl₃): δ = 1.27 (6 H, t, J = 7.1 Hz), 1.60 (1 H, d, J = 10.8 Hz), 1.79-1.86 (1 H, m), 2.50 (3 H, s), 2.51-2.58 (2 H, m), 2.69 (1 H, dd, J = 8.5, 9.0 Hz), 3.01 (1 H, br dd, J = 2.5, 5.1 Hz), 4.11-4.23 (4 H, m), 6.05-6.17 (1 H, m). ^¹³C NMR (62.5 MHz, CDCl₃): δ = 14.5, 14.6, 39.4, 39.5, 40.7, 45.7, 51.1, 61.1, 62.0, 73.1, 133.2, 136.1, 170.5, 171.2. MS (ES⁺): m/z calcd for C₁₄H₂₁NO₄: 268.1543; found: 268.1543.

14

Key Data for 7
^¹H NMR (400 MHz, CDCl₃): δ = 2.28 (3 H, s), 2.28-2.35 (1 H, m), 2.35-2.41 (1 H, m), 2.60-2.70 (1 H, m), 2.75-2.85 (1 H, m), 2.90 (1 H, d), 2.90 (1 H, d), 3.50-3.57 (1 H, br m), 3.70 (3 H, s), 5.20-5.28 (1 H, m), 5.73-5.81 (1 H, m). ^¹³C NMR (100 MHz, CDCl₃): δ = 39.0, 41.3, 42.6, 52.4, 55.1, 65.2, 72.3, 128.8 , 135.5, 172.3 MS (CI⁺): m/z (%) = 182 (100) [MH⁺], 122 (75), 79 and 49. HRMS: m/z calcd for C₁₀H₁₅NO₂: 182.1182; found: 182.1181.

15

The relative stereochemistry of 7 was deduced from NOE experiments, which will be reported elsewhere in due course.