Stereocontrolled Nucleophilic Additions of Lithiated Heterocycles to Nitrones. Synthesis and Structural Characterization of Novel Chiral (Hydroxyamino)methyl Heterocycles

Pedro Merino, Santiago Franco, Inmaculada Martínez, Francisco L. Merchan and Tomas Tejero
http://wzar.unizar.es/acad/fac/cie/quiorg/MTM.html
Departamento de Quimica Organica, ICMA, Facultad de Ciencias, Universidad de Zaragoza,E-50009 Zaragoza,Aragon,Spain
 

Physical and spectroscopic properties of (hydroxyamino)methylheterocycles
 
 
 Compound 9a
[a]D20 =  -7.8 (c 0.74, CHCl3); oil
1H NMR (CDCl3) d 1.25 (s, 3H), 1.28 (s, 3H), 3.70 (dd, 1H, J = 5.7, 7.9 Hz), 3.84 (d, 1H, J = 12.0 Hz), 3.94 (dd, 1H, J = 5.7, 8.2 Hz), 3.98 (d, 1H, J = 12.0 Hz), 4.38 (d, 1H, J = 6.8 Hz), 4.72 (ddd, 1H, J = 6.8, 7.9, 8.2 Hz), 6.45 (bs, 1H, ex. D2O), 7.20-7.35 (m, 5H), 7.38 (d, 1H, J = 3.2 Hz), 7.82 (d, 1H, J = 3.2 Hz).
13C NMR (CDCl3) d 25.5, 26.5, 61.7, 67.0, 68.6, 76.3, 109.6, 120.3, 127.5, 128.4, 129.4, 136.8, 142.0, 164.7.
 

Compound 9b
[a]D20 =  -9.0 (c 0.39, CHCl3); mp 157-159°C
1H NMR (CDCl3) d 1.28 (s, 3H), 1.32 (s, 3H), 3.71 (d, 1H, J = 13.0 Hz), 3.79 (d, 1H, J = 13.2 Hz), 4.05 (dd, 1H, J = 5.3, 8.5 Hz), 4.15 (dd, 1H, J = 5.5, 8.5 Hz), 4.16 (d, 1H, J = 7.7 Hz), 4.72 (pseudo dt, 1H, J = 5.4, 7.7 Hz), 6.43 (bs, 1H, ex. D2O), 7.24-7.32(m, 5H), 7.39 (d, 1H, J = 3.2 Hz), 7.82 (d, 1H, J = 3.2 Hz).
13C NMR (CDCl3) d 25.21, 26.7, 62.1, 67.7, 69.0, 76.5, 109.8, 120.1, 127.5, 128.3, 129.2, 136.9, 141.7, 165.5.
 

Compound 10a 
[a]D20 =  -28.9 (c 0.79, CHCl3); oil
1H NMR (CDCl3) d 1.31 (s, 3H), 1.37 (s, 3H), 3.54 (dd, 1H, J = 5.8, 8.6 Hz), 3.70 (d, 1H, J = 12.9 Hz), 3.84-3.92 (m, 3H), 4.73 (pseduo dt, 1H, J = 6.3, 8.7 Hz), 6.10 (bs, 1H, ex. D2O), 6.34 (d, 1H, J = 3.2 Hz), 6.39 (dd, 1H, J = 2.0, 3.2 Hz), 7.22-7.38 (m, 5H), 7.43 (d, 1H, J = 2.0 Hz).
13C NMR (CDCl3) d 25.5, 26.7, 61.7, 65.4, 67.1, 75.2, 109.8, 110.3, 110.4, 127.4, 128.3, 129.6, 137.0, 142.4, 149.9.

Compound 10b
[a]D20 =  -13.2 (c 1.00, CHCl3); mp 119-120°C
1H NMR (CDCl3) d 1.32 (s, 3H), 1.33 (s, 3H),  3.66 (d, 1H, J = 13.1 Hz), 3.72 (d, 1H, J = 13.1 Hz), 3.87 (d, 1H, J = 8.1 Hz), 4.02 (dd, 1H, J = 5.9, 8.5 Hz), 4.14 (dd, 1H, J = 6.1, 8.5 Hz), 4.67 (ddd, 1H, J = 5.9, 6.1, 8.1 Hz), 4.75 (bs, 1H, ex. D2O), 6.43 (s, 2H), 7.22-7.38 (m, 5H), 7.48 (d, 1H, J = 1.1 Hz).
13C NMR (CDCl3) d 25.5, 26.7, 62.1, 66.1, 67.9, 75.6, 109.5, 110.4, 110.5, 127.5, 128.4, 129.4, 137.2, 142.4, 150.1.

Compound 11a 
[a]D20 =  + 17.2 (c 1.50, CHCl3); mp 103-105°C
1H NMR (CDCl3) d 1.31 (s, 3H), 1.32 (s, 3H), 3.42 (s, 3H), 3.57 (d, 1H, J = 12.3 Hz), 3.90 (dd, 1H, J = 7.8, 9.0 Hz), 4.18 (dd, 1H, J = 6.3, 9.0 Hz), 4.21 (d, 1H, J = 12.3 Hz), 4.24 (d, 1H, J = 5.0 Hz), 4.69 (ddd, 1H, J = 5.0, 6.3, 7.8 Hz), 6.84 (d, 1H, J = 1.7 Hz), 7.02 (d, 1H, J = 1.7 Hz), 7.15 (bs, 1H, ex. D2O), 7.24-7.33 (m, 5H).
13C NMR (CDCl3) d 24.6, 26.3, 32.7, 61.4, 62.2, 68.2, 76.9, 109.0, 120.8, 126.7, 127.5, 128.4, 128.8, 136.5, 145.8.

Compound 11b 
[a]D20 =  -14.2 (c 0.88, CHCl3); mp 118-120°C
1H NMR (CDCl3) d 1.24 (s, 3H), 1.30 (s, 3H), 3.38 (s, 3H), 3.42 (d, 1H, J = 12.4 Hz), 3.57 (d, 1H, J = 9.3 Hz), 4.05 (dd, 1H, J = 5.7, 8.9 Hz), 4.09 (d, 1H, J = 12.4 Hz), 4.30 (dd, 1H, J = 6.5, 8.9 Hz), 4.75 (ddd, 1H, J = 5.8, 6.4, 9.4 Hz), 6.84 (d, 1H, J = 1.7 Hz), 7.04 (d, 1H, J = 1.7 Hz), 7.12 (bs, 1H, ex. D2O), 7.30-7.36 (m, 5H).
13C NMR (CDCl3) d 25.5, 25.6, 32.8, 59.7, 62.1, 66.7, 77.3, 108.1, 120.7, 126.8, 127.4, 128.3, 129.0, 136.7, 143.8.

Compound 12a
Rf (hexano:diethyl ether, 60:40) = 0.55; [a]D20 =  -24.9 (c 0.41, CHCl3); mp 117-119°C
1H NMR (CDCl3) d 1.37 (s, 3H), 1.42 (s, 3H), 3.48 (dd, 1H, J = 5.5, 9.0 Hz), 3.65 (d, 1H, J = 12.7 Hz), 3.75 (dd, 1H, J = 6.5, 9.0 Hz), 3.96 (d, 1H, J = 12.7 Hz), 4.00 (d, 1H, J = 9.4 Hz), 4.72 (ddd, 1H, J = 5.5, 6.5, 9.4 Hz), 5.35 (bs, 1H, ex. D2O), 6.9-7.4 (m, 8H).
13C NMR (CDCl3) d 225.6, 26.8, 61.4, 67.3, 72.1, 76.6, 110.1, 121.9, 123.8, 126.1, 126.6, 127.4, 128.5, 135.8, 137.0.

Compound 12b
Rf (hexano:diethyl ether, 60:40) = 0.65; [a]D20 =  -14.6 (c 0.32, CHCl3); mp 126-128°C
1H NMR (CDCl3) d 1.30 (s, 3H), 1.35 (s, 3H), 3.60 (d, 1H, J = 13.3 Hz), 3.78 (d, 1H, J = 13.3 Hz), 3.97 (dd, 1H, J = 6.3, 8.3 Hz), 4.05 (d, 1H, J = 7.2 Hz), 4.11 (dd, 1H, J = 6.5, 8.3 Hz), 4.65 (ddd, 1H, J = 6.3, 6.5, 8.3 Hz), 4.74 (bs, 1H, ex. D2O), 6.9-7.6 (m, 8H).
13C NMR (CDCl3) d 25.4, 26.7, 61.8, 67.3, 68.3, 77.0, 109.6, 122.1, 126.2, 126.4, 127.4, 128.3, 129.4, 136.8, 137.3.

Compound 13a 
Rf (hexano:diethyl ether, 60:40) = 0.48; [a]D20 =  -25.7 (c 0.36, CHCl3); mp 153-155°C
1H NMR (CDCl3) d 1.37 (s, 3H), 1.39 (s, 3H), 3.85 (dd, 1H, J = 6.5, 9.0 Hz), 4.00 (dd, 1H, J = 6.7, 9.0 Hz), 4.05 (d, 1H, J = 13.0 Hz), 4.12 (d, 1H, J = 13.0 Hz), 4.47 (d, 1H, J = 6.6 Hz), 4.83 (pseduo q, 1H, J = 6.5 Hz), 6.06 (bs, 1H, ex. D2O), 7.20-7.42 (m, 7 H), 7.91 (d, 1H, J = 80 Hz), 8.03 (d, 1H, J = 8.0 Hz).
13C NMR (CDCl3) d 25.6, 26.7, 62.0, 67.3, 70.0, 76.2, 109.8, 119.8, 121.7, 123.4, 125.6, 126.2, 127.7, 128.5, 129.4, 135.3, 137.1, 170.7.

Compound 13b
Rf (hexano:diethyl ether, 60:40) = 0.37; [a]D20 =  -31.2 (c 0.40, CHCl3); mp 188-190°C
1H NMR (CDCl3) d 1.29 (s, 3H), 1.37 (s, 3H), 3.83 (d, 1H, J = 13.0 Hz), 3.95 (d, 1H, J = 13.0 Hz), 4.16 (dd, 1H, J = 5.1, 8.8 Hz), 4.19 (d, 1H, J = 8.5 Hz), 4.22 (dd, 1H, J =6.1, 8.8 Hz), 4.81 (ddd, 1H, J = 5.1, 6.1, 8.5 Hz), 6.36 (bs, 1H, ex. D2O), 7.24-7.53 (m, 7H), 7.92 (d, 1H, J = 8.0 Hz), 8.07 (d, 1H, J = 8.0 Hz).
13C NMR (CDCl3) d 225.6, 27.1, 62.5, 68.0, 70.3, 77.0, 109.9, 119.4, 121.7, 123.3, 125.5, 126.2, 127.8, 128.6, 129.3, 136.0, 136.8, 170.4.
 
 Compound 14a 
Rf (hexano:diethyl ether, 60:40) = 0.35; [a]D20 =  -30.4 (c 0.26 , CHCl3); mp 129-131°C
1H NMR (CDCl3) d 1.38 (s, 3H), 1.42 (s, 3H), 3.67 (dd, 1H, J = 6.0, 8.7 Hz), 3.82 (d, 1H, J = 13.0 Hz), 3.95 (dd, 1H, J = 6.8, 8.7 Hz), 3.98 (d, 1H, J = 13.0 Hz), 4.07 (d, 1H, J =8.5 Hz), 4.84 (pseudo dt, 1H, J = 6.2, 8.5 Hz), 5.80 (bs (1H, ex. D2O), 6.76 (s, 1H), 7.20-7.464 (m, 9H).
13C NMR (CDCl3) d 25.6, 26.7, 61.8, 65.9, 67.1, 75.1, 111.3, 121.1, 122.9, 124.2, 124.3, 127.4, 128.1, 128.3, 128.4, 129.4, 129.7, 137.0, 152.7.

Compound 14b
Rf (hexano:diethyl ether, 60:40) = 0.49; [a]D20 =  -22.3 (c 0.41, CHCl3); mp 97-99°C
1H NMR (CDCl3) d 1.32 (s, 3H), 1.34 (s, 3H), 3.81 (d, 1H, J =13.0 Hz), 3.82 (d, 1H, J = 13.0 Hz), 4.01 (d, 1H, J = 8.6 Hz), 4.12 (dd, 1H, J =5.7, 8.7 Hz), 4.20 (dd, 1H, J = 6.1, 8.7 Hz), 4.60 (bs, 1H, ex. D2O), 4.77 (pseudo dt, 1H, J = 5.8, 8.6 Hz), 6.82 (s, 1H), 7.15-7.43 (m, 9H).
13C NMR (CDCl3) d 25.5, 26.8, 61.8, 66.2, 67.2, 75.2, 111.4, 121.2, 122.8, 124.1, 127.5, 127.6, 128.3, 128.4, 129.4, 137.1, 153.1.

Compound 15a 
Rf (hexano:diethyl ether, 60:40) = 0.50; [a]D20 =  -35.2 (c 0.30 , CHCl3); mp 102-104°C
1H NMR (CDCl3) d 1.38 (s, 3H), 1.40 (s, 3H), 3.60 (dd, 1H, J = 5.7, 8.8 Hz), 3.76 (d, 1H, J = 13.0 Hz), 3.85 (dd, 1H, J =6.4, 8.8 Hz), 3.99 (d, 1H, J = 13.0 Hz), 4.08 (d, 1H, J = 8.9 Hz), 4.77 (pseudo dt, 1H, J = 5.8, 8.9 Hz), 6.53 (bs, 1H, ex. D2O), 7.17 (s, 1H), 7.20-7.40 (m, 9H).
13C NMR (CDCl3) d 25.6, 26.9, 61.6, 67.2, 68.2, 76.6, 110.1, 122.2, 123.4, 124.2, 124.5, 125.1, 127.4, 128.3, 129.5, 137.0, 137.5, 138.7, 140.8.

Compound 15b
Rf (hexano:diethyl ether, 60:40) = 0.39; [a]D20 =  -22.3 (c 0.60, CHCl3); mp 127-129°C
1H NMR (CDCl3) d 1.33 (s, 3H), 1.39 (s, 3H), 3.70 (d, 1H, J =13.2 Hz), 3.86 (d, 1H, J = 13.2 Hz), 4.09 (dd, 1H, J =5.9, 8.6 Hz), 4.13 (d, 1H, J = 7.6 Hz), 4.19 (dd, 1H, J = 6.2, 8.6 Hz), 4.72 (ddd, 1H, J = 5.9, 6.2, 7.6 Hz), 4.85 (bs, 1H, ex. D2O), 7.18 (s, 1H), 7.21-7.46 (m, 9H)..
13C NMR (CDCl3) d 25.3, 26.7, 62.0, 68.0, 76.6, 109.6, 122.2, 124.5, 124.1, 124.2, 125.1, 127.5, 128.4, 129.4, 137.2, 137.3, 138.6, 139.0.
 
 
 

  Experimental procedures
 
 

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