Water-compatible one-pot organocatalytic asymmetric synthesis of cyclic nitrones. Application in intramolecular 1,3-dipolar cycloadditions

Article abstract of DOI:10.1016/j.tetlet.2011.08.138

Optically active five-membered cyclic nitrones are readily obtained in a one-pot procedure via the organocatalytic Michael addition of aldehydes to nitroolefins and in situ reductive cyclization. Application of the methodology to the synthesis of tricycli

Full text of DOI:10.1016/j.tetlet.2011.08.138

Water-compatible one-pot organocatalytic asymmetric synthesis of
cyclic nitrones with application in intramolecular 1,3-dipolar
cycloadditions
David Sádaba,a Ignacio Delso,a,b Tomás Tejero,a and Pedro Merino a*
a Laboratorio de Síntesis Asimétrica, Departamento de Química Orgánica, Instituto de Síntesis Química y
Catálisis Homogénea (ISQCH), Universidad de Zaragoza, CSIC, E-50009, Zaragoza, Aragon, Spain
b NMR Service, CEQMA, Institute of Chemical Synthesis and Homogeneous Catalysis (ISQCH),
University of Zaragoza, CSIC, E-50009 Zaragoza, Aragón, Spain, Spain
Supporting Information
Characterization of compounds
Me
Ph
N
O
Compound 5a: oil; [α]D25 +42 (c 0.42, CHCl3). 1H NMR (CDCl3, 400 MHz) δ (ppm)
1.25 (d, J = 6.9 Hz, 3H, CH3), 3.08-3.21 (m, 1H, H4), 3.27 (td, J = 9.1, 7.3 Hz, 1H, H3),
’
4.15 (ddt, J = 14.0, 8.9, 2.1 Hz, 1H, H2), 4.33 (dddd J = 13.8, 9.4, 2.1, 1.3 Hz, 1H, H2 ),
6.91-6.96 (m, 1H, H5), 7.22-7.42 (m, 5H, Ar). 13C NMR (CDCl3, 100 MHz) δ (ppm)
17.3 (CH3), 45.5 (C4), 48.7 (C3), 68.8 (C2), 127.2 (Ar), 127.7 (Ar), 129.2 (Ar), 139.6
(C5) 139.7 (Ar). HRMS Calculated for C11H13NO: 175.0997. Found: 175.1085 Anal
Calcd. for C11H13NO: C, 75.40; H, 7.48; N, 7.99. Found C, 75.59; H, 7.29; N, 7.60.

Ph
N
O
Compound 5b: oil; [α]D25 + (c 0.98, CHCl3). 1H NMR (CDCl3, 400 MHz) δ (ppm) 0.90
(t, J = 7.2 Hz, 3H, CH2CH2CH3), 1.29-1.45 (m, 2H, CH2CH2CH3), 1.53-1.63 (m, 2H,
CH2CH2CH3), 3.01-3.12 (m, 1H, H4), 3.34 (ddd, J = 9.6, 7.9, 6.4 Hz, 1H, H3), 4.09 (ddt,
’
J = 14.2, 7.9, 1.9 Hz, 1H, H2), 4.36 (dddd J = 13.9, 9.5, 2.2, 1.6 Hz, 1H, H2 ), 6.96-7.01
(m, 1H, H5), 7.23-7.42 (m, 5H, Ar). 13C NMR (CDCl3, 100 MHz) δ (ppm) 13.9
(CH2CH2CH3), 20.5 (CH2CH2CH3), 35.1 (CH2CH2CH3), 46.4 (C3), 50.8 (C4), 68.9 (C5),
127.1 (Ar), 127.5 (Ar), 129.1 (Ar), 138.2 (C2) 141.0 (Ar). HRMS Calculated for
C13H17NO: 203.1310. Found: 203.1393. Anal Calcd. for C13H17NO: C, 76.81; H, 8.43;
N, 6.89. Found C, 76.93; H, 8.54; N, 6.69.
Compound 5c: oil; [α]D25 +41 (c 0.98, CHCl3). 1H NMR (CDCl3, 400 MHz) δ (ppm)
0.89 (d, J = 6.8 Hz, 3H, CH(CH3)2), 0.91 (d, J = 6.8 Hz, 3H, CH(CH3)2), 1.82 (oct, J =
6.7 Hz, 1H, CH(CH3)2), 2.82-2.88 (m, 1H, H4), 3.35 (ddd, J = 9.6, 6.4, 5.5 Hz, 1H, H3),
’
3.95 (ddt, J = 14.4, 6.6, 6.0 Hz, 1H, H2), 4.31 (dddd J = 14.1, 9.6, 2.4, 1.8 Hz, 1H, H2 ),
6.23-6.95 (m, 1H, H5), 7.14-7.32 (m, 5H, Ar). 13C NMR (CDCl3, 100 MHz) δ (ppm)
19.7 (CH(CH3)2), 20.6 (CH(CH3)2), 31.5 (CH(CH3)2), 43.3 (C3), 58.0 (C4), 69.5 (C2),
127.0 (Ar), 127.4 (Ar), 129.2 (Ar), 137.6 (C5), 142.6 (Ar). HRMS Calculated for
C13H17NO: 203.1310. Found: 203.1379. Anal Calcd. for C13H17NO: C, 76.81; H, 8.43;
N, 6.89. Found C, 76.94; H, 8.59; N, 6.60.

MeO
N
O
Compound 5d: oil; [α]D25 +36 (c 0.18, CHCl3). 1H NMR (CDCl3, 400 MHz) δ (ppm)
0.87 (t, J = 7.3 Hz, 3H, CH2CH2CH3), 1.28-1.38 (m, 2H, CH2CH2CH3), 1.49-1.57 (m,
2H, CH2CH2CH3), 2.95-3.03 (m, 1H, H4), 3.26 (ddd, J = 9.4, 8.2, 6.5 Hz, 1H, H3), 3.79
(s, 3H, OCH3), 4.02 (ddt, J = 14.2, 8.2, 2.0 Hz, 1H, H2), 4.29 (dddd J = 14.2, 9.5, 2.3,
’
1.5 Hz, 1H, H2 ), 6.86-6.89 (m, 2H, Arpara), 6.93-6.65 (m, 1H, H5), 7.13-7.4218 (m, 2H,
Arpara). 13C NMR (CDCl3, 100 MHz) δ (ppm) 14.0 (CH2CH2CH3), 20.6 (CH2CH2CH3),
35.1 (CH2CH2CH3), 45.9 (C3), 50.9 (C4), 55.3 (OCH3) 69.1 (C2), 114.5 (Ar), 128.2(Ar),
132.9 (Ar), 138.3 (C5) 158.9 (Ar). HRMS Calculated for C14H19NO2: 233.1416. Found:
233.1485. Anal Calcd. for C14H19NO2: C, 72.07; H, 8.21; N, 6.00. Found C, 72.15; H,
8.02; N, 6.27.
O
N
O
Compound 5e: oil; [α]D25 +49 (c 0.23, CHCl3). 1H NMR (CDCl3, 400 MHz) δ (ppm)
0.86 (t, J = 7.3 Hz, 3H, CH2CH2CH3), 1.26-1.39 (m, 2H, CH2CH2CH3), 1.44-1.61 (m,
2H, CH2CH2CH3), 3.05-3.13 (m, 1H, H4), 3.39 (ddd, J = 9.1, 8.2, 6.6 Hz, 1H, H3), 4.08
’
(ddt, J = 14.0, 8.1, 2.0 Hz, 1H, H2), 4.17 (dddd J = 13.8, 9.5, 2.2, 1.5 Hz, 1H, H2 ), 6.09
(dt, J = 3.2, 0.7 Hz, 1H, Ar), 6.26 (dd, J = 3.2, 1.9 Hz, 1H, Ar), 6.83-6.85 (m, 1H, H5),
7.30 (dd, J = 1.9, 0.8 Hz, 1H, Ar). 13C NMR (CDCl3, 100 MHz) δ (ppm) 13.7
(CH2CH2CH3), 20.3 (CH2CH2CH3), 34.9 (CH2CH2CH3), 39.3 (C4), 47.3 (C3), 65.5 (C2),
106.0 (Ar), 110.2 (Ar), 137.5 (C2) 142.1 (Ar), 151.7 (Ar). HRMS Calculated for
C11H15NO2: 193.1103. Found: 193.1182. Anal Calcd. for C11H15NO2: C, 68.37; H, 7.82;
N, 7.25. Found C, 68.26; H, 7.66; N, 7.43.

Compound 9a: yellow oil; [α]D25 -25 (c 0.14, CHCl3). 1H NMR (CDCl3, 400 MHz) δ
(ppm) 1.49-1.77 (m, 3H, H3, H4, H4’), 1.88-2.00 (m, 1H, H3’), 2.64 (tdd, J = 8.7, 6.1, 2.4
Hz, 1H, H4a), 2.87-3.05 (m, 2H, H2a, H6), 3.18 (ddd, , J = 11.3, 9.1, 6.0 Hz, 1H, H5),
3.61-3.73 (m, 3H, H2, H2’, H6’), 4.17 (t, J = 8.3 Hz, 1H, H2a), 7.10-7.32 (m, 5H, Ar). 13C
NMR (CDCl3, 100 MHz) δ (ppm) 31.1 (C4), 31.5 (C3), 49.0 (C5), 50.0 (C2a), 53.7 (C4a),
64.5 (C6), 71.9 (C2), 77.5 (C2a), 125.5 (Ar), 128.6 (Ar), 128.6 (Ar), 144.7 (Ar). HRMS
Calculated for C14H17NO: 215.1310. Found [M+H]: 216.1375. Anal Calcd. for
C14H17NO: C, 78.10; H, 7.96; N, 6.51. Found C, 78,47; H, 8.32; N, 6.35.
MeO
H
N
H
H
O
Compound 9b: transparent oil; [α]D25 -9 (c 0.12, CHCl3). 1H NMR (CDCl3, 400 MHz)
δ (ppm) 1.57-1.84 (m, 3H, H3, H4, H4’), 1.99-2.09 (m, 1H, H3’), 2.69 (tdd, J = 8.6, 6.4,
1.9 Hz, 1H, H4a), 2.84-3.10 (m, 3H, H2a, H5, H6), 3.51-3.73 (m, 6H, H2, H2’, H6’, CH3O),
4.19 (t, J = 8.1 Hz, 1H, H2a), 6.69-6.76 (m, 2H, Ar), 6.99-7.05 (m, 2H, Ar). 13C NMR
(CDCl3, 100 MHz) δ (ppm) 31.0 (C4), 31.3 (C3), 47.8 (C5), 49.8 (C2a), 53.5 (C4a), 55.3
(CH3O), 64.1 (C6), 72.5 (C2), 77.2 (C2a), 114.1 (Ar), 128.5 (Ar), 132.8 (Ar), 158.4 (Ar).
HRMS Calculated for C15H19NO2: 245.1416. Found [M+H]: 246.1478. Anal Calcd. for
C15H19NO2: C, 73.44; H, 7.81; N, 5.71. Found C, 73.32; H, 7.98; N, 5.49.

Br
H
H
N
H
O
Compound 9c: yellow oil; [α]D25 -9.9 (c 0.10, CHCl3). 1H NMR (CDCl3, 400 MHz) δ
(ppm) 1.59-1.81 (m, 3H, H3, H4, H4’), 2.01-2.09 (m, 1H, H3’), 2.69 (ddd, J = 9.3, 8.9,
2.2 Hz, 1H, H4a), 3.00-3.08 (m, 2H, H2a, H6), 3.23 (ddd, J = 11.4, 9.2, 6.2 Hz, 1H, H5),
3.70-3.80 (m, 3H, H2, H2’, H6’), 4.27 (t, J = 8.3 Hz, 1H, H2a), 7.13-7.17 (m, 2H, Ar),
7.44-7.48 (m, 1H, Ar). 13C NMR (CDCl3, 100 MHz) δ (ppm) 31.0 (C4), 31.4 (C3), 48.5
(C5), 49.9 (C2a), 53.7 (C4a), 64.5 (C6), 71.9 (C2), 77.4 (C2a), 129.3 (Ar), 131.7 (Ar),
140.7 (Ar). HRMS Calculated for C14H16BrNO: 293.0415. Found [M+H]: 294.0502;
296.0483. Anal Calcd. for C14H16BrNO: C, 57.16; H, 5.48; Br, 27.16; N, 4.76. Found C,
57.36; H, 5.29; Br, 28.21; N, 4.94.
O
H
N
H
H
O
Compound 9d: yellow oil; [α]D25 -12 (c 0.25, CHCl3). 1H NMR (CDCl3, 400 MHz) δ
(ppm) 1.43-1.81 (m, 3H, H3, H4, H4’), 1.89-2.00 (m, 1H, H3’), 2.69 (td, J = 8.7, 1.9 Hz,
1H, H4a), 2.91 (tdd, , J = 8.4, 4.5, 1.1 Hz, 1H, H2a), 3.02 (ddd, J = 13.4, 11.3, 0.8 Hz,
1H, H6), 3.25 (ddd, , J = 11.2, 9.2, 6.0 Hz, 1H, H5), 3.57-3.71 (m, 3H, H2, H2’, H6’), 4.12
(t, J = 8.2 Hz, 1H, H2a), 5.98 (dt, J = 3.1, 0.7 Hz, 1H, Ar), 6.22 (dt, J = 3.1, 1.9 Hz, 1H,
Ar), 7.26 (dd, J = 1.8, 0.8 Hz, 1H, Ar). 13C NMR (CDCl3, 100 MHz) δ (ppm) 31.1 (C4),
31.4 (C3), 42.6 (C5), 49.8 (C4a), 50.9 (C2a), 62.0 (C6), 71.9 (C2), 77.1 (C2a), 104.9 (Ar),
110.1 (Ar), 141.4 (Ar), 155.3 (Ar). HRMS Calculated for C12H15NO2: 205.1103. Found
[M+H]: 207.1186. Anal Calcd. for C12H15NO2: C, 70.22; H, 7.37; N, 6.82. Found C,
70.46; H, 7.509; N, 6.73.

HPLC of compounds 9a-d
The racemic derivatives were prepared by using pyrrolidine, instead of 3, as a catalyst.
Compound 9a: (Chiralpak IC, hexane/iPrOH, 9:1, 1 mL/min)
Racemic:
Optically active:

MeO
H
H
N
H
O
Compound 9b: (Chiralpak IC, hexane/iPrOH, 9:1, 1 mL/min)
Racemic:
Optically active:

Br
H
H
N
H
O
Compound 9c: (Chiralpak IC, hexane/iPrOH, 4:1, 1 mL/min)
Racemic:
Optically active:

O
H
H
N
H
O
Compound 9d. (Chiralpak IC, hexane/iPrOH, 9:1, 1 mL/min)
Racemic:
Optically active:

Details on Theoretical Calculations
All calculations were performed with the GAUSSIAN 03 package.1 The hybrid density
functional theory B3LYP2 with the 6-31G* basis set35 were employed. Geometry
optimizations and vibrational analyses were performed without any constraint and the
transition structure was characterized by analysis of the normal mode corresponding to
its unique imaginary frequency.
1 Gaussian 03, Revision C.02, Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria,
G. E.; Robb, M. A.; Cheeseman, J. R.; Montgomery, Jr., J. A.; Vreven, T.; Kudin, K.
N.; Burant, J. C.; Millam, J. M.; Iyengar, S. S.; Tomasi, J.; Barone, V.; Mennucci, B.;
Cossi, M.; Scalmani, G.; Rega, N.; Petersson, G. A.; Nakatsuji, H.; Hada, M.; Ehara,
M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.;
Kitao, O.; Nakai, H.; Klene, M.; Li, X.; Knox, J. E.; Hratchian, H. P.; Cross, J. B.;
Bakken, V.; Adamo, C.; Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.;
Austin, A. J.; Cammi, R.; Pomelli, C.; Ochterski, J. W.; Ayala, P. Y.; Morokuma, K.;
Voth, G. A.; Salvador, P.; Dannenberg, J. J.; Zakrzewski, V. G.; Dapprich, S.;
Daniels, A. D.; Strain, M. C.; Farkas, O.; Malick, D. K.; Rabuck, A. D.;
Raghavachari, K.; Foresman, J. B.; Ortiz, J. V.; Cui, Q.; Baboul, A. G.; Clifford, S.;
Cioslowski, J.; Stefanov, B. B.; Liu, G.; Liashenko, A.; Piskorz, P.; Komaromi, I.;
Martin, R. L.; Fox, D. J.; Keith, T.; Al-Laham, M. A.; Peng, C. Y.; Nanayakkara, A.;
Challacombe, M.; Gill, P. M. W.; Johnson, B.; Chen, W.; Wong, M. W.; Gonzalez,
C.; and Pople, J. A.; Gaussian, Inc., Wallingford CT, 2004.
2 (a) Becke, A. D: J. Chem. Phys 1993, 98, 5648-5652. (b) Lee, C.; Yang, W.; Parr, R.
G. Phys. Rev. B 1998, 37, 785-789. (c) Miehlich, B.; Savin, A.; Stoll, H.; Preuss, H.
Chem. Phys. Lett. 1989, 157, 200-205.
3 (a) Ditchfield, R.; Hehre, W. J.; Pople, J. A. J. Chem. Phys 1971, 54, 724-728. (b)
Hehre, W.. J.; Ditchfield, R.; Pople, J. A. J. Chem. Phys 1972, 56, 2257-2261. (c)
Hariharan, P. C.; Pople, J. A. Mol. Phys. 1974, 27, 209-214. (d) Gordon, M. S:
Chem. Phys. Lett. 1980, 76, 163-168. (e) Franci, M. M.; Pietro, W. J.; Hehre, W. J.;
Binkley, J. S.; DeFrees, D. J.; Pople, J. A.; Gordon, M. S. J. Chem. Phys 1982, 77,
3654-3655. (f) Rassolow, V. A.; Pople, J. A:; Ratner, M. A:; Windus, T. L. J. Chem.
Phys 1998, 109, 1223-1229.

Figure S1. Reaction paths for the intramolecular cycloaddition of nitrones 8a-d. The R
substituent has been approached by a methyl group.
Coordinates of stationery points (B3LYP/6-31G(d))
SM
C
C
C
C
H
H
H
H
H
N
2.17594600 0.18546800 0.92860200
0.73498300 0.80414500 -0.78076800
0.29782700 -0.58803300 -0.43728100
1.47332800 -1.10155900 0.46455100
3.26728700 0.15303500 0.88299600
1.88212000 0.53160900 1.92400800
0.31288700 1.47354400 -1.51871300
0.23176600 -1.20654200 -1.34546400
1.06836500 -1.64331900 1.32669400
1.73153500 1.23285600 -0.04430400

O
C
H
H
H
C
H
H
C
H
H
C
H
C
H
H
2.30648600 2.35715700 -0.04896900
2.42286100 -2.02783800 -0.30456700
3.26033300 -2.34927700 0.32547900
1.89956000 -2.92566600 -0.65261700
2.83824600 -1.51798500 -1.18234300
-1.07688000 -0.65582500 0.26804000
-1.26409500 -1.70072200 0.55509000
-1.04037200 -0.07569000 1.19974700
-2.24746700 -0.15151000 -0.59650400
-2.10068300 0.90708700 -0.84441200
-2.24292200 -0.70400700 -1.54954300
-3.58112500 -0.32941600 0.07784800
-3.85864900 -1.35830600 0.31557500
-4.41360400 0.65833200 0.40827100
-4.17921500 1.69936900 0.19390000
-5.36246900 0.46703300 0.90233000
TS
C
C
C
C
H
H
H
H
H
C
H
C
H
H
C
H
0.81467400 -1.06854400 -0.86279800
-0.14476100 -0.15078600 1.05539900
0.85923300 0.88672000 0.61720700
1.69130200 0.13935700 -0.48175500
1.37781100 -1.98345000 -1.06980800
0.15171300 -0.87485100 -1.71647800
-0.54463700 -0.24382500 2.05788100
1.52056500 1.21014300 1.43111600
1.82916600 0.79159100 -1.35208700
-1.91462200 0.58168500 0.18631200
-2.33844200 0.96875800 1.11447000
0.06148100 2.11219800 0.09867200
-0.25466900 2.71103200 0.96411400
0.69360600 2.76348000 -0.51898200
-1.19374000 1.62711300 -0.65012000
-1.85034500 2.48225100 -0.86294800

H
C
H
H
N
O
C
H
H
H
-0.91972200 1.20154600 -1.62489600
-2.50193200 -0.56806300 -0.32890200
-3.27988200 -1.09038700 0.21459000
-2.41690200 -0.81700300 -1.38247400
-0.03584800 -1.28083100 0.32483700
-1.05297700 -2.07281300 0.23720200
3.06872100 -0.28846300 0.04066900
3.63149900 -0.83114100 -0.72777900
3.66422200 0.58089600 0.34250400
2.96863100 -0.94800900 0.91119400
PR
C
C
C
C
H
H
H
H
H
C
H
C
H
H
C
H
H
C
H
H
N
O
1.40198200 -1.34957000 0.08509000
-0.35078200 -0.12513300 1.02581100
0.56003600 0.93245800 0.31717500
1.68414300 0.10769200 -0.37323600
1.97347400 -1.58559100 0.99306000
1.63774100 -2.10823800 -0.66572700
-0.20113400 -0.16827700 2.10863300
0.98708000 1.61591400 1.06145700
1.54286300 0.16152600 -1.45861100
-1.81191400 0.15755400 0.59972200
-2.52706300 0.06888000 1.42329100
-0.38744900 1.71216500 -0.62665600
-0.08259700 2.75459700 -0.77371400
-0.39709700 1.23145100 -1.61169500
-1.77721000 1.58731900 0.02242300
-1.87595400 2.31013800 0.84348900
-2.59955900 1.78305400 -0.67639400
-2.03931600 -0.96997000 -0.43661400
-2.60299300 -1.79966600 0.01467200
-2.54975300 -0.63823600 -1.34627300
-0.01289300 -1.45275000 0.45577700
-0.74568000 -1.40621700 -0.82995900

C
H
H
H
3.10695700 0.56909300 -0.04492600
3.85541600 -0.07351900 -0.52495900
3.28476300 1.59511400 -0.38774800
3.29182600 0.54219000 1.03701100