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A Novel Green Synthesis of Thalidomide and Analogs
Ellis Benjamin1 and Yousef M. Hijji2*1Department of Chemistry, Stockton University 101 Vera King Farris Drive,Galloway, NJ
08205-9441. 2Department of Chemistry and Earth Sciences, Qatar University, P.O. Box 2713, Doha, Qatar
GC-MS and NMR Spectra for
2-(2,6-Dioxo-piperidin-3-yl)-isoindole-1,3-dione (1).
2-(2,6-Dioxo-piperidin-3-yl)-hexahydro-isoindole-1,3-dione (2).
3-(2,5-Dioxo-pyrrolidin-1-yl)-piperidine-2,6-dione (3).
3-(2,6-Dioxo-piperidin-3-yl)-3-aza-bicyclo[3.2.0]heptane-2,4-dione (4).
2-(2,6-dioxopiperidin-3-yl)-3a,4,7,7a-tetrahydro-1H-4,7-ethanoisoindole-1,3(2H)-
dione (5).
1. Experimental:
1
Standardized methods for the identification of products consisted of (GC - MS), 1H NMR, 13C
NMR, DEPT-C NMR, Melting Point, and Infrared Spectroscopy (IR). Every new compound
synthesized was completely analyzed by all corresponding techniques. Gas Chromatograph
Mass Spectrometry was performed using either a Shimadzu GC-17A and GC - MS-QP5050A
LabSolutions system or a Varian CP 3800 and Saturn 2200 system.
1H, 13C and DEPT-C NMR were performed on a Bruker 400 MHz in DMSO.d6. All solvent
(HPLC grade) were purchased from Fisher Scientific Corporation. All reagents were purchased
from Aldrich Chemical Company and were used without purification.
2
GC –MS Spectra and NMR spectra for compounds 1-5
2-(2,6-Dioxo-piperidin-3-yl)-isoindole-1,3-dione ( 1)
GC-MS:
5.0 7.5 10.0 12.5 15.0 17.5 20.0
10e6
20e6
30e6
40e6
TIC
50 75 100 125 150 175 200 225 250 275 300 325 3500e3
500e3
1000e3
1500e3
2000e3
2500e3
3000e3
3500e376
173
11150148
66130
20223018694 25841 213117 161
241 281 346
Figure 1: GC chromatogram and MS spectra of Thalidomide.
3
ppm (t1)0.05.010.015.0
0
100
200
300
400
500
N
O
ONH
O
O
Figure 2: H-NMR of Thalidomide (1)
ppm (t1)2.002.503.003.504.004.505.00
0
100
200
300
400
500
N
O
ONH
O
O
Figure 3: H-NMR of Thalidomide (1)Zoomed
4
ppm (t1)050100150200
-500
0
500
1000
1500
2000
2500
3000
3500
172.736169.829167.142
134.875131.225123.409
48.981
30.931
21.982
N
O
ONH
O
O
Figure 4 :13C-NMR of thalidomide (1)
5
2-(2,6-Dioxo-piperidin-3-yl)-hexahydro-isoindole-1,3-dione
5.0 7.5 10.0 12.5 15.0 17.5 20.0
25.0e6
50.0e6
TIC
50 75 100 125 150 175 200 225 250 275 300 3250e3
500e3
1000e3
1500e3
2000e3
2500e3
3000e3
11267
5441 82
154
153
84
111
179
264193136 236207 247 266 281 327298
Figure 5: GC chromatogram and MS spectra of compound 2
6
ppm (t1)5.010.0
0
100
200
300
400
500
600N
O
ONH
O
O
Figure 6: H-NMR of compound (2)
7
ppm (t1)1.001.502.002.503.00
0
100
200
300
400
500
600N
O
ONH
O
O
Figure 7: H-NMR of compound (2) zoomed
8
ppm (t1)5.06.07.08.09.010.011.012.0
0
100
200
300
400
500
600N
O
ONH
O
O
Figure 8: H-NMR of compound (2) zoomed.
9
ppm (t1)050100150200
0
5000
178.841178.752172.683169.394
48.758
38.82530.71023.12222.93021.11821.06821.019
N
O
ONH
O
O
Figure 9: 13C-NMR of compound (2)
10
3-(2,5-Dioxo-pyrrolidin-1-yl)-piperidine-2,6-dione:
5.0 7.5 10.0 12.5 15.0 17.5 20.0
5.0e6
10.0e6
15.0e6
20.0e6
25.0e6
30.0e6 TIC
50 75 100 125 150 175 200 225 250 275 300 3250e3
500e3
1000e3
1500e3
2000e3
2500e3
3000e355
111
125
56
83
4197
182139
210167153 168 209 327281234
Figure 10: GC chromatogram and MS spectra of (3)
11
``ppm (t1)5.010.0
0
500
1000
1500
2000
2500N
O
ONH
O
O
` Figure 11: H-NMR of compound (3)
12
ppm (t1)1.7501.8001.8501.900
0
50
100
150
200
250N
O
ONH
O
O
Figure 12: H-NMR of compound (3) zoomed.
13
ppm (t1)2.3002.3502.4002.4502.5002.5502.600
0
100
200
300
400
500
600
N
O
ONH
O
O
Figure 13: H-NMR of compound (3) Zoomed
14
ppm (t1)050100150200
-50
0
50
100
150
200
250
300
350
176.886172.685169.267
49.012
30.68027.95621.050
N
O
ONH
O
O
Figure 14: 13C-NMR of compound (3)
15
3-(2,6-Dioxo-piperidin-3-yl)-3-aza-bicyclo[3.2.0]heptane-2,4-dione:
5.0 7.5 10.0 12.5 15.0 17.5 20.0
25.0e6
50.0e6
75.0e6TIC
GC-MS chromatogram of compound 3.
50 75 100 125 150 175 200 225 250 275 300 325 3500.0e6
1.0e6
2.0e6
3.0e6
4.0e6
5.0e6
6.0e6 55126
96
112
11183
5641
151236
208165 180 193 215 271243 281256 295 341325
Figure 15: MS- Spectrum of Compound (4)
16
ppm (t1)0.05.010.015.0
0
100
200
300
400
500
N
O
ONH
O
O
Figure 16: H-NMR Spectrum of compound (4)
ppm (t1)2.002.50
0
100
200
300
400
500
N
O
ONH
O
O
Figure 17: H-NMR spectrum of compound (4) zoomed
17
ppm (t1)5.06.07.08.09.010.011.0
0
100
200
300
400
500
N
O
ONH
O
O
Figure 18: H-NMR spectrum of compound (4) zoomed.
ppm (t1)050100150200
0
50
100
150
200
179.049172.707169.386
49.061
37.97037.72830.73622.38222.14221.023
N
O
ONH
O
O
Figure 19: C-13 NMR ( 100 MHZ) spectra of compound (4).
18
2-(2,6-dioxopiperidin-3-yl)-3a,4,7,7a-tetrahydro-1H-4,7-ethanoisoindole-1,3(2H)-dione:
5.0 7.5 10.0 12.5 15.0 17.5 20.0
2500e3
5000e3
7500e3
10.0e6
12.5e6
15.0e6TIC
50 75 100 125 150 175 200 225 250 275 300 325 3500e3
500e3
1000e3
1500e3
2000e3
2500e3
78
178
20941 8454 99288112 21056 136 260149 165 182 231 243 341300 320
Figure 20: GC-MS spectrum of compound (5)
19
ppm (t1)0.05.010.0
0
500
1000
1500
N
O
ONH
O O
Figure 21: H-NMR spectrum of compound (5)
20
ppm (t1)1.001.502.002.503.00
0
50
100
150
200
250N
O
ONH
O O
Figure 22: H-NMR spectrum of compound (5) zoomed.
21
ppm (t1)5.06.07.08.09.010.011.012.0
0
50
100N
O
ONH
O O
Figure 23: H-NMR spectrum of compound (5) zoomed.
22
ppm (t1)050100150200
0
1000
2000
3000
4000
177.752177.717172.572168.733
132.094131.819
48.76343.38931.41031.28731.24430.49823.19023.00221.305
N
O
ONH
O O
Figure 24: C-13 NMR spectrum of compound (5).
23
