A Novel Green Synthesis of Thalidomide and Analogs

Article abstract of DOI:10.1155/2017/6436185

Thalidomide and its derivatives are currently under investigation for their antiangiogenic, immunomodulative, and anticancer properties. Current methods used to synthesize these compounds involve multiple steps and extensive workup procedures. Described herein is an efficient microwave irradiation green synthesis method that allows preparation of thalidomide and its analogs in a one-pot multicomponent synthesis system. The multicomponent synthesis system developed involves an array of cyclic anhydrides, glutamic acid, and ammonium chloride in the presence of catalytic amounts of 4-N,N-dimethylaminopyridine (DMAP) to produce thalidomide and structurally related compounds within minutes in good isolated yields.

Full text of DOI:10.1155/2017/6436185

Hindawi
Journal of Chemistry
Volume 2017, Article ID 6436185, 6 pages
https://doi.org/10.1155/2017/6436185
Research Article
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, USA
2Department of Chemistry and Earth Sciences, Qatar University, P.O. Box 2713, Doha, Qatar
Correspondence should be addressed to Yousef M. Hijji; yousef.hijji@qu.edu.qa
Received 13 November 2016; Accepted 18 January 2017; Published 20 February 2017
Academic Editor: Jose´ L. Arias Mediano
Copyright © 2017 Ellis Benjamin and Yousef M. Hijji. is is an open access article distributed under the Creative Commons
Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is
properly cited.
alidomide and its derivatives are currently under investigation for their antiangiogenic, immunomodulative, and anticancer
properties. Current methods used to synthesize these compounds involve multiple steps and extensive workup procedures.
Described herein is an efficient microwave irradiation green synthesis method that allows preparation of thalidomide and its
analogs in a one-pot multicomponent synthesis system. e multicomponent synthesis system developed involves an array of
cyclic anhydrides, glutamic acid, and ammonium chloride in the presence of catalytic amounts of 4-N,N-dimethylaminopyridine
(DMAP) to produce thalidomide and structurally related compounds within minutes in good isolated yields.
1. Introduction
thalidomide and its systematic derivatization within min-
utes. Microwave application in organic synthesis has seen
exponential growth over the last twenty years due to its easy
experimental conditions, rapid turnaround, easy workups,
and high yields. e speed at which microwave reactions
are done matches well with combinational processes to
synthesize derivatives for improved biological activity when
compared to low-yielding conventional synthesis especially
that of thalidomide and its analogs (24%). e power of
microwave synthesis is utilized for speeding the reaction
and providing an efficient convenient way of obtaining these
thalidomide variations or related compounds [44–46].
alidomide has a long and tragic past that stems from its
teratogenic effects. However, recent studies prove that it is an
effective immunomodulatory, antiangiogenic, and anticancer
pharmaceutical [1, 2]. is reemergence of thalidomide has
led to a number of FDA approved derivatives including
lenalidomide and pomalidomide (multiple myeloma) [3–5].
Currently thalidomide and its derivatives are used in the
treatment of numerous diseases including Crohn [6–8], Lep-
rosy [9–11], Graf-Versus-Host (GVHD) [12–14], and multiple
forms of cancer [15–17]. ey are also known to modulate
the expression patterns of several proteins including TNFꢀ
[18–22], IL1ꢁ [23–27], and COX2 [28–31]. In fact, discovery
of lenalidomide and pomalidomide had led scientists to
explore the modification of thalidomide (Figure 1) to improve
its efficacy and decrease its teratogenic and neurotoxic
effects. Although there are several synthetic methods for
making thalidomide many of the reported syntheses are ofen
multistep processes which use exotic or expensive reagents,
maintain long reaction times, and produce very low yields
[32–43].
alidomide and a series of its analogs (2–5) are shown
in Figure 2 and synthesized in a one-pot reaction (Scheme 1),
using mild conditions and inexpensive reagents, under green
(microwave) conditions with relatively high yields. e strat-
egy is based on utilizing the corresponding anhydrides, either
commercially available anhydrides or constructed based on
our earlier work of microwave assisted Diels Alder reaction
of maleic anhydride with the required 1,3-diene. e synthesis
of thalidomide (1) and derivatives (2–5) was accomplished in
a one-pot reaction of glutamic acid with the corresponding
anhydride and ammonium chloride with the use of DMAP as
a base catalyst mixture at 150∘C in 10 minutes. In this reaction
we were able to form both substituted and unsubstituted
Our novel microwave assisted synthesis of thalidomide
and its derivatives improves over current conventional and
microwave assisted syntheses through the high yields of

2
Journal of Chemistry
O
O
H2N
CO2H
DMAP
NH4Cl
MW, 150∘C
+
O
N
O
NH
CO2H
O
O
O
Scheme 1: e synthesis of thalidomide and its analogs. Microwave conditions: 10 minutes at 150∘C.
Glutamic ring (B)
O
O
O
N
O
O
N
NH
O
NH
O
O
N
O
O
O
NH
1 (86%)
2 (62%)
O
O
O
O
O
Phthalic ring (A)
N
N
O
Figure 1: e structure of thalidomide.
NH
NH
O
O
O
3 (48%)
4 (47%)
O
cyclic imides through two condensation reactions of the
cyclic anhydride and the glutamic acid moieties, respectively.
e formation of unsubstituted imide is based on the gen-
eration of ammonia through the removal of proton from
the ammonium chloride. e thalidomide derivatives pro-
duced a glutarimide ring with a diversity of cyclic anhydrides
bound.
N
O
O
N
O
H
5 (59%)
A primary benefit of our synthetic method over previous
thalidomide syntheses methods includes the ability to modify
the phthalic ring (Figure 1, moiety (A)). Although extensive
work has focused on the modification of glutamic ring
(Figure 1, moiety (B)) of thalidomide such as introduction
of dithiocarbamate in order to enhance its biological activ-
ities, the carbon backbone is modified so that it can allow
for variation in structure and functionality. is method
focuses on the modification of the phthalic ring moiety of
thalidomide (Figure 1), allowing for the addition of multiple
carbon skeletons including bicyclic systems. Our synthesis
allows for the exploration of the effects of ring size, ring
strain, increased polarity, and structural complexity in addi-
tion to stereochemistry. ese compounds may shed light
on structure-activity relationship in thalidomide derivatives
thereby improving their efficacy. Another benefit of this
method is the ability to easily introduce labeled nitrogen
through the use of ammonium-15N chloride in the reaction
mixture.
Although this process occurs in one pot, it involves a
multistep mechanism in which the amine of glutamic acid
has to form an amide acid with the cyclic anhydride. If
the cyclic amide-glutamic acid is not formed then reac-
tion seems to proceed towards byproduct formation with
the cyclic imide as the major product. A study to deter-
mine which catalyst could improve ammonia generation
and product formation of thalidomide in the microwave
Figure 2: alidomide and thalidomide analogs synthesized.
was done using thiourea, ammonium acetate, and ammo-
nium chloride/DMAP with phthalic anhydride using sim-
ilar molar ratios. Previous research in our laboratory has
found several ways to produce ammonia from ammonium
acetate and hydroxylamine (HCl)/DMAP with ammonium
acetate being the best [47, 48]. is study used GC-MS
for determining the ratio of unsubstituted cyclic imides
(phthalimide) to thalidomide. e data shows that ammo-
nium acetate is highly efficient at forming phthalimide (90%
yield) but not thalidomide (yield < 7%). On the other
hand, the reaction resulted in higher yields of thalidomide
when DMAP/NH Cl (43%) and thiourea (40%) were used,
4
Table 1.
e main byproduct formed when ammonium acetate is
used is a cyclic imide and this may be explained by the rapid
dissociation of ammonium acetate to give ammonia that
initiates quick imide formation. Differences in the reactivity
between ammonium acetate and ammonium chloride finds
that ammonium chloride is highly stable and does not
break down under microwave irradiation. e addition of
DMAP as a base catalyst to ammonium chloride causes it
to dissociate and generate ammonia at higher temperature,
allowing glutamic acid to first react with the anhydrides to

Journal of Chemistry
3
2
4
Figure 3: ORTEP drawings of compounds (3) and (4).
O
O
O
NH
+
NH
N
O
O
O
alidomide (major)
Phthalimide (minor)
Glutamic acid
NH4Cl, DMAP, MW
O
O
O
NH4OAc, glutamic acid
MW
NH4OAc, MW
O
NH
NH
O
O
O
Exclusive
Exclusive
Scheme 2: Synthesis of phthalimide and thalidomide.
1
Table 1: Comparison of thalidomide synthesis using DMAP/NH Cl,
and identified by spectroscopic analysis. (Detailed H and
13C NMR spectra and mass spectrometry data are pre-
sented in the Supplementary Material available online at
https://doi.org/10.1155/2017/6436185.) Further structural con-
firmation was provided by single crystal X-ray structural
identifications [49]. Compounds 3 and 4 ORTEP are pre-
sented in Figure 3. Compound 3 presents interesting struc-
tural features with 4- and 5-membered fused rings with the
piperidinedione ring at almost right angle with the pyrroli-
dine ring containing dihedral angles of 67.6∘ and 73.9∘ for
the cyclobutane and 2,6-dioxopiperidine rings, respectively.
Compound 5 has an intriguing structure that contains a
bicyclic system with 4 chiral centers, a double bond that is
a handle for further functionalization and a possibility of two
more chiral centers.
4
NH OAc, and thiourea in the monomode microwave at 150∘C for 10
4
minutes.
Reagent
Phthalimide
59%
alidomide
40%
iourea
DMAP NH Cl
Ammonium acetate
57%
90%
43%
7%
4
form the imide (moiety (A)) followed by the generation of
ammonia at higher temperature and the formation of the
2,6-dioxopiperidine, NH Cl ring later (moiety (B)). Long
4
term tests (over 30 minutes) of NH Cl under microwave
4
irradiation found that it does not readily break down and
needs the presence of the DMAP as a base catalyst to
initiate ammonia production allowing time for cyclic amide-
glutamic acid formation (Scheme 2).
In conclusion, we have developed a novel green one-pot
synthetic technique for the generation of thalidomide and its
analogs. Although this article shows only a small subset of
compounds, there are a limitless number of derivatives that
can be produced/derived using this technique. is technique
also has a wide variety of applications as it relates to the
production of thalidomide analogs that may be used for the
treatment of multiple diseases.
Compounds (1–5) were generated within minutes, even
though the yields are moderate due the competition with
ammonia generated in one-pot synthesis system. e yields
are acceptable given the ease and simplicity of the reac-
tion system. Compounds (1–5) were isolated, purified,

4
Journal of Chemistry
Appendix
3-(2,5-Dioxopyrrolidin-1-yl)-piperidine-2,6-dione. (3): white
1
solid yield (0.10 g, 48%). H NMR (400 MHz, DMSO-ꢂ6) ꢃ
11.0 (s, 1 H, NH), 4.9 (dd, 1 H, 12.5, 5.5 Hz), 3.3 (s, 1 H), 2.8
(m, 3 H), 2.5 (m, 1 H), 2.4 (m, 1 H), 1.9 (m, 1 H); 13C NMR
(100 MHz, DMSO-ꢂ6) 176.9, 172.7, 169.3, 49.0, 30.7, 28.0, 22.1;
MS m/z 210 (M+) 182, 167, 125, 112, 83, 68, 56 41.
Experimental
A CEM Discover monomode microwave was used for
microwave enhanced organic synthesis. Isolation procedures
use TLC as a basis for the column chromatography of the
materials. Gas Chromatography Mass Spectrometry (GC-
MS) will be used to quantify and identify the amounts
of product and possible byproducts found in the purified
materials.
Standardized methods for the identification of prod-
ucts 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.
All IR spectra were performed on a Perkin-Elmer Spec-
trum RX I IR system. All melting points determinations were
performed on a Laboratory Devices Mel-Temp II instrument.
1H, 13C, and DEPT-C NMR were performed on Bruker
400 MHz. All solvents (HPLC grade) were purchased from
Fisher Scientific Corporation. All reagents were purchased
from Aldrich Chemical Company and were used without
purification.
3-(2,6-Dioxopiperidin-3-yl)-3-aza-bicyclo[3.2.0]heptane-2,4-
dione. (4): a white solid (54% yield). 1H NMR (400 MHz,
DMSO-ꢂ6) ꢃ 11.06 (s, 1 H, NH), 4.95 (dd, 1 H, 12.5, 5.5 Hz),
2.84 (m, 2 H), 2.52 (m, 4 H), 2.02 (m, 2 H), 1.92 (m, 2 H);
13C NMR (100 MHz, DMSO-ꢂ6) 179.0 (C=O), 172.7 (C=O),
169.4 (C=O), 48.7 (CH), 49.1 (CH), 37.9 (CH), 37.7 (CH ),
2
30.7 (CH ), 22.1 (CH ), 22.0 (CH ), 21.0 (CH ); MS m/z 236
2
2
2
2
(M+) 208, 151, 106, 112, 96, 83, 55, 41.
(2,6-Dioxopiperidin-3-yl)-3a,4,7,7a-tetrahydro-1H-4,7-etha-
noisoindole-1,3(2H)-dione. (5): a white solid (62% yield). 1H
NMR (400 MHz, DMSO-d6) ꢃ 11.0 (s, 1 H, NH), 6.1 (m, 2
H), 4.8 (dd, 1 H, 12.5, 5.5 Hz), 3.0 (m, 4 H), 2.8 (m, 1 H), 2.5
(m, 1 H), 2.3 (m, 1 H), 1.7 (m, 1 H), 1.6 (d, 2 H, 7.5 Hz), 1.2 (d,
2 H, 7.5 Hz); 13C (100 MHz, DMSO-ꢂ6) ꢃ 177.75 (C=O), 177.71
(C=O), 172.57 (C=O), 168.73 (C=O), 132.09 (CH), 131.82
(CH), 48.75 (CH), 43.37 (CH), 31.39 (CH), 31.22 (CH), 30.48
(CH), 29.79 (CH), 23.17 (CH ), 22.98 (CH ), 22.87 (CH ),
2
2
2
21.29 (CH ); MS m/z 288 (M+) 260, 209, 178, 149, 136, 112, 99,
2
80, 78, 54, 41.
alidomide Synthesis
Disclosure
e statements made herein are solely the responsibility of the
authors.
2-(2,6-Dioxopiperidin-3-yl)isoindole-1,3-dione. (1): phthalic
anhydride (0.10 g, 0.68 mmol), glutamic acid (0.10 g,
0.68 mmol), DMAP (0.02 g, 0.16 mmol), and NH Cl (0.04 g,
4
0.75 mmol) were mixed thoroughly in a CEM-sealed vial
with a magnetic stirrer. e sample was heated for 10 min at
150∘C in a CEM Discover microwave powered at 150 W. It
was then cooled rapidly to 50∘C. When at room temperature
it was dissolved in 15 mL of (1 : 1) ethyl acetate : acetone. e
organic layer was washed with 2x (10 mL) distilled water and
then dried over sodium sulfate (anhydrous). e organic
layer was concentrated under vacuum. e residue was
treated with hexanes (30 mL) affording a white solid (0.14 g,
Competing Interests
e authors declare that they have no competing interests.
Acknowledgments
Yousef M. Hijji would like to thank QNRF for support: NPRP
award from Qatar National Research Fund (a member of
e Qatar Foundation) [NPRP-.7-495-1-094]. Ellis Benjamin
would like to thank the School of Natural Sciences and
Mathematics at Stockton University.
1
80%). mp 268–270∘C. H NMR (400 MHz, DMSO-ꢂ6) ꢃ
11.14 (s, 1 H, NH), 7.94 (m, 4 H, Ar), 5.17 (dd, 1 H, 12.5, 5.5 Hz),
2.92 (m, 1 H), 2.57 (m, 2), 2.09 (m, 1 H); 13C NMR (100 MHz,
DMSO-ꢂ6) 172.7, 169.8, 167.1, 134.9, 131.2,123.4, 49.0, 30.9,
22.0; MS m/z 258 (M+); 230, 213, 202, 173, 148, 111, 76,
50.
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