Synthesis and applications of 4-substituted 1-(4-iodophenyl)pyrrolidine-2,5-diones

Article abstract of DOI:10.1016/j.tetlet.2015.05.066

The synthesis of 4-substituted 1-(4-iodophenyl)pyrrolidine-2,5-dione derivatives was achieved through an addition reaction between amines and a thiol in the presence of PMDTA as a base and a copper salt. The derivatives containing a terminal acetylene moi

Full text of DOI:10.1016/j.tetlet.2015.05.066

Tetrahedron Letters 56 (2015) 4234–4241
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis and applications of 4-substituted
1-(4-iodophenyl)pyrrolidine-2,5-diones
Bakhat Ali a, Anwar Shamim b, Stanley N. S. Vasconcelos a, Hélio A. Stefani a,
⇑
a Departamento de Farmácia, Faculdade de Ciências Farmacêuticas, Universidade de São Paulo, São Paulo, SP, Brazil
b Instituto de Química, Universidade de São Paulo, São Paulo, SP, Brazil
a r t i c l e i n f o
a b s t r a c t
Article history:
The synthesis of 4-substituted 1-(4-iodophenyl)pyrrolidine-2,5-dione derivatives was achieved through
an addition reaction between amines and a thiol in the presence of PMDTA as a base and a copper salt.
The derivatives containing a terminal acetylene moiety were converted to the corresponding 1,4-triazolyl
derivatives. The 1-(4-iodophenyl)pyrrolidine-2,5-dione derivatives were functionalized through oxida-
tion alkylation and allylation reactions. In general, the compounds were obtained in moderate-to-good
yields.
Received 10 April 2015
Revised 11 May 2015
Accepted 18 May 2015
Available online 21 May 2015
Keywords:
Malic acid
Ó 2015 Elsevier Ltd. All rights reserved.
Maleimide
Aminopyrrolidine
1,4-Triazole
Functionalization
Introduction
Zhou et al. developed a small molecular targeted contrast agent
CREKA-Tris(Gd-DOTA)3 for effective molecular MRI of a cancer
Nitrogen-containing heterocycles are extensive in a large num-
ber of natural and unnatural products.1 Pyrrolidines and piperidi-
nes represent some of the most common core heterocyclic
structures among these series and a number of synthetic method-
ologies have been utilized for their synthesis or the preparation of
their derivatives.2 In this field, aminopyrrolidines are important
synthetic targets and polyhydroxylated aminopyrrolidines have
attracted interest because of their potential role as glycosidase
inhibitors.3 Oxopyrrolidines and 3-aminopyrrolidines are used as
chiral ligands4 and building blocks for the synthesis of bioactive
compounds.5,6
3-Aminopyrrolidine derivatives (1) are used as GlyT1 inhibitors
for the treatment of diseases such as neuro-/psychiatric disorders
and pain.7 Oxopyrrolidine derivatives (2) are inhibitors of methion-
ine amino peptidase (MetAP-2) and can also be used for the treat-
ment of tumors.8 Aminopyrrolidine derivatives (3) are also useful
intermediates for antibacterials9 (Fig. 1).
biomarker that is abundant in the tumor microenvironment.
CREKA-Tris(Gd-DOTA)3 resulted in strong and prolonged tumor
contrast enhancement. The small molecular peptide-targeted MRI
contrast agent holds great promise for clinical cancer molecular
imaging.15
Styslinger et al. presented a method that allows the facile site-
selective glycosylation of proteins with carbohydrates of variable
molecular weights (MWs). To demonstrate the usefulness of this
technology, hemoglobin (Hb) was site-selectively glycosylated
with a series of carbohydrates of increasing MW (from 504 to
ꢀ10,000). Hb was selected on the basis of the vast wealth of bio-
chemical and biophysical knowledge present in the literature and
because of its use as a precursor in the synthesis/formulation of
artificial red-blood-cell substitutes16 (Fig. 2).
R
R
NH
HN
HO
R
NH
Similarly, 3-mercaptooxopyrrolidines have also great impor-
tance as proteomic linkers.10 Advances in thiol-ene chemistry11
have been rapid over the last decade, as the highly versatile reac-
tivity of thiols with alkenes has been utilized across multiple areas
of macromolecular,12 biomolecular,13 and materials chemistry.14
R
N
3
R
R
O
O
O
O
O
O
N
S
N
O
R
O
Ph
1
2
⇑
Corresponding author. Tel.: +55 11 3091 3654; fax: +55 11 3815 441.
E-mail address: hstefani@usp.br (H.A. Stefani).
Figure 1. Structures of compounds 1–3.
http://dx.doi.org/10.1016/j.tetlet.2015.05.066
0040-4039/Ó 2015 Elsevier Ltd. All rights reserved.

B. Ali et al. / Tetrahedron Letters 56 (2015) 4234–4241
4235
Figure 2. Structure of mercapto oxopyrrolidine oligosaccharides.
OAc
O
Typical routes to aminopyrrolidines employ resolution of race-
mates,17 radical cyclization,18 or a chiral pool with carbohydrates19
O
and amino-acid derivatives20 as starting materials.
O
1. CH3COCl, reflux, 24h
HO
N
OH
2. 4-iodoaniline, THF, rt, 3h,
reflux, 1h
3. CH3COCl, reflux, 6h
According to previously published reports, 3-aminopyrrolidines
are prepared through an aza-Michael addition, either from
maleimide with amines using a base such as TMEDA (tetram-
ethylethylenediamine) or TMCDA (R,R)-N,N,N0,N0-tetramethyl-1,
2-diaminocyclohexane)21 or from aspartic acid.22 There are few
articles reported, but similar 3-aminopyrrolidine compounds are
commercially available. There are many reports on the Michael
addition of amines to electron-deficient alkenes.
These conjugate additions are carried out in the presence of a
strong base or acid.23 To avoid these harsh conditions, a number
of milder procedures have been developed using reagents such as
SnCl4/FeCl3,24 InCl3,25 CeCl3ꢁ7H2ONaI,26 Yb(OTf)3,27 Cu(OTf)2,28
CAN (cerium ammonium nitrate),29 Bi(NO3)3,30 Bi(OTf)3,31
LiClO4,32 KF/alumina,33 SmI2,34 Cu(acac)2/ionic liquid,35 ionic liq-
uid/quaternary ammonium salt in water,36 boric acid in water,37
b-cyclodextrin,38 ZrOCl2ꢁ8H2O,39 borax,40 bromodimethylsulfo-
nium bromide,41 [HP(HNCH2CH2)3N]NO3,42 cationic palladium
complexes,43 MnCl2,44 DBFOX-Ph(R)ꢁNi(ClO4)ꢁ6H2O,45 and so forth.
In our previous report, we prepared maleimide from malic
acid.46 In the present investigation, we explore a simple and gen-
eral procedure for the generation of maleimide and the conjugate
addition of a variety of amines in the presence of a catalytic
amount of copper(I) iodide in THF in a one-pot reaction.
O
OH
4
82%
I
5
Scheme 1. Synthesis of 1-(4-iodophenyl)-2,5-dioxopyrrolidin-3-yl acetate (5).
Buchwald performed the iodo substitution with an amine using
CuI47 and Hartwig later presented the same substitution with pal-
ladium.48 Initially, we used CuI (5 mol %), employing Et3N at 70 °C
for 24 h, and we obtained a mixture of products (Table 1, entry 1)
instead of getting the target product (Scheme 2).
Then, we used different palladium (Pd) and palladium–copper
(Pd/Cu) catalysts at 70 °C for 24 h with 2.5 equiv of amine. In the
next strategy, 1.2 equiv of amine and PMDTA (N,N,N0,N0,N00-pen-
tamethyldiethylenetriamine) were used with Pd and Pd/Cu
catalysts at 70 °C for 24 h and, in these cases, compound 7 was
the major product, which inspired us to increase the yield
further (Table 1, entries 8 and 9). As shown in Table 1, entry 9,
the yield of product
7 was 48%; when using Pd(PPh3)2Cl
(5%) + CuI (5%) as the catalyst, decreasing the reflux time to 3 h,
and using DMF as the solvent, the yield could be increased to
56% (Table 1, entry 10).
Next, using Pd(PPh3)2Cl (5%) + CuI (5%) catalysts and PMDTA at
room temperature in the presence of DMSO or DMF as the solvent,
the reaction resulted in yields of 55% and 58% (Table 1, entries 11
and 12, respectively). But, when CuI (30 mol %) was used under the
same conditions, it resulted in a 63% yield (Table 1, entry 13),
which was attributed to Cu–PMDTA complexation and the genera-
tion of maleimide and then addition of the amine, as presented in
our previous investigation.46 Then, we tried to put the catalyst
(CuI) and PMDTA in the reaction with the starting material and
stirred it for 2 h to generate maleimide and then addition of the
amine proceeded overnight, which gave a good yield of 70%
through a one-pot, two-step reaction and allowed the starting
material to be recovered (Table 1, entry 14).
Results and discussion
We obtained 1-(4-iodophenyl)-2,5-dioxopyrrolidin-3-yl acetate
(5) from
L
-malic acid according to our reported protocol,46 in which
L-malic acid was treated with acetyl chloride before 4-iodoaniline
was added at room temperature over 3 h, after which it was
refluxed for 1 h and again treated with acetyl chloride to give imide
(5) in 82% yield (Scheme 1).
With the starting material, 1-(4-iodophenyl)-2,5-dioxopyrro-
lidin-3-yl acetate, in hand and with the intention of obtaining
the target product by Buchwald–Hartwig methods, we surveyed
various catalysts, temperatures, and bases for the nucleophilic
substitution, but, to our surprise, this methodology failed to yield
the target product because, at elevated temperature, the reacting
amines were active sites for addition instead of substitution
reactions.
Using the above conditions, the bases PMDTA, Et3N, and DIPEA
were used, leading to yields ranging of 65–71% (Table 1, entries 15
and 16). The best result was obtained when PMDTA (1 equiv) and
Et3N (1 equiv) were used together as the base, giving an 88% yield

4236
B. Ali et al. / Tetrahedron Letters 56 (2015) 4234–4241
Table 1
OAc
O
Optimization of the reaction conditions
OAc
O
N
O
O
+
NH2
N
I
NH
OAc
HN
NH
O
O
6
N
O
O
+
NH2
N
I
+
5
O
O
N
target Product
Scheme 2. Buchwald cross-coupling reaction.
HN
6
5
I
7
nitro, p-methoxy, and fluorine groups, there was no addition reac-
tion to the formed maleimide. Similarly, when hydroxy-containing
reactants were surveyed, there was no observed reactivity (Table 2,
entry 2). Also, amino acids were evaluated for the addition reac-
tion, but showed no reactivity (Table 2, entry 6).
8
Entry Catalyst
Base
Solvent Yield (%)
7/8
1
2
3
4
5
6
CuI (5%)
Pd/Fe2O3 (5%)
Pd(OAc)2 (5%)
Pd(PPh3)2Cl (5%)
PdCl2 + CuI (5%)
Pd(PPh3)2Cl2
(5%) + CuI (5%)
CuI (5%) + Proline
(10%)
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
25:15a,c,f,g
23:15a,c,f,g
29:14a,c,f,g
28:15a,c,f,g
30:16a,c,f,g
29:18a,c,f,g
The reaction carried out with primary aliphatic amines worked
well with almost the same yields ranging from 78% to 83% (Table 2,
entries 11–13). Aliphatic amines containing branched alkyl groups
gave good yields from 66% to 75% (Table 2, entries 5–7). Similarly, a
primary-amine containing cyclic moiety gave an 83% yield
(Table 2, entry 13). The yield dropped when diamine was reacted,
giving a yield of 58% (Table 2, entry 4). For secondary amines, the
yields were 70% and 65% (Table 2, entries 1 and 3, respectively).
We also tried to further investigate the scope for the one-pot
synthesis of triazole. As mentioned above, the starting material
was dissolved in THF, the catalyst (CuI) was added, and then the
base PMDTA was added drop-wise, after which Et3N was
added in the same way and stirred for 2 h to generate maleimide;
then, the addition reaction of amine to the formed maleimide
proceeded overnight before the azide was added and stirred for a
further 6 h. All of the synthesized triazoles have good yields,
confirming the successful one-pot, three-step reaction (Table 3,
entries 1–5).46,50
Initially, when aliphatic azides were employed as the sub-
strates, the products were obtained in good yields 73%, 75%, and
68% (Table 3, entries 1, 2, and 5, respectively). Although only two
aromatic azides were used, it appears that the presence of an elec-
tron-donating or electron-withdrawing group influences the yield
of the reaction. The aromatic azide containing the p-methoxy sub-
stituent resulted in a yield of 77% and the aromatic azide contain-
ing p-iodine afforded the product in a 53% yield (Table 3, entries 3
and 4, respectively).
7
8
K3PO4
DMSO
DMSO
DMSO
DMF
31:12a,c,f,g
38:14a,c,g
48:10a,c,g
56:0a,c,h
55:0b,d,i
Pd(OAc)2
PMDTA
PMDTA
PMDTA
PMDTA
PMDTA
(5%) + CuBr (5%)
Pd(PPh3)2Cl
(5%) + CuI (5%)
Pd(PPh3)2Cl
(5%) + CuI (5%)
Pd(PPh3)2Cl
(5%) + CuI (5%)
Pd(PPh3)2Cl
(5%) + CuI (5%)
CuI (30%)
9
10
11
12
DMSO
DMF
58:0b,d,i
13
14
15
16
17
PMDTA
PMDTA
Et3N
THF
THF
THF
THF
63:0b,d,i
70:0b,d,i
71:0b,d,i
65:0b,d,i
88:0b,d,i
CuI (30%)
CuI (30%)
CuI (30%)
CuI (30%)
DIPEA
PMDTA (1 equiv) + Et3N THF
(1 equiv)
PMDTA (1 equiv) + Et3N THF
(1 equiv)
18
CuI (30%)
60:0b,e,h
19
20
—
CuI
PMDTA
—
THF
THF
Traces
nr
a
Starting material, amine, catalyst, and base added at the same time.
Starting material, catalyst, and base added at the same time and stirred for 2 h
and then amine was added and left stirring for overnight.
b
c
Temperature, entries 1–9 = 70 °C.
Temperature, entries 11–12 = rt.
d
The pyrrolidine-2,5-dione 7n (Table 2, entry 14) was converted
into the corresponding sulfoxide (11) and sulfone (12) by only
modulating the stoichiometry of the hydrogen peroxide in the
presence of ammonium molybdate51 with yields of 63% and 85%,
respectively (Scheme 3).
e
Temperature, entry 22 = ultrasonic bath rt.
Temperature, entries 8–20 = 1.2 equiv. benzylamine.
f
g
Reaction time, entries 1–9 = 24 h.
Reaction time, entry 10 = 3 h.
Reaction time, entries 11–17 = 18 h.
h
i
To show the versatility of the pyrrolidine-2,5-diones, acetylenic
compound 7k (Table 2, entry 11) was submitted to functionaliza-
tion of the terminal triple bond using n-bromo butane and allyl
bromide,52 with the same conditions for both reactions. In both
cases, the C-alkylated [(13) and (14)] and N-alkylated [(15) and
(16)] products were formed in an almost 2:1 ratio; the yields are
shown in Scheme 4.
(Table 1, entry 17). Similarly, the reaction was carried out with
ultrasonication, but, in this case, the yield decreased (Table 1, entry
18). The use of CuI and PMDTA is of paramount importance. In the
absence of CuI only traces of the desired product was observed and
in the absence of PMDTA no reaction occurred (Table 1, entries 19
and 20).
After optimizing the conditions, we synthesized a series of 1-(4-
iodophenyl)-3-(R-amino or R-thio)pyrrolidine-2,5-dione deriva-
tives (Table 2, entries 1–14).49 As shown in Table 2, primary and
secondary amines react smoothly with yields ranging from 58%
to 88%; similarly, a thiol gave an 86% yield (Table 2, entry 14)
and alcohols were found to be unreactive. It was found that, when
the reaction was carried out with substituted anilines containing
Conclusion
In conclusion, we have presented a simple methodology to
synthesize 4-substituted 1-(4-iodophenyl)pyrrolidine-2,5-dione
derivatives under mild conditions in moderate-to-good yields.
Also,
4-substituted
1-(4-iodophenyl)pyrrolidine-2,5-dione
derivatives were converted in a one-pot, three-step reaction to

B. Ali et al. / Tetrahedron Letters 56 (2015) 4234–4241
4237
Table 2
Synthesis of pyrrolidine-2,5-dione derivatives
R
X
OAc
O
O
O
O
O
O
N
I
N
N
I
CuI/PMDTA (1eq)/ Et3N (1eq)
THF, rt, 2 h
R
YH (6)
rt, 18 h
X = N, S
I
7a-n
5
Entry
1
Amines
Product
Yield (%)a
70
NH
N
6a
O
O
N
I
7a
HO
HO
2
nr
N
NH
OH
O
O
N
I
6b
OH
7b
3
4
5
65
58
75
N
NH
O
O
O
N
I
6c
7c
HN
NH2
H2N
NH2
6d
O
N
I
7d
H2N
HN
6e
O
O
N
I
7e
H2N
6
68
HN
6f
O
O
N
I
7f
(continued on next page)

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B. Ali et al. / Tetrahedron Letters 56 (2015) 4234–4241
Table 2 (continued)
Entry
Amines
Product
Yield (%)a
66
HN
7
H2N
6g
O
O
N
I
7g
O
O
OH
H2N
OH
8
nr
HN
HN
HN
HN
6h
O
O
O
O
O
O
N
7h
I
H2N
9
10
11
12
80
78
78
88
6i
O
N
7i
I
H2N
6j
O
N
7j
I
H2N
6k
O
N
7k
HN
I
H2N
O
N
6l
7l
I
NH2
HN
13
14
83
86
O
O
O
N
6m
6n
7m
I
S
SH
O
N
7n
I
a
Isolated yields.
1,4-triazolyl derivatives through the 1,3-cycloaddition reaction
catalyzed by CuI salt. The versatility of these compounds has been
shown by the oxidation of a sulfur derivative to the corresponding
sulfoxide and sulfone as well as the alkylation and allylation of a
terminal acetylenic derivative. These transformations render this
methodology a promising alternative route to access 4-substituted
1-(4-iodophenyl)pyrrolidine-2,5-dione derivatives with wide
structural diversity.

B. Ali et al. / Tetrahedron Letters 56 (2015) 4234–4241
4239
Table 3
Synthesis of 1,4-triazole pyrrolidine-2,5-dione derivatives
N
R
N
N
OAc
O
O
NH
CuI (30%)
PMDTA (1eq)
Et3N (1eq)
NH
O
O
N
H2N
6k
rt, overnight
N
I
R
N3
9a-e
O
O
O
O
N
N
I
6h
THF, rt, 2h
I
5
I
7k
10a-e
Entry
1
Azides
Product
Yield(%)a
N3
N
N
N
73
NH
9a
O
N
O
I
10a
N3
N
N
N
2
75
F
NH
F
9b
O
N
O
10b
I
N3
O
N
N
N
3
77
O
NH
9c
O
N
O
10c
I
N3
I
N
N
N
4
53
I
NH
9d
O
N
O
10d
I
N3
N
N
N
( )8
11
9e
5
68
NH
O
N
O
10e
I
a
Isolated yields.

4240
B. Ali et al. / Tetrahedron Letters 56 (2015) 4234–4241
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O
H2O2 (1 eq)
O
O
O
N
(NH4)2MoO4
CH3OH:H2O (2:1), 0 oC
S
I
63%
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O
N
11
O
N
S
O
H2O2 (4 eq)
I
7n
O
(NH4)2MoO4
CH3OH:H2O (2:1), 0 oC
I
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12
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O
N
Br
O
O
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27. Matsubara, S.; Yoshiyoka, M.; Utimoto, K. Chem. Lett. 1994, 5, 827.
28. Xu, L.-W.; Li, J.-W.; Xia, C.-G.; Zhou, S.-L.; Hu, X.-X. Synlett 2003, 2425.
29. Duan, Z.; Xuan, X.; Li, T.; Yang, C.; Wu, Y. Tetrahedron Lett. 2006, 47, 5433.
30. Srivastava, N.; Banik, B. K. J. Org. Chem. 2003, 68, 2109.
31. Varala, R.; Alam, M. M.; Adapa, S. R. Synlett 2003, 720.
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53%
25%
I
I
NH
13
15
O
O
N
N
O
NH
O
I
Br
+
7k
O
O
N
N
I
Na2SO3, CuI,
K2CO3
I
20%
40%
16
14
Scheme 4. Alkylation and allylation of compound 7k.
Acknowledgments
33. Shaikh, N. S.; Deshpande, V. H.; Bedekar, A. V. Tetrahedron 2001, 57, 9045.
34. Reboule, I.; Gil, R.; Collin, J. Tetrahedron Lett. 2005, 46, 7761.
35. Kantam, M. L.; Neeraja, V.; Kavita, B.; Neelima, B.; Chaudhuri, M. K.; Hussain, S.
Adv. Synth. Catal. 2005, 347, 763.
36. Karodia, N.; Liu, X.; Ludley, P.; Pletsas, D.; Stevenson, G. Tetrahedron 2006, 62,
11039.
The authors are grateful for the financial support provided by
FAPESP—São Paulo Research Foundation (Grant 2012/00424-2
and fellowship to B.A.—2012/17954-4) and CNPq—National
Council for Scientific and Technological Development
(308.320/2010-7).
37. Chaudhuri, M. K.; Hussain, S.; Kantam, M. L.; Neelima, B. Tetrahedron Lett. 2005,
46, 8329.
38. Surendra, K.; Krishnaveni, N. S.; Sridhar, R.; Rao, K. R. Tetrahedron Lett. 2006, 47,
2125.
39. Hashemi, M. M.; Eftekhari-Sis, B.; Abdollahifar, A.; Khalili, B. Tetrahedron 2006,
62, 672.
Supplementary data
40. Hussain, S.; Bharadwaj, S. K.; Chaudhuri, M. K.; Kalita, H. Eur. J. Org. Chem. 2007,
2, 374.
41. Khan, A. T.; Parvin, T.; Gazi, S.; Choudhury, L. H. Tetrahedron Lett. 2007, 48,
3805.
42. Fetterly, B. M.; Jana, N. K.; Verkade, J. G. Tetrahedron 2006, 62, 440.
43. Hii, K. K. Pure Appl. Chem. 2006, 78, 341.
Supplementary data (experimental details and analytical data
for all new compounds, including 1H and 13C NMR spectra) associ-
ated with this article can be found, in the online version, at http://
dx.doi.org/10.1016/j.tetlet.2015.05.066.
44. Roy, A.; Kundu, D.; Kundu, S. K.; Majee, A.; Hajra, A. Open Catal. J. 2010, 3, 34.
45. Zhuang, W.; Hazell, R. G.; Jorgenson, K. Chem. Commun. 2001, 240.
46. Stefani, H. A.; Ferrera, F. P.; Ali, B.; Pimenta, D. C. Tetrahedron Lett. 2014, 55,
4355.
References and notes
1. (a) Watson, P. S.; Jiang, B.; Scott, B. Org. Lett. 2000, 2, 3679; (b) Johnson, T. A.;
Curtis, M. D.; Beak, P. J. Am. Chem. Soc. 2001, 123, 2001.
47. Kwong, F. Y.; Klapars, A.; Buchwald, S. L. Org. Lett. 2002, 4, 581.
48. Vo, G. D.; Hartwig, J. F. J. Am. Chem. Soc. 2002, 131, 11049.
49. General procedure: CuI (30%) was added to 3-(benzylamino)-1-
(iodophenyl)pyrrolidine-2,5-dione (7l) in a solution of 5 (0.5 mmol) in dry
THF (3 mL), followed by drop-wise addition of PMDETA (0.5 mmol) at room
temperature. Et3N (0.5 mmol) was then added and left stirring for almost 2 h,
followed by drop-wise addition of amine 6 (0.5 mmol) to the solution and left
stirring overnight. The reaction mixture was then evaporated, neutralized with
0.1 N HCl solution, extracted with ethyl acetate, and the organic phase was
then washed with brine. The organic phase was dried over anhydrous Na2SO4,
2. For reviews of the synthesis of pyrrolidines and piperidines, see: (a) Fabio, B.;
Enzo, R. Tetrahedron 2006, 62, 7213; (b) Pei-Qiang, H. Synlett 2006, 1133; (c)
Bailey, P. D.; Millwood, P. A.; Smith, P. D. Chem. Commun. 1998, 633; (d)
Laschat, S.; Dickner, T. Synlett 2000, 1781; (e) Weintraub, P. M.; Sabol, S.; Kane,
J. M.; Borcherding, D. R. Tetrahedron 2003, 59, 2953; (f) Buffat, M. G. P.
Tetrahedron 2004, 60, 1701.
3. Fleet, G. W. J.; Karpas, A.; Dwek, R. A.; Fellows, L. E.; Tyms, A. S.; Petursson, S.;
Namgoong, S. K.; Ramsden, N. G.; Smith, P. W.; Son, J. C.; Wilson, F. X.; Witty, D.
R.; Jacob, G. S.; Rademacher, T. W. FEBS Lett. 1988, 237, 128.

B. Ali et al. / Tetrahedron Letters 56 (2015) 4234–4241
4241
filtered, and then evaporated under reduced pressure. The crude product 7l
was purified by column chromatography over silica gel using ethyl acetate/
hexane (1:9). 1H NMR (300 MHz, CDCl3) d ppm: 2.30 (br s, NH), 2.62 (dd,
J = 18.08, 5.09 Hz, 1H), 2.93 (dd, J = 18.08, 8.48 Hz, 1H), 3.77–3.78 (m, 3H),
6.96–7.04 (m, 2H), 7.23–7.35 (m, 5H), 7.70 (m, 2H); 13C NMR (75 MHz, CDCl3) d
ppm: 36.54, 51.89, 55.51, 94.11, 127.72, 127.96 (2C), 128.36, 128.77(3C),
131.31, 138.36 (3C), 173.68, 176.44. HRMS calcd for C17H16IN2O2 (M+H)+:
407.0178; found: 407.0147.
added to the stirring solution and stirred for about 2 h. Then, the solution was
evaporated, 0.1 N HCl solution was added, extracted with ethyl acetate, and
then the extract was washed with brine. The organic phase was dried over
anhydrous Na2SO4. The solvent was then removed under reduced pressure. The
crude product 10c was purified by column chromatography over silica gel
using ethyl acetate/hexane (1:1). 1H NMR (300 MHz, DMSO-d6) d ppm: 2.73–
2.85 (m, 2H), 3.34 (s, 3H), 3.89 (s, 2H), 5.35 (dd, J = 8.95, 4.43 Hz, 1H), 7.38–7.49
(m, 4H), 7.61–7.71 (m, 4H), 8.59 (s, 1H); 13C NMR (75 MHz, DMSO-d6) d ppm:
32.19, 50.40, 55.90, 69.84, 99.86, 111.91, 121.34 (2C), 127.96, 130.26, 130.40,
132.84, 132.98, 134.84, 137.35 (2C), 138.71, 158.93, 167.19, 169.57. HRMS
calcd for C20H19IN5O3 (M+H)+: 504.0454; found: 504.0398.
50. General procedure: 1-(iodophenyl)-3-(((1-(4-methoxyphenyl)-1H-1,2,3-triazol-
4-yl)methyl)amino)pyrrolidine-2,5-dione (10c): CuI (30%) was added to
a
solution of 5 (0.5 mmol) in dry THF (3 ml), followed by drop-wise addition of
PMDETA (0.5 mmol) at room temperature. Et3N (0.5 mmol) was then added
and left stirring for almost 2 h, followed by drop-wise addition of amine 6
(0.5 mmol) to the solution and left stirring overnight. Azide 9c (1.3 equiv) was
51. Palomo Coll, A. WO Patent 02/28852 A1; Chem. Abstr. 2002, 136, 294832.
52. Bieber, L. W.; Silva, M. F. Tetrahedron Lett. 2007, 48, 7088.