One-pot synthesis of oxoisoindoline-1,2,3-triazole hybrid by a Ugi–click reaction

Article abstract of DOI:10.1080/00397911.2016.1223313

1,2,3-Triazole-3-oxoisoindoline-1-carboxamide system was successfully synthesized by using a combination of Ugi and click reactions. This two-step, one-pot synthesis was started by the reaction of 2-formyl benzoic acid, propargyl amine, and cyclohexyl iso

Full text of DOI:10.1080/00397911.2016.1223313

Synthetic Communications
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One-pot Synthesis of Oxoisoindoline-1,2,3-triazole
Hybrid by a Ugi-click Reaction
Loghman Firoozpour, Sara Akrami, Fereshteh Goli-Garmroodi, Setareh
Moghimi, Mohammad Mahdavi, Afsaneh Zonoozi & Alireza Foroumadi
To cite this article: Loghman Firoozpour, Sara Akrami, Fereshteh Goli-Garmroodi, Setareh
Moghimi, Mohammad Mahdavi, Afsaneh Zonoozi & Alireza Foroumadi (2016): One-
pot Synthesis of Oxoisoindoline-1,2,3-triazole Hybrid by a Ugi-click Reaction, Synthetic
Communications, DOI: 10.1080/00397911.2016.1223313
To link to this article: http://dx.doi.org/10.1080/00397911.2016.1223313
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Date: 24 August 2016, At: 04:15

One-pot Synthesis of Oxoisoindoline-1,2,3-triazole Hybrid by a Ugi-click Reaction
Loghman Firoozpour1, Sara Akrami2, Fereshteh Goli-Garmroodi3, Setareh Moghimi3,
Mohammad Mahdavi1, Afsaneh Zonoozi2, Alireza Foroumadi 1,3
1Drug Design and Development Research Center, Tehran University of Medical
Sciences, Tehran, Iran
2School of Chemistry, College of Science, University of Tehran, , Tehran, Iran
3Department of Medicinal Chemistry, Faculty of Pharmacy and Pharmaceutical Sciences
Research Center, Tehran University of Medical Sciences, Tehran, Iran
Corresponding author: Alireza Foroumadi, E-mail: aforoumadi@yahoo.com
Abstract
1,2,3-Triazole-3-oxoisoindoline-1-carboxamide system was successfully synthesized by
using a combination of Ugi and click reaction. This two-step, one-pot synthesis was
started by the reaction of 2-formyl benzoic acid, propargyl amine and cyclohexyl
isocyanide in ethanol. The resultant Ugi adduct underwent copper-catalyzed click
reaction producing the desired products in good yields.
GRAPHICAL ABSTRACT
KEYWORDS: 1,2,3-Triazole, One-pot synthesis, Ugi-reaction, Multi-component
reaction, Click reaction.
1

INTRODUCTION
Multi-component reaction (MCR) is a powerful strategy for the one-pot construction of
diverse heterocyclic systems. Among them, isocyanide-based multi-component reactions
(IMCR) [1] are one of the highly investigated reactions, which benefit from outstanding
feature of isocyanides, meaning their ability to react with electrophiles and nucleophiles.
Therefore, this reaction provides an ideal way for the synthesis of libraries of
heterocycles. By employing Ugi reaction, a four-component, isocyanide-based process,[2]
molecular diversity could be accessed under mild condition in which the resultant
products are amenable for further transformations. Today, post Ugi transformations have
become an exciting research area to create more complex scaffolds.[3] Performing these
steps in a one-pot manner saves effort, time, and energy along with minimizing chemical
waste and purification steps, provided an opportunity to reach the green chemistry
principles.[4]
1,2,3-Triazole ring constitutes a significant functionality in diverse interesting
compounds [5] with a wide range of applications including in pharmacologically active
compounds,[6] dyes,[7] optically active materials,[8] agrochemicals [9] and synthesis of
macromolecular architectures.[10] The 1,3-dipolar cycloaddition reaction between azide
and alkyne [11] introduced by Sharpless [12] and Meldal [13] is a unique strategy for the
preparation of 1,2,3-triazoles. Therefore, the presence of alkyne moiety is necessary
which could be provided by commercially available triple-bond containing substrate.
This led to the serious restriction in substrate variation. In this context, novel starting
material should be designed to expand the collection of triazole-containing compounds.
2

Utilizing propargyl amine in three-component, four-center Ugi reaction resulted in alkyne
substituted oxoisoindoline derivatives. Based on the biological importance of
oxoisoindoline core,[14] it is highly desired to develop a simple and convenient method for
the synthesis of novel molecules incorporating triazole and isoindolinones in one-pot,
direct and atom economical manner.
RESULTS AND DISCUSSION
As our interest in developing novel heterocyclic compounds,[15] herein, we report the
highly efficient synthesis of 1H-1,2,3-triazol-oxoisoindoline system in one-pot manner.
As mentioned earlier, Ugi reaction has attracted special attention for combinatorial
library construction. In this regard, the protocol of our reaction was started by the Ugi
reaction between 2-formyl benzoic acid 1, propargyl amine 2 and cyclohexyl isocyanide
3 in ethanol. After 24 h, benzyl azides 6, prepared in situ from the reaction between
appropriate benzyl bromide or benzyl chloride with sodium azide (NaN3) in t-BuOH:H2O
(1:1) solvent system and in the presence of Et3N, along with 10 mol% CuI was added to
the crude Ugi adduct and the reaction was continued at room temperature for 24 h. The
overall transformation was carried out under mild condition and gave the pure products
after crystallization.
As shown in Table I, this reaction was successful in synthesizing ten new compounds
with various substituents at different positions. The structures of all the synthesized
compounds were established on the basis of 1H NMR, 13C NMR, IR, and elemental
analyses. In the 1H NMR spectrum of compound 7a, two singlets appear at 2.27 ppm
3

(methyl group) and 5.49 (methylene group). The most deshielded proton is related to NH
at 8.50 ppm, appeared as a doublet signal. The singlet at 8.06 ppm is assigned to triazole
proton. The signals of NCH and CH units were found as multiplets at 3.51-3.53 and 5.10-
5.13 ppm, respectively. In addition, the 13C NMR spectrum exhibited signals related to
carbonyl group at 165.3, 167.6 ppm.
CONCLUSION
In summary, we have discovered an efficient one-pot procedure comprising four-
component Ugi reaction and click reaction to prepare N-cyclohexyl-(2-substituted-1H-
1,2,3-triazol-4-yl)methyl)-3-oxoisoindoline-1-carboxamides. The desired products were
obtained in good yields at room temperature and separated without the need to tedious
work up step.
EXPERIMENTAL
Melting points were taken on a Kofler hot-stage apparatus and are uncorrected. 1H and
13C NMR spectra were recorded on a Bruker FT-500, using tetramethylsilane (TMS) as
an internal standard. The infrared (IR) spectra were obtained on a Nicolet Magna FT-IR
550 spectrophotometer (KBr disks). Mass spectra were recorded on an Agilent
Technology (HP) mass spectrometer operating at an ionization potential of 70 eV.
Elemental analyses were carried out with a Perkin-Elmer model 240-C apparatus.
4

General Procedure For The Synthesis Of Compounds 7a-J
A solution 2-formyl benzoic acid (1 mmol), propargyl amine (1 mmol), cyclohexyl
isocyanide (1 mmol) in ethyl alcohol (10 mL) was stirred for 24 h at room temperature
and then concentrated under reduced pressure. A solution of an arylmethyl chloride or
bromide (1.1 mmol), sodium azide (0.9 mmol), and triethylamine (1.3 mmol) in water (5
mL) and tert-butyl alcohol (5 mL) was stirred at room temperature for 1 h. This solution
was added to the crude Ugi adduct along with 10 mol% CuI and the reaction was
continued for another 24 h. Upon completion, the reaction was poured into ice-water and
the resultant solid was purified by recrystallization from ethyl acetate/petroleum ether.
N-Cyclohexyl-2-((1-(4-Methylbenzyl)-1H-1,2,3-Triazol-4-Yl)Methyl)-3-
Oxoisoindoline-1-Carboxamide (7a)
Yield: 0.36 g (83 %); off-white powder; mp 180-182 oC. IR (KBr): 3288, 3051, 2930,
2880, 1691, 1351, 1178, 841 cm-1. 1H NMR (500 MHz, DMSO-d6): δ = 1.13-1.27 (m,
5H), 1.54-1.56 (m, 2H), 1.67-1.75 (m, 3H), 2.27 (s, 3H), 3.51-3.53 (m, 1H), 4.15 (d, J =
15.5 Hz, 1H), 5.10-5.13 (m, 2H), 5.49 (s, 2H), 7.16 (d, J = 7.5 Hz, 2H), 7.21 (d, J = 7.5
Hz, 2H), 7.50-7.52 (m, 2H), 7.61 (t, J = 7.5 Hz, 1H), 7.70 (d, J = 7.5 Hz, 1H), 8.06 (s,
1H), 8.50 (d, J = 7.5 Hz, 1H) ppm. 13C NMR (125 MHz, DMSO-d6): δ = 20.6, 24.3, 25.1,
32.2, 36.2, 48.0, 52.6, 62.5, 122.9, 123.3, 123.4, 128.0, 128.6, 129.2, 131.3, 132.8, 137.4,
141.7, 142.1, 142.7, 165.3, 167.6. MS: m/z (%) = 444 ([M]+, 34), 428 (62), 338 (100),
296 (15), 91 (12), 77 (21). Anal. calcd. for C26H29N5O2: C, 70.41; H, 6.59; N, 15.79.
Found: C, 70.36; H, 6.64; N, 15.85.
5

SUPPORTING INFORMATION
Full experimental details and 1H and 13C NMR spectra are available. This material can
be found via the supplementary content section of this article’s web page.
ACKNOWLEGEMENTS
This work was supported and funded by Research Council of Tehran University of
Medical Sciences (TUMS).
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Table I. Synthesized products 7a-j.
Product Ar Isolated yield (%)
4-MeC6H4
83
65
68
71
73
75
76
7a
7b
7c
7d
7e
7f
2-FC6H4
3-FC6H4
4-FC6H4
2-ClC6H4
3-ClC6H4
4-ClC6H4
7g
7h
7i
2,3-diCl2C6H3 74
2,4-diCl2C6H3 72
4-BrC6H4
76
7j
9

Scheme 1. Tandem synthesis of 1,2,3-triazole derivatives of 3-oxoisoindoline-1-
carboxamide
10