Synthesis of functionalized N-triazolyl maleimides

Article abstract of DOI:10.1016/j.tetlet.2014.05.095

An easy and mild two-step one-pot reaction allowed the synthesis of functionalized N-triazolyl maleimide. Next, the addition of propargyl alcohol and propargyl amine to the N-acyliminium ion mediated by Lewis acid, In(OTf)₃, allowed the introduction of a second 1,2,3-triazol ring at position 5 of the amide. The products in both reactions were achieved in moderate to good yields.

Full text of DOI:10.1016/j.tetlet.2014.05.095

Accepted Manuscript
Synthesis of Functionalized N-Triazolyl Maleimides
Hélio A. Stefani, Fernando P. Ferreira, Bakhat Ali, Daniel C. Pimenta
PII:
S0040-4039(14)00926-5
DOI:
http://dx.doi.org/10.1016/j.tetlet.2014.05.095
TETL 44686
Reference:
Tetrahedron Letters
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Received Date:
Revised Date:
Accepted Date:
8 May 2014
22 May 2014
24 May 2014
Please cite this article as: Stefani, H.A., Ferreira, F.P., Ali, B., Pimenta, D.C., Synthesis of Functionalized N-
Triazolyl Maleimides, Tetrahedron Letters (2014), doi: http://dx.doi.org/10.1016/j.tetlet.2014.05.095
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Synthesis of Functionalized N-Triazolyl Maleimides
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Hélio A. Stefani,* Fernando P. Ferreira, Bakhat Ali, Daniel C. Pimenta

1
Tetrahedron Letters
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Synthesis of Functionalized N-Triazolyl Maleimides
*aHélio A. Stefani, bFernando P. Ferreira, aBakhat Ali, cDaniel C. Pimenta
aDepartamento de Farmácia, Faculdade de Ciências Farmacêuticas, Universidade de São Paulo, São Paulo, SP – Brasil. bDepartamento de Biofísica, Universidade
Federal de São Paulo, São Paulo, SP – Brazil. cLaboratório de Bioquímica e Biofísica. Instituto Butantan, São Paulo, SP - Brazil
Corresponding author: hstefani@usp.br, Tel 55 11 3091-3654; Fax 55 11 3815-4418
ARTICLE INFO
ABSTRACT
An easy and mild two-step one-pot reaction allowed the synthesis of functionalized N-triazolyl
maleimide. Next, the addition of propargyl alcohol and propargyl amine to the N-acyliminium
ion mediated by Lewis acid, In(OTf)3, allowed the introduction of a second 1,2,3-triazol ring at
position 5 of the amide. The products in both reactions were achieved in moderate to good
yields.
Article history:
Received
Received in revised form
Accepted
Available online
Keywords:
2009 Elsevier Ltd. All rights reserved.
Maleimide
Click Chemistry
Addition Reaction
N-Acyliminium ion
1,2,3-Triazole
when two groups19,13 independently introduced the use of copper
salts to obtain better yields and good regioselectivity.
This kind of reaction can be performed under different
conditions considered non-classical, including microwave
dielectric heating, ultrasound processing, the use of ionic liquids
as reaction media and continuous flow processing.20
N-Acyliminium ions are important intermediates that act as
electron-deficient carbocations in reactions with weak
nucleophiles in organic synthesis, mainly in intramolecular
reactions21 where they have found major use in the synthesis of
bothe natural and unnatural nitrogen-containing products.22,23
This reactivity affords advantages for carbon–carbon bond
formation, both in intermolecular and intramolecular processes.23
These species have been generated from amides or lactams,
which bear a good leaving group at the α-position of the nitrogen
atom in acidic media.
1. Introduction
Maleimide and its derivatives are important building blocks
used as antibacterial agents,1-4 pharmaceutical intermediates3,5,6
(Figure 1) crosslinking reagents for natural rubbers,7,8 resins in
integrated circuit
dies,9 adhesives for fiber-reinforced
composites10 and modifiers for engineering plastics,11 to mention
a few applications.
Different nucleophilic carbons react with N-acyliminium
ions, such as allyl-, alkyl-, aryl-, and alkynylmetals,
cyanotrimethylsilane (TMSCN), isonitriles, enol derivatives, and
aromatics.23
Figure 1. Biologically active maleimides
There are many approaches to synthesizing maleimide but the
simplest uses maleic anhydride;12 most papers describe
functionalization of the maleimide ring and not its de novo
synthesis. Hence there is a need to develop new methods to
synthesize the heterocyclic ring.
N-Heterocyclic compounds are broadly distributed in nature;
however, triazoles are not found in natural products.12,13
Synthetic 1,2,3-triazoles, due to their capacity for intermolecular
hydrogen bond formation, allow interactions with biological
receptors14 and find applications as agrochemical compounds,15
corrosion inhibitors, dyes16 and ionic liquids.17
In connection with our research interest in the preparation and
reactivity of N-acyliminium ions,24 we wish to report here a
general procedure to access various readily available N-triazolyl
maleimides and N-triazolyl-5-triazolyl pyrrolinones from the
corresponding addition reaction of alcohols to the N-acyliminium
ion mediated by In(OTf)3 and further transformation in 5-
triazolyl pyrrolinone.
Results and Discussion
The main synthetic route to 1,2,3-triazole rings is the 1,3-
dipolar cycloaddition reaction,18 which was improved in 2003
A simple and efficient methodology to synthesize N-triazolyl
maleimides was developed and is described here. The key step

2
Tetrahedron
was the synthesis of the N-propargyl pyrrolidone (2). L-Malic
Table 2. Synthesis of N-triazolyl maleimides
acid has proven to be a useful precursor for N-acyliminium ion
reactions leading to enantiopure pyrrolidone derivatives (2).25
The N-propargyl imide 2 was prepared in almost quantitative
yield from inexpensive L-malic acid 1, according to a procedure
from the literature26 (Scheme 1).
Entry
Azide
product
Yield (%)
1
68
Scheme 1. Synthesis of N-propargyl pyrrolidone
Acid 1 was successively treated with acetyl chloride,
propargyl amine and acetyl chloride to afford the respective
imide 2, generating the product in 95% yield.
2
71
With the starting material in hand, CuI was screened for
optimal triazole formation conditions using benzyl azide as a
model reagent in tetrahydrofuran as solvent. Representative
results are presented in Table 1 (entries 1–8).
Table 1. Screening of reaction conditions for the synthesis of the N-1,2,3-
triazole maleimide ring.
3
4
63
77
5
75
78
87
Entry
Cu mol%
PMDTA
(equiv.)
1.2
Reaction
Time (h)
Yield (%)
1
2
3
4
5
6
7
8
10
15
20
30
50
100
30
30
4
3
57
60
65
83
75
78
71
60a
1.2
1.2
1.2
1.2
2,5
1
6
7
1
1.2
1.0
1
1
18
-
aThe acetyl group was not eliminated
Table 1 shows us that reaction using 30 mol% CuI,
N,N,N′,N′,N′′-pentamethyldiethylenetriamine (PMDTA) (1.2
equiv)27 as base and tetrahydrofuran (THF) as solvent at room
temperature was the best reaction condition surveyed, leading to
83% yield of N-triazolyl maleimide (entry 4) in a 1 hour reaction.
When the reaction was carried out in the absence of PMDTA
(Table 1, entry 8) the product was still observed to form in 60%
yield; however, without elimination of the acetate group.
Using the conditions from Table 1, entry 4, the scope of the
reaction was investigated with a variety of organic azides. As
shown in Table 2, aromatic and non-aromatic organic azides
were found to react smoothly with N-propargyl pyrrolidone to
give N-triazolyl maleimides28 (4a-l) in yields ranging from 63%
to 87% (Table 2).
82
79
8
9
Table 2 shows that the presence of electron-withdrawing
substituents in aromatic azides such as Cl, OH, NO2 and Br does
not seem to have a negative effect on the reaction yield, which
ranged from 68% to 87% (Table 2, entries 1, 2, 4 and 7-9). The
location of the electron-withdrawing substituent, whether in the
ortho, meta or para position, did not substantially affect the yield
from the reactions.
10
69

3
Table
3.
Synthesis
of
N-1,2,3-triazolyl-5-(1,2,3-
11
77
triazolyl)pyrrolidones
12
83
Entry
Azide
Product
Yield
(%)
Aromatic azides with electron-donor substituents on the
a = Y = O =
72
aromatic ring gave 75% and 78%, yield to methoxy group at
para and ortho positions, respectively (Table 2, entries 5 and 6).
Examples derived from alkyl azides afforded the N-triazolyl
maleimide in yields ranging from 63% to 83% (Table 2, entries 3
and 10–12, respectively). It was observed that the reaction
temperature suddenly rose (rt to 40 oC) when the base was added
and a bluish ring appeared that changed to green during the
course of the reaction. The 1H nuclear magnetic resonance
(NMR), 13C NMR and mass spectral data were all in agreement
with the structure of the compounds.
1
b = Y = N =
67
c = Y = O =
77
2
d = Y = N =
71
In order to gain further insight into the reaction, in situ
Fourier transform infrared spectroscopy (FT-IR)29 was used to
monitor the reaction. During the experiment, a band of C=N at
1573 cm-1 was observed that started to increase until its
formation reached a maximum at 40 min. The C=C stretch band
is at 1647 cm-1 and the C=C-H bending vibrations were at 967
cm-1, 813 cm-1 and 779 cm-1. So triazole formation and removal
of the acetate group were accomplished in 40 min (Fig. 2).
e = Y = O =
68
3
f = Y = N =
67
Conclusion
In conclusion, we have developed an efficient two step one-
pot elimination and click chemistry reaction of N-propargyl
imide with aromatic- and alkyl azides promoted by CuI using
PMDTA as base, which allows the assembly of a wide range of
functionalized N-triazolyl maleimides. Next, the N-triazolyl
maleimides were submitted to the addition of propargyl alcohol
and propargyl amines through the N-acyliminum ion catalyzed by
Lewis acid, and then converted into the corresponding N-
triazolyl-5-triazolyl pyrrolidones in moderate to good yields.
Both transformations, of N-triazole maleimides and N-
triazole-5-triazolyl pyrrolidones, are operationally simple, the
substrate scope is wide, and the starting materials are readily
available.
Figure 2. Three-dimensional plot of the IR monitoring
Next, N-triazolyl maleimide 4l was successively treated with
sodium borohydride in ethanol/THF at -30 oC for 30 min leading
to 5, that was found as the only product,30 and then propargyl
alcohol or propargyl amine were added to the acyliminium ion
catalyzed by In(OTf)3 to afford the respective N-triazolyl-5-
propargyl pyrrolidones31 (6). (Scheme 2).
This study increases our understanding of the character of the
click chemistry reaction and the N-acyliminum ion but also sheds
important light on how to further expand its scope and utility.
Acknowledgments
The authors gratefully acknowledge financial support from
the São Paulo Research Foundation (FAPESP
2012/00424-2 and fellowship to BA 2012/17954-4) and The
National Council for Scientific and Technological Development
(CNPq) for a fellowship (308.320/2010–7 to HAS).
- grant
Scheme 2. Addition reaction of propargyl alcohol or propargyl amine
The standard reaction32 was carried out with N-triazolyl-5-
propargyl pyrrolidones (6) (1.0 mmol), 10 mol% CuI, PMDTA
(1.2 equiv), 1.2 equiv of organic azide and THF (5 mL) as
solvent. Using these conditions, the products were obtained in
yields ranging from 67% to 77% (Table 3).
Supplementary data

4
Tetrahedron
3817. c) Pilli, R. A.; Russowsky, D. Trends Org. Chem. 1997, 6, 101. d)
Supplementary data associated with this article can be found
in the online version. Experimental details and analytical data for
all new compounds, as well as the H and 13C NMR spectra, are
presented therein.
Zaugg, H. E. Synthesis 1984, 85-110. e) Zaugg, H. E. Synthesis 1984, 181.
24. a) Vieira, A. S.; Guadagnin, R. C.; Fiorante, P. F.; Ferreira, F. P.; Stefani,
H. A. Tetrahedron 2008, 64, 3306. b) Vieira, A. S.; Ferreira, F. P.;
Guarezemini, A. S.; Stefani, H. A. Aust. J. Chem. 2009, 62, 909. c) Caracelli,
I.; Ferreira, F. P.; Vieira, A. S.; Stefani, H. A.; De Simone, C. A.; Tiekink, E.
R. T. Acta Cryst. Section E 2010, E66, o3044. d) Vieira, A. S.; Fiorante, P.
F.; Zukerman-Schpector, J.; Alves, D.; Botteselle, G. V.; Stefani, H. A.
Tetrahedron 2008, 64, 7234.
1
References and notes
1.Matuszak, N.; Muccioli, G. G.; Labar, G.; Lambert, D. M. J. Med. Chem.
2009, 52, 7410.
25. For reviews of N-acyliminium ion chemistry, see: a) Yazici, A.; Pyne, S.
S. Synthesis 2009, 3, 339. b) Yazici, A.; Pyne, S. S. Synthesis 2009, 4,
513.x.x.209
2.Ferrara, J. T.; Cano, L. M.; Fonseca, M. E. Bioorg. Med. Chem. Lett. 2003,
3, 1825.
26. Louwrier, S.; Ostendorf, M.; Bomm, A.; Hiemstra, H.; Speckamp, W. N.
Tetrahedron 1996, 52, 2603.
27. Angelici, R. J.; Allison, J. W. Inorg. Chem. 1971, 10, 2238.
3.Danilenko, V. N.; Simonov, A. Y.; Lakatosh, S. A.; Kubbutat, M. H. G.;
Totzke, F.; Schächtele, C.; Elizarov, S. M.; Bekker, O. B.; Printsevskaya, S.
S.; Luzikov, Y. N.; Reznikova, M. I.; Shtil, A. A.; Preobrazhenskaya, M. N.
J. Med. Chem. 2008, 51, 7731.
28.General procedure: 1-((1-benzyl-1H-1,2,3-triazol-5-yl)methyl)-1H-
pyrrole-2,5-dione (4l) - To a solution of the 2,5-dioxo-1-(prop-2-yn-1-
yl)pyrrolidin-3-yl acetate (3l) (195.05 mg, 1.0 mmol, 1.0 equiv) in THF (5
mL) at 25 °C under a nitrogen atmosphere were added benzyl azide (160 mg,
1.2 mmol, 1.2 equiv) and CuI (57 mg, 0.3 mmol, 30 mol%). TMDTA (208
mg, 1.2 mmol, 1.2 equiv.) was then added dropwise. The reaction mixture
was stirred at room temperature for 1 h. TLC analysis revealed no starting
material. Next, the reaction was quenched with CH2Cl2 (20 mL) and the
organic phase was washed with saturated NH4Cl (10 mL) and then dried over
MgSO4. Evaporation under reduced pressure followed by column
chromatography on silica gel (40% ethyl acetate in hexanes) afforded the
product as a white solid. 1-((1-benzyl-1H-1,2,3-triazol-5-yl)methyl)-1H-
pyrrole-2,5-dione : The product was obtained as a beige solid, m.p. 115-116
4.Peifer, C.; Stoiber, T.; Unger, E.; Totzke, F.; Schächtele, C.; Marmé, D.;
Brenk, R.; Klebe, G.; Schollmeyer, D.; Dannhardt, G. J. Med. Chem. 2006,
49, 1271.
5.Jensen, L. H.; Renodon-Corniere, A.; Wessel, I.; Langer, S. W.; Søkilde,
B.; Carstensen, E. V.; Sehested, M.; Jensen, P. B. Mol. Pharmacol. 2002, 65,
1235.
6.Basurto, J. C.; Alcántara, I. V.; Fonseca, L. M. E.; Ferrara, J. G. T. Eur. J.
Med. Chem. 2005, 40, 732.
7.Klinpitusksa, P.; Somkieowan, S.; Waehamad, W-a.; Lopattananon, N. Adv.
Mat. Res. 2012, 488-9, 211.
8.Hunger, K.; Buschhaus, J.; Schmeling, N.; Staudt, C.; Pfeifer, A.;
Kleinermanns, K. Phys. Chem. Chem. Phys. 2012, 14, 4538.
9. a) Czubarow, P.; Suzuki, O.; Sato, T.; Yamada, K.; Matsumura, K.; Obata,
N. PCT Int. Appl. (2013), WO 2013018847 A1 20130207. b) Osada, S. U.S.
Pat. Appl. Publ. (2008), US 20080083995 A1 20080410.
10. Lv, X.; Wang, R.; Liu, W.; Jiang, L. Pigment and Resin Tech. 2012, 41,
34-41. b) Liu, P.; Guan, Q.; Gu, A.; Liang, G.; Yuan, L.; Chang, J. Applied
Surface Science 2011, 258, 572.
11. a)Badescu, G.; Bryant, P.; Swierkosz, J.; Khayrzad, F.; Pawlisz, E.; Farys,
M.; Cong, Y.; Muroni, M.; Rumpf, N.; Brocchini, S.; Godwin, A.
Bioconjugate Chem. 2014, 25, 460-469. b) Lee, E. K.; Kim, J. Y.; Chung, J.
W.; Lee, B-L.; Kang, Y. RSC Adv. 2014, 4, 293.
1
°C. Yield (224 mg, 83%); H NMR (300 MHz, CDCl3) δ ppm 4.67 ( s, 2H),
5.37 (s, 2H), 6.59 ( s, 2H), 7.25-7.26 ( m, 5H), 7.37 (s, 1H); 13C NMR (75
MHz, CDCl3) δ ppm 34.2, 54.1, 123.0, 128.1-129.1(7C), 134.2 (2C), 170.0
(2C); HRMS calcd for C14H12N4O2 (M+Na): 291.0858; found: 291.0846.
29.a) Le Gall, E.; Sengmany, S.; Hauréna, C.; Léonel, E.; Martens, T. J.
Organomet. Chem. 2013, 736, 27.
30. Mase, N.; Nishi, T.; Hiyoshi, M.; Ichihara, K.; Bessho, J.; Yoda, H.;
Takabe, K. J. Chem. Soc., Perkin. Trans. 1, 2002, 707.
31. Stefani. H. A.; Ali, B.; Ferreira, F. P. Tetrahedron Lett. 2014, 000, 000.
(in press) http://dx.doi.org/10.1016/j.tetlet.2014.03.104
32.General procedure: 5-((1-benzyl-1H-1,2,3-triazol-5-yl)methoxy)-1-((1-
benzyl-1H-1,2,3-triazol-5-yl)methyl)-1,5-dihydro-2H-pyrrol-2-one (7a) - To
a solution of the 1-((1-benzyl-1H-1,2,3-triazol-5-yl)methyl)-5-(prop-2-yn-1-
yloxy)-1,5-dihydro-2H-pyrrol-2-one (308.13 mg, 1.0 mmol, 1.0 equiv.) in
THF (5 mL) at 25 °C under a nitrogen atmosphere were added benzyl azide
(160 mg, 1.2 mmol, 1.2 equiv.) and CuI (19 mg, 0.1 mmol, 10 mol-%).
PMDTA (208 mg, 1.2 mmol, 1.2 equiv.) was then added dropwise. The
reaction mixture was stirred at room temperature for 1 h. TLC analysis
revealed no starting material. Next, the reaction was quenched with CH2Cl2
(20 mL) and the organic phase was washed with saturated NH4Cl (10 mL)
and then dried over MgSO4. Evaporation under reduced pressure followed by
column chromatography on silica gel (70% ethyl acetate in hexanes) afforded
the product as a colorless oil. 5-((1-benzyl-1H-1,2,3-triazol-4-yl)methoxy)-
1-((1-benzyl-1H-1,2,3-triazol-4-yl)methyl)pyrrolidin-2-one: The product
was obtained as a viscous yellow oil. Yield (321 mg, 72%); 1H NMR (300
MHz, CDCl3) δ ppm 2.09( t, J = 7.5, 7.8 Hz, 2H), 2.30( t, J = 7.8, 8.4 Hz,
2H), 4.20 ( s, 4H), 4.62 (s, 2H), 5.32 ( s, 3H), 7.20-7.23 ( m, 10H), 7.41 (s,
2H); 13C NMR (75 MHz, CDCl3) δ ppm 26.5, 26.9, 52.8, 53.5 (2C), 67.2,
91.2, 121.8, 126.8, 126.9 (2C), 127.0 (2C), 127.5 (2C), 127.8, 133.4, 134.4
(2C), 141.1 (2C), 176.5 (C); HRMS calcd for C24H25N7O2 (M+Na): 466.1967;
found: 466.1975.
12. a) Kanaoka, Y.; Machida, M.; Ban, Y.; Sekie, T. Chem. Pharm. Bull.
1967, 15, 1738. b) King, H. D.; Dubowchik, G. M.; Walker, M. A.
Tetrahedron Lett. 2002, 43, 1987. c) Li, K.; Yuan, C.; Zheng, S.; Fang, Q.
Tetrahedron Lett. 2012, 53, 4245.
13.Declerck, V.; Toupet, L.; Martinez, J.; Lamaty, F. J. Org. Chem. 2009, 74,
2004.
14.Tornφe, C. W.; Christensen. C.; Meldal, M. J. Org. Chem. 2002, 67, 3057.
14.Ohmatsu, K.; Kiyokawa, M.; Ooi, T. J. Am. Chem. Soc. 2011, 133, 1307.
15.Xia, Y.; Li, W.; Qu, F.; Fan, Z.; Liu, X.; Berro, C.; Rauzy, E.; Peng, L.
Org. Biomol. Chem. 2007, 5, 1695.
16.Orgueira, H. A.; Fokas, D.; Isome, Y.; Chan, P. C.-M.; Baldino, C. M.;
Tetrahedron Lett. 2005, 46, 2911.
17.Tseng, M.–C.; Cheng, H.–T.; Shen, M.–J.; Chu, Y.-H. Org. Lett. 2011, 13,
4434.
18.Harju, K.; Vahermo, M.; Mutikainen, I.; Yli-Kauhaluoma, J. J. Comb.
Chem. 2003, 5, 826.
19.Rostovtsev, V. V.; Green, L. G.; Fokin, V. V.; Sharpless, K.B. Angew.
Chem. Int. Ed. 2002, 41, 2596.
20.Kappe, C. O.; Eycken, E.V.; Chem. Soc. Rev. 2010, 39, 1280.
21. Maryanoff, B. E.; Zhang, H-C.; Cohen, J. H.; Turchi, I. J.; Maryanoff, C.
A. Chem. Rev. 2004, 104, 1431.
22. Hubert, J. C.; Wunberg, J. B. P. A.; Speckamp, W. N. Tetrahedron 1975,
31, 1437.
23. a) N-acyliminium ion chemistry, see: Koning, H.; Speckamp, W. N. in
Houben-Weyl, Stereoselective Synthesis (Eds G. Helmchen, R. W. Hoffmann,
J. Mulzer, E. Schaumann) 1995, Vol. E21, p. 1953 (Thieme Verlag:
Stuttgart). b) Speckamp, W. N.; Moolenaar, M. J. Tetrahedron 2000, 56,