Functionalization of 2-(S)-isopropyl-5-iodo-pyrimidin-4-ones through Cu(I)-mediated 1,3-dipolar azide-alkyne cycloadditions

Article abstract of DOI:10.1016/j.tetlet.2011.10.011

A series of 2-(S)-isopropyl-pyrimidinones functionalized at C5 with triazole rings, in which the substituents are found at N-1′ of the triazole ring, were synthesized. Through the azide-acetylene cycloaddition reaction, using CuI as a copper source and ul

Full text of DOI:10.1016/j.tetlet.2011.10.011

Tetrahedron Letters 52 (2011) 6883–6886
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Functionalization of 2-(S)-isopropyl-5-iodo-pyrimidin-4-ones through
Cu(I)-mediated 1,3-dipolar azide–alkyne cycloadditions
Hélio A. Stefani a, , Mônica F.Z.J. Amaral a, Flávia Manarin a, Rômulo A. Ando b, Nathália C.S. Silva a,
⇑
Eusebio Juaristi c
a Faculdade de Ciências Farmacêuticas, Universidade de São Paulo, São Paulo, SP, CEP 05508-000, Brazil
b Instituto de Química, Universidade de São Paulo, São Paulo, SP, Brazil
c Departamento de Química, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, Apartado Postal 14-740, 07000 México, D.F., Mexico
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of 2-(S)-isopropyl-pyrimidinones functionalized at C5 with triazole rings, in which the substitu-
ents are found at N-10 of the triazole ring, were synthesized. Through the azide–acetylene cycloaddition
reaction, using CuI as a copper source and ultrasonic waves as an energy source it was possible to obtain
products with yields ranging from 79% to 89% within 5 min or less. A preliminary study to gain further
insight into the reaction was performed using in situ ReactIR technology.
Received 19 September 2011
Revised 3 October 2011
Accepted 4 October 2011
Available online 12 October 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Pyrimidinones
1,2,3-Triazole
Cycloaddition
Sonogashira reaction
Click chemistry
Introduction
Regarding synthesis of triazoles, experiments by the Sharpless
group accelerated the 1,3-dipolar cycloaddition reaction, while
Heterocyclic compounds comprise the largest and one of the
most important groups in organic chemistry. A vast majority of
molecules that present physiological and therapeutic activities on
the pharmaceutical market have at least one heterocyclic nucleus.1
Among these, the pyrimidinones and triazoles have attracted par-
ticular interest since they are present in several drugs (Fig. 1), such
as antiretrovirals (1, 2), antifungals (3), antivirals (4), anti-allergic
(5), barbiturates (6, 7), and b-lactamase inhibitors (8), among many
others.2,3
maintaining regioselectivity, generating the 1,4-disubstituted tria-
zole only.7a This reaction is acknowledged as the most striking
example of click chemistry, defined as an approach to the synthesis
of various compounds based on ‘almost perfect’ carbon-hetero-
atom bonds formation.7b
It is well-known that organic reactions are accelerated by ultra-
sonic waves. Compared with traditional methodologies, this ap-
proach is very convenient, since it allows energy conservation
and minimizes residue production.8 In recent years, our group
has developed reactions for the synthesis of derivatives of several
classes of compounds using sonochemistry, such as imines,9 aryl-
acetylenes,10 symmetric 1,3-diines,11 1,3-enynes,12 symmetric
biaryls,13 and heterocycles.14 Beyond this, sonochemistry was used
to accelerate Suzuki–Miyaura cross-coupling reactions.15
In recent years, a growing number of research groups have
become interested in the derivatization of different types of
pyrimidinones. Juaristi, recently published a Letter on the synthesis
of 5-iodopyrimidinone with further functionalization through the
Sonogashira coupling reaction and subsequent synthesis of
a
-substituted b-aminoacids.4,5
As part of our ongoing research interests in sonochemistry16
and focusing on the derivatization of 2-(S)-isopropyl-5-alkynyl-
pyrimidin-4-ones into 2-(S)-isopropyl-5(1,2,3-triazoles)-pyrimi-
din-4-ones through Cu(I)-catalyzed alkyne–azide Huisgen [3+2]
cycloaddition reaction mediated by ultrasonic waves, a set of these
1,2,3-triazole compounds was synthesized.
Similarly, interest in the 1,2,3-triazole nucleus has increased
due to recent findings on its generation, biological activities, and
applications, particularly by the pharmaceutical industry which
uses these compounds as imidazoles, 1,2,4-triazoles, and tetrazoles
bioisosteres.6
2-(S)-Isopropyl-perhydropyrimidinone-6-carboxylic acid (2S,6S)-
10 was prepared via a condensation reaction of (S)-asparagine 9
with isobutyraldehyde, followed by in situ N-benzoylation
(Scheme 1).17 In the next step, after the recrystallization of the
⇑
Corresponding author.
E-mail address: hstefani@usp.br (H.A. Stefani).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.10.011

6884
H. A. Stefani et al. / Tetrahedron Letters 52 (2011) 6883–6886
O
N
N
O
Me
HO
H2N
NH
OH
N
N
F
N
O
N
N
N
N
O
N
O
O
S
N
N
O
N
HO
HO
N3
HO OH
F
2
4
3
1
Lamivudine
Fluconazole
Zidovudine
Ribavirin
O
S
O
O
O
NH
O
O
N
N
HN
O
HN
N
N
N
N
N
O
N
N
HN
HN
O
O
COONa
6
8
5
7
Phenobarbital
Pemirolast
Secobarbital
Tazobactam
Figure 1. Biologically active triazoles and pyrimidinones.
O
H
O
H
O
H2N
N
N
1. DIB / I2
1. KOH, (CH3)2CHCHO
(S)
N
I
(S)
N
2. BF3 Et2O
CH2Cl2, rt
(S)
CO2H
2. C6H5COCl, NaHCO3
H2O, 0 ºC
H2N
(S)
CO2H
O
O
C6H5
C6H5
(S)-9
asparagine
(2S,6S)-10
(S)-11
Scheme 1. Synthesis of 2-(S)-isopropyl-5-iodopyrimidinone (S)-11.
Based on the methodology described by Fiandanese,18 in which
they performed deprotection with TBAF and the azide–alkyne
cycloaddition reaction in one step in order to synthesize asymmet-
ric 4,40-bitriazoles 13 (Scheme 2), we could react the compound
(S)-11 with trimethylsilyl acetylene via a Sonogashira coupling
reaction.5 In this way, 2-(S)-isopropyl-5-ethynyl (trimethylsilyl)-
pyrimidinone (S)-14 was obtained in 85% yield (Scheme 3).
A test with (S)-14 and benzyl azide 15a was made in order to
visualize the reproducibility of the reaction with other derivatives
(Scheme 4). Therefore, using TBAF as the desilylation agent and CuI
as the copper source in the presence of 1,1,4,7,7-pentamethyldi-
ethylenetriamine (PMDETA), the reaction took place with THF as
the solvent at room temperature. The desired pyrimidinone func-
tionalized at the C5 with the 1,2,3-triazole ring (S)-16a was ob-
tained in 65% yield within 90 min.
Despite the good performance, the reaction was repeated to im-
prove yield and reduce time, running it with ultrasonic waves as a
source of energy, a process that is called cavitation.16 Thus, the
reaction time was reduced from 90 min to less than 5 min, and
the yield increased from 65% to 87%. It was observed that the reac-
tion occurred almost instantaneously with ultrasound.
Still, in order to improve the conditions even further, through
reducing the unnecessary use of reagents, a second test was per-
formed. This time, the experiment was performed without the
addition of PMDETA, as TBAF should have the same role as the base
R1 N3
N
N
N
N
N
N
N
N
N
SiMe3
CuI, TBAF, THF
PMDETA, rt, 2-4 hs
52-86%
R1
R
R
12
13
Scheme 2. Synthesis of asymmetric 4,40-bitriazoles.
H
O
H
O
N
N
PdCl2, CuI
(S)
N
I
TMS
(S)
N
TMS
PPh3,Et3N,
MeCN, N2
50ºC
O
O
C6H5
11
C6H5
14
(S)-
(S)-
Scheme 3. Synthesis of 2-(S)-isopropyl-5-ethynyl (trimethylsilyl)-pyrimidinone
(S)-14.
carboxylic acid 10 with methanol and hexane, BF3ꢀEt2O was added
(2 equiv) to the reaction mixture previously treated with the acid
DIB/I2 in the presence of BF3ꢀEt2O, leading to rapid conversion of
(S)-pyrimidinone into the corresponding 2-(S)-isopropyl-5-iodo-
pyrimidinone (S)-11,5 with 78% yield (Scheme 1).
N3
15a
H
N
O
H
N
O
N
N
N
SiMe3
CuI, TBAF, THF
PMDETA, rt
65%
N
N
O
O
C6H5
14
C6H5
16a
(S)-
(S)-
Scheme 4. Synthesis of 1,2,3-triazole ring (S)-16a.

H. A. Stefani et al. / Tetrahedron Letters 52 (2011) 6883–6886
6885
Table 1
Table 1 (continued)
Cu(I)-mediated 1,3-dipolar azide–alkyne cycloaddition
Entry
Azide
Triazole
H
N
O
H
N
O
N3
H
N
O
N
N
N
CuI, TBAF
SiMe3
R
15a-k
N3
N
N
N
THF, rt
N
N
R
ultrasound
5 minutes
O
O
N
O
Cl
9
C6H5
(S)-14
C6H5
(S)-16a-k
15i
C6H5
Cl
15i (81%)
Entry
Azide
Triazole
N3
H
N
O
N
H
N
O
N3
N
N
N
N
N
N
O
10
11
15a
N
O
1
I
C6H5
I
C6H5
15j
16j (87%)
16a (88%)
O
N
N3
H
N
O
N
H
N
NO2
N
N
NO2
N
N
CH3(CH2)11
N3
N
O
N
O
2
(CH2)11CH3
15b
Me
15k
C6H5
Me
C6H5
16k (83%)
16b (82%)
H
N
O
in promoting the insertion of Cu(I) in the acetylene after its desily-
lation. We found that the reaction would occur in the same man-
ner, and with 88% yield. In this context, we can conclude that
this cycloaddition reaction was successful with no need of a base.
With the discovery of this new condition, we explored in situ
deprotection with TBAF, followed by the azide–acetylene cycload-
dition reaction using ultrasonic waves as an energy source for all
the organic azides synthesized previously. The results are shown
in Table 1. All the examples were obtained in high yields within
less than 5 min, showing the versatility and applicability of this
reaction, since molecules with different functional groups in differ-
ent positions were used with no intolerances.
N
N
N
CH3(CH2)7
N3
15c
N
O
3
(CH2)7CH3
C6H5
16c (85%)
H
N
O
N
N
N
CH3(CH2)5
N3
4
N
O
(CH2)5CH3
15d
C6H5
In general, no significant differences in reactivity were observed
for the examined aromatic and aliphatic azides. However, aromatic
azides furnished yields ranging from 79% to 87% (entries 7–11),
whereas the aliphatic azides furnished the product in 82–89% yield
(entries 1–6). Replacing the organic azides with sodium azide
failed to facilitate cyclization under Cu-catalyzed conditions.
In order to gain further insight into the reaction of interest, a de-
tailed IR characterization19 was done for both the reactant and the
product, and to complement the vibrational assignment, density
functional theory (DFT) calculations were performed for both spe-
cies. The cycloaddition reaction was monitored in real-time by
in situ ReactIR spectroscopy (Table 1, entry 1). As can be observed
in Figure 2, a characteristic band at 1682 cmꢁ1 related to the starting
16d (89%)
H
N
O
N
N
N
N3
5
N
O
15e
C6H5
16e (84%)
H
H
O
N
N
N
N
CH3(CH2)3
N3
6
7
N
15f
O
O
C6H5
material was assigned to m(C@O)amide + m(C@O)ring, according to IR
16f (87%)
(DFT). After the addition of TBAF to promote the desilylation reac-
tion, a displacement of this band was observed in the spectrum, to
1670 cmꢁ1 and another band at 1625 cmꢁ1 was assigned to vibra-
tional stretching of (C@C)ring and (C@C)triazole in the triazole product.
Another region was examined during the process (Fig. 3). After
the copper iodide addition, there was a rapid increase in the bands
at 1331 and 1234 cmꢁ1, indicating that the triazole ring was
formed. The first one was related to the vibrational mode of the
O
N
N3
N
N
N
N
15g
C6H5
16g (83%)
O
H
pyrimidinone ring,
resented the vibrational stretching in the triazole ring,
(C@N)triazole (N@N)triazole
In summary, a mild reaction of functionalized dihydropyrimidi-
m(C–C)ring + m(C–N)ring. The second surface rep-
N3
N
N
N
N
N
m
+
m
.
8
O
NO2
15h
none 1,4-disubstituted 1,2,3-triazoles was developed employing a
sequence of Cu(I)-mediated 1,3-cycloaddition reactions of organic
azides with terminal alkynes in excellent yields. The execution
of this strategy was simple and suitable for rapid assembly of
C6H5
NO2
16h (79%)

6886
H. A. Stefani et al. / Tetrahedron Letters 52 (2011) 6883–6886
enantiomerically pure or enantioenriched
a-1,2,3-trizolyl b-amino
acids is possible via a hydrogenation-hydrolysis protocol.4,5
Acknowledgements
The authors would like to acknowledge Conselho Nacional de
Desenvolvimento Científico e Tecnológico (CNPq 300.613/2007-5)
and Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP
07/59404-2, 2010/15677-8, and 09/51850-9) for their financial
support.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.10.011.
Figure 2. In situ IR spectroscopy monitoring the 1,2,3-triazole formation.
References and notes
1. Eicher, T.; Hauptmann, S. The Chemistry of Heterocycles: Structure, Reactions,
Synthesis and Applications, 2nd ed.; Wiley-VCH, 2003.
2. Wannberg, J.; Dallinger, C.; Kappe, C. O.; Larhed, M. J. Comb. Chem. 2005, 7,
574.
3. Melo, O. J.; Donnici, C. L.; Augusti, R.; Ferreira, V. F.; Souza, M. C. B. V.; Ferreira,
M. L. G.; Cunha, A. C. Quim. Nova 2006, 29, 569.
4. Diaz-Sánchez, B. R.; Iglesias-Arteaga, M. A.; Melgar-Fernández, R.; Juaristi, E. J.
Org. Chem. 2007, 72, 4822.
5. Stefani, H. A.; Amaral, M. F. Z. J.; Reyes-Rangel, G.; Vargas-Caporali, J.; Juaristi, E.
Eur. J. Org. Chem. 2010, 33, 6393–6403.
6. Barreiro, E. J.; Fraga, C. A. M. Química Medicinal – As Bases Moleculares da Ação
dos Fármacos, 2nd ed.; Artmed, 2008.
7. (a) Rostovtsev, V. V.; Green, L. G.; Fokin, V. V.; Sharpless, K. B. Angew. Chem., Int.
Ed. 2002, 41, 2596; (b) Kolb, H. C.; Finn, M. G.; Sharpless, K. B. Angew. Chem., Int.
Ed. 2001, 40, 2004.
8. (a) Einhorn, C.; Einhorn, J.; Luche, J.-L. Synthesis 1989, 787; (b) Manson, T. J.
Chem. Soc. Rev. 1997, 26, 443; (c) Cintas, P.; Luche, J.-L. Green Chem. 1999, 1,
115; (d) Lenardão, E. J.; Freitag, R. A.; Dabdoub, M. J.; Batista, A. C. F.; Silveira, C.
C. Quim. Nova 2003, 26, 123.
9. Guzen, K. P.; Guarazemini, A. S.; Orfão, A. T. G.; Cella, R.; Stefani, H. A.; Pereira,
C. M. P. Tetrahedron Lett. 2007, 48, 1845.
10. Stefani, H. A.; Cella, R.; Dorr, F. A.; Pereira, C. M. P.; Gomes, F. P.; Zeni, G.
Tetrahedron Lett. 2005, 46, 2001.
11. Singh, F. V.; Amaral, M. F. Z. J.; Stefani, H. A. Tetrahedron Lett. 2009, 50,
2636.
Figure 3. In situ IR spectroscopy monitoring the 1,2,3-triazole formation.
12. Singh, F. V.; Weber, M.; Guadagnin, R. C.; Stefani, H. A. Synlett 2008, 1889.
13. Singh, F. V.; Stefani, H. A. Tetrahedron Lett. 2010, 51, 863.
14. Stefani, H. A.; Pereira, C. M. P.; Almeida, R. B.; Braga, R. C.; Guzen, K. P.; Cella, R.
Tetrahedron Lett. 2005, 46, 6833.
15. (a) Cella, R.; Stefani, H. A. Tetrahedron 2006, 62, 5656; (b) Cella, R.; Orfão, A. T.
G.; Stefani, H. A. Tetrahedron Lett. 2006, 47, 5075.
molecular complexity, with new bonds being formed. The new
1,2,3-triazoles were fully characterized by HRMS, IR, 1H, and 13C
NMR. A preliminary study to gain further insight into the reaction
was performed using in situ ReactIR technology. Further studies on
this methodology and applications of the reaction are currently ongo-
ing in our laboratory and will be reported in due course. Conversion
of the 5-1,2,3-triazoly-2-(S)-isopropyl-pyrimidinones products into
16. Cella, R.; Stefani, H. A. Tetrahedron 2009, 65, 2619.
17. Castellanos, E.; Reyes-Rangel, G.; Juaristi, E. Helv. Chim. Acta 2004, 87, 1016.
18. Fiandanese, V.; Bottalico, D.; Marchese, G.; Punzi, A.; Capuzzolo, F. Tetrahedron
2009, 65, 10573.
19. (a) Payette, J. N.; Yamamoto, H. J. Am. Chem. Soc. 2008, 130, 12276; (b) Hong, K.
B.; Donahue, M. G.; Johnston, J. N. J. Am. Chem. Soc. 2008, 130, 2323.