One-pot synthesis of 2,6-diamino-4-sulfonamidopyrimidines from sulfonyl azides, terminal alkynes and cyanoguanidine

Article abstract of DOI:10.1016/j.tetlet.2011.12.041

Ketenimine intermediates, generated in situ by the addition of copper acetylides to aryl- or alkylsulfonyl azides, are trapped by cyanoguanidine to yield 2,6-diamino-4-sulfonamidopyrimidine derivatives in moderate to good yields.

Full text of DOI:10.1016/j.tetlet.2011.12.041

Tetrahedron Letters 53 (2012) 942–943
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Tetrahedron Letters
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One-pot synthesis of 2,6-diamino-4-sulfonamidopyrimidines from sulfonyl
azides, terminal alkynes and cyanoguanidine
⇑
Issa Yavari , Manijeh Nematpour, Majid Ghazanfarpour-Darjani
Department of Chemistry, Tarbiat Modares University, PO Box 14115-175, Tehran, Iran
a r t i c l e i n f o
a b s t r a c t
Article history:
Ketenimine intermediates, generated in situ by the addition of copper acetylides to aryl- or alkylsulfonyl
azides, are trapped by cyanoguanidine to yield 2,6-diamino-4-sulfonamidopyrimidine derivatives in
moderate to good yields.
Received 26 October 2011
Revised 26 November 2011
Accepted 9 December 2011
Available online 16 December 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Cyanoguanidine
Sulfonamidopyrimidine
Copper iodide
Sulfonyl azide
Ketenimine
Nitrogen heterocycles are abundant in nature and are found in
many natural products such as vitamins, hormones, antibiotics,
and alkaloids.1 The pyrimidine moiety is a prominent structural
motif found in numerous bioactive compounds. Consequently, sev-
eral methods have been developed for the construction of this ring
system.2–5 Diaminopyrimidine derivatives are widely used as key
building blocks for pharmaceutical agents.6–8
Among several methods leading to the generation of keteni-
mines, the copper-catalyzed azide–alkyne cycloaddition reaction
has attracted much attention because of its mild conditions.9 The
in situ generated ketenimine intermediates can be trapped by var-
ious nucleophiles.10 In this way, frameworks of various heterocy-
cles were successfully synthesized.11–13 Applying this strategy,
we used cyanoguanidine to trap in situ generated ketenimines
and obtained 2,6-diamino-4-sulfonamidopyrimidine derivatives
(Scheme 1). Herein, we report the details of this letter.14
First, we studied the reaction between the ketenimine interme-
diate generated from phenylacetylene (1a) and p-toluensulfonyl
azide (2a) with cyanoguanidine (3). This reaction proceeded
smoothly at room temperature and afforded N1-(2,6-diamino-5-
phenyl-4-pyrimidinyl)-4-methyl-1-benzenesulfonamide (4a) in
an 83% yield. This result prompted us to optimize the reaction con-
ditions for the synthesis of other 2,6-diamino-4-sulfonamidopyr-
imidines (see Scheme 1).
solvents screened, tetrahydrofuran (THF) proved to be the best.
Thus, the optimized reaction conditions were as follows:
10 mol % of CuI, 1 mmol of the terminal alkyne 1, 1.2 mmol of
the sulfonyl azide 2 and 1 mmol of cyanoguanidine (3) in THF at
room temperature.
Phenylacetylene readily participated in the coupling to furnish
the corresponding diaminopyrimidine derivatives in good yields
(Scheme 1). Aliphatic acetylenes served as lower yielding sub-
strates compared to phenylacetylene. Aromatic and aliphatic sulfo-
nyl azides reacted efficiently and the corresponding products were
obtained in good yields.
The structuresof compounds4a–i were assigned from IR, 1H NMR,
13C NMR, and mass spectral data. The 1H NMR spectrum of 4a exhib-
itedfoursingletsforthe methyl(2.51 ppm), NH2 (4.28and4.50 ppm),
and NH (8.33 ppm) protons, along with characteristic multiplets for
the phenyl protons. The 13C NMR spectrum of 4a exhibited 13 signals
in agreement with the proposed structure. The mass spectrum of 4a
displayed the molecular ion peak at m/z = 355.
A plausible mechanism for the formation of compounds 4 is gi-
ven in Scheme 2. The yellow copper acetylide 5, formed from 1 and
CuI, undergoes a 1,3-dipolar cycloaddition reaction with sulfonyl
azide 2, to generate the triazole derivative 6.15 This intermediate
can then be converted into the ketenimine derivative 7, which is
attacked by cyanoguanidine (3) to afford 8. This intermediate
undergoes intramolecular cyclization and tautomerization to pro-
duce 4.
Several catalysts including CuI, CuBr, CuCl, Cu2O, and copper
powder were tested with CuI giving the best result. Among the
In summary, ketenimine intermediates generated by the addi-
tion of copper acetylides to sulfonyl azides are trapped by cyanogua-
nidine to yield 2,6-diamino-4-sulfonamidopyrimidine derivatives.
⇑
Corresponding author. Tel.: +98 21 82883465; fax: +98 21 82883455.
E-mail address: yavarisa@modares.ac.ir (I. Yavari).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.12.041

I. Yavari et al. / Tetrahedron Letters 53 (2012) 942–943
943
NH
O
O
NC
R
R
H
N
S
H
N
H
NH2
O
S
CuI (10 mol%),
Et3N, N2
NH2
1
N
R'
O
3
C
R'
N
N
THF, rt, 12 h
O
O
R
S
NH2
R'
N3
4
2
R
Yield (%)
R'
Product
4a
4b
4c
4d
4e
4f
Ph
p-tolyl
Ph
83
87
79
65
63
60
60
57
52
Ph
Ph
Me
n-Pr
n-Pr
n-Pr
n-Bu
n-Bu
n-Bu
p-tolyl
Ph
Me
p-tolyl
Ph
4g
4h
4i
Me
Scheme 1. Synthesis of compounds 4.
8. Curran, K. J.; Verheijen, J. C.; Kaplan, J.; Richard, D. J.; Toral-Barza, L.; Hollander,
I.; Lucas, J.; Ayral-Kaloustian, S.; Yu, K.; Zask, A. Bioorg. Med. Chem. Lett. 2010,
20, 1440.
9. Rostovtsev, V. V.; Green, L. G.; Fokin, V. V.; Sharpless, K. B. Angew. Chem., Int. Ed.
2002, 41, 2596.
R
Cu
Cu
_
CuI
N2
2
C
C
NTs
R
Cu
1
N
N
Ts
R
N
10. Wang, J.; Wang, J. J.; Zhu, Y. X.; Lu, P.; Wang, Y. G. Chem. Commun. 2011, 3275.
11. Cui, S. L.; Lin, X. F.; Wang, Y. G. Org. Lett. 2006, 8, 4517.
6
5
7
12. Cui, S. L.; Wang, J.; Wang, Y. G. Tetrahedron 2008, 64, 487.
13. Yao, W. J.; Pan, L. J.; Zhang, Y. P.; Wang, G.; Wang, X. Q.; Ma, C. Angew. Chem.,
Int. Ed. 2010, 49, 9210.
R
R
14. General procedure for the preparation of pyrimidines 4a–i: To a mixture of azide
2, (1.2 mmol), alkyne 1 (1 mmol), CuI (0.1 mmol), and Et3N (1 mmol) in THF
(2 mL) was slowly added, under N2 atmosphere, cyanoguanidine (3) (1 mmol).
The mixture was stirred at room temperature. After completion of the reaction
[about 12 h, TLC (EtOAc/hexane, 1:5) monitoring], the mixture was diluted
with CH2Cl2 (2 mL) and aqueous NH4Cl solution (3 mL), stirred for 30 min, and
the layers separated. The aqueous layer was extracted with CH2Cl2 (3 mL Â 3)
and the combined organic fractions dried (Na2SO4) and concentrated under
reduced pressure. The residue was purified by flash column chromatography
[silica gel (230–400 mesh; Merck), hexane/EtOAc, 5:1] to give the product.
N1-(2,6-Diamino-5-phenyl-4-pyrimidinyl)-4-methyl-1-benzenesulfonamide (4a).
NTs
HN
NTs
NC
intramolecular
cyclization
tautomerization
3
4
N
NH2
N
NH
NH2
NH2
8
9
Scheme 2. A plausible mechanism for the formation of compounds 4.
Cream powder; mp: 280–283 °C; yield: 0.29 g (83%). IR (KBr) (m
max, cmÀ1):
3551, 3450, 3323, 3300, 3250, 1325, 1140. 1H NMR (500 MHz, CDCl3): dH = 2.51
(3H, s, Me), 4.28 (2H, s, NH2), 4.50 (2H, s, NH2), 7.13 (2H, d, 3J = 7.9 Hz, Ar),
7.16–7.68 (5H, m, Ph), 7.98 (2H, d, 3J = 7.9 Hz, Ar), 8.33 (1H, s, NH). 13C NMR
(125.7 MHz, CDCl3): dC = 29.3 (Me), 124.0 (CH), 124.8 (2CH), 130.6 (2CH), 135.2
(2CH), 136.0 (2CH), 136.1 (C), 147.5 (C), 151.4 (C), 153.7 (C), 154.8 (C), 156.7
(C), 158.8 (C). EI-MS: m/z (%) = 355 (M+, 15), 339 (10), 323 (10), 278 (16), 170
The present method may be considered a practical route for the syn-
thesis of functionalized sulfonamidopyrimidines. The short reaction
times and readily available starting materials and catalyst are the
main advantages of this methodology.
(42), 155 (100), 108 (64), 91 (70), 77 (54). Anal. Calcd for
C17H17N5O2S
Supplementary data
(355.00): C, 57.45; H, 4.82; N, 19.70. Found: C, 57.79; H, 4.86; N, 19.81.
N1-(2,6-Diamino-5-phenyl-4-pyrimidinyl)-1-benzenesulfonamide (4b). Pale-
yellow powder; mp: 260–266 °C; yield: 0.29 g (87%). IR (KBr) (m
max, cmÀ1):
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.12.041.
3545, 3453, 3333, 3300, 3255, 1323. 1H NMR (500 MHz, CDCl3): dH = 4.20 (2H,
s, NH2), 4.42 (2H, s, NH2), 7.01 (2H, t, 3J = 7.1 Hz, Ar), 7.23 (1H, t, 3J = 7.1 Hz, Ar),
7.48 (2H, d, 3J = 7.1 Hz, Ar), 7.63 (2H, t, 3J = 7.2 Hz, Ar), 7.79 (1H, t, 3J = 7.2 Hz,
Ar), 7.87 (2H, d, 3J = 7.2 Hz, Ar), 9.00 (1H, s, NH). 13C NMR (125.7 MHz, CDCl3):
dC = 124.2 (2CH), 125.3 (2CH), 126.0 (2CH), 132.8 (CH), 134.8 (CH), 135.2 (2CH),
138.1 (C), 149.6 (C), 152.9 (C), 154.8 (C), 158.4 (C), 160.1 (C). EI-MS: m/z
(%) = 341 (M+, 10), 325 (11), 309 (10), 264 (18), 156 (23), 141 (100), 108 (40),
77 (50). Anal. Calcd for C16H15N5O2S (341.35): C, 56.29; H, 4.43; N, 19.37.
Found: C, 56.44; H, 4.46; N, 19.51.
References and notes
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Chichester, UK, 2002.
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3. Ahmad, O. K.; Hill, M. D.; Movassaghi, M. J. Org. Chem. 2009, 74, 8460.
4. Barthakur, M. G.; Borthakur, M.; Devi, P.; Saikia, C. J.; Saikia, A.; Bora, U.; Chetia,
A.; Boruah, R. C. Synlett 2007, 223.
5. Movassaghi, M.; Hill, M. D. J. Am. Chem. Soc. 2006, 128, 14254.
6. Bayrakdarian, M.; Butterworth, J.; Hu, Y.-J.; Santhakumar, V.; Tomaszewski, M.
J. Bioorg. Med. Chem. Lett. 2011, 21, 2102.
15. Sharpless and co-workers have established anhydrous conditions with CuI in
CHCl3/2, 6-lutidine at 0 °C to prevent intermediates of type
6 from
decomposing to enable selective formation of the desired 1-sulfonyltriazoles,
see: Yoo, E. J.; Ahlquist, M.; Kim, S. H.; Bae, I.; Fokin, V. V.; Sharpless, K. B.;
Chang, S. Angew. Chem., Int. Ed. 2007, 46, 1730.
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3887.