Safe and highly efficient syntheses of triazole drugs using Cu2O nanoparticle in aqueous solutions

Article abstract of DOI:10.1016/j.tetlet.2013.04.067

Triazole moiety is frequently employed in drug discovery and optimization. However, most syntheses of triazole drugs involve isolation of highly explosive azides. Herein we report safe and high efficient syntheses of triazole drugs in aqueous/organic solvent systems with Cu₂O nanoparticle (Cu ₂O-NP) as the catalyst of azide-alkyne cycloaddition (CuAAC). Since Cu₂O-NP can be efficiently dispensed in aqueous and some organic solvents, the azide solutions from the previous preparation could be used directly in the next CuAAC stage without isolation. Therefore, this synthetic strategy is safe, convenient, and high yielding for the syntheses of triazole drugs.

Full text of DOI:10.1016/j.tetlet.2013.04.067

Tetrahedron Letters 54 (2013) 3406–3409
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Safe and highly efficient syntheses of triazole drugs using Cu2O nanoparticle
in aqueous solutions
Jing-Han Wang a,b, Cheng-Wen Pan a,b, Yong-Tao Li a,b, Fan-Fei Meng a,b, Hong-Gang Zhou a,b
,
a,
Cheng Yang a,b, Quan Zhang a, Cui-Gai Bai b, , Yue Chen
⇑
⇑
a College of Pharmacy, The State Key Laboratory of Elemento-Organic Chemistry, Nankai University, Tianjin 300071, PR China
b High-Throughput Molecular Drug Discovery Center, Tianjin International Joint Academy of Biotechnology & Medicine, Tianjin 300457, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Triazole moiety is frequently employed in drug discovery and optimization. However, most syntheses of
triazole drugs involve isolation of highly explosive azides. Herein we report safe and high efficient syn-
theses of triazole drugs in aqueous/organic solvent systems with Cu2O nanoparticle (Cu2O-NP) as the cat-
alyst of azide–alkyne cycloaddition (CuAAC). Since Cu2O-NP can be efficiently dispensed in aqueous and
some organic solvents, the azide solutions from the previous preparation could be used directly in the
next CuAAC stage without isolation. Therefore, this synthetic strategy is safe, convenient, and high yield-
ing for the syntheses of triazole drugs.
Received 16 January 2013
Revised 12 April 2013
Accepted 17 April 2013
Available online 25 April 2013
Keywords:
Cu2O-NP
Azide–alkyne cycloaddition
Aqueous solution
Rufinamide
Ó 2013 Elsevier Ltd. All rights reserved.
Introduction
Results and discussion
Triazole moiety can be frequently found in clinical drugs or
drug candidates, probably due to its capability to form hydrogen
bonds with the active site,1 and triazoles were recently reported
to be isosteres of amides,2–4 olefins,5 and other heterocycles.6
The generation of triazoles in drugs was usually through the
copper-catalyzed azide–alkyne cycloaddition (CuAAC).7,8 The
catalyst systems that were employed in this type of ring formation
includes: CuSO4/NaAsc,8c CuI/DIEA,9 Cu(CH3CN)4PF6,10 and
CuBr/1,8-diaza-bicyclo [5.4.0]undec-7-ene (DBU)11 and nearly all
these catalyst systems were used either in organic solvents or aque-
ous solution. Chen and Kong recently reported the application of
Cu2O-NP as CuAAC catalyst under physiological conditions or in
organic solvents such as CH3CN and EtOH. This Cu2O-NP catalyst
demonstrated less cytotoxicity and superior efficiency than
traditionalsystems,12 and it was used as catalyst in the largering for-
mation of triazole-Epothilones.13 Thus, we report a safe and highly
efficient synthesis of triazole drugs using Cu2O-NP catalyst in aque-
ous/organic solvents for the key azide–alkyne cycloaddition stage,
and the synthesis of rufinamide is the first example we investigated.
Rufinamide is a drug with anticonvulsant activity, and it is used
for treating some kinds of epilepsies, especially Lennox–Gastaut
syndrome.14 Rufinamide contains structure of triazoles, and
several syntheses of rufinamide have been reported. All of these
syntheses began with 2,6-difluorobenzyl halide 1, followed by
treatment with sodium azide to obtain 2,6-difluorobenzyl azide
3, and then compound 3 undergoes a 1,3-dipolar cycloaddition
with different dipolarophiles to provide the precursors of rufina-
mide 5 or rufinamide 6 (Scheme 1).15–19
The azide 3 in these syntheses was isolated by concentration or
even purified by vacuum distillation at high temperature.16–19
These procedures are not safe for the highly explosive properties
of azide compounds. Therefore, we modified Attolino’s method20
for the synthesis of rufinamide. First of all, we applied H2O/CH3CN
solvent system with tetrabutylammonium chloride as phase trans-
fer additive (Scheme 2).
The reaction mixture after the azide substitution was used di-
rectly in the next Cu2O-NP catalyzed cycloaddition stage (Scheme
3), since the H2O/CH3CN solvent system in the first stage is com-
patible with Cu2O-NP catalyst.
Finally, concentrated ammonia was added to the cycloaddition
reaction mixture to convert compound 5 into rufinamide directly.
Filtration followed by washing with water and CH3OH provided
rufinamide in high purity (>99.0% by HPLC). In summary, rufina-
mide can be prepared by safe and efficient synthesis with simple
⇑
Corresponding authors. Tel./fax: +86 22 23508090.
E-mail addresses: bj20081120good@163.com (C.-G. Bai), yuechen@nankai.
edu.cn (Y. Chen).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.04.067

J.-H. Wang et al. / Tetrahedron Letters 54 (2013) 3406–3409
3407
F
F
F
O
dipolarophiles
4
NaN3
Bu4N+Cl-
2
N3
N
N
5
X
NH2
N
F
F
F
3
1
(1a) X= Br, (1b) X=Cl
Scheme 1. General formula of synthesis of rufinamide.
F
F
Table 1
The reaction conditions for preparation of rufinamide
NaN3
N3
X
F
F
Bu4N+Cl-
2
F
F
i), ii), iii)
X
O
3
1
N
N
(1a) X=Br, (1b) X=Cl
NH2
N
6
F
1
F
Scheme 2. The preparation of 2,6-difluorobenzyl azidea. aThe reaction condition
with 2,6-difluorobenzyl bromide or chloride was optimized to: H2O/CH3CN = 3:16
(V/V), concentration: 0.18 mol/L, azide: 3 equiv, tetrabutylammionium chloride
0.2 equiv temperature: 18–30 °C, reaction time: 2 h.
(1a) X=Br, (1b) X=Cl
Entry
Crude material
Catalyst
mol %
Isolated yield [%]
1a
1a
1a
1a
1a
1a
1a
1a
1b
1b
1b
1b
1b
1b
1b
1b
1b
1b
1b
1b
None
Cu2O
0
0
0
O
F
2a
6.0
0.6
3.0
6.0
9.0
12.0
1.0
2.0
3.0
4.0
5.0
6.0
9.0
12.0
3.0
6.0
6.0
5.0
F
3a
Cu2O-NP
Cu2O-NP
Cu2O-NP
Cu2O-NP
Cu2O-NP
Cu2O-NP
Cu2O-NP
Cu2O-NP
Cu2O-NP
Cu2O-NP
Cu2O-NP
Cu2O-NP
Cu2O-NP
Cu2O-NP
Cu2O-NP
CuSO4/NaAsc
Cu2O-NP
21.0
49.0
60.0
36.7
32.6
22.1
54.8
63.4
65.6
63.4
66.6
55.9
46.6
69.0
71.6
17.3
59.8
O
O
N3
4
4a
N
N
5a
F
Cu2O or CuSO4/NaAsc
O
N
6a
F
3
7a
5
8b
9b
Scheme 3. CuAAC reaction catalyzed with Cu2O-NP.
10a
11b
12b
13a
14a
15a
16c
17d
18a
19a
purification at the end of the preparation, and the overall time to
complete the synthesis and purification was reduced to about 10 h.
Therefore, a series of experiments were conducted to systemat-
ically investigate this synthesis of rufinamide (Table 1).
No products were observed when there was no catalyst (entry
1) or Cu2O powder (200 meshes) was applied as the catalyst (entry
2). Compound 2,6-difluorobenzyl bromide 1a was applied as the
starting material at first, and the yields of rufinamide were 21%,
49%, 60%, 36.7%, and 32.6% when the amounts of Cu2O-NP were
0.6%, 3.0%, 6.0%, 9.0%, and 12.0%, respectively (entries 3–7). Replace
compound 1a with 2,6-difluorobenzyl chloride 1b, and the reac-
tions were run with 1.0%, 2.0%, 3.0%, 4.0%, 5.0% 6.0%, 9.0%, and
12.0% of Cu2O-NP respectively (entries 8–15), and then higher
yields of rufinamide were obtained at different catalyst loadings.
These data indicated that 3–6% is the best range of the ratio of cat-
alyst. Thus, the optimal ratio of Cu2O-NP was set to 6%, and 2,6-
difluorobenzyl chloride was set as the starting material. This reac-
tion with the optimal condition was conducted in a gram scale (en-
tries 16 and 17), 69.0% and 71.6% yield of rufinamide was obtained,
respectively. Compared with the yield of this reaction with CuSO4/
NaAsc as the catalyst system (17.3% in entry 18), the higher yield
with Cu2O-NP (66.6% in entry 13) suggests that the Cu2O-NP is a
superior catalyst system than CuSO4/NaAsc. The possible reason
is that Cu2O-NP catalyst can be dispensed in both organic solvent
(CH3CN) and water, while the application of CuSO4/NaAsc system
requires solvent system with higher ratio of water. Moreover, note
that traditional methods of rufinamide applied high temperature
or distillation of explosive azide, while our syntheses of rufinamide
were carried on with water as one of the solvents in all stages of
reactions at room temperature, and the target product rufinamide
was obtained in high yield and purity after simple filtration. Final-
ly, the gram scale syntheses indicate that this procedure has high
potential to be applied for industrial production of rufinamide.
The second example is triazole analogues of imatinib, which
was synthesized by Arioli et al.3 Starting with compound 7,
(i) NaN3, tetrabutylammonium chloride, (ii) methyl propiolate, Cu2O-NP, (iii)
NH3ÁH2O.
a
Entries 1–7, 10, 13–15, and 18–19 were conducted with azide (1.45 mmol) and
alkyne (1.5 mmol) in CH3CN (8 mL) and H2O (1.5 mL), reaction time is 8 h, and the
solvent of last step is methanol.
Entries 8–9 and 11–12 were conducted with azide (1.45 mmol) and alkyne
(1.5 mmol) in CH3CN (8 mL) and H2O (1.5 mL), reaction time is 8 h, and the solvent
of last step is CH3CN.
Entry 16 was conducted with azide (5.0 g, 30.86 mmol) and alkyne (2.8 mL,
31.3 mmol) in CH3CN (80 mL) and H2O (20 mL), reaction time is 8 h, and the solvent
of last step is CH3CN.
Entry 17 was conducted with azide (5.0 g, 30.86 mmol) and alkyne (2.8 mL,
31.3 mmol) in CH3CN (80 mL) and H2O (20 mL), reaction time is 8 h, and the solvent
of last step is methanol.
b
c
d
oxidation followed by CuSO4/NaAsc catalyzed cycloaddition pro-
vides triazoles imatinib analogue 9a in overall yield of 61.5%. Here-
in we utilized synthetic strategy with Cu2O-NP catalyst, and to our
delight, the target molecule 9a was obtained in higher yield of
81.0% (Table 2, entry 1). Moreover, other analogues 9a, 9b, 9c,
and 9d were also obtained in satisfactory yields (Table 2, entries
2–5).
Conclusion
Cu2O-NP can be efficiently dispensed in water and in organic
solvent such as CH3CN and EtOH, and then Cu2O-NP is highly com-
patible with some organic solvents and water.10 Therefore, the syn-
thetic strategy with the application of Cu2O-NP to avoid the

3408
J.-H. Wang et al. / Tetrahedron Letters 54 (2013) 3406–3409
Table 2
The reaction conditions for preparation of analogue of imatinib
N
R
8a-8e
N
N
R
H
N
N
H
N
N
N
NH2
N
i), ii)
N
7
N
9a-9e
Entrya
1
Compound
R
Isolated yield [%]
81.0
N
9a
N
2
3
9b
9c
56.2
49.6
O
O
O
4
5
9d
9e
62.7
42.4
OH
(i) NaNO2, HCl, H2O, NaN3, (ii) Cu2O-NP.
a
All reactions were conducted with azide (0.514 mmol) and alkyne (0.467 mmol) in ethanol/H2O solution (15 mL, ethanol/water = 4:1),
reaction time is 8 h.
isolation of highly explosive azide is feasible, and then the azide
solutions from the previous preparation were used directly in the
next CuAAC stage. The examples of safe and highly efficient syn-
theses of rufinamide and triazole analogues of imatinib demon-
strated several advantages over the conventional step-wise
syntheses of triazole drugs with Cu2O/NaAsc: safe, higher yielding,
and time efficient. And the gram scale synthesis of rufinamide with
Cu2O-NP suggests that this strategy has high potential to be used
for the industrial production of triazole drugs.
mixture was heated to 65 °C and refluxed for 4 h, cooled to room
temperature, and filtered. The resulting solid was washed with
water and methanol to obtain rufinamide (5.25 g, 71.6%) as color-
less crystalline product. Mp: 242–244 °C. 1H NMR (400 MHz,
DMSO-d6) d 8.549 (s, 1H), 7.842 (br s, 1H), 7.566–7.470 (m, 2H),
7.215–7.174 (m, 2H), 5.723 (s, 2H). 13C NMR (100 MHz, DMSO-
d6) d 162.5, 161.7, 160.0, 143.3, 132.3, 127.4, 112.4, 111.5, 41.66.
MS (ESI+): 239.06.
Typical procedure for the synthesis of rufinamide without
concentration after ‘click reaction’
Experimental procedures
All reagents were of analytical grade and were dried and puri-
fied if necessary. 1H NMR and 13C NMR spectra were recorded on
a Bruker 400 spectrometer. Chemical shifts are reported in parts
per million (ppm) relative to either a tetramethylsilane internal
standard or solvent signals. Data are reported as follows: chemical
shift, multiplicity (s = singlet, d = doublet, br. = broad, m = multi-
plet), coupling constants, and integration. The melting point of
rufinamide was detected by a microscopic melting point meter.
The method of preparation of Cu2O-NP is same as lit. 12.
Synthesis of compound 6: A 250 mL two-necked round bottom
flask was charged with sodium azide (6.10 g, 93.8 mmol), com-
pound 2 (1.90 g, 6.84 mmol), and water (20 mL). After the solid
was completely dissolved, compound 1b (5.0 g, 30.86 mmol) and
CH3CN (80 mL) were added. The mixture was stirred at room tem-
perature for 3 h, and then the CH3CN layer was separated. To the
CH3CN solution were added Cu2O-NP (0.21 g) and compound 4
(2.80 mL, 31.3 mmol), and the reaction mixture was stirred for
8 h at room temperature under protection of inert gas. The mixture
was filtered and the filtrate was charged with 35% ammonia in
water (100 mL). The mixture was heated to 65 °C and refluxed
for 4 h, cooled to room temperature, and filtered. The resulting so-
lid was washed with water and methanol to obtain rufinamide
(5.10 g, 69.0%) as colorless crystalline product. Mp: 242–244 °C.
1H NMR (400 MHz, DMSO-d6) d 8.549 (s, 1H), 7.842 (br s, 1H),
7.566–7.470 (m, 2H), 7.215–7.174 (m, 2H), 5.723 (s, 2H). 13C
NMR (100 MHz, DMSO-d6) d 162.5, 161.7, 160.0, 143.3, 132.3,
127.4, 112.4, 111.5, 41.66. MS (ESI+): 239.06.
Typical procedure for the synthesis of rufinamide with
concentration after ‘click reaction’
Synthesis of compound 6: A 250 mL two-necked round bottom
flask was charged with sodium azide (6.10 g, 93.8 mmol), com-
pound 2 (1.90 g, 6.84 mmol), and water (20 mL). After the solid
was completely dissolved, compound 1a (5.0 g, 31.37 mmol) and
CH3CN (80 mL) were added. The mixture was stirred at room tem-
perature for 3 h, and then the CH3CN layer was separated. To the
CH3CN solution were added Cu2O-NP (0.42 g) and compound 4
(2.80 mL, 31.3 mmol), and the reaction mixture was stirred for
8 h at room temperature under protection of inert gas. The mixture
was filtered and the filtrate was concentrated, and was charged
with methanol (40 mL) and 35% ammonia in water (100 mL). The
Typical procedure for the synthesis of analogue of imatinib
Synthesis of compound 9a–9e: A two-necked round-bottom flask,
was charged with compound 7 (0.142 g, 0.514 mmol), NaNO2
(0.071 g, 1.028 mmol), and water (15 mL), and aqueous HCl

J.-H. Wang et al. / Tetrahedron Letters 54 (2013) 3406–3409
3409
(1.514 mmol) was added dropwise at 0 °C, and the reaction mix-
ture was stirred for 1 h. A solution of NaN3 (0.037 g, 0.565 mmol)
in water (5 mL) was added dropwise into the reaction mixture
slowly, and then the reaction mixture was stirred at the same tem-
perature for 2 h. The reaction was quenched and aqueous layer was
extracted by ethyl acetate (3 Â 10 mL). The organic layer was sep-
arated, concentrated to 10 mL, and was put into solution of 8(a–e)
(0.467 mmol) and Cu2O-NP (6.0 mol %) in ethanol/H2O solution
(15 mL, ethanol/water = 4:1). When the reaction was completed,
the ethanol was evaporated in reaction system and Cu2O-NP was
removed by filtration. The aqueous layer was extracted with ethyl
acetate (3 Â 10 mL), and the combined organic layers were dried
by anhydrous sodium sulfate, filtered, and were concentrated to af-
ford the crude product. The resulting residue was purified by silica
gel column chromatography to obtain compound 9(a–e) as solid.
Compound 9a: Yield: 81.0%. 1H NMR (400 MHz, CDCl3) d 9.319
(s, 1H), 9.505 (s, 1H), 8.771 (s, 1H), 8.591 (d, J = 5.2 Hz, 1H), 8.540
(d, J = 8.2 Hz, 1H), 8.226 (s, 1H), 7.902 (d, J = 8 Hz, 2H), 7.515
(m, 1H), 7.433–7.453 (m, 3H), 7.385 (d, J = 8 Hz, 1H), 7.285–7.300
(m, 2H), 3.592 (s, 2H), 2.578 (br s, 8H), 2.474 (s, 3H), 2.364 (s,
3H). 13C NMR (100 MHz, CDCl3) d 162.3, 160.0, 159.0, 151.5,
148.3, 147.9, 138.6, 138.4, 135.4, 134.6, 132.2, 131.1, 129.6,
129.1, 127.1, 125.6, 123.7, 117.3, 113.8, 111.9, 108.6, 62.7, 55.1,
53.0, 46.0, 17.7. MS (ESI+): 518.29.
8.353 (d, J = 8.0 Hz, 1H), 7.998 (s, 1H), 7.482 (s, 1H), 7.400–7.375
(m, 1H), 7.265 (d, J = 8.0 Hz, 1H), 7.199–7.186 (d, J = 5.2 Hz, 1H),
4.041 (t, J = 5.4 Hz, 2H), 3.087 (t, J = 5.6 Hz, 2H), 2.404 (s, 3H). 13C
NMR (100 MHz, CDCl3) d 162.2, 159.9, 159.3, 151.3, 148.1, 146.7,
138.5, 135.8, 134.9, 131.3, 126.1, 124.0, 123.9, 119.9, 114.2,
111.4, 108.8, 60.7, 29.0, 17.7. MS (ESI+): 374.41.
Acknowledgments
This work was supported by the National Natural Science Foun-
dation of China (NSFC) (No. 21072106 to Y.C. and No. 81102374 to
H.-G.Z.).
Supplementary data
Supplementary data (NMR spectra of compounds 6, 9a–9e and
photo of crystals of compound 6) associated with this article can be
found, in the online version, at http://dx.doi.org/10.1016/
j.tetlet.2013.04.067.
References and notes
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Compound 9b: Yield: 56.2%. 1H NMR (400 MHz, CDCl3) d 9.417
(s, 1H), 9.337 (s, 1H), 9.188 (s, 1H), 8.710 (d, J = 4.0 Hz, 1H), 8.605
(d, J = 4.0 Hz, 1H), 8.525 (s, 1H), 8.512 (s, 1H), 8.475–8.470
(d, J = 2.0 Hz, 1H), 8.113–7.947 (m, 4H), 7.686–7.661 (m, 1H),
7.574–7.498 (m, 5H), 2.389 (s, 3H). 13C NMR (100 MHz, CDCl3) d
162.1, 161.2, 160.1, 152.0, 148.7, 147.7, 139.6, 135.2, 134.9,
133.6, 133.2, 132.6, 132.3, 131.9, 129.1, 128.5, 128.4, 128.2,
127.2, 126.8, 124.3, 124.2, 124.2, 120.3, 116.0, 115.6, 108.8, 18.3.
MS (ESI+): 456.32.
Compound 9c: Yield: 49.6%. 1H NMR (400 MHz, CDCl3) d 9.310
(br s, 1H), 9.010 (s, 1H), 8.751 (d, J = 4.0 Hz, 1H), 8.571
(d, J = 5.2 Hz, 1H), 8.517 (d, J = 8.0 Hz, 1H), 8.166 (s, 1H), 7.582
(d, J = 1.6 Hz, 1H), 7.489 (t, J = 4.0 Hz, 1H), 7.439–7.348 (m, 3H),
7.222 (s, 1H), 6.954 (d, J = 8.0 Hz, 1H), 4.006 (s, 3H), 3.949 (s, 3H),
2.451 (s, 3H). 13C NMR (100 MHz, CDCl3) d 162.6, 160.2, 159.2,
151.7, 149.4, 149.3, 148.4, 148.2, 138.7, 135.7, 134.8, 132.5,
131.3, 127.1, 123.9, 123.4, 118.4, 116.9, 114.3, 112.3, 111.4,
109.1, 108.9, 56.1, 55.9, 17.8. MS (ESI+): 466.34.
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Compound 9d: Yield: 62.7%. 1H NMR (400 MHz, CDCl3) d 9.301
(s, 1H), 9.017 (d, J = 1.6 Hz, 1H), 8.756 (d, J = 1.6 Hz, 1H), 8.569–
8.513 (m, 1H), 8.136 (s, 1H), 7.865(d, J = 8.8 Hz, 2H), 7.510–7.479
(m, 1H), 7.425–7.400 (m, 1H), 7.343 (d, J = 8.0 Hz, 1H), 7.260
(d, J = 5.2 Hz, 1H), 7.229 (s, 1H), 7.002 (d, J = 8.8 Hz, 2H), 3.874
(s, 3H), 2.438 (s, 3H). 13C NMR (100 MHz, CDCl3) d 162.6, 160.1,
159.7, 159.2, 151.6, 148.4, 148.1, 138.7, 135.8, 134.9, 132.5,
131.3, 127.2, 127.0, 123.9, 123.1, 116.7, 114.3, 114.2, 112.2,
108.9, 55.4, 17.8. MS (ESI+): 436.35.
18. Portmann, R. U.S. Patent 6,156,907, 2000.
19. Whitney, H.; Erland, P. Tetrahedron Lett. 2010, 51, 3229–3231.
20. Attolino, E.; Colombo, L.; Mormino I.; Allegrini, P. U.S. Patent 2010/0234616 A1,
2010.
Compound 9e:Yield: 42.4%. 1H NMR (400 MHz, CDCl3) d 9.324 (s,
1H), 8.958 (d, J = 2.0 Hz, 1H), 8.706 (s, 1H), 8.499 (d, J = 5.2 Hz, 1H),