Copper-catalyzed alkyne cycloaddition on electron deficient azides via tetrazolo[1,5-a]pyrimidines

Article abstract of DOI:10.1002/jhet.449

(Chemical Equation Presented) Tetrazolo[1,5-a]pyrimidines are capable of serving as masked azides in copper-catalyzed Huisgen cyclization with a variety of terminal alkynes, providing a simple protocol for the generation of novel 4′-substituted 2-(1′,2′,3′-triazol-1′-yl) pyrimidines.

Full text of DOI:10.1002/jhet.449

July 2010
Copper-Catalyzed Alkyne Cycloaddition on Electron Deficient
Azides via Tetrazolo[1,5-a]pyrimidines
887
a
Linda I. Nilsson, Anne Ertan, Dirk Weigelt, * and Jens M. J. Nolsoe
b
a
a
¨
aMedicinal Chemistry, Local Discovery Research Area CNS and Pain Control, AstraZeneca R&D
So¨derta¨lje, So¨derta¨lje SE-151 85, Sweden
b
¨ ¨
Early Development, Pharmaceutical and Analytical R&D, AstraZeneca R&D Sodertalje,
¨
¨
Sodertalje SE-151 85, Sweden
*E-mail: dirk.weigelt@astrazeneca.com
Received December 18, 2009
DOI 10.1002/jhet.449
Published online 10 June 2010 in Wiley InterScience (www.interscience.wiley.com).
Tetrazolo[1,5-a]pyrimidines are capable of serving as masked azides in copper-catalyzed Huisgen cy-
clization with a variety of terminal alkynes, providing a simple protocol for the generation of novel 40-
substituted 2-(10,20,30-triazol-10-yl)pyrimidines.
J. Heterocyclic Chem., 47, 887 (2010).
INTRODUCTION
forcing conditions [7,8]. Conversely, the absence of any
mitigating functionality may result in a sluggish reaction
that demands elevated temperature and auxiliary reagent
to bring about conversion [9,10].
In recent years, the application of transition metals to
promote 1,3-dipolar cycloaddition between organic
azides and alkynes has effected a revitalization of the
field pioneered by Huisgen et al. in the 1960s [1]. This
surge of attention has been brought about by reports
from the research groups of Meldal and Sharpless, inde-
pendently demonstrating how the catalytic presence of
copper(I) facilitates a remarkable enhancement of reac-
tivity and regioselectivity, in the case of terminal
alkynes acting as the dipolarophile [2,3].
Observing the facile reaction between b-diketones 1
and 5-aminotetrazole 2 as an entry to 2-azidopyrimi-
dines 4, we wanted to explore their ability to undergo
alkyne cycloaddition within the context of copper(I) ca-
talysis [11].
RESULTS AND DISCUSSION
The intrinsic affinity of organic azides toward termi-
nal alkynes, realized in the established protocol, has
prompted Sharpless to coin the term ‘‘Click Chemistry’’
[4]. However, despite the many merits publicized to
endorse copper-catalyzed azide-alkyne cycloaddition
(CuAAC) [5,6], there is a notable absence of examples
involving electron deficient 1,3-dipoles.
The electron deficient 1,3-dipoles, projected as the
investigative starting point for CuAAC, were synthe-
sized by performing cyclodehydration on the appropriate
b-diketone 1 with 5-aminotetrazole 2, capitalizing on
the tautomeric equilibrium existing between tetra-
zolo[1,5-a]-pyrimidine
3
and 2-azidopyrimidine
4
In the instance of electron deficient hetaryl azides, the
authors of this article have only come across a handful
of articles entailing CuAAC [7–9]. The obvious reason
is the ability of the appended heterocycle to disperse
negative charge residing on the azide, thereby disrupting
its innate dipolar nature and hampering the concomitant
cycloaddition.
(Scheme 1). It was found that the presence of either
Bro¨nsted or Lewis acid in refluxing alcoholic solvent
advanced cyclodehydration, allowing the prerequisite
azides to be isolated in high purity by simple filtration
upon cooling of the reaction media (Table 1).
The coexistence of 3 and 4, through valence tautom-
ery, seems to be an inherent feature of fused tetrazoles.
However, the directional preference of the equilibrium
is subject to several factors, including phase, solvent,
temperature, and pH [12].
The reactivity can be improved through the introduc-
tion of electron donating substituents on the heterocyclic
moiety, enabling the CuAAC to take place under non-
C
V
2010 HeteroCorporation

¨
L. I. Nilsson, A. Ertan, D. Weigelt, and J. M. J. Nolsoe
888
Vol 47
Scheme 1
Table 1
Synthesis of 2-azidopyrimidines 4.a
Entry Compound
R
R0
Methodc Solvent Time (h) Yield (%)d DSC: Exotherm (J/g)e DSC: Peak interval (ꢀC)
1
2
4a
4a
4b
4b
4c
4c
4d
4d
4e
4e
Me
Me
Me
Me
Ph
Hb
Hb
A
B
A
B
A
B
A
B
A
B
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
MeOH
EtOH
EtOH
EtOH
n.d.
3
n.d.
17
42
98
84
43
23
0
1457
1578
1188
851
138–224
163–273
193–269
169–272
181–298
3
4
Me
Me
4
3
5
Me
Me
Ph
Ph
CO2Me
CO2Me
2
6
7
Ph
Ph
72
48
n.d.
48
n.d.
8
9
10
Ph
Ph
35
n.d.
1145
Ph
a The reactions were run with equimolar proportions of diketone 1 and aminotetrazole 2.
b The corresponding dimethyl acetal 1a was used.
c Method A: 10 mol % of conc. HCl (aq) in refluxing solvent. Method B: Preincubated solution of 10 mol % CuCl2 and 10 mol % Vitamin C at
ambient temperature.
d Isolated yield.
e The measured exotherms are >800 J/g, the compounds should thus be treated as potentially explosive. We strongly advise to take safety precau-
tions, as e.g. described in Bretherick’s Handbook of Reactive Chemical Hazards [14].
When applying single-crystal diffraction technique on
a select cyclodehydration product, subsequent X-ray
analysis clearly demonstrated that the compound pre-
ferred the azido-tautomer in the solid state (Fig. 1) [13].
Considering the generally high nitrogen content mani-
fest in 2-azidopyrimidines 4, the prepared compounds
were submitted to differential scanning calorimetry
(DSC) for the purpose of establishing safety margins
(Table 1). Based on the relative thermal stability and
yield, 4c was subsequently selected as the candidate
dipole to be tested in CuAAC (Scheme 2).
age, cycloaddition occurred only reluctantly, while the
ester counterpart participated readily (Table 2; entry 3,4).
To encourage swifter conversion, it was in turn opted
to perform the CuAAC in a nonpolar solvent. Seeing the
ability to delocalize charge within its interior, the pyrim-
idine featured in 4c effectively acts as an electronic
In accordance with the precognized conditions pub-
lished by Sharpless and coworkers [3], cycloaddition
was initially attempted utilizing an in situ generated
Cu(I)-catalyst and a polar solvent. However, no product
formation was observed and the reaction remained unre-
sponsive to alteration of temperature as well as elec-
tronic modulation of the dipolarophile 5 (Table 2; entry
1,2).
Surprisingly, when the catalytic constellation was
interchanged and Cu(I) instead was added directly, reac-
tion proceeded at elevated temperatures. Furthermore, it
became evident that the nature of the alkyne substituent
dramatically affected the rate. Thus, with an aryl append-
Figure 1. Crystal structure of compound 4d determined by single-crys-
tal diffraction technique at 200 K. [Color figure can be viewed in the
online issue, which is available at www.interscience.wiley.com.]
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

July 2010
Copper-Catalyzed Alkyne Cycloaddition on Electron Deficient Azides
via Tetrazolo[1,5-a]pyrimidines
889
Scheme 2
Table 2
Synthesis of 40-substituted 2-(10,20,30-triazol-10-yl)pyrimidines 6.a
Entry Compound
R00
Solvent Temp.(ꢀC) Catalyst/Loading (mol%) Time (h) Yieldc/Conversiond (%)
1
2
3
6a
6b
6a
6b
6a
6b
6c
6d
6e
6f
6g
6h
6i
6j
6k
6l
Ph
CO2Et
Ph
EtOH
EtOH
EtOH
EtOH
r.t. to d
r.t. to d
d
d
80
80
80
80
80
CuCl2þVit.C/10
CuCl2þVit.C/10
CuI/10
CuI/10
CuI/5
1 Week
1 Week
1 Week
n.d./No
n.d./No
n.d./Full
n.d./Full
64/Full
77/Full
56/Full
70/Full
67/Full
58/Full
73/Full
58/Full
71/Full
71/Full
72/Full
91/Full
79/Full
51/Full
4
CO2Et
Ph
4
2
2
15b
15b
15b
2
5
6
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
CO2Et
o-Toluyl
m-Toluyl
p-Toluyl
o-Anisyl
m-Anisyl
p-Anisyl
CuI/5
CuI/5
CuI/5
CuI/5
CuI/5
CuI/5
7
8
9
10
11
12
13
14
15
16
17
18
80
80
2
80
80
CuI/5
CuI/5
2
24
7
4-(Dimethylamino)phenyl Toluene
6-Methoxynaphth-2-yl
Benzyl
Toluene
Toluene
Toluene
Toluene
Toluene
80
80
CuI/5
CuI/5
2
Cyclopropyl
Diethoxymethyl
CO2Me
80
80
CuI/5
CuI/5
CuI/5
3
2
6m
6n
80
3
a The reactions were performed on an 0.47 mmol scale with equimolar proportions of azide 4c and alkyne 5.
b The reaction was run overnight.
c Isolated yield after recrystallization.
d The reactions were monitored by HPLC and LC-MS.
sink, draining the azide of its latent reactivity. Running
the CuAAC in a nonpolar solvent would thus a priori
act as a counter, disfavoring charge separation and
ensure a more well-behaved dipole. Gratifyingly, the
choice solvent proved efficacious in bringing about the
reaction: By changing from ethanol to toluene, rapid
reaction was realized with both aryl and ester appended
alkyne 5. Additionally, the catalytic mediation of copper
was underpinned on the account that 40-substituted 2-
(10,20,30-triazol-10-yl)pyrimidine 6 was the sole cyclized
product observed. In contrast to the preceding literature [3],
neither additional base nor the exclusion of oxygen was
needed, as none of the reported by-products were formed.
Having established workable conditions, the general-
ity of the CuAAC was tested by subjecting 2-azidopyr-
imi-dine 4c to an ensemble of terminal alkynes 5,
exploring both electronic and steric effects (Table 2;
entry 5–18). In the majority of cases, full conversion
was realized smoothly within a couple of hours and at
the latest after 24 h. The isolated yield of compound 6
varied between 51 and 91% after recrystallization,
which was performed to remove the catalyst.
CONCLUSIONS
This article outlines a novel protocol for highly selec-
tive copper-catalyzed 1,3-dipolar cycloaddition between
electron deficient hetaryl azides and a variety of termi-
nal alkynes. Applied on 2-azidopyrimidines, the protocol
allows smooth transformation to the corresponding 40-
substituted 2-triazolylpyrimidines in the absence of any
auxiliary reagents.
EXPERIMENTAL
NMR spectra were recorded either on a Bruker DPX400
NMR spectrometer operating at 400 MHz for 1H, and 101
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

¨
L. I. Nilsson, A. Ertan, D. Weigelt, and J. M. J. Nolsoe
890
Vol 47
MHz for 13C equipped with a 4-nucleus probe-head with Z-
gradients, or a Bruker Avance III 500 NMR spectrometer,
5 min, to give a colorless solution. 4,4-Dimethoxybutan-2-one
(1a) (100 mg, 0.76 mmol) and 1H-tetrazol-5-amine (2) (64.4
mg, 0.76 mmol) were added in sequence and the mixture was
stirred at ambient temperature for 3 h. Saturated NH4Cl (10 mL)
was added and the resulting suspension was extracted with
EtOAc (5 ꢁ 30 mL). The organic layers were dried with NaSO4
and evaporated in vacuo. The crude material was washed with
hot heptane, yielding the title compound as a pink solid after
failed recrystallization with MeOH/H2O. Yield: 19 mg, 17%. 1H
NMR (400 MHz, DMSO-d6): d 2.93 (s, 3H), 7.48 (d, J ¼ 4.3
Hz, 1H), 9.02 (d, J ¼ 4.3 Hz, 1H). MS: (ES) m/z 136 [Mþ1].
2-Azido-4,6-dimethylpyrimidine (4b)
Method A. Pentane-2,4-dione (1b) (0.103 mL, 1.00 mmol)
was dissolved in EtOH (2.5 mL) and hydrochloric acid, 37%
(0.1 mL) to give a colorless solution. 1H-Tetrazol-5-amine (2)
(85 mg, 1.00 mmol) was added and the resulting mixture
refluxed for 4 h. The formed suspension was evaporated to dry-
ness yielding a white solid, and the solid was redissolved in a
minimal amount of hot EtOH. The title compound precipitated
on cooling and was collected by suction filtration as a white
solid. Yield: 63 mg, 42%.
1
operating at 500 MHz for H and 126 MHz for 13C equipped
with a 5 mm TCI cryo probe-head with Z-gradients. Chemical
shifts are given in ppm down- and upfield from TMS (0.00
ppm). DMSO-d6 dH 2.49; dC 39.51 and CDCl3 dH 7.27; dC
77.00 were used as reference signals. All experiments were
performed at a sample temperature of 26ꢀC 6 2ꢀC. LC-MS
analyses were performed on a LC-MS system consisting of a
Waters Alliance 2795 HPLC, a Waters PDA 2996 diode array
detector, a Sedex 75 ELS detector, and a ZQ 2000 single
quadrupole mass spectrometer. The mass spectrometer was
equipped with an electrospray ion source (ES) operated in pos-
itive and negative ion mode. The capillary voltage was set to
3.3 kV and the cone voltage to 28 V, respectively. The mass
spectrometer was scanned between m/z 100 and 700 with a
scan time of 0.3 s. The diode array detector scanned from 200
to 400 nm. The temperature of the ELS detector was adjusted
to 40ꢀC, and the pressure was set to 1.9 bar. Separation was
performed on an Gemini C18 3.0 ꢁ 50, 3 lm (Phenomenex)
run at a flow rate of 1 mL/min. A linear gradient was applied
starting at 100% A (A: 10 mM NH4OAc in 5% CH3CN) end-
ing at 100% B (B: CH3CN) in 4 min followed by 100% B
until 5.5 min. The column oven temperature was set to 40ꢀC.
HPLC analyses were performed on an Agilent HP1100 system
consisting of a G1322A Micro Vacuum Degasser, a G1311A
Method B. CuCl2 (13.4 mg, 0.01 mmol) was dissolved in
EtOH (3 mL), resulting in a green solution. Ascorbic acid
(17.6 mg, 0.01 mmol) was added and the mixture was stirred
for 5 min to give a colorless, homogenous, mixture. Pentane-
2,4-dione (1b) (0.103 mL, 1.00 mmol) and 1H-tetrazol-5-
amine (2) (85 mg, 1.00 mmol) were added in sequence, and
the resulting mixture was stirred at ambient temperature for 3
h. Saturated NH4Cl (10 mL) was added and the resulting sus-
pension was extracted with EtOAc (5 ꢁ 30 mL). The organic
layers were dried with NaSO4 and evaporated in vacuo, yield-
ing the title compound as a white solid. Yield: 132 mg, 98%.
1H NMR (400 MHz, DMSO-d6): d 2.61 (m, 3H), 2.86 (s, 3H),
7.39 (s, 1H). MS: (ES): m/z 150 [Mþ1], 148 [M–1].
Quaternary Pump,
a G1367 Well-Plate Autosampler, a
G1316A Thermostated Column Compartment and a G1315A
Diode Array Detector. The diode array detector was scanned
from 200 to 400 nm, step and peak width were set to 2 nm
and 0.01 min, respectively. The column used was an Gemini
˚
C18, 3.0 mm ꢁ 50 mm, 3.0 lm, 110 A run at a flow rate of
1.0 mL/min. The column oven temperature was set to 40ꢀC. A
linear gradient was applied, starting at 100% A (A: 10 mM
NH4OAc in 5% CH3CN) and ending at 95% B (B: CH3CN)
after 6.5 min then 95% B for 0.5 min. High resolution mass
spectra (HRMS) were recorded on a Micromass Q-Tof micro
mass spectrometer equipped with a LockSpray source and con-
nected to an Acquity UPLC system with a PDA detector. All
analyses were acquired using positive mode electrospray ioni-
zation (ESIþ) in full scan, and Leucine Enkephalin (Sigma)
was used as the lock mass (m/z 556.2771) at a concentration
of 0.9 pmol/lL and a flow rate of 100 lL/min with a 1:10
split, ion source:waste. Cone Voltage was set to 54 to achieve
ꢂ200 counts for Leucine Enkephalin. Nitrogen was used as
the nebulizing and desolvation gas, with the source operated at
120ꢀC and the desolvation gas at 300ꢀC. Capillary voltage was
3000 V, Cone voltage 30 V. Argon was used as the collision
gas. Chromatographic separation for HRMS was achieved with
a 2.3 min linear gradient from 95% A (A: 10 mM NH4OAc in
MilliQ water þ 5% MeCN) to 95% B (B: MeCN) over an
ACQUITY UPLC BEH C18 1.7 lm, 2.1 mm ꢁ 50 mm col-
umn maintained at 65ꢀC and run at a flow rate of 0.7 mL/min
with a 1:5 split, ion source:waste. Analytes were diluted in
H2O:ACN (50:50) until suitable concentration for the LC-MS
analysis. DSC was performed in a Mettler Toledo DSC 820
equipped with a high-pressure gold-plated capsule in the tem-
perature range of 30–500ꢀC using a heating rate of 5 K/min.
2-Azido-4-methylpyrimidine (4a)
2-Azido-4-methyl-6-phenylpyrimidine (4c)
Method A. 1-Phenylbutane-1,3-dione (1c) (100 mg, 0.62
mmol) was dissolved in EtOH (2.5 mL) and hydrochloric acid,
37% (0.06 mL) to give a colorless solution. 1H-Tetrazol-5-
amine (2) (52.5 mg, 0.62 mmol) was added and the resulting
mixture was refluxed for 2 h. The formed suspension was evapo-
rated in vacuo, yielding a white solid. The solid was dissolved
in hot EtOH and cooled to ambient temperature, followed by
storage in the refrigerator overnight. The precipitated material
was collected by suction filtration to yield the title compound as
colorless, needle-like crystals. Yield: 111 mg, 84%. 1H NMR
(400 MHz, DMSO-d6) d 2.97 (s, 3H), 7.6–7.7 (m, 3H), 8.18 (s,
1H), 8.3–8.4 (m, 2H). MS; ES m/z 212 [Mþ1].
Method B. CuCl2 (4.2 mg, 0.03 mmol) was dissolved in
EtOH (3 mL), resulting in a green solution. Ascorbic acid (17.6
mg, 0.03 mmol) was added, and the mixture was stirred for 5
min to give a colorless, homogenous mixture. 1-Phenylbutane-
1,3-dione (1c) (100 mg, 0.62 mmol) and 1H-tetrazol-5-amine
(2) (52 mg, 0.62 mmol) were added in sequence, and the result-
ing mixture was stirred at ambient temperature for 72 h. Satu-
rated NH4Cl (10 mL) was added and the resulting suspension
was extracted with EtOAc (5 ꢁ 30 mL). The organic layers
were dried with NaSO4 and evaporated in vacuo. The crude ma-
terial was recrystallized in MeOH/H2O, yielding the titled com-
pound as colorless, needle-like, crystals. Yield: 56 mg, 43%.
2-Azido-4,6-diphenylpyrimidine (4d)
Method B. CuCl2 (10.1 mg, 0.07 mmol) was dissolved in
MeOH (2 mL), resulting in a green solution. Ascorbic acid (13.3
mg, 0.07 mmol) was added and the mixture was stirred for
Method A. 1,3-Diphenylpropane-1,3-dione (1d) (100 mg,
0.45 mmol) was dissolved in EtOH (2.5 mL) and hydrochloric
acid 37% (0.04 mL, 0.48 mmol) to give a colorless solution. 1H-
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

July 2010
Copper-Catalyzed Alkyne Cycloaddition on Electron Deficient Azides
via Tetrazolo[1,5-a]pyrimidines
891
Tetrazol-5-amine (2) (40 mg, 0.45 mmol) was added and the
resulting mixture was refluxed for 48 h. The mixture was cooled
to ambient temperature, followed by storage in the refrigerator
overnight. The precipitated material was collected by suction fil-
tration to yield the title compound as colorless, needle-like crys-
4-Methyl-6-phenyl-2-(4-m-tolyl-1H-1,2,3-triazol-1-yl)pyrimi-
dine (6d). Starting alkyne: 1-Ethynyl-3-methylbenzene (5d).
1
Reaction time: Overnight. Yield: 109 mg, 70%. H NMR (400
MHz, CDCl3): d 2.45 (s, 3H), 2.76 (s, 3H), 7.37 (t, J ¼ 7.5 Hz
1H), 7.5–7.6 (m, 3H), 7.63 (s, 1H), 7.64 (s, 1H), 7.78 (d, J ¼
7.5 Hz 1H), 7.86 (s, 1H), 8.2–8.3 (m, 2H), 8.91 (s, 1H).
13C NMR (101 MHz, CDCl3): d 21.4, 24.6, 115.4, 118.5,
123.2, 126.7, 127.4, 128.7, 129.1, 129.3, 130.0, 131.7, 135.5,
138.6, 148.0, 154.5, 166.0, 170.8. MS: (ES) m/z 328 [Mþ1].
HPLC: Rt ¼ 5.9 min. HRMS: Found 328.1569, calc. for
C20H18N5: 328.1562.
1
tals. Yield: 27.8 mg, 23%. H NMR (400 MHz, DMSO-d6): d
7.5–7.8 (m, 6H), 8.3–8.5 (m, 5H). MS: (ES) m/z 274 [Mþ1].
Methyl 2-azido-6-phenylpyrimidine-4-carboxylate (4e)
Method A. Methyl 2,4-dioxo-4-phenylbutanoate (1e) (100
mg, 0.48 mmol) was dissolved in EtOH (3 mL) and hydrochlo-
ric acid 37% (0.04 mL, 0.48 mmol) to give a colorless mix-
ture. 1H-Tetrazol-5-amine (2) (41.3 mg, 0.48 mmol) was
added and the resulting mixture was refluxed for 48 h. The so-
lution was cooled to ambient temperature, followed by storage
in the refrigerator overnight. The precipitated material was col-
lected by suction filtration to yield the title compound as color-
4-Methyl-6-phenyl-2-(4-p-tolyl-1H-1,2,3-triazol-1-yl)pyrimi-
dine (6e). Starting alkyne: 1-Ethynyl-4-methylbenzene (5e).
1
Reaction time: Overnight. Yield: 105 mg, 67%. H NMR (400
MHz, CDCl3): d 2.42 (s, 3H), 2.75 (s, 3H), 7.29 (d, J ¼ 8.0
Hz, 3H), 7.5–7.6 (m, 3H), 7.63 (s, 1H), 7.90 (d, J ¼ 8.0 Hz,
2H), 8.2–8.3 (m, 2H), 8.86 (s, 1H). 13C NMR (101 MHz,
CDCl3): d 21.3, 24.6, 115.4, 118.1, 126.00, 127.3, 127.4,
129.1, 129.5, 131.7, 135.5, 138.4, 148.0, 154.5, 166.0, 170.8.
MS: (ES) m/z 328 [Mþ1]. HPLC: Rt ¼ 5.9 min. HRMS:
Found 328.1568, calc. for C20H18N5: 328.1562.
2-(4-(2-Methoxyphenyl)-1H-1,2,3-triazol-1-yl)-4-methyl-6-phe-
nylpyrimidine (6f). Starting alkyne: 1-Ethynyl-2-methoxy-ben-
zene (49). Reaction time: 2 h. Yield: 95 mg, 58%. 1H NMR (400
MHz, CDCl3) d 2.77 (s, 3H), 4.03 (s, 3H), 7.04 (d, J ¼ 8.4 Hz,
1H), 7.13 (t, J ¼ 7.6 Hz, 1H), 7.2–7.4 (m, 1H), 7.6 (m, 3H),
7.64 (s, 1H), 8.2–8.3 (m, 2H), 8.5 (m, 1H), 9.10 (s, 1H). 13C
NMR (126 MHz, CDCl3): d 24.5, 55.5, 110.7, 115.3, 118.9,
120.9, 121.7, 127.4, 128.2, 129.0, 129.2, 131.6, 135.5, 143.3,
154.7, 155.9, 165.9, 170.6. MS: (ES) m/z 344 [Mþ1]. HPLC:
Rt ¼ 5.7 min. HRMS: Found 344.1522, calc. for C20H18N5O:
344.1511.
1
less, needle-like crystals. Yield: 43.4 mg, 35%. H NMR (400
MHz, DMSO-d6): d 3.96 (s, 3H), 7.6–7.7 (m, 3H), 8.2–8.3 (m,
3H). MS: (ES) m/z 256 [Mþ1].
General procedure for the synthesis of 40-substituted 2-
(10,20,30-triazol-10-yl)pyrimidines (6). Copper(I) iodide (9 mg,
0.05 mmol) was suspended in toluene (2 mL), whereupon the
alkyne (5) (0.47 mmol) was added, followed by 2-azido-4-
methyl-6-phenylpyrimidine (4c) (100 mg, 0.47 mmol) to yield
a heterogeneous mixture. The resulting reaction mixture was
heated to 80ꢀC for the time specified (Table 2) and full con-
version was observed according to HPLC. The volatiles were
evaporated in vacuo to afford the crude as a solid. The solid
was suspended/dissolved in a minimum of hot EtOH, and
water was subsequently added until a turbid liquid phase was
observed. Upon refrigeration/cooling precipitation ensued and
the product was isolated and dried to give the yield specified.
4-Methyl-6-phenyl-2-(4-phenyl-1H-1,2,3-triazol-1-yl)pyrimi-
dine (6a). Starting alkyne: Ethynylbenzene (5a). Reaction
2-(4-(3-Methoxyphenyl)-1H-1,2,3-triazol-1-yl)-4-methyl-6-phe-
nylpyrimidine (6g). Starting alkyne: 1-Ethynyl-3-methoxy-ben-
1
zene (5g). Reaction time: 2 h. Yield: 120 mg, 73%. H NMR
1
time: 2 h. Yield: 95 mg, 64%. H NMR (500 MHz, CDCl3): d
2.77 (s, 3H), 7.40 (t, J ¼ 7.5 Hz, 2H), 7.65 (s, 1H), 8.01 (d, J
¼ 7.8 Hz, 2H), 7.61–7.54 (m, J ¼ 7.1 Hz, 3H), 7.49 (t, J ¼
7.5 Hz, 2H), 8.21 (dd, J ¼ 6.8 Hz, 7.8 Hz, 2H), 8.94 (s, 1H).
13C NMR (126 MHz, CDCl3): d 24.6, 58.5, 115.5, 118.5,
126.1, 127.4, 128.5, 128.9, 129.1, 130.1, 131.8, 135.4, 147.9,
154.5, 166.0, 170.8. MS: (ES) m/z 314 [Mþ1]. HPLC: Rt¼ 4.6
min. HRMS: Found 314.1406, calc. for C19H16N5: 314.1400.
Ethyl 1-(4-methyl-6-phenylpyrimidin-2-yl)-1H-1,2,3-triazole-
4-carboxylate (6b). Starting alkyne: Ethyl propiolate (5b). Reac-
tion time: 2 h. Yield: 112 mg, 90%. 1H NMR (500 MHz,
CDCl3): d 1.47 (t, J ¼ 7.4 Hz, 3H), 2.76 (s, 3H), 4.50 (q, J ¼ 7.4
Hz, 2H), 7.5–7.6 (m, 3H), 7.69 (s, 1H), 8.19 (dd, J ¼ 7.2 Hz,
2H), 9.24 (s, 1H). 13C NMR (126 MHz, CDCl3): d 14.4, 24.6,
61.6, 116.1, 126.9, 127.4, 129.2, 132.0, 135.0, 140.3, 154.1,
160.6, 166.2, 171.1. MS: (ES) m/z 310 [Mþ1]. HPLC: Rt¼ 4.9
min. HRMS: Found 310.1305, calc. for C16H16N5O2: 310.1304.
4-Methyl-6-phenyl-2-(4-o-tolyl-1H-1,2,3-triazol-1-yl)pyrimi-
dine (6c). Starting alkyne: 1-Ethynyl-2-methylbenzene (5c).
Reaction time: Overnight. Yield: 88 mg, 56%. 1H NMR (400
MHz, CDCl3): d 2.58 (s, 3H), 2.78 (s, 3H), 7.3–7.4 (m, 3H),
7.5–7.6 (m, 3H), 7.66 (s, 1H), 7.9 (m, 1H), 8.2–8.3 (m, 2H),
8.80 (s, 1H). 13C NMR (101 MHz, CDCl3): d 21.40, 24.6,
115.4, 120.6, 126.1, 127.4, 128.5, 129.1, 129.3, 129.5, 130.9,
131.7, 135.4, 136.0, 147.3, 154.6, 166.0, 170.8. MS: (ES) m/z
328 [Mþ1]. HPLC: Rt ¼ 5.8 min. HRMS: Found 328.1570,
calc. for C20H18N5: 328.1562.
(400 MHz, CDCl3): d 2.76 (s, 3H), 3.91 (s, 3H), 6.9–7.0 (m,
1H), 7.38 (t, J ¼ 8.1 Hz, 1H), 7.5–7.6 (m, 5H), 7.64 (s, 1H),
8.2–8.3 (m, 2H), 8.91 (s, 1H). 13C NMR (126 MHz, CDCl3): d
24.6, 55.4, 111.1, 114.6, 115.5, 118.5, 118.7, 127.4, 129.1,
129.9, 131.4, 131.8, 135.4, 147.8, 154.4, 160.0, 166.0, 170.8.
MS: (ES) m/z 344 [Mþ1]. HPLC: Rt¼ 5.6 min. HRMS: Found
344.1503, calc. for C20H18N5O: 344.1511.
2-(4-(4-Methoxyphenyl)-1H-1,2,3-triazol-1-yl)-4-methyl-6-phe-
nylpyrimidine (6h). Starting alkyne: 1-Ethynyl-4-methoxy-ben-
zene (5h). Reaction time: 2 h. Yield: 95 mg, 58%. 1H NMR
(400 MHz, CDCl3): d 2.76 (s, 3H), 3.87 (s, 3H), 7.01 (d, J ¼ 8.8
Hz, 2H), 7.5–7.6 (m, 3H), 7.64 (s, 1H), 7.93 (d, J ¼ 8.8 Hz, 2H),
8.2–8.3 (m, 2 H), 8.84 (s, 1H). 13C NMR (101 MHz, CDCl3): d
24.6, 55.3, 114.2, 115.4, 117.6, 122.8, 127.2, 127.4, 128.2,
128.9, 129.1, 129.3, 131.3, 131.7, 132.4, 135.4, 147.8, 154.5,
159.8, 166.0, 170.8. MS: (ES) m/z 344 [Mþ1]. HPLC: Rt ¼ 5.5
min. HRMS: Found 344.1504, calc. for C20H18N5O: 344.1511.
N,N-Dimethyl-4-(1-(4-methyl-6-phenylpyrimidin-2-yl)-1H-
1,2,3-triazol-4-yl)aniline (6i). Starting alkyne: 4-Ethynyl-N,N-
dimethylbenzenamine (5i). Reaction time: 24 h. Yield: 120 mg,
71%. 1H NMR (400 MHz, CDCl3): d 2.75 (s, 3H), 3.02 (s,
6H), 6.82 (d, J ¼ 8.7 Hz, 2H), 7.5–7.6 (m, 3H), 7.62 (s, 1H),
7.87 (d, J ¼ 8.7 Hz, 2H), 8.2–8.3 (m, 2H), 8.78 (s, 1H). 13C
NMR (101 MHz, CDCl3): d 24.6, 40.5, 112.4, 115.2, 116.7,
127.1, 127.4, 129.1, 131.6, 135.6, 118.2, 148.4, 150.6, 154.6,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

¨
L. I. Nilsson, A. Ertan, D. Weigelt, and J. M. J. Nolsoe
892
Vol 47
165.9, 170.7. MS: (ES) m/z 357 [Mþ1]. HPLC: Rt ¼ 5.8 min.
HRMS: Found 357.1823, calc. for C21H21N6: 357.1828.
Acknowledgments. LN wants to acknowledge Dr. Sarah A.
Dunne and Dr. Simon Dunne in conjunction with the undergradu-
¨
ate program at Malardalens University. The authors are much
2-(4-(6-Methoxynaphthalen-2-yl)-1H-1,2,3-triazol-1-yl)-4-
methyl-6-phenylpyrimidine (6j). Starting alkyne: 2-ethynyl-6-
methoxynaphthalene (5j). Reaction time: 7 h. Yield: 133 mg,
71%. 1H NMR (400 MHz, CDCl3): d 3.31 (s, 3H), 3.90 (s,
3H), 7.1–7.3 (m, 3H), 7.3–7.4 (m, 1H), 7.6–7.7 (m, 3H), 7.94
(d, J ¼ 8.9 Hz, 2H), 8.2–8.3 (m, 2H), 8.4–8.5 (m, 2H), 8.59
(bs, 1 H), 9.60 (s, 1H). 13C NMR (126 MHz, CDCl3): d 24.6,
55.3, 105.7, 115.5, 118.3, 119.3, 124.6, 124.9, 125.3, 127.36,
127.43, 128.9, 129.1, 129.8, 131.8, 134.5, 135.4, 148.1, 154.5,
158.0, 166.0, 170.8. MS: (ES) m/z 394 [Mþ1]. HPLC: Rt ¼ 6.2
min. HRMS: Found 394.1660, calc. for C24H20N5O: 394.1668.
2-(4-Benzyl-1H-1,2,3-triazol-1-yl)-4-methyl-6-phenylpyrimi-
dine (6k). Starting alkyne: Prop-2-ynylbenzene (5k). Reaction
indebted to Dr. Alexandra Bernlind for generously providing her
expertise on NMR, to Mrs. Fanny Bjarnemark for performing the
HRMS contained within this article, and to Mrs. Nina Ahlqvist
for preparation of the DSC data.
REFERENCES AND NOTES
¨
[1] Huisgen, R.; Szeimies, G.; Mobius, L. Chem Ber 1967,
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¨
[2] Tornoe, C. W.; Christensen, C.; Meldal, M. J Org Chem
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1
[3] Rostovtsev, V. V.; Green, L. G.; Fokin, V. V.; Sharpless,
K. B. Angew Chem Int Ed 2002, 41, 2596.
time: 2 h. Yield: 112 mg, 72%. H NMR (400 MHz, CDCl3):
d 2.72 (s, 3H), 4.24 (s, 2H), 7.2-7.3 (m, 1H), 7.34 (d, J ¼ 4.6
Hz, 4H), 7.5–7.6 (m, 3H), 7.60 (s, 1H), 8.13 (dd, J ¼ 8.2 Hz,
7.2 Hz, 2H), 8.35 (s, 1H). 13C NMR (101 MHz, CDCl3): d
24.5, 32.2, 115.4, 120.7, 126.6, 127.4, 128.6, 128.8, 129.0,
131.7, 135.4, 138.7, 148.0, 154.5, 165.9, 170.7. MS: (ES) m/z
328 [Mþ1]. HPLC: Rt¼ 4.6 min. HRMS: Found 328.1552,
calc. for C20H18N5: 328.1562.
2-(4-Cyclopropyl-1H-1,2,3-triazol-1-yl)-4-methyl-6-phenylpyri-
midine (6l). Starting alkyne: Ethynylcyclopropane (5l). Reac-
tion time: 3 h. Yield: 119 mg, 91%. 1H NMR (400 MHz,
CDCl3): d 0.9–1.0 (m, 4H), 2.1–2.2 (m, 1H), 2.73 (s, 1H),
7.5–7.6 (m, 3H), 7.61 (s, 1H), 8.1–8.2 (m, 2H), 8.36 (s, 1H).
13C NMR (101 MHz, CDCl3): d 6.78, 7.89, 24.6, 115.2, 118.5,
127.4, 129.1, 131.7, 135.5, 154.5, 165.9, 170.7. MS: (ES) m/z
277 [Mþ1]. HPLC: Rt¼ 4.9 min. HRMS: Found 278.1409,
calc. for C16H16N5: 278.1406.
[4] Kolb, H. C.; Finn, M. G.; Sharpless, K. B. Angew Chem
Int Ed 2001, 40, 2004.
[5] Kolb, H. C.; Sharpless, K. B. Drug Discov Today 2003, 8, 1128.
[6] Sharpless, K. B.; Manetsch, R. Expert Opin Drug Discov
2006, 1, 525.
[7] Cosyn, L.; Palaniappan, K. K.; Kim, S.-K.; Duong, H. T.;
Gao, Z.-G.; Jacobson, K. A.; Van Calenbergh, S. J Med Chem 2006,
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[8] Gupte, A.; Boshoff, H. I.; Wilson, D. J.; Neres, J.; Labello,
N. P.; Somu, R. V.; Xing, C.; Barry C. E., III; Aldrich, C. C. J Med
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[9] Lu, R. J.; Tucker, J. A.; Zinevitch, T.; Kirichenko, O.;
Konoplev, V.; Kuznetsova, S.; Sviridov, S.; Pickens, J.; Tandel, S.;
Brahmachary, E.; Yang, Y.; Wang, J.; Freel, S.; Fisher, S.; Sullivan,
A.; Zhou, J.; Stanfield-Oakley, S.; Greenberg, M.; Bolognesi, D.; Bray,
B.; Koszalka; B.; Jeffs, P.; Khasanov, A.; Ma, Y-A.; Jefferies, C.; Liu,
C.; Proskurina, T.; Zhu, T.; Chucholowski, A.; Li, R.; Sexton, C. J
Med Chem 2007, 50, 6535.
2-(4-Diethoxymethyl-1H-1,2,3-triazol-1-yl)-4-methyl-6-phe-
nylpyrimidine (6m). Starting alkyne: 3,3-Diethoxyprop-1-yne
1
[10] Farmer, J. J.; Bhattacharjee, A.; Chen, Y.; Goldberg, J. A.;
Ippolito, J. A.; Kanyo, Z. F.; Lou, R.; Oyelere, A. K.; Sherer, E. C.;
Sutcliffe, J. A.; Wang, D.; Wu, Y.; Du, Y. PCT Int Appl WO 2005,
085266 A2, 332 p.
(43). Reaction time: 2 h. Yield: 127 mg, 79%. H NMR (400
MHz, CDCl3): d 1.29 (t, J ¼ 7.1 Hz, 6H), 2.81 (bs, 3H), 3.6–
3.8 (m, 4H), 5.87 (s, 1H), 7.5–7.6 (m, 3H), 7.66 (s, 1H), 8.1–
8.2 (m, 2H), 8.76 (s, 1H). 13C NMR (101 MHz, CDCl3): d
15.2, 24.7, 61.6, 96.5, 115.7, 121.4, 127.4, 129.1, 131.8, 135.3,
147.5, 166.0, 170.8. MS: (ES) m/z 278 [M–61]. HPLC: Rt ¼
4.9 min. HRMS: Found 294.1351, calc. for C16H16N5O:
294.1354 (The parent ion could not be observed. The observed
mass corresponds to [MþHþ – C2H6O].)
¨
[11] Nolsoe, J. M. J.; Ertan, A.; Svensson, M.; Weigelt, D.
J Heterocycl Chem 2010, 47.
[12] Wentrup, C. Tetrahedron 1970, 26, 4969.
[13] Compound 4d, C16 H11 N5 (Mr ¼ 273.30), Colorless, Rod,
˚
Monoclinic space group P 21/c, Z ¼ 4, a ¼ 11.437(1) A, b ¼
ꢀ
ꢀ
ꢀ
˚
˚
16.761(1) A, c ¼ 7.030(1) A, a ¼ 90 , b ¼ 94.435(2) , c ¼ 90 , V ¼
Methyl 1-(4-methyl-6-phenylpyrimidin-2-yl)-1H-1,2,3-tria-
zole-4-carboxylate (6n). Starting alkyne: Methyl propiolate
(37). Reaction time: 3 h. Yield: 77 mg, 51%. 1H NMR (400
MHz, CDCl3): d 2.76 (s, 3H), 4.03 (s, 3H), 7.69 (s, 1H), 7.5–
7.6 (m, 3H), 8.1–8.2 (m, 2H), 9.26 (s, 1H). 13C NMR (101
MHz, CDCl3): d 24.6, 52.4, 116.1, 127.0, 127.4, 129.2, 132.0,
135.0, 140.1, 154.1, 161.0, 166.2, 171.1. MS: (ES) m/z 296
[Mþ1]. HPLC: Rt ¼ 4.5 min. HRMS: Found 296.1137, calc.
for C15H14N5O2: 296.1147.
3
ꢀ
˚
1343.6(2) A , Mo Ka radiation, y ¼ 1.0–27.5 , 6126 measured reflec-
tions, T ¼ 200(2) K on Bruker-Nonius KappaCCD diffractometer. The
structure was solved using direct methods SIR97 (Altomare et al.,
1999). Program used to refine structure: SHELXL97 (Sheldrick, 1997).
Molecular graphics: PLATON (Spek, 2003). The final R[F2 > 2r(F2)]
¼ 0.0567 and wR ¼ [w ¼ 1/[r2(Fo2) þ (0.0730P)2], where P ¼ (F2o
þ
2F2c)/3.
[14] Urben, P. G. Bretherick’s Handbook of Reactive Chemical
Hazards, Vol. 1–2, 7th ed.; Elsevier: Oxford, 2007.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet