Synthesis and photophysical properties of alkynylated pyrimidines by site-selective sonogashira reactions of 2,4,5,6-tetrachloropyrimidine; First synthesis of tetraalkynyl-pyrimidines

Article abstract of DOI:10.1002/ejoc.201001622

A variety of novel alkynyl-substituted pyrimidines were prepared by the first site-selective Sonogashira cross-coupling reactions of 2,4,5,6-tetrachloropyrimidine. The products, di-, tri-, and tetraalkynyl- pyrimidines, exhibit fluorescence in the range o

Full text of DOI:10.1002/ejoc.201001622

FULL PAPER
DOI: 10.1002/ejoc.201001622
Synthesis and Photophysical Properties of Alkynylated Pyrimidines by
Site-Selective Sonogashira Reactions of 2,4,5,6-Tetrachloropyrimidine;
First Synthesis of Tetraalkynyl-pyrimidines
Imran Malik,[a] Zeeshan Ahmed,[a] Sebastian Reimann,[a,b] Iftikhar Ali,[a]
Alexander Villinger,[a] and Peter Langer*[a,b]
Keywords: Alkynes / Cross-coupling / Fluorescence / Palladium / Regioselectivity / Nitrogen heterocycles
A variety of novel alkynyl-substituted pyrimidines were pre-
pared by the first site-selective Sonogashira cross-coupling
reactions of 2,4,5,6-tetrachloropyrimidine. The products, di-,
tri-, and tetraalkynyl-pyrimidines, exhibit fluorescence in the
range of 395–470 nm. The synthesis of tetraalkynyl-pyrimid-
ines has not been previously reported, nor has the synthesis
of chlorinated di- and trialkynylated pyrimidines.
synthesis of dialkynyl- and trialkynyl-pyrimidines by Sono-
gashira reactions of 2,4,6-trichloropyrimidine has been pre-
viously reported.[9] Recently, we have reported the first
Suzuki–Miyaura cross-coupling reactions of 2,4,5,6-tetra-
chloropyrimidine.[10] Herein, we report a series of reactions
that constitute, to the best of our knowledge, the first Sono-
gashira reactions of 2,4,5,6-tetachloropyrimidine. All prod-
ucts, 4,6-dialkynyl-2,5-dichloropyrimidines, 2,4,6-trialkyn-
yl-5-chloropyrimidines, and tetraalkynylpyrimidines, exhi-
bit a fluorescence in the range of 395–470 nm. From a pre-
parative viewpoint, it is worth noting that the synthesis of
tetraalkynylpyrimidines has, to the best of our knowledge,
not been previously reported. This type of molecule not
only attracts attention because of its fluorescence proper-
ties, but also because of its beautiful symmetrical structure.
It is also worth noting that chlorinated di- and trialkynyl-
ated pyrimidines, related to those described herein, have not
previously been reported in the literature.
Introduction
The chemistry of pyrimidine and its derivatives has been
intensively studied because of the pharmacological and
physical properties of these important heterocycles. Pyrim-
idine derivatives, including uracil, thymine, cytosine, ad-
enine, and guanine, are fundamental building blocks of de-
oxyribonucleic acids (DNA) and ribonucleic acids (RNA).
Vitamin B1 (thiamine) is a well-known example of a natu-
rally occurring pyrimidine that is encountered in our daily
lives. Synthetic pyrimidine derivatives are used in the phar-
maceutical industry as potent drugs. For example, pyri-
methamine is used as an antimalarial and antiprotozoal
drug that is used in combination with sulfadiazine.[1] Pyrim-
idines also play a role as analgesic, antihypertensive, antipy-
retic, antiinflammatory, antineoplastic, antibacterial, anti-
protozoal, antifungal, antiviral, and antifolate drugs and as
pesticides, herbicides, and plant growth regulators.[2] In re-
cent studies it was shown that bicyclic pyrimidine nucleo-
sides are potent and selective inhibitors of Varicella Zoster
Virus (VZV) replication.[3] Tao Wang and co-workers re-
ported that pyrimidine derivatives were identified as potent
inhibitors of TrK kinase. The latter plays a critical role in
cell signaling and cancer related processes.[4] Pyrimidines
are also of considerable importance in the field of material
sciences. For example, they have been reported[5] to be ef-
ficient organic light emitting devices (OLED), which play
an important role in biological and material sciences.[6,7]
Monohalogenated pyrimidines have been used as build-
ing blocks in Negishi and Suzuki coupling reactions.[8] The
Results and Discussion
Synthesis
The Sonogashira reaction of commercially available
2,4,5,6-tetrachloropyrimidine (1) with a range of substi-
tuted arylacetylenes 2a–d (2.4 equiv.) afforded the 4,6-bis-
(arylethynyl)-2,5-dichloropyrimidines 3a–d in 73–91% yield
(Scheme 1, Table 1). The reaction conditions were carefully
optimized. The employment of either [Pd(PPh3)4] (5 mol-
%) or [Pd(OAc)2] (5 mol-%) in the presence of PCy3
(10 mol-%) both allowed product 3b to be prepared in mod-
erate yield. The use of [Pd(PPh3)2Cl2] (10 mol-%) allowed
the yield to be improved to 76%. Initially, the reactions
were carried out in a range of organic solvents, but the reac-
tions generally proceeded sluggishly. However, the reactions
[a] Institut für Chemie, Universität Rostock,
Albert Einstein Str. 3a, 18059 Rostock, Germany
[b] Leibniz-Institut für Katalyse an der Universität Rostock e.V.,
Albert Einstein Str. 29a, 18059 Rostock, Germany
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201001622.
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Synthesis of Fluorescent Alkynyl-pyrimidines
proceeded in good yields when diisopropylamine (DIPA)
was used (both as the solvent and base). To avoid multiple
coupling, the reactions were performed at 55 °C for a rela-
tively short period of time (2 h).
Scheme 2. Synthesis of 4a–f. Reagents and conditions:
1
(1.0 equiv.), 2a–c or 2e–g (3.6 equiv.), CuI (5 mol-%), [Pd(PPh3)2-
Cl2] (10 mol-%), DIPA, 70 °C, 2 h.
Scheme 1. Synthesis of 3a–d. Reagents and conditions:
1
Table 2. Synthesis of 4a–f.
(1.0 equiv.), 2a–d (2.4 equiv.), CuI (5 mol-%), [Pd(PPh3)2Cl2]
% Yield for 4[a]
(10 mol-%), DIPA, 55 °C, 2 h.
2
4
R
a
b
c
e
f
a
b
c
d
e
f
4-tBuC6H4
Ph
3-(MeO)C6H4
4-MeC6H4
nPent
80
71
77
84
68
69
Table 1. Synthesis of 3a–d.
2,3
R
% Yield for 3[a]
a
b
c
4-tBuC6H4
Ph
3-(MeO)C6H4
6-(MeO)C10H6
76
73
81
91
g
nPr
[a] Yield of isolated product.
d
[a] Yield of isolated product.
presence of DIPA (Scheme 3 and Table 3). The temperature
was increased to 85 °C and the reaction time was consider-
ably extended to 16 h.
The structure of product 3c was independently con-
firmed by a crystal structure X-ray analysis (Figure 1).[11]
The pyridine moiety and the two aryl groups were found to
be in plane, which might be due to electronic interactions
of the aryl groups or due to crystal packing effects.
Scheme 3. Synthesis of 5a–c. Reagents and conditions:
1
(1.0 equiv.), 2 (6.0 equiv.), CuI (5 mol-%), [Pd(PPh3)2Cl2] (10 mol-
%), DIPA (3 mL), dioxane (7 mL), 85 °C, 16 h.
Table 3. Synthesis of 5a–c.
2,5
R
% Yield for 5[a]
Figure 1. X-ray crystal structure of 3c.[11]
a
b
c
4-tBuC6H4
Ph
3-(MeO)C6H4
76
73
79
The Sonogashira reaction of 1 with different substituted
acetylenes (3.6 equiv.) afforded the 2,4,6-tri(alkynyl)-5-chlo-
ropyrimidines 4a–f in 68–84% yield (Scheme 2 and Table 2).
[a] Yield of isolated product.
The Suzuki–Miyaura reaction of 2,4,5,6-tetrachloropyr-
The reactions were carried out following the protocol dis- imidine with (4-methylphenyl)boronic acid (1.0 equiv.), in
cussed above for the synthesis of 3a–d. A slight increase in the presence of 5 mol-% [Pd(PPh3)2Cl2] (60 °C, 2 h), af-
the temperature proved to be important (70 °C, 2 h).
forded product 6 in 76% yield. The Sonogashira reaction
The synthesis of hitherto unknown 2,4,5,6-tetraalkynyl- of 6 with 3-ethynylanisole (2c; 1 equiv.) yielded 8 in 59%
pyrimidines was next studied. The application of the reac- yield. The reaction of 6 with 2 equiv. of 2c afforded product
tion conditions, as discussed above, for the synthesis of 7 in 67% yield. Likewise, product 9 was prepared from 1-
products 3 and 4, proved to be unsatisfactory in terms of pentyne (2g) in 54% yield (Scheme 4). During the optimiza-
yields (formation of complex mixtures). Unsuccessful tion of the reaction conditions, the temperature was found
attempts were made to improve the yields by addition of to play an important role. The mono Sonogashira reaction
various solvents (N,N-dimethylformamide (DMF), toluene, of 1 and 6 was best carried out at 55 °C, whereas the two-
xylene) using DIPA or triethylamine as the base. After ex- fold Sonogashira reactions of 6 had to be carried out at
tensive optimization, it was found that products 5a–c could 70 °C. Compounds 7–9 are conceptually related to recently
be obtained in good yields when dioxane was used in the reported combined Suzuki/Sonogashira products derived
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P. Langer et al.
FULL PAPER
from pyridine.[12] The structure of product 7 was indepen- 25 °C, are summarized in Table 4 (for the spectra, see the
dently confirmed by a crystal structure analysis (Fig- Supporting Information). All the compounds contain a
ure 2),[11] which shows that the aryl groups are slightly pyrimidine core; their absorption wavelengths (λabs) are in
twisted out of plane.
the UV region (297–371 nm) and their emission wave-
lengths (λem) (fluorescence) are in the UV or blue region
(395–470 nm). Pyrimidines containing methoxy-substituted
aryl groups exhibit absorption and emission bands in the
range of λabs = 301–367 nm and λem = 426–470 nm, respec-
tively. For tert-butyl derivatives, the absorption and emis-
sion wavelengths are in the range of λabs = 325–371 nm and
λem = 426–440 nm.
Table 4. Absorption and emission spectroscopic data of alkynylated
pyrimidines.
Product
λabs [nm]
lgε
λem [nm]
Stokes shift
[nm]
3a
3b
3c
371
354
367
3.86
3.35
3.74
426
395
470
55
41
103
λabs [nm]
lgε
λem [nm]
4b
4c
5a
5b
5c
7
312
301
325
316
302
297
4.25
3.73
4.01
4.32
4.11
4.19
406
426
440
426
438
405
94
125
115
110
136
108
The symmetrical Sonogashira products 3a and 3b exhibit
absorption bands λabs,max = 371 and 354 nm and emission
bands at λem,max = 426 and 395 nm, respectively, with
Stokes shifts of 55 and 41 nm. Compound 3c showed ab-
Scheme 4. Synthesis of products 6–9. Reagents and conditions: (i)
1 (1.0 equiv.), 4-methylphenylboronic acid (1.0 equiv.), [Pd(PPh3)2-
Cl2] (5 mol-%), K2CO3 (2 m, 1 mL), dioxane, 60 °C, 2 h; (ii) 2c
(1.0 equiv.), CuI (5 mol-%), [Pd(PPh3)2Cl2] (10 mol-%), DIPA
(5 mL), 55 °C, 2 h; (iii) 2c (2.0 equiv.), CuI (5 mol-%), [Pd-
(PPh3)2Cl2] (10 mol-%), DIPA (5 mL), 70 °C, 3 h; (iv) 2g
(2.0 equiv.), CuI (5 mol-%), [Pd(PPh3)2Cl2] (10 mol-%), DIPA,
70 °C, 3 h.
sorption at λabs,max = 376 nm and emission at λem,max
=
470 nm with a larger Stokes shift (103 nm). In fact, larger
Stokes shifts generally correspond with better fluorescence
properties. Thus, the electron-donating 3-methoxyphenyl
group of 3c seems to be advantageous. In the case of un-
symmetrical Sonogashira products, compound 4c (contain-
ing a 3-methoxyphenyl group) showed a large Stokes shift
(125 nm), whereas 4b showed a smaller, but still acceptable,
Stokes shift (94 nm). The same phenomenon was observed
for tetrakis(arylethynyl)pyrimidines 5a–c. Whereas com-
pound 5c showed a large Stokes shift (136 nm), 5a and 5b
exhibited relatively small shifts. The mixed Suzuki/Sonoga-
shira product 7 also showed a large Stokes shift (108 nm).
Conclusions
We have reported the synthesis of di-, tri-, and tetraalk-
ynylpyrimidines by the first Sonogashira reactions of
2,4,5,6-tetrachloropyrimidine. The synthesis of tetraalk-
ynylpyrimidines has been reported for the first time. All
products are blue fluorescence dyes. Promising fluorescence
properties, with regard to the Stokes shift, were observed
for di-, tri-, and tetraalkynylated pyrimidines containing a
m-methoxyphenyl substituent. This can be explained by
push–pull substitution. In fact, inspection of the X-ray crys-
Figure 2. X-ray crystal structure of 7.[11]
Absorption and Fluorescence
The UV/Vis and fluorescence spectroscopic data of vari- tal structures shows that the central pyrimidine core and
ous pyrimidine derivatives, measured in chloroform at the aryl groups are only slightly twisted out of plane, which
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Synthesis of Fluorescent Alkynyl-pyrimidines
2.4 mmol), CuI (5 mol-%), [Pd(PPh3)2Cl2] (10 mol-%), and diiso-
propylamine (5 mL), 3c was isolated as brown solid (331 mg, 81%),
m.p. 177–179 °C. 1H NMR (250 MHz, CDCl3): δ = 3.76 (s, 6 H,
2ϫOCH3), 6.93–6.97 (m, 2 H), 7.09–7.10 (m, 2 H), 7.17–7.25 (m,
4 H) ppm. 13C NMR (62.8 MHz, CDCl3): δ = 55.4 (CH3), 83.8,
101.9 (C), 117.2, 117.6 (CH), 121.3 (C), 125.4, 129.8 (CH), 132.1,
allows almost ideal electronic interaction between the aro-
matic moieties through the alkynyl bridge. The tetralkynyl-
ated pyrididines are also interesting in their own right be-
cause this type of alkynylated molecule has not been pre-
viously reported. Preliminary results suggest that different
alkynyl substituents can be introduced in a sequential man-
ner. The application of a one-pot approach proved to be
less efficient in terms of yield.
151.2, 158.0, 159.4 (C) ppm. IR (KBr): ν = 2974 (w), 2207 (m),
˜
1596 (m), 1518 (m), 1268 (s), 1151 (m), 1035 (m), 955 (w), 850 (m),
772 (s), 673 (s), 541 (m) cm–1. GC–MS (EI, 70 eV): m/z (%) = 408
(87) [M+], 379 (4), 356 (2), 331 (5), 281 (23), 253 (17), 207 (100),
170 (5), 147 (8). HRMS (EI, 70 eV): calcd. for C22H14Cl2N2O2 [M+]
408.04370; found 408.04320.
Experimental Section
2,5-Dichloro-4,6-bis[(6-methoxynaphthalen-2-yl)ethynyl]pyrimidine
(3d): Starting with 1 (217 mg, 1 mmol), 2-ethynyl-6-methoxynaph-
thalene (2d; 436 mg, 2.4 mmol), CuI (5 mol-%), [Pd(PPh3)2Cl2]
(10 mol-%), and diisopropylamine (5 mL), 3d was isolated as a
light-yellow solid (463 mg, 91 %); m.p. 206–208 °C. 1H NMR
(300 MHz, CDCl3): δ = 3.87 (s, 6 H, 2ϫOCH3), 7.07 (s, 2 H), 7.13
(d, J = 8.9 Hz, 2 H), 7.54 (d, J = 8.5 Hz, 2 H), 7.67 (d, J = 8.5 Hz,
2 H), 7.69 (d, J = 8.9 Hz, 2 H), 8.07 (s, 2 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 55.4 (OCH3), 84.2, 104.2 (C), 106.0 (CH),
114.7 (C), 120.1, 127.3 (CH), 128.1 (C), 128.8 (CH), 129.5 (C),
General Procedure for Sonogashira Cross-Coupling Reactions: A
suspension of 2,4,5,6-tetrachloropyrimidine, [Pd(PPh3)2Cl2]
(10 mol-%), and CuI (5 mol-%) in diisopropylamine was degassed
three times in a pressure tube. The acetylene derivative (1.2 equiv.
per chlorine atom) was then added by using a syringe. The mixture
was heated at the indicated temperature (60–80 °C) for 4–10 h then
filtered and the residue was washed with CH2Cl2. The filtrate was
washed with
a saturated solution of ammonium chloride
(2ϫ25 mL), water (2ϫ25 mL), and dried with anhydrous Na2SO4.
The solvent was removed in vacuo and the product was purified by
column chromatography on silica gel.
130.0, 134.1 (CH), 135.7, 152.0, 157.0, 159.6 (C) ppm. IR (KBr): ν
˜
= 2934 (w), 2199 (s), 1626 (m), 1515 (m), 1476 (s), 1394 (w), 1266
(s), 1225 (m), 1192 (m), 1176 (m), 1032 (m), 969 (m), 849 (m), 798
(m) cm–1. GC–MS (EI, 70 eV): m/z (%) = 508 (100) [M]+, 493 (3),
465 (22), 422 (12), 362 (3), 325 (6), 281 (4), 254 (10), 211 (21).
HRMS (EI, 70 eV): calcd. for C30H18Cl2N2O2 [M+] 508.07428;
found 508.07450.
General Procedure for Suzuki Cross-Coupling Reactions: The reac-
tion was carried out in a pressure tube. To a dioxane suspension
(3–5 mL) of 2,4,5,6-tetrachloropyrimidine, [Pd(PPh3)2Cl2] (3–
5 mol-%), and arylboronic acid was added an aqueous solution of
K2CO3 (2 m, 1–2 mL). The mixture was heated at the indicated
temperature (60–100 °C) for the indicated period of time (2–8 h),
then diluted with water and extracted with CH2Cl2 (3ϫ25 mL).
The combined organic layers were dried with Na2SO4, filtered and
the filtrate was concentrated in vacuo. The residue was purified by
flash chromatography (silica gel; ethyl acetate/heptanes).
2,4,6-Tris[(4-tert-butylphenyl)ethynyl]-5-chloropyrimidine (4a):
Starting with 1 (217 mg, 1 mmol), 4-(tert-butyl)phenylacetylene
(2a; 0.6 mL, 3.6 mmol), CuI (5 mol-%), [Pd(PPh3)2Cl2] (10 mol-%),
and diisopropylamine (5 mL), 4a was isolated as a deep-yellow so-
lid (468 mg; 80%); m.p. 227–229 °C. 1H NMR (250 MHz, CDCl3):
δ = 1.24 (s, 9 H, 3ϫCH3), 1.29 (s, 18 H, 6ϫCH3), 6.99 (d, J =
8.3 Hz, 3 H), 7.29 (d, J = 8.5 Hz, 3 H), 7.33 (d, J = 8.4 Hz, 3 H),
7.45 (d, J = 8.5 Hz, 3 H) ppm. 13C NMR (62 MHz, CDCl3): δ =
31.1, 31.4 (CH3), 34.7, 34.9, 84.9, 93.2, 97.4, 118.6, 124.8 (C), 125.4,
125.5, 127.4, 132.1 (CH), 134.0, 146.9, 151.6, 153.1, 156.0 (C) ppm.
4,6-Bis[(4-tert-butylphenyl)ethynyl]-2,5-dichloropyrimidine
(3a):
Starting with 1 (217 mg, 1 mmol), [4-(tert-butyl)phenyl]acetylene
(2a; 0.4 mL, 2.4 mmol), CuI (5 mol-%), [Pd(PPh3)2Cl2] (10 mol-%),
and diisopropylamine (5 mL), 3a was isolated as a yellowish, highly
1
viscous oil (350 mg, 76%). H NMR (250 MHz, CDCl3): δ = 1.24
(s, 18 H, 6ϫCH3), 7.34 (d, J = 8.5 Hz, 4 H), 7.52 (d, J = 8.5 Hz,
2 H), 7.54 (d, J = 8.4 Hz, 2 H) ppm. 13C NMR (75 MHz, CDCl3):
δ = 31.0 (CH3), 35.1, 84.0, 102.6, 117.4 (C), 125.7, 125.8, 132.5,
IR (KBr): ν = 2959 (m), 1504 (s), 1432 (s), 1356 (m), 1292 (m),
˜
1263 (s), 1133 (s), 1036 (s), 931 (m), 816 (s), 767 (m), 735 (w) cm–1.
GC–MS (EI, 70 eV): m/z (%) = 582 (70) [M]+, 567 (16), 552 (38),
537 (46), 518 (100), 482 (3), 462 (2), 447 (2), 410 (12), 382 (02), 344
(31). HRMS (EI, 70 eV): calcd. for C40H39ClN2 [M+] 582.28004;
found 582.28020.
132.7 (CH), 133.1, 151.3, 154.6, 158.0 (C) ppm. IR (KBr): ν = 2960
˜
(w), 2208 (s), 1516 (s), 1362 (m), 1259 (s), 1106 (m), 1016 (m), 922
(m), 832 (s), 774 (w) cm–1. GC–MS (EI, 70 eV): m/z (%) = 460 (33)
[M]+, 445 (100), 417 (7), 364 (3), 305 (7), 273 (5), 245 (6), 215
(45), 202 (33). HRMS (EI, 70 eV): calcd. for C28H26Cl2N2 [M+]
460.14685; found 460.14730.
5-Chloro-2,4,6-tris(phenylethynyl)pyrimidine (4b): Starting with 1
(217 mg, 1 mmol), phenylacetylene (2b; 0.4 mL, 3.6 mmol), CuI
(5 mol-%), [Pd(PPh3)2Cl2] (10 mol-%), and diisopropylamine
(5 mL), 4b was isolated as light-brown solid (294 mg, 71%); m.p.
220–222 °C. 1H NMR (300 MHz, CDCl3): δ = 7.30–7.40 (m, 10
H), 7.58–7.63 (m, 5 H) ppm. 13C NMR (62 MHz, CDCl3): δ = 84.4,
87.1, 89.2, 100.5, 120.8, 121.1 (C), 128.4, 128.6, 129.9, 130.5 (CH),
2,5-Dichloro-4,6-bis(phenylethynyl)pyrimidine (3b): Starting with 1
(217 mg, 1 mmol), phenylacetylene (2b; 0.2 mL, 2.4 mmol), CuI
(5 mol-%), [Pd(PPh3)2Cl2] (10 mol-%), and diisopropylamine
(5 mL), 3b was isolated as a light-brown solid (254 mg; 73%); m.p.
197–199 °C. 1H NMR (300 MHz, CDCl3): δ = 7.32–7.41 (m, 6 H),
7.59–7.62 (m, 4 H) ppm. 13C NMR (62 MHz, CDCl3): δ = 84.1,
102.0, 120.4 (C), 128.6, 130.8, 132.8 (CH), 137.1, 151.2, 158.0
132.0 (C), 132.7 (CH), 149.8, 150.4 (C) ppm. IR (KBr): ν = 3054
˜
(w), 2215 (s), 1512 (s), 1490 (m), 1363 (s), 1229 (m), 1177 (m), 1025
(m), 970 (m), 918 (w), 842 (w), 751 (s), 686 (s) cm–1. GC–MS (EI,
70 eV): m/z (%) = 414 (89) [M]+, 377 (60), 346 (20), 315 (12), 250
(27), 238 (23), 189 (33). HRMS (EI, 70 eV): calcd. for C28H15ClN2
[M+] 414.09215; found 414.09240.
(C) ppm. IR (KBr): ν = 2961 (w), 2209 (s), 1517 (s), 1471 (m), 1261
˜
(s), 1025 (m), 927 (m), 770 (m), 751 (s), 679 (s) cm–1. GC–MS (EI,
70 eV): m/z (%) = 348 (100) [M]+, 331 (1), 315 (2), 276 (4), 251 (8),
226 (3), 186 (2), 160 (20). HRMS (EI, 70 eV): calcd. for
C20H10Cl2N2 [M+] 348.02156; found 348.02110.
5-Chloro-2,4,6-tris[(3-methoxyphenyl)ethynyl]pyrimidine (4c): Start-
ing with 1 (217 mg, 1 mmol), 3-ethynyl anisole (2c; 0.45 mL,
3.6 mmol), CuI (5 mol-%), [Pd(PPh3)2Cl2] (10 mol-%), and diiso-
propylamine (5 mL), 4c was isolated as a deep-brown solid
2,5-Dichloro-4,6-bis(3-methoxyphenyl)ethynylpyrimidine (3c): Start-
ing with
1 (217 mg, 1 mmol), 3-ethynylanisole (2c; 0.3 mL,
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P. Langer et al.
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1
(388 mg, 77%); m.p. 163–165 °C. H NMR (250 MHz, CDCl3): δ 149.2, 151.2, 151.9, 152.3, 152.8 (C) ppm. IR (KBr): ν = 2959 (w),
˜
= 3.74 (s, 3 H, OCH3), 3.76 (s, 6 H, 2ϫOCH3), 6.87–6.96 (m, 3 H), 2209 (w), 1483 (m), 1398 (m), 1264 (m), 1106 (m), 1016 (m), 831
7.11–7.13 (m, 3 H), 7.18–7.25 (m, 6 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 55.3, 55.4 (OCH3), 84.2, 86.8, 89.2, 100.4 (C), 117.0,
117.1, 117.2, 117.4 (CH), 121.7, 122.0 (C), 125.3, 129.5, 129.7
(s), 634 (w), 560 (s) cm–1. GC–MS (EI, 70 eV): m/z (%) = 704 (100)
[M]+, 644 (9), 471 (2), 337 (12), 281 (2), 207 (4), 173 (39). HRMS
(EI, 70 eV): calcd. for C52H52N2 [M+] 704.41250; found 704.41482.
(CH), 132.0, 149.8, 150.4, 159.3, 159.4 (C) ppm. IR (KBr): ν =
˜
2,4,5,6-Tetrakis(phenylethynyl)pyrimidine (5b): Starting with 1
(217 mg, 1 mmol), phenylacetylene (2b; 0.62 mL, 6.0 mmol), CuI
(5 mol-%), [Pd(PPh3)2Cl2] (10 mol-%), dioxane (7 mL), and diiso-
propylamine (3 mL), 5b was isolated as a light-brown solid
2940 (w), 2214 (s), 1573 (m), 1513 (s), 1483 (m), 1368 (m), 1261 (s),
1162 (m), 1039 (s), 848 (m), 769 (s), 677 (s) cm–1. GC–MS (EI,
70 eV): m/z (%) = 504 (100) [M]+, 473 (3), 431 (2), 389 (4), 355
(12), 312 (22), 252 (31), 190 (31). HRMS (EI, 70 eV): calcd. for
C31H21ClN2O3 [M+] 504.12392; found 504.12410.
1
(349 mg; 73%); m.p. 188–190 °C. H NMR (300 MHz, CDCl3): δ
= 6.77–6.86 (m, 12 H), 7.02–7.11 (m, 8 H) ppm. 13C NMR
5-Chloro-2,4,6-tris(p-tolylethynyl)pyrimidine (4d): Starting with 1
(62.8 MHz, CDCl3): δ = 83.5, 86.2, 87.9, 90.0, 98.9, 103.4, 121.2,
(217 mg, 1 mmol), p-tolylacetylene (2e; 0.4 mL, 3.6 mmol), CuI 121.3, 122.3 (C), 128.4, 128.6, 128.7, 129.5, 129.8, 130.3, 131.7,
(5 mol-%), [Pd(PPh3)2Cl2] (10 mol-%), and diisopropylamine
132.6, 132.7 (CH), 150.3, 152.3 (C) ppm. IR (KBr): ν = 2918 (w),
˜
(5 mL), 4d was isolated as a yellow solid (383 mg, 84%); m.p. 102–
2213 (m), 1479 (s), 1398 (s), 1211 (w), 1067 (w), 970 (w), 797 (m),
1
104 °C. H NMR (300 MHz, CDCl3): δ = 2.30 (s, 3 H, CH3), 2.32 767 (m), 748 (s), 680 (s) cm–1. GC–MS (EI, 70 eV): m/z (%) = 480
(s, 6 H, 2 ϫ CH3), 7.09–7.15 (m, 8 H), 7.50 (d, J = 8.1 Hz, 4
(92) [M+], 375 (40), 330 (20), 305 (10), 260 (18), 218 (23). HRMS
H) ppm. 13C NMR (62.8 MHz, CDCl3): δ = 21.6, 21.7 (CH3), 84.2, (EI, 70 eV): calcd. for C36H20N2 [M+] 480.16292; found 480.16260.
86.8, 89.5, 100.9, 117.5, 118.1 (C), 129.2, 129.3, 132.6 (CH), 140.3,
2,4,5,6-Tetrakis[(3-methoxyphenyl)ethynyl]pyrimidine (5c): Starting
141.1, 149.8, 150.5 (C) ppm. IR (KBr): ν = 2918 (w), 2208 (s), 1682
˜
with 1 (217 mg, 1 mmol), 3-ethynylanisole (3c; 0.76 mL, 6.0 mmol),
CuI (5 mol-%), [Pd(PPh3)2Cl2] (10 mol-%), dioxane (7 mL), and di-
isopropylamine (3 mL), 5c was isolated as a deep-brown solid
(w), 1510 (s), 1479 (s), 1361 (m), 1226 (w), 1176 (m), 1019 (m), 969
(m), 907 (m), 810 (s), 727 (m) cm–1. GC–MS (EI, 70 eV): m/z (%)
= 456 (100) [M+], 422 (4), 280 (7), 264 (5), 230 (11), 174 (36), 139
(54). HRMS (EI, 70 eV): calcd. for C31H21ClN2 [M+] 456.13971;
found 456.13930.
1
(474 mg, 79%); m.p. 152–154 °C. H NMR (300 MHz, CDCl3): δ
= 3.72 (s, 6 H, 2 ϫ OCH3), 3.74 (s, 3 H, OCH3), 3.77 (s, 3 H,
OCH3), 6.81–6.85 (m, 2 H), 6.93–6.97 (m, 4 H), 7.00–7.03 (m, 2
H), 7.12–7.23 (m, 8 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 55.2,
55.3, 55.4 (OCH3), 83.5, 84.2, 86.8, 89.2, 100.4, 102.7 (C), 115.4,
116.9, 117.0, 117.1, 117.2, 117.3 (CH), 121.7, 122.0, 123.1 (C),
124.6, 125.3, 129.4, 129.5, 129.7 (CH), 149.8, 150.4, 159.2, 159.3,
5-Chloro-2,4,6-tri(hept-1-ynyl)pyrimidine (4e): Starting with 1
(217 mg, 1 mmol), 1-heptyne (2e; 0.5 mL, 3.6 mmol), CuI (5 mol-
%), [Pd(PPh3)2Cl2] (10 mol-%), and diisopropylamine (5 mL), 4e
was isolated as a yellowish, highly viscous oil (270 mg, 68%). 1H
NMR (250 MHz, CDCl3): δ = 0.84 (t, J = 7.1 Hz, 6 H, CH3), 1.07 159.4 (C) ppm. IR (KBr): ν = 2939 (w), 2213 (s), 1574 (m), 1513
˜
(t, J = 7.0 Hz, 3 H, CH3), 1.21–1.43 (m, 12 H), 1.53–1.64 (m, 6 H), (s), 1483 (m), 1367 (m), 1315 (m), 1261 (s), 1161 (m), 1039 (s), 848
2.33 (t, J = 7.1 Hz, 2 H), 2.41 (t, J = 7.2 Hz, 4 H) ppm. 13C NMR (m), 769 (s), 677 (s) cm–1. GC–MS (EI, 70 eV): m/z (%) = 600 (80)
(62 MHz, CDCl3): δ = 12.9, 13.9 (CH3), 19.7, 22.1, 27.7, 28.2, 29.5,
[M]+, 569 (60), 538 (34), 507 (100), 470 (51), 440 (12), 410 (17), 380
30.9, 40.8, 41.7 (CH2), 80.2, 91.2, 99.0, 131.5, 149.6, 150.2 (C) ppm. (32), 304 (56), 280 (40), 204 (12). HRMS (EI, 70 eV): calcd. for
IR (KBr): ν = 2930 (m), 2232 (w), 1604 (s), 1455 (m), 1165 (m), C40H28N2O4 [M+] 600.20221; found 600.20246.
˜
1079 (m), 783 (m), 760 (w) cm–1. GC–MS (EI, 70 eV): m/z (%) =
5-Chloro-2,4-bis[(3-methoxyphenyl)ethynyl]-6-(p-tolyl)pyrimidine
396 (90) [M]+, 382 (60), 368 (41), 344 (100), 330 (40), 316 (7), 301
(7): Starting with 6 (100 mg, 0.36 mmol), 3-ethynylanisole (2c;
(4), 287 (6), 231 (4), 209 (4). HRMS (EI, 70 eV): calcd. for
0.1 mL, 0.72 mmol), CuI (5 mol-%), [Pd(PPh3)2Cl2] (10 mol-%),
C25H33ClN2 [M+] 396.23160; found 396.23176.
and diisopropylamine (5 mL), 7 was isolated as a crystalline brown
5-Chloro-2,4,6-tri(pent-1-ynyl)pyrimidine (4f): Starting with 1
(217 mg, 1 mmol), 1-pentyne (2f; 0.3 mL, 3.6 mmol), CuI (5 mol- CDCl3): δ = 2.34 (s, 3 H, CH3), 3.72 (s, 3 H, OCH3), 3.74 (s, 3 H,
solid (114 mg, 67 %); m.p. 167–169 °C. 1H NMR (300 MHz,
%), [Pd(PPh3)2Cl2] (10 mol-%), and diisopropylamine (5 mL), 4f
OCH3), 6.85–6.93 (m, 2 H), 7.10–7.12 (m, 2 H), 7.19–7.25 (m, 6
was isolated as a brownish, highly viscous oil (216 mg, 69%). 1H
H), 7.69 (d, J = 8.2 Hz, 2 H) ppm. 13C NMR (75 MHz, CDCl3): δ
NMR (300 MHz, CDCl3): δ = 0.95 (t, J = 7.3 Hz, 6 H, CH3), 0.99 = 21.5 (CH3), 55.3 (OCH3), 55.4 (OCH3), 84.7, 87.3, 88.6, 99.3 (C),
(t, J = 7.4 Hz, 3 H, CH3), 1.53–1.64 (m, 6 H), 2.32 (t, J = 7.1 Hz,
2 H), 2.42 (t, J = 7.0 Hz, 4 H) ppm. 13C NMR (62 MHz, CDCl3):
δ = 13.5, 13.6 (CH3), 21.4, 21.7, 29.6, 30.1 (CH2), 79.1, 91.4, 103.1,
116.8, 117.0, 117.1, 117.2 (CH), 121.9, 122.2 (C), 125.2 (CH), 128.5
(C), 129.0, 129.3, 129.5, 129.6, 129.7 (CH), 132.7, 141.0, 150.2,
150.6, 159.3, 159.4, 164.1 (C) ppm. IR (KBr): ν = 3008 (w), 2214
˜
131.5, 149.7, 150.1 (C) ppm. IR (KBr): ν = 2926 (m), 2228 (m), (m), 1573 (w), 1525 (m), 1486 (s), 1357 (s), 1287 (m), 1255 (s), 1180
˜
1727 (w), 1515 (s), 1489 (s), 1359 (s), 1172 (m), 1080 (w), 962 (m),
(m), 1043 (m), 859 (m), 774 (s), 683 (s) cm–1. GC–MS (EI, 70 eV):
790 (m) cm–1. GC–MS (EI, 70 eV): m/z (%) = 312 (100) [M]+, 297 m/z (%) = 464 (100) [M+], 424 (61), 389 (09), 272 (02), 232 (27),
(21), 282 (40), 267 (13), 254 (15), 225 (23), 211 (33), 183 (43).
HRMS (EI, 70 eV): calcd. for C19H21ClN2 [M+] 312.14321; found
312.14336.
190 (10), 150 (06). HRMS (EI, 70 eV): calcd. for C29H21O2N2Cl
[M+] 464.12926; found 464.12920.
2,5-Dichloro-4-[(3-methoxyphenyl)ethynyl]-6-(p-tolyl)pyrimidine (8):
2,4,5,6-Tetrakis[(4-tert-butylphenyl)ethynyl]pyrimidine (5a): Starting Starting with 6 (100 mg, 0.36 mmol), 3-ethynylanisole (2c; 0.05 mL,
with 1 (217 mg, 1 mmol), 4-(tert-butyl)phenylacetylene (2a; 1.0 mL,
0.36 mmol), CuI (5 mol-%), [Pd(PPh3)2Cl2] (10 mol-%), and diiso-
6.0 mmol), CuI (5 mol-%), [Pd(PPh3)2Cl2] (10 mol-%), dioxane
propylamine (5 mL), 8 was isolated as a crystalline light-brown so-
1
(7 mL), and diisopropylamine (3 mL), 5a was isolated as a deep- lid (79 mg, 59%); m.p. 110–112 °C. H NMR (300 MHz, CDCl3):
brown solid (535 mg; 76%); m.p. 110–112 °C. 1H NMR (300 MHz, δ = 2.36 (s, 3 H, CH3), 3.75 (s, 3 H, OCH3), 6.91–6.95 (m, 1 H),
CDCl3): δ = 1.25 (s, 9 H, CH3), 1.26 (s, 18 H, CH3), 1.28 (s, 9 7.09–7.10 (m, 1 H), 7.17–7.25 (m, 4 H), 7.72 (d, J = 8.2 Hz, 2
H, CH3), 7.31–7.37 (m, 8 H), 7.49–7.56 (m, 8 H) ppm. 13C NMR H) ppm. 13C NMR (75 MHz, CDCl3): δ = 21.5 (CH3), 55.4
(75 MHz, CDCl3): δ = 30.0, 30.1 (CH3), 33.9, 34.0, 82.2, 85.0, 86.7,
89.2, 98.2, 102.4, 117.3 (C), 124.4, 124.6, 130.5, 131.4, 131.6 (CH),
(OCH3), 84.4, 100.7 (C), 117.2, 117.4 (CH), 121.6 (C), 125.3 (CH),
128.5 (C), 129.1, 129.6, 129.7 (CH), 131.9, 141.6, 152.2, 158.1,
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© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 2088–2093

Synthesis of Fluorescent Alkynyl-pyrimidines
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159.4, 165.8 (C) ppm. IR (KBr): ν = 3013 (w), 2935 (w), 2213 (w),
˜
1578 (m), 1481 (m), 1255 (s), 1151 (s), 1035 (s), 914 (m), 838 (m),
775 (s), 676 (s) cm–1. GC–MS (EI, 70 eV): m/z (%) = 368 (100)
[M]+, 333 (10), 325 (2), 303 (2), 290 (12), 227 (20), 184 (26), 140
(40). HRMS (EI, 70 eV): calcd. for C20H14ON2Cl2 [M+] 368.04777;
found 368.04752.
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5-Chloro-2,4-di(pent-1-ynyl)-6-(p-tolyl)pyrimidine (9): Starting with
6 (100 mg, 0.36 mmol), 1-pentyne (2f; 0.07 mL, 0.72 mmol), CuI
(5 mol-%), [Pd(PPh3)2Cl2] (10 mol-%), and diisopropylamine
(5 mL), 9 was isolated as a light-yellow semi-solid (66 mg, 54%).
1H NMR (300 MHz, CDCl3): δ = 0.95 (t, J = 7.4 Hz, 3 H, CH3),
0.98 (t, J = 7.3 Hz, 3 H, CH3), 1.53–1.64 (m, 4 H), 2.31 (s, 3 H,
CH3), 2.34 (t, J = 7.1 Hz, 2 H), 2.42 (t, J = 7.0 Hz, 2 H), 7.19 (d, J
= 8.1 Hz, 2 H), 7.62 (d, J = 8.3 Hz, 2 H) ppm. 13C NMR (62 MHz,
CDCl3): δ = 13.5, 13.7 (CH3), 21.3 (CH2), 21.4 (CH3), 21.5, 21.7
(CH2), 80.0, 90.7, 102.3 (C), 128.8, 129.5 (CH), 129.9, 132.8, 133.5,
150.2, 150.8, 163.7 (C) ppm. IR (KBr): ν = 2961 (w), 2232 (m),
˜
1611 (w), 1529 (m), 1492 (s), 1355 (s), 1179 (m), 1149 (m), 1035
(m), 821 (m), 795 (m), 756 (w) cm–1. GC–MS (EI, 70 eV): m/z (%)
= 336 (20) [M]+, 321 (4), 308 (100), 292 (3), 279 (3), 256 (1), 229
(20), 243 (10), 208 (15), 178 (21). HRMS (EI, 70 eV): calcd. for
C21H21ClN2 [M+] 336.13915; found 336.13930.
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Received: December 2, 2010
Published Online: March 1, 2011
Eur. J. Org. Chem. 2011, 2088–2093
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2093