Synthesis of aryl-substituted pyrimidines by site-selective Suzuki-Miyura cross-coupling reactions of 2,4,5,6-tetrachloro-pyrimidine

Article abstract of DOI:10.1002/adsc.201000020

Suzuki-Miyaura reactions of 2,4,5,6-tetrachloropyrimidine allow a convenient synthesis of mono-, di-, tri- and tetraarylpyrimidines which are not readily available by other methods. All reactions proceed with excellent site-selectivity.

Full text of DOI:10.1002/adsc.201000020

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DOI: 10.1002/adsc.201000020
Synthesis of Aryl-Substituted Pyrimidines by Site-Selective
Suzuki–Miyura Cross-Coupling Reactions of 2,4,5,6-Tetrachloro-
pyrimidine
Munawar Hussain,a Nguyen Thai Hung,a Rasheed Ahmad Khera,a Imran Malik,a
Dhafer Saber Zinad,a and Peter Langera,b,*
a
Institut fꢀr Chemie, Universitꢁt Rostock, Albert-Einstein-Str. 3a, 18059 Rostock, Germany
Fax : (+49)-381-498-6412; e-mail: peter.langer@uni-rostock.de
Leibniz-Institut fꢀr Katalyse e. V. an der Universitꢁt Rostock, Albert-Einstein-Str. 29a, 18059 Rostock, Germany
b
Received: January 10, 2010; Revised: May 12, 2010; Published online: June 8, 2010
Abstract: Suzuki–Miyaura reactions of 2,4,5,6-tetra-
chloropyrimidine allow a convenient synthesis of
mono-, di-, tri- and tetraarylpyrimidines which are
not readily available by other methods. All reac-
tions proceed with excellent site-selectivity.
Schomaker and Delia reported site-selective Suzuki–
Miyaura reactions of 2,4,6-trichloropyrimidine.[14]
2,4,5,6-Tetrachloropyrimidine represents an interest-
ing substrate because all four carbon atoms are halo-
genated. Nucleophilic substitution reactions of the
latter are known and allow the functionalization of
carbon atoms C-2, C-4 and C-6 while carbon atom C-
5 remains unattacked.[15] Herein, we report our results
related to Suzuki–Miyaura reactions of 2,4,5,6-tetra-
chloropyrimidine.[16] The reactions reported herein
provide a convenient access to a variety of aryl-substi-
tuted pyrimidines which are not readily available by
Keywords: nitrogen heterocycles; palladium; regio-
selectivity; Suzuki–Miyaura reaction
Pyrimidines are of considerable pharmacological im- other methods.
portance and occur in many synthetic drugs and natu-
The Suzuki–Miyaura reaction of commercially
ral products.[1,2] Pyrimidines represent a core structure available 2,4,5,6-tetrachloropyrimidine (1) with aryl-
in analgesic, antihypertensive, antipyretic, and anti-in- boronic acids 2a–h (4.4 equiv.) afforded the 2,4,5,6-
flammatory drugs. They also play a role as pesticides, tetraarylpyrimidines 3a–h (Scheme 1, Table 1). This
herbicides, and plant growth regulators.[3] l-Lathyrine type of molecule has been previously prepared by cy-
has been reported to show pollen growth inhibition, clocondensation reactions, however, their synthesis re-
antitumor and hypoglycemic activity.[4] Most of the quires several steps.[17] Products 3a–g were isolated in
syntheses known to date for the synthesis of substitut- good to excellent yields (both for electron-rich and
ed pyrimidines rely on the application of a building electron-poor arylboronic acids). The yield of 3h was
block approach. Pinner developed the first synthesis rather low and a considerable amount of the 2,4,6-tri-
of pyrimidines based on the cyclocondensation of aryl-5-chloropyrimidine was isolated (presumably due
amidines with 1,3-diketones.[5] A number of related to steric reasons). The reaction was thoroughly opti-
cyclocondensations have been reported.[6,7] Mꢀller mized for derivatives 3a–d (Table 2). The best yields
and co-workers reported an interesting palladium-cat- were obtained when PdACHTUNGTRNEG(UN PPh3)2Cl2 (5 mol%) was used
alyzed 3-component reaction for the synthesis of ami- as the catalyst (dioxane, 1008C, 8 h) (entry 1). Excel-
dines.[8] An alternative approach to substituted pyri-
midines is based on the functionalization of appropri-
ate pyrimidine derivatives. For example, nucleophilic
aromatic substitution reactions of Grignard reagents
with pyrimidines have been reported.[9,10] Monohalo-
genated pyrimidines have been successfully used in
Negishi[11] and Suzuki[12] coupling reactions. Polyhalo-
genated pyrimidines represent interesting substrates
for multiple coupling reactions. Nucleophilic aromatic
substitution reactions of 2,4,6-trichloropyrimidine
Scheme 1. Synthesis of 3a–h. Conditions: i, 2a–h (4.4 equiv.),
Pd(PPh3)2Cl2 (5 mol%), K2CO3 (H2O, 2M), dioxane, 1008C,
AHCTUNGTRENNUNG
with various nucleophiles have been studied.[10,13] 8 h; for 3a–g: 79–98% yields.
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Munawar Hussain et al.
COMMUNICATIONS
Table 1. Synthesis of 3a–h.
clusion, the conditions given in entries 4 and 14 of
Table 2 allowed us to prepare the products in excel-
lent yield using only 2.5 mol% of the palladium cata-
lyst.
The Suzuki–Miyaura reaction of 1 with arylboronic
acids 2b, e, f, h–j (3.0 equiv.) gave the 2,4,6-triaryl-5-
chloropyrimidines 4a–f (Scheme 2, Table 3). Good
yields were obtained both for electron-rich and elec-
2, 3
Ar
Yield [%] of 3[a]
a
b
c
d
e
f
Ph
98
95
93
91
89
82
4-MeC6H4
4-EtC6H4
4-(MeO)C6H4
4-FC6H4
2-(MeO)C6H4
3,5-Me2C6H3
3-PhC6H4
g
h
79
25+43[b]
[a]
Yields of isolated products.
Besides 3h, 2,4,6-triaryl-5-chloropyrimidine 4d was isolat-
[b]
ed in 43% yield.
lent yields were obtained when an aqueous solution
of K2CO3 (2M) (entry 1) or when K3PO4 were em-
Scheme 2. Synthesis of 4a–f. Conditions: i, 2b, e, f, h–j
(3.0 equiv.), PdACHTNUTRGNE(UNG PPh3)2Cl2 (2.0 to 5.0 mol%), K2CO3 (H2O,
ployed as the base (entry 5). The amount of catalyst 2M), dioxane, 808C, 5 h; 80–85% yields.
could be reduced to 2.5 mol% without decrease in
yield (entry 4). However, complex product mixtures
were formed when the amount of the catalyst was re- Table 3. Synthesis of 2,4,6-triaryl-5-chloropyrimidine 4a–f.
duced further (entries 2 and 3). The yields dropped
2
4
Ar
Yield [%] of 4[a]
when Pd
ence of XPhos or SPhos[18] were employed (entries 8–
10). The use of Pd(OAc)2 (5 mol%) in the presence
of P(t-Bu)3·HBF4 (entry 11) or of Pd(OAc)2 (5 mol%)
in the presence of triethanolamine and 2MK2CO3
(entry 12) gave unsatisfactory results. The employ-
ACHTUNGTRENNUNG(PPh3)4 or PdACHTUNGTREN(NUGN OAc)2 (5 mol%) in the pres-
b
e
f
h
i
a
b
c
d
e
f
4-MeC6H4
4-FC6H4
2-(MeO)C6H4
3-PhC6H4
3-CF3C6H4
4-CF3C6H4
83[b]
83[c]
81[c]
80[c]
82[b]
85[b]
AHCTUNGTRENNUNG
G
ACHTUNGTRENNUNG
j
ment of Pd
yields for 3b and 3d (entry 13). The amount of
Pd(OAc)2 could be reduced to 2.5 mol% when
(OEt)2Ph was used as the ligand (entry 14). In con-
ACHTUNGTRENNUNG(OAc)2 (5 mol%), PACHTUNGTRENN(GUN n-Bu)3 gave good
[a]
[b]
[c]
Yields of isolated products.
2.0 mol% of catalyst were used.
5.0 mol% of catalyst were used.
ACHTUNGTRENNUNG
PACHTUNGTRENNUNG
Table 2. Optimization of the reaction conditions for the synthesis of 3a–d.
Entry
Conditions
Yield [%]
Yield [%]
Yield [%]
Yield [%]
of 3a[a]
of 3b[a]
of 3c[a]
of 3d[a]
1
2
3
Pd
Pd
Pd
U
98
95
93
91
[b]
[b]
[b]
[b]
–
–
–
–
[c]
[c]
[c]
[c]
–
–
–
–
4
5
6
7
8
9
10
11
12
13
14
Pd
N
E
97
95
81
83
71
71
48
94
94
80
80
69
65
43
38
94
93
83
82
59
55
33
91
89
77
75
58
59
50
32
Pd
Pd
Pd
Pd
Pd
Pd
Pd
Pd
Pd
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
[e]
[e]
T
N
A
G
–
–
–
–
–
–
[e]
[d]
[e]
[d]
E
–
70
92
–
87
96
[e]
[e]
E
Pd
G
G
93
90
[a]
Yields of isolated products; all reactions were carried out in dioxane (1008C, 8 h).
[b]
[c]
[d]
[e]
Formation of a complex mixture of mono-, di-, tri-, and tetraarylpyrimidines and of starting material.
Approximately 80% conversion after 12 h (estimated by TLC).
Decomposition.
Experiment was not carried out.
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Synthesis of Aryl-Substituted Pyrimidines by Site-Selective Suzuki–Miyura Cross-Coupling
tron-poor arylboronic acids. During the optimization, Products 5a–c were prepared using 3 mol% of
it proved to be important to use exactly 3.0 equiv. of PdACTHUNGTRNEG(UN PPh3)2Cl2. Later, we have found that the use of
the boronic acid and to carry out the reaction at 808C only 1.25 mol% proved to be sufficient (products 5d–
(5 h) instead of 1008C (8 h) to avoid the formation of f). The reaction of 5a with arylboronic acids 2d, k
tetraarylpyrimidines. To a small extent, reduction of (1.0 equiv.) (808C, 5 h) gave the 2,4,6-triaryl-5-chloro-
the unreacted chloride group and formation of tet- pyrimidines 6a, b (Scheme 3, Table 5). The reaction of
raarylpyrimidines were observed as side reactions. All
products were prepared using PdACTHUNGTRNEG(UN PPh3)2Cl2. Initially,
Table 5. Synthesis of 6a, b and 7a, b.
5.0 mol% of the catalyst was used (4b–d). Later, we
have found that the use of 2.0 mol% of catalyst is suf-
ficient to achieve equally good yields (products 4a, e,
f).
The Suzuki–Miyaura reaction of 1 with arylboronic
acids 2a, b, d, i–k (2.0 equiv.) afforded the 4,6-diaryl-
2,5-dichloropyrimidines 5a–f (Scheme 3, Table 4). The
stoichiometry (employment of exactly 2.0 equiv. of
the arylboronic acid), the temperature (not more than
708C), and the reaction time (5 h) again played an
important role to avoid multiple-coupling reactions.
2
5
6, 7 Ar1
Ar2
Yield [%] of 6, 7[a]
k
d
d
c
a
a
a
d
6a
6b
7a
7b
Ph
Ph
Ph
4-ClC6H4
90[b]
4-(MeO)C6H4 86[b]
4-(MeO)C6H4 79[b]
3-CF3C6H4 4-EtC6H4
89[c]
[a]
[b]
[c]
Yields of isolated products.
3.0 mol% of catalyst were used.
1.25 mol% of catalyst were used.
5a, d with 2.0 instead of 1.0 equiv. of arylboronic acid
2c, d (1008C, 5 h) afforded the 2,4,5,6-tetraarylpyrimi-
dines 7a, b. Reduction of the unreacted chloride
group and multiple coupling were again observed as
side reactions, albeit, to a small extent.
The Suzuki–Miyaura reaction of 1 with arylboronic
acids 2b, d–f (1.0 equiv.) gave the 6-aryl-2,4,5-
trichloroACTHNUGTRNEUNGpyrimidines 8a–d (Scheme 4, Table 6). The
stoichiometry (employment of not more than
1.0 equiv. of the arylboronic acid), the temperature,
and the reaction time again played an important role
during the optimization. It proved to be important to
carry out the reaction at 608C for only 2 h to avoid
multiple-coupling reactions. All products were again
Scheme 3. Synthesis of 5a–f, 6a, b and 7a, b. Conditions: i,
2a, b, d, i–k (2.0 equiv.), Pd
K2CO3 (H2O, 2M), dioxane, 708C, 5 h; ii, 2d, k (1.0 equiv.),
Pd(PPh3)2Cl2 (3 mol%), K2CO3 (H2O, 2M), dioxane, 808C,
5 h; iii, 2c, d (2.0 equiv.), Pd(PPh3)2Cl2 (1.25 to 3 mol%),
ACHTUGNTRENUN(GN PPh3)2Cl2 (1.25 to 3.0 mol%),
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
K2CO3 (H2O, 2M), dioxane, 1008C, 5 h; for 5a–f, 6a, b, and
7a, b: 79–97% yields.
Scheme 4. Synthesis of 8a–d. Conditions: i, 2b, d–f
(1.0 equiv.), PdACHTNUTRGNE(UNG PPh3)2Cl2 (1.0 to 3.0 mol%), K2CO3 (H2O,
2M), dioxane, 608C, 2 h; 87–97% yields.
Table 4. Synthesis of 2,4,6-triaryl-5-chloropyrimidine 5a–f.
2
5
Ar1
Yield [%] of 5[a]
Table 6. Synthesis of 6-aryl-2,4,5-trichloropyrimidines 8a–d.
a
b
d
i
j
k
a
b
c
d
e
f
Ph
97[b]
85[b]
93[b]
90[c]
88[c]
84[c]
2
8
Ar
Yield [%] of 8[a]
4-MeC6H4
4-(MeO)C6H4
3-CF3C6H4
4-CF3C6H4
4-ClC6H4
b
d
e
f
a
b
c
4-MeC6H4
4-(MeO)C6H4
4-FC6H4
87[b]
95[c]
93[c]
97[c]
d
2-(MeO)C6H4
[a]
[b]
[c]
[a]
[b]
[c]
Yields of isolated products.
3.0 mol% of catalyst were used.
1.25 mol% of catalyst were used.
Yields of isolated products.
1.0 mol% of catalyst was used.
3.0 mol% of catalyst were used.
Adv. Synth. Catal. 2010, 352, 1429 – 1433
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Munawar Hussain et al.
COMMUNICATIONS
1611, 1523, 1513, 1511, 1483, 1468, 1433, 1333, 1325, 1321,
1274 (m), 1255 (s), 1178, 1117, 1097, 1038, 1018 (m), 961
(w), 866 (m), 822, 820, 806, 773, 766 (s), 728 (m), 692, 667,
632 (w), 614, 578, 562 (m) cmÀ1; GC-MS (EI, 70 eV): m/z
(%)=360 ([M]+, 100), 325 (33), 253 (11), 252 (4), 236 (9),
132 (10); HR-MS (EI, 70 eV): m/z=360.0431, calcd. for
C18H14Cl2N2O2 [M]+: 360.04323.
prepared using PdACHTUNRGTNEUNG(PPh3)2Cl2 as the catalyst. Although
3.0 mol% of the catalyst was used in most cases
(products 8b–d), the employment of only 1.0 mol% of
catalyst proved to be possible to achieve equally good
yields (product 8a).
The structures of all products were confirmed by
2D NMR methods (NOESY, HMBC) or by X-ray
crystal structure analyses.
5-Chloro-2-(4-methoxyphenyl)-4,6-diphenylpyrimidine
(6b): Starting with 1 (75 mg, 0.25 mmol), PdACHTUNGTRNEG(UN PPh3)2Cl2
In conclusion, we have reported a convenient syn-
thesis of mono-, di-, tri- and tetraarylpyrimidines by
Suzuki–Miyaura reactions of 2,4,5,6-tetrachloropyri-
midine. The products reported herein are not readily
available by other methods. All reactions proceed
with excellent site-selectivity. We are currently study-
ing the synthesis of unsymmetrical tetraarylpyrimi-
dines based on reactions of 6-aryl-2,4,5-trichloropyri-
midines 8 and of pyrimidines 4 and 6.
(6 mg, 3 mol%), dioxane (3 mL), 2MK2CO3 (1 mL) and 4-
methoxyphenylboronic acid (38 mg, 0.25 mmol), reaction
temperature: 808C for 5 h. 6b was isolated as a white solid;
1
yield: 80 mg (86%). H NMR (250 MHz, CDCl3): d=3.81 (s,
3H, OCH3), 6.90 (d, 2H, J=9.0 Hz, ArH), 7.43–7.50 (m,
6H, ArH), 7.82–7.87 (m, 4H, ArH), 8.44 (d, 2H, J=9.0 Hz,
ArH); 13C NMR (75.5 MHz, CDCl3): d=55.4 (OCH3), 113.8
(CH), 123 (C), 128.1 (CH), 129.5 (C), 129.7 (CH), 129.8
˜
(CH), 130.2 (CH), 137.3, 162.0, 164.5 (2C); IR (KBr): n=
3059, 3028, 3006, 2954, 2931, 2835 (w), 1608, 1560, 1534 (m),
1504, 1490 (s), 1468, 1444, 1423, 1385 (m), 1361 (s), 1302
(m), 1250 (s), 1174, 1106, 1075, 1058, 1037, 1030, 1002 (m),
980, 969, 958, 912, 864 (w), 838, 797, 787, 771 (m), 757 (s),
729 (m), 687 (s), 632, 615, 540 (m) cmÀ1; GC-MS (EI,
70 eV): m/z (%)=372 ([M]+, 100), 357 (3), 337 (4), 204 (12),
136 (22); HR-MS (EI, 70 eV): m/z=372.10278 calcd. for
C23H17ClN2O [M]+: 372.10294.
Experimental Section
General Procedure for Suzuki–Miyaura Reactions
The reaction was carried out in a pressure tube. To a diox-
ane suspension (3–5 mL) of the chlorinated pyrimidine, Pd-
ACHTUNGTRENNUNG(PPh3)2Cl2 (1–5 mol%) and of the arylboronic acid was
2,4,5-Trichloro-6-(4-methoxyphenyl)pyrimidine
Starting with 1 (217 mg, 1.0 mmol), Pd(PPh3)2Cl2 (21 mg,
3 mol%), dioxane (5 mL), 2MK2CO3 (2 mL) and 4-
methoxyphenylboronic acid (152 mg, 1.0 mmol), reaction
(8a):
AHCTUNGTRENNUNG
added an aqueous solution of K2CO3 (2M, 1–2 mL). The
mixture was heated at the indicated temperature (60–
1008C) under an argon atmosphere for the indicated period
of time (2–8 h). The reaction mixture was diluted with water
and extracted with CH2Cl2 (3ꢃ25 mL). The combined or-
ganic layers were dried (Na2SO4), filtered and the filtrate
was concentrated under vacuum. The residue was purified
by flash chromatography (silica gel, EtOAc/heptanes).
AHCTUNGTRENNUNG
temperature: 608C for 2 h. 8a was isolated as a white solid;
1
yield: 275 mg (95%). H NMR (300 MHz, CDCl3): d=3.82
(s, 3H, OCH3), 6.94 (d, 2H, J=9.0 Hz, ArH), 7.83 (d, 2H,
J=9.0 Hz, ArH); 13C NMR (75.5 MHz, CDCl3): d=55.5
(OCH3), 113.8 (CH), 126.8 (C), 131.7 (CH), 156.9, 161.4,
˜
162.2, 166.0 (C); IR (KBr): n=2971, 2928, 2836 (w), 1604,
1574, 1530, 1511, 1483, 1458, 1446, 1372, 1325, 1317, 1309,
1284 (m), 1253 (s), 1177, 1116, 1097, 1038, 1025 (m), 962
(w), 867 (m), 832, 820, 807, 774, 766 (s), 729 (m), 691, 668,
634 (w), 615, 579, 569, 537 (m) cmÀ1; GC-MS (EI, 70 eV):
m/z (%)=288 ([M]+, 100), 275 (04), 253 (17), 210 (14), 157
(7); HR-MS (EI, 70 eV): m/z=287.96228, calcd. for
C11H7Cl3N2O [M]+: 287.96240.
2,4,5,6-Tetraphenylpyrimidine (3a): Starting with
1
(87 mg, 0.40 mmol), Pd(PPh3)2Cl2 (15 mg, 5 mol%), dioxane
AHCTUNGTRENNUNG
(3 mL), K2CO3 (H2O, 2M, 1 mL) and phenylboronic acid
(215 mg, 1.76 mmol), reaction temperature: 1008C for 8 h.
3a was isolated as a white solid; yield: 150 mg (98%).
1H NMR (250 MHz, CDCl3): d=6.88–6.92 (m, 2H, ArH),
7.06–7.20 (m, 8H, ArH), 7.31–7.44 (m, 8H, ArH), 8.55–8.59
(m, 2H, ArH); 13C NMR (62.9 MHz, CDCl3): d=127.2 (C),
127.3, 127.8, 128.3, 128.4, 128.5, 128.6, 130.0, 130.6, 131.1
˜
(CH), 136.6, 137.8, 138.8, 162.9, 165.4 (C); IR (KBr): n= References
3059, 2916, 2852 (w), 1536, 1488 (s), 1442, 1370, 1298 (m),
1246 (s), 1194, 1179, 1090, 1079, 1024, 1000 (m), 965, 929,
912 (w), 866, 800, 750, 729, (m), 688 (s), 620, 614, 605, 592
(m) cmÀ1; GC-MS (EI, 70 eV): m/z (%)=383 ([M]+, 100),
331 (1), 305 (4), 280 (5), 178 (9); HR-MS (EI, 70 eV): m/z=
384.16299, calcd. for C22H20N2 [M]+: 384.16265.
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2,5-Dichloro-4,6-bis(4-methoxyphenyl)pyrimidine (5c):
Starting with 1 (217 mg, 1.0 mmol), Pd
3 mol%), dioxane (5 mL), 2MK2CO3 (2 mL) and 4-
methoxyphenylboronic acid (304 mg, 2.0 mmol), reaction
ACHTUGNTRNE(UNNG PPh3)2Cl2 (21 mg,
ACHTUNGTRENNUNG
temperature: 708C for 5 h. 5c was isolated as a white solid;
1
yield: 334 mg (93%). H NMR (300 MHz, CDCl3): d=3.84
(s, 6H, OCH3), 6.95 (d, 4H, J=9.1 Hz, ArH), 7.85 (d, 4H,
J=9.1 Hz, ArH); 13C NMR (75.5 MHz, CDCl3): d=55.4
(OCH3), 113.6 (CH), 124.6, 127.9 (C), 131.5 (CH), 158.0,
˜
161.6, 166.5 (C); IR (KBr): n=2878, 2966, 2935, 2826 (w),
1432
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Synthesis of Aryl-Substituted Pyrimidines by Site-Selective Suzuki–Miyura Cross-Coupling
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