Microwave-assisted, efficient and regioselective Pd-catalyzed C-phenylation of halopyrimidines

Article abstract of DOI:10.1016/j.tetlet.2006.04.082

We herein report that flash heating microwave irradiation is a helpful tool in the formation of arylpyrimidines from the corresponding halopyrimidines. The palladium-catalyzed cross-coupling reactions of 2,4-di- and 2,4,5-trihalopyrimidines with phenylboronic acid under the above conditions are described. By use of the appropriate catalyst and the adequate halopyrimidine, good regioselectivity can be achieved in the 2-, 4-, or 5-positions of the heterocycle. In addition, we show that this methodology is ameneable for the stepwise preparation of mono-, di-, and triphenylpyrimidines.

Full text of DOI:10.1016/j.tetlet.2006.04.082

Tetrahedron Letters 47 (2006) 4415–4418
Microwave-assisted, efficient and regioselective Pd-catalyzed
C-phenylation of halopyrimidines
Susana Conde Ceide and Antonio Garrido Montalban*
Department of Chemistry, Kemia Incorporated, 5871 Oberlin Drive, Suite 100, San Diego, CA 92121, USA
Received 30 September 2005; revised 15 April 2006; accepted 19 April 2006
Available online 12 May 2006
Abstract—We herein report that flash heating microwave irradiation is a helpful tool in the formation of arylpyrimidines from the
corresponding halopyrimidines. The palladium-catalyzed cross-coupling reactions of 2,4-di- and 2,4,5-trihalopyrimidines with phen-
ylboronic acid under the above conditions are described. By use of the appropriate catalyst and the adequate halopyrimidine, good
regioselectivity can be achieved in the 2-, 4-, or 5-positions of the heterocycle. In addition, we show that this methodology is amene-
able for the stepwise preparation of mono-, di-, and triphenylpyrimidines.
Ó 2006 Elsevier Ltd. All rights reserved.
The pyrimidine skeleton is commonly found in pharma-
ceutical drugs, fungicides, and herbicides.1 In particular,
triphenylpyrimidines are useful in the development of
advanced electronic and photonic devices.2 Historically,
functionalization of the pyrimidine system is obviated
by ring formation and careful synthetic design. This has
led to an extensive range of pyrimidine syntheses,3 where-
by halopyrimidines are key building blocks for further
functionalization. These compounds can react with a
wide variety of nucleophiles such as alkoxides, mercap-
tides, amines,4 and organometallic reagents,5 although
nucleophilic substitutions of 2,4-dichloropyrimidines are
generally not very regioselective.6 However, for the syn-
thesis of C-aryl derivatives involving palladium-catalyzed
cross-coupling reactions of organoboronic acids with 2,4-
dihalopyrimidines7 and 2,4,6-trihalopyrimidines,8 good
selectivity has been achieved in the 4-position, under con-
ventional conditions.
ventional methods but also achieve good regioselectivity
in the 2-, 4-, and 5-positions as a function of the catalyst
and the halopyrimidine employed.
2,4-Dihalopyrimidines: It has been reported that under
conventional thermal conditions with Pd(PPh3)4, the
reaction takes 4 h of heating and that the 4-phenyl pyr-
imidine (2) is obtained (80%) together with 2,4-diphenyl
pyrimidine (3, 10%) when 1 equiv of the boronic acid is
used.7b With 2 equiv of the boronic acid, 2,4-diphenyl
pyrimidine 3 is obtained after 6 h in 90% yield.7b Our ini-
tial experiments under microwave irradiation were thus
performed using Pd(PPh3)4 as the catalyst, K2CO3 as
the base and toluene–DMF (9:1) as the solvent in order
to establish conditions that could reproduce or improve
upon the above results using much shorter reaction times.
Reactions were carried out at different temperatures for a
period of 10 min using a Smith Microwave SynthesizerTM
(Biotage BA). At 150 °C, the expected product 2 was
obtained in 60% yield along with starting material (Table
1, entry 1). When the reaction was performed at 185 °C,
2 was obtained in an 85% yield accompanied by small
amounts (6%) of the disubstituted pyrimidine 3 (Table
1, entry 2). At higher temperature (200 °C), the forma-
tion of 3 increased at the cost of the monosubstituted
product 2 (Table 1, entry 3). With 2 equiv of the boronic
acid at 185 °C, the exclusive formation of the disubsti-
tuted product 3 was observed (Table 1, entry 4). With
these results in hand we then decided to try out a different
palladium catalyst. It has been reported that the use of
1,4-bis(diphenylphosphino)butanepalladium dichloride,
The rapid development of combinatorial and robotized
parallel synthesis has led to a growing demand for fast
reactions and efficient purification procedures.9 Thus
we decided to explore the utility of halopyrimidines in
the microwave assisted10 Suzuki-type cross-coupling
reaction, and demonstrate that we cannot only shorten
the reaction time dramatically when compared to con-
Keywords: Microwave; Palladium; Cross-coupling; Heterocycles;
Regioselectivity.
*
Corresponding author. Tel.: +1 858 964 1434; fax: +1 858 964
1413; e-mail: amontalban@kemia.com
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.04.082

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S. C. Ceide, A. G. Montalban / Tetrahedron Letters 47 (2006) 4415–4418
Table 1. Selectivity in the Suzuki coupling of 2,4-dichloropyrimidine
(1)
OMe
OMe
Cl
i
ii
N
N
N
N
N
N
Cl
Ph
Ph
PhB(OH)2
Cl
Ph
5
Ph
+
N
N
N
N
N
N
4
6
Cl
Cl
2
Ph
Scheme 1. Reagents and conditions: (i) PhB(OH)2, Pd(dppb)Cl2,
K2CO3, toluene–DMF (9:1), microwave irradiation, 10 min, 185 °C,
86%; (ii) HCl 6 N, 12 h, reflux then POCl3, 3 h, reflux, 83%.
1
3
Entry
Catalyst
PhB(OH)2
(No. equiv)
T (°C)
2 (%)
3 (%)
Cl
Cl
Cl
Ph
1
2
3
4
5
6
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(dppb)Cl2
Pd(dppb)Cl2
1
1
1
2
1
2
150
185
200
185
185
185
60
85
77
—
85
70
—
6
12
90
—
10
Cl
Ph
Ph
iii
Ph
i
ii
N
N
N
N
N
N
N
N
Cl
Cl
8
Ph
Ph
7
9
10
All reactions were performed using K2CO3 as base and toluene–DMF
(9:1) as solvent under high frequency microwaves (2.5 GHz) for 10 min.
Scheme 2. Reagents and conditions: (i) PhB(OH)2, Pd(dppb)Cl2 or
Pd(PPh3)4, K2CO3, toluene–DMF (9:1), microwave irradiation,
10 min, 185 °C, 58%; (ii) PhB(OH)2, Pd(dppb)Cl2 or Pd(PPh3)4,
K2CO3, toluene–DMF (9:1), microwave irradiation, 10 min, 185 °C,
65%; (iii) PhB(OH)2, Pd[P(t-Bu3)]2, K2CO3, toluene–DMF (9:1),
microwave irradiation, 10 min, 185 °C, 70%.
Pd(dppb)Cl2, is superior to Pd(PPh3)4 in the Suzuki-type
reactions of p-deficient heteroaryl chlorides.11 Thus, 2,4-
dichloropyrimidine was treated with this catalyst at
185 °C. Indeed, the reaction was much cleaner and with
no formation of the disubstituted product 3 (Table 1,
entry 5). In contrast, even with two equivalents of the
phenylboronic acid, the major product turned out to be
the mono-substituted derivative 2 (Table 1, entry 6).
The use of Pd(dppb)Cl2 as the catalyst represents a
clear advantage for the formation of the monosubstituted
product when compared to Pd(PPh3)4. However, all our
attempts to react pinacol phenyl boronic ester with
2,4-dichloropyrimidine in the presence of any of the
two catalysts were unfruitful and both reactants were
recovered unaltered.
ylpyrimidine (8) was isolated in 58% yield, accompanied
by small amounts of the 2-susbtituted- and 2,4-disubsti-
tuted-pyrimidines (7% and 10%, respectively). No signif-
icant difference with either Pd(PPh3)4 or Pd(dppb)Cl2 as
the catalyst was observed. Similar results have been pre-
viously described in the Stille coupling of 7 with phenyl-
tributyltin under conventional thermal conditions.15
When 8 was treated with a second equivalent of phen-
ylboronic acid, 5-chloro-2,4-diphenylpyrimidine (9)16
was isolated in 65% yield. Substitution at the 5-position
was achieved with the more reactive catalyst, Pd[P-
(t-Bu3)]2,17 to give the triphenylsubstituted pyrimidine
1018 in good yield (70%). Even reacting 7 with 3 equiv
of phenylboronic acid and Pd(PPh3)4 as the catalyst, led
only to the formation of the disubstituted product 9. In
contrast, Suzuki-type cross-coupling reactions of 2,4,6-
trichloropyrimidine under conventional conditions
(Pd(OAc)2, Na2CO3, PPh3, glyme/H2O, 70 °C, 18–24 h)
have been reported to give the 6-phenyl-, 4,6-diphenyl-,
and 2,4,6-triphenyl-pyrimide in 88%, 88%, and 93%
yields, respectively, depending on the amount of phen-
ylboronic acid used.8
The different reactivity of the 2- versus the 4-carbon in
2,4-dihalopyrimidines toward nucleophiles, may be due
to the better charge stabilization of the Meisenheimer
salt derived from attack at the 4-position (thermody-
namic control). The same trend is observed for the pal-
ladium-catalyzed cross-coupling reactions (vide supra).
Nevertheless, high yields of the product resulting from
the reaction at the less activated 2-position can be
achieved when the 4-position is blocked. For example,
reaction of commercially available 2-chloro-4-methoxy-
pyrimidine (4) using Pd(dppb)Cl2 as the catalyst under
the microwave conditions established above gave com-
pound 512 in 86% yield. The methoxy group that acts
as a dummy group, could be transformed back into
the chloride13 in two easy steps with an overall yield
of 71% as shown in Scheme 1. In addition, the methoxy
group allows the possibility of functionalizing the 5-
position using the ortho-lithiation methodology which
has been extensively described by Queguiner.14 Next
we decided to apply our findings to the Suzuki coupling
of 2,4,5-trihalopyrimidines.
With these results in hand, we decided to explore if the
same reactivity pattern would hold true for 2,4-dichloro-
5-bromopyrimidine (11). However, when 11 was reacted
with phenylboronic acid and Pd(PPh3)4 as the catalyst,
we obtained a ꢀ1:1 mixture of 1219 and 1320 (Table 2,
entry 1), whereas with Pd(dppb)Cl2 under the same
microwave conditions, the product ratio was shifted
toward 12 (Table 2, Entry 2). In both cases, a small
amount of the 4,5-disubstituted product was also
obtained (9%).
When we treated 12 with a second equivalent of phen-
ylboronic acid and Pd(PPh3)4 or Pd(dppb)Cl2 as the cat-
alyst, the second substitution took place in the more
reactive 4-position and the 2-chloro-4,5-diphenylpyrim-
2,4,5-Trihalopyrimidines: The commercially available
2,4,5-trichloropyrimidine (7) was treated with 1 equiv of
phenylboronic acid under the same microwave conditions
as described above (Scheme 2). The 2,5-dichloro-4-phen-

S. C. Ceide, A. G. Montalban / Tetrahedron Letters 47 (2006) 4415–4418
4417
Table 2. Selectivity in the Suzuki coupling of 2,4-dichloro-5-bromo-
pyrimidine (11)
boronic acid and Pd(PPh3)4 as the catalyst can be used.
As expected the 5-chloro-4-methoxy-2-phenylpyrimi-
dine (20)26 was the only product isolated (78%). The
second phenyl ring in the 5-position was introduced by
using Pd[P(t-Bu3)]2 as the catalyst to give 18 in 83%
yield. The methoxy group could easily be transformed
into the chloride 2127 after which the third phenyl ring
was introduced via Suzuki coupling using Pd(PPh3)4 to
give 10 in 81% yield (Scheme 5).
Br
Ph
Br
Cl
Cl
Ph
PhB(OH)2
+
N
N
N
N
N
N
Cl
Cl
Cl
12
11
13
Entry
Catalyst
12 (%)
13 (%)
Cl
Cl
1
2
Pd(PPh3)4
Pd(dppb)Cl2
30
60
23
10
Ph
OMe
ii
OMe
iii
X
i
v
7
10
N
N
N
N
N
N
Cl
19
Ph
Ph
Ph
Ph
20
18 X = OMe
21 X = Cl
iv
Ph
Ph
i
ii
12
N
N
N
N
Scheme 5. Reagents and conditions: (i) MeOH, Na, 2 h, rt then 7,
12 h, rt, 92%; (ii) PhB(OH)2, Pd(PPh3)4, K2CO3, toluene–DMF (9:1),
microwave irradiation, 10 min, 185 °C, 78%; (iii) PhB(OH)2, Pd[P-
(t-Bu3)]2, K2CO3, toluene–DMF (9:1), microwave irradiation, 10 min,
185 °C, 83%; (iv) HCl 6 N, 12 h, reflux then POCl3, 3 h, reflux, 79%; (v)
PhB(OH)2, Pd(PPh3)4, K2CO3, toluene–DMF (9:1), microwave irra-
diation, 10 min, 185 °C, 81%.
Cl
14
OMe
15
Scheme 3. Reagents and conditions: (i) PhB(OH)2, Pd(PPh3)4 or
Pd(dppb)Cl2, K2CO3, toluene–DMF (9:1), microwave irradiation,
10 min, 185 °C, 59%; (ii) MeOH, Na, 2 h, rt then 14, 12 h, rt, 85%.
In conclusion, we have developed a fast microwave
assisted method that, starting from easily available
halopyrimidines, allows us to introduce aryl groups
selectively in the 2-, 4-, or 5-positions of the pyrimidine
system depending on the choice of halopyrimidine and
the catalyst employed. We have extended this reaction
to demonstrate the preparation of mono, di, and triphe-
nylpyrimidines. We are currently examining the scope
of this methodology in the N- and O-arylation of
pyrimidines.
idine (14) was obtained in 59% yield (Scheme 3). The
selectivity in 1421 was unambigously confirmed by com-
paring the spectrocopic data of its methoxy derivative
1522 with that of 18. The methoxy derivative 18 was
prepared via the known pyrimidine 1623 followed by
sequential cross-coupling reactions as depicted in
Scheme 4.24
Br
Ph
Ph
OMe
ii
OMe
iii
OMe
i
Typical procedure for the Suzuki coupling reactions: A
2.0–5.0 mL microwave vial was charged with the halo-
pyrimidine (0.5 mmol), phenylboronic acid (1.1 equiv),
potassium carbonate (3.0 equiv), the corresponding cat-
alyst (ca. 5 mol %) in 1.8 mL toluene and 0.2 mL DMF.
The vial was purged three times with nitrogen and then
heated under microwave irradiation (2.5 GHz) for
10 min using a Smith Microwave SynthesizerTM(Biotage
BA) at different temperatures. After this time, the reac-
tion mixture was allowed to cool, filtered and the sol-
vents were removed in vacuo. Ethyl acetate was added
and the organic layer was washed with brine, separated,
and dried (MgSO4). The mixture was purified by reverse
phase chromatography.
11
N
N
N
N
N
N
Cl
Cl
Ph
16
17
18
Scheme 4. Reagents and conditions: (i) MeOH, Na, 2 h, rt then 11,
12 h, rt, 90%; (ii). PhB(OH)2, Pd(dppb)Cl2, K2CO3, toluene–DMF
(9:1), microwave irradiation, 10 min, 185 °C, 60%; (iii) PhB(OH)2,
Pd(PPh3)4, K2CO3, toluene–DMF (9:1), microwave irradiation,
10 min, 185 °C, 81%.
For the introduction of the third phenyl ring in the
2-position of 14, either Pd[P(t-Bu3)]2, Pd(PPh3)4 or
Pd(dppb)Cl2 as the catalyst proved successful. In fact
when we reacted 11 with 3 equiv of phenylboronic acid
and Pd(PPh3)4 as the catalyst, the trisubstituted product
10 was obtained in a 62% yield. Thus the order of the
stepwise introduction of three phenyl rings into the 2-,
4-, and 5-positions of the pyrimidine system can be
achieved depending on the choice of the starting trihalo-
pyrimidine and catalyst.
Acknowledgment
We are grateful to Kemia Inc., for support of this work.
In order to obtain the first arylation at the 2-position of
7, for example, first selective methoxylation at the 4-
position to give 2,5-dichloro-4-methoxypyrimidine
(19)25 followed by treatment with 1 equiv of phenyl-
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8.50–8.51 (m, 2H), 8.81 (s, 1H); MS [C16H11ClN2]: m/z
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1
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m/z (M+): Calcd 220, found 220. Compound 18: white
solid. 1H NMR (CDCl3): 4.16 (s, 3H), 7.26–7.28 (t,
J = 8.8 Hz, 1H), 7.40–7.50 (m, 5H), 7.62 (d, J = 8.8 Hz,
2H), 8.51 (s, 2H), 8.61 (s, 1H); MS [C17H14N2O]: m/z
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1
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compared the spectroscopic data of its dechlorinated
analogue with that of 5. Both compounds showed identical
1
chemical shifts in the H and 13C NMR spectra.
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