One-pot double Suzuki couplings of dichloropyrimidines

Article abstract of DOI:10.1055/s-0030-1258150

An effective one-pot, regioselective double Suzuki coupling of 2,4-dichloropyrimidine has been developed, which enables the quick and efficient synthesis of diarylated pyrimidines. The choice of solvent proved critical to the success of this reaction sequence, with alcoholic solvent mixtures affording much greater reactivity and requiring correspondingly lower temperatures than the use of polar aprotic solvents. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0030-1258150

PAPER
2721
One-Pot Double Suzuki Couplings of Dichloropyrimidines
One-Pot
D
oub
a
le Suzuki
C
m
ouplings of
D
ichlo
a
opyrimidin
n
es tha C. Anderson, Scott T. Handy*
Department of Chemistry, Middle Tennessee State University, Murfreesboro, TN 37132, USA
Fax +1(615)8985182; E-mail: shandy@mtsu.edu
Received 17 February 2010; revised 27 April 2010
pling reactions and two separate halogenations for a total
of four steps. (Scheme 1) When compared to a single step
condensation approach, the cross-coupling approach is
certainly less appealing.
Abstract: An effective one-pot, regioselective double Suzuki cou-
pling of 2,4-dichloropyrimidine has been developed, which enables
the quick and efficient synthesis of diarylated pyrimidines. The
choice of solvent proved critical to the success of this reaction se-
quence, with alcoholic solvent mixtures affording much greater re-
activity and requiring correspondingly lower temperatures than the
use of polar aprotic solvents.
stepwise approach
1. halogenate
N
N
2. couple
Key words: pyrimidines, Suzuki coupling, regioselectivity, palla-
dium-catalyzed, one-pot reaction
3. halogenate
4. couple
R1
N
N
R2
H
N
H
polycoupling approach
N
The pyrimidine nucleus is an important building block for
a variety of compounds of biological and materials inter-
est. For example, both the drugs Gleevec and Crestor fea-
ture pyrimidines at their core. (Figure 1). As a result of
this importance, a variety of methods have been reported
for the synthesis of substituted pyrimidines, including
classical condensation routes such as the Bignelli synthe-
sis and the Pinner synthesis.1 Another approach for the
synthesis of substituted pyrimidines is the use of transi-
tion-metal-catalyzed cross-coupling reactions.2 This
method has the advantages of wide functional group toler-
ance, allowing a single common intermediate to be diver-
sified into a large number of related products.
N
1. dihalogenate
2. dicouple
R1
R2
H
N
H
Scheme 1 Cross-coupling approaches
In an effort to overcome this problem of greater linearity
in coupling multiple substituents, we have been exploring
the concept of regioselective polycoupling reactions on
polyhaloheteroaromatics for the past few years.3,4 The
general idea is to install all of the necessary halogens in
one step, and then perform all of the couplings in a second
step by taking advantage of the intrinsic differences in re-
activity at different centers of the heteroaromatic ring to
sequentially add each substituent.5 In light of the impor-
tance of pyrimidines in synthesis and our prior success
with other dibromoheteroaromatics (including pyridines),
we undertook a study of 2,4-dichloropyrimidine.
HO
HO
HO2C
N
SO2Me
N
N
The regioselectivity of cross-coupling reactions of 2,4-
dichloropyrimidine and 2,4,6-trichloropyrimidine has
been established for a number of years6 (Scheme 2). The
observed preference for coupling initially at the 4-chloro
position has been described as unusual, though recent
computational work by Merlic and Houk indicates that it
is expected on the basis of calculated bond dissociation
energies.7 Most of the experimental work on pyrimidines
has focused on Suzuki couplings, with a variety of reac-
tion conditions being employed with generally good suc-
cess.8–10 It is interesting to note that in most cases, either
complete regioselectivity is reported or no mention is
made of the regioselectivity. However, Gong did report
only moderate selectivity (2.8:1.0) in favor of the 4-cou-
pled product when coupling with 4-carboxyphenylboron-
ic acid.9 By using a slow addition of an excess of the
dichloropyrimidine, though, complete regiocontrol could
be achieved. These same Gong reaction conditions, with-
out slow addition of the dichloropyrimidine, have been
employed by several other groups, though loss of regio-
control has not been noted in any of these other reports.10
Me
F
Crestor
N
N
N
N
HN
N
Me
O
Gleevec
Figure 1 Representative substituted pyrimidines
Despite this versatility, though, cross-coupling methods
are less efficient if multiple substituents are to be in-
stalled. For example, using a conventional approach the
installation of two substituents requires two separate cou-
SYNTHESIS 2010, No. 16, pp 2721–2724
Advanced online publication: 07.07.2010
DOI: 10.1055/s-0030-1258150; Art ID: M01310SS
© Georg Thieme Verlag Stuttgart · New York
x
x.
x
x
.
2
0
1
0

2722
S. C. Anderson, S. T. Handy
PAPER
failed to afford any coupling product. By increasing the
reaction temperature significantly, modest amounts of
coupling products could be isolated. In this case, the use
of ethanol as the alcoholic component was highly advan-
tageous (Table 2, entry 3). To further prevent the reaction
from running dry, toluene was also included as a cosol-
vent and this modification resulted in further improve-
ment.
N
PhB(OH)2
N
aq Na2CO3
Pd(OAc)2
PPh3
glyme
reflux, 18 h
Cl
N
Cl
Ph
N
Cl
Scheme 2 Regioselectivity in the Suzuki coupling of 2,4-dichloro-
pyrimidine
In light of our previous successes with one-pot double
Suzuki couplings of dihaloheteroaromatics, we were in-
terested in seeing if the same reaction conditions would be
applicable to commercially available 2,4-dichloropyrimi-
dine. Thus, the use of tetrakis(triphenylphosphine) palla-
dium(0), with either potassium or sodium carbonate in
either DMF–water or dioxane–water at 90 °C was ex-
plored. Initial results were not promising. Although some
reaction was clearly occurring (TLC and NMR analysis),
attempts to isolate pure products were exceedingly diffi-
cult, and isolated yields were below 20% of pure mono-
coupled product. These results were highly unexpected
considering our earlier successes in other systems as well
as the fact that some of these conditions had been em-
ployed in earlier literature reports of regioselective Suzuki
couplings of pyrimidines.
Table 2 Coupling at C2
4-MeOC6H4B(OH)2
N
N
Pd(Ph3P)4
K2CO3
solvent
Ph
N
Cl
Ph
N
C6H4(4-OMe)
Entry
Solvent
Temp (°C)
Yield (%)
NR
1
2
3
MeOH–toluene
MeOH–toluene
EtOH–toluene–H2O
r.t.
55
90
NR
52
With potential coupling conditions established for both
the first and second couplings, a one-pot double coupling
was attempted (Table 3, entry 1). A solvent mixture of
ethanol, toluene, and water was employed with potassium
carbonate as the base and palladium tetrakis(triphe-
nylphosphine) palladium(0) as the catalyst. The reaction
was heated to 55 °C in order to achieve complete con-
sumption of starting materials within 12 hours. In the ab-
sence of heat, many reactions were still not complete
within 24–48 hours. At this point, the second boronic acid
and more base were added and the reaction temperature
increased to 90 °C for 12 hours. Initially, this approach
was successful, but reproducibility issues were still noted.
Two factors aided in overcoming these issues. First, brief
degassing of the reaction mixture by bubbling argon
Fortunately, further searching of the literature led to a
patent report by Geneste and Sauer, which called for the
use of tetrakis(triphenylphosphine) palladium(0) with po-
tassium carbonate as base in methanol as the solvent at
room temperature.11 Gratifyingly, application of these
conditions afforded the monocoupled product 1 with com-
plete regioselectivity after 3–12 hours at room tempera-
ture (Table 1, entries 1 and 2). The yields were fairly low
(<40%), but the product was easily isolated from the reac-
tion, so this appeared to be a promising starting point. At-
tempts were made to improve the yield by heating the
reaction. Given the very limited temperature range acces-
sible using methanol, the solvent was changed to ethanol
(Table 1, entries 3 and 4). Even at room temperature, this
switch led to improved isolated yields, though heating to
55 °C resulted in very little further improvement.
Table 3 One-Pot Double Couplings
R1B(OH)2
Pd(Ph3P)4, K2CO3
EtOH–toluene–H2O
55 °C, 12 h
N
N
A further question was if a coupling at the C2 position
would also occur under the same reaction conditions
(Table 2). Not surprisingly, reactions at room temperature
then
Cl
N
Cl
R1
N
R2
R2B(OH)2
Pd(Ph3P)4, K2CO3
90 °C, 12 h
R1
R2
Yield (%)
Table 1 Solvent and Temperature Studies for the Monocoupling of
2,4-Dichloropyrimidine
Entry
1
2
3
4
5
6
7
8
Ph
4-MeOC6H4
Ph
84
39
62
65
95
62
21
15
PhB(OH)2
N
N
4-MeOC6H4
4-FC6H4
Ph
Pd(Ph3P)4
K2CO3
solvent
Cl
N
Cl
Ph
N
Cl
Ph
1
4-FC6H4
(E)-hept-1-enyl
4-MeOC6H4
Ph
Entry
Solvent
MeOH
MeOH
EtOH
Temp
Time
3 h
Yield (%)
4-MeOC6H4
(E)-hept-1-enyl
2-MeOC6H4
Ph
1
2
3
4
r.t.
37
30
47
51
r.t.
overnight
overnight
overnight
r.t.
2-MeOC6H4
EtOH
55 °C
Synthesis 2010, No. 16, 2721–2724 © Thieme Stuttgart · New York

PAPER
One-Pot Double Suzuki Couplings of Dichloropyrimidines
2723
action vial. The vial was shaken at 55 °C for 12 h. The resulting
crude product was partitioned between H2O (20 mL) and EtOAc (40
mL). The EtOAc layer was separated, dried, and the solvent was re-
moved in vacuo. The crude product was purified by flash column
chromatography on alumina (15% EtOAc hexanes as eluent) to af-
ford 65.2 mg (51%) of the 2-chloro-4-phenylpyrimidine as a yellow
solid;12 mp 109.5–111.5 °C.
through the reaction for 5 minutes helped to avoid catalyst
decomposition. Reproducibility was further improved by
adding a second dose of catalyst (10 mol%) with the sec-
ond boronic acid. The end result was a set of reaction con-
ditions that reliably afforded >80% isolated yields of this
double coupled product.
1H NMR (300 MHz, CDCl3): d = 7.65 (m, 3 H), 7.67 (d, J = 7.5 Hz,
1 H), 8.10 (d, J = 7.0 Hz, 2 H), 8.64 (d, J = 7.5 Hz, 1 H).
Armed with these reaction conditions, a range of boronic
acids was studied, including electron-rich and electron-
deficient aryls as well as an alkenyl boronic acid. Aryl bo-
ronic acids generally worked well, although the double
coupling with 4-methoxyphenylboronic acid followed by
phenylboronic acid always afforded much lower yields
(Table 3, entry 2). The alkenyl boronic acid also under-
Standard Dicoupling; 4-Phenyl-2-(4-methoxyphenyl)pyrimi-
dine; Typical Procedure (Table 3, Entry 1)
2,4-Dichloropyrimdine (100 mg, 0.67 mmol) was dissolved in a
mixture of toluene (2.9 mL), EtOH (0.7 mL), and H2O (0.7 mL).
The solution was degassed for 5 min with argon. At the end of 5
went cross-coupling in moderate to high yields (Table 3, min, phenylboronic acid (82 mg, 0.67 mmol), Pd(Ph3P)4 (21 mg,
0.18 mmol), and K2CO3 (278 mg, 2.01 mmol) were added to the re-
entries 5 and 6). Electron-withdrawing substituents on the
action vial. The vial was shaken at 55 °C for 12 h. After 12 h, 4-
boronic acid had very little impact on the yield. In general,
methoxyphenylboronic acid (90 mg, 0.78 mmol), Pd(Ph3P)4 (10
the reactions displaying lower yields were contaminated
mg, 0.09 mmol), and K2CO3 (278 mg, 2.01 mmol) were added to the
by larger amounts of boronic acid homocoupling prod-
reaction vial. The vial was shaken at 90 °C for an additional 12 h.
ucts, which made purification more difficult and likely re-
sulted in only partial conversion of the starting material
and monocoupled intermediate.
The resulting crude product was partitioned between H2O (20 mL)
and EtOAc (40 mL). The EtOAc layer was separated, dried, and
concentrated in vacuo. The crude product was purified by prepara-
tive TLC on silica gel (60 Å thickness) eluting with 0.5% MeOH in
CH2Cl2 to afford 147 mg (84%) of the purified, dicoupled product
as a brown solid; mp 83–85 °C.
The cross-coupling reactions were not very successful for
an ortho-substituted boronic acid (Table 3, entries 7 and
8). This is not surprising, as earlier work done with ortho-
substituted boronic acids has shown similar results.
Harsher reaction conditions, employing a stronger base
and higher reaction temperatures, could improve reactions
with sterically hindered boronic acids.
IR (neat): 3003, 2879, 1712, 1554, 1437, 1331, 1215, 1177, 1119,
1040, 911, 770 cm–1.
1H NMR (300 MHz, CDCl3): d = 3.90 (s, 3 H), 7.05 (d, J = 7.0 Hz,
2 H), 7.63–7.51 (m, J = 6 Hz, 4 H), 8.28–8.19 (m, 2 H), 8.55 (d,
J = 7.0 Hz, 2 H), 8.78 (d, J = 6 Hz, 1 H).
13C NMR (75 MHz, CDCl3): d = 164.1, 162.7, 158.0, 127.5, 129.4,
In conclusion, an effective one-pot, regioselective double
Suzuki coupling of 2,4-dichloropyrimidine has been de-
veloped. This method enables the quick and efficient syn-
thesis of diarylated pyrimidines. The choice of solvent
128.8, 128.1, 127.5, 112.4, 112.0, 111.8, 110.6, 56.0.
HRMS (EI): m/z calcd for C17H14N2O: 262.1106; found: 262.1105.
proved critical to the success of this reaction sequence, 4-(4-Methoxyphenyl)-2-phenylpyrimidine (Table 3, Entry 2)
The crude product was purified by preparative TLC on silica gel (60
with alcoholic solvent mixtures affording much greater
Å thickness) eluting with 0.5% MeOH in CH2Cl2 to afford 70 mg
reactivity and requiring correspondingly lower tempera-
tures than the use of polar aprotic solvents. Sterically hin-
dered boronic acids do not afford good yields of the
dicoupled products, but alkenyl and several aryl boronic
(39%) of the purified, dicoupled product as a brown oil.13
1H NMR (300 MHz, CDCl3): d = 3.88 (s, 3 H), 7.03 (d, J = 7.5 Hz,
2 H), 7.55–7.42 (m, 4 H), 8.22 (d, J = 7.0 Hz, 2 H), 8.64–8.48 (m, 2
H), 8.76 (d, J = 6 Hz, 1 H).
acids do work well. It is possible that the application of
microwave reaction conditions may help to overcome
some of these limitations.
4-(4-Fluorophenyl)-2-phenylpyrimidine (Table 3, Entry 3)
The crude product was purified by preparative TLC on silica gel (60
Å thickness) eluting with 40% EtOAc in hexanes to afford 103 mg
(62%) of the purified, dicoupled product as a tan solid; mp 53–
57 °C.
All 1H and 13C NMR spectra were recorded on a Jeol 300MHz NMR
with an automatic sample changer, or on a Jeol AS 500MHz NMR,
using CDCl3 as solvent. All chemical shifts (d) are reported in ppm,
using TMS as a standard. All IR spectra were collected on a Varian
800 FT-IR spectrometer. All reagents were ACS grade. All extrac-
tions from aqueous solution were dried over 97% anhyd MgSO4 and
evaporated using a Büchi rotary evaporator under reduced pressure.
TLC was performed using silica gel coated TLC plates. Preparative
TLC was performed using silica gel (60 Å thickness) coated glass
TLC plates.
IR (neat): 3003, 2879, 1712, 1554, 1437, 1331, 1215, 1177, 1119,
1040, 911, 770 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.22–7.14 (m, 2 H), 7.56–7.47 (m,
4 H), 8.22–8.17 (m, 2 H), 8.78 (d, 1 H, J = 6.0 Hz).
1
13C NMR (75 MHz, CDCl3): d = 165.1 (d, JC,F = 185 Hz), 163.3,
4
161.0, 157.6, 136.8, 132.4 (d, JC,F = 3 Hz), 129.8, 129.3 (d,
3JC,F = 8 Hz), 129.9, 127.4, 126.9, 116.2 (d, 2JC,F = 18 Hz).
HRMS (EI): m/z calcd for C16H11FN2: 250.0906; found: 250.0909.
2-Chloro-4-phenylpyrimidine
2,4-Dichloropyrimdine (100 mg, 0.67 mmol) was dissolved in a
mixture of toluene (2.9 mL), EtOH (0.7 mL), and H2O (0.7 mL).
The solution was degassed for 5 min with argon. At the end of 5
min, phenylboronic acid (82 mg, 0.67 mmol), Pd(Ph3P)4 (21 mg,
0.18 mmol), and K2CO3 (278 mg, 2.01 mmol) were added to the re-
2-(4-Fluorophenyl)-4-phenylpyrimidine (Table 3, Entry 4)
The crude product was purified by preparative TLC on silica gel (60
Å thickness) eluting with 40% EtOAc in hexanes to afford 109 mg
(65%) of the purified, dicoupled product as a yellow solid;14 mp 73–
76 °C.
Synthesis 2010, No. 16, 2721–2724 © Thieme Stuttgart · New York

2724
S. C. Anderson, S. T. Handy
PAPER
1H NMR (300MHz, CDCl3): d = 7.19–7.11 (m, 2 H), 7.58–7.49 (m,
4 H), 8.27–8.16 (m, 2 H), 8.59 (dd, J = 24, 7.5 Hz, 2 H), 8.78 (d,
J = 6.0 Hz, 1 H).
References
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of 2,4-dichloropyrimidine, see: Solberg, J.; Undheim, K.
Acta Chem. Scand. 1989, 43, 62.
2-[(E)-Hept-1-enyl]-4-(4-methoxyphenyl)pyrimidine (Table 3,
Entry 5)
The crude product was purified by preparative TLC on silica gel (60
Å thickness) eluting with 40% EtOAc in hexanes to afford 180 mg
(95%) of the purified, dicoupled product as yellow oil.
IR (neat): 3003, 2879, 1712, 1554, 1437, 1331, 1215, 1177, 1119,
1040, 911, 770 cm–1.
1H NMR (300 MHz, CDCl3): d = 0.90 (t, J = 8.0 Hz, 3 H), 1.25–1.45
(m, 6 H), 3.88 (s, 3 H), 6.41 (d, J = 15 Hz, 1 H), 6.90–6.99 (m, 3 H),
7.11–7.17 (m, 1 H), 7.24–7.18 (m, 1 H), 8.41 (d, J = 7.5 Hz, 2 H),
8.68 (d, J = 6 Hz, 1 H).
13C NMR (75 MHz, CDCl3): d = 164.0, 162.7, 161.5, 127.3, 140.1,
129.9, 128.0, 127.3, 114.1, 113.0, 58.0, 32.0, 31.1, 28.4, 23.3, 14.5.
HRMS (EI): m/z calcd for C18H22N2O: 282.1732; found: 282.1736.
4-[(E)-Hept-1-enyl]-2-(4-methoxyphenyl)pyrimidine (Table 3,
Entry 6)
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The crude product was purified by preparative TLC on silica gel (60
Å thickness) eluting with a 40% EtOAc in hexanes to afford 112 mg
(62%) of the purified, dicoupled product as yellow oil.
IR (neat): 3003, 2879, 1712, 1554, 1437, 1331, 1215, 1177, 1119,
1040, 911, 770 cm–1.
1H NMR (300 MHz, CDCl3): d = 0.79 (t, J = 7.0 Hz, 3 H), 1.35–
1.16 (m, 6 H), 2.09–1.98 (m, 2 H), 3.88 (s, 3 H), 6.45 (d, J = 14 Hz,
1 H), 7.08–6.98 (m, 3 H), 7.25–7.14 (m, 1 H), 8.51 (d, J = 7.5 Hz, 2
H), 8.61 (d, J = 6 Hz, 1 H).
13C NMR (75 MHz, CDCl3): d = 164.0, 162.2, 161.7, 157.3, 140.1,
129.2, 128.7, 128.0, 113.1, 112.2, 55.0, 31.3, 30.4, 27.4, 20.8, 13.5.
HRMS (EI): m/z calcd for C18H22N2O: 282.1732; found: 282.1731.
4-(2-Methoxyphenyl)-2-phenylpyrimidine (Table 2, Entry 7)
The crude product was purified by preparative TLC on silica gel (60
Å thickness) eluting with 0.5% MeOH in CH2Cl2 to afford 38 mg
(21%) of the purified, dicoupled product as yellow oil.13
1H NMR (300 MHz, CDCl3): d = 3.90 (s, 3 H), 7.03 (d, J = 7.0 Hz,
2 H), 7.59–7.51 (m, 4 H), 8.28–8.16 (m, 2 H), 8.55 (d, J = 6 Hz, 2
H), 8.78 (d, J = 6 Hz, 1 H).
2-(2-Methoxyphenyl)-4-phenylpyrimidine (Table 3, Entry 8)
The crude product was purified by preparative TLC on silica gel (60
Å thickness) eluting with 0.5% MeOH in CH2Cl2 to afford 27 mg
(15%) of the purified, dicoupled product as yellow oil.
(9) Gong, Y.; Pauls, H. W. Synlett 2000, 829.
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Wang, D.; Higaki, J.; Chakraborty, I.; Liclican, A.; Sideris,
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Wang, H.; Wang, J.; Feng, Y.; Dugar, S.; Levy, D. E.
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IR (neat): 3003, 2879, 1712, 1554, 1437, 1331, 1215, 1177, 1119,
1040, 911, 770 cm–1.
1H NMR (300 MHz, CDCl3): d = 3.89 (s, 3 H), 7.02 (t, J = 6.5 Hz,
1 H), 7.17–7.40 (m, 6 H), 7.89 (d, J = 7.0 Hz, 1 H), 8.40 (d, J = 7.0
Hz, 2 H), 8.78 (d, J = 6.0 Hz, 1 H).
13C NMR (75 MHz, CDCl3): d = 163.4, 161.4, 159.7, 157.3, 136.6,
129.0, 128.2, 128.0, 127.8, 127.4, 121.7, 119.5, 119.1, 114.3, 55.4.
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HRMS (EI): m/z calcd for C17H14N2O: 262.1106; found: 262.1103.
Acknowledgment
Financial support by the NIH (2R15GM074662-02A1) and a gift of
boronic acids by Frontier Scientific is gratefully acknowledged.
Synthesis 2010, No. 16, 2721–2724 © Thieme Stuttgart · New York