SNAr reactions of 2-methylthio-4-pyrimidinones in pivalic acid: Access to functionalized pyrimidinones and pyrimidines

Article abstract of DOI:10.1055/s-0031-1289744

Pivalic acid is a useful medium to effect the direct S_NAr displacement of 2-methylthio-4-pyrimidinones with a variety of anilines. Products are easily isolated in good to excellent yields, and following chlorination, provide an opportunity to r

Full text of DOI:10.1055/s-0031-1289744

PAPER
1109
SNAr Reactions of 2-Methylthio-4-pyrimidinones in Pivalic Acid:
Access to Functionalized Pyrimidinones and Pyrimidines
S
A
r
Reactions of 2-M
a
ethylthio-
4
t
-pyrim
t
idinone
h
s
in
P
ivalic
ecid w L. Maddess,* Rhiannon Carter
N
Department of Discovery Process Chemistry, Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA 02115, USA
Fax +1(617)9922403; E-mail: matthew_maddess@merck.com
Received 19 December 2011; revised 3 February 2012
approach 2). Surprisingly such a strategy has seen rela-
tively limited application,17–20 presumably because chlo-
ropyrimidines such as 3 are less readily accessed than the
2-regioisomer 2. Commercially available 2-methylthio-4-
Abstract: Pivalic acid is a useful medium to effect the direct SNAr
displacement of 2-methylthio-4-pyrimidinones with a variety of
anilines. Products are easily isolated in good to excellent yields, and
following chlorination, provide an opportunity to rapidly query
structure–activity relationships at the 4-position of functionalized pyrimidinone21 (4) appears to provide a most straightfor-
pyrimidines.
ward entry to scaffolds of this type. However, standard
conditions22 for displacement at C2 with a variety of
Key words: heterocycles, nucleophilic aromatic, solvent effects,
medicinal chemistry, regioselectivity
anilines require extended reaction times in refluxing di-
glyme.23 This low reactivity is further exacerbated with
electron-deficient nucleophiles, which often afford poor
yields24 or utilize an excess of the aniline in a fusion pro-
cedure.25
2-Anilinopyrimidinones and particularly pyrimidines
have historically enjoyed strong popularity as core scaf-
folds in drug discovery programs that target the treatment
of a variety of human malignancies.1–8 In large part, their
success can be attributed to an ability to form a bidentate
hydrogen bonding interaction with hinge amino acids in a
wide range of kinases.7 This promiscuous activity can
then be fine tuned by sequential modification of the pe-
ripheral substituents leading to various useful kinase se-
lectivity profiles.
With the goal of developing a general, scalable, and effi-
cient protocol for direct SNAr displacement at C2 of 2-
methylthio-4-pyrimidinones with anilines, we explored a
variety of additives and modified conditions in a represen-
tative system.26 Selected results are displayed in
Scheme 2 for reaction of 3-bromoaniline (5) with 4 in
which conversion into pyrimidinone 6 relative to the start-
ing material 4 was followed by HPLC as a function of
time.
Investigation of structure–activity relationships (SAR)
about the pyrimidine nucleus is most often performed by
exploitation of the differential reactivity of halopyrim-
idines, for example, 1.2–4 Specifically, the 4-position is
considerably more reactive towards both nucleophilic
aromatic substitution (C–X) and metal-mediated (C–X/
C–C) bond-forming processes.2–4,9–12 Although mixtures
of regioisomers are often formed to some extent,13–15 con-
ditions can at times be optimized to greatly favor the de-
sired 4-regioisomer16 readily providing scaffolds 2 to
explore the effects of functionalization at C2 (Scheme 1,
approach 1).
SNAr displacement under standard conditions in diglyme
without additive was, as expected, sluggish at 130 °C with
only 8% conversion being achieved after 24 hours. Addi-
tion of organic bases yielded at best no benefit (Hünig’s
base) or inhibited the reaction (DABCO). In contrast,
acidic additives [AcOH, pivalic acid (PivOH), or MSA]
provided markedly improved results with regards to con-
version in a trend roughly correlated with the strength of
the acid. Running the reaction in neat AcOH was superior
to that where it was used as an additive; however, the re-
action was observed to stall due to unproductive con-
sumption of the aniline via acylation by the solvent.27
Switching to pivalic acid resolved this issue and full con-
version was achieved in less than six hours with an overall
The complementary approach wherein substituents at C4
could be varied post C2 derivatization is of value to a ro-
bust medicinal chemistry effort in this area (3, Scheme 1,
approach 1
approach 2
Cl
Cl
R
N
O
CX or CC
coupling
1. HNAr
N
convenient
SAR
N
N
NH
4-selective
2. POCl3
N
NH
Ar
N
Cl
Cl
N
SMe
1
3
2
4
Scheme 1 SAR approaches to 2,4-disubstituted pyrimidines
SYNTHESIS 2012, 44, 1109–1118
x
x.
x
x.
2
0
1
2
Advanced online publication: 15.03.2012
DOI: 10.1055/s-0031-1289744; Art ID: M116611SS
© Georg Thieme Verlag Stuttgart · New York

1110
M. L. Maddess, R. Carter
PAPER
less); although slower rates were observed for electroni-
cally deactivated nucleophiles (Table 1, entries 13 to 16)
or sterically encumbered anilines (Table 1, entry 6). In all
cases, treatment of the isolated solids with phosphorus
oxychloride afforded the desired activated pyrimidine
scaffolds in good yield poised for derivatization at C4
(Table 1).
Table 1 PivOH Scope of SNAr Reactions of 4 with Anilinesa
X
O
N
PivOH
R
R
(9 volumes)
H2N
N
NH
+
130 °C
3–24 h
N
N
SMe
H
X = OH, A
X = Cl, B
4
(1.2 equiv)
POCl3
70 °C, 1 h
Entry Product
A
8
Yield
(%)b
B
Yield
(%)c
X
Br
Cl
F
Scheme 2 Additive effects: SNAr reaction of pyrimidinone 4 with 5
1
2
3
4
5
82
89
89
85
95
9
98
N
N
N
N
N
N
very clean reaction profile.28 On the whole, either neat
PivOH or MSA (1 equiv) in diglyme appear to be practical
systems to effect the desired transformation. Ultimately,
the former was chosen for further exploration of the reac-
tion scope given the improved impurity profile observed
(Table 1).
According to the optimized procedure,29 2-methylthio-4-
pyrimidinone (4) was mixed with the appropriate aniline
(1.2 equiv) and diluted with 9 volumes (relative to 4) of
pivalic acid.30 The resulting mixture was heated to an in-
ternal temperature of 130 °C and followed by HPLC until
the pyrimidinone starting material was consumed. Upon
cooling and addition of hexanes, the desired 2-substituted
products were obtained by simple filtration in sufficient
purity to use directly in subsequent transformations. Gen-
erally, yields were found to be good to excellent for a
variety of anilines tested including those containing
electron-withdrawing and/or reactive functional groups as
well as heterocyclic systems (Table 1, entries 13–17). In
most cases reaction times were conveniently short (6 h or
N
X
N
H
10
12
14
6
11
13
15
7
95
99
99
97
N
X
N
H
N
X
N
H
N
X
N
H
F
N
X
N
H
Br
6
16
67
17
70
X
N
Me
O
O
Me
O
PivOH
Br
Br
H2N
+
N
X
N
H
130 °C, 6 h
N
NH
Br
96%
N
O
N
SMe
O
H
Me
Me
41
42
(1.2 equiv)
7
8
18
20
91
81
19
21
99
95
X = OH, 43
N
N
POCl3, 70 °C
1 h, 85%
X = Cl, 44
N
X
N
H
X
O
PivOH
130 °C, 6 h
Br
Cl
Br
H2N
N
NH
+
89%
N
N
N
SMe
Cl
H
X = OH, 46
X = Cl, 47
N
N
H
41
45
(1.2 equiv)
POCl3, 70 °C
1 h, 88%
Scheme 3 PivOH SNAr reactions of 5-halopyrimidinone 41
Synthesis 2012, 44, 1109–1118
© Thieme Stuttgart · New York

PAPER
SNAr Reactions of 2-Methylthio-4-pyrimidinones in Pivalic Acid
1111
Table 1 PivOH Scope of SNAr Reactions of 4 with Anilinesa
(continued)
In an attempt to gain access to pyrimidines that would per-
mit exploration at C5 as well as C4, the known 5-iodo (40,
91%; I2, aq 1 N NaOH)31 and 5-bromo (41, 72%; NBS,
DMF)32 derivatives of 4 were prepared and subjected to
the pivalic acid SNAr conditions. Whilst the former suf-
fered from decomposition during the reaction conditions
giving rise to a complex mixture of products, the latter
bromide derivative 41 was found to provide satisfactory
results similar to those previously observed with 4
(Scheme 3).
X
O
PivOH
(9 volumes)
R
R
H2N
N
NH
+
130 °C
3–24 h
N
N
N
SMe
H
X = OH, A
X = Cl, B
4
(1.2 equiv)
POCl3
70 °C, 1 h
Entry Product
A
Yield
(%)b
B
Yield
(%)c
As an alternative entry to scaffolds such as 43, which per-
mits construction of the 5-iodo products, 2-anilinopyrim-
idinones can be efficiently halogenated after SNAr
displacement (Scheme 4). These sorts of multi-halogenat-
ed products provide interesting opportunities for selective
post-functionalization at multiple positions on the anili-
nopyrimidine core.
X
F
Br
I
Br
9
10
11
12
13
14
15
16
17
22
79
81
94
92
91
78
80
67
99
23
98
N
N
N
N
N
N
N
N
X
N
H
24
26
25
27
29
31
33
35
37
39
83
93
88
90
70
89
97
81
O
Br
X
Br
N
X
N
H
I
NIS, DMF, 70 °C
97%
NH
N
N
N
N
N
H
H
X = OH, 48
X = Cl, 49
6
POCl3, 70 °C
1 h, 96%
N
X
N
H
O
N
Br
X
N
Br
OMe
Br
NBS, DMF, 70 °C
73%
NH
28
30
32
34
36
38
N
N
H
N
X
N
H
OMe
O
N
H
X = OH, 50
X = Cl, 51
6
POCl3, 70 °C
1 h, 86%
OMe
O
N
Br
X
Br
Cl
NCS, AcOH, 90 °C
82%
N
X
N
H
NH
N
N
H
N
N
H
CF3
CN
F
X = OH, 52
X = Cl, 53
6
POCl3, 70 °C
1 h, 89%
N
X
N
H
Scheme 4 Alternative entry to C5-halogenated pyrimidinones
In addition to the substrate scope presented above, the
PivOH SNAr displacement conditions discussed thus far
have proven useful in a number of other contexts using
commercially available electrophiles (Scheme 5).
N
X
N
H
For example, both C6-substituted trifluoromethyl 54 and
hydroxypyrimidinones 61 underwent successful displace-
ment at C2 with aniline nucleophiles to afford, after chlo-
rination, scaffolds 57 and 60, respectively. For the former
54, both extended reaction times and slightly larger equiv-
alents of the aniline were required to obtain satisfactory
yields of the SNAr products 56 and 59. In contrast, 4,6-di-
hydroxy-2-methylthiopyrimidine (61) required only two
hours to reach full conversion, although in this case by-
product formation limited the isolated yield to 75%.
N
N
N
X
N
H
N
N
N
N
H
Br
a Reactions performed on 7 to 270 mmol scale of 4.
b Isolated yields corrected for weight percent as determined by 1H
NMR and HPLC.
The non-pyrimidinone starting materials 2-chloro-4-
methylpyrimidine (64) and 6,8-dibromoimidazo[1,2-
a]pyrazine (67) were both found to be viable substrates.
c Isolated yields.
© Thieme Stuttgart · New York
Synthesis 2012, 44, 1109–1118

1112
M. L. Maddess, R. Carter
PAPER
plates with UV indicator), and/or LC/MS [(30 mm × 2 mm, 2.0 mm
particle column; 2 mL injection; 3% to 98% MeCN–H2O + 0.05%
TFA gradient over 2.3 min; 0.9 mL/min flow; APCI; positive ion
mode; UV detection at 254 nm). Compounds were purified by crys-
tallization or forced flow column chromatography using silica gel
(230–400 mesh) and EtOAc–hexanes or MeOH–CH2Cl2 solvent
systems. Reported yields are based upon isolated mass of the de-
sired product and corrected for purity by weight percent as deter-
mined by 1H NMR or HPLC using purified standards when
appropriate. 1H and 13C NMR were recorded on a 500 or 600 MHz
spectrometer and are internally referenced to residual protio solvent
signals. Data for 1H NMR are reported as follows: chemical shift (d
ppm), multiplicity (standard abbreviations), integration and cou-
pling constant (Hz). Data for 13C NMR are reported in terms of
chemical shift (d ppm) and multiplicity as before when appropriate.
HRMS data was obtained from an LC/MSD TOF spectrometer.
Melting points were determined by differential scanning calorime-
try (heating rate: 10 °C/min, temperature range: 25 to 350 °C) using
a DSC Q200 from TA Instruments.
X
N
O
PivOH
H2N
135 °C, 44 h
N
NH
+
71%
F3C
N
F3C
N
SMe
H
X = OH, 56
X = Cl, 57
54
POCl3, 70 °C
55
(1.8 equiv)
1 h, 89%
X
O
PivOH
135 °C, 44 h
F
H2N
+
N
NH
85%
F3C
N
N
F3C
N
SMe
F
H
X = OH, 59
X = Cl, 60
54
58
(1.8 equiv)
POCl3, 70 °C
1 h, 79%
X
O
PivOH
130 °C, 2 h
H2N
N
NH
+
75%
X
N
N
HO
N
SMe
H
The preferred experimental apparatus for standard reaction scales
(~1 g) was 40 mL Chemglass disposable pressure release vials (CG-
4912-06) and 1–1/2 × 5/16 disposable stirbars from Fisher
(1451395). For large-scale reactions an overhead stirrer is recom-
mended.
X = OH, 62
X = Cl, 63
55
61
POCl3, 100 °C
1 h, 78%
(1.2 equiv)
Br
Br
PivOH
130 °C, 1.5 h
N
N
+
SNAr Reactions of 2-Methylthio-4-pyrimidinones in Pivalic
Acid; General Procedure A
89%
N
N
H
N
Cl
H2N
A mixture of the respective 2-methylthio-4-pyrimidinone and the
desired aniline (1.2 equiv) in PivOH (9 volumes) was heated to an
internal temperature of 130 °C.29,30 Stirring was maintained at this
temperature until the pyrimidinone was fully consumed or until
conversion was observed to stall. Heating was then discontinued
and the internal temperature slowly allowed too decrease. Upon
reaching 70 °C, hexanes (18 volumes) were added over 3 to 15 min.
The slurry was further cooled to r.t. where it was stirred for 30 min
prior to filtration through a medium glass frit. The filter cake was
subsequently washed with hexanes (2 × 3 to 5 volumes each), then
dried, to afford the desired 2-anilinopyrimidinones in suitable
purity34 for direct use in subsequent transformations. Compounds
10,22a 18,22a 28,35 and 3422a showed satisfactory spectroscopic data
in agreement with those reported in the literature.
64
65
66
(1.1 equiv)
O
O
Me
Me
100 °C, 1 h
Me
Br
Me
O
PivOH
NH
O
+
N
N
N
N
99%
N
Br
NH2
N
Br
67
42
(1.2 equiv)
68
Scheme 5 Expanded scope of PivOH SNAr reactions
SNAr displacement on the former 64 with 3-bromo-5-
methylaniline was complete in less than two hours, gave
an excellent yield of the desired product, and was easily
scaled to 1.17 mol (66). The latter 67 when reacted with
3,4-dimethoxyaniline afforded a single regioisomer of the
desired product 68 in yields and reaction times superior to
those reported in the literature (74%, >14 h).33
Chlorination of Pyrimidinone-4(3H)-ones with POCl3; General
Procedure B
A suspension of the respective 2-anilinopyrimidinone in POCl3 (12
equiv) was heated to an internal temperature of 70 °C. After ~ 1 h,
full conversion into the desired 4-chloropyrimidine was achieved
and heating was discontinued. The reaction mixture was cooled to
r.t. and the excess POCl3 removed by concentration in vacuo (care
to ensure proper ventilation during removal and disposal of the
POCl3 waste should be implemented). The residue was then diluted
with CH2Cl2 (20 volumes), and stirred with an equal volume of sat.
aq NaHCO3 until the evolution of CO2 ceased. The layers were then
separated; the aqueous extracted a second time with CH2Cl2 (20 vol-
umes), the combined organics dried (MgSO4), filtered, and concen-
trated in vacuo. Unless otherwise noted, purification by flash
chromatography (0 to 100% EtOAc–hexanes or 0 to 10% MeOH–
CH2Cl2) was used to afford analytically pure products. Compound
2935 showed satisfactory spectroscopic data in agreement with that
reported in the literature.
In conclusion, SNAr reaction of a variety of anilines with
2-methylthio-4-pyrimidinones in pivalic acid provides a
convenient entry to pharmaceutically relevant 2-anilino-
pyrimidinones and pyrimidines. This methodology is sim-
ple, scalable, high-yielding, tolerant of functional groups,
and should be of interest to medicinal chemistry programs
targeting kinase inhibitors.
Unless otherwise noted all reactions were performed in air-dried
glassware under a N2 atmosphere. HPLC grade solvents were used
with no additional purification or drying and all anilines and pyrim-
idinones were obtained either from commercial sources or prepared
by straightforward literature procedures. Reactions were monitored
by HPLC [C-18 column, 4.6 × 100 mm, 2.7 mm particle column;
40 °C; mobile phase: (A) 0.1% H3PO4–H2O; (B) MeCN, gradient
10–95% B in 6 min and hold at 95% B for 2 min; flow rate, 1.8 mL/
min (UV = 220 and 254 nm)], and/or TLC (0.25 mm silica gel
2-[(3-Bromophenyl)amino]pyrimidin-4(3H)-one (6)
Procedure A; yield: 8.1 g (99 wt%, 30.0 mmol, 95%); white solid;
mp 267 °C.
1H NMR (600 MHz, DMSO-d6): d = 11.04 (br s, 1 H), 9.12 (br s, 1
H), 8.02 (s, 1 H), 7.82 (s, 1 H), 7.46 (d, J = 7.5 Hz, 1 H), 7.21 (t,
J = 8.0 Hz, 1 H), 7.14 (d, J = 7.9 Hz, 1 H), 5.87 (s, 1 H).
Synthesis 2012, 44, 1109–1118
© Thieme Stuttgart · New York

PAPER
SNAr Reactions of 2-Methylthio-4-pyrimidinones in Pivalic Acid
1113
HRMS (EI): m/z calcd for C10H9BrN3O:265.9924; found: 265.9921
HRMS (EI): m/z calcd for C10H8ClFN3: 224.0385; found: 224.0386
(M + H).
(M + H).
N-(3-Bromophenyl)-4-chloropyrimidin-2-amine (7)
Procedure B; yield: 1.98 g (6.96 mmol, 97%); white solid; mp 103
°C.
2-[(3-Fluorophenyl)amino]pyrimidin-4(3H)-one (14)
Procedure A; yield: 30.8 g (99 wt%, 150 mmol, 85%); white solid;
mp 258 °C.
1H NMR (600 MHz, CDCl3): d = 8.29 (s, 1 H), 7.87 (s, 1 H), 7.65
(s, 1 H), 7.43 (s, 1 H), 7.17 (s, 2 H), 6.77 (d, J = 4.2 Hz, 1 H).
13C NMR (150 MHz, CDCl3): d = 161.7, 159.6, 159.1, 140.1, 130.4,
126.4, 122.9, 122.6, 118.3, 113.0.
1H NMR (600 MHz, DMSO-d6): d = 10.91 (br s, 1 H), 9.11 (br s, 1
H), 7.82 (s, 1 H), 7.72 (d, J = 11.7 Hz, 1 H), 7.39–7.13 (m, 2 H),
6.77 (t, J = 7.6 Hz, 1 H), 5.87 (s, 1 H).
HRMS (EI): m/z calcd for C10H9FN3O: 206.0730; found: 206.0723
(M + H).
HRMS (EI): m/z calcd for C10H8BrClN3: 283.9585; found:
283.9581 (M + H).
4-Chloro-N-(3-fluorophenyl)pyrimidin-2-amine (15)
Procedure B; yield: 1.40 g (6.26 mmol, 99%); white solid; mp 110
°C.
2-[(4-Bromophenyl)amino]pyrimidin-4(3H)-one (8)
Procedure A; yield: 1.58 g (97 wt%, 5.76 mmol, 82%); white solid;
mp 243 °C.
1H NMR (600 MHz, DMSO-d6): d = 10.89 (br s, 1 H), 9.02 (br s, 1
H), 7.76 (s, 1 H), 7.57 (d, J = 7.4 Hz, 2 H), 7.43 (d, J = 8.2 Hz, 2 H),
5.83 (s, 1 H).
1H NMR (600 MHz, DMSO-d6): d = 10.22 (s, 1 H), 8.41 (d, J = 5.2
Hz, 1 H), 7.69 (d, J = 12.2 Hz, 1 H), 7.42 (dd, J = 8.2, 0.9 Hz, 1 H),
7.26 (dd, J = 15.3, 8.1 Hz, 1 H), 6.93 (d, J = 5.2 Hz, 1 H), 6.74 (td,
J = 8.4, 2.2 Hz, 1 H).
13C NMR (150 MHz, DMSO-d6): d = 162.9 (d, J = 240.9 Hz),
160.6, 160.5, 160.1, 142.1 (d, J = 11.3 Hz), 130.6 (d, J = 9.7 Hz),
115.6 (d, J = 2.3 Hz), 112.7, 109.0 (d, J = 21.2 Hz), 106.4 (d,
J = 26.6 Hz).
HRMS (EI): m/z calcd for C10H9BrN3O:265.9924; found: 265.9919
(M + H).
N-(4-Bromophenyl)-4-chloropyrimidin-2-amine (9)
Procedure B; yield: 1.52 g (5.34 mmol, 98%); white solid; mp 126
HRMS (EI): m/z calcd for C10H8ClFN3: 224.0391; found: 224.0381
°C.
(M + H).
1H NMR (600 MHz, CDCl3): d = 8.26 (d, J = 5.2 Hz, 1 H), 7.48 (m,
3 H), 7.42 (d, J = 8.8 Hz, 2 H), 6.76 (d, J = 5.2 Hz, 1 H).
13C NMR (150 MHz, CDCl3): d = 162.0, 159.4, 158.6, 137.7, 132.2,
121.5, 116.2, 112.7.
2-[(2-Bromophenyl)amino]pyrimidin-4(3H)-one (16)
Procedure A; yield: 1.31 g (96 wt%, 4.73 mmol, 67%); white solid;
mp 198 °C.
1H NMR (600 MHz, DMSO-d6): d = 11.38 (br s, 1 H), 8.27 (br s, 1
H), 7.97 (s, 1 H), 7.61 (d, J = 7.8 Hz, 2 H), 7.33 (s, 1 H), 7.03 (s, 1
H), 5.75 (s, 1 H).
HRMS (EI): m/z calcd for C10H8BrClN3: 283.9585; found:
283.9582 (M + H).
HRMS (EI): m/z calcd for C10H9BrN3O 265.9924; found: 265.9920
(M + H).
4-Chloro-N-(4-chlorophenyl)pyrimidin-2-amine (11)36
Procedure B; yield: 1.25 g (5.21 mmol, 95%); white solid; mp 126
°C.
1H NMR (600 MHz, CDCl3): d = 8.25 (d, J = 5.2 Hz, 1 H), 7.71 (br
s, 1 H), 7.51 (d, J = 8.8 Hz, 2 H), 7.27 (d, J = 8.8 Hz, 2 H), 6.74 (d,
J = 5.2 Hz, 1 H).
N-(2-Bromophenyl)-4-chloropyrimidin-2-amine (17)
Procedure B; yield: 0.9 g (3.16 mmol, 70%); white solid; mp 59 °C.
1H NMR (600 MHz, CDCl3): d = 8.40 (dd, J = 8.3, 1.4 Hz, 1 H),
8.29 (d, J = 5.2 Hz, 1 H), 7.65 (s, 1 H), 7.54 (dd, J = 8.0, 1.4 Hz, 1
H), 7.36–7.28 (m, 1 H), 6.92 (td, J = 7.9, 1.5 Hz, 1 H), 6.79 (d,
J = 5.2 Hz, 1 H).
13C NMR (150 MHz, CDCl3): d = 161.7, 159.8, 159.1, 137.3, 129.2,
128.5, 121.2, 112.7.
13C NMR (150 MHz, CDCl3): d = 161.6, 159.7, 159.1, 136.6, 132.7,
128.3, 124.4, 121.4, 114.0, 113.2.
HRMS (EI): m/z calcd for C10H8Cl2N3: 240.0090; found: 240.0086
(M + H).
HRMS (EI): m/z calcd for C10H8BrClN3: 283.9585; found:
283.9582 (M + H).
2-[(4-Fluorophenyl)amino]pyrimidin-4(3H)-one (12)
Procedure A; yield: 1.84 g (70 wt%, 6.28 mmol, 89%); white solid;
mp 262 °C.
1H NMR (600 MHz, DMSO-d6): d = 11.30 (br s, 1 H), 8.91 (br s, 1
H), 7.70 (s, 1 H), 7.57 (s, 2 H), 7.11 (t, J = 8.5 Hz, 2 H), 5.78 (s, 1
4-Chloro-N-(4-methylphenyl)pyrimidin-2-amine (19)37
Procedure B; yield: 1.35 g (6.15 mmol, 99%); yellow solid; mp 113
°C.
1H NMR (600 MHz, CDCl3): d = 8.22 (s, 1 H), 7.72 (s, 1 H), 7.43
(d, J = 7.5 Hz, 2 H), 7.13 (d, J = 7.5 Hz, 2 H), 6.69 (d, J = 3.7 Hz, 1
H), 2.31 (s, 3 H).
H).
HRMS (EI): m/z calcd for C10H9FN3O: 206.0724; found: 206.0725
(M + H).
13C NMR (150 MHz, CDCl3): d = 161.7, 160.1, 158.8, 136.0, 133.5,
4-Chloro-N-(4-fluorophenyl)pyrimidin-2-amine (13)
Procedure B; yield: 1.35 g (6.04 mmol, 99%); white solid; mp 175
°C.
129.7, 120.6, 111.9, 21.1.
HRMS (EI): m/z calcd for C11H11ClN3: 220.0636; found: 220.0637
(M + H).
1H NMR (600 MHz, CDCl3): d = 8.25 (s, 1 H), 7.56–7.46 (m, 2 H),
7.35 (s, 1 H), 7.03 (t, J = 8.6 Hz, 2 H), 6.73 (d, J = 5.1 Hz, 1 H).
2-[(2,4-Dimethylphenyl)amino]pyrimidin-4(3H)-one (20)
Procedure A; yield: 1.82 g (68 wt%, 5.72 mmol, 81%); white solid;
mp 244 °C.
13C NMR (150 MHz, CDCl3): d = 161.9, 159.9, 159.1 (d, J = 242.0
Hz), 158.8, 134.5 (d, J = 2.8 Hz), 122.1 (d, J = 8.0 Hz), 115.8 (d,
J = 21.9 Hz), 112.4.
© Thieme Stuttgart · New York
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M. L. Maddess, R. Carter
PAPER
1H NMR (600 MHz, DMSO-d6): d = 11.33 (br s, 1 H), 8.01 (br s, 1
H), 7.65–7.41 (m, 2 H), 7.10–6.78 (m, 2 H), 5.65 (d, J = 5.7 Hz, 1
H), 2.21 (s, 3 H), 2.13 (s, 3 H).
1H NMR (600 MHz, DMSO-d6): d = 10.93 (br s, 1 H), 8.88 (br s, 1
H), 7.91 (s, 1 H), 7.78 (s, 1H), 7.29 (s, 1 H), 7.17 (s, 1 H), 5.83 (s, 1
H), 2.20 (s, 3 H).
HRMS (EI): m/z calcd for C12H14N3O: 216.1131; found: 216.1131
HRMS (EI): m/z calcd for C11H11IN3O: 327.9941; found: 327.9936
(M + H).
(M + H).
4-Chloro-N-(2,4-dimethylphenyl)pyrimidin-2-amine (21)
Procedure B; yield: 1.24 g (5.31 mmol, 95%); yellow solid; mp 61
4-Chloro-N-(3-iodo-5-methylphenyl)pyrimidin-2-amine (27)
Procedure B; yield: 1.85 g (5.35 mmol, 93%); white solid; mp 101
°C.
°C.
1H NMR (600 MHz, CDCl3): d = 8.18 (d, J = 5.2 Hz, 1 H), 7.57 (d,
J = 8.7 Hz, 1 H), 7.54 (s, 1 H), 7.06 (s, 2 H), 6.64 (d, J = 5.2 Hz, 1
H), 2.33 (s, 3 H), 2.26 (s, 3 H).
1H NMR (600 MHz, CDCl3): d = 8.25 (d, J = 4.7 Hz, 1 H), 7.81 (s,
1 H), 7.78 (s, 1 H), 7.26 (s, 1 H), 7.21 (s, 1 H), 6.73 (d, J = 4.8 Hz,
1 H), 2.26 (s, 3 H).
13C NMR (150 MHz, CDCl3): d = 161.6, 161.3, 159.5, 135.2, 134.0,
131.6, 131.6, 127.5, 124.5, 111.5, 21.2, 18.3.
13C NMR (150 MHz, CDCl3): d = 161.7, 159.6, 159.0, 140.8, 139.7,
133.2, 125.8, 120.0, 112.7, 94.5, 21.4.
HRMS (EI): m/z calcd for C12H13ClN3: 234.0793; found: 234.0797
HRMS (EI): m/z calcd for C11H10ClIN3: 345.9602; found: 345.9598
(M + H).
(M + H).
2-[(4-Bromo-3-fluorophenyl)amino]pyrimidin-4(3H)-one (22)
Procedure A; yield: 1.58 g (99 wt%, 5.55 mmol, 79%); white solid;
mp 297 °C.
Methyl 4-[(6-Oxo-1,6-dihydropyrimidin-2-yl)amino]benzoate
(30)19
Procedure A; yield: 1.69 g (93 wt%, 6.41 mmol, 91%); yellow solid;
mp 258 °C.
1H NMR (600 MHz, DMSO-d6): d = 11.08 (br s, 1 H), 9.33 (br s, 1
H), 8.09–7.71 (m, 2 H), 7.53 (t, J = 8.4 Hz, 1 H), 7.28 (d, J = 7.3 Hz,
1 H), 5.94 (s, 1 H).
1H NMR (600 MHz, DMSO-d6): d = 11.05 (br s, 1 H), 9.34 (br s, 1
H), 7.92–7.80 (m, 3 H), 7.76 (d, J = 8.4 Hz, 2 H), 5.93 (s, 1 H), 3.77
(s, 3 H).
HRMS (EI): m/z calcd for C10H8BrFN3O: 283.9829; found:
283.9826 (M + H).
HRMS (EI): m/z calcd for C12H12N3O3: 246.0873; found: 246.0869
(M + H).
N-(4-Bromo-3-fluorophenyl)-4-chloropyrimidin-2-amine (23)
Procedure B; yield: 1.56 g (5.16 mmol, 98%); white solid; mp 148
Methyl 4-[(4-Chloropyrimidin-2-yl)amino]benzoate (31)
°C.
Procedure B; yield: 1.47 g (5.57 mmol, 90%); white solid; mp 172
°C.
1H NMR (600 MHz, CDCl3): d = 8.32 (d, J = 5.2 Hz, 1 H), 8.00 (d,
J = 8.7 Hz, 2 H), 7.68 (d, J = 8.7 Hz, 2 H), 7.59 (s, 1 H), 6.81 (d,
J = 5.2 Hz, 1 H), 3.88 (s, 3 H).
13C NMR (150 MHz, CDCl3): d = 166.9, 161.7, 159.4, 159.0, 143.0,
131.1, 124.6, 118.4, 113.4, 52.2.
1H NMR (600 MHz, CDCl3): d = 8.29 (d, J = 4.7 Hz, 1 H), 7.73 (d,
J = 10.6 Hz, 1 H), 7.69 (s, 1 H), 7.41 (t, J = 8.0 Hz, 1 H), 7.06 (d,
J = 8.1 Hz, 1 H), 6.80 (d, J = 4.8 Hz, 1 H).
13C NMR (150 MHz, CDCl3): d = 161.8, 159.3, 159.3 (d, J = 245.1
Hz), 159.0, 139.6 (d, J = 10.2 Hz), 133.4 (d, J = 1.6 Hz), 116.1 (d,
J = 3.2 Hz), 113.3, 107.9 (d, J = 27.7 Hz), 102.0 (d, J = 21.4 Hz).
HRMS (EI): m/z calcd for C10H7BrClFN3: 301.9490; found:
HRMS (EI): m/z calcd for C12H11ClN3O2: 264.0534; found:
301.9489 (M + H).
264.0530 (M + H).
2-[(3-Bromo-5-methylphenyl)amino]pyrimidin-4(3H)-one (24)
Procedure A; yield: 62.0 g (99 wt%, 218 mmol, 81%); beige solid;
mp 304 °C.
1H NMR (600 MHz, DMSO-d6): d = 10.94 (br s, 1 H), 8.94 (br s, 1
H), 7.81 (s, 2 H), 7.25 (s, 1 H), 6.99 (s, 1 H), 5.85 (s, 1 H), 2.23 (s,
3 H).
2-{[4-(Trifluoromethyl)phenyl]amino}pyrimidin-4(3H)-one
(32)
Procedure A; yield: 1.67 g (75 wt%, 4.91 mmol, 78%); white solid;
mp 239 °C.
1H NMR (600 MHz, DMSO-d6): d = 11.60 (br s, 1 H), 9.45 (br s, 1
H), 8.07–7.45 (m, 5 H), 5.91 (s, 1 H).
HRMS (EI): m/z calcd for C11H11BrN3O: 280.0086; found:
HRMS (EI): m/z calcd for C11H9F3N3O: 256.0692; found: 256.0688
280.0096 (M + H).
(M + H).
N-(3-Bromo-5-methylphenyl)-4-chloropyrimidin-2-amine (25)
Procedure B; yield: 55 g (184 mmol, 83%); white solid; mp 102 °C.
4-Chloro-N-[4-(trifluoromethyl)phenyl]pyrimidin-2-amine(33)
Procedure B; yield: 0.90 g (3.29 mmol); white solid; mp 148 °C.
1H NMR (600 MHz, CDCl3): d = 8.26 (d, J = 5.2 Hz, 1 H), 7.78 (s,
1 H), 7.69 (s, 1 H), 7.19 (s, 1 H), 6.99 (s, 1 H), 6.74 (d, J = 5.2 Hz,
1 H), 2.28 (s, 3 H).
1H NMR (600 MHz, CDCl3): d = 8.31 (d, J = 5.1 Hz, 1 H), 7.71 (d,
J = 8.5 Hz, 2 H), 7.63 (s, 1 H), 7.57 (d, J = 8.5 Hz, 2 H), 6.82 (d,
J = 5.2 Hz, 1 H).
13C NMR (150 MHz, CDCl3): d = 161.6, 159.8, 159.1, 140.7, 139.9,
13C NMR (150 MHz, CDCl3): d = 161.7, 159.5, 159.1, 141.9, 126.5
(q, J = 3.8 Hz), 125.0 (q, J = 32.8 Hz), 124.4 (q, J = 269.4 Hz),
119.0, 113.4.
127.1, 122.6, 119.9, 119.1, 112.8, 21.6.
HRMS (EI): m/z calcd for C11H10BrClN3: 297.9747; found:
297.9751 (M + H).
HRMS (EI): m/z calcd for C11H8ClF3N3: 274.0353; found: 274.0349
(M + H).
2-[(3-Iodo-5-methylphenyl)amino]pyrimidin-4(3H)-one (26)
Procedure A; yield: 8.83 g (99 wt%, 27.0 mmol, 94%); light pink
solid; mp 322 °C.
4-[(4-Chloropyrimidin-2-yl)amino]benzonitrile (35)17
Procedure B; yield: 1.04 g (4.51 mmol, 89%); yellow solid; mp 211
°C.
Synthesis 2012, 44, 1109–1118
© Thieme Stuttgart · New York

PAPER
SNAr Reactions of 2-Methylthio-4-pyrimidinones in Pivalic Acid
1115
1H NMR (600 MHz, DMSO-d6): d = 10.52 (s, 1 H), 8.48 (d, J = 5.2
Hz, 1 H), 7.87 (d, J = 8.8 Hz, 2 H), 7.71 (d, J = 8.8 Hz, 2 H), 7.06
(d, J = 5.2 Hz, 1 H).
HRMS (EI): m/z calcd for C12H13BrN3O3: 326.0135; found:
326.0130 (M + H).
5-Bromo-4-chloro-N-(3,4-dimethoxyphenyl)pyrimidin-2-amine
(44)
Procedure B; yield: 1.24 g (3.60 mmol, 85%); yellow solid; mp 130
°C.
1H NMR (600 MHz, CDCl3): d = 8.35 (s, 1 H), 7.31 (s, 1 H), 7.21
(s, 1 H), 6.93 (dd, J = 8.6, 2.3 Hz, 1 H), 6.81 (d, J = 8.6 Hz, 1 H),
3.86 (s, 3 H), 3.84 (s, 3 H).
13C NMR (150 MHz, CDCl3): d = 160.5, 159.9, 158.6, 149.3, 146.0,
131.8, 112.7, 111.7, 106.7, 105.5, 56.4, 56.1.
13C NMR (150 MHz, DMSO-d6): d = 160.7, 160.7, 159.8, 144.7,
133.7, 120.0, 119.3, 113.7, 104.0.
HRMS (EI): m/z calcd for C11H8ClN4: 231.0432; found: 231.0433
(M + H).
2-[(5-Fluoro-4-methylpyridin-2-yl)amino]pyrimidin-4(3H)-one
(36)
Procedure A; yield: 1.53 g (68 wt%, 4.72 mmol, 67%); white solid;
mp 264 °C.
1H NMR (600 MHz, DMSO-d6): d = 12.67 (br s, 1 H), 11.29 (br s,
1 H), 8.22 (s, 1 H), 7.72 (d, J = 6.0 Hz, 1 H), 7.18 (d, J = 4.1 Hz, 1
H), 5.78 (d, J = 6.5 Hz, 1 H), 2.24 (s, 3 H).
HRMS (EI): m/z calcd for C12H12BrClN3O2: 343.9796; found:
343.9795 (M + H).
5-Bromo-2-[(4-chlorophenyl)amino]pyrimidin-4(3H)-one (46)
Procedure A; yield: 1.42 g (85 wt%, 4.03 mmol, 89%); yellow solid;
mp 253 °C.
HRMS (EI): m/z calcd for C10H10FN4O: 221.0833; found: 221.0833
(M + H).
4-Chloro-N-(5-fluoro-4-methylpyridin-2-yl)pyrimidin-2-amine
(37)
1H NMR (600 MHz, DMSO-d6): d = 11.39 (br s, 1 H), 9.02 (br s, 1
H), 8.02 (s, 1 H), 7.55 (d, J = 8.7 Hz, 2 H), 7.34 (d, J = 8.9 Hz, 2 H).
Procedure B; yield: 1.06 g (4.44 mmol, 97%); purified by crystalli-
zation (EtOAc–hexanes); white solid; mp 206 °C.
1H NMR (600 MHz, CDCl3): d = 9.14 (s, 1 H), 8.40 (d, J = 5.2 Hz,
1 H), 8.30 (d, J = 5.8 Hz, 1 H), 8.14 (s, 1 H), 6.84 (d, J = 5.2 Hz, 1
H), 2.38 (s, 3 H).
13C NMR (150 MHz, CDCl3): d = 161.6, 159.2, 158.8, 155.1 (d,
J = 247 Hz), 148.1 (d, J = 2.5 Hz), 133.5, 115.5 (d, J = 1.8 Hz),
113.6, 105.0, 15.4 (d, J = 2.9 Hz).
HRMS (EI): m/z calcd for C10H8BrClN3O: 299.9534; found:
299.9530 (M + H).
5-Bromo-4-chloro-N-(4-chlorophenyl)pyrimidin-2-amine (47)
Procedure B; yield: 1.70 g (5.33 mmol, 88%); white solid; mp 166
°C.
1H NMR (600 MHz, DMSO-d6): d = 10.29 (s, 1 H), 8.63 (s, 1 H),
7.64 (d, J = 8.9 Hz, 2 H), 7.31 (d, J = 8.9 Hz, 2 H).
HRMS (EI): m/z calcd for C10H9ClFN4: 239.0494; found: 239.0490
(M + H).
13C NMR (150 MHz, DMSO-d6): d = 161.4, 159.0, 158.6, 138.9,
129.1, 126.9, 121.5, 106.6.
HRMS (EI): m/z calcd for C10H7BrCl2N3: 317.9200; found:
317.9224 (M + H).
2-[(3-Bromo-8-methylquinolin-6-yl)amino]pyrimidin-4(3H)-
one (38)
Procedure A; yield: 11.2 g (95 wt%, 32.1 mmol, 99%); pink solid;
mp 299 °C.
1H NMR (600 MHz, DMSO-d6): d = 11.00 (br s, 1 H), 9.44 (br s, 1
H), 8.70 (d, J = 2.2 Hz, 1 H), 8.43 (d, J = 2.1 Hz, 1 H), 8.13 (s, 1 H),
7.83 (d, J = 6.0 Hz, 1 H), 7.64 (s, 1 H), 5.89 (d, J = 6.3 Hz, 1 H),
2.60 (s, 3 H).
2-[(3-Bromophenyl)amino]-5-iodopyrimidin-4(3H)-one (48)
To a suspension of 6 (1.0 g, 3.71 mmol) in DMF (7 mL) was added
NIS (0.92 g, 4.08 mmol). After 1 h, H2O (10 mL) containing
Na2SO3 (200 mg) was added dropwise resulting in decolorization
and the formation of a gum. The mixture was heated to 70 °C for 1
h, the resulting slurry cooled to r.t., filtered and washed with H2O
(2 × 10 mL) to afford the desired product; yield: 1.41 g (3.60 mmol,
97%); white solid; mp 244 °C.
1H NMR (600 MHz, DMSO-d6): d = 11.37 (br s, 1 H), 9.06 (br s, 1
H), 8.16 (s, 1 H), 7.91 (s, 1 H), 7.41 (d, J = 7.7 Hz, 1 H), 7.23 (t,
J = 8.0 Hz, 1 H), 7.18 (d, J = 7.8 Hz, 1 H).
HRMS (EI): m/z calcd for C14H12BrN4O: 331.0189; found:
331.0186 (M + H).
3-Bromo-N-(4-chloropyrimidin-2-yl)-8-methylquinolin-6-
amine (39)
Procedure B; yield: 1.63 g (4.66 mmol, 84%); purified by crystalli-
zation (EtOAc–hexanes); beige solid; mp 209 °C.
1H NMR (600 MHz, DMSO-d6): d = 10.34 (s, 1 H), 8.71 (d, J = 1.5
Hz, 1 H), 8.47 (d, J = 5.1 Hz, 1 H), 8.44 (d, J = 1.3 Hz, 1 H), 8.21
(s, 1 H), 7.75 (s, 1 H), 7.00 (d, J = 5.1 Hz, 1 H), 2.60 (s, 3 H).
13C NMR (150 MHz, DMSO-d6): d = 160.6, 160.2, 148.3, 142.2,
139.0, 137.6, 137.2, 130.4, 124.8, 117.9, 113.1, 111.9, 105.0, 18.4.
HRMS (EI): m/z calcd for C10H8BrIN3O: 391.8890; found:
391.8884 (M + H).
N-(3-Bromophenyl)-4-chloro-5-iodopyrimidin-2-amine (49)
Procedure B; yield: 1.30 g (3.16 mmol, 96%); white solid; mp 130
°C.
1H NMR (600 MHz, CDCl3): d = 8.57 (s, 1 H), 7.82 (d, J = 1.8 Hz,
1 H), 7.40 (dt, J = 6.8, 2.1 Hz, 1 H), 7.30 (s, 1 H), 7.22–7.14 (m, 2
HRMS (EI): m/z calcd for C14H11BrClN4: 348.9850; found:
348.9847 (M + H).
H).
13C NMR (150 MHz, CDCl3): d = 166.0, 163.7, 158.6, 139.7, 130.5,
126.7, 123.0, 122.5, 118.2, 80.4.
5-Bromo-2-[(3,4-dimethoxyphenyl)amino]pyrimidin-4(3H)-one
(43)
HRMS (EI): m/z calcd for C10H7BrClIN3: 409.8551; found:
409.8547 (M + H).
Procedure A; yield: 1.54 g (92 wt%, 4.34 mmol, 96%); grey solid;
mp 228 °C.
1H NMR (600 MHz, DMSO-d6): d = 11.24 (br s, 1 H), 8.68 (br s, 1
H), 7.95 (s, 1 H), 7.10 (d, J = 2.2 Hz, 1 H), 6.98 (dd, J = 8.6, 2.2 Hz,
1 H), 6.87 (d, J = 8.7 Hz, 1 H), 3.70 (s, 3 H), 3.69 (s, 3 H).
5-Bromo-2-[(3-bromophenyl)amino]pyrimidin-4(3H)-one (50)
To a suspension of 6 (1.0 g, 3.71 mmol) in DMF (7 mL) was added
NBS (0.727 g, 4.08 mmol). After 1 h, H2O (10 mL) containing
Na2SO3 (200 mg) was added. Additional H2O (30 mL) was added,
© Thieme Stuttgart · New York
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1116
M. L. Maddess, R. Carter
PAPER
the mixture extracted with 5% MeOH–EtOAc (2 × 30 mL), and the
combined organics were dried (MgSO4), filtered, and concentrated
in vacuo. The crude residue was taken up in i-PrOH (7 mL) and hex-
anes (21 mL) was added dropwise. After stirring for 1 h, this was
filtered and washed with hexanes (15 mL) to afford the desired
product; yield: 1.16 g (81 wt%, 2.72 mmol, 73%); white solid; mp
145 °C.
1H NMR (600 MHz, DMSO-d6): d = 11.51 (br s, 1 H), 9.12 (br s, 1
H), 8.07 (s, 1 H), 7.92 (s, 1 H), 7.41 (d, J = 7.6 Hz, 1 H), 7.23 (t,
J = 8.0 Hz, 1 H), 7.19 (d, J = 7.9 Hz, 1 H).
13C NMR (150 MHz, CDCl3): d = 163.4, 160.0, 157.9 (q, J = 36.1
Hz), 135.3, 134.0, 129.8, 120.2, 120.1 (q, J = 274.9 Hz), 107.8,
21.0.
HRMS (EI): m/z calcd for C12H10ClF3N3: 288.0515; found:
288.0513 (M + H).
2-[(4-Fluorophenyl)amino]-6-(trifluoromethyl)pyrimidin-
4(3H)-one (59)
Procedure A, using 4-fluoroaniline (1.8 equiv); yield: 1.17 g (94
wt%, 4.03 mmol, 85%); greyish blue solid; mp 236 °C.
HRMS (EI): m/z calcd for C10H8BrIN3O: 391.8890; found:
391.8884 (M + H).
1H NMR (600 MHz, DMSO-d6): d = 11.29 (s, 1 H), 9.27 (s, 1 H),
7.56 (s, 2 H), 7.15 (t, J = 8.8 Hz, 2 H), 6.24 (s, 1 H).
HRMS (EI): m/z calcd for C11H8F4N3O: 274.0604; found: 274.0608
(M + H).
5-Bromo-N-(3-bromophenyl)-4-chloropyrimidin-2-amine (51)
Procedure B; yield: 0.81 g (2.22 mmol, 86%); white solid; mp 128
°C.
1H NMR (600 MHz, CDCl3): d = 8.43 (s, 1 H), 7.82 (s, 1 H), 7.40
(d, J = 7.1 Hz, 1 H), 7.31 (s, 1 H), 7.22–7.13 (m, 2 H).
4-Chloro-N-(4-fluorophenyl)-6-(trifluoromethyl)pyrimidin-2-
amine (60)
Procedure B; yield: 0.86 g (2.95 mmol, 79%); yellow solid; mp 118
°C.
13C NMR (150 MHz, CDCl3): d = 160.5, 160.1, 157.9, 139.7, 130.5,
126.7, 123.0, 122.4, 118.1, 108.2.
1H NMR (500 MHz, CDCl3): d = 7.58–7.50 (m, 2 H), 7.35 (s, 1 H),
7.10–7.02 (m, 3 H).
HRMS (EI): m/z calcd for C10H7Br2ClN3: 361.8690; found:
361.8687 (M + H).
13C NMR (125 MHz, CDCl3): d = 163.6, 160.5, 159.2 (d, J = 166.8
Hz), 157.9 (q, J = 36.2 Hz), 133.9 (d, J = 2.8 Hz), 121.8 (d, J = 7.5
Hz), 120.1 (q, J = 275.5 Hz), 116.1 (d, J = 22.6 Hz), 108.3.
2-[(3-Bromophenyl)amino]-5-chloropyrimidin-4(3H)-one (52)
To a suspension of 6 (1.0 g, 3.71 mmol) in AcOH (7 mL) was added
NCS (0.727 g, 4.08 mmol). The mixture was heated to 90 °C for 4
h, cooled to r.t. and H2O was added (21 mL) dropwise. The slurry
was stirred for 1 h at r.t., filtered, and washed with H2O (2 × 10 mL)
to afford the desired product; yield: 0.98 g (95 wt%, 3.10 mmol,
82%); yellow solid; mp 254 °C.
1H NMR (600 MHz, DMSO-d6): d = 11.56 (br s, 1 H), 9.04 (br s, 1
H), 7.97 (s, 1 H), 7.92 (s, 1 H), 7.40 (d, J = 7.6 Hz, 1 H), 7.23 (t,
J = 8.0 Hz, 1 H), 7.19 (d, J = 7.9 Hz, 1 H).
HRMS (EI): m/z calcd for C11H7ClF4N3: 292.0265; found: 292.0294
(M + H).
6-Hydroxy-2-[(4-methylphenyl)amino]pyrimidin-4(3H)-one
(62)38
Procedure A; yield: 1.15 g (90 wt%, 4.76 mmol, 75%); white solid;
mp 268 °C.
1H NMR (600 MHz, DMSO-d6): d = 10.63 (br s, 2 H), 8.62 (s, 1 H),
7.44 (d, J = 7.8 Hz, 2 H), 7.08 (d, J = 7.7 Hz, 2 H), 4.81 (s, 1 H),
2.22 (s, 3 H).
HRMS (EI): m/z calcd for C10H8BrClN3O: 299.9539; found:
299.9551 (M + H).
HRMS (EI): m/z calcd for C11H12N3O2 218.0930; found: 218.0914
(M + H).
N-(3-Bromophenyl)-4,5-dichloropyrimidin-2-amine (53)
Procedure B; yield: 0.85 g (2.66 mmol, 89%); white solid; mp 120
°C.
1H NMR (600 MHz, CDCl3): d = 8.33 (s, 1H), 7.81 (s, 1H), 7.46–
7.33 (m, 2H), 7.22 – 7.10 (m, 2H).
13C NMR (150 MHz, CDCl3): d = 158.5, 157.8, 157.4, 139.8, 130.5,
126.6, 123.0, 122.4, 119.5, 118.0.
4,6-Dichloro-N-(4-methylphenyl)pyrimidin-2-amine (63)
Procedure B; yield: 0.86 g (2.95 mmol, 78%); white solid; mp 115
°C.
1H NMR (600 MHz, CDCl3): d = 7.41 (d, J = 8.4 Hz, 2 H), 7.30 (s,
1 H), 7.14 (d, J = 8.2 Hz, 2 H), 6.72 (s, 1 H), 2.31 (s, 3 H).
13C NMR (150 MHz, CDCl3): d = 162.0, 159.3, 135.3, 134.0, 129.8,
120.4, 111.1, 21.1.
HRMS (EI): m/z calcd for C10H7BrCl2N3: 317.9200; found:
317.9229 (M + H).
HRMS (EI): m/z calcd for C11H10Cl2N3: 254.0252; found: 254.0255
(M + H).
2-[(4-Methylphenyl)amino]-6-(trifluoromethyl)pyrimidin-
4(3H)-one (56)
N-(3-Bromo-5-methylphenyl)-4-methylpyrimidin-2-amine (66)
In a 3-necked 3 L flask equipped with an overhead stirrer, a mixture
of 64 (150 g, 1.17 mol) and 65 (239 g, 1.28 mol) in PivOH (948 mL)
was heated to an internal temperature of 130 °C. After stirring for
1.5 h, heating was discontinued and the mixture slowly cooled.
When the internal temperature had reached 70 °C, hexanes (1 L)
was added over a period of 30 min. The resulting slurry was stirred
at r.t. over the weekend, then cooled to –10 °C, and stirred for 1 h.
The mixture was filtered, washed with cold (–20 °C) hexanes (2 ×
200 mL), then dried to afford the desired product; yield: 364 g (79
wt%, 1.03 mol, 89%); brown solid. A small sample was diluted with
CH2Cl2, washed with sat. aq NaHCO3, dried (MgSO4), filtered, and
concentrated in vacuo. The resulting residue was purified by flash
chromatography to afford an analytical sample of 66; beige solid;
mp 76 °C.
Procedure A, using p-toluidine (1.8 equiv); yield: 0.91 g (99 wt%,
3.38 mmol, 71%); beige solid; mp 231 °C.
1H NMR (600 MHz, DMSO-d6): d = 11.16 (br s, 1 H), 9.06 (br s, 1
H), 7.41 (s, 2 H), 7.11 (d, J = 8.2 Hz, 2 H), 6.20 (s, 1 H), 2.23 (s, 3
H).
HRMS (EI): m/z calcd for C12H11F3N3O: 270.0854; found:
270.0866 (M + H).
4-Chloro-N-(4-methylphenyl)-6-(trifluoromethyl)pyrimidin-2-
amine (57)
Procedure B; yield: 0.85 g (2.66 mmol, 89%); yellow solid; mp 116
°C.
1H NMR (600 MHz, CDCl3): d = 7.44 (d, J = 8.4 Hz, 2 H), 7.30 (s,
1 H), 7.15 (d, J = 8.3 Hz, 2 H), 6.98 (s, 1 H), 2.32 (s, 3 H).
Synthesis 2012, 44, 1109–1118
© Thieme Stuttgart · New York

PAPER
SNAr Reactions of 2-Methylthio-4-pyrimidinones in Pivalic Acid
1117
1H NMR (600 MHz, DMSO-d6): d = 9.65 (s, 1 H), 8.32 (d, J = 5.0
Hz, 1 H), 7.94 (s, 1 H), 7.49 (s, 1 H), 6.88 (s, 1 H), 6.72 (d, J = 5.0
Hz, 1 H), 2.32 (s, 3 H), 2.21 (s, 3 H).
13C NMR (150 MHz, DMSO-d6): d = 168.2, 160.2, 158.1, 142.9,
140.6, 124.8, 122.0, 118.6, 118.5, 113.0, 24.3, 21.6.
(13) Edo, K.; Yamanaka, H.; Sakamoto, T. Heterocycles 1978, 9,
271.
(14) Delia, T. J.; Stark, D.; Glenn, S. K. J. Heterocycl. Chem.
1995, 32, 1177.
(15) Schomaker, J. M.; Delia, T. J. J. Heterocyl. Chem. 2000, 37,
1457.
(16) Peng, Z.-H.; Journet, M.; Humphrey, G. Org. Lett. 2006, 8,
395.
HRMS (EI): m/z calcd for C12H13BrN3: 278.0293; found: 278.0307
(M + H).
(17) Zeng, Z.-S.; Liang, Y.-H.; Feng, X.-Q.; Chen, F.-E.;
Pannecouque, C.; Balzarini, J.; De Clercq, E.
6-Bromo-N-(3,4-dimethoxyphenyl)imidazo[1,2-a]pyrazin-8-
amine (68)33
ChemMedChem 2010, 5, 837.
To a round-bottomed flask equipped with a large stir bar was added
67 (5 g, 18.1 mmol), 42 (3.32 g, 21.7 mmol), and PivOH (35 mL).
The resulting mixture was heated to an internal temperature of
100 °C and stirred for 1 h. Heating was discontinued, the reaction
mixture cooled to 70 °C, and a mixture of EtOH–hexanes (1:1, 70
mL) was added dropwise over 20 min. The slurry was stirred at r.t.
for 1 h, then filtered, and the resulting cake washed with EtOH–
hexanes (1:1, 35 mL). The dried solid was transferred to a round-
bottomed flask, diluted with 5% MeOH–CH2Cl2 (250 mL) and
treated with sat. aq NaHCO3 (250 mL) and stirred until both layers
were clear. The layers were separated, the aqueous portion extracted
a second time with 5% MeOH–CH2Cl2 (250 mL), and the combined
organics were dried (MgSO4), filtered, and concentrated in vacuo.
The crude residue was purified by flash chromatography to afford
the desired product; yield: 6.25 g (17.9 mmol, 99%); beige solid;
mp 165 °C. Compound 68 showed satisfactory spectroscopic data
in agreement with that reported in the literature.
(18) Bamborough, P.; Angell, R. M.; Bhamra, I.; Brown, D.;
Bull, J.; Christopher, J. A.; Cooper, A. W. J.; Fazal, L. H.;
Giordano, I.; Hind, L.; Patel, V. K.; Ranshaw, L. E.; Sims,
M. J.; Skone, P. A.; Smith, K. J.; Vickerstaff, E.;
Washington, M. Bioorg. Med. Chem. Lett. 2007, 17, 4363.
(19) Waelchi, R.; Bollbuck, B.; Bruns, C.; Buhl, T.; Eder, J.;
Feifel, R.; Hersperger, R.; Janser, P.; Revesz, L.; Zerwes, H.-
G.; Schlapbach, A. Bioorg. Med. Chem. Lett. 2006, 16, 108.
(20) Manley, P. J.; Balitza, A. E.; Bilodeau, M. T.; Coll, K. E.;
Hartman, G. D.; McFall, R. C.; Rickert, K. W.; Rodman, L.
D.; Thomas, K. A. Bioorg. Med. Chem. Lett. 2003, 13, 1673.
(21) 2-Methylthio-4-pyrimidinone may also be readily prepared
from 2-thiouracil: Barrett, H. W.; Goodman, I.; Dittmer, K.
J. Am. Chem. Soc. 1948, 70, 1753.
(22) (a) Spychala, J. Synth. Commun. 1997, 27, 1943. For a
recent report using refluxing BuOH, see: (b) Grigoryan, L.
A.; Kaldrikyan, M. A.; Melik-Ogandzhanyan, R. G.;
Arsenyan, F. G. Pharm. Chem. J. 2011, 45, 137.
(23) Conversion of thioethers into the corresponding sulfone is a
common strategy to increase reactivity of the electrophile,
but used rarely in the context of 2-methylthio-4-pyrimidi-
nones, for example, see: Gibson, C. L.; Huggan, J. K.;
Kennedy, A.; Kiefer, L.; Lee, J. H.; Suckling, C. J.;
Clements, C.; Harvey, A. L.; Hunter, W. N.; Tulloch, L. B.
Org. Biomol. Chem. 2009, 7, 1829.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.
Acknowledgment
The authors would like to thank Bridget Becker and Bruce Adams
for NMR support, and in addition Chuck Ross and Adam Beard for
HRMS analysis.
(24) For example, see example 2, page 15, of: Djung, J. F.-J.;
Golebiowski, A.; Hunter, J. A.; Shrum, G. P. US Patent
Appl. Publ. US 20070293525 A1, 2007; Chem. Abstr. 2008,
148, 79042.
(25) Feng, X.-Q.; Liang, Y.-H.; Zeng, Z.-S.; Chen, F.-E.;
Balzarini, J.; Pannecouque, C.; De Clercq, E.
References
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(26) Reactions performed on 1 mmol scale in sealed vials.
(27) Three examples have been previously reported in which
AcOH was used as a solvent for SNAr reactions of 2-
methylthio-4-pyrimidinones (see ref. 1).
(28) Pivalic acid (bp 164 °C/760 Torr) offers the additional
advantage of a wider convenient temperature operating
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(29) Methanethiol is generated during the course of the reaction;
a nitrogen sweep is recommended especially on large scale
with the outlet bubbled through a bleach scrubber.
(30) Efficient stirring is recommended and should it become
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M. L. Maddess, R. Carter
PAPER
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Synthesis 2012, 44, 1109–1118
© Thieme Stuttgart · New York