An efficient one-pot construction of substituted pyrimidinones

Article abstract of DOI:10.1016/j.tet.2006.09.047

A concise, scaleable synthesis of building block 10 for p38 kinase inhibitor B is described. The key step is the one-pot construction of 5-aryl-3-methyl-2-methylsulfanyl-6-pyridin-4-yl-3H-pyrimidin-4-one 4 from arylacetic acid ethyl ester 1. Subsequent hy

Full text of DOI:10.1016/j.tet.2006.09.047

Tetrahedron 62 (2006) 11714–11723
An efficient one-pot construction of substituted pyrimidinones
a
c
a
a
Yuelie Lu,a, Tingjian Xiang, Michael D. Bartberger, Charles Bernard, Tracy Bostick,
*
Liang Huang,a Longbin Liu,b Aaron Siegmund,b Gregory Sukay,a Gary Guo,d Maria Silva Elipe,d
Wanda Tormos,a Celia Dominguez,b Kevin Koch,e, Laurence E. Burgess, Thomas C. Basil,
e
e
*
Prabha Ibrahime and Conrad Hummele
aChemical Process Research and Development, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320-1799, USA
bChemical Research and Discovery, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320-1799, USA
cMolecular Structure and Design, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320-1799, USA
dAnalytical Chemistry, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320-1799, USA
eArray BioPharma Inc., Boulder, CO 80301, USA
Received 2 June 2006; revised 11 September 2006; accepted 13 September 2006
Available online 17 October 2006
Abstract—A concise, scaleable synthesis of building block 10 for p38 kinase inhibitor B is described. The key step is the one-pot construction
of 5-aryl-3-methyl-2-methylsulfanyl-6-pyridin-4-yl-3H-pyrimidin-4-one 4 from arylacetic acid ethyl ester 1. Subsequent hydrolysis of
the thiomethyl group to the hydroxy group and chlorination provided the key intermediate, 2-chloro-3-methyl-6-pyridin-4-yl-5-aryl-3H-
pyrimidin-4-one 10. This class of reactive building blocks enabled the rapid evaluation of a variety of side chains at the 2-position of the
pyrimidinone in SAR studies of inhibitors of p38 MAP kinase.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
reactive intermediate was desired. The resulting process
was ultimately used to prepare large quantities of particular
leads for preclinical studies.
Inhibition of p38 MAP kinase (p38a) has been proposed
as a disease-modifying approach toward the treatment of
inflammatory disorders.1–8 The vicinal aryl/pyridinyl hetero-
cycles A are the most widely studied early p38 inhibitors.2,3
Drug discovery efforts at Amgen have identified a variety of
aryl/pyridyl pyrimidinones B (Fig. 1) as potent and selective
inhibitors of p38a kinase. They can be generated via nucleo-
philic displacement of a leaving group at the 2-position by
amines (Scheme 1). In order to facilitate the exploration of
a broad array of substituents at the 2-position of this hetero-
cycle, a concise, scaleable process leading to a suitably
O
N
O
Ar
Ar
N
+
NHRR'
N
Py
2
LG
Py
N
NRR'
B
Scheme 1.
Early exploratory efforts involving ring formation of 5,6-
disubstituted-2-thiomethyl-pyrimidin-4-one 4 via conden-
sation of a b-keto-ester and thiourea are summarized in
Scheme 2. In this process, commercially available ethyl
2-(3-methylphenyl) acetate 1 was reacted with ethyl isonico-
tinate using NaH as a base to yield ethyl a-phenyl-b-oxo-
4-pyridinepropanoate 2 after column chromatography.9
When the b-ketoester 2 was treated with thiourea at 140 ꢀC
(melt) in the presence of a catalytic amount of pyridinium
p-toluenesulfonate, thiouracil 3 was isolated, but only in
low yield (<20%). The crude product also required repeated
recrystallization. Subsequent bis-methylation resulted in
2-thiomethyl-pyrimidin-4-one 4 along with a variety of by-
products, including S-monomethyl and O,S-dimethyl deriva-
tives, which were removed by column chromatography. Due
O
Ar
CH3
N
heterocycle
N
NRR'
N
N
A
B
Figure 1.
Keywords: Pyrimidinone; Methylisothiocyanate cyclization; Chlorination;
Nucleophilic displacement; Inhibitors of p38 MAP kinase.
* Corresponding authors. Tel.: +1 805 447 4691; fax: +1 805 480 1346
(Y.L.); tel.: +1 303 381 6600 (K.K.); e-mail addresses: yueliel@amgen.
com; kevin.koch@arraybiopharma.com
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.09.047

Y. Lu et al. / Tetrahedron 62 (2006) 11714–11723
11715
HS
O
CO2Et
O
NH
H2N
PPTS (cat.), 140°C
NaH, THF
+
OEt
OH
N
O
N
1
2
O
O
N
NaH, MeI, DMF
NH
SH
N
+
by-products
N
SMe
N
N
4
3
Scheme 2. Early route to 2-thiomethyl-pyrimidin-4-one.
to these issues, an alternative approach for construction of the
pyrimidinethione ring was investigated.
or sodium counterion also failed to provide any carbon–car-
bon bond formation. We envisaged that the use of a potassium
counterion might render the enolate more reactive.16 Indeed,
it was found that the potassium enolate of m-tolyl-acetic acid
ethyl ester 1, prepared with potassium tert-butoxide, reacted
with 4-cyanopyridine in DMF at room temperature to pro-
vide the corresponding 3-amino-2-alkenolate 5 along with
a by-product, characterized as bis-pyridyl pyrimidinone 6
(Scheme 4). Although 6 was isolated in only 10% yield,
this served to demonstrate the potential of this reaction
sequence to construct the desired heterocyclic ring system
in a stepwise, one-pot fashion.
The preparation of 4-pyrimidinethiones and related com-
pounds from enamines and acryl/aryl isothiocyanates has
been extensively investigated.10–14 Of particular relevance
to our target is the report of Hassan and co-workers14 describ-
ing the synthesis of a 2-thiouracil from 2-amino-nicotinate
and phenyl isothiocyanate. This encouraged us to utilize
the reactivity of 3-amino-2-alkenoates toward methyl iso-
thiocyanate (Scheme 3).
O
Ar
Py
H2N
Subsequent experiments produced some interesting observa-
tions: (i) the nitrile addition appeared to be faster and cleaner
when t-BuOK in t-BuOH was used as opposed to t-BuOK in
THF and (ii) use of KH in DMF or THF did not result in any
of the desired alkenoate 5, even though the dark purple color
of the KH–ester mixture was indicative of enolate anion
formation. It is likely that t-BuOH serves to either directly
protonate the incipient, nitrogen-centered anion generated
during attack of enolate 1 upon the nitrile substrate, or to
facilitate subsequent tautomerization to the more stable 5b.
B3LYP/6-31G* calculations fail to locate a non-tautomer-
ized minimum corresponding to 5a in the gas phase; its ex-
istence in solution is likely to be disfavored as well. In the
presence of protic solvents, formation of 5b is facilitated,
whereas in non-protic media, addition of 1 to the nitrile is
disfavored (Scheme 5).
Ar
N
+
X=C=NCH3
(X=O or S)
COOEt
Py
N
SMe
4
Scheme 3. Alternative approach to 2-thiomethyl-pyrimidin-4-one.
2. Results and discussion
2.1. Addition of alkanoate potassium enolates to nitriles
It has been reported that magnesium ester enolates can react
with nitriles to provide (Z)-3-amino-2-alkenolates in moder-
ate to good yields.15 Although nitriles are usually considered
to be inert to enolates, some pyridyl-derived analogs were
found to be reactive. Our first attempt to generate the magne-
sium enolate of ethyl 2-(3-methylphenyl) acetate 1 with mag-
nesium amide, as reported by Hiyama,15 in the presence of
4-cyanopyridine was unsuccessful. Presumably, Mg(NH2)2
is not of sufficient basicity to deprotonate the a-position of
1. In accordance with Hiyama’s results,15 the use of a lithium
A loose correlation is observed between nitrile electrophilic-
ity (as gauged by LUMO energy at the RHF/6-31G* level)
and both the calculated exothermicity of the model enolate
addition, as well as final yield of ‘one pot’ cyclization/
quenching product 4 (Table 1).
O
O
N
CN
O
NH
tBuOK/tBuOH, DMF, rt
OEt
NH2
OK
+
OEt
N
OEt
N
N
N
6 (10%)
5 (20%)
1
Scheme 4. Formation of 3-amino-2-alkenoate.

11716
Y. Lu et al. / Tetrahedron 62 (2006) 11714–11723
OEt
OEt
1) tBuOK/solvent, DMF, rt
2) 4-cyanopyridine/DMF
O
facilitated by
O
O
polar solvents
OEt
N
NH
N
N
5b
1
5a
disfavored
stable tautomer
Scheme 5. Addition of potassium ester enolates to nitriles.
Table 1. Computed electrophilicities and relative reactivities of aryl nitrile substrates
O
N
OCH3
O
O
MeNCS
MeI
+
Ar
C N
OCH3
N
Ar
SCH3
Ar
NH
1
2
5
4
2
Erxn (1+2/5)a,b
ꢁ9.9 (0.0)
E(LUMO), 2c
% Yield, 4d
N
N
C
C
+0.08353
0
N
ꢁ11.8 (L1.9)
ꢁ14.6 (L4.7)
ꢁ16.6 (L6.7)
+0.06960
+0.07126
+0.05903
0
N
C
30
N
N
C
50ꢁ60
N
O
N
C
ꢁ19.1 (L9.2)
+0.03844
40
N
a
b
c
d
Absolute (relative in bold) energies of reaction (kcal/mol) at the B3LYP/6-31G*+ZPE level.
All calculations performed with the Gaussian 9817 program system.
a.u., RHF/6-31G*//B3LYP/6-31G*.
From Table 2.
2.2. Quenching of the amino alkenoate anion by
electrophiles
This one-pot process, consisting of enolate/nitrile addition,
isothiocyanate addition/cyclization, and S-methylation, pro-
duced the desired 2-thiomethyl-pyrimidin-4-one 4, for which
an early medicinal chemistry route had required in three steps
(Scheme 2). In addition to the simplification of the procedure,
the overall yield increased by more than 10-fold. These
conditions require only 1 equiv each of t-BuOK, the nitrile,
methyl isothiocyanate, and iodomethane in relation to the
starting ester. The convenient temperature range of this
reaction (ꢁ5 to 25 ꢀC) is another attractive feature, enabling
successful scale-up to a multi-kilogram quantity.
With the chemistry leading to amino alkenoate anion 5
established, efforts were undertaken to trap and cyclize this
intermediate into the uracil- or thiouracil-like pyrimidinone
in a single step. Early attempts to quench 5 with methyl iso-
cyanate resulted in the formation of uracil 7 and bis-pyridyl
pyrimidinone 6 as 1:1 mixture based on HPLC area ratio
(Scheme 6).
In contrast, quenching 5 with methyl isothiocyanate in DMF
at room temperature afforded the corresponding thiouracil
8 in good conversion (w95%) (Scheme 6). Furthermore,
sequential addition of methyl isothiocyanate to 5, followed
by iodomethane, provided the desired 2-thiomethyl-pyrimi-
din-4-one 4 in 50% overall yield. Conveniently, the product
4 could be precipitated as an off-white solid by simple addi-
tion of an equal volume of water to the DMF and stirring at
ꢁ5 to 0 ꢀC for 48 h (Scheme 7).
2.3. The scope and limitation of the one-pot construction
When ethyl 2-(4-fluorophenyl) acetate was used as starting
material, a complex mixture along with 4-cyanopyridine
was obtained instead of the corresponding sulfide, possibly
arising from defluorination of the aryl ring upon generation
of the enolate. Therefore, the one-pot process was modified
to avoid potential decomposition or self-condensation of the

Y. Lu et al. / Tetrahedron 62 (2006) 11714–11723
11717
O
N
O
N
NH
+
N
OH
N
N
3) MeNCO/DMF, rt
N
6
7
OEt
1) tBuOK/tBuOH, DMF, rt
2) 4-cyanopyridine/DMF
O
O
OEt
NH
N
O
3) MeNCS/DMF, rt
1
N
5
N
SH
N
8
Scheme 6. Quenching of 3-amino-2-alkenoate.
O
OEt
O
1) tBuOK/tBuOH, DMF, rt
N
3) MeNCS/DMF, rt
O
2) 4-cyanopyridine/DMF
OEt
N
S
NH
N
N
1
5
8
O
N
4) MeI, 0°C to rt
5) H2O, -5 to 0°C, 48h
N
SMe
N
4
Scheme 7. The one-pot reaction.
alkenoate anion. In the improved procedure, t-BuOK/
t-BuOH was added to the premixed DMF solution of the
ester and 4-cyanopyridine, allowing for immediate addition
with the nitrile substrate upon enolate generation. The rest of
reaction sequence remains same (Scheme 8).
(E)-5 due in part to intramolecular hydrogen bonding and
p-stacking of the aromatic rings and 7.5 kcal/mol lower in
energy than its imine tautomer. The prediction of (Z)-5 as
the exclusive neutral species present upon protonation of
the anion of 5 was subsequently confirmed on the basis of
NOE experiments (see Section 3.6).
This one-pot reaction has been used to generate the 2-thio-
methyl-pyrimidin-4-ones 4 as reported in Table 2.
2.4. Conversion of the sulfide-pyrimidinones to the more
reactive chloro-pyrimidinones
Contrary to when generated in situ, aminoalkenoate 5,
isolated after work-up, reacted poorly with alkyl nitriles in
the presence of base or acid over a wide temperature range
(rt–120 ꢀC).18 Neutral enamine 5 could potentially exist as
either (E) or (Z)-isomers; B3LYP/6-31G* calculations pre-
dict (Z)-5 (Fig. 2) to be 6.1 kcal/mol lower in energy than
The thiomethyl moiety could, in principle, be used as a
leaving group to introduce amines at the 2-position. How-
ever, we found that this displacement required harsh con-
ditions (neat, high temperature, and sealed vessel), which
were not practical for scale-up. As the displacement of
R
O
1) DMF, 1.0 eq. tBuOK/tBuOH, rt
2) 1.0 eq. MeNCS/DMF, rt
R
CN
O
N
+
3) 1.0 eq. CH3I, 0°C
N
O
N
S
4) H2O, 0°C to rt, 16h
N
4
Scheme 8. The modified one-pot process.

11718
Y. Lu et al. / Tetrahedron 62 (2006) 11714–11723
Table 2. Syntheses of 2-thiomethyl-pyrimidin-4-ones 4 via Scheme 8
Entry Ester Nitrile
Product
Yield (%)
O
O
N
N
1
51
CN
CN
N
N
N
OEt
O
SCH3
N
4a
Cl
O
Cl
N
2
3
51
50
N
4b
O
SCH3
OEt
N
F
F
N
O
CN
CN
N
SCH3
OEt
N
4c
CF3
O
N
CF3
N
N
N
O
O
4
50
SCH3
Cl
OEt
N
Cl
4d
CH3
O
N
CN
N
5
50
SCH3
OEt
Cl
N
Cl
Cl
4e
Cl
O
Cl
Cl
N
O
6
7
8
9
65
63
40
60
CN
CN
CN
CN
N
N
SCH3
OEt
N
4f
O
N
N
N
O
O
N
SCH3
SCH3
OEt
OEt
N
4g
O
N
O
N
N
O
4h
Cl
O
N
Cl
N
O
N
SCH3
OEt
N
4i
(continued)

Y. Lu et al. / Tetrahedron 62 (2006) 11714–11723
11719
Table 2. (continued)
Entry
Ester
Nitrile
Product
Yield (%)
Cl
O
N
Cl
N
O
10
11
60
CN
CN
N
N
SCH3
OEt
N
4j
Cl
F
O
Cl
F
N
O
66
N
SCH3
OEt
N
4k
CF3
O
N
CF3
N
CN
N
O
12
25
SCH3
N
OEt
4l
O
N
N
CN
CN
O
O
13
30
N
N
SCH3
OEt
OEt
N
4m
O
14
0
N
N
SCH3
N
4n
O
N
O
15
CN
0
N
SCH3
OEt
4o
9
3
of the pH of the reaction solution to 6–7 precipitated the
desired hydroxypyrimidinones 9 (Scheme 9).
9
6
12
O
6
1
12
O
1
2
5
4
5
4
13
13
11
7
2
7
Standard procedures were applied for the conversion of ura-
cil 9 into the chloropyrimidinone 10, utilizing either PCl5,
SOCl2, or POCl3.20 The use of neat POCl3 as solvent under
reflux conditions afforded the best results (Scheme 9). After
chromatographic purification, the chloride 10 was used as
a reactive intermediate to introduce a variety of amines via
nucleophilic displacement under mild conditions. An exam-
ple is shown in Scheme 10.
8
8
O
14
14
O
3
11
21
17
16
20
18
10
10
NH2
H2N
16
15
15
19N
N19
21
17
20
18
(Z)-5 (exclusive species)
(E)-5 (not observed)
Figure 2.
chloro-pyrimidines with amino nucleophiles has been re-
ported to proceed under mild conditions,19 the 2-thiomethyl
moiety was converted to the more reactive corresponding 2-
chloro derivative. First, hydrolysis of the sulfide was readily
accomplished with aqueous sodium hydroxide in an organic
solvent system (e.g., dioxane or THF/MeOH). Adjustment
In summary, a concise, scaleable synthesis of 10, a building
block for p38 kinase inhibitors, has been realized. This new
route represents a significant improvement over the initial
medicinal chemistry route. The key step is the one-pot con-
struction of 5-aryl-3-methyl-2-methylsulfanyl-6-pyridin-4-

11720
Y. Lu et al. / Tetrahedron 62 (2006) 11714–11723
R
N
R
R
N
O
N
O
O
N
1) NaOH, 1,4-Dioxane, 80°C
POCl3, reflux
N
N
N
2) HCl, 0°C
SCH3
94%
85%
N
OH
Cl
N
4
9
10
Scheme 9. Conversion of the sulfide-pyrimidinone 4 to chloro-pyrimidinone 10.
R
R
O
N
O
DCM, K2CO3, rt
H2N
N
+
N
N
H
N
Cl
N
N
10
11
Scheme 10. Nucleophilic displacement of chloro-pyrimidinone 10 with amine.
yl-3H-pyrimidin-4-one 4 from aryl acetic acid ethyl ester 1
and 4-cyanopyridine via enolate/nitrile nucleophilic conden-
sation, isothiocyanate additon/cyclization, and subsequent
S-methylation using equimolar amounts of all reactants.
The convenient temperature range of this process (ꢁ5 ꢀC to
rt) and ease of isolation offer additional advantages. Subse-
quent hydrolysis of the thiomethyl group to the hydroxyl
group, followed by chlorination provided the key intermedi-
ate, 2-chloro-3-methyl-6-pyridin-4-yl-5-aryl-3H-pyrimidin-
4-one 10. This class of reactive building blocks enabled
the exploration of a variety of side chains at the 2-position
of the pyrimidinone in an effort to optimize potency and
in vivo efficacy.
(1.0 M in t-BuOH, 7 L, 7.0 mol). The resultant dark-red
solution was stirred at room temperature for 1.5 h. A DMF
solution of methyl isothiocyanate (8.4 mol dissolved in
614 mL DMF) was added to the dark-red solution at such
a rate that the internal temperature was maintained below
25 ꢀC. After the addition was complete, the mixture was
stirred at room temperature for 1 h. The solution was cooled
to 0 ꢀC, and methyl iodide (7.0 mol) was added at such a rate
that temperature remained below 5 ꢀC. The reaction mixture
was stirred for 1 h at room temperature, and then cooled to
0 ꢀC. Deionized water (21.5 L) was added at such a rate
that internal temperature was maintained below 10 ꢀC. The
resulting suspension was stirred at room temperature for
16 h. The solid was filtered off via an Aurora filter. The
wet cake was washed with water (3ꢂ3 L) and dried in an
oven under vacuum at 70 ꢀC to provide the desired pyrimi-
dinones.
3. Experimental
3.1. General
4a: 1H NMR (400 MHz, CDCl3) d 2.28 (s, 3H), 2.66 (s, 3H),
3.61 (s, 3H), 6.9 (d, J¼7.5 Hz, 1H), 7.03 (s, 1H), 7.08 (d,
J¼7.5 Hz, 1H), 7.15 (t, J¼7.5 Hz, 1H), 7.23 (d, J¼6 Hz,
2H), 8.46 (d, J¼6 Hz, 2H); 13C NMR (100 MHz, CDCl3)
d 15.0, 21.3, 30.8, 120.8, 123.8, 127.7, 128.2, 128.7, 131.1,
133.1, 137.8, 145.9, 149.4, 154.0, 161.0, 162.3. FTIR
(KBr) nmax 1659, 1596, 1571, 1540, 1525, 1409, 1367,
.
HRMS (ESI) m/e (M+H) calcd for C18H17N3OS 323.1092,
found 323.1079.
Solvents and reagents were obtained from commercial sour-
ces and used as received. Proton and carbon NMR spectra
were obtained using a Bruker Avance II 400 MHz spectro-
meter. The signals are reported in parts per million relative to
TMS using CDCl3 as a solvent (unless otherwise indicated).
The chemical shifts are reported in parts per million (ppm, d).
The coupling constants are reported in Hertz (Hz) using the
following abbreviations: s¼singlet, d¼doublet, t¼triplet,
q¼quartet, and m¼multiplet. High-resolution mass spectra
(HRMS) were acquired on a 7 Tesla Bruker Apex IV Four-
ier-Transform Mass Spectrometer (FTMS) using ESI ioniza-
tion modes. FTIR spectra were obtained using a Nicolet 410
FT-IR spectrophotometer. Mercaptan safety studies were
performed by the Wisconsin Occupational Health Lab of
Madison, Wisconsin. Column chromatography was per-
formed using silica gel 60-200 from EM Science. High-
pressure liquid chromatography (HPLC) was performed
with an Agilent 1100 series.
1347, 1310, 1188, 1165, 1099, 1088, and 1068 cmꢁ1
4b: 1H NMR (400 MHz, CDCl3) d 2.66 (s, 3H), 3.61 (s, 3H),
7.12 (d, J¼5.33 Hz, 2H), 7.22 (d, J¼3.82 Hz, 2H), 7.26 (d,
J¼5.33 Hz, 2H), 8.50 (d, J¼3.82 Hz, 2H); 13C NMR
(100 MHz, CDCl3) d 15.1, 30.9, 119.4, 123.9, 128.6,
131.8, 132.2, 134.0, 145.7, 149.7, 154.6, 161.8, 162.1.
HRMS (ESI) m/e (M+H) calcd for C17H14ClN3OS
344.0624, found 344.0618.
4c: 1H NMR (400 MHz, CDCl3) d 2.66 (s, 3H), 3.61 (s, 3H),
6.98 (d, J¼8.61 Hz, 2H), 7.15 (d, J¼8.61 Hz, 2H), 7.22 (d,
J¼5.87 Hz, 2H), 8.49 (d, J¼5.87 Hz, 2H); 13C NMR
(100 MHz, CDCl3) d 15.0, 30.9, 115.6, 119.6, 123.9, 129.2,
132.6, 145.8, 149.6, 154.5, 161.2, 162.3, 163.6. HRMS
(ESI) m/e (M+H) calcd for C17H14FN3OS 328.09144, found
328.09166.
3.2. General procedure for the preparation of 5-aryl-3-
methyl-2-methylsulfanyl-6-pyridin-4-yl-3H-pyrimidin-
4-one (4)
To a solution of the ester (6.9 mol) and 4-cyanopyridine
(7.0 mol) in DMF (15 L) was slowly added t-BuOK

Y. Lu et al. / Tetrahedron 62 (2006) 11714–11723
11721
4d: 1H NMR (400 MHz, CDCl3) d 2.67 (s, 3H), 3.63 (s, 3H),
6.96 (dd, J¼5.28, 1.37 Hz, 1H), 7.33 (d, J¼8.22 Hz, 1H),
7.35 (s, 1H), 7.43 (t, J¼8.22 Hz, 1H), 7.49 (s, 1H), 7.57 (d,
J¼7.63 Hz, 1H), 8.21 (d, J¼5.28 Hz, 1H); 13C NMR
(100 MHz, CDCl3) d 15.2, 31.0, 119.5, 122.5, 124.5, 125.2,
127.7, 129.0, 130.8, 131.1, 133.8, 134.2, 148.5, 149.3,
151.7, 153.7, 161.7, 162.7. HRMS (ESI) m/e (M+H) calcd
for C18H13ClF3N3OS 412.01927, found 412.04932.
31.0, 116.7, 118.4, 121.2, 123.8, 130.4, 130.8, 133.0,
145.5, 149.8, 154.9, 156.5, 159.0, 162.2. HRMS (ESI) m/e
(M+H) calcd for C17H13ClFN3OS 362.0530, found
362.0522.
4l: 1H NMR (400 MHz, CDCl3) d 2.66 (s, 3H), 3.62 (s, 3H),
6.95 (dd, J¼5.2, 1.24 Hz, 1H), 7.23 (dd, J¼3.8, 1.88 Hz,
2H), 7.33 (d, J¼5.17 Hz, 1H), 7.37 (d, J¼1.22 Hz, 1H),
8.53 (d, J¼3.7 Hz, 2H); 13C NMR (100 MHz, CDCl3)
d 15.1, 31.0, 120.7, 121.4, 122.4, 124.4, 125.4, 126.9,
127.3, 128.3, 130.0, 130.4, 133.4, 133.9, 144.2, 148.4,
149.6, 154.9, 156.5, 161.7, 162.2. HRMS (ESI) m/e
(M+H) calcd for C22H16F3N3OS 428.1044, found 428.1047.
4e: 1H NMR (400 MHz, CDCl3) d 2.30 (s, 3H), 2.66 (s, 3H),
3.61 (s, 3H), 6.90 (d, J¼7.43 Hz, 1H), 7.01 (m, 2H), 7.12 (d,
J¼7.63 Hz, 1H), 7.19 (t, J¼7.63 Hz, 1H), 7.41 (s, 1H), 8.18
(d, J¼5.09 Hz, 1H); 13C NMR (100 MHz, CDCl3) d 14.1,
20.4, 29.9, 120.3, 121.8, 123.5, 126.7, 127.5, 128.1, 130.1,
131.7, 137.2, 148.0, 148.1, 150.4, 151.7, 160.5, 161.2.
HRMS (ESI) m/e (M+H) calcd for C18H16ClN3OS
358.0781, found 358.0785.
4m: 1H NMR (400 MHz, CDCl3) d 2.27 (s, 3H), 2.66 (s, 3H),
3.61 (s, 3H), 6.9 (d, J¼7.5 Hz, 2H), 6.92 (d, J¼4.70 Hz, 1H),
7.06–7.15 (m, 4H), 7.55 (t, J¼4.70 Hz, 1H), 8.45 (d, J¼3 Hz,
1H), 8.70 (s, 1H); 13C NMR (100 MHz, CDCl3) d 15.0, 21.4,
30.8, 120.4, 122.4, 127.9, 128.3, 128.7, 131.4, 133.5, 134.1,
137.0, 138.0, 149.4, 150.8, 154.0, 161.0, 162.4. HRMS (ESI)
m/e (M+H) calcd for C18H17N3OS 324.1170, found
324.1171.
4f: 1H NMR (400 MHz, CDCl3) d 2.66 (s, 3H), 3.61 (s, 3H),
6.95 (dd, J¼5.2, 1.24 Hz, 1H), 7.23 (dd, J¼6.06, 1.57 Hz,
2H), 7.33 (d, J¼8.41 Hz, 1H), 7.37 (d, J¼1.76 Hz, 1H),
8.54 (dd, J¼6.26, 1.57 Hz, 2H); 13C NMR (100 MHz,
CDCl3) d 15.1, 31.0, 118.2, 123.8, 130.2, 130.3, 132.2,
132.5, 132.7, 133.4, 145.3, 149.8, 155.0, 161.8, 162.4.
HRMS (ESI) m/e (M+H) calcd for C17H13Cl2N3OS
378.02291, found 378.02324.
3.3. General procedure for the preparation of 5-aryl-2-
hydroxy-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one
(9)
4g: 1H NMR (400 MHz, CDCl3) d 2.69 (s, 3H), 3.67 (s, 3H),
7.25 (m, 3H), 7.48 (m, 2H), 7.77 (m, 4H), 8.45 (d, J¼7.24 Hz,
2H); 13C NMR (100 MHz, CDCl3) d 15.5, 31.4, 120.9, 124.4,
126.5, 126.8, 127.9, 128.1, 128.2, 128.3, 128.6, 128.8, 130.6,
131.2, 133.2, 133.6, 146.4, 149.9, 154.9, 161.8, 162.8.
HRMS (ESI) m/e (M+H) calcd for C21H17N3OS
360.11651, found 360.11635.
To a solution of the sulfide (1.32 mol) in 1,4-dioxane
(1.05 L) was added 2 N NaOH (6.6 mol, 5 equiv). The solu-
tion was heated to 80 ꢀC and allowed to stir overnight under
N2. Upon complete conversion, the reaction mixture was
cooled to 0 ꢀC. HCl 1 N (6.1 L) was added slowly until the
pH reached 7. The product was then collected on a fritted
glass funnel, and washed three times with copious amount
of water. The solid was then dried at 80 ꢀC in vacuo to pro-
vide the product as a white solid (94%). This product is of
suitable purity to be taken directly to the next step; however,
a cleaner reaction profile was obtained if the crude product
was further dried via azeotropic distillation with toluene.
4h: 1H NMR (400 MHz, CDCl3) d 2.69 (s, 3H), 3.64 (s, 3H),
7.25 (m, 5H), 7.48 (m, 2H), 7.75 (m, 2H), 7.83 (m, 2H), 7.93
(d, J¼7.24 Hz, 2H); 13C NMR (100 MHz, CDCl3) d 15.2,
31.0, 120.1, 126.4, 126.7, 126.8, 127.7, 128.0, 128.2,
128.5, 130.1, 130.6, 132.9, 133.3, 135.7, 138.6, 152.1,
161.6, 162.3. HRMS (ESI) m/e (M+H) calcd for
C21H17N3O2S 376.1119, found 376.1116.
9a (R¼m-CH3): 1H NMR (400 MHz, CDCl3) d 2.16 (s, 3H),
3.23 (s, 3H), 6.76 (d, J¼7.5 Hz, 1H), 6.9 (s, 1H), 6.98 (d,
J¼7.5 Hz, 1H), 7.04 (t, J¼7.5 Hz, 1H), 7.2 (d, J¼6.0 Hz,
2H), 8.48 (d, J¼6.0 Hz, 2H), 11.5 (s, 1H); 13C NMR
(100 MHz, CDCl3) d 20.9, 27.2, 111.8, 120.7, 123.7, 127.6,
128.5, 132.0, 132.7, 136.6, 140.3, 146.0, 149.5, 150.8,
162.8. FTIR (KBr) nmax 3056, 3041, 2917, 2776, 1720,
4i: 1H NMR (400 MHz, CDCl3) d 2.66 (s, 3H), 3.61 (s, 3H),
7.00 (d, J¼8.02 Hz, 1H), 7.17–7.19 (m, 1H), 7.22 (dd,
J¼6.26, 1.57 Hz, 2H), 7.25–7.27 (m, 2H), 8.50 (d,
J¼6.06 Hz, 2H); 13C NMR (100 MHz, CDCl3) d 15.1,
30.9, 119.3, 123.8, 129.1, 130.8, 134.2, 135.2, 145.5,
149.7, 154.8, 161.9, 162.0. HRMS (ESI) m/e (M+H) calcd
for C17H14ClN3OS 344.0624, found 344.0622.
1652, 1602, 1450, 1420, 1297, 1228, 1072, and 1004 cmꢁ1
.
Anal. Calcd for C17H15N3O2: C, 69.61; H, 5.15; N, 14.33.
Found: C, 69.50; H, 5.18; N, 14.45.
4j: 1H NMR (400 MHz, CDCl3) d 2.68 (s, 3H), 3.63 (s, 3H),
7.08 (dd, J¼7.63, 1.57 Hz, 1H), 7.17–7.29 (m, 4H), 7.41 (d,
J¼7.24 Hz, 1H), 8.48 (d, J¼5.87 Hz, 2H); 13C NMR
(100 MHz, CDCl3) d 15.1, 30.9, 118.8, 123.1, 127.1,
129.7, 129.8, 132.2, 133.0, 134.7, 145.5, 149.6, 155.3,
161.4, 162.4. HRMS (ESI) m/e (M+H) calcd for
C17H14ClN3OS 344.0624, found 344.0615.
3.4. General procedure for the preparation of 5-aryl-2-
chloro-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one
(10)
A three-necked, 2-L round-bottomed flask equipped with
a mechanical stirrer, a reflux condenser, temperature probe,
and gas inlet/exit was charged with the hydroxide (2 mol)
and then POCl3 (70 mol, 35 equiv). The suspension was
heated to reflux and a solution was obtained within
10 min. The reaction was allowed to proceed for 16 h at re-
flux, and the excess POCl3 was distilled under low pressure.
The resulting dark residue was allowed to cool to ꢁ5 to 0 ꢀC
4k: 1H NMR (400 MHz, CDCl3) d 2.66 (s, 3H), 3.62 (s, 3H),
6.95 (m, 1H), 7.03 (t, J¼8.60 Hz, 1H), 7.23 (dd, J¼6.06,
1.57 Hz, 2H), 7.32 (dd, J¼7.04, 2.15 Hz, 1H), 8.53 (d,
J¼6.06 Hz, 2H); 13C NMR (100 MHz, CDCl3) d 15.1,

11722
Y. Lu et al. / Tetrahedron 62 (2006) 11714–11723
and a mixture of dichloromethane/ice water was added.
Saturated aqueous NaHCO3 was added dropwise into the
cooled DCM/water solution with aggressive agitation. The
basic quenching was completed once the pH reached 6–7.
The phases were separated and the organic layer was
washed with a 10% aq solution of NaHCO3 followed by
water, and allowed to dry over Na2SO4. The crude chloride
was isolated after removal of solvent and purified by chro-
matography with ethyl acetate/hexanes to give the pure chlo-
ride (85%).
bond correlation (HMBC) spectra were determined using
gradient pulses for coherence selection. The HSQC spec-
trum was determined with decoupling during acquisition.
Delays corresponding to one bond 13C–1H coupling (ca.
145 Hz) for the low-pass filter and the 2–3 bond 13C–1H
long-range coupling (7.7 Hz) were used for the HMBC.
3.6.1. (Z)-3-Amino-3-pyridin-4-yl-2-m-tolyl-acrylic acid
ethyl ester ((Z)-5). H NMR (600 MHz, DMSO-d6) d 1.09
1
(t, J¼7.1 Hz, 3H, H-14), 2.09 (s, 3H, H-9), 4.04
(q, J¼7.1 Hz, 2H, H-13), 6.71 (d, J¼7.6 Hz, 1H, H-3), 6.74
(s, 1H, H-5), 6.79 (d, J¼7.6 Hz, 1H, H-1), 6.91 (t,
J¼7.6 Hz, 1H, H-2), 7.07 (d, J¼6.1 Hz, 2H, H-17, 21),
7.77 (d, J¼6.1 Hz, 1H, H-15), 8.38 (d, J¼6.1 Hz, 2H, H-
18, 20), 8.71 (d, J¼6.1 Hz, 1H, H-15); 13C NMR
(150 MHz, DMSO-d6) d 14.5 (C-14), 20.9 (C-9), 58.7 (C-
13), 97.1 (C-7), 123.5 (C-17, 21), 126.2 (C-1), 127.0 (C-2),
129.8 (C-3), 133.4 (C-5), 135.9 (C-4), 137.0 (C-6), 145.5
(C-16), 149.1 (C-18, 20), 150.3 (C-10), 169.0 (C-8).
10a (R¼m-CH3): 1H NMR (400 MHz, CDCl3) d 3.74 (s, 3H),
3.76 (s, 3H), 6.91 (d, J¼7.5 Hz, 1H), 7.02 (s, 1H), 7.16 (m,
4H), 8.48 (d, J¼6.0 Hz, 2H); 13C NMR (100 MHz, CDCl3)
d 21.3, 33.9, 123.5, 124.4, 127.4, 128.4, 129.2, 129.3,
130.8, 132.1, 138.1, 144.4, 147.8, 149.6, 154.6, 162.3.
FTIR (KBr) nmax 1662, 1582, 1551, 1532, 1414, 1350,
1167, and 1094 cmꢁ1. Anal. Calcd for C17H14Cl N3O2:
C, 65.49; H, 4.53; N, 13.45. Found: C, 65.41; H, 4.54; N,
13.26.
1
1D H NOE experiments using selective excitation with
3.5. General procedure for the preparation of 2-alkyl-
amino-5-aryl-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-
one (11)
a shaped pulse (gradient version) were used to determine
the stereochemistry of 5 (Fig. 2). Irradiation of the aromatic
protons at C-17, 21 elicited NOE signals from H-3 (weak),
H-5 (weak), and H-18, 20 (strong), confirming further that
the disposition of tolyl and the pyridine rings are such as
those for the (Z) isomer and suggestive of a stacking interac-
tion. Irradiation of the methyl protons at C-9 elicited NOE
signals from H-1 (weak), H-3 (strong), H-5 (strong), H-13
(weak), H-14 (weak), H-17, 21 (weak), and H-18, 20
(weak), indicating once again that compound 5 exists as
the (Z) isomer, with evidence of stacking of the aromatic
rings and a disposition of the ethyl group syn to the tolyl
ring. The distinct proton chemical shifts corresponding to
the primary amino group (d, 7.77 and 8.71 ppm) suggest
restricted rotation about the C–N bond.
A three-necked, 2-L round-bottomed flask equipped with
a mechanical stirrer, reflux condenser, temperature probe,
and gas inlet/exit were charged with 5-aryl-2-chloro-3-
methyl-6-pyridin-4-yl-3H-pyrimidin-4-one (0.15 mol), the
alkylamine (0.165 mol), dichloromethane (1 L, 0.15 M),
and potassium carbonate (0.165 mol). The reaction mixture
was stirred for 16 h at ambient temperature under nitrogen.
Water was then added into the reaction solution. The phases
were separated, and the organic layer was washed with a
10% aq solution of NaHCO3, followed by water, and
allowed to dry over Na2SO4. The crude product was isolated
after removal of solvent and purified by chromatography
with ethyl acetate/hexanes to give the pure product (90%).
Acknowledgements
1
11 (R¼o-F): H NMR (400 MHz, CDCl3) d 1.08 (s, 6H),
2.67 (s, 2H), 3.11 (s, 3H), 3.56 (d, J¼5.7 Hz, 2H), 5.30 (s,
1H), 6.90–6.94 (m, 2H), 7.05–7.09 (m, 2H), 7.12–7.14 (m,
2H), 7.23–7.25 (m, 2H), 7.29–7.36 (m, 3H), 8.40 (d,
J¼6.0 Hz, 2H); 13C NMR (100 MHz, CDCl3) d 25.9, 26.8,
36.1, 47.8, 51.4, 113.5, 115.1, 115.3, 124.0, 126.8, 128.6,
130.3, 132.8, 138.7, 146.9, 149.4, 152.5, 156.5, 162.6,
163.6. HRMS (ESI) m/e (M+H) calcd for C27H27FN4O
443.2242, found 443.2246.
The authors are grateful to Dr. Bo Shen and Duncan Smith
for technical assistance with HPLC, MS, and NMR experi-
ments, and to Dr. Thomas Storz for providing valuable
comments.
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