Suzuki coupling at the 2-position of densely functionalized pyrimidones

Article abstract of DOI:10.1055/s-2006-926414

A variety of ethyl 1-substituted 2-aryl-5-ethoxy-6-oxo-1,6- dihydropyrimidine-4-carboxylates were synthesized by efficient thermal or microwave-promoted Suzuki coupling of 2-chloro-N1-substituted precursors. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-926414

PAPER
1343
Suzuki Coupling at the 2-Position of Densely Functionalized Pyrimidones
Suzuki Coupli
t
ng in
D
e
ensely Fun
f
c
tionaliz
a
ed
P
yrimid
n
ones ia Colarusso,* Mélina Girardin, Immacolata Conte, Frank Narjes
IRBM-Merck Research Laboratories Rome, Via Pontina km 30.600, Pomezia 00040, Rome, Italy
Fax +39(069)1093654; E-mail: stefania_colarusso@merck.com
Received 23 November 2005; revised 8 December 2005
for the desired N-alkylated product, being furthermore
limited to the more reactive electrophiles, and hence to a
small number of substituents.
Abstract: A variety of ethyl 1-substituted 2-aryl-5-ethoxy-6-oxo-
1,6-dihydropyrimidine-4-carboxylates were synthesized by effi-
cient thermal or microwave-promoted Suzuki coupling of 2-chloro-
N1-substituted precursors.
Carbon–carbon bond formation in position 2 of the pyrimi-
done scaffold having the appropriate N1 substituent al-
ready in place was an attractive route for our purposes.
From a survey of the literature it was found that carbon–
carbon bond formation on 2-halopyrimidines via transi-
tion-metal-catalyzed3 cross-coupling reactions is well
documented. The analogous reaction on N1-substituted
pyrimidones has very little precedent4 despite the interest
in this class of compounds related to their wide range of
biological activities5.
Key words: antiviral agents, pyrimidones, cross-coupling
A recent research project revealed 1-substituted 2-aryl-5-
hydroxy-6-oxo-1,6-dihydropyrimidine-4-carboxylic ac-
ids (pyrimidones, 1) as a novel class of Hepatitis C virus
(HCV) RNA-dependent RNA polymerase inhibitors1,2
(Figure 1).
N1 substitution
O
Herein we report the Suzuki cross-coupling of densely
functionalized ethyl 1-substituted 2-chloro-5-ethoxy-6-
oxo-1,6-dihydropyrimidine-4-carboxylates with a variety
of boronic acids. For an easy access to the desired target
structures, it is mandatory that the N1-substituted pyrimi-
dones are readily accessible. Sochilin6 and co-workers
had described the synthesis of pyrimidone 5a. We applied
their methodology to access 2-chloropyrimidone 3a, as
well as the benzyl and phenyl analogues 3b and 3c, which
we needed to explore the scope and limitations of the
methodology.
R
OH
O
N
Ar = aryl, heteroaryl
OH
Ar
N
1
Figure 1 1-Substituted 2-aryl-5-hydroxy-6-oxo-1,6-dihydropyri-
midine-4-carboxylic acids 1
For a rapid exploration of the SAR (structure–activity re-
lationship) in the series, we were targeting an efficient
methodology to insert aryl groups in position 2 of the pyr-
imidone in the presence of different groups on the N1 ni-
trogen. The remaining substitution pattern of the
pyrimidone scaffold, which has been shown to be essen-
tial for biological activity,1,2 was kept fixed. The route
typically used1 for the synthesis of the pyrimidone scaf-
fold was not very efficient for a combined SAR in posi-
tions 1 and 2, since the aryl group was introduced early in
the synthesis from the amidoxime 2 (Scheme 1) and the
alkylation of N1 nitrogen proceeded with low selectivity
All three compounds were accessible in multigram quan-
tities by the four-step route shown in Scheme 2. Conden-
sation of commercially available N-substituted ureas with
diethyl 2-ethoxy-3-oxosuccinate6,7 afforded hydantoins
4a–c which underwent a base-promoted ring expansion to
the corresponding 2-hydroxypyrimidones 5a–c. Esterifi-
cation and reaction with phosphorous oxychloride afford-
ed the chlorides 3a–c which were obtained pure with only
one column chromatographic purification after the last
step.
R
O
N
O
N
1) CHCl3 or MeOH
NH2
OPG
OMe
R
OPG
OMe
N
N
MeOOC
COOMe
OH
Ar
N
2) xylene, 150 °C
3) protection
Ar
Ar
O
O
4) Cs2CO3, R-X, THF
2
N-alkylation
O-alkylation
Scheme 1 Typical synthetic route to pyrimidones1
SYNTHESIS 2006, No. 8, pp 1343–1350
x
x
.
x
x
.2
0
0
6
Advanced online publication: 28.03.2006
DOI: 10.1055/s-2006-926414; Art ID: Z22905SS
© Georg Thieme Verlag Stuttgart · New York

1344
S. Colarusso et al.
PAPER
O
OEt
OEt
EtO
EtO
O
N
O
N
O
N
COOEt
O
O
R
OEt
OH
R
OEt
OEt
AcCl
EtOH
R
OEt
OEt
O
N
N
HN
N
POCl3, DMF
1 N KOH
reflux
1 N HCl–AcOH
O
reflux
reflux
N,N-dimethyl-
aniline
or DMAP
reflux
O
HO
HO
N
Cl
O
R
O
O
R
N
NH2
H
3a: R = Me 85%
3b: R = Bna 37%
3c: R = Ph 73%
4a: R = Me 99%
4b: R = Bn 61%
4c: R = Ph 99%
5a: R = Me 76%
5b: R = Bn 83%
5c: R = Ph 73%
6a: R = Me 98%
6b: R = Bn 99%
6c: R = Ph 90%
R = Me, Bn, Ph
Scheme 2 Synthesis of ethyl 1-substituted 2-chloro-5-ethoxy-6-oxo-1,6-dihydropyrimidine-4-carboxylates 3a–c. a DMAP was used as cata-
lyst and the reaction was performed in a microwave apparatus at 200 °C.
We chose chloride 3a as initial substrate for the optimiza- 1,6-dihydropyrimidine-4-carboxylate. When we used
tion of the reaction conditions, using 3-methoxyphenylbo- K3PO4 as a base in the absence of water, the hydrolysis of
ronic acid as the coupling counterpart1 for the the chloride was suppressed and 7a was isolated in 80%
optimization. The results obtained are reported in Table 1. yield (Table 1, entry 3).
We initially cross-coupled 3a using the ‘classical’ tetra-
kis(triphenylphosphine)palladium(0) and 1,2-bis(diphen-
ylphosphinoethane)palladium(II) chloride. In both cases
complete consumption of 3a was observed in about four
hours and we were able to isolate 7a in 50% and 45%
yield, respectively (Table 1, entries 1 and 2).
Among the several other catalysts available in the litera-
ture, the Pd(0)/P(t-Bu)3 system, recently developed by Fu
and co-workers,8a,b seemed to us particularly attractive.
The system is reported to be highly active on a variety of
aryl chlorides, allows steric hindrance in both the cou-
pling components and tolerates a variety of functional
The major side-reactions, as judged by LC-MS, were hy- groups.
drolysis of 3a to the corresponding 2-hydroxy pyrimidone
6a and reduction of 3a to ethyl 5-ethoxy-1-methyl-6-oxo-
We were pleased to find that the reaction of 3a with 1.1
equivalents of 3-methoxyphenylboronic acid proceeded
with very high yield in the presence of Pd2dba3 (6 mol%)
and the air-stable [(t-Bu)3 PH]BF4 ligand9 (12 mol%) in
Table 1 Suzuki Coupling of 3a under Thermal Conditions
dioxane at 85 °C (Table 1, entry 4). With respect to con-
Entry
1
Boronic acid
3-methoxyphenyl
3-methoxyphenyl
3-methoxyphenyl
3-methoxyphenyl
phenyl
Conditionsa Product Yield (%)b
dition C (Table 1), which also gave a high isolated yield
of 7a, the Fu catalyst allowed an easier isolation of the
coupling product from the reaction by-products. These
conditions were then used to determine the scope and lim-
itations of the boronic acid partner (Scheme 3).
A
B
C
D
D
D
D
D
D
D
D
D
7a
7a
7a
7a
7b
7c
7d
7e
7f
50c
45c
80c
92c
86c
75
2
3
4
O
O
R
OEt
OEt
R
OEt
OEt
5
N
N
ArB(OH)2 (1.1 equiv)
dioxane
or
toluene–DMF
6
4-acetoxyphenyl
3-thienyl
Cl
N
Ar
N
O
O
7
99
R = Me 3a
R = Bn 3b
R = Ph 3c
7a–n
8a–c
9a–d
8
2-thienyl
79
9
4-methoxyphenyl
2-methoxyphenyl
1-naphthyl
58
Scheme 3 Suzuki cross-coupling of 2-chloropyrimidones
10
11
12
7k
7g
7h
40d
10d
0d
As shown by the data reported in Table 1, the reaction
proceeds smoothly with aryl- and heteroarylboronic acids
(entries 5–8), tolerating the presence of reactive function-
al groups and of electron-donating substituents (entries 6
and 9), with yields varying from moderate to high. In the
case of increased steric demand of the boronic acid coun-
terpart lower yields were observed, as for the coupling of
3a with 2-methoxyphenyl- and 1-naphthylboronic acids
(entry 10 and 11). In both cases, a considerable amount of
unreacted 3a was detected by LC-MS even after two days.
In the case of o-tolylboronic acid formation of product
was observable only in traces by LC-MS (entry 12) with
mostly unreacted starting material present.
o-tolyl
a Conditions A: Pd(PPh3)4 (10%), Na2CO3 (3.0 equiv), boronic acid
(1.5 equiv), DME–EtOH–H2O, 80 °C, 4 h; Conditions B:
Pd(dppe)Cl2 (10%), Na2CO3 (3.0 equiv), boronic acid (1.3 equiv), tol-
uene–H2O, 100 °C; Conditions C: Pd(PPh3)4 (10%), K3PO4 (3.0
equiv), boronic acid (1.1 equiv), toluene, 100 °C, 16 h; Conditions D:
Pd2(dba)3 (6%), [(t-Bu)3PH]BF4 (12%), KF (3.3 equiv), boronic acid
(1.1 equiv), dioxane, 85 °C, 16 h.
b Isolated yields.
c Average of two independent experiments.
d Isolated yield after 48 h, incomplete conversion of 3a.
Synthesis 2006, No. 8, 1343–1350 © Thieme Stuttgart · New York

PAPER
Suzuki Coupling in Densely Functionalized Pyrimidones
1345
To achieve good conversion also in the case of increased 1%, at least in simple coupling reactions, as entry 9
steric hindrance in the boronic acid component, we decid- shows. On the other hand, alkylboronic acids {which are
ed to investigate the reaction under controlled microwave reported to react in the presence of the Pd2(dba)3/
acceleration.10 High-speed synthesis using microwaves [(t-Bu)3PH]BF4 catalyst8b} are completely unreactive to-
has received great attention in the recent years.11 In the wards our substrate under both of the above-described re-
pharmaceutical industry, the drug discovery process action conditions (entry 10).
gained considerable benefit from the use of microwave
In order to study the effect of different substituents on the
synthesis due to its ability of greatly reduce reaction
N1 nitrogen, we then performed the Suzuki coupling
times, which concomitantly diminishes or suppresses the
under the optimized microwave conditions with 2-chloropyr-
imidones 3b and 3c (Scheme 3). As shown by the results
presented in Table 3, the N-benzyl derivative 3b under-
occurrence of side reactions and consequently increases
chemical yields.
When we performed the Suzuki coupling of 3a with o- went Suzuki coupling in the presence of 10% Pd (PPh3)4
tolylboronic acid under microwave irradiation, we ob- in high isolated yields both with phenyl- and 3-thienylbo-
served complete conversion of 3a with the formation of ronic acids (entries 1 and 3). The reaction tolerates the
7h in 86% isolated yield using Pd2(dba)3/[(t-Bu)3PH]BF4 presence of steric hindrance on the boronic acid counter-
in dioxane at 135 °C for 10 minutes (Table 2, entry 1). part as shown by the coupling with o-tolylboronic acid
These conditions did not tolerate further steric hindrance. (entry 2) which proceeded in 74% isolated yield. The
The 2,6-dimethylphenylboronic acid gave low conver- overall reactivity of 3b in the microwave-accelerated Su-
sion. No improvement was observed upon increasing the zuki coupling is substantially similar to the one of the N-
temperature and/or the reaction times, presumably due to methyl derivative 3a. In the case of the N-phenyl deriva-
decomposition of the Pd2(dba)3/[(t-Bu)3PH]BF4 catalyst. tive 3c, reactions were considerably slower, requiring 20
We decided to test Pd(PPh3)4 which had given good re- minutes of microwave heating in order to achieve com-
sults in the thermal reaction (Table 1, entry 3) and whose plete conversion (or not further progression in the case of
use in microwave-accelerated chemistry has already been incomplete reaction).
well documented.10,11
For 3c, the Pd2(dba)3/[(t-Bu)3PH]BF4 catalyst proved to
Irridiation of 3a and 2,6-dimethylphenylboronic acid in be superior to Pd(PPh3)4, this being consistent with the re-
the presence of 10% of Pd(PPh3)4 in toluene–DMF (5:1) ported higher efficiency of the former in the presence of
at 200 °C for five minutes gave the coupling product 7i in increased steric hindrance on the aryl chloride, but the
67% isolated yield (Table 2, entry 3). As the results in yields were substantially lower than in previous cases. As
Table 2 show, the microwave-accelerated methodology summarized by the results reported in Table 3, 3c coupled
with Pd(PPh3)4 as the catalyst is not only effective in the to phenylboronic acid in 84% yield (entry 4), to 4-meth-
case of increased steric hindrance, but also compatible oxyphenylboronic acid in 50% yield (entry 6), to o-tolyl-
with the presence of sensitive functional groups (entries boronic acid in 34% yield (entry 5) and only in trace
4–8). Furthermore, the catalyst loading can be reduced to amount to 2,6-dimethylphenylboronic acid (entry 7). In
the last example, apart from incomplete conversion, a ma-
jor side reaction was the reduction of 3c. For this particu-
Table 2 Suzuki Coupling of 3a under Microwave Heating
lar example, the use of the S-PHOS/Pd2(dba)3 catalyst12
Entry
Boronic acid
o-tolyl
Methoda Product Yield (%)
partially suppressed reduction but gave only a slightly in-
crease in yield of 9d (20% isolated). We are currently in-
vestigating whether this reaction can be further improved.
1
2
A
7h
7i
77
traces
67
81
82
84
65
70
88
0
2,6-dimethylphenyl
2,6-dimethylphenyl
1-naphthyl
A
In summary, we have reported the Suzuki coupling of
densely functionalized N1-substituted 2-chloropyrimi-
dones with a variety of boronic acids, which was virtually
unprecedented in the literature for such systems. A proper
choice of the reaction conditions (i.e. thermal or micro-
wave heating, use of different catalysts) allowed us to
couple sterically demanding as well as electronically de-
activated and heterocyclic boronic acids with isolated
yields ranging from moderate to excellent. We believe
that this methodology can be applied also to similar het-
erocyclic systems of potential interest in medicinal chem-
istry.
3
B
7i
4
B
7g
7j
5
2-naphthyl
B
6
2-methoxyphenyl
4-formylphenyl
styryl
B
7k
7l
7
B
8
B
7m
7b
7n
9
phenyl
C
10
cyclohexyl
A, B
In terms of the advantage offered to our drug discovery
process, the methodology represents a very important tool
to rapidly explore the structure–activity relationship in
position 2 of the pyrimidone ring while having a different
a Method A: Pd2(dba)3 (6%), [(t-Bu)3PH]BF4 (12%), KF, dioxane,
135 °C, 10 min; Method B: Pd(PPh3)4 (10%), K3PO4, toluene–DMF
(5:1), 200 °C, 10 min; Method C: Pd(PPh3)4 (1%), K3PO4, toluene–
DMF (5:1), 200 °C, 10 min.
Synthesis 2006, No. 8, 1343–1350 © Thieme Stuttgart · New York

1346
S. Colarusso et al.
PAPER
Table 3 Suzuki Coupling of 3b and 3c under Microwave Heating
Entry
Boronic acid
phenyl
Chloride
3b
Methoda
Product
8a
Yield (%)
1
2
3
4
5
6
7
B
B
D
D
D
D
D
82
o-tolyl
3b
8b
74
3-thienyl
3b
8c
78
phenyl
3c
9a
84
o-tolyl
3c
9b
34
4-methoxyphenyl
2,6-dimethylphenyl
3c
9c
50
3c
9d
traces
a Method B (see Table 2): Pd(PPh3)4 (10%), K3PO4 (3.0 equiv), boronic acid (1.1 equiv), toluene–DMF (5:1), 200 °C, 15 min; Method D:
Pd2(dba)3 (6%), [(t-Bu)3PH]BF4 (12%), KF (3.3 equiv), boronic acid (1.1 equiv), dioxane, 135 °C, 20 min.
3.87 (q, J = 6.8 Hz, 2 H), 2.91 (s, 3 H), 2.86* (s, 3 H), 1.29–1.22 (m,
3 H).
substituent on the N1 nitrogen. This provided the oppor-
tunity to synthesize derivatives which we were not able to
obtain by other routes.
Ethyl 2-Ethoxy(1-benzyl-2,5-dioxoimidazolidin-4-ylidene)-
ethanoate (4b)
The title compound was obtained analogously from 2-ethoxy-3-ox-
osuccinate and N-benzylurea as an off-white solid (61%).
1H NMR (300 MHz, DMSO-d6, 5:1 E/Z* ratio): d = 7.36–7.27 (m,
5 H), 4.62 (s, 2 H), 4.28 (q, J = 7.2 Hz, 2 H), 4.20* (q, J = 7.2 Hz, 2
H), 3.95* (q, J = 6.8 Hz, 2 H), 3.87 (q, J = 6.8 Hz, 2 H), 1.29–1.23
(m, 6 H).
Reagents and anhydrous solvents were obtained from commercial
sources and were used without further purification unless otherwise
noted. Petroleum ether (PE) used refers to the fraction boiling in the
range 40–65 °C.
Nuclear magnetic resonance (1H NMR, 13C NMR) spectra were ob-
tained on Bruker AMX 400 (400 MHz) or AMX 300 (300 MHz)
1
spectrometer. For H spectra chemical shifts are reported in ppm
Ethyl 2-Ethoxy(1-phenyl-2,5-dioxoimidazolidin-4-ylidene)-
ethanoate (4c)
The title compound was obtained analogously from 2-ethoxy-3-ox-
osuccinate and N-phenylurea as a white solid (99%).
1H NMR (400 MHz, DMSO-d6, 3:1 E/Z* ratio): d = 7.50–7.39 (m,
5 H), 4.32 (q, J = 6.8 Hz, 2 H), 4.30* (q, J = 6.8 Hz, 2 H), 4.05* (q,
J = 6.8 Hz, 2 H), 3.90 (q, J = 6.8 Hz, 2 H), 1.28–1.23 (m, 6 H).
relative to internal TMS or the residual solvent peak. Data are re-
ported as follows: chemical shift, multiplicity (s, singlet; d, doublet;
t, triplet; q, quartet; qui, quintet; m, multiplet; br, broad; app, appar-
ent), coupling constants and integration. Low-resolution mass spec-
tra (m/z) were recorded on a Perkin-Elmer API 100 (electrospray
ionization) mass spectrometer; only molecular and isotopic ions are
reported. High-resolution mass measurements were performed on a
Finnigan TSQ Quantum Ultra AM in Selected Ion Monitoring
Mode (SIM). Elemental analyses were performed on an Elemental
Analyzer EA1108 (Carlo Erba Strumentazione). Microwave heat-
ing was performed using a Smith CreatorTM microvawe reactor
(supplied by Personal Chemistry/Biotage).
Compounds 5a-c; 5-Ethoxy-2-hydroxy-1-methyl-6-oxo-1,6-di-
hydropyrimidine-4-carboxylic Acid (5a); Typical Procedure
Compound 4a (3.12 g, 12.9 mmol) was dissolved in aq 1 N KOH
(51.6 mL) and refluxed for 3 h. The mixture was cooled to 0 °C and
carefully acidified with conc. HCl. After overnight cooling (+4 °C)
led to the formation of a white precipitate, the mixture was filtered
and the precipitate was dried in vacuo. Product 5a was obtained as
a white solid (1.74 g, 63%).
Caution (!) The palladium catalysts tend to decompose under mi-
crowave heating with formation of a precipitate, presumably con-
sisting of palladium black, which can result in considerable
overheating. The sealed vials used for the microwave reactions
should therefore not be used for a second run of heating in the case
of incomplete reactions.
1H NMR (300 MHz, DMSO-d6): d = 14.2 (br s, 1 H), 10.89 (s, 1 H),
3.93 (q, J = 6.8 Hz, 2 H), 3.13 (s, 3 H), 1.20 (t, J = 6.8 Hz, 3 H).
13C NMR (75 MHz, DMSO-d6): d = 162.2, 161.3, 149.7, 132.4,
Flash Chromatography was performed either using 230–400 mesh
silica gel 60 (Merck) as stationary phase or by Jones Flashmaster
IITM and Flashmaster Personal purification systems, using pre-
packed IsoluteTM Si cartridges.
132.0, 69.3, 27.6, 15.4.
MS (ES–): m/z = 213 (M – H).
Anal. Calcd for C8H10N2O5·H2O: C, 41.38; H, 5.20; N, 12.13.
Found: C, 41.79; H, 5.15; N, 12.13.
Compounds 4a–c; Ethyl 2-Ethoxy(1-methyl-2, 5-dioxo-
imidazolidin-4-ylidene)ethanoate (4a); Typical Procedure
A mixture of diethyl 2-ethoxy-3-oxosuccinate6 (3 g, 12.9 mmol)
and N-methylurea (0.960 g, 12.9 mmol) was refluxed for 2 h in 1 M
HCl–AcOH (65 mL). The cooled reaction mixture was evaporated
to dryness and the residue co-evaporated with toluene and dried in
vacuo to afford 4a (3.12 g, 99%) as an off-white solid, which was
carried through without further purification.
1-Benzyl-5-ethoxy-2-hydroxy-6-oxo-1,6-dihydropyrimidine-4-
carboxylic Acid (5b)
This compound was obtained analogously from 4b; white solid;
yield: 83%.
1H NMR (300 MHz, DMSO-d6): d = 11.04 (s, 1 H), 7.34–7.22 (m,
5 H), 4.95 (s, 2 H), 3.93 (q, 2 H, J = 6.8 Hz), 1.20 (t, J = 6.8 Hz, 3 H).
13C NMR (75 MHz, DMSO-d6): d = 161.7, 160.8, 149.2, 136.8,
132.7, 131.6, 128.3, 127.5, 127.2, 69.0, 43.5, 15.0.
1H NMR (400 MHz, CDCl3, 3:1 E/Z* ratio): d = 10.46* (s, 1 H),
10.03 (s, 1 H), 4.28 (q, J = 7.2 Hz, 2 H), 3.94* (q, J = 7.2 Hz, 2 H),
Synthesis 2006, No. 8, 1343–1350 © Thieme Stuttgart · New York

PAPER
Suzuki Coupling in Densely Functionalized Pyrimidones
1347
MS (ES+): m/z = 291 (M + H).
Compounds 3a–c; Ethyl 2-Chloro-5-ethoxy-1-methyl-6-oxo-
1,6-dihydropyrimidine-4-carboxylate (3a); Typical Procedure
N,N-Dimethylaniline (0.856 mL, 6.76 mmol) was added to a stirred
solution of 6a (1.17g, 4.83 mmol) in POCl3 (34.5 mL) and the mix-
ture was refluxed overnight. Excess of POCl3 was evaporated in
vacuo and the residue was poured into ice-water and extracted with
Et2O. The combined ethereal layers were washed with brine, dried
(Na2SO4) and evaporated in vacuo. Purification by flash chromato-
graphy (SiO2, PE–EtOAc, 2:1) gave 3a (1.07 g, 85%) as a light-yel-
low oil, which solidified upon standing.
1H NMR (300 MHz, DMSO-d6): d = 4.30 (q, J = 6.8 Hz, 2 H), 4.13
(q, J = 6.8 Hz, 2 H), 3.53 (s, 3 H), 1.28 (t, J = 6.8 Hz, 3 H), 1.24 (t,
J = 6.8 Hz, 3 H).
13C NMR (75 MHz, DMSO-d6): d = 162.9, 159.2, 143.4, 142.1,
140.0, 68.2, 61.6, 33.78, 15.1, 13.9.
Anal. Calcd for C14H14N2O5: C, 57.93; H, 4.86; N, 9.65. Found: C,
58.34; H, 4.90; N, 9.62.
5-Ethoxy-2-hydroxy-6-oxo-1-phenyl-1,6-dihydropyrimidine-4-
carboxylic Acid (5c)
This compound was obtained analogously from 4c; off-white solid;
yield: 73%.
1H NMR (300 MHz, DMSO-d6): d = 11.03 (s, 1 H), 7.49–7.40 (m,
3 H), 7.26 (d, J = 7.2 Hz, 2 H), 3.95 (q, J = 7.1 Hz, 2 H), 1.21 (t,
J = 7.1 Hz, 3 H).
13C NMR (75 MHz, DMSO-d6): d = 161.7, 160.9, 149.2, 135.2,
132.8, 132.6, 128.9, 128.7, 128.3, 69.0, 15.1.
MS (ES+): m/z = 277 (M + H).
MS (ES+): m/z = 261 (M + H).
Anal. Calcd for C13H12N2O5: C, 56.52; H, 4.38; N, 10.14. Found: C,
56.53; H, 4.35; N, 10.01.
Anal. Calcd for C10H13ClN2O4·H2O: C, 46.08; H, 5.03; N, 10.75.
Found: C, 45.83; H, 4.89; N, 10.49.
Compounds 6a–c; Ethyl 5-Ethoxy-2-hydroxy-1-methyl-6-oxo-
1,6-dihydropyrimidine-4-carboxylate (6a); Typical Procedure
Acetyl chloride (9.41 mL, 132. 3 mmol) was added dropwise to ab-
solute EtOH (110 mL) at 0 °C. After stirring the resulting solution
for 20 min at r.t., 5a (1.42 g, 6.6.2 mmol) was added in one portion
and the mixture was refluxed overnight. The volatiles were evapo-
rated in vacuo and the residue was co-evaporated with toluene and
dried to give 6a (1.57g, 98%) as an off-white solid.
1H NMR (300 MHz, DMSO-d6): d = 11.03 (br s, 1 H), 4.30 (q, J =
7.1 Hz, 2 H), 3.95 (q, J = 7.1 Hz, 2 H), 3.14 (s, 3 H), 1.30 (t, J = 7.1
Hz, 3 H), 1.22 (t, J = 7.1 Hz, 3 H).
Ethyl 1-Benzyl-2-chloro-5-ethoxy-6-oxo-1,6-dihydropyrimi-
dine-4-carboxylate (3b)
This compound was obtained analogously from 6b in the presence
of catalytic amount of DMAP under microwave irradiation at
200 °C for 15 min; colorless oil; yield: 37%.
1H NMR (300 MHz, DMSO-d6): d = 7.40–7.27 (m, 5 H), 5.32 (s, 2
H), 4.32 (q, J = 6.9 Hz, 2 H), 4.18 (q, J = 6.9 Hz, 2 H), 1.30 (t, J =
6.9 Hz, 3 H), 1.26 (t, J = 6.9 Hz, 3 H).
13C NMR (75 MHz, DMSO-d6): d = 163.3, 160.1, 144.1, 142.8,
140.6, 134.3, 129.1, 128.6, 128.1, 69.6, 62.4, 50.5, 15.6, 14.3.
MS (ES+): m/z = 337 (M + H).
13C NMR (75 MHz, DMSO-d6): d = 160.8, 160.3, 149.3, 132.5,
130.6, 69.0, 62.3, 27.3, 15.0, 13.8.
MS (ES+): m/z = 243 (M + H).
Anal. Calcd for C16H17ClN2O5: C, 57.06; H, 5.09; N, 8.32. Found:
C, 57.33; H, 5.10; N, 8.26.
Anal. Calcd for C10H14N2O5: C, 49.58; H, 5.83; N, 11.56. Found: C,
49.65; H, 5.44; N, 11.02.
Ethyl 2-Chloro-5-ethoxy-6-oxo-1-phenyl-1,6-dihydropyrimi-
dine-4-carboxylate (3c)
This compound was obtained similarly from 6c; light-yellow solid;
Ethyl 1-Benzyl-5-ethoxy-2-hydroxy-6-oxo-1,6-dihydropyrimi-
dine-4-carboxylate (6b)
This compound was obtained analogously from 5b; white solid;
yield: 73%.
yield: 99%.
1H NMR (400 MHz, DMSO-d6): d = 7.59–7.48 (m, 5 H), 4.35 (d,
J = 7.1 Hz, 2 H) 4.17 (q, J = 7.1 Hz, 2 H), 1.32 (t, J = 7.1 Hz, 3 H),
1.26 (t, J = 7.1 Hz, 3 H).
13C NMR (75 MHz, DMSO-d6): d = 163.1, 159.3, 143.2, 142.3,
140.0, 137.0, 129.7, 129.4, 128.0, 68.4, 61.7, 15.1, 13.9.
1H NMR (300 MHz, DMSO-d6): d = 11.17 (br s, 1 H), 7.34–7.22
(m, 5 H), 4.95 (s, 2 H), 4.31(q, J = 7.1 Hz, 2 H), 3.93 (q, J = 7.1 Hz,
2 H), 1.30 (t, J = 7.1 Hz, 3 H), 1.22 (t, J = 7.1 Hz, 3 H).
13C NMR (75 MHz, DMSO-d6): d = 160.6, 160.2, 149.2, 136.7,
132.5, 131.1, 128.3, 127.5, 127.2, 69.1, 62.4, 43.5, 15.0, 13.7.
MS (ES+): m/z = 323 (M + H).
MS (ES+): m/z = 319 (M + H).
Anal. Calcd for C15H15ClN2O4: C, 55.82; H, 4.68; N, 8.68. Found:
C, 55.89; H, 4.72; N, 8.73.
Anal. Calcd for C16H18N2O5·1/2H2O: C, 58.71; H, 5.85; N, 8.56.
Found: C, 58.78; H, 5.51; N, 8.62.
Suzuki Coupling of Chlorides 3a–c; Ethyl 5-Ethoxy-2-(3-meth-
oxyphenyl)-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carbox-
ylate (7a); Typical Procedure (Thermal Condition D, Table 1)
Ethyl 2-chloro-5-ethoxy-1-methyl-6-oxo-1,6-dihydropyrimidine-
4-carboxylate (3a; 50 mg, 0.192 mmol), 3-methoxyphenylboronic
acid (32 mg, 0.211 mmol), Pd2(dba)3 (10 mg, 0.011 mmol),
[(t-Bu)3PH]BF4 (7 mg, 0.0023 mmmol) and spray-dried KF (38 mg,
0.65 mmol) were placed in an oven-dried flask and purged with ar-
gon. Anhydrous, degassed dioxane (0.65 mL) was added and the
mixture was purged with three vacuum/argon cycles, before being
heated at 85 °C in an inert atmosphere for 3 h. The cooled mixture
was diluted with EtOAc, filtered over a plug of Celite and the fil-
trate was evaporated in vacuo. The residue was purified by Flash-
master personal (SiO2, PE–EtOAc, 3:1) to give 7a as a colorless oil;
yield: 59 mg (92%).
Ethyl 5-Ethoxy-2-hydroxy-6-oxo-1-phenyl-1,6-dihydropyrimi-
dine-4-carboxylate (6c)
This compound was obtained analogously from 5c; off-white solid;
yield: 90%.
1H NMR (400 MHz, DMSO-d6): d = 11.18 (s, 1 H), 7.49–7.39 (m,
3 H), 7.28–7.26 (d, J = 7.2 Hz, 2 H), 4.34 (d, J = 7.1 Hz, 2 H) 3.98
(q, J = 7.1 Hz, 2 H), 1.32 (t, J = 7.1 Hz, 3 H), 1.22 (t, J = 7.1 Hz, 3
H).
13C NMR (75 MHz, DMSO-d6): d = 160.7, 160.4, 149.2, 135.2,
132.9, 131.4, 128.8, 128.7, 128.2, 69.1, 62.4, 15.0, 13.8.
MS (ES+): m/z = 305 (M + H).
Anal. Calcd for C15H16N2O5: C, 59.21; H, 5.30; N, 9.77. Found: C,
59.50; H, 5.31; N, 9.44.
Synthesis 2006, No. 8, 1343–1350 © Thieme Stuttgart · New York

1348
S. Colarusso et al.
PAPER
1H NMR (300 MHz, CDCl3): d = 7.42–7.36 (m, 1 H), 7.06–7.02 (m,
3 H), 4.40 (q, J = 7.2 Hz, 2 H), 4.32 (q, J = 7.2 Hz, 2 H), 3.84 (s, 3
H), 3.45 (s, 3 H), 1.41 (t, J = 7.2 Hz, 3 H), 1.39 (t, J = 7.2 Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 164.6, 160.4, 160.0, 155.2, 142.5,
141.6, 135.5, 130.1, 120.5, 116.4, 113.9, 69.1, 62.1, 55.6, 34.9,
15.6, 14.3.
1H NMR (300 MHz, CDCl3): d = 7.47 (d, J = 8.7 Hz, 2 H), 6.98 (d,
J = 8.7 Hz, 2 H), 4.40 (q, J = 7.2 Hz, 2 H), 4.35 (q, J = 7.2 Hz, 2 H),
3.86 (s, 3 H), 3.49 (s, 3 H), 1.40 (t, J = 7.2 Hz, 3 H), 1.37 (t, J = 7.2
Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 164.8, 161.4, 160.7, 155.4, 142.2,
141.8, 130.3, 126.7, 114.3, 69.1, 62.1, 55.6, 35.3, 15.7, 14.3.
MS (ES+): m/z = 333 (M + H).
MS (ES+): m/z = 333 (M + H).
Anal. Calcd for C17H20N2O5: C, 61.44; H, 6.07; N, 8.43. Found: C,
60.96; H, 6.01; N, 8.29.
Anal. Calcd for C17H20N2O5: C, 61.44; H, 6.07; N, 8.43. Found: C,
61.23; H, 6.14; N, 8.50.
7b
Suzuki Coupling of Chlorides 3a–c; Ethyl 5-Ethoxy-1-methyl-2-
(2-methylphenyl)-6-oxo-1,6-dihydropyrimidine-4-carboxylate
(7h) and Ethyl 5-Ethoxy-2-(2,6-dimethylphenyl)-1-methyl-6-
oxo-1,6-dihydropyrimidine-4-carboxylate (7i); Typical Proce-
dures (Microwave Conditions, Tables 2 and 3)
White solid; yield: 86%.
1H NMR (300 MHz, CDCl3): d = 7.9 (m, 5 H), 4.40 (q, J = 7.2 Hz,
2 H), 4.34 (q, J = 7.2 Hz, 2 H), 3.46 (s, 3 H), 1.41 (t, J = 7.2 Hz, 3
H), 1.36 (t, J = 7.2 Hz, 3 H).
Method A: Ethyl 2-chloro-5-ethoxy-1-methyl-6-oxo-1,6-dihydro-
pyrimidine-4-carboxylate (3a; 50 mg, 0.19 mmol), o-tolylbo-
ronic acid (32 mg, 0.21 mmol), Pd2(dba)3 (10 mg, 0.011 mmol),
[(t-Bu)3PH]BF4 (7 mg, 0.023 mmol) and spray-dried KF (38 mg,
0.65 mmol) were placed in an Smith Creator Microwave vial which
was sealed and flushed with argon. Anhydrous, degassed dioxane
(0.65 mL) was added and the mixture was heated at 135 °C in the
Smith Creator apparatus for 10 min. The cooled mixture was diluted
with EtOAc, filtered over a plug of Celite and the filtrate was evap-
orated in vacuo. The residue was purified by Flashmaster Personal
(SiO2; PE–EtOAc, 3:1) to give 7h as a white solid; yield: 46 mg
(77%) (Table 2).
13C NMR (75 MHz, CDCl3): d = 164.6, 160.4, 155.3, 142.5, 141.6,
134.3, 130.5, 128.9, 128.4, 69.0, 62.0, 34.9, 15.6, 14.3.
MS (ES+): m/z = 303 (M + H).
Anal. Calcd for C16H18N2O4: C, 63.56; H, 6.00; N, 9.27. Found: C,
63.39; H, 5.94; N, 9.21.
7c
White solid; yield: 75%.
1H NMR (300 MHz, CDCl3): d = 8.07 (d, J = 8.1 Hz, 2 H), 7.63 (d,
J = 8.1 Hz, 2 H), 4.41 (q, J = 7.2 Hz, 2 H), 4.36 (q, J = 7.2 Hz, 2 H),
3.45 (s, 3 H), 2.65 (s, 3 H), 1.43 (t, J = 7.2 Hz, 3 H), 1.38 (t, J = 7.2
Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 197.3, 164.5, 160.3, 154.1, 143.0,
141.4, 138.5, 138.4, 129.0, 128.8, 69.2, 62.2, 34.9, 26.9, 15.7, 14.3.
7h
1H NMR (300 MHz, CDCl3): d = 7.38–7.24 (m, 4 H), 4.40 (q, J =
7.2 Hz, 2 H), 4.35 (q, J = 7.2 Hz, 2 H), 3.28 (s, 3 H), 2.21 (s, 3 H),
1.44 (t, J = 7.2 Hz, 3 H), 1.38 (t, J = 7.2 Hz, 3 H).
MS (ES+): m/z = 345 (M + H).
13C NMR (75 MHz, CDCl3): d = 164.6, 160.3, 155.3, 142.6, 141.7,
135.7, 134.2, 130.9, 130.3, 127.9, 126.6, 69.1, 62.1, 33.5, 19.3,
15.7, 14.3.
Anal. Calcd for C18H20N2O5·1/2 H2O: C, 61.18; H, 6.00; N, 7.93.
Found: C, 61.41; H, 5.98; N, 7.90.
MS (ES+): m/z = 317 (M + H).
7d
Light-pink oil; yield: 99%.
Anal. Calcd for C17H20N2O4: C, 64.54; H, 6.37; N, 8.86. Found: C,
64.22; H, 6.28; N, 8.75.
1H NMR (300 MHz, CDCl3): d = 7.72 (d, J = 1.2 Hz, 1 H), 7.43 (dd,
J = 5.1, 3.0 Hz, 1 H), 7.31 (dd, J = 3.0, 1.2 Hz, 1 H), 4.41 (q, J = 7.2
Hz, 2 H), 4.35 (q, J = 7.2 Hz, 2 H), 3.55 (s, 3 H), 1.41 (t, J = 7.2 Hz,
3 H), 1.38 (t, J = 7.2 Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 164.64, 160.5, 151.1, 142.5, 141.7,
134.9, 128.6, 127.6, 126.8, 69.1, 62.1, 34.7, 15.7, 14.3.
Method B: Ethyl 2-chloro-5-ethoxy-1-methyl-6-oxo-1,6-dihydro-
pyrimidine-4-carboxylate (3a; 50 mg, 0.192 mmol), 2,6-dimeth-
ylphenylboronic acid (32 mg, 0.211 mmol), Pd(PPh3)4 (22 mg,
0.019 mmol) and K3PO4 (122 mg, 0.576 mmol) were placed in a
Smith Creator microwave vial which was sealed and flushed with
argon. Anhydrous toluene (1.6 mL) and DMF (0.3 mL) were added
and the mixture was heated at 200 °C in the microwave apparatus
for 10 min. The cooled mixture was diluted with EtOAc, filtered
over a plug of Celite and the filtrate was evaporated in vacuo. The
residue was purified by Flashmaster Personal (SiO2; PE–EtOAc,
3:1) to give 7i as a light-yellow oil; yield: 42 mg (67%) (Table 2).
MS (ES+): m/z = 309 (M + H).
Anal. Calcd for C14H16N2O4S: C, 54.53; H, 5.23; N, 9.08. Found: C,
54.33; H, 5.19; N, 9.00.
7e
Beige oil; yield: 79%.
7i
1H NMR (300 MHz, CDCl3): d = 7.54 (d, J = 5.1 Hz, 1 H), 7.47 (d,
J = 3.0 Hz, 1 H), 7.12 (m, 1 H), 4.41 (q, J = 7.2 Hz, 2 H), 4.34 (q,
J = 7.2 Hz, 2 H), 3.72 (s, 3 H), 1.40 (t, J = 7.2 Hz, 3 H), 1.40 (t, J =
7.2 Hz, 3 H).
1H NMR (300 MHz, CDCl3): d = 7.28–7.26 (m, 1 H), 7.12–7.10 (m,
2 H), 4.40 (q, J = 7.2 Hz, 2 H), 4.34 (q, J = 7.2 Hz, 2 H), 3.24 (s, 3
H), 2.12 (s, 6 H), 1.42 (t, J = 7.2 Hz, 3 H), 1.38 (t, J = 7.2 Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 164.6, 160.4, 155.0, 142.4, 142.0,
13C NMR (75 MHz, CDCl3): d = 164.4, 160.5, 149.3, 142.2, 141.7,
135.6, 134.0, 130.0, 128.2, 69.2, 62.1, 32.5, 19.5, 15.7, 14.3.
136.2, 130.4, 130.3, 127.7, 69.2, 62.1, 34.7, 15.6, 14.4.
MS (ES+): m/z = 331 (M + H).
MS (ES+): m/z = 309 (M + H).
Anal. Calcd for C18H22N2O4: C, 65.44; H, 6.71; N, 8.02. Found: C,
65.3; H, 6.69; N, 8.02.
Anal. Calcd for C14H16N2O4S: C, 54.53; H, 5.23; N, 9.08. Found: C,
54.32; H, 5.20; N, 9.07.
The following compounds were obtained by microwave-assisted
Method B (Tables 2 and 3).
7f
White solid; yield: 58%.
Synthesis 2006, No. 8, 1343–1350 © Thieme Stuttgart · New York

PAPER
Suzuki Coupling in Densely Functionalized Pyrimidones
1349
7g
Anal. Calcd for C18H20N2O4: C, 65.84; H, 6.14; N, 8.53. Found: C,
65.70; H, 6.12; N, 8.40.
White solid; yield: 81%.
1H NMR (300 MHz, CDCl3): d = 8.00–7.91 (m, 5 H), 4.42 (q, J =
7.2 Hz, 2 H), 4.40 (q, J = 7.2 Hz, 2 H), 3.24 (s, 3 H), 1.46 (t, J = 7.2
Hz, 3 H), 1.38 (t, J = 7.2 Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 164.3, 160.0, 154.4, 142.7, 141.6,
133.3, 131.5, 130.5, 130.1, 128.7, 127.6, 126.7, 126.5, 125.2, 124.0,
68.9, 61.9, 33.7, 15.5, 14.0.
8a
White solid; yield: 82%.
1H NMR (300 MHz, CDCl3): d = 7.48–7.21 (m, 8 H), 6.90–6.88 (m,
2 H), 5.19 (m, 2 H), 4.40 (q, J = 6.9 Hz, 2 H), 4.36 (q, J = 6.9 Hz, 2
H), 1.41 (t, J = 6.9 Hz, 3 H), 1.39 (t, J = 6.9 Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 164.7, 160.3, 155.7, 143.1, 141.7,
135.8, 134.4, 130.4, 128.83, 128.76, 128.5, 128.0, 127.3, 69.2, 62.2,
49.7, 15.7, 14.4.
MS (ES+): m/z = 353 (M + H).
Anal. Calcd for C20H20N2O4: C, 68.17; H, 5.72; N, 7.95. Found: C,
67.93; H, 5.67; N, 7.90.
MS (ES+): m/z = 379 (M + H).
7j
Anal. Calcd for C22H22N2O4: C, 69.83; H, 5.86; N, 7.40. Found: C,
69.86; H, 5.87; N, 7.35.
White crystalline solid; yield: 82%.
1H NMR (300 MHz, CDCl3): d = 8.05 (s, 1 H), 7.96–7.88 (m, 3 H),
7.62–7.53 (m, 3 H), 4.42 (q, J = 7.2 Hz, 2 H), 4.37 (q, J = 7.2 Hz, 2
H), 3.51 (s, 3 H), 1.43 (t, J = 7.2 Hz, 3 H), 1.40 (t, J = 7.2 Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 164.2, 159.3, 155.5, 141.4, 140.8,
133.2, 132.1, 131.6, 128.5, 128.4, 128.0, 127.7, 127.6, 127.0, 125.3,
68.0, 61.4, 34.6, 15.2, 14.0.
8b
Yellow oil; yield: 74%.
1H NMR (400 MHz, CDCl3): d = 7.36 (t, J = 1.2 Hz, 1 H), 7.22–7.14
(m, 5 H), 7.08 (d, J = 3.6 Hz, 1 H), 6.81 (d, J = 6.8 Hz, 1 H), 5.12
(d, J = 14.4 Hz, 1 H), 5.02 (d, J = 14.4 Hz, 1 H), 4.39 (q, J = 7.2 Hz,
4 H), 1.90 (s, 3 H), 1.43 (t, J = 7.2 Hz, 3 H), 1.38 (t, J = 7.2 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 164.6, 160.4, 155.3, 143.1, 141.7,
136.5, 135.4, 133.9, 130.8, 130.3, 128.6, 128.3, 128.14, 128.06,
126.1, 69.3, 62.2, 49.0, 19.2, 15.7, 14.3.
MS (ES+): m/z = 353 (M + H).
Anal. Calcd for C20H20N2O4: C, 68.17; H, 5.72; N, 7.95. Found: C,
67.87; H, 5.62; N, 7.80.
MS (ES+): m/z = 393 (M + H).
7k
White solid yield: 84%.
Anal. Calcd for C23H24N2O4·1/2H2O: C, 68.81; H, 6.28; N, 6.98.
Found: C, 68.33; H, 6.03; N, 6.88.
1H NMR (400 MHz, CDCl3): d = 7.46 (td, J = 8.4, 1.6 Hz, 1 H), 7.39
(dd, J = 7.6, 1.6 Hz, 1 H), 7.07 (t, J = 7.6 Hz, 1 H), 7.96 (d, J = 8.4
Hz, 1 H), 4.45–4.31 (m, 4 H), 3.82 (s, 3 H), 3.35 (s, 3 H), 1.44–1.36
(m, 6 H).
13C NMR (100 MHz, CDCl3): d = 164.8, 160.3, 156.5, 153.9, 142.7,
141.9, 132.1, 130.3, 123.9, 121.4, 111.0, 69.0, 62.0, 55.7, 33.3,
15.7, 14.3.
8c
Light-yellow solid, yield: 78%.
1H NMR (300 MHz, CDCl3): d = 7.43 (m, 1 H), 7.42–7.27 (m, 4 H),
7.12 (d, J = 5.1 Hz, 1 H), 6.99–6.98 (m, 2 H), 5.27 (s, 2 H), 4.42 (q,
J = 7.2 Hz, 2 H), 4.35 (q, J = 7.2 Hz, 2 H), 1.40 (t, J = 7.2 Hz, 6 H).
13C NMR (75 MHz, CDCl3): d = 164.7, 160.2, 151.6, 143.0, 141.8,
141.6, 135.9, 134.7, 129.1, 128.3, 128.0, 127.8, 126.7, 69.3, 62.2,
49.8, 15.7, 14.4.
MS (ES+): m/z = 333 (M + H).
Anal. Calcd for C17H20N2O5·1/2H2O: C, 59.81; H, 6.20; N, 8.21.
Found: C, 59.48; H, 6.01; N, 8.29.
MS (ES+): m/z = 385 (M + H).
7l
Anal. Calcd for C20H20N2O4S: C, 62.48; H, 5.24; N, 7.29. Found: C,
61.98; H, 5.31; N, 7.09.
White solid; yield: 65%.
1H NMR (300 MHz, CDCl3): d = 10.09 (s, 1 H), 8.02 (d, J = 8.1 Hz,
2 H), 7.71 (d, 2 H, J = 8.1 Hz), 4.41 (q, J = 6.9 Hz, 2 H), 4.37 (q,
J = 6.9 Hz, 2 H), 3.46 (s, 3 H), 1.43 (t, J = 6.9 Hz, 3 H), 1.38 (t, J =
6.9 Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 191.4, 164.5, 160.3, 153.8, 143.2,
141.4, 139.6, 137.6, 130.2, 129.4, 69.3, 62.3, 35.0, 15.7, 14.4.
Method C: This procedure is the same as Method B, except that 1%
of catalyst loading was used.
Compound 7b (see above for characterization) was obtained in 88%
isolated yield using this procedure.
Method D: This procedure is the same as Method A (Table 2), how-
ever, with a prolonged reaction time of 20 min. The following com-
pounds were obtained by this method:
MS (ES+): m/z = 331 (M + H).
Anal. Calcd for C17H18N2O5: C, 61.81; H, 5.49; N, 8.48. Found: C,
61.65; H, 5.44; N, 8.32.
9a
Yellow solid; yield: 84%.
7m
1H NMR (300 MHz, CDCl3): d = 7.35–7.08 (m, 10 H), 4.44 (q, J =
7.2 Hz, 2 H), 4.38 (q, J = 7.2 Hz, 2 H), 1.42 (t, J = 7.2 Hz, 3 H), 1.41
(t, J = 7.2 Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 164.7, 160.0, 154.5, 143.1, 141.8,
136.9, 134.4, 129.8, 129.4, 129.3, 129.1, 128.7, 128.1, 69.2, 62.2,
15.7, 14.3.
Yellow solid; yield: 70%.
1H NMR (300 MHz, CDCl3): d = 7.93 (d, J = 15.3 Hz, 1 H), 7.71 (d,
J = 8.1 Hz, 2 H), 7.57 (m, 2 H), 7.40 (m, 3 H), 6.96 (d, J = 15.3 Hz,
2 H), 4.44 (q, J = 7.2 Hz, 2 H), 4.29 (q, J = 7.2 Hz, 2 H), 3.68 (s, 3
H), 1.44 (t, J = 7.2 Hz, 3 H), 1.38 (t, J = 7.2 Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 165.0, 160.1, 151.9, 142.5, 142.2,
142.0, 135.3, 130.2, 129.1, 128.1, 117.7, 69.1, 62.1, 31.2, 15.6,
14.4.
MS (ES+): m/z = 365 (M + H).
Anal. Calcd for C21H20N2O4: C, 69.22; H, 5.53; N, 7.69. Found: C,
69.27; H, 5.53; N, 7.76.
MS (ES+): m/z = 329 (M + H).
Synthesis 2006, No. 8, 1343–1350 © Thieme Stuttgart · New York

1350
9b
S. Colarusso et al.
PAPER
HRMS: m/z calcd for C23H24N2O4: 392.4587; found: 392.4584.
White solid; yield: 34%.
1H NMR (300 MHz, CDCl3): d = 7.27–7.22 (m, 3 H), 7.07–7.02 (m,
6 H), 4.43 (q, J = 7.2 Hz, 2 H), 4.39 (q, J = 7.2 Hz, 2 H), 2.26 (s, 3
H), 1.42 (t, J = 7.2 Hz, 3 H), 1.41 (t, J = 7.2 Hz, 3 H).
13C NMR (100 MHz, DMSO-d6): d = 164.1, 159.0, 154.3, 141.8,
140.9, 136.4, 135.0, 133.9, 129.5, 129.0, 128.9, 128.6, 128.5, 124.7,
75.0, 68.1, 61.3, 19.1, 15.2, 13.9.
Acknowledgment
The authors gratefully thank Renzo Bazzo and Silvia Pesci for
NMR structural elucidation, and Francesca Naimo and Fabio Bo-
nelli for elemental analyses and HRMS. This work was partially
supported by a grant from the MIUR.
MS (ES+): m/z = 379 (M + H).
References
HRMS: m/z calcd for C22H23N2O4: 379.1658; found: 379.1657.
(1) Summa, V.; Petrocchi, A.; Matassa, V. G.; Taliani, M.;
Laufer, R.; De Francesco, R.; Pace, P. J. Med. Chem. 2004,
47, 5336.
(2) Stansfield, I.; Avolio, S.; Colarusso, S.; Gennari, N.; Narjes,
F.; Pacini, B.; Ponzi, S.; Harper, S. Bioorg. Med. Chem. Lett.
2004, 14, 5085.
(3) (a) Gong, Y.; Pauls, H. W. Synlett 2000, 829. (b) Cocuzza,
A. J.; Chideste, D. R.; Culp, S.; Fitzgerald, L.; Gilligan, P.
Bioorg. Med. Chem. Lett. 1999, 9, 1063.
9c
White solid; yield: 49%.
1H NMR (300 MHz, CDCl3): d = 7.38–7.31 (m, 3 H), 7.20 (d, J =
8.7 Hz, 2 H), 7.10 (d, J = 6.3 Hz, 2 H), 6.67 (d, J = 8.7 Hz, 2 H),
4.44 (q, J = 6.9 Hz, 2 H), 4.33 (q, J = 6.9 Hz, 2 H), 1.42 (t, J = 6.9
Hz, 3 H), 1.40 (t, J = 7.2 Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 164.8, 160.7, 160.2, 154.3, 142.7,
142.0, 137.2, 131.2, 129.4, 129.0, 128.7, 126.7, 113.5, 69.2, 62.2,
55.4, 15.7, 14.4.
(4) Zhang, D.; Sham, K.; Cao, G.-q.; Hungate, R.; Dominguez,
C. Tetrahedron Lett. 2002, 43, 8901.
MS (ES+): m/z = 395 (M + H).
(5) Wierenga, W.; Nicholas, J. A. In Comprehensive Medicinal
Chemistry, Vol. 3; Pergamon: London, 1990, 1122–1124.
(6) Ivin, B. A.; Rutkovskii, G. V.; Rusavskaya, T. N.; Smorygo,
N. A.; Sochilin, E. G. Khim. Get. Soed. 1974, 11, 1527;
Chem. Abstr. 1975, 82, 57638.
Anal. Calcd for C22H22N2O5: C, 66.99; H, 5.62; N, 7.10. Found: C,
66.98; H, 5.64; N, 7.16.
9d
(7) Wu, W. X. US Patent 5925764, 1999; Chem. Abstr. 1999,
This compound was obtained by the reaction of 3c with 2,6-dimeth-
ylphenylboronic acid using the conditions described.12
131, 87822.
(8) (a) Littke, A. F.; Fu, G. C. Angew. Chem. Int. Ed. 1998, 37,
3387. (b) Littke, A. F.; Dai, C.; Fu, G. C. J. Am. Chem. Soc.
2000, 122, 4020. (c) For an excellent review on Pd-
catalyzed cross-coupling of aryl chlorides, see: Littke, A. F.;
Fu, G. C. Angew. Chem. Int. Ed. 2002, 41, 4176.
(9) Netherton, M. R.; Fu, G. C. Org. Lett. 2001, 3, 4295.
(10) Lindström, P.; Tierney, J.; Wathey, B.; Westman, J.
Tetrahedron 2001, 57, 9225.
White solid; yield: 20%.
1H NMR (400 MHz, DMSO-d6): d = 7.27 (m, 5 H), 7.04 (t, J = 7.6
Hz, 1 H), 6.88 (d, J = 7.6 Hz, 2 H), 4.33 (q, J = 7.0 Hz, 2 H), 4.25
(q, J = 7.0 Hz, 2 H), 2.11 (s, 6 H), 1.31 (t, J = 7.0 Hz, 3 H), 1.30 (t,
J = 7.0 Hz, 3 H).
13C NMR (75 MHz, DMSO-d6): d = 163.96, 159.1, 154.0, 142.0,
141.3, 140.8, 135.8, 134.9, 133.7, 129.0, 128.9, 128.5, 126.9, 68.1,
61.4, 19.6, 15.2, 13.9.
(11) For a recent and comprehensive review on controlled
microwave heating in modern organic synthesis, see: Kappe,
O. C. Angew. Chem. Int. Ed. 2004, 43, 6250.
MS (ES+): m/z = 393 (M + H).
(12) Walker, S. D.; Barder, T. E.; Martinelli, J. R.; Buchwald, S.
Synthesis 2006, No. 8, 1343–1350 © Thieme Stuttgart · New York