Synthesis of nitrogen bicyclic scaffolds: Pyrimido[1,2-a]pyrimidine-2,6- diones

Article abstract of DOI:10.1016/j.tet.2010.10.059

The multi-step synthesis of 1,3,7-trisubstituted pyrimido[1,2-a] pyrimidinediones starting from isothiocyanates is described. These nitrogen bicycles were prepared by an iterative sequence of functionalization/ cyclocondensation reactions. [4+2] Cycloaddition reactions took place between diazadienic chains and various acyl chlorides providing sophisticated heterobicycles.

Full text of DOI:10.1016/j.tet.2010.10.059

Tetrahedron 66 (2010) 9912e9924
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis of nitrogen bicyclic scaffolds: pyrimido[1,2-a]pyrimidine-2,6-diones
,
Sylvain Grosjean a, Smail Triki b, Jean-Claude Meslin a, Karine Julienne a, David Deniaud a
*
a
ꢀ
ꢁ
ꢁ
ꢀ
ꢁ
Laboratoire Chimie Et Interdisciplinarite: Synthese, Analyse, Matiere (CEISAM), UMR CNRS 6230, UFR des Sciences et des Techniques, Universite de Nantes, 2, rue de la Houssiniere,
BP 92208, 44322 Nantes Cedex 3, France
b
ꢀ
ꢀ
Laboratoire de Chimie Electrochimie Moleculaires et Chimie Analytique (CEMCA), UMR 6521, Universite de Bretagne Occidentale, 6, avenue Victor Le Gorgeu, CS 93837,
29238 Brest Cedex 3, France
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 4 August 2010
Received in revised form 19 October 2010
Accepted 21 October 2010
Available online 28 October 2010
The multi-step synthesis of 1,3,7-trisubstituted pyrimido[1,2-a]pyrimidinediones starting from iso-
thiocyanates is described. These nitrogen bicycles were prepared by an iterative sequence of function-
alization/cyclocondensation reactions. [4þ2] Cycloaddition reactions took place between diazadienic
chains and various acyl chlorides providing sophisticated heterobicycles.
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
1,3-Diazabutadienes
[4þ2] Cycloaddition
Nitrogen heterocycles
Dihydropyrimidinones
Methylsulfanyl group
functionnalization
1. Introduction
Me2N
N
SMe
R1
S
R1
C
N
N
Pyrimidopyrimidine moieties are widely represented both in
natural and synthetic compounds, and usually display a broad range
of biological properties.1e3 Surprisingly, literature on general access
to [1,2-a]-analoguesdin which one of the three nitrogen atoms is at
the junction of the two cyclesdis rather limited, with the exception
of some examples of specific one-pot or microwave assisted reac-
tions.4e7 In addition to the potential therapeutic applications, the
pyrimido[1,2-a]pyrimidine compounds containing a guanidine-like
moiety in the structure are also studied as ligands for catalytic
activities.8e10
N
O
SMe
R1
functionnalization
cyclization
N
R2
R2CH2COCl
R3
O
N
NMe2
N
O
N
cyclization
N
R3CH2COCl
N
N
R2
R1
R2
R1
O
Scheme 1.
In this paper we describe an original and general method for the
synthesis of pyrimido[1,2-a]pyrimidine-2,6-diones with an iso-
thiocyanate starting material. Both heterocycles of the bicyclic
structure areobtainedthroughacyclocondensationreactionbetween
a diazadiene moiety and an acyl chloride. The synthesis is based on an
iterative sequence (diazadiene formation followed by cyclization re-
action) and consists of four parts (Scheme 1): functionalization of an
isothiocyanate into a diazadienic chain; first cycloaddition reaction
providing a pyrimidinone; introduction of a second diazadienic chain
onto the structure; and second cycloaddition reaction providing
a pyrimidopyrimidinedione.
2. Results and discussion
2.1. Pyrimidinone synthesis
The first step of the synthesis involved the conversion of com-
mercially available isothiocyanates into the corresponding thio-
ureas 1. Reactions were performed in a solution of ammonia in
methanol (7 M) in a sealed tube affording thioureas 1, which then
reacted with N,N-dimethylformamide dimethyl acetal (DMFDMA)
in dichloromethane to give thiazadienes 2. The thiocarbonyl groups
were then alkylated with methyl iodide in tetrahydrofuran to afford
2-methylsulfanyl diazadienium iodides 3 in good yields (Scheme 2).
* Corresponding author. E-mail address: david.deniaud@univ-nantes.fr (D.
Deniaud).
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.10.059

S. Grosjean et al. / Tetrahedron 66 (2010) 9912e9924
9913
S
i
R1
S
iii
R1
C
I
SMe
N
SMe
N
N
NH2
N
or ii
R1
H
R1
i
H
1a-h
N
NMe2
N
NMe2
3b-g
4b-g
I
S
SMe
N
iv
R1
H
R1
H
Scheme 3. Synthesis of diazadienes 4. Reagents and conditions: (i) saturated aqueous
NaHCO3, Et2O.
N
N
NMe2
N
NMe2
2a-h
3a-h
Scheme 2. Three-step synthesis of diazadienium iodides
3 from isothiocyanates.
Reagents and conditions: (i) NH3/MeOH 7 M (excess) for 1aef and 1h; (ii) From ben-
zoylisothiocyanate: N,N-dimethylhydrazine (1 equiv), EtOH, then HCl 4 M, H2O for 1g;
(iii) DMFDMA (1.2 equiv), CH2Cl2; (iv) MeI (1.05 equiv), THF.
Me2N
I
N
HN
SMe
R1
N
O
SMe
R1
Me2N
R2
N
O
SMe
R1
i
N
R2
N
3
5a-x
Scheme 4. Synthesis of pyrimidin-4(3H)-ones 5 from diazadienium iodides 3. Re-
The three-step synthetic sequence from isothiocyanates to dia-
zadienium iodides 3 proved to be attractive because of an easy
work-up, short reaction times, scalability and high yields. For ex-
ample 40 g of the compound 3b (R1¼pTol) was synthesized in one
batch in 95% overall yield. Diazadienium iodides 3aeh were
obtained with excellent yields independent of the nature of the R1
group (Table 1): hydrogen (entry 1), aryl (entries 2e4), alkyl (en-
tries 5 and 6), electron donating group (entry 7), and electron
withdrawing group (entry 8).11e13 The compound 1g (R1¼NMe2,
entry 7) was obtained by a different method in two steps through
reaction of N,N-dimethylhydrazine with benzoylisothiocyanate
followed by hydrolysis of the benzoyl group under acidic
conditions.
agents and conditions: (i) R2CH2COCl (3 equiv), NEt3 (4 equiv), CH2Cl2.
commercially available and were prepared from the corresponding
carboxylic acids (1,1,1-trifluoropropionic acid for 5b; N,N-dime-
thylglycine for 5g). The poor solubility of N,N-dimethylglycine in
common organic solvents is responsible for the dramatic decrease
of yield (11%). For compound 5f (entry 6), microwave irradiation
activation16 allowed us to improve the reaction yield from 65% to
95%. For compounds 5per (R1¼Ac, entries 16e18) low yields were
obtained due to partial deacetylation of the nitrogen atom.
Table 2
Synthesis of N-substituted pyrimidinones 5 from diazadienium iodides 3 (Scheme 4)
Table 1
Entry
R1
R2
Compd (5) (%)a
Synthesis of thioureas 1, thiazadienes 2, diazadienium iodides 3, and diazadienes 4
(Schemes 2 and 3)
1
2
3
4
5
6
7
8
pTol
pTol
pTol
pTol
pTol
pTol
pTol
Me
Me
Me
Me
Me
H
H
H
Ac
Ac
Ac
CO2Me
CF3
H
Ph
OMe
Me
NMe2
CO2Me
H
Ph
OMe
Me
CO2Me
H
Ph
CO2Me
H
Ph
CO2Me
H
Ph
CO2Me
H
Ph
5a (97)
5b (97)b
5c (95)
5d (85)
5e (90)
5f (95)c
5g (11)b
5h (91)
5i (86)
5j (74)
5k (62)
5l (73)
5m (82)
5n (68)
5o (80)
5p (37)
5q (47)
5r (10)
5s (76)
5t (84)
5u (72)
5v (79)
5w (78)
5x (95)
Entry R1
Compd (1) (%)a Compd (2) (%)d Compd (3) (%)e Compd (4) (%)f
1
2
3
4
5
6
7
8
H
pTol
Ph
mCl2Ph 1d (95)
Me
1ab
2a (100)
2b (99)
2c (94)
2d (95)
2e (98)
2f (95)
2g (97)
2h (96)
3a (100)
3b (100)
3c (98)
3d (99)
3e (98)
3f (98)
4a (d)
4b (96)
4c (98)
4d (94)
4e (76)
4f (88)
4g (78)
4h (d)
1b (98)
1cb
1eb
1f (95)
cHx
9
NMe2 1g (68)c
3g (95)
3h (98)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
Ac
1hb
a
b
c
Reagents and conditions: NH3/MeOH (7 M).
Commercially available.
From benzoylisothiocyanate: N,N-dimethylhydrazine (1 equiv), EtOH, then HCl
4 M, H2O.
d
DMFDMA (1.2 equiv), CH2Cl2.
MeI (1.05 equiv), THF.
Saturated aqueous NaHCO3, Et2O.
e
f
NMe2
NMe2
NMe2
mCl2Ph
mCl2Ph
mCl2Ph
A further neutralization step led to the formation of neutral
diazadienic chain containing compounds 4beg (Scheme 3). The
reaction was performed under basic conditions using aqueous
NaHCO3. However, diazabutadienes 4a (R1¼H) and 4h (R1¼Ac)
were not obtained, and analogues 4beg showed rapid degradation.
Conversely, all diazadienium salts 3aeh were very stable and
proved to be reactive in this ionic form.13,14 Indeed, the first cycli-
zation reaction took place between the diazadienium iodides 3 and
acyl chlorides in basic medium to give pyrimidin-4(3H)-ones 5
(Scheme 4).15 Intermediary cycloadducts were not isolated due to
spontaneous loss of dimethylamine; the tandem [4þ2] cycloaddi-
tion/deamination led to the formation of the expected pyrimidin-4
(3H)-one together with a secondary product (a N,N-dimethylamide
corresponding to the addition of dimethylamine onto the acyl
chloride), but this was easily removed by aqueous wash.
a
Reagents and conditions: R2CH2COCl (3 equiv), NEt3 (4 equiv), CH2Cl2.
b
R2CH2CO2H (3 equiv), (COCl)2 (3.3 equiv), DMF (0.1 equiv), CH2Cl2, 0 ꢀC; then 4b
(1.0 equiv), NEt3 (4 equiv), CH2Cl2.
c
Under microwave irradiation: 50 ꢀC, 60 W, 15 min.
2.2. From pyrimidinone rings to bicyclic structures
At this point we chose to limit our study to the five compounds
5aee (R1¼pTol) for the installation of the second ring. The para-
tolyl group was chosen for two main reasons: this group gave the
best general yields for the sequence from para-tolylisothiocyanate
to pyrimidinones 5 (except for 5g), and it showed a specific NMR
signal (a singlet between 2.4 and 2.6 ppm), which was a practical
tool to follow reaction progress.
Compounds 5aex were synthesized with moderate to excellent
yields (Table 2). For compounds 5b (R1¼pTol, R2¼CF3; entry 2) and
5g (R1¼pTol, R2¼NMe2; entry 7), the acyl chlorides were not

9914
S. Grosjean et al. / Tetrahedron 66 (2010) 9912e9924
As the methylsulfanyl group is often considered a leaving group,
We then undertook the nucleophilic displacement of the
methylsulfonyl group by ammonia on compounds 6cee (Table 3).
Gaseous ammonia was passed for 1 h through a solution of com-
pounds 6 in toluene, and the medium was stirred at room tem-
perature for 24 h. Under these conditions products 7c (R2¼H,
entry 4) and 7d (R2¼Ph, entry 5) were obtained in quantitative
yields. Sulfone 6e (R2¼OMe, entry 6) on the other hand was non-
reactive and recovered after the experiment. This result was at-
tributed to the electron donating effect of the OMe group, deacti-
vating substrate 6e to nucleophilic attack. However, nucleophilic
substitution was finally accomplished by use of formamide in
a sealed tube under microwave irradiation at 190 ꢀC.16 Under these
conditions ammonia is produced in situ by thermal decomposition
of formamide,23,24 giving rise to the formation of compound 7e,
which was not isolated but directly engaged in the next step.
With aminopyrimidinones 7 in hand, there were two remaining
steps to complete the bicyclic synthesis. Condensation of com-
pounds 7 with DMFDMA led to the formation of formamidines 8
(Scheme 7). Compounds 8aee were obtained after 3e6 h reaction
time in dichloromethane in good to excellent yields (Table 3) except
forcompound 8e (R2¼OMe, entry 6), which was isolated in 44% yield
over two steps from sulfone 6e. The second cyclization reaction took
place between compounds 8 and acyl chlorides R3CH2COCl. We
limited our study to three acyl chlorides: acetyl chloride (R3¼H),
methylmalonyl chloride (R3¼CO2Me), and methoxyacetyl chloride
(R3¼OMe). In contrast to the first cycloaddition reaction, this second
one had to be conducted at the reflux of dichloromethane.
we thought that the introduction of an amino group on the het-
erocyclic structure 5 could be achieved by direct nucleophilic dis-
placement with ammonia.17,18 This nucleophilic substitution
reaction proved to be possible only when R2 group was an electron
withdrawing group. In all other cases the reaction substrates were
recovered quantitatively. Thus, treatment of compounds 5a and 5b
(R2¼CO2Me or CF3) with ammonia solution in methanol afforded
the corresponding 2-aminopyrimidines 7a and 7b in quantitative
yield (Table 3, entries 1 and 3). In addition, for R2¼CO2Me, we could
efficiently perform the transformation of methyl carboxylate to
carboxamide 7a0 using large excess of ammonia (Scheme 5, Table 3,
entry 2).
Table 3
Synthesis of compounds 6, 7, and 8 (Schemes 5e7)
Entry
R1
R2
Compd (6) (%)a
Compd (7) (%)
Compd (8) (%)f
1
2
3
4
5
6
pTol
pTol
pTol
pTol
pTol
pTol
CO2Me
CONH2
CF3
H
Ph
d
7a (99)b
7a0 (85)c
7b (100)c
7c (100)d
7d (100)d
7ee
8a (89)
8a0 (90)
8b (92)
8c (78)
8d (91)
8e (44)g
d
d
6c (100)
6d (100)
6e (100)
OMe
a
Reagents and conditions: DMDO/acetone (0.08 M).
NH3/MeOH (7 M) (5 equiv).
NH3/MeOH (7 M) (large excess).
NH3 (g), toluene.
Under microwave irradiation: formamide, 190 ꢀC, 200 W, 5 min, not isolated.
DMFDMA (1.2 equiv), CH2Cl2.
b
c
d
e
f
g
Calculated yield over two steps from sulfone 6e.
R3
NMe2
N
NH2
O
N
O
NH2
R1
i
N
O
N
ii
7a
, 99%
O
MeO
N
N
N
O
N
N
R2
pTol
i
N
SMe
N
R2
R1
O
N
N
R2
R1
N
MeO2C
pTol
NH2
ii
O
7a-e
8a-e
9a-x
7a'
, 85%
O
H2N
5a
pTol
Scheme 7. Two-step synthesis of pyrimido[1,2-a]pyrimidine-2,6-diones
2-aminopyrimidinones 7. Reagents and conditions: (i) DMFDMA (1.2 equiv), CH2Cl2;
9 from
O
(ii) R3CH2COCl (3 equiv), NEt3 (3 equiv), CH2Cl2, reflux.
Scheme 5. Synthesis of 2-aminopyrimidinones 7. Reagents and conditions: (i) NH3/
MeOH (7 M) (5 equiv); (ii) NH3/MeOH (7 M) (large excess).
Reaction of compounds 8aee with acyl chlorides allowed us to
isolate 18 novel trisubstituted pyrimido[1,2-a]pyrimidine-2,6-dio-
nes 9aer in excellent yields (Table 4). The reactivity of for-
mamidines 8a,a0,b, with R2 being an electron withdrawing group,
was sluggish and the supplementary addition of 3 equiv of acyl
chloride/NEt3 after 3 h reaction time was necessary (entries 1e9).
In order to increase the reactivity of the other heterocyclic
substrates 5 toward nucleophiles, such as ammonia, we decided
to oxidize the methylsulfanyl group to a methylsulfoxide or
a methylsulfonyl group. In this way we aimed to increase the
electrophilicity of the carbon bearing the methylsulfanyl group.
Oxidation was first attempted by use of common oxidizing agents
such as m-CPBA and H2O2; but in these cases reactions only led to
carbonylated compounds corresponding to the hydrolysis of the
activated sulfur group (pyrimidine-2,4(1H,3H)-diones).17 The oxi-
dation reaction was finally achieved without any hydrolysis by
using a freshly distilled solution of dimethyldioxirane (DMDO) in
acetone, a powerful anhydrous oxidant.19e22 The use of less than
2 equiv of dioxirane led to a mixture of compounds (SMe, SOMe,
and SO2Me), whereas 2.5 equiv of oxidant afforded the methyl-
sulfone products exclusively and quantitatively (Scheme 6).
Table 4
Synthesis of trisubstituted pyrimido[1,2-a]pyrimidine-2,6-diones 9aer from com-
pounds 8aee (Scheme 7)
Entry
R1
R2
R3
Compd (9) (%)a
1
2
3
4
5
6
7
8
pTol
pTol
pTol
pTol
pTol
pTol
pTol
pTol
pTol
pTol
pTol
pTol
pTol
pTol
pTol
pTol
pTol
pTol
CO2Me
CO2Me
CO2Me
CONH2
CONH2
CONH2
CF3
CF3
CF3
H
H
H
Ph
Ph
Ph
OMe
OMe
OMe
CO2Me
H
OMe
CO2Me
H
OMe
CO2Me
H
OMe
CO2Me
H
OMe
CO2Me
H
OMe
CO2Me
H
9a (84)b
9b (89)b
9c (76)b
9d (72)b
9e (71)b
9f (94)b
9g (94)b
9h (93)b
9i (95)b
9j (72)
9
10
11
12
13
14
15
16
17
18
9k (77)
9l (84)
N
O
SMe
R1
N
O
SO2Me
N
O
NH2
R1
i
ii
or iii R2
9m (86)
9n (86)
9o (89)
9p (99)
9q (99)
9r (89)
N
N
N
R2
R2
R1
5c-e
6c-e
7c-e
OMe
Scheme 6. Oxidation and nucleophilic displacement of methylsulfanyl group.
Reagents and conditions: (i) DMDO/acetone (0.08 M); (ii) NH3 (g), toluene for 7c,d; (iii)
Under microwave irradiation: formamide, 190 ꢀC, 200 W, 5 min for 7e.
a
Reagents and conditions: R3CH2COCl (3 equiv), NEt3 (3 equiv), CH2Cl2, reflux.
The addition of 3 equiv of acyl chloride/NEt3 was necessary.
b

S. Grosjean et al. / Tetrahedron 66 (2010) 9912e9924
9915
The structure of compound 9j (entry 10) was determined by
3. Conclusions
single crystal X-ray diffraction.25 The molecular structure depicted
in Fig. 1 is in good agreement with the bicyclic structure expected
for 9. However, it should be pointed out that the eCO2Me (R3)
group slightly deviates from the mean plan of the bicyclic group
In conclusion, we have described an efficient multi-step syn-
thesis of 24 sophisticated 1,3,7-trisubstituted pyrimido[1,2-a]py-
rimidine-2,6-diones in high yields from commercially available
sources. This synthetic sequence allowed us to introduce different
groups into the structure, such as aryl and alkyl groups, or func-
tional groups with either electron withdrawing or donating effects.
One of the key steps of the synthetic pathway is the nucleophilic
displacement of the methylsulfanyl group by ammonia. Depending
on the electronic properties of the R1 groups oxidation to the
methylsulfonyl is occasionally required. Independent of the acti-
vating or deactivating effects of these groups, we were able to
perform this substitution reaction. Other key features of our
strategy are the elaboration of reactive diazadienic building blocks
and subsequent cyclization reactions. We are now focusing on the
synthesis of new puric nucleoside analogues from glyco-
sylisothiocyanates using a similar synthetic pathway.
ꢂ
(maximum deviation of 0.3 A for O3 and O4 oxygen atoms), while
the para-tolyl group forms a large dihedral angle of 77.22(5)ꢀ.26
4. Experimental section
4.1. General
Fig. 1. ORTEP25 view showing the bicyclic molecular structure of compound 9j (ther-
NMR spectra were recorded at room temperature with a Brucker
AC 300 spectrometer at 300 MHz (1H), 75 MHz (13C) and 300 MHz
(
mal ellipsoids are plotted at the 50% probability).26
19F). Chemical shifts are reported in parts per million (ppm);
In order to confirm these results, we next enlarged the study to
the N-methyl compounds 5h and 5j (R1¼Me; R2¼CO2Me or Ph)
(Table 5). As expected, the electron withdrawing methyl carboxyl-
ate group enabled the direct nucleophilic displacement of the
methylsulfanyl group (7f, entry 1), while the pyrimidinone bearing
a phenyl group needed to be activated by oxidation to sulfone 6g
with DMDO to achieve nucleophilic substitution (7g, entry 2).
Compounds 7f,g were then transformed into the corresponding
formamidines 8f,g by condensation with DMFDMA.
coupling constant are reported in units of Hertz [Hz]. Infrared (IR)
spectra were recorded with a Bruker Vector 22 FTIR using KBr films
or KBr pellets. Low-resolution mass spectra (MS) were recorded
with a Hewlett Packard 5989 A spectrometer. High-resolution mass
spectra (HRMS) were recorded with a Thermofisher hybrid LTQ-
orbitrap spectrometer (ESIþ) and with a Bruker Autoflex III
SmartBeam spectrometer (MALDI). Melting points were de-
termined in open capillary tubes and are uncorrected. All reagents
were purchased from Acros Organics or Aldrich and were used
without further purification. Column chromatographies were
conducted on silica gel Kieselgel SI60 (40e63 mm) from Merck.
Table 5
Synthesis of compounds 6g, 7f,g, and 8f,g (Schemes 5e7)
Reactions requiring anhydrous conditions were performed under
nitrogen. Dichloromethane was distilled from calcium hydride
under argon prior to use. Toluene and tetrahydrofuran were dis-
tilled from sodium/benzophenone under argon prior to use.
The compounds 1g, 2a,c,eeg,i,j, 3a,c,eeg,i,j, 5hej,ner have al-
ready been described in the literature.
Entry
R1
R2
Compd (6) (%)a
Compd (7) (%)
Compd (8) (%)d
1
2
Me
Me
CO2Me
Ph
d
7f (78)b
8f (99)
8g (96)
6g (100)
7g (100)c
a
Reagents and conditions: DMDO/acetone (0.08 M).
NH3/MeOH (7 M) (5 equiv).
NH3 (g), toluene.
b
c
d
DMFDMA (1.2 equiv), CH2Cl2.
4.2. General procedure for the preparation of N-substituted
thiourea 1
These compounds were engaged in the last cycloaddition
A solution of N-substituted isothiocyanate (p-tolylisothiocya-
nate for 1b, 3,5-dichlorophenylisothiocyanate for 1d and cyclo-
hexylisothiocyanate for 1f) (1 equiv) in methanolic ammonia (7 M,
large excess) was stirred at 50 ꢀC in a sealed tube for 6 h. After
concentration under reduced pressure, the resulting solid was
washed with a minimum of methanol.
reaction under the same conditions and with the same reaction
partners as in the para-tolyl study (Table 6). Formamidines 8f
(R2¼CO2Me) and 8g (R2¼Ph) afforded the bicyclic compounds 9seu
(entries 1e3) and 9vex (entries 4e6), respectively in good yields.
Table 6
4.2.1. 1-p-tolylthiourea (1b). White solid (3.768 g, 98%). Mp
Synthesis of trisubstituted pyrimido[1,2-a]pyrimidinediones 9sex from compounds
8f,g (Scheme 7)
185e186 ꢀC. IR (KBr):
n
¼3428 (s), 3274 (s), 3167 (s), 3078 (m),
3000e2800 (w), 1613, 1583, 1508, 1468 (m), 1535 (s), 1470 (w),
1310e1237 (m), 800 (m) cmꢁ1 1H NMR (300 MHz, DMSO-d6):
¼2.27 (s, 3H, PhCH3), 7.13 and 7.24 (AB system, 4H, J¼8.3 Hz, Har),
7.30 (br s, 2H, NH2), 9.57 (s, 1H, NH) ppm. 13C NMR (75 MHz, DMSO-
entry
R1
R2
R3
Compd (9) (%)a
.
1
2
3
4
5
6
Me
Me
Me
Me
Me
Me
CO2Me
CO2Me
CO2Me
Ph
Ph
Ph
CO2Me
H
OMe
CO2Me
H
9s (92)b
9t (66)b
9u (72)b
9v (98)
9w (95)
9x (99)
d
d6):
d
¼20.4 (PhCH3), 123.3 and 129.1 (4CHar), 133.7 and 136.4 (2Car),
180.9 (C]S) ppm. MS (EI, 70 eV): m/z (%)¼166 (65) [M]þ, 133 (17),
106 (100), 91 (21), 65 (11).
OMe
a
Reagents and conditions: R3CH2COCl (3ce:hsp sp¼"0.25"/>equiv), NEt3
4.2.2. 1-(3,5-Dichlorophenyl)thiourea (1d). White solid (2.655 g,
(3 equiv), CH2Cl2, reflux.
b
95%). Mp 175e177 ꢀC. IR (KBr):
n¼3447 (m), 3258 (m), 3095 (w),
The addition of 3 equiv of acyl chloride/NEt3 was necessary.

9916
S. Grosjean et al. / Tetrahedron 66 (2010) 9912e9924
3069 (w), 3009 (w), 1618 (s), 1577 (s), 1540 (m), 1472 (w), 1434 (m),
1389 (w) cmꢁ1. 1H NMR (300 MHz, DMSO-d6):
¼7.29 (s, 1H, Har),
7.60 (s, 2H, Har), 7.80 (br s, 2H, NH2), 9.93 (br s, 1H, NH) ppm. 13
NMR (75 MHz, DMSO-d6):
4.4. General procedure for the preparation of N-substituted
1,3-diazabutadienium iodides 3
d
C
d
¼120.5 (2CHar), 123.0 (CHar), 133.6
Methyl iodide (1.05 equiv) was added to a suspension of thia-
zadiene 2 (1.0 equiv) in THF. The mixture was stirred at room
temperature for 3 h for 3b, 6 h for 3d, and 3f. The solvent was re-
moved and the residue was crystallized from ether.
(2CareCl), 141.9 (Car), 181.3 (C]S) ppm. MS (EI, 70 eV): m/z (%)¼220
(53) [M]þ, 187 (20), 161 (100), 145 (15), 90 (38), 75 (22), 63 (57).
4.2.3. 1-Cyclohexylthiourea (1f). White solid (5.301 g, 95%). Mp
164e165 ꢀC. IR (KBr):
n
¼3333 (s), 3272 (s), 3076 (w), 2929 (m),
2857 (w), 1619 (s), 1561 (s), 1454 (m), 1370 (m), 1342 (w) cmꢁ1. 1H
NMR (300 MHz, DMSO-d6):
¼1.15e1.31 and 1.51e1.80 (m, 10H,
4.4.1. 4-Dimethylamino-2-methylsulfanyl-1-p-tolyl-1,3-diazabuta-
1,3-dienium iodide (3b). White solid (1.598 g, 100%). Mp
d
150e151 ꢀC. IR (KBr):
n
¼3141 (m), 3086 (m), 2984 (m), 1638 (s),
1590 (m), 1516 (s), 1502 (s), 1418 (m), 1387 (s), 821 (m) cmꢁ1 1H
NMR (300 MHz, CDCl3):
CH2), 3.89 (br s, 1H, NCH), 6.78 and 7.23 (2br s, 2H, NH2), 7.47 (d, 1H,
.
J¼7.8 Hz, NH) ppm. 13C NMR (75 MHz, DMSO-d6):
d
¼24.5 (2CH2),
d
¼2.35 (s, 3H, PhCH3), 2.44 (s, 3H, SCH3),
25.1 (CH2), 32.2 (2CH2), 52.1 (NCH), 181.8 (C]S) ppm. MS (EI,
70 eV): m/z (%)¼159 (20), 158 (100) [M]þ, 125 (12), 98 (18), 60 (77).
3.21 and 3.41 (2s, 6H, N(CH3)2), 7.19 and 7.34 (AB system, 4H,
J¼8.3 Hz, Har), 8.99 (s, 1H, H4), 11.15 (br s, 1H, NH) ppm. 13C NMR
(75 MHz, CDCl3):
d
¼15.0 (SCH3), 21.3 (PhCH3), 36.7 and 43.3 (N
(CH3)2), 122.6 and 130.1 (4CHar), 132.8 and 139.0 (2Car), 157.3 (C4),
177.6 (C2) ppm. MS (EI, 70 eV): m/z (%)¼236 (4) [MꢁI]þ, 235 (7), 188
(100), 91 (18), 65 (12), 44 (4).
4.3. General procedure for the preparation of N-substituted
1,3-thiazabutadienes 2
4.4.2. 4-Dimethylamino-1-(3,5-dichlorophenyl)-2-methylsulfanyl-
N,N-Dimethylformamide dimethyl acetal (1.2 equiv) was added
to a suspension of substituted thiourea 1 (1.0 equiv) in dichloro-
methane. The mixture was stirred at room temperature for 2 h for
2b, 3 h for 2d, and 2f. The solvent was removed and the residue was
crystallized from ether.
1,3-diazabuta-1,3-dienium iodide (3d). Yellow solid (4.190 g, 99%).
Mp 114e116 ꢀC. IR (KBr):
n
¼3142 (w), 3090 (w), 3050 (w), 2961 (w),
2920 (w), 1643 (s), 1586 (m), 1507 (s), 1440 (m), 1417 (m), 1395 (s),
1307 (w) cmꢁ1 1H NMR (300 MHz, CDCl3):
.
d
¼2.52 (s, 3H, SCH3),
3.26 and 3.47 (2s, 6H, N(CH3)2), 7.36 (s, 1H, Har), 7.44 (s, 2H, Har),
8.96 (s, 1H, H4), 11.42 (br s, 1H, NH) ppm. 13C NMR (75 MHz, CDCl3):
4.3.1. 4-Dimethylamino-2-p-tolylamino-1,3-thiazabuta-1,3-diene
d
¼21.0 (PhCH3), 37.0 and 43.5 (N(CH3)2), 124.7 (2CHar), 128.6 (CHar),
(2b). White crystal (3.970 g, 99%). Mp 155e156 ꢀC. IR (KBr):
n
¼3198
135.5 (2CareCl), 137.3 (Car), 157.9 (C4), 176.9 (C2) ppm. MS (EI,
70 eV): m/z (%)¼291 (5) [MꢁI]þ, 289 (8), 244 (59), 242 (100), 127
(13), 44 (13), 42 (23).
(m), 3168 (m), 3097 (m), 3030 (m), 2923 (w), 1626 (s), 1593 (m),
1541 (m), 1507 (m), 1479 (m), 1442 (m), 1370 (s), 1324 (m), 1159 (m),
1122 (m), 824 (m) cmꢁ1 1H NMR (300 MHz, CDCl3): major (63%)
.
d
¼2.31 (s, 3H, PhCH3), 3.10 and 3.20 (2 s, 6H, N(CH3)2), 7.09 and 7.33
4.4.3. 1-Cyclohexyl-4-dimethylamino-2-methylsulfanyl-1,3-dia-
zabuta-1,3-dienium iodide (3f). Yellow solid (9.786 g, 98%). Mp
(AB system, 4H, J¼8.1 Hz, Har), 8.52 (br s, 1H, NH), 8.88 (s, 1H, H4)
ppm. Minor (37%)
d¼2.33 (s, 3H, PhCH3), 7.16 and 7.58 (AB system,
109e111 ꢀC. IR (KBr):
n
¼3200 (m), 2967 (m), 2938 (w), 2915 (w),
2943 (w), 1643 (s), 1536 (s), 1499 (s), 1453 (m), 1398 (m), 1362 (w)
cmꢁ1 1H NMR (300 MHz, CDCl3):
4H, J¼8.1 Hz, Har), 8.38 (br s, 1H, NH), 8.94 (s, 1H, H4) ppm. 13C NMR
(75 MHz, CDCl3): major
d¼21.0 (PhCH3), 35.9 and 41.7 (N(CH3)2),
.
d
¼1.25 and 1.82e2.00 (m, 10H,
122.4 and 129.2 (4CHar), 134.2 and 136.4 (2Car), 162.8 (C4), 191.3
CH2), 2.48 (s, 3H, SCH3), 3.14 and 3.39 (2s, 6H, N(CH3)2), 3.62 (m, 1H,
(C2) ppm. Minor
d
¼36.4 and 41.7 (N(CH3)2), 124.1 and 129.2 (4CHar),
NCH), 8.83 (s, 1H, H4), 9.63 (br s, 1H, NH) ppm. 13C NMR (75 MHz,
164.1 (C4) ppm. MS (EI, 70 eV): m/z (%)¼221 (20) [M]þ, 115 (100), 91
CDCl3):
d
¼14.3 (SCH3), 24.7 and 31.6 (4 CH2), 36.1 and 42.6 (N
(11), 65 (9), 44 (15).
(CH3)2), 56.4 (NCH), 156.2 (C4), 175.6 (C2) ppm. MS (EI, 70 eV): m/z
(%)¼228 (11) [MꢁI]þ, 213 (8), 180 (47), 127 (14), 115 (10), 98 (100),
44 (7).
4.3.2. 4-Dimethylamino-2-(3,5-dichlorophenyl)amino-1,3-thiaza-
buta-1,3-diene (2d). White crystal (2.956 g, 95%). Mp 184e186 ꢀC.
IR (KBr):
(s), 1579 (s), 1479 (w), 1438 (m), 1352 (s), 1311 (m), 1256 (w) cmꢁ1
1H NMR (300 MHz, CDCl3):
¼3.15 and 3.25 (2s, 6H, N(CH3)2), 7.08
(br s, 1H, Har), 7.48 (br s, 2H, Har), 8.57 (br s, 1H, NH), 8.88 (s, 1H, H4)
n
¼3196 (m), 3095 (w), 3069 (w), 3027 (w), 2923 (w), 1626
.
4.5. General procedure for the preparation of N-substituted
1,3-diazabutadienes 4
d
ppm. 13C NMR (75 MHz, CDCl3):
d
¼36.6 and 42.0 (N(CH3)2), 120.4
To a suspension of compound 3 (1.0 equiv) in ether was added
a saturated solution of potassium hydrogencarbonate. The mixture
was stirred at room temperature for 2 h. After extraction with ethyl
acetate, the combined organic layers were washed with brine, dried
over magnesium sulfate, and concentrated under reduced pressure
to give 4.
(2CHar), 123.8 (CHar), 134.8 (2CareCl), 140.6 (Car), 164.1 (C4), 191.9
(C2) ppm. MS (EI, 70 eV): m/z (%)¼277 (12), 275 (18) [M]þ, 242 (4),
115 (100).
4.3.3. 2-Cyclohexylamino-4-dimethylamino-1,3-thiazabuta-1,3-di-
ene (2f). White crystal (6.212 g, 95%). Mp 117e119 ꢀC. IR (KBr):
n
¼3197 (m), 3013 (w), 2919 (m), 2851 (m), 1622 (s), 1531 (m), 1484
(w), 1443 (m), 1372 (s), 1356 (s), 1341 (m) cmꢁ1. 1H NMR (300 MHz,
CDCl3): major (68%)
¼1.23e2.14 (m, 10H, CH2), 3.03 and 3.13 (2s,
6H, N(CH3)2), 4.36 (m, 1H, NCH), 6.65 (br s, 1H, NH), 8.89 (s, 1H, H4)
ppm. Minor (32%)
¼1.23e2.14 (m, 10H, CH2), 3.10 and 3.17 (2s, 6H,
N(CH3)2), 4.06 (m,1H, NCH), 6.76 (br s,1H, NH), 8.85 (s,1H, H4) ppm.
13C NMR (75 MHz, CDCl3): major
¼24.7 and 32.2 (CH2), 35.5 and
4.5.1. 4-Dimethylamino-2-methylsulfanyl-1-p-tolyl-1,3-diazabuta-
1,3-diene (4b). White solid (610 mg, 96%). Mp 86e87 ꢀC. IR (KBr):
d
n
¼3077 (w), 3041 (w), 3022 (w), 2995 (w), 2956 (w), 2877 (w),1624
(s),1548 (s),1501 (m),1486 (m),1418 (s),1342 (s),1155 (m),1086 (s),
858 (w), 822 (w) cmꢁ1 1H NMR (300 MHz, CDCl3): major (80%)
d
.
d
¼2.31 (s, 3H, PhCH3), 2.39 (s, 3H, SCH3), 3.06 and 3.10 (2s, 6H, N
d
(CH3)2), 6.81 and 7.10 (AB system, 4H, J¼7.7 Hz, Har), 8.24 (s, 1H, H4)
41.2 (N(CH3)2), 53.2 (NCH), 162.3 (C4), 191.7 (C2) ppm. Minor
d¼25.4
ppm. Minor (20%)
d
¼2.31 (s, 3H, PhCH3), 2.47 (s, 3H, SCH3), 2.85 and
and 32.6 (CH2), 35.7 and 41.2 (N(CH3)2), 52.4 (NCH),163.4 (C4),190.5
(C2) ppm. MS (EI, 70 eV): m/z (%)¼214 (13), 213 (46) [M]þ, 115 (45),
98 (100), 83 (12), 44 (14).
2.98 (2 s, 6H, N(CH3)2), 6.97 (br s, 4H, Har), 7.78 (s, 1H, H4) ppm. 13
NMR (75 MHz, CDCl3):
¼14.8 (SCH3), 20.8 (PhCH3), 34.5 and 40.5
(N(CH3)2), 121.4 and 129.3 (4CHar), 132.3 and 147.6 (2Car), 153.9 (C4),
C
d

S. Grosjean et al. / Tetrahedron 66 (2010) 9912e9924
9917
164.6 (C2) ppm. MS (EI, 70 eV): m/z (%)¼235 (7) [M]þ, 188 (100), 91
concentrated under reduced pressure. The residue was purified by
chromatography on silica gel (ethyl acetate/petroleum ether: (6:4)
for 5g; dichloromethane/petroleum ether: (4:6) for 5b).
(17), 65 (12), 44 (13).
4.5.2. 4-Dimethylamino-1-(3,5-dichlorophenyl)-2-methylsulfanyl-
1,3-diazabuta-1,3-diene (4d). Colorless oil (65 mg, 94%). IR (neat):
4.6.1. 5-Methoxycarbonyl-2-methylsulfanyl-3-p-tolylpyrimidin-4
n
¼3061 (w), 2960 (w), 2927 (w), 2896 (w), 1691 (s), 1573 (w), 1486
(s), 1443 (m), 1330 (w), 1260 (w) cmꢁ1. 1H NMR (300 MHz, CDCl3):
¼2.43 (s, 3H, SCH3), 3.03 and 3.09 (2s, 6H, N(CH3)2), 6.86 (s, 1H,
Har), 6.99 (s, 2H, Har), 8.17 (s, 1H, H4) ppm. 13C NMR (75 MHz,
(3H)-one (5a). White solid (3.089 g, 97%). Mp 204e205 ꢀC. IR (KBr):
n
¼3098 (w), 3069 (w), 3057 (w), 3017 (w), 2962 (w), 2852 (w), 1743
(s), 1679 (m), 1568 (m), 1481 (s), 1375 (m), 1131 (m) cmꢁ1. 1H NMR
(300 MHz, CDCl3):
¼2.44 (s, 3H, SCH3), 2.49 (s, 3H, PhCH3), 3.88 (s,
3H, CO2CH3), 7.11 and 7,34 (AB system, 4H, J¼8.0 Hz, Har), 8.65 (s,
d
d
CDCl3):
d
¼15.0 (SCH3), 34.8 and 40.9 (N(CH3)2), 120.9 and 122.6
(CHar), 134.5 (2CareCl), 152.4 (Car), 157.9 (C4), 176.9 (C2) ppm. MS (EI,
70 eV): m/z (%)¼292 (2), 291 (7), 290 (3), 289 (10) [M]þ, 245 (8), 244
(63), 243 (12), 242 (100), 44 (5).
1H, H6) ppm. 13C NMR (75 MHz, CDCl3):
d
¼15.8 (SCH3), 21.5
(PhCH3), 52.3 (CO2CH3), 112.3 (C5), 128.0 and 130.7 (4 CHar), 132.7
and 140.8 (2Car), 158.2 (C6), 158.7 (C2), 165.1 (C4), 170.3 (CO2CH3)
ppm. MS (EI, 70 eV): m/z (%)¼290 (56) [M]þ, 259 (16), 243 (100),
175 (50), 91 (55), 59 (34), 47 (13).
4.5.3. 4-Dimethylamino-1-methyl-2-methylsulfanyl-1,3-diazabuta-
1,3-diene (4e). Colorless oil (115 mg, 76%). IR (neat):
2856 (w), 1432 (m), 1390 (m), 1359 (m), 1258 (w) cmꢁ1
(300 MHz, CDCl3): major (60%)
¼2.32 (s, 3H, SCH3), 2.86 (s, 3H,
NCH3), 2.99 and 3.18 (2 s, 6H, N(CH3)2), 8.72 (s, 1H, H4) ppm. Minor
(40%)
¼2.72 (s, 3H, SCH3), 3.04 and 3.22 (2s, 6H, N(CH3)2), 8.15 (s,
1H, H4) ppm. 13C NMR (75 MHz, CDCl3): major
¼14.2 (SCH3), 30.7
n
¼2924 (w),
.
1H NMR
4.6.2. 2-Methylsulfanyl-3-p-tolyl-5-trifluoromethylpyrimidin-4(3H)-
one (5b). White solid (1.106 g, 97%). Mp 183e184 ꢀC. IR (KBr):
d
n
¼3052 (w), 2983 (w), 2925 (w), 1697 (s), 1595 (m), 1501 (s), 1430
d
(w), 1388 (m), 1142 (m) cmꢁ1. 1H NMR (300 MHz, CDCl3):
d
¼2.44 (s,
d
3H, PhCH3), 2.47 (s, 3H, SCH3), 7.14 and 7.35 (AB system, 4H,
J¼8.1 Hz, Har), 8.20 (q, 1H, J¼1.0 Hz, H6) ppm. 13C NMR (75 MHz,
(NCH3), 35.5 and 41.8 (N(CH3)2), 157.3 (C4), 177.7 (C2) ppm. Minor
d
¼15.7 (SCH3), 31.5 (NCH3), 36.0 and 42.2 (N(CH3)2), 158.4 (C4),
CDCl3):
d
¼15.7 (SCH3), 21.5 (PhCH3), 112.8 (C5, q, J¼31 Hz), 122.8
173.4 (C2) ppm. MS (EI, 70 eV): m/z (%)¼159 (2) [M]þ, 112 (100), 86
(CF3, q, J¼270 Hz), 128.0 and 130.8 (4CHar), 132.0 and 141.0 (2Car),
(63), 58 (20).
151.6 (C6), 157.8 (C2), 169.6 (C4) ppm. 19F NMR (300 MHz, CDCl3):
d
¼ꢁ64.6 (CF3) ppm. MS (EI, 70 eV): m/z (%)¼301 (21), 300 (93)
4.5.4. 1-Cyclohexyl-4-dimethylamino-2-methylsulfanyl-1,3-dia-
[M]þ, 267 (20), 253 (100), 163 (74), 105 (15), 91 (34), 65 (17).
zabuta-1,3-diene (4f). Colorless oil (339 mg, 88%). IR (neat):
(w), 2854 (w), 1670 (m),1653 (m),1386 (w),1344 (w) cmꢁ1. 1H NMR
(300 MHz, CDCl3): major (80%)
¼1.26e1.31 and 1.83e1.99 (m, 10H,
CH2), 2.39 (s, 3H, SCH3), 2.95 and 3.01 (2s, 6H, N(CH3)2), 3.56e3.63
(m, 1H, NCH), 7.90 (s, 1H, H4) ppm. Minor (20%)
¼2.32 (s, 3H, SCH3),
2.92 and 2.98 (2s, 6H, N(CH3)2), 3.75e3.85 (m, 1H, NCH), 7.69 (s, 1H,
H4) ppm. 13C NMR (75 MHz, CDCl3):
CH2), 31.5 (N(CH3)2), 32.8 and 34.0 (2CH2), 36.5 (N(CH3)2), 52.5
(NCH), 162.6 (C4), 164.1 (C2) ppm. MS (CIþ, NH3): m/z¼228 (100)
[MþH]þ.
n
¼2930
4.6.3. 2-Methylsulfanyl-3-p-tolylpyrimidin-4(3H)-one (5c). Yellow
d
solid (1.218 g, 95%). Mp 124e126 ꢀC. IR (KBr):
n
¼3099 (w), 3050
(w), 3024 (w), 2948 (w), 2925 (w), 2857 (w), 1689 (s), 1571 (m),
1483 (s), 1377 (w), 1322 (m), 817 (w) cmꢁ1 1H NMR (300 MHz,
d
.
CDCl3):
d
¼2.42 (s, 3H, SCH3), 2.43 (s, 3H, PhCH3), 6.30 (d, 1H,
d
¼13.7 (SCH3), 24.5e27.5 (3
J¼6.5 Hz, H5), 7.15 and 7.34 (AB system, 4H, J¼8.1 Hz, Har), 7.83 (d,
1H, J¼6.5 Hz, H6) ppm. 13C NMR (75 MHz, CDCl3):
¼15.5 (SCH3),
d
21.4 (PhCH3), 111.0 (C5), 128.1e130.6 (4CHar), 133.0 and 140.4 (2Car),
152.4 (C6), 162.2 (C4), 164.8 (C2) ppm. MS (EI, 70 eV): m/z (%)¼233
(9), 232 (67) [M]þ, 199 (21), 185 (100), 91 (10), 77 (4).
4.6. General procedure for the preparation of pyrimidin-4
(3H)-ones 5
4.6.4. 2-Methylsulfanyl-5-phenyl-3-p-tolylpyrimidin-4(3H)-one
(5d). White solid (1.087 g, 85%). Mp 168e169 ꢀC. IR (KBr):
n
¼3064
(w), 3030 (w), 2988 (w), 2927 (w), 1684 (s), 1597 (w), 1581 (w),
1498 (s), 1485 (s), 1447 (m), 1367 (m), 813 (m) cmꢁ1 1H NMR
(300 MHz, CDCl3):
¼2.44 (s, 3H, PhCH3), 2.48 (s, 3H, SCH3), 7.20
and 7.38 (m, 5H, Har), 7.35 and 7.70 (AB system, J¼7.8 Hz, 4H, Har),
Method A (from acyl chlorides). Triethylamine (4.0 equiv) was
added to a solution of diazadienium iodide salt 3 (1.0 equiv) in
dichloromethane. Acyl chloride (3.0 equiv) was added dropwise to
the reaction medium at 0 ꢀC, and the reaction mixture was stirred
at room temperature over a period of 3e8 h (3 h for 5e,f,h,l,n,x; 6 h
for 5a,d,sev; 8 h for 5c,w). The solvent was then removed and the
residue was dissolved in dichloromethane, washed with water,
brine, dried with magnesium sulfate, and concentrated under re-
duced pressure. The residue was purified by chromatography on
silica gel (ethyl acetate/petroleum ether: (6:4) for 5a, 5c, 5f, and 5h;
ethyl acetate/petroleum ether: (5:5) for 5w; ethyl acetate/petro-
leum ether: (4:6) for 5e and 5v; ethyl acetate/petroleum ether:
(3:7) for 5l and 5x; ethyl acetate/petroleum ether: (2:8) for 5d).
Method B (from carboxylic acids). Oxalyl chloride (3.3 equiv) was
.
d
8.07 (s, 1H, H6) ppm. 13C NMR (75 MHz, CDCl3):
d
¼15.5 (SCH3), 21.5
(PhCH3), 122.7 (C5), 128.1e130.7 (9 CHar), 133.6 (2Car), 140.4 (Car),
150.0 (C6), 161.6 (C2), 163.2 (C4) ppm. MS (EI, 70 eV): m/z (%)¼309
(4), 308 (18) [M]þ, 116 (100), 91 (16), 89 (28), 77 (9), 65 (12).
4.6.5. 5-Methoxy-2-methylsulfanyl-3-p-tolylpyrimidin-4(3H)-one
(5e). White solid (1.941 g, 90%). Mp 149e150 ꢀC. IR (KBr):
n
¼3057
(w), 3027 (w), 3000 (w), 2974 (w), 2926 (w), 1690 (s), 1589 (s), 1518
(m), 1505 (s), 1459 (w), 1387 (w), 1305 (m), 1283 (s), 1024 (m) cmꢁ1
1H NMR (300 MHz, CDCl3):
¼2.40 (s, 3H, SCH3), 2.43 (s, 3H, PhCH3),
3.85 (s, 3H, OCH3), 7.14 and 7.33 (AB system, 4H, J¼8.3 Hz, Har), 7.46
.
d
added at 0 ꢀC to
a solution of carboxylic acid (3,3,3-tri-
fluoropropionic acid for 5b; N,N-dimethylglycine for 5g) (3.0 equiv)
in dichloromethane. A catalytic amount of N,N-dimethylformamide
(0.1 equiv) was added to the reaction medium and the reaction
mixture was stirred at room temperature for 1 h. The reaction
mixture was then introduced to a solution of diazadiene 3b
(1.0 equiv) in dichloromethane, and triethylamine (4.0 equiv) was
added dropwise to the reaction medium at 0 ꢀC, and the reaction
mixture was stirred at room temperature for 3 h. The solvent was
then removed and the residue was dissolved in dichloromethane,
washed with water, brine, dried with magnesium sulfate, and
(s, 1H, H6) ppm. 13C NMR (75 MHz, CDCl3):
d
¼15.4 (SCH3), 21.5
(PhCH3), 56.7 (OCH3), 128.3 (2CHar), 129.6 (C6), 130.6 (2CHar), 132.9
and 140.5 (2Car), 144.3 (C5), 154.5 (C2), 158.6 (C4) ppm. MS (EI,
70 eV): m/z (%)¼263 (16), 262 (100) [M]þ, 229 (40), 215 (24), 172
(17), 164 (24), 149 (20), 117 (26), 106 (50), 91 (32).
4.6.6. 5-Methyl-2-methylsulfanyl-3-p-tolylpyrimidin-4(3H)-one
(5f). White solid (881 mg, 95%). Mp 179 ꢀC. IR (KBr):
n
¼3060 (w),
3042 (w), 3000 (w), 2976 (w), 1677 (s), 1604 (w), 1499 (s), 1383 (w),
1310 (m), 1271 (m) cmꢁ1. 1H NMR (300 MHz, CDCl3):
¼2.05 (s, 3H,
d

9918
S. Grosjean et al. / Tetrahedron 66 (2010) 9912e9924
CH3), 2.41 (s, 3H, SCH3), 2.43 (s, 3H, PhCH3), 7.13 and 7.32 (AB sys-
tem, 4H, J¼8.0 Hz, Har), 7.73 (s, 1H, H6) ppm. 13C NMR (75 MHz,
(%)¼186 (7), 185 (6) [M]þ, 184 (10), 143 (31), 142 (100), 112 (13), 95
(23), 84 (17), 43 (19). MS (CIþ, NH3): m/z¼186 (100) [MþH]þ.
CDCl3):
d
¼13.4 (CH3), 15.4 (SCH3), 21.5 (PhCH3), 120.5 (C5), 128.3
and 130.6 (4CHar), 133.5 and 140.3 (2Car), 149.5 (C6), 154.5 and 158.6
(C2 and C4) ppm. MS (EI, 70 eV): m/z (%)¼246 (92) [M]þ, 213 (37),
199 (100), 171 (10), 105 (17), 91 (30), 65 (13).
4.6.13. 3-Dimethylamino-2-methylsulfanyl-5-phenylpyrimidin-4
(3H)-one (5u). White solid (89 mg, 72%). Mp 88e90 ꢀC. IR (KBr):
n
¼3057 (w), 3025 (w), 2980 (w), 2950 (w), 2887 (w), 1676 (s), 1566
(w), 1500 (s), 1439 (m), 1366 (s), 1285 (w) cmꢁ1. 1H NMR (300 MHz,
CDCl3):
¼2.29 (s, 3H, SCH3), 2.96 (s, 6H, N(CH3)2), 7.26e7.34 (m,
4.6.7. 5-Dimethylamino-2-methylsulfanyl-3-p-tolylpyrimidin-4(3H)-
one (5g). White solid (95 mg, 11%). Mp 139e141 ꢀC. IR (KBr):
d
2H, Har), 7.52e7.55 (m, 3H, Har), 7.81 (s, 1H, H6) ppm. 13C NMR
n
¼3060 (w), 3033 (w), 2980 (w), 2923 (w), 2862 (w), 1671 (s), 1570
(s), 1508 (s), 1459 (w), 1380 (m), 1336 (w), 1248 (m) cmꢁ1. 1H NMR
(300 MHz, CDCl3):
¼2.41 (s, 3H, PhCH3), 2.44 (s, 3H, SCH3), 2.86 (s,
6H, N(CH3)2), 7.15 and 7.34 (AB system, J¼8,7 Hz, 4H, Har), 7.36 (s,
1H, H6) ppm. 13C NMR (75 MHz, CDCl3):
(75 MHz, CDCl3):
d
¼14.6 (SCH3), 42.6 (N(CH3)2), 123.3 (C5), 127.9
(CHar), 128.4 (4CHar), 133.2 (Car), 149.3 (C6), 161.2 (C2), 166.4 (C4)
ppm. MS (EI, 70 eV): m/z (%)¼261 (12) [M]þ, 219 (23), 218 (100), 164
(14), 116 (47), 91 (32), 77 (9), 44 (19).
d
d
¼15.1 (SCH3), 21.3
(PhCH3), 41.6 (N(CH3)2), 128.3 and 130.3 (4CHar), 133.3 (Car), 134.4
(C6), 136.0 (C5), 140.0 (Car), 153.8 and 159.6 (C2 and C4) ppm. MS (EI,
70 eV): m/z (%)¼276 (18), 275 (100) [M]þ, 260 (22), 116 (13), 91 (57),
69 (23), 68 (27), 65 (19).
4.6.14. 3-(3,5-Dichlorophenyl)-5-methoxycarbonyl-2-methyl-
sulfanylpyrimidin-4(3H)-one (5v). White solid (326 mg, 79%). Mp
191e193 ꢀC. IR (KBr):
n
¼3077 (m), 2998 (w), 2948 (w), 2843 (w),
1738 (s), 1717 (m), 1676 (m), 1574 (s), 1565 (m), 1475 (s), 1432 (m),
1372 (m), 1328 (m), 806 (m) cmꢁ1 1H NMR (300 MHz, CDCl3):
¼2.54 (s, 3H, SCH3), 3.89 (s, 3H, OCH3), 7.19 (s, 2H, Har), 7.53 (s, 1H,
.
4.6.8. 5-Methoxycarbonyl-3-methyl-2-methylsulfanylpyrimidin-4
(3H)-one (5h). White solid (680 mg, 91%). Mp 110e111 ꢀC. IR
d
Har), 8.63 (s, 1H, H6) ppm. 13C NMR (75 MHz, CDCl3):
d¼15.8 (SCH3),
(KBr):
(s), 1685 (s), 1563 (m), 1492 (s), 1377 (m), 1365 (m) cmꢁ1. 1H NMR
(300 MHz, CDCl3):
¼2.64 (s, 3H, SCH3), 3.55 (s, 3H, NCH3), 3.89
n
¼3022 (w), 2995 (w), 2948 (w), 2850 (w), 1739 (s), 1697
52.5 (OCH3), 112.5 (C5), 127.4 and 130.9 (3CHar), 136.3 (2CareCl),
136.9 (Car), 158.3 (C2 and C6), 164.6 (C4), 169.3 (CO2CH3) ppm. MS
(EI, 70 eV): m/z (%)¼346 (30), 344 (42) [M]þ, 314 (31), 312 (43), 299
(64), 297 (100), 231 (46), 229 (61), 203 (38), 59 (34), 53 (92).
d
(s, 1H, OCH3), 8,55 (s, 1H, H6) ppm. 13C NMR (75 MHz, CDCl3):
d
¼15.4 (SCH3), 30.8 (NCH3), 52.3 (OCH3), 111.1 (C5), 157.4 (C6),
158.6 (C4), 165.1 (CO2CH3), 168.9 (C2) ppm. MS (EI, 70 eV): m/z
(%)¼214 (61) [M]þ, 183 (75), 169 (100), 167 (44), 136 (21), 99 (86),
88 (57), 73 (20).
4.6.15. 3-(3,5-Dichlorophenyl)-2-methylsulfanylpyrimidin-4(3H)-
one (5w). White solid (537 mg, 78%). Mp 214e216 ꢀC. IR (KBr):
n
¼3075 (m), 3058 (m), 1684 (s), 1575 (m), 1487 (s), 1419 (w), 1314
(m), 820 (m), 808 (m), 683 (m) cmꢁ1 1H NMR (300 MHz, CDCl3):
.
4.6.9. 3,5-Dimethyl-2-methylsulfanylpyrimidin-4(3H)-one
d
¼2.47 (s, 3H, SCH3), 6.29 (d, 1H, J¼6.6 Hz, H5), 7.20 (s, 2H, Har), 7.51
(5l). White solid (345 mg, 73%). Mp 86e88 ꢀC. IR (KBr):
n
¼2997
(w), 2921 (w), 2892 (w), 1670 (s), 1511 (s), 1407 (s), 1382 (m), 1326
(m) cmꢁ1 1H NMR (300 MHz, CDCl3):
¼1.99 (s, 3H, CH3), 2.51 (s,
(s, 1H, Har), 7.82 (d, 1H, J¼6.6 Hz, H6) ppm. 13C NMR (75 MHz,
CDCl3):
d
¼15.6 (SCH3), 111.2 (C5), 127.7 (2 CHar), 130.7 (CHar), 136.2
.
d
(2CareCl), 137.5 (Car), 152.6 (C6), 161.5 and 163.9 (C2 and C4) ppm.
MS (EI, 70 eV): m/z (%)¼288 (28), 287 (7), 286 (43) [M]þ, 255 (20),
253 (38), 241 (59), 240 (12), 239 (100).
3H, SCH3), 3.49 (s, 3H, NCH3), 7.62 (s, 1H, H6) ppm. 13C NMR
(75 MHz, CDCl3):
d
¼13.4 (CH3), 14.8 (SCH3), 30.4 (NCH3), 118.7 (C5),
149.0 (C6), 160.5 and 163.0 (C2 and C4) ppm. MS (EI, 70 eV): m/z
(%)¼171 (39), 170 (100) [M]þ, 169 (13), 125 (76), 124 (35), 96 (10), 95
(16), 57 (15).
4.6.16. 3-(3,5-Dichlorophenyl)-2-methylsulfanyl-5-phenylpyrimidin-
4(3H)-one (5x). White solid (207 mg, 95%). Mp 213e215 ꢀC. IR
(KBr):
1495 (s), 1363 (m), 1321 (m), 808 (m), 700 (m) cmꢁ1
(300 MHz, CDCl3):
¼2.52 (s, 3H, SCH3), 7.26 (s, 2H, Har), 7.35e7.43
n
¼3075 (w), 3025 (w), 2928 (w), 1674 (s), 1598 (w), 1575 (m),
4.6.10. 2-Methylsulfanylpyrimidin-4(3H)-one (5n). White solid
.
1H NMR
(440 mg, 68%). Mp 189e190 ꢀC. IR (KBr):
n
¼3440 (s), 3085 (w),
d
2926 (w), 1668 (s), 1546 (s), 1454 (m), 1372 (w), 1329 (m) cmꢁ1. 1H
(m, 3H, Har), 7.53 (m, 1H, Har), 7.66 (m, 2H, Har), 8.06 (s, 1H, H6) ppm.
NMR (300 MHz, CDCl3):
d
¼2.56 (s, 3H, SCH3), 6.12 (d, 1H, J¼6.6 Hz,
13C NMR (75 MHz, CDCl3):
d
¼15.5 (SCH3), 122.9 (C5), 127.7e128.5
H5), 7.84 (d, 1H, J¼6.6 Hz, H6), 12.97 (br s, 1H, NH) ppm. 13C NMR
(8CHar), 130.6 and 133.0 (2Car), 136.1 and 137.6 (2Car), 150.1 (C6),
161.0 and 162.1 (C2 and C4) ppm. MS (EI, 70 eV): m/z (%)¼363 (37),
362 (100) [M]þ, 331 (18), 329 (25), 315 (12), 116 (44).
(75 MHz, CDCl3):
d
¼13.4 (SCH3), 110.8 (C5), 154.2 (C6), 158.2 and
161.1 (C2 and C4) ppm. MS (EI, 70 eV): m/z (%)¼143 (35), 142 (100)
[M]þ, 114 (8), 96 (12), 95 (33), 44 (9).
4.6.11. 3-Dimethylamino-5-methoxycarbonyl-2-methylsulfanylpyr-
imidin-4(3H)-one (5s). White solid (87 mg, 76%). Mp 96e97 ꢀC. IR
4.7. General procedure for the preparation of 2-
methylsulfonylpyrimidinones 6
(KBr):
1446 (m), 1375 (m), 1290 (s), 1188 (w) cmꢁ1
CDCl3):
¼2.29 (s, 3H, SCH3), 2.91 (s, 6H, N(CH3)2), 3.78 (s, 3H,
n
¼2952 (w), 2929 (w), 1741 (s), 1687 (m), 1570 (m), 1472 (s),
.
1H NMR (300 MHz,
d
General procedure for the preparation of: a solution of dime-
thyldioxirane in acetone (2.5 equiv) was added to compound 5
(1.0 equiv) and the mixture was stirred at room temperature for 1 h
for 6cee, 30 min for 6g. The corresponding methylsulfonylpyr-
imidinone 6 was obtained as pure material after removal of the
solvent under reduced pressure.
CO2CH3), 8.40 (s, 1H, H6) ppm. 13C NMR (75 MHz, CDCl3):
d
¼14.7
(SCH3), 42.4 (N(CH3)2), 52.1 (CO2CH3), 112.3 (C5), 157.5 (C6), 158.4
(C4), 164.6 (CO2CH3), 173.1 (C2) ppm. MS (CIþ, NH3): m/z¼261 (100)
[MþNH4]þ.
4.6.12. 3-Dimethylamino-2-methylsulfanylpyrimidin-4(3H)-one
(5t). White solid (64 mg, 84%). Mp 92e94 ꢀC. IR (KBr):
n¼3067 (w),
4.7.1. 2-Methylsulfonyl-3-p-tolylpyrimidin-4(3H)-one (6c). White
2924 (w), 1621 (s), 1592 (m), 1545 (s), 1486 (w), 1424 (s), 1350 (m),
solid (82 mg, 100%). 1H NMR (300 MHz, CDCl3):
d
¼2.43 (s, 3H,
1286 (w) cmꢁ1
.
1H NMR (300 MHz, CDCl3):
d
¼2.31 (s, 3H, SCH3),
PhCH3), 3.32 (s, 3H, SO2CH3), 6.68 (d,1H, J¼6.6 Hz, H5), 7.23 and 7.33
2.97 (s, 6H, N(CH3)2), 6.08 (d,1H, J¼6.5 Hz, H5), 7.65 (d,1H, J¼6.5 Hz,
(AB system, 4H, J¼8.3 Hz, Har), 7.91 (d, 1H, J¼6.6 Hz, H6) ppm. 13
C
H6) ppm. 13C NMR (75 MHz, CDCl3):
d
¼14.7 (SCH3), 42.7 (N(CH3)2),
NMR (75 MHz, CDCl3):
d
¼21.5 (PhCH3), 41.2 (SO2CH3), 118.5 (C5),
111.7 (C5), 151.7 (C6), 162.1 (C2), 168.1 (C4) ppm. MS (EI, 70 eV): m/z
128.7 (2CHar), 129.6 (Car), 129.8 (2CHar), 140.8 (Car), 150.4 (C6), 156.3

S. Grosjean et al. / Tetrahedron 66 (2010) 9912e9924
9919
(C2), 160.8 (C4) ppm. MS (EI, 70 eV): m/z (%)¼264 (15) [M]þ, 202
system, 4H, J¼8.3 Hz, Har), 8.11 (d, 1H, J¼3.9 Hz, NH2), 8.48 (s, 1H,
(100), 185 (78), 104 (47), 78 (34), 65 (25).
H6) ppm. 13C NMR (75 MHz, DMSO-d6):
d
¼20.8 (PhCH3), 104.7 (C5),
128.1 and 130.6 (4CHar), 131.9 and 138.8 (2Car), 158.0, 160.4 and
162.0 (C2, C4, and C6), 165.1 (CONH2) ppm. MS (EI, 70 eV): m/z (%)¼
245 (20), 244 (88) [M]þ, 228 (78), 227 (27), 133 (53), 91 (100), 77
(20), 65 (27), 44 (16). HRMS (ESIþ): calcd for C12H12N4NaO2
[MþNa]þ 267.0853; found 267.0848.
4.7.2. 2-Methylsulfonyl-5-phenyl-3-p-tolylpyrimidin-4(3H)-one
(6d). White solid (335 mg, 100%). 1H NMR (300 MHz, CDCl3):
d
¼2.44 (s, 3H, PhCH3), 3.36 (s, 3H, SO2CH3), 7.28 and 7.34 (AB sys-
tem, 4H, J¼8.4 Hz, Har), 7.44 and 7.72 (m, 5H, Har), 8.09 (s, 1H, H6)
ppm. 13C NMR (75 MHz, CDCl3):
d¼21.6 (PhCH3), 41.3 (SO2CH3),
128.7e130.1 (9CHar), 130.5 and 132.0 (Car and C5), 140.8 (Car), 147.2
(C6), 154.8 (C2), 160.6 (C4) ppm. MS (EI, 70 eV): m/z (%)¼340 (3)
[M]þ, 279 (18), 278 (100), 161 (28), 144 (77), 117 (56), 105 (32), 90
(36), 89 (31).
4.8.3. 2-Amino-3-p-tolyl-5-trifluoromethylpyrimidin-4(3H)-one
(7b). Yellow solid (275 mg, 100%). Mp 199e202 ꢀC. IR (KBr):
n
¼3480 (s), 3325 (s), 2926 (w), 1709 (s), 1643 (s), 1601 (s), 1525 (s),
1489 (m), 1375 (w), 1331 (m) cmꢁ1 1H NMR (300 MHz, CDCl3):
.
d
¼2.43 (s, 3H, PhCH3), 5.69 (br s, 2H, NH2), 7.18 and 7.39 (AB system,
4.7.3. 5-Methoxy-2-methylsulfonyl-3-p-tolylpyrimidin-4(3H)-one
4H, J¼8.0 Hz, Har), 7.99 (s, 1H, H6) ppm. 13C NMR (75 MHz, CDCl3):
(6e). White solid (150 mg, 100%). Mp 260e261 ꢀC. IR (KBr):
n
¼2922
(w), 1643 (s), 1514 (m), 1476 (m), 1441 (w), 1280 (m), 1049 (w) cmꢁ1
1H NMR (300 MHz, CDCl3):
d
¼21.4 (PhCH3), 106.7 (C5, q, J¼20 Hz), 123.4 (CF3, q, J¼268 Hz),
.
127.8 (2CHar), 130.7 (Car), 131.6 (2CHar), 141.1 (Car), 154.2 (C6),
157.7 (C2), 158.3 (C4) ppm. MS (EI, 70 eV): m/z (%)¼270 (26), 269
(100) [M]þ, 268 (25), 248 (13), 133 (58), 118 (14), 91 (60), 65 (26).
HRMS (MALDI): calcd for C12H11F3N3O [MþH]þ 270.0849; found
270.0850.
d
¼2.43 (s, 3H, PhCH3), 3.29 (s,
3H, SO2CH3), 3.94 (s, 3H, OCH3), 7.23 and 7.32 (AB system,
4H, J¼8.1 Hz, Har), 7.39 (s, 1H, H6) ppm. 13C NMR (75 MHz, CDCl3):
d
¼21.6 (PhCH3), 41.5 (SO2CH3), 56.9 (OCH3), 124.7 (C6), 128.9
and 130.0 (4CHar), 132.9 and 140.8 (2Car), 158.3 (C6), 158.8
(C2), 165.1 (C4) ppm. MS (EI, 70 eV): m/z (%)¼295 (6), 294 (44)
[M]þ, 216 (14), 215 (100), 172 (56), 132 (18), 117 (64), 116 (28),
91 (25).
4.8.4. 2-Amino-3-p-tolylpyrimidin-4(3H)-one (7c). White solid
(180 mg, 100%). Mp 184e185 ꢀC. IR (KBr):
(w), 1680 (s), 1636 (s), 1580 (m), 1521 (s), 1457 (m), 1373 (w), 1313
n
¼3447 (s), 3316 (s), 2921
(m) cmꢁ1
.
1H NMR (300 MHz, CDCl3):
d
¼2.43 (s, 3H, PhCH3), 5.60
4.7.4. 3-Methyl-2-methylsulfonyl-5-phenylpyrimidin-4(3H)-one
(br s, 2H, NH2), 6.00 (d, 1H, J¼6.9 Hz, H5), 7.18 and 7.38 (AB system,
(6g). White solid (83 mg, 100%). 1H NMR (300 MHz, CDCl3):
d
¼3.47
4H, J¼8.1 Hz, Har), 7.58 (d, 1H, J¼6.9 Hz, H6) ppm. 13C NMR (75 MHz,
(s, 3H, SO2CH3), 3.92 (s, 3H, NCH3), 7.44e7.46 and 7.66e7.68 (m, 5H,
CDCl3):
d
¼21.4 (PhCH3), 105.1 (C5), 127.8 and 131.6 (4CHar), 131.7
Har), 7.97 (s, 1H, H6) ppm. 13C NMR (75 MHz, CDCl3):
d
¼30.7 (NCH3),
and 140.7 (2Car), 152.6 (C6), 155.6 (C2), 162.1 (C4) ppm. MS (EI,
70 eV): m/z (%)¼201 (34) [M]þ, 173 (20), 133 (14), 91 (22), 77 (14),
43 (100). HRMS (ESIþ): calcd for C11H12N3O [MþH]þ 202.0975;
found 202.0973.
40.8 (SO2CH3), 128.6 and 129.3 (5CHar), 129.6 and 132.1 (Car and C5),
146.9 (C6), 154.6 (C2), 160.2 (C4) ppm. MS (EI, 70 eV): m/z (%)¼264
(79) [M]þ, 185 (46), 116 (100), 89 (14).
4.8. General procedure for the preparation of 2-amino-
pyrimidinones 7
4.8.5. 2-Amino-5-phenyl-3-p-tolylpyrimidin-4(3H)-one (7d). White
solid (273 mg, 100%). Mp 209e212 ꢀC. IR (KBr):
n
¼3264 (s), 3122 (s),
1689 (s), 1630 (s),1592 (s), 1515 (s),1447 (m), 1401 (s), 1344 (m), 814
(m) cmꢁ1 1H NMR (300 MHz, CDCl3):
Method A (from 2-methylsulfanylpyrimidinones 5). A solution of
compound 5 (1.0 equiv) in methanolic ammonia (7 M, 5.0 equiv for
7a and 7f, large excess for 7a0 and 7b) was stirred at 50 ꢀC in
a sealed tube for 3e12 h (3 h for 7b; 12 h for 7a,a0,f). After con-
centration under reduced pressure, the resulting solid was washed
.
d
¼2.43 (s, 3H, PhCH3), 5.53
(br e, 2H, NH2), 7.22 and 7.37 (m, 5H, Har), 7.36 and 7.63 (AB system,
4H, J¼7.2 Hz, Har), 7.85 (s, 1H, H6) ppm. 13C NMR (75 MHz, CDCl3):
d
¼21.4 (PhCH3), 117.0 (C5), 127.2e131.4 (9 CHar), 132.1 and 134.4
(2Car), 140.3 (Car), 151.7 (C6), 154.9 (C2), 161.4 (C4) ppm. MS (EI,
70 eV): m/z (%)¼278 (23), 277 (100) [M]þ, 276 (40), 133 (31), 116
(21), 91 (86), 65 (32). HRMS (MALDI): calcd for C17H16N3O [MþH]þ
278.1288; found 278.1280.
with
a minimum of methanol. Method B (from 2-methyl-
sulfonylpyrimidinones 6). Gaseous ammonia was passed for 1 h
through a solution of compound 6 in toluene, and the medium was
stirred at room temperature for 24 h. The corresponding amino-
pyrimidinone 7 was obtained as pure material after removal of the
solvent under reduced pressure.
4.8.6. 2-Amino-3-methyl-5-methoxycarbonylpyrimidin-4(3H)-one
(7f). Yellow solid (200 mg, 78%). Mp 266e268 ꢀC. IR (KBr):
(m), 3122 (m), 3029 (m), 2957 (m), 2850 (w), 1740 (s), 1673 (s), 1580
(s), 1530 (m), 1508 (s), 1432 (m), 1365 (w), 1299 (s), 1059 (m), 817
n¼3365
4.8.1. 2-Amino-5-methoxycarbonyl-3-p-tolylpyrimidin-4(3H)-one
(7a). White solid (352 mg, 99%). Mp 245 ꢀC. IR (KBr):
n
¼3358 (m),
(m) cmꢁ1. 1H NMR (300 MHz, DMSO-d6):
d
¼3.24 (s, 3H, NCH3), 3.66
3025 (m), 2999 (m), 2950 (m), 1737 (s), 1672 (s), 1654 (s), 1571 (s),
(s, 3H, CO2CH3), 7.92 (br s, 2H, NH2), 8.32 (s, 1H, H6) ppm. 13C NMR
1508 (s), 1484 (s), 1433 (m), 1376 (w), 1057 (m), 801 (m) cmꢁ1. 1H
(75 MHz, DMSO-d6):
d
¼27.8 (NCH3), 50.8 (CO2CH3), 102.0 (C5), 158.1
NMR (300 MHz, CDCl3):
d
¼2.43 (s, 3H, PhCH3), 3.82 (s, 3H, CO2CH3),
and 158.6 (C2 and C4), 160.5 (C6), 164.8 (CO2CH3) ppm. MS (EI,
70 eV): m/z (%)¼183 (42) [M]þ, 152 (100), 124 (16), 83 (23), 69 (15),
57 (77), 53 (28). HRMS (ESIþ): calcd for C7H9N3NaO3 [MþNa]þ
206.0536; found 206.0533.
7.14 and 7.37 (AB system, 4H, J¼8.3 Hz, Har), 7.87 (br s, 2H, NH2),
8.54 (s, 1H, H6) ppm. 13C NMR (75 MHz, CDCl3):
d¼21.4 (PhCH3),
51.9 (CO2CH3), 106.2 (C5), 127.8 and 131.5 (4CHar), 131.4 and 140.8
(2Car), 158.3 and 159.0 (C2 and C6), 161.6 (C4), 165.1 (CO2CH3) ppm.
MS (EI, 70 eV): m/z (%)¼259 (10) [M]þ, 228 (18), 133 (47), 91 (100),
77 (22), 65 (38). HRMS (ESIþ): calcd for C13H13N3NaO3 [MþNa]þ
282.0849; found 282.0846.
4.8.7. 2-Amino-3-methyl-5-phenylpyrimidin-4(3H)-one (7g). White
solid (220 mg, 100%). Mp 165e166 ꢀC. IR (KBr):
n
¼3361 (m), 3118
(m), 1684 (m), 1646 (s), 1589 (m), 1525 (s), 1487 (w), 1400 (m), 1327
(w), 1208 (s), 1193 (s) cmꢁ1. 1H NMR (300 MHz, CDCl3):
¼3.51 (s,
3H, NCH3), 5.52 (br s, 2H, NH2), 7.29e7.41 and 7.57e7.60 (m, 5H,
d
4.8.2. 2-Amino-5-carbamoyl-3-p-tolylpyrimidin-4(3H)-one
(7a0). White solid (381 mg, 85%). Mp 330 ꢀC. IR (KBr):
n
¼3467 (m),
3357 (m), 3118 (w), 3044 (w), 1689 (s), 1650 (s), 1572 (m), 1476 (s),
1406 (m), 1310 (s), 821 (m) cmꢁ1 1H NMR (300 MHz, DMSO-d6):
¼2.39 (s, 3H, PhCH3), 7.14 (d, 1H, J¼3.9 Hz, NH2), 7.20 and 7.37 (AB
Har), 7.77 (s, 1H, H6) ppm. 13C NMR (75 MHz, CDCl3):
d
¼28.3 (NCH3),
116.8 (C5), 127.4 and 128.2e128.4 (5 CHar), 134.5 (Car), 150.5 (C6),
154.7 (C2), 161.0 (C4) ppm. MS (EI, 70 eV): m/z (%)¼202 (16), 201
(100) [M]þ, 144 (22), 117 (30), 116 (25), 89 (58), 77 (15), 57 (74).
.
d

9920
S. Grosjean et al. / Tetrahedron 66 (2010) 9912e9924
HRMS (ESIþ): calcd for C11H11N3O [MþH]þ 202.0975; found
J¼8.3 Hz, Har), 7.69 (d, 1H, J¼6.3 Hz, H6), 8.42 (s, 1H, N]CH) ppm.
202.0979.
13C NMR (75 MHz, CDCl3):
d
¼21.3 (PhCH3), 34.8 and 41.0 (N(CH3)2),
108.2 (C5), 127.9 and 129.4 (4CHar),135.0 and 137.5 (2Car), 153.4 (C6),
157.1 (N]CH), 160.1 (C2), 164.2 (C4) ppm. MS (EI, 70 eV): m/z (%)¼
257 (13), 256 (100) [M]þ, 188 (24), 185 (19), 128 (20), 99 (32), 91
(39), 44 (30). HRMS (ESIþ): calcd for C14H17N4O [MþH]þ 257.1397;
found 257.1394.
4.9. General procedure for the preparation of 2-[(N,N-
dimethylaminomethylen)amino]pyrimidinones 8
N,N-Dimethylformamide dimethyl acetal (1.2 equiv) was added
to a solution of aminopyrimidinone 7 (1.0 equiv) in dichloro-
methane. The mixture was stirred at room temperature for 3e6 h
(3 h for 8a0,bed,f; 6 h for 8a,e,g). The solvent was removed and the
residue purified by chromatography on silica gel (ethyl acetate for
8a, 8c, and 8f; ethyl acetate/petroleum ether: (9:1) for 8e; ethyl
acetate/petroleum ether: (8:2) for 8a0 and 8g; ethyl acetate/petro-
leum ether: (6:4) for 8d; ethyl acetate/petroleum ether: (2:8) for 8b).
4.9.5. 2-[(N,N-Dimethylaminomethylen)amino]-5-phenyl-3-p-tol-
ylpyrimidin-4(3H)-one (8d). White solid (210 mg, 91%). Mp 230 ꢀC.
IR (KBr):
(s), 1624 (s), 1579 (w), 1495 (s), 1486 (s), 1420 (m), 1377 (s), 916 (m)
cmꢁ1. 1H NMR (300 MHz, CDCl3):
¼2.39 (s, 3H, PhCH3), 2.76 and
3.09 (2 s, 6H, N(CH3)2), 7.09 and 7.72 (AB system, 4H, J¼8.0 Hz, Har),
7.23e7.39 (m, 5H, Har), 7.99 (s, 1H, H6), 8.50 (s, 1H, N]CH) ppm. 13
n
¼3039 (w), 3004 (w), 2927 (w), 2866 (w), 1668 (m), 1653
d
C
4.9.1. 2-[(N,N-Dimethylaminomethylen)amino]-5-methoxycarbonyl-
3-p-tolylpyrimidin-4(3H)-one (8a). White solid (383 mg, 89%). Mp
NMR (75 MHz, CDCl3):
d
¼21.4 (PhCH3), 34.9 and 41.1 (N(CH3)2),
119.7 (C5), 127.2e129.5 (9CHar), 134.9e137.5 (3Car), 151.4 (C4), 156.9
(N]CH), 159.1 (C2), 162.9 (C6) ppm. MS (EI, 70 eV): m/z (%)¼333
(21), 332 (100) [M]þ, 234 (58), 188 (80), 116 (63), 102 (86), 99 (87),
91 (83), 65 (38). HRMS (MALDI): calcd for C20H20N4NaO [MþNa]þ
355.1529; found 355.1543.
241e242 ꢀC. IR (KBr):
n
¼3064 (w), 3032 (w), 2972 (w), 2948 (w),
2925 (w), 1685 (s), 1635 (s), 1566 (m), 1481 (m), 1391 (m), 1343 (w),
1293 (s), 816 (m) cmꢁ1. 1H NMR (300 MHz, CDCl3):
d
¼2.35 (s, 3H,
PhCH3), 2.74 and 3.09 (2s, 6H, N(CH3)2), 3.81 (s, 3H, CO2CH3), 6.97
and 7.18 (AB system, 4H, J¼8.3 Hz, Har), 8.59 (br s, 2H, H6 and N]
CH) ppm. 13C NMR (75 MHz, CDCl3):
d¼21.3 (PhCH3), 35.2 and 41.4
4.9.6. 2-[(N,N-Dimethylaminomethylen)amino]-5-methoxy-3-p-tol-
(N(CH3)2), 51.8 (CO2CH3), 108.7 (C5), 127.8 and 129.4 (4CHar), 134.6
and 137.6 (2Car), 158.6 and 160.7 (C6 and N]CH), 162.5e165.1 (C2,
C4, and CO2CH3) ppm. MS (EI, 70 eV): m/z (%)¼315 (10), 314 (35)
[M]þ, 283 (15),188 (53),133 (30),132 (30), 99 (63), 91 (100), 65 (16).
HRMS (MALDI): calcd for C16H18N4NaO3 [MþNa]þ 337.1271; found
337.1265.
ylpyrimidin-4(3H)-one (8e). Yellow solid (31 mg, 45%). Mp
146e148 ꢀC. IR (KBr):
n
¼3035 (w), 3002 (w), 2926 (w), 1683 (s),
1629 (s), 1590 (m), 1508 (s), 1446 (m), 1390 (m), 1355 (m), 1308 (w)
cmꢁ1. 1H NMR (300 MHz, CDCl3):
d
¼2.38 (s, 3H, PhCH3), 2.68 and
3.03 (2 s, 6H, N(CH3)2), 3.84 (s, 3H, OCH3), 7.05 and 7.22 (AB system,
4H, J¼8.1 Hz, Har), 7.34 (s, 1H, H4), 8.31 (s, 1H, N]CH) ppm. 13C NMR
(75 MHz, CDCl3):
d
¼21.4 (PhCH3), 34.8 and 40.9 (N(CH3)2), 57.1
4.9.2. 5-Carbamoyl-2-[(N,N-dimethylaminomethylen)amino]-3-p-
tolylpyrimidin-4(3H)-one (8a0). White solid (220 mg, 90%). Mp
(OCH3), 128.0 and 129.5 (4CHar), 131.0 (C4), 134.8 and 137.7 (2Car),
142.4 (C5), 154.0 (C2), 156.1 (N]CH), 159.8 (C6) ppm. MS (EI, 70 eV):
m/z (%)¼286 (17) [M]þ, 121 (18), 91 (26), 44 (24), 43 (100). HRMS
(MALDI): calcd for C15H19N4O2 [MþH]þ 287.1503; found 287.1509.
245e246 ꢀC. IR (KBr):
n
¼3390 (m), 3245 (w), 3060 (w), 3039 (w),
2923 (w), 2867 (w), 1691 (s), 1648 (s), 1624 (s), 1561 (m), 1490 (s),
1473 (s), 1425 (s), 1375 (s), 1326 (m), 814 (m) cmꢁ1 1H NMR
(300 MHz, CDCl3):
.
d
¼2.40 (s, 3H, PhCH3), 2.77 and 3.13 (2 s, 6H, N
4.9.7. 2-[(N,N-Dimethylaminomethylen)amino]-5-methoxycarbonyl-
3-methylpyrimidin-4(3H)-one (8f). White solid (160 mg, 99%). Mp
(CH3)2), 5.57 (br s, 1H, NH2), 7.04 and 7.26 (AB system, 4H, J¼6.9 Hz,
Har), 8.65 (s, 1H, N]CH), 8.81 (br s, 1H, NH2), 8.82 (s, 1H, H6) ppm.
148e149 ꢀC. IR (KBr):
n
¼2996 (w), 2953 (w), 2878 (w), 1690 (s),
1658 (m), 1559 (m), 1486 (s), 1431 (m), 1378 (m), 1301 (m) cmꢁ1. 1H
NMR (300 MHz, CDCl3):
¼3.16 and 3.21 (2s, 6H, N(CH3)2), 3.53 (s,
3H, NCH3), 3.83 (s, 3H, CO2CH3), 8.49 (s, 1H, H6), 8.69 (s, 1H, N]CH)
ppm. 13C NMR (75 MHz, CDCl3):
13C NMR (75 MHz, CDCl3):
d¼21.4 (PhCH3), 35.3 and 41.5 (N(CH3)2),
109.6 (C5), 127.6 and 129.6 (4CHar), 134.4 and 138.1 (2Car), 158.6
(N]CH),159.8 (C6),161.8 and 163.8 (C2 and C4),166.3 (CONH2) ppm.
MS (EI, 70 eV): m/z (%)¼300 (15), 299 (100) [M]þ, 298 (30),188 (28),
99 (33), 91 (33), 84 (17), 49 (16), 44 (23). HRMS (MALDI): calcd for
C15H17N5NaO2 [MþNa]þ 322.1274; found 322.1272.
d
d¼29.5 (NCH3), 35.6 and 41.8 (N
(CH3)2), 51.8 (CO2CH3), 107.8 (C5), 159.3 (N]CH), 159.6 (C6), 160.7
and 162.0 (C2 and C4), 166.1 (CO2CH3) ppm. MS (EI, 70 eV): m/z (%)¼
239 (14), 238 (53) [M]þ, 207 (72), 194 (16), 167 (14), 136 (42), 112
(60), 98 (54), 83 (70), 69 (41), 59 (62), 53 (74), 42 (100). HRMS
(ESIþ): calcd for C10H14N4NaO3 [MþNa]þ 261.0958; found 261.0957.
4.9.3. 2-[(N,N-Dimethylaminomethylen)amino]-3-p-tolyl-5-tri-
fluoromethylpyrimidin-4(3H)-one (8b). Yellow solid (338 mg, 92%).
Mp 205e206 ꢀC. IR (KBr):
n
¼3067 (w), 3039 (w), 2928 (w), 1691 (s),
1634 (s), 1599 (m), 1486 (m), 1450 (m), 1397 (m), 1332 (m) cmꢁ1. 1H
NMR (300 MHz, CDCl3):
4.9.8. 2-[(N,N-Dimethylaminomethylen)amino]-5-phenyl-3-methyl-
d
¼2.38 (s, 3H, PhCH3), 2.75 and 3.10 (2 s,
pyrimidin-4(3H)-one (8g). Yellow solid (233 mg, 96%). Mp
6H, N(CH3)2), 7.03 and 7.22 (AB system, 4H, J¼7.8 Hz, Har), 8.07 (q,
175e177 ꢀC. IR (KBr):
n
¼3042 (w), 3030 (w), 2999 (w), 2963 (w),
2928 (w), 1641 (s), 1600 (m), 1569 (m), 1487 (s), 1445 (s), 1373 (m),
1325 (m) cmꢁ1. 1H NMR (300 MHz, CDCl3):
1H, J¼1.0 Hz, H6), 8.55 (s, 1H, N]CH) ppm. 13C NMR (75 MHz,
CDCl3):
d
¼21.3 (PhCH3), 35.2 and 41.4 (N(CH3)2), 109.2 (C5, q,
d
¼3.08 (s, 6H, N(CH3)2),
J¼31 Hz), 123.8 (CF3, q, J¼269 Hz), 127.9 and 129.5 (4CHar), 134.0
3.65 (s, 3H, NCH3), 7.27e7.43 (m, 3H, Har), 7.70e7.73 (m, 2H, Har),
7.91 (s, 1H, H6), 8.54 (s, 1H, N]CH) ppm. 13C NMR (75 MHz, CDCl3):
and 137.9 (2 Car), 153.2 (C6), 158.4 (N]CH), 160.0 and 162.1 (C2 and
C4) ppm. 19F NMR (300 MHz, CDCl3):
d
¼ꢁ63.6 (CF3) ppm. MS (EI,
d
¼29.5 (NCH3), 35.0 and 41.0 (N(CH3)2), 118.4 (C5), 126.7 and 128.0
70 eV): m/z (%)¼325 (21), 324 (100) [M]þ, 188 (33), 99 (44), 91 (91),
69 (23), 44 (39). HRMS (MALDI): calcd for C15H15F3N4NaO [MþNa]þ
347.1090; found 347.1103.
(5CHar), 135.1 (Car), 150.6 (C6), 157.5 (N]CH), 158.6 (C2), 162.5 (C4)
ppm. MS (EI, 70 eV): m/z (%)¼257 (21), 256 (100) [M]þ, 212 (51),158
(85), 116 (84), 98 (45), 89 (83), 44 (27), 42 (36). HRMS (ESIþ): calcd
for C14H17N4O [MþH]þ 257.1397; found 257.1400.
4.9.4. 2-[(N,N-Dimethylaminomethylen)amino]-3-p-tolylpyrimidin-
4(3H)-one (8c). White solid (182 mg, 78%). Mp 157e158 ꢀC. IR
4.10. General procedure for the preparation of pyrimido[1,2-
(KBr):
n
¼3088 (w), 3037 (w), 2918 (w), 2860 (w), 1670 (s), 1630 (s),
a]pyrimidine-2,6-diones 9
1568 (w), 1488 (s), 1423 (m), 1359 (m), 830 (m) cmꢁ1
.
1H NMR
(300 MHz, CDCl3):
d
¼2.37 (s, 3H, PhCH3), 2.71 and 3.05 (2 s, 6H, N
Acyl chloride (3.0 equiv) was added to
(1.0 equiv) in dichloromethane. Triethylamine (3.0 equiv) was
a solution of 8
(CH3)2), 6.15 (d, 1H, J¼6.3 Hz, H5), 7.05 and 7.22 (AB system, 4H,

S. Grosjean et al. / Tetrahedron 66 (2010) 9912e9924
9921
added dropwise to the reaction medium at 0 ꢀC, and the re-
action mixture was stirred at room temperature for 3e12 h (3 h
for 9m,p,s,uex; 6 h for 9aec,fei,o,q,r; 9 h for 9d,e; 12 h for
9jel,n,t). The solvent was then removed and the residue was
dissolved in dichloromethane, washed with water, brine, dried
with magnesium sulfate, and concentrated under reduced pres-
sure. The residue was purified by chromatography on silica gel
(ethyl acetate/petroleum ether: (7:3) for 9aed,f,l,m and seu;
ethyl acetate/petroleum ether: (6:4) for 9e and 9per; ethyl ac-
etate/petroleum ether: (5:5) for 9j,k, and 9vex; ethyl acetate/
petroleum ether: (3:7) for 9g,i,n, and o; ethyl acetate/petroleum
ether: (2:8) for 9h).
(s, 1H, H4) ppm. 13C NMR (75 MHz, CDCl3):
d
¼21.5 (PhCH3), 52.6
(CO2CH3), 108.5 (C7), 113.9 (C3), 127.6 and 130.9 (4CHar), 131.4 (Car),
139.7 (C4), 140.5 (Car), 159.8e160.2 (C2, C6, and C9a), 161.3 (C8), 163.6
and 163.8 (CO2CH3 and CONH2) ppm. MS (EI, 70 eV): m/z (%)¼355
(11), 354 (50) [M]þ, 353 (100), 158 (17), 133 (23), 132 (34), 91 (45),
65 (19), 53 (16). HRMS (MALDI): calcd for C17H14N4NaO5 [MþNa]þ
377.0862; found 377.0855.
4.10.5. 3-Carbamoyl-1-p-tolyl-1H-pyrimido[1,2-a]pyrimidine-2,6-di-
one (9e). White solid (28 mg, 71%). Mp 285 ꢀC. IR (KBr):
n
¼3358
(m), 3167 (m), 3105 (w), 3030 (w), 2920 (w), 2851 (w), 1703 (s),
1679 (s), 1620 (w), 1578 (m), 1497 (s), 1425 (m), 1377 (m) cmꢁ1. 1H
NMR (300 MHz, CDCl3):
d
¼2.43 (s, 3H, PhCH3), 5.87 (br s, 1H, NH2),
4.10.1. 3,7-Dimethoxycarbonyl-1-p-tolyl-1H-pyrimido[1,2-a]pyrimi-
dine-2,6-dione (9a). White solid (49 mg, 84%). Mp 236e238 ꢀC. IR
6.22 (d, 1H, J¼6.8 Hz, H7), 7.11 and 7.38 (AB system, 4H, J¼8.1 Hz,
Har), 7.78 (d, 1H, J¼6.8 Hz, H8), 8.50 (br s, 1H, NH2), 9.74 (s, 1H, H4)
(KBr):
1641 (w), 1564 (s), 1520 (s), 1505 (s), 1453 (m), 1380 (w), 1291 (m),
1204 (m), 1085 (m), 815 (m) cmꢁ1 1H NMR (300 MHz, CDCl3):
n
¼3058 (w), 3041 (s), 2959 (s), 2923 (w), 2854 (w), 1754 (s),
ppm. 13C NMR (75 MHz, CDCl3):
d
¼21.5 (PhCH3), 106.8 (C7), 113.1
(C3), 127.7 and 130.9 (4CHar), 132.0 (Car), 139.6 (C4), 140.5 and 142.5
(Car and C9a), 155.0 (C8), 156.6 and 160.5 (C2 and C6), 161.9 (CONH2)
ppm. MS (EI, 70 eV): m/z (%)¼297 (7), 296 (48) [M]þ, 295 (100), 270
(6), 252 (6), 185 (20), 130 (14), 117 (16), 91 (46), 65 (18), 53 (13).
HRMS (MALDI): calcd for C15H12N4NaO3 [MþNa]þ 319.0807; found
319.0816.
.
d
¼2.43 (s, 3H, PhCH3), 3.86 and 3.92 (2 s, 6H, 2CO2CH3), 7.08 and
7.35 (AB system, 4H, J¼8.3 Hz, Har), 8.58 (s, 1H, H8), 9.44 (s, 1H, H4)
ppm. 13C NMR (75 MHz, CDCl3):
d
¼21.2 (PhCH3), 52.3 and 53.0
(2CO2CH3), 107.5 (C7), 113.7 (C3), 127.5 and 130.4 (4CHar), 131.3 (Car),
138.4 (C4), 139.8 (Car), 151.8, 153.3 and 155.7 (C2, C6 and C9a), 161.4
(C8), 161.5 and 163.3 (2CO2CH3) ppm. MS (EI, 70 eV): m/z (%)¼369
(26) [M]þ, 368 (81), 175 (35), 132 (52), 131 (41), 91 (64), 77 (17), 65
(27), 59 (100), 53 (58). HRMS (MALDI): calcd for C18H15N3NaO6
[MþNa]þ 392.0859; found 392.0847.
4.10.6. 3-Carbamoyl-7-methoxy-1-p-tolyl-1H-pyrimido[1,2-a]pyrim-
idine-2,6-dione (9f). Yellow solid (41 mg, 94%). Mp 250 ꢀC. IR (KBr):
n
¼3180 (w), 3098 (w), 3065 (w), 3009 (w), 2924 (w), 2852 (w), 1714
(s),1597 (s),1544 (s),1510 (s),1477 (m),1427 (m),1363 (m),1267 (s),
884 (m), 813 (m) cmꢁ1. 1H NMR (300 MHz, CDCl3):
d
¼2.43 (s, 3H,
4.10.2. 3-Methoxycarbonyl-1-p-tolyl-1H-pyrimido[1,2-a]pyrimidine-
2,6-dione (9b). White solid (44 mg, 89%). Mp 200e202 ꢀC. IR (KBr):
PhCH3), 3.81 (s, 3H, OCH3), 5.89 (br s, 1H, NH), 7.10 and 7.37 (AB
system, 4H, J¼7.4 Hz, Har), 7.38 (s,1H, H8), 8.57 (br s,1H, NH), 9.71 (s,
n
¼3091 (w), 3077 (w), 3044 (w), 2957 (w), 2928 (w), 2849 (w),1744
1H, H4) ppm. 13C NMR (75 MHz, CDCl3):
d
¼21.5 (PhCH3), 57.2
(s), 1714 (s), 1697 (s), 1576 (m), 1505 (s), 1436 (m), 1364 (w), 1315
(OCH3), 112.9 (C3), 127.9 and 130.8 (4CHar), 131.4 (C8), 132.0 (Car),
139.4 (C4), 140.0 (Car), 140.7 and 142.5 (C7 and C9a), 153.5 (C6), 160.2
(C2), 162.0 (CONH2) ppm. MS (EI, 70 eV): m/z (%)¼327 (19), 326
(100) [M]þ, 325 (59), 283 (14), 238 (24), 143 (21), 130 (21), 117 (38),
91 (45), 65 (18). HRMS (MALDI): calcd for C16H14N4NaO4 [MþNa]þ
349.0913; found 349.0921.
(m), 1088 (m), 867 (m), 815 (m) cmꢁ1. 1H NMR (300 MHz, CDCl3):
d
¼2.43 (s, 3H, PhCH3), 3.93 (s, 3H, CO2CH3), 6.18 (d, 1H, J¼6.9 Hz,
H7), 7.10 and 7.35 (AB system, 4H, J¼8.3 Hz, Har), 7.78 (d, 1H,
J¼6.9 Hz, H8), 9.44 (s, 1H, H4) ppm. 13C NMR (75 MHz, CDCl3):
d
¼21.4 (PhCH3), 53.0 (CO2CH3),106.1 (C7),113.2 (C3),127.2 and 130.5
(4CHar), 132.1 (Car), 138.6 (C4), 139.7 (Car), 149.8 (C9a), 155.4 (C8),
156.3 and 156.8 (C2 and C6), 162.0 (CO2CH3) ppm. MS (EI, 70 eV): m/
z (%)¼312 (9), 311 (46) [M]þ, 310 (100),185 (22),132 (10), 91 (31), 77
(4), 65 (10). HRMS (MALDI): calcd for C16H13N3NaO4 [MþNa]þ
334.0804; found 334.0808.
4.10.7. 7-Methoxycarbonyl-1-p-tolyl-3-trifluoromethyl-1H-pyrimido
[1,2-a]pyrimidine-2,6-dione (9g). White solid (58 mg, 94%). Mp
223e224 ꢀC. IR (KBr):
n
¼3067 (w), 2953 (w), 2924 (w), 2853
(w), 1761 (s), 1740 (s), 1717 (s), 1580 (w), 1518 (s), 1445 (m),
1382 (m), 1260 (w) cmꢁ1 1H NMR (300 MHz, CDCl3):
.
d¼2.45 (s,
4.10.3. 7-Methoxy-3-methoxycarbonyl-1-p-tolyl-1H-pyrimido[1,2-a]
3H, PhCH3), 3.87 (s, 3H, CO2CH3), 7.11 and 7.37 (AB system, 4H,
pyrimidine-2,6-dione (9c). Yellow solid (41 mg, 76%). Mp
J¼7.8 Hz, Har), 8.60 (s, 1H, H8), 9.19 (q, 1H, J¼0.8 Hz, H4) ppm. 13C
215e216 ꢀC. IR (KBr):
n
¼3087 (w), 3055 (w), 3035 (w), 2987 (w),
NMR (75 MHz, CDCl3):
d¼21.4 (PhCH3), 52.5 (CO2CH3), 108.1
2928 (w), 2846 (w), 1716 (s), 1636 (w), 1594 (s), 1552 (s), 1514 (m),
(C7), 113.8 (q, J¼33.8 Hz, C3), 121.3 (q, J¼196.0 Hz, CF3), 127.6 and
130.6 (4 CHar), 130.9 (Car), 134.1 (C4), 140.3 (Car), 151.9, 153.4, and
155.1 (C2, C6, and C9a), 161.4 (C8), 163.2 (CO2CH3) ppm. 19F NMR
1454 (w), 1434 (m), 1362 (m), 1308 (m), 1266 (m), 813 (w) cmꢁ1. 1H
NMR (300 MHz, CDCl3):
d
¼2.43 (s, 3H, PhCH3), 3.82 (s, 3H, OCH3),
3.93 (s, 3H, CO2CH3), 7.09 and 7.35 (AB system, 4H, J¼8.3 Hz, Har),
(300 MHz, CDCl3):
d
¼ꢁ65.0 (CF3) ppm. MS (EI, 70 eV): m/z (%)¼380
7.41 (s, 1H, H8), 9.41 (s, 1H, H4) ppm. 13C NMR (75 MHz, CDCl3):
(8), 379 (100) [M]þ, 348 (11), 164 (11), 91 (15), 59 (52). HRMS
(MALDI): calcd for C17H12F3N3NaO4 [MþNa]þ 402.0678; found
402.0662.
d
¼21.5 (PhCH3), 53.0 (CO2CH3), 57.3 (OCH3), 113.2 (C3), 128.1 and
130.6 (4 CHar), 132.1 (C8), 138.4 (C4), 139.6 and 140.3 (2 Car), 143.0
(C7), 153.6e156.2 (C2, C6, and C9a), 162.1 (CO2CH3) ppm. MS (EI,
70 eV): m/z (%)¼341 (32) [M]þ, 340 (17), 243 (22),175 (35),132 (32),
131 (39), 117 (37), 116 (30), 91 (100), 65 (30), 59 (93), 53 (38), 49
(85). HRMS (MALDI): calcd for C17H15N3NaO5 [MþNa]þ 364.0909;
found 364.0909.
4.10.8. 1-p-Tolyl-3-trifluoromethyl-1H-pyrimido[1,2-a]pyrimidine-
2,6-dione (9h). White solid (51 mg, 93%). Mp 249e250 ꢀC. IR (KBr):
n
¼3067 (w), 2955 (w), 2925 (w), 2854 (w), 1728 (s), 1713 (s), 1660
(m), 1585 (m), 1505 (s), 1436 (m), 1371 (w), 1326 (m), 1267 (w)
cmꢁ1. 1H NMR (300 MHz, CDCl3):
d
¼2.45 (s, 3H, PhCH3), 6.22 (d, 1H,
4.10.4. 3-Carbamoyl-7-methoxycarbonyl-1-p-tolyl-1H-pyrimido[1,2-
a]pyrimidine-2,6-dione (9d). White solid (69 mg, 72%). Mp 295 ꢀC.
J¼6.9 Hz, H7), 7.12 and 7.37 (AB system, 4H, J¼8.1 Hz, Har), 7.81 (d,
1H, J¼6.9 Hz, H8), 9.17 (q, 1H, J¼1.2 Hz, H4) ppm. 13C NMR (75 MHz,
IR (KBr):
(w), 2852 (w), 1765 (s), 1745 (s), 1716 (s),1568 (m), 1501 (s), 1442 (s),
1373 (m), 1279 (w) cmꢁ1. 1H NMR (300 MHz, CDCl3):
n
¼3455 (s), 3396 (s), 3086 (w), 3045 (w), 2953 (w), 2925
CDCl3):
d
¼21.5 (PhCH3), 106.5 (C7), 113.2 (q, J¼33.5 Hz, C3), 121.1 (q,
J¼195.6 Hz, CF3), 127.8 and 130.7 (4CHar), 131.5 (Car), 134.0 (C4),
d¼2.47 (s, 3H,
140.0 (Car), 149.7 (C9a), 155.1 (C8), 155.5 and 156.7 (C2 and C6) ppm.
PhCH3), 3.91 (s, 3H, CO2CH3), 5.86 (br s, 1H, NH2), 7.12 and 7.41 (AB
system, 4H, J¼8.3 Hz, Har), 8.43 (s-e, 1H, NH2), 8.63 (s, 1H, H8), 9.83
19F NMR (300 MHz, CDCl3):
d
¼ꢁ64.9 (CF3) ppm. MS (EI, 70 eV): m/z
(%)¼321 (42) [M]þ, 320 (100), 185 (13), 116 (15), 91 (35), 53 (20).

9922
S. Grosjean et al. / Tetrahedron 66 (2010) 9912e9924
HRMS (MALDI): calcd for C15H11F3N3O2 [MþH]þ 322.0803; found
1692 (s), 1640 (m), 1571 (s), 1505 (s), 1452 (m), 1372 (m), 1348 (w)
cmꢁ1. 1H NMR (300 MHz, CDCl3):
322.0808.
d¼2.46 (s, 3H, PhCH3), 3.91 (s, 3H,
CO2CH3), 7.17 and 7.40 (AB system, 4H, J¼8.4 Hz, Har), 7.47 and 7.69
4.10.9. 7-Methoxy-1-p-tolyl-3-trifluoromethyl-1H-pyrimido[1,2-a]
pyrimidine-2,6-dione (9i). Yellow solid (53 mg, 95%). Mp
(m, 5H, Har), 8.67 (s, 1H, H4), 9.00 (s, 1H, H8) ppm. 13C NMR (75 MHz,
CDCl3):
d
¼21.5 (PhCH3), 52.5 (CO2CH3), 107.4 (C7), 123.8 (C3),
164e165 ꢀC. IR (KBr):
n
¼3049 (w), 2959 (w), 2854 (w), 1721 (s),
1705 (s), 1660 (m), 1595 (s), 1513 (s), 1458 (w), 1384 (w), 1367
(m), 1268 (s), 1040 (m) cmꢁ1 1H NMR (300 MHz, CDCl3):
127.8e130.7 (9CHar), 129.7 (C4), 131.0, 132.2, and 140.0 (3Car), 151.6
(C9a), 154.3 (C8), 159.4 (C6), 161.0 (C2), 164.2 (CO2CH3) ppm. MS (EI,
70 eV): m/z (%)¼388 (10), 387 (45) [M]þ, 386 (68),175 (15),132 (19),
116 (100),102 (30), 91 (35), 89 (55), 77 (17), 65 (25). HRMS (MALDI):
calcd for C22H18N3O4 [MþH]þ 388.1292; found 388.1284.
.
d¼2.44
(s, 3H, PhCH3), 3.83 (s, 3H, OCH3), 7.12 and 7.36 (AB system, 4H,
J¼8.0 Hz, Har), 7.41 (s, 1H, H8), 9.12 (s, 1H, H4) ppm. 13C NMR
(75 MHz, CDCl3):
d
¼21.4 (PhCH3), 57.2 (OCH3), 112.9 (q, J¼33.3 Hz,
C3), 121.1 (q, J¼195.8 Hz, CF3), 128.0 and 130.6 (4CHar), 131.5 (Car),
4.10.14. 3-Phenyl-1-p-tolyl-1H-pyrimido[1,2-a]pyrimidine-2,6-dione
131.9 (C8), 133.7 (C4), 139.8 (C7), 140.4 (Car), 142.5 (C9a), 153.5 and
(9n). White solid (38 mg, 86%). Mp 239e240 ꢀC. IR (KBr):
(w), 3069 (w), 3035 (w), 2950 (w), 2923 (w), 1710 (s), 1701 (s), 1635
(w), 1571 (m), 1504 (s), 1488 (s), 1444 (m), 1351 (m), 815 (m), 786
n
¼3099
155.2 (C2 and C6) ppm. 19F NMR (300 MHz, CDCl3):
d
¼ꢁ64.8 (CF3)
ppm. MS (EI, 70 eV): m/z (%)¼352 (19), 351 (100) [M]þ, 350 (73),
260 (35), 163 (38), 117 (33), 91 (74), 65 (26), 53 (26). HRMS
(MALDI): calcd for C16H12F3N3NaO3 [MþNa]þ 374.0728; found
374.0725.
(m) cmꢁ1. 1H NMR (300 MHz, CDCl3):
d
¼2.45 (s, 3H, PhCH3), 6.22 (d,
1H, J¼6.6 Hz, H7), 7.19 and 7.39 (AB system, 4H, J¼8.1 Hz, Har), 7.45
and 7.70 (m, 5H, Har), 7.83 (d, 1H, J¼6.6 Hz, H8), 8.93 (s, 1H, H4) ppm.
13C NMR (75 MHz, CDCl3):
d
¼21.5 (PhCH3), 105.8 (C7), 123.0 (C3),
4.10.10. 7-Methoxycarbonyl-1-p-tolyl-1H-pyrimido[1,2-a]pyrimi-
dine-2,6-dione (9j). White solid (35 mg, 72%). Mp 246e248 ꢀC. IR
128.0e130.7 (9CHar), 129.6 (C4), 131.4, 132.8, and 139.6 (3 Car), 149.6
(C9a), 154.8 (C8), 157.6 (C6), 159.7 (C2) ppm. MS (EI, 70 eV): m/z (%)¼
330 (10), 329 (69) [M]þ, 328 (100), 300 (10), 185 (13), 117 (17), 116
(46), 91 (13), 77 (5). HRMS (MALDI): calcd for C20H16N3O2 [MþH]þ
330.1237; found 330.1234.
(KBr):
(w), 1754 (s), 1722 (s), 1687 (m), 1646 (m), 1567 (m), 1519 (s), 1500
(s), 1455 (s), 1387 (m), 1352 (w), 865 (w), 814 (m) cmꢁ1 1H NMR
n
¼3092 (w), 3066 (w), 3040 (w), 2956 (w), 2924 (w), 2850
.
(300 MHz, CDCl3):
d
¼2.46 (s, 3H, PhCH3), 3.90 (s, 3H, CO2CH3), 6.56
(d, 1H, J¼8.3 Hz, H3), 7.12 and 7.39 (AB system, 4H, J¼7.5 Hz, Har),
8.65 (s, 1H, H8), 8.86 (d, 1H, J¼8.3 Hz, H4) ppm. 13C NMR (75 MHz,
4.10.15. 7-Methoxy-3-phenyl-1-p-tolyl-1H-pyrimido[1,2-a]pyrimi-
dine-2,6-dione (9o). Yellow solid (36 mg, 89%). Mp 215e216 ꢀC. IR
CDCl3):
d
¼21.6 (PhCH3), 52.5 (CO2CH3), 107.7 (C7), 111.5 (C3), 127.7
(KBr):
(s), 1701 (s), 1633 (w), 1584 (s), 1543 (s), 1494 (m), 1446 (m),
1385 (m), 1071 (m), 808 (w), 786 (m) cmꢁ1 1H NMR (300 MHz,
CDCl3):
¼2.45 (s, 3H, PhCH3), 3.84 (s, 3H, OCH3), 7.16 and 7.37
(AB system, 4H, J¼8.3 Hz, Har), 7.44 and 7.70 (m, 5H, Har), 7.48 (s,
1H, H8), 8.86 (s, 1H, H4) ppm. 13C NMR (75 MHz, CDCl3):
n
¼3056 (w), 3033 (w), 2965 (w), 2932 (w), 2852 (w), 1711
and 130.8 (4CHar), 131.7 (Car), 133.4 (C4), 140.1 (Car), 152.2 (C8), 154.2
(C9a), 159.4 (C6), 161.3 (C2), 164.0 (CO2CH3) ppm. MS (EI, 70 eV): m/z
(%)¼312 (7), 311 (30) [M]þ, 310 (65), 185 (19), 179 (28), 151 (23), 132
(16), 107 (22), 105 (30), 91 (49), 78 (17), 57 (100), 53 (18). HRMS
(MALDI): calcd for C16H13N3NaO4 [MþNa]þ 334.0804; found
334.0804.
.
d
d¼21.5
(PhCH3), 57.2 (OCH3), 122.8 (C3), 128.1e130.6 (9CHar), 129.5 (C4),
131.4 (Car), 132.1 (C8), 132.8 and 139.4 (2Car), 140.2 (C7), 143.4
(C9a), 154.0 (C6), 159.6 (C2) ppm. MS (EI, 70 eV): m/z (%)¼360 (24),
359 (100) [M]þ, 358 (42), 316 (15), 288 (19), 117 (20), 116 (90), 91
(9). HRMS (MALDI): calcd for C21H18N3O3 [MþH]þ 360.1343;
found 360.1353.
4.10.11. 1-p-Tolyl-1H-pyrimido[1,2-a]pyrimidine-2,6-dione
(9k). White solid (30 mg, 77%). Mp 226e227 ꢀC. IR (KBr):
n
¼3078
(w), 3042 (w), 2951 (w), 2920 (w), 1690 (s), 1646 (m), 1576 (m),
1492 (s), 1423 (m), 1378 (m), 820 (m) cmꢁ1 1H NMR (300 MHz,
.
CDCl3):
d
¼2.44 (s, 3H, PhCH3), 6.19 (d, 1H, J¼6.6 Hz, H7), 6.47 (d, 1H,
J¼8.3 Hz, H3), 7.13 and 7.37 (AB system, 4H, J¼8.4 Hz, Har), 7.80 (d,
1H, J¼6.6 Hz, H8), 8.76 (d, 1H, J¼8.3 Hz, H4) ppm. 13C NMR (75 MHz,
4.10.16. 3-Methoxy-7-methoxycarbonyl-1-p-tolyl-1H-pyrimido[1,2-
a]pyrimidine-2,6-dione (9p). White solid (22 mg, 99%). Mp
CDCl3):
d
¼21.5 (PhCH3), 106.2 (C7), 110.8 (C3), 127.9 and 130.7 (4
241e243 ꢀC. IR (KBr):
n
¼3030 (w), 2956 (w), 2925 (w), 2853 (w),
1751 (s), 1732 (s), 1651 (m), 1565 (w), 1518 (s), 1503 (s), 1443 (m),
1384 (m), 1286 (s), 818 (m) cmꢁ1 1H NMR (300 MHz, CDCl3):
CHar), 132.4 (Car), 133.1 (C4), 139.7 (Car), 150.1 (C9a), 155.0 (C8), 157.4
(C2), 159.9 (C6) ppm. MS (EI, 70 eV): m/z (%)¼254 (8), 253 (38) [M]þ,
252 (100), 185 (12), 117 (12), 91 (20), 84 (12). HRMS (MALDI): calcd
for C14H12N3O2 [MþH]þ 254.0930; found 254.0927.
.
d
¼2.46 (s, 3H, PhCH3), 3.90 (s, 3H, CO2CH3), 3.99 (s, 3H, OCH3), 7.11
and 7.38 (AB system, 4H, J¼8.3 Hz, Har), 8.38 (s, 1H, H4), 8.63 (s, 1H,
H8) ppm. 13C NMR (75 MHz, CDCl3):
d¼21.5 (PhCH3), 52.4 (CO2CH3),
4.10.12. 7-Methoxy-1-p-tolyl-1H-pyrimido[1,2-a]pyrimidine-2,6-di-
one (9l). White solid (37 mg, 84%). Mp 278e279 ꢀC. IR (KBr):
57.1 (OCH3),106.9 (C7),109.4 (C3),127.8 and 130.8 (4 CHar), 131.8 and
140.1 (2Car),142.9 (C4),149.6 (C9a),154.2 and 156.4 (C2 and C6),159.8
(C8), 164.3 (CO2CH3) ppm. MS (EI, 70 eV): m/z (%)¼342 (9), 341 (55)
[M]þ, 340 (100), 310 (15), 175 (10), 132 (22), 117 (15), 91 (23), 59
(16), 53 (14). HRMS (MALDI): calcd for C17H16N3O5 [MþH]þ
342.1084; found 342.1075.
n
¼3092 (w), 3066 (w), 3040 (w), 2956 (w), 2924 (w), 2850 (w),
1754 (s), 1722 (s), 1687 (m), 1646 (m), 1567 (m), 1519 (s), 1500 (s),
1455 (s), 1387 (m), 1352 (w), 865 (w), 814 (m) cmꢁ1 1H NMR
.
(300 MHz, CDCl3):
d
¼2.44 (s, 3H, PhCH3), 3.82 (s, 3H, OCH3), 6.43 (d,
1H, J¼8.3 Hz, H3), 7.12 and 7.37 (AB system, 4H, J¼8.3 Hz, Har), 7.43
(s,1H, H8), 8.72 (d,1H, J¼8.3 Hz, H4) ppm. 13C NMR (75 MHz, CDCl3):
4.10.17. 3-Methoxy-1-p-tolyl-1H-pyrimido[1,2-a]pyrimidine-2,6-di-
one (9q). White solid (45 mg, 99%). Mp 253e254 ꢀC. IR (KBr):
d
¼21.5 (PhCH3), 57.2 (OCH3), 110.7 (C3), 128.1 and 130.7 (4 CHar),
131.9 (C8), 132.4 and 139.6 (2Car), 132.8 (C4), 140.3 (C7), 143.3 (C9a),
153.9 (C6), 159.7 (C2) ppm. MS (EI, 70 eV): m/z (%)¼284 (24), 283
(100) [M]þ, 282 (93), 240 (31), 212 (95), 185 (79), 117 (77), 91 (99),
77 (43), 65 (21). HRMS (MALDI): calcd for C15H14N3O3 [MþH]þ
284.1035; found 284.1031.
n
¼3076 (w), 3034 (w), 2973 (w), 1716 (s), 1691 (s), 1649 (m), 1575
(m), 1516 (s), 1497 (s), 1456 (w), 1360 (w), 1169 (m) cmꢁ1. 1H NMR
(300 MHz, CDCl3):
d
¼2.44 (s, 3H, PhCH3), 3.95 (s, 3H, OCH3), 6.21 (d,
1H, J¼6.3 Hz, H7), 7.12 and 7.37 (AB system, 4H, J¼8.3 Hz, Har), 7.80
(d, 1H, J¼6.3 Hz, H8), 8.28 (s, 1H, H4) ppm. 13C NMR (75 MHz,
CDCl3):
d
¼21.5 (PhCH3), 57.1 (OCH3), 105.3 (C7), 109.2 (C4), 127.9 and
4.10.13. 7-Methoxycarbonyl-3-phenyl-1-p-tolyl-1H-pyrimido[1,2-a]
130.6 (4 CHar), 132.3 and 139.7 (2Car), 142.2 (C3), 147.7 (C9a), 153.7
(C8), 156.7 and 157.4 (C2 and C6) ppm. MS (EI, 70 eV): m/z (%)¼283
(62) [M]þ, 282 (100), 185 (35), 117 (15), 91 (28), 65 (14). HRMS
pyrimidine-2,6-dione (9m). White solid (40 mg, 86%). Mp
264e265 ꢀC. IR (KBr):
n
¼3095 (w), 3064 (w), 2957 (w), 1726 (s),

S. Grosjean et al. / Tetrahedron 66 (2010) 9912e9924
9923
(MALDI): calcd for C15H13N3NaO3 [MþNa]þ 306.0849; found
123.1 (C7), 128.8 and 129.1 (5 CHar), 129.6 (C4), 131.1 (Car), 150.5 (C8),
154.2 (C9a), 159.1 (C6), 160.7 (C2), 164.2 (CO2CH3) ppm. MS (EI,
70 eV): m/z (%)¼312 (14), 311 (82) [M]þ, 281 (14), 280 (100), 116
(47), 102 (14). HRMS (MALDI): calcd for C16H13N3NaO4 [MþNa]þ
334.0798; found 334.0812.
306.0850.
4.10.18. 3,7-Dimethoxy-1-p-tolyl-1H-pyrimido[1,2-a]pyrimidine-2,6-
dione (9r). White solid (29 mg, 89%). Mp 248e250 ꢀC. IR (KBr):
n
¼3091 (w), 3017 (w), 2945 (w),1704 (s),1656 (m),1594 (s),1543 (s),
1465 (s), 1426 (w), 1368 (m), 1327 (m), 1019 (m) cmꢁ1 1H NMR
.
4.10.23. 1-Methyl-3-phenyl-1H-pyrimido[1,2-a]pyrimidine-2,6-di-
(300 MHz, CDCl3):
d
¼2.43 (s, 3H, PhCH3), 3.82 and 3.95 (2 s, 6H,
one (9w). Yellow solid (47 mg, 95%). Mp 148e149 ꢀC. IR (KBr):
2 ꢀCH3), 7.11 and 7.36 (AB system, 4H, J¼8.4 Hz, Har), 7.46 (s, 1H, H8),
n
¼3097 (w), 3062 (w), 3002 (w), 2966 (w), 2925 (w), 1695 (s), 1652
8.22 (s,1H, H4) ppm. 13C NMR (75 MHz, CDCl3):
d¼21.5 (PhCH3), 57.2
(m), 1595 (s), 1550 (s), 1492 (m), 1446 (m), 1368 (m) cmꢁ1. 1H NMR
(2OCH3), 109.0 (C4), 128.0 and 130.7 (4CHar), 131.5 (C8), 132.4 and
139.6 (2 Car),140.0 (C9a),141.4 (C7),141.9 (C3),153.6 and 156.5 (C2 and
C6) ppm. MS (EI, 70 eV): m/z (%)¼314 (14), 313 (100) [M]þ, 312 (56),
270 (18), 242 (35), 227 (28),117 (33), 91 (14), 70 (11). HRMS (MALDI):
calcd for C16H15N3NaO4 [MþNa]þ 336.0955; found 336.0955.
(300 MHz, CDCl3):
d
¼3.70 (s, 3H, NCH3), 6.21 (d, 1H, J¼6.6 Hz, H7),
7.42e7.44 (m, 3H, Har), 7.61e7.64 (m, 2H, Har), 7.95 (d, 1H, J¼6.6 Hz,
H8), 8.78 (s, 1H, H4) ppm. 13C NMR (75 MHz, CDCl3):
d¼30.0 (NCH3),
105.5 (C7), 122.4 (C3), 128.6e129.0 (5CHar), 129.3 (C4), 131.6 (Car),
148.5 (C9a), 154.5 (C8), 157.5 (C6), 159.4 (C2) ppm. MS (EI, 70 eV): m/z
(%)¼254 (20), 253 (100) [M]þ, 225 (26), 224 (66), 197 (16), 196 (40),
116 (13), 109 (12). HRMS (ESIþ): calcd for C14H11N3NaO2 [MþNa]þ
276.0744; found 276.0735.
4.10.19. 3,7-Dimethoxycarbonyl-1-methyl-1H-pyrimido[1,2-a]pyrim-
idine-2,6-dione (9s). Yellow solid (45 mg, 92%). Mp 146e147 ꢀC. IR
(KBr):
1695 (s), 1643 (m), 1576 (m), 1507 (s), 1458 (s), 1445 (s), 1384 (m),
1130 (m), 821 (m) cmꢁ1. 1H NMR (300 MHz, CDCl3):
¼3.69 (s, 3H,
NCH3), 3.91 and 3.95 (2 s, 6H, 2CO2CH3), 8.77 (s, 1H, H8), 9.41 (s, 1H,
H4) ppm. 13C NMR (75 MHz, CDCl3):
n
¼3050 (w), 2992 (w), 2953 (w), 2849 (w), 1754 (s), 1735 (s),
4.10.24. 7-Methoxy-1-methyl-3-phenyl-1H-pyrimido[1,2-a]pyrimi-
dine-2,6-dione (9x). White solid (55 mg, 99%). Mp 183e184 ꢀC. IR
d
(KBr):
n
¼3097 (w), 3062 (w), 3002 (w), 2966 (w), 2925 (w), 2854
d¼30.4 (NCH3), 52.6 and 53.3
(2CO2CH3), 107.6 (C7), 113.3 (C3), 138.0 (C4), 151.0 (C9a), 153.7 and
155.9 (C2 and C6), 161.6 (C8),161.7 and 163.8 (2CO2CH3) ppm. MS (EI,
70 eV): m/z (%)¼294 (7), 293 (49) [M]þ, 263 (15), 262 (100), 235
(10), 167 (14), 99 (26), 91 (49), 83 (23), 71 (27), 69 (31), 59 (27), 57
(29), 53 (28), 43 (20). HRMS (MALDI): calcd for C12H11N3NaO6
[MþNa]þ 316.0540; found 316.0538.
(w), 1695 (s), 1595 (s), 1539 (m), 1491 (s), 1446 (s), 1390 (w), 1368
(w), 1245 (m), 1154 (w) cmꢁ1. 1H NMR (300 MHz, CDCl3):
d¼3.66 (s,
3H, NCH3), 3.88 (s, 3H, OCH3), 7.41e7.43 (m, 3H, Har), 7.59 (s, 1H, H8),
7.60e7.63 (m, 2H, Har), 8.73 (s, 1H, H4) ppm. 13C NMR (75 MHz,
CDCl3):
d
¼29.7 (NCH3), 57.3 (OCH3),122.3 (C3),128.6e129.0 (5CHar),
129.3 (C4), 131.7 (Car), 132.1 (C8), 140.0 (C7), 142.0 (C9a), 154.0 (C6),
159.2 (C2) ppm. MS (EI, 70 eV): m/z (%)¼284 (24), 283 (92) [M]þ,
268 (14), 254 (11), 240 (18), 185 (100), 116 (22), 44 (14), 40 (36).
HRMS (MALDI): calcd for C15H14N3O3 [MþH]þ 284.1030; found
284.1019.
4.10.20. 3-Methoxycarbonyl-1-methyl-1H-pyrimido[1,2-a]pyrimi-
dine-2,6-dione (9t). White solid (26 mg, 66%). Mp 190e191 ꢀC. IR
(KBr):
n
¼3094 (w), 3070 (w), 3011 (w), 2955 (w), 1742 (s), 1717 (s),
1679 (m), 1655 (m), 1576 (s), 1512 (s), 1442 (s), 1425 (s), 1370 (m),
800 (m) cmꢁ1
.
1H NMR (300 MHz, CDCl3):
d
¼3.62 (s, 3H, NCH3),
Acknowledgements
3.92 (s, 3H, CO2CH3), 6.20 (d, 1H, J¼6.6 Hz, H7), 7.92 (d, 1H, J¼6.6 Hz,
H8), 9.33 (s, 1H, H4) ppm. 13C NMR (75 MHz, CDCl3):
d¼29.9 (NCH3),
ꢀ ꢀ
The authors are grateful to the Conseil General de Loire-Atlan-
tique and to the CNRS for financial support.
53.0 (CO2CH3), 105.9 (C7), 112.5 (C3), 137.9 (C4), 148.8 (C9a), 155.3
(C8), 156.3 and 156.9 (C2 and C6), 162.1 (CO2CH3) ppm. MS (EI,
70 eV): m/z (%)¼236 (10), 235 (57) [M]þ, 204 (36),176 (20),148 (32),
136 (42), 109 (48), 92 (54), 91 (100), 81 (37), 79 (28), 68 (25), 55
(40), 53 (38). HRMS (MALDI): calcd for C10H9N3NaO4 [MþNa]þ
258.0485; found 258.0480.
References and notes
1. Snider, B. B.; Chen, J. S. Tetrahedron Lett. 1998, 39, 5697e5700.
2. Chereze, N.; Lochead, A.; Saady, M.; Slowinsky, F.; Yaiche, P., WO Patent 058908
A1, 2005.
3. Guo, T.; Hunter, R. C.; Zhang, R.; Greenlee, W. J. Tetrahedron Lett. 2007, 48,
613e615.
4. Adib, M.; Sayahi, M. H.; Ziyadi, H.; Bijanzadeh, H. R.; Zhu, L. G. Tetrahedron 2007,
63, 11135e11140.
5. Eynde, J. J. V.; Hecq, N.; Kataeva, O.; Kappe, C. O. Tetrahedron 2001, 57,
1785e1791.
6. Pathak, R.; Batra, S. Tetrahedron 2007, 63, 9448e9455.
7. Tu, S. J.; Li, C. M.; Li, G. G.; Cao, L. J.; Shao, Q. Q.; Zhou, D. X.; Jiang, B.; Zhou, J. F.;
Xia, M. J. Comb. Chem. 2007, 9, 1144e1148.
4.10.21. 7-Methoxy-3-methoxycarbonyl-1-methyl-1H-pyrimido[1,2-
a]pyrimidine-2,6-dione (9u). Yellow solid (32 mg, 72%). Mp
159e161 ꢀC. IR (KBr):
n
¼3089 (w), 3010 (w), 2973 (w), 2918 (w),
2839 (w), 1721 (s), 1703 (s), 1641 (m), 1598 (s), 1547 (s), 1474 (m),
1429 (m), 1393 (m), 1325 (s), 1089 (m), 802 (m) cmꢁ1 1H NMR
(300 MHz, CDCl3):
¼3.59 (s, 3H, NCH3), 3.87 (s, 3H, OCH3), 3.92 (s,
3H, CO2CH3), 7.54 (s, 1H, H8), 9.29 (s, 1H, H4) ppm. 13C NMR
.
d
8. Coles, M. P.; Hitchcock, P. B. Organometallics 2003, 22, 5201e5211.
9. Kafka, S.; Larissegger-Schnell, B.; Kappe, T. J. Heterocycl. Chem. 2004, 41,
717e721.
(75 MHz, CDCl3):
d
¼29.6 (NCH3), 53.0 (CO2CH3), 57.4 (OCH3), 112.6
(C3), 132.1 (C8), 137.6 (C4), 140.2 (C7), 141.9 (C9a), 153.7 and 156.1 (C2
and C6), 162.1 (CO2CH3) ppm. MS (EI, 70 eV): m/z (%)¼266 (15), 265
(81) [M]þ, 222 (26), 167 (100), 140 (59), 99 (73), 84 (28), 59 (37), 43
(33), 35 (69). HRMS (MALDI): calcd for C11H11N3NaO5 [MþNa]þ
288.0591; found 288.0584.
10. Wild, U.; Roquette, P.; Kaifer, E.; Mautz, J.; Hubner, O.; Wadepohl, H.; Himmel,
H. J. Eur. J. Inorg. Chem. 2008, 1248e1257.
11. Friot, C.; Reliquet, A.; Reliquet, F.; Meslin, J.-C. Phosphorus, Sulfur Silicon Relat.
Elem. 2000, 156, 135e149.
12. Landreau, C.; Deniaud, D.; Reliquet, F.; Reliquet, A.; Meslin, J.-C. Heterocycles
2000, 53, 2667e2677.
13. Landreau, C.; Deniaud, D.; Reliquet, A.; Reliquet, F.; Meslin, J.-C. J. Heterocycl.
Chem. 2001, 38, 93e98.
14. Friot, C.; Reliquet, A.; Reliquet, F.; Meslin, J.-C. Synthesis 2000, 695e702.
15. Mazumdar, S. J.; Mahajan, P. M. Tetrahedron 2001, 57, 1785e1791.
16. The microwave experiments were performed in sealed 10 ml vials under
pressurized conditions using the microwave platform MultiSYNTHÒ (Milestone
S.r.l.). The software algorithm regulates the microwave output power according
to the temperature. The temperature was controlled by IR and maintained
constant for the desired reaction/irradiation time, after a ramp time of 1 min. At
the end of the irradiation period, the reaction vessel was rapidly cooled to
ambient temperature with compressed air using the equipped cooling feature
(gas-jet cooling).
4.10.22. 7-Methoxycarbonyl-1-methyl-3-phenyl-1H-pyrimido[1,2-a]
pyrimidine-2,6-dione (9v). White solid (54 mg, 98%). Mp
169e170 ꢀC. IR (KBr):
n
¼3098 (w), 3052 (w), 3026 (w), 2955 (w),
2924 (w), 1732 (s), 1706 (s), 1688 (s), 1637 (m), 1579 (m), 1509 (s),
1429 (s), 1378 (m), 1311 (m) cmꢁ1 1H NMR (300 MHz, CDCl3):
¼3.74 (s, 3H, NCH3), 3.89 (s, 3H, CO2CH3), 7.42e7.44 (m, 3H, Har),
.
d
7.59e7.63 (m, 2H, Har), 8.77 (s, 1H, H4), 8.83 (s, 1H, H8) ppm. 13C
NMR (75 MHz, CDCl3):
d
¼30.3 (NCH3), 52.3 (CO2CH3), 106.9 (C3),

9924
S. Grosjean et al. / Tetrahedron 66 (2010) 9912e9924
17. Robin, A.; Julienne, K.; Meslin, J. C.; Deniaud, D. Eur. J. Org. Chem. 2006, 634e643.
18. Kikelj, V.; Grosjean, S.; Meslin, J. C.; Julienne, K.; Deniaud, D. Synthesis 2010,
2811e2815.
22. Adam, W.; Hadjiarapoglou, L. Top. Curr. Chem. 1993, 164, 45e62.
23. Kostakis, I. K.; Elomri, A.; Seguin, E.; Iannelli, M.; Besson, T. Tetrahedron Lett.
2007, 48, 6609e6613.
19. Adam, W.; Chan, Y. Y.; Cremer, D.; Gauss, J.; Scheutzow, D.; Schindler, M. J. Org.
Chem. 1987, 52, 2800e2803.
24. Nouira, I.; Kostakis, I. K.; Dubouilh, C.; Chosson, E.; Iannelli, M.; Besson, T.
Tetrahedron Lett. 2008, 49, 7033e7036.
20. Murray, R. W. Chem. Rev. 1989, 89, 1187e1201.
21. Adam, W.; Bialas, J.; Hadjiarapoglou, L. Chem. Ber. 1991, 124, 2377.
25. Farrugia, L. J. J. Appl. Crystallogr. 1997, 30 565e565.
26. CCDC reference number: 768714.