Original SRN1 reactions on new non-nitrated heterocyclic system

Article abstract of DOI:10.1055/s-0028-1083499

A new 3-bromo-2-(chloromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one was prepared and reacted under experimental conditions of S_RN1 reactions with different sulfur- and carbon-centered nucleophiles. A S_RN1 reaction in non-nitrated 4H-pyrid

Full text of DOI:10.1055/s-0028-1083499

2836
LETTER
Original SRN1 Reactions on New Non-Nitrated Heterocyclic System
S
1Reactions
o
é
nNe
w
N
on
m
-NitratedHeterocyc
i
lic System Szabo, Maxime D. Crozet, Patrice Vanelle*
R
N
Laboratoire de Pharmaco-Chimie Radicalaire, LPCR, Faculté de Pharmacie, Universités d’Aix-Marseille I, II, III – CNRS, UMR 6264:
Laboratoire Chimie Provence, 27 Bd Jean Moulin, 13385 Marseille Cedex 05, France
Fax +33(4)91794677; E-mail: patrice.vanelle@pharmacie.univ-mrs.fr
Received 2 July 2008
CO2Et
Abstract: A new 3-bromo-2-(chloromethyl)-4H-pyrido[1,2-a]py-
O
rimidin-4-one was prepared and reacted under experimental condi-
tions of SRN1 reactions with different sulfur- and carbon-centered
nucleophiles. A SRN1 reaction in non-nitrated 4H-pyrido[1,2-a]py-
rimidin-4-one series is described for the first time.
1)
Cl
N
O
NH2
PPA, 110 °C
Cl
N
2) Br2, CH2Cl2
3) LiCl, THF
N
Cl
Br
Cl
Key words: single-electron transfer, 4H-pyrido[1,2-a]pyrimidin-
4-one, inhibitors, alkylation, spectroscopy
1
Scheme 1 Preparation of 3-bromo-7-chloro-2-(chloromethyl)pyri-
do-[1,2-a]pyrimidin-4-one
A number of 4H-pyrido[1,2-a]pyrimidin-4-one deriva-
tives displays antioxidant,1 anticancer,2 vasodilator,3
antihypertensive4 as well as CNS5–8 activity. Furthermore,
some 4H-pyrido[1,2-a]pyrimidin-4-ones are able to po-
tentiate the antibacterial activity of some fluoroquino-
lones,9 and are also selective inhibitors of cell death in
mutant hungtingtin-expressing cells.10
equiv) at room temperature21,22 followed by a treatment
with lithium chloride in THF (Scheme 1).
Careful examination, by cyclic voltammetry, of the start-
ing material 1 [Epc1 = –1,45 V vs. SCE, first peak mea-
sured in DMF–NBu4PF6 (0.1 M)], indicated that this
substrate might be a good electron acceptor23 and this
therefore prompted us to use nitronate anion for studying
a possible SRN1 mechanism.24 Then, C-alkylation of ni-
tronate anion with this alkylating agent, not substituted
with a nitro group, could be expected.
Unimolecular radical nucleophilic substitution (SRN1) has
been found to be an excellent synthetic pathway for many
types of aromatic, heterocyclic, and aliphatic substrates
with suitable leaving groups.11–13 The SRN1 reaction was
shown to require substrates substituted with an electron-
attracting group at an appropriate position.14 Indeed, most
non-nitrated-substituted nitrobenzyl derivatives undergo
SN2 rather than SRN1 reaction.13,15 As well as non-nitrated
heterocycles studied for the moment resulted in O-alkyl-
ation reactions, or no reactivity at all was observed with
nitronate anions.16
Under SRN1 experimental conditions (inert atmosphere,
photostimulation), the reaction of 3-bromo-7-chloro-
2-(chloromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one (1)
with 2-nitropropane anion gave the ethylenic derivative 2
resulting from the consecutive C-alkylation and nitrous
acid elimination (Scheme 2).25 Sodium hydride (60%) in
DMSO was used to form the corresponding carbanion.
In continuation of our study on the reactivity of 2-(chloro-
methyl)-3-nitro-4H-pyrido[1,2-a]pyrimidin-4-one series
in electron-transfer reactions,17–19 and as part of a program
directed toward the preparation of more complex struc-
tures of pharmacological interest, we prepared 3-bromo-
7-chloro-2-(chloromethyl)-4H-pyrido[1,2-a]pyrimidin-4-
one (1) and studied its reactivity with different nucleo-
philes, under SRN1 experimental conditions, in order to
determine the reactivity of the non-nitrated heterocycle
under these conditions.
NO2
N
O
N
O
Cl
N
N
NaH, DMSO
Cl
Br
Cl
Br
N2, hν
1
2 49%
Scheme 2 Reaction of 1 with 2-nitropropane anion under SRN1 re-
action conditions
The starting material was obtained by condensing 2-ami-
no-5-chloropyridine with 4-chloroacetoacetate in PPA
using Ferrarini procedure20 providing 7-chloro-2-(chlo-
romethyl)-4H-pyrido[1,2-a]pyrimidin-4-one which was
brominated at 3-position with elemental bromine (1.1
The X-ray structure analysis of a crystal of 2 confirmed
that reactivity with 2-nitropropane anion takes place only
at chloromethyl group (Figure 1). No product of an even-
tual displacement of the bromine atom at 3-position or ar-
omatic substitution at 7-position was isolated.
In order to validate the hypothesis of a single-electron-
transfer mechanism, inhibition reactions were performed
by adding catalytic amounts (10 mol%) of CuCl2 or
TEMPO to the reaction mixture (Table 1), which are clas-
SYNLETT 2008, No. 18, pp 2836–2840
Advanced online publication: 15.10.2008
DOI: 10.1055/s-0028-1083499; Art ID: G21508ST
1
4
.1
1
.2
0
0
8
© Georg Thieme Verlag Stuttgart · New York

LETTER
SRN1 Reactions on New Non-Nitrated Heterocyclic System
2837
Table 2 Reaction of 1 with Alkyl Malonate Anions under SRN
1
Reaction Conditionsa
Entry
R1
Me
Et
R2
Time (min) Product (%)
1
2
3
Me
Et
50
45
3 (69)
4 (67)
5 (61)
Et
Bn
120
a All the reactions are performed using 1 equiv of 1, 3 equiv of alkyl
malonate, and 3 equiv of NaH in DMSO at r.t., under inert atmosphere
and photostimulation until disappearance of the starting material as
monitored by TLC.
The reactions of 1 with alkyl malonate anion provide the
expected C-alkylated products27 in moderate to good
yields (61–69%, Table 2).
Figure 1 ORTEP plot of 3-bromo-7-chloro-2-(2-methylprop-1-
enyl)-4H-pyrido[1,2-a]pyrimidin-4-one (2)
In the aim of verifying the nature of the mechanism, we
performed the inhibition reactions using CuCl2 and
TEMPO (Table 3). Catalytic amount of TEMPO com-
pletely stops the C-alkylation reaction (Table 3, entry 3),
and the starting material 1 is the only product collected af-
ter the reaction workup. This suggests that the reaction of
1 with diethyl malonate anion follows exclusively a free
radical chain mechanism (SRN1).
Table 1 Inhibition Reactions with 2-Nitropropane Aniona
Entry
Inhibitor
–
Product (%)
2 (49)
1
2
3
CuCl2
TEMPO
2 (18)
Table 3 Inhibition Reactions with Diethyl Malonate Aniona
2 (9)
a All the reactions are performed using 1 equiv of 1, 3 equiv of 2-ni-
tropropane, and 3 equiv of NaH in DMSO at r.t., under inert atmo-
sphere and photostimulation for 45 min.
Entry
Inhibitor
–
Product (%)
4 (67)
1
2
3
CuCl2
TEMPO
4 (28)
sical inhibitors used for the mechanistic studies of SRN1
reactions.26 For a coherent comparison, the reaction times
were identical for inhibition study and corresponded to the
optimized conditions without inhibitor.
4 (0)
a All the reactions are performed using 1 equiv of 1, 3 equiv of diethyl
malonate, and 3 equiv of NaH in DMSO at r.t., under inert atmosphere
and photostimulation for 45 min.
This reaction is strongly inhibited by TEMPO, a free rad-
ical scavenger.
Furthermore, C-alkylation was confirmed by X-ray struc-
ture analysis of a crystal of 4, showing that, like 2-nitro-
propane anion, malonate anions also react only with
chloromethyl group (Figure 2).
The nature of the nucleophile is crucial for SRN1 reactions
and therefore an understanding of the relationship be-
tween the nucleophile and the substrate, in single-elec-
tron-transfer reactions, is of use.13 We have thus
investigated the reactivity of 1 with other conventional
nucleophiles as for example, alkyl malonate anions
(Scheme 3, Table 2, entry 1–3).
In order to extend the reaction to a wide variety of nucleo-
philes, we continued the study with S-centered anions
(Scheme 4, Table 4).28 The reaction between the sodium
salt of arylsulfinic acids (Table 4, entries 1–3) or thiophe-
nol (Table 4, entry 4) and 1 in DMSO gave the required S-
alkylated products29 in good to excellent yields (78–92%).
CO2R1
N
O
N
CO2R1
CO2R2
CO2R2
Cl
N
N
NaH, DMSO
N
N
Ar
Cl
Br
Cl
Br
Cl
X
N2, hν
ArX–, Na+
O
N
N
DMSO
N2, hν
3 R1 = R2 = Me
4 R1 = R2 = Et
Cl
Br
Cl
Br
O
O
5 R1 = Et, R2 = Bn
6 X = SO2, Ar = Ph
1
Scheme 3 Reaction of 1 with alkyl malonate anions under SRN
reaction conditions
1
7 X = SO2, Ar = 4-MeC6H4
8 X = SO2, Ar = 4-ClC6H4
9 X = S, Ar = Ph
Scheme 4 Reaction of 1 with S-centered anions under SRN1 reaction
conditions
Synlett 2008, No. 18, 2836–2840 © Thieme Stuttgart · New York

2838
R. Szabo et al.
LETTER
Table 5 Inhibition Reactions with p-Tolylsulfinate and Thiophenol
Anions
Entry
1a
Anion
Inhibitor
–
Product (%)
7 (88)
4-MeC6H4SO2 , Na+
–
2a
4-MeC6H4SO2 , Na+
CuCl2
TEMPO
–
7 (80)
–
–
3a
4-MeC6H4SO2 , Na+
7 (71)
4b
PhS–, Na+
PhS–, Na+
PhS–, Na+
9 (92)
5b
CuCl2
TEMPO
9 (89)
6b
9 (88)
a All the reactions are performed using 1 equiv of 1, 2 equiv of sodium
arylsulfinate in DMSO at r.t., under inert atmosphere and photostim-
ulation for 90 min.
b All the reactions are performed using 1 equiv of 1, 2.2 equiv of
thiophenol, and 2.2 equiv of NaH in DMSO at r.t., under inert atmo-
sphere and photostimulation for 18 h.
Figure 2 ORTEP plot of diethyl 2-[(3-bromo-7-chloro-4-oxo-4H-
pyrido[1,2-a]pyrimidin-2-yl)methyl]malonate (4)
the first example of SRN1 on a non-nitrated heterocyclic
substrate. Generalization with other nitronate anions and
the pharmacological evaluation of synthesized com-
pounds are under active investigation. Others derivatives
with substituent on the 3-position will be synthesized to
study the effect on the reduction potential and on the SRN1
reactivity.
Table 4 Reaction of 1 with Alkyl Malonate Anions under SRN
Reaction Conditions
1
Entry
1a
Anion
Time (h)
Product (%)
6 (84)
PhSO2 , Na+
1
–
–
2a
4-MeC6H4SO2 , Na+
1.5
2.5
18
7 (88)
3a
4-ClC6H4SO2 , Na+
8 (78)
–
Acknowledgment
4b
PhS–, Na+
9 (92)
This work is supported by the CNRS and the Universities of Aix-
Marseille. The authors thank M. Médebielle for cyclic voltammetry
measurements, V. Remusat for NMR spectra recording, the Spec-
tropole team for various analytical measurements, and M. Giorgi for
the X-ray crystal-structure determinations.
a All the reactions are performed using 1 equiv of 1, 2 equiv of sodium
arylsulfinate in DMSO at r.t., under inert atmosphere and photostim-
ulation until disappearance of the starting material as monitored by
TLC.
b The reaction is performed using 1 equiv of 1, 2.2 equiv of thiophe-
nol, and 2.2 equiv of NaH in DMSO at r.t., under inert atmosphere and
photostimulation until disappearance of the starting material as mon-
itored by TLC.
References and Notes
(1) La Motta, C.; Sartini, S.; Mugnaini, L.; Simorini, F.; Taliani,
S.; Salerno, S.; Marini, A. M.; Da Settimo, F.; Lavecchia, A.;
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To identify the main mechanism of the reaction, we stud-
ied the reactivity of this last reaction by addition of inhib-
itor (Table 5, entries 2, 3, 5, and 6).
Reaction-rate decreases are not significant and the reac-
tions thus seem to follow a SN2 mechanism.
All these results lead to believe that 1 is an appropriate
substrate for single-electron-transfer reactions with C-
centered nucleophiles. Indeed, some examples from the
literature show that the carbonyl group is an electron-
transfer inducer in heterocyclic series.30 Furthermore, in
analogy with quinonic derivatives,31 the system formed by
a carbonyl group added to a bromine atom could stabilize
the intermediate radical, facilitating the SRN1 reaction.
(3) Tworowski, D.; Matsievitch, R. WO 110868, 2007; Chem.
Abstr. 2007, 147, 427370.
(4) Fujita, H.; Shimoji, Y.; Kojima, S.; Nishino, H.; Kamoshita,
K.; Endo, K.; Kobayashi, S.; Kumakura, S.; Sato, Y. Sankyo
Kenkyusho Nenpo 1977, 29, 75.
In conclusion, we have shown in this work that the 3-bro-
mo-7-chloro-2-(chloromethyl)-4H-pyrido[1,2-a]pyrimi-
din-4-one reacts with various carbon- and sulfur-centered
anions by substitution only at the chloromethyl group.
The reaction with C-centered nucleophiles is very proba-
bly mediated by SRN1 mechanism. These results constitute
(5) Van der Mey, M.; Windhorst, A. D.; Klok, R. P.; Herscheid,
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Synlett 2008, No. 18, 2836–2840 © Thieme Stuttgart · New York

LETTER
SRN1 Reactions on New Non-Nitrated Heterocyclic System
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(25) Analytical Data for 3-Bromo-7-chloro-2-(2-methylprop-
1-enyl)-4H-pyrido[1,2-a]pyrimidin-4-one (2)
Shiny white plates, mp 175 °C (EtOH–Et2O). 1H NMR (200
MHz, CDCl3): d = 2.03 (d, J = 1.2 Hz, 3 H), 2.18 (d, J = 1.2
Hz, 3 H), 6.58 (sept, J = 1.2 Hz, 1 H, CH), 7.55 (dd, J = 9.5,
0.8 Hz, 1 H), 7.64 (dd, J = 9.5, 2.2 Hz, 1 H), 9.02 (dd,
J = 2.2, 0.8 Hz, 1 H). 13C NMR (50 MHz, CDCl3): d = 20.5,
28.1, 102.4, 122.4, 124.2, 125.2, 127.1, 137.0, 146.5, 149.2,
154.4, 159.7. Anal. Calcd for C12H10BrClN2O: C, 45.96; H,
3.21; N, 8.93. Found: C, 45.74; H, 3.24; N, 8.86.
Crystal Data for Compound 2
C12H10BrClN2O, colorless prism (0.3 × 0.2 × 0.05 mm3),
MW = 313.58, monoclinic, space group P21/c (T = 293 K),
a = 7.1901(2) Å, b = 15.5874(4) Å, c = 11.3226(3) Å,
b = 107.471(1)°; V = 1210.44(6) Å3, Z = 4, Dcalc = 1.721 g
cm–1, m = 3.600 mm–1, F(000) = 624, index ranges –9 ≤ h ≤
9, 0 ≤ k ≤ 21, 0 ≤ l ≤ 15; q range = 2.29–28.68°, 154 variables
and 0 restraints, were refined for 2136 reflections with I ≥
2s(I) to R1 = 0.0403, wR2 = 0.1078, GooF = 1.050. CCDC
691139 contains the supplementary crystallographic data for
this paper. These data can be obtained free of charge at
www.ccdc.cam.ac.uk/data_request/cif of from the
Cambridge Crystallographic Data Centre, 12, Union Road,
Cambridge CB2 1EZ, UK; fax:+44 (1223)336033; email:
deposit@ccdc.cam.ac.uk.
(26) Chanon, M.; Tobe, M. L. Angew. Chem., Int. Ed. Engl. 1982,
21, 1.
(27) General Procedure and Analytical Data for Compounds
3–5
A solution of 60% NaH (3 equiv) in DMSO under an inert
atmosphere was treated with dialkyl malonate (3 equiv) and
stirred for 20 min. A solution of 1 (1 equiv) in DMSO was
then added and the mixture was irradiated with a 60 W
tungsten lamp and stirred until disappearance of the starting
material as monitored by TLC. At this time, the mixture was
poured into cold H2O. The aqueous solution was extracted
with EtOAc. The organic layers were washed with brine,
dried over anhyd Na2SO4, and evaporated under reduced
pressure. The residue was purified by chromatography
column on SiO2. Wanted products were recrystallized with
BuOH or i-PrOH.
(18) Terme, T.; Crozet, M. D.; Gellis, A.; Vanelle, P. Recent Res.
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Vanelle, P. Heterocycles 2008, 75, 925.
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Barontini, S.; Macchia, M.; Barili, P. L.; Hamdan, M.
J. Heterocycl. Chem. 1999, 36, 1065.
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M.; Pusztay, L.; Kiss, A. I.; Czako, L.; Abdirizak, O. H.
J. Heterocycl. Chem. 1985, 22, 481. (b) Dekeyser, M. A.;
Moore, R. C.; Pierce, B. J.; Hubbard, W. L.; Winchester, L.
EP 81945, 1983; Chem. Abstr. 1983, 100, 22795.
(22) Analytical Data for 3-Bromo-7-chloro-2-(chloromethyl)-
4H-pyrido[1,2-a]pyrimidin-4-one (1)
Dimethyl 2-{(3-Bromo-7-chloro-4-oxo-4H-pyrido[1,2-
a]pyrimidin-2-yl)methyl}malonate (3)
Pale yellow crystals, mp 147 °C (i-PrOH). 1H NMR (200
MHz, CDCl3): d = 3.55 (d, J = 7.4 Hz, 2 H), 3.77 (s, 6 H),
4.24 (t, J = 7.4 Hz, 1 H), 7.55 (d, J = 9.4 Hz, 1 H), 7.70 (dd,
J = 9.4, 2.2 Hz, 1 H), 9.04 (d, J = 2.2 Hz, 1 H). 13C NMR (50
MHz, CDCl3): d = 14.1, 36.0, 49.3, 61.6, 102.9, 124.9,
125.3, 127.0, 137.4, 146.9, 153.6, 162.2, 168.8. Anal. Calcd
for C14H12BrClN2O5: C, 41.66; H, 3.00; N, 6.94. Found: C,
41.52; H, 2.94; N, 6.94.
White needles, mp 175 °C (i-PrOH). 1H NMR (200 MHz,
CDCl3): d = 4.75 (s, 2 H), 7.67 (dd, J = 9.4, 0.7 Hz, 1 H),
7.75 (dd, J = 9.4, 2.2 Hz, 1 H), 9.06 (dd, J = 2.2, 0.7 Hz,
1 H). 13C NMR (50 MHz, CDCl3): d = 46.0, 103.0, 125.3,
125.5, 127.4, 137.9, 147.7, 154.1, 159.7. Anal. Calcd for
C9H5BrCl2N2O: C, 35.10; H, 1.64; N, 9.10. Found: C, 35.11;
H, 1.65; N, 8.96.
Diethyl 2-{(3-Bromo-7-chloro-4-oxo-4H-pyrido[1,2-
a]pyrimidin-2-yl)methyl}malonate (4)
White needles, mp 111 °C (BuOH). 1H NMR (200 MHz,
CDCl3): d = 1.27 (t, J = 7.1 Hz, 6 H), 3.53 (q, J = 7.4 Hz,
2 H), 4.22 (m, 5 H), 7.49 (d, J = 9.5 Hz, 1 H), 7.68 (dd,
J = 9.5, 2.3 Hz, 1 H), 9.03 (d, J = 2.3 Hz, 1 H). 13C NMR (50
MHz, CDCl3): d = 14.1, 36.0, 49.3, 61.6, 102.9, 124.9,
125.3, 127.0, 137.4, 146.9, 153.6, 162.2, 168.8. Anal. Calcd
for C16H16BrClN2O5: C, 44.52; H, 3.74; N, 6.49. Found: C,
44.76; H, 3.76; N, 6.46.
(23) (a) Médebielle, M.; Hohn, S.; Okada, E.; Myoken, H.;
Shibata, D. Tetrahedron Lett. 2005, 46, 7817.
(b) Médebielle, M.; Kato, K.; Dolbier, W. R. Jr. Tetrahedron
Lett. 2003, 44, 7871.
Crystal Data for Compound 4
C16H16BrClN2O5, colorless prism (0.3 × 0.2 × 0.05 mm3),
Synlett 2008, No. 18, 2836–2840 © Thieme Stuttgart · New York

2840
R. Szabo et al.
LETTER
3-Bromo-7-chloro-2-(tosylmethyl)-4H-pyrido[1,2-
MW = 431.67, triclinic, space group P1 (T = 293 K),
a = 8.0149(2) Å, b = 8.9522(2) Å, c = 12.8072(3) Å,
a = 81.6805(9)°, b = 76.2696(8)°, g = 81.9220(9)°;
V = 877.87(4) Å3, Z = 2, Dcalc = 1.633 g cm–1, m = 2.523
mm–1, F(000) = 436, index ranges –10 ≤ h ≤ 10, –11 ≤ k ≤
11, 0 ≤ l ≤ 17; q range = 1.65–28.69°, 228 variables and 0
restraints, were refined for 3563 reflections with I ≥ 2s(I) to
R1 = 0.0330, wR2 = 0.0889, GooF = 1.047. CCDC 691140
contains the supplementary crystallographic data for this
paper.
a]pyrimidin-4-one (7)
White needles, mp 225 °C (i-PrOH). 1H NMR (200 MHz,
CDCl3): d = 2.45 (s, 3 H), 4.79 (s, 2 H), 7.32 (d, J = 8.0 Hz,
2 H), 7.55 (dd, J = 9.5, 0.7 Hz, 1 H), 7.69–7.76 (m, 3 H), 9.01
(dd, J = 2.3, 0.7 Hz, 1 H). 13C NMR (50 MHz, CDCl3):
d = 21.7, 64.0, 105.9, 125.2, 125.6, 127.4, 128.6, 129.8,
136.5, 137.9, 145.3, 147.0, 153.5, 153.9. Anal. Calcd for
C16H12BrClN2O3S: C, 44.93; H, 2.83; N, 6.55; S, 7.50.
Found: C, 44.93; H, 2.78; N, 6.45; S, 7.23.
Benzyl Ethyl 2-{(3-Bromo-7-chloro-4-oxo-4H-pyrido-
[1,2-a]pyrimidin-2-yl)methyl}malonate (5)
3-Bromo-7-chloro-2-[(4-chlorophenyl-sulfonyl)methyl]-
4H-pyrido[1,2-a]pyrimidin-4-one (8)
Yellowish solid, mp 275 °C (BuOH). 1H NMR (200 MHz,
CDCl3): d = 1.23 (t, J = 7.2 Hz, 3 H), 3.54 (dd, J = 7.9, 7.0
Hz, 2 H), 4.20 (q, J = 7.2 Hz, 2 H), 4.24 (dd, J = 7.9, 7.0 Hz,
1 H), 5.18 (s, 2 H), 7.24–7.32 (m, 6 H), 7.64 (dd, J = 9.4, 2.3
Hz, 2 H), 8.97 (d, J = 2.3 Hz, 1 H). 13C NMR (50 MHz,
CDCl3): d = 14.0, 36.0, 49.3, 61.7, 67.0, 102.8, 128.8, 125.2,
126.9, 128.2, 128.3, 128.4, 135.4, 137.3, 146.7, 153.4,
161.8, 168.5, 168.6. Anal. Calcd for C21H18BrClN2O5: C,
51.09; H, 3.67; N, 5.67. Found: C, 51.24; H, 3.76; N, 5.74.
White needles, mp 263 °C (EtOAc). 1H NMR (200 MHz,
CDCl3): d = 4.80 (s, 2 H), 7.49 (dd, J = 9.5, 0.7 Hz, 1 H),
7.50 (d, J = 8.8 Hz, 2 H), 7.73 (dd, J = 9.5, 2.2 Hz, 1 H), 7.80
(d, J = 8.8 Hz, 2 H), 9.02 (dd, J = 2.2, 0.7 Hz, 1 H). 13C NMR
(50 MHz, CDCl3): d = 63.9, 105.8, 125.3, 125.7, 127.2,
129.5, 130.1, 137.9, 138.1, 141.0, 147.0, 153.1, 153.8. Anal.
Calcd for C15H9BrCl2N2O3S: C, 40.20; H, 2.02; N, 6.25; S,
7.16. Found: C, 40.31; H, 2.02; N, 6.30; S, 6.92.
3-Bromo-7-chloro-2-(phenylthiomethyl)-4H-pyrido[1,2-
a]pyrimidin-4-one (9)
(28) (a) Miyake, H.; Yamamura, K. Bull. Chem. Soc. Jpn. 1986,
59, 89. (b) Norris, R. K.; Wright, T. A. Aust. J. Chem. 1985,
38, 1107. (c) Palacios, S. M.; Alonso, R. A.; Rossi, R. A.
Tetrahedron 1985, 41, 4147. (d) Kornblum, N.; Kestner,
M. N.; Boyd, S. D.; Cattran, L. C. J. Am. Chem. Soc. 1973,
95, 3356.
White plates, mp 156 °C (i-PrOH). 1H NMR (200 MHz,
CDCl3): d = 4.37 (s, 2 H), 7.19–7.35 (m, 3 H), 7.45–7.48 (m,
2 H), 7.71 (d, J = 9.5 Hz, 1 H), 8.06 (dd, J = 9.5, 2.3 Hz,
1 H), 8.92 (d, J = 2.3 Hz, 1 H). 13C NMR (50 MHz, CDCl3):
d = 40.2, 101.6, 124.3, 125.4, 126.7, 127.3, 129.2, 129.6,
135.5, 138.5, 147.5, 153.6, 161.3. Anal. Calcd for
C15H10BrClN2OS: C, 47.20; H, 2.64; N, 7.34; S, 8.40.
Found: C, 47.00; H, 2.60; N, 7.46; S, 8.21.
(29) Analytical Data for Compounds 6–9
3-Bromo-7-chloro-2-(phenylsulfonyl-methyl)-4H-pyrido-
[1,2-a]pyrimidin-4-one (6)
Beige needles, mp 234 °C (i-PrOH). 1H NMR (200 MHz,
CDCl3): d = 4.81 (s, 2 H), 7.48–7.57 (m, 3 H), 7.64–7.74
(m, 2 H), 7.84–7.89 (m, 2 H), 9.01 (d, J = 2.0 Hz, 1 H).
13C NMR (50 MHz, CDCl3): d = 63.9, 105.9, 125.3, 125.6,
127.3, 128.6, 129.2, 134.1, 137.9, 139.4, 147.0, 153.3,
153.9. Anal. Calcd for C15H10BrClN2O3S: C, 43.55; H,
2.44; N, 6.77; S, 7.75. Found: C, 44.08; H, 2.53; N, 6.72;
S, 7.78.
(30) (a) Roydhouse, M. D.; Walton, J. C. Eur. J. Org. Chem. 2007,
1059..(b) Guastavino, J. F.; Barolo, S. M.; Rossi, R. A. Eur. J.
Org. Chem. 2006, 3898.
(31) (a) Vanelle, P.; Terme, T.; Giraud, L.; Crozet, M. P.
Tetrahedron Lett. 2001, 42, 391..(b) Vanelle, P.; Terme, T.;
Crozet, M. P. Tetrahedron Lett. 2000, 41, 6383..(c) Vanelle,
P.; Donini, S.; Terme, T.; Maldonado, J.; Roubaud, C.; Crozet,
M. P. Tetrahedron Lett. 1996, 37, 3323..(d) Crozet, M. P.;
Giraud, L.; Sabuco, J.-F.; Vanelle, P.; Barreau, M. Tetrahedron
Lett. 1991, 32, 4125.
Synlett 2008, No. 18, 2836–2840 © Thieme Stuttgart · New York

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