Suzuki-Miyaura cross-coupling reactions of halo derivatives of 4H-pyrido[1,2-a]pyrimidin-4-ones

Article abstract of DOI:10.1039/c1ob05505d

The palladium-catalyzed Suzuki-Miyaura cross-coupling reactions of halo derivatives of 4H-pyrido[1,2-a]pyrimidin-4-one with (het)arylboronic acids allow easy access to (het)aryl and vinyl derivatives of this bicycle in good to excellent yields, even from chloro derivatives. The sequence of reactivity of the halogen in the different positions of the ring system was also investigated. 6-Phenyl-4H-pyrido[1,2-a]pyrimidin-4-one could be prepared by thermal cyclization of isopropylidene (6-phenylpyrid-2-ylamino)methylenemalonate, together with a small amount of 7-phenyl-1,4-dihydro-1,8-naphthyridin-4-one.

Full text of DOI:10.1039/c1ob05505d

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PAPER
Suzuki–Miyaura cross-coupling reactions of halo derivatives of
4H-pyrido[1,2-a]pyrimidin-4-ones†
Annama´ria Molna´r,a,b Anita Kapros,b La´szlo´ Pa´rka´nyi,c Zolta´n Mucsi,b Ga´bor Vla´da and Istva´n Hermecz*d
Received 31st March 2011, Accepted 23rd June 2011
DOI: 10.1039/c1ob05505d
The palladium-catalyzed Suzuki–Miyaura cross-coupling reactions of halo derivatives of
4H-pyrido[1,2-a]pyrimidin-4-one with (het)arylboronic acids allow easy access to (het)aryl and vinyl
derivatives of this bicycle in good to excellent yields, even from chloro derivatives. The sequence of
reactivity of the halogen in the different positions of the ring system was also investigated.
6-Phenyl-4H-pyrido[1,2-a]pyrimidin-4-one could be prepared by thermal cyclization of isopropylidene
(6-phenylpyrid-2-ylamino)methylenemalonate, together with a small amount of
7-phenyl-1,4-dihydro-1,8-naphthyridin-4-one.
The 4H-pyrido[1,2-a]pyrimidin-4-one scaffold is a privileged
structure1 in medicinal chemistry, as the physical properties of
its derivatives usually meet the criteria of the “rule of five” for
the development of orally active drugs.2 The derivatives display
diverse biological activities, and some outstanding representatives
have been introduced into human therapy as analgesic, anti-
inflammatory, antiallergic or antipsychotic agents.3 Risperidone,
a member of this class, was one of the drugs most widely
prescribed worldwide in 2007.4 Paliperidone,5 the main metabolite
of risperidone, was recently introduced into human therapy as an
oral atypical antipsychotic for the treatment of bipolar disorders.
Its palmitate ester prodrug is currently under evaluation by the
FDA as a monthly injection for the treatment of schizophrenia.6
4H-Pyrido[1,2-a]pyrimidin-4-ones are usually synthesized from
2-aminopyridines, and functionalization of this bicyclic ring
system has not been explored, expect in positions 2 and 3.7 Direct
synthesis from 2-aminopyridines is sometimes accompanied by
poor yields. For example, the potent glycogen synthase kinase 3b
inhibitor 2-(4-pyridyl)-4H-pyrido[1,2-a]pyrimidin-4-ones could
be prepared in yields of only 10–28% in the reactions of 2-
aminopyridines and ethyl 3-(4-pyridyl)-3-oxopropionate in PPA
at 140–150 ◦C for 12 h.8
Palladium-catalyzed cross-coupling processes for carbon–
carbon bond formation of (het)aryl halides have become an
indispensable tool9 for synthetic and medicinal chemists in their
search for new derivatives with wide-ranging therapeutic potential.
Their industrial importance is continuously increasing.10 The
reactivities of the halo and pseudohalo derivatives of a broad
range of heterocycles are studied in cross-coupling reactions.11 One
of the most widely-used methods is the Suzuki–Miyaura reaction,
a powerful means with which to generate carbon–carbon bonds
via the palladium-catalyzed cross-coupling of electrophiles with
organoboranes.12
There has as yet been no systematic investigation of the
Suzuki–Miyaura coupling of halo derivatives of 4H-pyrido[1,2-
a]pyrimidin-4-ones. Merely a few examples are to be found of
the introduction of an aryl substituent into positions of 2,13 3,14
715 and 916 of 4H-pyrido[1,2-a]pyrimidin-4-one by the Suzuki–
Miyaura cross-coupling reaction. In most cases, Pd(PPh3)4 (3–5
mol%) was applied as catalyst and Na2CO3 as base in different
solvents (most frequently DME or THF). The reaction period
usually ranges from 3 h to 16 h.
Results and discussion
The present article furnishes an account of our investigations of
the sequence of reactivity of chloro, bromo and iodo substituents
at different positions17 on the 4H-pyrido[1,2-a]pyrimidin-4-one
skeleton in Suzuki–Miyaura cross-coupling reactions. Preparative
experiments were also performed.
It has been demonstrated that the reactivity in the palladium-
catalyzed cross-coupling reactions of heterocycles is mainly de-
termined by the relative ease of oxidative addition.18 Handy
and Zhang proposed a simple guide for predicting the sequence
of coupling (e.g. Suzuki) in polyheteroaromatics, based upon
the 1H NMR chemical shifts of the parent non-halogenated
heteroaromatics.19 Whilst there are exceptions, this appears to
aChemical Development, R&D, Chinoin Ltd, To´ utca 1-5, H-1045 Budapest,
Hungary
bDepartment of Organic Chemistry & Technology, Budapest University of
Technology and Economics, Budafoki u´t 8, H-1111 Budapest, Hungary
cInstitute of Structural Chemistry, Chemical Research Center, Hungarian
Academy of Sciences, Pusztaszeri u´t 59, H-1025 Budapest, Hungary
dExternal Pharmaceutical Department, Budapest University of Technology
and Economics, R&D, Chinoin Ltd, To´ utca 1-5, H-1045 Budapest
† Electronic supplementary information (ESI) available: Protocol for
Suzuki–Miyaura cross-couplings and analytical and 1H and 13C NMR
data for compounds 29–44. Cartesian coordinates of the optimized ground
state energy of compound 48. X-ray data for compound 48 (CIF). CCDC
reference number 816421. For ESI and crystallographic data in CIF or
other electronic format see DOI: 10.1039/c1ob05505d
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Table 1 Suzuki–Miyaura reactions of chloro derivatives 1–5 of 4H-pyrido[1,2-a]pyrimidin-4-one with phenylboronic acid 6
HPLC yield
Entry Chloro deriv. Positionof Cl Reaction period Ph deriv. HPLC yield of Ph deriv. Starting Cl compd. Reaction period of Ph deriv.
1
2
3
4
5
1
2
3
4
5
2
3
7
8
9
4 h
4 h
4 h
4 h
4 h
7
>99%
55%
67%
>99%
77%
<1%
~43%
~33%
<1%
~21%
1 h
1 h
87%
94%
8
9
10
11
Table 2 Suzuki–Miyaura reactions of monohalogen derivatives 1–5 and 13–19 of 4H-pyrido[1,2-a]pyrimidin-4-one with phenylboronic acid 6 during 4
h at 80 ◦
Entry
C
4H-Pyrido[1,2-a]pyrimidin-4-one
Compd.
X
Compd.
Ph position
HPLC yield
Starting halo derivative
Side-product 12
1
2
3
4
5
6
7
8
1
2-Cl
3-Cl
3-Br
3-I
7-Cl
7-Br
7-I
8-Cl
8-Br
9-Cl
9-Br
9-I
7
2
3
3
3
7
7
7
8
8
9
9
9
>99%
55%
73%
89%
67%
>99%
91%
>99%
>99%
77%
98%
98%
<1%
43%
25%
<1%
33%
<1%
<1%
<1%
<1%
21%
<1%
2%
2%
11%
<1%
<1%
9%
<1%
<1%
2%
2
8
13
17
3
14
18
4
15
5
16
19
8
8
9
9
9
10
10
11
11
11
9
10
11
12
<1%
<1%
2%
2%
be very useful in practice, particularly in the pharmaceutical
industry.20
On this basis, the expected reaction sequence for the chloro
derivatives 1–5 of 4H-pyrido[1,2-a]pyrimidin-4-one, for example
is as follows:
the 2-chloro (1) and 8-chloro (4) derivatives, the conversions were
over 99%, and we therefore repeated the reactions with a shorter
reaction period, 1 h. The reactivity sequence was predicted fairly
well by the rule of Handy and Zhang, as only a reversal of the
sequence for positions 2 and 8 was observed:
position 2 (8.31 ppm) > 8 (7.97 ppm) > 9 (7.70 ppm) > 7 (7.30
ppm) > 3 (6.34 ppm)
8 ≥ 2 > 9 > 7 > 3
The chemical shift of 6-H (8.96 ppm) does not help as it is
influenced by the anisotropic effect of the neighboring C4
O
group.21 We were interested in whether the practical rule of Handy
and Zhang is applicable in our case, as a reversal of the reactivity
sequence may be observed when the 1H NMR chemical shifts of
any two positions are within 0.2–0.3 ppm.
For the selection of a solvent and a catalyst [5 mol% PdCl2 or
Pd(PPh3)4], we performed preliminary investigations on the re-
action of 3-bromo-4H-pyrido[1,2-a]pyrimidin-4-one with phenyl-
boronic acid to yield the 3-phenyl derivative in the presence of
NaHCO3. Hydrodebromination was a significant side-reaction (5–
11%) in the presence of PdCl2 as catalyst in EtOH or DME. It
was also pronounced (8%) in NMP when Pd(PPh3)4 was used as
catalyst, and the reaction was slower than in DME. For more
detailed experiments, we finally chose Pd(PPh3)4 as catalyst and
DME as solvent.
We next investigated the reactivities of different halogens at
different positions of the bicyclic ring system, using compounds
1–5 and 13–19 with phenylboronic acid 6 (Table 2). The reaction
period was 4 h and the conversion was again checked by HPLC.
The sequence of reactivity of the halogens was in harmony with
that expected:24 I > Br > Cl.
As general conditions for coupling, we used a 5% excess of
the boronic acid with the 4H-pyrido[1,2-a]pyrimidin-4-one in
the presence of 5% freshly prepared22 Pd(PPh3)4 as catalyst. We
applied an aqueous solution of a weak base, NaHCO3, as the 4H-
pyrido[1,2-a]pyrimidin-4-one skeleton is sensitive to nucleophilic
ring opening.23 Two equivalents of NaHCO3 were used relative to
the boronic acid.
The coupling reactions were accompanied by different extents
of hydrodehalogenation to give unsubstituted 4H-pyrido[1,2-
a]pyrimidin-4-one 12. Hydrodehalogenation was most marked for
the compounds with the halogen in position 3, and especially
for the iodo derivative 17. We did not detect any homocoupled
products.
We carried out preparative experiments, too (Table 3). The
reaction conditions were not optimized. We used reaction periods
of 1 h (for iodo derivatives), 4 h, 24 h, 48 h and 96 h. The
We investigated the conversion of chloro derivatives 1–5 with
phenylboronic acid 6 after 4 h by HPLC (Table 1). In the cases of
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Table 3 Suzuki–Miyaura reactions of monohalogen derivatives 1–5 and 13–19 of 4H-pyrido[1,2-a]pyrimidin-4-one with boronic acids 6 and 20–28
Substituted 4H-pyrido[1,2-a]pyrimidin-4-ones
Entry
Compd.
X
Boronic acid
R
Position
Compd.
Reaction time
Isolated yield
1
2
3
4
5
6
7
8
1
2-Cl
2-Cl
2-Cl
2-Cl
2-Cl
2-Cl
2-Cl
2-Cl
2-Cl
2-Cl
3-Cl
3-Cl
3-Cl
3-Br
3-I
7-Cl
7-Cl
7-Cl
7-Cl
7-Br
7-I
6
Ph
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
7
7
7
7
7
7
8
8
8
8
9
9
9
7
4 h
4 h
4 h
24 h
4 h
91%
97%
91%
85%
93%
81%
87%
77%
99%
38%b
98%
92%
76%
70%
73%
92%
90%
51%
89%
91%
87%
97%
92%
81%
87%
82%
95%
89%
1
20
21
22
23
24
25
26
27
28a
6
4-MeOPh
4-F3CPh
2-AcPh
1-naphthyl
3-thienyl
3-pyridyl
4-pyridyl
1-pentenyl
CH2Ph
Ph
4-MeOPh
4-F3CPh
Ph
Ph
Ph
1-naphthyl
3-thienyl
4-pyridyl
Ph
Ph
Ph
29
30
31
32
33
34
35
36
37
8
1
1
1
1
24 h
96 h
96 h
24 h
96 h
48 h
72 h
96 h
24 h
24h
24 h
24 h
96 h
96 h
4 h
4 h
4 h
4 h
4 h
24 h
24 h
4 h
1
1
9
1
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
1
2
2
20
21
6
6
6
38
39
8
8
9
2
13
17
3
3
23
24
26
6
40
41
42
9
3
3
14
18
4
6
9
8-Cl
8-Br
8-Br
8-Cl
9-Cl
9-Br
9-I
6
10
10
43
44
11
11
11
15
15
4
5
16
19
6
Ph
20
27
6
4-MeOPh
1-pentenyl
Ph
Ph
Ph
6
6
4 h
a Benzylboronic acid pinacol ester was used. b The conversion was 74%. >99% conversion was achieved when Pd(dppf)Cl2 was used as catalyst under
similar reaction conditions.
longest reaction period (96 h) was necessary in the cases of the
electron-deficient pyridylboronic acids 25 and 26. The products
were isolated by column/flash chromatography. The substituents
on the phenyl ring of the arylboronic acids had little effect on the
reaction. The isolated yields were good to excellent (70–99%),
even in the case of chloro derivatives 1–5. Chloro derivatives
are usually more easily available at lower cost and they provide
wider diversity than other halo derivatives.25 It might be expected
that the reaction periods and reaction temperature could be
decreased by applying more electron-rich and/or s-donating
bulky phosphines,26 N-heterocyclic carbene27 ligands, or more
effective palladium catalysts,28 especially palladacycles,28b under
microwave conditions.29 Pentenylboronic acid 27 also provided
acceptable yields (Entries 9 and 25 in Table 3). In spite of the
promising conversion when pinacol borane 28 was used, 2-benzyl
derivative 37 could be isolated in only moderate yield, as it
was necessary to repeat the chromatographic step to obtain the
compound in pure form.
aminopyridine (Scheme 1), as the synthetic accessibility of 6-halo
derivatives of 4H-pyrido[1,2-a]pyrimidin-4-one is very limited.30
Scheme
1 Thermal cyclization of (6-phenylpyridin-2-ylamino)-
methylenemalonate (46)in diphenyl oxide.
Thermal
cyclization
of
(6-substituted
pyridin-2-
It was of interest to consider whether the missing 6-phenyl
derivative 48 could be obtained by thermal cyclization of pyridy-
laminomethylenemalonate 46, prepared in a one-pot reaction
of Meldrum’s acid, trimethyl orthoformate and 6-phenyl-2-
ylamino)methylenemalonates, e.g. 46, may lead to the formation
of kinetically controlled 4H-pyrido[1,2-a]pyrimidin-4-ones, e.g.
48, and/or the thermodynamically more stable 1,4-dihydro-
1,8-naphthyridin-4-ones, e.g. 47, depending on the steric and
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Table 4 Ground-state geometry of some 4H-pyrido[1,2-a]pyrimidin-4-ones 45a,b and 48, calculated DFT by B3LYP/6-311++G(2d,2p) level, and some
selected geometrical data determined by single-crystal X-ray determination
N5–C4 bond
length (pm)
C6–R bond
length (pm)
N5–N6–R
angle (deg)
C4–N5–C6
angle (deg)
Distance between
O and R (pm)
O
C4 ◊ ◊ ◊ C6–R
6-R
torsion angle (deg)
45a
45b
45ba
48
H
146.5
147.2
145.0(3)
147.3
107.8
150.5
150.4(3)
148.5
113.8
122.2
121.7(2)
121.5
116.9
120.8
121.1(2)
120.1
222.4
263.6
262.2
267.7
0.01
15.2
11.9
28.2
Me
Me
Ph
Ph
48a
145.7(2)
148.6(2)
120.6(1)
120.6(1)
268.6(2)
31.0(2)
a measured
Fig. 1 Calculated ground-state geometry of 48. a) The ring atoms of the bicycles are in the plane of the drawing. b) The N5–C9a bond is perpendicular
to the plane of the drawing. c) The line determined by C4 and C6 is almost perpendicular to the plane of the drawing.
Table 5 Charton’s
u steric parameters of the investigated 6-R
electronic properties of the substituent at position 6 of the
pyridine moiety and the applied reaction period.31 The driving
force of the formation of 1,4-dihydro-1,8-naphthyridin-4-ones
is the release of the strain in 4H-pyrido[1,2-a]pyrimidin-4-ones,
accumulated in the ground state between the C4 O group and
the C6 substituent. To minimize the steric strain in the ground
state of 4H-pyrido[1,2-a]pyrimidin-4-ones, the C6 substituent
and the C4 O group move in opposite directions out of the
plane of the bicycle.
We carried out DFT calculations to determine the potential
ground-state structure of 6-phenyl derivative 48. The result of the
calculation is depicted in Fig. 1, and the characteristic geometric
data are collected in Table 4, together with the corresponding
data on the unsubstituted and 6-methyl derivatives, 45a and 45b,
respectively.
For characterization of the steric demand of a substituent,
we used Charton’s u values,32 derived from the van der Waals
radii (Table 5). The phenyl group could be characterized by
minimum and maximum values. The actual size33 depends on
the interplanar angle (between the plane of the phenyl group
and the best plane of the bicycle), which is ~55◦ according to
the calculations. In accordance with the Charton’s u values, the
calculations also indicated that the steric demand of the 6-phenyl
group was somewhat greater than that of the 6-methyl group,
as the calculated O C4 ◊ ◊ ◊ C6–R torsion angle (28.2◦) is almost
twice that in 45b (15.2◦) (see rows 2 and 4 in the last column in
Table 4).
The above expectation is in accordance with the experimental
results. When aminomethylenemalonate 46 was added to boiling
diphenyl ether, and the reaction mixture was cooled to room
temperature within 2 min, we obtained 48 in 68% yield, ac-
companied by a 18% yield of 1,4-dihydro-1,8-naphthyridin-4-
one 47. Under similar conditions, isopropylidene (6-methyl-2-
substituents32
H
0
Me
Ph
Charton’s u value
0.52
0.57 (min); 2.15
(max); 1.66
pyridyl)aminomethylenemalonate afforded the main product 45b
with only a trace of 7-methyl-1,4-dihydro-1,8-naphthyridin-4-one.
It is interesting, that in the thermal cyclization of isopropylidene [2-
(4-methoxyphenyl)pyrimidin-2-ylaminomethylenemaloanate (a 6-
aza analog of 46) Lesher et al.34 obtained only the thermodynam-
ically more stable 2-(4-methoxyphenyl)-5,8-dihydropyrido[2,3-
d]pyrimidin-5-one (a 6-aza analog of 47) in a yield of 75%
when they applied a slightly longer reaction time (4 min). They
did not attempt to identify the nitrogen bridgehead bicycle, 6-
(4-methoxyphenyl)-4H-pyrimido[1,6-a]pyrimidin-4-one (an 7-aza
analog of 48). When we applied 5 min reaction period (instead
of 2 min) to the thermal cyclization of 46 (6-phenylpyridin-
2-ylamino)methylenemalonate 47 in boiling diphenyl ether 1,8-
naphthyridin-4-one formed in a higher yield (37%).
By crystallization from EtOH, we obtained a single-crystal of
48, which was suitable for single-crystal X-ray analysis (Fig. 2).
The agreement between the theoretical and experimental data on
48 was fair (see rows 4 and 5 in Table 4), considering that the
theoretical calculations gave data relating to a vacuum, while in
the solid state the crystal packaging exerts some influence on the
geometrical parameters. The measured O C4 ◊ ◊ ◊ C6–R torsion
angle (see Table 4) and the interplanar angle were 31(2)◦ and 54◦,
respectively. Intermolecular hydrogen-bonding and p–p stacking
stabilize the crystal structure of 48. Non-classical weak hydrogen-
bonding [C4 O ◊ ◊ ◊ H–C = 255.0 pm, and <(O ◊ ◊ ◊ H–C) = 169◦]
occurs between the oxygen of the C4 O group and one of the
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solution (0.6 ◦mL, 0.53 mmol) were introduced. The mixture was
heated to 80 C, after which Pd(PPh3)4 (14 mg, 0.01 mmol) was
added. After stirring at 80 ◦C for 1 h–96 h, the mixture was
allowed to cool to RT, and was then poured into water (3 mL),
and extracted with DCM (3 ¥ 3 mL). The combined organic
layers were dried over Na2SO4 and evaporated to dryness. The
crude product was purified by column chromatography on silica
gel [Kieselgel 60 (Reanal); eluent n-hexane : ethyl acetate = 1 : 1,
except for compounds 34, 35, 42, where 95 : 5 mixture of ethyl
acetate and methanol was used as eluent].
2-Phenyl-4H-pyrido[1,2-a]pyrimidin-4-one (7). Yellow crystals
◦
(51 mg, 91%; mp. 147–148 ◦C, Lit., mp 149.5–150 C,35 147.5–
◦
◦
◦
148 C,36 144–145 C,37 148–149 C38). UV lmax(EtOH)/nm 204
(e/dm3 mol-1 cm-1 26 800), 274 (27 500), 350 (8800) IR (KBr):
Fig. 2 Molecular diagram of 48 with the numbering atoms (ADP
ellipsoids represent 50% probabilities).
n
max/cm-1 3134 (C–HAr), 1710, 1671 (C O), 1631 (C N), 1556,
1531, 1498 (C CAr), 756, 673 [g( CH)Ar]. 1H NMR (200 MHz,
◦
3
4
meta-hydrogen atoms on the phenyl ring of another molecule,
and the perpendicular distance between the pyrimidone rings of
the two bicycles is 352.8(6) pm (see the Electronic supplementary
information†).
DMSO-d6, 27 C): d 8.95 (dd, J6,7 = 6.9 Hz, J6,8 = 1.6 Hz, 1H,
6-H), 8.21–8.16 (m, 2H, 2¢-H and 6¢-H), 7.96 (ddd, 3J7,8 = 6.9 Hz,
3J8,9 = 8.6 Hz, J6,8 = 1.6 Hz, 1H, 8-H), 7.74 (dd, J8,9 = 8.6 Hz,
4
3
4J7,9 = 1.2 Hz, 1H, 9-H), 7.53–7.50 (m, 3H, 4¢-H, 3¢-H and 5¢-H),
7.33 (dt, 3J6,7 = J7,8 = 6.9 Hz, 4J7,9 = 1.2 Hz, 1H, 7-H), 6.98 (s, 1H,
3
In conclusion, the palladium-catalyzed Suzuki–Miyaura cou-
pling of monohalogen derivatives of 4H-pyrido[1,2-a]pyrimidin-
4-one with various boronic acids proceeded smoothly under
mild reaction conditions, providing different (het)aryl and pen-
tenyl derivatives of 4H-pyrido[1,2-a]pyrimidin-4-one in good to
excellent yields. The reaction sequence for the halogen atoms
at different positions of this bicycle was 8 ≥ 2 > 9 > 7> 3,
which was predicted almost correctly by the rule of Handy and
Zhang. In accordance with the literature data, the sequence
of reactivity I > Br > Cl was observed at each position.
Enhanced hydrodehalogenation is characteristic for 3-halo deriva-
tives of 4H-pyrido[1,2-a]pyrimidin-4-one, and especially the 3-
iodo compound. The thermal cyclization of isopropylidene [(6-
phenylpyridin-2-yl)aminomethylene]malonate afforded 6-phenyl-
4H-pyrido[1,2-a]pyrimidin-4-one together with the thermody-
namically more stable 7-phenyl-1,4-dihydro-4H-1,8-naphthyridin-
4-one.
3-H). 13C NMR (50 MHz, DMSO-d6, 27 ◦C): d 160.8 (C-2), 158.1
(C-4), 151.1 (C-9a), 138.0 (C-8), 137.1 (C-1¢), 131.1 (C-4¢), 129.1
(C-3¢ and C-5¢), 127.64 (C-2¢ and C-6¢), 127.35 (C-6), 126.6 (C-9),
116.5 (C-7), 99.0 (C-3). MS(EI+): m/z = 222 [M+], 194, 78, 51.
HRMS(ES+) Calculated for C14H11N2O 223.0871 (MH+), found
223.0877.
3-Phenyl-4H-pyrido[1,2-a]pyrimidin-4-one (8). Yellow crystals
(55 mg, 98% (Cl); 39 mg, 70% (Br);◦41 mg, 73% (I); mp 167–168 ◦C,
◦
Lit., mp 167–168 C,23a 166–167 C39). UV lmax(EtOH)/nm 202
(e/dm3 mol-1 cm-1 29 900), 240 (15 100), 362 (17 100). IR (KBr):
n
max/cm-1 = 3136, 3093 (C–HAr), 1670 (C O), 1626 (C N), 1574,
1
1562, 1524, 1494 (C CAr), 773, 718 (g( CH)Ar). H NMR (200
MHz, DMSO-d6, 27 ◦C): d 9.11 (dd, 3J6,7 = 7.1 Hz, 4J6,8 = 1.6 Hz,
3
3
1H, 6-H), 8.61 (s, 1H, 2-H), 7.98 (ddd, J8,9 = 9.0 Hz, J7,8 = 7.8
4
3
4
Hz, J6,8 = 1.6 Hz, 1H, 8-H), 7.83 (dd, J2¢,3¢ = 7.2 Hz, J2¢,4¢ = 1.5
Hz, 2H, 2¢-H and 6¢-H), 7.74 (d, J8,9 = 9.0 Hz, 1H, 9-H), 7.46–
3
7.34 (overlapping m, 4H, 7-H, 3¢-H, 4¢-H and 5¢-H). 13C NMR (50
MHz, DMSO-d6, 27 ◦C): d 156.3 (C-4), 153.0 (C-2), 150.7 (C-9a),
137.4 (C-8), 134.8 (C-1¢), 128.6 (C-3¢, C-5¢, C-2¢ and C-6¢), 127.75
and 127.66 (C-6 and C-4¢), 126.4 (C-9), 117.2 (C-7), 115.4 (C-3).
MS(EI+): m/z = 222 [M+], 194, 78, 51. HRMS(ES+) Calculated
for C14H11N2O 223.0871 (MH+), found 223.0875.
Experimental
General information
Boronic acids, benzylboronic acid pinacol ester, PdCl2 and PPh3
were purchased from Aldrich and were used without further
purification. Melting points were recorded on a Bu¨chi 535
apparatus in open capillary tubes and are uncorrected. UV spectra
were recorded on an Agilent 8453 UV-Visible spectrometer, and
7-Phenyl-4H-pyrido[1,2-a]pyrimidin-4-one (9). Yellow crystals
[51 mg, 92% (Cl); 50 mg, 91% (Br); 48 mg, 87% (I); mp 138–139 ◦C].
UV lmax(EtOH)/nm 204 (e/dm3 mol-1 cm-1 25 600), 246 (20 700),
351 (12 900). IR (KBr): nmax/cm-1 3072 (C–HAr), 1695 (C O),
1628 (C N), 1557, 1524, 1497 (C ◦ CAr), 770, 695 (g( CH)Ar).
1H NMR (200 MHz, DMSO-d6, 27 C): d 9.10 (s, 1H, 6-H), 8.33–
8.28 (overlapping m, 2H, 2-H and 8-H), 7.79–7.73 (overlapping
m, 3H, 2¢-H, 6¢-H and 4¢-H), 7.57–7.39 (overlapping m, 3H, 3¢-H,
1
IR spectra with a VERTEX 70 instrument (KBr). The H and
13C NMR spectra were recorded on Bruker Avance-200 or 400
spectrometers in DMSO-d6 with internal standards, and J values
are given in Hz. Mass spectra (GC-MS) were performed on
a Shimadzu GCMS-QP2010S instrument, high resolution mass
spectra with a Waters LCT Premier XE instrument.
3
5¢-H and 9-H), 6.41 (d, J2,3 = 6.4 Hz, 1H, 3-H). 13C NMR (50
MHz, DMSO-d6, 27 ◦C): d 157.3 (C-4), 155.0 (C-2), 150.9 (C-
9a), 136.9 (C-8), 135.3 (C-1¢), 129.8 (C-3¢ and C-5¢), 129.2 (C-9),
129.0 (C-7), 127.2 (C-2¢ and C-6¢), 126.8 (C-4¢), 123.8 (C-6), 104.3
(C-3). MS(EI+): m/z = 222 [M+], 194, 154, 127, 77. HRMS(ES+)
Calculated for C14H11N2O 223.0871 (MH+), found 223.0876.
Suzuki–Miyaura cross-couplings
General procedure. To a solution of the monohalogenated
derivative of 4H-pyrido[1,2-a]pyrimidin-4-one17 (0.25 mmol),
boronic acid (0.26 mmol) in DME (1.5 mL) and 1 M NaHCO3
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8-Phenyl-4H-pyrido[1,2-a]pyrimidin-4-one (10). Yellow crys-
naphthyridin-4-one (47) (246 mg 18%, mp 286–287 ◦C) 1H NMR
(400 MHz, DMSO-d6, 27 ◦C): d 12.17 (d, 3J1,2 = 4.8 Hz, 1H, NH),
tals [54 mg, 97% (Cl); 51 mg, 92% (Br); mp 184–185 ◦C]. UV
l
max(EtOH)/nm 205 (e/dm3 mol-1 cm-1 29 300), 272 (18 700), 357
8.51 (d, 3J5,6 = 8.3 Hz, 1H, 5-H), 8.19 (dd, 3J2¢,3¢ = 7.8 Hz, 4J2¢,4¢
=
(14 700). IR (KBr): nmax/cm-1 = 3100 (C–HAr), 1673 (C O), 1632
1.4 Hz, 2H, 2¢-H and 6¢-H), 7.97 (d, 3J5,6 = 8.3 Hz, 1H, 6-H), 7.94
3 3
(C N), 1570, 1512, 1474 (C CAr), 770, 759 (g( CH)Ar).1H
(dd, J2,3 = 6.9 Hz, J1,2 = 4.8 Hz, 1H, 2-H), 7.58–7.53 (m, 3H,
◦
3
NMR (200 MHz, DMSO-d6, 27 C): d 9.01 (d, J6,7 = 7.4 Hz,
1H, 6-H), 8.32 (d, 3J2,3 = 6.3 Hz, 1H, 2-H), 8.00–7.94 (m, 3H, 9-H,
2¢-H and 6¢-H), 7.78 (dd, 3J6,7 = 7.4 Hz, 4J7,9 = 2.1 Hz, 1H, 7-H),
3¢-H, 4¢-H and 5¢-H), 6.11 (d, 3J2,3 = 6.9 Hz, 1H, 3-H). 13C NMR
◦
(100 MHz, DMSO-d6, 27 C): d 177.5 (C-4), 159.1 (C-7), 150.6
(C-8a), 140.7 (C-2), 137.6 (C-1¢), 136.0 (C-5), 130.5 (C-4¢), 129.1
(C-3¢ and C-5¢), 127.5 (C-2¢ and C-6¢), 119.3 (C-4a), 116.8 (C-6),
110.1 (C-3). MS(EI+): m/z = 222 [M+], 207, 194, 166, 140, 97, 84,
63, 51. HRMS(ES+) Calculated for C14H11N2O 223.0871 (MH+),
found 223.0870.
3
7.63–7.50 (m, 3H, 3¢-H, 5¢-H and 4¢-H), 6.37 (d, J2,3 = 6.3 Hz,
1H, 3-H). 13C NMR (50 MHz, DMSO-d6, 27 ◦C): d 157.1 (C-4),
155.5 (C-2), 152.1 (C-8), 147.8 (C-9a), 135.6 (C-1¢), 130.7 (C-4¢),
129.7 (C-3¢ and C-5¢), 127.8 (C-6), 127.6 (C-2¢ and C-6¢), 121.9 (C-
9), 115.3 (C-7), 103.8 (C-3). MS(EI+): m/z = 222 [M+], 194, 154,
140, 127, 97, 77, 63, 51. HRMS(ES+) Calculated for C14H11N2O
223.0871 (MH+), found 223.0877.
The mother liquor was diluted with n-hexane (40 mL) and
extracted with 2 M HCl. The pH of the separated aqueous phase
was adjusted to 8 with aqueous NaOH, and the precipitate was
filtered off, washed with water, and recrystallized from EtOH
to give 6-phenyl-4H-pyrido[1,2-a]pyrimidin-4-one (48) as yellow
crystals (610 mg, 44%; mp 173 ◦C). UV lmax(EtOH)/nm 203
(e/dm3 mol-1 cm-1 30 200), 250 (7800), 293 (8500) 359 (8900).
IR (KBr): nmax/cm-1 = 3058, 3046 (C–HAr), 1686 (C O), 1629
(C N), 1569, 1536, 1494 (C C◦Ar), 763, 700 (g( CH)Ar). 1H
9-Phenyl-4H-pyrido[1,2-a]pyrimidin-4-one (11). Yellow crys-
tals [46 mg, 82% (Cl); 53 mg, 95% (Br); 49 mg, 89% (I); mp 176
◦C]. UV lmax (EtOH)/nm 203 (e/dm3 mol-1 cm-1 28 200), 236
(10 000), 341 (13 200). IR (KBr): nmax/cm-1 = 3097, 3048 (C–HAr),
1674 (C O), 1623 (C N), 1573, 1528, 1496 (C ◦ CAr), 766, 702
[g( CH)Ar]. 1H NMR (200 MHz, DMSO-d6, 27 C): d 9.03 (dd,
3J6,7 = 7.2 Hz, 4J6,8 = 1.4 Hz, 1H, 6-H), 8.28 (d, 3J2,3 = 6.3 Hz, 1H,
2-H), 7.95 (dd, 3J7,8 = 6.8 Hz, 4J6,8 = 1.4 Hz, 1H, 8-H), 7.65–7.58
(m, 2H, 2¢-H and 6¢-H), 7.51–7.38 (overlapping m, 4H, 7-H, 3¢-H,
3
NMR (400 MHz, DMSO-d6, 27 C): d 8.21 (d, J2,3 = 6.2 Hz,
3
3
1H, 2-H), 7.83 (dd, J8,9 = 8.9 Hz, J7,8 = 6.9 Hz, 1H, 8-H), 7.60
(dd, 3J8,9 = 8.9 Hz, 4J7,9 = 1.4 Hz, 1H, 9-H), 7.38–7.34 (m, 3H, 2¢-H,
6¢-H and 4¢-H), 7.32–7.29 (m, 2H, 3¢-H and 5¢-H), 7.07 (dd, 3J7,8
=
3
4¢-H and 5¢-H), 6.43 (d, J2,3 = 6.3 Hz, 1H, 3-H). 13C NMR (50
6.9 Hz, 4J7,9 = 1.4 Hz, 1H, 7-H), 6.24 (d, 3J2,3 = 6.2 Hz, 1H, 3-H). 13C
NMR (100 MHz, DMSO-d6, 27 ◦C): d 159.1 (C-4), 153.45 (C-9a),
153.33 (C-2), 143.1 (C-6), 137.7 (C-1¢), 135.6 (C-8), 127.85 (C-4¢),
127.45 (C-2¢ and C-6¢), 126.7 (C-3¢ and C-5¢), 126.0 (C-9), 120.8
(C-7), 106.2 (C-3). MS(EI+): m/z = 222 [M+], 194, 167, 154, 127,
78, 51. HRMS(ES+) Calculated for C14H11N2O 223.0871 (MH+),
found 223.0868.
MHz, DMSO-d6, 27 ◦C): d 157.5 (C-4), 154.5 (C-2), 150.5 (C-9a),
137.3 (C-9 or C-1¢), 137.1 (C-8), 136.8 (C-1¢ or C-9), 130.4 (C-2¢
and C-6¢), 128.4 (C-4¢), 128.2 (C-3¢ and C-5¢), 126.9 (C-6), 116.4
(C-7), 104.0 (C-3). MS(EI+): m/z = 221[M - H+], 193, 154, 140,
127, 97, 77, 51. HRMS(ES+) Calculated for C14H11N2O 223.0871
(MH+), found 223.0876.
Isopropylidene (6-phenylpyridin-2-ylamino)methylenemalonate
(46). A 1 : 2 mixture of Meldrum’s acid (1.76 g, 12 mmol) and
HC(OMe)3 (3 mL, 25 mmol) was heated under reflux for 4 h,
and the reaction mixture was then evaporated to dryness. The
residue was dissolved in EtOH (20 mL), 2-amino-6-phenylpyridine
(1.70 g, 10 mmol) was added, and the reaction mixture was stirred
at ambient temperature overnight. The resulting precipitate was
filtered off, washed with EtOH, and re◦crystallized from EtOH.
Acknowledgements
A. M. acknowledges support through Sanofi-aventis and Pro-
Pogressio Foundation fellowships. This article is part 96 of
Nitrogen Bridgehead Compounds. For part 95, see ref. 31a.
References
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Yellow crystals (2.19 g, 68%; mp 208 C, decomp.). H NMR
(200 MHz, DMSO-d6, 27 ◦C): d 11.43 (br, 1H, NH), 9.39 (s, 1H,
CH), 8.10 (d, 3J2¢,3¢ = 8.0 Hz, 2H, 2¢-H and 6¢-H), 7.97 (t, 3J3,4
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Calcd for C18H16N2O4: C, 66.66; H, 4.97; N, 8.64. Found: C, 66.78;
H, 4.93; N, 8.65%.
7-Phenyl-1,4-dihydro-1,8-naphthyridin-4-one and (47) 6-
phenyl-4H-pyrido[1,2-a]pyrimidin-4-one
(48). Isopropylidene
(6-phenylpyridin-2-ylamino)methylenemalonate (46) (2.00 g,
◦
6.2 mmol) was added to Ph2O (20 g), preheated to 260 C. The
reaction mixture was heated at 260 ◦C for 2 min, and then quickly
cooled to room temperature, and the precipitate was filtered
off and washed with n-hexane to give 7-phenyl-1,4-dihydro-1,8-
6564 | Org. Biomol. Chem., 2011, 9, 6559–6565
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