A comparative synthesis of 6-benzyl-2,3-dihydroimidazo[2,1-a]phthalazine and 2H-7-benzyl-3,4-dihydropyrimido[2,1-a]phthalazine

Article abstract of DOI:10.1016/j.tetlet.2014.12.121

Two new synthetic strategies have been developed for the synthesis of a new class of cyclophthalazine derivatives. 6-Benzyl-2,3-dihydroimidazo[2,1-a]phthalazine and 2H-7-benzyl-3,4-dihydropyrimido[2,1-a]phthalazine were obtained (i) by intramolecular cyclization of the 2-(aminoalkyl)-4-benzyl-2H-phthalazin-1-one or (ii) by intramolecular cyclization of the corresponding 2-(4-benzylphthalazin-1(2H)-ylideneamino)alcohols previously prepared. The second of the described routes afforded the desired derivatives in high yields.

Full text of DOI:10.1016/j.tetlet.2014.12.121

Tetrahedron Letters 56 (2015) 828–830
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Tetrahedron Letters
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A comparative synthesis of 6-benzyl-2,3-dihydroimidazo
[
[
2,1-a]phthalazine and 2H-7-benzyl-3,4-dihydropyrimido
2,1-a]phthalazine
a,b
b
b
c
c,
⇑
Javier Munín , Lourdes Santana , Eugenio Uriarte , Fernanda Borges , Elías Quezada
a
Departamento de Farmacologia, Facultad de Farmacia, Universidad de Santiago de Compostela, 15782 Santiago de Compostela, Spain
Departamento de Química Orgánica, Facultad de Farmacia, Universidad de Santiago de Compostela, 15782 Santiago de Compostela, Spain
Departamento de Química e Bioquímica, Faculdade de Ciências, Universidade do Porto, Rua Campo Alegre 687, 4169-007 Porto, Portugal
b
c
a r t i c l e i n f o
a b s t r a c t
Article history:
Two new synthetic strategies have been developed for the synthesis of a new class of cyclophthalazine
derivatives. 6-Benzyl-2,3-dihydroimidazo[2,1-a]phthalazine and 2H-7-benzyl-3,4-dihydropyrimido[2,1-
a]phthalazine were obtained (i) by intramolecular cyclization of the 2-(aminoalkyl)-4-benzyl-2H-phthal-
azin-1-one or (ii) by intramolecular cyclization of the corresponding 2-(4-benzylphthalazin-1(2H)-ylide-
neamino)alcohols previously prepared. The second of the described routes afforded the desired
derivatives in high yields.
Received 24 October 2014
Revised 17 December 2014
Accepted 19 December 2014
Available online 29 December 2014
Keywords:
Synthesis
Ó 2015 Elsevier Ltd. All rights reserved.
Imidazophthalazine
Pyrimidophthalazine
Cyclization
Condensation
Some methodologies have been previously reported to obtain
dihydroimidazo and dihydropyrimido derivatives fused to other
heterocycles as phthalazines. These methods involve the reaction
of an aromatic heterocycle such as the phthalazinone (I) which is
made to react with phosphorus oxychloride to give the chloro
derivative (II). This chloro derivative (II) reacts with ethanolamine
affording the hydroxyalkylamine (III) and finally, by treating with
thionyl chloride and a base furnishes the tricycle (IV).1 Alterna-
tively, the phthalazinone (I) reacts with 2-aminoethylammonium
and 7 in Scheme 3) and to study their potential beneficial cardio-
vascular effects.
In this work, we evaluate the efficiency to prepare 6-benzyl-2,3-
dihydroimidazo[2,1-a]phthalazine (6) and 2H-7-benzyl-3,4-dihyd-
ropyrimido[2,1-a]phthalazine (7) through two different pathways
depicted in Scheme 3.
,2
(i) To obtain the 2-(aminoalkyl)-4-benzyl-2H-phthalazin-1-one
7
,8
by reaction of a benzalphthalide
with an appropriate
tosylate at 200–250 °C resulting in the formation of tricycle (IV)
aminoalkylhydrazine followed by intramolecular cyclization
according to the published procedure above.
3
9
(Scheme 1).
Furthermore, the treatment of the either hydroxyalkylamine (V)
(ii) To obtain the corresponding 2-(4-benzylphthalazin-1(2H)-
with mineral acids, or their corresponding tosyl5 and acyloxy
4
6
ylideneamino)alcohols by reaction of benzalphthalide with
7
,8
derivatives (VI), leads to tricyclic skeleton (VII), (Scheme 2).
hydrazine to yield the benzylphthalazinona followed by
reaction with an appropriate aminoalcohol and final
However, the previously described methodology to obtain IV
from I was not an effective procedure, as it resulted in practically
complete destruction of the starting material under the reaction
conditions while the other methodologies resulted in very low
1
0
cyclization.
Benzalphthalide 3 was secured by reacting phthalic anhydride
with phenylacetic acid in the presence of catalytic amounts of
potassium acetate using microwave irradiation (350 W, 15 min
1
–6
yield.
Because of these drawbacks, our goal was to optimize a
new synthetic route in order to get subsequently a large and
selected series of these tricyclic systems bearing a benzyl group
at the contiguous position to the nitrogen atom (compounds 6
1
1
(at 1 min intervals)), in 71% yield.
Following the route (i), reaction, at room temperature over-
night, of benzalphthalide 3 with an excess of 2-hydrazinoethan-
1
2,13
amine (synthesized via aziridine)
dissolved in ethanol,
⇑
Corresponding author. Tel.: +351 34881814936; fax: +351 34881594912.
E-mail address: elias.quezada@usc.es (E. Quezada).
resulted in 2-(2-aminoethyl)-4-benzyl-2H-phthalazin-1-one (4)14
http://dx.doi.org/10.1016/j.tetlet.2014.12.121
040-4039/Ó 2015 Elsevier Ltd. All rights reserved.
0

J. Munín et al. / Tetrahedron Letters 56 (2015) 828–830
829
R
O
R
O
O
O
N
NH
N
NH
OH
a
+
R = H, Ph
d
I
II Cl
O
1
2
b
a
R
R
N
N
c
N
NH
N
HN
III
OH
O
IV
O
3
Scheme 1. Reagents and conditions: (a) POCl
3
, rt; (b) H
, 200–250 °C.
2
NCH
2
2
CH OH, 95 °C; (c)
b
d
+
À
SOCl
, K
2 2
CO
3
; (d) H
2
NCH
2
CH
2
NH
3
p-MeC
H
4 4
SO
3
O
O
NH
N
a
NH
N
N
N
N
NH
HN
V
N
OH
VII
n
b
O
O
8
NH2
4
, n = 1
5
, n = 2
O
NH
N
c
e
HN
VI
OR
R = Tosyl, Acyl
+
Scheme 2. Reagents: (a) H ; (b)
D.
f
N
N
N
N
N
HN
, n = 1
n
n
OH
in a low yield (24%), which may be probably due to the instability
6, n = 1
, n = 2
9
7
10, n = 2
of the hydrazinoethanamine. However reaction of 3 with 3-hydraz-
1
5
inopropan-1-amine under the above described conditions affor-
Scheme 3. Reagents and conditions: (a) AcOK, MW 350 W, 15 min, 71%; (b)
N(CH CH NHNH , EtOH, rt, 12 h, n = 1 (24%), n = 2 (76%); (c) CH OCH CH OH,
reflux, 12 h, n = 1 (6%), n = 2 (11%); (d) H NNH /THF, 2 h, rt and 4 h, 60 °C, 99%; (e)
1
4
ded 2-(3-aminopropyl)-4-benzyl-2H-phthalazin-1-one (5) in a
markedly better yield (76%) due to the greater stability of 3-
hydrazinopropan-1-amine.
H
2
)
2 n
2
2
3
2
2
2
2
H
2
2 2 n 4 3 2 2
NCH (CH ) OH, reflux, 48 h, n = 1 (98%), n = 2 (97%); (f) CBr , P(Ph) , CH Cl ,
reflux, 12 h, n = 1 (60%), n = 2 (72%).
The 2-(aminoalkyl)-4-benzyl-2H-phthalazin-1-ones 4 and 5
were dissolved in ethylene glycol monomethyl ether9 and heated
under reflux overnight to afford, respectively, 6-benzyl-2,3-dihy-
droimidazo[2,1-a]phthalazine (6)16 in 6% yield and 2H-7-benzyl-
In summary, two new cyclophthalazine derivatives 6-benzyl-
2
,3-dihydroimidazo[2,1-a]phthalazine (6) and 2H-7-benzyl-3,4-
3
,4-dihydropyrimido[2,1-a]phthalazine (7)16 in 11% yield. Proba-
dihydropyrimido[2,1-a]phthalazine (7) have been synthesized
using two different synthetic strategies. Based on the obtained
yields, the selected route for the preparation of new derivatives
should be the intramolecular cyclization of the corresponding 2-
bly, these low yields can be explained by the low stability of the
-(aminoalkyl)-4-benzyl-2H-phthalazin-1-ones and under
these reaction conditions.
2
4
5
Alternatively compounds 6 and 7 were prepared from the ben-
zalphthalide (3) in three steps following the route (ii).
Firstly, reaction of 3 with hydrazine (1 M in THF) at room tem-
perature for 2 h followed by heating at 60 °C for 4 h, provided 4-
benzyl-2H-phthalazin-1-one (8)17 in almost quantitative yield.
The high yield of this reaction, allowed us to purify 8 by crystalli-
zation from EtOAc.
(
4-benzylphthalazin-1(2H)-ylideneamino)alcohols.
2-(4-Ben-
zylphthalazin-1(2H)-ylideneamino)alcohols were previously pre-
pared starting from benzalphthalide and condensation with
hydrazine gave the benzylphthalazinone. These reactions were
performed in nearly quantitative yields. The reaction of the ben-
zylphthalazinone with an appropriate aminoalcohol afforded after
cyclization compounds 6 and 7.
The 2-(4-benzylphthalazin-1(2H)-ylideneamino)alcohols (9)
and (10) were prepared in nearly quantitative yields (98% and
Acknowledgments
9
7%, respectively) by reaction under reflux of the benzylphthalazi-
none (8) with 2-aminoethanol and 3-aminopropan-1-ol, respec-
We are grateful to the Xunta de Galicia (10PXIB203303PR) for
financial support. E. Quezada thanks the Foundation for Science
and Technology (FCT, SFRH/BPD/74596/2010), Portugal.
1
8
tively. The high yields of these reactions, allowed to 9 and 10
to be purified by crystallization from CH CN. Finally the reaction
of the 2-(4-benzylphthalazin-1(2H)-ylideneamino)alcohols 9 and
0 with carbon tetrabromide and triphenylphosphine refluxing in
CH Cl overnight resulted in the 6-benzyl-2,3-dihydroimi-
3
1
References and notes
2
2
dazo[2,1-a]phthalazine (6) and 2H-7-benzyl-3,4-dihydropyrimi-
do[2,1-a]phthalazine (7), in yields of 60% and 72%, respectively.
1
.
Castle, R. N.; Takano, S. J. Heterocycl. Chem. 1966, 3, 381.
2. Cookson, R. F.; Rodway, R. E. J. Chem. Soc. Chem. Commun. 1972, 9, 511.

8
30
J. Munín et al. / Tetrahedron Letters 56 (2015) 828–830
3
.
Cookson, R. F.; Rodway, R. E. J. Chem. Soc., Perkin Trans. 1: Org. Bio.-Org. Chem.
854, 1975, 19.
Kormendy, K.; Ruff, F. Acta Chim. Hung. 1983, 112, 65.
was refluxed for 12 h under
evaporated under vacuum. The product was purified by flash
chromatography with silica gel (35–70 mesh) using EtOAc/(CH CO (8:2;
7:3 and 6:4) as the eluent. 6-Benzyl-2,3-dihydroimidazo[2,1-a]phthalazine (6)
2
N atmosphere and then the solvent was
1
4
5
.
.
3 2
)
Kormendy, K.; Ruff, F.; Kovesdi, I.; Pelczer, I. Acta Chimica Hungarica 1984, 117,
1
3
63.
and: White solid, mp 220–221 °C.
J = 9.1 Hz, 1H), 8.01 (m, 3H), 7.29 (m, 5H), 4.88 (t, J = 10.0 Hz, 2H), 2.44 (s, 2H),
4.37 (t, J = 10.0 Hz, 2H); 13C NMR (62.9 MHz, CDCl
) d 38.61, 42.40, 52.00,
117.92, 126.49, 127.18, 127.81, 128.22 (2C), 128.40, 128.87 (2C), 134.03,
3
H NMR (250 MHz, CDCl ) d 8.94 (d,
6
7
.
.
Kormendy, K.; Ruff, F.; Kovesdi, I. Acta Chim. Hung. 1988, 125, 99.
Del Olmo, E.; Armas, M. G.; Ybarra, M. I.; Lopez, J. L.; Oporto, P.; Gimenez, A.;
Deharo, E.; San Feliciano, A. Bioorg. Med. Chem. Lett. 2003, 13, 2769.
Viña, D.; Del Olmo, E.; Lopez-Pérez, J. L.; San Feliciano, A. Tetrahedron 2009, 65,
3
+
8
9
.
.
135.98, 136.52, 152.79, 153.31; HR-MS calcd for C17
15 3
H N (M) : 261.1266,
1
574.
found 261.1267. 2H-7-Benzyl-3,4-dihydropyrimido[2,1-a]phthalazine (7): White
1
Qian, J.; Xu, Y.; Qian, X.; Zhang, S. Chem. Phys. Chem. 1891, 2008, 9.
solid, mp 210–211 °C. H NMR (250 MHz, CDCl
(m, 3H), 7.28 (m, 5H), 4.52 (t, J = 6.0 Hz, 2H), 4.37 (s, 2H), 3.91 (t, J = 6.0 Hz, 2H),
2.36 (m, 2H). 13C NMR (62.9 MHz, CDCl
) d 18.43, 38.38, 39.01, 52.73, 121.33,
125.78, 126.03, 127.01, 127.11, 128.21 (2C), 128.73 (2C), 133.63, 134.92,
3
) d 9.44 (d, J = 9.2 Hz, 1H), 7.87
1
0. De Meijere, A.; Faber, D.; Heinecke, U.; Walsh, R.; Müller, T.; Apeloig, Y. Eur. J.
Org. Chem. 2001, 663.
3
1
1. Synthesis of (Z)-3-Benzyliden-3H-isobenzofuran-1-one (3): Phthalic anhydride
+
(1) (1.0 g, 6.75 mmol) and 2-phenylacetic acid (2) (1.102 g, 8.10 mmol) were
136.03, 148.89, 150.57; HR-MS calcd for C18
275.1423. Alternatively, compounds and
H
17
N
3
(M) : 275.1422, found
melted and KOAc (66 mg, 0.675 mmol) was added. The mixture was heated
6
7
were prepared by adding
(
(
the temperature is always maintained between 210 and 230 °C) under MW
350 W) for 15 min in 1 min periods until change of colour, then extracted with
triphenylphosphine (0.81 mmol) to a mixture of alcohol 9 or 10 (0.54 mmol)
and CBr (0.81 mmol) in dry CH Cl (10 mL). After stirring at reflux overnight,
the mixture was concentrated to dryness. The crude product was purified by
4
2
2
2 3 2
ethyl acetate and washed with Na CO 10% and H O until pH = 7. Residue was
purified by flash chromatography with silica gel (35–70 mesh) using hexane/
EtOAc (97:3) as the eluent to give 3: White solid, mp 90–91 °C. H NMR
flash chromatography with silica gel (35–70 mesh) using EtOAc/(CH
7:3 and 6:4) as the eluent.
3 2
) CO (8:2;
1
(
7
CDCl
250 MHz, CDCl
3
) d 7.92 (dt, J = 1.8; 7.7 Hz, 1H), 7.84 (dt, J = 1.5; 8.5 Hz, 2H),
17. Synthesis of 4-benzyl-2H-phthalazin-1-one (8). 3-Benzyliden-3H-isobenzofuran-
1-one (3) (4.5 mmol) was dissolved in hydrazine 1M in THF (9.0 mL, 9.0 mmol).
The mixture was stirred for 2 h at room temperature and for 4 h at 60 °C, in a
sealed tube. The mixture was cooled to room temperature and evaporated to
1
3
.73 (m, 2H), 7.54 (m, 1H), 7.34 (m, 3H), 6.41 (s, 1H); C NMR (62.9 MHz,
3
) d 107.00, 119.76, 123.31, 125.49, 128.36, 128.71 (2C), 129.72, 130.06
+
(
10 2
2C), 133.02, 134.44, 140.52, 144.50, 167.01; HR-MS calcd for C15H O (M) :
2
22.0681, found 222.0680.
dryness. The resulting solid was purified by crystallization in EtOAc, to give 8:
1
1
1
1
2. Chaikittisilp, W.; Didas, S. A.; Kim, H. J.; Jones, C. W. Chem. Mater. 2013, 25, 613.
3. Rademacher, P. Sci. Synth. 2009, 40b, 1133.
4. General procedure for the synthesis of 2-(alkylamine)-4-benzyl-2H-phthalazin-1-
white solid, mp 200–201 °C. H NMR (250 MHz, CDCl
(d, J = 7.4 Hz, 1H), 7.73 (m, 3H), 7.25 (m, 5H), 4.32 (s, 2H); C NMR (62.9 MHz,
CDCl ) d 38.85, 125.36, 126.73, 126.95, 128.24, 128.44 (2C), 128.68 (2C),
3
) d 11.46 (br s, 1H), 8.48
13
3
ones
1.8 mmol) and hydrazinoalkylamine (4.5 mmol) in EtOH (10 mL) was stirred
for 12 h at rt. The solvent was removed under vacuum and the residue was
purified by HPLC with Partisil 10 (Whatman column, 9 Â 900 mm, 5 m) using
CHCl /iPrOH (7:3) as eluent. 2-(2-Aminoethyl)-4-benzyl-2H-phthalazin-1-one
4
and 5.
A
solution of 3-benzyliden-3H-isobenzofuran-1-one (3)
129.78, 131.26, 133.40, 137.62, 146.38, 160.93. HR-MS calcd for C15
(M) : 236.095, found 236.0947.
18. General procedure for the synthesis of (4-Benzylphthalazin-1(2H)-
ylideneamino)alcohol (9) and (10). 4-Benzyl-2H-phthalazin-1-one (8) (1.27
mmol) was dissolved in the corresponding aminoalcohol (12.7 mmol) and
H
12
N
2
O
+
(
l
3
1
(4): White solid, mp 109–110 °C. H NMR (250 MHz, CDCl
3
) d 8.44 (d, J = 6.0 Hz,
refluxed for 48 h. The mixture was cooled to room temperature, CH
(100 mL) was added and washed with H O and brine. Organic phase was dried
over Na SO , filtered and evaporated to dryness. The resulting solid was
purified by crystallization using CH CN. 2-(4-Benzylphthalazin-1(2H)-
ylideneamino)ethanol (9): White solid, mp 171–172 °C. H NMR (250 MHz,
DMSO-d ) d 8.26 (d, J = 6.7 Hz, 1H), 7.95 (d, J = 6.8 Hz, 1H), 7.77 (m, 2H), 7.38
(br s, 1H), 7.20 (m, 5H), 4.94 (br s, 1H), 4.43 (s, 2H), 3.65 (m, 4H); C NMR
(62.9 MHz, DMSO-d ) d 38.43, 43.97, 59.73, 118.32, 122.47, 124.73, 125.70,
126.10 (2C), 128.38 (2C), 130.81 (2C), 131.43, 139.69, 149.91, 153.47; HR-MS
2 2
Cl
1
H), 7.71 (m, 3H), 7.27 (m, 5H), 4.34 (t, J = 6.0 Hz, 2H), 4.30 (s, 2H), 3.20 (t,
2
1
3
J = 6.0 Hz, 2H), 1.67 (br s, 2H); C NMR (62.9 MHz, CDCl
3
) d 38.88, 41.02, 53.52,
2
4
1
1
2
25.05, 126.70, 127.22, 128.17, 128.34 (2C), 128.68 (2C), 129.05, 131.17,
3
+
+
1
32.82, 137.71, 145.30, 159.63; HR-MS (ESI) calcd for C17
80.1444, found 280.1453. 2-(3-Aminopropyl)-4-benzyl-2H-phthalazin-1-one
) d 8.42 (d, J = 7.5, 1H), 7.67 (m, 3H),
.24 (m, 5H), 4.36 (t, J = 6.7, 2H), 4.30 (s, 2H), 2.77 (t, J = 6.7, 2H), 2.17 (br s, 2H),
.04 (m, 2H); 13C NMR (62.9 MHz, CDCl
) d 31.94, 38.74, 38.89, 47.97, 125.03,
26.66, 127.16, 128.09, 128.30 (2C), 128.64 (2C), 129.06, 131.12, 132.75,
18 3
H N O (M H ):
6
5): Yellow oil. 1H NMR (250 MHz, CDCl
13
(
3
7
2
1
1
2
6
3
+
+
(ESI) calcd for
17 18 3
C H N O (M H ): 280.1444, found 280.1439. 3-(4-
+
37.74, 145.26, 159.38; HR-MS calcd for C18
93.1521.
19 3
H N O (M) : 293.1528, found
Benzylphthalazin-1(2H)-ylideneamino)propan-1-ol (10): White solid, mp 150–
1
151 °C.
6
H NMR (250 MHz, DMSO-d ) d 8.25 (d, J = 6.9 Hz, 1H), 7.96 (d,
1
1
5. Hollis Showalter, H. D.; Johnson, J. L.; Hoftiezer, J. M. J. Heterocycl. Chem. 1986,
3, 1491.
6. General procedure for the synthesis of benzyl dihydroimidazo and
dihydropyrimido[2,1-a]phthalazine. A solution of 2-(alkylamine)-4-benzyl-2H-
phthalazin-1-one (4) (0.72 mmol) in ethylene glycol monomethyl ether (5 mL)
J = 6.8 Hz, 1H), 7.77 (m, 2H), 7.35 (br s, 1H), 7.21 (m, 5H), 4.71 (br s, 1H), 4.43 (s,
2
2H), 3.60 (t, J = 6.2 Hz, 2H), 3.52 (t, J = 6.2 Hz, 2H), 1.85 (m, 2H). 13C NMR
6
(62.9 MHz, DMSO-d ) d 32.05, 38.27, 38.44, 58.78, 118.31, 122.39, 124.74,
125.67, 126.10 (2C), 128.39 (2C), 130.80 (2C), 131.39, 139.71, 149.75, 153.43.
+
+
20 3
HR-MS (ESI) calcd for C18H N O (M H ): 294.1601, found: 294.1591.