New pyrrolo[2,1-a]phthalazine derivatives by one-pot three-component synthesis

Article abstract of DOI:10.1055/s-0030-1258035

The synthesis of the pyrrolo[2,1-a]phthalazine derivatives was performed by an efficient one-pot three-component reaction starting from phthalazine, 2-bromoacetophenones and nonsymmetrical and symmetrical acetylenic dipolarophiles in 1,2-epoxybutane as bo

Full text of DOI:10.1055/s-0030-1258035

LETTER
2407
New Pyrrolo[2,1-a]phthalazine Derivatives by One-Pot Three-Component
Synthesis
New
P
yrrolo[
2
l
,1-
a
]p
o
hthalazines rea Dumitrascu,*a Miron Teodor Caproiu,a Florentina Georgescu,b Bogdan Draghici,a Marcel Mirel Popa,a
Emilian Georgescub
a
Centre of Organic Chemistry ‘C. D. Nenitzescu’, Romanian Academy, Spl. Independentei 202B, Bucharest 060023, Romania
E-mail: fdumitra@yahoo.com
Oltchim Research Center, St. Uzinei 1, 240050 Ramnicu Valcea, Romania
b
Received 9 June 2010
Et
Abstract: The synthesis of the pyrrolo[2,1-a]phthalazine deriva-
tives was performed by an efficient one-pot three-component reac-
tion starting from phthalazine, 2-bromoacetophenones and
nonsymmetrical and symmetrical acetylenic dipolarophiles in 1,2-
epoxybutane as both reaction medium and HBr scavenger. The
structure of the compounds was assigned by IR and NMR spectros-
copy.
N
N
N
N
O
ArCOCH Br
+
+
E
2
COAr
2
3a–c
1
E
4
Scheme 1 One-pot synthesis of pyrrolo[2,1-a]phthalazines 4
Key words: 1,3-dipolar cycloaddition, N-ylide, pyrrolo[2,1-a]-
phthalazine, multicomponent reaction
hours, followed by partial solvent evaporation.7 The com-
pounds 4 were obtained in yields of 61–75%.
Pyrrolo[2,1-a]phthalazines are nitrogen-containing het-
erocyclic compounds which are of great interest due to
their biological activity and optical properties.1
The reaction mechanism implies the intermediate forma-
tion of the phthalazinium salt 6 from the corresponding
phthalazine and 2-bromoacetophenone. In the next step,
There have been reported two main synthetic strategies the bromide ion from the salts attacks the oxirane ring of
used in the preparation of pyrrolo[2,1-a]phthalazines 1,2-epoxybutane, resulting in ring opening with formation
starting either from phthalazine or pyrroles2 and only one of an alkoxide that generates the phthalazinium N-ylide 7.
synthesis starting from acyclic compounds.3 The known The N-ylide reacts with the activated alkyne 3 to give the
synthesis of pyrrolo[2,1-a]phthalazines via phthalazinium corresponding dihydropyrrolophthalazine 8. Finally, the
N-ylides4 involves a two-stage process which implies the pyrrolophthalazines 4a–o are obtained by the spontaneous
preparation and separation of the phthalazinium salts in situ dehydrogenation of the dihydropyrrolophthalazine
which are subsequently converted into pyrrolo[2,1-a]- intermediate (Scheme 2).
phthalazines by treatment with a base, to generate the cor-
responding phthalazinium N-ylide in the presence of acet-
Et
ylenic dipolarophile.
N
N
N
N+
O
Br–
1
2
+
COAr
Syntheses involving multicomponent and one-pot reac-
tions are of interest because they involve straightforward
one-step transformations starting from three or more com-
ponents.5 Our interest in obtaining new pyrroloazines by
conventional methods or by multicomponent one-pot
reactions6 has led us to extend our studies to pyrrolo[2,1-
a]phthalazines. Herein is presented for the first time
the three-component, one-pot synthesis of pyrrolo[2,1-a]-
phthalazine derivatives starting from commercially avail-
able materials. The key components are phthalazine 1, the
substituted bromoacetophenones 2, the nonsymmetrical
electron-deficient alkynes 3 and 1,2-epoxybutane which
acts both as solvent and as proton scavenger (Scheme 1).
The reaction takes place under mild conditions and in-
COAr
–
H+
6
7
E
N
N
N
N
– 2H
COAr
COAr
E
E
8
4
Scheme 2 The mechanism of the synthesis of compounds 4
The substituents of the new pyrrolo[2,1-a]phthalazine de-
rivatives 4 are given in Table 1.
volves the mixing of the components at reflux for 12 The structures of the compounds 4 were assigned by ele-
mental analysis, IR and NMR spectroscopy. The charac-
teristic IR spectroscopic features of the compounds 4 were
the carbonyl bands observed in the range 1690–1725 cm–1
for the carboxyl groups and in the range 1649–1680 cm–1
for the carbonyl group in the benzoyl moiety due to con-
jugation. The C–O vibration specific bands could be ob-
SYNLETT 2010, No. 16, pp 2407–2410
Advanced online publication: 12.08.2010
DOI: 10.1055/s-0030-1258035; Art ID: D14310ST
© Georg Thieme Verlag Stuttgart · New York
x
x
.x
x
.2
0
1
0

2408
F. Dumitrascu et al.
LETTER
modified procedure consists of adding the key compo-
nents of the reaction in a specific order. Thus the 2-
bromoacetophenones were added to the solution of
phthalazine in 1,2-epoxybutane and the mixture was kept
under stirring for 30 minutes before the acetylenic dipo-
larophile was added.8 One of the symmetrical acetylenic
dipolarophiles, the diisopropyl acetylenedicarboxylate
(DIPAD) was synthesized by a similar procedure reported
in Organic Synthesis for dimethyl acetylenedicarboxylate
(DMAD) and diethyl acetylenedicarboxylate (DEAD).9
Thus, the pyrrolo[2,1-a]phthalazines 5 were obtained in
good yields ranging between 61–80% (Scheme 3).
Table 1 Substituents of the Pyrrolo[2,1-a]phthalazine Derivatives 4
Compound
E
Ar
Mp (°C)
205–207
197–201
158–160
230–232
273–274
207–210
220–222
230–233
196–198
207–210
238–239
210–211
220–223
177–179
160–162
4a
4b
4c
4d
4e
4f
COMe
COMe
COMe
COMe
COMe
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Et
CO2Et
CO2Et
CO2Et
Ph
4-BrC6H4
4-MeOC6H4
3-O2NC6H4
4-O2NC6H4
C6H4C6H5
4-MeC6H4
4-FC6H4
4g
4h
4i
N
N
Et
1
3-BrC6H4
4-BrC6H4
3-O2NC6H4
C6H4C6H5
2-ClC6H4
3-BrC6H4
4-O2NC6H4
E
E
N
N
O
+
COAr
4j
ArCOCH2Br
3d–f
2
4k
4l
E
E
5
Scheme 3 One-pot synthesis of pyrrolo[2,1-a]phthalazines 5
4m
4n
4o
The reaction between phthalazinium N-ylides and sym-
metrical acetylenic dipolarophiles in different solvents
such as dichloromethane or benzene frequently gave mix-
tures of dihydropyrrolophthalazine with pyrrolophthala-
zine.1g,4d–f,10 In such cases the aromatization of the
hydrogenated intermediate was achieved with the oxidant
tetrakispyridine cobalt(II) dichromate (TPCD)4e,f which
was also used for aromatization of tetrahydro cycload-
ducts resulting from activated olefins and heteroaromatic
N-ylides.11 The one-pot multicomponent approach de-
scribed here avoids the formation of the hydrogenated in-
served at ca. 1080 cm–1 and ca. 1230 cm–1. The C=O bond
in the acyl moiety for the compounds 4a–e appeared at
around 1672 cm–1. The 1H NMR spectra of compounds 4
confirmed the regioselectivity of the cycloaddition as the
hydrogen H-2 appeared as a sharp singlet at ca. d = 7.70
ppm. At high resolution the hydrogen H-6 appeared as a
doublet with a coupling constant of 5JH6H10 = 0.8 Hz which
is consistent with a long-range coupling between H-6 and
H-10, confirmed by HH decoupling experiments. The H-
10 atom was strongly deshielded (d = ca. 9.80 ppm) due to
the proximity of the carbonyl group attached to the posi-
tion 1.
The 13C NMR spectra showed all the expected signals.
The spectra of pyrrolophthalazines presented the signals
of the carbonyl groups as are expected for compounds
with this structure. The carbon C-6 grafted on a double C–
N bond in the phthalazine moiety appeared strongly
deshielded (d = ca. 146 ppm) whereas the C-1 in the pyr-
role ring appeared shielded due the substituent directly at-
tached (d = ca. 117 ppm for compounds 4a–e and d = ca.
108 ppm 4f–o).
Table 2 Substituents on Compounds 5
Compound
E
Ar
Mp (°C)
229–231
192–194
176–178
181–183
178–180
125–127
153–155
153–154
168–169
163–165
147–148
148–150
168–169
5a
5b
5c
5d
5e
5f
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2i-Pr
CO2i-Pr
CO2i-Pr
Ph
4-MeC6H4
4-ClC6H4
3-BrC6H4
4-BrC6H4
Ph
5g
5h
5i
4-FC6H4
4-ClC6H4
4-BrC6H4
4-O2NC6H4
4-MeC6H4
4-ClC6H4
4-BrC6H4
Recently we reported that the one-pot method for synthe-
sis of pyrrolo[1,2-a]quinolines gave very poor yields
when using symmetrical dipolarophiles, because of the
poor reactivity of the quinoline with 2-bromoacetophen-
ones.6c,d However, in the case of phthalazine the one-pot
reaction could be realized using symmetrical dipolaro-
philes. Therefore, a procedure that avoids the isolation of
phthalazinium bromides was elaborated, by taking into
account the high reactivity of the phthalazine, compared
with quinoline, towards the 2-bromoacetophenones. The
5j
5k
5l
5m
Synlett 2010, No. 16, 2407–2410 © Thieme Stuttgart · New York

LETTER
New Pyrrolo[2,1-a]phthalazines
2409
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compounds.
Table 2 lists the substituents on compounds 5.
(5) (a) Dömling, A. Chem. Rev. 2006, 106, 17. (b) Zhu, J.;
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IR and NMR spectroscopy. It was observed that the sub-
stituent attached at C-2 influences the spatial interaction
between the carbonyl bond attached at C-1 and the hydro-
gen H-10 which appears shielded by ca. 1 ppm in com-
pounds 5 compared to compounds 4. It must be mentioned
that the pyrrolo[2,1-a]phthalazine derivatives 5 could be
prepared by a one-pot procedure starting directly from the
phthalazinium bromides obtained in a previous step and
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symmetrical and nonsymmetrical electron-deficient
alkynes in 1,2-epoxybutane.
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(7) General Procedure for the Synthesis of Pyrrolo[2,1-
a]phthalazines 4: Phthalazine 1 (5 mmol), phenacyl
bromide 2 (5 mmol)and nonsymmetrical acetylene 3 (5
mmol; methyl propiolate, ethyl propiolate, 3-butyn-2-one) in
1,2-epoxybutane (20 mL) were refluxed with stirring for 12
h. The solvent was partly removed by evaporation, MeOH
(10 mL) was added and the mixture was left overnight at r.t.
The solid was filtered, washed with a small quantity of cold
EtOH and crystallized from a suitable solvent. 3-Acetyl-1-
(4-methoxybenzoyl)pyrrolo[2,1-a]phthalazine (4c):
colorless crystals with mp 158–160 °C were obtained by
recrystallization from MeOH. Yield: 71%. Anal. Calcd
C21H16N2O3: C, 73.24; H, 4.68; N, 8.13. Found: C, 73.51; H,
4.97; N, 8.38. ATR-IR: 1089, 1256, 1659, 1672, 2986, 3050
cm–1. 1H NMR (300 MHz, CDCl3): d = 2.68 (s, 3 H, MeCO),
3.90 (s, 3 H, OMe), 7.00 (d, 2 H, J = 9.0 Hz, H-3¢, H-5¢), 7.60
(s, 1 H, H-2), 7.71–7.76 (m, 1 H, H-8), 7.85–7.91 (m, 2 H,
H-7, H-9), 7.97 (d, 2 H, J = 9.0 Hz, H-2¢, H-6¢), 8.72 (d, 1 H,
J = 0.8 Hz, H-6), 9.82–9.85 (m, 1 H, H-10). 13C NMR (75
MHz, CDCl3): d = 29.7 (MeCO), 55.7 (OMe), 113.9 (C-3¢,
C-5¢), 117.0 (C-1), 123.5 (C-2), 127.6, 127.7 (C-7, C-10),
122.3, 127.3, 129.2, 131.5 (C-3, C-6a, C-10a, C-10b), 130.0
(C-8), 132.3 (C-2¢, C-6¢), 132.9 (C-9), 132.9 (C-1¢), 146.9
(C-6), 163.5 (C-4¢), 183.7 (COAr), 193.8 (COMe).
(8) General Procedure for the Synthesis of Pyrrolo[2,1-
a]phthalazines 5; Method A: Phthalazine 1 (5 mmol)and
phenacyl bromide 2 (5 mmol) were stirred for 30 min in 1,2-
epoxybutane (20 mL) and then acetylenic dipolarophile
(DMAD, DEAD, DIPAD; 7 mmol) was added and the
reaction was kept under reflux for 12 h. The solvent was
partly removed by evaporation, MeOH (10 mL) was added
and the mixture was left overnight at r.t. The solid was
filtered, washed on a filter with cold EtOH and crystallized
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Synlett 2010, No. 16, 2407–2410 © Thieme Stuttgart · New York

2410
F. Dumitrascu et al.
LETTER
from a suitable solvent. Method B: Phthalazinium bromide
2 (5 mmol) and symmetrical acetylenic dipolarophile 3 (7
mmol) in 1,2-epoxybutane (20 mL) were refluxed for 24 h.
The workup of the reaction mixture was similar to method A.
Diethyl 1-(4-Chlorobenzoyl)pyrrolo[2,1-a]phthalazine-
1,2-dicarboxylate (5h): colorless crystals with mp 153–154
°C were obtained by recrystallization from MeOH. Yield:
77%. Anal. Calcd C24H19ClN2O5: C, 63.93; H, 4.25; Cl,
7.86; N, 6.21. Found: C, 64.27; H, 4.61; Cl, 8.19; N, 6.01.
ATR-IR: 1086, 1234, 1682, 1694, 1725, 2956, 3036 cm–1. 1H
NMR (300 MHz, CDCl3): d = 1.01 (t, 3 H, J = 7.1 Hz, Me),
1.40 (t, 3 H, J = 7.1 Hz, Me), 4.10 (q, 2 H, J = 7.1 Hz, CH2),
4.47 (q, 2 H, J = 7.1 Hz, CH2), 7.42 (d, 2 H, J = 8.6 Hz, H-
3¢, H-5¢), 7.62–7.67 (m, 1 H, H-8), 7.77–7.84 (m, 2 H, H-7,
H-9), 7.81 (d, 2 H, J = 8.9 Hz, H-2¢, H-6¢), 8.45 (s, 1 H, H-
6), 8.90–8.93 (m, 1 H, H-10). 13C NMR (75 MHz, CDCl3):
d = 13.6, 14.0 (2 × Me), 61.3, 62.7 (2 × CH2), 108.0 (C-1),
119.5, 121.1, 124.4, 126.6, 128.0 (C-2, C-3, C-6a, C-10a,
C-10b), 124.5 (C-10), 128.2, 133.4 (C-7, C-9), 128.8 (C-3¢,
C-5¢), 129.0 (C-8), 130.1 (C-2¢, C-6¢), 136.0 (C-4¢), 140.6
(C-1¢), 147.0 (C-6), 163.2, 165.2 (2 × COO), 185.8 (COAr).
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Synlett 2010, No. 16, 2407–2410 © Thieme Stuttgart · New York