Contributions to syntheses of pyrrolo[2,1-a]phthalazines

Article abstract of DOI:10.1007/s00706-011-0468-8

Structural elucidation of the dihydro derivatives obtained as by-products in the classic salt method synthesis of pyrrolo[2,1-a]phthalazines and acetylenic dipolarophiles was achieved by X-ray diffraction analysis of a representative compound. In addition, new pyrrolo[2,1-a]phthalazines were obtained by a one-pot three-component reaction that avoids the formation of the dihydro derivative intermediates. Springer-Verlag 2011.

Full text of DOI:10.1007/s00706-011-0468-8

Monatsh Chem (2011) 142:743–748
DOI 10.1007/s00706-011-0468-8
ORIGINAL PAPER
Contributions to syntheses of pyrrolo[2,1-a]phthalazines
•
Mino R. Caira Emilian Georgescu
•
•
•
Florentina Georgescu Florin Albota
Florea Dumitrascu
Received: 26 October 2010 / Accepted: 21 February 2011 / Published online: 18 March 2011
Ó Springer-Verlag 2011
Abstract Structural elucidation of the dihydro deriva-
tives obtained as by-products in the classic salt method
synthesis of pyrrolo[2,1-a]phthalazines and acetylenic di-
polarophiles was achieved by X-ray diffraction analysis of
a representative compound. In addition, new pyrrolo[2,1-
a]phthalazines were obtained by a one-pot three-compo-
nent reaction that avoids the formation of the dihydro
derivative intermediates.
phthalazinium N-ylides with electron-deficient alkynes or
alkenes is one of the most productive [10–16]. This syn-
thesis involves a two-stage process, in the first of which the
phthalazinium salts are prepared, and in the second, they
react with acetylenic or olefinic dipolarophiles in the
presence of a base which generates in situ the ylide
affording the pyrrolo[2,1-a]phthalazines. In the case of
symmetrical acetylenic dipolarophiles, dihydro derivative
intermediates were obtained mixed with the aromatic
pyrrolo[2,1-a]phthalazine, this outcome being of interest
from a stereochemical and mechanistic viewpoint. Herein
are reported the isolation and elucidation by X-ray dif-
fraction analysis of the structure of a dihydro derivative
cycloadduct obtained by the classic two-stage synthesis of
pyrrolo[2,1-a]phthalazine, as well as the synthesis of new
pyrrolo[2,1-a]phthalazines by a one-pot three-component
procedure that avoids the formation of the dihydro deriv-
atives, leading directly to the fully aromatic compounds.
The proposed synthetic strategy benefits from concepts
such as one-pot synthesis and ‘‘atom economy’’ in the
context of sustainable chemistry, which is of great interest
at present. Moreover, the hazardous chlorinated solvents
used in the classical approach are avoided by using an
epoxide which is more environmentally friendly.
Keywords Pyrrolo[2,1-a]phthalazine ꢀ
X-ray structure determination ꢀ N-ylides ꢀ
One-pot three-component reaction
Introduction
Pyrrolo[2,1-a]phthalazines are fused nitrogen-containing
compounds which are of particular interest owing to their
biological activity and optical properties [1–4]. Over time,
numerous studies regarding synthesis of pyrrolo[2,1-a]-
phthalazine derivatives have been reported [5–9]. Among
the synthetic strategies, 1,3-dipolar cycloaddition of
M. R. Caira
Department of Chemistry, University of Cape Town,
Rondebosch 7701, South Africa
e-mail: Mino.Caira@uct.ac.za
Results and discussion
E. Georgescu ꢀ F. Georgescu
1,3-Dipolar cycloaddition of heteroaromatic N-ylides with
acetylenic or olefinic dipolarophiles raises interesting ste-
reochemical features. The reaction of the heteroaromatic
N-ylides 1 with symmetrical dipolarophiles of type 2 leads
to the formation of the primary cycloadducts 3, which
under the reaction conditions, rearrange to the dihydro
derivatives of type 4 or 5 (Scheme 1). Intermediates of type
Oltchim Research Center, St. Uzinei 1,
240050 Ramnicu Valcea, Romania
F. Albota ꢀ F. Dumitrascu (&)
Centre of Organic Chemistry ‘‘C. D. Nenitzescu’’,
Roumanian Academy, Spl Independen¸tei 202B,
060023 Bucharest, Romania
e-mail: fdumitra@yahoo.com
123

744
M. R. Caira et al.
Scheme 1
Het
Het
Het
Het
Het
N
COR
COR
N
N
H
N
COR
N
COR
H
H
H
H
-2H
or
COR
H
1
E
E
E
E
E
E
E
E
E
E
2
3
4
5
(cis/trans)
(cis/trans)
6
7
6
8
9
N
N
N
DMAD/ Et3N
CH2Cl2
10a
N
10b
Br
3
COMe
10
H
CH2COMe
2
MeO2C
1
H
CO2Me
7
8
Scheme 2
4 and 5 are generally unstable, leading to the fully aromatic
compounds 6 by dehydrogenation [13, 14].
Isolation and characterization of hydrogenated inter-
mediates led to investigation of their structure with the aim
of elucidating the stereochemistry of the 1,3-dipolar
cycloaddition [13–16]. Nuclear magnetic resonance
(NMR) spectra of the dihydropyrrolophthalazines revealed
a high value of the coupling constant (J & 13 Hz) between
the two hydrogens in the pyrrolidine moiety. In the case of
1,10-phenanthroline (Het = 1,10-phenanthroline), a cyc-
loadduct of type 5 [17] was isolated, where the coupling
constant between pyrrolinic protons was reported as
4.8 Hz. X-ray analysis of dihydropyrrolophenanthroline of
type 5 clearly indicated a trans stereochemistry of the two
pyrrolinic protons. By comparing the NMR data of the
Fig. 1 Structure and conformation of 8
(H10, H11) were located unambiguously in a difference
electron density map and were added to the parent atoms in
idealized positions in a riding model (final H–C–C–H
torsion angle = 148.5°).
Hydrogenation of the planar phthalazinium moiety in 7
to yield the intermediate 8 (Scheme 2) induces significant
bond length and conformational changes. Thus, the shortest
and longest bond distances in the partially saturated
dihydropyrrolophenanthroline of type
5
and dihy-
dropyrrolophthalazine of type 4 the conclusion was that the
magnitude of the coupling constant in the case of com-
pounds of type 4 was sufficiently high to ascertain a cis
[13–16] stereochemistry for the two hydrogen atoms in
question. Thus, the hydrogenated intermediate 8 obtained
from the corresponding phthalazinium salt 7 with dimethyl
acetylenedicarboxylate (DMAD) was obtained according
to Scheme 2 with the aim of performing structural studies.
The NMR data for compound 8 are in good agreement
with the proposed structure. The high magnitude of the
coupling constant (13.2 Hz) could predict a cis configura-
tion. To establish unequivocally the configuration of the
two protons from the pyrroline moiety, the representative
dihydro derivative 8 was subjected to X-ray analysis,
leading to elucidation of the structure of compounds of
type 4. The X-ray data showed an unexpected trans
configuration.
˚
phthalazine ring of 8 are N2–C3 1.292(2) A and C9–C10
˚
1.502(2) A. This ring adopts an unusual conformation,
which very roughly resembles a half-chair form, atoms N1,
N2, C3, and C4 being roughly coplanar [dihedral angle
N1–N2–C3–C4 = -5.8(2)°] and with atoms C9 and C10,
respectively, below and above the plane as viewed in
Fig. 1. The conformation of the dihydropyrrole ring is very
close to an envelope (flap at C10), as found also in the
molecule 10b-methyl-1,3-diphenyl-1,10b-dihydropyrrol-
o[2,1-a]phthalazine [18]. However, while the interatomic
distances in the saturated phthalazine ring of 8 are very
similar to those in the related molecule [18], the endocyclic
torsion angles span the rather different respective ranges of
-5.8° to 44.3° and 1.0° to -14.0°. The variability in ring
conformations is attributed to the significantly different
steric and electronic influences of the respective substitu-
ents on the dihydropyrrole ring in the two molecules. In
molecule 8, the methyl group of the COOCH3 group
The trans stereochemistry in 8 is evident from Fig. 1,
where nonhydrogen atoms are represented as thermal
ellipsoids at the 50% probability level and H atoms are
drawn as spheres of arbitrary size. The relevant atoms
123

Contributions to syntheses of pyrrolo[2,1-a]phthalazines
745
6
7
Scheme 3
6'
5'
8
N
N
R
N
10b
3
E
+
ArCOCH2Br
+
CO
4'
9
Et
10a
1'
N
10
3'
2'
2
1
O
E
9
10
11
12
attached to C12 is disordered over two positions [C24a,
major component with site occupancy 0.742(4), and C24b
with site occupancy 0.258(4)]. In the crystal of 8, there are
only two unique intermolecular hydrogen bonds of type
C–HꢀꢀꢀO and there is no significant p-stacking.
group could be observed at 1,345 and 1,527 cm-1. The
regioselectivity of the cycloaddition reaction is highlighted
by 1H NMR spectroscopy. Thus, the hydrogen H-2 appears
as a sharp singlet at 7.56–7.66 ppm. The hydrogen H-6
appears as a deshielded singlet in the range 8.69–8.89 ppm
due to the vicinity of the nitrogen atom. The H-10 atom is
strongly deshielded (d & 9.80 ppm) due to the spatial
influence of the carbonyl group attached to position 1.
The 13C NMR spectra show all the expected signals. The
spectra of pyrrolophthalazines present the signals of the
carbonyl groups at expected chemical shifts. The main
signals are of carbon C-6 attached to a double C–N bond in
the phthalazine moiety which appears strongly deshielded
(d & 146 ppm) and of the C-1 in the pyrrole ring which
appears shielded due to the substituent directly attached
(d & 117 ppm for compounds 12a and 12b and
*108 ppm for 12c–12k).
In conclusion, based on the X-ray analysis, a trans
configuration was attributed to the dihydro derivative
intermediate 8 obtained by the classic two-stage synthesis
of pyrrolo[2,1-a]phthalazine. Also, new pyrrolo[2,1-a]
phthalazines were easily obtained by the one-pot three-
component procedure, avoiding the formation of the
dihydro derivatives. The proposed one-pot reaction is in
line with the current trend to address issues of
sustainability.
One-pot or one-pot multicomponent reactions are of
interest due to their simple procedures [19–28]. The one-
pot reactions starting from azine salts or the one-pot three-
component synthesis starting directly from azines proved
to be efficient in the case of both symmetrical and non-
symmetrical dipolarophiles [29–33]. These methods avoid
formation of hydrogenated derivatives and lead directly to
the aromatic compounds.
The starting materials for the one-pot three-component
synthesis of pyrrolo[2,1-a]phthalazines 12 were phthal-
azine 9, bromoacetophenones 10, and nonsymmetrical
acetylenic dipolarophiles 11. The reaction was carried out
in excess 1,2-epoxybutane with the role of generating the
phthalazinium ylide in situ and as reaction medium
(Scheme 3).
The one-pot three-component synthesis of pyrroloph-
thalazines involves in the first step the attack of the
bromide ion on the oxirane ring of 1,2-epoxybutane,
resulting in ring opening with formation of an alkoxide.
The alkoxide abstracts one of the methylene protons in the
bromide salt, generating the unstable phthalazinium
N-ylide. In the next step, 1,3-dipolar cycloaddition between
the N-ylide and acetylenic dipolarophile gives the primary
cycloadduct of type 3, which under the reaction conditions,
rearranges to the dihydropyrrolophthalazine of type 4,
leading via dehydrogenation to the pyrrolo[2,1-a]phthala-
zines 12.
Experimental
¨
Melting points were determined on a Boetius hot plate
apparatus. The elemental analysis was carried out on a
COSTECH Instruments EAS32 apparatus; their results
agreed favorably with the calculated values. The IR spectra
were recorded on a Fourier-transform (FT)-IR Bruker
Vertex 70 spectrometer. The NMR spectra were recorded
on a Varian Gemini 300 BB instrument, operating at
300 MHz for 1H and 75 MHz for 13C. Supplementary
evidence was given by heteronuclear correlation spectro-
scopy (HETCOR) and correlation spectroscopy (COSY)
experiments. Phthalazine, phenacyl bromides, DMAD,
methyl propiolate, triethylamine, and 1,2-epoxybutane
were obtained from Aldrich and were used without further
purification.
The structures of compounds 12 were assigned by ele-
mental analysis, infrared (IR), and NMR spectroscopy. The
characteristic IR spectral features of compounds 12 are the
carbonyl bands observed in the range 1,627–1,640 cm-1
for the carbonyl group in the benzoyl moiety, due to con-
jugation within the molecule. The carbonyl bands in the
acetyl moiety in compounds 12a and 12b appear at
1,658–1,662 cm-1, whereas for the carbomethoxy or car-
boethoxy the corresponding carbonyl bands appear in the
range 1,699–1,712 cm-1. The C–O vibration specific
bands could be observed at *1,090 and *1,250 cm-1. For
compound 12e the characteristic vibrations of the NO2
123

746
M. R. Caira et al.
Dimethyl
azine-1,2-dicarboxylate (8, C17H16N2O5)
3-acetyl-1,10b-dihydropyrrolo[2,1-a]phthal-
(s, 1H, H-6), 7.94–7.89 (m, 2H, H-7, H-9), 7.80–7.75 (m, 1H,
H-8), 7.66 (1H, s, H-2), 7.52–7.50 (m, 2H, H-20, H-60), 7.43
(t, 1H, J = 8.0 Hz, H-50), 7.18 (ddd, 1H, J = 8.0, 2.4,
1.1 Hz, H-40), 3.89 (s, 3H, MeO), 2.68 (s, 3H,
MeCO) ppm; 13C NMR (75 MHz, CDCl3): d = 193.7
(COMe), 184.5 (COAr), 159.8 (C-30), 147.0 (C-6), 140.4
(C-10), 133.0 (C-9), 130.2, 122.5, 119.0, 114.2 (C-20, C-40,
C-50, C-60), 129.7, 127.4, 127.1, 122.4 (C-3, C-6a, C-10a,
C-10b), 129.5, 127.8, 127.6 (C-7, C-8, C-10), 117.1 (C-1),
Into an ice-cooled mixture of 1.34 g phthalazinium salt 7
(5 mmol) and 0.79 g DMAD (5.5 mmol) in 25 cm3
dichloromethane was added dropwise, under continuous
stirring, 0.76 g triethylamine (7.5 mmol) dissolved in
5 cm3 dichloromethane. After 20 min the reaction mixture
was washed with water, and then the solvent was evapo-
rated under vacuum. The obtained residue was triturated
with cold ethanol and filtered. Yield 82%; m.p.: 135–
ꢀ
55.6 (MeO), 29.6 (MeCO) ppm; IR (ATR): m = 1,256,
1
137 °C (from 2-propanol); H NMR (300 MHz, CDCl3):
1,627, 1,662, 2,996, 3,038 cm-1
.
d = 7.53–7.48 (m, 1H, H-9), 7.53 (s, 1H, H-6), 7.43–7.36
(m, 2H, H-8, H-10), 7.29–7.25 (m, 1H, H-8), 5.13 (d, 1H,
J = 13.2 Hz, H-10b), 4.35 (d, 1H, J = 13.2 Hz, H-1),
3.90, 3.72 (2 s, 6H, MeO), 2.59 (s, 3H, MeCO) ppm; 13C
NMR (75 MHz, CDCl3): d = 195.7 (COMe), 173.0
(1-COO), 164.4 (2-COO), 154.9 (C-3), 142.2 (C-6),
131.8 (C-10), 130.9, 124.8 (C-6a, C-10a), 128.9, 124.8,
123.5 (C-7, C-8, C-9), 99.2 (C-2), 61.6 (C-10b), 53.0, 51.6
Methyl 3-benzoylpyrrolo[2,1-a]phthalazine-1-carboxylate
(12c, C20H14N2O3)
1
Yield 78%; m.p.: 231–233 °C (from methanol); H NMR
(300 MHz, CDCl3): d = 9.77–9.74 (m, 1H, H-10), 8.69 (s,
1H, H-6), 7.89–7.86 (m, 2H, H-20, H-60), 7.85–7.80 (m, 2H,
H-7, H-9), 7.69–7.64 (m, 1H, H-8), 7.63 (s, 1H, H-2), 7.56–
7.51 (m, 1H, H-40), 7.47–7.42 (m, 2H, H-30, H-50), 4.85 (s,
3H, Me) ppm; 13C NMR (75 MHz, CDCl3): d = 184.6
(COAr), 164.7 (COO), 146.5 (C-6), 139.1 (C-10), 133.0
(C-9), 132.5 (C-40), 130.4, 127.2, 126.8, 122.2 (C-3, C-6a,
C-10a, C-10b), 129.8, 127.6, 127.5 (C-7, C-8, C-10), 129.7
(C-30, C-50), 128.4 (C-20, C-60), 124.9 (C-2), 107.9 (C-1),
(2OMe), 52.2 (C-1), 30.7 (MeCO) ppm; IR (ATR):
-1
ꢀ
m = 1,687, 1,716, 2,950, 3,048 cm
.
Procedure for pyrrolo[2,1-a]phthalazines 12
ꢀ
51.9 (MeO) ppm; IR (ATR): m = 1,089, 1,265, 1,633,
A mixture of 0.65 g phthalazine 9 (5 mmol), phenacyl
bromide 10 (5 mmol), and nonsymmetrical acetylene 11
(7 mmol) in 20 cm3 1,2-epoxybutane was kept under stir-
ring at reflux temperature for 16 h. After the solvent was
partly removed by evaporation, 10 cm3 methanol was
added, and the mixture was left overnight at room tem-
perature. The solid was filtered, washed with a small
quantity of cold ethanol, and crystallized from a suitable
solvent.
1,704, 2,950, 3,025 cm-1
.
Methyl 3-(2-chlorobenzoyl)pyrrolo[2,1-a]phthalazine-1-
carboxylate (12d, C20H13ClN2O3)
1
Yield 75%; m.p.: 221–222 °C (from ethanol); H NMR
(300 MHz, CDCl3): d = 9.81–9.78 (m, 1H, H-10), 8.78
(s, 1H, H-6), 7.92–7.86 (m, 2H, H-7, H-9), 7.77–7.72 (m,
1H, H-8), 7.59 (s, 1H, H-2), 7.52–7.37 (m, 4H, H-30, H-40,
H-50, H-60), 3.89 (s, 3H, Me) ppm; 13C NMR (75 MHz,
CDCl3): d = 183.0 (COAr), 164.4 (COO), 146.8 (C-6),
139.7, 131.6 (C-10, C-20), 133.1 (C-9), 131.6, 127.1, 122.3
(C-3, C-6a, C-10a, C-10b), 131.1, 130.1, 126.7 (C-30, C-40,
C-50, C-60), 130.1, 127.7, 127.6 (C-7, C-8, C-10), 126.6
1-Acetyl-3-(2-methoxybenzoyl)pyrrolo[2,1-a]phthalazine
(12a, C21H16N2O3)
1
Yield 69%; m.p.: 147–149 °C (from ethanol); H NMR
(300 MHz, CDCl3): d = 9.75–9.72 (m, 1H, H-10), 8.61 (s,
1H, H-6), 7.82–7.77 (m, 2H, H-7, H-9), 7.68–7.63 (m, 1H,
H-8), 7.56 (s, 1H, H-2), 7.47–7.38 (m, 2H, H-40, H-60), 6.99
(bt, 1H, J = 7.4 Hz, H-50), 6.90 (bd, 1H, J = 7.6 Hz,
H-30), 3.59 (s, 3H, MeO), 2.56 (s, 3H, MeCO) ppm; 13C
NMR (75 MHz, CDCl3): d = 193.8 (COMe), 184.2
(COAr), 157.7 (C-20), 146.5 (C-2), 132.8 (C-9), 132.1,
130.0 (C-40, C-60), 130.2, 129.2, 127.1, 122.3 (C-3, C-6a,
C-10a, C-10b, C-10), 130.0 (C-60), 129.8, 127.8, 127.4 (C-7,
C-8, C-10), 124.9 (C-2), 120.6, 111.6 (C-30, C-50), 117.5
(C-2), 108.7 (C-1), 51.9 (MeO) ppm; IR (ATR):
-1
ꢀ
m = 1,091, 1,261, 1,634, 1,711, 2,952, 3,053 cm
.
Methyl 3-(4-nitrobenzoyl)pyrrolo[2,1-a]phthalazine-1-
carboxylate (12e, C20H13N3O5)
Yield 81%; m.p.: 250–252 °C (from ethanol); 1H NMR
(300 MHz, CDCl3 ? TFA): d = 9.76–9.73 (m, 1H, H-10),
8.89 (s, 1H, H-6), 8.40 (d, 2H, J = 8.8 Hz, H-30, H-50), 7.99–
8.06 (m, 4H, H-7, H-9, H-20, H-60), 7.91–7.86 (m, 1H, H-8),
7.58 (s, 1H, H-2), 3.98 (s, 3H, MeO) ppm; 13C NMR
(75 MHz, CDCl3 ? TFA): d = 184.3 (COAr), 165.1
(COO), 150.2 (C-40), 147.7 (C-6), 144.0 (C-10), 134.2
(C-9), 132.9, 126.3, 125.5, 122.8 (C-3, C-6a, C-10a, C-10b),
1310.4, 128.9, 128.4, 127.9 (C-2, C-6, C-7, C-8), 124.0 (C-30,
(C-1), 55.8 (MeO), 29.5 (MeCO) ppm; IR (ATR):
-1
ꢀ
m = 1,234, 1,627, 1,658, 2,951, 3,034 cm
.
1-Acetyl-3-(3-methoxybenzoyl)pyrrolo[2,1-a]phthalazine
(12b, C21H16N2O3)
1
ꢀ
C-5 ), 109.3 (C-1), 52.8 (MeO) ppm; IR (ATR): m = 1,096,
Yield 71%; m.p.: 171–173 °C (from ethanol); H NMR
1,265, 1,345, 1,527, 1,637, 1,710, 2,958, 3,029 cm-1
.
(300 MHz, CDCl3): d = 9.87–9.83 (m, 1H, H-10), 8.78
123

Contributions to syntheses of pyrrolo[2,1-a]phthalazines
747
Methyl 3-(2-methoxybenzoyl)pyrrolo[2,1-a]phthalazine-
1-carboxylate (12f, C21H16N2O4)
J = 7.1 Hz, Me) ppm; 13C NMR (75 MHz, CDCl3):
d = 182.1 (COAr), 164.1 (COO), 146.8 (C-6), 138.2,
136.6, 132.8 (C-10, C-20, C-40), 133.2 (C-9), 130.4, 130.2,
127.2 (C-30, C-50, C-60), 131.0, 127.2, 126.8, 122.4, (C-3,
C-6a, C-10a, C-10b), 130.1, 127.9, 127.7 (C-7, C-8, C-10),
126.1 (C-2), 109.5 (C-1), 61.0 (CH2), 14.6 (Me) ppm; IR
Yield 68%; m.p.: 181–183 °C (from acetonitrile); 1H NMR
(300 MHz, CDCl3): d = 9.80–9.77 (m, 1H, H-10), 8.74
(s, 1H, H-6), 7.88–7.84 (m, 2H, H-7, H-9), 7.74–7.69
(m, 1H, H-8), 7.62(s, 1H, H-2), 7.52–7.45 (m, 2H, H-40, H-60),
7.06 (bt, 1H, J = 7.4 Hz, H-50), 6.99 (bd, 1H, J = 7.6 Hz,
H-30), 3.89, 3.71 (2 s, 6H, 2MeO) ppm; 13C NMR (75 MHz,
CDCl3): d = 184.2 (COAr), 164.7 (COO), 157.5 (C-20),
146.3 (C-6), 132.9 (C-9), 131.8, 129.7, 129.6, 127.5, 127.4
(C-7, C-8, C-10, C-40, C-60), 130.3, 130.1, 128.6, 126.7, 122.1
(C-3, C-6a, C-10a, C-10b, C-10), 125.6 (C-2), 120.6, 111.6
(ATR): ꢀm = 1,092, 1,260, 1,636, 1,704, 2,970, 3,045 cm-1
.
Ethyl 3-(2-methoxybenzoyl)pyrrolo[2,1-a]phthalazine-
1-carboxylate (12j, C22H18N2O4)
1
Yield 71%; m.p.: 160–162 °C (from ethanol); H NMR
(300 MHz, CDCl3): d = 9.69–9.66 (m, 1H, H-10), 8.59 (s,
1H, H-6), 7.76–7.71 (m, 2H, H-7, H-9), 7.62–7.57 (m, 1H,
H-8), 7.56 (s, 1H, H-1), 7.43–7.34 (m, 2H, H-40, H-60), 6.96
(bt, 1H, J = 7.4 Hz, H-50), 6.88 (bd, 1H, J = 7.6 Hz,
H-30), 4.28 (q, 2H, J = 7.1 Hz, CH2), 3.59 (s, 3H, MeO),
1.29 (t, 3H, J = 7.1 Hz, MeCH2) ppm; 13C NMR (75 MHz,
CDCl3): d = 184.2 (COAr), 164.3 (COO), 157.6 (C-20),
146.2 (C-6), 132.8 (C-9), 131.9, 129.7, 129.6, 127.5, 127.4
(C-7, C-8, C-10, C-40, C-60), 130.3, 130.2, 128.6, 126.8,
122.1 (C-3, C-6a, C-10a, C-10b, C-10), 125.2 (C-2), 120.5,
111.6 (C-30, C-50), 108.7 (C-1), 60.7 (CH2), 55.8 (MeO),
(C-30, C-50), 108.2 (C-1), 55.8, 51.8 (2MeO) ppm; IR (ATR):
-1
ꢀ
m = 1,092, 1,251, 1,640, 1,712, 2,947, 3,032 cm
.
Methyl 3-(3-methoxybenzoyl)pyrrolo[2,1-a]phthalazine-
1-carboxylate (12g, C21H16N2O4)
Yield 77%; m.p.: 224–226 °C (from ethyl acetate); 1H
NMR (300 MHz, CDCl3): d = 9.79–9.76 (m, 1H, H-10),
8.76 (s, 1H, H-6), 7.88–7.82 (m, 2H, H-7, H-9), 7.72–7.66
(m, 1H, H-8), 7.66 (1H, s, H-2), 7.46–7.42 (m, 2H, H-20,
H-60), 7.36 (t, 1H, J = 8.0 Hz, H-50), 7.09 (ddd, 1H, J = 8.0,
2.4, 1.1 Hz, H-40), 3.87, 3.82 (2 s, 6H, 2MeO) ppm; 13C
NMR (75 MHz, CDCl3): d = 184.5 (COAr), 164.7 (COO),
159.8 (C-30), 146.6 (C-6), 140.5 (C-10), 133.1 (C-9), 130.5,
127.1, 126.9, 122.3 (C-3, C-6a, C-10a, C-10b), 129.9,
122.6, 119.0, 114.3 (C-20, C-40, C-50, C-60), 129.4, 127.7,
127.6 (C-7, C-8, C-10), 108.0 (C-1), 55.6, 52.0
ꢀ
14.5 (MeCH2) ppm; IR (ATR): m = 1,089, 1,239, 1,634,
1,699, 2,937, 3,038 cm-1
.
Ethyl 3-(3-methoxybenzoyl)pyrrolo[2,1-a]phthalazine-
1-carboxylate (12k, C22H18N2O4)
1
Yield 67%; m.p.: 181–183 °C (from ethanol); H NMR
(300 MHz, CDCl3): d = 9.85–9.82 (m, 1H, H-10), 8.76 (s,
1H, H-6), 7.93–7.88 (m, 2H, H-7, H-9), 7.77–7.72 (m, 1H,
H-8), 7.73 (1H, s, H-2), 7.55–7.51 (m, 2H, H-20, H-60), 7.43
(t, 1H, J = 8.0 Hz, H-50), 7.17 (ddd, 1H, J = 8.0, 2.4,
1.1 Hz, H-40), 4.42 (q, 2H, J = 7.1 Hz, CH2), 3.89 (s, 3H,
MeO), 1.42 (t, 3H, J = 7.1 Hz, CH3) ppm; 13C NMR
(75 MHz, CDCl3): d = 184.5 (COAr), 164.3 (COO), 159.8
(C-30), 146.5 (C-6), 140.5 (C-10), 133.0 (C-9), 130.3, 127.2,
126.9, 122.3 (C-3, C-6a, C-10a, C-10b), 129.8, 122.6,
119.0, 114.2 (C-20, C-40, C-50, C-60), 129.4, 127.7, 127.6
(C-7, C-8, C-10), 108.4 (C-1), 60.8 (CH2), 55.6 (MeO),
ꢀ
(2MeO) ppm; IR (ATR): m = 1,090, 1,259, 1,634, 1,704,
2,976, 3,037 cm-1
.
Methyl 3-(4-methoxybenzoyl)pyrrolo[2,1-a]phthalazine-
1-carboxylate (12h, C21H16N2O4)
Yield 72%; m.p.: 190–192 °C (from ethanol);1H NMR
(300 MHz, CDCl3): d = 9.79–9.76 (m, 1H, H-10), 8.70
(s, 1H, H-6), 7.97 (d, 2H, J = 8.8 Hz, H-20, H-60), 7.88–7.82
(m, 2H, H-7, H-9), 7.71–7.69 (m, 1H, H-8), 7.65 (s, 1H,
H-2), 6.99 (d, 2H, J = 8.8 Hz, H-30, H-50), 3.92, 3.88 (2 s,
6H, 2MeO) ppm; 13C NMR (75 MHz, CDCl3): d = 184.5
(COAr), 164.7 (COO), 163.4 (C-40), 146.3 (C-6), 132.9
(C-9), 132.2 (C-20, C-60), 129.5, 127.6, 127.3 (C-7, C-8,
C-10), 129.5, 127.6, 127.3 (C-7, C-8, C-10), 129.8, 126.8,
122.1, (C-3, C-6a, C-10a, C-10b), 123.5 (C-2), 113.7
ꢀ
14.5 (MeCH2) ppm; IR (ATR): m = 1,090, 1,259, 1,634,
1,704, 2,976, 3,037 cm-1
.
X-ray data collection
(C-30,C-50), 107.5 (C-1), 55.5, 51.8 (2MeO) ppm; IR
-1
A single crystal of 8 was mounted on a Nonius Kappa CCD
diffractometer and cooled in a constant stream of nitrogen
vapor. Intensity data were collected with graphite-mono-
ꢀ
(ATR): m = 1,090, 1,247, 1,636, 1,702, 2,945, 3,020 cm
.
Ethyl 3-(2,4-dichlorobenzoyl)pyrrolo[2,1-a]phthalazine-
1-carboxylate (12i, C21H14Cl2N2O3)
˚
chromated Mo Ka radiation (k = 0.71073 A). Data
1
Yield 75%; m.p.: 201–203 °C (from ethanol); H NMR
(300 MHz, CDCl3): d = 9.85–9.82 (m, 1H, H-10), 8.76 (s,
1H, H-6), 7.96–7.90 (m, 2H, H-7, H-9), 7.81–7.75 (m, 1H,
H-8), 7.65 (s, 1H, H-2), 7.49 (d, 1H, J = 2.0 Hz, H-30),
7.48 (d, 1H, J = 8.2 Hz, H-60), 7.39 (dd, 1H, J = 8.2,
2.0 Hz, H-50), 4.43 (q, 2H, J = 7.1 Hz, CH2), 1.41 (3H, t,
collection strategy was determined using the program
COLLECT [34], and data reduction, including Lorentz-
polarization corrections, was performed with DEMZO-
SMN [35]. Programs SHELXS-97 and SHELXL97 were
used for structure solution and full-matrix least-squares
refinement [36]. In the course of refinement, an alternative
123

748
M. R. Caira et al.
´
3. Mitsumori T, Bendikov M, Sedo J, Wudl F (2003) Chem Mater
15:3759
Table 1 Crystal data and refinement parameters for compound 8
Empirical formula
Formula weight (g mol-1
C17H16N2O5
4. Uff BC, Ghaem-Maghami G, Budhram RS, Wilson CL, Apatu JO
(1989) J Heterocycl Chem 26:571
)
328.32
5. Galin FZ, Sakhautdinov IM, Tukhavatullin OR (2007) Russ
Chem Bull Int Ed 53:2305
6. Siriwardana AI, Nakamura I, Yamamoto Y (2004) J Org Chem
69:3202
7. Komatsu M, Kasano Y, Yamaoka S, Minakata S (2003) Synthesis
35(9):1398
˚
Unit cell lengths (A)
8.6689(4), 9.2817(3), 11.0265(6)
Unit cell angles (°)
91.899(3), 106.522(2),
112.784(2)
3
Cell volume (A )
˚
773.84(6)
Temperature (K)
173(2)
8. Bridge AW, Hursthouse MB, Lehmann CW, Lythgoe DJ, Newton
CG (1993) J Chem Soc Perkin Trans 1:1839
9. Potts KT, Bordeaux KG, Kuehnling WR, Salsbury RL (1985) J
Org Chem 50:1677
Calculated density (g cm-3
Crystal size (mm3)
F(000)
)
1.409
0.09 9 0.11 9 0.16
344
˘
10. Zugravescu I, Petrovanu M (1976) N-Ylid chemistry. McGraw-
Hill, New York, p 239
Intensity scans (°)
h-range for data collection (°)
Range in hkl
u- and x-scans of 2.00°
3.34–26.39
-10, 10; -11, 11; -13, 13
6,101
11. Khlebnikov AF, Kostik EI, Kostikov RR (1993) Synthesis
25(6):568
12. Zhou J, Hu Y, Hu H (2000) J Heterocycl Chem 37:1165
13. Butnariu RM, Caprosu MD, Bejan V, Ungureanu M, Poiata A,
Tuchilus C, Florescu M, Mangalagiu I (2007) J Heterocycl Chem
44:1
14. Caprosu MC, Zbancioc GN, Moldoveanu CC, Mangalagiu I
(2004) Collect Czech Chem Commun 69:426
15. Dumitrascu F, Mitan CI, Draghici C, Caproiu MT, Raileanu D
(2001) Tetrahedron Lett 42:8379
16. Dumitrascu F, Draghici C, Caproiu MT, Dumitrescu D, Badoiu A
(2006) Rev Roum Chim 51:643
Total no. of reflections
Independent reflections
Reflections with I C 2r(I)
Data/parameters
3,157 (Rint = 0.0232)
2,553
13.6
Goodness of fit on F2
1.036
Final R indices [I C 2r(I)]
R1 = 0.0378
wR2 = 0.0893
R1 = 0.0532
wR2 = 0.0967
R indices (all data)
17. Dumitrascu F, Caira MR, Draghici C, Caproiu MT, Barbu L
(2009) Rev Chim (Bucharest) 60:851
18. Sharp JT, Wilson P, Parsons S, Gould RO (2000) J Chem Soc
Perkin Trans 1:1139
Largest diff. peak and hole (eA-3) -0.26 and 0.28
˚
¨
19. Domling A (2006) Chem Rev 106:17
position for methyl carbon atom C24A was located at
˚
1.5 A from carbonyl atom O22. The alternative position
20. Zhu J, Bienayme H (2005) Multicomponent reactions. Wiley-
VCH, Weinheim
21. Maisonneuve S, Xie J (2009) Synlett 20(18):2977
22. Reddy Udagandla C, Saikia Anil K (2010) Synlett 21(7):1027
23. Ranjabar-Karimi R, Beiki-Shoraki K, Amiri A (2010) Monatsh
Chem 141:1101
24. Keri RS, Hosamani KM (2010) Monatsh Chem 141:883
25. Gladkov ES, Sirko SN, Shishkina SV, Shishkin OV, Knyazeva
IV, Desenko SM, Chebanov VA (2010) Monatsh Chem 141:773
26. Wang HJ, Zhang XN, Zhang ZH (2010) Monatsh Chem 141:425
27. Yavari I, Sayyed-Alangy SZ, Hajinasiri R, Sajjadi-Ghotbabadi H
(2009) Monatsh Chem 140:209
28. Dumitrascu F, Draghici C, Caproiu MT, Dumitrescu DG, Popa
MM (2009) Rev Roum Chim 53:923
29. Georgescu E, Caira MR, Georgescu F, Draghici B, Popa MM,
Dumitrascu F (2009) Synlett 20(11):1795
30. Caira MR, Georgescu E, Georgescu F, Draghici B, Popa MM,
Dumitrascu F (2009) Arkivoc xii:242
was modeled as C24B with the site occupancy (s.o.f.) of
the two methyl groups refining as x and 1 - x. The domi-
nant position (C24A) had a final refined s.o.f. of 0.742(4).
All H atoms were located in difference Fourier syntheses
and were added in idealized positions with isotropic ther-
mal parameters 1.2–1.5 times those of their parent atoms.
Non-H atoms refined anisotropically. Table 1 lists crystal
data and other relevant refinement parameters. Full crys-
tallographic data for compound 8 have been deposited at
the Cambridge Crystallographic Data Centre, University
Chemical Laboratory, Cambridge, England (CCDC
796174).
31. Dumitrascu F, Caproiu MT, Georgescu F, Draghici B, Popa MM,
Georgescu E (2010) Synlett 21(16):2407
Acknowledgments M.R.C. thanks the University of Cape Town
and the National Research Foundation for research support.
32. Dumitrascu F, Georgescu E, Caira MR, Georgescu F, Popa MM,
Draghici B, Dumitrescu DG (2009) Synlett 20(20):3336
33. Georgescu E, Dumitrascu F, Georgescu F, Draghici C, Popa MM
(2010) Rev Roum Chim 55:217
References
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123