Reactions of ethyl cyanoformate with cycloimmonium salts: a direct pathway to fused or substituted azaheterocycles

Article abstract of DOI:10.1016/j.tet.2016.05.061

Aromatic cycloimmonium salts underwent different reaction pathways when treated with ethyl cyanoformate in triethyl amine medium, including selective γ-cyano substitutions (in case of phenanthrolinium and quinolinium salts) and 3+2 dipolar cycloadditions (for phthalazinium and isoquinolinium salts). When using phthalazinium salts, besides the 3+2 cycloaddition products (imidazo[2,1-a]phthalazines), we obtained 8,8a,16,16a-tetrahydropyrazino-[2,1-a;4,5-a′]-diphthalazines as secondary products via a 3+3 cycloaddition dimerization. The structures of the synthesized compounds have been proved by spectral data, and X-ray diffraction for three of the new derivatives.

Full text of DOI:10.1016/j.tet.2016.05.061

Tetrahedron xxx (2016) 1e9
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Reactions of ethyl cyanoformate with cycloimmonium salts: a direct
pathway to fused or substituted azaheterocycles
*
Cristina M. Al Matarneh, Mircea O. Apostu, Ionel I. Mangalagiu, Ramona Danac
Department of Chemistry, Faculty of Chemistry, ‘Al. I Cuza’ University of Iasi, 11 Carol I, Iasi 700506, Romania
a r t i c l e i n f o
a b s t r a c t
Article history:
Aromatic cycloimmonium salts underwent different reaction pathways when treated with ethyl cya-
Received 26 February 2016
Received in revised form 10 May 2016
Accepted 23 May 2016
Available online xxx
noformate in triethyl amine medium, including selective
g-cyano substitutions (in case of phenan-
throlinium and quinolinium salts) and 3þ2 dipolar cycloadditions (for phthalazinium and
isoquinolinium salts). When using phthalazinium salts, besides the 3þ2 cycloaddition products (imidazo
[2,1-a]phthalazines), we obtained 8,8a,16,16a-tetrahydropyrazino-[2,1-a;4,5-a0]-diphthalazines as sec-
ondary products via a 3þ3 cycloaddition dimerization. The structures of the synthesized compounds
have been proved by spectral data, and X-ray diffraction for three of the new derivatives.
Ó 2016 Elsevier Ltd. All rights reserved.
Keywords:
Ethyl cyanoformate
Heterocycles
3þ2 cycloaddition
g-Cyano substitution
Cycloimmonium salt
1. Introduction
the study of the reactions of ethyl cyanoformate with different
cycloimmonium salts (phthalazinium, quinolinium and iso-
Methyl cyanoformate, known as Mander’s reagent, is commonly
used to perform the regioselective methoxycarbonylation of lith-
ium enolates.1 Ethyl and methyl cyanoformates are also known for
quinolinium) in basic medium, and the results are presented
herein.
formation of
a-ketoesters from arylboronic acids in rhodium-
2. Results and discussion
catalysed reactions2 and for use as selective cyanoethox-
ycarbonylation reagents,3 cyanation reagents4,5 or dipolarophiles in
different cyclization reaction.6e9
In our first attempt to synthesize a new imidazophenanthroline
skeleton, we used 1,10-phenanthrolin-1-ium halides18 1 in basic
medium (trimethylamine in dichloromethane) for the generation
of the corresponding ylides in order to react with ethyl cyano-
formate in 3þ2 cycloaddition reaction. Instead the expected
cycloadducts 2, we obtained 4-cyano substituted 1,10-
phenanthrolines 3 (Scheme 1). Interestingly, in case of the re-
action of salt 1c, the final product 3c contained a methyl ester group
instead the initial amide group, this replacement probably occur-
ring during the column chromatography when we used CHCl3/
MeOH as eluent.
Imidazole is a therapeutically active moiety exploited in recent
years for the synthesis of diverse derivatives with various biological
activities.10 The fusion of two or more heterocycle rings results in
different classes of compound, and fused heterocycles containing
an imidazole ring are showing a broad range of properties including
biological activity11e13 optical14 or electron-transport properties.15
Inspired by a recent report of using ethyl cyanoformate as
a dipolarophile in the 3þ2 cycloaddition of pyridinium ylides, with
formation of a new fused imidazo[1,2-a]pyridine system,7 and as
a continuation of our work in the field of 3þ2 cycloaddition re-
actions,16,17 we decided to use ethyl cyanoformate in similar re-
actions of 1,10-, 1,7- and 4,7-phenanthrolinium ylides in order to
obtain new imidazophenanthroline systems. Surprisingly, instead
The structures of the compounds 3aec were established on the
basis of spectral analyses (NMR, IR) and X-ray diffraction for com-
pound 3a (Fig.1). Thus, the crystal structure of 3a indicates that this
compound has the following crystallographic characteristics:
ꢀ
ꢀ
the expected cycloadducts, we prepared new g-cyano-substituted
phenanthrolines. This interesting behaviour prompted us to extend
monoclinic, space group P21/c (no. 14), a¼4.973 A, b¼40.94 A,
3
ꢀ
ꢀ
ꢀ
c¼8.604 A,
that in the crystals of compound 3a a series of CeH/O and CeH/N
hydrogen bonds exists but no interactions.
b
¼96.11 , V¼1742.1 A , Z¼4. The analysis of data reveals
pep
Regarding the mechanism, we suppose that ethyl cyanoformate
reacts with triethylamine (TEA) used in excess and generates the
* Corresponding author. Tel.: þ40 232201342; e-mail address: rdanac@uaic.ro
(R. Danac).
http://dx.doi.org/10.1016/j.tet.2016.05.061
0040-4020/Ó 2016 Elsevier Ltd. All rights reserved.
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2
C.M. Al Matarneh et al. / Tetrahedron xxx (2016) 1e9
Scheme 1. Synthesis of 4-cyano-substituted 2-oxo-1,2-dihydro-1,10-phenanthrolines 3.
Spectral data and X-ray diffraction of compound 5b confirmed
the proposed structure 5. Interestingly, in the 1H NMR of com-
pounds 5, the hydrogen atoms at C-15 showed two strongly cou-
pled doublets induced by the asymmetry of carbon 10. The X-ray
structure of compound 5b (Fig. 2) indicates the following main
crystal data: orthorhombic, space group P212121 (no. 19),
3
ꢀ
ꢀ
ꢀ
ꢀ
a¼4.788 A, b¼14.184 A, c¼26.17 A, V¼1777 A , Z¼4. The crystallo-
graphic data shows that in the crystals of this compound a series of
CeH/O and CeH/N hydrogen bonds exists but no
pep in-
teractions are present.
Fig. 1. X-ray crystal structure of compound 3a with thermal ellipsoids at 50% proba-
bility level.
cyanide ion (CNꢁ). This ion acts as a nucleophile in reaction with
the in situ generated phenanthrolinium ylides, leading selectively
only to
are stabilised by
the final compounds 3. As for the regioselectivity, the
g
-cyano substituted 1,4-dihydro-1,10-phenanthrolines that
-oxidation in air during the work up, to lead to
-sub-
a
g
stitution takes place in accordance with the existing theory stipu-
lating that ‘soft’ nucleophiles (including cyanide ion) with high
polarizability attack selectively at the ‘softest’
g position of the
heterocycle.19e21
We continued our study using 1,7-phenanthrolin-7-ium salts22
4 as substrates for the reaction with ethyl cyanoformate under
similar conditions, and we obtained
1,7-phenanthrolines 5. In this case, derivatives 5 have not un-
dergone the -oxidation that was observed with the 1,10-
g-substituted-7,10-dihydro-
Fig. 2. X-ray crystal structure of compound 5b with thermal ellipsoids at 50% proba-
bility level.
a
phenathrolin-1-ium salts (Scheme 2).
With 4,7-phenanthrolin-4-ium salts23 6 treated under similar
conditions (Scheme 3), we isolated both g-cyano-substituted 1,4-
dihydro-4,7-phenanthrolines 7, and 3-oxo-3,4-dihydro-4,7-
phenanthrolines 8 (Scheme 3).
We then decided to extend the study to reactions of other
cycloimmonium salts under similar conditions. Thus, quinolinium
salts24 9 underwent similar
g-cyanation and a-oxidation yielding
compounds 10aec and other byproducts (11, 12 and 13) suggesting
an instability of the in situ ylides generated from the salts 9 under
the reaction conditions (Scheme 4).
Scheme 2. Synthesis of 10-cyano-substituted 1,7-phenanthrolines 5.
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C.M. Al Matarneh et al. / Tetrahedron xxx (2016) 1e9
3
Scheme 3. Synthesis of 1-cyano-substituted 4,7-phenanthrolines 7 and 8.
Scheme 4. Synthesis of 4-cyano substituted quinolines 10.
Interestingly, isoquinolinium salts25,26 14 having no available
position for cyanation yielded 3þ2 cycloadducts 15aec with imi-
dazo[2,1-a]isoquinoline structure together with few decomposition
coproducts (16, 17, 18) (Scheme 5).
g
-
dimerization via the [3þ3] cycloaddition of the corresponding
ylides.28
Luckily, we were able to grow a monocrystal of compound 21b
and to investigate the dimeric structure using X-ray diffraction.
Scheme 5. Synthesis of imidazoisoquinolines 15.
Finally, we investigated phthalazinium bromides27 19aec, also
Thus, the X-ray structure of compound 21b (Fig. 3) indicates the
without an unsubstituted position
g
to nitrogen, in similar reaction.
following main crystal data: triclinic, space group P-1 (no. 2),
¼67.18ꢀ,
b
¼74.71ꢀ,
g
¼82.89ꢀ,
ꢀ
ꢀ
ꢀ
As expected, we obtained the imidazo[2,1-a]phthalazines 20 as
product of 3þ2 cycloaddition. As secondary products in the same
reaction we isolated compounds 21 with 8,8a,16,16a-tetrahy-
dropyrazino-[2,1-a;4,5-a0]-diphthalazine structure (Scheme 6) by
a¼10.182 A, b¼13.366 A, c¼13.726 A,
a
3
ꢀ
V¼1660 A , Z¼2.
The crystallographic data shows that in the crystals of this com-
pound a series of interactions are present as can be seen in Fig. 4.
pep
Scheme 6. Synthesis of imidazophthalazines 20 and 8,8a,16,16a-tetrahydropyrazino-[2,1-a;4,5-a0]-diphthalazines 21.
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C.M. Al Matarneh et al. / Tetrahedron xxx (2016) 1e9
Fig. 3. X-ray crystal structure of compound 21b with thermal ellipsoids at 50% probability level.
Fig. 4.
pep Interactions in the crystal of compound 21b.
We also performed similar reactions using two pyridinium salts
of the cycloimmonium ylide and the possible initial formation of
the 1,4-dihydropyridine derivative.
In order to explain the different behaviour of reactivity of ethyl
cyanoformate in respect with the cycloimmonium ylides, having in
with unsubstituted pyridine ring 22, but unfortunately we were
able only to isolate and characterize from the reaction mixture the
corresponding para-substituted benzoic acid 23 (Scheme 7).
Scheme 7. Reaction of pyridinium salts 22 with ethyl cyanoformate in basic conditions.
Interestingly, Sandeep and collab,7 synthesized imidazo[1,2-a]
pyridines by similar reactions using 3- and 4-acetylpyridinium
salts. All these observations emphasize the importance of the
substituent with electron withdrawing ability on the stabilization
view the above results, we may conclude that the structure of the
ylide is determinant for the reaction pathway. Thus, when the
position of the ylide is free (canonical structure c), a nucleophilic
g
-
attack of the cyanide ion take place and the substitution product is
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C.M. Al Matarneh et al. / Tetrahedron xxx (2016) 1e9
5
obtained (this is the case of phenanthroline and quinoline de-
rivatives) (Scheme 8).
carbon nuclear magnetic resonance (dH
on a Bruker Avance 400 DRX (400 MHz), or a DRX-500 Bruker
,
dC) spectra were recorded
Scheme 8. The proposed mechanism for the synthesis of g-cyano substituted azaheterocycles.
When the
g
-position of the ylide is not free, the ylide reacts as
(500 MHz). The following abbreviations were used to designate
1,3-dipole (canonical structure e) in a 3þ2 dipolar cycloaddition to
ethyl cyanoformate, leading to the corresponding fused imidazo-
azaheterocycles. This is the case of isoquinoline and phthalazine
derivatives (Scheme 9).
chemical shift multiplicities: s¼singlet, d¼doublet, t¼triplet,
q¼quartet, m¼multiplet. All chemical shifts are quoted on the
d-
scale in ppm. Coupling constants are given in Hz. Mass spectra were
recorded on a HRMS Thermo Scientific Q Exactive spectrometer
Scheme 9. The proposed mechanism for the synthesis of the new fused imidazoheterocycles derivatives.
3. Conclusion
using DART in the positive mode; m/z values are reported in Dal-
tons. IR spectra were recorded on a FTIR Shimadzu or Jasco 660 plus
FTIR spectrophotometer. The microanalyses were in satisfactory
agreement with the calculated values: C, ꢂ0.15; H, ꢂ0.10; N, ꢂ0.30.
Thin layer chromatography (TLC) was carried out on Merck silica
gel 60F254 plates. Column chromatography was carried out on silica
gel (Roth 60, 0.04e0.063 mm). Visualization of the plates was
achieved using a UV lamp (lmax¼254 or 365 nm). All commercially
available products were used without further purification unless
otherwise specified.
Reactions of cycloimmonium salts with ethyl cyanoformate in
basic conditions undergo two different pathways depending of the
availability of the g-position of the heterocycle for a nucleophilic
cyanation. Thus, for 1,10-phenanthrolin-1-ium salts, 1,7-
phenanthrolin-7-ium salts, 4,7-phenanthrolin-4-ium salts and
quinolinium salts, ethyl cyanoformate acts as a source of cyanide
ion, leading selectively to the corresponding
compounds. In case of isoquinolinium and phthalazinium ylides
having bridged -position, ethyl cyanoformate acts as dipolarophile
g-cyano substituted
g
in 3þ2 dipolar cycloaddition, leading to new two classes of com-
pound with imidazo[2,1-a]isoquinoline and imidazo[2,1-a]phtala-
zine skeleton, respectively. From the reaction mixtures of
phthalazinium ylides with ethyl cyanoformate we isolated as by-
products
zine dimers.
4.2. X-ray crystallography
Crystallographic measurements for 3a, 5b and 21b were carried
out on a SuperNova, Dual, Cu at zero, Eos diffractometer. Single
crystals of compound 3a, 5b and 21b were obtained by crystalli-
zation from chloroform/methanol (1/1, v/v). A suitable crystal was
selected and used for the determination of structure using single
crystal X-ray diffraction method. The crystal was kept at 294 K
during data collection. The unit cell determination and data in-
tegration were carried out using the CrysAlisPro package of Oxford
Diffraction. Using Olex2,29 the structure was solved with the
ShelXS29 or ShelXT30 structure solution program using Direct
Methods and refined with the ShelXL31 refinement package using
Least Squares minimization.
8,8a,16,16a-tetrahydropyrazino[2,1-a:5,4-a0]diphthala-
4. Experimental section
4.1. Chemistry
All the reagents and solvents employed were used without
€
further purification. Melting points were recorded on an A. Kruss
Optronic Melting Point Meter KSPI and are uncorrected. Proton and
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6
C.M. Al Matarneh et al. / Tetrahedron xxx (2016) 1e9
The main crystallographic data together with refinement details
for C21H12ClN3O2: C 67.48; H 3.24; N 11.24. Found: C 67.45; H 3.19; N
11.32.
are summarized in Tables S1eS22 (ESI). CCDC 1453425 (3a),
1454004 (5b) and 1471832 (21b) contain the full crystallographic
data. These data can be obtained free of charge from the Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_-
request/cif.
4.4.3. Methyl 2-(4-cyano-2-oxo-1,10-phenanthrolin-1(2H)-yl) ace-
tate (3c). Obtained by general procedure at reflux. Purified by
column chromatography (DCM/MeOH (99/1, v/v)), then crystallized
from CHCl3/MeOH 1/1, v/v. Yellow solid, 45% yield;
mp¼189e193 ꢀC. Rf (1% MeOH/CH2Cl2) 0.72. IR (KBr),
n
(cmꢁ1):
4.3. Experimental procedure for synthesis of compounds 1, 4,
6, 9, 14, and 19
3026, 2924, 2236, 1748, 1667, 1612, 1543, 1462, 1219. 1H NMR
(CDCl3, 500 MHz, d(ppm)): 3.78 (1H, s, OMe), 5.95 (2H, s, H-15), 7.37
(1H, s, H-3), 7.58 (1H, dd, J¼8.5, 4.0 Hz, H-8), 7.74 (1H, d, J¼9.0 Hz,
1,10-Phenanthrolin-1-ium halides 1 were synthesized using the
procedure reported in Ref. 18, 1,7-phenanthrolin-7-ium salts 4 us-
ing the procedure reported in Ref. 22, 4,7-phenanthrolin-4-ium
salts 6 as in Ref. 23, quinolinium salts 9 as in Ref. 24, iso-
quinolinium salts 14 as in Refs. 25,26 and phthalazinium bromides
19 as in Ref. 27.
H-5), 8.02 (1H, d, J¼8.5 Hz, H-6), 8.25 (1H, dd, J¼8.5, 1.5 Hz, H-7),
8.28 (1H, dd, J¼4.0, 1.5 Hz, H-9). 13C NMR (CDCl3, 125 MHz,
d(ppm)):
50.3 (C-15), 52.5 (OMe), 114.8 (CN), 117.2 (C-13), 123.2 (C-8), 123.8
(C-4), 123.9 (C-6), 124.3 (C-5), 129.0 (C-3), 131.0 (C-12), 137.8 (C-11),
136.9 (C-7), 139.1 (C-14), 147.9 (C-9), 161.2 (C-2), 169.5 (C-16). Anal.
Calcd for C17H11N3O4: C 63.55; H 3.45; N 13.08. Found: C 63.45; H
3.40; N 13.15.
4.4. General procedure for synthesis of compounds 3, 5, 7, 8,
10, 15, 20 and 21
4.4.4. 2-(10-Cyano-1,7-phenanthrolin-7(10H)-yl)acetamide
(5a). Obtained by general procedure at reflux. Purified by crystal-
lization from CHCl3/MeOH 1/1, v/v. Brown solid, 98% yield;
The corresponding cycloimmonium salt (1 mmol, 1 equiv) and
ethyl cyanoformate (1.1 mmol, 1.1 equiv) were added to 5 mL of
dichloromethane and the obtained suspension was stirred under
N2 atmosphere at room temperature (rt). Triethylamine (TEA)
(3 mmol, 3 equiv) was added drop-wise over 30 min (magnetic
stirring) and the resulting mixture was then stirred for 24 h at
room temperature or reflux. Methanol (5 mL) was added and the
resulting mixture was kept for 24 h without stirring. In most of
the reaction a precipitate formed and it was collected by filtration
to give a powder which was washed with few mL methanol. The
product was crystallized from an appropriate solvent. For every
reaction mixture, parallel, we carried out column chromatogra-
phy of the reaction mixture in order to identify eventual
coproducts.
mp¼202e205 ꢀC. Rf (1% MeOH/CH2Cl2) 0.72. IR (KBr),
n
(cmꢁ1):
3387, 3202, 2234, 1670, 1610, 827. 1H NMR (DMSO-d6, 500 MHz,
d
(ppm)): 4.30 (1H, d, J¼17.5 Hz, H-15a), 4.40 (1H, d, J¼17.5 Hz, H-
15b), 4.89 (1H, dd, J¼7.5, 5.0 Hz, H-9), 5.75 (1H, d, J¼5.0 Hz, H-10),
6.55 (1H, d, J¼8.0 Hz, H-8), 7.15 (1H, d, J¼9.5 Hz, H-6), 7.25 (1H, s,
NH), 7.43 (1H, dd, J¼8.0 4.5 Hz, H-3), 7.60 (1H, s, NH), 7.91 (1H, dd,
J¼9.0 Hz, H-5), 8.27 (1H, d, J¼8.0 Hz, H-4), 8.91 (1H, d, J¼3.5 Hz, H-
2). 13C NMR (DMSO-d6, 125 MHz,
d(ppm)): 25.5 (C-10), 52.1 (C-15),
92.2 (C-9), 106.7 (CN), 115.0 (C-6), 119.2 (C-3), 120.9 (C-13), 123.2 (C-
11), 128.8 (C-5), 135.4 (C-8), 135.8 (C-4), 140.4 (C-12), 145.6 (C-14),
150.6 (C-2), 170.0 (C-16). Anal. Calcd for C15H12N4O: C 68.17; H 4.58;
N 21.20. Found: C 68.45; H 4.48; N 21.32.
4.4.5. 7-(2-(p-Tolyl)ethyl)-7,10-dihydro-1,7-phenanthroline-10-
carbonitrile (5b). Obtained by general procedure, at room temper-
ature or reflux. Purified by crystallization from CHCl3/MeOH 1/1, v/
v. Brown solid, 40% yield; mp¼197e200 ꢀC. Rf (1% MeOH/CH2Cl2)
4.4.1. 1-(2-(4-Methoxyphenyl)-2-oxoethyl)-2-oxo-1,2-dihydro-1,10-
phenanthroline-4-carbonitrile (3a). Obtained by general procedure,
at room temperature. Purified by column chromatography
(dichloromethane (DCM)/DCM/MeOH (98/2, v/v)), then crystal-
lized from CHCl3/MeOH, 1/1, v/v. Yellow solid, 50% yield;
0.76. IR (KBr),
(CDCl3, 500 MHz,
n
(cmꢁ1): 2227, 1681, 1604, 1226, 1177, 796. 1H NMR
d
(ppm)): 2.46 (1H, s, Me), 4.89 (1H, d, J¼18.5 Hz,
mp¼251e253 ꢀC. Rf (CH2Cl2) 0.55. IR (KBr),
n
(cmꢁ1): 2168, 1655,
H-15a), 5.06 (1H, dd, J¼7.5, 5.5 Hz, H-9), 5.27 (1H, d, J¼18.5 Hz, H-
15b), 6.00 (1H, s, H-10), 6.29 (1H, d, J¼8.0 Hz, H-8), 6.84 (1H, d,
J¼9.0 Hz, H-6), 7.35 (2H, d, J¼8.0 Hz, H-30), 7.38 (1H, dd, J¼8.0,
3.0 Hz, H-3), 7.65 (1H, d, J¼9.0 Hz, H-5), 7.93 (2H, d, J¼8 Hz, H-20),
8.07 (1H, d, J¼8.0 Hz, H-4), 8.95 (1H, d, J¼3.0 Hz, H-2). 13C NMR
1595, 1236. 1H NMR (CDCl3, 500 MHz,
d(ppm)): 3.93 (1H, s, OMe),
6.62 (2H, s, H-15), 7.03 (2H, d, J¼8.5 Hz, H-30), 7.42 (1H, s, H-3), 7.44
(1H, dd, J¼8.0, 4.5 Hz, H-8), 7.72 (1H, d, J¼8.5 Hz, H-5), 8.04 (3H, m,
H-20, H-6), 8.21 (1H, d, J¼8.0 Hz, H-7), 8.38 (1H, s, H-9). 13C NMR
(DMSO-d6 125 MHz,
d
(ppm)): 53.6 (C-15), 55.7 (OMe), 114.2 (C-30),
(CDCl3, 125 MHz, d(ppm)): 22.0 (Me), 26.0 (C-10), 56.4 (C-15), 94.8
114.8 (CN), 117.4 (C-12), 123.1 (C-8), 123.5 (C-5), 124.0 (C-20), 124.3
(C-4), 128.7 (C-10), 129.2 (C-3), 130.2 (C-6), 130.9 (C-13), 137.7 (C-7,
C-14, C-11), 147.34 (C-9), 161.0 (C-2), 163.5 (C-40), 191.3 (C-16). Anal.
Calcd for C22H15N3O3: C 71.54; H 4.09; N 11.38. Found: C 71.79; H
4.02; N 11.45.
(C-9), 106.5 (CN), 114.8 (C-6), 119.3 (C-3), 120.7 (C-13), 124.2 (C-11),
128.2 (C-20), 129.1 (C-5), 130.0 (C-30), 132.0 (C-10), 134.7 (C-8, C-4),
140.9 (C-12), 145.7 (C-40, C-14), 150.2 (C-2), 193.3 (C-16). Anal. Calcd
for C22H17N3O: C 77.86; H 5.05; N 12.38. Found: C 77.90; H 5.00; N
12.41.
4.4.2. 1-(2-(4-Chlorophenyl)-2-oxoethyl)-2-oxo-1,2-dihydro-1,10-
phenanthroline-4-carbonitrile (3b). Obtained by general procedure
at room temperature or reflux. Purified crystallization from CHCl3/
MeOH 1/1, v/v. Yellow solid, 45% yield; mp¼260e262 ꢀC. Rf (1%
4.4.6. 7-(2-(4-Chlorophenyl)-2-oxoethyl)-7,10-dihydro-1,7-
phenanthroline-10-carbonitrile (5c). Obtained by general pro-
cedure, at room temperature. Purified by column chromatography
(dichloromethane (DCM)/DCM/MeOH (97/3, v/v)), then crystal-
lized from CHCl3/MeOH, 1/1, v/v. Yellow solid, 55% yield;
MeOH/CH2Cl2) 0.72. IR (KBr),
1407, 994, 840. 1H NMR (CDCl3, 500 MHz,
n
(cmꢁ1): 3064, 2248, 1694, 1662, 1461,
d
(ppm)): 6.62 (2H, s, H-
mp¼191e193 ꢀC. Rf (1% MeOH/CH2Cl2) 0.72. IR (KBr),
n
(cmꢁ1):
d(ppm)):
15), 7.43 (1H, s, H-3), 7.44 (1H, dd, J¼8.5, 4.0 Hz, H-8), 7.56 (2H, d,
J¼8.5 Hz, H-30), 7.73 (1H, d, J¼8.5 Hz, H-5), 8.06 (3H, m, H-20, H-6),
8.20 (1H, dd, J¼8.5,1.5 Hz, H-7), 8.28 (1H, d, J¼2.5 Hz, H-9). 13C NMR
2230, 1688, 1222, 1089, 824. 1H NMR (DMSO-d6, 500 MHz,
4.94 (1H, dd, J¼8.0, 4.5 Hz, H-9), 5.42 (1H, d, J¼19.5 Hz, H-15a), 5.59
(1H, d, J¼19 Hz, H-15b), 5.80 (1H, d, J¼4.5 Hz, H-10), 6.56 (1H, d,
J¼7.5 Hz, H-8), 7.20 (1H, d, J¼9.5 Hz, H-6), 7.43 (1H, dd, J¼7.5,
4.0 Hz, H-3), 7.69 (2H, d, J¼8.0 Hz, H-19), 7.82 (1H, dd, J¼9.0 Hz, H-
5), 8.08 (2H, d, J¼8 Hz, H-18), 8.26 (1H, d, J¼8.5 Hz, H-4), 8.92 (1H, d,
(CDCl3,125 MHz, d(ppm)): 53.6 (C-15),114.9 (CN),117.4 (C-12),123.1
(C-8), 123.8 (C-4), 124.1 (C-6), 124.2 (C-5), 128.9 (C-3), 129.3 (C-30),
129.6 (C-20),130.9 (C-13),134.2 (C-10),137.1 (C-7),137.3 (C-11),138.4
(C-14), 139.7 (C-40), 147.5 (C-9), 161.2 (C-2), 191.0 (C-16). Anal. Calcd
J¼2.5 Hz, H-2). 13C NMR (DMSO-d6, 125 MHz,
d(ppm)): 25.3 (C-10),
Please cite this article in press as: Al Matarneh, C. M.; et al., Tetrahedron (2016), http://dx.doi.org/10.1016/j.tet.2016.05.061

C.M. Al Matarneh et al. / Tetrahedron xxx (2016) 1e9
7
55.9 (C-15), 92.8 (C-9), 106.7 (CN), 115.6 (C-6), 119.2 (C-3), 120.9 (C-
13), 123.3 (C-11), 128.7 (C-5), 129.0 (C-30), 130.0 (C-20), 133.4 (C-10),
135.0 (C-8),135.8 (C-4),138.8 (C-40),140.5 (C-12),145.6 (C-14),150.5
(C-2), 194.2 (C-16). Anal. Calcd for C21H14ClN3O: C 70.10; H 3.92; N
11.68. Found: C 70.08; H 3.88; N 11.72.
3016, 2918, 2309, 1691, 1649, 1504, 1231, 1096, 818. 1H NMR (CDCl3,
500 MHz,
d
(ppm)): 5.97 (2H, s, H-15), 7.41 (1H, d, J¼9.5 Hz, H-5),
7.44 (1H, s, H-2), 7.57 (2H, d, J¼8.5 Hz, H-30), 7.67 (1H, dd, J¼8.5,
4.0 Hz, H-9), 8.05 (2H, d, J¼8.5 Hz, H-20), 8.29 (1H, d, J¼9.5 Hz, H-6),
9.00 (1H, d, J¼3.5 Hz, H-8), 9.82 (1H, d, J¼9.0 Hz, H-10). 13C NMR
(CDCl3, 125 MHz, d(ppm)): 49.9 (C-15), 110.9 (C-11), 117.9 (C-1),
4.4.7. 2-(1-Cyano-4,7-phenanthrolin-4(1H)-yl)acetamide
(7a). Obtained by general procedure at reflux. Purified by crystal-
lization from CHCl3/MeOH 1/1, v/v. Yellow solid, 91% yield;
118.3 (C-5), 120.6 (CN), 123.4 (C-9), 124.8 (C-14), 129.7 (C-20), 129.8
(C-30), 131.0 (C-10), 131.1 (C-2), 132.7 (C-10), 135.9 (C-6), 140.4 (C-
12), 141.5 (C-40), 144.8 (C-13), 150.3 (C-8), 159.3 (C-3), 190.1 (C-16).
Anal. Calcd for C21H12ClN3O2: C 67.48; H 3.24; N 11.24. Found: C
67.51; H 3.20; N 11.29.
mp¼244e245 ꢀC. Rf (1% MeOH/CH2Cl2) 0.76. IR (KBr),
n
(cmꢁ1):
3341, 3168, 3055, 2193, 1675, 1673, 1503, 795. 1H NMR (DMSO-d6,
500 MHz,
d
(ppm)): 4.30 (1H, d, J¼17.5 Hz, H-15a), 4.41 (1H, d,
J¼17.5 Hz, H-15b), 4.82 (1H, dd, J¼7.5, 4.5 Hz, H-2), 5.80 (1H, d,
J¼4.5 Hz, H-1), 6.57 (1H, d, J¼8.0 Hz, H-3), 7.26 (1H, s, NH), 7.30 (1H,
d, J¼9.5 Hz, H-5), 7.60 (2H, m, H-9, NH), 8.33 (1H, d, J¼8.5 Hz, H-6),
8.33 (1H, d, J¼7.5 Hz, H-10), 8.78 (1H, d, J¼4.0 Hz, H-8). 13C NMR
4.4.11. 1-(2-(4-Methoxyphenyl)-2-oxoethyl)-2-oxo-1,2-
dihydroquinoline-4-carbonitrile (10a). Obtained by general pro-
cedure, at room temperature. Purified by column chromatography
(dichloromethane (DCM)/DCM/MeOH (97/3, v/v)), then crystal-
lized from CHCl3/MeOH, 1/1, v/v. Yellow solid, 40% yield;
(DMSO-d6, 125 MHz, d(ppm)): 25.9 (C-1), 52.2 (C-15), 90.4 (C-2),
104.7 (CN), 118.0 (C-5), 120.1 (C-11), 122.2 (C-9), 126.3 (C-14), 129.8
(C-10), 130.3 (C-6), 135.7 (C-3), 137.7 (C-12), 144.2 (C-8), 147.6 (C-
13), 170.0 (C-16). Anal. Calcd for C15H12N4O: C 68.17; H 4.58; N
21.20. Found: C 68.19; H 4.51; N 21.24.
mp¼195e197 ꢀC. Rf (1% MeOH/CH2Cl2) 0.58. IR (KBr),
n
(cmꢁ1):
2924, 2309, 1680, 1659, 1601, 1265, 1240, 1175. 1H NMR (CDCl3,
500 MHz, d(ppm)): 3.92 (3H, s, OMe), 5.77 (2H, s, H-11), 7.02 (2H, d,
J¼8.5 Hz, H-30), 7.05 (1H, d, J¼8.5 Hz, H-5), 7.20 (1H, s, H-3), 7.37
(1H, t, J¼7.5 Hz, H-7), 7.59 (1H, dt, J¼7.5, 1.0 Hz, H-6), 7.98 (1H, dd,
J¼8.0, 1.0 Hz, H-8), 8.06 (2H, d, J¼8.5 Hz, H-20). 13C NMR (CDCl3,
4.4.8. 4-(2-(4-Methoxyphenyl)-2-oxoethyl)-1,4-dihydro-4,7-
phenanthroline-1-carbonitrile (7c). Obtained by general procedure,
at room temperature. Purified by column chromatography
(dichloromethane (DCM)/DCM/MeOH (97/3, v/v)), then crystal-
lized from CHCl3/MeOH, 1/1, v/v. Yellow solid, 52% yield;
125 MHz, d
(ppm)): 48.8 (C-11), 55.8 (OMe), 114.4 (C-30), 114.7 (CN),
115.0 (C-5), 117.5 (C-9), 123.7 (C-7, C-4), 127.2 (C-8), 127.7 (C-10),
128.5 (C-3), 130.7 (C-20), 132.8 (C-6), 139.9 (C-10), 160.0 (C-2), 164.6
(C-40), 189.7 (C-12). Anal. Calcd for C19H14N2O3: C 71.69; H 4.43; N
8.80. Found: C 71.65; H 4.40; N 8.88.
mp¼157e160 ꢀC. Rf (CH2Cl2) 0.71. IR (KBr),
n
(cmꢁ1): 2167, 1674,
(ppm)): 3.91(3H, s,
1601,1237,1176, 829. 1H NMR (CDCl3, 500 MHz,
d
OMe), 4.85 (1H, d, J¼17.5 Hz, H-15a), 4.96 (1H, dd, J¼7.5, 5.0 Hz, H-
2), 5.27 (1H, d, J¼17.5 Hz, H-15b), 5.51 (1H, d, J¼5.0 Hz, H-1), 6.32
(1H, d, J¼7.5 Hz, H-3), 7.03 (3H, ad, J¼9.5 Hz, H-30, H-5), 7.50 (1H,
dd, J¼8.5, 4.5 Hz, H-9), 7.96 (1H, d, J¼9.0 Hz, H-6), 8.01 (2H, d,
J¼9.0 Hz, H-20), 8.19 (1H, d, J¼9.0 Hz, H-10), 8.82 (1H, dd, J¼4.0,
4.4.12. 1-(2-(4-Chlorophenyl)-2-oxoethyl)-2-oxo-1,2-
dihydroquinoline-4-carbonitrile (10b). Obtained by general pro-
cedure, at room temperature. Purified by column chromatography
(dichloromethane (DCM)/DCM/MeOH (97/3, v/v)), then crystal-
lized from CHCl3/MeOH, 1/1, v/v. Pale yellow solid, 40% yield;
1.0 Hz, H-8). 13C NMR (CDCl3, 125 MHz,
d(ppm)): 26.9 (C-1), 55.8
mp¼145e146 ꢀC. Rf (1% MeOH/CH2Cl2) 0.61. IR (KBr),
n
(cmꢁ1):
(OMe), 56.2 (C-15), 92.0 (C-2), 105.3 (CN), 114.5 (C-30), 117.4 (C-5),
119.5 (C-11), 122.5 (C-9), 127.0 (C-14), 127.5 (C-10), 129.6 (C-10),
131.6 (C-6), 130.5 (C-20), 135.1 (C-3), 137.7 (C-12), 145.1 (C-13), 148.1
(C-8), 164.6 (C-40)192.1 (C-16). Anal. Calcd for C22H17N3O2: C 74.35;
H 4.82; N 11.82. Found: C 74.38; H 4.80; N 11.88.
2922, 2308, 1692, 1651, 1589, 1230, 1094, 991, 752. 1H NMR (CDCl3,
500 MHz,
d
(ppm)): 5.76 (2H, s, H-11), 7.03 (1H, d, J¼8.5 Hz, H-5),
7.20 (1H, s, H-3), 7.39 (1H, t, J¼7.5 Hz, H-7), 7.54 (2H, d, J¼8.5 Hz, H-
30), 7.60 (1H, t, J¼7.5 Hz, H-6), 7.99 (1H, d, J¼8.0 Hz, H-8), 8.02 (2H,
d, J¼8.0 Hz, H-20). 13C NMR (CDCl3, 125 MHz,
d(ppm)): 49.1 (C-11),
114.5 (CN),114.8 (C-5),117.6 (C-9), 123.8 (C-7, C-4),127.3 (C-8),128.4
(C-3), 129.6 (C-20), 129.7 (C-30), 132.9 (C-6, C-10), 139.7 (C-10), 141.2
(C-40), 159.9 (C-2), 190.4 (C-12). Anal. Calcd for C18H11ClN2O2: C
66.99; H 3.44; N 8.68. Found: C 67.01; H 3.40; N 8.78.
4.4.9. 4-(2-(4-Methoxyphenyl)-2-oxoethyl)-3-oxo-3,4-dihydro-4,7-
phenanthroline-1-carbonitrile (8b). Obtained by general procedure,
at room temperature. Purified by column chromatography
(dichloromethane (DCM)/DCM/MeOH (97/3, v/v)), then crystal-
lized from CHCl3/MeOH, 1/1, v/v. Yellow solid, 20% yield;
4.4.13. 2-(4-Cyano-2-oxoquinolin-1(2H)-yl)acetamide
(10c). Obtained by general procedure at reflux. Purified by column
chromatography (dichloromethane (DCM)/DCM/MeOH (97/3, v/
v)), then crystallized from CHCl3/MeOH, 1/1, v/v. Yellow solid, 65%
yield; mp¼249e251 ꢀC. Rf (1% MeOH/CH2Cl2) 0.60. IR (KBr),
mp¼284e285 ꢀC. Rf (1% MeOH/CH2Cl2) 0.51. IR (KBr),
n
(cmꢁ1):
3028, 2814, 2224, 1688, 1661, 1601, 1505, 1238, 1182, 837. 1H NMR
(DMSO-d6, 500 MHz, d(ppm)): 3.90 (3H, s, OMe), 6.12 (2H, s, H-15),
7.16 (2H, d, J¼9.0 Hz, H-30), 7.69 (1H, s, H-2), 7.85 (1H, dd, J¼8.5,
4.0 Hz, H-9), 7.97 (1H, d, J¼9.5 Hz, H-5), 8.15 (2H, d, J¼8.5 Hz, H-20),
8.26 (1H, d, J¼10.0 Hz, H-6), 9.00 (1H, dd, J¼4.5, 1.0 Hz, H-8), 9.68
n
(cmꢁ1): 3393, 3192, 2918, 2849, 2236, 1678, 1657, 1593, 1422, 1292,
891. 1H NMR (DMSO-d6, 500 MHz,
d(ppm)): 4.90 (2H, s, H-11), 7.33
(1H, d, J¼8.5 Hz, H-10). 13C NMR (DMSO-d6, 125 MHz,
d
(ppm)): 50.1
(1H, s, NH), 7.42e7.48 (2H, m, H-5, H-7), 7.48 (1H, s, H-3), 7.70 (1H,
(C-15), 55.8 (OMe), 109.7 (C-11), 114.2 (C-30), 117.9 (C-1), 119.5 (CN),
120.0 (C-5),123.0 (C-9),123.7 (C-14),127.3 (C-10),130.5 (C-10),130.6
(C-2), 130.8 (C-20), 134.6 (C-6), 140.5 (C-12), 144.0 (C-13), 150.0 (C-
8), 158.8 (C-3), 164.0 (C-40), 190.7 (C-16). Anal. Calcd for
s, NH), 7.75 (1H, t, J¼8.5 Hz, H-6), 7.85 (1H, d, J¼8.0 Hz, H-8). 13
C
NMR (DMSO-d6,125 MHz, d(ppm)): 44.9 (C-11),114.6 (CN),115.6 (C-
5),116.5 (C-4),122.0 (C-9),123.4 (C-7), 125.8 (C-8),129.1 (C-3),132.6
(C-6), 139.7 (C-10), 159.2 (C-2), 168.1 (C-12). Anal. Calcd for
C
22H15N3O3: C 71.54; H 4.09; N 11.38. Found: C 71.52; H 4.01; N
C12H9ClN3O2: C 63.43; H 3.99; N 18.49. Found: C 63.40; H 3.96; N
11.42.
18.52.
4.4.10. 4-(2-(4-Chlorophenyl)-2-oxoethyl)-3-oxo-3,4-dihydro-4,7-
phenanthroline-1-carbonitrile (8c). Obtained by general procedure,
at room temperature. Purified by column chromatography
(dichloromethane (DCM)/DCM/MeOH (97/3, v/v)), then crystal-
lized from CHCl3/MeOH, 1/1, v/v. Yellow solid, 40% yield;
4.4.14. 1-Formyl-1,2,3,4-tetrahydroquinoline-2-carbonitrile
(13). Obtained by general procedure, at room temperature. Purified
by column chromatography (dichloromethane (DCM)/DCM/
MeOH (97/3, v/v)), then crystallized from CHCl3/MeOH, 1/1, v/v.
Brown solid, w5% yield; mp¼189e190 ꢀC. Rf (CH2Cl2) 0.62. IR (KBr),
mp¼282e283 ꢀC. Rf (1% MeOH/CH2Cl2) 0.51. IR (KBr),
n
(cmꢁ1):
n
(cmꢁ1): 2928, 2245, 1680, 1649, 1586, 1495, 1259, 764. 1H NMR
Please cite this article in press as: Al Matarneh, C. M.; et al., Tetrahedron (2016), http://dx.doi.org/10.1016/j.tet.2016.05.061

8
C.M. Al Matarneh et al. / Tetrahedron xxx (2016) 1e9
(CDCl3, 500 MHz,
d
(ppm)): 2.12e2.16 (1H, m, H-3a), 2.24e2.28 (1H,
d, J¼8.5 Hz, H-30), 7.84 (1H, t, J¼7.5 Hz, H-7), 7.89 (2H, d, J¼8.5 Hz,
H-20), 7.94 (1H, d, J¼8.0 Hz, H-6), 8.00 (1H, t, J¼7.5 Hz, H-8), 8.73
(1H, s, H-5), 8.96 (1H, d, J¼8.0 Hz, H-9). 13C NMR (CDCl3, 125 MHz,
m, H-3b), 2.80e2.85 (1H, m, H-4a), 3.05e3.11 (1H, m, H-4b), 5.61
(2H, d, J¼5.0 Hz, H-2), 8.72 (1H, s, H-11). 13C NMR (CDCl3, 125 MHz,
d(ppm)): 24.2 (C-4), 26.1 (C-3), 39.8 (C-2), 117.0 (CN), 117.7 (C-8),
d
(ppm)): 14.0 (CH2CH3), 55.8 (OMe), 61.8 (CH2CH3), 114.3 (C-30),
126.0 (C-7), 126.9 (C-9), 128.1 (C-6), 130.1 (C-5), 134.4 (C-10), 160.3
123.6 (C-13), 124.2 (C-9), 125.0 (C-10), 128.2 (C-6), 130.4 (C-2), 130.7
(C-10), 131.0 (C-7), 131.6 (C-3), 132.4 (C-20), 134.2 (C-8), 137.1 (C-11),
148.3 (C-5), 161.7 (C-14), 164.8 (C-40), 184.9 (C-15). Anal. Calcd for
(C-11). MS (DARTþ) (m/z): 187.09 (MþHþ). HRMS (DARTþ) calcd for
C
11H11N2O (MHþ) 187.0871. Found: 187.0874.
C21H17N3O4: C 67.19; H 4.56; N 11.19. Found: C 67.15; H 4.49; N 11.21.
4.4.15. Ethyl 3-carbamoylimidazo[2,1-a]isoquinoline-2-carboxylate
(15a). Obtained by general procedure, at reflux. Purified by col-
umn chromatography (dichloromethane (DCM)/DCM/MeOH (99/
1, v/v)), then crystallized from CHCl3/MeOH, 1/1, v/v. Beige solid,
50% yield; mp¼250e253 ꢀC. Rf (1% MeOH/CH2Cl2) 0.54. IR (KBr),
4.4.19. Ethyl
3-([1,10-biphenyl]-4-carbonyl)imidazo[2,1-a]phthala-
zine-2-carboxylate (20b). Obtained by general procedure, at room
temperature. Purified by column chromatography (dichloromethane
(DCM)/DCM/MeOH (99/1, v/v)), then crystallized from CHCl3/
MeOH, 1/1, v/v. Yellow solid, 37% yield; mp¼180e182 ꢀC. Rf (CH2Cl2)
n
(cmꢁ1): 3290, 3142, 2916, 2848, 1700, 1683, 1607, 1366, 1232. 1H
NMR (CDCl3, 500 MHz,
d
(ppm)): 1.08 (3H, t, J¼7.0 Hz, CH2CH3), 4.03
0.60. IR (KBr),
1H NMR (CDCl3, 500 MHz,
n
(cmꢁ1): 3030, 1722, 1657, 1603, 1526, 1219, 1184, 743.
(2H, q, J¼7.0 Hz, CH2CH3), 5.86 (1H, NH), 7.28 (1H, d, J¼7.5 Hz, H-5),
d(ppm)): 1.07 (3H, t, J¼7.0 Hz, CH2CH3),
7.69 (2H, m, H-7, H-8), 7.78 (1H, dd, J¼8.5, 3.0 Hz, H-6), 8.79 (1H, dd,
4.24 (2H, q, J¼7.0 Hz, CH2CH3), 7.40 (1H, t, J¼7.5 Hz, H-400), 7.46 (2H, t,
J¼7.5 Hz, H-300), 7.62 (2H, d, J¼7.5 Hz, H-200), 7.70 (2H, d, J¼9.0 Hz, H-
30), 7.82 (1H, t, J¼7.5 Hz, H-7), 7.94 (1H, d, J¼7.5 Hz, H-6), 7.96e8.00
(3H, m, H-20, H-8), 8.73 (1H, s, H-5), 8.84 (1H, d, J¼8.0 Hz, H-9). 13C
J¼8.5, 3.0 Hz, H-9), 9.60 (1H, d, J¼7.5 Hz, H-4), 10.02 (1H, NH). 13
C
NMR (CDCl3, 125 MHz, d(ppm)): 13.9 (CH2CH3), 61.8 (CH2CH3), 116.0
(C-5), 122.9 (C-2), 123.1 (C-11), 124.7 (C-9), 125.3 (C-4), 127.0 (C-6),
128.7 (C-8), 130.3 (C-7), 130.6 (C-10), 134.6 (C-3), 144.2 (C-12), 161.6
(C-14), 166.1 (C-13). Anal. Calcd for C15H13N3O3: C 63.60; H 4.63; N
14.83. Found: C 63.56; H 4.60; N 14.86.
NMR (CDCl3, 125 MHz, d(ppm)): 13.9 (CH2CH3), 61.7 (CH2CH3), 123.5
(C-13),123.7 (C-9),124.5 (C-200), 125.4 (C-10), 127.5 (C-30),128.2 (C-6),
128.6 (C-400), 129.1 (C-300), 130.3 (C-2), 130.4 (C-20), 130.7 (C-7), 132.7
(C-3), 134.1 (C-8), 136.1 (C-10), 137.4 (C-11), 139.7 (C-100), 147.0 (C-40),
148.2 (C-5), 162.1 (C-14), 186.3 (C-15). Anal. Calcd for C26H19N3O3: C
74.10; H 4.54; N 9.97. Found: C 74.06; H 4.46; N 10.01.
4.4.16. Ethyl 3-(4-methoxybenzoyl)imidazo[2,1-a]isoquinoline-2-
carboxylate (15b). Obtained by general procedure, at room tem-
perature. Purified by column chromatography (dichloromethane
(DCM)/DCM/MeOH (97/3, v/v)), then crystallized from CHCl3/
MeOH, 1/1, v/v. Yellow solid, 40% yield; mp¼137e140 ꢀC. Rf (1%
4.4.20. Ethyl 3-(4-bromobenzoyl)imidazo[2,1-a]phthalazine-2-
carboxylate (20c). Obtained by general procedure, at room tem-
perature. Purified by column chromatography (dichloromethane
(DCM)/DCM/MeOH (99/1, v/v)), then crystallized from CHCl3/
MeOH, 1/1, v/v. Yellow solid, 35% yield; mp¼243e245 ꢀC. Rf (1%
MeOH/CH2Cl2) 0.78. IR (KBr),
1323, 1251, 1177, 1028. 1H NMR (CDCl3, 500 MHz,
n
(cmꢁ1): 2922, 1730, 1628, 1591, 1504,
d
(ppm)): 0.98 (3H,
t, J¼7.0 Hz, CH2CH3), 3.87 (3H, s, OMe), 4.04 (2H, q, J¼7.0 Hz,
CH2CH3), 6.94 (2H, d, J¼8.5 Hz, H-30), 7.24 (1H, d, J¼7.5 Hz, H-5),
7.67e7.71 (2H, m, H-7, H-8), 7.75 (1H, dd, J¼7.0, 2.0 Hz, H-6), 7.87
(2H, d, J¼8.5 Hz, H-20), 8.42 (1H, d, J¼7.0 Hz, H-4), 8.60 (1H, dd,
MeOH/CH2Cl2) 0.62. IR (KBr),
1212, 1175, 754. 1H NMR (CDCl3, 500 MHz,
n
(cmꢁ1): 2986, 1735, 1660, 1583, 1525,
d(ppm)): 1.11 (3H, t,
J¼7.0 Hz, CH2CH3), 4.25 (2H, q, J¼7.0 Hz, CH2CH3), 7.62 (2H, d,
J¼8.5 Hz, H-30), 7.78 (2H, d, J¼8.5 Hz, H-20), 7.82 (1H, t, J¼7.5 Hz, H-7),
7.94 (1H, d, J¼8.0 Hz, H-6), 7.98 (1H, t, J¼7.5 Hz, H-8), 8.72 (1H, s, H-
J¼7.0, 1.5 Hz, H-9). 13C NMR (CDCl3, 125 MHz,
d(ppm)): 13.8
(CH2CH3), 55.7 (OMe), 61.7 (CH2CH3), 114.0 (C-30), 116.0 (C-5), 122.9
(C-4), 123.2 (C-11), 124.8 (C-9), 125.88 (C-2), 127.1 (C-6), 128.9 (C-8),
130.2 (C-7), 130.6 (C-10), 131.8 (C-20), 132.0 (C-10), 137.9 (C-3), 144.3
(C-12), 162.9 (C-13), 164.2 (C-40), 185.6 (C-14). Anal. Calcd for
5), 8.82 (1H, d, J¼8.0 Hz, H-9). 13C NMR (CDCl3, 125 MHz,
d(ppm)):
13.9 (CH2CH3), 61.8 (CH2CH3), 123.5 (C-13),123.7 (C-9),125.4 (C-10),
128.2 (C-6), 129.7 (C-40), 130.2 (C-2), 130.8 (C-7), 131.2 (C-20), 132.3
(C-30), 133.1 (C-3), 134.1 (C-8), 136.2 (C-10), 137.6 (C-11), 148.2 (C-5),
162.0 (C-14), 185.8 (C-15). Anal. Calcd for C20H14BrN3O3: C 56.62; H
3.33; N 9.90. Found: C 56.60; H 3.27; N 9.93.
C
22H18N2O4: C 70.58; H 4.85; N 7.48. Found: C 70.55; H 4.81; N 7.51.
4.4.17. Ethyl 3-(4-nitrobenzoyl)imidazo[2,1-a]isoquinoline-2-
carboxylate (15c). Obtained by general procedure, at room tem-
perature. Purified by crystallization from CHCl3/MeOH, 1/1, v/v.
Brown solid, 45% yield; mp¼184e186 ꢀC. Rf (CH2Cl2) 0.55. IR (KBr),
4.4.21. (8,8a,16,16a-Tetrahydropyrazino[2,1-a:5,4-a0]diphthalazine-
8,16-diyl)bis((4-methoxyphenyl)methanone) (21a). Obtained by
general procedure, at room temperature or reflux. Purified by col-
umn chromatography (dichloromethane (DCM)/DCM/MeOH (99/
1, v/v)), then crystallized from CHCl3/MeOH, 1/1, v/v. Pale orange
solid, 10% yield; mp¼269e270 ꢀC. Rf (CH2Cl2) 0.58. IR (KBr),
n
(cmꢁ1): 3034, 1732, 1643, 1520, 1344, 1321, 1215, 1200, 938, 787. 1H
NMR (CDCl3, 500 MHz,
d
(ppm)): 1.08 (3H, t, J¼7.0 Hz, CH2CH3), 4.02
(2H, q, J¼7.0 Hz, CH2CH3), 7.39 (1H, d, J¼7.0 Hz, H-5), 7.75e7.77 (2H,
m, H-7, H-8), 7.84 (1H, dd, J¼7.0, 2.5 Hz, H-6), 8.01 (2H, d, J¼8.5 Hz,
H-20), 8.34 (2H, d, J¼8.5 Hz, H-30), 8.64 (1H, d, J¼7.5 Hz, H-4), 8.88
n
(cmꢁ1): 2924, 2837, 1678,1603, 1510, 1254, 1082, 1030, 829, 768. 1H
(1H, dd, J¼7.0, 1.5 Hz, H-9). 13C NMR (CDCl3, 125 MHz,
d
(ppm)): 14.0
NMR (CDCl3, 500 MHz, d(ppm)): 3.79 (3H, s, OMe), 5.39 (1H, d,
(CH2CH3), 62.2 (CH2CH3), 117.0 (C-5), 123.1 (C-4, C-11), 123.9 (C-30),
124.6 (C-2), 125.1 (C-9), 127.2 (C-6), 129.3 (C-8), 130.0 (C-20), 130.8
(C-7), 131.0 (C-10), 141.0 (C-3), 144.6 (C-10), 145.4 (C-12), 150.3 (C-
40), 162.6 (C-13), 185.2 (C-14). Anal. Calcd for C21H15N3O5: C 64.78;
H 3.88; N 10.79. Found: C 64.81; H 3.85; N 10.82.
J¼9.5 Hz, H-2), 5.44 (1H, d, J¼9.5 Hz, H-1), 6.83 (2H, d, J¼8.5 Hz, H-
30), 7.09 (1H, d, J¼8.0 Hz, H-3), 7.13e7.20 (3H, m, H-4, H-5, H-6), 7.64
(1H, s, H-7), 8.03 (2H, d, J¼8.5 Hz, H-20). 13C NMR (CDCl3, 125 MHz,
d
(ppm)): 48.3 (C-2), 55.6 (OMe), 66.1 (C-1), 113.7 (C-30), 124.8 (C-
10), 125.0 (C-6), 127.0 (C-3), 128.4 (C-5), 128.9 (C-10), 130.7 (C-11),
131.1 (C-4), 132.0 (C-20), 138.7 (C-7), 163.8 (C-40), 193.2 (C-12). Anal.
Calcd for C17H14N2O2: C 73.37; H 5.07; N 10.07. Found: C 73.35; H
4.99; N 10.10. MS (DARTþ) (m/z): 279 (100), 557 (MþHþ).
4.4.18. Ethyl 3-(4-methoxybenzoyl)imidazo[2,1-a]phthalazine-2-
carboxylate (20a). Obtained by general procedure, at room tem-
perature or reflux. Purified by column chromatography (dichloro-
methane (DCM)/DCM/MeOH (99/1, v/v)), then crystallized from
CHCl3/MeOH, 1/1, v/v. Yellow solid, 35% yield; mp¼168e170 ꢀC. Rf
4.4.22. 8,8a,16,16a-tetrahydropyrazino[2,1-a:5,4-a0]diphthalazine-
8,16-diyl)bis([1,10-biphenyl]-4-ylmethanone (21b). Obtained by
general procedure, at room temperature. Purified by column
chromatography (dichloromethane (DCM)/DCM/MeOH (99/1, v/
v)), then crystallized from CHCl3/MeOH, 1/1, v/v. Yellow solid, 10%
(CH2Cl2) 0.60. IR (KBr),
1180. 1H NMR (CDCl3, 500 MHz,
CH2CH3), 3.83 (3H, s, OMe), 4.27 (2H, q, J¼7.0 Hz, CH2CH3), 6.95 (2H,
n
(cmꢁ1): 2994, 1703, 1661, 1595, 1317, 1255,
d(ppm)): 1.11 (3H, t, J¼7.0 Hz,
Please cite this article in press as: Al Matarneh, C. M.; et al., Tetrahedron (2016), http://dx.doi.org/10.1016/j.tet.2016.05.061

C.M. Al Matarneh et al. / Tetrahedron xxx (2016) 1e9
9
yield; mp¼269e271 ꢀC. Rf (1% MeOH/CH2Cl2) 0.78. IR (KBr),
(Copies of 1H and 13C NMR spectra of compounds 3a, 5c, 7b, 10a,
15c, 20a and 21a))) associated with this article can be found in the
online version, at http://dx.doi.org/10.1016/j.tet.2016.05.061. These
data include MOL files and InChiKeys of the most important com-
pounds described in this article.
n
(cmꢁ1): 3019, 2928, 1686, 1602, 1189, 1079, 760. 1H NMR (CDCl3,
500 MHz,
d
(ppm)): 5.36 (1H, d, J¼9.5 Hz, H-2), 5.44 (1H, d, J¼9.5 Hz,
H-1), 7.06 (1H, d, J¼6.5 Hz, H-3), 7.09 (1H, d, J¼7.5 Hz, H-6),
7.13e7.15 (2H, m, H-4, H-5), 7.29 (1H, t, J¼7.0 Hz, H-400), 7.29 (2H, t,
J¼7.5 Hz, H-300), 7.47 (2H, d, J¼7.5 Hz, H-200), 7.51 (2H, d, J¼8.5 Hz, H-
30), 7.62 (1H, s, H-7), 8.07 (2H, d, J¼8.0 Hz, H-20). 13C NMR (CDCl3,
125 MHz,
d
(ppm)): 48.2 (C-2), 66.4 (C-1), 124.8 (C-10), 125.2 (C-6),
References and notes
127.0 (C-3), 127.3 (C-30), 127.4 (C-200), 128.3 (C-400), 128.5 (C-5), 129.0
(C-300), 130.2 (C-20), 130.8 (C-4), 131.0 (C-11), 134.5 (C-10), 139.1 (C-
7), 140.0 (C-100), 146.2 (C-40), 194.1 (C-12). Anal. Calcd for
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(C-1), 124.6 (C-10), 125.3 (C-6), 127.0 (C-3), 128.7 (C-5), 128.9 (C-40),
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Acknowledgements
23. Al Matarneh, C. M.; Ciobanu, C. I.; Mangalagiu, I. I.; Danac, R. J. Serb. Chem. Soc.
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C. Al Matarneh is thankful for the financial support of grant
POSDRU/159/1.5/S/137750. We also thank the POSCCE-O 2.2.1,
SMIS-CSNR 13984-901, Project no. 257/28.09.2010, CERNESIM, for
the NMR and XRD experiments. We also thank Mr. Marius Niculaua
from Research Center for Oenology of Romanian AcademydIas¸ i
branch, for MS experiments.
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Supplementary data
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Supplementary data (Tables S1eS22 (Crystallographic data and
refinement details of compounds 3a, 5b and 21b), (Figures S1eS14
Please cite this article in press as: Al Matarneh, C. M.; et al., Tetrahedron (2016), http://dx.doi.org/10.1016/j.tet.2016.05.061