Synthesis of novel bis(Pyrido[2,1-a]isoquinolines) linked to aliphatic or aromatic core via ether linkage

Full text of DOI:10.1002/jhet.3565

Month 2019 Synthesis of Novel Bis(pyrido[2,1-a]isoquinolines) Linked to Aliphatic or
Aromatic Core via Ether Linkage
*
*
Fatma M. Saleh, Hamdi M. Hassaneen,
Amr M. Abdelmoniem, Ahmed H. M. Elwahy,
and
*
Ismail A. Abdelhamid
Chemistry Department, Faculty of Science, Cairo University, Giza 12613, Egypt
*E-mail: hamdi_251@yahoo.com; aelwahy@hotmail.com; ismail_shafy@yahoo.com
Received November 10, 2018
DOI 10.1002/jhet.3565
Published online 00 Month 2019 in Wiley Online Library (wileyonlinelibrary.com).
A synthesis of novel bis(pyrido[2,1-a]isoquinoline-1,3-dicarbonitriles) by the multicomponent reaction of
2-(6,7-dimethoxy-3,4-dihydroisoquinolin-1-yl)acetonitrile with the corresponding bis(aldehydes) and
malononitrile in the presence of basic catalysts was reported.
J. Heterocyclic Chem., 00, 00 (2019).
INTRODUCTION
RESULTS AND DISCUSSION
Isoquinolines are of considerable interest as they
constitute the core structural element of many alkaloids
In the first step, the bis(aldehydes) 1 were prepared
following the literature procedure via the reaction of
the appropriate hydroxyaldehydes with the respective
dibromoalkane in refluxing ethanol containing sodium
ethoxide [23,28,49,57]. The reaction of bis(aldehydes)
such as columbamine
I [1], palmatinem II [1],
papaverine III [2], and berberine IV [3]. They have a
wide range of bioactivities including anti-inflammatory
[4–6], cardiovascular [5], anticancer [7–9], antidepressant
[5,10], antimalarial [11], and anti-HIV [12]. In addition,
several patents indicated that azaphenanthrene of types V
and VI (Fig. 1) are useful for the treatment and/or
prophylaxis of diabetes or non-insulin-dependent diabetes
[13–15]. Moreover, the growing interest in the chemistry
of bis(heterocycles) has recently been recognized, many
of which show beneficial bioactivities [16–23] and find
use as pharmaceutical agents [16–19] or organic materials
[24,25]. Moreover, multicomponent reactions (MCRs)
provide rapid and easy access to plenty of heterocycles
[23,26–30]. MCRs have several advantages such as short
reaction times, selectivity, minimal manipulation, and
high atom economy [31–42]. Due to their efficiency and
simplicity, MCRs have been used in drug design [43,44].
Recently, there has been an increased interest in the
utility of Michael addition reaction in C─C bond
formation reactions [45–49]. In continuation to our
efforts to simplify the synthesis of significant biologically
active compounds [8,20,21,26,50–56], we report herein
the syntheses of novel bis(azaphenanthrene) analogues
via one-pot three-component reaction of bis(aldehydes)
with malononitrile
2
and 2-(6,7-dimethoxy-3,4-
dihydroisoquinolin-1-yl)acetonitrile 3 [58] in the presence
of a basic catalyst to give 4 was then studied. Our
preliminary study was focused on evaluation of different
solvents and catalysts for the reaction of 4,40-(ethane-1,2-
diylbis(oxy))dibenzaldehyde 1a or 2,20-(propane-1,3-
diylbis(oxy))dibenzaldehyde 1b with two equivalents of
both 2 and 3 (Scheme 1). The reactions were performed
in different solvents (water, ethanol, acetonitrile, and
dioxane) (Table 1). To find the best reaction conditions,
the reactions were also carried out in the presence of
various catalysts including triethylamine, piperidine,
DABCO, as well as piperidine/DABCO mixture under
conventional heating. The best yields were obtained
when the reactions were carried out in acetonitrile as a
solvent using piperidine/DABCO mixture as a catalyst
(Table 1, entry 4).
The structures of the bis(pyrido[2,1-a]isoquinoline-
1,3-dicarbonitriles) 4 were confirmed based on IR, MS,
1
and NMR spectra. Thus, the H NMR spectrum of 4b
revealed a characteristic singlet at 4.73 ppm for the
pyridine-H2. It also indicated a singlet signal at 6.13 ppm
for the amino group. All other signals appeared at their
expected positions.
and
malononitrile
with
2-(6,7-dimethoxy-3,4-
dihydroisoquinolin-1-yl)acetonitrile.
© 2019 Wiley Periodicals, Inc.

F. M. Saleh, H. M. Hassaneen, A. M. Abdelmoniem, A. H. M. Elwahy, and I. A. Abdelhamid
Vol 000
Figure 1. Examples of bioactive alkaloids incorporating isoquinoline moiety.
Scheme 1. Synthesis of bis(pyrido[2,1-a]isoquinoline-1,3-dicarbonitriles) linked to aliphatic core via ether linkage 4a,b.
Table 1
Optimizing the reaction conditions for the synthesis of bis(pyrido[2,1-a]isoquinoline-1,3-dicarbonitriles) 4.
(% Yield)
Et3N
Piperidine
DABCO
Piperidine–DABCO
Entry
Solvent
4a/4b
4a/4b
4a/4b
4a/4b
1
2
3
4
Water
Ethanol
1,4-Dioxane
Acetonitrile
Nil
Nil
Nil
Nil
Trace
33/31
50/43
Trace
40/35
65/58
25/22
38/33
67/60
32/30
45/42
72/68
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Bis(pyrido[2,1-a]isoquinolines)
Scheme 2. Synthesis of bis(pyrido[2,1-a]isoquinoline-1,3-dicarbonitriles) linked to aromatic core via ether linkage 4c–g.
Table 2
Bis(pyrido[2,1-a]isoquinoline-1,3-dicarbonitriles) 4c–g.
Aldehydes 1
Products 4
(Continues)
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F. M. Saleh, H. M. Hassaneen, A. M. Abdelmoniem, A. H. M. Elwahy, and I. A. Abdelhamid
Vol 000
Table 2
(Continued)
Aldehydes 1
Products 4
Scheme 3. Proposed pathway for the synthesis of the bis(pyrido[2,1-a]isoquinoline-1,3-dicarbonitriles) 4.
Journal of Heterocyclic Chemistry
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Month 2019
Bis(pyrido[2,1-a]isoquinolines)
Scheme 4. Stepwise synthesis of compounds 4a and 4g.
Encouraged by the earlier results, the bis(pyrido[2,1-a]
isoquinoline-1,3-dicarbonitriles) that are linked to
benzene core via phenoxymethyl linkage 4c–4g were also
prepared via the direct reaction of one mole of the
appropriate bis(aldehydes) 1c–1g, respectively, with two
moles of both 2 and 3 (Scheme 2 and Table 2).
here should provide facile access for novel
bis(functionalized)heterocycles.
EXPERIMENTAL
“Melting points were measured with a Stuart melting
point apparatus and are uncorrected. The IR spectra
The reaction involves the initial formation of
bis(arylidenemalononitriles)
5
via
Knoevenagel
were recorded using
a
FTIR Bruker–vector 22
condensation of one equivalent of bis(aldehyde)
derivatives 1 with two equivalents of malononitrile 2.
Compound 5 can be considered as a Michael acceptor,
spectrophotometer as KBr pellets. The H and 13C NMR
spectra were recorded in DMSO–d6 as solvent on Varian
Gemini NMR spectrometer at 300 MHz and 75 MHz,
respectively, using TMS as internal standard. Chemical
shifts are reported as δ values in ppm. Mass spectra were
recorded with a Shimadzu GCMS–QP–1000 EX mass
spectrometer in EI (70 eV) model. The elemental
analyses were performed at the Micro analytical center,
Cairo University” [59].
1
while
2-(6,7-dimethoxy-3,4-dihydroisoquinolin-1-yl)
acetonitrile 3 can be envisioned as the Michael donor. The
basic catalyst abstract hydrogen from compound 3 giving
3(I). Then, one mole of compound 5 was reacted with two
moles of 3(I) to yield the Michael adduct 6. The
intermediate 6 abstracts the proton again from the
conjugate acid (BH+) to afford 7. Intermediate 7
General procedure for synthesis of compounds 4a–g.
Method A. A mixture of bis(aldehydes) 1a–g (1 mmol),
malononitrile 2 (132 mg, 2 mmol), and 2-(6,7-dimethoxy-
tautomerizes into
8
that undergoes intramolecular
cyclization that involves both amino and cyano groups
leading to the formation of 9. Isomerization of compound
9 gave the final isolable products 4 (Scheme 3).
This pathway was confirmed by successful isolation of
the bis(arylidenemalononitriles) 5a [49] and 5g [28,49]
through the direct reaction of bis(aldehydes) 1a and 1g
with malononitrile 2. Subsequent reactions of 5a or 5g
3,4-dihydroisoquinolin-1-yl)acetonitrile
3
(460 mg,
2 mmol) was heated at reflux in dry acetonitrile (10 mL)
in the presence of piperidine/DABCO (0.1 mL/0.05 g) for
5 h. The excess solvent was evaporated at reduced
pressure. The crude product was crystallized from
EtOH/dioxane (10 mL, 1:1, v/v).
with
2-(6,7-dimethoxy-3,4-dihydroisoquinolin-1-yl)
Method
B
(for 4a and 4g).
A
mixture of
acetonitrile 3 affords the respective compounds 4a and 4g
in 75% and 68% (Scheme 4).
bis(alrylidenemalononitriles) 5a or 5g (1 mmol) and
2-(6,7-dimethoxy-3,4-dihydroisoquinolin-1-yl)acetonitrile
3 (460 mg, 2 mmol) was heated at reflux in dry acetonitrile
(10 mL) in the presence of piperidine/DABCO (0.1 mL/
0.05 g) for 5 h. The excess solvent was evaporated at
reduced pressure. The crude product was crystallized from
CONCLUSION
We have developed an efficient synthesis of novel
bis(azaphenanthrene-dicarbonitriles) that are linked to
aliphatic or aromatic spacer via phenoxymethyl groups.
Full characterization of these compounds is reported. We
assume that the new synthetic methodology discussed
EtOH/dioxane (10 mL, 1:1, v/v).
2,20-((Ethane-1,2-diylbis(oxy))bis(4,1-phenylene))bis(4-
amino-9,10-dimethoxy-6,7-dihydro-2H-pyrido[2,1-a]
isoquinoline-1,3-dicarbonitrile) (4a).
Yellowish green
crystals (method A, 594 mg, 72%; method B, 619 mg,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

F. M. Saleh, H. M. Hassaneen, A. M. Abdelmoniem, A. H. M. Elwahy, and I. A. Abdelhamid
Vol 000
75%), mp 306–308°C, IR (KBr): ν 3433, 3335 (2NH2),
2286, 2190 (2CN) cmꢀ1 1H NMR (300 MHz,
(m, 16H, ArH) ppm, 13C NMR (75 MHz, DMSO-d6): δ
,
28.2 (NCH2CH2), 42.3 (CH), 44.3 (NCH2CH2), 55.6
(OCH3), 55.7 (OCH3), 57.8 (C3), 69.5 (OCH2), 83.6
(C1), 110.8 (Ar─CH), 111.3 (Ar─CH), 112.6 (Ar─CH),
120.1 (CN), 121.1 (CN), 121.6 (Ar─C), 126.7 (Ar─CH),
128.5 (Ar─CH), 128.6 (Ar─CH), 128.7 (Ar─CH), 129.7
(Ar─C), 130.5 (Ar─CH), 132.1 (Ar─CH), 137.5, 146.0,
146.7, 150.6, 153.2 (Ar─C), 155.3 (C─NH2) ppm, MS
(EI, 70 eV): m/z 902 [M]+, Anal. Calcd for C54H46N8O6:
C, 71.83; H, 5.13; N, 12.41. Found: C, 71.48; H, 5.45;
DMSO-d6): δ 2.85 (m, 4H, 2NCH2CH2), 3.57 (m, 4H,
2NCH2CH2), 3.75 (s, 6H, 2CH3O-9), 3.82 (s, 6H,
2CH3O-10), 4.22 (s, 2H, 2CH), 4.29 (s, 4H, 2OCH2),
6.22 (br s, 4H, 2NH2), 6.95–7.59 (m, 12H, ArH) ppm,
13C NMR (75 MHz, DMSO-d6): δ 28.0 (NCH2CH2),
41.5 (CH), 43.7 (NCH2CH2), 55.6 (OCH3), 55.7 (OCH3),
58.1 (C3), 66.3 (OCH2), 84.3 (C1), 110.7 (Ar─CH),
112.5 (Ar─CH), 114.5 (Ar─CH), 117.8 (CN), 119.9
(CN), 121.0, 121.4 (Ar─C), 127.9 (Ar─CH), 133.9,
145.3, 146.6, 150.5, 152.6 (Ar─C), 157.6 (C─NH2)
ppm, MS (EI, 70 eV): m/z 826 [M]+, Anal. Calcd for
C48H42N8O6: C, 69.72; H, 5.12; N, 13.55. Found: C,
N, 12.09.
2,20-(((1,3-Phenylenebis(methylene))bis(oxy))bis(4,1-
phenylene))bis(4-amino-9,10-dimethoxy-6,7-dihydro-2H-
pyrido[2,1-a]isoquinoline-1,3-dicarbonitrile)
(4e).
Yellowish green crystals (686 mg, 76%), mp 180–182°C,
IR (KBr): ν 3433, 3339 (2NH2), 2285, 2216 (2CN)
69.38; H, 5.54; N, 13.18.
2,20-((Propane-1,3-diylbis(oxy))bis(4,1-phenylene))bis(4-
amino-9,10-dimethoxy-6,7-dihydro-2H-pyrido[2,1-a]
1
cmꢀ1, H NMR (300 MHz, DMSO-d6): δ 2.86 (m, 4H,
isoquinoline-1,3-dicarbonitrile) (4b).
Yellow crystals
2NCH2CH2), 3.46 (m, 4H, 2NCH2CH2), 3.75 (s, 6H,
2CH3O-9), 3.82 (s, 6H, 2CH3O-10), 4.21 (s, 2H, 2CH),
5.12 (m, 4H, 2OCH2), 6.22 (br s, 4H, 2NH2), 6.98–7.89
(m, 16H, ArH) ppm, 13C NMR (75 MHz, DMSO-d6): δ
28.0 (NCH2CH2), 40.6 (CH), 42.3 (NCH2CH2), 55.8
(OCH3), 56.1 (OCH3), 58.4 (C3), 69.3 (OCH2), 84.3
(C1), 110.8 (Ar─CH), 112.7 (Ar─CH), 114.8 (Ar─CH),
117.8, 120.0 (CN), 121.4 (CN), 127.1 (Ar─C), 127.9
(Ar─CH), 128.6 (Ar─C), 130.1 (Ar─CH), 130.3
(Ar─CH), 130.6 (Ar─CH), 134.0, 137.4, 145.4, 146.8,
150.7, 152.7 (Ar─C), 157.7 (C─NH2) ppm, MS (EI,
70 eV): m/z 902 [M]+, Anal. Calcd for C54H46N8O6: C,
71.83; H, 5.13; N, 12.41. Found: C, 71.57; H, 5.02; N,
(571 mg, 68%), mp 248–250°C, IR (KBr): ν 3434, 3339
1
(2NH2), 2287, 2217 (2CN) cmꢀ1, H NMR (300 MHz,
DMSO-d6): δ 2.35 (m, 2H, OCH2CH2), 2.91 (m, 4H,
2NCH2CH2), 3.53 (m, 4H, 2NCH2CH2), 3.75 (s, 6H,
2CH3O-9), 3.82 (s, 6H, 2CH3O-10), 4.25 (m, 4H,
2OCH2), 4.73 (s, 2H, 2CH), 6.13 (br s, 4H, 2NH2), 6.90–
7.65 (m, 12H, ArH) ppm, 13C NMR (75 MHz,
DMSO-d6): δ 28.0 (NCH2CH2), 28.6 (OCH2CH2), 34.6
(CH), 42.2 (NCH2CH2), 55.5 (OCH3), 55.6 (OCH3), 57.6
(C3), 65.2 (OCH2), 83.2 (C1), 110.7 (Ar─CH), 111.9
(Ar─CH), 119.9 (Ar─CH), 120.9 (CN), 121.4 (CN),
127.9, 128.3 (Ar─C), 130.4 (Ar─CH), 131.6, 146.1,
146.6, 150.5, 153.2 (Ar─C), 155.3 (C─NH2) ppm, MS
(EI, 70 eV): m/z 840 [M]+, Anal. Calcd for C49H44N8O6:
C, 69.99; H, 5.27; N, 13.33. Found: C, 69.73; H, 5.10;
12.67.
2,20-(((1,4-Phenylenebis(methylene))bis(oxy))bis(2,1-
phenylene))bis(4-amino-9,10-dimethoxy-6,7-dihydro-2H-
pyrido[2,1-a]isoquinoline-1,3-dicarbonitrile) (4f).
Yellow
N, 13.48.
crystals (650 mg, 72%), mp 192–194°C, IR (KBr): ν
2,20-(((1,2-Phenylenebis(methylene))bis(oxy))bis(2,1-
phenylene))bis(4-amino-9,10-dimethoxy-6,7-dihydro-2H-
1
3434, 3336 (2NH2), 2285, 2219 (2CN) cmꢀ1, H NMR
(300 MHz, DMSO-d6): δ 2.84 (m, 4H, 2NCH2CH2), 3.45
(m, 4H, 2NCH2CH2), 3.74 (s, 6H, 2CH3O-9), 3.81 (s,
6H, 2CH3O-10), 4.76 (s, 2H, 2CH), 5.17 (m, 4H,
2OCH2), 6.18 (br s, 4H, 2NH2), 6.95–7.60 (m, 16H,
ArH) ppm, 13C NMR (75 MHz, DMSO-d6): δ 28.1
(NCH2CH2), 41.6 (CH), 42.3 (NCH2CH2), 55.7 (OCH3),
55.9 (OCH3), 57.7 (C3), 69.6 (OCH2), 83.6 (C1), 110.9
(Ar─CH), 111.3 (Ar─CH), 112.7 (Ar─CH), 120.0 (CN),
120.5 (CN), 121.2 (Ar─CH), 121.5 (Ar─C), 127.1
(Ar─C), 127.5 (Ar─CH), 128.5, 130.5 (Ar─C), 132.2
(Ar─CH), 136.7, 146.0, 146.7, 150.6, 153.2 (Ar─C),
155.4 (C─NH2) ppm, MS (EI, 70 eV): m/z 902 [M]+,
Anal. Calcd for C54H46N8O6: C, 71.83; H, 5.13; N,
pyrido[2,1-a]isoquinoline-1,3-dicarbonitrile)
(4c).
Yellowish orange crystals (659 mg, 73%), mp 308–
310°C, IR (KBr): ν 3437, 3341 (2NH2), 2289, 2219
(2CN) cmꢀ1, 1H NMR (300 MHz, DMSO-d6): δ 2.87 (m,
4H, 2NCH2CH2), 3.60 (m, 4H, 2NCH2CH2), 3.73 (s, 6H,
2CH3O-9), 3.81 (s, 6H, 2CH3O-10), 4.75 (s, 2H, 2CH),
5.22 (m, 4H, 2OCH2), 6.17 (br s, 4H, 2NH2), 6.94–7.62
(m, 16H, ArH) ppm, MS (EI, 70 eV): m/z 902 [M]+,
Anal. Calcd for C54H46N8O6: C, 71.83; H, 5.13; N,
12.41. Found: C, 71.59; H, 4.89; N, 12.18.
2,20-(((1,3-Phenylenebis(methylene))bis(oxy))bis(2,1-
phenylene))bis(4-amino-9,10-dimethoxy-6,7-dihydro-2H-
pyrido[2,1-a]isoquinoline-1,3-dicarbonitrile)
(4d).
Yellowish green crystals (623 mg, 69%), mp 182–184°C,
IR (KBr): ν 3434, 3339 (2NH2), 2287, 2217 (2CN)
12.41. Found: C, 71.62; H, 4.96; N, 12.05.
2,20-(((1,4-Phenylenebis(methylene))bis(oxy))bis(4,1-
phenylene))bis(4-amino-9,10-dimethoxy-6,7-dihydro-2H-
1
cmꢀ1, H NMR (300 MHz, DMSO-d6): δ 2.84 (m, 4H,
pyrido[2,1-a]isoquinoline-1,3-dicarbonitrile) (4g).
crystals (Method A, 596 mg, 66%; Method B, 613 mg,
68%), mp 208–210°C, IR (KBr): ν 3432, 3340 (2NH2),
Yellow
2NCH2CH2), 3.44 (m, 4H, 2NCH2CH2), 3.74 (s, 6H,
2CH3O-9), 3.80 (s, 6H, 2CH3O-10), 4.76 (s, 2H, 2CH),
5.10 (m, 4H, 2OCH2), 6.17 (br s, 4H, 2NH2), 6.91–7.60
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DOI 10.1002/jhet

Month 2019
Bis(pyrido[2,1-a]isoquinolines)
2288, 2214 (2CN) cmꢀ1, 1H NMR (300 MHz, DMSO-d6):
δ 2.99 (m, 4H, 2NCH2CH2), 3.43 (m, 4H, 2NCH2CH2),
3.76 (s, 6H, 2CH3O-9), 3.82 (s, 6H, 2CH3O-10), 4.21 (s,
2H, 2CH), 5.01 (m, 4H, 2OCH2), 6.22 (br s, 4H, 2NH2),
6.97–7.89 (m, 16H, ArH) ppm, 13C NMR (75 MHz,
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DMSO-d6):
δ 28.1 (NCH2CH2), 42.3 (CH), 44.2
(NCH2CH2), 55.7 (OCH3), 55.9 (OCH3), 58.4 (C3), 69.1
(OCH2), 84.2 (C1), 110.8 (Ar─CH), 114.8 (Ar─CH),
115.1 (Ar─CH), 120.0 (CN), 120.5 (CN), 127.9
(Ar─CH), 128.5, 130.2 (Ar─C), 130.5 (Ar─CH), 134.0
(Ar─C), 136.7, 145.4, 146.8, 150.7, 152.7 (Ar─C),
157.7 (C─NH2) ppm, MS (EI, 70 eV): m/z 902 [M]+,
Anal. Calcd for C54H46N8O6: C, 71.83; H, 5.13; N,
12.41. Found: C, 71.59; H, 4.85; N, 12.67.
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