One-Pot Sequential Synthesis of Fused Isoquinolines via Intramolecular Cyclization/Annulation and their Photophysical Investigation

Article abstract of DOI:10.1002/adsc.201900543

One of the cyano group of γ-keto malononitrile gets hydrolyzed selectively to an amide in the presence of copper(II) acetate monohydrate. The in situ generated amide undergo an intramolecular dehydrative cyclization to a 1,2-dihydropyridone intermediate.

Full text of DOI:10.1002/adsc.201900543

Title: One-Pot Sequential Synthesis of Fused Isoquinolines via
Intramolecular Cyclization/Annulation and their Photophysical
Investigation
Authors: Bhisma Patel, AMITAVA RAKSHIT, Prasenjit Sau, and
SUBHENDU GHOSH
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10.1002/adsc.201900543
Advanced Synthesis & Catalysis
FULL PAPER
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
One-Pot Sequential Synthesis of Fused Isoquinolines via
Intramolecular Cyclization/Annulation and their Photophysical
Investigation
Amitava Rakshit,a Prasenjit Sau,a Subhendu Ghosh,a Bhisma K. Patela,*
a
Department of Chemistry, Indian Institute of Technology Guwahati,
Guwahati-781039, Assam, India
Fax: (+91)361-26909762
E-mail: patel@iitg.ac.in
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
Abstract. One of the cyano group of -keto malononitrile gets hydrolyzed selectively to an amide in the presence of
copper(II) acetate monohydrate. The in situ generated amide undergo an intramolecular dehydrative cyclization to a 1,2-
dihydropyridone intermediate. Further annulation of the 1,2-dihydropyridone with an internal alkyne in the same pot
produce a fused isoquinolone, 4-oxo-2,6,7-triaryl-4H-pyrido[2,1-a]isoquinoline-3-carbonitrile. This one-pot process is
associated with the formation of one CC, two CN, two CC and a CO bonds. The final synthesis is a four-step process
consisting of selective hydrolysis of a cyano group to an amide, dehydrative cyclization of the amide to a cyclic amide,
aromatization of the cyclic amide (2-oxo-1,2,3,4-tetrahydropyridine moiety) to a 2-oxo-1,2-dihydropyridine and finally,
the CH/NH annulation with an alkyne. Density functional theory calculation reveals that the highest occupied
molecular orbital (HOMO) is localized at the central core extending to the nitrile group and a negligible contribution from
the two phenyl rings of the diphenylacetylene. On the other hand, the lowest unoccupied molecular orbital (LUMO) is
also localized at the identical central core and extended up to the other phenyl ring. The calculated ΔE(LUMO HOMO) is in the

range of 2.88 to 3.45 eV and the compounds display emission in the green region (502560) nm and absorption (max) in
the range of (454490) nm. Therefore, these molecules may find application in bio-imaging, theranostics and various
applications in material science.
Keywords: Isoquinoline; Ru; CH activation; CH/NH annulation; DFT; photoluminescence.
Introduction
numerous organic transformations use isoquinolones
as one of the key intermediate.[11] Therefore, it is
desirable to develop synthetic protocols for these
potentially active heterocycles as target structures for
biological evaluation and application in material
science. Recently, Jeganmohan group have reported a
cobalt catalyzed annulation of benzamides with
alkynes to synthesize isoquinolines [Scheme 1, (i)].[12]
Van der Eycken, et al. described a microwave-
Various heterocyclic compounds having potential
biological activities have been synthesized via
Michael
adduct
with
numerous
carbon
nucleophiles.[1] Malononitrile is one of the useful and
convenient precursors for the synthesis of a wide
range of fused N- and O- heterocyclic skeletons.[2]
Over the years, many publications have appeared for
nitrogen-containing
six-membered
heterocyclic
assisted
Ru(II)-catalyzed
highly
efficient
systems highlighting their biological importance as
well as photophysical properties. In the midst of
fused-ring nitrogen heterocycles, isoquinolines and
isoquinolones are special class possessing
comprehensive biological activities (Figure 1) and
exists in many synthetic drugs and natural
products.[35] Further, organic fluorescent molecules,
used in organic light emitting diodes (OLEDs),[6]
liquid crystal displays (LCDs)[7] and fluorescent
dyes[8] are important in bridging between the
synthetic organic chemistry and material science.[9]
Due to fascinating luminescent[10a,b,c] properties
substituted fused isoquinolines[10d] play a significant
role in material science (Figure 1). Moreover,
intermolecular CH functionalization sequence to
access substituted isoquinolones using -amino esters
as the directing group [Scheme 1, (ii)].[13] Of late,
transition-metal-catalyzed CH bond activation[14,15]
has gained great attention for the synthesis of
bioactive complex nitrogen-containing fused
heterocycles,
especially,
isoquinolines
and
isoquinolones. In this context Rh(III), Pd(II), Ni(II)
and Ru(II) catalysts are most common and have been
used extensively to obtain isoquinolones[16] via the
oxidative coupling between an internal alkyne and an
amide. Recently a two-step protocol has been
achieved utilizing two different catalytic systems for
the synthesis of highly functionalized molecules.[17]
1
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10.1002/adsc.201900543
Advanced Synthesis & Catalysis
The development of one-pot strategies is often
ineffective because each step provides several by-
products along with unreacted starting materials.
continued for 5 h, during this period all the starting
materials got consumed giving 1,2-dihydropyridone
intermediate (1ʹ) as the major product along with
significant amounts of other uncharacterized by-
products.
Figure 1. Representative biologically active, natural
product
and
highly
fluorescent
fused
isoquinoline/isoquinolones.
Inspired by transition-metal-catalyzed direct
annulation of CH bonds[18] and the advantage of
two-step protocol we envisaged the synthesis of 4-
oxo-2,6,7-triphenyl-4H-pyrido[2,1-a]isoquinoline-3-
carbonitrile (1a) from a Michael-adduct,[19] 2-(3-oxo-
1,3-diphenylpropyl)malononitrile (1). The selective
hydrolysis of one of the cyano group in -keto
dicyano compound (1) would led to an amide similar
to hydrolysis of methylenemalononitrile [Scheme 1,
(iii)].[20] The in situ generated monoamide may
undergo an intermolecular dehydrative cyclization
followed by aromatization/oxidation to form a cyclic
amide, 1,2-dihydropyridone which has potential
CH/NH sites for annulation with an alkyne to
afford
4-oxo-2,6,7-triphenyl-4H-pyrido[2,1-
Scheme 1. Strategies for the synthesis of fused
isoquinolones.
a]isoquinoline-3-carbonitrile (1a). This reaction
involves an intramolecular dehydrative cyclization
followed by an intermolecular annulation with an
alkyne to obtained a fused isoquinolone framework
[Scheme 1, (v)].
To this crude reaction mixture, diphenylacetylene
(a) (1 equiv.) and [Ru(p-cymene)Cl2]2 (5 mol %)
were added and the reaction was allowed to proceed
for 12 h. The reaction was found to be much cleaner
and the product (1a) was isolated in 30% yield. The
product was separated and characterized by
Results and Discussion
1
spectroscopic analysis (IR, HNMR, 13CNMR, and
Our initial investigation started using 2-(3-oxo-1,3-
diphenylpropyl)malononitrile (1) (0.2 mmol),
diphenylacetylene (a) (1 equiv.), Cu(OAc)2·H2O (1
equiv.), and [Ru(p-cymene)Cl2]2 (2 mol %) in glacial
HRMS) and the structure was found to be 4-oxo-
2,6,7-triphenyl-4H-pyrido[2,1-a]isoquinoline-3-
carbonitrile (1a). Finally, the structure of the product
(1a) was reconfirmed by single crystal X-ray
diffraction study (Figure 2). This one-pot

AcOH at 110 C. Interestingly, the reaction resulted
in the formation of a new yellow fluorescent spot
(viewed under 365 nm UV lamp) as observed by TLC.
Unfortunately, the compound could not be separated
for characterization as it was associated with several
other side products. However, a decent amount (18%)
of expected cyclic 1,2-dihydropyridone intermediate
transformation
of
2-(3-oxo-1,3-
diphenylpropyl)malononitrile (1) to a 4-oxo-2,6,7-
triphenyl-4H-pyrido[2,1-a]isoquinoline-3-carbonitrile
(1a) is accompanied by the formation of new CC,
CN, CC and CO bonds. Observing the structure
of the product it is evident that the amidic carbonyl
group in the product (1a) is not the original carbonyl
group of the starting material (1). Thus, it may
possibly be originating by the selective hydrolysis of
viz.
2-oxo-4,6-diphenyl-1,2-dihydropyridine-3-
carbonitrile (1ʹ) could be isolated [Scheme 1, (iv)].
Encourage by the success of our anticipated strategy
we adopted a two-step protocol. In the first step the 2-
(3-oxo-1,3-diphenylpropyl)malononitrile (0.2 mmol)
(1) was treated with Cu(OAc)2·H2O (1 equiv.) in
AcOH (2 mL) at 110 C and the reaction was
18
one of the cyano group. An O incorporated product
was detected when the typical reaction was carried
2
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10.1002/adsc.201900543
Advanced Synthesis & Catalysis
18
out in the presence of H2 O, thereby confirming
water to be the source of oxygen in the product (1a).
Although, synthetic strategies of some of the
isoquinolone involve CH bond activation and
annulation of various amides with internal alkynes
employing transition metal catalysts[12-14] we feel our
report exploring the alternative pattern would be
useful to the synthetic community.
partner in the presence of Cu(OAc)2·H2O and [Ru(p-
cymene)Cl2]2. Fixing the conditions [i.e. diphenyl
acetylene (a) (1 equiv.), Cu(OAc)2·H2O (1 equiv.)
and [Ru(p-cymene)Cl2]2 (5 mol %)] of the second
step (i.e. annulating step), reaction parameters for the
first steps (i.e. hydrolytic-dehydrative cyclization)
were varied. Among various solvents such as p-
xylene (00%), toluene (00%), DMF (00%) and
DMSO (00%) were tested (Table 1, entries 25) all
were found to be ineffective compared to AcOH
(45%) (Table 1, entry 1). When the reaction was
carried out in the absence of Cu(II)-catalyst very poor
yield (<10%) of (18a) was detected (Table 1, entry 6),
suggesting the involvement of copper salt in
facilitating the reaction, possibly via the coordination
with the cyano (CN) group. The selective hydrolysis
of one of the cyano group in the presence of Cu(II)
catalyst is in agreement with earlier report.[20] An
improvement in the yield (55%) was observed when
the ligand 1,10-phenanthroline (10 mol %) was used
(Table 1, entry 7). Keeping the catalyst loading
constant (10 mol %), an increase in the ligand loading
to 15 and 20 mol % improved the yield to 60 and
65% respectively (Table 1, entry 89).
Figure 2. ORTEP diagram of compound (1a) with 40%
ellipsoid probability. [21a]
Encouraged by the above one-pot two-fold
sequential synthesis of fused isoquinoline, further
optimizations were carried out by varying various
reaction parameters using 2-(1-(4-chlorophenyl)-3-
oxo-3-(p-tolyl)propyl)malononitrile (18) as the model
substrate and diphenylacetylene (a) as the annulating
Table 1. Optimization of the reaction conditions for the first step.[a-e]
Entry
1
Catalyst (mol %)
Ligand (mol %)
Solvent
AcOH
Yield (%)[b]
45
Cu(OAc)2·H2O (10)
2
3
4
Cu(OAc)2·H2O (10)
Cu(OAc)2·H2O (10)
Cu(OAc)2·H2O (10)
p-xylene
Toluene
DMF
00
00
00
5
6
7
8
Cu(OAc)2·H2O (10)
DMSO
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
00
<10
55
60
65
65
55
48
28
Cu(OAc)2·H2O (10)
Cu(OAc)2·H2O (10)
Cu(OAc)2·H2O (10)
Cu(OAc)2·H2O (20)
Cu(OAc)2·H2O (10)
Cu(OAc)2·H2O (10)
Cu(OAc)2·H2O (10)
Cu(OAc)2·H2O (10)
Cu(OAc)2·H2O (10)
Cu(OAc)2·H2O (10)
Cu(OAc)2·H2O (10)
1,10-phenanthroline (10)
1,10-phenanthroline (15)
1,10-phenanthroline (20)
1,10-phenanthroline (20)
2,2’-bipyridyl (20)
L-proline (20)
Jhon Phos (20)
PPh3 (20)
9
10
11
12
13
14
15
16
17
27
1,10-phenanthroline (20)
1,10-phenanthroline (20)
1,10-phenanthroline (20)
26c
42d
67e
a) Reaction condition: 2-(1-(4-chlorophenyl)-3-oxo-3-(p-tolyl)propyl)malononitrile (18) (0.2 mmol), catalyst (mol %),
ligand (mol %) at 110 C for 5 h. b) Isolated yields. c) Temperature 90 C. d) Temperature 130 C. e) Yield after 12 h.
Maintaining the ligand loading to 20 mol % and
increasing the catalyst loading up to 20 mol % did not
alter the product yield (65%) any further (Table 1,
entry 10). With Cu(OAc)2·H2O (10 mol %) as the
suitable catalyst and AcOH as the solvent the use of
other ligands such as 2,2ʹ-bipyridyl (52%), L-proline
3
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10.1002/adsc.201900543
Advanced Synthesis & Catalysis
(48%), JhonPhos (28%), PPh3 (27%) were screened
(Table 1, entries 1114). All the ligands tested gave
lower yields compared to 1,10-phenanthroline (65%)
(Table 1, entry 9). Reaction carried out both at higher
130 C (42%) or lower 90 C (26%) temperature was
detrimental to the product formation (Table 1, entries
15 and 16). No significant improvement in the overall
yield (67%) was observed when the hydrolytic
dehydrative-cyclization step of the reaction mixture
was maintained up to 12 h. After screening of various
reaction parameters, the optimized condition for this
transformation in the first step is the use of 2-(1-(4-
chlorophenyl)-3-oxo-3-(p-tolyl)propyl)malononitrile
(18) (0.2 mmol), Cu(OAc)2·H2O (10 mol %), and
additive Cu(OAc)2·H2O loading increased from 10 to
50 mol % (Table 2, entries 710). No significant
improvement in the product yield (53%) was
observed even when the additive loading was
increased up to 1 equiv. (Table 2, entry 11). Since the
intermediate dihydropyridone (18ʹ) form in the first
step precipitated in AcOH medium, thus, it was felt
necessary to have additional co-solvent in the second
step to make the medium homogeneous. Among few
t
representative solvents tested such as AmOH (18%),
MeOH (12%), iso-propanol (16%) (Table 2, entries
1215), PEG-400 proved to be the best choice,
affording the annulated product (18a) in 72% yield
(Table 2, entry 15). No major improvement in the
yield was observed even when the quantity of
diphenylacetylene (a) was increased to 1.5 equiv.
(74%) and 2 equiv. (75%) (Table 2, entries 16 and
17). Both decrease (80 C) or increase (130 C) in the
reaction temperature resulted lowering in the product
yields (36% and 42% respectively) (Table 2, entries
18 and 19). When the reaction was stopped after 12 h
the product (18a) was isolated in lower yield (59%)
as substantial amount of intermediate 1,2-
dihydropyridone remain unconsumed (Table 2, entry
20). To see the efficacy in a step wise process, the
intermediate 1ꞌ was isolated in 82% yield that was

1,10-phenanthroline (20 mol %), at 110 C in AcOH
(2 mL) (Table 1, entry 9).
Maintaining the optimized condition for the
hydrolytic-dehydrative cyclization step (Table 1,
entry 9), further optimization was carried out for the
annulation step using [Ru(p-cymene)Cl2]2 as the
catalyst in AcOH at 110 C. Increasing the amount of
catalyst loading (from 2 to 5 mol %) marginally
enhanced the yield of the desired product (27 to 38%,
Table 2, entries 12). No significant improvement in
the product yield (40%) was observed even when the
catalyst loading was increased to 10 mol % (Table 2,
entry 3). Among the additives such as, AgSbF6 (31%), subsequently subjected to the annulation step which
AgOTf (33%), Cu(OAc)2 (36%) and Cu(OAc)2·H2O
(38%) (Table 2, entries 47), the later proved to be
the best choice (Table 2, entry 7). The yield
progressively improved from 38 to 52% as the
provided 64% yield of the product (1a), thus giving
an overall yield of 52%. Although this two-step yield
(52%) is slightly better than the one step process
(45%) for convenience we preferred the later.
Table 2. Optimization for the second step.[a-h]
Entry
Catalyst (mol %)
Additive (mol %)
Solvent
Yield (%)[b]
1
2
3
4
5
6
7
8
[Ru(p-cymene)Cl2]2 (2)
[Ru(p-cymene)Cl2]2 (5)
[Ru(p-cymene)Cl2]2 (10)
[Ru(p-cymene)Cl2]2 (5)
[Ru(p-cymene)Cl2]2 (5)
[Ru(p-cymene)Cl2]2 (5)
[Ru(p-cymene)Cl2]2 (5)
[Ru(p-cymene)Cl2]2 (5)
[Ru(p-cymene)Cl2]2 (5)
[Ru(p-cymene)Cl2]2 (5)
[Ru(p-cymene)Cl2]2 (5)
[Ru(p-cymene)Cl2]2 (5)
[Ru(p-cymene)Cl2]2 (5)
[Ru(p-cymene)Cl2]2 (5)
[Ru(p-cymene)Cl2]2 (5)
[Ru(p-cymene)Cl2]2 (5)
[Ru(p-cymene)Cl2]2 (5)
[Ru(p-cymene)Cl2]2 (5)
[Ru(p-cymene)Cl2]2 (5)
[Ru(p-cymene)Cl2]2 (5)
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
27
38
40
31
33
36
38
42
46
52
53c
18
12
16
72
74d
75e
36f
42g
59h
AgSbF6 (10)
AgOTf (10)
Cu(OAc)2 (10)
Cu(OAc)2·H2O (10)
Cu(OAc)2·H2O (20)
Cu(OAc)2·H2O (30)
Cu(OAc)2·H2O (50)
Cu(OAc)2·H2O (100)
Cu(OAc)2·H2O (50)
Cu(OAc)2·H2O (50)
Cu(OAc)2·H2O (50)
Cu(OAc)2·H2O (50)
Cu(OAc)2·H2O (50)
Cu(OAc)2·H2O (50)
Cu(OAc)2·H2O (50)
Cu(OAc)2·H2O (50)
Cu(OAc)2·H2O (50)
9
AcOH
AcOH
10
11
12
13
14
15
16
17
18
19
20
AcOH
tAmOH
MeOH
iso-propanol
PEG-400
PEG-400
PEG-400
PEG-400
PEG-400
PEG-400
4
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10.1002/adsc.201900543
Advanced Synthesis & Catalysis
a) Reaction condition: 2-(1-(4-chlorophenyl)-3-oxo-3-(p-tolyl)propyl)malononitrile (18) (0.2 mmol), diphenylacetylene (a)

(0.2 mmol), catalyst (mol %) additive (mol %.) at 110 C for 24 h. b) Isolated yields. c) 1 equiv. additive was used. d) 1.5
e)

g)

h)
equiv. of (a) was used. 2 equiv. of (a) was used. f) Temperature 80 C. Temperature 130 C. Yield after 12 h
This one-pot two-step synthesis of 4-oxo-2,6,7-
triaryl-4H-pyrido[2,1-a]isoquinoline-3-carbonitrile
was then explored with various other -keto-
malononitriles with diphenylacetylene (a) under the
optimized reaction condition (Scheme 2). A substrate
(1), having both unsubstituted phenyl rings coupled
with diphenylacetylene (a), yielding its fused
isoquinoline (1a, 45%) in moderate yield (Scheme 2).
Reactants having an electron-neutral substituent (-H)
in the phenyl ring attached towards keto group and
electron-donating substituents such as p-Me (2), p-
OMe (3), p-SMe (4), and p-Ph (5) in the other phenyl
ring reacted successfully with diphenylacetylene (a),
yielding their fused isoquinolines (2a), (3a), (4a) and
(5a) in 51%, 55%, 52% and 48% yields respectively
(Scheme 2). When the phenyl ring - to the
malononitrile is substituted with electron-
withdrawing substituents such as p-Cl (6), o-Br (7),
and m-NO2 (8) all provided their respective products
(6a, 49%), (7a, 45%) and (8a, 35%) (Scheme 2). This
methodology was equally successful when the phenyl
ring - to the malononitrile is unsubstituted and the
aroyl phenyl ring is substituted with either electron-
donating p-Me (9), and p-OMe (10) or electron-
withdrawing groups such as p-CF3 (11), p-F (12), p-
Cl (13), p-Br (14) and p-NO2 (15) all yielded their
respective fused isoquinolines (9a, 45%), (10a, 42%),
(11a, 59%), (12a, 57%), (13a, 53%), (14a, 52%), and
(15a, 30%). Although, the yields obtained here is not
high but considering the number of steps involved in
the process, such as selective hydrolysis of a cyano
group to an amide, followed by a dehydrative
cyclization of an unreactive amide, aromatization and
finally, the CH/NH annulation with an alkyne,
these yields are very well acceptable. This protocol
was explored to a substrate (16), having a naphthyl
ring instead of a phenyl ring and to another substrate
respectively. Besides flexible keto substrates in
(Scheme 2), a cyclic -keto substrate (23) underwent
efficient transformation to its fused isoquinoline
product (23a) in 56% yield. Further, a furan (24) or a
thiophene (25) bearing substrates were quite
compatible and yielded their resultant products (24a,
41%) and (25a, 43%) respectively. To evaluate the
potential of this two-step process and to expand the
scope of this reaction, (18) and (a) were reacted on a
1 mmol scale which provided isoquinolone (18a) in
62% yield (Scheme 2).
(17) having
a
1-naphthyl ring towards the
malononitrile and a 2-naphthyl ring towards the keto
side, both provided their respective products (16a)
and (17a) in 44% and 43% yields (Scheme 2).
Similarly, the presence of various other substituents
either electron-donating groups (EDGs) or electron-
withdrawing groups (EWGs) in any or both the
phenyl rings all provided their anticipated products.
As demonstrated earlier, the substrate (18) having
EDG p-Me and EWG p-Cl gave good yield (72%) of
the product (18a). Other Michael adducts bearing
EWG p-Br/EWG p-Cl (19) and EDG p-OMe/EWG p-
NO2 (20) both provided their resultant products (19a,
58%) and (20a, 25%) respectively. Observing the
trends in the yield obtained in Scheme 2, there is no
correlation between the nature of the substituents
present in either of the phenyl rings. Besides mono-
substituted phenyl rings, di-substituted aryl rings -to
malononitrile side such as 2,6-dichloro (21) and 3,4-
diOMe (22) reacted efficiently giving good yields of
their products (21a, 57%) and (22a, 61%)
a Reaction conditions: (i) 125 (0.2 mmol), Cu(OAc)2·H2O
(0.02 mmol), 1,10-phenanthroline (0.04 mmol), and glacial

AcOH (2 mL) at 110 C for 5 h. (ii) diphenylacetelene (a)
(0.2
mmol),
[Ru(p-cymene)Cl2]2
(0.01
mmol),
Cu(OAc)2·H2O (0.1 mmol) and PEG-400 (2 mL) at 110 C
for 24 h. b) Yield after 12 h, c) Yield reported for 1 mmol
scale.
Scheme 2. Substrate scope for the synthesis of 4-Oxo-
2,6,7-triphenyl-4H-pyrido[2,1-a]isoquinoline-3-
carbonitriles.[a-c]
5
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10.1002/adsc.201900543
Advanced Synthesis & Catalysis
In order to further expand the scope of this
a) Reaction conditions: (i) 1/18 (0.2 mmol), Cu(OAc)2·H2O
methodology, the compatibility of various alkynes
was tested with two selected -keto malononitriles
namely, (1) and (18) (Scheme 3). The reaction
proceeded smoothly with different symmetrical 1,2-
diarylacetylenes (be), possessing either electron-
donating groups such as p-Me (b), p-OMe (c) or
electron-withdrawing groups such as p-F (d), and m-
Cl (e) irrespective of their position of attachments.
All underwent efficient annulation when reacted with
-keto malononitrile (1) providing their expected
fused isoquinolines (1b, 46%), (1c, 48%), (1d, 41%),
and (1e, 42%) respectively. Besides symmetrical 1,2-
diarylacetylenes (be), an aliphatic symmetrical
alkyne, 4-octyne (g), upon reaction with (1) provided
51% yield of the product (1g) (Scheme 3). All these
symmetrical internal alkynes (bg) reacted
competently with another -keto malononitrile (18),
providing their corresponding annulated products
(18b, 75%), (18c, 78%), (18d, 61%), (18e, 55%),
(18f, 58%), and (18g, 71%) respectively (Scheme 3).
Observing the trend in the yields for substrates (1)
and (18) with various substituted aryl alkynes (bf),
it was found that aryl alkynes possessing electron-
donating substituents (p-Me, p-OMe) provided better
yields than the aryl alkynes having electron-
withdrawing substituents (p-F, m-Cl, and p-Br)
(Scheme 3).
(0.02 mmol), 1,10-phenanthroline (0.04 mmol), and glacial

AcOH (2 mL).at 110 C for 5 h. (ii) bk (0.2 mmol),
[Ru(p-cymene)Cl2]2 (0.01 mmol), Cu(OAc)2·H2O (0.1
mmol) and PEG-400 (2 mL) at 110 C for 24 h.
Scheme 3. Substrate scope for alkynes.[a]
To check the regioselectivity of this CH/NH
annulation, in an unsymmetrical alkyne, 1-phenyl-1-
propyne (h), whether it is taking place towards the
phenyl side or the alkyl side, it was reacted with (18)
under an identical condition. The reaction provided a
regio-isomeric mixture of (18h) and (18hʹ) in 2.4 : 1
ratio in a combined yield of 63%, suggesting the
attachment of the benzylic carbon to the N atom of
the in situ generated 2-pyridone intermediate. The
structure of the major regioisomer (18h) was
confirmed by X-ray crystallography analysis (Scheme
3).[21b] Further, another unsymmetrical alkyne, 1-
phenyl-1-butyne (i) also afforded a regio isomeric
mixture of products (18i) and (18iʹ) in the ratio of
2.3 : 1 in a combined yield of 65% which is almost
identical to that of product obtained from alkyne (h).
This preferential reactivity of the N atom at the
benzylic carbon of an unsymmetrical internal
alkynes[16] (h) and (i) leading to regioselective
CH/NH annulation is similar to other (CH/OH
and CH/SH) hetero annulation reactions.[22] Highly
electron-deficient symmetrical aliphatic alkynes, such
as
dimethylacetylenedicarboxylate
(j)
and
diethylacetylenedicarboxylate (k) both failed to react
with substrate (18) giving no traces of the annulated
products (18j) and (18k). It should be mentioned here
that these electron-deficient alkynes (j and k) reacts
efficiently during CH/SH annulation process[22b]
demonstrating the lower propensity for CH/NH
annulation. This method is however unsuccessful for
terminal alkynes such as phenyl acetylene (l) giving
no annulated product (18l).
Whether the electronic effect of the substituents
(R1) on the aroyl phenyl ring have any influence on
the reaction, an equimolar mixture of substrates
having an electron-donating p-OMe (10) and an
electron-withdrawing p-F (12) were reacted with
diphenylacetylene (a) (Scheme 4 (i)). The ratio of the
products (10a) : (12a) obtained was 1 : 2.53,
suggesting a slightly higher reactivity of electron-
withdrawing substrate p-F (12) compared to electron-
donating substrate p-OMe (10) [(Scheme 4 (i)].
Further, to see the effect of substituents, either an
EDG p-Me (2) or an EWG p-Cl (6) present on the
phenyl rings (R2 i.e. -to malononitrile) were reacted
with diphenylacetylene (a). The ratio of the products
2a : 6a obtained was 1 : 0.80 [Scheme 4 (ii)]
suggesting the preferential reactivity of electron-
donating substituents (R2) in this annulation reaction.
Next, the nature of the substituents present on the
phenyl rings of the alkynes was investigated. In an
intermolecular competition reaction between an
electron-rich alkyne p-OMe (c) and a relatively
electron-deficient alkyne p-F (d), both yielded their
annulated products (1c) and (1d) in the ratio of 1 :
6
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10.1002/adsc.201900543
Advanced Synthesis & Catalysis
0.80 suggesting a slight preferential reactivity of the
electron-rich alkyne (c) over the electron-deficient
alkyne p-F (d) [Scheme 4 (iii)].
Next, to understand the mechanism and nature of
the CH bond activation, whether the CH
metalation step is reversible or irreversible a
deuterium-scrambling experiment was performed.
The deuterium exchange experiment on the isolated
intermediate (2ʹ) in the absence of an alkyne under
the
standard
reaction
Scheme 4. Intermolecular competition experiments.
condition in D2O did not afford any deuterium
exchange at the ortho-CH of the annulating phenyl
ring, suggesting an irreversible CRu bond
formation[23a] [Scheme 5, (i)]. Further, in an
intermolecular competition experiment between (6)
and its deuterated analogue (6-d5) with (a), an
observed kH/kD = 3.00 signifies the irreversible CH
bond cleavage to be the rate-limiting step [Scheme 5,
(ii)].[23b,c]
Mechanism
Based on the above isotopic experiments and from
previous reports,[13,24,25] a plausible mechanism is
depicted in Scheme 6. In the first step, one of the
nitrile (CN) group of the substrate (1) is hydrolyzed
selectively to a mono amidic intermediate (I). The
NH2 of the amide then attacks at the carbonyl group
and undergoes a dehydrative-cyclization to produce a
six-membered cyclic intermediate (II). The
intermediate (II) is oxidized/aromatized under the
reaction conditions to an aromatic pyridone
intermediate (III). Formation of intermediate (I), (II)
and (III) has been detected by the HRMS analysis of
the reaction aliquots at various time intervals [see
Supporting Information (SI)]. In the second step the
catalyst [RuCl2(p-cymene)]2 undergoes ligand
exchange with Cu(OAc)2·H2O to generate the active
catalytic species, which coordinates with the nitrogen
atom of the intermediate (III) via NH deprotonation.
This is then followed by ortho CH bond activation
through the elimination of AcOH, forming a five-
membered ruthenacycle (V). Further coordination of
the alkyne (a), followed by an alkyne insertion and
reductive elimination afforded the final product (1a)
via the intermediate (VI). The active catalyst species
is then regenerated by the oxidant Cu(OAc)2·H2O and
air for the next catalytic cycle (Scheme 6).
Scheme 5. Experiments with isotopically labelled
compounds.
7
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10.1002/adsc.201900543
Advanced Synthesis & Catalysis
Scheme 6. Plausible reaction mechanism.
isoquinolines respectively are 3.42, 3.41, 3.34 and
3.43 eV (Figure 4). When a 1,2-dialkylacetylene,
namely, 4-octyne (g) was replaced with the
diphenylacetylene (a) in the fused isoquinolines
moiety (1g), the energy gap was found to be 3.39 eV
(Figure 4). The calculated ΔE(LUMOHOMO) energy of
various other substituents either in the acceptor
(LUMO) or in the donor (HOMO) are summarized in
Figure S13, Figure S14 and Figure S15 (SI).
Theoretical Investigation
The crystal structure of (1a) reveals the presence of a
slightly twisted 4H-pyrido[2,1-a]isoquinoline-3-one
core and the three phenyl rings are out of the
molecular plane. While the aroyl ring is part of the
4H-pyrido[2,1-a]isoquinoline-3-one core, the phenyl
ring - to the malononitrile is twisted out of the
planar core with a dihedral angle of 42.58. The two
phenyl rings originating from the diphenylacetylene
moiety are also twisted out of the molecular plane
with a dihedral angle of 78.16 and 85.24
respectively. To further ascertain the geometry and
electronic structure of the annulated fused
isoquinoline, density functional theory (DFT)
calculations were performed with a B3LYP/6-31G (d,
p) basis set level in acetonitrile solvent modeled by
the PCM approach (the Gaussian 09 programme).[26]
The density functional theory (DFT) calculation of
(1a) reveals that the electron density in the highest
occupied molecular orbital (HOMO) is localized at
the central core extending to the nitrile and minor
contributions from the two phenyl rings originating
from the diphenylacetylene. Whereas the lowest
unoccupied molecular orbital (LUMO) is again
localized at the central core and extended up to the
phenyl ring originating from the
malononitrile (Figure 3).
 to the
In a donor--acceptor (D--A) type system the
ΔE(LUMOHOMO) energy can be directly correlated with
the presence of either electron-donating or electron-
withdrawing groups on the donor (HOMO) or the
acceptor (LUMO) part of the molecule.[27] Here, since
both the HOMO and LUMO are localized on the
central molecular core with very insignificant
contributions from the three phenyl rings, no proper
correlation between the HOMO-LUMO energy gap
could be found due the presence of EDG or EWG
groups. The calculated ΔE(LUMOHOMO) energy gap for
unsubstituted (1a), p-Me substituted (1b), p-OMe
substituted (1c) and p-F substituted (1d)
Figure 3. a) Optimized structure of 1a; b) Molecular
orbitals amplitude plots of HOMO and LUMO of 1a using
density functional theory calculation at the B3LYP/6-31G
(d, p) basis set level in acetonitrile solvent modelled by the
PCM approach.
8
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10.1002/adsc.201900543
Advanced Synthesis & Catalysis
Figure 4. DFT optimized structures and HOMO-LUMO energy level diagrams of synthesized compounds (1a),
(1b), (1c), (1d), and (1g) respectively using the B3LYP/6-31G (d, p) basis set level in acetonitrile solvent
modelled by PCM approach.
15a, 18a, 20a, 1b, 1c, 1d, 1g, 18c, 18d, and 18h) in
Figure S16 and the results are summarized in Table.
Photophysical Properties
S1 (SI). All these synthesized compounds showed
As stated earlier in the result and discussion section
strong absorptions, with the positions of maximum
that the newly synthesized compounds having highly
ranging from 454490 nm. The compounds exhibit
conjugated fused isoquinoline core display yellow
three distinct absorption maxima, a band in the region
fluorescent when viewed under 365 nm UV lamp. In
of 313321 nm, a band in the region of 428467 nm
solution, these class of fused conjugated heterocycles
and another in the region of 454490 nm. In
exhibits an intense yellowish green color. Therefore,
dichloromethane solution (105 M) one of fused
their photophysical properties such as UV visible and
isoquinoline derivative (1a) showed absorption peaks
photoluminescence were investigated. The absorption
at 318, 431, and 458 nm with high extinction
spectra (λabs) and emission spectra (λem) were
coefficients (ε) of 27000, 26000 and 35000 L mol−1
measured for a few selected compounds in CH2Cl2.
cm−1, respectively (Table S1, SI).
The UV-Vis spectra of compounds (1a, 2a, 3a, 6a,
8a) are shown in Figure 5(a) and for (10a, 12a, 13a,
9
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10.1002/adsc.201900543
Advanced Synthesis & Catalysis
The fluorescence emissions of some selected
of the substituents effects with the HOMO-LUMO
energy levels could be correlated since both the
HOMO and LUMO are localized at the same central
part of the molecule. These synthesized heterocyclic
compounds having several phenyl rings are emissive
under 365 nm UV lamp, so beyond synthesis the UV-
Vis and fluorescence spectra of some selected
compounds were also examined. These molecules
may therefore find application in fluorescent probes,
optoelectronics applications in organic light emitting
diode (OLEDs) and various other applications in
material science.
fused isoquinoline compounds were also recorded,
which are summarized in Table S1 (SI). The emission
spectra of (1a, 2a, 3a, 6a, 8a), in dichloromethane
solution (105 M) is shown in Figure 5(b), and for
compounds (10a, 12a, 13a, 15a, 18a, 20a, 1b, 1c, 1d,
1g, 18c, 18d, and 18h) in Figure S17 (SI). All
exhibiting strong fluorescence emission in the range
of 502560 nm which belongs to the green region of
the visible light spectrum.
0.6
(a)
1a
2a
3a
6a
Experimental Section
0.5
8a
0.4
General information:
0.3
0.2
0.1
0.0
All the reagents and solvents used were purchased from
commercial available sources and used without further
purification. HPLC grade solvents were purchase from
commercial sources. Organic extracts were dried over
anhydrous sodium sulphate. Solvents were removed in a
rotary evaporator under reduced pressure. Silica gel (60-
120 mesh size) was used for the column chromatography.
Reactions were monitored by TLC on silica gel 60 F254
(0.25mm). All NMR spectra were recorded in CDCl3 with
tetramethylsilane (TMS) as the internal standard and few
were taken in DMSO-d6 in 600 and 400 MHz NMR. The
1H spectra were referenced to the residual CDCl3 (7.26
ppm) whereas for DMSO-d6 it is 2.50 ppm. The 13C spectra
were referenced to the residual CDCl3 (77.230 ppm) and
for DMSO-d6 it is 39.50 ppm. All 19F NMR spectra were
recorded in 400 MHz, and hexafluorobenzene (C6F6) was
taken as reference. Mass spectra were recorded using ESI
mode (Q-TOF MS analyzer). IR spectra were recorded in
KBr or neat in FT-IR spectrometer. All UV experiments
were performed at a probe concentration of 105 M in 1 mL
250
300
350
400
450
500
550
600
Wavelength (nm)
(b)
1a
2a
3a
6a
8a
400
450
500
550
600
650
Wavelength (nm)
Figure 5. a) UV-VIS spectra, b) Photoluminescence
spectra of (1a, 2a, 3a, 6a, and 8a) in CH2Cl2 (1 x 10-5 M)

quartz cuvettes of path length 1 cm at 25 C in UV/VIS
Spectrometer. Photoluminescence were carried out at a
concentration of 105 M in 1 mL quartz cuvettes at 25 C in
Spectrofluorometer in HPLC grade dichloromethane
solution.
Conclusion
In conclusion, we have utilized a Michael-adduct -
keto malononitrile, obtained from the reaction
between ,-unsaturated aromatic ketone and
malononitrile as the substrate for the CH/NH
annulation with an alkyne. In this one-pot sequential
two component synthesis of π-conjugated fused ring
N-containing heterocycle 4-oxo-2,6,7-triaryl-4H-
General Procedure for the Synthesis of 2-(3-oxo-1,3-
diarylpropyl)malononitrile (1-25)[19]
Compounds 1-25 were synthesized as per the following the
method described in S. Lin, Y. Wei, F. Liang. Chem.
Commun. 2012, 48, 9879.
pyrido[2,1-a]isoquinoline-3-carbonitrile
is
General Procedure for the Synthesis of 4-Oxo-2,6,7-
triphenyl-4H-pyrido[2,1-a]isoquinoline-3-carbonitrile
(1a) from 2-(3-Oxo-1,3-diphenylpropyl)malononitrile
(1) and Diphenylacetylene (a)
accomplished via the formation of six new bonds
namely a CC, two CN, two CC and a CO bonds.
The success of the strategies lies in the selective
hydrolysis of one of the cyano group of -keto
malononitrile to an aromatic cyclic amide and finally
CH/NH annulation with disubstituted alkynes in
the presence of Ru(II) catalyst. This process is
compatible to a range of substituents present in
various coupling partners. On the basis of DFT
calculation the positions and electronic nature of MO
levels were investigated but no significant correlation
To an oven-dried 10 mL round bottom flask was added 2-
(3-oxo-1,3-diphenylpropyl)malononitrile (1) (55 mg, 0.2
mmol), Cu(OAc)2·H2O (4 mg, 0.02 mmol), 1,10-
phenanthroline (7 mg, 0.04 mmol), and glacial AcOH (2
mL). The reaction mixture was heated in an oil bath at 110
C for 5 h. Then to this reaction mixture was added
10
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10.1002/adsc.201900543
Advanced Synthesis & Catalysis
diphenylacetylene (a) (36 mg, 0.2 mmol), [Ru(p-
cymene)Cl2]2 (6 mg, 0.01 mmol), Cu(OAc)2·H2O (20 mg,
0.1 mmol) and PEG-400 (2 mL). The reaction mixture was
further heated for 24 h. Then the reaction mixture was
cooled to room temperature, admixed with ethyl acetate
(25 mL) and the organic layer was washed with saturated
sodium bicarbonate solution (1 x 5 mL). The organic layer
was dried over anhydrous sodium sulfate (Na2SO4), and
solvent was evaporated under reduced pressure. The crude
product so obtained was purified over a column of silica
gel (hexane / ethyl acetate, 9:1) to give pure 4-oxo-2,6,7-
triphenyl-4H-pyrido[2,1-a]isoquinoline-3-carbonitrile (1a)
(40 mg, yield 45%). The identity and purity of the product
was confirmed by spectroscopic analysis.
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Acknowledgements
B. K. P acknowledges the support of this research by the
Department of Science and Technology (DST/SERB)
(EMR/2016/007042) and MHRD: 5-5/2014-TS-VII (SB/S1/OC-
53/2013), New Delhi and CIF for instrumental facilities.
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10.1002/adsc.201900543
Advanced Synthesis & Catalysis
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10.1002/adsc.201900543
Advanced Synthesis & Catalysis
FULL PAPER
Graphical Abstract
Intramolecular Cyclization,
CH Activation and Annulation
A. Rakshit, P. Sau, S. Ghosh and
B. K. Patel*
Page No. – Page No.
One-Pot Sequential Synthesis
of Fused Isoquinolines via
Intramolecular
Annulation
Cyclization/
and their
Photophysical Investigation
Keywords:
Isoquinoline; Ru;
CH/NH
DFT;
CH
activation;
annulation;
photoluminescence.
14
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