Rapid and Atom Economic Synthesis of Isoquinolines and Isoquinolinones by C–H/N–N Activation Using a Homogeneous Recyclable Ruthenium Catalyst in PEG Media

Article abstract of DOI:10.1002/ejoc.201900366

Herein, we report an atom-efficient, rapid, green, and sustainable approach to synthesize isoquinolines and isoquinolinones using a homogeneous recyclable ruthenium catalyst in PEG Media assisted by microwave energy. Dibenzoylhydrazine was used for C–H/N–N activation reactions for the first time in combination with ketazine as oxidizing directing groups for annulation reactions with internal alkynes. The developed protocol is environmentally benign due to significantly shortened times with an easy extraction method, higher atom economy, external oxidant and silver or antimony salt free conditions, applicability to a gram scale synthesis, use of biodegradable solvent and wide substrate scope with higher product yields. Moreover, it is worth noting that the established methodology allowed reuse of the catalytic system for up to five successive runs with minimal loss in activity.

Full text of DOI:10.1002/ejoc.201900366

A Journal of
Accepted Article
Title: Rapid and Atom Economic Synthesis of Isoquinolines and
Isoquinolinones by C-H/N-N Activation using Homogeneous
Recyclable Ruthenium Catalyst in PEG Media
Authors: Dewal Sureshrao Deshmukh, Neha Gangwar, and
Bhalchandra Mahadeo Bhanage
This manuscript has been accepted after peer review and appears as an
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content of this Accepted Article.
To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201900366
Link to VoR: http://dx.doi.org/10.1002/ejoc.201900366
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10.1002/ejoc.201900366
European Journal of Organic Chemistry
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Rapid and Atom Economic Synthesis of Isoquinolines and
Isoquinolinones by C-H/N-N Activation using Homogeneous
Recyclable Ruthenium Catalyst in PEG Media
Dewal S. Deshmukh,[a] Neha Gangwar,[a] and Bhalchandra M. Bhanage*[a]
Extensively used homogeneous catalytic systems with
organic solvents are non-reusable and also catalyst recovery from
the reaction mixture is challenging. Besides, some threats may
occur to the environment due to use of volatile organic
compounds. Overcoming these issues, some eco-friendly
alternative processes, e.g. heterogeneous catalysis,[3] application
of supercritical carbon dioxide (CO2)[4] and ionic liquids[5] as
solvents have been proposed. Out of those, heterogeneous
catalysis is limited by the drawback of possible leaching of
catalyst into reaction mixture. While supercritical CO2 is a system
with high pressure and also releases CO2 gas. Conversely, ionic
liquids are generally costly, methods for their synthesis are
laborious, and their toxicities and environmental safeties are still
unknown, which probably become hurdle in its evolvement as a
solvent for greener methodologies.
Thus, in order to conquer all the above-mentioned
restrictions, a considerable concentration has been paid to
develop potent, non-hazardous and recyclable catalytic methods
for the sustainable advancement of a chemical enterprise. In this
perspective, polyethylene glycols (PEGs) proved as an
appropriate medium for environmentally gentle and secured
organic conversions due to its properties like thermal stability,
minimal vapour pressure, biodegradable, inexpensiveness, easily
recoverable, low toxicity and stability in acidic as well as basic
medium.[6] In light of the significance of polyethylene glycols as a
solvent, our research group has considerably contributed in the
area of catalysis as well as synthesis.[7]
In last few decades, microwave-assisted synthetic
methodology has become a progressively prominent approach in
the scientific community. It has competence for expeditious,
uniform and selective heating as well as thermal quenching which
resulted in vivid improvement in the rates, efficiency and yields of
a various chemical reaction.[8] It also opens up new prospects in
the form of novel reactions which could not succeed using
conventional heating. The technology has also other advantages
like low operating cost, minimal side reactions resulting in
increasing atom economy and cleaner processing. These
leverages are all substantial to green and sustainable chemistry.
Chemical transformation via catalytic C–H functionalization
represents a potent strategy over conventional methodologies in
synthetic organic chemistry, considering its high atom and step
economy, efficiency, elegance and environmental impact.[9] In last
few years, ruthenium catalysts have been emerged as an
economic and promising substitute for organic transformations
comprising rhodium catalysed C–H activation reactions.[10]
Concerning the catalytic mechanism of these reactions,
valuable transition-metal catalysts need to be recycled in its active
oxidation state. To assist this, stoichiometric amounts of external
oxidizing agents, such as copper or silver salts, benzoquinone or
potassium persulfate are often needed, for the regeneration of
active catalytic species, which subsequently produces an
equivalent quantity of by-products. Thus, for the sake of
overcoming these drawbacks, a novel redox-neutral strategy by
using oxidizing directing group for regeneration of the active
catalyst was pioneered intensively in recent years.[11] Moreover,
this innovative strategy has the clear advantages of improved
levels of reactivity and selectivity with better yields and the
concomitant cleavage of the directing group has been also
observed.
Abstract: Herein, we report an atom-efficient, rapid, green and
sustainable approach to synthesize isoquinolines and isoquinolinones
using homogeneous recyclable ruthenium catalyst in PEG Media
assisted by microwave energy. Dibenzoylhydrazine was used for C-
H/N-N activation reactions for the first time in combination with
ketazine as oxidizing directing groups for annulation reactions with
internal alkynes. The developed protocol is environmentally benign
due to significantly shortened time with easy extraction method,
higher atom economy, external oxidant and silver or antimony salt free
conditions, applicability to
a gram scale synthesis, use of
biodegradable solvent and wide substrate scope with higher product
yields. Moreover, it is worth noting that the established methodology
allowed to reuse the catalytic system up to five successive runs with
minimal loss in activity.
Introduction
Isoquinolines and isoquinolinones represents a class of
synthetically and pharmaceutically indispensable N-containing
heterocyclic scaffolds with broad ranges of biological activities.[1]
Additionally, their derivatives have enormous applications in the
synthesis of photo-initiators, organic light-emitting diodes,
alkaloids, inhibitors and ligands.[2] (Scheme 1)
Scheme 1. Representative biologically active and other important molecules
consist of isoquinoline and isoquinolinone skeleton.
[a]
Department of Chemistry, Institute of Chemical Technology,
Mumbai-400019, India
E-mail: bm.bhanage@ictmumbai.edu.in;
bm.bhanage@gmail.com
bmbhanage.weebly.com
Supporting information for this article is given via a link at the end of
the document
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10.1002/ejoc.201900366
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Due to the wealth of isoquinoline and isoquinolinone
moieties, several multistep synthetic approaches are developed
for their synthesis,[12] while they are limited with numerous
shortcomings like low regioselectivity, poor yields, and lengthier
reaction periods in some cases. A potent alternate route to
overcome these limitations was provided by annulation reactions
with alkynes via ortho C–H functionalization[13] (Scheme 2). These
transformations are reported with various directing groups using
different transition metal catalysts with stoichiometric amount of
external oxidants. Later, progressing in this area, oxidizing
directing groups were successfully employed to avoid the use of
external oxidants[14] (Scheme 2). Such reactions generally
proceed through cleavage of N−N, N−O, N−S and N−Cl bonds of
directing groups which acts as internal oxidants, leaving the
cleaved fraction in reaction mixture as a by-product. Despite
several advantages of these methodologies, these are still
suffered with undesirable side products.
Various ketazine directed C-H activation reactions are
previously reported.[15] In our concern, azine and
dibenzoylhydrazine could be one of the best directing groups for
the synthesis of isoquinolines and isoquinolinones respectively
using C–H activation strategy. Both nitrogen atoms of these
directing groups could be effectively encompassed to the
anticipated isoquinoline and isoquinolinone products through
sequential C–H activation with higher atom economy avoiding
side product generation. Considering this, Huang[16] and Li[17]
groups have reported the synthesis of isoquinolines with azine as
directing group using Rh catalysts independently (Scheme 2).
Although, these methods could achieve higher atom economy, it
requires expensive Rh catalyst, external oxidants, acid additives
and silver salts. On the other hand, to the best of our knowledge,
hydrazides were rarely explored as a directing group[18] and
synthesis of isoquinolinones using dibenzoylhydrazine as a
directing group is not reported. Also most of the previous
protocols for the synthesis of isoquinolines and isoquinolinones
are reported in non-recyclable homogeneous catalytic systems
with volatile organic solvents using conventional heating for
longer reaction durations, having its own disadvantages.
Therefore, it would be of great value to overcome all these
shortcomings and to establish an atom economical, rapid,
efficient and environmentally benign protocol for the synthesis of
isoquinolines and isoquinolinones. On account of this, an attempt
was made for their synthesis using atom economic directing
groups, homogeneous recyclable catalytic media and microwave
strategy. Continuing our work in the synthesis of N-
heterocycles,[19] herein we report microwave assisted, external
oxidant free synthesis of isoquinolines and isoquinolinones by
annulation of ketazines and dibenzoylhydrazine with internal
alkynes using Ru catalyst in PEG-400 solvent, a homogeneous
reusable catalytic system. Furthermore, the proposed strategy
worked efficiently in significantly short time with no silver salt or
acid additives.
Results and Discussion
We initiated our study with the annulation reaction of
ketazine 1a and diphenylacetylene 2a using ruthenium
complexes as a catalyst, AgSbF6 & NaOAc as additives and PEG-
400 as a solvent using microwave heating at 140 oC for 15
minutes to synthesize isoquinoline 3aa (Table 1). At the outset,
three ruthenium catalysts, RuCl3•H2O, Cp*Ru(COD)Cl and [Ru(p-
cymene)Cl2]2 were attempted to test our hypothesis, out of which
only [Ru(p-cymene)Cl2]2 could generate the anticipated product
3aa in considerable yield (Table 1, entries 1−3). Optimum catalyst
concentration study was performed with catalyst concentration of
10 mol% and 3 mol%. Increase in catalyst concentration to 10
mol% couldn’t provide any significant improvement in the yield of
the product 3aa, while lowering catalyst concentration to 3 mol%
lead to decrease in product yield (Table 1, entries 4 and 5). Next,
we checked the effect of temperature on the efficiency of given
reaction under similar conditions and time. On performing
reaction at 150 oC, product 3aa was observed in 57% yield, while
no significant effect was observed on the product yield on further
increase in reaction temperature (Table1, entry 6 and 7).
Investigating the optimum time, the reaction was performed at
o
Scheme 2. Synthesis of isoquinolines and isoquinolinones via transition-
metal-catalysed C–H functionalization
different durations keeping the constant temperature at 150 C.
Decreasing time to 10 minutes, no substantial effect on the
product yield was observed, while product 3aa obtained in 42%
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Table 1. Optimization of reaction parameters[a]
Entry
1
Catalyst
Additive 1
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
KPF6
Additive 2
Temp (oC)
140
140
140
140
140
150
160
150
150
150
150
150
150
150
150
150
150
150
Time (min)
Yield[b] (%)
RuCl3·H2O
NaOAc
15
15
15
15
15
15
15
10
8
-
trace
38
2
Cp*Ru(COD)Cl
NaOAc
3
[Ru(p-cymene)Cl2]2
[Ru(p-cymene)Cl2]2
[Ru(p-cymene)Cl2]2
[Ru(p-cymene)Cl2]2
[Ru(p-cymene)Cl2]2
[Ru(p-cymene)Cl2]2
[Ru(p-cymene)Cl2]2
[Ru(p-cymene)Cl2]2
[Ru(p-cymene)Cl2]2
[Ru(p-cymene)Cl2]2
[Ru(p-cymene)Cl2]2
[Ru(p-cymene)Cl2]2
[Ru(p-cymene)Cl2]2
[Ru(p-cymene)Cl2]2
[Ru(p-cymene)Cl2]2
[Ru(p-cymene)Cl2]2
NaOAc
4[c]
5[d]
6
NaOAc
40
NaOAc
23
NaOAc
57
7
NaOAc
59
8
NaOAc
56
9
NaOAc
42
10
NaOAc
10
10
10
10
10
10
10
10
10
58
11
-
NaOAc
trace
57
12
KPF6
-
-
-
-
-
-
-
13[e]
14[f]
15[f],[g]
16[f],[h]
17[f],[i]
18[f],[j]
KPF6
73
KPF6
89
KPF6
53
KPF6
68
KPF6
trace
26
KPF6
[a] ketazine 1a (0.5) mmol, diphenylacetylene 2a (1 mmol), [Ru(p-cymene)Cl2]2 (5 mol %), Additive 1 (30 mol%), Additive 2 (20 mol %), PEG-400 (5 mL),
Microwave heating; [b] GC yield based on amount of 2a; [c] 10 mol% [Ru(p-cymene)Cl2]2 was used; [d] 3 mol% [Ru(p-cymene)Cl2]2 was used. [e] 40 mol%
additive 1 was used; [f] 50 mol% additive 1 was used; [g] PEG-200 used as solvent; [h] PEG-600 used as solvent; [i] ethylene glycol used as solvent; [j] under
standard condition without microwave irradiation (conventional oil-bath heating).
yield only on performing the reaction for 8 minutes (Table 1,
entries 8 and 9). Considering the toxicity and environmental
stresses of AgSbF6, it is ideal to replace it with some equally
efficient and comparatively less hazardous additive. In this
concern, KPF6 could be one of the best replacements to make
proposed protocol greener. Attempting the reaction with KPF6 as
one of the additives could lead the product 3aa with similar
efficiency as with AgSbF6 providing 58% yield (Table 1, entry 10).
Several workers reported activation of C-H bond in absence of
acetate source also. [10j][14j][20] So, next, the necessity of KPF6 and
NaOAc as additives was checked by performing the reaction in its
absence. In absence of KPF6 trace amount of product was
observed, while there was no role of NaOAc for this
transformation (Table 1, entries 11 and 12). Further, increasing
the concentration of KPF6 stepwise, substantial increase in the
product yield was observed. 89% yield was obtained when
reaction was performed using 50 mol% KPF6 (Table 1, entries 13
and 14). A series of solvents (i.e. PEG-200, PEG-600 and
ethylene glycol) was screened for the proposed methodology
under similar reaction conditions. But no other solvent could be
as much effective as PEG-400 to generate the desired product
(Table 1, entries 15−17). When the reaction was performed under
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10.1002/ejoc.201900366
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o
conventional oil-bath heating at 150 C for 10 min, the starting
substrate 1a never reached full consumption and isoquinoline 3aa
was obtained only in 26% yield. This indicated that use of
microwave irradiation is indispensable for the reaction to be
efficient. (Table 1, entry 18) Thus the optimized reaction
parameters for the annulation reaction of alkynes with ketazines
are: 1a (0.5 mmol), 2a (1 mmol), Ru catalyst (5 mol%), additive 1
(50 mol%), solvent 5 mL, 150 oC (microwave heating), 10 min. In
light of the above results, we then subjected dibenzoylhydrazine
4a for annulation with internal alkynes 2a under the similar
reaction conditions to extend the scope of the reaction. We were
pleased to find that, dibenzoylhydrazine also worked efficiently
under the proposed protocol to generate isoquinolinones
(Optimization studies for the same is provided in supplementary
information). Optimized reaction parameters for the annulation
reaction of alkynes with dibenzoylhydrazine are: 4a (0.5 mmol),
2a (1 mmol), Ru catalyst (5 mol%), additive 1 (50 mol%), additive
2 (30 mol%), solvent 5 mL, 160 oC (microwave heating), 15 min.
After the optimized reaction conditions were established, we
next explored the application scope of this reaction with a variety
of ketazines and internal alkynes. A series of ketazines bearing
electron donating and withdrawing groups at different positions of
phenyl ring was well tolerated for annulation with various alkynes
for the synthesis of corresponding isoquinolines in good to
excellent yields (Table 2). First, azines with electron donating
groups (i.e. –Me and –OMe) at para position of phenyl rings
smoothly underwent the annulation process to generate the
expected isoquinolines 3ba and 3ca in 90% and 92% yields
respectively. When azines with electron withdrawing groups (i.e.
–Br, –Cl, –F and –NO2) at para position of phenyl rings were
employed for this protocol, desired isoquinolines 3da, 3ea, 3fa
and 3ga were successfully obtained in 84%, 81%, 83% and 73%
yields respectively. The positions of these substituents on phenyl
rings of azine could marginally affect the yields of the respective
isoquinoline products. Electron donating as well as electron
withdrawing groups (i.e. –Me, –OMe, –NO2 and –Cl) at meta
position of phenyl rings of azines were tested, out of which azines
with –Me, –NO2 and –Cl could generate single desired
isoquinoline products 3ha, 3ja and 3ka in 84%, 62% and 78%
yields respectively. While azine with –OMe at meta position of
phenyl ring provided two regioselective isomeric products 3ia and
3ia’ in 51% and 34% yields respectively. These results are
noteworthy and possibly because of steric reason. Likewise,
azine with –OMe group at ortho position of phenyl rings also could
produce desired isoquinoline 3la in 74% yield. In the case of 1m,
bearing two groups that have opposite electronic properties, the
reaction proceeded to generate product 3ma with good overall
yield. We were pleased to find that ketazines derived from
propiophenone, cyclopropyl phenyl ketone, benzophenone, 1-
tetralone and 1-acetyl naphthalene also underwent annulation
reaction smoothly to produce desired products 3na, 3oa, 3pa,
3qa and 3ra in 87%, 85%, 90%, 68% and 71% yields respectively.
Encouraged by these results, we attempted the heterocyclic
azines for annulation with internal alkynes under similar protocol,
thus affording reasonable yields of the corresponding heterocyclic
compounds 3sa and 3ta in 85% and 78% yields respectively.
Unfortunately, azine derived from benzaldehyde, 1u failed to
Table 2. Ruthenium catalysed annulations of ketazines with alkynes[a]
[Reaction conditions: [a] ketazine 1 (0.5 mmol), alkyne 2 (1 mmol), [Ru(p-
cymene)Cl2]2 (5 mol%), KPF6 (50 mol%), PEG-400 (5 mL), 150 oC
(microwave heating), 10 min, isolated yield based on amount of 2.
participate in this annulation reaction. Next, different internal and
terminal alkynes were tested for the developed methodology. Out
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of which, 1-phenyl-1-propyne, 1-phenyl-1-butyne and 3-hexyne
furnished the desired products 3ab, 3ac and 3ad in 83%, 86%
and 80% yields, respectively. The regioselectivity of the products
3ab and 3ac may be due to the steric reasons. While, a terminal
alkyne like phenyl acetylene was incompatible with the proposed
protocol as no desired compound could be identified.
Extending scope of the reaction, next, a broad range of
substituted dibenzoylhydrazine was also briefly examined for the
annulation with internal alkynes (Table 3). Both electron donating
and electron withdrawing groups could produce appreciable
amount of isoquinolinones successfully under the given protocol.
Dibenzoylhydrazine with electron donating groups (e.g. –Me, –
OMe and –t-Bu) at para position of phenyl rings provided
corresponding isoquinolinone products 5ba, 5ca and 5da in
The synthesis of isoquinolines and isoquinolinones could be
further performed at gram scale. For instance, 5 mmol (1.181 g)
of 1a when reacted with 10 mmol (1.782 g) of 2a under the
optimized reaction conditions, could generate 1-methyl-3,4-
diphenylisoquinoline 3aa in 83% yield. Also, when 5 mmol (1.201
g) of 4a reacted with 10 mmol (1.782 g) of 2a, produced desired
product 3,4-diphenylisoquinolin-1(2H)-one 5aa in 69% yield.
With the delightful results with Ru catalyst in PEG-400, we
then investigated the reusability of the solvent as well as the
catalyst (Figure 1). The annulation reaction of ketazine 1a and
dibenzoylhydrazine 4a was conducted with diphenylacetylene 2a
under the optimized reaction conditions separately. After initial
experimentation, the extraction of reaction mixture was performed
with 4-5 mL of diethyl ether for four to five times. The upper
extracted layer consist of product mixture was then purified with
column chromatography. The lower layer containing [RuCl2(p-
cymene)]2/additives/PEG-400 was heated at 50-60 oC to
eliminate trace quantity of miscible ether and then assigned to a
76%,77%
and
73%
yields
respectively.
Similarly,
dibenzoylhydrazine with electron withdrawing groups (e.g. –Br
and –F) at para position could generate the respective products
5ea and 5fa in 67% and 63% yields respectively. Effect of the
positions of the substituents on the yields of the isoquinolinone
products was next examined. –Cl at meta position of phenyl rings
of dibenzoylhydrazine could produce the corresponding product
5ga in 59% yield. Next, dibenzoylhydrazine derived from 2-
naphthoyl chloride 4h also underwent annulation reaction
successfully leading to product 5ha in 68% yield. Last, aliphatic
internal alkyne i.e. 3-hexyne could successfully subjected for
annulation with dibenzoylhydrazine forming the product 5ad in
70% yield.
Table 3. Ruthenium catalysed annulations of dibenzoylhydrazine with
alkynes[a]
Reaction conditions: [a] Reaction conditions: dibenzoylhydrazine 1 (0.5
mmol), alkyne 2 (1 mmol), [Ru(p-cymene)Cl2]2 (5 mol%), KPF6 (50 mol%),
NaOAc (30 mol%) PEG-400 (5 mL), 160 oC (microwave heating), 15 min,
isolated yield based on amount of 2.
Figure 1. (a) Procedure to reuse catalyst and solvent system, (b) The catalyst
recyclability study for annulation of 1,2-Bis(1-phenylethylidene)hydrazine 1a
and N,N′-Dibenzoylhydrazine 4a with diphenylacetylene 2a.
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Experimental procedure for the ruthenium catalysed isoquinoline
synthesis
second run for the annulation reaction by loading the same
substrates. The outcomes of these and four consecutive
experiments were consistent in their yields of 89%, 88%, 88%,
85% and 83% respectively for ketazine and 74%, 73%, 71%, 71%
and 70% respectively for dibenzoylhydrazine (Figure 1a). We
were pleased to observe that the catalytic system could be
recycled and reused up to five times with minimal loss of activity
and the minute decrease in yield might be owing to loss of product
and catalyst during work-up.
A microwave vessel containing magnetic stir bar was charged with
ketazine 1a (0.5 mmol, 118 mg), diphenylacetylene 2a (1 mmol, 178 mg),
[Ru(p-cymene)Cl2]2 (5 mol% 16 mg), KPF6 (50 mol%, 46 mg) and PEG-
400 (5 mL). The reaction mixture was allowed to stir at 150 oC using
microwave irradiation of 100 W power for 10 minutes. At the end of the
reaction, the reaction mixture was cooled and diluted with diethyl ether.
The upper layer of diethyl ether contains a product mixture which is directly
used for purification. The product was purified through a silica gel column
using pet ether and ethyl acetate as eluents to give pure 3aa.
Experimental procedure for the ruthenium catalysed isoquinolinone
synthesis
Conclusions
A microwave vessel containing magnetic stir bar was charged with
dibenzoylhydrazine 4a (0.5 mmol, 120 mg), diphenylacetylene 2a (1 mmol,
178 mg), [Ru(p-cymene)Cl2]2 (5 mol% 16 mg), KPF6 (50 mol%, 46 mg),
NaOAc (30 mol%, 13 mg) and PEG-400 (5 mL). The reaction mixture was
In summary, we have employed ketazine and dibenzoylhydrazine
for annulation reaction with alkynes via C−H/N−N bond activation
to synthesize isoquinolines and isoquinolinones respectively. The
proposed protocol works efficiently under microwave conditions
in Ru/PEG as a homogeneous recyclable catalytic system.
Dibenzoylhydrazine, a novel directing group acts as an internal
oxidant along with ketazine for the C−H activation reactions.
Microwave strategy could significantly reduce the reaction time to
minutes as compared to previously reported conventional heating
for longer times to synthesize isoquinolines and isoquinolinones.
The catalytic media could be reused for 5 times with minimal loss
in activity. The mentioned approach works efficiently in absence
of external oxidant as well as silver salt in biodegradable solvent.
Further, we could scale up the given protocol to gram level with
minute effect on the product yield. All the above-mentioned
characteristics of the methodology makes it more sustainable and
eco-friendlier. Moreover, a wide range of isoquinoline and
isoquinolinone derivatives could be synthesized with good to
excellent yields under a proposed scheme.
o
allowed to stir at 160 C using microwave irradiation of 100 W power for
15 minutes. At the end of the reaction, the reaction mixture was cooled
and diluted with diethyl ether. The upper layer of diethyl ether contains a
product mixture which is directly used for purification. The product was
purified through a silica gel column using pet ether and ethyl acetate as
eluents to give pure 5aa.
Experimental characterization data for isoquinoline (3) and
isoquinolinone (4) products
1-Methyl-3,4-diphenylisoquinoline (3aa)[14t]: Pale yellow solid; mp 154-156
oC; 1H NMR (500 MHz, CDCl3) δ 8.23 – 8.20 (m, 1H), 7.68 – 7.66 (m, 1H),
7.62 – 7.59 (m, 2H), 7.39 – 7.34 (m, 5H), 7.27 – 7.17 (m, 5H), 3.11 (s, 3H);
13C NMR (126 MHz, CDCl3) δ 157.75, 149.29, 140.81, 137.49, 136.01,
131.39, 130.27, 130.02, 129.27, 128.20, 127.62, 127.15, 126.97, 126.59,
126.25, 126.14, 125.57, 22.69; GCMS (EI 70 eV) m/z (% rel. inten.) 295
(M+), 294, 252, 146.
1,6-Dimethyl-3,4-diphenylisoquinoline (3ba)[14t]: White solid; mp 159–161
oC; 1H NMR (500 MHz, CDCl3) δ 8.10 (d, 1H), 7.44 – 7.35 (m, 7H), 7.26 –
7.17 (m, 5H), 3.07 (s, 3H), 2.44 (s, 3H); 13C NMR (126 MHz, CDCl3) δ
157.39, 149.47, 141.00, 140.34, 137.68, 136.23, 131.44, 130.26, 128.81,
128.76, 128.17, 127.57, 127.04, 126.87, 125.49, 125.09, 124.54, 22.62,
22.16.; GCMS (EI 70 eV) m/z (% rel. inten.) 309 (M+), 308, 252, 146.
Experimental Section
General experimental details and materials
All chemicals and solvents were purchased with high purities and used
without further purification. PEGs were dried prior to use by the literature
methods. Microwave-assisted annulation reactions were carried out in
Multiwave PRO microwave reactor (Anton Paar GmbH, Graz, Austria). The
progress of the reaction was monitored by gas chromatography (GC) with
a flame ionization detector (FID) with a capillary column (30 m × 0.25 mm
× 0.25 μm) and thin layer chromatography (using silica gel 60 F-254 plates).
The products were visualized with a 254 nm UV lamp. GC-MS (Rtx- 17, 30
m × 25 mm ID, film thickness (df = 0.25 μm) (column flow 2 mL min-1,
80 °C to 240 °C at 10 °C min-1 rise) was used for the mass analysis of the
products. Products were purified by column chromatography on 100-200
mesh silica gel. The 1H NMR spectras were recorded on an Agilent
Technologies 400 MHz and 500 MHz spectrometer using
tetramethylsilane (TMS) as an internal standard. The 13C NMR spectras
were recorded on 100 MHz and 126 MHz and Chemical shifts were
reported in parts per million (δ) relative to tetramethylsilane (TMS) as an
internal standard. Coupling constant (J) values were reported in hertz (Hz).
Splitting patterns of proton are described as s (singlet), d (doublet), dd
6-Methoxy-1-methyl-3,4-diphenylisoquinoline (3ca)[14t]: Pale yellow solid;
o
m.p. 179-181 C; 1H NMR (500 MHz, CDCl3) δ 8.11 (d, J = 9.1 Hz, 1H),
7.36 – 7.30 (m, 5H), 7.26 – 7.18 (m, 6H), 6.92 (d, J = 2.2 Hz, 1H), 3.73 (s,
3H), 3.04 (s, 3H); 13C NMR (126 MHz, CDCl3) δ 160.61, 156.99, 149.98,
138.10, 137.77, 131.27, 130.22, 128.27, 127.57, 127.49, 127.10, 126.91,
121.85, 118.75, 104.47, 55.22, 22.56; GCMS (EI 70 eV) m/z (% rel. inten.)
325 (M+), 324, 281, 154, 146.
6-Bromo-1-methyl-3,4-diphenylisoquinoline (3da)[14t]: Slightly yellow solid;
m.p. 192-194 oC; 1H NMR (500 MHz, CDCl3) δ 8.08-8.03 (m, 1H), 7.82 –
7.80 (m, 1H), 7.68-7.64 (m, 1H), 7.36 – 7.26 (m, 5H), 7.24 – 7.20 (m, 5H),
3.07 (s, 3H); 13C NMR (126 MHz, CDCl3) δ 157.81, 150.54, 140.51, 137.40,
136.77, 131.29, 130.21, 130.06, 128.45, 128.42, 128.36, 127.68, 127.48,
127.34, 127.22, 125.14, 124.59, 22.69; GCMS (EI 70 eV) m/z (% rel.
inten.) 375 (M+2), 373 (M+), 374, 372, 293, 292, 252, 147, 139, 125.
1
(doublet of doublet), t (triplet) and m (multiplet) in H NMR spectroscopic
analysis. The products were confirmed by GCMS, LRMS, 1H and 13C NMR
spectroscopy analysis.
6-Chloro-1-methyl-3,4-diphenylisoquinoline (3ea)[14t]: Pale yellow solid;
m.p. 171-173 oC; 1H NMR (500 MHz, CDCl3) δ 8.15 (d, 1H), 7.63 (s, 1H),
7.53 (dd, J = 5.3, 3.1Hz), 7.39 – 7.26 (m, 5H), 7.21 – 7.17 (m, 5H), 3.07 (s,
3H); 13C NMR (126 MHz, CDCl3) δ 157.68, 150.49, 140.43, 137.13, 136.79,
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201900366
European Journal of Organic Chemistry
FULL PAPER
136.47, 131.26, 130.19, 128.43, 127.67, 127.50, 127.46, 127.38, 127.22,
125.12, 124.40, 22.67; GCMS (EI 70 eV) m/z (% rel. inten.) 331 (M+2),
329 (M+), 330, 328, 252, 146.
– 2.81 (m, 1H), 1.43 – 1.36 (m, 2H), 1.16 – 1.14 (m, 2H); 13C NMR (126
MHz, CDCl3) δ 160.58, 148.54, 140.99, 137.87, 136.18, 131.43, 130.45,
129.71, 128.71, 128.10, 127.36, 127.09, 126.89, 126.85, 126.42, 126.26,
124.91, 13.64, 9.42; GCMS (EI 70 eV) m/z (% rel. inten.) 321 (M+), 320,
243, 152.
6-Fluoro-1-methyl-3,4-diphenylisoquinoline (3fa)[14t]
: White solid; m.p.
145-147 oC; 1H NMR (400 MHz, CDCl3) δ 8.21 (dd, J = 9.1, 5.6 Hz, 1H),
7.35 – 7.29 (m, 6H), 7.26 – 7.23 (m, 1H), 7.20 – 7.17 (m, 5H), 3.06 (s, 3H);
13C NMR (126 MHz, CDCl3) δ 164.24, 162.28, 157.52, 150.30, 140.46,
138.00, 137.11, 131.19, 130.20, 128.69, 128.61, 128.41, 127.66, 127.39,
127.17, 123.42, 116.82, 116.62, 109.98, 109.80, 22.80; GCMS (EI 70 eV)
m/z (% rel. inten.) 313 (M+), 312, 270, 155.
o
1,3,4-Triphenylisoquinoline (3pa)[14t]: Yellow solid; m.p. 169 - 171 C; 1H
NMR (500 MHz, CDCl3) δ 8.21 (d, J = 4.5 Hz, 1H), 7.86 – 7.84 (m, 2H),
7.75 (d, J = 8.3 Hz, 1H), 7.64 – 7.52(m, 5H), 7.46 – 7.38 (m, 5H), 7.34–
7.27 (m, 2H), 7.22 – 7.12 (m, 3H); 13C NMR (126 MHz, CDCl3) δ 159.58,
149.69, 140.80, 139.72, 137.52, 137.00, 131.36, 130.47, 130.26, 129.84,
129.84, 128.59, 128.34, 127.57, 127.55, 127.32, 127.04, 126.6, 126.05,
125.45; GCMS (EI 70 eV) m/z (% rel. inten.) 357 (M+), 171, 145, 118.
1,7-Dimethyl-3,4-diphenylisoquinoline (3ha)[14t]: Slightly yellow solid; 131-
133 oC; 1H NMR (500 MHz, CDCl3) δ 7.98 (s, 1H), 7.59 -7.55 (m, 1H), 7.45
– 7.33 (m, 6H), 7.27–7.17 (m, 5H), 3.08 (s, 3H), 2.59 (s, 3H); 13C NMR
(126 MHz, CDCl3) δ 157.02, 148.56, 140.98, 137.71, 136.44, 134.19,
132.12, 131.38, 130.27, 129.11, 128.16, 127.59, 127.06, 126.83, 126.33,
126.11, 124.53, 22.72, 21.91; GCMS (EI 70 eV) m/z (% rel. inten.) 309
(M+), 308, 252, 146, 139.
1-Methyl-3,4-diphenylbenzo[h]isoquinoline (3ra)[14t]: Slightly yellow solid;
mp 142-144 °C; 1H NMR (500 MHz, CDCl3) δ 8.92 (d, J = 8.2 Hz, 1H), 7.93
(d, J = 7.7 Hz, 1H), 7.80 -7.73 (m, 2H), 7.67 (t, J = 6.0 Hz, 1H), 7.58 – 7.55
(m, 1H), 7.45 – 7.43 (m, 2H), 7.39 – 7.36 (m, 3H), 7.27 – 7.21 (m, 5H),
3.46 (s, 3H);13C NMR (126 MHz, CDCl3) δ 155.42, 150.81, 140.43, 137.95,
137.28, 132.97, 131.66 , 131.26, 130.23, 129.75, 128.77, 128.29, 127.92,
127.69, 127.30, 127.30, 126.91, 126.68, 124.21, 123.96, 30.48; GCMS
(EI 70 eV) m/z (% rel. inten.) 345 (M+), 344, 302, 164.
7-Methoxy-1-methyl-3,4-diphenylisoquinoline (3ia)[14t]: Yellow solid; m.p.
121-123 oC; 1H NMR (500 MHz, CDCl3) δ 7.59 (dd, J = 9.2, 2.4 Hz, 1H),
7.41 – 7.32 (m, 6H), 7.27 – 7.15 (m, 6H), 3.99 (s, 3H), 3.05 (s, 3H); 13C
NMR (126 MHz, CDCl3) δ 157.88, 156.00, 147.60, 137.64, 131.36, 131.34,
130.23, 129.25, 128.17, 128.03, 127.58, 127.31, 127.11, 126.77, 122.35,
103.47, 55.51, 22.82; GCMS (EI 70 eV) m/z (% rel. inten.) 325 (M+), 324,
281, 140, 139.
7-Methyl-4,5-diphenylthieno[2,3-c]pyridine (3sa)[14t]: White solid; m.p. 145-
147 oC; 1H NMR (500 MHz, CDCl3) δ 7.63 (d, J = 3.4 Hz, 1H), 7.37 – 7.27
(m, 5H), 7.24 – 7.20 (m, 6H), 2.93 (s, 3H); 13C NMR (126 MHz, CDCl3) δ
151.37, 150.79, 145.77, 140.20, 138.16, 134.27, 134.25, 131.14, 130.53,
130.32, 128.26, 127.73, 127.18, 127.13, 124.27, 23.57; GCMS (EI 70 eV)
m/z (% rel. inten.) 301 (M+), 300, 258, 150, 149.
5-Methoxy-1-methyl-3,4-diphenylisoquinoline (3ia’)[14p]: White solid; mp.
145-147 °C; 1H NMR (500 MHz, CDCl3) δ 7.80 (d, J = 8.4 Hz, 1H), 7.54 (t,
J = 8.1 Hz, 1H), 7.30 – 7.23 (m, 2H), 7.20 – 7.04 (m, 8H), 6.97 (d, J = 7.6
Hz, 1H), 3.41 (s, 3H), 3.06 (s, 3H); 13C NMR (126 MHz, CDCl3) δ 157.09,
156.78, 150.97, 141.47, 141.37, 130.37, 130.22, 127.90, 127.75, 127.41,
127.29, 127.12, 126.47, 125.63, 118.04, 110.12, 55.54, 23.35; GCMS (EI
70 eV) m/z (% rel. inten.) 325 (M+), 324, 308, 154.
4-ethyl-1-methyl-3-phenylisoquinoline (3ac)[14t]: White solid; m.p. 121-123
oC; 1H NMR (500 MHz, CDCl3) δ 8.18 (d, J = 3.8 Hz, 1H), 8.09 (d, J = 3.9
Hz, 1H), 7.75 (t, J = 7.6 Hz, 1H), 7.61 (t, J = 7.6 Hz, 1H), 7.53 – 7.35 (m,
5H), 3.03 - 2.97 (m, 5H), 1.27 (t, J = 7.4 Hz, 3H); 13C NMR (126 MHz,
CDCl3) δ 155.86 , 150.56, 141.66 , 135.16, 129.94, 129.20, 128.65, 128.18,
127.45, 126.69, 126.35, 126.25, 124.16, 22.46, 21.68, 15.73; GCMS (EI
70 eV) m/z (% rel. inten.) 247 (M+), 246, 232, 231, 230, 115.
7-Chloro-1-methyl-3,4-diphenylisoquinoline (3ka)[14b]: White solid; m.p.
143-145 °C; 1H NMR (500 MHz, CDCl3) δ 8.17 (d, J = 2.2 Hz, 1H), 7.63 –
7.59 (m, 1H), 7.53 – 7.51 (m, 1H), 7.37 – 7.26 (m, 5H), 7.22 – 7.19 (m, 5H),
3.06 (s, 3H); 13C NMR (126 MHz, CDCl3) δ 156.86, 149.70, 140.46, 137.00,
134.43, 132.32, 131.27, 130.76, 130.20, 129.06, 128.34, 128.18, 127.67,
127.39, 127.16, 126.84, 124.53, 22.66; GCMS (EI 70 eV) m/z (% rel.
inten.) 331 (M+2), 329 (M+), 330, 328, 293, 252, 146.
3,4-Diethyl-1-methylisoquinoline (3ad)[14b]: Yellow liquid; b.p. 140-142 oC;
1H NMR (500 MHz, CDCl3) δ 8.09 (d, J = 8.4 Hz, 1H), 7.98 (d, J = 8.6 Hz,
1H), 7.66 (t, J = 8.7 Hz, 1H), 7.50 (t, J = 8.8 Hz, 1H), 3.07 – 2.91 (m, 7H),
1.37 – 1.27 (m, 6H); 13C NMR (126 MHz, CDCl3) δ 155.77, 152.48, 135.14,
129.54, 127.24, 126.15, 126.05, 125.30, 123.35, 28.45, 22.31, 20.68,
15.26, 14.96; GCMS (EI 70 eV) m/z (% rel. inten.) 199 (M+), 198, 184, 170,
128, 91.
6-Chloro-1,7-dimethyl-3,4-diphenylisoquinoline (3ma) [19b]: Slightly yellow
solid; m.p. 158-160 oC ; 1H NMR (500 MHz, CDCl3) δ 8.19 (d, J = 3.6 Hz,
1H), 7.50 (d, J = 3.4 Hz, 1H), 7.36 – 7.26 (m, 5H), 7.24 - 7.13 (m, 5H), 3.05
(s, 3H), 2.46 (s, 3H); 13C NMR (126 MHz, CDCl3) δ 156.56, 149.69, 141.72,
139.25, 137.19, 134.81, 133.73, 131.28, 130.97, 129.30, 128.31, 127.63,
127.53, 127.32, 127.12, 125.89, 125.66, 22.40, 21.00; GCMS (EI 70 eV)
m/z (% rel. inten.) 345 (M+2), 343 (M+), 342, 307, 265, 154, 146.
3,4-diphenylisoquinolin-1(2H)-one (5aa)[14u]: Colourless solid; m.p. 252-
254 oC; 1H NMR (500 MHz, CDCl3) δ 9.35 (s, 1H), 8.49 (s, 1H), 7.61 – 7.18
(m, 13H); 13C NMR (126 MHz, cdcl3) δ 162.55, 144.99, 138.68, 136.84,
135.56, 134.99, 132.78, 131.79, 129.14, 128.70, 128.41, 127.46, 127.36,
126.72, 125.73, 125.00, 112.63.
1-Ethyl-3,4-diphenylisoquinoline (3na)[14t]: White solid; m.p. 114-116 oC;
1H NMR (500 MHz, CDCl3) δ 8.28 – 8.25 (m, 1H), 7.70-7.68 (m, 1H), 7.60
– 7.58 (m, 2H), 7.42 – 7.33 (m, 5H), 7.26 – 7.19 (m, 5H), 3.47 (dd, J = 7.5,
2.6 Hz, 2H), 1.56 (t, J = 6.2 Hz, 3H); 13C NMR (126 MHz, cdcl3) δ 162.30,
149.22, 141.03, 137.70, 136.35, 131.40, 130.36, 129.77, 129.01, 128.23,
127.58, 127.12, 126.92, 126.48, 126.42, 125.29 125.17, 28.81, 14.04;
GCMS (EI 70 eV) m/z (% rel. inten.) 309 (M+), 308, 293, 280, 154, 146.
6-methyl-3,4-diphenylisoquinolin-1(2H)-one (5ba)[14u]: White solid; m.p.
274-276 oC; 1H NMR (500 MHz, CDCl3) δ 9.84 (s, 1H), 8.34 (d, J = 8.0 Hz,
1H), 7.33 – 7.14 (m, 12H), 2.38 (s, 3H); 13C NMR (126 MHz, CDCl3) δ
162.78, 143.36, 138.83, 137.25, 135.86, 135.05, 131.86, 129.36, 128.53,
128.35, 128.23, 127.44, 127.23, 125.34, 122.91, 117.22, 22.13.
6-methoxy-3,4-diphenylisoquinolin-1(2H)-one (5ca)[13f]: Off white solid;
1
m.p. 288-290 oC; H NMR (500 MHz, CDCl3) δ 9.46 (s, 1H), 8.42 (d, J =
1-Cyclopropyl-3,4-diphenylisoquinoline (3oa) [13g]: White solid; m.p. 149-
151 oC; 1H NMR (500 MHz, CDCl3) δ 8.51 (d, J = 7.8 Hz, 1H), 7.67 – 7.55
(m, 3H), 7.38 – 7.34 (m, 5H), 7.27 – 7.21 (m, 2H), 7.20 -7.17 (m, 3H), 2.87
8.6 Hz, 1H), 7.34 – 7.10 (m, 11H), 6.75 (d, J = 1.8 Hz, 1H), 3.74 (s, 3H);
13C NMR (126 MHz, CDCl3) δ 163.42, 162.12, 141.04, 137.44, 135.43,
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201900366
European Journal of Organic Chemistry
FULL PAPER
134.77, 131.64, 129.49, 129.12, 128.81, 128.49, 128.45, 127.50, 115.90,
107.55, 55.36.
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6-(tert-butyl)-3,4-diphenylisoquinolin-1(2H)-one (5da)[13f]: White solid; m.p.
286-288 oC; 1H NMR (500 MHz, CDCl3) δ 9.54 (s, 1H), 8.43 (s, 1H), 8.00
-7.18 (m, 12H), 1.25 (s, 9H); 13C NMR (126 MHz, CDCl3) δ 160.74, 156.57,
138.70, 136.60, 134.98, 131.80, 129.88, 129.22, 128.66, 128.40, 128.33,
127.37, 127.13, 125.23, 125.08, 121.88, 118.11, 35.37, 30.97.
6-bromo-3,4-diphenylisoquinolin-1(2H)-one (5ea)[14u]: White solid; m.p.
278-280 oC; 1H NMR (500 MHz, CDCl3) δ 9.37 (s, 1H), 8.34 (s, 1H), 7.60
– 7.15 (m, 12H); 13C NMR (126 MHz, CDCl3) δ 161.58, 140.78, 140.29,
135.85, 134.54, 131.74, 130.23, 129.22, 129.10, 129.03, 128.67, 128.52,
127.76, 127.40, 127.24, 123.85, 113.93, 79.19.
6-fluoro-3,4-diphenylisoquinolin-1(2H)-one (5fa)[14u]: White solid; m.p. 256-
o
1
258 C; H NMR (500 MHz, CDCl3) δ 9.61 (s, 1H), 8.52 (dd, J = 8.9, 5.9
Hz, 1H), 7.36 – 7.00 (m, 12H).
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7-Chloro-3,4-diphenylisoquinolin-1(2H)-one (5ga)[14u]: White solid; m.p.
243-245 oC; 1H NMR (500 MHz, CDCl3) δ 9.29 (s, 1H), 8.50 (s, 1H), 7.67
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3,4-Diphenylbenzo[g]isoquinolin-1(2H)-one (5ha)[14b]: Pale yellow solid;
m.p. 281-283 oC; 1H NMR (500 MHz, CDCl3) δ 9.12 (s, 1H), 8.92 (s, 1H),
8.10 – 8.08 (m, 1H), 7.81 – 7.79 (m, 2H), 7.57 – 7.26 (m, 12H). 13C NMR
(126 MHz, CDCl3) δ 163.16, 138.20, 135.80, 135.63, 135.25, 135.17,
134.61, 131.84, 131.47, 129.29, 129.10, 128.91, 128.68, 128.52, 128.49,
128.37, 128.11, 127.48, 126.41, 124.76, 116.95.
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Acknowledgments
The author D.S.D. would like to thank University Grant
Commission (UGC), New Delhi, India for providing a Senior
Research Fellowship under Basic Science Research (BSR)
scheme [F.25-1/2014-15(BSR)/F.7-227/2009 (BSR), 16th Feb
2015].
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Keywords: C-H/N-N activation • Oxidant free • Ruthenium •
Microwave-assisted • Isoquinolines • Isoquinolinones
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Entry for the Table of Contents
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C–H activation*
Dewal S. Deshmukh, Neha Gangwar,
Bhalchandra M. Bhanage*
Page No. – Page No.
Rapid and Atom Economic Synthesis
of Isoquinolines and Isoquinolinones
by C-H/N-N Activation using
Homogeneous Recyclable Ruthenium
Catalyst in PEG Media
An atom-efficient, rapid, green and sustainable approach has been developed for
the synthesis of isoquinolines and isoquinolinones by annulation via C-H/N-N
activation using homogeneous recyclable ruthenium catalyst in PEG media.
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