N-Tosylhydrazone directed annulation via C-H/N-N bond activation in Ru(ii)/PEG-400 as homogeneous recyclable catalytic system: a green synthesis of isoquinolines

Article abstract of DOI:10.1039/C8OB01082J

A green and sustainable methodology for the synthesis of isoquinolines using Ru(ii)/PEG-400 as a homogeneous recyclable catalytic system has been demonstrated. N-Tosylhydrazone, a rarely explored directing group, has been successfully employed for an annu

Full text of DOI:10.1039/C8OB01082J

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N-Tosylhydrazone directed annulation via C-H/N-N bond
activation in Ru(II)/PEG-400 as homogeneous recyclable catalytic
system: a green synthesis of isoquinolines†
Received 00th January 20xx,
Accepted 00th January 20xx
Dewal S. Deshmukh and Bhalchandra M. Bhanage*
DOI: 10.1039/x0xx00000x
www.rsc.org/
A green and sustainable methodology for the synthesis of isoquinolines using Ru(II)/PEG-400 as a homogeneous recyclable
catalytic system has been demonstrated. N-tosylhydrazone, a rarely explored directing group has been successfully
employed for the annulation type of reaction with alkynes via C-H/N-N activation. Short reaction time with a simple
extraction procedure, wide substrate scope with high yields of products, easily prepared substrates, biodegradable solvent
and scalability up to the gram level enhances the efficiency and sustainability of the proposed protocol. Further, the
expensive ruthenium based homogeneous catalytic system could be reused up to a fourth consecutive cycle without any
loss in its activity.
avoiding the practice of any perilous and costly solvents
became essential for the sustainable advancement of a chemical
enterprise.3 To satisfy both recyclability and environmental
Introduction
The area of transitionꢀmetalꢀcatalyzed direct activation of inert
C−H bonds in synthetic organic chemistry has gained
considerable attention. Such methodology represents a stateꢀofꢀ
theꢀart for the conversion of organic molecules in account of
high atom and step economy, efficiency, environmental impact,
and elegance as it reduces the unnecessary prefunctionalization
of starting material. Due to the unique advantages offered by
this strategy over traditional methods of synthesis, it became a
novel toolbox of organic chemists. This approach can also open
the doors of new possibilities of retrosynthetic pathways to
build complex organic scaffolds.1
Homogeneous catalytic systems using organic solvents are
well established for C–H functionalization reactions. Still, this
approach faces many challenges at the industrial scale as these
they require nonꢀreusable, expensive catalyst systems and
issues related to the catalyst recovery/recycle. Heterogeneous
catalysis for C–H activation can overcomes these disadvantages
as it provides the prospect for ease of separation and recycling
of the catalyst along with hassleꢀfree product purification and
probably continuous or several processing of compounds.2
Though, leaching of the catalyst into reaction mixture is the
serious drawback, thereby limiting its applicability. Moreover,
most of the solvents in these systems are volatile organic
compounds which are responsible for severe environmental
threats. Thus, the development of nonhazardous alternatives
concerns, some environmentally benign methodologies like
employment of supercritical carbon dioxide4 (CO2) and ionic
liquids5 as solvents have been evolved. A major complication
associated with supercritical CO2 is being an “underꢀpressure”
system and also discharges CO2 gas, so it has limited scope for
its application. On the other hand, the main disadvantage which
becomes hurdle in the evolvement of the ionic liquids as a
solvent is that these compounds are expensive, they have
tedious synthetic methods, their environmental safeties and
toxicities are still anonymous. To overcome all these
constraints, substantial attention has been devoted towards the
development of a potent and recyclable catalytic method for C–
H activation reactions. In this context, polyethylene glycols
(PEGs) can serve as a replacement for traditional solvents in
synthetic chemistry. Possessing negligible vapour pressure,
inexpensiveness, thermally stable, biodegradable, stable in both
acidic and basic media, easily recoverable, relatively low in
cost and low toxicity, Polyethylene glycols serve as
a
compatible reaction medium for environmentally benign and
safe organic transformations.6 In addition, possessing particular
properties, PEGs have been employed for catalyst
immobilization7,
nanoparticle
stabilisation8,
ligand
stabilization9 and as a phase transfer catalysts10. The toxicity
profile and ecological encumbrance are known for a range of
PEG molecular weights. Considering the advantages presented
by PEG as a green and sustainable solvent system, our group
has come up with several valuable contributions in the area of
synthetic methodology as well as catalysis.11
Department of Chemistry, Institute of Chemical Technology (ICT), Mumbai, India. E-
mail: bm.bhanage@gmail.com, bm.bhanage@ictmumbai.edu.in;
Fax: +91 2233611020; Tel: +91 2233612601
†Electronic supplementary informaꢀon (ESI) available: 1H NMR, 13C NMR, GCMS
and HRMS. See DOI:
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shortcomings, annulation of different aromatic moieties with
internal alkynes via C–H bond functionalization has become an
effective tool for the single step synthesis of substituted
isoquinolines. Most of these organic transformations via C–H
activation are catalyzed by rhodium16 and cobalt17 complexes
.
In recent years, ruthenium complexes have gained renown
as promising and economic replacements of rhodium catalysts
for C–H bond functionalization reactions.18 However, only one
methodology for the synthesis of isoquinolines by using
ruthenium complex as a catalyst in homogeneous media has
been reported by Ackermann et al.19 Various directing groups
are known for this approach toward substituted isoquinoline
synthesis through N–O, N–C and N–N bond cleavage (Scheme
Scheme 1 Examples of important drugs and other useful molecules containing an
isoquinoline skeleton.
Heterocyclic compounds with nitrogen as heteroatom are 2). In literature,
omnipresent in abundant natural, pharmaceutical and synthetic
directing group for C–H bond functionalization.20 To the best of
bioactive molecules. Out of them, isoquinolines form one of the our knowledge, there is no report on –tosylhydrazone directed
N–tosylhydrazone has rarely been explored as a
N
most important classes with diverse biological activities like annulations reaction with internal alkynes. Therefore, an
cardiovascular, antiꢀtumor, antiꢀHIV, antiꢀinflammatory, antiꢀ attempt was made to study this directing group for annulations
malarial, etc.12 For instance, papaverine and jatrorrhizine are as well as different C–H functionalization reactions. In
the molecules containing isoquinoline scaffold and are effective addition, all the previous protocols for substituted isoquinoline
drugs for treatment of erectile dysfunction and antiꢀ synthesis have been reported in nonꢀreusable homogeneous
inflammatory effect respectively.13 In addition, isoquinoline reaction media. Existing literature lacks a green and sustainable
derivatives are utilized in the synthesis of various alkaloids, route for this particular synthesis. Earlier we have reported the
organic lightꢀemitting diodes, ligands, and inhibitors14 (Scheme molecular iodine catalyzed synthesis of quinazolines by
1).
benzylic sp3 C–H bond amination.21 In continuation to our
Due to the wealth of isoquinoline skeletons in various research work in green and sustainable chemistry, herein, we
molecules, a plethora of multistep synthetic methods has been aimed for the synthesis of isoquinoline using ruthenium
reported for their generation.15 However, these suffer from
catalysed homogeneous recyclable catalytic media.
Previous reports:
One time use of catalyst and solvent
Results and discussion
R1
R1
H
R3
X
[M]
N
N
R2
We initiated our investigation by choosing the annulation
Ar
Ar
R3
reaction of 4ꢀmethylꢀ
hydrazide 1a with diphenylacetylene 2a for the synthesis of 1ꢀ
methylꢀ3,4ꢀdiphenylisoquinoline 3aa as model reaction
(Table 1). At first, three commercially available ruthenium
catalysts such as RuCl3.H2O, Cp*Ru(COD)Cl and [Ru(
N′ꢀ(1ꢀphenylethylidene)benzenesulfonylꢀ
R2
R1
R1
R1
R1
N
OAc
NH2
OH
N
N
N
N
Ar
Ar
Ar
Ar
a
[RhCp*Cl2
[CoCp*(CO)I2] (Ackermann, 2015)
2 (Ackermann, 2012)
[CoCp*(CO)I2] (Cheng, 2016)
]2 (Chiba, 2010)
[RhCp*Cl2]2 (Li, 2014)
[RhCp*Cl2
Rh(PPh3 3Cl (Cheng, 2009)
[Ru(p-cymene)Cl2
]2 (Zhao, 2011)
[RhCp*Cl2]2 (Sun, 2015)
)
]
pꢀ
[CoCp*(CO)I2] (Sundararaju, 2015)
R1
cymene)Cl2]2 were tested for model reaction at 100 °C for 12 h
in the presence of Cu(OAc)2 as an oxidant and AgSbF6 as an
additive in 1,2ꢀdichloroethane. Among these three ruthenium
R1
R1
H
N
Ar
NHBoc
N
N
N
N
Ar
Ar
Ar
N
R
Co(acac)2 (Zhu, 2016)
R1
[CoCp*(CO)I2] (Zhu, 2016)
[RhCp*Cl2]2 (Huang, 2014)
R1
catalysts, [Ru(pꢀcymene)Cl2]2 exhibited the highest catalytic
activity, providing 76% yield of the desired product 3aa (Table
1; entries 1–3). In order to make proposed protocol more
greener and catalytic media reusable, the reaction was
attempted in PEGꢀ400 as a biodegradable solvent. Gratifyingly,
desired product was obtained giving 74% yield (Table 1, entry
4). PEG–200, PEG–600, PEG–2000 and PEG–6000 were also
tested, out of which only PEGꢀ200 and PEGꢀ600 could furnish
the reaction to give 57% and 49% product yield respectively
(Table 1, entries 6–9). Ultimately, PEGꢀ400 found to be a
potent solvent for proposed protocol. Next, a range of additives
such as CuO, NaOAc, Zn(OAc)2, AgOAc, CsOAc, KOAc were
also screened for this reaction. Among these, except Zn(OAc)2
all other additives were found to be less effective in comparison
N2
N
N
NHP(O)(OEt)2
N
N
Ar
Ar
Ar
[RhCp*Cl2]2 (Chiba, 2011)
RhCp*(MeCN)3(SbF6
)
2 (Xu, 2013)
[RhCp*Cl2]2 (Cheng, 2013)
Reuse of catalyst and biodegradable solvent
R1
This work:
R1
[Ru(p-cymene)Cl2]2,
H
R3
N
N
AgSbF6, Cu(OAc)2,
N
Ts
R2
Ar
Ar
PEG-400, 110 oC, 3 h
N-N cleavage
R3
H
R2
25 examples upto 93% yield
Homogeneous recyclable catalytic system
PEG as a biodegradable green solvent
Rarely explored directing group
Short reaction duration
Easy work up process
Wide substrate scope
Easily prepared substrates
Scalability up to gram level
Scheme
functionalization
2 Synthesis of isoquinolines via transition-metal-catalysed C-H
several drawbacks like poor yields, low regioselectivity and
longer reaction duration in some cases. To overcome these
2 | J. Name., 2012, 00, 1-3
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Table 1 Optimization of reaction parametersa
Table 2 Ruthenium catalyzed annulations of N-tosylhydrazone with alkynea
Entry
1
Catalyst
Solvent
1,2-DCE
1,2-DCE
1,2-DCE
PEG-400
PEG-200
PEG-600
PEG-2000
PEG-6000
PEG-400
PEG-400
PEG-400
PEG-400
PEG-400
PEG-400
PEG-400
PEG-400
PEG-400
PEG-400
PEG-400
PEG-400
PEG-400
PEG-400
Oxidant
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
CuO
Yieldb(%)
Trace
24
RuCl3.H2O
2
Cp*Ru(COD)Cl
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
[Ru(p-cymene)Cl2]2
[Ru(p-cymene)Cl2]2
[Ru(p-cymene)Cl2]2
[Ru(p-cymene)Cl2]2
76
4
74
6
57
7
49
8
–
9
–
10
11
12
13
14
15
16c
17d
18e
19f
20g
21h
22i
23j
trace
21
NaOAck
k
Zn(OAc)2
AgOAck
62
trace
trace
18
CsOAck
1
2
3
Yieldb
(%)
Entry
1
N-tosylhydrazone
alkyne
product
KOAck
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
43
1a
2a
88
48
77
3aa
53
89
2
3
4
1b
1c
2a
2a
90
93
82
86
3ba
3ca
88
64
a Reaction conditions: 1a (0.5 mmol), 2a (0.6 mmol), catalyst (5 mol%), AgSbF6 10
b
c
mol%, oxidant (0.5 mmol), solvent (3.0 mL), 100 °C, 12 h. GC yield. KPF6 was
e
used as an additive instead of AgSbF6. d 3 mol % [Ru(p-cymene)Cl2]2 was used.
10 mol % [Ru(p-cymene)Cl2]2. f 80 oC, 12h. g 110 oC, 12h. h 120 oC, 12h. i 110 oC, 3
1d
1e
2a
2a
h. j 110 oC, 2h. k salts used as an additive.
3da
with Cu(OAc)2 (Table 1, entries 10–15). Subsequently, AgSbF6
was replaced by KPF6 as an additive, however the efficiency of
reaction with KPF6 was found to be less than that of AgSbF6
(Table 1, entry 16). Next, the effect of catalyst loading was
determined. Lowering in catalyst concentration to 3 mol% leads
to a decrease in the yield of 3aa whereas with 10 mol% of
catalyst no significant increase in yield of 3aa was noted (Table
1, entries 17 and 18). Later, to study the effect of temperature
the reaction was attempted at lower and higher temperatures at
a constant duration of 12 hours. When the reaction temperature
was decreased to 80 oC, only 53% product yield could be
5
6
7
8
79
72
64
3ea
3fa
1f
2a
2a
1g
3
ga
2a
2a
83
51
o
obtained while increasing temperature to 110 C increased the
1h
1i
3ha
product yield to 89%. Thereafter, increasing the temperature
above 110°C did not produce any significant change in the
product yield (Table 1, entries 19–21). Further, reduction in the
reaction duration from 12 h to 3 h, did not lead to any
3i
a
9
N
remarkable change in the yield, however
a subsequent
38
59
Ph
reduction to 2 h decreased the product yield to 64% (Table 1,
entries 22 and 23). Thus the optimized reaction conditions are:
O
Ph
3ia’
4ꢀmethylꢀ
N
′ꢀ(1ꢀphenylethylidene)benzenesulfonylhydrazide 1a
:
0.5 mmol, diphenylacetylene 2a
:
0.6 mmol, [Ru(pꢀ
10
2a
3
cymene)Cl2]2: 5 mol%, Cu(OAc)2: 1 eqt, AgSbF6: 10 mol%,
PEGꢀ400: 3 mL, 110 oC, 3 h.
1j
ja
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Reaction conditions: a N-tosylhydrazone 1 (0.5 mmol), alkyne 2 (0.6 mmol), [Ru(p-
cymene)Cl2]2 (5 mol%), AgSbF6 10 mol%, Cu(OAc)2 (0.5 mmol), PEG-400 (3.0 mL),
110 °C, 3 h. b GC yield.
11
12
2a
2a
2a
75
80
73
1k
3ka
3la
With the identified optimized reaction conditions in hand,
the synthetic versatility of the proposed protocol is highlighted
1l
by screening the compatibility of a diverse set of aromatic
Nꢀ
O
tosylhydrazones bearing both electron donating as well as
electron withdrawing substituent (Table 2). The outcomes
revealed that, reactions progressed effortlessly and tolerated a
varied range of functional groups including methyl, methoxy,
chloro, bromo, fluoro and nitro to afford respective products in
good to excellent yields. Without any substitution on the phenyl
N
13
14
15
16
Ph
1m
Ph
3ma
1n
1o
1p
2a
2a
2a
91
87
83
3na
ring of
Nꢀtosylhydrazone, compound 3aa was obtained with
yield of 88% (Table 2, entry 1). The introduction of electron
donating groups like –Me and –OMe at para position of phenyl
ring of hydrazones enhanced the corresponding product yields
to 90% and 93% respectively (Table 2, entries 2 and 3) while
electron withdrawing groups like –Br, –Cl, –F and –NO2 at the
para position affected the reaction efficiency and resulted in
82%, 79%, 72% and 64% product yields (Table 2, entries 4–7).
The position of the substituent on the phenyl ring of the
hydrazine reactant showed only a marginal effect on the
product yield. When the substituent at the meta position of
hydrazones was screened, it is worth noting that the
regioselectivity of the reaction mostly depends on the steric
hindrance due to substituent. For instance –Me, –NO2 and –Cl
at meta position of hydrazones gave single desired products
3oa
3pa
17
18
19
1q
1r
1s
2a
2a
2a
46
85
76
3qa
3ra
3ha, 3ja and 3ka exclusively with 83%, 59% and 75% yield
respectively, while –OMe at the meta position of hydrazine
gave two different regioselective products 3ia and 3ia’ with
51% and 38% yields respectively (Table 2, entries 8–11).
3sa
3ta
3ua
3va
20
21
22
1t
1u
1v
2a
2a
2a
84
80
57
Disubstituted
Nꢀtosylhydrazones easily underwent the
annulation reaction to give the corresponding products 3la in
80% yield (Table 2, entry 12). Ortho substituted hydrazone also
could be employed successfully for the same reaction to give
73% of 3ma (Table 2, entry 13). Subsequently,
Nꢀ
tosylhydrazones of propiophenone, cyclopropyl phenyl ketone,
benzophenone, benzil and 1ꢀtetralone could also be used as
substrates, leading to formation of the corresponding
substituted isoquinolines 3na
87%, 83%, 46% and 85% product yield respectively (Table 2,
entries 14–18). Gratifyingly, ꢀtosylhydrazone of 1ꢀ
acetylnaphthalene also worked for the proposed reaction giving
respective product 3sa with 76% yield (Table 2, entry 19).
, 3oa, 3pa, 3qa and 3ra with 91%,
23
24
1a
1a
2b
2c
77
N
3ab
3ac
84
81
Moreover,
could afford the products 3ta
N
ꢀtosylhydrazones of heterocyclic ketones also
3ua and 3va with yields of 84%,
,
80% and 57% respectively (Table 2, entries 20–22). For further
exploration of the substrate scope, we next turned our attention
to investigate the scope of internal alkynes for the established
annulation reaction. To our delight, 3ꢀhexyne, 1ꢀphenylꢀ1ꢀ
25
26
27
1a
1w
1a
2d
2a
2e
3ad
butyne and 1ꢀphenylꢀ1ꢀpropyne reacted efficiently with
tosylhydrazone of acetophenone to give desired isoquinoline
moieties 3ab 3ac and 3ad with 77%, 84% and 81% yields
Nꢀ
-
-
3wa
,
respectively (Table 2, entries 23–25). Hydrazone derived from
aldehyde and terminal alkynes could not furnish the reaction
under proposed protocol (Table 2, entries 26 and 27). This is
3ae
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may be due to competitive dimer formation of terminal alkynes activity and the slight reduction in yield might be due to loss of
in presence of Cu salts.
product during workꢀup.
The evolved synthetic protocol could be scaled up to gram
Fascinated by the versatility and potency of the
quantity for the synthesis of substituted isoquinolines with no ruthenium(II) catalyzed C–H/N–N functionalized annulation
hassle. For example, the reaction of 5 mmol (1.44 g) of 1a with reactions, to examine the electronic effects of the two coupling
6 mmol (1.06 g) 2a under the optimized reaction conditions partners on the competence of this catalysis, intermolecular
produced
the
corresponding
product
1ꢀMethylꢀ3,4ꢀ competition reactions were performed. An intermolecular
competition experiment between para substituted
diphenylisoquinoline 3aa in 76% yield.
N
ꢀ
Having gratifying results with Ru(II)/PEGꢀ400 as a green tosylhydrazones 1c and 1e for the coupling with
catalytic system, further we examined this for its reusability.
For this, annulation reaction of 1a with diphenylacetylene 2a
(a)
Scheme 3 Intermolecular competition reactions
(b)
diphenylacetylene 2a under the standard conditions could
provide evidence about the electronic effects of the paraꢀ
substituent on the reaction. GC study of the crude product
exposed that, 3c and 3e were obtained with the product yield
36% and 23% respectively (Scheme 3), indicating that the
annulation occurred more favourably with the electronꢀrich
Nꢀ
tosylhydrazone 3c Likewise, intermolecular competition
.
experiments with diphenylacetylene 2a and 3ꢀhexyne 2b with
1arevealed the aromatic internal alkynes to be inherently much
more reactive than aliphatic ones.
On the basis of previous reports and experimental
observations18a, 18c, 18d a catalytic cycle for the Ru(II) catalyzed
oxidative annulation via C–H bond functionalization and N–N
bond breakage in the presence of Cu(OAc)2 has been proposed
(Scheme 4). Initially, –Cl of the catalyst might be removed by
silver salt forming AgCl. Cu(OAc)2 functions as a potent
additive for the generation of the cationic ruthenium(II)
carboxylate with hexafluoroantimonate. The rutheniumꢀ
catalyzed oxidative annulation starts from ortho C–H bond
activation of 1a with loss of acetic acid to afford a fiveꢀ
Figure 1 (a) Procedure for the reuse of catalyst and solvent system, (b) The
4-methyl-N′-(1-
catalyst
phenylethylidene)benzenesulfonylhydrazide 1a with diphenylacetylene 2a
recyclability
study
for
annulation
of
.
was conducted using 5 mol% [Ru(pꢀcymene)Cl2]2 under the
standard reaction conditions. After completion of reaction, the
reaction mixture was extracted with 5–7 mL of diethyl ether for
three to four times. The extracted diethyl ether contained the
product mixture was then subjected for purification. The
remaining solvent layer that contained PEG and catalyst could
then be reused for the next reaction. The PEG layer was heated
at 50–60 oC for 15 minutes to remove miscible traces of diethyl
ether and was then subjected for second run of annulation by
charging with the same substrates. The reusability and
recyclability was performed following the same procedure for
the synthesis of 1a. The results of this and three successive
experiments were consistent in yields 86%, 86%, 85% and 83%
respectively (Figure 1). It was observed that the catalyst could
work efficiently up to the 4th recycle with negligible loss in its
membered ruthenacycle
A. This is followed by coordination of
the metal with diphenylacetylene 2a forming intermediate B.
Subsequently, migratory insertion of the alkyne takes place to
generate intermediate
C. The desired annulated product 3aa is
obtained by the reductive elimination of the intermediate
C
with N–N bond cleavage and regeneration of catalytically
active species by the oxidant simultaneously.
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1
products were confirmed by GCMS, H and 13C NMR spectroscopy
analysis.
General procedure for the synthesis of isoquinoline derivatives (3)
An ovenꢀdried tube equipped with a magnetic stirrer bar was charged
with Nꢀtosylhydrazone (0.5 mmol), alkyne (0.6 mmol), [Ru(pꢀ
cymene)Cl2]2 (5 mol%), silver hexafluoroantimonate (AgSbF6) (10
mol%) and copper acetate (Cu(OAc)2) (0.5 mmol). Subsequently,
the tube was evacuated, purged with nitrogen gas three times and
sealed. Then, PEGꢀ400 (3 mL) was added via syringe under nitrogen
atmosphere and and the sealed tube was placed in a preheated oil
o
bath at 110 C for 3h. After completion of the reaction, the reaction
mixture was allowed to cool down to room temperature and then
extracted with 5–7 mL of diethyl ether for three to four times.
Extracted diethyl ether was concentrated under reduced pressure to
get the crude residue which was then purified by silica gel column
chromatography using pet ether/ethyl acetate as eluent to afford the
desired pure product 3.
Scheme 4 Plausible reaction mechanism for annulation of N-tosylhydrazone with
alkyne.
1-Methyl-3,4-diphenylisoquinoline (3aa). Pale yellow solid; mp
154ꢀ156 oC; 1H NMR (400 MHz, CDCl3) δ 8.18 – 8.20 (m, 1H),
7.64 – 7.66 (d, J = 3.1 Hz, 1H), 7.57 – 7.59 (m, 2H), 7.36 – 7.32 (m,
5H), 7.24 – 7.15 (m, 5H), 3.07 (s, 3H); GCMS (EI 70 eV) m/z (%
rel. inten.) 295 (M+, 51), 294 (100), 252 (21), 146 (13), 139 (9).
Conclusions
In summary, this work reports
annulation with alkynes via CꢀH/NꢀN activation for the
synthesis of substituted isoquinolines. The developed
Nꢀtosylhydrazone directed
methodology is more economical and greener as
a
1,6-Dimethyl-3,4-diphenylisoquinoline (3ba). White solid; mp
159–161 oC; 1H NMR (400 MHz, CDCl3) δ 8.09 (d, J = 8.9 Hz, 1H),
7.42 – 7.29 (m, 7H), 7.24 – 7.13 (m, 5H), 3.04 (s, 3H), 2.43 (s, 3H);
13C NMR (101 MHz, CDCl3) δ 157.37, 149.55, 141.13, 140.22,
137.72, 136.18, 131.43, 130.23, 128.73, 128.69, 128.15, 127.55,
homogeneous recyclable catalytic system Ru(II)/PEGꢀ400
efficiently worked for this transformation. This catalytic system
could be reused up to fourth cycle with negligible loss in
catalytic activity. In addition to that, the proposed protocol
could be scaled up to gram level with minimal effect on the 127.00, 126.81, 125.45, 125.06, 124.52, 22.68, 22.14; GCMS (EI 70
product yield. Moreover, a variety of substrates could be eV) m/z (% rel. inten.) 309 (M+, 52), 308 (100), 252 (14), 146 (17),
successfully employed under a proposed scheme with good to 139 (10).
excellent yields.
6-Methoxy-1-methyl-3,4-diphenylisoquinoline (3ca). Pale yellow
o
solid; m.p. 179ꢀ181 C; 1H NMR (500 MHz, CDCl3) δ 8.12 (d, J =
Experimental section
General experimental details and materials
9.1 Hz, 1H), 7.38 – 7.30 (m, 5H), 7.27 – 7.15 (m, 6H), 6.94 (d, J =
4.2 Hz, 1H), 3.74 (s, 3H), 3.04 (s, 3H); 13C NMR (126 MHz, CDCl3)
δ 160.55, 157.02, 150.12, 141.18, 138.06, 137.85, 131.30, 130.22,
All chemicals and solvents were purchased with high purities and
128.61, 128.28, 127.57, 217.47, 127.10, 126.88, 121.88, 118.71,
used without further purification. PEGs were dried prior to use by
104.47, 55.21, 22.65; GCMS (EI 70 eV) m/z (% rel. inten.) 325
the literature methods. The progress of the reaction was monitored
(M+, 52), 324 (100), 281 (24), 154 (9), 146 (10), 139 (8).
by gas chromatography (GC) with a flame ionization detector (FID)
with a capillary column (30 m × 0.25 mm × 0.25 ꢁm) and thin layer
6-Bromo-1-methyl-3,4-diphenylisoquinoline
yellow solid; m.p. 192ꢀ194 C; H NMR (400 MHz, CDCl3) δ 8.04
(3da).
Slightly
o
1
chromatography (using silica gel 60 Fꢀ254 plates). The products
were visualized with a 254 nm UV lamp. GCꢀMS (Rtxꢀ 17, 30 m ×
25 mm ID, film thickness (df = 0.25 ꢁm) (column flow 2 mL minꢀ1 ,
80 °C to 240 °C at 10 °C minꢀ1 rise) was used for the mass analysis
of the products. HRMS analysis was done commercially. Products
were purified by column chromatography on 100ꢀ200 mesh silica
gel. The 1H NMR spectras were recorded on 400 MHz and 500 MHz
spectrometer using tetramethylsilane (TMS) as an internal standard.
The 13C NMR spectras were recorded on 100 MHz and 125 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 (doublet of doublet), t
(d, J = 8.9 Hz, 1H), 7.80 (d, J = 1.8 Hz, 1H), 7.65 (dd, J = 8.9, 1.9
Hz, 1H), 7.37 – 7.33 (m, 5H), 7.24 – 7.16 (m, 5H), 3.04 (s, 3H); 13
C
NMR (101 MHz, CDCl3) δ 157.77, 150.58, 140.58, 137.38, 136.79,
131.27, 130.18, 130.01, 128.41, 128.34, 128.30, 127.65, 127.45,
127.30, 127.17, 125.06, 124.57, 22.70; GCMS (EI 70 eV) m/z (%
rel. inten.) 375 (M+2, 51), 373 (M+, 53), 374 (100), 372 (95), 293
(20), 292 (21), 277 (7), 252 (17), 250 (8), 147 (41), 139 (18), 125
(9).
6-Chloro-1-methyl-3,4-diphenylisoquinoline (3ea). Pale yellow
o
solid; m.p. 171ꢀ173 C; 1H NMR (400 MHz, CDCl3) δ 8.12 (d, J =
8.9 Hz, 1H), 7.61 (s, 1H), 7.51 (dd, J = 8.9, 1.0 Hz, 1H), 7.35 – 7.33
(m, 5H), 7.20 – 7.17 (m, 5H), 3.04 (s, 3H); 13C NMR (101 MHz,
1
(triplet) and m (multiplet) in H NMR spectroscopic analysis. The
6 | J. Name., 2012, 00, 1-3
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CDCl3) δ 157.66, 150.58, 140.58, 137.08, 136.84, 136.35, 131.26, 22.62, 20.96; HRMS (ESI) calcd. For C23H18ClN [M+H]: 344.1206,
130.17, 128.40, 127.65, 127.42, 127.34, 127.16, 125.09, 124.38 , found: 344.1202.
22.74; GCMS (EI 70 eV) m/z (% rel. inten.) 331 (M+2, 26), 329
(M+, 79), 330 (63), 328 (100), 293 (12), 252 (24), 146 (35).
1-Ethyl-3,4-diphenylisoquinoline (3na). White solid; m.p. 114ꢀ116
1
oC; H NMR (400 MHz, cdcl3) δ 8.26 – 8.24 (m, 1H), 7.67 – 7.66
6-Fluoro-1-methyl-3,4-diphenylisoquinoline (3fa). White solid; (m, 1H), 7.58 – 7.56 (m, 2H), 7.41 – 7.32 (m, 5H), 7.25 – 7.16 (m,
m.p. 145ꢀ147 oC; 1H NMR (400 MHz, cdcl3) δ 8.23 – 8.19 (m, 1H), 5H), 3.45 (q, J = 7.6 Hz, 2H), 1.54 (t, J = 7.6 Hz 3H); 13C NMR
7.35 – 7.31 (m, 6H), 7.26 – 7.23 (m, 1H), 7.20 – 7.14 (m, 5H), 3.05 (101 MHz, cdcl3) δ 162.27, 149.26, 141.11, 137.73, 136.32, 131.39,
(s, 3H); 13C NMR (101 MHz, CDCl3) δ 164.40, 161.90, 157.49, 130.34, 129.70, 128.94, 128.21, 127.56, 127.09, 126.88, 126.43,
150.37, 140.63, 138.08, 137.10, 131.17, 130.17, 128.66, 128.57, 126.40, 125.27, 125.14, 28.83, 14.01; GCMS (EI 70 eV) m/z (% rel.
128.38, 127.64, 127.36, 127.13, 123.41, 116.80, 116.55, 109.97, inten.) 309 (M+, 55), 308 (100), 293 (13), 280 (7), 154 (7), 146 (8),
109.75, 22.85; GCMS (EI 70 eV) m/z (% rel. inten.) 313 (M+, 51), 139 (6).
312 (100), 314 (8), 270 (15), 155 (9).
1-Cyclopropyl-3,4-diphenylisoquinoline (3oa). White solid; m.p.
1,7-Dimethyl-3,4-diphenylisoquinoline (3ha). Slightly yellow 149ꢀ151 oC; H NMR (400 MHz, cdcl3) δ 8.49 – 8.47 (m, 1H), 7.65
1
1
solid; 131ꢀ133 oC; H NMR (400 MHz, CDCl3) δ 7.95 (s, 1H), 7.55 – 7.63 (m, 1H), 7.61 – 7.54 (m, 2H), 7.37 – 7.33 (m, 5H), 7.23 –
(d, J = 8.4 Hz, 1H), 7.42 – 7.32 (m, 6H), 7.22 – 7.16 (m, 5H), 3.04 7.20 (m, 2H), 7.16 – 7.15 (m, 3H), 2.85 – 2.79 (m, 1H), 1.39 – 1.37
(s, 3H), 2.56 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 157.12, 148.76, (m, 2H), 1.14 – 1.12 (m, 2H); 13C NMR (101 MHz, cdcl3) δ 160.55,
141.21, 137.89, 136.50, 134.30, 132.17, 131.51, 130.38, 129.18, 148.66, 141.14, 137.97, 136.11, 131.43, 130.42 , 129.59, 128.24,
128.26, 127.69, 127.15, 126.91, 126.45, 126.22, 124.62, 22.86, 128.01, 127.33, 127.04, 126.81, 126.33, 126.26, 126.22, 124.83,
22.00; GCMS (EI 70 eV) m/z (% rel. inten.) 309 (M+, 77), 308 13.62, 9.38; GCMS (EI 70 eV) m/z (% rel. inten.) 321 (M+, 68), 320
(100), 252 (18), 146 (25), 139 (10).
(100), 243 (11), 152 (10).
7-Methoxy-1-methyl-3,4-diphenylisoquinoline (3ia). Yellow solid; 1,3,4-Triphenylisoquinoline (3pa). Yellow solid; m.p. 169ꢀ171 oC;
o
1
m.p. 121ꢀ123 C; H NMR (400 MHz, CDCl3) δ 7.56 (d, J = 15.2 1H NMR (400 MHz, CDCl3) δ 8.20 (d, J = 8.3 Hz, 1H), 7.85 – 7.83
Hz, 1H), 7.37 – 7.30 (m, 6H), 7.24 – 7.13 (m, 6H), 3.96 (s, 3H), 3.01 (m, 2H), 7.74 (d, J = 8.5 Hz, 1H), 7.62 – 7.49 (m, 5H), 7.46 – 7.35
(s, 3H); 13C NMR (101 MHz, CDCl3) δ 158.02, 156.14, 147.90, (m, 5H), 7.33 – 7.31 (m, 2H), 7.24 – 7.16 (m, 3H); 13C NMR (101
141.21, 137.90, 131.50, 131.41, 130.37, 129.31, 128.29, 128.16, MHz, CDCl3) δ 159.81, 149.64, 140.90, 139.81, 137.55, 136.97,
127.70, 127.47, 127.22, 126.86, 122.35, 103.71, 55.64, 23.00; 131.36, 130.46, 130.24, 129.96, 129.78, 128.55, 128.33, 127.56,
GCMS (EI 70 eV) m/z (% rel. inten.) 325 (M+, 84), 324 (100), 281 127.51, 127.30, 127.00, 126.60, 126.03, 125.44; GCMS (EI 70 eV)
(39), 162 (9), 140 (12), 139 (17).
m/z (% rel. inten.) 357 (M+, 95), 171 (100), 145 (5), 118 (8).
5-Methoxy-1-methyl-3,4-diphenylisoquinoline (3ia’). White solid; 1-Methyl-3,4-diphenylbenzo[h]isoquinoline (3sa). Slightly yellow
1
mp. 145ꢀ147 °C; H NMR (400 MHz, CDCl3) δ 7.79 (d, J = 8.4 Hz, solid; mp 142ꢀ144 °C; 1H NMR (400 MHz, CDCl3) δ 8.90 (d, J = 8.1
1H), 7.52 (t, J = 8.1 Hz, 1H), 7.24 – 7.21 (m, 2H), 7.16 – 7.09 (m, Hz, 1H), 7.91 (d, J = 7.3 Hz, 1H), 7.78 – 7.71 (m, 2H), 7.66 – 7.63
8H), 6.95 (d, J = 7.7 Hz, 1H), 3.39 (s, 3H), 3.03 (s, 3H); 13C NMR (m, 1H), 7.54 (d, J = 8.7 Hz, 1H), 7.42 (d, J = 4.5 Hz, 2H), 7.34 (s,
(101 MHz, CDCl3) δ 157.08, 156.83, 151.05, 141.59, 141.41, 3H), 7.25 – 7.19 (m, 5H), 3.43 (s, 3H); 13C NMR (101 MHz, CDCl3)
130.36, 130.20, 127.90, 127.75, 127.41, 127.29, 127.12, 126.45, δ 155.40, 150.90, 140.59, 138.01, 137.20, 132.95, 131.65, 131.12,
125.61, 118.02, 110.05, 55.53, 23.41; GCMS (EI 70 eV) m/z (% rel. 130.19, 129.64, 128.72, 128.25, 127.64, 127.28, 127.17, 127.14,
inten.) 325 (M+, 81), 324 (100), 308 (37), 154 (29), 146 (11).
126.84, 126.60, 124.20, 123.92, 30.52; GCMS (EI 70 eV) m/z (%
rel. inten.) 345 (M+, 61), 344 (100), 302 (17), 171 (9), 164 (16).
7-Chloro-1-methyl-3,4-diphenylisoquinoline (3ka). White solid;
m.p. 143ꢀ145 °C; 1H NMR (400 MHz, CDCl3) δ 8.15 (d, J = 1.2 Hz,
7-Methyl-4,5-diphenylthieno[2,3-c]pyridine (3ta). White solid;
1H), 7.60 (d, J = 9.0 Hz, 1H), 7.50 (dd, J = 9.0, 1.2 Hz, 1H), 7.34 – m.p. 145ꢀ147 oC; 1H NMR (400 MHz, DMSOꢀd6) δ 8.03 (d, J = 5.4
7.33 (m, 5H), 7.24 – 7.17 (m, 5H), 3.03 (s, 3H); 13C NMR (101 Hz, 1H), 7.33 – 7.25 (m, 5H), 7.20 – 7.08 (m, 6H), 2.77 (s, 3H); 13
C
MHz, CDCl3) δ 156.84, 149.75, 140.55, 137.02, 134.39, 132.25, NMR (101 MHz, DMSOꢀd6) δ 151.24, 150.46, 145.76, 140.65,
131.25, 130.68, 130.17, 128.99, 128.32, 128.15, 127.65, 127.36, 138.19, 133.93, 133.49, 130.66, 130.50, 128.83, 128.10, 127.89,
127.11, 126.82, 124.50, 22.70; GCMS (EI 70 eV) m/z (% rel. inten.) 127.76, 127.44, 123.95, 23.62; GCMS (EI 70 eV) m/z (% rel. inten.)
331 (M+2, 18), 329 (M+, 56), 330 (42), 328 (100), 293 (10), 252 301 (M+, 57), 300 (100), 285 (4), 258 (16), 150 (12), 149 (9).
(14), 146 (24).
3,4-Diethyl-1-methylisoquinoline (3ab). Yellow liquid; b.p. 140ꢀ
6-Chloro-1,7-dimethyl-3,4-diphenylisoquinoline (3la). Slightly 142 oC; 1H NMR (400 MHz, CDCl3) δ 8.06 (d, J = 8.3 Hz, 1H), 7.96
yellow solid; m.p. 158ꢀ160 oC ; 1H NMR (400 MHz, CDCl3) δ 8.16 (d, J = 8.5 Hz, 1H), 7.64 (t, J = 7.7 Hz, 1H), 7.48 (t, J = 7.6 Hz, 1H),
(s, 1H), 7.47 (s, 1H), 7.32 (d, J = 5.7 Hz, 5H), 7.21 – 7.10 (m, 5H), 3.03 (q, J = 7.6 Hz, 2H), 2.95 (q, J = 7.6 Hz, 2H), 2.90 (s, 3H), 1.33
3.01 (s, 3H), 2.43 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 156.53, (t, J = 7.6 Hz, 3H), 1.27 (t, J = 7.6 Hz, 3H); 13C NMR (101 MHz,
149.69, 140.74, 138.69, 137.23, 134.71, 133.71, 131.29, 130.16, CDCl3) δ 155.75, 152.52, 135.11, 129.48, 127.17, 126.12, 126.05,
128.41, 128.27, 127.60, 127.49, 127.24, 126.99, 125.65, 125.06, 125.25, 123.32, 28.47, 22.33, 20.66, 15.24, 14.95; GCMS (EI 70 eV)
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m/z (% rel. inten.) 199 (M+, 45), 198 (100), 184 (25), 170 (10), 128
(14), 115 (9), 91 (10).
FunesꢀArdoiz, T. R. Belderrain, A. Caballero, F. Maseras, G.
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4-ethyl-1-methyl-3-phenylisoquinoline (3ac). White solid; m.p.
121ꢀ123 oC ; 1H NMR (400 MHz, CDCl3) δ 8.16 (d, J = 8.3 Hz, 1H),
8.07 (d, J = 8.3 Hz, 1H), 7.73 (t, J = 7.6 Hz, 1H), 7.59 (t, J = 7.6 Hz,
1H), 7.51 – 7.36 (m, 5H), 3.01– 2.96 (m, 5H), 1.25 (t, J = 7.4 Hz,
3H); 13C NMR (101 MHz, CDCl3) δ 155.82, 150.69, 141.83, 135.12,
129.80, 129.17, 128.52, 128.13, 127.37, 126.68, 126.28, 126.14,
124.12, 22.48, 21.64, 15.67; GCMS (EI 70 eV) m/z (% rel. inten.)
247 (M+, 56), 246 (100), 232 (17), 231 (21), 230 (13), 217 (7), 115
(14).
5
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Conflicts of interest
There are no conflicts to declare.
Acknowledgements
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.25ꢀ1/2014ꢀ15(BSR)/F.7ꢀ227/2009 (BSR), 16th Feb
2015]. The author D.S.D. would also like to acknowledge a
PhD Research Scholar Subhash L. Yedage for his help during
preparation of this manuscript.
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DOI: 10.1039/C8OB01082J
N-Tosylhydrazone directed annulation via C-H/N-N bond activation in
Ru(II)/PEG-400 as homogeneous recyclable catalytic system: a green
synthesis of isoquinolines
Dewal S. Deshmukh and Bhalchandra M. Bhanage*
Department of Chemistry, Institute of Chemical Technology, N. Parekh Marg, Matunga,
Mumbai–400019. India. Tel.: +91-22-33612601; fax: +91-22-33611020 bm.bhanage@gmail.com,
bm.bhanage@ictmumbai.edu.in
A green and sustainable methodology for the synthesis of isoquinolines using Ru(II)/PEG-400 as
homogeneous recyclable catalytic system and N-tosylhydrazone, a rarely explored directing
group has been reported.