Hydrophilic Pd-phosphines catalyzed one-pot synthesis of substituted isoquinolines, furopyridines and thienopyridines in aqueous medium

Article abstract of DOI:10.1016/j.tetlet.2018.12.035

A first example of simple and efficient hydrophilic Pd-phosphine complexes catalyzed one-pot three-component reaction of ortho-bromo aldehydes, terminal alkynes and ammonium acetate proceeds through the tandem coupling-imination-annulation path for the synthesis of substituted isoquinolines, furopyridines and thienopyridines in good to excellent yields in green aqueous medium at mild temperature was described.

Full text of DOI:10.1016/j.tetlet.2018.12.035

Accepted Manuscript
Hydrophilic Pd-phosphines catalyzed one-pot synthesis of substituted isoqui-
nolines, furopyridines and thienopyridines in aqueous medium
Veeranna Guguloth, Narasimha Swamy Thirukovela, Ramesh Balaboina,
Suresh Paidakula, Ravinder Vadde
PII:
S0040-4039(18)31477-1
https://doi.org/10.1016/j.tetlet.2018.12.035
TETL 50498
DOI:
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
30 September 2018
13 December 2018
16 December 2018
Please cite this article as: Guguloth, V., Thirukovela, N.S., Balaboina, R., Paidakula, S., Vadde, R., Hydrophilic
Pd-phosphines catalyzed one-pot synthesis of substituted isoquinolines, furopyridines and thienopyridines in
aqueous medium, Tetrahedron Letters (2018), doi: https://doi.org/10.1016/j.tetlet.2018.12.035
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Tetrahedron Letters
Hydrophilic Pd-phosphines catalyzed one-pot synthesis of substituted
isoquinolines, furopyridines and thienopyridines in aqueous medium
Veeranna Guguloth,a Narasimha Swamy Thirukovelaa, Ramesh Balaboina,a Suresh Paidakula,a Ravinder Vadde,*a
aDepartment of Chemistry, Kakatiya University, Warangal, Telangana State-506009, India, Tel :+91-9533945588, Email:
ravichemkuc@gmail.com;
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A first example of simple and efficient hydrophilic Pd-phosphine
complexes catalyzed one-pot three-component reaction of ortho-bromo
aldehydes, terminal alkynes and ammonium acetate proceeds through the
tandem coupling-imination-annulation path for the synthesis of substituted
isoquinolines, furopyridines and thienopyridines in good to excellent
yields in green aqueous medium at mild temperature was described.
Available online
Keywords:
Hydrophilic Pd-complexes
Ortho-Bromo aldehydes
One-pot three-component approach
Green solvent medium
Homogeneous catalysis
2009 Elsevier Ltd. All rights reserved.
Isoquinolines and their derivatives are one of the
most significant class of fused-heterocyclic compounds
and play a substantial responsibility in huge number of
pharmacological activities.1-2 Therefore, the great
efforts have been devoted, to develop effective
methodologies for their synthesis. The classical
synthesis of isoquinoline derivatives viz., Pictet-
Spengler3 Pomeranz-Fritsch4 and Bischler-Napieralski 5
reactions usually proceed through some typical
conditions. To overcome the demerits of traditional
methods, few Pd-Cu6 and Cu7-9 catalysed one-pot
protocols involving tandem conversions to achieve
isoquinoline derivatives were well described. However,
all the above catalytic systems require toxic organic
solvents and high reaction temperatures6-9 for their
greater proficiency. Hence, the development of suitable
metal catalysts for the one-pot synthesis of substituted
isoquinolines in environmentally benign solvents under
mild temperature is still remains a motivating and
highly necessary goal.
The implementation of sustainable chemical
synthesis, as per green chemistry protocols, reactions
conducting in aqueous solvent system have become
special interest to scientific commune as well as
industry10. As well, water could influence on the
reaction rates and selectivities, because of hydrophobic
interactions. In response to the above stated features,
our group have long been working on the development
of some new water soluble polar phosphine ligands11
and their corresponding Rh and Ru-catalysts were
successively utilized for hydroformylation12 and
hydrothialation13 reactions in eco-friendly aqueous
media. In continuation of our group work, we herein,
first time report the catalytic efficacy of some new Pd-
complexes composed with polar phosphine ligands for
the one-pot three-component reaction of ortho-bromo
aldehdyes, terminal alkynes and ammonium acetate to
afford substituted isoquinolines, furopyridines and
thienopyridines in green aqueous medium under mild
temperature.

Tetrahedron Letters
To choose the suitable catalytic conditions, at first,
indicated that the use of Cu as a co-catalyst is necessary
for the synthesis of 4a (Table 1, entry 16). The effects
of various bases were also investigated (Table S1, ESI).
we have studied the one-pot reaction of 2-
bromobenzaldehyde (1a), phenyl acetylene (2a) and
ammonium acetate (3a) in the presence of K2CO3 and
using different types of catalysts including (Cu, Pd and
Pd/Cu) in (1: 4) in THF-water media. The particulars of
reaction conditions and results were shown in table 1.
From the table 1, no desired product 4a was observed,
when we used both Cu(I) alone and Pd(II) alone as
catalysts at 65 oC even after 12 hours (Table 1, entries
1-3). The same reaction was also sluggish in the case of
Pd(OAc)2/CuI combination (Table 1, entry 4). On the
other hand, the moderate yield of 4a was obtained
Table 1. Optimization of the reaction conditions.
Entry
Catalyst (mol %)
Temp
(oC)
Time(h) Yield
(%)b
NR
1
2
CuI (6)
65
65
12
o
using PdCl2(PPh3)2/CuI as catalyst at 50 C after 6
NR
NR
Pd(OAc)2 (4)
12
12
hours (Table 1, entry 5). Encouraged by this result, we
further intended to examine the efficacy of our aqueous
stable 3 mol% of Pd-polar phosphines (Pd-(L1-L7)
[generated in-situ from the reaction of 1 : 2 ratio of
Pd(OAc)2 & polar phosphine ligands (L1-L7) as shown
in figure 1] + 5 mol% of CuI catalytic systems.
65
65
50
50
50
50
50
50
50
50
50
50
RT
50
3
PdCl2(PPh3)2 (4)
Pd(OAc)2(4)/CuI(5)
PdCl2(PPh3)2(4)/CuI(5)
12
6
4
trace
54
74
83
82
87
84
76
84
87
59
5
4
6
Pd-L1(3)/CuI (5)
Pd-L2(3)/CuI (5)
7
4
4
4
4
4
4
4
5
Pd-L3(3)/CuI (5)
Pd-L4(3)/CuI (5)
Pd-L5(3)/CuI (5)
Pd-L6(3)/CuI (5)
Pd-L7(3)/CuI (5)
Pd-L4(2)/CuI (5)
Pd-L4(1)/CuI (5)
Pd-L4(2)/CuI (5)
8
9
10
11
12
13
14
15
8
51
16
Pd-L4 (3)
10
NR
a
Reaction conditions: Reaction was carried out with 1mmol of 1a, 1.2mmol
of 2a, 1.5mmol of 3a using 2mmol of K2CO3 in 2 mL of (1:4) THF-H2O.b
Isolated yields after coloumn chromatography. NR = no reaction.
The above optimized conditions in our hand, we
further explored our one-pot three component
methodology to synthesize various substituted
isoquinolines, furopyridines & thienopyridines and
their results were depicted in table 2. From the table 2,
it is found that all the used 2-bromobenzaldehyde and
phenylacetylene derivatives were compatible to furnish
substituted isoquinolines in good to excellent yields
(Table 2, entries 4a-4m). However, the yields of
corresponding isoquinolines were high in the case of 2-
bromobenzaldehydes and phenylacetylenes bearing
electron-withdrawing groups (Table 2, entries 4e-4f)
and 4l-4m). On the other hand, the aliphatic alkynes
were less reactive and decrease in the yields of desired
product was observed as compared to aromatic alkynes
(Table 2, entries 4g-4h and 4k). In addition, the
present one-pot approach was also well-suited to
Figure 1. Hydrophilic phosphine ligands used in the present
study.
Remarkably, all the Pd-(L1-L7) complexes have
allowed the fast accomplishment of the one-pot
reaction and provided the product 4a with good to
excellent yields in the range of 74-87% at 50 oC (Table
1, entries 6-12). Among them, the best result was
observed in the case of Pd-L4 complex (Table 1, entry
9). The different catalyst concentration and temperature
studies revealed that the 2 mol % of Pd-L4 at 50 oC was
the suitable choice for the present approach (Table 1,
entry 13). The reaction of 1a, 2a and 3a using 2mol %
of Pd-L4 in the absence of CuI was also none, which

synthesize
furopyridines
and
thienopyridines
derivatives in moderate to good yields (Table 1, entries
4n-4r). The formation of all the compounds was
13
confirmed by 1H-NMR, C-NMR and mass spectral
data, which are reliable with the reported data
previously.6-9
Table 2. Substrate scope
Scheme 1. A plausible reaction mechanism
In conclusion, we have first time established the
simple and efficient hydrophilic Pd-phosphine catalytic
system for the one-pot three-component synthesis of
isoquinoline,
furopyridine
and
thienopyridine
derivatives in good to excellent yields in
environmentally benign aqueous medium under mild
temperature.
Acknowledgements
The author Veeranna Guguloth thankful to the UGC-
New Delhi for providing financial support.
A Supplementary data
a All products were characterized by 1H and 13C NMR spectroscopy.
b Isolated yields after column chromatography.
Experimental details, characterization data of 4a-4r
products can be found, in the online version, at
http://dx.doi.org/
Based on our present results (Table 1) and from the
literature support6,9, a plausible catalytic cycle for the
above one pot three-component reaction was proposed.
As shown in scheme 1, initially, the Pd-catalyzed
coupling of o-bromo aldehydes with terminal alkynes
occur to form o-alkynyl aldehyde intermediate A,
which on further condensation reaction with reaction
with ammonia to give imine intermediate B. Later, the
π-coordination between CuI and alkyne of intermediate
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Conceptsand

Hydrophilic Pd-phosphines catalyzed one-pot
synthesis of substituted isoquinolines,
furopyridines and thienopyridines in aqueous
medium
Veeranna Guguloth,a Narasimha Swamy
Thirukovelaa, Ramesh Balaboina,a Suresh
Paidakula,a Ravinder Vadde,*a
aDepartment of Chemistry, Kakatiya University,
Warangal, Telangana State-506009, India,
Tel :+91-9533945588, Email:
ravichemkuc@gmail.com;
Graphical abstract

Tetrahedron Letters
Highlights
 Hydrophilic Pd-phosphine/CuI catalysed
one-pot three component approach
 Synthesis of isoquinolines, furopyridines
and thienopyridines in aqueous medium
 Relatively better results compared to
previous reports