AgI-promoted one-pot synthesis of aminoindolizines via sequential Mannich-Grignard addition and intramolecular cyclization in water

Article abstract of DOI:10.1002/jhet.4184

The efficient synthesis of aminoindolizines in ecofriendly water with broad substrate scope from the mild and readily available AgI-catalyzed one-pot three-component reaction of pyridine-2-carboxaldehyde, secondary amines, and terminal alkynes proceeds th

Full text of DOI:10.1002/jhet.4184

AgI promoted one-pot synthesis of aminoindolizines via sequential Mannich-Grignard
addition and intramolecular cyclization in water
Veeranna Gugulotha, Ramesh Balaboinaa, Suresh Paidakulaa, Narasimha Swamy Thirukovelab*, Ravinder Vaddea*
aDepartment of Chemistry, Kakatiya University, Warangal, T.S. India; Email: ravichemkuc@gmail.com
bDepartment of Chemistry, Chaitanya (Deemed to be University), Warangal, T.S. India; Email: thirukovelann@gmail.com
Abstract:
The efficient synthesis of aminoindolizines in eco-friendly water with broad substrate scope from the mild and readily available AgI
catalyzed one-pot three-component reaction of pyridine-2-carboxaldehyde, secondary amines and terminal alkynes proceeds through
the sequential Mannich-Grignard addition as well as intramolecular cyclization was reported for the first time.
Introduction:
The Indolizine is a significant heterocycle, since it is an
important skeleton for several biologically active compounds,
few of them are naturally available [1], whereas, others are only
synthetically obtainable. In addition, this nucleus was found as a
potent pharmacophore which exhibit numerous pharmacological
activities such as anti-leishmanial [2a], anti-convulsant [2b], anti-
inflammatory [2c], anti-tubercular [2d] calcium entry blocker
[2e], herbicidal [2f], anti-oxidant [2g], histamine H3 receptor
antagonist [2h], anti-herpes [2i] and anti-HIV [2j] activities. It
also acts as CNS depression agent [2k] and even displays active
cardiovascular properties [2l]. Furthermore, indolizines have the
capability to converse multi-drug resistance [2m] as well as
persuade apoptosis via mitochondrial path over several cancer
cell lines [2n].
Consequently, the great efforts were made to develop suitable
and efficient protocols for the synthesis of indolizine derivatives
and tandem Sonogashira coupling-intramolecular cyclizations
[14-15] in environmentally benign aqueous media. Due to the
outstanding catalytic proficiency of silver, in the activation of
alkyne functionality via its π or σ-coordination leading to
achieve successive organic transformations [16] and in
continuation of our group interest towards the sustainable
chemical synthesis, we herein, report the readily available and
mild AgI catalyzed one-pot three-component reaction of
pyridine-2-carboxaldehyde, secondary amines and terminal
alkynes to achieve aminoindolizines in green water medium.
To set the appropriate catalytic conditions, initially, we have
examined the one-pot three-component reaction of pyridine-2-
carboxaldehyde (1a), morpholine (2a) and phenylacetylene (3a)
in recent years [3]. Interestingly, in majority of the cases,
transition metals promoted C–C and C–N bond formations have
been well employed to afford these moieties. Remarkably, metal
catalyzed three-component coupling reaction of 2-
pyridinecarboxaldehyde, secondary amines and terminal alkynes
have been emerged as one of the efficient protocol to synthesize
these scaffolds, in terms of easy availability of starting materials,
atom- economy and energy consumption etc., As a result, few
metal catalysts like Au [4], Ag [5], Cu [6], Zn [7] and Fe [8]
were used for the above one-pot synthesis. Despite the efficiency
of these catalytic systems, few limitations have been noticed
such as (i) the use of expensive catalyst [4], additive [8] and
organic solvents [5, 6a, c-g, & 7-8], (ii) high reaction
temperature [6, 7a-d, 8] and catalyst loading [5, 6a-b, 7-8], (iii)
low substrate scope and [6c and 6e] and (iv) the use of
heterogeneous Cu catalysts which have special synthetic
procedures [6c-g].
The application of sustainable organic synthesis, according to
green chemistry principles, the reactions performing in aqueous
solvent system have always been a special and motivating
attention to both the scientific and industrial community [9].
Accordingly, we have developed some metal catalyzed organic
transformations namely hydroformylation [10], hydrothiolation
[11], cross dehydrogenative coupling [12], nitrile hydration [13]
o
at 70 C temperature under N2 condition in water using various
3 mol% metal salts. The uncatalyzed reaction was unsuccessful
to give the desired product 4-(3-phenylindolizin-1-
yl)morpholine (4a) (Table 1, entry 1). The reaction also did not
take place using CuI, Cu(OTf)2, CuBr, FeCl3, and ZnCl2 (Table
1, entries 2-6), whereas, low yields of product 4a was obtained
using CuCl, AuCl and AuBr3 (Table 1, entries 7-9). In order to
improve the yield of one-pot product 4a, finally we have
intended to examine the catalytic efficacy of some Ag-salts. It
has been found that all the complete or partly water soluble Ag
salts like Ag2O, AgNO3, AgOAc, Ag2SO4, AgOTf, AgPF6,
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AgSbF6, AgBF4 and AgF were provided the desired product 4a
in the range of 35-46%, along with the formation of picolinic
acid with quantitative yield (Table 1, entries 10-18). In order to
reduce the reduction of Ag-catalytic system by pyrdine-2-
carboxaldehyde in water, we intended to use some water
insoluble Ag catalytic systems. Accordingly, the water insoluble
Ag-salts such as AgI, AgBr and AgCl have efficiently promoted
the one-pot three-component reaction of 1a, 2a and 3a to
achieve the targeted 4a in the range of 59-86% yields without
the formation of picolinic acid (Table 1, entries 19-21).
Particularly, the highly water insoluble AgI was found to be
optimal as compared to the rest of the silver halides (Table 1,
entry 21). Different catalyst concentration studies revealed that
2 mol% AgI was the optimal for the present one-pot approach
amines and terminal alkynes and their results were shown in table
2. In the case of secondary amines, all the aliphatic cyclic amines
and dibenzylamine were afforded the corresponding
aminoindolizines in high yields(Table 2, entries 4a-4q).
However, the moderate yield of corresponding aminoindolizines
obtained in the case of acyclic amine (Table 2, entry 4r). In
addition, phenylacetylene (Table 2, entries 4a, 4g, 4n-4o and 4r)
as well as several phenylacetylenes bearing different substituents
including –Me (Table 2, entries 4b and 4h), –OMe (Table 2,
entries 4c and 4i), –CF3 (Table 2, entry 4j), –Br (Table 2, entry
4k), –Cl (Table 2, entry 4l) and –NO2 (Table 2, entry 4d) led to
the respective aminoindolizines in good to excellent yields (Table
2, entries 4a-4q). On the other hand, the moderate yields of the
corresponding indolizines were achieved using aliphatic alkynes
(Table 2, entries 4e, 4m and 4p) may be due to the instability of
the derivatives that decomposed rapidly in the course of the
column chromatography. Besides, heteroaryl alkyne, 3-ethynyl
thiophene was found to suitable to afford the desired
aminoindolizine in good yield (Table 2, entry 4f) under the
current optimization conditions devoid of any complications.
o
(Table 1, entry 22). Reducing reaction temperature from 70 C
has also led to lessen the yield of 4a consecutively (Table 1,
entry 24). The AgI catalyzed one-pot three-component reaction
of 1a, 2a and 3a was also sluggish in the presence of open air
(Table 1, entry 25).
Table 1. Optimization of reaction conditions
Table 2. Substrate scope
Entry
1
Catalyst (mol%)
-
T(oC)
-
Time (h)
15
Yield 4a (%)[b]
-
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
CuI (3)
Cu(OTf)2 (3)
CuBr (3)
FeCl3 (3))
ZnCl23)
70
70
70
70
70
70
70
70
70
70
70
70
70
70
70
70
70
70
70
70
70
70
55
70
15
15
15
15
15
15
15
15
15
15
15
15
15
15
15
15
15
15
15
15
16
19
18
15
-
-
-
-
-
CuCl(3)
17
24
29
35
39
41
46
43
44
42
43
42
59
69
86
86
53
64
8c
AuCl (3)
AuBr3(3)
Ag2O (3)
AgNO3 (3)
AgOAc (3)
Ag2SO4 (3)
AgOTf (3)
AgPF6 (2)
AgSbF6 (3)
AgBF4 (3)
AgF (3)
AgCl (3)
AgBr (3)
AgI(3)
AgI (2)
AgI (1)
AgI (2)
AgI (2)
aPyrdine-2-carboxaldehyde 1a (1.0 mmol), morpholine (2a) (1.2 mmol),
phenylacetylene (3a) (1.2 mmol), water (2 mL) and N2 atmosphere. bIsolated
yields after column chromatography. cOpen air atmosphere.
The above optimized conditions in our hand, we further
expanded the present one-pot approach to various secondary
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better as compared to prior works. Further, the efforts are under
progress to enhance the substrate scope.
Keywords:
Aminoindolizines, One-pot three-component reaction, Mannich-
Grignard addition, Intramolecular cyclization.
Conflict of interest:
The authors declare that they have no conflict of interest.
Acknowledgements
The author Veeranna Guguloth thankful to UGC New Delhi,
India for providing senior research fellowship.
aAgI (0.02 mmol), Pyrdine-2-carboxaldehyde 1a (1.0 mmol), secondary
amines (2a-2f) (1.2 mmol), terminal alkynes (3a-3k) (1.2 mmol), water
(2 mL) and N2 condition. bIsolated yields after coloumn chromatography.
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