Silver-Catalyzed Synthesis of Substituted Pyridine Derivatives from N-Propargylic α-Enamino Esters

Article abstract of DOI:10.1002/ejoc.201700559

A wide range of substituted pyridine derivatives were synthesized in moderate to good yields from N-propargylic α-enamino esters. The synthetic strategy involved regioselective addition of a propargylamine to the α-carbon atom of an alkynyl ester to produce the N-propargylic α-enamino ester, which acted as the key intermediate in the synthesis.

Full text of DOI:10.1002/ejoc.201700559

A Journal of
Accepted Article
Title: Silver Catalyzed Synthesis of Substituted Pyridine Derivatives
from N-Propargylic α-Enamino Esters
Authors: Sakthivel Shanmugam, Ashish Sharma, and Rengarajan
Balamurugan
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201700559
Link to VoR: http://dx.doi.org/10.1002/ejoc.201700559
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10.1002/ejoc.201700559
European Journal of Organic Chemistry
COMMUNICATION
Silver Catalyzed Synthesis of Substituted Pyridine Derivatives
from N-Propargylic α-Enamino Esters
Shanmugam Sakthivel,[a] Ashish Sharma,[a] and Rengarajan Balamurugan*[a]
Dedication ((optional))
Abstract: A wide range of substituted pyridine derivatives were
synthesized in moderate to good yields from a N-propargylic α-
enamino ester. The synthetic strategy involves regioselective addition
of propargyl amine to the α-carbon of the alkynyl ester to produce N-
propargylic α-enamino ester which acts as the key intermediate for
the synthesis of the pyridine derivatives.
β-enaminone under basic conditions.9 Arcadi and co-workers
developed a gold catalyzed approach for the synthesis of pyridine
derivatives involving initial amination, annulation followed by
aromatization.10 In this reaction, propargylamine reacts with
ketone/aldehyde bearing α-hydrogens under gold and copper
catalysis. Few other reports for the synthesis of pyridine
derivatives from carbonyl compounds and propargyl amines are
also known.11 As seen above, most of the known methods employ
N-propargylic β-enaminones either as starting material or
intermediate. However, studies addressing the reactivity and
synthetic utility of corresponding -enaminone/-enamino ester
counterparts are very limited.12 In 2005, Ramachandran et al.
reported the quantitative conversion of alkyl propiolate into (E)-
dialkyl hex-2-en-4-ynedioate using catalytic DABCO.13 (E)-Dialkyl
hex-2-en-4-ynedioate undergo α-addition regioselectively upon
reaction with amine nucloeophiles.14 Shih-Ching and co-workers
reported many interesting synthetic methodologies using PPh3
nucleophile for α-addition with (E)-diethyl hex-2-en-4-ynedioate.15
Here in, we report the preparation of N-propargylic α-enaminones
from the reaction of (E)-diethyl hex-2-en-4-ynedioate with
propargyl amines and their cyclization using silver catalyst as an
alternate protocol for the synthesis of highly functionalized
pyridine derivatives.
.
Introduction
Pyridine is one of the most privileged structural motif present
in several biologically important natural products.1 In fact, a
number of marketed drugs and pharmaceutically important
compounds contain pyridine subunit and the number is growing
steadily.2 The diverse bioactivitities of the pyridine derivatives
persistently attract the researchers to develop alternate protocols
for their synthesis. In addition to the conventional Hantzsch,
Chichibabin, Bohlmann-Rahtz and Bonnemann methods for the
synthesis of pyridine derivatives,3 different approaches have been
developed for the synthesis of pyridine derivatives in recent
years.4 Still, owing to the growing medicinal importance of
pyridine heterocycles, alternate methods to access highly
functionalized derivatives under mild reaction conditions are
always in demand.
N-Propargylic β-enaminones are important and versatile
intermediates in organic synthesis and have been used for the
synthesis of many important N-heterocyclic compounds.5 Pyridine
derivatives can also be synthesized from N-propargylic β-
enaminones using transition metal catalysts. In this context, a
pioneering work was reported by Cacchi et al. for the synthesis of
pyridine derivatives from N-propargylic β-enaminones through
CuΙ catalyzed intramolecular cyclization.6 Later, Wan et al.
reported the synthesis of substituted pyridine derivatives using N-
sulfonyl, N-propargylic β-enaminones by one pot reaction
comprising of aza-Claisen rearrangement, electrocyclization and
elimination cascade.7 Iodine and base-mediated synthesis of
pyridine derivatives was reported by Zora et al. in 2015.8 This
reaction involves iodine-mediated electocyclization in acetonitrile
under reflux conditions. In 2015, an interesting method was
reported by Cheng et al. for the synthesis of substituted pyridines.
In this method external nucleophiles were used with N-propargylic
Results and Discussion
In continuation of our research to utilize the easily accessible (E)-
diethyl hex-2-en-4-ynedioate 1 as building block for the synthesis
of interesting organic compounds,16 we started our studies
towards the preparation of the key intermediate N-propargylic α-
enamino esters. The advantage of this substrate is that it has two
esters and an alkene functionalities which can be synthetically
manipulated to introduce complexity and more importantly it can
easily be accessed. Initially, we treated the enyne diester 1 with
[a]
S.Sakthivel, A. Sharma, Prof. Dr. R Balamurugan
School of Chemistry, University of Hyderabad,
Gachibowli, Hyderabad 500046, India
Fax: +91-40-2301-2460
E-mail: bala@uohyd.ac.in
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10.1002/ejoc.201700559
European Journal of Organic Chemistry
COMMUNICATION
commercially available propargyl amine in dichloromethane at
room temperature for 24 h and isolated the compound 3 in 28%
of yield. The configuration of the diene was found to be E, E as
reported in the simple amine addition.14a The reaction condition
was optimized to improve the yield of the product and only
selected results are presented in table 1.17 After extensive
optimization, it was found that N-propargylic α-enamino ester 3
was obtained in 56% yield when the reaction was carried out
using 2 equivalents of propargyl amine with respect to enyne
diester 1 in THF at 0-5 °C.
Table 1 Optimization of reaction condition for the preparation N-propargylic α-
enamino esters 3
Enyne/
amine
ratio
Time
(h)
Temperature
(°C)
S.No
Solvent
Yield %a
1
2
3
4
5
CH2Cl2
Ethanol
Toluene
THF
21
26
24
20
12
rt
1:1
1:1
1:1
1:2
1:2
28
Figure 1. Synthesis of N-propargylic α-enamino ester derivatives
.
rt-reflux
rt-reflux
0-5
35 (7)b
33 (9)b
56
We then started our investigation to understand the
reactivity of N-propargylic α-enamino ester 3a for the synthesis of
substituted pyridines using different transition metal catalysts.
The results of screening experiments are summarized in table 2.
Initially, we observed the formation of pyridine derivative 4a in
48% along with the corresponding α, β-saturated analogue 5a in
34% of yield, using PPh3AuCl/AgSbF6 catalytic system. AuΙ
catalyst alone was inactive for the transformation whereas
oxophilic AuΙΙΙ catalyst could transform N-propargylic α-enamino
ester 3a into pyridine derivative 4a in lower yields (Table 2, entries
3-5). Copper catalysts were also tested for the same conversion.
Among them, copper triflate resulted in 67% of the expected
product along with 1% of α, β-saturated analogue 5 (Table 2, entry
6) and other copper catalysts resulted in lower yields of the
product and poor conversion (Table 2, entries 7-10). Interestingly,
silver salts were found to catalyze the reaction more efficiently
(Table 2, entries 12-15). Among them AgBF4 resulted the
formation of the pyridine derivative in 80% yield along with 4% of
α, β-saturated analogue (Table 2, entry 14).18 In addition, other
metal based Lewis acids, such as Sn(OTf)2 and FeCl3 were found
to be ineffective to promote the transformation (Table 2, entries
11 and 16).
THF
0-10
50
[a] isolated yield. [b] % of recovered enyne diester.
Having optimized condition in our hand, different substituted
propargyl amines were reacted with (E)-diethyl hex-2-en-4-
ynedioate 1 and corresponding N-propargylic α-enamino esters
3a-3o were prepared in moderate to good yields. Reaction of
phenyl propargyl amine 2b with (E)-diethyl hex-2-en-4-ynedioate
(1) resulted in better yield of the product 3b 75% than that with
simple propargyl amine 2a. Phenyl propargyl amines having
electron donating group in the meta position and electron
withdrawing substituents resulted in moderate yields of the
products 3c, 3f and 3h. Similar trend was observed in the
synthesis of 3l, 3m and 3n as well. α-Phenyl substituted propargyl
amines resulted in the formation of corresponding N-propargylic
α-enamino esters 3i-3k as an inseparable mixture of E, E diene
with small amounts of E, Z diene. The substituted propargyl
amines 2b-2n were prepared following literature protocols and the
details are presented in the supporting information.
AgBF4 was chosen for further optimization to find out appropriate
solvent. Among the different solvents used for screening, dioxane
was found to be superior solvent which resulted in 77% yield of
the product 4a along with 3% of α, β-saturated analogue 5a in 2
h (Table 3, entry 5). Although dichloromethane was equally
efficient in terms of yield, more amount of 5a was obtained (Table
3, entry 7).
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10.1002/ejoc.201700559
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Table 2. Catalyst Screening
substituent 3b resulted in lower yield of 4b (50%) compared to the
compound 3a, (80% of 4a). Formation of thiophene substituted
pyridine 4e and di aryl substituted pyridines 4i-4k required longer
reaction times ranging from 11 to 29 hours. Longer reaction times
required for the formation of compounds 4i-4k might be attributed
to the steric crowding present in the corresponding N-propargylic
α-enamino esters 3i-3k. Even 2,3,6-trisubustituted pyridines (4m-
4o) could be obtained by starting from corresponding benzyl
propargyl amines added substrates (3m-3o).
S.No.
Catalyst (5 mol %)
Time (h)
Yield % (4:5)a
1
2
3
4
PPh3AuCl
PPh3AuCl/AgSbF6
NaAuCl4
24
7
No reaction
82 (58:42)
11 (87:13)
38.0
Table 3. Solvent screening with AgBF4
30
24
AuCl3
5
6
7
8
AuCl3/AgSbF6
Cu(OTf)2
CuI
4
38 (93:7)
S.No.
Solvent
CH3CN
Ethanol
Toluene
CH3NO2
1,4-Dioxane
DCE
Yield % (4:5)a
71 (92:8)
Time (h)
26
2
67 (99:1)
1
2
3
4
5
6
7
24
24
11 (78:12) (30)b
35 (95:5) (9)b
61 (77:23)
56 (77:23)
45 (76:24)
80 (96:4)
26
CuBr2
24
24
9
CuCl2
24
24
8 (97:3) (22)b
3 (93:7)
2.0
15
10
Cu(OAc)2
74 (80:20)
79 (65:35)
11
12
Sn(OTf)2
AgOTf
24
10
No reaction
79 (93:7)
CH2Cl2
24
[a] % of α, β-saturated analogue.
13
AgSbF6
2
78 (93:7)
14
15
16
AgBF4
AgNTf2
FeCl3
2
80 (96:4)
5
77 (84:16)
No reaction
24
[a] % of α, β-saturated analogue. [b] % of recovered starting material.
Then one pot domino sequence was attempted. Reacting
compound 1 with 2 equivalents of 2a in the presence of AgBF4 did
not result in the corresponding pyridine derivative. This reaction
resulted in Michael product in 10-15% yield. In another reaction
catalyst was added after the formation of Michael adduct. But the
propargylamine present in the reaction deactivated the catalyst
and no pyridine product was obtained. Therefore a reaction was
set up using equimolar amounts of 1 and 2a. However, in this
reaction Michael adduct formation was very sluggish and addition
of AgBF4 after 24 h resulted in only 3% of the pyridine product.
Therefore reacting Michael adduct with AgBF4 is the appropriate
way to obtain the pyridine product.
After identifying the optimum condition for the cyclization of N-
propargylic α-enamino ester derivative 3a compounds 3b-3o
which were prepared by trivial protocols were attempted.
Substrates having both electron donating and withdrawing groups
in the aryl ring were subjected to cyclization using AgBF4 catalyst
in dry dioxane to obtain substituted pyridine derivatives in
moderate to good yields. -Enaminono ester with simple phenyl
Figure 2. Synthesized pyridine derivatives
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bottom flask, AgBF4 (0.05 equiv.) was added at room temperature. After
completion of the reaction, as monitored by TLC, solvent was evaporated
and the crude product was purified using column chromatography to get
the desired compounds 4.
A
plausible mechanism for the formation of pyridine
derivatives is outlined in figure 3. Initially, the silver salt
coordinates with the alkyne of I and facilitates an intramolecular
nucleophilic attack of the enamine to the activated alkyne II by a
6-endo-dig cyclization to result in the intermediate III.
Protodemetalation in intermediate III regenerates the catalyst for
further catalytic cycle and the obtained intermediate IV upon
aromatization leads to the formation pyridine derivative V.6
Formation of small amounts of α, β-saturated analogue VI might
be due to the reduction of double bond by the hydride transfer
from intermediate IV during the course of its aromatization
process similar to hydrogenation reaction using Hantzsch ester.19
Acknowledgements
The authors thank UPE-2, Unversity of Hyderabad, for financial
support. S.S thanks the Council of Scientific and Industrial
Research (CSIR), India for a fellowship.
Keywords: α-addition • enamine • silver catalysis • propargyl
amine • pyridine
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In summary, we have developed a facile method for the synthesis
of highly substituted pyridine derivatives from an easily accessible
six carbon building block. Silver catalyst alone could effect the
cyclization of N-propargylic α-enamino ester to pyridine
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Entry for the Table of Contents (Please choose one layout)
Layout 2:
COMMUNICATION
Key Topic* Pyridines synthesis
Shanmugam Sakthivel, Ashish Sharma
and Rengarajan Balamurugan*
Page No. – Page No.
Silver Catalyzed Synthesis of
Efficient synthesis of substituted pyridines via cyclization of easily accessible N-
propargylic α-enamino esters
Substituted Pyridine Derivatives from
N-Propargylic α-Enamino Esters
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