An unusual route to synthesize indolizines through a domino SN2/michael addition reaction between 2-mercaptopyridine and nitroallylic acetates

Article abstract of DOI:10.1002/ejoc.201801426

A straightforward synthesis of indolizines has been demonstrated from the reaction of 2-mercaptopyridine and nitroallylic acetates in the presence of a base. The products were obtained in good isolated yield under relatively mild reaction conditions. The

Full text of DOI:10.1002/ejoc.201801426

A Journal of
Accepted Article
Title: An Unusual Route to Synthesize Indolizines via a Domino SN2/
Michael Addition Reaction Between 2-Mercaptopyridine and
Nitroallylic Acetates
Authors: Suparna Roy
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European Journal of Organic Chemistry
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COMMUNICATION
An Unusual Route to Synthesize Indolizines via a Domino
S 2/Michael Addition Reaction Between 2-Mercaptopyridine and
N
Nitroallylic Acetates
*
[a]
Suparna Roy
Abstract: We have demonstrated a straightforward synthesis of
indolizines from the reaction of 2-mercaptopyridine and nitroallylic
acetates in the presence of a base. The products were obtained in
good isolated yield in a relatively mild reaction condition. The
mechanistic insight of the reaction has been revealed by performing
some control experiments demonstrating the reaction initiates via a
N
sequential S 2/Michael addition reaction followed by removal of S-
moiety. The unconventional application of nitroallylic acetate has
been realized.
Scheme 2. Nitroallylic acetate in relevant reactions.
[
2b,3]
during the course of the reaction.
Step wise cyclization of the
Introduction
derivatives of 2-mercaptopyridinium salts towards indolizines
[3]
has been documented in a few discrete cases. The sequence
commenced with C‒C bond forming reaction when 2-
a
Development of new synthetic routes for the generation of
indolizines continues to be a striking area of research in organic
chemistry. The fact is evidenced by persistent flow of
mercaptopyridine derivatives reacted with active methylene
compounds in the presence of a base (Scheme 1). Moreover,
generation of indolizines has been proposed from a S-containing
[
1-4]
numerous research publications over the years.
In this regard
[
4a]
intermediate via extrusion of sulfur moiety.
one of the widely used methods involves 1,3-dipolar
cycloaddition reaction between pyridinium salt and a suitable
On the other hand, nitroallylic acetates are basically the Baylis-
[
1a,e,2]
Hillman adducts generated from ethyl glyoxalate and β-
dipolarophile.
A large variety of 2-substituted pyridines have
[5,6]
been used as powerful synthetic precursors to access various
indolizine frameworks but often required a transition metal-
catalyst to trigger the reaction.
nitrostyrenes.
The allylic acetates substituted with adjacent
electron withdrawing groups are said to have “all electophilic
[
6i]
[
1a,f,g,l,2a-c]
position.” They have been subjected to react with various
2-Mercaptopyridine
dinucleophilic components for the synthesis of a number of
heterocycles. In a previous report nitroallylic acetates delivered
indolizines when reacted with ethyl 2-pyridylacetate and 2-
derivatives are brought into the scope of such transformation but
with limited access which requires removal of sulfur moiety
[
6]
[
6i]
pyridylacetonitrile.
S-containing heterocycles when reacted with nitroallylic acetates
via an S 2 reaction followed by ring closure process (Scheme
thus manifesting the systematic dinucleophilic and
dielectrophilic behaviours of mercapto-substituted N-heterocycle
Again, 2-mercaptobenzimidazole delivered
N
[
6k]
2);
Scheme 1. Previous concept for the formation of indolizine from 2-
mercaptopyridine derivatives.
[
a]
Dr. Suparna Roy
Division of Organic Chemistry
CSIR-National Chemical Laboratory
Pune 411 008, India
E-mail: r.suparna@ncl.res.in
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
Fig.
1 Selected examples of natural products and biologically active
compounds containing indolizine skeleton.
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European Journal of Organic Chemistry
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COMMUNICATION
and nitroallylic acetates respectively. We herein, present a one-
pot unconventional route to indolizines from the reaction
between 2-mercaptopyridine and nitroallylic acetates in the
the presence of ammonium acetate (1 equiv.) though with
inferior yield (26%) (entry 11). The reaction worked in absence
of any base in MeOH but with low yield (30%) (entry 12). Then
presence of a base via an S
N
2/Michael addition reaction
3 2
various solvents (IPA, 1,4-dioxan, DMF, CF CH OH) were
sequence followed by removal of S-moiety (Scheme 2).
screened without any base but failed to obtain optimum yield
(see SI). 2,6-lutidine was employed as a base to optimize the
reaction conditions. After several attempts we understood that
excessive nitroallylic acetate is needed for completion of the
reaction. The fact can be rationalized by partial decomposition of
Indolizines are integral part of a number of naturally occurring
alkaloids such as swainsonine, camptothecin, cryptowoline,
castanospermine, lamellarin, rhazinilam etc and synthetic drugs
[7]
having pharmacological activities (Fig. 1a). It has been found
simply functionalized indolizines can have interesting biological
acetate in the presence of
a base. So after extensive
[8]
activities (Fig. 1b). In addition, these compounds are known to
investigation when we carried out the reaction between 2-
mercaptopyridine and nitroallylic acetate (1a, 2 equiv.) in the
[
9]
have fluorescent properties and can be used as dyestuffs.
presence of 2,6-lutidine (1 equiv.) in CS
2
for 2 days the product
3a was obtained in 75% isolated yield along with minor
Results and Discussion
regioisomer 3a' in <5% isolated yield (entry 14). We found that
equivalent amount of base was optimal for the reaction as
catalytic amount of the same afforded the product in 64% yield
in longer reaction time (entry 15). Again nitroallylic acetate was
decomposed on using excess base (entry 16).
In our very first attempt we carried out reaction between
nitroallylic acetate 1a and 2-mercaptopyridine (2, 1 equiv.) in the
presence of quinidine (20 mol%) in DCM for 24 h (Table 1, entry
Next, the generality of the methodology has been established
1). Indolizine 3a was obtained in 28% isolated yield as a product.
with the optimized reaction condition.
A wide variety of
The initial result prompted us to find out the suitable base for the
reaction. We carried out the reaction in the presence of various
nucleophilic bases e. g DABCO, Et N, DIPA, DBU, DMAP and
3
pyridine (entries 2-7). But in all the cases reaction rendered
either decomposition of reactants or complex mixture except
pyridine which afforded trace amount of the product. When 2,6-
lutidine (1 equiv.) was employed the yield of the reaction was
nitroallylic acetates has been brought into the substrate scope to
obtain indolizine derivatives in good to moderate yields (Table 2).
It has been found that nitroallylic acetates substituted with
electron releasing groups on aryl ring worked well to afford the
[
a, b]
Table 2. Scope of substrates.
2 3
slightly improved to 38% (Table 1, entry 8). Again use of K CO
resulted in decomposition of starting materials(Table 1, entry 9).
NaOMe afforded the product only in 18% isolated yield (Table 1,
entry 10). The reaction even worked in
[
a]
Table 1. Optimization of reaction condition.
Entry
Solvent
Base
Time
h)
Yield 3a
(%)
28
ND
ND
ND
Decomp.
ND
trace
38
Decomp.
18
26
30
[
b]
(
[
c]
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
MeOH
DCM
DCM
MeOH
Quinidine
DABCO
Et N
3
DIPA
DBU
24
24
8
10
0.5
8
24
24
10
24
24
24
24
48
88
24
DMAP
Pyridine
2,6-Lutidine
CO
NaOMe
K
2
3
0
1
2
3
4
5
6
NH
-
4
OAc
CCl
4
2,6-Lutidine
2,6-Lutidine
2,6-Lutidine
2,6-Lutidine
49
75
64
Decomp.
[
[
[
d]
e]
f]
CS
CS
CS
2
2
2
[
a] Al the reactions were carried out between 2-mercaptopyridine (0.2 mmol,
2.2 mg), and nitroallylic acetates (4 mmol) in the presence of 2,6-lutidine (0.2
mmol, 24 µl) in CS (2 mL) at room temperature for 24-48 h. [b] Isolated yield
[
a] Al the reactions were carried out in 0.2 mmol scale of reactants at room
temperature. [b] Isolated yield of the product after column chromatography. [c]
0 mol% of quinidine was used. [d] Nitroallylic acetate (2 equiv.) was used. [e]
2
2
2
of the products after column chromatography. [c] Nitroallylic acetate (1.5
equiv.) was used and the reaction was kept stirring for 3 days. [d] Product was
isolated with slight minor isomer.
Nitroallylic acetate (2 equiv.) and base (20 mol%) was used. [f] Base (2 equiv.)
was used. ND = not detected.
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European Journal of Organic Chemistry
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COMMUNICATION
corresponding products in good yields irrespective of their
position (3b-g). Whereas, 2,4-dimethoxy substituted one
afforded the product in low isolated yield. Various halo
substituted nitroallylic acetates were well-tolerated in the present
methodology and provided the products in good to moderate
yields (3h-m). The reaction did not work in case of 2-
bromophenyl substituted nitroallyl acetate which can be
rationalized by proximal steric bulk. Electron withdrawing group
substituted nitroallylic acetate was also susceptible for the
reaction to afford the corresponding indolizine in 50% isolated
yield (3n). Again, 2-fural substituted indolizine was not obtained
in our current protocol.
We have intended to include 2-mercaptopyridines with various
substitution profiles in this methodology (Fig. 2). Unfortunately,
5-trifluoromethyl 2-mercaptopyridine (4) and 6-methyl 2-
mercaptopyridine (5) did not fit in the optimized reaction
conditions and failed to deliver the corresponding products. The
probable reason could be based on electronic and steric
grounds respectively.
Scheme 3 Control experiments.
Fig. 2 Limitation of the reaction methodology.
Next, some control experiments were performed to enlighten the
mechanistic insight of the reaction methodology towards
indolizines (Scheme 3). At first we carried out reaction between
2-mercaptopyridine and β-nitrostyrene (Scheme 3a). But there
was no reaction at all as both the starting materials were intact.
Next when we employed primary nitroallylic acetate (6) for the
same reaction; the product 7 obtained only after nucleophilic
substitution reaction (Scheme 3b). The results implied that the
reaction initiates via an S 2 reaction and a suitably positioned
N
ester group is required for further cyclization via Michael addition.
Again, similar reaction with 2-mercaptopyrimidine (8) resulted in
N
product (9) after S 2 reaction (Scheme 3c). Less nucleophilic
pyrimidine moiety perhaps restricted further cyclization. It was
also observed that synthesis of 7 and 9 could be achieved in
absence of a base in comparable isolated yields. Reaction did
not work when methylated 2-mercaptopyridine (10) and
quaternary allylic acetate (11) were used in two discrete cases
Scheme 4 Plausible reaction mechanism.
(
Scheme 3d and e). This again emphasized that the reaction
initiates via an S 2 reaction.
On the basis of the above mentioned experiments done we
predict that the reaction proceeds through an S 2/Michael
N
Conclusions
N
addition sequence (Scheme 4). The subsequent ring contraction
towards indolizine can be rationalized via the formation of
episulfide intermediate (Eschenmoser sulfide contraction). The
first step involves an S 2 reaction between 2-mercaptopyridine
N
and nitroallylic acetate at a tertiary carbon centre. The resulting
intermediate then undergoes intramolecular Michael addition
We have demonstrated a base-mediated reaction between 2-
mercaptopyridine and nitroallylic acetates to deliver substituted
indolizines. A number of nitroallylic acetates were susceptible for
the methodology to obtain the product in high to moderate yields.
The mechanism of the reaction has been understood as a
N
sequential S 2 reaction at less likely tertiary centre followed by
reaction to generate
a cyclic pyridinium ion which gets
Michael addition and aromatization process. The result definitely
discloses the versatility of nitroallylic acetate as an efficient
precursor for the synthesis of indolizine moiety in a rather
unusual manner.
deprotonated in the presence of a base at active methylenic site
and forms an episulfide intermediate. Subsequent aromatization
via elimination of nitrous acid and removal of S-moiety delivers
[
4a]
the product as indolizine. The formation of minor regioisomer
can be realised as a side reaction initiates via an S 2' reaction.
N
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European Journal of Organic Chemistry
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Acknowledgement
Author acknowledges Department of Science and Technology,
Government of India for financial support vide reference no.
SR/WOS-A/CS-60/2016 under Women Scientist Scheme to
carry out this work. Author thanks Dr. C. V. Ramana, CSIR-NCL
for his mentorship.
Keywords: Domino reaction • Indolizine • Michael addition •
Nitroallylic acetate • S 2 reaction
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European Journal of Organic Chemistry
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COMMUNICATION
Entry for the Table of Contents
Layout 2:
COMMUNICATION
Synthetic method
Suparna Roy*
An Unusual Route to Synthesize
Indolizines via a Domino S
Addition Reaction Between
N
2/Michael
2-
Mercaptopyridine and Nitroallylic
Acetates
An unusual reaction between 2-mercaptopyridine and nitroallylic acetates has been
N
demonstrated. The reaction initiates by a domino sequence including an S 2
reaction at tertiary centre followed by Michael addition and removal of S-moiety to
deliver substituted indolizines as products.
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