Copper-Catalyzed Carbon-Nitrogen/Carbon-Selenium Bonds Formation: Synthesis of 2-(Organochalcogenyl)-indolizines

Article abstract of DOI:10.1002/adsc.201700166

The copper-catalyzed cyclization of propargylpyridines with diorganyl dichalcogenides was applied to the synthesis of 2-(organochalcogenyl)-indolizines. A systematic study of the cyclization system revealed that the mutual action between copper(I) iodide

Full text of DOI:10.1002/adsc.201700166

Title: Copper-catalyzed Carbon-Nitrogen/Carbon-Selenium Bonds
Formation: Synthesis of 2-(Organochalcogenyl)-Indolizines
Authors: Tales Goulart
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Advanced Synthesis & Catalysis
10.1002/adsc.201700166
FULL PAPER
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Copper-catalyzed Carbon-Nitrogen/Carbon-Selenium Bonds
Formation: Synthesis of 2-(Organochalcogenyl)-Indolizines
a
b
, a
Tales A. C. Goulart, Davi F. Back and Gilson Zeni*
a
Laboratꢀrio de Síntese, Reatividade, Avaliaꢁꢂo Farmacolꢀgica e Toxicolꢀgica de Organocalcogꢃnios CCNE, UFSM,
Santa Maria, Rio Grande do Sul, Brazil 97105-900.
E-mail: gzeni@ufsm.br; Fax: (+55)55-3220-8978; Tel: (+55)55-3220-9611.
b
Laboratꢀrio de Materiais Inorgꢄnicos, Departamento de Química, UFSM, Santa Maria, Rio Grande do Sul, Brazil 97105-
9
00.
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
Abstract. The copper catalyzed cyclization of propargyl This protocol was efficient to diorganyl diselenides and
pyridines with diorganyl dichalcogenides was applied to the ditellurides but ineffective to diorganyl disulfides. In
synthesis of 2-(organochalcogenyl)-indolizines. Systematic addition, the obtained 2-(organochalcogenyl)-indolizines
study of the cyclization system revealed that the mutual were readily transformed to more complex products by
action between copper(I) iodide and diorganyl reaction with boronic acids using palladium-catalyzed
dichalcogenides is essential for the formation of indolizines cross-coupling conditions.
in good yields avoiding the formation of hydrogenated Keywords: heterocycles, indolizines, copper, selenium,
indolizine.
The standard reaction conditions were selenides
compatible with many functional groups in the substrates,
such as methyl, chlorine, fluorine, methoxyl and
trifluoromethyl.
cyclization undergo problems, such as high
temperature, limited generality, harsh conditions,
the need to employ stoichiometric quantities of
copper reagents and numerous synthetic steps.
Over the past years, significant progress has been
achieved in this field regarding the effect of several
Introduction
The use of transition-metal catalysis has long been
a fertile research source of laboratories and
industries because this chemistry delivers various
processes and a broad range of new compounds in
[4]
[
5]
[6]
[7]
high yields and selectivity.[1]
ligands, such as diols, diamines, amino acids,
amino alcohols,
In particular,
[8]
[9]
phosphoramidites,
phosphine oxides,[10] pyridine N-oxide,[11] β-
diketones and β-keto esters.
oxime-
transition-metal catalyzed reactions have been
employed as an efficient strategy to access carbon-
and heterocycles.[
[
12]
2]
After these
In this field, the palladium-
improvements, the methodologies became more
attractive being that nowadays they can be carried
out at lower temperatures, under milder conditions
and using catalytic amount of the copper salts.[
Reactions involving copper salts in the formation
of heterocycles from functionalized alkynes have
catalyzed cyclization reactions are the most
effective routes for the synthesis of these
compounds.[3] However, with the need to develop
cleaner and cheaper catalytic systems for the
cyclization reaction, copper salts have become a
valuable alternative for the construction of carbo-,
hetero- and macrocycles. The earliest examples of
traditional methods for the copper-promoted
13]
[14]
also been reported in the literature.
This
methodology generally is based on the
coordination of copper salts with unsaturated
1
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Advanced Synthesis & Catalysis
10.1002/adsc.201700166
o
carbon-carbon
bonds,
activating
toward
but increasing the reaction temperature to 100 C
nucleophile attack, which is located at a suitable
distance to provide mainly five- or six- membered
the yields were not improved but lower them
(Table 1, entry 2). We found that changing the
solvent to DMSO produced 2a in 55 % yield and
indolizine 3 in 14% yield (Table 1, entry 3). When
the reaction was carried out under an inert
atmosphere (argon) the cyclized products 2a and
3a were obtained together with a complex mixture
of side products, suggesting that an inert
atmosphere is not necessary to this reaction (Table
1, entry 4). The use of bases increased the reaction
yields and selectivity, whereas the best result was
rings.
The copper-catalyzed cyclization of
propargylic pyridine 1, in which the nitrogen atom
is the nucleophile, is an efficient route to the
[15]
preparation of indolizines 3 (Scheme 1).
The
functionalization of indolizines at C-2 position via
copper-catalyzed cyclization of propargylic
pyridines, cited in the previous references, is,
however, practically absent and many of these
have appeared recently.[
15a],
[16]
Indolizine
compounds are of interest with respect to their
observed with Na
2
CO (2 equiv), which gave the
3
[17]
well-known physical, chemical
and biological
desired 2-(phenylselanyl)-indolizine 2a in 73%
yield together with trace amount of indolizine 3a
(Table 1, entries 5-11). This suggests that the
presence of base is crucial for the success of the
cyclization and its function is attributed to
deprotonation of salt III, an intermediate formed in
the cyclization step (See mechanism discussion,
Scheme 4). Next, we studied the influence of other
solvents in this reaction; N,N-dimethylformamide
and N,N-dimethylacetamide gave 2a in comparable
results as that of obtained with DMSO (Table 1,
entries 12 and 13). Toluene, 1,4-dioxane and THF
properties[18] as well as the use as synthetic
building blocks.[
19]
Herein, we reported the
cooperative action between copper salt and
diorganyl diselenides to promote the cyclization of
propargyl pyridines 1 and to incorporate an
organoselenium moiety at C-2 position of the
indolizines 2 (Scheme 1). The introduction of an
organochalcogen moiety in the structure of the
indolizines is usefulness, especially because of
possibility for the carbon-chalcogen bond be
readily replaced by carbon-hydrogen, carbon-
halogen and carbon-carbon bonds,[20] increasing
the structural complexity of the indolizine nucleus.
gave
dichloromethane gave only the indolizine 3a in
6% yield (Table 1, entries 14-17). We then
a
complex product mixture whereas
8
examined the effect of diphenyl diselenide amount
on the cyclization of propargyl pyridine 1a and the
results showed that decreasing the amount of
diselenide from 1.5 to 1.0 and 0.75 equivalents the
product 2a was obtained in moderate yields (Table
Scheme 1. General scheme: previous (a) and present
studies (b) on the cyclization of propargyl pyridines
catalyzed by copper.
1, entries 18 and 19). We also adjusted the amount
of base and this study showed that a base loading
of 1.5 and 1.0 equivalents gave the product in
similar yields, but the yields were reduced if
compared with those with 2.0 equivalents (Table 1,
entries 20 and 21). In an attempt to examine the
copper source effect, different copper(I) and
copper(II) salts were tested, the use of other copper
catalysts, gave either similar or lower yields than
that of copper(I) iodide (Table 1, entries 22-26).
Further studies revealed that temperature had an
important influence on the yield of the reaction
because an apparent increase in the catalytic
activity was observed when the reaction was run in
Results and Discussion
In the screening experiment aiming to optimize the
reaction conditions, the first cyclization reaction
was carried out by the addition of diphenyl
diselenide (1.5 equiv) to a solution of CuI (20
mol%) in dimethylformamide (3 mL), under air
atmosphere, in an open flask at room temperature.
After 15 min at this temperature, propargyl
pyridine 1a (0.25 mmol) was added and the
reaction was stirred at room temperature for 4 h.
This reaction condition resulted in the formation of
2-(phenylselanyl)-indolizine 2a and indolizine 3a
o
in 15% and 46% yields, respectively (Table 1,
entry 1). Following the same reaction condition
DMF at 60 C (Table 1, entries 27 and 29).
Additional investigations indicated that the
2
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Advanced Synthesis & Catalysis
10.1002/adsc.201700166
1
1
1
1
1
1
2
2
2
4
5
6
7
8
9
0
1
2
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
Na
Na
Na
Na
Na
Na
2
2
2
2
2
2
CO
CO
CO
CO
CO
CO
3
3
3
3
3
3
(2)
(2)
(2)
(2)
(2)
(2)
toluene
dioxane
THF
-
<5
<5
<5
86
<5[c]
10[f]
10
cyclization proceeded smoothly with CuI (10
mol%) giving 2-(phenylselanyl)-indolizine 2a
however, the optimization revealed that 20 mol%
was the most appropriate to the reaction in terms of
yield (Table 1, entry 30). The progress of the
reaction was monitored by TLC to determine the
necessary reaction time for the complete
consumption of the starting material. We observed
that 2.0 h was the required time taken for the
reactions to be completed. After the reaction
parameters had been established, we concluded
that the addition of propargyl pyridine 1a (0.25
-
<5
-
2 2
CH Cl
DMSO
DMSO
DMSO
DMSO
DMSO
61
52
69
67
59
Na
2
Na
Na
CO
3
(1.5)
2
2
CO
3
3
(1)
(2)
<5
-
CuC
l
CuC
N
CuB
r
CuC
CO
2
2
2
3
4
5
Na
Na
Na
Na
2
2
2
2
2
CO
CO
CO
CO
3
3
3
3
3
(2)
(2)
(2)
(2)
DMSO
DMSO
DMSO
DMSO
53
22
57
61
-
-
-
mmol) and Na
2
CO
3
(2 equiv), to a previous
l
2
prepared solution of diphenyl diselenide (1.5
equiv) and of CuI (20 mmol%) in
dimethylformamide (3 mL), under air atmosphere
in an open flask at room temperature and running
26
CuB
13
<5[g]
6[g]
11[h]
6[g], [i]
r
2
2
2
2
3
7
8
9
0
CuI
CuI
CuI
CuI
Na
Na
Na
Na
CO
CO
CO
CO
(2)
(2)
(2)
(2)
DMSO
DMF
DMF
DMF
67
81
76
75
2
2
2
3
3
3
0
the reaction at 60 C for 2 h is the best condition to
obtain the 2-(phenylselanyl)-indolizine 2a in
higher yield (Table 1, entry 28). Although all
reaction conditions tested gave a variable mixture
of 2a and 3a, they could be separated by column
chromatography using hexane/ethyl acetate (9:1)
[
a] The reaction was performed by addition of diphenyl
diselenide (1.5 equiv) to a solution of CuI (20 mmol%) in
solvent (3 mL), under air atmosphere in an open flask at
room temperature. After 15 min at this temperature, it was
added propargyl pyridine 1a (0.25 mmol) and the reaction
was stirred at room temperature until complete conversion
of the starting material.
[
[
[
[
[
[
[
[
as eluent.
The structural assignment of 2-
(
phenylselanyl)-indolizine was based on NMR
b] Yields of purified products.
analysis and confirmed by X-ray diffraction, which
showed the exact position of the cyclization as a 5-
endo-dig process (Figure 1).
c] Reaction was carried out with PhSeSePh (1.0 equiv).
0
d] Reaction was carried out at 100 C.
e] Reaction was carried under argon atmosphere.
f] Reaction was carried out with PhSeSePh (0.75 equiv).
Table 1. Effect of different reaction parameters on the
0
g] Reaction was carried out at 60 C.
[
a]
preparation of 2-(phenylselanyl)-indolizine 2a
0
h] Reaction was carried out at 80 C.
i] Reaction was carried out with CuI (10 mol%).
entry
copp
er
salt
base
(equiv)
solvent
yield[b]
2a (%)
(%)
3a
46
1
2
CuI
-
-
DMF
DMF
15
c],[d
CuI
<5
<5[
]
3
4
5
6
7
8
9
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
-
-
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMF
55
19
60
-
14
41[e]
20
-
3
NaHCO (2)
t-BuOK(2)
CO (2)
CO
PO
NEt
Cs CO
K
2
3
44
73
45
23
17
76
68
4
Na
2
3
(2)
<5
3
K
3
4
(2)
1
1
1
1
0
1
2
3
3
(2)
(2)
59
10
6
2
3
Na
2
2
CO
3
(2)
(2)
Figure 1. ORTEP drawings (ellipsoids set at 50 %
probability) of the compound 2a (CCDC 1520324).[21]
Na
CO
3
DMA
9
3
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Advanced Synthesis & Catalysis
10.1002/adsc.201700166
After the studies of optimization conditions, we
focused our attention on the generality of the
process applying the standard cyclization
conditions to the reaction of diverse propargyl
2h-k in good yields (Table 2, entries 8-11),
although indolizine 2j has been obtained in a low
32% yields. This low yield can be attributed more
by the negative influence of diorganyl diselenide
than by the structure of propargyl pyridines. With
regard to the presence of withdrawing group at the
aromatic ring of the propargyl pyridines, the
chlorine atom lead to poorer results than electron-
donating groups (Table 2, entries 12-14). The
hypothesis that the withdrawing group next to the
alkyne deactivates the carbon-carbon bond,
decreasing the reactivity, is considered to explain
the behavior of these substrates. In addition, the
presence of bulky 2-naphthyl group at the triple
bond did not give the cyclized product 2o (Table 2,
entry 15), suggesting that the steric hindrance
pyridines
1
with
a
range of diorganyl
dichalcogenides (Table 2). First, to investigate the
influence of the diorganyl diselenides on the
synthesis of 2-(organoselenyl)-indolizine 2, we
studied the reaction of propargyl pyridine 1a with
diorganyl diselenides bearing different substituents
on the structure (Table 2, entries 1-7). By
examining the influence of the electron-donating
groups on the aromatic ring of diselenides we
found that methyl and methoxyl groups in the para
position reacted smoothly giving the product in
good yields, however, ortho methyl group bounded
to the aromatic ring reduced the reactivity (Table 2, exerted by the naphthyl group hampers the
entries 1-4). Probably, the steric hindrance exerted
by the methyl group on the ortho position
decreased the reactivity for the cyclization course.
Next, we tested the influence of electron-
withdrawing groups on the aromatic ring of
diorganyl diselenides. The reactions with
diselenides having para chloro and meta
trifluoromethyl groups on the aromatic ring gave
selenium attack at the carbon-carbon triple bond.
We also evaluated the substituent effects on the
pyridine ring. While the reaction of propargyl
pyridine 1f with diphenyl and bis-(p-chlorophenyl)
diselenide provided good yields of products, the
reaction with bis-(o-methoxyphenyl) diselenide
decreased the yield (Table 2, entries 16-18). The
failure to obtain indolizine 2q was due to
decomposition of the cyclized products during the
purification processes. When the reaction was
carried out using the propargyl pyridine 1g, which
has a terminal alkyne, the indolizine 2s, with two
phenyl selenium groups in the structure, was
obtained in 30% yield (Table 2, entry 19). The
generation of 2s could be explained in terms of
selenoacetylene 4 formation, which could undergo
further cyclization reaction. In order to prove this
hypothesis we ran the reaction under optimized
conditions but proceeding with the workup after 30
min. The GCMS analysis of the crude reaction
mixture indicated the consumption of the starting
material 1g and the presence of a 1:1 mixture of
2e and 2f in 84 and 53% yields, respectively,
proving the pronounced influence of a strongly
withdrawing group in the meta position on the
outcome of the cyclization (Table 2, entries 5 and
6). The reactivity of alkyl diselenide was also
studied. When dibutyl diselenide was employed as
organoselenium source the corresponding 2-
hydrogenated indolizine 3 (Scheme 1) was
obtained in almost quantitative yield (Table 2,
entry 7). This behavior can be attributed to the
presence of the alkyl group directly bonded to the
selenium atom that undergoes beta-selenoxide
elimination, during the workup or purification
process,[
22]
giving the indolizine without the
selenium group incorporated in the structure. Next, selenoacetylene 4 and indolizine 2s. The use of
the reactivity of various substituted propargyl
pyridines 1b-e, each one bearing a substituent at
the aromatic ring directly bonded to the triple
bond, was evaluated in the direct cyclization with
diorganyl diselenides (Table 2, entries 8-15). By
examining the influence of electron-donating
groups on the aromatic rings of the propargyl
pyridines we found that substrates bearing methyl
or methoxyl group cyclized to afford the products
propargyl pyridine ethyl acetate 1h, instead of
methyl acetate derivatives, was also tested and the
reaction system was suitable for the cyclization,
yielding the corresponding indolizines 2t-w
without any major byproducts and in very similar
yields (Table 2, entries 20-23). These results
prompted us to study the influence of chalcogen
atom on the cyclization reaction by using diorganyl
disulfides and ditellurides instead of diselenides.
4
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Advanced Synthesis & Catalysis
10.1002/adsc.201700166
9
1b
6 4 2
(p-Me-C H Se)
The reaction of propargyl pyridine 1a with
diphenyl disulfides, upon optimized cyclization
conditions, did not afford the product (Table 2,
entry 24). This negative result can be rationalized
through the strength of the sulfur-sulfur bond that
prevents its cleavage by copper salt. Replacing
diselenides by ditellurides had no negative effect
on the yields, as the cyclization reaction of
propargyl pyridines 1a-c with bis-(4-chlorophenyl)
ditelluride and dibutyl ditelluride gave the
indolizines 2y-ad in moderate to good yields
2i-81 (2 h)
1
b
6 4 2
(p-Cl-C H Se)
1
0
2
j-32 (4 h)
(p-Me-C
6 4
H
Se)
2
(
Table 2, entries 25-30).
1
1
1
2
1
c
Table 2. Synthesis of 2-(organochalcogenyl)-
indolizines 2[a]
2k-75 (2 h)
(p-Me-C
6 4
H
Se)
2
1
d
3
entr
y
propargyl
pyridines 1
(R Y)
2
2-(organoselenyl)-
indolizine 2, yield (%),
reaction time
[b]
2l-63 (2 h)
1d
(PhSe)
2
(PhSe)
2
1
2
1
3
4
1
1
a
a
2
a-81 (2 h)
6 4 2
(p-Me-C H Se)
2
2
m-64 (3 h)
1
d
6 4 2
(p-Cl-C H Se)
2
2
b-72 (2 h)
c-50 (18 h)
1
1
1
1
a
a
(o-Me-C
H
6 4
Se)
2
n-54 (7 h)
3
4
(
PhSe)
PhSe)
2
(p-MeO-C
6
H Se)
4 2
5
2
d-71 (1.5 h)
1
e
1
a
(p-Cl-C
6 4
H
Se)
2
2o-not formed (2 h)
(
2
5
16
1
1
f
f
2
2
e-84 (2.5 h)
f-53 (4 h)
2
2
p-80 (2 h)
q-21 (1 h)
1
1
a
a
(m-CF
3
-C
6
H
4
Se)
2
(o-MeO-C
6
H
4 2
Se)
1
1
7
8
6
7
(BuSe)
2
1
f
6 4 2
(p-Cl-C H Se)
2
2
g-not formed (2 h)
(PhSe)
2
2
2
r-72 (2 h)
s-30 (3 h)
(PhSe)
2
8
1
b
19
1
g
h-65 (2 h)
5
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Advanced Synthesis & Catalysis
10.1002/adsc.201700166
(PhSe)
2
room temperature. After 15 min at this temperature, it was
added propargyl pyridine 1a (0.25 mmol) and the base.
0
The reaction was stirred at 60 C for the time indicated in
2
0
the table 2.
1
1
h
h
2
2
2
t-73 (2 h)
u-62 (2 h)
v-60 (6 h)
[b] Isolated yield after column chromatography.
(p-MeO-C
6
H
4 2
Se)
Next, we focused attention on the application of
the optimized reaction conditions found in Table 1,
entry 28 to the 2-alkynyl pyridines 1i-j as outlined
in Scheme 2. Tertiary propargyl pyridine 1i
underwent a tandem cyclization/1,2-migration
2
2
1
2
1
1
h
h
3 6 4 2
(m-CF -C H Se)
[
23]
[15c]
when treated with platinum or copper salts
give indolizinone derivatives 5. Under our
to
optimized reaction conditions the pyridine 1i did
not give the expected indolizinone 5 and only
unreacted starting material was recovered together
with unidentified mixture of products even by
changing the reaction conditions (Scheme 2, eq 1
and 2). In the presence of a Lewis acid, the 2-
alkynyl pyridine 1j would generate a propargylic
carbocation I, which is in equilibrium with an
allenic carbocation II via Meyere-Schuster
6 4 2
(p-Cl-C H Se)
2
2
3
4
2
w-70 (3.5 h)
x-0 (1 h)
1
1
a
(PhS)
2
2
b
(PhTe)
2
[24]
rearrangement.
With the aim of enlarging the
scope of our methodology, we envisioned the
application of Meyer-Schuster rearrangement in
the preparation of indolizines 6 by reaction of 2-
alkynyl pyridine 1j with diphenyl diselenide and
copper(I) iodide. Instead, the CGMS analysis of
the crude reaction mixture only showed the
presence of starting material 1j and diphenyl
diselenide (Scheme 2, eq 3).
2
2
5
6
2
2
y-74 (1 h)
1
c
(p-Cl-C
(p-Cl-C
6
H
4
Te)
2
z-70 (1.5 h)
1
b
6
H
4
Te)
2
2
2
7
8
2
2
aa-65 (1 h)
1
1
a
(BuTe)
(BuTe)
2
ab-53 (1.5 h)
b
2
2
3
9
0
2
ac-47 (1 h)
1
c
(BuTe)
2
2
ad-70 (2 h)
Scheme 2. Cyclization reaction with substrate
analogues.
[
a] The reaction was performed by addition of diphenyl
diselenide (1.5 equiv) to a solution of CuI (20 mmol%) in
solvent (3 mL), under air atmosphere in an open flask at
In order to rationalize the factors, which could
govern the mechanism aspect of this cyclization
6
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Advanced Synthesis & Catalysis
10.1002/adsc.201700166
reaction, we performed some control experiments
as following: (a) The reaction of propargyl
pyridine 1b with copper(I) iodide (20 mmol%),
under optimized conditions, in the absence of
diphenyl diselenide gave the indolizine 3a in 54%
yield (Scheme 3, eq 1). In this case, the copper(I)
iodide activates the triple bond to the nitrogen
nucleophilic attack giving the indole indolizine 3a.
product 2 with the insertion of an organoselenium
moiety at C-2 position of the indolizine (Scheme
4).
(
b) No reaction occurred when diphenyl diselenide
was added to a previous prepared solution of
copper(I) iodide and indolizine 3a (Scheme 3, eq
2
2
). This experiment implies that a C(sp) -Cu
intermediated might not be the active species to
promote cyclization of propargyl pyridine 1b. (c)
When we carried out the reaction by a sequential
addition of all reagents, instead of previous
mixture of copper(I) iodide and diphenyl
diselenide, a mixture of 2h and 3a were obtained in
6
1 and 18% yields, respectively (Scheme 3,
equation 3). The experiments described in scheme
, equations 2 and 3 suggest that a selenium
3
Scheme 3. Control experiments for the mechanistic study.
electrophilic species alone is unable to promote the
cyclization reaction and that the mutual action
between copper(I) iodide and diphenyl diselenide
is essential for the formation of 2a in good yield.
(
d) The radical pathway was not discarded;
however, when to the reaction of 1b with diphenyl
diselenide, under optimized conditions, was added
TEMPO, a radical inhibitor, 2h was obtained in
76% yield (Scheme 3, eq 4). This result indicates
that the pathway does not follow the typical radical
addition, where the radical source is PhSe. After
these studies, it seems clear that the 2-
(
organoselenyl)-indolizines
2
formation is
dependent on the copper-selenolate complex
previously formed. Based on above investigation
and the knowledge that in the copper(I)-catalyzed
cross-coupling the copper is easily admitted as a
complex having an oxidation state +3[25] and that
this complex could be stabilized by the chalcogen
atom,[ we propose that the cyclization involves:
Scheme 4. Proposed mechanism.
2
Organochalcogen substrates, which have a C(sp )-
26]
Se bond, were recognized as attractive starting
materials for diverse transformations due to their
regio and stereoselectivity, mild reaction
conditions and tolerance to many functional groups
avoiding protection group chemistry.
application of unsaturated organotellurim
substrates employing palladium catalyzed cross-
coupling has also been described.[28] In this case,
they behave as aryl or vinyl carbocation
(
i) the copper-selenolate species III coordinates to
the carbon-carbon bond to generate the
intermediate IV, which activates the carbon-carbon
bond towards nitrogen attack. (ii) the anti attack of
nitrogen atom on the activated intermediate IV
produces the salt V, which after deprotonation
leads to 2-copper-indolizine VI. (iii) The reductive
elimination of copper gives the desired cyclized
[27]
The
7
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Advanced Synthesis & Catalysis
10.1002/adsc.201700166
equivalents. They react in a manner similar to
essential for the formation of indolizines in good
yields avoiding the undesirable formation of
hydrogenated indolizine. The introduction of
organochalcogen moiety in the C2 position of the
indolizine confers wide utility to the final product
through conversion of the organochalgen group
into other substituents. An application of our
[29]
Heck,[30]
halides or triflates in Sonogashira,
Suzuki[
31]
and Stille
[32]
cross-coupling reactions
with palladium as the catalyst. Therefore, there are
some advantages to use tellurides, such as easy
access, by stereoselective reactions, and the
enhanced stability of these compounds. The
potential application of 2-(organochalcogenyl)-
indolizines 2 prepared by our methodology is
approach
was
described
applying
2-
(organotellurenyl)-indolizines as substrates in
palladium cross-coupling reactions, under classical
Suzuki protocols affording the corresponding
2
unquestionable because the C(sp )-chalcogen bond
finds applications in the transition metal-catalyzed
cross-coupling reactions with nucleophiles, such as
terminal alkynes, boronic acid, thiols and phenols
allowing the introduction of various functional
groups to the indolizines ring. This led us to
explore the possibility to use 2-(organotellurenyl)-
indolizine 2ab and 2ac derivatives as substrates in
palladium cross-coupling reactions, under classical
Suzuki protocols. Under Suzuki reaction condition
products in moderate to good yields.
The
structures of 2-(organochalcogenyl)-indolizines
1
13
agree with H and C NMR spectra as listed in the
Experimental Section. In addition, the crystal
structure of twelve compounds (Supporting
Information, Figures 1-12) provided proof of the
exact position of the cyclization as a 5-endo-dig
cyclization process.
2-(butyltellurenyl)-indolizines underwent smooth
cross-coupling upon exposure to (p-chlorophenyl)-
boronic acid affording 2-(p-chlorophenyl)-
indolizines 7a and 7c in good yields (Scheme 5).
In contrast with earlier results obtained to (p-
chlorophenyl)-boronic acid, p-tolylboronic acid
also afforded the Suzuki product, however the
yield of 7b was lower (Scheme 5).
Experimental Section
General procedure for the CuI-catalyzed cyclization:
The appropriate diorganoyl dichalcogenide (0.375
mmol; 1.5 equiv) was added to a solution of DMF (1.5
mL) and CuI (20 molꢅ%) under an air atmosphere. The
resulting solution was stirred for 15 min at room
temperature. After this time, the appropriate propargyl
pyridines (0.25 mmol) in DMF (1,5 mL) and Na
2 3
CO
(
0.50 mmol) was added and the resulting solution was
heated at 60ꢅ°C for the time indicated in table 2. The
mixture was filtered through silica gel with ethyl
acetate/hexane and concentrated under vacuum. 3-
Phenyl-2-(phenylselanyl)indolizin-1-yl acetate (2a):
Was isolated by column chromatography (hexane:ethyl
acetate 99:1) as a green solid. Yield: 0.082 g (81%); mp
1
1
19-121 °C. H NMR (CDCl
3
, 400 MHz): δ (ppm) 7.90
(
(
6
dt, J = 7.3, 1.0 Hz, 1H), 7.41-7.34 (m, 5H), 7.23-7.18
Scheme 5. Suzuki cross-coupling reactions on 2-
m, 3H), 7.14-7.10 (m, 3H), 6.66-6.62 (m, 1H), 6.40-
(
organotellurenyl)-indolizines 2ab and 2ac.
.36 (m, 1H), 2.20 (s, 3H). 13C{ H}NMR (CDCl
1
3
, 100
MHz): δ (ppm) 169.4, 132.6, 130.4, 130.2, 129.8, 128.8,
1
1
28.6, 128.2, 126.0, 125.2, 123.1, 122.1, 117.4, 116.1,
11.1, 104.4, 20.4. MS (EI, 70 eV; m/z (relative
Conclusions
intensity)): 407 (11), 365 (35), 287 (21), 106 (49), 78
In conclusion, we found that copper(I) iodide and
diorganyl dichalcogenides are valuable cyclization
promoters of propargyl pyridines to prepare 2-
(
100). HRMS calcd for C22
+
H
18NO
2
Se (ESI-TOF, [M +
H] ) 408.0503, found 408.0509.
(
organochalcogenyl)-indolizines. A detailed study
3
-Phenyl-2-(p-tolylselanyl)indolizin-1-yl acetate (2b):
related to the effect of reaction conditions on
product distribution was carried out. The results
clearly pointed out that the mutual action between
copper(I) iodide and diorganyl dichalcogenides is
Was isolated by column chromatography (hexane:ethyl
acetate 99:1) as a yellow solid. Yield: 0.076 g (72%); mp
1
156-158 °C. H NMR (CDCl , 400 MHz): δ 7.89 (dt, J =
3
7.3, 1.0 Hz, 1H), 7.42-7.34 (m, 5H), 7.18 (dt, J = 9.1, 1.2
8
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Advanced Synthesis & Catalysis
10.1002/adsc.201700166
Hz, 1H), 7.13-7.11 (m, 2H), 6.95-6.92 (m, 2H), 6.65-6.60 Acknowledgements
(
m, 1H), 6.39-6.35 (m, 1H), 2.24 (s, 3H), 2.22 (s, 3H).
C{ H}NMR (CDCl , 100 MHz): δ (ppm) 169.5, 135.9,
3
30.5, 130.3, 129.7, 128.9, 128.7, 128.6, 128.2, 125.1,
23.1, 122.1, 117.3, 116.2, 111.1, 104.9, 20.9, 20.4. MS
1
3
1
We are grateful to FAPERGs, CAPES and CNPq for the
financial support. CNPq is also acknowledged for the
fellowships.
1
1
(
EI, 70 eV; m/z (relative intensity)): 421 (12), 379 (31),
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1
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26.5, 126.0, 125.3, 123.2, 122.1, 117.4, 116.2, 111.2,
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32.8, 130.6, 130.4, 128.6, 128.2, 124.8, 123.0, 122.4,
22.0, 117.3, 116.1, 114.6, 111.0, 105.7, 55.2, 20.5. MS
(
2
C
EI, 70 eV; m/z (relative intensity)): 437 (12), 395 (16),
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0
hexane:ethyl acetate 99:1) as a yellow solid. Yield:
[
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.092 g (84%); mp 184-186 °C. H NMR (CDCl
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5
1
(
1
1
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3
1
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CDCl
3
30.5, 130.1, 129.0, 128.7, 128.4, 125.3, 123.1, 122.1,
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(
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42.0118.
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0
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FULL PAPER
Copper-catalyzed Carbon-Nitrogen/Carbon-
Selenium Bonds Formation: Synthesis of 2-
(
Organochalcogenyl)-Indolizines
Adv. Synth. Catal. Year, Volume, Page – Page
a
b
Tales A. C. Goulart, Davi F. Back and Gilson
Zeni
a, *
1
1
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