Nucleophilic cyclization of o-alkynylbenzamides promoted by iron(III) chloride and diorganyl dichalcogenides: Synthesis of 4-organochalcogenyl-1H-isochromen-1-imines

Article abstract of DOI:10.1002/ejoc.201403534

We have developed a method for the preparation 4-organochalcogenyl-1H-isochromen-1-imines from o-alkynylbenzamides. This electrophile-promoted nucleophilic cyclization achieved by treatment with a combination of iron salts and diorganyl dichalcogenides. FeCl₃ and diorganyl dichalcogenides reacted with o-alkynylbenzamides under aerobic conditions at room temperature and in the absence of additives to give 4-organochalcogenyl-1H-isochromen-1-imines in good yields and with good selectivities. The reaction took place with 0.5 equiv. of the diorganyl dichalcogenides, which demonstrates that both halves of the diorganyl dichalcogenides (RYYR → 2RY) were incorporated into the final product. Mechanistic studies suggested that the regioselectivity of the cyclization is governed by a seleniranium ion, a key intermediate formed by the electrophilic addition of the organochalcogen moiety to the carbon-carbon triple bond. The utility of the 4-organochalcogenyl-1H-isochromen-1-imines was also demonstrated by their application as starting materials in Suzuki and Sonogashira cross-coupling reactions.

Full text of DOI:10.1002/ejoc.201403534

FULL PAPER
DOI: 10.1002/ejoc.201403534
Nucleophilic Cyclization of o-Alkynylbenzamides Promoted by Iron(III)
Chloride and Diorganyl Dichalcogenides: Synthesis of 4-Organochalcogenyl-
1H-isochromen-1-imines
Jose S. S. Neto,[a] Davi F. Back,[b] and Gilson Zeni*[a]
Keywords: Synthetic methods / Cyclization / Oxygen heterocycles / Selenium / Tellurium / Alkynes / Iron
We have developed a method for the preparation 4-organo-
demonstrates that both halves of the diorganyl dichalco-
chalcogenyl-1H-isochromen-1-imines from o-alkynylbenz- genides (RYYRǞ2RY) were incorporated into the final prod-
amides. This electrophile-promoted nucleophilic cyclization
achieved by treatment with a combination of iron salts and
diorganyl dichalcogenides. FeCl3 and diorganyl dichalco-
genides reacted with o-alkynylbenzamides under aerobic
conditions at room temperature and in the absence of addi-
tives to give 4-organochalcogenyl-1H-isochromen-1-imines
in good yields and with good selectivities. The reaction took
place with 0.5 equiv. of the diorganyl dichalcogenides, which
uct. Mechanistic studies suggested that the regioselectivity
of the cyclization is governed by a seleniranium ion, a key
intermediate formed by the electrophilic addition of the or-
ganochalcogen moiety to the carbon–carbon triple bond. The
utility of the 4-organochalcogenyl-1H-isochromen-1-imines
was also demonstrated by their application as starting mate-
rials in Suzuki and Sonogashira cross-coupling reactions.
have found widespread use in organic chemistry as nucleo-
philes or electrophiles.[8] Through such reactions, organo-
chalcogens have been used to prepare coordination com-
plexes with silver,[9] rhodium,[10] palladium,[11] copper,[12]
zinc,[13] nickel,[14] and platinum.[15] Therefore, much atten-
tion has been focussed on to the application of these inter-
mediates in the preparation of various classes of chalcogen
compounds by different reactions. Such reactions include
the hydrochalcogenation reaction of alkenes and alkynes,[16]
the carbonylative chalcogenation of alkynes,[17] carbon–
selenium bond formation,[18] carbon–carbon bond forma-
tion,[19] and carbon–hydrogen bond chalcogenation.[20]
Chalcogen–metal complexes are also used in the synthesis
of natural products.[21] Recently, our research group and
others have described the application of organochalcogen–
iron complexes as powerful tools for the synthesis of hetero-
cycles.[22] The main advantage of this approach is that both
halves of diorganyl dichalcogenides (2RY from RYYR) may
be incorporated into the final products, which makes the
method more useful and valuable in terms of atom econ-
omy. In addition, the low price and low toxicity of iron salts
make them very suitable for use in organic transformations,
with a positive impact on the advancement of green chemis-
try and significant environmental benefits.[23] In this paper,
we describe the preparation of 4-organochalcogenyl-1H-
isochromen-1-imines 2 using diorganyl dichalcogenides and
iron(III) chloride to promote the cyclization of o-alkynyl-
benzamides 1 (Scheme 1), which expands the use of organo-
chalcogens in organic synthesis. Recently, it was proposed
that the halocyclization reaction[24] of o-alkynylbenzamides
1 proceeds through a 5-exo-dig mode to preferentially give
Introduction
Organochalcogen compounds, especially selenium deriv-
atives, are versatile and useful synthetic intermediates be-
cause they can be used for the construction of new bonds in
a highly selective fashion under mild reaction conditions.[1]
Additionally, many compounds containing organochalcog-
ens have various biological activities.[2] Organochalcogen
moieties, which can act as hydrogen-bond acceptors or elec-
tron donors in the active sites of enzymes, are key structural
units for the biological activity of compounds containing
these groups. For example, some organoselenium deriva-
tives have shown potential to be used as anticancer,[3] anti-
inflammatory, antibacterial, and antifungal agents.[4] As a
result of their pharmacological effects, the development of
new methods for the synthesis of chalcogen derivatives has
attracted considerable attention. The most commonly used
methods for the introduction of a chalcogen moiety into
organic molecules are based on the transformation of the
elemental chalcogen into a nucleophilic,[5] electrophilic,[6] or
radical species.[7] In addition, organochalcogens react with
most metals to form chalcogen–metal complexes, which
[a] Laboratório de Síntese, Reatividade, Avaliação Farmacológica
e Toxicológica de Organocalcogênios, CCNE, Universidade
Federal de Santa Maria, Santa Maria,
Rio Grande do Sul 97105-900, Brazil
E-mail: gzeni@ufsm.br
http://www.ufsm.br
[b] Laboratório de Materiais Inorgânicos, CCNE, Universidade
Federal de Santa Maria,
Santa Maria, Rio Grande do Sul 97105-900, Brazil
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201403534.
Eur. J. Org. Chem. 2015, 1583–1590
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1583

J. S. S. Neto, D. F. Back, G. Zeni
FULL PAPER
Scheme 1. General scheme.
isobenzofuran-1(3H)-imines 3 (Scheme 1).[25] The innov- triple bond, is required to complex with these donor ligands
ative features of our approach are the preparation of six- (Scheme 2).
membered isochromen-1-imines 2 instead of five-membered
isobenzofuran-1(3H)-imine derivatives 2Ј. In addition, the
introduction of a chalcogen functionality at the 4-position
of the isochromene ring offers attractive possibilities for
synthetic transformations.
Table 1. Effect of different reaction parameters on the preparation
of 4-organochalcogenyl-1H-isochromen-1-imine 2a.[a]
Results and Discussion
As a typical general procedure, a mixture of diphenyl dis-
elenide and FeCl3 in CH2Cl2 (3 mL) was stirred for 15 min
at room temperature under aerobic conditions, followed by
the addition of o-alkynylbenzamides 1a. To determine the
parameters that affect the yield and selectivity in the forma-
tion of 4-organochalcogenyl-1H-isochromen-1-imine 3a
formation, this model reaction was studied with several dif-
ferent molar ratios of diphenyl diselenide and FeCl3, dif-
ferent bases, different solvents, and different iron sources
(Table 1). We first examined the effect of the iron source on
the cyclization reaction (Table 1, entries 1–6). The reaction
was screened with different iron salts, and FeCl3 was chosen
for further studies as it gave a 50% yield of 4-organochalco-
genyl-1H-isochromen-1-imine 3a (Table 1, entry 6). The
molar ratio of diphenyl diselenide and FeCl3 was also
studied; a ratio of 2.0:0.5 was found to be the most efficient
(Table 1, entry 11), although other combinations were also
effective (Table 1, entries 8–15). The fact that 0.5 equiv. of
diphenyl diselenide was used implies that both the phenyl
selenide (PhSe) moieties were transferred into the final
product, which indicates that the cyclization process is atom
efficient. FeCl3 reacts with diphenyl diselenide to incorpo-
rate one PhSe moiety into the substrate, and deliver other
moiety to the reaction medium as selenol (PhSeH). Since
the reactions were carried out under aerobic conditions, the
selenol species (PhSe) was rapidly oxidized by air to regen-
erate diselenides, which could again react with FeCl3. To
confirm this hypothesis, we carried out the reaction under
an argon atmosphere. Under these conditions, a decrease
in the yield of cyclized product 3a was observed (Table 1,
entry 16). The cyclization required 2 equiv. of FeCl3 to form
the product in good yields. We believe that one equivalent
of FeCl3 reacts with the diphenyl diselenide to form the
intermediate, which promotes the cyclization and the incor-
poration of PhSe into the heterocycle. The second equiva-
Entry [Fe] (equiv.)
(PhSe)2 equiv. Solvent
Yield [%][b]
[c]
1
2
FeCl3 (0.5)
FeCl2·4H2O
(2.0)
1.0
0.5
CH2Cl2
CH2Cl2
–
–
[c]
3
FeCl3·6H2O
(2.0)
0.5
CH2Cl2
27
[c]
4
5
Fe(acac)3 (2.0)
Fe0 (2.0)
0.5
0.5
1.0
1.0
1.0
1.0
0.75
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH3NO2
dioxane
DMSO
DMF
–
–
[c]
6
7
8
9
FeCl3 (1.0)
FeCl3 (1.5)
FeCl3 (2.0)
FeCl3 (3.0)
FeCl3 (2.0)
FeCl3 (2.0)
FeCl3 (1.5)
FeCl3 (1.0)
FeCl3 (0.75)
FeCl3 (0.5)
FeCl3 (2.0)
FeCl3 (2.0)
FeCl3 (2.0)
FeCl3 (2.0)
FeCl3 (2.0)
50
55
80
78
10
11
12
13
14
15
16
17
18
19
20
79
83 (80)[d]
65
31
22
31
68[e]
6
70
[c]
–
–
[c]
[a] The reaction was carried out by the addition of PhSeSePh to a
solution of iron salts in solvent (3 mL) at room temperature under
aerobic conditions. After 15 min, the o-alkynylbenzamide 1a
(0.25 mmol) was added. [b] Yields were determined by GC analysis.
[c] The starting material was recovered. [d] Yield of purified prod-
uct. [e] The reaction was carried out under an argon atmosphere;
acac = acetoacetate.
Scheme 2. The preference for 6-endo-dig over 5-exo-dig cyclization.
We also screened other solvents, and CH2Cl2 was found
lent of FeCl3, due to the strong affinity of this salt for nitro- to be the most effective (Table 1, entries 18–20). During
gen and oxygen atoms as well as for the carbon–carbon these optimization reactions, we isolated furan derivative
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Nucleophilic Cyclization of o-Alkynylbenzamides
2aЈ in 5–20% yield after purification by chromatography. In chromen-1-imines (i.e., 2) were isolated as the major prod-
attempt to improve the selectivity of the reaction, we ucts. The electronic properties of the substituents on the
changed the reaction parameters, but no significant effect aromatic rings of the diorganyl diselenides had no influence
was observed. The structures of 2 and 2Ј were assigned on the outcome of the reactions. For example, electron-neu-
based on NMR analysis, and confirmed by X-ray diffrac- tral, electron-rich or electron-poor diaryl diselenides gave
tion (Supporting Information, Figure S1 for compound 2q, similar results in terms of the ratio of five- to six-membered
and Figure S2 for compound 2qЈ). Thus the cyclization was ring products, although the presence of electron-with-
revealed to be a 6-endo-dig process for 2, and a 5-exo-dig drawing groups, such as Cl and CF3, gave the best selectiv-
process for 2Ј.
ity (Table 2, 2a–2f). The presence of electron-withdrawing
In further optimization studies, some important trends substituents in diselenides decreases the electron density on
were observed. For example, when the standard reaction the seleniranium ion, which makes it more reactive towards
described in Table 1 (entry 11) was carried out in the pres- attack by oxygen nucleophiles. The experimental results
ence of a radical inhibitor (hydroquinone) or a radical scav- show that the steric properties of the substituents on the
enger (1,4-dinitrobenzene), the product (i.e., 2a) was ob- diselenides did not exert a significant effect. As seen for
tained in 74 and 76% yield, respectively. These results indi- 2g, a high selectivity was obtained for the cyclization using
cate that this cyclization might not follow the typical radical bis(naphthyl)diselenide. This is probably because the pres-
pathway, where the radical source is a PhSe radical. The
combination of FeCl3 and diphenyl diselenide could lead to
the in situ formation of PhSeCl, a source of electrophilic
selenium, which could be the promoter of the cyclization.
To eliminate this hypothesis, the reaction of FeCl3 and di-
phenyl diselenide was carried out under standard condi-
tions in the absence of o-alkynylbenzamide 1a, and no
PhSeCl was detected in the analysis of the crude reaction
mixture. In addition, when o-alkynylbenzamide 1a was
treated with PhSeCl, previously prepared by the reaction of
diphenyl diselenide with thionyl chloride,[26] the 4-organo-
chalcogenyl-1H-isochromen-1-imine (i.e., 2a) was obtained
in only 10% yield. These experiments clearly indicate that
a selenium species alone is not sufficient to promote the
cyclization of o-alkynylbenzamides 1a, and that cooperative
action between diphenyl diselenide and FeCl3 is essential
for a good yield of the cyclized product. We believe that the
preference for the 6-endo-dig over the 5-exo-dig cyclization
is due to: a) the positive influence of the π bonds of the
aromatic ring, which increases the electron density in the
carbon–carbon triple bond and induces the formation of
the seleniranium ion; b) the greater ability of the chalcogens
to stabilize a positive charge in the adjacent position, to-
gether with the oxophilic character of iron, probably drives
the attack of the oxygen to C-1 of the seleniranium ion (i.e.,
I) rather than C-2 (Scheme 2); c) the cyclization involving
weaker oxygen nucleophiles such as o-alkynylbenzamides
proceeds preferentially by a 6-endo-dig process because the
5-exo-dig process leads to a more strained five-membered
heterocycle.[27]
Table 2. Synthesis of 4-organoselenyl-1H-isochromen-1-imines 2.[a]
2
R
R1
R2
R3
Ratio 2/2Ј,[b]
Reaction time [h]
2a
2b
2c
2d
2e
2f
2g
2h
2i
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
p-MeC6H4
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
p-MeC6H4
p-MeOC6H4 86:14, 18
C6H5
86:14, 4
84:16, 4
97:3, 3
84:16, 3
92:8, 4
93:7, 24
65:35, 2.5
68:32, 4
81:19, 6
82:18, 9
78:22, 2
68:32, 18
94:6, 4
p-ClC6H4
p-FC6H4
m-CF3C6H4
1-naphthyl
C2H5
n-C4H9
C6H5
C6H5
2j
2k
2l
p-MeOC6H4 C6H5
p-ClC6H4
t-C4H9
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
p-MeC6H4
p-MeOC6H4 C6H5
o-MeOC6H4 C6H5
p-ClC6H4
p-FC6H4
1-naphthyl
n-C4H9
C6H5
C6H5
C6H5
C6H5
2m
2n
2o
2p
2q
2r
2s
2t
94:6, 8
96:4, 8
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
63:37, 2
87:13, 14
100:0, 6
54:46, 4
71:29, 12
71:29, 12
Next, we were interested in using the optimized reaction
conditions for the synthesis of several different 4-organo-
selenyl-1H-isochromen-1-imines 2. Thus, we explored the
effects of other substituents on the conversion and the ratio
of five- vs. six-membered rings (Table 2). All the reactions
were carried out following the optimized procedure shown
in Table 1, entry 11: addition of PhSeSePh (0.5 equiv.,
0.125 mmol) to a solution of FeCl3 (2.0 equiv.) in CH2Cl2
(3 mL) at room temperature under aerobic conditions. After
15 min, the o-alkynylbenzamides (i.e., 1; 0.25 mmol) were
added, and the reactions were run at room temperature for
2u p-MeO C6H5
2v p-F C6H5
C6H5
[a] The reaction was carried out by the addition of diorganyl dis-
elenides (0.5 equiv., 0.125 mmol) to a solution of FeCl3 (2.0 equiv.,
0.5 mmol) in CH2Cl2 (3 mL) at room temperature under aerobic
conditions. After 15 min, the o-alkynylbenzamides 1 (0.25 mmol)
was added. Reaction progress was monitored by TLC to determine
the time necessary for the complete consumption of starting mate-
rial. [b] The ratio of five- vs. six-membered ring product was deter-
1
the time indicated. In all cases, the six-membered iso- mined by H NMR spectroscopy and GC analysis.
Eur. J. Org. Chem. 2015, 1583–1590
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J. S. S. Neto, D. F. Back, G. Zeni
FULL PAPER
ence of the naphthyl group does not obstruct the backside as a result of an electronic effect rather than a steric effect
attack of the oxygen on the seleniranium ion. The opti- (Table 2, 2s). In contrast, the cyclization of o-alkynylbenz-
mized reaction conditions were also tested with dialkyl dis- amide 1l, which has an alkyl chain directly bonded to the
elenides. The reaction worked well with diethyl and dibutyl alkyne, gave an inseparable 1:1 mixture of regioisomers 2t
diselenides to give the cyclized products (i.e., 2h and 2i; and 2tЈ (Table 2, 2t). Thus, the regioselectivity of this reac-
Table 2). However, a loss of selectivity was seen in these tion strongly depends on the nature of the alkyne. We con-
cases. It can be postulated that the alkyl chain decreases the sidered a hypothesis that the absence of π bonds next to the
stabilization of the positive charge on C-1, which results in alkyne caused a decrease in the reactivity of C-1, resulting
a competitive attack by the oxygen on C-2.
in the nucleophilic attack being shared between C-1 and C-
The effect of the substituent bonded to the nitrogen atom 2; this could explain the loss in the regioselectivity observed
was also investigated, and the phenyl group was replaced with this substrate (Scheme 2, intermediate I).
by various substituents, including electron-rich and elec-
We then extended our protocol to o-alkynylbenzamides
tron-poor phenyl groups and a tert-butyl substituent 1m and 1n to investigate the influence of different func-
(Table 2, 2j–2m). Although aryl substituents with both elec- tional groups on the aromatic ring bearing the alkyne and
tron-withdrawing and electron-donating groups gave the amide substituents. When an electron-donating (MeO) or
products with similar selectivities (Table 2, 2j–2l), the tert- an electron-withdrawing (F) group was installed on the aro-
butyl group resulted in an increase in the amount of the matic ring, the cyclization reaction proceeded smoothly to
five-membered-ring product (Table 2, 2m). This indicates give the cyclized products with moderate selectivity
that the steric effect of the tert-butyl group on the nitrogen (Table 2, 2u and 2v).
atom disfavours this reaction.
We then investigated whether diorganyl disulfides and di-
These cyclization conditions also worked well with o-alk- organyl ditellurides could also be used under the optimized
ynylbenzamides with different substituents on the alkyne reaction conditions, and the results are shown in Table 3.
moiety (Table 2, 2n–2t). Generally, the selectivity of o-alk- Concerning the use of disulfides instead of diselenides, we
ynylbenzamides having aromatic groups with electron-do- found a limitation in this approach. For example, treatment
nating substituents directly attached to the alkyne was bet- of o-alkynylbenzamide 1a with diphenyl disulfide or di-
ter than that obtained with electron-withdrawing groups methyl disulfide under the optimized conditions resulted in
(Table 2, 2n–2r). These results are consistent with the dis- the formation of only trace amounts of the product, to-
cussion of the reaction mechanism above (Scheme 2); the gether with unreacted starting material, even if the reaction
attachment of an electron-donating group to the alkyne re- parameters, such as temperature, reaction time, and the ra-
sults in an increase in electron density in the carbon–carbon tio of reagents, were altered (Table 3, 3a and 3b). The reac-
triple bond, and an increase in its reactivity.
tion of o-alkynylbenzamides 1 was then carried out with
o-Alkynylbenzamide 1h was used as a substrate to exam- diorganyl ditellurides (Table 3, 3c–3j). When o-alkynyl-
ine the regioselectivity involved in the competition reaction benzamide 1a was used, moderate yields of 3 were obtained
between the carbonyl oxygen vs. the methoxy oxygen with diaryl ditellurides bearing electron-neutral and elec-
(Table 2, 2p). As shown in Scheme 3, o-alkynylbenzamide tron-withdrawing substituents on the aromatic ring. Unsub-
1h, which has a methoxy substituent at the ortho position stituted diphenyl ditelluride gave a slightly better yield
of the aryl group, could undergo an electrophile-promoted (Table 3, 3c and 3d). Under the same conditions, the reac-
cyclization reaction to give benzofuran derivative 2pЈЈ tion of alkynylbenzamide 1a with dibutyl ditelluride, a di-
(Scheme 3, pathway b).[28] Under our conditions, 4-(phen- alkyl ditelluride, also gave the corresponding cyclized prod-
ylselanyl)-1H-isochromen-1-imine 2p was obtained exclu- uct, i.e., 4-butyltellurenyl-1H-isochromen-1-imine 3e, in
sively, and benzofuran derivative 2pЈЈ was not observed at moderate yield (Table 3, 3e). Substituted o-alkynylbenz-
all (Table 2, 2p, and Scheme 3, pathway a). This high selec- amides such as 1b, 1d, and 1n (Table 3, 3f–3j) also under-
tivity can be attributed to the relatively high nucleophilicity went the cyclization reaction with ditellurides in good yields
of the oxygen atom of the carbonyl moiety, and to the resis- except for alkynylbenzamide 1n, which gave only a 38%
tance of the methoxy group to demethylation and ring clo- yield of (4-nitrophenyl)tellurenyl-1H-isochromen-1-imine
sure.[29]
(Table 3, 3j). In this case, the electronic effect of the nitro
The direct attachment of a naphthyl group to the alkyne group might contribute to reducing the reactivity of the
had a significant positive effect on the selectivity, and six- oxygen nucleophile. In all the reactions using diorganyl
membered heterocycle 2s was obtained exclusively, probably ditellurides, a complete absence of isobenzofuran-1(3H)-
Scheme 3. Preparation of 4-(phenylselanyl)-1H-isochromen-1-imine 2p and benzofuran derivative 2pЈЈ.
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Nucleophilic Cyclization of o-Alkynylbenzamides
imine derivatives was observed. The structures of 4-organo- yields without modification of the selenium moiety
tellurium-1H-isochromen-1-imines 3 were assigned based (Scheme 5).[37]
on NMR spectroscopic analysis, and confirmed by X-ray
diffraction (Supporting Information, Figure S3 for com-
pound 3j). This indicated the cyclization was a 6-endo-dig
process. These results clearly indicate that the strong polar-
izability of the tellurium lone-pair electrons directs the at-
tack of the oxygen nucleophile to give a 6-endo-dig cycliza-
tion exclusively.
Table 3. Synthesis of 4-organochalcogen-1H-isochromen-1-imines
3.[a]
Scheme 4. Suzuki- and Sonogashira-type cross-coupling reactions
of 4-butyltellurenyl-1H-isochromen-1-imine 3e.
3
R1
R2
Yield[b] of 3 [%],
reaction time [h]
3a
3b
3c
3d
3e
3f
C6H5
C6H5
C6H5
C6H5
C6H5S
MeS
C6H5Te
p-ClC6H4Te
n-C4H9Te
C6H5Te
p-ClC6H4Te
C6H5Te
p-ClC6H4Te
C6H5Te
–,[c] 24
–,[c] 18
68, 12
58, 12
56, 12
68, 12
87, 12
88, 12
74, 4
C6H5
p-MeC6H4
p-MeC6H4
p-ClC6H4
p-ClC6H4
p-NO2C6H4
Scheme 5. Preparation of 4-(arylselenyl)-3-phenyl-1H-isochromen-
ones 6a and 6b.
3g
3h
3i
3j
38, 12
Conclusions
[a] The reaction was carried out by the addition of diorganyl di-
chalcogenides (0.75 equiv., 0.5 mmol) to a solution of FeCl3 (2.0
equiv., 0.5 mmol) in CH2Cl2 (3 mL) at room temperature under
In conclusion, we have established that o-alkynylbenz-
amides undergo a cyclization reaction upon treatment
with diorganyl dichalcogenides and iron(III) chloride to
give preferentially 4-organochalcogenyl-1H-isochromen-1-
imines by a 6-endo-dig process. Our optimization studies
showed that the cyclization reactions proceeded under aero-
bic conditions, at room temperature, and in the absence of
aerobic conditions. After 15 min, the o-alkynylbenzamides
1
(0.25 mmol) were added, and the resulting mixture was heated to
38 °C. Reaction progress was monitored by TLC to determine the
time necessary for the complete consumption of starting material.
[b] Yield of purified product. [c] The starting material was reco-
vered.
Substituted chromenones are important heterocycles that additives. The optimized reaction conditions could be ap-
are found in a variety of natural products, biologically plied to o-alkynylbenzamides bearing a wide range of func-
active compounds, and pharmaceuticals with antimicro- tional groups, including electron-donating and electron-
bial,[30] anticancer,[31] antioxidant and anti-inflamma- withdrawing substituents. Our experiments revealed a selec-
tory,[32] anti-HIV,[33] and anticoagulant[34] activities. To tivity for 6-endo-dig over 5-exo-dig cyclization, which was
prove the utility of introducing an organotellurium moiety controlled by the greater ability of the chalcogen atom to
into the structure of isochromen-1-imines, we tested the re- stabilize a positive charge in the adjacent position. Analysis
activity of these compounds in Suzuki and Sonogashira of the products and studies of the mechanism indicated that
palladium-catalysed reactions (Scheme 4). It is well known the first step of this cyclization involves the formation of a
that compounds with a C(sp2)–Te bond are alternative sub- seleniranium ion by the electrophilic addition of the or-
strates for palladium-catalysed reactions in which they be- ganochalcogen moiety to the carbon–carbon triple bond.
have as electrophiles.[19] Thus, the reaction of 3e with phen- This seleniranium ion is the key intermediate that guides
ylboronic acid under Suzuki conditions gave 4 in 68% iso- the selectivity.
lated yield.[35] In addition, the reaction of 3e with phenyl-
A significant feature of this protocol is that the reactions
acetylene under Sonogashira conditions gave 5 in 65% yield were carried out using iron salts, which are readily available,
(Scheme 3).[36] We then examined the possibility of using inexpensive, and relatively non-toxic. Also, diorganyl di-
4-arylselenyl-1H-isochromen-1-imines as substrates for the chalcogenides were useful not only as cyclizing agents but
preparation of chromenones. Thus, treatment of 4-arylse- also to introduce an organochalcogen functionality into
lenyl-1H-isochromen-1-imines 2a and 2c with hydrochloric quinolone and isochromen-1-imine rings. The introduction
acid led to their hydrolysis and the formation of 4-(aryl- of an organochalcogen moiety in an isochromen-1-imine
selenyl)-3-phenyl-1H-isochromenones 6a and 6b in good confers a wide utility to the product as the organochalcogen
Eur. J. Org. Chem. 2015, 1583–1590
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1587

J. S. S. Neto, D. F. Back, G. Zeni
FULL PAPER
132.7, 132.4, 129.8, 129.5, 129.4, 128.6, 127.8, 127.6, 127.4, 126.2,
124.1, 123.8, 122.8, 103.4 ppm. MS (EI, 70 eV): m/z (%) = 454 (25)
[M + 1], 453 (33), 451 (17), 348 (15), 296 (100), 281 (29), 267 (30),
207 (48), 196 (15), 135 (39), 102 (32), 77 (45), 51 (13). HRMS (ESI-
TOF): calcd. for C27H19NOSe [M + Na]+ 476.0530; found
476.0535.
group may subsequently be transformed into other substit-
uents. As an application of our approach, we showed that
4-organochalcogenyl-1H-isochromen-1-imines could be
used as substrates for Suzuki and Sonogashira coupling re-
actions to give the corresponding products in moderate to
good yields. The structures of the 4-organochalcogenyl-1H-
(Z)-N-{4-[(4-Chlorophenyl)selanyl]-3-phenyl-1H-isochromen-1-
ylidene}aniline (2d): Obtained (0.095 g, 78%) as a pale grey solid,
m.p. 228–230 °C. 1H NMR (CDCl3, 400 MHz): δ = 8.48 (d, J =
9.0 Hz, 1 H), 7.88 (d, J = 9.3 Hz, 1 H), 7.58–7.46 (m, 4 H), 7.42–
7.24 (m, 8 H), 7.19 (s, 3 H), 7.10 (t, J = 7.3 Hz, 1 H) ppm. 13C
NMR (CDCl3, 100 MHz): δ = 158.2, 148.4, 145.9, 134.5, 134.1,
131.0, 129.5, 129.4, 128.7, 128.6, 127.7, 127.6, 124.2, 123.9, 122.9,
103.4 ppm. MS (EI, 70 eV): m/z (%) = 488 (7) [M + 1], 487 (16),
381 (11), 296 (66), 267 (31), 253 (17), 207 (100), 190 (22), 165 (33),
163 (14), 105 (38), 77 (40), 73 (30). HRMS (ESI-TOF): calcd. for
C27H18ClNOSe [M + Na]+ 510.0140; found 510.0145.
1
isochromen-1-imines are consistent with their H and 13C
NMR spectral data, as listed in the Experimental Section.
In addition, the crystal structures of 2p, 2pЈ, and 3j (Sup-
porting Information, Figures S1, S2, and S3) provided
proof of the exact position of the cyclization, demonstrating
that it occurred as a 6-endo-dig process.
Experimental Section
General Procedure for the Synthesis of 4-Organoselenyl-1H-iso-
chromen-1-imines 2: Dichloromethane (3 mL), FeCl3 (0.082 g,
0.5 mmol), and the diorganyl dichalcogenide (0.125 mmol) were
added to a Schlenk tube under air. The resulting solution was
stirred at room temperature for 15 min. After this time, the appro-
priate o-alkynylbenzamide 1 (0.25 mmol) was added, and the reac-
tion mixture was stirred at room temperature for the time indicated
in Table 2. The mixture was dissolved in ethyl acetate, and this
solution was washed with a saturated solution of NH4Cl, dried
with MgSO4, and concentrated in vacuo. The residue was purified
by column chromatography over silica gel (hexane/ethyl acetate,
92:8) to give 4-organoselenyl-1H-isochromen-1-imines 2.
(Z)-N-{4-[(4-Fluorophenyl)selanyl]-3-phenyl-1H-isochromen-1-
ylidene}aniline (2e): Obtained (0.087 g, 74%) as a white solid, m.p.
194–196 °C. H NMR (CDCl3, 400 MHz): δ = 8.45 (d, J = 7.8 Hz,
1
1 H), 7.84 (d, J = 7.8 Hz, 1 H), 7.55–7.43 (m, 5 H), 7.41–7.24 (m,
10 H), 7.07 (t, J = 7.3 Hz, 1 H) ppm. 13C NMR (CDCl3, 100 MHz):
1
δ = 161.9 (d, J = 246 Hz), 157.9, 148.5, 145.9, 132.7, 134.9, 134.3,
130.9 (d, 3J = 7.3 Hz), 129.9, 129.6, 128.7, 128.6, 127.7, 127.6,
127.5, 126.5 (d, 4J = 3.7 Hz), 124.2, 123.9, 122.9, 116.6 (d, 2J =
22 Hz), 104.1 ppm. MS (EI, 70 eV): m/z (%) = 472 (10) [M + 1],
471 (49), 365 (17), 364 (10), 296 (100), 267 (23), 190 (15), 165 (22),
77 (37). HRMS (ESI-TOF): calcd. for C27H18FNOSe [M + H]+
472.0616; found 472.0623.
(Z)-N-[3-Phenyl-4-(p-tolylselanyl)-1H-isochromen-1-ylidene]aniline
(2a): Obtained (0.053 g, 45%) as a white solid, m.p. 209–211 °C.
1H NMR (CDCl3, 400 MHz): δ = 8.43 (d, J = 7.8 Hz, 1 H), 7.91
(d, J = 7.8 Hz, 1 H), 7.55–7.49 (m, 3 H), 7.42 (t, J = 7.6 Hz, 1 H),
7.37–7.27 (m, 5 H), 7.24–7.22 (m, 2 H), 7.13 (d, J = 8.1 Hz, 2 H),
7.06 (t, J = 8.1 Hz, 1 H), 7.00 (d, J = 8.1 Hz, 2 H), 2.21 (s, 3 H)
ppm. 13C NMR (CDCl3, 100 MHz): δ = 157.7 148.7, 146.1, 136.2,
134.9, 134.3, 132.7, 130.2, 129.8, 129.5, 128.9, 128.6, 128.5, 128.4,
127.9, 127.6, 127.4, 124.1, 123.8, 121.8, 103.7, 20.9 ppm. MS (EI,
70 eV): m/z (%) = 469 (7) [M + 1], 467 (35), 362 (28), 297 (27), 296
(100), 267 (38), 207 (21), 190 (22), 105 (34), 77 (52), 51 (12). HRMS
(ESI-TOF): calcd. for C28H21NOSe [M + H]+ 468.0867; found
468.0873.
General Procedure for the Synthesis of 4-Organotellurium-1H-iso-
chromen-1-imines (3): Dichloromethane (3 mL), FeCl3 (0.082 g,
0.5 mmol), and the diorganyl dichalcogenide (0.1875 mmol) were
added to a Schlenk tube under air. The resulting solution was
stirred at room temperature for 15 min. After this time, the appro-
priate o-alkynylbenzamide 1 (0.25 mmol) was added, and the reac-
tion mixture was stirred at reflux temperature for the time indicated
in Table 3. The mixture was dissolved in ethyl acetate, and this
solution was washed with a saturated solution of NH4Cl, dried
with MgSO4, and concentrated in vacuo. The residue was purified
by column chromatography over silica gel (hexane/ethyl acetate,
90:10) to give 4-organotellurium-1H-isochromen-1-imines 3.
(Z)-N-[3-Phenyl-4-(phenyltellanyl)-1H-isochromen-1-ylidene]aniline
(3c): Obtained (0.086 g, 68%) as a pale yellow solid, m.p. 101–
103 °C. 1H NMR (CDCl3, 400 MHz): δ = 8.42 (d, J = 7.6 Hz, 1
H), 7.94 (d, J = 7.8 Hz, 1 H), 7.50 (t, J = 7.33 Hz, 1 H), 7.44–7.22
(m, 12 H), 7.18–7.09 (m, 3 H), 7.04 (t, J = 7.1 Hz, 1 H) ppm. 13C
NMR (CDCl3, 100 MHz): δ = 159.9, 149.0, 146.0, 136.4, 136.1,
134.8, 132.8, 132.4, 129.8, 129.7, 129.5, 128.6, 128.5, 127.6, 127.4,
127.3, 123.8, 123.0, 116.1, 92.5 ppm. MS (EI, 70 eV): m/z (%) =
502 (4) [M + 1], 501 (5), 355 (4), 296 (55), 267 (23), 208 (21), 207
(100), 191 (22), 165 (39), 133 (19), 96 (14), 77 (30), 73 (37). HRMS
(ESI-TOF): calcd. for C27H19NOTe [M + H]+ 504.0607; found
504.0617.
(Z)-N-{4-[(4-Methoxyphenyl)selanyl]-3-phenyl-1H-isochromen-1-
ylidene}aniline (2b): Obtained (0.042 g, 35%) as a pale yellow solid,
m.p. 178–180 °C. 1H NMR (CDCl3, 400 MHz): δ = 8.42 (d, J =
8.5 Hz, 1 H), 7.96 (d, J = 8.6 Hz, 1 H), 7.54–7.49 (m, 3 H), 7.41
(t, J = 7.9 Hz, 1 H), 7.37–7.27 (m, 5 H), 7.24–7.21 (m, 2 H), 7.15
(d, J = 8.8 Hz, 2 H), 7.05 (t, J = 6.4 Hz, 1 H), 6.72 (d, J = 8.8 Hz,
2 H), 3.71 (s, 3 H) ppm. 13C NMR (CDCl3, 100 MHz): δ = 158.7,
157.7, 146.0, 135.2, 134.9, 134.3, 132.6, 131.5, 131.1, 129.7, 129.6,
128.6, 128.5, 127.9, 127.8, 127.6, 127.4, 124.1, 123.8, 122.9, 115.2,
104.6, 55.2 ppm. MS (EI, 70 eV): m/z (%) = 484 (4) [M + 1], 483
(16), 355 (6), 341 (9), 326 (58), 311 (16), 283 (21), 281 (39), 253
(24), 207 (100), 193 (11), 177 (12), 165 (24), 147 (12), 133 (20), 96
(14), 77 (15), 76 (43). HRMS (ESI-TOF): calcd. for C28H21NO2Se
[M + H]+ 484.0816; found 484.0819.
(Z)-N-{4-[(4-Chlorophenyl)tellanyl]-3-phenyl-1H-isochromen-1-
ylidene}aniline (3d): Obtained (0.078 g, 58%) as a white solid, m.p.
1
194–196 °C. H NMR (CDCl3, 400 MHz): δ = 8.43 (d, J = 9.0 Hz,
(Z)-N-[3-Phenyl-4-(phenylselanyl)-1H-isochromen-1-ylidene]aniline 1 H), 7.88 (d, J = 9.32 Hz, 1 H), 7.52 (t, J = 7.3 Hz, 1 h), 7.45–
(2c): Obtained (0.091 g, 80%) as a pale yellow solid, m.p. 152–
154 °C. 1H NMR (CDCl3, 400 MHz): δ = 8.43 (d, J = 7.6 Hz, 1
H), 7.89 (d, J = 7.8 Hz, 1 H), 7.55–7.45 (m, 3 H), 7.41 (t, J =
6.8 Hz, 1 H), 7.35–7.11 (m, 12 H), 7.05 (t, J = 6.8 Hz, 1 H) ppm.
7.35 (m, 4 H), 7.32–7.21 (m, 8 H), 7.09–7.02 (m, 3 H) ppm. 13C
NMR (CDCl3, 100 MHz): δ = 160.1, 149.0, 145.8, 136.3, 136.2,
135.9, 133.8, 132.9, 132.2, 130.0, 129.6, 129.7, 128.8, 128.6, 127.7,
127.6, 123.9, 123.8, 123.0, 113.6, 92.6 ppm. MS (EI, 70 eV): m/z
13C NMR (CDCl3, 100 MHz): δ = 157.9, 148.6, 146.0, 134.7, 134.2, (%) = 537 (10), 535 (8), 297 (100), 267 (23), 190 (14), 176 (9), 164
1588
www.eurjoc.org
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2015, 1583–1590

Nucleophilic Cyclization of o-Alkynylbenzamides
[3]
[4]
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D. G. Hilmey, M. Abe, M. I. Nelen, C. E. Stilts, G. A. Baker,
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(18), 105 (9), 88 (4), 77 (4), 73 (2). HRMS (ESI-TOF): calcd. for
C27H18ClNOTe [M + H]+ 538.0217; found 538.0222.
(Z)-N-[4-(Butyltellanyl)-3-phenyl-1H-isochromen-1-ylidene]-aniline
1
(3e): Obtained (0.068 g, 56%) as a yellow solid, m.p. 60–62 °C. H
NMR (CDCl3, 400 MHz): δ = 8.42 (d, J = 7.1 Hz, 1 H), 8.02 (d,
J = 7.3 Hz, 1 H), 7.60 (t, J = 7.8 Hz, 1 H), 7.52–7.15 (m, 10 H),
7.03 (t, J = 7.1 Hz, 1 H), 1.55–1.49 (m, 2 H), 1.33–1.14 (m, 4 H),
0.77 (t, J = 7.3 Hz, 3 H) ppm. 13C NMR (CDCl3, 100 MHz): δ =
158.11, 146.18, 136.5, 132.7, 132.3, 130.0, 129.6, 128.5, 128.4,
127.6, 127.5, 123.7, 123.6, 123.0, 89.2, 33.0, 24.7, 13.2, 9.6 ppm.
MS (EI, 70 eV): m/z (%) = 482 (2) [M + 1], 481 (3), 405 (5), 355
(6), 341 (7), 397 (21), 287 (40), 267 (12), 253 (18), 207 (100), 191
(17), 165 (19), 135 (11), 132 (16), 96 (16), 77 (14), 73 (33). HRMS
(ESI-TOF): calcd. for C25H23NOTe [M + H]+ 484.0920; found
484.0927.
[6]
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(Z)-4-Methyl-N-[3-phenyl-4-(phenyltellanyl)-1H-isochromen-1-yl-
idene]aniline (3f): Obtained (0.088 g, 68%) as a pale yellow solid,
m.p. 162–164 °C. 1H NMR (CDCl3, 400 MHz): δ = 8.41 (d, J =
7.6 Hz, 1 H), 7.92 (d, J = 8.8 Hz, 1 H), 7.51–7.43 (m, 3 H), 7.40–
7.29 (m, 6 H), 7.22–7.07 (m, 7 H), 2.26 (s, 3 H) ppm. 13C NMR
(CDCl3, 100 MHz): δ = 160.1, 148.6, 143.2, 136.6, 136.0, 134.8,
133.4, 132.7, 132.4, 129.9, 129.8, 129.6, 124.2, 128.6, 127.6, 127.4,
127.33, 124.1, 123.3, 116.2, 92.6, 21.0 ppm. MS (EI, 70 eV): m/z
(%) = 518 (3) [M + 1], 517 (12), 517 (12), 515 (10), 311 (28), 310
(100), 295 (21), 281 (13), 267 (22), 207 (21), 190 (16), 176 (14), 165
(43), 132 (5), 91 (10), 77 (27), 65 (12). HRMS (ESI-TOF): calcd.
for C28H21NOTe [M + H]+ 518.0764; found 518.0769.
[9]
[10]
[11]
[12]
[13]
(Z)-N-{4-[(4-Chlorophenyl)tellanyl]-3-phenyl-1H-isochromen-1-
ylidene}-4-methylaniline (3g): Obtained (0.120 g, 87%) as a pale yel-
low solid, m.p. 155–157 °C. 1H NMR (CDCl3, 400 MHz): δ = 8.47
(d, J = 7.9 Hz, 1 H), 7.91 (d, J = 7.8 Hz, 1 H), 7.56–7.32 (m, 10
H), 7.24 (d, J = 8.3 Hz, 2 H), 7.15–7.12 (m, 4 H), 2.34 (s, 3 H)
ppm. 13C NMR (CDCl3, 100 MHz): δ = 160.2, 148.3, 143.0, 136.4,
136.0, 135.6, 133.7, 133.4, 132.7, 132.1, 129.9, 129.7, 129.6, 129.5,
127.6, 127.4, 124.0, 123.2, 113.7, 92.6, 20.9 ppm. MS (EI, 70 eV):
m/z (%) = 552 (2) [M + 1], 551 (12), 311 (10), 281 (28), 253 (16),
208 (21), 207 (100), 191 (20), 165 (14), 133 (23), 96 (21), 77 (10),
73 (42). HRMS (ESI-TOF): calcd. for C28H20ClNOTe [M + H]+
552.0374; found 552.0378.
[14]
[15]
[16]
[17]
CCDC-1015515 (for 2q), -1015404 (for 2qЈ), and -1015403 (for 3j)
contain the supplementary crystallographic data for this paper.
These data can be obtained free of charge from the Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_
request/cif.
Acknowledgments
The authors are grateful to Conselho Nacional de Desenvolvi-
mento Científico e Tecnológico, Coordenação de Aperfeiçoamento
de Pessoal de Nível Superior, and Fundação de Amparo à Pesquisa
do Estado do Rio Grande do Sul for the fellowship and financial
support.
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Eur. J. Org. Chem. 2015, 1583–1590
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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J. S. S. Neto, D. F. Back, G. Zeni
FULL PAPER
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Received: November 26, 2014
Published Online: January 27, 2015
1590
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