Application of copper(I) iodide/diorganoyl dichalcogenides to the synthesis of 4-organochalcogen isoquinolines by regioselective C-N and C-chalcogen bond formation

Article abstract of DOI:10.1002/chem.201201618

A copper-catalyzed cyclization of (ortho-alkynyl)benzaldimines with diorganoyl dichalcogenides allowed the synthesis of 4-organochalcogen isoquinolines, whereas the presence of base in the reaction medium inhibited the product formation producing the undesirable isoquinoline without the organochalcogen atom at the 4-position. The cyclization reaction was carried out by using CuI (20 %) as a catalyst with diorganoyl dichalcogenides (1.5 equiv) in the presence of DMF at 100 °C. Furthermore, the reaction did not require an argon atmosphere and was carried out in an open flask. The cyclization reaction tolerated a variety of functional groups both in ortho- alkynylbenzaldimines and diorganoyl dichalcogenides, such as trifluoromethyl, chloro, fluorine, and methoxyl, to give the six-membered heterocyclic ring exclusively through a 6-endo-dig cyclization process. The organochalcogen group present at the 4-position of the isoquinoline ring was further subjected to a selective chalcogen-lithium exchange reaction followed by the addition of aldehydes to afford the desired secondary alcohols in good yields. The obtained isoquinolines also proved to be suitable substrates for the Suzuki and Sonogashira coupling conditions affording the corresponding products through C-C bond formation. Copper-catalyzed cyclization of (ortho-alkynyl)benzaldimines with diorganoyl dichalcogenides enabled the synthesis of 4-organochalcogen isoquinolines (see scheme). The cyclization reaction tolerated a variety of functional groups both in the (ortho-alkynyl)benzaldimines and the diorganoyl dichalcogenides, such as trifluoromethyl, chloro, fluoro and methoxyl, to give the six-membered heterocycle through a 6-endo-dig cyclization process. Copyright

Full text of DOI:10.1002/chem.201201618

FULL PAPER
DOI: 10.1002/chem.201201618
Application of Copper(I) Iodide/Diorganoyl Dichalcogenides to the
À
Synthesis of 4-Organochalcogen Isoquinolines by Regioselective C N and
À
C Chalcogen Bond Formation
Andrꢀ L. Stein,[a] Filipe N. Bilheri,[a] Juliana T. da Rocha,[a] Davi F. Back,[b] and
Gilson Zeni*[a]
Abstract: A copper-catalyzed cycliza-
tion of (ortho-alkynyl)benzaldimines
with diorganoyl dichalcogenides al-
lowed the synthesis of 4-organochalco-
gen isoquinolines, whereas the pres-
ence of base in the reaction medium
inhibited the product formation pro-
ducing the undesirable isoquinoline
without the organochalcogen atom at
the 4-position. The cyclization reaction
was carried out by using CuI (20%) as
tion did not require an argon atmos-
phere and was carried out in an open
flask. The cyclization reaction tolerated
a variety of functional groups both in
ortho-alkynylbenzaldimines and diorga-
noyl dichalcogenides, such as trifluoro-
methyl, chloro, fluorine, and methoxyl,
to give the six-membered heterocyclic
ring exclusively through a 6-endo-dig
cyclization process. The organochalco-
gen group present at the 4-position of
the isoquinoline ring was further sub-
jected to a selective chalcogen–lithium
exchange reaction followed by the ad-
dition of aldehydes to afford the de-
sired secondary alcohols in good yields.
The obtained isoquinolines also proved
to be suitable substrates for the Suzuki
and Sonogashira coupling conditions
affording the corresponding products
Keywords: copper iodide · cycliza-
tion · isoquininoline · selenium · tel-
lurium
À
a catalyst with diorganoyl dichalco
N
through C C bond formation.
ACHTUNGTRENNUNGides (1.5 equiv) in the presence of
DMF at 1008C. Furthermore, the reac-
Introduction
which has been reported as a antimicrobial, anti-tumor,
anti-leukemic and anti-neoplastic agent[8] and Ribarivin,
which is a selective inhibitor of enterovirus.[9]
Nitrogen-containing heterocycles are ubiquitous in natural
products and bioactive molecules, and numerous studies on
their chemistry and synthesis have been reported thus far.[1]
Among these, isoquinoline derivatives are known to present
a wide range of biological activities, and have proven to be
antifungal,[2] antitumor,[3] antibacterial,[4] and antiprotozoic[5]
drugs as well as antineoplastics.[6] Examples of the therapeu-
tic potential and efficacy of biologically active isoquinoline
motifs include Berberine, which has been shown to be
useful as anti-cancer and anticonvulsant agent;[7] Coralyne,
The classical methods used for the construction of the iso-
quinolines framework, the Pomeranz–Fritsch,[10] Bischeler–
Napieralski,[11] and Pictet–Spengler reactions,[12] require
severe conditions that do not agree with an environmentally
friendly concept. These reactions are often limited because
of unavailability of suitably substituted and, sometimes, the
requirement of strong acids in combination with high tem-
peratures.[13] Some of these drawbacks have been overcome
by the recent development in transition-metal-catalyzed cy-
AHCTUNGTREGcNNUN lization reactions, which allow the construction of target
heterocyclic skeletons under relatively mild conditions.[14]
From the recent viewpoint of environmentally benign or
green chemistry, the development of cost-effective, mild,
and alternative methodologies are of considerable inter-
est.[15] Part of our recent research in the development of the
new alternative system to the cyclization of unsaturated sub-
[a] A. L. Stein, F. N. Bilheri, J. T. da Rocha, Prof. Dr. G. Zeni
Departamento de Quꢀmica Orgꢁnica
Laboratꢂrio de Sꢀntese Reatividade
Avaliażo Farmacolꢂgica e Toxicolꢂgica de OrganocalcogÞnios
Universidade Federal de Santa Maria Santa Maria
Rio Grande do Sul - 97105-900 (Brazil)
strates[16] revealed that a mixture of diorganoyl dichalco
ACHTUNGTRENNUNGgen-
AHCTUNGTREGiNNNU des and copper salts was a good alternative to the classical
electrophilic[17] and transition-metal-based cyclizations.[18] In
this context, to the best of our knowledge, there is no exam-
E-mail: gzeni@pq.cnpq.br
[b] Prof. Dr. D. F. Back
Departamento de Quꢀmica Inorgꢁnica
Laboratꢂrio de Materiais Inorgꢁnicos
Universidade Federal de Santa Maria Santa Maria
Rio Grande do Sul, 97105-900 (Brazil)
ple of a benzaldimine cyclization promoted by copper/di
ACHTUNGTRENNUNGor-
AHCTUNGTREGgNNUN anoyl dichalcogenides. Therefore, we decided to further ex-
plore the potential of this new approach to the cyclization
reaction and organochalcogen insertion onto benzaldimines
to prepare 4-organochalcogen isoquinolines 2 (Scheme 1).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201201618.
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Table 1. Influence of the reaction conditions in the CuI/PhSeSePh cycli-
zation of (ortho-alkynyl)benzaldimines.[a]
Scheme 1. General reaction scheme.
Entry
Cu source
[mol%]
PhSeSePh
[equiv]
Solvent
T
t
Yield
2a/2a’ [%]
G
E
[8C]
[h]
1[b,c]
2[c]
3c
4
5
6
7
8
9
CuI (10)
10
10
10
10
20
20
20
20
20
20
20
20
20
20
20
1
1
1
1
2
1
1.5
2
1.2
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
–
DMSO
DMSO
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMSO
DMA
dioxane
toluene
DMF
DMF
DMF
DMF
100
100
100
100
100
100
100
100
100
100
80
RT
100
100
100
100
100
100
100
100
24
24
24
24
24
24
12
12
12
12
12
24
24
12
24
24
24
24
24
24
–
–
The main advantage of our methodology is that the use of
the copper/diorganoyl dichalcogenide system as the cyclizing
agent generates the product with an organochalcogen group
in the structure, which becomes the heterocycles useful in-
termediates in many processes, including transition-metal-
catalyzed carbon–carbon bond formation, under relatively
mild reaction conditions.[19] Moreover, there has been grow-
ing interest in the transition-metal-catalyzed reactions of or-
ganoselenium compounds and highly selective transforma-
tions of chalcogen compounds have been developed through
palladium or copper catalysts.[20] Additionally, the study of
organoselenium compounds as therapeutic agents has in-
creased in the last decades due to a variety of these organo-
chalcogens biologically active.[21] The retrosynthetic analysis
to include the organochalcogen group into isoquinoline
structures required the use of 2-bromobenzaldehydes, termi-
nal alkynes and tert-butylamine as the starting materials and
copper/diorganoyl dichalcogenide cyclization as the key step
(Scheme 2).
trace
44/30
52/12
72/–
82/–
80/–
68/–
36/–
60/–
trace/–
60/–
10[b]
11
12
13
14
15
16
17
18
19
20
73/–
–
23/–
–
–/57
38
–
20
CuBr (20)
CuCl2 (20)
1.5
1.5
31
[a] Reaction conditions: (ortho-alkynyl)benzaldimine (0.25 mmol), di-
phenyl diselenide, copper salt in solvent (3 mL) under an air atmosphere.
[b] An argon atmosphere was used. [c] This reaction was carried out with
K2CO3 (5 equiv).
phenyl diselenide amount to 2 equiv, and the cyclized prod-
uct 2a’, without incorporation of PhSe in the structure, was
again formed (Table 1, entry 5). However, when the reaction
was performed using CuI (20 mol%), the desired isoquino-
line 2a was obtained in 72% yield, in the complete absence
of 2a’ (Table 1, entry 6). Fortunately, the cyclization reaction
using 1.5 equiv diphenyl diselenide and 20 mol% CuI
(Table 1, entry 7) was complete in a shorter time than the
same reaction using 20 mol% CuI and 1.0 equiv diphenyl
diselenide (Table 1, entry 6), to give the desired product in
82% yield, without the formation of a detectable amount of
2a’. No remarkable increase in the product yield was ob-
served when the amount of diphenyl diselenide was in-
creased from 1.5 to 1.2 and 2.0 equiv in the presence of
20 mol% of CuI, although the use of 1.2 equiv did afford
the product 2 in the lowest yield (Table 1, entries 8 and 9).
Assuming that the oxi-reducing property of diphenyl disele-
nide, and the consequent formation of a diphenyl disele-
nide–CuI complex,[23] is responsible for this cyclization pro-
cess, we speculated that the cyclization reaction of (ortho-al-
kynyl)benzaldimines would be hampered under an inert at-
mosphere. To test our hypothesis, the reaction conditions
(listed in entry 7, Table 1) were used and the reaction was
carried out under argon atmosphere; as predicted, under
these conditions the cyclized product was obtained in a poor
yield (Table 1, entry 10). This result implies that, in the pres-
ence of oxygen, all the selenolate anion (PhSeÀ) is oxidized
to form diphenyl diselenide (PhSeSePh). These results are
Scheme 2. Retrosynthetic analysis.
Results and Discussion
The required precursors (ortho-alkynyl)benzaldimines 1a–g
were synthesized in good yields by the reaction of appropri-
ate 2-bromobenzaldehydes with terminal alkynes under So-
nogashira catalysis conditions followed by the condensation
reaction with tert-butylamine.[22]
The copper cyclization reaction was initially investigated
by reacting diphenyl diselenide (1 equiv), K2CO3 (5 equiv)
and CuI (10 mol%) in DMSO or DMF with substrate 1a
(0.25 mmol), under argon or air atmosphere, for 24 h at
1008C. However, these reaction conditions were ineffective
and the desired product 2a was not obtained (Table 1, en-
tries 1–3). When the reaction of (ortho-alkynyl)benzaldi-
mines 1a was carried out under the same conditions, but in
the absence of a base (K2CO3), compound 2a was obtained
in 44% yield, followed by 30% yield of undesirable 2a’, al-
though a longer reaction time (24 h) was required for the
complete consumption of 1a (Table 1, entry 4). These results
showed that the presence of base appears to inhibit the cy-
ACHTUNGTRENNUNG
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Synthesis of 4-Organochalcogen Isoquinolines
FULL PAPER
in agreement with other studies, which suggest that diphenyl
diselenide has a clear preference for oxidative addition to
copper salts.[24] The great influence of temperature on the
reaction became apparent when the isoquinoline 2a was ob-
tained in 60% yield at 808C, whereas only a trace of this
product was detected at room temperature (Table 1, en-
tries 11 and 12). The solvent effect was also significant in
the present intramolecular cyclization (Table 1, entries 13–
16). The copper salt displayed good results in polar solvents,
such as DMSO and DMA (Table 1, entries 13 and 14). In
contrast, dioxane and toluene gave no product or very low
yield under the same conditions (Table 1, entries 15 and 16).
Furthermore, both copper iodide and diphenyl diselenide
played crucial roles; no desired isoquinoline 2a was ob-
served when either was omitted (Table 1, entries 17 and 18).
As was the case for the reaction conditions with base
(Table 1, entries 1–3), the use of copper iodide in the ab-
sence of diphenyl diselenide resulted in the formation of
a 2a’ in 57% yield. These results are in accordance with the
experiments shown in Table 1, entry 10, which suggests that
a diphenyl diselenide/CuI complex should be required not
only to activate the triple bond to promote the cyclization,
but also as an organochalcogen source. Although the reac-
tion with other copper salts has been examined, a lower
yield of 2a was obtained with CuBr and CuCl2 (Table 1, en-
tries 19 and 20).
On the basis of the results shown in Table 1, we under-
took a systematic study applying the conditions of entry 7 to
several substituted diorganoyl dichalcogenides and to differ-
ent (ortho-alkynyl)benzaldimines to test the tolerance of
functional groups as well as their effects on the conversion.
These results are collected in Table 2. The yields of com-
pounds 2 varied depending on the nature of the diorganoyl
dichalcogenide. Whereas diorganoyl dichalcogenides bearing
neutral, mild electron-donating, or electron-withdrawing
groups on the aromatic ring provided the best yields of 2
(Table 2, entries 1 and 5), the presence of strong electron-
donating group decreased the yield drastically (Table 2,
entry 6). The results in Table 2 also showed that only a mod-
erate yield of product was obtained for the cyclization be-
products (Table 2, entries 9–10). A number of thiol precur-
sors were screened for the reactions with copper salts;[27]
however, a few examples have been reported when a disul-
fide was employed as substrate.[28] As an example, the cycli-
zation with diaryl disulfide is presented in Table 2, entry 11,
which gave the cyclized product in 47% yield. To elaborate
the general reactivity of the present protocol with other
(ortho-alkynyl)benzaldimines, we substituted the phenyl
group directly bonded to alkyne for alkyl and aryl substitut-
ed groups as well as adding functional groups to the main
ring of (ortho-alkynyl)benzaldimines. The experimental re-
sults are summarized in Table 2, entries 12–14 show that
there was no significant difference of reactivity between
methyl, fluorine and methoxyl groups bonded to aryl group,
since they gave the cyclized products equally in good yields.
The latter substrate, with a methoxyl group at the ortho po-
sition, would give a competitive cyclization when a cyclizing
agent, such as PhSeSePh/CuI, is used. Therefore, we were
pleased to find that the cyclization with (ortho-alkynyl)
ACHTUNGTRENNUNGbenz-
AHCTUNGTRENNUNG
line 2n through N-cyclization, in the complete absence of
benzofuran derivatives. The ratio of products in this compet-
itive cyclization depends on the various factors, such as elec-
tronic- (relative nucleophilicity of the functional groups, po-
larization of the carbon–carbon triple bond, and the cationic
nature of the intermediate) and steric effects (hindrance and
geometrical alignment of the functional groups), and also by
the nature of the nucleophilic source. We observed that our
result is in complete agreement with the study reported by
Larock et al., which showed that if the substrate has a com-
peting nitrogen and oxygen, the N-cyclization is predomi-
nant.[29] Furthermore, we found that the reaction with sub-
strate 1e, having an alkyl substituent directly bonded to the
triple bond, also worked well under the standard reaction
conditions; although the diaryl diselenide with a chlorine
atom directly bonded to the aromatic ring gave the product
in moderate yield (Table 2, entries 15–17). Finally, to exam-
ine the generality of the cyclization of (ortho-alkynyl)
ACHTUNGTRENNUNGbenz-
AHCTUNGTRENNUNG
al benzaldimines were subjected to the optimized cyclization
reactions conditions. In these cases, the reaction of fluorine
substituted analogue 1 f with both unsubstituted and chlo-
AHCTUNGTREGrNNNU ine substituted diaryl diselenides afforded the cyclized
products in moderate yields (Table 2, entries 18 and 19).
Similarly, benzaldimines, having a dioxole group, reacted
tween diACHTUNGTRENNUNG(o-tolyl) diselenide and CuI, in which the steric hin-
drance of the o-tolyl group may exert significant negative ef-
fects (Table 2, entry 7). Apparently under the optimized
conditions, dialkyl diselenides should exhibit a lower chemi-
cal reactivity with the copper salt than other aryl disele-
nides. This lower reactivity could be explained by the ab-
sence of p bonds next to the selenium atom. This is in con-
trast to the observed results in which dialkyl diselenide led
to the cyclized product in 57% yield (Table 2, entry 8). Be-
cause of the synthetic importance of organotellurium deriva-
tives, such as the use as substrate in palladium-catalyzed
carbon–carbon bond formation[25] and synthesis of natural
products,[26] we also wish to carry out the cyclization reac-
tions of (ortho-alkynyl)benzaldimines with dialkyl and diaryl
ditellurides. From the results shown in Table 2, it is possible
to conclude that neither the dialkyl nor the diaryl group of
ditellurides significantly influenced the yields of cyclized
with diphenyl diselenide and diACTHNUGRTNEUNG(p-tolyl) diselenide to give
quinolines 2t and 2u, in 69 and 61% yields, respectively
(Table 2, entries 20 and 21). There are several examples re-
ported in the literature in which the cyclization reactions
proceed through the addition of the electrophilic source to
C(sp) bonds of alkynes, followed by a nucleophilic attack
giving a mixture of 5-exo versus 6-endo cyclizations.[30] The
majority of theoretical and experimental studies to under-
stand this regiochemistry suggest that it is strongly depen-
dent on the electronic and steric effects as well as the nature
of the transition-metal source. In this context, in view of the
high nucleophilicity of the nitrogen atom and considering
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Table 2. Cyclization reactions of (o-alkynyl)benzaldimines mediated by CuI/diorganoyl diselenides.[a]
(ortho-alkynyl)-
benzaldimines
R3YYR3
Product
Yield
[%]
(ortho-alkynyl)-
benzaldimines
R3YYR3
Product
Yield
[%]
1
2
1a
2a
2b
82
77
12 1b
2l
64
65
1a
1a
1a
1a
13 1c
2m
3
4
5
2c
2d
2e
74
69
87
14 1d
15 1e
16 1e
2n
2o
2p
66
77
71
6
7
8
9
1a
1a
1a
1a
2 f
2g
2h
45
57
57
17 1e
18 1 f
19 1 f
2q
2r
2s
2t
42
53
64
69
2i
77
63
47
20 1g
21 1g
10 1a
11 1a
2j
2k
2u
61
[a] Reaction conditions: (ortho-alkynyl)benzaldimene (0.25 mmol), diorganoyl dichalcogenides (1.5 equiv), CuI (20 mol%) in DMF (5 mL) at 1008C for
12 h under an air atmosphere.
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Synthesis of 4-Organochalcogen Isoquinolines
FULL PAPER
the steric effect of the tBu
group, our cyclization method-
ology showed to be highly re-
gioselective, providing the de-
sired isoquinoline 2, through
a 6-endo-dig cyclization process,
as the unique regioisomer,
Scheme 4. Reactions of Suzuki cross-coupling.
which was confirmed by spec-
tral data and supported by X-
ray
diffraction
analysis
(Figure 1, the Supporting Information).[31] Neither the iso-
meric five-membered ring products, formed through a 5-
exo-dig process (Table 1, entry 7), nor the product involving
the simple cyclization without the organochalcogen atom at
the 4-position were detected under the standard conditions.
One of the most powerful applications of organotellurim
compounds is the ability to undergo tellurium–lithium ex-
change reactions with lithium reagents. This tellurium–lithi-
um exchange reaction proceeds very easily to give to an or-
ganolithium intermediate, which reacts with a wide range of
electrophiles, providing various structures with additional
functionalities.[25] As a demonstration of the usefulness of
the prepared 4-organochalcogen isoquinolines, we carried
out tellurium–lithium exchange reactions of 4-butyltelluro
isoquinoline 2j, followed by the reaction with aldehydes, for
the formation of more functionalized isoquinolines. As ex-
pected, reaction of n-butyllithium (1.0 equiv) with 4-butyl-
telluro isoquinoline 2j (1.0 equiv) in THF (3 mL), at À788C
gave the lithium intermediate 3’, which after reaction with
aldehydes, afforded the corresponding secondary alcohol
3a–d in 43–77% yields (Scheme 3).
Recently, a new application of organotellurium com-
pounds employing palladium-catalyzed cross-coupling was
described,[19] in which they behave as aryl or vinyl carbocat-
ion equivalents and react in a manner similar to vinylic hal-
ides or triflates in the Sonogashira,[32] Heck,[33] Suzuki[34] and
Stille[35] cross-coupling reactions. This led us to explore the
possibility of using these 4-chalcogen isoquinolines as sub-
strates in palladium cross-coupling reactions, under classical
Suzuki and Sonogashira protocols. Under Suzuki reaction
conditions, 4-butyltelluro isoquinoline 2j underwent smooth
cross-coupling upon exposure to boronic acids affording 4-
aryl isoquinoline 4a–c in excellent yields (Scheme 4). In
contrast with earlier results obtained in Suzuki cross-cou-
pling, the direct treatment of 4-butyltelluro isoquinoline 2j
with propargylic alcohol, PdCl2, and Et3N in methanol,
under Sonogashira conditions, also afforded the cross-cou-
pling product; however, even in this case, the yield of 5 was
substantially lower (44%; Scheme 5).
Scheme 5. Reactions of Sonogashira cross-coupling.
Based on the understanding that in the CuI-catalyzed
cross coupling, copper is easily admitted as a copper com-
plex having an oxidation state +3[24a] and that this complex
could be stabilized by the selenium atom,[27a] we proposed
a plausible mechanism to support the current CuI-catalyzed
cyclization, as illustrated in Scheme 6. The mechanism in-
volves the following steps: 1) The interaction of CuI with
the diorganoyl dichalcogenide leads to the CuIII tetracoordi-
nated square-planar chalcogenolate a; 2) the alkyne coordi-
nation to the metal center provides the cationic organo-CuIII
complex b; 3) nucleophilic anti-attack of the nitrogen atom
on the activated triple bond leads to the intermediate c;
À
4) reductive elimination gives the C Se bond and anionic
complex ArSeCu[36] and 5) cleavage of the tert-butyl group
Scheme 3. Reaction of 4-lithio isoquinoline intermediate with aldehydes.
Scheme 6. Proposed reaction mechanism.
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G. Zeni et al.
5H); 13C NMR (CDCl3, 50 MHz): d=158.5, 153.2, 142.1, 138.5, 133.1,
131.7, 129.8, 129.6, 129.1, 128.6, 128.2, 128.0, 128.0, 127.6, 127.4, 126.1,
121.3 ppm; MS (EI, 70 eV): m/z (relative intensity): 361 (76), 284 (100),
280 (69), 203 (33), 176 (60), 127 (5), 77 (27), 51 (19); elemental analysis
calcd (%) for C21H15NSe: C 70.00; H 4.20; found: C 70.23, H 4.28.
from the nitrogen releases the 4-organochalcogen isoquino-
lines 2 and chalcogenol species (ArYH), which is oxidized
under an air atmosphere, regenerating dichalcogenide and
CuI in the catalytic cycle. The competing processes is the
cyclization of the starting material to afford the isoquinoline
2a’, without incorporation of PhSe in the structure, promot-
ed by a hydrogen transfer to the intermediate c.
General procedure for the reaction of intermediate 3-phenyl-4-lithioiso-
quinoline with nBuLi: nBuLi (0.25 mmol, of a 2.5m solution in hexane)
was added (in one portion) to a two-necked round-bottomed flask, under
argon, containing a solution of 2j (0.25 mmol) in THF (3 mL) at À788C.
The reaction mixture was stirred for 15 min, and then a solution of the
appropriated aldehyde (0.3 mmol) in THF (2 mL) at À788C was added.
The reaction mixture was allowed to stir at room temperature for 2 h.
After this, the mixture was diluted with ethyl acetate (20 mL) and
washed with a saturated solution of NH4Cl (20 mL). The organic phase
was separated, dried over MgSO4, and concentrated under vacuum. The
residue was purified by flash chromatography and eluted with ethyl ace-
tate/hexane to give 3a (0.055 g, 67%) as a white solid.
Conclusion
A catalytic approach to 4-(organochalcogen)isoquinolines of
potential interest has been developed through the intramo-
lecular cyclization of (ortho-alkynyl)benzaldimines with di-
organoyl dichalcogenides under copper catalysis. A detailed
study related to the effect of the reaction conditions on
product distribution was carried out. The results showed
that the presence of base in the medium inhibited the prod-
uct formation releasing the undesirable isoquinoline without
the organochalcogen at the 4-position. By contrast, the cycli-
zation carried out in the absence of base under air atmos-
phere afforded 4-(organochalcogen)isoquinoline exclusively
through a 6-endo-dig cyclization process. The optimized con-
ditions worked well with a broad range of (ortho-alkynyl)-
benzaldimines and diorganoyl dichalcogenides to afford the
corresponding products with high regioselectivity and in
good yields. The presence of an organochalcogen substituent
in the isoquinoline structure allowed further structural elab-
oration through conversion of the chalcogen group into
other substituents. For example, when the compound 2j was
applied to the tellurium–lithium exchange conditions, fol-
lowed by reaction with aldehydes, the corresponding second-
ary alcohols were obtained in high yields. Furthermore, we
have also successfully applied the isoquinoline 2j as a sub-
strate in Suzuki and Sonogashira coupling conditions afford-
(3-Phenylisoquinolin-4-yl)ACTHUNRTGNEUNG(p-tolyl)methanol (3a): M.p. 146–1488C;
1H NMR (CDCl3, 200 MHz): d=9.08 (s, 1H), 8.11–8.06 (m, 1H), 7.92–
7.88 (m, 1H), 7.54–7.38 (m, 4H), 7.30 À7.05 (m, 8H), 6.39 (s, 1H), 3.74
(sl, 1H) 2.30 (s, 3H); 13C NMR (CDCl3, 100 MHz): d=152.1, 140.6,
140.1, 136.3, 134.7, 130.0, 129.2, 128.9, 128.6, 128.1, 128.0, 127.8, 127.1,
126.7, 125.9, 71.6, 21.0 ppm; MS (EI, 70 eV): m/z (relative intensity): 325
(82), 238 (20), 207 (100), 73 (60); elemental analysis calcd (%) for
C23H19NO: C 84.89; H 5.89; found: C 84.96, H 5.92.
General procedure for the Suzuki–Miyaura cross-coupling reaction: Tri-
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
the reaction mixture was heated to reflux for 90 min with stirring, then
cooled to room temperature and diluted with ethyl acetate (30 mL). The
organic layer was washed with saturated solution of NH4Cl (2ꢄ10 mL)
and water (2ꢄ10 mL), dried over MgSO4, and concentrated under
vacuum. Purification by silica gel chromatography (eluting with hexane/
ethyl acetate 9.0:1.0) yielded 4a (0.063 g, 86%) as white solid.
1
3-Phenyl-4-p-tolylisoquinoline (4a): H NMR (CDCl3, 200 MHz): d=9.35
(s, 1H), 8.04–7.98 (m, 1H), 7.72–7.65 (m, 1H), 7.62–7.53 (m, 2H), 7.41–
7.35 (m, 2H), 7.27–7.09 (m, 7H), 2.38 ppm (s, 3H); 13C NMR (CDCl3,
100 MHz): d=151.5, 150.3, 140.9, 136.9, 136.1, 134.1, 131.0, 130.6, 130.3,
130.2, 128.9, 127.5, 127.4, 127.4, 126.9, 126.7, 125.6, 21.2 ppm; MS (EI,
70 eV): m/z (relative intensity): 294 (100), 179 (11), 139 (23), 73 (8); ele-
mental analysis calcd (%) for C22H17N: C 89.46; H 5.80; found: C 89.65,
H 5.86.
À
ing the corresponding products through C C bond forma-
tion in moderate to good yields. In addition, all the com-
pounds prepared in this manuscript are solids or oils, com-
pletely odorless, and very stable, which can be purified and
stored in the lab in a simple flask for more than one month.
General procedure for the Sonogashira cross-coupling reaction: Com-
pound 2j (25 mmol) was added to a two-necked round-bottomed flask
(25 mL) under an argon atmosphere containing [PdCl2] (20 mol%), CuI
(20 mol%) and dry methanol (3 mL). After stirring the mixture for 5 min
at room temperature, propargyl alcohol (0.5 mmol) and Et3N (0.25 mL)
were added. The reaction was stirred at room temperature for 6 h. After
this time the solid part was filtered under vacuum. Brine was then added
to the filtrate and the solution was extracted with dichloromethane (3ꢄ
25 mL). The combined organic layers were dried over MgSO4 and con-
centrated under vacuum. The residue was purified by flash chromatogra-
phy eluting with hexane/ethyl acetate (70:30) to give 5 (0.029 g, 44%) as
light yellow solid.
Experimental Section
General procedure for the CuI-catalyzed cyclization: The appropriate di-
organoyl dichalcogenide (0.375 mmol; 1.5 equiv) was added to a solution
of DMF (3 mL) and CuI (20 mol%) under an air atmosphere. The result-
ing solution was stirred for 15 min at room temperature. Next, the appro-
priate ortho-alkynylbenzaldimines (0.25 mmol) in DMF (2 mL) was
added and the resulting solution was heated at 1008C for 12 h. After this,
the solution was cooled to room temperature, diluted with ethyl acetate
(10 mL), and washed with saturated aq. NaHCO3 (3ꢄ10 mL). The organ-
ic phase was separated, dried over MgSO4, and concentrated under
vacuum. The residue was purified by flash chromatography on silica gel
using ethyl acetate/hexane (1:20) as eluent to give 2a (0.074 g, 82%) as
a pale yellow solid.
3-(3-phenylisoquinolin-4-yl)prop-2-yn-1-ol
(5):
1H NMR
(CDCl3,
200 MHz): d=9.26 (s, 1H), 8.37–8.33 (m, 1H), 8.04–7.97 (m, 3H), 7.82–
7.71 (m, 1H), 7.67–7.60 (m, 1H), 7.52–7.38 (m, 3H), 4.55 (s, 2H),
2.04 ppm (sl, 1H); 13C NMR (CDCl3, 100 MHz): d=154.6, 151.7, 139.8,
136.8, 131.4, 129.8, 128.6, 127.9, 127.8, 127.6, 126.5, 111.9, 97.3, 81.7,
51.8 ppm; MS (EI, 70 eV): m/z (relative intensity): 259 (29), 206 (100),
132 (13), 73 (32); HRMS (ESI): m/z calcd for C18H13NO: 259.0997
[M+H]; found: 259.1004.
3-Phenyl-4-(phenylselenyl)isoquinoline (2a): M.p 112–1148C; 1H NMR
(CDCl3, 200 MHz): d=9.34 (s, 1H), 8.45 (d, J=8.4 Hz, 1H), 8.02 (d, J=
8.3 Hz, 1H), 7.75–7.53 (m, 4H), 7.43–7.36 (m, 3H), 7.10–1.00 ppm (m,
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Synthesis of 4-Organochalcogen Isoquinolines
FULL PAPER
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Received: May 8, 2012
Published online: && &&, 2012
Chem. Eur. J. 2012, 00, 0 – 0
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G. Zeni et al.
Cyclization
A. L. Stein, F. N. Bilheri,
J. T. da Rocha, D. F. Back,
G. Zeni* ....................... &&&& — &&&&
Application of Copper(I) Iodide/
Diorganoyl Dichalcogenides to the
Synthesis of 4-Organochalcogen
À
Isoquinolines by Regioselective C N
Copper-catalyzed cyclization of (ortho-
alkynyl)benzaldimines with diorganoyl
dichalcogenides enabled the synthesis
of 4-organochalcogen isoquinolines
(see scheme). The cyclization reaction
tolerated a variety of functional groups
both in the (ortho-alkynyl)benzaldi-
À
and C Chalcogen Bond Formation
mines and the diorganoyl dichalcoge-
nides, such as trifluoromethyl, chloro,
fluoro and methoxyl, to give the six-
membered heterocycle through a 6-
endo-dig cyclization process.
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These are not the final page numbers!