Synthesis of 2-Acylselenophenes via Iodine-Promoted Nucleophilic Cyclization of [2-(Butylselanyl)phenyl]-propynols

Article abstract of DOI:10.1002/adsc.201500569

We describe the synthesis of [2-(butylselanyl)phenyl]propynols and their application as substrates in intramolecular iodine-promoted nucleophilic cyclization reactions for the preparation of 2-acylselenophenes. [2-(Butylselanyl)phenyl]propynols were prepared by nucleophilic aromatic substitution reactions of 2-halobenzaldehydes with lithium butylselenolate followed by alkynylation of the carbonyl function with lithium acetylides. Effects of solvent, temperature, reaction time and iodine amount on the efficiency of the cyclization reactions were investigated. The results demonstrated that the best yields of 2-acylselenophenes were obtained when iodine (1.1 equiv.) and ethanol (3 mL) at room temperature were applied to [2-(butylselanyl)phenyl]propynols. The utility of 2-acylselenophene derivatives was also studied through alkynylation of a carbonyl group to obtain the alkynol derivatives followed by an electrophilic cyclization reaction to give selenophene-fused aromatic compounds. The 2-acylselenophene was also applied as a substrate in cyanation reactions.

Full text of DOI:10.1002/adsc.201500569

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DOI: 10.1002/adsc.201500569
Synthesis of 2-Acylselenophenes via Iodine-Promoted Nucleo-
philic Cyclization of [2-(Butylselanyl)phenyl]-propynols
Renan P. Pistoia,a Juliano A. Roehrs,a Davi F. Back,b and Gilson Zenia,*
a
Laboratório de Síntese, Reatividade, Avaliażo Farmacológica e Toxicológica de OrganocalcogÞnios, CCNE, UFSM,
Santa Maria, Rio Grande do Sul, Brazil (homepage: www.ufsm.br) 97105-900
E-mail: gzeni@ufsm.br
Laboratório de Materiais Inorgânicos, CCNE, UFSM, Santa Maria, Rio Grande do Sul, Brazil 97105-900
b
Received: June 12, 2015; Revised: August 13, 2015; Published online: November 17, 2015
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201500569.
Abstract: We describe the synthesis of [2- iodine (1.1 equiv.) and ethanol (3 mL) at room tem-
(butylselanyl)phenyl]propynols and their application perature were applied to [2-(butylselanyl)phenyl]pro-
as substrates in intramolecular iodine-promoted nu- pynols. The utility of 2-acylselenophene derivatives
cleophilic cyclization reactions for the preparation of was also studied through alkynylation of a carbonyl
2-acylselenophenes. [2-(Butylselanyl)phenyl]propy- group to obtain the alkynol derivatives followed by
nols were prepared by nucleophilic aromatic substi- an electrophilic cyclization reaction to give seleno-
tution reactions of 2-halobenzaldehydes with lithium phene-fused aromatic compounds. The 2-acylseleno-
butylselenolate followed by alkynylation of the car- phene was also applied as a substrate in cyanation
bonyl function with lithium acetylides. Effects of sol- reactions.
vent, temperature, reaction time and iodine amount
on the efficiency of the cyclization reactions were in-
vestigated. The results demonstrated that the best Keywords: alkynes; cyclization; heterocycles; sele-
yields of 2-acylselenophenes were obtained when nides; selenophenes
Introduction
phorus and sulfur species, are available.[1c] This is also
the key step to define competition between endo-dig/
Electrophile-promoted nucleophilic cyclization repre- trig versus exo-dig/trig models. A series of guidelines
sents one of the most significant and effective meth- known as Baldwinꢀs rules,[9] which depend on the
ods available in synthetic chemistry for the cyclization structural and electronic effects involved in the ring
of unsaturated substrates.[1] It allows the selective con- closure processes, was recently reevaluated by Alabu-
struction of carbocycles and heterocycles, particularly gin in a comprehensive review.[10] Extensive works
those containing five- and six-membered rings. In the have been carried out by using 5-endo and 5-exo ring
course of this cyclization, the first step requires the closures in the preparation of furans,[11] thiophenes,[12]
activation of carbon-carbon bonds of the unsaturated selenophenes,[13] pyrroles,[14] indoles,[15] indolizines[16]
substrates by an electrophile towards to nucleophilic and lactones.[17] In addition, electrophile-promoted
attack. There are many types of electrophilic source nucleophilic cyclization via 6-endo closure has been
including IPy2BF4,[2] gold reagent,[3] halogens,[4] frequently utilized to construct a wide range of carbo-
NXS,[5]
trichloroisocyanuric
acid
(TCCA),[6] cycles and heterocycles, such as isoquinolines,[18] qui-
I(coll)2PF6/BF3·OEt2 and organochalcogen electro- nolines,[19] chromenes[20] and coumarins.[21] Finally, the
philes,[8] that can be used to this end. In particular, last step of this cyclization involves the removal of
the use of halogens, especially bromine and iodine, is the group bonded to the nucleophile via SN2 displace-
of considerable interest as the resulting halogenated ment by the species present in the reaction mixture to
products are versatile intermediates for organic syn- generate the cyclized product. It is known that orga-
thesis. In the second step of the electrophile-promot- noselenium compounds are useful and important
ed nucleophilic cyclization, the anti-nucleophilic functional groups in organic synthesis.[22] They have
attack at the activated carbon-carbon bond takes been used in a variety of transformations, for exam-
place. Several methods, which use a wide variety of ple, carbon-carbon,[23] carbon-lithium,[24] carbon-halo-
nucleophiles, such as nitrogen, oxygen, carbon, phos- gen[25] and carbon-hydrogen bond formation.[26] In ad-
[7]
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Renan P. Pistoia et al.
dition, organoselenium compounds have received example, electron-rich and electron-deficient lithium
considerable attention during the last two decades be- acetylides added to the carbonyl group affording [2-
cause of the variety of biological activities reported (butylselanyl)phenyl]propynols 2a–h in good yields
for these compounds.[27] Selenophene is one recog- (Table 1). The influence of different substituents in
nized class of organoselenium compounds that exhib- the aromatic ring of aldehydes was also investigated.
its a wide range of biological activities[28] and applica- The results demonstrated that aryl butyl selenides 1,
tions in material science.[29] The electrophile-promot- containing an electron-donating methoxy group, re-
ed nucleophilic cyclization of suitable alkynes, using acted with different lithium acetylides to afford [2-
a halogen as electrophilic source, is a very efficient (butylselanyl)phenyl]propynols 2i–m in good yields,
strategy for the preparation of 3-haloselenophenes.[30] while the presence of the electron-withdrawing chlor-
Until now, only a few examples for the preparation of ine group, often gave moderate yields of [2-
2-acylselenophenes have been reported in the litera- (butylselanyl)phenyl]propynols 2n–q (Table 1). The
ture, most of them usually require multistep sequen- reactions of aryl butyl selenides, having an additional
ces.[31] Because of the pharmacological activities,[32] butylselanyl group at the para-position, with electron-
material science applications[33] and potential utility as rich lithium acetylides produced [2-(butylselanyl)phe-
versatile key intermediates in organic synthesis, one nyl]propynols 2r and 2s in good yields; however, the
of the most important challenges in the synthesis of reaction with an electron-deficient lithium acetylide
selenophenes is the development of a cyclization pro- gave the [2-(butylselanyl)phenyl]propynols 2t in 32%
tocol, which is able to cyclize and introduce a carbonyl yield (Table 1).
group at the 2-position using a one-step protocol. In
Our initial attempts for the electrophile-promoted
the present study, we report that the selenium atom nucleophilic cyclization of [2-(butylselanyl)phenyl]-
of [2-(butylselanyl)phenyl]propynols 2 is a suitable propynols 2 involved the determination of the best re-
nucleophile for the preparation of 2-acylselenophenes action conditions to identify a general synthetic pro-
3
via iodine-promoted nucleophilic cyclization cedure. We began our studies with the experimental
(Scheme 1).
screening of a variety of solvents, temperatures, reac-
tion times and molar ratios of reagents in the cycliza-
tion reaction of [2-(butylselanyl)phenyl]propynol 2a
with iodine. Thus, the reaction carried out with di-
chloromethane as solvent, using 1.5 equiv. of iodine,
at room temperature gave the selenophene 3a in 58%
yield (Table 2, entry 1). A significant effect on the re-
action yield was observed by changing the solvent
from dichloromethane to ethanol, which gave the se-
lenophene 3a in 77% yield (Table 2, entry 2). The ef-
fects of iodine loading amount were also studied and
the increase in the iodine loading to 2.0 equiv. did not
improve significantly the reaction yield. The use of
0.5 equiv. of iodine did not give the product, in such
a case, a 1:1 mixture of starting material and vinylic
iodide III was obtained (Table 2, entries 3–8). When
the substrate 2a was treated with iodine (1.1 equiv.) in
Scheme 1. General scheme.
Results and Discussion
[2-(Butylselanyl)phenyl]propynols 2 were prepared in EtOH, under an inert atmosphere of argon, seleno-
three steps from commercially available 2-halobenzal- phene 3a was obtained in 90% yield after 12 h
dehydes. Thus, for the introduction of the butylselanyl (Table 1, entry 9). Although good results were found
group, the lithium butylselenolate was generated by by using an inert atmosphere, owing to its limitation
reaction of elemental selenium (1 equiv.) with n-BuLi with respect to economic and operational aspects,
(1 equiv.), in THF at À788C for 30 min. The nucleo- aerobic conditions were adopted for further studies. It
philic aromatic substitution reactions of 2-halobenzal- has been reported that iodine would be recovered in
dehydes with lithium butylselenolate afforded the aryl the reaction medium in the presence of DMSO, be-
butyl selenides 1 in 63–75% yields. The alkynylation coming a catalytic reagent.[35] In our study, the yield
of selenides 1 with lithium acetylides gave [2-(butylse- of selenophene 3a decreased considerably when the
lanyl)phenyl]propynols 2.[34] All details for the prepa- reaction was run with a catalytic amount of iodine
ration of [2-(butylselanyl)phenyl]propynols 2 are pre- (20 mol%) in the presence of DMSO, even under
sented in Table 1. The reaction conditions were com- aerobic conditions, and no product was formed when
patible with diverse aryl butyl selenides 1 and the rate it was run in the absence of iodine (Table 2, en-
of the reaction was not sensitive to the electronic tries 10–12). The explanation for these results is the
nature of substituents on the lithium acetylides. For fast formation of vinylic iodide III (Scheme 2), as in-
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Synthesis of 2-Acylselenophenes via Iodine-Promoted Nucleophilic Cyclization
Table 1. Synthesis of [2-(butylselanyl)phenyl]propynols 2 by alkynylation of aryl butyl selenides 1.
termediate, by total consumption of starting [2-(butyl- confirmed the complete consumption of [2-
selanyl)phenyl]propynol 2a with
a stoichiometric (butylselanyl)phenyl]propynol 2a after 30 min and
amount of iodine (see mechanism discussion; showed the formation of vinylic iodide III as a major
Scheme 2). With the aim to provide further evidence product. After 3.5 h, there was a complete consump-
for this hypothesis, we carried out the reaction of [2- tion of the vinylic iodide III giving the selenophene
(butylselanyl)phenyl]propynol
2a
with
iodine 3a in 82% yield (Table 2, entry 14). We found that the
(1.1 equiv.) in ethanol, at room temperature while minimal amount of solvent necessary for the cycliza-
monitoring the consumption of the starting material tion was 5 mL. When a smaller amount of solvent
by TLC. After 30 min, we observed the complete con- (2.0, 3.0 and 4.0 mL) was employed, the yields were
sumption of [2-(butylselanyl)phenyl]propynol 2a, significantly decreased. Among the solvents screened,
however at this reaction time, the selenophene 3a was DMSO suppressed the product formation, MeOH af-
obtained in poor yield (Table 2, entry 13). In a second forded similar yield, whereas dioxane, CH3NO2,
experiment, the reaction of [2-(butylselanyl)phenyl]- CH3CN, DMF, THF, hexane and DCE gave inferior
propynol 2a with iodine, using the same reaction con- yields if compared to those obtained with dichlorome-
ditions, was monitored by GC-MS. These analyses thane (Table 2, entries 15–23).
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Table 2. Effect of different reaction parameters on prepara-
tion of 2-acylselenophene 3a.[a]
Entry
Iodine (equiv.)
Solvent
Yield [%]
1
2
3
4
5
6
7
8
1.5
1.5
2.0
1.25
1.1
1.0
0.75
0.5
1.1
0.05
0.05
–
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
CH2Cl2
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
DMSO
MeOH
dioxane
CH3NO2
CH3CN
DMF
58
77
78
75
88
75
71
0
9
90[c]
30[b]
0[c]
0
10
11
12
13
14
15
16
17
18
19
20
21
22
23
Scheme 2. Proposed mechanism for the synthesis of 2-acylse-
lenophenes 3.
59[d]
82[e]
0
84
25
64
67
35
56
60
26
a pronounced steric effect of an aryl group having
methoxy substituents at the ortho or meta position
has influenced the yields of reactions, the 2-acylse-
lenophenes 3d and 3e were obtained in acceptable
yields (Table 3, entries 4 and 5). [2-(Butylselanyl)phe-
nyl]propynols with a terminal alkyne and those
having electron-withdrawing aryl groups or alkyl
chain attached to alkyne gave the products in good
yields but the reaction time was extended (Table 3,
entries 6–8). This methodology could also be extend-
ed to the [2-(butylselanyl)phenyl]propynols bearing
both chlorine and methoxy groups at the central aro-
matic ring. In these cases, significant influences in the
yields were only observed when the groups attached
to alkyne were changed. Similar to that found for un-
substituted central aromatic ring, electron-donating
aryl groups bonded to the alkyne gave the seleno-
phenes in higher yields than those with electron-with-
drawing aryl groups or an alkyl chain (Table 3, en-
tries 9–18). The optimized reaction conditions also
worked well with [2-(butylselanyl)phenyl]propynols
having an additional butylselanyl at the para-position
THF
hexane
DCE
[a]
The reaction was performed by the addition of iodine in
solvent (3 mL) to a solution of [2-(butylselanyl)phenyl]-
propynol 2a (0.25 mmol) in EtOH (2 mL), at room tem-
perature, under aerobic conditions. The resulting mixture
was stirred at room temperature for 12 h.
The reaction was carried using EtOH (3 mL) and DMSO
(1 mL).
The reaction was carried out under an argon atmosphere.
The reaction was stirred at room temperature for 30 min
and monitored by TLC.
[b]
[c]
[d]
[e]
The reaction was stirred at room temperature for 3.5 h
and monitored by GC-MS.
Based on the above studies, the best reaction condi- giving the corresponding selenophenes 3s–u in good
tions for the iodine-promoted nucleophilic cyclization yields (Table 3, entries 19–21). The structures of all
were the addition of iodine in EtOH (3 mL) to a solu- products 3 were unambiguously elucidated by their
tion
of
[2-(butylselanyl)phenyl]propynol
2a NMR data and confirmed by single crystal X-ray dif-
(0.25 mmol) in EtOH (2 mL), at room temperature, fraction (compound 3k, Figure S1, Supporting Infor-
under aerobic conditions for 3.5 h. After the optimiza- mation).[36]
tion of the reaction conditions, we started an investi-
As hypothesized in the optimization studies, we be-
gation of the applicability of this protocol to function- lieve that the key intermediate in the iodine-promot-
alized [2-(butylselanyl)phenyl]propynols 2 and the re- ed nucleophilic cyclization of [2-(butylselanyl)phe-
sults are shown in Table 3. The reaction of [2-(butyl- nyl]propynols 2 is the vinylic iodide III (Scheme 2).
selanyl)phenyl]propynols containing neutral and elec- To probe this hypothesis and get insights into the re-
tron-donating aryl groups directly bonded to alkyne action pathways, we tried to identify the key vinylic
gave the corresponding 2-acylselenophene derivatives iodide III. For this purpose, the [2-(butylselanyl)phe-
in good yields (Table 3, entries 1 and 3). Although nyl]propynol 2a was reacted with iodine under the op-
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Synthesis of 2-Acylselenophenes via Iodine-Promoted Nucleophilic Cyclization
Table 3. Synthesis of 2-acylselenophenes 3.[a]
Table 3. (Continued)
[a]
The reaction was performed by the addition of iodine in
EtOH (3 mL) to a solution of [2-(butylselanyl)phenyl]-
propynol 2 (0.25 mmol) in EtOH (2 mL), at room tem-
perature, under aerobic conditions. The resulting mixture
was stirred at room temperature for the time indicated in
Table.
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Renan P. Pistoia et al.
timized reaction conditions as shown in Table 1. Sam- bonds. The utility of 2-acylselenophene derivatives
ples of this reaction were taken at one minute inter- was initially studied through alkynylation of the car-
vals and analyzed by GC-MS. After 30 min, there was bonyl group to obtain alkynol derivatives followed by
complete consumption of [2-(butylselanyl)phenyl]pro- the electrophilic cyclization reaction to give the se-
pynol 2a and the formation of vinylic iodide III and lenophene-fused aromatic compounds (Scheme 3).
butyl iodide as major products. These results are sig-
nificant because they indicate that the removal of
a butyl group from the selenium atom occurs before
the hydroxy migration (see mechanism discussion;
Scheme 2). In addition, the formation of butyl iodide
provides evidence that one portion of iodide acts as
nucleophile in the substitution of the butyl group
bonded to the selenium atom. All attempts to isolate
this intermediate failed and in all cases, the crude re-
action turned into a black solid with complete decom-
position. Furthermore, we tried to assign its structure
1
1
by H NMR. Figure 1 collects the H NMR spectra of
the reaction of [2-(butylselanyl)phenyl]propynol 2a
with iodine, under the optimized reactions using
CDCl3 as solvent, monitored at 5 min, 15 min and
1
30 min intervals. The H NMR spectrum of [2-(butyl-
selanyl)phenyl]propynol 2a (Figure 1a) showed the
presence of a characteristic signal for carbinolic hy-
drogen at 6.15 ppm (H1). After 5 min, we observed
the appearance of a signal at 5.92 ppm corresponding
to the hydrogen (H2) of the carbinolic center of vinyl-
ic iodide III. The disappearance of a signal at
6.15 ppm and the appearance of a signal at 5.92 ppm
were followed for 30 min (Figure 1c and d). After
Scheme 3. Synthetic applications of 2-acylselenophenes.
For this purpose, the 2-acylselenophene 3a reacted
that, there was the consumption of the starting mate- with (p-tolyl)ethynyllithium and (4-methoxyphenyl)-
rial giving the selenophene 3a which showed the H-ar- ethynyllithium giving the 1-(benzo[b]selenophen-2-
omatic signal at 8.12 ppm corresponding to the hydro- yl)-1,3-diphenylprop-2-yn-1-ol 4a and 4b in 62% and
gen (H3) of the selenophene ring (Figure 1e). There- 76% yields, respectively (Scheme 3). In the presence
fore, we assumed that the vinylic iodide III is formed of electrophilic selenium species (BuSeBr), seleno-
very fast and once it has been formed, it rearranges to phenes 4a and 4b gave fused selenophenes 5a and 5b
selenophene 2. Based on the assigned structure for in 53% and 56% yields, respectively, through an elec-
the vinylic iodide III, the formation of 2-acylseleno- trophilic aromatic substitution/electrophilic cycliza-
phenes 3 can be explained through the initial forma- tion sequence[1c] via selenophene 4a’–4b’ (Scheme 3).
tion of the iodonium ion I, which was obtained by the
We also examined the reactivity of 2-acylseleno-
coordination of the carbon-carbon triple bonds to I2. phene 3f as substrate in the cyanation reaction.[38] The
The anti-nucleophilic attack of the selenium atom at reaction of 2-acylselenophene 3f with NH2OH·HCl in
the activated iodonium intermediate produces the salt DMSO at 90 8C for 3 h gave the benzo[b]seleno-
II via a selective intramolecular 5-exo-dig cycliza- phene-2-carbonitrile 6 in 82% yield (Scheme 4).
tion.[10] The removal of the alkyl group via SN2 dis-
placement by the iodide anion, present in the reaction
mixture, generates the vinylic iodide III and butyl
iodide. The 1,3-migration of the hydroxy, via allylic
cation IV,[12c] gives the alcohol V, which affords the 2-
acylselenophenes
(Scheme 2).
3
after elimination of HI
Scheme 4. Cyanation reaction of 2-acylselenophene 3f.
It is recognized that 2-acylselenophene derivatives
are essential for a great number of biological activities
that include antimicrobial, cytotoxic and growth in- Conclusions
hibitory properties.[37] Considering the high reactivity
of the carbonyl group, we envisioned that 2-acylsele- In conclusion, arylpropynols containing a butylselanyl
nophenes should be also important synthetic inter- substituent at the C-2 position were synthesized using
mediates for the formation of new carbon-carbon nucleophilic aromatic substitution reactions of 2-halo-
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Synthesis of 2-Acylselenophenes via Iodine-Promoted Nucleophilic Cyclization
Figure 1. 1H NMR spectra in CDCl3 (400 MHz): a) [2-(butylselanyl)phenyl]propynol 2a.; b) reaction of [2-(butylselanyl)phe-
nyl]propynol 2a with iodine, under the optimized reactions at 5 min; c) reaction of [2-(butylselanyl)phenyl]propynol 2a with
iodine, under the optimized reactions at 15 min; d) reaction of [2-(butylselanyl)phenyl]propynol 2a with iodine, under the
optimized reactions at 30 min; e) selenophene 3a.
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127.0, 125.8, 125.0, 113.7, 55.4; MS (EI, 70 eV): m/z (relative
intensity)=317 [M+1, (25)], 316 (100), 208 (10), 135 (100),
107 (13), 89 (18), 77 (100); HR-MS (ESI-TOF): m/z=
317.0085, calcd. for C16H13O2Se (M+H+): 317.0081.
benzaldehydes with lithium butylselenolate followed
by alkynylation of a carbonyl function with lithium
acetylides. A variety of aliphatic, aromatic and termi-
nal lithium acetylides was effective to afford [2-(butyl-
selanyl)phenyl]propynols in good yields. Their reactiv-
ity toward intramolecular iodine-promoted nucleo-
philic cyclization reaction was studied to provide 2-
acylselenophenes. The key intermediate for the cycli-
zation reaction, vinylic iodide, was identified by GC-
Benzo[b]selenophen-2-yl(3-methoxyphenyl)methanone
(3d): Yellow oil; yield: 0.082 g (52%); 1H NMR (CDCl3,
400 MHz): d=8.04 (s, 1H), 7.90–7.81 (m, 2H), 7.45–7.34 (m,
5H), 7.31–7.10 (m, 1H), 3.82 (s, 3H); 13C NMR (CDCl3,
100 MHz): d=190.4, 159.7, 147.2, 144.4, 141.8, 138.9, 136.1,
129.5, 128.0, 127.4, 126.0, 125.2, 121.73, 118.7, 113.9, 55.5;
MS (EI, 70 eV): m/z (relative intensity)=317 [M+1, (25)],
316 (100), 209 (70), 180 (26), 135 (40), 89 (45), 77 (29); HR-
MS (ESI-TOF): m/z=317.0083, calcd. for C16H13O2Se (M+
H+): 317.0081.
Benzo[b]selenophen-2-yl(2-methoxyphenyl)methanone
(3e): Yellow oil; yield: 0.083 g (52%); 1H NMR (CDCl3,
400 MHz): d=7.94–7.91 (m, 1H), 7.84 (s, 1H), 7.82–7.79 (m,
1H), 7.51–7.43 (m, 2H), 7.38–7–36 (m, 2H), 7.07–7.02 (m,
2H), 3.81 (s, 3H); 13C NMR (CDCl3, 100 MHz): d=190.8,
157.1, 144.7, 141.8, 136.5, 131.9, 129.3, 128.2, 128.0, 127.3,
126.2, 125.2, 120.3, 111.7, 55.8; MS (EI, 70 eV): m/z (relative
intensity)=317 [M+1, (25)], 316 (100), 284 (14), 208 (80),
181 (28), 134 (48), 77 (28); HR-MS (ESI-TOF): m/z=
317.0088, calcd. for C16H13O2Se (M+H+): 317.0081.
Benzo[b]selenophene-2-carbaldehyde (3f): White solid;
yield: 0.071 g (68%); mp 72–738C; 1H NMR (CDCl3,
400 MHz): d=9.97 (s, 1H), 8.23 (s, 1H), 7.95–7.91 (m, 2H),
7.44–7.41 (m, 2H); 13C NMR (CDCl3, 100 MHz): d=185.8,
146.9, 144.0, 141.0, 138.5, 128.1, 128.0, 126.4, 125.4. MS (EI,
70 eV): m/z (relative intensity)=211 [M+1, (25)], 210
(100), 206 (37), 181 (32), 102 (79), 89 (100), 73 (27); HR-MS
(ESI-TOF): m/z=210.9668, calcd. for C9H7OSe (M+H+):
210.9662.
1
MS and H NMR experiments. These studies afforded
valuable insights into the mechanism of the cycliza-
tion reaction steps, demonstrating that the selenium
nucleophilic cyclization and hydroxy migration are
the key steps for the cyclization reaction. This result
also revealed that the selenium cyclization occurs
before the hydroxy migration.
Experimental Section
General Procedure for the Synthesis of 2-Acylseleno-
phenes 3
To
a
solution of [2-(butylselanyl)phenyl]propynols
2
(0.25 mmol) in EtOH (3 mL) was added molecular iodine
(1.1 equiv.) dissolved in EtOH (2 mL) at room temperature
under an air atmosphere. The reaction mixture was allowed
to stir at room temperature for 3.5 h. The reaction was
quenched using saturated aqueous Na2S2O3 and extracted by
ethyl acetate (3”10 mL). The combined organic layers were
dried over anhydrous MgSO4 and concentrated under
vacuum to yield the crude product, which was purified by
flash chromatography on silica gel using 9:1 hexane and
ethyl acetate as eluent.
Benzo[b]selenophen-2-yl(4-chlorophenyl)methanone (3g):
1
Yellow solid; yield: 0.113 g (72%); mp 118–1208C; H NMR
(CDCl3, 400 MHz): d=7.98 ( s, 1H), 7.91–7.88 (m, 1H),
7.86–7.83 (m, 1H), 7.80 (d, J=8.3 Hz, 2H), 7.46 (d, J=
8.3 Hz, 2H), 7.38–7.36 (m, 2H); 13C NMR (CDCl3,
100 MHz): d=189.2, 146.7, 144.3, 141.6, 138.7, 135.8, 135.7,
130.5, 128.7, 127.9, 127.4, 125.9, 125.2. MS (EI, 70 eV): m/z
(relative intensity)=321 [M+1, (25)], 320 (30), 208 (46),
180 (18), 110 (86), 89 (100), 75 (84); HR-MS (ESI-TOF): m/
z=320.9590, calcd. for C15H10ClOSe (M+H+): 320.9585.
1-(Benzo[b]selenophen-2-yl)pentan-1-one (3h): Yellow
Benzo[b]selenophen-2-yl(phenyl)methanone (3a): Yellow
1
oil; yield: 0.116 g (82%); H NMR (CDCl3, 400 MHz): d=
8.05 (s, 1H), 7.96–7.85 (m, 4H), 7.65–7.47 (m, 3H), 7.44–
7.36 (m, 2H); 13C NMR (CDCl3, 100 MHz): d=190.7, 147.3,
144.3, 141.8, 137.5, 135.9, 132.3, 129.1, 128.4, 128.0, 127.3,
125.9, 125.1; MS (EI, 70 eV): m/z (relative intensity)=287
[M+1, (25)], 286 (38), 206 (10), 181 (19), 105 (62), 89 (67),
77 (90); HR-MS (ESI-TOF): m/z=286.9979, calcd. for
C15H11SeO (M+H+): 286.9975.
1
solid; yield: 0.125 g (94%); mp 74–768C; H NMR (CDCl3,
400 MHz): d=8.10 (s, 1H), 7.86–7.83 (m, 2H), 7.37–7.30 (m,
2H), 2.94 (t, J=7.4 Hz, 2H), 1.74 (qui, J=7.4 Hz, 2H), 1.41
(sex, J=7.4 Hz, 2H), 0.94 (t, J=7.4 Hz, 3H); 13C NMR
(CDCl3, 100 MHz): d=195.9, 148.3, 144.0, 141.9, 132.4,
128.2, 127.7, 126.1, 125.1, 38.3, 26.9, 22.4, 13.8; MS (EI,
70 eV): m/z (relative intensity)=267 [M+1, (25)], 266 (23),
223 (50), 181 (38), 115 (23), 102 (16), 89 (100); HR-MS
(ESI-TOF): m/z=267.0291, calcd. for C13H15OSe (M+H+):
267.0288.
7-Methoxybenzo[b]selenophen-2-yl)(phenyl)methanone
(3i): Yellow solid; yield: 0.110 g (70%); mp 105–1088C;
1H NMR (CDCl3, 400 MHz): d=8.00 (s, 1H), 7.85 (d, J=
7.2 Hz, 2H), 7.55 (t, J=7.2 Hz, 1H), 7.48–7.42 (m, 3H), 7.30
(t, J=7.8 Hz, 1H), 6.76 (d, J=7.8 Hz, 1H), 3.92 (s, 3H);
13C NMR (CDCl3, 100 MHz): d=190.6,156.2, 147.4, 142.4,
137.4, 136.0, 133.3, 132.1, 129.0, 128.3, 126.6, 120.2, 106.5,
55.6. MS (EI, 70 eV): m/z (relative intensity)=317 [M+1,
Benzo[b]selenophen-2-yl(p-tolyl)methanone (3b): Yellow
solid; yield: 0.121 g (81%); mp 107–1088C; 1H NMR
(CDCl3, 400 MHz): d=8.04 (s, 1H), 7.95–7.92 (m, 1H),
7.88–7.85 (m, 1H), 7.80 (d, J=8.15 Hz, 2H), 7.41–7.37 (m,
2H), 7.32 (d, J=7.8 Hz, 2H), 2.45 (s, 3H);13C NMR (CDCl3,
100 MHz): d=190.42, 147.51, 144.15, 143.13, 141.81, 135.69,
134.74, 129.39, 129.17, 127.91, 127.21, 125.96, 125.14, 21.17;
MS (EI, 70 eV): m/z (relative intensity)=301 [M+1, (25)],
300 (48), 208 (39), 119 (100), 91 (76), 65 (37);anal. (%)
calcd. for C16H12OSe: C 64.22, H 4.04; found: C 64.39, H
4.09.
Benzo[b]selenophen-2-yl(4-methoxyphenyl)methanone
(3c): Yellow solid; yield: 0.113 g (72%); mp 121–1238C;
1H NMR (CDCl3, 400 MHz): d=8.01 (s, 1H), 7.90 (d, J=
8.9 Hz, 3H), 7.55–7.93 (m, 1H), 7.39–7.33 (m, 2H), 6.98 (d,
J=8.9 Hz, 2H), 3.86 (s, 3H); 13C NMR (CDCl3, 100 MHz):
d=189.2, 163.1, 147.5, 143.9, 141.7, 134.8, 131.5, 129.9, 127.7,
3662
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Synthesis of 2-Acylselenophenes via Iodine-Promoted Nucleophilic Cyclization
(25)], 316 (30), 208 (46), 180 (18), 110 (86), 89 (100), 75
(84); HR-MS (ESI-TOF): m/z=317.0083, calcd. for
C16H13O2Se (M + H+): 317.0081.
J=7.8 Hz, 1H), 7.62 (t, J=7.8 Hz, 1H), 7.54 (t, J=7.9 Hz,
2H), 7.38 (d, J=7.8 Hz, 1H), 7,30 (t, J=7.9 Hz, 1H);
13C NMR (CDCl3, 100 MHz): d=189.2, 147.1, 145.4, 139.9,
139.2, 135.4, 133.3, 132.8, 130.7, 129.0, 128.1, 125.4, 124.5.
MS (EI, 70 eV): m/z (relative intensity)=320 [M+1, (25)],
319 (24), 242 (43), 178 (15), 122 (13), 105 (84), 77 (100):
7-Methoxybenzo[b]selenophen-2-yl)(p-tolyl)methanone
(3j): Yellow solid; yield: 0.116 g (70%); mp 86–888C;
1H NMR (CDCl3, 400 MHz): d=8.00 (s, 1H), 7.79 (d, J=
8.2 Hz, 2H), 7.46 (d, J=7.8 Hz, 1H), 7.33 (t, J=7.8 Hz,
1H), 7.29 (d, J=8.2 Hz, 2H), 6.80 (d, J=7.8 Hz, 1H), 3.96
(s, 3H), 2.24 (s, 3H); 13C NMR (CDCl3, 100 MHz): d=
190.4, 156.2, 147.7, 143.1, 143.0, 35.7, 134.7, 133.3,129.3,
129.1, 126.6, 120.1, 106.4, 55.7, 21.5; MS (EI, 70 eV): m/z
(relative intensity)=331 [M+1, (25)], 330 (2), 283 (18), 207
(100), 156 (50), 102 (65), 77 (74); HR-MS (ESI-TOF): m/z=
331.0241, calcd. for C17H15O2Se (M+H+): 331.0237.
7-Methoxybenzo[b]selenophen-2-yl)(4-methoxyphenyl)-
methanone (3k): Yellow solid; yield: 0.112 g (65%); mp
109–1118C; 1H NMR (CDCl3, 400 MHz): d=8.03 (s, 1H),
7.90 (d, J=8.8 Hz, 2H), 7.48 (d, J=7.9 Hz, 1H), 7.35 (t, J=
7.9 Hz, 1H), 6,98 (d, J=8.8 Hz, 2H), 6.80 (d, J=7.9 Hz,
1H), 3.97 (s, 3H), 3.87 (s, 3H); 13C NMR (CDCl3,
100 MHz): d=189.3, 163.1, 156.2, 147.9, 143.1, 135.1, 133.1,
131.6, 129.9, 126.6, 120.0, 113.7, 106.3, 55.7, 55.4; MS (EI,
70 eV): m/z (relative intensity)=347 [M+1, (25)], 346 (24),
281 (6), 207 (15), 135 (10), 107 (16), 77 (26); HR-MS (ESI-
TOF): m/z=347.0190, calcd. for C17H15O3Se (M+H+):
347.0186.
HR-MS
C15H10ClOSe (M+H+): 320.9585.
(4-Chlorobenzo[b]selenophen-2-yl)(p-tolyl)methanone
(ESI-TOF):
m/z=320.95895,
calcd.
for
(3p): Yellow solid; yield: 0.133 g (81%); mp 107–1088C;
1H NMR (CDCl3, 400 MHz): d=8.22 (d, J=8.6 Hz 1H),
7.91–7.84 (m, 3H), 7.56 (d, J=8.6 Hz, 1H), 7.49–7.45 (m,
3H), 2.50 (s, 3H); 13C NMR (CDCl3, 100 MHz): d=189.2,
139.2, 133.3, 132.6, 130.7, 129.5, 129.3, 129.0, 128.0, 127.7,
125.4, 125.2, 124.5, 21.6; MS (EI, 70 eV): m/z (relative inten-
sity)=335 [M+1, (25)], 334 (34), 242 (17), 179 (9), 119 (10),
91 (54), 65 (27); HR-MS (ESI-TOF): m/z=334.9743, calcd.
for C16H12ClOSe (M+H+): 334.9742.
(4-Chlorobenzo[b]selenophen-2-yl)(4-methoxyphenyl)me-
thanone (3q): Yellow solid; yield: 0.126 g (72%); mp 92–
1
948C; H NMR (CDCl3, 400 MHz): d=8.24 (s, 1H), 7.97–
7.93 (m, 2H), 7.81 (d, J=7.9 Hz, 1H), 7.39 (d, J=7.9 Hz,
1H), 7.30 (t, J=7.9 Hz, 1H), 7.04–7.00 (m, 2H), 3.90 (s,
3H); 13C NMR (CDCl3, 100 MHz): d=188.9, 163.4, 148.7,
144.9, 140.0, 132.4, 132.2, 129.6, 127.6, 125.2, 124.6, 124.4,
113.9, 55.5; MS (EI, 70 eV): m/z (relative intensity)=351
[M+1, (25)], 350 (5), 281 (17), 207 (96), 193 (15), 113 (17),
73 (34); HR-MS (ESI-TOF): m/z=350.9695, calcd. for
C16H12ClO2Se (M+H+): 350.9691.
(4-Chlorophenyl)(7-methoxybenzo[b]selenophen-2-yl)me-
thanone (3l): Yellow solid; yield: 0.079 g (45%); mp 125–
1
1288C; H NMR (CDCl3, 400 MHz): d=8.02 (s, 1H), 7.83
(d, J=8.4 Hz, 2H), 7.48 (d, J=8.4 Hz, 3H), 7.37 (t, J=
7.9 Hz, 1H), 6,83 (d, J=7.9 Hz, 1H), 3.99 (s, 3H); 13C NMR
(CDCl3, 100 MHz): d=189.5, 156.4, 147.2, 143.0, 138.7,
136.0, 135.9, 133.7, 130.6, 128.8, 126.8, 120.3, 106.7, 55.8; MS
(EI, 70 eV): m/z (relative intensity)=351 [M+1, (25)], 350
(2), 281 (37), 207 (100), 190 (17), 113 (17), 73 (35); HR-MS
(ESI-TOF): m/z=350.9693, calcd. for C16H12ClO2Se (M+
H+): 350.9691.
(4-Chlorobenzo[b]selenophen-2-yl)(4-chlorophenyl)me-
thanone (3r): Yellow solid; yield: 0.142 g (80%); mp 120–
1228C; H NMR (CDCl3, 400 MHz): d=8.25 (s, 1H), 7.91–
785 (m, 3H), 7,56 (d, J=8.5 Hz, 2H), 7.57–7.36 (m, 2H);
13C NMR (CDCl3, 100 MHz): d=189.2, 147.8, 145.3, 139.9,
139.1, 135.4, 133.3, 132.8, 130.7, 129.0, 128.1, 125.4, 124.5;
MS (EI, 70 eV): m/z (relative intensity)=355 [M+1, (25)],
354 (44), 281 (34), 242 (71), 139 (100), 111 (85), 75 (49);
HR-MS (ESI-TOF): m/z=354.9158, calcd. for C15H9Cl2OSe
(M+H+): 354.9196.
1
1-(7-Methoxybenzo[b]selenophen-2-yl)pentan-1-one (3m):
1
Yellow solid; yield: 0.077 g (52%); mp 78–798C; H NMR
(CDCl3, 400 MHz): d=8.11 (s, 1H), 7.47(d, J=7.9 Hz, 1H),
7.33 (t, J=7.9 Hz, 1H), 6,78(d, J=7.9 Hz, 1H), 3.94 (s, 3H),
2.95 (t, J=7.5 Hz, 2H), 1.75 (qui, J=7.5 Hz, 2H), 1.41 (sex,
J=7.5 Hz, 2H), 0.96 (t, J=7.5 Hz, 3H); 13C NMR (CDCl3,
100 MHz): d=195.9, 156.2, 148.6, 143.1, 133.1, 132.6, 126.5,
119.9, 106.3, 55.6, 38.2, 26.9, 22.4, 13.8. MS (EI, 70 eV): m/z
(relative intensity)=297 [M+1, (25)], 296 (60), 238 (100),
210 (16), 180 (20), 102 (11), 89 (29); HR-MS (ESI-TOF):
m/z=297.0395, calcd. for C14H17O2Se (M+H+): 297.0394.
(6-Chloro-3-methylbenzo[b]selenophen-2-yl)(phenyl)me-
thanone (3n): Yellow solid; yield: 0.085 g (51%); mp 124–
{6-(Butylselanyl)benzo[b]selenophen-2-yl}(phenyl)metha-
none (3s): Yellow oil; yield: 0.157 g (75%); 1H NMR
(CDCl3, 400 MHz): d=7.90 (d, J=7.8 Hz, 2H), 7.85 (d, J=
8.2 Hz, 2H), 7.67 (d, J=8.2 Hz, 1H), 7.57 (t, J=7.3 Hz,
1H), 7.50–7.41 (m, 3H), 2.98 (t, J=7.4 Hz, 2H), 1.71 (qui,
J=7.4 Hz, 2H), 1.43 (sex, J=7.4 Hz, 2H), 0.92 (t, J=
7.4 Hz, 3H); 13C NMR (CDCl3, 100 MHz): d=190.3, 146.6,
144.9, 139.9, 137.6, 135.6, 132.2, 131.9, 128.9, 128.5, 128.3,
127.9, 127.8, 31.9, 27.4, 22.8, 13.4; MS (EI, 70 eV): m/z (rela-
tive intensity)=423 [M+1, (25)], 422 (13), 286 (4), 206 (9),
105 (100), 77 (27), 57 (5); HR-MS (ESI-TOF): m/z=
422.9770, calcd. for C19H19Se2O (M+H+): 422.9766.
1
1268C; H NMR (CDCl3, 400 MHz): d=8.85–7.83 (m, 3H),
7.70 (d, J=7.8 Hz, 1H), 7.58 (tt, J=7.8 Hz, J=1.3 Hz, 1H),
7.46 (td, J=7.8 Hz, J=1.3 Hz, 2H), 7,38 (dd, J=7.8 Hz, J=
1.9 Hz, 1H), 2.36 (s, 3H); 13C NMR (CDCl3, 100 MHz): d=
192.3, 143.1, 141.3, 139.7, 139.2, 139.0, 133.3, 132.8, 129.2,
128.4, 126.3, 125.8, 125.1, 15.8; MS (EI, 70 eV): m/z (relative
intensity)=335 [M+1, (25)], 334 (36), 298 (39), 149 (52),
114 (13), 105 (36), 77 (100). HR-MS (ESI-TOF): m/z=
334.9749, calcd. for C16H12ClOSe (M+H+): 334.9742.
{6-(Butylselanyl)benzo[b]selenophen-2-yl}(p-tolyl)metha-
none (3t): Yellow solid; yield: 0.146 g (67%); mp 131–
1328C; H NMR (CDCl3, 400 MHz): d=8.01–8.00 (m, 1H),
1
7.98–7.97 (m, 1H), 7.80–7.77 (m, 2H), 7.70 (d, J=8.2 Hz,
1H), 7.46 (dd, J=8.3 Hz, J=1.5 Hz, 1H), 7.32–7.30 (m,
2H), 3.01 (t, J=7.5 Hz, 2H), 2.45 (s, 3H), 1.74 (qui, J=
7.5 Hz, 2H), 1.46 (sex, J=7.5 Hz, 2H), 0.92 (t, J=7.5 Hz,
3H); 13C NMR (CDCl3, 100 MHz): d=190.2, 147.1, 145.0,
143.1, 135.2, 134.9, 131.7, 129.3, 129.1, 128.8, 128.7, 128.3,
127.8, 32.1, 27.7, 22.9, 21.6, 13.5; MS (EI, 70 eV;): m/z (rela-
tive intensity)=436 [M+1, (25)], 435 (2), 345 (18), 281 (24),
(4-Chlorobenzo[b]selenophen-2-yl)(phenyl)methanone
(3o): Yellow oil; yield: 0.107 g (67%); 1H NMR (CDCl3,
400 MHz): d=8.24 (s, 1H), 7.91 (d, J=7.9 Hz, 2H), 7.80 (d,
Adv. Synth. Catal. 2015, 357, 3655 – 3665
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FULL PAPERS
Renan P. Pistoia et al.
207 (100), 135 (20), 73 (27); HR-MS (ESI-TOF): m/z=
436.9930, calcd. for C20H21OSe2 (M+H+): 436.9923.
[14] R. Spina, E. Colacino, B. Gabriele, G. Salerno, J. Marti-
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{6-(Butylselanyl)benzo[b]selenophen-2-yl}(4-chlorophe-
nyl)methanone (3u): Yellow solid; yield: 0.148 g (65%); mp
75–768C; H NMR (CDCl3, 400 MHz): d=7.99 (s, 1H), 7.94
[15] N. A. Danilkina, A. E. Kulyashova, A. F. Khlebnikov,
S. Bräse, I. A. Balova, J. Org. Chem. 2014, 79, 9018–
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1
(s, 1H), 7.81 (d, J=8.5 Hz, 2H), 7.70 (d, J=8.3 Hz, 1H),
7.49–7.45 (m, 3H), 3.01 (t, J=7.5 Hz, 2H), 1.74 (qui, J=
7.5 Hz, 2H), 1.45 (sex, J=7.5 Hz, 2H), 0.93 (t, J=7.5 Hz,
3H); 13C NMR (CDCl3, 100 MHz): d=189.2, 146.3, 145.2,
140.0, 138.7, 135.8, 135.5, 132.6, 130.5, 128.8, 128.7, 128.0,
127.9, 32.0, 27.8, 22.9, 13.5; MS (EI, 70 eV): m/z (relative in-
tensity)=457 [M+1, (25)], 456 (9), 281 (18), 207 (52), 138
(100), 111 (22), 73 (22); HR-MS (ESI-TOF): m/z=456.9378,
calcd. for C19H18ClOSe2 (M+H+): 456.9377.
[16] S. T. Heller, T. Kiho, A. R. H. Narayan, R. Sarpong,
Angew. Chem. Int. Ed. 2013, 52, 11129–11133.
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Acknowledgements
We are grateful to FAPERGS, CAPES and CNPq for finan-
cial support. CNPq and CAPES are also acknowledged for
the fellowships (R. P. P. and G. Z.).
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