Palladium-catalyzed direct arylation of selenophene

Article abstract of DOI:10.1021/jo500094t

An efficient and convenient method was developed for the regioselective formation of 2-aryl- or 2,5-diarylselenophenes via a palladium-catalyzed direct arylation. This protocol is suitable for a wide range of aryl halides containing different functional groups. The 2-arylated substrates can undergo an additional regioselective direct arylation event furnishing symmetrical or unsymmetrical 2,5-diaryl selenophenes in good yield. Competition experiments and the role of the acid additive are in agreement with a concerted metalation deprotonation (CMD) pathway.

Full text of DOI:10.1021/jo500094t

Article
pubs.acs.org/joc
Palladium-Catalyzed Direct Arylation of Selenophene
Daniel S. Rampon,†,‡ Ludger A. Wessjohann,‡ and Paulo H. Schneider*,†
†Instituto de Química, Departamento de Química Organ
Alegre-RS, Brazil
̂
ica, Universidade Federal do Rio Grande do Sul, UFRGS, 91501-970 Porto
‡Department of Bioorganic Chemistry, Leibniz Institute of Plant Biochemistry, Weinberg 3, 06120 Halle (Saale), Germany
S
* Supporting Information
ABSTRACT: An efficient and convenient method was
developed for the regioselective formation of 2-aryl- or 2,5-
diarylselenophenes via a palladium-catalyzed direct arylation.
This protocol is suitable for a wide range of aryl halides
containing different functional groups. The 2-arylated
substrates can undergo an additional regioselective direct
arylation event furnishing symmetrical or unsymmetrical 2,5-
diaryl selenophenes in good yield. Competition experiments and the role of the acid additive are in agreement with a concerted
metalation deprotonation (CMD) pathway.
INTRODUCTION
RESULTS AND DISCUSSION
■
■
The palladium-catalyzed direct arylation of several (hetero)-
arenes via direct C−H bond activation using aryl halides has
brought a synthesis revolution in recent years.1 Such couplings
are very attractive to replace classical Stille,2 Suzuki,3 or Negishi
palladium-catalyzed type couplings,4 as they do not require the
preliminary synthesis of one or two organometallic derivatives.
Therefore, these reactions are atom-economical and produce
less waste.
Up to now, a wide range of electron-rich and electron-poor
(hetero)aromatic compounds have been successfully employed
in palladium-catalyzed direct arylations,5 but despite the recent
advances, such transformations with selenophenes have been
accomplished only for the synthesis of analogues for dye-
sensitized photovoltaic cells, and no mechanistic considerations
were displayed.5m Since catalyst poisoning by organoselenium
species is one of the limiting factors in transition-metal-
catalyzed transformations,6 it is important to understand the
pathways for these reactions. On the other hand, many efforts
are directed toward the synthesis and design of organoselenium
compounds, particularly due to their ability to mimic natural
compounds with important biological properties, like anti-
oxidant, antitumor, antimicrobial, and antiviral ones.7 In
addition, chalcogen derivatives have been intensively studied
in the development of organic materials with technological
interest, such as electroconductive polymers, solar cells, organic
semiconductors, and liquid crystals.8
Suitable reaction conditions were developed with commercially
available selenophene (1) and bromobenzene (2a). The first
attempt was performed under Fagnou direct arylation
conditions.5a The catalytic system was composed of Pd(OAc)2,
an alkylphosphine as its phosphoniumtetrafluoroborate salt
(PCy3·HBF4), pivalic acid as a co-catalyst, and potassium
carbonate as a base in DMA (N,N-dimethylacetamide).
However, only poor yields of product 3a could be achieved.
After screening several parameters,11 we could obtain the
desired direct coupling product (3a) with complete selectivity
for the 2-arylation, albeit in only 18% yield. Increasing the
catalyst and base load or applying longer reaction times in
DMF (N,N-dimethylformamide) did not improve the result.
This prompted us to reevaluate the process in order to
determine if any benefits would result from the appropriate
choice of ligand, base, or additive in the reaction between 1 and
2a (Table 1).
First, we observed that the amount of pivalic acid is an
important feature since an improvement of the yield from 18%
to 30% was achieved when 60 mol % of PivOH was used
(Table 1, entries 1 and 2). A further increase in the amount of
pivalic acid above 60 mol % does not improve the yield beyond
that observed with 60 mol %. In another set of experiments, a
variety of phosphine ligands were screened. It was observed
that the use of strong σ-donor phosphines or such with a wide
cone angle led to a decrease in yield (entries 1−4). This is in
sharp contrast to previous reports concerning direct arylations
of related heterocycles.5 Indeed, we found a correlation
between the phosphine cone angle and the yield,12 wherein
reduced phosphine cone angles increase the catalyst activity
(entries 2−7), and therefore, better results of product 3a were
To date, to promote a cross-coupling reaction with the
selenophene ring (1), a previous activation either as a halide or
as an organometallic (B, Mg, Sn, and Zn) is required.9 Direct
arylation would avoid the need for prefunctionalization of the
selenophene, thus reducing the number of steps to prepare
these 2-arylated products. This fact and our continuous interest
in the synthesis of organoselenium compounds10 prompted us
to explore a new approach on the palladium-catalyzed direct
arylation of selenophene.
Received: January 15, 2014
© XXXX American Chemical Society
A
dx.doi.org/10.1021/jo500094t | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
a
a
Table 1. Optimization of Direct Arylation of Selenophene
Table 2. Scope of the Direct Arylation of Selenophene (1)
b
yield
entry
phosphine (mol %)
additive (mol %)
base
(%)
1
PCy3·HBF4 (8)
PCy3·HBF4 (8)
P(t-Bu)2Me·HBF4 (8) PivOH (60)
P(o-tol)3 (8)
XPhos (8)
PPh3 (8)
PivOH (30)
PivOH (60)
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Cs2CO3
K3PO4
KOAc
18
30
46
8
2
3
4
PivOH (60)
PivOH (60)
PivOH (60)
PivOH (60)
PivOH (60)
PivOH (60)
PivOH (60)
butyric acid (60)
AcOH (60)
5
55
73
82
37
46
68
42
71
29
0
6
7
PPh3 (16)
PPh3 (16)
PPh3 (16)
PPh3 (16)
PPh3 (16)
PPh3 (16)
PPh3 (16)
PPh3 (16)
8
9
10
11
12
13
14
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
CF3CO2H (60)
HCO2H (60)
PivOH (60)
PivOH (60)
c
15
80
60
d
16
PPh3 (8)
a
Conditions: 2a (0.1 mmol, 1 equiv), 1 (3 equiv), base (3 equiv), acid
additive (mol %), Pd(OAc)2 (4 mol %), phosphine (mol %), DMF (1
b
c
mL), under 24 h and 100 °C. HPLC assay yield. Pd(PPh3)4 (4 mol
%). PdCl2(PPh3)2 (4 mol %).
d
reached with PPh3 as ligand (entries 6 and 7, respectively). The
observation that less bulky, electron-deficient phosphines can
provide a better outcome in direct arylation has previously been
noted.13 It is plausible that the use of such ligands may facilitate
the arene binding by creating a more electron-deficient
palladium metal atom or by providing a vacant site for arenes
undergoing an easy displacement from the metal center.14
Additionally, by increasing the amount of PPh3 to 16 mol %,
higher yields were achieved (82%) (entry 7). Several bases and
acid additives were tested (entries 7−14), and we found that
the combination of PPh3−Pd(OAc)2 with PivOH−K2CO3
afforded the best yields of 2-phenylselenophene (3a). Further
screening of the palladium sources showed that Pd(PPh3)4 and
PdCl2(PPh3)2 also proved to be effective for this method
(entries 15 and 16). It is worth mentioning that the formation
of 2,5-diarylation side reaction product was observed only in
small amounts.
To explore the scope and limitation of this method, the
coupling reactions between a variety of aryl halides (2a−s) and
selenophene (1) were investigated under the improved
conditions (Table 2). In each case, the reaction regioselectively
provided the 2-arylation product in moderate to excellent yield
(30−93%). The reaction is compatible with a variety of
functional groups, such as oxo, nitro, ester, ether or halogen
substituents. Both electron-withdrawing (entries 3−12) and
electron-releasing (entries 13−19) aryl halides were found to
be reactive. Direct arylation of selenophene 1 is also successful
with heteroaryl bromides, such as 3-bromopyridine, to provide
the desired coupling product in 70% yield (entry 12). The
effect of steric hindrance at the aryl group was briefly evaluated.
Arylation occurred with 1-bromo-2-methylbenzene (entry 15)
in similar yield (65%) as with the para derivative (entry 13),
but no conversion was observed with 2-bromo-1,3,5-trimethyl-
a
Conditions: aryl halide (2a−s) (0.5 mmol, 1 equiv), 1 (3 equiv),
Pd(OAc)2 (4 mol %), PPh3 (16 mol %), PivOH (60 mol %), K2CO3
(1.5 mmol), DMF (5 mL), 100 °C for 24 h, N2. Isolated yields. 48 h.
b
c
benzene. Another relevant feature of this protocol is that,
surprisingly, aryl iodides react with 1 furnishing the desired
products in good to excellent yields (entries 2, 4, 7, 9, 11, 14,
17, and 19). These results are in contrast to earlier reports
about inhibition of such reactions due to catalyst poisoning by
the iodide anion in direct arylations.1g,15 Perhaps, in this
system, the selenophene ring (1) binds more effectivelyto Pd
and overcomes the deleterious effect of iodide anion
accumulation.16
In order to generate 2,5-diarylselenophenes, a more than 2-
fold excess of aryl iodide equivalents was used relative to
selenophene (1), and extended reaction times and increased
catalyst amounts were applied (Scheme 1). However, when the
reaction was performed using 3.3 equiv of aryl iodide, no
improvement on the yields were observed, and only trace of
direct triarylation of selenophene was found, suggesting that
this methodology is highly selective for arylation of 2,5
positions. The substituted diaryl selenophene derivatives 4a,
4b, and 4c were obtained by double direct arylation in suitable
yields. In addition, 2-arylated substrates can also undergo a
sequential regioselective direct arylation event. Thus, the
second reaction of 3b or 3k furnishes the interesting
unsymmetrical 2,5-diaryl selenophenes 4d, 4e, and 4f in
B
dx.doi.org/10.1021/jo500094t | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
Scheme 1. Synthesis of Symmetrical and Unsymmetrical 2,5-Diarylselenophenes
excellent yields (Scheme 1). As expected by previous studies,
about distortion−interaction analysis of the C−H bond
cleavage of a wide range of (hetero)aromatics through the
concerted metalation−deprotonation pathway (CMD),18a C2-
substituted aryl selenophenes were also more reactive than the
parent selenophene.
arylation implies that the arene C−H bond functionalization
would follow a CMD mechanism.
In an attempt to add additional insights into the reaction
pathway, an experiment using selenophene (1) and iodoben-
zene (2l) under optimized conditions was followed by 31P and
77Se NMR spectroscopy.11 For this purpose, all reagents were
added in an NMR tube at room temperature, and the two peaks
related to PPh3 (δ = −5.51 ppm) and (PPh3)2Pd(OAc)2 (δ =
25.51 ppm) (relative to 85% H3PO4) were quickly detected on
31P NMR spectroscopy (see the Support Information). After 15
min at room temperature, the 31P NMR spectrum also
displayed a narrow singlet at δ = 22.43 ppm for the four-
coordinate arylpalladium iodide complex (PPh3)2Pd(Ar)I,20
indicating a fast oxidative addition of PhI on the transient 14-
electron intermediate Pd(PPh3)2. The reaction was continued
for more than 24 h at 100 °C, and even after this time, the 31P
NMR spectrum did not present any additional signal, only
displaying the peak for (PPh3)2Pd(OAc)2 (δ= 25.51 ppm),
indicating that this complex is stable under these conditions.
Despite the excess of PPh3, the signal for free PPh3 is not
detected after longer reaction times, suggesting that PPh3 is
involved in at least one rapid equilibrium.21 By following the
reaction through 77Se NMR, we were only able to see the peak
relative to selenophene (1) (δ = 605.39 ppm) under the
reaction conditions, and after 24 h of reaction the peak of 2-
phenylselenophene (3a) (δ = 588.83 ppm) appeared, indicating
that other possible intermediates were formed faster than the
77Se NMR time scale.
Considering the importance and versatility of C−C cross-
coupling reactions via direct C−H activation, it is imperative to
develop a mechanistic understanding of these reactions for
different substrates. Several pathways have been proposed for
direct arylations.1d,17 The SEAr mechanism and concerted
metalation deprotonation (CMD) pathways have the strongest
experimental and theoretical support in reactions with π-
excessive aromatics. Previous studies on the mechanism of
direct arylations have highlighted the effect of a remote
substituent on the reactivity of C−H bonds,18 and since
selenophenes are known to react via SEAr in other reactions,19
an intermolecular competition experiment was performed to
determine which pathway was operative. Under the standard
conditions, 1.1 equiv of iodobenzene (2l) was reacted in the
presence of both electron-deficient 2-(4-nitrophenyl)-
selenophene (3b) and electron-rich 2-phenylselenophene
(3a) (Scheme 2).
Interestingly, it was seen in this intermolecular competition
experiment that the aryl iodide 2l reacted most readily with the
more electron-deficient 2-(4-nitrophenyl)selenophene (3b)
(4e:4a = 4:1), which is contrary to what would be expected
if SEAr was the acting mechanism. Furthermore, the crucial role
of pivalate as proton shuttle in this regioselective direct
On the basis of these results, a plausible reaction pathway is
illustrated in Scheme 3. The oxidative addition of aryl halide (X
= Br, I) to (PPh3)2Pd(0) forms the intermediate (PPh3)2Pd-
(Ar)X (A), which in the reaction with PivOK generates a κ2-
bound pivalate on the palladium metal (B). Selenophene can
displace one of the carboxylate oxygens and coordinate to the
metal center.13d,22 This species can then react with selenophene
through a CMD transition state (C) to give a biarylpalladium-
(II) species (D) that through reductive elimination gives 2-
arylated selenophenes and regenerates the catalyst.
Scheme 2. Competition Experiment and Product
Distribution for Direct Arylation of 2-Arylselenophenes
C
dx.doi.org/10.1021/jo500094t | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
column. HRMS spectra were obtained from a Fourier transform ion
cyclotron resonance (FT-ICR) mass spectrometer equipped with an
Infinity cell, a 7.0 T superconducting magnet, an RF-only hexapole ion
guide, and an external electrospray ion source (off axis spray) and with
ESI(+)-MS and tandem ESI(+)-MS/MS using a hybrid high-
resolution and high accuracy MicrOTOF-Q II mass spectrometer.
General Experimental Procedure I for the Palladium-
Catalyzed Direct 2-Arylation of Selenophene. A 25 mL screw-
cap vial containing a magnetic stirring bar was flame-dried under
vacuum and filled with nitrogen after cooling to room temperature. To
this vessel were added K2CO3 (1.5 mmol, 3 equiv), Pd(OAc)2 (4 mol
%), PPh3 (16 mol %), and PivOH (60 mol %). The aryl halide (0.5
mmol, 1 equiv) was added at this point if solid, and then DMF (0.1
M) and selenophene were added. The flask was placed in an oil bath
and heated to 100 °C with constant stirring over the indicated time.
After completion of the reaction, the resulting mixture was cooled to
room temperature, diluted with EtOAc, washed with saturated brine (3
× 20 mL) and water (20 mL), dried over Na2SO4, and filtered. The
residue obtained was purified by flash column chromatography over
silica gel (hexane/EtOAc = 98:2, unless otherwise indicated).
Scheme 3. Proposed Catalytic Cycle for the Direct Arylation
of Selenophenes
2-Phenylselenophene (3a).9b Yield: 96 mg (93%). White solid.
1
Mp: 56−58 °C. H NMR (400 MHz, CDCl3) δ (ppm): 7.92 (d, J =
5.6 Hz, 1H), 7.56 (d, J = 7.6 Hz, 2H), 7.45 (d, J = 3.8 Hz, 1H), 7.37−
7.25 (m, 4H). 13C NMR (100 MHz, CDCl3) δ (ppm): 150.8, 136.4,
130.6, 129.9, 128.9, 127.5, 126.3, 125.2. MS (EI, 70 eV): m/z 208
[M+].
CONCLUSION
■
In conclusion, an efficient palladium-catalyzed direct arylation
method for selenophene regioselective at the C-2 and
subsequently at the C-5-position has been developed. The
versatile method allows the synthesis of a large variety of 2-aryl
or symmetric 2,5-diarylselenophenes in one step in good to
excellent yields. The 2-arylated substrates can undergo an
additional arylation to furnish unsymmetric 2,5-diarylseleno-
phenes in good yields. The crucial role of the acid additive,
competition experiments, and 31P NMR studies are also in
agreement with a CMD mechanism.
2-(4-Nitrophenyl)selenophene (3b).22 Yield: 113 mg (90%).
Yellow solid. Mp: 142−145 °C. 1H NMR (400 MHz, CDCl3) δ
(ppm): 8.21 (d, J = 8.8 Hz, 2H), 8.11 (d, J = 5.6 Hz, 1H), 7.67 (d, J =
8.8 Hz, 2H), 7.64 (d, J = 3.8 Hz, 1H), 7.38 (dd, J = 3.9 and 5.6 Hz,
1H). 13C NMR (100 MHz, CDCl3) δ (ppm): 147.7, 146.2, 142.5,
133.2, 131.1, 128.0, 126.5, 124.4. MS (EI, 70 eV): m/z 253 [M+].
2-(4-Chlorophenyl)selenophene (3c).9b Yield: 77 mg (64%). Pale
green solid. Mp: 135−138 °C. 1H NMR (400 MHz, CDCl3) δ (ppm):
7.93 (d, J = 5.6 Hz, 1H), 7.46 (d, J = 8.4 Hz, 2H), 7.41 (d, J = 3.6 Hz,
1H), 7.30 (m, 3H). 13C NMR (100 MHz, CDCl3) δ (ppm): 149.3,
134.8, 130.6, 130.4, 129.1, 129.0, 127.5, 125.7. MS (EI, 70 eV): m/z
242 [M+].
EXPERIMENTAL SECTION
■
General Methods. All starting materials were purchased from
commercial suppliers and used without further purification. All
reactions were carried out under a nitrogen atmosphere in oven-
dried glassware with magnetic stirring. DMF (dimethylformamide),
DMA (dimethylacetamide), DMSO (dimethyl sulfoxide), and toluene
were dried, purified, and degassed under classical methods.1 Solvents
used in extraction and purification were distilled prior to use.
Phosphonium salts were obtained from commercial suppliers, stored
in a desiccator and used without further purification. Palladium sources
were stored in a desiccator and were weighed out to air unless
otherwise specified. Thin-layer chromatography (TLC) was performed
using silica gel 60 F254 aluminum sheets, and the visualization of the
spots has been done under UV light (254 nm) or stained with iodine
vapor. Products were purified by flash chromatography on silica gel 60
M, 230−400 mesh. Melting points were measured using an BX43
microscope equipped with a hot stage apparatus. HPLC analysis were
performed with a LiChroCART column LiChrospher C18 100 Å 5 μm
(i.d. 4 mm, length 125 mm) at 210 and 254 nm, 2−100% MeCN in
Methyl 4-(Selenophene-2-yl)benzoate (3d).23 Yield: 90 mg (68%).
White solid. Mp: 134−135 °C. 1H NMR (400 MHz, CDCl3) δ (ppm):
8.02 (d, J = 8.0 Hz, 2H), 8.02 (d, J = 5.2 Hz, 1H), 7.61 (d, J = 8.4 Hz,
2H), 7.57 (d, J = 3.6 Hz, 1H), 7.34 (dd, J = 5.6 and 3.9 Hz, 1H). 13C
NMR (100 MHz, CDCl3) δ (ppm): 166.7, 149.3, 140.6, 131.6, 130.8,
130.2, 128.8, 126.7, 126.0, 52.1. MS (EI, 70 eV): m/z 266 [M+].
HRMS (ESI, M+) calcd for C12H10O2Se+: [M + Na]+ 288.9744, found
[M + Na]+ 288.9739.
Methyl 3-(Selenophene-2-yl)benzoate (3e). Yield: 86 mg (65%).
1
White solid. Mp: 42−44 °C. H NMR (400 MHz, CDCl3) δ (ppm):
8.23 (s, 1H), 7.95 (m, 2H), 7.73 (d, J = 8.0 Hz, 1H), 7.53 (d, J = 4.0
Hz, 1H), 7.42 (t, J = 8.0 Hz, 1H), 7.33 (dd, J = 5.6 and 3.8 Hz, 1H),
3.94 (s, 3H). 13C NMR (100 MHz, CDCl3) δ (ppm): 166.7, 149.4,
136.7, 130.8, 130.7, 130.6, 130.5, 128.9, 128.4, 127.2, 126.0, 52.2. MS
(EI, 70 eV): m/z 266 [M+]. HRMS (ESI, M+) calcd for C12H10O2Se+:
[M + Na]+ 288.9744, found [M + Na]+ 288.9740.
1-(4-(Selenophene-2-yl)phenyl)ethanone (3f).9b Yield: 75 mg
(60%). White solid. Mp: 125−127 °C. 1H NMR (400 MHz,
CDCl3) δ (ppm): 8.03 (d, J = 5.5 Hz, 1H), 7.94 (d, J = 8.5 Hz,
2H), 7.63 (d, J = 8.5 Hz, 2H), 7.59 (d, J = 3.8 Hz, 1H), 7.35 (dd, J =
5.6 and 3.8 Hz, 1H), 2.60 (s, 3H). 13C NMR (100 MHz, CDCl3) δ
(ppm): 197.2, 149.2, 140.7, 135.8, 131.8, 130.8, 129.1, 126.8, 126.1,
26.5. MS (EI, 70 eV): m/z 250 [M+]. HRMS (ESI, M+) calcd for
C12H10OSe+: [M + Na]+ 272.9795, found [M + Na]+ 272.9795.
3-(Selenophene-2-yl)pyridine (3g). Yield: 73 mg (70%). Light
1
water over 20 min gradient, and hold at 100% MeCN for 5 min. H,
13C, 31P, and 77Se NMR spectra were recorded at 300 or 400, 75 or
100, 121, and 57 MHz on a magnetic resonance spectrometer using
CDCl3 as solvent unless stated. The H and 13C chemical shifts were
1
reported in parts per million (δ) referenced to residual solvent signals
at δH/C 7.26/77.00 (CDCl3) relative to tetramethylsilane (TMS) as
internal standard. 31P and 77Se NMR chemical shifts were reported in
parts per million (δ) referenced to 85% H3PO4 in D2O and diphenyl
diselenide in DMSO-d6, respectively. Coupling constants J (Hz) were
directly taken from the spectra and are not averaged. Splitting patterns
are designated as s (singlet), d (doublet), t (triplet), q (quartet), m
(multiplet), and br (broad). Low-resolution mass spectra were
obtained with a GC−MS-QP5050 mass spectrometer interfaced with
a GC-17A gas chromatograph equipped with a DB-17 MS capillary
1
brown oil. H NMR (400 MHz, CDCl3) δ (ppm): 8.83 (s, 1H), 8.51
(s, 1H), 8.03 (d, J = 5.6 Hz, 1H), 7.87 (d, J = 8.0 Hz, 1H), 7.53 (d, J =
3.8 Hz, 1H), 7.35 (m, 2H). 13C NMR (100 MHz, CDCl3) δ (ppm):
147.4, 146.3, 145.8, 134.1, 132.8, 131.8, 130.8, 126.1, 124.0. MS (EI,
70 eV): m/z 209 [M+]. HRMS (ESI, M+) calcd for C9H7NSe+ [M +
H]+ 209.9822, found [M + H]+ 209.9820.
D
dx.doi.org/10.1021/jo500094t | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
2-(p-Tolyl)selenophene (3h).9b Yield: 63 mg (57%). White solid.
Mp: 27−30 °C. H NMR (400 MHz, CDCl3) δ (ppm): 7.87 (d, J =
temperature, diluted with EtOAc, washed with saturated brine (3 × 20
mL) and water (20 mL), dried over Na2SO4, and filtered. The residue
obtained was purified by flash column chromatography over silica gel
(hexane/EtOAc = 96:4).
1
5.6 Hz, 1H), 7.44 (d, J = 8.0 Hz, 2H), 7.40 (d, J = 3.7 Hz, 1H), 7.28
(m, 1H), 7.15 (d, J = 7.9 Hz, 2H), 2.33 (s, 3H). 13C NMR (100 MHz,
CDCl3) δ (ppm): 149.4, 137.4, 133.6, 129.6, 128.9, 127.5, 125.9,
125.6, 21.2. MS (EI, 70 eV): m/z 222 [M+].
2-(4-Nitrophenyl)-5-(p-tolyl)selenophene (4d).25 Yield: 298 mg
1
(87%). Yellow solid. Mp: Cr 180.6 °C, N 193.7 °C I. H NMR (300
2-(o-Tolyl)selenophene (3i).9b Yield: 72 mg (65%). Colorless oil.
1H NMR (400 MHz, CDCl3) δ (ppm): 8.00 (d, J = 5.6 Hz, 1H), 7.38
MHz, CDCl3) δ (ppm): 8.25 (d, J = 8.9 Hz, 2H), 7.71−7.63 (m, 4H),
7.50 (d, J = 8.2 Hz, 2H), 7.23 (d, J = 7.9 Hz, 2H), 2.40 (s, 3H). 13C
NMR (75 MHz, CDCl3) δ (ppm): 153.6, 145.7, 142.5, 138.5, 132.9,
129.8, 129.2, 129.1, 126.2, 126.1, 124.5, 21.3. MS (EI, 70 eV): m/z 343
[M+]. HRMS (ESI, M+) calcd for C17H13NO2Se+: [M + H]+ 344.0190,
found [M + H]+ 344.0189.
(d, J = 6.7 Hz, 1H), 7.31 (m, 1H), 7.21 (m, 4H), 2.41 (s, 3H). 13C
NMR (100 MHz, CDCl3) δ (ppm): 149.4, 136.2, 135.6, 130.7, 130.6,
130.5, 129.6, 128.5, 127.7, 125.8, 21.2. MS (EI, 70 eV): m/z 222 [M+].
2-(3-Methoxyphenyl)selenophene (3j).24 Yield: 82 mg (69%).
Colorless oil. 1H NMR (400 MHz, CDCl3) δ (ppm): 7.92 (d, J = 5.6
Hz, 1H), 7.45 (d, J = 3.8 Hz, 1H), 7.31−7.22 (m, 2H), 7.15 (d, J = 7.8,
1H), 7.01 (s, 1H), 6.83 (dd, J = 8.2 and 2.4, 1H), 3.83 (s, 3H). 13C
NMR (100 MHz, CDCl3) δ (ppm): 159.9, 150.6, 137.7, 130.5, 130.1,
129.8, 125.4, 119.0, 112.9. 112.0, 55.3. MS (EI, 70 eV): m/z 238 [M+].
HRMS (ESI, M+) calcd for C11H10OSe+ [M + H]+ 238.9975, found
[M + H]+ 238.9971.
2-(4-Nitrophenyl)-5-phenylselenophene (4e).6 Mp: 208−210 °C.
1H NMR (300 MHz, CDCl3) δ (ppm): 8.22 (d, J = 8.9, 2H), 7.69−
7.57 (m, 5H), 7.50 (d, J = 4.1 Hz, 1H), 7.24−7.33 (m, 3H). 13C NMR
(75 MHz, CDCl3) δ (ppm): 165.0, 153.4, 146.7, 146.4, 142.5, 135.7,
129.1, 128.4, 126.6, 126.2, 126.1, 124.4. MS (EI, 70 eV): m/z 329
[M+]. HRMS (ESI, M+) calcd for C16H11NO2Se+: [M + H]+ 330.0033,
found [M + H]+ 330.0031.
2-(4-Methoxyphenyl)-5−4-(nitrophenyl)selenophene (4f).25 Mp:
2-(4-Methoxyphenyl)selenophene (3k).,24 Yield: 56 mg (47%).
White solid. Mp: 107−109 °C. 1H NMR (400 MHz, CDCl3) δ (ppm):
7.84 (d, J = 5.6 Hz, 1H), 7.48 (d, J = 8.7 Hz, 2H), 7.33 (d, J = 3.7 Hz,
1H), 7.27 (dd, J = 5.6 and 3.8, 1H), 6.88 (d, J = 8.7 Hz, 2H), 3.80 (s,
3H). 13C NMR (100 MHz, CDCl3) δ (ppm): 159.2, 150.6, 130.5,
128.8, 127.7, 127.5, 124.1, 114.2, 55.3. MS (EI, 70 eV): m/z 238 [M+].
General Experimental Procedure II for the Palladium-
Catalyzed Direct 2,5-Arylation of Selenophene. A 50 mL
screw-cap vial containing a magnetic stirring bar was flame-dried
under vacuum and filled with nitrogen after cooling to room
temperature. To this vessel were added K2CO3 (2.2 equiv), Pd(OAc)2
(8 mol %), PPh3 (32 mol %), and PivOH (60 mol %). The aryl halide
(2.2 equiv) was added at this point if solid. After, DMF (0.1 M) and
selenophene (1 equiv) were added. The flask was placed in an oil bath
and heated to 100 °C with constant stirring over the indicated time.
After completion of the reaction, the resulting mixture was cooled to
room temperature, diluted with EtOAc, washed with saturated brine (3
× 30 mL) and water (30 mL), dried over Na2SO4, and filtered. The
residue obtained was purified by flash column chromatography over
silica gel (hexane/EtOAc = 95:5, unless otherwise indicated).
2-Diphenylselenophene (4a).9b Yield: 511 mg (60%). White solid.
Mp: 172−173 °C. 1H NMR (400 MHz, CDCl3) δ (ppm): 7.56 (d, J =
7.3 Hz, 4H), 7.44 (s, 2H), 7.36 (t, J = 7.5 Hz, 4H), 7.27 (t, J = 7.3 Hz,
2H). 13C NMR (100 MHz, CDCl3) δ (ppm): 149.8, 136.3, 128.9,
127.6, 126.2, 126.0. MS (EI, 70 eV): m/z 284 [M+].
1
Cr 170.2 °C, N 220.0 °C I. H NMR (300 MHz, CDCl3) δ (ppm):
8.15 (d, J = 8.9, 2H), 7.58 (d, J = 8.9, 2H), 7.53 (d, J = 4.1 Hz, 1H),
7.45 (d, J = 8.8, 2H), 7.31 (d, J = 4.1, 1H), 6.86 (d, J = 8.8, 2H), 3.78
(s, 3H). 13C NMR (75 MHz, CDCl3) δ (ppm): 159.9, 153.4, 145.2,
142.6, 129.2, 128.6, 127.6, 127.5, 125.9, 125.5, 124.5, 114.5, 55.4. MS
(EI, 70 eV): m/z 359 [M+]. HRMS (ESI, M+) calcd for
C17H13NO3Se+: 359.0061, found 359.0094.
ASSOCIATED CONTENT
■
S
* Supporting Information
Complete set of conditions for the reaction optimization,
1
competition experiment, and H, 13C, and 31P NMR spectra of
compounds 3 and 4. This material is available free of charge via
the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: paulos@iq.ufrgs.br.
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
2,5-Bis(3-methoxyphenyl)selenophene (4b). Yield: 556 mg (54%).
We are grateful to CAPES, CNPq, INCT-CMN, and
FAPERGS for financial and technical support. Furthermore,
CNPq is acknowledged for a Ph.D. fellowship to D.S.R.
1
Pale orange solid. Mp: 73−74 °C. H NMR (400 MHz, CDCl3) δ
(ppm): 7.44 (s, 2H), 7.29 (t, J = 7.9 Hz, 2H), 7.16 (d, J = 7.8 Hz, 2H),
7.10 (m, 2H), 6.84 (dd, J = 8.2 and 2.0 Hz, 2H), 3.86 (s, 6H). 13C
NMR (100 MHz, CDCl3) δ (ppm): 160.0, 149.7, 137.6, 129.9, 126.3,
118.7, 113.1, 111.7, 55.3.MS (EI, 70 eV): m/z 344 [M+]. HRMS (ESI,
M+) calcd for C18H16O2Se+ [M + H]+ 345.0394, found [M + H]+
345.0383.
REFERENCES
■
(1) (a) Lyons, T. W.; Sanford, M. S. Chem. Rev. 2010, 110, 1147.
(b) Ackermann, L.; Vicente, R.; Kapdi, A. R. Angew. Chem., Int. Ed.
2009, 48, 9792. (c) Chen, X.; Engle, K. M.; Wang, D.-H.; Yu, J.-Q.
Angew. Chem., Int. Ed. 2009, 48, 5094. (d) Ackermann, L. Chem. Rev.
2011, 111, 1315. (e) Campeau, L.-C.; Stuart, D. R.; Fagnou, K.
Aldrichimica Acta 2007, 40, 35. (f) Seregina, I. V.; Gevorgyan, V. Chem.
Soc. Rev. 2007, 36, 1173. (g) Campeau, L.-C.; Fagnou, K. Chem.
Commun. 2006, 1253. (h) Alberico, D.; Scott, M. E.; Lautens, M.
Chem. Rev. 2007, 107, 174.
Dimethyl 3,3′-(Selenophene-2,5-diyl)dibenzoate (4c). Yield: 743
mg (62%). Green solid. Mp: 119−120 °C. 1H NMR (400 MHz,
CDCl3) δ (ppm): 8.23 (s, 2H), 7.95 (d, J = 7.7 Hz, 2H), 7.73 (d, J =
7.8 Hz, 2H), 7.53 (s, 2H), 7.44 (t, J = 7.8 Hz, 2H), 3.95 (s, 6H). 13C
NMR (100 MHz, CDCl3) δ (ppm): 166.6, 149.1, 136.4, 130.9, 130.2,
129.0, 128.6, 127.0, 126.9, 52.2. MS (EI, 70 eV): m/z 400 [M+].
HRMS (ESI, M+) calcd for C20H16O4Se+ [M + Na]+ 423.0112, found
[M + Na]+ 423.0112.
General Experimental Procedure III for the Synthesis of
Unsymmetrical 2,5-Diarylselenophenes. A 25 mL screw-cap vial
containing a magnetic stirring bar was flame-dried under vacuum and
filled with nitrogen after cooling to room temperature. To this vessel
were added K2CO3 (1.1 equiv), Pd(OAc)2 (4 mol %), PPh3 (16 mol
%), and PivOH (60 mol %). The aryl halide (1.1 equiv) was added at
this point. After, DMF (0.1 M) and 2-(4-nitrophenyl)selenophene
(3b) (1 equiv) were added. The flask was placed in an oil bath and
heated to 100 °C with constant stirring over the indicated time. After
completion of the reaction, the resulting mixture was cooled to room
(2) Espinet, P.; Echavarren, E. M. Angew. Chem., Int. Ed. 2004, 43,
4704.
(3) Suzuki, A. Angew. Chem., Int. Ed. 2011, 50, 6722.
(4) Negishi, E.-I. Angew. Chem., Int. Ed. 2011, 50, 6738.
́
(5) (a) Liegault, B.; Lapointe, D.; Caron, L.; Vlassova, A.; Fagnou, K.
J. Org. Chem. 2009, 74, 1826. (b) Guchhait, S. K.; Kandekar, S.;
Kashyap, M.; Taxak, N.; Bharatam, P. V. J. Org. Chem. 2012, 77, 8321.
(c) Ueda, K.; Yanagisawa, S.; Yamaguchi, J.; Itami, K. Angew. Chem.,
Int. Ed. 2010, 49, 8946. (d) Reddy, V. P.; Qiu, R.; Iwasaki, T.; Kambe,
N. Org. Lett. 2013, 15, 1290. (e) Bensaid, S.; Roger, J.; Beydoun, K.;
Roy, D.; Doucet, H. Synth. Commun. 2011, 41, 3524. (f) Campeau, L.-
E
dx.doi.org/10.1021/jo500094t | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
C.; Rousseaux, S.; Fagnou, K. J. Am. Chem. Soc. 2005, 127, 18020.
(g) Campeau, L.-C.; Stuart, D. R.; Leclerc, J.-P.; Bertrand-Laperle, M.;
Villemure, E.; Sun, H.-Y.; Lasserre, S.; Guimond, N.; Lecavallier, M.;
Chem.Eur. J. 2007, 13, 792. (c) Campeau, L.-C.; Parisien, M.;
Leblanc, M.; Fagnou, K. J. Am. Chem. Soc. 2004, 126, 9186.
(d) Lafrance, M.; Lapointe, D.; Fagnou, K. Tetrahedron. 2008, 64,
6015. (e) Engle, K. M.; Wang, D.-H.; Yu, J.-Q. J. Am. Chem. Soc. 2010,
132, 14137. (f) Zhuravlev, F. A. Tetrahedron Lett. 2006, 47, 2929.
(14) (a) Biswas, B.; Sugimoto, M.; Sakaki, S. Organometallics 2000,
Fagnou, K. J. Am. Chem. Soc. 2009, 131, 3291. (h) Carrer, A.; Brinet,
̈
D.; Florent, J.-C.; Rousselle, P.; Bertounesque, E. J. Org. Chem. 2012,
77, 1316. (i) Chen, L.; Bruneau, C.; Dixneuf, P. H.; Doucet, H. Green
Chem. 2012, 14, 1111. (j) Fu, H. Y.; Chen, L.; Doucet, H. J. Org. Chem.
2012, 77, 4473. (k) Yokooji, A.; Satoh, T.; Miura, M.; Nomura, M.
Tetrahedron. 2004, 60, 6757. (l) Tamba, S.; Okubo, Y.; Tanaka, S.;
Monguchi, D.; Mori, A. J. Org. Chem. 2010, 75, 6998. (m) Tamba, S.;
Fuji, R.; Mori, A.; Hara, K.; Koumura, N. Chem. Lett. 2011, 40, 922.
(n) Do, H.-Q.; Khan, R. M. K.; Daugulis, O. J. Am. Chem. Soc. 2008,
130, 15185.
́
19, 3895. (b) Rene, O.; Fagnou, K. Adv. Synth. Catal. 2010, 352, 2116.
(15) (a) Campeau, L.-C.; Parisien, M.; Jean, A.; Fagnou, K. J. Am.
Chem. Soc. 2006, 128, 581. (b) Leclerc, J.-P.; Fagnou, K. Angew. Chem.,
Int. Ed. 2006, 46, 7781. (c) Wang, J.-X.; McCubbin, J. A.; Jin, M.;
Laufer, R. S.; Mao, Y.; Crew, A. P.; Mulvihill, M. J.; Snieckus, V. Org.
Lett. 2008, 10, 2923.
(16) Amatore, C.; Jutand, A. Acc. Chem. Res. 2000, 33, 314.
(17) Gallego, G. M.; Sierra, M. A. Chem. Rev. 2011, 111, 4857.
(18) (a) Gorelsky, S. I.; Lapointe, D.; Fagnou, K. J. Org. Chem. 2012,
77, 658. (b) Lane, B. S.; Brown, M. A.; Sames, D. J. Am. Chem. Soc.
2005, 127, 8050.
(19) (a) Lebedev, M. V.; Nenajdenko, V. G.; Balenkova, E. S.
Synthesis 1998, 89. (b) Cyranski, M. K.; Krygowski, T. M. Topics in
Heterocyclic Chemistry: Aromaticity in Heterocyclic Compounds; Spring-
er: Heidelberg, 2009. (c) Umezawa, S. Bull. Chem. Soc. Jpn. 1936, 11,
775. (d) Yur’ev, Yu. K.; Zaitseva, E. L.; Rozantsev, G. G. Zh. Obshch.
Khim. 1960, 30, 2207. (e) Kim, K.; Jo, C.; Easwaramoorthi, S.; Sung,
J.; Kim, D. H.; Churchill, D. G. Inorg. Chem. 2010, 49, 4881. (f) Arena,
G.; Cali, R.; Maccarone, E.; Passerini, A. J. Chem. Soc., Perkin Trans. 2
1993, 1941.
(6) (a) Rhoden, C. R. B.; Zeni, G. Org. Biomol. Chem. 2011, 9, 1301.
(b) Beletskaya, I. P.; Ananikov, V. P. Chem. Rev. 2011, 111, 1596.
(7) (a) Nogueira, C. W.; Zeni, G.; Rocha, J. B. T. Chem. Rev. 2004,
104, 6255. (b) Mugesh, G.; du Mont, W.-W.; Sies, H. Chem. Rev. 2001,
101, 2125. (c) Nascimento, V.; Alberto, E. E.; Tondo, D. W.;
Dambrowski, D.; Detty, M. R.; Nome, F.; Braga, A. L. J. Am. Chem.
Soc. 2012, 134, 138. (d) Shabaan, S.; Ba, L. A.; Abbas, M.; Burkholz,
T.; Denkert, A.; Gohr, A.; Wessjohann, L. A.; Sasse, F.; Weber, W.;
Jacob, C. Chem. Commun. 2009, 4702. (e) Doering, M.; Ba, L. A.;
Lilienthal, N.; Nicco, C.; Scherer, C.; Abbas, M.; Zada, A. L. P.; Coriat,
R.; Burkholz, T.; Wessjohann, L. A.; Diederich, M.; Batteux, F.;
Herling, M.; Jacob, C. J. Med. Chem. 2010, 53, 6954.
(8) (a) Kim, B.; Yeom, H. R.; Yun, M. H.; Kim, J. Y.; Yang, C.
Macromolecules 2012, 45, 8658. (b) Gao, D.; Hollinger, J.; Seferos, D.
S. ACS Nano 2012, 6, 7114. (c) Edmund, F.; McNeil, P.; McNeil, A. J.
Macromolecules 2012, 45, 5948. (d) Haid, S.; Mishra, A.; Uhrich, C.;
(20) (a) Amatore, C.; Pfluger, F. Organometallics 1990, 9, 2276.
̈
(b) Fauvarque, J.-F.; Pfluger, F. J. Organomet. Chem. 1981, 208, 419.
̈
(c) Amatore, C.; Azzabi, M.; Jutand, A. J. Am. Chem. Soc. 1991, 113,
8375. (d) Negishi, E.-I.; Takahashi, T.; Akiyoshi, K. J. Chem. Soc.,
Chem. Commun. 1986, 1338.
Pfeiffer, M.; Bauerle, P. Chem. Mater. 2011, 23, 4435. (e) Okamoto,
̈
T.; Kudoh, K.; Wakamiya, A.; Yamaguchi, S. Org. Lett. 2005, 7, 5301.
(f) Takimiya, K.; Kunugi, Y.; Konda, Y.; Ebata, H.; Toyotakimia, Y.;
Otsubo, T. J. Am. Chem. Soc. 2006, 128, 3044. (g) Patra, A.; Wijsboom,
Y. H.; Leitus, G.; Bendikov, M. Chem. Mater. 2011, 23, 896. (h)
Handbook of Thiophene-based Materials; Perepichka, I. F., Perepichka,
D. F., Eds.; Wiley-VCH: Weinheim, 2009. (i) Rampon, D. S.;
(21) Amatore, C.; Carre,
metallics 1995, 14, 1818.
́
E.; Jutand, A.; M’Barki, M. R. Organo-
(22) (a) Gronowitz, S.; Johnson, I.; Hornfeldt, A. B. Chem. Scr. 1975,
7, 111. (b) Ng, S.-C.; Xu, L. Adv. Mater. 1998, 18, 1525.
(23) Matyushecheva, G. I.; Tolmachev, A. I.; Shulezhko, A. A.;
Shulezhko, L. M.; Yagupolskii, L. M. Zh. Obshch. Khim. 1976, 46, 162.
(24) Fringuelli, F.; Serena, B.; Taticchi, A. J. Am. Chem. Soc., Perkin
Trans. 2 1980, 7, 971.
Rodembusch, F. S.; Schneider, J. M. F. M.; Bechtold, I. H.; Gonca̧ lves,
P. F. B.; Merlo, A. A.; Schneider, P. H. J. Mater. Chem. 2010, 20, 715.
(j) Mei, J.; Diao, Y.; Appleton, A. L.; Fang, L.; Bao, Z. J. Am. Chem. Soc.
2013, 135, 6724.
(25) Prim, D.; Joseph, D.; Kirsch, G. Phosphorus, Sulfur Silicon Relat.
Elem. 1994, 1−4, 137.
(9) (a) Prediger, P.; Brandao, R.; Nogueira, C. W.; Zeni, G. Eur. J.
̃
Org. Chem. 2007, 5422. (b) Prediger, P.; Moro, A. V.; Nogueira, C. W.;
Savegnago, L.; Menezes, P. H.; Rocha, J. B. T.; Zeni, G. J. Org. Chem.
2006, 71, 3786. (c) Barros, O. S. R.; Nogueira, C. W.; Stangherlin, E.
C.; Menezes, P. H.; Zeni, G. J. Org. Chem. 2006, 71, 1552. (d) Barros,
O. S. R.; Favero, A.; Nogueira, C. W.; Menezes, P. H.; Zeni, G.
Tetrahedron Lett. 2006, 47, 2179. (e) Schumacher, R. F.; Alves, D.;
Brandao, R.; Nogueira, C. W.; Zeni, G. Tetrahedron Lett. 2005, 46,
̃
2647. (f) Schumacher, R. F.; Alves, D.; Brandao, R.; Nogueira, C. W.;
̃
Zeni, G. Tetrahedron Lett. 2008, 49, 538. (g) Alghamdi, A. A. B.;
Watters, D. C.; Yi, H.; Al-Faifi, S.; Almeataq, M. S.; Coles, D.;
Kingsley, J.; Lidzey, D. G.; Iraqi, A. J. Mater. Chem. A 2013, 1, 5165.
(h) Stedt, T.; Frejd, T. Organometallics 1983, 5, 598. (i) Takahashi, K.;
Gunji, A. Heterocycles 1996, 43, 941. (j) Shabana, R.; Galal, A.; Mark,
H. B., Jr.; Zimmer, H.; Gronowitz, S.; Hornfeldt, A.-B. Phosphorus,
̈
Sulfur Silicon Relat. Elem. 1990, 239.
(10) (a) Rampon, D. S.; Rodembusch, F. S.; Lourega, R.; Gonca̧ lves,
P. F. B.; Merlo, A. A.; Schneider, P. H. J. Braz. Chem. Soc. 2010, 21,
2100. (b) Rampon, D. S.; Giovenardi, R.; Silva, T. L.; Rambo, R. S.;
Merlo, A. A.; Schneider, P. H. Eur. J. Org. Chem. 2011, 7066.
(c) Radatz, C. S.; Alves, D.; Schneider, P. H. Tetrahedron 2013, 28,
1316. (d) Schwab, R. S.; Schneider, P. H. Tetrahedron 2012, 23, 10499.
(e) Abbas, M.; Wessjohann, L. A. Org. Biomol. Chem. 2012, 10, 9330.
(11) See the Supporting Information for details.
(12) (a) Bilbrey, J. A.; Kazez, A. H.; Locklin, J.; Allen, W. D. J.
Comput. Chem. 2013, 34, 1189. (b) Tolman, C. A. Chem. Rev. 1977,
77, 313.
(13) (a) Yanagisawa, S.; Sudo, T.; Noyori, R.; Itami, K. J. Am. Chem.
Soc. 2006, 128, 11748. (b) Hitce, J.; Retailleau, P.; Baudoin, O.
F
dx.doi.org/10.1021/jo500094t | J. Org. Chem. XXXX, XXX, XXX−XXX