Transition-Metal-Free Iodine Catalyzed Selenocayanation of Styrenyl Bromides and an Easy Access to Benzoselenophenes via Intermediacy of Styrenyl Selenocyanate

Article abstract of DOI:10.1021/acs.orglett.7b02571

A convenient procedure has been developed for the synthesis of styrenyl selenocyanates and benzoselenophenes from readily available styrenyl bromides by reaction with potassium selenocyanate in the presence of iodine under specified conditions. A series of both compounds have been obtained by this procedure. The synthesis of styrenyl selenocyanates has not been previously reported, and thus this method is of much significance.

Full text of DOI:10.1021/acs.orglett.7b02571

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX-XXX
Transition-Metal-Free Iodine Catalyzed Selenocayanation of Styrenyl
Bromides and an Easy Access to Benzoselenophenes via
Intermediacy of Styrenyl Selenocyanate
Pintu Maity, Bidisha Paroi, and Brindaban C. Ranu*
Department of Organic Chemistry, Indian Association for the Cultivation of Science, Jadavpur, Kolkata 700032, India
S
* Supporting Information
ABSTRACT: A convenient procedure has been developed for the synthesis of styrenyl selenocyanates and benzoselenophenes
from readily available styrenyl bromides by reaction with potassium selenocyanate in the presence of iodine under specified
conditions. A series of both compounds have been obtained by this procedure. The synthesis of styrenyl selenocyanates has not
been previously reported, and thus this method is of much significance.
Scheme 1. Iodine Catalyzed Selenocyanation of Styrenyl
Bromides
he organoselenium compounds, in general, are of
Tconsiderable interest because of their potential biological
activities, such as antiviral, antihypertensive, antioxidant,
antimicrobial, and antitumor properties.1 Interestingly, among
organoselenium compounds, the selenocyanate derivatives
showed promising chemoprevention for certain types of cancer.2
Besides possessing good chemopreventive properties the
organo-selenocyanates are found to be useful antioxidants.3They
They also play an important role as intermediates in organic
synthesis4 and have useful applications in material science and
nanotechnology.5 Thus, development of efficient synthetic
methods for the organo-selenocyanates is of much significance.
However, the procedures for selenocyanation are limited.6
Traditionally, the aliphatic selenocyanates are prepared from the
corresponding bromides by reaction with potassium selenocya-
nate in dry acetone at room temperature.6 However, this
protocol is not effective for vinyl halides; they are obtained by the
reaction of vinyl selenolate with cyanogen bromide.7 A few
procedures are also available for the selenocyanation of aromatic
compounds using SeO2/CNCH2CN or CAN/KSeCN systems.
Recently, a N-iodosuccinimide catalyzed oxidative selenocyana-
tion of electron-rich arenes has been reported.8 Surprisingly, to
the best of our knowledge, selenocyanation of styrenyl
derivatives has not been addressed in any report, although
styrenyl selenocyanates having more functionality might be of
potential to material and drug development. This led us to
develop an effective and general approach for the synthesis of
styrenyl selenocyanates, and we report here a molecular iodine
(I2) catalyzed efficient selenocyanation of styrenyl bromides with
KSeCN in the absence of any transition metal (Scheme 1a).
Interestingly, it was observed that if the reaction is continued for
a longer time with electron-donating group substituted styrenyl
bromides, the corresponding benzoselenophenes are formed in
one pot (Scheme 1b).
The benzoselenophenes have received considerable interest,
as they have useful applications in the pharmaceutical industry9
and materials science.10 The general approach to their synthesis
involves cyclization of an alkynyl arene bearing an ortho-selenium
functional group.11 Besides Larock’s electrophilic cyclization11a,b
and Nakamura’s alkynophilic metal (Au or Pt) catalyzed
cyclization,12 a few other routes, particularly the reaction of α-
haloethynylbenzene and sodium selenide,13 cyclization of
arylalkynes under selenobromination conditions combined
with an acid induced 3,2-aryl shift,14 and copper catalyzed C−
Se coupling/cyclization of ortho-alkenyl-aryl iodide,15 are
noteworthy. However, all these procedures involve tedious
multistep preparation of the starting alkyne derivatives. In
contrast, our strategy constitutes a one-pot reaction using
commercially available chemicals.
To optimize the reaction conditions, a series of experiments
were performed with variation in catalyst, solvent, temperature,
and time for a representative reaction of (E)-1-(2-bromovinyl)-
4-methylbenzene and potassium selenocyanate (KSeCN) to
obtain (E)-1-methyl-4-(2 selenocyanatovinyl)benzene. The
results are summarized in Table 1. After careful screening of
Received: August 25, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b02571
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Organic Letters
Letter
a
Table 1. Optimization of Reaction Conditions
Scheme 2. Iodine Catalyzed Selenocyanation of Styrenyl
a b
,
Bromides
b
entry
catalyst (mol %)
solvent
temp (°C) time (h) yield (%)
1
I2 (20)
I2 (20)
I2 (20)
I2 (20)
I2 (20)
I2 (20)
NaI (20)
PhI(OAc)2 (20)
−
I2 (20)
I2 (20)
I2 (20)
I2 (20)
I2 (20)
I2 (30)
I2 (15)
I2 (20)
I2 (20)
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMF
110
110
110
110
100
90
12
18
24
30
24
24
24
24
24
24
24
24
24
24
24
24
24
24
45
53
70
65
75
60
−
2
3
4
5
6
7
100
100
100
100
100
100
100
100
100
100
100
100
8
−
−
9
10
11
12
13
14
15
16
63
55
35
53
trace
67
69
73
65
NMP
dioxane
CH3CN
toluene
DMSO
DMSO
DMSO
DMSO
c
17
d
18
a
Reaction conditions: a mixture of (E)-1-(2-bromovinyl)-4-methyl-
benzene (1.0 mmol), KSeCN (1.2 mmol), and catalyst (20 mol %) in
b
dry DMSO (2.5 mL) was heated under argon. Yield of isolated
c
d
products. KSeCN (1.5 mmol). KSeCN (1.0 mmol).
a
the reaction conditions it was found that the best yield was
obtained using 20 mol % I2 in DMSO (dimethyl sulfoxide) at 100
°C for 24 h (Table 1, entry 5, highlighted). The use of other
iodonium salts such as sodium iodide (NaI) and phenyl-
iodoniumdiacetate (PhI(OAc)2) did not produce any product
(Table 1, entries 7 and 8). The use of other solvents such as
DMF, NMP, dioxane, and CH3CN provided a relatively low
yield, whereas toluene is not effective (Table 1, entries 10−14).
The reactions are less efficient when they are performed at higher
(110 °C) and lower temperature (90 °C) than 100 °C (Table 1,
entries 3 and 6). Heating at 100 °C for 24 h is optimum to obtain
the best yield (Table 1, entries 1−2 and 4). The reaction did not
occur in the absence of I2 (Table 1, entry 9). The amount of
catalyst (I2) loading was optimized to 20 mol %. The use of 30
and 15 mol % produced lower yields (Table 1, entries 15 and 16).
The reaction did not provide a better result using 1.5 and 1.0
equiv of KSeCN in place of 1.2 equiv (Table 1, entries 17 and
18).
With the optimized conditions in hand, we next turned our
attention toward exploring the scope of this reaction (Scheme 2).
The unsubstituted and alkyl substituted (E)-(2-bromovinyl)-
benzene underwent a clean reaction to produce the correspond-
ing styrenyl selenocyanates (Scheme 2, 1−7) in good yields.
Halogen (I, Br, Cl, and F) substituted styrenyl bromides also
provided the corresponding products (Scheme 2, 9−14, 23, 26,
29, and 32) under these conditions. The reaction is highly
chemoselective, as the halogens (I, Br, Cl, and F) on the aromatic
ring remained intact, and these can be used for further
functionalization. Trifluoromethyl (CF3), oxytrifluoromethyl
(OCF3), and strong electron-withdrawing group (NO2 and
CO2Me) substituted styrenyl bromides participated in this
reaction to afford the selenocyanated products (Scheme 2, 15−
18). The electron-donating group (OMe) substituted styrenyl
bromide produced the corresponding selenocyanate (8)
Reaction conditions: a mixture of styrenyl bromide (1.0 mmol),
KSeCN (1.2 mmol), and iodine (20 mol %) in dry DMSO (2.5 mL)
was heated at 100 °C (90 °C for alkoxy and benzyloxy protected vinyl
b
bromides) under argon for 24 h. Yield of isolated products.
together with a small amount (∼5%) of 4-methoxy benzosele-
nophene under the standardized reaction conditions. However, if
the reaction is performed at 90 °C the corresponding electron-
releasing group substituted selenocyantes (Scheme 2, 21−32)
were obtained as sole products. This reaction is also applicable to
naphthalene derivatives, (E)-2-(2-bromovinyl)naphthalene and
(E)-1-(2-bromovinyl)naphthalene, to furnish the products
(Scheme 2, 19 and 20) in good yields. Heteroarene (thiophene)
vinyl bromides reacted under this procedure to produce the
corresponding products (Scheme 2, 33 and 34) in moderate
yields.
As mentioned above, a small amount of benzoselenophene
was formed in the reaction of electron-rich styrenyl bromides
under standardized conditions. However, if the reaction is
continued at 110 °C for 42 h benzoselenophenes are obtained as
only products. A series of electron-rich benzoselenophenes
(Scheme 3, 35−55) has been synthesized from the correspond-
ing styrenyl bromides bearing methoxy, dimethoxy, trimethoxy,
ethoxy, butyloxy, pentyloxy, dodecyloxy, and allyloxy groups on
the benzene rings and the details were summarized in Scheme 3.
Iodo- and bromo-containing electron-rich styrenyl bromides also
underwent reactions by this procedure to provide the
selenophenes with the iodo and bromo group unaffected
(Scheme 3, 50−54, 57−60). Benzyloxy protected styrenyl
bromides furnished the corresponding products without any
difficulty (Scheme 3, 56−60). These electron-rich benzoseleno-
phenes are useful precursors to biologically important molecules
and have been synthesized earlier using a multistep procedure14
in contrast to our single step one.
B
DOI: 10.1021/acs.orglett.7b02571
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Organic Letters
Letter
Scheme 3. Iodine Catalyzed Synthesis of Benzoselenophenes
from Styrenyl Bromides and Potassium Selenocyanate
Scheme 4. Cyclization without any Strong Electronic and
Steric Influence of the Substituent
a b
,
NMR spectral data in analogy with those of 54. Notably, the N-
iodosuccinimide catalyzed oxidative selenocyanation method8
did not work for styrenyl bromides in our hands, and this is the
first report of a general method for the synthesis of styrenyl
selenocyanates.
The importance of styrenyl selenocyanate as a useful synthon
has been demonstrated by the transformation of 4-methoxystyr-
enyl selenocyanate to styrenyl diselenide and en-ynyl selenide by
two different reactions (see Scheme S1 in SI).
To understand the reaction mechanism, we turned our
attention toward finding the intermediate and nature of the
reaction pathway (radical/ionic). As mentioned above, the
reaction of styrenyl bromide and KSeCN in the presence of I2 for
24 h produced styrenyl selenocyanate, whereas continuation for a
longer time furnished benzoselenophene. Thus, it is likely that
selenocyanate is an intermediate to benzoselenophene. To
establish this hypothesis a separate reaction was performed
starting with selenocyante under the same conditions, and it was
found that benzoselenophene was formed exclusively. A kinetic
study of the reaction progress by gas chromatographic analysis
also proved the intermediacy of selenocyanate (see SI).
To find whether the reaction is going by a radical/ionic
pathway, a representative reaction with 4-methyl styrenyl
bromide and KSeCN was performed under the conditions for
the formation of selenocyanate, using TEMPO ((2,2,6,6-
tetramethylpiperidin-1-yl)oxyl) as a radical quencher (see
Scheme S2 in SI). It was revealed that TEMPO does not have
any effect on the reaction. This indicates that selenocyanate
formation is not likely to go by the radical pathway. Next, a
reaction of 4-methoxy styrenyl bromide and KSeCN under the
conditions for the formation of benzoselenophene has been
carried out in the presence of TEMPO and it was found that the
reaction has been completely arrested. This indicates that this
reaction might undergo the radical pathway. For further
confirmation, two additional reactions using 4-methoxy styrenyl
selenocyanate as starting material in the presence and absence of
TEMPO under the same conditions were performed. In the
absence of TEMPO the corresponding benzoselenophene was
obtained in good yield, whereas the other reaction in the
presence of TEMPO was not effective. These observations
established that the first step of selenocyanate formation is an
a
Reaction conditions: a mixture of styrenyl bromide (1.0 mmol),
KSeCN (1.2 mmol), iodine (20 mol %) in dry DMSO (2.5 mL) was
b
heated at 110 °C under argon for 42 h. Yield of isolated products.
In principle, cyclization of intermediate styrenyl selenocyanate
to selenophene may occur at two adjacent C−H sites. However,
the electronic factors have strong influence in the cyclization
process. Usually, an alkoxy substituent directs the cyclization to
occur at its para-position if it is free and single products are
formed (Scheme 3). In the absence of a strong electron push by
an electron-donating substituent at the para-position with
respect to vinyl substituent, cyclization occurs at both ortho-
and para-positions and a mixture of regioisomeric selenophenes
were obtained (Scheme 4, 61, 62 and 67, 68). Interestingly, if
there is an iodo-substitutent at the adjacent position, cyclization
may occur at this site too with elimination of an iodo-substitutent
along with an adjacent C−H site (Scheme 4, 63, 64 and 65, 66).
The elimination of an iodo-substituent may be facilitated by its
good leaving character.
In general, the reactions are clean and pure compounds are
obtained by simple column chromatography of the crude
products. All compounds are characterized satisfactorily by
spectroscopic data (IR, H NMR, 13C NMR, HRMS) and
1
elemental analysis. The styrenyl selenocyantes are all new
compounds and reported for the first time. The benzoseleno-
phenes, except one, are also new. For confirmation of
regiochemistry, the structure of one of the selenophenes
(Scheme 3, 54) has been established by X-ray crystallographic
analysis (ORTEP figure; see Supporting Information (SI)).16
The other related compounds are characterized by H and 13C
1
C
DOI: 10.1021/acs.orglett.7b02571
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Organic Letters
Letter
Notes
ionic process and the second step toward benzoselenophene is a
radical one.
Based on these results, a possible reaction pathway has been
outlined (Scheme 5). The styrenyl bromide reacts with iodine to
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are pleased to acknowledge the financial support from the
Indian National Science Academy, New Delhi for the award of an
INSA Senior Scientist position to B.C.R. P.M. thanks CSIR for
his fellowships.
Scheme 5. Possible Reaction Pathway
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form a cycloiodinium ion (A) which is then attacked by the
−SeCN nucleophile to furnish (2-bromo-1-iodo-2-seleno-
cyanatoethyl)benzene (B). This intermediate B provides the
corresponding trans styrenyl selenocyanate and I2 via the E2
mechanism. In the next step toward benzoselenophene synthesis,
selenocyanate is homolytically cleaved to afford a styrenyl
selenium radical (electrophilic nature) which is approached by
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to benzoselenophene through oxidation and H+ elimination.
In conclusion, we have demonstrated a general, versatile, and
trsansition-metal-free synthesis of styrenyl selenocyanate and
benzoselenophenes by the reaction of readily available styrenyl
bromides and KSeCN in the presence of iodine under specified
conditions. Although all types of styrenyl bromides participate in
the selenocyanation reaction, only electron-rich styrenyl
bromides led to the formation of benzoselenophenes via the
intermediacy of styrenyl selenocyanates. A possible reaction
pathway has been suggested based on experimental results.
Notably, this is the first report for the synthesis of biologically
potential styrenyl selenocyates. The benzoselenophenes that are
prepared earlier by multistep procedure14 are obtained in single
step by this protocol. Certainly, this method is of great potential
for easy access to styrenyl selenocyanates and electron-rich
benzoselenophenes.
ASSOCIATED CONTENT
* Supporting Information
■
S
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The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.7b02571.
Crystallographic data for 54 (CIF)
Typical experimental procedure and characterization data
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1
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(PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: ocbcr@iacs.res.in.
ORCID
Brindaban C. Ranu: 0000-0001-9020-1401
D
DOI: 10.1021/acs.orglett.7b02571
Org. Lett. XXXX, XXX, XXX−XXX