Facile, regioselective oxidative selenocyanation of: N -aryl enaminones under transition-metal-free conditions

Article abstract of DOI:10.1039/c9nj05845a

A direct and straightforward approach for the regioselective selenocyanation of N-aryl enaminones through sp² C-H functionalization has been realized at room temperature. In this study, KSeCN as the selenocyanate reagent and K₂S₂O₈ as the oxidizing agent are employed under transition-metal-free conditions. The present methodology was also applied for the synthesis of selenocyanated chromones, indoles and anilines in good to excellent yields.

Full text of DOI:10.1039/c9nj05845a

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Facile, regioselective oxidative selenocyanation of
N-aryl enaminones under transition-metal-free
conditions†
Cite this:DOI: 10.1039/c9nj05845a
Ganesh Shivayogappa Sorabad
and Mahagundappa Rachappa Maddani
*
Received 23rd November 2019,
Accepted 7th January 2020
A direct and straightforward approach for the regioselective selenocyanation of N-aryl enaminones
2
through sp C–H functionalization has been realized at room temperature. In this study, KSeCN as the
2 2 8
selenocyanate reagent and K S O as the oxidizing agent are employed under transition-metal-free
DOI: 10.1039/c9nj05845a
conditions. The present methodology was also applied for the synthesis of selenocyanated chromones,
indoles and anilines in good to excellent yields.
rsc.li/njc
Introduction
Selenocyanation has been found to be an efficient and facile
method for obtaining organoselenocyanates, which play important
roles in a wide range of biologically active molecules and agro-
chemicals, and find useful applications in material science as well
1
as nanotechnology. It has been found that the presence of the
selenocyanate (SeCN) group results in enhanced therapeutic
potentials when compared to the thiocyanate (SCN) group in
2
,3
organic scaffolds. In addition, several useful organic transfor-
4
mations are achieved using the selenocyanate group. Hence,
incorporation of selenocyanate into organic molecules has
become an important area of research for synthetic research
groups. Generally, organoselenocyanates have been prepared by
5
reactions that involve (i) direct substitution, (ii) metal-mediated
6
coupling, and (iii) non-metallic reagent-mediated C–H seleno-
7
cyanation of activated arenes, (iv) without the use of seleno-
cyanating agents. Among these, non-metallic reagent-mediated
8
Scheme 1 Earlier and present methods of selenocyanation.
selenocyanations have received much attention as the other
methods make use of prefunctionalized substrates, additives
and/or toxic transition metals, as well as excess loading of reagents
The synthetic utility of enaminones containing enamine and
and longer reaction times. Moreover, metal-free C–H bond enone groups as reactive sites is fascinating as these can be
9
10
functionalizations have grown increasingly popular in organic efficiently converted into useful heterocycles and biologically
1
1
synthesis as they can eliminate prefunctionalized substrates and important molecules. Besides, enaminones have been inves-
1
2
the possibility of metal contamination, providing better selectivity tigated for the role of ligands in metal-mediated organic
and yields in short periods of time. Thus, direct C–H bond transformations. Therefore, the chemical modification of simple
selenocyanation is more economical and practical. Accordingly, enaminones has become an important area of research for many
several electron-rich systems have been selenocyanated under chemists. In this direction, enaminones have been employed for
transition-metal-free conditions (Scheme 1).
various chemical transformations via direct a-C–H functionalization/
13
14
activation processes using both metals and metal-free conditions.
These functionalized enaminones gained enormous attention in
synthetic chemistry owing to their flexibility as valuable precursors
and they can provide new avenues for further chemical trans-
Department of Post-Graduate Studies and Research in Chemistry Mangalore
University, Mangalgangothri-574199, India. E-mail: mahagundappa@gmail.com,
mahgundappa@mangaloreuniversity.ac.in
†
Electronic supplementary information (ESI) available. See DOI: 10.1039/c9nj05845a formations. Owing to the ever-increasing importance of both
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selenocyanate and enaminones, it is of great interest to synthe- (96%) yield (Table 1, entry 6). A similar reaction in THF was
size molecules containing both selenocyanate and enaminone not successful and 2a was obtained in much lower quantity
moieties. Thus, the introduction of a selenocyanate group into (Table 1, entry 7). Reactions in EtOAc, cyclohexane, toluene,
enaminones is promising and may lead to molecules with MeOH, DMF, DMSO and DCM were not very impressive and the
enhanced biological activity.
product 2a was obtained in the yield range of 63–76% (Table 1,
Therefore, in continuation of our efforts in developing entries 8–14). In the same way, water as green solvent was
C–H functionalization strategies towards useful organic trans- employed for the present study and we found that the reaction
15
formations, herein we wish to present an efficient selenocyanation produced the product 2a in only moderate yield (Table 1, entry
of N-aryl enaminones using readily available KSeCN as the seleno- 15). Based on the above results, the screening of several other
2 2 8
cyanating agent and K S O as the oxidizing agent under mild oxidants was performed employing DCE as the solvent. Per-
reaction conditions (Scheme 1). To the best of our knowledge, oxides such as aq. H O , aq. tert-butyl hydroperoxide (TBHP)
2
2
such a convenient method for the synthesis of selenocyanated and a solution of TBHP in decane were examined as oxidants
enaminones via C–H bond selenocyanation has not been reported. but they were found to not be effective for selenocyanation
and the starting material was isolated unchanged (Table 1,
entries 16–18). Reactions using molecular oxygen and ceric
ammonium nitrate (CAN) were also unsuccessful and we observed
Results and discussion
the formation of 2a in very low yields (Table 1, entries 19 and 20).
Thus, among several oxidants, K S O was chosen as the oxidant
2 2 8
for the present selenocyanation. After all the above screening
studies, we chose the optimized reaction conditions as 1a
We initiated the optimization of the reaction conditions by
screening the equivalents of KSeCN and K
dichloroethane (DCE) and acetonitrile (ACN) at room temperature
Table 1, entries 1–5). These experiments showed that DCE is a
better solvent than CAN and 2 equivalents of KSeCN and
equivalents of K S O are required for the formation of the
2 2 8
S O with 1a in
(
(
1.0 equiv.), KSeCN (2.0 equiv.) and K S O (2.5 equiv.) in
2 2 8
DCE at room temperature for 2 h.
2
2
2 8
The substrate scope was investigated using various substituted
enaminones under the optimized reaction conditions, as shown in
Table 2.
desired product 2a in good yield.
Subsequently, we found that increasing the quantity of
K
2
S
2
O
8
to 2.5 equivalents furnished the product 2a in excellent
We were delighted to find that most of the tested substrates
furnished good to excellent yields. Enaminones containing
electron-donating groups, such as alkyl and alkoxy, underwent
smooth selenocyanation and furnished their corresponding
products 2b–e in very good yields. Similarly, fluorine- and
chlorine-substituted enaminones also provided their selenocyanated
products 2f–j in admirable yields. Notably, we introduced a naphthyl
moiety in enaminones and subsequently reacted them under opti-
mized reaction conditions to obtain their corresponding products
a
Table 1 Optimization of the reaction conditions
(
2k and 2l) in very good yields. We also incorporated heteroaryls,
such as furan and thiophene moieties, into enaminones and
Yield (%) subjected them to our present reaction conditions. Furoyl
b
Entry Solvent
KSeCN (equiv.) Oxidant (equiv.)
enaminone provided the corresponding product 2m in 83%
yield. Similarly, thiophene-incorporated enaminones also gave
the selenocyanated products 2n–p in the yield range of 85–88%.
Interestingly, we also attempted the present selenocyanation
with cyclic enaminones (3a–e) and observed the formation of
the respective selenocynated products 4a–e with good to excellent
yields, as shown in Table 3.
Inspired by the above results, our curiosity pushed us to
explore the present selenocyanation in the synthesis of seleno-
cyanated chromones from hydroxy-substituted enaminones
(5a–d), as shown in Table 4. Several hydroxy-substituted enaminones
underwent selenocyanation and cyclization under the present
reaction conditions to produce the corresponding seleno-
cyanated chromones 6a–d in very good yields. We then examined
the application of the present strategy using a few indoles and
anilines as substrates. In this context, under optimized conditions
substituted indoles gave the corresponding selenocyanated indoles
(7a–c; 96–99%) in excellent yields, while anilines produced the
selenocyanated anilines in slightly lower yields (8a–d; 70–73%) as
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
DCE
ACN
ACN
DCE
DCE
DCE
THF
EtOAc
1.0
1.5
2.0
1.5
2.0
2.0
2.0
2.0
K
K
K
K
K
K
K
K
K
K
K
K
K
K
K
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
(1.5)
(1.5)
(2.0)
(1.5)
(2.0)
(2.5)
(2.5)
(2.5)
(2.5)
(2.5)
(2.5)
(2.5)
(2.5)
(2.5)
(2.5)
Trace
20
45
56
80
96
Trace
67
63
65
76
51
72
62
68
NR
NR
Cyclohexane 2.0
0
1
2
3
4
5
6
7
8
9
0
Toluene
MeOH
DMF
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
DMSO
DCM
c
H
2
O
DCE
DCE
DCE
DCE
DCE
H
2
O
2
(2.5.)
TBHP (2.5)
TBHP in decane (2.5) NR
O
2
Trace
30
CAN (2.5)
a
All reactions were carried out using enaminone 1a (0.60 mmol), KSeCN
(1.5 mmol) in DCE (3 mL) at room temperature
(1.2 mmol), and K
S
2 2
O
8
b
c
for 2 h. Isolated yields based on 1a. Reaction carried out at reflux
temperature for 2 h.
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a
a
Table 2 Direct a-C–H selenocyanation to N-aryl enaminones
Table 3 Selenocyanation of cyclic enaminones
a
All selenocyanation reactions were carried out using cyclic enaminone
3
(0.69 mmol), KSeCN (1.39 mmol), and K
2
S
2
O
8
(1.74 mmol) in DCE
(3 mL) at room temperature for 2 h.
a
Table 4 Synthesis of selenocyanated chromones
a
All selenocyanation reactions were carried out using enaminone 1
(1.5 mmol) in DCE (3 mL)
(0.60 mmol), KSeCN (1.2 mmol), and K
2 2 8
S O
at room temperature for 2 h.
shown in Table 5. Additionally, we also investigated a similar
strategy for thiocyanation of N-aryl enaminones using potassium
thiocyanate (KSCN) as the thiocyanation agent, as shown in
Table 6. Parent enaminone 1a gave the thiocyanated product
9a in 79% yield. Similarly, methyl- and methoxy-substituted
enaminones underwent smooth thiocyanation and furnished
the corresponding products in satisfactory yields (9b and 9c).
Naphthoyl enaminone also gave the similar thiocyanated product temperature for 2 h.
a
All reactions were carried out using hydroxy enaminone 5 (0.60 mmol),
(1.5 mmol) in DCE (3 mL) at room
2 2 8
KSeCN (1.2 mmol), and K S O
(9d) in 89% yield.
After all of the above success, we investigated the scalability
of the present strategy by scaling it up in gram-scale conditions, gram-scale reaction is a simple and straightforward protocol for
as shown in Scheme 2. 1.5 g of enaminone (1a) under optimized the synthesis of various selenocyanated enaminones.
reaction conditions furnished 2.05 g of selenocyanated product
To gain further insight into the mechanism of the present
2a (93%) without any significant loss of yield. Therefore, this selenocyanation, we performed a few control experiments. The
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a
Table 5 Selenocyanation of indoles and anilines
a
All selenocyanation reactions were carried out using indole (0.84 mmol),
(1.5 mmol) in DCE
aniline (1.075 mmol), KSeCN (1.2 mmol), and K
2 2 8
S O
(3 mL) at room temperature for 2 h.
a
Table 6 Thiocyanation of enaminones
a
All thiocyanation reactions were carried out using enaminone 1
(1.5 mmol) in DCE (3 mL)
(0.60 mmol), KSCN (1.2 mmol), and K
2 2 8
S O
at room temperature for 2 h.
Scheme 2 Synthesis of 2a on gram scale.
Scheme 3 Control experiment and tentative mechanism.
reaction of 1a under optimized reaction conditions without the the unreacted enaminone was recovered. This particular reaction
use of K S O did not give the selenocyanated product (eqn (I), (eqn (II), Scheme 3) suggests the possibility of the reaction
2
2 8
Scheme 3). This reaction indicates that an oxidizing agent is proceeding through a free radical mechanism. Thus, on the basis
16
necessary for the present selenocyanation reaction. In a sub- of the above results and previous literature, we herein are
sequent reaction of 1a under optimized conditions, we added proposing tentative reaction mechanisms for the present seleno-
TEMPO (2,2,6,6-tetramethyl-1-piperidinyloxy), a well-known radical cyanation as shown in Scheme 3. Initially, SeCN radical A is
scavenger. This TEMPO-mediated reaction was unsuccessful; generated by the oxidation of KSeCN. In path I, the radical A
the corresponding product was formed in trace amounts and reacts with N-aryl enaminone 1 to give alkyl radical species B,
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which is then oxidized by K
S O
2 2 8
to give species C. Finally,
thio/selenocyanate: O. S. Sohn, E. S. Fiala, P. Upadhyaya,
K. Chae and K. El-Bayoumy, Carcinogenesis, 1999, 20, 615.
3 W. Ji, S. Jing, Z. Liu, J. Shen, J. Ma, D. Zhu, D. Cao, L. Zheng
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4 S. Redon, A. R. O. Kosso, J. Broggi and P. Vanelle, Tetrahedron
Lett., 2017, 58, 2771.
+
elimination of H from C affords the desired product 2. Alternatively,
in path II radical A dimerizes to selenocyanogen (SeCN)2 D.
Subsequently, electrophilic substitution of electrophile D to 1
also affords species C, as shown in path II (Scheme 3).
5
6
E. H. Riague and J. C. Guillemin, Organometallics, 2002, 21, 68.
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Experimental
Typical synthetic procedure
N-Aryl enaminone (0.60 mmol), KSeCN (2 equiv., 1.20 mmol),
7
8
and K S O (1.50 mmol) in ethylene dichloride (DCE) (3 mL)
2
2 8
were stirred at room temperature for 2 h. After completion of
the reaction (monitored by TLC), the reaction mixture was
(a) A. V. Kachanov, O. Y. Slabko, O. V. Baranova, E. V.
Shilova and V. A. Kaminskii, Tetrahedron Lett., 2004, 45, 4461;
quenched using a saturated solution of NaHCO
with dichloromethane (3 Â 15 mL). The combined organic layer
was dried over Na SO and concentrated under reduced pressure.
3
then extracted
(b) A. R. O. Kosso, J. Broggi, S. Redon and P. Vanelle, Synlett,
2018, 1215; (c) S. Redon, A. R. O. Kosso, J. Broggi and P. Vanelle,
2
4
Tetrahedron Lett., 2017, 58, 2771.
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The crude product was purified on silica gel by column chromato-
graphy using hexane/EtOAc to obtain the pure product.
9
45, 936; (b) K. M. Engle, T. S. Mei, M. Wasa and J. Q. Yu, Acc.
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Conclusions
In summary, we have disclosed a transition-metal-free method
110, 890.
2
for a-sp C–H selenocyanation of N-aryl enaminones under
1
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proceeded in good yields and tolerated a wide range of functional
groups. The present strategy was also applied for the synthesis
of selenocyanated chromones in excellent yields. Controlled
experiments suggest that this reaction likely proceeds via a
radical pathway. The present protocol provides a new avenue for
the formation of selenocyanated N-aryl enaminone derivatives,
and it will gain more attention in synthetic and pharmaceutical
chemistry.
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(
2
j) G. Chen, Z. Wang, X. Zhang and X. Fan, J. Org. Chem.,
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Acknowledgements
1
We gratefully acknowledge DST-SERB (No. DST-SERB-2016-
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2
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