A catalyst-free approach to 3-thiocyanato-4H-chromen-4-ones

Article abstract of DOI:10.1039/c6ra13303g

A facile and efficient approach to 3-thiocyanato-4H-chromen-4-ones was realized at room temperature. In the presence of KSCN and K₂S₂O₈, various enaminones underwent thiocyanation and cyclization, affording 3-thiocyanatochromenones in good yields. In addition, one-pot synthesis of 3-thiocyanatochromenones from 2-hydroxylacetophenones was also developed.

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A Catalyst-Free Approach To 3-Thiocyanato-4H-chromen-4-ones
Xiao-Zhuan Zhang, Dao-Liang Ge, Shan-Yong Chen*, and Xiao-Qi Yu*
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
DOI: 10.1039/b000000x
one (1a) and KSCN were used to test our hypothesis. In the
presence of K2S2O8, the reaction did undergo as we expected,
50 affording the product in 70% yield (Table 1, entry 1). After
optimization of the amounts of KSCN and K2S2O8, an increased
yield (85%) was obtained by stirring the mixture in DCE at room
temperature for 6 h. When DCE was replaced by other solvents,
the reactions gave lower yields (Entries 5ꢀ13). Notably, we found
55 that a decreased yield was obtained when the reaction was
conducted under an argon atmosphere (Entry 14 vs entry 4).
Therefore, the optimal reaction conditions are following: 1a (0.4
mmol), K2S2O8 (2 equiv), KSCN (3 equiv), DCE (2 mL); stirring
under air atmosphere at room temperature for 6 h.
5
Abstract: A facile and efficient approach to 3-thiocyanato-
4H-chromen-4-ones was realized at room temperature. In
the presence of KSCN and K2S2O8, various enaminones
underwent thiocyanation and cyclization, affording 3-
thiocyanatochromenones in good yields. In addition, one-
10 pot synthesis of 3-thiocyanatochromenones from 2-
hydroxylacetophenones was also developed
.
Introduction
Aryl thiocyanates are versatile intermediates for various sulfurꢀ
containing derivatives such as sulfides, thiocarbamates and
15 related heterocyclic compounds.1 Aryl thiocyanates can be
prepared via two classic methods. One is the direct electrophilic
thiocyanation of electronꢀrich arenes2 and another is the coupling
of diazonium salt with metal thiocyanates under Sandmeyerꢀtype
conditons.3 Metalꢀcatalyzed coupling reaction of aryl halide or
20 analogue with thiocyanate salt has been developed recently,
which is a good complement to the traditional methods.4 In these
reported approaches, preformed or prefunctionalized aromatic
rings are needed. From the point of view of atomꢀ and stepꢀ
economy, a tandem thiocyanation/cyclization reaction, where the
25 heterocyclic is constructed at the same time, is highly desirable.
60
Table 1 Optimization of reaction conditionsa
KSCN
(equiv)
K2S2O8
(equiv)
Entry
solvent
yieldb (%)
Chromones and their derivatives exit widely in natural products
and have been identified with a variety of biologicalactivities.5
Therefore, the synthesis of chromone derivatives has been studied
extensively.6 For example, sulfenylation with TsNHNH2, TsCl or
30 TsNa6a.6b.6c, regioselective oxidative amination with azoles5c,
trifluoromethylthiolation6e were reported recently. However, the
synthesis of thiocyanatochromenones is overlooked. It is wellꢀ
known that functional groups affect biological activity, thus the
combination of thiocyanates with chromones may generate new
35 biologically active compounds. Nevertheless, we found the
reported methods2a,2d such as I2/KSCN, K2S2O8/KSCN at elevated
temperature were invalid for the thiocyanation of chromones,
indicating that the thiocyanation of chromones is more difficult
than we imagined. We hypothesized that dimethyl amino group in
40 enaminones can serve as an activation group, which could
facilitate the thiocyanation, and act as a leaving group for
cyclization. Herein, we report a facile, efficient, and metalꢀfree
method to synthesize 3ꢀthiocyanatoꢀ4HꢀChromenꢀ4ꢀone with
simple and readily available KSCN as the sulfur source under
45 mild conditions.
1
2
3
4
5
6
7
8
2
1
3
3
3
3
3
3
1.5
1.5
1.5
2
DCE
DCE
70
62
80
85
17
63
n.d
24
19
DCE
DCE
CH3CN
H2O
2
2
2
THF
2
DMF
1,4ꢀ
dioxane
9
3
2
10
11
12
13
14c
15
3
3
3
3
3
3
2
2
2
2
2
0
HOAc
CH2Cl2
EA
54
31
7
EtOH
DCE
20
50
n.d
DCE
aReaction conditions:1a (0.4 mmol), solvent (2 mL), open flask.
bIsolated yields, n.d = no detected, The reaction is carried out
c
Results and discussion
65 under argon atmosphere.
Firstly, (E)ꢀ3ꢀ(dimethylamino)ꢀ1ꢀ(2ꢀhydroxyphenyl)propꢀ2ꢀenꢀ1ꢀ
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With the optimized reaction conditions in hand, the scope of
substrates was investigated, and the results are summarized in
Scheme 1. To our delight, most of the tested substrates afforded
good yields. All haloꢀsubstituted compounds gave the
corresponding 3ꢀthiocyanatoꢀ4Hꢀchromenꢀ4ꢀones in excellent
yields (3c-3e, 3g-3k). The substrates bearing halo substituents at
the paraꢀposition or metaꢀposition of the phenol groups achieved
similar yields (3c vs 3g, 3d vs 3h, 3e vs 3i). When the benzene
moiety was replaced by a naphthalene moiety for compounds 1,
group of the product 3a could undergo cycloaddition reaction
with NaN3 to afford 3aa in 71% yield.
Scheme 2. Scope of 2-hydroxyacetophenones for the one-
pot Thiocyanation
5
10 the corresponding 3ꢀthiocyanatochromone 3f was obtained in
good yield. Enaminones containing a CN or NO2 substituent at
the paraꢀposition of the phenol group hardly underwent this
transformation (data not shown).
Scheme 1. Exploration of Substrate Scopea,b
15
45
Scheme 3. Synthesis of 3a on a Gram Scale
50 Scheme 4. Synthetic Utility of This Reaction
O
O
H
SCN
S
N
ZnCl2 (1 equiv)
N
N
N
71%
NaN3(1.2 equiv)
iPrOH,50oC
O
O
3a
3aa
To gain further insight into the reaction mechanism, several
control experiments were performed (Scheme 5). When (E)ꢀ3ꢀ
(dimethylamino)ꢀ1ꢀphenylpropꢀ2ꢀenꢀ1ꢀone instead of enaminone
55 1a was subjected to the reaction, the expected 2ꢀthiocyanatoꢀ1Hꢀ
indenꢀ1ꢀone was not observed (Scheme 5, eq 1). This result
shows that the hydroxy group of enaminones might play a key
role in the reaction. Chromone did not provide the product,
indicating that chromone was not involved in the reaction process
aReaction conditions:1(0.4 mmol), KSCN (2 equiv), DCE(2 mL),open
flask. bIsolated yields
20
Various enaminones 1 were prepared via the condensation of 2ꢀ
hydroxyacetophenones with DMFꢀDMA. We wondered if the
condensation and the thiocyanation would occur in one pot to 60 (Scheme 5, eq 2). When TEMPO (2,2,6,6ꢀtetraꢀmethylꢀ1ꢀpiperiꢀ
provide a convenient way to 3ꢀthiocyanatochromones. This
25 hypothesis was investigated by the following experiments: the
mixture of 2ꢀhydroxyacetpheone (1 mmol) and DMFꢀDMA (1
mmol) was refluxed for 60 minutes. After cooling to room
temperature, KSCN (3 mmol), K2S2O8 (2 mmol), and DCE (5
mL) were added. Then the resulting mixture was stirred at room
30 temperature for 6 hours under open flask. To our delight, 81%
isolated yield of 3a was obtained (Scheme 2). Encouraged by this
result, we applied this oneꢀpot strategy to other 2ꢀ
hydroxyacetophenones. As shown in Scheme 2, the tested 2ꢀ
hydroxyacetophenones proceeded well, affording the desired
35 products in moderate to good yields.
dinyloxy) was added into the reaction system, a distinctly
decreased yield was obtained (Scheme 5, eq 3). Besides, he
t
formation of (SCN)2 was not observed (for experiments see
Supporting Information ).
65 Scheme 5. Control Experiments
To demonstrate the utility of this method, we conducted the
reaction on a gram scale; the yield was obtained in 89% with a
slight increase (Scheme 3). Furthermore, the potential synthetic
utilities of 3 were also investigated (Scheme 4，for details see
40 the Supporting Information). As shown in Scheme 4, the SCN
2
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On the basis of the experimental results above and previous
related literature,2d,6e,7,8 a plausible mechanism is proposed in
Scheme 4. Firstly, SCN radical was generated by the oxidation of
KSCN.2d Subsequently, the addition of SCN radical to the double
bond of 1 gave radical intermediate A8, which was oxidized to
carbocation intermediate B. Finally, the intramolecular
50
55
60
65
70
75
80
85
90
5
2
cyclization of
B followed by the elimination of N, Nꢀ
dimethylamine afforded the desired product 3.
10 Scheme 6. Proposed Mechanism
KSCN+K2S2O8
SCN
O
3
4
SCN
O
R
N
O
R
3
OH
1
5
-HNMe2
O
SCN
R
O
OH
N
SCN
A
H
R
K2S2O8
O
N
O
C
SCN
N
R
OH
B
Conclusions
In summary, we have developed a facile and efficient approach to
3ꢀthiocyanatoꢀ4Hꢀchromenꢀ4ꢀone with easily available KSCN as
15 thiocyanation agents. 2ꢀhydroxyacetophenones also give
moderate to good yields through oneꢀpot twoꢀstep reactions.
Importantly, the finally product can converted into other useful
structures. This method enriches current chromone chemistry and
sulfur chemistry，and will be a highly valuable and practical
20 approach in pharmaceutical industry. Further studies on the
applications of this reaction are in progress in our laboratory.
6
7
8
H. Yang, X.ꢀH. Duan, J.ꢀF. Zhao and L.ꢀN. Guo, Org. Lett.
2015 ,17 , 1998
.
Acknowledgment
YꢀY. Yu, Adwait R. Ranade, and Gunda I. Georg. Adv.Synth &
Catal 2014, 356,3510.
This work was supported financially by the National Program on
25 Key Basic Research Project of China (973 Program,
2013CB328905) and the National Science Foundation of China
(Grant No. 21202107, 21321061 and J1103315).
Notes and references
30
Key Laboratory of Green Chemistry and Technology, Ministry of
Education, College of Chemistry, Sichuan University, Chengdu, 610064,
P. R. China. Tel. & Fax: (86)-28-85415886
E-mail: chensy@scu.edu.cn, xqyu@scu.edu.cn
35 † Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/b000000x/
‡ Footnotes should appear here. These might include comments relevant
to but not central to the matter under discussion, limited experimental and
40 spectral data.
1
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45
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A Catalyst-Free Approach To 3-Thiocyanato-4H-chromen-4-ones
Xiao-Zhuan Zhang, Dao-Liang Ge, Shan-Yong Chen*, and Xiao-Qi Yu*
Key Laboratory of Green Chemistry and Technology, Ministry of Education, College of Chemistry,
Sichuan University, Chengdu, 610064, P. R. China
E-mail: chensy@scu.edu.cn, xqyu@scu.edu.cn
A facile and efficient approach to 3-thiocyanato-4H-chromen-4-ones was realized at
room temperature. In the presence of KSCN and K2S2O8, various enaminones
underwent thiocyanation and cyclization, affording 3-thiocyanatochromenones in good
yields. In addition, one-pot synthesis of 3-thiocyanatochromenones from
2-hydroxylacetophenones was also developed.
O
O
SCN
K2S2O8
N
room temperature
open flask
R
KSCN
R
DCE,rt,6h
OH
O
metal-free
15 examples
up to 93% yield
O
O
KSCN
SCN
K2S2O8
DMF-DMA
reflux,1h
one-pot
room temperature
open flask
R
R
DCE,rt, 6 h
OH
O
metal-free
6 examples
yields 52%-81%