Iodine-mediated synthesis of sulfur-bridged enaminones and chromones: Via double C(sp2)-H thiolation

Article abstract of DOI:10.1039/c7ob00619e

The reactions of various enaminones with elemental sulfur giving rise to both sulfur-bridged enaminones and chromones have been realized via iodine promotion. All products were furnished by means of double C(sp²)-H bond thiolation without using

Full text of DOI:10.1039/c7ob00619e

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DOI: 10.1039/C7OB00619E
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Iodine‐mediated synthesis of sulfur‐bridged enaminones and
chromones via double C(sp2)‐H thiolation
Yong Gao,a Li Wei,a Yunyun Liua,* and Jie‐Ping Wana,*
Received 00th January 20xx,
Accepted 00th January 20xx
The reactions of various enaminones with elemental sulfur giving rise to both sulfur bridged enaminones and chromones
have been realized via iodine promotion. All products were furnished by means of double C(sp2)‐H bond thiolation without
using any metal catalyst or sensitive oxidant, providing a simple and efficient protocol for the synthesis of divergent sulfur
derivatives of enaminones.
DOI: 10.1039/x0xx00000x
www.rsc.org/
synthesized. Interestingly, most of the known elemental sulfur‐
based C‐S bond construction reactions are run with the
catalysis of transition metal,5 and transition metal‐free
methods enabling sulfur‐based C‐S bond formation are yet
scarcely available.6 Therefore, in order to further explore the
potential of elemental sulfur in organic synthesis, developing
practical coupling reactions forming C‐S bonds without
transition metal catalysis is of high significance.
Introduction
Transition metal‐catalyzed C‐H activation reactions have won
splendid success as powerful synthetic tactic during the last
decade. It is inarguable that these catalytic transformations is
now serving as indispensable tools in modern organic synthesis
because of the inherent feature of step economy embedded in
the direct transformation of naturally occurring C‐H bonds.1
On the other hand, in line with the transition metal‐catalyzed
models, the metal‐free C‐H bond cross coupling reactions have
also emerged in recently years as highly significant strategy in
the synthesis of numerous organic products.2 Comparing with
the transition metal‐catalyzed C‐H activation and other cross‐
coupling chemistry, the most notable features of the metal‐
free C‐H bond elaboration are the low catalytic cost and free of
trace metal contamination resulted from the metal catalysis,
which is particularly crucial for the synthesis of biologically
relevant organic compounds.3 However, a major challenge in
the metal‐free C‐H bond transformation is that most of the
stable C‐H bonds are hard to activate without the insertion of
transition metal catalyst, which consequently restricts the
designation of abundant applicable metal‐free C‐H elaboration
approaches. In this context, developing more and greener
methods allowing direct C‐H transformation is currently highly
demanding work.
Enaminones are synthons with ubiquitous application in
organic synthesis, which enables synthesis of highly diverse
types of organic products.7 Accordingly, the synthesis of
polyfunctionalized enaminones via the elaboration of simple
enaminones has also attracted extensive research interest.
One such elaboration route is the direct C‐H functionalization
of enaminones by employing either transition metal catalysis
or transition metal‐free tactic.8 In 2016, our group has
identified the first C‐S bond forming reaction of enaminones
via the catalysis of KIO3 wherein thiophenols are used as the
sulfenylating reagents,9 and other groups later reported
10
different catalytic approaches such as TBHP/TBAI catalysis
and palladium catalysis11 for similar synthesis. Additionally, by
making use of this featured transformation, we have recently
accomplished the transition metal‐free synthesis of 3‐
sulfenylated chromones via tandem C‐H sulfenylation and
intramolecular C‐N bond oxygenation.12 In continuous to our
efforts in developing novel synthetic approaches based on the
coupling transformation of the enaminone C‐H bond,13 we
report herein the first elemental sulfur‐based double C‐H
thiolation of enaminones with iodine promotion, which allows
the facile and clean synthesis of various sulfur bridged
enaminones and chromones.
Elemental sulfur is one of the most easily available raw
chemicals with enriched storage in natural, and it is of high
potential as “S” source in the synthesis of many sulfur‐
containing organic molecules.4 Notably, elemental sulfur has in
recent years found impressive application in the C‐S bond
formation reactions via various coupling protocols, by which a
huge number of sulfur containing compounds have been
Results and discussion
To start the investigation, the optimization on reaction
conditions based on the model assembly of enaminone 1a, p‐
methylaniline 2a and sulfur powder 8. The initial screening on
a. College of Chemistry and Chemical Engineering, Jiangxi Normal University,
Nanchang 330022, P. R. China.
Email: wanjieping@jxnu.edu.cn; chemliuyunyun@jxnu.edu.cn
Electronic Supplementary Information (ESI) available: [general experimental
information, full characterization data and 1H/13C NMR spectra of all products]. See
DOI: 10.1039/x0xx00000x
various non‐metal promoters, including TBHP, iodine, BPO and
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PhI(AcO)2, proved that I2 was the only applicable species Table 2), alkyl (4j, Table 2) displayed general tolerance to the
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DOI: 10.1039/C7OB00619E
enabling the expect double C‐H thiolation to yield sulfur synthesis. On the other hand, the aryl primary amines,
bridged enaminone product 4a (entries 1‐4, Table 1). The same including those ones containing different types of substituents
reaction performed at different temperatures indicated that in ortho‐ meta‐ or para‐ site as well as heteroaryl amine (4u
,
product 4a was given with the optimal yield in the tested Table 2) were also all applicable. However, alkyl amine was not
range (40‐100 oC) at 90 oC (entries 5‐8, Table 1). Subsequently, able to provide corresponding N‐alkyl product under the
the entries in different reaction media such as DMSO, dioxane, present condition. The products were mostly acquired with
elthyl lactate (EL) and toluene showed that each of these moderate to good yields, and relatively lower product yield
solvent could mediate the formation of 4a, but all with inferior occured in the entry using alkyl (R1) functionalized enaminone
yield (entries 9‐12, Table 1). In addition, the entries with either
higher or lower loading of molecular iodine didn’t lead to
further increase in the product yield (entries 13‐14, Table 1).
Subsequently, the control entry conducted in the presence of
(4j, Table 2).
Table 2 The reaction of various enaminones and amines with sulfur powdera
4 equiv. mole of TEMPO gave similarly high yield of 4a
,
implying that the reaction did not involve free radical
intermediate (entry 15, Table 1). And another entry performed
under N2 also gave similar 4a with similar yield, suggesting that
the presence of air did not impact the reaction (entry 16, Table
1).
R1
C6H5
Ar
4‐MeC6H4
4‐MeC6H4
4‐MeC6H4
4‐MeC6H4
4‐MeC6H4
4‐MeC6H4
4‐MeC6H4
4‐MeC6H4
4‐MeC6H4
4‐MeC6H4
C6H5
2‐MeC6H4
3‐MeOC6H4
3‐ClC6H4
3‐NO2C6H4
4‐BrC6H4
Product
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
4q
4r
Yieldb (%)
69
Table 1 Optimization on reaction conditionsa
4‐MeC6H4
3‐MeOC6H4
2‐MeC6H4
4‐ClC6H4
3,4‐MeO2C6H3
3,4‐Cl2C6H3
2‐naphthyl
thiophen‐2‐yl
i‐Butyl
C6H5
73
71
65
67
75
62
58
61
52
68
64
70
61
57
60
63
T (oC)
60
60
60
60
40
80
90
100
90
90
90
90
90
90
90
90
Yieldb (%)
trace
38
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
Entry
1
2
3
4
5
6
7
8
Promoter
TBHP
I2
BPO
Solvent
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMSO
dioxane
EL
toluene
DMF
DMF
DMF
DMF
nr
nr
31
56
67
65
48
51
62
58
63
37
64
65
PhI(AcO)2
4‐FC6H4
4‐IC6H4
4‐EtOCOC6H4
2,4‐Me2C6H3
4‐Mepyridin‐2‐yl
I2
I2
I2
I2
I2
I2
I2
I2
I2
I2
I2
I2
55
65
74
56
4s
4t
4u
C6H5
C6H5
9
aConditions: enaminone 1 (0.5 mmol), amine 2 (0.5 mmol), sulfur 3 (1.0 mmol), I2
(0.25 mmol) in 2 mL DMF, heating at 90 oC for 12 h. bYield of isolated product
based on enaminone 1.
10
11
12
13c
14d
As the efforts in exploring the expanded application, some NH‐
enaminones
e
15
5 containing cyclohexenone structure were then
f
16
employed to the standard catalytic conditions for the potential
synthesis of sulfur bridged cyclic enaminones. While such
products could only be accessed via copper‐catalyzed
enaminone C‐H thiolation in known literature,5i we were
delight to find that our metal‐free catalytic approach was
found to be practically applicable for the synthesis of target
aGeneral conditions: enaminone 1a (0.2 mmol), amine 2a (0.2 mmol), sulfur 3 (0.4
mmol) and promoter (0.1 mmol) in 2 mL solvent, stirred at 90 oC for 12 h. bYield
of isolated products base on 1a. cThe loading of I2 was 0.2 mmol. dThe loading of
I2 was 0.06 mmol. eReaction in the presence of 0.8 mmol TEMPO. fUnder N2.
Following the work on reaction optimization, examination on
the scope of this metal‐free protocol toward the synthesis of
sulfur bridged enaminones was carried out by subjecting
products 6 with fair yields (Scheme 1).
different enaminones
when performed in 0.5 mmol substrate scale, the synthesis of
sulfur bridged enaminones was found with broad application
scope. For the N,N‐dimethyl enaminone , the reactant with
1 and amines 2. As shown in Table 2,
4
1
various substructures of functionalized phenyls, heteroaryl (4i
,
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Scheme 1 The synthesis of sulfur bridged cyclohexenone‐based enaminones
step for the cascade reaction. Finally, running thVeiewreAartcictleioOnnlionef
9a with iodine by standard treatmeDnOt I:g10a.v10e39n/Co7OiBs0o0la6b19leE
iodinated species (Eq 6, Scheme 3), implying that iodine may
act as Lewis acid and do not participate the redox
transformation.
Interestingly,
enaminones
standard catalytic condition enabled the formation of sulfur
bridged chromones as products (Scheme 2). Unlike the
synthesis of and , the construction of involved in the
when
o‐hydroxylphenyl
functionalized
7
was employed as the enaminone substrate, the
8
4
6
8
annulations based on the intramolecular C‐N bond
oxygenation and the double C‐H thiolation. However, it should
Conclusions
In conclusion, by employing elemental sulfur as “S” source
and iodine as promoter, we have successfully achieved the
double C‐H thiolation reaction of enaminones, which allowed
the environmentally benign and economical synthesis of sulfur
bridged enaminones and chromones. The metal‐ and sensitive
oxidant‐free conditions as well as the open air operation
featured in this synthetic method ensure its high usefulness in
the synthesis of these elaborated enaminones and chromones.
be noted that reaction giving
group in the substrates . The enaminone containing electron
withdrawing group such as chlorine atom in the phenyl ring of
, for example, was not able undergo the reaction to yield
8 was sensitive to the functional
7
7
corresponding sulfur bridged chromone product.
O
O
O
standard
conditions
S
N
R
R
R
S8
OH
O
O
8a: R = H,
8b: R = 5-Me, 55%
8c: R = 4-OMe, 57%
51%
8
7
Experimental section
Scheme 2 Synthesis of sulfur bridged chromones
General procedure for the synthesis of sulfur bridged
enaminones 4
In order to gain some information in the possible reaction
process, a series of control experiments were conducted. First,
the N,N‐dimethyl enaminone 1a was found not reactive when
subjected with sulfur powder under standard reaction
conditions (Eq 1, Scheme 3). On the other hand, the reaction
of 1a and primary amine 2a reacted smoothly to give NH‐
based enaminone 9a with high yield (Eq 2, Scheme 3). No
reaction took place between the two substrates without using
iodine (Eq 3, Scheme 3). An additional entry of the model
reaction without using iodine led to the formation of the
target sulfur bridged enaminone 4a with very low yield (Eq 4,
Scheme 3), suggesting that iodine was crucial for the titled
double C‐H thiolation reaction. On the other hand, using
directly the NH‐enaminone 9a and elemental sulfur gave
target product 4a with reasonable yield (Eq 5, Scheme 3),
supporting that the transamination in Eq (2) was the initial
To a 25 mL round‐bottom flask were added enaminone
1 (0.5
mmol), amine (0.5 mmol), sulfur powder (1.0 mmol), I2
2
3
(0.25 mmol) and DMF (2 mL). Then the mixture was heated up
to 90 oC, and stirred at the same temperature for 12 hours
under air atmosphere (TLC). After cooling down to room
temperature, 5 mL of water was added, and the resulting
mixture was extracted with ethyl acetate. The organic phases
were collected and washed with small amount of water. After
drying with anhydrous Na2SO4, the solid was filtered and the
solvent was removed at reduced pressure. The resulting
residue was subjected to flash silica gel column
chromatography to provide pure products with the elution of
mixed petroleum ether/ethyl acetate (v/v = 10:1).
General procedure for the synthesis of sulfur bridged
enaminones 6 and chromones 8
To a 25 mL round‐bottom flask were added enaminone
5 or 7
(0.5 mmol), sulfur powder (1.0 mmol), I2 (0.25 mmol) and
3
DMF (2 mL). Then the mixture was heated up to 90 oC, and
stirred at the same temperature for 12 hours under air
atmosphere (TLC). After cooling down to room temperature, 5
mL of water was added, and the resulting mixture was
extracted with ethyl acetate. The organic phases were
collected and washed with small amount of water. After drying
with anhydrous Na2SO4, the solid was filtered and the solvent
was removed at reduced pressure. The resulting residue was
subjected to flash silica gel column chromatography to provide
pure products with the elution of mixed petroleum ether/ethyl
acetate (v/v = 10:1).
Acknowledgements
This work is financially supported by National Natural Science
Foundation of China (21562025), Natural Science Foundation
of Jiangxi Province (20161ACB21010) and the Science Fund for
Scheme 3 Control experiments
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