Copper-Catalyzed Domino Synthesis of 2-Arylthiochromanones through Concomitant C-S Bond Formations Using Xanthate as Sulfur Source

Article abstract of DOI:10.1021/acs.orglett.5b02977

An efficient domino process for the synthesis of thioflavanones has been described using a copper catalyst without addition of any external ligand. A variety of thioflavanones have been synthesized from easily accessible 2′-iodochalcones or 2′-bromochalco

Full text of DOI:10.1021/acs.orglett.5b02977

Letter
pubs.acs.org/OrgLett
Copper-Catalyzed Domino Synthesis of 2‑Arylthiochromanones
through Concomitant C−S Bond Formations Using Xanthate as
Sulfur Source
Subramani Sangeetha, Pandi Muthupandi, and Govindasamy Sekar*
Department of Chemistry, Indian Institute of Technology Madras, Chennai 600036, Tamil Nadu, India
S
* Supporting Information
ABSTRACT: An efficient domino process for the synthesis of
thioflavanones has been described using a copper catalyst without
addition of any external ligand. A variety of thioflavanones have been
synthesized from easily accessible 2′-iodochalcones or 2′-bromochal-
cones in excellent yield through in situ incorporation of sulfur using
xanthate as an odorless sulfur source. This domino process proceeds
through Cu-catalyzed C(aryl)−S bond formation by the coupling reaction
of xanthate with 2′-halochalcones followed by C−S bond cleavage of
thioester then S−C bond formation by intramolecular Michael addition.
ment of a new catalytic method which can overcome these
ulfur-containing compounds are extensively found in many
1
Spharmaceutical and bioactive natural products. Specifically, complications is still a primary topic of interest.
As part of our ongoing research toward Cu-catalyzed in situ
thioflavanones (2-phenylthiochroman-4-ones) and their ana-
logues display a variety of biological activities such as antifungal,
antibacterial, antioxidant, and inhibitory activity of nitric oxide
production.2 Furthermore, thioflavanones have been shown to
induce apoptosis in human breast cancer cell lines, thereby
serving as potent molecules for cancer treatment.3 Generally,
synthesis of thioflavanone requires sulfur-incorporated starting
materials. For example, the Michael addition of thiophenol with
ethyl cinnamates followed by Friedel−Crafts acylation,4
reduction of thioflavones to thioflavanones,5 cyclization of 2′-
mercaptochalcone,6 and domino reaction of 2′-iodothiophenol,
allene, and carbon monoxide using Pd catalyst7 have been
reported. Recently, synthesis of 2-arylthiochroman-4-ones using
sodium hydrosulfide solution was reported.8 However, these
methods are associated with several limitations such as a very
unpleasant smell of the thiol precursor, air-sensitive starting
material, costly metal catalyst, low yield, product mixtures, and a
required multistep synthesis. Therefore, the synthesis of
thioflavanones via an efficient catalytic method which can
overcome all these difficulties is highly desirable.
The carbon−sulfur bond constitutes a great proportion of
bond-forming reactions in organic synthesis. Thus, attention has
been drawn toward the investigation of catalytic methods for the
construction of a C−S bond.9 Transition-metal catalysts have
emerged as an efficient tool for C(aryl)−S bond formation.10
However, transition-metal-catalyzed domino reactions which
involve in situ incorporation of sulfur through concomitant
formation of two or more C−S bonds for the construction of
sulfur-containing cyclic architecture are less explored.11 The
strong coordination and adsorption ability of sulfur compounds
to transition metals concern the deactivation of catalyst,10a which
in turn limits development in this field. Hence, the accomplish-
generation of thiol using xanthate as a thiol surrogate, we have
reported one-pot synthesis of arylthioethers, benzothiazoles, and
benzothiophenes.12 Herein, we report Cu-catalyzed domino
synthesis of 2-arylthiochroman-4-ones from 2′-halochalcones
using odorless potassium ethyl xanthogenate as sulfur source
(Scheme 1).
Scheme 1. Domino Synthesis of 2-Arylthiochroman-4-ones
via Cu-Catalyzed Concomitant Formation of Two C−S Bonds
Initially, the reaction was performed with 2′-iodochalcone 1a
and potassium ethyl xanthogenate (3 equiv) in the presence of 10
mol % of Cu(OAc)2 and 10 mol % of 1,1′-binaphthyl-2,2′-
diamine [( )-BINAM] in N,N-dimethylformamide at 80 °C. To
our delight, the domino reaction yielded 78% of 2-phenyl-
thiochroman-4-one 2a through concomitant formation of two
C−S bonds (Table 1, entry 1). To understand the role of ligand,
the reaction was conducted without ligand. Interestingly, the
reaction yielded 86% of product (entry 2), and this result clearly
shows that ligand is not necessary for this reaction. The reaction
was studied with copper salts and solvents in the absence of
ligand to improve the efficiency of the reaction. Although the
reaction yielded the product with all copper salts, copper acetate
Received: October 14, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b02977
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Letter
a
a
Table 1. Optimization of Reaction Conditions
Scheme 2. Domino Synthesis of 2-Arylthiochroman-4-ones
b
xanthate
(equiv)
temp
(°C)
time
(h)
yield
entry
Cu salt
solvent
(%)
c
1
Cu(OAc)2
Cu(OAc)2
CuCl2
3
3
DMF
80
80
80
80
80
80
80
70
60
50
70
70
70
70
70
5
2
78
2
DMF
86
79
75
83
77
96
95
81
74
63
76
97
3
3
DMF
7
4
CuBr2
3
DMF
2
5
CuBr
3
DMF
6
6
CuCl
3
DMF
5
7
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
3
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
2
8
3
3
9
3
12
18
48
15
6
10
11
12
13
14
15
3
1
1.5
2
2
d
13
24
81
2
00
a
Standard reaction conditions: 1a (0.5 mmol), xanthate, and Cu
b
c
catalyst (10 mol %) in solvent (2 mL). Isolated yield. 10 mol % of
( )-BINAM was used as ligand. 5 mol % of Cu(OAc)2 was used.
d
remained to be the best choice as it provided the highest yield in a
short reaction time (entries 3−6 vs 2). In the study of solvent,
when the reaction was performed in dimethyl sulfoxide, a drastic
increase in yield of the product 2a (96%) was observed (entry 7).
In temperature study, when the reaction temperature was
reduced to 70 °C, the reactivity and yield were not altered much
(entry 8). However, further decrease in the temperature affected
the reactivity and yield (entries 9 and 10).
Next, various equivalents of xanthate were studied. The
reaction with 1 equiv of xanthate did not progress to full
completion, and the product was isolated in 63% yield (entry 11).
The reaction with 1.5 equiv of xanthate required longer reaction
time and provided 76% yield for the product (entry 12).
However, reaction with 2 equiv of xanthate gave 97% yield in 6 h
(entry 13). Moreover, the reactivity and yield of the product was
dropped when 5 mol % of Cu(OAc)2 was used (entry 14). Very
importantly, there was no product formation without Cu(OAc)2
catalyst (entry 15). From the optimization studies, it was found
that the reaction proceeded smoothly with 2 equiv of xanthate
and 10 mol % of Cu(OAc)2 in DMSO at 70 °C.
To explore the efficiency of the domino reaction, various 2′-
iodochalcones were exposed to the optimized reaction
conditions for the synthesis of 2-arylthiochromanones (Scheme
2). The domino reaction of 2′-iodochalcones with electron-
donating substituents progressed effortlessly and gave the
corresponding products 2a−g in excellent yield. The 2′-
iodochalcones with chloro, bromo, and fluoro substituents,
which can be useful in further derivatization, were found to be
suitable for this domino reaction (2h−j). The electron-
withdrawing group substituted 2′-iodochalcones were well
tolerated, and corresponding products 2k and 2l were isolated
in good yield.
a
Reaction conditions: 1 (0.5 mmol), xanthate (1 mmol) and
Cu(OAc)2 (10 mol %) in DMSO (2 mL) at 70 °C.
yield. Interestingly, substrates containing unprotected hydroxyl
groups were well tolerated and gave the products 2s and 2t in
good yield. Besides aryl groups, substrates with heteroaryl groups
were also found to be appropriate for this domino reaction, and
the corresponding products 2u−w were obtained in notable
yield. When 2′-iodochalcone, which was prepared from 2′-
iodoacetophenone and cinnamaldehyde, was subjected to
optimized reactions conditions, 2x was isolated in 77% yield.
Next, optimized reaction conditions were applied to 2′-
iodochalcones having substituents at the iodo-attached aryl
ring. The substituents such as bromo, phenyl, and acetylene were
applicable for the domino reaction and produced the
corresponding thioflavanones 2y, 2z, and 2aa in excellent yield.
Above all, dioxo-substituted 2′-iodochalcone was a reasonable
substrate and gave the corresponding thioflavanones 2ab in 88%
yield. The structure of 2h was unambiguously confirmed by
single-crystal XRD analysis (Figure 1).
It is noteworthy to mention that reactivity and yield are not
affected by the steric effect of substituents. For example, the
domino reaction of ortho-substituted 2′-iodochalcones took
place readily and provided the thioflavanones 2m−r in admirable
An attempt was then made to achieve the domino synthesis of
thioflavanones from less reactive 2′-bromochalcones 3. When
the optimized reaction conditions were applied to 2′-
bromochalcone 3a, the product formation was not observed.
B
DOI: 10.1021/acs.orglett.5b02977
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Scheme 5. Functionalization of Thioflavanones
Figure 1. Single-crystal X-ray structure of compound 2h (CCDC no.
1426817). Ellipsoids represent 30% probability level.
However, when the reaction temperature was increased to 100
°C, completion of the reaction was observed in 12 h and product
2a was isolated in 83% yield (Scheme 3). Other substituted 2′-
Scheme 3. Domino Synthesis of 2-Arylthiochroman-4-ones
a
from Less Reactive 2′-Bromochalcones
Initially, the domino reaction was quenched with hydrochloric
acid, but thiol was not observed. Since thiol can move to a
Michael or coupling reaction immediately, it could be very
difficult to detect. Then, it was speculated that the reactivity can
be controlled if the reaction is conducted in moderate or less
polar solvent as the reaction is very facile in DMSO solvent.
Interestingly, compound 10a was isolated in 14% yield when the
reaction was conducted in ethyl acetate (Scheme 6a). Similarly,
a
Reaction conditions: 3 (0.5 mmol), xanthate (1 mmol), and
Cu(OAc)2 (10 mol %) in DMSO (2 mL) at 100 °C.
Scheme 6. Controlled Reactions
bromochalcones were also found to be suitable substrates for this
domino reaction and provided the thioflavanones 2a, 2b, 2f, 2m,
and 2r in admirable yield.
To evaluate the efficacy of this domino reaction in gram scale,
the reaction was investigated with 1 g of 2′-iodochalcone.
Interestingly, the thioflavanone 2a was isolated in excellent yield
(93%) in 6 h without compromising the optimized reaction
conditions (Scheme 4).
Scheme 4. Gram-Scale Synthesis
Thioflavanones can be easily functionalized to a variety of
important chemical entities (Scheme 5). For example, sulfur was
oxidized to sulfone (4a) with excess m-chloroperbenzoic acid
(m-CPBA) and sulfoxide (5a) as a 1:1 mixture of diastereomers
with controlled oxidation. The keto group of thioflavanone was
reduced to alcohol (6a) as single diastereomer by simple
reduction with sodium borohydride. Reductive amination of
thioflavanones gave amine (7a) as 1:1 mixture of diastereomers.
The thioflavanone was completely reduced to 2-phenylthiochro-
man (8a). The active methylene group was reacted with aldehyde
to give substituted thiochromenone (9a).
To understand the mechanism of newly developed domino
reaction, an investigation was led to observe any possible
intermediates. As the reaction is expected to proceed either
through coupling followed by Michael addition or Michael
addition followed by coupling, reactions were conducted to trap
the appropriate intermediate.
compound 10a was observed with other less polar solvents such
as 1,4-dioxane and toluene. These results confirm that the
reaction proceeds through formation of compound 10a. When
compound 10a was exposed to optimized reaction conditions,
94% of 2a was isolated in 1 h (Scheme 6b). The reaction without
xanthate took 18 h to give 2a in 82% yield (Scheme 6c), whereas
the reaction with only 1 equiv of xanthate was completed in 1 h
(Scheme 6d). These reactions clearly show that both copper
acetate and xanthate can promote the Michael addition
independently. However, xanthate is more facile toward Michael
addition than copper acetate (Scheme 6c vs Scheme 6d).
C
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Furthermore, it was noticed that addition of water (10 equiv)
with DMSO increased the reactivity, and the reaction had gone
to completion in 5 h, whereas the reaction with dry DMSO under
N2 atmosphere decreased the reactivity and the reaction took 13
h for completion. These reactions are evidence for involvement
of residual water in DMSO or adventitious water in the reaction
medium.
ACKNOWLEDGMENTS
■
We thank the DST New Delhi (Project No. SB/S1/OC-72/
2013) for financial support for this project. S.S. thanks
IITMadras for a fellowship. P.M. thanks DST for a fellowship.
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iodochalcone with copper acetate may give intermediate A,
which in the presence of potassium ethyl xanthate leads to
intermediate B. The reductive elimination of intermediate B
provides intermediate C, which was isolated in less polar solvent.
Then, intermediate C undergoes Michael addition with the help
of copper acetate and potassium ethyl xanthate to give the
product. However, a detailed mechanistic study and application
of this newly developed methodology and its asymmetric version
are in progress.
In conclusion, we have developed an efficient domino process
for the synthesis of thioflavanones from 2′-iodochalcone using
copper catalyst without addition of any external ligand and
xanthate as the sulfur precursor. The domino reaction proceeds
through in situ incorporation of sulfur by concomitant formation
of two carbon−sulfur bonds to provide thioflavanones in
excellent yield. Thioflavanones were also synthesized from 2′-
bromochalcones and derivatized to other important organic
molecules. This method can be a general approach for the
synthesis of thioflavanones as the reaction requires easily
accessible starting materials, avoids the unpleasant smell of
thiol precursor, uses inexpensive copper catalyst, and provides
excellent yield.
ASSOCIATED CONTENT
* Supporting Information
■
(12) (a) Prasad, D. J. C.; Naidu, A. N.; Sekar, G. Tetrahedron Lett. 2009,
50, 1411. (b) Prasad, D. J. C.; Sekar, G. Org. Lett. 2011, 13, 1008.
(c) Prasad, D. J. C.; Sekar, G. Org. Biomol. Chem. 2013, 11, 1659.
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.5b02977.
Detailed experimental procedures, characterization data,
and copies of NMR spectra (PDF)
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: gsekar@iitm.ac.in.
Notes
The authors declare no competing financial interest.
D
DOI: 10.1021/acs.orglett.5b02977
Org. Lett. XXXX, XXX, XXX−XXX