Ammonium iodide-mediated regioselective chalcogenation of chromones with diaryl disulfides and diselenides

Article abstract of DOI:10.1080/00397911.2017.1364766

A metal-free method for the synthesis of 3-chalcogenyl-chromones/quinolones from chromones/quinolones and diorganyl dichalcogenides using ammonium iodide under air was developed. This approach allowed the preparation of a wide range of 3-selenyl- and 3-sulfenyl-chromones/quinolones in good to excellent yields.

Full text of DOI:10.1080/00397911.2017.1364766

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: http://www.tandfonline.com/loi/lsyc20
Ammonium Iodide-Mediated Regioselective
Chalcogenation of Chromones with Diaryl
Disulfides and Diselenides
Tao Guo
To cite this article: Tao Guo (2017): Ammonium Iodide-Mediated Regioselective Chalcogenation
of Chromones with Diaryl Disulfides and Diselenides, Synthetic Communications, DOI:
10.1080/00397911.2017.1364766
To link to this article: http://dx.doi.org/10.1080/00397911.2017.1364766
View supplementary material
Accepted author version posted online: 11
Aug 2017.
Submit your article to this journal
Article views: 12
View related articles
View Crossmark data
Full Terms & Conditions of access and use can be found at
http://www.tandfonline.com/action/journalInformation?journalCode=lsyc20
Download by: [Australian Catholic University]
Date: 21 August 2017, At: 06:16

Ammonium iodide-mediated regioselective chalcogenation of
chromones with diaryl disulfides and diselenides
Tao Guo*
School of Chemistry and Chemical Engineering, Henan University of Technology, Zhengzhou,
Henan, China
School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, Henan, China
*Address correspondence to Tao Guo. Tele: + 86 371 6775 6718. E-mail: taoguo@haut.edu.cn
ABSTRACT
A metal-free method for the synthesis of 3-chalcogenyl-chromones/quinolones from
chromones/quinolones and diorganyl dichalcogenides using ammonium iodide under air was
developed. This approach allowed the preparation of a wide range of 3-selenyl- and
3-sulfenyl-chromones/quinolones in good to excellent yields.
GRAPHICAL ABSTRACT
1

KEYWORDS: 3-selenyl-chromones, 3-sulfenyl-chromones, chalcogenation, c-s/se bond,
quinolone
Introduction
Recently, there has been an increasing interest for efficient methods to construction of the
C–S and C-Se bonds owing to their important roles as structural motifs in a wide range of
biologically and pharmaceutically active compounds (Figure 1).[1] In addition,
organochalcogenides (S, Se) play an important role in material sciences,[2] and also have
fundamental applications in organic synthesis and catalysis.[3] As a consequence, significant
efforts have been devoted to the synthesis of new sulfur/selenium-containing substances through
selective C-S/Se bond formation in the last few decades.[4]
Among the wide range of strategies employed, metal-catalyzed C-H bond activation has
proven to be one of the most powerful approaches for the synthesis of organochalcogen
compounds. Palladium and nickel are often used as the choice of metal catalysts.[5] Recently,
Zeni and co-workers reported a copper oxide nanoparticle-catalyzed synthesis of
2-(organochalcogen)thiazoles via direct C-H bond activation in thiazoles, avoiding using noble
metal catalyst (Scheme 1a).[6] With the development of green chemistry and the enhancement of
people’s awareness of environmental protection, many researchers have paid much attention to
screening various non-metal reagents for the synthesis of organochalcogen compounds. For
instance, Braga realized an easy access to 3-chacogenyl-indoles from indoles and diorganyl
2

dichalcogenides using DMSO/I2 under metal-free condition in good to excellent yields (Scheme
1b).[7] Very recently, Braga and co-workers developed an efficient and regioselective
iodide-induced chalcogenation of imidazo[1,2-a]pyridines with diorganoyl dichalcogenides in
the absence of a metal catalyst (Scheme 1c).[8] From the examples above, we found that the
diorganoyl dichalcogenides were proved to be promising chalcogenation reagents with the
substrate compatibility and stability. Thus, more transformations related to diorganoyl
dichalcogenides as chalcogenation reagents are still needed to be explored.
Chromones represent one of the most prevalent structural heterocycles in natural
products, plant physiology and pharmaceuticals. Their low toxicity and extensive biological and
pharmaceutical activities, including antitumor,[9] antibacterial,[10] and antioxidant,[11] have led
them to the development of a variety of general approaches for synthesizing their large number
of derivatives or analogs. To synthesize these valuable derivatives, we herein report an
ammonium iodide-mediated chalcogenation of chromones/quinolones with diaryl disulfides and
diselenides for the synthesis of ArS/ArSe-substituted chromones/quinolones derivatives (Scheme
1d). This approach uses air as the oxidant instead of pure oxygen or other oxidants, without a
metal catalyst.
Results and Discussion
Chromone derivatives and diaryl disulfides are commercially available while diaryl
diselenides could be readily prepared in gram-scale according to the known procedures.[12] Our
3

effort was initially focused on the direct sulfenylation of chromone 1a with diphenyl disulfide 2a
as a model reaction. The results are summarized in Table 1. First, TBHP and K2S2O8 were
employed as the oxidant, and CuI was used as catalyst at 100C in DMF; Both reactions did not
give the desired product 3a (entries 1-2). Using DMSO as a oxidant with CuI gave 30% yield of
3a (entry 3). When I2 was selected as a catalyst with DMSO, a slightly decreased yield was
obtained (entry 4). By conducting the catalyst with KI, only a trace amount of the product was
observed (entry 5). The combination of NH4I and DMSO in DMF at 100C resulted in 3a at a
46% isolated yield (entry 6). Upon raising the temperature to 135C, 3a was obtained in 61%
yield (entry 7). To our excitement, it was found that using NH4I with air in DMF was greatly
beneficial for the improvement of yield (entry 8). With an attempt to improve the efficiency of
the reaction, further efforts related to the influence of solvents were examined. With dioxane and
toluene as solvent, 3a was isolated in 33% and 51% yields, respectively (entries 9-10). DMAc
was the most suitable solvent and gave the best result in 88% yield (entry 11). In relation to the
sources of iodine in the reaction system, a negative effect was observed when KI, I2 and TBAI
were used instead of NH4I and this resulted in 35%, 48% and 17% yields of the product 3a,
respectively (entries 12-14). Metal catalyst, such as FeCl3, CuBr were proved to be less effective
(entries 15-16). In addition, obviously decreased yields were obtained while further attempt to
adjusting the reaction concentration and temperature (entries 17-19). Further modifications, such
as catalyst loading, reaction time, and decreasing the amount of diphenyl disulfide did not
4

provide improvement of the yield of 3a. Therefore, we decided to use conditions in entry 11 as
the standard reaction conditions.
After successfully identifying the optimal reaction conditions for the synthesis of
3-sulfanyl-chromone, we turned our attention to the substrate scope and generality. A wide range
of chromones were first evaluated in the reaction with diphenyl disulfide (2a). Chromones with
electron-donating and weak electron-withdrawing substituents (such as Me, MeO, F, Cl, and Br)
at the 6-position or 7-position of the ring gave the desired products (3a−f) in good to excellent
yields. It is worth noting that Me and Cl-disubstituted chromones also exhibited good reactivity
and provided the expected product in 78% yield (3 g). To expand the scope of this method,
various diaryl disulfides were evaluated in reaction with chromones. The reaction efficiency was
not significantly affected by the electronic variation of substrates. The sulfenylation reactions of
chromone 1a with the electron-donating groups, such as methyl and methoxy groups at para-
and meta- positions in diphenyl disulfide proceeded smoothly affording the corresponding
products 3hꢀ, 3j-3k in 91%, 71%, 84% yields, respectively. Similar yields were observed with
electron-withdrawing groups, such as halogenated diaryl disulfides (3l, 3n). The efficiency of the
sulfenylation was slightly affected by steric hindrance. For instance, ortho-chloro-diphenyl
disulfide as sulfenylation reagent gave an obviously decreased yield (33 mm). It was gratifying
to find that polycyclic, and heterocyclic disulfides could also be applied, furnishing the desired
products 3o and 3p in 80% and 51% yields (Table 2).
5

After exploring the versatility and diversity of the present ammonium iodide-mediated
coupling reactions of chromones with diaryl disulfides, its application toward the synthesis of
diverse selenylchromones was explored. We were pleased to observe that selenenylation of
chromone derivatives went smoothly, affording the corresponding 3-selenyl-chromones in
45%–73% yields. Notably, diaryl diselenides and chromones with electron-rich (Me, OCH3) and
electron-poor (Cl, Br, F) groups on the phenyl ring were tolerated under these coupling
conditions. Furthermore, the presence of the strong electron-withdrawing group, such as 6-nitro
chromone, generated the product 5 h in 45% yield. Moveover, expanding the scope from the
diaryl diselenide to polycyclic diselenide was also possible, leading to the formation of 5o in
57% yield (Table 3).
To further examine whether our reaction conditions are also suitable for the
chalcogenation of other compounds, the reactions of quinolone with diphenyl disulfide and
diselenide were carried out under the same reaction conditions. Quinolone represents a
significant class of organic molecules with core entities in many commercially available drugs,
including Ofloxacin, Perfloxacin, Enoxacin, Ciprofloxacin, etc. Luckily, the chalcogenation
reactions worked well, giving the desired products 7a, 7b in 68% and 53% yields, respectively.
These results have displayed a wide application scope of our method (Scheme 2).
To investigate the reaction mechanism, some control experiments were conducted. 86%
and 85% yields of 3a were obtained in the presence of the radical inhibitor (TEMPO, 2.0 equiv.)
6

or radical scavenger (BHT, 2.0 equiv.). These results could indicate that radical intermediates are
not involved in these couplings (Scheme 3). On the basis of these data and previous studies,[13]
a
possible reaction mechanism for the current ammonium iodide-mediated regioselective
chalcogenation of chromones was proposed as shown in Scheme 4. First, NH4I was split into
NH3 and HI at 135C, and then HI was further oxidized to iodine with air. Then coordination of
the chalcogenation reagents with iodine gives electrophilic species ArY–I, which further reacted
with chromone to form reaction intermediate II. Finally, deprotonation of II to give the
corresponding products.
Conclusion
In summary, we have developed a novel and regioselective ammonium iodide-mediated
C-S/C-Se bond-formation protocol involving chromones/quinolones with diaryl disulfides and
diselenides with air as oxidant. This strategy provides a convenient and efficient route for the
preparation of diverse 3-sulfenyl- and 3-selenyl-chromone/quinolone derivatives. Many
functional groups tolerated well under the standard conditions, delivering good to excellent
yields of chromone/quinolone derivatives. Further library construction and biological activity
evaluation of the derivatives are ongoing in our laboratory.
Experimental
General
7

Reactions were monitored by thin layer chromatography (TLC), on glass plates coated
with silica gel with fluorescent indicator (Huanghai, HSGF254). Flash chromatography was
performed on silica gel (Huanghai, 300–400) using PE-EtOAc as eluent. 1H NMR and 13C NMR
spectra were recorded on a Bruker (500, 400 MHz) with chemical shift values in ppm relative to
TMS (δH 0.00 and δC 0.0) or residual chloroform (δH 7.28 and δC 77.1) as standard. Mass
spectra were recorded on Thermo-Q Exactive Plus instrument or HP-5989A instrument.
General procedure
0.5 mL DMAC was added into the flask charged with 0.25 mmol of flavones, 0.25 mmol
of diaryl dichalcogenides, NH4I (1 mmol). The mixture was stirred at 135C for 12 hours, then
cooled down to room temperature, diluted with 20 mL ethyl acetate and washed with 10 mL
H2O. The aqueous layer was extracted twice with ethyl acetate (5 mL) and the combined organic
phase was dried over Na2SO4. After evaporation of the solvents the residue was purified by flash
column chromatography (silica gel, PE/EtOAc = 5:1) to afford the desired products 3.
Complete experimental details are available online in the Supplemental Material.
Acknowledgments
Financial support from Open Project of Grain&Corn Engineering Technology Research
Center in State Administration of Grain (No. 24400042), Doctor Fund of Henan University of
Technology (No. 2013BS053), Colleges and Universities Key Research Program Foundation of
8

Henan Province (No.17A150006), Science and Technology Foundation of Henan Province
(No.172102310621) and Fundamental Research Funds for the Henan Provincial Colleges and
Universities in Henan University of Technology (No. 2015QNJH08) are greatly appreciated. The
authors are also thankful to Jun Liu, Henan University of Technology, for her assistance for the
NMR analysis.
References
[1] (a) Manjare, S. T.; Kim, Y.; Churchill, D. G. Acc. Chem. Res. 2014, 47, 2985; (b) Manna, D.;
Roy, G.; Mugesh, G. Acc. Chem. Res. 2013, 46, 2706; (c) Press, D. J.; Back, T. G. Org.
Lett. 2011, 13, 4104; (d) Sancineto, L.; Mariotti, A.; Bagnoli, L.; Marini, F.; Desantis, J.;
Iraci, N.; Santi, C.; Pannecouque, C.; Tabarrini, O. J. Med. Chem. 2015, 58, 9601; (e)
Rafique, J.; Saba, S.; Canto, R. F. S.; Frizon, T. E. A.; Hassan, W.; Waczuk, E. P.; Jan,
M.; Back, D. F.; Da Rocha, J. B. T.; Braga, A. L. Molecules, 2015, 20, 10095; (f) Zhao,
W.; Xie, P.; Bian, Z.; Zhou, A.; Ge, H.; Niu, B.; Ding, Y. RSC Adv. 2015, 5, 59861; (g)
Zhong, S.; Liu, Y.; Cao, X.; Wan, J.-P. Chem. Cat. Chem. 2017, 9, 465; (h) Ren, R.; Wu,
Z.; Zhu, C. Chem. Commun. 2016, 52, 8160; (i) Wang, M.; Wu, Z.; Zhu, C. Org. Chem.
Front. 2017, 4, 427.
[2] (a) Frizon, T. E.; Rafique, J.; Saba, S.; Bechtold, I. H.; Gallardo, H.; Braga, A. L. Eur. J. Org.
Chem. 2015, 16, 3470; (b) Gu, J.; Zhao, Z.-Q.; Ding, Y.; Chen, H.-L.; Zhang, Y.-W.;
Yan, C.-H. J. Am. Chem. Soc. 2013, 135, 8363; (c) Patra, A.; Wijsboom, Y. H.; Leitus,
G.; Bendikov, M. Chem. Mater. 2011, 23, 896; (d) Haid, S.; Mishra, A.; Weil, M.;
Uhrich, C.; Pfeiffer, M.; Bäuerle, P. Adv. Funct. Mater. 2012, 22, 4322.
[3] (a) Modha, S. G.; Mehtab, V. P.; Eycken, E. V. V. Chem. Soc. Rev. 2013, 42, 5042; (b)
Godoi, B.; Schumacher, R. F.; Zeni, G. Chem. Rev. 2011, 111, 2937; (c) Kyne, S. H.;
Schiesser, C. H. Chem. Commun. 2014, 50, 12040; (d) Zhu, F.; Wang, Z.-X. Org. Lett.
2015, 17, 1601; (e) Cresswell, A. J.; Eey, S. T.-C.; Denmark, S. E. Nat. Chem. 2015, 7,
146; (f) Luo, J.; Zhu, Z.; Liu, Y.; Zhao, X. Org. Lett. 2015, 17, 3620; (g) Trenner, J.;
Depken, C.; Weber, T.; Breder, A. Angew. Chem. Int. Ed. 2013, 52, 8952; (h) Singh, F.
V.; Wirth, T. Org. Lett. 2011, 13, 6504; (i) Tidei, C.; Sancineto, L.; Bagnoli, L.;
Battistelli, B.; Marini, F.; Santi, C. Eur. J. Org. Chem. 2014, 27, 5968; (j) Movassagh, B.;
Yousefi, A.; Momeni, B. Z.; Heydari, S. Synlett 2014, 25, 1385; (k) Movassagh, B.;
Takallou, A. Synlett 2015, 26, 2247; (l) Mohammadi, E.; Movassagh, B. Tetrahedron
Lett. 2014, 55, 1613.
9

[4] (a) Samanta, R.; Antonchick, A. P. Angew. Chem., Int. Ed. 2011, 50, 5217; (b) Shen, C.; Xia,
H.; Yan, H.; Chen, X.; Ranjit, S.; Xie, X.; Tan, D.; Lee, R.; Yang, Y.; Xing, B.; Huang,
K.-W.; Zhang, P.; Liu, X. Chem. Sci. 2012, 3, 2388; (c) Xu, R.; Wan, J.-P.; Mao, H.; Pan,
Y. J. Am. Chem. Soc. 2010, 132, 15531; (d) Yang, Y.; Hou, W.; Qin, L.; Du, J.; Feng, H.;
Zhou, B.; Li, Y. Chem.–Eur. J. 2014, 20, 416; (e) Zhu, J.; Chen, Z.; Xie, H.; Li, S.; Wu,
Y. Org. Lett. 2010, 12, 2434; (f) Zhao, W.; Xie, P.; Bian, Z.; Zhou, A.; Ge, H.; Zhang,
M.; Ding, Y.; Zheng, L. J. Org. Chem. 2015, 80, 9167; (g) Ding, Y.; Wu, W.; Zhao, W.;
Li, Y.; Xie, P.; Huang, Y.; Liu, Y.; Zhou, A. Org. Biomol. Chem. 2016, 14, 1428; (h)
Wang, D.; Guo, S.; Zhang, R.; Lin, S.; Yan, Z. RSC Adv. 2016, 6, 54377; (i) Ravi, C.;
Mohan, D. C.; Adimurthy, S. Org. Biomol. Chem. 2016, 14, 2282; (j) Paul, S.; Shrestha,
R.; Edison, T. N. J. I.; Lee, Y. R.; Kim, S. H. Adv. Synth. Catal. 2016, 358, 3050; (k)
Rafique, J.; Saba, S.; Rosário, A. R.; Braga, A. L. Chem.–Eur. J. 2016, 22, 11854; (l)
Ravi, C.; Mohan, D. C.; Adimurthy, S. Org. Lett. 2014, 16, 2978; (m) Huang, D; Chen,
J.; Dan, W.; Ding, J.; Liu, M.; Wu, H. Adv. Synth. Catal. 2012, 354, 2123; (n) Ferreira,
N. L.; Azeredo, J. B.; Fiorentin, B. L.; Braga, A. L. Eur. J. Org. Chem. 2015, 23, 5070.
[5] (a) Iwasaki, M.; Kaneshika, W.; Tsuchiya, Y.; Nakajima, K.; Nishihara, Y. J. Org. Chem.
2014, 79, 11330; (b) Müller, T.; Ackermann, L. Chem.–Eur. J. 2016, 22, 14151; (c) Qiu,
R.; Reddy, V. P.; Iwasaki, T.; Kambe, N. J. Org. Chem. 2015, 80, 367; (d) Jin, W.;
Zheng, P.; Law, G.-L.; Wong, W.-T. J. Organomet. Chem. 2016, 812, 66.
[6] Rosario, A. R.; Casola, K. K.; Oliveira, C. E. S.; Zeni, G. Adv. Synth. Catal. 2013, 355, 2960.
[7] Azeredo, J. B.; Godoi, M.; Martins, G. M.; Silveira, C. C.; Braga, A. L. J. Org. Chem. 2014,
79, 4125.
[8] Rafique, J.; Saba, S.; Rosário, A. R.; Braga, A. L. Chem.-Eur. J. 2016, 22, 11854.
[9] (a) Han, C. Cancer Lett. 1997, 114, 153; (b) Birt, D. F.; Hendrich, S.; Wang, W.; Pharmacol.
Ther. 2001, 90, 157.
[10] (a) Xu, H. X.; Lee, S. F.. Phytother. Res. 2001, 15, 39; (b) Hamiltonmiller, J. M. T.
Antimicrob. Agents Chemother. 1995, 39, 2375.
[11] (a) Grassmann, J.; Hippeli, S.; Elstner, E. F. Plant Physiol. Biochem. 2002, 40, 471; (b)
Miura, S.; Watanabe, J.; Sano, M.; Tomita, T.; Osawa, T.; Hara, Y.; Tomita, I. Biol.
Pharm. Bull. 1995, 18, 1.
[12] (a) Li, Z.; Ke, F.; Deng, H.; Xu, H.; Xiang, H.; Zhou, X. Org. Biomol. Chem. 2013, 11,
2943; (b) Singh, D.; Deobald A. M.; Camargo, L. R. S.; Tabarelli, F.; Rodrigues, O. E.
D.; Braga, A. L. Org. Lett. 2010, 12, 3288.
[13] (a) Dai, C.; Xu, Z.; Huang, F.; Yu, Z.; Gao, Y.-F. J. Org. Chem. 2012, 77, 4414; (b) Li, Z.;
Hong, J.; Zhou, X. Tetrahedron 2011, 67, 3690; (c) Zhao, W.; Zhou, A. Chem. Cat.
Chem. 2015, 7, 3464; (d) Parumala, S. K. R.; Peddinti, R. K. Green Chem. 2015, 17,
4068.
10

Table 1. Screening and optimization of the reaction conditions
Entrya
1
Catalyst
CuI
Oxidant
TBHP
K2S2O8
DMSO
DMSO
DMSO
DMSO
DMSO
air
Solvent
DMF
Temp. (oC)
100
Yieldb [%]
NR
NR
30
2
CuI
DMF
100
3
CuI
DMF
100
4
I2
DMF
100
28
5
KI
DMF
100
trace
46
6
NH4I
NH4I
NH4I
NH4I
NH4I
NH4I
KI
DMF
100
7
DMF
135
61
8
DMF
135
78
9
air
dioxane
toluene
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
135
33
10
11
12
13c
14
15
16
17d
18e
air
135
51
air
135
88
air
135
35
I2
air
135
82
TBAI
FeCl3
CuBr
NH4I
NH4I
air
135
17
air
135
NR
NR
62
air
135
air
135
air
135
73
11

19
NH4I
NH4I
air
air
DMAc
DMAc
110
135
58
66
20f
aReaction conditions: chromone 1a (0.25 mmol), diphenyl disulfide 2a (1.0 equiv.), KI and I2 (1.0 equiv.), NH4I (4.0 equiv.),
metal catalyst (0.2 equiv.), Oxidant (3.0 equiv.), solvent (0.5mLꢀ), 12hꢀ. b Isolated yields. c I2 (2.0 equiv.). d DMAc (0.25mLꢀ). e
DMAc (1mLꢀ). f NH4I (2.0 equiv.).
12

Table 2. Synthesis of 3-sulfanyl-chromones ab
––––––––––––––––––––––––––––––––––––––––––––––––––––––
a Reaction conditions: chromone 1 (0.25 mmol), diphenyl disulfide 2 (1.0 equiv.), NH4I (4.0 equiv.), DMAc (0.5mLꢀ), 12hꢀ under
air. b Isolated yields.
13

Table 3. Synthesis of 3-selenyl-chromonesab
–––––––––––––––––––––––––––––––––––––––––––––––––––––––
a Reaction conditions: chromone 1 (0.25 mmol), diaryl diselenide 4 (1.0 equiv.), NH4I (5.0 equiv.), DMF (0.5mLꢀ), 12hꢀ under
air. b Isolated yields.
14

Figure 1. biologically active organochalcogen compounds.
15

Scheme 1. chalcogenation methods with the use of diorganoyl dichalcogenides.
16

Scheme 2. Synthesis of 3-sulfenyl- and 3-selenyl-quinolones.
17

Scheme 3. Control experiments.
18

Scheme 4. Proposed mechanism for the formation of 3 or 5.
19