KIO3-catalyzed aerobic cross-coupling reactions of enaminones and thiophenols: Synthesis of polyfunctionalized alkenes by metal-free C-H sulfenylation

Article abstract of DOI:10.1021/acs.orglett.5b03608

The synthesis of polyfunctionalized aminothioalkenes has been realized via the direct C-H sulfenylation of enaminones and analogous enamines. These cross-coupling reactions have been achieved by simple KIO₃ catalysis under aerobic conditions wi

Full text of DOI:10.1021/acs.orglett.5b03608

Letter
pubs.acs.org/OrgLett
KIO3‑Catalyzed Aerobic Cross-Coupling Reactions of Enaminones
and Thiophenols: Synthesis of Polyfunctionalized Alkenes by
Metal-Free C−H Sulfenylation
Jie-Ping Wan,*,† Shanshan Zhong,† Lili Xie,† Xiaoji Cao,‡ Yunyun Liu,† and Li Wei†
†College of Chemistry and Chemical Engineering, Jiangxi Normal University, Nanchang 330022, China
‡Research Centre of Analysis and Measurement, Zhejiang University of Technology, 18 Chaowang Road, Hangzhou,
Zhejiang 310014, China
S
* Supporting Information
ABSTRACT: The synthesis of polyfunctionalized aminothioalkenes has
been realized via the direct C−H sulfenylation of enaminones and
analogous enamines. These cross-coupling reactions have been achieved
by simple KIO3 catalysis under aerobic conditions without employing
any transition metal catalyst or additional oxidant. The employment of
bio-based green solvent ethyl lactate as the reaction medium constitutes
another sustainable feature of the present work.
cocatalyzed arylation of a cyclic enaminone C−H bond for the
he functionalization of alkene C−H bonds represents a
Tclass of fundamental transformations in contemporary synthesis of α-aryl enaminones (Scheme 1A). Du and Zhao have
organic synthesis.1 The transition-metal-catalyzed Heck reaction,
for example, has been identified as a highly practical strategy in
realized the C−H oxygenation of primary enamines for the facile
synthesis of aminoalkenyl esters and oxazoles (Scheme 1B).16
Recently, the group17 has again developed an interesting method
both laboratory and industrial synthesis because it offers the
generally applicable pathway of Pd-catalyzed C−H alkenylation.2
for the synthesis of diaminoalkenes via TBHP/TBAI-promoted
enaminone C−H amination by using phthalimides or azoles as
amine sources (Scheme 1C). Amazingly, although the construc-
tion of C−C, C−N, and C−O bond formations via the cross-
coupling of the enaminone C−H bond have been achieved, corre-
sponding cross-coupling reactions toward C−S bond formation
have not been reported despite the known report of enamide
C−H sulfenylation.18 Based on our research interest in both the
chemistry of enaminones13b−f and C−H bond functionaliza-
tion,19 we report the first example of the C−S bond-formation-
based synthesis of polyfunctionalized aminothioalkenes via
enaminone C−H sulfenylation under metal-free, aerobic condi-
tions by utilizing only a catalytic amount of KIO3 in a green
medium (Scheme 1D).
The exploration starts from the coupling reaction between
enaminone 1a and thiophenol 2a. First, a blank reaction in
DMSO without using catalyst did not give any product (entry 1,
Table 1). When ionic iodine reagents such as CuI, KI,
PhI(OAc)2, and KIO3 were employed, the C−H sulfenylation
of enaminone 1a giving product 3a was observed. The KIO3
exhibited much higher activity in promoting the formation of 3a
Following the booming progress of transition metal catalysis
and oxidative coupling chemistry,3 a number of complementary
versions, such as radical process-based oxidative alkene C−H
alkylation,4 arylation,5 alkenylation,6 and acylation,7 have been
developed to enable more sophisticated alkenylation-based
syntheses. Similar to the advances in C−C bond-forming
reactions, the transition-metal-catalyzed direct generation of
C−heteroatom bonds, including C−N,8 C−S,9 and C−P10
bonds via alkene C−H functionalization, has also achieved
splendid progress in recent years.
On the other hand, following the daily increasing concern with
the development of sustainable organic synthesis, transition-
metal-free catalysis has rapidly evolved as a new trend in the
chemistry of C−H functionalization.11 In this context, research
on metal-free alkene C−H functionalization has accordingly
received dramatic attention.12 Enaminones are a class of useful
functional alkenes showing prevalent application in the synthesis
of organic products with enriched structural diversity.13 Due
to the invaluable utilities of enaminones, developing efficient
methodologies to synthesize polyfunctionalized enaminones or
heterocycles containing an enaminone backbone by direct C−H
functionalization has attracted much interest.14 As typical examples,
Georg and co-workers15 have reported the Pd(OA)2/Cu(OA)2
Received: December 22, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b03608
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
reaction medium suggested that conventional organic solvents
could generally mediate the reaction; however, we were delighted
to find that ethyl lactate (EL), a biomass-derived, nontoxic, and
biodegradable chemical, turned out to be the most favorable
medium (entries 7−12, Table 1).20 Additional experiments at
reducing the amount of KIO3 proved that the 30 mol % loading
was appropriate (entries 13−15, Table 1). Finally, examination
of the effect of reaction temperature implied that 90 °C heating
was favored in the reaction (entries 16−18, Table 1).
Scheme 1. Different Catalytic Methods for Enaminone C−H
Functionalization
Investigation of the application scope of this method using
different substrates was then conducted under the optimized
conditions.21 At first, a class of different N,N-dimethylamino-
functionalized enaminones were subjected with p-tolylthiophe-
nol, and the results from the reactions demonstrated general
tolerance of enaminones, including both aryl- and alkyl-
functionalized ones in the synthesis of corresponding amino-
thioalkenes (3a−3o, Figure 1). Besides aryl-functionalized
a
Table 1. Optimization of the Reaction Conditions
b
entry
catalyst
CuI
solvent (mL)
t (°C)
yield (%)
1
2
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMF
toluene
CH3CN
EtOH
1,4-dioxane
EL
100
100
100
100
100
100
100
100
reflux
reflux
100
100
100
100
100
110
90
nr
15
20
45
60
trace
70
15
35
25
18
75
80
84
80
78
85
80
3
KI
4
PhI(OAc)2
KIO3
MnO2
KIO3
KIO3
KIO3
KIO3
KIO3
KIO3
KIO3
KIO3
KIO3
KIO3
KIO3
KIO3
5
6
7
8
9
10
11
12
c
13
EL
d
14
EL
e
15
EL
d
16
EL
d
17
EL
d
18
EL
80
Figure 1. Application scope of E-configured enamines. General
conditions: 1 (0.3 mmol), 2 (0.36 mmol), KIO3 (0.09 mmol) in
1.5 mL of EL, stirred at 90 °C for 12 h (TLC). The yield of isolated
product based on 1 was reported.
a
General conditions: 1a (0.3 mmol), 2a (0.36 mmol), catalyst
(0.3 mmol) in solvent (1.5 mL), stirred for 12 h (nr = no reaction).
b
c
Yield of isolated product based on 1a. Catalyst (0.15 mmol).
d
e
Catalyst (0.09 mmol). Catalyst (0.06 mmol).
enaminones, alkyl ketone-based enaminones also showed good
compatibility (3l and 3m, Figure 1). In addition, a more notable
point was that analogous electron-deficient enamines, including
cyano- and nitro-substituted enamines, also displayed smooth
(entries 2−5, Table 1) than other reagents. On the other hand,
MnO2 was not able to allow the transformation (entry 6, Table 1).
Subsequently, the entries using solvents of different polarity as the
B
DOI: 10.1021/acs.orglett.5b03608
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
applicability in the synthesis of cyano- and nitro-substituted
alkenes via this sulfenylation process (3n and 3o, Figure 1).
Afterward, the reactions employing different thiophenols and
enaminones bearing different N-substitution gave satisfactory
results (3p−3u, Figure 1). Finally, the sulfenylation of cyclic
enaminones proceeded identically well to provide polyfunction-
alized cyclic alkenes 3v−3x (Figure 1).
Scheme 4. Proposed Reaction Mechanism
After examining the general sulfenylation of the enaminones
with E-configuration, we employed acyclic NH and NH2-
functionalized enaminones 4 with Z-configuration. As shown
in Scheme 2, the sulfenylation of these enaminones was found to
Scheme 2. Sulfenylation of NH and NH2 Enaminones with
Z-Configuration
planar CN−R3 structure in intermediate 8 displays no impact
on the stereoselectivity before the regeneration of the CC
bond in 9. However, it should be noted that an accurate
mechanism requires more comprehensive investigation.
In conclusion, we have disclosed a new catalytic method that
consists of KIO3/air for the α-sulfenylation of enaminones and
related enamines via direct C−H bond transformation wherein a
novel catalytic behavior of KIO3 as a hypervalent iodate catalyst is
proposed. Besides the benign metal-free, aerobic atmosphere
conditions, the present method exhibits an additional advantage
of sustainability by employing the green bio-based EL as an
efficient reaction medium to enable the general application of the
aminothioalkene synthesis.
be analogously efficient in this green catalytic system to provide
products 5. The results and the aforementioned synthesis of
products 3 clearly confirmed the general applicability of this
synthetic method toward these new aminothioalkenes.
To acquire insight into the reaction mechanism, control
experiments were conducted. First, the reaction in the presence
of TEMPO (1 equiv) gave a yield of 3a similar to that of the
reaction under standard conditions, excluding the possibility of a
radical pathway in the reaction (eq 1, Scheme 3). In addition, the
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.5b03608.
Scheme 3. Control Experiments
Experimental procedures, characterization data, and
1H/13C NMR spectra of all products (PDF)
Crystallographic data of 3c (CIF)
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: wanjieping@jxnu.edu.cn.
Notes
entry under O2 gave target 3a with equally good yield (eq 2,
Scheme 3). No reaction took place in the entry using only 1a;
on the other hand, the formation of disulfide 6, a transformation
known to proceed easily under aerobic conditions,22 was
observed with high yield in the entry using only thiophenol
2a (eqs 3 and 4, Scheme 3). The subsequent employment
of 6 with enaminone 1a proved that product 3a could be
normally obtained in the presence of KIO3 (eq 5, Scheme 3),
and no reaction was observed in the corresponding blank entry
(eq 6, Scheme 3).
Based on these results, a possible mechanism was tenta-
tively proposed for the reactions (Scheme 4). Originally, the
hypervalent iodate couples the enamine at the α-position via
its isomeric version 7 to give intermediate 9 through the
zwitterion 8. Further formation of 10 takes place by releasing
KOH, and the incorporation of the in situ generated disulfide 6
with 10 produces target products and intermediate 11. The
interaction of KOH and 11 allowed the regeneration of thiols
2 and iodate for recycling. The Z/E-stereoselectivity can be
attributed to the structural stability of the products because the
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work is financially supported by the National Natural and
Science Foundation of China (21562025) and the Natural and
Science Foundation of Jiangxi Province (20151BAB203008).
REFERENCES
■
(1) (a) Tang, S.; Liu, K.; Liu, C.; Lei, A. Chem. Soc. Rev. 2015, 44, 1070.
(b) Kozhushkov, S. I.; Ackermann, L. Chem. Sci. 2013, 4, 886. (c) Wang,
D.-H.; Engle, K. M.; Shi, B.-F.; Yu, J.-Q. Science 2010, 327, 315.
(2) (a) Dounay, A. B.; Overman, L. E. Chem. Rev. 2003, 103, 2945.
(b) McCartney, D.; Guiry, P. J. Chem. Soc. Rev. 2011, 40, 5122.
(c) Oestreich, M. The Mizoroki−Heck Reaction; Wiley: Hoboken, NJ,
2009.
(3) (a) Liu, C.; Zhang, H.; Shi, W.; Lei, A. Chem. Rev. 2011, 111, 1780.
(b) Shi, W.; Liu, C.; Lei, A. Chem. Soc. Rev. 2011, 40, 2761. (c) Li, C.-J.
Acc. Chem. Res. 2009, 42, 335. (d) Liu, C.; Liu, D.; Lei, A. Acc. Chem. Res.
2014, 47, 3459. (e) Yeung, C. S.; Dong, V. M. Chem. Rev. 2011, 111,
1215.
C
DOI: 10.1021/acs.orglett.5b03608
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(4) (a) Liu, C.; Tang, S.; Liu, D.; Yuan, J.; Zheng, L.; Meng, L.; Lei, A.
Angew. Chem., Int. Ed. 2012, 51, 3638. (b) Mao, Z.; Huang, F.; Yu, H.;
Chen, J.; Yu, Z.; Xu, Z. Chem. - Eur. J. 2014, 20, 3439. (c) Liu, D.; Liu, C.;
Li, H.; Lei, A. Chem. Commun. 2014, 50, 3623. (d) Zhu, Y.; Wei, Y.
Chem. Sci. 2014, 5, 2379. (e) Ikeda, Y.; Nakamura, T.; Yorimitsu, H.;
Oshima, K. J. Am. Chem. Soc. 2002, 124, 6514. (f) Bloome, K. S.;
McMahen, R. L.; Alexanian, E. J. J. Am. Chem. Soc. 2011, 133, 20146.
(5) (a) Sun, C.-L.; Gu, Y.-F.; Wang, B.; Shi, Z.-J. Chem. - Eur. J. 2011,
17, 10844. (b) Shirakawa, E.; Zhang, X.; Hayashi, T. Angew. Chem., Int.
Ed. 2011, 50, 4671.
(6) (a) Shang, X.; Liu, Z.-Q. Chem. Soc. Rev. 2013, 42, 3253. (b) Hu, X.-
H.; Zhang, J.; Yang, X.-F.; Xu, Y.-H.; Loh, T.-P. J. Am. Chem. Soc. 2015,
137, 3169.
(7) Wang, J.; Liu, C.; Yuan, J.; Lei, A. Angew. Chem., Int. Ed. 2013, 52,
2256.
(8) (a) Rogers, M. M.; Kotov, V.; Chatwichien, J.; Stahl, S. S. Org. Lett.
2007, 9, 4331. (b) Lu, J.; Jin, Y.; Liu, H.; Jiang, Y.; Fu, H. Org. Lett. 2011,
13, 3694. (c) Zheng, J.; Huang, L.; Huang, C.; Wu, W.; Jiang, H. J. Org.
Chem. 2015, 80, 1235. (d) Liwosz, T. W.; Chemler, S. R. Chem. - Eur. J.
2013, 19, 12771. (e) Maity, S.; Zheng, N. Angew. Chem., Int. Ed. 2012,
51, 9562. (f) Naveen, T.; Maity, S.; Sharma, U.; Maiti, D. J. Org. Chem.
2013, 78, 5949. (g) Yang, Y.; Ni, F.; Shu, W.-M.; Yu, S.-B.; Gao, M.; Wu,
A.-X. J. Org. Chem. 2013, 78, 5418.
(17) Yuan, Y.; Hou, W.; Zhang-Negrerie, D.; Zhao, K.; Du, Y. Org. Lett.
2014, 16, 5410.
(18) (a) Shen, C.; Zhang, P.; Sun, Q.; Bai, S.; Hor, T. S. A.; Liu, X.
Chem. Soc. Rev. 2015, 44, 291. (b) Yang, L.; Wen, Q.; Xiao, F.; Deng, G.-
J. Org. Biomol. Chem. 2014, 12, 9519.
(19) (a) Wan, J.-P.; Wang, H.; Liu, Y.; Ding, H. Org. Lett. 2014, 16,
5160. (b) Liu, Y.; Wang, H.; Wan, J.-P. J. Org. Chem. 2014, 79, 10599.
(20) For references on EL-based green chemistry, see: (a) Gu, Y.;
́ ̂
Jerome, F. Chem. Soc. Rev. 2013, 42, 9550. (b) Pereira, C. S. M.; Silva, V.
M. T. M.; Rodrigues, A. E. Green Chem. 2011, 13, 2658. (c) Aparicio, S.;
Alcalde, R. Green Chem. 2009, 11, 65. (d) Bennett, J. S.; Charles, K. L.;
Miner, M. R.; Heuberger, C. F.; Spina, E. J.; Bartels, M. F.; Foreman, T.
Green Chem. 2009, 11, 166. (e) Edwards, G. A.; Trafford, M. A.;
Hamilton, A. E.; Buxton, A. M.; Bardeaux, M. C.; Chalker, J. M. J. Org.
Chem. 2014, 79, 2094. (f) Wan, J.-P.; Wang, C.; Zhou, R.; Liu, Y. RSC
Adv. 2012, 2, 8789.
(21) CCDC 1434766 (3c) contains the supplementary crystallo-
graphic data for this paper. These data can be obtained free of charge
from the Cambridge Crystallographic Data Centre via www.ccdc.cam.
ac.uk/data_request/cif.
(22) (a) Liu, Y.; Wang, H.; Wang, C.; Wan, J.-P.; Wen, C. RSC Adv.
2013, 3, 21369. (b) Wang, H.; Huang, G.; Sun, Y.; Liu, Y. J. Chem. Res.
2014, 38, 96.
(9) (a) Taniguchi, N. Synlett 2011, 2011, 1308. (b) Tu, H.-Y.; Hu, B.-
L.; Deng, C.-L.; Zhang, X.-G. Chem. Commun. 2015, 51, 15558.
(c) Yang, L.; Wen, Q.; Xiao, F.; Deng, G.-J. Org. Biomol. Chem. 2014, 12,
9519. (d) Zhang, C.; McClure, J.; Chou, C. J. J. Org. Chem. 2015, 80,
4919.
(10) (a) Pan, X.-Q.; Zou, J.-P.; Zhang, G.-L.; Zhang, W. Chem.
Commun. 2010, 46, 1721. (b) Mi, X.; Huang, M.; Zhang, J.; Wang, C.;
Wu, Y. Org. Lett. 2013, 15, 6266. (c) Yuan, J.-W.; Li, Y.-Z.; Yang, L.-R.;
Mai, W.-P.; Mao, P.; Xiao, Y.-M.; Qu, L.-B. Tetrahedron 2015, 71, 8178.
(11) (a) Hari, D. P.; Schroll, P.; Konig, B. J. Am. Chem. Soc. 2012, 134,
̈
2958. (b) Antonchick, A. P.; Samanta, R.; Kulikov, K.; Lategahn, J.
Angew. Chem., Int. Ed. 2011, 50, 8605. (c) Xia, J.-B.; Zhu, C.; Chen, C. J.
Am. Chem. Soc. 2013, 135, 17494. (d) Jiang, Q.; Xu, B.; Zhao, A.; Jia, J.;
Liu, T.; Guo, C. J. Org. Chem. 2014, 79, 8750. (e) Badsara, S. S.; Liu, Y.-
C.; Hsieh, P.-A.; Zeng, J.-W.; Lu, S.-Y.; Liu, Y.-W.; Lee, C.-F. Chem.
́
Commun. 2014, 50, 11374. (f) Guastavino, J. F.; Buden, M. E.; Rossi, R.
A. J. Org. Chem. 2014, 79, 9104. (g) Yang, F.-L.; Tian, S.-K. Angew.
Chem., Int. Ed. 2013, 52, 4929.
(12) (a) Zhu, L.; Yu, H.; Guo, Q.; Chen, Q.; Xu, Z.; Wang, R. Org. Lett.
2015, 17, 1978. (b) Tang, S.; Wu, Y.; Liao, W.; Bai, R.; Liu, C.; Lei, A.
Chem. Commun. 2014, 50, 4496. (c) Zhao, W.; Xie, P.; Bian, Z.; Zhou,
A.; Ge, H.; Zhang, M.; Ding, Y.; Zheng, L. J. Org. Chem. 2015, 80, 9167.
(d) Zheng, Y.; Li, X.; Ren, C.; Zhang-Negrerie, D.; Du, Y.; Zhao, K. J.
Org. Chem. 2012, 77, 10353.
(13) (a) Zhang, Z.-J.; Ren, Z.-H.; Wang, Y.-Y.; Guan, Z.-H. Org. Lett.
2013, 15, 4822. (b) Wan, J.-P.; Cao, S.; Liu, Y. J. Org. Chem. 2015, 80,
9028. (c) Cao, S.; Zhong, S.; Xin, L.; Wan, J.-P.; Wen, C. ChemCatChem
2015, 7, 1478. (d) Wan, J.-P.; Zhou, Y.; Cao, S. J. Org. Chem. 2014, 79,
9872. (e) Wan, J.-P.; Pan, Y.-J. Chem. Commun. 2009, 2768. (f) Wan, J.-
P.; Zhou, Y.; Liu, Y.; Sheng, S. Green Chem. 2016, 18, 402. (g) Edwankar,
R. V.; Edwankar, C. R.; Namjoshi, O. A.; Deschamps, J. R.; Cook, J. M. J.
Nat. Prod. 2012, 75, 181. (h) Wan, J.-P.; Lin, Y.; Cao, X.; Liu, Y.; Wei, L.
Chem. Commun. 2016, 52, 1270.
(14) (a) Bi, L.; Georg, G. I. Org. Lett. 2011, 13, 5413. (b) Yu, Y.-Y.; Bi,
L.; Georg, G. I. J. Org. Chem. 2013, 78, 6163. (c) Yu, Y.-Y.; Niphakis, M.
J.; Georg, G. I. Org. Lett. 2011, 13, 5932. (d) Wurtz, S.; Rakshit, S.;
̈
Neumann, J. J.; Droge, T.; Glorius, F. Angew. Chem., Int. Ed. 2008, 47,
̈
7230. (e) Gu, Z.-Y.; Zhu, T.-H.; Cao, J.-J.; Xu, X.-P.; Wang, S.-Y.; Ji, S.-J.
ACS Catal. 2014, 4, 49. (f) Yu, W.; Du, Y.; Zhao, K. Org. Lett. 2009, 11,
2417. (g) Lian, X.-L.; Ren, Z.-H.; Wang, Y.-Y.; Guan, Z.-H. Org. Lett.
2014, 16, 3360.
(15) Ge, H.; Niphakis, M. J.; Georg, G. I. J. Am. Chem. Soc. 2008, 130,
3708.
(16) Liu, X.; Cheng, R.; Zhao, F.; Zhang-Negrerie, D.; Du, Y.; Zhao, K.
Org. Lett. 2012, 14, 5480.
D
DOI: 10.1021/acs.orglett.5b03608
Org. Lett. XXXX, XXX, XXX−XXX