Sulfur-mediated difunctionalization of internal and terminal alkynes for the synthesis of α-acetoxy ketones

Article abstract of DOI:10.1016/j.tetlet.2020.151707

The sulfur-mediated difunctionalization of alkynes is reported to give α-acetoxy ketones in a one-pot operation under mild conditions with 19–92% yield. By using wet potassium acetate as both the aqueous base and nucleophilic reagent, both terminal alkynes and internal alkynes could be converted into the α-acetoxy ketone products.

Full text of DOI:10.1016/j.tetlet.2020.151707

Tetrahedron Letters xxx (xxxx) xxx
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Sulfur-mediated difunctionalization of internal and terminal alkynes
for the synthesis of
a-acetoxy ketones
Zhong Zhang a,b, Pingfan Li a,
⇑
a College of Chemistry, Beijing University of Chemical Technology, Beijing 100029, China
b State Key Laboratory of Microbial Technology, Shandong University, Qingdao, Shandong 266237, China
a r t i c l e i n f o
a b s t r a c t
Article history:
The sulfur-mediated difunctionalization of alkynes is reported to give
operation under mild conditions with 19–92% yield. By using wet potassium acetate as both the aqueous
base and nucleophilic reagent, both terminal alkynes and internal alkynes could be converted into the
a-acetoxy ketones in a one-pot
Received 21 December 2019
Revised 29 January 2020
Accepted 3 February 2020
Available online xxxx
a-acetoxy ketone products.
Ó 2020 Elsevier Ltd. All rights reserved.
Keywords:
Activated sulfoxides
Difunctionalization of alkynes
Triflic anhydrides
a-Acetoxy ketones
Introduction
Pummerer reactions [9], such as the functionalization of alkyne
substrates. For example, the propargylic CAH alkylation and aryla-
tion of alkyl substituted alkynes have been reported by Procter’s
group and our group, respectively [10]. During our recent study
The alkyne motif is an important functional group in organic
synthesis and the transformations of carbon-carbon triple bonds
have been extensively researched [1]. Traditionally, the conversion
on the difunctionalization of internal alkynes to prepare a-substi-
of alkynes to
a
-acetoxy ketones requires several steps: mercury-
tuted ketones [5], we found that terminal alkynes did not give the
desired products due to the strong basicity of sodium hydroxide,
leading to alkynyl sulfonium salts as the elimination products
[10]. It was thus reasoned that if we conducted the reaction under
relatively weak basic reaction condition to avoid the elimination
pathway, such as using potassium acetate to replace sodium
hydroxide, phenyl substituted internal, as well as terminal alkynes
catalyzed hydration of the carbon-carbon triple bonds, bromina-
tion of the resulting ketones, and then nucleophilic substitution
of the
into
Hou and co-workers utilized PhI(OAc)2 as an oxidant to prepare
-acetoxy ketones from terminal alkynes and acetic acid
a
-bromo ketones. One-step methods for converting alkynes
a-acetoxy ketones are still rare in the literature [2]. In 2009,
a
(Scheme 1a, condition A) [3]. Zhang group and Xiang group
reported a similar transformation with gold catalysts and 8-
methylquinoline N-oxide as the oxidant, respectively (Scheme 1a,
condition B) [4]. We have recently reported a general method for
the difunctionalization of internal alkynes, however, terminal alky-
nes failed to undergo the desired reaction pathway (Scheme 1b)
[5]. Herein, we report a one-pot method for the oxidative hydration
of both terminal alkynes and internal alkynes through a sulfur-
mediated reaction using an activated sulfoxide reagent
(Scheme 1c).
could give the desired a-acetoxy ketones.
At the outset, alkyne 1a was chosen as the model substrate to
optimize the reaction conditions. A solution of 1 equivalent of
alkyne and 1.2 equivalents of diphenyl sulfoxide was treated with
1.2 equivalents of triflic anhydride. When the wet potassium acet-
ate (5 equivalents, calculated as anhydrous KOAc) was added to the
solution and stirred at room temperature, the
a-acetoxy ketone
product 3a was afforded in 40% yield (Table 1, entry 1). Upon
increasing the reaction temperature to 40 °C, the yield increased
to 71% (Entry 2). Other bases such as LiOAc and NaOAc were tested,
but the yield was not improved (Entries 3–4). In order to increase
the reaction temperature further, solvents with higher boiling
points such as MeCN and DCE were used, but the yields decreased
to 33% and 65%, respectively (Entries 5–6). When mixtures of
MeCN or DCE with CH2Cl2 were used in step 2, the product 3a
In recent years, activated sulfoxides [6–8] have been widely
applied in reactions beyond the traditional Swern oxidation or
⇑
Corresponding author.
E-mail address: lipf@mail.buct.edu.cn (P. Li).
https://doi.org/10.1016/j.tetlet.2020.151707
0040-4039/Ó 2020 Elsevier Ltd. All rights reserved.
Please cite this article as: Z. Zhang and P. Li, Sulfur-mediated difunctionalization of internal and terminal alkynes for the synthesis of
Tetrahedron Letters, https://doi.org/10.1016/j.tetlet.2020.151707
a-acetoxy ketones,

2
Z. Zhang, P. Li / Tetrahedron Letters xxx (xxxx) xxx
Table 1
Optimization of the reaction conditions.
Entry
Solvent
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
MeCN
DCE
CH2Cl2/DCE
CH2Cl2/MeCN
CH2Cl2
CH2Cl2
CH2Cl2
Reagent
T (°C)
Yield 3a (%)a
1
2
3
4
5
6
7
8
KOAc
KOAc
LiOAcÁ2H2O
NaOAcÁ3H2O
KOAc
KOAc
KOAc
KOAc
KOAc
r.t
40b
71(69b)
11
52
33
65
55
29
58
40
40
40
82
84
60
60
40
40
40
40
9c
10d
11e
12f
KOAc
KOAc
KOAc
60
62b
13b
CH2Cl2
a
b
c
d
e
f
NMR yield.
Isolated yield.
An additional 2.5 equivÁH2O was added in step 2.
An additional 5 equivÁH2O was added in step 2.
PhS(O)Me was added instead of Ph2SO.
DMSO was added instead of Ph2SO.
Scheme 1. Synthesis of a-acetoxy ketones from alkynes.
was obtained in moderate yields (Entries 7–8). We also tried to add
additional water in step 2, but the yield was not improved (Entries
9–10). When DMSO or methyl phenyl sulfoxide were used to
replace diphenyl sulfoxide, the yield decreased to 62% or 13%,
respectively (Entries 11–12).
With the optimized reaction conditions in hand, we then inves-
tigated the scope of the internal alkynes. As shown in Scheme 2,
the alkyl phenyl alkynes gave the corresponding products in good
to moderate yields (3a-3f). When alkyne 1g was used as the sub-
strate, the expected product 3g was not detected presumably due
to steric hindrance of the tert-butyl group. Alkyne 1h gave the pro-
duct in 79% yield, which indicated that the reactivity of a terminal
alkene is worse than a phenyl conjugated alkyne. Diphenyl substi-
tuted alkyne 1i gave the product 3i in 19% yield. When alkyne 1n
was used as the substrate, the product 3n was afforded in 19% yield
Scheme 2. Scope of alkynes. Reagents and conditions: 1) 1a (0.4 mmol), Ph2SO (0.48 mmol), Tf2O (0.48 mmol), CH2Cl2 (2 mL), À78 °C to 0 °C; 2) wet potassium acetate
(196 mg), 40 °C, 12 h. Isolated yield after column chromatography.
Please cite this article as: Z. Zhang and P. Li, Sulfur-mediated difunctionalization of internal and terminal alkynes for the synthesis of
Tetrahedron Letters, https://doi.org/10.1016/j.tetlet.2020.151707
a-acetoxy ketones,

Z. Zhang, P. Li / Tetrahedron Letters xxx (xxxx) xxx
3
while the electrophilic cyclization product 4n was afforded in 74%
yield [7e]. Electron-donating groups, such as methoxy and methyl
on the phenyl ring gave the -acetoxy ketones 3j and 3k in 48%
and 64% yield, respectively. Fluoro and acyl substituted phenyl
alkynes gave the -acetoxy ketones 3l and 3m in 80% and 63%
yield, respectively.
References
[1] (a) J.P. Brand, J. Waser, Chem. Soc. Rev. 41 (2012) 4165–4179;
a
(b) F. Diederich, P.J. Stang, R.R. Tykwinski (Eds.), Acetylene Chemistry, Wiley-
VCH, Weinheim, Germany, 2005;
(c) X. Ren, Z. Lu, Chin. J. Catal. 40 (2019) 1003–1019.
[2] P.K. Prasad, R.N. Reddi, S. Arumugam, Org. Biomol. Chem. 16 (2018) 9334–
9348.
a
We also examined the reaction scope of some terminal alkynes.
Methoxy and methyl substituted terminal alkynes 1o and 1p gave
the products 3o and 3p in 48% and 64% yield, respectively. Halogen
substituted alkynes 1r and 1s gave the corresponding products in
good yields. When the phenyl ring contained the strong electron-
withdrawing cyano group, the desired product 3t was not detected.
meta-Acetylamino substituted alkyne afforded product 3u in 45%
yield. The yield of ortho-fluoro substituted product 3v decreased
to 22% due to the stronger inductive effect.
[3] (a) D.-L. Mo, L.-X. Dai, X.-L. Hou, Tetrahedron Lett. 50 (2009) 5578–5581;
(b) G. Deng, J. Luo, Tetrahedron 69 (2013) 5937–5944.
[4] (a) K. Ji, Y. Zhao, L. Zhang, Angew. Chem. Int. Ed. 52 (2013) 6508–6512;
(b) C. Wu, Z. Liang, D. Yan, W. He, J. Xiang, Synthesis 45 (2013) 2605–2611.
[5] Z. Zhang, Y. Luo, H. Du, J. Xu, P. Li, Chem. Sci. 10 (2019) 5156–5161.
[6] (a) L.H.S. Smith, S.C. Coote, H.F. Sneddon, D.J. Procter, Angew. Chem. Int. Ed. 49
(2010) 5832–5844;
(b) A.P. Pulis, D.J. Procter, Angew. Chem. Int. Ed. 55 (2016) 9842–9860;
(c) A. Shafir, Tetrahedron Lett. 57 (2016) 2673–2682;
(d) H. Yorimitsu, The Chemical Record 17 (2017) 1156–1167;
(e) T. Yanagi, K. Nogi, H. Yorimitsu, Tetrahedron Lett. 59 (2018) 2951–2959;
(f) L. Meng, J. Zeng, Q. Wan, Synlett 29 (2018) 148–156;
(g) Z.-Y. Tian, Y.-T. Hu, H.-B. Teng, C.-P. Zhang, Tetrahedron Lett. 59 (2018)
299–309;
(h) D. Chen, Y. Fu, X. Cao, J. Luo, F. Wang, S. Huang, Org. Lett. 21 (2019) 5600–
5605;
(i) X. Meng, D. Chen, X. Cao, J. Luo, F. Wang, S. Huang, Chem. Commun. 55
(2019) 12495–12498.
In summary, we have expanded the reaction scope for the sul-
fur-mediated difunctionalization of alkynes. By using potassium
acetate as the base and nucleophile, both internal and terminal
phenyl alkynes could react smoothly to give
a-acetoxy ketones.
This one-pot/two-step reaction operation is simpler than our pre-
viously reported [5] one-pot/three-step protocol.
[7] (a) For our group’s research on activated sulfoxide mediated reaction, see: G.
Hu, J. Xu, P. Li Org. Lett. 16 (2014) 6036–6039;
(b) Z. Zhang, H. Du, J. Xu, P. Li, Chem. Commun. 52 (2016) 11547–11550;
(c) G. Hu, J. Xu, P. Li, Org. Biomol. Chem. 16 (2018) 4151–4158;
(d) Y. Shi, P. Li, Tetrahedron Lett. 59 (2018) 3104–3107;
(e) Z. Zhang, P. He, H. Du, J. Xu, P. Li, J. Org. Chem. 84 (2019) 4517–4524;
(f) H. Luo, G. Hu, P. Li, J. Org. Chem. 84 (2019) 10569–10578;
(g) J. Huang, G. Hu, S. An, D. Chen, M. Li, P. Li, J. Org. Chem. 84 (2019) 9758–
9769.
Declaration of Competing Interest
The authors declare that they have no known competing finan-
cial interests or personal relationships that could have appeared
to influence the work reported in this paper.
[8] (a) D. Kaiser, L.F. Veiros, N. Maulide, Chem. Eur. J. 22 (2016) 4727–4732;
(b) T. Stopka, M. Niggemann, N. Maulide, Angew. Chem. Int. Ed. 56 (2017)
13270–13274;
Acknowledgments
(c) Q.H. Nguyen, N.H. Nguyen, H. Kim, S. Shin, Chem. Sci. 10 (2019) 8799–
8805.
[9] (a) J.B. Arterburn, Tetrahedron 57 (2001) 9765–9788;
(b) A.J. Mancuso, D. Swern, Synthesis 1981 (1981) 165–185;
(c) D. Gamba-Sánchez, F. Garzón-Posse, Mol. Rearrang. Org. Synth. (2015)
661–702.
This research was supported in part by National Natural Science
Foundation of China (21402005) and the Fundamental Research
Funds for the Central Universities (XK-1802-6, 12060093063).
[10] (a) G. Hu, J. Xu, P. Li, Org. Chem. Front. 5 (2018) 2167–2170;
(b) V.G. Nenajdenko, P.V. Vertelezkij, E.S. Balenkova, Synthesis 1997 (1997)
351–355;
Appendix A. Supplementary data
(c) J.A. Fernández-Salas, A.J. Eberhart, D.J. Procter, J. Am. Chem. Soc. 138 (2016)
790–793.
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tetlet.2020.151707. These data include
MOL files and InChiKeys of the most important compounds
described in this article.
Please cite this article as: Z. Zhang and P. Li, Sulfur-mediated difunctionalization of internal and terminal alkynes for the synthesis of
Tetrahedron Letters, https://doi.org/10.1016/j.tetlet.2020.151707
a-acetoxy ketones,