Iodobenzene-catalyzed synthesis of α,α′-dihydroxy ketones: In situ generation of [bis(trifluoroacetoxy)iodo]benzene

Article abstract of DOI:10.1080/00397911.2015.1121279

Exposure of ethynyl carbinols to oxone/(CF₃CO)₂O in the presence of a catalytic amount of iodobenzene afforded α,α′-dihydroxy ketones in good yield, which are common structural motifs in natural products and biologically active compo

Full text of DOI:10.1080/00397911.2015.1121279

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
Iodobenzene-Catalyzed Synthesis of α ,α ′-
Dihydroxy Ketones: In Situ Generation of
[Bis(Trifluoroacetoxy)iodo]benzene
Chengqun Chen, Minghua You & Hong Chen
To cite this article: Chengqun Chen, Minghua You & Hong Chen (2015): Iodobenzene-Catalyzed
Synthesis of α ,α ′-Dihydroxy Ketones: In Situ Generation of [Bis(Trifluoroacetoxy)iodo]benzene,
Synthetic Communications, DOI: 10.1080/00397911.2015.1121279
To link to this article: http://dx.doi.org/10.1080/00397911.2015.1121279
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Date: 25 November 2015, At: 06:06

Iodobenzene-Catalyzed Synthesis of α,α′-Dihydroxy Ketones: In Situ Generation of
[Bis(trifluoroacetoxy)iodo]benzene
Chengqun Chen1, Minghua You1, Hong Chen1
1Department of Chemical Engineering, Fuzhou University Zhicheng College, Fuzhou,
P.R. of China
Address correspondence to Chengqun Chen, Department of Chemical Engineering,
Fuzhou University Zhicheng College, Fuzhou 350001, P.R. of China. E-mail:
ccq0591@yeah.net
Abstract
Exposure of ethynyl carbinols to oxone / (CF3CO)2O in the presence of a catalytic
amount of iodobenzene afforded α, α′- dihydroxy ketones in good yield, which are
common structural motifs in natural products and biologically active compounds.
Compared with traditional methods, this method is more convenient and avoids using
stoichiometric amounts of hypervalent iodine reagents.
KEYWORDS: oxone, ethynyl carbinol, iodobenzene, α, α′- dihydroxy ketones
INTRODUCTION
There is clearly significant interest in the synthesis of compounds possessing the α, α′-
dihydroxy ketone functionality, which is found in several natural products and
1

biologically active compounds, such as pirarubicin and betamethasone. 1 α, α′- dihydroxy
ketones also can be easily transferred into a range of compounds including ketosugars and
2-amino-1,3-diols.2 α, α′- dihydroxy ketone can be prepared via various ways, including a
five steps procedure to aromatic analogues and an enantioselective chiral auxiliary
strategy reported by Enders et al，1, 3 but it requires many steps and suffers from
environmental problems. It has also been prepared by formation of α, α′- dihydroxy
ketones using Transketolase (TK) or the biomimetic TK reaction using
N-methylmorpholine.4 Wild-type TKs have been noted to tolerate some
non-a-hydroxylated aliphatic aldehydes, but compared to a-hydroxyaldehydes lower
substrate activities were reported. 4c The biomimetic TK reaction typically used
stoichiometric amounts of N-methylmorpholine (NMM) and yields were dependent upon
the acceptor aldehyde used, but in the absence of amine the reaction did not proceed. 4a
Therefore, a simple and efficient conversion method for preparing α, α′- dihydroxy
ketones would be an important step in organic synthesis and medicinal chemistry.
Meanwhile, much attention has been paid to hypervalent iodine (III) reagents in recent
years due to their interesting activity, ready availability, and ease of handling.5, 6
Hypervalent iodine(III) reagents, such as phenyliodine diacetate (PIDA) and
phenyliodine di(trifluoroacetate) (PIFA), have been extensively employed in organic
synthesis as popular and useful oxidants due to their unique and beneficial properties.
However, stoichiometric amounts of hypervalent iodine reagents are required and
2

equimolecular amounts of iodobenzene are produced as a waste in the reaction. To
overcome this drawback, Ochiai and co-workers have developed an efficient method for
catalytic α-oxidation of ketones. The method involves in situ generation of hypervalent
phenyl-λ3-iodanes by the oxidation of a catalytic amount of iodobenzene with m-CPBA.7
In our laboratory, we have been extensively utilizing these reagents to perform a variety
of organic transformations. We now report here a facile synthesis of α, α′- dihydroxy
ketones by oxidizing ethynyl carbinols to oxone / (CF3CO)2O in the presence of a
catalytic amount of iodobenzene (Table 1), compared with the biomimetic TK reaction,
this method is more convenient, and it also avoids using stoichiometric amounts of
hypervalent iodine reagents.
RESULTS AND DISCUSSION
Exposure of ethynyl carbinols to oxone (2.7 equiv) /(CF3CO)2O (2.0 mmol) in the
presence of a catalytic amount (20 mol%) of iodobenzene at 90 ℃for 24 hours afforded α,
α′- dihydroxy ketones in 76% yield (Table 1, entry 2). The effect of temperature on the
reaction was studied. As show in Table 1, raising the temperature to 100℃resulted in a
decrease in the yield to 68% (Table 1, entry 3). If 30% aq H2O2 was uesd instead of
oxone, no reaction was observed, whereas the yield dropped sharply when CF3COOOH
or m-CPBA was used as oxidant (Table 1, entries 4-6). As water is stronger nucleophile
than trifluoroacetic acid, α, α′-ditrifluoroacetoxy ketones would not be obtained.8 When
3

acetic anhydride was used instead of trifluoroacetic anhydride, the product yield
decreased from 76% to 65%, it showed that the electron-withdrawing ligand would
increase the oxidative efficiency of hypervalent iodine reagents (Table 1, entries 2, 7), if
there was no ligand, it gave a obvious decreased yield (26%) of 2-phenylbut-3-yn-2-ol
(Table 1, entry 8).
Accordingly, substrate generality of the protocol to various α, α′- dihydroxy ketones was
examined (Table 2). The reaction was observed with ethynyl carbinols in which R1 is an
aromatic group and R2 is an aliphatic group (Table 2, entries 2−9). Oxidation reactions
were observed with functionalized molecules bearing para substitutions on phenyl ring
(Table 2, entries 2-7), that ethynyl carbinols bearing electron-donating groups on the
phenyl ring were converted into the corresponding α, α′- dihydroxy ketones in good
yields，whereas substrates bearing electron-withdrawing groups on the phenyl ring gave
lower yields(Table 2, entry 7). ethynyl carbinols bearing meta substitutions on phenyl
ring (Table 2, entries 8-9) as well as substrate bearing para substitutions were converted
into the corresponding allyl alcohols in fair yields. The reaction ran smoothly to furnish
the desired products in high yields when both R1 and R2 were aromatic substituted
ethynyl carbinols (Table 2, entries 10−13). When R1 and R2 were acyclic aliphatic groups,
there was a decrease in the yield (Table 2, entries 14−16).
4

To understand the mechanism better, the reaction was carried out with
but-3-yn-2-ylbenzene under the standard conditions; no reaction was observed (Scheme
1-1). This result revealed that the OH group of ethynylcarbinol have participated the
oxidation process. When chiral ethynylcarbinol (R)-2-phenylbut-3-yn-2-ol was subjected
to the reaction conditions, only racemic product was afforded in 73% yield (Scheme 1-2).
On the basis of the experimental results and the previous reports9 we proposed a tentative
mechanism, as shown in Scheme 2. First, the alkynyliodonium salt is formed from 1 in
the presence of PhI(OCOCF3)2. Then, a Michael-type addition of the ortho-OH group to
the alkynyliodonium salt a provides intermediate b. A carbocation intermediate c could
be obtained from the epoxide intermediate b. Then, intermediate c can be trapped by H2O
to form intermediate d. Reductive elimination or substitution of the phenyliodonium salt
provides α, α′-dihydroxy ketone 2.
CONCLUSION
In conclusion, the conversion of ethynyl carbinols to corresponding α, α′- dihydroxy
ketones using oxone and trifluoroacetic anhydride as a terminal oxidant has been
accomplished in good yields. This method has some advantages such as mild reaction
conditions, simple procedure and overcome this drawback that iodobenzene are produced
as a waste in the reaction. Further investigation focused on expanding the scope of
substrates of this method is currently in progress.
5

EXPERIMENTAL
All reactions were performed under an atmosphere of air. Commercially available
reagents were used without further purification. NMR spectra were performed on a
Bruker Avance III 400 spectrometer (1H: 400 MHz; 13C: 100 MHz). 1H NMR chemical
shifts were determined relative to Me4Si (0.0 ppm) as an internal standard. 13C NMR
chemical shifts were determined relative to CDCl3 (77.0 ppm). IR spectra recorded on
Perkin-Elmer 2000 FTIR spectrometer. HRMS date were determined on a Bruker
Daltonics APEXII 47e FT-ICR spectrometer.Mass spectra were recorded by the EI
method on a HP 5998 mass spectrometer.
Typical Procedure
A solution of 3.1 g oxone, 2.0 ml trifluoroacetic anhydride and 10 ml H2O was stirred for
4 hours at 40 °C, and then cooled to room temperature. 2-Phenylbut-3-yn-2-ol (292 mg, 2
mmol) and iodobenzene (41 mg, 0.2 mmol) in 30 ml CH3CN were added at room
temperature. The resulting solution was stirred for 24 hours at 90 °C (The progress of the
reaction was monitored by TLC). 10 ml CH2Cl2 was added. The mixture was neutralized
with a cooled 10% aqueous sodium carbonate solution and extracted with CH2Cl2 (100
ml × 3). The combined organic phase was washed with brine, dried over anhydrous
MgSO4, filtered, and concentrated. The residue was purified by column chromatography
6

[silica gel (200-300 mesh), petroleum ether-EtOAc (8:1)] to give 1,
3-dihydroxy-3-phenylbutan-2-one (273.7 mg, 76%).
ACKNOWLEDGMENTS
We gratefully acknowledge the Fuzhou University Zhicheng College, for the support of
this work.
SUPPLEMENTAL MATERIAL
Supplemental data for this article can be accessed on the publisher’s website.
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8

Table 1 Exposure of 2-phenylbut-3-yn-2-ol under various
conditionsa
Entry Oxidant
Yield/% b
56
Temperature/℃
1
oxone
70
2
oxone
90
76
3
oxone
100
90
68
4
30% H2O2
NRc
20
5
CF3COOOH 90
6
m-CPBA
oxone
90
90
90
43
7d
8e
65
oxone
26
a Reaction conditions: 2-phenylbut-3-yn-2-ol (2 mmol), oxidant (5 mmol), (CF3CO)2O(2
mL), PhI (0.2 equiv.), H2O–CH3CN (1 : 4, v/v) for 24 h.
b Isolated yields.
c NR, no reaction.
d Ac2O was used instead of (CF3CO)2O.
e (CF3CO)2O was not used.
9

Table 2 Exposure of ethynyl carbinols to oxone /
(CF3CO)2Oa
Entry
1
yield(%)b
76
R1
R2
Ph
Me
Me
Me
Me
Me
2
4-MePh
4-ClPh
4-BrPh
4-IPh
75
3
72
4
82
5
80
6
4-MeOPh Me
4-NO2Ph Me
86
7
58
8
3-MePh
3-BrPh
Ph
Me
Me
Ph
73
9
81
10
11
12
13
14
86
4-MePh
4-ClPh
Ph
4-MePh 62
4-ClPh 85
Bn
81
63
15
Me
Me
71
10

16
Me
Et
74
a Reaction conditions: ethynyl carbinol (2 mmol), oxidant (5 mmol), (CF3CO)2O(2 mL),
PhI (0.2 equiv.), H2O–CH3CN (1 : 4, v/v) for 24 h.
b Isolated yields.
11

Scheme 1. Mechanism Studies
12

Scheme 2. A Plausible Mechanism for the Oxidation Process
13