α-Acetoxyarone synthesis via iodine-catalyzed and tert-butyl hydroperoxide-mediateded self-intermolecular oxidative coupling of aryl ketones

Article abstract of DOI:10.3762/bjoc.13.107

We present a metal-free method for α-acetoxyarone synthesis by self-intermolecular oxidative coupling of aryl ketones using I₂?tert-butyl hydroperoxide (TBHP). Under the optimum conditions, various aryl ketones gave the corresponding products i

Full text of DOI:10.3762/bjoc.13.107

α-Acetoxyarone synthesis via iodine-catalyzed and tert-butyl
hydroperoxide-mediateded self-intermolecular oxidative
coupling of aryl ketones
Liquan Tan*, Cui Chen and Weibing Liu
Letter
Open Access
Address:
Beilstein J. Org. Chem. 2017, 13, 1079–1084.
College of Chemical Engineering, Guangdong University of
Petrochemical Technology, 2 Guandu Road, Maoming 525000, P. R.
China. Fax: +86-668-2923575; Tel: +86-668-2923444
doi:10.3762/bjoc.13.107
Received: 12 April 2017
Accepted: 16 May 2017
Published: 06 June 2017
Email:
Liquan Tan* - touching522@gdupt.edu.cn
Associate Editor: D. Y.-K. Chen
* Corresponding author
© 2017 Tan et al.; licensee Beilstein-Institut.
License and terms: see end of document.
Keywords:
aryl ketones; iodine; self-intermolecular oxidative coupling;
self-sequential assembly; TBHP
Abstract
We present a metal-free method for α-acetoxyarone synthesis by self-intermolecular oxidative coupling of aryl ketones using
I2−tert-butyl hydroperoxide (TBHP). Under the optimum conditions, various aryl ketones gave the corresponding products in mod-
erate to excellent yields. A series of control experiments were performed; the results suggest the involvement of radical pathways.
Multiple radical intermediates were generated in situ and the overall process involved several different reactions, which proceeded
self-sequentially in a single reactor. A labeling experiment using 18O-labeled H2O confirmed that the oxygen in the product was
derived from TBHP, not from H2O in the TBHP solvent.
Introduction
In recent years, α-acetoxyaryl ketones have attracted consider- and transition-metal-catalyzed direct oxidative coupling reac-
able interest because this structural motif is found in a variety of tions of carbonyl compounds with carboxylic acids (or their
biologically active natural products and pharmaceuticals, and surrogates) [8,9]. Recently, robust approaches using organohy-
α-acetoxyaryl ketones are widely used as synthetic intermedi- pervalent iodine reagents and peroxide-mediated oxidative cou-
ates [1-5]. Traditional methods for the preparation of α-acyloxy pling have been developed [10,11]. Although impressive
ketones focus on the substitution reactions of α-halo carbonyl progress has been made [12], examples of the synthesis of
compounds with alkaline carboxylates or carboxylic acids [6,7], α-acetoxyaryl ketones through self-intermolecular oxidative
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Beilstein J. Org. Chem. 2017, 13, 1079–1084.
coupling of aryl ketones are still rare. Yan and coworkers re- Results and Discussion
ported the preparation of α-acyloxyaryl ketones from aryl ke- In our first attempt, the reaction of acetophenone (1a) in the
tones using a Pybox-copper(II) catalyst [13]. However, the sub- presence of an I2–TBHP system gave the desired product 2a in
strate scope was limited to α-substituted aryl ketones, and 46% yield. The yield increased to 71% when the reaction time
acetophenones were unsuitable for this conversion. In addition, was prolonged to 24 h (Table 1, entries 1–3). The reaction did
this method requires harsh catalytic conditions, using scarce not occur in the absence of I2 or Na2CO3, indicating that these
iron and copper complexes. The development of novel metal- species both play important roles in this reaction (Table 1,
free methods for the preparation of α-acetoxyaryl ketones is entries 4 and 5). The reaction was almost unaffected by the sol-
therefore an attractive target for organic chemists. Simple, inex- vent (Table 1, entries 3, 6−8). Acetonitrile was slightly more
pensive, and metal-free methods [14,15], involving safe and effective than the other solvents tested. An increase in the
clean oxidation procedures, need to be developed. Here, we amount of TBHP from 2.0 equiv to 4.0 equiv significantly
report a metal-free, novel, and efficient self-intermolecular oxi- affected the reaction efficiency, leading to a pronounced
dative coupling procedure for the synthesis of α-acetoxyaryl ke- increase in the yield (Table 1, entry 9). Further increasing the
tones from aryl ketones using I2 and tert-butyl hydroperoxide TBHP loading did not have any beneficial effect (Table 1, entry
(TBHP) [16-18] (Scheme 1). Several oxidative cross-coupling 10). An increase in the amount of I2 from 0.1 equiv to 0.5 equiv
methods have been developed for the synthesis of α-acetoxy ke- did not affect product formation (Table 1, entry 11). However,
tones from ketone derivatives and carboxylic acids [10], decreasing the amount of Na2CO3 from 1.0 equiv to 0.1 equiv
benzylic alcohols [19], toluene derivatives [20,21] and alkenes significantly decreased the product yield. The effects of other
[22,23] using TBHP as the oxidant (Scheme 1). However, to the peroxides, i.e., di-tert-butyl peroxide (DTBP), benzoyl
best of our knowledge, this is the first example of the use of peroxide, dicumyl peroxide (DCP), cumene hydroperoxide
TBHP as the oxidant for the construction of α-acetoxyaryl ke- (CHP), potassium hydrogen persulfate, and 3-chloroperoxy-
tones from aryl ketones via self-intermolecular oxidative cou- benzoic acid (m-CPBA), on the reaction were investigated. All
pling.
these peroxides gave sluggish reactions with poor yields, except
Scheme 1: Previous and present approaches.
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Beilstein J. Org. Chem. 2017, 13, 1079–1084.
Table 1: Optimization studiesa.
Entry
peroxide (2.0 equiv)
solvent
Time (h)
Yield%b
1
2
TBHP
TBHP
CH3CN
CH3CN
12
24
46
71
3
4c
TBHP
TBHP
CH3CN
CH3CN
CH3CN
dioxane
DCE
36
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
71
0
5d
6
TBHP
0
TBHP
70
68
63
84
84
84
33
23
47
29
11
11
81
trace
84
7
TBHP
8
TBHP
cyclohexane
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
9
TBHP (4.0)
TBHP (6.0)
TBHP (4.0)
TBHP (4.0)
DTBP (4.0)
benzoyl peroxide (4.0)
DCP (4.0)
CHP (4.0)
K2S2O8 (4.0)
m-CPBA (4.0)
TBHP (4.0)
TBHP (4.0)
10
11e
12f
13
14
15
16
17
18
19g
20h
aReaction conditions: 1a (0.5 mmol), I2 (0.1 equiv), TBHP (2.0 equiv), Na2CO3 (1.0 equiv), solvent (2.0 mL); bGC yield; cwithout I2; dwithout Na2CO3;
eI2: 0.5 equiv; fNa2CO3: 0.1 equiv; greaction temperature: rt; hreflux.
m-CPBA, which gave the desired product 2a in 81% yield acetophenones gave better results than ortho- and meta-substi-
(Table 1, entries 13–18). Finally, we investigated the effect of tuted acetophenones (2b, 2c, and 2d). The scope of this reac-
reaction temperature to this transformation, which indicated that tion was extended by varying the aliphatic part of the arone
the optimum reaction temperature is: 70 °C (Table 1, entries 19 (1j–n); for example, propiophenones and butyrophenones all
and 20).
reacted as anticipated to give the desired α-acetoxyaryl ketones
2j–n in moderate yields. In addition, different substituents on
After the optimization study, the generality of the optimum the phenyl ring had no discernible impact on the outcome.
conditions with various substituted aryl ketones was investigat- 1-(Thiophen-2-yl)ethanone (1i), which has a heteroaryl func-
ed (Scheme 2). Initially, acetophenone derivatives 1a–h were tionality, gave 2i in 83% isolated yield.
used; various electron-donating (i.e., methyl and methoxy) and
electron-withdrawing (i.e., F−, Br−, and Cl−) substituents were A series of control experiments were performed to clarify the
well-tolerated under our reaction conditions. Acetophenones reaction mechanism (Scheme 3). When the reactions were per-
bearing electron-withdrawing substituents performed slightly formed in the presence of an excess of the free-radical scav-
better in this reaction than those bearing electron-donating sub- enger 2,2,6,6-tetramethylpiperidine-N-oxyl, product formation
stituents, and afforded the desired product in relatively high was completely suppressed (Scheme 3, reaction 1), indicating
yields (2f, 2g, and 2h).
that a radical pathway may be involved in this reaction. The
oxygen source was identified by performing the reaction with
The position of a given substituent on the phenyl ring of aceto- excess 18O-labeled H218O; 2a was obtained in 79% yield, with
phenone affected the reaction slightly, and para-substituted no 18O in the product; this excludes the possibility of the
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Beilstein J. Org. Chem. 2017, 13, 1079–1084.
Scheme 2: Substrate scope. (All of these reactions were carried out on a 2.0 mmol scale using CH3CN (2.0 mL) as a solvent.)
oxygen being derived from H2O in the TBHP solvent iodination of aryl ketones with I2 and TBHP [24,25]. An I−/I2
(Scheme 3, reaction 2).When 2-iodo-1-phenylethanone was redox cycle promotes tert-butoxyl and tert-butylperoxyl radical
used as a surrogate of 1a under the optimum conditions or in the formation from TBHP [26-28]. In the presence of TBHP and I2,
absence of I2, 2a was isolated in 91% and 87% yields, respec- α-iodoaryl ketones 5 and 6 are oxidized to a 1,2-diketone inter-
tively (Scheme 3, reactions 3 and 4). We also observed that 2a mediate 7 and an α-carbonyl radical 9, which can be further
was obtained in almost quantitative yields when 1a was reacted transformed to tert-butyl perester 8 and cation 11 [22]. The I−
with tert-butylperoxybenzoate (TBPB) or benzoic acid under anion can be reoxidized by tert-butyl perester 8 to regenerate I2,
the standard conditions (Scheme 3, reactions 5 and 6). These a tert-butoxyl radical, and an aromatic acid anion under alka-
results suggest that 2-iodo-1-phenyl ketone, TBPB, and benzoic line conditions. Finally, the reactions between intermediates 8
acid are generated in situ from 1a as intermediates.
and 9, 10 and 11 or 5 all afford the final product, according to
previous reports [22,29].
The mechanism has not yet been clarified in detail. A probable
catalytic cycle is proposed in Scheme 4 based on the above ex- Conclusion
perimental results and previous literature reports. The process In summary, we have developed an efficient, novel, and metal-
begins with the formation of α-iodoaryl ketones 5 and 6 via free synthesis of α-acetoxyaryl ketones from aryl ketones using
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Beilstein J. Org. Chem. 2017, 13, 1079–1084.
Scheme 3: Control reactions for clarifying the mechanism.
Scheme 4: Plausible mechanism.
I2−TBHP. A facile α-acylation reaction involving self-intermo- single reactor. The reaction conditions are mild and the sub-
lecular oxidative coupling of aryl ketones was observed for the strate scope is broad. This method has good potential applica-
first time in the presence of I2−TBHP. Multiple radical interme- tions in organic synthesis and medicinal chemistry. The inside
diates are generated in situ, and the overall process involves of the reaction mixture has not been studied in depth, but we
several different reactions, which proceed self-sequentially in a have begun mechanistic studies.
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Beilstein J. Org. Chem. 2017, 13, 1079–1084.
25.Mupparapu, N.; Vishwakarma, R. A.; Ahmed, Q. N. Tetrahedron 2015,
71, 3417. doi:10.1016/j.tet.2015.03.088
Supporting Information
26.Lai, J.; Chang, L.; Yuan, G. Org. Lett. 2016, 18, 3194.
doi:10.1021/acs.orglett.6b01412
Supporting Information File 1
Full experimental details and copies of NMR spectral data.
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-13-107-S1.pdf]
27.Uyanik, M.; Ishihara, K. ChemCatChem 2012, 4, 177.
doi:10.1002/cctc.201100352
28.Finkbeiner, P.; Nachtsheim, B. J. Synthesis 2013, 45, 979.
doi:10.1055/s-0032-1318330
29.Zhu, M.; Wei, W.; Yang, D.; Cui, H.; Cui, H.; Sun, X.; Wang, H.
Org. Biomol. Chem. 2016, 14, 10998. doi:10.1039/C6OB02173E
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