Transformation of aryl acyloin O-alkyl and O-phenyl derivatives to ketones

Article abstract of DOI:10.1080/00397910600978564

The treatment of aryl acyloin (α-hydroxyketone) O-alkyl and O-phenyl derivatives with 2-3 equiv of Zn and 1-2 equiv of NH4Cl in ethanol, refluxing for 20-120 min, gave the corresponding ketones with excellent yields. Further, α,β-epoxy ketones can be efficiently transformed to β-hydroxy ketones, and 2,2-dialkoxy-1-phenyl ketone also can be dealkoxylated to 1-phenyl ketone. Copyright Taylor & Francis Group, LLC.

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Transformation of Aryl Acyloin O‐Alkyl and
O‐Phenyl Derivatives to Ketones
Zhiyi Yao a , Deju Ye a , Hong Liu a , Kaixian Chen a & Hualiang Jiang a b
a Center for Drug Discovery and Design, State Key Laboratory of Drug
Research, Shanghai Institute of Materia Medica, Shanghai Institutes for
Biological Sciences, and Graduate School, Chinese Academy of Sciences,
Shanghai, China
b School of Pharmacy, East China University of Science and Technology,
Shanghai, China
Published online: 25 Jul 2007.
To cite this article: Zhiyi Yao , Deju Ye , Hong Liu , Kaixian Chen & Hualiang Jiang (2007): Transformation of
Aryl Acyloin O‐Alkyl and O‐Phenyl Derivatives to Ketones, Synthetic Communications: An International Journal
for Rapid Communication of Synthetic Organic Chemistry, 37:1, 149-156
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Synthetic Communicationsw, 37: 149–156, 2007
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910600978564
Transformation of Aryl Acyloin O-Alkyl
and O-Phenyl Derivatives to Ketones
Zhiyi Yao, Deju Ye, Hong Liu, and Kaixian Chen
Center for Drug Discovery and Design, State Key Laboratory of Drug
Research, Shanghai Institute of Materia Medica, Shanghai Institutes for
Biological Sciences, and Graduate School, Chinese Academy of
Sciences, Shanghai, China
Hualiang Jiang
Center for Drug Discovery and Design, State Key Laboratory of Drug
Research, Shanghai Institute of Materia Medica, Shanghai Institutes for
Biological Sciences, and Graduate School, Chinese Academy of
Sciences, Shanghai, China and School of Pharmacy, East China
University of Science and Technology, Shanghai, China
Abstract: The treatment of aryl acyloin (a-hydroxyketone) O-alkyl and O-phenyl
derivatives with 2–3 equiv of Zn and 1–2 equiv of NH4Cl in ethanol, refluxing for
20–120 min, gave the corresponding ketones with excellent yields. Further,
a,b-epoxy ketones can be efficiently transformed to b-hydroxy ketones, and
2,2-dialkoxy-1-phenyl ketone also can be dealkoxylated to 1-phenyl ketone.
Keywords: aryl acyloin O-derivatives, deoxygenation, 2,2-dialkoxy-1-phenyl
ethanone, a,b-epoxy ketones
INTRODUCTION
The reductive transformation of acyloins and acyloin O-acyl derivatives to
ketones is one of the important processes in the synthesis of natural
products.[1] Reactions utilizing various reagents for this kind of transformation
Received in Japan March 24, 2006
Address correspondence to Hong Liu, Shanghai Institute of Materia Medica,
Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Zhangjiang Hi-Tech Park,
Shanghai 201203, China. E-mail: hliu@mail.shcnc.ac.cn
149

150
Z. Yao et al.
Scheme 1. Transformation of aryl acyloin O-derivatives to ketones with Zn/NH4Cl.
have been reported.[2–5] However, not only are the reported reagents complex
and difficult to prepare, but also the yields of reaction are not ideal. Therefore,
several methods have been devised to try to improve the reaction.[6] First,
Yanagita et al.[7] reported that acyloin O-acyl derivatives can be transformed
to ketones with Zn in glacial acetic acid after refluxing for 24 h with a yield of
50%, and then Ibuka et al.[8] reported and optimized the transformation of
acyloin O-acyl and O-mesyl derivatives to ketones with a yield of 99%.
However, the reagents reported for the transformation of acyloin O-alkyl
and O-phenyl derivatives to the corresponding ketones are limited.[9]
In the present communication, we used Zn/NH4Cl as the reagent for this
transformation and good to excellent yields were reached (Scheme 1). The
application of this reagent is summarized in Table 1. The aryl acyloin
O-phenyl was synthesized by the reaction of the corresponding 2-bromo-1-
aryl-ethanones with phenol in the presence of potassium carbonate at reflux
in good yields.[10] All the aryl acyloin O-alkyl derivatives were purchased
from Aldrich.
RESULTS AND DISCUSSION
Using phenyl acyloin O-phenyl (1a) as a model compound, we optimized the
reaction conditions by testing several parameters, such as reaction solvent,
different amounts of Zn and NH4Cl, and reaction time. The results are
summarized in Table 2. We compared the reaction yields using ethanol and
CH2Cl2 as reaction solvents during the synthesis of compound 2a. The
result indicated that the reaction is more efficient when taking ethanol as
solvent (99%, 30 min) than when taking CH2Cl2 as solvent (27%, 18 h).
Compound 1a was separately dephenoxylated with 0.1, 1.5, and 2.5 equiv
of Zn and 1.5 equiv of NH4Cl in ethanol at reflux and different reaction
times. After 30 min, the conversion rate of 1a achieved 100% (yield 99%)
using 2.5 equiv of Zn (Entry 6). When using 2.5 equiv of Zn without
NH4Cl, nearly no depheoxylation was produced (Entry 7), and with 0.5,
1.0, and 1.5 equiv of NH4Cl, the yields increased with the amounts of
NH4Cl. With 1.5 equiv of NH4Cl, the reaction completed (yield 99%).
After 2 h, the reactions with the lower amount of 1.5 equiv of Zn were
incomplete with a corresponding conversion rate of 80% (yield 75%). This

Transformation of O-Alkyl and O-Phenyl Derivatives
151
Table 1. Examples of transformation from aryl acyloin O-alkyl and O-phenyl
derivatives to ketones with Zn/NH4Cl
Time Yield
(min) (%)a
Compound
Substrate
Compound
Product
PhCOMe
PhCOMe
1a
1b
1c
1d
1e
PhCOCH2OPh
PhCOCH2OMe
PhCOCH2OAc
2a
2a
2a
2a
2e
30
30
20
30
30
99
93
99
99
90
PhCOMe
PhCOMe
PhCOCH2OCH2(Me)2
2,3-(OCH2CH2O)-
PhCOCH2OMe
2,3-(OCH2CH2O)-
PhCOMe
1f
2,3-(OCH2CH2O)-
PhCOCH2OPh
2e
2e
2,3-(OCH2CH2O)-
PhCOMe
30
30
96
93
1g
2,3-(OCH2CH2O)-Ph
COCH2OCH(Me)2
4-MeOPhCOCH2OPh
2,5-(MeO)2Ph
2,3-(OCH2CH2O)-
PhCOMe
1h
1i
2h
2i
4-MeOPhCOMe
2,5-(MeO)2
PhCOMe
30
30
99
99
COCH2OPh
1j
4-ClPhCOCH2OPh
4-CF3PhCOCH2OPh
4-FPhCOCH2OPh
PhCOCH(Ph)OMe
PhCOCH(Ph)OPh
PhCOCH(Ph)
2j
2k
2l
4-ClPhCOMe
4-CF3PhCOMe
4-FPhCOMe
PhCOCH2Ph
PhCOCH2Ph
PhCOCH2Ph
30
30
97
74
90
93
99
96
1k
1l
30
1m
1n
1o
2m
2m
2m
120
120
120
OCH(CH3)2
PhCH2CH2OPh
3-PhOPhCOOH
1p
1q
No reaction
No reaction
30
30
0
0
aIsolated yields.
Table 2. Comparison of dephenoxylation methods for compound 1a
Zn
(equiv)
NH4Cl
(equiv)
Time
(min)
Product
(yield, %)
Entry
1a
2a
3
2.5
2.5
0.1
1.5
1.5
2.5
2.5
2.5
2.5
2.5
1.5
1.5
1.5
1.5
1.5
1.5
0.0
0.5
1.0
1.5
30
18 h
30
0
27
10
57
75
99
0
4
30
5
2 h
30
6
7b
8
30
30
55
70
99
9
10
30
60
aThe solvent is dry CH2Cl2.
bThe reaction was refluxing in absolute EtOH under N2.

152
Z. Yao et al.
indicates that the optimization of the dephenoxylation conditions by increas-
ing the amount of Zn may be more useful than extending the reaction time.
The optimum results were usually obtained when 5 mM of the starting
material was allowed to react with 2–3 equiv of Zn and 1–2 equiv of
NH4Cl turning in 5–10 mL of ethanol at reflux for 20–120 min. The
products were obtained by column chromatography with silica gel.
The reactions of dealkoxylation and dephenoxylation of aryl acyloin
O-derivatives under the optimized conditions are summarized in Table 1.
The results indicate that O-phenyl derivatives (compounds 1a and 1f, in
Table 1) are easy to reductively cleave by Zn/NH4Cl, but the O-methyl
group is relatively stable under the same condition (compounds 1b and 1e).
No obvious change has been seen for the yields of dealkoxylate and dephenox-
ylate when the phenyl of phenyl acyloin (compounds 1a–1d) was changed to
1,4-benzodioxane (compounds 1e–1g). Moreover, compounds with electron-
donating groups such as p-MeO- and 2,5-MeO- (compounds 1h, 1i) are much
easily dephenoxylated, whereas compounds with strong electron-withdrawing
groups such as p-CF3- or p-F- (compounds 1k, 1l) gave lower product yields.
At last, introduction of a phenyl to the Ca atoms for the compounds 1m–1o
prolonged the reaction time. All of the Ca-phenyl substituted aryl acyloin
O-derivatives need ꢀ2 h to finish the reaction, and yields are excellent
(Table 1).
To determine whether the reagent had an effect on the dephenoxylation
of aryl ether without carbonyl, we mixed benzyl phenyl ether (compound
1p) and 3-phenoxybenzoic acid (compound 1q) with Zn/NH4Cl. No
product was determined after 30 min for these two reactions, indicating that
the adjacent carbonyl is necessary in the substrates to be dephenoxylated by
Zn/NH4Cl.
Yamakawa and Nishitani[11] has reported using zinc in acetic acid to open
the a,b-epoxy ketones to get the b-hydroxy ketones in only 53% yield,
together with enone as a side product, and then Hasegawa et al. used an
effective photoinduced reagent of 1,3-dimethyl-2-phenylbenzimidazoline
(DMPBI) acetic acid[12] to optimize the transformation. All of the conversions
are 100% (yield .80%) after 1 h. However, the side products of this reaction
could not be isolated completely. Here, we applied our reagent to this trans-
formation by taking trans-1,3-diphenyl-2,3-epxoypropane-1-one (3, in
Scheme 2) as the substrate; the yield of the b-hydroxy ketone (4) is 93%
after 30 min in CH2Cl2 at reflux. In the whole process, no a-hydroxy
Scheme 2. Transformation of a,b-epoxy ketones to b-hydroxy ketones.

Transformation of O-Alkyl and O-Phenyl Derivatives
153
ketone and enone were generated, and the b-hydroxy ketone is the exclusive
product. Our method may be an efficient and clean approach for the transform-
ation of a,b-epoxy ketones to b-hydroxy ketones.
To date, most of the reports on the 2,2-dialkoxy-1-phenyl ethanone,
which can be easily transformed from the oxo-phenylacetaldehyde[13] (5),
are about their deprotections to give the corresponding 1,2-dione[14]
(Scheme 3). We tried to apply our reagent to the 2,2-diethoxy-1-phenyl
ethanone (6) by using 2–3 equiv of Zn and 1–2 equiv of NH4Cl in ethanol
at reflux; after 30 min, the yields of 2-ethoxyl-1-phenyl-ethanone (7) and
1-phenyl ethanone (2a) are 36% and 56%, respectively, whereas with
additional 2–3 equiv of Zn and 1–2 equiv of NH4Cl and expanding the
time to 4 h, 1-phenyl ethanone was the exclusive product (yield 99%), as
shown in Scheme 3. The results indicate that Zn/NH4Cl may provide a
novel method for transforming 1,2-dione to ketone. Remarkably, the dealkox-
ylation and dephenoxylation of aryl acyloin O-alkyl and O-phenyl derivatives
with Zn/NH4Cl can be carried out in an aqueous medium with very mild
conditions.
We propose a reaction mechanism (Scheme 4) for the transformation.
Initially, a zinc atom coordinates with the ketone and Ca-oxygen atoms,
forming a five-membered cyclic transition state (8). This complexation
forces a flat conformation, facilitating the donation of a pair of electrons
from the zinc to the ketone oxygen and then promoting the release of the
anion of the O-alkyl or O-phenyl to form a zinc enolate (9), which is the
same as the intermediate depicted by Fu¨rstner in which the metal was Ti.[9]
Afterward, the final ketone will be produced through neutralization and tauto-
merization. The experiment of deuteration of the intermediacy of zinc enolate
9 using D2O instead of NH4Cl was done. After one night, the conversion rate
of 2-methoxy-1-phenyl-ethanone (1b) to 2-deuterio-1-phenyl-ethanone is
nearly 100%.
In summary, a convenient and efficient method for dealkoxylation and
dephenoxylation of aryl acyloin O-alkyl and O-phenyl derivatives with Zn/
NH4Cl in EtOH is described, and its mechanism is proposed. This method
can also be efficient for the transformation of a,b-epoxy ketones
to b-hydroxy ketones. We also reported, for the first time, a direct way of
transforming 2,2-dialkoxy-1-phenyl ethanone to 1-phenyl ethanone.
Scheme 3. Transformation of 2,2-diethoxy-1-phenyl ethanone with Zn/NH4Cl: (a)
2–3 equiv of Zn and 1–2 equiv of NH4Cl, 30 min, 7: 36%, 2a: 56%; (b) 4–6 equiv
of Zn and 2–4 equiv of NH4Cl, 4 h, 7: 0%, 2a: 99%.

154
Z. Yao et al.
Scheme 4. Proposed mechanism for the dealkoxylation and dephenoxylation of aryl
acyloin O-alkyl and O-phenyl derivatives by Zn/NH4Cl.
EXPERIMENTAL
IR spectra were measured with a Perkin-Elmer 598B spectrometer using KBr
pellets. NMR spectra were determined on a Bruker AMX-400 instrument in
CDCl3. MS spectra were recorded on a MAT-95 spectrometer. Products are
characterized by comparison of their spectral data (1H NMR, IR) to those
reported in the literature.
A typical procedure is as follow: 5 mmol each of aryl O-derivatives were
dissolved in 5 mL of EtOH, and a certain amount of Zn and NH4Cl were
added. Then the mixture was stirred for a period of time at reflux. Zn was
filtered off, and EtOH was removed under vacuum. Then 5 mL of H2O was
added to the remains and the system was extracted with CH2Cl2 three
times. On evaporation of the solvent, pure ketones were obtained by
column chromatography with silica gel.
1-(2,3-Dihydro-1,4-benzodioxin-6-yl)-ethanone.[15] 1H NMR (400 MHz,
CDCl3): d 2.58 (s, 3H), 4.24 (m, 2H), 4.26 (m, 2H), 6.90 (d, 1H,
J ¼ 8.8 Hz), 7.48 (d, 1H, J ¼ 8.8 Hz), 7.50 (s, 1H).
3-Hydroxy-1,3-diphenyl-1-propanone.[16] 1H NMR (400 MHz, CDCl3): d
3.38 (d, 2H, J ¼ 6.4 Hz), 3.60 (s, 1H, OH), 5.35 (t, 1H, J ¼ 6.4 Hz), 7.32
(t, 1H, J ¼ 7.2), 7.38 (t, 2H, J ¼ 7.2), 7.46 (m, 4H), 7.59 (t, 1H, J ¼ 7.2),
7.96 (d, 2H, J ¼ 7.2).
2-Ethoxy-1-phenyl-ethanone.[17] 1H NMR (400 MHz, CDCl3): d 2.20 (t, 3H,
J ¼ 7.0), 4.25 (q, 2H, J ¼ 7.0), 5.22 (s, 2H), 7.30 (t, 1H, J ¼ 7.2), 7.38 (t, 2H,
J ¼ 7.2), 7.90 (d, 2H, J ¼ 7.2).
ACKNOWLEDGMENTS
We gratefully acknowledge financial support from the State Key Program of
Basic Research of China (Grant 2002CB512802), the National Natural
Science Foundation of China (Grants 20372069, 29725203, and 20472094),
the Basic Research Project for Talent Research Group from the Shanghai
Science and Technology Commission, the Key Project from the Shanghai

Transformation of O-Alkyl and O-Phenyl Derivatives
155
Science and Technology Commission (Grant 02DJ14006), the Key Project for
New Drug Research from Chinese Academy of Sciences (CAS), and the 863
Hi-Tech Program (Grants 2002AA233061, 2002AA104270, 2002AA233011,
and 2003AA235030).
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