Direct Synthesis of α-Alkoxy Ketones by Oxidative C–O Bond Formation

Article abstract of DOI:10.1002/ejoc.201600723

A convenient method to prepare α-alkoxy ketones has been developed by oxidative coupling of aryl methyl ketones and alcohols. With aqueous tert-butyl hydroperoxide (6.0 equiv.) as the oxidant, tetrabutylammonium iodide (20 mol-%) as the catalyst, and TsNHNH₂(1.0 equiv.) as the additive, ketones underwent direct alkoxylation to give α-methoxy or α-ethoxy ketones in moderate to good yields.

Full text of DOI:10.1002/ejoc.201600723

DOI: 10.1002/ejoc.201600723
Full Paper
α-Alkoxy Ketones
Direct Synthesis of α-Alkoxy Ketones by Oxidative C–O Bond
Formation
Hui Yu,*[a] Yilan Xu,[a] Yan Fang,[a] and Rui Dong[a]
Abstract: A convenient method to prepare α-alkoxy ketones %) as the catalyst, and TsNHNH2 (1.0 equiv.) as the additive,
has been developed by oxidative coupling of aryl methyl ket-
ones and alcohols. With aqueous tert-butyl hydroperoxide
(6.0 equiv.) as the oxidant, tetrabutylammonium iodide (20 mol-
ketones underwent direct alkoxylation to give α-methoxy or α-
ethoxy ketones in moderate to good yields.
Introduction
dized further to give an ester[11] or α,α-dimethoxy ketone as
the final product (Scheme 1a, b).[12] Herein, as a continuation
of our efforts on TBHP-mediated oxidative coupling reactions,
we report a new tetrabutylammonium iodide (TBAI) catalyzed
synthesis of α-alkoxy ketones under mild and metal-free condi-
tions (Scheme 1c).
α-Alkoxy ketones are important building blocks of many syn-
thetically meaningful compounds, such as ligands for Ru com-
plexes for transfer hydrogenation reactions,[1] or bioactive com-
pounds for drug discovery, such as ꢀ-adrenergic blockers and
HIV-1 integrase inhibitors.[2] These compounds could also serve
as precursors for the preparation of chiral alcohols.[3] As a result
of the versatile properties of α-alkoxy ketones, various synthetic
methods have been developed. The most frequently used
methods included the alcoholysis of enol acetates,[4] silyl enol
ethers,[5] or α-diazo ketones,[6] but these methods suffer from
disadvantages, such as requiring multiple steps and harsh con-
ditions. Another route to α-alkoxy ketones was the nucleophilic
addition of nitriles by α-alkoxy ylides or Grignard reagents, but
yields were relatively low, and anhydrous reaction conditions
were needed.[7] Thus, development of new and convenient syn-
thetic pathways to α-alkoxy ketones is still in demand.
In recent years, because of its high efficiency and environ-
ment-friendly properties, tert-butyl hydroperoxide (TBHP)/
nBu4NI system has emerged as an attractive metal-free catalytic
system and has been used successfully for the formation of
carbon–carbon and carbon–heteroatom bonds.[8] In most cases,
these reactions were carried out under mild conditions, and
only small molecules such as H2O and tBuOH are released as
the main byproducts. With this new method, varied syntheti-
cally or pharmaceutically useful compounds have been pre-
pared in good yields. Consequently, we proposed that α-alkoxy
ketones might also be synthesized by such an oxidative C–O
bond-forming process.[9] Oxone and polystyrene-bound
PhI(OAc)2 has been used as an oxidant to convert aceto-
phenone into α-methoxy ketone in MeOH, but yields were
poor.[10] Another challenge was that the obtained α-methoxy
ketone was sensitive to oxidative conditions and was easily oxi-
Scheme 1. Oxidative coupling reaction of a ketone and alcohol. TMP = 2,2,6,6-
tetramethylpiperidine; mCPBA = meta-chloroperoxybenzoic acid.
Results and Discussion
Initially, acetophenone (1a) was chosen as the model substrate
with which to optimize reaction conditions alongside the addi-
tive, catalyst, solvent, and temperature. As shown in Table 1,
the reaction of 1a with TBHP (6.0 equiv., 70 % solution in water)
was examined in MeOH (2 mL) with TBAI (20 mol-%) as the
catalyst at room temperature, and 16 h later only 15 % of the
desired product 3a was isolated (Table 1, Entry 1). TsOH or
TsNH2 (1.0 equiv.) was added to the reaction mixture, but the
yield did not improve significantly (Table 1, Entries 2, 3). To our
delight, a satisfactory yield (83 %) was obtained with TsNHNH2
(1.0 equiv.) as an additive, and by decreasing the amount of
TsNHNH2 to 0.5 equiv. a yield of 69 % was obtained (Table 1,
Entry 4). The reaction proceeded less efficiently with other
hydrazide additives, such as NsNHNH2, PhSO2NHNH2, and
[a] Department of Chemistry, Tongji University,
Siping Road 1239, Shanghai 200092, P. R. China
E-mail: yuhui@tongji.edu.cn
http://chemweb.tongji.edu.cn/Teachers/Organic
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/ejoc.201600723.
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PhCONHNH2 (Table 1, Entries 5–7). Next, a wide range of iodine methylacetophenone and 4-fluro-3-methoxyacetophenone,
sources was screened, and TBAI was determined to be the best were converted into the corresponding products in moderate
(Table 1, Entry 8–11). Change of the oxidant to anhydrous TBHP yields (Table 2, 3n–o). Propiophenone was also tested, but no
(5
M
in decane) or cumene hydroperoxide (CHP) caused lower reaction occurred (Table 2, 3p).
yields (Table 1, Entry 12–13). When the amount of TBHP was
decreased to 4.0 equiv. and 2.0 equiv., the yield of 3a was de-
creased to 68 % and 46 %, respectively (Table 1, Entry 14). Fur-
thermore, a higher temperature did not improve the yield of
3a, and a 53 % yield was observed when the reaction was car-
ried out at 45 °C (Table 1, Entry 15). A 1:1 mixture of MeOH/
CH3CN was tested as solvent, and only 23 % of the product was
isolated (Table 1, Entry 16) Thus, the optimized conditions for
this reaction are summarized as follows: 1a (0.5 mmol),
TsNHNH2 (0.5 mmol), TBAI (0.1 mmol), and TBHP (3.0 mmol,
70 % solution in water), at room temperature in MeOH (2 mL)
for 16 h.
Table 2. TBAI-catalyzed synthesis of α-methoxy ketone.[a]
Table 1. Optimization of reaction conditions for α-methoxy ketone.[a]
Entry
Additive
Catalyst
Oxidant
Yield[b] [%]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
–
TBAI
TBAI
TBAI
TBAI
TBAI
TBAI
TBAI
I2
NH4I
NaI
NIS
TBAI
TBAI
TBAI
TBAI
TBAI
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
CHP
15
17
20
TsOH
TsNH2
TsNHNH2
83 (69[c]
35
)
[d]
NsNHNH2
PhSO2NHNH2
PhCONHNH2
TsNHNH2
TsNHNH2
TsNHNH2
TsNHNH2
TsNHNH2
TsNHNH2
TsNHNH2
TsNHNH2
TsNHNH2
23
20
48
22
24
54
58
75
[a] The reaction was performed with acetophenone (0.5 mmol), TsNHNH2
(0.5 mmol), TBAI (0.1 mmol), and TBHP (70 wt.-% in water, 3.0 mmol) in
methanol (2.0 mL) at room temperature for 16 h. [b] Isolated yields. [c] Yield
determined by NMR spectroscopy.
TBHP[e]
TBHP
TBHP
TBHP
68,[f] 46[g]
53[h]
23[i]
[a] The reaction was carried out with 1a (0.5 mmol), 2a (2.0 mL), oxidant
(6.0 equiv.), and MeOH (2.0 mL), at room temperature for 16 h. [b] Isolated
yields. [c] TsNHNH2 (0.5 equiv.) was added. [d] NsNHNH2 = para-nitro-
Encouraged by the facile synthesis of α-methoxy ketones,
the scope of the reaction was extended to the formation of α-
ethoxy ketones. Reaction of acetophenone and ethanol gave
the desired product 4a in 73 % yield under the optimized reac-
tion conditions (Table 3, 4a). Different substituted aceto-
phenones were also examined, and the corresponding products
were obtained in 45–65 % yields (Table 3, 4b–4e), but no prod-
uct was found when 4-bromoacetophenone was employed as
substrate, which exhibited a reactivity difference of MeOH and
EtOH in this reaction (Table 3, 4f). Heterocyclic substrate 2-acet-
ylfuran gave a 77 % product yield under the optimized reaction
conditions (Table 3, 4g). The disubstituted acetophenone 3,4-
dimethylphenyl methyl ketone afforded the corresponding
product in 40 % yield (Table 3, 4h). When other alcohols, such
as propanol or butanol, were employed, no desired products
were observed because of poor nucleophilicity of the alcohols,
and hydrazone was formed as the major product (Table 3, 4i).
To gain insights into the reaction mechanism, control experi-
benzenesulfonyl hydrazide. [e] TBHP (5
M in decane) was used. [f] TBHP
(4.0 equiv.) was used. [g] TBHP (2.0 equiv.) was used. [h] Reaction carried out
at 45 °C. [i] MeOH/CH3CN = 1:1.
Under the optimized reaction conditions, the substrate scope
was examined, and the results are summarized in Table 2. Dif-
ferent substituted acetophenones were investigated, and the
corresponding products were obtained in moderate to good
yields regardless of the electron-donating or electron-withdraw-
ing groups on the para or meta position of the benzene ring
(Table 2, 3b–i). Marked steric hindrance effects were observed,
and no product was isolated when 2-chloroacetophenone was
used as a substrate (Table 2, 3j). 6-Methoxy-2-acetonaphthone
gave the desired product in 54 % yield (Table 2, 3k). Hetero-
cyclic substrates, such as 2-acetylfuran and 2-acetylthiophene,
underwent smooth reactions to provide products, but the iso-
lated yields were low as a result of the volatility of the products ments were carried out, and the results are shown in Scheme 2.
(Table 2, 3l–m). Disubstituted acetophenones, such as 3,4-di- A radical pathway was excluded, because the reaction pro-
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Table 3. TBAI-catalyzed synthesis of α-ethoxy ketones.[a]
also excluded (Scheme 2b). Next, in the absence of TsNHNH2,
acetophenone was treated with TBAI and TBHP in MeOH for 1 h;
α-iodoacetophenone (6) was isolated in 15 % yield (Scheme 2c).
Then α-iodoacetophenone (6) was prepared and subjected to
the optimized reaction conditions; 3a was obtained in 48 %
yield in the presence of much iodine (Scheme 2d). Finally, a
mixture of acetophenone 1a/α-iodoacetophenone (6) (80:20)
was stirred in MeOH in the presence of TBHP (6.0 equiv.) and
TsNHNH2 (1.0 equiv.) for 16 h. Compound 3a was isolated in
85 % yield (Scheme 2e). These results indicate that α-iodoaceto-
phenone (6) might be a key intermediate of the reaction.
By taking into account the above results, a possible mecha-
nism is proposed in Scheme 3. Iodination of aryl methyl ketone
1 gives α-iodoacetophenone A, which reacts with TsNHNH2 to
afford α-iodo hydrazone B. Then B is converted into azoalkene
C and releases HI, which is oxidized by TBHP to regenerate I2.[13]
Then, addition of MeOH to in situ generated azoalkene C gives
α-methoxy hydrazone D, which is further hydrolyzed to furnish
[a] The reaction was performed with acetophenone (0.5 mmol), TsNHNH2
(0.5 mmol), TBAI (0.1 mmol, 20 mol-%), and TBHP (70 wt.-% in water,
3.0 mmol) in ethanol or propanol (2.0 mL) at room temperature for 16 h.
[b] Isolated yields.
ceeded well in the present of (2,2,6,6-tetramethyl-1-piperidin-
yl)oxidanyl (TEMPO, 1.0 equiv.; Scheme 2a). To reveal the role
of TsNHNH2 in this reaction, in a two-step one-pot procedure,
acetophenone and TsNHNH2 was stirred in MeOH for 1 h and
hydrazone 5 was formed in 90 % yield. Subsequent addition of
TBAI and TBHP to the resulting solution gave only trace
amounts of the product after the mixture had been stirred for
16 h; thus, the possibility of hydrazone 5 as an intermediate was
Scheme 3. Possible reaction pathway.
Scheme 2. Control experiments.
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with acetophenone (0.5 mmol), TsNHNH2 (0.5 mmol, 1.0 equiv.),
TBAI (0.1 mmol, 20 mol-%), TBHP (70 wt.-% in H2O, 3.0 mmol,
6.0 equiv.), and the mixture was stirred in MeOH or EtOH (2 mL) at
room temperature for 16 h. Then the reaction mixture was diluted
with diethyl ether (10 mL), washed with saturated Na2S2O3 (1 mL),
dried with Na2SO4, and filtered. The solvent was removed under
reduced pressure, and the crude product was purified by flash chro-
matography with silica gel by gradient elution with ethyl acetate in
petroleum ether to obtain the corresponding product.
the desired product 3. More details for the mechanism still
need further investigation.
Finally, aiming at the formation of α-trifluoroethoxy ketones,
the reaction performed in trifluoroethanol (2 mL) was also ex-
amined. Interestingly, no expected α-trifluoroethoxy ketone
was found, but α-hydroxy ketones were isolated in 30–67 %
yields (Table 4, 7a–7e).[14] However, in the case of 4-fluoroaceto-
phenone, only trace amounts of the corresponding α-hydroxy
ketone was obtained, and α-tosyl ketone 7f was formed in 35 %
yield as the main product (Table 4).[15]
2-Methoxy-1-phenylethan-1-one (3a):[16] Colorless oil. 1H NMR
(400 MHz, CDCl3): δ = 7.94 (d, J = 7.4 Hz, 2 H), 7.59 (t, J = 7.4 Hz, 1
H), 7.48 (t, J = 7.7 Hz, 2 H), 4.73 (s, 2 H), 3.52 (s, 3 H) ppm. 13C
NMR (101 MHz, CDCl3): δ = 196.1, 134.8, 133.5, 128.7, 127.8, 75.2,
59.4 ppm.
Table 4. TBAI-catalyzed synthesis of α-hydroxy ketones.[a]
2-Methoxy-1-(4-methylphenyl)ethan-1-one (3b):[17] Colorless oil.
1H NMR (400 MHz, CDCl3): δ = 7.84 (d, J = 8.2 Hz, 2 H), 7.27 (d, J =
8.0 Hz, 2 H), 4.70 (s, 2 H), 3.51 (s, 3 H), 2.42 (s, 3 H) ppm. 13C NMR
(101 MHz, CDCl3): δ = 195.7, 144.4, 133.5, 129.3, 127.8, 75.1, 59.3,
21.6 ppm.
2-Methoxy-1-(4-methoxyphenyl)ethan-1-one (3c):[18] Colorless
1
oil. H NMR (400 MHz, CDCl3): δ = 7.93 (d, J = 8.9 Hz, 2 H), 6.94 (d,
J = 8.8 Hz, 2 H), 4.66 (s, 2 H), 3.88 (s, 3 H), 3.50 (s, 3 H) ppm. 13C
NMR (101 MHz, CDCl3): δ = 194.6, 163.7, 130.2, 127.9, 113.8, 75.1,
59.3, 55.4 ppm.
1-(4-Hydroxyphenyl)-2-methoxyethan-1-one (3d):[18] Yellowish
1
solid. H NMR (400 MHz, CDCl3): δ = 7.88 (d, J = 8.8 Hz, 2 H), 6.92
(d, J = 8.8 Hz, 2 H), 4.70 (s, 2 H), 3.51 (s, 3 H) ppm. 13C NMR
(101 MHz, CDCl3): δ = 194.8, 160.8, 130.4, 115.6, 75.0, 59.4,
29.6 ppm.
[a] The reaction was performed with acetophenone (0.5 mmol), TsNHNH2
(0.5 mmol), TBAI (0.1 mmol), and TBHP (70 wt.-% in water, 3.0 mmol) in
trifluoroethanol (2.0 mL) at room temperature for 16 h. [b] Isolated yield.
1-(4-Fluorophenyl)-2-methoxyethan-1-one (3e): Yellowish solid.
1H NMR (400 MHz, CDCl3): δ = 7.99 (dd, J = 8.8, 5.4 Hz, 2 H), 7.15
(t, J = 8.6 Hz, 2 H), 4.68 (s, 2 H), 3.51 (s, 3 H) ppm. 13C NMR (101 MHz,
CDCl3): δ = 194.6, 166.2 (d, J = 248 Hz), 130.7, 130.6, 115.9, 75.2,
59.3 ppm. HRMS (ESI-TOF): calcd. for C9H9FNaO2 [M + Na]+ 191.0479;
found 191.0479.
Conclusion
We have developed a simple and efficient method for the syn-
thesis of α-alkoxy ketones through a direct alkoxylation reac-
tion mediated by a TBAI/TBHP system. With the aid of TsNHNH2,
aryl methyl ketones coupled to methanol and ethanol to give
α-methoxy and α-ethoxy ketones, respectively, in moderate to
good yields. The reactions could be carried out under environ-
mentally friendly and mild conditions. Further studies to under-
stand the mechanism of this oxidative coupling reaction and to
extend this protocol to synthetic applications are still ongoing
in our laboratory.
1-(4-Chlorophenyl)-2-methoxyethan-1-one (3f):[5a] White solid.
1H NMR (400 MHz, CDCl3): δ = 7.81 (d, J = 8.5 Hz, 2 H), 7.62 (d, J =
8.5 Hz, 2 H), 4.66 (s, 2 H), 3.50 (s, 3 H) ppm. 13C NMR (101 MHz,
CDCl3): δ = 195.3, 133.5, 131.9, 129.4, 128.7, 75.2, 59.4 ppm.
1-(4-Bromophenyl)-2-methoxyethan-1-one (3g):[19] White solid.
1H NMR (400 MHz, CDCl3): δ = 7.82 (d, J = 8.5 Hz, 2 H), 7.62 (d, J =
8.5 Hz, 2 H), 4.66 (s, 2 H), 3.50 (s, 3 H) ppm. 13C NMR (101 MHz,
CDCl3): δ = 195.3, 133.5, 132.0, 129.5, 128.7, 75.3, 59.4 ppm.
N-[3-(2-Methoxyacetyl)phenyl]acetamide (3h): White solid. 1H
NMR (400 MHz, CDCl3): δ = 8.67 (s, 1 H), 8.10 (s, 1 H), 7.94 (d, J =
7.9 Hz, 1 H), 7.60 (d, J = 7.7 Hz, 1 H), 7.39 (t, J = 7.9 Hz, 1 H), 4.72
(s, 2 H), 3.48 (s, 3 H), 2.23 (s, 3 H) ppm. 13C NMR (101 MHz, CDCl3):
δ = 196.0, 169.2, 138.9, 135.1, 129.3, 125.0, 123.1, 118.7, 75.1, 59.3,
24.3 ppm. HRMS (ESI-TOF): calcd. for C11H13NNaO3 [M + Na]+
230.0788; found 230.0796.
Experimental Section
General Methods: Commercially available reagents were used as
received without further purification. Reaction mixtures were mag-
netically stirred and monitoring was done by thin layer chromatog-
raphy with silica gel 60 F254 plates, which were visualized by fluo-
rescence quenching at 254 nm. For chromatographic purifications,
analytically pure solvents were used with silica gel (300–400 mesh)
1-(3-Chlorophenyl)-2-methoxyethan-1-one (3i):[20] White solid.
1H NMR (400 MHz, CDCl3): δ = 7.92 (s, 1 H), 7.82 (d, J = 7.8 Hz, 1 H),
7.57 (d, J = 10.9 Hz, 1 H), 7.43 (t, J = 7.9 Hz, 1 H), 4.68 (s, 2 H), 3.51
(s, 3 H) ppm. 13C NMR (101 MHz, CDCl3): δ = 195.1, 136.2, 135.1,
133.5, 130.0, 128.1, 126.0, 75.4, 59.5 ppm.
1
as the solid support. H and 13C NMR chemical shifts are reported
relative to the chemical shift of the residual solvent signal. Refer-
ence peaks for chloroform in 1H and 13C NMR spectra were set at
δ = 7.26 ppm and 77.0 ppm, respectively.
2-Methoxy-1-(6-methoxynaphthalen-2-yl)ethan-1-one (3k):[19]
White solid. 1H NMR (400 MHz, CDCl3): δ = 8.38 (s, 1 H), 7.96 (dd,
J = 8.6, 1.6 Hz, 1 H), 7.83 (d, J = 9.0 Hz, 1 H), 7.77 (d, J = 8.6 Hz, 1
H), 7.20 (dd, J = 8.9, 2.5 Hz, 1 H), 7.14 (d, J = 2.3 Hz, 1 H), 4.81 (s, 2
Typical Experimental Procedure for the Synthesis of α-Alkoxy
Ketones 3a–3p and 4a–4h: A 25 mL Schlenk tube was charged
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H), 3.94 (s, 3 H), 3.54 (s, 3 H) ppm. 13C NMR (101 MHz, CDCl3): δ = 1 H), 6.56 (dd, J = 3.6, 1.7 Hz, 1 H), 4.58 (s, 2 H), 3.65 (q, J = 7.0 Hz,
195.7, 159.8, 137.4, 131.1, 130.1, 129.3, 127.7, 127.2, 124.1, 119.8, 2 H), 1.30 (t, J = 5.8 Hz, 3 H) ppm. 13C NMR (101 MHz, CDCl3): δ =
105.7, 75.2, 59.4, 55.3 ppm.
185.9, 150.9, 146.5, 118.1, 112.1, 73.1, 67.3, 15.0 ppm. HRMS (ESI-
TOF): calcd. for C8H10NaO3 [M + Na]+ 177.0522; found 177.0503.
2-(3-Methoxyprop-1-en-2-yl)furan (3l):[5a] Colorless oil. 1H NMR
(400 MHz, CDCl3): δ = 7.61 (d, J = 1.0 Hz, 1 H), 7.33 (d, J = 3.6 Hz,
1-(3,4-Dimethylphenyl)-2-ethoxyethan-1-one (4h): Colorless oil.
1 H), 6.59–6.55 (m, 1 H), 4.55 (s, 2 H), 3.51 (s, 3 H) ppm. 13C NMR 1H NMR (400 MHz, CDCl3): δ = 7.72 (s, 1 H), 7.67 (d, J = 7.9 Hz, 1 H),
(101 MHz, CDCl3): δ = 185.5, 152.1, 146.5, 117.9, 112.2, 74.7,
59.5 ppm.
7.21 (d, J = 7.9 Hz, 1 H), 4.73 (s, 2 H), 3.64 (q, J = 7.0 Hz, 2 H), 2.31
(s, 6 H), 1.29 (t, J = 7.0 Hz, 3 H) ppm. 13C NMR (101 MHz, CDCl3):
δ = 196.2, 143.0, 137.0, 132.8, 129.8, 128.9, 125.5, 73.4, 67.1, 20.0,
19.7, 15.0 ppm. HRMS (ESI-TOF): calcd. for C12H16NaO2 [M + Na]+
215.1043; found 215.1065.
2-Methoxy-1-(thiophen-2-yl)ethan-1-one (3m):[5a] Colorless oil.
1H NMR (400 MHz, CDCl3): δ = 7.86 (d, J = 3.8 Hz, 1 H), 7.69 (d, J =
4.9 Hz, 1 H), 7.18–7.13 (m, 1 H), 4.56 (s, 2 H), 3.51 (s, 3 H) ppm. 13C
NMR (101 MHz, CDCl3): δ = 189.8, 140.9, 134.0, 132.5, 128.1, 75.8, Typical Experimental Procedure for the Synthesis of α-Alkoxy
59.5 ppm.
Ketones 7a–7e: A 25 mL Schlenk tube was charged with aceto-
phenone (0.5 mmol), TsNHNH2 (0.5 mmol, 1.0 equiv.), TBAI
(0.1 mmol, 20 mol-%), TBHP (70 wt.-% in H2O, 3.0 mmol, 6.0 equiv.),
and the mixture was stirred in trifluoroethanol (2 mL) at room tem-
perature for 16 h. Then the reaction mixture was diluted with di-
ethyl ether (10 mL), washed with saturated Na2S2O3 (1 mL), dried
with Na2SO4, and filtered. The solvent was removed under reduced
pressure, and the crude product was purified by flash chromatogra-
phy with silica gel by gradient elution with ethyl acetate in petro-
leum ether to obtain the corresponding product.
1-(3,4-Dimethylphenyl)-2-methoxyethan-1-one (3n): Colorless
oil. 1H NMR (400 MHz, CDCl3): δ = 7.71 (s, 1 H), 7.66 (dd, J = 7.8,
1.5 Hz, 1 H), 7.22 (d, J = 7.9 Hz, 1 H), 4.70 (s, 2 H), 3.51 (s, 3 H), 2.32
(s, 6 H) ppm. 13C NMR (101 MHz, CDCl3): δ = 195.9, 143.2, 137.1,
132.7, 129.9, 128.8, 125.5, 77.3, 59.37, 20.1, 19.7, 18.4 ppm. HRMS
(ESI-TOF): calcd. for
201.0891.
C11H14NaO2 [M
+
Na]+ 201.0886; found
1-(4-Fluoro-3-methoxyphenyl)-2-methoxyethan-1-one
(3o):
1
White solid. H NMR (400 MHz, CDCl3): δ = 7.75 (d, J = 9.2 Hz, 1 H),
7.71 (dd, J = 11.7, 1.9 Hz, 1 H), 7.01 (t, J = 8.3 Hz, 1 H), 4.63 (s, 2 H),
3.96 (s, 3 H), 3.50 (s, 3 H) ppm. 13C NMR (101 MHz, CDCl3): δ = 194.0,
153.2, 152.2, 150.7, 125.3, 115.7, 112.4, 75.1, 59.3, 56.2 ppm. HRMS
(ESI-TOF): calcd. for C10H11FNaO3 [M + Na]+ 221.0584; found
221.0585.
2-Hydroxy-1-phenylethan-1-one (7a):[14a] White solid. 1H NMR
(400 MHz, CDCl3): δ = 7.93 (d, J = 7.5 Hz, 2 H), 7.64 (t, J = 7.4 Hz, 1
H), 7.51 (t, J = 7.7 Hz, 2 H), 4.89 (s, 2 H), 3.56 (s, 1 H) ppm. 13C NMR
(101 MHz, CDCl3): δ = 198.3, 134.2, 133.3, 128.9, 127.6, 65.4 ppm.
2-Hydroxy-1-(p-tolyl)ethan-1-one (7b):[14a] White solid. 1H NMR
(400 MHz, CDCl3): δ = 7.82 (d, J = 8.2 Hz, 2 H), 7.30 (d, J = 8.1 Hz,
2 H), 4.86 (s, 2 H), 2.43 (s, 4 H) ppm. 13C NMR (101 MHz, CDCl3): δ =
197.9, 130.2, 129.6, 129.1, 127.7, 65.2, 21.7 ppm.
2-Ethoxy-1-phenylethan-1-one (4a):[5a] Colorless oil. 1H NMR
(400 MHz, CDCl3): δ = 7.94 (d, J = 7.3 Hz, 2 H), 7.58 (t, J = 7.3 Hz, 1
H), 7.47 (t, J = 7.7 Hz, 2 H), 4.75 (s, 2 H), 3.65 (q, J = 7.0 Hz, 2 H),
1.29 (t, J = 7.0 Hz, 3 H) ppm. 13C NMR (101 MHz, CDCl3): δ = 196.4,
134.8, 133.3, 128.5, 127.7, 73.4, 67.1, 14.9 ppm.
2-Hydroxy-1-(4-methoxyphenyl) ethan-1-one (7c):[14a] White
1
solid. H NMR (400 MHz, CDCl3): δ = 7.90 (d, J = 8.9 Hz, 2 H), 6.97
(d, J = 8.9 Hz, 2 H), 4.83 (s, 2 H), 3.89 (s, 3 H), 3.60 (s, 1 H) ppm. 13C
NMR (101 MHz, CDCl3): δ = 196.7, 164.3, 129.9, 126.3, 114.1, 64.9,
55.5 ppm.
2-Ethoxy-1-(p-tolyl)ethan-1-one (4b): Yellowish solid. 1H NMR
(400 MHz, CDCl3): δ = 7.85 (d, J = 8.2 Hz, 2 H), 7.27 (d, J = 4.4 Hz,
2 H), 4.73 (s, 2 H), 3.65 (q, J = 7.0 Hz, 2 H), 2.42 (s, 3 H), 1.30 (d, J =
7.0 Hz, 3 H) ppm. 13C NMR (101 MHz, CDCl3): δ = 196.16, 144.32,
132.45, 129.77, 129.31, 127.96, 73.45, 67.16, 21.67, 15.05 ppm. HRMS
1-(3,4-Dimethylphenyl)-2-hydroxyethan-1-one (7d): White solid.
1H NMR (400 MHz, CDCl3): δ = 7.74–7.57 (m, 2 H), 7.28–7.20 (m, 1
H), 4.83 (d, J = 11.0 Hz, 2 H), 2.34 (t, J = 13.2 Hz, 7 H) ppm. 13C NMR
(101 MHz, CDCl3): δ = 198.1, 144.0, 137.4, 131.2, 130.1, 128.7, 125.3,
65.2, 20.1, 19.7 ppm.
(ESI-TOF): calcd. for C11H14NaO2 [M
201.0891.
+
Na]+ 201.0886; found
2-Ethoxy-1-(4-methoxyphenyl)ethan-1-one (4c): Yellowish solid.
1H NMR (400 MHz, CDCl3): δ = 7.95 (d, J = 8.9 Hz, 2 H), 6.94 (d, J =
8.9 Hz, 2 H), 4.69 (s, 2 H), 3.88 (s, 3 H), 3.64 (q, J = 7.0 Hz, 2 H), 1.29
(t, J = 7.0 Hz, 3 H) ppm. 13C NMR (101 MHz, CDCl3): δ = 195.1, 163.7,
130.2, 128.0, 113.8, 73.4, 67.1, 55.4, 15.10 ppm. HRMS (ESI-TOF):
calcd. for C11H14NaO3 [M + Na]+ 217.0835; found 217.0844.
1-(4-Bromophenyl)-2-hydroxyethan-1-one (7e):[14a] White solid.
1H NMR (400 MHz, CDCl3): δ = 7.79 (d, J = 8.5 Hz, 2 H), 7.66 (d, J =
8.5 Hz, 2 H), 4.85 (s, 2 H), 3.46 (s, 1 H) ppm. 13C NMR (101 MHz,
CDCl3): δ = 197.5, 132.4, 132.10, 129.6, 129.1, 65.4 ppm.
1
1-(4-Fluorophenyl)-2-tosylethan-1-one (7f): White solid. H NMR
2-Ethoxy-1-(4-hydroxyphenyl)ethan-1-one (4d):[5a] Yellowish
(400 MHz, CDCl3): δ = 8.06–7.95 (m, 2 H), 7.75 (d, J = 8.0 Hz, 2 H),
7.34 (d, J = 7.9 Hz, 2 H), 7.14 (t, J = 8.4 Hz, 2 H), 4.71 (s, 2 H), 2.44
(s, 3 H) ppm. 13C NMR (101 MHz, CDCl3): δ = 186.6, 166.5 (d, J =
249 Hz), 145.5, 135.7, 132.3, 129.9, 128.6, 116.3, 115.9, 63.7,
21.7 ppm. HRMS (ESI-TOF): calcd. for C15H13FNaO3S [M + Na]+
315.0467; found 316.0501.
1
solid. H NMR (400 MHz, CDCl3): δ = 7.86 (d, J = 8.8 Hz, 2 H), 6.94
(d, J = 8.8 Hz, 2 H), 4.75 (s, 2 H), 3.66 (q, J = 7.0 Hz, 2 H), 1.27 (t, J =
7.0 Hz, 3 H) ppm. 13C NMR (101 MHz, CDCl3): δ = 195.7, 161.5, 130.5,
127.1, 115.7, 73.0, 67.3, 14.9 ppm.
N-[3-(2-Ethoxyacetyl)phenyl]acetamide (4e): White solid. 1H NMR
(400 MHz, CDCl3): δ = 8.29 (s, 1 H), 8.05 (s, 1 H), 7.96 (d, J = 8.1 Hz,
1 H), 7.63 (d, J = 7.7 Hz, 1 H), 7.41 (t, J = 7.9 Hz, 1 H), 4.77 (s, 2 H),
3.64 (q, J = 7.0 Hz, 2 H), 2.23 (s, 3 H), 1.27 (t, J = 7.0 Hz, 3 H) ppm.
13C NMR (101 MHz, CDCl3): δ = 196.3, 169.0, 138.8, 135.3, 129.3,
124.9, 123.3, 118.8, 73.4, 67.2, 24.4, 15.0 ppm. HRMS (ESI-TOF): calcd.
for C12H15NNaO3 [M + Na]+ 244.0950; found 244.0983.
Supporting Information (see footnote on the first page of this
article): Synthesis and characterization data and copies of the 1H
and 13C NMR spectra.
Acknowledgments
2-Ethoxy-1-(furan-2-yl)ethan-1-one (4g): Colorless oil. 1H NMR
Financial support from Tongji University (20123231) is gratefully
(400 MHz, CDCl3): δ = 7.60 (d, J = 1.6 Hz, 1 H), 7.35 (d, J = 3.6 Hz, acknowledged.
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Received: June 14, 2016
Published Online: ■
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Full Paper
α-Alkoxy Ketones
H. Yu,* Y. Xu, Y. Fang, R. Dong ....... 1–7
Direct Synthesis of α-Alkoxy Ket-
ones by Oxidative C–O Bond Forma-
tion
The direct oxidative coupling of aryl TBAI (20 mol-%) as the catalyst, aryl
methyl ketones and alcohols is de- methyl ketones undergo a direct alk-
scribed in this paper. With TsNHNH2 oxylation process to provide α-meth-
(1.0 equiv.) as the additive, aqueous oxy or α-ethoxy ketones in moderate
TBHP (6.0 equiv.) as the oxidant, and to good yields.
DOI: 10.1002/ejoc.201600723
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