N,N-Dimethylformamide (DMF) as a Source of Oxygen to Access α-Hydroxy Arones via the α-Hydroxylation of Arones

Article abstract of DOI:10.1021/acs.joc.6b02751

An unprecedented α-hydroxylation strategy was developed for the synthesis of α-hydroxy arones using N,N-dimethylformamide (DMF) as an oxygen source. Control experiments demonstrated that the oxygen atom of the hydroxy group in the α-hydroxy arones produced in this reaction was derived from DMF. This new reaction therefore not only provides an alternative strategy for the α-hydroxylation of arones but also highlights the possibility of using the inexpensive common solvent DMF as a source of oxygen in organic synthesis.

Full text of DOI:10.1021/acs.joc.6b02751

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Note
DMF as a source of oxygen to access alpha-
hydroxy arones via alpha-hydroxylation of arones
Weibing Liu, Cui Chen, and Peng Zhou
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b02751 • Publication Date (Web): 24 Jan 2017
Downloaded from http://pubs.acs.org on January 25, 2017
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N,NꢀDimethylformamide (DMF) as a source of oxygen to access αꢀhydroxy
arones via the αꢀhydroxylation of arones
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Weibing Liu*, Cui Chen, Peng Zhou
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College of Chemical Engineering, Guangdong University of Petrochemical Technology, 2 Guandu Road,
Maoming 525000, P. R. China.
O
O
I2 (1.2 equiv.)
O
R1
R1
CuO (1.0 equiv.)
+
N
R
R
N2, 100 °C, 24 h
OH
Abstract: An unprecedented αꢀhydroxylation strategy was developed for the synthesis of
αꢀhydroxy arones using N,Nꢀdimethylformamide (DMF) as an oxygen source. Control
experiments demonstrated that the oxygen atom of the hydroxy group in the αꢀhydroxy arones
produced in this reaction was derived from DMF. This new reaction therefore not only provides
an alternative strategy for the αꢀhydroxylation of arones, but also highlights the possibility of
using the inexpensive common solvent DMF as a source of oxygen in organic synthesis.
In recent years, αꢀhydroxyketones1 have attracted considerable interest because of their potential
application to the synthesis of biologically active compounds and natural products.2 For this reason, a
large number of methods have been developed for the synthesis of αꢀhydroxyketones.3 One of the most
commonly used approaches for the synthesis of compounds belonging to this structural class involves
the oxidation of silylenol ethers or enolates with a suitable oxidant such as a metal oxidant, hypervalent
iodine reagent or peroxide.4 However, αꢀhydroxyketones can also be prepared by the reduction of
diketones.5
N,NꢀDimethylformamide (DMF) is a popular, inexpensive, a protic polar solvent, which is widely
used as a solvent in various organic reactions.6 DMF is also used as a reagent7 and a multipurpose
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precursor for the introduction of various functional groups such as –CHO,8 –CO,9 –CON(CH3)2,10
–N(CH3)2,11 –CN,12 ꢀ=CH13 and –H14 moieties in organic chemistry. Li and coꢀworkers recently reported
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a
transitionꢀmetalꢀfree approach for the synthesis of 2‑aryliminochromenes from arynes,
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N,Sꢀketeneacetals and DMF, where DMF was used as a source of oxygen to form the
chromeneskeleton.15 Despite the success of this procedure, there have been very few reports in the
literature pertaining to the use of DMF as an oxygen source in organic transformations (Scheme 1).16
Herein, we report an efficient process for the synthesis of αꢀhydroxy arones from arones using DMF as a
source of oxygen for the hydroxyl group (Scheme 1).
Scheme 1. DMF as a source of oxygen in organic transformations.
Reported works:
Heteroatom
insertion
O
N
N
O
+
N
N
N
R1
R2
R1
R2
Ref. 11c
O
Cu
This work:
O
O
R1
I2 / CuO
100 °C
R1
+
N
R
R
OH
We initially investigated the reaction of propiophenone (1a) with DMF under a variety of different
conditions to determine the optimum conditions for this transformation (Table 1). When the reaction
was conducted in the presence of CuO (1.0 equiv.) and I2 (1.2 equiv.) in DMF at 100 °C, we observed a
moderate yield of the desired αꢀhydroxylated product 2a after 16 h (63%). Increasing the reaction time
to 24 or 32 h led to a minor increase in the yield to 75% (Table 1, entries 1–3). A variety of different
copper species were investigated in the reaction, including CuCl2, CuBr2, Cu(OAc)2, Cu2O, CuCl,
CuBr, CuI, but CuO was found to be the most efficient oxidant in terms of the yield of
2ꢀhydroxyꢀ1ꢀphenylpropanꢀ1ꢀone (2a) (Table 1, entries 4–10). It is noteworthy that CuCl2, Cu2O and
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CuCl were found to be totally ineffective for this αꢀhydroxylation process, affording none of desired
product (Table 1, entries 4,7–8). However, the use of CuI as a surrogate for CuO afforded the desired
product 2a in 69% yield by GC (Table 1, entry 10). The reaction did not afford any of the desired
product when it was conducted in the absence of CuO or iodine (I2), which indicated that these two
species play a corporative role in this reaction. We also investigated the effects of adding different
amounts of CuO and I2 to the reaction and found that the optimal amounts of these two materials were
1.0 and 1.2 equivalents, respectively (Table 1, entries 12–14). Interestingly, we obtained different yields
for the desired αꢀhydroxylated product 2a when the reaction was conducted under oxygen (75%) and
nitrogen (84%) atmospheres, indicating that O2 is less effective for this transformation (Table 1, entries
15–16). Finally, we investigated the effect of the temperature on the reaction, and the results showed
that the optimal temperature was 100 °C. Increasing the reaction temperature to 120°C did not lead to a
further increase in the yield, whereas reducing the reaction temperature to 60°C led to a pronounced
decrease in the yield (Table 1, entries 17–18). It is noteworthy that several other metal salts and metal
oxides were evaluated in this reaction, including FeCl2, FeCl3, NiCl2, MgO and CaO, but all failed to
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afford any of the desired product.
Table 1. Optimization studiesa
O
O
Copper salts, I2 (1.2 equiv.)
DMF, 100°C
OH
2a
1a
Entry
Copper salts (1.0 equiv.)
Time (h)
16
Yield%b
63
1
2
3
4
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7
CuO
CuO
24
75
CuO
32
75
CuCl2
CuBr2
Cu(OAc)2
Cu2O
24
ꢀꢀꢀ
24
trace
trace
ꢀꢀꢀ
24
24
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CuCl
CuBr
CuI
24
24
24
24
24
24
24
24
24
24
24
ꢀꢀꢀ
13
69
ꢀꢀꢀ
63
72
59
66
84
84
47
10
11
ꢀꢀꢀ
12c
13d
14e
15f
16g
17g,h
18g,i
CuO
CuO
CuO
CuO
CuO
CuO
CuO
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aReaction conditions: 1a (0.25 mmol), DMF (2.0 mL); GC yield; I2: 0.5 equiv.; I2: 1.0 equiv.; CuO:
0.5 equiv.; fO2 (balloon); gN2 (balloon); h Reaction temperature: 120°C; iReaction temperature: 60°C.
With the optimized conditions in hand, we proceeded to investigate the scope of this
αꢀhydroxylation reaction using a wide range of different propiophenones 1a−g (Scheme 2). Pleasingly,
all of the propiophenones tested reacted smoothly under the optimized conditions to give the
corresponding αꢀhydroxylated products 2 in 57−85% yields. A comparison of the results for the
different substrates revealed that the electronic effects of the substituents on the benzene ring played an
important role in this transformation. For example, propiophenones bearing electronꢀdonating groups
(e.g., Meꢀ, Etꢀ and methoxyꢀ groups) reacted much more effectively than those bearing
electronꢀwithdrawing groups (e.g., Fꢀ and Clꢀ) to afford the corresponding αꢀhydroxylated products 2
in higher yields. The scope of this reaction was further extended to a series of αꢀsubstituted arones
(1h–n), which all reacted as anticipated to give the corresponding αꢀhydroxy arones (2h–n) in
moderate to good isolated yields (59–86%). It is noteworthy that heterocyclic ketone substrates,
including 1ꢀ(thiophenꢀ2ꢀyl)butanꢀ1ꢀone (1m) and 1ꢀ(thiophenꢀ2ꢀyl)propanꢀ1ꢀone (1n), reacted as arone
surrogates under the optimized conditions to afford the corresponding αꢀhydroxylated products 2m and
2n. To determine whether the reaction could be applied to other ketones, we employed
4ꢀphenylbutanꢀ2ꢀone and acetophenone as the partners of αꢀsubstituted arones under the same
b
c
d
e
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conditions. Unfortunately, these two reactions failed to undergo the desired conversion, with the former
providing (E)ꢀ4ꢀphenylbutꢀ3ꢀenꢀ2ꢀone (2o) as the main product. Compound 2o was most likely formed
from 3ꢀhydroxyꢀ4ꢀphenylbutanꢀ2ꢀone, which would be generated in situ from 4ꢀphenylbutanꢀ2ꢀone.
Scheme 2. Synthesis of αꢀhydroxy arones (2a–o) from αꢀsubstituted arones (All of these reactions were
carried out on a 1.0 mmol scale using DMF (2.0 mL) as a solvent.The number in parentheses is the
isolated yield of propiophenone 1a (10.0 mmol scale) after purification by column chromatography).
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O
O
I2 (1.2 equiv.)
CuO (1.0 equiv.)
O
R1
R1
+
N
R
R
N2, 100 °C, 24 h
OH
O
1
2
O
O
Ph
OH
OH
OH
Et
2a 77% (73%)
2c 84%
2b 78%
O
O
HO
F
F
OH
OH
2e 57%
Cl
O
2f 61%
2d 61%
O
O
O
Ph
OH
OH
OH
2g 85%
HO
O
2i 59%
2h 74%
O
HO
Ph
Ph
Cl
F
OH
O
O Cl
2l 61%
2k 66%
2j 62%
O
O
O
S
Ph
2o 76%
OH
S
HO
2n 79%
2m 86%
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Scheme 3. Investigation of the reaction mechanism.
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O
O
Standard conditions
TEMPO
1a
1a
+
+
O
N
2a (77%)
2a (0%)
Standard conditions
N
+
2a (83%)
2a (0%)
I
I2 (1.2 equiv.)
CuO (1.0 equiv.)
9
O
O
O
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O
N2, 100 °C, 24 h
N2, 100 °C, 24 h
N
+
I
I2 (1.2 equiv.)
CuO (1.0 equiv.)
O
O
1a
1a
+
S
2a (0%)
O
N2, 100 °C, 24 h
CuO (1.0 equiv.)
N2, 100 °C, 24 h
N
+
2a (83%)
I
O
Standard conditions
H218O (2.0 equiv.)
+
2a (76%)
N
To develop better understanding of the mechanism of this hydroxylation, we conducted several
trial experiments in parallel (Scheme 3). Under the optimized conditions, compound 1a was completely
consumed to give the desired αꢀhydroxylation product 2a, even when the reaction was conducted in the
presence of the radical scavenger TEMPO. This result suggested that this transformation did not
proceed via a radical mechanism. However, compound 1a failed to afford any of the desired product 2a
when the reaction was conducted in dioxane or DMSO instead of DMF. Furthermore, when the
reaction of 1a was carried out in the presence of 2.0 equivalents of H218O, 2a was obtained in 76%
yield with no 18Oꢀlabeled in the product, thereby excluding the possibility of the hydroxyl group being
derived from H2O in the DMF solvent. We also noticed that this reaction afforded 2a in 69% yield
when cuprous iodide (CuI) was used instead CuO (Table 1, entry 10). Taken together, the results of
these experiments demonstrate that the oxygen atom of the hydroxyl group in the product is derived
from DMF. Furthermore, when 2ꢀiodoꢀ1ꢀphenylpropanꢀ1ꢀone was used as a substrate instead of
propiophenone under the optimized conditions or in the absence of I2, compound 2a was isolated in
83% yield. In contrast, these reactions failed to afford any of the desired product when they were
conducted in the absence of CuO. These results therefore suggest that 2ꢀiodoꢀ1ꢀphenylpropanꢀ1ꢀone
could be generated in situ as an intermediate from 1a.
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Based on the results of the experiments described above, we have proposed a plausible mechanism for
this conversion, which is shown in Scheme 4. Briefly, propiophenone 1a would undergo an iodination
reaction to generate the key intermediate αꢀiodo propiophenone A.17 The subsequent nucleophilic
attack of DMF to A would lead to the formation of iminium B in the presence of CuO and DMF, which
would be hydrolyzed to give the final product 2a.
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Scheme 4. Proposed mechanism for the αꢀhydroxylation.
O
O
OH
2a
1a
I2/CuO
hydrolysis
HI
O
O
O
N
I
DMF
CuO
B
A
In conclusion, we have developed a simple and efficient strategy for the synthesis of αꢀhydroxy
arones from readily available starting materials including arones, copper oxide, iodine and DMF. This
method could expand the use of DMF as a source of oxygen for the synthesis of αꢀhydroxy arones.
EXPERIMENTAL SECTION
General Information. All the reactions were carried out at 100 °C for 24 h under N2 atmosphere in
a roundꢀbottom flask equipped with magnetic stir bar. Unless otherwise stated, all reagents and
1
solvents were purchased from commercial suppliers and used without further purification. H
NMR and 13C NMR spectra were recorded on a 400 MHz spectrometer in solutions of CDCl3
using tetramethylsilane as the internal standard, δ values are given in ppm and coupling constants
(J) in Hz. HRꢀMS were obtained on a QꢀTOF micro spectrometer.
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Typical procedure: 2ꢀhydroxyꢀ1ꢀphenylpropanꢀ1ꢀone (2a)
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A mixture of propiophenone (1a) (134 mg, 1.0 mmol), CuO (79 mg, 2.0 mmol), iodine (305 mg,
1.2 mmol) and DMF (2.0 mL) was added successively in a roundꢀbottom flask under a N2 balloon,
and the resulting soln. stirred for 24 h at 100 °C. The mixture was purified by column
chromatography on silica gel to afford product 2a with PE/ethyl acetate = 10/1 as the eluent.
2-hydroxy-1-phenylpropan-1-one (2a)18
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1
Yield: 77% (115 mg); H NMR (CDCl3, 300 Hz) δ 7.93 (d, J = 7.2 Hz, 2H), 7.63 (t, J = 7.2 Hz, 1H),
7.51 (t, J = 7.6 Hz, 2H), 5.16 (q, J = 7.2 Hz, 1H), 3.67 (s, 1H), 1.46 (d, J = 7.0 Hz, 1H); 13C NMR
(CDCl3, 75 Hz) δ 202.3, 133.9, 133.3, 128.8, 128.6, 69.3, 22.2.
2-hydroxy-1-p-tolylpropan-1-one (2b) 19
1
Yield: 77% (128 mg); H NMR (CDCl3, 300 Hz) δ 7.83 (d, J = 7.2 Hz, 2H), 7.30 (d, J = 7.2 Hz, 2H),
5.12 (q, J = 7.2 Hz, 1H), 3.02 (s, 1H), 2.43 (s, 3H), 1.44 (d, J = 7.2 Hz, 3H); 13C NMR (CDCl3, 75 Hz)
δ 201.9, 145.0, 130.7, 129.5, 128.7, 69.1, 22.4, 21.7.
1-(4-ethylphenyl)-2-hydroxypropan-1-one (2c)
Yield: 77% (150 mg); Pale yellow oil; 1H NMR (CDCl3, 300 Hz) δ 7.84 (d, J = 7.2 Hz, 2H), 7.31 (d, J
= 7.2 Hz, 2H), 2.72 (q, J = 7.2 Hz, 2H), 2.21 (s, 1H), 1.44 (d, J = 7.2 Hz, 3H), 1.23 (t, J = 6.8 Hz, 3H);
13C NMR (CDCl3, 75 Hz) δ 201.9, 151.1, 130.9, 128.9, 128.3, 69.1, 29.0, 18.3, 15.0; HRMS (ESI):
calcd for C11H15O2: [M+H+] 179.1066, found 179.1082.
1-(4-fluorophenyl)-2-hydroxypropan-1-one (2d) 19
1
Yield: 77% (102 mg); H NMR (CDCl3, 300 Hz) δ 7.96 (dd, J = 7.2 Hz, J = 9.0 Hz, 2H), 7.18 (t, J =
7.2 Hz, 2H), 5.27 (q, J = 7.2 Hz, 1H), 3.16 (s, 1H), 1.43 (d, J = 7.2 Hz, 3H); 13C NMR (CDCl3, 75 Hz)
δ 200.7, 166.2 (d, 1JC-F = 254.9 Hz), 131.4, 131.3, 129.7, 129.7, 116.2, 115.9, 69.2, 22.2.
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1-(3-fluorophenyl)-2-hydroxypropan-1-one (2e) 19
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1
Yield: 77% (96 mg); H NMR (CDCl3, 300 Hz) δ 7.70 (d, J = 8.0 Hz, 1H), 7.61 (d, J = 7.0 Hz, 1H),
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7.48 (q, J = 8.0 Hz, 1H), 7.30 (t, J = 8.0 Hz, 1H), 5.10 (q, J = 7.2 Hz, 1H), 3.59 (s, 1H), 1.44 (d, J = 7.2
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1
Hz, 3H); 13C NMR (CDCl3, 75 Hz) δ 201.2, 162.8 (d, JC-F = 247.3 Hz), 135.4, 135.3, 130.6, 130.5,
124.3, 124.3, 121.1, 120.9, 115.5, 115.3, 69.5, 22.1.
1-(4-chlorophenyl)-2-hydroxypropan-1-one (2f) 19
1
Yield: 77% (112 mg); H NMR (CDCl3, 300 Hz) δ 7.86 (d, J = 7.2 Hz, 2H), 7.47 (d, J = 7.2 Hz, 2H),
5.11 (q, J = 7.2 Hz, 1H), 2.89 (s, 1H), 1.45 (d, J = 7.2 Hz, 3H); 13C NMR (CDCl3, 75 Hz) δ 201.2,
140.5, 131.6, 130.0, 129.2, 69.3, 22.1.
2-hydroxy-1-(4-methoxyphenyl)propan-1-one (2g) 20
1
Yield: 77% (153 mg); H NMR (CDCl3, 300 Hz) δ 7.93 (d, J = 7.2 Hz, 2H), 6.96 (d, J = 7.2 Hz, 2H),
5.11 (q, J = 7.2 Hz, 1H), 3.83 (s, 3H), 2.98 (s, 1H), 1.44 (d, J = 7.2 Hz, 3H); 13C NMR (CDCl3, 75 Hz)
δ 200.6, 164.1, 131.0, 126.0, 114.0, 68.8, 55.5, 22.6.
2-hydroxy-1-phenylpentan-1-one (2h) 21
1
Yield: 77% (132 mg); H NMR (CDCl3, 300 Hz) δ 7.92 (d, J = 7.2 Hz, 2H), 7.62 (t, J = 7.2 Hz, 1H),
7.51 (t, J = 7.6 Hz, 2H), 5.09 (q, J = 7.2 Hz, 1H), 3.69 (s, 1H), 1.48 (m, 4H), 0.92 (t, J = 6.8 Hz, 3H);
13C NMR (CDCl3, 75 Hz) δ 202.2, 133.9, 133.7, 128.8, 128.5, 72.9, 37.9, 18.2, 13.8.
2-hydroxy-2-methyl-1-phenylpropan-1-one (2i) 19
1
Yield: 77% (96 mg); H NMR (CDCl3, 300 Hz) δ 8.01 (d, J = 7.2 Hz, 2H), 7.47 (t, J = 7.2 Hz, 1H),
7.45 (t, J = 7.2 Hz, 2H), 3.19 (s, 1H), 1.64 (s, 3H); 13C NMR (CDCl3, 75 Hz) δ 204.7, 133.7, 132.9,
129.6, 128.4, 76.2, 28.4.
4-chloro-1-(4-fluorophenyl)-2-hydroxybutan-1-one (2j)
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Yield: 77% (134 mg); Orange oil; H NMR (CDCl3, 300 Hz) δ 8.00 (dd, J = 7.2 Hz, J = 9.0 Hz, 2H),
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2.25 (m, 1H), 1.86 (m, 1H); 13C NMR (CDCl3, 75 Hz) δ 199.6, 166.4 (d, JC-F = 255.6 Hz), 131.5,
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131.4, 129.4, 129.4, 116.4, 116.2, 69.4, 41.4, 38.9; HRMS (ESI): calcd for C10H11ClFO2: [M+H+]
217.0426, found 217.0441.
1-(4-chlorophenyl)-2-hydroxybutan-1-one (2k) 22
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Yield: 77% (130 mg); H NMR (CDCl3, 300 Hz) δ 7.86 (d, J = 7.2 Hz, 2H), 7.48 (d, J = 7.2 Hz, 2H),
5.02 (q, J = 7.2 Hz, 1H), 3.17 (s, 1H), 1.92 (m, 1H), 1.60 (m, 1H), 0.94 (d, J = 7.2 Hz, 3H); 13C NMR
(CDCl3, 75 Hz) δ 200.9, 140.4, 132.0, 129.8, 129.2, 73.9, 28.8, 8.82.
2-hydroxy-1,2-diphenylethanone (2l) 23
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Yield: 77% (129 mg); H NMR (CDCl3, 300 Hz) δ 7.93 (d, J = 8.0 Hz, 2H), 7.54 (d, J = 8.0 Hz, 1H),
7.41 (t, J = 8.0 Hz, 2H), 7.30 (m, 5H), 5.97 (s, 1H), 4.56 (s, 1H); 13C NMR (CDCl3, 75 Hz) δ 199.1,
138.9, 133.8, 133.4, 129.1, 129.1, 128.6, 128.5, 127.7, 76.2.
2-hydroxy-1-(thiophen-2-yl)butan-1-one (2m) 21
Yield: 77% (146 mg); 1H NMR (CDCl3, 300 Hz) δ 7.77 (dd, J = 1.2 Hz, J = 5.1 Hz, 1H), 7.73 (dd, J =
1.2 Hz, J = 5.1 Hz, 1H), 7.18 (dd, J = 1.2 Hz, J = 5.1 Hz, 1H), 4.86 (q, J = 6.9 Hz, 1H), 2.88 (s, 1H),
1.98 (m, 1H), 1.71 (m, 1H), 0.99 (t, J = 7.2 Hz, 3H); 13C NMR (CDCl3, 75 Hz) δ 194.5, 139.9, 134.6,
132.8, 128.3, 74.8, 29.8, 8.96.
2-hydroxy-1-(thiophen-2-yl)propan-1-one (2n) 19
Yield: 77% (140 mg); 1H NMR (CDCl3, 300 Hz) δ 7.77 (dd, J = 1.2 Hz, J = 5.1 Hz, 1H), 7.74 (dd, J =
1.2 Hz, J = 5.1 Hz, 1H), 7.19 (dd, J = 1.2 Hz, J = 5.1 Hz, 1H), 4.97 (q, J = 6.9 Hz, 1H), 3.60 (s, 1H),
1.53 (t, J = 7.2 Hz, 3H); 13C NMR (CDCl3, 75 Hz) δ 195.0, 139.4, 134.7, 133.0, 128.3, 70.1, 23.1.
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Yield: 77% (111 mg); H NMR (CDCl3, 300 Hz) δ 7.55 (m, 3H), 7.41 (m, 3H), 6.73 (d, J = 16.2 Hz,
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1H), 2.39 (s, 3H); 13C NMR (CDCl3, 75 Hz) δ 198.4, 143.4, 134.4, 130.5, 128.9, 128.2, 127.1, 27.5.
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Supporting Information Available: Copies of H and 13C NMR of all the new compounds. This
material is available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Authors
*Eꢀmail: lwb409@gdupt.edu.cn
Acknowledgements
We thank the Guangdong Provincial Department of Science and Technology (No.916014) and the
Department of Education of Guangdong Province (No.916021) for financial support.
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