Catalytic oxidation of silyl enol ethers to 1,2-diketones employing nitroxyl radicals

Article abstract of DOI:10.1055/s-0031-1290528

A novel and efficient method for the preparation of 1,2-diketones is reported. A series of -diketones were readily prepared by the nitroxyl-radical-catalyzed oxidation of silyl enol ethers using magnesium monoperoxyphthalate hexahydrate (MMPP6H) as the co-oxidant. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0031-1290528

LETTER
▌1025
lCettaertalytic Oxidation of Silyl Enol Ethers to 1,2-Diketones Employing Nitroxyl
Radicals
Catalytic Oxidation of Silyl Enol Ethers to 1,2-Diketones
Masaki Hayashi,a Masatoshi Shibuya,b Yoshiharu Iwabuchi*b
a
Process Technology Research Laboratories, Daiichi Sankyo Co., LTD, 1-12-1, Shinomiya, Hiratsuka, Kanagawa 254-0014, Japan
b
Department of Organic Chemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3 Aobayama, Sendai 980-8578, Japan
Fax +81(22)7956845; E-Mail: iwabuchi@mail.pharm.tohoku.ac.jp
Received: 14.01.2012; Accepted after revision: 14.02.2012
monium ion, are converted into 1,2-diketones by
Abstract: A novel and efficient method for the preparation of 1,2-
thermolysis. However, this method has rarely been used
diketones is reported. A series of α-diketones were readily prepared
for synthesizing 1,2-diketones owing to the need for a
by the nitroxyl-radical-catalyzed oxidation of silyl enol ethers using
stoichiometric amount of TEMPO. In addition, the
TEMPO moiety is converted into its corresponding amine
after the thermolysis of the N–O bond of an α-aminooxy
ketone, which impedes the construction of a redox cata-
lyst system. To address these issues, we have developed a
redox catalytic cycle, in which the oxidation of an α-ami-
nooxy ketone intermediate to N-oxide regenerates oxoam-
monium ions,11 thereby completing the catalytic cycle.
We envisaged that a less hindered class of nitroxyl radi-
cals, such as AZADO (2-azaadamantane N-oxyl; Figure
1) (2) and Nor-AZADO (9-azanoradamantane N-oxyl)
(3)12 will accommodate productive interactions between
an intermediate and an oxidant.
magnesium monoperoxyphthalate hexahydrate (MMPP⋅6H2O) as
the co-oxidant.
Key words: oxidation, catalysis, enols, diketones, nitroxyl radical
1,2-Diketones are an important class of compounds fre-
quently found in substructures of natural products and bi-
ologically active compounds.1 Moreover, they constitute
important intermediates in organic and medicinal chemis-
try as precursors of various biologically active heterocy-
clic compounds, such as imidazoles, triazoles, pyrazines,
and quinoxalines.2
The direct oxidation of α-methylene ketones or their de-
rivatives is an important transformation for the synthesis
of 1,2-diketones. The conventional methods for this trans-
formation, which are based on the use of stoichiometric
amounts of toxic metal oxidants such as selenium oxide,3
pyridinium chlorochromate,4 and potassium permanga-
nate,5 have limited applications owing to the expanding
demand for environmental conservation.
Herein, we report a practical method for the synthesis of
diketones catalyzed by nitroxyl radicals using
MMPP⋅6H2O as the co-oxidant.
N
N
N
•
O
•
•
O
O
Several metal-free methods of synthesizing diketones, in-
cluding the DMSO-mediated oxidation of α-methylene
ketones or α-bromo ketones,6 the photooxygenation of en-
amino ketones,7 and the microwave-promoted oxidation
of α-nosyloxy ketones by pyridine N-oxide,8 have been
developed. However they have disadvantages for practi-
cal use, such as strongly acidic conditions, cryogenic con-
ditions, photooxidative conditions, and microwave
irradiation conditions.
TEMPO (1)
AZADO (2)
Nor-AZADO (3)
Figure 1 Structures of TEMPO, AZADO, and Nor-AZADO
We first examined the stoichiometric reaction of deoxy-
–
benzoine 4 and AZADO+BF4 (5),13 the oxoammonium
salt derived from AZADO, in which the expected addition
reaction proceeded to give 6 in high yield at room temper-
ature, although the reaction required a rather long time
(Scheme 1, 91% after 24 h).
Recently, Jiang et al. have reported an excellent DABCO-
catalyzed procedure.9 Various benzil derivatives can be
obtained from α-methylene ketones in high yield, al-
though the process requires high reaction temperatures.
We then changed the substrate to a more reactive silyl
enol ether 7a, in which the addition reaction proceeded
rapidly and the desired alkoxyl amine 6 was generated
quantitatively. It was found that clean oxidation to benzil
8a was realized by the one-pot oxidation of 6 using
MMPP⋅6H2O as the oxidant (Scheme 1).
Hunter and Barton reported an alternative process for syn-
thesizing 1,2-diketones using an oxoammonium ion de-
rived from 2,2,6,6-tetramethylpipedine 1-oxyl [TEMPO
(1); Figure 1].10 They demonstrated that α-aminooxy ke-
tones, prepared by the addition of ketones to an oxoam-
We next explored the catalytic conditions (Table 1). The
treatment of 7a in the presence of 1.5 equivalents of
–
MMPP⋅6H2O and 20 mol% AZADO+BF4 (5) at room
temperature for 24 hours afforded 7a in 68% yield (Table
1, entry 1), along with α-hydroxylated by-products 9 and
10, which were generated through the direct Rubottom
oxidation14 of 7a. The reaction time was prolonged when
SYNLETT 204012, 237, 1025–1030
Advanced online publication: 29.03.2012
DOI: 10.1055/s-0031-1290528; Art ID: ST-2012-U0036-L
© Georg Thieme Verlag Stuttgart · New York
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6

1026
M. Hayashi et al.
LETTER
–
BF4
N+
O
O
AZADO+BF4– (5)
Ph
N
O
(1 equiv)
Ph
Ph
O
Ph
p-TsOH⋅H2O (0.2 equiv)
4
MeCN, r.t., 24 h
6 (91%)
O
AZADO+BF4– (4)
MMPP⋅6H2O
O
Ph
OTBS
(1 equiv)
(1 equiv)
Ph
Ph
Ph
Ph
O
MeCN
r.t., 2 h
Ph
MeCN, 0 °C, 5 min
N
O
7a
8a (93%)
6
Scheme 1 Stoichiometric reaction of oxoammonium ion
a nitroxyl radical was used as the catalyst instead of verse addition of 7a (Method B, Table 1, entry 6), in
oxoammonium salt (Table 1, entry 2). The reaction was which the direct Rubottom oxidation of 7a was sup-
sensitive to the structure of the nitroxyl radical (Table 1, pressed and the yield increased to 86%. We also con-
entries 2–4). Hindered TEMPO did not work as a catalyst firmed that no 8a was formed in the absence of a catalyst
under the conditions (1%, Table 1, entry 3). Meanwhile, (Table 1, entry 7).
the yield of 8a was highest when least-hindered Nor-
We attempted the reaction of deoxybenzoine 4 instead of
silyl enol ether 7a under the optimized catalytic condi-
tions (Table 1, entry 6), in which no 8a was formed.
AZADO12f was used, even though the reaction was not
completed even after 30 hours (60%, Table 1, entry 4).
Upon obtaining the results of the above experiments, we
The scope and limitations of this catalytic system are
investigated additives for accelerating the reaction. We
shown in Table 2. Most of the reactions to form benzil de-
examined the reaction in the presence of LiBF4 with a
rivatives proceeded in moderate to high yield (55–85%,
–
view to generate Nor-AZADO+BF4 (11) in situ,15 in
Table 2, entries 1–9). An electron-withdrawing group at
which the reaction was completed within two hours (Ta-
the aromatic ring lowered the yield (55%, Table 2, entry
ble 1, entry 5). However the yield remained at 61% be-
5). Heterocyclic substrates such as indole and benzooxa-
zole derivatives were converted into their corresponding
diketones in high yield (81–89%, Table 2, entries 10 and
cause the direct Rubottom oxidation of 7a was also
accelerated by LiBF4. A significant improvement in the
yield was achieved by changing the procedure to the re-
Table 1 Experimental Conditions and Results for the Catalytic Oxidation of 7a to 8a
catalyst (20 mol%)
MMPP⋅6H2O (1.5 equiv)
O
O
O
OTBS
Ph
Ph
Ph
Ph
+
+
Ph
Ph
Ph
Ph
MeCN, r.t.
7a
O
8a
OTBS
OH
10
9
Methoda
A
Production ratiob 7a/8a/9/10
Entry
1
Catalyst (20 mol%)
Additive (2 equiv) Time (h)
24
Yield
68%
AZADO+BF4
–
N.D./75/22/N.D.
2
3
4
5
6
7
A
A
A
A
B
B
AZADO
30
30
30
38/42/12/3
8/1/76/4
48%
1%
TEMPO
Nor-AZADO
Nor-AZADO
Nor-AZADO
29/55/8/2
60%
61%
86%
–
LiBF4
LiBF4
2
2
2
N.D./64/25/7
N.D./92/3/4
N.D./N.D./62/19
a Method A: MMPP⋅6H2O (1.5 equiv) was added to the mixture of 7a (0.5 mmol), catalyst (20 mol%) and additive (2 equiv) in MeCN (5 mL).
Method B: A solution of 7a (0.5 mmol) in MeCN (5 mL) was added to the mixture of MMPP⋅6H2O (1.5 equiv), catalyst (20 mol%) and additive
(2 equiv) in MeCN (5 mL).
b The ratio of HPLC peak area; N.D. = not detected.
Synlett 2012, 23, 1025–1030
© Georg Thieme Verlag Stuttgart · New York

LETTER
Catalytic Oxidation of Silyl Enol Ethers to 1,2-Diketones
1027
–
BF4
N+
O
O
Nor-AZADO+BF4– (11)
MMPP⋅6H2O
O
Ph
N
OTBS
(1 equiv)
(1 equiv)
Ph
Ph
Ph
Ph
O
Ph
MeCN
0 °C, 5 min
MeCN
r.t.
O
7a
12 (100%)
8a
without additives:
2 h, 94%
with LiBF4 (2 equiv): 0.5 h, 93%
N
O
HO
OTBS
Nor-AZADOH (20 mol%)
Ph
Ph
Ph
MMPP⋅6H2O (1 equiv)
LiBF4 (2 equiv)
Ph
O
7a
8a (83%)
MeCN, r.t., 2 h
Scheme 2 Isolation and oxidation of intermediate 12
11). Silyl enol ethers that have an alkyl substituent result- dized to 8a in high yield with MMPP⋅6H2O, and the reac-
ed in moderate yield (37–68%, Table 2, entries 12–14).
tion was accelerated by the addition of LiBF4, which
indicate an effect of LiBF4 as Lewis acid. We also demon-
strated that Nor-AZADOH, which is supposed to be
formed after oxidation of 12, catalyze the reaction, prov-
ing that the reaction involves redox catalyst system.
To study the reaction pathway, we isolated the α-amino-
oxy ketone intermediate 12, which was readily prepared
–
by the addition reaction of 7a with Nor-AZADO+BF4
(11)13 (Scheme 2). It was also confirmed that 12 was oxi-
Table 2 Scope and Limitation
Nor-AZADO (20 mol%)
MMPP⋅6H2O (1.5 equiv)
OTBS
O
LiBF4 (2 equiv)
R2
R2
R1
R1
MeCN, r.t.
O
7
8
Entrya
Substrate
Product
Time (h)
Yield (%)
OTBS
O
1
2
85
O
7b
8b
OTBS
O
O
2
3
4
3
3
2
81
81
83
O
O
Cl
Cl
7c
8c
OTBS
Br
Br
8d
7d
O
OTBS
O
F
F
7e
8e
© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 1025–1030

1028
M. Hayashi et al.
LETTER
Table 2 Scope and Limitation (continued)
Nor-AZADO (20 mol%)
MMPP⋅6H2O (1.5 equiv)
OTBS
O
LiBF4 (2 equiv)
R2
R2
R1
R1
MeCN, r.t.
O
7
8
Entrya
Substrate
Product
Time (h)
Yield (%)
OTBS
O
5
26
55
O
NC
NC
7f
8f
OMe
OMe
OTBS
O
6
7
1
3
84
68
O
MeO
MeO
8g
7g
Cl
Cl
O
OTBS
OTBS
O
Cl
Cl
8h
7h
O
Cl
Cl
8
9
20
21
76
63
O
7i
8i
OTBS
O
Cl
Cl
O
7j
7k
7l
8j
OMe
OMe
O
TBSO
10
3
89
N
O
N
SO2Ph
SO2Ph
8k
OMe
OMe
O
TBSO
O
11
12
2
1
81
68
O
O
8l
OTBS
O
O
7m
8m
Synlett 2012, 23, 1025–1030
© Georg Thieme Verlag Stuttgart · New York

LETTER
Catalytic Oxidation of Silyl Enol Ethers to 1,2-Diketones
1029
Table 2 Scope and Limitation (continued)
Nor-AZADO (20 mol%)
MMPP⋅6H2O (1.5 equiv)
OTBS
O
LiBF4 (2 equiv)
R2
R2
R1
R1
MeCN, r.t.
O
7
8
Entrya
13
Substrate
Product
Time (h)
Yield (%)
44
O
OTBS
1
O
8n
7n
OTBS
O
14
3
37
major/minor = 83:17
O
7o
8o
a Reaction procedure: A solution of 7 (0.5 mmol) in MeCN (5 mL) was added to the mixture of MMPP⋅6H2O (1.5 equiv), catalyst (20 mol%)
and additive (2 equiv) in MeCN (5 mL).
To exclude another plausible route involving an initial On the basis of the above results, we propose a plausible
Rubottom oxidation followed by the oxidation of α-hy- pathway for the catalytic oxidation of silyl enol ethers to
droxy ketone 9, we treated the α-hydroxylated by-prod- 1,2-diketones (Scheme 4). The reaction involves the ini-
ucts 9 and 10 with Nor-AZADO, MMPP⋅6H2O, and tial formation of the α-aminooxy ketone 12 with the addi-
LiBF4 under the reaction conditions (Scheme 3), in which tion of 7a to Nor-AZADO+X–, which is generated in situ
no reaction was observed in the case of 9, and the oxida- through the oxidation of Nor-AZADO. Then, 8a and Nor-
tion of 10 resulted in moderate yield.
AZADOH are produced through the oxidation of 12 by
MMPP⋅6H2O. Nor-AZADOH is oxidized to Nor-
AZADO+X– by MMPP⋅6H2O to complete the catalytic cycle.
Nor-AZADO (20 mol%)
MMPP⋅6H2O (1.5 equiv)
O
O
O
In summary, we have demonstrated a novel method for
the synthesis of 1,2-diketones through the nitroxyl-radi-
cal-catalyzed oxidation of silyl enol ethers using
MMPP⋅6H2O as the oxidant at room temperature.16 The
simple operation and mild room temperature and metal-
free conditions are advantages for the practical synthesis
of 1,2-diketones.
LiBF4 (2 equiv)
Ph
Ph
Ph
+
Ph
Ph
Ph
MeCN, r.t., 2 h
OTBS
O
OTBS
9
8a (0%)
9 (96%)
Nor-AZADO (20 mol%)
MMPP⋅6H2O (1.5 equiv)
LiBF4 (2 equiv)
O
O
O
Ph
Ph
Ph
+
Ph
Ph
Ph
MeCN, r.t., 2 h
OH
O
8a (52%)
OH
Acknowledgment
10
9 (24%)
This work was partly supported by a Grant-in-Aid for Scientific Re-
search (B) (No. 21390001), and by a Grant-in-Aid for Young Sci-
entists (A) (No. 23689001) from the Japan Society for the
Promotion of Science (JSPS).
Scheme 3 Oxidation of 9 and 10
MMPP⋅6H2O
N
•
O
N
Nor-AZADO
HO
Nor-AZADOH
–X
N+
O
O
O
MMPP
Ph
N
OTBS
Nor-AZADO+X–
Ph
Ph
Ph
Ph
O
Ph
O
7a
8a
12
Scheme 4 Plausible reaction pathway
© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 1025–1030

1030
M. Hayashi et al.
LETTER
(9) Qi, C.; Jiang, H.; Huang, L.; Chen, Z.; Chen, H. Synthesis
2011, 387.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.onmorinftIangoimnuSpinorttfoIangiStupor
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(16) General Procedure for the Catalytic Oxidation of Silyl
Enol Ether to 1,2-Diketone: To a solution of MMPP⋅6H2O
(565 mg, 0.994 mmol), Nor-AZADO (18 mg, 0.133 mmol)
and LiBF4 (124 mg, 1.33 mmol) in MeCN (6.6 mL) was
added dropwise a solution of 7a (206 mg, 0.663 mmol) in
MeCN (6.6 mL) over 4 h and stirred for 2 h at r.t. Solutions
of 5% aq NaHCO3 (5 mL) and 20% aq Na2S2O3 (5 mL) were
added and the aqueous layer was extracted with CH2Cl2. The
organic layer was dried over Na2SO4 and concentrated under
reduced pressure. The residue was purified by silica gel
column chromatography to afford 8a (120 mg, 0.571 mmol,
86%).
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