Formation of C-O bond via cross-dehydrogenative coupling between isochroman and oxime under metal-free oxidation conditions

Article abstract of DOI:10.1055/s-0032-1317960

DDQ-mediated C-O bond formation through cross-dehydrogenative coupling (CDC) reaction without any metal catalyst under mild conditions was developed. Series of isochromans and oximes could be employed as substrates, and the products were obtained in good yields. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0032-1317960

LETTER
▌211
letter
Formation of C–O Bond via Cross-Dehydrogenative Coupling between
Isochroman and Oxime under Metal-Free Oxidation Conditions
Formation of C–O Bond via Cross-Dehydrogenative Coupling
Hua-Feng He, Kai Wang, Bo Xing, Guorong Sheng, Tingxuan Ma, Weiliang Bao*
Department of Chemistry, Xi Xi Campus, Zhejiang University, Hangzhou, Zhejiang 310028, P. R. of China
Fax +86(571)88273814; E-mail: wlbao@css.zju.edu.cn
Received: 14.10.2012; Accepted after revision: 09.12.2012
benzoquinone (DDQ) in toluene at room temperature. To
our delight, the expected product 3b was obtained. Then,
we investigated the effect of temperature, and the best
yield of 3b was observed at 30 °C. Afterwards, variations
of oxidants were compared with each other, and DDQ
gave the highest yield. Subsequently, some metal cata-
lysts were examined. To our surprise, the removal of the
metal catalyst improved the yield of 3b. Therefore, we en-
visaged that in this procedure the metal catalyst played no
Abstract: DDQ-mediated C–O bond formation through cross-de-
hydrogenative coupling (CDC) reaction without any metal catalyst
under mild conditions was developed. Series of isochromans and
oximes could be employed as substrates, and the products were
obtained in good yields.
Key words: cross-dehydrogenative coupling, C–H activation,
DDQ, metal-free, oxidation
As one kind of extensively existing chemical bond in nat-
ural products and pharmaceutical molecules, the forma-
tion of C–O bond was always the pursuit of chemists.
Traditionally, Ullmann-type C–O coupling,1 Williamson
reaction,2 etc. were employed to form the C–O bond.
There are some general shortages of these methods, for
example, they all need prefunctionalization of substrates,
usually conducted under harsh conditions, and exhibited
low selectivity. Among the sea of synthetic methodology,
constructing C–O bond via direct C–H activation/C–H
functionalization attracted more and more attention be-
cause of its convenience, high efficiency, and atom-econ-
omy.3
Table 1 Optimization of Reaction Conditionsa
O
O
OH
N
N
+
O
1
2
3b
Entry
Temp
(°C)
Metal
catalyst
Oxidant
Solvent
Yield
(%)b
1
2
r.t.
50
0
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuBr
–
DDQ
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
THF
56
75
18
79
67
<5
<5
<5
<5
<5
64
92
37
93
78
77
In 2004, Li and co-workers reported the direct alkynyl-
ation of tetrahydroisoquinoline.4 Since then, great efforts
have been directed towards the study of cross-dehydroge-
native coupling (CDC) reactions. To date, thousands reac-
tions of these types were reported.5 However, most of the
CDC-type reactions employed transition metals as the cat-
alyst, which was not environmentally benign. It would be
more desired that the CDC-type reaction could be con-
ducted without any metal catalyst.6 Our group disclosed
some work on metal-free CDC-type reactions.7 In 2006,
Li and co-workers reported the coupling between isochro-
man and ketone.8 As a very important module of many
bioactive molecules, the derivatization of isochroman was
a significant work in chemistry.9 Herein, we would report
a CDC-type reaction of isochroman with oximes, con-
ducted directly under oxidative condition without metal
catalyst.
DDQ
3
DDQ
4
30
60
30
30
30
30
30
30
30
30
30
30
30
DDQ
5
DDQ
6
BQ
7
O2
8
t-BuOOBu-t
Cu(OAc)2
Ag2CO3
DDQ
9
10
11
12
13
14
15
16
DDQ
–
DDQ
Firstly, isochroman (1a) and p-methylbenzaldoxime (2b)
were chosen to optimize the reaction conditions. The re-
action conditions were originally selected as 10% mmol
CuI and 1.2 equivalents 2,3-dichloro-5,6-dicyano-1,4-
–
DDQ
CH2Cl2
MeCN
DMF
–
DDQ
–
DDQ
a Reaction conditions: substrate (0.5 mmol), copper catalyst (0.05
mmol), N2 atmosphere.
SYNLETT 2013, 24, 0211–0214
Advanced online publication: 03.01.2013
DOI: 10.1055/s-0032-1317960; Art ID: ST-2012-W0886-L
© Georg Thieme Verlag Stuttgart · New York
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
b Isolated yield based on isochroman.

212
H.-F. He et al.
LETTER
part. Hence, the screen of solvents was conducted under yields, but even acetone oxime gave a low yield. Fural-
the absence of metal catalyst, and dichloromethane doxime also reacted with isochroman to give the corre-
proved to be the most suitable solvent. Finally, under the sponding product in lower yield. The relatively low yields
optimized reaction conditions, dichloromethane was used of 3k and 3m may both result from the low stability of the
as the solvent and DDQ as the oxidant at 30 °C (Table 1, corresponding oximes under these reaction conditions. At
entry 14).
the same time, the relatively small steric hindrance of the
furan ring led to the cis and trans isomers 3m and 3m′. On
the other hand, the derivatives of isochroman, 2,4-di-
hydro-1H-benzo[f]isochromene and 6H-benzo[c]chromene,
reacted smoothly with ketoximes and gave the corre-
sponding products 3n, 3o, and 3p separately in moderate
yields.
With the optimized conditions in hand, the scope of the re-
action was explored. Series of substituted benzaldoximes
were employed to react with isochroman (1a) to study the
effects of different substituents. According to the experi-
ment results, the influence of the electronic effect was not
obvious. Both the electron-withdrawing substituents and
the electron-donating substituents could profit the conver- Based on these experiments and literature reports,10
a
sion. Meanwhile, the effect of steric hindrance was also mechanism is postulated in Scheme 2. Under the effect of
investigated. As shown in Scheme 1, the derivatives of DDQ, the oxygen atom of isochroman loses one electron
para-, meta-, and ortho-bromo benzaldoximes gave the to form the oxygen radical cation. One of the hydrogen at-
corresponding products 3e, 3f, and 3g, respectively. The oms adjacent to the oxygen radical is captured by DDQ to
yield of the ortho-substituted one was relatively low. form an oxonium cation. In addition, the oxime hydrogen
Ketoximes could also couple with isochroman to give the is removed by DDQ to give the oxygen anion. The latter
corresponding products in moderate yields. Comparing 3i attacks the oxonium carbocation to form the product. In
and 3j, it appears that the electronic effect and steric hin- order to understand the mechanism, isochroman (1) and p-
drance of ketoximes may decrease the corresponding chlorobenzaldehyde oxime were chosen to conduct the
R1
O
N
DDQ (1.2 equiv), 30 °C
CH2Cl2, 24 h
N
+
OH
O
R2
O
1
2
3
R1
R2
3a, R3 = H, 85%
O
O
3b, R3 = 4-Me, 93%
3c, R3 = 4-MeO, 66%
3d, R3 = 4-Cl, 82%
3e, R3 = 4-Br, 85%
3f, R3 = 3-Br, 92%
3g, R3 = 2-Br, 74%
3h, R3 = 4-O2N, 57%
O
N
O
O
N
N
O
R3
3i, 77%
3j, 56%
O
N
O
O
O
3k, 51%
3l, 62%
3m, 35%
3m', 29%
O
O
N
O
N
O
O
3o, R3 = 4-Me, 49%
3p, R3 = 4-Br, 44%
3n, 59%
O
O
N
O
N
O
R3
Scheme 1 Scope of the CDC. Reagents and conditions: isochroman (0.5 mmol), oxime (0.5 mmol), and DDQ (0.6 mmol), in CH2Cl2 (3 mL)
were stirred under the protection of N2 at 30 °C for 24 h.
Synlett 2013, 24, 211–214
© Georg Thieme Verlag Stuttgart · New York

LETTER
Formation of C–O Bond via Cross-Dehydrogenative Coupling
213
O
O
CN
O–
Cl
CN
CN
Cl
Cl
NC
+
O
O
O
H
H
Cl
CN
Cl
–O
Cl
CN
OH
Ph
N
OH
O
N
+
O+
OH
O
CN
Cl
Cl
Ph
N
O–
Ph
CN
OH
Scheme 2 Probable mechanistic route
J. Org. Chem. 2009, 74, 3675. (e) Naidu, A. B.; Sekar, G.
Synthesis 2010, 579. (f) Hosseinzadeh, R.; Tajbakhsh, M.;
Mohadjerani, M.; Alikarami, M. Synlett 2005, 1101.
experiment in the presence of TEMPO (a radical inhibi-
tor). In that case, only about 10% yield of the product 3d
was obtained (compared to 82% yield in Scheme 1). In
other words, the reaction mechanism probably involves a
radical pathway.
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In conclusion, a new efficient cross-dehydrogenative cou-
pling (CDC) reaction under oxidative conditions has been
developed. Series of oximes could react with isochroman,
and the derivatives and the target product were obtained in
moderate to good yields.
General Procedure11
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DDQ (120 mg, 0.6 mmol) was added to an oven-dried Schlenk tube
charged with a magnetic stir bar. Equipped with a constant-pressure
funnel, the Schlenk tube was evacuated and backfilled with N2 (3
×). Then CH2Cl2 (1 mL) was added as solvent. Isochroman (0.5
mmol) and oxime (0.5 mmol) in CH2Cl2 (2 mL) was added to the
funnel through syringe and dropped into the Schlenk tube within 2
h. The reaction was conducted at 30 °C for 24 h and monitored by
TLC. After completion of the reaction, the mixture was filtered and
washed with EtOAc. Then the solvent was removed, and the crude
was purified by column chromatography (eluent: PE–EtOAc, 30:1
to 40:1).
(h) Ghobrial, M.; Harhammer, K.; Mihovilovic, M. D.;
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Acknowledgement
This work was financially supported by the Natural Science Foun-
dation of China (No. 21072168).
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.SnoIufproig
m
iotSrat
ungIifoop
r
t
Reference and Notes
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© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 211–214

214
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LETTER
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MHz, CDCl3): δ = 8.15 (s, 1 H), 7.58 (d, J = 8.0 Hz, 2 H),
7.34 (d, J = 8.0 Hz, 3 H), 7.31–7.25 (m, 2 H), 7.17 (d, J =
8.0 Hz, 1 H), 6.36 (s, 1 H), 4.18 (td, J1 = 11.8 Hz, J2 = 3.2
Hz, 1 H), 4.03–3.98 (m, 1 H), 3.12–3.03 (m, 1 H), 2.65 (dd,
J1 = 16.4 Hz, J2 = 2.0 Hz, 1 H). 13C NMR (100 MHz,
CDCl3): δ = 150.64, 134.82, 131.81, 131.74, 130.09, 128.58,
128.48, 127.87, 127.35, 126.34, 99.10, 58.36, 27.75. HRMS
(EI): m/z [M]+ calcd for C16H15NO2: 253.1103; found:
253.1105.
Compound 3i: blue oil; yield 77%. IR (neat): ν = 2935, 1711,
1493, 1274, 1095, 984, 922, 746 cm–1. 1H NMR (400 MHz,
CDCl3): δ = 7.74–7.72 (m, 2 H), 7.37–7.35 (m, 4 H), 7.30–
7.23 (m, 2 H), 7.17 (d, J = 8.0 Hz, 1 H), 6.40 (s, 1 H), 4.18
(td, J1 = 11.7 Hz, J2 = 3.5 Hz, 1 H), 4.02–3.98 (m, 1 H),
3.11–3.03 (m, 1 H), 2.65 (d, J = 16.0 Hz, 1 H), 2.25 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 156.48, 136.22, 134.86,
132.23, 129.21, 128.36, 128.25, 128.03, 126.27, 126.18,
98.98, 58.43, 27.85, 13.20. HRMS (EI): m/z [M]+ calcd for
C17H17NO2: 267.1259; found: 267.1257.
Compound 3p: yellow solid; yield 44%. IR (neat): ν = 2971,
1700, 1590, 1486, 1244, 1005, 918, 750 cm–1. 1H NMR (400
MHz, CDCl3): δ = 7.92 (s, 1 H), 7.88 (t, J = 6.8 Hz, 2 H),
7.55–7.41 (m, 7 H), 7.28 (t, J = 8.0 Hz, 1 H), 7.14–7.11 (m,
2 H), 6.84 (s, 1 H). 13C NMR (100 MHz, CDCl3): δ = 150.41,
150.13, 132.36, 131.87, 130.90, 130.45, 130.10, 129.53,
129.22, 128.76, 127.88, 127.45, 127.15, 124.52, 122.82,
122.40, 121.89, 120.94, 118.31, 99.80. HRMS (EI): m/z
[M]+ calcd for C20H14BrNO2: 379.0208; found: 379.0206.
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(11) Typical Analytical Data of the Products
Compound 3a: colorless oil; yield 85%. IR (neat): ν = 2939,
1740, 1492, 1316, 1208, 1096, 928, 748 cm–1. 1H NMR (400
Synlett 2013, 24, 211–214
© Georg Thieme Verlag Stuttgart · New York