Direct sequential C-O and C-C formation via double sp2 C-H bond activations to construct 6H-benzo[c]chromen-6-ones

Article abstract of DOI:10.1055/s-0030-1259724

A new method for the direct ortho acyloxylation of sp² C-H bond with various carboxylic acids was developed. A novel strategy to synthesize 6H-benzo[c]chromen-6-one derivatives was designed via Pd-catalyzed double activations of adjacent sp

Full text of DOI:10.1055/s-0030-1259724

LETTER
883
Direct Sequential C–O and C–C Formation via Double sp2 C–H Bond
Activations to Construct 6H-Benzo[c]chromen-6-ones
New
Method for
h
D
irect ortho
a
A
cyloxylat
n
ion of sp2 C–g
H
Bond -Liang Sun,a Jia Liu,a,b Yang Wang,a Xiao Zhou,a Bi-Jie Li,a Zhang-Jie Shi*a,c
a
Beijing National Laboratory of Molecular Sciences (BNLMS), PKU Green Chemistry Centre and Key Laboratory of Bioorganic
Chemistry and Molecular Engineering of Ministry of Education, College of Chemistry, Peking University, Beijing, P. R. of China
Fax +86(10)62760890; E-mail: zshi@pku.edu.cn
b
c
Department of Chemistry, China Agricultural University, Beijing, P. R. of China
State Key Laboratory of Organometallic Chemistry, Chinese Academy of Sciences, Shanghai, P. R. of China
Received 4 December 2010
Dedicated to Prof. Xiyan Lu and Prof. Lixin Dai
Transition-metal-catalyzed direct C–H functionalization,
particularly palladium-catalyzed reactions, have been
widely developed and applied in organic synthesis.3
Among these methods, highly regioselective transforma-
tions of C–H bonds into new C–X bonds (X = Cl, O, etc.)
have been reported.4 Sanford and co-workers have report-
ed methods on Pd-catalyzed directed acetoxylation and
methoxylation of sp2 aand sp3 C–H bonds, as well as
mechanistic investigations.5 Yu and Cheng also reported
directed ortho Cu-catalyzed acyloxylation of sp2 C–H
bonds.6 From these studies, the challenge of the formation
of aryl C–O from C–H with different carboxylates or car-
boxylic acids as nucleophiles was also addressed. Herein,
we demonstrate the selective C–O formation with various
carboxylic acids and subsequent C–H activation to con-
struct 6H-benzo[c]chromen-6-one scaffolds for the first
time, expanding the utility of the recent C–H activation
methods in synthetic chemistry.
Abstract: A new method for the direct ortho acyloxylation of sp2
C–H bond with various carboxylic acids was developed. A novel
strategy to synthesize 6H-benzo[c]chromen-6-one derivatives was
designed via Pd-catalyzed double activations of adjacent sp2 C–H
bonds.
Key words: C–H bond activation, ortho acyloxylation, 6H-ben-
zo[c]chromen-6-one
6H-Benzo[c]chromen-6-one is a common core structure
existing in various natural products, as well as many phar-
maceutical compounds, such as families of graphislac-
tones and chrysomycins (Figure 1).1 Many methods have
been presented to construct such a unit by different re-
search groups in the past.2 Based on these previous studies
and our recent work, we proposed a new strategy to syn-
thesize this unique scaffold through direct sequential C–O
and C–C formation via selective Pd(II)-catalyzed double
C–H activations (Scheme 1).
Because O-methyl oximyl group has been successfully
applied for ortho acetoxylation and amination4a,5d and also
it can be further transformed into other functional groups,
we selected O-methyl aryloximes as the substrates. We
first tested PhI(RCO2)2 as an oxidant as well as various
carboxylates. We found that the reaction occurred well in
the presence of two equivalents of PhCOOH (2a) with
PhI(PhCO2)2 in PhNO2 and the desired product 3a was
isolated in 71% yield (Scheme 2). We found that the reac-
tion can be complicated and give the corresponding ester
products with either the oxidant PhI(RCO2)2 or carboxylic
acid used.
OH OMe
OMe
R2H2C
OMe
OH
MeO
O
O
R
OH
OH
O
O
HO
OR1
graphislactone A R1 = R2 = H
graphislactone B
graphislactone C
O
chrysomycin A R = CH=CH2
chrysomycin B R = Me
R
R
1 = Me, R2 = H
1 = H, R2 = OH
Figure 1 Natural products and pharmaceutical compounds with
6H-benzo[c]chromen-6-one as a core structure
NOMe
H
NOMe
O
Pd(OAc)2 (10 mol%)
Ph
PhI(PhCOO)2 (2.0 equiv)
PhCOOH
(2.0 equiv)
+
PhNO2, 90 °C
71%
O
O
O
O
DG
H
X
1a
2a
3a
O
R2
H
H
Scheme 2 Conditions A, with PhI(PhCOO)2 as an oxidant
R2
R1
+
R1
We further searched for a universal oxidant for the reac-
tion. Many organic and inorganic oxidants were tested.
Although some of them, such as K2S2O8, showed partial
activity, it was not sufficient for further application. Due
to the differences in their nucleophilicities, various car-
Scheme 1 A new strategy via Pd-catalyzed double C–H activation
SYNLETT 2011, No. 7, pp 0883–0886
x
x.
x
x.
2
0
1
1
Advanced online publication: 10.03.2011
DOI: 10.1055/s-0030-1259724; Art ID: W34610ST
© Georg Thieme Verlag Stuttgart · New York

884
C.-L. Sun et al.
LETTER
boxylic acids were further tested under the same condi-
tions. Equal amounts of carboxylic acids were submitted
to the reaction in the presence of PhI(OAc)2 as an oxidant.
To our disappointment, a comparable reactivity of acetic
acid, benzoic acid and cinnamic acid was observed, as
monitored by GC (Scheme 3). However, the result did im-
ply that the selectivity might be controlled by the simple
increase of the ratio of different acids.
reduced pressure
acid exchange
PhI(OAc)2
PhI(PhCO2)2
+ AcOH
PhCOOH +
NOMe
NOMe
O
Pd(OAc)2 (10 mol%)
PhI(OAc)2 (1.5 equiv)
Ph
H
+
PhCOOH
(5.0 equiv)
O
PhNO2
r.t. then 90 °C
under reduced pressure
1a
2a
3a (85%)
Scheme 5 Conditions C. with a lower amount of carboxylic acids
and acid-exchange process under reduced pressure
NOMe
H
NOMe
O
Pd(OAc)2 (10 mol%)
PhI(OAc)2 (2.0 equiv)
R2
R2COOH
+
(85%). Importantly, the amount of acid could be de-
creased to five equivalents (based on 1a; Scheme 5).
O
PhNO2, 90 °C
2 = Me (1.0 equiv)
2 = Ph (5.0 equiv)
2 = styryl (5.0 equiv)
3b R2 = Me, 18%
3a R2 = Ph, 25%
1a
R
R
R
Various carboxylic acids were further tested under the op-
timized conditions (Table 1). Benzoic acids bearing elec-
tron-donating groups worked well and the corresponding
products 3 were obtained in good to excellent isolated
yields. C–X bonds were compatible, which could be fur-
ther transformed into different functionalities. However,
benzoic acids bearing electron-withdrawing groups such
as NO2 and benzoyl gave lower yields. 2-Naphthalic acid
and 2-furic acid also gave the corresponding products in
moderate yields. It is important to note that cinnamic acid
and its derivatives worked well. Obviously, this modified
conditions was not suitable for short chain aliphatic acids,
such as propanoic acid, due to their relatively lower boil-
ing points. Thus, the original protocol condition B is bet-
ter suited for such substrates.
3s R2 = styryl, 23%
Scheme 3 Comparable reactivity of acetic acid, benzoic acid and cin-
namic acid
After the systematical screening, we found that five times
of benzoic acid [based on the acetate of PhI(OAc)2] could
suppress the ortho acetoxylation from acetate present in
the oxidant and the designed o-benzoyloxylated product
3a was obtained in 90% yield. Different aliphatic acids
were tested and all the reactions showed high selectivity
and efficiency, and the activity was not significantly af-
fected by their boiling points and steric hindrance
(Scheme 4). It is very important to note that this method
offers an efficient approach to form different aryl C–O
with simple PhI(OAc)2 as the only oxidant by avoiding
the side acetoxylation.
Further exploration to expand this transformation to dif-
ferent O-methyl aryl oximes was investigated (Figure 2).
All the reactions were carried out in good conversions un-
der the modified conditions. Substituted O-methyl ace-
NOMe
NOMe
Pd(OAc)2 (10 mol%)
H
O
R
PhI(OAc)2 (2.0 equiv)
PhNO2, 90 °C
Table 1 Directed ortho Acyloxylations of O-Methyl Oximes 1aa,b
RCOOH
+
(20 equiv)
O
NOMe
H
NOMe
O
1a
3a R = Ph, 90%
Pd(OAc)2 (10 mol%)
PhI(OAc)2 (1.5 equiv)
R
3b R = Me, 81%
3c R = Et, 72%
3d R = n-Bu, 76%
3e R = i-Bu, 62%
3f R = t-Bu, 76%
+
RCOOH
O
PhNO2, 90 °C
1a
2
3
Scheme 4 Conditions B, with an excess amount of aliphatic acids
Entry R
Yield
(%)
Entry R
Yield
(%)
Mechanistically, an acid exchange might take place at
either initiating stage with PhI(OAc)2 or the last stage
before reductive elimination to produce 3 with Pd com-
plexes.5b We proposed that an acid exchange may occur
first. Further exploration offered evidence for this as-
sumption. PhI(OAc)2 was transformed into the corre-
sponding PhI(RCO2)2 under reduced pressure in the
absence of 1a.7 The following steps were the same as de-
scribed in Sanford’s research.5 Supposedly, after the ex-
change of acids, acetic acid was efficiently removed and
the corresponding PhI(RCO2)2 was generated in situ
(Scheme 5). Thus, we further optimized the reaction for
this ortho acyloxylation. After stirring under reduced
pressure at room temperature for one hour, the reaction
mixture was heated to 90 °C for another 24 hours and the
desired product was obtained in the comparable yield
1
2
3
4
5
6
7
8
p-MeC6H4
p-MeOC6H4
o-IC6H4
3g, 76
3h, 76
3i, 86
3j, 78
3k, 66
3l, 50
9
2-naphthyl
3o, 55
3p, 37
3q, 61
3r, 66
3s, 86
10 2-furyl
11 Bn
o-BrC6H4
o-ClC6H4
o-BzC6H4
m-NO2C6H4
12 PhCH2CH2
13 styryl
14 4¢-MeO-styryl 3t, 69
3m, 39 15 3¢-MeO-styryl 3u, 73
m-NO2-p-MeOC6H4 3n, 57
16 4¢-Me-styryl 3v, 74
a Reaction conditions: 1a (0.2 mmol), 2 (1.0 mmol), Pd(OAc)2 (0.02
mmol), and PhI(OAc)2 (0.3 mmol) in PhNO2 (3 mL), r.t., 1 h, then 90
°C, reduced pressure, for an appropriate time.
b Isolated yields.
Synlett 2011, No. 7, 883–886 © Thieme Stuttgart · New York

LETTER
New Method for Direct ortho Acyloxylation of sp2 C–H Bond
885
H
NOMe
H
MeO
MeO
OMe NOMe
OMe NOMe
MeO
MeO
H
O
H
O
H
Pd(PPh3)2Cl2
NaOAc
Pd(OAc)2
PhI(OAc)2
1j
+
DMA, 130 °C
H
O
PhNO2, 90 °C
COOH
O
I
I
5a 70%
6a 72%
2d
MeO
O
O
MeO
MeO
N
O
O
N
N
O
O
MeO
5b 62%
6b 78%
5c 74%
6c 60%
5d 86%
6d 55%
Scheme 6 Double C–H activation towards 6H-benzo[c]chromen-6-one; DMA = N, N-dimethylacetamide
tion, which is a well-studied Pd-catalyzed cross-coupling
of C–H with C–X bond.8 With this strategy, various 6H-
benzo[c]chromen-6-one derivatives 6a–d were obtained
in moderate to good yields (Scheme 6). Further efforts to
apply this method to natural product synthesis are still un-
derway.
NOMe
OBz
NOMe
OBz
F
MeON
OBz
MeO
t-Bu
OMe
4b
(70%)
4a
(85%)
4c
(87%)
In conclusion, we have developed a novel method for the
direct ortho acyloxylation of sp2 C–H bond with various
carboxylic acids. A new strategy to synthesize 6H-ben-
zo[c]chromen-6-one derivatives was further developed
via highly selective sequential Pd-catalyzed double acti-
vations of sp2 C–H bond.
Ph
NOMe
OBz
NOMe
OBz
MeON
OBz
4d
(80%)
4e
(67%)
4f
(69%)
H
NOMe
OBz
H
NOMe
OBz
Supporting Information for this article is available online at
H
NOMe
OBz
MeO
http://www.thieme-connect.com/ejournals/toc/synlett.
MeO
MeO
OMe
4g
(61%)
MeO
Acknowledgment
4h
(82%)
4i
(63%)
Support of this work by a starter grant from the Peking University
and the grant from the National Sciences of Foundation of China
(No. 20542001, 20521202, 20672006) and the ’973’ Project from
the MOST of China (2009CB825300) are greatfully acknowledged.
Figure 2 Directed ortho benzoyloxylation of various O-methyl ox-
imes; all the reactions were carried out on a 0.2 mmol scale under con-
ditions C and isolated yields are reported
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Synlett 2011, No. 7, 883–886 © Thieme Stuttgart · New York

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LETTER
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