One-pot access to cinnamates via direct oxidative c-h transformation of allylarenes

Article abstract of DOI:10.1055/s-0032-1318146

A highly selective combination of ruthenium complex and oxidant, which catalyzes the oxidative C-H esterification of allylarenes to the corresponding bis-(E)-cinnamates and (E)-cinnamates, is described. The one-pot route was carried out by olefinic migration of allylarenes with RuCl₂(PPh ₃)₃ and DDQ-mediated allylic oxidation of the resulting internal alkenes with various alcohols in good yields. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0032-1318146

LETTER
▌487
letter
One-Pot Access to Cinnamates via Direct Oxidative C–H Transformation of
Allylarenes
Synthesis of Cinnamates
Meng-Yang Chang,* Shin-Ying Lin, Chieh-Kai Chan
Department of Medicinal and Applied Chemistry, Kaohsiung Medical University, Kaohsiung 807, Taiwan
Fax +886(7)3125339; E-mail: mychang@kmu.edu.tw
Received: 14.12.2012; Accepted after revision: 10.01.2013
bisdihydrobenzofurans, benzo[j]fluoranthen-12-ones),9
Abstract: A highly selective combination of ruthenium complex
the one-pot domino synthetic route for preparing bis-(E)-
cinnamate 3a is described from the direct double esterifi-
cation of bisallylbenzene 2a with different conditions, as
and oxidant, which catalyzes the oxidative C–H esterification of
allylarenes to the corresponding bis-(E)-cinnamates and (E)-cinna-
mates, is described. The one-pot route was carried out by olefinic
migration of allylarenes with RuCl2(PPh3)3 and DDQ-mediated shown in Table 1. To trigger the synthetic work of skele-
allylic oxidation of the resulting internal alkenes with various
alcohols in good yields.
ton 3, 3,3′-diallyl-4,4′-bisbenzyloxybiphenyl (2a) was
first chosen as the starting substrate in the investigation of
Key words: allylarenes, C–H esterification, cinnamates
the direct oxidative C–H transformation of the terminal al-
kene and it could be prepared from 4,4′-bisphenol (1) via
a three-step known procedure of O-allylation, Claisen
rearrangement, and O-benzylation).9c
For the selective transition-metal-promoted oxidative
functionalization of catalytic C(sp3)–H bond activation,1
the specific allylic transformation of allylarenes has been
installed as the various allylic C(sp3)–H functionalized
derivatives in these important synthetic protocols and ap-
plications, for example, aldehydes,2 ketones,3 amines,4 ni-
triles,5 alkanes,6 acetates,7 and arenes.8 In particular, the
stereospecific allylic C–H activation of allylarenes using
catalysts based on Pd,1–8 Fe,5 and Cu5 having diversified
nucleophiles and different oxidants gives the correspond-
ing allylic molecules (Scheme 1).
Next, when we initially employed oxygen as an oxidant
for the PdCl2(MeCN)2-mediated treatment of 2a with
MeOH in CH2Cl2, only <5% yield of 3a was isolated. In-
ternal olefin 4 was obtained as the major product (70%),
and 2a was recovered in 20% yield (Table 1, entry 1).
Changing the oxidant to six equivalents of tert-butyl hy-
droperoxide, we found that 3a (20%), 4 (50%), and 5
(15%) were obtained via a tandem process of olefin mi-
gration and then oxidative esterification or bond cleavage.
Compound 2a was also recovered with a 10% yield (Table
1, entry 2). Next, the reaction was treated with cerium am-
monium nitrate (CAN, 6 equiv); 3a (36%), 4 (38%), and
5 (20%) were provided in similar product distribution (Ta-
ble 1, entry 3). Furthermore, when the oxidant was re-
placed with DDQ (10 equiv),10 the yield of the desired 3a
was increased to 48%, and 6 was isolated with a 14% yield
(Table 1, entry 4). Compund 5 was determined by single-
crystal X-ray crystallography.11 After increasing the cata-
lytic amounts of PdCl2(MeCN)2 and changing the reaction
solvent (CH2Cl2, DCE, toluene) and volume (10 or 20
mL), 3a provided similar yields (70–76%, Table 1, entries
5–10). To our delight, changing the catalyst from
PdCl2(MeCN)2 to RuCl2(PPh3)3,12 3a provided better
yields (80–90%) for entries 11–15 (Table 1). According to
the above-mentioned synthetic procedure, we envisioned
that the optimized one-pot esterification conditions
should involve the one-pot synthesis of bis-o-allylben-
zene with alcohol via the combination of RuCl2(PPh3)3
(10 mol%), DDQ (10 equiv), and CH2Cl2 (10 mL).
[M], oxidant, NuH
Nu
ref. 1–8
X
X
[M] = Pd, Cu, Fe
oxidants = O2, TBHP, DDQ, BQ
NuH = H2O, AcOH, azides, amines, 1,3-dicarbonyls
O
[Ru], DDQ, ROH
OR
our work
X
X
Scheme
1
Direct transformation from allylarenes to allylic
derivatives via C(sp3)–H functionalization
Among the most synthetic approaches for allylic C(sp3)–
H bond activation, one-pot and direct double esterification
of a bisallylarene skeleton via the combination of a
RuCl2(PPh3)3 catalyst and DDQ oxidant (2,3-dichloro-
5,6-dicyano-1,4-benzoquinone) using alcohols as the nu-
cleophiles has not been reported. In continuation of our re-
cent investigation with the starting material 4,4′-bisphenol
(1) for synthesizing the structural skeleton of polyphenyls,
So far, there are fewer examples to describe the one-pot
and direct oxidative esterification of 2 bearing the allylic
C–H bond with alcohols by RuCl2(PPh3)3 and DDQ under
air atmosphere.10i,13 The product 3a was confirmed
through 1H NMR analysis. It exhibited two doublets at δ
= 8.10 and 6.62 ppm for olefinic CH protons. One CH2
proton appeared as one singlet of methylene (δ = 5.20) and
the other CH3 singlet of the methyl ester group appeared
SYNLETT 2013, 24, 0487–0490
Advanced online publication: 25.01.2013
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0032-1318146; Art ID: ST-2012-W1070-L
© Georg Thieme Verlag Stuttgart · New York

488
M.-Y. Chang et al.
LETTER
at δ = 3.80 ppm. However, the related resolutions of the expected bi-tert-butyl biscinnamate with 83% or 85%
meso and dl isomers were not observed from the NMR yield. This phenomenon showed that the tert-butyl group
spectrum. Perhaps the given distance between the two was so bulky that it could not attack the in situ generated
conjugated esters was so long that the free rotation of the cinnamaldehyde to form the desired skeleton of biscinna-
side-chain arms in between easily resulted.
mate 3.
Table 1 Allylic C–H Bond Transformation of 2aa–f
Table 2 Synthesis of 3a,b
OR
OR
O
OR
OBn
OBn
O
OBn
OBn
CHO
CHO
CHO
OR1
Y
RuCl2(PPh3)3
CH2Cl2
cat.
solvent
+
oxidant
MeOH
DDQ, R1OH
OR1
OMe
CHO
OR
2a–c
OR
3a–d,f–m
O
OR
3e R = Bn
3n R = C5H9
OBn
2a
OBn
O
OBn
OBn
5 (X-ray)
4
3a Y = OMe
6 Y = H
Entry Catalyst (mmol%), Solvent (mL), Oxidant (equiv) Yield (%)b
Entry
Reactants 2
R1OH
Yield of 3 (%)b
<5c
20d
30e
48f
76
75
75
72
72
70
80
83
90
82
80
1
2
2a R = Bn
2a R = Bn
2a R = Bn
2a R = Bn
2a R = Bn
2b R = Me
2b R = Me
2b R = Me
2b R = Me
2c R = C5H9
2c R = C5H9
2c R = C5H9
2c R = C5H9
2c R1 = C5H9
MeOH
EtOH
3a 90
3b 88
3c 80
3d 87
3e 83
3f 92
3g 90
3h 84
3i 90
1
2
PdCl2(MeCN)2 (2), CH2Cl2 (10), O2
PdCl2(MeCN)2 (2), CH2Cl2 (10), t-BuO2H (6)
PdCl2(MeCN)2 (2), CH2Cl2 (10), CAN (6)
PdCl2(MeCN)2 (2), CH2Cl2 (10), DDQ (4)
PdCl2(MeCN)2 (2), CH2Cl2 (10), DDQ (10)
PdCl2(MeCN)2 (5), CH2Cl2 (10), DDQ (10)
PdCl2(MeCN)2 (10), CH2Cl2 (10), DDQ (10)
PdCl2(MeCN)2 (10), (CH2Cl)2 (10), DDQ (10)
PdCl2(MeCN)2 (10), toluene (10), DDQ (10)
PdCl2(MeCN)2 (10), CH2Cl2 (20), DDQ (10)
RuCl2(PPh3)3 (5), CH2Cl2 (10), DDQ (6)
RuCl2(PPh3)3 (5), CH2Cl2 (10), DDQ (10)
RuCl2(PPh3)3 (10), CH2Cl2 (10), DDQ (10)
RuCl2(PPh3)3 (10), DCE (10), DDQ (10)
RuCl2(PPh3)3 (10), toluene (10), DDQ (10)
3
i-PrOH
3
4
EtOCH2CH2OH
t-BuOH
4
5
5
6
MeOH
6
7
EtOH
7
8
i-PrOH
8
9
EtOCH2CH2OH
MeOH
9
10
11
12
13
14
3j 92
3k 90
3l 86
10
11
12
13
14
15
EtOH
i-PrOH
EtOCH2CH2OH
t-BuOH
3m 90
3n 85
a All reactions were run with 2 (0.4 mmol), RuCl2(PPh3)3 (10 mmol%),
CH2Cl2 (10 mL), alcohols (R1OH, 1 mL), and DDQ (900 mg, 4.0 mmol)
a All reactions were run with 2a (120 mg, 0.4 mmol), catalyst
(2–10 mmol%), CH2Cl2 (10–20 mL), MeOH (1 mL), and oxidants
(1.6–4.0 mmol) at reflux.
at reflux.
b Compounds 3a–n were >95% pure as determined by 1H NMR
analysis.
b Th product 3a was >95% pure as determined by 1H NMR analysis.
c Compound 4 was isolated with 70% yield, and 20% of 2a were
recovered.
We extend this useful protocol to 2-allyl-1-methoxynaph-
thalene (7), which was prepared from Claisen rearrange-
ment of 1-allyloxynaphthalene followed by O-
methylation from the intermediate 1-naphthol. We found
that products 8a–c were easily formed as the sole isomers
with 82–90% yield by the combination of
RuCl2(PPh3)3/DDQ with different types of alcohol. Under
the same conditions, attempts to apply the protocol for 1-
allyl-2-methoxybenzene (9) were also successful. Com-
pounds 10a–e were obtained in high yield (86–90%), as
shown in Table 3.
d Compounds 4 (50%), 5 (15%), and 2a (10%) were obtained.
e Compounds 4 (38%) and 5 (20%) were obtained.
f Compound 6 (14%) was isolated.
Changing the substitutent of 2 (2a R = Bn, 2b R = Me, 2c
R = C5H9), 3a–n were isolated with 83–92% yield by one-
pot oxidative RuCl2(PPh3)3/DDQ-mediated allylic esteri-
fication of 2 with five alcohols (MeOH, EtOH, i-PrOH,
EtOCH2CH2OH, and t-BuOH) in CH2Cl2 at reflux for
three hours (Table 2). When treatment of 2a or 2c reacted
with tertiary alcohol (t-BuOH, Table 2, entries 5 and 14),
we observed that biscinnamaldehyde 3e or 3n replaced the
How is 10a produced?2,5 As shown in Scheme 2, the initial
event for the ruthenium-catalyzed migration of 9 may be
Synlett 2013, 24, 487–490
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of Cinnamates
489
considered as the formation of intermediates A and B via
the equilibrium by [3,3]-sigmatropic rearrangement.14 In-
termediate B should exist as the major state through the
chelated Ru-complex. Furthermore, intermediate B is
subjected to the regioselective nucleophilic attack of
MeOH to afford intermediate C from a less hindering site.
Finally, product 10a is subsequently formed through allyl-
ic oxidation of intermediate C with DDQ and molecular
oxygen (from air) followed by dehydroxylative oxidation
of intermediate D.15,16 Ru(0) is oxidized to generate active
Ru(II) by excess amounts of DDQ. From the possible re-
action mechanism, we believe that excess DDQ plays an
important dual functional role between activating Ru(0)
and allylic C–H bonds during the one-pot direct oxidative
transformation.
HCl
9
OMe
RuCl(PPh3)3
RuCl2(PPh3)3
Ru(II)
A
DDQ
MeO
RuCl(PPh3)3
Ru(0) + HCl + Ph3P
OMe
MeOH
B
regioselective
MeOH
OMe
C
OH
OMe
O
Table 3 Synthesis of 8 and 10a,b
DDQ + O2
(from air)
10a
OMe
O
OMe
OMe
D
OR1
Scheme 2 Proposed reaction mechanism of the direct transformation
for 10a2,5
7
8a–c
RuCl2(PPh3)3, CH2Cl2
OBn
OBn
O
OR1
OR1
DDQ, R1OH
OMe
RuCl2(PPh3)3, CH2Cl2
OMe
O
OMe
CHO
OR1
DDQ, d-alcohols
9
10a–d
10e
OBn
OBn
O
R1OH
Yields of
2a
11a R1 = CD3, 88%
11b R1 = CD2CD3, 85%
Entry
Reactants
7 and 9
8 and 10 (%)b
Scheme 3 Synthesis of 11
1
2
3
4
5
6
7
8
7
7
7
9
9
9
9
9
MeOH
8a 82
8b 90
i-PrOH
In summary, we have successfully presented a synthetic
methodology for different alkyl cinnamates 8 and 10, and
biscinnamates 3, which involve one-pot oxidative esterifi-
cation of skeletons 2, 7, and 9 with the combination of
RuCl2(PPh3)3/DDQ in good yield. The novel allylic C–H
bond route showed that RuCl2(PPh3)3 is an excellent cata-
lyst source to promote the formation of the olefinic migra-
tion, and that DDQ is an oxidant for mono and double
allylic esterification. Considering the utility of the skele-
ton of 4,4′-bisphenol (1), the development of these facile
and novel synthetic approaches is significant.
EtOCH2CH2OH
MeOH
8c 83
10a 88
10b 86
10c 90
10d 86
10e 86
EtOH
i-PrOH
EtOCH2CH2OH
t-BuOH
a All reactions were run with 7or 9(0.4 mmol), RuCl2(PPh3)3 (10 mmol%),
CH2Cl2 (10 mL), alcohols (R1OH, 1 mL), and DDQ (450 mg, 2.0 mmol)
at reflux.
b Compounds 8a–c or 10a–e were >95% pure as determined by 1H
NMR analysis.
Acknowledgment
The authors would like to thank the National Science Council of the
Republic of China for its financial support (NSC 99-2113-M-037-
006-MY3).
Under RuCl2(PPh3)3/DDQ conditions, reactions for 2a
with CD3OD and C2D5OD were further studied, as shown
in Scheme 3. By controlling the R1 group of alcohols (a,
MeOH-d; b, EtOH-d), the desired biscinnamates 11a,b
with the deuterium group were only isolated with 80–88%
yields. We believe that the presented experimental results
should provide a potential application for isotope chemis-
try.
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© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 487–490

490
M.-Y. Chang et al.
LETTER
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