Chemoselective RuO4 oxidation of phenyl or p-methoxyphenyl groups to carboxylic acid functions in the presence of a tetrahydropyran ring

Article abstract of DOI:10.1055/s-2004-829119

We describe the first example of a chemoselective oxidation of phenyl and p-methoxyphenyl groups to carboxylic acid functions in the presence of a tetrahydropyran ring, using 0.02 mol% of RuCl₃ and a co-oxidant. The use of NaIO₄ as c

Full text of DOI:10.1055/s-2004-829119

PAPER
1767
Chemoselective RuO Oxidation of Phenyl or p-Methoxyphenyl Groups to
4
Carboxylic Acid Functions in the Presence of a Tetrahydropyran Ring
C
L
hemoselective
.
R
uO
O
xida
S
tion of Pheny
.
l
or
p
-Metho
M
xyphenyl
G
roups . Miranda, M. L. A. A. Vasconcellos*
4
Núcleo de Pesquisas de Produtos Naturais, Universidade Federal do Rio de Janeiro, Lab. H0-27, Bloco H, CCS, Ilha do Fundão,
Rio de Janeiro, CEP 21941-590, RJ, Brasil
Fax +55(21)22702683; E-mail: mlaav@nppn.ufrj.br
Received 8 March 2004; revised 13 April 2004
Cl
Abstract: We describe the first example of a chemoselective oxida-
tion of phenyl and p-methoxyphenyl groups to carboxylic acid func-
tions in the presence of a tetrahydropyran ring, using 0.02 mol% of
HO2C
O
HO C
O
RuCl and a co-oxidant. The use of NaIO as co-oxidant in H O–
2
3
4
2
CH CN–CCl as the solvent system led to diketone 7. The change
3
4
1
2
of the co-oxidant from sodium periodate to periodic acid and re-
moval of water from the solvent system led to carboxylic acid 2 in
good yield as the sole product .
Figure 1 (+/–)-6-Ethyl-tetrahydro-pyran-2-carboxylic acid (1) and
(+/–)-4-chloro-6-ethyl-tetrahydro-pyran-2-carboxylic acid (2).
Key words: oxidation, catalysis, aromatic, ruthenium tetroxide,
tetrahydropyran, Prins reaction, Barbier reaction
(
+/–)-2,4,6-cis,cis-4-Chloro-2-ethyl-6-phenyl-tetrahydro-
pyran (4) was prepared in two steps through Barbier reac-
9
tion of allyl bromide with benzaldehyde (89% yield of 3),
10
Ruthenium tetroxide has long been known as a vigorous followed by an efficient Prins reaction of the 1-phenyl-
oxidant, capable of readily cleaving carbon-carbon double but-3-en-1-ol (3) with propanal in 85% yield (Scheme 1).
1
bonds and aromatic groups. The reaction can be carried
out with catalytic amounts of RuO which is neither ex-
O
OH
4
Br
plosive nor poisonous and therefore has advantages over
2
the ozonolysis reaction. Due to the economical and prac-
3
tical advantages of working with aromatic substrates, the
Mg, THF, 89%
3
use of phenyl groups has been suggested as a synthetic
4
precursor for the carboxylic acid functionality. Synthetic
O
protocols based on the ruthenium(III) chloride/NaIO ox-
4
AlCl3, CH2Cl2, 85%
idation, where RuO is prepared in situ, have been pub-
4
3
lished. However, the generality of the method is far from
Cl
O
that expected for its use because only a few functional
groups resist this oxidative process. For example, tetrahy-
dropyrans and tetrahydrofurans are commonly converted
H
H
5
to lactones. That is, the use of RuO oxidation is an effi-
4
cient synthetic protocol to convert 2,6-dimethyltetrahy-
drofuran to 2,5-hexanedione and tetrahydropyran to 1,5-
pentanodioic acid.
4
6
Scheme 1 Synthesis of (+/–)-2,4,6-cis,cis-4-chloro-2-ethyl-6-phe-
nyl-tetrahydropyran (4).
In this paper, we describe a chemoselective oxidation of
the phenyl and p-methoxyphenyl groups to the carboxylic
acids of (+/–)-2,4,6-cis,cis-4-chloro-2-ethyl-6-phenyl-tet- The Prins cyclization is highly diastereoselective for the
rahydropyran 4 (Scheme 1) and (+/–)-2,4,6-cis,cis-4- preparation of tetrahydropyran skeletons, leading to tet-
1
0
chloro-2-ethyl-6-(4-methoxyphenyl)-tetrahydropyran
6
rahydropyrans 2,4,6-all-cis-substituted. The relative cis
(
Scheme 2). This was done with the aim to prepare the stereochemistry between C and C in 4 was confirmed
2
4
chlorinated acid 2 (Figure 1), a precursor of the tetrahy- through the coupling constant between the benzylic hy-
7
dropyran acid 1, recently described as a new structure drogen and the CH group in C (J = 11.3 Hz and 2.1 Hz,
2
3
class having analgesic properties.8
Figure 2 left side) as well as between the hydrogen on the
carbon C and the CH in C (J = 12 Hz and 4.5 Hz,
4
2
3
Figure 2, right side), which are consistent with these hy-
drogens occupying the axial position.
The product 6 could not be obtained via the Prins reaction
between the allylated product of p-methoxybenzaldehyde
and propanal, probably due to the Oxonia-Cope re-
SYNTHESIS 2004, No. 11, pp 1767–1770
Advanced online publication: 01.07.2004
x
x.
x
x
.
2
0
0
4
DOI: 10.1055/s-2004-829119; Art ID: M01604SS
Georg Thieme Verlag Stuttgart · New York
11
arrangement. On the other hand, this compound was ef-
©

1
768
L. S. M. Miranda, M. L. A. A. Vasconcellos
PAPER
The substrate 4 was submitted to the ruthenium tetroxide
1
1.3 Hz
12 Hz
H
6
H
5
O
mediated oxidation using RuCl /co-oxidant under various
3
5
6
Cl
O
Cl
3
conditions and the results are summarized in Table 1. The
4
2
H
4
3 2
H
12
H
use of Sharpless protocol for the ruthenium tetroxide
H
mediated oxidations led to the formation of product 7 de-
rived from the oxidation of the tetrahydropyran ring (entry
4.5 Hz
2.1 Hz
Figure 2 Relative stereochemistry of (+/–)-2,4,6-cis,cis-4-chloro- 1). When the co-oxidant was changed from sodium perio-
2
-ethyl-6-phenyl-tetrahydropyran (4).
date to periodic acid, a 1:1 mixture of the desired acid 2
and the diketone 7 was obtained (entry 2). In the water-
free solvent system and when periodic acid was used as
co-oxidant, product 2 was chemoselectively obtained (en-
tries 4 and 5). Under strictly anhydrous conditions an im-
provement in the chemoselectivety of the product 2 over
ficiently prepared through the Prins reaction between p-
methoxybenzaldehyde with hex-5-en-3-ol (5) (70%),
which was obtained by a Barbier reaction between propa-
nal and allylbromide in 74% yield (Scheme 2).
7
could be also obtained (entry 6, 52% yield). No reaction
was observed with sodium periodate as co-oxidant, under
anhydrous condition (entry 3), due to the insolubility of
sodium periodate in the water-free solvent system. In
view of increasing the chemical yield, substrate 6 was ox-
idized in place of 4 leading to the desired product 2 only
(
72% yield, entry 7).
The use of periodic acid in place of sodium periodate as
13
co-oxidant has already been reported in the literature. Its
use is justified by the fact that it keeps the reaction media
homogeneous, while the sodium iodate formed by reduc-
tion of sodium periodate, precipitates and often stops the
catalytic cycle (Figure 3). This may lead to a removal of
ruthenium salts from the solution, leading in some cases
13
to poor yields. Periodic acid is also advantageous in the
Scheme
2
Synthesis of (+/–)-2,4,6-cis-4-chloro-2-ethyl-6-(4- present case because it is soluble in the water-free solvent
methoxyphenyl)-tetrahydropyran.
system, making it the co-oxidant of choice for the anhy-
drous conditions used.
Table 1 Ruthenium Tetroxide Mediated Oxidation of 4
Cl
Cl
O
Cl
O
RuCl3/co-oxidant
condition HO2C
+
Ar
Ar
O
O
4
or 6
7
2
Entry
Ar
Solvent system
H O–CH CN–CCl
4
Co-oxidant
NaIO4
2:7a
1
2
3
4
5
6
Ph
0:100
2
3
Ph
H O–CH CN–CCl
H IO
6
50:50
2
3
4
5
Ph
CH CN–CCl
NaIO4
H IO
No reaction
67:33
3
4
4
Ph
CH CN–CCl
3
5
6
6
6
6
b
Ph
CH CN –CCl
H IO
75:25
3
4
5
c
87:13 (52%)d
100:0 (72%)d
Ph
CH CN–CCl
H IO
3
4
4
5
c
7
p-MeOPh
CH CN–CCl
H IO
3
5
a
Analyzed by capillary gas chromatography mass spectrometry.
CH CN distilled from CaH prior to use.
Strictly anhydrous conditions were used.
Chemical yields of 2 after purification by column flash chromatography.
b
c
d
3
2
Synthesis 2004, No. 11, 1767–1770 © Thieme Stuttgart · New York

PAPER
Chemoselective RuO Oxidation of Phenyl or p-Methoxyphenyl Groups
1769
4
to the usually high entropy of activation for these reac-
tions. The oxidation would then afford a ketal intermedi-
ate, which would furnish the diketone 7. This transition
state, for the production of the diketone 7, could be a low
energy one, due to the solvation by the water present in the
solvent system. The presence of periodic acid as the co-
oxidant could also lead to a lower aqueous activity, which
would slow the tetrahydropyran oxidation rate, allowing
the preferential phenyl group oxidation (Table 1, entry 7).
Figure 3 Proposed catalytic cycle for the RuO mediated oxidation
of organic substrates.
4
In conclusion, we have observed the first efficient
chemoselective example, which converts phenyl and p-
methoxypheny groups to carboxylic acids in presence of
the tetrahydropyran moiety.
The mechanism of ruthenium tetroxide mediated oxida-
tion has been extensively investigated for conversion of
1
4
2
ethers to esters (Scheme 3) but rarely for olefins and ar-
1
5
omatic groups.
The increasing removal of water from commercial
CH CN and CCl (Table 1, entry 4), to anhydrous CH CN
In RuO mediated oxidation reaction of ethers, it has been
4
3
4
3
demonstrated that the kinetics of the reaction is related to
the water content of the reaction medium. Such sensitivity
varies with the reaction conditions ranging from 5 times to
(
entry 5), and complete anhydrous conditions (entry 6)
was fundamental to the chemoselective oxidation of the
phenyl and p-methoxyphenyl groups over the tetrahydro-
pyran ring due to a decreasing rate of tetrahydropyran ox-
idation with the anhydrous conditions.
6
14
1
0 times faster in the presence of water.
The presence of the p-methoxy group (electron-releasing
group) in 6 improves the aromatic oxidation, over the tet-
rahydropyran ring, which leads to an increased chemose-
lectivity and chemical yield.
O
R
O
O
O
O
O
+
RuO4
Ru
R
O
Ru
OH
H
R
O
O
O
Finally, the chloro derivative of the analgesic acid 1, 2 (4-
chloro-6-ethyl-tetrahydro-pyran-2-carboxylic acid), was
prepared in good yield, using a simple and cheap oxida-
tive protocol.
O
R
O
Scheme 3 Synchronous mechanism for the ether oxidation by
RuO4.
1H NMR and 13C NMR spectra were obtained on Varian Spectrom-
eter at 200 MHz and 50 MHz in CDCl with CHCl as internal ref-
3
3
1
4
An already proposed synchronous mechanism does not erence (d = 7.26 ppm and 77.0 ppm), respectively. TLC analyses
lead to carbocationic character in the transition state were performed with 0.2–0.5 mm precoated silica gel plates (GF-
2
54). Elemental analyses were performed on a Vario EL instrument.
(
Scheme 3). On the other hand, an ionic mechanism is
more appropriate to explain the effect of water in the reac-
tion rate. Carbocationic character of the transition state at
the slow step can be suggested (Scheme 4), instead of a
complete concerted mechanism, due to the anchimeric as-
Typical Procedure
In a dry round bottom flask were placed periodic acid (1.8 g, 7.9
mmol), and anhyd CH CN (7 mL, freshly distilled from CaH ), with
3
2
vigorous stirring until dissolution occurred. A solution of 3 (194
sistance of the adjacent oxygen atom as well as the adja- mg, 0.86 mmol) in anhyd CCl (7 mL) was then added followed by
4
cent phenyl group at carbon 2. Steric effects could also the addition of ruthenium trichloride trihydrate (0.4 mg). The mix-
ture was left stirring for 24 h at r.t, and the solvent evaporated under
play a role in inhibiting the synchronous mechanism due
H
H
[RuO4H] -1
O
O
+
O
δ+
Cl
O
H
O
Cl
RuO4
Cl
H H
H
H
H
δ−
H
O
Oδ−
O
H
O
H
H
O
H
H
Ru
O
H
H
4
O
δ−
O
O
δ−
O
Cl
O
OH
RuO4
Cl
OH
O
Cl
O
7
H
Scheme 4 Proposed mechanism for the oxidation of the tetrahydropyran ring of 4.
Synthesis 2004, No. 11, 1767–1770 © Thieme Stuttgart · New York

1
770
L. S. M. Miranda, M. L. A. A. Vasconcellos
PAPER
1
3
reduced pressure. The residue was re-suspended and filtered
through a small column of silica gel with 3% EtOAc in hexane fol-
lowed by elution with 5% MeOH in CH Cl . After evaporation of
C NMR (50 MHz, CDCl ): d = 9.6, 28.2, 38.5, 40.9, 41.5, 54.2,
3
74.6, 78.4, 173.0.
2
2
+
MS (EI, 70 eV): m/z (%) = 156 (0.9) [M – HCl], 138 (8.9), 127
15.1), 111 (100), 99 (40), 81 (58), 55 (74).
MeOH–CH Cl , the mixture was purified by flash chromatography,
2
2
(
yielding 86 mg (52%) of 2 as a light yellowed oil that solidified
upon standing.
Anal. Calcd for C H ClO : C, 49.88; H, 6.80; O, 24.92. Found: C,
4
8
13
3
9.76; H, 6.74; O, 25.02.
1
-Phenyl-but-3-en-1-ol (3)16
IR (neat): 3375, 3075, 3065, 2932, 2906, 1641, 1454, 1047, 1029,
16, 758 cm .
3
-Chloro-1-(4-methoxyphenyl)-heptane-1,5-dione (7)
1
–1
H NMR (200 MHz, CDCl ): d = 1.1 (t, J = 7.2 Hz, 3 H), 2.47 (q,
J = 6.96 Hz, 2 H), 3.0 (d, J = 7.1 Hz, 2 H), 3.5 (d, J = 6.96 Hz, 2 H),
4
9
3
1
H NMR (200 MHz, CDCl ): d = 2.1 (s, OH, 1 H), 2.5 (m, 2 H), 4.7
t, J = 6 Hz, 1 H), 5.1 (br s, 1 H), 5.2 (m, 1 H), 5.8 (m, 1 H), 7.3 (m,
3
.7 (q, J = 6.6 Hz, 1 H), 7.5 (m, 3 H), 8.0 (d, J = 7.4 Hz, 2 H).
(
1
3
C NMR (50 MHz, CDCl ): d = 7.3, 36.6, 40.9, 45.9, 49.9, 128.2,
5
H).
3
1
28.2, 128.5, 128.5, 133.4, 136.8, 196.2, 207.5.
1
3
C NMR (50 MHz, CDCl ): d = 43.5, 73.1, 117.9, 125.5, 125.6,
3
1
27.3, 128.1, 128.1, 134.3, 143.4.
Acknowledgment
4
-Chloro-2-ethyl-6-phenyl-tetrahydropyran (4)
We thank Capes and CNPq for financial support.
IR (neat): 3087, 2962, 2932, 2876, 2850, 1453, 1368, 1329, 755,
6
–1
99 cm .
1
H NMR (200 MHz, CDCl ): d = 0.95 (t, J = 7.2 Hz, 3 H), 1.6 (m,
H), 2.2 (m, 1 H), 2.4 (m, 1 H), 3.4 (m, 1 H), 4.2 (tt, J = 12, 4.5 Hz,
H), 4.4 (dd, J = 11.3, 2.1 Hz, 1 H), 7.3 (m, 5 H).
3
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4
1
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(
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3
2
7
8.2, 126.6, 127.4, 128.2, 141.4.
(
+
+
MS (EI, 70 eV): m/z (%) = 224 (21.4) [M ], 226 (7.14) [M + 2],
95 (21.4), 197 (7.2), 159 (7.5), 131 (39.2), 107 (100), 83 (25).
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Anal.Calcd for C H ClO: C, 69.48; H, 7.62; O, 7.12. Found: C,
13
17
(
(
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–
1
4
1
H NMR (200 MHz, CDCl ): d = 0.9 (t, J = 7.33 Hz, 3 H), 1.5 (m,
3
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5
.2 ( m, 1 H), 5.7 (m, 1 H).
1
3
C NMR (50 MHz, CDCl ): d = 9.70, 29.13, 41.19, 71.86, 117.65,
3
1
34.77.
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4
-Chloro-2-ethyl-6-(4-methoxyphenyl)-tetrahydropyran (6)
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1
–1
034, 828, 555 cm .
1
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m, 4 H), 2.20 (dq, J = 12.7, 2.2 Hz, 1 H), 2.35 (dq, J = 12.9, 2.2 Hz,
3
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(
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(
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3
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5
6.02, 77.97, 78.15, 113.67, 127.03, 133.69, 158.98.
+
+
MS (EI, 70 eV): m/z (%) = 254 (6.25) [M ], 256 (1.9) [M + 2], 219
(
(
11.25), 182 (1.25), 161 (7.5), 136 (100), 121 (9.3), 109 (7.55), 91
11.9).
(
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6
1
4
19
2
(
(
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6
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–
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1
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3
(
(
Synthesis 2004, No. 11, 1767–1770 © Thieme Stuttgart · New York