Selenium dioxide-mediated methoxyhydroxylation of cyclic arylolefin

Article abstract of DOI:10.1016/j.tetlet.2010.01.020

Selenium dioxide-mediated methoxyhydroxylation of cyclic arylolefin with the modest yields is described. This facile strategy was also used to synthesize several 4-arylpyridines, 3-hydroxy-4-arylpyridines, and 3,4-diarylpyridines. Crown Copyright

Full text of DOI:10.1016/j.tetlet.2010.01.020

Tetrahedron Letters 51 (2010) 1430–1433
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Selenium dioxide-mediated methoxyhydroxylation of cyclic arylolefin
*
Meng-Yang Chang , Chung-Han Lin, Yeh-Long Chen
Department of Medicinal and Applied Chemistry, Kaohsiung Medical University, Kaohsiung 807, Taiwan
a r t i c l e i n f o
a b s t r a c t
Article history:
Selenium dioxide-mediated methoxyhydroxylation of cyclic arylolefin with the modest yields is
described. This facile strategy was also used to synthesize several 4-arylpyridines, 3-hydroxy-4-arylpyri-
dines, and 3,4-diarylpyridines.
Received 23 November 2009
Revised 30 December 2009
Accepted 8 January 2010
Available online 13 January 2010
Crown Copyright Ó 2010 Published by Elsevier Ltd. All rights reserved.
1. Introduction
The structure of methoxyalcohol 2 with trans-configuration was
determined by single-crystal X-ray analysis (see Diagram 1). We
The contrasting chemical behaviors of 4-aryl-1,2,3,6-tetrahy-
dropyridines are of interest.1 Because the structural skeleton is
known as a building partner in the synthesis of related compounds
with potential pharmaceutical activities, our previous study devel-
oped a number of convenient procedures which allow the prepara-
tion of coerulescine and baclofen via a pinacol to pinacolone
rearrangement reaction.2 As part of an ongoing investigation in this
area, we have developed the useful transformations that exploit
the unique reactivity of the peroxyselenous ester derived from
selenium dioxide and hydrogen peroxide in methanol to cyclic
arylolefins.
In general, selenium dioxide displays an important mode of inter-
action with olefins, involving an initial ene reaction followed by a
[2,3]-sigmatropic rearrangement.3 The utility of this reagent as a
selective allylic oxidant has been amplified by the addition of co-oxi-
dant hydrogen peroxide which effectively prevents interference.
Other selenium dioxide-catalyzed oxidative rearrangement reac-
tionshavealso beenreported.4 Oneofthesimplestwaysof preparing
have confirmed that water from aqueous hydrogen peroxide as-
sisted the formation of diol 3. Furthermore, by adjusting the sol-
vent of hydrogen peroxide as the methanol5 or dioxane, the
yields of methoxyalcohol 2 (93%) or diol 3 (84%) were increased.
To our knowledge, there is currently no experimental report on
the selenium dioxide-mediated methoxyhydroxylation and dihydr-
oxylation.
The possible methoxyhydroxylation reaction mechanism has
been proposed as follows. Presumably, selenium dioxide exists as
a form of peroxyselenous methylester in the hydrogen peroxide
of methanol solution. When the epoxidation of olefin 1 is gener-
ated, it is assumed that the formation of the intermediate epoxide
can be converted to methoxyalcohol 2 by means of a nucleophilic
attack of epoxide with methanol with regio- and stereosensitivity.
To further reinvestigate the reaction mechanism, two-step trans-
formation was examined. Epoxidation of olefin 1 with m-chloro-
peroxybenzoic acid was tested. Then, treatment of the resulting
epoxide with selenium dioxide (2.0 equiv) in methanol yielded
methoxyalcohol 2. The yield of two steps is 68%. Therefore, we
believed that epoxidation is the first step during the selenium
dioxide-mediated reaction. During the one-pot process, the
cis-1,2-methoxyalcohol framework was not observed under this
reaction condition.
a-methoxy alcohol is selective O-methylation of 1,2-diol, which can
be easily done by dihydroxylation. Many reports on selective protec-
tion focus on the hydroxyl group of diol or ring-opening of epoxide
by nucleophilic attack of alcohols. Under the condition of their
experiments, the major problems involve the difficulty in selective
protection of 1,2-diol or ring-opening of epoxide ring.
When the amount of selenium dioxide was removed from the
reaction system, we found that a nearly equivalent amount of ole-
fin 1 was recovered. For the catalytic amount of selenium dioxide
2. Results and discussion
To initiate our work, oxidation of olefin 1 (1.0 mmol) with sele-
nium dioxide (2.0 equiv) and hydrogen peroxide (2 mL) in metha-
nol (20 mL) at reflux temperature for 5 h provided methoxyalcohol
2 at a 68% yield and diol 3 at a 22% yield (Eq. 1).
Ph
MeO Ph
HO Ph
OH
OH
SeO2, H2O2(aq)
MeOH, reflux
N
N
N
Ms
Ms
Ms
2 (68%)
3 (22%)
1
* Corresponding author.
E-mail addresses: mychang624@yahoo.com.tw, mychang@kmu.edu.tw (M.-Y.
Chang).
Equation 1. SeO2-mediated reaction of olefin 1.
0040-4039/$ - see front matter Crown Copyright Ó 2010 Published by Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.01.020

M.-Y. Chang et al. / Tetrahedron Letters 51 (2010) 1430–1433
1431
Table 1
SeO2-mediated reaction of 1Aa with H2O2 in alcoholsa
Entry
ROH (20 mL)
Time (h)
Yieldsb (%)
1
2
3
4
5
6
7
8
9
Methanol
Methanol
Ethanol
5
25
5
25
5
25
5
3Aa/2Aa/5=61/24/ND
3Aa/2Aa/5=16/30/37
3Aa/4Aaa/5=39/40/ND
3Aa/4Aaa/5=8/20/50
3Aa/4Aab/5=26/32/ND
3Aa/4Aab/5=5/14/40
3Aa/4Aac/5=52/ND/ND
3Aa/4Aac/5=trace/ND/48
3Aa/4Aad/5=31/ND/ND
Ethanol
Isopropanol
Isopropanol
t-Butanol
t-Butanol
Phenol
25
5
a
The reactions were run on 1 mmol scale with alcohol at reflux temperature
using selenium dioxide (2 equiv) and aqueous hydrogen peroxide (2 mL).
b
ND is no detected product.
Ph
Ph
HO Ph
RO Ph
OH
SeO2, H2O2(aq)
ROH, reflux
OH
O
Diagram 1. X-ray structure of compound 2.
N
Bs
N
Bs
NH
Bs
N
Bs
(0.3 equiv), the lower conversion was still generated. Olefin 1 was
recycled in 66% yield. Furthermore, when selenium dioxide
(1.3 equiv) was added to the reaction mixture, the products 2
(63%), 3 (20%), and trace olefin 1 were obtained during a 10-h per-
iod. In comparison with the amount of selenium dioxide, 2 equiv is
the appropriate condition to shorten the reaction time. For screen-
ing other epoxidizing agent, we had tried to use m-chloroperoxy-
benzoic acid (2.0 equiv) instead of hydrogen peroxide in the
selenium dioxide-mediated reaction of olefin 1. We found that
the residue mixture of m-chlorobenzoic acid and excess m-chloro-
peroxybenzoic acid was not easy to separate clearly from the prod-
uct mixture by chromatography. The isolation procedure of
products 2 and 3 was inconvenient than that of the oxidant hydro-
gen peroxide. To test the efficiency of the selenium dioxide-medi-
ated reaction, several arylolefins were prepared to demonstrate the
methoxyhydroxylation and dihydroxylation. As shown in Scheme
1, these starting six-membered materials included five 4-aryl-
1,2,5,6-tetrahydropyridines 1Aa–1Ae (a, Ar = Ph; b, Ar = 4-FPh; c,
Ar = 3-CF3Ph; d, Ar = 2-MeOPh; e, Ar = 3-CF3-4-ClPh), 4-(4-fluoro-
phenyl)-1,2,3,6-tetrahydropyran 1B, and 4-methyl-1-(4-fluoro-
phenyl)-1-cyclohexene 1C.
1Aa
3Aa
5
2Aa
4Aaa (R=Et)
4Aab (R=i-Pr)
4Aac (R=t-Bu)
4Aad (R=Ph)
Equation 2. SeO2-mediated reaction of olefin 1Aa with alcohols.
in the 78–89% range and those of products 3Aa–3Ac were in the
72–82% range.6 We had tried to study the synthesis of five-mem-
bered 3-phenylpyrroline using the same treatment, but the at-
tempt was unsuccessful. Although the synthetic application has
been decreased, the present work is complementary to existing
methodology. After many trials, different alcohol solvents were ex-
plored next.
As shown in Table 1 and Eq. 2, several alcohols were investigated
to determine the reaction of olefin 1Aa in the presence of water. For
methanol, products 3Aa and 2Aa were obtained in 61% and 24%
yields (entry 1). The result is similar to Eq. 1. In particular, a part
of diol 3Aa was converted to aminoketone 5 due to overoxidation
under longer time conditions (entry 2). For ethanol, products 3Aa
and 4Aaa provided 39% and 40% yields (entry 3), respectively. The
ratio of alkoxyalcohol/diol (from 2.5 to 1) was decreased. A part
of diol 3Aa was also converted to aminoketone 5 (entry 4). In com-
parison with selenium dioxide-mediated alkoxyhydroxylation of
olefin 1Aa with methanol or ethanol, the poorer overall yields of
products 3Aa and 4Aab showed that the steric effect of isopropanol
controlled the distribution of products and yields (entry 5). Entry 6
also showed results similar to those of entry 4, but the overall yield
With compounds 1Aa–1Ac and 1B–1C in hand, two reaction
conditions were examined. Skeleton 1 was subjected to oxidation
using selenium dioxide and hydrogen peroxide in methanol or
dioxane at reflux temperature. As revealed by TLC analysis, the
starting materials disappeared with the appearance of a major
product during a 5-h period. Isolation of the product after aqueous
workup and characterization indicated the structural skeletons 2
and 3. The isolated yields of products 2Aa–2Ae and 2B–2C were
Ar
HO Ar
MeO Ar
OH
OH
SeO2, H2O2(aq)
dioxane, reflux
SeO2, H2O2(MeOH)
MeOH, reflux
X
X
X
3Aa, X=NBs, Ar=Ph (82%)
1Aa, X=NBs, Ar=Ph
2Aa, X=NBs, Ar=Ph (89%)
3Ab, X=NBs, Ar=4-FPh (72%)
1Ab, X=NBs, Ar=4-FPh
2Ab, X=NBs, Ar=4-FPh (78%)
2Ac, X=NBs, Ar=3-CF3Ph (85%)
2Ad, X=NBs, Ar=2-MeOPh (83%)
3Ac, X=NBs, Ar=3-CF3Ph (75%) 1Ac, X=NBs, Ar=3-CF3Ph
1Ad, X=NBs, Ar=2-MeOPh
1Ae, X=NBs, Ar=3-CF3-4-ClPh 2Ae, X=NBs, Ar=3-CF3-4-ClPh (88%)
1B, X=O, Ar=4-FPh
2B, X=O, Ar=4-FPh (85%)
1C, X=CHMe, Ar=4-FPh
2C, X=CHMe, Ar=4-FPh (79%)
Scheme 1. SeO2-mediated trans-methoxyhydroxylation and dihydroxylation of olefin 1.

1432
M.-Y. Chang et al. / Tetrahedron Letters 51 (2010) 1430–1433
Ar
N
Ar
N
MeO Ar
MeO Ar
OH
Jones ox.
O
OH
NBS, HOAc
NaH, THF
N
Bs
N
Bs
2Aa, Ar=Ph
6Aa (69%)
6Ab (73%)
6Ac (66%)
6Ad (77%)
6Ae (70%)
7Aa (89%)
8Aa (69%)
8Ab (60%)
8Ac (64%)
8Ad (66%)
2Ab, Ar=4-FPh
7Ab (80%)
7Ac (88%)
7Ad (86%)
7Ae (83%)
2Ac, Ar=3-CF3Ph
2Ad, Ar=2-MeOPh
2Ae, Ar=4-Cl-3-CF3Ph
Scheme 2. Synthesis of 4-arylpyridines 6Aa–6Ae and 3-hydroxy-4-arylpyridines 8Aa–8Ad.
MeO Ph
Ph
Ph
N
O
Ar1B(OH)2, K3PO4,
OMs
Ar1
MsCl, Py.
(52%)
NiCl2(dppe), Zn, THF
N
Bs
N
7Aa
9Aa, Ar1=Ph (72%)
9Ab, Ar1=3-OMePh (66%)
9Ac, Ar1=4-OMePh (71%)
8B
Ph3P=CHCO2Et
DCM, (95%)
Ph
Ph
MeO Ph
CO2Et
CO2Et
CO2Et
BF3-OEt2
H2, Pd/C
N
Bs
N
Bs
N
Bs
DCM, (87%)
EtOH, (91%)
10
11
12
Scheme 3. Synthesis of 3,4-diarylpyridines 9Aa–9Ac and compound 12.
Ph
OMe
OH
Ph
OH
OH
a 69% yield as shown in Scheme 2. Similarly, the reaction of
methoxyalcohols 2Abꢀ2Ae also furnished the resulting 4-arylpyri-
dines 6Ab–6Ae with 66–77% yields.
Ph
Ph
Ph
Ph
SeO2, H2O2(aq)
MeOH, reflux
We next turned our attention to the synthesis of 3-hydroxypyr-
idine. 3-Hydroxypyridines are important structural units found in
numerous bioactive compounds.9 Oxidation of alcohols 2Aa–2Ad
with Jones reagent in acetone at room temperature resulted
in the corresponding ketones 7Aa–7Ad being produced with
80–89% yields. The structure of ketone 7Aa was determined by sin-
gle-crystal X-ray analysis.10 Based on the experimental simplicity,
the preparation of ketone 7Aa was also conducted in a multigram
scale (0.1 mol) with a 75% overall yield. Treatment of ketones
7Aa–7Ad with sodium hydride in tetrahydrofuran at reflux
temperature produced 3-hydroxypyridines 8Aa–8Ad in 60–69%
yields. Compound 8Aa is the key precursor in the synthesis of 3-
phenyltropane analogs with some potent activities by 1,3-dipolar
cycloaddition.11 Furthermore, synthesis of diarylpyridines was de-
scribed as follows. The aromatization process was also achieved via
the reaction of ketone 7Aa with methanesulfonyl chloride in pyri-
dine at reflux temperature and mesylate 8B provided a 52% yield as
shown in Scheme 3. For introducing the 3-aryl group, Percec’s
coupling protocol was examined.12
N
N
Ms
N
Ms
Ms
14 (73%)
15 (20%)
13
Equation 3. SeO2-mediated reaction of olefin 13.
is poorer. By changing isopropanol to t-butanol, diol 3Aa was
obtained as the major product in a 52% yield during a 5-h reaction
time (entry 7). The product 5 was still generated with a 48% yield as
a nearly sole isomer (entry 8). This is a new approach to the synthe-
sis of b-aminoarylketone7 via selenium dioxide-mediated oxidative
bond cleavage with t-butanol. The evidence demonstrated that the
steric hindrance was a key factor for the introduction of alcohol into
the quaternary center. Reaction time was another factor in deter-
mining the bond cleavage of olefin. As shown in entry 9, because
the nucleophilic ability of phenol was poorer than that of water,
diol 3Aa gave only a 31% yield. Similar results were obtained with
the additive ethylene glycol.
To reinvestigate the applicability of the facile methoxyhydroxy-
lation reaction, we studied the synthesis of substituted pyridine
analogs, including 4-arylpyridines, 3-hydroxy-4-arylpyridines,
and 3,4-diarylpyridines. 4-Arylpyridines are of high interest in or-
ganic chemistry due to their potential agrochemical and pharma-
ceutical activities and several synthetic procedures have
appeared during recent years.8 After screening numerous condi-
tions, treatment of 2Aa with N-bromosuccinimide in acetic acid
at reflux temperature produced the desired 4-arylpyridine 6Aa at
Nickel complex-catalyzed Suzuki coupling of mesylate 8B with
three kinds of phenylboronic acid analogs gave diarylpyridines
9Aa–9Ac in 66–72% yields. On the other hand, when compound
7Aa was reacted with Wittig reagent, the sole olefin 10 was ob-
tained in a 95% yield. Also, conjugated diene 11 was isolated by
dehydration of compound 10 with boron trifluoride etherate at re-
flux temperature with a 87% yield. Selective hydrogenation of 11
produced 12 at a 91% yield. Noteworthy, unsaturated esters 11
and 12 were the piperidine-based analogs of cocaine.13

M.-Y. Chang et al. / Tetrahedron Letters 51 (2010) 1430–1433
1433
(222 mg, 2.0 mmol) in methanol or dioxane (20 mL) at rt. The reaction mixture
was stirred at reflux for 5 h. Saturated sodium bicarbonate solution (2 mL) was
added to the reaction mixture and the solvent was concentrated. The residue
was extracted with dichloromethane (3 Â 20 mL). The combined organic layers
were washed with brine, dried, filtered, and evaporated to afford crude
product. Purification on silica gel (hexane/AcOEt = 6/1–2/1) afforded
Finally, we examined an extension of the above-mentioned
method to the synthesis of methoxyalcohol 14 and diol 15 (Eq.
3). The selenium dioxide-mediated reaction of exocyclic arylolefin
13 under the above-mentioned condition successfully furnished
the trans-methoxyhydroxylation and dihydroxylation reactions.
The structures of methoxyalcohol 14 and diol 15 were determined
by single-crystal X-ray analysis.14
compounds
2 and 3. For compound 2Aa: Mp= 137–138 °C (recrystallized
from hexane and ethyl acetate); IR (CHCl3) 3519, 2940, 1338, 1168, 1123,
576 cmÀ1; HRMS (ESI, M++1) calcd for C18H22NO4S 348.1270, found 348.1271;
1H NMR (400 MHz): d 7.84–7.81 (m, 2H), 7.66–7.48 (m, 8H), 3.84–3.74 (m, 3H),
3.10 (dd, J = 2.8, 13.2 Hz, 1H), 2.84 (s, 3H), 2.66–2.52 (m, 2H), 2.12 (br s, 1H),
2.08 (br d, J = 14.8 Hz, 1H); 13C NMR (100 MHz): d 142.06, 136.45, 132.95 (2Â),
130.47, 129.18 (2Â), 128.98, 127.55 (2Â), 124.77, 123.72, 77.17, 71.05, 49.67,
48.12, 41.46, 24.27; Anal. Calcd for C18H21NO4S: C, 62.23; H, 6.09; N, 4.03.
Found: C, 62.38; H, 6.21; N, 4.33. For compound 3Aa: Mp= 177–178 °C
(recrystallized from hexane and ethyl acetate); IR (CHCl3) 3489, 2921, 1336,
1169, 1078, 729 cmÀ1; HRMS (ESI, M++1) calcd for C17H20NO4S 334.1113, found
334.1113; 1H NMR (400 MHz): d 7.82–7.78 (m, 3H), 7.70–7.49 (m, 7H), 3.85–
3.74 (m, 3H), 3.11 (dd, J = 1.2, 12.0 Hz, 1H), 2.85 (ddd, J = 2.4, 11.6, 12.8 Hz, 1H),
2.74 (ddd, J = 4.4, 12.8, 13.6 Hz, 1H), 1.74 (br d, J = 13.6 Hz, 1H), 1.68 (br s, 2H);
13C NMR (100 MHz): d 145.53, 136.28, 133.06 (2Â), 129.39, 129.23 (2Â),
128.89, 127.59 (2Â), 124.86, 122.66, 72.11, 70.57, 48.36, 41.79, 31.41; Anal.
Calcd for C17H19NO4S: C, 61.24; H, 5.74; N, 4.20. Found: C, 61.31; H, 5.83; N,
4.41.
3. Conclusion
In summary, we have presented a synthetic method for 4-aryl-
pyridines, 3-hydroxy-4-arylpyridines, and 3,4-diarylpyridines
which involved selenium dioxide-mediated methoxyhydroxylation
of 4-aryl-1,2,3,6-tetrahydropyridines. Considering the utility of
these heterocyclic aromatic compounds, the development of the
general synthetic approaches is significant.
Acknowledgment
7. (a) Misra, M.; Luthra, R.; Singh, K. L.; Sushil, K.. In Comprehensive Natural
Products Chemistry; Barton, D. H. R., Nakanishi, K., Meth-Cohn, O., Eds.;
Pergamon: Oxford, UK, 1999; Vol. 4, p 25; (b) Staunton, J.; Wilkinson, B. Top.
Curr. Chem. 1998, 195, 49; (c) Cardillo, G.; Tomasini, C. Chem. Soc. Rev. 1996,
117; (d) Juaristi, E.; Lopez-Ruiz, H. Curr. Med. Chem. 1999, 6, 983; (e) Wabnitz, T.
C.; Spencer, J. B. Tetrahedron Lett. 2002, 43, 3891; (f) Wabnitz, T. C.; Spencer, J. B.
Org. Lett. 2003, 5, 2141.
The authors would like to thank the National Science Council of
the Republic of China for financial support.
References and notes
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J. Tetrahedron 2001, 57, 1923; (b) Feuerstein, M.; Doucet, H.; Santelli, M.
Tetrahedron Lett. 2001, 42, 5659; (c) Stanforth, S. P. Tetrahedron 1997, 54, 263;
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K. J. Med. Chem. 2008, 51, 760. and cited references therein.
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653; (b) Lu, J. Y.; Arndt, H. D. J. Org. Chem. 2007, 72, 4205; (c) Lu, J. Y.; Keith, J.
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therein.
10. CCDC 752928 (2), 752931 (3Ac), 752932 (4Aab) and 752933 (7Aa) contain the
supplementary crystallographic data for this paper. This data can be obtained
free of charge via www.ccdc.cam.ac.uk/conts/retrieving.html (or from the
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deposit@ccdc.cam.ac.uk).
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5.
A solution of hydrogen peroxide in methanol is prepared from sodium
peroxide. Sodium peroxide is added to an ice-cold dilute solution of 20%
sulfuric acid in methanol, in small doses at a time. Sodium sulfate is removed
by recrystallization, and a dilute solution of hydrogen peroxide in methanol is
obtained. The concentration of the freshly prepared solution of hydrogen
peroxide in methanol was nearly 38–42% (v/v) by titrating with the solution of
potassium permanganate (0.02 M).
14. CCDC 752929 (15) and 752930 (14) contain the supplementary
crystallographic data for this Letter. These data can be obtained free of
charge via www.ccdc.cam.ac.uk/conts/retrieving.html (or from the CCDC, 12
Union Road, Cambridge CB2 1EZ, UK; fax: 44-1223-336033; e-mail:
deposit@ccdc.cam.ac.uk).
6. Selenium dioxide-mediated reaction of compound 1 into compounds 2 or 3 is
as follows: A solution of hydrogen peroxide (2 mL) in methanol or water was
added dropwise to a solution of compound 1 (1.0 mmol) with selenium dioxide