Concise synthesis of 3-arylpiperidines

Article abstract of DOI:10.3987/COM-06-10717

We present an easy and straightforward synthesis of 3-arylpiperidines by Grignard addition of piperidin-3-one with different arylmagnesium bromide reagents and acidic dehydroxylation of the resulting tertiary alcohol with the combination of triethylsilane and boron trifluoride etherate. This facile strategy was further used to synthesize preclamol. A highly regioselective dehydration of 3-arylpiperidin-3-ol with boron trifluoride etherate was investigated for preparing 3-aryl-1,4,5,6-tetrahydropyridine skeleton. A novel selenium dioxide mediated dihydroperoxidation of 3-aryl-1,4,5,6-tetrahydropyridine was also examined.

Full text of DOI:10.3987/COM-06-10717

HETEROCYCLES, Vol. 68, No. 6, 2006
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HETEROCYCLES, Vol. 68, No. 6, 2006, pp. 1173 - 1183. © The Japan Institute of Heterocyclic Chemistry
Received, 2nd March, 2006, Accepted, 10th April, 2006, Published online, 11th April, 2006. COM-06-10717
CONCISE SYNTHESIS OF 3-ARYLPIPERIDINES
Meng-Yang Chang,*,a Ru-Ting Hsu,b Hua-Ping Chena and Pei-Jung Lina
aDepartment of Applied Chemistry, National University of Kaohsiung,
b
Kaohsiung 811, Taiwan. Department of Nursing, Shu-Zen College of Medicine
and Management, Kaohsiung 821, Taiwan. Email: mychang@nuk.edu.tw
Abstract – We present an easy and straightforward synthesis of 3-arylpiperidines
by Grignard addition of piperidin-3-one with different arylmagnesium bromide
reagents and acidic dehydroxylation of the resulting tertiary alcohol with the
combination of triethylsilane and boron trifluoride etherate. This facile strategy
was further used to synthesize preclamol. A highly regioselective dehydration of
3-arylpiperidin-3-ol with boron trifluoride etherate was investigated for preparing
3-aryl-1,4,5,6-tetrahydropyridine skeleton. A novel selenium dioxide mediated
dihydroperoxidation of 3-aryl-1,4,5,6-tetrahydropyridine was also examined.
1. INTRODUCTION
3-Arylpiperidines have been investigated since the early 1980s in view of their therapeutic dopaminergic
activities.1-2 The most active of these compounds is 3-(3-hydroxyphenyl)-N-propylpiperidine (3-PPP,
preclamol),3-4 reported to be the first selective D2-like dopamine autoreceptor agonist.4 The N-propyl
substituent has been suggested to be the most effective substitutions among several 3-arylpiperidines with
different substituents on the aromatic ring.5 These potent dopaminergic substances could be effective
antipsychotic agents with therapeutic effect in the treatment of schizophrenia and Parkinson’s disease.
Due to its biological and pharmacological importance, there have been several reports on the synthesis of
preclamol and the related analogs.3
R'
OH
N
R
N
3-arylpiperidines
3-PPP
Figure 1. Structures of 3-arylpiperidines and 3-PPP

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2. RESULTS AND DISCUSSION
2.1. Synthesis of 3-arylpiperidines
Very recently we reported the preparation of 4-aryl-1,2,5,6-tetrahydropyridines from 4-hydroxypiperidine
and explored the related applications in the synthesis of racemic coerulescine, horsfiline, baclofen and
fluoxetine.6 To demonstrate the synthetic utility of the methodology and continue our investigation on the
application of this approach, we describe an easy and straightforward synthesis of 3-arylpiperidines (1)
from piperidin-3-ones via two simple steps as illustrated in Scheme 1.
O
Ar
Ar
(2) Et3SiH, BF3-OEt2
(two-step yield)
(1) ArMgBr, THF
OH
N
R
N
R
N
R
R=Ms
3Aa, C6H5
3Ab, 3-MeOC6H4
3Ac, 4-MeOC6H4
R=Ts
3Ba, C6H5
3Bb, 3-MeOC6H4
3Bc, 4-MeOC6H4
2A, R=Ms
2B, R=Ts
1Aa, (90%); 1Ba, (86%)
1Ab, (88%); 1Bb, (86%)
1Ac, (85%); 1Bc, (84%)
1Ad, (82%); 1Bd, (83%)
3Ad, 3,4-CH2O2C6H3 3Bd, 3,4-CH2O2C6H3
Scheme 1. Synthesis of 3-arylpiperidines (1Aa~1Ad and 1Ba~1Bd)
For the preparation of different 3-arylpiperidines (1), the starting materials piperidin-3-ones (2A and 2B)
were respectively obtained by mesylation or tosylation of commercially available 3-hydroxypiperidine
with mesyl chloride or tosyl chloride and triethylamine in dichloromethane and followed by Jones
oxidation of the resulting sulfonyl alcohol in acetone. Next, there are two remarkable transformations
were further examined. One is the rapid access to produce a wide variety of 3-arylpiperidin-3-ols (3) by
Grignard addition of piperidin-3-ones (2A, R=Ms; 2B, R=Ts) with different arylmagnesium bromide
reagents (a, Ar=C6H5; b, Ar=3-MeOC6H4; c, Ar=4-MeOC6H4; d, Ar=3,4-CH2O2C6H3) in tetrahydrofuran
o
at -78 C. The other is the acidic dehydroxylation of 3-arylpiperidin-3-ols (3) with triethylsilane and
boron trifluoride etherate at room temperature. The two-step synthesis of 3-arylpiperidines (1) was
provided in 82~90% yields. Two synthetic procedures were monitored by TLC until the reaction was
completed. The overall simple procedure was achieved within one working day.
2.2. Synthesis of 3-aryl-1,4,5,6-tetrahydropyridines
We had also tried to study the synthesis of 3-alkylpiperidine by the acidic dehydroxylation. The model
substrate 3-methyl-1-tosylpiperidin-3-ol was treated with the combination of triethylsilane and boron
trifluoride etherate, but the desired 3-methyl-1-tosylpiperidine was provided in only 35% yield. The
1
unexpected major product was an inseparated olefinic mixture. By H NMR spectral analysis, the
3-methyl-1,4,5,6-tetrahydropyridine was produced as the major product accompanied with a trace amount
of 3-methyl-1,2,5,6-tetrahydropyridine in ca. 8:1 ratio (Eq. 1).

HETEROCYCLES, Vol. 68, No. 6, 2006
1175
Et3SiH, BF3-OEt2
+
OH
[Eq. 1]
N
N
N
Ts
Ts
Ts
H2, 10% Pd/C
(46%)
(35%)
Equation 1. Reaction of 3-methyl-1-tosylpiperidin-3-ol with boron trifluoride etherate
With this result in hand, direct hydrogenation of the resulting olefinic mixture with hydrogen and a
catalytic amount of 10% palladium on activated carbon was achieved to 3-methylpiperidine in nearly
quantitative yield. Therefore the synthesis of 3-alkylpiperidine was accomplished from piperidin-3-one (2)
via the Grignard addition, dehydration (and dehydroxylation), and hydrogenation. In comparison with the
3-substituted piperidin-3-ol between alkyl and aryl group, we believe the 3-aryl functional group is an
important factor and provides a stable benzylic radical in the acidic dehydroxylation process. While
poring over the related literature of the dehydration conditions,7 we found that 3-substituted
1,2,5,6-tetrahydropyridine was usually provided as the major or sole product by various acidic reagents,
such as p-toluenesulfonic acid, p-toluenesulfonic acid on silica gel, acetic acid/acetyl chloride, oxalic acid,
trifluoroacetic acid, and thionyl chloride.7 Among these acid-mediated dehydration reports, we only found
that Sui’s unique synthetic strategy was similar to our results.8
These interesting reports triggered our attention to further examine the dehydration of 3-aryl group of
piperidin-3-ol skeleton (3). As shown in Scheme 2, 3-aryl-1,4,5,6-tetrahydropyridines (4) were yielded as
the sole products by treatment of 3-arylpiperidin-3-ols with boron trifluoride etherate in dichloromethane
at room temperature. The related mechanism and differences between 3-aryl and 3-alkyl group were not
clear.8 Here we developed a novel dehydration condition with the high regioselectivity by an appropriate
Lewis acid for synthesizing 1,4,5,6-tetrahydropyridine skeleton. To our best knowledge, the Lewis
acid-catalyzed regioselective dehydration reaction of 3-arylpiperidin-3-ol with high yield had not been
reported in the literature. The formed structural framework (4) was useful building block for the
preparation of natural products and pharmaceutical compounds with potential biological activities.8,9 The
present synthetic work is complementary to existing methodology.
Ar
Ar
BF3-OEt2, DCM
OH
N
R
N
R
3Aa, R=Ms, Ar=C6H5
3Ad, R=Ms, Ar=3,4-CH2O2C6H3
3Ba, R=Ts, Ar=C6H5
4Aa, (91%)
4Ad, (82%)
4Ba, (89%)
4Bc, (88%)
3Bc, R=Ts, Ar=4-MeOC6H4
Scheme 2. Synthesis of 3-aryl-1,4,5,6-tetrahydropyridines (4Aa, 4Ad, 4Ba, and 4Bc)

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2.3. Synthesis of 3-aryl-1-propylpiperidines
Because of the importance of N-propyl substituent on the 3-arylpiperidine skeleton, we turn our attention
to change the 1-substituent as the propyl group.5 Unfortunately, the desired 1-propylpiperidin-3-one was
afforded in very low yield by treatment of 1-propylpiperidin-3-ol with different oxidants. In order to
achieve the synthesis of 3-aryl-1-propylpiperidines (5), we used N-sulfonyl group in place of N-propyl
group as shown in Scheme 3. With the enough amounts of 3-arylpiperidines (1), the conversion was
achieved though the desulfonation with sodium amalgam in methanol and followed by in situ propylation
of the resultant desulfonated 3-arylpiperidine with propionaldehyde and sodium cyanoborohydride. The
3-(3-methoxyphenyl)-1-propylpiperidine (5b) was a key intermediate in the preparation of preclamol.
Compound (5b) was treated with 48% hydrogen bromide to yield the preclamol.3k A new and facile
strategy for the synthesis of preclamol from 3-hydroxypiperidine was provided.
Ar
Ar
1) Na/Hg, MeOH
N
R
N
2) CH3CH2CHO, NaCNBH3
1Aa~1Ac
and
1Ba~1Bc
5a, Ar=C6H5 (66%);
5b, Ar=3-MeOC6H4 (62%);
5c, Ar=4-MeOC6H4 (58%)
Scheme 3. Synthesis of 3-aryl-1-n-propylpiperidines (5a, 5b and 5c)
2.4. Synthesis of 2,3-bis-tert-butylperoxy-3-phenylpiperidine
In order to investigate the other applications of the 3-aryl-1,4,5,6-tetrahydropyridine skeleton (4), allylic
oxidation was next chosen to examine. When treatment of 3-phenyl-1,4,5,6-tetrahydropyridines10 (4Aa,
R=Ms; 4Ba, R=Ts) with selenium dioxide and tert-butyl hydroperoxide (TBHP) in dichloromethane, the
unexpected 2,3-bis-tert-butylperoxy-3-phenylpiperidines (6A and 6B) were generated as the major
products in only 16% and 24% yield (Scheme 4). We reported the novel selenium dioxide mediated
dihydroperoxidation reaction of 3-phenyl-1,4,5,6-tetrahydropyridines (4Aa and 4Ba). The structure of
compound (6B) was determined by single-crystal X-Ray analysis as shown in diagram 1.
TBHP, SeO2
O O
N
R
PHCO2H, DCM
N
R
O
O
4Aa, R=Ms
4Ba, R=Ts
6A, (16%)
6B, (24%)
Scheme 4. Synthesis of 2,3-bis-tert-butylperoxy-3-phenylpiperidines (6A and 6B)

HETEROCYCLES, Vol. 68, No. 6, 2006
1177
Diagram 1. X-Ray crystallography of compound (6B)
According to the X-Ray structural analysis, two tert-butyl hydroperoxy groups were arranged as the trans
configuration. We had also tried to study the other compounds (4Ad and 4Bd) with the electron-donating
group, but the predicted products were provided in trace yields (<5%) under the above reaction conditions.
To improve the poor reaction condition, the model substrate 3-phenyl-1,4,5,6-tetrahydropyridine (4Aa)
was treated with other commercial available reagents (e.g. m-chloroperoxybenzoic acid and dibenzoyl
peroxide). The unsuccessful reaction was still obtained under the similar conditions. Although the
synthetic application is decreased, the present work is novel and interesting methodology. How is the
dihydroperoxidation reaction of compounds (4Aa and 4Ba) initiated by selenium dioxide in
dichloromethane? However, the initial event may be considered to be the formation of the intermediate (I)
from selenium dioxide and excess tert-butyl hydroperoxide.11 Mechanically it is not clear if the reaction
follows the same pathway as shown in Scheme 5.
O
O
O
O
O Se
Ph
Ph
O
O O
Se
O O
N
R
N
R
4
Ph
Ph
Ph
O O
O
O
O
O
O
N
R
Se
N
R
O
N
R
O
O
O
O
O
6
Scheme 5. The possible mechanism of dihydroperoxidation reaction by selenium dioxide

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3. CONCLUSION
In summary, we developed a facile and straightforward methodology to synthesize two building blocks
3-arylpiperidines and 3-aryl-1,4,5,6-tetrahydropyridines. For the application and investigation of
piperidin-3-one, a new synthetic study toward preclamol was also reported. We are currently studying the
related application of the dihydroperoxidation reaction by selenium dioxide.
4. EXPERIMENTAL
4.1. General. Tetrahydrofuran (THF) was distilled prior to use from a deep-blue solution of
sodium-benzophenone ketyl. All other reagents were obtained from commercial sources and used without
further purification. Reaction was routinely carried out under an atmosphere of dry nitrogen with
magnetic stirring. Extract was dried with anhydrous magnesium sulfate before concentration in vacuo.
Crude product was purified using column chromatography on silica gel.
4.2. A representative procedure of compounds (1) is as follows: A solution of arylmagnesium bromide
(3.3 mmol) in tetrahydrofuran (10 mL) was added to a stirred solution of 1-mesyl or 1-tosyl
piperidin-3-one (2A and 2B) (2.0 mmol) in tetrahydrofuran (20 mL) at -78 oC. The reaction mixture was
stirred at room temperature for 2 h. Water (5 mL) was added to the reaction mixture and the mixture was
filtered through a short plug of Celite. The filtrate was concentrated under reduced pressure. The residue
was extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried,
filtered and evaporated to afford crude product under reduced pressure. Without further purification,
boron trifluoride etherate (1 mL) was added to a stirred solution of the crude product and triethylsilane (2
mL) in dichloromethane (2 mL) at rt. The reaction mixture was stirred at 0 oC for 4 h. Saturated sodium
bicarbonate solution (5 mL) was added to the reaction mixture and the solvent was concentrated under
reduced pressure. The residue was extracted with ethyl acetate (3 x 50 mL). The combined organic layers
were washed with brine, dried, filtered and evaporated to afford crude product. Purification on silica gel
(hexane/ethyl acetate = 4/1~2/1) afforded compounds (1Aa~1Ad and 1Ba~1Bd). Representative data for
1
compound (1Aa): HRMS (ESI, M++1) calcd for C12H18NO2S 240.1058, found 240.1060; H NMR (300
MHz, CDCl3) δ 7.39-7.22 (m, 5H), 3.95-3.81 (m, 2H), 2.96-2.82 (m, 1H), 2.80 (s, 3H), 2.67-2.60 (m, 2H),
2.11-1.48 (m, 4H); 13C NMR (75 MHz, CDCl3) δ 142.68, 128.90 (2x), 127.37 (2x), 127.28, 52.69, 46.47,
42.50, 34.87, 30.95, 25.27. For compound (1Ab): HRMS (ESI, M++1) calcd for C13H20NO3S 270.1164,
1
found 270.1168; H NMR (300 MHz, CDCl3) δ 6.82-6.76 (m, 4H), 3.89-3.78 (m, 2H), 3.79 (s, 3H),
2.90-2.76 (m, 1H), 2.79 (s, 3H), 2.71-2.60 (m, 2H), 2.07-1.53 (m, 4H); 13C NMR (75 MHz, CDCl3)
δ 160.01, 144.33, 129.88, 119.67, 113.43, 112.28, 55.46, 52.60, 46.46, 42.52, 34.85, 30.95, 25.45. For
1
compound (1Ac): H NMR (300 MHz, CDCl3) δ 7.18 (d, J = 8.1 Hz, 2H), 6.84 (d, J = 8.1 Hz, 2H),

HETEROCYCLES, Vol. 68, No. 6, 2006
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3.89-3.79 (m, 2H), 3.80 (s, 3H), 2.84-2.78 (m, 1H), 2.80 (s, 3H), 2.72-2.53 (m, 2H), 2.09-1.58 (m, 4H);
13C NMR (75 MHz, CDCl3) δ 158.75, 134.77, 128.30 (2x), 114.24 (2x), 55.51, 52.92, 46.44, 41.62, 34.83,
31.11, 25.52. For compound (1Ad): HRMS (ESI, M++1) calcd for C13H18NO4S 284.0957, found
1
284.0960; H NMR (300 MHz, CDCl3) δ 6.67-6.62 (m, 3H), 5.91 (s, 2H), 3.83-3.78 (m, 2H), 2.88-2.56
(m, 3H), 2.78 (s, 3H), 2.03-1.44 (m, 4H); 13C NMR (75 MHz, CDCl3) δ 147.98, 146.62, 136.60, 120.38,
108.60, 107.72, 101.23, 52.86, 46.40, 42.24, 34.86, 31.23, 25.47. For compound (1Ba): HRMS (ESI,
1
M++1) calcd for C18H22NO2S 316.1371, found 316.1375; H NMR (300 MHz, CDCl3) δ 7.63 (d, J = 8.1
Hz, 2H), 7.36-7.18 (m, 7H), 3.91-3.81 (m, 2H), 2.95-2.82 (m, 1H), 2.44 (s, 3H), 2.37-2.17 (m, 2H),
1.98-1.72 (m, 3H), 1.50-1.35 (m, 1H); 13C NMR (75 MHz, CDCl3) δ 143.78, 142.86, 133.38, 129.95 (2x),
128.85 (2x), 127.92 (2x), 127.44 (2x), 127.20, 52.94, 46.68, 42.38, 30.72, 25.27, 21.80. For compound
1
(1Bb): HRMS (ESI, M++1) calcd for C19H24NO3S 346.1477, found 346.1481; H NMR (300 MHz,
CDCl3) δ 7.64 (d, J = 8.1 Hz, 2H), 7.37-7.20 (m, 3H), 6.80-6.65 (m, 3H), 3.92-3.81 (m, 2H), 3.78 (s, 3H),
2.90-2.78 (m, 1H), 2.43 (s, 3H), 2.36-2.20 (m, 2H), 1.97-1.73 (m, 3H), 1.51-1.36 (m, 1H); 13C NMR (75
MHz, CDCl3) δ 159.94, 144.51, 143.80, 133.40, 129.95 (2x), 127.95 (2x), 127.89, 119.78, 113.54, 112.15,
55.46, 52.87, 46.68, 42.40, 30.69, 25.22, 21.78. For compound (1Bc): HRMS (ESI, M++1) calcd for
C19H24NO3S 346.1477, found 346.1479; 1H NMR (300 MHz, CDCl3) δ 7.58 (d, J = 8.1 Hz, 2H), 7.26 (d,
J = 8.1 Hz, 2H), 7.02 (d, J = 8.4 Hz, 2H), 6.78 (d, J = 8.4 Hz, 2H), 3.89-3.78 (m, 2H), 3.78 (s, 3H),
2.80-2.73 (m, 1H), 2.39 (s, 3H), 2.22-2.03 (m, 2H), 1.94-1.68 (m, 3H), 1.41-1.26 (m, 1H); 13C NMR (75
MHz, CDCl3) δ 158.69, 143.64, 134.95, 133.43, 129.85 (2x), 128.33 (2x), 127.92 (2x), 114.16 (2x), 55.50,
53.17, 46.62, 41.48, 30.85, 25.29, 21.77. For compound (1Bd): HRMS (ESI, M++1) calcd for
C19H22NO4S 360.1270, found 360.1271; 1H NMR (300 MHz, CDCl3) δ 7.57 (d, J = 8.1 Hz, 2H), 7.25 (d,
J = 8.1 Hz, 2H), 6.65-6.48 (m, 3H), 5.88 (s, 2H), 3.80-3.73 (m, 2H), 2.80-2.69 (m, 1H), 2.38 (s, 3H),
2.21-2.03 (m, 2H), 1.89-1.63 (m, 3H), 1.36-1.19 (m, 1H); 13C NMR (75 MHz, CDCl3) δ 147.93, 146.57,
143.68, 136.79, 133.42, 129.88 (2x), 127.91 (2x), 120.47, 108.56, 107.72, 101.20, 53.11, 46.60, 42.10,
31.03, 25.24, 21.77.
4.3. A representative procedure of compounds (4) is as follows: A solution of boron trifluoride
etherate (0.5 mL) in dichloromethane (2 mL) was added to a stirred solution of compounds (3Aa, 3Ad,
o
o
3Ba and 3Bc) (1.0 mmol) in dichloromethane (10 mL) at 0 C. The reaction mixture was stirred at 0 C
for 1 h. Saturated sodium bicarbonate solution (5 mL) was added to the reaction mixture and the solvent
was concentrated under reduced pressure. The residue was extracted with ethyl acetate (3 x 30 mL). The
combined organic layers were washed with brine, dried, filtered and evaporated to afford crude products
under reduced pressure. Purification on silica gel (hexane/ethyl acetate = 5/1) afforded compounds (4Aa,
4Ad, 4Ba and 4Bc). Representative data for compound (4Aa): HRMS (ESI, M++1) calcd for C12H16NO2S

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238.0902, found 238.0905; 1H NMR (300 MHz, CDCl3) δ 7.42-7.21 (m, 5H), 7.02 (s, 1H), 3.65-3.58 (m,
2H), 2.92 (s, 3H), 2.56-2.43 (m, 2H), 2.14-2.02 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 139.68, 128.79
(2x), 126.95, 124.73 (2x), 121.92, 119.35, 43.81, 37.83, 24.08, 21.86. For compound (4Ad): HRMS (ESI,
1
M++1) calcd for C13H16NO4S 282.0800, found 282.0802; H NMR (300 MHz, CDCl3) δ 6.92-6.75 (m,
4H), 5.94 (s, 2H), 3.59-3.52 (m, 2H), 2.89 (s, 3H), 2.43-2.37 (m, 2H), 2.08-1.96 (m, 2H); 13C NMR (75
MHz, CDCl3) δ 134.14, 121.12 (2x), 119.29, 118.20 (2x), 108.46, 105.43, 101.29, 43.74, 37.76, 24.47,
1
21.86. For compound (4Bc): HRMS (ESI, M++1) calcd for C19H22NO3S 344.1320, found 344.1323; H
NMR (300 MHz, CDCl3) δ 7.72 (d, J = 8.1 Hz, 2H), 7.36 (d, J = 8.1 Hz, 2H), 7.30 (d, J = 8.4 Hz, 2H),
7.09 (s, 1H), 6.88 (d, J = 8.4 Hz, 2H), 3.80 (s, 3H), 3.43-3.38 (m, 2H), 2.41 (s, 3H), 2.38-2.30 (m, 2H),
1.85-1.76 (m, 2H).
4.4. A representative procedure of compounds (5) is as follows: 6% Sodium amalgam (Na/Hg, 1.0 g)
and sodium phosphate (355 mg, 2.5 mmol) were added to a stirred solution of compounds (1Aa~1Ac and
1Ba~1Bc) (1.0 mmol) in methanol (15 mL) at room temperature. The reaction mixture was vigorously
stirred at rt for 2 h. The residue was filtered and washed with methanol (2 x 10 mL). The combined
organic layers were washed with brine, dried, filtered and evaporated to afford crude product under
reduced pressure. Without further purification, sodium cyanoborohydride (80 mg, 2.0 mmol) was added
to a solution of the resulting amine and n-propylaldehyde (120 mg, 2.0 mmol) in the co-solvent of
tetrahydrofuran and methanol (10 mL, v/v=1/1) at rt. The reaction mixture was stirred for 18 h at rt.
Saturated sodium bicarbonate solution (1 mL) was added to the reaction mixture and the solvent was
concentrated under reduced pressure. The residue was extracted with ethyl acetate (3 x 30 mL). The
combined organic layers were washed with brine, dried, filtered and evaporated to afford crude product
under reduced pressure. Purification on silica gel (hexane/ethyl acetate = 1/1) afforded compounds
(5a~5c). Representative data for compound (5a): HRMS (ESI, M++1) calcd for C14H22N 204.1752, found
1
204.1753; H NMR (400 MHz, CDCl3) δ 7.30-7.26 (m, 2H), 7.23-7.17 (m, 3H), 3.06-2.99 (m, 2H), 2.85
(tt, J = 3.5, 11.7 Hz, 1H), 2.36-2.31 (m, 2H), 2.02-1.90 (m, 3H), 1.79-1.72 (m, 2H), 1.58-1.39 (m, 3H),
0.88 (t, J = 7.4 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 144.67, 128.37 (2x), 127.30 (2x), 126.35, 61.17,
61.07, 53.82, 42.73, 31.54, 25.62, 19.87, 12.00. For compound (5b): HRMS (ESI, M++1) calcd for
C15H24N 234.1858, found 234.1861; 1H NMR (400 MHz, CDCl3) δ 7.20 (t, J = 7.9 Hz, 1H), 6.82-6.72 (m,
3H), 3.78 (s, 3H), 3.07-3.01 (m, 2H), 2.88 (t, J = 11.6 Hz, 1H), 2.38-2.34 (m, 2H), 2.04-1.91 (m, 3H),
1.81-1.77 (m, 2H), 1.60-1.40 (m, 3H), 0.89 (t, J = 7.4 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 159.68,
146.68, 129.36, 119.60, 113.27, 111.50, 60.99, 60.93, 55.16, 53.81, 42.61, 31.43, 25.42, 19.73, 11.94.
HRMS (ESI, M++1) calcd for C15H24N 234.1858, found 234.1861; 1H NMR (400 MHz, CDCl3) δ 7.12 (d,
J = 8.7 Hz, 2H), 6.82 (d, J = 8.7 Hz, 2H), 3.75 (s, 3H), 3.12-3.08 (m, 2H), 2.91 (tt, J = 3.3, 11.9 Hz, 1H),

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2.45-2.39 (m, 2H), 2.09-1.99 (m, 2H), 1.93-1.77 (m, 3H), 1.61-1.53 (m, 2H), 1.48-1.38 (m, 1H), 0.88 (t, J
13
= 7.4 Hz, 3H); C NMR (100 MHz, CDCl3) δ 158.25, 135.97, 128.06, 113.88 (3x), 60.68, 60.57, 53.43,
41.07, 31.26, 30.04, 24.94, 19.19, 11.86.
4.5. A representative procedure of compounds (6) is as follows: Selenium dioxide (60 mg, 0.54 mmol)
and tert-butyl hydroperoxide (70% in water, 100 mg, 0.78 mmol) were added to a stirred solution of
compounds (4Aa and 4Ba) (0.32 mmol) and benzoic acid (100 mg, 0.82 mmol) in dichloromethane (10
mL) at room temperature. The reaction mixture was vigorously stirred at refluxed temperature for 10 h.
Saturated sodium bicarbonate solution (5 mL) was added to the reaction mixture and the solvent was
concentrated under reduced pressure. The residue was extracted with ethyl acetate (3 x 30 mL). The
combined organic layers were washed with brine, dried, filtered and evaporated to afford crude product
under reduced pressure. Purification on silica gel (hexane/ethyl acetate = 4/1) afforded compounds (6A
o
and 6B). Representative data for compound (6B): mp 149-151 C (hexane/ethyl acetate); HRMS (ESI,
1
M++1) calcd for C26H38NO6S 492.2420, found 492.2422; H NMR (500 MHz, CDCl3) δ 7.88 (d, J = 8.5
Hz, 2H), 7.54 (d, J = 7.5 Hz, 2H), 7.35 (t, J = 7.5 Hz, 2H), 7.28 (d, J = 7.5 Hz, 1H), 7.23 (d, J = 7.5 Hz,
2H), 5.73 (s, 1H), 3.46 (dd, J = 2.5, 13.0 Hz, 1H), 3.15 (td, J = 2.5, 13.0 Hz, 1H), 2.43-2.39 (m, 1H), 2.39
(s, 3H), 2.20-2.07 (m, 2H), 1.57-1.54 (m, 1H), 1.22 (s, 9H), 0.83 (s, 9H); 13C NMR (125 MHz, CDCl3) δ
142.58, 141.82, 138.30, 129.07 (2x), 127.80 (2x), 127.48 (2x), 127.32, 126.91 (2x), 87.48, 81.10, 79.72,
79.49, 39.37, 26.62 (3x), 25.85 (3x), 24.98, 21.40, 20.42; Anal. Calcd for C26H37NO6S C, 63.52; H, 7.09;
N, 2.85. Found C, 63.36; H, 7.13; N, 3.01. Single-crystal X-Ray diagram: crystal of compound (6B) was
grown by slow diffusion of ethyl acetate into a solution of compound (6B) in dichloromethane to yield
colorless prism. The compound crystallizes in the monoclinic crystal system, space group P21/c(No. 14),
a=10.472(2) Å, b=29.329(6) Å, c=8.9052(18) Å, V=2719.9(9) Å3, Z=4, dcalcd=1.201 g/cm3, F(000)=1056,
2θ range 1.96~26.01o, R indices (all data) R1 = 0.1674, wR2 = 0.1428.
ACKNOWLEDGEMENTS
The authors would like to thank the National Science Council (NSC 94-2113-M-390-001) of the Republic
of China for financial support. We also thank Prof. Michael Y. Chiang (National Sun Yat-Sen University)
for structural determination of compound (6B) by X-Ray diffraction analysis.
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