Synthesis of tetrahydrobenzoisoquinolinols, tetrahydropyrindines, and hexahydroquinolines from 4-aryltetrahydropyridines

Article abstract of DOI:10.1016/j.tet.2011.04.089

A straightforward synthesis of tetrahydrobenzoisoquinolinols 2, tetrahydropyrindines 3, and hexahydroquinolines 4 from versatile intermediate 6 is reported. Two key transformations were carried out by intramolecular Friedel-Crafts cyclization and ring-clo

Full text of DOI:10.1016/j.tet.2011.04.089

Tetrahedron 67 (2011) 4552e4558
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Synthesis of tetrahydrobenzoisoquinolinols, tetrahydropyrindines, and
hexahydroquinolines from 4-aryltetrahydropyridines
*
Meng-Yang Chang , Ming-Fang Lee, 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:
Received 3 March 2011
Received in revised form 17 April 2011
Accepted 22 April 2011
Available online 5 May 2011
A straightforward synthesis of tetrahydrobenzoisoquinolinols 2, tetrahydropyrindines 3, and hexahy-
droquinolines 4 from versatile intermediate 6 is reported. Two key transformations were carried out by
intramolecular FriedeleCrafts cyclization and ring-closing metathesis in moderate yields. Skeleton 6 was
easily prepared from the known starting material 4-aryl-4-methoxypiperidin-3-ones 7 via Wittig ole-
fination with Ph3P¼CHCO2Et, deconjugation with 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), and boron
trifluoride etherate (BF3eOEt2)-catalyzed addition of the corresponding iminium ion with
allyltrimethylsilane.
Keywords:
Tetrahydrobenzoisoquinolinols
Tetrahydropyrindines
Hexahydroquinolines
FriedeleCrafts cyclization
Ring-closing metathesis
Ó 2011 Elsevier Ltd. All rights reserved.
1. Introduction
group into vinyl, allyl, and carboxylate group is indeed expected to
shorten the syntheses of targets by utilizing simple synthetic
The importance of heterocycles with nitrogen-containing
functional groups in natural and synthetic products has stimu-
lated the development of efficient methodologies.1 Recently, we
have introduced a straightforward approach for synthesizing dia-
rylhexahydrobenzo[f]isoquinolines 5 with a 3-azadecalin system
via the rearrangement reaction from the structural skeleton of
4-aryl-1,2,5,6-tetrahydropyridines 1.2 To demonstrate the synthetic
application of 4-aryl-1,2,5,6-tetrahydropyridines 1, the synthetic
strategies for tetrahydrobenzo[f]isoquinolinols 2,3 tetrahydropyr-
indines 3,4 and hexahydroquinolines 45 were investigated. The
synthetic strategy of skeletons 2, 3, and 4 was shown in Fig. 1.
transformation without the protecting group manipulation.
As shown in Scheme 1, skeleton 6 was provided from skeleton 8
via deconjugation and Lewis acid-promoted the intermolecular
addition with allyltrimethylsilane in 50e65% overall yield of two-
steps, respectively. Therefore, an easy five-step synthetic step of
skeleton 8 from skeleton 1 (P¼Bs, Ar¼a, Ph; b, 4-FPh; c, 3-CF3Ph; d,
3-CF3-4-ClPh; P¼Ms e, Ph) involves: (1) selenium dioxide-
mediated trans-methoxyhydroxylation reaction of skeleton 1 with
hydrogen peroxide in methanol; (2) Jones oxidation of the resulting
secondary methoxyalcohol; (3) Wittig olefination of ketone 7; (4)
deconjugation of skeleton 8 with 1,8-diazabicyclo[5.4.0]undec-7-
ene, and (5) a boron trifluoride etherate-promoted addition of the
corresponding iminium ion with allyltrimethylsilane.2b,c The 3-ac-
etate functional group plays an important role to allow the different
carbonecarbon bond formation as a useful activating arm. The
structure of compound 6a was determined using single-crystal
X-ray analysis.6
With the skeleton 6 in hand, synthesis of skeleton 2 was ex-
amined. The intramolecular FriedeleCrafts cyclization was chosen
as the key step to produce skeleton 2 with tricyclic ring system.7 As
shown in Scheme 2, compound 2a or 2b was isolated in 40% and
35% yield of three-steps by (i) hydrolysis of skeleton 6 with aqueous
sodium hydroxide solution (2 N) at reflux for 10e15 h, (ii) acylation
of the corresponding acid with thionyl chloride at reflux temper-
ature for 10e15 h, and (iii) intramolecular FriedeleCrafts cycliza-
tion and with aluminum trichloride in dichloromethane for 2e3 h,
2. Results and discussion
These styrene-type substructures have been synthesized from
various sources, and some of them show interesting biological
activities.3e5 These moieties are also important part of other more
complex products. Considering the molecular diversity of target
skeletons 2, 3, and 4 using the versatile intermediate 6 is a major
challenge. Functionalization of the acetate group at C-3 position of
intermediate 6 is probably one of the most promising strategies
toward this purpose. The direct introduction of acetate functional
* Corresponding author. Tel.: þ886 7 3121101x2220; e-mail address: mychang@
kmu.edu.tw (M.-Y. Chang).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.04.089

M.-Y. Chang et al. / Tetrahedron 67 (2011) 4552e4558
4553
Ar
Ph
(ref. 1)
Ar
OMe
O
Ar
OMe
Ph
1) SeO , H O
Ar = Ph, 4-FPh, 3-CF Ph
3
2
2
2
Ph P=CHCO Et
CO Et
2
3
2
3-CF -4-ClPh
3
H
2) Jones ox.
P = SO Ph, SO Me
2 2
N
P
N
P
N
P
N
P
5
1
7
8
1) DBU, THF
2) BF -OEt ,
allylTMS, DCM
Ar
3
2
R
ring-closing metathesis
Ar = Ph, 3-CF Ph
3
P = SO Ph
2
N
S
Ph
OH
Ar
CO Et
2
3
3
O
O
Friedel-Crafts acylation
Ar = Ph, 4-FPh
P = SO Ph
2
Ar
N
N
P
ring-closing metathesis
2
6
S
Ph
Ar = Ph, 3-CF -4-ClPh
3
O
O
P = SO Ph
2
N
S
Ph
versatile intermediate
with C-3 acetate group
4
O
O
Fig. 1. Synthetic strategy toward tetrahydrobenzoisoquinolinols 2, tetrahydropyrindines 3, and hexahydroquinolines 4.
bicyclic ring system.8 As shown in Scheme 3, skeleton 3 (Ar¼a, Ph;
b, 3-CF3Ph) were prepared using the simple four-steps protocol and
are described as follows: (i) by reduction of ester 6 with lithium
aluminum hydride at rt for 2e3 h; (ii) mesylation of alcohol 9 with
mesyl chloride in pyridine at rt for 10e12 h; (iii) 1,8-diazabicyclo
[5.4.0]undec-7-ene-promoted elimination of mesylate 10 at reflux
for 10e12 h; and (iv) ring-closing metathesis of skeleton 11 with
the second generation Grubbs’ catalyst at reflux for 1e2 h. Skeleton
3 exhibited a conformationally restricted character of s-trans dienyl
conformer.
R
1
R
2
R
2
R
1
OMe
1) DBU, THF
CO Et
CO Et
2
2
2) BF -OEt , allylTMS,
3
2
N
P
N
P
DCM
P = SO Ph
P = SO Ph
2
2
8a, R = R = H
6a, R = R = H (56%)
1 2
1
2
Ar
CO Et
Ar
Ar
2
8b, R = F, R = H
6b, R = F, R = H (60%)
1 2
1
2
2
2
OH
OMs
8c, R = H, R = CF
6c, R = H, R = CF (65%)
1 2 3
MsCl,
LAH, THF
1
3
3
8d, R = Cl, R = CF
6d, R = Cl, R = CF (50%)
1
1 2 3
P = SO Me
P = SO Me
pyridine
2
2
N
S
Ph
N
S
Ph
N
S
Ph
8e, R = R = H
6e, R = R = H (61%)
1 2
1
2
O
O
O
O
O
O
Scheme 1. Synthesis of skeleton 6.
6a, Ar = Ph
9a (78%)
9b (80%)
10a (82%)
10b (75%)
6d, Ar = 3-CF Ph
3
followed by a tautomeric aromaticity. This experimental procedure
offers a general and efficient alternative to the intramolecular
FriedeleCrafts cyclization. According to literature report, an ex-
tended conjugation at C-4 position of benzo[f]isoquinoline skeleton
can possess some potential biological activity.3aꢀc The allyl func-
tional group is a key ingredient in many therapeutic agents,3a as
important bioactive components in pharmaceutical research.
Ar
Ar
nd
Grubbs 2 cat.
DBU, THF
N
S
N
S
Ph
3a (59%)
3b (70%)
(CH Cl)
2
2
O
O
O
O
Ph
11a (75%)
11b (82%)
Scheme 3. Synthesis of tetrahydropyrindines 3.
R
R
1
1
R
R
2
2
When skeleton 11 was subjected to a ring-closing metathesis
reaction employing first generation Grubbs’ catalyst, the expected
bicyclic skeleton 3 was generated in low yield (for 3a, 19%; for 3b,
13%) under a number of conditions (prolonged reaction time, ele-
vated temperature, different solvents). The ring strain existed in the
desired bicyclic [4.3.0] product might retard the normally facile
intramolecular annulation. The amino group in the piperidine ring
might potentially chelate the metal center of the first generation
Grubbs’ catalyst to form unproductive complex. Therefore, we next
turn our attention to examine the second generation Grubbs’ cat-
alyst, which has higher thermal stability and lower sensitivity to
double bond migration. Using similar reaction conditions, com-
pound 3a or 3b was obtained as the major product in 59% or 70%
yield, respectively.
OH
CO Et
2
1) 2N NaOH, THF
2) SOCl , DCM
2
N
S
Ph
N
S
Ph
4
3) AlCl , DCM
3
O
O
O
O
6a, R = R = H
6b, R = F, R = H
2a, R = R = H (40%)
2b, R = F, R = H (35%)
1 2
1
2
1
2
1
2
Scheme 2. Synthesis of tetrahydrobenzoisoquinolinols 2.
With the successful results, we further expanded the scope of
the strategy to ring-closing metathesis. Ring-closing metathesis
was chosen as the next key step to produce skeletons 3 or 4 with
Furthermore, synthetic approach of skeleton 4 is similar to
skeleton 3 by the four-step protocol as shown in Scheme 4.

4554
M.-Y. Chang et al. / Tetrahedron 67 (2011) 4552e4558
Aldehydes 12a and b were yielded by reduction of skeleton 6 (Ar¼a,
Ph; b, 3-CF3-4-ClPh) with lithium aluminum hydride, and followed
by PCC-mediated oxidation of alcohol 6. Then, Wittig olefination of
skeleton 12 and ring-closing metathesis of skeleton 13 were pro-
vided skeleton 4. This typical experimental procedure offers
a general and efficient alternative to the ring-closing metathesis.
dioxide (222 mg, 2.0 mmol) in methanol (20 mL) at rt. The reaction
mixture was stirred at reflux temperature 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 (3ꢁ20 mL). The combined organic layers were
washed with brine, dried, filtered, and evaporated to afford crude
product. Jones reagent (3 mL) was added to a solution of the
Ar
CO Et
Ar
Ar
2
resulting crude
a-methoxyalcohol in acetone (15 mL) at rt. The
OH
LAH, THF
PCC, DCM
reaction mixture was stirred at rt for 20 min. Isopropanol (1 mL)
was added to the reaction mixture and the solvent was concen-
trated. The residue was extracted with dichloromethane
(3ꢁ20 mL). The combined organic layers were washed with brine,
dried, filtered, and evaporated to afford crude skeleton 7. Without
further purification, ethyl triphenylphosphoranylidene acetate
(348 mg, 1.0 mmol) was added to a solution of the resulting crude
product in dichloromethane (15 mL). The reaction mixture was
stirred at reflux temperature for 3 h and then the solvent was
concentrated. The reaction mixture was extracted with dichloro-
methane (3ꢁ15 mL). The combined organic layers were washed
with brine, dried, filtered, and evaporated to afford crude product.
Purification on silica gel (hexane/AcOEt¼4/1) afforded skeleton 8.
CHO
N
S
Ph
N
S
Ph
9a
N
S
Ph
12a (70%)
12b (75%)
O
O
O
O
O
O
6a, Ar = Ph
6c, Ar = 3-CF -4-ClPh
9c (69%)
3
Ar
Ar
nd
Grubbs 2 cat.
Ph P=CH ,
3
2
DCM
N
N
(CH Cl)
2
2
S
Ph
S
Ph
O
O
O
O
13a (66%)
13b (72%)
4a (70%)
4b (62%)
4.2.1. (1-Benzenesulfonyl-4-methoxy-4-phenylpiperidin-3-ylidene)
acetic acid ethyl ester (8a). Yield 75% (three-steps); viscous oil; IR
(CHCl3) 3526, 2946, 1769, 1164 cmꢀ1; HRMS (ESI, Mþþ1) calcd for
C22H26NO5S 416.1532, found 416.1533; 1H NMR (400 MHz):
Scheme 4. Synthesis of hexahydroquinolines 4.
3. Conclusion
In summary, we have successfully presented
d 7.85e7.82 (m, 2H), 7.62e7.50 (m, 3H), 7.37e7.27 (m, 3H), 7.21e7.18
(m, 2H), 5.74 (s, 1H), 4.93 (d, J¼14.0 Hz, 1H), 4.20 (q, J¼7.2 Hz, 2H),
4.00 (d, J¼14.0 Hz, 1H), 3.58e3.52 (m, 1H), 3.31e3.25 (m, 1H), 2.97
(s, 3H), 2.40e2.33 (m, 1H), 2.03e1.97 (m, 1H), 1.29 (t, J¼7.2 Hz, 3H);
a
new and
straightforward synthetic methodology for producing the struc-
tural skeletons of tetrahydrobenzo[f]isoquinolinols 2, tetrahy-
dropyrindines 3, and hexahydroquinolines 4 by the two key steps
of intramolecular FriedeleCrafts cyclization and ring-closing
metathesis in moderate yields. Further investigation is required
regarding the synthesis of desulfonated compounds of skeletons 2,
3, and 4 and their structureeactivity in the context of psychoto-
mimetic effects. Considering the utility of these heterocyclic aro-
matic compounds, the development of these general synthetic
approaches is significant.
13C NMR (100 MHz):
d 165.66, 151.04, 138.54, 137.44, 132.71, 129.06
(2ꢁ), 128.55 (2ꢁ), 127.97, 127.62 (2ꢁ), 127.38 (2ꢁ), 120.25, 79.84,
60.62, 50.82, 43.72, 42.32, 35.67, 14.16; Anal. Calcd for C22H25NO5S:
C, 63.59; H, 6.06; N, 3.37. Found: C, 63.71; H, 5.92; N, 3.52.
4.2.2. [1-Benzenesulfonyl-4-methoxy-4-(4-fluorophenyl)piperidin-3-
ylidene]acetic acid ethyl ester (8b). Yield 56% (three-steps); viscous
oil; IR (CHCl3) 3525, 2944, 1767, 1168 cmꢀ1; HRMS (ESI, Mþþ1)
calcd for C22H25FNO5S 434.1438, found 434.1435; 1H NMR
(400 MHz):
d 7.84e7.81 (m, 2H), 7.62e7.50 (m, 3H), 7.20e7.15
4. Experimental section
4.1. General
(m, 2H), 7.06e7.00 (m, 2H), 5.69 (s, 1H), 4.92 (d, J¼14.0 Hz, 1H), 4.20
(q, J¼7.2 Hz, 2H), 3.97 (d, J¼14.0 Hz, 1H), 3.56e3.51 (m, 1H), 3.25
(dt, J¼3.2, 10.0 Hz, 1H), 2.95 (s, 3H), 2.33 (ddd, J¼4.0, 10.0, 14.0 Hz,
1H), 2.01 (ddd, J¼3.2, 5.6, 14.0 Hz, 1H), 1.29 (t, J¼7.2 Hz, 3H); 13C
Tetrahydrofuran (THF) was distilled prior to use. All other re-
agents and solvents were obtained from commercial sources and
used without further purification. Reactions were routinely carried
out under an atmosphere of dry nitrogen with magnetic stirring.
Products in organic solvents were dried with anhydrous magnesium
sulfate before concentration in vacuo. Melting points were de-
termined with an SMP3 melting apparatus. Infrared spectra were
recorded with a PerkineElmer 100 series FTIR spectrometer. 1H and
13C NMR spectra were recorded on a Varian INOVA-400 spectrom-
eteroperating at 200/400 and at 50/100 MHz, respectively. Chemical
NMR (100 MHz): d 165.54, 163.46, 161.00, 151.01, 137.29, 134.38,
132.77,129.25,129.08 (2ꢁ),127.61 (2ꢁ),120.21,115.61,115.40, 79.46,
60.69, 50.72, 43.66, 42.24, 35.57, 14.14; Anal. Calcd for C22H24FNO5S:
C, 60.95; H, 5.58; N, 3.23. Found: C, 61.22; H, 5.82; N, 3.43.
4.2.3. [1-Benzenesulfonyl-4-methoxy-4-(3-trifluoromethylphenyl)pi-
peridin-3-ylidene]acetic acid ethyl ester (8c). Yield 69% (three-
steps); viscous oil; IR (CHCl3) 3529, 2933, 1766, 1170 cmꢀ1; HRMS
(ESI, Mþþ1) calcd for C23H25F3NO5S 484.1406, found 484.1407; 1H
NMR (400 MHz): d 7.87e7.84 (m, 2H), 7.64e7.47 (m, 5H), 7.41e7.37
shifts (
d
) are reported in parts per million (ppm) and the coupling
(m, 2H), 5.60 (d, J¼0.8 Hz, 1H), 5.24 (dd, J¼1.2, 14.0 Hz, 1H), 4.21
(q, J¼7.2 Hz, 2H), 3.77 (dd, J¼1.2, 14.0 Hz, 1H), 3.68e3.62 (m, 1H),
3.26e3.19 (m, 1H), 3.00 (s, 3H), 2.26 (ddd, J¼4.4, 10.4, 14.0 Hz, 1H),
2.00 (ddd, J¼8.4, 11.2, 14.0 Hz, 1H), 1.30 (t, J¼7.2 Hz, 3H); 13C NMR
constants (J) are given in hertz. High resolution mass spectra
(HRMS) were measured with a mass spectrometer Finnigan/Thermo
Quest MAT 95XL. X-ray crystal structures were obtained with an
Enraf-Nonius FR-590 diffractometer (CAD4, Kappa CCD). Elemental
analyses were carried out with Heraeus Vario III-NCSH, Heraeus
CHN-OS-Rapid Analyzer or Elementar Vario EL III.
(100 MHz):
d 165.29, 162.86, 149.81, 140.38, 137.40, 132.88, 130.86,
129.14 (2ꢁ),127.61 (2ꢁ),124.88,124.85,123.88,123.85,121.12, 79.87,
60.84, 51.11, 43.67, 42.04, 36.59,14.12; Anal. Calcd for C23H24F3NO5S:
C, 57.13; H, 5.00; N, 2.90. Found: C, 57.44; H, 5.31; N, 3.12.
4.2. A representative procedure of skeleton 8 is as follows2
4.2.4. [1-Benzenesulfonyl-4-methoxy-4-(4-chloro-3-triflu-
oromethylphenyl)piperidin-3-ylidene]acetic acid ethyl ester (8d).
Yield 78% (three-steps); viscous oil; IR (CHCl3) 3523, 2952, 1766,
A solution of hydrogen peroxide in methanol (2 mL) was added
dropwise to a solution of compound 1 (1.0 mmol) with selenium

M.-Y. Chang et al. / Tetrahedron 67 (2011) 4552e4558
4555
1166 cmꢀ1; HRMS (ESI, Mþþ1) calcd for C23H24ClF3NO5S 518.1016,
6.96e6.90 (m, 2H), 6.79e6.74 (m, 2H), 5.98e5.88 (m, 1H), 5.14e5.10
(m, 2H), 4.66e4.63 (m, 1H), 4.19e4.08 (m, 2H), 3.87 (dd, J¼6.4,
14.0 Hz, 1H), 3.41e3.33 (m, 1H), 2.95 (d, J¼16.4 Hz, 1H), 2.88 (d,
J¼16.4 Hz, 1H), 2.62e2.56 (m, 1H), 2.46e2.38 (m, 1H), 1.91e1.77 (m,
1
found 518.1018; H NMR (400 MHz):
d 7.86e7.83 (m, 2H), 7.64e7.48
(m, 5H), 7.30 (dd, J¼2.4, 10.8 Hz, 1H), 5.60 (d, J¼0.4 Hz, 1H), 5.27 (d,
J¼14.8 Hz, 1H), 4.21 (q, J¼7.2 Hz, 2H), 3.71 (d, J¼14.8 Hz, 1H),
3.68e3.62 (m, 1H), 3.22e3.15 (m, 1H), 2.99 (s, 3H), 2.22 (ddd, J¼4.4,
10.8,14.8 Hz,1H),1.99 (dd, J¼3.6,14.0 Hz,1H),1.30 (t, J¼7.2 Hz, 3H); 13C
2H), 1.25 (t, J¼7.2 Hz, 3H); 13C NMR (100 MHz):
d 170.89, 163.07,
160.62, 141.52, 136.81, 136.79, 135.86, 134.54, 132.31, 129.23, 128.85
(2ꢁ), 127.33 (2ꢁ), 117.51, 115.40, 115.19, 60.95, 55.72, 38.00, 37.17,
36.68, 29.59, 14.17; Anal. Calcd for C24H26FNO4S: C, 64.99; H, 5.91;
N, 3.16. Found: C, 65.29; H, 6.21; N, 3.45.
NMR (100 MHz): d 165.11, 149.52, 138.70, 137.32, 132.91, 131.92, 131.75,
129.16 (2ꢁ), 128.80, 127.59 (2ꢁ), 126.26, 126.16, 123.95, 121.16, 79.65,
60.92, 51.12, 43.64, 41.92, 36.54, 14.10.
4.2.5. (1-Methanesulfonyl-4-methoxy-4-phenylpiperidin-3-ylidene)
acetic acid ethyl ester (8e). Yield 60% (three-steps); viscous oil; IR
(CHCl3) 3522, 2943, 1765, 1165 cmꢀ1; HRMS (ESI, Mþþ1) calcd
for C17H24NO5S 354.1375, found 354.1377; 1H NMR (400 MHz):
4.3.3. [2-Allyl-1-benzenesulfonyl-4-(3-trifluoromethylphenyl)-
1,2,5,6-tetrahydropyridin-3-yl]acetic acid ethyl ester (6c). Yield 65%
(two-steps); viscous oil; IR (CHCl3) 3538, 2929, 1766 cmꢀ1; HRMS
(ESI, Mþþ1) calcd for C25H27F3NO4S 494.1613, found 494.1617; 1H
d
7.41e7.32 (m, 5H), 5.91 (s, 1H), 4.62 (d, J¼14.0 Hz, 1H), 4.48
NMR (400 MHz): d 8.00e7.97 (m, 2H), 7.60e47 (m, 4H), 7.37 (t,
(d, J¼14.0 Hz, 1H), 4.19 (q, J¼7.2 Hz, 2H), 3.58e3.54 (m, 2H), 3.06
(s, 3H), 2.88 (s, 3H), 2.54 (ddd, J¼4.4, 8.0, 14.0 Hz, 1H), 2.13e2.07
(ddd, J¼4.0, 6.4, 14.0 Hz, 1H), 1.27 (t, J¼7.2 Hz, 3H); 13C NMR
J¼7.6 Hz, 1H), 7.03 (d, J¼7.6 Hz, 1H), 6.96 (s, 1H), 5.99e5.89 (m, 1H),
5.16e5.11 (m, 2H), 4.69e4.66 (m, 1H), 4.19e4.07 (m, 2H), 3.95e3.90
(m, 1H), 3.43e3.35 (m, 1H), 2.88 (s, 2H), 2.63e2.57 (m, 1H),
2.47e2.39 (m, 1H), 1.92e1.85 (m, 2H), 1.24 (t, J¼7.2 Hz, 3H); 13C
(100 MHz):
d
165.87, 151.87, 137.94, 128.72 (2ꢁ), 128.27, 127.60 (2ꢁ),
119.45, 79.79, 60.66, 50.72, 43.32, 42.11, 37.05, 35.11, 14.11; Anal.
Calcd for C17H23NO5S: C, 57.77; H, 6.56; N, 3.96. Found: C, 57.48; H,
6.29; N, 4.21.
NMR (100 MHz): d 170.59, 141.61, 141.48, 135.57, 134.42, 132.54,
131.02, 128.92 (2ꢁ), 128.14, 127.39 (2ꢁ), 124.64, 124.57, 124.10,
124.03, 123.99, 117.61, 61.07, 55.83, 37.87, 37.04, 36.79, 29.35, 14.08.
4.3. A representative procedure of skeleton 6 is as follows
4 . 3 . 4 . [ 2 - A l l yl - 1 - b e n z e n e s u l fo nyl - 4 - ( 4 - c h l o ro - 3 - t r i -
fluoromethylphenyl)-1,2,5,6-tetrahydropyridin-3-yl] acetic acid ethyl
ester (6d). Yield 50% (two-steps); viscous oil; IR (CHCl3) 3541,
2936, 1767 cmꢀ1; HRMS (ESI, Mþþ1) calcd for C25H26ClF3NO4S
1,8-Diazabicyclo[5.4.0]undec-7-ene (1.52 g, 10.0 mmol) was
added to a solution of skeleton 8 (0.8 mmol) in tetrahydrofuran
(10 mL) at reflux temperature. The reaction mixture was stirred at
reflux temperature for 20 min. Water (1 mL) was added to the
reaction mixture and the solvent was concentrated. The residue
was extracted with ethyl acetate (3ꢁ20 mL). The combined organic
layers were washed with brine, dried, filtered, and evaporated to
afford crude product. Without further purification, a solution of
boron trifluoride etherate (0.5 mL) in dichloromethane (1 mL) was
added to a stirred solution of the resulting enamine product in
allyltrimethylsilane (1 mL) and dichloromethane (3 mL) at rt. The
reaction mixture was stirred at rt for 15 min. Saturated sodium
bicarbonate solution (2 mL) was added to the reaction mixture and
the solvent was concentrated under reduced pressure. The residue
was extracted with ethyl acetate (3ꢁ30 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 acetate¼6/1e3/1) afforded skeleton 6.
528.1223, found 528.1225; 1H NMR (400 MHz):
d 7.98e7.95 (m,
2H), 7.59e7.47 (m, 3H), 7.39 (d, J¼8.0 Hz, 1H), 7.03 (d, J¼2.0 Hz, 1H),
6.97 (dd, J¼2.0, 8.0 Hz, 1H), 5.97e5.87 (m, 1H), 5.14e5.10 (m, 2H),
4.67e4.63 (m, 1H), 4.19e4.07 (m, 2H), 3.94e3.89 (m, 1H), 3.41e3.33
(m, 1H), 2.89 (d, J¼16.4 Hz, 1H), 2.84 (d, J¼16.4 Hz, 1H), 2.61e2.55
(m, 1H), 2.45e2.33 (m, 1H), 1.89e1.82 (m, 2H), 1.25 (t, J¼7.2 Hz,
3H); 13C NMR (100 MHz):
d 170.42, 141.38, 139.68, 134.60, 134.28,
132.57, 132.17, 131.57, 128.91 (2ꢁ), 128.80, 127.36 (2ꢁ), 127.01,
126.92, 123.95, 121.23, 117.67, 61.18, 55.81, 37.76, 36.95, 36.79,
29.24, 14.05.
4.3.5. (2-Allyl-1-methanesulfonyl-4-phenyl-1,2,5,6-tetrahydropyr-
idin-3-yl)acetic acid ethyl ester (6e). Yield 61% (two-steps);
mp¼67e69 ꢂC (recrystallized from hexane and ethyl acetate); IR
(CHCl3) 3544, 2938, 1766 cmꢀ1; HRMS (ESI, Mþþ1) calcd for
C19H26NO4S 364.1583, found 364.1585; 1H NMR (400 MHz):
d
7.36e7.26 (m, 3H), 7.11e7.08 (m, 2H), 5.97e5.87 (m,1H), 5.16e5.11
4.3.1. (2-Allyl-1-benzenesulfonyl-4-phenyl-1,2,5,6-tetrahydropyr-
idin-3-yl)acetic acid ethyl ester (6a). Yield 56% (two-steps);
mp¼99e101 ꢂC (recrystallized from hexane and ethyl acetate); IR
(CHCl3) 3540, 2934, 1765 cmꢀ1; HRMS (ESI, Mþþ1) calcd for
C24H28NO4S 426.1739, found 426.1742; 1H NMR (400 MHz):
(m, 2H), 4.31 (dd, J¼3.6, 9.2 Hz, 1H), 4.12 (q, J¼7.2 Hz, 2H), 3.98 (ddt,
J¼1.2, 7.5, 15.2 Hz, 1H), 3.43 (ddd, J¼5.2, 12.0, 15.2 Hz, 1H), 3.12 (d,
J¼17.2 Hz, 1H), 3.07 (s, 3H), 2.89 (d, J¼17.2 Hz, 1H), 2.62e2.52 (m,
2H), 2.48e2.39 (m, 1H), 2.28 (ddd, J¼0.8, 4.4, 18.4 Hz, 1H), 1.23 (t,
J¼7.2 Hz, 3H); 13C NMR (100 MHz):
d 172.54, 140.85, 136.72, 134.57,
d
8.01e7.98 (m, 2H), 7.58e7.47 (m, 3H), 7.26e7.18 (m, 3H),
128.62 (2ꢁ), 127.71 (2ꢁ), 127.58, 127.48, 117.39, 61.01, 54.90, 39.80,
37.99, 36.82, 36.24, 30.01, 14.12; Anal. Calcd for C19H25NO4S: C,
62.78; H, 6.93; N, 3.85. Found: C, 62.97; H, 7.21; N, 3.98.
6.81e6.78 (m, 2H), 6.01e5.90 (m, 1H), 5.16e5.10 (m, 2H), 4.70e4.67
(m, 1H), 4.19e4.16 (m, 2H), 3.88 (dd, J¼6.4, 14.0 Hz, 1H), 3.42e3.24
(m, 1H), 2.99 (d, J¼16.4 Hz, 1H), 2.89 (d, J¼16.4 Hz, 1H), 2.64e2.57
(m, 1H), 2.48e2.40 (m, 1H), 1.93e1.78 (m, 2H), 1.25 (t, J¼7.2 Hz, 3H);
4.4. A representative procedure of skeleton 2 is as follows
13C NMR (100 MHz):
d 170.98, 141.59, 140.99, 136.78, 134.64, 132.35,
128.83 (2ꢁ), 128.33 (2ꢁ), 127.56 (2ꢁ), 127.33 (2ꢁ), 127.14, 126.71,
117.41, 60.83, 55.68, 38.05, 37.25, 36.68, 29.45, 14.17; Anal. Calcd for
C24H27NO4S: C, 67.74; H, 6.40; N, 3.29. Found: C, 67.91; H, 6.29;
N, 3.60.
A solution of skeleton 6 (0.5 mmol) and sodium hydroxide so-
lution (2 N, 5 mL) in tetrahydrofuran (10 mL) was refluxed for
10e15 h. The reaction was traced by TLC until the skeleton 6 was
completely consumed. The reaction solution was cooled to rt and
concentrated until one third of the solution remained. The
remained solution was extracted with ethyl acetate (3ꢁ10 mL). The
aqueous phase was cooled in ice-bath and acidified by adding
concentrated hydrochloric acid to pH 2. The aqueous solution was
extracted with ethyl acetate (3ꢁ20 mL), and the extracts were
washed with brine. The combined organic layers were washed with
brine, dried, filtered, and evaporated to afford crude product under
4.3.2. [2-Allyl-1-benzenesulfonyl-4-(4-fluorophenyl)-1,2,5,6-tetrahy-
dropyridin-3-yl]acetic acid ethyl ester (6b). Yield 60% (two-steps);
mp¼84e86 ꢂC (recrystallized from hexane and ethyl acetate); IR
(CHCl3) 3544, 2930, 1767 cmꢀ1; HRMS (ESI, Mþþ1) calcd for
C24H27FNO4S 444.1645, found 444.1644; 1H NMR (400 MHz):
d
7.99e7.96 (m, 2H), 7.58e7.54 (m, 1H), 7.51e7.47 (m, 2H),

4556
M.-Y. Chang et al. / Tetrahedron 67 (2011) 4552e4558
reduced pressure. Without further purification, thionyl chloride
(5 mL) was added to a stirred solution of the resulting acid product
in dichloromethane (5 mL) at rt. The reaction mixture was stirred at
reflux for 10e15 h and the solvent was concentrated under reduced
pressure. Aluminum chloride (134 mg, 1.0 mmol) was added to
a stirred solution of the residue in dichloromethane (10 mL) at rt.
The reaction mixture was stirred at rt for 2e3 h. Saturated sodium
bicarbonate solution (2 mL) was added to the reaction mixture and
the solvent was concentrated under reduced pressure. The residue
was extracted with ethyl acetate (3ꢁ30 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 acetate¼6/1e3/1) afforded skeleton 2.
55.01, 37.91, 37.17, 33.48, 20.03; Anal. Calcd for C22H25NO3S: C,
68.90; H, 6.57; N, 3.65. Found: C, 69.21; H, 6.39; N, 3.32.
4.5.2. 2-(2-Allyl-1-benzenesulfonyl-4-(3-trifluoromethylphenyl)-
1,2,5,6-tetrahydropyridin-3-yl)ethanol (9b). Yield 80%; viscous oil;
IR (CHCl3) 3623, 2946, 1198 cmꢀ1; HRMS (ESI, Mþþ1) calcd for
C23H25F3NO3S 452.1447, found 452.1450; 1H NMR (400 MHz):
d
7.95e7.92 (m, 2H), 7.63e7.58 (m, 1H), 7.53e7.45 (m, 3H),
7.40e7.36 (m, 1H), 7.04 (d, J¼7.6 Hz, 1H), 6.97 (s, 1H), 5.81e5.70 (m,
1H), 5.10e5.02 (m, 2H), 4.46 (dd, J¼3.2, 9.6 Hz, 1H), 4.01 (dd, J¼7.2,
14.8 Hz, 1H), 3.55e3.51 (m, 2H), 3.39 (ddd, J¼5.2, 12.0, 15.2 Hz, 1H),
2.61e2.54 (m, 1H), 2.42e2.32 (m, 1H), 2.30e2.21 (m, 1H), 2.19e2.12
(m, 1H), 2.05e1.98 (m, 1H), 1.93e1.92 (m, 1H), 1.89 (br s, 1H); 13C
NMR (100 MHz):
d 141.63, 141.05, 135.44, 134.14, 132.75, 130.96,
4.4.1. 4-Allyl-3-benzenesulfonyl-1,2,3,4-tetrahydrobenzo[f]iso-
quinolin-6-ol (2a). Yield 40% (three-steps); viscous oil; IR (CHCl3)
3650, 3298, 2929, 1149 cmꢀ1; HRMS (ESI, Mþþ1) calcd for
C22H22NO3S 380.1320, found 380.1322; 1H NMR (400 MHz):
129.85, 129.24, 129.15 (2ꢁ), 127.24 (2ꢁ), 124.32, 124.26, 124.10,
123.99, 117.69, 66.91, 54.93, 37.61, 37.02, 30.21, 29.74.
4.5.3. 2-(2-Allyl-1-benzenesulfonyl-4-(4-chloro-3-tri-
fluoromethylphenyl)-1,2,5,6-tetrahydropyridin-3-yl) ethanol (9c).
Yield 69%; viscous oil; IR (CHCl3) 3618, 2944,1199 cmꢀ1; HRMS (ESI,
Mþþ1) calcd for C23H24ClF3NO3S 486.1118, found 486.1121; 1H NMR
d
8.15e8.13 (m, 1H), 7.74 (d, J¼7.2 Hz, 2H), 7.63e7.61 (m, 1H),
7.46e7.42 (m, 2H), 7.35e7.32 (m, 1H), 7.26e7.18 (m, 2H), 6.52
(s, 1H), 5.98 (br s, 1H), 5.93e5.83 (m, 1H), 5.12e5.05 (m, 3H), 4.11
(dd, J¼6.8 Hz, 1H), 3.60e3.52 (m, 1H), 2.84 (dd, J¼4.4, 16.8 Hz, 1H),
(400 MHz):
d 7.94e7.92 (m, 2H), 7.63e7.58 (m, 1H), 7.53e7.48 (m,
2.70e2.57 (m, 3H); 13C NMR (100 MHz):
d
150.20, 140.74, 134.52,
2H), 7.40 (d, J¼8.0 Hz, 1H), 7.08 (d, J¼2.0 Hz, 1H), 7.01 (dd, J¼2.0,
8.0 Hz, 1H), 5.77e5.67 (m, 1H), 5.10e5.01 (m, 2H), 4.46e4.43
(m, 1H), 4.00 (dd, J¼7.2, 14.8 Hz, 1H), 3.61e3.50 (m, 2H), 3.38 (ddd,
J¼4.8, 12.0, 15.2 Hz, 1H), 2.58e2.52 (m, 1H), 2.40e2.23 (m, 2H),
2.19e2.10 (m, 1H), 2.06e1.99 (m, 1H), 1.92e1.86 (m, 2H); 13C NMR
133.03, 132.82, 132.38, 128.72 (2ꢁ), 126.91 (2ꢁ), 126.83, 124.95,
123.91, 122.47, 122.18, 120.15, 117.70, 107.17, 56.46, 41.04, 38.58,
22.63; Anal. Calcd for C22H21NO3S: C, 69.63; H, 5.58; N, 3.69. Found:
C, 69.87; H, 5.79; N, 3.94.
(100 MHz):
d 140.81, 140.41, 134.31, 132.76, 132.71, 132.62, 132.49,
4.4.2. 4-Allyl-3-benzenesulfonyl-8-fluoro-1,2,3,4-tetrahydrobenzo[f]
isoquinolin-6-ol (2b). Yield 35% (three-steps); mp¼166e169 ꢂC
(recrystallized from hexane and ethyl acetate); IR (CHCl3) 3661,
3320, 2934, 1157 cmꢀ1; HRMS (ESI, Mþþ1) calcd for C22H21FNO3S
131.55, 128.94 (3ꢁ), 127.51 (3ꢁ), 127.17, 127.02, 117.41, 60.54, 54.74,
37.62, 36.95, 33.31, 29.77; Anal. Calcd for C23H23ClF3NO3S: C, 56.85;
H, 4.77; N, 2.88. Found: C, 57.09; H, 4.93; N, 3.11.
398.1226, found 398.1230; 1H NMR (400 MHz):
d
7.78e7.75 (m, 2H),
4.6. A representative procedure of skeleton 10 is as follows
7.70 (dd, J¼2.8, 10.4 Hz, 1H), 7.60 (dd, J¼5.6, 9.2 Hz, 1H), 7.37
(tt, J¼1.2, 6.8 Hz, 1H), 7.30e7.25 (m, 2H), 7.20 (ddd, J¼2.8, 8.4,
12.0 Hz, 1H), 6.58 (s, 1H), 5.96 (s, 1H), 5.91e5.81 (m, 1H), 5.11e5.04
(m, 3H), 4.09 (ddt, J¼1.2, 6.8, 14.8 Hz, 1H), 3.54 (ddd, J¼4.8, 11.6,
14.8 Hz, 1H), 2.83 (dd, J¼1.2, 4.8 Hz, 1H), 2.80e2.55 (m, 3H); 13C
Methanesulfonyl chloride (230 mg, 2.0 mmol) was added to
a stirred solution of skeleton 9 (0.5 mmol) in the co-solvent of
pyridine (5 mL) and dichloromethane (10 mL) at ice bath. The re-
action mixture was stirred at rt for 10e12 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 EtOAc (3ꢁ50 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 acetate¼3/1e1/1) afforded
skeleton 10.
NMR (100 MHz):
d 161.45, 159.01, 149.69, 140.55, 134.44, 132.51,
132.27, 129.82, 128.76 (2ꢁ), 127.01 (2ꢁ), 124.95, 124.91, 120.24,
116.65, 107.98, 106.35, 56.24, 40.93, 38.46, 22.80.
4.5. A representative procedure of skeleton 9 is as follows
Lithium aluminum hydride (76 mg, 2.0 mmol) was added to
a stirred solution of skeleton 6 (0.5 mmol) in tetrahydrofuran
(5 mL) at ice-bath. The mixture was further stirred for 2e3 h at rt.
The reaction was quenched with 15% ammonium chloride solution
(1 mL) at ice-bath and the mixture was concentrated under reduced
pressure. Water (10 mL) was added to the residue, and the mixture
was extracted with EtOAc (3ꢁ20 mL). The combined organic layers
were washed with brine, dried, filtered, and evaporated to give
crude product under reduced pressure. Purification on silica gel
(hexane/ethyl acetate¼3/1e1/1) afforded skeleton 9.
4.6.1. Methanesulfonic acid 2-(2-allyl-1-benzenesulfonyl-4-phenyl-
1,2,5,6-tetrahydropyridin-3-yl)ethyl ester (10a). Yield 82%; viscous
oil; IR (CHCl3) 3498, 2930, 1151 cmꢀ1; HRMS (ESI, Mþþ1) calcd for
C23H28NO5S2 462.1409, found 462.1411; 1H NMR (400 MHz):
d
7.91e7.88 (m, 2H), 7.62e7.57 (m, 1H), 7.55e7.50 (m, 2H), 7.27e7.18
(m, 3H), 6.74e6.71 (m, 2H), 5.91e5.81 (m, 1H), 5.13e5.07 (m, 2H),
4.45 (dd, J¼2.8, 9.2 Hz, 1H), 3.95 (t, J¼6.8 Hz, 2H), 3.91 (dd, J¼7.2,
15.2 Hz, 1H), 3.34 (ddd, J¼5.2, 12.0, 15.2 Hz, 1H), 2.89 (s, 3H),
2.59e2.35 (m, 3H), 2.27e2.11 (m, 1H), 2.10e2.04 (m, 1H), 1.88
4.5.1. 2-(2-Allyl-1-benzenesulfonyl-4-phenyl-1,2,5,6-tetrahydropyr-
idin-3-yl)ethanol (9a). Yield 78%; viscous oil; IR (CHCl3) 3610, 2938,
1191 cmꢀ1; HRMS (ESI, Mþþ1) calcd for C22H26NO3S 384.1633,
(dd, J¼4.8, 17.2 Hz, 1H); 13C NMR (100 MHz):
d 141.11, 141.90, 136.69,
134.35, 132.58, 128.06 (2ꢁ), 128.58 (2ꢁ), 128.34, 127.30 (2ꢁ), 127.14
(3ꢁ), 117.49, 67.40, 55.13, 37.76, 37.26, 37.14, 30.14, 29.78; Anal.
Calcd for C23H27NO5S2: C, 59.85; H, 5.90; N, 3.03. Found: C, 59.62; H,
6.24; N, 3.41.
found 384.1635; 1H NMR (400 MHz):
d 7.94e7.91 (m, 2H), 7.62e7.58
(m, 1H), 7.53e7.49 (m, 2H), 7.28e7.18 (m, 3H), 6.81e6.78 (m, 2H),
5.81e5.70 (m, 1H), 5.10e5.02 (m, 2H), 4.41 (dd, J¼3.2, 9.6 Hz, 1H),
4.00 (dd, J¼6.8, 14.8 Hz, 1H), 3.51 (dd, J¼6.4, 12.0 Hz, 2H), 3.39 (ddd,
J¼5.2, 12.0, 15.2 Hz, 1H), 2.60e2.53 (m, 1H), 2.43e2.32 (m, 2H),
2.25e2.16 (m, 1H), 2.04e1.91 (m, 2H), 1.65 (br s, 1H); 13C NMR
4.6.2. Methanesulfonic acid 2-(2-allyl-1-benzenesulfonyl-4-(3-tri-
fluoromethylphenyl)-1,2,5,6-tetrahydropyridin-3-yl)ethyl ester (10b).
Yield 75%; mp¼95e97 ꢂC (recrystallized from hexane and ethyl
acetate); IR (CHCl3) 3476, 2938, 1151 cmꢀ1; HRMS (ESI, Mþþ1) calcd
for C24H27F3NO5S2 530.1283, found 530.1285; 1H NMR (400 MHz):
(100 MHz):
d 141.63, 141.02, 135.14, 134.65, 132.53, 130.31, 128.91
(2ꢁ), 128.39 (2ꢁ), 127.67 (2ꢁ), 127.44 (2ꢁ), 126.81, 117.19, 61.06,

M.-Y. Chang et al. / Tetrahedron 67 (2011) 4552e4558
4557
d
7.93e7.90 (m, 2H), 7.64e7.60 (m, 1H), 7.56e7.42 (m, 3H), 7.41e7.38
2.80e2.71 (m, 1H), 2.43e2.28 (m, 1H); 13C NMR (50 MHz):
d
145.33,
(m, 1H), 6.99 (d, J¼7.6 Hz, 1H), 6.91 (br s, 1H), 5.91e5.81 (m, 1H),
5.14e5.09 (m, 2H), 4.50 (dd, J¼3.2, 9.6 Hz,1H), 4.01 (dt, J¼1.2, 6.4 Hz,
2H), 3.94 (dd, J¼7.2, 15.2 Hz, 1H), 3.38 (ddd, J¼5.2, 12.0, 15.2 Hz, 1H),
2.95 (s, 3H), 2.60e2.54 (m, 1H), 2.44e2.36 (m, 2H), 2.30e2.25
(m, 1H), 2.12e2.03 (m, 1H), 1.89 (dd, J¼5.2, 18.0 Hz, 1H); 13C NMR
137.29, 135.98, 133.82, 131.88, 128.23 (2ꢁ), 128.12 (2ꢁ), 127.62 (2ꢁ),
127.28 (2ꢁ), 126.82, 123.98, 113.22, 60.32, 40.29, 38.23, 31.22.
4.8.2. 1-Benzenesulfonyl-4-(3-trifluoromethylphenyl)-2,3,7,7a-tetra-
hydro-1H-[1]pyrindine (3b). Yield 70%; viscous oil; IR (CHCl3) 3533,
2975, 1184 cmꢀ1; HRMS (ESI, Mþþ1) calcd for C21H18F3NO2S
(100 MHz):
d 142.27, 140.93, 134.44, 133.71, 132.66, 131.87, 131.25,
128.94 (2ꢁ), 128.92, 127.47 (3ꢁ), 124.69, 124.58, 123.70, 123.59,
406.1089, found 406.1092; 1H NMR (200 MHz):
d 7.88e7.82 (m, 2H),
117.30, 60.73, 54.93, 37.70, 36.99, 33.38, 29.82.
7.56e7.42 (m, 4H), 7.01 (d, J¼7.6 Hz, 1H), 6.96 (br s, 1H), 6.44
(d, J¼8.0 Hz, 1H), 6.12e6.08 (m, 1H), 3.91e3.87 (m, 3H), 3.06e2.95
(m, 2H), 2.81e2.73 (m, 1H), 2.44e2.32 (m, 1H); 13C NMR (50 MHz):
4.7. A representative procedure of skeleton 11 is as follows
d
141.88, 141.21, 135.00, 134.87, 132.92, 132.68, 131.33, 129.01 (3ꢁ),
DBU (460 mg, 3.0 mmol) was added to a solution of skeleton 10
(0.3 mmol) in tetrahydrofuran (10 mL) at reflux temperature. The
reaction mixture was stirred at reflux temperature for 10e12 h.
Water (1 mL) was added to the reaction mixture and the solvent
was concentrated. The residue was extracted with ethyl acetate
(3ꢁ20 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 acetate¼
6/1e3/1) afforded skeleton 11.
128.90, 127.19 (3ꢁ), 126.19, 123.90, 114.14, 58.94, 39.78, 37.21, 29.09.
4.9. A representative procedure of skeleton 12 is as follows
A solution of skeleton 9 (0.5 mmol) in dichloromethane (5 mL)
was added to a mixture of pyridinium chlorochromate (432 mg,
2.0 mmol) and Celite (200 mg) in dichloromethane (10 mL). After
being stirred at rt for 2e3 h, the mixture was filtered through
a short silica gel column. The filtrate was dried, filtered, and
evaporated to yield crude compound. Purification on silica gel
(hexane/ethyl acetate¼6/1e3/1) afforded skeleton 12.
4.7.1. 6-Allyl-1-benzenesulfonyl-4-phenyl-5-vinyl-1,2,3,6-tetrahy-
dropyridine (11a). Yield 75%; viscous oil; IR (CHCl3) 3512, 2983,
1179 cmꢀ1; HRMS (ESI, Mþþ1) calcd for C22H24NO2S 366.1528,
4.9.1. (2-Allyl-1-benzenesulfonyl-4-phenyl-1,2,5,6-tetrahydropyr-
idin-3-yl)acetaldehyde (12a). Yield 70%; mp¼85e88 ꢂC (recrystal-
lized from hexane and ethyl acetate); IR (CHCl3) 3532, 2943, 1754,
1162 cmꢀ1; HRMS (ESI, Mþþ1) calcd for C22H24NO3S 382.1477,
found 366.1530; 1H NMR (400 MHz):
d 7.86e7.83 (m, 2H),
7.57e7.53 (m, 1H), 7.47e7.43 (m, 2H), 7.24e7.19 (m, 3H), 6.64e6.60
(m, 2H), 6.11 (dd, J¼11.2, 18.0 Hz, 1H), 6.06e5.96 (m, 1H), 5.22 (d,
J¼18.0 Hz, 1H), 5.16e5.11 (m, 2H), 5.00 (d, J¼11.2 Hz, 1H), 4.88 (dd,
J¼2.0, 10.4 Hz, 1H), 4.05e3.98 (m, 1H), 3.49 (dt, J¼8.8, 15.2 Hz, 1H),
2.65e2.59 (m, 1H), 2.48e2.34 (m, 1H), 2.09e2.05 (m, 2H); 13C NMR
found 382.1478; 1H NMR (400 MHz):
d
9.24 (t, J¼2.0 Hz, 1H),
7.99e7.96 (m, 2H), 7.61e7.57 (m, 1H), 7.54e7.49 (m, 2H), 7.26e7.18
(m, 3H), 6.70e6.67 (m, 2H), 5.95e5.85 (m, 1H), 5.13e5.03 (m, 2H),
4.43 (dd, J¼3.6, 9.2 Hz, 1H), 3.97 (dd, J¼6.8, 14.8 Hz, 1H), 3.40 (ddd,
J¼5.6, 11.6, 15.2 Hz, 1H), 3.05 (d, J¼17.2 Hz, 1H), 2.98 (dd, J¼1.2,
17.2 Hz, 1H), 2.55e2.48 (m, 1H), 2.44e2.36 (m, 1H), 2.09e1.93 (m,
(100 MHz):
d 141.38, 140.55, 136.55, 134.95, 133.40, 132.39, 131.47,
128.90 (2ꢁ), 128.13 (2ꢁ), 128.05 (2ꢁ), 127.13, 127.00 (2ꢁ), 116.97,
112.66, 52.71, 37.63, 37.60, 29.10.
2H); 13C NMR (100 MHz):
d 198.64, 141.28, 140.75, 137.90, 134.30,
4.7.2. 6-Allyl-1-benzenesulfonyl-4-(3-trifluoromethylphenyl)-5-vi-
nyl-1,2,3,6-tetrahydropyridine (11b). Yield 82%; viscous oil; IR
(CHCl3) 3519, 2988, 1182 cmꢀ1; HRMS (ESI, Mþþ1) calcd for
C23H23F3NO2S 434.1402, found 434.1404; 1H NMR (400 MHz):
132.48, 128.93 (3ꢁ), 128.54, 127.32, 127.26 (4ꢁ), 125.13, 117.56,
56.00, 46.15, 38.01, 36.97, 29.54.
4 . 9 . 2 . ( 2 - A l l yl - 1 - b e n z e n e s ul fo nyl - 4 - ( 4 - ch l o ro- 3 - t r i -
fluoromethylphenyl)-1,2,5,6-tetrahydropyridin-3-yl)acetaldehyde
(12b). Yield 75%; viscous oil; IR (CHCl3) 3540, 2949, 1758,
1170 cmꢀ1; HRMS (ESI, Mþþ1) calcd for C23H22ClF3NO3S 484.0961,
d
7.86e7.83 (m, 2H), 7.59e7.55 (m, 1H), 7.48e7.44 (m, 3H), 7.35
(t, J¼7.6 Hz, 1H), 6.88 (d, J¼7.6 Hz, 1H), 6.71 (s, 1H), 6.06e5.95
(m, 2H), 5.29 (d, J¼17.6 Hz,1H), 5.17e5.13 (m, 2H), 5.07 (d, J¼11.2 Hz,
1H), 4.88 (dd, J¼2.0, 10.4 Hz, 1H), 4.09e4.03 (m, 1H), 3.54e3.45 (m,
1H), 2.64e2.58 (m, 1H), 2.48e2.40 (m, 1H), 2.09e2.05 (m, 2H); 13C
found 484.0966; 1H NMR (400 MHz):
d 9.42 (br s, 1H), 7.99e7.96
(m, 2H), 7.62e7.58 (m,1H), 7.55e7.46 (m, 2H), 7.38 (d, J¼8.0 Hz,1H),
6.91 (d, J¼2.0 Hz, 1H), 6.87 (dd, J¼2.0, 8.0 Hz, 1H), 5.92e5.82
(m,1H), 5.13e5.06 (m, 2H), 4.43 (dd, J¼3.6, 9.2 Hz,1H), 3.98 (dd, J¼6.4,
14.8 Hz,1H), 3.38 (ddd, J¼5.2,11.6,14.8 Hz,1H), 3.05 (d, J¼17.2 Hz, 1H),
2.98 (dd, J¼1.2, 17.2 Hz, 1H), 2.52e2.45 (m, 1H), 2.42e2.34 (m, 1H),
NMR (100 MHz):
d 141.30, 141.24, 134.96, 134.67, 132.69, 132.60,
131.49, 128.96 (2ꢁ), 128.67, 127.05 (2ꢁ), 125.07, 125.00, 124.03,
123.95, 123.91, 117.14, 113.89, 52.64, 37.48, 37.43, 28.95.
4.8. A representative procedure of skeleton 3 is as follows
2.01e1.86 (m, 2H); 13C NMR (100 MHz):
d 197.60, 141.20, 139.61,
135.65, 134.01, 132.71, 132.68, 131.93, 131.79, 129.01 (3ꢁ), 127.37 (3ꢁ),
Grubbs second catalyst (12 mg, 1.4% mmol) was added to a so-
lution of skeleton 11 (0.3 mmol) in 1,2-dichloroethane (5 mL) at
reflux temperature. The reaction mixture was stirred at reflux
temperature for 1e2 h. Water (1 mL) was added to the reaction
mixture and the solvent was concentrated. The residue was
extracted with ethyl acetate (3ꢁ20 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 acetate¼6/1e3/1) afforded skeleton 3.
126.55, 126.45, 117.85, 56.15, 46.24, 37.77, 36.86, 29.43.
4.10. A representative procedure of skeleton 13 is as follows
A solution of n-butyllithium (1.6 M in THF, 1.8 mmol) was added
to a stirred solution of methyl triphenylphosphonium iodide
(810 mg, 2.0 mmol) in tetrahydrofuran (10 mL) at ꢀ78 ꢂC. The re-
action mixture was stirred at ꢀ78 ꢂC for 30 min. A solution of
skeleton 12 (0.5 mmol) in tetrahydrofuran (5 mL) was added to
a reaction mixture. The reaction mixture was stirred at ꢀ30 ꢂC for
1e2 h. Water (1 mL) was added to the reaction mixture and the
solvent was concentrated. The residue was extracted with ethyl
acetate (3ꢁ20 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
acetate¼6/1e3/1) afforded skeleton 13.
4.8.1. 1-Benzenesulfonyl-4-phenyl-2,3,7,7a-tetrahydro-1H-[1]pyr-
indine (3a). Yield 59%; viscous oil; IR (CHCl3) 3529, 2974,
1182 cmꢀ1; HRMS (ESI, Mþþ1) calcd for C20H20NO2S 338.7815,
found 338.7822; 1H NMR (200 MHz):
d 7.88e7.84 (m, 2H),
7.61e7.56 (m, 3H), 7.32e7.17 (m, 5H), 6.38 (d, J¼8.4 Hz, 1H),
6.08e6.05 (m, 1H), 3.90e3.85 (m, 3H), 3.05e2.96 (m, 2H),

4558
M.-Y. Chang et al. / Tetrahedron 67 (2011) 4552e4558
4.10.1. 5,6-Diallyl-1-benzenesulfonyl-4-phenyl-1,2,3,6-tetrahy-
dropyridine (13a). Yield 66%; viscous oil; IR (CHCl3) 3522, 2976,
1187 cmꢀ1; HRMS (ESI, Mþþ1) calcd for C23H26NO2S 380.1684,
5.66e5.61 (m, 1H), 5.56e5.50 (m, 1H), 4.76e4.70 (m, 1H),
4.04e3.92 (m, 1H), 3.20e3.16 (m, 1H), 2.44e2.38 (m, 2H), 2.21e2.15
(m, 2H), 1.92e1.87 (m, 2H); 13C NMR (50 MHz):
d 142.38, 140.89,
found 380.1682; 1H NMR (400 MHz):
d
7.89e7.86 (m, 2H), 7.61e7.55
134.12, 133.11, 132.71, 132.66, 131.52, 131.12, 129.00 (3ꢁ), 127.21
(m, 1H), 7.52e7.43 (m, 2H), 7.26e7.17 (m, 3H), 6.69e6.67 (m, 2H),
5.99e5.90 (m,1H), 5.56e5.46 (m,1H), 5.20e4.94 (m, 4H), 4.44 (br s,
J¼6.4 Hz, 1H), 3.97 (dd, J¼6.4, 14.8 Hz, 1H), 3.39 (ddd, J¼5.2, 12.0,
17.6 Hz, 1H), 2.77 (dd, J¼5.6, 15.2 Hz, 1H), 2.63e2.57 (m, 1H),
2.52e2.37 (m, 2H), 2.11e2.01 (m, 1H), 1.91 (dd, J¼5.6, 17.6 Hz, 1H);
(3ꢁ), 126.88, 125.12, 117.98, 55.83, 41.23, 39.20, 36.88, 29.12.
Acknowledgements
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). The project is also supported by a grant from the
Kaohsiung Medical Research Foundation (KMU-Q100004).
13C NMR (100 MHz):
d 141.62, 141.46, 135.42, 134.89, 133.66, 132.33,
131.02, 128.83 (2ꢁ), 128.14 (2ꢁ), 127.61 (2ꢁ), 127.28 (2ꢁ), 126.79,
117.12, 117.07, 54.45, 38.38, 37.14, 35.46, 29.62.
4.10.2. 5,6-Diallyl-1-benzenesulfonyl-4-(4-chloro-3-tri-
fluoromethylphenyl)-1,2,3,6-tetrahydropyridine (13b). Yield 72%;
viscous oil; IR (CHCl3) 3520, 2968, 1182 cmꢀ1; HRMS (ESI, Mþþ1)
calcd for C24H24ClF3NO2S 482.1168, found 482.1170; 1H NMR
References and notes
1. For reviews on the synthesis of piperidine, see: (a) Buffat, M. G. P. Tetrahedron
2004, 60, 1701; (b) Weintraub, P. M.; Sabol, J. S.; Kane, J. M.; Borcherding, D. R.
Tetrahedron 2003, 59, 2953; (c) Sorbera, L. A.; Serradell, N.; Bolos, J.; Rosa, E.;
Bozzo, J. Drugs Future 2007, 32, 674; (d) Laschat, S.; Dickner, T. Synthesis 2000,
1781; (e) Kallstrom, S.; Leino, R. Bioorg. Med. Chem. 2008, 16, 601.
2. (a) Chang, M.-Y.; Lin, C.-H.; Chen, Y.-L.; Chang, C.-Y.; Hsu, R.-T. Org. Lett. 2010, 12,
1176; (b) Chang, M.-Y.; Lin, C.-H.; Chen, Y.-L. Tetrahedron Lett. 2010, 51, 1430; (c)
Chang, M.-Y.; Lee, M.-F.; Lee, N.-C.; Huang, Y.-P.; Lin, C.-H. Tetrahedron Lett. 2011,
52, 588.
3. For synthesis of tetrahydrobenzo[f]isoquinoline: (a) Mikhailovskii, A. G.; Bubnov,
Y. N.; Syropyatov, B. Y.; Dolzhenko, A. V.; Timofeeva, Y. P. Pharm. Chem. J. 1999, 33,
128; (b) Mikhailovskii, A. G.; Vakhrin, M. I. Chem. Heterocycl. Compd. 2002, 38,
205; (c) Polygalova, N. N.; Mikhailovskii, A. G. Chem. Heterocycl. Compd. 2006, 42,
959 For hexahydrobenzo[f]isoquinoline: (d) Russell, M. G. N.; Baker, R.; Bill-
ington, D. C.; Knight, A. K.; Middlemiss, D. N.; Noble, A. J. J. Med. Chem. 1992, 35,
2025; (e) Wikstrom, H.; Andersson, B.; Elebring, T.; Svensson, K.; Carlsson, A.;
Largent, B. J. Med. Chem. 1987, 30, 2169; (f) Van de Waterbeemd, H.; El Tayar, N.;
Testa, B.; Wikstrom, H.; Largent, B. J. Med. Chem. 1987, 30, 2175; (g) Moriarty, E.;
Carr, M.; Bonham, S.; Carty, M. P.; Aldabbagh, F. Eur. J. Med. Chem. 2010, 45, 3762;
(h) Menard, M.; Rivest, P.; Morris, L.; Meunier, J.; Perron, Y. G. Can. J. Chem. 1974,
52, 2316; (i) Zimmerman, D. M. GB Patent 2,126,583, 1984. (j) Lalezari, I.; Nabahi,
L. S. J. Heterocycl. Chem. 1980, 17, 1761; (k) Pratap, R.; Raghunandan, R.; Maulik, P.
R.; Ram, V. J. Tetrahedron Lett. 2007, 48, 7982; (l) Ali, M.; El-Sayed, A. A.; Ham-
mouda, H. A. J. Prakt. Chem. 1973, 315, 1090.
(400 MHz):
d 7.98e7.96 (m, 2H), 7.64e7.58 (m, 1H), 7.55e7.49
(m, 2H), 7.40 (d, J¼8.0 Hz,1H), 6.94 (d, J¼2.0 Hz,1H), 6.89 (dd, J¼2.0,
8.0 Hz, 1H), 6.00e5.91 (m, 1H), 5.60e5.48 (m, 1H), 5.27e4.90
(m, 4H), 4.32 (br s, J¼6.4 Hz, 1H), 3.91 (dd, J¼6.4, 14.8 Hz, 1H), 3.22
(ddd, J¼5.2, 12.0, 17.6 Hz, 1H), 2.64 (dd, J¼5.6, 15.2 Hz, 1H),
2.60e2.51 (m, 1H), 2.50e2.38 (m, 2H), 2.10e2.00 (m, 1H), 1.88 (dd,
J¼5.6, 17.6 Hz, 1H); 13C NMR (50 MHz):
d 142.10, 140.02, 135.82,
133.92, 132.81, 132.79, 131.67, 131.35, 129.33 (3ꢁ), 127.58 (3ꢁ),
127.61, 127.28, 126.59, 117.32, 116.88, 55.13, 40.12, 37.49, 36.92,
29.88.
4.11. A representative procedure of skeleton 4 is as follows
Grubbs second catalyst (12 mg, 1.4% mmol) was added to a so-
lution of skeleton 13 (0.3 mmol) in 1,2-dichloroethane (5 mL) at
reflux temperature. The reaction mixture was stirred at reflux
temperature for 1e2 h. Water (1 mL) was added to the reaction
mixture and the solvent was concentrated. The residue was
extracted with ethyl acetate (3ꢁ20 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 acetate¼6/1e3/1) afforded skeleton 4.
4. For synthesis of tetrahydropyrindine, see: (a) Hong, B.-C.; Wu, J.-L.; Gupta, A. K.;
Hallur, M. S.; Liao, J. H. Org. Lett. 2004, 6, 3453 and cited references herein; (b)
Larini, P.; Guarna, A.; Occhiato, E. G. Org. Lett. 2006, 8, 781; (c) Hong, B.-C.; Gupta,
A. K.; Wu, M.-F.; Liao, J.-H.; Lee, G.-H. Org. Lett. 2003, 5, 1689; (d) Kolb, S.;
Goddard, M. L.; Loukaci, A.; Mondesert, O.; Ducommun, B.; Braud, E.; Garbay, C.
Eur. J. Med. Chem. 2010, 45, 896; (e) Sasaki, Y.; Shigenaga, A.; Fujii, N.; Otaka, A.
Tetrahedron 2007, 63, 2000.
ꢀ
5. For synthesis of hexahydroquinoline, see: (a) Chou, S. S. P.; Cai, Y. L. Tetrahedron
2011, 67, 1183 and cited references herein; (b) Chou, S. S. P.; Chung, Y. C.; Chen, P.
A.; Chiang, S. L.; Wu, C. J. J. Org. Chem. 2011, 76, 692.
6. CCDC 795949 (6a) contains 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 CCDC, 12 Union Road, Cambridge CB2 1EZ, UK; fax:
44-1223-336033; e-mail: deposit@ccdc.cam.ac.uk).
7. For FriedeleCrafts acylation reaction, see: (a) Heaney, H. In Comprehensive Or-
ganic Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon: Oxford, 1991; Vol. 2,
p 733; (b) Olah, G. A. In FriedeleCrafts Chemistry; John Wiley and Sons: New York,
NY, 1973; For reviews on the intramolecular FriedeleCrafts acylation reaction,
see: (c) Heaney, H. In Comprehensive Organic Synthesis; Trost, B. M., Fleming, I.,
Eds.; Pergamon: Oxford, 1991; Vol. 2, p 753; (d) Sethna, S. In FriedeleCrafts and
Related Reactions; Olah, G. A., Ed.; Interscience: New York, NY, 1964; Vol. 3, p 911;
(e) Gore, P. H. Chem. Rev. 1955, 55, 229.
4.11.1. 1-Benzenesulfonyl-4-phenyl-1,2,3,5,8,8a-hexahydroquinoline
(4a). Yield 70%; viscous oil; IR (CHCl3) 3533, 2968, 1178 cmꢀ1
;
HRMS (ESI, Mþþ1) calcd for C21H22NO2S 352.1371, found 352.1377;
1H NMR (200 MHz):
d 7.91e7.86 (m, 2H), 7.55e49 (m, 3H),
7.27e7.21 (m, 3H), 6.92e6.87 (m, 2H), 5.63e5.57 (m,1H), 5.56e5.42
(m, 1H), 4.66e4.61 (m, 1H), 3.99e3.88 (m, 1H), 3.41e3.38 (m, 1H),
2.48e2.40 (m, 2H), 2.15e2.08 (m, 2H), 1.89e1.68 (m, 2H); 13C NMR
(50 MHz):
d
142.34, 136.12, 133.91, 132.33, 131.02, 128.66 (2ꢁ),
128.04 (2ꢁ), 127.72 (2ꢁ), 127.30 (2ꢁ), 126.53, 124.58, 117.79, 56.12,
38.79, 37.28, 35.88, 30.12.
8. For ring-closing metathesis, see: (a) Grubbs, R. H.; Miller, S. J.; Fu, G. C. Acc. Chem.
Res. 1995, 28, 446; (b) Schmalz, H. G. Angew. Chem., Int. Ed. Engl. 1995, 34, 1833;
(c) Schuster, M.; Blechert, S. Angew. Chem., Int. Ed. 1997, 36, 2036; (d) Armstrong,
S. K. J. Chem. Soc., Perkin Trans. 1 1998, 371; (e) Philips, A. J.; Abell, A. D. Al-
drichimica Acta 1999, 32, 75; (f) Pandit, U. K.; Overkleeft, H. S.; Borer, B. C.;
Bieraugel, H. Eur. J. Org. Chem. 1999, 5, 959; (g) Wright, D. L. Curr. Org. Chem. 1999,
3, 75; (h) Maier, M. E. Angew. Chem., Int. Ed. 2000, 39, 2073; (i) Felpin, F. X.;
Lebreton, J. Eur. J. Org. Chem. 2003, 9, 3693; (j) Cossy, J. Chem. Rec. 2005, 5, 70.
4.11.2. 1-Benzenesulfonyl-4-(4-chloro-3-trifluoromethylphenyl)-
1,2,3,5,8,8a-hexahydroquinoline (4b). Yield 62%; viscous oil; IR
(CHCl3) 3539, 2970, 1181 cmꢀ1; HRMS (ESI, Mþþ1) calcd for
C22H19ClF3NO2S 454.0855, found 454.0859; 1H NMR (200 MHz):
d
7.93e7.89 (m, 2H), 7.60e7.55 (m, 1H), 7.50e7.44 (m, 2H), 7.32
(d, J¼8.0 Hz, 1H), 6.89 (d, J¼2.0 Hz, 1H), 6.84 (dd, J¼2.0, 8.0 Hz, 1H),