The Construction of 3-Methyl-4-arylpiperidines via a trans- Perhydroindolic Acid-Catalyzed Asymmetric Aza-Diels-Alder Reaction

Article abstract of DOI:10.1002/adsc.201500550

An efficient trans-perhydroindolic acid-catalyzed asymmetric aza-Diels-Alder reaction of cyclic 1-azadienes and propanal was developed for the synthesis of chiral 3-methyl-4-aryldehydropiperidine derivatives (up to 98% yield and 99% ee). Such scaffolds are often found in bioactive compounds and medicines. A gram-scale reaction was carried out with a low catalyst loading to give the desired product in high yield and with excellent enantioselectivity. The resulting dehydropiperidine derivatives can be further transformed to chiral 3-methyl-4-aryl-substituted piperidines with high efficiency.

Full text of DOI:10.1002/adsc.201500550

FULL PAPERS
DOI: 10.1002/adsc.201500550
The Construction of 3-Methyl-4-arylpiperidines via a trans-
Perhydroindolic Acid-Catalyzed Asymmetric Aza-Diels–Alder
Reaction
Qianjin An,a Jiefeng Shen,a Nicholas Butt,a Delong Liu,a,* Yangang Liu,a
and Wanbin Zhanga,b,*
a
School of Pharmacy, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, Peopleꢀs Republic of China
School of Chemistry and Chemical Engineering, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240,
b
Peopleꢀs Republic of China
Fax: (+86)-21-5474-3265; phone: (+86)-21-5474-3265; e-mail: dlliu@sjtu.edu.cn or wanbin@sjtu.edu.cn
Received: June 6, 2015; Revised: September 8, 2015; Published online: November 12, 2015
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201500550.
Abstract: An efficient trans-perhydroindolic acid-cat- uct in high yield and with excellent enantioselectivi-
alyzed asymmetric aza-Diels–Alder reaction of cyclic ty. The resulting dehydropiperidine derivatives can
1-azadienes and propanal was developed for the syn- be further transformed to chiral 3-methyl-4-aryl-sub-
thesis of chiral 3-methyl-4-aryldehydropiperidine de- stituted piperidines with high efficiency.
rivatives (up to 98% yield and 99% ee). Such scaf-
folds are often found in bioactive compounds and Keywords: asymmetric catalysis; aza-Diels–Alder re-
medicines. A gram-scale reaction was carried out action; 3-methyl-4-arylpiperidines; trans-perhydroin-
with a low catalyst loading to give the desired prod- dolic acid
Introduction
NHC catalyst derived from l-pyroglutamic acid.[7] In
2012, Smith et al. developed a benzotetramisole-medi-
Chiral piperidine derivatives are among the most
prevalent nitrogen ring systems present in numerous
bioactive natural products and medicines (Figure 1).[1]
These scaffolds are found in a total of 72 currently
marketed small-molecule drugs approved by the Food
and Drug Administration (FDA).[2] Due to their chal-
lenging synthesis, the majority of chiral piperidine de-
rivatives are obtained via extraction from bioactive
natural products.[3] Considering its flexibility and effi-
ciency, the asymmetric aza-Diels–Alder reaction is
one of the most promising methodologies for the con-
struction of piperidines with multiple stereocen-
ters.[4–9] Several catalytic systems have been applied
successfully to the above reaction. In 2006, Bode and
co-workers reported a chiral N-heterocyclic carbene
(NHC)-catalyzed aza-Diels–Alder reaction between
dienophiles and a,b-unsaturated imines, giving chiral
dihydropyridinone products in good yields and with
remarkable enantioselectivities.[5] The following year,
Carretero et al. reported a chiral Lewis acid-mediated
aza-Diels–Alder reaction of 1-azadienes and enol
ethers to afford functionalized piperidine deriva-
tives.[6] Ye and co-workers developed an efficient
asymmetric aza-Diels–Alder reaction by using an Figure 1. Representative chiral piperidine derivatives.
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Qianjin An et al.
ated transformation for the synthesis of chiral poly- Results and Discussion
substituted dihydropyridones.[8] Chen and co-workers
reported an asymmetric aza-Diels–Alder reaction of We carried out the asymmetric aza-Diels–Alder reac-
aldehydes or ketones with 1-azadienes to provide pi- tion of cyclic 1-azadiene (1a) and propanal in the
peridine derivatives with excellent asymmetric re- presence of 1 equiv. N,N-dimethylaminopyridine
sults.[9] In order to prepare a more diverse range of (DMAP) in dichloromethane (DCM) at 158C.
chiral piperidine derivatives, the search for readily Adduct 2a was obtained using 10 mol% of the chiral
available and efficient chiral organocatalysts for use secondary amine catalysts. As shown in Table 1, trans-
in asymmetric aza-Diels–Alder reactions is a worth-
while endeavor.
Table 1. Screening for the reaction conditions.[a]
Our group has disclosed an efficient synthetic route
to trans-perhydroindolic acid, a key intermediate re-
quired for the synthesis of trandolapril and its isomer-
ic by-products.[10] These proline-like molecules have
proved to be excellent organocatalysts in several
types of asymmetric reaction.[10,11] Recently, a trans-
perhydroindolic acid-catalyzed aza-Diels–Alder reac-
tion of simple aldehydes and cyclic N-sulfonylimines
was developed, providing polysubstituted piperidine
derivatives in high yields and with excellent enantio-
selectivities [Scheme 1, Eq. (1)].[11e] However, poor
diastereoselectivities accompanied these promising re-
sults. By using a,b-unsaturated aldehydes, we were
able to obtain piperidine derivatives in high yields
and with excellent diastereo- and enantioselectivities
via a tandem reaction [Scheme 1, Eq. (2)].[11f] Un-
fortunately, these methodologies cannot be used to
prepare 3-methyl-4-aryl-substituted dehydropiperi-
dines, scaffolds which are found in a variety of bioac-
tive compounds and medicines (Figure 1).[12] We
herein report the synthesis of such scaffolds via
Entry Cat. Solvent Additive
Yield [%][b] ee [%][c]
a
trans-perhydroindolic acid-catalyzed aza-Diels–
1
2
3
4
5
6
I
DCM
DCM
DCM
DCM
DCM
DMAP
DMAP
DMAP
DMAP
DMAP
97
93
95
98
À68
8
Alder reaction of cyclic 1-azadienes and propanal
[Scheme 1, Eq. (3)].[13]
II
III
IV
V
I
I
I
NR
trace
85
60
39
–
–
95
63
58
–
CHCl3 DMAP
CH3CN DMAP
7[d]
8[d]
9
EtOH
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DMAP
–
I
trace
10
11
12
13
14
15
16[e]
17[f]
I
I
I
I
I
I
I
I
benzoic acid trace
DABCO
Et3N
DIPEA
TMEDA
Na2CO3
DMAP
DMAP
–
95
92
92
92
46
97
79
91
97
95
95
91
96
98
[a]
The reactions of 1a (26.9 mg, 0.1 mmol) and propanal
(10 equiv.) were carried out in a solvent using a chiral
catalyst (10 mol%) in the presence of an additive
(1 equiv.) at 158C for 6 h, affording 7:1 dr (determined
by 1H NMR spectra of the crude products).
Isolated yields.
Determined by chiral HPLC.
dr=2:1.
258C.
08C for 24 h.
[b]
[c]
[d]
[e]
[f]
Scheme 1. The construction of chiral piperidines.
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The Construction of 3-Methyl-4-arylpiperidines
Table 2. Screening for substrate scope.[a]
perhydroindolic acid (I) showed high reaction activity
as well as good enantioselectivity (entry 1). For com-
parison, proline and other proline-like organocatalysts
(II–IV) were also examined. The desired product was
obtained in high yield but only 68% ee when (II) was
used (entry 2). Use of cis-perhydroindolic acid (III)
gave the desired product with 8% ee, albeit with
quantitative conversion (entry 3). No reaction oc-
curred when using (S)-indoline-2-carboxylic acid (IV)
as an organocatalyst (entry 4). Finally, the proline de-
rivative, (S)-diphenylprolinol O-TMS ether (V), was
examined and only a trace amount of product was ob-
tained (entry 5). We therefore chose I for further in-
vestigations.
The effect of solvent on the reaction was investigat-
ed (entries 6–8). CHCl3 gave the desired cyclo-adduct
in 85% yield and 95% ee (entry 6). When CH3CN was
used, the reaction conditions provided only moderate
yield and enantioselectivity (entry 7). The protic alco-
hol EtOH gave the desired product in 39% yield and
with 58% ee (entry 8). DCM was found to be the best
solvent for this reaction. Our attention next turned to
screening for effective additives for the asymmetric
aza-Diels–Alder reaction (entries 9–14). Only trace
amounts of product were obtained in the presence/ab-
sence of acidic additives such as benzoic acid (en-
Entry X
R1
R2
Yield dr[c] ee
[%][b]
[%][d]
1
2
3
4
5
6
7
8
1a, n/a
H
H
H
H
H
H
H
H
H
H
H
H
Ph
97
92
88
95
93
90
90
7.0:1 98[e]
2.1:1 97/70
2.3:1 96/93
2.4:1 98/97
2.3:1 97/72
2.5:1 97/99
2.5:1 98/99
2.4:1 97/90
2.0:1 97/90
2.4:1 99/83
2.5:1 92/90
2.4:1 93/94
3.0:1 96[e]
2.5:1 98/72
2.8:1 97[e]
2.4:1 95/68
2.2:1 94/31
2.9:1 98/70
2.0:1 99/64
2.7:1 97[e]
6.1:1 88[e]
1b, n/a
1c, n/a
1d, n/a
1e, n/a
1f, n/a
1g, n/a
1h, n/a
1i, n/a
1j, n/a
1k, n/a
1l, n/a
2-FC6H4
3-FC6H4
4-FC6H4
4-ClC6H4
4-BrC6H4
4-CH3C6H4
4-CH3OC6H4 88
2-CH3OC6H4 85
3-CH3OC6H4 85
2-naphthyl
2-thienyl
Ph
Ph
Ph
9
10
11
12
13
14
15
16
17
18
88
90
90
98
95
93
95
94
90
93
75
1m, n/a 5-t-Bu
1n, O
1o, O
1p, O
1q, O
1r, O
1s, O
1t, O
1u, O
H
6-F
6-Cl
6-Br
6-CH3
6-OCH3 Ph
7-Br
H
Ph
Ph
Ph
tries 9 and 10). Conversely, the reactions proceeded 19
20
Ph
t-Bu
smoothly in the presence of organic bases to give 2a
21[f]
in excellent yields and enantioselectivities (entries 11–
14). Use of inorganic bases such as Na2CO3 gave the
desired product with high enantioselectivity but low
yield (entry 15). DMAP proved to be the best addi-
tive according to a combination of reaction activity
and stereoselectivity.
Temperature had only a slight effect on the enan-
tioselectivity but a more pronounced effect on reac-
tion activity. Increasing the reaction temperature to
258C resulted in a slight decrease in ee (entry 16). Re-
action at 08C resulted in a sharp decrease in reaction
activity but enantioselectivity remained unchanged
(entry 17). The optimal reaction conditions were
therefore found to be 10 mol% I in DCM in the pres-
ence of azadiene and 1.0 equiv. DMAP at 158C.
[a]
Unless otherwise specified, all the reactions of
1 (0.1 mmol) and propanal (10 equiv.) were carried out in
DCM using catalyst I (10 mol%) in the presence of
DMAP (1 equiv.) at 158C for 24 h, affording 2 with dr
from 2:1 to 7:1 (see Experimental Section).
Isolated yields of the products containing the major and
minor isomers.
[b]
[c]
[d]
[e]
Determined by 1H NMR.
Determined by chiral HPLC.
The enantiomers of the minor isomers are difficult to
separate.
This reaction was carried out in DCM using catalyst I
(20 mol%) in the presence of DMAP (2 equiv.) at 258C
for 24 h.
[f]
With the optimal reaction conditions in hand, the catalytic results were also observed (entries 11 and
applicability of the asymmetric aza-Diels–Alder reac- 12). A tert-butyl substituted five-membered cyclic 1-
tion to different substrates was evaluated (Table 2). azadiene 1m also gave the corresponding product in
Five-membered cyclic 1-azadienes bearing different excellent yield and good ee (entry 13). Subsequently,
substituent groups were first examined. Excellent six-membered cyclic 1-azadienes possessing different
enantioselectivities and high yields were observed for substituent groups were examined under the optimal
aromatic cyclic 1-azadienes bearing electron-with- reaction conditions. Excellent enantioselectivities and
drawing substituents (entries 2–6). Similarly, aromatic high yields were observed for substrates bearing both
cyclic 1-azadienes bearing electron-donating substitu- electron-withdrawing and electron-donating substitu-
ents also provided excellent results (entries 7–10). Up ents (entries 14–20). A six-membered cyclic 1-aza-
to 99% ee was obtained for a substrate bearing an diene 1u (R2 =t-Bu) was also subjected to the Diels–
MeO group at the 3-position of the phenyl ring Alder reaction, giving the corresponding product in
(entry 10). When the phenyl ring was replaced by moderate yield and good diastereo- and enantioselec-
either a naphthalene or a thiophene ring, excellent tivity (entry 21).
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Qianjin An et al.
An X-ray crystallography study was performed to ceeded slowly, and only 25% conversion was observed
determine the absolute configuration of the asymmet- even after 24 h at room temperature.
ric aza-Diels–Alder reaction products. A single crystal
To evaluate the practicality of this catalytic process,
of the product 2k was obtained via recrystallization a gram-scale reaction of 1a with propanal was carried
from ethyl acetate. X-ray crystal analysis shows that out with a relatively low catalyst loading. As shown in
the hydroxy group and naphthyl ring lie on the same Scheme 3, product 2a could be obtained in 86% yield
side of the six-membered piperidine ring, while the and with 90% ee when only 0.5 mol% of I was used
methyl group points towards the opposite direction (S/C=200). The resulting piperidine ring systems (2a)
(Figure 2).[14]
bearing contiguous multiple stereocenters have the
potential to participate in a variety of transformations.
For example, the hydroxy group and enamide can be
reduced simultaneously in the presence of Et3SiH/
BF3·Et2O to give chiral 3-methyl-4-aryl-substituted pi-
peridine 3a in high yield and ee.[15]
Conclusions
In summary, we have developed an efficient asymmet-
ric aza-Diels–Alder reaction of cyclic 1-azadienes and
propanal for the synthesis of chiral 3-methyl-4-aryl-
substituted piperidines in good yields (up to 98%)
and with excellent enantioselectivities (up to 99%). A
gram-scale reaction was carried out with a relatively
low catalyst loading to give the desired product in
86% yield and with 90% ee. The resulting piperidine
Figure 2. X-ray structure of compound 2k.
Based on our previous research and the absolute ring of 2a can be further transformed to the chiral 3-
configuration of the product 2k, a reaction pathway methyl-4-aryl substituted piperidine 3a with excellent
has been proposed (Scheme 2). Catalyst I reacts with results.
one molecule of propanal to generate an enamine.
The enamine then reacts with one molecule of 1a to
form the intermediate B via the transition state A (di-
rected by catalyst I). After the hydrolysis of B, alde-
Experimental Section
hyde C is formed. The resulting piperidine product 2a
is finally obtained (in the presence of DMAP) via top
surface attack of the sulfimide to the aldehyde group.
To determine that the final product was obtained via
the hydrolysis of B, we performed a control experi-
ment in the presence of 4Š MS. The reaction pro-
General
1H NMR (400 MHz) and 13C NMR (100 MHz) spectra were
recorded on a Varian MERCURY plus-400 spectrometer
with TMS as an internal standard. High resolution mass
spectra (HR-MS) were recorded at the Analysis Center of
Shanghai Jiao Tong University. Enantioselectivity was mea-
Scheme 2. Proposed reaction pathway.
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The Construction of 3-Methyl-4-arylpiperidines
Scheme 3. Gram-scale synthesis with low catalyst loading.
sured by high performance liquid chromatography
(HPLC) using Daicel Chiralcel AS-H and IC-3 columns
with n-hexane/i-PrOH as an eluent. Column chromatogra-
phy was performed using 100–200 mesh silica gel. Melting
points were measured with SGW X-4 micro melting point
apparatus.
a
(d, J=7.6 Hz, 1H), 7.74 (d, J=7.6 Hz, 1H), 7.65 (t, J=
7.2 Hz, 1H), 7.56 (t, J=7.6 Hz, 1H), 7.36–7.32 (m, 2H),
7.28–7.21 (m, 3H), 5.83 (t, J=1.2 Hz, 1H), 5.58 (d, J=
2.8 Hz, 1H), 4.26 (dd, J=5.2, 2.0 Hz, 1H), 2.42–2.39 (m,
1H), 0.63 (d, J=7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3):
d=140.9, 133.2, 132.0, 129.9, 129.5, 128.6, 128.5, 128.4, 126.7,
121.2, 121.1, 102.9, 77.0, 38.3, 37.1, 11.7; HR-MS (ESI):
m/z=328.1009, calcd for C18H18NO3S [M+H]+: 328.1007;
IR (KBr): n=2965, 2925, 1715, 1646, 1540, 1495, 1470, 1454,
1378, 1307, 1179, 1060, 1001, 943, 758, 702, 574, 526 cmÀ1.
(7R,8S,9R)-9-(2-Fluorophenyl)-7-hydroxy-8-methyl-8,9-di-
hydro-7H-benzo[4,5]isothiazolo[2,3-a]pyridine 5,5-dioxide
(2b): Rf =0.25 (petroleum ether/EtOAc 4:1); white solid;
yield: 21.5 mg (62%); mp 60–618C; 1H NMR (400 MHz,
CDCl3): d=7.84–7.81 (m, 1H), 7.67–7.61 (m, 2H), 7.58–7.54
(m, 1H), 7.29–7.21 (m, 2H), 7.16–7.06 (m, 2H), 5.70 (d, J=
1.6 Hz, 1H), 5.68 (d, J=2.4 Hz, 1H), 4.00 (dd, J=11.6,
2.4 Hz, 1H), 3.55 (s, 1H), 2.26–2.17 (m, 1H), 1.06 (dd, J=
6.8, 0.4 Hz, 1H); 13C NMR (100 MHz, CDCl3): d=161.3 (d,
J=246.9 Hz), 133.5, 132.3, 130.2, 130.1 (d, J=3.7 Hz), 130.0,
129.6, 129.5, 128.9, 128.8, 124.7 (d, J=2.7 Hz), 124.2, 121.5
(d, J=3.0 Hz), 115.8 (d, J=22.5 Hz), 105.4, 76.0, 39.4, 35.5,
15.2; HR-MS (ESI): m/z=346.0914, calcd. for C18H17NO3SF
[M+H]+: 346.0913; IR (KBr): n=2971, 2931, 1671, 1598,
1584, 1499, 1470, 1454, 1380, 1305, 1226, 1181, 1154, 1061,
1043, 1031, 985, 951, 757, 660, 602 cmÀ1; HPLC (Chiralcel
IC-3, n-hexane/i-PrOH=90:10, UV=254 nm, flow rate=
0.9 mLminÀ1): tR1 =55.47 min (minor) and tR2 =58.15 min
(major); ee=97%; [a]2D5: À72.5 (c 0.5, CH3OH).
General Procedure for the Aza-Diels–Alder Addition
trans-Perhydroindolic acid I (1.7 mg, 0.01 mmol), DMAP
(12.2 mg, 0.10 mmol) and propanal (10.0 equiv., 1.0 mmol)
were dissolved in DCM (1 mL) at 158C and the resulting so-
lution was stirred for 5 min. The appropriate cyclic 1-aza-
diene (0.10 mmol) was then added to the solution and the
reaction mixture was stirred at 158C until the complete con-
sumption of cyclic 1-azadiene (monitored by TLC). The sol-
vent was evaporated and the crude product was purified by
flash column chromatography on silica gel (PE/EA=10/1–6/
1) to give the adduct 2.
(7R,8S,9R)-7-Hydroxy-8-methyl-9-phenyl-8,9-dihydro-7H-
benzo[4,5]isothiazolo[2,3-a]pyridine 5,5-dioxide (2a): Rf =
0.25 (petroleum ether/EtOAc 4:1); white solid; yield:
27.7 mg (85%); mp 142–1438C; 1H NMR (400 MHz,
CDCl3): d=7.83 (d, J=8.0 Hz, 1H), 7.64–7.63 (m, 2H),
7.58–7.54 (m, 1H), 7.37–7.34 (m, 2H), 7.31–7.29 (m, 1H),
7.24 (d, J=7.2 Hz, 2H), 5.73 (d, J=2.8 Hz, 1H), 5.70 (d, J=
2.0 Hz, 1H), 3.65 (s, 1H), 3.56 (dd, J=11.2, 2.4 Hz, 1H),
2.18–2.10 (m, 1H), 1.03 (d, J=6.8 Hz, 3H); 13C NMR
(100 MHz, CDCl3): d=142.8, 133.5, 132.2, 130.4, 130.2,
130.1, 128.9, 128.8, 128.5, 127.3, 121.5, 121.5, 106.6, 76.1,
42.7, 40.1, 15.4; HR-MS (ESI): m/z=328.1010, calcd. for
C18H18NO3S [M+H]+: 328.1007; IR (KBr): n=3480, 2923,
2852, 1662, 1600, 1494, 1470, 1453, 1379, 1305, 1181, 1152,
1060, 1038, 946, 759, 702, 573, 529 cmÀ1; HPLC (Chiralcel
AS-H, n-hexane/i-PrOH=80:20, UV=254 nm, flow rate=
0.7 mLminÀ1): tR1 =18.68 min (minor) and tR2 =38.85 min
(major); ee=98%; [a]2D5: À40.5 (c 0.2, CH3OH).
(7S,8S,9R)-9-(2-Fluorophenyl)-7-hydroxy-8-methyl-8,9-di-
hydro-7H-benzo[4,5]isothiazolo[2,3-a]pyridine 5,5-dioxide
(2b’): Rf =0.23 (petroleum ether/EtOAc 4:1); white solid;
1
yield: 10.2 mg (30%); mp 113–1148C; H NMR (400 MHz,
CDCl3): d=7.84 (d, J=7.6 Hz, 1H), 7.77 (d, J=7.6 Hz, 1H),
7.69–7.65 (m, 1H), 7.59 (t, J=7.2 Hz, 1H), 7.30–7.23 (m,
2H), 7.15 (d, J=7.6 Hz, 1H), 7.10–7.06 (m, 1H), 5.78 (d, J=
1.6 Hz, 1H), 5.61 (s, 1H), 4.60 (dd, J=5.2, 2.4 Hz, 1H), 3.69
(s, 1H), 2.60–2.56 (m, 1H), 0.68 (d, J=7.2 Hz, 3H);
13C NMR (100 MHz, CDCl3): d=161.17 (d, J=245.7 Hz),
133.4, 132.3, 130.50 (d, J=3.9 Hz), 130.2, 129.8, 129.2, 128.76
(d, J=8.2 Hz), 128.1, 124.1 (d, J=2.9 Hz), 121.5, 121.4, 115.7
(7S,8S,9R)-7-Hydroxy-8-methyl-9-phenyl-8,9-dihydro-7H-
benzo[4,5]isothiazolo[2,3-a]pyridine 5,5-dioxide (2a’): Rf =
0.23 (petroleum ether/EtOAc 4:1); white solid; yield: 4.0 mg
1
(12%); mp 99–1008C; H NMR (400 MHz, CDCl3): d=7.82
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(d, J=22.0 Hz), 102.2, 77.3, 35.2, 32.5, 12.3; HR-MS (ESI):
m/z=346.0910, calcd. for C18H17NO3SF [M+H]+: 346.0913;
IR (KBr): n=2923, 2851, 1668, 1489, 1470, 1455, 1380, 1307,
1268, 1226, 1180, 1152, 1135, 1060, 1034, 1003, 945, 789, 757,
597 cmÀ1; HPLC (Chiralcel AS-H, n-hexane/iPrOH=80:20,
alcel AS-H, n-hexane/i-PrOH=80:20, UV=254 nm, flow
rate=0.5 mLminÀ1):
tR1 =27.83 min (minor) and tR2 =
66.64 min (major); ee=98%; [a]25: À65.8 (c 0.2, CH3OH).
(7S,8S,9R)-9-(4-Fluorophenyl)D-7-hydroxy-8-methyl-8,9-di-
hydro-7H-benzo[4,5]isothiazolo[2,3-a]pyridine 5,5-dioxide
(2d’): Rf =0.17 (petroleum ether/EtOAc 4:1); white solid;
yield: 9.7 mg (28%); mp 128–1308C; 1H NMR (400 MHz,
CDCl3): d=7.84 (d, J=7.6 Hz, 1H), 7.76 (d, J=7.6 Hz, 1H),
7.69–7.65 (m, 1H), 7.58 (t, J=7.6 Hz, 1H), 7.25–7.21 (m,
2H), 7.07–7.03 (m, 2H), 5.79–5.78 (m, 1H), 5.60 (s, 1H),
4.27–4.25 (m, 1H), 3.75 (s, 1H), 2.40–2.37 (m, 1H), 0.65 (d,
J=7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=162.02 (d,
J=243.8 Hz), 136.9, 133.4, 132.4, 130.3, 130.2, 130.1, 129.7,
129.0, 121.4 (d, J=12.4 Hz), 115.5 (d, J=21.1 Hz), 102.7,
77.2, 37.9, 37.3, 11.9; HR-MS (ESI): m/z=346.0913, calcd.
for C18H17NO3SF [M+H]+: 346.0913; IR (KBr): n=2926,
2854, 1667, 1603, 1509, 1470, 1454, 1417, 1380, 1308, 1266,
1179, 1157, 1087, 1060, 1003, 847, 811, 761, 703, 631,
617 cmÀ1; HPLC (Chiralcel AS-H, n-hexane/i-PrOH=80:20,
UV=254 nm, flow rate=0.4 mLminÀ1):
tR1 =40.86 min
(major) and tR2 =44.23 min (minor); ee=70%; [a]2D5: À27.3
(c 0.1, CH3OH).
(7R,8S,9R)-9-(3-Fluorophenyl)-7-hydroxy-8-methyl-8,9-di-
hydro-7H-benzo[4,5]isothiazolo[2,3-a]pyridine 5,5-dioxide
(2c): Rf =0.20 (petroleum ether/EtOAc 4:1); white solid;
yield: 21.1 mg (61%); mp 69–708C; 1H NMR (400 MHz,
CDCl3): d=7.83 (d, J=8.0 Hz, 1H), 7.67–7.62 (m, 2H),
7.59–7.55 (m, 1H), 7.34–7.28 (m, 1H), 7.03 (d, J=7.6 Hz,
1H), 7.01–6.93 (m, 2H), 5.69 (d, J=2.0 Hz, 2H), 3.62 (s,
1H), 3.57 (dd, J=11.6, 2.4 Hz, 1H), 2.13–2.09 (m, 1H), 1.04
(d, J=6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=163.2
(d, J=245.3 Hz), 145.5, 133.5, 132.3, 130.4, 130.3, 129.9,
128.8, 124.5, 121.6(d, J=5.5 Hz), 115.6 (d, J=21.3 Hz),
114.3(d, J=20.7 Hz), 105.6, 75.9, 42.6, 40.1, 15.4; HR-MS
(ESI): m/z=346.0917, calcd. for C18H17NO3SF [M+H]+:
346.0913; IR (KBr): n=2962, 2924, 2854, 1670, 1614, 1588,
1486, 1470, 1450, 1379, 1305, 1261, 1182, 1153, 1095, 1038,
1023, 966, 929, 789, 764, 713, 700, 664, 601 cmÀ1; HPLC
(Chiralcel AS-H, n-hexane/i-PrOH=80:20, UV=254 nm,
UV=254 nm, flow rate=0.5 mLminÀ1):
tR1 =48.46 min
(minor) and tR2 =91.13 min (major); ee=97%; [a]2D5: À11.5
(c 0.2, CH3OH).
(7R,8S,9R)-9-(4-Chlorophenyl)-7-hydroxy-8-methyl-8,9-di-
hydro-7H-benzo[4,5]isothiazolo[2,3-a]pyridine 5,5-dioxide
(2e): Rf =0.19 (petroleum ether/EtOAc 4:1); white solid;
yield: 23.4 mg (65%); mp 79–808C; 1H NMR (400 MHz,
CDCl3): d=7.83 (d, J=7.6 Hz, 1H), 7.66–7.64 (m, 2H),
7.60–7.56 (m, 1H), 7.33–7.31 (m, 2H), 7.18–7.16 (m, 2H),
5.69 (d, J=2.4 Hz, 1H), 5.67 (d, J=2.4 Hz, 1H), 3.54 (dd,
J=11.2, 2.4 Hz, 1H), 2.13–2.05 (m, 1H), 1.03 (d, J=6.8 Hz,
3H); 13C NMR (100 MHz, CDCl3): d=141.3, 133.6, 133.1,
130.4, 130.1, 129.9, 129.1, 128.8, 121.6, 105.8, 76.0, 42.2, 40.1,
flow rate=0.7 mLminÀ1): tR1 =19.88 min (minor) and tR2
58.82 min (major); ee=96%; [a]25: À68.0 (c 0.2, CH3OH).
=
(7S,8S,9R)-9-(3-Fluorophenyl)D-7-hydroxy-8-methyl-8,9-di-
hydro-7H-benzo[4,5]isothiazolo[2,3-a]pyridine 5,5-dioxide
(2c’): Rf =0.18 (petroleum ether/EtOAc 4:1); white solid;
yield: 9.2 mg (27%); mp 60–618C; 1H NMR (400 MHz,
CDCl3): d=7.84 (d, J=8.0 Hz, 1H), 7.77 (d, J=7.6 Hz, 1H),
7.68 (t, J=7.2 Hz, 1H), 7.59 (t, J=7.6 Hz, 1H), 7.33 (dd, J=
14.8, 7.2 Hz, 1H), 7.07 (d, J=7.6 Hz, 1H), 6.99 (d, J=
9.2 Hz, 2H), 5.79 (s, 1H), 5.60 (s, 1H), 4.29–4.27 (m, 1H),
3.77 (s, 1H), 2.44–2.39 (m, 1H), 0.66 (d, J=7.2 Hz, 3H);
13C NMR (100 MHz, CDCl3): d=163.1 (d, J=244.7 Hz),
143.9 (d, J=6.6 Hz), 133.51, 132.4, 130.3, 130.15 (d, J=
8.1 Hz), 129.7, 129.1, 124.4, 121.50 (d, J=7.2 Hz), 115.6 (d,
J=21.3 Hz), 113.94 (d, J=21.0 Hz), 102.0, 38.4, 37.3, 11.9;
HR-MS (ESI): m/z=346.0915, calcd. for C18H17NO3SF [M+
H]+: 346.0913; IR (KBr): n=2921, 2850, 1667, 1614, 1588,
1487, 1470, 1453, 1307, 1267, 1242, 1180, 1151, 1090, 1060,
1003, 970, 918, 788, 760, 653, 573 cmÀ1; HPLC (Chiralcel
AS-H, n-hexane/i-PrOH=80:20, UV=254 nm, flow rate=
0.5 mLminÀ1): tR1 =30.29 min (major) and tR2 =34.00 min
(minor); ee=93%; [a]2D5: À7.8 (c 0.1, CH3OH).
15.4;
HR-MS
(ESI):
m/z=362.0623,
calcd.
for
C18H17NO3SCl [M+H]+: 362.0618; IR (KBr): n=2924, 2853,
1491, 1470, 1407, 1305, 1182, 1153, 1090, 1060, 1038, 1014,
984, 950, 823, 757, 722, 616, 602 cmÀ1; HPLC (Chiralcel AS-
H, n-hexane/i-PrOH=80:20, UV=254 nm, flow rate=
0.6 mLminÀ1): tR1 =25.59 min (minor) and tR2 =55.83 min
(major); ee=97%; [a]2D5: À45.3 (c 0.1, CH3OH).
(7S,8S,9R)-9-(4-Chlorophenyl)-7-hydroxy-8-methyl-8,9-di-
hydro-7H-benzo[4,5]isothiazolo[2,3-a]pyridine 5,5-dioxide
(2e’): Rf =0.17 (petroleum ether/EtOAc 4:1); white solid;
yield: 10.2 mg (28%); mp 82–838C; 1H NMR (400 MHz,
CDCl3): d=7.84 (d, J=7.6 Hz, 1H), 7.76 (d, J=8.0 Hz, 1H),
7.68 (td, J=7.6, 1.2 Hz, 1H), 7.59 (td, J=8.0, 0.8 Hz, 1H),
7.34 (d, J=8.4 Hz, 2H), 7.21 (d, J=8.0 Hz, 2H), 5.78 (dd,
J=2.4, 1.2 Hz, 1H), 5.60 (d, J=2.8 Hz, 1H), 4.26 (dd, J=
5.2, 2.4 Hz, 1H), 3.68 (s, 1H), 2.42–2.37 (m, 1H), 0.65 (d,
J=6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=139.4,
133.2, 132.6, 132.0, 130.1, 129.8, 128.9, 128.6, 121.3, 121.1,
109.9 102.0, 77.1, 37.8, 36.9, 11.7; HR-MS (ESI): m/z=
362.0620, calcd. for C18H17NO3SCl [M+H]+: 362.0618; IR
(KBr): n=2917, 2848, 1715, 1660, 1646, 1490, 1470, 1456,
1409, 1379, 1339, 1308, 1260, 1181, 1152, 1135, 1060, 1014,
1003, 942, 843, 760, 615 cmÀ1; HPLC (Chiralcel AS-H, n-
(7R,8S,9R)-9-(4-Fluorophenyl)-7-hydroxy-8-methyl-8,9-di-
hydro-7H-benzo[4,5]isothiazolo[2,3-a]pyridine 5,5-dioxide
(2d): Rf =0.18 (petroleum ether/EtOAc 4:1); white solid;
yield: 23.2 mg (67%); mp 72–738C; 1H NMR (400 MHz,
CDCl3): d=7.83 (d, J=8.0 Hz, 1H), 7.66–7.64 (m, 2H),
7.59–7.55 (m, 1H), 7.22–7.18 (m, 2H), 7.06–7.02 (m, 2H),
5.69 (d, J=2.4 Hz, 2H), 3.55 (dd, J=11.2, 2.4 Hz, 1H),
2.13–2.05 (m, 1H), 1.03 (d, J=6.8 Hz, 3H); 13C NMR
(100 MHz, CDCl3): d=160.0 (d, J=162.4 Hz), 138.5, 133.5,
132.2, 130.4, 130.2 (d, J=7.8 Hz), 130.0 (d, J=8.6 Hz), 128.6,
127.1, 121.5, 115.7 (d, J=21.2 Hz), 106.2, 76.0, 42.0, 40.3,
15.4; HR-MS (ESI): m/z=346.0916, calcd. for C18H17NO3SF
[M+H]+: 346.0913; IR (KBr): n=2970, 2931, 1670, 1603,
1508, 1470, 1379, 1304, 1222, 1181, 1156, 1061, 1038, 1016,
984, 950, 832, 784, 757, 732, 631, 618, 602 cmÀ1; HPLC (Chir-
hexane/i-PrOH=80:20,
UV=254 nm,
flow
rate=
0.6 mLminÀ1): tR1 =30.01 min (major) and tR2 =39.82 min
(minor); ee=72%; [a]2D5: À9.5 (c 0.1, CH3OH).
(7R,8S,9R)-9-(4-Bromophenyl)-7-hydroxy-8-methyl-8,9-di-
hydro-7H-benzo[4,5]isothiazolo[2,3-a]pyridine 5,5-dioxide
(2f): Rf =0.19 (petroleum ether/EtOAc 4:1); white solid;
yield: 26.0 mg (64%); mp 76–778C; 1H NMR (400 MHz,
3632
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ꢁ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2015, 357, 3627 – 3638

FULL PAPERS
The Construction of 3-Methyl-4-arylpiperidines
CDCl3): d=7.83 (d, J=8.0 Hz, 1H), 7.65–7.64 (m, 2H),
7.61–7.55 (m, 1H), 7.48–7.46 (m, 2H), 7.13–7.11 (m, 2H),
5.68 (d, J=2.4 Hz, 1H), 5.67 (d, J=2.4 Hz, 1H), 3.53 (dd,
J=11.2, 2.4 Hz, 1H), 2.11–2.06 (m, 1H), 1.02 (d, J=6.8 Hz,
3H); 13C NMR (100 MHz, CDCl3): d=141.9, 133.6, 132.3,
132.0, 130.5, 129.9, 128.8, 121.6, 121.1, 105.7, 76.0, 42.3, 40.1,
525 cmÀ1; HPLC (Chiralcel AS-H, n-hexane/i-PrOH=80:20,
UV=254 nm, flow rate=0.5 mLminÀ1):
tR1 =28.01 min
(major) and tR2 =32.67 min (minor); ee=99%; [a]2D5: +30.3
(c 0.1, CH3OH).
(7R,8S,9R)-7-Hydroxy-9-(4-methoxyphenyl)-8-methyl-8,9-
dihydro-7H-benzo[4,5]isothiazolo[2,3-a]pyridine 5,5-dioxide
(2h): Rf =0.15 (petroleum ether/EtOAc 4:1); white solid;
yield: 22.2 mg (62%); mp 71–728C; 1H NMR (400 MHz,
CDCl3): d=7.83 (d, J=7.6 Hz, 1H), 7.64–7.61 (m, 2H),
7.58–7.54 (m, 1H), 7.17–7.14 (m, 2H), 6.90–6.87 (m, 2H),
5.72 (d, J=2.4 Hz, 1H), 5.69 (d, J=1.6 Hz, 1H), 3.81 (s,
3H), 3.50 (dd, J=10.8, 2.4 Hz, 2H), 2.13–2.05 (m, 1H), 1.03
(d, J=6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=158.8,
134.8, 133.5, 132.2, 130.2, 130.1, 129.6, 129.4, 128.3, 121.5,
121.5, 114.3, 106.9, 76.0, 55.5, 41.8, 40.3, 15.4; HR-MS (ESI):
m/z=358.1118, calcd. for C19H20NO4S [M+H]+: 358.1113;
IR (KBr): n=2923, 2852, 1511, 1468, 1302, 1247, 1179, 1152,
1305, 755 cmÀ1; HPLC (Chiralcel IC-3, n-hexane/i-PrOH=
15.4;
HR-MS
(ESI):
m/z=406.0116,
calcd.
for
C18H17NO3SBr [M+H]+: 406.0113; IR (KBr): n=2923, 2853,
1487, 1470, 1452, 1402, 1304, 1182, 1153, 1093, 1072, 1060,
1038, 984, 950, 820, 757, 612 cmÀ1; HPLC (Chiralcel AS-H,
n-hexane/i-PrOH=80:20,
UV=254 nm,
flow
rate=
0.5 mLminÀ1): tR1 =31.32 min (minor) and tR2 =78.03 min
(major); ee=97%; [a]2D5: À60.1 (c 0.1, CH3OH).
(7S,8S,9R)-9-(4-Bromophenyl)-7-hydroxy-8-methyl-8,9-di-
hydro-7H-benzo[4,5]isothiazolo[2,3-a]pyridine 5,5-dioxide
(2f’): Rf =0.17 (petroleum ether/EtOAc 4:1); white solid;
yield: 10.4 mg (26%); mp 90–918C; 1H NMR (400 MHz,
CDCl3): d=7.85–7.82 (m, 1H), 7.76 (d, J=7.6 Hz, 1H), 7.68
(td, J=7.6, 1.2 Hz, 1H), 7.61–7.57 (m, 1H), 7.49 (d, J=
8.4 Hz, 1H), 7.16 (d, J=8.4 Hz, 1H), 5.77 (dd, J=2.8,
1.2 Hz, 1H), 5.59 (d, J=2.4 Hz, 1H), 4.25 (dd, J=5.6,
2.8 Hz, 1H), 3.72 (s, 1H), 2.41–2.37 (m, 1H), 0.65 (d, J=
6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=137.4, 130.7,
129.4, 128.9, 127.6, 127.5, 126.8, 126.3, 118.7, 118.6, 118.0,
99.4, 35.3, 34.3, 9.1; HR-MS (ESI): m/z=406.0114, calcd. for
C18H17NO3SBr [M+H]+: 406.0113; IR (KBr): n=2922, 2850,
1666, 1488, 1470, 1404, 1379, 1307, 1260, 1234, 1179, 1152,
90:10, UV=254 nm, flow rate=1.0 mLminÀ1): tR1
=
69.35 min (minor) and tR2 =75.34 min (major); ee=97%;
[a]25: À50.3 (c 0.1, CH3OH).
(D7S,8S,9R)-7-Hydroxy-9-(4-methoxyphenyl)-8-methyl-8,9-
dihydro-7H-benzo[4,5]isothiazolo[2,3-a]pyridine 5,5-dioxide
(2h’): Rf =0.14 (petroleum ether/EtOAc 4:1); colorless oil;
1
yield: 9.2 mg (26%); H NMR (400 MHz, CDCl3): d=7.83
(d, J=8.0 Hz, 1H), 7.75 (d, J=8.0 Hz, 1H), 7.68–7.64 (m,
1H), 7.57 (t, J=7.2 Hz, 1H), 7.18 (d, J=8.4 Hz, 1H), 6.90
(d, J=8.8 Hz, 1H), 5.82 (dd, J=2.4, 0.8 Hz, 1H), 5.59 (s,
1H), 4.23 (dd, J=5.6, 2.8 Hz, 1H), 3.82 (s, 3H), 3.68 (s,
1H), 2.40–2.36 (m, 1H), 0.66 (d, J=7.2 Hz, 3H); 13C NMR
(100 MHz, CDCl3): d=158.7, 133.4, 133.1, 132.3, 130.1,
129.9, 129.7, 128.8, 121.5, 121.3, 114.1, 103.5, 77.3, 55.5, 37.8,
37.4, 12.0; HR-MS (ESI): m/z=358.1115, calcd. for
C19H20NO4S [M+H]+: 358.1113; IR (KBr): n=2922, 2849,
1748, 1732, 1715, 1697, 1609, 1540, 1151, 1469, 1378, 1339,
1330, 1248, 1176, 1151, 1134, 1087, 1002, 942, 841, 760, 630,
566 cmÀ1; HPLC (Chiralcel AS-H, n-hexane/i-PrOH=80:20,
135, 1060, 1009, 942, 919, 842, 806, 760, 674, 614, 580 cmÀ1
;
HPLC (Chiralcel AS-H, n-hexane/i-PrOH=80:20, UV=
254 nm, flow rate=0.5 mLminÀ1): tR1 =38.90 min (major);
ee=99%; [a]25: À6.1 (c 0.1, CH3OH).
(7R,8S,9R)D-7-Hydroxy-8-methyl-9-(p-tolyl)-8,9-dihydro-
7H-benzo[4,5]isothiazolo[2,3-a]pyridine 5,5-dioxide (2g):
Rf =0.25 (petroleum ether/EtOAc 4:1); white solid; yield:
1
22.0 mg (64%); mp 74–758C; H NMR (400 MHz, CDCl3):
d=7.83 (d, J=7.6 Hz, 1H), 7.64–7.63 (m, 2H), 7.59–7.54 (m,
1H), 7.15 (q, J=8.0 Hz, 4H), 5.72 (d, J=2.8 Hz, 1H), 5.69
(d, J=2.4 Hz, 1H), 3.51 (dd, J=11.2, 2.4 Hz, 1H), 2.36 (s,
3H), 2.16–2.09 (m, 1H), 1.03 (d, J=6.8 Hz, 3H); 13C NMR
(100 MHz, CDCl3): d=139.7, 137.0, 133.5, 132.2, 130.2,
130.1, 129.6, 128.6, 128.3, 121.5, 121.5, 106.9, 76.2, 42.3, 40.1,
21.3, 15.5; HR-MS (ESI): m/z=342.1163, calcd. for
C19H20NO3S [M+H]+: 342.1164; IR (KBr): n=2923, 2853,
1513, 1470, 1305, 1265, 1181, 1153, 1110, 1060, 1038, 1021,
983, 950, 818, 755, 735, 637, 603 cmÀ1; HPLC (Chiralcel AS-
H, n-hexane/i-PrOH=80:20, UV=254 nm, flow rate=
0.5 mLminÀ1): tR1 =23.45 min (major) and tR2 =47.50 min
(minor); ee=98%; [a]2D5: À57.5 (c 0.2, CH3OH).
UV=254 nm, flow rate=0.5 mLminÀ1):
tR1 =47.33 min
(major) and tR2 =59.12 min (minor); ee=90%; [a]2D5: +2.6 (c
0.1, CH3OH).
(7R,8S,9R)-7-Hydroxy-9-(2-methoxyphenyl)-8-methyl-8,9-
dihydro-7H-benzo[4,5]isothiazolo[2,3-a]pyridine 5,5-dioxide
(2i): Rf =0.17 (petroleum ether/EtOAc 4:1); white solid;
yield: 20.2 mg (57%); mp 84–858C; 1H NMR (400 MHz,
CDCl3): d=7.82–7.80 (m, 1H), 7.62–7.61 (m, 2H), 7.56–7.52
(m, 1H), 7.28–7.24 (m, 1H), 7.17 (dd, J=7.6, 1.6 Hz, 1H),
6.97–6.91 (m, 2H), 5.69 (d, J=2.8 Hz, 2H), 4.16 (dd, J=
11.2, 2.0 Hz, 1H), 3.83 (s, 3H), 3.51 (s, 1H), 2.28–2.21 (m,
1H), 1.03 (d, J=6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3):
d=157.8, 133.4, 132.1, 130.9, 130.2, 130.0, 129.2, 128.2, 121.4,
121.1, 111.0, 107.3, 76.2, 55.6, 39.4, 35.0, 15.2; HR-MS (ESI):
m/z=358.1114, calcd. for C19H20NO4S [M+H]+: 358.1113;
IR (KBr): n=2926, 2837, 1598, 1492, 1469, 1438, 1304, 1243,
1181, 1154, 1026, 949, 755, 664, 619 cmÀ1; HPLC (Chiralcel
IC-3, n-hexane/i-PrOH=90:10, UV=254 nm, flow rate=
1.0 mLminÀ1): tR1 =78.53 min (major) and tR2 =88.16 min
(minor); ee=97%; [a]2D5: À52.9 (c 0.4, CH3OH).
(7S,8S,9R)-7-Hydroxy-8-methyl-9-(p-tolyl)-8,9-dihydro-
7H-benzo[4,5]isothiazolo[2,3-a]pyridine 5,5-dioxide (2g’):
Rf =0.23 (petroleum ether/EtOAc 4:1); white solid; yield:
8.8 mg (26%); mp 68–698C; 1H NMR (400 MHz, CDCl3):
d=7.83 (d, J=8.0 Hz, 1H), 7.76 (d, J=7.6 Hz, 1H), 7.67 (t,
J=7.2 Hz, 1H), 7.57 (t, J=7.6 Hz, 1H), 7.17 (s, 4H), 5.84–
5.83 (m, 1H), 5.60 (s, 1H), 4.24 (dd, J=5.2, 2.4 Hz, 1H),
3.70 (s, 1H), 2.42–2.38 (m, 1H), 2.36 (s, 3H), 0.66 (d, J=
7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=138.0, 136.6,
133.4, 132.3, 130.1, 129.9, 129.3, 128.8, 128.6, 121.4, 121.4,
103.4, 77.3, 38.2, 37.4, 21.2, 12.0; HR-MS (ESI): m/z=
342.1165, calcd. for C19H20NO3S [M+H]+: 342.1164; IR
(KBr): n=2924, 2853, 1667, 1514, 1470, 1456, 1308, 1235,
1178, 1152, 1135, 1088, 1060, 1020, 1003, 943, 760, 632, 593,
(7S,8S,9R)-7-Hydroxy-9-(2-methoxyphenyl)-8-methyl-8,9-
dihydro-7H-benzo[4,5]isothiazolo[2,3-a]pyridine 5,5-dioxide
(2i’): Rf =0.15 (petroleum ether/EtOAc 4:1); white solid;
yield: 10.1 mg (28%); mp 72–738C; 1H NMR (400 MHz,
CDCl3): d=7.83–7.81 (m, 1H), 7.75 (d, J=8.0 Hz, 1H),
Adv. Synth. Catal. 2015, 357, 3627 – 3638
ꢁ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
3633

FULL PAPERS
Qianjin An et al.
7.67–7.63 (m, 1H), 7.55 (t, J=8.0 Hz, 1H), 7.28–7.24 (m,
1H), 7.18 (dd, J=7.6, 1.2 Hz, 1H), 6.95 (td, J=7.6, 1.2 Hz,
1H), 6.90 (d, J=8.4 Hz, 1H), 5.80 (dd, J=2.4, 0.8 Hz, 1H),
5.59 (d, J=3.2 Hz, 1H), 4.65 (dd, J=5.2, 2.8 Hz, 1H), 3.86
(s, 3H), 2.67–2.64 (m, 1H), 0.61 (d, J=6.8 Hz, 3H);
13C NMR (100 MHz, CDCl3): d=157.4, 133.3, 132.3, 130.0,
130.0, 129.8, 129.4, 128.8, 128.1, 121.4, 121.3, 120.4, 110.4,
104.2, 77.6, 55.6, 33.9, 32.6, 12.6; HR-MS (ESI): m/z=
358.1114, calcd. for C19H20NO4S [M+H]+: 358.1113; IR
(KBr): n=2929, 2837, 1668, 1598, 1585, 1492, 1470, 1438,
1397, 1305, 1241, 1179, 1135, 1112, 1050, 1025, 1002, 943,
918, 753, 735, 723, 615, 597, 587 cmÀ1; HPLC (Chiralcel AS-
H, n-hexane/i-PrOH=80:20, UV=254 nm, flow rate=
0.4 mLminÀ1): tR1 =46.51 min (major) and tR2 =62.12 min
(minor); ee=90%; [a]25: À31.5 (c 0.2, CH3OH).
128.7, 128.6, 127.9, 127.8, 127.6, 126.6, 126.5, 126.0, 121.6,
121.5, 106.5, 76.1, 42.9, 40.1, 15.5; HR-MS (ESI): m/z=
378.1166, calcd. for C22H20NO3S [M+H]+: 378.1164; IR
(KBr): n=2958, 2918, 2852, 1468, 1305, 1262, 1181, 1153,
1093, 1060, 1018, 802, 753 cmÀ1; HPLC (Chiralcel AS-H, n-
hexane/i-PrOH=80:20,
UV=254 nm,
flow
rate=
0.6 mLminÀ1): tR1 =27.88 min (minor) and tR2 =65.55 min
(major); ee=92%; [a]2D5: À101.1 (c 0.1, CH3OH).
(7S,8S,9R)-7-Hydroxy-8-methyl-9-(naphthalen-2-yl)-8,9-
dihydro-7H-benzo[4,5]isothiazolo[2,3-a]pyridine 5,5-dioxide
(2k’): Rf =0.16 (petroleum ether/EtOAc 4:1); white solid;
yield: 9.5 mg (25%); mp 189–1908C; 1H NMR (400 MHz,
CDCl3): d=7.86–7.81 (m, 5H), 7.72–7.71 (m, 1H), 7.69 (dd,
J=8.0, 1.2 Hz, 1H), 7.59 (t, J=7.2 Hz, 1H), 7.50–7.47 (m,
2H), 7.41 (dd, J=8.4, 1.6 Hz, 1H), 5.98 (dd, J=2.4, 1.2 Hz,
1H), 5.65 (d, J=2.4 Hz, 1H), 4.45 (dd, J=5.2, 2.4 Hz, 1H),
3.81 (s, 1H), 2.55–2.52 (m, 1H), 0.75–0.60 (t, J=7.2 Hz,
3H); 13C NMR (100 MHz, CDCl3): d=138.7, 133.6, 133.4,
132.6, 130.2, 129.8, 129.0, 128.3, 127.8, 127.8, 127.1, 126.4,
125.9, 121.5, 103.0, 38.7, 37.3, 12.1; HR-MS (ESI): m/z=
378.1165, calcd. for C22H20NO3S [M+H]+: 378.1164; IR
(KBr): n=2926, 2853, 1715, 1667, 1632, 1598, 1507, 1470,
1379, 1181, 1152, 1135, 1087, 1060, 967, 938, 920, 816, 759,
738, 614, 589 cmÀ1; HPLC (Chiralcel AS-H, n-hexane/i-
(7R,8S,9R)-7-HydroDxy-9-(3-methoxyphenyl)-8-methyl-8,9-
dihydro-7H-benzo[4,5]isothiazolo[2,3-a]pyridine 5,5-dioxide
(2j): Rf =0.15 (petroleum ether/EtOAc 4:1); white solid;
yield: 21.3 mg (60%); mp 62–638C; 1H NMR (400 MHz,
CDCl3): d=7.83 (d, J=7.6 Hz, 1H), 7.65–7.63 (m, 2H),
7.59–7.55 (m, 1H), 7.26–7.25 (m, 1H), 6.84–6.82 (m, 1H),
6.78–6.77 (m, 1H), 5.73 (d, J=2.8 Hz, 1H), 5.69 (t, J=
2.4 Hz, 1H), 3.81 (s, 3H), 3.53 (dd, J=11.2, 2.4 Hz, 1H),
3.45 (t, J=2.0 Hz, 1H), 2.18–2.13 (m, 1H), 1.05 (d, J=
6.8 Hz, 1H); 13C NMR (100 MHz, CDCl3): d=160.0, 144.5,
133.5, 132.2, 130.2, 130.0, 129.9, 128.4, 121.5, 121.4, 121.2,
114.5, 112.5, 106.3, 75.8, 55.4, 42.6, 40.1, 15.5; HR-MS (ESI):
m/z=358.1111, calcd. for C19H20NO4S [M+H]+: 358.1113;
IR (KBr): n=2921, 1852, 1598, 1584, 1486, 1469, 1304, 1262,
1181, 1154, 1036, 957, 763, 702 cmÀ1; HPLC (Chiralcel AS-
H, n-hexane/i-PrOH=80:20, UV=254 nm, flow rate=
0.5 mLminÀ1): tR1 =32.43 min (minor) and tR2 =70.94 min
(major); ee=99%; [a]2D5: À60.4 (c 0.1, CH3OH).
PrOH=80:20, UV=254 nm, flow rate=0.5 mLminÀ1): tR1
=
39.61 min (major) and tR2 =48.67 min (minor); ee=90%;
[a]25: À6.9 (c 0.2, CH3OH).
(D7R,8S,9R)-7-Hydroxy-8-methyl-9-(thiophen-2-yl)-8,9-di-
hydro-7H-benzo[4,5]isothiazolo[2,3-a]pyridine 5,5-dioxide
(2l): Rf =0.25 (petroleum ether/EtOAc 4:1); colorless oil;
1
yield: 21.2 mg (63%); H NMR (400 MHz, CDCl3): d=7.82
(d, J=7.6 Hz, 1H), 7.67–7.64 (m, 2H), 7.59–7.55 (m, 1H),
7.25–7.23(m, 1H), 7.00–6.97 (m, 1H), 6.95–6.94 (m, 1H),
5.76–5.75 (m, 1H), 5.69 À5.68(m, 1H), 3.92 (d, J=11.2 Hz,
1H), 2.20–2.14 (m, 1H), 1.12 (dd, J=7.2, 1.6 Hz, 1H);
13C NMR (100 MHz, CDCl3): d=146.1, 133,6, 132.3, 130.6,
130.3, 128.1, 127.0, 125.8, 124.6, 121.7, 121.5, 106.0, 75.9,
40.7, 38.0, 15.6; HR-MS (ESI): m/z=334.0581, calcd. for
C16H16NO3S2 [M+H]+: 334.0572; IR (KBr): n=2967, 2927,
2852, 1670, 1470, 1305, 1181, 1154, 1060, 983, 944, 762, 703,
603 cmÀ1; HPLC: (Chiralcel IC-3, n-hexane/i-PrOH=90:10,
(7S,8S,9R)-7-Hydroxy-9-(3-methoxyphenyl)-8-methyl-8,9-
dihydro-7H-benzo[4,5]isothiazolo[2,3-a]pyridine 5,5-dioxide
(2j’): Rf =0.14 (petroleum ether/EtOAc 4:1); colorless oil;
1
yield: 8.9 mg (25%); H NMR (400 MHz, CDCl3): d=7.83
(d, J=7.6 Hz, 1H), 7.76 (d, J=8.0 Hz, 1H), 7.67 (t, J=
7.6 Hz, 1H), 7.57 (t, J=7.6 Hz, 1H), 7.29 (d, J=8.0 Hz,
1H), 6.87 (d, J=7.6 Hz, 1H), 6.83–6.81 (m, 2H), 5.84 (s,
1H), 5.60 (s, 1H), 4.25 (dd, J=5.2, 2.0 Hz, 1H), 3.82 (s,
3H), 2.44–2.41 (m, 1H), 0.66 (d, J=7.2 Hz, 3H); 13C NMR
(100 MHz, CDCl3): d=159.9, 142.8, 133.4, 132.3, 130.2,
129.8, 129.6, 128.8, 121.5, 121.4, 121.1, 114.8, 112.0, 102.9,
77.3, 55.4, 38.6, 37.3, 12.0; HR-MS (ESI): m/z=358.1113,
calcd. for C19H20NO4S [M+H]+: 358.1113; IR (KBr): n=
2928, 1716, 1697, 1600, 1588, 1488, 1470, 1455, 1434, 1378,
1306, 1269, 1180, 1152, 1048, 1003, 954, 918, 760, 699, 625,
574, 524 cmÀ1; HPLC (Chiralcel AS-H, n-hexane/i-PrOH=
UV=254 nm, flow rate=0.9 mLminÀ1):
tR1 =46.22 min
(minor) and tR2 =53.02 min (major); ee=93%; [a]2D5: À30.2
(c 0.2, CH3OH).
(7S,8S,9R)-7-Hydroxy-8-methyl-9-(thiophen-2-yl)-8,9-di-
hydro-7H-benzo[4,5]isothiazolo[2,3-a]pyridine 5,5-dioxide
(2l’): Rf =0.23 (petroleum ether/EtOAc 4:1); white solid;
yield: 8.8 mg (27%); mp 58–598C; 1H NMR (400 MHz,
CDCl3): d=7.83 (d, J=7.6 Hz, 1H), 7.76 (d, J=7.6 Hz, 1H),
7.68 (t, J=7.2 Hz, 1H), 7.59 (t, J=7.6 Hz, 1H), 7.23 (d, J=
5.2 Hz, 1H), 7.01 (dd, J=4.8, 3.2 Hz, 1H), 6.95 (d, J=
2.8 Hz, 1H), 5.84 (d, J=1.6 Hz, 1H), 5.60 (d, J=2.8 Hz,
1H), 4.55 (dd, J=5.2, 2.4 Hz, 1H), 2.51–2.47 (m, 1H), 0.75
(d, J=7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=144.4,
133.4, 132.4, 130.3, 129.6, 128.6, 127.1, 125.3, 124.2, 121.5,
102.4, 37.9, 34.4, 12.1; HR-MS (ESI): m/z=334.0576, calcd.
for C16H16NO3S2 [M+H]+: 334.0572; IR (KBr): n=2924,
2852, 1716, 1666, 1470, 1379, 1309, 1252, 1181, 1153, 1088,
80:20, UV=254 nm, flow rate=0.5 mLminÀ1): tR1
=
44.61 min (major) and tR2 =61.83 min (minor); ee=84%;
[a]25: À8.9 (c 0.2, CH3OH).
(D7R,8S,9R)-7-Hydroxy-8-methyl-9-(naphthalen-2-yl)-8,9-
dihydro-7H-benzo[4,5]isothiazolo[2,3-a]pyridine 5,5-dioxide
(2k): Rf =0.18 (petroleum ether/EtOAc 4:1); white solid;
1
yield: 23.7 mg (63%); mp 106–1078C; H NMR (400 MHz,
CDCl3): d=7.85–7.81 (m, 5H), 7.72 (s, 1H), 7.65 (dd, J=
6.4, 1.2 Hz, 2H), 7.59–7.55 (m, 1H), 7.50–7.47 (m, 2H), 7.36
(dd, J=8.4, 1.6 Hz, 1H), 5.79 (d, J=2.4 Hz, 1H), 5.74 (s,
1H), 3.74 (dd, J=11.2, 2.4 Hz, 1H), 3.61 (s, 1H), 2.31–2.23
(m, 1H), 1.06 (d, J=6.8 Hz, 3H); 13C NMR (100 MHz,
CDCl3): d=140.2, 133.7, 133.5, 132.8, 132.3, 130.3, 130.1,
1060, 1002, 933, 817, 761, 696, 635, 619, 593, 575 cmÀ1
;
HPLC (Chiralcel IC-3, n-hexane/i-PrOH=90:10, UV=
254 nm, flow rate=0.9 mLminÀ1): tR1 =63.17 min (major)
3634
asc.wiley-vch.de
ꢁ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2015, 357, 3627 – 3638

FULL PAPERS
The Construction of 3-Methyl-4-arylpiperidines
and tR2 =38.85 min (minor); ee=94%; [a]2D5: À5.5 (c 0.1,
CH3OH).
for C18H18NO4S [M+H]+: 344.0957; IR (KBr): n=2924,
2852, 1715, 1646, 1456, 1386, 1312, 1203, 1176, 1133, 1097,
1057, 1025, 1010, 872, 853, 809, 784, 758, 703, 664, 579,
562 cmÀ1; HPLC (Chiralcel AS-H, n-hexane/i-PrOH=90:10,
(7R,8S,9R)-2-(tert-Butyl)-7-hydroxy-8-methyl-9-phenyl-
8,9-dihydro-7H-benzo[4,5]isothiazolo[2,3-a]pyridine 5,5-di-
oxide (2m): Rf =0.41 (petroleum ether/EtOAc 4:1); white
solid; yield: 25.8 mg (68%); mp 95–968C; 1H NMR
(400 MHz, CDCl3): d=7.76 (dd, J=8.4, 0.4 Hz, 1H), 7.64–
7.60 (m, 2H), 7.40–7.36 (m, 2H), 7.34–7.28 (m, 3H), 5.76 (d,
J=2.8 Hz, 1H), 5.70 (d, J=2.4 Hz, 1H), 3.57 (dd, J=11.2,
2.4 Hz, 1H), 2.21–2.13 (m, 1H), 1.35 (s, 9H), 1.04 (d, J=
6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=157.8, 143.0,
130.1, 129.6, 128.9, 128.8, 128.5, 128.1, 127.3, 121.1, 117.9,
106.0, 76.1, 42.8, 40.1, 35.7, 31.3, 15.4; HR-MS (ESI): m/z=
384.1637, calcd. for C22H26NO3S [M+H]+: 384.1633; IR
(KBr): n=2962, 2873, 1668, 1602, 1576, 1491, 1478, 1452,
1431, 1365, 1305, 1262, 1186, 1151, 1101, 972, 865, 762, 735,
702, 674, 628 cmÀ1; HPLC: (Chiralcel AS-H, n-hexane/i-
UV=254 nm, flow rate=0.6 mLminÀ1):
tR1 =27.78 min
(minor) and tR2 =30.44 min (major); ee=72%; [a]2D5: À11.0
(c 0.1, CH3OH).
(8R,9S,10R)-2-Fluoro-8-hydroxy-9-methyl-10-phenyl-9,10-
dihydro-8H-benzo[e]pyrido[1,2-c][1,2,3]oxathiazine 6,6-di-
oxide (2o): Rf =0.25 (petroleum ether/EtOAc 8:1); white
solid; yield: 25.4 mg (70%); mp 125–1268C; 1H NMR
(400 MHz, CDCl3): d=7.37–7.34 (m, 2H), 7.31–7.29 (m,
1H), 7.25–7.22 (m, 3H), 7.11 (dd, J=9.2, 4.8 Hz, 1H), 7.05–
7.02 (m, 1H), 5.73 (d, J=2.4 Hz, 1H), 5.71 (d, J=2.4 Hz,
1H), 3.49 (dd, J=12.0, 2.8 Hz, 1H), 2.12–2.04 (m, 1H), 0.99
(d, J=6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=160.4
(d, J=244.2 Hz), 144.3, 142.1, 129.0, 128.6, 128.2, 127.5,
121.0 (d, J=8.6 Hz), 117.5 (d, J=24.1 Hz), 111.8, 111.4 (d,
J=26.1 Hz), 79.8, 42.1, 39.1, 15.5; HR-MS (ESI): m/z=
362.0859, calcd. for C18H17NO4SF [M+H]+: 362.0862; IR
(KBr): n=2930, 2854, 1588, 1560, 1481, 1452, 1440, 1389,
1267, 1166, 1070, 1046, 979, 868, 763, 703, 601 cmÀ1; HPLC:
(Chiralcel AS-H, n-hexane/i-PrOH=90:10, UV=254 nm,
PrOH=80:20, UV=254 nm, flow rate=0.6 mLminÀ1): tR1
=
13.05 min (minor) and tR2 =16.87 min (major); ee=96%;
[a]25: À25.0 (c 0.2, CH3OH).
(D7S,8S,9R)-2-(tert-Butyl)-7-hydroxy-8-methyl-9-phenyl-
8,9-dihydro-7H-benzo[4,5]isothiazolo[2,3-a]pyridine 5,5-di-
oxide (2m’): Rf =0.39 (petroleum ether/EtOAc 4:1); white
solid; yield: 8.6 mg (22%); mp 184–1858C; 1H NMR
(400 MHz, CDCl3): d=7.76–7.72 (m, 2H), 7.62 (dd, J=8.4,
1.6 Hz, 1H), 7.39–7.35 (m, 2H), 7.30 (d, J=7.6 Hz, 3H),
5.86–5.84 (m, 1H), 5.60 (t, J=2.2 Hz, 1H), 5.60 (t, J=
2.4 Hz, 1H), 4.28 (dd, J=5.2, 2.4 Hz, 1H), 3.68 (d, J=
2.4 Hz, 1H), 2.44–2.40 (m, 1H), 1.38 (s, 9H), 0.67 (d, J=
7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=157.7, 141.3,
129.9, 129.7, 129.2, 128.8, 128.6, 128.0, 126.9, 121.1, 117.7,
102.5, 77.3, 38.6, 37.3, 35.7, 31.3, 12.0; HR-MS (ESI): m/z=
384.1635, calcd. for C22H26NO3S [M+H]+: 384.1633; IR
(KBr): n=3061, 3028, 2964, 2926, 2854, 1667, 1602, 1492,
1487, 1452, 1432, 1365, 1347, 1304, 1268, 1231, 1187, 1153,
1105, 1091, 1050, 1005 cmÀ1; [a]25: À45.2 (c 0.1, CH3OH).
(8R,9S,10R)-8-Hydroxy-9-meDthyl-10-phenyl-9,10-dihydro-
8H-benzo[e]pyrido[1,2-c][1,2,3]oxathiazine 6,6-dioxide (2n):
Rf =0.25 (petroleum ether/EtOAc 8:1); colorless oil; yield:
23.9 mg (70%); 1H NMR (400 MHz, CDCl3): d=7.58 (dd,
J=8.0, 1.2 Hz, 1H), 7.38–7.29 (m, 5H), 7.24–7.20 (m, 2H),
7.13 (dd, J=8.4, 0.8 Hz, 1H), 5.75 (d, J=2.4 Hz, 2H), 3.49
(dd, J=10.0, 2.4 Hz, 1H), 3.11 (s, 1H), 2.13–2.05 (m, 1H),
1.00 (d, J=6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=
142.5, 130.5, 129.1, 128.9, 128.8, 128.7, 128.3, 127.3, 126.6,
124.9, 119.3, 110.5, 79.8, 42.1, 39.1, 15.5; HR-MS (ESI): <br/
Ym/z=344.0957, calcd. for C18H18NO4S [M+H]+: 344.0957;
IR (KBr): n=2916, 1849, 1345, 1598, 1560, 1452, 1383, 1203,
1171, 1039, 807, 789, 758, 701, 678 cmÀ1; HPLC (Chiralcel
AS-H, n-hexane/i-PrOH=90:10, UV=254 nm, flow rate=
0.8 mLminÀ1): tR1 =15.69 min (minor) and tR2 =23.92 min
(major); ee=98%; [a]2D5: À40.7 (c 0.1, CH3OH).
flow rate=0.7 mLminÀ1): tR1 =16.48 min (major) and tR2
24.30 min (minor); ee=97%; [a]2D5: À34.4 (c 0.1, CH3OH).
=
(8S,9S,10R)-2-Fluoro-8-hydroxy-9-methyl-10-phenyl-9,10-
dihydro-8H-benzo[e]pyrido[1,2-c][1,2,3]oxathiazine 6,6-di-
oxide (2o’): Rf =0.23 (petroleum ether/EtOAc 8:1); white
solid; yield: 9.1 mg (25%); mp 61–628C; 1H NMR
(400 MHz, CDCl3): d=7.67 (dd, J=9.2, 6.0 Hz, 1H), 7.36–
7.31 (m, 2H), 7.24 (d, J=7.2 Hz, 3H), 7.02–6.97 (m, 1H),
6.87 (dd, J=8.4, 2.4 Hz, 1H), 5.77 (s, 1H), 5.64 (s, 1H),
4.17–4.15 (m, 1H), 3.58 (s, 1H), 2.37–2.29 (m, 1H), 0.67 (d,
J=7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=162.8 (d,
J=251.6 Hz), 140.6, 128.7, 128.5, 128.4, 127.1, 126.8, 125.9
(d, J=9.3 Hz), 114.2 (d, J=22.1 Hz), 107.1 (d, J=25.6 Hz),
106.2 (d, J=2.2 Hz), 81.2, 37.6, 35.8, 11.7; HR-MS (ESI):
m/z=362.0865, calcd. for C18H17NO4SF [M+H]+: 362.0862;
IR (KBr): n=2922, 2851, 1748, 1731, 1715, 1697, 1615, 1563,
1540, 1502, 1429, 1394, 1339, 1267, 197, 1096, 974, 921, 820,
749, 703, 518 cmÀ1; [a]D25: À8.5 (c 0.1, CH3OH).
(8R,9S,10R)-2-Chloro-8-hydroxy-9-methyl-10-phenyl-9,10-
dihydro-8H-benzo[e]pyrido[1,2-c][1,2,3]oxathiazine 6,6-di-
oxide (2p): Rf =0.25 (petroleum ether/EtOAc 8:1); white
solid; yield: 24.8 mg (66%); mp 59–608C; 1H NMR
(400 MHz, CDCl3): d=7.54 (d, J=2.4 Hz, 1H), 7.38–7.34
(m, 2H), 7.32–7.28 (m, 2H), 7.25–7.22 (m, 2H), 7.07 (dd, J=
8.8, 2.0 Hz, 1H), 5.74 (t, J=2.4 Hz, 1H), 3.48 (dd, J=11.6,
2.4 Hz, 1H), 3.17 (s, 1H), 2.12–2.04 (m, 1H), 0.99 (d, J=
6.8 Hz, 1H); 13C NMR (100 MHz, CDCl3): d=146.7, 142.1,
132.2, 130.4, 129.0, 128.7, 127.9, 127.5, 124.7, 121.5, 120.8,
112.0, 79.9, 42.1, 39.1, 15.5; HR-MS (ESI): m/z=378.0571,
calcd. for C18H17NO4SCl [M+H]+: 378.0576; IR (KBr): n=
2968, 2931, 1719, 1641, 602, 1491, 1421, 1392, 1205, 1181,
1113, 1075, 1045, 962, 875, 830, 703, 609 cmÀ1; HPLC (Chir-
alcel AS-H, n-hexane/i-PrOH=90:10, UV=254 nm, flow
(8S,9S,10R)-8-Hydroxy-9-methyl-10-phenyl-9,10-dihydro-
8H-benzo[e]pyrido[1,2-c][1,2,3]oxathiazine 6,6-dioxide (2n’):
Rf =0.23 (petroleum ether/EtOAc 8:1); colorless oil; yield:
1
9.6 mg (28%); H NMR (400 MHz, CDCl3): d=7.71 (d, J=
8.0 Hz, 1H), 7.38–7.34 (m, 3H), 7.28–7.25 (m, 4H), 7.14 (d,
J=8.0 Hz, 1H), 5.87 (s, 1H), 5.66 (s, 1H), 4.19–4.18 (m,
1H), 3.64 (s, 1H), 2.36–2.33 (m, 1H), 0.70 (d, J=6.8 Hz,
3H); 13C NMR (100 MHz, CDCl3): d=148.3, 141.1, 130.5,
129.6, 128.9, 128.7, 127.0, 126.6, 124.6, 120.0, 119.5, 106.5,
81.3, 37.9, 36.1, 11.9; HR-MS (ESI): m/z=344.0956, calcd.
rate=0.6 mLminÀ1):
tR1 =16.32 min (minor) and tR2 =
25.77 min (major); ee=95%; [a]2D5: À20.3 (c 0.2, CH3OH).
(8S,9S,10R)-2-Chloro-8-hydroxy-9-methyl-10-phenyl-9,10-
dihydro-8H-benzo[e]pyrido[1,2-c][1,2,3]oxathiazine 6,6-di-
oxide (2p’): Rf =0.23 (petroleum ether/EtOAc 8:1); white
solid; yield: 10.3 mg (27%); mp 46–478C; 1H NMR
Adv. Synth. Catal. 2015, 357, 3627 – 3638
ꢁ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
3635

FULL PAPERS
Qianjin An et al.
(400 MHz, CDCl3): d=7.65 (d, J=2.4 Hz, 1H), 7.36 (t, J=
7.2 Hz, 2H), 7.32–7.27 (m, 2H), 7.24 (d, J=6.8 Hz, 2H),
7.07 (d, J=8.8 Hz, 1H), 5.85 (d, J=1.6 Hz, 1H), 5.63 (s,
1H), 4.17 (dd, J=5.6, 2.8 Hz, 1H), 3.60 (s, 1H), 2.37–2.30
(m, 1H), 0.67 (d, J=7.2 Hz, 3H); 13C NMR (100 MHz,
CDCl3): d=146.4, 140.4, 132.0, 130.1, 128.5, 128.4, 128.1,
126.9, 124.2, 121.2, 120.7, 107.8, 81.2, 37.8, 35.7, 11.7; HR-
MS (ESI): m/z=378.0577, calcd. for C18H17NO4SCl [M+
H]+: 378.0576; IR (KBr): n=2925, 2853, 1646, 1602, 1496,
1472, 1423, 1393, 1299, 1204, 1179, 1102, 1055, 1027, 1010,
954, 873, 833, 785, 736, 681, 593 cmÀ1; HPLC (Chiralcel AS-
H, n-hexane/i-PrOH=90:10, UV=254 nm, flow rate=
0.6 mLminÀ1): tR1 =21.23 min (major) and tR2 =23.90 min
(minor); ee=68%; [a]2D5: À7.1 (c 0.1, CH3OH).
H]+: 358.1113; IR (KBr): n=2968, 2929, 1719, 1642, 1600,
1560, 1485, 1452, 1420, 1384, 1205, 1179, 1131, 1119, 1045,
967, 856, 760, 703, 675, 602 cmÀ1; HPLC: (Chiralcel AS-H,
n-hexane/i-PrOH=90:10,
UV=254 nm,
flow
rate=
0.8 mLminÀ1): tR1 =12.33 min (minor) and tR2 =19.29 min
(major); ee=98%; [a]2D5: À19.1 (c 0.2, CH3OH).
(8S,9S,10R)-8-Hydroxy-2,9-dimethyl-10-phenyl-9,10-dihy-
dro-8H-benzo[e]pyrido[1,2-c][1,2,3]oxathiazine 6,6-dioxide
(2r’): Rf =0.21 (petroleum ether/EtOAc 8:1); white solid;
yield: 8.6 mg (24%); mp 50–518C; 1H NMR (400 MHz,
CDCl3): d=7.49 (s, 1H), 7.36 (d, J=7.2 Hz, 2H), 7.29 (t, J=
5.6 Hz, 3H), 7.16 (d, J=8.4 Hz, 1H), 7.02 (d, J=8.4 Hz,
1H), 5.84 (d, J=1.6 Hz, 1H), 5.65 (s, 1H), 4.18 (dd, J=5.6,
2.4 Hz, 1H), 3.59 (s, 1H), 2.37 (s, 3H), 0.69 (d, J=7.2 Hz,
3H); 13C NMR (100 MHz, CDCl3): d=141.2, 136.4, 131.2,
130.1, 128.7, 128.7, 128.4, 127.6, 127.0, 124.8, 119.2, 119.0,
106.1, 81.3, 37.9, 36.1, 21.2, 11.9; HR-MS (ESI): m/z=
358.1114, calcd. for C19H20NO4S [M+H]+: 358.1113; IR
(KBr): n=2923, 2852, 716, 1562, 1555, 1486, 1453, 1386,
1189, 1132, 1095, 1055, 895, 829, 761, 702, 655, 574,
502 cmÀ1; HPLC (Chiralcel AS-H, n-hexane/i-PrOH=90:10,
(8R,9S,10R)-2-Bromo-8-hydroxy-9-methyl-10-phenyl-9,10-
dihydro-8H-benzo[e]pyrido[1,2-c][1,2,3]oxathiazine 6,6-di-
oxide (2q): Rf =0.25 (petroleum ether/EtOAc 8:1); white
solid; yield: 27.4 mg (65%); mp 64–658C; 1H NMR
(400 MHz, CDCl3): d=7.68 (d, J=2.0 Hz, 1H), 7.45 (dd, J=
8.4, 2.0 Hz, 1H), 7.38–7.35 (m, 2H), 7.32–7.29 (m, 1H),
7.25–7.22 (m, 2H), 7.01 (d, J=8.8 Hz, 1H), 5.73 (t, J=
2.4 Hz, 2H), 3.49 (dd, J=11.6, 2.8 Hz, 1H), 2.11–2.04 (m,
1H), 0.99 (d, J=6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3):
d=147.3, 142.1, 133.3, 129.0, 128.7, 127.8, 127.7, 127.5, 121.9,
121.1, 119.7, 112.0, 79.9, 42.2, 39.1, 15.5; HR-MS (ESI):
m/z=422.0063, calcd. for C18H17NO4SBr [M+H]+: 422.0062;
IR (KBr): n=2931, 2877, 1719, 1641, 1600, 1548, 1492, 1469,
UV=254 nm, flow rate=0.6 mLminÀ1):
tR1 =23.47 min
(major) and tR2 =25.97 min (minor); ee=70%; [a]2D5: À4.7 (c
0.1, CH3OH).
(8R,9S,10R)-8-Hydroxy-2-methoxy-9-methyl-10-phenyl-
9,10-dihydro-8H-benzo[e]pyrido[1,2-c][1,2,3]oxathiazine 6,6-
dioxide (2s): Rf =0.16 (petroleum ether/EtOAc 8:1); white
solid; yield: 22.4 mg (60%); mp 58–598C; 1H NMR
(400 MHz, CDCl3): d=7.38–7.34 (m, 2H), 7.32–7.29 (m,
1H), 7.26–7.24 (m, 2H), 7.05 (d, J=8.8 Hz, 1H), 7.00 (d, J=
3.2 Hz, 1H), 6.88 (dd, J=9.2, 3.2 Hz, 1H), 5.73 (d, J=
2.4 Hz, 1H), 5.69 (d, J=2.4 Hz, 1H), 3.77 (s, 3H), 3.48 (dd,
J=11.6, 2.8 Hz, 1H), 3.11 (s, 1H), 2.12–2.03 (m, 1H), 0.98
(d, J=6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=157.7,
142.5, 142.3, 129.0, 128.7, 128.2, 127.4, 120.7, 120.3, 116.8,
110.5, 108.9, 79.8, 56.0, 42.2, 39.1, 15.6; HR-MS (ESI): m/z=
374.1069, calcd. for C19H20NO5S [M+H]+: 374.1062; IR
(KBr): n=2931, 2850, 1603, 1583, 1559, 1485, 1452, 1384,
1327, 1301, 1204, 1175, 1035, 973, 856, 757, 703, 676,
603 cmÀ1; HPLC (Chiralcel AS-H, n-hexane/i-PrOH=90:10,
1453, 1392, 1324, 1204, 1180, 1045, 828, 789, 702, 606 cmÀ1
;
HPLC (Chiralcel AS-H, n-hexane/i-PrOH=90:10, UV=
254 nm, flow rate=0.6 mLminÀ1): tR1 =16.75 min (minor)
and tR2 =26.84 min (major); ee=94%; [a]2D5: À9.2 (c 0.2,
CHCl3).
(8S,9S,10R)-2-Bromo-8-hydroxy-9-methyl-10-phenyl-9,10-
dihydro-8H-benzo[e]pyrido[1,2-c][1,2,3]oxathiazine 6,6-di-
oxide (2q’): Rf =0.23 (petroleum ether/EtOAc 8:1); white
solid; yield: 12.4 mg (30%); mp 57–588C; 1H NMR
(400 MHz, CDCl3): d=7.81 (d, J=2.0 Hz, 1H), 7.47 (dd, J=
8.8, 2.0 Hz, 1H), 7.38 (t, J=7.2 Hz, 1H), 7.30 (d, J=6.8 Hz,
1H), 7.26 (d, J=7.2 Hz, 2H), 7.02 (d, J=8.8 Hz, 1H), 5.86
(s, 1H), 5.65 (s, 1H), 4.19 (dd, J=5.2, 2.4 Hz, 1H), 3.63 (s,
1H), 2.36–2.32 (m, 1H), 0.69 (d, J=6.8 Hz, 3H); 13C NMR
(100 MHz, CDCl3): d=147.2, 140.6, 133.3, 129.1, 128.7,
128.3, 127.4, 127.1, 121.2, 119.8, 108.1, 81.5, 38.0, 36.0, 11.9;
HR-MS (ESI): m/z=422.0065, calcd. for C18H17NO4SBr
[M+H]+: 422.0062; IR (KBr): 2925, 2853, 1716, 1646, 1602,
1496, 1469, 1453, 1393, 1297, 1204, 1178, 1134, 1097, 1056,
1027, 1010, 949, 872, 854, 751, 732, 625, 587 cmÀ1; HPLC
(Chiralcel AS-H, n-hexane/i-PrOH=90:10, UV=254 nm,
UV=254 nm, flow rate=0.8 mLminÀ1):
tR1 =20.28 min
(minor) and tR2 =28.31 min (major); ee=99%; [a]2D5: À25.3
(c 0.1, CH3OH).
(8S,9S,10R)-8-Hydroxy-2-methoxy-9-methyl-10-phenyl-
9,10-dihydro-8H-benzo[e]pyrido[1,2-c][1,2,3]oxathiazine 6,6-
dioxide (2s’): Rf =0.14 (petroleum ether/EtOAc 8:1); white
solid; yield: 11.2 mg (30%); mp 52–538C; 1H NMR
(400 MHz, CDCl3): d=7.37 (t, J=7.2 Hz, 2H), 7.30–7.25
(m, 3H), 7.14 (d, J=2.8 Hz, 1H), 7.07 (d, J=8.8 Hz, 1H),
6.91 (dd, J=9.2, 2.8 Hz, 1H), 5.81 (s, 1H), 5.65 (s, 1H), 4.19
(dd, J=5.6, 2.4 Hz, 1H), 3.83 (s, 3H), 3.56 (s, 1H), 2.37–2.30
(m, 1H), 0.69 (d, J=7.2 Hz, 3H); 13C NMR (100 MHz,
CDCl3): d=157.5, 142.0, 140.8, 129.4, 128.7, 128.5, 128.4,
126.8, 120.2, 116.1, 108.8, 106.3, 81.0, 55.8, 37.7, 35.7, 11.7;
HR-MS (ESI): m/z=374.1061, calcd. for C19H20NO5S [M+
H]+: 374.1062; IR (KBr): n=2924, 2852, 1716, 1697, 1646,
1602, 1555, 1486, 1434, 1386, 1301, 1250, 1202, 1174, 1093,
1032, 968, 857, 759, 702, 656 cmÀ1; HPLC (Chiralcel AS-H,
flow rate=0.6 mLminÀ1): tR1 =22.38 min (major) and tR2
26.02 min (minor); ee=31%; [a]2D5: À1.9 (c 0.1, CH3OH).
(8R,9S,10R)-8-Hydroxy-2-methoxy-9-methyl-10-phenyl-
=
9,10-dihydro-8H-benzo[e]pyrido[1,2-c][1,2,3]oxathiazine 6,6-
dioxide (2r): Rf =0.23 (petroleum ether/EtOAc 8:1); color-
1
less oil; yield: 25.0 mg (70%); H NMR (400 MHz, CDCl3):
d=7.38–7.34 (m, 3H), 7.31–7.27 (m, 1H), 7.26–7.25 (m,
1H), 7.24 (s, 1H), 7.15–7.12 (m, 1H), 7.01 (d, J=8.4 Hz,
1H), 5.73 (d, J=2.4 Hz, 1H), 5.71 (d, J=2.4 Hz, 1H), 3.48
(dd, J=11.6, 2.8 Hz, 1H), 3.15 (s, 1H), 2.31 (s, 3H), 2.12–
2.03 (m, 1H), 0.98 (d, J=6.8 Hz, 3H); 13C NMR (100 MHz,
CDCl3): d=142.7, 136.4, 131.3, 129.0, 128.9, 128.7, 128.3,
127.3, 125.1, 119.5, 119.0, 110.1, 79.7, 42.1, 39.1, 21.2, 15.6;
HR-MS (ESI): m/z=358.1106, calcd. for C19H20NO4S [M+
n-hexane/i-PrOH=90:10,
UV=254 nm,
flow
rate=
0.6 mLminÀ1): tR1 =38.25 min (minor) and tR2 =41.69 min
(major); ee=64%; [a]2D5: À6.3 (c 0.1, CH3OH).
3636
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ꢁ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2015, 357, 3627 – 3638

FULL PAPERS
The Construction of 3-Methyl-4-arylpiperidines
(8R,9S,10R)-3-Bromo-8-hydroxy-9-methyl-10-phenyl-9,10-
dihydro-8H-benzo[e]pyrido[1,2-c][1,2,3]oxathiazine 6,6-di-
oxide (2t): Rf =0.27 (petroleum ether/EtOAc 8:1); pale
yellow oil; yield: 28.5 mg (68%). 1H NMR (400 MHz,
CDCl3): d=7.42 (d, J=8.4 Hz, 1H), 7.37–7.33 (m, 3H),
7.31–7.28 (m, 2H), 7.23 (d, J=7.6 Hz, 2H), 5.74 (dd, J=5.2,
2.4 Hz, 2H), 3.46 (dd, J=12.0, 2.4 Hz, 1H), 2.11–2.04 (m,
1H), 0.98 (d, J=6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3):
d=148.3, 142.2, 129.9, 129.0, 128.7, 128.2, 127.5, 125.9, 123.3,
122.6, 119.1, 111.4, 79.9, 42.1, 39.1, 15.6; HR-MS (ESI):
m/z=422.0060, calcd. for C18H17NO4SBr [M+H]+: 422.0062;
IR (KBr): n=2928, 2852, 1719, 1701, 1641, 1598, 560, 1479,
1452, 1390, 1265, 1203, 1181, 1078, 1046, 989, 887, 811,
702 cmÀ1; HPLC (Chiralcel AS-H, n-hexane/i-PrOH=90:10,
flash column chromatography on silica gel (PE/EA=6/1) to
give the adduct 2a; yield: 1.12 g (86%, 3.0:1 dr and 90% ee).
To 2a (32.7 mg, 0.1 mmol) was added a solution of tri-
ethylsilane (0.2 mmol in 2 mL anhydrous DCM) and a solu-
tion of BF3·Et2O (28 mL, 0.22 mmol) at room temperature.
The reaction mixture was stirred for 12 h. The reaction was
quenched with aqueous NaHCO3 and extracted with DCM
(3”30 mL). The organic layer was dried over Na2SO4 and
concentrated. The residue was purified by flash column
chromatography on silica gel to afford the desired product
3a as a colorless solid; yield: 28.2 mg (90%); Rf =0.26 (pe-
troleum ether/EtOAc 4:1); mp 124–1258C; 1H NMR
(400 MHz, CDCl3): d=7.83 (d, J=6.8 Hz, 1H), 7.57–7.52
(m, 2H), 7.32 (t, J=8.4 Hz, 3H), 7.26–7.24 (m, 1H), 7.19–
7.16 (m, 2H), 4.41 (dd, J=11.6, 2.8 Hz, 1H), 3.96 (dd, J=
13.2, 4.4 Hz, 1H), 2.84 (dd, J=12.8, 11.2 Hz, 1H), 2.48 (td,
J=12.0, 3.6 Hz, 1H), 2.37 (dt, J=13.2, 3.2 Hz, 1H), 2.12–
2.04 (m, 1H), 1.75 (dd, J=24.8, 12.8 Hz, 1H), 0.78 (d, J=
6.4 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=143.3, 138.2,
135.4, 132.8, 129.4, 128.9, 127.6, 127.1, 123.3, 121.5, 58.8,
49.8, 46.5, 38.6, 35.3, 16.8; HR-MS (ESI): m/z=314.1206,
calcd. for C18H20NO2S [M+H]+: 314.1215; IR (KBr): n=
3060, 3028, 2924, 2870, 1601, 1495, 1454, 1292, 1227, 1173,
1129, 1059, 756, 736, 702, 644 cmÀ1; HPLC (Chiralcel AS-H,
UV=254 nm, flow rate=0.6 mLminÀ1):
tR1 =13.81 min
(minor) and tR2 =16.36 min (major); ee=97%; [a]2D5: À27.2
(c 0.2, CH3OH).
(8S,9S,10R)-3-Bromo-8-hydroxy-9-methyl-10-phenyl-9,10-
dihydro-8H-benzo[e]pyrido[1,2-c][1,2,3]oxathiazine 6,6-di-
oxide (2t’): Rf =0.25 (petroleum ether/EtOAc 8:1); white
solid; yield: 10.6 mg (25%); mp 49–508C; 1H NMR
(400 MHz, CDCl3): d=7.54 (d, J=8.8 Hz, 1H), 7.39–7.32
(m, 3H), 7.28 (s, 1H), 7.23 (d, J=6.0 Hz, 3H), 5.85 (d, J=
2.4 Hz, 1H), 5.63 (d, J=2.4 Hz, 1H), 4.15 (dd, J=5.6,
2.4 Hz, 1H), 3.65 (s, 1H), 2.37–2.29 (m, 1H), 0.67 (d, J=
7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=148.0, 140.5,
129.6, 128.7, 128.5, 128.4, 126.9, 125.4, 123.1, 122.5, 118.8,
107.1, 81.2, 37.7, 35.8, 11.7; HR-MS (ESI): m/z=422.0064,
calcd. for C18H17NO4SBr [M+H]+: 422.0062; IR (KBr): n=
2924, 2852, 1716, 1697, 1646, 1596, 1563, 1540, 1507, 1497,
1453, 1391, 1202, 1097, 1073, 1009, 888, 812, 747, 702, 586,
564 cmÀ1; [a]2D5: À1.5 (c 0.1, CH3OH).
n-hexane/i-PrOH=80:20,
UV=254 nm,
flow
rate=
0.6 mLminÀ1): tR1 =62.17 min (minor) and tR2 =78.02 min
(major); ee=92%; dr=3.0:1; [a]2D5: À1.9 (c 0.4, CHCl3).
Acknowledgements
(8R,9S,10R)-10-(tert-Butyl)-8-hydroxy-9-methyl-9,10-dihy-
dro-8H-benzo[e]pyrido[1,2-c][1,2,3]oxathiazine 6,6-dioxide
(2u): Rf =0.46 (petroleum ether/EtOAc 4:1); white solid;
This work was partially supported by the National Natural
Science Foundation of China (No. 21232004, 21372152,
21402117 and 21450110059), Nippon Chemical Industrial
Co., Ltd. and Shanghai Jiao Tong University (SJTU). We
thank the Instrumental Analysis Center of SJTU for HR-MS
analysis. We also thank Prof. Tsuneo Imamoto and Dr. Ma-
sashi Sugiya of Nippon Chemical Industrial Co., Ltd. for
helpful discussions.
1
yield: 24.2 mg (75%); mp 139–1408C; H NMR (400 MHz,
CDCl3): d=7.67 (dd, J=8.0, 1.6 Hz, 1H), 7.33 (td, J=7.6,
1.6 Hz, 1H), 7.28–7.23 (m, 1H), 7.10 (dd, J=8.0, 1.2 Hz,
1H), 5.68 (dd, J=2.4, 1.2 Hz, 1H), 5.45 (d, J=2.4 Hz, 1H),
3.51 (s, 1H), 2.57 (dd, J=4.8, 2.4 Hz, 1H), 2.35–2.32 (m,
1H), 1.07 (s, 9H), 0.95 (d, J=7.2 Hz, 3H); 13C NMR
(100 MHz, CDCl3): d=148.1, 130.1, 128.6, 126.5, 124.4,
120.3, 119.4, 105.8, 82.5, 40.7, 32.5, 28.8, 28.1, 13.4; HR-MS
(ESI): m/z=324.1268, calcd. for C16H22NO4S [M+H]+:
324.1270; IR (KBr): n=2962, 2872, 1456, 1385, 1204, 1174,
1099, 1069, 1036, 855, 795, 754, 650, 561 cmÀ1; HPLC: (Chir-
alcel IC-3, n-hexane/i-PrOH=92:8, UV=254 nm, flow
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tR1 =16.22 min (minor) and tR2 =
25.87 min (major); ee=88%; dr=6.1:1; [a]2D5: À29.4 (c 0.2,
CH3OH).
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(30 mL) at 158C and the resulting solution was stirred for
5 min. Cyclic 1-azadine 1a (1.07 g, 3.97 mmol) was then
added and the reaction mixture was stirred at 158C until the
complete consumption of 1a (monitored by TLC). The sol-
vent was evaporated and the crude product was purified by
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asc.wiley-vch.de
3637

FULL PAPERS
Qianjin An et al.
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