Preparation of trans-2-Substituted-4-halopiperidines and cis-2-Substituted-4-halotetrahydropyrans via AlCl3-Catalyzed Prins Reaction

Article abstract of DOI:10.1021/acs.joc.6b00725

A general and practical method for the preparation of trans-2-substituted-4-halopiperidines and cis-2-substituted-4-halotetrahydropyrans is reported. Using 5 mol % of AlCl₃ as the catalyst and 2 equiv of trimethylsilyl halides as the halide sou

Full text of DOI:10.1021/acs.joc.6b00725

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Article
Preparation of trans-2-substituted-4-halopiperidines and cis-2-
substituted-4-halotetrahydropyrans via AlCl3-catalyzed Prins reaction
Gong-Qing Liu, Bin Cui, Rong Xu, and Yue-Ming Li
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b00725 • Publication Date (Web): 23 May 2016
Downloaded from http://pubs.acs.org on May 24, 2016
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Preparation
of
trans-2-substituted-4-halopiperidines
and
cis-2-substituted-4-halotetrahydropyrans via AlCl -catalyzed Prins reaction
3
†
‡
†
†
*,†
GongꢀQing Liu, Bin Cui, Rong Xu, YueꢀMing Li
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†
State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin
Key Laboratory of Molecular Drug Research, Nankai University, Tianjin 300071, People’s
Republic of China
‡
Present address: College of Pharmacy, Nantong University, 19 Qixiu Road, Nantong 226001,
People’s Republic of China
Eꢀmail: ymli@nankai.edu.cn
Abstract Graphics
AlCl (5 mol%)
Halide source (2 equiv)
3
X
Z
O
+
ZH
R
H
CH Cl , r. t.
2
2
R
Z = NTs, O
X = F, Cl, Br, I
R = Alkyl, Aryl, H
1
02 examples
up to 93% isolated yield
Abstract
A general and practical method for the preparation of transꢀ2ꢀsubstitutedꢀ4ꢀhalopiperidines
and cisꢀ2ꢀsubstitutedꢀ4ꢀhalotetrahydropyrans is reported. Using 5 mol% of AlCl as the
3
catalyst and 2 equiv of trimethylsilyl halides as the halide sources, azaꢀPrins cyclization of
Nꢀtosyl homoallylamine or Prins cyclization of homoallylic alcohol with carbonyl
compounds
could
be
readily
realized,
giving
the
corresponding
transꢀ2ꢀsubstitutedꢀ4ꢀhalopiperidines or cisꢀ2ꢀsubstitutedꢀ4ꢀhalotetrahydropyrans in high
yields and satisfactory diastereoselectivity.
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Introduction
Sixꢀmembered ring heterocycles such as piperidines and tetrahydropyrans are important
structural motifs in a variety of biologically interesting compounds, and can be used as useful
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building blocks for the synthesis of complex natural products. In addition, these structures
2
also constitute the important part of the privileged structures in drug research and discovery.
To this end, different methods have been developed for the constructions of piperidines and
tetrahydropyrans. Of the variety of methods developed, Prinsꢀtype cyclization of homoallylic
amines/alcohols with carbonyl compounds would be one of the most attractive strategies for
the formation of these heterocycles. Since the first publication of H SO ꢀmediated addition of
2
4
3
formaldehyde to alkenes by Prins, considerable work has been carried out to expand the
4
5
application scope of this transformation: different Brønsted and Lewis acids such as TfOH,
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pꢀTSA, TFA, HF, BF
3
, FeX
3
,
Sc(OTf)
3
,
Ga(III), In(III),
2
I ,
Au(I), TMSOTf
have been successfully applied in Prinsꢀtype cyclization reactions. Further, Prins reactions
have also been used as key steps for the syntheses of an increasing number of natural
17
products. It is our purpose to develop mild and convenient method for the construction of
substituted piperidine and tetrahydropyran structures. In this paper, we wish to report
AlCl
3
ꢀcatalyzed Prins reactions as a continuation of our program on the construction of
18
nitrogenꢀ and oxygenꢀcontaining heterocycles.
Results and Discussions
Recently, we have shown that 3ꢀhalopiperidines could be obtained via intramolecular
haloamination of unfunctionalized olefins. The reactions were carried out using Cu(II), iodine
or hypervalent iodine as the reaction promoters, and the corresponding haloamination
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products could be obtained in good isolated yields at ambient temperature in the absence of
1
8
anhydrous conditions (Scheme 1, eq. 1). As 4ꢀhalopiperidines could be used as important
building blocks in the synthesis of different natural products and biologically active
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compounds, developing a concise and general strategy for the construction of such
heterocycles would also be highly desirable (Scheme 1, eq. 2). Based on our understanding of
Lewis acidꢀcatalyzed intramolecular cyclizaton reactions, the azaꢀPrins reaction between
Nꢀtosyl homoallylamine (1) and 4ꢀmethylbenzaldehyde (2) was proposed, and the
preliminary results were summarized in Table 1.
Scheme 1. Schematic presentation of halopiperidines
a
Table 1. Optimization of the reaction conditions
entry
catalyst
chloride source
TMSCl
isolated yield (%)
1
2
AlCl
AlCl
3
3
83
14
TBSCl
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AlCl
AlCl3
AlCl
3
(nBu)
4
NCl
<5
22
17
70
63
43
55
<5
LiCl
3
ZnCl
2
0
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CuCl
CuBr
TMSCl
TMSCl
TMSCl
TMSCl
TMSCl
CuF
2
Zn(OTf)2
ꢀ
10
a
2 2
Reaction conditions: the reactions were conducted in 0.5 mmol scale in 2 mL CH Cl at
room temperature.
3
The results in Table 1 indicated that AlCl ꢀcatalyzed azaꢀPrins cyclization of 1 and 2
proceeded readily when TMSCl was used as the chloride source. In the presence of 5 mol%
of AlCl
3
and 2 equiv of TMSCl, 2ꢀ(4ꢀmethylphenyl)ꢀ4ꢀchloropiperidine 3a was obtained in
.
83% isolated yield (entry 1). Other Lewis acids such as CuI, CuF
2
, CuCl
2
2H
2
O, Cu(OAc)
2
,
CuSO or MgBr were not efficient enough to promote the reaction, possibly due to the
4
2
20
relatively weak Lewis acidity of these catalysts. Also, low yields were observed when
TBSCl, (nBu) NCl, LiCl or ZnCl were used as the chloride sources (entries 2 to 5). No
4
2
product was detected in the absence of AlCl
by the catalyst (entry 17).
3
(entry 10), indicating the important role played
Substrates bearing different sulfonyl groups were also tested to study the electronic effect of
the sulfonamides on the course of the reaction. As shown in Table 2, substituents on aromatic
ring had significant impact on the outcomes of the reactions. Arenesulfonyl groups bearing
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electronꢀdonating groups on benzene rings generally gave high isolated yields (entries 1 and
2
vs entry 3), and arenesulfonyl group with an electronꢀwithdrawing group on benzene ring
was unfavorable for the reaction (entry 4). This was possibly because of the slow formation
of the reaction intermediate sulfoniminium due to the low reactivity of the
pꢀnitrobenzenesulfonamide. Substrate with small methanesulfonyl group on nitrogen atom
gave moderate isolated yield with slight drop of the diastereoselectivity (entry 5).
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a
Table 2. The scope of the sulfonamides
Cl
N
Cl
N
AlCl (5 mol%)
TMSCl ( 2 equiv)
3
O
O
HN S R1
+
+
CH Cl , r. t., 24 h
R
H
2
2
O
R
R
R = p-CH C H
SO R1
SO R1
3
6
4
2
2
trans-3
cis-3
1
b
entry
R
isolated yield (%)
83 (3a)
trans : cis
98:2
1
2
3
4
5
pꢀMePh
pꢀMeOPh
Ph
88 (3b)
91:9
78 (3c)
95:5
pꢀO NPh
51 (3d)
95:5
2
CH
3
66 (3e)
86:14
a
2 2
Reaction conditions: the reactions were conducted in 0.5 mmol scale in 2 mL CH Cl at
b
1
room temperature. Diastereoisomeric ratios were determined by H NMR.
Encouraged by these preliminary results, different aldehydes were subjected to this azaꢀPrins
reaction to test the scope of the protocol. As shown in Table 3, aromatic, heteroaromatic,
aliphatic and α,βꢀunsaturated aldehydes underwent azaꢀPrins cyclization with Nꢀtosyl
homoallylamine, giving the corresponding 4ꢀchloropiperidines in good isolated yields with
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high diastereoselectivity.
Table 3. The scope of aldehydes in AlCl -catalyzed aza-Prins cyclization reaction
a
3
Cl
Cl
AlCl (5 mol%)
3
O
TMSCl ( 2 equiv)
0
1
2
3
4
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9
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9
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9
0
+
+
NHTs
R
H
CH Cl , r. t., 24 h
2
2
N
R
N
R
Ts
Ts
trans-4
cis-4
b
entry
R
isolated yield (%)
74 (4a)
77 (4b)
87 (4c)
85 (4d)
92 (4e)
80 (4f)
trans : cis
89:11
87:13
96:4
1
2
3
4
5
6
7
8
9
2ꢀMePh
3ꢀMePh
4ꢀMeOPh
3ꢀMeOPh
2ꢀMeOPh
Ph
95:5
87:13
96:4
4ꢀiPrPh
4ꢀFPh
84 (4g)
75 (4h)
70 (4i)
95:5
96:4
2ꢀFPh
90:10
91:9
10
4ꢀClPh
3ꢀClPh
4ꢀBrPh
4ꢀtBuPh
4ꢀCNPh
80 (4j)
11
78 (4k)
78 (4l)
89:11
90:10
96:4
12
13
84 (4m)
63 (4n)
60 (4o)
51 (4p)
14
96:4
15
4ꢀCO
2
MePh
Ph
99:1
16
4ꢀNO
2
99:1
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2ꢀfuranyl
H
84 (4q)
90 (4r)
86 (4s)
81 (4t)
92 (4u)
90 (4v)
93 (4w)
91 (4x)
83 (4y)
67 (4z)
ꢀ
96:4
ꢀ
C
2
H
5
89:11
86:14
98:2
89:11
97:3
92:8
91:9
93:7
ꢀ
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nꢀC
3
H
7
iꢀC
iꢀC
3
H
H
7
4
9
nꢀC H
5
11
nꢀC
6
H
13
25
PhCH
2
26
PhCH=CH
2ꢀpyridinyl
27
a
2 2
Reaction conditions: the reactions were conducted in 0.5 mmol scale in 2 mL CH Cl at
b
1
room temperature. Diastereoisomeric ratios were determined by H NMR.
As shown in Table 3, transꢀ2ꢀsubstituted 4ꢀchloropiperidines were obtained with moderate to
good isolated yields and satisfactory diastereoselectivity. The electronic properties of the
aromatic aldehydes showed some effect on the course of the reactions. In general, aromatic
aldehydes bearing electronꢀdonating groups on the benzene rings gave relatively higher
yields than aromatic aldehydes bearing electronꢀwithdrawing groups on the benzene rings
(
compounds 4aꢀ4g vs 4hꢀ4p), and a wide range of functional groups such as Me, MeO, tBu,
ꢀX, ꢀCO Me, ꢀCN and ꢀNO2 were tolerated during the reactions. Furthermore, the
2
heteroatomꢀcontaining furfural could also undergo cyclization under the optimal conditions
(4q). The trans stereochemistry was ascertained by single crystal Xꢀray diffraction
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experiment on Compound 4j. As shown in Figure 1, 4j bore a typical chair conformation with
pꢀchlorophenyl group at the axial position, chlorine atom and pꢀtoluenesulfonyl group stayed
at the equatorial positions. This result is in good agreement with a related azaꢀPrinsꢀRitter
0
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4
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9
0
5
b
reaction reported by Reddy.
Figure 1. ORTEP drawing of 4j with the thermal ellipsoids at 30% probability. Hydrogen
atoms were omitted for clarity.
Furthermore, this method was also effective for aliphatic aldehydes, and the corresponding
transꢀ2ꢀalkylꢀ4ꢀchloropiperidines could be obtained in good yields (4rꢀ4y). Also, the current
reaction system was applicable to the acidꢀsensitive cinnamaldehyde, and product 4z could be
obtained in moderate isolated yield. This compound has been used as key intermediate for the
13d
synthesis of alkaloid natural products. Nꢀtosyl homoallylamine and picolinaldehyde failed
to react under the optimized reaction conditions, possibly due to the overꢀcoordination of the
nitrogen atom to AlCl which decreased the catalytic activity of the latter.
3
After the successful synthesis of transꢀ2ꢀsubstituted 4ꢀchloropiperidines, our attention turned
to the synthesis of transꢀ2ꢀsubstituted 4ꢀbromopiperidines. Fache et al. showed that TMSBr
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or TMSI alone could be used to promote azaꢀPrins cyclizations of allylsulfonamides with
aldehydes/ketones. The reactions were carried out under solventꢀ and metalꢀfree conditions,
and the products
δꢀsultams could be obtained in good isolated yields. However, mixtures of
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4
ꢀhalopiperidines and dihydropiperidines were obtained when Nꢀtosyl homoallylamine and
2
1
aldehydes were subjected to azaꢀPrins reactions under the same conditions. In the current
study, when 5 mol% of AlCl was used as catalyst, no dihydropiperidine products were
3
detected, and a variety of transꢀ2ꢀsubstituted 4ꢀbromopiperidines could be obtained in good
isolated yields (Table 4). When different aromatic aldehydes were subjected to the reactions,
electronꢀrich aromatic aldehydes gave higher yields than their electronꢀdeficient counterparts.
The structure and relative stereochemistry of transꢀ2ꢀsubstituted 4ꢀbromopiperidines were
22
established by an Xꢀray diffraction experiment on compound 5o.
a
Table 4. Synthesis of 4-bromopiperidines
Br
Br
AlCl (5 mol%)
3
O
TMSBr ( 2 equiv)
+
+
NHTs
R
H
CH Cl , r. t., 24 h
2
2
N
R
N
R
Ts
Ts
trans-5
cis-5
b
entry
R
isolated yield (%)
82 (5a)
trans : cis
94:6
1
2
3
4
5
6
4ꢀMePh
3ꢀMePh
4ꢀMeOPh
3ꢀMeOPh
2ꢀMeOPh
Ph
87 (5b)
91:9
91 (5c)
91:9
87 (5d)
90:10
97:3
84 (5e)
93 (5f)
99:1
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4ꢀiPrPh
4ꢀtBuPh
4ꢀFPh
81 (5g)
87 (5h)
80 (5i)
82 (5j)
78 (5k)
83 (5l)
60 (5m)
65 (5n)
53 (5o)
65 (5p)
71 (5q)
89 (5r)
90 (5s)
87 (5t)
93 (5u)
93 (5v)
82 (5w)
94 (5x)
70 (5y)
82 (5z)
94:6
98:2
96:4
89:11
96:4
95:5
99:1
99:1
98:2
92:8
99:1
99:1
ꢀ
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0
1
0
2ꢀFPh
1
1
2
3
4
4ꢀClPh
4ꢀBrPh
4ꢀCNPh
1
1
1
4ꢀCO
2
MePh
15
4ꢀNO
2
Ph
1
6
4ꢀCF
3
Ph
17
4ꢀHOPh
2ꢀFuranyl
H
1
8
19
2
0
C
2
H
5
88:12
86:14
92:8
90:10
88:12
86:14
89:11
21
iꢀC
iꢀC
3
4
H
H
7
2
2
9
23
nꢀC H
5
11
2
4
6
nꢀC H
13
25
PhCH=CH
PhCH
2
6
2
a
2 2
Reaction conditions: the reactions were conducted in 0.5 mmol scale in 2 mL CH Cl at
b
1
room temperature. Diastereomeric ratios were determined by H NMR.
1
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Sabitha et al. reported the preparation of 4ꢀiodopiperidines via TMSIꢀpromoted azaꢀPrins
reactions. In the presence of 1 equiv of TMSI, azaꢀPrins reaction of Nꢀtosyl homoallylamine
with aliphatic aldehydes produced transꢀ2ꢀalkylꢀ4ꢀiodoꢀ1ꢀtosylpiperidines in good isolated
yields, and good selectivity for aliphatic aldehyde was observed when both aliphatic and
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
2
3
aromatic aldehydes were present in the reaction mixture. To our delight, preparation of
2
ꢀarylꢀ4ꢀiodopiperidine compounds could be realized via AlCl
3
ꢀcatalyzed azaꢀPrins reactions
of aromatic aldehydes using TMSI as the iodide source (Table 5).
a
Table 5. Synthesis of 4-iodopiperidines
I
I
AlCl (5 mol%)
3
O
TMSI ( 2 equiv)
+
+
NHTs
R
H
CH Cl , r. t., 24 h
2
2
N
R
N
R
Ts
Ts
trans-6
cis-6
b
entry
R
isolated yield (%)
81 (6a)
trans : cis
92:8
1
2
3
4
5
6
7
8
9
4ꢀMePh
3ꢀMePh
2ꢀMePh
4ꢀMeOPh
3ꢀMeOPh
2ꢀMeOPh
Ph
86 (6b)
79 (6c)
94:6
90:10
90:10
92:8
65 (6d)
72 (6e)
78 (6f)
93:7
73 (6g)
92:8
4ꢀiPrPh
4ꢀtBuPh
4ꢀFPh
80 (6h)
85 (6i)
90:10
95:5
1
0
84 (6j)
96:4
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2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
1
1
2ꢀFPh
4ꢀClPh
3ꢀClPh
4ꢀBrPh
2ꢀBrPh
88 (6k)
81 (6l)
88 (6m)
89 (6n)
77 (6o)
68 (6p)
60 (6q)
71 (6r)
86 (6s)
84 (6t)
82 (6u)
88 (6v)
91 (6w)
83 (6x)
85 (6y)
73 (6z)
89:11
92:8
94:6
90:10
91:9
93:7
95:5
94:6
ꢀ
12
13
14
15
16
17
18
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
4ꢀCF
3
Ph
4ꢀCO MePh
2
2
4ꢀPhCH OPh
19
H
2
0
C
2
H
5
87:13
90:10
91:9
89:11
88:12
88:12
90:10
21
nꢀC
3
H
7
2
2
iꢀC H7
3
23
3 7 2
iꢀC H CH
2
4
nꢀC
nꢀC
5
H
11
25
6
H
13
2
6
PhCH
2
a
2 2
Reaction conditions: the reactions were conducted in 0.5 mmol scale in 2 mL CH Cl at
b
1
room temperature. Diastereomeric ratios were determined by H NMR.
As shown in Table 5, both aliphatic aldehydes and aromatic aldehydes could undergo
azaꢀPrins reactions. The corresponding transꢀ2ꢀsubstituted 4ꢀiodopiperidines were obtained
in good yields and high diastereoselectivity, and the formation of dihydropiperidines was not
2
1
observed. Again, electronꢀrich aromatic aldehydes gave products in high yields compared to
1
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the electronꢀdeficient aromatic aldehydes.
1
The structure and stereochemistry of the compounds were also established by H NMR and
NOE experiments on compound 6n. Major diastereomer bore a typical chair conformation
10
11
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13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
where the two substituents are trans to each other (Figure 2). Proton H has two large
4
couplings (J = 14.5 Hz) indicating its axial position with diaxial couplings with H3ax and H5ax
These results indicated that the iodide atom stayed at the equatorial position at C . This was
further confirmed by a NOESY cross peak between H and H6a. A small coupling (J = 4.1 Hz)
of H proton indicated that it stayed at equatorial position, and the pꢀbromophenyl group
stayed at axial position of C . The axial orientation of the pꢀbromophenyl group was further
.
4
4
2
2
4
confirmed by the NOESY cross peaks between Hꢀortho and H . The couplings and H3a/H5a
NOE correlation also provided additional support for the structure. These results were also in
22
agreement with Xꢀray diffraction experiment.
The structure of minor diastereomer 6n shown in Figure 2 was deduced from the NMR data,
where the two substituents are cis to each other. The coupling constants observed for J(H4–
H
3a) and J(H3a–H
2
) were all greater than 10.0 Hz indicating that these protons stayed at axial
positions, and the pꢀbromophenyl group stayed at the equatorial position of C . This
, H6a, and H
2
strucuture was also confirmed by the presence of NOE crossꢀpeaks between H
4
2
22
as well as crossꢀpeaks between H3a and H5a
.
H
H
5
H
H
H
6
NTs
H
H
5
H
6
NTs
H
I
H
3
4
H
2
I
H
Br
3
H
4
H
2
H
H
trans-6n Br
cis-
6n
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2
2
2
2
2
2
2
2
2
3
3
3
3
3
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3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Figure 2. Characteristic NOEs of 6n
In addition to the synthesis of 4ꢀchloroꢀ, 4ꢀbromoꢀ and 4ꢀiodopiperidines, synthesis of
2
4
4
ꢀfluoropiperidines could also be realized under current reaction conditions. After the
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
screening of different fluoride sources, BF ·Et O was found to be the most suitable one for
3
2
the reaction, and several 4ꢀfluoropiperidines compounds could be obtained in good isolated
2
5
yields (Table 6). However, poor diastereoselectivities were observed for most reactions. We
reasoned that this was due to the small size of the fluoride anion which caused poor
diastereodiscrimination during the attack of the fluoride to the reaction intermediate.
The crystal structure of the transꢀdiastereomer of the 4ꢀfluoropiperidine 7d was determined
22
by Xꢀray crystallography. Launay et al. reported the microwaveꢀassisted azaꢀPrins reactions
3 2
of Nꢀtosyl homoallylamine to generate 4ꢀfluoropiperidines using BF ·Et O as the fluoride
9b
source. However, the yields dropped dramatically when electronꢀrich aromatic aldehydes
were subjected to the reactions. Therefore, the current method provided a new approach that
was complementary to the known methods for the synthesis of 4ꢀfluoropiperidines.
a
Table 6. Synthesis of 4-fluoropiperidines
F
F
AlCl (5 mol%)
3
.
O
BF OEt (2 equiv)
3
2
Ts
N
H
+
+
R
H
CH Cl , r. t., 8 h
2 2
N
R
N
Ts
R
Ts
trans-7
cis-7
b
entry
R
isolated yield
trans : cis
48:52
1
2
3
4ꢀMePh
4ꢀMeOPh
Ph
80 (7a)
82 (7b)
75 (7c)
46:54
44:56
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7
4ꢀFPh
4ꢀClPh
4ꢀBrPh
76 (7d)
84 (7e)
81 (7f)
86 (7g)
41:59
47:53
45:55
42:58
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
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37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
2
4ꢀNO Ph
a
Reaction conditions: the reactions were conducted in 0.5 mmol scale in 2 mL CH Cl at
2
2
b
1
room temperature. Diastereomeric ratios were determined by H NMR.
3
Subsequently, ketones were also tested in AlCl ꢀcatalyzed azaꢀPrins reactions, and
spiroꢀpiperidines with quaternary centers could be obtained in moderate isolated yields when
cyclic ketones were subjected to the reactions with TMSBr as the bromide source (Table 7,
entries 4 and 5). TMSCl or TMSI failed to react under current conditions.
a
Table 7. aza-Prins reactions of
N
-tosyl homoallylamine with various ketones
X
AlCl (5 mol%)
3
O
TMSX (2 equiv)
Ts
+
N
H
R
CH Cl , r. t., 24 h
R
R
2
2
N
R
Ts
8
a - 8c
entry
TMSX
TMSCl
TMSBr
TMSI
R
isolated yield (%)
1
2
3
4
5
Me
Me
Me
NR
46(8a)
<5
TMSBr
TMSBr
ꢀ(CH ) ꢀ
51(8b)
40(8c)
2
4
ꢀ(CH
2
)
5
ꢀ
a
2 2
Reaction conditions: the reactions were conducted in 0.5 mmol scale in 2 mL CH Cl at
1
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1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
room temperature.
After azaꢀPrins cyclization of Nꢀtosyl homoallylamine with a variety of aldehydes, the scope
of the reaction was further extended to homoallylic alcohol. As shown in Table 8, TMSCl
gave the highest yields and diastereoselectivity for Prins reaction of a variety of aldehydes
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(entries 1ꢀ3). It was noteworthy that cisꢀhalotetrahydropyrans were obtained as the major
products in all cases.
a
Table 8. Synthesis of 4-halotetrahydropyrans
AlCl (5 mol%)
TMSX (2 equiv)
3
X
X
O
+
+
OH
R
H
CH Cl , r. t., 12 h
2
2
O
R
O
R
trans-9
cis-9
halide
isolated yield (%)
b
entry
X
R
trans : cis
source
TMSCl
TMSBr
1
2
3
4
5
6
7
8
9
Cl
Br
F
Ph
Ph
Ph
87 (9a)
83 (9b)
83 (9c)
86 (9d)
89 (9e)
90 (9f)
86 (9g)
91 (9h)
93 (9i)
< 1:99
10:90
BF
3
·OEt
2
12:88
TMSCl
TMSCl
TMSCl
TMSCl
TMSCl
TMSCl
Cl
Cl
Cl
Cl
Cl
Cl
4ꢀMePh
4ꢀMeOPh
4ꢀClPh
< 1:99
< 1:99
< 1:99
< 1:99
< 1:99
< 1:99
4ꢀBrPh
4ꢀFPh
2
4ꢀNO Ph
a
2 2
Reaction conditions: the reactions were conducted in 0.5 mmol scale in 2 mL CH Cl at
1
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b
1
room temperature. Diastereomeric ratios were determined by H NMR.
The current study showed that reactions of Nꢀtosyl homoallylamine gave
transꢀhalopiperidines as the major products (Table 1ꢀ5), whereas reactions of homoallylic
alcohol afforded cisꢀhalotetrahydropyrans as the major isomers (Table 8). The
transꢀselectivity for azaꢀPrins cyclization may be attributed to the steric repulsion between Ts
and R groups. Due to this repulsion, the Lewis acidꢀassisted formation of Eꢀsulfoniminium
10
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23
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25
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35
36
37
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40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
26
intermediate would be more favorable during the reaction. azaꢀPrins cyclization proceeded
via a sixꢀmembered ring transitionꢀstate with the Ts group at the equatorial position and the R
group at the axial position, and attack of the halide anion occurred from equatorial direction,
2
7
leading to transꢀhalopiperidine as the major product (Scheme 2, path a).
Scheme 2. Plausible reaction pathway in the aza-Prins cyclization of
homoallylamine
N
-tosyl
X
a
X
Ts
Ts
N
N
a
H
H
R
R
N
R
X
b
Ts
E-iminium ion
b
I
Trans
Major product
c
X
c
X
Ts
N
Ts
N
R
R
N
R
d
H
H
d
Ts
Cis
Minor product
X
II
Z-iminium ion
2
8
In the case of homoallylic alcoholꢀinvolved Prins reaction, the R group staying at equatorial
position of the transition state (B) would be more favorable, and the attack of halide anion
took place from the equatorial direction, producing cisꢀdisubstituted tetrahydropyran as the
1
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1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
major product (Scheme 3, path d).
Scheme 3. Plausible reaction pathways in the Prins cyclization of homoallylic alcohol
a
X
X
O
O
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
a
H
H
R
R
O
Trans
Minor product
R
X
A
b
b
III
c
X
c
X
O
R
O
R
O
R
d
H
H
Cis
Major product
X
d
B
IV
Conclusion
In summary, we have shown that AlCl
Nꢀtosyl homoallylamine and Prins reaction of homoallylic alcohol with a variety of carbonyl
compounds. Using 5 mol% of AlCl as the catalyst and 2 equiv of trimethylsilyl halide as the
3
was effective to catalyze azaꢀPrins reactions of
3
halide sources, both transꢀhalopiperidines and cisꢀhalotetrahydropyrans could be obtained in
good isolated yields with satisfactory diastereoselectivity. The reactions could be easily
carried out at ambient temperature, and air or moisture showed less effect on the course of the
reactions. These features made the current reaction system a useful method for the
preparation of a variety of substituted piperidines and tetrahydropyrans which could be used
as useful building blocks for organic synthesis and drug synthesis.
Experimental Section
General experimental information: Reagents were used as received without further
purification unless otherwise indicated. Solvents were dried and distilled prior to use.
Reactions were monitored with thin layer chromatography using silica gel GF254 plates.
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Organic solutions were concentrated in vacuo with rotavapor. Flash column chromatography
was performed using silica gel (200ꢀ300 meshes). Petroleum ether used had a boiling point
range of 60ꢀ90 °C. Melting points were measured on a digital melting point apparatus without
correction of the thermometer. Nuclear magnetic resonance spectra were recorded at ambient
10
11
12
13
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15
16
17
18
19
20
21
22
23
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46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
3
temperature (unless otherwise stated) at 400 MHz (100 MHz for C) in CDCl
3
. Chemical
shifts are reported in ppm ( ) using TMS as internal standard, and spinꢀspin coupling
δ
constants (J) are given in Hz. Infrared (IR) spectra were recorded with KBr pellet, and
ꢀ1
wavenumbers were given in cm . High resolution mass spectrometry (HRMS) analyses were
carried out on 7.0T FTICR HRꢀESIꢀMS.
General procedure for Prins reaction: In a 10 mL sealed tube were added Nꢀtosyl
homoallylamine or homoallylic alcohol (0.5 mmol), aldehyde (0.5 mmol), AlCl
and TMSX (1 mmol) in dry CH Cl (2 mL). The mixture was stirred at room temperature for
a given time. Then CH Cl (10 mL) was added and the mixture was washed with H O, dried
3
(0.025 mmol)
2
2
2
2
2
over MgSO , and concentrated to give crude residue, which was purified by flash column
4
chromatography to give the corresponding products.
The diastereomeric ratios were determined by comparing the integrations of Hꢀ2 signals of
1
the H NMR spectra of the products.
4
-Chloro-2-(p-tolyl)-1-tosylpiperidine (3a). The compound (151 mg, 83%, trans: cis = 98:2)
was purified by flash chromatography using petroleum ether/ethyl acetate (40:1) as eluent.
1
transꢀ4ꢀChloroꢀ2ꢀ(pꢀtolyl)ꢀ1ꢀtosylpiperidine (major diastereomer, oil): H NMR (400 MHz,
CDCl
3
) δ = 7.68 (d, J = 8.1 Hz, 2H), 7.24 (d, J = 8.1 Hz, 2H), 7.11 (d, J = 8.2 Hz, 2H), 7.06
(
d, J = 8.2 Hz, 2H), 5.27 (d, J = 3.9 Hz, 1H), 3.91 – 3.75 (m, 2H), 2.98 – 2.88 (m, 1H), 2.66 –
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1
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1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
2
.60 (m, 1H), 2.36 (s, 3H), 2.24 (s, 3H), 1.86 – 1.71 (m, 2H), 1.46 (dd, J = 12.8, 4.7 Hz, 1H);
1
3
C NMR (100 MHz, CDCl
2.9, 41.4, 37.7, 35.2, 21.6, 21.0. NMR data were in agreement with the reported results.
-Chloro-1-(4-methoxyphenylsulfonyl)-2-( -tolyl)piperidine (3b). The compound (167 mg,
8%, trans: cis = 91:9) was purified by flash chromatography using petroleum ether/ethyl
3
) δ = 143.6, 138.1, 137.2, 134.2, 130.0, 129.7, 127.0, 126.5, 55.9,
29
5
4
8
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
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7
8
9
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0
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9
0
p
acetate (10:1) as eluent. transꢀ4ꢀChloroꢀ1ꢀ(4ꢀmethoxyphenylsulfonyl)ꢀ2ꢀ(pꢀtolyl)piperidine
1
(major diastereomer, oil): H NMR (400 MHz, CDCl
3
) δ = 7.73 (d, J = 8.1 Hz, 2H), 7.12 (d, J
=
8.1 Hz, 2H), 7.07 (d, J = 8.2 Hz, 2H), 6.91 (d, J = 8.2Hz, 2H), 5.26 (d, J = 3.8 Hz, 1H),
3.91 – 3.80 (m, 5H), 3.01 – 2.90 (m, 1H), 2.70 – 2.58 (m, 1H), 2.25 (s, 3H), 1.87 – 1.76 (m,
13
2H), 1.50 (qd, J = 12.8, 4.7 Hz, 1H); C NMR (100 MHz, CDCl
3
) δ = 162.9, 137.1, 134.3,
132.6, 129.7, 129.1, 126.5, 114.5, 55.9, 55.7, 53.0, 41.3, 37.7, 35.3, 21.0. IR: 3000, 2930,
ꢀ1
1
+
2
057, 1598, 1511, 1455, 1303, 1026, 933, 734 cm . HRMS–ESI (m/z): [M+H] calcd for
S, 380.1087; found: 380.1087.
-Chloro-1-benzenesulfonyl-2-( -tolyl)piperidine (3c). The compound (136 mg, 78%,
trans: cis = 95:5) was purified by flash chromatography using petroleum ether/ethyl acetate
19 3
C H22ClNO
4
p
(30:1) as eluent. transꢀ4ꢀChloroꢀ1ꢀbenzenesulfonylꢀ2ꢀ(pꢀtolyl)piperidine (major diastereomer,
1
white solid, mp = 97ꢀ99 °C): H NMR (400 MHz, CDCl
3
) δ = 7.85 – 7.77 (m, 2H), 7.54 –
7
.50 (m, 1H), 7.46 (t, J = 7.5 Hz, 2H), 7.10 (d, J = 8.3 Hz, 2H), 7.06 (d, J = 8.3 Hz, 2H), 5.30
(d, J = 4.1 Hz, 1H), 3.91 – 3.79 (m, 2H), 3.01 – 2.92 (m, 1H), 2.68 – 2.60 (m, 1H), 2.24 (s,
13
3H), 1.88 – 1.72 (m, 2H), 1.46 (qd, J = 12.9, 4.7 Hz, 1H); C NMR (100 MHz, CDCl
3
) δ =
139.9, 136.2, 133.0, 131.7, 128.6, 128.3, 125.8, 125.4, 54.9, 51.7, 40.3, 36.7, 34.2, 19.9. IR:
ꢀ1
+
3
054, 2964, 1514, 1448, 1371, 1159, 922, 738 cm . HRMS–ESI (m/z): [M+H] calcd for
2
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18 2
C H20ClNO S, 350.0982; found: 350.0973.
cisꢀ4ꢀChloroꢀ1ꢀ(4ꢀmethoxyphenylsulfonyl)ꢀ2ꢀ(pꢀtolyl)piperidine (minor diastereomer, white
1
solid, mp = 161ꢀ162 °C): H NMR (400 MHz, CDCl
3
) δ = 7.48 (d, J =8.9 Hz, 2H), 7.02 (d, J
10
11
12
13
14
15
16
17
18
19
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=
8.1 Hz, 2H), 6.96 (d, J = 8.1 Hz, 2H), 6.80 (d, J = 8.9 Hz, 2H), 4.51 (t, J = 5.9 Hz, 1H),
4
.07 – 3.97 (m, 1H), 3.87 – 3.79 (m, 1H), 3.78 (s, 3H), 3.30 (ddd, J = 13.6, 6.8, 3.8 Hz, 1H),
.39 – 2.30 (m, 1H), 2.23 (s, 3H), 2.17 (dt, J = 14.3, 4.3 Hz, 1H), 2.07 (ddd, J = 12.5, 8.0, 3.7
2
1
3
Hz, 1H), 1.83 (dtd, J = 13.8, 7.0, 3.5 Hz, 1H). C NMR (100 MHz, CDCl
3
) δ = 162.7, 136.8,
1
2
36.4, 131.3, 129.4, 128.7, 126.9, 113.9, 57.7, 55.6, 54.3, 41.6, 40.0, 34.0, 21.0. IR: 3030,
ꢀ1
+
980, 2069, 1610, 1510, 1436, 1026, 955, 727 cm . HRMS–ESI (m/z): [M+H] calcd for
S, 350.0982; found: 350.0973.
4-Chloro-1-(4-nitrophenylsulfonyl)-2-( -tolyl)piperidine (3d). The compound (100 mg,
1%, trans: cis = 95:5) was purified by flash chromatography using petroleum ether/ethyl
18 2
C H20ClNO
p
5
acetate (15:1) as eluent. transꢀ4ꢀChloroꢀ1ꢀ(4ꢀnitrophenylsulfonyl)ꢀ2ꢀ(pꢀtolyl)piperidine
1
(major diastereomer, white solid, mp = 158ꢀ160 °C): H NMR (400 MHz, CDCl ) δ = 8.29 (d,
3
J = 8.6 Hz, 2H), 7.94 (d, J = 8.6 Hz, 2H), 7.06 (d, J = 8.1 Hz, 2H), 7.02 (d, J = 8.1 Hz, 2H),
.31 (s, 1H), 3.94 – 3.85(m, 1H), 3.08 (t, J = 12.6 Hz, 1H), 2.69 (d, J = 13.6 Hz, 1H), 2.25 (s,
5
13
3H), 1.96 (d, J = 11.6 Hz, 1H), 1.85 (td, J = 13.1, 5.3 Hz, 1H), 1.63 – 1.47 (m, 1H); C NMR
(100 MHz, CDCl ) δ = 148.9, 145.6, 136.6, 132.5, 128.7, 127.1, 125.4, 123.5, 55.4, 51.2,
3
ꢀ1
40.8, 37.4, 34.4, 19.9. IR: 3030, 2966, 1604, 1526, 1401, 1351, 1165, 1011, 855, 755 cm .
+
HRMS–ESI (m/z): [M+H] calcd for C18
H
19ClN
O
2 4
S, 395.0832; found: 395.0821.
-tolyl)piperidine (3e). The compound (95 mg, 66%, trans:
cis = 86:14) was purified by flash chromatography using petroleum ether/ethyl acetate (15:1)
4-Chloro-1-methanesulfonyl-2-(
p
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as eluent. transꢀ4ꢀChloroꢀ1ꢀmethanesulfonylꢀ2ꢀ(pꢀtolyl)piperidine (major diastereomer, white
1
solid, mp = 75ꢀ78 °C): H NMR (400 MHz, CDCl
3
) δ = 7.18 (d, J = 8.2 Hz, 2H), 7.13 (d, J =
8
3
–
1
9
2
4
8
.2 Hz, 2H), 5.23 (d, J = 4.5 Hz, 1H), 3.97 (tt, J = 11.8, 4.1 Hz, 1H), 3.87 – 3.79 (m, 1H),
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8
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0
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4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
.10 – 3.01 (m, 1H), 2.89 (s, 3H), 2.83 – 2.75 (m, 1H), 2.28 (s, 3H), 2.20 – 2.10 (m, 1H), 2.09
13
2.01 (m, 1H), 1.87 – 1.79 (m, 1H); C NMR (100 MHz, CDCl
3
) δ = 136.4, 133.2, 128.8,
25.5, 54.9, 51.7, 40.3, 40.0, 37.9, 35.1, 19.9. IR: 3030, 2963, 1726, 1513, 1456, 1324, 1153,
ꢀ1
+
61, 854 cm . HRMS–ESI (m/z): [M+H] calcd for C13
2
H18ClNO S, 288.0825; found:
88.0817.
-Chloro-2-(o-tolyl)-1-tosylpiperidine (4a). The compound (134 mg, 74%, trans: cis =
9:11) was purified by flash chromatography using petroleum ether/ethyl acetate (50:1) as
1
eluent. transꢀ4ꢀChloroꢀ2ꢀ(oꢀtolyl)ꢀ1ꢀtosylpiperidine (major diastereomer, oil): H NMR (400
MHz, CDCl
6.87 – 6.79 (m, 1H), 5.23 (t, J = 5.2 Hz, 1H), 4.21 – 4.13 (m, 1H), 3.87 – 3.83 (m, 1H), 2.70 –
.60 (m, 1H), 2.45 – 2.35 (m, 1H), 2.35 – 2.30 (m, 1H), 2.31 – 2.23 (m,4H), 2.21 (s, 3H),
3
) δ = 7.26 (d, J = 8.3 Hz, 2H), 7.07 – 6.98 (m, 4H), 6.90 (d, J = 7.6 Hz, 1H),
2
1
3
2.05 – 1.97 (m, 1H); C NMR (100 MHz, CDCl
3
) δ = 143.0, 137.6, 136.9, 135.7, 131.0,
129.2, 129.0, 127.4, 127.0, 125.6, 54.0, 53.9, 43.5, 39.7, 34.8, 21.5, 19.6. IR: 3059, 2958,
ꢀ
1
+
1598, 1490, 1452, 1329, 1158, 937, 857 cm . HRMS–ESI (m/z): [M+H] calcd for
S, 364.1138; found: 364.1138.
-tolyl)-1-tosylpiperidine (4b). The compound (140 mg, 77%, trans: cis =
7:13) was purified by flash chromatography using petroleum ether/ethyl acetate (40:1) as
19 2
C H22ClNO
4-Chloro-2-(
m
8
eluent. transꢀ4ꢀChloroꢀ2ꢀ(mꢀtolyl)ꢀ1ꢀtosylpiperidine (major diastereomer, white solid, mp =
1
9
8ꢀ99 °C): H NMR (400 MHz, CDCl
3
) δ = 7.69 (d, J = 8.2 Hz, 2H), 7.26 (d, J = 8.2 Hz, 2H),
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.16 (dd, J = 14.2, 6.2 Hz, 1H), 7.04 – 6.96 (m, 3H), 5.29 (d, J = 4.1 Hz, 1H), 4.00 – 3.73 (m,
H), 3.08 – 2.84 (m, 1H), 2.69 – 2.60 (m, 1H), 2.38 (s, 3H), 2.24 (s, 3H), 1.87 – 1.76 (m, 2H),
1
3
.50 (qd, J = 12.8, 4.7 Hz, 1H); C NMR (100 MHz, CDCl
3
) δ = 142.5, 137.7, 137.1, 136.2,
10
11
12
13
14
15
16
17
18
19
20
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28.9, 127.8, 127.1, 126.2, 125.9, 122.5, 55.0, 51.9, 40.4, 36.8, 34.2, 20.6. IR: 3061, 2958,
ꢀ1
+
491, 1452, 1340, 1092, 935, 800 cm . HRMS–ESI (m/z): [M+H] calcd for C19
2
H22ClNO S,
64.1138; found: 364.1137.
-Chloro-2-(4-methoxyphenyl)-1-tosylpiperidine (4c). The compound (165 mg, 87%, trans:
cis = 96:4) was purified by flash chromatography using petroleum ether/ethyl acetate (40:1)
as eluent. transꢀ4ꢀChloroꢀ2ꢀ(4ꢀmethoxyphenyl)ꢀ1ꢀtosylpiperidine (major diastereomer, white
1
solid, mp = 104ꢀ105 °C): H NMR (400 MHz, CDCl
3
) δ = 7.68 (d, J = 8.3 Hz, 2H), 7.24 (d, J
= 8.1 Hz, 2H), 7.14 (d, J = 8.3 Hz, 2H), 6.81 – 6.75 (m, 2H), 5.25 (d, J = 4.3 Hz, 1H), 3.89 –
.79 (m, 2H), 3.70 (s, 3H), 3.00 – 2.85 (m, 1H), 2.63 – 2.55 (m, 1H), 2.36 (s, 3H), 1.85 – 1.78
3
13
(m, 1H), 1.78 – 1.71 (m, 1H), 1.46 (dd, J = 12.8, 4.7 Hz, 1H); C NMR (100 MHz, CDCl
3
) δ
=
158.8, 143.6, 138.0, 130.0, 129.1, 127.8, 126.9, 114.3, 55.6, 55.3, 52.9, 41.3, 37.6, 35.2,
30
21.6. NMR data were in agreement with the reported results.
4-Chloro-2-(3-methoxyphenyl)-1-tosylpiperidine (4d). The compound (161 mg, 85%, trans:
cis = 95:5) was purified by flash chromatography using petroleum ether/ethyl acetate (50:1)
as eluent. transꢀ4ꢀChloroꢀ2ꢀ(3ꢀmethoxyphenyl)ꢀ1ꢀtosylpiperidine (major diastereomer, white
1
solid, mp = 106ꢀ108 °C): H NMR (400 MHz, CDCl ) δ = 7.69 (d, J = 8.1 Hz, 2H), 7.25 (d, J
3
=
8.1 Hz, 2H), 7.19 – 7.11 (m, 1H), 6.81 (d, J = 7.7 Hz, 1H), 6.75 – 6.71 (m, 2H), 5.28 (d, J =
4.2 Hz, 1H), 3.91 – 3.77 (m, 2H), 3.67 (s, 3H), 3.01 – 2.91 (m, 1H), 2.67 – 2.57 (m, 1H), 2.37
13
(s, 3H), 1.87 – 1.76 (m, 2H), 1.50 (dd, J = 12.8, 4.8 Hz, 1H); C NMR (100 MHz, CDCl
3
) δ
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=
159.2, 142.6, 138.1, 136.9, 129.0, 128.9, 125.9, 117.6, 111.5, 111.5, 55.0, 54.2, 51.8, 40.4,
29
36.7, 34.2, 20.5. NMR data were in agreement with the reported results.
4-Chloro-2-(2-methoxyphenyl)-1-tosylpiperidine (4e). The compound (174 mg, 92%, trans:
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
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7
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9
0
cis = 87:13) was purified by flash chromatography using petroleum ether/ethyl acetate (40:1)
as eluent. transꢀ4ꢀChloroꢀ2ꢀ(2ꢀmethoxyphenyl)ꢀ1ꢀtosylpiperidine (major diastereomer, oil):
1
3
H NMR (400 MHz, CDCl ) δ = 7.53 (d, J = 8.2 Hz, 2H), 7.17 – 7.10 (m, 3H), 6.99 (d, J =
7.5 Hz, 1H), 6.72 (dd, J = 14.6, 7.8 Hz, 2H), 5.50 (d, J = 3.7 Hz, 1H), 4.03 – 3.96 (m, 1H),
3.85 – 3.75 (m, 1H), 3.72 (s, 3H), 3.53 – 3.43 (m, 1H), 2.70 – 2.60 (m, 1H), 2.33 (s, 3H), 2.03
13
(dd, J = 8.3, 4.5 Hz, 1H), 1.83 – 1.78 (m, 1H), 1.61 (dd, J = 12.3, 5.1 Hz, 1H); C NMR (100
MHz, CDCl ) δ = 155.2, 142.1, 136.5, 128.5, 127.4, 126.3, 126.1, 125.9, 119.0, 109.6, 54.1,
3
ꢀ1
52.9, 52.0, 42.2, 38.3, 34.5, 20.5. IR: 3063, 2894, 1655, 1597, 1439, 1159, 937, 864, 761 cm .
+
HRMS–ESI (m/z): [M+H] calcd for C19
H
22ClNO
3
S, 380.1087; found: 380.1084.
1
cisꢀ4ꢀChloroꢀ2ꢀ(2ꢀmethoxyphenyl)ꢀ1ꢀtosylpiperidine (minor diastereomer, oil): H NMR (400
MHz, CDCl ) δ = 7.57 (d, J = 8.0 Hz, 2H), 7.23 (d, J = 7.9 Hz, 2H), 7.16 (t, J = 7.9 Hz, 1H),
3
6.83 (d, J = 7.6 Hz, 1H), 6.73 (d, J = 11.5 Hz, 2H), 4.76 (t, J = 5.5 Hz, 1H), 4.14 (s, 1H), 3.90
–
3.78 (m, 1H), 3.72 (s, 3H), 3.58 – 3.42 (m, 1H), 2.50 – 2.36 (m, 4H), 2.27 (d, J = 14.4 Hz,
13
1H), 2.18 – 2.06 (m, 1H), 1.87 (d, J = 13.5 Hz, 1H). C NMR (100 MHz, CDCl
3
) δ = 159.4,
143.4, 141.2, 129.5, 129.0, 127.3, 119.3, 112.6, 112.4, 56.9, 55.0, 54.0, 40.8, 39.1, 33.7, 21.5.
ꢀ1
+
IR: 3050, 2900, 1650, 1600, 1439, 1143, 950, 864, 745 cm . HRMS–ESI (m/z): [M+H]
calcd for C19 S, 380.1087; found: 380.1084.
H
22ClNO
3
4-Chloro-2-phenyl-1-tosylpiperidine (4f). The compound (139 mg, 80%, trans: cis = 96:4)
was purified by flash chromatography using petroleum ether/ethyl acetate (40:1) as eluent.
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transꢀ4ꢀChloroꢀ2ꢀphenylꢀ1ꢀtosylpiperidine (major diastereomer, oil): H NMR (400 MHz,
CDCl ) δ = 7.68 (d, J = 8.2 Hz, 2H), 7.27 – 7.08 (m, 7H), 5.31 (d, J = 4.6 Hz, 1H), 3.91 –
.83 (m, 1H), 3.83 – 3.75 (m, 1H), 2.98 – 2.89 (m, 1H), 2.64 (dd, J = 12.0, 1.6 Hz, 1H), 2.35
3
3
10
11
12
13
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49
50
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53
54
55
56
57
58
59
60
1
3
(
s, 3H), 1.83 – 1.75 (m, 2H), 1.46 (dd, J = 12.8, 4.7 Hz, 1H); C NMR (100 MHz, CDCl ) δ
3
=
143.7, 137.9, 137.3, 130.0, 129.0, 127.5, 126.9, 126.5, 56.1, 52.9, 41.4, 37.7, 35.2, 21.6.
10a
NMR data were in agreement with the reported results.
4
-Chloro-2-(4-isopropylphenyl)-1-tosylpiperidine (4g). The compound (164 mg, 84%,
trans: cis = 95:5) was purified by flash chromatography using petroleum ether/ethyl acetate
(
40:1) as eluent. transꢀ4ꢀChloroꢀ2ꢀ(4ꢀisopropylphenyl)ꢀ1ꢀtosylpiperidine (major diastereomer,
1
oil): H NMR (400 MHz, CDCl
3
) δ = 7.68 (d, J = 8.1 Hz, 2H), 7.24 (d, J = 8.1 Hz, 2H), 7.14
(d, J = 8.5 Hz, 2H), 7.11 (d, J = 8.5 Hz, 2H), 5.28 (d, J = 4.4 Hz, 1H), 3.88 – 3.81 (m, 2H),
.01 – 2.93 (m, 1H), 2.83 – 2.78 (m, 1H), 2.65 (dd, J = 7.1, 5.4 Hz, 1H), 2.36 (s, 3H), 1.86 –
3
1
3
1.73 (m, 2H), 1.49 (dd, J = 12.8, 4.7 Hz, 1H), 1.15 (d, J = 6.9 Hz, 6H); C NMR (100 MHz,
CDCl ) δ = 147.0, 142.5, 137.0, 133.5, 128.9, 126.0, 125.9, 125.5, 54.9, 51.9, 40.3, 36.7, 34.2,
3
ꢀ1
32.6, 22.9, 22.9, 20.5. IR: 3029, 2960, 1597, 1457, 1340, 1159, 835, 726 cm . HRMS–ESI
+
(m/z): [M+H] calcd for C21
H
26ClNO
2
S, 392.1451; found: 392.1454.
4-Chloro-2-(4-fluorophenyl)-1-tosylpiperidine (4h). The compound (138 mg, 75%, trans:
cis = 96:4) was purified by flash chromatography using petroleum ether/ethyl acetate (50:1)
1
as eluent. transꢀ4ꢀChloroꢀ2ꢀ(4ꢀfluorophenyl)ꢀ1ꢀtosylpiperidine (major diastereomer, oil): H
NMR (400 MHz, CDCl
(m, 2H), 6.96 (t, J = 8.6 Hz, 2H), 5.27 (d, J = 3.3 Hz, 1H), 3.94 – 3.75 (m, 2H), 3.00 – 2.80
m, 1H), 2.63 – 2.59 (m, 1H), 2.38 (s, 3H), 1.89 – 1.72 (m, 2H), 1.46 (qd, J = 12.8, 4.7 Hz,
3
) δ = 7.68 (d, J = 8.2 Hz, 2H), 7.27 (d, J = 8.2 Hz, 2H), 7.25 – 7.18
(
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9
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1
2
5
H); F NMR (376 MHz, CDCl
3
) δ = ꢀ115.2. C NMR (100 MHz, CDCl
3
) δ = 161.0 (d, J =
47.0 Hz), 142.7, 136.8, 132.0, 129.0, 127.3 (d, J = 8.2 Hz), 125.9, 114.80 (d, J = 21.2 Hz),
ꢀ1
4.5, 51.5, 40.3, 36.6, 34.0, 20.6. IR: 3045, 2961, 1600, 1507, 1456, 1159, 931, 737 cm .
0
1
2
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9
0
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9
0
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9
0
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7
8
9
0
1
2
3
4
5
6
7
8
9
0
+
HRMS–ESI (m/z): [M+H] calcd for C H ClFNO S, 368.0887; found: 368.0884.
18
19
2
1
cisꢀ4ꢀChloroꢀ2ꢀ(2ꢀfluorophenyl)ꢀ1ꢀtosylpiperidine (minor diastereomer, oil): H NMR (400
MHz, CDCl ) δ = 7.45 (d, J = 8.2 Hz, 2H), 7.22 – 7.12 (m, 4H), 7.02 – 6.91 (m, 1H), 6.88 –
.81 (m, 1H), 4.83 – 4.68 (m, 1H), 3.99 (ddd, J = 11.9, 8.0, 4.1 Hz, 1H), 3.44 – 3.28 (m, 1H).
.95 – 3.88 (m, 1H), 2.44 – 2.32 (m, 4H), 2.16 (dt, J = 14.2, 4.3 Hz, 1H), 2.10 – 2.01 (m, 1H),
3
6
3
1
1
13
.91 – 1.83 (m, 1H). C NMR (100 MHz, CDCl ) δ= 158.5 (d, J = 245.2 Hz), 143.4, 136.1,
3
29.5, 129.09 (d, J = 8.6 Hz), 128.8 (d, J = 3.9 Hz), 127.3(d, J = 12.0 Hz), 123.9 (d, J = 3.4
19
3
Hz), 115.3 (d, J = 22.2 Hz), 54.1, 52.9, 42.3, 39.3, 33.9, 21.5. F NMR (376 MHz, CDCl ) δ
ꢀ1
=
ꢀ116.3. IR: 3050, 2900, 1590, 1498, 1450, 1110, 937, 736 cm . HRMS–ESI (m/z): HRMS–
+
ESI (m/z): [M+H] calcd for C18
2
H19ClFNO S, 368.0887; found: 368.0884.
4
-Chloro-2-(2-fluorophenyl)-1-tosylpiperidine (4i). The compound (128 mg, 70%, trans:
cis = 90:10) was purified by flash chromatography using petroleum ether/ethyl acetate (20:1)
1
as eluent. transꢀ4ꢀChloroꢀ2ꢀ(2ꢀfluorophenyl)ꢀ1ꢀtosylpiperidine (major diastereomer, oil): H
NMR (400 MHz, CDCl
3
) δ = 7.56 (d, J = 8.2 Hz, 1H), 7.17 (d, J = 8.2 Hz, 1H), 7.10 (dd, J =
1
2.4, 4.5 Hz, 2H), 7.03 – 6.88 (m, 2H), 5.39 (d, J = 2.3 Hz, 1H), 3.98 – 3.86 (m, 2H), 3.42 –
3.27 (m, 1H), 2.70 (d, J = 13.7 Hz, 1H), 2.34 (s, 3H), 2.14 – 1.95 (m, 2H), 1.75 (1d, J = 11.9,
13
4
.8 Hz, 1H); C NMR (100 MHz, CDCl
3
) δ = 158.7 (d, J = 245.2 Hz), 142.5, 136.0, 128.6,
128.1 (d, J = 8.6 Hz), 127.5 (d, J = 3.8 Hz), 125.6, 124.7 (d, J = 12.0 Hz), 123.0 (d, J = 3.4
19
Hz), 115.0 (d, J = 22.6 Hz), 52.3, 43.0, 42.3, 39.3, 34.7 20.2; F NMR (376 MHz, CDCl
3
) δ
2
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ꢀ
1
=
ꢀ114.0. IR: 3064, 2928, 1596, 1488, 1453, 1344, 1094, 938, 760 cm . HRMS–ESI (m/z):
+
HRMS–ESI (m/z): [M+H] calcd for C18
H
19ClFNO
2
S, 368.0887; found: 368.0892.
4
-Chloro-2-(4-chlorophenyl)-1-tosylpiperidine (4j). The compound (153 mg, 80%, trans:
10
11
12
13
14
15
16
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18
19
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60
cis = 91:9) was purified by flash chromatography using petroleum ether/ethyl acetate (40:1)
as eluent. transꢀ4ꢀChloroꢀ2ꢀ(4ꢀchlorophenyl)ꢀ1ꢀtosylpiperidine (major diastereomer, white
1
solid, mp = 117ꢀ119 °C): H NMR (400 MHz, CDCl
3
) δ = 7.67 (d, J = 8.2 Hz, 2H), 7.29 –
7.21 (m, 4H), 7.17 (d, J = 8.7 Hz, 2H), 5.26 (d, J = 4.4 Hz, 1H), 3.90 – 3.83 (m, 1H), 3.77 (tt,
J = 11.9, 4.0 Hz, 1H), 2.96 – 2.86 (m, 1H), 2.62 – 2.56 (m, 1H), 2.37 (s, 3H), 1.88 – 1.72 (m,
13
2
H), 1.45 (qd, J = 12.8, 4.7 Hz, 1H); C NMR (100 MHz, CDCl ) δ = 142.8, 136.7, 134.9,
3
132.4, 129.0, 128.1, 127.0, 125.9, 54.6, 51.5, 40.3, 36.5, 34.0, 20.6. NMR data were in
29
agreement with the reported results.
Crystal data for transꢀ4j: C18
H
19Cl
2
NO
2
S, M = 384.30, triclinic, a = 9.3985 (19) Å, b = 9.900
3
(2) Å, c = 10.611 (2) Å, α = 76.87 (3)°, β = 83.63 (3)°, γ = 74.00 (3)°, V = 923.0 (3) Å , T =
ꢀ1
2
93 (2) K, space group P 1¯ , Z = 2, ꢁ (MoKα) = 0.475 mm , 11457 reflections measured,
4352 independent reflections (Rint = 0.0429). The final R
1
values were 0.0452 (I>2σ (I)). The
2
final wR (F ) values were 0.0933 (I> 2σ (I)). The final R
1
values were 0.0939 (all data). The
2
2
final wR (F ) values were 0.1064 (all data). The goodness of fit on F was 1.013.
4-Chloro-2-(3-chlorophenyl)-1-tosylpiperidine (4k). The compound (149 mg, 78%, trans:
cis = 89:11) was purified by flash chromatography using petroleum ether/ethyl acetate (50:1)
as eluent. transꢀ4ꢀChloroꢀ2ꢀ(3ꢀchlorophenyl)ꢀ1ꢀtosylpiperidine (major diastereomer, white
1
solid, mp = 107ꢀ108 °C): H NMR (400 MHz, CDCl
3
) δ = 7.67 (d, J = 8.2 Hz, 2H), 7.26 (d, J
=
8.2 Hz, 2H), 7.22 – 7.09 (m, 4H), 5.27 (d, J = 3.9 Hz, 1H), 3.95 – 3.86 (m, 1H), 3.78 (tt, J =
2
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1.9, 3.9 Hz, 1H), 3.01 – 2.89 (m, 1H), 2.64 – 2.55 (m, 1H), 2.38 (s, 3H), 1.90 – 1.75 (m, 2H),
1
3
1
1
1
3
.49 (qd, J = 12.8, 4.7 Hz, 1H); C NMR (100 MHz, CDCl
3
) δ = 143.9, 139.8, 137.7, 135.1,
30.3, 130.1, 127.7, 126.9, 126.8, 124.8, 55.7, 52.5, 41.5, 37.7, 35.1, 21.6. IR: 3086, 2963,
0
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0
ꢀ1
+
594, 1490, 1158, 1096, 855, 734 cm . HRMS–ESI (m/z): [M+H] calcd for C H Cl NO S,
1
8
19
2
2
84.0592; found: 384.0592.
1
cisꢀ4ꢀChloroꢀ2ꢀ(3ꢀchlorophenyl)ꢀ1ꢀtosylpiperidine (minor diastereomer, oil): H NMR (400
MHz, CDCl ) δ = 7.49 (d, J = 8.3 Hz, 2H), 7.20 – 7.13 (m, 3H), 7.13 – 7.06 (m, 2H), 7.01 (s,
H), 4.73 (t, J = 5.6 Hz, 1H), 4.13 – 4.05 (m, 1H), 3.74 (ddd, J = 13.0, 9.4, 3.3 Hz, 1H), 3.54
3
1
–
1
3.45 (m, 1H), 2.40 – 2.31 (m, 4H), 2.22 – 2.14 (m, 1H), 2.00 (ddd, J = 13.4, 9.1, 4.1 Hz,
13
H), 1.84 – 1.78 (m, 1H). C NMR (100 MHz, CDCl
3
) δ = 142.6, 140.5, 135.8, 133.0, 128.6,
128.3, 126.2, 126.1, 125.9, 124.0, 55.2, 52.8, 39.4, 37.8, 32.4, 20.5. IR: 3090, 2954, 1610
ꢀ1
+
1
500, 1137, 1096, 837, 723 cm . HRMS–ESI (m/z): [M+H] calcd for C18
384.0592; found: 384.0592.
-(4-Bromophenyl)-4-chloro-1-tosylpiperidine (4l). The compound (166 mg, 78%, trans:
2 2
H19Cl NO S,
2
cis =90:10) was purified by flash chromatography using petroleum ether/ethyl acetate (40:1)
1
as eluent. transꢀ2ꢀ(4ꢀBromophenyl)ꢀ4ꢀchloroꢀ1ꢀtosylpiperidine (major diastereomer, oil): H
NMR (400 MHz, CDCl
3
) δ = 7.66 (d, J = 8.6Hz, 2H), 7.37 (d, J = 8.6 Hz, 2H), 7.25 (d, J =
8
.0 Hz, 2H), 7.11 (d, J = 8.0 Hz, 2H), 5.23 (d, J = 4.2 Hz, 1H), 3.89 – 3.84 (m, 1H), 3.80ꢀ3.72
(m, 1H), 2.96 – 2.84 (m, 1H), 2.60 – 2.54 (m, 1H), 2.36 (s, 3H), 1.89 – 1.78 (m, 2H), 1.79 –
13
1.70 (m, 1H), 1.44 (dd, J = 12.8, 4.7 Hz, 1H); C NMR (100 MHz, CDCl
3
) δ = 143.8, 137.7,
136.6, 132.1, 130.1, 128.4, 126.9, 121.5, 55.7, 52.5, 41.4, 37.5, 35.1, 21.7. IR: 3087, 2968,
ꢀ1
+
1649, 1595, 1490, 1333, 1257, 1197, 1093, 935, 837 cm . HRMS–ESI (m/z): [M+H] calcd
2
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for C18
H
19BrClNO
cisꢀ2ꢀ(4ꢀBromophenyl)ꢀ4ꢀchloroꢀ1ꢀtosylpiperidine (minor diastereomer, oil): H NMR (400
MHz, CDCl ) δ = 7.48 (d, J = 8.0 Hz, 2H), 7.17 (d, J = 8.0 Hz, 2H), 7.12 (d, J = 8.5 Hz, 2H),
.08 (d, J = 8.5 Hz, 2H), 4.67 (t, J = 5.4 Hz, 1H), 4.17 – 4.02 (m, 1H), 3.84 – 3.65 (m, 1H),
.54 – 3.34 (m, 1H), 2.41 – 2.29 (m, 4H), 2.24 – 2.12 (m, 1H), 2.02 – 1.92 (m, 1H), 1.79 (dd,
2
S, 428.0087; found: 428.0073.
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60
7
3
13
J = 13.8, 3.3 Hz, 1H). C NMR (100 MHz, CDCl
3
) δ = 143.6, 138.0, 136.8, 132.9, 129.7,
1
1
4
2
28.5, 128.2, 127.4, 56.4, 53.9, 40.6, 38.9, 33.5, 21.5. IR: 3090, 2970, 1649, 1589, 1477,
ꢀ1
+
260, 1190, 1093, 944, 821 cm . HRMS–ESI (m/z): [M+H] calcd for C18
2
H19BrClNO S,
28.0087; found: 428.0073.
-(4-tert-Butylphenyl)-4-chloro-1-tosylpiperidine (4m). The compound (170 mg, 84%,
trans: cis = 96:4) was purified by flash chromatography using petroleum ether/ethyl acetate
(30:1) as eluent. transꢀ2ꢀ(4ꢀtertꢀButylphenyl)ꢀ4ꢀchloroꢀ1ꢀtosylpiperidine (major diastereomer,
1
oil): H NMR (400 MHz, CDCl
3
) δ = 7.69 (d, J = 8.2 Hz, 2H), 7.28 (d, J = 8.2 Hz, 2H), 7.25
(d, J = 8.2 Hz, 2H), 7.15 (d, J = 8.2 Hz, 2H), 5.29 (d, J = 4.3 Hz, 1H), 3.90 – 3.83 (m, 2H),
3.03 – 2.94 (m, 1H), 2.69 – 2.62 (m, 1H), 2.38 (s, 3H), 1.88 – 1.76 (m, 2H), 1.50 (qd, J =
13
12.7, 4.7 Hz, 1H), 1.23 (s, 9H); C NMR (100 MHz, CDCl
3
) δ = 150.4, 143.5, 138.1, 134.2,
130.0, 127.0, 126.23, 125.9, 55.9, 53.0, 41.4, 37.7, 35.23, 34.5, 31.3, 21.6. IR: 3033, 2961,
ꢀ1
+
1597, 1511, 1453, 1406, 1340, 1158, 1093, 855, 723 cm . HRMS–ESI (m/z): [M+H] calcd
for C H ClNO S, 406.1608; found: 406.1611.
22
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2
4-(4-Chloro-1-tosylpiperidin-2-yl)benzonitrile (4n). The compound (118 mg, 63%, trans:
cis = 96:4) was purified by flash chromatography using petroleum ether/ethyl acetate (40:1)
as eluent. transꢀ4ꢀ(4ꢀChloroꢀ1ꢀtosylpiperidinꢀ2ꢀyl)benzonitrile (major diastereomer, white
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