Synthesis of Substituted Piperidines via Cationic Palladium(II)-Catalyzed Reductive Coupling of N -Tosyl-Tethered Alkynones

Article abstract of DOI:10.1055/s-0036-1588803

A cationic palladium(II) complex catalyzed reductive coupling of N -tosyl-tethered alkynones for the synthesis of functionalized piperidines was successfully developed. This reaction was initiated by hydropalladation of the alkyne and quenched by addition to the intramolecular carbonyl group. The substituent on the alkyne is key to the reaction.

Full text of DOI:10.1055/s-0036-1588803

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2017, 49, A–F
special topic
A
en
X. Zhang et al.
Special Topic
Synthesis
Synthesis of Substituted Piperidines via Cationic Palladium(II)-
Catalyzed Reductive Coupling of N-Tosyl-Tethered Alkynones
R1
Xiaojuan Zhang
Xiuling Han*
Zhiyong Hu
Xiyan Lu*
H
OH
[(dppp)Pd(H2O)2](BF4)2
(5 mol%)
O
R2
R1
R2
CH3CH2OH/DCE (5:1)
70 °C
N
N
Ts
Ts
24 examples
up to 86% yield
State Key Laboratory of Organometallic Chemistry, Shanghai
Institute of Organic Chemistry, Chinese Academy of Sciences,
345 Lingling Road, Shanghai, 200032, P. R. of China
xlhan@mail.sioc.ac.cn
xylu@mail.sioc.ac.cn
Published as part of the Special Topic Modern Strategies for
Heterocycles Synthesis
Received: 06.03.2017
Accepted after revision: 30.03.2017
Published online: 03.05.2017
groups.6 Among many approaches to heterocycles catalyzed
by palladium, few examples are available to produce piperi-
dines.7
DOI: 10.1055/s-0036-1588803; Art ID: ss-2017-c0141-st
Our group has been focused on palladium(II)-catalyzed
reactions for several years. Recently, we developed the re-
ductive cyclization of alkynones for the synthesis of pyrroli-
dine or hydroquinoline derivatives by using ethanol as a hy-
drogen source.8 These reactions were initiated by the hy-
dropalladation of alkynes and quenched by addition to the
intramolecular carbonyl groups. The use of cationic palladi-
um complexes is the key for the success of the process. Al-
though there are many examples of intermolecular reduc-
tive coupling of alkynes and carbonyl compounds, the in-
tramolecular version is rare and using palladium(II) as the
catalyst has not been previously reported in the literature.9
As an extension of our studies on this chemistry, we decid-
ed to employ the intramolecular reductive cyclization of
alkynones to synthesize functionalized piperidines. Herein,
we report the results of this study.
Abstract A cationic palladium(II) complex catalyzed reductive cou-
pling of N-tosyl-tethered alkynones for the synthesis of functionalized
piperidines was successfully developed. This reaction was initiated by
hydropalladation of the alkyne and quenched by addition to the intra-
molecular carbonyl group. The substituent on the alkyne is key to the
reaction.
Key words addition reaction, hydropalladation, palladium(II)-cata-
lyzed, piperidine, reductive coupling
Saturated heterocycles are essential substructures in a
large variety of natural and synthetic bioactive compounds.
Piperidines are of particular interest due to their presence
in a myriad of natural products exhibiting significant bio-
logical and pharmacological activity (Scheme 1).1 In addi-
tion, they are also important starting materials for con-
structing other complex heterocycles.2 As a result, consid-
erable efforts have been devoted toward the development
of efficient methods for the synthesis of this class of six-
membered nitrogen-containing compounds.3 Among the
developing methods to prepare piperidines, the metal-cata-
lyzed heterocyclization of amino derivatives has emerged
as a powerful and efficient strategy that is particularly in-
teresting in terms of both atom-economy and readily avail-
able precursors.4
OH
H
O
OH
N
N
Ph
H
Cl
Me
sedamine
F
haloperidol
F
Palladium-catalyzed coupling reactions have become a
powerful tool in organic synthesis due to their utility in af-
fecting a broad range of very useful organic transformations
under relatively mild reaction conditions.5 There are nu-
merous applications of palladium catalysis in the prepara-
tion of heterocycles with good regio- and stereoselective
control and toleration for a wide variety of functional
O
O
OH
OH
N
O
Me
HO
N
H
traxoprodil
paroxetine
Scheme 1 Selected bioactive piperidine derivatives
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–F

B
X. Zhang et al.
Special Topic
Synthesis
In our previous work, it was found when N-tosyl-teth-
ered alkynone 1a reacted in ethanol as the solvent under
the catalysis of a cationic palladium complex, a reductive
coupling occurred to give piperidine 2a.8a Therefore, sub-
strate 1a was chosen as the model compound to test the re-
action conditions. First, the influence of the catalyst was in-
vestigated: [(dppp)Pd(H2O)2](BF4)2 gave the best yield of 2a
of all of the tested cationic palladium complexes (Table 1,
entries 1–4) when EtOH was used as the solvent and hydro-
gen source at 70 °C. The in situ prepared cationic palladium
gave lower yields (Table 1, entries 5 and 6). Substrate 1a
was poorly soluble in ethanol, but upon addition of DCE
substrate 1a dissolved completely. We tested the reaction in
different ratios of EtOH and DCE and found that 5:1 gave
the best result (Table 1, entries 7–10). Increasing or de-
creasing the concentration of the reactant lowered the yield
(Table 1, entries 11 and 12). Addition of water also inhibited
the coupling (Table 1, entry 13). Without EtOH, no reaction
occurred (Table 1, entries 14 and 15). Using i-PrOH as the
hydrogen source gave only a low yield of the product (Table
1, entry 16). When the temperature was lowered to 50 °C or
raised to 90 °C, the yield of the product was reduced (Table
1, entries 17 and 18). The stereochemistry of the exocyclic
double bond in 2a was assigned as E, as confirmed by sin-
gle-crystal X-ray crystallography.10
With the optimized reaction conditions in hand (Table
1, entry 7), the substrate scope was examined and the re-
sults are shown in Table 2. First, the effect of substituents
on the carbonyl group (R2) was investigated. When R2 was
an aryl group bearing a fluoro, chloro, trifluoromethyl, or
methyl substituent, the reactions proceeded smoothly to
give the corresponding products in moderate yields (Table
2, entries 1, 2, 4 and 5). However, when R2 was a bromo-
substituted aryl group, only a very low yield was obtained
(Table 2, entry 3). Substrate bearing a 1-naphthyl or 2-thie-
nyl ketone can also give the corresponding piperidines 2g
and 2h successfully (Table 2, entries 6 and 7). Then the aryl
group was changed to an alkyl group and the results
showed that substrates with linear alkyl groups reacted
well to form the products in moderate yields. However, ste-
rically hindered alkyl groups, such as Cy or t-Bu, totally pre-
vented the reaction (Table 2, entries 8–13). For the substitu-
ent on the alkyne (R1), only medium-sized groups such as
TBS (tert-butyldimethylsilyl), TES (triethylsilyl), and t-Bu
give good results comparable to TMS; linear or more bulky
groups inhibited the reaction (Table 2, entries 14–21). The
reason for this cannot be explained at present. When the
tethered group in the substrate was changed to NBn or
C(CO2Et)2, no reaction occurred at all (Table 2, entries 22
and 23).
Table 1 Optimization of Reaction Conditionsa
TMS
H
OH
O
Ph
cationic Pd(II)
EtOH, 70 °C
TMS
Ph
N
N
Ts
Ts
1a
2a
Entry
Catalyst
Solvent (mL)
Yieldb (%)
47
EtOH
DCE
1
2
[(dppp)Pd(H2O)2](BF4)2
[(dppb)Pd(H2O)2](BF4)2
[(dppp)Pd(H2O)2](OTf)2
[(dppe)Pd(H2O)2](OTf)2
(dppp)PdCl2 + AgBF4
1
0
0
0
0
0
0
c
1
–
3
1
27
7
4
1
c
5
1
–
6
[(MeCN)4Pd](BF4)2 + dppp
[(dppp)Pd(H2O)2](BF4)2
[(dppp)Pd(H2O)2](BF4)2
[(dppp)Pd(H2O)2](BF4)2
[(dppp)Pd(H2O)2](BF4)2
[(dppp)Pd(H2O)2](BF4)2
[(dppp)Pd(H2O)2](BF4)2
[(dppp)Pd(H2O)2](BF4)2
[(dppp)Pd(H2O)2](BF4)2
[(dppp)Pd(H2O)2](BF4)2
[(dppp)Pd(H2O)2](BF4)2
[(dppp)Pd(H2O)2](BF4)2
[(dppp)Pd(H2O)2](BF4)2
1
15
7
1
0.2
0.3
0.4
0.6
0.1
0.4
0.2
1
78 (75)d
63
Next, we used two cationic palladium complexes which
contained (S,S)-bdpp or (R)-binap as the chiral ligand to ex-
plore the asymmetric version of this reductive cyclization
preliminarily. However, the result is very poor (Scheme 2).
8
0.9
0.8
0.6
0.5
2
9
59
10
11
12
13e
14
15e
16f
17g
18h
59
35
TMS
H
OH
58
O
Ph
(L*)Pd(H2O)2(BF4)2 (7.5 mol%)
1
24
TMS
Ph
EtOH/DCE (5:1)
70 °C
c
0
–
N
N
Ts
Ts
c
0
1
–
1a
2a
0
0.2
0.2
0.2
15
37
62
L*: (S,S)-bdpp 73% yield, 15% ee
L*: (R)-binap 17% yield, 50% ee
1
Scheme 2 Preliminarily studies for asymmetric cyclization of 1a
1
a Reaction conditions: 1a (0.1 mmol), Pd catalyst (0.0075 mmol), solvent,
70 °C, stirring, 5–8 h, unless otherwise noted.
b 1H NMR yield.
Similar to our previous work,8 deuterium-labeling ex-
periments were conducted subsequently to examine the re-
action mechanism. The use of CH3CH2OD as the hydrogen
source and cosolvent afforded 2a in 68% yield with no deu-
terium incorporation into the product (Scheme 3, eq 1). On
c No reaction.
d Isolated yield in parentheses.
e H2O (0.2 mL) was added.
f i-PrOH (1.0 mL) was added to replace EtOH.
g The reaction was carried out at 50 °C.
h The reaction was carried out at 90 °C.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–F

C
X. Zhang et al.
Special Topic
Synthesis
the other hand, the reaction using CH3CD2OH provided 2a
with deuterium (93%) at the vinyl position in 58% yield
(Scheme 3, eq 2).
H
OH
Ph
TMS
N
O
[(dppp)Pd(H2O)2](BF4)2
(7.5 mol%)
TMS
Ph
CH3CH2OD/DCE (5:1)
70 °C, 6 h
(1)
Based on above results and our previous work,8 a possi-
ble mechanism was proposed as shown in Scheme 4. First,
the Pd–hydroxyl complex A, generated from the cationic
palladium catalyst, reacts with EtOH to give Pd–ethoxide
complex B. Subsequently, β-hydride elimination of B pro-
duces Pd–H complex C, which is inserted by the alkyne to
yield intermediate D. Addition of the carbon–palladium
bond to the intramolecular carbonyl group in the interme-
diate D offers E. Finally, protonolysis of E generates the
product.
N
Ts
Ts
2a
1a
no deuterium incorporation
68% yield
D
OH
TMS
O
[(dppp)Pd(H2O)2](BF4)2
(7.5 mol%)
Ph
TMS
(2)
Ph
CH3CD2OH/DCE (5:1)
70 °C, 6 h
N
Ts
N
Ts
2a
1a
93% deuterium incorporation
58% yield
Table 2 Substrate Scopea
Scheme 3 Deuterium-labeling experiments
R1
H
OH
O
R2
[(dppp)Pd(H2O)2](BF4)2
– 2H2O
H
P
P
OH2
OH2
R1
P
O
P
– 2HBF4
R2
EtOH/DCE (5:1)
70 °C
2
Pd
2BF4
H
Pd
Pd
P
O
H
P
2BF4
Y
Y
–
–
1
2
OH
R2
Entry
Y
R1
R2
Product Yieldb (%)
R1
P
P
OH
+
EtOH
Pd
BF4
1
2
NTs
NTs
NTs
NTs
NTs
NTs
NTs
NTs
NTs
NTs
NTs
NTs
NTs
NTs
NTs
NTs
NTs
NTs
NTs
NTs
NTs
NBn
TMS
TMS
4-FC6H4 (1b)
4-ClC6H4 (1c)
4-BrC6H4 (1d)
4-F3CC6H4 (1e)
4-MeC6H4 (1f)
1-naphthyl (1g)
2-thienyl (1h)
Et (1i)
2b
2c
2d
2e
2f
58
54
16
79
49
69
31
76
58
56
75
N
–
Ts
H2O
A
2
+
3
TMS
TMS
TMS
TMS
TMS
TMS
TMS
TMS
TMS
TMS
TMS
TBS
TES
TIPS
Ph
–
P
P
O
H
OPd BF4
+
Pd
R2
4
H
–
R1
BF4
5
B
N
Ts
6
2g
2h
2i
E
7
CH3CHO
–
BF4
H
O
8
+
P
H
+
Pd
Pd
R1
R2
9
n-Pr (1j)
2j
–
BF4
P
C
10
11
12
13
14
15
16
17
18
19
20
21
22
23
(CH2)4Me (1k)
Bn (1l)
2k
2l
R1
N
Ts
O
D
d
R2
Cy (1m)
2m
2n
2o
2p
2q
2r
–
–
d
N
t-Bu (1n)
Ph (1o)
Ts
86
74
1
Ph (1p)
Scheme 4 Possible mechanism for the cyclization reaction
d
Ph (1q)
–
–
–
d
d
Ph (1r)
In summary, a reductive coupling reaction of N-tosyl-
tethered alkynones catalyzed by a cationic palladium(II)
complex was developed. The substituent on the alkyne (R1
in substrate 1) is the key for the reaction. This process pro-
vides a convenient method for the synthesis of substituted
piperidines. Further study will be focused on asymmetric
version and application of the reaction.
Bu
Ph (1s)
2s
2t
t-Bu
Me
Ph (1t)
85c
e
Ph (1u)
2u
2v
2w
2x
–
d
H
Ph (1v)
–
d
TMS
TMS
Ph (1w)
–
d
C(CO2Et)2
Ph (1x)
–
a Reaction conditions: substrate 1 (0.1 mmol), [(dppp)Pd(H2O)2](BF4)2
(0.0075 mmol), EtOH (1 mL)/DCE (0.2 mL), 70 °C, stirring.
b Isolated yield.
c The reaction was carried out at r.t.
All reactions were performed with freshly distilled and dried sol-
vents. All solvents were distilled using standard procedures. Unless
otherwise noted, reagents were obtained from commercial sources
d No reaction.
e The reaction was complicated and the products were not determined.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–F

D
X. Zhang et al.
Special Topic
Synthesis
and used without further purification. 1H NMR (400 MHz) and 13C
NMR (100 MHz) spectra were recorded in CDCl3 using a 400 MHz
spectrometer. HRMS were carried out on a mass spectrometer with a
TOF analyzer (ESI, EI). Infrared spectra were recorded on a FT-IR spec-
trophotometer. Melting points were determined by using a local hot-
stage melting point apparatus and are uncorrected. For column chro-
matography, silica gel of 200–300 mesh size was used.
13C NMR (100 MHz, CDCl3): δ = 151.8, 143.7, 141.6, 133.4, 133.1,
129.7, 129.5, 128.4, 127.8, 127.7, 75.9, 48.3, 42.8, 38.7, 21.5, –0.2.
HRMS (ESI): m/z [M + H]+ calcd for C22H29ClNO3SSi: 450.1320; found:
450.1318.
(E)-4-(4-Bromophenyl)-1-tosyl-3-[(trimethylsilyl)methyl-
ene]piperidin-4-ol (2d)
Substrate 1a is a known compound which was prepared according to
the reported procedure8a and other substrates 1b–x were synthesized
by a similar method. For preparations of 1b–x, see the Supporting In-
formation.
White solid; yield: 8 mg (16%); mp 141.8–143.9 °C.
IR (KBr): 3467, 2951, 1686, 1630, 1598, 1587, 1486, 1460, 1377, 1348,
1329, 1307, 1250, 1162, 1093, 1072, 932, 866, 838, 811, 666, 548 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.65 (d, J = 8.2 Hz, 2 H), 7.46 (d, J = 8.5
Hz, 2 H), 7.33 (d, J = 8.0 Hz, 2 H), 7.20 (d, J = 8.5 Hz, 2 H), 5.39 (s, 1 H),
3.97 (d, J = 12.8 Hz, 1 H), 3.69 (d, J = 12.8 Hz, 1 H), 3.36–3.33 (m, 1 H),
3.17–3.11 (m, 1 H), 2.44 (s, 3 H), 2.39–2.33 (m, 1 H), 1.90–1.85 (m, 1
H), 1.70 (s, 1 H), 0.16 (s, 9 H).
13C NMR (100 MHz, CDCl3): δ = 151.7, 143.7, 142.2, 133.1, 131.3,
129.7, 129.5, 128.1, 127.7, 121.6, 76.0, 48.3, 42.8, 38.6, 21.5, –0.2.
Piperidines 2a–x; General Procedure
The solution of [(dppp)Pd(H2O)2](BF4)2 (5.6 mg, 7.5 mol%) and alky-
none 1 (0.1 mmol) in EtOH (1.0 mL) and DCE (0.2 mL) was stirred at
70 °C until completion (TLC monitoring). After cooling the mixture to
r.t., the solvents were removed under vacuum, and the residue was
purified by flash column chromatography (EtOAc/petroleum ether
1:5) to obtain the product 2.
HRMS (ESI): m/z [M + H]+ calcd for C22H29BrNO3SSi: 494.0815; found:
494.0805.
(E)-4-Phenyl-1-tosyl-3-[(trimethylsilyl)methylene]piperidin-4-ol
(2a)
(E)-1-Tosyl-4-[4-(trifluoromethyl)phenyl]-3-[(trimethylsi-
White solid; yield: 31 mg (75%); mp 135.6–136.4 °C.
lyl)methylene]piperidin-4-ol (2e)
IR (KBr): 3507, 2958, 2929, 2866, 1490, 1335, 1159, 854, 756, 661 cm–1
.
White solid; yield: 38 mg (79%); mp 147.4–149.5 °C.
1H NMR (400 MHz, CDCl3): δ = 7.65 (d, J = 8.4 Hz, 2 H), 7.35–7.28 (m, 7
H), 5.47 (s, 1 H), 3.90 (d, J = 12.8 Hz, 1 H), 3.79 (d, J = 12.8 Hz, 1 H),
3.30–3.19 (m, 2 H), 2.49–2.43 (m, 4 H), 1.93–1.87 (m, 1 H), 1.77 (s, 1
H), 0.17 (s, 9 H).
13C NMR (100 MHz, CDCl3): δ = 152.3, 143.7, 143.0, 133.4, 129.9,
129.0, 128.5, 127.9, 127.8, 126.4, 76.3, 48.7, 43.2, 38.7, 21.7, 0.1.
IR (KBr): 3472, 2951, 1632, 1618, 1599, 1460, 1408, 1382, 1332, 1308,
1296, 1252, 1223, 1163, 1120, 1071, 1039, 931, 859, 838, 666, 549
cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.65 (d, J = 8.2 Hz, 2 H), 7.58 (d, J = 8.3
Hz, 2 H), 7.46 (d, J = 8.2 Hz, 2 H), 7.33 (d, J = 8.0 Hz, 2 H), 5.31 (s, 1 H),
4.09 (d, J = 12.8 Hz, 1 H), 3.64 (d, J = 13.2 Hz, 1 H), 3.46–3.41 (m, 1 H),
3.13–3.07 (m, 1 H), 2.44 (s, 3 H), 2.41–2.33 (m, 1 H), 1.91–1.85 (m, 2
H), 0.15 (s, 9 H).
HRMS (ESI): m/z [M + H]+ calcd for C22H30NO3SSi: 417.1710; found:
417.1710.
13C NMR (100 MHz, CDCl3): δ = 151.6, 147.4, 143.8, 133.1, 130.0,
129.8, 127.7, 126.8, 125.1, 76.1, 48.2, 42.6, 38.8, 21.5, –0.2.
HRMS (ESI): m/z [M + H]+ calcd for C23H29F3NO3SSi: 484.1584; found:
(E)-4-(4-Fluorophenyl)-1-tosyl-3-[(trimethylsilyl)methyl-
ene]piperidin-4-ol (2b)
484.1603.
Pale yellow oil; yield: 25 mg (58%).
IR (KBr): 3480, 2956, 1708, 1622, 1599, 1508, 1462, 1407, 1351, 1306,
(E)-4-(p-Tolyl)-1-tosyl-3-[(trimethylsilyl)methylene]piperidin-4-
ol (2f)
1250, 1227, 1163, 1090, 1037, 986, 929, 839, 815, 751, 664 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.64 (d, J = 8.2 Hz, 2 H), 7.35–7.25 (m, 4
H), 7.00 (t, J = 8.7 Hz, 2 H), 5.43 (s, 1 H), 3.90 (d, J = 12.8 Hz, 1 H), 3.74
(d, J = 12.8 Hz, 1 H), 3.33–3.23 (m, 1 H), 3.22–3.12 (m, 1 H), 2.43 (s, 3
H), 2.41–2.35 (m, 1 H), 1.92–1.87 (m, 1 H), 1.80 (s, 1 H), 0.16 (s, 9 H).
13C NMR (100 MHz, CDCl3): δ = 152.1, 143.7, 133.1, 129.7, 129.1,
128.1, 128.0, 127.7, 115.2, 115.0, 75.8, 48.4, 42.9, 38.7, 21.5, –0.1.
White solid; yield: 21 mg (49%); mp 160.5–162.0 °C.
IR (KBr): 3507, 2957, 1597, 1509, 1492, 1461, 1348, 1334, 1303, 1250,
1221, 1184, 1163, 1118, 1091, 1073, 1039, 987, 972, 934, 865, 816,
751, 662, 547 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.65 (d, J = 8.2 Hz, 2 H), 7.31 (d, J = 8.0
Hz, 2 H), 7.20 (d, J = 8.2 Hz, 2 H), 7.13 (d, J = 8.1 Hz, 2 H), 5.51 (s, 1 H),
3.83 (d, J = 2.8 Hz, 2 H), 3.24 (t, J = 5.2 Hz, 2 H), 2.46–2.43 (m, 4 H),
2.33 (s, 3 H), 1.91–1.87 (m, 1 H), 1.74 (s, 1 H), 0.17 (s, 9 H).
HRMS (ESI): m/z [M + H]+ calcd for C22H29FNO3SSi: 434.1616; found:
434.1612.
13C NMR (100 MHz, CDCl3): δ = 152.5, 143.8, 140.0, 137.6, 133.6,
129.9, 129.3, 128.8, 127.9, 126.4, 76.2, 48.8, 43.3, 38.7, 21.7, 21.2, 0.2.
HRMS (ESI): m/z [M + H]+ calcd for C23H32NO3SSi: 430.1867; Found:
430.1865.
(E)-4-(4-Chlorophenyl)-1-tosyl-3-[(trimethylsilyl)methyl-
ene]piperidin-4-ol (2c)
White solid; yield: 24 mg (54%); mp 124.4–125.2 °C.
IR (KBr): 3465, 2953, 1626, 1597, 1489, 1460, 1400, 1348, 1331, 1305,
1249, 1219, 1158, 1092, 1071, 1043, 991, 947, 856, 838, 811, 748, 666
(E)-4-(Naphthalen-1-yl)-1-tosyl-3-[(trimethylsilyl)methyl-
ene]piperidin-4-ol (2g)
cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.67 (d, J = 8.2 Hz, 2 H), 7.37–7.27 (m, 6
H), 5.41 (s, 1 H), 3.98 (d, J = 12.4 Hz, 1 H), 3.72 (d, J = 12.8 Hz, 1 H),
3.42–3.30 (m, 1 H), 3.26–3.06 (m, 1 H), 2.45 (s, 3 H), 2.42–2.36 (m, 1
H), 1.92–1.86 (m, 1 H), 1.75 (s, 1 H), 0.18 (s, 9 H).
White solid; yield: 32 mg (69%); mp 162.8–163.2 °C.
IR (neat): 3481, 2953, 1598, 1500, 1459, 1344, 1159, 856, 748, 662
cm–1
.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–F

E
X. Zhang et al.
Special Topic
Synthesis
1H NMR (400 MHz, CDCl3): δ = 7.87–7.79 (m, 4 H), 7.67 (d, J = 7.6 Hz, 2
H), 7.51–7.48 (m, 2 H), 7.36–7.31 (m, 3 H), 5.47 (s, 1 H), 4.03 (d, J =
12.8 Hz, 1 H), 3.77 (d, J = 12.4 Hz, 1 H), 3.43–3.78 (m, 1 H), 3.28–3.19
(m, 1 H), 2.59–2.52 (m 1 H), 2.43 (s, 3 H), 1.98–1.92 (m, 1 H), 1.85 (s, 1
H), 0.17 (s, 9 H).
13C NMR (100 MHz, CDCl3): δ = 152.2, 143.8, 140.8, 133.4, 133.2,
132.8, 129.9, 129.7, 128.3, 128.0, 127.9, 127.6, 126.4, 126.36, 125.0,
124.9, 76.5, 48.6, 43.1, 38.7, 21.7, 0.1.
IR (KBr): 3514, 2954, 2932, 2858, 1622, 1598, 1466, 1349, 1305, 1249,
1164, 1090, 999, 957, 909, 856, 815, 729, 663 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.65 (d, J = 8.4 Hz, 2 H), 7.33 (d, J = 8.0
Hz, 2 H), 5.70 (s, 1 H), 4.10 (d, J = 12.4 Hz, 1 H), 3.48–3.43 (m, 1 H),
3.24 (d, J = 12.8 Hz, 1 H), 2.87–2.81 (m, 1 H), 2.44 (s, 3 H), 1.80–1.73
(m, 2 H), 1.49–1.41 (m, 2 H), 1.38 (s, 1 H), 1.25–1.20 (m, 6 H), 0.83 (t,
J = 7.2 Hz, 3 H), 0.18 (s, 9 H).
13C NMR (100 MHz, CDCl3): δ = 152.7, 143.6, 133.1, 129.7, 127.7,
124.3, 73.4, 48.5, 43.5, 38.2, 36.8, 32.0, 22.5, 22.4, 21.5, 14.0, 0.0.
HRMS (ESI): m/z [M + H]+ calcd for C26H32NO3SSi: 466.1867; found:
466.1865.
HRMS (ESI): m/z [M + H]+calcd for C21H36NO3SSi: 410.2180; found:
410.2181.
(E)-4-(Thiophen-2-yl)-1-tosyl-3-[(trimethylsilyl)methylene]piper-
idin-4-ol (2h)
(E)-4-Benzyl-1-tosyl-3-[(trimethylsilyl)methylene]piperidin-4-ol
White solid; yield: 13 mg (31%); mp 49.8–50.4 °C.
(2l)
IR (neat): 3474, 2953, 2857, 1623, 1597, 1345, 1159, 837, 661 cm–1
.
White solid; yield: 32 mg (75%); mp 116.5–117.7 °C.
1H NMR (400 MHz, CDCl3): δ = 7.63 (d, J = 8.0 Hz, 2 H), 7.30 (d, J = 8.0
Hz, 2 H), 7.24 (d, J = 4.8 Hz, 1 H), 6.94 (t, J = 4.4 Hz, 1 H), 6.87–6.86 (m,
1 H), 5.89 (s, 1 H), 4.10 (d, J = 12.4 Hz, 1 H), 3.52–3.48 (m, 2 H), 3.01–
2.95 (m, 1 H), 2.47–2.42 (m, 4 H), 2.13–2.04 (m, 2 H), 0.21 (s, 9 H).
13C NMR (100 MHz, CDCl3): δ = 151.4, 148.0, 143.7, 133.5, 129.9,
127.8, 127.5, 127.3, 125.8, 125.3, 74.2, 48.7, 43.6, 39.8, 21.6, 0.0.
IR (KBr): 3495, 2954, 2928, 2856, 1615, 1598, 1495, 1456, 1389, 1338,
1306, 1248, 1186, 1162, 1119, 1090, 1004, 987, 958, 936, 849, 815,
749, 662 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.66 (d, J = 8.0 Hz, 2 H), 7.33 (d, J = 8.0
Hz, 2 H), 7.24–7.20 (m, 3 H), 7.02 (d, J = 6.8 Hz, 2 H), 5.50 (s, 1 H), 4.15
(d, J = 12.8 Hz, 1 H), 3.44 (d, J = 12.8 Hz, 2 H), 2.96 (d, J = 12.8 Hz, 1 H),
2.88 (d, J = 13.6 Hz, 1 H), 2.70 (d, J = 13.2 Hz, 1 H), 2.43 (s, 3 H), 1.84–
1.78 (m, 1 H), 1.73–1.66 (m, 1 H), 1.54 (s, 1 H), 0.13 (s, 9 H).
HRMS (ESI): m/z [M + H]+ calcd for C20H28NO3S2Si: 422.1274; found:
422.1275.
13C NMR (100 MHz, CDCl3): δ = 151.5, 143.7, 135.7, 133.1, 130.5,
129.8, 128.1, 127.8, 126.9, 125.6, 73.0, 48.7, 43.4, 37.6, 21.6, –0.09.
HRMS (ESI): m/z [M + H]+ calcd for C23H32NO3SSi: 430.1867; found:
(E)-4-Ethyl-1-tosyl-3-[(trimethylsilyl)methylene]piperidin-4-ol
(2i)
430.1876.
White solid; yield: 28 mg (76%); mp 61.6–63.5 °C.
IR (KBr): 3515, 2954, 2897, 2854, 1625, 1598, 1495, 1464, 1350, 1305,
1263, 1250, 1167, 1120, 1092, 1050, 974, 883, 840, 751, 664 cm–1
.
(E)-3-[(tert-Butyldimethylsilyl)methylene]-4-phenyl-1-tosyl-
piperidin-4-ol (2o)
1H NMR (400 MHz, CDCl3): δ = 7.65 (d, J = 8.4 Hz, 2 H), 7.33 (d, J = 8.0
Hz, 2 H), 5.71 (s, 1 H), 4.13 (dd, J = 12.8, 1.6 Hz, 1 H), 3.51–3.45 (m, 1
H), 3.18 (d, J = 12.8 Hz, 1 H), 2.84–2.77 (m, 1 H), 2.44 (s, 3 H), 1.82–
1.73 (m, 2 H), 1.59–1.40 (m, 2 H), 1.25 (s, 1 H), 0.75 (t, J = 7.6 Hz, 3 H),
0.18 (s, 9 H).
White solid; yield: 39 mg (86%); mp 161.8–164.2 °C.
IR (KBr): 3503, 2956, 2926, 2855, 1615, 1598, 1494, 1470, 1445, 1423,
1363, 1351, 1337, 1304, 1253, 1217, 1166, 1119, 1094, 1038, 983,
928, 828, 760, 702, 667 cm–1
.
13C NMR (100 MHz, CDCl3): δ = 152.5, 143.8, 133.1, 129.9, 127.9,
124.8, 73.6, 48.7, 43.7, 38.1, 29.5, 21.7, 7.3, 0.2.
HRMS (ESI): m/z [M + Na]+ calcd for C18H29NNaO3SSi: 390.1530;
found: 390.1538.
1H NMR (400 MHz, CDCl3): δ = 7.64 (d, J = 8.2 Hz, 2 H), 7.30 (m, 7 H),
5.45 (s, 1 H), 3.91 (d, J = 12.4 Hz, 1 H), 3.73 (d, J = 12.8 Hz, 1 H), 3.34–
3.29 (m, 1 H), 3.20–3.14 (m, 1 H), 2.51–2.44 (m, 1 H), 2.43 (s, 3 H),
1.95–1.89 (m, 1 H), 1.76 (s, 1 H), 0.84 (s, 9 H), 0.20 (s, 3 H), 0.11 (s, 3
H).
13C NMR (100 MHz, CDCl3): δ = 153.0, 143.6, 143.0, 133.0, 129.7,
128.2, 127.7, 127.6, 126.6, 126.2, 76.3, 48.6, 43.0, 38.5, 26.3, 21.5,
16.9, –4.4.
HRMS (ESI): m/z [M + H]+ calcd for C25H36NO3SSi: 458.2180; found:
458.2199.
(E)-4-Propyl-1-tosyl-3-[(trimethylsilyl)methylene]piperidin-4-ol
(2j)
White solid; yield: 22 mg (58%); mp 108.7–110.9 °C.
IR (KBr): 3463, 2955, 2927, 2852, 1711, 1620, 1598, 1370, 1345, 1250,
1218, 1166, 1088, 980, 881, 758, 665 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.65 (d, J = 8.0 Hz, 2 H), 7.33 (d, J = 8.0
Hz, 2 H), 5.71 (s, 1 H), 4.10 (d, J = 12.4 Hz, 1 H), 3.49–3.44 (m, 1 H),
3.22 (d, J = 12.4 Hz, 1 H), 2.87–2.80 (m, 1 H), 2.44 (s, 3 H), 1.83–1.70
(m, 2 H),1.50–1.37 (m, 3 H), 1.31–1.23 (m, 1 H), 1.17–1.11 (m, 1 H),
0.85 (t, J = 7.2 Hz, 3 H), 0.18 (s, 9 H).
13C NMR (100 MHz, CDCl3): δ = 152.7, 143.6, 133.1, 129.7, 127.7,
124.3, 73.4, 48.5, 43.6, 39.1, 38.3, 21.5, 16.1, 14.3, 0.0.
(E)-4-Phenyl-1-tosyl-3-[(triethylsilyl)methylene]piperidin-4-ol
(2p)
White solid; yield: 34 mg (74%); mp 110.1–111.2 °C.
IR (KBr): 3500, 2948, 2928, 2868, 1618, 1597, 1492, 1456, 1444, 1417,
1298, 1216, 1183, 1118, 1094, 1070, 1018, 983, 928, 877, 815, 758,
700, 667 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.62 (d, J = 8.0 Hz, 2 H), 7.32–7.24 (m, 7
H), 5.42 (s, 1 H), 3.79 (d, J = 12.4 Hz, 1 H), 3.73 (d, J = 12.8 Hz, 1 H),
3.26–3.15 (m, 2 H), 2.48–2.41 (m, 4 H), 1.94–1.88 (m, 1 H), 1.74 (s, 1
H), 0.91 (t, J = 8.0 Hz, 9 H), 0.64 (q, J = 7.6 Hz, 6 H).
13C NMR (100 MHz, CDCl3): δ = 153.2, 143.6, 142.9, 133.0, 129.7,
128.3, 127.8, 127.6, 126.2, 125.8, 76.3, 48.9, 43.1, 38.6, 21.5, 7.6, 4.4.
HRMS (ESI): m/z [M + H]+ calcd for C19H32NO3SSi: 382.1867; found:
382.1871.
(E)-4-Pentyl-1-tosyl-3-[(trimethylsilyl)methylene]piperidin-4-ol
(2k)
Yellow oil; yield: 23 mg (56%).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–F

F
X. Zhang et al.
Special Topic
Synthesis
HRMS (ESI): m/z [M + H]+ calcd for C25H36NO3SSi: 458.2180; found:
458.2167.
Koide, K. Org. Lett. 2004, 6, 1947. (d) Gitto, R.; De Luca, L.; Ferro,
S.; Scala, A.; Ronsisvalle, S.; Parenti, C.; Prezzavento, O.; Buemi,
M. R.; Chimirri, A. Bioorg. Med. Chem. 2014, 22, 393.
(3) For reviews, see: (a) Rubiralta, M.; Giralt, E.; Diez, A. Piperidine:
Structure, Preparation, Reactivity, and Synthetic Applications of
Piperidine and Its Derivatives; Elsevier: Amsterdam, 1991.
(b) Bailey, P. D.; Millwood, P. A.; Smith, P. D. Chem. Commun.
1998, 633. (c) Harrity, J. P. A.; Provoost, O. Org. Biomol. Chem.
2005, 3, 1349. (d) Girling, P. R.; Kiyoi, T.; Whiting, A. Org.
Biomol. Chem. 2011, 9, 3105. (e) Wanner, M. J.; Koomen, G. J.
Pure Appl. Chem. 1996, 68, 2051.
(4) (a) Patil, N. T.; Kavthe, R. D.; Shinde, V. S. Tetrahedron 2012, 68,
8079. (b) Nakamura, I.; Yamamoto, Y. Chem. Rev. 2004, 104,
2127. (c) Müller, T. E.; Hultzsch, K. C.; Yus, M.; Foubelo, F.; Tada,
M. Chem. Rev. 2008, 108, 3795.
(5) For selected reviews on palladium-catalyzed coupling reactions,
see: (a) Alonso, F.; Beletskaya, I. P.; Yus, M. Tetrahedron 2008,
64, 3047. (b) Negishi, E.; Anastasia, L. Chem. Rev. 2003, 103,
1979. (c) Surry, D. S.; Buchwald, S. L. Angew. Chem. Int. Ed. 2008,
47, 6338. (d) Doucet, H.; Hierso, J.-C. Angew. Chem. Int. Ed. 2007,
46, 834. (e) Enthaler, S.; Company, A. Chem. Soc. Rev. 2011, 40,
4912. (f) Kambe, N.; Iwasaki, T.; Terao, J. Chem. Soc. Rev. 2011,
40, 4937. (g) Knappke, C. E. I.; Jacobi von Wangelin, A. Chem. Soc.
Rev. 2011, 40, 4948. (h) Molnár, Á. Chem. Rev. 2011, 111, 2251.
(i) Selander, N.; Szabó, K. J. Chem. Rev. 2011, 111, 2048.
(6) For reviews, see: (a) Vlarr, T.; Ruijter, E.; Orru, R. V. A. Adv. Synth.
Catal. 2011, 353, 809. (b) Wu, X.-F.; Neumann, H.; Beller, M.
Chem. Rev. 2013, 113, 1. (c) Beccalli, E. M.; Broggini, G.;
Martinelli, M.; Sottocornola, S. Chem. Rev. 2007, 107, 5318.
(d) Zeni, G.; Larock, R. C. Chem. Rev. 2006, 106, 4644.
(e) Majumdar, K. C.; Chattopadhyay, B.; Maji, P. K.;
Chattopadhyay, S. K.; Samanta, S. Heterocycles 2010, 81, 517.
(f) Majumdar, K. C.; Samanta, S.; Sinha, B. Synthesis 2012, 44,
817.
(E)-3-(2,2-Dimethylpropylidene)-4-phenyl-1-tosylpiperidin-4-ol
(2t)
White solid; yield: 34 mg (85%); mp 131.2–132.0 °C.
IR (KBr): 3504, 2960, 1597, 1492, 1468, 1446, 1366, 1337, 1307, 1270,
1214, 1166, 1092, 1042, 1018, 981, 938, 756, 666 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.67 (d, J = 8.2 Hz, 2 H), 7.37–7.26 (m, 7
H), 5.33 (s, 1 H), 4.19 (d, J = 12.8 Hz, 1 H), 3.75 (d, J = 13.2 Hz, 1 H),
3.35–3.30 (m, 1 H), 3.18–3.12 (m, 1 H), 2.48–2.41 (m, 4 H), 1.90–1.85
(m, 1 H), 1.63 (s, 1 H), 1.12 (s, 9 H).
13C NMR (100 MHz, CDCl3): δ = 143.6, 143.5, 140.2, 135.4, 133.3,
129.7, 128.2, 127.7, 127.4, 126.3, 75.6, 44.2, 42.8, 38.9, 32.1, 31.2,
21.5.
HRMS (ESI): m/z [M + H]+ calcd for C23H30NO3S: 400.1941; found:
400.1957.
Funding Information
We thank the National Natural Science Foundation of China
(21232006, 21642002) and the Chinese Academy of Sciences for fi-
nancial support.
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0036-1588803.
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References
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Cordell, G. A., Ed.; Academic Press: San
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(10) CCDC 1534327 (2a) contains the supplementary crystallo-
graphic data for this paper. The data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/getstructures.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–F