One-pot preparation of 3-chloropiperidine compounds via Cu(II)-promoted intramolecular chloroamination of unfunctionalized olefins

Article abstract of DOI:10.1016/j.tet.2013.05.022

3-Chloropiperidine compounds were obtained via Cu(II)-promoted one-pot intramolecular chloroamination of N-benzyl-4-penten-1-amines and subsequent rearrangement. The reaction conditions leading to this skeleton were studied, and the structure of the product was confirmed by NMR as well as X-ray diffraction experiments.

Full text of DOI:10.1016/j.tet.2013.05.022

Tetrahedron 69 (2013) 5867e5873
Contents lists available at SciVerse ScienceDirect
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journal homepage: www.elsevier.com/locate/tet
One-pot preparation of 3-chloropiperidine compounds via Cu(II)-
promoted intramolecular chloroamination of unfunctionalized
olefins
,
b
,
,
Run-Lin Li a y, Gong-Qing Liu b y, Wei Li b, Yu-Mei Wang b, Lin Li b, Lili Duan b,
Yue-Ming Li b
,
*
a School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, People’s Republic of China
b College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, 94 Weijin Road, Tianjin 300071,
People’s Republic of China
a r t i c l e i n f o
a b s t r a c t
Article history:
3-Chloropiperidine compounds were obtained via Cu(II)-promoted one-pot intramolecular chloroami-
nation of N-benzyl-4-penten-1-amines and subsequent rearrangement. The reaction conditions leading
to this skeleton were studied, and the structure of the product was confirmed by NMR as well as X-ray
diffraction experiments.
Received 25 January 2013
Received in revised form 17 April 2013
Accepted 10 May 2013
Available online 16 May 2013
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
3-Chloropiperidine
2-Chloromethylpyrrolidine
N-Benzyl-4-penten-1-amine
Chloroamination
Copper chloride
hydroxyl group to chlorine (Eq. 1, Scheme 1).6 Later, Gottlich et al.
€
1. Introduction
developed a free radical procedure for the intramolecular chlor-
Nitrogen-containing compounds are very important in both
pharmaceutical and agrochemical industries, and constructions of
nitrogen-containing skeletons have attracted significant attention
in the past years. In addition to their application as functional
groups in anticancer agents (nitrogen mustards),1 vicinal halo-
amines such as 2-chloromethylpyrrolidines or 3-chloropiperidines
have also appeared as subunits of several natural products such as
benzastatins,2 cylindricines,3 or securamines.4
oamination of 4-penten-1-amine compounds. In their series stud-
ies, the substrate was first converted to NeCl derivative using
a chlorination agents such as NCS followed by Cu(I)-catalyzed free
radical cyclization. The reactions were carried out at elevated
temperature, and 3-chloropiperidines were obtained as final
R
R
R
N
N
N
MsCl/Et3N
TBAC/DMF
Different methods have been reported for the preparation of 2-
halomethylpyrrolidines and 3-chloropiperidines. Early works in-
volved the intramolecular haloamination of an aminoalkene in the
presence of dihalogen as being detailed by Horning and Muchow-
ski.5 This method suffered from the utilization of stoichiometric
amount of dihalogen, which in turn hampered its application for
the preparation of vicinal haloamines. Practical construction of 3-
chloropiperidines was realized using 3-hydroxypiperidine com-
pounds as starting materials followed by transformation of
Eq. 1
Cl
OH
R
OMs
R
R
R'
N
NCS
CuCl
Cl
N
R
R
R
H
N
50 °C
R'
R'
Eq. 2
Cl
R
R
Cl
Pd(II)/H2O2/CaCl2/HOAc
R
R
H
N
PG = Ts, RCO-
PG
N
Eq. 3
* Corresponding author. Tel.: þ86 22 23504028; fax: þ86 22 23507760; e-mail
PG
address: ymli@nankai.edu.cn (Y.-M. Li).
y
Scheme 1. Literature methods for the preparation of 3-chloropiperidines.
Run-Lin Li and Gong-Qing Liu contributed equally to this work.
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.05.022

5868
R.-L. Li et al. / Tetrahedron 69 (2013) 5867e5873
products (Eq. 2, Scheme 1).7 Tetrabutylammonium iodide,8 sam-
marium iodide9 or palladium-catalyst10 were also effective for the
conversion of N-chloroamines to 3-chloropiperidines. Lu et al.
showed that O-allylic carbamates could undergo haloamination
reaction using Pd(OAc)2/CuX2 system.11 Chemler et al. showed that
N-tosyl-o-allylaniline could be converted to the corresponding
bromomethyl heterocyclic compounds with Pd(OCOCF3)2/CuBr2
system.12 Liu et al. realized the intramolecular chloroamination of
different amide substrates using Pd(OAc)2/H2O2/CaCl2 system (Eq.
3, Scheme 1).13
was converted to the corresponding chloroamination product by
the action of another molecule of CuCl2 (Scheme 3).
Lu, Chemler, and Liu have reported the Pd-catalyzed chlor-
oamination of unfunctionalized olefins in the presence of copper
Ph
Ph
Ph
Ph
CuCl2
CuCl2
Ph Ph
H
N
Cl
Cu
Cl
Bn
N
N
Bn
Bn
Very recently, asymmetric haloaminations of
a,b-unsaturated
Scheme 3. Cu(II)-promoted chloroamination.
substrates were also realized in the presence of chiral catalysts.14
Using chiral scandium complexes as catalysts, asymmetric chloro-
15
,
bromo-,16 and iodoamination17 of
a
,b
-unsaturated substrates
halides. Several control experiments were then carried out to see if
the current reactions were promoted by Cu(II), or caused by metal
impurities (especially by contaminated palladium). The results
were summarized in Table 1. These results indicated that conven-
tional metals such as Ni, Co, Fe, Ag, Ru, Mn or Cr had little effect on
the course of the reaction. Pd(II) could increase the rate of the re-
action, but this was not proportional to the amount of Pd(II) added.
These results indicated that the current reaction was promoted by
Cu(II) rather than by the metal impurities possibly presented in the
commercially available copper salt.
gave the corresponding
with high ees.
a-halo-b-amido-products in high yields
Copper compounds have shown application in hydroamination of
several CeC multibonds.18 For examples, Cu(I) salts were used to
catalyze the hydroamination of alkynes,19,20 allenes,21 and alkenes22
using amines, carbamates, sulfonamides, and carboxamides as ni-
trogen sources, leading to hydroaminated products in good yields.23
More examples include Cu(CH3CN)4PF4-catalyzed hydroamination
of alkynes24 and vinyl arenes.25 On the other hand, only a few cases
were reported for Cu(II)-catalyzed hydroamination reactions. Cu(II)-
exchanged montmorillonite26 and AlSBA-1527 were used for
hydroamination of C^C triple bonds, Cu(OTf)2ediphosphine was
used for hydroamination of olefins with sulfonamides,28 and
Cu(OTf)2-catalyzed intramolecular hydroamination of homoallylic
amino alcohols gave dihydropyrroles and dihydroquinolines in
moderate yields.29 Cu(II)-carboxylate was effective in intramolecular
carboamination of unactivated olefins with sulfonamides,30 CuBr or
CuBr2edppe in combination with silver salts catalyzed the in-
termolecular hydroamination of olefins with sulfonamide.31
Table 1
Effect of metal ions on the course of reactiona
100 mol %CuCl2·2H2O
Ph Ph
H
N
Bn
10 mol % Additive
THF RT. 1 h
1a
Ph
Ph
Ph
Ph
Cl
Cl
+
N
N
We are interested in developing new and efficient methods for
CeN bond formation using commercially available and easy-to-
handle inorganic salts. In this paper, we wish to report our stud-
ies on Cu(II)-promoted chloroamination of unfunctionalized olefins
and a new method for the preparation of 3-chloropiperidines.
Bn
2a'
Bn
2a
Entry
Additive
None
NiCl2$6H2O
CoCl2$6H2O
FeCl3
AgOAc
RuCl3
MnCl3$4H2O
CrCl3$6H2O
Conversionb
74
2a
2a0
1
2
3
4
5
6
7
8
9
8
7
13
9
11
5
9
13
19
15
66
65
64
65
59
65
71
64
81
85
72
77
74
70
70
79
77
99
99
2. Results and discussions
In our previous report, we have shown that Cu(II) was able to
promote an intramolecular chloroamination of 4-penten-1-amine
and 5-hexen-1-amine type substrates, leading to the correspond-
ing 2-chloromethylpyrrolidines or 2-chloromethylpiperidines in
good isolated yields.32 The reaction was carried out at room tem-
perature using stoichiometric amount of CuCl2$2H2O as promoter.
Markovnikov chloroamination compound was obtained as the
major product, plus small amount of anti-Markovnikov compound
as the minor product (Scheme 2).
c
Pd(OAc)2
c
10
PdCl2
a
Reaction conditions: 100 mol % CuCl2$2H2O, reaction time 1 h.
Determined by crude NMR analysis.
Pd(OAc)2 (or PdCl2) of 5 mol %, reaction time: 1 h.
b
c
Somfai et al. indicated that 2-chloromethylpyrrolidine com-
pounds could isomerize to the corresponding 3-chloropiperidine
compounds in chlorine solvents at ambient temperature.33 How-
ever, our study indicated that 2-chloromethylpyrrolidines were
stable enough to survive a rotavapor evaporation in non-chlorine
solvents such as THF, and it is possible to isolate 2-chloro
methylpyrrolidines under such conditions.32 However, conversion
indeed took place at elevated temperatures, leading to 3-
chloropiperidines as the final products.
Ph
( )n
Ph
( )n
N
Bn
minor
Cl
Ph
Cu(II)
Ph
Ph Ph
( )n
+
Cl
NHBn
N
Bn
major
n = 1 or 2
Reaction conditions: 100 mol% CuCl2·2H2O, THF, 3 hours.
To extend the application scope of this reaction, we first studied
in details the one-pot preparation of 3-chloropiperidine com-
pounds. N-(4-Methylbenzyl)-2,2-diphenylpent-4-en-1-amine (1b)
was chosen as the model substrate. The preliminary results in-
dicated that high temperature was generally needed for one-pot
conversion of 4-penten-1-amine to the corresponding 3-
chloropiperidines. This is in agreement with our previous finding
Scheme 2. Intramolecular chloroamination of N-benzylpent-4-en-1-amine.
The reaction followed a hydroamination mechanism, in which
C]C double bond was first activated upon coordination with Cu(II),
intramolecular nucleophilic attack of amino group on the activated
C]C double bond gave an aminocuperation intermediate, which

R.-L. Li et al. / Tetrahedron 69 (2013) 5867e5873
5869
that high temperature is favorable for the conversion of 2-
instead of toluene as the reaction medium due to its ease of removal
and its low toxicity. CuCl2$2H2O (1 equiv) was used throughout the
reaction to ensure a fast conversion of the substrate to the kinetic
product 2-chloromethylpyrrolidine.
Thus, N-substituted 4-penten-1-amine substrates and 1 equiv of
CuCl2$2H2O were first mixed inTHFand were allowed to stir at room
temperature for 3 h.32 After the completion of the chloroamination
reaction, the reaction mixtures were refluxed for additional 18 h to
ensure a complete conversion of any remained 2-chloromethyl
pyrrolidines to 3-chloropiperidines. Products 3-chloropiperidines
could be obtained after removal of inorganic salts. Representative
results were summarized in Table 3.
chloropyrrolidines to 3-chloropiperidines (Table
mentary data).
1 in Supple
As CuCl2$2H2O was used as both reaction promoter and chlorine
source, at least 50 mol % of CuCl2$2H2O should be used for chlor-
oamination of the substrates. Further increasing the amount of
CuCl2 didn’t show beneficial effect on the course of the reaction.
CuCl2$2H2O and CuCl2 gave similar results, indicating that water
has little deteriorative effect on the reaction. CuCl2$2H2O was
chosen for further studies due to its ease of handling.
After having a general understanding of the reaction, different
substrates were refluxed in toluene to study the scope of the re-
action, and the results were listed in Table 2.
Table 3
One-pot two-step preparation of 3-chloropiperidines
Table 2
CuCl2$2H2O-promoted formation of 3-chloropiperidine skeleton
R1
Cl
R1
R1 R1
R1 R1
100 mol% CuCl2·2H2O
H
N
R1 R1
CuCl2·2H2O (50 mol%)
H
R2
THF, rt for 3 h, then reflux for 18 h
N
N
R2
R2
Toluene, reflux, 24 h
N
Cl
R2
1
2
Entry
Substrates
R1
R2
Isolated yield (%)
1
2
3
4
5
6
7
1a
1c
1g
1i
1j
1h
1l
Ph
Ph
Ph
CH3
-(CH2)5-
Ph
PhCH2
4-MeOPhCH2
4-NO2PhCH2
Bn
Bn
i-Bu
Bn
88
91
86
93
86
85
82
Entry
Substrate
R1
R2
Yielda (%)
1
2
3
4
5
6
1a
1b
1c
1d
1e
1f
Ph
Ph
Ph
Ph
Ph
Ph
PhCH2
4-MePhCH2
4-MeOPhCH2
4-FPhCH2
4-(i-Pr)PhCH2
4-BrPhCH2
62
47
33
53
21
58
H
7
8
9
1g
1h
1i
1j
1k
1l
1m
1n
1o
1p
1q
Ph
Ph
CH3
e(CH2)5e
Ph
H
Ph
Ph
Ph
4-O2NPhCH2
i-Bu
Bn
Bn
i-Pr
Bn
H
Ac
Ts
68
44
54
53
51
66
Ph Ph
H
N
8a
1r
60
Ph
Bn
10
11
12
13
14
15
16
17
Ph Ph
H
9b
1s
1a
87
N
Bn
No reaction
No reaction
No reaction
No reaction
No reaction
10c
Ph
PhCH2
99d
Ph
Ph
Ph
H
Boc
4-O2NPh
a
Cl
Product structure:
(2r).
(2s).
a
N
Isolated yields.
Ph
Bn
Ph
Ph
As shown in Table 2, the reactivity of nitrogen atom was sig-
nificantly influenced by the substituents on it. 3-Chloropiperidine
products were obtained for secondary amine substrates such as
1ae1l (Table 2, entries 1e12). Primary aminoalkene 1m (Table 2,
entry 12), amides (acetamide 1n and sulfonamide 1o, Table 2, en-
tries 14 and 15), and N-Boc substrate 1p (Table 2, entry 16) failed to
react after being refluxed in toluene for 24 h. Bulky N-substituent
such as isopropyl could be tolerated, and substrates 1h and 1k gave
the corresponding products in 44% and 51% isolated yields, re-
spectively (Table 2, entries 8 and 11). Substrate 1l produced the 3-
chloropiperidine product in 66% isolated yield (Table 2, entry 7),
indicating that ThorpeeIngold effect has less influence on the re-
action. Aniline substrate 1q failed to react, possibly due to its low
nucleophilicity (Table 2, entry 17).
Results in Table 2 showed that only moderate yields were ob-
tained when the reaction mixtures were refluxed from the very be-
ginning. This is possibly due to the weakened coordination of the
substrates to Cu(II) at elevated temperature. A one-pot two-
step sequence was then proposed to improve the yield of the re-
action. As we have shown, fast conversion of the substrates to 2-
chloromethylpyrrolines (plus small amount of 3-chloropiperi
dines) could be realized when the substrates and stoichiometric
amount of Cu(II) were allowed to react at room temperature for 3 h,32
the resulting mixture could be converted to 3-chloropiperidines at
elevated temperature. We then combined these two steps together
to prepare 3-chloropiperidines as our final products. THF was used
b
Product structure:
Cl
N
Bn
Ultrapure CuCl2 (99.99% metal basis) was used.
Conversion determined by crude NMR analysis.
c
d
As shown in Table 3, 3-chloropiperidines could be obtained in
good isolated yields. Both non-ThorpeeIngold (1l) and Thorpe-
eIngold (1a, 1c and 1ge1l) substrates could be converted to 3-
chloropiperidines in good yields, indicating the applicability of
this reaction. Again, reactionwith ultrapureCuCl2 gave similar result
(entry 10). In addition toterminal olefins, di-substituted substrate 1r
was also tested. However, under similar conditions no 3-chloropi
peridines was observed, and the corresponding substituted chlor-
omethyl product was isolated in 60% yields (entry 8). 5-Hexen-1-
amine substrate 1s produced the 2-chloromethylpiperidines in
87% yield under similar conditions, and rearrangement to the cor-
responding seven-membered ring product was not observed
(entry 9).
To further confirm the skeleton of 3-chloropiperdine, com-
pound 2b was crystallized from hexane and was subjected to X-ray
crystallographic experiments. Fig. 1 gave the ORTEP drawing of
compound 2b. Several substituents are connected to a piperidine
ring, the six-membered ring is in a chair conformation with two
phenyl groups in equatorial and axial positions, and the N-benzyl
group in the equatorial position. Therefore, compound 2b was

5870
R.-L. Li et al. / Tetrahedron 69 (2013) 5867e5873
(100 MHz, CDCl3)
d
¼139.81, 131.84, 128.90, 127.99, 127.10, 121.94,
120.43, 51.85, 43.98.35
To a suspension of LiAlH4 (1.52 g, 40 mmol) in ether (130 mL)
was added 2.33 g (10 mmol) 2,2-diphenyl-4-pentenenitrile at 0 ꢀC.
The mixture was warmed slowly to room temperature and stirred
overnight. The resulting suspension was cooled to 0 ꢀC and
quenched by slow addition of 6 M NaOH (50 mL). The resulting
mixture was extracted with ether (100 mLꢁ4), the combined ether
extracts were dried (MgSO4) and concentrated to give 2,2-
diphenyl-4-pentenylamine (1m) (2.01 g, 85%) as a pale yellow,
viscous oil. 1H NMR (300 MHz, CDCl3)
5.51e5.27 (m, 1H), 5.17e4.83 (m, 2H), 3.31 (s, 2H), 2.92 (d, J¼7.0 Hz,
2H), 0.77 (s, 2H). 13C NMR (75 MHz, CDCl3)
¼146.33, 134.69,
128.24, 128.11, 126.10, 117.72, 51.50, 48.62, 41.17.35
d
¼7.37e6.91 (m, 10H),
Fig. 1. ORTEP drawing of 2b. Hydrogen atoms were omitted for clarity.
d
unambiguously confirmed as N-(4-methylbenzyl)-3,3-diphenyl-5-
4.2.2. Preparation of N-benzyl-2,2-diphenyl-4-pentenylamine
(1a). A solution of 1m (1.19 g, 5 mmol) and benzaldehyde (0.54 g,
5.1 mmol) in MeOH (20 mL) was stirred at room temperature for
5 h, then treated with NaBH4 (0.29 g, 7.5 mmol) and the mixture
was stirred overnight. The resulting mixture was treated with
water (50 mL), 1 M NaOH (20 mL) and was extracted with CH2Cl2
(100 mLꢁ3). The combined organic layer was dried (MgSO4) and
concentrated. The resulting oily residue was chromatographed
(petroleum ether/dichloromethane¼3:1) to give 1a (1.32 g, 81%) as
chloropiperidine.34
3. Conclusion
In summary, a one-pot procedure was developed for the
preparation of 3-chloropiperidine skeleton. The reaction was
carried out using stoichiometric amount of copper chloride as
both the reaction promoter and the chlorine source. The reaction
first produced 2-chloromethylpyrrolidines, which were then
converted to 3-chloropiperidines at elevated temperature. The
reaction tolerates oxygen and moisture, and special care was not
needed.
a viscous oil. 1H NMR (300 MHz, CDCl3)
d
¼7.21e7.07 (m, 15H),
5.40e5.12 (m, 1H), 4.86 (m, 2H), 3.64 (s, 2H), 3.12 (s, 2H), 2.96 (d,
J¼7.0 Hz, 2H), 0.91 (br s, 1H). 13C NMR (100 MHz, CDCl3)
¼147.05,
d
140.92, 135.07, 128.40, 128.27, 128.17, 128.12, 126.91, 126.18, 117.87,
55.45, 54.37, 50.34, 41.81.35
The substituted arylmethyl(2,2-diphenyl-4-pentenyl)amines
were synthesized via reductive amination of 1m with the re-
spective aldehydes similar to that used to synthesize 1a.
4. Experimental
4.1. General remarks
4.2.3. N-(4-Methylbenzyl)-2,2-diphenylpent-4-en-1-amine (1b). 1H
Reactions were carried out using commercially available re-
agents in oven-dried apparatus. 1H and 13C NMR spectra were
recorded on a Bruker DRX 400 spectrometer at 298 K using deu-
terated chloroform as solvent and TMS as the internal reference.
Column chromatography was performed employing 200e300
mesh silica gel. Thin layer chromatography (TLC) was performed on
silica gel GF254. HRMS analyses were carried out with Varian FTICR-
MS 7.0 T. Unless otherwise indicated, starting materials and re-
agents used in reactions were purchased from J&K Scientific Inc. or
Aladdin and were used as received without further purification.
CuCl2$2H2O was purchased from Tianjin Chemicals Co., ultrapure
CuCl2$2H2O used for control experiments was purchased from
Aladdin (Product No. C111683-10g, 99.99% metal basis).
NMR (400 MHz, CDCl3)
5.03e4.83 (m, 2H), 3.66 (s, 2H), 3.19 (s, 2H), 3.03 (d, J¼7.1 Hz, 2H),
2.30 (s, 3H), 0.81 (br s, 1H). 13C NMR (100 MHz, CDCl3)
d¼7.26e7.05 (m, 14H), 5.39e5.23 (m, 1H),
d¼146.94,
137.76, 135.00, 128.94, 128.15, 128.00, 127.91, 126.00, 118.23, 55.38,
53.99, 50.25, 41.72, 21.14.36
4.2.4. N-(4-Methoxybenzyl)-2,2-diphenylpent-4-en-1-amine
(1c). 1H NMR (400 MHz, CDCl3)
d
¼7.29e7.07 (m, 12H), 6.80 (d,
J¼7.6 Hz, 2H), 5.33 (m, 1H), 4.93 (m, 2H), 3.77 (s, 3H), 3.64 (s, 2H),
3.18 (s, 2H), 3.02 (d, J¼7.0 Hz, 2H), 0.98 (br s, 1H). 13C NMR
(100 MHz, CDCl3)
d
¼158.58, 146.82, 134.95, 132.78, 129.08, 128.11,
127.97, 125.93, 117.70, 113.63, 55.28, 55.24, 53.61, 50.19, 41.69.22a
4.2.5. N-(4-Fluorobenzyl)-2,2-diphenylpent-4-en-1-amine (1d). 1H
X-ray crystallography was performed on Bruker SMART-1000
equipped with CCD area detector.
NMR (400 MHz, CDCl3)
d
¼7.35e7.20 (m, 12H), 7.01 (t, J¼8.4 Hz, 2H),
5.50e5.32 (m, 1H), 5.00 (m, 2H), 3.73 (s, 2H), 3.24 (s, 2H), 3.09 (d,
4.2. Preparation of substrates35
J¼7.0 Hz, 2H), 0.95 (br s, 1H). 13C NMR (100 MHz, CDCl3)
¼163.14,
d
160.73, 146.84, 134.89, 129.50, 129.42, 128.11, 128.04, 126.07, 117.67,
115.09, 114.88, 55.26, 53.47, 50.20, 41.68. 19F NMR (100 MHz, CDCl3)
4.2.1. Preparation of 2,2-diphenyl-4-pentenylamine (1m). To a sus-
pension of NaH (1.32 g, 55 mmol) in DMF (50 mL) was added slowly
a solution of diphenylacetonitrile (9.65 g, 50 mmol) in DMF (20 mL),
and the resulting mixture was stirred at room temperature for 1 h.
The resulting bright yellow suspension was cooled to 0 ꢀC, treated
with allyl bromide (6.66 g, 55 mmol), warmed to room tempera-
ture, and stirred at room temperature for 12 h. The resulting so-
lution was poured into ice/water (200 mL) and was extracted with
CH2Cl2 (100 mLꢁ3). The combined organic layer was washed with
water (50 mLꢁ2), dried with MgSO4, and concentrated to give
crude 2,2-diphenyl-4-pentenenitrile (10.83 g, 93%). This compound
was used in subsequent step without further purification. 1H NMR
d
¼ꢂ116.20.22a
4.2.6. N-(4-Isopropylbenzyl)-2,2-diphenylpent-4-en-1-amine
(1e). 1H NMR (400 MHz, CDCl3)
d
¼7.27e7.10 (m, 14H), 5.41e5.29
(m, 1H), 4.93 (m, 2H), 3.67 (s, 2H), 3.21 (s, 2H), 3.03 (d, J¼6.9 Hz,
2H), 2.85 (hept, J¼6.9 Hz, 1H), 1.22 (d, J¼6.9 Hz, 6H), 0.85 (br s, 1H).
13C NMR (100 MHz, CDCl3)
d
¼147.35, 146.97, 138.22, 135.01, 128.17,
128.02, 127.95, 126.30, 126.02, 117.65, 55.46, 54.03, 50.27, 41.71,
33.85, 24.16. HRMS-ESI (m/z): [MþH]þ calcd for C27H31N, 370.2529;
found: 370.2533.
(400 MHz, CDCl3)
d
¼7.46e7.19 (m, 10H), 5.70 (ddt, J¼17.1, 10.2,
4.2.7. N-(4-Bromobenzyl)-2,2-diphenylpent-4-en-1-amine (1f). 1H
7.0 Hz, 1H), 5.31e5.05 (m, 2H), 3.12 (d, J¼7.0 Hz, 2H). 13C NMR
NMR (400 MHz, CDCl3)
d¼7.45e7.39 (m, 3H), 7.31e7.28 (m 3H), 7.23

R.-L. Li et al. / Tetrahedron 69 (2013) 5867e5873
5871
(d, J¼7.0 Hz, 2H), 7.19 (d, J¼8.2 Hz, 4H), 7.11 (d, J¼8.2 Hz, 2H),
(400 MHz, CDCl3)
d
¼7.33e7.17 (m, 10H), 5.51e5.36 (m, 1H),
5.38e5.32 (m, 1H), 4.99 (dd, J¼33.1, 13.6 Hz, 2H), 3.69 (s, 2H), 3.21
4.99e4.98 (m, 2H), 4.95 (s, 1H), 3.96 (d, J¼5.8 Hz, 2H), 2.85 (d,
(s, 2H), 3.07 (d, J¼7.0 Hz, 2H), 1.27 (br s, 1H). 13C NMR (100 MHz,
J¼7.1 Hz, 2H), 1.83 (s.3H). 13C NMR (100 MHz, CDCl3)
¼169.97,
d
CDCl3)
d
¼146.72, 139.70, 134.81, 131.28, 129.69, 129.23, 128.03,
145.22, 133.66, 128.34, 128.02, 126.58, 118.65, 50.39, 46.04, 42.12,
23.41.22a
126.07, 120.46, 117.70, 55.20, 53.47, 50.13, 41.60.35
4.2.8. N-(4-Nitrobenzyl)-2,2-diphenylpent-4-en-1-amine
(1g). 1H
4.2.15. Preparation of N-(2,2-diphenylpent-4-enyl)-4-methylbenzene-
sulfonamide (1o). To a solution of 1m (1.0 mmol) in 10 mL of dry
toluene were added p-toluenesulfonyl chloride (1.0 mmol) and dry
pyridine (0.5 mL, 2 mmol). The mixture was stirred at 25 ꢀC for 24 h,
diluted with 5 mL of 1 N HCl (aq), and was extracted with Et2O
(30 mLꢁ3). The combined organic layer was dried over MgSO4, fil-
tered, and concentrated in vacuo. The resulting oily residue was
chromatographed (petroleum ether/dichloromethane¼4:1) to give
NMR (400 MHz, CDCl3)
d
¼8.16 (d, J¼8.7 Hz, 2H), 7.40 (d,
J¼8.7 Hz, 2H), 7.30 (d, J¼7.6 Hz, 4H), 7.24 (d, J¼7.2 Hz, 2H), 7.20
(d, J¼7.4 Hz, 4H), 5.44e5.23 (m, 1H), 5.00 (dd, J¼37.2, 13.6 Hz,
2H), 3.84 (s, 2H), 3.22 (s, 2H), 3.09 (d, J¼7.0 Hz, 2H), 0.96 (br s,
1H). 13C NMR (100 MHz, CDCl3)
d
¼148.57, 146.55, 134.73, 128.50,
128.10, 128.01, 126.57, 126.19, 123.49, 117.77, 55.38, 53.42, 50.14,
41.55.35
1o (0.27 g, 70%) as a viscous oil. 1H NMR (400 MHz, CDCl3)
d¼7.59 (d,
4.2.9. N-Isobutyl-2,2-diphenylpent-4-en-1-amine (1h). 1H NMR
J¼8.2 Hz, 2H), 7.39e7.13 (m, 8H), 7.08e7.00 (m, 4H), 5.35e5.14 (m,
1H), 5.01e4.86 (m, 2H), 3.88 (t, J¼6.5 Hz, 1H), 3.52 (d, J¼6.5 Hz, 2H),
2.89 (d, J¼7.1 Hz, 2H), 2.41 (s, 3H). 13C NMR (100 MHz, CDCl3)
(300 MHz, CDCl3)
d
¼7.43e7.17 (m, 10H), 5.44 (dt, J¼17.1, 8.5 Hz, 1H),
5.05 (dd, J¼37.5, 13.3 Hz, 2H), 3.24 (s, 2H), 3.09 (d, J¼7.0 Hz, 2H),
2.39 (d, J¼6.8 Hz, 2H), 1.79e1.63 (m, 1H), 0.83 (d, J¼6.6 Hz, 6H), 0.47
d
¼144.54, 143.37, 136.33, 133.16, 129.68, 128.40, 127.71, 127.13,
(s, 1H). 13C NMR (100 MHz, CDCl3)
d
¼147.06, 135.14, 128.13, 127.97,
126.70, 119.08, 49.45, 49.32, 41.27, 21.55.41
125.96, 117.58, 58.52, 55.96, 50.21, 41.68, 27.85, 20.56.22a
4.2.16. tert-Butyl 2,2-diphenylpent-4-enylcarbamate (1p). To a solu-
tion of the 2,2-diphenylpent-4-en-1-amine (1m) (2 mmol) in THF
(20 mL) were added at 0 ꢀC Et3N (12 mmol) and DMAP (about
0.01 g). To the reaction mixture was added di-tert-butyl dicar-
bonate (2.4 mmol) and the solution was stirred at this temperature
for 6 h. The reaction mixture was quenched with ice and water
(30 mL) and extracted with CH2Cl2 (3ꢁ30 mL). The combined or-
ganic layer was washed with brine (20 mL), dried (MgSO4), and
concentrated. Compound 1p was obtained after column chroma-
tography (petroleum ether/dichloromethane¼5:1). 1H NMR
4.2.10. N-Benzyl-2,2-dimethylpent-4-en-1-amine (1i). Compound
1i was prepared via reductive amination of 2,2-dimethylpent-4-
enal8 with benzylamine similar to that used to prepare 1a. 1H
NMR (400 MHz, CDCl3)
d
¼7.58e7.13 (m, 5H), 5.99e5.74 (m, 1H),
5.11 (d, J¼13.6 Hz, 2H), 3.88 (s, 2H), 2.47 (s, 2H), 2.13 (d, J¼7.4 Hz,
2H), 1.29 (s, 1H), 1.00 (d, J¼1.0 Hz, 6H). 13C NMR (100 MHz, CDCl3)
d
¼141.10, 135.68, 128.36, 128.05, 126.83, 116.86, 59.76, 54.80, 44.73,
34.46, 25.64.35
4.2.11. N-Benzyl-1-(1-(but-3-enyl)cyclohexyl)methylamine
(1j). Compound 1j was prepared from cyclohexanenitrile employing
a method similar to that used to synthesize 1a.37 1H NMR (400 MHz,
(400 MHz, CDCl3)
d
¼7.31e7.16 (m,10H), 5.42 (td, J¼16.4, 7.4 Hz,1H),
5.07e4.82 (m, 2H), 4.14 (s, 1H), 3.85 (d, J¼5.4 Hz, 2H), 2.86 (d,
J¼6.8 Hz, 2H), 1.38 (s, 9H). 13C NMR (100 MHz, CDCl3)
¼155.76,
d
CDCl3)
d
¼
d
7.35e7.00 (m, 5H), 5.90e5.70 (m, 1H), 4.94 (dd, J¼30.9,
145.50, 133.88, 128.24, 128.07, 126.40, 118.48, 79.01, 49.96, 47.18,
41.79, 28.83.42
13.6 Hz, 2H), 3.74 (d, J¼6.0 Hz, 2H), 2.37 (dd, J¼6.4, 4.0 Hz, 2H), 1.85 (d,
J¼6.4 Hz, 2H), 1.48e1.19 (m, 12H), 0.88 (br s, 1H). 13C NMR (100 MHz,
CDCl3)
d¼141.07, 139.91, 128.34, 128.09, 126.84, 113.88, 54.74, 36.02,
4.2.17. Preparation of N-(4-nitrophenyl)-2,2-diphenylpent-4-en-1-
amine (1q). To a solution of 4-nitroaniline (1.5 mmol) and 5-
bromo-1-pentene (1 mmol) in DMF (30 mL) was added K2CO3
(30 mmol). The mixture was stirred overnight at 70 ꢀC. The mixture
was allowed to cool to room temperature and washed with water
(10 mL). The aqueous phase was extracted with Et2O (3ꢁ30 mL).
The combined organic layers were washed with brine, dried, and
concentrated. The resulting oily residue was chromatographed
(petroleum ether/ethyl acetate¼15:1) to give 1q (0.08 g, 41%) as
35.15, 34.34, 27.61, 26.60, 21.68.38
4.2.12. N-(Isopropyl)-2,2-diphenylpent-4-en-1-amine (1k). 1H NMR
(300 MHz, CDCl3)
d
¼7.19e7.03 (m, 10H), 5.28 (ddt, J¼17.1, 10.0,
7.1 Hz, 1H), 4.99e4.70 (m, 2H), 3.11 (s, 2H), 2.91 (d, J¼7.1 Hz, 2H),
2.54 (hept, J¼6.2 Hz, 1H), 0.84 (d, J¼6.3 Hz, 6H), 0.26 (br s, 1H). 13C
NMR (100 MHz, CDCl3)
d
¼147.07, 135.02, 128.11, 127.93, 125.90,
117.55, 53.64, 49.97, 49.26, 41.61, 23.13.39
a colorless oil. 1H NMR (400 MHz, CDCl3)
d
¼7.99 (d, J¼9.1 Hz, 2H),
4.2.13. Preparation of N-benzylpent-4-en-1-amine (1l). To a solu-
tion of benzylamine (5 mmol) and 5-bromo-1-pentene (1 mmol)
in ethanol (30 mL) was added NaI (0.1 mmol). The mixture was
stirred overnight at 75 ꢀC and the solvent was removed in vacuo.
The resulting oily residue was chromatographed (petroleum
ether/ethyl acetate¼5:1) to give 1l (0.09g, 53%) as a clear oil. 1H
6.44 (d, J¼9.1 Hz, 2H), 5.75 (ddt, J¼16.9, 10.2, 6.7 Hz, 1H), 5.07e4.82
(m, 2H), 4.06 (br s, 1H), 3.15 (dd, J¼13.1, 6.7 Hz, 2H), 2.10 (q,
J¼7.0 Hz, 2H), 1.74e1.62 (m, 2H). 13C NMR (100 MHz, CDCl3)
d
¼153.85, 137.50, 137.24, 126.48, 115.52, 110.93, 42.70, 31.01, 28.01.
HRMS-ESI (m/z): [MþH]þ calcd for C11H14N2O2, 207.1128; found:
207.1128.
NMR (400 MHz, CDCl3)
d
¼7.21e7.13 (m, 5H), 5.70 (m, 1H),
4.98e4.80 (m, 2H), 3.67 (s, 2H), 2.53 (t, J¼7.2 Hz, 2H), 2.02 (br s,
4.2.18. (E)-N-Benzyl-2,2,5-triphenylpent-4-en-1-amine (1r). Oil. 1H
1H), 2.01e1.95 (m, 2H), 1.58e1.43 (m, 2H). 13C NMR (100 MHz,
NMR (400 MHz, CDCl3)
1H), 5.78e5.70 (m, 1H), 3.73 (s, 2H), 3.25 (s, 2H), 3.19 (d, J¼7.3 Hz,
2H), 1.29 (br s, 1H). 13C NMR (100 MHz, CDCl3)
d¼7.49e7.14 (m, 20H), 6.34 (d, J¼15.8 Hz,
CDCl3)
d
¼140.24, 138.44, 128.41, 128.19, 126.97, 114.71, 53.93,
48.80, 31.56, 29.15.40
d
¼146.94, 144.12,
137.91, 132.96, 128.61, 128.51, 128.41, 128.20, 128.12, 127.63, 126.92,
126.72, 126.24, 126.20, 55.27, 54.20, 50.83, 40.70.32
4.2.14. Preparation of N-(2,2-diphenylpent-4-enyl)acetamide (1n). To
a solution of acetic anhydride (1.0 mmol) in CH2Cl2 (2 mL) was
added 1m (1.0 mmol) in a dropwise manner. The reaction mixture
was stirred overnight and quenched with 1 M NaOH. The organic
layer was dried over MgSO4, filtered, and concentrated. The crude oil
was purified by chromatography (petroleum ether/dichloro
methane¼5:1) to give 1n (0.18 g, 65%) as a colorless oil. 1H NMR
4.2.19. N-Benzyl-2,2-diphenylhex-5-en-1-amine
(400 MHz, CDCl3)
(1s). 1H
NMR
d
¼7.34e7.09 (m,15H), 5.75 (tt, J¼16.5, 6.4 Hz,1H),
4.97e4.83 (m, 2H), 3.68 (s, 2H), 3.18 (s, 2H), 2.32 (dd, J¼9.9, 6.1 Hz,
2H), 1.64 (dd, J¼15.5 6.7 Hz, 2H), 1.64 (d, J¼5.2 Hz, 2H), 0.84 (br s,
1H). 13C NMR (100 MHz, CDCl3)
d¼147.27, 139.32, 129.35, 128.40,

5872
R.-L. Li et al. / Tetrahedron 69 (2013) 5867e5873
128.21, 128.16, 128.04, 127.88, 126.12, 114.31, 55.28, 50.40, 42.70,
36.42, 28.83.32
160.93, 147.24, 144.79, 133.32, 130.82, 130.74, 128.47, 128.42, 128.14,
126.45, 126.41, 126.04, 115.31, 115.10, 61.89, 61.71, 61.37, 53.52,
48.22, 45.89. 19F NMR (376 MHz, CDCl3)
d¼ꢂ115.03. HRMS-ESI (m/
4.3. One-pot procedure for the synthesis of3-Chloropiperidines
z): [MþH]þ calcd for C24H23ClFN, 380.1576; found: 380.1573.
The reaction was carried out in open air system. To a 100 mL
flask were added 1 mmol alkenylamine, 50 mol % CuCl2$2H2O, and
20 mL of toluene. The reaction mixture was refluxed for 24 h. After
cooling to room temperature, the reaction mixture was washed
with water (25 mLꢁ3), dried over MgSO4, and was concentrated to
give an oil. Flash column chromatography (petroleum ether/ethyl
acetate¼100:1) gave the corresponding products.
4.4.5. N-(4-Isopropylbenzyl)-5-chloro-3,3-diphenylpiperidine
(2e). White solid. Mp 98e99 ꢀC. 1H NMR (400 MHz, CDCl3)
d
¼7.43e6.96 (m, 14H), 3.89 (tt, J¼11.8, 4.0 Hz, 1H), 3.74e3.52 (m,
3H), 3.26 (dd, J¼10.3, 4.2 Hz, 1H), 3.09e2.88 (m, 2H), 2.43e2.32 (m,
2H), 2.23 (t, J¼10.6 Hz, 1H), 1.31 (dd, J¼6.9, 0.6 Hz, 6H). 13C NMR
(100 MHz, CDCl3)
d¼148.07, 147.39, 144.96, 134.91, 129.22, 128.61,
128.35, 128.05, 126.44, 126.36, 125.93, 62.20, 62.08, 61.24, 53.70,
48.29, 46.02, 33.84, 24.08. HRMS-ESI (m/z): [MþH]þ calcd for
C27H30ClN, 404.2140; found: 404.2140.
4.4. One-pot two-step preparation of 3-chloropiperidines
The reaction was carried out in open air system. To a 100 mL
flask were added 1 mmol alkenylamine, 100 mol % CuCl2$2H2O,
and 20 mL of THF. The reaction mixture was stirred at room
temperature for 3 h, and then refluxed for 18 h. After cooling to
room temperature, the reaction mixture was washed with water
(25 mLꢁ3), dried over MgSO4, and was concentrated to give an
oil. Flash column chromatography (petroleum ether/ethyl
acetate¼100:1) gave the corresponding products.
4.4.6. 1-(4-Bromobenzyl)-5-chloro-3,3-diphenylpiperidine (2f). 1H
NMR (400 MHz, CDCl3)
d
¼7.56 (d, J¼7.7 Hz, 2H), 7.40e7.16 (m, 12H),
3.97 (tt, J¼11.6, 3.9 Hz, 1H), 3.68e3.58 (m, 3H), 3.28 (dd, J¼10.2,
4.1 Hz, 1H), 3.12 (d, J¼12.6 Hz, 1H), 2.48e2.37 (m, 2H), 2.31 (t,
J¼10.5 Hz, 1H). 13C NMR (100 MHz, CDCl3)
¼146.05, 143.61, 135.54,
d
130.38, 129.79, 127.31, 127.04, 125.35, 125.28, 124.95, 120.18, 60.84,
60.67, 60.25, 52.30, 47.10, 44.72. HRMS-ESI (m/z): [MþH]þ calcd for
C24H23BrClN, 440.0775; found: 440.0776.
4.4.1. N-Benzyl-5-chloro-3,3-diphenylpiperidine (2a). Oil. 1H NMR
4.4.7. N-(4-Nitrobenzyl)-2-(chloromethyl)-4,4-diphenylpyrrolidine
(400 MHz, CDCl3)
d
¼7.44e7.17 (m, 15H), 3.94 (ddd, J¼14.9, 8.1,
(2g). 1H NMR (400 MHz, CDCl3)
d
¼8.33e7.27 (m, 14H), 4.27 (d,
3.9 Hz, 1H), 3.73e3.64 (m, 3H), 3.30 (dd, J¼10.2, 3.8 Hz, 1H), 3.08 (d,
J¼14.2 Hz, 1H), 3.93 (d, J¼9.6 Hz, 1H), 3.81 (d, J¼14.2 Hz, 1H),
J¼12.5 Hz, 1H), 2.40 (dd, J¼26.3, 12.4 Hz, 2H), 2.29 (t, J¼10.6 Hz,1H).
3.48e3.41 (m, 2H), 3.26 (d, J¼8.8 Hz, 1H), 3.12e3.08 (m, 2H), 2.77
13C NMR (100 MHz, CDCl3)
d
¼146.23, 143.79, 136.50, 128.21, 127.47,
(d, J¼12.8 Hz, 1H). 13C NMR (100 MHz, CDCl3)
¼128.61, 127.93,
d
127.28, 127.00, 126.36, 125.33, 125.30, 124.88, 61.44, 60.90, 60.29,
52.53, 47.14, 44.85. HRMS-ESI (m/z): [MþH]þ calcd for C24H24ClN,
362.1670; found: 362.1669.
127.40, 127.24, 127.21, 127.18, 125.80, 125.60, 125.25, 125.04, 122.68,
122.60, 64.08, 63.30, 57.95, 52.08, 46.17, 41.10. HRMS-ESI (m/z):
[MþH] calcd for C24H23ClN2O2: 407.1521; found: 407.1525.
4.4.2. N-(4-Methylbenzyl)-5-chloro-3,3-diphenylpiperidine
4.4.8. 5-Chloro-1-isobutyl-3,3-diphenylpiperidine (2h). 1H NMR
(2b). White solid. Mp 135e136 ꢀC. 1H NMR (400 MHz, CDCl3)
(400 MHz, CDCl3)
d
¼7.35e7.31 (m, 2H), 7.17 (dd, J¼15.1, 7.1 Hz, 4H),
d
¼7.42e7.01 (m, 14H), 3.89 (ddd, J¼15.1, 8.1, 3.9 Hz, 1H), 3.65e3.54
(m, 3H), 3.32e3.22 (m, 1H), 3.03 (d, J¼12.3 Hz, 1H), 2.40 (s, 3H),
2.38e2.19 (m, 3H). 13C NMR (100 MHz, CDCl3)
7.11e7.03 (m, 4H), 3.75 (tt, J¼10.9, 3.9 Hz, 1H), 3.47 (d, J¼12.1 Hz,
1H), 3.15 (dd, J¼10.1, 3.7 Hz, 1H), 2.89e2.83 (m, 1H), 2.24 (dd,
J¼24.7, 12.6 Hz, 1H), 2.15 (d, J¼12.2 Hz, 1H), 2.10 (d, J¼7.2 Hz, 2H),
2.02 (t, J¼10.5 Hz,1H), 1.79 (td, J¼13.4, 6.7 Hz,1H), 0.86 (d, J¼3.4 Hz,
d
¼146.31, 143.88,
135.96, 133.38, 128.19, 127.95, 127.54, 127.29, 126.99, 125.37, 125.30,
124.86, 61.18, 60.84, 60.29, 52.62, 47.16, 44.91, 20.14. HRMS-ESI (m/
z): [MþH]þ calcd for C25H26ClN, 376.1827; found: 376.1826.
Crystal data for compound 2b: C24H24NCl, M¼375.92, mono-
3H), 0.85 (d, J¼3.4 Hz, 3H). 13C NMR (100 MHz, CDCl3)
¼146.51,
d
144.24, 127.67, 127.28, 126.90, 125.40, 125.28, 124.81, 65.62, 62.56,
60.53, 52.81, 47.27, 45.11, 24.58, 20.10, 19.81. HRMS-ESI (m/z):
[MþH]þ calcd for C21H26ClN, 328.1827; found: 328.1828.
clinic, a¼11.830(4) A, b¼10.224(4) A, c¼16.394(6) A,
a
¼90.00ꢀ,
ꢀ
ꢀ
ꢀ
3
ꢀ
ꢀ
b
¼92.623(5)ꢀ,
¼90.00 , V¼1980.8(13) A , T¼113(2) K, space group
g
P2(1)/c, Z¼4,
m
(Mo K
a
)¼0.202 mmꢂ1, 22,442 reflections measured,
4.4.9. N-Benzyl-3-chloro-5,5-dimethylpiperidine
(400 MHz, CDCl3)
(2i). 1H
NMR
4806 independent reflections (Rint¼0.0496). The final R1 value was
d
¼7.34e7.11 (m, 5H), 4.03 (ddt, J¼11.8, 10.8,
0.0400 (I>2
s
(I)). The final wR(F2) value was 0.0961 (I>2
s
(I)). The
4.5 Hz, 1H), 3.47 (d, J¼13.4 Hz, 1H), 3.38 (d, J¼13.4 Hz, 1H),
3.16e2.92 (m, 1H), 2.31 (d, J¼11.0 Hz, 1H), 1.92 (t, J¼10.7 Hz, 1H),
1.67 (d, J¼11.1 Hz, 1H), 1.33e1.17 (m, 2H), 0.98 (s, 3H), 0.80 (s, 3H).
final R1 value was 0.0523 (all data). The final wR(F2) value was
0.1023 (all data).34
13C NMR (100 MHz, CDCl3)
d
¼138.53, 128.68, 128.28, 127.06, 64.52,
4.4.3. N-(4-Methoxybenzyl)-5-chloro-3,3-diphenylpiperidine
62.33, 61.93, 54.26, 48.41, 33.41, 29.32, 25.12. HRMS-ESI (m/z):
(2c). White solid. Mp 99e100 ꢀC. 1H NMR (400 MHz, CDCl3)
[MþH]þ calcd for C14H20ClN: 238.1357; found: 238.1360.
d
¼7.14e7.22 (m, 12H), 7.02 (d, J¼7.7 Hz, 1H), 6.81 (d, J¼8.5 Hz, 1H),
3.78 (d, J¼13.4 Hz, 1H), 3.75 (s, 3H), 3.51e3.47 (m, 3H), 3.14 (d,
J¼8.5 Hz, 1H), 2.92 (d, J¼12.6 Hz, 1H), 2.26 (t, J¼12.2 Hz, 1H), 2.13
4.4.10. 2-Benzyl-4-chloro-2-azaspiro[5.5]undecane (2j). 1H NMR
(400 MHz, CDCl3)
d
¼7.32e7.28 (m, 5H), 4.15 (t, J¼11.3 Hz, 1H), 3.59
(dd, J¼25.8, 11.4 Hz, 2H). 13C NMR (100 MHz, CDCl3)
d¼157.72,
(d, J¼13.3 Hz,1H), 3.46 (d, J¼13.3 Hz,1H), 3.19 (d, J¼7.3 Hz,1H), 2.71
(d, J¼11.4 Hz, 1H), 2.19 (d, J¼11.6 Hz,1H), 2.07 (t, J¼10.5 Hz, 1H), 1.65
(d, J¼11.2 Hz, 2H), 1.47e1.11 (m, 8H), 0.99e0.77 (m, 2H). 13C NMR
146.34, 143.89, 129.42, 128.57, 127.52, 127.31, 127.01, 125.42, 125.31,
124.88, 112.66, 60.85, 60.75, 60.36, 54.26, 52.64, 47.19, 44.96.
HRMS-ESI (m/z): [MþH]þ calcd for C25H26ClNO, 392.1776; found:
392.1768.
(100 MHz, CDCl3)
d
¼138.68, 128.64, 128.26, 127.06, 62.63, 62.41,
62.06, 54.05, 38.37, 36.09, 32.94, 29.77, 26.64, 21.60, 21.56. HRMS-
ESI (m/z): [MþH]þ calcd for C17H24ClN: 278.1670; found: 278.1672.
4.4.4. N-(4-Fluorobenzyl)-5-chloro-3,3-diphenylpiperidine
(2d). White solid. Mp 109e110 ꢀC. 1H NMR (400 MHz, CDCl3)
4.4.11. N-Isopropyl-5-chloro-3,3-diphenylpiperidine (2k). Oil. 1H
d
¼7.24e6.90 (m, 14H), 3.78 (tt, J¼11.8, 4.0 Hz, 1H), 3.54e3.44 (m,
NMR (400 MHz, CDCl3)
d
¼7.51e7.14 (m, 10H), 3.94e3.83 (m, 1H),
3H), 3.11 (dd, J¼10.3, 4.3 Hz, 1H), 2.95e2.90 (m, 1H), 2.29e2.18 (m,
3.59 (d, J¼12.1 Hz, 1H), 3.22 (d, J¼6.3 Hz, 1H), 3.08e2.97 (m, 2H),
2H), 2.12 (t, J¼10.6 Hz, 1H). 13C NMR (100 MHz, CDCl3)
¼163.50,
d
2.53e2.29 (m, 3H), 1.15 (d, J¼6.6 Hz, 3H), 1.12 (d, J¼6.6 Hz, 3H). 13C

R.-L. Li et al. / Tetrahedron 69 (2013) 5867e5873
5873
€
€
7. (a) Gottlich, R. Synthesis 2000, 1561e1564; (b) Heuger, G.; Kalsow, S.; Gottlich,
R. Eur. J. Org. Chem. 2002, 1848e1854; (c) Schulte-Wulwer, I. A.; Helaja, J.;
NMR (100 MHz, CDCl3)
d
¼146.7, 144.3, 127.5, 127.3, 127.0, 125.4,
125.3, 124.8, 56.7, 56.1, 53.6, 53.5, 47.0, 45.4, 16.8, 16.5. HRMS-ESI
€
Gottlich, R. Synthesis 2003, 1886e1890.
8. Noack, M.; Gottlich, R. Eur. J. Org. Chem. 2002, 3171e3178.
9. Gottlich, R.; Noack, M. Tetrahedron Lett. 2001, 42, 7771e7774.
10. Helaja, J.; Gottlich, R. Chem. Commun. 2002, 720e721.
11. Lei, A. W.; Lu, X. Y.; Liu, G. S. Tetrahedron Lett. 2004, 45, 1785e1788.
12. Manzoni, M. R.; Zabawa, T. P.; Kasi, D.; Chemler, S. R. Organometallics 2004, 23,
5618e5621.
13. Yin, G. Y.; Wu, T.; Liu, G. S. Chem.dEur. J. 2012, 18, 451e455.
14. Li, G.; Kotti, S. R. S. S.; Timmons, C. Eur. J. Org. Chem. 2007, 2007, 2745e2758.
15. Cai, Y.; Liu, X.; Jiang, J.; Chen, W.; Lin, L.; Feng, X. J. Am. Chem. Soc. 2011, 133,
5636e5639.
(m/z): [MþH]þ calcd for C20H24ClN, 314.1670; found: 314.1667.
€
€
€
4.4.12. N-Benzyl-3-chloropiperidine (2l). Oil. 1H NMR (400 MHz,
CDCl3)
d
¼7.40e7.09 (m, 5H), 4.06e3.99 (m,1H), 3.57 (s, 2H), 3.07 (d,
J¼9.4 Hz, 1H), 2.74 (d, J¼11.2 Hz, 1H), 2.26e2.11 (m, 3H), 1.83e1.79
(m, 1H), 1.67e1.56 (m, 2H). 13C NMR (100 MHz, CDCl3)
d¼136.8,
127.9, 127.2, 126.1, 61.7, 60.2, 55.1, 51.8, 33.8, 23.8.43
16. Cai, Y.; Liu, X.; Hui, Y.; Jiang, J.; Wang, W.; Chen, W.; Lin, L.; Feng, X. Angew.
Chem., Int. Ed. 2010, 49, 6160e6164.
17. Cai, Y.; Liu, X.; Li, J.; Chen, W.; Wang, W.; Lin, L.; Feng, X. Chem.dEur. J. 2011, 17,
14916e14921.
18. Yadav, J. S.; Antony, A.; Rao, T. S.; Subba Reddy, B. V. J. Organomet. Chem. 2011,
696, 16e36.
19. Krasnova, L. B.; Hein, J. E.; Fokin, V. V. J. Org. Chem. 2010, 75, 8662e8665.
20. Han, J.; Xu, B.; Hammond, G. B. J. Am. Chem. Soc. 2009, 132, 916e917.
21. Tsuhako, A.; Oikawa, D.; Sakai, K.; Okamoto, S. Tetrahedron Lett. 2008, 49,
6529e6532.
4.4.13. N-Benzyl-2-(chloro(phenyl)methyl)-4,4-diphenylpyrrolidine
(2r). Oil. 1H NMR (400 MHz, CDCl3)
d
¼7.72e6.89 (m, 20H), 4.74 (d,
J¼12.9 Hz, 1H), 4.33 (d, J¼5.3 Hz, 1H), 3.86 (d, J¼9.8 Hz, 1H),
3.69e3.43 (m, 2H), 2.82 (d, J¼10.0 Hz, 1H), 2.76e2.65 (m, 1H), 2.08
(d, J¼13.1 Hz, 1H). 13C NMR (100 MHz, CDCl3)
¼145.75, 139.43,
d
127.46, 127.30, 127.23, 127.18, 126.86, 126.40, 125.93, 125.48, 125.08,
68.34, 67.95, 63.03, 61.28, 52.10, 40.73.32
22. (a) Ohmiya, H.; Moriya, T.; Sawamura, M. Org. Lett. 2009, 11, 2145e2147; (b)
Munro-Leighton, C.; Delp, S. A.; Alsop, N. M.; Blue, E. D.; Gunnoe, T. B. Chem.
Commun. 2008, 111e113; (c) Munro-Leighton, C.; Delp, S. A.; Blue, E. D.; Gun-
noe, T. B. Organometallics 2007, 26, 1483e1493.
23. Qin, H. B.; Yamagiwa, N.; Matsunaga, S.; Shibasaki, M. Chem. Asian J. 2007, 2,
150e154.
24. (a) Muller, T. E.; Pleier, A. K. J. Chem. Soc., Dalton Trans. 1999, 583e587; (b)
Muller, T. E.; Grosche, M.; Herdtweck, E.; Pleier, A. K.; Walter, E.; Yan, Y. K.
Organometallics 2000, 19, 170e183.
25. Peng, C.; Cheng, J. J.; Wang, H. B. Adv. Synth. Catal. 2008, 350, 2359e2364.
26. Joseph, T.; Shanbhag, G. V.; Halligudi, S. B. J. Mol. Catal. A: Chem. 2005, 236,
139e144.
27. Shanbhag, G. V.; Joseph, T.; Halligudi, S. B. J. Catal. 2007, 250, 274e282.
28. Taylor, J. G.; Whittall, N.; Hii, K. K. Org. Lett. 2006, 8, 3561e3564.
29. Rao, W. D.; Kothandaraman, P.; Koh, C. B.; Chan, P. W. H. Adv. Synth. Catal. 2010,
352, 2521e2530.
30. Sherman, E. S.; Fuller, P. H.; Kasi, D.; Chemler, S. R. J. Org. Chem. 2007, 72,
3896e3905.
4.4.14. N-Benzyl-2-(chloromethyl)-5,5-diphenylpiperidine (2s). 1H
NMR (400 MHz, CDCl3)
d
¼7.63e7.04 (m,15H), 4.17 (d, J¼13.3 Hz,1H),
3.89e3.76 (m, 2H), 3.46 (t, J¼12.6 Hz, 2H), 2.91e2.82 (m,1H), 2.73 (d,
J¼12.4 Hz, 1H), 2.65e2.51 (m, 1H), 2.42e2.34 (m, 1H), 2.01e1.88 (m,
1H), 1.87e1.74 (m, 1H). 13C NMR (100 MHz, CDCl3)
d¼147.92, 146.62,
138.66, 129.55, 128.38, 128.18, 127.93, 127.44, 127.30, 125.99, 125.75,
61.26, 60.43, 59.13, 46.36, 45.15, 33.24, 25.76.32
Acknowledgements
We acknowledge the financial support from National Natural
Science Foundation of China (NSFC 20972072, NSFC 21272121). R.-
L.L. is a graduate student registered in SYSU and this work is carried
out in NKU.
31. Michon, C.; Medina, F.; Capet, F.; Roussel, P.; Agbossou-Niedercorn, F. Adv. Synth.
Catal. 2010, 352, 3293e3305.
32. Liu, G.-Q.; Li, W.; Li, Y.-M. Adv. Synth. Catal. 2013, 355, 395e402.
33. Sjoholm, A.; Hemmerling, M.; Pradeille, N.; Somfai, P. J. Chem. Soc., Perkin Trans.
ꢀ
Supplementary data
€
1 2001, 891e899.
34. CCDC 832148 (2b) contains the supplementary crystallographic data for this
paper. These data can be obtained free of charge from The Cambridge Crys-
tallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
35. Bender, C. F.; Widenhoefer, R. A. J. Am. Chem. Soc. 2005, 127, 1070e1071.
36. Hesp, K. D.; Stradiotto, M. Org. Lett. 2009, 11, 1449e1452.
37. Mlinaric-Majerski, K.; Margeta, R.; Veljkovic, J. Synlett 2005, 2089e2091.
38. Zhang, R.; Xu, Q.; Mei, L.-Y.; Li, S.-K.; Shi, M. Tetrahedron 2012, 68, 3172e3178.
39. Bauer, E. B.; Andavan, G. T. S.; Hollis, T. K.; Rubio, R. J.; Cho, J.; Kuchenbeiser, G.
R.; Helgert, T. R.; Letko, C. S.; Tham, F. S. Org. Lett. 2008, 10, 1175e1178.
40. Gribkov, D. V.; Hultzsch, K. C. Angew. Chem., Int. Ed. 2004, 43, 5542e5546.
41. Lovick, H. M.; Michael, F. E. J. Am. Chem. Soc. 2010, 132, 1249e1251.
42. Rosewall, C. F.; Sibbald, P. A.; Liskin, D. V.; Michael, F. E. J. Am. Chem. Soc. 2009,
131, 9488e9489.
Supplementary data associated with this article can be found in
the online version, at http://dx.doi.org/10.1016/j.tet.2013.05.022.
References and notes
ꢁ
ꢁ
1. Pors, K.; Shnyder, S. D.; Teesdale-Spittle, P. H.; Hartley, J. A.; Zloh, M.; Searcey, M.;
Patterson, L. H. J. Med. Chem. 2006, 49, 7013e7023.
2. Kim, W. G.; Kim, J. P.; Kim, C. J.; Lee, K. H.; Yoo, I. D. J. Antibiot. 1996, 49, 20e25.
3. Blackman, A. J.; Li, C.; Hockless, D. C. R.; Skelton, B. W.; White, A. H. Tetrahedron
1993, 49, 8645e8656.
4. Rahbæk, L.; Christophersen, C. J. Nat. Prod. 1997, 60, 175e177.
5. Horning, D. E.; Muchowski, J. M. Can. J. Chem.-Rev. 1974, 52, 1321e1330.
6. Scarcey, M.; Patterson, L. H.; Pors, K.; Casely-Hayford, M. WO 2006/097730.
43. Hayashi, K.; Kujime, E.; Katayama, H.; Sano, S.; Shiro, M.; Nagao, Y. Chem.
Pharm. Bull. 2009, 57, 1142e1146.