The effect of hydrogen bond on Br?nsted acid-catalyzed intramolecular hydroamination of unfunctionalized olefins

Article abstract of DOI:10.1016/j.tet.2015.07.003

The catalytic activity of benzoic acid could be increased by introducing a hydrogen bond donor group at the ortho-position. Preliminary DFT calculation indicated that the activation of CC double bond was realized by the action of both the carboxyl group and the hydrogen bond donor. The amino group was brought to the activated CC bond by the interaction between the carboxyl oxygen and amino proton. This interaction also increased the nucleophilicity of the amino group. Thus, in the presence of 20 mol % of 2-(trifluoromethanesulfonamido)benzoic acid, intramolecular hydroamination of unfunctionalized olefins gave the corresponding products in up to 95% isolated yields.

Full text of DOI:10.1016/j.tet.2015.07.003

Tetrahedron 71 (2015) 7003e7009
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
The effect of hydrogen bond on Brønsted acid-catalyzed
intramolecular hydroamination of unfunctionalized olefins
,b,
Ting-Ting Li a, Gong-Qing Liu a, Yu-Mei Wang a, Bin Cui a, Hui Sun a, Yue-Ming Li a
*
a College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin 300071, People’s Republic of China
b CAS Key Laboratory of Synthetic Chemistry of Natural Substances, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
345 Lingling Road, Shanghai 200032, 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:
The catalytic activity of benzoic acid could be increased by introducing a hydrogen bond donor group at
the ortho-position. Preliminary DFT calculation indicated that the activation of C]C double bond was
realized by the action of both the carboxyl group and the hydrogen bond donor. The amino group was
brought to the activated C]C bond by the interaction between the carboxyl oxygen and amino proton.
This interaction also increased the nucleophilicity of the amino group. Thus, in the presence of 20 mol %
of 2-(trifluoromethanesulfonamido)benzoic acid, intramolecular hydroamination of unfunctionalized
olefins gave the corresponding products in up to 95% isolated yields.
Received 18 April 2015
Received in revised form 29 June 2015
Accepted 1 July 2015
Available online 8 July 2015
Keywords:
Hydroamination
4-Penten-1-amine
5-Hexen-1-amine
2-Methylpyrrolidine
2-Methylpiperidine
Ó 2015 Elsevier Ltd. All rights reserved.
1. Introduction
groups of the substrates, leading to the formation of ammoniums,
which could not further react with free olefins in the absence of
Nitrogen-containing heterocycles are the privileged structures
in medicinal chemistry and have played important roles in drug
research and development.1 As a result, significant efforts have
been made to develop new methods for CeN bond formation and
for nitrogen-containing heterocycle construction.2 In addition to
conventional functional group transformation reactions,3 hydro-
amination reaction should also be one of the most straightfor-
ward and efficient methods for the formation of CeN bonds and
for the construction of nitrogen-containing heterocycles.4 In the
past decades, progresses have been made in this area, and
hydroamination of different types of substrates have been re-
alized both chemo- and stereoselectively using organo-
lanthanides,5 main group compounds,6 group IV compounds,7
noble metal compounds,8 and other transition metal com-
pounds9 as catalysts.
additional catalysts. Strong Lewis acids would coordinate more
strongly with the amino groups, rendering the latter less reactive.11
For these obvious reasons, sulfonamide substrates were mostly
used in Brønsted acid-catalyzed hydroamination of unfunctional-
ized olefins to partially reduce the interaction between nitrogen
atoms with the catalysts.12 This approach was generally successful,
and good to excellent isolated yields could be obtained in most
cases in Brønsted as well as heteropoly acids-catalyzed hydro-
amination reaction of N-electron deficient substrates.13 Similar
results could also be obtained when different Lewis acids were used
as catalysts,14 but more and more evidences showed that the re-
actions were promoted by the corresponding Brønsted acids
formed during the reaction.15
Efforts have been made to develop different Brønsted acids for
efficient hydroamination of unfunctionalized olefins bearing N-
electron rich amino groups.16 Using phosphoric acid diesters as
organocatalysts, different N-electron rich substrates were con-
verted to the corresponding hydroamination products, and the
reactions could proceed stereoselectively in the presence of chiral
catalyst.17 Shapiro et al. showed that dithiophosphoric acid was an
efficient organocatalyst for hydroamination of 1,3-diene substrates.
The successfulness of the catalyst system relied on the special
structure of the 1,3-diene substrates, which could easily be attacked
by the catalyst, and the relatively easy leaving group property of the
In contrast to the achievements in metal-catalyzed hydro-
amination reactions, Brønsted acid-catalyzed hydroamination of
unfunctionalized olefins bearing N-electron rich amino groups was
relatively less pursued due to the buffering effect of the amino
group.10 Strong Brønsted acids would first interact with amino
* Corresponding author. Tel.: þ86 22 23504028; fax: þ86 22 23507760; e-mail
address: ymli@nankai.edu.cn (Y.-M. Li).
http://dx.doi.org/10.1016/j.tet.2015.07.003
0040-4020/Ó 2015 Elsevier Ltd. All rights reserved.

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T.-T. Li et al. / Tetrahedron 71 (2015) 7003e7009
Table 1
thiol group, which ensured the regeneration of the catalyst to
complete catalytic circle.18
Intramolecular hydroamination of 1a in the presence of different bifunctional
compoundsa,b
It is our purpose to understand the rationale for organocatalytic
intramolecular hydroamination reactions. In this paper, we wish to
report our progress on the design of bifunctional Brønsted acids,
and the application of such catalysts in intramolecular hydro-
amination of N-electron rich olefin substrates.
Entry
Catalyst
Conversion of 1a (%)
2. Results and discussion
1
2
3
4
5
6
7
8
o-TfNHPhCOOH (2a)
NR
30
63
74
71
35
22
<20
20
68
43
76
80
92
L
L
L
-N-Ts Pro (2b)
-N-Ts-Phe (2c)
-N-Ts-Val (2d)
In our course of developing new methods for intramolecular
hydroamination of unfunctionalized olefins bearing electron rich
amino groups, we found that the Lewis acid catalysts should bear
balanced Lewis acidity such that the C]C double bonds could be
activated, and over-coordination of the catalyst to the amino groups
should be avoided so that the reactivity of the amino groups could
be maintained.19 Similar trends were also observed for Brønsted
acid-catalyzed reactions. While at most half amount of the sub-
strate could be converted when trifluoromethanesulfonic acid or
methanesulfonic acid was used, high conversion was observed
when trifluoroacetic acid was used under otherwise identical
conditions,20 and Brønsted acid with acidity lower than this point
was not successful for the reaction.
Mandelic acid (2e)
(þ)-Tartaric acid (2f)
L-N-Ts Ser (2g)
o-NH2PhCOOH (2h)
o-MeNHPhCOOH (2i)
o-MeTfNPhCOOH (2j)
o-AcNHPhCOOH (2k)
o-MsNHPhCOOH (2l)
o-TsNHPhCOOH (2m)
o-TfNHPhCOOH
9
10
11
12
13
14
a
Reactions were carried out in a sealed tube with 0.5 mmol of 1a, 0.1 mmol of
catalyst, and 2 mL of xylene at 130 ꢀC.
b
Conversions were based on crude NMR analysis of the reaction mixture.
Given that intramolecular hydroamination is an entropy un-
favorable process,21 catalysts bearing additional functional groups,
which could bring nitrogen atom close to C]C double bond would
show some benefit for the reactions. Inspired by this rationale, we
tested a variety of bifunctional Brønsted acids, and found that
hydroxyarenecarboxylic acids showed higher activity than other
catalysts (Scheme 1).22
entry 10). The tethering group acted as hydrogen bond donor (entry
9 vs entries 11e14), and increasing the hydrogen bond donor ability
led to significant increase of the activity of the catalysts (entries
11e14). Stereoselectivity was not observed for 2b to 2g-catalyzed
reactions, possibly due to the high reaction temperature applied.
The results in Table 1 showed that compound 2n (2-(tri-
fluoromethanesulfonamido)benzoic acid) gave the highest yield.
This compound was then used as catalyst for further study. To find
the most suitable conditions for the intramolecular hydro-
amination of 1a, reactions in different solvents were carried out,
and the results were summarized in Table 2.
R1
R1
R1 R1
(
)
n
3-hydroxy-2-naphthoic acid
xylene, reflux, 24 h
H
N
R2
(
)
n
N
R2
1
2
Table 2
Scheme 1. 3-Hydroxy-2-naphthoic acid-catalyzed intramolecular hydroamination.
Effects of solvents and temperature on the intramolecular hydroamination of 1aa
Entry
Solvent
T/ꢀC
3ab (%)
To find new organocatalysts suitable for intramolecular hydro-
amination of N-electron rich substrates, and to further understand
the effect of additional functional groups on the catalytic activity of
the catalysts, several easily available bifunctional compounds were
tested for intramolecular hydroamination of N-benzyl-2,2-
diphenyl-4-penten-1-amine (1a). Previous reaction conditions
such as catalyst loading, reaction medium, reaction time, and re-
action temperature were adopted,22 and the results were summa-
rized in Table 1.
As shown in Table 1, carboxyl group was essential for hydro-
amination of substrate 1a, and compound lacking of the carboxyl
group (2a) was unable to promote the reaction and the starting
material was recovered (entry 1). N-Toluenesulfonyl proline (2b)
gave 30% with the recovery of starting material yield (entry 2), N-
toluenesulfonyl phenylalanine (2c) and N-toluenesulfonyl valine
(2d) gave 63% and 74% yields, respectively (entries 3 and 4), re-
vealing the important role of the additional functional groups
played during the cyclization. Similar result was also observed
when mandelic acid (2e) was used as catalyst (entry 5). Multi-
functional compounds such as tartaric acid (2f) or N-toluene-
sulfonyl serine (2g) failed to give good results (entries 6 and 7),
possibly due to the interference of the additional functional groups
on the reaction. 2-Aminobenzoic acids 2h and 2i gave poor results,
possibly due to the formation of inner salts (entries 8 and 9). The
formation of inner salt could be avoided when the amino group was
sulfonylated (2j), and this led to the increase of reactivity (entry 9 vs
1
2
3
4
5
6
7
8
Xylene
DMF
130
130
130
100
100
90
90
80
80
70
rt
60
90
100
110
120
130
130
130
92
46
10
63
12
29
19
Trace
12
NR
NR
NR
6
47
61
83
91
92
92
DMSO
Toluene
Dioxane
Benzene
DCE
EtOH
CHCl3
THF
Xylene
Xylene
Xylene
Xylene
Xylene
Xylene
Xylene
Xylene
Xylene
9
10
11
12
13
14
15
16
17c
18d
19e
a
Reactions were carried out in a sealed tube with 0.5 mmol of 1a, 0.1 mmol of 2n,
and 2 mL of xylene.
b
Based on crude NMR analysis of the reaction mixture.
c
The amount of solvent¼0.5 mL.
d
The amount of solvent¼1 mL.
e
The amount of solvent¼4 mL.
As shown in Table 2, high temperature was generally favorable
for the intramolecular hydroamination reaction (entry 1 vs entries
11e16), no reaction was observed when the reactions were carried

T.-T. Li et al. / Tetrahedron 71 (2015) 7003e7009
7005
out at temperatures below 70 ꢀC (entries 8e12), this is also in
agreement with the literature results.12 Reactions carried out in
protic solvent (entry 8) or polar aprotic donor solvents such as DMF
(entry 2), DMSO (entry 3), dioxane (entry 5) or THF (entry 10) gave
poor results, possibly due to the solvation of the catalyst, which in
turn affected its interaction with substrate. Reactions carried out in
aromatic hydrocarbons such as toluene or xylene gave better re-
sults, and the amount of solvent (the concentration of the reagents)
showed less effect on the results. Xylene was then chosen as the
reaction medium for its good performance in the study. The con-
version increased with the increase of the catalyst loading (Table 3),
and 20 mol % of catalyst was enough for the reaction.
halogen, nitro, cyano were tolerated on the aromatic ring, and the
electronic effect of the benzyl groups showed little impact on the
reaction (entries 1e8). The heteroatom-containing substrate also
underwent hydroamination in high yield under the optimal con-
ditions (entry 9). Alkyl substituents, such as butyl or allyl groups on
nitrogen atom showed little effect on the reaction (entries 10e12).
ThorpeeIngold effect was observed in the reaction.23 The size of
2,2-geminal substituents showed some impact on the reaction,
substrates with smaller 2,2-geminal substituents were less reactive
(entries 19 and 20), and substrate lacking of 2,2-geminal sub-
stituents were unable to react (entry 23). Cyclization of 5-hexen-1-
amines took longer time than 4-penten-1-amines due to the un-
favorable entropy feature of the reaction (entries 13e18 and entries
20, 22).21 N-(Sulfon)amide substrates failed to react possibly due to
the reduced nucleophilicity of the nitrogen atoms (entries 24 and
25).
In their study of directed intermolecular Cope-type hydro-
amination of allylic amines with N-alkylhydroxyamines, Beau-
chemin et al. proposed a synergistic interaction between the allylic
amine and the N-alkylhydroxyamine (4).24 Jacobsen et al. showed
that hydrogen bond donor groups in thiourea catalysts would be
able to stabilize the dipolar transition structure (5), and catalyzed
the asymmetric Cope-type intramolecular hydroamination reaction
under mild conditions (Fig. 1).25
Table 3
Effect of catalyst loading on the course of the reactiona
Entry
2n (mol %)
3ab (%)
1
2
3
4
5
6
5
10
15
20
30
50
44%
56%
79%
92%
95%
>99%
a
Reactions were carried out in a sealed tube with 0.5 mmol of 1a and 2 mL of
xylene. Reaction time: 24 h, reaction temperature: 130 ꢀC.
b
Based on crude NMR analysis of the reaction mixture.
S
R1
Thus, different substrates were subjected to intramolecular
hydroamination to study the application scope of the catalyst, and
the results were summarized in Table 4. As shown in Table 4,
intramolecular hydroamination of N-electron-rich olefins pro-
ceeded readily, giving the corresponding pyrrolidine and piperidine
products in good isolated yields. Functionalities such as alkyl,
N
H
N
H
O
H
H
N
H
H
N
O
R2
N
H
4
5
Fig. 1. The hydrogen bond effect in Cope-type hydroamination reactions.
Table 4
Intramolecular hydroamination of unfunctionalized olefins catalyzed by 2-(tri-
fluoromethanesulfonamido)benzoic acida
To get mechanistic insights into the reaction, DFT calculation
was carried to study the possible interaction between the sub-
strates and the catalysts. Hartwig et al. showed that protonation of
sulfonamide
occurred
after
the
addition
of
tri-
fluoromethanesulfonic acid. In the current study, we assumed that
the amino groups were also protonated after mixing the catalyst
with the substrates. Therefore, the ammonium form of substrate 1s
and the benzoate form of the catalyst 2n was subjected to transition
state search at b3lyp/6-311Gþþ(d,p) level. The optimized transi-
tion state of the reaction was given in Fig. 2. This structure showed
that protons from both the sulfonamide and the carboxylic acid
would interact with C]C double bond, leading to an efficient ac-
tivation of the latter. The reaction was also made possible by the
Entry
R1
R2
n
Time/h
Isolated yield (%)
1
2
3
4
5
6
7
8
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Bn
1
1
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
1
2
1
2
1
1
1
24
24
24
24
24
24
24
24
24
87 (3a)
93 (3b)
90 (3c)
89 (3d)
95 (3e)
85 (3f)
90 (3g)
90 (3h)
91 (3i)
91 (3j)
78 (3k)
94 (3l)
74 (3m)
85 (3n)
81 (3o)
78 (3p)
80 (3q)
72 (3r)
57 (3s)
20 (3t)
78 (3u)
62 (3v)
NR
4-MeBn
4-MeOBn
4-FBn
4-ClBn
4-O2NBn
4-NCBn
4-(CH3)2CHBn
2-PyCH2
i-Bu
n-Bu
CH2]CHeCH2e
Bn
4-MeBn
4-MeOBn
4-FBn
4-ClBn
4-O2NBn
Bn
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
24
24
24
160
160
160
160
160
160
100
100
72
120
100
100
100
Ph
Ph
Me
Me
e(CH2)5e
e(CH2)5e
H
Bn
Bn
Bn
Bn
Ts
Ac
Ph
Ph
NR
NR
a
Reactions were carried out in sealed tube with 0.5 mmol of 1a, 0.1 mmol of
Fig. 2. Transition state for 2n-catalyzed intramolecular hydroamination of 1s. Irrele-
catalyst, and 2 mL of xylene.
vant hydrogen atoms were omitted for clarity.

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T.-T. Li et al. / Tetrahedron 71 (2015) 7003e7009
hydrogen bond between carboxyl oxygen and amine hydrogen,
which brought the amino group close enough to the activated C]C
double bond. This hydrogen bond also increased the nucleophilicity
of the amino group.
of 60e90 ꢀC. Melting points were measured on a digital melting-
point apparatus without correction of the thermometer. Nuclear
magnetic resonance spectra were recorded at ambient temperature
at 400 MHz (100 MHz for 13C, 376 MHz for 19F) in CDCl3 or DMSO-
On the basis of literature reports and the preliminary DFT cal-
culation, a tentative reaction mechanism was depicted in Scheme 2.
Ammonium benzoate I was first formed when substrate was
allowed to mix with catalyst. Interaction of C]C double bond with
protons from both the carboxyl group and the sulfonamido group
led to the activation of the C]C double bond, and hydrogen bond
between carboxyl oxygen and amino hydrogen brought the amino
group close to the reaction center as depicted in Fig. 2. Intra-
molecular nucleophilic attack of amino group on the activated C]C
double bond gave intermediate III. Proton exchange released the
catalyst and completed the catalytic cycle.
d6. Chemical shifts are reported in parts per million (d, ppm) using
TMS as internal standard, and spin-spin coupling constants (J) are
given in hertz. High-resolution mass spectrometry (HRMS) analy-
ses were carried out on IonSpec 7.0T FTICR HR-ESI-MS. Substrates
used were prepared according to our previous works.20,19 Catalysts
are either commercially available or prepared via conventional
esterification/saponification reactions.
4.2. Method for density functional theory calculation
The calculation was performed with Gaussian 09 Revision B.
0126 at b3lyp/6-311Gþþ(d,p) level. Intermediate I in Scheme 2 was
used as the starting input in transition state search. The only
imaginary frequency corresponding to the activation of C]C dou-
ble bond was obtained.
NHTf
COOH
H
N
Ph
substrate
H
N
Ph
4.3. General procedure for intramolecular hydroamination
reactions
H
H O
Tf
N
O
Ph
Ph
N
A sealed tube was charged with dry xylene (2 mL), substrate
(0.5 mmol), and catalyst (0.1 mmol, 20 mol %). The tube was then
sealed and was heated in an oil bath (130 ꢀC) for a given time. The
reaction mixture was cooled to room temperature. The sealed tube
was opened with care. The mixture was concentrated and was
purified by flash column chromatography to give the corresponding
products.
product
I
H
N
N
Ph
H
H
H
O
OOC
NHTf
Tf
N
O
III
4.3.1. 1-Benzyl-2-Methyl-4,4-diphenylpyrrolidine (3a). Compound
3a was prepared according to the general procedure and isolated as
a white solid (142 mg, 87%) after column chromatography (petro-
leum ether/ethyl acetate¼20:1); mp¼67e68 ꢀC. 1H NMR (400 MHz,
II
Scheme 2. A tentative reaction mechanism for 2n-catalyzed intramolecular hydro-
amination reaction.
CDCl3)
d
¼7.33e7.05 (m, 15H), 4.00 (d, J¼13.2 Hz, 1H), 3.56 (d,
J¼9.9 Hz, 1H), 3.17 (d, J¼13.3 Hz, 1H), 2.87e2.79 (m, 1H), 2.79e2.65
3. Conclusions
(m, 2H), 2.12 (dd, J¼12.6, 7.7 Hz, 1H), 1.08 (d, J¼5.9 Hz, 3H). 13C NMR
(100 MHz, CDCl3)
126.8,126.4,126.2,125.8,124.8, 65.4, 58.6, 57.0, 51.5, 47.0,18.5. NMR
data were in agreement with reported results.27
d
¼149.6, 147.7, 139.0, 128.2, 127.6, 127.2, 127.1,
In summary, trifluoromethanesulfonamido group can be used as
a useful functional group to increase the catalytic activity of benzoic
acid in intramolecular hydroamination of unfunctionalized olefins
bearing N-electron-rich amino groups. Preliminary DFT calculation
indicated that the introduced trifluoromethanesulfonamido group
acted as an additional hydrogen bond donor to activate the C]C
double bond, and hydrogen bond between carboxyl oxygen and
amino hydrogen brought the amino group close to the reaction
center. In the presence of such catalyst, both 4-penten-1-amine and
5-hexen-1-amine substrates could be cyclized, leading to the cor-
responding 2-methylpyrrolidines and 2-methylpiperidines in good
isolated yields. The current work would shed light on the design of
new organocatalysts for intramolecular hydroamination of
unfunctionalized olefins.
4.3.2. 1-(4-Methylbenzyl)-2-methyl-4,4-diphenylpyrrolidine
(3b). Compound 3b was prepared according to the general pro-
cedure and isolated as a white solid (158 mg, 93%) after column
chromatography
(petroleum
ether/ethyl
acetate¼25:1);
mp¼74e75 ꢀC. 1H NMR (400 MHz, CDCl3)
d¼7.22e6.90 (m, 14H),
3.94 (d, J¼13.1 Hz,1H), 3.54 (d, J¼9.9 Hz, 1H), 3.10 (d, J¼13.1 Hz, 1H),
2.87e2.73 (m, 1H), 2.76e2.59 (m, 2H), 2.23 (s, 3H), 2.09 (dd, J¼12.7,
7.7 Hz, 1H), 1.05 (d, J¼6.0 Hz, 3H). 13C NMR (100 MHz, CDCl3)
d
¼149.6, 147.7, 135.9, 135.2, 127.8, 127.5, 127.1, 126.7, 126.4, 126.2,
124.7, 124.3, 65.3, 58.5, 56.6, 51.4, 47.0, 20.1, 18.5. NMR data were in
agreement with reported results.19
4. Experimental section
4.1. General information
4.3.3. 1-(4-Methoxybenzyl)-2-methyl-4,4-diphenylpyrrolidine
(3c). Compound 3c was prepared according to the general pro-
cedure and isolated as a white solid (160 mg, 90%) after column
chromatography (petroleum ether/ethyl acetate¼20:1); mp¼86 ꢀC.
Reagents were used as received without further purification
unless otherwise specified. Solvents were dried and distilled prior
to use. Reactions were monitored with thin layer chromatography
using silica gel GF254 plates. Solvents were removed in vacuo with
rotavapor. Column chromatography was performed using silica gel
(200e300 meshes). Petroleum ether used had a boiling point range
1H NMR (400 MHz, CDCl3)
d
¼7.27e7.05 (m, 12H), 6.85 (d, J¼8.6 Hz,
2H), 4.01 (d, J¼13.0 Hz, 1H), 3.79 (s, 3H), 3.61 (d, J¼9.8 Hz, 1H), 3.18
(d, J¼13.0 Hz, 1H), 2.90 (dd, J¼12.8, 7.8 Hz, 1H), 2.84e2.76 (m, 1H),
2.74 (d, J¼9.9 Hz, 1H), 2.18 (dd, J¼12.7, 7.8 Hz, 1H), 1.14 (d, J¼6.0 Hz,
3H). 13C NMR (100 MHz, CDCl3)
128.1, 127.8, 127.4, 127.3, 125.8, 125.4, 113.6, 66.3, 59.5, 57.3, 55.2,
d
¼158.5, 150.7, 148.8, 132.1, 129.7,

T.-T. Li et al. / Tetrahedron 71 (2015) 7003e7009
7007
52.5, 48.0, 19.5. NMR data were in agreement with reported
chromatography
(petroleum
ether/ethyl
acetate¼10:1);
results.27
mp¼83e85 ꢀC. 1H NMR (400 MHz, CDCl3)
¼8.51e8.41 (m, 1H),
d
7.55 (td, J¼7.7, 1.7 Hz,1H), 7.36 (d, J¼7.8 Hz, 1H), 7.22e6.93 (m, 12H),
4.08 (d, J¼14.4 Hz, 1H), 3.60 (d, J¼9.9 Hz, 1H), 3.51 (d, J¼14.4 Hz,
1H), 2.94 (d, J¼9.9 Hz, 1H), 2.86e2.73 (m, 1H), 2.20 (dd, J¼12.3,
7.7 Hz, 1H), 1.10 (d, J¼5.8 Hz, 3H). 13C NMR (100 MHz, CDCl3)
4.3.4. 1-(4-Fluorobenzyl)-2-methyl-4,4-diphenylpyrrolidine
(3d). Compound 3d was prepared according to the general pro-
cedure and isolated as a white solid (153 mg, 89%) after column
chromatography (petroleum ether/ethyl acetate¼20:1); mp¼91 ꢀC.
d
¼160.5, 150.3, 148.9, 148.4, 136.4, 128.2, 127.9, 127.2, 125.9, 125.5,
1H NMR (400 MHz, CDCl3)
d
¼7.33e7.12 (m, 12H), 6.98 (t, J¼8.7 Hz,
122.8, 121.8, 66.5, 59.7, 59.7, 52.9, 47.8, 19.5. NMR data were in
agreement with reported results.9b
2H), 4.00 (d, J¼13.2 Hz, 1H), 3.59 (d, J¼9.8 Hz, 1H), 3.21 (d,
J¼13.2 Hz, 1H), 2.90 (dd, J¼12.7, 7.8 Hz, 1H), 2.81 (dd, J¼13.6, 7.5 Hz,
1H), 2.75 (d, J¼9.8 Hz, 1H), 2.20 (dd, J¼12.7, 7.7 Hz, 1H), 1.14 (d,
4. 3.10. 1-Isopropyl-2-methyl-4, 4-diphenylpyrrolidine
(3j). Compound 3j was prepared according to the general pro-
cedure and isolated as an oil (133 mg, 91%) after column chroma-
tography (petroleum ether/ethyl acetate¼5:1); 1H NMR (400 MHz,
J¼6.0 Hz, 3H). 13C NMR (100 MHz, CDCl3)
¼150.5, 148.6, 135.8,
d
135.8, 130.0, 128.1, 127.8, 127.4, 127.2, 125.8, 125.4, 115.0, 66.3, 59.6,
57.2, 52.5, 47.9, 19.5. NMR data were in agreement with reported
results.9d
CDCl3)
d
¼7.61e6.92 (m, 10H), 3.90 (d, J¼9.6 Hz, 1H), 2.92 (dd,
J¼12.8, 7.6 Hz, 1H), 2.84 (d, J¼9.6 Hz, 1H), 2.77e2.65 (m, 1H), 2.48 (t,
J¼11.0 Hz, 1H), 2.26e2.10 (m, 2H), 1.94e1.77 (m, 1H), 1.16 (d,
J¼6.0 Hz, 3H),1.05 (t, J¼10.5 Hz, 3H), 0.99 (d, J¼6.6 Hz, 3H). 13C NMR
4.3.5. 1-(4-Chlorobenzyl)-2-methyl-4,4-diphenylpyrrolidine
(3e). Compound 3e was prepared according to the general pro-
cedure and isolated as a white solid (171 mg, 95%) after column
(100 MHz, CDCl3)
d
¼151.4, 148.9, 128.2, 127.9, 127.7, 127.4, 125.9,
chromatography
(petroleum
ether/ethyl
acetate¼20:1);
125.5, 67.5, 62.7, 60.3, 52.8, 48.1, 27.8, 21.5, 21.0,19.7. NMR data were
mp¼90e91 ꢀC. 1H NMR (400 MHz, CDCl3)
d
¼7.18e6.98 (m, 14H),
in agreement with reported results.9d
3.90 (d, J¼13.4 Hz,1H), 3.50 (d, J¼9.8 Hz,1H), 3.11 (d, J¼13.4 Hz,1H),
2.80 (dd, J¼12.6, 7.8 Hz, 1H), 2.72 (ddd, J¼13.7, 9.7, 3.6 Hz, 1H), 2.66
(d, J¼9.8 Hz, 1H), 2.11 (dd, J¼12.6, 7.6 Hz, 1H), 1.04 (d, J¼5.9 Hz, 3H).
4.3.11. 1-Butyl-2-methyl-4,4-diphenylpyrrolidine (3k). Compound
3k was prepared according to the general procedure and isolated as
an oil (114 mg, 78%) after column chromatography (petroleum
13C NMR (100 MHz, CDCl3)
d
¼150.5, 148.7, 138.8, 132.5, 130.0, 128.4,
128.3, 128.0, 127.5, 127.3, 126.0, 125.6, 66.5, 59.7, 57.4, 52.7, 48.0,
19.6. NMR data were in agreement with reported results.16
ether/ethyl acetate¼40:1); 1H NMR (400 MHz, CDCl3)
¼7.53e6.86
d
(m, 10H), 3.91 (d, J¼9.9 Hz, 1H), 2.90e2.70 (m, 3H), 2.64 (dd, J¼13.9,
7.6 Hz, 1H), 2.21e2.03 (m, 2H), 1.56e1.50 (m, 2H), 1.38e1.34 (m,
2H), 1.09 (d, J¼6.1 Hz, 3H), 0.93 (t, J¼7.3 Hz, 3H). 13C NMR (100 MHz,
4.3.6. 1-(4-Nitrobenzyl)-2-methyl-4,4-diphenylpyrrolidine
(3f). Compound 3f was prepared according to the general pro-
cedure and isolated as a white solid (158 mg, 85%) after column
CDCl3)
d
¼150.8, 148.9, 128.2, 127.9, 127.5, 127.2, 125.8, 125.4, 66.8,
60.4, 53.9, 52.6, 48.0, 31.1, 20.9, 19.4, 14.1. HRMS-ESI (m/z): [MþH]þ
chromatography
(petroleum
ether/ethyl
acetate¼15:1);
calcd for C21H27N, 294.2195; found: 294.2220.
mp¼123e124 ꢀC. 1H NMR (400 MHz, CDCl3)
d¼8.15 (d, J¼8.6 Hz,
2H), 7.50 (d, J¼8.4 Hz, 2H), 7.28e7.10 (m, 10H), 4.10 (d, J¼14.3 Hz,
1H), 3.59 (d, J¼9.7 Hz, 1H), 3.40 (d, J¼14.3 Hz, 1H), 2.95e2.86 (m,
2H), 2.84 (d, J¼9.7 Hz, 1H), 2.27 (q, J¼11.0 Hz, 1H), 1.17 (d, J¼5.5 Hz,
4.3.12. 1-Allyl-2-methyl-4,4-diphenylpyrrolidine (3l). Compound 3l
was prepared according to the general procedure and isolated as
a white solid (130 mg, 94%) after column chromatography (petro-
leum ether/ethyl acetate¼30:1); mp¼62e63 ꢀC. 1H NMR (400 MHz,
3H). 13C NMR (100 MHz, CDCl3)
d
¼150.0, 148.3, 148.2, 147.0, 129.0,
128.2, 127.9, 127.3, 127.0, 126.0, 125.7, 123.5, 66.4, 59.7, 57.3, 52.7,
47.6, 19.5. NMR data were in agreement with reported results.27
CDCl3)
d
¼7.26e6.94 (m, 10H), 5.97e5.75 (m, 1H), 5.19e4.90 (m,
2H), 3.76 (d, J¼10.0 Hz, 1H), 3.56e3.34 (m, 1H), 2.83e2.65 (m, 3H),
2.67e2.56 (m, 1H), 2.09 (dd, J¼12.9, 8.2 Hz, 1H), 1.03 (d, J¼6.1 Hz,
4.3.7. 1-(4-Cyanobenzyl)-2-methyl-4,4-diphenylpyrrolidine
(3g). Compound 3g was prepared according to the general pro-
cedure and isolated as a white solid (158 mg, 90%) after column
3H). 13C NMR (100 MHz, CDCl3)
d
¼149.5, 147.8, 135.5, 127.1, 126.9,
126.4, 126.1, 124.8, 124.4, 115.5, 65.6, 58.6, 55.9, 51.5, 47.0, 18.3.
HRMS-ESI (m/z): [MþH]þ calcd for C20H24N, 278.1895; found:
278.1907.
chromatography
(petroleum
ether/ethyl
acetate¼40:1);
mp¼102e104 ꢀC. 1H NMR (400 MHz, CDCl3)
d
¼7.54e7.05 (m, 14H),
4.00 (d, J¼14.2 Hz, 1H), 3.50 (d, J¼9.7 Hz, 1H), 3.28 (d, J¼14.2 Hz,
1H), 2.87e2.70 (m, 3H), 2.27e2.08 (m, 1H), 1.08 (d, J¼5.8 Hz, 3H).
4.3.13. 1-Benzyl-2-methyl-5,5-diphenylpiperidine (3m). Compound
3m was prepared according to the general procedure and isolated
as an oil (126 mg, 74%) after column chromatography (petroleum
13C NMR (100 MHz, CDCl3)
d
¼150.0, 148.4, 146.1, 132.1, 129.0, 128.2,
127.9, 127.3, 127.1, 126.0, 125.6, 119.0, 110.6, 66.5, 59.7, 57.6, 52.7,
ether/ethyl acetate¼50:1); 1H NMR (400 MHz, CDCl3)
¼7.40e6.93
d
47.7, 19.5. NMR data were in agreement with reported results.27
(m, 15H), 4.04 (d, J¼13.3 Hz, 1H), 3.35 (d, J¼12.2 Hz, 1H), 3.13 (d,
J¼13.3 Hz, 1H), 2.51e2.37 (m, 3H), 2.23e2.09 (m, 1H), 1.64e1.56
(m, 1H), 1.36 (ddd, J¼24.7, 9.4, 3.2 Hz, 1H), 1.13 (d, J¼6.1 Hz, 3H).
4.3.8. 1-(4-Isopropylbenzyl)-2-methyl-4,4-diphenylpyrrolidine
(3h). Compound 3h was prepared according to the general pro-
cedure and isolated as an oil (166 mg, 90%) after column chroma-
tography (petroleum ether/ethyl acetate¼20:1); 1H NMR
13C NMR (100 MHz, CDCl3)
d¼147.5, 145.7, 138.4, 129.0, 128.5,
127.4, 126.9, 126.6, 126.0, 125.8, 124.6, 124.3, 59.9, 57.9, 55.1, 45.5,
33.2, 29.9, 17.6. NMR data were in agreement with reported
results.28
(400 MHz, CDCl3)
d
¼7.46e6.93 (m, 14H), 4.04 (d, J¼13.3 Hz, 1H),
3.65 (d, J¼9.9 Hz, 1H), 3.21 (d, J¼13.3 Hz, 1H), 2.90e2.85 (m, 2H),
2.81e2.76 (m, 2H), 2.19 (dd, J¼12.5, 7.8 Hz, 1H), 1.24 (dd, J¼6.9,
1.5 Hz, 6H), 1.14 (dd, J¼5.9, 1.4 Hz, 3H). 13C NMR (100 MHz, CDCl3)
4.3.14. 1-(4-Methylbenzyl)-2-methyl-5,5-diphenylpiperidine
(3n). Compound 3n was prepared according to the general pro-
cedure and isolated as an oil (151 mg, 85%) after column chroma-
tography (petroleum ether/ethyl acetate¼40:1); 1H NMR
d
¼149.7, 147.7, 146.2, 136.3, 127.4, 127.0, 126.7, 126.4, 126.2, 125.2,
124.7, 124.3, 65.4, 58.5, 56.6, 51.5, 47.0, 32.7, 23.1, 23.0,18.5. NMR
data were in agreement with reported results.19
(400 MHz, CDCl3)
d
¼7.47e7.15 (m,14H), 4.15 (d, J¼13.2 Hz,1H), 3.50
(d, J¼12.3 Hz, 1H), 3.24 (d, J¼13.2 Hz, 1H), 2.56e2.55 (m, 3H), 2.50
(s, 3H), 2.30 (t, J¼11.8 Hz, 1H), 1.78e1.71 (m, 1H), 1.55e1.43 (m, 1H),
4.3.9. 1-(2-Pyridinyl)methyl-2-methyl-4,4-diphenylpyrrolidine
(3i). Compound 3i was prepared according to the general pro-
cedure and isolated as a white solid (149 mg, 91%) after column
1.27 (dd, J¼6.1, 1.8 Hz, 3H). 13C NMR (100 MHz, CDCl3)
¼147.6,
d
145.7, 135.2, 128.4, 127.7, 127.5, 127.2, 126.9, 126.6, 126.0, 124.6,

7008
T.-T. Li et al. / Tetrahedron 71 (2015) 7003e7009
124.2, 59.8, 57.5, 55.0, 45.5, 33.2, 29.9, 20.1, 17.5. HRMS-ESI (m/z):
[MþH]þ calcd for C26H29N, 256.2395; found: 256.2373.
4.05 (d, J¼13.8 Hz, 1H), 3.13 (d, J¼13.8 Hz, 1H), 2.36 (dd, J¼11.3,
1.8 Hz, 1H), 2.29 (s, 1H), 1.74 (d, J¼11.3 Hz, 1H), 1.66e1.52 (m, 2H),
1.41 (dtd, J¼12.9, 4.3, 2.0 Hz, 1H), 1.27e1.20 (m, 1H), 1.17 (d,
J¼6.2 Hz, 3H), 1.00 (s, 3H), 0.85 (s, 3H). 13C NMR (100 MHz, CDCl3)
4.3.15. 1-(4-Methoxybenzyl)-2-methyl-5,5-diphenylpiperidine
(3o). Compound 3o was prepared according to the general pro-
cedure and isolated as an oil (150 mg, 81%) after column chroma-
tography (petroleum ether/ethyl acetate¼30:1); 1H NMR
d¼140.6, 128.5, 128.0, 126.4, 63.9, 58.3, 56.6, 37.1, 31.6, 30.9, 28.9,
25.2, 18.9. NMR data were in agreement with reported results.29
(400 MHz, CDCl3)
d
¼7.32e7.03 (m, 12H), 6.87 (d, J¼8.5 Hz, 2H), 3.97
4.3.21. 2-Benzyl-3-methyl-2-azaspiro[4.5]decane (3u). Compound
3u was prepared according to the general procedure and isolated as
an oil (94 mg, 78%) after column chromatography (petroleum
(d, J¼13.1 Hz, 1H), 3.79 (s, 3H), 3.33 (d, J¼12.2 Hz, 1H), 3.05 (d,
J¼13.1 Hz, 1H), 2.46e2.39 (m, 2H), 2.37 (d, J¼12.4 Hz, 1H), 2.15 (td,
J¼12.9, 3.5 Hz,1H),1.64e1.53 (m,1H),1.34 (d, J¼12.0 Hz,1H),1.11 (d,
ether/ethyl acetate¼20:1); 1H NMR (400 MHz, CDCl3)
¼7.26 (m,
d
J¼6.1 Hz, 3H). 13C NMR (100 MHz, CDCl3)
d¼157.6, 147.6, 145.8,
5H), 4.01 (d, J¼13.3 Hz, 1H), 3.07 (d, J¼13.3 Hz, 1H), 2.77 (d,
J¼9.3 Hz, 1H), 2.54e2.39 (m, 1H), 1.86 (d, J¼9.4 Hz, 1H), 1.74 (dd,
J¼12.4, 6.9 Hz, 1H), 1.45e1.14 (m, 11H), 1.13 (d, J¼6.0 Hz, 3H). 13C
130.3, 129.5, 127.4, 126.9, 126.6, 126.0, 124.6, 124.2, 112.4, 59.7, 57.1,
55.0, 54.2, 45.5, 33.2, 20.0, 17.3. HRMS-ESI (m/z): [MþH]þ calcd for
C
26H29NO, 372.2295; found: 372.2317.
NMR (100 MHz, CDCl3)
d
¼140.0, 128.6, 128.0, 126.5, 66.7, 59.0, 58.0,
47.0, 39.3, 38.5, 26.1, 23.6, 23.5, 19.3. NMR data were in agreement
4.3.16. 1-(4-Fluorobenzyl)-2-methyl-5,5-diphenylpiperidine
(3p). Compound 3p was prepared according to the general pro-
cedure and isolated as a white solid (140 mg, 78%) after column
with reported results.27
4 . 3 . 2 2 . 2 - B e n z yl - 3 - m e t hyl - 2 - a z a s p i r o [ 5 . 5 ] u n d e c a n e
(3v). Compound 3v was prepared according to the general pro-
cedure and isolated as an oil (79 mg, 62%) after column chroma-
tography (petroleum ether/ethyl acetate¼40:1); 1H NMR
chromatography
(petroleum
ether/ethyl
acetate¼40:1);
mp¼90e92 ꢀC. 1H NMR (400 MHz, CDCl3)
d¼7.33e6.82 (m, 14H),
3.90 (d, J¼13.2 Hz, 1H), 3.23 (d, J¼12.2 Hz, 1H), 2.99 (d, J¼12.8 Hz,
1H), 2.42e2.22 (m, 3H), 2.07 (t, J¼12.3 Hz, 1H), 1.59e1.47 (m, 1H),
1.34e1.20 (m, 1H), 1.07e0.96 (m, 3H). 13C NMR (100 MHz, CDCl3)
(400 MHz, CDCl3)
d
¼7.45e6.75 (m, 7H), 3.93 (d, J¼13.8 Hz,1H), 2.98
(d, J¼13.8 Hz, 1H), 2.45 (d, J¼11.6 Hz, 1H), 2.18 (s, 1H), 1.55 (d,
d
¼148.5, 146.7, 135.2, 130.8, 128.4, 128.1, 127.7, 127.1, 125.8, 125.4,
J¼11.5 Hz, 1H), 1.48e1.10 (m, 14H), 1.05 (d, J¼6.2 Hz, 3H). 13C NMR
115.0, 114.8. 60.9, 58.1, 56.2, 46.6, 34.3, 31.1, 18.7. HRMS-ESI (m/z):
[MþH]þ calcd for C25H26FN, 360.2095; found: 360.2121.
(100 MHz, CDCl3)
d
¼139.7, 127.5, 126.9, 125.4, 60.7, 57.2, 56.2, 36.9,
33.6, 32.1, 29.8, 25.9, 20.6, 17.9. NMR data were in agreement with
reported results.27
4.3.17. 1-(4-Chlorobenzyl)-2-methyl-5,5-diphenylpiperidine
(3q). Compound 3q was prepared according to the general pro-
cedure and isolated as an oil (150 mg, 80%) after column chroma-
tography (petroleum ether: ethyl acetate¼50:1); 1H NMR
Acknowledgements
We acknowledge the financial support from National Natural
Science Foundation of China (NSFC 20972072, NSFC 21272121).
(400 MHz, CDCl3)
d¼7.21e6.93 (m, 14H), 3.90 (d, J¼13.5 Hz, 1H),
3.23 (d, J¼12.3 Hz, 1H), 3.02 (d, J¼13.5 Hz, 1H), 2.42e2.30 (m, 3H),
2.12e2.00 (m, 1H), 1.61e1.49 (m, 1H), 1.29 (d, J¼12.0 Hz, 1H), 1.29 (d,
J¼12.0 Hz, 3H). 13C NMR (100 MHz, CDCl3)
¼147.4, 145.5, 137.0,
d
Supplementary data
131.5, 129.7, 127.3, 127.1, 127.0, 126.7, 126.0, 124.7, 124.4, 60.0, 57.2,
55.2, 45.5, 33.1, 29.9, 17.6. HRMS-ESI (m/z): [MþH]þ calcd for
Preparation of catalysts, general procedure for the operation,
DFT calculation results for the transition state, and copies of NMR
spectra of the products. Supplementary data associated with this
article can be found in the online version, at http://dx.doi.org/
10.1016/j.tet.2015.07.003.
C
25H26ClN, 376.1795; found: 376.1824.
4.3.18. 1-(4-Nitrobenzyl)-2-methyl-5,5-diphenylpiperidine
(3r). Compound 3r was prepared according to the general pro-
cedure and isolated as an oil (139 mg, 72%) after column chroma-
tography (petroleum ether/ethyl acetate¼30:1); 1H NMR
References and notes
(400 MHz, CDCl3)
d
¼8.11 (d, J¼8.7 Hz, 2H), 7.42 (d, J¼8.6 Hz, 2H),
7.25e6.78 (m, 10H), 4.00 (d, J¼14.3 Hz, 1H), 3.23 (dd, J¼20.0, 8.1 Hz,
2H), 2.50e2.37 (m, 3H), 2.16e2.04 (m, 1H), 1.64e1.53 (m, 1H),
1.41e1.29 (m, 1H), 1.03 (d, J¼6.1 Hz, 3H). 13C NMR (100 MHz, CDCl3)
1. (a) DeSimone, R. W.; C, K. S.; Mitchell, S. A.; Darrow, J. W.; Pippin, D. A. Comb.
Chem. High Throughput Screen. 2004, 7, 473; (b) Costantino, L.; Barlocco, D. Curr.
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d
¼147.1, 146.8, 146.1, 145.3, 128.8, 127.2, 127.1, 126.8, 125.8, 124.8,
124.6, 122.3, 60.7, 57.5, 55.5, 45.6, 33.1, 29.9, 17.5. HRMS-ESI (m/z):
[MþH]þ calcd for C25H26N2O2, 387.2095; found: 387.2070.
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acetate¼30:1); 1H NMR (400 MHz, CDCl3)
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d
5. Hong, S.; Marks, T. J. Acc. Chem. Res. 2004, 37, 673.
(d, J¼13.2 Hz, 1H), 2.64 (d, J¼9.1 Hz, 1H), 2.61e2.50 (m, 1H), 1.94 (d,
J¼9.1 Hz,1H),1.72 (dd, J¼12.4, 7.3 Hz,1H),1.31 (dd, J¼12.3, 9.0 Hz,1H),
1.14 (d, J¼6.0 Hz, 3H), 1.07 (s, 3H), 0.97 (s, 3H). 13C NMR (100 MHz,
6. (a) Beller, M.; Breindl, C. Tetrahedron 1998, 54, 6359; (b) Crimmin, M. R.; Casely,
I. J.; Hill, M. S. J. Am. Chem. Soc. 2005, 127, 2042; (c) Zhang, X.; Emge, T. J.;
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CDCl3)
d
¼140.1, 128.7, 128.1, 126.6, 68.4, 59.8, 58.1, 49.1, 35.4, 30.7,
29.3, 19.5. NMR data were in agreement with reported results.27
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Angew. Chem., Int. Ed. 2007, 46, 3410; (c) Shen, X.; Buchwald, S. L. Angew. Chem.,
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4.3.20. 1-Benzyl-2,5,5-trimethylpiperidine (3t). Compound 3t was
prepared according to the general procedure and isolated as an oil
(21 mg, 20%) after column chromatography (petroleum ether/ethyl
acetate¼40:1); 1H NMR (400 MHz, CDCl3)
¼7.47e7.18 (m, 5H),
d

T.-T. Li et al. / Tetrahedron 71 (2015) 7003e7009
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