Trifluoroacetic acid-promoted intramolecular hydroamination of unfunctionalized olefins bearing electron-rich amino groups

Article abstract of DOI:10.1016/j.tet.2014.06.061

Trifluoroacetic acid was found to be effective in intramolecular hydroamination of unfunctionalized olefins bearing electron-rich amino groups, and the corresponding N-heterocycles were obtained in good isolated yields. The scope of the substrates was inv

Full text of DOI:10.1016/j.tet.2014.06.061

Tetrahedron 70 (2014) 5696e5703
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Trifluoroacetic acid-promoted intramolecular hydroamination of
unfunctionalized olefins bearing electron-rich amino groups
*
Gong-Qing Liu, Bin Cui, Hui Sun, Yue-Ming Li
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:
Received 16 April 2014
Received in revised form 10 June 2014
Accepted 17 June 2014
Available online 21 June 2014
Trifluoroacetic acid was found to be effective in intramolecular hydroamination of unfunctionalized
olefins bearing electron-rich amino groups, and the corresponding N-heterocycles were obtained in good
isolated yields. The scope of the substrates was investigated, and a possible reaction mechanism was
proposed. Substituents on C]C double bonds and amino groups of the substrates showed drastic effects
on the course of the reactions.
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
Hydroamination
4-Penten-1-amine
5-Hexen-1-amine
Trifluoroacetic acid
2-Methylpyrrolidine
2-Methylpiperidine
1. Introduction
Nitrogen-containing organic compounds constitute the most
important part of privileged structures and have played vital roles
in medicinal chemistry.1 To this end, continuous efforts have been
devoted towards the formation of CeN bonds and the construction
of nitrogen-containing heterocyclic skeletons.2 For example,
electrophile-induced cyclization of N-protected pent-4-en-1-
amines or pent-4-en-1-imines with bromine3 or PhSeBr4 pro-
Scheme 1. Schematic presentation of hydroamination of unactivated olefins.
amine nitrogen and the electron-rich C]C double bond, although
the direct addition of amines to alkenes is thermodynamically
3
feasible (DG z 14.7 kJ/mol for the addition of ammonia to ethyl-
duced the bromo- or functionalized heterocycles, and LiAlH4 or
ene).8 Moreover, the negative reaction entropy feature impedes the
use of elevated temperatures to overcome the activation barrier.
Therefore, a catalyst was generally required to promote the
hydroamination of unfunctionalized olefins.
tributylstannane5 reduction of these compounds gave 2-
methylpyrrolidines in good yields. In such a way, a variety of
substituted pyrrolidines and piperidines could be obtained via ring
expansion of substituted aziridines6 or azetidines.7
Over the past decades, huge efforts have been made towards
transition metal-catalyzed hydroamination and a variety of effi-
cient catalysts have been developed as a result.9 These catalysts
include organolanthanides and related compounds,9f,g group IV
compounds,9e,10 noble metal compounds from palladium,11 plati-
num,12 silver,13 gold,14 rhodium,15 iridium,16 and ruthenium17 as
well as some first row transition metal compounds.18
In contrast, Brønsted acid-promoted hydroamination of
unfunctionalized olefins bearing electron-rich amino groups is still
at the primitive stage mainly due to the buffering effect of the
amino group.11b,19 For Brønsted acid-mediated hydroamination, it
is essential to form a carbenium ion intermediate via protonation of
In addition to these traditional methods, hydroamination, direct
addition of an NeH bond to unsaturated carbonecarbon bonds
(Scheme 1), has been proved to be a waste-free and highly atom-
economical method for the construction of CeN bonds and
nitrogen-containing heterocycles.
In the absence of a catalyst, hydroamination of unfunctionalized
olefins is generally difficult to occur due to a high activation barrier
caused by electrostatic repulsion between the lone pair of the
* 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.2014.06.061
0040-4020/Ó 2014 Elsevier Ltd. All rights reserved.

G.-Q. Liu et al. / Tetrahedron 70 (2014) 5696e5703
5697
C]C double bond, and the hydroamination product will be pro-
duced by trapping the thus formed carbenium ion with nucleo-
philic amines. However, in the presence of more basic amino
groups, amines would be much easy to get protonated, and alkenes
are usually not protonated to give the carbenium ion intermediate.
Protonation of amines would in turn decrease the nucleophilicity of
the amino groups, rendering the reaction difficult to take place.
In order to achieve sufficient degree of alkene protonation, less
basic amino groups, such as arylamine19,20 or sulfonamides21 have
frequently been used for Brønsted acid-catalyzed hydroamination
of alkenes. The rate determining step for these reactions was the
formation of a carbenium ion via proton transfer to the C]C double
bond. Trapping of the carbenium ion with sulfonamide nitrogen
furnished the hydroamination product. Successful examples for
hydroamination of unfunctionalized olefins bearing electron rich
nitrogen sources were very rare. Ackermann et al. showed that in
the presence of 10e20 mol % of BINOL-derived phosphoric acids,
intramolecular hydroamination of several N-alkyl-pent-4-en-1-
acid as well as free amino group in the reaction system, while the
use of a strong Brønsted acid would force the equilibrium towards
the deprotonated acids and the ammonium.
Based on our understanding of Lewis and Brønsted acid-
catalyzed hydroamination of electron-rich amine substrates, we
assumed that hydroamination of N-electron rich aminoalkenes
should be possible using mono-functional Brønsted acid as catalyst.
To test this assumption, N-benzyl-2,2-diphenylpent-4-en-1-amine
(1a) was subjected to intramolecular hydroamination in the pres-
ence of different inexpensive and easily available Brønsted acids.
Compound 1a was chosen as model substrate due to its ease of
preparation and its UV absorption property, which made it easy to
monitor the reaction.24 Further, substrates bearing 2,2-geminal
substituents would be cyclized more easily as a result of Thorpe-
eIngold effect.26 Xylene was first chosen as the reaction medium
based on previous studies, and the results were summarized in
Table 1.
amine
substrates
produced
the
corresponding
2-
methylpyrrolidine products in good yields after 20e24 h of re-
action at 130 ꢀC. Some extent of enantioselectivity was also ob-
served when optically pure chiral phosphoric acid was used as the
catalyst.22 The same group also showed that intramolecular
hydroamination could be realized using amine salts as acid surro-
gates.23 Toste et al. showed that 3,3’-disubstituted BINOL-derived
dithiophosphoric acid was effective for intramolecular asymmet-
ric hydroamination of both 1,2- and 1,3-dienes bearing sulfonami-
des.21a The successfulness of this work relied on the high reactivity
of the sulfur-containing organocatalyst as well as the high re-
activity of both allene and 1,3-diene substrates. These current re-
sults indicate that it is essential to fully understand the effects of
acidity of the organocatalysts on the course of the organocatalytic
hydroamination reactions. In this paper, we wish to report our re-
cent results on CF3COOH-catalyzed intramolecular hydroamination
of N-electron-rich unfunctionalized olefins.
Table 1
Hydroamination of 1a using different acidsa
Entry
Acid
1a:2ab
1
2
3
4
5
6
7
8
None
TsOH
CSA
TfOH
CH3SO3H
TFA
AcOH
Citric acid
Fumaric acid
100
93
89
61
54
<1
86
68
0
7
11
39
46
>99
14
32
9
88
12
10
11
12
13
14
15
16
17
L
-Tartaric acid
73
>95
82
71
>95
76
27
<5
18
29
<5
24
2. Results and discussion
Formic acid
Malonic acid
Oxalic acid
HCl
H2SO4
HNO3
Recently we have shown that zinc salts were able to promote
intermolecular and intramolecular hydroamination of N-electron-
rich unfunctionalized olefins, and ZnI2 was found to be more suit-
able than ZnBr2, ZnCl2 or Zn(OTf)2 in intramolecular hydro-
amination reaction.24 These preliminary results indicated that in
order for a meaningful hydroamination to take place, the catalyst
should bear balanced Lewis acidity, i.e., the Lewis acidity of the
catalyst should be strong enough so that it could efficiently activate
the substrate C]C double bond, but would not over-coordinate
with amino group to diminish the nucleophilicity of the latter. It
was believed that during ZnI2-catalyzed hydroamination reactions,
the C]C double bond was activated upon zinc coordination, and
intramolecular hydroamination was made possible as a result of
nucleophilic attack of amino groups on the activated C]C double
bond.
Studies also indicated that in addition to zinc halides, such as
zinc iodide, the corresponding hydrogen halides were also able to
promote the hydroamination of electron-rich amine substrates al-
though in a less effective manner. Encouraged by these preliminary
results, we carried out a thorough study on Brønsted acid-catalyzed
intramolecular hydroamination of N-electron-rich unfunctional-
ized olefins, and found that 3-hydroxy-2-naphthoic acid was also
able to promote the intramolecular hydroamination of N-benzyl 4-
penten-1-amines and 5-hexen-1-amines.25
>95
68
<5
32
H3PO4
The bold signifies the best result in entry 6.
a
The reactions were carried out with 0.5 mmol of 1a, 2 mL of xylene, and
0.1 mmol (20 mol %) of acids. Sealed tube was used in the reaction to avoid the
evaporation of solvents. Care must be taken when opening the sealed tube.
b
Based on 1H NMR analysis of the reaction mixtures.
As shown in Table 1, no desired product was observed in the
absence of acid (Table 1, entry 1), indicating the important role
played by Brønsted acid. Sulfonic acids could promote the reaction
but gave product below moderate yields (Table 1, entries 2e5).
Complete conversion of 1a was observed when trifluoroacetic acid
was employed (Table 1, entry 6). However, treatment of 1a with
AcOH gave a rather low yield of 14% (Table 1, entry 7), indicating
that the Brønsted acid must have enough acidity to promote the
reaction. This observation was in good agreement with previous
reactions catalyzed by Lewis acids in such a way that the catalyst
should bear balanced Lewis acidity to ensure the activation of C]C
double bond in one aspect, and to maintain the reactivity of amino
groups on the other. Other common organic acids were also in-
vestigated, but failed to give satisfactory yields (Table 1, entries
8e13). Inorganic acids generally gave poor results, possibly due to
the presence of large amount of water, and the strong Brønsted acid
nature of these compounds (Table 1, entries 14e17). These pre-
Study showed that the acidity of the catalyst was very crucial for
successful intramolecular hydroamination of 4-penten-1-amines
and 5-hexen-1-amines bearing electron-rich amino groups. The
use of a weak Brønsted acid allows the preservation of some free
liminary results indicated that in order for
a meaningful

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G.-Q. Liu et al. / Tetrahedron 70 (2014) 5696e5703
Table 3
hydroamination to occur, the acid catalyst should have balanced
acidity, and preferably without the involvement of water. It was
noteworthy that 24% of 2a could be obtained when concd H2SO4
was used as catalyst, which was in disagreement with the obser-
vations made by Hartwig that the intramolecular addition of
amines without an electron-withdrawing group did not occur
when concentrated sulfuric acid was used.21c This may be attrib-
uted to the use of different substrates. While substrate without
geminal-dialkyl groups was used in Hartwig’s study, Thorpe-
eIngold substrate 1a was used in the current study. Cyclization of
the latter was easier than the former due to the ThorpeeIngold
effect. Other strong inorganic acids gave conversions less than
sulfuric acid, possibly due to the large amount of water presented in
these acids.
After the finding of a suitable acid for hydroamination reaction,
the effects of temperature and catalyst loading on the course of the
reaction were studied and the results were summarized in Table 2.
As these results indicated, reducing the reaction time led to poor
conversions (Table 2, entry 1 vs entry 2). Lowering the amount of
catalyst to 10 mol % led to the drop of conversion (Table 2, entry 3),
but this could be overcome by elongating the reaction time to 36 h
(Table 2, entry 4). Temperature also showed drastic effect on the
course of the reaction, and only half of the substrate was converted
when the reaction was carried out at 110 ꢀC (Table 2, entry 5).
In order to find a more suitable reaction condition, the reaction
carried out in different solvents was examined and the results were
listed in Table 3. As these results indicated, high boiling point sol-
vents were superior to low boiling point ones (entries 8e11
vs entries 1e7), and toluene or 1,4-dioxane was more suitable for
the reaction. 1,4-Dioxane was finally chosen as the solvent for fur-
ther study due to its good performance as well as its relatively low
toxicity and its ease of removal. Some strong acids were checked in
this solvent and showed no improvements (entries 14e17).27 Re-
action in xylene was not further pursued due to the issue of solvent
removal.
Hydroamination of 1a in different solventsa
Entry
Solvent
T (ꢀC)
1a:2ab
1
2
3
4
5
6
7
8
THF
CH3CN
DCE
Hexane
Acetone
MeOH
Benzene
Toluene
1,4-Dioxane
DMF
80
80
80
80
80
89
91
92
>95
>95
>95
87
53
50
73
70
26
4
90
93
91
93
11
9
8
<5
<5
<5
13
47
50
27
30
74
96
10
7
80
80
110
110
110
110
110
110
110
110
110
110
9
10
11
12c
13c
14d
15e
16f
17g
NMP
Toluene
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
9
7
The bold signifies the best result in entry 13.
a
The reactions were carried out with 0.5 mmol of 1a, 2 mL of solvent, and
0.05 mmol (10 mol %) of TFA. Sealed tube was used in the reaction to avoid the
evaporation of solvents. Care must be taken when opening the sealed tube.
b
Based on 1H NMR analysis of the reaction mixtures.
c
Reaction time¼48 h.
d
10 mol % of TfOH was used.
e
10 mol % of CH3SO3H was used.
10 mol % of citric acid was used.
10 mol % of H3PO4 was used.
f
g
aromatic rings were tolerated, and the electronic effect of the
benzylamines had little impact on the course of the reaction (Table
4, entries 1e10). Alkyl substituents, such as isopropyl, isobutyl at
the nitrogen atom also showed little effect on the course of the
reaction (Table 4, entries 11 and 12). Furthermore, the heteroatom-
containing substrates also underwent the cyclization efficiently
under the optimal conditions (Table 4, entries 13 and 14). Thor-
peeIngold effect28 was observed in the reaction, and changing the
gem-diphenyl groups to other small gem-dialkyl groups on the
main chain resulted in a drop of yields (Table 4, entries 1e14
vs entries 15e17). Linear aminoalkene lacking of gem-substituents
(1r) failed to react possibly due to lack of ThorpeeIngold effect
(Table 4, entry 18). 5-Hexen-1-amines generally gave poor results
possibly due to the unfavorable entropy feature of the reaction
(Table 4, entries 19 and 20).29
Based on the above observations and previous literature
reports,21c,30 a tentative reaction mechanism was proposed in
Scheme 2. Firstly, amino group is protonated by TFA (step 1), and
high temperature is needed to generate the free amine and the acid.
The second step is the rate limiting step in which the proton is
transferred to C]C double bond to give a carbenium ion (step 2).21c
The thus formed carbenium ion is trapped by amino group, leading
to the formation of hydroamination product (step 3). This mecha-
nism indicates that in the proton transfer step, the amino group
should be brought close to C]C double bond in space.31 Therefore,
dialkyl substitution at main chain is essential, and this also ac-
counts for the fact that substrates bearing small substituents (Table
4, entries 16 and 17) or lacking of substituents on the main chain
(entry 18) show poor reactivity.
Table 2
Hydroamination of 1a under different conditionsa
Entry
TFA (mol %)
Temp/time
1a:2ab
1
2
3
4
5
20
20
10
10
10
130 ꢀC, 24 h
130 ꢀC, 12 h
130 ꢀC, 24 h
130 ꢀC, 36 h
110 ꢀC, 48 h
<1
39
24
<1
48
>99
61
76
>99
52
a
The reactions were carried out with 0.5 mmol of 1a and 2 mL of xylene. Sealed
tube was used in the reaction to avoid the evaporation of solvents. Care must be
taken when opening the sealed tube.
b
Based on 1H NMR analysis of the reaction mixtures.
With the optimized reaction conditions in hand, the scope of the
substrates was studied by varying the substituents on both nitro-
gen atom and the main chain, and the results were presented in
Table 4.
As shown in Table 4, intramolecular hydroamination of N-elec-
tron-rich olefins proceeded readily, giving the corresponding pyr-
rolidine products in good to excellent isolated yields. Substrates
bearing different N-substituents did not significantly influence the
reaction outcomes (Table 4, entries 1e14). Notably, methyl, iso-
propyl, methoxy, fluoro, chloro, bromo, nitro, cyano or ester on the
To further test the influence of steric effect of the reaction, di-
and trisubstituted aminoalkenes 1u and 1v were synthesized and
subjected to hydroamination reaction under the standard condi-
tions. As can be predicted, only trace amount of cyclization

G.-Q. Liu et al. / Tetrahedron 70 (2014) 5696e5703
5699
Table 4
Intramolecular hydroamination of unactivated alkenesa
R1
R1
R1 R1
( )n
H
N
10 mol % TFA
R2 110 °C, 48 h
dioxane
CH3
( )n
1a - 1t
N
R2
2a - 2t
n = 1, 2
Entry
1
Substrates
Product
Isolated yield
R¼H (1a)
R¼H (2a)
93%
2
3
4
5
6
7
8
9
R¼Me (1b)
R¼OMe (1c)
R¼i-Pr (1d)
R¼F (1e)
R¼Me (2b)
R¼OMe (2c)
R¼i-Pr (2d)
R¼F (2e)
93%
94%
90%
90%
88%
83%
86%
86%
90%
R¼Cl (1f)
R¼Cl (2f)
R¼Br (1g)
R¼Br (2g)
R¼NO2 (1h)
R¼CN (1i)
R¼CO2Me (1j)
R¼NO2 (2h)
R¼CN (2i)
R¼CO2Me (2j)
10
11
12
13
14
R¼i-Pr (1k)
R¼i-Pr (2k)
82%
88%
87%
80%
R¼i-Bu (1l)
R¼i-Bu (2l)
2-Furanyl (1m)
2-Pyridyl (1n)
2-Furanyl (2m)
2-Pyridyl (2n)
15
16
(1o)
(1p)
(2o)
(2p)
65%
46%
17
18
19
(1q)
(1r)
(1s)
(2q)
(2r)
(2s)
16%
No reaction
43%
20
(1t)
(2t)
36%
a
The reactions were carried out with 0.5 mmol of substrate, 2 mL of dioxane, and 0.05 mmol (10 mol %) of TFA. Sealed tube was used in the reaction to avoid the evaporation
of solvents. Care must be taken when opening the sealed tube.

5700
G.-Q. Liu et al. / Tetrahedron 70 (2014) 5696e5703
(HRMS) analyses were carried out on IonSpec 7.0T FTICR HR-ESI-
MS.
4.2. General procedure for TFA-catalyzed intramolecular
hydroamination
A sealed tube was charged with dry 1,4-dixoane (2 mL), ami-
noalkene (0.5 mmol), and trifluoroacetic acid (0.05 mmol,
10 mol %). The tube was then sealed and was heated in an oil bath
(110 ꢀC). The reaction mixture was stirred at this temperature for
48 h and was cooled to room temperature. The sealed tube was
opened with care, and 30 mL of CH2Cl2 was added. The mixture was
washed with aqueous Na2CO3, dried (MgSO4), and concentrated to
give an oil, which was purified by flash column chromatography to
give the corresponding products.
Scheme 2. Proposed reaction mechanism.
products were detected for both substrates. This may be attributed
to the steric hindrance of these substrates, which pushed the amino
groups away from the reaction center, and rendering the reactions
difficult to proceed.
4.2.1. 1-Benzyl-2-methyl-4,4-diphenylpyrrolidine (2a). Compound
2a was purified by flash chromatography on silica gel (petroleum
ether/ethyl acetate¼20:1) in 93% yield as
a
white solid.
Mp 67e68 ꢀC. 1H NMR (400 MHz, CDCl3)
d
¼7.45e6.93 (m, 15H),
3.99 (d, J¼13.2 Hz,1H), 3.55 (d, J¼9.9 Hz,1H), 3.14 (d, J¼13.2 Hz,1H),
2.82 (dd, J¼12.7, 7.7 Hz, 1H), 2.77e2.72 (m, 1H), 2.68 (d, J¼9.9 Hz,
1H), 2.11 (dd, J¼12.7, 7.7 Hz, 1H), 1.07 (d, J¼6.0 Hz, 3H). 13C NMR
(100 MHz, CDCl3)
d¼149.57, 147.64, 139.01, 127.52, 127.14, 127.07,
126.75, 126.36, 126.17, 125.71, 124.73, 124.33, 65.38, 58.59, 56.94,
51.44, 46.93, 18.46. 1H NMR and 13C NMR data agreed with those
reported previously.32
4.2.2. 2-Methyl-1-(4-methylbenzyl)-4,4-diphenylpyrrolidine
(2b). Compound 2b was purified by flash chromatography on silica
gel (petroleum ether/ethyl acetate¼25:1) in a 93% yield as a white
3. Conclusions
solid. Mp 74e75 ꢀC. 1H NMR (400 MHz, CDCl3)
d¼7.41e7.01 (m,
14H), 4.08 (d, J¼13.1 Hz, 1H), 3.65 (d, J¼9.9 Hz, 1H), 3.23 (d,
J¼13.1 Hz, 1H), 2.94 (dd, J¼12.8, 7.7 Hz, 1H), 2.87e2.82 (m, 1H), 2.78
(d, J¼9.9 Hz, 1H), 2.37 (s, 3H), 2.22 (dd, J¼12.8, 7.7 Hz, 1H), 1.19 (d,
In summary, the acidity of a Brønsted acid was essential for
promoting the intramolecular hydroamination of unfunctionalized
olefins bearing electron rich nitrogen sources. Trifluoroacetic acid
showed the highest activity among commonly available inorganic
and organic acids tested. In the presence of 10 mol % trifluoroacetic
acid, N-alkyl-pent-4-en-1-amines were converted to the corre-
sponding 2-methylpyrrolidines in good isolated yields. Thorpe-
eIngold effect was observed during the reaction. The amino group
and the C]C double must close to each other in order for a mean-
ingful hydroamination to take place. The current work would shed
light on the understanding of Brønsted acid-catalyzed intra-
molecular cyclization of unfunctionalized olefins.
J¼6.0 Hz, 3H). 13C NMR (100 MHz, CDCl3)
¼150.82, 148.89, 137.07,
d
136.38, 129.03, 128.67, 128.25, 127.94, 127.57, 127.39, 125.90, 125.50,
66.51, 59.73, 57.82, 52.60, 48.15, 21.27, 19.65. HRMSeESI (m/z):
[MþH]þ calcd for C25H27N, 342.2216; found: 342.2221.
4.2.3. 1-(4-Methoxybenzyl)-2-methyl-4,4-diphenylpyrrolidine
(2c). Compound 2c was purified by flash chromatography on silica
gel (petroleum ether/ethyl acetate¼20:1) in 94% yield as a white
solid. Mp 86 ꢀC. 1H NMR (400 MHz, CDCl3)
d
¼7.36e7.10 (m, 12H),
6.91 (d, J¼8.5 Hz, 2H), 4.07 (d, J¼13.0 Hz, 1H), 3.85 (s, 3H), 3.67 (d,
J¼9.9 Hz, 1H), 3.23 (d, J¼13.0 Hz, 1H), 2.96 (dd, J¼12.8, 7.8 Hz, 1H),
2.90e2.81 (m, 1H), 2.80 (d, J¼9.9 Hz, 1H), 2.24 (dd, J¼12.8, 7.8 Hz,
4. Experimental section
4.1. General information
1H), 1.20 (d, J¼6.0 Hz, 3H). 13C NMR (100 MHz, CDCl3)
¼158.53,
d
150.70, 148.82, 132.11, 129.72, 128.15, 127.84, 127.47, 127.28, 125.80,
125.40, 113.60, 66.35, 59.57, 57.31, 55.29, 52.46, 48.07, 19.54. 1H
NMR and 13C NMR data agreed with those reported previously.32
All starting materials were purchased from commercial sources
and were used as received. All solvents used in the reactions were
dried and distilled from appropriate drying agents prior to use. A
sealed tube was used in the reaction to avoid the evaporation of the
solvent, but this is not a must. Reactions were monitored by thin
layer chromatography using silica gel GF254 plates. Flash column
chromatography was performed using silica gel (200e300 meshes).
Petroleum ether used had a boiling point range of 60e90 ꢀC. 1H and
13C NMR (400 and 100 MHz, respectively) spectra were recorded
with Bruker Avance DRX-400 NMR Spectrometer in CDCl3. 1H NMR
4.2.4. 1-(4-Isopropylbenzyl)-2-methyl-4,4-diphenylpyrrolidine
(2d). Compound 2d was purified by flash chromatography on silica
gel (petroleum ether/ethyl acetate¼20:1) in 90% yield as oil. 1H
NMR (400 MHz, CDCl3)
d
¼7.44e7.16 (m, 14H), 4.19 (d, J¼13.3 Hz,
1H), 3.79 (d, J¼9.9 Hz, 1H), 3.35 (d, J¼13.3 Hz, 1H), 3.09e2.99 (m,
2H), 2.98e2.94 (m, 1H), 2.92 (d, J¼9.7 Hz, 1H), 2.33 (dd, J¼12.6,
7.8 Hz, 1H), 1.39 (d, J¼7.0 Hz, 6H), 1.29 (d, J¼6.0 Hz, 3H). 13C NMR
(100 MHz, CDCl3)
d
¼149.02, 150.86, 148.86, 147.42, 137.44, 128.59,
chemical shifts were reported in parts per million (
d) relative to
128.23, 127.92, 127.59, 127.40, 126.35, 125.89, 125.50, 66.58, 59.68,
57.62, 52.56, 48.16, 34.08, 24.25, 24.20, 19.53. HRMSeESI (m/z):
[MþH]þ calcd for C27H31N, 370.2529; found: 370.2532.
tetramethylsilane (TMS). Data are reported as follows: chemical
shift, multiplicity (s¼singlet, br s¼broad singlet, d¼doublet,
t¼triplet, q¼quartet, m¼multiplet), coupling constants (Hertz) and
integration. 13C NMR chemical shifts are reported in ppm from
tetramethylsilane (TMS). High resolution mass spectrometry
4.2.5. 1-(4-Fluorobenzyl)-2-methyl-4,4-diphenylpyrrolidine
(2e). Compound 2e was purified by flash chromatography on silica

G.-Q. Liu et al. / Tetrahedron 70 (2014) 5696e5703
5701
gel (petroleum ether/ethyl acetate¼20:1) in 90% yield as a white
solid. Mp 91 ꢀC. 1H NMR (400 MHz, CDCl3)
1.08 (d, J¼5.7 Hz, 3H). 13C NMR (100 MHz, CDCl3)
d
¼167.15, 150.37,
d¼7.48e7.01 (m, 14H),
148.57, 145.78, 129.61, 128.78, 128.44, 128.19, 127.89, 127.38, 127.16,
125.88, 125.52, 66.50, 59.77, 57.77, 52.64, 52.02, 47.86, 19.52. 1H
NMR and 13C NMR data agreed with those reported previously.18d
4.06 (d, J¼13.2 Hz, 1H), 3.64 (d, J¼9.8 Hz, 1H), 3.26 (d, J¼13.2 Hz,
1H), 2.96 (dd, J¼12.6, 7.8 Hz, 1H), 2.91e2.83 (m, 1H), 2.80 (d,
J¼9.8 Hz, 1H), 2.25 (dd, J¼12.6, 7.8 Hz, 1H), 1.19 (d, J¼5.9 Hz, 3H). 13
C
NMR (100 MHz, CDCl3)
d
¼161.87 (d, JCeF¼244 Hz), 150.53, 148.67,
4. 2.11. 1-Isopropyl-2-methyl-4, 4-diphenylpyrrolidine
(2k). Compound 2k was purified by flash chromatography on silica
gel (petroleum ether/ethyl acetate¼5:1) in 82% yield as oil. 1H NMR
135.80, 129.99 (d, JCeF¼7.8 Hz), 128.18, 127.87, 127.42, 127.21, 125.67
(d, JCeF¼38.7 Hz), 115.09, 114.88, 66.37, 59.61, 57.21, 52.52, 47.97,
19.53. 19F NMR (376 MHz, CDCl3)
d
¼ꢁ116.39. 1H NMR, 13C NMR and
(400 MHz, CDCl3)
d
¼7.56e6.98 (m, 10H), 3.82 (d, J¼9.6 Hz, 1H),
19F NMR data agreed with those reported previously.32
3.13e3.00 (m, 3H), 2.90 (dd, J¼12.7, 8.0 Hz, 1H), 2.19 (dd, J¼12.7,
7.8 Hz, 1H), 1.23 (d, J¼6.7 Hz, 3H), 1.03 (d, J¼6.2 Hz, 3H), 1.00 (d,
4.2.6. 1-(4-Chlorobenzyl)-2-methyl-4,4-diphenylpyrrolidine
(2f). Compound 2f was purified by flash chromatography on silica
gel (petroleum ether/ethyl acetate¼20:1) in 88% yield as a white
J¼6.4 Hz, 3H). 13C NMR (100 MHz, CDCl3)
¼150.11, 149.02, 128.19,
d
127.92, 127.41, 127.28, 125.78, 125.41, 59.32, 55.39, 52.22, 48.84,
47.20, 22.66, 20.61, 15.64. HRMSeESI (m/z): [MþH]þ calcd for
solid. Mp 91 ꢀC. 1H NMR (400 MHz, CDCl3)
d
¼7.35e6.93 (m, 14H),
C20H25N, 280.2060; found: 280.2064.
3.94 (d, J¼13.4 Hz,1H), 3.51 (d, J¼9.8 Hz,1H), 3.13 (d, J¼13.4 Hz,1H),
2.83 (dd, J¼12.7, 7.8 Hz, 1H), 2.75 (dt, J¼13.5, 6.6 Hz, 1H), 2.67 (d,
4 . 2 .12 . 1 - I s o b u t yl - 2 - m e t hyl - 4 , 4 - d i p h e nyl p y r ro l i d i n e
(2l). Compound 2l was purified by flash chromatography on silica
gel (petroleum ether/ethyl acetate¼30:1) in 88% yield as oil. 1H
J¼9.8 Hz, 1H), 2.13 (dd, J¼12.7, 7.7 Hz, 1H), 1.07 (d, J¼5.9 Hz, 3H). 13
C
NMR (100 MHz, CDCl3)
d
¼149.39, 147.54, 137.63, 131.34, 128.80,
127.29, 127.12, 126.82, 126.33, 126.12, 124.81, 124.44, 65.32, 58.58,
56.21, 51.48, 46.84, 18.46. 1H NMR and 13C NMR data agreed with
those reported previously.33
NMR (400 MHz, CDCl3)
d
¼7.63e6.98 (m, 10H), 3.93 (d, J¼9.6 Hz,
1H), 2.94 (dd, J¼12.8, 7.6 Hz, 1H), 2.87 (d, J¼9.6 Hz, 1H), 2.78e2.67
(m, 1H), 2.54e2.47 (m, 1H), 2.28e2.10 (m, 2H), 1.95e1.83 (m, 1H),
1.18 (d, J¼6.0 Hz, 3H), 1.09 (d, J¼6.6 Hz, 3H), 1.01 (d, J¼6.6 Hz, 3H).
4.2.7. 1-(4-Bromobenzyl)-2-methyl-4,4-diphenylpyrrolidine
(2g). Compound 2g was purified by flash chromatography on silica
gel (petroleum ether/ethyl acetate¼50:1) in 83% yield as a white
13C NMR (100 MHz, CDCl3)
d¼151.38, 148.96, 128.21, 127.88, 127.68,
127.38, 125.88, 125.48, 67.52, 62.72, 60.36, 52.80, 48.15, 27.85, 21.49,
21.00, 19.69. 1H NMR and 13C NMR data agreed with those reported
previously.35
solid. Mp 93e94 ꢀC. 1H NMR (400 MHz, CDCl3)
d¼7.52 (d, J¼8.1 Hz,
2H), 7.35e7.22 (m, 12H), 4.09 (d, J¼13.4 Hz, 1H), 3.69 (d, J¼9.8 Hz,
1H), 3.29 (d, J¼13.4 Hz, 1H), 3.00 (dd, J¼12.6, 7.8 Hz, 1H), 2.95e2.88
(m, 1H), 2.85 (d, J¼9.8 Hz, 1H), 2.31 (dd, J¼12.6, 7.8 Hz, 1H), 1.24 (d,
4.2.13. 1-(Furan-2-ylmethyl)-2-methyl-4,4-diphenylpyrrolidine
(2m). Compound 2m was purified by flash chromatography on
silica gel (petroleum ether/ethyl acetate¼50:1) in 87% yield as oil.
J¼5.9 Hz, 3H). 13C NMR (100 MHz, CDCl3)
¼150.44, 148.60, 139.24,
d
131.39, 130.26, 129.23, 128.19, 127.82, 127.40, 127.18, 125.94, 125.42,
66.39, 59.66, 57.33, 52.57, 47.89, 19.53. 1H NMR and 13C NMR data
agreed with those reported previously.34
1H NMR (400 MHz, CDCl3)
d
¼7.30e7.03 (m, 11H), 6.26 (s, 1H), 6.11
(s, 1H), 3.88 (d, J¼14.3 Hz, 1H), 3.67 (d, J¼9.8 Hz, 1H), 3.43 (d,
J¼14.3 Hz, 1H), 2.93 (d, J¼9.9 Hz, 1H), 2.84e2.65 (m, 2H), 2.12 (dd,
J¼11.4, 7.4 Hz, 1H), 1.07 (d, J¼5.2 Hz, 3H). 13C NMR (100 MHz, CDCl3)
4.2.8. 2-Methyl-1-(4-nitrobenzyl)-4,4-diphenylpyrrolidine
(2h). Compound 2h was purified by flash chromatography on silica
gel (petroleum ether/ethyl acetate¼15:1) in 86% yield as a white
d
¼153.05, 150.35, 148.68, 141.79, 128.18, 127.98, 127.41, 127.18,
125.83, 125.49, 110.11,107.83, 66.13, 58.80, 52.48, 49.29, 47.91, 19.20.
1H NMR and 13C NMR data agreed with those reported
previously.18b
solid. Mp 123e124 ꢀC. 1H NMR (400 MHz, CDCl3)
d
¼8.22 (d,
J¼8.4 Hz, 2H), 7.56 (d, J¼8.4 Hz, 2H), 7.44e7.15 (m, 10H), 4.16 (d,
J¼14.3 Hz, 1H), 3.64 (d, J¼9.7 Hz, 1H), 3.46 (d, J¼14.3 Hz, 1H),
3.01e2.92 (m, 2H), 2.88 (d, J¼9.7 Hz, 1H), 2.33 (dd, J¼12.6, 7.8 Hz,
4.2.14. 2-((2-Methyl-4,4-diphenylpyrrolidin-1-yl)methyl)pyridine
(2n). Compound 2n was purified by flash chromatography on silica
gel (petroleum ether/ethyl acetate¼10:1) in 80% yield as a white
1H), 1.23 (d, J¼5.3 Hz, 3H). 13C NMR (100 MHz, CDCl3)
¼149.02,
d
147.27, 147.21, 145.95, 127.95, 127.19, 126.91, 126.25, 126.00, 125.01,
124.61, 122.49, 65.41, 58.67, 56.27, 51.67, 46.57, 18.45. 1H NMR and
13C NMR data agreed with those reported previously.12b
solid. Mp 83e85 ꢀC. 1H NMR (400 MHz, CDCl3)
d
¼8.46 (d, J¼4.4 Hz,
1H), 7.56 (td, J¼7.7, 1.4 Hz, 1H), 7.37 (d, J¼7.7 Hz, 1H), 7.24e7.01 (m,
11H), 4.09 (d, J¼14.4 Hz, 1H), 3.60 (d, J¼9.9 Hz, 1H), 3.50 (d,
J¼14.4 Hz, 1H), 2.93 (d, J¼9.8 Hz, 1H), 2.83 (ddd, J¼19.7, 12.6, 7.1 Hz,
2H), 2.21 (dd, J¼12.1, 7.6 Hz, 1H), 1.10 (d, J¼5.7 Hz, 3H). 13C NMR
4.2.9. 4-((2-Methyl-4,4-diphenylpyrrolidin-1-yl)methyl)benzonitrile
(2i). Compound 2i was purified by flash chromatography on silica
gel (petroleum ether/ethyl acetate¼40:1) in 86% yield as a white
(100 MHz, CDCl3)
d
¼159.43, 149.38, 147.87, 147.48, 135.37, 127.13,
126.86, 126.41, 126.14, 124.82, 124.48, 121.74, 120.77, 65.51, 58.64,
58.61, 51.83, 46.76, 18.42. 1H NMR and 13C NMR data agreed with
those reported previously.18b
solid. Mp 102e104 ꢀC. 1H NMR (400 MHz, CDCl3)
d
¼7.65 (d,
J¼8.1 Hz, 2H), 7.51 (d, J¼8.1 Hz, 2H), 7.45e7.07 (m, 10H), 4.14 (d,
J¼14.1 Hz, 1H), 3.64 (d, J¼9.7 Hz, 1H), 3.40 (d, J¼14.2 Hz, 1H),
3.06e2.90 (m, 2H), 2.88 (d, J¼9.7 Hz, 1H), 2.32 (dd, J¼11.5, 6.4 Hz,
4.2.15. 2-Benzyl-3-methyl-2-azaspiro[4.5]decane (2o). Compound
2o was purified by flash chromatography on silica gel (petroleum
ether/ethyl acetate¼20:1) in 65% yield as oil. 1H NMR (400 MHz,
1H), 1.22 (d, J¼5.0 Hz, 3H). 13C NMR (100 MHz, CDCl3)
¼150.18,
d
148.40, 146.14, 132.16, 129.07, 128.28, 127.98, 127.36, 127.11, 126.01,
125.68, 119.13, 110.65, 66.50, 59.72, 57.63, 52.75, 47.72, 19.56. 1H
NMR and 13C NMR data agreed with those reported previously.18d
CDCl3)
d
¼7.44e7.25 (m, 5H), 4.09 (d, J¼13.2 Hz, 1H), 3.16 (d,
J¼13.2 Hz, 1H), 2.85 (d, J¼9.3 Hz, 1H), 2.66e2.49 (m, 1H), 1.94 (d,
J¼9.3 Hz, 1H), 1.82 (dd, J¼12.4, 7.0 Hz, 1H), 1.56e1.30 (m, 11H), 1.22
4.2.10. Methyl
4-((2-methyl-4,4-diphenylpyrrolidin-1-yl)methyl)
(d, J¼5.9 Hz, 3H). 13C NMR (100 MHz, CDCl3)
¼140.04, 128.70,
d
benzoate (2j). Compound 2j was purified by flash chromatography
on silica gel (petroleum ether/ethyl acetate¼40:1) in 90% yield as
128.12, 126.56, 66.85, 59.06, 58.12, 47.20, 39.60, 38.70, 26.24, 23.71,
23.54, 19.09. 1H NMR and 13C NMR data agreed with those reported
previously.12b
oil. 1H NMR (400 MHz, CDCl3)
d
¼7.91 (d, J¼8.1 Hz, 2H), 7.35 (d,
J¼8.1 Hz, 2H), 7.27e6.97 (m, 10H), 4.02 (d, J¼13.8 Hz, 1H), 3.83 (s,
3H), 3.52 (d, J¼9.8 Hz,1H), 3.24 (d, J¼13.8 Hz,1H), 2.81 (ddd, J¼26.0,
12.9, 7.4 Hz, 2H), 2.71 (d, J¼9.8 Hz, 1H), 2.15 (dd, J¼12.3, 7.3 Hz, 1H),
4.2.16. 4,4-Diallyl-1-benzyl-2-methylpyrrolidine (2p). Compound
2p was purified by flash chromatography on silica gel (petroleum

5702
G.-Q. Liu et al. / Tetrahedron 70 (2014) 5696e5703
ether/ethyl acetate¼60:1) in 46% yield as oil. 1H NMR (400 MHz,
€
€
9. (a) Muller, T. E.; Beller, M. Chem. Rev. 1998, 98, 675; (b) Muller, T. E.; Pleier, A.-K.
J. Chem. Soc., Dalton Trans. 1999, 583; (c) Seayad, J.; Tillack, A.; Hartung, C. G.;
Beller, M. Adv. Synth. Catal. 2002, 344, 795; (d) Pohlki, F.; Doye, S. Chem. Soc. Rev.
2003, 32, 104; (e) Bytschkov, I.; Doye, S. Eur. J. Org. Chem. 2003, 935; (f) Hong, S.;
Marks, T. J. Acc. Chem. Res. 2004, 37, 673; (g) Hultzsch, K. C. Org. Biomol. Chem.
2005, 3, 1819; (h) Hultzsch, K. C. Adv. Synth. Catal. 2005, 347, 367; (i) Aillaud, I.;
CDCl3)
d¼7.49e7.03 (m, 5H), 5.96e5.44 (m, 2H), 5.17e4.79 (m, 4H),
3.94 (d, J¼13.3 Hz, 1H), 2.99 (d, J¼13.3 Hz, 1H), 2.63 (d, J¼9.5 Hz,
1H), 2.54e2.34 (m, 1H), 2.12e2.07 (m, 2H), 1.98 (d, J¼5.2 Hz, 2H),
1.88 (d, J¼9.5 Hz, 1H), 1.69 (dd, J¼12.7, 7.2 Hz, 1H), 1.29 (dd, J¼12.7,
9.2 Hz, 1H), 1.06 (d, J¼6.0 Hz, 3H). 13C NMR (100 MHz, CDCl3)
€
Collin, J.; Hannedouche, J.; Schulz, E. Dalton Trans. 2007, 5105; (j) Muller, T. E.;
Hultzsch, K. C.; Yus, M.; Foubelo, F.; Tada, M. Chem. Rev. 2008, 108, 3795; (k)
Hannedouche, J.; Schulz, E. Chem.dEur. J. 2013, 19, 4972.
d
¼140.11, 135.80, 135.42, 128.50, 128.06, 126.57, 117.15, 116.99,
10. (a) Lee, A. V.; Schafer, L. L. Eur. J. Inorg. Chem. 2007, 2243; (b) Zi, G. F. J. Orga-
nomet. Chem. 2011, 696, 68.
64.54, 59.42, 57.74, 44.81, 44.45, 43.45, 41.64, 19.21. HRMSeESI (m/
z): [MþH]þ calcd for C18H26N, 256.2065; found: 256.2063.
11. (a) Meguro, M.; Yamamoto, Y. Tetrahedron Lett. 1998, 39, 5421; (b) Kawatsura,
M.; Hartwig, J. F. J. Am. Chem. Soc. 2000, 122, 9546; (c) Nettekoven, U.; Hartwig,
J. F. J. Am. Chem. Soc. 2002, 124, 1166; (d) Johns, A. M.; Utsunomiya, M.; Incarvito,
C. D.; Hartwig, J. F. J. Am. Chem. Soc. 2006, 128, 1828; (e) Michael, F. E.; Cochran,
B. M. J. Am. Chem. Soc. 2006, 128, 4246.
12. (a) Brunet, J. J.; Cadena, M.; Chu, N. C.; Diallo, O.; Jacob, K.; Mothes, E. Organ-
ometallics 2004, 23, 1264; (b) Bender, C. F.; Widenhoefer, R. A. J. Am. Chem. Soc.
2005, 127, 1070; (c) Karshtedt, D.; Bell, A. T.; Tilley, T. D. J. Am. Chem. Soc. 2005,
127, 12640.
4.2.17. 1-Benzyl-2,4,4-trimethylpyrrolidine (2q). Compound 2q was
purified by flash column chromatography on silica gel (petroleum
ether/ethyl acetate¼30:1) in 16% yield as oil. 1H NMR (400 MHz,
CDCl3)
d
¼7.42e7.24 (m, 5H), 4.06 (d, J¼13.2 Hz, 1H), 3.15 (d,
J¼13.2 Hz, 1H), 2.68 (d, J¼9.1 Hz, 1H), 2.65e2.54 (m, 1H), 1.99 (d,
J¼9.1 Hz,1H),1.77 (dd, J¼12.4, 7.3 Hz,1H),1.42e1.30 (m,1H),1.20 (d,
J¼6.0 Hz, 3H), 1.12 (s, 3H), 1.02 (s, 3H).13C NMR (100 MHz, CDCl3)
13. Giner, X.; Najera, C. Synlett 2009, 3211.
14. (a) Bender, C. F.; Widenhoefer, R. A. Chem. Commun. 2006, 4143; (b) Brouwer, C.;
He, C. Angew. Chem., Int. Ed. 2006, 45, 1744; (c) Han, X. Q.; Widenhoefer, R. A.
Angew. Chem., Int. Ed. 2006, 45, 1747.
15. (a) Beller, M.; Trauthwein, H.; Eichberger, M.; Breindl, C.; Herwig, J.; Muller, T.
E.; Thiel, O. R. Chem.dEur. J. 1999, 5, 1306; (b) Utsunomiya, M.; Kuwano, R.;
Kawatsura, M.; Hartwig, J. F. J. Am. Chem. Soc. 2003, 125, 5608; (c) Shen, X. Q.;
Buchwald, S. L. Angew. Chem., Int. Ed. 2010, 49, 564.
16. (a) Dorta, R.; Egli, P.; Zurcher, F.; Togni, A. J. Am. Chem. Soc. 1997, 119, 10857; (b)
Zhou, J. R.; Hartwig, J. F. J. Am. Chem. Soc. 2008, 130, 12220; (c) Hesp, K. D.;
Tobisch, S.; Stradiotto, M. J. Am. Chem. Soc. 2010, 132, 413.
17. (a) Schaffrath, H.; Keim, W. J. Mol. Catal. A Chem. 2001, 168, 9; (b) Utsunomiya,
M.; Hartwig, J. F. J. Am. Chem. Soc. 2004, 126, 2702; (c) Yi, C. S.; Yun, S. Y. Org. Lett.
2005, 7, 2181.
18. (a) Zulys, A.; Dochnahl, M.; Hollmann, D.; Lohnwitz, K.; Herrmann, J. S.; Roesky,
P. W.; Blechert, S. Angew. Chem., Int. Ed. 2005, 44, 7794; (b) Dochnahl, M.;
Pissarek, J. W.; Blechert, S.; Lohnwitz, K.; Roesky, P. W. Chem. Commun. 2006,
3405; (c) Taylor, J. G.; Whittall, N.; Hii, K. K. Org. Lett. 2006, 8, 3561; (d) Ohmiya,
H.; Moriya, T.; Sawamura, M. Org. Lett. 2009, 11, 2145; (e) Zhou, L.; Bohle, D. S.;
Jiang, H. F.; Li, C. J. Synlett 2009, 937; (f) Dochnahl, M.; Lohnwitz, K.; Luhl, A.;
Pissarek, J. W.; Biyikal, M.; Roesky, P. W.; Blechert, S. Organometallics 2010, 29,
2637; (g) Rao, W. D.; Kothandaraman, P.; Koh, C. B.; Chan, P. W. H. Adv. Synth.
Catal. 2010, 352, 2521; (h) Luhl, A.; Nayek, H. P.; Blechert, S.; Roesky, P. W. Chem.
Commun. 2011, 8280; (i) Jenter, J.; Luhl, A.; Roesky, P. W.; Blechert, S. J. Orga-
nomet. Chem. 2011, 696, 406; (j) Mukherjee, A.; Sen, T. K.; Ghorai, P. K.; Samuel,
P. P.; Schulzke, C.; Mandal, S. K. Chem.dEur. J. 2012, 18, 10530; (k) Turnpenny, B.
W.; Hyman, K. L.; Chemler, S. R. Organometallics 2012, 31, 7819.
19. Anderson, L. L.; Arnold, J.; Bergman, R. G. J. Am. Chem. Soc. 2005, 127, 14542.
20. (a) Cherian, A. E.; Domski, G. J.; Rose, J. M.; Lobkovsky, E. B.; Coates, G. W. Org.
Lett. 2005, 7, 5135; (b) Lapis, A. A. M.; DaSilveira Neto, B. A.; Scholten, J. D.;
Nachtigall, F. M.; Eberlin, M. N.; Dupont, J. Tetrahedron Lett. 2006, 47, 6775; (c)
Marcsekova, K.; Doye, S. Synthesis 2007, 145; (d) Yin, Y.; Zhao, G. Chim. Oggi. e
Chem. Today 2007, 25, 42.
21. (a) Shapiro, N. D.; Rauniyar, V.; Hamilton, G. L.; Wu, J.; Toste, F. D. Nature 2011,
470, 245; (b) Haskins, C. M.; Knight, D. W. Chem. Commun. 2002, 2724; (c)
Schlummer, B.; Hartwig, J. F. Org. Lett. 2002, 4, 1471; (d) Motokura, K.; Nakagiri,
N.; Mori, K.; Mizugaki, T.; Ebitani, K.; Jitsukawa, K.; Kaneda, K. Org. Lett. 2006, 8,
4617; (e) Yin, Y.; Zhao, G. Heterocycles 2006, 68, 23; (f) Rosenfeld, D. C.; Shekhar,
S.; Takemiya, A.; Utsunomiya, M.; Hartwig, J. F. Org. Lett. 2006, 8, 4179; (g)
Yadav, J. S.; Reddy, B. V. S.; Raju, A.; Ravindar, K.; Narender, R. Lett. Org. Chem.
2008, 5, 651; (h) Liu, P. N.; Xia, F.; Zhao, Z. L.; Wang, Q. W.; Ren, Y. J. Tetrahedron
Lett. 2011, 52, 6113; (i) Henderson, L.; Knight, D. W.; Williams, A. C. Synlett 2012,
d
¼140.10, 128.72, 128.08, 126.59, 68.41, 59.80, 58.06, 49.14, 35.39,
30.65, 29.28, 19.49. 1H NMR and 13C NMR data agreed with those
reported previously.12b
4.2.18. 1-Benzyl-2-methyl-5,5-diphenylpiperidine (2s). Compound
2s was purified by flash chromatography on silica gel (petroleum
ether/ethyl acetate¼50:1) in 43% yield as an oil. 1H NMR (400 MHz,
CDCl3)
d
¼7.32e6.90 (m, 15H), 3.96 (d, J¼13.3 Hz, 1H), 3.27 (d,
J¼12.3 Hz, 1H), 3.05 (d, J¼13.3 Hz, 1H), 2.35 (dt, J¼21.9, 6.1 Hz, 3H),
2.14e2.03 (m, 1H), 1.59e1.49 (m, 1H), 1.35e1.23 (m, 1H), 1.05 (d,
J¼6.1 Hz, 3H). 13C NMR (100 MHz, CDCl3)
¼148.64, 146.80, 139.51,
d
129.54, 128.52, 128.06, 127.99, 127.67, 127.10, 126.93, 125.70, 125.35,
61.03, 58.97, 56.17, 46.61, 34.30, 31.05, 18.70. 1H NMR and 13C NMR
data agreed with those reported previously.36
4 . 2 .19 . 2 - B e n z yl - 3 - m e t h yl - 2 - a z a s p i r o [ 5 . 5 ] u n d e c a n e
(2t). Compound 2t was purified by flash chromatography on silica
gel (petroleum ether/ethyl acetate¼50:1) in 36% yield as an oil. 1H
NMR (400 MHz, CDCl3)
d
¼7.34e7.27 (m, 4H), 7.23e7.19 (m, 1H),
3.99 (d, J¼14.0 Hz, 1H), 3.05 (d, J¼14.0 Hz, 1H), 2.52 (d, J¼11.6 Hz,
1H), 2.27e2.22 (m, 1H), 1.62 (d, J¼11.2 Hz, 1H), 1.54e1.28 (m, 10H),
1.17e1.03 (m, 7H). 13C NMR (100 MHz, CDCl3)
d
¼140.7, 128.5, 128.0,
126.4, 61.6, 58.3, 57.2, 37.9, 34.8, 33.2, 30.8, 26.9, 21.6, 19.1. 1H NMR
and 13C NMR data agreed with those reported previously.36
Acknowledgements
We acknowledge the financial support from National Natural
Science Foundation of China (NSFC 20972072, NSFC 21272121).
ꢀ
1667; (j) Mathia, F.; Szolcsanyi, P. Org. Biomol. Chem. 2012, 10, 2830.
22. Ackermann, L.; Althammer, A. Synlett 2008, 995.
Supplementary data
23. Ackermann, L.; Kaspar, L. T.; Althammer, A. Org. Biomol. Chem. 2007, 5, 1975.
24. (a) Liu, G.-Q.; Li, Y.-M. Tetrahedron Lett. 2011, 52, 7168; (b) Liu, G.-Q.; Li, W.;
Wang, Y.-M.; Ding, Z.-Y.; Li, Y.-M. Tetrahedron Lett. 2012, 53, 4393.
25. Wang, Y.-M.; Li, T.-T.; Liu, G.-Q.; Zhang, L.; Duan, L.; Li, L.; Li, Y.-M. RSC Adv. 2014,
4, 9517.
26. Beesley, R. M.; Ingold, C. K.; Thorpe, J. F. J. Chem. Soc., Trans. 1915, 107, 1080.
27. We thank the reviewers for their invaluable suggestions.
28. (a) Sammes, P. G.; Weller, D. J. Synthesis 1995, 1205; (b) Kaneti, J.; Kirby, A. J.;
Koedjikov, A. H.; Pojarlieff, I. G. Org. Biomol. Chem. 2004, 2, 1098; (c) Jung, M.
E.; Piizzi, G. Chem. Rev. 2005, 105, 1735; (d) Crimmin, M. R.; Arrowsmith, M.;
Barrett, A. G. M.; Casely, I. J.; Hill, M. S.; Procopiou, P. A. J. Am. Chem. Soc. 2009,
131, 9670; (e) Patil, N. T.; Raut, V. S.; Kavthe, R. D.; Reddy, V. V. N.; Raju, P. V. K.
Tetrahedron Lett. 2009, 50, 6576; (f) Kostal, J.; Jorgensen, W. L. J. Am. Chem.
Soc. 2010, 132, 8766; (g) Duncan, C.; Biradar, A. V.; Asefa, T. ACS Catal. 2011, 1,
736.
Supplementary data include Table 1 with pKa values of the acids
and copies of NMR spectra of the products. Supplementary data
related to this article can be found at http://dx.doi.org/10.1016/
j.tet.2014.06.061.
References and notes
1. (a) DeSimone, R. W.; Curie, 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. Med. Chem. 2006, 13, 65.
2. Trost, B. M.; Fleming, I. Comprehensive Organic Synthesis: Selectivity, Strategy and
Efficiency in Modern Organic Chemistry; Pergamon, 1991.
3. De Kimpe, N.; Boelens, M.; Piqueur, J.; Baele, J. Tetrahedron Lett. 1994, 35, 1925.
4. De Kimpe, N.; Boelens, M. J. Chem. Soc., Chem. Commun. 1993, 916.
5. De Smaele, D.; De Kimpe, N. J. Chem. Soc., Chem. Commun. 1995, 2029.
6. D’Hooghe, M.; Aelterman, W.; De Kimpe, N. Org. Biomol. Chem. 2009, 7, 135.
7. Van Brabandt, W.; Van Landeghem, R.; De Kimpe, N. Org. Lett. 2006, 8, 1105.
8. (a) Steinborn, D.; Taube, R. Z. Chem. 1986, 26, 349; (b) Taube, R. In Applied
Homogeneous Catalysis; Behr, A., Neubert, P., Eds.; 2012; p 507.
29. (a) Denisova, T. G.; Denisov, E. T. Russ. Chem. Bull. 2002, 51, 949; (b) Dzudza, A.;
Marks, T. J. Chem.dEur. J. 2010, 16, 3403.
30. Miura, K.; Hondo, T.; Nakagawa, T.; Takahashi, T.; Hosomi, A. Org. Lett. 2000, 2,
385.
31. (a) MacDonald, M. J.; Schipper, D. J.; Ng, P. J.; Moran, J.; Beauchemin, A. M. J. Am.
Chem. Soc. 2011, 133, 20100; (b) Guimond, N.; MacDonald, M. J.; Lemieux, V.;
Beauchemin, A. M. J. Am. Chem. Soc. 2012, 134, 16571.

G.-Q. Liu et al. / Tetrahedron 70 (2014) 5696e5703
5703
32. Hashmi, A. S. K.; Rudolph, M.; Schymura, S.; Visus, J.; Frey, W. Eur. J. Org. Chem.
2006, 4905.
35. Leitch, D. C.; Payne, P. R.; Dunbar, C. R.; Schafer, L. L. J. Am. Chem. Soc. 2009, 131,
18246.
33. Hesp, K. D.; Stradiotto, M. Org. Lett. 2009, 11, 1449.
34. 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, 1175.
36. Zhang, R.; Xu, Q.; Mei, L.-Y.; Li, S.-K.; Shi, M. Tetrahedron 2012, 68, 3172.