Enantioselective Synthesis of 2-Substituted Pyrrolidines via Intramolecular Reductive Amination

Article abstract of DOI:10.1055/s-0037-1611533

Catalyzed by the complex generated in situ from iridium and the chiral ferrocene ligand, tert -butyl (4-oxo-4-arylbutyl)carbamate substrates were deprotected and then reductively cyclised to form 2-substituted arylpyrrolidines in a one-pot manner, in which the intramolecular reductive amination was the key step. A range of chiral 2-substituted arylpyrrolidines were synthesised in up to 98percent yield and 92percent ee.

Full text of DOI:10.1055/s-0037-1611533

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2019, 51, A–G
special topic
A
en
H. Zhou et al.
Special Topic
Synthesis
Enantioselective Synthesis of 2-Substituted Pyrrolidines via
Intramolecular Reductive Amination
Huan Zhou
O
HN
1. TFA, CH2Cl2
NH(Boc)
Wenlei Zhao
Tao Zhang
2. Ir-L, 50 atm H2
Ti(OiPr)4 (1.2 equiv)
DABCO (20 mol%)
Et3N (10 mol%)
R
R
Haodong Guo
Haizhou Huang*
Mingxin Chang*
80~92% ee
85~95% yield
14 examples
PtBu2
toluene/THF, 50 °C, 13 h
Ar2P
0
0
0
0-0
0
0
2-5
4
0
7-
3
4
0
3
Fe
Ar: 4-CF3-C6H4
*N-deprotection and intramolecular
reductive amination in one-pot
*Concise synthesis of chiral pyrrolidines
Shaanxi Key Laboratory of Natural Products & Chemical Biology, College of
Chemistry & Pharmacy, Northwest A&F University, 22 Xinong Road, Yangling,
Shaanxi 712100, P. R. of China
(R)-(S)-L
mxchang@nwsuaf.edu.cn
Published as part of the Special Topic Amination Reactions in Organic Synthesis
Received: 19.03.2109
Accepted after revision: 12.04.2019
Published online: 07.05.2019
metric synthesis of suvorexant in excellent yield and stere-
oselectivity.9b The iodine-bridged dimeric iridium complex-
es displayed preeminent stereoselectivity in the IARA for
the preparation of bioactive chiral tetrahydroisoquino-
lines.9c In the same year Hou et al. reported the ferrocene-
based (R,R)-f-SPIROPHOS with iridium-catalysed intramo-
lecular asymmetric reductive amination.7 Owing to the dis-
tinguished merits of the IARA reaction in the synthesis of
chiral cyclic amines, the development of this reaction is
highly desirable. Herein, we report the iridium–diphos-
phine ligand catalysed IRAR for the synthesis of 2-substi-
tuted arylpyrrolidines concisely and efficiently. With the
help of three additives, the 2-arylpyrrolidines were ob-
tained in up to 92% ee.
DOI: 10.1055/s-0037-1611533; Art ID: ss-2019-c0051-st
Abstract Catalyzed by the complex generated in situ from iridium and
the chiral ferrocene ligand, tert-butyl (4-oxo-4-arylbutyl)carbamate
substrates were deprotected and then reductively cyclised to form 2-
substituted arylpyrrolidines in a one-pot manner, in which the intramo-
lecular reductive amination was the key step. A range of chiral 2-substi-
tuted arylpyrrolidines were synthesised in up to 98% yield and 92% ee.
Key words asymmetric catalysis, intramolecular reductive amination,
iridium, chiral ligand, arylpyrrolidine
Optically active 2-substituted arylpyrrolidines are ubiq-
uitous and important structural motifs in natural products
and pharmaceutical compounds.1 For example, darifenacin
(for urinary incontinence),2 (–)-crispine A (natural product
with antitumor activity),3 TRVP1 antagonist,4 and McN-
4612-Z (Figure 1).5 Consequently, to satisfy the demand for
enantiomerically pure pyrrolidines, many synthetic meth-
ods have been developed.
We started our investigation by using tert-butyl (4-oxo-
4-phenylbutyl) carbamate (1a) as the model substrate. The
Boc protecting group was removed under trifluoroacetic
acid and nitrogen atmosphere conditions. After the acid
Among them, procedures utilising molecular hydrogen
as the reductant, asymmetric reduction of cyclic imines or
enamines6 and asymmetric reductive amination (ARA),7 are
especially efficient. In comparison, asymmetric reductive
amination is more attractive for avoiding the imine prepa-
ration step.
Reductive amination (RA) is the most utilised method
for the synthesis of pharmaceutical related and bulk funda-
mental amines.8 However, successful examples of intramo-
lecular asymmetric reductive amination (IARA) are very
limited. In 2003, Wills and co-workers applied the Noyori
transfer-hydrogenation catalytic system in the first IARA
reaction to prepare 1-methyl-6,7-dimethoxytetrahydroiso-
quinoline in 85% yield with 88% ee.9a Later, Merck chemists
successfully utilised the same catalytic system in the asym-
N
N
O
NH2
O
darifenacin
McN-4612-Z
F
O
MeO
MeO
NH2
N
N
O
F
TRVP1 antagonist
(–)-crispine A
Figure 1 Bioactive 2-substituted arylpyrrolidines
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–G

B
H. Zhou et al.
Special Topic
Synthesis
and solvent had been removed, the resulting residue was
subjected to asymmetric reductive amination utilising the
Ir–(R)-BINAP (Figure 2) catalytic system. Unfortunately,
only imine intermediate 3 was formed (Table 1, entry 1). It
is well known that additives are crucial in many asymmet-
ric hydrogenation reactions of imines;10 thus, several com-
mon additives were examined. The addition of Ti(OiPr)4
greatly enhanced the reactivity by promoting the formation
of the imine intermediate11 and the reduction thereafter
(entry 2). Although other single additives, such as potassi-
um iodide, molecular iodine, sodium tetrafluoroborate, p-
toluenesulfonic acid, and triethylamine, exerted little or no
positive influence (entries 3–7), the combination of 20
mol% of KI and 1.2 equiv of Ti(OiPr)4 delivered much better
stereoselectivity (entry 8). The iodine anion might replace
the chloride anion of the iridium complex.10a,b With the ad-
dition of another additive, Et3N, both the reaction yield and
selectivity could be further improved (entry 9). In a brief
solvent screening, toluene was found to provide the best
yield and enantioselectivity (entry 13–15). The iodine-
bridged dimeric iridium-(R)-BINAP complex12 did not dis-
play better performance, as in our previous research.9c
O
O
PPh2
PPh2
PPh2
PPh2
PPh2
O
O
O
O
PPh2
O
O
(R)-SYNPHOS (L3)
(R)-BINAP (L1)
(R)-SEGPHOS (L2)
O
F
Cy2P
O
O
O
PPh2
PPh2
PPh2
O
O
F
F
PPh2
PPh2
Fe
O
F
O
(R)-DIFLUORPHOS (L6)
(S)-(R)-JOSIPHOS (L4)
(R)-GARPHOS (L5)
F3C
N
O
P
O
P
N
P
Fe
PPh2
Fe
O
F3C
(R)-MONOPHOS (L7) (R)-L8
(R)-(S)-L9
Table 1 Optimization of the Reaction Conditionsa
Figure 2 Structures of chiral phosphine ligands
HN
N
O
NH(Boc)
1. TFA, CH2Cl2
+
Several commercially available chiral phosphorus li-
gands, (R)-SEGPHOS, (R)-SYNPHOS, (S)-(R)-JOSIPHOS, (R)-
GARPHOS, (R)-DIFLUORPHOS, (R)-MONOPHOS and phos-
phine-oxazoline ligand L8 (Figure 2) complexed with
[{Ir(cod)Cl}2] were evaluated.13 Good results were observed
for (R)-SEGPHOS and (R)-DIFLUORPHOS. Although the en-
antioselectivity of the product from (S)-(R)-JOSIPHOS was
not as good as those from (R)-SEGPHOS and DIFLUORPHOS,
the reactivity was better. We therefore continued to exam-
ine the ferrocene-based chiral ligand L9. To our delight, the
ee was improved to 79% with excellent yield (Table 2, entry
9), and when triethylamine was replaced with 1,4-diazabi-
cyclo[2.2.2]octane (DABCO),14 the ee value of the product,
was further enhanced to 90% (entry 10). We speculated that
DABCO or Et3N may be used for acid-base neutralisation or
to facilitate the heterolytic cleavage of the hydrogen mole-
cule during the catalytic cycle. Meanwhile the use of a mix-
ture of toluene/THF (5:1) allowed the reaction to proceed
smoothly with 92% ee (entry 11).
To verify the universality of the Ir-L1 catalytic system, a
series of tert-butyl(4-oxo-4-aryllbutyl) carbamates were
prepared and examined under the optimal reaction condi-
tions (Scheme 1). For the para-substituted substrates 1b–h,
their electronic properties or the steric properties had
modest influence on reaction enantioselectivity or reactivi-
ty and good yields (94–98%) and ee values (85–89%) were
obtained. When the substituents on the phenyl ring were at
the meta-position, all substrates 1i–l were smoothly con-
2. Ir-(R)-BINAP
solvent, additives
H2 (50 atm), 50 °C
2a
3
1a
Entry
Solvent
Additivesb
2a/3c
1:99
ee (%)c
1
2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
EtOAc
THF
–
–
25
–
Ti(OiPr)4
79:21
0:100
0:100
20:80
23:77
26:74
83:17
86:14
78:22
70:30
60:40
11:89
35:65
82:18
3
KI
4
I2
–
5
NaBF4
16
9
6
TsOH
7
Et3N
27
30
41
14
47
5
8
Ti(OiPr)4, KI
Ti(OiPr)4, KI, Et3N
Ti(OiPr)4, KI, K2CO3
Ti(OiPr)4, KI, morpholine
Ti(OiPr)4, KI, TsOH
Ti(OiPr)4, KI, Et3N
Ti(OiPr)4, KI, Et3N
Ti(OiPr)4, KI, Et3N
9
10
11
12
13
14
15
20
38
64
toluene
a Reaction conditions: [Ir(cod)Cl]2/(R)-BINAP/1a (0.5:1:100), H2 (50 atm),
50 °C, 13 h.
b Ti(OiPr)4 (1.2 equiv); Et3N (20 mol%); K2CO3 (20 mol%); morpholine (20
mol%); TSOH (20 mol%); NaBF4 (10 mol%); I2 (20 mol%); KI (20 mol%).
c Ratios and ee values were determined by HPLC on a chiral stationary phase
after the products were converted into the corresponding trifluoroacet-
amide.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–G

C
H. Zhou et al.
Special Topic
Synthesis
Table 2 Screening of Chiral Ligandsa
verted into the corresponding 2-arylpyrrolidines with sub-
tle difference in reactivity and stereoselectivity. As for the
ortho-substituted substrates 1m and 1n, both the yields
and ee values decreased, which might stem from the steric
hindrance of those compounds.
For the chain-enlarged substrate 1o, the yield and ee for
the corresponding piperidine product 2o were limited to
95% and 80%, respectively. But this catalytic system did not
work well for the alkyl-substituted pyrroline and only 32%
ee was achieved for 2p. The 2-(thiophen-2-yl)pyrrolidine
product was also not obtained from the corresponding
starting material by using this procedure.
To explore the practical application of our method, a
gram-scale experiment was conducted. The substrate 1a (4
mmol) could be successfully converted into the correspond-
ing product 2a with 94% yield and 90% enantioselectivity
(Scheme 2).
O
HN
NH(Boc)
1. TFA, CH2Cl2
2. Ir-(R)-BINAP
toluene, additives
H2 (50 atm), 50 °C
1a
2a
Entry
Ligand
Yield (%)b
ee (%)b
1
2
(R)-L1
(R)-L2
(R)-L3
(S)-(R)-L4
(R)-L5
(R)-L6
(R)-L7
(R)-L8
(R)-L9
(R)-L9
(R)-L9
82
86
73
95
98
95
88
69
98
94
98
64
89
69
60
–
3
4
5
6
83
10
23
79
90
92
7
8
9
HN
*
O
10c
11d
NH(Boc)
1. TFA, CH2Cl2
2. Ir-L9, additives
toluene/THF (5:1)
a Reaction conditions: [Ir(cod)Cl]2/Ligand/1a (0.5:1:100), toluene (2 mL),
Ti(OiPr)4 (1.2 equiv), Et3N (20 mol%), KI (20 mol%), H2 (50 atm), 50 °C, 13 h.
b Ratios and ee values were determined by HPLC on a chiral stationary phase
after the products were converted into the corresponding trifluoroacet-
amide.
2a
92% yield, 90% ee
1a
(4 mmol, 1.05 g)
Scheme 2 Gram-scale reaction
c Ti(OiPr)4 (1.2 equiv), DABCO (20 mol%), KI (20 mol%).
To summarise, we have developed an efficient proce-
dure for the preparation of chiral 2-arylpyrrolidines, which
combines the N-Boc deprotection and intramolecular hy-
d Ti(OiPr)4 (1.2 equiv), DABCO (20 mol%), KI (20 mol%), toluene/THF (5:1).
HN
*
O
NH(Boc)
1. TFA, CH2Cl2
R
R
2. Ir-L9, additives
toluene/THF (5:1)
1
2
HN
*
HN
HN
HN
HN
HN
*
F
Et
MeO
Me
tBu
2a
2b
2c
2d
2e
2f
98% yield, 92%
97% yield, 88% ee 98% yield, 90% ee 98% yield, 88% ee
97% yield, 89% ee 94% yield, 89% ee
ee
HN
*
HN
HN
HN
*
HN
*
HN
*
F3C
Cl
OMe
2i
95% yield, 89% ee 94% yield, 85% ee 97% yield, 88% ee
Me
F
Cl
2l
94% yield, 89% ee
2g
2h
2k
2j
90% yield, 85% ee
95% yield, 88% ee
HN
*
HN
*
HN
*
HN
OMe
2n
Me
2m
2oa
2p
91% yield, 32% ee
85% yield, 80% ee 85% yield, 83% ee 95% yield, 80% ee
Scheme 1 Scope of the reaction. Reagents and conditions: [Ir]/ligand/1 (1:1:100), Ti(OiPr)4 (1.2 equiv), DABCO (20 mol%), KI (20 mol%), toluene/THF
(5:1), H2 (50 atm), 50 °C, 13 h; ee values were determined by HPLC analysis on a chiral stationary phase after the products were converted into the
corresponding trifluoroacetamide. a Ir-(R)-SEGPHOS (L2) was used.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–G

D
H. Zhou et al.
Special Topic
Synthesis
drogenative asymmetric reductive amination steps in a sin-
gle pot. In the key reductive amination step, the iridium
along with the ferrocene-based chiral ligand, transformed
the tert-butyl-(4-oxo-4-aryllbutyl) carbamate substrates
into bioactive pyrrolidines in good yields and ee values. The
use of Ti(OiPr)4, Et3N and KI greatly enhanced the level of re-
action conversion as well as the stereoselectivity. This pro-
cedure is concise and operationally simple, offering an at-
tractive method for the synthesis of chiral pyrrolidines.
1H NMR (500 MHz, CDCl3):  = 7.98 (d, J = 8.8 Hz, 1 H), 6.97 (d, J =
8.9 Hz, 1 H), 4.71 (s, 0 H), 3.91 (s, 2 H), 3.26 (q, J = 6.7 Hz, 1 H), 3.02 (t,
J = 7.2 Hz, 1 H), 1.97 (m, J = 7.0 Hz, 1 H), 1.47 (s, 9 H).
tert-Butyl (4-(4-(tert-Butyl)phenyl)-4-oxobutyl)carbamate (1d)
Isolated yield: 75% (1.29 g); white solid.
1H NMR (500 MHz, CDCl3):  = 7.94 (d, J = 8.5 Hz, 2 H), 7.51 (d, J =
8.5 Hz, 2 H), 4.72 (s, 1 H), 3.26 (q, J = 6.7 Hz, 2 H), 3.04 (t, J = 7.1 Hz,
2 H), 1.98 (m, J = 7.0 Hz, 2 H), 1.46 (s, 9 H), 1.38 (s, 9 H).
13C NMR (126 MHz, CDCl3):  = 199.48, 156.81, 156.07, 134.27,
128.04, 125.53, 79.10, 40.20, 35.68, 35.11, 31.10, 28.41, 24.61.
All reactions were performed in a nitrogen-filled glovebox or under
nitrogen using standard Schlenk techniques unless otherwise noted.
Column chromatography was performed using silica gel (200–300
mesh). 1H and 13C NMR spectral data were obtained with Bruker 500
MHz spectrometers. Chemical shifts are reported in ppm. Enantio-
meric excess values were determined by chiral HPLC with an Agilent
1220 Series instrument.
tert-Butyl (4-(4-Ethylphenyl)-4-oxobutyl)carbamate (1e)
Isolated yield: 80% (1.26 g); white solid.
1H NMR (500 MHz, CDCl3):  = 7.93 (d, J = 6.3 Hz, 2 H), 7.32 (d, J =
6.4 Hz, 2 H), 4.69 (s, 2 H), 3.26 (s, 2 H), 3.05 (t, J = 6.2 Hz, 2 H), 2.75 (q,
J = 7.7 Hz, 2 H), 1.98 (s, 2 H), 1.47 (s, 9 H), 1.30 (t, J = 6.6 Hz, 3 H).
13C NMR (126 MHz, CDCl3):  = 199.47, 156.06, 150.08, 134.58,
The above prepared tert-Butyl-2-oxopyrrolidine-1-carboxylate (20
mmol) was dissolved in anhydrous THF (50 mL) in a three-necked,
round-bottomed flask equipped with a mechanical stirrer and cooled
to –78 °C under nitrogen. To the solution was added dropwise a solu-
tion of the RMgBr Grignard reagent (24 mmol). The reaction mixture
was stirred at –78 °C for 2 h and then warmed slowly to room tem-
perature for 12 more hours. Then it was quenched with 2 M HCl (30
mL) and extracted with CH2Cl2. The combined organic phases was
washed with brine, dried over anhydrous Na2SO4, and concentrated
under vacuum to yield the crude product, which was purified with
column chromatography (EtOAc/Petroleum ether) to give the desired
product.7,15
128.30, 128.12, 79.16, 40.21, 35.69, 28.96, 28.41, 24.62, 15.24.
tert-Butyl (4-(4-Fluorophenyl)-4-oxobutyl)carbamate (1f)7
Isolated yield: 74% (1.10 g); white solid.
1H NMR (500 MHz, CDCl3):  = 7.90 (d, J = 8.1 Hz, 2 H), 7.30 (d, J =
9.4 Hz, 1 H), 4.70 (s, 1 H), 3.26 (q, J = 6.6 Hz, 2 H), 3.04 (t, J = 7.2 Hz,
2 H), 1.97 (p, J = 7.1 Hz, 2 H), 1.47 (s, 9 H).
tert-Butyl (4-(4-Chlorophenyl)-4-oxobutyl)carbamate (1g)7
Isolated yield: 70% (1.1 g); white solid.
1H NMR (500 MHz, CDCl3):  = 7.94 (d, J = 8.6 Hz, 2 H), 7.48 (d, J =
8.5 Hz, 2 H), 4.67 (s, 1 H), 3.27 (q, J = 6.6 Hz, 2 H), 3.04 (t, J = 7.1 Hz,
2 H), 1.98 (p, J = 7.0 Hz, 2 H), 1.47 (s, 9 H).
tert-Butyl (4-Oxo-4-arylbutyl)carbamate (1): General Procedure
60% NaH (2.38 g, 64 mmol) was slowly added to a solution of 2-pyrro-
lidinone (4.25 g, 50 mmol) in anhydrous THF (100 mL) at 0 °C. A solu-
tion of di-tert-butyl dicarbonate (11.99 g, 55 mmol) in THF (50 mL)
was slowly added to the above mixture after 1 h. The reaction was
stirred at r.t. for 12 h, then quenched with saturated NH4Cl solution
and concentrated under vacuum. The mixture was extracted with
CH2Cl2 (3 × 50 mL) and the organic layers were collected. The organic
layers were washed with brine, dried over Na2SO4, and concentrated
under vacuum. The crude product was purified by recrystallisation
(EtOAc/petroleum ether). tert-Butyl 2-oxopyrrolidine-1-carboxylate
(colourless oil, yield: 93%).7,15
tert-Butyl (4-Oxo-4-(4-(trifluoromethyl)phenyl)butyl)carbamate
(1h)7
Isolated yield: 40% (0.71 g); white solid.
1H NMR (500 MHz, CDCl3):  = 8.10 (d, J = 8.1 Hz, 2 H), 7.77 (d, J =
8.1 Hz, 2 H), 4.69 (s, 1 H), 3.28 (q, J = 6.7 Hz, 2 H), 3.10 (t, J = 7.1 Hz,
2 H), 2.00 (p, J = 7.0 Hz, 2 H), 1.46 (s, 9 H).
tert-Butyl (4-(3-Methoxyphenyl)-4-oxobutyl)carbamate (1i)7
Isolated yield: 45% (0.75 g); white solid.
1H NMR (500 MHz, CDCl3):  = 7.63–7.49 (m, 2 H), 7.41 (t, J = 7.9 Hz,
1 H), 7.15 (dd, J = 8.1, 2.6 Hz, 1 H), 4.69 (s, 1 H), 3.90 (s, 3 H), 3.27 (q,
J = 6.7 Hz, 2 H), 3.06 (t, J = 7.1 Hz, 2 H), 1.98 (m, J = 7.0 Hz, 2 H), 1.47
(s, 9 H).
tert-Butyl (4-Oxo-4-phenylbutyl)carbamate (1a)7
Isolated yield: 76% (1.08 g); white solid.
1H NMR (500 MHz, CDCl3):  = 8.00 (dd, J = 8.4, 1.4 Hz, 2 H), 7.65–7.56
(m, 1 H), 7.51 (t, J = 7.7 Hz, 2 H), 4.69 (s, 1 H), 3.27 (q, J = 6.7 Hz, 2 H),
3.08 (t, J = 7.1 Hz, 2 H), 1.99 (m, J = 7.0 Hz, 2 H), 1.47 (s, 9 H).
tert-Butyl (4-Oxo-4-(m-tolyl)butyl)carbamate (1j)7
Isolated yield: 64% (0.9 g); white solid.
tert-Butyl (4-Oxo-4-(p-tolyl)butyl)carbamate (1b)7
1H NMR (500 MHz, CDCl3):  = 7.79 (d, J = 12.4 Hz, 2 H), 7.46–7.35 (m,
2 H), 4.71 (s, 1 H), 3.26 (q, J = 6.7 Hz, 2 H), 3.05 (t, J = 7.2 Hz, 2 H), 2.45
(s, 3 H), 1.98 (m, J = 7.0 Hz, 2 H), 1.47 (s, 9 H).
Isolated yield: 80% (1.19 g); white solid.
1H NMR (500 MHz, CDCl3):  = 8.03 (dd, J = 8.8, 5.4 Hz, 2 H), 7.17 (t, J =
8.6 Hz, 2 H), 4.69 (s, 1 H), 3.26 (q, J = 6.6 Hz, 2 H), 3.04 (t, J = 7.1 Hz,
2 H), 1.98 (m, J = 7.0 Hz, 2 H), 1.46 (s, 9 H).
tert-Butyl (4-(3-Fluorophenyl)-4-oxobutyl)carbamate (1k)7
Isolated yield: 72% (1.09 g); white solid.
tert-Butyl (4-(4-Methoxyphenyl)-4-oxobutyl)carbamate (1c)7
Isolated yield: 80% (1.26 g); white solid.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–G

E
H. Zhou et al.
Special Topic
Synthesis
1H NMR (500 MHz, CDCl3):  = 7.78 (d, J = 7.8 Hz, 1 H), 7.68 (dt, J = 9.4,
2.4 Hz, 1 H), 7.49 (td, J = 8.0, 5.5 Hz, 1 H), 4.68 (s, 1 H), 3.27 (q, J =
6.6 Hz, 2 H), 3.05 (t, J = 7.1 Hz, 2 H), 1.99 (m, J = 7.0 Hz, 2 H), 1.47 (s,
9 H).
1H NMR (500 MHz, CDCl3):  = 7.43 (dd, J = 6.7, 3.0 Hz, 2 H), 7.37 (q, J =
3.6 Hz, 3 H), 4.46 (dd, J = 10.0, 6.6 Hz, 1 H), 3.48–2.95 (m, 2 H), 2.39
(ddd, J = 12.1, 9.7, 4.8 Hz, 1 H), 2.22 (tdd, J = 10.1, 4.6, 2.1 Hz, 2 H),
2.09 (dddt, J = 15.9, 12.8, 8.6, 4.1 Hz, 1 H).
13C NMR (126 MHz, CDCl3):  = 134.19, 129.33, 129.05, 127.71, 63.26,
44.80, 31.60, 23.76.
tert-Butyl (4-(3-Chlorophenyl)-4-oxobutyl)carbamate (1l)7
Isolated yield: 73% (1.17 g); white solid.
Enantiomeric excess was determined by HPLC for the corresponding
1H NMR (500 MHz, CDCl3):  = 8.00 (d, J = 7.1 Hz, 1 H), 7.64–7.55 (m,
1 H), 7.47 (dt, J = 28.2, 7.8 Hz, 2 H), 4.71 (s, 1 H), 3.26 (t, J = 6.9 Hz,
2 H), 3.06 (dt, J = 14.2, 7.1 Hz, 2 H), 1.99 (dt, J = 10.8, 5.2 Hz, 2 H), 1.46
(s, 9 H).
trifluoroacetamide, Chiralpak OD-H column, Hex/IPA
mL/min, 220 nm.
= 95:5, 1
(S)-2-(p-Tolyl)pyrrolidine (2b)6g,7
Yield: 97% (31.2 mg); colourless oil; ee 88%.
tert-Butyl (4-Oxo-4-(o-tolyl)butyl)carbamate (1m)7
1H NMR (500 MHz, CDCl3):  = 7.31 (d, J = 1.6 Hz, 2 H), 7.18 (d, J =
7.9 Hz, 2 H), 4.42 (dd, J = 10.0, 6.6 Hz, 1 H), 3.32–3.09 (m, 2 H), 2.37 (s,
4 H), 2.21 (tdd, J = 10.3, 4.7, 2.2 Hz, 2 H), 2.08 (tdt, J = 10.8, 7.8, 3.2 Hz,
1 H).
13C NMR (126 MHz, CDCl3):  = 139.27, 131.27, 129.69, 127.56, 63.06,
44.68, 31.55, 23.76, 21.16.
Isolated yield: 65% (0.97 g); white solid.
1H NMR (500 MHz, CDCl3):  = 7.66 (dd, J = 7.6, 1.6 Hz, 1 H), 7.39 (td,
J = 7.5, 1.4 Hz, 1 H), 7.32–7.20 (m, 2 H), 4.72 (s, 1 H), 3.24 (t, J = 6.8 Hz,
2 H), 2.98 (t, J = 7.1 Hz, 2 H), 2.52 (s, 3 H), 1.94 (m, J = 7.0 Hz, 2 H), 1.46
(s, 9 H).
Enantiomeric excess was determined by HPLC for the corresponding
trifluoroacetamide, Chiralpak IA-3 column, Hex/IPA = 95:5, 1 mL/min,
220 nm.
tert-Butyl (4-(2-Methoxyphenyl)-4-oxobutyl)carbamate (1n)7
Isolated yield: 70% (1.10 g); white solid.
1H NMR (500 MHz, CDCl3):  = 7.72 (dd, J = 7.7, 1.8 Hz, 1 H), 7.50 (ddd,
J = 8.8, 7.3, 1.8 Hz, 1 H), 7.10–6.93 (m, 2 H), 4.70 (s, 1 H), 3.95 (s, 3 H),
3.24 (q, J = 6.7 Hz, 2 H), 3.06 (t, J = 7.2 Hz, 2 H), 1.93 (m, J = 7.1 Hz,
2 H), 1.47 (s, 9 H).
(S)-2-(4-Methoxyphenyl)pyrrolidine (2c)6g,7
Yield: 98% (34.7 mg); colourless oil; ee 90%.
1H NMR (500 MHz, CDCl3):  = 7.35 (d, J = 8.7 Hz, 2 H), 6.96–6.80 (m,
2 H), 4.46 (dd, J = 10.0, 6.6 Hz, 1 H), 3.82 (s, 3 H), 3.38–3.20 (m, 2 H),
2.37 (td, J = 10.3, 9.3, 4.9 Hz, 1 H), 2.29–2.17 (m, 2 H), 2.16–2.05 (m,
1 H).
tert-Butyl (5-Oxo-5-phenylpentyl)carbamate (1o)7
Isolated yield: 85% (1.19 g); white solid.
1H NMR (500 MHz, CDCl3):  = 8.05–7.90 (m, 2 H), 7.63–7.56 (m, 1 H),
7.50 (t, J = 7.7 Hz, 2 H), 4.65 (s, 1 H), 3.21 (q, J = 6.7 Hz, 2 H), 3.05 (t, J =
7.2 Hz, 2 H), 1.82 (m, J = 7.3 Hz, 2 H), 1.62 (m, J = 7.0 Hz, 2 H), 1.48 (s,
9 H).
13C NMR (126 MHz, CDCl3):  = 160.31, 129.10, 125.95, 114.36, 62.94,
55.31, 44.60, 31.33, 23.72.
Enantiomeric excess was determined by HPLC for the corresponding
trifluoroacetamide, Chiralpak IA-3 column, Hex/IPA = 95:5, 1 mL/min,
220 nm.
tert-Butyl (4-Cyclohexyl-4-oxobutyl)carbamate (1p)7
(–)-2-(4-(tert-Butyl)phenyl)pyrrolidine (2d)16
Yield: 98% (39.8 mg); colourless oil; ee 88%.
1H NMR (500 MHz, CDCl3):  = 7.41 (d, J = 8.3 Hz, 2 H), 7.36 (d, J =
8.2 Hz, 2 H), 4.46 (dd, J = 9.7, 6.7 Hz, 1 H), 3.33–3.06 (m, 2 H), 2.42–
2.29 (m, 1 H), 2.26–2.14 (m, 2 H), 2.07 (dtd, J = 12.0, 7.7, 3.9 Hz, 1 H),
1.33 (s, 9 H).
Isolated yield: 30% (0.4 g); white solid.
1H NMR (500 MHz, CDCl3):  = 4.61 (s, 1 H), 3.15 (q, J = 6.7 Hz, 2 H),
2.52 (t, J = 7.1 Hz, 2 H), 2.37 (ddt, J = 11.2, 7.0, 3.4 Hz, 1 H), 1.91–1.74
(m, 6 H), 1.47 (s, 9 H), 1.41–1.15 (m, 6 H).
2-Substituted Arylpyrrolidines (2): General Procedure
The mixture of substrate 1 (0.2 mmol) and TFA (6 equiv) in CH2Cl2
was stirred under nitrogen for 3 h. After all the acid and solvent had
been removed under vacuum, the obtained substance was transferred
to a nitrogen-filled glovebox and dissolved in a mixed solvent of tolu-
ene/THF (5:1, 1 mL). Ti(OiPr)4 (0.24 mmol), DABCO (0.04 mmol), Ir-L9
(0.002 mmol) and KI (0.04 mmol) were added subsequently to the
above solution. The total solution was made to 3.0 mL. The resulting
vial was transferred to an autoclave, which was charged with 50 atm
of H2, and stirred at 50 °C for 13 h. The solution was quenched with
aqueous sodium bicarbonate solution. The organic phase was concen-
trated and the metal complex was removed by using a short silica
plug to give the chiral 2-substituted arylpyrrolidines product, which
was then converted into the corresponding trifluoroacetamide with
trifluoroacetic anhydride and analysed by chiral HPLC to determine
the enantiomeric excess.
13C NMR (126 MHz, CDCl3):  = 152.50, 131.19, 127.38, 126.01, 63.00,
44.78, 34.66, 31.58, 31.21, 23.70.
Enantiomeric excess was determined by HPLC for the corresponding
trifluoroacetamide, Chiralpak OD-H column, Hex/IPA = 90:10, 1
mL/min, 220 nm.
(–)-2-(4-Ethylphenyl)pyrrolidine (2e)17
Yield: 97% (33.9 mg); colourless oil; ee 89%.
1H NMR (500 MHz, CDCl3):  = 7.34 (d, J = 8.0 Hz, 2 H), 7.21 (d, J =
7.8 Hz, 2 H), 4.44 (dd, J = 10.0, 6.6 Hz, 1 H), 3.30–3.08 (m, 2 H), 2.66 (q,
J = 7.6 Hz, 2 H), 2.37 (ddd, J = 11.8, 10.0, 5.0 Hz, 1 H), 2.20 (dddd, J =
17.2, 9.6, 7.3, 3.4 Hz, 2 H), 2.06 (dtt, J = 20.0, 8.5, 4.3 Hz, 1 H), 1.25 (t,
J = 7.6 Hz, 3 H).
13C NMR (126 MHz, CDCl3):  = 145.61, 131.40, 128.53, 127.70, 63.12,
44.72, 31.54, 28.53, 23.70, 15.40.
(S)-2-Phenylpyrrolidine (2a)6g,7
Yield: 98% (28.8 mg); colourless oil; ee 92%.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–G

F
H. Zhou et al.
Special Topic
Synthesis
Enantiomeric excess was determined by HPLC for the corresponding
trifluoroacetamide, Chiralpak OD-H column, Hex/IPA = 90:10, 1
mL/min, 220 nm.
13C NMR (126 MHz, CDCl3):  = 138.94, 134.35, 129.99, 128.89,
128.16, 124.71, 63.26, 44.77, 31.69, 23.80, 21.19.
13C NMR (126 MHz, CDCl3):  = 163.79, 136.65, 136.59, 130.76,
130.70, 123.32, 123.29, 116.40, 116.24, 114.90, 114.72, 62.56, 44.89,
31.43, 31.42, 23.66.
(S)-2-(4-Fluorophenyl)pyrrolidine (2f)6g,7
Yield: 94% (31.0 mg); colourless oil; ee 89%.
1H NMR (500 MHz, CDCl3):  = 7.42 (dd, J = 8.6, 5.3 Hz, 2 H), 7.14–6.97
(m, 2 H), 4.45 (dd, J = 10.4, 6.6 Hz, 1 H), 3.38–3.16 (m, 2 H), 2.44–2.35
(m, 1 H), 2.31–2.18 (m, 2 H), 2.15–2.06 (m, 1 H).
Enantiomeric excess was determined by HPLC for the corresponding
trifluoroacetamide, Chiralpak OD-H column, Hex/IPA = 90:10, 1
mL/min, 220 nm.
(S)-2-(3-Fluorophenyl)pyrrolidine (2k)7
Yield: 90% (29.7 mg); colourless oil; ee 85%.
13C NMR (126 MHz, CDCl3):  = 129.79 (d, J = 7.5 Hz), 116.04 (d, J =
22.5 Hz), 62.67, 44.69, 31.54, 23.73.
19F NMR (470 MHz, CDCl3):  = –75.7.
1H NMR (500 MHz, CDCl3):  = 7.35 (td, J = 8.0, 5.8 Hz, 1 H), 7.26–7.16
(m, 2 H), 7.08 (td, J = 8.4, 2.4 Hz, 1 H), 4.49 (dd, J = 10.2, 6.7 Hz, 1 H),
3.44–3.23 (m, 2 H), 2.43 (ddt, J = 9.2, 6.7, 3.3 Hz, 1 H), 2.24 (dtdd, J =
20.8, 10.6, 4.9, 3.1 Hz, 2 H), 2.17–2.08 (m, 1 H).
13C NMR (126 MHz, CDCl3):  = 163.79, 136.62 (d, J = 7.3 Hz), 130.73
(d, J = 8.2 Hz), 123.30 (d, J = 3.2 Hz), 116.32 (d, J = 20.9 Hz), 114.81 (d,
J = 22.6 Hz), 62.56, 44.89, 31.43, 23.66.
Enantiomeric excess was determined by HPLC for the corresponding
trifluoroacetamide, Chiralpak OD-H column, Hex/IPA
mL/min, 220 nm.
= 98:2, 1
(S)-2-(4-Chlorophenyl)pyrrolidine (2g)6g,7
Yield: 95% (34.3 mg); colourless oil; ee 89%.
1H NMR (500 MHz, CDCl3):  = 7.35 (d, J = 2.2 Hz, 4 H), 4.39 (dd, J =
10.1, 6.6 Hz, 1 H), 3.34–3.11 (m, 2 H), 2.39 (ddd, J = 13.6, 6.8, 3.8 Hz,
1 H), 2.29–2.04 (m, 3 H).
19F NMR (470 MHz, CDCl3):  = –75.7.
Enantiomeric excess was determined by HPLC for the corresponding
trifluoroacetamide, Chiralpak OD-H column, Hex/IPA = 90:10, 1
mL/min, 220 nm.
13C NMR (126 MHz, CDCl3):  = 135.26, 133.21, 129.19, 129.08, 62.57,
44.89, 31.70, 23.84.
(–)-2-(3-Chlorophenyl)pyrrolidine (2l)6g,7
Enantiomeric excess was determined by HPLC for the corresponding
trifluoroacetamide, Chiralpak OD-H column, Hex/IPA
mL/min, 220 nm.
Yield: 94% (34.0 mg); colourless oil; ee 89%.
= 98:2, 1
1H NMR (500 MHz, CDCl3):  = 7.42 (dd, J = 6.8, 3.1 Hz, 2 H), 7.38–7.36
(m, 2 H), 4.44 (q, J = 9.2, 8.7 Hz, 1 H), 3.25 (ddt, J = 49.4, 11.5, 5.1 Hz,
2 H), 2.40 (ddd, J = 12.3, 9.7, 4.8 Hz, 1 H), 2.28–2.18 (m, 2 H), 2.13–
2.07 (m, 1 H).
13C NMR (126 MHz, CDCl3):  = 134.20, 130.36, 129.51, 129.35,
129.06, 127.63, 63.27, 44.83, 31.55, 23.79.
(–)-2-(4-(Trifluoromethyl)phenyl)pyrrolidine (2h)18
Yield: 95% (40 mg); colourless oil; ee 85%.
1H NMR (500 MHz, CDCl3):  = 7.64 (d, J = 8.2 Hz, 2 H), 7.58 (d, J =
8.2 Hz, 2 H), 4.47 (dd, J = 9.7, 6.7 Hz, 1 H), 3.34–3.14 (m, 2 H), 2.48–
2.36 (m, 1 H), 2.26–2.02 (m, 3 H).
13C NMR (126 MHz, CDCl3):  = 147.78, 129.41 (q, J = 31.9 Hz), 127.03,
125.37 (q, J = 3.7 Hz), 123.15, 62.06, 46.72, 34.26, 25.28.
Enantiomeric excess was determined by HPLC for the corresponding
trifluoroacetamide, Chiralpak OD-H column, Hex/IPA = 90:10, 1
mL/min, 220 nm.
19F NMR (470 MHz, CDCl3):  = –62.9.
(–)-2-(o-Tolyl)pyrrolidine (2m)7
Enantiomeric excess was determined by HPLC for the corresponding
trifluoroacetamide, Chiralpak OD-H column, Hex/IPA
mL/min, 220 nm.
Yield: 85% (24.7 mg); colourless oil; ee 80%.
= 95:5, 1
1H NMR (500 MHz, CDCl3):  = 7.51 (dd, J = 5.6, 3.5 Hz, 1 H), 7.26 (dd,
J = 5.8, 3.4 Hz, 2 H), 7.19 (t, J = 4.6 Hz, 1 H), 4.75 (dd, J = 9.6, 6.8 Hz,
1 H), 3.41–3.15 (m, 2 H), 2.39 (s, 4 H), 2.23 (qd, J = 7.1, 6.1, 2.3 Hz,
1 H), 2.15–2.04 (m, 1 H).
13C NMR (126 MHz, CDCl3):  = 136.57, 133.01, 130.93, 128.99,
126.90, 126.01, 59.03, 45.13, 32.07, 23.97, 19.41.
(–)-2-(3-Methoxyphenyl)pyrrolidine (2i)6g,7
Yield: 97% (34.3 mg); colourless oil; ee 88%.
1H NMR (500 MHz, CDCl3):  = 7.27 (t, J = 7.9 Hz, 1 H), 6.99 (t, J =
5.6 Hz, 2 H), 6.95–6.81 (m, 1 H), 4.43 (dd, J = 9.9, 6.7 Hz, 1 H), 3.81 (s,
3 H), 3.37–3.09 (m, 2 H), 2.46–2.33 (m, 1 H), 2.29–2.15 (m, 2 H), 2.15–
1.98 (m, 1 H).
Enantiomeric excess was determined by HPLC for the corresponding
acetamide, Chiralpak OD-H column, Hex/IPA = 95:5, 1 mL/min, 220
nm.
13C NMR (126 MHz, CDCl3):  = 160.05, 135.69, 130.10, 119.78,
115.59, 112.49, 63.31, 55.31, 44.77, 31.66, 23.67.
(–)-2-(2-Methoxyphenyl)pyrrolidine (2n)6g,7
Enantiomeric excess was determined by HPLC for the corresponding
trifluoroacetamide, Chiralpak OD-H column, Hex/IPA = 80:20, 1
mL/min, 220 nm.
Yield: 85% (30.0 mg); colourless oil; ee 83%.
1H NMR (500 MHz, CDCl3):  = 7.44 (dd, J = 7.6, 1.7 Hz, 1 H), 7.26 (td,
J = 7.8, 1.7 Hz, 1 H), 7.00–6.95 (m, 1 H), 6.90 (d, J = 8.1 Hz, 1 H), 4.42 (t,
J = 7.7 Hz, 1 H), 3.88 (s, 3 H), 3.22 (ddd, J = 10.3, 7.6, 5.3 Hz, 1 H), 3.05
(ddd, J = 10.3, 8.2, 6.8 Hz, 1 H), 2.22 (dtd, J = 12.6, 7.7, 5.1 Hz, 1 H),
1.91 (dtdd, J = 25.4, 12.5, 8.9, 5.0 Hz, 2 H), 1.79–1.61 (m, 1 H).
13C NMR (126 MHz, CDCl3):  = 157.21, 130.64, 128.92, 122.26,
120.85, 110.84, 55.38, 53.44, 45.36, 30.02, 24.16.
(–)-2-(m-Tolyl)pyrrolidine (2j)6g,7
Yield: 95% (30.6 mg); colourless oil; ee 88%.
1H NMR (500 MHz, CDCl3):  = 7.27–7.22 (m, 2 H), 7.19 (dd, J = 12.4,
7.6 Hz, 2 H), 4.40 (dd, J = 10.0, 6.7 Hz, 1 H), 3.33–3.00 (m, 2 H), 2.35 (s,
4 H), 2.27–2.15 (m, 2 H), 2.08 (pt, J = 7.5, 3.5 Hz, 1 H).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–G

G
H. Zhou et al.
Special Topic
Synthesis
Enantiomeric excess was determined by HPLC for the corresponding
(5) (a) Maryanoff, B. E.; McComsey, D. F.; Costanzo, M. J.; Setler, P.
E.; Gardocki, J. F.; Shank, R. P.; Schneider, C. R. J. Med. Chem.
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Chem. Soc. 1989, 111, 2487.
trifluoroacetamide, Chiralpak OD-H column, Hex/IPA
mL/min, 220 nm.
= 95:5, 1
(S)-2-Phenylpiperidine (2o)6g,7
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Yield: 80% (30.6 mg); colourless oil; ee 58%.
1H NMR (500 MHz, CDCl3):  = 7.45 (dd, J = 6.6, 3.0 Hz, 2 H), 7.38–7.33
(m, 3 H), 3.93 (dd, J = 12.5, 3.0 Hz, 1 H), 2.98–2.68 (m, 2 H), 2.15 (qd,
J = 12.7, 3.0 Hz, 1 H), 2.01 (td, J = 15.0, 7.3 Hz, 2 H), 1.85 (tt, J = 13.4,
4.0 Hz, 1 H), 1.75 (d, J = 14.8 Hz, 1 H), 1.59 (dddd, J = 16.9, 13.4, 8.8,
3.9 Hz, 1 H).
13C NMR (126 MHz, CDCl3):  = 136.59, 129.16, 128.98, 127.62,
127.60, 61.05, 45.19, 29.84, 23.21, 21.76.
Enantiomeric excess was determined by HPLC for the corresponding
trifluoroacetamide, Chiralpak OJ-H column, Hex/IPA
mL/min, 220 nm.
= 95:5, 1
(–)-2-Cyclohexylpyrrolidine (2p)7
Yield: 91% (17 mg); colourless oil.
1H NMR (500 MHz, CDCl3):  = 3.29 (t, J = 7.6 Hz, 2 H), 3.20 (t, J =
8.3 Hz, 1 H), 2.23–2.06 (m, 2 H), 2.03–1.85 (m, 2 H), 1.81–1.63 (m,
6 H), 1.39–0.94 (m, 6 H).
13C NMR (126 MHz, CDCl3):  = 66.06, 45.04, 40.07, 31.06, 29.93,
28.90, 25.82, 25.47, 25.28, 23.75.
Enantiomeric excess was determined by HPLC for the corresponding
benzoylamide, Chiralpak OD-H column, Hex/IPA = 90:10, 1 mL/min,
220 nm.
Funding Information
Financial support from the National Natural Science Foundation of
China (21772155, 21402155 and 21602172) is gratefully acknowl-
edged.
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Supporting Information
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Supporting information for this article is available online at
https://doi.org/10.1055/s-0037-1611533.
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–G