Visible Light Photoredox-Catalyzed α-Alkylation of Cyclic Tertiary Arylamines

Article abstract of DOI:10.1021/acs.joc.9b02347

An efficient method was successfully developed to obtain cyclic β-amino ketones via visible-light photoredox catalysis. With this catalytic system, vinyl azides and N-Ph pyrrolidines react to form cyclic β-amino ketones by α-amino radical addition. This method provides a simple, mild, straightforward, and novel paradigm to prepare important β-amino ketones.

Full text of DOI:10.1021/acs.joc.9b02347

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Article
Visible Light Photoredox-Catalyzed #-
Alkylation of Cyclic Tertiary Arylamines
Ji-Tao Xu, Guo-Qiang Xu, Zhu-Yin Wang, and Peng-Fei Xu
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b02347 • Publication Date (Web): 23 Oct 2019
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Visible Light Photoredox-Catalyzed α-Alkylation of Cyclic Tertiary
6
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Arylamines
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9
Ji-Tao Xu†, Guo-Qiang Xu†, Zhu-Yin Wang† and Peng-Fei Xu*,†
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†State Key Laboratory of Applied Organic Chemistry, College of Chemistry and Chemical
Engineering, Lanzhou University, Lanzhou 730000, P. R. China
O
PC
N3
N2
Ar
+
+
H
N
N
H2O
Ar
Ar
Ar
33 examples
up to 82% yield
Mild and green reaction conditions
Broad substrate scopes
Overall redox-neutral transformation
Step- and atom- economy
ABSTRACT：An efficient method was successfully developed to obtain cyclic β-amino ketones via
visible-light photoredox catalysis. With this catalytic system, vinyl azides and N-Ph pyrrolidines react
to form cyclic β-amino ketones by α-amino radical addition. This method provides a simple, mild,
straightforward and novel paradigm to prepare important β-amino ketones.
INTRODUCTION
β-Amino ketones are versatile synthetic building blocks in organic synthesis, which can be easily
converted into a range of useful and valuable derivatives including β-amino alcohols, β-amino acids
and functionalized carbonyl compounds,1 and therefore attracts increasing attention from the synthetic
community. Moreover, β-amino carbonyl derivatives are well accepted as key synthetic intermediates
of numerous drugs and biologically active natural products.2 As important bioactive substances, they
are still widely used with functionalities spanning from anti-inflammatory,3 anticancer,4 antibacterial,5
anti-tuberculosis,6,7 antihypertensive activities2,8 and so on.
Among many methods towards the synthesis of β-amino ketones, Mannich reaction has been studied
by organic chemists for decades.9 Several synthetic strategies for accessing cyclic β-amino ketones
have been developed (Scheme 1a).10 However, for the construction of ring substituted β-amino ketones,
some issues still exist, such as substrate pre-functionalization,10c,d employment of highly toxic tin
reagents,10d,e poor functional-group tolerance,10b poor step-economy10a and atom-economy10d and so on,
which dramatically limit their wide applications. Thus, the development of a more mild and green,
more step- and atom- economy approach to the synthesis of ring substituted β-amino ketones is highly
desired. Herein, we report a novel visible light photoredox-catalyzed strategy to synthesize ring
substituted β-amino ketones (Scheme 1b).
Due to its atom and step economy,11 direct functionalization of C−H bonds has drawn a great deal of
attention in organic chemistry community.12 Recently, a variety of new methods and strategies for the
C−H direct functionalization have been established.13 In the past few years, visible-light photoredox
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catalysis has emerged as
a
mild and sustainable platform for constructing important
nitrogen-containing heterocyclic skeletons, and a powerful activation strategy for the discovery and
invention of new chemical transformations.14 In view of the prevalence of saturated
nitrogen-containing heterocycles in pharmaceuticals and natural products,15 we wondered whether
β-amino ketones could be synthesized through photoredox-catalyzed direct functionalization of
C(sp3)−H bonds, which would not only broaden the substrate scopes for the synthesis of β-amino
ketones and therefore avoid the pre-functionalization of substrates, but also provide a novel synthetic
approach.
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Scheme 1. Typical Strategies for Accessing Cyclic β-Amino Ketones
a: previous works
Mannich reactionref.10a
O
Cl
O
Ph
O
cat.
, PhMe
N
+
+
reflux
N
Ph
H
Ar
Cl
Reduction of imines and Michael type of aminationref.10e
Reducing
agent
CHO
O
NAr
+
H2NAr
Ph
Ph
Ph
N
O
O
Ar
RA = Di-n-butyliodotin Hydride (n-Bu2SnIH)
Nucleophilic substitutionref.10d
OTMS
O
Sn(NTf2)4
rt, MeCN
Ph
O
O
OH
+
N
N
Ph
PMB
PMB
b: this work (photoredox, radical pathway)
N3
O
Ru(bpy)3(PF6)2 (3 mol %)
+
+
N2
Ar
H
N
N
Ar
i-PrCO2K (2.0 equiv), DMF (2 mL), N2
H2O (1.0 equiv), -10 oC, 450-455 nm
Ar
Ar
RESULTS AND DISCUSSION
Based on the previous work,16 we chose N-phenyl pyrrolidine and vinyl azide as the model
substrates to synthesize a β-amino ketone under various reaction conditions. We were pleased to obtain
3aa in 22% yield (Table1, entry 1) as the target product when Ru(bpy)3(PF6)2 and KOAc were used
with the irradiation of blue LED strips after 24 h at 25 ℃. Ru(bpy)3(PF6)2 was proved to an optimal
photocatalyst (see the Supporting Information). Further investigation of the solvents revealed that DMF
was optimal for the reaction (Table1, entry 2). Next, we found that i-PrCO2K was an efficient base to
promote the reaction after screening of common bases (Table1, entry 3). To our delight, the yield of
this reaction was increased to 60% when N-phenyl pyrrolidine was used in 3.0 equiv and
Ru(bpy)3(PF6)2 in 3 mol % (Table1, entry 4). Even better results were obtained (Table1, entry 5) when
H2O (1.0 equiv) was added to the reaction system, and it was also found that low temperatures and
specific wavelength blue light irradiation improved the results (Table1, entry 6). Finally, the highest
reaction efficiency was observed when the reaction was irradiated at 450–455 nm at –10 ℃ (Table1,
entry 7). Control experiments demonstrated that both light and photoredox catalysts were essential to
the reactions and the base was necessary to improve the reaction efficiency (Table1, entry 8). Target
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product 3aa was not available without irradiation or in the absence of the photocatalyst (Table 1,
entries 9−10).
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Table 1. Optimization of the Reaction Conditionsa
8
9
O
N3
Ru(bpy)3(PF6)2 (3 mol %)
N
N
+
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i-PrCO2K (2.0 equiv), DMF (2 mL), N2
H2O (1.0 equiv), -10 oC, 450-455 nm
2a
1a
3aa
entry
1
photocatalyst
base (equiv)
KOAc (1.0)
solvent
DCM
DMF
DMF
DMF
DMF
DMF
DMF
DCM
DCM
DCM
yield (%)b
Ru(bpy)3(PF6)2
22
2
KOAc (1.0)
Ru(bpy)3(PF6)2
Ru(bpy)3(PF6)2
Ru(bpy)3(PF6)2
Ru(bpy)3(PF6)2
Ru(bpy)3(PF6)2
Ru(bpy)3(PF6)2
Ru(bpy)3(PF6)2
Ru(bpy)3(PF6)2
-
32
3
i-PrCO2K(1.0)
i-PrCO2K (2.0)
i-PrCO2K (2.0)
i-PrCO2K (2.0)
i-PrCO2K (2.0)
-
40
4 c
5 d
6 e
7 f
8
60
63
72
81
19
9 g
10
i-PrCO2K (1.0)
i-PrCO2K (1.0)
n.d.
n.d.
aConditions: Reactions performed with 1a (0.2 mmol), 2a (0.2 mmol), photocatalyst (1 mol %), solvent
(2 mL) at 25 ℃ under nitrogen atmosphere and blue LEDs strips for 24 h. For detailed experimental
procedures, see the Supporting Information. bIsolated yield. c1a (0.6 mmol), 2a (0.2 mmol),
d
photocatalyst (3 mol %), blue LEDs strips at 25 ℃; 1a (0.6 mmol), 2a (0.2 mmol), photocatalyst (3
e
mol %), blue LEDs strips, H2O (1.0 equiv) at 25 ℃ for 12 h; 1a (0.6 mmol), 2a (0.2 mmol),
photocatalyst (3 mol %) at 0 ℃ and 420–425 nm for 12 h; f1a (0.6 mmol), 2a (0.2 mmol), photocatalyst
(3 mol %) at –10 ℃ and 450–455 nm for 12 h; gIn the dark.
With the reaction conditions optimized, we then explored the scope of N-aryl pyrrolidine derivatives.
As shown in Scheme 2, a range of N-aryl pyrrolidines bearing electron-donating and
electron-withdrawing substituents were compatible substrates. Generally, N-aryl pyrrolidines with
electron-withdrawing substituents in the meta- or para- position gave better results than those with
electron-donating substituents in this transformation (3ab-ak). The corresponding products with
substituents such as F, Cl, Br were obtained in moderate to good yields. The ortho- position of the aryl
group in N-aryl pyrrolidine could only be a small sterically hindered F (3al). If it was an other larger
group, it would not be able to react due to steric hindrance. A variety of cyclic amines were
investigated in this transformation, and seven-mumbered ring substrate also gave the corresponding
product (3am). Moreover, other saturated heterocyclic ring systems such as piperazine, and morpholine
were also amenable to this transformation (3an, 3ao). Furthermore, acyclic and unsymmetrical
dialkylanilines underwent functionalization smoothly in this protocol (3ap, 3aq) as well.
Scheme 2. Substrate of Various N-Aryl Pyrrolidinesa
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O
Ph
N3
Ru(bpy)3(PF6)2 (3 mol %)
N
N
+
6
7
8
9
i-PrCO2K (2.0 equiv), N2, DMF (2 mL)
-10 oC, H2O (1.0 equiv), 450-455 nm
Ph
R
R
O
1
(3.0 equiv)
O
2a
(1.0 equiv)
3
O
O
O
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Ph
Ph
Ph
Ph
Ph
N
N
N
N
N
Br
F
Cl
Me
3aa
81%
3ab
3ac
56%
82%
3ad
58%
3ae
41%
O
O
O
O
O
Ph
Ph
Ph
N
N
Ph
N
Ph
N
N
F
Cl
tBu
O
Br
66%
Me
3ag
3ah
3ai
3aj
41%
60%
59%
3af
48%
Boc
O
O
N
N
O
N
O
O
Ph
Ph
O
N
N
N
Ph
Ph
F
Ph
Me
57%
3ao
20%
3am
3an
19%
48%
3ak
3al
32%
O
O
Ph
N
Ph
N
3ap
18%
3aq
64%, dr = 1:1
aReaction conditions: 1 (0.6 mmol), 2a (0.2 mmol), photocatalyst (3 mol %), i-PrCO2K (2.0 equiv) ,
H2O (1.0 equiv) in DMF (2 mL) at –10 ℃ under nitrogen atmosphere for 12 h. For detailed
experimental procedures, see the supporting information. bIsolated yield.
Next, we examined the generality of this transformation with respect to different vinyl azides. As
shown in Scheme 3, it was found that the electron-donating and electron-withdrawing substituents of
vinyl azides had no significant effect in the transformation, and the corresponding products were
obtained in moderate yields (3ar-bd). Furthermore, the X-ray crystal structure of product 3at was
successfully determined (see the Supporting Information). Moreover, our approach displayed high
tolerance towards other important heterocycles, including pyridine (3be), and thiophene (3bf). These
common motifs are typically found in drug molecules. However, it was worth mentioning that only
vinyl azides attached to C(sp2)–C(sp2) bonds could undergo this kind of functionalization successfully
in this protocol (3bg). For α-alkyl vinyl azides, there are no conjugation effect between vinyl azides
and other unsaturated bonds, which will not be conducted to the reaction.
Scheme 3. Scope of Vinyl Azidesa
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O
N3
Ru(bpy)3(PF6)2 (3 mol %)
N
+
i-PrCO2K (2.0 equiv), N2, DMF (2 mL)
-10 oC, H2O (1.0 equiv), 450-455 nm
N
Ph
R
R
Ph
3
7
8
9
1a
2
3.0 equiv
O
1.0 equiv
N
O
O
O
N
N
N
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F
MeO
F
Cl
3au
62%
3ar
3as
3at
65%
58%
54%
O
O
O
O
N
N
N
N
F
Cl
Br
Me
3ax
3ay
57%
61%
3av
3aw
54%
53%
O
O
O
O
N
CO2Me
N
N
N
OMe
Me
Br
3bc
40%
3ba
59%
3bb
48%
3az
58%
O
O
O
O
N
N
N
N
N
S
b
3bg
24%
3bd
3be
3bf
21%
44%
34%
aReaction conditions: 1a (0.6 mmol), 2 (0.2 mmol), photocatalyst (3 mol %), i-PrCO2K (2.0 equiv) ,
H2O (1.0 equiv) in DMF (2 mL) at –10 ℃ under nitrogen atmosphere for 12 h. For detailed
experimental procedures, see the supporting information, isolated yield. b1a (4.0 equiv) was used.
When a gram-scale reaction was performed, the transformation proceeded smoothly to afford
β-amino ketone product 3aa with good results (Scheme 4, a). It’s well known that β-amino ketone 3aa
is a versatile synthetic intermediate which could be further converted to various compounds (Scheme 4,
b). For example, transition-metal-free selective C–H benzylation of 3aa was successfully achieved in
86% yield based on methods previously reported by our group.17 Moreover, a sequential visible-light
photocatalyzed dehydrogenation/[2 + 2] cycloaddition was achieved to obtain the compound 5
according to the method also previously reported by our group16a. Furthermore, the product 3aa could
be easily transformed into β-amino alcohol 6 in excellent yield with 1.24:1 dr. In addition, the
α-heteroarylation of 3aa was carried out via photoredox catalysis through a homolytic aromatic
substitution pathway in moderate yield and 1.8:1 dr.18 Finally, the Grignard reaction of 3aa with
phenylmagnesium bromide provided diaryl-β-amino alcohol 8 in 90% yield.
Scheme 4. Synthetic Applications of Compound 3aa
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O
a
Ph
N3
Ru(bpy)3(PF6)2 (3 mol %)
N
N
+
(1)
Ph
i-PrCO2K (2.0 equiv), N2, DMF (80 mL)
-10 oC, H2O (1.0 equiv)
blue LEDs, 48 h
24 mmol
8 mmol
1.16 g
1.50 g
71% yield
b
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MeO2C
O
MeO2C
N
O
HO
5
, 56%, dr = 1.1:1
b
N
N
OH
a
c
6
, >99%, dr = 1.24:1
O
N
NO2
4
, 86%
e
d
O
HO
N
N
N
S
8
, 90%
7,
58%, dr = 1.8:1
Reaction conditions: (a) 3aa (0.1 mmol), 2-(bromomethyl)-4-nitrophenol (0.1 mmol), K2HPO4 (1.1
equiv), DCM (2 mL), N2, rt, 28 h. (b) 3aa (0.1 mmol), Ru(bpy)3(PF6)2 (1 mol %), DMAD (0.3 mmol),
PFNB (0.15 mmol), KOAc (0.4 mmol), DCM (2 mL), N2, 23 W CFL, 96 h. (c) NaBH4 (1.5 equiv) in
EtOH, rt. (d) 3aa (0.3 mmol), 2-chloro-benzothiazole (0.2 mmol), Ir(ppy)2(dtbbpy)PF6 (1 mmol %),
NaOAc (2.0 equiv), DMA (2 mL), N2, 23 W CFL. (e) PhMgBr (2.0 equiv) in THF, 0 ℃-rt, 4 h.
Further experiments were carried out to gain insight into the mechanism of this reaction (see the
Supporting Information). Stern-Volmer experiments illustrated that the luminescence emission of
2+
excited-state *Ru(bpy)3 was quenched by N-phenyl pyrrolidine more efficiently (Figure 1, a and b).
2+
Significantly, the luminescence emission of excited-state *Ru(bpy)3 was not quenched by vinyl
azides, which was consistent with our designed reduction quenching mechanism. The quantum yield of
the model reaction of 1a with 2a was calculated to be 4.83 (see the Supporting Information), which
showed that the reaction proceeded through radical chain propagation process. Under the standard
conditions, when 1.0 equiv TEMPO and 3.0 equiv TEMPO were added into the reaction mixture
separately, the yield of desired product 3aa decreased to 46% and 32%, respectively (Figure 1, c).
Furthermore, BHT-trapped iminyl radical generated by α-amino radicals reacting with vinyl azides
could be successfully detected by HRMS, suggesting a mechanism involving radical. Besides, when
1.0 equiv H218O was added into the reaction mixture, the product was labeled by 18O was successfully
detected by HRMS (Figure 1, d).
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c
O
Ph
N3
N
standard conditions
TEMPO (x equiv)
N
(1)
+
Ph
TEMPO (1.0 equiv) 48% yield
TEMPO (3.0 equiv) 32% yield
18O
d
Ph
N3
Ru(bpy)3(PF6)2 (3 mol %)
i-PrCO2K (2.0 equiv), N2, DMF (2 mL)
N
N
+
(2)
Ph
-10 oC, H218O (1.0 equiv)
blue LEDs,12 h
detected by HRMS
Figure 1. Mechanistic investigations: (a) Fluorescence quenching experiments with Ru(bpy)3(PF6)2
and variable N-Ph pyrrolidine 1a (mM). (b) Stern-Volmer plot of Ru(bpy)3(PF6)2 and variable N-Ph
pyrrolidine 1a. (c) Radical trapping experiment. (d) H218O isotope labeling experiment.
Based on a series of mechanistic experiments, a plausible mechanism for the photoredox-catalyzed
transformation is shown in Scheme 5. First, the single-electron transfer from the substrate amine (1a)
[the oxidative potential of N-phenyl pyrrolidine is 0.74 V versus saturated calomel electrode (SCE) in
CH3CN] to visible light excited photocatalyst *Ru(bpy)3 (II) (*RuII/RuI = 0.84 V) initiates the first
2+
+
catalytic cycle and provides the electron-rich Ru(bpy)3 (III) and the amine radical cation (IV). Next
the amine radical cation (IV) reacting with the base generates α-amino radical (V). The C–H bonds
adjacent to the nitrogen atom in intermediate IV are weakened by about 40 kcal/mol and so could
undergo deprotonation by i-PrCO2K to give α-amino radical V.19 Radical addition of α-amino radical
(V) to vinyl azide 2a generates the iminyl radical (VI), which is subsequently reduced by the reductive
photocatalyst to form the imine anion intermediate (VIII). Finally, the hydrolysis of imine anion (VIII)
affords the desired β-amino ketone product 3aa.
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2+
*
[Ru(bpy)3]
II
N
Ph
1a
SET
7
8
9
Photoredox
Catalysis
H
N
Ph
IV
[Ru(bpy)3]2+
[Ru(bpy)3]+
I
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III
i-PrCO2K
-H+
N
SET
N
N3
Ph
N
-N2
VIII
N
Ph
N
Ph
H2O
2a
VI
V
O
IV
BHT
tBu
1a
chain propagation
Ph
Ph
N
O
N
tBu
VII
detected by HRMS
N
3aa
Scheme 5. Proposed reaction mechanism.
CONCLUSION
In summary, we have developed a novel synthetic method to obtain ring substituted β-amino ketones
through visible-light photoredox catalysis. This mild visible-light photocatalysis provides an alternative
method to achieve α-alkylation of cyclic tertiary arylamines to obtain cyclic β-amino ketones which are
valuable and versatile intermediates in modern organic synthesis, and further studies on β-amino
ketone compounds are currently underway in our laboratory.
EXPERIMENTAL SECTION
General information. All glassware was thoroughly oven-dried. Chemicals and solvents were either
purchased from commercial suppliers or purified by standard techniques. Thin-layer chromatography
(TLC) plates were visualized by exposure to ultraviolet light and/or staining with phosphomolybdic
acid followed by heating on a hot plate. Flash chromatography was carried out using silica gel (200–
300 mesh). 1H NMR and 13C NMR spectra were recorded on a Bruker Avance III 400 MHz or Agilent
Inova 600 MHz. The spectra were recorded in CDCl3 as solvent at room temperature, 1H and 13C NMR
chemical shifts are reported in ppm relative to the residual solvent peak. The residual solvent signals
were used as references and the chemical shifts were converted to the TMS scale (CDCl3: δ H = 7.26
ppm, δ C = 77.00 ppm). Data for 1H NMR are reported as follows: chemical shift (δ ppm), multiplicity
(s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, dd = doublet), integration, coupling
constant (Hz) and assignment. Data for 13C NMR are reported as chemical shift. HRMS were
performed on a Bruker Apex II mass instrument (ESI).
Vinyl azides were synthesized according to reported procedures.20,21
Cyclic amines were synthesized according to reported procedures.22
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General catalysis procedure for the synthesis of product 3:
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A dried quartz tube was charged with the catalyst Ru(bpy)3(PF6)2 (3 mol %, 5.2 mg), the base
i-PrCO2K (2.0 equiv, 0.4 mmol, 50.4 mg) and then DMF (2.0 mL) was added via a syringe. Next,
1-phenylpyrrolidine 1a (3.0 equiv, 0.6 mmol, 88.3 mg), vinyl azide 2a (0.2 mmol, 1.0 equiv, 29.3 mg)
and H2O (0.2 mmol, 3.6 mg, 1.0 equiv) were added via a syringe. The reaction mixture was degassed
by three cycles of freeze-pump-thaw. After the mixture was thoroughly degassed, the reaction was
cooled to –10 ℃ ， and then irradiated under a 450–455 nm blue LEDs in Parallel Light Reactor
(WP-TEC-1020). After 12 h, completion of the reaction, water was added and the organic product was
extracted with ethyl acetate. The crude mixture was purified by flash chromatography (silica gel,
petroleum ether/ethyl acetate = 50:1–20:1) to afford the pure product 3aa (42.7 mg, 81% yield) as a
yellow solid.
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Procedure for scale-up preparation of 3aa
The catalyst Ru(bpy)3(PF6)2 (3 mol %, 208 mg), the base i-PrCO2K (2.0 equiv, 16 mmol, 2 g) were
weighed into an oven-dried 150 mL round-bottom flask with magnetic stirring and DMF (80 mL) was
then added. Next, 1-phenylpyrrolidine 1a (3.0 equiv, 24 mmol, 3.53 g), vinyl azide 2a (8 mmol, 1.0
equiv, 1.16 g) and H2O (8 mmol, 144 mg, 1.0 equiv) were added via a syringe. The reaction mixture
was degassed by three cycles of freeze-pump-thaw. The resulting mixture was stirred at –10 ℃ for 48 h
under irradiation of 18 W blue LEDs. After completion of the reaction, water was added and the
organic product was extracted with ethyl acetate. The crude mixture was purified by flash
chromatography (silica gel, petroleum ether/ethyl acetate = 50:1–20:1) to afford the pure product 3aa
(1.50 g, 71% yield).
1-Phenyl-2-(1-phenylpyrrolidin-2-yl)ethan-1-one (3aa), yellow solid, 81% yield, 42.7 mg, mp = 116–
118 ℃; 1H NMR (400 MHz, CDCl3): δ 8.01–7.88 (m, 2H), 7.57–7.55 (m, 1H), 7.48–7.44 (m, 2H),
7.25–7.21 (m, 2H), 6.68 (t, J = 8.0 Hz, 1H), 6.60 (d, J = 12 Hz, 2H), 4.45 (m, 1H), 3.48–3.43 (m, 1H),
3.38 (dd, J = 16 Hz, 4 Hz, 1H), 3.22 (q, J = 8 Hz, 1H), 3.02 (dd, J = 16 Hz, 12 Hz, 1H), 2.16 (m, 1H),
2.04 (m, 2H), 1.92–1.77 (m, 1H); 13C{1H} NMR (150 MHz, CDCl3) δ 201.5, 148.5, 139.1, 135.1,
131.3, 130.5, 129.9, 117.7, 113.9, 56.5, 49.8, 43.1, 33.4, 25.1; HRMS (ESI): [M + H]+ calcd for
[C18H20NO]: 266.1539, found: 266.1542.
2-(1-(4-Fluorophenyl)pyrrolidin-2-yl)-1-phenylethan-1-one (3ab), yellow solid, 56% yield, 32.0 mg,
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mp = 94–96 ℃; H NMR (400 MHz, CDCl3): δ 7.95–7.93 (m, 2H), 7.59–7.55 (m, 1H), 7.48–7.44 (m,
2H), 6.96–6.91 (m, 2H), 6.52–6.49 (m, 2H), 4.41–4.35 (m, 1H), 3.44–3.39 (m, 1H), 3.30 (dd, J = 16
Hz, 4 Hz, 1H), 3.17 (q, J = 8 Hz, 1H), 3.03 (dd, J = 16 Hz, 12 Hz, 1H), 2.23–2.13 (m, 1H), 2.08–2.00
(m, 2H), 1.85–1.79 (m, 1H); 13C{1H} NMR (100 MHz, CDCl3): δ 199.5, 154.9 (d, J = 232 Hz), 143.3,
137.1, 133.3, 128.7, 128.0, 115.8 (d, J = 22 Hz), 112.4 (d, J = 7 Hz), 55.0, 48.4, 41.1, 31.6, 23.3;
HRMS (ESI): [M+H]+ calcd for [C18H19FNO]: 284.1445, found: 284.1447.
(2-(1-(4-Chlorophenyl)pyrrolidin-2-yl)-1-phenylethan-1-one (3ac), yellow solid, 82% yield, 48.9 mg,
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mp = 124–126 ℃; H NMR (400 MHz, CDCl3): δ 7.94–7.92 (m, 2H), 7.59–7.55 (m, 1H), 7.48–7.44
(m, 2H), 7.16–7.14 (m, 2H), 6.51–6.49 (m, 2H), 4.43–4.37 (m, 1H), 3.44–3.39 (m, 1H), 3.29 (dd, J =
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16 Hz, 4 Hz, 1H), 3.18 (q, J = 8 Hz, 1H), 3.03 (dd, J = 16 Hz, 8 Hz, 1H), 2.22–2.13 (m, 1H), 2.08–
2.01 (m, 2H), 1.86–1.81 (m, 1H); 13C{1H} NMR (100 MHz, CDCl3): δ 199.4, 145.1, 137.0, 133.4,
129.2, 128.7, 128.0, 120.6, 113.0, 54.8, 48.1, 40.9, 31.6, 23.2; HRMS (ESI): [M+H]+ calcd for
[C18H19ClNO]: 300.1150, found: 300.1155.
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2-(1-(4-Bromophenyl)pyrrolidin-2-yl)-1-phenylethan-1-one (3ad), yellow solid, 58% yield, 40.0 mg,
mp = 125–127 ℃; 1H NMR (600 MHz, CDCl3) δ 7.94–7.93 (m, 2H), 7.58–7.56 (m, 1H), 7.47–7.45 (m,
2H), 7.28–7.27 (m, 2H), 6.47–6.45 (m, 2H), 4.41–4.38 (m, 1H), 3.43–3.39 (m, 1H), 3.29 (d, J = 18 Hz,
1H), 3.18 (q, J = 12 Hz, 1H), 3.03 (dd, J = 18 Hz, 6 Hz, 1H), 2.20–2.14 (m, 1H), 2.05–2.03 (m, 2H),
1.85–1.82 (m, 1H); 13C{1H} NMR (150 MHz, CDCl3) δ 199.3, 145.4, 137.0, 133.3, 132.0, 128.7,
128.0, 113.6, 107.7, 54.8, 48.1, 40.8, 31.5, 23.2; HRMS (ESI): [M+H]+ calcd for [C18H19BrNO]:
344.0645, found: 344.0652.
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1-Phenyl-2-(1-(p-tolyl)pyrrolidin-2-yl)ethan-1-one (3ae), yellow solid, 41% yield, 22.9 mg, mp = 104–
106 ℃; 1H NMR (600 MHz, CDCl3) δ 7.95–7.94 (m, 2H), 7.58–7,56 (m, 1H), 7.47–7.45 (m, 2H), 7.05
–7.04 (m, 2H), 6.54–6.52 (m, 2H), 4.42–4.39 (m, 1H), 3.46–3.42 (m, 1H), 3.38–3.35 (m, 1H), 3.19 (q,
J = 6 Hz, 1H), 3.01 (dd, J = 18 Hz, 6 Hz, 1H), 2.25 (s, 3H), 2.20–2.13 (m, 1H), 2.05–2.00 (m, 2H),
1.84–1.80 (m, 1H). 13C{1H} NMR (150 MHz, CDCl3) δ 199.7, 144.5, 137.1, 133.2, 129.9, 128.6,
128.0, 124.9, 112.0, 54.6, 48.1, 41.2, 31.4, 23.2, 20.2; HRMS (ESI): [M+H]+ calcd for [C18H22NO]:
280.1696, found: 280.1700.
2-(1-(4-Methoxyphenyl)pyrrolidin-2-yl)-1-phenylethan-1-one (3af), yellow solid, 48% yield, 28.4 mg,
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mp = 91–93 ℃; H NMR (400 MHz, CDCl3): δ 7.96–7.93 (m, 2H), 7.58–7.55 (m, 1H), 7.48–7.44 (m,
2H), 6.87–6.83 (m, 2H), 6.58–6,56 (m, 2H), 4.39–4.34 (m, 1H), 3.75 (s, 3H), 3.47–3.39 (m, 1H), 3.34
(dd, J = 16 Hz, 4 Hz, 1H), 3.17 (q, J = 8 Hz, 1H), 3.01 (dd, J = 16 Hz, 12 Hz, 1H), 2.25–2.10 (m, 1H),
2.06–1.99 (m, 2H), 1.84–1.78 (m, 1H); 13C{1H} NMR (100 MHz, CDCl3): δ 199.8, 151.0, 141.5,
137.2, 133.2, 128.6, 128.0, 115.3, 112.9, 56.0, 55.1, 48.6, 41.4, 31.6, 23.3; HRMS (ESI): [M+H]+ calcd
for [C19H22NO2]: 296.1645, found: 296.1646.
2-(1-(4-(Tert-butyl)phenyl)pyrrolidin-2-yl)-1-phenylethan-1-one (3ag), yellow solid, 41% yield, 26.2
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mg, mp = 101–103 ℃; H NMR (400 MHz, CDCl3): δ 7.96–7.94 (m, 2H), 7.58–7.55 (m, 1H), 7.48–
7.44 (m, 2H), 7.28–7.22 (m, 2H), 6.58–6.55 (m, 2H), 4.44–4.39 (m, 1H), 3.48–3.44 (m, 1H), 3.40 (dd,
J = 16 Hz, 4 Hz, 1H), 3.20 (q, J = 8 Hz, 1H), 3.00 (dd, J = 20 Hz, 8 Hz, 1H), 2.22–2.08 (m, 1H), 2.06–
1.99 (m, 2H), 1.89–1.75 (m, 1H), 1.28 (s, 9H); 13C{1H} NMR (100 MHz, CDCl3): δ 199.7, 144.4,
138.4, 137.16, 133.2, 128.7, 128.1, 126.2, 111.5, 54.6, 48.1, 41.4, 33.7, 31.6, 31.5, 23.3; HRMS (ESI):
[M+H]+ calcd for [C22H28NO]: 322.2165, found: 322.2166.
2-(1-(3-Fluorophenyl)pyrrolidin-2-yl)-1-phenylethan-1-one (3ah), yellow solid, 60% yield, 34.2 mg,
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mp = 90–92 ℃; H NMR (600 MHz, CDCl3) δ 7.94 (d, J = 6 Hz, 2H), 7.58–7.56 (m, 1H), 7.47–7.45
(m, 2H), 7.16–7.12 (m, 1H), 6.37–6.35 (m, 2H), 6.29–6.27 (m, 1H), 4.43–4.39 (m, 1H), 3.44–3.41 (m,
1H), 3.33 (dd, J = 17.3, 2.4 Hz, 1H), 3.20 (q, J = 8.5 Hz, 1H), 3.04 (dd, J = 18 Hz, 6 Hz, 1H), 2.21–
2.15 (m, 1H), 2.07–2.02 (m, 2H), 1.87–1.83 (m, 1H); 13C{1H} NMR (150 MHz, CDCl3) δ 199.2, 164.2
(d, J = 240.0 Hz), 148.0 (d, J = 10.5 Hz), 137.0, 133.3 (d, J = 4.5 Hz), 130.4, 128.7 (d, J = 12 Hz),
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128.0 (d, J = 12 Hz) , 107.6, 102.3, 98.9, 54.8, 48.1, 40.9, 31.4, 23.1; HRMS (ESI): [M+H]+ calcd for
[C18H19FNO]: 284.1445, found: 284.1451.
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2-(1-(3-Chlorophenyl)pyrrolidin-2-yl)-1-phenylethan-1-one (3ai), yellow solid, 59% yield, 35.3 mg,
mp = 91–93 ℃; 1H NMR (400 MHz, CDCl3): δ 7.95–7.93 (m, 2H), 7.59–7.55 (m, 1H), 7.48–7.44 (m,
2H), 7.13–7.09 (m, 1H), 6.64–6.61 (m, 1H), 6.55–6.54 (m, 1H), 6.47–6.44 (m, 1H), 4.44–4.38 (m, 1H),
3.46–3.37 (m, 1H), 3.31 (dd, J = 16 Hz, 4 Hz, 1H), 3.19 (q, J = 8 Hz, 1H), 3.02 (dd, J = 20 Hz, 8 Hz,
1H), 2.21–2.12 (m, 1H), 2.08–2.00 (m, 2H), 1.89–1.79 (m, 1H); 13C{1H} NMR (100 MHz, CDCl3): δ
199.3, 147.5, 137.0, 135.3, 133.4, 130.3, 128.7, 128.0, 115.6, 111.7, 110.1, 54.7, 48.0, 40.9, 31.4, 23.1;
HRMS (ESI): [M+H]+ calcd for [C18H19ClNO]: 300.1150, found: 300.1155.
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2-(1-(3-Bromophenyl)pyrrolidin-2-yl)-1-phenylethan-1-one (3aj), yellow solid, 66% yield, 45.2 mg,
mp = 87–89 ℃; 1H NMR (400 MHz, CDCl3): δ 7.95–7.93 (m, 2H), 7.59–7.56 (m, 1H), 7.48–7.45 (m,
2H), 7.07–7.03 (m, 1H), 6.78–6.76 (m, 1H), 6.71–6.70 (m, 1H), 6.51–6.48 (m, 1H), 4.43–4.38 (m, 1H),
3.44 –3.39 (m, 1H), 3.31 (dd, J = 16 Hz, 4 Hz, 1H), 3.19 (q, J = 8 Hz, 1H), 3.01 (dd, J = 20 Hz, 8 Hz,
1H), 2.21–2.10 (m, 1H), 2.07–2.00 (m, 2H), 1.90–1.76 (m, 1H); 13C{1H} NMR (100 MHz, CDCl3): δ
199.3, 147.7, 137.0, 133.4, 130.6, 128.7, 128.1, 123.6, 118.5, 114.6, 110.6, 54.7, 47.9, 40.8, 31.4, 23.1;
HRMS (ESI): [M+H]+ calcd for [C18H19BrNO]: 344.0645, found: 344.0647.
1-Phenyl-2-(1-(m-tolyl)pyrrolidin-2-yl)ethan-1-one (3ak), yellow solid, 57% yield, 31.7 mg, mp = 82–
84 ℃; 1H NMR (600 MHz, CDCl3) δ 7.75–7.74 (m, 2H), 7.39–7.33 (m, 2H), 7.24–7.22 (m, 2H), 6.69–
6.66 (m, 1H), 6.60 (d, J = 6 Hz, 2H), 4.45–4.42 (m, 1H), 3.46–3.43 (m, 1H), 3.38–3.35 (m, 1H), 3.22
(q, J = 6 Hz, 1H), 3.01 (dd, J = 18 Hz, 6 Hz, 1H), 2.40 (s, 3H), 2.20–2.13 (m, 1H), 2.06–2.01 (m, 2H),
1.88–1.80 (m, 1H); 13C{1H} NMR (150 MHz, CDCl3) δ 199.8, 146.5, 138.4, 137.2, 133.9, 129.4, 128.6,
128.5, 125.2, 115.7, 111.9, 54.5, 47.9, 41.1, 31.4, 23.1, 21.3; HRMS (ESI): [M+H]+ calcd for
[C19H22NO]: 280.1696, found: 280.1699.
2-(1-(2-Fluorophenyl)pyrrolidin-2-yl)-1-phenylethan-1-one (3al), white solid, 32% yield, 18.0 mg, mp
= 86–88 ℃; 1H NMR (600 MHz, CDCl3) δ 7.93–7.92 (m, 2H), 7.56–7.54 (m, 1H), 7.46–7.43 (m, 2H),
7.02–6.98 (m, 2H), 6.77–6.73 (m, 1H), 6.72–6.69 (m, 1H), 4.54–4.50 (m, 1H), 3.67–3.63 (m, 1H), 3.38
(dd, J = 18 Hz, 6 Hz, 1H), 3.28–3.23 (m, 1H), 2.94 (dd, J = 18 Hz, 6 Hz, 1H), 2.31–2.25 (m, 1H), 2.00
–1.90 (m, 2H), 1.75–1.70 (m, 1H); 13C{1H} NMR (150 MHz, CDCl3) δ 199.4, 152.8 (d, J = 240 Hz),
137.2, 136.0 (d, J = 10.5 Hz), 133.0, 128.5, 128.0, 124.5 (d, J = 3 Hz), 118.2 (d, J = 4.5 Hz), 116.5 (d,
J = 4.5 Hz), 116.4 (d, J = 22.5 Hz), 55.8 (d, J = 4.5 Hz), 50.6 (d, J = 4.5 Hz), 42.7, 31.8, 23.4; HRMS
(ESI): [M+H]+ calcd for [C18H19FNO]: 284.1445, found: 284.1448.
1-Phenyl-2-(1-phenylazepan-2-yl)ethan-1-one (3am), yellow solid, 19% yield, 11.0 mg, mp = 101–103
℃; 1H NMR (600 MHz, CDCl3) δ 7.95–7.94 (m, 2H), 7.57–7.55 (m, 1H), 7.47–7.44 (t, J = 7.8 Hz, 2H),
7.23–7.20 (m, 2H), 6.73–6.72 (m, 2H), 6.65–6.63 (m, 1H), 4.33–4.28 (m, 1H), 3.53–3.51 (m, 1H), 3.27
–3.13 (m, 3H), 2.33–2.28 (m, 1H), 1.83–1.81 (m, 1H), 1.80–1.76 (m, 1H), 1.73–1.71 (m, 1H), 1.69–
1.60 (m, 1H), 1.48–1.42 (m, 1H), 1.33–1.29 (m, 2H); 13C{1H} NMR (150 MHz, CDCl3) δ 199.5, 147.8,
137.4, 133.1, 129.5, 128.6, 128.1, 115.2, 110.5, 54.1, 43.6, 42.1, 35.3, 29.8, 27.6, 25.4; HRMS (ESI):
[M+H]+ calcd for [C20H24NO]: 294.1852, found: 294.1858.
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Tert-butyl 3-(2-oxo-2-phenylethyl)-4-phenylpiperazine-1-carboxylate (3an), yellow solid, 48% yield,
36.3 mg, mp = 118–120 ℃; 1H NMR (400 MHz, CDCl3): δ 7.87 (d, J = 8 Hz, 2H), 7.55–7.52 (m, 1H),
7.43–7.40 (m, 2H), 7.29–7.21 (m, 3H), 6.94–6.92 (m, 2H), 6.86–6.83 (m, 1H), 4.57–4.55 (m, 1H), 4.25
(s, 1H), 4.11–4.07 (m, 1H), 3.51–3.33 (m, 2H), 3.29 (d, J = 13.6 Hz, 1H), 3.16–3.00 (m, 2H), 2.73–
2.67 (m, 1H), 1.20 (s, 9H); 13C{1H} NMR (100 MHz, CDCl3): δ 198.5, 154.9, 149.1, 136.8, 133.3,
129.5, 128.6, 128.0, 119.8, 119.8, 116.0, 79.9, 77.4, 51.7, 47.0, 42.9, 33.4, 28.1; HRMS (ESI): [M+H]+
calcd for [C23H29N2O3]: 381.2173, found: 381.2176.
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1-Phenyl-2-(4-phenylmorpholin-3-yl)ethan-1-one (3ao), yellow solid, 20% yield, 11 mg, mp = 115–
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117 ℃; H NMR (400 MHz, CDCl3): δ 7.90–7 89 (m, 2H), 7.55–7.52 (m, 1H), 7.44–7.40 (m, 2H),
7.31–7.21 (m, 3H), 6.92–6.90 (m, 2H), 6.86–6.82 (m, 1H), 4.46–4.43 (m, 1H), 4.07–4.03 (m, 1H),
3.93–3.84 (m, 2H), 3.79–3.70 (m, 2H), 3.29–3.26 (m, 1H), 3.22–3.15 (m, 1H), 2.81–2.76 (m, 1H);
13C{1H} NMR (100 MHz, CDCl3): δ 199.3, 148.9, 136.9, 133.3, 129.5, 128.6, 128.0, 119.5, 115.2, 69.7,
67.0, 51.2, 43.3, 33.5; HRMS (ESI): [M+H]+ calcd for [C18H20NO2]: 282.1489, found: 282.1489.
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3-(Methyl(phenyl)amino)-1-phenylpropan-1-one (3ap), colorless oil, 18% yield ， 8.8 mg; H NMR
(600 MHz, CDCl3) δ 7.94–7.92 (m, 2H), 7.57–7,55 (m, 1H), 7.46–7.44 (m, 2H), 7.26–7.23 (m, 2H),
6.75 (d, J = 6 Hz, 2H), 6.72 (d, J = 6 Hz, 1H), 3.85–3.82 (m, 2H), 3.25–3.23 (m, 2H), 2.97 (s, 3H);
13C{1H} NMR (100 MHz, CDCl3): δ 199.5, 148.6, 136.9, 133.2, 129.3, 128.6, 128.1, 116.6, 112.4,
48.0, 38.6, 35.2; HRMS (ESI): [M+H]+ calcd for [C16H17NO]: 240.1383, found: 240.1383.
2-(5-Methyl-1-phenylpyrrolidin-2-yl)-1-phenylethan-1-one (3aq), colorless oil, 64% yield, 35.8 mg; 1H
NMR (400 MHz, CDCl3) (mixture of diastereoisomers): δ 7.99–7.95 (m, 2H), 7.94–7.90 (m, 2H), 7.62
–7.50 (m, 2H), 7.49–7.42 (m, 4H), 7.25–7.17 (m, 5H), 6.73–6.57 (m, 7H), 4.60–4.49 (m, 1H), 4.38–
4.32 (m, 1H), 4.09–4.02 (M, 1H), 3.88–3.81 (m, 1H), 3.57 (dd, J = 20 Hz, 4 Hz, 1H), 3.42–3.33 (m,
1H), 3.04 (dd, J = 16 Hz, 8 Hz, 1H), 2.90 (dd, J = 16 Hz, 8 Hz, 1H), 2.37–2.09 (m, 4H), 1.74 (m, 4H),
1.32–1.30 (m, 3H), 1.15–1.14 (m, 3H); 13C{1H} NMR (100 MHz, CDCl3) (mixture of
diastereoisomers): δ 199.9, 199.5, 146.7, 144.6, 137.2, 137.1, 133.2, 133.2, 129.4, 129.3, 128.6, 128.6,
128.0, 128.0, 115.9, 115.3, 113.4, 112.1, 56.6, 55.8, 53.8, 52.7, 44.0, 39.9, 32.2, 30.8, 30.3, 28.8, 21.7,
18.3; HRMS (ESI): [M+H]+ calcd for [C19H22NO]: 280.1696, found: 280.1697.
1-(2-fluorophenyl)-2-(1-phenylpyrrolidin-2-yl)ethan-1-one (3ar), yellow solid, 58% yield, 32.6 mg, mp
= 87–89 ℃; 1H NMR (400 MHz, CDCl3): δ 7.89–7.85 (m, 1H), 7.55–7.49 (m, 1H), 7.25–7.20 (m, 3H),
7.15–7.10 (m, 1H), 6.69–6.65 (m, 1H), 6.62–6.57 (m, 2H), 4.47–4.41 (m, 1H), 3.52–3.34 (m, 2H), 3.26
–3.15 (m, 1H), 3.03 (m, 1H), 2.23–2.10 (m, 1H), 2.09–1.96 (m, 2H), 1.87–1.77 (m, 1H); 13C{1H} NMR
(100 MHz, CDCl3): δ 198.0 (d, J = 4 Hz), 162.0 (d, J = 253 Hz), 146.6, 134.6 (d, J = 9 Hz), 130.4 (d, J
= 4 Hz), 129.4, 126.0 (d, J = 12 Hz), 124.5 (d, J = 4 Hz), 116.8 (d, J = 23 Hz), 115.7, 111.9, 54.3, 47.9,
46.3 (d, J = 7 Hz), 31.6, 23.2; HRMS (ESI): [M+H]+ calcd for [C18H19FNO]: 284.1445, found:
284.1452.
1-(2-Methoxyphenyl)-2-(1-phenylpyrrolidin-2-yl)ethan-1-one (3as), colorless oil, 54% yield, 31.7 mg;
1H NMR (600 MHz, CDCl3) δ 7.71–7.69 (m, 1H), 7.49–7.44 (m, 1H), 7.24–7.20 (m, 2H), 7.05–7.01
(m, 1H), 6.99–6.95 (m, 1H), 6.70–6.66 (m, 1H), 6.64–6.61 (m, 2H), 4.42–4.36 (m, 1H), 3.86 (s, 3H),
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3.44–3.41 (m, 2H), 3.21–3.16 (m, 1H), 3.02 (dd, J = 20 Hz, 8 Hz, 1H), 2.10–1.99 (m, 3H), 1.86–1.83
(m, 1H); 13C{1H} NMR (150 MHz, CDCl3) δ 202.0, 158.4, 146.8, 140.1, 133.4, 130.1, 129.2, 120.7,
115.5, 111.9, 111.5, 55.5, 54.8, 47.9, 46.5, 31.4, 23.2; HRMS (ESI): [M+H]+ calcd for [C19H22NO2]:
296.1645, found: 296.1650.
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mp = 88–90 ℃; H NMR (600 MHz, CDCl3) δ 7.71–7.70 (m, 1H), 7.63–7.61 (m, 1H), 7.44–7.41 (m,
1H), 7.27–7.22 (m, 3H), 6.69–6.67 (m, 1H), 6.60–6.58 (m, 2H), 4.45–4.42 (m, 1H), 3.47–3.44 (m, 1H),
3.36 (dd, J = 18 Hz, 6 Hz, 1H), 3.24 (q, J = 12 Hz, 1H), 3.01 (dd, J = 18 Hz, 6 Hz, 1H), 2.20–2.14 (m,
1H), 2.06–2.02 (m, 2H), 1.84–1.80 (m, 1H); 13C{1H} NMR (150 MHz, CDCl3) δ 198.3, 162.9 (d, J =
246.0 Hz), 146.4, 139.2, 130.3（d, J = 7.5 Hz）, 129.4, 123.8 (d, J = 3.0 Hz), 120.2 (d, J = 21.0 Hz)，
115.9, 114.7（d, J = 22.5 Hz）, 112.0, 54.4, 47.9, 41.3, 31.5, 23.1; HRMS (ESI): [M+H]+ calcd for
[C18H19FNO]: 284.1445, found: 284.1446.
1-(3-Chlorophenyl)-2-(1-phenylpyrrolidin-2-yl)ethan-1-one (3au), yellow solid, 62% yield, 36.0 mg,
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mp = 95–97 C; H NMR (600 MHz, CDCl3) δ 7.92–7.91 (m, 1H), 7.82–7.80 (m, 1H), 7.55–7.53 (m,
1H), 7.41–7.39 (m, 1H), 7.25–7.22 (m, 2H), 6.70–6.67 (m, 1H), 6.59–6.58 (m, 2H), 4.45–4.41 (m, 1H),
3.49–3.42 (m, 1H), 3.37–3.33 (m, 1H), 3.22 (q, J = 6 Hz, 1H), 2.99 (dd, J = 18 Hz, 6 Hz, 1H), 2.22–
2.15 (m, 1H), 2.07–2.01 (m, 2H), 1.85–1.78 (m, 1H); 13C{1H} NMR (150 MHz, CDCl3) δ 198.3, 146.4,
138.6, 135.0, 133.1, 130.0, 129.4, 128.2, 126.1, 115.9, 111.9, 54.4, 47.9, 41.3, 31.4, 23.1; HRMS (ESI):
[M+H]+ calcd for [C18H19ClNO]: 300.1150, found: 300.1150.
1-(3-Bromophenyl)-2-(1-phenylpyrrolidin-2-yl)ethan-1-one (3av), colorless oil, 54% yield, 37.2 mg;
1H NMR (400 MHz, CDCl3): δ 8.07–8.06 (m, 1H), 7.86–7.84 (m, 1H), 7.70–7.68 (m, 1H), 7.35–7.31
(m, 1H), 7.25–7.18 (m, 2H), 6.70–6.67 (m, 1H), 6.59–6.57 (m, 2H), 4.45–4.40 (m, 1H), 3.48–3.43 (m,
1H), 3.37–3.32 (m, 1H), 3.22 (q, J = 8 Hz, 1H), 2.98 (dd, J = 16 Hz, 8 Hz, 1H), 2.23–2.13 (m, 1H),
2.10– 1.94 (m, 2H), 1.87–1.71 (m, 1H); 13C{1H} NMR (100 MHz, CDCl3): δ 198.2, 146.4, 138.8,
136.1, 131.2, 130.3, 129.5, 126.5, 123.1, 115.9, 111.9, 54.4, 47.9, 41.3, 31.5, 23.2; HRMS (ESI):
[M+H]+ calcd for [C18H19BrNO]: 344.0645, found: 344.0653.
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2-(1-Phenylpyrrolidin-2-yl)-1-(m-tolyl)ethan-1-one (3aw), colorless oil, 53% yield, 29.4 mg; H NMR
(600 MHz, CDCl3) δ 7.75–7.73 (m, 2H), 7.38–7.33 (m, 2H), 7.24–7.22 (m, 2H), 6.69–6.66 (m, 1H),
6.61–6.60 (m, 2H), 4.45–4.42 (m, 1H), 3.47–3.43 (m, 1H), 3.38–3.35 (m, 1H), 3.22 (q, J = 6 Hz, 1H),
3.01 (dd, J = 18 Hz, 6 Hz, 1H), 2.40 (s, 3H), 2.21–2.14 (m, 1H), 2.06–2.01 (m, 2H), 1.86–1.82 (m,
1H); 13C{1H} NMR (150 MHz, CDCl3) δ 199.7, 146.5, 138.4, 137.2, 133.9, 129.4, 128.6, 128.5, 125.2,
115.7, 111.9, 54.5, 47.9, 41.2, 31.4, 23.1, 21.3; HRMS (ESI): [M+H]+ calcd for [C19H22NO]: 280.1696,
found: 280.1701.
1-(4-Fluorophenyl)-2-(1-phenylpyrrolidin-2-yl)ethan-1-one (3ax), yellow solid, 57% yield, 32.4 mg,
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mp = 85–87 ℃; H NMR (600 MHz, CDCl3) δ 7.98–7.95 (m, 2H), 7.25–7.21 (m, 2H), 7.13–7.10 (m,
2H), 6.69–6.67 (m, 1H), 6.60–6.59 (m, 2H), 4.46–4.40 (m, 1H), 3.46–3.43 (m, 1H), 3.35–3.32 (m, 1H),
3.22 (q, J = 12 Hz, 1H), 3.00 (dd, J = 18 Hz, 12 Hz, 1H), 2.21–2.14 (m, 1H), 2.06–2.01 (m, 2H), 1.85–
1.81 (m, 1H); 13C{1H} NMR (150 MHz, CDCl3) δ 197.9, 165.8 (d, J = 255.0 Hz), 146.4, 133.6, 130.7
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(d, J = 4.5 Hz), 129.4, 115.8, 115.7 (d, J = 21.8 Hz), 111.9, 54.5, 47.9, 41.0, 31.5, 23.1; HRMS (ESI):
[M+H]+ calcd for [C18H19FNO]: 284.1445, found: 284.1447.
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mp = 119–121 ℃; 1H NMR (600 MHz, CDCl3) δ 7.88–7.87 (m, 2H), 7.43–7.42 (d, J = 6 Hz, 2H), 7.25
–7.21 (m, 2H), 6.70–6.67 (m, 1H), 6.60–6.58 (m, 2H), 4.45–4.41 (m, 1H), 3.46–3.43 (m, 1H), 3.35–
3.32 (m, 1H), 3.22 (q, J = 6 Hz, 1H), 2.99 (dd, J = 18 Hz, 6 Hz, 1H), 2.20–2.14 (m, 1H), 2.05–2.01 (m,
2H), 1.85–1.81 (m, 1H); 13C{1H} NMR (150 MHz, CDCl3) δ 198.3, 146.4, 139.7, 135.4, 129.4, 129.3,
128.9, 115.9, 111.9, 54.5, 47.9, 41.1, 31.4, 23.1; HRMS (ESI): [M+H]+ calcd for [C18H19ClNO]:
300.1150, found: 300.1157.
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1-(4-Bromophenyl)-2-(1-phenylpyrrolidin-2-yl)ethan-1-one (3az), yellow solid, 58% yield, 40.0 mg,
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mp = 113–115 ℃; H NMR (400 MHz, CDCl3): δ 7.79 (d, J = 12 Hz, 2H), 7.60–7.58 (m, 2H), 7.24–
7.20 (m, 2H), 6.70–6.66 (m, 1H), 6.59–6.57 (m, 2H), 4.45–4.40 (m, 1H), 3.49–3.39 (m, 1H), 3.36–3.30
(m, 1H), 3.21 (q, J = 8 Hz, 1H), 2.98 (dd, J = 16 Hz, 8 Hz, 1H), 2.22–2.12 (m, 1H), 2.09–1.96 (m, 2H),
1.88–1.74 (m, 1H); 13C{1H} NMR (100 MHz, CDCl3): δ 198.6, 146.4, 135.8, 132.0, 129.6, 129.5,
128.5, 115.9, 111.9, 54.4, 47.9, 41.1, 31.5, 23.2; HRMS (ESI): [M+H]+ calcd for [C18H19BrNO]:
344.0645, found: 344.0652.
2-(1-Phenylpyrrolidin-2-yl)-1-(p-tolyl)ethan-1-one (3ba), yellow solid, 59% yield, 32.9 mg, mp = 92–
94 ℃; 1H NMR (400 MHz, CDCl3): δ 7.84–7.82 (m, 2H), 7.24–7.19 (m, 4H), 6.66–6.64 (m, 1H), 6.60–
6.58 (m, 2H), 4.45–4.40 (m, 1H), 3.46–3.41 (m, 1H), 3.35–3.30 (m, 1H), 3.19 (q, J = 8 Hz, 1H), 2.98
(dd, J = 16 Hz, 8 Hz, 1H), 2.39 (s, 3H), 2.21–2.07 (m, 1H), 2.07–1.95 (m, 2H), 1.88–1.77 (m, 1H);
13C{1H} NMR (100 MHz, CDCl3): δ 199.2, 146.6, 144.1, 134.8, 129.4, 129.4, 128.2, 115.8, 112.0, 54.7,
47.9, 41.0, 31.5, 23.2, 21.7; HRMS (ESI): [M+H]+ calcd for [C19H22NO]: 280.1696, found: 280.1697.
1-(4-Methoxyphenyl)-2-(1-phenylpyrrolidin-2-yl)ethan-1-one (3bb), yellow solid, 48% yield, 28.5 mg,
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mp = 90–92 ℃; H NMR (400 MHz, CDCl3): δ 7.94–7.92 (m, 2H), 7.26–7.22 (m, 3H), 6.94–6.92 (m,
2H), 6.69–6.66 (m, 1H), 6.62–6.60 (m, 2H), 4.46–4.41 (m, 1H), 3.87 (s, 3H), 3.48–3.43 (m, 1H), 3.36–
3.28 (m, 1H), 3.21 (q, J = 8 Hz, 1H), 2.98 (dd, J = 16 Hz, 8 Hz, 1H), 2.23–2.10 (m, 1H), 2.07–2.01 (m,
2H), 1.90–1.78 (m, 1H); 13C{1H} NMR (100 MHz, CDCl3): δ 198.1, 163.6, 146.5, 130.4, 130.3, 129.4,
115.7, 113.8, 111.9, 55.5, 54.7, 47.9, 40.7, 31.4, 23.2; HRMS (ESI): [M+H]+ calcd for [C19H22NO2]:
296.1645, found: 296.1648.
Methyl 4-(2-(1-phenylpyrrolidin-2-yl)acetyl)benzoate (3bc), yellow solid, 40% yield, 25.7 mg, mp =
113–115 ℃; 1H NMR (400 MHz, CDCl3): δ 8.13–8.10 (m, 2H), 8.00–7.97 (m, 2H), 7.26–7.21 (m, 2H),
6.70–6.67 (m, 1H), 6.60–6.58 (m, 2H), 4.51–4.39 (m, 1H), 3.95 (s, 3H), 3.48–3.41 (m, 1H), 3.40 (dd, J
= 16 Hz, 4 Hz, 1H), 3.23 (q, J = 8 Hz, 1H), 3.04 (dd, J = 16 Hz, 8 Hz, 1H), 2.24–2.14 (m, 1H), 2.08–
2.00 (m, 2H), 1.86–1.81 (m, 1H); 13C{1H} NMR (100 MHz, CDCl3): δ 199.1, 166.2, 146.4, 140.2,
134.0, 129.9, 129.5, 128.0, 115.9, 112.0, 54.4, 52.5, 47.9, 41.6, 31.5, 23.2; HRMS (ESI): [M+H]+ calcd
for [C20H22NO3]: 324.1594, found: 324.1596.
1-([1,1'-Biphenyl]-4-yl)-2-(1-phenylpyrrolidin-2-yl)ethan-1-one (3bd), yellow solid, 44% yield, 29.9
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7.61 (m, 2H), 7.49–7.45 (m, 2H), 7.42–7.38 (m, 1H), 7.29–7.19 (m, 3H), 6.70–6.66 (m, 1H), 6.63–
6.61 (m, 2H), 4.52–4.42 (m, 1H), 3.52–3.43 (m, 1H), 3.42–3.37 (m, 1H), 3.23 (q, J = 8 Hz, 1H), 3.05
(dd, J = 16 Hz, 8 Hz, 1H), 2.26–2.13 (m, 1H), 2.13–1.99 (m, 2H), 1.95–1.76 (m, 1H); 13C{1H} NMR
(100 MHz, CDCl3): δ 199.2, 146.5, 145.9, 139.8, 135.9, 129.4, 129.0, 128.6, 128.3, 127.3, 115.8,
112.0, 54.6, 47.9, 41.2, 31.5, 23.2; HRMS (ESI): [M+H]+ calcd for [C24H24NO]: 342.1852, found:
342.1860.
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2-(1-Phenylpyrrolidin-2-yl)-1-(pyridin-2-yl)ethan-1-one (3be), colorless oil, 34% yield, 12.3 mg; H
NMR (600 MHz, CDCl3) δ 8.71–8.70 (m, 1H), 8.07–8.05 (m, 1H), 7.86–7.84 (m, 1H), 7.50–7.48 (m,
1H), 7.24–7.23 (m, 3H), 6.76 (d, J = 12 Hz, 2H), 6.68–6.66 (m, 1H), 4.48–4.44 (m, 1H), 3.67 (dd, J =
18 Hz, 6 Hz, 1H), 3.47–3.45 (m, 1H), 3.24–3.15 (m, 2H), 2.18–2.11 (m, 1H), 2.06–2.01 (m, 2H), 1.87–
1.84 (m, 1H); 13C{1H} NMR (150 MHz, CDCl3) δ 201.3, 153.6, 149.0, 146.6, 136.8, 129.2, 127.1, 121.
7, 115.6, 112.1, 55.1, 47.7, 41.0, 30.9, 23.1; HRMS (ESI): [M+H]+ calcd for [C17H19N2O]: 267.1492,
found: 267.1497.
2-(1-Phenylpyrrolidin-2-yl)-1-(thiophen-2-yl)ethan-1-one (3bf), yellow solid, 21% yield, 23 mg (0.8
mmol of vinyl azide), mp = 105–107 ℃; 1H NMR (600 MHz, CDCl3) δ 7.67–7.66 (m, 1H), 7.65–7.64
(m, 1H), 7.25–7.22 (m, 2H), 7.13–7.11 (m, 1H), 6.70–6.67 (m, 1H), 6.64–6.63 (m, 2H), 4.41–4.39 (m,
1H), 3.46–3.43 (m, 1H), 3.31–3.28 (m, 1H), 3.21 (q, J = 18 Hz, 1H), 2.94 (dd, J = 18 Hz, 6 Hz, 1H),
2.16–2.10 (m, 1H), 2.07–2.03 (m, 2H), 1.93–1.88 (m, 1H); 13C{1H} NMR (150 MHz, CDCl3) δ 192.2,
146.4, 144.8, 133.8, 132.0, 129.4, 128.1, 115.9, 112.0, 54.9, 47.9, 41.9, 31.2, 23.1; HRMS (ESI):
[M+H]+ calcd for [C16H18NOS]: 272.1104, found: 272.1106.
1-(Cyclohex-1-en-1-yl)-2-(1-phenylpyrrolidin-2-yl)ethan-1-one (3bg), white solid, 24% yield, 12.9 mg,
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mp = 73–75 ℃; H NMR (600 MHz, CDCl3) δ 7.23–7.20 (m, 2H), 6.86–6.85 (m, 1H), 6.67–6.64 (m,
1H), 6.57–6.56 (m, 2H), 4.31–4.28 (m, 1H), 3.42–3.39 (m, 1H), 3.18 (q, J = 6 Hz, 1H), 2.99 (d, J = 12
Hz, 1H), 2.69 (dd, J = 18 Hz, 12 Hz, 1H), 2.29–2.19 (m, 4H), 2.13–2.04 (m, 1H), 2.04–1.96 (m, 2H),
1.78–1.75 (m, 1H), 1.65–1.56 (m, 4H); 13C{1H} NMR (150 MHz, CDCl3) δ 200.5, 146.6, 140.5, 139.7,
129.3, 115.6, 111.9, 54.8, 47.8, 39.4, 31.3, 26.1, 23.1, 23.0, 21.9, 21.5; HRMS (ESI): [M+H]+ calcd for
[C18H24NO]: 270.1852, found: 270.1855.
2-(1-(4-(2-Hydroxy-5-nitrobenzyl)phenyl)pyrrolidin-2-yl)-1-phenylethan-1-one (4)17, yellow oil, 86%
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yield, 35.8 mg, Rf = 0.15 (petroleum ether/ethyl acetate = 4/1); H NMR (600 MHz, CDCl3) δ 8.03–
8.02 (m, 1H), 8.00–7.98 (m, 1H), 7.94–7.93 (m, 2H), 7.58–7.56 (m, 1H), 7.47–7.44 (m, 2H), 7.09 (s,
2H), 6.87 (d, J = 12 Hz, 1H), 6.54 (d, J = 6 Hz, 2H), 4.42–4.39 (m, 1H), 3.92 (s, 2H), 3.46–3.39 (m,
1H), 3.34 (dd, J = 18 Hz, 6 Hz, 1H), 3.18 (q, J = 6 Hz, 1H), 3.05 (dd, J = 18 Hz, 12 Hz, 1H), 2.17–
2.11 (m, 1H), 2.07–2.00 (m 2H), 1.83–1.80 (m, 1H); 13C{1H} NMR (150 MHz, CDCl3) δ 200.4, 160.1,
145.5, 141.3, 137.0, 133.5, 129.8, 129.1, 128.7, 128.1, 126.5, 124.8, 124.0, 115.7, 112.4, 54.7, 48.0,
41.2, 35.3, 31.5, 23.1; HRMS (ESI): [M+H]+ calcd for [C25H25N2O4]: 417.1809, found: 417.1814.
Dimethyl-3-(2-oxo-2-phenylethyl)-2-phenyl-2-azabicyclo[3.2.0]hept-6-ene-6,7-dicarboxylate
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yellow solid, 56% yield, 23.8 mg and 21.5 mg, dr = 1.1/1, Rf = 0.28, 0.3 (petroleum ether/ethyl acetate
= 4/1), mp = 95–97 ℃; 1H NMR (600 MHz, CDCl3) δ 7.89 (d, J = 6 Hz, 2H), 7.57–7.55 (m, 1H), 7.46–
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7.43 (m, 2H), 7.25–7.22 (m, 2H), 6.83 (d, J = 12 Hz, 2H), 6.75–6.73 (m, 1H), 5.09 (d, J = 6 Hz, 1H),
5.02–4.97 (m, 1H), 3.83–3.81 (m, 1H), 3.79 (s, 3H), 3.75 (s, 3H), 3.35 (dd, J = 18 Hz, 6 Hz, 1H), 3.21
(dd, J = 18 Hz, 12 Hz, 1H), 2.38–2.33 (m, 1H), 2.08 (d, J = 16 Hz, 1H); 13C{1H} NMR (150 MHz,
CDCl3) δ 199.3, 162.3, 161.5, 146.5, 145.3, 143.9, 136.8, 133.3, 129.4, 128.6, 128.1, 117.4, 113.0,
60.9, 56.1, 52.1, 45.9, 42.3, 30.7; HRMS (ESI): [M+H]+ calcd for [C24H24NO5]: 406.1649, found:
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406.1653. 1-Phenyl-2-(1-phenylpyrrolidin-2-yl)ethan-1-ol (6), colorless oil, 99% yield, 26.5 mg; H
NMR (400 MHz, CDCl3): δ 7.38–7.31 (m, 4H), 7.30–7.18 (m, 3H), 6.78–6.53 (m, 3H), 4.79–4.76 (m,
1H), 4.14–4.09 (m, 1H), 3.42–3.38 (m, 1H), 3.18–3.12 (m, 1H), 2.24–2.17 (m, 1H), 2.06–1.97 (m, 4H),
1.94– 1.83 (m, 1H), 1.59–1.52 (m, 1H); 13C{1H} NMR (100 MHz, CDCl3): δ 147.6, 144.5, 129.1,
128.6, 127.8, 126.0, 116.0, 112.4, 73.0, 56.4, 48.9, 42.6, 31.1, 23.7; HRMS (ESI): [M+H]+ calcd for
[C18H22NO]: 268.1696, found: 268.1698.
2-(5-(Benzo[d]thiazol-2-yl)-1-phenylpyrrolidin-2-yl)-1-phenylethan-1-one (7)18, yellow solid, 58%
yield, 46.1 mg, dr = 1.8/1, Rf = 0.27，0.13 (petroleum ether/ethyl acetate = 10/1), mp = 74–76 ℃; 1H
NMR (400 MHz, CDCl3): δ 7.99–7.94 (m, 3H), 7.75–7.73 (m, 1H), 7.59–7.56 (m, 1H), 7.48–7.43 (m,
3H), 7.33–7.30 (m, 1H), 7.19–7.15 (m, 2H), 6.71–6.67 (m, 3H), 5.32 (d, J = 8 Hz, 1H), 5.00–4.96 (m,
1H), 3.55–3.50 (m, 1H), 3.03 (dd, J = 16 Hz, 8 Hz, 1H), 2.77–2.61 (m, 1H), 2.61–2.44 (m, 1H), 2.24
(dd, J = 16 Hz, 8 Hz, 1H), 1.94–1.90 (m, 1H); 13C{1H} NMR (100 MHz, CDCl3): δ 199.3, 178.6,
153.7, 143.9, 136.9, 135.0, 133.5, 129.5, 128.7, 128.1, 125.9, 124.8, 122.7, 121.9, 117.5, 114.0, 60.4,
55.0, 38.8, 31.8, 28.9; HRMS (ESI): [M+H]+ calcd for [C25H23N2OS]: 399.1526, found: 399.1533.
1,1-Diphenyl-2-(1-phenylpyrrolidin-2-yl)ethan-1-ol (8), colorless oil, 90% yield, 31.0 mg, Rf = 0.26
1
(petroleum ether/ethyl acetate = 20/1); H NMR (600 MHz, CDCl3) δ 7.45–7.44 (m, 2H), 7.42–7.40
(m, 2H), 7.36–7.24 (m, 6H), 7.08–7.06 (m, 2H), 6.59 (q, J = 6 Hz, 1H), 6.32 (d, J = 6 Hz, 2H), 3.86–
3.83 (m, 1H), 3.43–3.39 (m, 1H), 3.11–3.06 (m, 1H), 2.59–2.55 (m, 1H), 2.49 (s, 1H), 2.33–2.29 (m,
1H), 1.98–1.93 (m, 1H), 1.89–1.84 (m, 1H), 1.74–1.70 (m, 1H), 1.61–1.59 (m, 1H); 13C{1H} NMR
(150 MHz, CDCl3) δ 147.5, 147.1, 129.0, 128.2, 128.1, 127.1, 127.0, 126.34 126.2, 115.6, 112.4, 97.4,
77.8, 54.9, 48.1, 43.8, 31.8, 23.3; HRMS (ESI): [M+H]+ calcd for [C24H26NO]: 344.2009, found:
344.2014.
ASSOCIATED CONTENT
Supporting Information
The X-ray crystallographic data (CIF) for product 3at (CIF), copies of 1 H, 13 C spectra for all products
are available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: xupf@lzu.edu.cn
ORCID
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Peng-Fei Xu: 0000-0002-5746-758X
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Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENT
We are grateful to the NSFC (21632003, 21871116, 21572087 and 21801102), the key program of
Gansu province (17ZD2GC011) and the “111” program from the MOE of P. R. China for financial
support.
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