Investigation towards the reductive amination of levulinic acid by B(C6F5)3/hydrosilane system

Article abstract of DOI:10.1016/j.tet.2020.131394

The selective transformation of the renewable biomass resources into the highly value-added platform chemicals is essentially important for sustainable chemistry. Here we report a simple and highly efficient strategy for the synthesis of N-heterocyclic co

Full text of DOI:10.1016/j.tet.2020.131394

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Investigation towards the reductive amination of levulinic acid by B(C F ) /
6 5 3
hydrosilane system
Tianlong Wang, Hai Xu, Jianghua He, Yuetao Zhang
PII:
S0040-4020(20)30556-1
https://doi.org/10.1016/j.tet.2020.131394
TET 131394
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 5 April 2020
Revised Date: 5 July 2020
Accepted Date: 7 July 2020
Please cite this article as: Wang T, Xu H, He J, Zhang Y, Investigation towards the reductive amination
of levulinic acid by B(C F ) /hydrosilane system, Tetrahedron (2020), doi: https://doi.org/10.1016/
6 5 3
j.tet.2020.131394.
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Graphical Abstract

Investigation towards the reductive amination of levulinic acid
by B(C6F5)3/hydrosilane system
Tianlong Wang, Hai Xu,* Jianghua He* and Yuetao Zhang*
State Key Laboratory of Supramolecular Structure and Materials, College of Chemistry, Jilin
University, Changchun, Jilin, 130012, China.
E-mail: xuhai@jlu.edu.cn; hjh2015@jlu.edu.cn; ytzhang2009@jlu.edu.cn
ABSTRACT
The selective transformation of the renewable biomass resources into the highly
value-added platform chemicals is essentially important for sustainable chemistry.
Here we report a simple and highly efficient strategy for the synthesis of
N-heterocyclic compounds from the reductive amination of the bio-derived levulinic
acid and a wide range of anilines by metal-free B(C6F5)3/hydrosilane catalyst system.
Through adjusting the amounts of hydrosilane, we can synthesize a series of
pyrrolidones or pyrrolidines, respectively. Isotope-labeled NMR experiments were
conducted to investigate the possible reaction pathway.
Key words: B(C6F5)3; hydrosilane; levulinic acid; N-heterocyclic compounds;
reductive amination
1

1. Introduction
The selective transformation of the renewable biomass resources into the highly
value-added platform chemicals is essentially important for sustainable chemistry
[1,2]. As one of the top ten platform chemicals, levulinic acid (LA) derived from the
acidic hydrolysis of carbohydrates [3] has been employed for the production of many
valuable fine chemicals [4,5]. Among them, N-substituted pyrrolidone derivatives
have received intense attention due to their wide application in solvents, surfactants,
drug racetams as well as its utilization of LA in the valorization of biomass [6]. In last
decades, many catalyst based on homogeneous and heterogeneous systems have been
developed to synthesize pyrrolidones from LA. Most of them utilized formic acid
(formate) [7-13] or H2 [14-22] as reducing reactants.
As an efficient and mild reducing reagent, hydrosilane has been widely applied in
the reduction of unsaturated compounds [23]. Recently, it was also utilized for the
reductive amination of LA to produce N-substituted pyrrolidones and pyrrolidines in
the presence of transition-metal catalyst [24-27]. In 2016, Sakai group reported the
first example for the synthesis of pyrrolidones and pyrrolidines catalyzed by In(OAc)3
and InI3, respectively [24], whereas Liu group employed AlCl3/RuCl3 and ionic liquid
as catalysts to synthesize the N-substituted lactams [25, 26]. More recently, Darcel
group developed an iron-based catalyst system to realize the synthesis of pyrrolidones
or pyrrolidines, respectively [27].
On the other hand, B(C6F5)3 is known as a powerful metal-free Lewis acid for the
activation of hydrosilane in many organic synthesis [28] and the reduction of lignin
2

and lignin model compounds [29-31]. Recently, our group successfully employed the
combination of B(C6F5)3 with various hydrosilanes to achieve the highly
C3-regioselective silyated indoles from the convergent disproportionation reaction of
indoles [32]. Besides, the application of some classic organic reactions enabled us to
achieve highly efficient cleavage of the C-C bonds in both lignin model compounds
and native lignin and produce useful aromatics in high to excellent yields [33-35].
More recently, Fu et al reported one example for the transformation of the
biomass-derived LA into pyrrolidones or pyrrolidines in 86% and 91% yields,
respectively, during their investigation towards the B(C6F5)3-catalyzed N-alkylation of
amines with carbonyl acids by using silane as reducing agent [36]. However, detailed
study of this reaction is still lacking. Therefore, we believed that the application of the
B(C6F5)3/hydrosilation system to the reductive amination of biomass-derived LA will
not only produce the useful N-heterocyclic compounds, but also provide important
foundation to biomass valorization. Here we reported a simple and highly efficient
synthetic strategy for synthesis of pyrrolidone and pyrrolidine from the reductive
amination of LA with a variety of anilines catalyzed by B(C6F5)3/hydrosilane system.
Moreover, by adjusting the amounts of hydrosilane, a series of pyrrolidone or
pyrrolidine derivatives could be produced in high to excellent yields. The
1
investigation towards the reaction pathway by H NMR spectroscopy were also
included into this study.
3

Scheme 1 Controllable synthesis of pyrrolidones or pyrrolidines. (One example was
reported in reference 36 by using B(C6F5)3/PMHS (polymethylhydro-siloxane)
catalyst system)
2. Result and Discussion
2.1 Optimization of the reaction
By using PhSiH3 as hydrogen resource, we selected LA and 4-methylaniline as
substrates to optimize the reaction conditions(Table 1). It turned out that after heating
at 120 ºC for 6 h, only 4% yield of pyrrolidones was obtained in the absence of
catalyst (Table 1, entry 1) whereas 5 mol% B(C6F5)3 can significantly enhance the
yield of 3a to 99% (Table 1, entry 2). It should be noted that 2.5 mol% B(C6F5)3 can
produce 3a in 99% yield but the employment of 1.25 mol% B(C6F5)3 drastically
decreased the yield of 3a to 50% (Table 1, entries 3 and 4). For reaction performed
with a lower temperature of 100 ºC or shorter reaction time of 3 h, incomplete LA
conversion and lower product yield of 3a were obtained (Table 1, entries 5 and 6).
The study of the solvent effects indicated that toluene (TOL) stood out among the
investigated solvents while CH2Cl2 or THF produced 3a in lower yields of 89% and
92%, respectively (Table 1, entries 7 and 8). In sharp contrast, the employment of
4

protic solvent such as methanol only produced 7% yield of 3a, probably due to the
irreversible coordination between B(C6F5)3 and the hydroxy group of methanol
molecules (Table 1, entry 9) [37]. For comparison, several boron Lewis acid catalysts,
such as BF3
OEt2, BCl3, BBr3, B(OiPr)3 and BPh3 were also evaluated for the
•
reductive amination reactions and exhibited much lower activity than B(C6F5)3 (Table
1, entries 10-14). Previous study indicated that the large steric hindrance and the
strong electron-deficient properties enabled B(C6F5)3 to effectively activate
hydrosilane to form (C6F5)3B···H···Si active species [38], which is essentially
important for the hydrosilylation of the imine intermediate generated from the
reaction of LA with aniline. Since the properties of hydrosilane also have significant
impact on the reaction, several hydrosilanes were screened for the reductive amination
reactions. The yield of 3a was dramatically decreased with the increasing number of
bulky electron-withdrawing group on hydrosilanes: (PhSiH3 (99%) > Ph2SiH2 (89%) >>
Ph3SiH (7%), Table S1, entries 1-3). The steric hindrance is also found to have impact
on the reaction. Such as hydrosilanes with bulky substituents tend to have much lower
yield of 3a (Ph3SiH (7%) ≈ (OEt)3SiH (4%) << Et3SiH (83%), Table S1, entries 3-5).
For more, complex hydrosilanes, the yield of 3a is determined by the comprehensive
effects of both the electron and steric hindrance of the hydrosilanes. For example,
polymethylhydrosiloxane (PMHS) produced 3a in 86% yield (Table S1, entry 6)
whereas both PhMe2SiH and 1,1,3,3-tetramethyldisiloxane(TMDS) (Table S1, entries
7 and 8) showed comparable product yields as PhSiH3 did. Interestingly, replacing
PhSiH3 with 10 bar H2 almost quenched the reaction and furnished 3a in less than 1%
5

yield (Table S1, entry 9), which indicated that the hydrosilylation reduction went
through the (C6F5)3B···H···Si active species [39].
Table 1. Optimization of the reductive amination of LA with aniline.a
Catalyst
(mol%)
Time
(h)
Temp.
(ºC)
Yield
(%)
Entry
Solvent
1
2
no
6
6
6
6
6
3
6
6
6
6
6
6
6
6
TOL
TOL
120
120
120
120
100
120
120
120
120
120
120
120
120
120
4
B(C6F5)3 (5)
B(C6F5)3 (2.5)
B(C6F5)3 (1.25)
99
99
50
72
77
89
92
7
3
TOL
4
TOL
5
B(C6F5)3 (2.5)
B(C6F5)3 (2.5)
TOL
6
TOL
B(C6F5)3 (2.5)
B(C6F5)3 (2.5)
B(C6F5)3 (2.5)
7
CH2Cl2
THF
8
9
CH3OH
TOL
10
11
12
13
14
BF3
•
OEt2 (2.5)
15
14
14
18
22
BCl3 (2.5)
BBr3 (2.5)
TOL
TOL
BPh3 (2.5)
TOL
B(OiPr)3 (2.5)
TOL
a Conditions: 0.25 mmol LA, 0.25 mmol aniline or 4-methylaniline, 0.25 mmol PhSiH3, 1 mL TOL. Yield was
determined by HPLC with standard curves.
2.2. The scope of anilines for the reductive amination of LA to pyrrolidones
With the optimized reaction conditions in hand, we examined the scope of anilines
(2) with a variety of substituents for reaction performed with a 1:1:1 LA: anilines:
PhSiH3 ratio in TOL and heated at 120 ºC, by using LA (1) as a model substrate and
6

PhSiH3 as reducing agent (Table 2). It only took 1.5 h for simple aniline without
substituents (2b) to reach quantitative conversion and furnish pyrrolidone 3b in 97%
yield (Table 2, entry 2), but 6 h is required for the other anilines to reach full
consumption of substrates. It should be noted that this B(C6F5)3/PhSiH3 catalyst
system can tolerate a wide range of anilines bearing para-substituted groups including
both the electron-donating methyl group and the electron-withdrawing groups such as
F, Cl, Br, furnishing corresponding pyrrolidone derivatives in high to excellent yields
(3a, 99%; 3c, 99%; 3d, 98%; 3e, 98%; 3f, 93%) (Table 2, entries 1 and 3-6). However,
the employment of aniline bearing a strong electron-withdrawing 4-CF3 group led to a
drastically decreased product yield of 74% for 3g (Table 2, entry 7), probably due to
the side reactions resulted from the strong electron-withdrawing effect of CF3- group,
which is consistent with the previous report [25]. We also examined the effectiveness
of the substituent position on the reaction by using anilines with a Cl- group at
varying position. Compared with 2d possessing a para-Cl group, 2h having a meta-Cl
substituent showed comparable reactivity and produced 98% yield of 3h whereas 2i
bearing an ortho-Cl group produced 3i in a slightly decreased yield of 93% (Table 2,
entries 8 and 9), implying that the substituent position did not have significant impact
on the reaction. However, this B(C6F5)3/hydrosilane system is not applicable to the
reduction amination of aliphatic amines, such as benzylamine and n-octylamine (Table
2, entries 10 and 11), similar results have been observed in different catalyst systems
[37].
Table 2. The scope of anilines for the reductive amination of LA to pyrrolidones.a
7

(1) 3a, 99% (93%)
(2) 3b, 97%b (89%)
(3) 3c, 99% (91%)
(6) 3f, 93% (85%)
(9) 3i, 93% (87%)
(4) 3d, 98% (90%)
(5) 3e, 98% (89%)
(7) 3g, 74% (64%)
(10) 3j trace
(8) 3h, 98% (88%)
(11) 3k trace
a Conditions: 0.25 mmol LA, 0.25 mmol aniline, 2.5 mol% B(C6F5)3, 0.25 mmol PhSiH3, 1 mL TOL, 6 h. b 1.5 h,
120 ºC. Yield was determined by HPLC with standard curves, isolated yield was given in parentheses.
2.3. Scope of anilines for the reductive amination of LA to pyrrolidines
Previous studies showed that B(C6F5)3/hydrosilane system was effective for the
reduction of amides to amines [40, 41]. The identification of such highly efficient
catalyst system for preparation of pyrrolidones from LA promoted us to investigate
whether this B(C6F5)3/hydrosilane system is applicable for the direct synthesis of
pyrrolidine from LA. To our delight, by using LA and 4-methylaniline (2a) as
substrates, the reaction performed with a 1:1:2 LA:2a:PhSiH3 ratio afforded 56%
yield of pyrrolidone 3a and 43% yield of pyrrolidine 4a, respectively (Table S2, entry
1). Increasing the amounts of PhSiH3 to 3 equiv., we observed that the product yield
8

of 3a is reaching the maximum value of 68% within 2.5 h, then gradually decreasing
whereas the product yield of 4a kept increasing to reach 98% within 24 h (Fig. S1),
which clearly indicated the gradual transformation of 3a into 4a along with the
reaction time. Therefore, we envisioned that the synthesis of either pyrrolidone or
pyrrolidine derivatives could be achieved by adjusting the amounts of hydrosilane (1
or 3 equiv.), which is less than the previously reported (2 or 4 equiv.) [25-27],
suggesting that the B(C6F5)3 can efficiently activate PhSiH3 for the reductive
amination of LA. Next, a 1:3 LA/PhSiH3 ratio was employed for the direct synthesis
of pyrrolidines from LA by using the above-mentioned aniline derivatives as
substrates (Table 3). Similar activity could be obtained for reactions using anilines
bearing para-substituents (2a, 2c to 2f), furnishing the corresponding pyrrolidines in
high to excellent yields (4a, 98%; 4c, 98%; 4d, 93%; 4e, 92%; 4f, 93%, Table 3,
entries 1 and 3-6 ) whereas the presence of 4-CF3 group in 2g almost quenched the
reaction and furnished trace amounts of 4g in up to 24 h, further confirming the
effects of strong electron-withdrawing substituent on the reduction of pyrrolidone to
pyrrolidine [25] (Table 3, entry 7). Compared with 4d, the anilines substituted with Cl
group at ortho- and meta- position produced the corresponding pyrrolidines in
relatively lower yields (4h 73% and 4i, 67%; Table 3, entries 8 and 9). Moreover,
different hydrosilanes were also evaluated their effectiveness on the synthesis of
pyrrolidines (Table S2). PhSiH3 showed the best performance among the investigated
hydrosilanes (Table S2, entries 2-7). It should be noted that neither PhMe2SiH nor
TMDS could transform the pyrrolidones into pyrrolidines, thus not applicable to the
9

synthesis of pyrrolidines (Table S2, entries 8 and 9). Moreover, by using
4-acetobutyric acid as substrate (Scheme 2A), the reaction performed with a 1:1
LA/PhSiH3 ratio and heated at 120 ºC for 6 h afforded a six-member N-containing
heterocyclic pyrrolidone 3l in 93% yield whereas the reaction performed with a 1:3
LA/PhSiH3 ratio and heated at 120 ºC for 24 h afforded a six-member N-containing
heterocyclic pyrrolidine 4l in 88% yield, indicating this method was not limited to the
synthesis of five-member lactam products. Switching to 2-carboxybenzaldehyde
enabled us to achieve pharmaceutically important N-arylisoindolinone derivatives [42]
3m and 4m in 98% and 92% yields, respectively (Scheme 2B).
Table 3. Scope of anilines for the reductive amination of LA to pyrrolidines a
(2) 4b, 92%b (83%)
(1) 4a, 98% (93%)
(3) 4c, 98% (88%)
(4) 4d, 93% (85%)
(5) 4e, 92% (83%)
(6) 4f, 93% (82%)
(9) 4i, 67% (62%)
(7) 4g, trace
(10) 4j trace
(8) 4h, 73% (65%)
(11) 4k trace
a Conditions: 0.25 mmol LA, 0.25 mmol aniline, 2.5 mol% B(C6F5)3, 0.75 mmol PhSiH3, 1 mL TOL, 120 ºC, 24 h.
10

b 6 h. Yield was determined by HPLC with standard curves, isolated yield was given in parentheses.
(A)
(B)
Scheme 2. Reductive amination of 4-acetylbutyric acid and 2-carboxybenzaldehyde with aniline respectively.
Conditions: (A) 0.25 mmol 4-acetylbutyric acid, 0.25 mmol aniline, 2.5 mol% B(C6F5)3, 1 mL TOL. (B) 0.25
mmol 2-carboxybenzaldehyde and aniline, 2.5 mol% B(C6F5)3, 1 mL TOL. Yield was determined by HPLC,
isolated yield was given in parentheses.
2.4 Mechanistic study
According to the previous literatures, there were two alternative pathways for the
synthesis of pyrrolidone from the reductive amination of LA with aniline (Scheme 3).
At first, ketimine I was generated from the condensation of LA and aniline, which can
be directly reduced by hydrosilane to produce the cyclic pyrrolidone through pathway
A [24, 27]. In the alternative pathway B [25, 26], ketimine I first underwent
imine-enamine tautomerization [43,44] to furnish enamine III, which can be
transformed into a five-member intermediates IV or V during the cyclization process.
11

There is an equilibrium between intermediates IV and V. Both IV and V can be
reduced to pyrrolidone. To verify which pathway is more preferred by our system, we
1
perform the isotope-labeled H NMR experiments to by using the deuterium-labelled
hydrosilane (Ph2SiD2) as reducing agent (Fig. 1). The comparison of 1H NMR spectra
revealed that only the H(b) of pyrrolidone product has been deuterated (Fig. S3b). If
the reaction went through pathway B, the reduction would take place at the C=C
double bond of IV or V, thus furnishing the deuterated H(c) or H(d). Therefore, we
can safely draw the conclusion that the pathway A is adopted by the reaction.
Furthermore, we turned our attention to investigate the intermediate during the
reductive amination by in situ NMR experiments. As revealed by Scheme 4a and Fig.
S4, LA and aniline could not generate imine I spontaneously or in the presence of
B(C6F5)3. We did not observe I during the reductive amination process, probably due
to its unstable structure (Fig. S6). A 1:7 molar ratio of intermediate II to 3b was
observed after 30 min of reaction (Scheme 4b and Fig. S5), which was similar with
that reported by Fischmeister et al. [45]. After that, the amount of intermediate II
decreased with the reaction time. It almost disappeared at 60 min and was completely
converted to 3b after 1.5 h. However, the produced small amounts of II tends to be
easily and rapidly transformed into 3b, we could not isolate the intermediate II. The
above results could further confirm our pathway. Briefly, aniline first reacted with the
carbonyl group of LA to produce ketimine I, which is similar to the reported in
previous literature [36]. The hydrosilylation reduction occurred at the C=N bond of I,
which was subsequently hydrolyzed to yield intermediate II. Finally, stable
12

five-member pyrrolidone product 3b would be generated through dehydration.
Scheme 3. Two alternative pathways proposed for the reductive amination of LA to pyrrolidone.
Fig. 1. Overlay of the 1H NMR spectra of Ph2SiD2 and in-situ NMR reaction obtained for the reductive amination
of LA to pyrrolidone. Conditions: (top) 0.1 mmol LA, 0.1 mmol aniline, 0.1 mmol Ph2SiH2, 2.5 mol% B(C6F5)3,
0.5 mL C7D8, 120 ºC,1.5 h. (bottom): 0.1 mmol Ph2SiD2 instead of Ph2SiH2.
13

Scheme 4. Reaction intermediate in the reductive amination. Conditions: 0.125 mmol LA, 0.125 mmol aniline,
0.125 mmol PhSiH3, 2.5 mol% B(C6F5)3, 0.5 mL C7D8, 120 ºC.
2.5. Reuse experiment
We also investigated the reuse capability of B(C6F5)3 for the production of
pyrrolidone from the reductive amination of LA and simple aniline into pyrrolidone in
Fig. 2. After full conversion of substrates was reached for the first run, the second
batch of reaction mixture containing both the starting materials (LA and aniline) and
reducing reactant PhSiH3 were immediately added to the NMR tube. Near quantitative
conversion of substrates can be maintained after three runs, but it decreased for the
fourth run, probably due to the partial deactivation of the catalyst.
Conversion of LA (%)
100
80
60
40
20
0
1
2
3
Runs
Fig. 2 Reusability of B(C6F5)3 catalyst for the reductive amination of levulinic acid with aniline. Conditions: 0.125
mmol levulinic acid, 0.125 mmol aniline, 0.125 mmol PhSiH3, 2.5 mol% B(C6F5)3 in 0.5 mL C7D8, 120 ºC, 1.5 h.
Conversion was determined by 1H NMR analysis.
14

3. Conclusion
In summary, we employed the metal-free B(C6F5)3/PhSiH3 system to synthesize
N-heterocyclic compounds, including pyrrolidones and pyrrolidines, from the
reductive amination of biomass-derived LA with a variety of anilines. Adjusting the
molar ratio of LA to hydrosilane enabled us to achieve pyrrolidones or pyrrolidines in
high to excellent yields, respectively. Moreover, the combination of the detailed
experimental data and isotope-labeled experiments led to the possible reaction
pathway, thereby providing the much-needed insights into reaction mechanism.
4. Experimental Section
4.1 General Information
Levulinic acid (98%), methyl levulinate (98%), ethyl levulinate (98%), butyl
levulinate (98%), 4-methylaniline (98%), 4-chloroaniline (98%), 4-methoxyaniline
(98%), 4-fluoroaniline (98%), 4-bromoaniline (98%), 4-trifuloroaniline (98%),
3-chloroaniline (98%), 2-chloroaniline (98%), polymethylhydrosiloxane (PMHS, 98%)
Ph2SiH2
(98%),
Et3SiH
(98%),
Ph3SiH
(98%),
(OEt)3SiH
(98%),1,1,3,3-tetramethyldisiloxane (TMDS, 98%) were provided by Energy
Chemical. PhSiH3 was obtained from J&K Scientific Ltd. Solvents were purchased
from Adamas company. B(C6F5)3 was prepared according to literature procedures
[46].
1
NMR spectra were recorded on Bruker Avance II 500 (500 MHz, H; 126 MHz,
19
1
13C and 471 MHz, F) instrument at room temperature. H and 13C spectra were
referenced to internal solvent resonances and are reported as parts per million relative
15

19
to SiMe4, and F relative to CFCl3. The reaction mixture was analyzed using Waters
High Performance Liquid Chromatograph (HPLC) system equipped with autosampler,
C18 column (Length: 150 mm, Internal diameter: 4.6 mm, 35 ºC) and UV/Vis
detector (λ = 254 nm). CH3CN: H2O = 70: 30 was used as mobile phase with a flow
rate of 1 mL/min for the analysis of the products.
4.2 Typical Procedures
The reductive amination of LA and aniline was performed in a thick wall tube with a
Teflon screw cap (10 mL volume). In a typical experiment, under air atmosphere, 0.25
mmol LA, 0.25 mmol aniline, 2.5 mol% B(C6F5)3 and 1 mL toluene were added into
the reactor. One or three equiv. PhSiH3 was used for the synthesis of pyrrolidone or
pyrrolidine respectively. Then, the reactor was heated in oil bath for the desired time.
Upon the completion of reaction, the product yield was determined by HPLC with
standard curves of pure products. The pure samples were isolated by column
chromatography on silica gel with the eluent (petroleum ether: ethyl acetate = 1:1) for
pyrrolidones and (petroleum ether: ethyl acetate = 10:1) for pyrrolidines.
4.3 Spectral data
1-(4-methylphenyl)-5-methylpyrrolidin-2-one (3a)
Yellow solid; 1H NMR (500 MHz, CDCl3) δ 1.22 (d, J = 6.3 Hz, 3H), 1.73-1.80 (m,
1H), 2.36 (s, 3H), 2.38-2.42 (m, 1H), 2.52-2.59 (m, 1H), 2.62-2.67 (m, 1H), 4.24-4.30
13
(m, 1H), 7.21-7.26 (m, 4H) ppm. C NMR (126 MHz, CDCl3) δ 20.2, 21.0, 26.8,
31.29, 55.8, 124.2, 129.6, 134.9, 135.6, 174.2 ppm.
5-Methyl-1-phenylpyrrolidin-2-one (3b)
16

Colorless oil; 1H NMR (500 MHz, CDCl3) δ 1.22 (d, J = 5.0 Hz, 3H), 1.74-1.81 (m,
1H), 2.35-2.42 (m, 1H), 2.52-2.59 (m, 1H), 2.63-2.69 (m, 1H), 4.30-4.34 (m, 1H),
7.21-7.24 (m, 2H), 7.37-7.42 (m, 4H) ppm. 13C NMR (126 MHz, CDCl3) δ 20.2, 26.7,
31.4, 55.6, 124.0, 125.7, 128.9, 137.6, 174.2 ppm.
1-(4-Fluorophenyl)-5-methylpyrrolidin-2-one (3c)
Colorless oil; 1H NMR (500 MHz, CDCl3) δ 1.20 (d, J = 6.3 Hz, 3H), 1.73-1.80 (m,
1H), 2.36-2.42 (m, 1H), 2.52-2.58 (m, 1H), 2.61-2.67 (m, 1H), 4.22-4.28 (m, 1H),
7.08-7.11 (m, 2H), 7.32-7.35 (m, 2H) ppm. 13C NMR (126 MHz, CDCl3) δ 20.1, 26.8,
31.2, 55.9, 115.8 (d, J = 22.3 Hz), 126.0 (d, J = 8.2 Hz), 133.5 (d, J = 2.9 Hz), 159.5,
161.4, 174.3 ppm. 19F NMR (470 MHz, CDCl3) 116.2 ppm.
1-(4-Chlorophenyl)-5-methylpyrrolidin-2-one (3d)
1
Colorless oil; H NMR (500 MHz, CDCl3) δ 1.20 (d, J = 10.5 Hz, 3H), 1.69-1.81
(m, 1H), 2.30-2.42(m, 1H), 2.47-2.67 (m, 1H), 4.22-4.32 (m, 1H), 7.34-7.37 (m, 4H)
ppm. 13C NMR (126 MHz, CDCl3) δ 16.0, 26.6, 31.2, 55.4, 124.9, 129.0, 130.8, 136.2,
174.2 ppm.
1-(4-Bromophenyl)-5-methylpyrrolidin-2-one (3e)
1
Yellow oil; H NMR (500 MHz, CDCl3) δ 1.23 (d, J = 6.3 Hz, 3H), 1.74-1.81 (m,
1H), 2.36-2.43 (m, 1H), 2.52-2.59 (m, 1H), 2.63-2.69 (m, 1H), 4.27-4.33 (m, 1H),
7.31-7.32 (m, 2H), 7.51-7.53 (m, 2H) ppm. 13C NMR (126 MHz, CDCl3) δ 20.0, 26.6,
31.3, 55.4, 118.7, 126.2, 132.0, 136.7, 174.2 ppm.
1-(4-Methoxyphenyl)-5-methylpyrrolidin-2-one (3f)
Yellow solid; 1H NMR (500 MHz, CDCl3) δ 1.19 (d, J = 6.2 Hz, 3H), 1.74-1.79 (m,
17

1H), 2.35-2.42 (m, 1H), 2.52-2.67 (m, 2H), 3.82 (s, 1H), 4.18-4.22 (m, 1H), 6.94 (d,
8.8 Hz, 2H), 7.25 (d, J = 9.0 Hz, 2H) ppm. 13C NMR (126 MHz, CDCl3) δ 20.3, 26.9,
31.2, 55.5, 56.1, 114.3, 126.1, 130.4,157.8, 174.3 ppm.
1-(4-(trifluoromethyl)phenyl)-5-methylpyrrolidin-2-one (3g)
Colorless oil; 1H NMR (500 MHz, CDCl3) δ 1.27 (d, J = 6.2 Hz, 3H), 1.78-1.84 (m,
1H), 2.38-2.45 (m, 1H), 2.54-2.61 (m, 1H), 2.67-2.73 (m, 1H), 4.38-4.44 (m, 1H),
13
7.59-7.67 (m, 4H) ppm. C NMR (126 MHz, CDCl3) δ 19.9, 26.5, 31.3, 55.1, 122.7,
19F NMR (470 MHz, CDCl3) 126.1 (q, J = 3.75 Hz), 140.9, 174.3 ppm.
1-(3-Chlorophenyl)-5-methylpyrrolidin-2-one (3h)
1
Colorless oil; H NMR (500 MHz, CDCl3) δ 1.22 (d, J = 10.4 Hz, 3H), 1.70-1.81
(m, 1H), 2.31-2.43 (m, 1H), 2.47-2.70 (m, 1H), 4.24-4.35 (m, 1H), 7.15 - 7.20 (m,
1H), 7.29-7.31 (m, 2H), 7.44-7.45 (m, 1H) ppm. 13C NMR (126 MHz, CDCl3) δ 20.0,
26.5, 31.3, 55.4, 121.5, 123.6, 125.5, 129.9, 134.5, 138.9, 174.2 ppm.
1-(2-Chlorophenyl)-5-methylpyrrolidin-2-one (3i)
Colorless oil; 1H NMR (500 MHz, CDCl3) δ 1.22 (d, J = 6.3 Hz, 3H), 1.76-1.84 (m,
1H), 2.40-2.46 (m, 1H), 2.56-2.60 (m, 2H), 4.18-4.22 (m, 1H), 7.20-7.22 (m, 1H),
7.27-7.31 (m, 2H), 7.46-7.48 (m, 1H) ppm. 13C NMR (126 MHz, CDCl3) δ 20.2, 27.8,
30.7, 56.2, 127.6, 129.1, 130.4, 130.6, 132.9, 135.0, 175.0 ppm.
1-Phenyl-6-methylpyrrolidin-2-one (3l)
1
Colorless oil; H NMR (500 MHz, CDCl3) δ 1.07 (d, J = 6.45 Hz, 3H), 1.71-1.76
(m, 1H), 1.82-1.87 (m, 1H), 1.97-2.01 (m, 1H), 2.08-2.12 (m, 1H), 2.53-2.56 (m, 2H),
3.90-3.94 (m, 2H), 7.16-7.18 (m, 1H), 7.27-7.30 (m, 1H), 7.38-7.42 (t, J = 7.75 Hz,
18

13
2H) ppm. C NMR (126 MHz, CDCl3) δ 18.3, 20.9, 30.8, 32.8, 55.7, 127.1, 128.1,
129.1, 141.6, 170.3 ppm.
2-phenylisoindolin-1-one (3m)
1
White solid; H NMR (500 MHz, CDCl3) δ 4.89 (s, 2H), 7.20-7.23 (m, 1H),
13
7.44-7.64 (m, 5H), 7.89-7.97 (m, 3H). C NMR (126 MHz, CDCl3) δ 50.7, 119.5,
122.6, 124.2, 124.5, 128.4, 129.2, 132.1, 133.3, 139.5, 140.1, 67.5 ppm.
1-(4-methylphenyl)-5-methylpyrrolidin-2-one (4a)
1
Yellow solid; H NMR (500 MHz, CDCl3) δ 1.20 (d, J = 6.20 Hz, 3H), 1.70-1.73
(m, 1H), 1.9-2.00 (m, 1H), 2.01-2.11 (m, 2H), 2.29 (s, 3H), 3.14-3.19 (m, 1H),
3.43-3.46 (m, 1H), 3.84-3.90 (m, 1H), 6.56 (d, J = 8.05 Hz, 2H), 7.07 (d, J = 6.70 Hz,
2H) ppm. 13C NMR (126 MHz, CDCl3) 19.5, 20.2, 23.4, 33.2,48.5, 53.7, 111.9, 124.2,
129.7, 145.3 ppm.
1-phenyl-2-methylpyrrolidine (4b)
Colorless oil; 1H NMR (500 MHz, CDCl3) δ 1.17 (d, 10.6 Hz, 3H), 1.67-1.72 (m,
1H), 1.93-2.12 (m, 3H), 3.11-3.19 (m, 1H), 3.38-3.45 (m, 1H), 3.83-3.91 (m, 1H),
6.56-6.66 (m, 3H), 7.19-7.24 (m, 2H) ppm. 13C NMR (126 MHz, CDCl3) δ 19.4, 23.3,
33.2, 48.2, 53.6, 111.8, 115.14 129.2, 147.2 ppm.
1-(4-Fluorophenyl)-2-methylpyrrolidine (4c)
1
Colorless oil; H NMR (500 MHz, CDCl3) δ 1.20 (d, J = 6.3 Hz), 1.73-1.75 (m,
1H), 1.99-2.03 (m, 1H), 2.08-2.13 (m, 2H), 3.13-3.18 (m, 1H), 3.42-3.45 (m, 1H),
13
3.82-3.87 (m, 1H), 6.52-6.55 (m, 2H), 6.96-6.99 (m, 2H) ppm. C NMR (126 MHz,
CDCl3) δ 19.4, 23.4, 33.2, 48.7, 54.1, 112.2, 112.2, 115.4, 115.6, 144.0, 153.7, 155.6
19

ppm. 19F NMR (470 MHz, CDCl3) 131.2 (m, 1F).
1-(4-Chlorophenyl)-2-methylpyrrolidine (4d)
1
Colorless oil; H NMR (500 MHz, CDCl3) δ 1.20 (d, J = 6.3 Hz), 1.72-1.75 (m,
1H), 1.99-2.12 (m, 3H), 3.15-3.20 (m, 1H), 3.40-3.44 (m, 1H), 3.86-3.91 (m, 1H),
6.46-6.63, (m, 4H), 7.12-7.15 (m, 1H) ppm. 13C NMR (126 MHz, CDCl3) δ 19.2, 23.3,
33.1, 48.29, 53.8, 112.8, 119.9, 128.9, 145.8 ppm.
1-(4-Bromophenyl)-2-methylpyrrolidine (4e)
Yellow solid; 1H NMR (500 MHz, CDCl3) δ 1.18 (d, J = 6.2 Hz, 3H), 1.71-1.74 (m,
1H), 1.71-2.14 (m, 4H), 3.12-3.17 (m, 1H), 3.38-3.42 (m, 1H), 3.83-3.88 (m, 1H),
13
6.47 (d, J =8.5Hz, 2H), 7.30 (d, J = 8.9 Hz, 2H) ppm. C NMR (126 MHz, CDCl3)
19.1, 23.3, 33.1, 48.2, 53.7, 106.9, 113.4, 131.7, 146.1 ppm.
1-(4-Methoxyphenyl)-2-methylpyrrolidine (4f)
1
Yellow solid; H NMR (500 MHz, CDCl3) δ 1.20 (d, J = 6.15 Hz, 3H), 1.71-1.73
(m, 1H), 1.98-2.00(m, 1H), 2.07-2.11 (m, 2H), 3.13-3.18 (m, 1H), 3.42-3.46 (m, 1H),
3.80 (s, 3H), 3.81-3.84 (m, 1H), 6.59 (d, J = 9.0 Hz, 2H), 6.89 (d, J = 8.50 Hz, 2H)
13
ppm. C NMR (126 MHz, CDCl3) δ 19.7, 23.4, 33.3, 49.0, 54.1, 56.0, 112.7, 115.1,
142.4, 150.6 ppm.
1-(3-Chlorophenyl)-2-methylpyrrolidine (4h)
Colorless oil; 1H NMR (500 MHz, CDCl3) δ 1.20 (d, J = 6.3 Hz, 3H), 1.72-1.76 (m,
1H), 1.99-2.15 (m, 3H), 3.15-3.20 (m, 1H), 3.40-3.44 (m, 1H), 3.86-3.91 (m, 1H),
6.47 (d, J = 10.8 Hz, 1H), 6.57 (t, J = 2.3 Hz, 1H), 6.63 (d, J = 7.8Hz, 1H), 7.14 (t, J =
13
8.2 Hz, 1H) ppm. C NMR (126 MHz, CDCl3) δ 19.1, 23.2, 33.0, 48.1, 53.7, 110.0,
20

111.5, 114.91, 130.0, 135.0, 148.1 ppm.
1-(2-Chlorophenyl)-2-methylpyrrolidine (4i)
Colorless oil; 1H NMR (500 MHz, CDCl3) δ 1.07 (d, J = 6.1 Hz, 3H), 1.59-1.67 (m,
1H), 1.80-1.86 (m, 1H), 1.94-2.01 (m, 1H), 2.19-2.25 (m, 1H), 2.97-3.01 (m, 1H),
3.84-3.89 (m, 1H), 3.95-4.01 (m, 1H), 6.84-6.87 (m, 1H), 6.96-6.98 (m, 1H),
7.17-7.20 (m, 1H), 7.33-7.35 (m, 1H) ppm. 13C NMR (126 MHz, CDCl3) δ 19.0, 24.0,
33.9, 52.39.54.55, 119.2, 121.1, 126.2, 126.9, 130.9, 146.5 ppm.
1-Phenyl-6-methylpiperidin-2-one (4l)
1
Colorless oil; H NMR (500 MHz, CDCl3) δ 1.05 (d, J = 6.65 Hz, 3H), 1.60-1.74
(m, 4H), 1.79-1.82 (m, 1H), 1.90-1.95 (m, 1H), 3.00-3.05 (m, 1H), 3.25-3.29 (m, 1H),
6.87 (t, J = 7.30 Hz, 1H), 7.00 (d, J = 8.10 Hz, 2H), 7.29 (t, J = 7.75 Hz, 2H) ppm. 13C
NMR (126 MHz, CDCl3) δ 14.0, 19.9, 27.0, 31.9, 45.2, 51.5, 117.7, 119.2, 129.0,
151.5 ppm.
2-phenylisoindolin (4m)
1
White solid; H NMR (500 MHz, CDCl3) δ 4.7 (s, 4H) 6.72-6.74 (m, 2H),
13
6.78-6.81 (s, 1H), 7.33-7.40 (m, 6H). C NMR (126 MHz, CDCl3) δ 53.7, 111.6,
116.2, 122.6, 127.2, 129.4, 138.0, 147.2 ppm.
Conflicts of interest
There are no conflicts to declare
Acknowledgments
This work was supported by the National Natural Science Foundation of China (Grant
21

no. 21975102, 21871107, 21774042).
Appendix A. Supplementary data
The following is the Supplementary data to this article
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Metal-free catalysis
Wide substrate scope
Up to 99% product yields
Systematic mechanistic study

Declaration of interests
☒ The authors declare that they have no known competing financial interests or personal relationships
that could have appeared to influence the work reported in this paper.
☐The authors declare the following financial interests/personal relationships which may be considered
as potential competing interests:
Yuetao Zhang