Synthesis of α-benzylated amides via electrocatalytic Favorskii rearrangement of 1, 3-diarylacetones

Article abstract of DOI:10.1016/j.tet.2018.03.033

Electrolysis of 1,3-diarylacetones with aliphatic amines in Bu₄NI/CH₃CN to racemic Favorskii amides via benzyl group rearrangement has been developed. The electroconversion is easily conducted in a simple undivided cell under constan

Full text of DOI:10.1016/j.tet.2018.03.033

Accepted Manuscript
Synthesis of α-benzylated amides via electrocatalytic Favorskii rearrangement of 1, 3-
diarylacetones
Wei Liu, Wei Huang, Tianlei Lan, Haijuan Qin, Cheng Yang
PII:
S0040-4020(18)30276-X
10.1016/j.tet.2018.03.033
TET 29373
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 19 December 2017
Revised Date: 12 March 2018
Accepted Date: 14 March 2018
Please cite this article as: Liu W, Huang W, Lan T, Qin H, Yang C, Synthesis of α-benzylated amides
via electrocatalytic Favorskii rearrangement of 1, 3-diarylacetones, Tetrahedron (2018), doi: 10.1016/
j.tet.2018.03.033.
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Synthesis of α-benzylated amides via
electrocatalytic Favorskii rearrangement of
1, 3-diarylacetones
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Wei Liu , Wei Huang, Tianlei Lan, Haijuan Qin and Cheng Yang
College of Science, Tianjin University of Science and Technology, Tianjin 300457, P. R. China

1
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Tetrahedron
journal homepage: www.elsevier.com
Synthesis of α-benzylated amides via electrocatalytic Favorskii rearrangement of 1, 3-
diarylacetones
Wei Liua, , Wei Huangb, Tianlei Lanb, Haijuan Qinc and Cheng Yangd
a College of Science, Tianjin University of Science and Technology, Tianjin 300457, P. R. China
b Material Science & Chemical Engineering Institute, Tianjin University of Science and Technology, Tianjin 300457, P. R. China
c Analysis Center, Tianjin University of Science and Technology, Tianjin 300457, P. R. China
d College of Pharmacy, Nankai University, Tianjin 300071, P. R. China
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Electrolysis of 1,3-diarylacetones with aliphatic amines in Bu4NI/CH3CN to racemic Favorskii
amides via benzyl group rearrangement has been developed. The electroconversion is easily
conducted in a simple undivided cell under constant-current conditions at room temperature. The
electrocatalytic Favorskii rearrangement of 1,3-diarylacetones including electron-withdrawing
substituents was favored and gave a good yield of α-benzylated amides. When several
unsymmetrical ketones were employed as substrates, this rearrangement with moderate
regioselectivity was observed. This chemistry also provides an efficient approach to construct a
chiral center at α-position of amides.
Available online
Keywords:
electrosynthesis
Favorskii rearrangement
amide
2009 Elsevier Ltd. All rights reserved
.
iodide
1,3-diarylacetones
———
Corresponding author. Tel.: +86-2260600812; e-mail: liuwei2006@tust.edu.cn

2
Tetrahedron
1. Introduction
Table 1
ACCEPTED MANUSCRIPT
Optimization of the reaction conditions.a
The Favorskii rearrangement is a well-known organic name
reaction that uses α-haloketones as substrates.1 When α-
haloketones are treated with a nucleophilic base, carboxylic
acids, esters and amides are usually obtained as reaction products
via the C-C skeletal rearrangement. Besides base, by the
employment of hypervalent iodine reagents,2 acid,3 enzyme,4
photochemistry5 or electrochemistry,6 some novel Favorskii
rearrangements have been also developed. To date, some reviews
by Butkus7 and Yus8 discussed synthetic applications of this
rearrangement.
Entry Anode-
Cathode
Supporting
electrolyte
(equiv)
Solvent
Current
density
Yieldb
(%)
(mA/cm2)
1
Pt-Pt
C-C
Bu4NI(1)
Bu4NI(1)
Bu4NI(1)
Bu4NI(1)
Bu4NI(1)
Bu4NBr(1)
Bu4NCl(1)
Bu4NBF4(1)
LiClO4(1)
KI(1)
CH3CN
CH3CN
CH3CN
CH3OH
DMF
6
6
6
6
6
6
6
6
6
6
4
12
2
4
4
4
4
4
4
75
63
64
37
42
50
trace
0
In the past decade, electroorganic synthesis that employs
electrons as reagents, has been developed to be a versatile and
environment-friendly synthetic tool and become increasingly
2
3
C-Pt
Pt-Pt
Pt-Pt
Pt-Pt
Pt-Pt
Pt-Pt
Pt-Pt
Pt-Pt
Pt-Pt
Pt-Pt
Pt-Pt
Pt-Pt
Pt-Pt
Pt-Pt
Pt-Pt
Pt-Pt
Pt-Pt
attractive.
A search of the literature based around the
4
electrochemically induced Favorskii rearrangement revealed only
a few references to similar rearrangements of ketones or a-halo
ketones in the presence of base. Among them, electrochemically
induced Favorskii rearrangement of ketones under iodides-
methanol system formed mainly the corresponding esters. For
example, electrolysis of aliphatic cyclic ketones in methanol in
the presence of sodium halides in an undivided cell resulted in
ring-contracted esters as main products.9,10 In addition, aliphatic
open-chain ketones under similar reaction conditions formed α,β-
unsaturated carboxylic esters.11,12 The above several reactions
need high constant current density which was more than 100
mA/cm2. When a-polyhaloketones took the place of ketones as
substrates through controlled potential electrolysis, the
corresponding α,β-unsaturated amides as the Favorskii
rearranged products were obtained in aprotic solvents such as
DMF13 and CH3CN14. To the best of our knowledge, a direct
one–pot transformation of ketones into saturated amides via
electrochemically induced Favorskii rearrangement has not been
reported. Our group’s research has been focused on the
development of green and efficient electrosynthetic
methodologies for C-H activation reactions. Herein, the synthesis
of α-benzylated amides from 1,3-diarylacetones is achieved via
Favorskii rearrangement, in which migration of benzyl group led
to formation of one chiral center at α-position of amides through
electrochemical methods.
5
6
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN+H2O
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
7
8
9
0
10c
11
12
13
14d
15
16
17e
18f
19g
73
81
61
67
66
78
65
67
76
0
Bu4NI(1)
Bu4NI(1)
Bu4NI(1)
Bu4NI(1)
Bu4NI(2)
Bu4NI(0.5)
Bu4NI(1)
Bu4NI(1)
Bu4NI(1)
a
Reaction conditions: dibenzyl ketone 1a (1 mmol), pyrrolidine 2a (2 mmol), and
supporting electrolyte in 25 mL of solvent, undivided cell, the constant-current
electrolysis, 4.5 F/mol.
b 1H NMR yields using 1,3,5-trimethoxybenzene as an internal standard.
c 1 mL H2O as co-solvent,
d 8 F/mol was passed.
2. Results and discussion
e 2a (1 mmol).
We began our investigation with optimizing the reaction
conditions for the electrocatalytic rearrangement of the easily
available dibenzyl ketone 1a, which was chosen as a model
substrate and electrolyzed (Table 1). Cyclic voltammetry (CV)
experiments of the substrates in acetonitrile were conducted (see
ESI, Fig. S1). The constant current electrolysis of a mixture of 1a
(1 mmol) and pyrrolidine 2a (2 mmol) using platinum electrodes
was carried out in Bu4NI/CH3CN at room temperature in a simple
undivided cell. To our delight, the desired product 3a was
obtained in 75% yield (entry 1). The yield decreased when
graphite rod was used as electrode material. Moreover, a
dramatic corrosion of graphite rod cathode was observed under
this electrolysis condition (entry 2-3). Other solvents such as
methanol (entry 4) and DMF (entry 5) could not promote this
transformation. The choice of supporting electrolyte has also a
substantial impact on the reaction outcome. When Bu4NI was
replaced by another halide salt, such as Bu4NBr, product 3a was
obtained in 50% yield (entry 6), indicating that bromide is also
efficient for this reaction. However, Bu4NCl didn’t lead to
acceptable result (entry 7). The use of Bu4NBF4 (entry 8) or
LiClO4 (entry 9) led to almost no product formation. Further
f 2a (3 mmol).
g H-type cell, the distance between two electrodes is about 4 cm.
electrolyte screening disclosed that Bu4NI provided the best
yields of 3a, although KI (entry 10) and Bu4NI were almost
equally effective. The above results reveal that the iodide ion is
more important for the electrocatalytic Favorskii rearrangement
reaction than others.
The effect of current density on the reaction was also
examined. The reaction did not proceed without electrolysis. It
was found that yield of 3a was improved to 81% when a current
density of 4 mA/cm2 was employed instead of 6 mA/cm2 (entry
11-13). In addition, extending electrolysis time (8 F/mol) could
not improve the yield (entry 14). Though 0.5 equiv Bu4NI also
gave the good result (65%, entry 16), the assay of the amount of
Bu4NI disclosed that 1 equiv of Bu4NI was fit in order to obtain
the highest yield (81%, entry 11) in Table 1. It suggested 0.5
equiv Bu4NI was not enough due to side reactions which could
also consume Bu4NI. Attempt on decreasing and increasing the
amount of amine 2a led to decreased reaction yields (entry 17
and 18). No desired product 3a could be obtained in two-
compartment cell (entry 19).

3
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Table 2
Synthesis of α-benzylated arylacetamides from symmetrical ketones.a
Yieldb
(%)
Yieldb
(%)
Entry
Substrate
Product
Entry
Substrate
Product
1
73
8d
38
40
29
3a
3b
3c
3h
3i
2
3
66
79
9d
10
3j
4
5c
6
69
77
64
32
11
12
13
14
37
60
3d
3k
3l
N
O
I
I
3e
mess
mess
3f
7d
3g
a Reaction conditions: ketones 1 (1 mmol), pyrrolidine 2a (2 mmol), and Bu4NI (1 mmol) as supporting electrolyte in 25 mL of CH3CN, undivided cell, Pt-Pt, the constant-
current electrolysis, 4.5 F/mol.
b Isolated yields.
c 2 mA/cm2 was used.
d 8 mA/cm2 was used and 6 F/mol was consumed.
With the optimized conditions in hand (Table 1, entry 11), the
scope of this electrochemical transformation was surveyed next.
As shown in Table 2, changing the substituent of substrate 1 on
the phenyl ring was carried out. Simple dibenzyl ketone could
obtain the desired product 3a in good yield. Halide substituents
including F, Cl, and Br were well tolerated under electrochemical
conditions, obtaining corresponding product 3b-d in good yields
too. When iodine was as the substituent, a current density of 2
mA/cm2 was employed instead of 4 mA/cm2 in order to avoid
cleavage of C-I bond (3e). Beside of halide, dibenzyl ketones
including strong electron-withdrawing substituents such as nitro
group proceeded smoothly to afford the corresponding product 3f
in good yield. However, dibenzyl ketones including electron-
donating substituents such as methyl group, which is substituted
at different positions of the phenyl ring, gave drastically
decreased reaction yields (3g-i). Furthermore, it was found that
dibenzyl ketones containing methoxyl group did not undergo the
Favorskii rearrangement even though the longer reaction time
and higher current density was used. The simple amides 3j and
3k were obtained instead of the desired products, respectively.
Further investigation revealed that the steric size of naphthyl ring
slightly affected the efficiency of the reaction (3l). Besides 1,3-
diarylactones, aliphatic ketones without benzyl group such as
cyclohexanone (Table 2, entry 13) and heptan-4-one (Table 2,
entry 14) were also electrolyzed under our optimized conditions,
no desired Favorskii rearrangement product was isolated due to
the form of many intractable by-products. Based upon these
observations, we suggested that substrates including benzyl

4
Tetrahedron
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Table 3
Synthesis of α-benzylated amides from unsymmetrical ketones.a
Yield
(%)
Yield
(%)
Entry
Substrate
Product
Entry
Substrate
Product
1
31
28
44
32
25
4
3p
3m
2
3
5
3n
3o
3q
a Reaction conditions were the same as those of Table 2. Isolated yields were shown.
Table 4
Substrate scope of other amines.a
Entry
Amine
Product
Yield (%)
Entry
Amine
Product
Yield (%)
H
N
O
1
61
7
49
3r
3s
3x
2
63
8
mess
3
4
52
0
9
mess
0
3t
10
5
6
29
35
11
12
0
3u
3v
mess
a Reaction conditions were the same as those of Table 2. Isolated yields were shown.

5
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Figure 1. Structure of molecules 3m with the atoms being
represented as displacement ellipsoids at 30% probability level.
group were necessary for this rearrangement and electron-
withdrawing substituents on phenyl ring were favored.
Figure 2. Structure of molecules 3t and its enantisomer with the
atoms being represented as displacement ellipsoids at 30%
probability level.
With the successful synthesis of α-benzylated arylacetamides
3 from symmetrical ketones, we next applied the electrochemical
method to the more challenging attempt of constructing complex
product 3 (Table 3). Surprisingly, the amides 3m-q as the sole
rearrangement products from unsymmetrical ketones 1 were
obtained in acceptable yields and their isomers 4 were not
detected in situ 1H NMR monitoring. We found that the
migration capability of benzyl group depended on electronic
effect of substituents in this transformation. As a result, the
migration of benzyl group including electron-withdrawing
substituents happened more easily than benzyl group including
electron-donating substituents under the standard conditions. For
example, p-chlorobenzyl group (3m) and p-nitrobenzyl group (3o)
migrated to α-C position of carbonyl group prior to p-
methylbenzyl group, respectively. The structure of 3m was
confirmed by single-crystal X-ray diffraction studies.15 Similarly,
p-nitrobenzyl group migrated prior to p-chlorobenzyl group in
product 3n. It is noteworthy that the benzyl alkyl ketones could
also undergo benzyl group migration to furnish α-benzylated
amides in acceptable yields (3p and 3q, 31% and 28% yields,
respectively).
1,3-diphenylpropan-2-one 5 and pyrrolidine finished in 10
minutes under room temperature and gave good yield of 3a (eq.
2), which suggests that 5 may be a key intermediate in this
transformation.
Based on the experimental results and literature reports,17
a
plausible mechanism of the reaction between ketone 1 and
pyrrolidine 2a is proposed. As illustrated in Scheme 1, the
reaction begins with the anodic oxidation of iodide to generate
molecular iodine, which undergoes reaction with ketone 1 to
form α-iodo ketone A. Secondary amines 2a can promote
Favorskii rearrangements by the formation of an enamine B. In
the general case, the cyclopropanone intermediate C attacked by
2a should open on the side that gives the more stable carbanion D.
Finally, α-Benzylated amides 3 are obtained by hydrolysis of D.
As shown in Table 4, the reactions of dibenzyl ketone 1a with
various amines were investigated. Cyclic secondary aliphatic
amines proceeded smoothly and afforded the corresponding α-
benzylated amides 3r-t in 52-63% isolated yield. The structure of
3t was confirmed by single-crystal X-ray diffraction studies
(Figure 2).16 X-ray crystallography revealed that compound 3t
crystallized as a racemic mixture in the solid state. However,
2,2,6,6-tetramethylpiperidine (entry 4) was not
a suitable
coupling partner owing to the steric hindrance. Acyclic aliphatic
amine also reacted with 1a, albeit in a bit lower yield (3u-x). On
the contrary, arylamines were unreactive due to poor
nucleophilicity (entry 8-12).
1
Scheme 1. Control experiments. H NMR yields using 1,3,5-
trimethoxybenzene as an internal.
3. Conclusions
To further demonstrate the practicability of this transformation,
the gram-scale electrolysis was also explored using 5 mmol of 1a
(1.05 g) under the standard reaction conditions. Product 3a was
isolated in a 69 % yield without significant loss of reaction
efficiency.
In conclusion, an efficient electrochemical protocol for the
synthesis of α-benzylated amides via the Favorskii rearrangement
of 1,3-diarylacetones has been developed. Neither high current
density nor α-haloketones were needed in this transformation.
Importantly, the experimental set-up, with an undivided cell at
ambient conditions, is very simple. Gram-scale reaction
demonstrated the practicality of the protocol.
In order to better understand the reaction mechanism, two
control experiments were conducted. As shown in Scheme 1,
when molecular iodine took place of Bu4NI, the desired product
3a was obtained in a 37% yield without electrolysis (eq. 1).
Therefore, the in situ generated molecular iodine was suggested
to be one of the active species. Moreover, the reaction of 1-iodo-
It was found that iodide ion and aliphatic amines play a
significant role in the transformation. The electrocatalytic
Favorskii rearrangement of symmetrical 1,3-diarylacetones

6
Tetrahedron
ACCEPTED MANUSCRIPT
Scheme 2. Proposed reaction mechanism.
including electron-withdrawing substituents was favored and
gave a good yield of racemic α-benzylated arylacetamides.
Notably, the unsymmetrical ketones were also suitable for this
reaction, affording the sole products in acceptable yields with
moderate regioselectivity.
4.2.1. 2,3-Diphenyl-1-(1-pyrrolidinyl)-1-propanone (3a)
Purification by chromatography (petroleum ether/EtOAc = 6:1,
Rf = 0.25) afforded 3a as a white solid (224 mg, 73%); mp: 83-
1
84 °C; H NMR (400 MHz, CDCl3) δ 7.28 (d, J = 4 Hz, 4H),
7.25-7.12 (m, 4H), 7.10 (d, J = 6.9 Hz, 2H), 3.82 (t, J = 7.3 Hz,
1H), 3.49 (dd, J = 13.4, 6.5 Hz, 1H), 3.40 (d, J = 27.3 Hz, 2H),
3.20 (d, J = 27.3 Hz, 2H), 2.95 (dd, J = 13.4, 6.5 Hz, 1H), 1.73 (s,
4H); 13C NMR (100 MHz, CDCl3) δ 171.0, 140.0, 139.5, 129.1,
128.5, 128.2, 128.1, 126.9, 126.0, 53.0, 46.2, 45.9, 40.9, 25.9,
24.1; HRMS(ESI-TOF) m/z: calcd for C19H21NONa+ [M+Na+]
302.1515, found 302.1515.
4. Experimental
4.1 General
All chemicals were purchased from Sigma-Aldrich and were
used without further purification. All products were purified
through silica gel chromatography (200-300 mesh). Column
chromatography was carried out with light petroleum ether (bp.
60-90 °C)/ethyl acetate as eluent. Melting points were
determined using an SGW-X4B digital melting point apparatus
and were uncorrected. 1H and 13C spectra were recorded in CDCl3
on a 400 MHz Bruker Avance DPX spectrometer. Coupling
constants were referred to as J values in Hz. X-ray single-crystal
diffraction data collected on a Rigaku SuperNova dual four-
circle diffractometer. ESI mass spectra were acquired using a
Bruker ESQUIRELCTM ESI ion trap spectrometer. High-
resolution mass spectral (HRMS) analysis data were measured on
a Waters Synapt G1 UPLC-Q-TOF instrument.
4.2.2.
2,3-Bis(4-fluorophenyl)-1-(1-pyrrolidinyl)-1-propanone
(3b)
Purification by chromatography (petroleum ether/EtOAc = 5:1,
Rf = 0.18) afforded 3b as a white solid (208 mg, 66%) ; mp: 90-
1
92 °C; H NMR (400 MHz, CDCl3) δ 7.25-7.18 (m, 2H), 7.03-
7.00 (m, 2H), 6.99-6.94 (t, J = 8.4 Hz, 2H), 6.93-6.85 (t, J = 8.8
Hz, 2H), 3.74 (t, J = 7.6 Hz, 1H), 3.49-3.34 (m, 3H), 3.26-3.22
(m, 1H), 3.20-3.10 (m, 1H), 2.89 (dd, J = 13.6, 7.0 Hz, 1H), 1.85-
1.68 (m, 4H); 13C NMR (100 MHz, CDCl3) δ 170.7, 161.9 (d, JC-
F = 244 Hz, 1C), 161.5 (d, JC-F = 242 Hz, 1C), 135.4 (d, JC-F = 3.3
Preparative electrolysis and cyclic voltammetry was performed
using a CHI605D Electrochemical Analyser (Chenhua Co. Ltd.,
Shanghai, China). Cyclic voltammetry was performed in a three-
compartment cell. The working electrode used in the
voltammetry experiments was a platinum disk (2 mm in diameter)
and platinum sheet was used as counter electrode. All potentials
were referred to Ag/AgCl electrode.
Hz, 1C), 134.9 (d, JC-F = 3.3 Hz, 1C), 130.6 (d, JC-F= 7.8 Hz, 1C),
129.7 (d, JC-F = 8.0 Hz, 1C), 115.5 (d, JC-F = 21.3 Hz, 1C), 114.9
(d, JC-F = 21.1 Hz, 1C), 52.4, 46.3, 46.0, 40.2, 26.0, 24.1;
HRMS(ESI-TOF) m/z: calcd for C19H19F2NONa+ [M+Na+]
338.1327, found 338.1325.
4.2.3. 2,3-Bis(4-chlorophenyl)-1-(pyrrolidin-1-yl)propan-1-one
(3c)
4.2 Preparative electrolysis
The preparative-scale electrolysis was performed in an
undivided cell fitted with Pt sheet electrodes having an area of 3
cm2 (the distance is about 1 cm). A 25 ml solution of acetonitrile
containing n-Bu4NI (1 mmol), dibenzyl ketone derivatives 1 (1
mmol) and amine 2 (2 mmol) was stirred magnetically. The
constant-current electrolysis was carried out at current density of
4 mA/cm2 at room temperature. The electrolysis was stopped
when 4.5 or 6 F/mol of electricity was passed. The final
electrolyte was concentrated under reduced pressure; a saturated
aqueous sodium chloride solution was then added and the
mixture was extracted with ethyl acetate. The organic layer was
dried over sodium sulfate and concentrated. The products were
purified by column chromatography on silica gel using ethyl
acetate/petroleum ether as the eluent.
Purification by chromatography (petroleum ether/EtOAc =5:1,
Rf = 0.21) afforded 3c as a white solid (274 mg, 79%) ; mp: 94-
1
96 °C; H NMR (400 MHz, CDCl3) δ 7.25 (d, J = 8.0 Hz, 2H),
7.20-7.17 (m, 4H), 7.00 (d, J = 7.9 Hz, 2H), 3.73 (t, J = 7.4 Hz,
1H), 3.43-3.38 (m, 3H), 3.25 (s, br 1H), 3.13 (s, br, 1H), 2.88 (dd,
J = 13.5, 6.9 Hz, 1H), 1.75 (s, 4H); 13C NMR (100 MHz, CDCl3)
δ 170.3, 138.1, 137.5, 133.0, 132.0, 130.5, 129.5, 128.8, 128.3,
52.4, 46.2, 46.0, 40.2, 25.9, 24.1; HRMS(ESI-TOF) m/z: calcd
for C19H21Cl2NONa+ [M+Na+] 370.0736, found 370.0736.
4.2.4.
2,3-Bis(4-bromophenyl)-1-(1-pyrrolidinyl)-1-propanone
(3d)
Purification by chromatography (petroleum ether/EtOAc = 5:1,
Rf = 0.30) afforded 3d as a white solid (301 mg, 69%) ; mp: 101-
1
103 °C; H NMR (400 MHz, CDCl3) δ 7.41 (d, J = 8.4 Hz, 2H),
7.33 (d, J = 8.3 Hz, 2H), 7.13 (d, J = 8.4 Hz, 2H), 6.95 (d, J = 8.3

7
Hz, 2H), 3.71 (t, J = 7.4 Hz, 1H), 3.52-3.31 (m, 3H), 3.26 (s, br,
1H), 3.13 (s, br, 1H), 2.86 (dd, J = 13.5, 6.9 Hz, 1H), 1.75 (d, J =
2.8 Hz, 4H); 13C NMR (100 MHz, CDCl3) δ 170.2, 138.6, 138.1,
131.8, 131.3, 130.9, 129.9, 121.1, 120.1, 52.4, 46.3, 46.1, 40.2,
25.9, 24.1; HRMS(ESI-TOF) m/z: calcd for C19H21Br2NONa+
[M+Na+] 457.9726, found 457.9724.
7.09 (d, J = 7.9 Hz, 2H), 7.03-6.98 (m, 4H), 3.76 (t, J = 7.6 Hz,
ACCEPTED MANUSCRIPT
1H), 3.50-3.33 (m, 3H), 3.29-3.21 (m, 1H), 3.20-3.12 (m, 1H),
2.87 (dd, J = 13.5, 6.4 Hz, 1H), 2.31 (s, 3H), 2.28 (s, 3H), 1.78-
1.67 (m, 4H); 13C NMR (100 MHz, CDCl3) δ 171.3, 137.2, 136.7,
136.5, 135.4, 129.3, 129.0, 128.8, 128.1, 52.7, 46.2, 45.9, 40.6,
25.9, 24.1, 21.1, 21.0; HRMS(ESI-TOF) m/z: calcd for
C21H25NONa+ [M+Na+] 330.1828, found 330.1832.
4.2.5. 2,3-Bis(4-iodophenyl)-1-(1-pyrrolidinyl)-1-propanone (3e)
4.2.10. (4-Methoxyphenyl)(pyrrolidin-1-yl)methanone (3j)
Purification by chromatography (petroleum ether/EtOAc = 5:1,
Rf = 0.23) afforded 3e as a white solid (409 mg, 77%); mp: 149-
151 °C; H NMR (400 MHz, CDCl3) δ 7.61 (d, J = 8.3 Hz, 2H),
Purification by chromatography (petroleum ether/EtOAc = 1:1,
Rf = 0.23) afforded 3j as a yellow oil (60 mg, 29%); H NMR
1
1
7.53 (d, J = 8.2 Hz, 2H), 7.01 (d, J = 8.3 Hz, 2H), 6.83 (d, J = 8.2
Hz, 2H), 3.69 (t, J = 7.4 Hz, 1H), 3.50-3.32 (m, 3H), 3.25 (s, br,
1H), 3.12 (s, br, 1H), 2.84 (dd, J = 13.5, 6.8 Hz, 1H), 1.75 (s, 4H);
13C NMR (100 MHz, CDCl3) δ 170.1, 139.3, 138.8, 137.8, 137.3,
131.3, 130.2, 92.7, 91.5, 52.5, 46.3, 46.1, 40.3, 25.9, 24.1;
HRMS(ESI-TOF) m/z: calcd for C19H19I2NONa+ [M+Na+]
553.9448, found 553.9442.
(400 MHz, CDCl3) δ 7.52 (d, J = 8.4 Hz, 2H), 6.90 (d, J = 8.7 Hz,
2H), 3.83 (s, 3H), 3.63 (t, J = 6.8 Hz, 2H), 3.48 (t, J = 6.5 Hz,
2H), 1.97-1.92 (m, 2H), 1.90-1.85 (m, 2H); 13C NMR (100 MHz,
CDCl3) δ 169.4, 160.7, 129.3, 129.1, 113.3, 55.3, 49.8, 46.3, 26.4,
24.4; HRMS(ESI-TOF) m/z: calcd for C12H15NO2Na+ [M+Na+]
228.0995, found 228.1007.
4.2.11. benzo[d][1,3]dioxol-5-yl(pyrrolidin-1-yl)methanone (3k)
4.2.6. 2,3-Bis(4-nitrophenyl)-1-(1-pyrrolidinyl)-1-propanone (3f)
Purification by chromatography (petroleum ether/EtOAc = 1:1,
Rf = 0.28) afforded 3k as a yellow oil (81 mg, 37%); H NMR
1
Purification by chromatography (petroleum ether/EtOAc = 2:1,
Rf = 0.2) afforded 3f as a yellow solid (237 mg, 64%) ; mp: 160 −
161 °C; H NMR (400 MHz, CDCl3) δ 8.18 (d, J = 8.7 Hz, 2H),
(400 MHz, CDCl3) δ 7.06 (dd, J = 8.0, 1.6 Hz, 1H), 7.03 (d, J =
1.2 Hz, 1H), 6.81 (d, J = 8.0 Hz, 1H), 5.99 (s, 2H), 3.62 (t, J =
6.9 Hz, 2H), 3.46 (t, J = 6.6 Hz, 2H), 1.97-1.85 (m, 4H); 13C
NMR (100 MHz, CDCl3) δ 169.0, 148.8, 147.4, 131.0, 121.8,
108.1, 107.9, 101.4, 49.8, 46.4, 26.5, 24.5; HRMS(ESI-TOF) m/z:
calcd for C12H13NO3Na+ [M+Na+] 242.0788, found 242.0787.
1
8.10 (d, J = 8.7 Hz, 2H), 7.47 (d, J = 8.8 Hz, 2H), 7.28 (d, J = 8.6
Hz, 2H), 3.95 (dd, J = 8.3, 6.6 Hz, 1H), 3.61 (dd, J = 13.5, 8.3 Hz,
1H), 3.50-3.37 (m, 2H), 3.34-3.28 (m, 1H), 3.14-3.10 (m, 1H),
3.06 (dd, J = 13.5, 8.3 Hz, 1H), 1.87-1.77 (m, 4H); 13C NMR
(100 MHz, CDCl3) δ 168.8, 147.3, 146.8, 146.7, 145.9, 123.0,
129.0, 124.1, 123.7, 52.5, 46.4, 46.3, 40.5, 25.9, 24.1;
HRMS(ESI-TOF) m/z: calcd for C19H19N3O5Na+ [M+Na+]
392.1217, found 392.1220.
4.2.12. 2,3-Dinaphthyl-1-(1-pyrrolidinyl)-1-propanone (3l)
Purification by chromatography (petroleum ether/EtOAc = 5:1,
Rf = 0.2) afforded 3l as a white solid (227 mg, 60%) ; mp: 54-
1
56 °C; H NMR (400 MHz, CDCl3) δ 8.10 (d, J = 8.0 Hz, 1H),
4.2.7.
2,3-bis(2-methylphenyl)-1-(1-pyrrolidinyl)-1-propanone
7.83 (d, J = 7.8 Hz, 2H), 7.80-7.70 (m, 3H), 7.64 (d, J = 7.8 Hz,
1H), 7.52-7.45 (m, 3H), 7.40 (t, J = 7.2 Hz, 1H), 7.29 (td, J = 7.6,
1.2 Hz, 1H), 7.23-7.16 (m, 2H), 4.77 (dd, J = 7.9, 5.8 Hz, 1H),
4.20 (dd, J = 14.2, 8.0 Hz, 1H), 3.54-3.39 (m, 3H), 3.10-3.04 (m,
1H), 2.78-2.73 (m, 1H), 1.71-1.52 (m, 4H); 13C NMR (100 MHz,
CDCl3) δ 171.5, 136.3, 136.1, 133.78, 133.77, 132.0, 131.4,
129.0, 128.8, 127.5, 127.2, 126.8, 126.0, 125.9, 125.8, 125.6,
125.4, 125.4, 125.3, 123.6, 122.4, 46.8, 46.2, 37.3, 26.9, 25.9,
24.0; HRMS(ESI-TOF) m/z: calcd for C27H25NONa+ [M+Na+]
402.1828, found 402.1829.
(3g)
Purification by chromatography (petroleum ether/EtOAc = 6:1,
Rf = 0.25) afforded 3g as a colorless oil (98 mg, 32%) ; 1H NMR
(400 MHz, CDCl3) δ 7.56-7.50 (m, 1H), 7.20 (t, J = 7.5 Hz, 1H),
7.12 (td, J = 7.6, 1.2 Hz, 1H), 7.06 (d, J = 3.9 Hz, 2H), 7.04-6.95
(m, 2H), 6.88 (d, J = 7.4 Hz, 1H), 4.02 (t, J = 7.2 Hz, 1H), 3.52-
3.52 (m, 3H), 3.23-3.19 (m, 1H), 2.95-2.90(m, 2H), 2.19 (s, 3H),
1.93 (s, 3H), 1.79-1.67 (m, 4H); 13C NMR (100 MHz, CDCl3) δ
171.8, 138.04, 138.02, 136.5, 135.8, 130.03, 130.00, 129.9, 127.7,
126.8, 126.7, 126.2, 125.7, 46.9, 46.1, 45.6, 37.7, 26.0, 24.1, 19.4,
19.1; HRMS(ESI-TOF) m/z: calcd for C21H25NONa+ [M+Na+]
330.1828, found 330.1830.
4.2.13.
2-(4-Methylphenyl)-3-(4-chlorophenyl)-1-(1-
pyrrolidinyl)-1-propanone (3m)
Purification by chromatography (petroleum ether/EtOAc = 5:1,
Rf = 0.27) afforded 3m as a white solid (144 mg, 44%) ; mp: 93-
95 °C; 1H NMR (400 MHz, CDCl3) δ 7.19-7.13 (m, 4H), 7.09 (d,
J = 7.6 Hz, 2H), 7.03 (d, J = 8.4 Hz, 2H), 3.72 (dd, J = 8.4, 6.8
Hz, 1H), 3.46-3.39 (m, 3H), 3.27 (s, br, 1H), 3.15 (s, br, 1H),
2.88 (dd, J = 13.5, 6.8 Hz, 1H), 2.32 (s, 3H), 1.73 (s, 4H); 13C
NMR (100 MHz, CDCl3) δ 170.8, 138.7, 136.7, 136.1, 131.7,
130.6, 129.3, 128.2, 128.0, 52.7, 46.2, 46.0, 40.3, 25.9, 24.1, 21.1;
HRMS(ESI-TOF) m/z: calcd for C20H22ClNONa+ [M+Na+]
350.1282, found 350.1282.
4.2.8. 2,3-Bis(3-methylphenyl)-1-(1-pyrrolidinyl)-1-propanone
(3h)
Purification by chromatography (petroleum ether/EtOAc = 5:1,
Rf = 0.23) afforded 3h as a colorless oil (118 mg, 38%); 1H NMR
(400 MHz, CDCl3) δ 7.18-7.10 (m, 3H), 7.08-7.03 (m, 2H), 6.97
(d, J = 7.6 Hz, 1H), 6.91 (d, J = 11.5 Hz, 2H), 3.78 (dd, J = 8.6,
6.0 Hz, 1H), 3.48-3.43 (m, 2H), 3.42-3.33 (m, 1H), 3.24-3.15 (m,
2H), 2.87 (dd, J = 13.4, 6.0 Hz, 1H), 2.32 (s, 3H), 2.28 (s, 3H),
1.77-1.70 (m, 4H); 13C NMR (100 MHz, CDCl3) δ 171.1, 140.1,
139.6, 138.2, 137.6, 129.9, 128.7, 128.3, 128.0, 127.7, 126.7,
126.1, 125.3, 52.9, 46.2, 45.9, 40.9, 25.9, 24.1, 21.4, 21.3;
HRMS(ESI-TOF) m/z: calcd for C21H25NONa+ [M+Na+]
330.1828, found 330.1831.
4.2.14. 2-(4-Nitrophenyl)-3-(4-chlorophenyl)-1-(1-pyrrolidinyl)-
1-propanone (3n)
Purification by chromatography (petroleum ether/EtOAc = 3:1,
Rf = 0.18) afforded 3n as a yellow solid (115 mg, 32%) ; mp:
115-116 °C; H NMR (400 MHz, CDCl3) δ 8.08 (d, J = 8.8 Hz,
2H), 7.29-7.26 (m, 2H), 7.24 (d, J = 7.4 Hz, 2H), 7.18 (d, J = 8.8
Hz, 2H), 3.78 (t, J = 7.4 Hz, 1H), 3.54 (dd, J = 13.5, 8.0 Hz, 1H),
3.49-3.36 (m, 2H), 3.32-3.26 (m, 1H), 3.13-3.08 (m, 1H), 3.02
(dd, J = 13.5, 6.9 Hz, 1H), 1.85-1.73 (m, 4H); 13C NMR (100
4.2.9. 2,3-Bis(4-methylphenyl)-1-(1-pyrrolidinyl)-1-propanone
(3i)
1
Purification by chromatography (petroleum ether/EtOAc = 5:1,
Rf = 0.25) afforded 3i as a white solid (126 mg, 40%); mp: 71-
1
73 °C; H NMR (400 MHz, CDCl3) δ 7.18 (d, J = 8.0 Hz, 2H),

8
Tetrahedron
MHz, CDCl3) δ 169.7, 147.5, 146.6, 137.0, 133.3, 130.1, 129.4,
Purification by chromatography (petroleum ether/EtOAc =
ACCEPTED MANUSCRIPT
129.1, 123.5, 52.1, 46.3, 46.1, 40.7, 25.9, 24.1; HRMS(ESI-TOF)
m/z: calcd for C19H19ClN2O3Na+ [M+Na+] 381.0976, found
381.0978.
10:1, Rf = 0.23) afforded 3t as a white solid (160 mg, 52%) ; mp:
1
92-94 °C; H NMR (400 MHz, CDCl3) δ 7.31-7.27 (m, 4H),
7.25-7.20 (m, 3H), 7.17-7.13 (m, 3H), 3.95 (dd, J = 8.7, 5.9 Hz,
1H), 3.72-3.66 (m, 1H), 3.52 (dd, J = 13.3, 8.6 Hz, 1H), 3.47-
3.41 (m, 1H), 3.25-3.19 (m, 1H), 3.16-3.09 (m, 1H), 2.92 (dd, J =
13.3, 5.9 Hz, 1H), 1.65-1.56 (m, 2H), 1.43-1.30 (m, 3H), 1.29-
1.17 (m, 3H); 13C NMR (100 MHz, CDCl3) δ 171.7, 140.2, 140.1,
129.3, 128.6, 128.1, 128.0, 126.9, 126.0, 51.4, 47.7, 46.4, 41.6,
29.1, 27.4, 26.6, 26.2; HRMS(ESI-TOF) m/z: calcd for
C21H25NOH+ [M+H+] 308.2009, found 308.2017.
4.2.15. 2-(4-Nitrophenyl)-3-(4-methylphenyl)-1-(1-pyrrolidinyl)-
1-propanone (3o)
Purification by chromatography (petroleum ether/EtOAc = 3:1,
Rf = 0.22) afforded 3o as a yellow solid (85 mg, 25%) ; mp: 115-
116 °C; H NMR (400 MHz, CDCl3) δ 8.06 (d, J = 8.4 Hz, 2H),
1
7.24 (d, J = 8.8 Hz, 2H), 7.13-7.08 (m, 4H), 3.76 (t, J = 7.4 Hz,
1H), 3.55 (dd, J = 13.4, 8.0 Hz, 1H), 3.50-3.36 (m, 2H), 3.33-
3.27 (m, 1H), 3.15-3.10 (m, 1H), 3.02 (dd, J = 13.5, 6.8 Hz, 1H),
2.32 (s, 3H), 1.84-1.69 (m, 4H); 13C NMR (100 MHz, CDCl3) δ
170.3, 148.2, 146.5, 137.0, 135.4, 130.1, 129.5, 127.9, 123.4,
52.4, 46.2, 46.1, 40.8, 25.9, 24.1, 21.1; HRMS(ESI-TOF) m/z:
calcd for C20H22N2O3Na+ [M+Na+] 361.1523, found 361.1528.
4.2.21. N,N-diethyl-α-phenylbenzenepropanamide (3u)
Purification by chromatography (petroleum ether/EtOAc =
10:1, Rf = 0.25) afforded 3u as a yellow oil (83 mg, 29%); H
1
NMR (400 MHz, CDCl3) δ 7.28 (d, J = 4.4 Hz, 4H), 7.25-7.19
(m, 3H), 7.17-7.09 (m, 3H), 3.90 (dd, J = 8.4, 6.1 Hz, 1H), 3.49
(dd, J = 13.4, 8.4 Hz, 1H), 3.39-3.18 (m, 3H), 3.06-2.96 (m, 1H),
2.92 (dd, J = 13.3, 6.2 Hz, 1H), 1.02 (t, J = 7.1 Hz, 3H), 0.84 (t, J
= 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 171.5, 140.1,
140.1, 129.2, 128.6, 128.1, 127.9, 126.9, 126.0, 51.2, 41.7, 41.6,
40.6, 14.2, 12.8; HRMS(ESI-TOF) m/z: calcd for C19H23NONa+
[M+Na+] 304.1672, found 304.1680.
4.2.16. 2-Methyl-3-phenyl-1-(1-piperidinyl)-1-propanone (3p)
Purification by chromatography (petroleum ether/EtOAc =3:1,
1
Rf = 0.17) afforded 3p as a colorless oil (67.9 mg, 31%); H
NMR (400 MHz, CDCl3) δ 7.28-7.23 (m, 2H), 7.18 (d, J = 7.6
Hz, 3H), 3.45-3.40 (m, 2H), 3.31-3.25 (m, 1H), 3.01-2.92 (m,
2H), 2.82-2.74 (m, 1H), 2.64 (dd, J = 13.0, 6.4 Hz, 1H), 1.83-
1.64 (m, 4H), 1.17 (d, J = 6.8 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ 174.3, 140.1, 128.9, 128.1, 126.1, 46.2, 45.5, 40.5, 40.4,
25.9, 24.1, 17.3; HRMS(ESI-TOF) m/z: calcd for C14H19NONa+
[M+Na+] 240.1359, found 240.1357.
4.2.22. 2,3-Diphenyl-N-propyl-propionamide (3v)
Purification by chromatography (petroleum ether/EtOAc = 8:1,
Rf = 0.22) afforded 3v as a white solid (94 mg, 35%) ; mp: 63-
65 °C; H NMR (400 MHz, CDCl3) δ 7.33-7.27 (m, 4H), 7.25-
1
7.12 (m, 4H), 7.13-7.08 (m, 2H), 5.29 (s, br, 1H), 3.58-3.50 (m,
2H), 3.19-3.03 (m, 2H), 3.01-2.94 (m, 1H), 1.40-1.31 (m, 2H),
0.74 (t, J = 7.4 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 172.6,
139.8, 139.8, 129.0, 128.7, 128.2, 128.1, 127.3, 126.1, 55.8, 41.3,
39.7, 22.7, 11.1; HRMS(ESI-TOF) m/z: calcd for C18H21NOH+
[M+H+] 268.1696, found 268.1697.
4.2.17. 2-Butyl-3-phenyl-1-(1-piperidinyl)-1-propanone (3q)
Purification by chromatography (petroleum ether/EtOAc =3:1,
1
Rf = 0.27) afforded 3q as a colorless oil (70 mg, 28%); H NMR
(400 MHz, CDCl3) δ 7.27-7.22 (m, 2H), 7.28-7.16 (m, 3H), 3.43-
3.31 (m, 2H), 3.24-3.18 (m, 1H), 2.95-2.88 (m, 1H), 2.76-2.67
(m, 3H), 1.83-1.21 (m, 8H), 0.89 (t, J = 7.2 Hz, 3H); 13C NMR
(100 MHz, CDCl3) δ 173.8, 140.2, 128.9, 128.1, 126.0, 46.5, 46.3,
45.4, 39.6, 35.1, 25.8, 24.1, 20.8, 14.1; HRMS(ESI-TOF) m/z:
calcd for C16H23NONa+ [M+Na+] 268.1672, found 268.1670.
4.2.23. N-hexyl-2,3-diphenyl-propionamide (3x)
Purification by chromatography (petroleum ether/EtOAc =
10:1, Rf = 0.22) afforded 3x as a white solid (152 mg, 49%) ; mp:
52-54 °C; 1H NMR (400 MHz, CDCl3) δ 7.29 (d, J = 4.3 Hz, 4H),
7.25-7.18 (m, 3H), 7.16-7.09 (m, 3H), 5.37 (s, br, 1H), 3.57-3.51
(m, 2H), 3.20-3.04 (m, 2H), 3.00-2.94 (m, 1H), 1.35-1.08 (m,
8H), 0.84 (t, J = 7.0 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ
172.5, 139.8, 139.8, 128.9, 128.6, 128.2, 128.0, 127.2, 126.1,
55.7, 39.7, 39.6, 31.3, 29.3, 26.3, 22.4, 13.9; HRMS(ESI-TOF)
m/z: calcd for C21H27NONa+ [M+Na+] 332.1985, found 332.1990.
4.2.18. 2,3-Diphenyl-1-(1-azetidinyl)-1-propanone (3r)
Purification by chromatography (petroleum ether/EtOAc = 3:1,
Rf = 0.2) afforded 3r as a white solid (162 mg, 61%); mp: 85-
1
86 °C; H NMR (400 MHz, CDCl3) δ 7.30 (d, J = 4.3 Hz, 4H),
7.27-7.22 (m, 3H), 7.19-7.16 (m, 1H), 7.12 (d, J = 7.5 Hz, 2H),
3.97-3.87 (m, 2H), 3.83 (t, J = 7.6 Hz, 2H), 3.57 (dd, J = 8.7, 6.2
Hz, 1H), 3.44 (dd, J = 13.3, 8.7 Hz, 1H), 2.92 (dd, J = 13.3, 6.0
Hz, 1H), 2.14-1.97 (m, 2H); 13C NMR (100 MHz, CDCl3) δ
172.2, 139.9, 139.3, 129.1, 128.6, 128.2, 128.1, 127.0, 126.2,
50.0, 49.9, 47.8, 40.2, 14.9; HRMS(ESI-TOF) m/z: calcd for
C18H19NONa+ [M+Na+] 288.1359, found 288.1363.
Acknowledgements
This work was supported by the National Natural Science
Foundation of China (21302139).
Appendix A. Supplementary data
Supplementary data related to this article can be found at
References
4.2.19 2,3-Diphenyl-1-(1-piperidinyl)-1-propanone (3s)
Purification by chromatography (petroleum ether/EtOAc =
10:1, Rf = 0.22) afforded 3s as a white solid (186 mg, 63%) ; mp:
1
1.
2.
3.
(a) Favorskii , A. J. Russ. Phys. Chem. Soc. 1894, 26, 590; (b) Kende,
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Ashida, Y.; Tanaka, A.; Hosomi, K.; Nakamura, A.; Misaki, T.;
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75-76 °C; H NMR (400 MHz, CDCl3) δ 7.29-7.25 (m, 2H),
7.23-7.19 (m, 5H), 7.17-7.13 (m, 1H), 7.08 (d, J = 7.2 Hz, 2H),
3.98 (t, J = 7.2 Hz, 1H), 3.63-3.57 (m, 1H), 3.50 (dd, J = 13.6,
7.9 Hz, 1H), 3.44-3.41 (m, 1H), 3.26 (t, J = 5.6 Hz, 2H), 2.94 (dd,
J = 13.5, 6.8 Hz, 1H), 1.50-1.37 (m, 4H), 1.17-1.07 (m, 1H),
0.97-0.86(m, 1H); 13C NMR (100 MHz, CDCl3) δ 170.6, 140.2,
140.1, 129.2, 128.6, 128.1, 127.9, 126.8, 126.0, 50.9, 46.7, 43.3,
41.1, 25.9, 25.5, 24.5; HRMS(ESI-TOF) m/z: calcd for
C20H23NONa+ [M+Na+] 316.1672, found 316.1673.
4.
5.
6.
(a) Carelli, I.; Curulli, A.; Inesi, A.; Zeuli, E. J. Chem. Research (S)
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Commun. 1982, 20, 1176; (c) Barba, F.; Elinson, M. N.; Escudero, J.;
Feducovich, S. K. Tetrahedron 1997, 53, 4427.
4.2.20. 2,3-Diphenyl-1-(1-azepanyl)-1-propanone (3t)

9
7.
Knochel, P.; Molander, G. A. Comprehensive Organic Synthesis (2nd
Edition); 2014, 3, 853.
ACCEPTED MANUSCRIPT
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Guijarro, D.; Yus, M. Curr. Org. Chem. 2005, 9, 1713.
Barba, F.; Elinson, M. N.; Escudero, J.; Feducovich, S. K. Tetrahedron
Lett. 1996, 37, 5759.
10. Elinson, M. N.; Dorofeev, A. S.; Feducovich, S. K.; Nasybullin, R. F.;
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15. CCDC 1828276 (3m) contains the supplementary crystallographic data
for this paper. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre.
16. CCDC 1590162 (3t) contains the supplementary crystallographic data
for this paper. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre.
17. Liang, S.; Zeng, C. C.; Tian, H. Y.; Sun, B. G.; Luo, X. G.; Ren, F. Z. J.
Org. Chem. 2016, 81, 11565.

ACCEPTED MANUSCRIPT
An efficient electrochemical protocol for the synthesis of racemic α-benzylated
amides via the Favorskii rearrangement of 1,3-diarylacetones
Highlights:
non-halogenated ketones
undivided cell
low current density
electron-withdrawing substituents favored
moderate regioselectivity