Palladium-Catalyzed β-C(sp3)-H Arylation of Aliphatic Ketones Enabled by a Transient Directing Group

Article abstract of DOI:10.1021/acs.joc.1c00646

The direct arylation of aliphatic ketones has been developed via Pd-catalyzed β-C(sp3)-H bond functionalization with 2-(aminooxy)-N,N-dimethylacetamide as a novel transient directing group (TDG), which showed remarkable directing ability to generate arylated products in moderate to good yields. Furthermore, the reaction can tolerate abundant substrate of ketones and aryl iodides. This study expands the scope of applications for TDGs.

Full text of DOI:10.1021/acs.joc.1c00646

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Palladium-Catalyzed β‑C(sp3)−H Arylation of Aliphatic Ketones
Enabled by a Transient Directing Group
Yangyang Wang, Gaorong Wu, Xiaobo Xu, Binghan Pang, Shaowen Liao,* and Yafei Ji*
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ABSTRACT: The direct arylation of aliphatic ketones has been developed via Pd-catalyzed β-C(sp3)−H bond functionalization
with 2-(aminooxy)-N,N-dimethylacetamide as a novel transient directing group (TDG), which showed remarkable directing ability
to generate arylated products in moderate to good yields. Furthermore, the reaction can tolerate abundant substrate of ketones and
aryl iodides. This study expands the scope of applications for TDGs.
liphatic ketones are common structural moieties in natural
contributions have been made in the past few years, the research
on extension of new TDGs is absolutely essential.
To our knowledge, the alkoxyamino group is more
nucleophilic than the amino group. Alkoxyamino can easily
transform to oxime ether in the presence of ketone or aldehyde,
which is more stable than imine, and oxime ethers exhibit an
1
Aproducts and medicine molecules.
The conventional
reactive site of aliphatic ketones is the α-carbon center or the
carbonyl group.2 β-C−H functionalization via transition-metal-
catalyzed C−H activation offers another promising β-carbon
reaction site of aliphatic ketones; this straightforward method-
ology to access valuable chemicals and build up molecular
complexity is of great research interest in organic chemistry and
medicinal sciences. In recent years, numerous effective routes
have been established to functionalize the β-C−H of aliphatic
ketones through transition-metal-catalyzed directed C−H
activation with a directing group (DG).3 However, installation
and removal of the directing group have always been
accompanied by additional steps. Furthermore, the functional
groups of complex compounds may be incompatible with these
additional steps.4 These challenges limit the development of
metal-catalyzed C−H activation reaction with DG.
Scheme 1. Transition-Metal-Catalyzed C−H Bond
Functionalization of Aldehydes/Ketones
For this decade, some researchers proposed to use a transient
directing group to solve this challenge.5 There is no requirement
for TDG to be attached to substrate, and the TDG is reversibly
involved in C−H activation reaction. In 1997, Jun’s group first
described the Rh(I)-catalyzed C−H bonds functionalization of
aldehydes using 2-amino-3-picoline as a TDG.6 After that,
various strategies using catalytic TDGs have also been employed
by Ru catalyst.7 In 2016, Yu’s group first used amino acids as
transient ligands to realize Pd-catalyzed arylation of o-alkyl
benzaldehydes and aliphatic ketones.8 Up to now, a series of Pd-
catalyzed C−H activations has been achieved by different TDGs
such as 3-aminopropanoic acids,9 acetohydrazide,10 2-amino-2-
methyl-propionic acid,11 anthranilic acid,11,12 α-benzyl bal-
anine,13 and so on. Then, Wei’s group found using amino amide
as a TDG can realize C−H arylation of aliphatic ketones and
aldehydes, but carbonyl compounds with steric hindrance could
not be arylated by this method (Scheme 1A).14 Although great
Received: March 19, 2021
Published: May 5, 2021
https://doi.org/10.1021/acs.joc.1c00646
© 2021 American Chemical Society
J. Org. Chem. 2021, 86, 7296−7303
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Note
a
excellent directing ability for transition-metal-catalyzed C−H
bond activation.4a,15 A lot of work has been demonstrated by the
pioneer researchers using oxime ethers as the internal directing
groups.16 In 2018, Yu’s group reported the first example of Pd-
catalyzed γ-C(sp3)−H activation of ketones directed by a
practical 2,2-dimethyl aminooxyacetic acid auxiliary (Scheme
1B).17 But, so far, oxime ether-oriented transient C−H
activation reaction has never been reported. Inspired by this
reaction and our previous research on oxime ether-oriented C−
H bond arylation reactions.18 Herein, we reported 2-(amino-
oxy)-N,N-dimethylacetamide as a new TDG to arylate the β-
C(sp3)−H bonds of aliphatic ketones (Scheme 1C).
Table 1. Optimization of the Reaction Conditions
To test our idea, we carried out a cross-coupling reaction of 2-
methyl-2-pentanone (1a) and methyl 4-the 4-iodobenzote (2a)
using Pd(OAc)2 as the catalyst, AgOAc as oxidant, and L1 as the
directing group in the mixed solvent of hexafluoroisopropanol
(HFIP) and acetic acid (9:1) under nitrogen atmosphere.19
Then, the mixture was stirred at 130 °C for 36 h. To our delight,
the desired product methyl 4-(2-ethyl-3-oxobutyl)benzoate
(3a) was obtained in a yield of 22% (entry 1). This result
clearly indicated that introducing 2-aminooxy acetamides as the
transient directing group was a feasible route. To improve the
yield, a series of different volume ratios of HFIP and AcOH as
the cosolvent were tested, and the results are summarized in
Table 1 (entries 1−5). When a 3:1 mixture of HFIP and acetic
acid as the cosolvent was used, a relatively high yield (39%) was
achieved (entry 3). Considering the great importance of TDG in
this reaction, we continued our investigation of palladium-
catalyzed site-selective arylation of aliphatic ketones with a focus
on the effect of ligand structure toward the process. A series of 2-
aminooxy acetamides was synthesized and evaluated. When L2,
L5, L6, L7, and L8 were used, L6 improved the yield best. The
result turns out that aliphatic amines are more conducive to this
reaction than aromatic amines, and L6 gave the best yield of 68%
(entry 10). When the carbonyl group has a substituent at the α-
position, the reaction yield significantly decreased to 14%, which
may be caused by the steric hindrance (entry 7). It is noteworthy
that no product 3a was obtained when the amide group was
changed to pyridine in this reaction (entry 8). Following the
screen of TDGs, we then carried out an intensive survey of the
palladium catalysts, silver salts additive and other reaction
conditions. A series of Pd-catalysts could catalyze the reaction,
while Pd(OAc)2 proved to be optimal (entries 13−16). As
demonstrated in Table 1 (entries 17−19), AgOAc gave a higher
yield than other silver salts. When different amounts of TDGs
were tested, the result proved that 50 mol % of TDGs was
beneficial for the reaction (entries 20 and 21). When the
reaction temperature was reduced from 130 to 110 °C, the yield
was significantly decreased (entry 22). The yield decreased
slightly as we continued to increase the temperature to 140 °C
(entry 23). Further, reducing the reaction time to 24 h, the yield
was 62% (entry 24). According to the above results, the best
reaction conditions were 10 mol % of Pd(OAc)2, 50 mol % of
L6, and 2 equiv of AgOAc in HFIP/AcOH (3:1) at 130 °C for
36 h.
yield
b
entry
catalyst
ligand additive
solvents
(%)
1
2
3
4
5
6
7
8
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(TFA)2
Pd(pph3)2
PdCl2
Pd(acac)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
L1
L1
L1
L1
L1
L2
L3
L4
L5
L6
L7
L8
L6
L6
L6
L6
L6
L6
L6
L6
L6
L6
L6
L6
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgTFA
Ag2CO3
AgF
HFIP/AcOH (9:1)
HFIP/AcOH (5:1)
HFIP/AcOH (3:1)
HFIP/AcOH (1:1)
AcOH
22
35
39
30
15
49
14
NR
52
68
58
61
60
51
34
49
64
57
49
44
52
45
66
62
HFIP/AcOH (3:1)
HFIP/AcOH (3:1)
HFIP/AcOH (3:1)
HFIP/AcOH (3:1)
HFIP/AcOH(3:1)
HFIP/AcOH (3:1)
HFIP/AcOH (3:1)
HFIP/AcOH (3:1)
HFIP/AcOH (3:1)
HFIP/AcOH (3:1)
HFIP/AcOH (3:1)
HFIP/AcOH (3:1)
HFIP/AcOH (3:1)
HFIP/AcOH (3:1)
HFIP/AcOH (3:1)
HFIP/AcOH (3:1)
HFIP/AcOH (3:1)
HFIP/AcOH (3:1)
HFIP/AcOH (3:1)
9
10
11
12
13
14
15
16
17
18
19
c
20
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
d
21
e
22
f
23
g
24
a
Reaction conditions: 1a (0.2 mmol), 2a (0.4 mmol), Pd source (0.02
mmol), ligand (0.1 mmol), Ag salts (0.4 mmol), solvent (2 mL), 130
°C, N2, 36 h. Isolated yields. 30 mol % of ligand. 70 mol % of
b
c
d
e
f
g
ligand. 110 °C, 36 h. 140 °C, 36 h. 130 °C, 24 h.
effect of different substitution positions on the benzene ring on
the reaction yield, we found that both meta- and para-substituted
aryl iodides were suitable coupling partners. The results clearly
demonstrated great functional group compatibility in this
catalytic process. Notably, halogen-substituted aryl iodides (F,
Cl, or Br) afforded the corresponding products (3d−3e). To our
satisfaction, desired yields of products were generated using 2-
fluoroiodobenzene and 2,4-difluoroiodobenzene as the coupling
partners (3o and 3p). These preserved halogen groups enable
further manipulation of the β-arylated products. Additionally,
the reaction with 2-iodonaphthalene gave a middle yield of 47%
(3q). Unfortunately, no desired product (3r) was obtained
when we screened 4-iodopyridine, which may be influenced by
the strong coordination of the pyridine nitrogen with the
palladium.12
With the optimal reaction conditions in hand, we used 2-
methyl-2-pentanone (1a) as the model substrate to survey the
scope of aryl iodides for the β-C(sp3)−H arylation. As shown in
Scheme 2, a broad range of aryl iodides bearing either an
electron-donating (alkoxyl or alkyl) or electron-withdrawing
group (ester, trifluoromethyl, or nitro) were well-tolerated to
provide desired products with excellent site selectivity in
moderate to good yields (3a−3h). When investigating the
Following the screen of aryl iodides, we carried out the study
on a variety of aliphatic ketones with methyl 4-iodobenzoate
under the optimal conditions (Scheme 3). Linear aliphatic
ketones (3v−3x) were introduced in this protocol to give the
desired compounds with excellent site selectivity in moderate
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Note
a
Scheme 2. Scope of Aryl Iodides in C(sp3)−H Arylation
Scheme 3. Scope of Aliphatic Ketones in C(sp3)−H
a
Arylation
a
Conditions: aliphatic ketones 1 (0.2 mmol, 1.0 equiv), ArI 2 (0.4
mmol, 2.0 equiv), Pd(OAc)2 (10 mol %), ligand (0.1 mmol), AgOAc
(2 equiv), HFIP/AcOH = 3:1 (2 mL), 130 °C, N2, 36 h. Yields
correspond to isolated products.
Scheme 4. 1.0 mmol Scale Reaction
a
Conditions: aliphatic ketones 1 (0.2 mmol, 1.0 equiv), ArI 2 (0.4
mmol, 2.0 equiv), ligand (0.1 mmol), Pd(OAc)2 (10 mol %), AgOAc
(2 equiv), HFIP/AcOH = 3:1 (2 mL), 130 °C, N2, 36 h. Yields
correspond to isolated products.
Scheme 5. Proposed Mechanism
yields. The yield gradually decreased with increasing of the
substituent at the α-carbon of butanone, which may be caused
by the steric hindrance (3s−3u). When symmetrical 3-
pentanone and 2,4-dimethyl-3-pentanone having two or more
reaction sites were used, only one monosubstituted product was
detected (3y and 3z). Slightly bulkier ketones were tolerated
because of the strong nucleophilic of alkoxyamino (3u and 3z).
Furthermore, in this catalytic system, substrates 1aa and 1ab (2-
methyl cyclic ketone) also provided the monosubstituted β-
arylated products at methyl positions in good yields (3aa, 3ab).
In addition, the cyclic sp3 C−H bonds of 1-cyclopentyl-
ethanone and cyclopropyl methyl ketone were also arylated to
give the corresponding monosubstituted products in consid-
erable yields with excellent site selectivity and high diaster-
eoselectivity (3ac−3ad). To justify the usefulness of this
method, 1.0 mmol scale reaction was also examined to give a
good yield (Scheme 4).
On the basis of above results and previous research, a plausible
reaction mechanism is presented in Scheme 5. First,
condensation of aliphatic ketones with the TDG provide the
oxime ether intermediate A. Next, the coordination of the oxime
ether intermediate A to a palladium species generates the
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Note
3-(4-Fluorobenzyl)pentan-2-one (3c). Compound 3c was isolated
corresponding chelated cyclometalated Pd-complex B. Cyclo-
metalated Pd-complex B forms the [5, 6]-bicyclic palladium
intermediate C by releasing one molecule of acetic acid. Then,
oxidative addition of intermediate C and aryl iodide generates
the palladium(IV) species D. Finally, reductive elimination of
the palladium complex D followed by the ligand dissociation and
iodide abstraction by AgOAc provides the intermediate F, and
then F was hydrolyzed with the present of acetic acid to give the
TDG and the desired product 3.
as a colorless oil (21.35 mg, 55% yield) by column chromatography on
1
silica gel (eluents: petroleum ether/ethyl acetate = 40:1); H NMR
(400 MHz, CDCl3, ppm): δ 7.12−7.06 (m, 2H), 6.99−6.92 (m, 2H),
2.88−2.83 (m, 1H), 2.75−2.62 (m, 2H), 2.00 (s, 3H), 1.66−1.61 (m,
1H), 1.55−1.48 (m, 1H), 0.89 (t, J = 7.5 Hz, 3H); 13C{1H} NMR (100
MHz, CDCl3, ppm): δ 212.4, 161.6(d, 1JCF = 242), 135.5, 130.4 (d, 2JCF
= 79), 115.35 (d, 3JCF = 21), 56.4, 36.6, 30.4, 24.7, 11.7; HRMS (EI):
m/z [M]+ calcd for C12H15FO: 194.1107; found: 194.1111.
3-(4-Chlorobenzyl)pentan-2-one (3d). Compound 3d was isolated
as a yellow oil (21.84 mg, 52% yield) by column chromatography on
In conclusion, a direct C(sp3)−H arylation reaction of
aliphatic ketones with aryl iodides was achieved using 2-
(aminooxy)-N,N-dimethylacetamide as a novel TDG through
the oxime ether intermediate. A good selectivity for the β-
C(sp3)−H bond insertion with monosubstituted products,
rather than those of γ-C(sp3)−H and relatively reactive α-
C(sp3)−H, is observed. The reaction showed good substrate
compatibility and could tolerate slightly bulkier ketones by the
substrate expansion experiment. This research offers valuable
insight for the future design and application of transient
directing groups. At present, further efforts are ongoing to
render other C−H functionalizations using aminooxy deriva-
tives as TDGs.
1
silica gel (eluents: petroleum ether/ethyl acetate = 40:1); H NMR
(400 MHz, CDCl3, ppm): δ 7.22 (d, J = 8.4 Hz, 2H), 7.07 (d, J = 8.3 Hz,
2H), 2.88−2.82 (m, 1H), 2.75−2.68 (m, 1H), 2.66−2.61 (m, 1H), 2.01
(s, 3H), 1.71−1.62 (m, 1H), 1.54−1.45 (m, 1H), 0.88 (t, J = 7.5 Hz,
3H); 13C{1H} NMR (100 MHz, CDCl3, ppm): δ 212.0, 138.4, 132.1,
130.3, 128.7, 56.1, 36.6, 30.3, 24.7, 11.6; HRMS (EI): m/z [M]+ calcd
for C12H15ClO: 210.0811; found: 210.0814.
3-(4-Bromobenzyl)pentan-2-one (3e). Compound 3e was isolated
as a yellow oil (24.90 mg, 49% yield) by column chromatography on
1
silica gel (eluents: petroleum ether/ethyl acetate = 40:1); H NMR
(400 MHz, CDCl3, ppm): δ 7.38 (d, J = 8.4 Hz, 2H), 7.02 (d, J = 8.4 Hz,
2H), 2.87−2.82 (m, 1H), 2.75−2.67 (m, 1H), 2.64−2.60 (m, 1H), 2.02
(s, 3H), 1.65−1.60 (m, 1H), 1.54−1.48 (m, 1H), 0.89 (t, J = 7.4 Hz,
3H); 13C{1H} NMR (100 MHz, CDCl3, ppm): δ 212.0, 138.9, 131.7,
130.7, 120.2, 56.1, 36.7, 30.4, 24.7, 11.6; HRMS (EI): m/z [M]+ calcd
for C12H15BrO: 254.0306; found: 254.0310.
EXPERIMENTAL SECTION
■
3-([1,1′-Biphenyl]-4-ylmethyl)pentan-2-one (3f). Compound 3f
was isolated as a colorless oil (28.74 mg, 57% yield) by column
chromatography on silica gel (eluents: petroleum ether/ethyl acetate =
40:1); 1H NMR (400 MHz, CDCl3, ppm): δ 7.61−7.57 (m, 2H), 7.52
(d, J = 8.2 Hz, 2H), 7.44 (dd, J1 = 10.4, J2 = 4.8 Hz, 2H), 7.37−7.30 (m,
1H), 7.23 (d, J = 8.1 Hz, 2H), 2.97−2.92 (m, 1H), 2.86−2.69 (m, 2H),
2.06 (s, 3H), 1.73−1.67 (m, 1H), 1.63−1.51 (m, 1H), 0.93 (t, J = 7.5
Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3, ppm): δ 212.5, 140.9,
139.2, 138.9, 129.4, 128.8, 127.2, 127.1, 56.2, 37.1, 30.3, 24.7, 11.70;
HRMS (EI): m/z [M]+ calcd for C18H20O: 252.1514; found: 252.1516.
3-(4-Methylbenzyl)pentan-2-one (3g). Compound 3g was isolated
as a yellow oil (23.21 mg, 61% yield) by column chromatography on
General Information. All reagents, including aliphatic ketones 1
and aryl iodides 2, were obtained from commercial sources and used as
received without further purification unless otherwise stated. All
solvents were dried over 4 Å molecular sieves. Reaction products were
purified via column chromatography on silica gel (300−400 mesh).
Melting points were determined using an open capillary and
uncorrected. NMR spectra were recorded on Bruker AV400 or
AV600 in CDCl3 with tetramethylsilane (TMS) as an internal standard;
chemical shifts δ were given in ppm and coupling constants J in Hz.
HRMS were measured on a QSTAR Pulsar I LC/TOF MS mass
spectrometer.
1
General Procedure for the Synthesis of Products 3. A 10 mL
Schlenk tube was charged with L6 (11.81 mg, 0.1 mmol), Pd(OAc)2
(4.49 mg, 0.02 mmol), and AgOAc (66.76 mg, 0.4 mmol). The tube was
evacuated and filled with N2 three times. Then, aliphatic ketones 1 (0.2
mmol), aryl iodides 2 (0.4 mmol), and the mixture of HFIP (1.5 mL)
and HOAc (0.5 mL) were quickly added into the tube. The reaction
mixture was stirred at room temperature for 10 min and then heated to
130 °C using an oil bath for 36 h. After cooling to room temperature,
the reaction mixture was diluted with EtOAc (15 mL), washed with
water three times, and the organic phase was concentrated in vacuo.
The desired arylated product 3 was purified by flash chromatography
on silica gel.
Methyl 4-(2-Ethyl-3-oxobutyl)benzoate (3a). Compound 3a was
isolated as a colorless oil (31.84 mg, 68% yield) by column
chromatography on silica gel (eluents: petroleum ether/ethyl acetate
= 20:1); 1H NMR (400 MHz, CDCl3, ppm): δ 7.96 (d, J = 8.2 Hz, 2H),
7.24 (d, J = 8.2 Hz, 2H), 3.90 (s, 3H), 3.02−2.86 (m, 1H), 2.82−2.63
(m, 2H), 2.01 (s, 3H), 1.72−1.61 (m, 1H), 1.60−1.48 (m, 1H), 0.95−
0.81 (t, J = 7.4 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3, ppm): δ
211.7, 167.0, 145.3, 129.8, 128.9, 128.2, 55.7, 52.0, 37.1, 30.2, 24.6,
11.4; HRMS (EI): m/z [M]+ calcd for C14H18O3: 234.1256; found:
234.1258.
silica gel (eluents: petroleum ether/ethyl acetate = 40:1); H NMR
(400 MHz, CDCl3, ppm): δ 7.09 (d, J = 8.0 Hz, 2H), 7.04 (d, J = 8.1 Hz,
2H), 2.87−2.82 (m, 1H), 2.78−2.71 (m, 1H), 2.68−2.62 (m, 1H), 2.31
(s, 3H), 2.02 (s, 3H), 1.70−1.60 (m, 1H), 1.58−1.45 (m, 1H), 0.89 (t, J
= 7.4 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3, ppm): δ 211.8,
167.0, 145.4, 129.8, 128.9, 128.3, 55.7, 52.0, 37.2, 30.3, 24.6, 11.5;
HRMS (EI): m/z [M]+ calcd for C13H18O: 190.1358; found: 190.1360.
3-(4-Methoxybenzyl)pentan-2-one (3h). Compound 3h was
isolated as a colorless oil (25.97 mg, 63% yield) by column
chromatography on silica gel (eluents: petroleum ether/ethyl acetate
= 40:1); 1H NMR (400 MHz, CDCl3, ppm): δ 7.05 (d, J = 8.5 Hz, 2H),
6.81 (d, J = 8.5 Hz, 2H), 3.78 (s, 3H), 2.84−2.79 (m, 1H), 2.76−2.56
(m, 2H), 2.00 (s, 3H), 1.67−1.61 (m, 1H), 1.57−1.43 (m, 1H), 0.88 (t,
J = 7.4 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3, ppm): δ 212.8,
158.1, 131.8, 129.9, 113.9, 56.6, 55.4, 36.8, 30.4, 24.6, 11.8; HRMS
(EI): m/z [M]+ calcd for C13H18O2: 206.1307; found: 206.1309.
3-(3-Nitrobenzyl)pentan-2-one (3i). Compound 3i was isolated as a
yellow oil (25.65 mg, 58% yield) by column chromatography on silica
1
gel (eluents: petroleum ether/ethyl acetate = 20:1); H NMR (400
MHz, CDCl3, ppm): δ 8.06−8.00 (m, 2H), 7.49−7.41 (m, 2H), 3.05−
3.00 (m, 1H), 2.85−2.73 (m, 2H), 2.05 (s, 3H), 1.72−1.59 (m, 1H),
1.61−1.51 (m, 1H), 0.92 (t, J = 7.5 Hz, 3H); 13C{1H} NMR (100 MHz,
CDCl3, ppm): δ 211.1, 148.4, 142.1, 135.4, 129.4, 123.7, 121.5, 55.6,
36.3, 30.1, 24.7, 11.4; HRMS (ESI): m/z [M + H]+ calcd for
C12H15NO3: 222.1130; found: 222.1129.
3-(4-Nitrobenzyl)pentan-2-one (3b). Compound 3b was isolated as
a yellow oil (27.41 mg, 62% yield) by column chromatography on silica
1
gel (eluents: petroleum ether/ethyl acetate = 20:1); H NMR (400
MHz, CDCl3, ppm): δ 8.10 (d, J = 8.7 Hz, 2H), 7.30 (d, J = 8.7 Hz, 2H),
3.04−2.98 (m, 1H), 2.81−2.72 (m, 2H), 2.03 (s, 3H), 1.67−1.64 (m
1H), 1.56−1.48(m, 1H), 0.90 (t, J = 7.5 Hz, 3H); 13C{1H} NMR (100
MHz, CDCl3, ppm): δ 211.1, 147.9, 146.6, 129.8, 123.7, 55.6, 36.6,
30.1, 24.7, 11.4; HRMS (EI): m/z [M]+ calcd for C12H15NO3:
221.1052; found: 221.1054.
3-(3-(Trifluoromethyl)benzyl)pentan-2-one (3j). Compound 3j
was isolated as a yellow oil (27.82 mg, 57% yield) by column
chromatography on silica gel (eluents: petroleum ether/ethyl acetate =
40:1); 1H NMR (400 MHz, CDCl3, ppm): δ 7.45 (d, J = 7.8 Hz, 1H),
7.40 (s, 1H), 7.38−7.26 (m, 2H), 2.98−2.94 (m, 1H), 2.81−2.69 (m,
2H), 2.03 (s, 3H), 1.69−1.61 (m, 1H), 1.58−1.47 (m, 1H), 0.91 (t, J =
7299
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Note
7.4 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3, ppm): δ 211.8, 140.9,
132.5, 131.0, 129.0, 125.6−125.5(m), 123.3, 122.9, 55.9, 36.9, 30.3,
24.7, 11.5; HRMS (EI): m/z [M]+ calcd for C13H15F3O: 244.1075;
found: 244.1072.
3.09−3.03 (m, 1H), 2.91−2.82 (m, 2H), 2.02 (s, 3H), 1.71−1.66 (m,
1H), 1.60−1.53 (m, 1H), 0.92 (t, J = 7.4 Hz, 3H); 13C{1H} NMR (100
MHz, CDCl3, ppm): δ 212.5, 137.4, 133.6, 132.2, 128.2, 127.7, 127.6,
127.4, 127.3, 126.1, 125.5, 56.2, 37.7, 30.4, 24.7, 11.7; HRMS (EI): m/z
[M]+ calcd for C16H18O: 226.1358; found: 226.1360.
3-(3-Fluorobenzyl)pentan-2-one (3k). Compound 3k was isolated
as a colorless oil (19.79 mg, 51% yield) by column chromatography on
Methyl 4-(3-Oxobutyl)benzoate (3s). Compound 3s was isolated as
1
silica gel (eluents: petroleum ether/ethyl acetate = 40:1); H NMR
a colorless oil (25.56 mg, 62% yield) by column chromatography on
1
(400 MHz, CDCl3, ppm): δ 7.22 (td, J1 = 7.9, J2 = 6.2 Hz, 1H), 6.94−
6.83 (m, 3H), 2.92−2.86 (m, 1H), 2.79−2.73 (m, 1H), 2.69−2.64(m,
1H), 2.03 (s, 3H), 1.70−1.61 (m, 1H), 1.56−1.49 (m, 1H), 0.90 (t, J =
7.5 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3, ppm): δ 212.0, 162.9
(d, 1JCF = 244,) 142.5 (d, 3JCF = 7.2), 130.0 (d, 3JCF = 8.3), 124.6, 115.8
silica gel (eluents: petroleum ether/ethyl acetate = 20:1); H NMR
(400 MHz, CDCl3, ppm): δ 7.93 (d, J = 8.3 Hz, 2H), 7.24 (d, J = 8.3 Hz,
2H), 3.88 (s, 3H), 2.93 (t, J = 7.5 Hz, 2H), 2.77 (t, J = 7.5 Hz, 2H), 2.13
(s, 3H); 13C{1H} NMR (100 MHz, CDCl3, ppm): δ207.4, 167.1, 146.6,
129.9, 128.5, 128.2, 52.1, 44.6, 30.2, 29.7; HRMS (EI): m/z [M]+ calcd
for C12H14O3: 206.0943; found: 206.0944
Methyl 4-(2-Methyl-3-oxobutyl)benzoate (3t). Compound 3t was
isolated as a colorless oil (24.65 mg, 56% yield) by column
chromatography on silica gel (eluents: petroleum ether/ethyl acetate
= 20:1); 1H NMR (400 MHz, CDCl3, ppm): δ 7.95 (d, J = 8.2 Hz, 2H),
7.22 (d, J = 8.1 Hz, 2H), 3.90 (s, 3H), 3.08−3.03 (m, 1H), 2.90−2.78
(m, 1H), 2.64−2.60 (m, 1H), 2.09 (s, 3H), 1.10 (d, J = 7.0 Hz, 3H);
13C{1H} NMR (100 MHz, CDCl3, ppm): δ 211.7, 167.1, 145.4, 129.9,
129.1, 128.4, 52.1, 48.6, 38.8, 29.0, 16.47; HRMS (EI): m/z [M]+ calcd
for C13H16O3: 220.1099; found: 220.1101.
Methyl 4-(2,2-Dimethyl-3-oxobutyl)benzoate (3u). Compound 3u
was isolated as a colorless oil (22.48 mg, 48% yield) by column
chromatography on silica gel (eluents: petroleum ether/ethyl acetate =
20:1); 1H NMR (400 MHz, CDCl3, ppm): δ 7.93 (d, J = 8.3 Hz, 2H),
7.17 (d, J = 8.3 Hz, 2H), 3.90 (s, 3H), 2.86 (s, 2H), 2.11 (s, 3H), 1.13 (s,
6H); 13C{1H} NMR (100 MHz, CDCl3, ppm): δ 213.6, 167.2, 143.6,
130.4, 129.4, 128.5, 52.2, 48.7, 45.2, 26.2, 24.5; HRMS (EI): m/z [M]+
calcd for C14H18O3: 234.1256; found: 234.1253.
2
(d, 2JCF = 21), 113.3 (d, JCF = 21), 55.9, 36.9, 30.4, 30.3, 24.7, 11.6.
HRMS (EI): m/z [M]+ calcd for C12H15FO: 194.1107; found:
194.1110.
3-(3-Chlorobenzyl)pentan-2-one (3l). Compound 3l was isolated
as a yellow oil (22.69 mg, 54% yield) by column chromatography on
1
silica gel (eluents: petroleum ether/ethyl acetate = 40:1); H NMR
(400 MHz, CDCl3, ppm): δ 7.21−7.15 (m, 2H), 7.13 (s, 1H), 7.01 (d, J
= 6.8 Hz, 1H), 2.89−2.83 (m, 1H), 2.77−2.70 (m, 1H), 2.65−2.60 (m,
1H), 2.02 (s, 3H), 1.68−1.59 (m, 1H), 1.56−1.45 (m, 1H), 0.88 (t, J =
7.5 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3, ppm): δ 211.7, 141.9,
134.3, 129.8, 128.9, 127.2, 126.5, 55.8, 36.8, 30.2, 24.6, 11.5; HRMS
(EI): m/z [M]+ calcd for C12H15ClO: 210.0811; found: 210.0809.
3-(3-Bromobenzyl)pentan-2-one (3m). Compound 3m was
isolated as a yellow oil (29.98 mg, 59% yield) by column
chromatography on silica gel (eluents: petroleum ether/ethyl acetate
= 40:1); 1H NMR (400 MHz, CDCl3, ppm): δ 7.30 (d, J = 8.7 Hz, 2H),
7.12 (t, J = 7.6 Hz, 1H), 7.05 (d, J = 7.7 Hz, 1H), 2.88−2.82 (m, 1H),
2.76−2.69 (m, 1H), 2.64−2.59 (m, 1H), 2.02 (s, 3H), 1.67−1.60 (m,
1H), 1.55−1.45 (m, 1H), 0.88 (t, J = 7.5 Hz, 3H); 13C{1H} NMR (100
MHz, CDCl3, ppm): δ 211.7, 142.3, 131.9, 130.1, 129.4, 127.6, 122.5,
55.8, 36.7, 30.3, 24.6, 11.5; HRMS (EI): m/z [M]+ calcd for
C12H15BrO: 254.0306; found: 254.0305.
Methyl 4-(3-Oxohexyl)benzoate (3v). Compound 3v was isolated
as a colorless oil (23.88 mg, 51% yield) by column chromatography on
1
silica gel (eluents: petroleum ether/ethyl acetate = 20:1); H NMR
(400 MHz, CDCl3, ppm): δ 7.97 (d, J = 8.1 Hz, 2H), 7.27 (d, J = 8.1 Hz,
2H), 3.92 (s, 3H), 2.97 (t, J = 7.5 Hz, 2H), 2.76 (t, J = 7.5 Hz, 2H), 2.39
(t, J = 7.3 Hz, 2H), 1.67−1.54 (m, 2H), 0.91 (t, J = 7.4 Hz, 3H);
13C{1H} NMR (100 MHz, CDCl3, ppm): δ 211.8, 167.1, 145.4, 129.8,
128.9, 128.3, 55.7, 52.0, 37.2, 30.3, 24.6, 11.5; HRMS (EI): m/z [M]+
calcd for C14H18O3: 234.1256; found: 234.1259.
3-(3-Methylbenzyl)pentan-2-one (3n). Compound 3n was isolated
as a colorless oil (20.15 mg, 53% yield) by column chromatography on
1
silica gel (eluents: petroleum ether/ethyl acetate = 40:1); H NMR
(400 MHz, CDCl3, ppm): δ 7.16 (t, J = 7.5 Hz, 1H), 7.01−6.93 (m,
3H), 2.87−2.82 (m, 1H), 2.78−2.70 (m, 1H), 2.66−2.61 (m, 1H), 2.32
(s, 3H), 2.03 (s, 3H), 1.66−1.60 (m, 1H), 1.56−1.48 (m, 1H), 0.89 (t, J
= 7.4 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3, ppm): δ 212.7,
139.8, 138.2, 129.8, 128.5, 127.1, 126.0, 56.3, 37.5, 30.3, 24.7, 21.6,
11.8; HRMS (EI): m/z [M]+ calcd for C13H18O: 190.1358; found:
190.1355.
Methyl 4-(3-Oxoheptyl)benzoate (3w). Compound 3w was isolated
as a colorless oil (28.80 mg, 58% yield) by column chromatography on
1
silica gel (eluents: petroleum ether/ethyl acetate = 20:1); H NMR
(400 MHz, CDCl3, ppm): δ 7.97 (d, J = 8.1 Hz, 2H), 7.29 (d, J = 3.6 Hz,
2H), 3.92 (s, 3H), 2.97 (t, J = 7.5 Hz, 2H), 2.77 (t, J = 7.5 Hz, 2H), 2.41
(t, J = 7.4 Hz, 2H), 1.60−1.54 (m, 2H), 1.38−1.28 (m, 2H), 0.91 (t, J =
7.3 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3, ppm): δ 209.9, 167.2,
146.9, 129.9, 128.5, 128.2, 52.1, 43.8, 42.9, 29.8, 25.9, 22.4, 13.9;
HRMS (EI): m/z [M]+ calcd for C15H20O3: 248.1412; found:
248.1410.
Methyl 4-(2-Methyl-3-oxoheptyl)benzoate (3x). Compound 3x
was isolated as a colorless oil (28.84 mg, 55% yield) by column
chromatography on silica gel (eluents: petroleum ether/ethyl acetate =
20:1); 1H NMR (400 MHz, CDCl3, ppm): δ 7.92 (d, J = 8.2 Hz, 2H),
7.19 (d, J = 8.2 Hz, 2H), 3.87 (s, 3H), 3.03−2.98 (m, 1H), 2.85−2.80
(m, 1H), 2.60−2.55 (m, 1H), 2.42−2.34(m, 1H), 2.26−2.18 (m, 1H),
1.47−1.40 (m, 2H), 1.24−1.25 (m, 2H), 1.06 (d, J = 7.0 Hz, 3H), 0.82
(t, J = 7.3 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3, ppm): δ 213.8,
167.1, 145.5, 129.8, 129.1, 128.3, 52.1, 47.8, 41.8, 39.0, 25.6, 22.3, 16.8,
13.9; HRMS (EI): m/z [M]+ calcd for C16H22O3: 262.1569; found:
262.1567.
3-(2-Fluorobenzyl)pentan-2-one (3o). Compound 3o was isolated
as a colorless oil (14.36 mg, 37% yield) by column chromatography on
1
silica gel (eluents: petroleum ether/ethyl acetate = 40:1); H NMR
(400 MHz, CDCl3, ppm): δ 7.19−7.10 (m, 2H), 7.06−6.96 (m, 2H),
2.94−2.68 (m, 3H), 2.05 (s, 3H), 1.69−1.63 (m, 1H), 1.59−1.45 (m,
1H), 0.89 (t, J = 7.4 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3, ppm):
3
δ 212.2, 161.3 (d, 1JCF = 243), 131.5 (d, JCF = 4.7), 128.2 (d, 3JCF
=
2
2
8.1), 126.7 (d, JCF = 16), 124.12, 115.4 (d, JCF = 22), 54.56, 30.74,
30.11, 24.60, 11.58; HRMS (EI): m/z [M]+ calcd for C12H15FO:
194.1107; found: 194.1109.
3-(2,4-Difluorobenzyl)pentan-2-one (3p). Compound 3p was
isolated as a colorless oil (18.24 mg, 43% yield) by column
chromatography on silica gel (eluents: petroleum ether/ethyl acetate
= 40:1); 1H NMR (400 MHz, CDCl3, ppm): δ 7.09 (dd, J1 = 15.2, J2 =
8.5 Hz, 1H), 6.85−6.68 (m, 2H), 2.90−2.65 (m, 3H), 2.05 (s, 3H),
1.70−1.61 (m, 1H), 1.55−1.48 (m, 1H), 0.90 (t, J = 7.4 Hz, 3H);
13C{1H} NMR (100 MHz, CDCl3, ppm): δ 211.9, 161.7 (dd, JCF = 245,
Methyl 4-(3-Oxopentyl)benzoate (3y). Compound 3y was isolated
12), 161.0 (dd, JCF = 246, 12), 132.1 (dd, JCF = 94, 6.4), 122.5 (dd, JCF
=
as a colorless oil (25.09 mg, 57% yield) by column chromatography on
5.8, 3.6), 111.2 (dd, JCF = 20.8, 3.7), 103.9 (dd, JCF = 25, 16), 54.6, 30.1,
30.0, 24.6, 11.5; HRMS (EI): m/z [M]+ calcd for C12H14F2O:
212.1013; found: 212.1011.
1
silica gel (eluents: petroleum ether/ethyl acetate = 20:1); H NMR
(400 MHz, CDCl3, ppm): δ 7.94 (d, J = 8.2 Hz, 2H), 7.24 (d, J = 8.2 Hz,
2H), 3.89 (s, 3H), 2.95 (t, J = 7.5 Hz, 2H), 2.74 (t, J = 7.5 Hz, 2H), 2.40
(q, J = 7.3 Hz, 2H), 1.04 (t, J = 7.3 Hz, 3H); 13C{1H} NMR (100 MHz,
CDCl3, ppm): δ 210.2, 167.1, 146.5, 129.6, 128.5, 128.2, 52.2, 52.1,
43.4, 36.3, 29.8, 7.8; HRMS (EI): m/z [M]+ calcd for C13H16O3:
220.1099; found: 220.1102.
3-(Naphthalen-2-ylmethyl)pentan-2-one (3q). Compound 3q was
isolated as a yellow oil (21.26 mg, 47% yield) by column
chromatography on silica gel (eluents: petroleum ether/ethyl acetate
1
= 40:1); H NMR (400 MHz, CDCl3, ppm): δ 7.81−7.75 (m, 3H),
7.59 (s, 1H), 7.48−7.41 (m, 2H), 7.30 (dd, J1 = 8.4, J2 = 1.2 Hz, 1H),
7300
https://doi.org/10.1021/acs.joc.1c00646
J. Org. Chem. 2021, 86, 7296−7303

The Journal of Organic Chemistry
pubs.acs.org/joc
Note
Methyl 4-(2,4-Dimethyl-3-oxopentyl)benzoate (3z). Compound
3z was isolated as a colorless oil (21.34 mg, 43% yield) by column
chromatography on silica gel (eluents: petroleum ether/ethyl acetate =
20:1); 1H NMR (400 MHz, CDCl3, ppm): δ 7.93 (d, J = 8.2 Hz, 2H),
7.21 (d, J = 8.2 Hz, 2H), 3.90 (s, 3H), 3.05−2.91 (m, 2H), 2.63−2.44
(m, 2H), 1.10 (d, J = 6.6 Hz, 3H), 1.01 (d, J = 6.9 Hz, 3H), 0.85 (d, J =
6.9 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3, ppm): δ 211.8, 167.0,
145.4, 129.8, 128.9, 128.3, 55.7, 52.0, 37.2, 30.3, 24.6, 11.5; HRMS
(EI): m/z [M]+ calcd for C15H20O3: 248.1412; found: 248.1411.
Methyl 4-((2-Oxocyclopentyl)methyl)benzoate (3aa). Compound
3aa was isolated as a colorless oil (27.39 mg, 59% yield) by column
chromatography on silica gel (eluents: petroleum ether/ethyl acetate =
20:1); 1H NMR (400 MHz, CDCl3, ppm): δ 7.93 (d, J = 8.2 Hz, 2H),
7.22 (d, J = 8.2 Hz, 2H), 3.88 (s, 3H), 3.17 (dd, J = 13.9, 4.2 Hz, 1H),
2.58 (dd, J = 13.9, 9.4 Hz, 1H), 2.38−2.28 (m, 2H), 2.13−2.02 (m,
2H), 1.97−1.90 (m, 1H), 1.77−1.68 (m, 1H), 1.54−1.47 (m, 1H);
13C{1H} NMR (100 MHz, CDCl3, ppm): δ 219.7, 167.1, 145.6, 129.8,
filtered off, and the filtrate was evaporated to get L1 as a brown powder
(116.1 mg, 95%).
2-(Aminooxy)-N-phenylacetamide (L1). Compound L1 was
isolated as a brown powder (116.13 mg, 74% yield) by column
chromatography on silica gel (eluents: petroleum ether/ethyl acetate =
3:1), mp: 100.9−104.1 °C; 1H NMR (400 MHz, CDCl3, ppm): δ 8.16
(s, 1H), 7.56 (d, J = 7.7 Hz, 2H), 7.33 (t, J = 8.0 Hz, 2H), 7.13 (t, J = 7.4
Hz, 1H), 5.80 (s, 2H), 4.28 (s, 2H); 13C{1H} NMR (100 MHz, CDCl3,
ppm): δ 168.1, 137.2, 129.1, 124.7, 120.1, 75.2; HRMS (EI): m/z [M]+
calcd for C8H10N2O2: 166.0742; found: 166.0743.
2-(Aminooxy)-N-isopropylacetamide (L2). Compound L2 was
isolated as a yellow oil (101.72 mg, 77% yield) by column
chromatography on silica gel (eluents: petroleum ether/ethyl acetate
= 3:1); 1H NMR (400 MHz, CDCl3, ppm): δ 6.28 (s, 1H), 5.73 (s, 2H),
4.06 (s, 2H), 4.13−4.01 (m, 1H), 1.12 (d, J = 6.4, 2H); 13C{1H} NMR
(100 MHz, CDCl3, ppm): δ 168.8, 74.9, 40.8, 22.7; HRMS (EI): m/z
[M]+ calcd for C5H12N2O2: 132.0899; found: 132.0901
2-(Aminooxy)-N-isopropylpropanamide (L3). Compound L3 was
isolated as a yellow oil (61.41 mg, 42% yield) by column
chromatography on silica gel (eluents: petroleum ether/ethyl acetate
= 3:1), mp: 61.1−63.2 °C; 1H NMR (400 MHz, CDCl3, ppm): δ 6.10
(s, 1H), 5.09 (s, 2H), 4.15−4.03 (m, 2H), 1.33 (d, J = 6.8 Hz, 3H), 1.17
(d, J = 6.4 Hz, 2H), 1.15 (d, J = 6.4 Hz, 2H); 13C{1H} NMR (100 MHz,
CDCl3, ppm): δ 172.0, 81.3, 40.9, 22.9, 17.4; HRMS (EI): m/z [M]+
calcd for C6H14N2O2: 146.1055; found: 146.1058.
2-(Aminooxy)-N-cyclohexylacetamide (L5). Compound L5 was
isolated as a white power (147.14 mg, 79% yield) by column
chromatography on silica gel (eluents: petroleum ether/ethyl acetate
= 3:1), mp: 86.3−89.1 °C; 1H NMR (400 MHz, CDCl3, ppm): δ 6.25
(s, 1H), 5.48 (s, 2H), 4.09 (s, 2H), 3.88−3.64 (m, 1H), 1.88 (d, J = 12.0
Hz, 2H), 1.75−1.39 (m, 3H), 1.39−1.29 (m, 2H), 1.18−1.10 (m, 3H);
13C{1H} NMR (100 MHz, CDCl3, ppm): δ 168.6, 75.0, 47.7, 33.1, 25.5,
24.9; HRMS (EI): m/z [M]+ calcd for C8H16N2O2: 172.1212; found:
172.1215.
2-(Aminooxy)-N,N-dimethylacetamide (L6). Compound L6 was
isolated as a white oil (93.84 mg, 71% yield) by column
chromatography on silica gel (eluents: petroleum ether/ethyl acetate
= 3:1); 1H NMR (400 MHz, CDCl3, ppm): δ 4.29 (s, 2H), 2.90 (s, 3H),
2.86 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3, ppm): δ 169.5, 72.6,
35.6, 35.3; HRMS (EI): m/z [M-H]+ calcd for C4H10N2O2: 118.0742;
found: 118.0740.
2-(Aminooxy)-N-methylacetamide (L7). Compound L7 was
isolated as a yellow oil (90.96 mg, 77% yield) by column
chromatography on silica gel (eluents: petroleum ether/ethyl acetate
= 3:1); 1H NMR (400 MHz, CDCl3, ppm): δ 6.59 (s, 1H), 4.12 (d, J =
2.7 Hz, 2H), 2.83 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3, ppm): δ
170.8, 74.9, 25.7; HRMS (EI): m/z [M]+ calcd for C3H8N2O2:
104.0586; found: 104.0587.
129.0, 128.3, 52.1, 50.8, 38.1, 35.7, 29.2, 20.6; HRMS (EI): m/z [M]+
calcd for C14H16O3: 232.1099; found: 232.1096.
Methyl 4-((2-Oxocyclohexyl)methyl)benzoate (3ab). Compound
3ab was isolated as a colorless oil (32.49 mg, 66% yield) by column
chromatography on silica gel (eluents: petroleum ether/ethyl acetate =
20:1); 1H NMR (400 MHz, CDCl3, ppm): δ 7.94 (d, J = 8.2 Hz, 2H),
7.23 (d, J = 8.1 Hz, 2H), 3.90 (s, 3H), 3.26 (dd, J = 13.7, 4.9 Hz, 1H),
2.60−2.53 (m, 1H), 2.50−2.39 (m, 2H), 2.36−2.28 (m, 1H), 2.10−
1.96 (m, 2H), 1.88−1.80 (m, 1H), 1.71−1.56 (m, 2H), 1.39−1.31 (m,
1H); 13C{1H} NMR (100 MHz, CDCl3, ppm): δ 212.2, 167.2, 146.2,
129.8, 129.3, 128.1, 52.3, 42.3, 35.7, 33.7, 28.1, 25.2; HRMS (EI): m/z
[M]+ calcd for C15H18O3: 246.1256; found: 246.1259.
Methyl 4-((1R,2S)-2-acetylcyclopropyl)benzoate (3ac). Com-
pound 3ac was isolated as a colorless oil (16.14 mg, 37% yield) by
column chromatography on silica gel (eluents: petroleum ether/ethyl
acetate = 20:1); 1H NMR (400 MHz, CDCl3, ppm): δ 7.94 (d, J = 8.2
Hz, 2H), 7.13 (d, J = 8.2 Hz, 2H), 3.90 (s, 3H), 2.60−2.49 (m, 1H),
2.31 (s, 3H), 2.28−2.24 (m, 1H), 1.73−1.69 (m, 1H), 1.43−1.39 (m,
1H); 13C{1H} NMR (100 MHz, CDCl3, ppm): δ 206.5, 167.0, 146.0,
129.9, 128.5, 126.0, 52.2, 33.3, 31.1, 28.8, 19.7; HRMS (EI): m/z [M]+
calcd for C13H14O3: 218.0943; found: 218.0940.
Methyl 4-((1R,2S)-2-acetylcyclopentyl)benzoate (3ad). Com-
pound 3ad was isolated as a colorless oil (26.09 mg, 53% yield) by
column chromatography on silica gel (eluents: petroleum ether/ethyl
acetate = 20:1); 1H NMR (400 MHz, CDCl3, ppm): δ 7.96 (d, J = 8.3
Hz, 2H), 7.30 (d, J = 8.2 Hz, 2H), 3.89 (s, 3H), 3.39−3.32 (m, 1H),
3.05−3.01 (m, 1H), 2.21−2.08 (m, 2H), 2.02 (s, 3H), 1.93−1.85 (m,
2H), 1.79−1.73 (m, 2H); 13C{1H} NMR (100 MHz, CDCl3, ppm): δ
210.1, 167.1, 150.2, 130.0, 128.4, 127.4, 60.3, 52.1, 48.4, 35.6, 30.2,
30.0, 25.5; HRMS (EI): m/z [M]+ calcd for C15H18O3: 246.1256;
found: 246.1253.
General Procedure for the Synthesis of Ligands L1, L2, L3, L5,
L6, L7, and L8. Et3N (1.1 mmol) was added to a solution of aniline (1
mmol) in anhydrous DCM (10 mL) under N2. The reaction mixture
was stirred at 0 °C. Then, a solution of the chloroacetyl chloride (1.1
mmol) in anhydrous DCM was added. The reaction mixture was stirred
at the same temperature for 6 h. After that, the reaction mixture was
washed with water and dried with Na2SO4. Then, the solvent was
removed under vacuum to get the crude 2-chloro-N-phenylacetamide
as a brown solid (160.92 mg, 95%). K2CO3 (195.44 mg, 1.5 equiv) was
added to a solution of 2-chloro-N-phenylacetamide (160 mg, 1 equiv)
and N-hydroxyphthalimide (185.82 mg, 1.2 equiv) in anhydrous DMF
(20 mL) at room temperature. Then, the mixture was refluxed with an
oil bath for 6 h under N2. Then, the solvent was evaporated under
reduced pressure. The residue obtained underwent extraction from
CH2Cl2 and sat. NH4Cl solution, and the combined organic layer was
washed with brine and dried over Na2SO4. The crude product was
purified on a silica gel column using petroleum ether/dichloromethane
(3:1 v/v) as the eluent to give the intermediate as an white solid (219
mg, yield: 78%). Then, to a solution of intermediate (219 mg) in THF
(10 mL) was added hydrazine monohydrate (10 equiv) at room
temperature. The mixture was refluxed in an oil bath for 2 h, and the
reaction mixture was cooled to room temperature. The precipitate was
2-(Aminooxy)-N,N-diethylacetamide (L8). Compound L8 was
isolated as a yellow oil (116.96 mg, 73% yield) by column
chromatography on silica gel (eluents: petroleum ether/ethyl acetate
= 3:1); 1H NMR (400 MHz, CDCl3, ppm): δ 5.34 (s, 2H), 4.33 (s, 2H),
3.36 (q, J = 7.1 Hz, 2H), 3.16 (q, J = 7.2 Hz, 2H), 1.15 (t, J = 7.2 Hz,
3H), 1.11 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3, ppm):
δ 168.7, 72.6, 40.7, 40.1, 14.1, 13.0; HRMS (EI): m/z [M]+ calcd for
C6H14N2O2: 146.1055; found: 146.1053.
General Procedure for the Synthesis of Ligand L4. To a
solution of pyridin-2-ylmethanol (1 mmol), PPh3 (1.1 mmol), and N-
hydroxyphthalimide (1.5 mmol) in anhydrous THF (10 mL) was
added the DIAD (1.1 mmol) via injection slowly under N2 at room
temperature. The resulting solution was stirred at room temperature for
12 h, and then the mixture was washed with water and dried with
Na2SO4. The solution was concentrated in vacuo to provide a crude
product, which was further purified via column chromatography on
silica gel using petroleum ether/dichloromethane (3:1 v/v) as the
eluent to supply the intermediate (157.6 mg, 79%). Then, to a solution
of intermediate (157.6 mg) in THF (10 mL) was added hydrazine
monohydrate (10 equiv) at room temperature. The mixture was
refluxed in an oil bath for 2 h and then cooled to room temperature. The
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J. Org. Chem. 2021, 86, 7296−7303

The Journal of Organic Chemistry
pubs.acs.org/joc
Note
precipitate was filtered off, and filtrate was evaporated to get L4 as
yellow oil (85.93 mg, 88%).
ACKNOWLEDGMENTS
■
We gratefully thank the National Natural Science Foundation of
China (Project No. 21676088) for financial support.
O-(Pyridin-2-ylmethyl)hydroxylamine (L4). Compound L4 was
isolated as a yellow oil (93.75 mg, 76% yield) by column
chromatography on silica gel (eluents: petroleum ether/ethyl acetate
= 2:1); 1H NMR (400 MHz, CDCl3, ppm): δ 8.56 (d, J = 4.1 Hz, 1H),
7.67 (t, J = 7.6 Hz, 1H), 7.34 (d, J = 7.6, 1H), 7.18 (t, J = 7.2 Hz, 1H),
5.51 (s, 2H), 4.80 (s, 2H); 13C{1H} NMR (100 MHz, CDCl3, ppm): δ
157.8, 149.4, 136.7, 122.7, 121.9, 78.3; HRMS (ESI): m/z [M + H]+
calcd for C6H8N2O: 125.0715; found: 125.0716.
Procedure for 1.0 mmol Scale Reaction. A 10 mL Schlenk tube
was charged with L6 (59.05 mg, 0.5 mmol), Pd(OAc)2 (22.45 mg, 0.1
mmol), and AgOAc (333.80 mg, 2 mmol). The tube was evacuated and
filled with N2 three times. Then, aliphatic ketones 1a (100 mg, 1 mmol),
aryl iodides 2a (523 mg, 2 mmol), and the mixture of HFIP (3 mL) and
HOAc (1 mL) were quickly added into the tube. The reaction mixture
was stirred at room temperature for 10 min and then heated to 130 °C
using an oil bath for 36 h. After cooling to room temperature, the
reaction mixture was diluted with EtOAc (15 mL), washed with water
three times, and the organic phase was concentrated in vacuo. The the
desired arylated product 3a was purified by flash chromatography on
silica gel as a colorless oil (150 mg, 64% yield).
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ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.1c00646.
Experimental procedures and spectral data (PDF)
AUTHOR INFORMATION
■
Corresponding Authors
Yafei Ji − Engineering Research Centre of Pharmaceutical
Process Chemistry, Ministry of Education; School of Pharmacy,
East China University of Science and Technology, Shanghai
200237, P.R. China; orcid.org/0000-0002-3562-6703;
Email: jyf@ecust.edu.cn
Shaowen Liao − Shanghai Jinli Pharmaceutical Co. Ltd.,
Shanghai 201507, P.R. China; orcid.org/0000-0002-
8320-6148; Email: Liaoshw@gmail.com
Authors
Yangyang Wang − Engineering Research Centre of
Pharmaceutical Process Chemistry, Ministry of Education;
School of Pharmacy, East China University of Science and
Technology, Shanghai 200237, P.R. China
Gaorong Wu − Engineering Research Centre of Pharmaceutical
Process Chemistry, Ministry of Education; School of Pharmacy,
East China University of Science and Technology, Shanghai
200237, P.R. China
Xiaobo Xu − Engineering Research Centre of Pharmaceutical
Process Chemistry, Ministry of Education; School of Pharmacy,
East China University of Science and Technology, Shanghai
200237, P.R. China
Binghan Pang − Engineering Research Centre of
Pharmaceutical Process Chemistry, Ministry of Education;
School of Pharmacy, East China University of Science and
Technology, Shanghai 200237, P.R. China
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.1c00646
Notes
The authors declare no competing financial interest.
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