Amide Oxygen-Assisted Palladium-Catalyzed Hydration of Alkynes

Article abstract of DOI:10.1021/acs.joc.5b01178

Herein, an amide oxygen-assisted palladium-catalyzed hydration reaction of alkynes is realized to prepare a series of o-acylacetanilide derivatives with high yield, and single regioselectivity under mild reaction conditions. This transformation is simple,

Full text of DOI:10.1021/acs.joc.5b01178

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Amide Oxygen-Assisted Palladium-Catalyzed
Hydration of Alkynes
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Zhenming Zhang,† Lihuan Wu,†,‡ Jianhua Liao,† Wanqing Wu,*,† Huanfeng Jiang,*,†
Jianxiao Li, † Jiawei Li †
†School of Chemistry and Chemical Engineering, South China University of Technology,
Guangzhou 510640, P. R. China
‡College of Chemistry and Chemical Engineering, Zhaoqing University, Zhaoqing 526060, P. R.
China
Fax: (+86) 20ꢀ8711ꢀ2906; Eꢀmail: cewuwq@scut.edu.cn, jianghf@scut.edu.cn
Abstract: Herein, an amide oxygenꢀassisted palladiumꢀcatalyzed hydration reaction
of alkynes is realized to prepare a series of orthoꢀacylacetanilide derivatives with high
yield and single regioselectivity under mild reaction conditions. This transformation is
simple and practical, which can be performed on a gram scale. Evaluation of the
mechanism shows that the reaction should involve an oxypalladation process and the
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1,3ꢀoxazine compound is proved to be a key intermediate.
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INTRODUCTION
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Functionalization of alkynes has always been a charming and useful research area in
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organic synthesis.1 Hydration of alkynes (Scheme 1a), as one of the most efficient
addition reactions of alkynes, is a useful strategy for constructing carbonyl motif
which occurs ubiquitous in organic compounds. In the past, the toxic mercury salts
combined with acids were used as reliable catalysts for alkyne hydration reactions.2 In
recent years, many impressive achievements have been developed in applying other
metals instead of toxic Hg(II) salts as catalysts. Notably, Auꢀcatalyzed hydration of
alkynes is an representative strategy for constructing ketones from alkynes.3 Moreover,
many other metal catalysts, such as Fe,4 Pd,5 Pt,6 Ru,7 Ti,8 Ir,9 etc.,10 have also been
applied in hydration of alkynes. In addition, an ionic liquid system containing strong
acid has been successfully developed.11 Although the above methods are favorable,
there are still some limitations as following: (i) the substrates are usually restricted to
simple terminal alkynes; (ii) the nonterminal alkyne substrates show a low
regioselectivity; (iii) harsh reaction conditions such as strong acid, ligand or high
temperature are required in these reactions. Expecially, when the transition metal Pd
was used as catalyst in the hydration of alkynes, an amine substrate is generally
needed in the reaction to get the hydration products through hydroamination.5a, 5b
Clearly, it remains a continuing challenge to develop general and efficient methods for
the hydration of complex alkynes under mild and simple conditions.
In recent years, we have been doing efforts to develop new strategies on
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functionalization of alkynes.12 In these studies, nucleopalladation of alkynes, such as
halopalladation, aminopalladation and oxypalladation, displayed a distinctive reaction
pathway for constructing carbonꢀheteroatom bonds under mild conditions.13 We
envision that the oxypalladation of alkynes, which undergo an addition of alkynes
with oxygen atom as well as hydration of alkynes, might provide a new method to
expand the application of alkyne hydration.
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Scheme 1. Hydration of Alkynes
In addition, orthoꢀacylacetanilide skeleton is one of the most important structural
motifs and resourceful intermediates in natural products and medicinal compounds.14
In the early reports, oxidation of indoles is the general method for the synthesis of
orthoꢀacylacetanilide derivatives.15 Very recently, Pdꢀcatalyzed CꢀH activation of
acetanilides with different acyl sources to construct orthoꢀacylacetanilide was also
reported.16 Herein, we disclose an amide oxygenꢀassisted palladiumꢀcatalyzed
hydration of alkynes through an oxypalladation pathway under simple and mild
conditions, affording a series of orthoꢀacylacetanilide derivatives in good to excellent
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yields with single regioselectivity (Scheme 1b).
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RESULTS AND DISCUSSION
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Nꢀ(2ꢀ(Phenylethynyl)phenyl)acetamide (1) was chosen as the model substrate to
screen the best reaction conditions for the hydration reaction, and Pd(OAc)2 was
applied to initiate the investigation. As shown in Table 1, to our delight, the desired
hydration product 1a was observed in 98% GC yield when using Pd(OAc)2 (5 mol %)
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as the catalyst and AcOH as the solvent at 80 C (entry 1). And it is discovered that
only < 5% yield of 1a was produced when the reaction proceeded with Pd(dba)2 (entry
2). As expected, when the Pd(OAc)2 catalyst was not included or Cu(OAc)2 was used
as catalyst in this reaction system, the hydration product was not observed (entries 3
and 4). Different solvents were then screened to study the efficiency of this reaction.
Only a trace amount of the desired product could be obtained in toluene, but the
addition of water could enhance the yield of the hydration product. Similar result was
obtained when using MeCN as the reaction media. The above observations revealed
that the key role of H2O came from solvent for the success of this transformation
(entries 5ꢀ7). Interestingly, it was found that the reaction temperature was inversely
related to the reaction time. And the excellent results were generally obtained at 80 oC
for 3 h or RT for 12 h (entries 8ꢀ11). The loading of Pd(OAc)2 had a slight effect on
the yield but the reaction time need to be extended (entries 12 and 13). In addition,
when other catalysts of hydration such as PtCl2 and Au(PPh3)Cl were used, no
reaction occurred (entries 14 and 15). Thus, the optimal reaction conditions were
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Pd(OAc)2 (5 mol %) in AcOH at room temperature (Table 1, entry 11).
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Table 1. Optimization of Reaction Conditionsa
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Entry
1
Cat.
Solvent
HOAc
HOAc
HOAc
HOAc
toluene
Temp. (oC) Time (h) Yield (%) b
Pd(OAc)2
Pd(dba)2
ꢀꢀ
80
80
80
80
80
8
98
2
12
8
<5
3
NR
NR
trace
24
4
Cu(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
PtCl2
8
5
6c
8
toluene/H2O 80
8
7
MeCN
HOAc
HOAc
HOAc
HOAc
HOAc
HOAc
HOAc
HOAc
80
8
37
8
80
3
96
9
60
8
90
10
11
12d
13e
14
15
R.T.
R.T.
R.T.
R.T.
R.T.
R.T.
8
74
12
48
144
12
12
98 (90)
83
81
NR
NR
Au(PPh3)Cl
a The reaction was carried out with 1 (0.50 mmol), catalyst (5 mol %) in solvent (1.0 mL).
Determined by GC using dodecane as the internal standard, isolated yield in parentheses.
toluene/H2O = 4/1. d 2.5 mol % of Pd(OAc)2 was used. e 0.5 mol % of Pd(OAc)2.
b
c
With the optimal reaction conditions in hand, we then investigated the substrate
scope of this Pdꢀcatalyzed hydration of Nꢀacetamide alkynes (Table 2). It was found
that a variety of Nꢀ(2ꢀ(phenylethynyl)aryl)acetamides could be converted to the
corresponding products in good to excellent yields. The benzene ring was found to be
tolerant of substituents at R that were electronꢀwithdrawing groups including ꢀF (2a),
ꢀCl (3a), ꢀCN (4a), ꢀCF3 (5a) and ꢀCOOMe (6a), and electronꢀdonating groups such
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as 4ꢀMe (7a) and 5ꢀMe (8a) in this reaction system. Pleasingly, heterocycle ring such
as pyridine was also compatible with the process and the desired product 9a could be
obtained in 81% yield.
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Table 2. Scope of the Hydration of Alkynes (1-24)a
a The reaction was carried out with alkyne (0.50 mmol), Pd(OAc)2 (5 mol %) in HOAc (1.0 mL) at
room temperature. b The byproduct 22b from esterification of 22a with HOAc was obtained in
23% yield.
Different groups on the other side of alkynes were then investigated. For the
different aromatic groups on the other side of alkynes, the substrates containing
electronꢀwithdrawing groups (ꢀCl, ꢀBr) could be transferred to the corresponding
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products 10a and 11a in 80% and 82% high yields. When the substituent was methyl
group, the hydration product was formed in good yields as well (12a and 13a).
Importantly, good yields could be also obtained when the substrates containing
3ꢀthienyl (14a) and 3ꢀpyridyl (15a) substituent were used. Various alkyl groups such
as propyl, tꢀbutyl, cyclohexyl and cyclopropyl were found to be compatible in this
reaction and the desired products 16aꢀ19a could be achieved in good to excellent
yields (78ꢀ93%). The hydration product Nꢀ(2ꢀacetylphenyl)acetamide (20a) could be
obtained when the terminal alkyne was used. Furthermore, this hydration reaction was
also effective with the substrates bearing acidꢀsensitive functional groups. For
example, the exclusive formation of 21a was achieved from the reaction of alkyne
ester. Substrate 22 with a free hydroxyl group reacted smoothly to give the hydration
product in 65% yield and the esterification byproduct in 23% yield. An acetamido
substrate was also found to be suitable for this reaction and converted to the
corresponding products (23a) in 83% yield. In addition, the alkyne substrate
containing linear CN group exhibited similar reactivity, and excellent result was
obtained for the desired product (24a).
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We have also examined the scope of this hydration reaction with regard to different
amide substrate (Table 3). Both the substrates bearing alkanoyl and aroyl groups
could participate efficiently to give the hydration products in good to excellent yields
(25aꢀ38a). For the aryl acyl groups, both electronꢀrich and ꢀpoor substitutions on the
Table 3. Scope of the Hydration of Alkynes (25-39)a
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O
t-Bu
O
CF3
NH
O
O
NH
NH
O
NH
O
O
O
27a (83%)
28a (84%)
25a (74%)
26a (90%)
O
O
O
O
NH Cl
NH
NH
NH
O
O
O
O
31a (85%)
32a (87%)
30a (85%)
29a (86%)
F
F
F
F
O
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O
O
Br
CF3
NH
NH
NH
NH
O
F
O
O
O
33a (80%)
34a (85%)
35a (89%)
36a (76%)
O
O
O
O
O
O
S
NH
NH
NH
O
O
O
39b (69%)b
37a (89%)
38a (84%)
a The reaction was carried out with alkynes (0.50 mmol), Pd(OAc)2 (5 mol %) in HOAc (1.0 mL)
at room temperature. b Nꢀ(2ꢀ(pentꢀ1ꢀynyl)phenyl)acrylamide 39 was used as substrate.
different positions are all tolereated (30aꢀ35a). Moreover, the reaction with
pentafluoroꢀNꢀ(2ꢀ(pentꢀ1ꢀynyl)phenyl)benzamide (36) as the substrate could also
execute this transformation under standard conditions in 76% yield. To our delight,
this method was successfully applied to the substrates containing 2ꢀfuranyl and
2ꢀthienyl groups, and these substrates were smoothly converted to the corresponding
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products (37a and 38a) in 89% and 84% yields, respectively. Furthermore, the
acrylamide substrate could be transferred to the hydration byproduct 39b in 69% yield.
We inferred that an addition reaction between hydration product 39a with HOAc
occurred.
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It should be noted that this transformation could also be suitable for linear alkyl
internal alkynes. To our surprise, the hydration products (40b and 41b) were obtained
in 31% and 36% yields when butꢀ3ꢀynꢀ1ꢀamine was employed as the substrate in this
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reaction at 80 C (Scheme 2). However, only a trace amount of the theoretical
hydration products (40a and 41a) according to the hydration reactions of substrates
1ꢀ39 those were just observed.
Scheme 2. Hydration of Linear Internal Alkynes
In addition, a satisfactory result (85% isolated yield) was obtained when the
reaction was performed on gramꢀscale under the standard conditions (Scheme 3).
Scheme 3. Gram-Scale Experiment
To demonstrate the potential applications of this hydration product as a useful
building block in organic synthesis, the newly formed orthoꢀacylacetanilides were
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employed for further transformations to construct a series of functionalized products
(Scheme 4). For example, deprotection of 1a was achieved by 4 M HCl at reflux in
EtOH in 95% yield. Also, the reduction of 1a with NaBH4 delivered the
corresponding product 1ab in excellent yield. Moreover, the product 17a could
efficiently undergo an intramolecular condensation reaction to afford a quinolone
derivative 17aa in 79% yield that may find its applications in antibiotic drugs.
Scheme 4. Transformations of ortho-Acylacetanilides
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To understand the mechanistic pathway more clearly, some control experiments
were carried out (Scheme 5). The results showed that 1,2ꢀdiphenylethyne (eq. 1),
2ꢀ(phenylethynyl)aniline (eq. 2) and tertiary amido internal alkyne (eq. 3) failed to
afford the hydration products under the standard conditions, which indicated that the
secondary amides were necessary. In addation, the reason that the corresponding
hydration of tertiary amido internal alkyne did not proceed may be due to that the
intermediate can not carry out the protonation of palladium species and then stop the
catalytic cycle.17a, 17b Moreover, the potential intermediate 1b was synthesized in the
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presence of the Pd(OAc)2 system in MeCN at 80 C,17c, 17d and this oxypalladation
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product 1b could be smoothly converted to 1a in complete conversion under the
standard reaction conditions for 8 h (eq. 4 and 5), suggesting that the oxypalladation
process played an important role in the formation of the final hydration product.
Scheme 5. Control Experiments
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Then, we further performed isotope labelled experiments to verify the
oxypalladation pathway in this reaction (see the Supporting Information for details).
Nꢀ(2ꢀ(Phenylethynyl)phenyl)acetamide (1a) was used in this hydration reaction in
AcOD solvent. It was as expected that the hydration product 1a-D (D/H = 7/1
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detected by H NMR) was isolated (Scheme 6, eq. 1). Subsequently, the product
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1a-O18 could be detected when H2O18 was added in Ac2O solvent in the presence of
Pd(OAc)2 catalyst (Scheme 6, eq. 2). Hydrolysis of 1a-O18 showed that the O18 atom
is on the amide rather than the carbonyl moiety. These results indicated that an oxygen
exchange process should occur during this alkyne hydration reaction.
Scheme 6. Isotope Labelled Experiments
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On the basis of the above observations, a tentative mechanism for this Pdꢀcatalyzed
hydration of alkynes is proposed (Scheme 7). First, intermediate I was initially
produced by the coordination of palladium catalyst to the triple bond. Then
intramolecular oxypalladation occurred to give 1,3ꢀoxazine vinylpalladium
intermediate II. Subsequently, protonolysis of vinylpalladium produced intermediate
III. Following, under the acidic conditions, the addition of imine with water and
ringꢀopening reaction generated intermediate IV. Finally, the desired hydration
product was formed through the isomerization of intermediate IV.
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Scheme 7. The Proposed Reaction Mechanism
CONCLUSION
In summary, we have developed an efficient and useful amide oxygenꢀassisted
palladiumꢀcatalyzed hydration of alkynes through an oxypalladation pathway under
mild conditions. This transformation with good functional group tolerance provides a
convenient and practical method for the synthesis of orthoꢀacylacetanilide derivatives
in good to excellent yields with single regioselectivity. Moreover, the simple reaction
conditions and experiment operation are some of the additional features of this
protocol.
EXPERIMENTAL SECTION
General methods. All solvents and commercialized reagents were used without
1
further purifications. H, 13C and 19F NMR data were recorded on a DRXꢀ400 NMR
1
Spectrometer with CDCl3 as the solvent. H shifts were referenced to CDCl3 at 7.26
ppm. 13C shifts were referenced to CDCl3 at 77 ppm. IR spectra were obtained with an
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infrared spectrometer on either potassium bromide pellets or liquid films between two
potassium bromide pellets. GC−MS data were obtained on Thermo using electron
ionization. HRMS was carried out on a highꢀresolution mass spectrometer
(LCMSꢀITꢀTOF). TLC was performed using commercially available 100−400 mesh
silica gel plates (GF254).
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General Procedure. To a mixture of alkyne (0.5 mmol), Pd(OAc)2 (5 mol %) was
added HOAc (1.0 mL) in a test tube (1.0 mL) equipped with a magnetic stirring bar.
The mixture was stirred at room temperature for 12 h. After the reaction was
completed, the residue was directly subjected to silica gel column chromatography or
purification of the mixture on a preparative TLC to afford the desired product.
N-(2-(2-Phenylacetyl)phenyl)acetamide (1a)[18]
o
Yield: 90% (114 mg); White solid, mp 97ꢀ99 C; TLC Rf = 0.39 (PE/EA = 4/1, v/v);
1H NMR (400 MHz, CDCl3) δ 11.63 (s, 1H), 8.75 (d, J = 8.4 Hz, 1H), 8.03 (d, J = 8.4
Hz, 1H), 7.54 (t, J = 8.0 Hz, 1H), 7.36 (t, J = 7.2 Hz, 2H), 7.30 (d, J = 6.8 Hz, 1H),
7.24 (d, J = 7.2 Hz, 2H), 7.11 (t, J = 8.0 Hz, 1H), 4.34 (s, 2H), 2.18 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ 202.2, 169.6, 141.5, 135.3, 134.3, 131.2, 129.5, 128.8, 127.2,
122.4, 121.1, 121.0, 46.7, 25.6 ppm; νmax(KBr)/cmꢀ1 3299, 2923, 1696, 1582, 1450,
1298, 988, 755; MS (EI) m/z 65, 92, 120, 144, 162, 253.
N-(4-Fluoro-2-(2-phenylacetyl)phenyl)acetamide (2a)
Yield: 93% (126 mg); White solid, mp 115ꢀ117 oC; TLC Rf = 0.56 (PE/EA = 4/1, v/v);
1H NMR (400 MHz, CDCl3) δ 11.41 (s, 1H), 8.77 (dd, J = 5.2 Hz, J = 8.8 Hz, 1H),
7.68 (d, J = 9.6 Hz, 1H), 7.38 (t, J = 7.2 Hz, 2H), 7.33ꢀ7.23 (m, 4H), 4.30 (s, 2H),
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2.18 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 201.2, 169.4, 158.3 (J = 242.2 Hz),
137.8 (J = 2.2 Hz), 133.6, 129.5, 128.9, 127.4, 123.0 (J = 7.0 Hz), 122.3, 122.1, 117.0
(J = 23.2 Hz), 46.8, 25.4 ppm; 19F NMR (376 MHz, CDCl3) δ ꢀ118.55 ppm;
νmax(KBr)/cmꢀ1 3236, 2916, 1685, 1598, 1519, 1326, 1161, 988, 726; MS (EI) m/z 65,
83, 91, 110, 138, 162, 180, 271; HRMSꢀESI (m/z): calcd for C16H14FNNaO2 [M+Na]+:
294.0901, found: 294.0906.
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N-(4-Chloro-2-(2-phenylacetyl)phenyl)acetamide (3a)
Yield: 92% (132 mg); White solid, mp 159ꢀ161 oC; TLC Rf = 0.33 (PE/EA = 4/1, v/v);
1H NMR (400 MHz, CDCl3) δ 11.53 (s, 1H), 8.78 (d, J = 8.8 Hz, 1H), 8.01 (s, 1H),
7.53 (d, J = 9.2 Hz, 1H), 7.41 (t, J = 7.2 Hz, 2H), 7.35 (d, J = 6.4 Hz, 1H), 7.27 (t, J =
13
6.8 Hz, 2H), 4.35 (s, 2H), 2.21 (s, 3H); C NMR (100 MHz, CDCl3) δ 201.2, 169.5,
140.0, 135.0, 133.6, 130.6, 129.6, 128.9, 127.4, 127.3, 122.5, 122.2, 46.7, 25.5 ppm;
νmax(KBr)/cmꢀ1 3216, 2919, 1736, 1504, 1294, 1181, 861, 751; MS (EI) m/z 65, 91, 99,
126, 154, 178, 196, 287; HRMSꢀESI (m/z): calcd for C16H14ClNNaO2 [M+Na]+:
310.0605, found: 310.0609.
N-(4-Cyano-2-(2-phenylacetyl)phenyl)acetamide (4a)
Yield: 88% (122 mg); White solid, mp 173ꢀ175 oC; TLC Rf = 0.35 (PE/EA = 4/1, v/v);
1H NMR (400 MHz, CDCl3) δ 11.82 (s, 1H), 8.92 (d, J = 9.2 Hz, 1H), 8.34 (s, 1H),
7.75 (d, J = 8.8 Hz, 1H), 7.39 (t, J = 7.2 Hz, 2H), 7.32 (t, J = 7.2 Hz, 1H), 7.24 (d, J =
7.2 Hz, 2H), 4.35 (s, 2H), 2.42 (s, 3H), 2.23 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
201.1, 169.9, 144.9, 137.8, 135.5, 133.1, 129.5, 129.0, 127.6, 121.4, 120.8, 118.0,
105.6, 46.8, 25.7 ppm; νmax(KBr)/cmꢀ1 2923, 2228, 1703, 1511, 1300, 1000, 964, 692;
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MS (EI) m/z 73, 117, 145, 187, 207, 278; HRMSꢀESI (m/z): calcd for C17H14N2NaO2
[M+Na]+: 301.0947, found: 301.0950.
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N-(2-(2-Phenylacetyl)-5-(trifluoromethyl)phenyl)acetamide (5a)
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Yield: 82% (131 mg); White solid, mp 141ꢀ143 oC; TLC Rf = 0.64 (PE/EA = 4/1, v/v);
1H NMR (400 MHz, CDCl3) δ 11.76 (s, 1H), 8.83 (d, J = 8.8 Hz, 1H), 8.28 (s, 1H),
7.73 (d, J = 8.4 Hz, 1H), 7.37 (d, J = 7.2 Hz, 3H), 7.24 (d, J = 6.8 Hz, 2H), 4.37 (s,
2H), 2.20 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 201.5, 170.1, 144.0, 133.4, 131.6 (q,
J = 6.7 Hz, J = 3.5 Hz), 129.55, 129.30, 128.93, 128.17 (q, J = 7.3 Hz, J = 3.5 Hz),
127.5, 125.3, 121.2, 120.5, 46.8, 25.5 ppm; 19F NMR (376 MHz, CDCl3) δ ꢀ62.37
ppm; νmax(KBr)/cmꢀ1 3300, 2926, 1643, 1581, 1527, 1449, 1221, 827, 754; MS (EI)
m/z 66, 91, 140, 160, 188, 230, 321; HRMSꢀESI (m/z): calcd for C17H14F3NNaO2
[M+Na]+: 344.0869, found: 344.0866.
Methyl 4-acetamido-3-(2-phenylacetyl)benzoate (6a)
Yield: 75% (116 mg); White solid, mp 158ꢀ160 oC; TLC Rf = 0.63 (PE/EA = 4/1, v/v);
1H NMR (400 MHz, CDCl3) δ 11.85 (s, 1H), 8.85 (d, J = 9.2 Hz, 1H), 8.79 (s, 1H),
8.18 (d, J = 8.8 Hz, 1H), 7.37 (d, J = 7.2 Hz, 2H), 7.31 (d, J = 7.2 Hz, 1H), 7.27 (d, J
= 6.4 Hz, 2H), 4.42 (s, 2H), 3.95 (s, 3H), 2.22 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
202.0, 169.8, 165.8, 145.1, 136.0, 133.8, 133.1, 129.6, 128.9, 127.4, 123.7, 120.4,
120.4, 52.3, 46.8, 25.7 ppm; νmax(KBr)/cmꢀ1 3306, 2925, 1725, 1653, 1544, 1299,
1092, 832, 721; MS (EI) m/z 65, 91, 119, 135, 150, 178, 202, 220, 311; HRMSꢀESI
(m/z): calcd for C18H17NNaO4 [M+Na]+: 334.1050, found: 334.1054.
N-(4-Methyl-2-(2-phenylacetyl)phenyl)acetamide (7a)[19]
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Yield: 94% (126 mg); White solid, mp 66ꢀ68 C; TLC Rf = 0.37 (PE/EA = 4/1, v/v);
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1H NMR (400 MHz, CDCl3) δ 11.54 (s, 1H), 8.67 (d, J = 8.4 Hz, 1H), 7.85 (s, 1H),
7.40 (d, J = 6.8 Hz, 3H), 7.34 (d, J = 6.8 Hz, 1H), 7.27 (d, J = 7.6 Hz, 2H), 4.37 (s,
2H), 2.40 (s, 3H), 2.20 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 202.1, 169.4, 139.1,
136.0, 134.3, 131.8, 131.2, 129.6, 128.8, 127.2, 121.2, 121.0, 46.7, 25.5, 20.9 ppm;
νmax(KBr)/cmꢀ1 3030, 2923, 1695, 1589, 1518, 1298, 1174, 831, 720; MS (EI) m/z 65,
77, 106, 134, 158, 176, 267.
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N-(5-Methyl-2-(2-phenylacetyl)phenyl)acetamide (8a)
Yield: 90% (120 mg); White solid, mp 121ꢀ123 oC; TLC Rf = 0.50 (PE/EA = 4/1, v/v);
1H NMR (400 MHz, CDCl3) δ 11.74 (s, 1H), 8.64 (s, 1H), 7.94 (d, J = 8.0 Hz, 1H),
7.39 (t, J = 7.2 Hz, 2H), 7.32 (d, J = 7.2 Hz, 1H), 7.27 (d, J = 7.2 Hz, 2H), 6.95 (d, J =
8.4 Hz, 1H), 4.33 (s, 2H), 2.42 (s, 3H), 2.21 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
201.7, 169.6, 146.8, 141.7, 134.5, 131.3, 129.5, 128.8, 127.1, 123.3, 121.1, 118.8,
46.6, 25.6, 22.2 ppm; νmax(KBr)/cmꢀ1 3029, 1686, 1540, 1361, 1204, 810, 764; MS (EI)
m/z 77, 106, 134, 158, 176, 207, 267; HRMSꢀESI (m/z): calcd for C17H17NNaO2
[M+Na]+: 290.1151, found: 290.1156.
N-(4-(2-Phenylacetyl)pyridin-3-yl)acetamide (9a)
Yield: 81% (103 mg); White solid, mp 124ꢀ126 oC; TLC Rf = 0.29 (PE/EA = 1/1, v/v);
1H NMR (400 MHz, CDCl3) δ 11.00 (s, 1H), 10.04 (s, 1H), 8.47 (d, J = 4.8 Hz, 1H),
7.75 (d, J = 5.2 Hz, 1H), 7.38 (t, J = 7.2 Hz, 2H), 7.32 (t, J = 7.2 Hz, 1H), 7.23 (d, J =
7.6 Hz, 2H), 4.36 (s, 2H), 2.22 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 202.2, 169.2,
144.8, 143.9, 135.3, 133.0, 129.5, 129.0, 127.6, 125.5, 122.2, 46.8, 25.1 ppm;
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νmax(KBr)/cmꢀ1 3287, 3030, 2926, 1704, 1596, 1414, 818, 733, 603; MS (EI) m/z 66,
93, 121, 163, 236, 254; HRMSꢀESI (m/z): calcd for C15H15N2O2 [M+H]+: 255.1128,
found: 255.1130.
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N-(2-(2-(3-Bromophenyl)acetyl)phenyl)acetamide (10a)
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Yield: 80% (133 mg); White solid, mp 86ꢀ88 C; TLC Rf = 0.36 (PE/EA = 4/1, v/v);
1H NMR (400 MHz, CDCl3) δ 11.56 (s, 1H), 8.74 (d, J = 8.8 Hz, 1H), 7.97 (d, J = 8.0
Hz, 1H), 7.55 (t, J = 7.6 Hz, 1H), 7.43ꢀ7.40 (m, 2H), 7.22 (t, J = 7.6 Hz, 1H),
7.17ꢀ7.10 (m, 2H), 4.30 (s, 2H), 2.18 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 201.3,
169.7, 141.5, 136.4, 135.5, 132.7, 131.0, 130.4, 130.2, 128.3, 122.7, 122.5, 121.0,
121.0, 46.1, 25.6 ppm; νmax(KBr)/cmꢀ1 3077, 3001, 1695, 1583, 1526, 1298, 1200, 757,
600; MS (EI) m/z 66, 92, 120, 144, 162, 267, 332; HRMSꢀESI (m/z): calcd for
C16H14BrNNaO2 [M+Na]+: 354.0100, found: 354.0103.
N-(2-(2-(4-Chlorophenyl)acetyl)phenyl)acetamide (11a)
Yield: 82% (118 mg); White solid, mp 114ꢀ116 oC; TLC Rf = 0.73 (PE/EA = 4/1, v/v);
1H NMR (400 MHz, CDCl3) δ 11.57 (s, 1H), 8.75 (d, J = 8.4 Hz, 1H), 8.00 (d, J = 8.0
Hz, 1H), 7.56 (t, J = 7.6 Hz, 1H), 7.33 (d, J = 8.0 Hz, 2H), 7.17 (d, J = 7.6 Hz, 2H),
7.13 (t, J = 7.2 Hz, 1H), 4.32 (s, 2H), 2.19 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
201.6, 169.7, 141.5, 135.5, 133.2, 132.6, 131.0, 128.9, 122.4, 121.1, 121.0, 45.9, 25.5
ppm; νmax(KBr)/cmꢀ1 3228, 2919, 1689, 1585, 1449, 1329, 1194, 985, 749; MS (EI)
m/z 65, 92, 120, 144, 162, 287; HRMSꢀESI (m/z): calcd for C16H14ClNNaO2
[M+Na]+: 310.0605, found: 310.0608.
N-(2-(2-p-Tolylacetyl)phenyl)acetamide (12a)[20]
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Yield: 69% (92 mg); White solid, mp 87ꢀ89 oC; TLC Rf = 0.59 (PE/EA = 4/1, v/v); 1H
NMR (400 MHz, CDCl3) δ 11.65 (s, 1H), 8.75 (d, J = 8.4 Hz, 1H), 8.03 (d, J = 8.0 Hz,
1H), 7.54 (t, J = 8.0 Hz, 1H), 7.45 (dd, J = 7.6 Hz, J = 19.2 Hz, 1H), 7.20ꢀ7.16 (m,
2H), 7.13ꢀ7.09 (m, 2H), 4.30 (s, 2H), 2.34 (s, 3H), 2.18 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 202.4, 169.6, 141.5, 136.9, 135.2, 131.2, 131.1, 129.5, 129.4, 122.3, 121.2,
120.9, 46.4, 25.6, 21.1 ppm; νmax(KBr)/cmꢀ1 3025, 2923, 1699, 1519, 1449, 1298, 988,
754; MS (EI) m/z 65, 92, 120, 144, 162, 267.
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N-(2-(2-(2,4-Dimethylphenyl)acetyl)phenyl)acetamide (13a)
Yield: 66% (93 mg); White solid, mp 104ꢀ106 oC; TLC Rf = 0.39 (PE/EA = 4/1, v/v);
1H NMR (400 MHz, CDCl3) δ 11.63 (s, 1H), 8.78 (d, J = 8.4 Hz, 1H), 8.06 (d, J = 8.0
Hz, 2H), 7.57 (t, J = 7.6 Hz, 1H), 7.14 (t, J = 7.6 Hz, 1H), 7.06 (s, 1H), 6.99 (s, 2H),
4.34 (s, 2H), 2.32 (s, 3H), 2.20 (s, 3H), 2.16 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
202.2, 169.6, 141.4, 137.2, 136.7, 135.2, 131.3, 130.8, 130.4, 130.0, 127.0, 122.4,
121.3, 121.0, 44.3, 25.6, 21.1, 19.6 ppm; νmax(KBr)/cmꢀ1 2919, 1694, 1585, 1450,
1301, 1163, 987, 747; MS (EI) m/z 77, 89, 115, 152, 178, 204, 221, 263, 281;
HRMSꢀESI (m/z): calcd for C18H19NNaO2 [M+Na]+: 304.1308, found: 304.1308.
N-(2-(2-(Thiophen-3-yl)acetyl)phenyl)acetamide (14a)
Yield: 83% (108 mg); White solid, mp 104ꢀ106 oC; TLC Rf = 0.37 (PE/EA = 4/1, v/v);
1H NMR (400 MHz, CDCl3) δ 11.63 (s, 1H), 8.76 (d, J = 8.4 Hz, 1H), 8.00 (d, J = 8.0
Hz, 1H), 7.55 (t, J = 8.0 Hz, 1H), 7.35ꢀ7.33 (m, 1H), 7.11 (s, 2H), 7.00 (d, J = 4.8 Hz,
1H), 4.36 (s, 2H), 2.20 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 201.6, 169.6, 141.5,
135.3, 133.9, 131.1, 128.6, 126.1, 123.2, 122.4, 121.0, 41.3, 25.6 ppm; νmax(KBr)/cmꢀ1
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3250, 3097, 2925, 1690, 1584, 1447, 983, 764, 643; MS (EI) m/z 65, 92, 120, 144,
162, 259; HRMSꢀESI (m/z): calcd for C14H13NNaO2S [M+Na]+: 282.0559, found:
282.0558.
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N-(2-(2-(Pyridin-3-yl)acetyl)phenyl)acetamide (15a)
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Yield: 88% (112 mg); White solid, mp 125ꢀ127 C; TLC Rf = 0.52 (pure EA); H
NMR (400 MHz, CDCl3) δ 11.51 (s, 1H), 8.76 (d, J = 8.8 Hz, 1H), 8.51 (d, J = 13.6
Hz, 2H), 8.03 (d, J = 8.0 Hz, 1H), 7.60 (t, J = 7.6 Hz, 2H), 7.32 (t, J = 6.0 Hz, 1H),
7.16 (t, J = 7.6 Hz, 1H), 4.37 (s, 2H), 2.19 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
200.8, 169.5, 150.5, 148.4, 141.5, 137.4, 135.6, 130.8, 122.5, 121.1, 120.9, 43.6, 25.5
ppm; νmax(KBr)/cmꢀ1 3240, 2920, 1688, 1582, 1451, 1299, 1197, 757, 713; MS (EI)
m/z 73, 93, 120, 162, 207, 254; HRMSꢀESI (m/z): calcd for C15H15N2O2 [M+H]+:
255.1128, found: 255.1132.
N-(2-Pentanoylphenyl)acetamide (16a)[21]
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Yield: 92% (101 mg); White solid, mp 59ꢀ60 C; TLC Rf = 0.44 (PE/EA = 4/1, v/v);
1H NMR (400 MHz, CDCl3) δ 11.74 (s, 1H), 8.72 (d, J = 8.4 Hz, 1H), 7.90 (d, J = 8.0
Hz, 1H), 7.51 (t, J = 7.6 Hz, 1H), 7.09 (t, J = 7.6 Hz, 1H), 3.00 (t, J = 7.6 Hz, 2H),
2.22 (s, 3H), 1.74ꢀ1.66 (m, 2H), 1.46ꢀ1.37 (m, 2H), 0.96 (t, J = 7.6 Hz, 3H); 13C NMR
(100 MHz, CDCl3) δ 205.2, 169.4, 141.0, 134.7, 130.7, 122.2, 121.5, 120.8, 39.7, 26.7,
25.5, 22.4, 13.9 ppm; νmax(KBr)/cmꢀ1 3209, 2959, 1695, 1584, 1447, 1194, 973, 783;
MS (EI) m/z 65, 92, 120, 135, 162, 177, 219.
N-(2-(3,3-Dimethylbutanoyl)phenyl)acetamide (17a)[17a]
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Yield: 92% (107 mg); White solid, mp 88ꢀ90 C;TLC Rf = 0.52 (PE/EA = 4/1, v/v);
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1H NMR (400 MHz, CDCl3) δ 11.72 (s, 1H), 8.72 (d, J = 8.4 Hz, 1H), 7.90 (d, J = 7.6
Hz, 1H), 7.52 (t, J = 7.6 Hz, 1H), 7.09 (t, J = 7.6 Hz, 1H), 2.89 (s, 2H), 2.24 (s, 3H),
1.07 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 205.3, 169.4, 140.8, 134.7, 131.3, 123.1,
122.1, 120.9, 51.3, 31.8, 30.1, 25.6 ppm; νmax(KBr)/cmꢀ1 3217, 2989, 1692, 1584,
1446, 1167, 954, 755; MS (EI) m/z 65, 92, 120, 135, 162, 233.
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N-(2-(2-Cyclohexylacetyl)phenyl)acetamide (18a)
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Yield: 93% (120 mg); yellow oil; TLC Rf = 0.67 (PE/EA = 4/1, v/v); H NMR (400
MHz, CDCl3) δ 11.76 (s, 1H), 8.73 (d, J = 8.4 Hz, 1H), 7.89 (d, J = 8.0 Hz, 1H), 7.52
(t, J = 8.0 Hz, 1H), 7.10 (t, J = 7.6 Hz, 1H), 2.85 (d, J = 6.8 Hz, 2H), 2.23 (s, 3H),
1.85ꢀ1.92 (m, 1H), 1.77ꢀ1.65 (m, 5H), 1.34ꢀ1.24 (m, 2H), 1.21ꢀ1.15 (m, 1H),
13
1.07ꢀ0.98 (m, 2H); C NMR (100 MHz, CDCl3) δ 204.9, 169.5, 141.0, 134.8, 130.9,
122.2, 121.9, 120.8, 47.6, 34.9, 33.4, 26.2, 26.1, 25.5 ppm; νmax(KBr)/cmꢀ1 3256, 2925,
2850, 1700, 1583, 1449, 1301, 958, 755; MS (EI) m/z 65, 92, 120, 136, 162, 177, 216,
259; HRMSꢀESI (m/z): calcd for C16H21NNaO2 [M+Na]+: 282.1464, found:
282.1469.
N-(2-(2-Cyclopropylacetyl)phenyl)acetamide (19a)
Yield: 78% (85 mg); White solid, mp 73ꢀ75 oC; TLC Rf = 0.34 (PE/EA = 4/1, v/v); 1H
NMR (400 MHz, CDCl3) δ 11.76 (s, 1H), 8.74 (d, J = 8.8 Hz, 1H), 7.85 (d, J = 8.0 Hz,
1H), 7.52 (t, J = 7.6 Hz, 1H), 7.08 (t, J = 7.6 Hz, 1H), 2.93 (d, J = 6.8 Hz, 2H), 2.23 (s,
13
3H), 1.16ꢀ1.10 (m, 1H), 0.62 (d, J = 7.6 Hz, 2H), 0.20 (d, J = 4.8 Hz, 2H); C NMR
(100 MHz, CDCl3) δ 204.7, 169.5, 141.2, 134.9, 130.8, 122.2, 121.3, 120.8, 45.2, 25.6,
6.8, 4.5 ppm; νmax(KBr)/cmꢀ1 3393, 2931, 1699, 1577, 1517, 1446, 1236, 755; MS (EI)
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m/z 65, 92, 120, 144, 162, 217; HRMSꢀESI (m/z): calcd for C13H15NNaO2 [M+Na]+:
240.0995, found: 240.0999.
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N-(2-Acetylphenyl)acetamide (20a)[16a]
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Yield: 85% (75 mg); White solid, mp 72ꢀ74 oC; TLC Rf = 0.42 (PE/EA = 4/1, v/v); 1H
NMR (400 MHz, CDCl3) δ 11.69 (s, 1H), 8.72 (d, J = 8.4 Hz, 1H), 8.68 (d, J = 8.0 Hz,
13
1H), 7.53 (t, J = 7.6 Hz, 1H), 7.10 (t, J = 7.2 Hz, 1H), 2.65 (s, 3H), 2.22 (s, 3H); C
NMR (100 MHz, CDCl3) δ 202.8, 169.5, 141.0, 135.1, 131.6, 122.3, 121.7, 120.7,
28.6, 25.5 ppm; νmax(KBr)/cmꢀ1 3217, 2924, 1689, 1586, 1450, 1234, 960, 767; MS
(EI) m/z 66, 92, 120, 135, 162, 177.
3-(2-Acetamidophenyl)-3-oxopropyl acetate (21a)
o
Yield: 90% (112 mg); White solid, mp 95ꢀ97 C; TLC Rf = 0.33 (PE/EA = 2/1, v/v);
1H NMR (400 MHz, CDCl3) δ 11.60 (s, 1H), 8.74 (d, J = 8.4 Hz, 1H), 7.89 (d, J = 8.0
Hz, 1H), 7.56 (t, J = 8.0 Hz, 1H), 7.12 (t, J = 7.6 Hz, 1H), 4.50 (t, J = 6.0 Hz, 2H),
3.38 (t, J = 6.0 Hz, 2H), 2.24 (s, 3H), 2.05 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
201.4, 171.0, 169.6, 141.1, 135.4, 130.7, 122.4, 121.3, 120.9, 59.4, 38.6, 25.5, 20.9
ppm; νmax(KBr)/cmꢀ1 3296, 2923, 1740, 1698, 1583, 1526, 1240, 1038, 756; MS (EI)
m/z 73, 92, 120, 146, 189, 249; HRMSꢀESI (m/z): calcd for C13H15NNaO4 [M+Na]+:
272.0893, found: 272.0896.
N-(2-(4-Hydroxybutanoyl)phenyl)acetamide (22a)
o
1
Yield: 65% (72 mg); White solid, mp 78ꢀ80 C; TLC Rf = 0.36 (pure EA); H NMR
(400 MHz, CDCl3) δ 11.67 (s, 1H), 8.69 (d, J = 8.4 Hz, 1H), 7.94 (d, J = 8.0 Hz, 1H),
7.52 (t, J = 8.0 Hz, 1H), 7.09 (t, J = 7.6 Hz, 1H), 3.74 (t, J = 6.0 Hz, 2H), 3.17 (t, J =
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6.8 Hz, 2H), 2.63 (br, 1H), 2.22 (s, 3H), 2.04ꢀ1.96 (m, 2H); 13C NMR (100 MHz,
CDCl3) δ 204.9, 169.6, 140.8, 134.9, 130.8, 122.4, 121.6, 120.8, 61.8, 36.5, 27.2, 25.5
ppm; νmax(KBr)/cmꢀ1 2957, 2929, 1652, 1526, 1450, 1302, 1055, 756; MS (EI) m/z 77,
92, 120, 160, 203, 221; HRMSꢀESI (m/z): calcd for C12H15NNaO3 [M+Na]+:
244.0944, found: 244.0946.
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4-(2-Acetamidophenyl)-4-oxobutyl acetate (22b)
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1
Yield: 23% (30 mg); White solid, mp 90ꢀ92 C; TLC Rf = 0.56 (pure EA); H NMR
(400 MHz, CDCl3) δ 11.66 (s, 1H), 8.74 (d, J = 8.8 Hz, 1H), 7.92 (d, J = 8.0 Hz, 1H),
7.55 (t, J = 8.0 Hz, 1H), 7.12 (t, J = 7.6 Hz, 1H), 4.18 (t, J = 6.0 Hz, 2H), 3.13 (t, J =
7.2 Hz, 2H), 2.24 (s, 3H), 2.12ꢀ2.07 (m, 2H), 2.05 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 203.7, 171.0, 169.5, 141.0, 135.1, 130.5, 122.3, 121.4, 120.9, 63.6, 36.2,
25.6, 23.4, 20.9 ppm; νmax(KBr)/cmꢀ1 2965, 2873, 1740, 1609, 1527, 1458, 1325, 1073,
763; MS (EI) m/z 65, 92, 120, 162, 221, 263; HRMSꢀESI (m/z): calcd for
C14H17NNaO4 [M+Na]+: 286.1050, found: 286.1057.
N-(3-(2-Acetamidophenyl)-3-oxopropyl)acetamide (23a)
o
1
Yield: 83% (103 mg); White solid, mp 135ꢀ137 C; TLC Rf = 0.19 (pure EA); H
NMR (400 MHz, CDCl3) δ 11.63 (s, 1H), 8.72 (d, J = 8.4 Hz, 1H), 7.88 (d, J = 7.6 Hz,
1H), 7.55 (t, J = 8.0 Hz, 1H), 7.11 (t, J = 7.6 Hz, 1H), 6.27 (s, 1H), 3.65 (q, J = 5.6 Hz,
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J = 11.2 Hz, 2H), 3.29 (t, J = 5.6 Hz, 2H), 2.24 (s, 3H), 1.98 (s, 3H); C NMR (100
MHz, CDCl3) δ 203.7, 170.2, 169.4, 141.1, 135.4, 130.8, 122.5, 121.1, 120.8, 39.5,
34.5, 25.6, 23.3 ppm; νmax(KBr)/cmꢀ1 3299, 2925, 1653, 1525, 1450, 1301, 1201, 981,
757; MS (EI) m/z 65, 92, 120, 134, 146, 162, 188, 230, 248; HRMSꢀESI (m/z): calcd
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for C13H16N2NaO3 [M+Na]+: 271.1053, found: 271.1057.
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N-(2-(5-Cyanopentanoyl)phenyl)acetamide (24a)
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Yield: 84% (103 mg); White solid, mp 112ꢀ114 oC; TLC Rf = 0.49 (PE/EA = 1/1, v/v);
1H NMR (400 MHz, CDCl3) δ 11.65 (s, 1H), 8.74 (d, J = 8.4 Hz, 1H), 7.90 (d, J = 8.0
Hz, 1H), 7.55 (t, J = 8.0 Hz, 1H), 7.11 (t, J = 8.0 Hz, 1H), 3.10 (t, J = 6.8 Hz, 2H),
2.43 (t, J = 6.8 Hz, 2H), 2.24 (s, 3H), 1.94ꢀ1.87 (m, 2H), 1.81ꢀ1.73 (m, 2H); 13C NMR
(100 MHz, CDCl3) δ 203.5, 169.4, 141.1, 135.2, 130.5, 122.4, 121.3, 120.9, 119.4,
38.7, 25.6, 24.9, 23.3, 17.2 ppm; νmax(KBr)/cmꢀ1 3302, 2926, 1705, 1643, 1581, 1527,
1295, 1221, 827, 754; MS (EI) m/z 66, 92, 120, 134, 162, 186, 244; HRMSꢀESI (m/z):
calcd for C14H16N2NaO2 [M+Na]+: 267.1104, found: 267.1108.
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N-(2-Pentanoylphenyl)formamide (25a)
Yield: 74% (76 mg); White solid, mp 58ꢀ60 oC; TLC Rf = 0.58 (PE/EA = 4/1, v/v); 1H
NMR (400 MHz, CDCl3) δ 11.64 (s, 1H), 8.74 (d, J = 8.4 Hz, 1H), 8.48 (s, 1H), 7.94
(d, J = 8.0 Hz, 1H), 7.55 (t, J = 7.6 Hz, 1H), 7.16 (t, J = 7.6 Hz, 1H), 3.02 (t, J = 7.2
Hz, 2H), 1.75ꢀ1.67 (m, 2H), 1.46ꢀ1.37 (m, 2H), 0.97 (t, J = 7.2 Hz, 3H); 13C NMR
(100 MHz, CDCl3) δ 205.2, 159.8, 139.8, 134.8, 130.8, 123.0, 121.7, 120.8, 39.7, 26.7,
22.4, 13.9 ppm; νmax(KBr)/cmꢀ1 3253, 2960, 1702, 1518, 1451, 1197, 970, 755; MS
(EI) m/z 65, 77, 92, 120, 135, 148, 163, 177, 205; HRMSꢀESI (m/z): calcd for
C12H15NNaO2 [M+Na]+: 228.0995, found: 228.0998.
N-(2-Pentanoylphenyl)butyramide (26a)
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Yield: 90% (111 mg); yellow oil; TLC Rf = 0.51 (PE/EA = 10/1, v/v); H NMR (400
MHz, CDCl3) δ 11.75 (s, 1H), 8.77 (d, J = 8.4 Hz, 1H), 7.90 (d, J = 8.0 Hz, 1H), 7.51
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(d, J = 8.0 Hz, 1H), 7.08 (d, J = 7.2 Hz, 1H), 3.00 (t, J = 6.8 Hz, 2H), 2.41 (t, J = 6.8
Hz, 2H), 1.83ꢀ1.67 (m, 4H), 1.46ꢀ1.38 (m, 2H), 1.03ꢀ0.95 (m, 6H); 13C NMR (100
MHz, CDCl3) δ 205.2, 172.5, 141.1, 134.8, 130.7, 122.1, 121.5, 120.8, 40.6, 39.7,
26.8, 22.4, 19.0, 13.9, 13.7 ppm; νmax(KBr)/cmꢀ1 3068, 2925, 1717, 1648, 1453, 1236,
1168, 995, 698; MS (EI) m/z 71, 92, 120, 136, 162, 177, 190, 205, 247; HRMSꢀESI
(m/z): calcd for C15H21NNaO2 [M+Na]+: 270.1465, found: 270.1469.
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N-(2-Pentanoylphenyl)pivalamide (27a)[22]
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Yield: 83% (108 mg); yellow oil; TLC Rf = 0.45 (PE/EA = 10/1, v/v); H NMR (400
MHz, CDCl3) δ 11.96 (s, 1H), 8.80 (d, J = 7.6 Hz, 1H), 7.92 (d, J = 8.0 Hz, 1H), 7.53
(t, J = 8.0 Hz, 1H), 7.09 (t, J = 7.6 Hz, 1H), 3.02 (t, J = 7.2 Hz, 2H), 1.76ꢀ1.69 (m,
2H), 1.46ꢀ1.39 (m, 2H), 1.35 (s, 3H), 0.96 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ13C NMR (101 MHz, CDCl3) δ 205.2, 178.4, 141.4, 134.8, 130.8, 122.0,
121.9, 120.9, 40.4, 39.8, 27.6, 27.0, 22.4, 13.9 ppm; νmax(KBr)/cmꢀ1 2962, 2870, 1690,
1523, 1447, 1300, 1158, 921, 755; MS (EI) m/z 57, 92, 146, 120, 135, 162, 176, 204,
261.
2,2,2-Trifluoro-N-(2-pentanoylphenyl)acetamide (28a)
o
Yield: 84% (115 mg); White solid, mp 62ꢀ64 C; TLC Rf = 0.49 (PE/EA = 8/1, v/v);
1H NMR (400 MHz, CDCl3) δ 13.01 (s, 1H), 8.68 (d, J = 8.4 Hz, 1H), 8.02 (d, J = 8.0
Hz, 1H), 7.62 (t, J = 7.6 Hz, 1H), 7.28 (t, J = 7.6 Hz, 1H), 3.06 (t, J = 7.2 Hz, 2H),
1.77ꢀ1.70(m, 2H), 1.48ꢀ1.39(m, 2H), 0.97 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ 205.6, 155.6 (q, J = 37.3 Hz), 138.4, 135.1, 131.1, 124.6, 122.4, 121.1,
115.5 (q, J = 215.2 Hz), 39.6, 26.5, 22.3, 13.8 ppm; 19F NMR (376 MHz, CDCl3) δ
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ꢀ76.24 ppm; νmax(KBr)/cmꢀ1 2963, 2872, 1732, 1533, 1285, 1156, 902, 759; MS (EI)
m/z 66, 91, 102, 146, 168, 216, 231, 273; HRMSꢀESI (m/z): calcd for
C13H14F3NNaO2 [M+Na]+: 296.0869, found: 296.0872.
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N-(2-Pentanoylphenyl)-2-phenylacetamide (29a)
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Yield: 86% (126 mg); yellow oil; TLC Rf = 0.46 (PE/EA = 10/1, v/v); H NMR (400
MHz, CDCl3) δ 11.74 (s, 1H), 8.72 (d, J = 8.4 Hz, 1H), 7.81 (d, J = 8.0 Hz, 1H), 7.46
(t, J = 8.0 Hz, 1H), 7.37ꢀ7.32 (m, 4H), 7.28ꢀ7.25 (m, 1H), 7.03 (t, J = 7.6 Hz, 1H),
3.72 (s, 2H), 2.91 (t, J = 7.2 Hz, 2H), 1.68ꢀ1.60 (m, 2H), 1.40ꢀ1.31 (m, 2H), 0.94 (t, J
= 7.2 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ 204.9, 170.4, 140.8, 134.6, 134.6,
130.7, 129.5, 128.8, 127.2, 122.4, 122.0, 120.9, 46.0, 39.7, 26.8, 22.4, 14.0. ppm;
νmax(KBr)/cmꢀ1 3061, 2859, 1772, 1631, 1446, 1195, 1067, 907, 758; MS (EI) m/z 65,
91, 120, 135, 162, 177, 204, 238, 253, 295; HRMSꢀESI (m/z): calcd for C19H21NNaO2
[M+Na]+: 318.1465, found: 318.1469.
N-(2-Pentanoylphenyl)benzamide (30a)[23]
o
Yield: 85% (119 mg); White solid, mp 61ꢀ63 C; TLC Rf = 0.69 (PE/EA = 4/1, v/v);
1H NMR (400 MHz, CDCl3) δ 12.73 (s, 1H), 8.97 (d, J = 8.4 Hz, 1H), 8.08 (d, J = 7.2
Hz, 2H), 7.96 (d, J = 8.0 Hz, 1H), 7.58ꢀ7.46 (m, 4H), 7.13 (t, J = 7.6 Hz, 1H), 3.04 (t,
13
J = 7.6 Hz, 2H), 1.77ꢀ1.70 (m, 2H), 1.47ꢀ1.38 (m, 2H), 0.96 (t, J = 7.2 Hz, 3H); C
NMR (100 MHz, CDCl3) δ 205.7, 166.1, 141.4, 135.0, 134.9, 132.0, 131.0, 130.6,
128.9, 128.8, 127.5, 122.5, 121.9, 121.0, 39.9, 27.0, 22.5, 13.9 ppm; νmax(KBr)/cmꢀ1
2960, 1682, 1527, 1303, 1168, 754, 704; MS (EI) m/z 77, 105, 146, 176, 196, 224,
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Yield: 85% (125 mg); yellow oil; TLC Rf = 0.58 (PE/EA = 10/1, v/v); H NMR (400
MHz, CDCl3) δ 12.14 (s, 1H), 8.95 (d, J = 8.4 Hz, 1H), 7.94 (d, J = 8.0 Hz, 1H), 7.62
(d, J = 8.0 Hz, 1H), 7.57 (d, J = 7.6 Hz, 1H), 7.35 (t, J = 7.2 Hz, 1H), 7.30ꢀ7.25 (m,
2H), 7.13 (t, J = 7.2 Hz, 1H), 3.00 (t, J = 7.2 Hz, 2H), 2.55 (s, 3H), 1.71ꢀ1.64 (m, 2H),
1.42ꢀ1.34 (m, 2H), 0.93 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 205.2,
168.8, 141.2, 137.0, 136.4, 134.9, 131.5, 130.9, 130.4, 127.2, 126.1, 122.6, 122.0,
120.9, 39.8, 26.8, 22.4, 20.3, 13.9 ppm; νmax(KBr)/cmꢀ1 3232, 2929, 1767, 1628, 1210,
1070, 908, 758; MS (EI) m/z 65, 91, 119, 146, 176, 210, 238, 295; HRMSꢀESI (m/z):
calcd for C19H22NO2 [M+H]+: 296.1645, found: 296.1643.
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2-Chloro-N-(2-pentanoylphenyl)benzamide (32a)
Yield: 87% (137 mg); White solid, mp 70ꢀ71 oC; TLC Rf = 0.46 (PE/EA = 10/1, v/v);
1H NMR (400 MHz, CDCl3) δ 12.18 (s, 1H), 8.93 (d, J = 8.4 Hz, 1H), 7.96 (d, J = 8.0
Hz, 1H), 7.64 (d, J = 7.2 Hz, 1H), 7.59 (d, J = 8.0 Hz, 1H), 7.46 (d, J = 7.6 Hz, 1H),
7.39ꢀ7.34 (m, 2H), 7.17 (t, J = 7.2 Hz, 1H), 3.01 (t, J = 7.2 Hz, 2H), 1.72ꢀ1.64 (m,
2H), 1.43ꢀ1.35 (m, 2H), 0.94 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ
205.2, 165.9, 140.6, 136.3, 134.9, 131.4, 131.3, 130.9, 130.6, 129.2, 127.1, 123.0,
122.2, 121.2, 39.8, 26.8, 22.4, 13.9 ppm; νmax(KBr)/cmꢀ1 3196, 2924, 1764, 1682,
1203, 1057, 908, 757; MS (EI) m/z 75, 111, 139, 146, 176, 230, 258, 315; HRMSꢀESI
(m/z): calcd for C18H18ClNNaO2 [M+Na]+: 338.0918, found: 338.0922.
3-Bromo-N-(2-pentanoylphenyl)benzamide (33a)
o
Yield: 80% (143 mg); White solid, mp 84ꢀ86 C; TLC Rf = 0.52 (PE/EA = 8/1, v/v);
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1H NMR (400 MHz, CDCl3) δ 12.73 (s, 1H), 8.90 (d, J = 8.4 Hz, 1H), 8.21 (s, 1H),
7.96 (d, J = 7.6 Hz, 2H), 7.66 (d, J = 7.6 Hz, 1H), 7.58 (t, J = 7.6 Hz, 1H), 7.38 (t, J =
8.0 Hz, 1H), 7.14 (t, J = 7.6 Hz, 1H), 3.04 (t, J = 6.8 Hz, 2H), 1.76ꢀ1.70 (m, 2H),
1.46ꢀ1.38 (m, 2H), 0.97 (t, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 205.7,
164.5, 141.1, 136.9, 135.0, 134.9, 131.2, 131.0, 130.3, 125.6, 123.1, 122.8, 121.9,
121.0, 39.8, 26.9, 22.5, 14.0 ppm; νmax(KBr)/cmꢀ1 3062, 2936, 1776, 1628, 1440, 1200,
1044, 911, 760; MS (EI) m/z 76, 92, 104, 134, 146, 155, 183, 276, 302, 359;
HRMSꢀESI (m/z): calcd for C18H18BrNNaO2 [M+Na]+: 382.0413, found: 382.0409.
N-(2-Pentanoylphenyl)-3-(trifluoromethyl)benzamide (34a)
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o
Yield: 85% (148 mg); White solid, mp 78ꢀ80 C; TLC Rf = 0.44 (PE/EA = 8/1, v/v);
1H NMR (400 MHz, CDCl3) δ 12.87 (s, 1H), 8.92 (d, J = 8.4 Hz, 1H), 8.37 (s, 1H),
8.22 (d, J = 7.6 Hz, 1H), 7.98 (d, J = 8.0 Hz, 1H), 7.81 (d, J = 7.6 Hz, 1H), 7.66 (t, J =
7.6 Hz, 1H), 7.59 (t, J = 7.6 Hz, 1H), 7.16 (t, J = 7.6 Hz, 1H), 3.05 (t, J = 6.4 Hz, 2H),
1.77ꢀ1.70 (m, 2H), 1.46ꢀ1.38 (m, 2H), 0.97 (t, J = 6.8 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ 205.8, 164.5, 141.0, 135.8, 135.1, 131.61 (q, J = 65.3 Hz, J = 32.6 Hz),
131.1, 130.1, 129.4, 128.4 (q, J = 7.0 Hz, J = 3.4 Hz), 125.1 (q, J = 7.9 Hz, J = 3.9
Hz), 122.9, 122.4, 121.9, 121.0, 39.8, 26.9, 22.4, 13.9 ppm; 19F NMR (376 MHz,
CDCl3) δ ꢀ62.79 ppm; νmax(KBr)/cmꢀ1 3057, 2923, 1758, 1628, 1419, 1199, 1095, 936,
754; MS (EI) m/z 65, 95, 134, 145, 173, 264, 292, 349; HRMSꢀESI (m/z): calcd for
C19H18F3NNaO2 [M+Na]+: 372.1182, found: 372.1185.
4-Ethyl-N-(2-pentanoylphenyl)benzamide (35a)
Yield: 89% (137 mg); yellow solid, mp 63ꢀ65 oC; TLC Rf = 0.48 (PE/EA = 10/1, v/v);
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1H NMR (400 MHz, CDCl3) δ 12.68 (s, 1H), 8.96 (d, J = 8.4 Hz, 1H), 7.99 (d, J = 7.2
Hz, 2H), 7.91 (d, J = 8.0 Hz, 1H), 7.53 (t, J = 7.6 Hz, 1H), 7.32 (d, J = 7.6 Hz, 2H),
7.07 (t, J = 7.2 Hz, 1H), 2.99 (t, J = 7.2 Hz, 2H), 2.70 (q, J = 14.8 Hz, J = 7.2 Hz, 2H),
1.73ꢀ1.67 (m, 2H), 1.43ꢀ1.35 (m, 2H), 1.25 (t, J = 7.2 Hz, 3H), 0.94 (t, J = 7.2 Hz,
3H); 13C NMR (100 MHz, CDCl3) δ 205.5, 166.0, 148.6, 141.5, 134.9, 132.3, 131.0,
128.3, 127.6, 122.3, 121.8, 120.9, 39.8, 28.8, 26.9, 22.5, 15.3, 14.0 ppm;
νmax(KBr)/cmꢀ1 3131, 2918, 1689, 1548, 1529, 1366, 1158, 969, 755; MS (EI) m/z 79,
105, 133, 146, 224, 252, 309; HRMSꢀESI (m/z): calcd for C20H23NNaO2 [M+Na]+:
332.1621, found: 332.1625.
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2,3,4,5,6-Pentafluoro-N-(2-pentanoylphenyl)benzamide (36a)
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Yield: 76% (141 mg); yellow oil; TLC Rf = 0.60 (PE/EA = 10/1, v/v); H NMR (400
MHz, CDCl3) δ 12.45 (s, 1H), 8.82 (d, J = 8.4 Hz, 1H), 8.00 (d, J = 7.6 Hz, 1H), 7.61
(t, J = 7.6 Hz, 1H), 7.23 (t, J = 7.6 Hz, 1H), 3.04 (t, J = 6.8 Hz, 2H), 1.72ꢀ1.65 (m,
2H), 1.45ꢀ1.36 (m, 2H), 0.95 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ
205.5, 156.0, 145.5 (dm, J = 256.1 Hz), 143.8 (dm, J = 256.4 Hz), 139.8, 139.02 (dm,
J = 254.7 Hz), 135.0, 130.9, 123.8, 122.0, 121.1, 39.6, 26.6, 22.28, 13.8 ppm; 19F
NMR (376 MHz, CDCl3) δ ꢀ140.5 (dd, J = 21.4 Hz, J = 6.8 Hz, 2F), ꢀ150.7 (t, J =
20.7 Hz, 1F), 160.1 (m, 2F) ppm; νmax(KBr)/cmꢀ1 3360, 2919, 1727, 1628, 1509, 1200,
1010, 957, 694; MS (EI) m/z 66, 92, 134, 146, 167, 176, 196, 286, 314, 329, 371;
HRMSꢀESI (m/z): calcd for C18H14F5NNaO2 [M+Na]+: 394.0837, found: 394.0840.
N-(2-Pentanoylphenyl)furan-2-carboxamide (37a)
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Yield: 89% (121 mg); White solid, mp 90ꢀ92 C; TLC Rf = 0.69 (PE/EA = 4/1, v/v);
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1H NMR (400 MHz, CDCl3) δ 12.68 (s, 1H), 8.89 (d, J = 8.8 Hz, 1H), 7.96 (d, J = 8.0
Hz, 1H), 7.63 (s, 1H), 7.57 (t, J = 8.0 Hz, 1H), 7.26 (d, J = 3.2 Hz, 1H), 7.14 (t, J =
7.6 Hz, 1H), 6.55(d, J = 1.6 Hz, 1H), 3.05 (t, J = 7.6 Hz, 2H), 1.79ꢀ1.72 (m, 2H),
1.48ꢀ1.39 (m, 2H), 0.97 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 205.2,
157.0, 148.3, 145.0, 140.7, 134.8, 130.9, 122.5, 121.9, 121.0, 115.3, 112.2, 39.8, 26.9,
22.5, 13.9 ppm; νmax(KBr)/cmꢀ1 2953, 2867, 1647, 1586, 1524, 1311, 974, 754; MS
(EI) m/z 67, 95, 146, 186, 214, 229, 271; HRMSꢀESI (m/z): calcd for C16H17NNaO3
[M+Na]+: 294.1101, found: 294.1105.
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N-(2-Pentanoylphenyl)thiophene-2-carboxamide (38a)
Yield: 84% (120 mg); White solid, mp 92ꢀ93 oC; TLC Rf = 0.49 (PE/EA = 10/1, v/v);
1H NMR (400 MHz, CDCl3) δ 12.73 (s, 1H), 8.83 (d, J = 8.4 Hz, 1H), 7.91 (d, J = 8.0
Hz, 1H), 7.81 (s, 1H), 7.53ꢀ7.50 (m, 2H), 7.13ꢀ7.06 (m, 2H), 3.00 (t, J = 7.2 Hz, 2H),
1.73ꢀ1.66 (m, 2H), 1.44ꢀ1.36 (m, 2H), 0.95 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ 205.2, 168.8, 141.2, 137.0, 136.4, 134.9, 131.5, 130.9, 130.4, 127.2, 126.1,
122.6, 122.0, 120.9, 39.8, 26.8, 22.4, 20.3, 13.9 ppm; νmax(KBr)/cmꢀ1 3240, 2922,
1688, 1582, 1451, 1299, 1166, 988, 757; MS (EI) m/z 83, 111, 146, 176, 202, 230,
287; HRMSꢀESI (m/z): calcd for C16H17NNaO2S [M+Na]+: 310.0872, found:
310.0877.
3-Oxo-3-(2-pentanoylphenylamino)propyl acetate (39b)
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Yield: 69% (100 mg); yellow oil; TLC Rf = 0.45 (PE/EA = 4/1, v/v); H NMR (400
MHz, CDCl3) δ 11.79 (s, 1H), 8.67 (d, J = 8.8 Hz, 1H), 7.86 (d, J = 8.0 Hz, 1H), 7.47
(t, J = 7.6 Hz, 1H), 7.05 (t, J = 7.6 Hz, 1H), 4.38 (t, J = 6.0 Hz, 2H), 2.95 (t, J = 7.2
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