Trifluoroacetic acid-catalyzed synthesis of N -(1-(3-chlorophenyl)-3-aryl- 3-oxopropyl)-2-(4-nitrophenyl)acetamides via Dakin-west reaction

Article abstract of DOI:10.1080/00397911.2013.796381

A series of novel N-(1-(3-chlorophenyl)-3-aryl-3-oxopropyl)-2-(4- nitrophenyl) acetamides were synthesized using p-nitrophenylacetonitrile, m-chlorobenzaldehyde, and aryl methyl ketones as starting materials and trifluoroacetic acid (TFA) as catalyst. This realized an improved Dakin-West reaction in which p-nitrophenylacetonitrile was involved. The chemical structures of up to 15 target molecules were characterized by ¹H NMR, ¹³C NMR, and high-resolution mass spectrometry. This method provides a facile synthetic protocol under more moderate reaction conditions, smaller dosage (0.40 mol%) and hence lower cost of catalyst, and simpler posttreatment in comparison to other known methods. A reaction mechanism is proposed in which hydroxyacetophenone is first catalytically converted into the corresponding acetoxyacetophenone prior to be involved in the subsequent Dakin-West reaction that eventually leads to hydroxyl-acetylated target compounds. [Supplementary materials are available for this article. Go to the publisher's online edition of Synthetic Communications for the following free supplemental resource(s): Full experimental and spectral details.]

Full text of DOI:10.1080/00397911.2013.796381

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Trifluoroacetic Acid-Catalyzed Synthesis of N-(1-(3-
chlorophenyl) -3-aryl-3-oxopropyl)-2-(4-nitrophenyl)
acetamides via Dakin-West Reaction
Hui-Hui Tian a , Li Fan a , Xing-Hua Zhang a , Cheng-He Zhou a , Guang-Ming Zhou a & Da-
Cheng Yang a
a School of Chemistry and Chemical Engineering , Southwest University , Chongqing , China
Accepted author version posted online: 27 Aug 2013.
To cite this article: Synthetic Communications (2013): Trifluoroacetic Acid-Catalyzed Synthesis of N-(1-(3-chlorophenyl) -3-
aryl-3-oxopropyl)-2-(4-nitrophenyl) acetamides via Dakin-West Reaction, Synthetic Communications: An International Journal
for Rapid Communication of Synthetic Organic Chemistry, DOI: 10.1080/00397911.2013.796381
To link to this article: http://dx.doi.org/10.1080/00397911.2013.796381
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Trifluoroacetic Acid-Catalyzed Synthesis of N-(1-(3-chlorophenyl)
-3-aryl-3-oxopropyl)-2-(4-nitrophenyl) acetamides via Dakin-West Reaction
Hui-Hui Tian1, Li Fan1, Xing-Hua Zhang1, Cheng-He Zhou1, Guang-Ming Zhou1,
Da-Cheng Yang1
1School of Chemistry and Chemical Engineering, Southwest University, Chongqing,
China
Corresponding Authors: E-mail: hxfanl@swu.edu.cn, hxydc@swu.edu.cn
Abstract
A series of novel N-(1-(3-chlorophenyl)-3-aryl-3-oxopropyl)-2-(4-nitrophenyl)
acetamides were synthesized using p-nitrophenylacetonitrile, m-chlorobenzaldehyde and
aryl methyl ketones as starting materials and trifluoroacetic acid (TFA) as catalyst. This
for the first time realized an improved Dakin-West reaction in which
p-nitrophenylacetonitrile was involved. The chemical structures of up to fifteen target
molecules were characterized by 1H NMR, 13C NMR, and HR MS. This method provides
a facile synthetic protocol under more moderate reaction conditions, smaller dosage (0.40
mol%), and hence lower cost, of catalyst and simpler post-treatment in comparison to
other known methods. A reaction mechanism is proposed in which hydroxyacetophenone
is first catalytically converted into corresponding acetoxyacetophenone prior to be
involved in the subsequent Dakin-West reaction that eventually leads to hydroxyl
acetylated target compounds.
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[Supplementary materials are available for this article. Go to the publisher’s online edition
of Synthetic Communications® for the following free supplemental resource(s): Full
experimental and spectral details.]
KEYWORDS: Multicomponent reaction, Dakin-West reaction, trifluoroacetic acid,
β-arylacetamido ketone, p-nitrophenyl acetonitrile
INTRODUCTION
One-pot, multicomponent reactions (MCRs) have attracted much attention since it was
put forward by Strecker in 1850[1]. MCRs can be used to synthesize complicated and
diverse molecules in a very fast, convenient and time-saving manner, and thus become
one of the best tools in combinatorial chemistry for establishing appropriate compound
libraries[2]. For the above reasons, to some extent, the discovery of novel MCRs and the
improvement of known MCRs have become increasingly active research subjects in
recent years[3].
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Nitrogen-containing molecules are ubiquitous in nature[4]. Among clinical drugs,
nitrogen-containing molecules are usually predominant. For example, among the eighteen
new chemical entities marketed in 2008, sixteen of which contain nitrogen atom[5].
β-Acetamido ketones, one of the nitrogen-containing molecules, are versatile
intermediates for the synthesis of important organic molecules like 1,3-amino alcohols[6]
present in antibiotic drugs such as nikkomycins or neopolyoxins[7], β-amino acids[8] and
γ-lactams[9]. Moreover, β-Acetamido ketones has been reported as a potential
α-glucosidase inhibitor[10]. Our laboratory has also found that some β-acetamido ketones
possess antidiabetic activation activities[11]. Thus, any efficient synthetic method of
β-acetamido ketones is highly desirable.
What makes us very excited is that the improved Dakin-West reactionis not only a MCRs,
but also the most convenient method for the synthesis of β-acetamido ketones. Currently,
studies on the improved Dakin-West reaction mainly focus on the discovery of new
catalysts[12] and novel molecules including chiral molecules[13].Our group has found that
trifluoroacetic acid (TFA) is an efficient catalyst for the synthesis of β-acetamido
ketone[14]. However, to our best knowledge, the improved Dakin-West reaction of
p-nitrophenyl- acetonitrile with aromatic aldehydes and enolizable aryl methyl ketones
has not been observed so far. In view of this, we introduced p-nitrophenylacetonitrile for
the first time into the improved Dakin-West reaction to prepare a series of novel
β-(p-nitrophenyl)acetamido ketones. The synthetic procedure is outlined in Scheme 1.
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Interestingly, the hydroxyl- containing ketones directly produced the hydroxyl acetylated
β-acetamido ketones in this one-pot improved Dakin-West reaction, which provides a
new way to synthesize this novel kind of compounds.
RESULTS AND DISCUSSION
Currently, acetylation of β-amino ketones[15], Mannich-type reaction of acetamides[16]
,
and Michael addition of α, β-unsaturated ketones with acetamides[17] are the usual options
to synthesize β-acetamido ketones. However, the most classical and facile synthetic
method is the improved Dakin-West reaction. (One paragraph has been deleted herein)
Recently, the studies of the improved Dakin-West reaction have made remarkable
progress, including ketones being extended from simple methyl ketones to cyclic
ketones[18], aryl alkyl ketones[19] and β-ketoesters[20]. In addition, other nitriles like
benzonitrile, phenylacetonitrile, acrylonitrile as well as ethyl cyanoacetate are also
reported[19]. An increasingly wider range of catalysts are documented, including Lewis
acid[20], proton acid[21], heteropoly acid[22], polymer resin[23] and ZnO nanoparticles[24]
.
However, the catalysts available for the Dakin-West reaction of benzonitrile or
phenylacetonitrile are limited to a small group of species such as ZrOCl2·8H2O[25]
SiCl4-ZnCl2[19] or BiOCl[26]
,
.
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In previous studies[11,14] we identified TFA as an efficient catalyst for some Dakin-West
reactions of acetonitile, in the absence of phenylacetonitrile or substituted
phenylacetonitrile. In an attempt to extend the application scope of TFA, we embarked on
an investigation to the improved Dakin-West reaction of p-nitrophenylacetonitrile. Not
surprisingly, for a start the reaction of p-nitrophenylacetonitrile, aryl methyl ketone, and
aromatic aldehyde in the presence of 0.30 mol% TFA did not proceed at any appreciable
rate. Therefore we decided to probe the reaction conditions of a model reaction as shown
in Equation 1 below.
Effect Of Catalyst On The Model Reaction
It is known that the above mentioned catalysts for the improved Dakin-West reaction
generally lead to decent yields. However, these catalysts also suffer serious drawbacks
such as significant cost[27], high active temperature[28] and tedious purifications[29]
.
Consequently, development of efficient, cheap and readily available catalysts for the
synthesis of β-arylacetamido ketone is highly desirable.
For the above model reaction, no catalyst has been reported till to now. To realize this
coupling reaction, a series of candidates were screened, including SiCl4-ZnCl2,
ZrOCl2•8H2O, TFA, FeCl3•6H2O, SnCl2•2H2O and CeCl3•7H2O, with the experimental
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results summarized in Table 1 below.
ZrOCl2·8H2O[25] and SiCl4-ZnCl2[19] (entries 1 and 2) show steady progress as evident by
TLC, but the coloration of the reaction system, close to dark brown, seriously hinders the
observation and post-treatment of the products. On the other hand, FeCl3•6H2O,
SnCl2•2H2O and CeCl3•7H2O catalysts (entries 6 ~ 8) result in fairly low yields, mainly
due to abundant by-products. However, in the case of TFA as catalyst, which was
pioneered by our group for the improved Dakin-West reaction[11,14], the model reaction
achieves the highest yield at TFA loading 0.40 mol% (entry 4). Considering the smaller
dosage, and hence lower cost, of catalyst and simpler post-treatment in comparison to
other known methods, we decide to use TFA loading of 0.40 mol% for the improved
Dakin-West reaction with p-nitrophenylaceto- nitrile, m-chlorobenzaldehyde and aryl
methyl ketones as starting materials.
Thermal Effect On The Model Reaction
The thermal effect is examined by conducting the model reaction at different temperature.
At 30°C in CHCl3, there is no sign of any target product on TLC plate; at 60°C in CHCl3,
the point of main product is not obvious. However, at 45°C in CHCl3, and 35°C in DCM,
the points of a single product are overwhelming. Consequently the optimal reaction
temperature is fixed at 45 in CHCl3 and 35°C in DCM.
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Effect Of Solvent On The Model Reaction
For the above model reaction, DCM, THF, CH3OH, CHCl3, or without using any solvent,
are systematically tested. Using CH3OH as the solvent, there is no point of target product
appeared on TLC plate. In THF, or in the case of no solvent, no reaction is observed for
up to 100 hours. While in DCM or CHCl3, the main product appears gradually. Therefore
all the subsequent reactions are carried out in the presence of 0.40 mol% TFA in DCM at
35 or CHCl3 at 45.
Encouraged by these remarkable results of the model reaction, a variety of acetophenones
with electron-withdrawing or -donating substituent(s) are screened to evaluate the scope
of substrates in the TFA-catalyzed, multicomponent one-pot reaction. Consequently, a
series of β-(p-nitrophenyl)acetamido ketones are prepared under optimal conditions, and
the results are displayed in Table 2.
In the CHCl3 series (Figure 1), the reaction using 3,4-dichloroacetophenone as starting
material reached a yield over 76%, while that using 4-chloroacetophenone only had a
yield of 53.1%, indicating the impact of the number and location of chlorine atom on the
yield. For different substitution group at the identical location of acetophenone, the yields
are in line with the trend of the electron-withdrawing ability of the substituents, for
example, TM-03 (4-F)>TM-04 (4-Cl)>TM-06 (4-Br)>TM-08 (4-CH3)>TM-10
(4-i-Bu)>TM-11 (4-OCH3); TM-01 (3-NO2)>TM-05 (3-Br); and TM-02
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(3,4-diCl)>TM-09 (3,4-diCH3). However, 4-nitroacetophenone led to no product. On the
other hand, for substituents in the para position, aromatic ketones with
electron-withdrawing groups reacted faster than electron-donating groups. These results
highlight the remarkable impact on the final yield by the electron density distribution. It
is probable that the electron-withdrawing effect of the substituent made the enolization of
carbonyl easier, resulting in the attack of the intermediate formed previously by aldehyde
and nitrile more conducive, eventually led to more vigorous reaction.
For the DCM series (Figure 2), the yield of the reaction involving double substituted
acetophenone by chloro atom tend to be lower than a mono substituted counterpart, for
example, TM-02 (3,4-diCl)<TM-04 (4-Cl). For different substituent(s) at the identical
location of acetophenone, the stronger the electron-withdrawing effect of the substituent(s)
on the aromatic ketones, the higher the yield generally. Among them,
3-nitroacetophenone led to an excellent yield of 87.2% in DCM. In contrast to the CHCl3
series, the acetophenones with electron-withdrawing substituent(s) reacted more slowly
than that with electron-donating substitutent(s), which showed that the rate of reaction
changed along with different solvent, probably due to the difference in solubility and
reaction temperature originated from solvent itself. But the strict trend of these reactions
in CHCl3 and CH2Cl2 does not display sufficiently, the root reason remains unclear to us.
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The reaction of hydroxyacetophenone to yield hydroxyl acetylated β-acetamido ketones
could have taken two drastically different pathway. I.e. either hydroxyacetophenone was
initially converted into corresponding acetoxyacetophenone, as catalyzed by TFA, and
then participated in the improved Dakin-West reaction which led to hydroxyl acetylated
target molecule (B); or all reactants initially participated in the improved Dakin-West
reaction which afforded the intermediate product (A) which was in turn converted into
the final target molecules (B), as shown in Scheme 2.
Given the fact that existing literatures hardly cover any kinetic insight[30], we diligently
designed the following experiments to unravel the plausible reaction pathway:
Procedure 1. To a solution of hydroxyacetophenone in CHCl3, acetyl chloride was added
dropwise, stirred continuously at 15-17 and monitored by TLC.
Procedure 2. To a solution of hydroxyacetophenone and acetyl chloride in CHCl3, TFA
was added dropwise, stirred continuously at 15-17 and monitored by TLC.
Procedure 3. Conventional one-pot synthesis at 15-17 .
Procedure 4. To a solution of hydroxyacetophenone and acetyl chloride in CHCl3, TFA
was added dropwise. After stirring for 2 hours at 15-17 , p-nitrophenylacetonitrile and
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m-chlorobenzaldehyde were added sequentially. Then common post-treatment was
followed.
Procedure 5. Instead of hydroxyacetophenone, acetoxyacetophenone (prepared
previously by Procedure 5’) was used as the starting material.
Procedure 5’. To a solution of hydroxyacetophenone and solid Na2CO3 in CHCl3, AcCl
was added dropwise in ice bath. After stirring for half an hour, the mixture was stirred at
35 , stirred continuously and monitored by TLC;
Procedure 6. The resultant hydroxyl acetylated β-acetamido ketones were selectively
deacetylated in LiOH-H2O, or NaOH-H2O in THF, or acetone to yield the corresponding
deacetylated products.
In procedure 1, hydroxyacetophenone reacted with acetyl chloride to ultimately produce
acetoxyacetophenone over a period of several hours, evident of sluggish reaction rate in
the absence of an effective catalyst. However in procedure 2 where TFA was present,
significant acetoxyacetophenone formed within one hour, indicating that TFA greatly
accelerate the formation of acetoxyacetophenone.
In procedure 4, a new spot emerged within 4 hours on TLC plate, identical to the new
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substance generated by procedures 3 and 5. In the same time frame,
hydroxyacetophenone remained in procedure 2 but almost completely disappeared in
procedure 4; in comparison, acetoxyacetophenone remained in procedure 2 and 4,
indicating a promotion effect of the conversion of hydroxyacetophenoneone into
acetoxyacetophenone. These experimental results uncovered important mechanistic
insight in that hydroxyacetophenone is first converted into acetoxyacetophenone which
then subsequently leads to acetylated β-acetamido ketones in the improved Dakin-West
reaction.
In procedures 3-5, the reaction time was sequentially reduced corresponding to
increased yield, suggesting acetoxyacetophenone being a more favorable reactant than
hydroxyaceto -phenone. Also the mutual promotion between acetylation and the
Dakin-West reaction process made procedure 4 faster than procedure 3, which also
confirm the aforementioned hypothesis.
The experimental results show that the yield of the reaction participated by m-hydroxy-
acetophenone is higher than that of p-hydroxyacetophenone, that is, TM-12> TM-13. For
deacetylation reaction, TM-13 is easier than TM-12, as the later requires stronger base
and takes longer time to complete, which proves that meta-acetylated product is more
stable, easier to generate, and hence the higher yield.
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On the basis of all the above results, we propose the mechanism as follows in Figure 3.
The presence of acetyl chloride is necessary for the transformation and the reactions in its
absence give lower yield or even none of the desired product even after several hours.
In conclusions, this research presents TFA as an efficient catalyst for the improved
Dakin-West reaction involving m-chlorobenzaldehyde, p-nitrobenzeneacetonitrile and
aryl methyl ketones as starting materials, that produce
N-(1-(3-chlorophenyl)-3-aryl-3-oxopropyl) -2-(4-nitrophenyl)acetamides. This
investigation for the first time establishes the reaction pathway of hydroxyacetophenone,
in which TFA initially catalyzes the conversion of hydroxyacetophenone into
corresponding acetoxyacetophenone, followed by the Dakin-West reaction that eventually
leads to hydroxyl acetylated target compounds. This study has also expanded the
application scope of TFA and laid the foundation for further research on the Dakin-West
reaction with p-nitrophenylacetonitrile.
EXPERIMENTAL
General Procedure For The Synthesis Of Β-Arylacetamido Ketones
To a solution of p-nitrophenylacetonitrile (1.0 mmol), m-chlorobenzaldehyde (1.2 mmol)
and acetyl chloride (0.4 mL) in CHCl3 (3 mL), TFA (0.40 mol%) was added dropwise in
ice bath. After half an hour, aromatic ketone (1.2 mmol) was added into the mixture at a
controlled temperature of 45 . The progress of the reaction was monitored by TLC. On
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completion, ice water (5 mL) was poured into the reaction mixture and stirred thoroughly
before the solution was adjusted to pH 7 with saturated NaHCO3. Subsequently, the
reaction mixture was extracted with DCM. The organic layer was dried over Na2SO4, and
filtered. The filtrate was evaporated under reduced pressure. The crude product obtained
was recrystallized from a mixture of ethyl acetate/petroleum (ratio of volume, 1/3) or in
methanol to afford the pure product.
Reasoning Experiments Of Reaction Process
Procedure 1. To a solution of hydroxyacetophenone (1.0 mmol) in CHCl3 (1 mL), acetyl
chloride (0.4 mL) was added dropwise, stirred continuously at 15-17 and monitored by
TLC.
Procedure 2. To a solution of hydroxyacetophenone (1.0 mmol) and acetyl chloride (0.4
mL) in CHCl3 (1 mL), TFA (0.40 mol%) was added dropwise, stirred continuously at
15-17 and monitored by TLC.
Procedure 3. To a solution of p-nitrophenylacetonitrile (1.0 mmol),
m-chlorobenzaldehyde (1.2 mmol) and acetyl chloride (0.4 mL) in CHCl3 (3 mL), TFA
(0.40 mol%) was added dropwise in ice bath. After half an hour, hydroxyacetophenone
(1.0 mmol) was added into the mixture at 45 . The progress of the reaction was monitored
by TLC. On completion, ice water (5 mL) was poured into the reaction mixture and
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stirred thoroughly before the solution was adjusted to pH 7 with saturated NaHCO3.
Subsequently, the reaction mixture was extracted with DCM. The organic layer was dried
over Na2SO4, and filtered. The filtrate was evaporated under reduced pressure. The crude
product obtained was recrystallized from a mixture of ethyl acetate/petroleum (ratio of
volume, 1/3) or in methanol to afford the pure product.
Procedure 4. To a solution of hydroxyacetophenone (1.0 mmol), and acetyl chloride (0.4
mL) in CHCl3 (3 mL), TFA (0.40 mol%) was added dropwise in ice bath. After two hours,
p-nitrophenylacetonitrile (1.1 mmol), m-chlorobenzaldehyde (1.5 mmol) were added into
the mixture at 45 . The progress of the reaction was monitored by TLC. On completion,
the post-treatment was the same as Procedure 3.
Procedure 5. Instead of hydroxyacetophenone, acetoxyacetophenone was used as the
starting material, then common operation was followed as Procedure 3.
Procedure 5’. To a solution of hydroxyacetophenone (1.0 mmol) and solid Na2CO3 (0.6
mmol) in CHCl3 (1 mL), AcCl (0.4 mL) was added dropwise in ice bath. 30 min later, the
mixture was stirred at 35 . The progress of the reaction was monitored by TLC. On
completion, filtered, and the filtrate was evaporated under reduced pressure to give oil,
which was used directly in the subsequent Dakin-West reaction.
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Procedure 6. To a solution of the product 12 or 13 (1.0 mmol) in acetone or THF (3 mL),
1 N LiOH-H2O or NaOH-H2O (4 mL) was added dropwise in ice bath. Subsequently, the
reaction mixture was stirred at ambient temperature (16-20 ) and the progress of the
reaction was monitored by TLC. On completion, the reaction mixture was evaporated
under reduced pressure. After the removal of the solvent, the solution was adjusted to pH
3-4 with 2 N H2SO4 in ice bath, instantaneous precipitation of a lot of yellow solid which
was filtered, and the filter cake was washed with water (1 mL×3) to afford the pure
product.
Spectral Data For N-(1-(3-Chlorophenyl)-3-Oxo-3-Phenylpropyl)-2-(4-Nitrophenyl)
Acetamide (TM-07)
Yellowy powder; yield: 43.4% (in CHCl3) and 66.2% (in DCM).
1H NMR (600 MHz, DMSO-d6): δ 3.44-3.64 (m, 4H, COCH2CH and NHCOCH2),
5.34-5.38 (m, 1H, CHN), 7.28-7.34 (m, 3H, Ar-H), 7.38 (s, 1H, Ar-H), 7.48 (d, J = 9.00
Hz, 2H, Ar-H), 7.53 (t, J = 7.80 Hz, 2H, Ar-H), 7.65 (t, J = 7.80 Hz, 1H, Ar-H), 7.97 (d, J
= 7.80 Hz, 2H, Ar-H), 8.15 (d, J = 8.40 Hz, 2H, Ar-H), 8.72 (d, J = 7.20 Hz, 1H, NH)
ppm. 13C NMR (101 MHz, DMSO-d6): δ 196.8, 168.3, 146.2, 145.3, 144.3, 136.4, 133.4,
133.0, 130.3, 130.2, 128.7, 128.1, 126.9, 126.4, 125.4, 123.3, 48.8, 44.2, 41.9 ppm. HR
MS calcd for C23H19ClN2O4Na 445.0931, found 445.0924.
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ACKNOWLEDGEMENT
This project is supported by “National Natural Science Foundation of China” (No.
21172181) and “The Chongqing Science and Technology research project" (2011AB5001,
2011AC1053). The authors are also grateful to Mr. Qunli Luo, Mr Chengbin Gong and
Mr Ning Wang for their assistance in measuring 1H and 13C NMR spectra.
SUPPLEMENTARY CONTENT
Supporting Information: full experimental detail, 1H and 13C NMR spectra, and HR MS
are available online.
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Table 1. Effect of catalysts on the model reactiona
Entry
Catalyst
SiCl4-ZnCl2
Amount (mol%)
5.0
Yield b (%)
38.4
1
2
3
4
5
6
7
8
ZrOCl2·8H2O
TFA
20.0
0.30
0.40
0.50
10.0
20.0
10.0
56.4
<10
66.4
58.5
18.5
8.5
TFA
TFA
FeCl3·6H2O
SnCl2·2H2O
CeCl3·7H2O
23.9
a The reactions were performed in CH2Cl2 at 35 for 24 h, aided by AcCl (0.4 mL ), and in
the following amount: p-nitrophenylacetonitrile (0.5 mmol), m-chlorobenzaldehyde (0.6
mmol), and acetophenone (0.6 mmol).
b Isolated yield based on p-nitrophenylacetonitrile.
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Table 2. Experimental results under optimal conditionsa
Compd.
R
Time (h)
Yield (%)
m. p. ( )
CHCl3 DCMc CHCl3 DCMc
b
b
3-NO2
53
28
52
41
47
47
33
64
64
75
67
25
20
5
47
47
40
45
40
40
36
25
26
25
18
/
60.5
76.9
74.6
53.1
54.2
47.6
43.4
41.4
44.1
30.5
28.1
70.0
60.5
56.2
65.5
87.2
45.7
63.4
68.0
41.2
34.3
66.2
45.8
35.5
39.7
18.3
/
202.6-204.6
193.2-195.2
167.1-169.0
196.4-198.2
204.8-205.6
221.7-223.5
163.5-164.8
165.3-167.5
152.9-154.5
127.1-128.9
210.5-212.8
151.1-152.5
157.8-159.2
160.1-161.5
243.0-244.8
TM-01
3,4-diCl
4-F
TM-02
TM-03
TM-04
TM-05
TM-06
TM-07
TM-08
TM-09
TM-10
TM-11
TM-12
TM-13
TM-14
TM-15
4-Cl
3-Br
4-Br
H
4-CH3
3,4-diCH3
4-i-Bu
4-OCH3
3-OAc (R1)
4-OAc (R1)
3-OH
/
/
4-OH
1
a The reactions were performed in the following amount: p-nitrophenylacetonitrile (1.0
mmol), m-chlorobenzaldehyde (1.2 mmol), and aryl methyl ketones (1.2 mmol).
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b at 45
c at 35
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Scheme 1. The improved Dakin-West reaction among p-nitrophenylacetonitrile,
m-chlorobenzaldehyde and aryl alkyl ketones
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Scheme 2. Plausible reaction pathway
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Figure 1. Time-yield-substituent relationships of CHCl3 series
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Figure 2. Time-yield-substituent relationships of DCM series
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Figure 3. Suggested mechanism for the synthesis of β-arylacetamido ketone
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