Metal-Free Decarboxylative Trichlorination of Alkynyl Carboxylic Acids: Synthesis of Trichloromethyl Ketones

Article abstract of DOI:10.1002/adsc.201701116

2,2,2-Trichloroacetophenone derivatives were synthesized via decarboxylative trichlorination from arylpropiolic acids and trichloroisocyanuric acid (TCCA). The reaction was performed in the presence of water at room temperature, and the desired products were obtained in good yields. The reaction showed good functional group tolerance towards halide, cyano, nitro, ketone, ester and aldehyde groups. In addition, the 2,2,2-trichloroacetophenone derivatives were readily transformed into esters, amides, and hydrazides. Based on experiments with H₂¹⁸O (water-¹⁸O), we proposed a cationic reaction pathway as the mechanism and suggested two different pathways for producing aryl- and alkyl-substituted propiolic acids. (Figure presented.).

Full text of DOI:10.1002/adsc.201701116

Title: Metal-Free Decarboxylative Trichlorination of Alkynyl Carboxylic
Acids : Synthesis of Trichloromethylketones
Authors: Aravindan Jayaraman, Eunjeong Cho, Francis Mariaraj
Irudayanathan, Jimin Kim, and Sunwoo Lee
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201701116
Link to VoR: http://dx.doi.org/10.1002/adsc.201701116

10.1002/adsc.201701116
Advanced Synthesis & Catalysis
FULL PAPER
DOI: 10.1002/adsc.200((will be filled in by the editorial staff))
Metal-Free Decarboxylative Trichlorination of Alkynyl
Carboxylic Acids: Synthesis of Trichloromethyl Ketones.
Aravindan Jayaraman, Eunjeong Cho, Francis Mariaraj Irudayanathan, Jimin Kim,
Sunwoo Lee*
Department of Chemistry, Chonnam National University, Gwangju 500-757, Republic of Korea
Fax: (+82) 62-530-3389
E-mail: sunwoo@chonnam.ac.kr
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.200######.
Abstract. 2,2,2-Trichloroacetophenone derivatives In
addition,
the
2,2,2-trichloroacetophenone
were synthesized via decarboxylative trichlorination derivatives were readily transformed into esters,
from arylpropiolic acids and trichloroisocyanuric acid amides, and hydrazides. Based on experiments with
18
(TCCA). The reaction was performed in the presence H2 O (water-18O), we proposed a cationic reaction
of water at room temperature, and the desired products pathway as the mechanism and suggested two
were obtained in good yields. The reaction showed different pathways for producing aryl- and alkyl-
good functional group tolerance towards halides, substituted propiolic acids
cyano, nitro, ketone, ester and aldehyde groups.
Keywords:
Metal-free;
propiolic
acid;
trichloroisocyanuric acid; room temperature;
trichloromethyl ketone;
alkyl 2,2,2-trichloroethanol, which is prepared from
the reaction of an aldehyde with sodium
trichloroacetate or chloroform, was reported (Scheme
1a).[3] Togo reported that Grignard reagents react with
received chloral followed by reaction with tBuOCl to produce
Introduction
Trichloromethyl
ketones
have
considerable attention as key structures in various trichloromethyl ketones (Scheme 1b).[4] One example
bioactive compounds such as agricultural herbicides, of a palladium-catalyzed coupling reaction with
fungicides, and pesticides (Figure 1),[1] and have been phenyl boronic acid and trichloroacetonitrile has also
used as valuable building blocks in organic syntheses. been reported (Scheme 1c).[5] However, these
In addition, they can be employed as acyl chloride methods have disadvantages such as the requirement
surrogates, because they are stable, not sensitive to of inert conditions, lack of functional group tolerance,
moisture, and are readily purified by column and harsh reaction conditions.
chromatography.[2]
As part of our ongoing interest in decarboxylative
reactions of propiolic acid derivatives, we found that
Figure 1. Bioactive 2,2,2-trichloroacetophenone
derivatives.
2,2,2-trichloroacetophenone
phenylpropiolic acid
formed
reacted
when
with
was
trichloroisocyanuric acid (TCCA). TCCA is a
commonly used chlorinating agent[6] and has several
advantages such as low cost, commercial availability,
stability, and easy handling.[7] Thus, we envision that
this transformation could be useful in providing a
variety of 2,2,2-trichloroacetophenone derivatives
because diverse aryl propiolic acid derivatives can be
readily prepared from aryl halides and propiolic
acid.[8] Herein, we report a simple and mild synthetic
method
trichloroacetophenones
trichlorination of aryl propiolic acids.
for
the
preparation
from
of
2,2,2-
Although they contain potentially reactive
functional groups and have a variety of potential
applications, their general preparation methods have
not been well established. Oxidation of 1-aryl or 1-
decarboxylative
1
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10.1002/adsc.201701116
Advanced Synthesis & Catalysis
[a]Reaction conditions: 1a (0.3 mmol) and TCCA (0.3 mmol) were reacted
with H2O (x equiv) in solvent (1.0 mL) at 25 °C. [b]Determined by gas
chromatography (GC) with an internal standard. cReaction temperature:
0 °C to 25 °C
To improve the product yield, we further studied
the amount of water and TCCA used as well as
reaction temperature effects. The results of these
investigations are summarized in Table 2. The
reactions performed with 16.0 equiv of water
provided maximized 2a yields (entries 1 – 6). When
1.1 equiv of TCCA was used, the product yield
increased to 89% (entry 7). However, when that
amount was increased to 1.2 and 1.5 equiv of TCCA,
the product yields decreased to 73% and 67%,
respectively (entries 8 and 9). Increasing the reaction
o
temperature to 50 and 80 C did not give satisfactory
Scheme 1. Synthesis of 2,2,2-trichloroacetophenones.
results (entries 10 and 11). Based on these results, the
optimized condtions are as follows: alkynyl
carboxylic acid (1.0 equiv), TCCA (1.1 equiv) and
H2O (16.0 equiv) reacted in CH3CN at 25 oC for 12h.
Results and Discussion
Phenylpropiolic acid was reacted with TCCA in
CH3CN/H2O at room temperature. We first employed
Table 2. The effect of the amount of water, TCCA
metal catalysts which have shown good activty and temperature.[a]
towards decarboxylative couplings. The reactions
using Pd(OAc)2 and Pd(PPh3)2Cl2 afforded 2,2,2-
trichloroacetophenone (2a) in 37% and 45% yields,
respectively (entries 1 and 2). Other metal catalysts
such as CuI, AgOAc, and Ni(acac)2 gave the desired
products in moderate yields (entries 3 – 5).
Surprisingly, 2a was formed with 61% yield in the
absence of a metal catalyst (entry 6). When the
reaction was conducted in the absence of H2O, a trace
amount of the desired product was formed (entry 7).
When the amount of H2O was increased to 16 equiv,
the product yield reached 86% (entry 8). Ether-type
solvents such as THF and 1,4-dioxane gave
unsatisfactory results (entries 9 and 10). When the
reaction was conducted in DMSO, the products‘ yield
was very poor because of heating in the reaction
mixture (entry 11). In DMF and DMAc, the desired
products were obtained in good yields, but were lower
than that obtained in CH3CN (entry 12 and 13).
Entry H2O (x equiv) TCCA (y equiv) Temp. (oC) 2a Yield (%)[b]
1
2
2.0
4.0
1.0
1.0
1.0
1.0
1.0
1.0
1.1
1.2
1.5
1.1
1.1
25
25
25
25
25
25
25
25
25
50
80
13
33
75
79
75
60
89
73
67
77
52
3
4
5
6
7
8
9
10
11
10.0
14.0
25.0
30.0
16.0
16.0
16.0
16.0
16.0
[a]Reaction conditions: 1a (0.3 mmol) and TCCA (y equiv) were reacted
with H2O (x equiv) in CH3CN (1.0 mL). [b]Determined by gas
chromatography with an internal standard.
Table 1. Optimization of the synthesis of 2,2,2-
Next the substrate scope was evaluated and various
aryl propiolic acids were tested, and the results are
summarized in Table 3. As expected, 2,2,2-
trichloroacetophenone (2a) was obtained in 89%
isolated yield from phenylpropiolic acid (1a).
Phenylpropiolic acids with halides such as chloride,
bromide, and fluoride were transformed into the
trichloroacetophenone.[a]
Entry
Solvent
catalyst
H2O (equiv) 2a Yield (%)[b]
corresponding
2,2,2-trichloroacetophenone
derivatives 2b, 2c, 2d, 2e, 2f, and 2g in 63%, 70%,
61%, 75%, 68% and 72% yields, respectively.
Trifluoromethyl-substituted propiolic acid gave the
desired product 2h with 68% yield. Arylpropiolic
acids containing carbonyl derivative groups such as
cyano, ketone, and ester moieties provided the desired
products 2i, 2j, and 2k in good yields. However,
arylpropiolic acid with an aldehyde group afforded 2l
in 42% yield. 1-Naphthyl- and 4’-biphenyl propiolic
acids afforded 2m and 2n in 51% and 57% yields,
1
2
3
4
5
6
7
8
9
10
11[c]
12[c]
13[c]
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
THF
Pd(OAc)2
Pd(PPh3)2Cl2
CuI
AgOAc
6.0
6.0
6.0
6.0
6.0
37
45
41
49
40
61
trace
86
37
58
Ni(acac)2
-
-
-
-
-
-
-
-
6.0
-
16.0
16.0
16.0
16.0
16.0
16.0
1,4-dioxane
DMSO
DMF
trace
81
72
DMAc
respectively.
3-(Thiophen-2-yl)propiolic
acid
2
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10.1002/adsc.201701116
Advanced Synthesis & Catalysis
provided 2o in 46% yield. Ortho-, meta-, and para- substitution reactions. Specifically, esters are easily
methyl-substituted phenylpropiolic acids showed prepared and stable, and can be readily transformed
similar reactivities in the transformation, and gave into other carbonyl-containing compounds.[9] Amides
2,2,2-trichloroacetophenone derivatives 2p, 2q, and are key functional groups in biomolecules.[10]
2r in 61%, 60%, and 63% yields, respectively. 3-(4- Numerous synthetic methods for the preparation of
tert-Butyl)phenylpropiolic acid gave the desired esters and amides have been developed. Among them,
product 2s in 64% yield. The nitro-substituted the substitution of acyl halides with alcohols or
phenylpropiolic acids were transformed into the amines are the most straightforward, due to the high
desired products 2t, 2u, and 2v in 66%, 41%, and reactivity of the acyl halides. However, the use of
45% yields, respectively.
acyl chlorides has some drawbacks such as instability
and moisture sensitivity. As an alternative reagent and
surrogate, we used 2,2,2-trichloromethyl ketones in
acyl substitution reactions. As shown in Scheme 2, a
number of alcohols, amines, and hydrazines reacted
with trichloroacetophenone. The reactions with
methanol, benzyl alcohol, allyl alcohols, propargyl
alcohols, and isopropanol provided esters 3, 4, 5, 6,
and 7 in good yields. The reaction with ammonia gave
benzamide 9 in 81% yield. Secondary and primary
amines afforded amides 8 and 10 in good yields. As
expected, an amino alcohol afforded 11 in 62% yield.
Hydrazines afforded 12 and 13 in good yields. When
the acyl substitution reactions were sequentially
conducted with phenylpropiolic acid, the desired
esters, amides, and hydrazides were formed, although
their yields were a bit lower than those of the direct
substitution reactions.
Table 3. Synthesis of 2,2,2-trichloromethyl ketone
derivatives.[a]
[a]Reaction conditions: 1 (2.0 mmol), TCCA (2.2 mmol), and H2O (32.0
mmol) were reacted in CH3CN (5.0 mL) at 25 °C for 12 h. The numbers in
parentheses are isolated yields.
Based on the obtained results, we can arrive at the
following conclusions: 1) the electronic properties of
the substituents on the phenyl ring affected the
transformation, and aryl propiolic acids with electron-
withdrawing groups afforded the desired products in
good yields. For starting materials with electron-
Scheme
2.
Transformations
of
2,2,2-
o
donating groups, the product yield depended on the trichloroacetophenone. Conditions: a) Et3N, 50 C,
o
o
substituent. Alkyl-substituents on the phenyl ring
afforded the desired products in moderate yields.
However, we failed to obtain the desired product for
precursors with methoxy-substituents; 2) no steric
effects were observed in this transformation; 3) the
tolerance of other carbonyl substituents, such as
ketone, ester, and aldehyde, provided an opportunity
for further transformation; 4) tolerated halide
functionalities could be used as coupling partners in
metal-catalyzed cross coupling reactions; and 5)
trichloromethyl ketones were readily purified by
column chromatography on silica gel and were stable
toward moisture at room temperature. However, we
found that hydrolysis took place when it was allowed
to react with water at high temperatures. (>80 oC)
THF; b) DBU, 30 C, THF; c) 25 C, THF. The
numbers in parentheses are the isolated yields (yield
from 2a / yield of sequential reaction from 1a).
To evaluate the reactivity of 2,2,2-trichloromethyl
ketones in acyl substitution reactions, 2k was allowed
to react with piperidine or benzylamine. As shown in
Scheme 3, substituted amides 14 and 15 bearing
methyl esters were formed in 88%, and 82% yields,
respectively. Primary and secondary amines were not
substituted at the ester, but instead at the
trichloromethyl ketone group. These results revealed
that the trichloromethyl ketone group was more
reactive than the esters in the acyl substitution
reaction. This selectivity allowed for further
transformation at the ester group. Finally,
Aryl esters and amides are important core structures
in organic synthesis and they can be prepared via acyl
3
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10.1002/adsc.201701116
Advanced Synthesis & Catalysis
unsymmetrically substituted diamide 16 was obtained
from 14 and 15 using the developed procedure.
(2,6-di-tert-butyl-4-methylphenol) with 1.0 and 3.0
equiv, the product yields were 65% and 60%,
respectively. These results indicate that cationic
chloride is likely involved in the major reaction
pathway in this synthetic process.
Based on our results, we propose two different
reaction pathways, as shown in Scheme 5.
Phenylproiolic acid could react with TCCA to
generate alkenyl chloronium intermediate A, which is
followed by intramolecular cyclization to provide
cyclic ester B. Nucleophilic attack by water on the
carbonyl carbon of ester B would drive the ring
opening. Further reaction with dichlorocyanuric acid
would produce the dichlorinated intermediate C.
Subsequent decarboxylation would give dichlrovinyl
alcohol D, which would then react with
monochlorocyanuric acid to give the desired 2,2,2-
trichloroacetophenone. Reaction pathway I was
supported by the lack of formation of 2a-18O, because
the oxygen from water could be released as carbon
dioxide via decarboxylation. In the case of the
reaction with methyl phenylpropiolate, water could
add to alkenyl chloronium intermediate E to give
Scheme 3. Synthesis of unsymmetrically substituted
o
diamide. Conditions: a) DBU, 25 C, toluene; b)
o
o
KOtBu, 30 C, THF; C) NaOMe, 80 C, piperidine
o
(neat); d) NaOMe, 60 C, benzylamine (neat). The
numbers in parentheses are the isolated yields.
To study the reaction pathway, phenylpropiolic acid
and methyl phenylpropiolate were independently
allowed to react with water bearing oxygen-18
monochlorinated
F.
Then
reaction
with
18
dichlorocyanuric acid would provide 18. In this
pathway, the oxygen originating from the water
molecule remains in the final product.
(H2 O) in the presence of TCCA, as shown in
Scheme 4. In the case of the reaction between 1a and
18
H2 O, the exact mass for 2,2,2-trichloroacetophenone
bearing oxygen-18 was not found in the measured
high-resolution mass spectrometry (HRMS). HRMS
revealed a molecular mass of 222.9484, which is the
exact molecular mass of 2a (C8H5Cl3O, m/z
calculated for [M+H]+: 222.9484) with oxygen-16.
When methyl phenylpropiolate 17 was reacted with
18
H2 O, dichlorinated product 18 was formed in 55%
yield. A molecular mass of 248.9974 was observed in
16
18
HRMS, which corresponded to C10H8Cl2 O2 O (m/z
calculated for [M+H]+: 248.9971). Analysis of the
HRMS data revealed that the ratio of 18-16O to 18-
18O was 1:3, suggesting that water reacts differently
in these two reactions. When phenylacetylene was
18
employed in the reaction with TCCA and H2 O, 2,2-
dichloroacetophenone with incorporated oxygen-18
18
Scheme 5. Proposed reaction pathway for aryl-
substituted propiolic acid and ester.
was found in HRMS. (C8H7Cl2 O, m/z calculated for
[M+H]+: 190.9909, found : 190.9850).
To expand this methodology toward alkyl-
substituted propiolic acids, we employed 2-octynoic,
2-hexynoic, and 2-pentynoic acids. The results are
summarized in Table 4. When 2-octynoic acid was
allowed to react with TCCA under the optimized
conditions, 1,1,1-trichloroheptan-2-one (20a) and
dichlorinated furanone 21a were obtained in 25% and
21% yields, respectively. In addition, unidentified
mixtures were detected by GC-MS (entry 1).
However, trichloroacetyl compounds could not be
obtained from 2-hexynoic and 2-pentynoic acids.
Based on GC-MS analysis, dichlorinated lactones 21b
Scheme 4. Determination of the role of water in the
developed reaction.
When phenylpropiolic acid and TCCA were
reacted in the presence of the radical scavenger BHT
4
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10.1002/adsc.201701116
Advanced Synthesis & Catalysis
and 21c were isolated in 15% and 12% yields, Experimental Procedure 1: To a 20-mL screw cap
respectively (entries 2 and 3).
vial added aryl propiolic acid (2.0 mmol, 1.0 equiv),
trichloroisocyanuric acid (511 mg, 2.2 mmol, 1.1
equiv) and water (576 mg, 32.0 mmol, 16.0 equiv) in
acetonitrile (5.0 mL). The solution was stirred at
25 °C for 12 h. The resulting mixture charged to the
separating funnel added water, extracted with EtOAc.
The organic layer washed with water and dried over
anhydrous MgSO4. After removing the EtOAc under
vacuum, the crude product was purified by column
chromatography on a silica gel column with n-
hexane/ethyl acetate as eluent to obtain the desired
product.
Table 4. Reaction of alkyl-substituted propiolic acids
and TCCA.[a]
Entry
Propiolic acid
Product (yield)
1
2
3
19a
19b
19c
R = n-C4H9
R = C2H5
R = CH3
20a (25%)
21a (21%)
21b (15%)
21c (12%)
20b (-)
20c (-)
2,2,2-Trichloro-1-phenylethanone
(2a)[11]
:
[a]Reaction conditions: 19 (2.0 mmol), TCCA (2.0 mmol), and H2O (32.0
mmol) were reacted in CH3CN (5.0 mL) at 25 °C for 6 h. The numbers in
parentheses are the isolated yields.
Phenylpropiolic acid (292 mg, 2.0 mmol) afforded
2,2,2-trichloro-1-phenylethanone (2a) (398 mg, 1.78
To explain the formation of dichlorinated furanone mmol, 89% yield) as a colorless liquid; 1H NMR (500
21, we proposed reaction pathway III, as shown in
Scheme 6. Alkyl-substituted propiolic acid produced
the alkenyl chlorinium intermediate G. The
dichlorocyanuric acid abstracts a proton from G to
give the allenic intermediate H, which further reacts
with dichlorocyanuric acid to afford the cyclic
chlorinium intermediate I. Finally, cyclization of the
carboxylic acid produces dichlorofuranone 21.
MHz, CDCl3): δ 8.26 (d, J = 7.4 Hz, 2H), 7.64 (t, J =
7.5 Hz, 1H), 7.50 (t, J = 7.5 Hz, 2H); 13C{1H} NMR
(125 MHz, CDCl3) δ 181.2, 134.3, 131.5, 129.1,
128.4, 95.4; HRMS (FAB) m/z cacld. for C8H5Cl3O
[M+H]+: 222.9484, found: 222.9482.
2,2,2-Trichloro-1-(4-chlorophenyl)ethanone
(2b)[11] : 3-(3-chlorophenyl)propiolic acid (361 mg,
2.0
mmol)
afforded
2,2,2-trichloro-1-(4-
chlorophenyl)ethanone (2b) (325 mg, 1.26 mmol,
1
63% yield) as a colorless liquid; H NMR (500 MHz,
CDCl3): δ 8.20 (s, 1H), 8.14 (d, J = 8.0 Hz, 1H), 7.61
13
(d, J = 8.0 Hz, 1H), 7.44 (t, J = 8.0 Hz, 1H); C{1H}
NMR (125 MHz, CDCl3) δ 180.1, 134.7, 134.2, 131.3,
130.7, 129.6, 129.4, 94.9; HRMS (FAB) m/z cacld.
for C8H4Cl4O [M+H]+: 256.9095, found: 256.9095.
2,2,2-trichloro-1-(3-chlorophenyl)ethanone (2c) : 3-
(3-chlorophenyl)propiolic acid (361 mg, 2.0 mmol)
afforded 2,2,2-trichloro-1-(3-chlorophenyl)ethanone
(2c) (361 mg, 1.4 mmol, 70% yield) as a colorless
Scheme 6. Proposed reaction pathway for alkyl-
substituted propiolic acid.
Conclusion
1
liquid; H NMR (500 MHz, CDCl3): δ 8.20 (s, 1H),
In summary, we developed a novel synthetic
8.14 (d, J = 8.0 Hz, 1H), 7.61 (d, J = 8.0 Hz, 1H),
7.44 (t, J = 8.0 Hz, 1H); 13C{1H} NMR (125 MHz,
CDCl3) δ 180.1, 134.7, 134.2, 131.3, 130.7, 129.6,
129.4, 94.9; HRMS (FAB) m/z cacld. for C8H4Cl4O
[M+H]+: 256.9095, found: 256.9095.
method
for
the
preparation
of
2,2,2-
trichloroacetophenones from arylpropiolic acids and
trichloroisocyanuric acid. This reaction was
conducted at room temperature in the absence of
metal catalyst and showed good functional group
tolerance towards halide, cyano, nitro, ketone, and
ester groups. We demonstrated that 2,2,2-
trichloroacetophenones could be easily transformed
into their corresponding esters, amides, and
hydrazides. In addition, trichloromethyl ketones
showed higher reactivities in the acyl substitution
reaction than the esters. Based on the experimental
1-(4-Bromophenyl)-2,2,2-trichloroethanone
(2d)[12] : 3-(4-Bromophenyl)propiolic acid (450 mg,
2.0 mmol) afforded 1-(4-bromophenyl)-2,2,2-
trichloroethanone (2d) (369 mg, 1.22 mmol, 61%
1
yield) as a colorless liquid; H NMR (500 MHz,
CDCl3) δ 8.12 (d, J = 8.9 Hz, 2H), 7.64 (d, J = 9.0 Hz,
2H); 13C{1H} NMR (125 MHz, CDCl3) δ 180.4, 132.9,
131.8, 129.9, 127.8, 95.1; HRMS (FAB) m/z cacld.
for C8H4BrCl3O [M+H]+: 300.8589, found: 300.8589.
1-(3-Bromophenyl)-2,2,2-trichloroethanone (2e) :
3-(3-Bromophenyl)propiolic acid (450 mg, 2.0 mmol)
afforded 1-(3-bromophenyl)-2,2,2-trichloroethanone
(2e) (453 mg, 1.5 mmol, 75% yield) as a colorless
18
results obtained using H2 O, we proposed a
mechanism for the formation of intermediate B, 3-
chloro-2H-oxet-2-one. Although alkyl-substituted
propiolic acids resulted in low or no yields of the
trichloroacetyl compounds, dichlorofuranones were
successfully obtained.
Experimental Section
1
liquid; H NMR (600 MHz, CDCl3) δ 8.35 (s, 1H),
8.19 (d, J = 6.7 Hz, 1H), 7.75 (d, J = 8.0 Hz, 1H),
5
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10.1002/adsc.201701116
Advanced Synthesis & Catalysis
7.38 (t, J = 8.0 Hz, 1H); 13C{1H} NMR (150 MHz, 95.0, 26.9; HRMS (FAB) m/z cacld. for C10H7Cl3O2
CDCl3) δ 180.0, 137.0, 134.1, 130.9, 129.8, 122.5, [M+H]+: 264.9590, found: 264.9589.
94.8; HRMS (FAB) m/z cacld. for C8H4BrCl3O Methyl 4-(2,2,2-trichloroacetyl)benzoate (2k) : 3-
[M+H]+: 300.8589, found: 300.8589.
(4-(Methoxycarbonyl)phenyl)propiolic acid (563 mg,
1-(3-Fluorophenyl)-2,2,2-trichloroethanone (2f) : 2.0 mmol) afforded methyl 4-(2,2,2-
3-(3-Fluorophenyl)propiolic acid (328 mg, 2.0 mmol) trichloroacetyl)benzoate (2k) (405 mg, 1.44 mmol,
1
afforded 1-(3-fluorophenyl)-2,2,2-trichloroethanone 72% yield); H NMR (500 MHz, CDCl3) δ 8.29 (d, J
(2f) (338 mg, 1.36 mmol, 68% yield) as a colorless = 8.9 Hz, 2H), 8.14 (d, J = 8.9 Hz, 2H), 3.97 (s, 3H);
1
liquid; H NMR (600 MHz, CDCl3) δ 8.05-8.07 (m, 13C{1H} NMR (125 MHz, CDCl3) δ 180.9, 165.8,
1H), 7.92-7.95 (m, 1H), 7.47-7.51 (m, 1H), 7.33-7.37 134.7, 132.8, 131.3, 129.4, 95.0, 52.6; HRMS (FAB)
(m, 1H); 13C{1H} NMR (150 MHz, CDCl3) δ 182.7 (d, m/z cacld. for C10H7Cl3O3 [M+H]+: 280.9539, found:
JC-F = 2.5 Hz), 164.6 (d, JC-F = 246.8 Hz), 133.5 (d, JC- 280.9540.
F = 7.0 Hz), 132.7 (d, JC-F = 7.7 Hz), 129.8 (d, JC-F
=
4-(2,2,2-trichloroacetyl)benzaldehyde (2l) : 3-(4-
3.2 Hz), 124.0 (d, JC-F = 21.2 Hz), 120.9 (d, JC-F = 23.9 formylphenyl)propiolic acid (348 mg, 2.0 mmol)
Hz), 97.5; HRMS (FAB) m/z cacld. for C8H4FCl3O afforded 4-(2,2,2-trichloroacetyl)benzaldehyde (2l)
[M+H]+: 240.9390, found: 240.9392.
(211 mg, 0.84 mmol, 42% yield); 1H NMR (500 MHz,
CDCl3) δ 10.13 (s, 1H), 8.39 (d, J = 8.3 Hz, 2H), 8.01
2,2,2-Trichloro-1-(3,5-difluorophenyl)ethanone
(2g) : 3-(3,5-Difluorophenyl)propiolic acid (364.2 mg, (d, J = 8.8 Hz, 2H); 13C{1H} NMR (125 MHz,
2.0
mmol)
afforded
2,2,2-trichloro-1-(3,5- CDCl3) δ 191.2, 180.9, 139.4, 134.0, 131.9, 129.3,
difluorophenyl)ethanone (2g) (373.6 mg, 1.44 mmol, 94.8; HRMS (FAB) m/z cacld. for C9H5Cl3O2
1
72% yield) as a colorless liquid; H NMR (500 MHz, [M+H]+: 250.9433, found: 250.9433.
CDCl3) δ 7.80-7.75 (m, 2H), 7.13-7.08 (m, 1H);
2,2,2-Trichloro-1-(naphthalen-1-yl)ethanone
13C{1H} NMR (125 MHz, CDCl3) δ 179.1 (t, JC-F
=
(2m)1 : 3-(Naphthalen-1-yl)propiolic acid (392.4 mg,
2.8 Hz), 163.4 (d, JC-F = 11.9 Hz), 161.4 (d, JC-F = 11.9 2.0 mmol) afforded 2,2,2-trichloro-1-(naphthalen-1-
Hz), 131.8 (t, JC-F = 8.7 Hz), 114.7 (d, JC-F = 7.1 Hz), yl)ethanone (2m) (279 mg, 1.02 mmol, 51% yield);
114.5 (d, JC-F = 7.1 Hz), 109.8 (t, JC-F = 25.1 Hz), 1H NMR (500 MHz, CDCl3) δ 8.16 (d, J = 7.3 Hz,
94.5; HRMS (FAB) m/z cacld. for C8H3Cl3F2O [M]+: 1H), 8.04 (d, J = 8.3 Hz, 1H), 7.98 (d, J = 7.7 Hz, 1H),
257.9218, found: 257.9221.
7.91 (d, J = 7.4 Hz, 1H), 7.61 (t, J = 6.9 Hz, 1H), 7.57
13
(t, J = 6.8 Hz, 1H), 7.52 (t, J = 7.3 Hz, 1H); C{1H}
2,2,2-Trichloro-1-(4-
(trifluoromethyl)phenyl)ethanone(2h)[11]
:
3-(4- NMR (151 MHz, CDCl3) δ 186.0, 133.5, 132.6, 131.0,
Trifluoromethyl)propiolic acid (428 mg, 2.0 mmol) 129.9, 128.6, 128.0, 127.3, 126.7, 125.1. 123.8, 96.1;
afforded
2,2,2-trichloro-1-(4- HRMS (FAB) m/z cacld. for C12H7Cl3O3 [M+H]+:
(trifluoromethyl)phenyl)ethanone (2h) (396 mg, 1.36 272.9641, found: 272.9642.
mmol, 68% yield) as a colorless liquid; 1H NMR (500
1-([1,1'-Biphenyl]-4-yl)-2,2,2-trichloroethanone
MHz, CDCl3) δ 8.37 (d, J = 8.2 Hz, 2H), 7.77 (d, J = (2n) : 3-([1,1'-Biphenyl]-4-yl)propiolic acid (444 mg,
8.3 Hz, 2H); 13C{1H} NMR (125 MHz, CDCl3) δ 2.0 mmol) afforded 1-([1,1'-biphenyl]-4-yl)-2,2,2-
180.5, 135.3 (q, JC-F = 32.9 Hz), 132.3 (d, JC-F = 1.0 trichloroethanone (2n) (342 mg, 1.14 mmol, 57%
Hz), 131.7, 125.5 (q, JC-F = 3.7 Hz), 123.2 (q, JC-F
=
yield); 1H NMR (500 MHz, CDCl3) δ 8.35 (d, J = 8.9
271.4 Hz), 94.8; HRMS (FAB) m/z cacld. for Hz, 2H), 7.72 (d, J = 8.9 Hz, 2H), 7.64-7.67 (m, 2H),
C8H4Cl3F3O [M+H]+: 290.9358, found: 290.9358.
7.50 (t, J = 7.2 Hz, 2H), 7.44 (t, J = 7.4 Hz, 1H);
4-(2,2,2-Trichloroacetyl)benzonitrile (2i) : 3-(4- 13C{1H} (125 MHz, CDCl3) δ 180.8, 147.0, 139.3,
Cyanophenyl)propiolic acid (342 mg, 2.0 mmol) 132.2, 129.1, 128.7, 127.6, 127.3, 127.0, 95.5; HRMS
afforded 4-(2,2,2-trichloroacetyl)benzonitrile (2i) (FAB) m/z cacld. for C14H9Cl3O [M+H]+: 298.9797,
(408 mg, 1.64 mmol, 82% yield) as a colorless liquid; found: 298.9797.
1H NMR (500 MHz, CDCl3) δ 8.34 (d, J = 8.8 Hz, 2,2,2-Trichloro-1-(thiophen-2-yl)ethanone (2o)[11]
:
2H), 7.80 (d, J = 8.8 Hz, 2H); 13C{1H} NMR (125 3-(Thiophen-2-yl)propiolic acid (304 mg, 2.0 mmol)
MHz, CDCl3) δ 180.2, 132.8, 132.1, 131.7, 117.4, afforded 2,2,2-trichloro-1-(thiophen-2-yl)ethanone
117.4, 94.5; HRMS (FAB) m/z cacld. for C9H4Cl3NO (2o) (211 mg, 0.92 mmol, 46% yield); H NMR (500
[M+H]+: 247.9437, found: 247.9439.
MHz, CDCl3) δ 8.17 (dd, J = 4.0, 1.1 Hz, 1H), 7.80
1
1-(4-Acetylphenyl)-2,2,2-trichloroethanone (2j) : 3- (dd, J = 5.0, 1.1 Hz, 1H), 7.20 (dd, J = 5.0, 4.0 Hz,
(4-Acetylphenyl)propiolic acid (376 mg, 2.0 mmol) 1H); 13C{1H} (125 MHz, CDCl3) δ 175.1, 137.1,
afforded 1-(4-acetylphenyl)-2,2,2-trichloroethanone 136.7, 134.0, 128.4, 95.0; HRMS (FAB) m/z cacld.
1
(2j) (414 mg, 1.56 mmol, 78% yield); H NMR (500 for C6H3Cl3OS [M+H]+: 228.9048, found: 228.9048.
MHz, CDCl3) δ 8.32 (d, J = 8.9 Hz, 2H), 8.04 (d, J = 2,2,2-Trichloro-1-(o-tolyl)ethanone (2p)[11] : 3-(o-
13
8.9 Hz, 2H), 2.66 (s, 3H); C{1H} NMR (125 MHz, Tolyl)propiolic acid (320 mg, 2.0 mmol) afforded
CDCl3) δ 197.0, 180.9, 140.7, 132.8, 131.6, 128.0, 2,2,2-trichloro-1-(o-tolyl)ethanone (2p) (290 mg, 1.22
1
mmol, 61% yield); H NMR (500 MHz, CDCl3) δ
6
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10.1002/adsc.201701116
Advanced Synthesis & Catalysis
7.91 (d, J = 7.9 Hz, 1H), 7.44 (t, J = 7.6 Hz, 1H), 7.33 nitrophenyl)propiolic acid (442 mg, 2.0 mmol)
(d, J = 7.7 Hz, 1H), 7.27 (t, J = 6.6 Hz, 1H), 2.43 (s, afforded
2,2,2-trichloro-1-(4-methoxy-2-
3H); 13C{1H} (125 MHz, CDCl3) δ 186.1, 138.7, nitrophenyl)ethanone (2v) (267 mg, 0.9 mmol, 45%
132.2, 131.7, 131.5, 128.3, 125.1, 96.0, 20.7; HRMS yield); 1H NMR (500 MHz, CDCl3) δ 7.74 (d, J = 2.5
(FAB) m/z cacld. for C9H7Cl3O [M+H]+: 236.9641, Hz, 1H), δ 7.58 (d, J = 8.5 Hz, 1H), 7.30 (dd, J = 8.6,
13
found: 236.9641.
2.6 Hz, 1H), 3.95 (s, 3H); C{1H} NMR (125 MHz,
2,2,2-Trichloro-1-(m-tolyl)ethanone (2q)[11] : 3-(m- CDCl3) δ 186.3, 161.9, 147.4, 129.9, 122.5, 120.5,
Tolyl)propiolic acid (320 mg, 2.0 mmol) afforded 109.3, 94.8, 56.3; HRMS (FAB) m/z cacld. for
2,2,2-trichloro-1-(m-tolyl)ethanone (2q) (285 mg, 1.2 C9H7Cl3NO4 [M+H]+: 297.9441, found: 297.9441.
1
mmol, 60% yield); H NMR (500 MHz, CDCl3) δ
Experimental Procedure 2 (Transformation of
2,2,2-trichloroacetophenone):
8.07 (d, J = 7.9 Hz, 1H), 8.04 (s, 1H), 7.44 (d, J =
7.6 Hz, 1H), 7.38 (t, J = 7.7 Hz, 1H), 2.44 (s, 3H);
13C{1H} (125 MHz, CDCl3) δ 181.5, 138.4, 135.1,
132.0, 129.1, 128.6, 128.2, 95.6, 21.4; HRMS (FAB)
m/z cacld. for C9H7Cl3O [M+H]+: 236.9641, found:
236.9641.
To a 20-mL screw cap vial added 2,2,2-trichloro-1-
phenylethanone (2a) (1.5 mmol, 1.0 equiv), amine or
alcohol (1.5 mmol, 1.0 equiv), Et3N or DBU (1.5
mmol, 1.0 equiv), in THF (5.0 mL). The solution was
stirred at 25-50 °C for 12 h. The resulting mixture
charged to the separating funnel added water,
extracted with EtOAc. The organic layer washed with
water and dried over anhydrous MgSO4. After
removing the EtOAc under vacuum, the crude product
was purified by column chromatography on a silica
gel column with n-hexane/ethyl acetate as eluent to
give the desired product.
2,2,2-Trichloro-1-(p-tolyl)ethanone (2r)[11] : 3-(p-
Tolyl)propiolic acid (320 mg, 2.0 mmol) afforded
2,2,2-trichloro-1-(p-tolyl)ethanone (2r) (299 mg, 1.26
1
mmol, 63% yield); H NMR (500 MHz, CDCl3) δ
8.17 (d, J = 8.4 Hz, 2H), 7.29 (d, J = 8.7, 2H), 2.44 (s,
3H); 13C{1H} NMR (125 MHz, CDCl3) δ 180.9, 145.6,
131.7, 129.1, 126.2, 95.6, 21.8; HRMS (FAB) m/z
cacld. for C9H7Cl3O [M+H]+: 236.9641, found:
236.9641.
Methyl benzoate (3)[14] : Followed by procedure 2
with triethylamine (152 mg, 1.5 mmol, 1.0 equiv) and
methanol (96 mg, 3.0 mmol, 2.0 equiv) afforded
1-(4-(Tert-butyl)phenyl)-2,2,2-trichloroethanone
(2s)[13] : 3-(4-(Tert-butyl)phenyl)propiolic acid (404
mg, 2.0 mmol) afforded 1-(4-(tert-butyl)phenyl)-
2,2,2-trichloroethanone (2s) (358 mg, 1.28 mmol,
1
methyl benzoate (3) (174 mg, 1.28 mmol, 85%); H
NMR (500 MHz, CDCl3) δ 8.04 (d, J = 7.1 Hz, 2H),
7.54 (t, J = 7.4 Hz, 1H), 7.43 (t, J = 8.0 Hz, 2H), 3.91
(s, 3H); 13C{1H} NMR (125 MHz, CDCl3) δ 167.1,
132.9, 130.1, 129.5, 128.3, 52.1; MS (EI) m/z = 136
(M+).
1
64% yield); H NMR (500 MHz, CDCl3) δ 8.22 (d, J
= 9.0 Hz, 2H), 7.51 (d, J = 9.0 Hz, 2H), 1.36 (s, 9H);
13C{1H} NMR (125 MHz, CDCl3) δ 180.8, 158.4,
131.7, 126.1, 125.5, 95.6, 35.3, 31.0; HRMS (FAB)
m/z cacld. for C12H11Cl3O [M+H]+: 279.0110, found:
279.0110.
Benzyl benzoate (4)[15] : Followed by procedure 2
with DBU (228 mg, 1.5 mmol, 1.0 equiv) and benzyl
alcohol (162 mg, 1.5 mmol, 1.0 equiv) afforded
2,2,2-Trichloro-1-(4-nitrophenyl)ethanone (2t)[12]
:
1
benzyl benzoate (4) (257 mg, 1.21 mmol, 81%); H
3-(4-Nitrophenyl)propiolic acid (382 mg, 2.0 mmol)
afforded 2,2,2-trichloro-1-(4-nitrophenyl)ethanone
NMR (500 MHz, CDCl3) δ 8.10-8.13 (m, 2H), 7.56-
7.59 (m, 1H), 7.48-7.49 (m, 1H), 7.40-7.47 (m, 5H),
7.35-7.38 (m, 1H), 5.40 (s, 2H). 13C{1H} NMR (125
MHz, CDCl3) δ 166.4, 136.1, 133.1, 130.2, 129.7,
128.6, 128.4, 128.3, 128.2, 66.7; MS (EI) m/z = 212
(M+).
1
(2t) (354 mg, 1.32 mmol, 66% yield); H NMR (500
MHz, CDCl3) δ 8.41 (d, J = 9.2 Hz, 2H), 8.34 (d, J =
9.1 Hz, 2H); 13C{1H} NMR (125 MHz, CDCl3) δ
180.1, 150.6, 134.5, 132.4, 123.5, 94.5; HRMS (FAB)
m/z cacld. for C8H4Cl3NO3 [M]+: 266.9257, found:
266.9257
Allyl benzoate (5)[16] : Followed by procedure 2 with
DBU (228 mg, 1.5 mmol, 1.0 equiv) and allyl alcohol
(87 mg, 1.5 mmol, 1.0 equiv) afforded allyl benzoate
2,2,2-Trichloro-1-(2-methyl-5-
nitrophenyl)ethanone
nitrophenyl)propiolic acid (410 mg, 2.0 mmol)
afforded 2,2,2-trichloro-1-(2-methyl-5-
(2u)
:
3-(2-methyl-5-
1
(5) (215 mg, 1.33 mmol, 89%); H NMR (500 MHz,
CDCl3) δ 8.06-8.08 (m, 2H), 7.55 (t, J = 7.5 Hz, 1H),
7.43 (t, J = 7.4 Hz, 2H), 6.0-6.07 (m, 1H), 5.42 (dq, J
= 17.2, 1.5 Hz, 1H), 5.29 (dq, J = 10.5, 1.3 Hz, 1H),
4.83 (dt, J = 5.7, 1.5 Hz, 2H); 13C{1H} NMR (125
MHz, CDCl3) δ 166.2, 133.0, 132.2, 130.1, 129.6,
128.4, 118.2, 65.5; MS (EI) m/z = 162 (M+).
nitrophenyl)ethanone (2u) (232 mg, 0.82 mmol, 41%
yield); 1H NMR (500 MHz, CDCl3) δ 8.74 (d, J = 2.4
Hz, 1H), 8.29 (dd, J = 8.5, 2.4 Hz, 1H), 7.51 (d, J =
13
8.5 Hz, 1H), 2.51 (s, 3H); C{1H} NMR (125 MHz,
CDCl3) δ 184.3, 145.9, 145.3, 133.5, 132.4, 125.9,
123.2, 95.1, 20.9; HRMS (FAB) m/z cacld. for
C9H6Cl3NO3 [M+H]+: 281.9492, found: 281.9492.
2,2,2-Trichloro-1-(4-methoxy-2-
Prop-2-yn-1-yl benzoate (6)[16] : Followed by
procedure 2 with DBU (228 mg, 1.5 mmol, 1.0 equiv)
and propargyl alcohol (84 mg, 1.5 mmol, 1.0 equiv)
afforded prop-2-yn-1-yl benzoate (6) (184 mg, 1.15
nitrophenyl)ethanone (2v)
:
3-(4-methoxy-2-
7
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10.1002/adsc.201701116
Advanced Synthesis & Catalysis
mmol, 77%); 1H NMR (500 MHz, CDCl3) δ 8.07 (d, J 1H), 7.74-7.76 (m, 2H), 7.50 (t, J = 7.4 Hz, 1H), 7.41
= 7.2 Hz, 2H), 7.57 (t, J = 7.5 Hz, 1H), 7.44 (t, J = 7.4 (t, J = 7.8 Hz, 2H), 3.9 (br s, 2H); 13C{1H} NMR (125
Hz, 2H), 4.92 (d, J = 2.5 Hz, 2H), 2.52 (t, J = 2.5 Hz, MHz, CDCl3) δ 168.7, 132.6, 131.9, 128.7, 126.9; MS
1H); 13C{1H} NMR (125 MHz, CDCl3) δ 165.8, 133.3, (EI) m/z = 136 (M+).
129.8, 129.4, 128.4, 77.7, 75.0, 52.5; MS (EI) m/z = N'-Phenylbenzohydrazide (13)[22] : Followed by
160 (M+).
procedure 2 with DBU (228 mg, 1.5 mmol, 1.0 equiv)
Isopropyl benzoate (7)[17] : Followed by procedure 2 and phenylhydrazine (162 mg, 1.5 mmol, 1.0 equiv)
with DBU (228 mg, 1.5 mmol, 1.0 equiv) and afforded N'-phenylbenzohydrazide (13) (181 mg, 0.85
1
isopropyl alcohol (180 mg, 3.0 mmol, 2.0 equiv) mmol, 57%); H NMR (500 MHz, CDCl3) δ 8.11 (s
afforded isopropyl benzoate (7) (203 mg, 1.24 mmol, 1H), 7.83 (d, J = 7.5 Hz, 2H), 7.56 (t, J = 7.4 , 1H),
1
83%); H NMR (500 MHz, CDCl3) δ 8.04 (d, J = 7.1 7.46 (t, J = 7.7 , 2H), 7.22-7,26 (m, 2H), 6.92 (t, J =
Hz, 2H), 7.54 (t, J = 7.4 Hz, 1H), 7.43 (t, J = 7.4 Hz, 7.9, 3 H), 6.4 (s, 1H); 13C{1H} NMR (125 MHz,
2H), 5.26 (sept, J = 6.3 Hz, 1H), 1.37 (d, J = 6.3 Hz, CDCl3) δ 167.8, 148.0, 132.3, 129.2, 128.8, 127.1,
6H); 13C{1H} NMR (125 MHz, CDCl3) δ 166.1, 132.7, 121.5, 113.8; MS (EI) m/z = 212 (M+).
130.9, 129.5, 128.2, 68.3, 22.0; MS (EI) m/z = 164
(M+).
Experimental Procedure 3 (Sequential reaction -
transformation of 2,2,2- trichloroacetophenone):
Phenyl(piperidin-1-yl)methanone (8)[18] : Followed
by procedure 2 with DBU (228 mg, 1.5 mmol, 1.0 To a 20-mL screw cap vial added phenyl propiolic
equiv) and piperidine (128 mg, 1.5 mmol, 1.0 equiv) acid (219 mg, 1.5 mmol, 1.0 equiv),
afforded phenyl(piperidin-1-yl)methanone (8) (263 trichloroisocyanuric acid (349 mg, 1.5 mmol, 1.0
mg, 1.39 mmol, 93%); 1H NMR (500 MHz, CDCl3) δ equiv) and water (432 mg, 24.0 mmol, 16.0 equiv) in
7.37 (s, 5H), 3.69 (s, 2H), 3.32 (s, 2H), 1.65 (s, 4H), acetonitrile (4.0 mL). The solution was stirred at
1.49 (s, 2H); 13C{1H} NMR (125 MHz, CDCl3) δ 25 °C for 12 h. Then charged amine or alcohol (3.0
170.3, 136.5, 129.3, 128.4, 126.8, 48.8, 43.1, 26.5, mmol, 2.0 equiv) and Et3N or DBU (3.0 mmol, 2.0
25.6, 24.6; MS (EI) m/z = 189 (M+).
equiv). The solution was further stirred at 25 °C for
Benzamide (9)[19] : Followed by procedure 2 with 12 h. The resulting mixture charged to the separating
aq.ammonia (210 mg, 6.0 mmol, 4.0 equiv) afforded funnel added water, extracted with EtOAc. The
1
benzamide (9) (146 mg, 1.21 mmol, 81%); H NMR organic layer washed with water and dried over
(500 MHz, CDCl3) δ 7.82 (d, J = 7.2 Hz, 2H), 7.52 (t, anhydrous MgSO4. After removing the EtOAc under
J = 7.4 Hz, 1H), 7.44 (t, J = 7.4 Hz, 2H), 6.24 (br s, vacuum, the crude product was purified by column
2H); 13C{1H} NMR (125 MHz, CDCl3) δ 169.7, 133.4, chromatography on a silica gel column with n-
132.0, 128.6, 127.3; MS (EI) m/z = 121 (M+).
hexane/ethyl acetate as eluent to give the desired
N-Benzylbenzamide (10)[18] : Followed by procedure product.
2 with triethylamine (152 mg, 1.5 mmol, 1.0 equiv) Methyl benzoate (3)[14] : Followed by procedure 3
and benzylamine (161 mg, 1.5 mmol, 1.0 equiv) with triethylamine (303 mg, 3.0 mmol, 2.0 equiv) and
afforded N-benzylbenzamide (10) (285 mg, 1.35 methanol (96 mg, 3.0 mmol, 2.0 equiv) afforded
mmol, 90%); 1H NMR (500 MHz, CDCl3) δ 7.79 (d, J methyl benzoate (3) (124 mg, 0.91 mmol, 61%).
= 7.1 Hz, 2H), 7.49 (t, J = 7.4 Hz, 1H), 7.42 (t, J = 7.8 Benzyl benzoate (4)[15] : Followed by procedure 3
Hz, 2H), 7.27-7.36 (m, 5H), 6.54 (s, 1H), 4.64 (d, J = with DBU (457 mg, 3.0 mmol, 2.0 equiv) and benzyl
5.7 Hz, 2H); 13C{1H} NMR (125 MHz, CDCl3) δ alcohol (162 mg, 3.0 mmol, 2.0 equiv) afforded
167.3, 138.1, 134.3, 131.5, 128.7, 128.5, 127.8, 127.5, benzyl benzoate (4) (172 mg, 0.81 mmol, 54%).
126.9, 44.1; MS (EI) m/z = 211 (M+).
Allyl benzoate (5)[16] : Followed by procedure 3 with
N-(2-Hydroxyethyl)benzamide (11)[20] : Followed by DBU (457 mg, 3.0 mmol, 2.0 equiv) and allyl alcohol
procedure 2 with triethylamine (152 mg, 1.5 mmol, (87 mg, 3.0 mmol, 2.0 equiv) afforded allyl benzoate
1.0 equiv) and 2-aminoethanol (92 mg, 1.5 mmol, 1.0 (5) (138 mg, 0.85 mmol, 57%).
equiv) afforded N-(2-hydroxyethyl)benzamide (11) Prop-2-yn-1-yl benzoate (6)[16] : Followed by
1
(154 mg, 0.93 mmol, 62%); H NMR (500 MHz, procedure 3 with DBU (457 mg, 3.0 mmol, 2.0 equiv)
CDCl3) δ 7.70-7.72 (m, 2H), 7.40 (t, J = 7.5 Hz, 1H), and propargyl alcohol (84 mg, 3.0 mmol, 2.0 equiv)
7.34 (s, 1H), 7.29 (t, J = 7.4 Hz, 2H), 4.25 (s, 1H), afforded prop-2-yn-1-yl benzoate (6) (117 mg, 0.73
3.70 (t, J = 4.7 Hz, 2H), 3.49 (m, 2H); 13C{1H} NMR mmol, 49%).
(125 MHz, CDCl3) δ 168.7, 133.9, 131.5, 128.4, Benzamide (9)[19] : Followed by procedure 3 with
126.9, 61.5, 42.7; MS (EI) m/z = 165 (M+).
aq.ammonia (210 mg, 6.0 mmol, 4.0 equiv) afforded
Benzohydrazide (12)[21] : Followed by procedure 2 benzamide (9) (99 mg, 0.82 mmol, 55%).
with DBU (228 mg, 1.5 mmol, 1.0 equiv) and N-Benzylbenzamide (10)[18] : Followed by procedure
hydrazine monohydrate (150 mg, 3.0 mmol, 2.0 3 with triethylamine (303 mg, 3.0 mmol, 2.0 equiv)
equiv) afforded benzohydrazide (12) (122 mg, 0.9 and benzylamine (161 mg, 3.0 mmol, 2.0 equiv)
1
mmol, 60%); H NMR (500 MHz, CDCl3) δ 7.99 (s,
8
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10.1002/adsc.201701116
Advanced Synthesis & Catalysis
afforded N-benzylbenzamide (10) (238 mg, 1.13 CDCl3) δ 169.2, 166.4, 140.8, 130.8, 129.8, 126.7,
mmol, 75%).
52.3, 48.6, 43.1, 26.5, 25.6, 24.5; MS (EI) m/z = 247
N-(2-Hydroxyethyl)benzamide (11)[20] : Followed by (M+).
procedure 3 with triethylamine (303 mg, 3.0 mmol, N-Benzyl-4-(piperidine-1-carbonyl)benzamide (16)
2.0 equiv) and 2-aminoethanol (92 mg, 3.0 mmol, 2.0 from (14) : To a 20-mL screw cap vial added methyl
equiv) afforded N-(2-hydroxyethyl)benzamide (11) 4-(benzylcarbamoyl)benzoate (14) (404 mg, 1.5
(104 mg, 0.63 mmol, 42%).
mmol), piperidine (5.0 ml) and NaOMe (243 mg, 4.5
Benzohydrazide (12)[21] : Followed by procedure 3 mmol, 3.0 equiv). The reaction mixture was warmed
with DBU (457 mg, 3.0 mmol, 2.0 equiv) and to 80°C and maintained for 24 h. Cooled to 25 °C
hydrazine monohydrate (150 mg, 3.0 mmol, 2.0 charged to the separating funnel added water,
equiv) afforded benzohydrazide (12) (90 mg, 0.66 extracted with EtOAc. The organic layer washed with
mmol, 44%).
water and dried over anhydrous MgSO4. After
N'-Phenylbenzohydrazide (13)[22] : Followed by removing EtOAc under vacuum, the crude product
procedure 3 with DBU (457 mg, 3.0 mmol, 2.0 equiv) was purified by column chromatography on a silica
and phenylhydrazine (162 mg, 3.0 mmol, 2.0 equiv) gel column with n-hexane/ethyl acetate as eluent to
afforded N'-phenylbenzohydrazide (13) (132 mg, 0.62 give
N-benzyl-4-(piperidine-1-carbonyl)benzamide
1
mmol, 41%).
(16) (303 mg, 0.94 mmol, 63% yield); H NMR (500
MHz, CDCl3) δ 7.76 (d, J = 8.5 Hz, 2H), 7.28-7.34 (m,
7H), 7.03 (t, J = 5.5 Hz, 1H), 4.62 (d, J = 5.8 Hz, 2H),
Experimental Procedure (Unsymmetrical diamide):
Methyl 4-(benzylcarbamoyl)benzoate (14)[23] : To a 3.65 (br s, 2H), 3.24 (br s, 2H), 1.65 (br s, 4H), 1.47
20-mL screw cap vial added methyl 4-(2,2,2- (br s, 2H). 13C{1H} NMR (125 MHz, CDCl3) δ 169.3,
trichloroacetyl)benzoate (2k) (422 mg, 1.5 mmol), 166.7, 138.6, 138.4, 135.2, 128.4, 127.7, 127.2, 127.1,
benzylamine (161 mg, 1.5 mmol, 1.0 equiv) and DBU 126.4, 48.5, 43.7, 42.9, 26.3, 25.4, 24.3; HRMS (EI)
(228 mg, 1.5 mmol, 1.0 equiv) in toluene (7 mL). m/z cacld. for C20H22N2O2 [M]+: 322.1681, found:
The solution was stirred at 25 °C for 12 h. The 322.1678.
resulting mixture was charged to the separating funnel N-Benzyl-4-(piperidine-1-carbonyl)benzamide (16)
added water, extracted with EtOAc. The organic layer from (15) : To a 20-mL screw cap vial added methyl
washed with water and dried over anhydrous MgSO4. 4-(piperidine-1-carbonyl)benzoate (15) (371 mg, 1.5
After removing EtOAc under vacuum, the crude mmol), benzylamine (5 ml) and NaOMe (162 mg, 3.0
product was purified by column chromatography on a mmol, 2.0 equiv). The reaction mixture was warmed
silica gel column with n-hexane/ethyl acetate as to 60 °C and maintained for 24 h. Then cooled to
eluent to give methyl 4-(benzylcarbamoyl)benzoate 25 °C charged to the separating funnel added water,
1
(14) (355 mg, 1.32 mmol, 88% yield); H NMR (500 extracted with EtOAc. The organic layer washed with
MHz, CDCl3) δ 8.06 (d, J = 8.7 Hz, 2H), 7.83 (d, J = water and dried over anhydrous MgSO4. After
8.6 Hz, 2H), 7.29-7.35 (m, 5H), 6.68 (br s, 1H), 4.63 removing EtOAc under vacuum, the crude product
(d, J = 5.7, 2H), 3.92 (s, 3H). 13C{1H} NMR (125 was purified by column chromatography on a silica
MHz, CDCl3) δ 166.5, 166.3, 138.3, 137.8, 132.7, gel column with n-hexane/ethyl acetate as eluent to
129.8, 128.8, 128.0, 127.8, 127.1, 52.4, 44.3; MS (EI) give
N-benzyl-4-(piperidine-1-carbonyl)benzamide
m/z = 269 (M+).
(16) (300 mg, 0.93 mmol, 62% yield).
Methyl 4-(piperidine-1-carbonyl)benzoate (15)[24]
:
18
To a 20-mL screw cap vial added methyl 4-(2,2,2-
Experimental Procedure 1 (H2 O was used):
trichloroacetyl)benzoate (2k) (422 mg, 1.5 mmol),
Methyl
2,2-dichloro-3-oxo-3-phenylpropanoate
piperidine (127 mg, 1.5 mmol, 1.0 equiv) and (18) : Methyl 3-phenylpropiolate (17) (320 mg, 2.0
potassium tertiary butoxide (168 mg, 1.5 mmol, 1.0 mmol) afforded methyl 2,2-dichloro-3-oxo-3-
equiv) in THF (7 mL). The solution was stirred at phenylpropanoate (18) (272 mg, 1.1 mmol, 55%
25 °C for 12 h. The resulting mixture was charged to yield); NMR (500 MHz, CDCl3) δ 8.03 (d, J = 7.4 Hz,
the separating funnel added water, extracted with 2H), 7.61 (t, J = 7.4 Hz, 1H), 7.47 (t, J = 7.7 Hz, 2H),
EtOAc. The organic layer washed with water and 3.85 (s, 3H). 13C{1H} NMR (125 MHz, CDCl3) δ
dried over anhydrous MgSO4. After removing EtOAc 183.3, 164.6, 134.3, 130.7, 130.1, 128.7, 81.7, 55.0;
16
18
under vacuum, the crude product was purified by HRMS (FAB) m/z cacld. for C10H8Cl2 O2 O
column chromatography on a silica gel column with [M+H]+: 248.9971, found: 248.9974.
n-hexane/ethyl acetate as eluent to give methyl 4-
(piperidine-1-carbonyl)benzoate (15) (304 mg, 1.23
mmol, 82% yield); H NMR (500 MHz, CDCl3) δ
8.05 (d, J = 8.2 Hz, 2H), 7.43 (d, J = 8.2 Hz, 2H),
3.91 (s, 3H), 3.70 (br s, 2H), 3.27 (br s, 2H), 1.67 (br
s, 4H), 1.49 (br s, 2H). 13C{1H} NMR (125 MHz,
Experimental Procedure 4:
1
To a 20-mL screw cap vial added alkyl propiolic acid
(280 mg, 2.0 mmol, 1.0 equiv), trichloroisocyanuric
acid (465 mg, 2.0 mmol, 1.0 equiv) and water (576
9
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10.1002/adsc.201701116
Advanced Synthesis & Catalysis
spectral data were obtained from the Korea Basic
Science Institute, Gwangju branch.
mg, 32.0 mmol, 16.0 equiv) in acetonitrile (5.0 mL).
The solution was stirred at 25 °C for 6 h. The
resulting mixture charged to the separating funnel
added water, extracted with EtOAc. The organic layer
washed with water and dried over anhydrous MgSO4.
After removing the EtOAc under vacuum, the crude
product was purified by column chromatography on a
silica gel column with n-hexane/ethyl acetate as
eluent to give the desired product and dichlorinated
lactone.
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This research was supported by the National
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FULL PAPER
Metal-Free Decarboxylative Trichlorination of
Alkynyl Carboxylic Acids: Synthesis of
Trichloromethylketones.
Adv. Synth. Catal. Year, Volume, Page – Page
Aravindan Jayaraman, Eunjeong Cho, Francis
Mariaraj Irudayanathan, Jimin Kim, Sunwoo Lee*
12
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