An Efficient Protocol for the Preparation of Ynones from Esters and Acid Chlorides

Full text of DOI:10.1002/bkcs.11450

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DOI: 10.1002/bkcs.11450
BULLETIN OF THE
W. K. Shin et al.
KOREAN CHEMICAL SOCIETY
An Efficient Protocol for the Preparation of Ynones from Esters and
Acid Chlorides
Won Kyu Shin, Yu Ri Kim, So Hee Im, Ashok Kumar Jaladi, Shankaraiah Gundeti, and Duk
*
Keun An
Department of Chemistry, Kangwon National University, and Institute for Molecular Science and Fusion
Technology, Chunchon 200-701, Republic of Korea. *E-mail: dkan@kangwon.ac.kr
Received January 29, 2018, Accepted March 12, 2018
Keywords: Ynones, Partial alkynylation, Phenyl acetylide, Carbonyl derivatives, Morpholine
Ynones (α,β-acetylenic ketones) are important structural
motifs that are widely distributed in bioactive natural prod-
ucts.1 The synthesis of ynones is a hot topic of research
owing to their potential utility as versatile building blocks for
several organic molecules and other materials.2 In general,
ynones are prepared by the addition of acetylides to carbonyl
compounds, followed by oxidation,3 metal-catalyzed Sonoga-
shira coupling of terminal alkynes to carbonyl derivatives,
and carbonylative Sonogashira coupling of alkynes to aryl
halides and triflates in presence of carbon monoxide4,5
(Scheme 1). However, the reported methods often involve the
use of toxic and expensive metals and ligands. Recently,
transition-metal-free synthesis of ynones has been attempted
with the aim of making the process less hazardous.6 Despite
such significant efforts, the development of an efficient and
robust method toward the synthesis of this valuable interme-
diate is of continuous interest in organic synthesis.
efficient protocol under ambient temperature, without the
use of any Lewis acid.
Our initial attempts were directed toward the synthesis of
ynones from ester moieties. A model reaction of phenyl
acetylene with ethyl benzoate was selected for optimization
of the reaction parameters such as mole ratios of phenyl
acetylide and morpholine, temperature, and reaction time.
The results are listed in Table 1.
When the reaction was performed at 0 ꢀC with 4.0 equiv of
lithium phenyl acetylide, partial alknylation of ethyl benzoate
occurred to furnish the ynone in reasonable yield (67%),
along with the amide (entry 1). The ynone yield increased
(86%) with an increase in the reaction time (entry 3), and no
starting ester was detected under these conditions. However,
a similar reaction at room temperature led to a decreased rate
of ynone formation (entries 4–5). The change in the mole
ratio of morpholine had no significant effect on the ynone
conversion (entries 6–8). From the experimental data, the
optimized conditions for the partial alkynylation of carbonyl
esters in this system were established as follows: 1.1 equiv
morpholine; 4.0 equiv lithium phenyl acetylide; 0 ꢀC.
As part of our ongoing research, we recently reported the
synthesis of ynones by the nucleophilic addition of lithium
acetylide to acetyl chlorides and esters in presence of
BF3 OEt2 at −78 ꢀC (Scheme 2).7
.
Table 1. Optimization of reaction conditions for synthesis of
ynone from ethyl benzoate.
Based on previous experience and literature reports,8 we
herein report the preparation of ynones by a modified and
i) Nucleophilic
addition
O
R
X
ii) Oxidation
O
O
M: metal, Pd/Cu
X: H, Cl, NMe2
Sonogashira coupling
R
+
M
R1
(M = H, metal)
R
X
R1
Morpholine Lithium phenyl
Entry (equiv) cetylide (equiv) Temp. Time (h)
Yield of
ynonea
CO, M: H; Pd
X: Cl, Br, I, OTf
Carbonylative
Sonogashira coupling
R
X
1
2
3
4
5
6
7
8
a
1.1
4.0
0 ꢀC
1
3
6
3
6
6
6
6
67
79
86
79
64
81
58
44
Scheme 1. Methods for preparation of ynones.
1.1
4.0
rt
O
H
1) n-BuLi, THF, -78 o
C
N
0 ꢀC
R1
2.1
3.1
4.1
4.0
4.0
4.0
R
H
2) esters or acid chlorides
R
O
.
3) BF3 OEt2
Aryl derivatives
only
Yields were determined by gas chromatography.
Scheme 2. Synthesis of ynones from esters and acid chlorides.
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KOREAN CHEMICAL SOCIETY
Table 2. Yields of ynone from representative esters.a
Table 3. Optimization of reaction conditions for synthesis of
ynone from benzoyl chloride.
Entry
1
Ester
R
Product
Yield (%)b
83
Morpholine
(equiv)
Lithium phenyl
acetylide (equiv)
Time
(min)
Yield
(%)a
O
O
Bu
Entry
OEt
Bu
Ph
1
2
3
4
5
a
1.0
1.5
2.0
2.0
4.0
4.0
30
30
10
30
10
64
83
93
94
96
O
O
2
3
Ph
85
77
OEt
O
O
4.0
OEt
Ph
F
F
Yields were determined by gas chromatography.
O
O
O
4
5
73
87
Cl
Cl
OEt
OEt
Ph
Ph
We then optimized the conditions for ynone synthesis from
acyl chlorides by considering the difference between the reac-
tivity of acyl chlorides and esters toward nucleophilic acetylide
addition (Table 3). Accordingly, a model reaction involving the
treatment of benzoyl chloride with phenyl acetylide was carried
out. A moderate yield (64%) of the ynone was obtained with
2.0 equiv of lithium phenyl acetylide within 30 min (entry 1).
A change in the mole ratio of phenyl acetylide from 2.0 to 4.0
equiv increased the yield of the desired ynone to 83% (entry 2).
A slight increase in the morpholine mole ratio led to a high
yield of the ynone (93%) in a short time (entry 3). However,
with a further increase in the morpholine ratio, there was no
notable difference in the product yield (entries 4–5).
O
Cl
Cl
O
O
6
7
73
76
OEt
Ph
Br
Br
O
O
OEt
Ph
Br
Br
O
O
8
9
81
78
OEt
Ph
O
O
It was demonstrated that because of the equilibrium
between lithium acetylide and morpholine amide (generated
in situ), a slight excess of the reagent is necessary to pro-
mote this transformation with good conversion.3c
OEt
OEt
Ph
MeO
MeO
O
O
10
11
12
a
39
48
82
Ph
O
Next, various acid chlorides with aromatic, heteroaro-
matic, and aliphatic functionalities were subjected to the
optimized reaction conditions to furnish the corresponding
ynones (Table 4). Most of the derivatives having electron-
rich and electron-deficient substituents smoothly underwent
this transformation and afforded ynones in good to excel-
lent yields (72–96%; entries 1–10). A heteroaromatic acid
chloride, furan-2-carbonyl chloride, also furnished the cor-
responding ynone in 82% yield (entry 11). Aliphatic acid
chlorides furnished the corresponding ynones in the pres-
ence of 3.0 equiv morpholine and 8.0 equiv phenyl acety-
lide with respect to the starting compound (entries 12–13).
A plausible mechanism for the ynone synthesis from acid
chloride is presented in Scheme 3. Lithium phenyl acetylide
generated by the reaction with n-BuLi first reacts with morpho-
line to form lithium morpholide. The reaction of this lithium
morpholide with benzoyl chloride and subsequent elimination
of LiCl would lead to the formation of a stable morpholine
amide.7b The amide reacts with lithium phenyl acetylide (pre-
sent in the reaction mixture) to afford a propargylic alcohol
complex by coordination with lithium through a stable seven-
membered transition state. Subsequent quenching of this inter-
mediate would furnish the desired ynone (Scheme 3).
O
OEt
Ph
O
O
OEt
Ph
Morpholine : Phenylacetylene : Ester = 1.1:4.0:1.0.
Isolated yields after silica column chromatography.
b
With the optimized reaction conditions for the ester function-
ality in hand, we explored the efficiency of this condition by
examining the various carboxylic esters. As shown in Table 2,
various esters with electron-withdrawing and electron-donating
substituents smoothly underwent conversion to the correspond-
ing ynones in good yields (73–87%; entries 1–9). However, ali-
phatic esters afforded lower yields (39–48%) of ynones (entries
10–11) under the reaction conditions. Generally, carboxylic
esters participate to a lesser extent in the partial alkynylation due
to possible over-addition reactions. Furthermore, ethyl cinna-
mate, an α,β-unsaturated ester, gave 82% yield of cinnamalde-
hyde (entry 12). Hence, acyl chlorides are often utilized for this
transformation considering the change in reactivity.
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Table 4. Yields of ynones from representative acid chlorides.a
H
N
Ph
Li
H
N
O
O
n-BuLi
O
R
Cl
Ph
H
Ph
Li
Li
N
Ph
H
O
O
Isolated
yield (%)
O
Li
Entry
1
R
Acid chloride
Product
Li
N
O
O
O
R
N
NH4Cl (aq)
R
O
O
O
Bu
91
N
R
R
Cl
- LiCl
Ph
O
1
(
)
Cl
Ph
Ph
Li
Bu
Ph
Scheme 3. Proposed mechanism for ynone synthesis from acid
O
O
2
3
Ph
86
84
chloride.
Cl
method affords ynones in good to excellent yields starting
from various esters and acid chlorides. The in situ genera-
tion of morpholine amide, non-requirement of Lewis acids,
and ambient reaction conditions make this system suitable
for ynone synthesis from commercially available reagents.
O
O
Cl
Ph
F
F
O
O
4
5
88
96
Cl
Cl
Cl
Ph
Ph
O
O
Experimental
Cl
Cl
Cl
Br
General. All glassware used was dried thoroughly in an
oven, assembled hot, and cooled under a stream of dry nitrogen
prior to use. All reactions and manipulations of air- and
moisture-sensitive materials were carried out using standard
techniques for the handling of air-sensitive materials. All chemi-
cals were commercial products of the highest purity, which
were further purified before use by using standard methods.
THF was dried over sodiumbenzophenone and distilled. n-
butyllithium, esters, aldehydes, and morpholine were purchased
from Aldrich Chemical Company (St. Louis, MO, USA), Alfa
Aesar (Milwaukee, WI, USA), and Tokyo Chemical Industry
O
O
O
6
7
Ph
91
95
Br
Cl
Ph
Ph
O
Cl
Br
Br
O
O
8
96
86
72
Cl
Ph
O
O
9
1
Cl
Company (TCI, Tokyo, Japan). H NMR spectra were mea-
Ph
sured at 300 or 400 MHz with CDCl3 as a solvent at ambient
temperature unless otherwise indicated and the chemical shifts
were recorded in parts per million downfield from tetramethyl-
silane (0 ppm) or based on residual CHCl3 (7.26 ppm) as an
internal standard. 13C NMR spectra were recorded at 75 or
100 MHz with CDCl3 as a solvent and referenced to the central
line of the solvent (77.0 ppm). The coupling constants (J) are
reported in Hertz. Analytical thin-layer chromatography (TLC)
was performed on glass precoated with silica gel (silica gel
60 F254, Merck, Darmstadt, Germany). Column chromatogra-
phy was carried out using 70–230 mesh silica gel (Merck) at
normal pressure. Gas chromatography analyses were performed
on a Younglin Acme 6000 M (Younglin, Anyang, Gyeonggi-
do, South Korea) and 6100GC FID (Younglin, Anyang,
Gyeonggi-do, South Korea) chromatography, using an HP-5
(Agilent Technologies, Santa clara, CA, USA) capillary column
(30 m). All GC yields were determined with the use of naph-
thalene as internal standard and authentic mixture.
O
O
10
Cl
Ph
MeO
MeO
O
O
11
12b
13b
a
82
59 (86)c
57
O
O
Cl
Ph
O
O
Cl
Ph
O
O
Cl
Ph
Acetylide anion : n-BuLi : morpholine : acid
chloride = 4.1:4.0:1.5:1.0.
b
c
Acetylide anion : n-BuLi : morpholine : acid
chloride = 8.1:8.0:3.0:1.0.
Yield was determined by gas chromatography.
Partial Alkynylation of Esters to Corresponding
Ynones. The following experimental procedure for the par-
tial alkynylation of ethyl benzoate to 1,3-diphenylprop-2-yn-1-
one is representative. A dry and argon-flushed flask, equipped
with a magnetic stirring bar and a septum, was charged with
In summary, we have identified a simple and efficient
synthesis route to ynones via the partial alkynylation of car-
bonyl derivatives such as esters and acid chlorides in the
presence of lithium phenyl acetylide and morpholine. This
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KOREAN CHEMICAL SOCIETY
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was stirred for 10 min again. The reaction was stopped by aque-
ous NH4Cl (aq) (10 mL) and extracted with diethyl ether (2 ×
10 mL). The combined organic layers were dried over MgSO4.
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one. All products in Table 4 were confirmed by comparison
with NMR data reported of authentic sample.7
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