Stereoselective, Cascade Synthesis of trans-Enynones through Coupling-Isomerization Reaction

Article abstract of DOI:10.1021/acs.joc.5b01780

A mild, cascade methodology based on the modified Cadiot-Chodkiewicz reaction was developed for the stereoselective synthesis of trans-enynones. By this methodology, structurally divergent trans-enynones, which are embedded with sensitive functional groups, were synthesized. Control experiments suggested that the CuCl alone does not have a role in the isomerization step, whereas the CuCl-piperidine complex (formed during the cross coupling) may have a rate enhancing effect. Furthermore, additional sets of control experiments favor the involvement of unimolecular [1,2]-H shift rather than a homobimolecular proton abstraction during the isomerization step.

Full text of DOI:10.1021/acs.joc.5b01780

Article
pubs.acs.org/joc
Stereoselective, Cascade Synthesis of trans-Enynones through
Coupling-Isomerization Reaction
Bhavani Shankar Chinta and Beeraiah Baire*
Department of Chemistry, Indian Institute of Technology Madras, Chennai 600036, Tamilnadu India
S
* Supporting Information
ABSTRACT: A mild, cascade methodology based on the modified Cadiot−Chodkiewicz reaction was developed for the
stereoselective synthesis of trans-enynones. By this methodology, structurally divergent trans-enynones, which are embedded with
sensitive functional groups, were synthesized. Control experiments suggested that the CuCl alone does not have a role in the
isomerization step, whereas the CuCl−piperidine complex (formed during the cross coupling) may have a rate enhancing effect.
Furthermore, additional sets of control experiments favor the involvement of unimolecular [1,2]-H shift rather than a
homobimolecular proton abstraction during the isomerization step.
Scheme 1. Classical Cadiot−Chodkiewicz Reaction and Our
Designed Coupling-Isomerization Cascade
INTRODUCTION
■
From practical considerations and green chemistry point of
view cascade (tandem) reactions are ideal techniques in organic
synthesis for building complex structures.1 In most cases, these
approaches provide mild reaction conditions there by imparting
high tolerance for many functional groups. trans-Enynones are
very useful building blocks in organic synthesis,2a−c e.g.,
synthesis of furans,3a total synthesis of natural products,3b etc.
However, very few methods2a,b,4 have been developed for the
generation of these structural units, with limited substrate scope
and functional group tolerance because of the harsh reaction
conditions. Therefore, developments of mild, efficient, and
stereoselective protocols are very much in need for the
synthesis of trans-enynones.
Herein we report a highly stereoselective, and mild, coupling-
isomerization cascade methodology for the synthesis of trans-
enynones, that is tolerant to many sensitive functional groups.
The classical Cadiot−Chodkiewicz reaction5 is the CuCl-
catalyzed cross coupling between two terminal alkynes, one
with terminal hydrogen (alkyne-H) and the other with a
terminal bromide (alkyne-Br) to yield an unsymmetrical diyne
unit (Scheme 1A). In principle any amine (primary, secondary,
or tertiary and cyclic or acyclic) base should be able to promote
this cross coupling reaction.6 With this background, we
envisioned that in the presence of a suitable amine as base in
combination with CuCl in Cadiot−Chodkiewicz reaction of a
terminal alkyne (alkyne-H) and an alkynyl bromide (alkyne-
Br), where one of the alkyne is also a primary or secondary
propargylic alcohol (Scheme 1B), it should be possible to
promote a coupling-isomerization cascade to generate
thermodynamically preferred trans-enynones with high stereo-
selectivity. To the best of our knowledge, no isomerization has
been reported in the classical Cadiot−Chodkiewicz reaction.7
RESULTS AND DISCUSSION
To test our hypothesis, initially we have examined various
amines, such as, n-butyl amine (primary), diisopropyl amine
■
Received: August 2, 2015
Published: September 23, 2015
© 2015 American Chemical Society
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Table 1. Screening of Various Amine Bases for Coupling-Isomerization Cascade to trans-Enynones
yield (%)
entry
Method A
X
Y
base/solvent
temperature
time (h)
2
2′
1
H
H
H
H
H
H
Br
Br
Br
Br
Br
Br
Et3N
0 °C→RT
0 °C→RT
0 °C
0 °C→RT
0 °C→RT
0 °C→RT
22
16
3
−
−
66
39
5
46
43
−
−
57
2
pyridine
piperidine
pyrrolidine
iPr2NH
3
4
6
5
22
6
6
n-BuNH2
5
29
Method B
7
Br
Br
Br
Br
Br
Br
H
H
H
H
H
H
Et3N
0 °C→RT
0 °C→RT
0 °C
0 °C
0 °C→RT
0 °C
26
16
3
−
−
78
32
−
54
77
−
−
64
8
pyridine
piperidine
pyrrolidine
iPr2NH
9
10
11
12
3
26
3
n-BuNH2
24
12
(acyclic-secondary), piperidine (cyclic-secondary), pyrrolidine
(cyclic-secondary), triethyl amine (acyclic-tertiary), and pyr-
idine (cyclic-tertiary) to identify a suitable base that can
promote cross coupling as well as isomerization. The results of
this study are presented in Table 1. Two complementary
methods have been developed. In method A, alcohol is on the
alkyne-H partner 1 (entries 1−6, Table 1), and in method B
(entries 7−12, Table 1), alcohol is on the alkyne-Br partner 1′.
Phenylacetylene and its bromide were used as alkyne-H in
method B and as alkyne-Br in method A, respectively. Initially,
method A was investigated. When Et3N (entry 1) was used,
only the cross coupling product 2′ was obtained after stirring
for 22 h at room temperature, and not even a trace amount of
enynone 2 was detected. Similarly, use of pyridine also resulted
in the formation of only the coupled product 2′ (entry 2). On
the other hand, when piperidine and pyrrolidine were
employed, trans-enynone 2 was isolated as the sole product
(entries 3 and 4, Table 1) after 3 and 6 h, respectively. The
structures of enynone 2 and diynol 2′ were confirmed by the
spectroscopic data (1H and 13C NMR, IR, and HRMS).
With the optimized reaction conditions in hand, we next
studied the scope for various aryl propargylic alcohols 3a−l and
3a′−l′ Table 2. Both methods A and B have been employed for
majority of the substrates. All the para-substituted aryl
propargyl alcohols 3a−d and 3a′−d′ underwent smooth
coupling-isomerization cascade with excellent (∼100%) stereo-
Table 2. Scope of Various Aryl Propargylic Alcohols in the
Coupling-Isomerization Cascade to trans-Enynones
i
Surprisingly, Pr2NH gave very low conversion to enynone 2
(∼5%) after 22 h, and the diynol 2′ was isolated in 57% yield
(entry 5). In contrast, nBuNH2 was not at all effective either for
coupling or for isomerization, as it gave only 5% of enynone 2
and 29% of 2′ after 6 h (entry 6). Hence in method A
piperidine was found to be best amine for the proposed cascade
to generate trans-enynone quickly, selectively, and efficiently.
In method B (entries 7−12, Table 1), the alcohol functional
group was kept on the alkyne-Br, and the reactions were carried
out using the same amines as in method A. In this method also
piperidine (entry 9) was the best amine to afford the trans-
enynone 2 selectively and efficiently. On the other hand, Et3N,
i
pyridine, and Pr2NH (entries 7, 8, and 11) were inert to give
any trace of enynone 2, even after long stirring at RT. In the
case of n-BuNH2 (entry 12), the formation of enynone 2 was
observed but in poor yield (24%). Overall, in both methods A
and B, piperidine8 stands out to be the amine of choice for
selective and efficient trans-enyone generation.
a
b
c
Time = 8 h. Time = 16 h. Only alcohol 12′ was isolated in 77 and
95% yields in methods A and B, respectively.
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selectivity to afford the corresponding trans-enynones 4−7
(entries 1−4, Table 2) in good to excellent yields. Only in case
of p-OMe (3d and 3d′) the reaction time was longer (8 h), but
there was no compromise either on the selectivity or the yield.
All the ortho-substituted propargyl alcohols 3e−j and 3e′−j′
including halogens, methyl, and NHBoc substituted derivatives
gave the corresponding trans-enynones 8−13 in good yields. In
case of the o-Me derivative, isomerization was slow and took
about 16 h. With o-OMe (entry 9, Table 2) only the coupled
alcohol 12′ was isolated, and enynone 12 was not formed even
after prolonged reaction times.10
Scheme 3. Scope of Various Alkyne-H Partners in Method B
for Diverse trans-Enynones
In addition to the spectroscopic characterization, we have
also confirmed the structure of trans-enynone 13 by the single
crystal X-ray diffraction analysis9 of trans-enynone 13′, and the
ORTEP diagram is depicted in Figure 2 of the Supporting
Information (SI).
The m-Br derivatives 3k and 3k′ generated the correspond-
ing enynone 14 in excellent yield, whereas with m-NO2 alcohol
3l (entry 12, Table 2) the cascade process was relatively slow (8
h) and less efficient (36%) to give 15. Overall, para-substituted
derivatives were relatively faster and higher in efficiency than
corresponding ortho-substituted counterparts. From Table 2 it
is clear that both methods A and B are equally good in terms of
efficiency and selectivity toward the formation of trans-enynone
derivatives.
functional groups like tertiary alcohols, OTBS-ethers, esters,
and olefins were found to be stable under the reaction
conditions. Several substituted aryl acetylenes 23a−e were
used, to generate structurally diverse trans-enynones 24−28. In
all cases yields were moderate and reactions were faster (3 h)
except for 27, which required 9 h.
Various aliphatic alkynes 23f−k have also been employed, to
prepare corresponding trans-enynones 29−33 in good yields. In
presence of tertiary alcohols 23f−g, the cascade was smooth
and generated the enynones 29 and 30. Whereas with
secondary alcohol 23l, the first step, i.e., cross coupling was
clean to give the coupled diynol 35, but it did not undergo
isomerization even after stirring the reaction mixture for
prolonged period. Surprisingly, the corresponding TBS-ether
23k underwent smooth coupling-isomerization cascade to yield
the trans-enynone 34 in good yield.
To extend the utility of this methodology, we have studied
(Scheme 2) this cascade process with various heteroaromatics
Scheme 2. Coupling-Isomerization Cascade with Hetero-
Aromatic and Cyclic Propargylic Alcohols in Method A
To show the preparatory value of this cascade process, we
have carried out the reaction on 1 mmol scale for substrates 1,
1′, 3b, and 3b′, in both methods A and B (Table 3). The
reactions were very clean and afforded the corresponding trans-
enynones 2 and 5 without much drop in efficiency.
After preparing structurally diverse trans-enynones, we have
performed few control experiments (Scheme 4) in order to
understand the role of CuCl and piperidine in the isomerization
step. In first case (condition A, Scheme 4B), the diynol 36 was
treated with CuCl (0.1 equiv) and pipyridine (0.1 M), and in
second case (condition B, Scheme 4), diynol 36 was treated
with pipyridine (0.1 M) alone. In both cases, the isomerization
was smooth to yield the enynone 11. Quite, surprisingly it was
observed (by TLC monitoring) that the reaction time was
similar, i.e., ∼48 h at RT for both conditions. In third case,
when 36 was treated with CuCl alone in 1,2-dichlorobenzene,
no isomerization was observed even after 48 h. These
experiments clearly suggest that CuCl alone does not play a
role in the isomerization step. But interestingly, the overall two
stage cascade process, i.e., coupling-isomerization took about 16
h to give the enynone 11 starting from 3h (or) 3h′ (Scheme
4A). These observations lead us to propose that during the
coupling reaction, a complex formed between CuCl and
piperidine might have helped in enhancing the rate of the
isomerization as compared to conditions A and B (Scheme 4B),
where it is not possible to form the same complex because of
absence of coupling reaction. At this stage we do not have any
direct experimental evidence for the presence and structure of
the complex and its interaction with coupled products, e.g., 36.
a
b
In method B 56% of 18 was isolated. Time = 8 h.
like 2-furanyl, 2-thienyl, 3-pyridinyl, and 1-naphthyl, and also 2-
bromo-1-cyclopentenyl propargylic alcohols 16a−e as alkyne-H
partners in method A, using phenylacetylene bromide as the
alkyne-Br partner. All these substrates smoothly underwent the
coupling-isomerization cascade and gave the corresponding
trans-enynones 17−20 in moderate yields. Interestingly, in case
of 2-bromo-1-cyclopentenyl propargylic alcohol 16e, we have
directly isolated the 1,3-diketone 21, instead of bromo-enynone
22. We propose Michael addition of water to 22 followed by
elimination of bromide to yield 21. The structure of the 21 was
confirmed by both spectroscopic data as well as single crystal X-
ray difraction analysis,11 and its ORTEP diagram is presented in
Figure 3 of the SI.
We have also studied the scope of using various alkyne-H
partners 23a−k in method B (Scheme 3), keeping phenyl
propargyl alcohol as the alkyne-Br partner. Various sensitive
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Table 3. Scale up Experiments
entry
alcohol
X
Z
Y
product
yield (%)
1
2
3
4
1
H
H
Br
H
2
2
5
5
62
68
79
67
1′
3b
Br
H
H
Cl
Cl′
Br
H
3b′
Br
abstraction. Upon protonation, 39′ gives an allenol-alkyne 40,
which undergoes a stereoselective enol-ketone tautomerization
to give the trans-enynone 41.12
Scheme 4. Control Experiments To Understand the Role of
CuCl on Isomerization Step
To get some insights into the proposed mechanism, in
particular to identify whether the isomerization step involves
unimolecular [1,2]H shift or homobimolecular proton
abstraction, we have designed and performed few control
experiments using diynol 2′ as the substrate. From Table 4, it is
Table 4. Control Experiments to Identify the Unimolecular
[1,2]H Shift vs Homobimolecular Proton abstraction
10 min
40 min
80 min
entry
piperidine (M)
2′
2
2′
2
2′
2
a
1
2
3
0.26
0.13
0.04
1
1
1
0.5
0.8
6.5
1
1
1
2.5
4.0
35
1
100
50
1
0
100
a
Based on our understanding of this cascade transformation
so far, we proposed a possible mechanism in Scheme 5. In the
first step, two alkyne units undergo Cadiot−Chodkiewicz cross
coupling to give the diynol 37. In the next step, 37 is
transformed to the alkoxide ion 38 by piperidine. 38 is
converted to 39 which is a resonance strucutre of allenyl anion
39′, either by [1,2] proton shift or by homobimolecular proton
Time = 130 min.
evident that, as the concentration of the alcohol 2′ decreases
(reaction dilution increases, entries 1−3), the rate of isomer-
ization to 2 increases at any time point of the reaction
(monitored by 1H NMR spectroscopy, see Figure 1, Supporting
Scheme 5. Proposed Mechanism For the trans-Enynone Formation
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atmosphere, were added N-bromosuccinimide (NBS, 1.1 equiv) and
AgNO3 (0.1 equiv), and the reaction mixture was stirred for 2 h at RT.
Reaction mixture was diluted with water (15 mL) and extracted with
dichloromethane (CH2Cl2, 3 × 10 mL). The combined organic layer
was washed with brine (15 mL) and dried over MgSO4. Evaporation of
the solvent and purification of the crude mixture by flash column
chromatography (9:1, hexane:EtOAc or hexanes for alkynyl bromides)
gave the corresponding bromopropargylic alcohol or alkynyl bromide
in 85−97% yields.
Information). It implies that the isomerization may be a
unimolecular process dependent on alcohol concentration. On
the other hand, as the concentration of the base piperidine
increases (entries 1−3), the rate of isomerization is also
increasing. These observations clearly support that there is an
initial formation of an alkoxide 38 from alcohol 37 (this step is
dependent on piperidine concentration). Next the alkoxide 38
may undergo a unimolecular process, i.e., 1,2-H shift via 38a
rather than a homobimolecular proton abstraction via 38b, to
generate a propargylic carbanion 39 then to form an allenic
carbanion 39′. If the alkoxide 38 followed the bimolecular
proton abstraction process, rate of the isomerization reaction
would drop as the dilution of the reaction increases, which is
contrary to the observed results in Table 4. Hence we propose
that the unimolecular procees might have a lower energy path.
3-Bromo-1-(4-bromophenyl)prop-2-yn-1-ol (3c′). Alkyne14 (250
mg 1.66 mmol), N-bromosuccinimide (325 mg, 1.83 mmol), AgNO3
(28 mg, 0.17 mmol), and acetone (7 mL) were stirred for 2 h at RT.
Purification by flash chromatography (9:1; hexane:EtOAc) gave
bromide 3c′ (290 mg, 1.27 mmol, 77%) as light yellow oil. 1H
NMR (400 MHz, CDCl3): δ = 7.48 (2 H, d, J = 8.4 Hz), 7.35 (2 H, d,
J = 8.3 Hz), 5.38 (1 H, d, J = 4.8 Hz), 3.5 (1 H, br s) ppm.
13C{1H}NMR (100 MHz, CDCl3): δ = 138.9, 131.8, 128.3, 122.6,
79.4, 64.7, and 47.8 ppm. IR (neat): 3352, 2923, 2922, 2853, 2211,
1593, 1409, 1054, 796, 622, and 548 cm−1. GCMS: 280 and 278 (M),
209 and 211 (M-Br), 185 (M-Br and -C2H), 157 (M-OH, -C2H, and
-Br). HRESI-MS: [C9H6Br2ONa]+ = [M + Na]+ requires 310.8678;
found 310.8669. TLC: Rf = 0.5 (4:1, Hex/EtOAc).
CONCLUSIONS
■
In conclusion, stereoselective and cascade synthesis of trans-
enynones has been achieved via “CuCl-piperidine” promoted,
coupling-isomerization reaction. This mild methodology gave
access to structurally diverse trans-enynones, which are
embedded with various sensitive functional groups and has
shown preparatory value as well. Both complementary methods
A and B can be operative for all substrates. This is the first time
trans-enynones are synthesized in a Cadiot−Chodkiewicz
reaction. Control experiments suggested that CuCl alone
does not have any effect on the isomerization step, but there
is a rate enhancing effect of “CuCl-piperidine complex”
(formed during the coupling reaction). We have also performed
another set of control experiments to differentiate between two
possible mechanisms for isomerization step. These exper-
imients favor the involvement of unimolecular [1.2]-H shift
rather than a homobimolecular proton abstraction for the
formation of propargylic carbanion from alkoxide during the
isomerization step.
3-Bromo-1-(2-bromophenyl)prop-2-yn-1-ol (3f′). Alkyne15 (300
mg 1.42 mmol), NBS (278 mg, 1.57 mmol), AgNO3 (24 mg, 0.142
mmol), and acetone (8 mL) were stirred for 2 h at RT. Purification by
flash chromatography (9:1; hexane:EtOAc) gave the corresponding
1
bromide 3f′ (400 mg, 1.38 mmol, 98%) as light yellow oil. H NMR
(400 MHz, CDCl3): δ = 7.70 (1 H, d, J = 7.6 Hz), 7.55 (1 H, d, J = 8.0
Hz), 7.35 (1 H, t, J = 7.4 Hz), 7.15 (1 H, t, J = 7.4 Hz), 5.78 (1 H, s),
3.03 (1 H, br s) ppm. 13C{1H}NMR (100 MHz, CDCl3): δ = 138.9,
131.8, 128.3, 122.6, 79.4, 64.7, and 47.8 ppm. IR (neat): 3355, 3070,
2922, 2854, 2211, 1600, 1508, 1416, 1227, 1160, 1051, 985, 842, and
556 cm−1. GCMS: 289.9 (M), 209 and 211 (M-Br), 131 (M-Br2), 106
(M-Br2, M-C2H). HRESI-MS: [C9H7Br2O]+ = [M + H]+ requires
288.8858; found 288.8867. TLC: Rf = 0.5 (4:1, Hex/EtOAc).
3-Bromo-1-(3-bromophenyl)prop-2-yn-1-ol (3k′). Alkyne16 (240
mg 1.14 mmol), NBS (221 mg, 1.25 mmol), AgNO3 (19.3 mg, 0.114
mmol), and acetone (8 mL) were stirred for 2 h at RT. Purification by
flash chromatography (9:1; hexane:EtOAc) gave the bromide 3k′ (260
mg, 0.09 mmol, 79%) as light yellow oil. 1H NMR (400 MHz,
CDCl3): δ = 7.63 (1 H, s), 7.40 (2 H, m), 7.22 (1 H, t, J = 7.8 Hz),
5.40 (1 H, d, J = 4.2 Hz), 2.62 (1 H, br s) ppm. 13C{1H}NMR (100
MHz, CDCl3): δ 142.1, 131.7, 130.3, 129.7, 125.2, 122.8, 79.3, 64.7,
and 48.2 ppm. IR (neat): 3400, 2921, 2847, 2363, 2211, 1638, 1576,
1470, 1425, 1252, 1186, 1054, 992, 784, 704, and 603 cm−1. GCMS:
289.9 (M), 209 and 211 (M-Br), 183 and 185 (M-Br, M-C2H), 155
and 157 (M-OH, M-C2H and M-Br). HRESI-MS: [C9H6Br2ONa]+ =
[M + Na]+ requires 310.8678; found 310.8684. TLC: Rf = 0.5 (4:1;
Hex/EtOAc).
EXPERIMENTAL SECTION
■
General Methods. Reactions were monitored by thin-layer
chromatography (TLC) carried out on Merck silica plates using UV-
light and anisaldehyde or potassium permanganate stains for
visualization. Column chromatography was performed on silica gel
(60−120 mesh) using hexanes and ethyl acetate as eluents. NMR data
were recorded on 400 and 500 MHz spectrometers. 13C and 1H
chemical shifts in NMR spectra were referenced relative to signals of
CDCl3 (δ 7.263 ppm for 1H and 77.16 ppm for 13C). Chemical shifts δ
and coupling constants J are given in ppm (parts per million) and Hz
(hertz), respectively. HRMS were recorded by electron spray
ionization (ESI) method on a Q-TOF Micro with lock spray source.
Known compounds data have been compared with the reported data,
and references were given appropriately. Characterization data for new
compounds are given below. 1H and 13C{1H}NMR spectra for all new
compounds are given in the SI.
3-Bromo-1-(4-chlorophenyl)prop-2-yn-1-ol (3b′). Alkyne17 (240
mg 1.45 mmol), NBS (282 mg, 1.59 mmol), AgNO3 (24.5 mg, 0.144
mmol), and acetone (8 mL) were stirred at RT for 2 h. Purification by
flash chromatography (6:1; hexane:EtOAc) gave the bromide 3b′ (320
1
mg, 1.31 mmol, 91%) as a colorless viscous oil. H NMR (400 MHz,
CDCl3): δ = 7.40 (2 H, d, J = 8.4 Hz), 7.30 (2 H, d, J = 8.6 Hz), 5.39
(1 H, s), 2.77 (1 H, br s) ppm. 13C{1H}NMR (100 MHz, CDCl3): δ =
138.4, 134.5, 128.9, 128.0, 79.5, 64.7, and 47.9 ppm. IR (neat): 3373,
2922, 2855, 2211, 1590, 1485, 1409, 1263, 1088, 1052, 984, 837, 802,
724, and 551 cm−1. HRESI-MS: [C9H6BrClO]+ = [M + H]+ requires
244.9369; found 244.9368. TLC: Rf = 0.5 (4:1; Hex/EtOAc).
General Procedure for the Synthesis of Propargyl Alcohols
with Terminal Hydrogen. To an ice-cold solution of aldehyde in
anhydrous THF (5 mL/0.2 mmol) under nitrogen atmosphere was
added ethynylmagnesium bromide (1.5 eq., 0.5 M in THF), and the
reaction mixture was stirred for 2−4 h (monitored by TLC analysis) 0
°C. Reaction mixture was diluted with saturated aq. NH4Cl (10 mL)
and extracted with ethyl acetate (3 × 10 mL). The combined organic
layer was washed with brine (10 mL) and dried over MgSO4.
Evaporation of the solvent and purification of the crude mixture by
flash column chromatography (9:1, hexane: EtOAc) gave the
corresponding propargylic alcohols in 80−95% yields.
3-Bromo-1-(2-iodophenyl)prop-2-yn-1-ol (3g′). Alkyne18 (200 mg
0.78 mmol), NBS (151 mg, 0.85 mmol), AgNO3 (13 mg, 0.08 mmol),
and acetone (7 mL) were stirred for 2 h at RT. Purification by flash
chromatography (9:1; hexane:EtOAc) gave the bromide 3g′ (250 mg,
0.75 mmol, 96%) as yellow oil. 1H NMR (400 MHz, CDCl3): δ = 7.76
(1 H, dd, J = 0.8 and 7.9 Hz), 7.63 (1 H, dd, J = 1.5 and 7.8 Hz), 7.32
(1 H, td, J = 0.7 and 7.7 Hz), 6.95 (1 H, td, J = 1.6 and 7.7 Hz), 5.58
(1 H, s), 2.62 (1 H, br s) ppm. 13C{1H}NMR (100 MHz, CDCl3): δ =
141.9, 139.8, 130.4, 128.9, 128.2, 97.9, 79.1, 69.4, and 48.0 ppm. IR
(neat): 3385, 3050, 2922, 2844, 2211, 1586, 1432, 1265, 1190, 1053,
General Procedure for the Synthesis of Bromo-Propargyl
Alcohols or Bromoalkynes. To the solution of propragyl alcohol or
alkyne,13 in anhydrous acetone (2 mL/mmol) under nitrogen
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989, 752, and 607 cm−1. GCMS: 336.9 (M), 257 (M-Br), 232 (M-B,
M-C2H), 203 (M-COH, M-C2H, and M-Br). HRESI-MS:
[C9H6BrIONa]+ = [M + Na]+ requires 358.8539; found 358.8524.
TLC: Rf = 0.5 (4:1; Hex/EtOAc).
temperature for several hours. Reaction mixture was diluted with
EtOAc (10 mL/0.2 mmol), saturated aq. NH4Cl (10 mL), and
extracted with ethyl acetate (3 × 10 mL). The combined organic layer
was washed with brine (10 mL) and dried over MgSO4. Evaporation of
the solvent and purification of the crude mixture by flash column
chromatography gave the corresponding trans-enynone.
3-Bromo-1-(4-methoxyphenyl)prop-2-yn-1-ol (3d′). Alkyne17
(200 mg 0.78 mmol), NBS (151 mg, 0.85 mmol), AgNO3 (13 mg,
0.08 mmol), and acetone (7 mL) were stirred for 2 h at RT. Purified
by flash chromatography (9:1; hexane:EtOAc) gave the bromide 3d′
(E)-1,5-Diphenylpent-2-en-4-yn-1-one (2). The enynone 2 was
prepared following the method A from propargyl alcohol (30 mg, 0.23
mmol), phenyl acetylene bromide22 (45 mg, 0.25 mmol), freshly
degassed piperidene (2.2 mL), and CuCl (2 mg, 0.023 mmol) and was
stirred for 3 h at 0 °C. Purification by flash column chromatography
(19:1; hexane:EtOAc gave the trans- enynone 2 (35 mg, 0.66 mmol,
1
(250 mg, 0.75 mmol, 96%) as light yellow oil. H NMR (400 MHz,
CDCl3): δ = 7.37 (2 H, d, J = 8.7 Hz), 6.90 (2 H, d, J = 8.7 Hz), 5.34
(1 H, s), 3.76 (3 H, s), 2.80 (1 H, br s) ppm. 13C{1H}NMR (100
MHz, CDCl3): δ 159.7, 132.4, 128.1, 114.0, 80.1, 64.9, 55.3, and 46.9
ppm. IR (neat): 3408, 3054, 2927, 2836, 2380, 2210, 1596, 1489,
1459, 1246, 1046, 982, 753, and 610 cm−1. GCMS: 241 (M), 225 and
227 (M-OH), 210 (M-OH and OCH3), 136 (M-OH, M-C2Br).
HRESI-MS: [C10H10BrO2]+ = [M + H]+ requires 240.9859; found
240.9853. TLC: Rf = 0.5 (4:1, Hex/EtOAc).
1
66%) as a pale yellow solid. In method B, the yield = 78%. H NMR
(400 MHz, CDCl3): δ = 7.98 (2 H, dd, J = 1.4 and 8.2 Hz), 7.55−7.59
(1 H, tt, J = 1.3 and 6.5 Hz), 7.45−7.52 (4 H, m), 7.40−7.44 (1 H, d, J
= 15.5 Hz), 7.32−7.38 (2 H, m), 7.12 (1 H, d, J = 15.4 Hz).
13C{1H}NMR (100 MHz, CDCl3): δ = 189.0, 137.5, 133.3, 133.3,
132.2, 129.5, 128.9, 125.2, 122.4, 99.4, and 87.9 ppm. IR (neat): 3054,
2922, 2851, 2362, 2194, 1658, 1582, 1444, 1253, 1210, 999, 957, 756,
and 691 cm−1. HR ESI-MS: [C17H12O]+ = [M + H]+ requires
233.0966; found 233.0974. TLC: Rf = 0.6 (19:1, Hex/EtOAc). Mp:
86−88 °C.
3-Bromo-1-(2-methoxyphenyl)prop-2-yn-1-ol (3i′). Alkyne16 (200
mg 0.78 mmol), NBS (151 mg, 0.85 mmol), AgNO3 (13 mg, 0.08
mmol), and acetone (7 mL) were stirred for 2 h at RT. Purified by
flash chromatography (9:1; hexane:EtOAc) gave the bromide 3i′ (250
1
mg, 0.744 mmol, 96%) as a light yellow oil. H NMR (400 MHz,
(E)-1-(4-Fluorophenyl)-5-phenylpent-2-en-4-yn-1-one (4). The
enynone 4 was prepared following the method A from propargyl
alcohol23 (50 mg, 0.33 mmol), phenyl acetylene bromide (66 mg, 0.36
mmol), freshly degassed piperidene (3.3 mL), and CuCl (3.3 mg, 0.33
mmol) stirred for 3 h at 0 °C. Purification by flash chromatography
(19:1; hexane:EtOAc) gave trans-enynone 4 (64 mg, 0.26 mmol, 78%)
as a yellow viscous oil. In method B yield = 83%. 1H NMR (400 MHz,
CDCl3): δ = 8.00−8.04 (2 H, m), 7.50 (2 H, m), 7.35−7.40 (4 H, m),
7.10−7.18 (3 H, m). 13C{1H}NMR (100 MHz, CDCl3): δ = 187.2,
167.1, 164.6, 133.3, 133.7, 132.6, 132.1, 129.5, 128.6, 125.4, 122.3,
116.0, 115.8, 99.6, and 87.8 ppm. IR (neat): 3054, 2922, 2851, 1657,
1592, 1322, 1249, 1002, 834, 757, 681, and 535 cm−1. HR ESI-MS:
[C17H11FO]+ = [M + H]+ requires 251.0872; found 251.0884. TLC:
Rf = 0.6 (19:1, Hex/EtOAc).
(E)-1-(4-Chlorophenyl)-5-phenylpent-2-en-4-yn-1-one (5). The
enynone 5 was prepared following the method A from propargyl
alcohol24 (50 mg, 0.301 mmol), phenyl acetylene bromide (60 mg,
0.33 mmol), freshly degassed piperidene (3 mL), and CuCl (3 mg,
0.03 mmol) stirred for 3 h at 0 °C. Purification by flash
chromatography (19:1; hexane:EtOAc) gave the trans enynone 5
(76 mg, 0.285 mmol, 92%) as a yellow solid. In method B yield = 85%.
1H NMR (400 MHz, CDCl3): δ = 7.90 (2 H, d, J = 8.7 Hz), 7.50 (2 H,
m), 7.43 (2 H, d, J = 8.7 Hz), 7.35 (4 H, m), 7.10 (1 H, d, J = 15.4
Hz). 13C{1H}NMR (100 MHz, CDCl3): δ = 187.6, 139.8, 135.7,
132.6, 132.1, 130, 129.6, 129.1, 128.6, 125.7, 122.2, 99.9, and 87.8
ppm. IR (neat): 3069, 2921, 2855, 2210, 1647, 1589, 1400, 1263,
1099, 1021, 963, 815, 744, 536, and 486 cm−1. HR ESI-MS:
[C17H11ClO]+ = [M + H]+ requires 267.0577; found 267.0578. TLC:
Rf = 0.6 (19:1, Hex/EtOAc). Mp: 88−89 °C.
(E)-1-(4-Bromophenyl)-5-phenylpent-2-en-4-yn-1-one (6). The
enynone 6 was prepared following the method A from propargyl
alcohol (50 mg, 0.23 mmol), phenyl acetylene bromide (47 mg, 0.26
mmol), freshly degassed piperidene (2.3 mL), and CuCl (2.3 mg,
0.023 mmol) stirred for 6 h at 0 °C. Purification by flash
chromatography (19:1; hexane:EtOAc) gave trans-enynone 6 (53
mg, 0.17 mmol, 75%) as a yellow viscous oil. In method B yield = 79%.
1H NMR (400 MHz, CDCl3): δ = 7.80 (2 H, d, J = 8.6 Hz), 7.60 (2 H,
d, J = 8.6 Hz), 7.50 (2 H, m), 7.35 (4 H, m), 7.10 (1 H, d, J = 15.4
Hz). 13C{1H}NMR (100 MHz, CDCl3): δ = 187.2, 167.1, 164.6,
133.3, 133.7, 132.6, 132.1, 129.5, 128.6, 125.4, 122.3, 116.0, 115.8,
99.6, and 87.8 ppm. IR (neat): 3054, 2922, 2851, 2187, 1657, 1592,
1322, 1249, 1002, 834, 757, 681, and 535 cm−1. HR ESI-MS:
[C17H11BrO]+ = [M + H]+ requires 311.0072; found 311.0080. TLC:
Rf = 0.7 (19:1, Hex/EtOAc).
CDCl3): δ = 7.46 (1 H, d, J = 7.5 Hz), 7.27 (1 H, t, J = 8.0 Hz), 6.95
(1 H, t, J = 7.5 Hz), 6.87 (1 H, d, J = 8.3 Hz), 5.64 (1 H, s), 3.83 (3 H,
s), 3.19 (1 H, br s) ppm. 13C{1H}NMR (100 MHz, CDCl3): δ =
156.7, 129.8, 128.2, 127.8, 120.9, 111.0, 79.6, 61.9, 55.6, and 46.1 ppm.
IR (neat): 3410, 3011, 2924, 2844, 2337, 2210, 1604, 1509, 1459,
1251, 1172, 1033, 829, and 567 cm−1. GCMS: 241 (M), 225 and 227
(M-OH), 161 (M-Br), 135 and 137 (M-OH, M-C2H, and M-Br).
HRESI-MS: [C10H10BrO2]+ = [M + H]+ requires 240.9859; found
240.9865. TLC: Rf = 0.5 (4:1, Hex/EtOAc).
3-Bromo-1-(thiophen-2-yl) prop-2-yn-1-ol (16b′). Alkyne19 (200
mg, 0.76 mmol), NBS (151 mg, 0.85 mmol), AgNO3 (13 mg, 0.07
mmol), and acetone (7 mL) were stirred. Purified by flash
chromatography (9:1; hexane:EtOAc) gave bromide 16b′ (250 mg,
0.744 mmol, 96%) as light yellow oil. 1H NMR (400 MHz, CDCl3): δ
= 7.25 (1 H, d, J = 5.0 Hz), 7.10 (1 H, d, J = 3.4 Hz), 6.93 (1 H, dd, J
= 1.5 and 4.7 Hz), 3.05 (1 H, br s) ppm. 13C{1H}NMR (100 MHz,
CDCl3): δ 143.7, 126.8, 126.3, 125.7, 79.2, 61.0, 47.3 ppm. IR (neat):
3403, 2921, 2855, 2363, 2210, 1595, 1459, 1413, 1367, 1120, 1036,
701, 432 cm−1. GCMS: 215 (M), 203, 178, 155, 127, 102. HRESI-MS:
[C7H5BrOSNa]+ = [M + Na]+ requires 238.9137; found 238.9144.
TLC: Rf = 0.5 (4:1, Hex/EtOAc).
1-(2-Bromocyclopent-1-en-1-yl) prop-2-yn-1-ol (16e). Aldehyde20
(350 mg, 2 mmol), ethynylmagnesium bromide (0.5 M in THF, 3.0
mmol, 6.0 mL), dry THF (10 mL) were stirred. Purification of the
crude by flash chromatography (9:1; hexane: EtOAc) gave the alcohol
1
16e (360 mg, 1.8 mmol, 90%) as a yellow oil. H NMR (400 MHz,
CDCl3): δ = 5.30 (1 H, d, J = 1.8 Hz), 2.66 (3 H, m), 2.54 (2 H, m),
2.50 (1 H, d, J = 2.3 Hz), 1.97 (2 H, m) ppm. 13C{1H}NMR (100
MHz, CDCl3): δ = 138.7, 119.5, 81.9, 73.6, 59.9, 40.3, 29.9, 21.4 ppm.
IR (neat): 3428, 3301, 3052, 2965, 2852, 2360, 1648, 1428, 1265,
1085, 1025, 1008, 867, 733, 546 cm−1. HRESI-MS: [C8H8Br] = [M-
OH] requires 182.9809; found 182.9808. TLC: Rf = 0.5 (4:1, Hex/
EtOAc).
General Procedures for Coupling-Isomerization Cascade.
Method A. To the solution of propargyl alcohol13 (1 equiv), and
alkyne bromide21 (1.1 equiv) in freshly degassed amine (piperidine)
(1 mL/0.1 mmol) at 0 °C under nitrogen atmosphere, was added
CuCl (0.1 equiv), and the reaction mixture was stirred either at 0 °C
or at room temperature for several hours. Reaction mixture was diluted
with EtOAc (10 mL/0.2 mmol), saturated with aq. NH4Cl (10 mL),
and extracted with ethyl acetate (3 × 10 mL). The combined organic
layer was washed with brine (10 mL) and dried over MgSO4.
Evaporation of the solvent and purification of the crude mixture by
flash column chromatography gave the corresponding trans-enynone.
Method B. To the solution of bromo propargyl alcohol (1 equiv),
and alkyne (1.1 equiv) in freshly degassed amine (piperidine) (1 mL/
0.1 mmol) at 0 °C under nitrogen atmosphere, was added CuCl (0.1
equiv), and the reaction mixture was stirred either at 0 °C or at room
(E)-1-(4-Methoxyphenyl)-5-phenylpent-2-en-4-yn-1-one (7). The
enynone 7 was prepared following the method A from propargyl
alcohol (50 mg, 0.34 mmol), phenyl acetylene bromide (68 mg, 0.38
mmol), freshly degassed piperidene (3.5 mL), and CuCl (3.3 mg,
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DOI: 10.1021/acs.joc.5b01780
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The Journal of Organic Chemistry
Article
0.034 mmol) stirred for 9 h at 0 °C. Purification by flash
chromatography (19:1; hexane:EtOAc) gave the trans-enynone 6
(65 mg, 0.25 mmol, 73%) as a viscous yellow oil. In method B yield =
82%. 1H NMR (400 MHz, CDCl3): δ = 8.00 (2 H, d, J = 8.8 Hz), 7.50
(2 H, m), 7.42 (1 H, d, J = 15.6 Hz), 7.35 (3 H, m), 7.10 (1 H, d, J =
15.4 Hz), 6.95 (2 H, d, J = 8.8 Hz), 3.86 (3 H, s). 13C{1H}NMR (100
MHz, CDCl3): δ = 187.2, 163.8, 133.2, 132.1, 131.0, 130.3, 129.4,
128.6, 124.3, 122.5, 114.1, 98.7, 88.0, and 55.6 ppm. IR (neat): 3058,
2921, 2853, 2196, 1646, 1594, 1423, 1323, 1255, 1169, 1020, 833, 755,
679, 615, and 458 cm−1. HRESI-MS:[C18H14O2]+ = [M + H]+ requires
263.1072; found 263.1078. TLC: Rf = 0.6 (9.5:0.5, Hex/EtOAc).
(E)-1-(2-Fluorophenyl)-5-phenylpent-2-en-4-yn-1-one (8). The
enynone 8 was prepared following the method A from propargyl
alcohol25 (50 mg, 0.33 mmol), phenyl acetylene bromide (66 mg, 0.36
mmol), freshly degassed piperidene (3.3 mL), and CuCl (3.2 mg, 0.03
mmol) and was stirred for 6 h at 0 °C. Purification by flash
chromatography (19:1; hexane:EtOAc) gave trans-enynone 8 (45 mg,
ppm. IR (neat): 3061, 2928, 2862, 2195, 1654, 1588, 1447, 1308,
1258, 1207, 1031, 757, 689, and 452 cm−1. HRESI-MS: [C18H14O]+ =
[M + H]+ requires 247.1123; found 247.1118. TLC: Rf = 0.6 (19:1,
Hex/EtOAc).
tert-Butyl (E)-[2-(5-Phenylpent-2-en-4-ynoyl) phenyl] carbamate
(13). The enynone 13 was prepared following the method A from
propargyl alcohol28 (160 mg, 0.65 mmol), phenyl acetylene bromide
(128 mg, 0.71 mmol), freshly degassed piperidene (6.4 mL), and CuCl
(6.4 mg, 0.065 mmol) and was stirred for 8 h at 0 °C. Purification by
flash chromatography (19:1; hexane:EtOAc) gave trans enynone 13
1
(147 mg, 0.45 mmol, 67%) as a yellow solid. H NMR (400 MHz,
CDCl3): δ = 10.8 (1 H, s), 8.47 (1 H, d, J = 8.5 Hz), 7.84 (1 H, d, J =
7.9 Hz), 7.51 (3 H, m), 7.45 (1 H, d, J = 15.4 Hz), 7.35 (3 H, m), 7.09
(1 H, d, J = 15.4 Hz), 7.02 (1 H, t, J = 7.5 Hz), 1.53 (9 H, s).
13C{1H}NMR (100 MHz, CDCl3): δ = 191.4, 153.1, 142.3, 135.0,
134.2, 132.1, 130.7, 129.5, 128.6, 125.4, 122.2, 121.9, 121.15, 119.5,
100.0, 87.8, 80.6, and 28.3 ppm. IR (neat): 3355, 2980, 2849, 2925,
2341, 1730, 1638, 1579, 1521, 1449, 1248, 1153, 1023,753 and 528
cm−1. HR ESI-MS:[C22H21NO3]+ = [M + H]+ requires 348.1600;
found 348.1587. TLC: Rf = 0.6 (19:1, Hex/EtOAc). Mp: 82−84 °C.
(E)-1-(2-Aminophenyl)-5-phenylpent-2-en-4-yn-1-one (13′). To
an ice-cold solution of N-Boc trans-enynone 13 (80 mg, 0.25 mmol)
in dry CH2Cl2 under nitrogen atmosphere was added trifluoro acetic
acid (TFA) (0.1 mL, 0.37 mmol), and the reaction was stirred at 0 °C
for 4 h. The solvent was removed under reduced pressure, and crude
was diluted with CH2Cl2 (10 mL) and neutralized with saturated aq.
NaHCO3 (10 mL). The aqueous phase was extracted with CH2Cl2 (2
× 10 mL). The combined organic layer was washed with brine
solution (10 mL) and dried over MgSO4. Evaporation of the solvent
and purification of the crude by flash chromatography (19:1;
hexane:EtOAc) gave amine 13′ (45 mg, 0.182 mmol, 79%) as a
brown solid. It was recrystallized from hexane-EtOAc mixture. 1H
NMR (400 MHz, CDCl3): δ = 7.74−7.75 (1 H, dd, J = 1.4 and 8.6
Hz) 7.46−7.50 (3 H, m), 7.30−7.32 (3 H, m), 7.21−7.26 (1 H, m),
7.00 (1 H, d, J = 15.4 Hz), 6.60−6.65 (2 H, m), 6.30 (2 H, br s).
13C{1H}NMR (100 MHz, CDCl3): δ = 190.7, 151.4, 134.7, 134.5,
132.07, 131.15, 129.3, 128.6, 123.2, 122.6, 118.2, 117.4, 116.1, 98.2,
88.1 ppm. IR (neat): 3470, 2924, 2853, 2189, 1637, 1606, 1571, 1459,
1330, 1360, 1288, 1243, 1207, 1162, 1024, 988, 954, 914, 860, 751,
685, 524 cm−1. TLC: Rf = 0.6 (19:1, Hex/EtOAc). GC-MS: 247.1
(M), 230.0, 218.0, 207.0, 183, 165.1, 102.1, 91.1. Mp: 85−86 °C.
HRESI-MS: [C17H14NO]+ = [M + H]+ requires 248.1070; found
248.1082.
1
0.18 mmol, 55%) as a brown oil. H NMR (400 MHz, CDCl3): δ =
7.80 (1 H, td, J = 1.8 and 7.8 Hz), 7.50 (3 H, m), 7.35 (3 H, m), 7.25
(2 H, m), 7.10−7.15 (1 H, ddd, J = 0.8, 2.6, and 8.3 Hz), 7.03−7.07 (1
H, dd, J = 1.6 and 15.6 Hz). 13C{1H}NMR (100 MHz, CDCl3): δ =
187.6, 162.8, 160.3, 136.5, 134.5, 132.2, 131.1, 129.5, 128.6, 125.2,
124.7, 122.3, 116.8, 100.1, 87.8 ppm. IR (neat): 3068, 2925, 2855,
2363, 2197, 1654, 1586, 1480, 1453, 1325, 1270, 1201, 1101, 1007,
956, 755, 689, and 533 cm−1. HRESI-MS: [C17H11FO]+ = [M + H]+
requires 251.0872; found 251.0867. TLC: Rf = 0.6 (19:1, Hex/
EtOAc).
(E)-1-(2-Bromophenyl)-5-phenylpent-2-en-4-yn-1-one (9). The
enynone 9 was prepared following the method A from propargyl
alcohol26 (50 mg, 0.24 mmol), phenyl acetylene bromide (47 mg, 0.26
mmol), freshly degassed piperidene (2.3 mL), and CuCl (2.3 mg,
0.024 mmol) stirred for 9 h at 0 °C. Purification by flash
chromatography (19:1; hexane:EtOAc) gave the trans-enynone 9
(48 mg, 0.154 mmol, 65%) as a yellow viscous oil. In method B yield =
55%. 1H NMR (400 MHz, CDCl3): δ = 7.80 (2 H, d, J = 8.6 Hz), 7.60
(2 H, d, J = 8.6 Hz), 7.50 (2 H, m), 7.35 (4 H, m), 7.10 (1 H, d, J =
15.4 Hz). 13C{1H}NMR (100 MHz, CDCl3): δ = 187.2, 167.1, 164.6,
133.3, 133.7, 132.6, 132.1, 129.5, 128.6, 125.4, 122.3, 116.0, 115.8,
99.6, and 87.8 ppm. IR (neat): 3058, 2922, 2852, 2195, 1644, 1589,
1401, 1262, 1115, 962, 738, 542, and 453 cm−1. GCMS (method):
311.0, 281.0, 221.1, 207.0, 191.1, 147.1, 135.1, 105.1, 85.1. HRESI-MS:
[C17H11BrONa]+ = [M + Na]+ requires 332.9885; found 332.9871.
TLC: Rf = 0.6 (19:1 hexane:EtOAc).
(E)-1-(2-Iodophenyl)-5-phenylpent-2-en-4-yn-1-one (10). The
enynone 10 was prepared following the method A from propargyl
alcohol27 (50 mg, 0.193 mmol), phenyl acetylene bromide (38 mg,
0.213 mmol), freshly degassed piperidine (2 mL), and CuCl (2 mg,
0.02 mmol) stirred for 9 h at 0 °C. Purification by flash
chromatography (19:1; hexane:EtOAc) gave the trans-enynone 10
(37 mg, 0.10 mmol, 53%) as a brown oil. In method B yield = 57%. 1H
NMR (400 MHz, CDCl3): δ = 7.90 (1 H, dd, J = 0.7 and 7.8 Hz), 7.48
(2 H, dd, J = 2.0 and 7.5 Hz), 7.30−7.40 (5 H, m), 7.10−7.40 (1 H, td,
J = 1.8 and 7.8 Hz), 6.92 (1 H, d, J = 16 Hz), 6.76 (1 H, d, J = 16 Hz).
13C{1H}NMR (100 MHz, CDCl3): δ = 194.6, 143.7, 140.3, 136.5,
132.2, 131.7, 129.7, 128.7, 128.6, 128.1, 127.3, 122.1, 101.8, 92.2, and
87.2 ppm. IR (neat): 3061, 2921, 2851, 2192, 1652, 1583, 1420, 1289,
1095, 1010, 952, 755, 681, and 620 cm−1. HR ESI-MS:[C17H11IO]+ =
[M + H]+ requires 358.9933; found 358.9939. TLC: Rf = 0.6 (19:1,
Hex/EtOAc).
(E)-5-Phenyl-1-(o-tolyl) pent-2-en-4-yn-1-one (11). The enynone
11 was prepared following the method A from propargyl alcohol (50
mg, 0.342 mmol), phenyl acetylene bromide (68 mg, 0.38 mmol),
freshly degassed piperidene (3.4 mL), and CuCl (3.3 mg, 0.035 mmol)
stirred for 9 h at 0 °C. Purification by flash chromatography (19:1;
hexane:EtOAc) gave the trans- enynone 11 (59 mg, 0.24 mmol, 70%)
as a yellow oil. In method B yield = 67%. 1H NMR (400 MHz,
CDCl3): δ = 7.50 (3 H, m), 7.38 (4 H, m), 7.28 (2 H, m), 7.05 (1 H,
d, J = 16 Hz), 6.86 (1 H, d, J = 16 Hz), 2.40 (3 H, s). 13C{1H}NMR
(100 MHz, CDCl3): δ = 194.6, 138.0, 137.6, 137.5, 132.1, 131.6,
131.1, 129.5, 128.6, 128.5, 125.9, 125.6, 122.3, 100.3, 87.3, and 20.5
(E)-1-(3-Bromophenyl)-5-phenylpent-2-en-4-yn-1-one (14). The
enynone 14 was prepared following the method A from propargyl
alcohol29 (60 mg, 0.28 mmol), phenyl acetylene bromide (56 mg,
0.312 mmol), freshly degassed piperidene (2.8 mL), CuCl (3 mg, 0.03
mmol) stirred for 6 h at 0 °C. Purification by flash chromatography
(19:1; hexane:EtOAc) gave the trans-enynone 14 (70 mg, 0.225 mmol,
81%) as a yellow solid. In method B yield = 93%. 1H NMR (400 MHz,
CDCl3): δ = 8.00 (1 H, s), 7.88 (1 H, d, J = 7.7 Hz), 7.68 (1 H, d, J =
7.9 Hz), 7.50 (2 H, dd, J = 2.2 and 7.2 Hz), 7.35 (5 H, m), 7.13 (1 H,
d, J = 15.4 Hz). 13C{1H}NMR (100 MHz, CDCl3): δ = 187.5, 139.1,
136, 132.4, 132.2, 131.6, 130.3, 129.6, 128.6, 127.1, 126.0, 123.1, 122.2,
100.2, and 87.7 ppm. IR (neat): 3072, 2923, 2855, 2363, 2194, 1660,
1584, 1419, 1320, 1252, 1205, 957, 751, and 689 cm−1. HRESI-MS:
[C17H11BrO]+ = [M + H]+ requires 311.0072; found 311.0075. TLC:
Rf = 0.6 (19:1, Hex/EtOAc). Mp: 87−89 °C.
(E)-1-(3-Nitrophenyl)-5-phenylpent-2-en-4-yn-1-one (15). The
enynone 15 was prepared following the method A from propargyl
alcohol (50 mg, 0.28 mmol), phenyl acetylene bromide (56 mg, 0.31
mmol), freshly degassed piperidene (2.8 mL), and CuCl (2.8 mg,
0.028 mmol) and was stirred for 7 h at 0 °C. Purification by flash
chromatography (19:1; hexane:EtOAc) gave trans-enynone 15 (28
1
mg, 0.10 mmol, 36%) as a brown viscous oil. H NMR (400 MHz,
CDCl3): δ = 8.80 (1 H, s), 8.45 (1 H, d, J = 8.0 Hz), 8.35 (1 H, d, J =
7.8 Hz), 7.70 (1 H, t, J = 8.0 Hz), 7.55 (2 H, dd, J = 1.9 and 8.0 Hz),
7.40 (4 H, m), 7.23 (1 H, d, J = 15.4 Hz). 13C{1H}NMR (100 MHz,
CDCl3): δ = 186.7, 148.6, 138.7, 134.1, 132.3, 131.7, 130.1, 129.9,
128.7, 127.5, 127.3, 123.4, 122.1, 101.3, and 87.7 ppm. IR (neat):
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The Journal of Organic Chemistry
Article
3079, 2924, 2849, 2355, 2193, 1655, 1582, 1528, 1441, 1349, 1251,
1211, 1093, 1020, 957, 735, 689, and 539 cm−1. HRESI-MS:
[C17H11NO3]+ = [M + H]+ requires 278.0817; found 278.0807
TLC: Rf = 0.6 (19:1, Hex/EtOAc).
mmol) stirred for 8 h at 0 °C. Purification by flash chromatography
(19:1; hexane:EtOAc) gave trans-enynone 20 (50 mg, 0.18 mmol,
45%) as a brown oil. 1H NMR (400 MHz, CDCl3): δ = 8.40 (1 H, d, J
= 8.3 Hz), 7.97 (1 H, d, J = 8.2 Hz), 7.88 (1 H, d, J = 7.6 Hz), 7.77 (1
H, d, J = 7.0 Hz), 7.50 (6 H, m), 7.34 (3 H, m), 7.20 (1 H, d, J = 16
Hz), 6.96 (1 H, d, J = 16 Hz). 13C{1H}NMR (100 MHz, CDCl3): δ =
193.8, 137.8, 136.0, 134.0, 132.4, 132.1, 130.6, 129.5, 128.6, 128.6,
127.8, 127.8, 126.7, 126.08, 125.7, 124.5, 122.3, 100.5, and 87.5 ppm.
IR (neat): 3054, 2923, 2854, 2358, 2191, 1656, 1577, 1449, 1304,
1250, 1178, 1102, 964, 778, 690, and 509 cm−1. HRESI-MS:
[C21H14O]+ = [M + H]+ requires 283.1123; found 283.1117. TLC:
Rf = 0.6 (19:1, Hex/EtOAc).
(Z)-2-[(E)-1-Hydroxy-5-phenylpent-2-en-4-yn-1-ylidene]-
cyclopentan-1-one (21). The enynone 21 was prepared following the
method A from propargyl alcohol33 (55 mg, 0.28 mmol), phenyl
acetylene bromide (54 mg, 0.3 mmol), freshly degassed piperidene
(2.7 mL), CuCl (2.7 mg, 0.027 mmol) stirred for 3 h at 0 °C.
Purification by flash chromatography (19:1; hexane:EtOAc) gave trans
-enynone 21 (36 mg, 0.15 mmol, 54%) as a yellow solid. It was
recrystallized from (1:1) hexane-MeOH solvent system. 1H NMR
(400 MHz, CDCl3): δ = 13.0 (1 H, br s), 7.48 (2 H, dd, J = 1.4 and 7.6
Hz), 7.34 (3 H, m), 6.80 (1 H, d, J = 15.6 Hz), 6.45 (1 H, d, J = 15.6
Hz), 2.67 (2 H, t, J = 7.2 Hz), 2.43 (2 H, t, J = 7.9 Hz),1.96 (2 H, m).
13C{1H}NMR (100 MHz, CDCl3): δ = 211.3, 161.6, 132.0, 131.9,
1-(2-Methoxyphenyl)-5-phenylpenta-2,4-diyn-1-ol (12′). The diy-
nol 12′ was prepared following the method A from propargyl alcohol
(50 mg, 0.31 mmol), phenyl acetylene bromide (61 mg, 0.34 mmol),
freshly degassed piperidene (3 mL), and CuCl (3 mg, 0.031 mmol)
stirred for 3 h at 0 °C. Purification by flash chromatography (9:1;
hexane:EtOAc) gave the coupled alcohol 12′ (62 mg, 0.24 mmol,
1
77%) as a yellow oil. In method B yield = 95%. H NMR (400 MHz,
CDCl3): δ = 7.50 (1 H, dd, J = 1.6 and 7.5 Hz), 7.45 (2 H, dd, J = 1.4
and 7.9 Hz), 7.22−7.38 (4 H, m), 6.97 (1 H, dt, J = 0.9 and 7.5 Hz),
6.90 (1 H, d, J = 8.3 Hz), 5.75 (1 H, s), 3.86 (3 H, s). 13C{1H}NMR
(100 MHz, CDCl3): δ = 156.8, 132.6, 130.0, 129.3, 128.4, 128.0,
121.6, 121.1, 111.1, 81.9, 78.9, 73.6, 70.3, 61.9, and 55.7 ppm. IR
(neat): 3419, 3061, 2923, 2847, 2376, 2195, 1595, 1484, 1458, 1245,
1095, 1024, 752, 685, and 624 cm−1. GC-MS: 265.1, 221.1, 207.0,
191.1, 147.1, 135.1, 105.1, 85.1. TLC: Rf = 0.4 (9:1, Hex/EtOAc).
(E)-1-(Furan-2-yl)-5-phenylpent-2-en-4-yn-1-one (17). The eny-
none 17 was prepared following the method A from propargyl
alcohol30 (70 mg, 0.57 mmol), phenyl acetylene bromide (114 mg,
0.63 mmol), freshly degassed piperidene (5.7 mL), and CuCl (6 mg,
0.06 mmol) stirred for 3 h at 0 °C. Purification by flash
chromatography (19:1; hexane:EtOAc) gave trans-enynone 17 (55
129.1, 128.5, 122.7, 118.9, 111.8, 98.4, 88.3, 38.2, 25.4, 20.6 ppm. IR
(neat): 3455, 2923, 2852, 2371, 2189, 1645, 1610, 1568, 1488, 1443,
1360, 1227, 949, 818, 757, 693, 622, 527, 456 cm−1. GC-MS
(method): 239.1 (M), 218.1, 189.1, 165.1, 126.1. HRESI-MS:
[C16H15O2]+ = [M + H]+ requires 239.1067; found 239.1070. TLC:
Rf = 0.6 (19:1, Hex/EtOAc). Mp: 90−92 °C.
1
mg, 0.25 mmol, 43%) as a light yellow solid. H NMR (400 MHz,
CDCl3): δ = 7.64 (1 H, dd, J = 0.6 and 1.6 Hz), 7.52 (2 H, dd, J = 1.8
and 6.9 Hz), 7.35−7.39 (3 H, m), 7.27−7.31 (2 H, m), 7.15 (1 H, d, J
= 15.6 Hz), 6.58 (1 H, dd, J = 1.7 and 3.6 Hz). 13C{1H}NMR (100
MHz, CDCl3): δ = 176.7, 153.1, 147.1, 132.7, 132.1, 129.5, 128.5,
124.4, 122.3, 118.3, 112.7, 99.6, 87.8 ppm. IR (neat): 3055, 2926,
2854, 2364, 2195, 1654, 1587, 1465, 1414, 1395, 1324, 1265, 1160,
1089, 1053, 1028, 959, 912, 823, 738, and 530 cm−1. HR ESI-MS:
[C15H11O2]+ = [M + H]+ requires 223.0754; found 223.0761. TLC: Rf
= 0.6 (19:1, Hex/EtOAc). Mp: 72−74 °C.
(E)-5-Phenyl-1-(thiophen-2-yl) pent-2-en-4-yn-1-one (18). The
enynone 18 was prepared following the method A from propargyl
alcohol (50 mg, 0.36 mmol), phenyl acetylene bromide (72 mg, 0.4
mmol), freshly degassed piperidene (3.6 mL), and CuCl (3.5 mg,
0.037 mmol) stirred for 3 h at 0 °C. Purification by flash
chromatography (19:1; hexane:EtOAc) gave trans-enynone 18 (33
mg, 0.14 mmol, 38%) as a brown viscous oil. In method B yield = 56%.
1H NMR (400 MHz, CDCl3): δ = 7.80 (1 H, dd, J = 1.0 and 4.0 Hz),
7.68 (1 H, dd, J = 1.1 and 4.9 Hz), 7.50 (2 H, dd, J = 2.8 and 6.9 Hz),
7.35 (3 H, m), 7.28 (1 H, d, J = 15.4 Hz), 7.14 (2 H, m).
13C{1H}NMR (100 MHz, CDCl3): δ = 180.8, 144.8, 134.6, 133.0,
132.4, 132.1, 129.5, 128.6, 128.5, 124.5, 122.3, 99.6, and 87.7 ppm. IR
(neat): 3054, 2979, 2926,2853, 2362, 2195, 1644, 1583, 1514, 1414,
1357, 1325, 1264, 1211, 1064, 972, 861, 809, 735, 535, 415 cm−1.
HRESI-MS: [C15H10OS]+ = [M + H]+ requires 239.0531; found
239.0523. TLC: Rf = 0.6 (19:1 hexane:EtOAc).
(E)-5-Phenyl-1-(pyridin-3-yl)pent-2-en-4-yn-1-one (19). The eny-
none 19 was prepared following the method A from propargyl
alcohol31 (60 mg, 0.45 mmol), phenyl acetylene bromide(89 mg, 0.5
mmol), freshly degassed piperidene (4.5 mL), and CuCl (4.4 mg,
0.045 mmol) stirred for 8 h at 0 °C. Purification by flash
chromatography (6:1; hexane:EtOAc) gave trans-enynone 19 (41
mg, 0.18 mmol, 41%) as a brown solid. 1H NMR (400 MHz, CDCl3):
δ = 9.17 (1 H, s), 8.78 (1 H, d, J = 4.5 Hz), 8.24 (1 H, d, J = 8.0 Hz),
7.34−7.50 (7 H, m), 7.15 (1 H, d, J = 15.5 Hz). 13C{1H}NMR (100
MHz, CDCl3): δ = 187.6, 153.6, 149.9, 135.9, 132.7, 132.3, 132.2,
129.7, 128.6, 126.4, 123.8, 122.2, 100.7, and 87.6 ppm. IR (neat):
3054, 2923, 2854, 2357, 2197, 1657, 1583, 1421, 1316, 1260, 1004,
960, 854, 753, 683, 547, and 431 cm−1. HR ESI-MS: [C16H11NO]+ =
[M + H]+ requires 234.0919; found 234.0923; TLC: Rf = 0.5 (7:3,
Hex/EtOAc); Mp: 70−71 °C.
(E)-5-(4-Methoxyphenyl)-1-phenylpent-2-en-4-yn-1-one (24).
The enynone 24 was prepared following the method B from. terminal
bromide34 (50 mg, 0.24 mmol), alkyne35 (41 mg, 0.26 mmol), freshly
degassed piperidene (2.3 mL), and CuCl (2.35 mg, 0.024 mmol)
stirred for 8 h at 0 °C. Purification by flash chromatography (19:1;
hexane:EtOAc) gave trans-enynone 24 (35 mg, 0.134 mmol, 56%) as
an yellow viscous oil. 1H NMR (400 MHz, CDCl3): δ = 7.98 (2 H, d, J
= 7.4 Hz), 7.58 (1 H, t, J = 7.4 Hz), 7.47 (4 H, m), 7.39 (1 H, d, J =
15.5 Hz), 7.13 (1 H, d, J = 15.4 Hz), 6.89 (2 H, d, J = 8.7 Hz), 3.83 (3
H, s). 13C{1H}NMR (100 MHz, CDCl3): δ = 189.1, 160.7, 137.6,
133.9, 133.2, 132.3, 128.8, 128.6, 125.7, 114.5, 114.3, 100.2, 87.2, and
55.5 ppm. IR (neat): 3054, 2926, 2853, 2361, 2333, 2191, 1657, 1580,
1509, 1462, 1322, 1306, 1263, 1211, 1174, 1029, 1002, 958, 834, 739,
702, and 537 cm−1. HRESI-MS: [C18H14O2]+ = [M + H]+ requires
263.1072; found 263.1061. TLC: Rf = 0.6 (9:1, Hex/EtOAc).
(E)-5-(3-Methoxyphenyl)-1-phenylpent-2-en-4-yn-1-one (25).
The enynone 25 was prepared following the method B from terminal
bromide (70 mg, 0.34 mmol), alkyne36 (56 mg, 0.36 mmol), freshly
degassed piperidene (3.3 mL), and CuCl (3.2 mg, 0.034 mmol) stirred
for 8 h at 0 °C. Purification by flash chromatography (19:1
hexane:EtOAc) gave trans-enynone 25 (60 mg, 0.21 mmol, 63%) as
1
a brown oil. H NMR (400 MHz, CDCl3): δ = 7.90 (2 H, d, J = 8.5
Hz), 7.57 (1 H, m), 7.48 (2 H, t, J = 7.8 Hz), 7.42 (1 H, d, J = 15.5
Hz), 7.25 (1 H, m), 7.10 (2 H, m), 7.02 (1 H, m), 6.90 (1 H, m), 3.80
(3 H, s). 13C{1H}NMR (100 MHz, CDCl3): δ = 189.0, 159.5, 137.4,
133.3, 131.8, 129.7, 128.8, 128.7, 125.1, 124.7, 123.3, 116.8, 116.2,
99.3, 87.6, and 55.4 ppm. IR (neat): 3050, 2923, 2851, 2362, 2341,
2194, 1658, 1597, 1463, 1423, 1329, 1267, 1210, 1175, 1039, 1006,
958, 857, 739, 692, and 477 cm−1. HRESI-MS: [C18H14O2]+ = [M +
H]+ requires 263.1072; found 263.1081. TLC: Rf = 0.6 (9:1, Hex/
EtOAc).
(E)-5-[(1,1′-Biphenyl)-4-yl]-1-phenylpent-2-en-4-yn-1-one (26).
The enynone 26 was prepared following the method B from terminal
bromide (50 mg, 0.24 mmol), alkyne37 (46 mg, 0.26 mmol), freshly
degassed piperidene (2.3 mL), and CuCl (2.35 mg, 0.024 mmol)
stirred for 8 h at 0 °C. Purification by flash chromatography (19:1;
hexane:EtOAc) gave trans-enynone 26 (44 mg, 0.14 mmol, 59%) as a
yellow solid. 1H NMR (400 MHz, CDCl3): δ = 7.97 (2 H, dd, J = 1.4
and 7.1 Hz), 7.55 (8 H, m), 7.45 (4 H, m), 7.35 (1 H, m), 7.12 (1 H,
d, J = 15.4 Hz). 13C{1H}NMR (100 MHz, CDCl3): δ = 188.9, 142.2,
(E)-1-(Naphthalen-1-yl)-5-phenylpent-2-en-4-yn-1-one (20). The
enynone 20 was prepared following the method A from propargyl
alcohol32 (75 mg, 0.4 mmol), phenyl acetylene bromide (82 mg, 0.45
mmol), freshly degassed piperidene (4 mL), and CuCl (4 mg, 0.04
10215
DOI: 10.1021/acs.joc.5b01780
J. Org. Chem. 2015, 80, 10208−10217

The Journal of Organic Chemistry
Article
140.1, 137.4, 133.9, 133.3, 133.1, 133.0, 132.6, 129.0, 128.8, 128.6,
128.0, 127.2, 127.1, 125.2, 121.2, 99.4, and 88.6 ppm. IR (neat): 3065,
3033, 2922, 2855, 2362, 2341, 2187, 1653, 1580, 1455, 1399, 1317,
1256, 1117, 952, 840, 763, 690, and 457 cm−1. HRESI-MS:
[C23H16O]+ = [M + H]+ requires 309.1279; found 309.1293. TLC:
Rf = 0.6 (9:1, Hex/EtOAc). Mp: 76−77 °C.
(E)-5-(3,4-Dihydronaphthalen-1-yl)-1-phenylpent-2-en-4-yn-1-
one (31). The enynone 31 was prepared following the method B from
terminal bromide (70 mg, 0.34 mmol), propargyl alcohol41 (56 mg,
0.36 mmol), freshly degassed piperidene (3.3 mL), and CuCl (3.2 mg,
0.034 mmol) stirred for 8 h at 0 °C. Purification by flash
chromatography (19:1; hexane:EtOAc) gave trans-enynone 31 (30
mg, 0.105 mmol, 32%) as a brown oil. 1H NMR (400 MHz, CDCl3): δ
= 7.99 (2 H, dd, J = 1.4 and 8.5 Hz), 7.55−7.60 (2 H, m), 7.50 (2 H,
m), 7.42 (1 H, d, J = 15.5 Hz), 7.18−7.24 (4 H, m), 6.60 (1 H, t, J =
5.0 Hz), 2.81 (2 H, t, J = 8.1 Hz), 2.45 (2 H, m). 13C{1H}NMR (100
MHz, CDCl3): δ = 189.1, 138.5, 137.5, 133.3, 133.0, 132.1, 128.8,
128.7, 128.1, 127.7, 126.9, 125.4 125.1, 121.8, 97.7, 88.9, 27.1, and 24.1
ppm. IR (neat): 3058, 3025, 2925, 2851, 2185, 1656, 1586, 1449,
1297, 1288, 1210, 1012, 957, 768, and 695 cm−1. HRESI-MS:
[C21H16O]+ = [M + H]+ requires 285.1279; found 285.1280. TLC: Rf
= 0.6 (19:1, Hex/EtOAc).
Methyl (E)-2-(5-oxo-5-phenylpent-3-en-1-yn-1-yl) Benzoate (27).
The enynone 27 was prepared following the method B from terminal
bromide (50 mg, 0.24 mmol), alkyne38 (39 mg, 0.26 mmol), freshly
degassed piperidene (2.3 mL), and CuCl (2.3 mg, 0.024 mmol) stirred
for 8 h at 0 °C. Purification by flash chromatography (19:1;
hexane:EtOAc) gave trans-enynone 27 (21 mg, 0.08 mmol, 32%) as
1
a brown oil. H NMR (400 MHz, CDCl3): δ = 8.12 (3 H, m), 7.45−
7.65 (7 H, m), 7.20 (1 H, d, J = 15.5 Hz), 3.90 (3 H, s). 13C{1H}NMR
(100 MHz, CDCl3): δ = 189.0, 166.3, 137.3, 135.4, 134.5, 133.7,
133.3, 132.1, 131.9, 130.9, 130.7, 129.0, 128.8, 128.7, 125.2, 122.8,
97.7, 92.2, and 52.4 ppm. IR (neat): 3061, 2926, 2854, 2358, 2193,
1732, 1658, 1578, 1441, 1258, 1131, 1086, 1002, 955, 738, 658, and
539 cm−1. HRESI-MS: [C19H14O3]+ = [M + H]+ requires 291.1021;
found 291.1016. TLC: Rf = 0.6 (9:1, Hex/EtOAc).
(E)-5-(Cyclohex-1-en-1-yl)-1-phenylpent-2-en-4-yn-1-one (32).
The enynone 32 was prepared following the method B from terminal
bromide (100 mg, 0.48 mmol), alkyne (56 mg, 0.52 mmol), freshly
degassed piperidene (4.7 mL), and CuCl (4.71 mg, 0.05 mmol) stirred
for 22 h at 0 °C to RT. Purification by flash chromatography (19:1;
hexane:EtOAc) gave trans-enynone 32 (72 mg, 0.31 mmol, 64%) as a
(E)-5-(3,5-Dimethylphenyl)-1-phenylpent-2-en-4-yn-1-one (28).
The enynone 28 was prepared following the method B from terminal
bromide (50 mg, 0.24 mmol), alkyne39 (34 mg, 0.26 mmol), freshly
degassed piperidene (2.3 mL), and CuCl (2.3 mg, 0.024 mmol) stirred
for 8 h at 0 °C. Purification by flash chromatography (19:1;
hexane:EtOAc) gave trans-enynone 28 (30 mg, 0.12 mmol, 49%) as
a brown viscous oil. 1H NMR (400 MHz, CDCl3): δ = 7.98 (2 H, dd, J
= 1.4 and 8.3 Hz), 7.56−7.60 (1 H, tt, J = 1.2 & 8.0 Hz), 7.50 (2 H,
m), 7.40 (1 H, d, J = 15.5 Hz), 7.15 (2 H, m), 7.12 (1 H, d, J = 15.5
Hz), 7.00 (1 H, s), 2.30 (6 H, s). 13C{1H}NMR (100 MHz, CDCl3): δ
= 189.1, 139.4, 138.2, 137.5, 133.2, 133.0, 131.5, 129.9, 128.8, 128.6,
125.2, 122.06, 114.2, 100.1, 87.3, and 21.2 ppm. IR (neat): 3056, 2923,
2853, 2362, 2192, 1659, 1598, 1581, 1447, 1337, 1280, 1210, 1179,
1011, 956, 852, 773,738, 692, and 461 cm−1. HRESI-MS: [C19H16O]+
= [M + H]+ requires 261.1279; found 261.1282. TLC: Rf = 0.6 (9:1,
Hex/EtOAc).
(E)-5-(1-Hydroxy-1,2,3,4-tetrahydronaphthalen-1-yl)-1-phenyl-
pent-2-en-4-yn-1-one (29). The enynone 29 was prepared following
the method B from terminal bromide (50 mg, 0.24 mmol), propargyl
alcohol40 (45 mg, 0.26 mmol), freshly degassed piperidine (2.3 mL),
and CuCl (2.35 mg, 0.024 mmol) stirred for 8 h at 0 °C. Purification
by flash chromato-graphy (9:1; hexane:EtOAc) gave trans-enynone 29
(36 mg, 0.10 mmol, 45%) as a brown oil. 1H NMR (400 MHz,
CDCl3): δ = 7.90 (2 H, dd, J = 1.4 and 8.6 Hz), 7.75 (1 H, dd, J = 2.7
and 7.5 Hz), 7.57 (1 H, m), 7.48 (2 H, t, J = 7.8 Hz), 7.35 (1 H, d, J =
15.6 Hz), 7.25 (2 H, m), 7.15 (1 H, m), 6.95 (1 H, d, J = 15.6 Hz),
2.85 (2 H, m), 2.26 (2 H, t, J = 5.7 Hz), 2.29 (2 H, m), 1.60 (1 H, br
s). 13C{1H}NMR (100 MHz, CDCl3): δ = 189.0, 138.5, 137.2, 136.2,
133.8, 133.3, 129.4, 128.8, 128.7, 128.5, 127.9, 126.8, 124.7, 114.2,
103.3, 82.5, and 68.5 ppm. IR (neat): 3436, 2923, 2851, 2365, 2341,
1655, 1588, 1447, 1327, 1288, 1210, 1078, 1011,963, 763, 695, and
542 cm−1. HRESI-MS: [C21H18O2]+ = [M + H]+ requires 303.1385;
found 303.1371. TLC: Rf = 0.5 (9:1, Hex/EtOAc).
1
brown oil. H NMR (400 MHz, CDCl3): δ = 7.95 (2 H, dd, J = 1.4
and 8.6 Hz), 7.55 (1 H, tt, J = 1.2 and 7.3 Hz), 7.45 (2 H, t, J = 7.8
Hz), 7.30 (1 H, d, J = 15.4 Hz), 7.02 (1 H, d, J = 15.4 Hz), 6.28 (1 H,
m), 2.10 (4 H, m) 1.60 (4 H, m). 13C{1H}NMR (100 MHz, CDCl3):
δ = 189.0, 138.5, 137.4, 133.1, 132.1, 128.7, 128.5, 125.8, 120.6, 102.0,
85.7, 28.9, 26.1, 22.2, and 21.3 ppm. IR (neat): 3054, 3019, 2929,
2855, 2363, 2181, 1657, 1577, 1448, 1327, 1300, 1221, 1179, 1013,
957, 917, 857, 775, 695, and 578 cm−1. HRESI-MS: [C17H16O]+ = [M
+ H]+ requires 237.1279; found 237.1273. TLC: Rf = 0.6 (9:1, Hex/
EtOAc).
(E)-6-[(tert-Butyldimethylsilyl) oxy]-1-phenylhex-2-en-4-yn-1-one
(33). The enynone 33 was prepared following the method B from
terminal bromide42 (101 mg, 0.4 mmol), propargyl alcohol (50 mg,
0.37 mmol), freshly degassed piperidene (3.7 mL), and CuCl (3.6 mg,
0.04 mmol) stirred for 8 h at 0 °C. Purification by flash
chromatography (19:1; hexane:EtOAc) gave trans-enynone 33 (56
mg, 0.18 mmol, 48%) as a yellow oil. 1H NMR (400 MHz, CDCl3): δ
= 7.90 (2 H, dd, J = 1.4 and 8.2 Hz), 7.55 (1 H, tt, J = 1.3 and 6.6 Hz),
7.32−7.35 (2 H, m), 7.16−7.2 (1 H, d, J = 15.6 Hz), 6.85−6.90 (1 H,
dt, J = 1.9 & 15.6 Hz), 4.48 (2 H, d, J = 2.0 Hz), 0.80 (9 H, s), 0.15 (6
H, s). 13C{1H}NMR (100 MHz, CDCl3): δ = 189.1, 137.3, 133.6,
133.3, 128.8, 128.7, 124.8, 98.3, 83.1, 52.4, 31.7, 25.9, and 18.4 ppm.
IR (neat): 3063, 2954, 2927, 2855, 2367, 2342, 1722, 1662, 1595,
1521, 1463, 1365, 1287, 1257, 1213, 1160, 1086, 1010, 837, 778, and
694 cm−1. HRESI-MS: [C18H24O2Si]+ = [M + H]+ requires 301.1624;
found 301.1630. TLC: Rf = 0.6 (19:1, Hex/EtOAc).
(2E)-6-[(tert-butyldimethylsilyl)oxy]-1-phenylpentadeca-
2,7,9,11,13-pentaen-4-yn-1-one (34). The enynone 34 was prepared
following the method B from terminal bromide (50 mg, 0.24 mmol),
alkyne43 (77 mg, 0.26 mmol), freshly degassed piperidene (2.3 mL),
and CuCl (2.36 mg, 0.024 mmol) stirred for 8 h at 0 °C to RT.
Purification by flash chromatography (19:1 hexane:EtOAc) gave trans-
1
(E)-5-(1-Hydroxycyclohexyl)-1-phenylpent-2-en-4-yn-1-one (30).
The enynone 30 was prepared following the method B from terminal
bromide (100 mg, 0.48 mmol), cyclohexanol (65 mg, 0.52 mmol),
freshly degassed piperidene (4.7 mL), and CuCl (4.71 mg, 0.05 mmol)
stirred for 8 h at 0 °C. Purification by flash chromatography (9:1;
hexane:EtOAc) gave trans-enynone 29 (82 mg, 0.32 mmol, 67%) as a
enynone 34 (30 mg, 0.07 mmol, 30%) as a yellow oil. H NMR (400
MHz, CDCl3): δ = 7.80 (2 H, dd, J = 1.4 and 8.2 Hz), 7.41−7.45 (1 H,
tt, J = 1.3 and 6.6 Hz), 7.31−7.35 (2 H, m), 7.11 (1 H, d, J = 6.0 Hz),
6.74−6.78 (1 H, dd, J = 1.8 and 15.6 Hz), 4.39 (1 H, td, J = 1.6 and 6.5
Hz), 1.56 (2 H, m), 1.28 (2 H, m), 1.13 (15 H, m), 0.75 (9 H, s), 0.01
(3 H, s), −0.02 (3 H, s). 13C{1H}NMR (100 MHz, CDCl3): δ =
189.2, 137.3, 133.4, 133.3, 128.9, 128.6, 125.2, 101.9, 82.4, 63.9, 38.5,
32.0, 31.7, 29.8, 29.6, 29.4, 29.3, 25.9, 25.3, 22.8, 18.4, 14.2, −4.3, and
−4.8 ppm. IR (neat): 3536, 3438, 3061, 2922, 2853, 2206, 1734, 1664,
1589, 1461, 1288, 1163, 1087, 1021, 961, 835, 774, and 693 cm−1.
HRESI-MS: [C27H42NaO2Si]+ = [M + Na]+ requires 449.2852; found
449.2860. TLC: Rf = 0.6 (9:1, Hex/EtOAc).
1
brown oil. H NMR (400 MHz, CDCl3): δ = 7.96 (2 H, dd, J = 1.4
and 7.2 Hz), 7.58 (1 H, tt, J = 1.2 and 6.6 Hz), 7.48 (2 H, t, J = 8.0
Hz), 7.29 (1 H, d, J = 15.6 Hz), 6.93 (1 H, d, J = 15.6 Hz), 2.18 (1 H,
br s), 1.97 (2 H, m), 1.54−1.74 (8 H, m). 13C{1H}NMR (100 MHz,
CDCl3): δ = 189.0, 137.2, 133.6, 133.3, 128.8, 128.6, 124.9, 103.2,
82.4, 69.3, 39.8, 25.2, and 23.3 ppm. IR (neat): 3430 (OH), 3058,
2932, 2855, 2206, 1656, 1590, 1448, 1328, 1276, 1212, 1178, 1070,
963, 736, 696, 525, and 416 cm−1. HR ESI-MS: [C17H18O2]+ = [M +
H]+ requires 255.1385; found 255.1374. TLC: Rf = 0.6 (4:1, Hex/
EtOAc).
1-Phenylpentadeca-2,4-diyne-1,6-diol (35). The diynol 35 was
prepared following the method B from terminal bromide (50 mg, 0.24
mmol), alkyne44 (48 mg, 0.26 mmol), freshly degassed piperidene (2
mL), and CuCl (2 mg, 0.019 mmol) stirred for 9 h at 0 °C to RT.
10216
DOI: 10.1021/acs.joc.5b01780
J. Org. Chem. 2015, 80, 10208−10217

The Journal of Organic Chemistry
Article
Purification by flash chromatography (9:1; hexane:EtOAc) gave
coupled alcohol 35 (38 mg, 0.12 mmol, 51%) as a brown oil. H
Tam, W. Org. Lett. 2004, 6, 4543. (c) Fang, Z.; Wills, M. Org. Lett.
2014, 16, 374.
1
NMR (400 MHz, CDCl3): δ = 7.50−7.51 (2 H, d, J = 7.0 Hz), 7.33−
7.40 (3 H, m), 5.52 (1 H, s), 4.40−4.44 (1 H, t, J = 8.0 Hz), 1.68−1.72
(2 H, m), 1.41−1.43 (4 H, m), 1.25 (9 H, m), 0.86−0.89 (6 H, t, J =
6.2 Hz). 13C{1H}NMR (100 MHz, CDCl3): δ = 139.7, 128.9, 128.8,
126.7, 114.2, 81.5, 78.9, 70.7, 68.9, 65.1, 63.0, 37.6, 32.0, 29.8, 29.6,
29.4, 29.0, 25.1, 22.8, and 14.2 ppm. IR (neat): 3528, 3401, 3061,
2922, 2853, 2206, 1734, 1664, 1589, 1461, 1288, 1213, 1163, 1087,
1021, 961, 835, 774, 693, 630, 543, and 426 cm−1. TLC: Rf = 0.5 (4:1,
Hex/EtOAc). HRESI-MS: [C21H29O2]+ = [M + H]+ requires
313.2162; found 313.2169.
(8) We have performed the cascade reaction using low amounts of
piperidine in various degassed solvents like 1,2-dichlorobenzene (S:P;
4:1), and THF (S:P; 4:1). Here we observed that the coupling was
smooth and quick but the isomerization was very slow and took about
30 h for completion and gave the trans-enynone 2 in 50% and 55%
respective yields in 1,2-dichlorobenzene and THF.
(9) Crystallographic data information for 13′ has been deposited
with the Cambridge Crystallographic Data Centre with
CCDC1405917. Further details were given in Figure 4 of the
Supporting Information and accompanying CIF file.
(10) Even after stirring the pure diynol 12′ with piperidine for 24 h at
RT, there was no formation of enynone 12.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.5b01780.
■
(11) Crystallographic data information for 21 has been deposited
with the Cambridge Crystallographic Data Centre with
CCDC1405918. Further details were given in Figure 5 of the
Supporting Information and accompanying CIF file.
S
1H and 13C{1H}NMR spectra of all new compounds
synthesized during this study and ORTEP diagrams for
compounds 13′ and 21 (PDF)
X-ray crystallographic information (CIF) for 13′ (CIF)
X-ray crystallographic information (CIF) for 21 (CIF)
(12) Braun, R. U.; Ansorge, M.; Muller, T. J. J. Chem. - Eur. J. 2006,
̈
12, 9081.
(13) Matsuya, Y.; Koiwai, A.; Sugimoto, D. K.; Toyooki, N.
Tetrahedron Lett. 2012, 53, 5955.
(14) Xu, C.; Xu, M.; Yang, L.; Li, C. J. Org. Chem. 2012, 77, 3010.
(15) Park, J.; Yun, J.; Kim, J.; Jang, D.; Park, C. H.; Lee, K. Synth.
Commun. 2014, 44, 1924.
(16) Corey, E. J.; Niimura, K.; Konishi, Y.; Hashimoto, S.; Hamada,
Y. Tetrahedron Lett. 1986, 27, 2199.
AUTHOR INFORMATION
Corresponding Author
* E-mail: beeru@iitm.ac.in.
Notes
■
(17) Xu, C.; Xu, M.; Yang, L.; Li, C. J. Org. Chem. 2012, 77, 3010.
(18) Mark, R.; Reinhard, B. Tetrahedron Lett. 1997, 38, 7353.
(19) Chena, P.; Zhua, X. J. Mol. Catal. B: Enzym. 2013, 97, 184.
(20) Pwaar, S. K.; Wang, C.; Bhunia, S.; Jadhav, A. M.; Liu, R. Angew.
Chem., Int. Ed. 2013, 52, 7559.
The authors declare no competing financial interest.
(21) Zatalochnaya, O. V.; Gevorgyan, V. Org. Lett. 2013, 15, 2562.
(22) Ghosh, N.; Nayak, S.; Prabagar, B.; Sahoo, A. K. J. Org. Chem.
2014, 79, 2453.
(23) Chena, P.; Zhua, X. J. Mol. Catal. B: Enzym. 2013, 97, 184.
(24) Xu, C.; Xu, M.; Yang, L.; Li, C. J. Org. Chem. 2012, 77, 3010.
(25) Xu, S.; Zhuang, X.; Pan, X.; Zhang, Z.; Duan, L.; Liu, Y.; Zhang,
L.; Ren, X.; Ding, K. J. Med. Chem. 2013, 56, 4631.
(26) Park, J.; Yun, J.; Kim, J.; Jang, D.; Park, C. H.; Lee, K. Synth.
Commun. 2014, 44, 1924.
(27) Mark, R.; Reinhard, B. Tetrahedron Lett. 1997, 38, 7353.
(28) Seppanen, O.; Muuronen, M.; Helaja, J. Eur. J. Org. Chem. 2014,
2014, 4044.
(29) Corey, E. J.; Niimura, K.; Konishi, Y.; Hashimoto, S.; Hamada,
Y. Tetrahedron Lett. 1986, 27, 2199.
(30) Singh, V. Synth. Commun. 2010, 40, 1280.
(31) Galli, U.; Ercolano, E.; Carraro, L.; Blasi, R.; Sorba, G.;
Canonico, P. L.; Genazzani, A.; Tron, G. C.; Bilington, R. A.
ChemMedChem 2008, 3, 771.
(32) Bhanuchandra, M.; Kuram, M. R.; Sahoo, A. K. Org. Biomol.
Chem. 2012, 10, 3538.
(33) Pawar, S. K.; Wang, C.; Bhunia, S. A.; Jadhav, M.; Liu, R. Angew.
Chem., Int. Ed. 2013, 52, 7559.
(34) Ghosh, N.; Nayak, S.; Prabagar, B.; Sahoo, A. K. J. Org. Chem.
ACKNOWLEDGMENTS
■
We thank Indian Institute of Technology Madras, Chennai for
the financial support through CHY/13-14/622/NFSC/BEER
grant. B.S.C. thanks IIT Madras for HTRA fellowship. We
thank Mr Ramkumar for single crystal X-ray analysis.
REFERENCES
■
(1) (a) Tietze, L. F. Chem. Rev. 1996, 96, 115. (b) Wasilke, J.-C.;
Obrey, S. J.; Baker, T.; Bazan, G. C. Chem. Rev. 2005, 105, 1001.
(c) Nicolaou, K. C.; Edmonds, D. J.; Bulger, P. G. Angew. Chem., Int.
Ed. 2006, 45, 7134. (d) Kirsch, S. F. Synthesis 2008, 2008, 3183.
(e) Nicolaou, K. C.; Chen, J. S. Chem. Soc. Rev. 2009, 38, 2993.
(2) (a) Cheng, M.; Hulce, M. J. Org. Chem. 1990, 55, 964.
(b) Krause, N. Chem. Ber. 1991, 124, 2633. (c) Arndt, S.; Handke, G.;
Krause, N. Chem. Ber. 1993, 126, 251. (d) Purpura, M.; Krause, N. Eur.
J. Org. Chem. 1999, 1999, 267.
(3) (a) Reddy, C. R.; Reddy, M. D. J. Org. Chem. 2014, 79, 106.
(b) Toshima, H.; Aramaki, H.; Ichihara, A. Tetrahedron Lett. 1999, 40,
3587.
(4) Chen, J.; Fan, G.; Liu, Y. Org. Biomol. Chem. 2010, 8, 4806.
(5) (a) Chodkiewicz, W. Ann. Chim. Paris 1957, 2, 819. (b) Cadiot,
P.; Chodkiewicz, W. In Chemistry of Acetylenes, Viehe, H. G., Ed.;
Marcel, Dekker: New York, 1969, 597. (c) Marino, J. P.; Nguyen, H.
N. J. Org. Chem. 2002, 67, 6841. (d) Nishihara, Y.; Ikegashira, K.;
Hirabayashi, K.; Ando, J.; Mori, A.; Hiyama, A. T. J. Org. Chem. 2000,
65, 1780. (e) Bellina, F.; Carpita, A.; Mannocci, L.; Rossi, R. Eur. J.
Org. Chem. 2004, 2004, 2610. (f) Jiang, H.-F.; Wang, A.-Z. Synthesis
2007, 2007, 1649. (g) Reddy, B. V. S.; Rao, R. N.; Kumaraswamy, B.;
Yadav, J. S. Tetrahedron Lett. 2014, 55, 4590. (h) Kraus, G. A.; Bae, J.;
Wu, L.; Wurtele, E. Molecules 2006, 11, 758. (i) Sindhu, K. S.;
Thankachan, A. P.; Sajitha, P. S.; Anilkumar, G. Org. Biomol. Chem.
2015, 13, 6891.
2014, 79, 2453.
(35) Chang, H.; Liao, Y.; Liu, R. J. Org. Chem. 2007, 72, 8139.
(36) Nishi, M.; Kuninobu, Y.; Takai, K. Org. Lett. 2012, 14, 6116.
(37) Li, H.; Petersen, J. L.; Wang, K. J. Org. Chem. 2001, 66, 7804.
(38) Mehta, S.; Larock, R. C. J. Org. Chem. 2010, 75, 1652.
(39) Trost, B. M.; Pinkerton, A. B. Tetrahedron Lett. 2000, 41, 9627.
(40) Nandi, G. C.; Rathman, B. M.; Laali, K. Tetrahedron Lett. 2013,
54, 6258.
(41) Das, B. C.; Tang, X.; Evans, T. Tetrahedron Lett. 2012, 53, 1316.
(42) Lam, T. Y.; Wang, Y.; Danheiser, R. L. J. Org. Chem. 2013, 78,
9396.
(6) Alami, M.; Ferri, F. Tetrahedron Lett. 1996, 37, 2763.
(7) (a) See Scheme 5, compound 10j in Bowling, N. P.; Burrmann,
N. J.; Halter, R. J.; Hodges, J. A.; McMahon, R. J. J. Org. Chem. 2010,
75, 6382. (b) Villeneuve, K.; Riddell, N.; Jordan, R. W.; Tsui, G. C.;
(43) Grie, R.; Eugenekhaskin, G.; Foltz, J. L.; Schaefer, P. W.; Gries,
G. J. Chem. Ecol. 2003, 29, 2201.
(44) Steven, A.; Fleming, R. Tetrahedron Lett. 2005, 46, 8095.
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DOI: 10.1021/acs.joc.5b01780
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