Microwave-Assisted Organocatalytic Intramolecular Knoevenagel/Hetero Diels-Alder Reaction with O-(Arylpropynyloxy)-Salicylaldehydes: Synthesis of Polycyclic Embelin Derivatives

Article abstract of DOI:10.1021/acs.joc.6b01818

A highly efficient and regioselective approach to new polycyclic embelin derivatives through a domino Knoevenagel condensation/intramolecular hetero Diels-Alder reaction using O-(arylpropynyloxy)-salicylaldehydes in the presence of ethylenediamine diacetate (EDDA) is reported. This organocatalyzed protocol is compatible toward a wide range of aryl-substituted alkynyl ethers with electron-donating and electron-withdrawing groups. When other active methylene compounds were subjected to this domino reaction the corresponding adducts were obtained in high yield.

Full text of DOI:10.1021/acs.joc.6b01818

Subscriber access provided by CORNELL UNIVERSITY LIBRARY
Article
Microwave-assisted organocatalytic intramolecular Knoevenagel/
hetero Diels-Alder reaction with O-(arylpropynyloxy)-
salicylaldehydes. Synthesis of polycyclic embelin derivatives.
Pedro Martín-Acosta, Gabriela Feresin, Alejandro Tapia, and Ana Estevez-Braun
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b01818 • Publication Date (Web): 28 Sep 2016
Downloaded from http://pubs.acs.org on September 30, 2016
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a free service to the research community to expedite the
dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts
appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been
fully peer reviewed, but should not be considered the official version of record. They are accessible to all
readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered
to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published
in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just
Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor
changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers
and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors
or consequences arising from the use of information contained in these “Just Accepted” manuscripts.
The Journal of Organic Chemistry is published by the American Chemical Society.
1155 Sixteenth Street N.W., Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the
course of their duties.

Page 1 of 76
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Microwave-assisted organocatalytic intramolecular Knoevenagel/
hetero
Diels-Alder
reaction
with
O-(arylpropynyloxy)-
salicylaldehydes. Synthesis of polycyclic embelin derivatives.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
†
‡
‡
,†
Pedro Martín-Acosta, Gabriela Feresin, Alejandro Tapia, Ana Estévez-Braun*
†
Instituto Universitario de Bio-Orgánica Antonio González (CIBICAN), Departamento
de Química Orgánica, Universidad de La Laguna, Avda. Astrofísico Francisco Sánchez
Nº 2, 38206, La Laguna, Tenerife, Spain
*
E-mail: aestebra@ull.es
‡
Instituto de Biotecnología-Instituto de Ciencias Básicas, Universidad Nacional de San
Juan, Av. Libertador General San Martín 1109 (O), CP 5400, San Juan, Argentina
ꢀ
1
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 2 of 76
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
I
O
R2
OH
9
R2
CHO
O
O
CHO
HO
O
O
O
R2
O
9
embelin
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
R1
HO
R1
10 mol % EDDA
DCE, MW, 120 ºC, 10 min
O
R1
5 examples
8-100 %
3
3
A highly efficient and regioselective approach to new polycyclic embelin
derivatives through a domino Knoevenagel condensation /intramolecular hetero Diels-
Alder reaction using O-(arylpropynyloxy)-salicylaldehydes in the presence of
ethylenediamine diacetate (EDDA) is reported. This organocatalyzed protocol is
compatible toward a wide range of aryl-substituted alkynyl ethers with electron-
donating and electron-withdrawing groups. When other active methylene compounds
were subjected to this domino reaction the corresponding adducts were obtained in high
yield.
ꢀ
2
ACS Paragon Plus Environment

Page 3 of 76
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Introduction
Natural products scaffolds have been well recognised as “privileged structures”
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
in terms of their ability to be the basis for successful drugs. An assessment of all FDA-
approved new molecular entities (NMEs) reveals that natural products and their
2
derivatives represent over one-third of all NMEs. Such scaffolds can be used as cores
of compound libraries. As a privileged scaffold, the benzoquinone core is ubiquitous in
3
many bioactive natural products and pharmaceuticals. Understandably, particular
emphasis has been put on the development of methodologies for its synthesis, with an
aim to develop facile and efficient protocols to provide benzoquinone and
4
benzoquinone-based compound libraries.
Embelin (1) is a naturally occurring alkyl substituted hydroxybenzoquinone and
a major constituent of the Andean medicinal plant Oxalis erythrorhiza Gillies ex Hook
5
&
Arn, belonging to the Oxalidaceae family.
6
7
It has been reported that embelin possess antidepressant, antitumor, anti-
8
9
10
11
12
inflammatory, analgesic, antioxidant, antidiabetic, wound healing, and
1
3
antibacterial properties. All these activities make embelin a “promiscuous
1
4
15
compound” due specific interactions with multiple targets such as 5-lipoxygenase,
1
6
17
18
19
20
21
the stress chaperone mortalin, XIAPs, NFκB, STAT-3, Akt and mTOR, and
consequently an interesting scaffold for synthesizing new and more selective
therapeutic agents.
Since that increased molecular complexity in natural products and diverse
22
compounds, is associated with improved selectivity and frequency of binding, the
development of libraries of complex compounds with balanced physicochemical
properties could led to obtain compounds having efficient binding with specific
ꢀ
3
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 4 of 76
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
23
biological targets. In this sense, the use of domino reactions is a good synthetic
2
4
strategy for the construction of complex polycyclic scaffolds.
In recent years the domino-Knoevenagel-hetero-Diels-Alder reaction, developed
by Tietze’s group, has emerged as a powerful process that not only allows the efficient
synthesis of complex compounds but also permits the preparation of highly diverse
molecules, specially pyran and pyrano-fused carbocycles. These pyran and pyrano-
fused ring systems represent important molecular frameworks, which are found in a
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
5
wide range of natural and synthetic bioactive molecules.
There are numerous examples of the use of unsaturated aromatic- and aliphatic
aldehydes with several 1,3-dicarbonyl compounds in intramolecular domino
Knoevenagel-hetero-Diels-Alder reaction (DKHDA). However, the use of alkynes as
dienophiles in DKHDA reactions is limited due to their low reactivity compared to
2
6
alkenes. In most of cases non-activated terminal alkynes have been used. Thus the
pioneer works of Balalaie et al reported the use of CuI as an efficient Lewis acid for
27
activation of various non-activated alkynes using different organic solvents, inclusive
2
8
trifluoroethanol. In these cases the formation of an intermediate copper acetylide is
postulated which is consistent with the observation that only terminal acetylenes
participate in the reaction, and end-capped substrates do not undergo the cycloaddition
reaction. Immobilized ZrO
2
-nanopowder in the ionic liquid 1-butyl-3-
] was used as a suitable Lewis-acid for DKHDA
methylimidazolium nitrate [bmim][NO
3
2
9
reactions with unactivated terminal alkynes. Parmar et al reported a solvent-free
tetrabutylammonium-hydrogensulfate catalysed DKHDA using 2-
30
(
alkynyloxy)acetophenones with pyrazolones.
Most of the examples of DKHDA with non-activated terminal alkynes use 1,3-
2
7a
dicarbonyl compounds such as 1,3-indanedione, Meldrum’s acid and dimethyl
ꢀ
4
ACS Paragon Plus Environment

Page 5 of 76
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
31
27c
barbituric acid. Some active methylene compounds such as 4-hydroxy-coumarin,
2
7b
30, 32
benzoylacetonitrile, 1-phenyl-3-methyl pyrazolone,
dihydroindole-2-thione, 4-
3
3
hydroxydithiocoumarin have been also used, but 2-hydroxy-1,4-benzoquinones have
never been employed in this kind of transformation involving alkynes.
To the best of our knowledge, there are not any papers on intramolecular
DKHDA reactions using non terminal alkynes type O-(arylpropynyloxy)-
salicylaldehydes. Due to our interest in the preparation of bioactive embelin
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
3a,13b, 25c
derivatives
and, since this natural benzoquinone (1) contains a 2-hydroxy-1,4-
quinonic moiety which is a synthetic equivalent to a 1,3-dicarbonyl compound, this
molecule is an adequate substrate for DKHDA reactions using the mentioned non-
terminal alkynes. Thus, a series of angular polycyclic embelin derivatives with two
points of diversity could be obtained and some compounds result more selective and
efficient than embelin (1) in biological bioassays.
Results and discussion
Compounds that contain an aldehyde functionality together with a suitably placed 3-
phenylprop-2-yn-1-oxy moiety are substrates which have never been studied before in
the DKHDA protocol. These types of compounds were formed from the corresponding
O-propargylated salicylaldehydes and aryl iodides via Sonogashira cross-coupling
reactions. The starting O-propargylated salicylaldehydes (4) were obtained in excellent
2 3
yields by reaction of salicylaldehyde derivatives and propargyl bromide using K CO in
3
4
dimethylformamide.
For the Sonogashira cross-coupling reactions, initially we selected the reaction
3
5
conditions published by Kwong et al for the preparation of terminal-substituted
alkynyl ethers. They used Pd(PPh
3
)
2
Cl
2
(3 mol%), Cu I (6 mol%), piperidine (2 equiv)
ꢀ
5
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 76
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
and dry toluene under nitrogen at 30ºC. Using these conditions in the reaction of
propargylated aldehyde 4a and 1-iodo-4-methoxybenzene (5a), the resulting alkynyl
ether (6a) was obtained in 56 % yield. In order to improve this yield we carried out the
reaction using other aprotic and more polar solvents such as DMSO and DMF but we
did not obtain a higher yield (43% DMSO, 58% DMF), only when THF was used a
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
8
6% yield was achieved. Table 1 summarizes the yields obtained in the preparation of a
variety of aryl-substituted alkynyl ethers with two points of diversity.
Table 1. Preparation of aryl-substituted alkynyl ethers (6a-6ai)
R2
CHO
I
6 mol % CuI
CHO
O
3
mol % Pd(PPh ) Cl
3
2
2
O
+
THF, piperidine
R1
R2
R1
6
4
5
a
Entry
R
1
R
2
product
6a
yield (%)
86
1
2
3
4
5
6
7
8
9
1
5-Cl
5-Cl
5-Cl
5-Cl
5-Cl
5-Cl
5-Cl
5-Br
5-Br
5-Br
5-Br
5-Br
4-OCH
3-OCH
2-OCH
3-OH
H
3
3
3
6b
6c
97
74
6d
6e
69
98
3-NO
3-CF
2
6f
100
96
3
6g
4-OCH
3-OCH
2-OCH
3-OH
H
3
3
3
6h
6i
85
88
0
6j
57
11
6k
6l
38
1
2
94
ꢀ
6
ACS Paragon Plus Environment

Page 7 of 76
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
1
1
1
1
3
4
5
6
5-Br
5-Br
H
3-NO
3-CF
2
6m
6n
88
82
64
85
61
83
78
84
86
82
84
56
61
87
98
87
85
97
59
55
98
90
100
3
4-OCH
3-OCH
2-OCH
3-OH
H
3
3
3
6o
H
6p
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
17
H
6q
1
1
2
2
2
8
9
0
1
2
H
6r
H
6s
H
3-NO
3-CF
2
6t
H
3
6u
4-OCH
4-OCH
4-OCH
4-OCH
4-OCH
4-OCH
4-OCH
3
3
3
3
3
3
3
4-OCH
3-OCH
2-OCH
3-OH
H
3
3
3
6v
23
6w
6x
2
2
2
2
2
4
5
6
7
8
6y
6z
3-NO
3-CF
2
6aa
6ab
6ac
6ad
6ae
6af
6ag
6ah
6ai
3
29
4-CO
4-CO
4-CO
4-CO
4-CO
4-CO
4-CO
2
2
2
2
2
2
2
C
C
C
C
C
C
C
2
2
2
2
2
2
2
H
H
H
H
H
H
H
5
5
5
5
5
5
5
4-OCH
3-OCH
2-OCH
3-OH
H
3
3
3
3
3
3
3
3
0
1
2
3
4
3-NO
3-CF
2
35
3
a
Isolated yield
ꢀ
The reaction appeared to be quite general with respect to a wide variety of
functional groups such as -Cl, -Br, -OMe, and - CO in salicylaldehyde. The best
2
2 5
C H
ꢀ
7
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 76
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
yields were obtained with iodo-benzenes having electron-withdrawing substituents as 1-
iodo-3-nitrobenzene (entries 6, 13, 20, 27, 34) and 1-iodo-3-(trifluoromethyl)benzene
(entries 7, 14, 21, 28, 35). However, the steric hindrance of the iodo-benzenes had
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
significant effect on the reaction, and the yields were decreased for 1-iodo-2-
methoxybenzene (entries 3, 10, 17, 24, 31). Only in one case, with the bromo-
salicylaldehyde derivative (entry 10), together the formation of the corresponding aryl-
substituted alkynyl ethers (6j, 57%), an alkyne dimer was also obtained in 26% yield.
To optimize the DKHDA reaction conditions, the reaction of compound 6a and
embelin (1) was chosen as a model reaction. We decided to carry out the reaction using
ethylendiamine diacetate (EDDA, 10 mol %) as an effective organocatalyst for the
initial Knoevenagel condensation. In the first attempt we investigated if in the absence
of other additional catalyst, the DKHDA adduct could be formed. We were delighted to
find that adduct 7a was obtained in 23% in refluxing ethanol (Table 2, entry 1). A series
of solvents (acetonitrile, toluene, dichloromethane, and dichloethane) were investigated
(entries 2-5). Amongst the solvents tested, dichloroethane provided the best yield (entry
5). We also carried out the DKHDA reaction without EDDA (entry 6), and adduct 7a
was achieved in low yield (9%). When the reaction was performed at room temperature
compound 7a was obtained in 47% yield after 24 h (entry 7). In order to improve the
yield, microwave irradiation was also used and, adduct 7a was obtained in 93% yield in
DCE at 120º C, for 10 min.
ꢀ
8
ACS Paragon Plus Environment

Page 9 of 76
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Table 2. Optimization of the DKHDA reaction between 1 and 6a
OMe
OMe
O
CHO
O
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
OH
O
O
9
9
+
HO
Cl
HO
O
O
O
6a
1
7a
Cl
a
Yield
(%)
Entry
Conditions
1
2
3
4
5
6
7
10 mol% EDDA, EtOH, reflux, 3 h
10 mol% EDDA, CH CN, reflux, 3 h
23
48
50
66
68
9
3
10 mol% EDDA, toluene, reflux, 3.5 h
10 mol% EDDA, DCM, reflux, 5.5 h
10 mol% EDDA, DCE, reflux, 3.5 h
DCM, reflux, 12h
10 mol% EDDA, DCM, rt, 24 h
47
93
8
10 mol% EDDA, DCE, MW, 120°C, 10 min
a
Isolated yield
With the optimized protocol in hand, the scope of this domino process was then
assessed through the variation of aryl-substituted alkynyl ethers 6 (Table 3). Diversely
substituted angular embelin adducts could be prepared in good yields (up to 100%),
demonstrating the versatility of this domino process. As a general trend, the DKHDA
reaction is tolerant to a large variety of aryl-substituted alkynyl ethers with electron-
donating and electron-withdrawing groups. This substituent diversity results very
attractive for the establishment of structure-activity relationships after biological
evaluation.
ꢀ
9
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 76
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Table 3. Synthesis of novel tetracyclic embelin adducts
R2
R2
O
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
O
CHO
OH
O
O
10 mol % EDDA
9
9
+
HO
HO
R1
DCE, MW, 120 ºC, 10 min
O
O
O
1
6
7
R1
OCH
3
H CO
3
O
O
O
O
O
O
O
O
O
O
O
9
9
OCH
3
9
OH
9
HO
HO
HO
HO
O
O
O
O
O
7
d
7
9
a
7b
98% Cl
7c
65% Cl
9
0%
3% Cl
Cl
OCH
3
O
O
O
O
O
O
O
O
9
9
NO
2
9
CF
3
9
HO
HO
HO
HO
O
O
O
O
O
O
O
O
7
9
e
7f
100%
7g
86%
7h
73%
4%
Cl
Cl
Cl
Br
O
O
O
O
O
O
O
O
O
9
OH
9
9
OCH
3
9
OCH
3
HO
HO
HO
HO
O
O
O
O
O
O
O
7
5
l
7
i
7j
57%
7k
75% Br
7%
8
1%
Br
Br
Br
OCH
3
O
O
O
O
O
O
O
O
9
OCH
3
9
NO
2
9
CF3
9
HO
HO
HO
HO
O
O
O
O
O
O
O
O
7m
8%
7n
94%
7o
88%
7p
70%
8
Br
Br
ꢀ
ꢀ
H3CO
O
O
O
O
O
O
O
O
O
O
O
9
9
OH
9
9
NO2
HO
HO
HO
HO
O
O
O
O
O
7
8
t
7
8
q
7r
80%
7s
83%
2%
0%
ꢀ
10
ACS Paragon Plus Environment

Page 11 of 76
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
OCH
3
3
H CO
O
O
O
O
O
O
O
O
O
O
O
O
9
CF
3
9
9
OCH3
9
HO
HO
HO
HO
O
O
O
O
7
8
u
3%
7v
82%
7w
72%
7x
50%
OCH
O
3
OCH3
OCH
O
3
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
O
O
O
O
O
O
O
O
O
O
9
OH
9
9
CF
3
9
NO
2
HO
HO
HO
HO
O
O
O
O
7
7
y
2%
7z
92%
7ab
38%
7
6
aa
2%
OCH
O
3
OCH3
O
OCH
3
OCH
O
3
OCH
3
O
O
O
O
O
O
O
O
9
9
OCH
3
9
OH
9
OCH
3
HO
HO
HO
HO
O
O
O
7
5
ac
8%
7ad
66%
7ae
67%
O
O
7
5
af
6%
CO
O
2
C
2
H
5
CO
O
2
C
2
H
5
CO C H
2
2
5
2 2 5
CO C H
O
O
O
O
O
O
9
NO
2
CF3
9
9
HO
HO
HO
O
O
O
O
7
8
ah
2%
7ai
85%
7
ag
80%
CO
2
C
2
H
5
CO
2
C
2
H
5
2 2 5
CO C H
ꢀ
The reaction can be rationalized via the formation of a Knoevenagel adduct
intermediate, which undergoes an intramolecular hetero-Diels-Alder reaction to form 7
Scheme 1). The process is regioselective since only the 1,4-benzoquinone adduct is
(
obtained from the more electron-poor heterodiene. Two new fused rings next to the
benzoquinone core and three σ bonds (two C-C σ bonds and one C-O σ bond) were
formed in this domino reaction. The regiosubstitution of the corresponding adducts was
confirmed by the two- and three-bond correlations detected in the HMBC spectrum and
13
4f, 13b, 25
also by the C NMR chemical shifts of the quinone carbonyls.
ꢀ
ꢀ
11
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 12 of 76
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
The introduction of a phenyl group in the alkyne favours the energy of HOMO
of the dienophile and for this reason is not necessary an additional activation of the
triple bond when aryl-end-capped alkynes are involved. In fact when the reaction of
embelin was carried out with the terminal alkyne derivative 4a (5-chloro-2-(prop-2-yn-
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2 2
-yloxy)benzaldehyde) under the same reaction conditions (10 mol% EDDA, CH Cl ,
MW, 120 ºC, 10 min) the formation of the corresponding adduct was not detected.
R2
R2
O
R2
CHO
O
O
OH
O
O
O
O
9
9
O
+
9
HO
HO
R1
O
HO
O
O
1
6
7
R1
R1
Scheme 1. Plausible formation of compounds 7
In order to see the scope of this protocol regarding the 1,3 dicarbonyl component, we
carried out the DKHDA reaction with the following 1,3-dicarbonyl compounds:
cyclohexanedione (8), dimedone (9) and barbituric acid (10). The active methylene
compounds 4-hydroxy-6-methyl-2H-pyran-2-one (11), 4-hydroxycoumarin (12) and 2-
hydroxy-1,4-naphthoquinone (13), which are of interest from a biological point of view,
were also used. The results are summarized in Scheme 2. As we can see all enolizable
symmetric cyclic 1,3-dicarbonyls annulated efficiently with 5-chloro-2-((3-phenylprop-
2-yn-1-yl)oxy)benzaldehyde (6a) by this one-pot domino procedure. With respect to
the compounds 11-13 two different products easy to separate by chromatography were
obtained as a consequence of the cycloaddition reaction with the two heterodienes
present in the corresponding Knoevenagel adduct intermediate. Thus from the reaction
ꢀ
12
ACS Paragon Plus Environment

Page 13 of 76
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
with 4-hydroxy-6-methyl-2H-pyran-2-one (11), 4H-pyran-4-one (17a) and 2H-pyran-2-
one (17b) derivatives were formed in a 1:1 ratio. In a similar way the pyrano[2,3-
c]chromone (18a) and the pyrano[2,3-c]coumarin (18b) were obtained by using 4-
hydroxy-coumarin (12). In this case the compounds were obtained in a 1:1.5 ratio in
favours of the coumarin derivative formed from the heterodiene intermediate involving
the keto carbonyl group instead of the lactone carbonyl group. Finally when the
DKHDA between 6a and 2-hydroxynaphthoquinone (13) was carried out, the
corresponding 1,4-naphthoquinone (19a) and 1,2-naphthoquinone (19b) were obtained
in a 1.5:1 ratio in favours of the p-naphthoquinone formed from the more electron-poor
heterodiene. The structures of the adducts (14-19) were unequivocally determined using
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
D and 2D NMR spectroscopy.ꢀ
ꢀ
Cl
Cl
O
O
Cl
O
O
O
O
O
HN
1
5 (94%)
O
O
O
N
H
O
HN
O
OMe
OMe
1
4 (87%)
O
N
H
O
1
6 (89%)
10
O
OMe
O
9
O
O
O
OMe
O
8
CHO
O
O
O
1
9a
O
(55%)
Cl
6a
O
Cl
O
OH
OH
11
+
O
O
Cl
O
OH
O
1
3
1
2
O
O
Cl
Cl
1
9b
Cl
Cl
O
(31%)
O
O
O
O
O
O
O
+
+
O
O
OMe
O
O
O
O
O
O
OMe
OMe
1
8a (37%)
18b (56%)
OMe
OMe
17a (45%)
17b (45%)
Scheme 2. Scope of the reaction regarding 1,3-dicarbonyl compounds.
Conclusions
ꢀ
13
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 14 of 76
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
In conclusion, we have reported a microwave-assisted intramolecular approach for the
synthesis of a set of new angular tetracyclic embelin derivatives. To the best of our
knowledge, these are the first examples of intramolecular DKHDA reaction using O-
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(arylpropynyloxy)-salicylaldehydes. The presence of the phenyl group is essential to
favours the intramolecular cycloaddition reaction. Diversely substituted embelin
adducts could be prepared in good yields from a large variety of aryl-substituted alkynyl
ethers with electron-donating and electron-withdrawing groups. This efficient
organocatalyzed protocol was successfully applied to a variety of active methylene
compounds. We expect that some of the synthesized compounds, with increased
molecular complexity, result more active and selective than our starting compound, the
natural benzoquinone embelin (1). The corresponding biological assays are in progress.
Experimental section
General Experimental Procedures. IR spectra were obtained using a Fourier
Transform Infrared spectrometer. NMR spectra were recorded in CDCl
3
or DMSO at
1
13
5
00 or 600 MHz for H NMR and 125 or 150 MHz for C NMR. Chemical shifts are
1
13
given in (δ) parts per million and coupling constants (J) in hertz (Hz). H and C
spectra were referenced using the solvent signal as internal standard. Melting points
were taken on a capillary melting point apparatus and are uncorrected. Microwave
reactions were conducted in sealed glass vessels (capacity 5 mL) using a CEM Discover
microwave reactor. HREIMS were recorded using a high-resolution magnetic trisector
(EBE) mass analyzer. Analytical thin-layer chromatography plates used were Polygram-
Sil G/UV254. Preparative thin-layer chromatography was carried out with Analtech
silica gel GF plates (20 x 20 cm, 1000 Microns) using appropriate mixtures of ethyl
acetate and hexanes. All solvents and reagents were purified by standard techniques
ꢀ
14
ACS Paragon Plus Environment

Page 15 of 76
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
36
reported or used as supplied from commercial sources. All compounds were named
using the ACD40 Name-Pro program, which is based on IUPAC rules. The embelin (1)
used in the reactions was obtained from Oxalis erythrorhiza Gillies ex Hook. & Arn.
following the procedure described in reference 5.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
General Procedure for the Synthesis of O-propargylated salicylaldehydes (4a-4e).
To a solution of the corresponding salicylaldehyde (1.0 mmol) in DMF (5 mL) was
2 3
added anhydrous K CO (152.7 mg, 1.1 mmol) followed by propargyl bromide (0.13
mL, 1.1 mmol). The reaction mixture was stirred at room temperature until
disappearance of the starting salicylaldehyde. Ice water (100 mL) was then added and
the product was quantitatively obtained by filtration.
5
-chloro-2-(prop-2-yn-1-yloxy)benzaldehyde (4a). Following the general procedure,
to a solution of 0.5 g (3.2 mmol) of 5-chlorosalicylaldehyde and 0.49 g (3.5 mmol) of
CO in dry DMF (5 mL), 0.4 mL (3.5 mmol) of propargyl bromide was added to
obtain the propargylated salicylaldehyde 4a in a quantitative yield. H-NMR (500
K
2
3
34a
1
MHz, CDCl
3
) δ 2.58 (1H, t, J=2.3 Hz), 4.83 (2H, d, J = 2.3 Hz), 7.09 (1H, d, J = 8.9
13
Hz), 7.51 (1H, dd, J = 2.7, 8.9 Hz), 7.81 (1H, d, J=2.7 Hz, 1H), 10.40 (s, 1H); C-NMR
(125 MHz, CDCl
3
2
) δ 56.7 (CH ), 76.9 (CH), 77.0 (C), 114.9 (CH), 126.4 (C), 127.5 (C),
1
28.2 (CH), 135.2 (CH), 158.1 (C), 188.2 (CH).
5
-bromo-2-(prop-2-yn-1-yloxy)benzaldehyde (4b). Following the general
procedure, to a solution of 0.5 g (2.5 mmol) of 5-bromosalicylaldehyde and 0.38 g (2.7
mmol) of K CO in dry DMF (5 mL), 0.31 mL (2.7 mmol) of propargyl bromide was
added to obtain the propargylated salicylaldehyde 4b in a quantitative yield. H-NMR
500 MHz, CDCl ) δ 2.59 (1H, t, J = 2.4 Hz), 4.83 (2H, d, J = 2.4 Hz, 2H), 7.09 (d, J =
2
3
3
4a
1
(
3
1
3
8
.8 Hz, 1H), 7.51 (dd, J = 2.8, 8.9 Hz, 1H), 7.81 (d, J =2.7 Hz, 1H), 10.41 (s, 1H); C-
ꢀ
15
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 16 of 76
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
NMR (125 MHz, CDCl
127.7 (C), 128.1 (CH), 135.2 (CH), 158.1 (C), 188.2 (CH).
-(prop-2-yn-1-yloxy)benzaldehyde (4c). Following the general procedure, to a
solution of 0.5 g (4.1 mmol) of salicylaldehyde and 0.62 g (4.5 mmol) of K CO in dry
DMF (5 mL), 0.5 mL (4.5 mmol) of propargyl bromide was added to obtain the
3 2
) δ 55.8 (CH ), 76.9 (CH), 77.2 (C), 115.0 (CH), 126.5 (C),
2
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
3
34a
1
propargylated salicylaldehyde 4c in a quantitative yield. H-NMR (500 MHz, CDCl
3
)
δ 2.57 (1H, t, J = 2.2 Hz), 4.83 (2H, t, J = 2.4 Hz), 7.09 (1H, td, J = 2.9, 7.7 Hz), 7.12
(dd, J = 1.7, 8.4 Hz, 1H), 7.57 (m, 1H), 7.86 (ddd, J=1.7, 3.4, 7.6 Hz, 1H), 10.49 (s,
1
3
1
H); C-NMR (125 MHz, CDCl
21.7 (CH), 125.6 (C), 128.6 (CH), 135.7 (CH), 159.8 (C), 189.5 (CH).
-methoxy-2-(prop-2-yn-1-yloxy)benzaldehyde (4d). Following the general
procedure, to a solution of 0.50 g (3.2 mmol) of 4-methoxysalicylaldehyde and 0.49 g
3.5 mmol) of K CO in dry DMF (5 mL), 0.4 mL (3.5 mmol) of propargyl bromide
3 2
) δ 56.4 (CH ), 76.5 (CH), 77.7 (C), 113.2 (CH),
1
4
(
2
3
3
4b
was added to obtain the propargylated salicylaldehyde (4d) in a quantitative yield.
1
H-NMR (500 MHz, CDCl
3
) δ 2.58 (1H, t, J=2.4 Hz), 3.88 (3H, s), 4.80 (2H, d, J=2.4
13
Hz), 6.60 (m, 2H), 7.84 (1H, d, J=9.1 Hz, 1H), 10.30 (1H, s); C-NMR (125 MHz,
CDCl
3 3 2
) δ 55.7 (CH ), 55.4 (CH ), 76.6 (CH), 77.6 (C), 99.5 (CH), 106.8 (CH), 119.6
(C), 130.7 (CH), 161.5 (C), 165.9 (C), 188.1 (CH).
Ethyl-4-formyl-3-(prop-2-yn-1-yloxy)benzoate (4e). Following the general
procedure, to a solution of 0.30 g (1.5 mmol) of 4-formyl-3-hydroxybenzoate and 0.24
g (1.7 mmol) of K
2 3
CO in dry DMF (5 mL), was added 0.15 mL (1.7 mmol) of
propargyl bromide to obtain the propargylated salicylaldehyde 4e in a quantitative
3
4b 1
yield.
3
H-NMR (500 MHz, CDCl ) δ 1.39 (3H, t, J=7.3 Hz), 2.59 (1H, t, J=2.4 Hz),
4
.37 (2H, q, J=7.2 Hz), 4.89 (1H, d, J=2.4 Hz), 7.17 (1H, d, J=8.7 Hz), 8.25 (2H, dd,
1
3
J=2.3, 8.8 Hz, 2H), 8.51 (1H, d, J=2.3 Hz, 1H), 10.46 (s, 1H); C-NMR (125 MHz,
ꢀ
16
ACS Paragon Plus Environment

Page 17 of 76
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
3 3 2 2
CDCl ) δ 14.3 (CH ), 56.7 (CH ), 61.2 (CH ), 76.9 (CH), 77.0 (C), 113.1 (CH), 124.5
(C), 125.3 (C), 130.6 (CH), 136.8 (CH), 162.6 (C), 165.4 (C), 188.5 (CH).
ꢀ
General Procedure for the Sonogashira Cross-Coupling of Aryl Iodides with
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Propargylated Salicylaldehydes
To a mixture of 50 mg of the propargylated salicylaldehyde, iodobenzene (1.1 equiv),
and piperidine (2.0 equiv) in 1 mL of dry THF under an Ar atmosphere, Pd(PPh
mol %) and CuI (6 mol %) were added successively. The reaction mixture was stirred at
0°C until complete consumption of starting salicylaldehyde. Then the solvent was
3 2 2
) Cl (3
3
removed under reduced pressure provided, and the residue was purified by column
chromatography on silica gel (hexane/EtOAc) to afford the phenyl propargylated
salicylaldehyde derivative.
5
-chloro-2-((3-(4-methoxyphenyl)prop-2-yn-1-yl)oxy)benzaldehyde (6a). Following the
general procedure, the treatment of 50 mg (0.26 mmol) of 5-chloro-2-(prop-2-yn-1-
yloxy)benzaldehyde 4a with 4-iodoanisole (67.2 mg, 0.27 mmol), Pd(PPh Cl (5.4
3
)
2
2
mg, 3 mol %), CuI (2.9 mg, 6 mol %) and piperidine (51 µL, 0.5 mmol) in dry THF (1
mL) under an Ar atmosphere at 30°C for 2.5 h, followed by evaporation of the solvent
under reduced pressure and purification on silica gel column chromatography
(Hex/EtOAc, 7:3) afforded 66.9 mg (86%) of compound 6a as a yellow oil. IR (neat)
ν
max 2256, 1696, 1632, 1523, 1474, 1432, 1325, 1225, 1202, 1187, 1154, 1122, 1032,
-
1 1
1010, 961, 897, 744, 705, 632 cm ; H-NMR (500 MHz, CDCl
3
) δ 3.81 (s, 3H), 5.03 (s,
2
2
H), 6.84 (d, J = 8.2 Hz, 2H), 7.18 (d, J = 8.6 Hz, 2H), 6.74 (s, 3H), 7.33 (d, J = 8.6 Hz,
1
3
H), 7.52 (dd, J = 2.0, 8.6 Hz, 1H), 7.82 (d, J = 1.8 Hz, 1H), 10.45 (s, 1H); C-NMR
(125 MHz, CDCl
3
) δ 55.3 (CH ), 57.8 (CH ), 81.1 (C), 88.6 (C), 113.7 (C), 114.0 (CH x
3
2
2
), 115.2 (CH x 2), 126.4 (C), 127.2 (C), 133.4 (CH x 2), 135.2 (CH), 158.5 (C), 160.2
+
(
C), 188.5 (CH); EIMS m/z 300 (M , 4), 286 (11), 277 (16), 262 (100), 183 (48), 155
ꢀ
17
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 18 of 76
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
35
+
(
13 3
48); HREIMS 300.0565 (calcd for C17H O Cl (M ) 300.0553), 287.0313 (calcd. for
3
7
+
C
16 10 3 3
H O Cl (M -CH ) 287.0289).
5
-chloro-2-((3-(3-methoxyphenyl)prop-2-yn-1-yl)oxy)benzaldehyde (6b). Following the
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
general procedure, the treatment of 50 mg (0.26 mmol) of 5-chloro-2-(prop-2-yn-1-
yloxy)benzaldehyde with 3-iodoanisole (32.2 µL, 0.27 mmol), Pd(PPh Cl (5.4 mg, 3
3
)
2
2
mol %), CuI (2.9 mg, 6 mol %) and piperidine (51 µL, 0.5 mmol,) in dry THF (1 mL)
under an Ar atmosphere at 30°C for 2.5h, followed by evaporation of the solvent under
reduced pressure and purification on silica gel column chromatography (Hex/EtOAc,
7
:3) afforded 75.8 mg (97 %) of compound 6b as a yellow oil. IR (neat) νmax 1670,
-
1
589, 1473, 1400, 1288, 1258, 1223, 1180, 1126, 995, 957, 899, 810, 752, 687, 648 cm
1
1
;
3
H-NMR (500 MHz, CDCl ) δ 3.79 (s, 3H), 5.04 (s, 2H), 6.90 (ddd, J = 0.5, 2.5, 8.3
Hz, 2H), 6.95 (dd, J= 1.3, 2.4 Hz, 1H), 7.01 (dt, J= 1.1, 7.6 Hz, 1H), 7.17 (d, J = 8.9
Hz, 1H), 7.22 (t, J= 8.1 Hz, 1H), 7.53 (dd, J = 2.7, 8.9 Hz, 1H), 7.82 (d, J= 2.7 Hz, 1H),
13
1
3 2 3
0.46 (s, 1H); C-NMR (125 MHz, CDCl ) δ 55.7 (CH ), 57.3 (CH ), 82.2 (C), 88.5
(C), 115.3 (CH), 115.6 (CH), 116.7 (CH), 122.6 (C), 124.3 (CH), 126.6 (C), 127.4 (C),
1
28.1 (CH), 129.5 (CH), 135.2 (CH), 158.4 (C), 159.4 (C), 188.3 (CH); EIMS m/z 300
+
(
[M ], 10), 270 (1), 237 (1), 145 (100), 102 (13); HREIMS 302.0513 (calcd for
3
7
+
35
+
C
17 13 3 13 3
H O Cl (M ) 302.0524), 300.0540 (calcd. for C17H O Cl (M ) 300.0553).
5
-chloro-2-((3-(2-methoxyphenyl)prop-2-yn-1-yl)oxy)benzaldehyde (6c). Following the
general procedure, the treatment of 50 mg (0.26 mmol) of 5-chloro-2-(prop-2-yn-1-
yloxy)benzaldehyde with 2-iodoanisole (35.1 µL, 0.27 mmol), Pd(PPh Cl (5.4 mg, 3
3
)
2
2
mol %), CuI (2.9 mg, 6 mol %) and piperidine (51 µL, 0.5 mmol) in dry THF (1 mL)
under an Ar atmosphere at 30°C for 3h, followed by evaporation of the solvent under
reduced pressure and purification on silica gel column chromatography (Hex/ EtOAc,
ꢀ
18
ACS Paragon Plus Environment

Page 19 of 76
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
7
:3) afforded 57.6 mg (74 %) of compound 6c. IR (neat) νmax 2222, 1678, 1593, 1477,
-
1
1438, 1396, 1265, 1223, 1184, 1126, 1045, 1003, 960, 895, 810, 744, 706, 644 cm .
1
H-NMR (500 MHz, CDCl
3
) δ 3.85 (s, 3H), 5.09 (s, 2H), 6.87 (d, J = 8.5 Hz, 1H), 6.90
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(
td, J = 0.9, 7.5 Hz, 1H), 7.24 (d, J= 8.9 Hz, 1H), 7.32 (m, 1H), 7.36 (dd, J= 1.6, 7.5 Hz,
1
3
1
H), 7.52 (dd, J = 2.9, 8.9 Hz, 1H), 7.82 (d, J = 2.7 Hz, 1H), 10.46 (s, 1H); C-NMR
(125 MHz, CDCl
3
) δ 55.8 (CH ), 58.1 (CH ), 85.1 (C), 86.4 (C), 110.7 (CH), 110.8 (C),
2
2
115.6 (CH), 120.5 (CH), 126.6 (C), 127.2 (C), 127.9 (CH), 130.6 (CH), 133.7 (CH),
+
1
1
3
5
35.1 (CH), 158.6 (C), 160.3 (C), 188.5 (CH); EIMS m/z 300 (M , 4), 281 (4), 262 (3),
3
7
+
13 3
82 (2), 145 (100), 115 (39); HREIMS 302.0540 (calcd for C17H O Cl (M )
3
5
+
02.0524), 300.0537 (calcd. for C17
13 3
H O Cl (M ) 300.0553).
-chloro-2-((3-(3-hydroxyphenyl)prop-2-yn-1-yl)oxy)benzaldehyde (6d). Following the
general procedure, the treatment of 50 mg (0.26 mmol) of 5-chloro-2-(prop-2-yn-1-
yloxy)benzaldehyde with 3-hydroxyphenol (59.4 mg, 0.27 mmol), Pd(PPh Cl (5.4
3
)
2
2
mg, 3 mol %), CuI (2.9 mg, 6 mol %) and piperidine (51 µL, 0.5 mmol) in dry THF (1
mL) under an Ar atmosphere at 30°C for 2.5 h, followed by evaporation of the solvent
under reduced pressure and purification on silica gel column chromatography (Hex/
EtOAc, 7:3) afforded 51.4 mg (69 %) of compound 6d. IR (neat) νmax 1674, 1577,
-
1
1
439, 1412, 1373, 1292, 1269, 1199, 1126, 1022, 987, 894, 814, 783, 744, 687 cm ;
1
3
H-NMR (500 MHz, CDCl ) δ 5.02 (s, 2H), 6.85 (dd, J = 2.0, 8.1 Hz, 1H), 6.90 (dd, J=
1.4, 2.3 Hz, 1H), 7.08 (dt, J = 1.3, 7.7 Hz, 1H), 7.16 (m, 2H), 7.52 (dd, J = 2.7, 8.8 Hz,
13
1
3 2
H), 7.81 (d, J = 2.6 Hz, 1H), 10.43 (s, 1H); C-NMR (125 MHz, CDCl ) δ 57.8 (CH ),
82.3 (C), 88.3 (C), 115.4 (CH), 116.7 (CH), 118.5 (CH), 122.7 (C), 124.2 (CH), 126.4
(C), 127.4 (C), 128.1 (CH), 129.7 (CH), 135.4 (CH), 155.5 (C), 158.5 (C), 188.9 (CH);
+
EIMS m/z 286 (M , 13), 262 (11), 219 (60), 183 (10), 131 (100); HREIMS 288.0356
ꢀ
19
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 20 of 76
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
37
+
35
+
(
calcd. for C16
H
11
O
3
Cl (M ) 288.0367), 286.0387 (calcd. for C16
H
11
O
3
Cl (M )
2
86.0397).
-chloro-2-((3-phenylprop-2-yn-1-yl)oxy)benzaldehyde (6e). Following the general
5
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
procedure, the treatment of 50 mg (0.26 mmol) of 5-chloro-2-(prop-2-yn-1-
2
yloxy)benzaldehyde with iodobenzene (35.5 µL, 0.27 mmol), Pd(PPh Cl (5.4 mg, 3
3
)
2
mol %), CuI (2.9 mg, 6 mol %) and piperidine (51 µL, 0.5 mmol) in dry THF (1 mL)
under an Ar atmosphere at 30°C for 3h, followed by evaporation of the solvent under
reduced pressure and purification on silica gel column chromatography (Hex/EtOAc,
37
7
1
7
1
1
1
:3) afforded 69.0 mg (98 %) of compound 6e as a yellow oil. IR (neat) νmax 1678,
597, 1574, 1477, 1415, 1377, 1272, 1238, 1207, 1173, 1123, 1049, 995, 895, 810, 779,
-
1 1
09, 687, 667 cm ; H-NMR (500 MHz, CDCl
3
) δ 5.04 (s, 2H), 7.17 (d, J = 8.8 Hz,
H), 7.32 (m, 3H), 7.41 (m, 2H), 7.52 (dd, J = 2,8, 8.8 Hz, 1H), 7.82 (d, J = 2.7 Hz,
1
3
3 2
H), 10.45 (s, 1H); C-NMR (125 MHz, CDCl ) δ 57.3 (CH ), 82.4 (C), 88.6 (C),
15.3 (CH), 121.7 (C), 126.6 (C), 127.4 (C), 128.1 (CH), 128.4 (CH x 2), 131.8 (CH x
+
2), 135.2 (CH), 158.5 (C), 188.3 (CH); EIMS m/z 270 (M , 16), 240 (2), 207 (2), 154
37
+
(
11 2
3), 115 (100); HREIMS 272.0425 (calcd for C16H O Cl (M ) 272.0418), 270.0455
3
5
+
(
11 2
calcd. for C16H O Cl (M ) 270.0448).
5-chloro-2-((3-(3-nitrophenyl)prop-2-yn-1-yl)oxy)benzaldehyde (6f).
Following the general procedure, the treatment of 50 mg (0.26 mmol) of 5-chloro-2-
(
prop-2-yn-1-yloxy)benzaldehyde with 3-nitro-iodobenzene (67.2 mg, 0.27 mmol),
Pd(PPh Cl (5.4 mg, 3 mol %), CuI (2.9 mg, 6 mol %) and piperidine (51 µL, 0.5
3
)
2
2
mmol) in dry THF (1 mL) under an Ar atmosphere at 30°C for 3h, followed by
evaporation of the solvent under reduced pressure and purification on silica gel column
chromatography (Hex/EtOAc, 7:3) afforded 82.8 mg (100 %) of compound 6f. IR (neat)
ν
max 3522, 3398, 3086, 1674, 1589, 1524, 1477, 1350, 1227, 1169, 1061, 976, 902, 814,
ꢀ
20
ACS Paragon Plus Environment

Page 21 of 76
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
-1
1
7
37, 671 cm ; H-NMR (500 MHz, CDCl
3
) δ 5.07 (s, 2H), 7.14 (d, J = 8.9 Hz, 1H),
7.52 (t, J=8.0 Hz, 1H), 7.55 (dd, J= 2.7, 8.7 Hz, 1H), 7.72 (dt, J= 1.2, 7.7 Hz, 1H), 7.84
(
d, J= 2.7 Hz, 1H), 8.21 (ddd, J= 1.1, 2.3, 8.3 Hz, 1H), 8.28 (t, J= 1.8 Hz, 1H), 10.46 (s,
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
3
1
3 2
H); C-NMR (125 MHz, CDCl ) δ 57.3 (CH ), 85.1 (C), 85.9 (C), 115.0 (CH), 123.5
(
C), 123.8 (CH), 126.5 (C), 126.6 (CH), 127.6 (C), 128.3 (C), 129.6 (C), 135.3 (CH),
+
1
37.5 (CH), 148.1 (C), 158.2 (C), 188.1 (CH); EIMS m/z 300 (M , 10), 270 (1), 237 (1),
3
7
+
13 3
145 (100), 102 (13); HREIMS 302.0513 (calcd for C17H O Cl (M ) 302.0524),
3
5
+
3
00.0540 (calcd. for C17
13 3
H O Cl (M ) 300.0553).
5
-chloro-2-((3-(4-trifluoromethylphenyl)prop-2-yn-1-yl)oxy)benzaldehyde (6g).
Following the general procedure, the treatment of 50 mg (0.26 mmol) of 5-chloro-2-
prop-2-yn-1-yloxy)benzaldehyde with 4-trifluoromethyl-1-iododbenzene (38.9 µL,
.27 mmol), Pd(PPh Cl (5.4 mg, 3 mol %), CuI (2.9 mg, 6 mol %) and piperidine (51
(
0
3
)
2
2
µL, 0.5 mmol) in dry THF (1 mL) under an Ar atmosphere at 30°C for 3h, followed by
evaporation of the solvent under reduced pressure and purification on silica gel column
chromatography (Hex/EtOAc, 7:3) afforded 84.9 mg (96 %) of compound 6g as a oil
yellow. IR (neat) νmax 3522, 3398, 3074, 2874, 1682, 1593, 1744, 1331, 1258, 1215,
-1
1
1
3
161, 1084, 976, 899, 802, 683 cm ; H-NMR (500 MHz, CDCl ) δ 5.06 (s, 2H), 7.15
(d, J = 8.9 Hz, 1H), 7.46 (t, J = 7.7 Hz, 1H), 7.54 (dd, J = 2,7, 8.7 Hz, 1H), 7.60 (t, J =
13
7
.3 Hz, 2H), 7.68 (s, 1H), 7.83 (d, J = 2.8 Hz, 1H), 10.45 (s, 1H); C-NMR (125 MHz,
CDCl
3 2
) δ 57.4 (CH ), 84.0 (C), 86.9 (C), 115.0 (CH), 122.6 (C), 125.6 (CH, JC-F= 2.7
Hz), 126.5 (C), 127.5 (C), 128.2 (CH x 2), 128.6 (C, JC-F= 3.7 Hz), 129.0 (CH), 131.1
+
(
C, JC-F= 34.1 Hz), 134.9 (CH), 135.2 (CH), 158.2 (C), 188.1 (CH); EIMS m/z 338 (M ,
3
7
13 3
16), 308 (3), 272 (5), 182 (100); HREIMS 302.0513 (calcd for C17H O Cl
35
3
02.0524), 300.0540 (calcd. for C17
H
13
O
3
Cl 300.0553).
ꢀ
21
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 22 of 76
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
5
-bromo-2-((3-(4-methoxyphenyl)prop-2-yn-1-yl)oxy)benzaldehyde (6h). Following the
general procedure, the treatment of 50 mg (0.21 mmol) of 5-bromo-2-(prop-2-yn-1-
yloxy)benzaldehyde with 4-iodoanisole (51.6 mg, 0.27 mmol), Pd(PPh Cl (4.4 mg, 3
3
)
2
2
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
mol %), CuI (2.5 mg, 6 mol %) and piperidine (42 µL, 0.5 mmol) in dry THF (1 mL)
under an Ar atmosphere at 30°C for 3h, followed by evaporation of the solvent under
reduced pressure and purification on silica gel column chromatography (Hex/EtOAc,
4
:1) afforded 58.4 mg (85 %) of compound 6h as a yellow oil. IR (neat) νmax 2218,
2203, 1678, 1597, 1508, 1474, 1400, 1292, 1254, 1238, 1192, 1254, 1238, 1192, 1123,
-1
1
1
029, 1018, 999, 972, 922, 879, 791, 640, 621 cm ; H-NMR (500 MHz, CDCl
δ 3.80 (s, 3H), 5.03 (s, 2H), 6.83 (d, J = 7.8 Hz, 2H), 7.12 (d, J = 9.1 Hz, 2H), 7.35 (d, J
8.7 Hz, 2H), 7.65 (dd, J = 2.5, 8.8 Hz, 1H), 7.95 (d, J = 2.5 Hz, 1H), 7.52 (dd, J = 2.0,
3
)
=
1
3
8
5
.6 Hz, 1H), 7.82 (d, J = 1.8 Hz, 1H), 10.45 (s, 1H); C-NMR (125 MHz, CDCl
3
) δ
5.3 (CH ), 57.7 (CH ), 81.1 (C), 88.6 (C), 113.7 (C), 114.0 (CH x 2), 114.4 (C), 115.6
3
2
(CH), 126.9 (C), 131.1 (CH), 133.4 (CH x 2), 138.1 (CH), 159.0 (C), 160.2 (C), 188.3
+
(CH); EIMS m/z 344 (M , 29), 314 (6), 262 (4), 145 (100), 102 (70); HREIMS
81
79
3
3
46.0019 (calcd for C17
44.0048).
13 3 13 3
H O Br 346.0028), 344.0067 (calcd. for C17H O Br
5-bromo-2-((3-(3-methoxyphenyl)prop-2-yn-1-yl)oxy)benzaldehyde (6i). Following the
general procedure, the treatment of 50 mg (0.21 mmol) of 5-bromo-2-(prop-2-yn-1-
3 2 2
yloxy)benzaldehyde with 3-iodoanisole (26.3 µL, 0.27 mmol), Pd(PPh ) Cl (4.4 mg, 3
mol %), CuI (2.5 mg, 6 mol %) and piperidine (42 µL, 0.5 mmol) in dry THF (1 mL)
under an Ar atmosphere at 30°C for 3h, followed by evaporation of the solvent under
reduced pressure and purification on silica gel column chromatography (Hex/EtOAc,
38
4
1
:1) afforded 63.7 mg (88 %) of compound 6i as a yellow oil. IR (neat) νmax 1674,
589, 1477, 1377, 1323, 1269, 1230, 1207, 1180, 1122, 1084, 1041, 1022, 1003, 987,
ꢀ
22
ACS Paragon Plus Environment

Page 23 of 76
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
-1
1
8
83, 837, 783, 702, 682, 652 cm ; H-NMR (500 MHz, CDCl
2H), 6.90 (ddd, J = 0.8, 2.6, 8.2 Hz, 1H), 6.93 (dd, J = 1.6, 2.5 Hz, 1H), 7.01 (dt, J =
.2, 7.7 Hz, 1H), 7.11 (d, J = 8.9 Hz, 1H), 7.22 (t, J = 7.9 Hz, 1H), 7.65 (dd, J = 2.6, 8.8
3
) δ 3.78 (s, 3H), 5.03 (s,
1
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
3
Hz, 1H), 7.96 (d, J = 2.6 Hz, 1H), 10.43 (s, 1H); C-NMR (125 MHz, CDCl
3
) δ 55.3
(
CH ), 57.6 (CH ), 82.1 (C), 88.5 (C), 114.4 (C), 115.5 (CH), 115.6 (CH), 116.7 (CH),
3 2
1
22.6 (C), 124.3 (CH), 126.8 (C), 129.5 (CH), 131.1 (CH), 138.1 (CH), 158.9 (C),
+
159.3 (C), 188.2 (CH); EIMS m/z 344 (M , 14), 314 (2), 262 (2), 145 (100), 102 (30);
8
1
13 3
HREIMS 346.0036 (calcd for C17H O Br 346.0028), 344.0050 (calcd. for
7
9
17 13 3
C H O Br 344.0048).
5-bromo-2-((3-(2-methoxyphenyl)prop-2-yn-1-yl)oxy)benzaldehyde (6j). Following the
general procedure, treatment of 50 mg (0.21 mmol) of 5-bromo-2-(prop-2-yn-1-
yloxy)benzaldehyde with 2-methoxy-1-iodobenzene (28.7 µL, 0.22 mmol),
Pd(PPh
3 2 2
) Cl (3% mol, 4.4 mg), CuI (6% mol, 2.5 mg) and piperidine (2 eq. 0.5 mmol,
4
2 µL) in dry THF (1 ml) under an Ar atmosphere at 30°C for 2.5 h, followed by
evaporation of the solvent under reduced pressure and purification on silica gel column
chromatography (Hex/AcOEt, 7:3), afforded the corresponding product 6j (50.7 mg,
7
0%) together the alkyne dimer 6j´ (13.3 mg, 25%).
6j: IR (neat) νmax 3526, 3402, 2874, 2223, 1686, 1589, 1477, 1385, 1265, 1223, 1061,
-1 1
1
3
007, 957, 891, 810, 744, 648, 633 cm ; H-NMR (500 MHz, CDCl ) δ 3.86 (s, 3H),
5.09 (s, 2H), 6.87 (d, J = 8.3 Hz, 1H), 6.90 (td, J = 1.2, 7.8 Hz, 1H), 7.19 (d, J = 8.8
Hz, 1H), 7.32 (ddd, J = 1.7, 7.9, 8.3 Hz), 7.36 (dd, J = 1.7, 7.6 Hz, 1H), 7.66 (dd, J =
1
3
2
.6, 8.9 Hz, 1H), 7.96 (d, J = 2.7 Hz, 1H), 10.44 (s, 1H); C-NMR (125 MHz, CDCl
3
)
δ 55.8 (CH ), 58.0 (CH ), 85.1 (C), 86.4 (C), 110.7 (CH), 110.8 (C), 114.4 (C), 116.0
3
2
(
CH), 120.5 (CH), 126.9 (C), 130.6 (CH), 131.0 (CH), 133.7 (CH), 138.0 (CH), 159.0
+
(
C), 160.3 (C), 188.4 (CH); EIMS m/z 345 ((M+1) , 3), 328 (2), 262 (30), 183 (14), 145
ꢀ
23
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 24 of 76
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
81
(
13 3
100); HREIMS 346.0041 (calcd for C17H O Br 346.0028), 344.0052 (calcd. for
7
9
C
17 13 3
H O Br 344.0048).
-
1 1
6
j´: IR (neat) νmax 3522, 3398, 1620, 1473, 1396, 1061, 972, 852, 806, 667 cm ; H-
NMR (500 MHz, CDCl ) δ 4.90 (s, 2H), 6.97 (d, J = 8.7 Hz, 1H), 7.66 (dd, J= 2.6, 8.8
Hz, 1H), 7.96 (d, J = 2.6 Hz, 1H), 10.37 (s, 1H); C-NMR (125 MHz, CDCl
CH ), 71.9 (C), 73.8 (C), 115.0 (C), 115.1 (CH), 126.8 (C), 131.4 (CH), 138.2 (CH),
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
3
1
3
3
) δ 57.0
(
2
+
158.3 (C), 187.8 (CH); ESI(+)-MS m/z 498 ((M+Na) , 100), 449 (52); HR-ESIMS
79
4
96.9000 (calcd. for C20
H
12
O
4
Br
2
Na 496.8994), 498.8980 (calcd. for
7
9
81
81
C
20 12 4 12 4 2
H O Br BrNa 496.8994), 500.8959 (calcd. for C20H O Br Na 500.8969).
5
-bromo-2-((3-(3-hydroxyphenyl)prop-2-yn-1-yl)oxy)benzaldehyde (6k). Following the
general procedure, the treatment of 50 mg (0.21 mmol) of 5-bromo-2-(prop-2-yn-1-
yloxy)benzaldehyde with 3-iodophenol (48.5 mg, 0.22 mmol), Pd(PPh Cl (4.4 mg, 3
3
)
2
2
mol %), CuI (2.5 mg, 6 mol %) and piperidine (42 µL, 0.5 mmol) in dry THF (1 mL)
under an Ar atmosphere at 30°C for 3h, followed by evaporation of the solvent under
reduced pressure and purification on silica gel column chromatography (Hex/EtOAc,
3
1
6
1
:7), afforded 26.7 mg (38%) of compound 6k as a yellow oil. IR (neat) νmax 1678,
589, 1469, 1439, 1392, 1269, 1269, 1207, 1180, 1123, 1011, 991, 879, 852, 810, 771,
-
1 1
82, 651 cm ; H-NMR (500 MHz, CDCl
3
) δ 5.03 (s, 2H), 6.84 (dd, J = 2.4, 8.1 Hz,
H), 6.89 (dd, J = 1.2, 2.5 Hz, 1H), 6.98 (dt, J = 1.2, 7.6 Hz, 2H), 7.11 (d, J = 8.9 Hz),
7.18 (t, J = 7.8 Hz, 1H), 7.67 (dd, J = 2.6, 8.9 Hz, 1H), 7.96 (d, J = 2.7 Hz, 1H), 10.42
13
(
3 2
s, 1H); C-NMR (125 MHz, CDCl ) δ 57.6 (CH ), 82.3 (C), 88.2 (C), 114.5 (C), 114.9
(C), 115.7 (CH), 116.6 (CH), 118.4 (CH), 122.7 (C), 124.3 (CH), 129.7 (CH), 131.2
+
(
CH), 138.2 (CH), 155.5 (C), 158.9 (C), 188.6 (CH); EIMS m/z 329 (M , 5), 277 (15),
8
1
2
3
11 3
19 (68), 199 (100), 130 (49); HREIMS 331.9885 (calcd for C16H O Br 331.9871),
7
9
29.9887 (calcd. for C16
H
11
O
3
Br 329.9892).
ꢀ
24
ACS Paragon Plus Environment

Page 25 of 76
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
5
-bromo-2-((3-phenylprop-2-yn-1-yl)oxy)benzaldehyde (6l). Following the general
procedure, the treatment of 50 mg (0.21 mmol) of 5-bromo-2-(prop-2-yn-1-
2
yloxy)benzaldehyde with 3-iodobenzene (29.0 µL, 0.27 mmol), Pd(PPh Cl (4.4 mg, 3
3
)
2
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
mol %), CuI (2.5 mg, 6 mol %) and piperidine (42 µL, 0.5 mmol) in dry THF (1 mL)
under an Ar atmosphere at 30°C for 3h, followed by evaporation of the solvent under
reduced pressure and purification on silica gel column chromatography (Hex/EtOAc,
3
8
4
:1) afforded 62.1 mg (94 %) of compound 6l as a yellow oil. IR (neat) νmax 2987,
2886, 2233, 1647, 1585, 1474, 1458, 1400, 1276, 1223, 1122, 1180, 1157, 1142, 1069,
-1
1
9
3
95, 957, 887, 806, 752, 686, 652 cm ; H-NMR (500 MHz, CDCl ) δ 5.04 (s, 2H),
7.13 (d, J = 8.9 Hz, 1H), 7.33 (m, 3H), 7.42 (m, 2H), 7.66 (dd, J = 2.6, 8.8 Hz, 1H),
13
7
3 2
.97 (d, J = 2.6 Hz, 1H), 10.44 (s, 1H); C-NMR (125 MHz, CDCl ) δ 57.6 (CH ), 82.3
(C), 88.6 (C), 114.5 (C), 115.6 (CH), 121.7 (C), 126.9 (C), 128.4 (CH x 2), 129.1 (CH),
+
131.2 (CH), 131.8 (CH x 2), 138.1 (CH), 158.9 (C), 188.2 (CH); EIMS m/z 316 (M ,
81
5
3
5
11 2
5), 287 (8), 235 (7), 207 (9), 115 (100); HREIMS 315.9923 (calcd for C16H O Br
7
9
15.9922), 313.9933 (calcd. for C16
11 2
H O Br 313.9942).
-bromo-2-((3-(3-nitrophenyl)prop-2-yn-1-yl)oxy)benzaldehyde (6m). Following the
general procedure, the treatment of 50 mg (0.21 mmol) of 5-bromo-2-(prop-2-yn-1-
yloxy)benzaldehyde with 3-nitro-1-iodobenzene (54.9 mg, 0.27 mmol), Pd(PPh Cl
4.4 mg, 3 mol %), CuI (2.5 mg, 6 mol %) and piperidine (42 µL, 0.5 mmol) in dry THF
1 mL) under an Ar atmosphere at 30°C for 3h, followed by evaporation of the solvent
3
)
2
2
(
(
under reduced pressure and purification on silica gel column chromatography (Hex/
EtOAc, 7:3) afforded 66.9 mg (88 %) of compound 6m as a yellow oil. IR (neat) νmax
1682, 1589, 1524, 1466, 1393, 1342, 1273, 1219, 1177, 1119, 1018, 979, 879, 814, 733,
-1
1
6
7
3
71, 652 cm ; H-NMR (500 MHz,CDCl ) δ 5.07 (s, 2H), 7.09 (d, J = 8.9 Hz, 1H),
.52 (t, J = 8.0 Hz, 1H), 7.66 (dd, J = 2.6, 8.9 Hz, 1H), 7.72 (dt, J = 1.3, 7.7 Hz, 1H),
ꢀ
25
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 26 of 76
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
7
1
1
1
3
3
5
.89 (d, J = 2.6 Hz, 1H), 8.21 (ddd, J = 1.0, 2.3, 8.3 Hz, 1H), 8.28 (t, J = 1.8 Hz, 1H),
1
3
3 2
0.44 (s, 1H); C-NMR (125 MHz, CDCl ) δ 57.3 (CH ), 85.0 (C), 86.0 (C), 114.8 (C),
15.3 (CH), 123.4 (C), 123.8 (CH), 124.9 (C), 126.7 (CH), 126.9 (C), 129.6 (CH),
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
+
31.4 (CH), 137.5 (CH), 138.2 (CH), 158.6 (C), 188.0 (CH); EIMS m/z 360 (M , 9),
8
1
4
30 (3), 252 (5), 160 (100), 114 (56); HREIMS 360.9779 (calcd for C16H10NO Br
7
9
60.9773), 358.9785 (calcd. for C16
4
H10NO Br 358.9793).
-bromo-2-((3-(3-trifluoromethylphenyl)prop-2-yn-1-yl)oxy)benzaldehyde (6n).
Following the general procedure, the treatment of 50 mg (0.21 mmol) of 5-bromo-2-
prop-2-yn-1-yloxy)benzaldehyde with 3-trifluoromethyl-1-iodobenzene 3-nitro-1-
iodobenzene (31.8 µL, 0.27 mmol), Pd(PPh Cl (4.4 mg, 3 mol %), CuI (2.5 mg, 6
mol %) and piperidine (42 µL, 0.5 mmol) in dry THF (1 mL) under an Ar atmosphere at
0°C for 3h, followed by evaporation of the solvent under reduced pressure and
(
3
)
2
2
3
purification on silica gel column chromatography (Hex/EtOAc, 7:3) afforded 66.4 mg
(82 %) of compound 6n as a yellow oil. IR (neat) νmax 1682, 1589, 1470, 1435, 1393,
-1
1
331, 1273, 1219, 1177, 1157, 1115, 1099, 1076, 1007, 972, 883, 806, 690, 660 cm ;
1
3
H-NMR (500 MHz, CDCl ) δ 5.05 (s, 2H), 7.09 (d, J = 8.9 Hz, 1H), 7.46 (t, J = 7.8
Hz, 1H), 7.59 (dd, J = 1.8, 7.7 Hz, 2H), 7.67 (m, 2H), 7.96 (d, J = 2.6 Hz, 1H), 10.43 (s,
1
3
1
H); C-NMR (125 MHz, CDCl
3 2
) δ 57.4 (CH ), 84.0 (C), 86.9 (C), 114.6 (C), 115.3
(CH), 122.6 (C), 125.7 (CH, JC-F= 3.7 Hz), 127.9 (C, JC-F= 268.7 Hz), 128.6 (CH, JC-F
=
3
.9 Hz), 129.0 (CH), 131.1 (C, JC-F= 33.6 Hz), 130.4 (C), 131.3 (CH), 134.9 (CH),
+
138.1 (CH), 158.7 (C), 188.1 (CH); EIMS m/z 381 (M , 25), 352 (8), 275 (11), 182
8
1
10 3 2
(100); HREIMS 383.9793 (calcd for C17H F O Br 383.9796), 381.9824 (calcd. for
7
9
C
17 10 3 2
H F O Br 381.9816).
2-((3-(4-methoxyphenyl)prop-2-yn-1-yl)oxy)benzaldehyde (6o). Following the general
procedure, the treatment of 50 mg (0.31 mmol) of 2-(prop-2-yn-1-yloxy)benzaldehyde
ꢀ
26
ACS Paragon Plus Environment

Page 27 of 76
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
3 2 2
with 4-iodoanisole (76.7 mg, 0.27 mmol), Pd(PPh ) Cl (6.6 mg, 3 mol %), CuI (3.6
mg, 6 mol %) and piperidine (60 µL, 0.5 mmol) in dry THF (1 mL) under an Ar
atmosphere at 30°C for 3h, followed by evaporation of the solvent under reduced
pressure and purification on silica gel column chromatography (Hex/EtOAc, 7:3)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
3
7
afforded 53.0 mg (64 %) of compound 6o as a yellow oil. IR (neat) νmax 3521, 3398,
-1
1
2
237, 1682, 1597, 1508, 1458, 1223, 1099, 1030, 957, 825, 752, 640 cm ; H-NMR
500 MHz, CDCl ) δ 3.80 (s, 3H), 5.04 (s, 2H), 6.83 (d, J = 8.7 Hz, 2H), 7.08 (t, J= 7.5
Hz, 1H), 7.21 (d, J = 8.4 Hz, 1H), 7.37 (d, J = 8.7 Hz, 2H), 7.57 (m, 1H), 7.87 (dd, J =
(
3
1
3
1
8
.5, 7.7 Hz, 1H), 10.53 (s, 1H); C-NMR (125 MHz, CDCl
3 3 2
) δ 55.3 (CH ), 57.5 (CH ),
1.6 (C), 88.1 (C), 113.5 (CH), 113.9 (C), 114.0 (CH x 2), 121.5 (CH), 125.6 (C), 128.5
(CH), 133.4 (CH x 2), 135.7 (CH
2
), 160.1 (C), 160.2 (C), 189.8 (CH); EIMS m/z 266
+
+
(M , 20), 237 (7), 145 (100), 102 (10); HREIMS 266.0945 (calcd for C17
H
14
O
3
(M )
2
66.0943).
-((3-(3-methoxyphenyl)prop-2-yn-1-yl)oxy)benzaldehyde (6p). Following the general
2
procedure, the treatment of 50 mg (0.31 mmol) of 2-(prop-2-yn-1-yloxy)benzaldehyde
with 3-iodoanisole (39 µL, 0.32 mmol), Pd(PPh Cl (6.6 mg, 3 mol %), CuI (3.6 mg, 6
3
)
2
2
mol %) and piperidine (60 µL, 0.5 mmol) in dry THF (1 mL) under an Ar atmosphere at
30°C for 3h, followed by evaporation of the solvent under reduced pressure and
purification on silica gel column chromatography (Hex/EtOAc, 7:3) afforded 70.4 mg
(85 %) of compound 6p as a yellow oil. IR (neat) νmax 1682, 1593, 1458, 1369, 1285,
-
1 1
1
261, 1211, 1157, 1103, 1042, 1022, 987, 864, 833, 791, 764, 687, 648 cm ; H-NMR
(
500 MHz, CDCl ) δ 3.78 (s, 3H), 5.04 (s, 2H), 6.89 (ddd, J = 0.9, 2.6, 8.3 Hz, 1H),
3
6
2
.95 (dd, J = 1.4, 2.5 Hz, 1H), 7.02 (dt, J = 1.2, 7.7 Hz, 1H), 7.08 (m, 1H), 7.21 (m,
H), 7.57 (ddd, J = 1.8, 7.3, 9.0 Hz, 1H), 7.87 (dd, J = 1.8, 7.7 Hz, 1H), 10.53 (s, 1H);
1
3
C-NMR (125 MHz, CDCl
3
) δ 55.2 (CH
3
2
), 57.3 (CH ), 82.7 (C), 88.0 (C), 113.4 (CH),
ꢀ
27
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 28 of 76
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
1
1
15.4 (CH), 116.7 (CH), 121.5 (CH), 122.8 (C), 124.2 (CH), 125.5 (C), 128.5 (CH),
+
29.4 (CH), 135.7 (CH), 159.3 (C), 160.0 (C), 189.6 (CH); EIMS m/z 266 (M , 44), 237
+
(10), 145 (100), 102 (17); HREIMS 266.0958 (calcd for C17
H
14
O
3
(M ) 266.0943).
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
-((3-(2-methoxyphenyl)prop-2-yn-1-yl)oxy)benzaldehyde (6q). Following the general
procedure, the treatment of 50 mg (0.31 mmol) of 2-(prop-2-yn-1-yloxy)benzaldehyde
with 2-iodoanisole (42.6 µL, 0.32 mmol), Pd(PPh Cl (6.6 mg, 3 mol %), CuI (3.6 mg,
mol %) and piperidine (60 µL, 0.5 mmol) in dry THF (1 mL) under an Ar atmosphere
3
)
2
2
6
at 30°C for 3h, followed by evaporation of the solvent under reduced pressure and
purification on silica gel column chromatography (Hex/EtOAc, 7:3) afforded 50.0 mg
(61 %) of compound 6q as a yellow oil. IR (neat) νmax 2233, 1686, 1597, 1481, 1458,
-
1 1
1
369, 1265, 1250, 1215, 1161, 1099, 1018, 960, 833, 752, 694, 648 cm ; H-NMR (500
) δ 3.85 (s, 3H), 5.09 (s, 2H), 6.86 (d, J = 8.4 Hz, 1H), 6.89 (td, J = 1.0, 7.5
Hz, 1H), 7.07 (m, 1H), 7.27 (d, J = 8.4 Hz, 1H), 7.30 (ddd, J = 1.8, 7.5, 9.2 Hz, 1H),
.37 (dd, J = 1.7, 7.6 Hz, 1H), 7.57 (ddd, J = 1.9, 7.3, 9.1 Hz, 1H), 7.87 (dd, J = 1.8, 7.7
MHz, CDCl
3
7
1
3
Hz, 1H), 10.54 (s, 1H); C-NMR (125 MHz, CDCl
3
3 2
) δ 55.7 (CH ), 57.6 (CH ), 84.6
(C), 86.9 (C), 110.6 (CH), 111.0 (C), 113.7 (CH), 120.4 (CH), 121.4 (CH), 125.5 (C),
1
28.3 (CH), 129.5 (C), 130.4 (CH), 133.7 (CH), 135.6 (CH), 160.2 (C), 189.8 (CH);
+
EIMS m/z 266 (M , 10), 249 (14), 235 (10), 145 (100), 115 (50); HREIMS 266.0935
+
(calcd for C17
H
14
O
3
(M ) 266.0943).
2
-((3-(3-hydroxyphenyl)prop-2-yn-1-yl)oxy)benzaldehyde (6r). Following the general
procedure, the treatment of 50 mg (0.31 mmol) of 2-(prop-2-yn-1-yloxy)benzaldehyde
with 3-iodophenol (72.1 mg, 0.32 mmol), Pd(PPh Cl (6.6 mg, 3 mol %), CuI (3.6 mg,
3
)
2
2
6 mol %) and piperidine (60 µL, 0.5 mmol) in dry THF (1 mL) under an Ar atmosphere
at 30°C for 3h, followed by evaporation of the solvent under reduced pressure and
purification on silica gel column chromatography (Hex/EtOAc, 7:3) afforded 64.8 mg
ꢀ
28
ACS Paragon Plus Environment

Page 29 of 76
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
(
78 %) of compound 6r. IR (neat) νmax 3398, 2924, 1682, 1597, 1470, 1288, 1211,
-
1 1
1053, 787, 756, 687, 652 cm ; H-NMR (500 MHz, CDCl
3
) δ 3.87 (s, 1H), 4.99 (s, 2H),
.59 (ddd, J = 0.6, 2.1, 8.5 Hz, 1H), 6.67 (d, J = 2.2 Hz, 1H), 6.86 (dd, J = 1.8, 8.1 Hz,
H), 6.93 (s, 1H), 6.97 (d, J = 7.8 Hz, 1H), 7.15 (t, J = 7.9 Hz, 1H), 7.84 (d, J = 8.7 Hz,
6
1
1
1
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
3
H), 10.30 (s, 1H); C-NMR (125 MHz, CDCl
3 2
) δ 57.4 (CH ), 82.9 (C), 87.7 (C),
13.6 (CH), 116.4 (CH), 118.4 (CH), 121.6 (CH), 123.0 (C), 124.4 (CH), 125.6 (C),
128.6 (CH), 129.7 (CH), 135.8 (CH), 155.4 (C), 160.1 (C), 189.9 (CH); HRESIMS
2
75.0688 (calcd. for C16
12 3
H O Na 275.0684).
2
-((3-phenylprop-2-yn-1-yl)oxy)benzaldehyde (6s). Following the general procedure,
the treatment of 50 mg (0.31 mmol) of 2-(prop-2-yn-1-yloxy)benzaldehyde (0.31 mmol)
with iodobenzene (43.1 µL, 0.32 mmol), Pd(PPh Cl (6.6 mg, 3 mol %), CuI (3.6 mg,
3
)
2
2
6 mol %) and piperidine (60 µL, 0.5 mmol) in dry THF (1 mL) under an Ar atmosphere
at 30°C for 3h, followed by evaporation of the solvent under reduced pressure and
purification on silica gel column chromatography (Hex/EtOAc, 7:3) afforded 56.8 mg
3
9
(78 %) of compound 6s. IR (neat) νmax 1678, 1659, 1593, 1481, 1458, 1400, 1373,
1
285, 1261, 1218, 1192, 1165, 1107, 1042, 995, 957, 914, 829, 756, 725, 687, 652, 609
-
1 1
cm . H-RMN (500 MHz, CDCl
3
) δ 5.05 (s, 2H), 7.09 (t, J = 7.0 Hz, 1H), 7.21 (d, J =
8
.7 Hz, 1H), 7.32 (m, 3H), 7.43 (m, 2H), 7.58 (ddd, J = 1.8, 7.5, 9.0 Hz, 1H), 7.88 (dd, J
1
3
=
3 2
1.7, 7.7 Hz, 1H), 10.54 (s, 1H); C-NMR (125 MHz, CDCl ) δ 57.3 (CH ), 82.9 (C),
8
1
8.1 (C), 113.4 (CH), 121.5 (CH), 121.9 (C), 125.6 (C), 128.3 (CH x 2), 128.5 (CH),
+
28.9 (CH), 131.8 (CH x 2), 135.7 (CH), 160.1 (C), 189.7 (CH); EIMS m/z 236 (M ,
+
77), 206 (50), 120 (45), 114 (100); HREIMS 236.0836 (calcd for C16
H
12
O
2
(M )
2
36.0837).
-((3-(3-nitrophenyl)prop-2-yn-1-yl)oxy)benzaldehyde (6t). Following the general
2
procedure, the treatment of 50 mg (0.31 mmol) of 2-(prop-2-yn-1-yloxy)benzaldehyde
ꢀ
29
ACS Paragon Plus Environment