One-Pot Conversion of Aldehydes and Aryl Halides to Disubstituted Alkynes via Tandem Seyferth-Gilbert Homologation/Copper-Free Sonogashira Coupling

Article abstract of DOI:10.1021/acs.joc.9b01367

A practically convenient protocol has been developed to convert a mixture of an aldehyde, aryl halide, and the Bestmann-Ohira reagent into disubstituted acetylene via a successive addition of base (Cs₂CO₃) and a Pd(II) catalyst, allowing sufficient time after addition of each of these reagents for the tandem processes (Seyferth-Gilbert homologation and Sonogashira coupling) to occur. Notably, for the latter reaction, no copper catalyst was required.

Full text of DOI:10.1021/acs.joc.9b01367

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Note
One-pot Conversion of Aldehydes and Aryl Halides
to Disubstituted Alkynes via Tandem Seyferth-Gilbert
Homologation/Copper-Free Sonogashira Coupling
Alexander Sapegin, and Mikhail Krasavin
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b01367 • Publication Date (Web): 17 Jun 2019
Downloaded from http://pubs.acs.org on June 17, 2019
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One-pot Conversion of Aldehydes and Aryl Halides to Disubstituted
Alkynes via Tandem Seyferth-Gilbert Homologation/Copper-Free
Sonogashira Coupling
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Alexander Sapegin and Mikhail Krasavin*
Saint Petersburg State University, Saint Petersburg 199034, Russia
ABSTRACT: A practically convenient protocol has been developed to convert a mixture of an
aldehyde, aryl halide and the Bestmann-Ohira reagent into disubstituted acetylene via a
successive addition of base (Cs2CO3) and a Pd(II) catalyst – and allowing sufficient time after
addition of each of these reagents for the tandem processes (Seyferth-Gilbert homologation and
Sonogashira coupling) to occur. Notably, for the latter reaction, no copper catalyst was required.
(1.4 equiv.)
1) Cs2CO3, MeOH
R
30 oC, 4 h
O
Ar(Het) C C R
+
Ac
P(O)(OMe)2
(2.0 equiv.)
(Het)Ar-X
(1.0 equiv.)
2) Pd(OAc)2, Xphos
40 oC, 12 h
28 examples
26-84%
N2
Diaryl alkynes have a broad utility in synthetic organic, medicinal and materials chemistry. In
particular, they are employed in preparation of conducting polymers,1 materials with useful
photophysical properties2 and liquid crystals.3 Despite its inherently high lipophilicity, the rod-
like diarene alkyne scaffold can be found embedded in the structure of compounds intended for
medicinal use, for example, as follicle-stimulating hormone receptor (FSHR) antagonists (1) for
fertility control and prevention of osteoporosis,4 anxiolytic neurokinin NK-1 and NK-2 receptor
modulators (2),5 anti-inflammatory cyclooxygenase-2 inhibitors (3),6 antiproliferative agents (4)7
(Figure 1).
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Figure 1. Examples of biologically active compounds based on 1,2-diaryl alkyne scaffold.
4
5
OMe
6
O
7
8
9
NH
O
HO
1
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N
N
H
O
SO2Me
NMe2
N
2
3
F
F
CONHPh
4
Perhaps, the most prominent utility of diaryl alkynes in synthetic chemistry is as building blocks
in various annelation reactions. These are eloquently exemplified by Asao-Yamomoto annelation
of o-formyl diaryl alkynes,8 annelation of 2-pyridones to 2-quinolones,9 annelation of 1,2-
arylidene diamines to quinoxalines,10 annelation of anilines11 and o-iodoanilines (the Larock
heteroannulation) to give indoles,12 annelation of o-unsubstituted aromatic methyl hydroxamate
to deliver an isoquinolone nucleus,13 the ‘heptagon’ annelation of 1-iodo-8-phenyl naphthalene14
and somewhat analogous annelation involving positions 1 and 7 of isatin.15 Additionally, diaryl
alkynes are prominent starting materials for the oxidation to benzils (1,2-diaryl ethan-1,2-
diones)16 and can be involved in various transition metal catalyzed arylation reactions,17
sometimes accompanied by alkyne dimerization18 (Figure 2).
Among various latest coupling approaches to the synthesis of diaryl alkynes involving alkynoic
acids,19 alkynyl iodonium salts,20 alkynyl organometallic reagents,21 1-haloalkynes,22 and alkynyl
sulfones,23 the Sonogashira coupling of terminal alkynes with an aryl halide24 remains perhaps
the most popular method. The monoaryl alkyne partner for the Sonogashira reaction can, in turn,
be conveniently elaborated from the respective aromatic aldehyde using the Seyferth-Gilbert
homologation.24 The latter, especially its version employing the Bestmann-Ohira reagent,25
generally proceeds under relatively mild conditions and conveniently links the diversity of diaryl
alkynes thus obtainable to the vast range of commercially available aromatic aldehydes.
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Figure 2. Examples of the uses of 1,2-diaryl alkynes as building blocks for synthesis.
4
5
6
7
8
Ar1
CHO
Ar2
= DAA
DAA
Ar1
Ar2
Asao-Yamamoto
benzannulation
9
Cu(OTf)2
TFA
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Ar1
Ph
H
H
Ar2
Ar1
Quinolone
synthesis
DAA
N
O
N
O
Ar1
Ar2
(Cp*RhCl2)2
Py
Ar2 Py
N
NH2
NH2
DAA
NBS
Quinoxaline
synthesis
R
R
N
Ar2
DAA
Aniline
annelation
Ar1
PdCl2
Cu(OAc)2
NH2
N
H
Ar2
I
Larock
heteroannulation
DAA
Ar1
PdCl2
Cu(OAc)2
NH2
N
H
O
O
OMe
DAA
PIFA
Isoquinolone
synthesis
OMe
Ar2
N
H
N
Ar
Ar
H
Ar1
DAA
Heptagon
benzannulation
Pd(OAc)2
PAr3
AgCO3
Ar2
I
Ar1
O
N
O
DAA
O
Isatin
annelation
O
Pd(OAc)2
AgOAc
Ar1 = Ar2
Ar2
N
H
Ar1
Ar1
Ar2
Ar2
oxidant
Ar1
O
Benzil
synthesis
DAA
DAA
(MLn)
O
Ar1
Ar3B(OH)2
Ar3
Arylation-
dimerization
Ar2
Ar2
Ni(OAc)2
B2pin2
Ar1
Considering this, combining the Seyferth-Gilbert protocol with Sonogashira coupling in a one-
pot format would provide a practically convenient alternative to other methods of converting
aldehydes directly to diaryl alkynes such as addition - double elimination reaction of aldehydes
with aryl sulfonylmethane synthons25 which require the use of sensitive organometallic reagents,
silyl halides and thoroughly controlled dry and inert atmosphere. Even the recently introduced
organocatalytic coupling of aldehydes with benzyl chlorides under strongly basic conditions26
suffers from similar inconvenience. It is therefore surprising that such one-pot methods (Figure
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3) have not been investigated to-date. In our current program aimed at screening for novel co-
crystallization partners for active pharmaceutical ingredients,27 we required an expedient and
convenient access to a wide range of diaryl alkynes from aromatic aldehydes. Considering the
above-stated methodology void and certain scope and practicality limitations of the known
methods to directly convert certain ketones into disubstituted alkynes,28 we set off to investigate
a possibility of in situ preparation of a monoaryl alkyne from the respective aromatic aldehyde
followed by same-pot Sonogashira coupling of the former with an aryl halide already present in
the reaction mixture triggered by the addition of a transition-metal catalyst. Herein, we present
the results of these studies.
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Figure 3. Approaches to the direct conversion of aldehydes to diaryl alkynes via (a) addition –
double elimination and (b) one-pot Seyferth-Gilbert/Sonogashira sequence investigated in this
work.
1) nBuLi
2) R'CHO
3) TMSCl
SO2Ph
R
LDA
R'
OLi
R
R
R'
R'
(a)
(b)
R
SO2Ph
Me3Si
- PhSO2H
-Me3SiOH
N2
Ac
P(O)(OMe)2
base
MLn
R
O
R
+
+
R'-X
R'-X
Initial screening of the conditions was performed with benzaldehyde, the Bestmann-Ohira
reagents and phenyl iodide and included variations of the solvent, temperature, catalyst for the
Sonogoshira coupling and reaction time (Table 1). An initial attempt to expose all the reaction
components (including 4 equiv. of K2CO3) to a palladium(II) catalyst with (entry 1) or without
(entry 2) the addition of Cu(I) iodide resulted in no desired product, presumably due to Pd-
induced decomposition of the Bestmann-Ohira reagent. Separating the two chemical events (the
terminal alkyne formation and the addition of a Pd(II)/Cu(I) catalyst system) led to the formation
of the desired diphenylethyne albeit in negligible yield (entry 3). Significant improvement of the
yield was achieved by changing the base to cesium carbonate, the solvent to methanol and
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running the two steps of the one-pot protocol for 4 and 12 hours, at 30 and 40 ºC, respectively
(entry 7); the latter temperature and time regimen proved to be optimal in subsequent
experiments (vide infra). Interestingly, by merely excluding CuI from the catalyst system, the
yield was raised nearly two-fold (entry 8) and, therefore, subsequent optimization (entries 8-15)
was carried out in copper-free format29 by varying the Pd(II) catalyst system and the phosphine
ligand. The optimal yield (entry 15) was achieved with 2-dicyclohexylphosphino-2′,4′,6′-
triisopropylbiphenyl (Xphos) as the ligand. Employing 4 equivalents of base (entries 15-17) was
proved to be optimal while adding other solvents to the reaction medium (entries 18-23) did
neither improve nor drastically affect the product yield. One notable exception is the addition of
water (entry 19) which led to no product formation at all.
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Table 1. Optimization experiments for the one-pot diaryl alkyne synthesis.
Base
Solvent
Catalyst
system
N2
I
+
+
O
Ac
P(O)(OMe)2
T1 (oC), t1 (h)
T2 (oC), t2 (h)
Base
(equiv.)
Catalyst system
(mol.%)
T1
(ºC)
T2
(ºC)
Entry
Solvent
EtOH
t1 (h) t2 (h)
Yield (%)
Pd(OAc)2 (2), PPh3 (4),
No
reaction
No
reaction
1
2
3
4
5
6
7
K2CO3 (4)
K2CO3 (4)
K2CO3 (4)
K2CO3 (4)
Cs2CO3 (4)
Cs2CO3 (4)
Cs2CO3 (4)
24
24
r. t.
r. t.
r. t.
r. t.
r. t.
30
CuI (4)a
EtOH
Pd(OAc)2 (2), PPh3 (4)a
Pd(OAc)2 (2), PPh3 (4),
CuI (4)
Pd(OAc)2 (2), PPh3 (4),
CuI (4)
Pd(OAc)2 (2), PPh3 (4),
CuI (4)
Pd(OAc)2 (2), PPh3 (4),
CuI (4)
EtOH
12
12
8
12
12
12
12
12
3
MeOH
MeOH
MeOH
MeOH
8
17
18
24
4
Pd(OAc)2 (2), PPh3 (4),
CuI (4)
4
30
40
8
9
10
11
MeOH
MeOH
MeOH
MeOH
Cs2CO3 (4)
Cs2CO3 (4)
Cs2CO3 (4)
Cs2CO3 (4)
Pd(OAc)2 (2), PPh3 (4)
Pd(OAc)2 (2)
Pd(PPh3)4 (2)
Pd(PPh3)2Cl2
Pd(OAc)2 (2), BINAPb
(4)
4
4
4
4
12
12
12
12
30
30
30
30
40
40
40
40
41
30
45
51
12
13
MeOH
MeOH
Cs2CO3 (4)
Cs2CO3 (4)
4
4
12
12
30
30
40
40
56
63
Pd(OAc)2 (2),
Xantphosb (4)
14
15
16
17
MeOH
MeOH
MeOH
MeOH
Cs2CO3 (4) Pd(OAc)2 (2), Xphos (4)
Cs2CO3 (4) Pd(OAc)2 (4), Xphos (8)
Cs2CO3 (3) Pd(OAc)2 (4), Xphos (8)
Cs2CO3 (5) Pd(OAc)2 (4), Xphos (8)
4
4
4
4
12
12
12
12
30
30
30
30
40
40
40
40
76
84
62
83
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MeOH/H2O
(1:1)
No
reaction
18
Cs2CO3 (4) Pd(OAc)2 (4), Xphos (8)
4
12
30
40
MeOH/MeCN
(1:1)
MeOH/THF
(1:1)
MeOH/DMF
(1:1)
MeOH/CH2Cl2
(1:1)
19
20
21
22
23
Cs2CO3 (4) Pd(OAc)2 (4), Xphos (8)
Cs2CO3 (4) Pd(OAc)2 (4), Xphos (8)
Cs2CO3 (4) Pd(OAc)2 (4), Xphos (8)
Cs2CO3 (4) Pd(OAc)2 (4), Xphos (8)
Cs2CO3 (4) Pd(OAc)2 (4), Xphos (8)
4
4
4
4
4
12
12
12
12
12
30
30
30
30
30
40
40
40
40
40
70
66
49
80
74
10
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12
13
14
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26
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28
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MeOH/Toluene
(1:1)
a
b
The catalyst was added immediately after mixing the starting reagent; BINAP - 2,2′-
bis(diphenylphosphino)-1,1′-binaphthyl,
Xantphos
-
4,5-bis(diphenylphosphino)-9,9-
dimethylxanthene.
With the optimized reaction conditions at hand, we proceeded to investigate the scope of the
newly developed one-pot protocol for the conversion of a mixture of an aldehyde and aryl halide
into disubstituted alkyne using a range of halogenated (hetero)arenes and aromatic as well as
aliphatic aldehydes (Table 2).
Table 2. Scope investigation of the one-pot synthesis of disubstituted alkynes 5a-aa.
1) Cs2CO3
30 oC, 4 h
(Het)
Ar
Hal
Ac
P(O)(OMe)2
(Het)
Ar
C
+
R
C
+
O
R
2) Pd(OAc)2, XPhos
40 oC , 12 h
N2
5a-aa
Hal
Yield
(%)
Entry
1
(Het)
Ar
Product
R
O
O
PhI
PhI
84
76
5a
MeO
O
2
5b
MeO
O
3
4
PhI
PhI
80
71
5c
OMe
MeO
OMe
O
OMe
5d
OMe
O
MeO
5
6
PhI
PhI
73
0
MeO
HO
OMe
O
5e
--
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HO
O
7
8
9
PhI
--
--
0
0
3
4
5
6
7
8
9
O
PhI
OH
O
MeO2C
PhI
PhI
74
MeO2C
O2N
5f
O
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
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30
31
32
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34
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36
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39
40
41
42
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46
47
48
49
50
51
52
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60
10
11
50
63
5g
O2N
OMe
O2N
O
PhI
OMe
5h
O2N
S
O
82 (79)b
61
S
12
13
PhI
PhI
5i
5j
O
O
N
O
N
14
PhI
PhI
56
O
O
O
5k
O
15
16
--
0
O
NO2
54
N
F
5l
N
F
F
NO2
I
F
O
17
68
5m
O2N
NO2
18
19
74
35
O
5n
Cl
I
O
O
O
5o
5p
Cl
Cl
Cl
O
I
20
21
67
73
Cl
Cl
Me
O
S
S
5q
I
N
N
22
23
69
20
O
5r
N
5s
Cl
I
O
N
Cl
24
55
5s'
N
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I
O
25
45a
5t
N
Cl
N
6
7
8
9
Br
26
27
28
84
62
0
5u
5v
Br
10
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O
NO2
O2N
Br
OH
--
CN
Cl
O
O
Br
5w
29
30
41
47
NC
Cl
Cl
Cl
MeS
Br
S
MeS
S
5x
OBn
N
O
N
S
31
32
45
S
Br
OBn
5y
H2N
N
Br
Br
F
O
26 a
N
NH2
5z
F
F
Br
O
33
48
5aa
--
--
--
34
35
36
0
0
0
N
Cl
O
O
N
N
Cl
Cl
a The product of mono-coupling was detected in the reaction mixture by mass-spectrometric and
1H NMR analysis in <10% yield but its attempted isolation failed. b Gram-scale synthesis.
As it can be seen from the data presented in Table 1, the reaction generally displayed a broad
scope with respect to both the aldehyde (aromatic, heteroaromatic and aliphatic alike) and
(hetero)aryl halide partners and gave the target disubstituted alkynes 5 in good to excellent
yields. Notable exceptions were provided by the attempts to use unprotected
hydroxybenzaldehydes (entries 6-8) and (E)-cinnamaldehyde (entry 14). The latter finding was
in line with our analysis of the literature which revealed that cinnamaldehydes are generally
transformed into respective alkynes by methods other than Seyferth-Gilbert homologation.30
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Luckily, the anticipated enyne core (which in itself is of importance in synthetic organic
chemistry29) was accessed by an umpolung approach from p-tolualdehyde and stiryl bromide
(entry 33). Similarly notable is the outcome of the reaction with substrates capable of undergoing
double Sonogashira coupling (such as 2-chloro-3-iodopyridine or 2-amino-3,5-dibromopyridine).
In this case, the major product was the product of the double Sonogashira coupling while the
monocoupling product was isolated in low yield (entry 23) or was observed in <10% quantity in
the reaction mixture but could not be isolated (entries 25 and 32). This observation can be
rationalized by the electron-withdrawing character of the first alkyne group introduced which
increases the reactivity of the second haloheteroarene moiety toward the second Sonogashira
coupling.
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In summary, we have developed a convenient, practically simple one-pot synthesis of
disubstituted alkynes from a mixture of an aldehyde, halo(hetero)arene, Bestmann-Ohira reagent
and cesium carbonate whereby the initial Seyferth-Gilbert homologation product is channeled to
the copper-free Sonogashira coupling event by the addition of a palladium catalyst mixed with
Xphos ligand. The overall outcome of this process is similar to the earlier described direct
conversion of aldehydes to disubstituted alkynes using benzyl aryl sulfone anion addition -
double-elemination process. However, it does not require strictly anhydrous conditions and the
use of low temperature as well as employing a strong lithium amide base and, therefore, can be
conveniently adopted to the preparation of arrays of disubstituted alkynes in a combinatorial
format.
EXPERIMENTAL SECTION
1
General. NMR spectroscopic data were recorded with a 400 spectrometer (400.13 MHz for H
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and 100.61 MHz for C) in CDCl3 and were referenced to residual solvent proton signal (δH =
7.26 ppm) and solvent carbon signal (δC = 77.00 ppm). Mass spectra were recorded with a an
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ESI-qTOF spectrometer (electrospray ionization mode). Column chromatography was performed
on 230–400 mesh silica gel.
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Pd(OAc)2, Cs2CO3, dimethyl (2-oxopropyl)phosphonate, 4-acetamidobenzenesulfonyl azide,
aldehydes and aryl halides was purchased from Alfa Aesar and Sigma-Aldrich, and used
without further purification.
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Dimethyl (1-diazo-2-oxopropyl)phosphonate (Bestmann-Ohira reagent). Although it is
commercially available from a number of reagent vendors, this rather expensive reagent can be
cheaply and conveniently prepared according to the following procedure.
To a solution of dimethyl (2-oxopropyl)phosphonate (4.56 g, 27.6 mmol) in acetonitrile (30 mL)
K2CO3 (4.58 g, 33.1 mmol) was added. The suspension was stirred at r. t. for 1 h. A solution of
4-acetamidobenzenesulfonyl azide (7.3 g, 30.3 mmol) in acetonitrile (15 mL) was added
dropwise over 10 min and the mixture was stirred at r. t. overnight. The mixture was filtered
through a pad of Celite and the solvent removed in vacuo. The resulting residue was purified on
an automated cartridge flash chromatography system (25 g silica cartridge, eluent - 0→50%
EtOAc in CH2Cl2) to give 4.2 g (24.8 mmol, 79%) of the title compound as a colored liquid. 1H
NMR (400 MHz, CDCl3) δ 3.83 (s, 3H), 3.80 (s, 3H), 2.23 (s, 3H) ppm.
General Procedure 1 for the Optimization of the Reaction Conditions. To an oven-dried
Schlenk tube equipped with a magnetic stirring bar the solvent (1.5 mL), iodobenzene (51.0 mg,
0.25 mmol), benzaldehyde (36.3 mg, 0.34 mmol), an dimethyl (1-diazo-2-
oxopropyl)phosphonate (96.1 mg, 0.50 mmol) were added. The reaction vessel was cooled in an
ice bath and the base was added. The mixture was stirred under argon at temperature T1 until the
HPLC analysis of the reaction mixture showed maximum conversion (Time1) of benzaldehyde.
After Time1 lapsed, a solution of the catalyst in the same solvent (1.5 mL) was added and the
reaction mixture was stirred at temperature T2 until HPLC analysis of the reaction mixture
showed full conversion (Time2) of ethynylbenzene. The reaction mixture was diluted with H2O
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(5 mL) and extracted with CH2Cl2 (5 mL). The organic extract was washed with brine (10 mL),
dried over anhydrous Na2SO4, filtered, and concentrated on a rotary evaporator. The resulting
residue was purified by an automated cartridge flash purification systems (5 g silica cartridge,
eluent - 0→20% - CH2Cl2 in cyclohexane).
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General Procedure 2 for the Preparation of Compounds 5a-y. To an oven-dried Schlenk tube
equipped with a magnetic stirring bar MeOH (1.5 mL), aryl iodide (bromide) (0.25 mmol, 1
equiv.), aldehyde (0.34 mmol, 1.4 equiv.) and dimethyl (1-diazo-2-oxopropyl)phosphonate (96.1
mg, 0.50 mmol, 2 equiv.) were added. The reaction mixture was cooled in an ice bath and
Cs2CO3 (325.2 mg, 1.00 mmol, 4 equiv.) was added. The reaction mixture was stirred under
argon in an oil bath heated at 30oC for 4 h. A solution of Pd(OAc)2 (4.5 mg, 0.01 mmol, 0.04
equiv.) and XPhos (9.5 mg, 0.02 mmol, 0.08 equiv.) in MeOH (1.5 mL) was add and the stirring
continued at 40oC for 12 h. On cooling to r. t., the reaction mixture was diluted with H2O (5 mL)
and extracted with CH2Cl2 (5 mL). The extract was washed with brine (10 mL), dried over
anhydrous Na2SO4, filtered, and concentrated on a rotary evaporator. The resulting residue was
purified by column chromatography on silica gel using an appropriate gradient 0→20% of
CH2Cl2 in cyclohexane as eluent.
1,2-Diphenylethyne (5a) synthesized from iodobenzene (51.0 mg, 0.25 mmol) and benzaldehyde
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(36.3 mg, 0.34 mmol); yield 37.6 mg (0.21 mmol, 84%); white solid; mp 60-62 ºC. H NMR
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(400 MHz, CDCl3) δ 7.62 – 7.54 (m, 4H), 7.44 – 7.33 (m, 6H) ppm. C{1H} NMR (101 MHz,
CDCl3) δ 131.7 (2C), 128.4 (2C), 128.3 (2C), 123.3(2C), 89.4 (2C) ppm. HRMS (ESI), m/z
calcd for C14H11 [M+H]+ 179.0855, found 179.0851.
1-Methoxy-4-(phenylethynyl)benzene (5b) synthesized from iodobenzene (51.0 mg, 0.25 mmol)
and 4-methoxybenzaldehyde (46.2 mg, 0.34 mmol); yield 39.7 mg (0.19 mmol, 76%); white
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solid; mp 56-58 ºC. H NMR (400 MHz, CDCl3) δ 7.57 – 7.49 (m, 4H), 7.41 – 7.32 (m, 3H),
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6.91 (d, J = 8.9 Hz, 2H), 3.86 (s, 3H) ppm. C{1H} NMR (101 MHz, CDCl3) δ 159.6, 133.0
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(2С), 131.5 (2С), 128.3 (2C), 127.9, 123.6, 115.4, 114.0 (2C), 89.4, 88.1, 55.3 ppm. HRMS
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(ESI), m/z calcd for C15H13O [M+H]+ 209.0961, found 209.0957.
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1-Methoxy-3-(phenylethynyl)benzene (5с) synthesized from iodobenzene (51.0 mg, 0.25 mmol)
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and 3-methoxybenzaldehyde (46.2 mg, 0.34 mmol); yield 41.8 mg (0.20 mmol, 80%); white
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solid; mp 74-76 ºC. H NMR (400 MHz, CDCl3) δ 7.63 – 7.53 (m, 2H), 7.44 – 7.32 (m, 3H),
7.35 – 7.22 (m, 1H), 7.21 – 7.04 (m, 2H), 6.98 – 6.90 (m, 1H), 3.86 (s, 3H) ppm. 13C{1H} NMR
(101 MHz, CDCl3) δ 159.4, 131.7 (2C), 129.4, 128.3 (2C), 124.2, 124.1, 123.2, 117.0, 116.4,
115.4, 89.3, 89.2, 55.2 ppm. HRMS (ESI), m/z calcd for C15H13O [M+H]+ 209.0961, found
209.0968.
1-Methoxy-2-(phenylethynyl)benzene (5d) synthesized from iodobenzene (51.0 mg, 0.25 mmol)
and 2-methoxybenzaldehyde (46.2 mg, 0.34 mmol); yield 37.1 mg (0.18 mmol, 71%); colorless
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oil. H NMR (400 MHz, CDCl3) δ 7.64 – 7.57 (m, 2H), 7.54 (dd, J = 7.6, 1.7 Hz, 1H), 7.41 –
7.30 (m, 4H), 6.98 (td, J = 7.5, 1.0 Hz, 1H), 6.94 (dd, J = 8.4, 1.0 Hz, 1H), 3.95 (s, 3H) ppm.
13C{1H} NMR (101 MHz, CDCl3) δ 159.9, 133.6, 131.6 (2C), 129.7, 128.2 (2C), 128.1, 123.6,
120.5, 112.5, 110.7, 93.4, 85.7, 55.8 ppm. HRMS (ESI), m/z calcd for C15H13O [M+H]+
209.0961, found 209.0959.
2,4-Dimethoxy-1-(phenylethynyl)benzene (5e) synthesized from iodobenzene (51.0 mg, 0.25
mmol) and 2,4-dimethoxybenzaldehyde (56.5 mg, 0.34 mmol); yield 43.6 mg (0.18 mmol, 73%);
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white solid; mp 44-46 ºC. H NMR (400 MHz, CDCl3) δ 7.60 – 7.52 (m, 2H), 7.45 (d, J = 8.2
Hz, 1H), 7.38 – 7.25 (m, 3H), 6.54 – 6.44 (m, 2H), 3.92 (s, 3H), 3.86 (s, 3H) ppm. C{1H}
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NMR (101 MHz, CDCl3) δ 161.2, 161.2, 134.3, 131.5 (2C), 128.2 (2C), 127.7, 123.9, 105.0,
104.9, 98.5, 92.0, 85.8, 55.8, 55.4 ppm. HRMS (ESI), m/z calcd for C16H15O2 [M+H]+ 239.1067,
found 239.1061.
Methyl 4-(phenylethynyl)benzoate (5f) synthesized from iodobenzene (51.0 mg, 0.25 mmol) and
methyl 4-formylbenzoate (55.8 mg, 0.34 mmol); yield 43.8 mg (0.19 mmol, 74%); white solid;
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mp 118-121 ºC. H NMR (400 MHz, CDCl3) δ 8.05 (d, J = 8.5 Hz, 2H), 7.61 (d, J = 8.5 Hz,
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2H), 7.59 – 7.47 (m, 2H), 7.47 – 7.34 (m, 3H), 3.95 (s, 3H) ppm. C{1H} NMR (101 MHz,
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CDCl3) δ 166.5, 131.7 (2C), 131.5 (2C), 129.5 (3C), 128.7, 128.4 (2C), 128.0, 122.7, 92.3, 88.6,
52.2 ppm. HRMS (ESI), m/z calcd for C16H13O2 [M+H]+ 237.0910, found 237.0914.
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1-Nitro-2-(phenylethynyl)benzene (5g) synthesized from iodobenzene (51.0 mg, 0.25 mmol) and
3-nitrobenzaldehyde (51.3 mg, 0.34 mmol); yield 29.3 mg (0.13 mmol, 50%); yellow solid; mp
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54-57 ºC. H NMR (400 MHz, CDCl3) δ 7.64 – 7.57 (m, 2H), 7.54 (dd, J = 7.6, 1.7 Hz, 1H),
7.41 – 7.30 (m, 4H), 6.98 (td, J = 7.5, 1.0 Hz, 1H), 6.94 (dd, J = 8.4, 1.0 Hz, 1H), 3.95 (s, 3H)
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ppm. C{1H} NMR (101 MHz, CDCl3) δ 148.2, 137.2, 131.8 (2C), 129.3, 129.0, 128.5 (2C),
126.4, 125.1, 122.8, 122.2, 91.9, 86.8 ppm. HRMS (ESI), m/z calcd for C14H10NO2 [M+H]+
224.0706, found 224.0703.
1-Methoxy-4-nitro-2-(phenylethynyl)benzene (5h) synthesized from iodobenzene (51.0 mg, 0.25
mmol) and 2-fluoro-5-nitrobenzaldehyde (57.5 mg, 0.34 mmol); yield 40.1 mg (0.16 mmol,
63%); yellow solid; mp 69-71 ºC. 1H NMR (400 MHz, CDCl3) δ 8.40 (d, J = 2.8 Hz, 1H), 8.23
(dd, J = 9.1, 2.8 Hz, 1H), 7.62 – 7.57 (m, 2H), 7.45 – 7.36 (m, 3H), 6.99 (d, J = 9.1 Hz, 1H), 4.04
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(s, 3H) ppm. C{1H} NMR (101 MHz, CDCl3) δ 164.4, 141.1, 131.8 (2C), 129.7, 128.8, 128.4
(2C), 126.1, 125.5, 113.7, 110.2, 95.4, 83.3, 56.7 ppm. HRMS (ESI), m/z calcd for C15H12NO3
[M+H]+ 254.0812, found 254.0810.
3-(Phenylethynyl)thiophene (5i) synthesized from iodobenzene (51.0 mg, 0.25 mmol) and
thiophene-3-carbaldehyde (38.1 mg, 0.34 mmol); yield 37.9 mg (0.21 mmol, 82%); white solid;
mp 45-47 ºC. 1H NMR (400 MHz, CDCl3) δ 7.58 – 7.51 (m, 3H), 7.41 – 7.34 (m, 3H), 7.33 (dd,
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J = 5.0, 3.0 Hz, 1H), 7.23 (dd, J = 5.0, 1.1 Hz, 1H) ppm. C{1H} NMR (101 MHz, CDCl3) δ
131.5 (2C), 129.9, 128.5, 128.3 (2C), 128.2, 125.3, 123.2, 122.3, 88.8, 84.5 ppm. HRMS (ESI),
m/z calcd for C12H9S [M+H]+ 185.0419, found 185.0415.
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(Cyclohexylethynyl)benzene (5j) synthesized from iodobenzene (51.0 mg, 0.25 mmol) and
cyclohexanecarbaldehyde (38.1 mg, 0.34 mmol); yield 28.2 mg (0.15 mmol, 61%); colorless oil.
1H NMR (400 MHz, CDCl3) δ 7.43 (d, J = 9.7 Hz, 2H), 7.33 – 7.26 (m, 3H), 2.68 – 2.57 (m,
1H), 1.96 – 1.91 (m, 2H), 1.86 – 1.70 (m, 2H), 1.60 – 1.55 (m, 4H), 1.41 – 1.34 (m, 4H) ppm.
13C{1H} NMR (101 MHz, CDCl3) δ 131.5 (2C), 128.1 (2C), 127.4, 124.1, 94.4, 80.5, 32.7 (2C),
29.6, 25.9 (2C), 24.9 ppm. HRMS (ESI), m/z calcd for C14H17 [M+H]+ 185.1325, found
185.1321.
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2-(4-Phenylbut-3-yn-1-yl)isoindoline-1,3-dione (5k) synthesized from iodobenzene (51.0 mg,
0.25 mmol) and 3-(1,3-dioxoisoindolin-2-yl)propanal (69.0 mg, 0.34 mmol); yield 38.3 mg (0.14
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mmol, 56%); yellow solid; mp 89-92 ºC. H NMR (400 MHz, (CD3)2CO) δ 7.92 – 7.85 (m,
4H), 7.52 – 7.49 (m, 2H), 7.43 – 7.36 (m, 3H), 4.10 (t, J = 6.6 Hz, 2H), 3.76 (t, J = 6.6 Hz, 2H)
ppm. 13C{1H} NMR (101 MHz, (CD3)2CO) δ 167.4 (2C), 134.3 (2C), 132.0, 131.8 (2C), 128.8
(2C), 128.5 (2C), 123.0 (2C), 122.3, 83.3, 78.24, 39.2, 28.7 ppm. HRMS (ESI), m/z calcd for
C18H14NO2 [M+H]+ 276.1019, found 276.1015.
3-((4-Nitrophenyl)ethynyl)pyridine (5l) synthesized from 1-iodo-4-nitrobenzene (62.3 mg, 0.25
mmol) and nicotinaldehyde (36.4 mg, 0.34 mmol); yield 30.3 mg (0.14 mmol, 54%); yellow
solid; mp 107-109 ºC. 1H NMR (400 MHz, CDCl3) δ 8.81 (d, J = 2.5 Hz, 1H), 8.62 (dd, J = 4.9,
1.7 Hz, 1H), 8.25 (d, J = 8.8 Hz, 2H), 7.86 (dt, J = 7.8, 1.9 Hz, 1H), 7.70 (d, J = 8.8 Hz, 2H),
7.40 – 7.31 (m, 1H) ppm. 13C{1H} NMR (101 MHz, CDCl3) δ 152.4, 149.5, 147.3, 138.6, 132.4
(2C), 129.3, 123.7 (2C), 123.1, 119.3, 90.9, 90.5 ppm. HRMS (ESI), m/z calcd for C13H9N2O2
[M+H]+ 225.0659, found 225.0656.
1,2-Difluoro-4-((4-nitrophenyl)ethynyl)benzene (5m) synthesized from 1-iodo-4-nitrobenzene
(62.3 mg, 0.25 mmol) and 3,4-difluorobenzaldehyde (48.3 mg, 0.34 mmol); yield 44.2 mg (0.17
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mmol, 68%); yellow solid; mp 115-117 ºC. H NMR (400 MHz, CDCl3) δ 8.25 (d, J = 8.7 Hz,
1H), 7.68 (d, J = 8.7 Hz, 1H), 7.43 – 7.36 (m, 1H), 7.36 – 7.29 (m, 1H), 7.20 (dt, J = 10.1, 8.3
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Hz, 1H) ppm. 13C{1H} NMR (101 MHz, CDCl3) δ 151.8 (dd, J = 103.4, 13.0 Hz), 149.3 (dd, J =
103.4, 13.0 Hz), 138.6, 132.3 (2C), 128.6 (dd, J = 6.6, 3.7 Hz), 124.8, 123.7 (2C), 120.81 (d, J =
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18.7 Hz), 118.9 (dd, J = 7.8, 4.2 Hz), 117.8 (d, J = 18.7 Hz), 92.1, 87.8 ppm. F{1H} NMR
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(376 MHz, , CDCl3) δ -133.97 (d, J = 21.3 Hz), -136.44 (d, J = 21.3 Hz) ppm. HRMS (ESI),
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m/z calcd for C14H8F2NO2 [M+H]+ 260.0518, found 260.0516.
1-Nitro-4-(pent-1-yn-1-yl)benzene (5n) synthesized from 1-iodo-4-nitrobenzene (62.3 mg, 0.25
mmol) and butyraldehyde (29.3 mg, 0.34 mmol); yield 37.6 mg (0.19 mmol, 74%); yellow oil.
1H NMR (400 MHz, CDCl3) δ 8.19 – 8.14 (m, 2H), 7.56 – 7.51 (m, 2H), 2.45 (t, J = 7.1 Hz,
2H), 1.67 (q, J = 7.3 Hz, 2H), 1.08 (t, J = 7.4 Hz, 3H) ppm. 13C{1H} NMR (101 MHz, CDCl3) δ
146.6, 132.2, 131.2 (2С), 123.4 (2С), 96.5, 79.4, 21.9, 21.5, 13.5 ppm. HRMS (ESI), m/z calcd
for C11H12NO2 [M+H]+ 190.0863, found 190.0865.
2-((3-Сhlorophenyl)ethynyl)furan (5o) synthesized from 1-chloro-3-iodobenzene (59.6 mg, 0.25
mmol) and furan-2-carbaldehyde (32.6 mg, 0.34 mmol) in 35% (17.8 mg, 0.09 mmol) yield;
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white solid; mp 72-75 ºC. H NMR (400 MHz, CDCl3) δ 7.54 (t, J = 1.8 Hz, 1H), 7.50 – 7.45
(m, 1H), 7.42 (dt, J = 7.3, 1.5 Hz, 1H), 7.38 – 7.25 (m, 2H), 6.71 (dd, J = 3.3, 0.7 Hz, 1H), 6.46
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(dd, J = 3.4, 1.9 Hz, 1H) ppm. C{1H} NMR (101 MHz, CDCl3) δ 143.9, 136.7, 134.2, 131.1,
129.6, 129.4, 128.9, 124.0, 115.8, 111.1, 91.8, 80.5 ppm. HRMS (ESI), m/z calcd for C12H8ClO
[M+H]+ 203.0258, found 203.0257.
1,2-Dichloro-3-(o-tolylethynyl)benzene (5p) synthesized from 1-iodo-2-methylbenzene (54.5 mg,
0.25 mmol) and 2,3-dichlorobenzaldehyde (59.5 mg, 0.34 mmol) in 67% (43.7 mg, 0.17 mmol)
yield; white solid; mp 146-148 ˚C. 1H NMR (400 MHz, CDCl3) δ 7.59 – 7.54 (m, 1H), 7.51 (dd,
J = 7.7, 1.5 Hz, 1H), 7.44 (dd, J = 8.1, 1.5 Hz, 1H), 7.32 – 7.26 (m, 2H), 7.25 – 7.17 (m, 2H),
2.58 (s, 3H) ppm. 13C{1H} NMR (101 MHz, CDCl3) δ 140.7, 134.1, 133.3, 132.5, 132.1, 131.2,
129.9, 129.6, 128.9, 126.9, 125.6, 122.3, 94.4, 89.6, 20.8 ppm. HRMS (ESI), m/z calcd for
C15H11Cl2 [M+H]+ 261.0232, found 261.0229.
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2-(p-Tolylethynyl)thiophene (5q) synthesized 1-iodo-2-methylbenzene (54.5 mg, 0.25 mmol) and
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thiophene-2-carbaldehyde (38.1 mg, 0.34 mmol) in 73% (36.3 mg, 0.17 mmol) yield; white
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solid; mp 64-66 ˚C. H NMR (400 MHz, CDCl3) δ 7.44 (d, J = 7.8 Hz, 2H), 7.33 – 7.26 (m,
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2H), 7.18 (d, J = 7.8 Hz, 2H), 7.03 (dd, J = 5.1, 3.7 Hz, 1H), 2.40 (s, 3H) ppm. C{1H} NMR
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(101 MHz, CDCl3) δ 138.6, 131.6, 131.3 (2С), 129.1 (2С), 127.0, 126.9, 123.6, 119.8, 93.2,
81.9, 21.5 ppm. HRMS (ESI), m/z calcd for C13H11S [M+H]+ 199.0576, found 199.0574.
4,4-Dimethyl-6-(p-tolyl)hex-5-ynenitrile (5r) synthesized 1-iodo-2-methylbenzene (54.5 mg,
0.25 mmol) and 4,4-dimethyl-5-oxopentanenitrile (42.5 mg, 0.34 mmol) in 69% (35.8 mg, 0.17
mmol) yield; colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.30 (d, J = 7.8 Hz, 2H), 7.12 (d, J =
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7.8 Hz, 2H), 2.64 – 2.54 (m, 2H), 2.36 (s, 3H), 1.94 – 1.85 (m, 2H), 1.35 (s, 6H) ppm. C{1H}
NMR (101 MHz, CDCl3) δ 138.0, 131.4 (2С), 129.0 (2С), 120.1, 120.0, 93.2, 82.2, 38.7, 31.6,
28.9 (2С), 21.4, 13.7 ppm. HRMS (ESI), m/z calcd for C15H18N [M+H]+ 212.1434, found
212.1437.
2-Chloro-3-(cyclopentylethynyl)pyridine (5s) synthesized from 2-chloro-3-iodopyridine (59.8
mg, 0.25 mmol) and cyclopentanecarbaldehyde (33.4 mg, 0.34 mmol) in 20% (10.3 mg, 0.05
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mmol) yield; white solid; mp 109-111 ˚C. H NMR (400 MHz, CDCl3) δ 8.28 (dd, J = 4.8, 1.9
Hz, 1H), 7.73 (dd, J = 7.7, 1.9 Hz, 1H), 7.17 (dd, J = 7.7, 4.8 Hz, 1H), 3.01 – 2.83 (m, 1H), 2.13
– 1.94 (m, 4H), 1.71 – 1.54 (m, 3H), 8.41 (dd, J = 4.9, 1.8 Hz, 1H), 7.65 (dd, J = 7.9, 1.8 Hz,
13
1H), 7.10 (dd, J = 7.9, 4.8 Hz, 1H), 3.02 – 2.83 (m, 1H), 1.85 – 1.53 (m, 8H) ppm. C{1H}
NMR (101 MHz, CDCl3) δ 152.3, 147.1, 139.3, 125.9, 121.9, 96.8, 77.2, 33.7 (2C), 31.0, 25.9
(2C) ppm. HRMS (ESI), m/z calcd for C12H13ClN [M+H]+ 206.0731, found 206.0728.
2,3-Bis(cyclopentylethynyl)pyridine (5sʹ) synthesized from 2-chloro-3-iodopyridine (59.8 mg,
0.25 mmol) and cyclopentanecarbaldehyde (33.4 mg, 0.34 mmol) in 55% (36.3 mg, 0.14 mmol)
yield; white solid; mp 173-175 ˚C. 1H NMR (400 MHz, CDCl3) δ 8.41 (dd, J = 4.9, 1.8 Hz, 1H),
7.65 (dd, J = 7.9, 1.8 Hz, 1H), 7.10 (dd, J = 7.9, 4.8 Hz, 1H), 3.02 – 2.83 (m, 2H), 2.13 – 1.97
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(m, 4H), 1.92 – 1.71 (m, 8H), 1.70 – 1.53 (m, 4H) ppm. C{1H} NMR (101 MHz, CDCl3) δ
147.7, 145.5, 138.7, 123.2, 121.3, 101.1, 98.7, 79.2, 76.9, 33.8, 33.6, 30.9 (2C), 30.8 (2C), 25.2
(2C), 25.1 (2C) ppm. HRMS (ESI), m/z calcd for C19H22N [M+H]+ 264.1747, found 264.1749.
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2,3-Bis(m-tolylethynyl)pyridine (5t) synthesized 2-chloro-3-iodopyridine (59.8 mg, 0.25 mmol)
and 3-methylbenzaldehyde (41.1 mg, 0.34 mmol) in 45% (34.7 mg, 0.11 mmol) yield; white
solid; mp 190-192 ˚C. 1H NMR (400 MHz, CDCl3) δ 8.57 (dd, J = 4.8, 1.7 Hz, 1H), 7.85 (dd, J
= 7.9, 1.7 Hz, 1H), 7.52 – 7.40 (m, 4H), 7.32 – 7.19 (m, 5H), 2.36 (s, 3H), 2.35 (s, 3H) ppm.
13C{1H} NMR (101 MHz, CDCl3) δ 148.6, 145.2, 138.6, 138.1, 138.0, 132.8, 132.36, 130.07,
129.84, 129.22, 128.77, 128.37, 128.32, 123.19, 122.56, 122.2, 121.9, 96.3, 93.7, 87.7, 85.7,
21.2, 21.1 ppm. HRMS (ESI), m/z calcd for C23H18N [M+H]+ 308.1434, found 308.1430.
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1-Methyl-4-(phenylethynyl)benzene (5u) synthesized from bromobenzene (39.3 mg, 0.25 mmol)
and 4-methylbenzaldehyde (41.1 mg, 0.34 mmol) in 84% (40.5 mg, 0.21 mmol) yield; white
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solid; mp 69-71 ˚C. H NMR (400 MHz, CDCl3) δ 7.62 – 7.55 (m, 2H), 7.49 (d, J = 8.1 Hz,
2H), 7.44 – 7.32 (m, 3H), 7.21 (d, J = 7.9 Hz, 2H), 2.42 (s, 3H) ppm. 13C{1H} NMR (101 MHz,
CDCl3) δ 138.4, 131.5 (2C), 131.4 (2C), 129.1 (2C), 128.3 (2C), 128.1, 123.5, 120.2, 89.6, 88.7,
21.5 ppm. HRMS (ESI), m/z calcd for C15H13 [M+H]+ 193.1012, found 193.1009.
1-Methyl-4-((4-nitrophenyl)ethynyl)benzene (5v) synthesized from 1-bromo-4-nitrobenzene
(50.5 mg, 0.25 mmol) and 4-methylbenzaldehyde (41.1 mg, 0.34 mmol) in 62% (36.9 mg, 0.16
1
mmol) yield; yellow solid; mp 154-156 ˚C. H NMR (400 MHz, CDCl3) δ 8.23 (d, J = 8.9 Hz,
2H), 7.67 (d, J = 8.9 Hz, 2H), 7.48 (d, J = 8.1 Hz, 2H), 7.22 (d, J = 8.1 Hz, 2H), 2.42 (s, 3H)
13
ppm. C{1H} NMR (101 MHz, CDCl3) δ 146.8, 139.6, 132.1 (2C), 131.7 (2C), 130.5, 129.3
(2C), 123.6 (2C), 119.0, 95.1, 87.0, 21.6 ppm. HRMS (ESI), m/z calcd for C15H12NO2 [M+H]+
238.0863, found 238.0860.
2-(4-((2,4-Dichlorophenyl)ethynyl)phenyl)acetonitrile
(5w)
synthesized
from
2-(4-
bromophenyl)acetonitrile (49.0 mg, 0.25 mmol) and 2,4-dichlorobenzaldehyde (59.5 mg, 0.34
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mmol) in 41% (45.7 mg, 0.16 mmol) yield; white solid; mp 82-85 ˚C. H NMR (400 MHz,
CDCl3) δ 7.53 – 7.39 (m, 4H), 7.32 – 7.19 (m, 3H), 3.42 (s, 2H) ppm. 13C{1H} NMR (101 MHz,
CDCl3) δ 137.1, 135.2, 134.5, 129.8, 129.3 (2C), 127.8, 126.9 (2C), 120.7, 83.3 (2C), 79.2 ppm.
HRMS (ESI), m/z calcd for C16H10Cl2N [M+H]+ 286.0185, found 286.0184.
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2-((4-(Methylthio)phenyl)ethynyl)thiophene (5x) synthesized from 2-bromothiophene (40.8 mg,
0.25 mmol) and 4-(methylthio)benzaldehyde (48.7 mg, 0.34 mmol) in 47% (27.1 mg, 0.12
mmol) yield; white solid; mp 95-97 ˚C. 1H NMR (400 MHz, CDCl3) δ 7.45 (d, J = 8.5 Hz, 2H),
7.33 – 7.27 (m, 2H), 7.23 (d, J = 8.5 Hz, 2H), 7.03 (dd, J = 5.1, 3.7 Hz, 1H), 2.52 (s, 3H) ppm.
13C{1H} NMR (101 MHz, CDCl3) δ 139.6, 131.7, 131.6, 127.1 (3C), 125.8, 123.4 (2C), 119.2,
92.8, 82.7, 15.3 ppm. HRMS (ESI), m/z calcd for C13H11S2 [M+H]+ 231.0297, found 231.0295.
2-((2-(Benzyloxy)phenyl)ethynyl)thiazole (5y) synthesized from 2-bromothiazole (41.2 mg, 0.25
mmol) and 2-(benzyloxy)benzaldehyde (72.2 mg, 0.34 mmol) in 45% (32.9 mg, 0.12 mmol)
yield; white solid; mp 71-73 ˚C. 1H NMR (400 MHz, CDCl3) δ 7.51 – 7.57 (m, 4H), 7.40 – 7.44
(m, 3H), 7.28 – 7.37 (m, 3H), 6.94 – 6.98 (m, 3H), 5.23 (s, 2H) ppm. 13C{1H} NMR (101 MHz,
CDCl3) δ 159.8, 136.8, 134.2, 134.1, 130.1, 128.5 (2C), 127.8, 127.6, 126.9 (2C), 120.8, 112.8
(2C), 112.1, 81.4, 80.1, 70.4 ppm. HRMS (ESI), m/z calcd for C18H14NOS [M+H]+ 292.0791,
found 292.0788.
3,5-Bis((3-fluorophenyl)ethynyl)pyridin-2-amine (5z) synthesized from 3,5-dibromopyridin-2-
amine (62.3 mg, 0.25 mmol) and 3-fluorobenzaldehyde (43.4 mg, 0.35 mmol) in 26% (48.8 mg,
1
0.15 mmol) yield; white solid; mp 163-165 ˚C. H NMR (400 MHz, CDCl3) δ 8.27 (d, J = 2.2
Hz, 1H), 7.77 (d, J = 2.2 Hz, 1H), 7.41 – 7.30 (m, 4H), 7.23 (td, J = 10.1, 2.4 Hz, 2H), 7.15 –
13
7.02 (m, 2H), 5.19 – 5.47 (br s, 2H) ppm. C{1H} NMR (101 MHz, CDCl3) δ 163.65, 161.20,
157.90, 151.50, 142.38, 130.17 (d, J = 8.6 Hz), 129.94 (d, J = 8.8 Hz), 127.4 (d, J = 3.1 Hz),
127.3 (d, J = 3.1 Hz), 125.0 (d, J = 9.5 Hz), 124.1 (d, J = 9.5 Hz), 118.3 (d, J = 18.9 Hz), 118.1
(d, J = 18.7 Hz), 116.2 (d, J = 21.2 Hz), 115.5 (d, J = 21.2 Hz), 109.4, 102.3, 94.5 (d, J = 3.4
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Hz), 88.9 (d, J = 3.6 Hz), 87.0, 84.3 ppm. HRMS (ESI), m/z calcd for C21H13F2N2 [M+H]+
4
5
331.1041, found 331.1038.
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(E)-1-Methyl-4-(4-phenylbut-3-en-1-yn-1-yl)benzene
(5aa)
synthesized
from
(E)-(2-
9
bromovinyl)benzene (45.7 mg, 0.25 mmol) and 4-methylbenzaldehyde (41.1 mg, 0.34 mmol) in
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58% (31.6 mg, 0.16 mmol) yield; colorless oil. H NMR (400 MHz, CDCl3) δ 7.55 – 7.20 (m,
9H), 7.07 (d, J = 16.2 Hz, 1H), 6.43 (d, J = 16.2 Hz, 1H), 2.40 (s, 3H) ppm. 13C{1H} NMR (101
MHz, CDCl3) δ 140.8, 138.3, 136.4, 131.4 (2C), 129.1 (2C), 128.7 (2C), 128.5, 126.2 (2C),
120.3, 108.3, 92.0, 88.31, 21.5 ppm. HRMS (ESI), m/z calcd for C17H15 [M+H]+ 219.1168,
found 219.1165.
Gram-Scale Synthesis of 5i. To an oven-dried Schlenk tube equipped with a magnetic stirring
bar MeOH (60 mL), iodobenzene (1.5 g, 7.3 mmol, 1 equiv.), thiophene-3-carbaldehyde (1.2 g,
10.2 mol, 1.4 equiv.) and dimethyl (1-diazo-2-oxopropyl)phosphonate (2.8 g, 14.6 mmol, 2
equiv.) were added. The reaction mixture was cooled in an ice bath and Cs2CO3 (13.9 g, 43.0
mmol, 4 equiv.) was added. The reaction mixture was stirred under argon in an oil bath heated at
30oC for 4 h. A solution of Pd(OAc)2 (67 mg, 0.3 mmol, 0.04 equiv.) and XPhos (285 mg, 0.6
mmol, 0.08 equiv.) in MeOH (60 mL) was add and the stirring continued at 40oC for 12 h. On
cooling to r. t., the reaction mixture was diluted with H2O (400 mL) and extracted with CH2Cl2
(40 mL). The extract was washed with brine (100 mL), dried over anhydrous Na2SO4, filtered,
and concentrated on a rotary evaporator. The resulting residue was purified by column
chromatography on silica gel using an appropriate gradient 0→20% of CH2Cl2 in cyclohexane as
eluent to provide 5i (1.1 g, 5.8 mmol, 79% yield).
ASSOCIATED CONTENT
Supporting Information
1
13
Copies of H and C NMR spectra. This material is available free of charge via the Internet at
http://pubs.acs.org.
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AUTHOR INFORMATION
Corresponding Author
*E-mail: m.krasavin@spbu.ru
ORCID
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Alexander Sapegin: 0000-0002-6364-1126
Mikhail Krasavin: 0000-0002-0200-4772
Notes
The authors declare no competing financial interest.
ACKNOWLEDGEMENTS
This research was supported by the Russian Science Foundation (project grant 17-73-20185).
NMR and mass spectrometry studies were performed at the Research Centre for Magnetic
Resonance, the Centre for Chemical Analysis and Materials Research of Saint Petersburg State
University Research Park.
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