Synthesis of functionalized unsymmetrical 1,3-butadiene-3-yne derivatives from β-halo styrene derivatives and their application in the synthesis of trisubstituted pyridines

Article abstract of DOI:10.1039/c7ra07128k

An approach for the synthesis of functionalized unsymmetrical 1,3-butadiene-3-yne derivatives is reported starting from β-halo styrene and phenyl acetylene derivatives in the presence of PdCl₂ and CuI catalysts. Functional groups such as aldehyde, cyano and ester groups are well tolerated and afford the desired functionalized dienynes. Further, these 1,3-buta-diene-3-yne derivatives are utilized for the synthesis of novel trisubstituted pyridine derivatives.

Full text of DOI:10.1039/c7ra07128k

RSC Advances
View Article Online
View Journal | View Issue
PAPER
Synthesis of functionalized unsymmetrical 1,3-
butadiene-3-yne derivatives from b-halo styrene
derivatives and their application in the synthesis of
trisubstituted pyridines†
Cite this: RSC Adv., 2017, 7, 46704
Vijayalakshmi Bandi, Veerababurao Kavala, Che-Hao Hsu, Ashok Konala,
Bharath Kumar Villuri, Trimurtulu Kotipalli, Chun-Wei Kuo and Ching-Fa Yao
*
An approach for the synthesis of functionalized unsymmetrical 1,3-butadiene-3-yne derivatives is reported
starting from b-halo styrene and phenyl acetylene derivatives in the presence of PdCl2 and CuI catalysts.
Functional groups such as aldehyde, cyano and ester groups are well tolerated and afford the desired
functionalized dienynes. Further, these 1,3-buta-diene-3-yne derivatives are utilized for the synthesis of
novel trisubstituted pyridine derivatives.
Received 29th June 2017
Accepted 22nd September 2017
DOI: 10.1039/c7ra07128k
rsc.li/rsc-advances
literature for the synthesis of functionalized dienynes. Herein,
we report the synthesis of functionalized unsymmetrical 1,3-
Introduction
butadiene-3-yne derivatives from b-halo styrene derivatives.
While our work is under progress, Swamy and coworkers re-
ported the synthesis of norbornadienes/norbornenes starting
from alkynyldienols in the presence of Au catalyst.10 The start-
ing material alkynyldienol is obtained from Sonogashira cross-
coupling of 3-bromoenals to terminal alkynes followed by
alkyne addition and reduction. Although they prepared dieny-
nal derivative, further studies are not carried out on the role of
the functional group during the alkyne addition step to enynal
derivative.
Enynes are the predominant structures in modern organic
chemistry since their derivatives are important intermediates in
the synthesis of highly substituted aromatic rings and are found
in various pharmaceutical drugs.1 1,3- and 1,4-disubstituted
enynes are also interesting derivatives of enynes, which exist in
various polymers2 and biologically active molecules.3 Owing to
their applications, various methods for the synthesis of 1,3- and
1,4-disubstituted enynes are well known in the literature. A
literature survey on the synthesis of 1,3-butadiene-5-yne deriv-
atives revealed various reports with Ni,4 Pd5 and lanthanide6 and
actinide7 catalysts being well documented for the trimerization
of silyl alkynes and terminal alkynes. On the other hand, limited
reports are available for the synthesis of 1,3-butadiene-3-yne
derivatives, which are also 1,3-enynes. For instance, Wu et al.
synthesized various symmetrical 1,3-diaryl-2-arylethynyl-1,3-
butadienes by the Pd-catalyzed trimerization of arylalkynes.8
Later, Oro et al. reported the synthesis of 1,3-diaryl/alkyl-2-
trimethylsilylethynyl-1,3-butadienes by cross-trimerization of
terminal alkynes with trimethylsilylacetylene through C–H
activation using rhodium(I)–pyridine-N-heterocyclic carbene
catalyst.9 Both the reported methods have certain limitations
such as low yields and limited scope.
Results and discussion
As a part of our interest in developing fascinating methodolo-
gies11 for the synthesis of variety of heterocyclic compounds, we
planned to carry out Sonogashira coupling between b-bromo
cinnamaldehyde and phenyl acetylene under standard reaction
conditions in the presence of CuI/Pd(PPh3)2Cl2 bicatalytic
system in acetonitrile solvent at room temperature for one hour.
Under this reaction condition, unknown product 4 is observed
in trace amounts along with the expected enynal product 3
(entry 1, Table 1). From 1H and 13C-NMR studies, X-ray crys-
tallography studies12 the structure of 4 is conrmed. We realized
that the dienynal derivative 4 is formed by the addition of one
more alkyne moiety to enynal derivative 3. In order to improve
the yield of dienynal 4, we screened the reaction further. There
is substantial increase in the yield of dienynal 4, when we used
excess of phenyl acetylene (entry 2, Table 1). Next, the yield of
the desired product was slightly improved when the reaction
As a result, an efficient method for the synthesis of unsym-
metrical 1,3-butadiene-3-yne derivatives is highly desirable and
also to the best of our knowledge, very few reports exists in the
Department of Chemistry, National Taiwan Normal University, 88, Section 4,
Tingchow Road, Taipei, Taiwan 116, Republic of China. E-mail: cheyaocf@ntnu.
edu.tw
† Electronic supplementary information (ESI) available. CCDC 1557911, 1556913,
1556912, 1556914 and 1557912. For ESI and crystallographic data in CIF or other
electronic format see DOI: 10.1039/c7ra07128k
ꢀ
temperature increased to 50 C (entry 3, Table 1). Further, we
added triphenyl phosphine as ligand to improve the yield of the
46704 | RSC Adv., 2017, 7, 46704–46712
This journal is © The Royal Society of Chemistry 2017

View Article Online
Paper
RSC Advances
Table 1 Optimization studies
Yield (%)b
2
T
(ꢀC)
Entrya
Pd catalyst (mmol)
Cul (mmol)
(mmol)
Time (h)
3
4
1
2
3
4
5
6
7
8
PdCl2(PPh3)2 (0.1)
PdCl2(PPh3)2 (0.05)
PdCl2(PPh3)2 (0.05)
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
1.2
2.5
2.5
2.5
2.5
2.5
2.5
3.0
4.0
2.5
2.5
2.5
2.5
2.5
rt
rt
1
2
1.5
1.5
1.5
2
3
2
2
24
0.25
0.25
2
66
Trace
—
Trace
70
74
76
80
92
89
70
78
—
50
50
50
50
50
50
50
50
50
50
50
50
PdCl2(PPh3)2 (0.05)/PPh3 (0.1)
PdCl2 (0.05)/PPh3 (0.1)
PdCl2 (0.05)/PPh3 (0.1)
PdCl2 (0.05)/PPh3 (0.1)
PdCl2 (0.05)/PPh3 (0.1)
PdCl2 (0.05)/PPh3 (0.1)
Pd(PPh3)4 (0.05)/PPh3 (0.1)
Pd(OAc)2 (0.05)
—
Trace
Trace
Trace
Trace
Trace
35
—
—
—
Trace
9
10
11
12
13
14c
85
80
—
Pd(OAc)2 (0.05)/PPh3 (0.1)
Pd(OAc)2 (0.1)
Pd(OAc)2 (0.05)
2
88
a
All the reactions are carried out in 1 mmol scale using 5.6 equiv. of TEA in the acetonitrile solvent (3.0 mL). b NMR yields. c Dioxane was used as
solvent.
desired product (entry 4, Table 1). However, there was no (0.1 mmol), TEA (5.6 mmol) afforded the desired dienynal
marked improvement in yield of the product was observed in products in good to excellent yields as shown in Table 2. By
this reaction. Then, we replaced Pd(PPh3)2Cl2 with simple xing phenyl acetylene as one of the reacting partner, the scope
palladium catalyst such as palladium chloride and triphenyl of the other reacting partner (Z)-3-bromo-3-arylacrylaldehyde
phosphine, to our surprise, the reaction produced good yield of derivatives is examined. Electron donating substituents such
the desired product aer 1.5 h (entry 5, Table 1). Further, we as Me and OMe on the phenyl ring of (Z)-3-bromo-3-
observed dramatic improvement in the yield of the desired arylacrylaldehyde derivatives furnished the desired dienynal
product when reaction time extends to 2 h, (entry 6, Table 1). derivatives in good to excellent yields (Table 2, entries 2, 3). On
Moreover, further extending the reaction showed negative the other hand, good to moderate yields of the dienyal deriva-
impact on the reaction (entry 7, Table 1). No improvement in tives are observed with electron withdrawing substituents like
the yield of dienynal derivative was observed with further 4-Br, 3-Br and 4-Cl, 3-NO2 (Table 2, entries 4 to 7). To our
additional amounts of phenylacetylene (entries 8–9, Table 1). delight, 1- and 2-naphthyl acrylaldehyde derivatives also affor-
Dienynal derivative 4 is not observed, when reaction carried out ded the desired dienyal derivatives in good yields (Table 2,
in the presence of Pd(PPh3)4 (entry 10, Table 1). Next we entries 8 to 9). Good yields of the dienynal derivatives are ob-
screened the reaction with palladium acetate as catalyst. tained when disubstituted electron donating derivatives such
Dienynal derivative formed in 85%, when b-bromo styrene as dimethyl, dimethoxy are subjected to optimized reaction
reacts with phenyl acetylene in the presence of Pd(OAc)2 (entry conditions (Table 2, entries 10 to 14). Subsequently, we explored
11, Table 1). As the result with Pd(OAc)2 was encouraging, we the substrate scope of
2
by xing (Z)-3-bromo-3-
screened the reaction in various conditions with Pd(OAc)2 phenylacrylaldehyde as one of the reacting partners. 4-Me, 4-
(entries 12–14, Table 1). It was found that the reaction produced isobutyl phenyl acetylenes furnished corresponding dienyal
better yield in dioxane solvent in the presence of palladium derivatives in moderate yields under the optimized reaction
acetate. Moreover, from optimization studies, it is observed that conditions (Table 2, entries 15 and 16). However, when the
an excellent yield of the desired product 4 is obtained in 92% reaction was carried out with ortho and meta substituted phenyl
with 1 equiv. of b-bromo cinnamaldehyde, 2.5 equiv. of phenyl acetylenes, desired dienynal derivatives were not observed
acetylene in the presence of PdCl2 (0.05 mmol), PPh3 (0.1 mmol), (Table 2, entries 17 and 18).
CuI (0.1 mmol) in acetonitrile solvent for 2 h at 50 ꢀC.
To expand scope of our methodology, we turned our atten-
Having the optimized conditions in hand, we check the tion towards other functional group such as cyano group
feasibility of the reaction with various substrates on both the instead of aldehyde. We prepared 3-chloro-3-phenylacrylonitrile
reacting partners. The substrate scope of (Z)-3-bromo-3- and subjected to the optimized reaction conditions with phenyl
arylacrylaldehyde derivatives with various aryl acetylenes in acetylene. To our delight, the corresponding dienyne derivative
the presence of PdCl2 (0.05 mmol), PPh3 (0.1 mmol), and CuI 6 is isolated in 71% yield as a separable mixture of E and Z
This journal is © The Royal Society of Chemistry 2017
RSC Adv., 2017, 7, 46704–46712 | 46705

View Article Online
RSC Advances
Paper
Table 2 Scope of the reaction with respect to 3-bromo-3-phenyl- Table
3
Scope of the reaction with respect to 3-chloro-3-
acrylal derivatives
phenylacrylonitrile
Yieldb (%)
Time
(h)
Yieldb
(%)
Time
(h)
Entrya Ar1
Ar2
6 E/Z
E/Z ratioc
Entrya Ar1
Ar2
Product
4
1
2
3
4
5
6
7
8
9
C6H5
4-CH3C6H4
2-CH3C6H4
C6H5
C6H5
C6H5
12
12
12
12
12
12
12
6a/60a 71
6b/60b 69
1:2
3:7
1:0
1:2:3
1:5
0:1
5:4
3:5
2:5
1
2
3
4
5
6
7
8
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4p
4p
4o
4q
90
80
75
70
68
73
54
70
68
71
81
62
71
68
74
65
—
—
4-MeC6H4
4-OMeC6H4
4-BrC6H4
3-BrC6H4
4-ClC6H4
3-NO2C6H4
1-C10H17
2-C10H17
2,4-(CH3)2C6H3
2,5-(CH3)2C6H3
3,4-(CH3)2C6H3
3,4-(OCH3)2C6H3 C6H5
4-isobutylC6H4
C6H5
C6H5
C6H5
6c
38
4-OCH3C6H4 C6H5
6d/60d 68
6e/60e 53
4-ClC6H4
1-C10H7
2-C10H7
C6H5
C6H5
C6H5
C6H5
4-CH3C6H4 14
4-ClC6H4 14
60f
41
6g/60g 66
6h/60h 55
C6H5
6i/60i
49
9
a
10
11
12
13
14
15
16
17c
18c
Reaction conditions: 5 (1 mmol), 2 (2.5 equiv.), TEA (5.6 equiv.), PdCl2
(5 mol%), PPh3 (10 mol%), CuI (10 mol%) and MeCN (3.0 mL) at 70 ꢀC.
b
c
Isolated yields. Ratio of E/Z calculated based on crude 1H NMR
spectra.
C6H5
4-MelC6H4
4-isobutylC6H4 2.5
2-NO2C6H4
3-ClC6H4
8 in 76% yield. From 1H and 13C-NMR studies, X-ray crystal-
lography studies12 the structure of 8 is conrmed. To investigate
the role of functional group in the present protocol, we prepared
chloro stilbene derivative 9 and treated with phenyl acetylene
under the optimized reaction conditions. To our surprise
desired dienyne derivative is not observed which conrms the
vital role of functional group i.e., CHO, CN, COOEt in b-halo
styrene derivative in affording the desired 1,3-butadiene-3-yne
derivatives as shown in Scheme 1.
In order to enhance the synthetic utility of the current
protocol, novel 2,3,5-trisubstituted pyridine derivatives are
prepared from dienyal derivatives 4 and phenyl hydrazine in the
presence of iodine as shown in Table 4. Trisubstituted pyridine
derivatives are also obtained when the reaction carried with
glycine methyl ester and NH4Cl albeit in low yield under similar
conditions. Reaction of dienynal 4a with phenyl hydrazine in
the presence of iodine in DCM at rt, furnished the dienyne
hydrazine intermediate. However, when we replaced DCM with
toluene and enhanced the temperature to 60 ꢀC, to our delight
trisubstituted pyridine is obtained in 66% yield (Table 4, entry
10
10
C6H5
a
Reaction conditions: 1 (1 mmol), 2 (2.5 equiv.), TEA (5.6 equiv.), PdCl2
(5 mol%), PPh3 (10 mol%), CuI (10 mol%) and MeCN (3.0 mL) at 50 ꢀC.
b
Isolated yields. c Formation of dienyne product was not observed.
isomers (6/60) at 70 ꢀC (Table 3, entry 1). The structures of these
dienyne E and Z isomers are further conrmed from X-ray
crystallography studies.12 Electron donating groups such as 4-
Me, 2-Me, 4-OMe on the phenyl ring of 3-chloro-3-
arylacrylonitrile afforded mixture of dienynes with 69%, 38%
and 68% respectively (Table 3, entries 2 to 4). Interestingly in
the case of 2-methyl substituted acrylonitrile derivative exclu-
sive formation of E-isomer takes place. On the other hand, in
the presence of electron withdrawing group such as Cl, desired
dienyne isomers obtained in 53% yield (Table 3, entry 5). To
investigate the further scope of the reaction, we
treated 1-naphthyl-3-chloroacrylonitrile or 2-naphthyl-3-
chloroacrylonitrile with phenyl acetylene to afford correspond-
ing dienyne derivatives in 41% and 66% yield respectively
(Table 3, entries 6 and 7). In the case of 1-naphthyl group, only Z
isomer is formed. Furthermore, reaction of 3-chloro-3-
phenylacrylonitrile with 4-Me and 4-Cl substituted phenyl
acetylenes afford the desired dienyne derivatives in 55 and 49%
yields respectively (Table 3, entries 8 and 9).
The scope of the present protocol is further elaborated with
the ester functional group by examining with methyl 3-chloro-3-
phenylacrylate under the optimized reaction conditions. To our
delight, methyl 3-chloro-3-phenylacrylate 7 reacts with phenyl
acetylene in the presence of PdCl2, PPh3, and CuI, TEA in
CH3CN solvent at 60 ꢀC afforded the desired dienyne derivative
Scheme 1 Scope with methyl 3-chloro-3-phenylacrylate.
46706 | RSC Adv., 2017, 7, 46704–46712
This journal is © The Royal Society of Chemistry 2017

View Article Online
Paper
RSC Advances
Table 4 Synthesis of trisubstituted pyridine derivatives
Experimental section
General information
Reagents and solvents were purchased from various commer-
cial sources and were used directly without any further puri-
cation. Column chromatography was performed with 63–200
mesh silica gel. 1H and 13C NMR spectra were recorded at
400 and 100 MHz, respectively. Chemical shis are reported in
parts per million (d) using chloroform as internal standards and
coupling constants are expressed in Hertz. Melting points were
recorded using an electro thermal capillary melting point
apparatus and are uncorrected.
Entrya Ar1
Ar2
Time (h) Product Yieldb (%)
1
2
3
4
5
6
7
8
9
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
9
10a
10b
10c
10d
10e
10f
66
68
62
58
46
53
58
50
56
4-OMeC6H4
4-ClC6H4
3-NO2C6H4
1-C10H17
2-C10H17
4-MeC6H4
9
10
11
10
10
15
16
General procedure for the synthesis of (E)-4-((E)-benzylidene)-
3,6-diphenylhex-2-en-5-ynal derivatives (4a–4o)
10g
10h
10i
Triethyl amine (567 mg, 5.6 equiv.), palladium chloride (9 mg,
5 mol%), triphenyl phosphine (26 mg, 10 mol%), copper iodide
(20 mg, 10 mol%) and phenyl acetylene (255 mg, 2.5 equiv.)
were added successively to a stirred solution of (Z)-3-bromo-3-
phenylacrylaldehyde (210 mg, 1.0 mmol) in acetonitrile under
nitrogen atmosphere. The reaction mixture was heated to 50 ꢀC
and monitored by TLC. Aer completion of the reaction, the
resulting reaction mixture was cooled to room temperature and
solvent was removed under reduced pressure. Now add ethyl
acetate and ltered through celite pad to remove metal cata-
lysts. Later organic layer was washed with brine and dried over
MgSO4. The resulting crude compound was puried by ash
column chromatography (eluent: petroleum ether/ethyl acetate)
20 : 1 on silica gel to afford desired product.
3,4-(MeO)2C6H3 C6H5
C6H5
4-MeC6H4 20
a
Reaction conditions: 4 (0.5 mmol), phenyl hydrazine (0.75 mmol), I2
(0.15 mmol), toluene (4.0 mL) at 60 ꢀC. b Isolated yields.
1). The structure of 10a is further conrmed from X-ray crys-
tallography studies.12
Both electron donating and withdrawing substituents afford
the desired trisubstituted pyridine derivatives in moderate to
good yield. For instance, with methoxy and methyl substituents
desired trisubstituted pyridine derivative is isolated in
moderate yields (Table 4, entries 2, 7–9). Electron withdrawing
groups such as chloro and nitro substituents afford the pyridine
derivative in 62% and 58% yield respectively (Table 4, entry 3
and 4). However, 46% and 53% yields of pyridine derivatives
were obtained successively in the case of 1-naphthyl and 2-
naphthyl derivatives (Table 4, entries 5 and 6).
General procedure for the synthesis of (E)-4-((E)-benzylidene)-
3,6-diphenylhex-2-en-5-ynenitrile derivatives (6a–6j)
Triethyl amine (567 mg, 5.6 equiv.), palladium chloride (9 mg,
5 mol%), triphenyl phosphine (26 mg, 10 mol%), copper iodide
(20 mg, 10 mol%) and phenyl acetylene (255 mg, 2.5 equiv.)
were added successively to a stirred solution of 3-chloro-3-
phenylacrylnitrile (164 mg, 1.0 mmol) in acetonitrile under
nitrogen atmosphere. The reaction mixture was heated to 70 ꢀC
and monitored by TLC. Aer completion of the reaction, the
resulting reaction mixture was cooled to room temperature and
solvent was removed under reduced pressure. Now add ethyl
acetate and ltered through celite pad to remove metal cata-
lysts. Later organic layer was washed with brine. The organic
layer was separated; dried over anhydrous MgSO4 and ltered
the dried organic layer, then concentrated it to obtain the crude
product. The resulting crude compound was puried by ash
column chromatography (eluent: petroleum ether/ethyl acetate)
20 : 1 on silica gel to afford desired product.
The proposed mechanism for the formation of pyridine
derivatives is shown in Fig. 1. In the presence of iodine, dienyal
derivative 4 reacts with phenyl hydrazine to form hydrazone
intermediate. This hydrazone intermediate will undergo elec-
trocyclic reaction followed by the elimination of aniline affords
the desired pyridine derivative 10. To the best of our knowledge
no reports are available in the literature in which phenyl
hydrazine acts as nitrogen source for the synthesis of pyridine
derivatives.
Procedure for the synthesis of methyl (E)-4-((E)-benzylidene)-
3,6-diphenylhex-2-en-5-ynoate (8)
Triethyl amine (567 mg, 5.6 equiv.), palladium chloride (9 mg,
5 mol%), triphenyl phosphine (26 mg, 10 mol%), copper iodide
(20 mg, 10 mol%) and phenyl acetylene (255 mg, 2.5 equiv.)
Fig. 1 A plausible mechanism for the formation of pyridine derivative. were added successively to a stirred solution of methyl 3-chloro-
This journal is © The Royal Society of Chemistry 2017
RSC Adv., 2017, 7, 46704–46712 | 46707

View Article Online
RSC Advances
Paper
3-phenylacrylate (197 mg, 1.0 mmol) in acetonitrile under
nitrogen atmosphere. The reaction mixture was heated to 60 ꢀC
and monitored by TLC. Aer completion of the reaction, the
resulting reaction mixture was cooled to room temperature and
solvent was removed under reduced pressure. Now add ethyl
acetate and ltered through celite pad to remove metal cata-
lysts. Later organic layer was washed with brine. The organic
layer was separated; dried over anhydrous MgSO4 and ltered
the dried organic layer, then concentrated it to obtain the crude
product. The resulting crude compound was puried by ash
column chromatography (eluent : petroleum ether/ethyl
acetate) 20 : 1 on silica gel to afford desired product.
(2E,4E)-4-benzylidene-3-(4-bromophenyl)-6-phenylhex-2-en-
1
ꢀ
5-ynal (4d). Yellow solid, mp: 148–149 C. H NMR (400 MHz,
CDCl3) dH (ppm): 9.43 (d, J ¼ 8.2 Hz, 1H), 7.93–7.91 (m, 2H),
7.65–7.63 (m, 2H), 7.57–7.54 (m, 2H), 7.41–7.34 (m, 6H), 7.26–
7.23 (m, 2H), 6.95 (d, J ¼ 8.1 Hz, 1H), 6.71 (s, 1H). 13C NMR (100
MHz, CDCl3) dC (ppm): 193.5, 159.3, 143.6, 135.4, 133.9, 132.0,
131.9, 131.8, 130.2, 129.6, 129.3, 128.8, 128.6, 123.7, 122.6,
122.5, 99.5, 85.5; HRMS (EI) m/z calcd for C25H17BrO (M+):
412.0463, found 412.0463.
(E)-4-((E)-Benzylidene)-3-(3-bromophenyl)-6-phenylhex-2-en-
1
ꢀ
5-ynal (4e). Yellow solid, mp: 109–110 C. H NMR (400 MHz,
CDCl3) dH (ppm): 9.44 (d, J ¼ 8.0 Hz, 1H), 7.93–7.91 (m, 2H), 7.64
(dt, J ¼ 5.2 Hz, J ¼ 1.5 Hz, 1H), 7.58–7.54 (m, 3H), 7.41–7.36 (m,
7H), 7.32–7.30 (m, 1H), 6.95 (d, J ¼ 8.1 Hz, 1H), 6.71 (s, 1H). 13
C
General procedure for the synthesis of 2,4-diphenyl-3-
(phenylethynyl)pyridine derivatives (10a–10f)
NMR (100 MHz, CDCl3) dC (ppm): 193.3, 158.7, 143.5, 136.9,
135.2, 133.1, 132.9, 132.2, 131.6, 130.1, 130.0, 129.5, 129.1, 128.9,
128.6, 128.5, 128.2, 122.7, 122.4, 122.3, 99.3, 85.2; HRMS (ESI) m/
z calcd for C25H18OBr (M + H)+: 413.0541, found 413.0541.
(2E,4E)-4-Benzylidene-3-(4-chlorophenyl)-6-phenylhex-2-en-
Phenyl hydrazine (162 mg, 1.5 mmol.), and iodine (76 mg, 0.3
mmol) were added successively to a stirred solution of (E)-4-((E)-
benzylidene)-3,6-diphenylhex-2-en-5-ynal (334 mg, 1.0 mmol) in
ꢀ
toluene. The reaction mixture was heated to 60 C and moni-
1
ꢀ
5-ynal (4f). Yellow solid, mp: 147–148 C. H NMR (400 MHz,
CDCl3) dH (ppm): 9.44 (d, J ¼ 8.1 Hz, 1H), 7.92 (d, J ¼ 6.8 Hz, 2H),
7.57–7.55 (m, 2H), 7.49 (d, J ¼ 8.2 Hz, 2H), 7.41–7.34 (m, 6H),
tored by TLC. Aer completion of the reaction, the resulting
reaction mixture was cooled to room temperature and treated
with hypo solution to quench iodine. The organic layer was
extracted with ethyl acetate, washed with brine. The organic
layer was separated; dried over anhydrous MgSO4 and ltered
the dried organic layer, then concentrated it to obtain the crude
product. The resulting crude compound was puried by ash
column chromatography (eluent : petroleum ether/ethyl
acetate) 10 : 1 on silica gel to afford desired product.
7.31 (d, J ¼ 8.2 Hz, 2H), 6.96 (d, J ¼ 8.1 Hz, 1H), 6.72 (s, 1H). 13
C
NMR (100 MHz, CDCl3) dC (ppm): 193.5, 159.4, 143.6, 135.5,
135.4, 133.5, 131.8, 131.7, 130.3, 130.2, 129.7, 129.3, 129.0,
128.8, 128.6, 122.7, 122.6, 99.5, 85.6; HRMS (EI) m/z calcd for
C
25H17ClO (M+): 368.0968, found 368.0968.
(2E,4E)-4-Benzylidene-3-(3-nitrophenyl)-6-phenylhex-2-en-5-
ynal (4g). Yellow solid, mp: 178–179 ꢀC. 1H NMR (400 MHz,
CDCl3) dH (ppm): 9.40 (d, J ¼ 8.1 Hz, 1H), 8.39–8.37 (m, 1H),
8.27 (s, 1H), 7.91–7.89 (m, 2H), 7.73–7.71 (m, 2H), 7.57–7.55 (m,
Spectral data of compounds
2H), 7.42–7.37 (m, 6H), 7.02 (d, J ¼ 8.1 Hz, 1H), 6.61 (s, 1H). 13
C
(E)-4-((E)-benzylidene)-3,6-diphenylhex-2-en-5-ynal
(4a).
Yellow solid, mp: 162–162 ꢀC. 1H NMR (400 MHz, CDCl3) dH
(ppm): 9.52 (d, J ¼ 8.2 Hz, 1H), 7.91–7.89 (m, 2H), 7.57–7.55 (m,
2H), 7.50–7.48 (m, 3H), 7.40–7.34 (m, 8H), 6.96 (d, J ¼ 8.2 Hz,
1H), 6.75 (s, 1H). 13C NMR (100 MHz, CDCl3) dC (ppm): 194.2,
160.8, 143.7, 135.6, 135.1, 131.8, 130.5, 130.3, 130.1, 129.4,
129.3, 129.2, 128.8, 128.7, 128.6, 122.9, 122.8, 99.3, 85.8; HRMS
(EI) m/z calcd for C25H18O (M+): 334.1358, found 334.1358.
(2E,4E)-4-benzylidene-6-phenyl-3-(p-tolyl)hex-2-en-5-ynal (4b).
Yellow solid, mp: 112–113 ꢀC. 1H NMR (400 MHz, CDCl3) dH
(ppm): 9.43 (d, J ¼ 8.1 Hz, 1H), 7.90–7.88 (m, 2H), 7.55–7.53 (m,
2H), 7.38–7.31 (m, 6H), 7.27–7.21 (m, 4H), 6.91 (d, J ¼ 8.0 Hz,
1H), 6.77 (s, 1H), 2.43 (s, 3H). 13C NMR (100 MHz, CDCl3) dC
(ppm): 194.3, 161.0, 143.5, 139.3, 135.7, 132.0, 131.8, 130.5,
130.2, 130.0, 129.3, 129.2, 128.7, 128.6, 123.1, 122.8, 99.2, 86.0,
21.5; HRMS (EI) m/z calcd for C26H20O (M+): 348.1514, found
348.1514.
NMR (100 MHz, CDCl3) dC (ppm): 192.5, 157.7, 148.5, 143.7,
136.9, 136.3, 135.2, 131.8, 130.5, 130.3, 130.2, 129.9, 129.4,
128.8, 128.7, 125.1, 124.3, 122.4, 122.3, 99.9, 85.1; HRMS (EI) m/
z calcd for C25H17NO3 (M+): 379.1208, found 379.1208.
(2E,4E)-4-Benzylidene-3-(naphthalen-1-yl)-6-phenylhex-2-en-
1
ꢀ
5-ynal (4h). Yellow solid, mp: 167–168 C. H NMR (400 MHz,
CDCl3) dH (ppm): 9.10 (d, J ¼ 8.1 Hz, 1H), 7.83–7.76 (m, 2H),
7.67–7.64 (m, 3H), 7.48–7.31 (m, 9H), 7.25–7.14 (m, 3H), 7.06 (d,
J ¼ 7.8 Hz, 1H), 6.46 (s, 1H). 13C NMR (100 MHz, CDCl3) dC
(ppm): 197.3, 160.1, 143.3, 135.5, 133.6, 132.5, 131.8, 130.6,
130.2, 130.0, 129.6, 129.2, 128.8, 128.6, 128.5, 128.4, 127.4,
126.7, 125.9, 125.2, 122.8, 122.5, 99.4, 85.6; HRMS (EI) m/z calcd
for C29H20O (M+): 384.1514, found 384.1514.
(2E,4E)-4-Benzylidene-3-(naphthalen-2-yl)-6-phenylhex-2-en-
1
ꢀ
5-ynal (4i). Yellow solid, mp: 196–197 C. H NMR (400 MHz,
CDCl3) dH (ppm): 9.47 (d, J ¼ 8.2 Hz, 1H), 7.98–7.91 (m, 6H),
7.89–7.60 (m, 4H), 7.47 (dd, J ¼ 8.4, 1.3 Hz, 1H), 7.42–7.35 (m,
6H), 7.07 (d, J ¼ 8.1 Hz, 1H), 6.79 (s, 1H). 13C NMR (100 MHz,
CDCl3) dC (ppm): 194.2, 160.8, 143.9, 135.6, 133.5, 132.9, 132.5,
131.8, 130.3, 130.2, 130.1, 129.9, 129.2, 128.8, 128.6, 128.4,
128.1, 127.6, 127.3, 127.2, 122.9, 122.8, 99.3, 85.9; HRMS (EI) m/
z calcd for C29H20O (M+): 384.1514, found 384.1514.
(2E,4E)-4-benzylidene-3-(4-methoxyphenyl)-6-phenylhex-2-
en-5-ynal (4c). Yellow solid, mp: 165–166 ꢀC. 1H NMR (400 MHz,
CDCl3) dH (ppm): 9.47 (d, J ¼ 8.0 Hz, 1H), 7.94–7.92 (m, 2H),
7.58–7.56 (m, 2H), 7.40–7.28 (m, 8H), 7.03–7.00 (m, 2H), 6.94 (d,
J ¼ 8.0 Hz, 1H), 6.83 (s, 1H), 3.87 (s, 3H). 13C NMR (100 MHz,
CDCl3) dC (ppm): 194.3, 160.7, 160.5, 143.5, 135.7, 132.0, 131.7,
130.2, 129.9, 129.3, 129.1, 128.7, 128.6, 127.0, 123.1, 122.8,
114.1, 99.2, 86.1, 55.53; HRMS (EI) m/z calcd for C26H20O2 (M+):
364.1463, found 364.1463.
(2E,4E)-4-Benzylidene-3-(2,4-dimethylphenyl)-6-phenylhex-2-
en-5-ynal (4j). Yellow liquid, 1H NMR (400 MHz, CDCl3) dH
46708 | RSC Adv., 2017, 7, 46704–46712
This journal is © The Royal Society of Chemistry 2017

View Article Online
Paper
RSC Advances
(ppm): 9.35 (d, J ¼ 8.2 Hz, 1H), 7.91–7.89 (m, 2H), 7.60–7.58 (m, CDCl3) dH (ppm): 9.41 (d, J ¼ 8.1 Hz, 1H), 7.85 (d, J ¼ 8.1 Hz, 2H),
2H), 7.41–7.34 (m, 6H), 7.14–7.10 (m, 3H), 6.99 (d, J ¼ 8.2 Hz, 7.50–7.47 (m, 5H), 7.36–7.34 (m, 2H), 7.19–7.15 (m, 4H), 6.95 (d, J
1H), 6.66 (s, 1H), 2.41 (s, 3H), 2.20 (s, 3H). 13C NMR (100 MHz, ¼ 8.2 Hz, 1H), 6.71 (s, 1H), 2.52 (d, J ¼ 7.2 Hz, 2H), 2.49 (d, J ¼
CDCl3) dC (ppm): 194.4, 160.9, 142.4, 139.0, 136.6, 135.7, 131.8, 7.2 Hz, 2H), 1.94–1.84 (m, 2H), 0.94 (d, J ¼ 6.6 Hz, 6H), 0.90 (d, J ¼
131.4, 131.3, 130.5, 130.3, 130.0, 129.4, 129.1, 128.7, 128.6, 6.6 Hz, 6H). 13C NMR (100 MHz, CDCl3) dC (ppm): 194.2, 161.3,
126.8, 122.8, 122.2, 99.1, 85.6, 21.4, 19.7; HRMS (EI) m/z calcd 144.4, 143.5, 143.2, 135.2, 133.2, 131.5, 130.5, 130.2, 129.5, 129.4,
for C27H22O (M+): 362.1671, found 362.1671.
(2E,4E)-4-benzylidene-3-(2,5-dimethylphenyl)-6-phenylhex-2- HRMS (EI) m/z calcd for C33H34O (M+): 446.2610, found 446.2612.
en-5-ynal (4k). Yellow solid, 1H NMR (400 MHz, CDCl3) dH
(E)-4-((E)-Benzylidene)-3,6-diphenylhex-2-en-5-ynenitrile (6a).
129.1, 129.0, 128.5, 121.9, 120.1, 99.7, 85.5, 45.6, 45.5, 30.3, 22.5;
1
(ppm): 9.35 (d, J ¼ 8.3 Hz, 1H), 7.91–7.89 (m, 2H), 7.60–7.58 (m, Colorless solid, mp: 110–112 ꢀC. H NMR (400 MHz, CDCl3) dH
2H), 7.41–7.31 (m, 6H), 7.22–7.17 (m, 2H), 7.03 (s, 1H), 6.98 (d, J (ppm): 7.89–7.87 (m, 2H), 7.57–7.50 (m, 5H), 7.43–7.35 (m, 8H),
¼ 8.2 Hz, 1H), 6.65 (s, 1H), 2.37 (s, 3H), 2.19 (s, 3H). 13C NMR 6.73 (s, 1H), 6.31 (s, 1H). 13C NMR (100 MHz, CDCl3) dC (ppm):
(100 MHz, CDCl3) dC (ppm): 194.3, 160.9, 142.5, 135.7, 135.6, 161.7, 143.5, 135.5, 135.3, 131.7, 130.2, 130.1, 129.7, 129.4, 129.3,
134.3, 133.6, 131.8, 131.0, 130.4, 130.3, 130.0, 129.9, 129.2, 128.9, 128.8, 128.6, 122.5, 121.0, 118.0, 99.4, 98.8, 85.4; HRMS
129.1, 128.7, 128.5, 122.8, 122.0, 99.1, 85.6, 21.1, 19.2; HRMS (ESI) m/z calcd for C25H18N (M + H)+: 332.1439, found 332.1440.
(EI) m/z calcd for C27H22O (M+): 362.1671, found 362.1671.
(Z)-4-((E)-Benzylidene)-3,6-diphenylhex-2-en-5-ynenitrile
(2E,4E)-4-Benzylidene-3-(3,4-dimethylphenyl)-6-phenylhex-2- (60a). Colorless solid, mp: 114–115 ꢀC. 1H NMR (400 MHz, CDCl3)
en-5-ynal (4l). Yellow solid, mp: 143–144 ꢀC. 1H NMR (400 MHz, dH (ppm): 8.04 (d, J ¼ 7.5 Hz, 2H), 7.54 (d, J ¼ 7.0 Hz, 2H), 7.47–
CDCl3) dH (ppm): 9.40 (d, J ¼ 8.1 Hz, 1H), 7.86–7.84 (m, 2H), 7.39 (m, 8H), 7.32–7.30 (m, 3H), 7.06 (s, 1H), 5.67 (s, 1H). 13C
7.51–7.48 (m, 2H), 7.32–7.26 (m, 6H), 7.16 (d, J ¼ 8.1 Hz, 1H), NMR (100 MHz, CDCl3) dC (ppm): 161.9, 142.3, 137.6, 135.4,
7.05–7.01 (m, 2H), 6.87 (d, J ¼ 8.1 Hz, 1H), 6.75 (s, 1H), 2.28 (s, 131.7, 130.6, 129.9, 129.8, 128.9, 128.8, 128.6, 128.5, 128.5, 122.9,
3H), 2.25 (s, 3H). 13C NMR (100 MHz, CDCl3) dC (ppm): 194.4, 118.4, 117.2, 98.9, 95.7, 87.1; HRMS (ESI) m/z calcd for C25H18N
161.1, 143.5, 137.9, 136.9, 135.7, 132.3, 131.7, 131.6, 130.2, (M + H)+: 332.1439, found 332.1439.
129.9, 129.7, 129.1, 129.0, 128.7, 128.5, 128.0, 123.0, 122.8, 99.1,
(E)-4-((E)-Benzylidene)-6-phenyl-3-(p-tolyl)hex-2-en-5-ynenitrile
86.0, 19.9, 19.8; HRMS (EI) m/z calcd for C27H22O (M+): (6b). Colorless solid, mp: 130–132 ꢀC. 1H NMR (400 MHz, CDCl3)
362.1671, found 362.1671.
dH (ppm): 7.94 (d, J ¼ 6.8 Hz, 2H), 7.60 (s, 2H), 7.46–7.36 (m, 10H),
(2E,4E)-4-benzylidene-3-(3,4-dimethoxyphenyl)-6-phenylhex- 6.83 (s, 1H), 6.32 (s, 1H), 2.49 (s, 3H). 13C NMR (100 MHz, CDCl3)
1
2-en-5-ynal (4m). Yellow solid, mp: 166–167 ꢀC. H NMR (400 dC (ppm): 161.7, 143.3, 139.7, 135.3, 132.5, 131.7, 130.1, 130.0,
MHz, CDCl3) dH (ppm): 9.49 (d, J ¼ 8.0 Hz, 1H), 7.92 (d, J ¼ 129.6, 129.2, 128.8, 128.5, 122.5, 121.1, 118.1, 99.2, 98.3, 85.6,
6.8 Hz, 2H), 7.57–7.55 (m, 2H), 7.40–7.35 (m, 6H), 6.98–6.90 (m, 21.5; HRMS (EI) m/z calcd for C26H20N (M+ + H): 346.1596, found
3H), 6.86–6.84 (m, 2H), 3.97 (s, 3H), 3.89 (s, 3H). 13C NMR (100 346.1598.
MHz, CDCl3) dC (ppm): 194.2, 160.6, 150.0, 149.0, 143.4, 135.6,
(Z)-4-((E)-Benzylidene)-6-phenyl-3-(p-tolyl)hex-2-en-5-ynenitrile
131.7, 130.2, 130.0, 129.3, 129.1, 128.7, 128.6, 127.4, 123.7, (60b). Colorless solid, mp: 114–116 ꢀC. 1H NMR (400 MHz, CDCl3)
122.9, 122.8, 113.5, 111.1, 99.2, 86.0, 56.2, 56.1; HRMS (EI) m/z dH (ppm): 8.06 (d, J ¼ 7.2 Hz, 2H), 7.47–7.39 (m, 7H), 7.35–7.32 (m,
calcd for C27H22O3 (M+): 394.1569, found 394.1569.
3H), 7.28–7.24 (m, 2H), 7.06 (s, 1H), 5.67 (s, 1H), 2.43 (s, 3H). 13
C
(2E,4E)-4-benzylidene-3-(4-isobutylphenyl)-6-phenylhex-2- NMR (100 MHz, CDCl3) dC (ppm): 161.8, 142.1, 141.0, 135.4,
en-5-ynal (4n). Yellow solid, mp: 139–140 ꢀC. 1H NMR (400 MHz, 134.6, 131.7, 129.8, 129.6, 128.9, 128.6, 128.5, 128.4, 123.0, 118.5,
CDCl3) dH (ppm): 9.38 (d, J ¼ 8.1 Hz, 1H), 7.84–7.82 (m, 2H), 117.4, 98.7, 94.8, 87.2, 21.6; HRMS (ESI) m/z calcd for C26H20N (M
7.50–7.47 (m, 2H), 7.31–7.28 (m, 6H), 7.25–7.16 (m, 3H), 6.87 (d, + H)+: 346.1596, found 346.1595.
J ¼ 8.1 Hz, 1H), 6.72 (m, 1H), 2.49 (d, J ¼ 7.2 Hz, 2H), 1.90–1.84
(E)-4-((E)-Benzylidene)-6-phenyl-3-(o-tolyl)hex-2-en-5-ynenitrile
(m, 1H), 0.87 (d, J ¼ 6.6 Hz, 6H). 13C NMR (100 MHz, CDCl3) dC (6c). Yellow thick liquid, H NMR (400 MHz, CDCl3) dH (ppm):
(ppm): 194.3, 161.1, 143.5, 143.1, 135.6, 132.2, 131.7, 130.3, 7.94–7.92 (m, 2H), 7.66–7.64 (m, 2H), 7.49–7.47 (m, 3H), 7.45–7.37
130.2, 129.9, 129.3, 129.2, 129.1, 128.7, 128.5, 122.9, 122.8, 99.2, (m, 6H), 7.27 (s, 1H), 6.63 (s, 1H), 6.48 (s, 1H), 2.34 (s, 3H). 13C
85.9, 45.3, 30.3, 22.5; HRMS (EI) m/z calcd for C29H26O (M+): NMR (100 MHz, CDCl3) dC (ppm): 161.5, 142.6, 136.0, 135.2,
1
390.1984, found 390.1984.
135.0, 131.7, 130.7, 130.1, 130.1, 129.4, 129.3, 129.1, 128.8, 128.6,
(E)-4-((E)-4-Methylbenzylidene)-3-phenyl-6-(p-tolyl)hex-2-en-
128.5, 126.4, 122.4, 117.5, 99.6, 99.3, 84.9, 19.4; HRMS (ESI) m/z
5-ynal (4o). Yellow solid, mp: 140 ꢀC. 1H NMR (400 MHz, CDCl3) calcd for C26H20N (M + H)+: 346.1596, found 346.1598.
dH (ppm): 9.41 (d, J ¼ 8.1 Hz, 1H), 7.82 (d, J ¼ 8.1 Hz, 2H), 7.49–
(E)-4-((E)-Benzylidene)-3-(4-methoxyphenyl)-6-phenylhex-2-
7.46 (m, 5H), 7.36–7.34 (m, 2H), 7.19 (dd, J ¼ 8.0 Hz, J ¼ 4.0 Hz, en-5-ynenitrile (6d). Pale yellow gummy liquid. 1H NMR (400
4H), 6.94 (d, J ¼ 8.1 Hz, 1H), 6.70 (s, 1H), 2.40 (s, 3H), 2.37 (s, MHz, CDCl3) dH (ppm): 7.88–7.86 (m, 2H), 7.53–7.51 (m, 2H),
3H). 13C NMR (100 MHz, CDCl3) dC (ppm): 194.3, 161.2, 143.5, 7.39–7.32 (m, 8H), 7.00–6.98 (m, 2H), 6.77 (s, 1H), 6.21 (s, 1H),
140.5, 139.4, 135.2, 133.0, 131.7, 131.6, 130.5, 130.3, 129.9, 3.85 (s, 3H). 13C NMR (100 MHz, CDCl3) dC (ppm): 161.5, 160.7,
129.5, 129.3, 129.2, 129.1, 129.1, 128.6, 128.5, 122.0, 119.8, 99.5, 143.3, 135.3, 131.7, 130.9, 130.1, 130.0, 129.3, 128.8, 128.6,
85.4, 21.8, 21.7; HRMS (ESI) m/z calcd for C27H23O (M + H)+: 127.5, 122.5, 121.2, 118.3, 114.3, 99.2, 97.9, 85.7, 55.4; HRMS
363.1749, found 363.1747.
(ESI) m/z calcd for C26H20NO (M + H)+: 362.1545, found
(E)-4-((E)-4-Isobutylbenzylidene)-6-(4-isobutylphenyl)-3-phenyl 362.1548.
hex-2-en-5-ynal (4p). Yellow thick liquid, 1H NMR (400 MHz,
This journal is © The Royal Society of Chemistry 2017
RSC Adv., 2017, 7, 46704–46712 | 46709

View Article Online
RSC Advances
Paper
MHz, CDCl3) dC (ppm): 162.0, 143.3, 140.6, 139.6, 135.7, 132.7,
131.6, 130.2, 129.6, 129.4, 128.9, 120.1, 119.5, 118.2, 99.7, 98.3,
85.1, 21.8, 21.7 HRMS (ESI) m/z calcd for C27H22N (M + H)+:
360.1752, found 360.1753.
(Z)-4-((E)-Benzylidene)-3-(4-methoxyphenyl)-6-phenylhex-2-
en-5-ynenitrile (60d). Pale brown solid, mp: 104–105 ꢀC. 1H NMR
(400 MHz, CDCl3) dH (ppm): 8.06 (d, J ¼ 7.9 Hz, 2H), 7.51 (d, J ¼
8.7 Hz, 2H), 7.45–7.40 (m, 5H), 7.33–7.32 (m, 3H), 7.07 (s, 1H),
6.94 (d, J ¼ 8.6 Hz, 2H), 5.62 (s, 1H), 3.85 (s, 3H). 13C NMR (100
MHz, CDCl3) dC (ppm): 161.7, 161.3, 141.9, 135.4, 131.6, 129.9,
129.8, 129.7, 129.5, 128.9, 128.6, 128.5, 122.9, 118.4, 117.6,
114.2, 98.5, 93.5, 87.2, 55.5; HRMS (ESI) m/z calcd for C26H20NO
(M + H)+: 362.1545, found 362.1547.
(E)-4-((E)-benzylidene)-3-(4-chlorophenyl)-6-phenylhex-2-en-
5-ynenitrile (6e). Colorless solid, mp: 140–142 ꢀC. 1H NMR (400
MHz, CDCl3) dH (ppm): 7.92–7.90 (m, 2H), 7.58–7.56 (m, 2H),
7.50 (d, J ¼ 8.4 Hz, 2H), 7.44–7.35 (m, 8H), 6.71 (s, 1H), 6.31 (s,
1H). 13C NMR (100 MHz, CDCl3) dC (ppm): 160.5, 143.4, 135.9,
135.1, 133.9, 131.7, 130.7, 130.3, 130.2, 129.4, 129.3, 128.8,
128.7, 122.3, 120.7, 117.7, 99.6, 99.1, 85.2; HRMS (ESI) m/z calcd
for C25H17ClNO (M + H)+: 366.1050, found 366.1044.
(Z)-4-((E)-4-Methylbenzylidene)-3-phenyl-6-(p-tolyl)hex-2-en-
1
5-ynenitrile (6’h). Yellow liquid, H NMR (400 MHz, CDCl3) dH
(ppm): 7.92 (d, J ¼ 8.2 Hz, 2H), 7.50–7.47 (m, 2H), 7.43–7.35 (m,
3H), 7.28 (d, J ¼ 8.0 Hz, 2H), 7.21 (d, J ¼ 8.2 Hz, 2H), 7.09 (d, J ¼
8.2 Hz, 2H), 6.98 (s, 1H), 5.58 (s, 1H), 2.37 (s, 3H), 2.31 (s, 1H).
13C NMR (100 MHz, CDCl3) dC (ppm): 162.0, 142.0, 140.1, 139.0,
137.7, 132.7, 131.4, 130.4, 129.7, 129.3, 129.2, 128.7, 128.5,
119.9, 117.4, 117.3, 99.1, 95.3, 86.7, 21.6; HRMS (ESI) m/z calcd
for C27H22N (M + H)+: 360.1752, found 360.1754.
(E)-4-((E)-4-Chlorobenzylidene)-6-(4-chlorophenyl)-3-phenylhex-
1
2-en-5-ynenitrile (6i). Colorless solid, mp: 175–176 ꢀC. H NMR
(400 MHz, CDCl3) dH (ppm): 7.78–7.76 (m, 2H), 7.52–7.50 (m, 3H),
7.47–7.44 (m, 2H), 7.41–7.33 (m, 6H), 6.67 (s, 1H), 6.24 (s, 1H). 13
C
NMR (100 MHz, CDCl3) dC (ppm): 161.3, 142.2, 136.0, 135.8, 135.2,
133.7, 132.9, 131.3, 129.9, 129.3, 129.0, 128.9, 121.4, 120.7, 117.7,
99.2, 98.6, 86.0; HRMS (EI) m/z calcd for C25H15NCl2 (M+):
399.0582, found 399.0582.
(Z)-4-((E)-Benzylidene)-3-(4-chlorophenyl)-6-phenylhex-2-en-
5-ynenitrile (60e). Colorless solid, mp: 128–130 ꢀC. 1H NMR (400
MHz, CDCl3) dH (ppm): 8.04–8.02 (m, 2H), 7.49–7.39 (m, 9H),
7.34–7.30 (m, 3H), 7.06 (s, 1H), 5.64 (s, 1H). 13C NMR (100 MHz,
CDCl3) dC (ppm): 160.6, 142.5, 136.8, 135.9, 135.2, 131.7, 130.1,
129.8, 129.8, 129.2, 129.1, 128.7, 128.6, 122.7, 117.9, 117.0, 99.0,
96.0, 86.8; HRMS (ESI) m/z calcd for C25H17ClNO (M + H)+:
366.1050, found 366.1049.
(Z)-4-((E)-4-Chlorobenzylidene)-6-(4-chlorophenyl)-3-phenylhex-
1
ꢀ
2-en-5-ynenitrile (60i). Colorless solid, mp: 150–151 C. H NMR
(400 MHz, CDCl3) dH (ppm): 7.92 (d, J ¼ 8.5 Hz, 2H), 7.51–7.38 (m,
7H), 7.32–7.27 (m, 4H), 7.00 (s, 1H), 5.67 (s, 1H). 13C NMR (100
MHz, CDCl3) dC (ppm): 161.4, 141.2, 137.4, 135.8, 135.3, 133.7,
132.9, 130.9, 130.7, 129.0, 128.9, 128.9, 128.5, 121.1, 118.8, 117.1,
98.2, 96.1, 87.6; HRMS (ESI) m/z calcd for C25H15NCl2 (M + H)+:
400.0660, found 400.0655.
Methyl (Z)-4-((E)-benzylidene)-3,6-diphenylhex-2-en-5-ynoate
(8). Colorless solid, mp: 101–102 ꢀC. 1H NMR (400 MHz, CDCl3)
dH (ppm): 8.01 (d, J ¼ 7.6 Hz, 2H), 7.64–7.61 (m, 2H), 7.45–7.35
(m, 8H), 7.31–7.30 (m, 3H), 6.75 (s, 1H), 6.29 (s, 1H), 3.75 (s, 3H).
13C NMR (100 MHz, CDCl3) dC (ppm): 166.6, 154.7, 139.4, 139.2,
136.1, 131.6, 129.7, 129.3, 129.0, 128.7, 128.6, 128.5, 128.4,
128.4, 123.4, 119.3, 118.1, 96.4, 88.5, 51.7; HRMS (EI) m/z calcd
for C26H20O2 (M+): 364.1463, found 364.1463.
2,4-Diphenyl-3-(phenylethynyl)pyridine (10a). Pale yellow
solid, mp: 123–124 ꢀC. 1H NMR (400 MHz, CDCl3) dH (ppm):
8.66 (d, J ¼ 5.0 Hz, 1H), 8.02–7.99 (m, 2H), 7.73–7.71 (m, 2H),
7.54–7.45 (m, 6H), 7.31 (d, J ¼ 5.0 Hz, 1H), 7.26–7.21 (m, 3H),
7.11–7.09 (m, 2H). 13C NMR (100 MHz, CDCl3) dC (ppm): 161.2,
152.6, 148.1, 140.1, 138.8, 131.3, 129.8, 129.4, 128.9, 128.8,
128.6, 128.4, 128.3, 128.1, 127.9, 123.2, 122.3, 116.5, 97.9, 87.3;
HRMS (ESI) m/z calcd for C25H18N (M + H)+: 332.1439, found
332.1441.
4-(4-Methoxyphenyl)-2-phenyl-3-(phenylethynyl)pyridine (10b).
Colorless solid, mp: 85–86 ꢀC. 1H NMR (400 MHz, CDCl3) dH
(ppm): 8.62 (d, J ¼ 5.0 Hz, 1H), 7.99–7.97 (m, 2H), 7.71 (d, J ¼
8.6 Hz, 2H), 7.52–7.44 (m, 3H), 7.29–22 (m, 4H), 7.15–7.13 (m, 2H),
7.04 (d, J ¼ 8.6 Hz, 2H), 3.89 (s, 3H). 13C NMR (100 MHz, CDCl3) dC
(ppm): 161.4, 160.3, 152.0, 148.0, 140.2, 131.2, 131.0, 130.7, 129.8,
128.8, 128.6, 128.4, 127.9, 123.2, 122.2, 116.3, 113.7, 97.7, 87.6,
55.5; HRMS (ESI) m/z calcd for C26H20NO (M + H)+: 362.1545,
found 362.1544.
(E)-4-((E)-Benzylidene)-3-(naphthalen-1-yl)-6-phenylhex-2-en-
1
ꢀ
5-ynenitrile (60f). Colorless solid, mp: 95–96 C. H NMR (400
MHz, CDCl3) dH (ppm): 8.07–8.05 (m, 3H), 7.90–7.86 (m, 3H),
7.62–7.51 (m, 3H), 7.47–7.37 (m, 5H), 7.33–7.27 (m, 3H), 7.09 (s,
1H), 5.81 (s, 1H). 13C NMR (100 MHz, CDCl3) dC (ppm): 161.8,
142.5, 135.4, 134.8, 134.3, 133.1, 131.7, 130.0, 128.9, 128.9,
128.8, 128.6, 128.5, 127.9, 127.6, 127.0, 125.2, 122.9, 118.4,
117.3, 98.9, 96.0, 87.1; HRMS (ESI) m/z calcd for C29H20N (M +
H)+: 382.1596, found 382.1596.
(E)-4-((E)-Benzylidene)-3-(naphthalen-2-yl)-6-phenylhex-2-en-
5-ynenitrile (6g). Colorless solid, mp: 170–172 ꢀC. 1H NMR (400
MHz, CDCl3) dH (ppm): 8.00–7.87 (m, 6H), 7.63–7.56 (m, 4H),
7.50–7.34 (m, 7H), 6.76 (s, 1H), 6.41 (s, 1H). 13C NMR (100 MHz,
CDCl3) dC (ppm): 161.6, 143.7, 135.2, 133.7, 133.2, 132.9, 130.1,
130.1, 129.4, 129.2, 128.8, 128.7, 128.6, 128.6, 128.0, 127.3,
126.9, 126.5, 122.4, 121.0, 118.0, 99.4, 99.1, 85.5. HRMS (ESI) m/
z calcd for C29H20N (M + H)+: 382.1596, found 382.1598.
(Z)-4-((E)-Benzylidene)-3-(naphthalen-2-yl)-6-phenylhex-2-en-
5-ynenitrile (60g). Colorless solid, mp: 103–105 ꢀC. 1H NMR (400
MHz, CDCl3) dH (ppm): 8.08–8.05 (m, 3H), 7.91–7.87 (m, 3H),
7.62–7.52 (m, 3H), 7.48–7.39 (m, 5H), 7.31–7.25 (m, 3H), 7.10 (s,
1H), 5.81 (s, 1H). 13C NMR (100 MHz, CDCl3) dC (ppm): 161.8,
142.4, 135.4, 134.8, 134.2, 133.1, 131.7, 129.9, 129.8, 128.9,
128.9, 128.8, 128.6, 128.5, 127.9, 127.6, 127.0, 125.2, 122.9,
118.4, 117.3, 98.9, 96.0, 87.1; HRMS (ESI) m/z calcd for C29H20N
(M + H)+: 382.1596, found 382.1596.
(E)-4-((E)-4-Methylbenzylidene)-3-phenyl-6-(p-tolyl)hex-2-en-
5-ynenitrile (6h). Colorless Solid, mp: 195–196 ꢀC. 1H NMR (400
MHz, CDCl3) dH (ppm): 7.79 (d, J ¼ 8.2 Hz, 2H), 7.51–7.44 (m,
5H), 7.39–7.37 (m, 2H), 7.20 (dd, J ¼ 8.0 Hz, J ¼ 10.0 Hz, 4H),
6.66 (s, 1H), 6.27 (s, 1H), 2.41 (s, 3H), 2.37 (s, 3H). 13C NMR (100
4-(4-Chlorophenyl)-2-phenyl-3-(phenylethynyl)pyridine (10c).
Colorless solid, mp: 155–156 ꢀC. 1H NMR (400 MHz, CDCl3) dH
46710 | RSC Adv., 2017, 7, 46704–46712
This journal is © The Royal Society of Chemistry 2017

View Article Online
Paper
RSC Advances
(ppm): 8.68 (d, J ¼ 5.0 Hz, 1H), 8.02–7.99 (m, 2H), 7.71–7.67 (m, 152.6, 147.9, 139.0, 138.8, 137.3, 131.2, 129.7, 129.4, 129.2, 128.7,
2H), 7.55–7.47 (m, 5H), 7.33–7.26 (m, 4H), 7.16–7.13 (m, 2H). 13
C
128.6, 128.2, 122.1, 120.2, 116.5, 98.1, 86.9, 21.7, 21.6; HRMS (EI)
NMR (100 MHz, CDCl3) dC (ppm): 161.5, 151.2, 148.3, 139.9, m/z calcd for C27H21N (M+): 359.1674, found 359.1675.
137.2, 135.1, 131.3, 130.7, 129.8, 129.0, 128.8, 128.6, 128.5,
128.0, 123.0, 122.1, 116.4, 98.2, 86.9; HRMS (ESI) m/z calcd for
Conclusions
C25H17ClN (M + H)+: 366.1050, found 366.1053.
4-(3-Nitrophenyl)-2-phenyl-3-(phenylethynyl)pyridine (10d).
Colorless solid, mp: 180–181 ꢀC. 1H NMR (400 MHz, CDCl3) dH
(ppm): 8.72 (d, J ¼ 5.0 Hz, 1H), 8.67–8.66 (m, 1H), 8.36–8.33 (m,
1H), 8.05–7.98 (m, 3H), 7.72–7.68 (m, 1H), 7.53–7.47 (m, 3H),
7.34 (d, J ¼ 5.0 Hz, 1H), 7.27–7.21 (m, 3H), 7.10–7.07 (m, 2H).
13C NMR (100 MHz, CDCl3) dC (ppm): 161.7, 149.6, 148.5, 148.3,
140.4, 139.7, 135.4, 131.3, 129.7, 129.4, 129.2, 129.0, 128.6,
128.1, 124.4, 123.7, 122.5, 121.9, 116.4, 99.0, 86.3; HRMS (ESI)
m/z calcd for C25H17N2O2 (M + H)+: 377.1290, found 377.1291.
4-(Naphthalen-1-yl)-2-phenyl-3-(phenylethynyl)pyridine (10e).
In conclusion, an approach for the synthesis of unsymmetrical
functionalized (CHO, CN, COOEt) 1,3-butadiene-3-yne deriva-
tives is reported starting from b-halo styrene derivatives and
phenyl acetylenes in the presence of PdCl2 and CuI catalysts.
Good yields and wide substrate scope makes this protocol
noteworthy. Also, these 1,3-buta-diene-3-ynals are utilized for
the synthesis of novel 2,3,5-trisubstituted pyridine derivatives.
Further efforts to synthesize complex heterocyclic derivatives
from 1,3-buta-diene-3-ynals are currently underway in our
laboratory.
1
Colorless gummy liquid, H NMR (400 MHz, CDCl3) dH (ppm):
8.77 (d, J ¼ 4.8 Hz, 1H), 8.15–8.12 (m, 2H), 8.01–7.98 (m, 2H),
7.76–7.74 (m, 1H), 7.63–7.59 (m, 1H), 7.56–7.45 (m, 6H), 7.39 (d, J
¼ 4.8 Hz, 1H). 7.17–7.06 (m, 3H), 6.63–6.60 (m, 2H). 13C NMR
(100 MHz, CDCl3) dC (ppm): 160.3, 152.5, 148.0, 139.8, 137.0,
133.6, 131.2, 131.1, 129.8, 129.0, 128.9, 128.4, 128.4, 128.1, 127.9,
127.2, 126.5, 126.1, 126.1, 125.2, 123.6, 122.8, 118.5, 98.7, 86.9;
HRMS (ESI) m/z calcd for C29H20N (M + H)+: 382.1598, found
382.1596.
Conflicts of interest
There are no conicts to declare.
Acknowledgements
Financial support by the Ministry of Science and Technology of
the Republic of China (MOST 103-2113-M-003-008-MY3),
National Taiwan Normal University (103-07-C) and Instrumen-
tation Centre at National Taiwan Normal University is gratefully
acknowledged. The authors are grateful to Ms. Hsiu-Ni Huan,
Ms. Chiu-Hui He and Ting-Shen Kuo for providing HRMS, NMR
spectral and Crystallographic data respectively.
4-(Naphthalen-2-yl)-2-phenyl-3-(phenylethynyl)pyridine (10f).
1
Colorless gummy liquid, H NMR (400 MHz, CDCl3) dH (ppm):
8.69 (d, J ¼ 5.0 Hz, 1H), 8.22 (s, 1H), 8.04–7.86 (m, 6H), 7.59–7.46
(m, 5H), 7.42 (d, J ¼ 5.0 Hz, 1H), 7.26–7.16 (m, 3H), 7.05–7.04 (m,
2H). 13C NMR (100 MHz, CDCl3) dC (ppm): 161.5, 152.4, 148.2,
140.1, 136.3, 133.4, 133.2, 131.3, 129.8, 128.9, 128.8, 128.6, 128.5,
128.4, 127.9, 127.8, 127.1, 126.9, 126.6, 123.1, 122.6, 121.3, 116.7,
98.1, 87.4; HRMS (ESI) m/z calcd for C29H20N (M + H)+: 382.1596,
found 382.1597.
Notes and references
2-Phenyl-3-(phenylethynyl)-4-(p-tolyl)pyridine (10g). Yellow
gummy liquid, 1H NMR (400 MHz, CDCl3) dH (ppm): 8.65 (d, J ¼
8.6 Hz, 1H), 8.02 (d, J ¼ 7.4 Hz, 2H), 7.66 (d, J ¼ 7.8 Hz, 2H),
7.54–7.48 (m, 3H), 7.34–7.27 (m, 6H), 7.16–7.15 (m, 2H), 2.47 (s,
3H). 13C NMR (100 MHz, CDCl3) dC (ppm): 161.3, 152.4, 148.0,
140.1, 138.8, 135.8, 131.2, 129.8, 129.2, 128.9, 128.8, 128.5,
128.4, 127.9, 123.2, 122.3, 116.4, 97.7, 87.4, 21.5; HRMS (EI) m/z
calcd for C26H19N (M+): 345.1517, found 345.1521.
4-(3,4-Dimethoxyphenyl)-2-phenyl-3-(phenylethynyl)pyridine
(10h). Light yellowish brown gummy liquid, 1H NMR (400 MHz,
CDCl3) dH (ppm): 8.63 (d, J ¼ 5.0 Hz, 1H), 7.98 (d, J ¼ 6.8 Hz, 2H),
7.52–7.46 (m, 3H), 7.38–7.37 (m, 1H), 7.31–7.26 (m, 5H), 7.13–
7.11 (m, 2H), 7.02–7.00 (m, 1H), 3.97 (s, 3H), 3.88 (s, 3H). 13C
NMR (100 MHz, CDCl3) dC (ppm): 161.6, 152.1, 149.7, 148.5,
148.1, 140.2, 131.4, 131.3, 129.8, 128.9, 128.7, 128.5, 127.9,
123.2, 122.2, 122.0, 116.3, 112.8, 111.0, 97.9, 87.6, 56.2, 56.1;
HRMS (EI) m/z calcd for C27H21NO2 (M+): 391.1572, found
391.1573.
1 (a) B. M. Trost and J. T. Masters, Chem. Soc. Rev., 2016, 45,
2212; (b) M. Gholami and R. R. Tykwinski, Chem. Rev.,
2006, 106, 4997; (c) D. J. Faulkner, Nat. Prod. Rep., 2001, 18, 1.
2 (a) Z. Liu, I. Schmidt, P. Thamyongkit, R. S. Loewe,
D. Syomin, J. R. Diers, Q. Zhao, V. Misra, J. S. Lindsey and
D. F. Bocian, Chem. Mater., 2005, 17, 3728; (b) M. Gholami
and R. R. Tykwinski, Chem. Rev., 2006, 106, 4997.
¨
¨
3 (a) M. Dorer, N. Tschammer, K. Hamperl, H. Hubner and
P. Gmeiner, J. Med. Chem., 2008, 51, 6829; (b) T. H. Jones,
R. M. M. Adams, T. F. Spande, H. M. Garrafo, T. Kaneko
and T. R. Schultz, J. Nat. Prod., 2012, 75, 1930.
4 (a) N. Matsuyama, H. Tsurugi, T. Satoh and M. Miura, Adv.
Synth. Catal., 2008, 350, 2274; (b) K. Ogata, H. Murayama,
J. Sugasawa, N. Suzuki and S.-i. Fukuzawa, J. Am. Chem.
Soc., 2009, 131, 3176; (c) K. Ogata, J. Sugasawa, Y. Atsuumi
and S.-i. Fukuzawa, Org. Lett., 2010, 12, 148; (d) K. Ogata,
Y. Atsuumi and S.-i. Fukuzawa, Org. Lett., 2011, 13, 122.
5 (a) B. M. Trost, M. T. Sorum, C. Chan, A. E. Harms and
¨
4-Phenyl-2-(p-tolyl)-3-(p-tolylethynyl)pyridine (10i). Light
yellowish brown gummy liquid, H NMR (400 MHz, CDCl3) dH
G. Ruhter, J. Am. Chem. Soc., 1997, 119, 698; (b) J. Krause,
1
G. Cestaric, K.-J. Haack, K. Seevogel, W. Storm and
¨
(ppm): 8.63 (d, J ¼ 5.0 Hz, 1H), 7.95–7.93 (m, 2H), 7.72–7.69 (m,
2H), 7.53–7.46 (m, 3H), 7.31–7.25 (m, 3H), 7.06–7.01 (m, 4H), 2.45
(s, 3H), 2.31 (s, 3H). 13C NMR (100 MHz, CDCl3) dC (ppm): 160.9,
K.-R. Porschke, J. Am. Chem. Soc., 1999, 121, 9807.
6 A. Haskel, T. Straub, A. K. Dash and M. S. Eisen, J. Am. Chem.
Soc., 1999, 121, 3014.
This journal is © The Royal Society of Chemistry 2017
RSC Adv., 2017, 7, 46704–46712 | 46711

View Article Online
RSC Advances
Paper
7 (a) T. Straub, A. Haske and M. S. Eisen, J. Am. Chem. Soc.,
1995, 117, 6364; (b) A. K. Dash, I. Gourevich, J. Q. Wang,
J. Wang, M. Kapon and M. S. Eisen, Organometallics, 2001,
20, 5084.
8 Y.-T. Wu, W.-C. Lin, C.-J. Liu and C.-Y. Wu, Adv. Synth. Catal.,
2008, 350, 1841.
2017, 53, 1676; (d) A. Konala, C.-W. Kuo, L. Lin,
T.-T. Chiang, C.-Y. Huang, T.-H. Yang, V. Kavala and
C.-F. Yao, Chem. Commun., 2016, 52, 7870; (e) V. Kavala,
C.-C. Wang, Y.-H. Wang, C.-W. Kuo, D. Janreddy,
W.-C. Huang, T.-S. Kuo, C. H. He, M.-L. Chen and
C.-F. Yao, Adv. Synth. Catal., 2014, 356, 2609.
´
´
9 (a) L. Rubio-Perez, R. Azpıroz, A. D. Giuseppe, V. Polo, 12 See ESI† for further details. 4a (CCDC no. 1557911), 6a
(CCDC no. 1556913), 60a (CCDC no. 1556912), 8 (CCDC no.
1556914), 10a (CCDC no. 1557912): (a) W. Yang, Z. Ruan,
Y. Wang, K. V. Kirk, Z. Ma, B. J. Arey, C. B. Cooper,
R. Seethala, J. H. M. Feyen and J. K. Dickson Jr, J. Med.
Chem., 2009, 52, 1204; (b) A. Basnet, P. Thapa, R. Karki,
Y. Na, Y. Jahng, B.-S. Jeong, T. C. Jeong, C.-S. Lee and
E.-S. Lee, Bioorg. Med. Chem., 2007, 15, 4351; (c) H. Huang,
J. Cai, L. Tang, Z. Wang, F. Li and G.-J. Deng, J. Org. Chem.,
2016, 81, 1499; (d) S. M. Gomha and K. K. Dawood, J.
Heterocycl. Chem., 2017, 54, 1943.
´
R. Castarlenas, J. J. Perez-Torrente and L. A. Oro, Chem.–
Eur. J., 2013, 19, 15304; (b) R. Azpıroz, L. Rubio-Perez,
R. Castarlenas, J. J. Perez-Torrente and L. A. Oro,
ChemCatChem, 2014, 6, 2587.
´
´
´
10 A. Uruvakili, G. Gangadhararao and K. C. Kumara Swamy,
Org. Biomol. Chem., 2015, 13, 10060.
11 (a) C.-Y. Huang, V. Kavala, C.-W. Kuo, A. Konala, T.-H. Yang
and C.-F. Yao, J. Org. Chem., 2017, 82, 1961; (b) S. S. Ichake,
A. Konala, V. Kavala, C.-W. Kuo and C.-F. Yao, Org. Lett.,
2017, 19, 54; (c) T.-H. Yang, C.-W. Kuo, V. Kavala,
A. Konala, C.-Y. Huang and C.-F. Yao, Chem. Commun.,
46712 | RSC Adv., 2017, 7, 46704–46712
This journal is © The Royal Society of Chemistry 2017