Copper-Catalyzed One-Pot Synthesis of 1,3-Enynes from 2-Chloro-N-(quinolin-8-yl)acetamides and Terminal Alkynes

Article abstract of DOI:10.1021/acs.joc.0c01102

A method for the chemo-, regio-, and stereoselective one-pot synthesis of 1,3-enynes is described. The reaction of 2-chloro-N-(quinolin-8-yl)acetamides with terminal alkynes proceeds smoothly in the presence of a copper catalyst at room temperature to produce (E)-1,3-enynes in satisfactory to excellent yields. The mechanism study reveals that the cross-dimerization of internal alkynes generated in situ with terminal alkynes proceeds via allene intermediates. The directing group 8-aminoquinoline plays a key role in the current selective synthesis of (E)-1,3-enynes.

Full text of DOI:10.1021/acs.joc.0c01102

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Note
Copper-catalyzed One-pot Synthesis of 1,3-Enynes from 2-
Chloro-N-(quinolin-8-yl)acetamides and Terminal Alkynes
Lifan Zhu, Hongyu Guo, Xiujuan Feng, Yoshinori Yamamoto, and Ming Bao
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.0c01102 • Publication Date (Web): 02 Jun 2020
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Copper-catalyzed One-pot Synthesis of 1,3-Enynes from
2-Chloro-N-(quinolin-8-yl)acetamides and Terminal Alkynes
Lifan Zhu,a# Hongyu Guo,a# Xiujuan Feng,*a Yoshinori Yamamoto,a,b and Ming Bao*a
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a State Key Laboratory of Fine Chemicals, Dalian University of Technology, Dalian 116023, China
b Department of Chemistry, Graduate School of Science, Tohoku University, Sendai 980-8578, Japan
and Research Organization of Science and Technology, Ritsumeikan University, Kusatsu, Shiga
525-8577, Japan
fengxiujuan@dlut.edu.cn; mingbao@dlut.edu.cn
AQ
NH
O
(i) Cu cat., Base
O
N
+
Cl
Ar
Ar
AQ =
AQ
(ii) Ligand,
R
R
34 examples, up to 95% yield
ABSTRACT: A method for the chemo-, regio-, and stereoselective one-pot synthesis of
1,3-enynes is described. The reaction of 2-chloro-N-(quinolin-8-yl)acetamides with
terminal alkynes proceeds smoothly in the presence of a copper catalyst at room
temperature to produce (E)-1,3-enynes in satisfactory to excellent yields. The mechanism
study reveals that the cross-dimerization of internal alkynes generated in situ with
terminal alkynes proceeds via allene intermediates. The directing group 8-aminoquinoline
plays a key role in the current selective synthesis of (E)-1,3-enynes.
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1,3-Enynes are valuable synthons in the field of organic chemistry and can be used for
the synthesis of natural products, pharmaceuticals, and functional materials.1 Numerous
synthetic methods, including the name reaction (Wittig and Horner–Wadsworth–Emmons
reactions),2 the transition metal-catalyzed cross-coupling reaction,3 the reaction involving
metal carbene,4 and the dimerization of alkynes,5-8 have been developed to synthesize
1,3-enynes. Among these methods, the dimerization of alkynes has attracted considerable
attention due to its perfect atomic economy. However, the competitive
homo-dimerization of the terminal alkyne frequently occurs in the cross-dimerization of
internal alkynes with terminal alkynes. The internal alkyne bearing an
electron-withdrawing group7 or the terminal alkyne having a bulky alkylsilyl group8 is
utilized for target cross-dimerization, which proceeds via the carbometalation or the
hydrometallation of internal alkyne, to inhibit a side reaction (Scheme 1, previous work).
These starting materials are not readily available, resulting in the narrow substrate scope
of cross-dimerization. Therefore, the development of a new method for the synthesis of
1,3-enynes by using readily available and inexpensive starting materials and a
cost-effective catalyst is highly desirable.
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In the course of our research on alkyne chemistry,9 we succeeded in the chemo-, regio-,
and stereoselective one-pot tandem synthesis of 1,3-enynes by using simple and readily
available terminal alkynes and a Cu catalyst (Scheme 1, this work). In the current work,
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the cross-dimerization of internal alkynes generated in situ with terminal alkynes
proceeded via allene intermediates. The results are reported in this paper.
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Scheme 1. Cross-dimerization between Terminal and Internal Alkynes
Previous Work
R2
R3
cat. Pd, Ru, Rh, Ir, Ni, Co
R1
R2
R3
+
R1
limited substrate scope
noble metal is usually needed
poor selectivity in most cases
R1
M
H
R3
M
or
R2
R2
R3
This Work
O
AQ
Cl
O
Ar
AQ
Ar
O
R
cat. Cu
+
Ar
AQ
R
O
NH
N
N
Cu
N
AQ =
Ar
R
mild reaction conditions
simple and abundant feedstocks
cost-effective copper catalyst
high chemo-, regio- and stereoselectivity
In our initial studies, the reaction of 2-chloro-N-(quinolin-8-yl)acetamide (1a) with
phenylacetylene (2a) was selected as a model to optimize the reaction conditions. The
results are shown in Table 1. The model reaction was first tested using different Cu
catalysts, including Cu(I) and Cu(II) salts, in toluene at room temperature in the presence
of Cs2CO3 and 1,10-phenanthroline (L1) (entries 1‒5). Results indicated that CuI
possessed relatively higher catalytic activity than others. The desired product,
(E)-3-benzylidene-5-phenyl-N-(quinolin-8-yl)pent-4-ynamide (3a) with 73% yield was
obtained (entry 3). The ligand was subsequently screened using CuI as the catalyst in
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toluene. No reaction or only 9% yield of 3a was observed when
4,4′-di-tert-butyl-2,2′-bipyridine (L2, entry 6) and bathocuproine (L3, entry 7) instead of
L1 were examined. The solvent was finally screened using CuI and L1 as catalyst and
ligand, respectively. Among the solvents tested, dichloromethane (DCM) was the best
(entries 3, 8‒10). The yield of 3a increased with decreasing amount of DCM (entries
10‒12). This observation suggested that the relatively high concentration of the starting
materials was favorable for the target reaction. The yield of 3a increased to 91% by
reducing the base loading (entry 13). 2-Chloro-N-phenylacetamide (1b, entry 14) and
2-chloro-N-methyl-N-(quinolin-8-yl)acetamide (1c, entry 15) were used instead of 1a to
examine the effect of directing groups (DG). Only a small amount of the desired product
3ab was obtained when 1b was used as the starting material (entry 14). The desired
product 3ac was not formed when 1c was examined (entry 15). These results suggested
that 8-aminoquinoline (AQ) was necessary as a powerful DG to promote the target
reaction. Therefore, the subsequent cross-dimerization of various terminal alkynes was
conducted in the presence of CuI (10 mol %), L1 (20 mol %), and Cs2CO3 (1.2 equiv.) in
DCM at room temperature for 48 h.
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Table 1. Screening of Reaction Conditionsa
DG
O
cat. Cu (10 mol %)
O
+
Cl
Ph
ligand, Cs2CO3
solvent, rt, 48 h
Ph
DG
Ph
1
3
2a
NH
N
NH
N
N
1a
1b
1c
, DG =
, DG =
, DG =
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Entry
Catalyst
Ligand
Solvent
(mL)
Yield
(%)b
69
54
73
67
71
0
1
2
CuCl
CuBr
CuI
L1
L1
L1
L1
L1
L2
L3
L1
L1
L1
L1
L1
L1
L1
L1
Toluene (2)
Toluene (2)
Toluene (2)
Toluene (2)
Toluene (2)
Toluene (2)
Toluene (2)
CH3CN (2)
THF (2)
3
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4
CuCl2
Cu(OAc)2
CuI
5
6
7
CuI
9
8
CuI
0
9
CuI
41
74
63
86
91
9
10
11
12
13c
14c,d
15c,e
CuI
DCM (2)
DCM (4)
DCM (1)
DCM (1)
DCM (1)
DCM (1)
N
CuI
CuI
CuI
CuI
CuI
0
N
N
N
N
N
tBu
tBu
Ph
Ph
L1
L2
L3
aReaction conditions: 1a (0.4 mmol), 2a (1.2 mmol), Cu catalyst (0.04 mmol, 10 mol %), ligand (0.08
mmol, 20 mol %), and Cs2CO3 (0.8 mmol) in solvent at room temperature (rt) under N2 atmosphere
b
1
c
for 48 h. Determined through H NMR spectroscopy by using CH2Br2 as an internal standard. 0.48
mmol Cs2CO3 was used as a base. d1b was used instead of 1a. e1c was used instead of 1a.
The substrate scope of terminal alkynes was initially examined using the optimized
conditions (Scheme 2). The reactions of aryl acetylenes bearing electron-withdrawing
groups (F, Br, and CF3) on the para-positions of benzene rings proceeded smoothly to
provide the corresponding 1,3-enyne products 3b‒3d with 77%–81% yields. The X-ray
crystallography of 3d confirmed that the stereostructure of the 1,3-enyne product was an
E-isomer. The reactions of para-methyl phenylacethylene (2e) and para-tert-butyl
phenylacetylene (2f) also proceeded smoothly to furnish 1,3-enyne products 3e and 3f
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with 83% and 85% yields, respectively. These results indicated that the reactivity of
terminal arylalkynes was not significantly influenced by the electronic property of the
substituent linked on the benzene ring. The Cl atom and the MeO group linked on
different positions (ortho-, meta-, and para-positions) of the benzene ring did not
strongly influence the reactivity of terminal arylalkynes. The desired 1,3-enyne products
3g‒3l with 69%–88% yields were obtained. The heterocycle- and fused aromatic
ring-containing terminal alkynes 2m and 2n, respectively, were finally examined. The
desired products 3m and 3n were obtained in excellent yields (93% and 91%,
respectively).
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Scheme 2. Scope of Terminal Alkynesa,b
AQ
CuI (10 mol %)
O
L1
O
(20 mol %)
+
Cl
Cs2CO3 (1.2 equiv.)
DCM (0.4 M), rt, 48 h
Ar
Ar
AQ
Ar
1a
2
3
AQ
AQ
AQ
F
Br
O
O
O
F
Br
3a
3b
3c
, 77%
, 86%
, 81%
AQ
AQ
AQ
CF3
R
O
O
O
Cl
Cl
F3C
R
3d
3g
, o-Cl, 84%
, 78%
3e
3f
, R = Me, 83%
3h
, m-Cl, 88%
, p-Cl, 69%
, R = tBu 85%
3i
AQ
AQ
AQ
O
O
O
S
OMe
MeO
S
3j
3m
3n
, 91%
, o-OMe, 94%
, 93%
3k
3l
, m-OMe, 95%
, p-OMe, 83%
aReaction conditions: 1a (0.4 mmol), 2 (1.2 mmol), CuI (10 mol %), L1 (20 mol %), and Cs2CO3
(0.48 mmol) in DCM (1 mL) at room temperature (rt) under N2 atmosphere for 48 h. bIsolated yields.
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Encouraged by the success in the one-pot synthesis of 1,3-enyne from the reaction of
1a with a terminal alkyne, we synthesized 1,3-enyne by using two different terminal
alkynes (Scheme 3). We conducted the reaction in two steps to avoid the undesired
homo-dimerization of terminal alkyne. The Sonogashira-type coupling reaction of 1a
with the first terminal alkyne was completed within 16 or 24 h, and the mixture was
added with the second terminal alkyne and ligand L1. Then, the resulting mixture was
stirred at room temperature for 24 h. The tandem reaction of 1a, 2a, and a second
terminal arylalkyne, including 2b‒2d, 2o, and 2p bearing electron-withdrawing groups
(F, Br, CF3, NO2, and COOMe) on the para-position of the benzene rings also proceeded
smoothly to provide 1,3-enyne products 4a‒4e with 53%‒73% yields. The 1,3-enyne
products 4f‒4h were obtained in relatively high yields (76%‒82%) when the terminal
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t
n
alkynes 2e, 2f, and 2q bearing electron-donating groups (Me, Bu, and Pen) on the
para-position of benzene rings were utilized as the second terminal alkynes. Terminal
alkynes with Cl or OMe on the ortho-, meta-, and para-positions of the benzene rings
were found suitable as second terminal alkynes in the one-pot tandem reaction. The
1,3-enyne products 4i‒4n with 67%‒89% yields were obtained. The subsequent
investigation revealed that the aliphatic terminal alkyne and the heterocycle- and fused
aromatic ring-containing terminal alkynes were also suitable substrates for the current
one-pot tandem reaction. The desired products 4o‒4q were obtained in 68%‒88% yields.
Finally, we changed the first terminal alkyne 2a to 2i, 2l and 2n, and used 2a as the
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second terminal alkyne. Tandem reactions also proceeded smoothly to produce the
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desired 1,3-enynes 4r‒4t with 67%‒88% yields.
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Scheme 3. Synthesis of 1,3-Enyne by using Two Different Terminal Alkynesa,b
AQ
CuI (10 mol %)
Cs2CO3 (1.2 eq.)
O
O
R
+
Cl
DCM (0.4 M)
Ar
Ar
L1
(20 mol %), rt, 24 h
AQ
35 oC, 16 or 24 h
R
1a
2
4
step 1
step 2
AQ
AQ
AQ
O
O
O
F
Br
F3C
4a
4b
4c
, 73%
, 62%
AQ
, 69%
AQ
O
O
O2N
MeOOC
AQ
4d
4e
, 70%
, 53%
AQ
AQ
O
O
O
MeO
Cl
R
4f
, R = Me, 80%
4i
4j
4k
4l
, o-OMe, 88%
, o-Cl, 89%
, m-Cl, 79%
, p-Cl, 67%
, R = tBu, 82%
4m
, m-OMe, 88%
4n
, p-OMe, 79%
4g
4h
, R = nPen, 76%
AQ
O
AQ
AQ
O
O
S
nBu
4o
4p
4q
, 76%
, 68%
, 88%
AQ
AQ
AQ
OMe
Cl
O
O
O
c
c
c
4r
4s
, 67%
, 77%
4t
, 88%
aReaction conditions: Step 1) 1a (0.4 mmol), 2 (0.4 mmol), CuI (0.04 mmol, 10 mol %), and
Cs2CO3 (0.48 mmol) in DCM (1 mL) at 35 ºC under N2 atmosphere for 16 h; Step 2) The reaction
mixture was added with another terminal alkyne (0.8 mmol) and 1,10-phenanthroline (0.08 mmol, 20
b
c
mol %) and stirred at room temperature (rt) under N2 atmosphere for 24 h. Isolated yields. The
reaction was carried out for 24 h in Step 1. See SI for details.
Control experiments were conducted to gain insight into the mechanism (Scheme 4). A
mixture of alkyne and allene was obtained when 1a and 2a were reacted without a ligand.
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This mixture can be completely transformed to the corresponding 1,3-enyne compound
3a just by the addition of ligand L1 (92% yield, Scheme 4, Eq. 1). This result suggested
that a ligand was necessary for cross-dimerization. No desired product was detected when
the internal alkyne 5 was treated under standard conditions (Scheme 4, Eq. 2) because
alkyne 5 cannot isomerize to allene isomer due to the absence of α-H. Also, no desired
product was detected when α-Cl acetophenone (6) was treated under standard conditions
(Scheme 4, Eq. 3). This result revealed that an appropriate DG played an essential role in
the catalytic cycle.
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Scheme 4. Control Experiments
O
O
Ph
Ph
CuI (10 mol %)
Cs2CO3 (1.2 equiv.)
O
AQ
AQ
+
+
Cl
Ph
DCM (0.4 M), rt, 24 h
AQ
1a
2a
mixture
(near 1:1)
> 90% yield
(1)
AQ
2a L1
,
O
Ph
24 h
Ph
3a
,
92%
AQ
CuI (10 mol %)
Cs2CO3 (1.2 equiv.)
O
Ph
O
Ph
O
+
(2)
L1
(20 mol %)
Ph
AQ
AQ
Ph
DCM (0.4 M), 24 h
Ph
5
2a
not determined
S.M. recovered
O
O
Ph
Ph
O
CuI (10 mol %)
Cs2CO3 (1.2 equiv.)
Ph
Ph
O
Cl
+
+
(3)
L1
(20 mol %)
DCM(0.4 M), 24 h
Ph
Ph
Ph
2a
Ph
6
not determined
mixture
64% yield
Scheme 5. Gram-scale Synthesis and Product Derivatization
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AQ
4
5
6
7
8
9
CuI (10 mol %),
L1
O
O
(20 mol %)
+
(1)
Cl
Ph
Cs2CO3 (1.2 equiv.)
DCM (0.4 M), rt, 48 h
AQ
1a
2a
, 0.66 g (3 mmol)
3a
, 0.96 g (82% yield)
OEt
AQ
O
O
BF3·Et2O (6 eq.)
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(2)
EtOH, 100 °C, 15 h
3a
7,
82% yield
Substrate 1a was scaled up to 3 mmol to verify the usefulness of the current
cross-dimerization reaction. Treating 3 mmol (0.66 g) 1a at standard conditions resulted
in a slightly decreased yield (0.96 g, 82% yield; Scheme 5, Eq. 1) compared with the
small-scale reaction was observed. The DG AQ was removed by alcoholysis with ethanol
in the presence of BF3·Et2O. The product, ethyl-(E)-3-benzylidene-5-phenylpent-4-ynoate
(7), with 82% yield was obtained. This product can be used for further manipulation to
produce useful compounds10 (Scheme 5, Eq. 2).
On the basis of previous reports11 and the experimental results, a plausible mechanism
is illustrated in Scheme 6. Initially, a Sonogashira-type coupling reaction between 1a and
terminal alkyne 2a occurred in the presence of CuI and Cs2CO3 to produce a tautomer of
allene A and internal alkyne A′. Then, the Cu catalyst coordinated to A in the presence of
Cs2CO3 to generate a chelated Cu complex B, which reacted with 2a in the presence of
Cs2CO3 to generate intermediate C. The intermediate C subsequently underwent
intramolecular regio- and stereoselective carbocupration to generate intermediate D.
Finally, the protonolysis of intermediate D occurred to yield the desired product 3a and
regenerate the Cu catalyst.
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Scheme 6. Proposed Mechanism
8
9
O
Ph
O
Ph
Ph
2a
1a
Sonogashira-type coupling
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AQ
AQ
A'
A
3a
A
+ Cs2CO3
+ Cs2CO3
Cu(L)X
X = Cl or I
L, CsHCO3
L, CsHCO3
Ph
O
H
O
N
N
Cu
X
Cu
X
N
N
Ph
Ph
D
B
Cs2CO3
O
N
2a
Cs2CO3
CsX
CsHCO3
Cu
N
CsX, CsHCO3
Ph
Ph
C
In summary, a convenient and efficient method for the chemo-, regio-, and
stereoselective synthesis of 1,3-enynes was developed in this work. The Cu-catalyzed
one-pot tandem reaction of 2-chloro-N-(quinolin-8-yl)acetamides and terminal alkynes
proceeded smoothly at mild reaction conditions to produce (E)-1,3-enynes in satisfactory
to excellent yields. The wide availability of the simple terminal alkynes, cost effectivity
of Cu catalyst, mild reaction conditions, good functional group tolerance, and
experimental simplicity rendered the current method highly useful for the synthesis of
(E)-1,3-enynes.
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EXPERIMENTAL SECTION
General Information.
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1
13
Solvents were used without further drying. H and C NMR spectra were recorded on
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1
either a Bruker Avance II-400 spectrometer (400 MHz for H, 100 MHz for 13C) or a
Bruker Avance III-500 spectrometer (500 MHz for H, 125 MHz for 13C); CDCl3 and
1
TMS were used as a solvent and an internal standard, respectively. Chemical shifts are
reported in ppm downfield (δ) from TMS, the coupling constants J are given in Hz. The
peak patterns are indicated as follows: s, singlet; d, doublet; t, triplet; dd, doublet of
doublets; m, multiplet; q, quartet. TLC was carried out on SiO2 (silica gel 60 F254,
Merck) and the spots were located with UV light. Flash chromatography was carried out
on SiO2 (silica gel 60, 200-300 mesh). IR spectra were recorded on a NEXUS FT-IR
spectrometer. High resolution mass spectra were recorded on either a Q-TOF mass
spectrometry or a GC-TOF mass spectrometry. The starting materials were purchased
from Energy Chemicals Co. Ltd.
Procedure 1: Synthesis of 2-Chloro-N-(quinolin-8-yl)acetamide (1a).12a A reaction
flask was charged with a mixture of 8-aminoquinoline (1.5 g, 10.35 mmol) and
dichloromethane (60 mL) at 0 ºC. Then 4 mL of dry Et3N and 1.5 mL of chloroacetyl
chloride were dropped to the solution over a few minutes. The reaction mixture was
stirred at 0 ºC for 3 h. The resultant mixture was evaporated under a reduced pressure to
remove the solvent. The product 1a was purified via silica gel chromatography (eluent:
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petroleum ether/ethyl acetate = 5:1). Yield: 81%, Yellow solid (1.85 g, 81% yield). H
NMR (CDCl3, 400 MHz) δ 10.85 (bs, 1H), 8.82 (d, J = 4.9 Hz, 1H), 8.72 (dd, J = 4.0, 4.8
Hz 1H) 8.12 (d, J = 9.0 Hz, 1H), 7.53−7.48 (m, 2H), 7.43 (dd, J = 8.2, 4.2 Hz, 1H), 4.30
(s, 2H).
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Procedure 2: Synthesis of 2-Chloro-N-methyl-N-(quinolin-8-yl)acetamide (1c).12a,b
A
reaction flask was charged with a mixture of 8-aminoquinoline (0.65 g, 4.5 mmol), CH3I
(0.85 g, 6 mmol), K2CO3 (0.63 g, 4.5 mmol), and DMF (15 mL). After the reaction
mixture was stirred at room temperature for 24 h, 10 mL of H2O was added. The reaction
mixture was extracted with EtOAc (3×10 mL) and the combined organic phases were
dried over Na2SO4. The organic phases were evaporated under a reduced pressure to
remove the solvent. The product N-methylquinolin-8-amine was purified via silica gel
chromatography (eluent: petroleum ether/ethyl acetate = 5:1). Yield: 60% (0.43 g).
A reaction flask was charged with a mixture of N-methylquinolin-8-amine (0.32 g, 2
mmol) and dichloromethane (12 mL) at 0 ºC. Then 1 mL of dry Et3N and 0.3 mL of
chloroacetyl chloride were dropped to the solution over a few minutes. The reaction
mixture was stirred at 0 ºC for 3 h. The resultant mixture was evaporated under a reduced
pressure to remove the solvent. The product 1c was purified via silica gel
chromatography (eluent: petroleum ether/ethyl acetate = 5:1). Yield: 76% (0.356 g).
Brown solid, 1H NMR (CDCl3, 400 MHz) δ 8.97 (d, J = 3.9 Hz, 1H), 8.24 (d, J = 8.1 Hz,
1H), 7.89 (d, J = 8.2 Hz, 1H), 7.72−7.70 (m, 1H), 7.63−7.59 (m, 1H), 7.50 (dd, J = 4.1,
8.2 Hz, 1H), 3.75 (s, 2H), 3.44 (s, 3H). 13C{1H}NMR (DMSO, 100 MHz) δ 160.9, 147.3,
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147.0, 132.5, 131.1, 129.7, 127.4, 123.4, 123.2, 118.2, 56.0, 29.1. IR (neat): 2951, 2915,
2848, 1463, 1376, 1151, 939, 718, (cm-1); HRMS (ESI) m/z: [M+H]+ calcd for
C12H12ClN2O 235.0638; found 235.0640.
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Procedure 3: Synthesis of 2,2-Dimethyl-4-phenyl-N-(quinolin-8-yl)but-3-ynamide
(5).12a,c A reaction flask was charged with a mixture of 8-aminoquinoline (0.65 g, 4.5
mmol) and dichloromethane (30 mL) at 0 ºC. Then 2 mL of dry Et3N and 0.85 mL of
2-bromo-2-methylpropionyl bromide were dropped to the solution over a few minutes.
The reaction mixture was stirred at 0 ºC for 3 h. The resultant mixture was evaporated
under
a
reduced
pressure
to
remove
the
solvent.
The
product
2-bromo-2-methyl-N-(quinolin-8-yl)propanamide was purified via silica gel
chromatography (eluent: petroleum ether/ethyl acetate = 5:1). Yield: 84% (1.11 g). White
solid, 1H NMR (CDCl3, 400 MHz) δ 11.06 (bs, 1H), 8.89 (dd, J = 1.5, 4.2 Hz, 1H), 8.76
(dd, J = 3.0, 6.0 Hz, 1H), 8.19 (dd, J = 1.5, 8.3 Hz, 1H), 7.60−7.55 (m, 2H), 7.50 (dd, J =
4.2, 8.3 Hz, 1H), 2.17 (s, 6H); 13C{1H}NMR (CDCl3, 100 MHz) δ 170.3, 148.6, 138.9,
136.3, 134.3, 128.0, 127.2, 122.1, 121.7, 116.3, 61.7, 32.4.
A
reaction
flask
was
charged
with
a
mixture
of
2-bromo-2-methyl-N-(quinolin-8-yl)propanamide (2 mmol, 0.59 g), phenylacetylene (2a,
3 mmol), CuBr (0.2 mmol, 10 mol%), 1,10-phenanthroline (0.4 mmol, 20 mol%),
Cs2CO3 (4 mmol, 2 equiv.), and toluene (4.0 mL) under nitrogen atmosphere. The
reaction mixture was stirred at room temperature for 24 h. The resultant mixture was
evaporated under a reduced pressure to remove the solvent. The product
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2,2-dimethyl-4-phenyl-N-(quinolin-8-yl)but-3-ynamide (5) was purified via silica gel
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chromatography (eluent: petroleum ether/ethyl acetate = 10:1). Yield: 79% (0.497 g).
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Colorless oil, H NMR (CDCl3, 400 MHz) δ 11.48 (bs, 1H), 8.85 (dd, J = 1.1, 7.3 Hz,
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1H), 8.72 (dd, J = 1.4, 4.2 Hz, 1H), 8.14 (dd, J =1.3, 8.3 Hz, 1H), 7.76−7.73 (m, 2H),
7.58−7.50 (m, 2H), 7.45−7.40 (m, 4H), 1.74 (s, 6H). 13C{1H}NMR (CDCl3, 100 MHz) δ
172.4, 148.2, 139.1, 136.3, 134.6, 131.8, 128.3, 128.3, 128.0, 127.4, 123.0, 121.8, 121.6,
116.3, 91.9, 85.8, 40.8, 27.7.
Procedure 4: Copper-Catalyzed One-Pot Synthesis of 1,3-Enynes Using One Kind of
Terminal Alkyne.
A
reaction flask was charged with
a
mixture of
2-chloro-N-(quinolin-8-yl)acetamide (1a, 0.4 mmol), terminal alkyne (2, 1.2 mmol, 3.0
equiv.), CuI (0.04 mmol, 10 mol%), 1,10-phenanthroline (L1, 0.08 mmol, 20 mol%),
Cs2CO3 (0.48 mmol, 1.2 equiv.), and DCM (1.0 mL) under nitrogen atmosphere. The
reaction mixture was stirred at room temperature for 48 h. The resultant mixture was
evaporated under a reduced pressure to remove the solvent. The product 3 was purified
via silica gel chromatography (eluent: petroleum ether/ethyl acetate = 10:1).
(E)-3-Benzylidene-N,5-diphenylpent-4-ynamide (3ab) Colorless oil (12.1 mg, 9% yield).
1H NMR (CDCl3, 400 MHz) δ 7.83 (bs, 1H), 7.53−7.48 (m, 4H), 7.41−7.35 (m, 4H),
7.34−7.30 (m, 6H), 7.25 (s, 1H), 7.11 (dd, J = 7.4, 7.4 Hz, 1H), 3.58 (s, 2H).
13C{1H}NMR (CDCl3, 100 MHz) δ 167.6, 140.3, 137.7, 135.3, 131.6, 129.0, 128.9, 128.8,
128.5, 128.4, 124.5, 122.5, 120.0, 116.6, 91.1, 90.9, 41.5.
(E)-3-Benzylidene-5-phenyl-N-(quinolin-8-yl)pent-4-ynamide (3a). Colorless oil (133.7
mg, 86% yield). 1H NMR (CDCl3, 400 MHz) δ 10.46 (bs, 1H), 8.85 (d, J = 7.5 Hz, 1H),
8.45 (d, J = 4.2 Hz, 1H), 8.06 (d, J = 8.2 Hz, 1H), 7.53−7.45 (m, 6H), 7.39 (dd, J = 7.6,
7.6 Hz, 2H), 7.33−7.23 (m, 6H), 3.71 (s, 2H); 13C{1H}NMR (CDCl3, 100 MHz) δ 164.5,
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144.4,136.0, 134.9, 132.4, 131.9, 131.0, 128.1, 125.3, 124.9, 124.6, 124.5, 124.4, 124.2,
123.6, 119.4, 118.0, 117.8, 113.4, 113.0, 87.7, 87.1, 38.4. IR (neat): 3340, 3053, 2922,
1683, 1525, 1486, 1424, 1326, 825, 790, 754, 690, (cm-1); HRMS (EI) m/z: [M]+calcd for
C27H20N2O 388.1587; found 388.1569.
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(E)-3-(4-Fluorobenzylidene)-5-(4-fluorophenyl)-N-(quinolin-8-yl)pent-4-ynamide (3b).
White solid (137.8 mg, 81% yield), mp 197‒200 oC. 1H NMR (CDCl3, 400 MHz) δ 10.41
(bs, 1H), 8.84 (d, J = 6.9 Hz, 1H), 8.50 (s, 1H), 8.14 (d, J = 8.2 Hz, 1H), 7.57−7.45 (m,
6H), 7.40−7.38 (m, 1H), 7.21 (s, 1H), 7.09 (dd, J = 8.4, 8.4 Hz, 2H), 6.99 (dd, J = 8.4, 8.4
1
Hz, 2H), 3.67 (s, 2H); 13C{1H}NMR (CDCl3, 100 MHz) δ 168.1, 162.5 (d, JC-F = 248.7
1
3
Hz), 162.5 (d, JC-F = 247.4 Hz), 148.2, 138.6, 138.5, 136.3, 134.5, 133.7 (d, JC-F = 8.2
Hz), 131.7 (d, 4JC-F = 3.3 Hz), 130.8 (d, 3JC-F = 8.0 Hz), 127.9, 127.4, 121.8, 121.6, 119.1
4
2
2
(d, JC-F = 3.7 Hz), 116.9, 116.7, 115.7 (d, JC-F = 21.4 Hz), 115.6 (d, JC-F = 21.9 Hz),
90.8, 89.7, 42.0. IR (neat): 3338, 2921, 1675, 1539, 1506, 1486, 1330, 1230, 1159, 831,
786, 759 (cm-1); HRMS (EI) m/z: [M]+ calcd for C27H18N2OF2 424.1387; found 424.1376.
(E)-3-(4-Bromobenzylidene)-5-(4-bromophenyl)-N-(quinolin-8-yl)pent-4-ynamide (3c).
White solid (167.8 mg, 77% yield), mp 213‒215 oC. 1H NMR (CDCl3, 400 MHz) δ 10.37
(bs, 1H), 8.83 (dd, J = 1.58, 7.2 Hz, 1H), 8.52 (dd, J = 1.6, 4.2 Hz, 1H), 8.13 (dd, J = 1.6,
8.3 Hz, 1H), 7.56−7.50 (m, 4H), 7.42−7.38 (m, 5H), 7.33 (d, J = 8.5 Hz, 2H), 7.17 (s, 1H),
3.66 (s, 2H); 13C{1H}NMR (CDCl3, 100 MHz) δ 167.8, 148.2, 138.8, 138.5, 136.3, 134.5,
134.3, 133.2, 131.8, 131.5, 130.6, 127.9, 127.4, 122.7, 122.5, 121.9, 121.9, 121.6, 117.7,
116.7, 92.2, 90.1, 42.0. IR (neat): 3340, 2922, 1677, 1537, 1485, 1427, 1331, 1011, 817,
789, 758, 693 (cm-1); HRMS (EI) m/z: [M]+ calcd for C27H18N2OBr2 543.9786; found
543.9793.
(E)-N-(Quinolin-8-yl)-3-(4-(trifluoromethyl)benzylidene)-5-(4-(trifluoromethyl)phenyl)pe
o
nt-4-ynamide (3d). White solid (164.4 mg, 78% yield), mp 187‒190 C. 1H NMR (500
MHz, Chloroform-d) δ 10.34 (bs, 1H), 8.84 (dd, J = 1.5, 7.3 Hz, 1H), 8.53 (dd, J = 1.6,
4.2 Hz, 1H), 8.14 (dd, J =1.6, 8.3 Hz, 1H), 7.69‒7.65 (m, 4H), 7.58‒7.50 (m, 6H),7.39
(dd, J = 4.2, 8.3 Hz, 1H), 7.31 (s, 1H), 3.69 (s, 2H); 13C{1H}NMR (125 MHz, CDCl3) δ
2
167.5, 148.1, 139.0, 138.8, 138.5, 136.3, 134.4, 132.0, 130.2 (q, JC-F = 32.5 Hz), 130.1
(q, 2JC-F = 32.4 Hz), 129.3, 128.0, 127.4, 126.6, 125.6 (q, 3JC-F = 3.7 Hz), 125.2 (q, 3JC-F
=
1
1
3.7 Hz), 123.9 (q, JC-F = 270.6 Hz), 124.0 (q, JC-F = 270.5 Hz), 122.0, 121.7, 119.0,
116.8, 92.9, 90.0, 41.9. IR (neat): 3339, 2923, 1684, 1617, 1525, 1487, 1325, 1168, 1112,
1067, 841, 829, 793 (cm-1); HRMS (EI) m/z: [M]+ calcd for C29H18N2OF6 524.1323;
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(E)-3-(4-Methylbenzylidene)-N-(quinolin-8-yl)-5-(p-tolyl)pent-4-ynamide (3e). White
o
solid (138.0 mg, 83% yield), mp 140−142 C. 1H NMR (CDCl3, 400 MHz) δ 10.48 (bs,
8
9
1H), 8.85 (d, J = 7.4 Hz, 1H), 8.49 (d, J = 4.1 Hz, 1H), 8.10 (d, J = 8.3 Hz, 1H),
7.55−7.47 (m, 2H), 7.42−7.38 (m, 4H), 7.35 (dd, J = 4.2, 8.3 Hz, 1H), 7.25 (s, 1H),
7.21−7.19 (m, 2H), 7.10−7.08 (m, 2H), 3.71 (s, 2H), 2.35 (s, 3H), 2.34 (s, 3H);
13C{1H}NMR (CDCl3, 100 MHz) δ 168.5, 148.2, 139.5, 138.7, 138.4, 138.1, 136.1, 134.7,
132.9, 131.7, 129.3, 129.0, 129.0, 127.9, 127.3, 121.7, 121.5, 120.1, 116.7, 116.4, 91.0,
90.8, 42.2, 21.6, 21.3. IR (neat): 3340, 2921, 1683, 1526, 1486, 1424, 1327, 1164, 816,
791, 757, 583 (cm-1); HRMS (EI) m/z: [M]+ calcd for C29H24N2O 416.1889; found
416.1878.
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(E)-3-(4-(tert-Butyl)benzylidene)-5-(4-(tert-butyl)phenyl)-N-(quinolin-8-yl)pent-4-ynamid
e (3f). White solid (170.6 mg, 85% yield), mp 172−174 oC. 1H NMR (CDCl3, 400 MHz)
δ 10.51 (bs, 1H), 8.86 (dd, J = 1.2, 7.4 Hz, 1H), 8.42 (dd, J = 1.6, 4.2 Hz, 1H), 8.08 (dd, J
= 1.6, 8.3 Hz, 1H), 7.54−7.41 (m, 8H), 7.33−7.29 (m, 3H), 7.25 (s, 1H), 3.73 (s, 2H),
1.31 (s, 9H), 1.30 (s, 9H); 13C{1H}NMR (CDCl3, 100 MHz) δ 168.5, 151.6, 151.2, 148.2,
139.4, 138.7, 136.1, 134.8, 132.9, 131.5, 128.8, 127.9, 127.3, 125.6, 125.2, 121.6, 121.4,
120.2, 116.7, 116.5, 91.0, 90.8, 42.4, 34.8, 34.7, 31.3, 31.2. IR (neat): 3327, 2962, 1686,
1526, 1486, 1424, 1327, 1267, 826, 791, 756, 563 (cm-1); HRMS (EI) m/z: [M]+ calcd for
C35H36N2O 500.2828; found 500.2817.
(E)-3-(2-Chlorobenzylidene)-5-(2-chlorophenyl)-N-(quinolin-8-yl)pent-4-ynamide (3g).
o
White solid (154.2 mg, 84% yield), mp 91−92 C. 1H NMR (CDCl3, 400 MHz) δ 10.38
(bs, 1H), 8.83 (d, J = 7.1 Hz, 1H), 8.49 (d, J = 3.2 Hz, 1H), 8.10 (d, J = 8.1 Hz, 1H), 7.76
(d, J = 7.4 Hz, 1H), 7.55−7.48 (m, 3H), 7.44−7.41 (m, 2H), 7.37−7.25 (m, 4H),
7.31−7.14 (m, 2H), 3.65 (s, 2H); 13C{1H}NMR (CDCl3, 100 MHz) δ 167.9, 148.1, 138.6,
137.2, 136.2, 136.1, 134.6, 133.9, 133.8, 133.4, 130.8, 129.6, 129.6, 129.4, 129.2, 127.9,
127.3, 126.9, 126.3, 122.9, 121.8, 121.6, 1188, 116.7, 95.4, 88.2, 42.0. IR (neat): 3339,
2923, 1683, 1525, 1486, 1425, 1328, 1053, 826, 791, 753, 693 (cm-1); HRMS (EI) m/z:
[M]+ calcd for C27H18N2OCl2 456.0796; found 456.0807.
(E)-3-(3-Chlorobenzylidene)-5-(3-chlorophenyl)-N-(quinolin-8-yl)pent-4-ynamide (3h).
White solid (161.6 mg, 88% yield), mp 148−150 oC. 1H NMR (CDCl3, 400 MHz) δ 10.34
(bs, 1H), 8.84 (d, J = 6.8 Hz, 1H), 8.60 (s, 1H), 8.14 (d, J = 8.0 Hz, 1H), 7.57−7.48 (m,
5H), 7.42−7.40 (m, 1H), 7.36−7.26 (m, 4H), 7.22−7.19 (m, 2H), 3.68 (s, 2H);
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13C{1H}NMR (CDCl3, 100 MHz) δ 167.6, 148.3, 138.7, 138.5, 137.2, 136.3, 134.5, 134.5,
134.1, 131.6, 129.9, 129.9, 129.5, 129.0, 128.7, 128.3, 128.0, 127.3, 127.1, 124.6, 121.9,
121.7, 118.3, 116.8, 91.9, 89.8, 42.0. IR (neat): 3343, 2921, 1682, 1558, 1538, 1486,
1327, 886, 823, 788, 679, 586 (cm-1); HRMS (EI) m/z: [M]+ calcd for C27H18N2OCl2
456.0796; found 456.0802.
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(E)-3-(4-Chlorobenzylidene)-5-(4-chlorophenyl)-N-(quinolin-8-yl)pent-4-ynamide (3i).
White solid (126.2 mg, 69% yield), mp 217‒220 oC. 1H NMR (CDCl3, 400 MHz) δ 10.38
(bs, 1H), 8.84 (d, J = 7.0 Hz, 1H), 8.52 (d, J = 3.2 Hz, 1H), 8.14 (d, J = 8.2 Hz, 1H),
7.57−7.48 (m, 4H), 7.42−7.36 (m, 5H), 7.26 (d, J = 8.3 Hz, 2H), 7.20(s, 1H), 3.67 (s, 2H);
13C{1H}NMR (CDCl3, 100 MHz) δ 167.8, 148.2, 138.7, 138.5, 136.3, 134.5, 134.5, 134.2,
133.9, 133.0, 130.3, 128.9, 128.6, 127.9, 127.4, 121.8, 121.6, 121.5, 117.6, 116.7, 92.0,
89.9, 42.0. IR (neat): 3337, 2923, 1675, 1536, 1486, 1425, 1329, 1094, 822, 787, 757,
687 (cm-1); HRMS (EI) m/z: [M]+ calcd for C27H18N2OCl2 456.0796; found 456.0798.
(E)-3-(2-Methoxybenzylidene)-5-(2-methoxyphenyl)-N-(quinolin-8-yl)pent-4-ynamide (3j).
Colorless oil (169.0 mg, 94% yield). 1H NMR (CDCl3, 400 MHz) δ 10.49 (bs, 1H), 8.86
(d, J = 7.5 Hz, 1H), 8.40 (s, 1H), 8.09 (d, J = 8.1 Hz, 1H), 7.55 (d, J = 7.4 Hz, 1H),
7.55−7.43i (m, 3H), 7.39 (s, 1H), 7.33−7.23 (m, 3H), 6.99 (dd, J = 7.4, 7.4 Hz, 1H),
6.90−6.79 (m, 3H), 3.82 (s, 3H), 3.67 (m, 5H); 13C{1H}NMR (CDCl3, 100 MHz) δ 168.8,
160.1, 157.1, 148.1, 136.0, 135.3, 134.9, 133.7, 130.3, 129.7, 129.6, 127.9, 127.3, 124.7,
121.5, 121.4, 120.5, 120.3, 117.3, 116.6, 110.6, 110.5, 95.4, 87.1, 55.6, 55.4, 42.5. IR
(neat): 3343, 2932, 1682, 1526, 1486, 1463, 1425, 1247, 1025, 827, 792, 754 (cm-1);
HRMS (EI) m/z: [M]+ calcd for C29H24N2O3 448.1787; found 448.1777.
(E)-3-(3-Methoxybenzylidene)-5-(3-methoxyphenyl)-N-(quinolin-8-yl)pent-4-ynamide
(3k). White solid (170.2 mg, 95% yield), mp 130−133 oC. 1H NMR (CDCl3, 400 MHz) δ
10.45 (bs, 1H), 8.85 (dd, J = 1.5, 7.4 Hz, 1H), 8.50 (dd, J = 1.6, 4.2 Hz, 1H), 8.11 (dd, J =
1.6, 8.3 Hz, 1H), 7.56−7.48 (m, 2H), 7.37 (dd, J = 4.2, 8.2 Hz, 1H), 7.31 (dd, J = 7.9, 7.9
Hz, 1H), 7.26 (d, J = 1.6 Hz, 1H), 7.20 (dd, J = 7.9, 7.9 Hz, 1H), 7.13−7.09 (m, 3H),
7.02−7.01 (m, 1H), 6.87 (dd, J = 2.5, 8.2 Hz, 1H), 3.84 (s, 3H), 3.73 (s, 2H), 3.72 (s, 3H);
13C{1H}NMR (CDCl3, 100 MHz) δ 168.2, 159.7, 159.3, 148.3, 139.8, 136.9, 136.1, 134.7,
129.6, 129.3, 127.9, 127.3, 124.4, 121.7, 121.5, 121.5, 117.3, 116.7, 116.5, 115.1, 114.4,
114.0, 91.1, 90.8, 55.4, 55.2, 42.3. IR (neat): 3341, 2924, 1684, 1525, 1486, 1425, 1326,
1044, 826, 789, 757, 686 (cm-1); HRMS (EI) m/z: [M]+ calcd for C29H24N2O3 448.1787;
found 448.1777.
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(E)-3-(4-Methoxybenzylidene)-5-(4-methoxyphenyl)-N-(quinolin-8-yl)pent-4-ynamide (3l).
White solid (148.8 mg, 83% yield), mp 112−114 oC. 1H NMR (CDCl3, 400 MHz) δ 10.52
(bs, 1H), 8.85 (dd, J = 1.4, 7.4 Hz, 1H), 8.47 (dd, J = 1.6, 4.2 Hz, 1H), 8.09 (dd, J = 1.6,
8.3 Hz, 1H), 7.55−7.43 (m, 6H), 7.34 (dd, J = 4.2, 8.2 Hz, 1H), 7.18 (s, 1H), 6.94−6.91
(m, 2H), 6.83−6.81 (m, 2H), 3.80 (s, 3H), 3.79(s, 3H), 3.71 (s, 2H); 13C{1H}NMR
(CDCl3, 100 MHz) δ 168.6, 159.6, 159.4, 148.2, 138.7, 138.7, 136.1, 134.8, 133.2, 130.5,
128.5, 127.9, 127.3, 121.6, 121.5, 116.7, 115.4, 115.3, 114.0, 113.9, 90.6, 90.4, 55.3, 55.3,
42.3. IR (neat): 3323, 2927, 1682, 1604, 1525, 1424, 1327, 1251, 1031, 827, 792, 669
(cm-1); HRMS (EI) m/z: [M]+ calcd for C29H24N2O3 448.1787; found 448.1779.
(E)-N-(Quinolin-8-yl)-5-(thiophen-2-yl)-3-(thiophen-2-ylmethylene)pent-4-ynamide (3m).
Yellow oil (148.8 mg, 93% yield). 1H NMR (CDCl3, 400 MHz) δ 10.42 (bs, 1H), 8.81 (d,
J = 7.4 Hz, 1H), 8.55 (d, J = 4.0 Hz, 1H), 8.07 (d, J = 8.1 Hz, 1H), 7.52−7.45 (m, 2H),
7.36−7.30 (m, 4H), 7.25 (d, J = 5.1 Hz, 1H), 7.22 (d, J = 3.6 Hz, 1H), 7.05 (dd, J = 4.2,
4.4 Hz, 1H), 6.96 (dd, J = 4.2, 4.5 Hz, 1H), 3.87 (s, 2H); 13C{1H}NMR (CDCl3, 100 MHz)
δ 167.3, 148.3, 138.7, 138.6, 136.1, 134.5, 132.2, 132.0, 129.7, 127.9, 127.7, 127.6, 127.5,
127.3, 127.1, 123.2, 121.7, 121.5, 116.6, 114.0, 95.5, 84.6, 42.5. IR (neat): 3322, 3103,
2923, 1683, 1525, 1485, 1423, 1327, 1161, 826, 791, 700 (cm-1); HRMS (EI) m/z: [M]+
calcd for C23H16N2OS2 400.0704; found 400.0696.
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(E)-5-(Naphthalen-2-yl)-3-(naphthalen-2-ylmethylene)-N-(quinolin-8-yl)pent-4-ynamide
(3n). White solid (178.4 mg, 91% yield), mp 138−140 oC. 1H NMR (CDCl3, 400 MHz) δ
10.53 (bs, 1H), 8.91 (d, J = 7.6 Hz, 1H), 8.45 (d, J = 4.2 Hz, 1H), 8.08−8.05 (m, 2H),
8.01 (s, 1H), 7.90−7.63 (m, 7H), 7.57−7.57 (m, 2H), 7.48−7.45 (m, 6H), 7.28 (dd, J = 4.2,
8.2 Hz, 1H), 3.84 (s, 2H); 13C{1H}NMR (CDCl3, 100 MHz) δ 168.3, 148.2, 139.9, 138.7,
136.2, 134.7, 133.3, 133.2, 133.0, 132.9, 132.8, 131.7, 128.6, 128.5, 128.5, 128.2, 127.9,
127.9, 127.8, 127.8, 127.6, 127.4, 126.8, 126.7, 126.6, 126.5, 126.4, 121.7, 121.5, 120.5,
117.5, 116.8, 91.9, 91.5, 42.4. IR (neat): 3347, 3053, 2922, 1683, 1526, 1485, 1424, 1326,
1264, 823, 791, 745, 475 (cm-1); HRMS (EI) m/z: [M]+ calcd for C35H24N2O 488.1889;
found 488.1884.
Procedure 5: Copper-Catalyzed One-Pot Synthesis of 1,3-Enynes Using Two Kinds
of Terminal Alkynes. A reaction flask was charged with a mixture of
2-chloro-N-(quinolin-8-yl)acetamide (1a) (0.4 mmol), a first-step alkyne (2a, 2i, 2l, and
2n) (0.4 mmol, 1.0 equiv.), CuI (0.04 mmol, 10 mol%), Cs2CO3 (0.48 mmol, 1.2 equiv.),
and DCM (1.0 mL) under nitrogen atmosphere. After the reaction mixture was stirred at
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35 ºC for 16 or 24 h, the flask was cooled to room temperature. 1,10-Phenanthroline (L1,
0.08 mmol, 20 mol%) and a second-step alkyne (2, 0.8 mmol, 2.0 equiv.) were added into
the mixture under nitrogen atmosphere. The reaction mixture was stirred at room
temperature for 24 h. The resultant mixture was evaporated under a reduced pressure to
remove the solvent. The product 4 was purified via silica gel chromatography (eluent:
petroleum ether/ethyl acetate = 10:1).
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(E)-3-Benzylidene-5-(4-fluorophenyl)-N-(quinolin-8-yl)pent-4-ynamide (4a). White solid
o
(101.6 mg, 62% yield), mp 129−131 C. 1H NMR (CDCl3, 400 MHz) δ 10.41 (bs, 1H),
8.85 (d, J = 7.4 Hz, 1H), 8.50 (d, J = 3.9 Hz, 1H), 8.11 (d, J = 8.2 Hz, 1H), 7.55−7.44 (m,
6H), 7.42−7.35 (m, 3H), 7.32−7.27 (m, 2H), 6.97 (dd, J = 8.6, 8.6 Hz, 2H), 3.71 (s, 2H);
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13C{1H}NMR (CDCl3, 100 MHz) δ 168.2, 162.5 (d, JC-F = 249.7 Hz), 148.1, 139.8,
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138.6, 136.2, 135.6, 134.6, 133.7 (d, JC-F = 8.4 Hz), 129.0, 128.6, 128.2, 127.9, 127.4,
121.7, 121.6, 119.2 (d, 4JC-F = 3.5 Hz), 117.0, 116.7, 115.5 (d, 2JC-F = 22.0 Hz), 91.0, 89.6,
42.1. IR (neat): 3348, 2922, 1684, 1597, 1526, 1506, 1326, 1230, 1156, 835, 791, 754
(cm-1); HRMS (EI) m/z: [M]+ calcd for C27H19N2OF 406.1481; found 406.1479.
(E)-3-Benzylidene-5-(4-bromophenyl)-N-(quinolin-8-yl)pent-4-ynamide (4b). White solid
o
(128.6 mg, 69% yield), mp 119−121 C. 1H NMR (CDCl3, 400 MHz) δ 10.39 (bs, 1H),
8.85 (d, J = 7.4 Hz, 1H), 8.52 (d, J = 4.0 Hz, 1H), 8.11 (d, J = 8.2 Hz, 1H), 7.55−7.48 (m,
4H), 7.41−7.28 (m, 9H), 3.71 (s, 2H); 13C{1H}NMR (CDCl3, 100 MHz) δ 168.1, 148.2,
140.2, 138.6, 136.2, 135.5, 134.6, 133.2, 131.5, 129.0, 128.7, 128.2, 127.9, 127.4, 122.6,
122.1, 121.8, 121.6, 116.9, 116.7, 92.4, 89.6, 42.0. IR (neat): 3446, 1681, 1526, 1485,
1424, 1385, 1326, 823, 790, 755, 697, (cm-1); HRMS (EI) m/z: [M]+ calcd for
C27H19N2OBr 466.0681, 468.0660; found 466.0675, 468.0634.
(E)-3-Benzylidene-N-(quinolin-8-yl)-5-(4-(trifluoromethyl)phenyl)pent-4-ynamide (4c).
White solid (133.8 mg, 73% yield), mp 122−125 oC. 1H NMR (CDCl3, 400 MHz) δ 10.37
(bs, 1H), 8.86 (dd, J = 1.0, 7.3 Hz, 1H), 8.52 (dd, J = 1.4, 4.1 Hz, 1H), 8.12 (dd, J = 1.3,
8.3 Hz, 1H), 7.58−7.49 (m, 8H), 7.43−7.36 (m, 3H), 7.4−7.28 (m, 2H), 3.73 (s, 2H);
13C{1H}NMR (CDCl3, 125 MHz) δ 168.0, 148.1, 140.9, 138.6, 136.3, 135.4, 134.5, 131.9,
129.9 (q, 2JC-F = 32.6 Hz), 129.0, 128.7, 128.4, 128.0, 127.4, 126.9, 125.1 (q, 3JC-F = 3.7
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Hz), 123.9 (q, JC-F = 270.6 Hz), 121.8, 121.6, 116.7, 93.6, 89.1, 41.9. IR (neat): 3346,
2924, 1685, 1615, 1526, 1486, 1324, 1166, 1125, 1065, 842, 826, 791 (cm-1); HRMS (EI)
m/z: [M]+ calcd for C28H19N2OF3 456.1449; found 456.1448.
(E)-3-Benzylidene-5-(4-nitrophenyl)-N-(quinolin-8-yl)pent-4-ynamide (4d). Yellow solid
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(92.3 mg, 53% yield), mp 201−203 C. 1H NMR (CDCl3, 400 MHz) δ 10.33 (bs, 1H),
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(m, 3H), 7.36−7.33 (m, 2H), 3.74 (s, 2H); C{1H}NMR (CDCl3, 100 MHz) δ 167.8,
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148.1, 146.9, 141.8, 138.5, 136.4, 135.2, 134.4, 132.4, 130.0, 129.1, 128.7, 128.6, 128.0,
127.4, 123.5, 121.9, 121.7, 116.7, 116.5, 96.5, 88.6, 41.7. IR (neat): 3441, 2924, 1683,
1588, 1520, 1486, 1341, 1097, 852, 823, 790, 748 (cm-1); HRMS (EI) m/z: [M]+ calcd for
C27H19N3O3 433.1426; found 433.1423.
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Methyl-(E)-4-(3-benzylidene-5-oxo-5-(quinolin-8-ylamino)pent-1-yn-1-yl)benzoate (4e).
o
White solid (125.0 mg, 70% yield), mp 127−129 C. 1H NMR (CDCl3, 400 MHz) δ 10.
41 (bs, 1H), 8.85 (dd, J = 1.3, 7.4 Hz, 1H), 8.51 (dd, J =1.6, 4.2 Hz, 1H), 8.11 (dd, J =1.5,
8.3 Hz, 1H), 7.95 (d, J = 8.4 Hz, 2H), 7.55−7.48 (m, 6H), 7.43−7.30 (m, 5H), 3.90 (s, 3H),
3.73 (s, 2H); 13C{1H}NMR (CDCl3, 100 MHz) δ 168.0, 166.5, 148.2, 140.8, 138.6, 136.2,
135.4, 134.6, 131.7, 129.5, 129.4, 129.1, 128.7, 128.4, 127.9, 127.8, 127.3, 121.8, 121.6,
116.8, 116.7, 94.3, 89.9, 52.2, 41.9. IR (neat): 3430, 2924, 1720, 1683, 1600, 1526, 1486,
1435, 1276, 1108, 826, 791, 769 (cm-1); HRMS (EI) m/z: [M]+ calcd for C29H22N2O3
446.1630; found 446.1621.
(E)-3-Benzylidene-N-(quinolin-8-yl)-5-(p-tolyl)pent-4-ynamide (4f). White solid (129.0
mg, 80% yield), mp 128−131 oC. 1H NMR (CDCl3, 400 MHz) δ 10.47 (bs, 1H), 8.85 (d, J
= 7.5 Hz, 1H), 8.49 (d, J = 3.7 Hz, 1H), 8.08 (d, J = 8.2 Hz, 1H), 7.53−7.45 (m, 4H),
7.40−7.37(m, 4H), 7.33 (dd, J = 4.3, 8.3 Hz, 1H), 7.31−7.26 (m, 2H), 7.09−7.07(m, 2H),
3.71 (s, 2H), 2.33 (s, 3H); 13C{1H}NMR (CDCl3, 100 MHz) δ 168.3, 148.2, 139.4, 138.7,
138.5, 136.1, 135.7, 134.7, 131.7, 129.0, 128.6, 128.0, 127.9, 127.3, 121.7, 121.5, 120.1,
117.3, 116.7, 91.0, 90.8, 42.2, 21.6. IR (neat): 3434, 2922, 1682, 1525, 1486, 1424, 1385,
1326, 1164, 816, 791, 753, 700 (cm-1); HRMS (EI) m/z: [M]+ calcd for C28H22N2O
402.1732; found 402.1736.
(E)-3-Benzylidene-5-(4-(tert-butyl)phenyl)-N-(quinolin-8-yl)pent-4-ynamide (4g). White
o
solid (145.6 mg, 82% yield), mp 132−135 C. 1H NMR (CDCl3, 400 MHz) δ 10.48 (bs,
1H), 8.85 (dd, J = 1.5, 7.5 Hz, 1H), 8.43 (dd, J = 1.7, 4.2 Hz, 1H), 8.08 (dd, J = 1.7, 8.3
Hz, 1H), 7.54−7.50 (m, 3H), 7.48−7.37 (m, 5H), 7.34−7.27 (m, 5H), 3.71 (s, 2H), 1.30 (s,
9H); 13C{1H}NMR (CDCl3, 100 MHz) δ 168.4, 151.7, 148.2, 139.4, 138.6, 136.1, 135.7,
134.7, 131.6, 129.0, 128.6, 128.1, 127.9, 127.3, 125.3, 121.7, 121.5, 120.1, 117.3, 116.7,
91.0, 90.8, 42.2, 34.8, 31.2. IR (neat): 3344, 2962, 1683, 1525, 1486, 1424, 1327, 1265,
1165, 826, 791, 757, 698 (cm-1); HRMS (EI) m/z: [M]+ calcd for C31H28N2O 444.2202;
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(E)-3-Benzylidene-5-(4-pentylphenyl)-N-(quinolin-8-yl)pent-4-ynamide (4h). White solid
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(139.0 mg, 76% yield), mp 106−109 C. 1H NMR (CDCl3, 400 MHz) δ 10.54 (bs, 1H),
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7.38−7.31 (m, 3H), 7.15 (d, J = 7.8 Hz, 2H), 3.76 (s, 2H), 2.63 (t, J = 7.6 Hz, 2H), 1.64
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(tt, J = 7.2,7.2 Hz, 2H), 1.40−1.32 (m, 4H), 0.94 (t, J = 6.8 Hz, 3H); C{1H}NMR
(CDCl3, 100 MHz) δ 168.3, 148.2, 143.5, 139.4, 138.7, 136.1, 135.7, 134.7, 131.8, 129.0,
128.6, 128.4, 128.0, 127.9, 127.3, 121.7, 121.5, 120.3, 117.3, 116.7, 91.1, 90.8, 42.2, 35.9,
31.4, 30.9, 22.5, 14.1. IR (neat): 3346, 2925, 1684, 1525, 1486, 1424, 1326, 1262, 825,
753, 699 (cm-1); HRMS (EI) m/z: [M]+ calcd for C32H30N2O 458.2358; found 458.2347.
(E)-3-Benzylidene-5-(2-chlorophenyl)-N-(quinolin-8-yl)pent-4-ynamide (4i). Colorless oil
(150.6 mg, 89% yield). 1H NMR (CDCl3, 400 MHz) δ 10.44 (bs, 1H), 8.85 (d, J = 7.4 Hz,
1H), 8.45 (s, 1H), 8.08 (d, J = 8.3 Hz, 1H), 7.55−7.46 (m, 5H), 7.42−7.38 (m, 2H),
7.35−7.29 (m, 4H), 7.22−7.14 (m, 2H), 3.75 (s, 2H); 13C{1H}NMR (CDCl3, 100 MHz) δ
168.2, 148.1, 140.4, 138.6, 136.1, 136.1, 135.5, 134.6, 133.4, 129.3, 129.2, 129.1, 128.6,
128.3, 127.9, 127.3, 126.4, 123.1, 121.7, 121.6, 117.0, 116.7, 96.4, 87.5, 42.0. IR (neat):
3444, 2923, 1683, 1525, 1486, 1474, 1425, 1386, 1327, 825, 791, 755 (cm-1); HRMS (EI)
m/z: [M]+ calcd for C27H19N2OCl 422.1186; found 422.1187.
(E)-3-Benzylidene-5-(3-chlorophenyl)-N-(quinolin-8-yl)pent-4-ynamide (4j). White solid
(134.0 mg, 79% yield), mp 98−100 C. 1H NMR (CDCl3, 400 MHz) δ 10.40 (bs, 1H),
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8.86 (dd, J = 1.6, 7.3 Hz, 1H), 8.57 (dd, J = 1.6, 4.2 Hz, 1H), 8.12 (dd, J = 1.6, 8.3 Hz,
1H), 7.56−7.48 (m, 5H), 7.43−7.25 (m, 7H), 7.22−7.18 (m, 1H), 3.71 (s, 2H);
13C{1H}NMR (CDCl3, 125 MHz) δ 168.1, 148.3, 140.4, 138.6, 136.2, 135.4, 134.6, 134.1,
131.6, 129.8, 129.4, 129.0, 128.6, 128.5, 128.3, 128.0, 127.3, 124.8, 121.8, 121.6, 116.8,
116.7, 92.4, 89.2, 42.0. IR (neat): 3340, 3060, 1683, 1590, 1525, 1486, 1424, 1385, 1327,
1165, 788, 752 (cm-1); HRMS (EI) m/z: [M]+ calcd for C27H19N2OCl 422.1186; found
422.1181.
(E)-3-Benzylidene-5-(4-chlorophenyl)-N-(quinolin-8-yl)pent-4-ynamide (4k). White solid
(113.0 mg, 67% yield), mp 135−136 C. 1H NMR (CDCl3, 400 MHz) δ 10.41 (bs, 1H),
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8.86 (d, J = 7.3 Hz, 1H), 8.51 (dd, J = 1.2, 4.1 Hz, 1H), 8.12 (dd, J = 1.1, 8.2 Hz, 1H),
7.56−7.49 (m, 4H), 7.42−7.36 (m, 5H), 7.33−7.24 (m, 4H), 3.71 (s, 2H); 13C{1H}NMR
(CDCl3, 100 MHz) δ 168.2, 148.2, 140.2, 138.6, 136.3, 135.5, 134.6, 134.3, 133.0, 129.0,
128.7, 128.6, 128.6, 128.2, 127.9, 127.4, 121.8, 121.6, 116.9, 116.7, 92.2, 89.5, 42.0. IR
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(neat): 3338, 2926, 1683, 1525, 1487, 1424, 1385, 1326, 1089, 825, 790, 757 (cm-1);
HRMS (EI) m/z: [M]+ calcd for C27H19N2OCl 422.1186; found 422.1175.
(E)-3-Benzylidene-5-(2-methoxyphenyl)-N-(quinolin-8-yl)pent-4-ynamide (4l). Colorless
oil (146.9 mg, 88% yield). 1H NMR (CDCl3, 400 MHz) δ 10.49 (bs, 1H), 8.85 (d, J = 7.5
Hz, 1H), 8.40 (s, 1H), 8.08 (d, J = 8.3 Hz, 1H), 7.54−7.52 (m, 3H), 7.47−7.45 (m, 2H),
7.39 (dd, J = 7.6, 7.6 Hz, 2H), 7.32−7.24 (m, 4H), 6.86 (t, J = 7.5 Hz, 1H), 6.81 (d, J =
8.3 Hz, 1H), 3.74 (s, 2H), 3.70 (s, 3H); 13C{1H}NMR (CDCl3, 100 MHz) δ 168.4, 160.1,
148.1, 139.3, 138.7, 136.0, 135.8, 134.8, 133.7, 129.8, 129.0, 128.6, 128.0, 127.9, 127.3,
121.6, 121.5, 120.3, 117.4, 116.7, 112.4, 110.6, 95.4, 87.4, 55.7, 42.3. IR (neat): 3343,
2925, 1682, 1525, 1487, 1425, 1327, 1248, 1024, 826, 792, 753 (cm-1); HRMS (EI) m/z:
[M]+ calcd for C28H22N2O2 418.1681; found 418.1690.
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(E)-3-Benzylidene-5-(3-methoxyphenyl)-N-(quinolin-8-yl)pent-4-ynamide (4m). Colorless
oil (146.8 mg, 88% yield). 1H NMR (CDCl3, 400 MHz) δ 10.46 (bs, 1H), 8.86 (d, J = 7.4
Hz, 1H), 8.50 (dd, J = 1.2, 4.1 Hz, 1H), 8.09 (dd, J = 1.1, 8.2 Hz, 1H), 7.54–7.47 (m, 4H),
7.40 (dd, J = 7.6, 7.6 Hz, 2H), 7.36–7.29 (m, 3H), 7.19 (dd, J = 7.9, 7.9 Hz, 1H), 7.10 (d,
J = 7.6 Hz, 1H), 7.01 (s, 1H), 6.86 (dd, J = 8.2, 2.4 Hz, 1H), 3.72 (s, 2H), 3.70 (s, 3H);
13C{1H}NMR (CDCl3, 100 MHz) δ 168.3, 159.2, 148.3, 139.9, 138.6, 136.2, 135.6, 134.7,
129.3, 129.0, 128.6, 128.2, 127.9, 127.3, 124.4, 124.1, 121.7, 121.6, 117.1, 116.7, 116.4,
115.1, 91.1, 90.7, 55.2, 42.1. IR (neat): 3336, 2924, 1685, 1525, 1486, 1424, 1326, 1238,
1044, 826, 790, 754 (cm-1); HRMS (EI) m/z: [M]+ calcd for C28H22N2O2 418.1681; found
418.1670.
(E)-3-Benzylidene-5-(4-methoxyphenyl)-N-(quinolin-8-yl)pent-4-ynamide (4n). White
o
solid (132.0 mg, 79% yield), mp 116−118 C. 1H NMR (CDCl3, 400 MHz) δ 10.48 (bs,
1H), 8.86 (d, J = 7.4 Hz, 1H), 8.50 (d, J = 3.8 Hz, 1H), 8.10 (d, J = 8.1 Hz, 1H),
7.55−7.47 (m, 4H), 7.45−7.34 (m, 5H), 7.31−7.27 (m, 1H), 7.24 (s, 1H), 6.82 (d, J = 8.6
13
Hz, 2H), 3.80 (s, 3H), 3.71 (s, 2H); C{1H}NMR (CDCl3, 100 MHz) δ 168.4, 159.7,
148.2, 139.0, 138.6, 136.1, 135.8, 134.7, 133.3, 129.0, 128.6, 128.0, 127.9, 127.3, 121.7,
121.5, 117.3, 116.7, 115.2, 113.9, 90.9, 90.1, 55.3, 42.2. IR (neat): 3338, 2925, 1682,
1601, 1524, 1442, 1326, 1249, 1030, 827, 791, 700 (cm-1); HRMS (EI) m/z: [M]+ calcd
for C28H22N2O2 418.1681; found 418.1676.
(E)-3-Benzylidene-N-(quinolin-8-yl)non-4-ynamide (4o). Colorless oil (99.6 mg, 68%
yield). 1H NMR (CDCl3, 400 MHz) δ 10.33 (bs, 1H), 8.85 (dd, J = 1.4, 7.4 Hz, 1H), 8.79
(dd, J = 1.6, 4.2 Hz, 1H), 8.14 (dd, J = 1.6, 8.3 Hz, 1H), 7.56−7.48 (m, 2H), 7.46−7.41 (m,
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3H), 7.36 (dd, J = 7.6, 7.6 Hz, 2H), 7.28–7.25 (m, 1H), 7.11 (s, 1H), 3.60 (s, 2H), 2.38 (t,
J = 7.1 Hz, 2H), 1.49 (tt, J = 7.0, 7.1 Hz, 2H), 1.36 (tq, J = 7.1, 7.3 Hz, 2H), 0.78 (t, J =
7.3 Hz, 3H); 13C{1H}NMR (CDCl3, 100 MHz) δ 168.5, 148.1, 138.7, 138.3, 136.2, 135.9,
134.7, 128.8, 128.5, 128.0, 127.7, 127.4, 121.6, 121.5, 117.9, 116.7, 92.1, 82.3, 42.4, 30.7,
22.0, 19.3, 13.5. IR (neat): 3351, 2956, 2930, 1683, 1525, 1486, 1424, 1385, 1326, 826,
791, 752 (cm-1); HRMS (EI) m/z: [M]+ calcd for C25H24N2O 368.1889; found 368.1881.
(E)-3-Benzylidene-N-(quinolin-8-yl)-5-(thiophen-2-yl)pent-4-ynamide (4p). Yellow oil
(138.6 mg, 88% yield). 1H NMR (CDCl3, 400 MHz) δ 10.42 (bs, 1H), 8.84 (dd, J = 1.2,
7.4 Hz, 1H), 8.55 (dd, J = 1.5, 4.2 Hz, 1H), 8.09 (dd, J = 1.5, 8.3 Hz, 1H), 7.54−7.46 (m,
4H), 7.41−7.34 (m, 3H), 7.31−7.22 (m, 4H), 6.95 (dd, J = 3.8, 5.0 Hz, 1H), 3.70 (s, 2H);
13C{1H}NMR (CDCl3, 100 MHz) δ 168.1, 148.3, 139.9, 138.6, 136.1, 135.6, 134.6, 132.3,
129.0, 128.6, 128.2, 127.9, 127.5, 127.3, 127.1, 123.2, 121.7, 121.6, 116.9, 116.7, 95.0,
83.9, 41.8. IR (neat): 3341, 2924, 1683, 1525, 1486, 1424, 1386, 1327, 1162, 826, 791,
754 (cm-1); HRMS (EI) m/z: [M]+ calcd for C25H18N2OS 394.1140; found 394.1142.
(E)-3-Benzylidene-5-(naphthalen-2-yl)-N-(quinolin-8-yl)pent-4-ynamide (4q). White
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solid (132.6 mg, 76% yield), mp 100−102 C. 1H NMR (CDCl3, 400 MHz) δ 10.51 (bs,
1H), 8.88 (dd, J = 1.0, 7.5 Hz, 1H), 8.46 (dd, J = 1.6, 4.2 Hz, 1H), 8.07 (dd, J = 1.5, 8.3
Hz, 1H), 7.98 (s, 1H), 7.79−7.67 (m, 3H), 7.56−7.51 (m, 4H), 7.48−7.39 (m, 5H),
7.32−7.27 (m, 3H), 3.76 (s, 2H); 13C{1H}NMR (CDCl3, 100 MHz) δ 168.3, 148.2, 139.9,
138.7, 136.2, 135.7, 134.7, 132.9, 132.8, 131.7, 129.1, 128.6, 128.5, 128.2, 127.9, 127.9,
127.8, 127.8, 127.4, 126.7, 126.6, 121.7, 121.5, 120.4, 117.2, 116.7, 91.8, 91.2, 42.2. IR
(neat): 3343, 2924, 1683, 1526, 1486, 1424, 1385, 1327, 1264, 1162, 825, 791, 699
(cm-1); HRMS (EI) m/z: [M]+ calcd for C31H22N2O 438.1732; found 438.1727.
(E)-3-(4-Methoxybenzylidene)-5-phenyl-N-(quinolin-8-yl)pent-4-ynamide (4r). Colorless
oil (129.5 mg, 77% yield). 1H NMR (CDCl3, 400 MHz) δ 10.50 (bs, 1H), 8.85 (d, J = 7.4
Hz, 1H), 8.43 (d, J = 4.1 Hz, 1H), 8.08 (d, J = 8.2 Hz, 1H), 7.54−7.46 (m, 6H), 7.34−7.28
(m, 4H), 7.21 (s, 1H), 6.93 (d, J = 8.7 Hz, 2H), 3.80 (s, 3H), 3.72 (s, 2H); 13C{1H}NMR
(CDCl3, 100 MHz) δ 168.5, 159.5, 148.2, 139.5, 138.6, 136.1, 134.7, 131.8, 130.6, 128.3,
128.2, 128.2, 127.9, 127.3, 123.3, 121.7, 121.5, 116.7, 115.1, 114.1, 91.9, 90.3, 55.3, 42.3.
IR (neat): 3342, 2926, 1682, 1605, 1525, 1487, 1424, 1385, 1327, 1254, 1032, 826, 756
(cm-1); HRMS (EI) m/z: [M]+ calcd for C28H22N2O2 418.1681; found 418.1675.
(E)-3-(4-Chlorobenzylidene)-5-phenyl-N-(quinolin-8-yl)pent-4-ynamide (4s). White solid
o
(113.6 mg, 67% yield), mp 134−137 C. 1H NMR (CDCl3, 400 MHz) δ 10.44 (bs, 1H),
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8.83 (dd, J = 1.2, 7.4 Hz, 1H), 8.45 (dd, J = 1.4, 4.2 Hz, 1H), 8.10 (dd, J = 1.4, 8.3 Hz,
1H), 7.55−7.48 (m, 6H), 7.37−7.33 (m, 3H), 7.31−7.26 (m, 3H), 7.19 (s, 1H), 3.67 (s,
2H); 13C{1H}NMR (CDCl3, 100 MHz) δ 168.0, 148.2, 138.6, 138.3, 136.2, 134.6, 134.0,
131.8, 130.3, 128.8, 128.5, 128.3, 127.9, 127.3, 123.0, 121.8, 121.6, 117.8, 116.7, 91.2,
91.1, 42.1. IR (neat): 3344, 2922, 1683, 1526, 1487, 1424, 1327, 1165, 1094, 825, 791,
755 (cm-1); HRMS (EI) m/z: [M]+ calcd for C27H19N2OCl 422.1186; found 422.1193.
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(E)-3-(Naphthalen-2-ylmethylene)-5-phenyl-N-(quinolin-8-yl)pent-4-ynamide
(4t).
Yellow oil (154.9 mg, 88% yield). 1H NMR (CDCl3, 400 MHz) δ 10.49 (bs, 1H), 8.89 (dd,
J = 1.1, 7.6 Hz, 1H), 8.44 (dd, J = 1.6, 4.2 Hz, 1H), 8.07 (dd, J = 1.6, 8.3 Hz, 1H), 8.04 (s,
1H), 7.89−7.79 (m, 3H), 7.61 (dd, J = 1.6, 8.5 Hz, 1H), 7.55−7.44 (m, 6H), 7.41 (s, 1H),
7.33−7.26 (m, 4H), 3.80 (s, 2H); 13C{1H}NMR (CDCl3, 100 MHz) δ 168.3, 148.2, 139.8,
138.6, 136.2, 134.7, 133.3, 133.1, 132.9, 131.9, 128.5, 128.5, 128.4, 128.3, 128.2, 127.9,
127.6, 127.3, 126.8, 126.5, 126.4, 123.2, 121.7, 121.5, 117.4, 116.7, 91.6, 91.1, 42.3. IR
(neat): 3346, 2923, 1682, 1604, 1525, 1486, 1424, 1326, 1263, 825, 791, 756 (cm-1);
HRMS (EI) m/z: [M]+ calcd for C31H22N2O 438.1732; found 438.1737.
Procedure 6: Control Experiments. A reaction flask was charged with a mixture of
2-chloro-N-(quinolin-8-yl)acetamide (1a, 0.4 mmol), phenylacetylene (2a, 0.4 mmol, 1.0
equiv.), CuI (0.04 mmol, 10 mol%), Cs2CO3 (0.48 mmol, 1.2 equiv.), and DCM (1.0 mL)
under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 24 h.
The resultant mixture was evaporated under a reduced pressure to remove the solvent.
The product was purified through a silica gel column (eluent: petroleum ether/ethyl
acetate = 10:1). Mixture of allene and internal alkyne: >90% total yield.
A reaction flask was charged with a mixture of allene and internal alkyne (0.4 mmol),
phenylacetylene (2a, 0.8 mmol, 2 equiv.), CuI (0.04 mmol, 10 mol%),
1,10-phenanthroline (L1, 0.08 mmol, 20 mol%), Cs2CO3 (0.2 mmol, 0.5 equiv.), and
DCM (1.0 mL) under nitrogen atmosphere. The reaction mixture was stirred at room
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temperature for 24 h. The resultant mixture was evaporated under a reduced pressure to
remove the solvent. The product 3a was purified via silica gel chromatography (eluent:
petroleum ether/ethyl acetate = 10:1). 3a: 92% yield.
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A
reaction
flask
was
charged
with
a
mixture
of
2,2-dimethyl-4-phenyl-N-(quinolin-8-yl)but-3-ynamide (5, 0.4 mmol), phenylacetylene
(2a, 0.8 mmol, 2 equiv.), CuI (0.04 mmol, 10 mol%), 1,10-phenanthroline (L1, 0.08
mmol, 20 mol%), Cs2CO3 (0.48 mmol, 1.2 equiv.), and DCM (1.0 mL) under nitrogen
atmosphere. The reaction mixture was stirred at room temperature for 24 h. The resultant
mixture was evaporated under a reduced pressure to remove the solvent. The residue
obtained was separated through a silica gel column (eluent: petroleum ether/ethyl acetate
= 10:1). Starting material 5 was recovered.
A reaction flask was charged with a mixture of 2-chloroacetophenone (6, 0.4 mmol),
phenylacetylene (2a, 1.2 mmol, 3 equiv.), CuI (0.04 mmol, 10 mol%),
1,10-phenanthroline (L1, 0.08 mmol, 20 mol%), Cs2CO3 (0.48 mmol, 1.2 equiv.), and
DCM (1.0 mL) under nitrogen atmosphere. The reaction mixture was stirred at room
temperature for 24 h. The resultant mixture was evaporated under a reduced pressure to
remove the solvent. The residue obtained was separated through a silica gel column
(eluent: petroleum ether/ethyl acetate = 10:1). A mixture of allene and internal alkyne
was obtained.
Procedure 7: Gram-Scale Reaction. A reaction flask was charged with a mixture of
2-chloro-N-(quinolin-8-yl)acetamide (1a, 0.66 g, 3 mmol), phenylacetylene (2a, 9 mmol,
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3.0 equiv.), CuI (0.3 mmol, 10 mol%), 1,10-phenanthroline (L1, 0.6 mmol, 20 mol%),
Cs2CO3 (3.6 mmol, 1.2 equiv.), and DCM (8.0 mL) under nitrogen atmosphere. The
reaction mixture was stirred at room temperature for 48 h. The resultant mixture was
evaporated under a reduced pressure to remove the solvent. The product 3a was purified
via silica gel chromatography (eluent: petroleum ether/ethyl acetate = 10:1). 3a: 82%
yield (0.956 g).
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Procedure 8: Deprotection Reaction.11a A reaction flask was charged with a mixture of
(E)-3-benzylidene-5-phenyl-N-(quinolin-8-yl)pent-4-ynamide (3a, 0.4 mmol), BF3·Et2O
(2.4 mmol, 6 equiv.), and EtOH (4 mL) under nitrogen atmosphere. The reaction mixture
was stirred at 100 ºC for 15 h. The resultant mixture was evaporated under a reduced
pressure to remove the solvent. The product 7 was purified via silica gel chromatography
1
(eluent: petroleum ether/ethyl acetate = 20:1). 7: 82% yield. Colorless oil, H NMR
(CDCl3, 400 MHz) δ 7.47 (dd, J =2.9, 6.4 Hz, 2H), 7.39−7.27 (m, 8H), 7.15 (s, 1H), 4.23
(q, J = 7.1 Hz, 2H), 3.47 (s, 2H), 1.29 (t, J = 7.1 Hz, 3H); 13C{1H}NMR (CDCl3, 100
MHz) δ 170.6, 138.9, 135.9, 131.6, 128.7, 128.5, 128.3, 128.3, 127.9, 123.2, 117.2, 90.8,
89.8, 61.1, 38.2, 14.3. IR (neat): 2916, 2848, 1736, 1466, 1371, 1236, 1125, 1019, 935,
875, 718 (cm-1); HRMS (EI) m/z: [M]+ calcd for C20H18O2 290.1307; found 290.1304.
SUPPORTING INFORMATION
The Supporting Information is available free of charge on the ACS Publications website.
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Optimization studies, mechanistic study data, X-ray data and NMR spectra. (PDF)
AUTHOR INFORMATION
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Corresponding Author
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*E-mail: fengxiujuan@dlut.edu.cn; mingbao@dlut.edu.cn
Author Contributions
#L.Z. and H.G. contributed equally to this work.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
We are grateful to the National Natural Science Foundation of China (Nos. 21573032 and
21773021) for their financial support. This work was also supported by the Fundamental
Research Funds for the Central Universities (No. DUT20ZD217). This work was also
supported by LiaoNing Revitalization Talents Program (XLYC1802030).
REFERENCES
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Cross-Addition of Terminal Alkynes to Ynol Ethers and Synthesis of
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The Sonogashira Reaction: A Booming Methodology in Synthetic Organic
Chemistry. Chem. Rev. 2007, 107, 874–922.
(4) For selected examples, see: (a) Zhou, L.; Ye, F.; Ma, J.; Zhang, Y.; Wang, J.
Palladium-Catalyzed Oxidative Cross-Coupling of N-Tosylhydrazones or
Diazoesters with Terminal Alkynes: A Route to Conjugated Enynes. Angew. Chem.,
Int. Ed. 2011, 50, 3510–3514. (b) Zhang, Z.; Zhou, Q.; Yu, W.; Li, T.; Wu, G.;
Zhang, Y.; Wang, J. Cu(I)-Catalyzed Cross-Coupling of Terminal Alkynes with
Trifluoromethyl Ketone N-Tosylhydrazones: Access to 1,1-Difluoro-1,3-Enynes.
Org. Lett. 2015, 17, 2474–2477.
(5) For selected examples, see: (a) Trost, B. M.; Chan, C.; Ruhter, G. Metal-Mediated
Approach to Enynes. J. Am. Chem. Soc. 1987, 109, 3486–3487. (b) Xu, C.; Du, W.;
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