Copper-Catalyzed Regioselective and Stereoselective Coupling of Grignard Reagents with Pent-1-en-4-yn-3-yl Benzoates: A Shortcut to (Z) -1,5-Disubstituted Pent-3-en-1-ynes from Accessible Starting Materials

Article abstract of DOI:10.1021/acs.joc.8b02275

Copper-catalyzed coupling of Grignard reagents with pent-1-en-4-yn-3-yl benzoates occurs regioselectively at the terminal alkenyl carbon rather than the alkynyl site, leading to the stereoselective formation of unexpected (Z)-1,5-disubstituted pent-3-en-1-ynes without generation of the initially expected alkenyl allene products. By using easily accessible starting materials, this reaction can provide direct access to thermodynamically unfavorable Z-configured enynes, which widely exist in many bioactive natural products, such as the anti-inflammatory components in henna.

Full text of DOI:10.1021/acs.joc.8b02275

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Note
Copper-Catalyzed Regio- and Stereo-Selective Coupling of Grignard
Reagents with Pent-1-en-4-yn-3-yl Benzoates: A Shortcut to (Z)-1,5-
Disubstituted Pent-3-en-1-ynes from Accessible Starting Materials
Fenglin Chen, Yanjiao Chen, Hongen Cao, Qing Xu, and Lei Yu
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b02275 • Publication Date (Web): 18 Oct 2018
Downloaded from http://pubs.acs.org on October 19, 2018
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Copper-Catalyzed Regio- and Stereo-Selective
Coupling of Grignard Reagents with Pent-1-en-4-yn-
3-yl Benzoates: A Shortcut to (Z)-1,5-Disubstituted
Pent-3-en-1-ynes from Accessible Starting Materials
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Fenglin Chen,†,‡,§,# Yanjiao Chen,†,‡,# Hongen Cao,†,‡ Qing Xu‡ and Lei Yu,*,†,‡
† Jiangsu Key Laboratory of Zoonosis, Yangzhou University, Yangzhou, 225009, China
‡
School of Chemistry and Chemical Engineering, Yangzhou University, Yangzhou, 225002,
China
§ School of Chemistry and Chemical Engineering, Nanjing University, Nanjing, 210093, China
ABSTRACT: Copper-catalyzed coupling of Grignard reagents with pent-1-en-4-yn-3-yl
benzoates occurs regioselectively at the terminal alkenyl carbon rather than the alkynyl site,
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leading to the stereoselective formation of unexpected (Z)-1,5-disubstituted pent-3-en-1-ynes
without generation of the initially expected alkenyl allene products. By using easily accessible
starting materials, this reaction can provide direct access to thermodynamically unfavorable Z-
configured enynes, which widely exist in many bioactive natural products, such as the anti-
inflammatory components in henna.
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Enyne structures are useful synthetic building blocks that have been widely employed in the
construction of a variety of organic skeletons, such as allenes,1 dienes,2 aromatic rings,3
heterocycles,4 etc.5 Among the enynes, (Z)-1,5-disubstituted pent-3-en-1-ynes (Z-PEYs, Figure 1)
are a class of important compounds not only for their broad applications in synthesis but also for
their versatile bioactivities. Recently, several components isolated from henna (Lawsoniainermis
L., Figure 1) were corroborated to be Z-PEYs possessing impressive anti-inflammatory
activities.6 However, the quantities of these bioactive natural products are very limited through
the isolation from henna. This limitation encouraged the synthetic chemists to develop practical
methods for the synthesis of these enynes starting from cheap and easily available chemicals.
Figure 1. Z-PEYs (left) separated from henna (right).
From the retro-synthetic perspective, the structure of Z-PEYs can be considered as the
combination of an enyne moiety and an ally moiety (Figure 1). Although both moieties can be
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readily built via a variety of methods,7 the stereo-selective construction of Z-PEYs has not been
well established. To our knowledge, the synthesis of Z-PEYs was only sporadically reported in
the literature. For example, one method was achieved by dehydration of propynyl alcohols and as
an isolated example in enyne preparation.8 Although this method required high loadings of the
expensive catalysts [Pd(PPh3)4 (10 mol %)], toxic or corrosive dehydrants such as SnCl2 (150
mol %) and polyphosphoric acid trimethylsilyl ester (PPSE), it gave only low yields of the
products and low Z/E selectivities (Scheme 1, path A). There are also other examples on the
reactions of pent-1-en-4-yn-3-ols and their silicon ethers to produce PEYs,9 but despite the use of
expensive catalysts such as Au(III),9a many of them suffered the low selectivity of the target
product while the thermodynamically stable E-isomers were usually obtained as the major
products.9c Wu et. al. have developed a palladium-catalyzed cross coupling of 1-chlorobut-1-en-
3-ynes with 9-benzyl-9-bora-bicyclo[3.3.1]nonane(B-benzyl-9-BBN) to prepare Z-PEYs
(Scheme 1, path B).10 However, the low availability of the Z-configured substrates and the high
price of catalysts and benzyl sources limited its further applications in large-scale production.
Besides, the Z-PEYs might be synthesized via Sonogashira couplings of terminal alkynes with
vinyl halides, but despite the use of expensive Pd catalysts, the Z-configured vinyl halides as
starting materials were not easy to obtain.11 Recently, we accidentally found that catalyzed by
copper, the Grignard reagents could react with pent-1-en-4-yn-3-yl benzoates to produce Z-PEYs
in good yields with high regio- and stereo-selectivities (Scheme 1, path C). The method afforded
a direct access to the useful analogues from available starting materials such as the terminal
alkene, acrolein, halohydrocarbons, etc. Herein, we wish to report our findings.12
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Scheme 1. Methods for the Synthesis of Z-PEYs
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(A)
Ph
OH
Ph
Pd(PPh3)4/SnCl2
DMI, 70 oC (ref 8a)
or PPSE (ref 8b)
Ph
Ph
53%, Z/E = 80/20
or 54%, Z/E = 67/33
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(B)
Ar
B-benzyl-9-BBN
Pd(PPh3)4/Cs2CO3/H2O Ar
60 oC, 12 h
Ph
Cl
50-82% (ref. 10)
(C)
R1
OBz
R2MgX, CuI (2 mol %)
R1
(this work)
ether, 0 oC to rt
R2
overnight, N2
We initially synthesized the substrate 1a via the classical method13 and tested its reaction with
PhMgBr in the presence of CuBr catalyst. However, PEY 4a was obtained in 24% yield, while
the desired products such as alkenyl allene 2a and pent-1-en-4-yne 3a were not observed
(Scheme 2). It was notable that the thermodynamically unstable Z-isomer was the major product
and that the Z/E selectivity of the reaction could reach 92/8.
Scheme 2. Reaction of 1a with PhCuMgBr
Since Z-PEYs are useful compounds for anti-inflammatory drug developments, we reasoned
that it would be of practical significance to optimize the conditions of the above reaction (Table
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1). Screenings of catalysts indicated that CuI was a better catalyst (entries 3 vs 1–2, 4) and that
the reaction could not happen without catalyst (entry 5). Although substrate 1a was not
completely converted in these reactions, we failed to enhance the 4a yield by prolonging the
reaction time. In the CuI-catalyzed reaction of 1a with PhMgBr (entry 3), 4a was obtained in
only 37% yield after 48 h and biphenyl, which was the coupling by-product of the Grignard
reagent in the presence of Cu catalyst could be clearly observed in TLC. A series of substrates (1)
were then synthesized and tested to examine the effects of the protection group such as the
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acyloxy (AcO), benzoyloxy (BzO),
pivaloyloxy (PivO), pentanoyloxy (n-BuCO2),
methoxymethoxy (MOMO) or OCO2Me (entries 6-10). Despite a slight decrease in Z/E
selectivity, BzO should be a better protection group, and with 1-phenylpent-4-en-1-yn-3-yl
benzoate (1c) as the starting material, the yield of 4a was enhanced to 76% (entry 7). Further
o
screenings demonstrated that by cooling with ice-water (0 C to rt), the yield of 4a could be
enhanced to 81% (entries 11 vs 7, 12). Excess Grignard reagent was necessary for the reaction
because it might be consumed by the side-reactions such as the coupling reaction to produce
biphenyl in the presence of copper, and 2 equivalent of PhMgBr versus 1c was found to be more
preferable (entries 11 vs 13–15).
Table 1. Condition Optimizationsa
entry
cat.
R (1a)
T
4a/% (Z/E)c
26 (88/12)
24 (92/8)
1
2
CuCl
CuBr
Me (1a)
Me (1a)
rtb
rt
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3
CuI
CuBr2
-
Me (1a)
rt
rt
rt
rt
rt
rt
rt
35 (94/6)
23 (87/13)
0 (-)
4
Me (1a)
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5
Me (1a)
6
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
Ac (1b)
55 (80/20)
76 (76/24)
45 (70/30)
58 (75/25)
0 (-)
7
Bz (1c)
8
Piv (1d)
n-BuC(O) (1e)
9
10
11
12
13d
14d
MOM or CO2Me (1f-g) rt
Bz (1c)
Bz (1c)
Bz (1c)
Bz (1c)
Bz (1c)
0oC-r.t.
81 (80/20)
59 (76/24)
77 (74/26)
67 (78/22)
52 (77/23)
-15oC-r.t.
0oC-r.t.
0oC-r.t.
0oC-r.t.
15d
a
Unless otherwise noted, the reaction conditions were as follows: 1 mmol of 1, 2 mmol of
PhMgBr, 0.02 mmol of catalyst and 4 mL of ether (solvent) were employed. bRoom temperature
o
c
1
(25 C). Isolated yields based on 1 outside the parentheses; Z/E ratio calculated from H NMR
d
inside the parentheses. 3 mmol (entry 13), 1.5 mmol (entry 14) or 1.2 mmol (entry 15) of
PhMgBr was employed respectively.
A series of Z-PEYs 4 were then synthesized to examine the scope of this reaction (Table 2).
Generally, aryl Grignard reagents afforded the desired product 4 in acceptable yields and Z/E
selectivities (entries 1–18 and 28–31). For alkyl Grignard reagents, the results were quite
different depending on substituent geometry. The linear alkyl Grignard reagents resulted in
decreased yields of the products 4 (entries 19–25). In contrast, the product yields of the reactions
with cyclic alkyl Grignard reagents were enhanced (entries 26–27). The anions of Grignard
reagents also affected product yields and the results showed some rules depending on the
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substitutes in substrate: For Grignard reagents bearing electron donation groups, bromo anion led
to a slightly higher product yield than the reactions with the Grignard reagents with iodo anion
(entries 3 vs 4; 5 vs 6; 7 vs 8); But for Grignard reagents bearing electro withdrawing groups, the
rules were completely reversed (entries 9 vs 10, 11 vs 12, 13 vs 14). It was interesting that
although the reaction of CH3MgBr with 1a led to very poor 4k yield at 12%, after adding one
equivalent of MgI2 (vs the Grignard reagent), the product yield could be enhanced to 41%. This
result demonstrated that the reaction might be influenced by the anion effect, which might be
exerted on its interaction with the catalytic metal Cu(I). Moreover, both CH3MgBr and CH3MgI
led to poor Z/E selectivity in product, probably due to the too high reactivity and low steric
hindrance of methyl anion that allowed its attack from both direction of the reaction site.
Substituent effects on alkynes were investigated and it was found that alkyl substitutes on alkyne
such as n-Butyl led to an extremely high yield at 98% (entry 28). Electron-deficient or -enriched
aryl substituted alkyl substrates both led to the desired product 4 smoothly in moderate to good
yields (entries 29–31).
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Table 2. Synthesis of Z-PEYs 4a
entry
R1
R2MgX
4: yield/% (Z/E)b
4a: 81 (80/20)
4a: 99 (83/17)
4b: 69 (70/30)
4b: 57 (69/31)
1
2
3
4
C6H5
C6H5
C6H5
C6H5
C6H5MgBr
C6H5MgI
p-MeC6H4MgBr
p-MeC6H4MgI
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C6H5
o-MeC6H4MgBr
o-MeC6H4MgI
p-MeOC6H4MgBr
p-MeOC6H4MgI
p-FC6H4MgBr
p-FC6H4MgI
p-ClC6H4MgBr
p-ClC6H4MgI
o-ClC6H4MgBr
o-ClC6H4MgI
3,5-(CF3)2C6H3MgBr
1-C10H8MgBr
1-C10H8MgI
2-C10H8MgBr
CH3MgBr
4c: 88 (86/14)
4c: 86 (79/21)
4d: 61 (78/22)
4d: 55 (77/23)
4e: 66 (92/8)
4e: 76 (82/18)
4f: 83 (90/10)
4f: 84 (89/11)
4g: 77 (91/9)
4g: 93 (91/9)
4h: 75 (81/19)
4i: 70 (96/4)
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C6H5
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C6H5
8
C6H5
9
C6H5
10
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C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
4i: 49 (95/5)
C6H5
4j: 26 (73/27)
4k: 12 (31/69)
4k: 54 (53/47)
4l: 36 (81/19)
4l: 62 (83/17)
4m: 37 (87/13)
4n: 33 (89/11)
4o: 34 (87/13)
4p: 64 (85/15)
4q: 65 (90/10)
4r: 98 (81/19)
4s: 56 (67/33)
4t: 82 (72/28)
4u: 58 (81/19)
C6H5
C6H5
CH3MgI
C6H5
C2H5MgBr
C6H5
C2H5MgI
C6H5
n-C4H9MgBr
n-C8H17MgBr
i-C3H7MgBr
c-C5H9MgBr
c-C6H11MgBr
C6H5MgBr
C6H5
C6H5
C6H5
C6H5
n-C4H9
p-ClC6H4
p-MeC6H4
p-MeOC6H4
C6H5MgBr
C6H5MgBr
C6H5MgBr
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b
aReactions were performed under the conditions described by Table 1, entry 11. Isolated yields
based on 1 outside the parentheses; Z/E ratio calculated from 1H NMR inside the parentheses.
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A series of typical substrates with similar structures to 1 were then employed to react with
PhMgBr in the presence of CuI catalyst. However, the reactions of simple allylic esters 5 and 6,
biallylic ester 7, terminal substituted alkene 8 or terminal unsubstituted alkyne 9 with PhMgBr
all led to a series of unidentified by-product complexes (Scheme 3), as observed by thin layer
chromatography (TLC). The result showed that carbon-carbon triple bond in substrate was
necessary to direct the reaction and terminal substituted alkynyl and unsubstituted alkenyl
moieties were all crucial structures for substrate of the reaction.
Scheme 3. Control Experiments
OBz
OBz
OBz
Bun
PhMgBr
CuI (2 mol %)
ether, 0 oC to rt, N2
Ph
5
6
7
complexes
Ph
BzO
BzO
Me
overnight
Ph
9
8
Ph
On the basis of the above experimental results as well as literature precedent,14 a plausible
mechanism is given below. Reactions of Grignard reagent with CuX catalyst generate copper
reagent 10,14 which then coordinates with the carbon-carbon triple bond of substrate 1 and gives
the organometallic intermediate 11. With the assistance of X- anion that existed abundantly in
solution from Grignard reagent or catalyst, intermediate 11 rapidly afforded the product 4 and
regenerated catalyst CuX. Cooperation of carbon-carbon triple bond with copper should be the
key point to facilitate the reaction and determine the configuration of product 4 (Scheme 4).
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Scheme 4. Possible Mechanisms
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In conclusion, we developed a concise method for the synthesis of Z-1,5-disubstitutedpent-3-
en-1-yne derivatives, which exist in natural products isolated from henna and were of good
application potential in anti-inflammatory drug development. Compared with known synthetic
routes, the method unexpectedly constructed the thermodynamically disfavored Z-configured
molecules with high regio- and stereo- selectivities from easily accessible starting materials.
Investigations on the application of these analogues are underway in our laboratory.
EXPERIMENTAL SECTION
General Methods. Substrate 1 were prepared through the reaction of alkynyl magnesium
bromide (Grignard reagent) with acrylaldehyde derivatives and then with benzoyl chloride for
the protection of hydroxide. Similar experimental details were described in literature.13 Grignard
reagents were purchased or prepared from the halohydrocarbons with magnesium powder via
standard procedure. Other chemicals, catalysts and solvents were all purchased and the solvents
were dehydrated before use. Flash column chromatogram separations were performed with silica
gel G as the stationary phases. All reactions were monitored by TLC (silica gel GF254 plate)
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and/or GC analysis. 1,5-disubstituted pent-3-en-1-ynes 4 were all purified by column
chromatogram. In most cases, the Z and E isomers of 4 were unable to separate and their ratios
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1
1
could be calculated from H NMR spectra by comparing the peak areas of the allylic CH2. H
and 13C NMR and NOESY spectra were recorded on a Bruker Avance 600 instrument (600 MHz
for 1H and 150 MHz for 13C NMR spectroscopy) by using CDCl3 as the solvent and Me4Si as the
1
13
internal standard. Chemical shifts for H and C NMR were referred to internal Me4Si (0 ppm)
and J-values were shown in Hz. Melting points were measured using a WRS-2A digital
instrument. Mass spectra were measured on a Thermo Trace DSQ II or a Shimadzu GCMS-
QP2010 Ultra spectrometer (EI). Elemental analysis was performed on an Elementar Vario EL
cube instrument. HRMS (ESI or APCI) analysis was measured on a Bruker micro TOF-Q II or
Agilent Q-TOF 6520 instrument.
General Procedure for Preparation of 4. The solution of Grignard reagent (2 mmol) in ether (4
o
mL) was cooled to 0 C with ice-water bath. Under nitrogen protection, 3.8 mg of CuI (0.02
mmol) was added. The solution was stirred for 10 min and turned black. Then, a solution of 1 (1
mmol) in ether (2 mL) was slowly injected. The mixture was stirred overnight and the
temperature slowly rose to room temperature. The reaction was quenched by a solution of
saturated NH4Cl (10 mL) and extracted by ether (5 mL, 3 times). The combined organic layer
was dehydrated by Na2SO4. The solvent could be evaporated under vacuum and the residue was
purified through flash column chromatogram (eluent: petroleum ether).
Characterization of the Products. (Z)-Pent-3-en-1-yne-1,5-diyldibenzene (4a). 215.8 mg, 99%
yield. Oil. IR (film): νmax 3061, 3027, 2910, 2192, 1662, 1598, 1490, 1452, 1393, 1280, 1177,
1070, 1029, 955, 915, 829, 755, 691 cm-1; H NMR (600 MHz, CDCl3, TMS): δ 7.47–7.45 (m,
1
2H), 7.32–7.29 (m, 5H), 7.26 (d, J = 7.2 Hz, 2H), 7.21 (t, J = 7.2 Hz, 1H), 6.12 (dt, J = 7.8 Hz, J
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= 10.8 Hz, 1H), 5.80 (d, J = 10.8 Hz, 1H), 3.75 (d, J = 7.8 Hz, 2H); C{1H} NMR (150 MHz,
CDCl3): δ 141.9, 139.8, 131.6, 128.6, 128.4, 128.2, 126.3, 123.5, 110.0, 93.8, 86.3, 36.8; MS (EI,
70 eV): m/z (%) 218 (100) [M+], 217 (92), 202 (50); Known compound.10
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(Z)-1-Methyl-4-(5-phenylpent-2-en-4-yn-1-yl)benzene (4b). 160.1 mg, 69% yield. Oil. IR
(film): νmax 3022, 2921, 2191, 1732, 1662, 1597, 1513, 1489, 1442, 1262, 1178, 1108, 1023, 956,
915, 805, 756, 690 cm-1; 1H NMR (600 MHz, CDCl3, TMS): δ 7.46–7.44 (m, 2H), 7.31–7.25 (m,
3H), 7.14 (d, J = 8.4 Hz, 2H), 7.09 (d, J = 7.8 Hz, 2H), 6.09 (dt, J = 7.8 Hz, J = 10.8 Hz, 1H),
5.77 (d, J = 10.8 Hz, 1H), 3.70 (d, J = 7.8 Hz, 2H), 2.30 (s, 3H); 13C{1H} NMR (150 MHz,
CDCl3): δ 142.4, 136.8, 135.9, 131.7, 129.4, 128.6, 128.5, 128.3, 123.7, 109.8, 93.9, 86.5, 36.5,
21.2; MS (EI, 70 eV): m/z (%) 232 (99) [M+], 217 (100), 215 (79); HRMS (ESI-TOF) m/z:
[M+H]+ Calcd for C18H17 233.1325; Found 233.1320.
(Z)-1-Methyl-2-(5-phenylpent-2-en-4-yn-1-yl)benzene (4c). 204.2 mg, 88% yield. Oil. IR
(film): νmax 3021, 2925, 2191, 1949, 1801, 1733, 1663, 1596, 1490, 1442, 1394, 1278, 1175,
1
1107, 1028, 957, 913, 843, 753, 690 cm-1; H NMR (600 MHz, CDCl3, TMS): δ 7.45–7.44 (m,
2H), 7.28–7.24 (m, 4H), 7.13-7.11 (m, 3H), 5.99 (dt, J = 7.2 Hz, J = 10.8 Hz, 1H), 5.76 (d, J =
10.8 Hz, 1H), 3.71 (d, J = 7.2 Hz, 2H), 2.33 (s, 3H); 13C{1H} NMR (150 MHz, CDCl3): δ 141.6,
138.1, 136.6, 131.7, 130.5, 129.3, 128.6, 128.4, 126.7, 126.4, 123.7, 110.0, 94.3, 86.5, 34.9, 19.8;
MS (EI, 70 eV): m/z (%) 232 (65) [M+], 217 (100), 215 (71); HRMS (ESI-TOF) m/z: [M+H]+
Calcd for C18H17 233.1325; Found 233.1322.
(Z)-1-Methoxy-4-(5-phenylpent-2-en-4-yn-1-yl)benzene (4d). 151.5 mg, 61% yield. Oil. IR
(film): νmax 3029, 2907, 2834, 2199, 1952, 1883, 1723, 1610, 1511, 1463, 1441, 1301, 1247,
1177, 1107, 1035, 957, 915, 820, 756, 691 cm-1; 1H NMR (600 MHz, CDCl3, TMS): δ 7.46–7.44
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(m, 2H), 7.29–7.28 (m, 3H), 7.16 (d, J = 8.4 Hz, 2H), 6.83 (d, J = 8.4 Hz, 2H), 6.08 (dt, J = 7.2
Hz, J = 10.8 Hz, 1H), 5.76 (d, J = 10.8 Hz, 1H), 3.74 (s, 3H), 3.67 (d, J = 7.8 Hz, 2H); 13C{1H}
NMR (150 MHz, CDCl3): δ 158.3, 142.5, 131.6, 129.6, 128.8, 128.5, 128.3, 123.6, 114.1, 109.7,
93.8, 86.5, 55.3, 35.9; MS (EI, 70 eV): m/z (%) 248 (100) [M+], 233 (69), 202 (65); HRMS (ESI-
TOF) m/z: [M+H]+ Calcd for C18H17O 249.1274; Found 249.1263.
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(Z)-1-Fluoro-4-(5-phenylpent-2-en-4-yn-1-yl)benzene (4e). 179.6 mg, 76% yield. Oil. IR
(film): νmax 3110, 2923, 2190, 1888, 1725, 1661, 1601, 1509, 1442, 1392, 1224, 1158, 1096,
1
1027, 979, 916, 824, 757, 691 cm-1; H NMR (600 MHz, CDCl3, TMS): δ 7.46–7.44 (m, 2H),
7.32–7.27 (m, 3H), 7.20-7.18 (m, 2H), 6.97 (t, J = 8.4 Hz, 2H), 6.06 (dt, J = 7.2 Hz, J = 10.8 Hz,
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1H), 5.79 (d, J = 10.2 Hz, 1H), 3.69 (d, J = 7.8 Hz, 2H); C{1H} NMR (150 MHz, CDCl3): δ
161.6 (d, JC-F = 242.6 Hz), 141.6, 135.4 (d, JC-F = 3.0 Hz), 131.6, 130.0 (d, JC-F = 8.0 Hz), 128.4,
128.3, 123.4, 115.4 (d, JC-F = 21.2 Hz), 110.2, 94.0, 86.1, 35.9; MS (EI, 70 eV): m/z (%) 236
(100) [M+], 235 (44), 215 (41); HRMS (APCI-TOF) m/z: [M-H]- Calcd for C17H12F 235.0929;
Found 235.0910.
(Z)-1-Chloro-4-(5-phenylpent-2-en-4-yn-1-yl)benzene (4f). 212.3 mg, 84% yield. Oil. IR
(KBr): νmax 3027, 2913, 1896, 1666, 1595, 1490, 1407, 1177, 1091, 1015, 914, 841, 805, 755,
690 cm-1; 1H NMR (600 MHz, CDCl3, TMS): δ 7.44–7.43 (m, 2H), 7.28–7.27 (m, 3H), 7.23 (d, J
= 8.4 Hz, 2H), 7.14 (d, J = 8.4 Hz, 2H), 6.02 (dt, J = 7.2 Hz, J = 10.8 Hz, 1H), 5.79 (d, J = 10.2
Hz, 1H), 3.67 (d, J = 7.8 Hz, 2H); 13C{1H} NMR (150 MHz, CDCl3): δ 141.2, 138.2, 132.2,
131.6, 130.0, 128.8, 128.5, 128.4, 123.5, 110.6, 94.2, 86.2, 36.1; MS (EI, 70 eV): m/z (%) 252
(83) [M+], 217 (84), 215 (100); HRMS (APCI-TOF) m/z: [M-H]- Calcd for C17H12Cl 251.0633;
Found 251.0623.
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(Z)-1-Chloro-2-(5-phenylpent-2-en-4-yn-1-yl)benzene (4g). 235.4 mg, 93% yield. Oil. IR
(KBr): νmax 3059, 3026, 2924, 2191, 1801, 1662, 1594, 1572, 1489, 1442, 1393, 1264, 1126,
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1052, 914, 834, 752, 690 cm-1 1H NMR (600 MHz, CDCl3, TMS): δ 7.35–7.34 (m, 2H), 7.23–
;
7.16 (m, 5H), 7.06-6.99 (m, 2H), 5.98 (dt, J = 7.8 Hz, J = 10.2 Hz, 1H), 5.70 (d, J = 10.8 Hz, 1H),
3.75 (d, J = 7.8 Hz, 2H); 13C{1H} NMR (150 MHz, CDCl3): δ 140.0, 137.5, 134.1, 131.6, 130.5,
129.6, 128.5, 128.3, 127.9, 127.1, 123.6, 110.9, 94.5, 86.2, 34.5; MS (EI, 70 eV): m/z (%) 252
(12) [M+], 217 (100), 215 (77); HRMS (APCI-TOF) m/z: [M-H]- Calcd for C17H12Cl 251.0633;
Found 251.0627.
(Z)-1-(5-Phenylpent-2-en-4-yn-1-yl)-3,5-bis(trifluoromethyl)benzene (Z-4h). 215.9 mg, 61%
yield. Oil. IR (film): νmax 2926, 2193, 1951, 1802, 1664, 1622, 1490, 1376, 1279, 1173, 1134,
1
903, 842, 757, 690 cm-1; H NMR (600 MHz, CDCl3, TMS): δ 7.74 (s, 1H), 7.71 (s, 2H), 7.46–
7.45 (m, 2H), 7.31–7.30 (m, 3H), 6.08 (dt, J = 7.8 Hz, J = 10.2 Hz, 1H), 5.92 (d, J = 10.8 Hz,
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1H), 3.85 (d, J = 7.2 Hz, 2H); C{1H} NMR (150 MHz, CDCl3): δ 142.1, 136.0, 134.1, 132.2,
131.7, 128.5 (d, JC-F = 21.6), 126.5, 126.3 (q, JC-F = 260.0 Hz), 125.8 (d, JC-F = 2.6 Hz), 124.2,
110.1, 94.9, 86.5, 34.6; MS (EI, 70 eV): m/z (%) 354 (100) [M+], 215 (33), 115 (21); HRMS
(APCI-TOF) m/z: [M-H]- Calcd for C19H11F6 353.0770; Found 353.0761.
(E)-1-(5-Phenylpent-2-en-4-yn-1-yl)-3,5-bis(trifluoromethyl)benzene (E-4h). 50.4 mg, 14%
yield. Oil. IR (film): νmax2927, 2200, 1952, 1801, 1733, 1623, 1491, 1377, 1278, 1173, 1133,
1037, 958, 902, 843, 802, 757, 683 cm-1; 1H NMR (600 MHz, CDCl3, TMS): δ 7.68 (s, 1H), 7.57
(s, 2H), 7.36–7.34 (m, 2H), 7.23–7.22 (m, 3H), 6.24 (dt, J = 7.2 Hz, J = 15.6 Hz, 1H), 5.73 (d, J
= 15.6 Hz, 1H), 3.54 (d, J = 7.2 Hz, 2H); MS (EI, 70 eV): m/z (%) 354 (100) [M+], 215 (33), 115
(22); HRMS (APCI-TOF) m/z: [M-H]- Calcd for C19H11F6 353.0770; Found 353.0761.
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(Z)-1-(5-Phenylpent-2-en-4-yn-1-yl)naphthalene (4i). 187.9 mg, 70% yield. Oil. IR (film): νmax
3055, 2906, 1948, 1804, 1718, 1596, 1489, 1441 1394, 1259, 1164, 1070, 1026, 966, 913, 856,
778, 755, 690 cm-1; 1H NMR (600 MHz, CDCl3, TMS): δ 8.14 (d, J = 8.4 Hz, 1H), 7.81 (d, J =
7.8 Hz, 1H),7.70 (t, J = 4.8 Hz, 1H), 7.50-7.47 (m, 3H), 7.43 (t, J = 7.2 H, 1H), 7.36 (d, J = 4.8
Hz, 2H), 7.29-7.26 (m, 3H), 6.12 (dt, J = 7.2 Hz, J = 10.8 Hz, 1H), 5.80 (d, J = 10.2 Hz, 1H),
4.15 (d, J = 7.8 Hz, 2H); 13C{1H} NMR (150 MHz, CDCl3): δ 142.3, 138.8, 131.9, 131.7, 131.5,
128.7 (×2), 128.5, 128.4, 124.4, 123.1, 122.6, 120.4 (×3), 112.2, 95.0, 85.4, 36.0; MS (EI, 70
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eV): m/z (%) 268 (100) [M+], 267 (65), 252 (65); HRMS (ESI-TOF) m/z: [M+H]+ Calcd for
C21H17 269.1325; Found 269.1327.
(Z)-2-(5-Phenylpent-2-en-4-yn-1-yl)naphthalene (4j). 69.7 mg, 26% yield. Oil. IR (film): νmax
3052, 2923, 2199, 1924, 1718, 1596, 1489, 1441, 1391, 1265, 1024, 953, 853, 813, 754, 690 cm-
1; 1H NMR (600 MHz, CDCl3, TMS): δ7.84-7.82 (m, 1H), 7.77-7.75 (m, 1H),7.69-7.66 (m, 3H),
7.57 (s, 1H), 7.39-7.37 (m, 3H), 7.33-7.30 (m, 3H), 6.07 (dt, J = 7.2 Hz, J = 10.8 Hz, 1H), 5.74
(d, J = 10.2 Hz, 1H), 3.80 (d, J = 7.2 Hz, 2H); 13C{1H} NMR (150 MHz, CDCl3): δ 141.8, 137.3,
133.8, 132.3, 131.6, 128.5, 128.4, 128.3, 127.7, 127.6, 127.4, 126.8, 126.1, 125.5, 123.6, 110.2,
94.1, 86.4, 37.0; MS (EI, 70 eV): m/z (%) 268 (100) [M+], 267 (82), 252 (68); HRMS (ESI-TOF)
m/z: [M+H]+ Calcd for C21H17 269.1325; Found 269.1314.
1-(Hex-3-en-1-ynyl)benzene (4k). 84.2 mg, 54% yield. Oil. IR (film): νmax 3021, 2967, 2934,
2876, 2190, 1951, 1889, 1717, 1662, 1596, 1490, 1442, 1375, 1261, 1157, 1070, 1028, 955, 914,
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874, 800, 756, 690 cm-1; Z-isomer: H NMR (600 MHz, CDCl3, TMS): δ 744-7.41 (m, 2H),
7.30-7.27 (m, 3H), 5.96 (dt, J = 7.8 Hz, J = 10.2 Hz, 1H), 5.64 (d, J = 10.8 Hz, 1H), 2.19-2.15
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(m, 2H), 1.06 (t, J = 7.2 Hz, 3H); E-isomer: H NMR (600 MHz, CDCl3, TMS): δ 744-7.41 (m,
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2H), 7.30-7.27 (m, 3H), 6.28 (dt, J = 6.6 Hz, J = 15.6 Hz, 1H), 5.69 (d, J = 15.6 Hz, 1H), 2.43-
2.38 (m, 2H), 1.04 (t, J = 7.8 Hz, 3H); Z and E mixtures: 13C{1H} NMR (150 MHz, CDCl3):
δ146.5, 145.8, 131.5, 131.4, 128.3 (×2), 128.0, 127.9, 123.7(×2), 108.8, 108.4, 93.5, 88.4, 88.0,
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86.4, 26.4, 23.9, 13.5, 13.0; MS (EI, 70 eV): m/z (%) 156 (100) [M+], 115 (85), 141 (82); Known
compound (Z: ref. 15a; E: ref.15b).
(Z)-Hept-3-en-1-yn-1-ylbenzene (4l). 105.4 mg, 62% yield. Oil. IR (film): νmax 2967, 2933,
1
2873, 2201, 1718, 1599, 1490, 1445, 1379, 1281, 1172, 1071, 1027, 971, 757, 691 cm-1; H
NMR (600 MHz, CDCl3, TMS): δ 7.44-7.43 (m, 2H), 7.31-7.29 (m, 3H), 5.98 (dt,J = 7.2 Hz, J =
10.8 Hz, 1H), 5.69 (d, J = 10.8 Hz, 1H), 2.40-2.36 (m, 2H), 1.51-1.47 (m, 2H), 0.97 (t, J = 7.2
Hz, 3H); 13C{1H} NMR (150 MHz, CDCl3): δ 144.1, 131.4, 128.3, 128.0, 123.8, 109.2, 93.4,
86.5, 32.4, 22.2, 13.8; MS (EI, 70 eV): m/z (%) 170 (31) [M+], 163 (100), 141 (37); Known
compound.15c
(Z)-1-(Non-3-en-1-ynyl)benzene (4m). 73.4 mg, 37% yield. Oil. IR (film): νmax 2956, 2930,
1
2859, 2191, 1717, 1664, 1490, 1457, 1376, 1278, 1173, 1136, 1070, 1028, 756, 690 cm-1; H
NMR (600 MHz, CDCl3, TMS): δ 7.44-7.43 (m, 2H), 7.31-7.28 (m, 3H), 5.97 (dt, J = 7.2 Hz, J
= 10.8 Hz, 1H), 5.67 (d, J = 10.8 Hz, 1H), 2.41-2.38 (m, 2H), 1.46 (t, J = 7.2 Hz, 2H), 1.35-1.33
(m, 4H), 0.90 (t, J = 6.6 Hz, 3H); 13C{1H} NMR (150 MHz, CDCl3): δ 144.4, 131.4, 128.3,
128.0, 123.8, 109.0, 93.4, 86.5, 31.5, 30.4, 28.6, 22.6, 14.1; MS (EI, 70 eV): m/z (%) 198 (51)
[M+], 128 (100), 141 (63); Known compound.15d
(Z)-1-(Tridec-3-en-1-ynyl)benzene (4n). 83.9 mg, 33% yield. Oil. IR (film): νmax 3021, 2925,
2854, 2191, 1665, 1596, 1490, 1464, 1377, 1278, 1175, 1138, 1069, 1028, 979, 755, 690 cm-1;
1H NMR (600 MHz, CDCl3, TMS): δ 7.44-7.43 (m, 2H), 7.30-7.28 (m, 3H), 5.97 (dt, J = 7.2 Hz,
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J = 10.8 Hz, 1H), 5.67 (d, J = 10.8 Hz, 1H), 2.41-2.37 (m, 2H),1.45 (t, J = 7.2 Hz, 2H), 1.33-1.26
(m, 12H), 0.87 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (150 MHz, CDCl3): δ 144.4, 131.4, 128.3,
128.0, 123.8, 109.0, 93.4, 86.6, 32.0, 30.4, 29.7, 29.5, 29.4, 29.3, 28.9, 22.8, 14.2; MS (EI, 70
eV): m/z (%) 254 (27) [M+], 128 (100), 141 (45); Anal. Calcd for C19 H26: C, 89.70; H, 10.30.
Found: C, 89.62; H, 10.31.
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(Z)-(6-Methylhept-3-en-1-yn-1-yl)benzene 4o. 62.6 mg, 34% yield. Oil. IR (film): νmax 3021,
2957, 2870, 2190, 1950, 1880, 1718, 1663, 1596, 1490, 1465, 1368, 1336, 1263, 1168, 1069,
1
1029, 979, 915, 827, 756, 690 cm-1; H NMR (600 MHz, CDCl3, TMS): δ 7.44-7.42 (m, 2H),
7.31-7.27 (m, 3H), 5.99 (dt, J = 7.8 Hz, J = 10.8 Hz, 1H), 5.72 (d, J = 11.4 Hz, 1H), 2.31-2.29
(m, 2H), 1.78-1.74 (m, 1H), 0.96 (d, J = 6.6 Hz, 6H); 13C{1H} NMR (150 MHz, CDCl3): δ 143.0,
131.4, 128.3, 127.9, 123.8, 109.8, 93.4, 86.7, 39.5, 28.5, 22.4; MS (EI, 70 eV): m/z (%) 184 (33)
[M+], 141 (100), 141 (97); Anal. Calcd for C14H16: C, 91.25; H, 8.75. Found: C, 91.20; H, 8.68.
(Z)-(5-Cyclopentylpent-3-en-1-yn-1-yl)benzene (4p). 134.4 mg, 64% yield. Oil. IR (film): νmax
3020, 2950, 2867, 2190, 1947, 1878, 1727, 1664, 1596, 1489, 1443, 1398, 1349, 1262, 1175,
1
1069, 1028, 978, 913, 755, 690 cm-1; H NMR (600 MHz, CDCl3, TMS): δ 7.43-7.41 (m, 2H),
7.29-7.25 (m, 3H), 5.98 (dt, J = 7.2 Hz, J = 10.8 Hz, 1H), 5.68 (d, J = 10.8 Hz, 1H), 2.42-2.39
(m, 2H), 1.96-1.91 (m, 1H), 1.78-1.73 (m, 2H), 1.65-1.62 (m, 2H), 1.54-1.51 (m, 2H), 1.25-1.22
(m, 2H); 13C{1H} NMR (150 MHz, CDCl3): δ 143.5, 131.4, 128.3, 128.0, 123.9, 109.3, 93.4,
86.8, 39.8, 36.5, 32.4, 25.2; MS (EI, 70 eV): m/z (%) 210 (26) [M+], 128 (100), 141 (72); Anal.
Calcd for C16H18: C, 91.37; H, 8.63. Found: C, 91.28; H, 8.65.
(Z)-(5-Cyclohexylpent-3-en-1-yn-1-yl)benzene (4q). 145.7 mg, 65% yield. Oil. IR (film): νmax
3059, 2923, 2851, 2191, 1702, 1664, 1598, 1490, 1447, 1263, 1173, 1097, 1070, 1029, 979, 915,
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756, 690 cm-1; 1H NMR (600 MHz, CDCl3, TMS): δ 7.44-7.42 (m, 2H), 7.31-7.26 (m, 3H), 5.99
(dt, J = 7.2 Hz, J = 10.8 Hz, 1H), 5.70 (dt, J = 1.2 Hz, J = 10.8 Hz, 1H), 2.30 (dt, J = 1.2 Hz, J =
7.2 Hz, 2H), 1.76-1.62 (m, 6H), 1.44-1.39 (m, 1H), 1.26-1.14 (m, 2H), 1.04-0.97 (m, 2H);
13C{1H} NMR (150 MHz, CDCl3): δ 143.0, 131.4, 128.3, 127.9, 123.8, 109.7, 93.3, 86.8, 38.2,
38.0, 33.2, 26.6, 26.4; MS (EI, 70 eV): m/z (%) 224 (31) [M+], 128 (100), 141 (67); HRMS
(APCI-TOF) m/z: [M-H]- Calcd for C17H19 223.1492; Found 223.1480.
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(Z)-Non-2-en-4-yn-1-ylbenzene (4r). 194.2 mg, 98% yield. Oil. IR (film): νmax 3026, 2958,
2931, 2871, 2212, 1944, 1733, 1601, 1495, 1454, 1392, 1326, 1261, 1015, 1029, 920, 800, 739,
698 cm-1; 1H NMR (600 MHz, CDCl3, TMS): δ 7.21 (t, J = 7.2 Hz, 2H), 7.17-7.12 (m, 3H), 5.88
(dt, J = 7.2 Hz, J = 10.8 Hz, 1H), 5.49 (d, J = 10.8 Hz, 1H), 3.56 (d, J = 7.8 Hz, 2H), 2.31-2.28
(m, 2H), 1.49-1.45 (m, 2H), 1.40-1.36 (m, 2H), 0.85 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (150
MHz, CDCl3): δ 140.3, 128.6 (×2), 127.2, 126.2, 110.5, 94.9, 77.4, 36.5, 31.1, 22.1, 19.4, 13.7;
MS (EI, 70 eV): m/z (%) 198 (17) [M+], 141 (100), 91 (86); Known compound.8b
(Z)-1-Chloro-4-(5-phenylpent-3-en-1-yn-1-yl)benzene (4s). 141.1 mg, 56% yield. Oil. IR
(film): νmax 3027, 2924, 2198, 1900, 1662, 1589, 1488, 1396, 1264, 1201, 1091, 1014, 951, 827,
737, 698 cm-1; 1H NMR (600 MHz, CDCl3, TMS): δ 7.38-7.24 (m, 9H), 6.13 (dt, J = 7.8 Hz, J =
10.2Hz, 1H), 5.78 (d, J = 10.8 Hz, 1H), 3.73 (d, J = 7.8 H, 2H); 13C{1H} NMR (150 MHz,
CDCl3): δ 142.4, 139.6, 132.9, 132.7, 128.7 (×2), 128.6, 126.4, 122.0, 109.8, 92.9, 87.2, 36.8;
MS (EI, 70 eV): m/z (%) 252 (78) [M+], 215 (100); HRMS (APCI-TOF) m/z: [M-H]- Calcd for
C17H12Cl 251.0633; Found 251.0613.
(Z)-1-Methyl-4-(5-phenylpent-3-en-1-yn-1-yl)benzene (4t). 190.4 mg, 82% yield. Oil. IR (film):
νmax 3026, 2919, 2190, 1905, 1655, 1602, 1508, 1452, 1269, 1180, 1105, 1030, 956, 920, 815,
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741, 698, cm-1; 1H NMR (600 MHz, CDCl3, TMS): δ 7.34 (d, J = 7.8 Hz, 2H), 7.29-7.25 (m, 5H),
7.09 (d, J = 7.8 Hz, 2H), 6.07 (dt, J = 7.8 Hz, J = 10.2Hz, 1H), 5.77 (d, J = 10.2 Hz, 1H), 3.73 (d,
J = 7.8 H, 2H), 2.31 (s, 3H); 13C{1H} NMR (150 MHz, CDCl3): δ 142.6, 141.6, 139.9, 138.4,
131.5, 129.3, 128.7, 126.4, 120.6, 110.2, 94.1, 85.8, 36.8, 21.6; MS (EI, 70 eV): m/z (%) 232
(100) [M+], 215 (96), 217 (89) ; Known compound.10
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(Z)-1-Methoxy-4-(5-phenylpent-3-en-1-yn-1-yl)benzene (4u). 144.0 mg, 58% yield. Oil. IR
(film): νmax 3026, 2956, 2836, 2540, 2191, 2147, 1889, 1734, 1602, 1567, 1508, 1454, 1291,
1249, 1172, 1106, 1032, 956, 921, 831, 742, 699, 610 cm-1; 1H NMR (600 MHz, CDCl3, TMS):
δ 7.38 (d, J = 9.0 Hz, 2H), 7.27-7.23 (m, 4H), 7.19-7.16 (m, 1H), 6.81 (d, J = 9.0 Hz, 2H), 6.05
(dt, J = 7.2 Hz, J = 10.8 Hz, 1H), 5.77 (d, J = 10.8 Hz, 1H), 3.74 (s, 3H), 3.72 (d, J = 7.8 Hz, 2H);
13C{1H} NMR (150 MHz, CDCl3): δ 159.7, 141.1, 140.0, 133.1, 128.8, 128.7, 126.3, 115.7,
114.1, 110.2, 93.9, 85.1, 55.3, 36.8; Known compound.10
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the ACS Publications website at
DOI: 10.1021/.
Details for the determination of the Z/E ratio via 1 H NMR and NMR spectra of the products.
AUTHOR INFORMATION
Corresponding Author
*E-mail: yulei@yzu.edu.cn
Author Contributions
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# Authors F.C. and Y.C. contributed equally.
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Notes
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The authors declare no competing financial interest.
ACKNOWLEDGMENT
This work was supported by the Open Project Program of Jiangsu Key Laboratory of Zoonosis
(R1509, R1609), NNSFC (21202141, 21672163), Priority Academic Program Development
(PAPD) of Jiangsu Higher Education Institutions and Jiangsu Provincial Six Talent Peaks Project
(XCL-090). We thank Prof. Chunhua Zhou at School of Horticulture and Plant Protection of
YZU for photographing and providing us the picture of henna. We thank Prof. Shaolin Zhu at
Nanjing University and Prof. Zhiming Pan at Yangzhou University for their kind supports.
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