Copper-Catalyzed Regio- and Stereo-Selective Coupling of Grignard

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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)-1,5Disubstituted 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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The Journal of Organic Chemistry

Copper-Catalyzed Regio- and Stereo-Selective Coupling of Grignard Reagents with Pent-1-en-4-yn3-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,*,†,‡ †

‡

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,

1 ACS Paragon Plus Environment

The Journal of Organic Chemistry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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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 Zconfigured enynes, which widely exist in many bioactive natural products, such as the antiinflammatory components in henna.

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-en3-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 Scheme 1. Methods for the Synthesis of Z-PEYs



(A)

OH Pd(PPh3)4/SnCl2 DMI, 70 oC (ref 8a) or PPSE (ref 8b)

Ph

Ph (B) Ar

R1

Ph

Ph 53%, Z/E = 80/20 or 54%, Z/E = 67/33

B-benzyl-9-BBN Cl

(C)

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OBz

Pd(PPh3)4/Cs2CO3/H2O Ar Ph 60 oC, 12 h 50-82% (ref. 10) R2MgX, CuI (2 mol %) ether, 0 oC to rt overnight, N2

R1

R2

(this work)

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 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 screenings demonstrated that by cooling with ice-water (0 oC 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

1

CuCl

Me (1a)

rtb

26 (88/12)

2

CuBr

Me (1a)

rt

24 (92/8)



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3

CuI

Me (1a)

rt

35 (94/6)

4

CuBr2

Me (1a)

rt

23 (87/13)

5

-

Me (1a)

rt

0 (-)

6

CuI

Ac (1b)

rt

55 (80/20)

7

CuI

Bz (1c)

rt

76 (76/24)

8

CuI

Piv (1d)

rt

45 (70/30)

9

CuI

n-BuC(O) (1e)

rt

58 (75/25)

10

CuI

MOM or CO2Me (1f-g)

rt

0 (-)

11

CuI

Bz (1c)

0oC-r.t.

81 (80/20)

12

CuI

Bz (1c)

-15oC-r.t.

59 (76/24)

13d

CuI

Bz (1c)

0oC-r.t.

77 (74/26)

14d

CuI

Bz (1c)

0oC-r.t.

67 (78/22)

15d

CuI

Bz (1c)

0oC-r.t.

52 (77/23)

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 (25 oC). cIsolated yields based on 1 outside the parentheses; Z/E ratio calculated from 1H NMR inside the parentheses. d3 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). Table 2. Synthesis of Z-PEYs 4a

entry

R1

R2MgX

4: yield/% (Z/E)b

1

C6H5

C6H5MgBr

4a: 81 (80/20)

2

C6H5

C6H5MgI

4a: 99 (83/17)

3

C6H5

p-MeC6H4MgBr

4b: 69 (70/30)

4

C6H5

p-MeC6H4MgI

4b: 57 (69/31)



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5

C6H5

o-MeC6H4MgBr

4c: 88 (86/14)

6

C6H5

o-MeC6H4MgI

4c: 86 (79/21)

7

C6H5

p-MeOC6H4MgBr

4d: 61 (78/22)

8

C6H5

p-MeOC6H4MgI

4d: 55 (77/23)

9

C6H5

p-FC6H4MgBr

4e: 66 (92/8)

10

C6H5

p-FC6H4MgI

4e: 76 (82/18)

11

C6H5

p-ClC6H4MgBr

4f: 83 (90/10)

12

C6H5

p-ClC6H4MgI

4f: 84 (89/11)

13

C6H5

o-ClC6H4MgBr

4g: 77 (91/9)

14

C6H5

o-ClC6H4MgI

4g: 93 (91/9)

15

C6H5

3,5-(CF3)2C6H3MgBr

4h: 75 (81/19)

16

C6H5

1-C10H8MgBr

4i: 70 (96/4)

17

C6H5

1-C10H8MgI

4i: 49 (95/5)

18

C6H5

2-C10H8MgBr

4j: 26 (73/27)

19

C6H5

CH3MgBr

4k: 12 (31/69)

20

C6H5

CH3MgI

4k: 54 (53/47)

21

C6H5

C2H5MgBr

4l: 36 (81/19)

22

C6H5

C2H5MgI

4l: 62 (83/17)

23

C6H5

n-C4H9MgBr

4m: 37 (87/13)

24

C6H5

n-C8H17MgBr

4n: 33 (89/11)

25

C6H5

i-C3H7MgBr

4o: 34 (87/13)

26

C6H5

c-C5H9MgBr

4p: 64 (85/15)

27

C6H5

c-C6H11MgBr

4q: 65 (90/10)

28

n-C4H9

C6H5MgBr

4r: 98 (81/19)

29

p-ClC6H4

C6H5MgBr

4s: 56 (67/33)

30

p-MeC6H4

C6H5MgBr

4t: 82 (72/28)

31

p-MeOC6H4

C6H5MgBr

4u: 58 (81/19)


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a

Reactions were performed under the conditions described by Table 1, entry 11. bIsolated yields

based on 1 outside the parentheses; Z/E ratio calculated from 1H NMR inside the parentheses. 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 Bun

Ph 5

6

BzO

Ph

OBz

OBz

Ph

7

Me BzO

8

PhMgBr CuI (2 mol %)

complexes ether, 0 oC to rt, N2 overnight Ph

9

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

In conclusion, we developed a concise method for the synthesis of Z-1,5-disubstitutedpent-3en-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 could be calculated from 1H NMR spectra by comparing the peak areas of the allylic CH2. 1H 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 internal standard. Chemical shifts for 1H and 13C 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 GCMSQP2010 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 mL) was cooled to 0 oC 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; 1H NMR (600 MHz, CDCl3, TMS): δ 7.47–7.45 (m, 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



Page 12 of 25

= 10.8 Hz, 1H), 5.80 (d, J = 10.8 Hz, 1H), 3.75 (d, J = 7.8 Hz, 2H); 13C{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 (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);

13

C{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, 1107, 1028, 957, 913, 843, 753, 690 cm-1; 1H 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 (ESITOF) m/z: [M+H]+ Calcd for C18H17O 249.1274; Found 249.1263. (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, 1027, 979, 916, 824, 757, 691 cm-1; 1H 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, 1H), 5.79 (d, J = 10.2 Hz, 1H), 3.69 (d, J = 7.8 Hz, 2H);

13

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);

13

C{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.



Page 14 of 25

(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, 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, 903, 842, 757, 690 cm-1; 1H 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, 1H), 3.85 (d, J = 7.2 Hz, 2H); 13C{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.


Page 15 of 25 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


(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 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 cm1 1

; H 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, 874, 800, 756, 690 cm-1; Z-isomer: 1H 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 (m, 2H), 1.06 (t, J = 7.2 Hz, 3H); E-isomer: 1H NMR (600 MHz, CDCl3, TMS): δ 744-7.41 (m,



Page 16 of 25

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), 2.432.38 (m, 2H), 1.04 (t, J = 7.8 Hz, 3H); Z and E mixtures:

13

C{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, 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, 2873, 2201, 1718, 1599, 1490, 1445, 1379, 1281, 1172, 1071, 1027, 971, 757, 691 cm-1; 1H 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);

13

C{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, 2859, 2191, 1717, 1664, 1490, 1457, 1376, 1278, 1173, 1136, 1070, 1028, 756, 690 cm-1; 1H 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);

13

C{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; 1

H 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,


Page 17 of 25 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


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);

13

C{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. (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, 1029, 979, 915, 827, 756, 690 cm-1; 1H 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, 1069, 1028, 978, 913, 755, 690 cm-1; 1H 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);

13

C{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,



Page 18 of 25

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); 13

C{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. (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);

13

C{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);

13

C{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,


Page 19 of 25 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


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);

13

C{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 (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); 13

C{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: [email protected] Author Contributions



Page 20 of 25

# Authors F.C. and Y.C. contributed equally. Notes 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. REFERENCES (1) (a) Huang, Y.-M.; del Pozo, J.; Torker, S.; Hoveyda, A. H. Enantioselective Synthesis of Trisubstituted

Allenyl–B(pin)

Compounds

by

Phosphine–Cu-Catalyzed

1,3-Enyne

Hydroboration. Insights Regarding Stereochemical Integrity of Cu-Allenyl Intermediates. J. Am. Chem. Soc. 2018, 140, 2643−2655. (b) Gao, D.-W.; Xiao, Y.-Y.; Liu, M.-Y.; Liu, Z.; Karunananda, M. K.; Chen, J. S.; Engle, K. M. Catalytic, Enantioselective Synthesis of Allenyl Boronates. ACS Catal. 2018, 8, 3650−3654. (c) Tap, A.; Blond, A.; Wakchaure, V. N.; List, B. Chiral Allenes via Alkynylogous Mukaiyama Aldol Reaction. Angew. Chem. Int. Ed. 2016, 55, 8962−8965. (d) Hu, F.; Xia, Y.; Ma, C.; Zhang, Y.; Wang, J. Cu(I)-Catalyzed Synthesis of Furan-Substituted Allenes by Use of Conjugated Ene-yne Ketones as Carbene Precursors. J. Org. Chem. 2016, 81, 3275−3285. (e) Wang, M.; Liu, Z.-L.; Zhang, X.; Tian, P.-P.; Hu, Y.-H.; Loh, T.-P. Synthesis of Highly Substituted Racemic and Enantioenriched Allenylsilanes via Copper-


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