楊天宇, 黃丹鳳, 王克虎, 蘇瀛鵬, 胡雨來(lái)

(西北師范大學(xué) 化學(xué)化工學(xué)院，甘肅 蘭州 730070)

·研究論文·

鎂粉促進(jìn)“一鍋法”合成α,β-炔基酮類化合物

楊天宇, 黃丹鳳, 王克虎, 蘇瀛鵬, 胡雨來(lái)*

(西北師范大學(xué) 化學(xué)化工學(xué)院，甘肅 蘭州 730070)

報(bào)道了鎂粉(4)促進(jìn)下，以Weinreb 酰胺(1a～1j, 1l～1n, 1p～1r)、苯乙炔(2)和正丁基溴(3)為原料，“一鍋法”合成α,β-炔酮類化合物(5a～5j, 5l～5n, 5p～5r)的反應(yīng)。結(jié)果表明：在最優(yōu)反應(yīng)條件(THF為溶劑，3 1.1 mmol, 4 1.25 mmol,混拌2 h;加入2 0.75 mmol, 攪拌1 h;加入1 0.5 mmol,于室溫反應(yīng))下，5a～5j, 5l～5n, 5p～5r產(chǎn)率45%～86%，其結(jié)構(gòu)經(jīng)1H NMR和13C NMR確證。

一鍋法合成; 鎂粉促進(jìn); Weinreb酰胺; 苯乙炔;α,β-炔基酮

α,β-炔酮類化合物同時(shí)含有碳碳叁鍵和羰基兩種官能團(tuán)，反應(yīng)性質(zhì)活潑，是有機(jī)合成中重要的合成砌塊，廣泛用于雜環(huán)化合物的合成[1-5]。此外，許多天然產(chǎn)物、生物活性物種及有機(jī)中間體也含有炔酮結(jié)構(gòu)單元[6-14]。尋找簡(jiǎn)單，便捷，高效的合成炔酮類化合物的方法成為化學(xué)家們關(guān)注的重點(diǎn)。

目前，合成該類化合物的方法主要有：(1)炔基化合物與醛發(fā)生加成氧化反應(yīng)[15-18]；(2)末端炔與鹵化物通過(guò)Sonogashira羰基化反應(yīng)[7,19-25]；(3)末端炔或炔基化合物與羧酸衍生物發(fā)生Sonogashira酰基化反應(yīng)[2,7,26-32]；(4)高價(jià)碘類炔基試劑與醛類化合物發(fā)生自由基形式的炔基化反應(yīng)[33-34]；(5)α-酮酸的脫羧炔酮化反應(yīng)[35]；(6)末端炔與鹵化物發(fā)生異腈插入反應(yīng)[36]。

Weinreb酰胺(1)作為?；铣善鰤K廣泛應(yīng)用于有機(jī)合成中[37-44]。1與金屬氫化物反應(yīng)制得醛，與有機(jī)鋰或鎂試劑反應(yīng)制得酮，金屬試劑過(guò)量也不會(huì)導(dǎo)致產(chǎn)物進(jìn)一步反應(yīng)。這一特點(diǎn)使1在含羰基化合物的合成中占有重要地位。本課題組報(bào)道了鎂粉(4)促進(jìn)Weinreb酰胺和鹵代烴經(jīng)“一鍋法”合成酮類化合物的反應(yīng)[45]，發(fā)現(xiàn)鎂粉促進(jìn)的“一鍋法”反應(yīng)可避免預(yù)先制備活潑鹵代烴的Grignard試劑。轉(zhuǎn)而通過(guò)鎂粉與鹵代烴的原位反應(yīng)生成Grignard試劑，然后直接與其它反應(yīng)物發(fā)生反應(yīng)。

本文以Weinreb 酰胺(1a～1j, 1l～1n, 1p～1r)、苯乙炔(2)和正丁基溴(3)為原料，“一鍋法”合成α,β-炔酮類化合物(5a～5j, 5l～5n, 5p～5r, Scheme 1)，產(chǎn)率45%～86%，其結(jié)構(gòu)經(jīng)1H NMR和13C NMR確證。

Scheme 1

1 實(shí)驗(yàn)部分

1.1 儀器與試劑

X-4B型顯微熔點(diǎn)儀(溫度未校正)；Varian Mercury 400 plus型核磁共振儀和Agilent DD2600型核磁共振儀(CDCl3為溶劑，TMS為內(nèi)標(biāo))。

石油醚(沸程60～90 ℃)和乙酸乙酯,工業(yè)級(jí)；1按文獻(xiàn)[46]方法合成；其余所用試劑均為分析純，THF使用前經(jīng)除水除氧處理。

1.2 5的合成通法

氬氣保護(hù)下，在干燥的兩口瓶中加入4 0.03 g(1.25 mmol)和THF 1 mL，于室溫?cái)嚢?0 min；滴加3 0.15 g(1.1 mmol)，滴畢，加熱至微沸(約2 min)，冷卻至室溫，攪拌2 h；緩慢滴加2 0.07 g(0.75 mmol)的THF(2 mL)溶液，滴畢，攪拌1 h；滴加1(0.5 mmol)，滴畢，于室溫反應(yīng)至終點(diǎn)(TLC檢測(cè))。加入飽和氯化銨溶液10 mL淬滅反應(yīng)，用乙酸乙酯(3×10 mL)萃取，合并有機(jī)相，用無(wú)水硫酸鎂干燥，減壓蒸出乙酸乙酯，殘余物經(jīng)硅膠柱層析[洗脫劑：V(石油醚) ∶V(乙酸乙酯)=30 ∶1]純化得5。

1,3-二苯基-2-丙炔-1-酮(5a)[24]： 黃色液體，產(chǎn)率86%;1H NMRδ: 8.23～8.22(m, 2H), 7.69～7.68(m, 2H), 7.63(t,J=6.0 Hz, 1H), 7.53～7.47(m, 3H), 7.42(t,J=6.0 Hz, 2H);13C NMRδ: 178.0, 136.9, 134.1, 133.0, 130.8, 129.5, 128.6, 128.5, 120.1, 93.1, 86.9。

1-苯基-3-(4-甲苯基)-2-丙炔-1-酮(5b)： 淡黃色固體，產(chǎn)率82%, m.p.64～66 ℃(68～70 ℃[28]);1H NMRδ: 8.11(d,J=6.0 Hz, 2H), 7.66(d,J=6.0 Hz, 2H), 7.45(t,J=6.0 Hz, 1H), 7.39(t,J=9.0 Hz, 2H), 7.29(d,J=6.0 Hz, 2H), 2.41(s, 3H);13C NMRδ: 177.5, 145.1, 134.5, 132.9, 130.6, 129.5, 129.2, 128.5, 120.1, 92.5, 86.9, 21.7。

1-苯基-3-(3-甲苯基)-2-丙炔-1-酮(5c)[28]： 黃色液體，產(chǎn)率80%;1H NMRδ: 8.03(d,J=6.0 Hz, 1H), 7.99(s, 1H), 7.66(d,J=6.0 Hz, 2H), 7.45(t,J=6.0 Hz, 1H), 7.41～7.37(m, 4H), 2.42(s, 3H);13C NMRδ: 178.0, 138.3, 136.7, 134.8, 132.9, 130.6, 129.6, 128.5, 128.4, 126.9, 120.0, 92.7, 86.9, 21.2。

1-苯基-3-(2-甲苯基)-2-丙炔-1-酮(5d)[28]： 黃色液體，產(chǎn)率74%;1H NMRδ: 8.30(d,J=6.0 Hz, 1H), 7.65(d,J=12.0 Hz, 2H), 7.45(t,J=6.0 Hz, 2H), 7.40～7.34(m, 3H), 7.27(d,J=12.0 Hz, 1H), 2.67(s, 3H);13C NMRδ: 179.7, 140.4, 135.6, 133.1, 132.8, 132.1, 130.5, 128.6, 125.8, 120.3, 91.8, 88.3, 21.9。

1-苯基-3-(4-氯苯基)-2-丙炔-1-酮(5e)： 白色固體，產(chǎn)率71%, m.p.96～98 ℃(104～105 ℃[28]);1H NMRδ: 8.13(d,J=6.0 Hz, 2H), 7.66(d,J=6.0 Hz, 2H), 7.47～7.45(m, 3H), 7.41～7.39(m, 2H);13C NMRδ: 176.4, 140.6, 135.2, 133.0, 130.9, 130.7, 128.9, 128.6, 119.7, 93.5, 86.5。

1-苯基-3-(3-氯苯基)-2-丙炔-1-酮(5f)： 白色固體，產(chǎn)率67%, m.p.93～95 ℃(86～90 ℃[16]);1H NMRδ: 8.15(s, 1H), 8.09(d,J=12.0 Hz, 1H), 7.67(d,J=12.0 Hz, 2H), 7.58(d,J=6.0 Hz, 1H), 7.49～7.40(m, 4H);13C NMRδ: 176.3, 138.3, 134.8, 133.9, 133.1, 131.0, 130.0, 129.2, 128.7, 127.6, 119.7, 93.9, 86.4。

1-苯基-3-(2-氯苯基)-2-丙炔-1-酮(5g)[47]： 橘紅色液體，產(chǎn)率45%;1H NMRδ: 8.09(d,J=6.0 Hz, 1H), 7.65(d,J=6.0 Hz, 2H), 7.48～7.47(m, 3H), 7.42～7.39(m, 3H);13C NMRδ: 176.7, 135.8, 133.5, 133.3, 133.1, 132.5, 131.5, 130.9, 128.7, 126.8, 120.0, 93.9, 88.3。

1-苯基-3-(4-甲氧基苯基)-2-丙炔-1-酮(5h)： 白色固體，產(chǎn)率82%, m.p.93～95 ℃(98～99 ℃[28]);1H NMRδ: 8.18(d,J=6.0 Hz, 2H), 7.65(d,J=6.0 Hz, 2H), 7.44(t,J=9.0 Hz, 1H), 7.39(t,J=9.0 Hz, 2H), 6.97(d,J=6.0 Hz, 2H), 3.85(s, 3H);13C NMRδ: 176.4, 164.3, 132.7, 131.7, 130.4, 130.1, 128.5, 120.1, 113.7, 92.1, 86.8, 55.4。

1-苯基-3-(4-氟苯基)-2-丙炔-1-酮(5i)： 白色固體，產(chǎn)率73%, m.p.48～50 ℃(47～49 ℃[29]);1H NMRδ: 8.24～8.22(m, 2H), 7.66(d,J=12.0 Hz, 2H), 7.47(t,J=9.0 Hz, 1H), 7.41(t,J=6.0 Hz, 2H), 7.17(t,J=9.0 Hz, 2H);13C NMRδ: 176.2, 166.3(d,JC-F=255.0 Hz), 133.3(d,JC-F=3.0 Hz), 133.0, 132.1(d,JC-F=10.5 Hz), 130.8, 128.6, 119.8, 115.7 (d,JC-F=22.5 Hz), 93.2, 86.5;19F NMRδ: -63.54。

1-苯基-3-(4-三氟甲基苯基)-2-丙炔-1-酮(5j)： 淡黃色固體，產(chǎn)率68%, m.p.65～67 ℃(70～73 ℃[28]);1H NMRδ: 8.30(d,J=6.0 Hz, 2H), 7.76(d,J=6.0 Hz, 2H), 7.68(d,J=6.0 Hz, 2H), 7.49～7.47(m, 1H), 7.41(t,J=9.0 Hz, 2H);13C NMRδ: 176.5, 139.3, 135.0 (q,JC-F=31.5 Hz), 133.1, 131.1, 129.6, 128.7, 125.5(q,J=4.5 Hz), 123.5(q,JC-F=271.5 Hz), 119.5, 94.3, 86.5;19F NMRδ: -63.53。

1-苯基-3-(3,5-二氯苯基)-2-丙炔-1-酮(5l)： 黃色固體，產(chǎn)率55%, m.p.80～82 ℃;1H NMRδ: 8.02～8.01(m, 2H), 7.68(d,J=6.0 Hz, 2H), 7.56～7.55(m, 1H), 7.52～7.49(m, 1H), 7.43(t,J=6.0 Hz, 2H);13C NMRδ: 174.9, 139.1, 135.6, 133.5, 133.2, 131.2, 128.7, 127.6, 119.3, 94.7, 86.1; HR-MS(ESI)m/z: Calcd for C15H8OCl2{[M+H]+}275.002 5, found 275.002 2。

3-苯基-1-(2-萘基)-2-丙炔-1-酮(5m)： 白色固體，產(chǎn)率77%, m.p.82～84 ℃(81～83 ℃[29]);1H NMRδ: 8.71(s, 1H), 8.17(d,J=12.0 Hz, 1H), 7.95(d,J=12.0 Hz, 1H), 7.85～7.81(m, 2H), 7.68(t,J=6.0 Hz, 2H), 7.57～7.50(m, 2H), 7.45～7.37(m, 3H);13C NMRδ: 177.6, 135.9, 134.2, 132.9, 132.4, 132.2, 130.6, 129.7, 128.8, 128.5, 128.3, 127.7, 126.8, 123.7, 120.0, 92.9, 87.0。

3-苯基-1-(1-萘基)-2-丙炔-1-酮(5n)： 淡黃色固體，產(chǎn)率64%, m.p.85～87 ℃( 92～94 ℃[28]);1H NMRδ: 9.25(d,J=6.0 Hz, 1H), 8.63 (d,J=12.0 Hz, 1H), 8.05(d,J=6.0 Hz, 1H), 7.88(d,J=12.0 Hz, 1H), 7.66(d,J=9.0 Hz, 3H), 7.57～7.53(m, 2H), 745～7.37(m, 3H);13C NMRδ: 179.6, 135.0, 134.5, 133.8, 132.8, 130.6, 130.5, 128.9, 128.6, 128.5, 126.7, 126.0, 124.4, 120.2, 91.6, 88.4。

1,4-二苯基-3-丁炔-2-酮(5p)[22]： 黃色液體，產(chǎn)率53%;1H NMRδ: 7.45(d,J=6.0 Hz, 2H), 7.42(d,J=6.0 Hz, 1H), 7.37(t,J=9.0 Hz, 2H), 7.34(s, 1H), 7.33～7.29(m, 4H), 3.92(s, 2H);13C NMRδ: 185.2, 133.2, 133.1, 130.8, 129.8, 128.7, 128.5, 127.4, 119.8, 92.9, 87.7, 52.1。

1,5-二苯基-1-戊烯-4-炔-3-酮(5q)[17]： 黃色液體，產(chǎn)率49%;1H NMRδ: 7.91(d,J=16.2 Hz, 1H), 7.65(d,J=7.2 Hz, 2H), 7.59(t,J=3.9 Hz, 2H), 7.47～7.35(m, 6H), 6.86(d,J=16.2 Hz, 1H);13C NMRδ: 178.1, 148.2, 134.0, 132.8, 131.1, 130.5, 129.0, 128.6, 128.6, 128.5, 120.1, 91.5, 86.6。

1-苯基-4-己烯-1-炔-3-酮(5r)[29]： 黃色液體，產(chǎn)率48%;1H NMRδ: 7.60(d,J=8.4 Hz, 2H), 7.45(t,J=7.8 Hz, 1H), 7.39(t,J=7.8 Hz, 2H), 7.32～7.26(m, 1H), 6.26(d,J=15.6 Hz, 1H), 2.03(d,J=6.6 Hz, 3H);13C NMRδ: 178.3, 149.4, 134.0, 132.8, 130.5, 128.6, 120.2, 91.0, 86.2, 18.4。

2 結(jié)果與討論

2.1 5a的合成條件優(yōu)化

以5a的合成(Scheme 2)為例，研究了物料比r[n(1a) ∶n(2) ∶n(3) ∶n(4)]和反應(yīng)溶劑對(duì)5a產(chǎn)率的影響，結(jié)果見(jiàn)表1。

Scheme 2表1 反應(yīng)條件篩選和優(yōu)化aTable 1 Optimization of the synthesis conditions for 5a

Entryr溶劑產(chǎn)率/%11∶1∶1.3∶1.5THF3521∶1∶1.5∶1.8THF4331∶1.1∶1.5∶1.8THF6241∶1.5∶1.5∶1.8THF6751∶1.5∶2∶2.3THF7661∶1.5∶2.2∶2.5THF8671∶1.5∶2.5∶2.8THF848b1∶1.5∶2.2∶2.5THF569c1∶1.5∶2.2∶2.5THF010d1∶1.5∶2.2∶2.5THF70111∶1.5∶2.2∶2.5Et2O74121∶1.5∶2.2∶2.51,4-dioxane0

a反應(yīng)條件同1.2；b氬氣氛下，2, 3和4于室溫?cái)嚢? h;加入1a 0.5 mmol；c氬氣氛下，在THF中滴加3 7～8滴，滴畢，加入4，反應(yīng)10 min;緩慢加入剩余的3, 2和1a 0.5 mmol；d氬氣氛下，先加入3和4，于室溫?cái)嚢? h，緩慢加入2和1a 0.5 mmol的混合溶液。

由表1可以看出，Entry 1～7為r對(duì)5a產(chǎn)率的影響，隨著2, 3和4的用量增大，產(chǎn)率逐漸升高，當(dāng)r=1 ∶1.5 ∶2.2 ∶2.5時(shí)，產(chǎn)率最高(86%)。 Entry 7～10為加料順序?qū)Ψ磻?yīng)的影響，先將2, 3和4混合，于室溫?cái)嚢璺磻?yīng)1 h后再加入1a，產(chǎn)率僅56%。將少量3和4加入體系中引發(fā)反應(yīng)，然后加入剩余的3, 2和1a，反應(yīng)不能發(fā)生。將3和4先于室溫?cái)嚢璺磻?yīng)1 h；然后緩慢加入2和1a，產(chǎn)率也較低(70%)。最后，我們研究了反應(yīng)溶劑對(duì)產(chǎn)率的影響(Entry 6, 11, 12),乙醚為溶劑，反應(yīng)能夠發(fā)生，但產(chǎn)率較低(74%)；1,4-二氧六環(huán)為溶劑，反應(yīng)不能進(jìn)行。

綜上所述，合成5a的最佳條件為：THF為溶劑，3 1.1 mmol, 4 1.25 mmol,混拌2 h;加入2 0.75 mmol, 攪拌1 h;加入1a 0.5 mmol,于室溫反應(yīng)。

2.2 反應(yīng)普適性

在最優(yōu)反應(yīng)條件下，我們換用其他Weinreb酰胺進(jìn)行反應(yīng)(Scheme 3)，研究該合成方法的普適性，結(jié)果見(jiàn)表2。

Scheme 3表2 鎂粉促進(jìn)Weinreb酰胺和苯乙炔的 “一鍋法”反應(yīng)研究aTable 2 Study on the “one-pot” reaction of Weinreb amines with phenylacetylene promoted by magnesium

EntryR產(chǎn)物產(chǎn)率/%1C6H55a8624-MeC6H45b8233-MeC6H45c8042-MeC6H45d7454-ClC6H45e7163-ClC6H45f6772-ClC6H45g4584-MeOC6H45h8294-FC6H45i73104-CF3C6H45j68112,6-(MeO)2C6H35k0123,5-Cl2C6H35l55132-naphthalenyl5m77141-naphthalenyl5n64153-pyridinyl5onr16C6H5CH25p5317C6H5CH=CH5q4918CH3CH=CH5r4819t-butyl5s020adamantyl5t0

a反應(yīng)條件同表1中加料方式c。

由表2可見(jiàn)，在鎂粉促進(jìn)下，大多數(shù)芳香族Weinreb酰胺都能和苯乙炔，正丁基溴發(fā)生“一鍋法”反應(yīng)得到α,β-炔酮類化合物(Entry 1～10, 12～14)。 Weinreb酰胺苯環(huán)上的取代基對(duì)產(chǎn)率有較大影響，苯環(huán)上連有供電子基，產(chǎn)率比吸電子基高,但當(dāng)苯環(huán)上連有兩個(gè)取代基時(shí)，情況有所不同。如2,6-二甲氧基芳香Weinreb酰胺不能發(fā)生反應(yīng)(Entry 11)， 3,5-二氯芳香Weinreb酰胺可以反應(yīng)，產(chǎn)率55%(Entry 12)。此外，取代基在苯環(huán)上的位置對(duì)反應(yīng)也有影響，無(wú)論取代基是吸電子基還是供電子基，取代基位于苯環(huán)對(duì)位的Weinreb酰胺的產(chǎn)率均高于取代基在鄰位和間位的(Entry 2～4和Entry 5～7)。當(dāng)Weinreb酰胺的取代基為萘環(huán)時(shí)，反應(yīng)可以進(jìn)行(Entry 13～14)，但是雜環(huán)Weinreb酰胺不能發(fā)生反應(yīng)(Entry 15)。對(duì)于側(cè)鏈有苯環(huán)的Weinreb酰胺, 如取代基是芐基，肉桂基和巴豆基時(shí)，反應(yīng)可以進(jìn)行，但產(chǎn)率降低(Entry 16～18)。空間位阻較大(叔丁基和金剛烷基)的脂肪族Weinreb酰胺作底物,沒(méi)有合成預(yù)計(jì)的目標(biāo)產(chǎn)物(Entry 19～20)。

報(bào)道了一種鎂粉促進(jìn)“一鍋法”合成α,β-炔基酮類化合物的方法。該方法具有操作簡(jiǎn)便、條件溫和和反應(yīng)時(shí)間短等優(yōu)點(diǎn)，為α,β-炔基酮類化合物的合成提供了一定參考。

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“One-Pot” Synthesis ofα,β-Alkynones Promoted by Magnesium Powder

YANG Tian-yu, HUANG Dan-feng, WANG Ke-hu, SU Ying-peng, HU Yu-lai*

(College of Chemistry and Chemical Engineering, Northwest Normal University, Lanzhou 730070, China)

“One-pot” synthesis ofα,β-alkynones(5a～5j, 5l～5n, 5p～5r) from Weinreb amides(1a～1j, 1l～1n, 1p～1r) and phenylacetylene(2) promoted by magnesium powder(4) in the presence ofn-butyl bromide(3) was reported. The results indicated that under the optimum reaction conditions(THF as solvent, 3 1.1 mmol, 4 1.25 mmol, stirring for 2 h; then add 2 0.75 mmol, stirring for 1 h; add 1 0.5 mmol, reaction at rt), the yield of 5a～5j, 5l～5n, 5p～5r were 45%～86%. The structures were confirmed by1H NMR and13C NMR.

one-pot synthesis; magnesium powder promotion; Weinreb amide; phenylacetylene;α,β-alkynone

2016-10-21;

2017-01-05

國(guó)家自然科學(xué)基金資助項(xiàng)目(21262031, 21462037)

楊天宇(1990-)，男，回族，遼寧沈陽(yáng)人，碩士研究生，主要從事有機(jī)合成的研究。 E-mail: maxli101@sina.com

胡雨來(lái)，教授，博士生導(dǎo)師, E-mail: huyl@nwnu.edu.cn

O622.4

A

10.15952/j.cnki.cjsc.1005-1511.2017.02.16264