镁粉促进“一锅法”合成α,β-炔基酮类化合物

杨天宇, 黄丹凤, 王克虎, 苏瀛鹏, 胡雨来

(西北师范大学 化学化工学院，甘肃 兰州 730070)

·研究论文·

镁粉促进“一锅法”合成α,β-炔基酮类化合物

杨天宇, 黄丹凤, 王克虎, 苏瀛鹏, 胡雨来*

(西北师范大学 化学化工学院，甘肃 兰州 730070)

报道了镁粉(4)促进下，以Weinreb 酰胺(1a～1j, 1l～1n, 1p～1r)、苯乙炔(2)和正丁基溴(3)为原料，“一锅法”合成α,β-炔酮类化合物(5a～5j, 5l～5n, 5p～5r)的反应。结果表明：在最优反应条件(THF为溶剂，3 1.1 mmol, 4 1.25 mmol,混拌2 h;加入2 0.75 mmol, 搅拌1 h;加入1 0.5 mmol,于室温反应)下，5a～5j, 5l～5n, 5p～5r产率45%～86%，其结构经1H NMR和13C NMR确证。

一锅法合成; 镁粉促进; Weinreb酰胺; 苯乙炔;α,β-炔基酮

α,β-炔酮类化合物同时含有碳碳叁键和羰基两种官能团，反应性质活泼，是有机合成中重要的合成砌块，广泛用于杂环化合物的合成[1-5]。此外，许多天然产物、生物活性物种及有机中间体也含有炔酮结构单元[6-14]。寻找简单，便捷，高效的合成炔酮类化合物的方法成为化学家们关注的重点。

目前，合成该类化合物的方法主要有：(1)炔基化合物与醛发生加成氧化反应[15-18]；(2)末端炔与卤化物通过Sonogashira羰基化反应[7,19-25]；(3)末端炔或炔基化合物与羧酸衍生物发生Sonogashira酰基化反应[2,7,26-32]；(4)高价碘类炔基试剂与醛类化合物发生自由基形式的炔基化反应[33-34]；(5)α-酮酸的脱羧炔酮化反应[35]；(6)末端炔与卤化物发生异腈插入反应[36]。

Weinreb酰胺(1)作为酰基化合成砌块广泛应用于有机合成中[37-44]。1与金属氢化物反应制得醛，与有机锂或镁试剂反应制得酮，金属试剂过量也不会导致产物进一步反应。这一特点使1在含羰基化合物的合成中占有重要地位。本课题组报道了镁粉(4)促进Weinreb酰胺和卤代烃经“一锅法”合成酮类化合物的反应[45]，发现镁粉促进的“一锅法”反应可避免预先制备活泼卤代烃的Grignard试剂。转而通过镁粉与卤代烃的原位反应生成Grignard试剂，然后直接与其它反应物发生反应。

本文以Weinreb 酰胺(1a～1j, 1l～1n, 1p～1r)、苯乙炔(2)和正丁基溴(3)为原料，“一锅法”合成α,β-炔酮类化合物(5a～5j, 5l～5n, 5p～5r, Scheme 1)，产率45%～86%，其结构经1H NMR和13C NMR确证。

Scheme 1

1 实验部分

1.1 仪器与试剂

X-4B型显微熔点仪(温度未校正)；Varian Mercury 400 plus型核磁共振仪和Agilent DD2600型核磁共振仪(CDCl3为溶剂，TMS为内标)。

石油醚(沸程60～90 ℃)和乙酸乙酯,工业级；1按文献[46]方法合成；其余所用试剂均为分析纯，THF使用前经除水除氧处理。

1.2 5的合成通法

氩气保护下，在干燥的两口瓶中加入4 0.03 g(1.25 mmol)和THF 1 mL，于室温搅拌10 min；滴加3 0.15 g(1.1 mmol)，滴毕，加热至微沸(约2 min)，冷却至室温，搅拌2 h；缓慢滴加2 0.07 g(0.75 mmol)的THF(2 mL)溶液，滴毕，搅拌1 h；滴加1(0.5 mmol)，滴毕，于室温反应至终点(TLC检测)。加入饱和氯化铵溶液10 mL淬灭反应，用乙酸乙酯(3×10 mL)萃取，合并有机相，用无水硫酸镁干燥，减压蒸出乙酸乙酯，残余物经硅胶柱层析[洗脱剂：V(石油醚) ∶V(乙酸乙酯)=30 ∶1]纯化得5。

1,3-二苯基-2-丙炔-1-酮(5a)[24]： 黄色液体，产率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)： 淡黄色固体，产率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]： 黄色液体，产率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]： 黄色液体，产率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)： 白色固体，产率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)： 白色固体，产率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]： 橘红色液体，产率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)： 白色固体，产率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)： 白色固体，产率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)： 淡黄色固体，产率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)： 黄色固体，产率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)： 白色固体，产率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)： 淡黄色固体，产率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]： 黄色液体，产率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]： 黄色液体，产率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]： 黄色液体，产率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 结果与讨论

2.1 5a的合成条件优化

以5a的合成(Scheme 2)为例，研究了物料比r[n(1a) ∶n(2) ∶n(3) ∶n(4)]和反应溶剂对5a产率的影响，结果见表1。

Scheme 2表1 反应条件筛选和优化aTable 1 Optimization of the synthesis conditions for 5a

Entryr溶剂产率/%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反应条件同1.2；b氩气氛下，2, 3和4于室温搅拌1 h;加入1a 0.5 mmol；c氩气氛下，在THF中滴加3 7～8滴，滴毕，加入4，反应10 min;缓慢加入剩余的3, 2和1a 0.5 mmol；d氩气氛下，先加入3和4，于室温搅拌1 h，缓慢加入2和1a 0.5 mmol的混合溶液。

由表1可以看出，Entry 1～7为r对5a产率的影响，随着2, 3和4的用量增大，产率逐渐升高，当r=1 ∶1.5 ∶2.2 ∶2.5时，产率最高(86%)。 Entry 7～10为加料顺序对反应的影响，先将2, 3和4混合，于室温搅拌反应1 h后再加入1a，产率仅56%。将少量3和4加入体系中引发反应，然后加入剩余的3, 2和1a，反应不能发生。将3和4先于室温搅拌反应1 h；然后缓慢加入2和1a，产率也较低(70%)。最后，我们研究了反应溶剂对产率的影响(Entry 6, 11, 12),乙醚为溶剂，反应能够发生，但产率较低(74%)；1,4-二氧六环为溶剂，反应不能进行。

综上所述，合成5a的最佳条件为：THF为溶剂，3 1.1 mmol, 4 1.25 mmol,混拌2 h;加入2 0.75 mmol, 搅拌1 h;加入1a 0.5 mmol,于室温反应。

2.2 反应普适性

在最优反应条件下，我们换用其他Weinreb酰胺进行反应(Scheme 3)，研究该合成方法的普适性，结果见表2。

Scheme 3表2 镁粉促进Weinreb酰胺和苯乙炔的 “一锅法”反应研究aTable 2 Study on the “one-pot” reaction of Weinreb amines with phenylacetylene promoted by magnesium

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

a反应条件同表1中加料方式c。

由表2可见，在镁粉促进下，大多数芳香族Weinreb酰胺都能和苯乙炔，正丁基溴发生“一锅法”反应得到α,β-炔酮类化合物(Entry 1～10, 12～14)。 Weinreb酰胺苯环上的取代基对产率有较大影响，苯环上连有供电子基，产率比吸电子基高,但当苯环上连有两个取代基时，情况有所不同。如2,6-二甲氧基芳香Weinreb酰胺不能发生反应(Entry 11)， 3,5-二氯芳香Weinreb酰胺可以反应，产率55%(Entry 12)。此外，取代基在苯环上的位置对反应也有影响，无论取代基是吸电子基还是供电子基，取代基位于苯环对位的Weinreb酰胺的产率均高于取代基在邻位和间位的(Entry 2～4和Entry 5～7)。当Weinreb酰胺的取代基为萘环时，反应可以进行(Entry 13～14)，但是杂环Weinreb酰胺不能发生反应(Entry 15)。对于侧链有苯环的Weinreb酰胺, 如取代基是苄基，肉桂基和巴豆基时，反应可以进行，但产率降低(Entry 16～18)。空间位阻较大(叔丁基和金刚烷基)的脂肪族Weinreb酰胺作底物,没有合成预计的目标产物(Entry 19～20)。

报道了一种镁粉促进“一锅法”合成α,β-炔基酮类化合物的方法。该方法具有操作简便、条件温和和反应时间短等优点，为α,β-炔基酮类化合物的合成提供了一定参考。

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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

国家自然科学基金资助项目(21262031, 21462037)

杨天宇(1990-)，男，回族，辽宁沈阳人，硕士研究生，主要从事有机合成的研究。 E-mail: maxli101@sina.com

胡雨来，教授，博士生导师, E-mail: huyl@nwnu.edu.cn

O622.4

A

10.15952/j.cnki.cjsc.1005-1511.2017.02.16264