CN113121318B - 一种联/杂芳烃类化合物及其制备方法 - Google Patents
一种联/杂芳烃类化合物及其制备方法 Download PDFInfo
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- CN113121318B CN113121318B CN202110406890.6A CN202110406890A CN113121318B CN 113121318 B CN113121318 B CN 113121318B CN 202110406890 A CN202110406890 A CN 202110406890A CN 113121318 B CN113121318 B CN 113121318B
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- diazonium salt
- grinding
- stainless steel
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- 238000002360 preparation method Methods 0.000 title abstract description 29
- 150000002430 hydrocarbons Chemical class 0.000 title description 2
- -1 hetero aromatic hydrocarbon compound Chemical class 0.000 claims abstract description 74
- 238000000227 grinding Methods 0.000 claims abstract description 51
- 238000006243 chemical reaction Methods 0.000 claims abstract description 48
- 239000012954 diazonium Substances 0.000 claims abstract description 41
- 238000000034 method Methods 0.000 claims abstract description 24
- 150000003254 radicals Chemical class 0.000 claims abstract description 11
- 239000002994 raw material Substances 0.000 claims abstract description 7
- 238000006254 arylation reaction Methods 0.000 claims abstract description 6
- 230000009471 action Effects 0.000 claims abstract description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 75
- 229910001220 stainless steel Inorganic materials 0.000 claims description 60
- 239000010935 stainless steel Substances 0.000 claims description 60
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 44
- 239000003480 eluent Substances 0.000 claims description 37
- 239000007787 solid Substances 0.000 claims description 34
- 238000003801 milling Methods 0.000 claims description 31
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 24
- 239000011541 reaction mixture Substances 0.000 claims description 24
- 238000004440 column chromatography Methods 0.000 claims description 23
- 150000001875 compounds Chemical class 0.000 claims description 23
- 239000003208 petroleum Substances 0.000 claims description 22
- 239000000843 powder Substances 0.000 claims description 22
- 150000001989 diazonium salts Chemical class 0.000 claims description 17
- IOJUPLGTWVMSFF-UHFFFAOYSA-N benzothiazole Chemical compound C1=CC=C2SC=NC2=C1 IOJUPLGTWVMSFF-UHFFFAOYSA-N 0.000 claims description 16
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- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
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Abstract
本发明公开了一种联/杂芳烃类化合物及其制备方法,所述联/杂芳烃类化合物结构式如式3所示;所述制备方法为:以式1所示的芳基四氟硼酸重氮盐化合物及式2所示的杂芳烃化合物为原料,在研磨助剂作用下,通过机械研磨的方式进行自由基型C‑H芳基化反应,获得如式3所示的联/杂芳烃类化合物;本发明首次采用机械研磨的方式直接诱导芳基四氟硼酸重氮盐C‑N键裂解,进行自由基C‑H芳基化反应,快速、高效地制备联/杂芳烃类化合物,具有无溶剂、操作简便、体系清洁廉价、反应快速高效等显著优势。
Description
技术领域
本发明属于有机化学合成领域,尤其涉及一种联/杂芳烃类化合物及其制备方法,是一种通过机械力直接诱导自由基反应生成的无溶剂机械研磨合成方法。
背景技术
联/杂芳烃类化合物在生物医药,精细化工等领域具有多种重要用途,并且广泛存在于天然产物以及药物活性分子中。例如,天然产物和厚朴酚,海罂粟碱等;临床上被广泛用于抗肿瘤(依鲁替尼和伊马替尼),解热镇痛(芬布芬),降血压(氯沙坦),降尿酸(非布索坦)等领域。因此,一种简单、通用且可持续的策略来获得联/杂芳烃类化合物始终在化学合成领域保持着极高的需求。
联/杂芳烃类化合物的制备通常有三种方法,包括过渡金属催化交叉偶联,过渡金属催化C−H键活化和基于自由基反应的C−H杂芳基化反应。前两种方法可实现较高的化学反应性和选择性,但往往需要贵金属催化剂,氧化剂和预官能团化的底物。此外,有机溶剂的大量使用和严苛反应条件较大地限制了这两类反应的可持续发展。近几年,随着自由基化学的发展,廉价易得的芳基四氟硼酸重氮盐参与的C−H杂芳基化反应逐渐成为构建联/杂芳烃类化合物的重要手段,根据芳基自由基的引发方式主要可以分为如下两类:
(a) 与光催化剂、外源性还原剂之间发生单电子转移引发自由基,比如文献:(1)J. Am. Chem. Soc., 2012, 134, 2958–2961. (2) J. Org. Chem., 2014, 79, 10682–10688. (3) Angew. Chem. Int. Ed. 2018, 57, 10625–10629. (4) Science 2019,366, 1500–1504.
(b) 与弱亲核试剂、碱试剂作用生成复合物引发自由基,比如文献:(1) Org.Biomol. Chem., 2018, 16, 4942–4953. (2) Chem.–Asian J., 2018, 13, 325–333.
这些方法均不可避免的使用外源性还原剂(如光催化剂、压电材料)或者弱亲核试剂、碱试剂等作为自由基引发剂。因此,一种更好的以芳基四氟硼酸重氮盐为自由基前体的联/杂芳烃类化合物合成策略需具备以下特点:1)反应体系简单、易得;2)反应温和高效;3)最大程度减少有机溶剂的使用。
近年来,机械研磨技术已经成为促进有机合成反应的一个重要途径,与一般的溶液反应相比,机械研磨反应通常采用无溶剂研磨的方式进行,避免了反应过程中环境不友好的有机溶剂的过度使用,能够显著提高反应速率,缩短反应时间。此外,机械研磨手段在诱导聚合物化学键断裂、协同化学催化剂促进自由基反应方面具有广阔的前景,然而,目前尚未有直接利用机械力激发小分子化合物化学键裂解,参与自由基反应的报道。
因此,利用机械力直接诱导芳基四氟硼酸重氮盐裂解形成活性杂芳基自由基是对传统合成联/杂芳烃类化合物的重大突破,能够有效革除有机溶剂及光催化剂、外源性还原试剂、弱亲核试剂或碱试剂的使用,具有经济性高,反应条件温和,效率高等优势。
发明内容
本发明的目的是提供一种无溶剂、操作简便、体系廉价、环境友好、反应高效的联/杂芳烃类化合物及其制备方法。
为实现上述目的,本发明采用如下技术方案:
本发明的一种联/杂芳烃类化合物的制备方法,其特征在于所述方法为:以式1所示的芳基四氟硼酸重氮盐及式2所示的HetAr/Ar为原料,在研磨助剂作用下,通过机械研磨的方法进行自由基型C−H芳基化反应,采用TLC点板(取样溶于丙酮中)跟踪反应进度,反应结束后,所得反应混合物经分离纯化,即获得式3所示联/杂芳烃类化合物;
式中R代表对氟苯基,对氯苯基,对溴苯基,对硝基苯基,对甲氧基苯基,间氯苯基,2-吡啶基,2-苯并噻唑基,结构式如:
进一步地,式1所示的芳基四氟硼酸重氮盐化合物为下列之一:对氟苯四氟硼酸重氮盐、对氯苯四氟硼酸重氮盐、对溴苯四氟硼酸重氮盐、对硝基苯四氟硼酸重氮盐、对甲氧基苯四氟硼酸重氮盐、间氯苯四氟硼酸重氮盐、2-((四氟-λ5-硼烷基)二氮烯基)吡啶、2-((四氟-λ5-硼烷基)二氮烯基)苯并[d]噻唑;
式2中的HetAr/Ar为1,3,5-三甲氧基苯、均三甲苯、对二甲苯、对二氯苯、吡嗪、2-甲基噻吩、苯并噻唑、1,3-二甲基吲哚、2-苯基-2H-吲唑。
进一步地,本发明还限定了芳基四氟硼酸重氮盐、式2所示的HetAr/Ar及研磨助剂的投料物质的量之比为1.0 : 2.0~5.0 : 3.0~15.0。
进一步地,本发明还限定了芳基四氟硼酸重氮盐为下列之一:对氟苯四氟硼酸重氮盐、对氯苯四氟硼酸重氮盐、对溴苯四氟硼酸重氮盐、对硝基苯四氟硼酸重氮盐、对甲氧基苯四氟硼酸重氮盐、间氯苯四氟硼酸重氮盐、2-((四氟-λ5-硼烷基)二氮烯基)吡啶、2-((四氟-λ5-硼烷基)二氮烯基)苯并[d]噻唑;
2-((四氟-λ5-硼烷基)二氮烯基)吡啶、2-((四氟-λ5-硼烷基)二氮烯基)苯并[d]噻唑的结构式如下所示:
进一步地,本发明还限定了研磨助剂为下列一种或任意两种等物质的量的组合:氯化钠、溴化钠、碘化钠、氯化钾、溴化钾、碘化钾、氯化锂、溴化锂、氯化镁、溴化镁。
进一步地,本发明还限定了式1所示的芳基四氟硼酸重氮盐与研磨助剂的投料物质的量之比优选为1.0 : 3.0~8.0。
进一步地,本发明还限定了机械研磨方法为:将原料、研磨助剂及不锈钢小球分别加入不锈钢研磨罐中,拧紧研磨罐盖,并将其置于振摆式研磨仪中,在10~30 Hz研磨频率下机械研磨,TLC跟踪至原料反应完全;机械研磨的反应时间为20~70分钟,优选为30~40分钟。
更进一步地,本发明还限定了反应混合物分离纯化的方法为:将全部反应混合物从球磨罐中倒出,取出不锈钢球,得到固体粉末,用体积比为100:1~5:1的石油醚和乙酸乙酯为洗脱剂,对固体粉末进行柱层析分离,收集含目标化合物的洗脱液,进行减压蒸馏,即得式3所示的联/杂芳烃类化合物纯品。
本发明还限定了一种联/杂芳烃类化合物,它由本发明权利要求1-8 中任意一项所述的制备方法制得。
本发明所述的方法适用于联/杂芳烃类化合物的构建。
本发明有益效果主要体现在:
1)本发明方法首次采用机械研磨的方式直接诱导芳基四氟硼酸重氮盐裂解进行自由基芳基化反应,快速、高效地制备了联/杂芳烃类化合物;
2)本发明方法反应体系简单,能够有效革除光催化剂、外源性还原试剂、弱亲核试剂或碱试剂的使用;
3)本发明方法反应在无溶剂条件下进行,在降低反应成本的同时,减少了潜在的环境污染及安全隐患的问题。
综上所述,本发明方法的优点包括:反应时间短、体系简单、成本低、操作简便、环境友好,是一种具有较好推广前景的绿色化学合成方法。
具体实施方式
下面结合具体实施例对本发明方法进行进一步描述,但本发明的保护范围并不仅限于此。
实施例1 4'-氯-2,4,6-三甲氧基-1,1'-联苯的制备
在15 ml不锈钢制研磨罐中加入对氯苯四氟硼酸重氮盐(113.2 mg, 0.5 mmol),1,3,5-三甲氧基苯(336.4 mg, 2.0 mmol),氯化钠(146.3 mg, 2.5 mmol),再加入1颗直径12 mm的不锈钢球,将研磨罐拧紧,放入振摆式研磨仪中,在30 Hz的频率下研磨30分钟。反应结束后,将全部反应混合物从研磨罐中倒出,取出不锈钢球,将固体粉末直接用石油醚和乙酸乙酯(体积比为100 : 1)的洗脱剂进行柱层析分离,所得含目标化合物的洗脱液减压浓缩,得到4'-氯-2,4,6-三甲氧基-1,1'-联苯,76.6 mg,收率55%。
白色固体,熔点:90.3–93.3 ℃,1H NMR (400 MHz, Chloroform-d) δ 7.36–7.33(m, 2H), 7.29–7.25 (m, 2H, subtracting CDCl3), 6.23 (s, 2H), 3.87 (s, 3H),3.73 (s, 6H)。
实施例2 4'-氯-2,4,6-三甲氧基-1,1'-联苯的制备
在15 ml不锈钢制研磨罐中加入对氯苯四氟硼酸重氮盐(113.2 mg, 0.5 mmol),1,3,5-三甲氧基苯(336.4 mg, 2.0 mmol),溴化钠(257.3 mg, 2.5 mmol),再加入1颗直径10 mm的不锈钢球,将研磨罐拧紧,放入振摆式研磨仪中,在30 Hz的频率下研磨30分钟。反应结束后,将全部反应混合物从研磨罐中倒出,取出不锈钢球,将固体粉末直接用石油醚和乙酸乙酯(体积比为100 : 1)的洗脱剂进行柱层析分离,所得含目标化合物的洗脱液减压浓缩,得到4'-氯-2,4,6-三甲氧基-1,1'-联苯,71.1 mg,收率51%。物性数据同实施例1。
实施例3 4'-氯-2,4,6-三甲氧基-1,1'-联苯的制备
在15 ml不锈钢制研磨罐中加入对氯苯四氟硼酸重氮盐(113.2 mg, 0.5 mmol),1,3,5-三甲氧基苯(336.4 mg, 2.0 mmol),氯化钾(186.3 mg, 2.5 mmol),再加入2颗直径10 mm的不锈钢球,将研磨罐拧紧,放入振摆式研磨仪中,在25 Hz的频率下研磨60分钟。反应结束后,将全部反应混合物从研磨罐中倒出,取出不锈钢球,将固体粉末直接用石油醚和乙酸乙酯(体积比为100 : 1)的洗脱剂进行柱层析分离,所得含目标化合物的洗脱液减压浓缩,得到4'-氯-2,4,6-三甲氧基-1,1'-联苯,75.2 mg,收率54%。物性数据同实施例1。
实施例4 4'-硝基-2,4,6-三甲氧基-1,1'-联苯的制备
在25 ml不锈钢制研磨罐中加入对硝基苯四氟硼酸重氮盐(118.5 mg, 0.5mmol),1,3,5-三甲氧基苯(420.5 mg, 2.5 mmol),氯化钠(87.8 mg, 1.5 mmol),再加入2颗直径8 mm的不锈钢球,将研磨罐拧紧,放入振摆式研磨仪中,在10 Hz的频率下研磨70分钟。反应结束后,将全部反应混合物从研磨罐中倒出,取出不锈钢球,将固体粉末直接用石油醚和乙酸乙酯(体积比为40 : 1)的洗脱剂进行柱层析分离,所得含目标化合物的洗脱液减压浓缩,得到4'-硝基-2,4,6-三甲氧基-1,1'-联苯,55.0 mg,收率38%。
黄色固体,熔点:167.2–168.3 ℃,1H NMR (400 MHz, Chloroform-d) δ 8.24–8.19 (m, 2H), 7.53–7.49 (m, 2H), 6.24 (s, 2H), 3.88 (s, 3H), 3.74 (s, 6H)。
实施例5 2,4,4',6-四甲氧基-1,1'-联苯的制备
在50 ml不锈钢制研磨罐中加入对甲氧基苯四氟硼酸重氮盐(110.1 mg, 0.5mmol),1,3,5-三甲氧基苯(252.3 mg, 1.5 mmol),氯化钠(438.8 mg, 7.5 mmol),再加入1颗直径12 mm的不锈钢球,将研磨罐拧紧,放入振摆式研磨仪中,在20 Hz的频率下研磨50分钟。反应结束后,将全部反应混合物从研磨罐中倒出,取出不锈钢球,将固体粉末直接用石油醚和乙酸乙酯(体积比为40 : 1)的洗脱剂进行柱层析分离,所得含目标化合物的洗脱液减压浓缩,得到2,4,4',6-四甲氧基-1,1'-联苯,59.0 mg,收率43%。
白色固体,熔点:101.1–102.9 ℃,1H NMR (400 MHz, Chloroform-d) δ 7.31–7.20 (m, 2H), 7.01–6.85 (m, 2H), 6.23 (s, 2H), 3.86 (s, 3H), 3.83 (s, 3H),3.73 (s, 6H)。
实施例6 4'-溴-2,4,6-三甲基-1,1'-联苯的制备
在15 ml不锈钢制研磨罐中加入对溴苯四氟硼酸重氮盐(135.4 mg, 0.5 mmol),均三甲苯(240.4 mg, 2.0 mmol),溴化钾(297.5 mg, 2.5 mmol),再加入1颗直径12 mm的不锈钢球,将研磨罐拧紧,放入振摆式研磨仪中,在30 Hz的频率下研磨30分钟。反应结束后,将全部反应混合物从研磨罐中倒出,取出不锈钢球,将固体粉末直接用石油醚和乙酸乙酯(体积比为40 : 1)的洗脱剂进行柱层析分离,所得含目标化合物的洗脱液减压浓缩,得到4'-溴-2,4,6-三甲基-1,1'-联苯,75.7 mg,收率55%。
白色固体,熔点:70.2–71.3 ℃,1H NMR (400 MHz, Chloroform-d) δ 7.60–7.51(m, 2H), 7.06–7.00 (m, 2H), 6.96 (s, 2H), 2.35 (s, 3H), 2.01 (s, 6H)。
实施例7 4'-甲氧基-2,4,6-三甲基-1,1'-联苯的制备
在15 ml不锈钢制研磨罐中加入对甲氧基苯四氟硼酸重氮盐(110.1 mg, 0.5mmol),均三甲苯(240.4 mg, 2.0 mmol),氯化锂(106.0 mg, 2.5 mmol),再加入1颗直径12mm的不锈钢球,将研磨罐拧紧,放入振摆式研磨仪中,在30 Hz的频率下研磨20分钟。反应结束后,将全部反应混合物从研磨罐中倒出,取出不锈钢球,将固体粉末直接用石油醚和乙酸乙酯(体积比为40 : 1)的洗脱剂进行柱层析分离,所得含目标化合物的洗脱液减压浓缩,得到4'-甲氧基-2,4,6-三甲基-1,1'-联苯,57.7 mg,收率51%。
无色固体,熔点:73.1–74.2 ℃,1H NMR (400 MHz, Chloroform-d) δ 7.08 (d,J = 8.7 Hz, 2H), 7.01–6.94 (m, 4H), 3.88 (s, 3H), 2.35 (s, 3H), 2.04 (s, 6H)。
实施例8 3'-氯-2,4,6-三甲基-1,1'-联苯的制备
在15 ml不锈钢制研磨罐中加入间氯苯四氟硼酸重氮盐(113.2 mg, 0.5 mmol),均三甲苯(240.4 mg, 2.0 mmol),溴化锂(217.0 mg, 2.5 mmol),再加入1颗直径12 mm的不锈钢球,将研磨罐拧紧,放入振摆式研磨仪中,在30 Hz的频率下研磨30分钟。反应结束后,将全部反应混合物从研磨罐中倒出,取出不锈钢球,将固体粉末直接用石油醚和乙酸乙酯(体积比为40 : 1)的洗脱剂进行柱层析分离,所得含目标化合物的洗脱液减压浓缩,得到3'-氯-2,4,6-三甲基-1,1'-联苯,63.4 mg,收率55%。
无色液体,1H NMR (400 MHz, Chloroform-d) δ 7.44–7.33 (m, 2H), 7.20 (s,1H), 7.08 (d, J = 7.1 Hz, 1H), 6.99 (s, 2H), 2.38 (s, 3H), 2.05 (s, 6H)。
实施例9 2-(4-氟苯基)-5-甲基噻吩的制备
在15 ml不锈钢制研磨罐中加入对氟苯四氟硼酸重氮盐(105.0 mg, 0.5 mmol),2-甲基噻吩(196.4 mg, 2.0 mmol),氯化钠/氯化钾(43.9 : 55.9 mg, 0.75 : 0.75mmol),再加入1颗直径12 mm的不锈钢球,将研磨罐拧紧,放入振摆式研磨仪中,在30 Hz的频率下研磨30分钟。反应结束后,将全部反应混合物从研磨罐中倒出,取出不锈钢球,将固体粉末直接用石油醚和乙酸乙酯(体积比为100 : 1)的洗脱剂进行柱层析分离,所得含目标化合物的洗脱液减压浓缩,得到2-(4-氟苯基)-5-甲基噻吩,61.5 mg,收率64%。
白色固体,熔点:64–67 ℃,1H NMR (500 MHz, Chloroform-d) δ 7.53–7.48 (m,2H), 7.08–7.01 (m, 3H), 6.76–6.69 (m, 1H), 2.51 (d, J = 1.0 Hz, 3H)。
实施例10 2-(5-甲基噻吩)-2-吡啶的制备
在15 ml不锈钢制研磨罐中加入2-((四氟-λ5-硼烷基)二氮烯基)吡啶(96.2 mg,0.5 mmol),2-甲基噻吩(196.4 mg, 2.0 mmol),碘化钾(664.0 mg, 4.0 mmol),再加入1颗直径12 mm的不锈钢球,将研磨罐拧紧,放入振摆式研磨仪中,在30 Hz的频率下研磨30分钟。反应结束后,将全部反应混合物从研磨罐中倒出,取出不锈钢球,将固体粉末直接用石油醚和乙酸乙酯(体积比为100 : 1)的洗脱剂进行柱层析分离,所得含目标化合物的洗脱液减压浓缩,得到2-(5-甲基噻吩)-2-吡啶,58.7 mg,收率67%。
白色固体,熔点:77–78 ℃,1H-NMR (500 MHz, Chloroform-d) δ 2.52 (s, 3H),6.76 (d, J = 3.5 Hz, 1H), 7.09 (dd, J = 7.1, 4.9 Hz, 1H), 7.38 (d, J = 3.5Hz, 1H), 7.57 (d, J = 8.0 Hz, 1H), 7.64 (td, J = 7.7, 1.7 Hz, 1H), 8.53 (dd,J = 4.9, 1.7 Hz, 1H)。
实施例11 2-(4-甲基环戊-1,3-二烯-1-基)苯并[d]噻唑的制备
在15 ml不锈钢制研磨罐中加入2-((四氟-λ5-硼烷基)二氮烯基)苯并[d]噻唑(124.5 mg, 0.5 mmol),苯并噻唑(270.4 mg, 2.0 mmol),氯化钠(146.3 mg, 2.5 mmol),再加入1颗直径12 mm的不锈钢球,将研磨罐拧紧,放入振摆式研磨仪中,在30 Hz的频率下研磨30分钟。反应结束后,将全部反应混合物从研磨罐中倒出,取出不锈钢球,将固体粉末直接用石油醚和乙酸乙酯(体积比为40 : 1)的洗脱剂进行柱层析分离,所得含目标化合物的洗脱液减压浓缩,得到2-(4-甲基环戊-1,3-二烯-1-基)苯并[d]噻唑,67.1 mg,收率58%。
黄色液体,1H NMR (400 MHz, Chloroform-d) δ 7.99 (d, J = 8.0 Hz, 1H),7.83 (d, J = 8.0 Hz. 1H), 7.47−7.43 (m, 2H), 7.35−7.32 (m, 1H), 6.80−6.79 (m,1H), 2.56 (s, 3H)。
实施例12 2-(4-甲氧基苯基)吡嗪的制备
在15 ml不锈钢制研磨罐中加入对甲氧基苯四氟硼酸重氮盐(110.1 mg, 0.5mmol),吡嗪(160.2 mg, 2.0 mmol),氯化钠(146.3 mg, 2.5 mmol),再加入1颗直径12 mm的不锈钢球,将研磨罐拧紧,放入振摆式研磨仪中,在30 Hz的频率下研磨50分钟。反应结束后,将全部反应混合物从研磨罐中倒出,取出不锈钢球,将固体粉末直接用石油醚和乙酸乙酯(体积比为5 : 1)的洗脱剂进行柱层析分离,所得含目标化合物的洗脱液减压浓缩,得到2-(4-甲氧基苯基)吡嗪,40.0 mg,收率43%。
黄色固体,熔点:85.6–87.0 ℃,1H NMR (400 MHz, Chloroform-d) δ 8.97 (d,J = 1.3 Hz, 1H), 8.57 (dd, J = 2.4, 1.6 Hz, 1H), 8.43 (d, J = 2.5 Hz, 1H),8.02–7.92 (m, 2H), 7.07–6.96 (m, 2H), 3.87 (s, 3H)。
实施例13 2-(4-氯苯基)苯并[d]噻唑的制备
在15 ml不锈钢制研磨罐中加入对氯苯四氟硼酸重氮盐(113.2 mg, 0.5 mmol),苯并噻唑(270.4 mg, 2.0 mmol),氯化钠(146.3 mg, 2.5 mmol),再加入1颗直径12 mm的不锈钢球,将研磨罐拧紧,放入振摆式研磨仪中,在30 Hz的频率下研磨30分钟。反应结束后,将全部反应混合物从研磨罐中倒出,取出不锈钢球,将固体粉末直接用石油醚和乙酸乙酯(体积比为20 : 1)的洗脱剂进行柱层析分离,所得含目标化合物的洗脱液减压浓缩,得到2-(4-氯苯基)苯并[d]噻唑,70.0 mg,收率57%。
白色固体,熔点:110.1–112.3 ℃,1H NMR (400 MHz, Chloroform-d) δ 8.07(d, J = 8.1 Hz, 1H), 8.02 (d, J = 8.6 Hz, 2H), 7.89 (d, J = 8.0 Hz, 1H),7.56–7.49 (m, 1H), 7.49–7.44 (m, 2H), 7.42–7.37 (m, 1H)。
实施例14 3-(4-氯苯基)-2-苯基-2H-吲唑的制备
在15 ml不锈钢制研磨罐中加入对氯苯四氟硼酸重氮盐(113.2 mg, 0.5 mmol),2-苯基-2H-吲唑(194.2 mg, 1.0 mmol),氯化钠(146.3 mg, 2.5 mmol),再加入1颗直径12mm的不锈钢球,将研磨罐拧紧,放入振摆式研磨仪中,在30 Hz的频率下研磨30分钟。反应结束后,将全部反应混合物从研磨罐中倒出,取出不锈钢球,将固体粉末直接用石油醚和乙酸乙酯(体积比为30 : 1)的洗脱剂进行柱层析分离,所得含目标化合物的洗脱液减压浓缩,得到3-(4-氯苯基)-2-苯基-2H-吲唑,62.5 mg,收率41%。
黄色固体,熔点:132.8–133.9 ℃,1H NMR (400 MHz, Chloroform-d) δ 7.81(d, J = 8.8 Hz, 1H), 7.68 (d, J = 8.5 Hz, 1H), 7.40 (m, 8H), 7.29 (d, J = 8.5Hz, 2H), 7.17 (dd, J = 8.4, 6.7 Hz, 1H)。
实施例15 2-(4-甲氧基苯基)-1,3-二甲基吲哚的制备
在15 ml不锈钢制研磨罐中加入对甲氧基苯四氟硼酸重氮盐(110.1 mg, 0.5mmol),1,3-二甲基吲哚(363.0 mg, 2.5 mmol),碘化钠(374.8 mg, 2.5 mmol),再加入1颗直径12 mm的不锈钢球,将研磨罐拧紧,放入振摆式研磨仪中,在30 Hz的频率下研磨30分钟。反应结束后,将全部反应混合物从研磨罐中倒出,取出不锈钢球,将固体粉末直接用石油醚和乙酸乙酯(体积比为50 : 1)的洗脱剂进行柱层析分离,所得含目标化合物的洗脱液减压浓缩,得到2-(4-甲氧基苯基)-1,3-二甲基吲哚,109.3 mg,收率87%。
黄色固体,熔点:125.6–126.8 ℃,1H NMR (400 MHz, Chloroform-d) δ 7.68(d, J = 7.8 Hz, 1H), 7.40 (d, J = 8.2 Hz, 3H), 7.33 (t, J = 7.6 Hz, 1H),7.27–7.21 (m, 1H), 7.10 (d, J = 8.6 Hz, 2H), 3.94 (s, 3H), 3.67 (s, 3H), 2.37(s, 3H)。
实施例16 4'-甲氧基-2,5-二甲基-1,1'-联苯的制备
在15 ml不锈钢制研磨罐中加入对甲氧基苯四氟硼酸重氮盐(110.1 mg, 0.5mmol),对二甲苯(212.4 mg, 2.0 mmol),溴化镁/氯化钠(230.1 : 73.1 mg, 1.25 : 1.25mmol),再加入1颗直径12 mm的不锈钢球,将研磨罐拧紧,放入振摆式研磨仪中,在30 Hz的频率下研磨30分钟。反应结束后,将全部反应混合物从研磨罐中倒出,取出不锈钢球,将固体粉末直接用石油醚和乙酸乙酯(体积比为40 : 1)的洗脱剂进行柱层析分离,所得含目标化合物的洗脱液减压浓缩,得到4'-甲氧基-2,5-二甲基-1,1'-联苯,39.3 mg,收率37%。
无色液体,1H NMR (400 MHz, Chloroform-d) δ 7.29–7.21 (m, 2H), 7.16 (d,J = 7.7 Hz, 1H), 7.06 (d, J = 7.1 Hz, 2H), 6.99–6.91 (m, 2H), 3.86 (s, 3H),2.35 (s, 3H), 2.24 (s, 3H)。
实施例17 3'-氯-2,5-二甲基-1,1'-联苯的制备
在15 ml不锈钢制研磨罐中加入间氯苯四氟硼酸重氮盐(113.2 mg, 0.5 mmol),对二甲苯(212.4 mg, 2.0 mmol),氯化镁/溴化钾(119.0 : 148.8 mg, 1.25 : 1.25mmol),再加入1颗直径12 mm的不锈钢球,将研磨罐拧紧,放入振摆式研磨仪中,在30 Hz的频率下研磨30分钟。反应结束后,将全部反应混合物从研磨罐中倒出,取出不锈钢球,将固体粉末直接用石油醚和乙酸乙酯(体积比为40 : 1)的洗脱剂进行柱层析分离,所得含目标化合物的洗脱液减压浓缩,得到3'-氯-2,5-二甲基-1,1'-联苯,45.5 mg,收率42%。
无色液体,1H NMR (400 MHz, Chloroform-d) δ 7.36–7.29 (m, 3H), 7.20(dt, J = 6.5, 2.0 Hz, 1H), 7.17 (d, J = 7.7 Hz, 1H), 7.09 (d, J = 7.8 Hz,1H), 7.03 (s, 1H), 2.35 (s, 3H), 2.23 (s, 3H)。
实施例18 2,5-二氯-4'-甲氧基-1,1'-联苯的制备
在15 ml不锈钢制研磨罐中加入对甲氧基苯四氟硼酸重氮盐(110.1 mg, 0.5mmol),对二氯苯(294.0 mg, 2.0 mmol),氯化钠(87.8 mg, 1.5 mmol),再加入1颗直径12mm的不锈钢球,将研磨罐拧紧,放入振摆式研磨仪中,在30 Hz的频率下研磨30分钟。反应结束后,将全部反应混合物从研磨罐中倒出,取出不锈钢球,将固体粉末直接用石油醚和乙酸乙酯(体积比为40 : 1)的洗脱剂进行柱层析分离,所得含目标化合物的洗脱液减压浓缩,得到2,5-二氯-4'-甲氧基-1,1'-联苯,46.8 mg,收率37%。
白色固体,熔点:51.3–52.5 ℃,1H NMR (400 MHz, Chloroform-d) δ 7.41–7.34(m, 3H), 7.33 (d, J = 2.5 Hz, 1H), 7.23 (dd, J = 8.5, 2.6 Hz, 1H), 7.00–6.95(m, 2H), 3.86 (s, 3H)。
对比例1 4'-溴-2,4,6-三甲基-1,1'-联苯的制备(Chem. Sci., 2017, 8,2885.)
在密封的反应管中加入对溴苯四氟硼酸重氮盐(27 mg,0.1 mmol),PPh3AuNTf2(7.8 mg,0.1 mmol,10 mol%)和Ru(bpy)3(PF6)2(2.2 mg,2.5mol%)。将密封管包裹在铝箔中,冻融脱气,随后加入CH3CN(1 ml)和均三甲苯(36 mg,0.3mmol)加入密封管中。除去铝箔,在室温和蓝色LED光照条件下反应16小时。TLC跟踪反应进度,反应结束后,用10 ml乙酸乙酯稀释反应液,水洗,乙酸乙酯萃取(10 ml×3),无水硫酸镁干燥,减压蒸除溶剂后用石油醚和乙酸乙酯(体积比为40 : 1)的洗脱剂进行柱层析分离,所得目标化合物的洗脱液减压浓缩,得到4'-溴-2,4,6-三甲基-1,1'-联苯,20.0 mg,收率73%。(对比实施例6)
对比例2 2-(4-氯苯基)苯并[d]噻唑的制备(Org. Biomol. Chem., 2019,17,4364.)
在密封的反应管中加入对氯苯四氟硼酸重氮盐(45,0.2 mmol),cercosporin(1.1mg,0.2 mol%),苯并噻唑(162 mg, 6 equiv.)和干燥的DMSO(2ml)。冻融脱气,在阳光下放置8小时。TLC跟踪反应进度,反应结束后,盐水洗涤,乙酸乙酯萃取,无水硫酸钠干燥,减压蒸除溶剂后用石油醚和乙酸乙酯(体积比为20 : 1)的洗脱剂进行柱层析分离,所得目标化合物的洗脱液减压浓缩,得到2-(4-氯苯基)苯并[d]噻唑,29.0 mg,收率60%。(对比实施例13)
由上述对比例可知,在机械化学条件下直接诱导芳基四氟硼酸重氮盐C−N键裂解,进行自由基C−H芳基化反应制备联/杂芳烃类化合物与传统的溶液反应方法相比,反应过程无需使用环境不友好的高沸溶剂如DMSO,无需添加额外的过渡金属催化剂(PPh3AuNTf2, Ru(bpy)3(PF6)2);反应时间大大缩短(分别由原来的16 h缩短至30 min;8h缩短至30 min);机械研磨反应后无需进行溶液萃取洗涤处理,可直接经柱层析分离纯化得到纯的目标产物,操作相对简便,环境友好,体系清洁廉价,反应快速高效。
Claims (7)
1.一种联/杂芳烃类化合物的制备方法,其特征在于所述方法为:以式1所示的芳基四氟硼酸重氮盐及式2所示的HetAr/Ar为原料,在研磨助剂作用下,通过机械研磨的方法进行自由基型C-H芳基化反应,反应结束后,所得反应混合物经分离纯化,即获得式3所示联/杂芳烃类化合物;
式中R代表对氟苯基,对氯苯基,对溴苯基,对硝基苯基,对甲氧基苯基,间氯苯基,2-吡啶基,2-苯并噻唑基;
式2中的HetAr/Ar为1,3,5-三甲氧基苯、均三甲苯、对二甲苯、对二氯苯、吡嗪、2-甲基噻吩、苯并噻唑、1,3-二甲基吲哚、2-苯基-2H-吲唑;
所述研磨助剂为下列一种或任意两种等物质的量的组合:氯化钠、溴化钠、碘化钠、氯化钾、溴化钾、碘化钾、氯化锂、溴化锂、氯化镁、溴化镁。
2.根据权利要求1所述的一种联/杂芳烃类化合物的制备方法,其特征在于所述式1所示的芳基四氟硼酸重氮盐、式2所示的HetAr/Ar及研磨助剂的投料物质的量之比为1.0:2.0~5.0:3.0~15.0。
3.根据权利要求1所述的一种联/杂芳烃类化合物的制备方法,其特征在于所述式1所示的芳基四氟硼酸重氮盐为下列之一:对氟苯四氟硼酸重氮盐、对氯苯四氟硼酸重氮盐、对溴苯四氟硼酸重氮盐、对硝基苯四氟硼酸重氮盐、对甲氧基苯四氟硼酸重氮盐、间氯苯四氟硼酸重氮盐、2-((四氟-λ5-硼烷基)二氮烯基)吡啶、2-((四氟-λ5-硼烷基)二氮烯基)苯并[d]噻唑。
4.根据权利要求1所述的一种联/杂芳烃类化合物的制备方法,其特征在于式1所示的芳基四氟硼酸重氮盐与研磨助剂的投料物质的量之比为1.0:3.0~8.0。
5.根据权利要求1所述的一种联/杂芳烃类化合物的制备方法,其特征在于所述的机械研磨方法为:将原料、研磨助剂及不锈钢小球分别加入不锈钢研磨罐中,拧紧研磨罐盖,并将其置于振摆式研磨仪中,在10~30Hz研磨频率下机械研磨,TLC跟踪至原料反应完全。
6.根据权利要求5所述一种联/杂芳烃类化合物的制备方法,其特征在于机械研磨的反应时间为20~70分钟。
7.根据权利要求1所述的一种联/杂芳烃类化合物的制备方法,其特征在于反应混合物分离纯化的方法为:将全部反应混合物从球磨罐中倒出,取出不锈钢球,得到固体粉末,用体积比为100:1~5:1的石油醚和乙酸乙酯为洗脱剂,对固体粉末进行柱层析分离,收集含目标化合物的洗脱液,进行减压蒸馏,即得式3所示的联/杂芳烃类化合物纯品。
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Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102515995A (zh) * | 2011-11-24 | 2012-06-27 | 浙江工业大学 | 一种偶联芳香化合物的制备方法 |
CN102643152A (zh) * | 2012-05-14 | 2012-08-22 | 黑龙江大学 | 一种纳米钯催化联苯类化合物的绿色合成方法 |
CN107353227A (zh) * | 2016-05-09 | 2017-11-17 | 浙江工业大学 | 一种机械力促进下合成联苯o-甲基肟醚类化合物和联苯羰基类化合物的方法 |
CN108484411A (zh) * | 2018-04-19 | 2018-09-04 | 浙江工业大学 | 一种机械力促进碳-氮键形成的方法 |
-
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Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102515995A (zh) * | 2011-11-24 | 2012-06-27 | 浙江工业大学 | 一种偶联芳香化合物的制备方法 |
CN102643152A (zh) * | 2012-05-14 | 2012-08-22 | 黑龙江大学 | 一种纳米钯催化联苯类化合物的绿色合成方法 |
CN107353227A (zh) * | 2016-05-09 | 2017-11-17 | 浙江工业大学 | 一种机械力促进下合成联苯o-甲基肟醚类化合物和联苯羰基类化合物的方法 |
CN108484411A (zh) * | 2018-04-19 | 2018-09-04 | 浙江工业大学 | 一种机械力促进碳-氮键形成的方法 |
Non-Patent Citations (3)
Title |
---|
Dual gold and photoredox catalyzed C-H activation of arenes for aryl-aryl cross couplings;Gauchot, V. et al;《Chemical Science》;20170127;第8卷(第4期);第2885-2889页 * |
Mechanically Activated Solid-State Synthesis of Phenylhydrazone Derivatives via High-Speed Ball Milling;Zhu, Xingyi et al;《Letters in Organic Chemistry》;20141231;第11卷(第8期);第621-626页 * |
Perylenequinonoid-catalyzed photoredox activation for the direct arylation of (het)arenes with sunlight;Zhang, Shiwei et al;《Organic & Biomolecular Chemistry》;20190409;第17卷(第17期);第4364-4369页 * |
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