CN110218229B - 一种β-巯基氮杂磷杂环类衍生物及其制备方法 - Google Patents
一种β-巯基氮杂磷杂环类衍生物及其制备方法 Download PDFInfo
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Classifications
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Abstract
本发明公开了一种β‑巯基氮杂磷杂环类衍生物及其制备方法,包括以下步骤:将炔烃、磷试剂、异硫氰酸三甲基硅酯、铜催化剂和过氧化物溶于溶剂中,于30~70℃下反应,获得β‑硫氰基烯基膦酰类衍生物;然后以β‑硫氰基烯基膦酰类衍生物为原料,在锌催化剂和醋酸的存在下,制备得到β‑硫羰基膦酰类衍生物;然后以β‑硫羰基膦酰类衍生物为原料,在亚磷酸酯、三氟甲磺酸亚铜、二叔丁基过氧化物存在下,制备得到β‑硫羰基双膦酰类衍生物;最后以β‑硫羰基双膦酰类衍生物为原料,在乙醇钠、盐酸存在下,制备得到β‑巯基氮杂磷杂环类衍生物。本发明步骤简单、反应条件温和、目标产物的收率高、污染小、反应操作和后处理过程简单,适合于工业化生产。
Description
本发明属于发明名称为一种β-硫氰基烯基膦酰类衍生物及其制备方法、申请日为2017年9月8日、申请号为201710808044.0发明申请的分案申请,属于衍生物的制备方法部分。
技术领域
本发明属于有机化合物的制备技术领域,具体涉及一种β-巯基氮杂磷杂环类衍生物及制备方法。
背景技术
有机膦药物在治疗癌症、消炎、抗骨质疏松等领域具有重要的应用价值;有机膦合成酶是一类重要的抗癌药物,它可以加快肿瘤细胞的凋亡速度,从而起到抗癌的作用。此外,有机膦化合物还具有消炎作用,对多发性关节炎具有良好的治疗效果(Kamel, A. A.,Geronikaki, A., Abdou, W. M. Inhibitory effect of novel S, N-bisphosphonateson some carcinoma cell lines, osteoarthritis, and chronic inflammation. Eur. J. Med. Chem. 2012, 51, 239.)。
W. M. Abdou等人公开了一种含S, N的双磷酸酯类化合物的合成方法,并对化合物的抗癌和消炎活性进行测试,体外测试结果表明,化合物对测试的乳腺癌细胞、宫颈癌细胞、肝癌细胞、结肠癌细胞都表现出明显的抗癌活性;此外,它们对多发性关节炎也具有较好的消炎活性,值得一提的是,化合物对正常细胞没有表现出明显的毒性,具有较好的应用前景。该方法以苯并噻嗪-2,4-二硫酮为原料,经过二磷酰基亚甲基化、脱CS2、环化等过程得到化合物;原料难得、路线长、反应条件苛刻、无选择性,且反应中释放出有毒液体CS2,极易挥发,有恶臭味,可经呼吸道和皮肤侵入人体,伤害神经系统和血管,造成心血管疾病。因此开发反应条件温和、适用范围广泛、反应步骤简洁、原材料简单易得的合成方法非常重要。
发明内容
本发明的目的是提供一种制备β-硫氰基烯基膦酰类衍生物及相关衍生产品的方法,其具有原料来源简单、反应条件温和、后处理简单、产率高等优点。
为达到上述发明目的,本发明采用的技术方案是:一种制备β-硫氰基烯基膦酰类衍生物的方法,包括以下步骤:将炔烃、磷试剂、异硫氰酸三甲基硅酯、铜催化剂和过氧化物溶于溶剂中,于30~70℃下反应,获得β-硫氰基烯基膦酰类衍生物。
本发明还公开了一种β-硫羰基膦酰类衍生物的制备方法,包括以下步骤:将炔烃、磷试剂、异硫氰酸三甲基硅酯、铜催化剂和过氧化物溶于溶剂中,于30~70℃下反应,获得β-硫氰基烯基膦酰类衍生物;然后以β-硫氰基烯基膦酰类衍生物为原料,在锌催化剂和醋酸的存在下,制备得到β-硫羰基膦酰类衍生物。
本发明还公开了一种β-硫羰基双膦酰类衍生物的制备方法,包括以下步骤:将炔烃、磷试剂、异硫氰酸三甲基硅酯、铜催化剂和过氧化物溶于溶剂中,于30~70℃下反应,获得β-硫氰基烯基膦酰类衍生物;然后以β-硫氰基烯基膦酰类衍生物为原料,在锌催化剂和醋酸的存在下,制备得到β-硫羰基膦酰类衍生物;然后以β-硫羰基膦酰类衍生物为原料,在亚磷酸酯、三氟甲磺酸亚铜、二叔丁基过氧化物存在下,制备得到β-硫羰基双膦酰类衍生物。
本发明还公开了一种β-巯基氮杂磷杂环类衍生物的制备方法,包括以下步骤:将炔烃、磷试剂、异硫氰酸三甲基硅酯、铜催化剂和过氧化物溶于溶剂中,于30~70℃下反应,获得β-硫氰基烯基膦酰类衍生物;然后以β-硫氰基烯基膦酰类衍生物为原料,在锌催化剂和醋酸的存在下,制备得到β-硫羰基膦酰类衍生物;然后以β-硫羰基膦酰类衍生物为原料,在亚磷酸酯、三氟甲磺酸亚铜、二叔丁基过氧化物存在下,制备得到β-硫羰基双膦酰类衍生物;最后以β-硫羰基双膦酰类衍生物为原料,在乙醇钠、盐酸存在下,制备得到β-巯基氮杂磷杂环类衍生物。
本发明还公开了一种β-硫代吲哚酮类衍生物的制备方法,包括以下步骤:将炔烃、磷试剂、异硫氰酸三甲基硅酯、铜催化剂和过氧化物溶于溶剂中,于30~70℃下反应,获得β-硫氰基烯基膦酰类衍生物;然后以β-硫氰基烯基膦酰类衍生物为原料,在锌催化剂和醋酸的存在下,制备得到β-硫羰基膦酰类衍生物;然后以β-硫羰基膦酰类衍生物为原料,在亚磷酸酯、三氟甲磺酸亚铜、二叔丁基过氧化物存在下,制备得到β-硫羰基双膦酰类衍生物;最后以β-硫羰基双膦酰类衍生物为原料,在亚碘酰苯、四正丁基碘化胺存在下,制备得到β-硫代吲哚酮类衍生物。
本发明还公开了炔烃、磷试剂、异硫氰酸三甲基硅酯作为原料在制备β-硫氰基烯基膦酰类衍生物中的应用;或者铜催化剂、过氧化物作为添加剂在制备β-硫氰基烯基膦酰类衍生物中的应用。
上述应用中,将炔烃、磷试剂、异硫氰酸三甲基硅酯、铜催化剂和过氧化物溶于溶剂中,于30~70℃下反应,获得β-硫氰基烯基膦酰类衍生物。
本发明中,所述炔烃的化学结构式为下列化学结构中的一种:
其中,R1选自烷基、烷氧基、卤素、硝基、氰基、酯基中的一种;Y选自O、S、N中的一种;R3选自烷基、烷氧基、卤素中的一种。
本发明所述磷试剂如下列结构通式所示:
其中R4选自烷氧基或芳基。
本发明所述铜催化剂的化学式为CuXn,其中X为Cl、Br、I或SCN中的一种;n为1或2;
本发明所述β-硫氰基烯基膦酰类衍生物如下列化学结构通式所示:
本发明所述β-硫羰基膦酰类衍生物如下列化学结构通式所示:
本发明所述β-硫羰基双膦酰类衍生物如下列化学结构通式所示:
本发明所述β-巯基氮杂磷杂环类衍生物如下列化学结构式所示:
本发明所述β-硫代吲哚酮类衍生物如下列化学结构式所示:
本发明所述溶剂选自乙醇、乙腈、四氢呋喃、丙酮、甲苯、N,N-二甲基甲酰胺或N-甲基吡咯烷酮中的一种。
本发明所述炔烃可以如下列化学结构式:
优选的,所述炔烃选自: 苯乙炔、2-甲基氨基苯乙炔、4-甲基苯乙炔、4-甲氧基苯乙炔、4-氟苯乙炔、4-氯苯乙炔、4-溴苯乙炔、4-硝基苯乙炔、4-乙炔基苯甲酸甲酯、3-甲基苯乙炔、3-甲氧基苯乙炔、3-氯苯乙炔、2-氯苯乙炔、二苯乙炔、2-乙炔基噻吩、2-乙炔基吡啶、4-苯基丁炔、5-苯基戊炔、1-苯基丁炔-3-酮、2-环丙基乙炔、正庚-1-炔、正壬-1-炔、正癸-1-炔、己-3-炔、甲基炔丙基醚、二(炔丙基)醚、三甲基硅基乙炔中的一种;所述磷试剂选自: 二甲基亚磷酸酯、二乙基亚磷酸酯、二苯氧膦、二(4-甲氧基苯基)氧膦或二(4-氰基苯基)氧膦中的一种。
上述技术方案中,利用薄层层析色谱(TLC)跟踪反应直至完全结束。
上述技术方案中,按摩尔比,炔烃∶磷试剂∶异硫氰酸三甲基硅酯∶铜催化剂∶过氧化物为1∶(1~3)∶(1~3)∶(0.1~0.3)∶(1~3)。
上述技术方案中,反应结束后对产物进行柱层析分离提纯处理。
上述技术方案的反应过程可表示为:
由于上述技术方案的运用,本发明与现有技术相比具有下列优点:
1、本发明使用炔烃衍生物为起始物,原料易得、毒性低、成本低廉、种类多。
2、本发明适用范围广,不仅适用于芳基炔烃,对普通烷基炔烃同样适用。
3、本发明所用硫氰基试剂易得、价廉。
4、本发明公开的方法中,反应条件温和,反应时间短,目标产物的收率高,反应操作和后处理过程简单,适合于工业化生产。
具体实施方式
下面结合实施例对本发明作进一步描述:
实施例一:(2-苯基-2-硫氰基)乙烯基二苯氧膦的合成
以苯乙炔、二苯基氧膦作为原料,其反应步骤如下:
在反应瓶中加入苯乙炔(0.041克,0.4 mmol),二苯氧磷(0.081克,0.4 mmol),异硫氰酸三甲基硅酯(0.052克,0.4 mmol),CuCl(0.04g, 0.04 mmol),过氧化叔丁醇(0.051克,0.4 mmol)和乙醇(3 mL),70℃反应;
反应结束后得到的粗产物经柱层析分离(乙酸乙酯:石油醚 = 1:1),得到目标产物(产率84%)。产物的分析数据如下:1H NMR (400 MHz, CDCl3): δ 7.85 – 7.71 (m,4H), 7.67 – 7.39 (m, 11H), 6.62 (d, J = 19.1 Hz, 1H)。
实施例二:(2-(4-甲苯基)-2-硫氰基))乙烯基二苯氧膦的合成
以4-甲基苯乙炔、二苯基氧膦作为原料,其反应步骤如下:
在反应瓶中加入4-甲基苯乙炔(0.046克,0.4 mmol),二苯氧磷(0.162克,0.8mmol),异硫氰酸三甲基硅酯(0.104克,0.8 mmol),CuCl(0.08g, 0.08 mmol),过氧化叔丁醇(0.102克,0.8 mmol)和乙腈(3 mL),60℃反应;
反应结束后得到的粗产物经柱层析分离(乙酸乙酯:石油醚 = 1:1),得到目标产物(产率86%)。产物的分析数据如下:1H NMR (400 MHz, CDCl3): δ 7.81 – 7.71 (m,4H), 7.61 – 7.49 (m, 6H), 7.44 – 7.40 (d, J = 8.1 Hz, 2H), 7.24 (s, 2H), 6.60(d, J = 19.1 Hz, 1H), 2.39 (s, 3H)。
实施例三:(2-(3-甲苯基)-2-硫氰基))乙烯基二苯氧膦的合成
以3-甲基苯乙炔、二苯基氧膦作为原料,其反应步骤如下:
在反应瓶中加入3-甲基苯乙炔(0.046克,0.4 mmol),二苯氧磷(0.243克,1.2mmol),异硫氰酸三甲基硅酯(0.154克,1.2 mmol),CuCl(0.12g, 0.12 mmol),过氧化叔丁醇(0.154克,1.2 mmol)和丙酮(3 mL),50℃反应;
反应结束后得到的粗产物经柱层析分离(乙酸乙酯:石油醚 = 1:1),得到目标产物(产率89%)。产物的分析数据如下:1H NMR (400 MHz, CDCl3): δ 7.88 – 7.79 (m,4H), 7.66 – 7.54 (m, 6H), 7.48 – 7.30 (m, 3H), 7.24 (d, J = 19.0 Hz,1H), 2.37(s, 3H)。
实施例四:(2-(3-甲氧基苯基)-2-硫氰基))乙烯基二苯氧膦的合成
以3-甲氧基苯乙炔、二苯基氧膦作为原料,其反应步骤如下:
在反应瓶中加入3-甲氧基苯乙炔(0.053克,0.4 mmol),二苯氧磷(0.081克,0.4mmol),异硫氰酸三甲基硅酯(0.052克,0.4 mmol),CuBr(0.056g, 0.04 mmol),过氧化叔丁醇(0.154克,1.2 mmol)和四氢呋喃(3 mL),40℃反应;
反应结束后得到的粗产物经柱层析分离(乙酸乙酯:石油醚 = 1:1),得到目标产物(产率83%)。产物的分析数据如下:1H NMR (400 MHz, CDCl3): δ 7.73 – 7.70 (m,4H), 7.62 – 7.47 (m, 6H), 7.39 – 7.33 (m, 1H), 7.10 (d, J = 7.7 Hz, 1H), 7.05– 6.95 (m, 2H), 6.63 (d, J = 19.2 Hz, 1H), 3.85 (s, 3H)。
实施例五:(2-(4-甲氧基苯基)-2-硫氰基))乙烯基二苯氧膦的合成
以4-甲氧基苯乙炔、二苯基氧膦作为原料,其反应步骤如下:
在反应瓶中加入4-甲氧基苯乙炔(0.053克,0.4 mmol),二苯氧磷(0.081克,0.4mmol),异硫氰酸三甲基硅酯(0.052克,0.4 mmol),CuBr(0.112g, 0.08 mmol),过氧化叔丁醇(0.154克,1.2 mmol)和甲苯(3 mL),30℃反应;
反应结束后得到的粗产物经柱层析分离(乙酸乙酯:石油醚 = 1:1),得到目标产物(产率91%)。产物的分析数据如下:1H NMR (400 MHz, CDCl3): δ 7.8 – 7.72 (m,4H), 7.60 – 7.48 (m, 8H), 6.95 (d, J = 8.8 Hz, 2H), 6.58 (d, J = 18.9 Hz,2H), 3.85 (s, 3H)。
实施例六:(2-(2-氯苯基)-2-硫氰基))乙烯基二苯氧膦的合成
以2-氯苯乙炔、二苯基氧膦作为原料,其反应步骤如下:
在反应瓶中加入2-氯苯乙炔(0.054克,0.4 mmol),二苯氧磷(0.081克,0.4mmol),异硫氰酸三甲基硅酯(0.052克,0.4 mmol),CuBr(0.056g, 0.04 mmol),过氧化叔丁醇(0.154克,1.2 mmol)和N,N-二甲基甲酰胺(3 mL),50℃反应;
反应结束后得到的粗产物经柱层析分离(乙酸乙酯:石油醚 = 1:1),得到目标产物(产率82%)。产物的分析数据如下:1H NMR (400 MHz, CDCl3): δ 7.81 – 7.70 (m,4H), 7.62 – 7.56(m, 2H), 7.55 – 7.48 (m, 5H), 7.41 – 7.34 (m, 3H), 6.49 (d, J= 19.8 Hz, 1H)。
实施例七:(2-(3-氯苯基)-2-硫氰基))乙烯基二苯氧膦的合成
以3-氯苯乙炔、二苯基氧膦作为原料,其反应步骤如下:
在反应瓶中加入3-氯苯乙炔(0.054克,0.4 mmol),二苯氧磷(0.162克,0.8mmol),异硫氰酸三甲基硅酯(0.104克,0.8 mmol),CuI(0.076g, 0.04 mmol),过氧化叔丁醇(0.154克,1.2 mmol)和N-甲基吡咯烷酮(3 mL),50℃反应;
反应结束后得到的粗产物经柱层析分离(乙酸乙酯:石油醚 = 1:1),得到目标产物(产率80%)。产物的分析数据如下:1H NMR (400 MHz, CDCl3): δ 7.90 – 7.79 (m,4H), 7.77 (s, 1H), 7.66 – 7.52 (m, 9H), 7.38 (d, J = 18.6 Hz, 1H)。
实施例八:(2-(4-氯苯基)-2-硫氰基))乙烯基二苯氧膦的合成
以4-氯苯乙炔、二苯基氧膦作为原料,其反应步骤如下:
在反应瓶中加入4-氯苯乙炔(0.054克,0.4 mmol),二苯氧磷(0.162克,0.8mmol),异硫氰酸三甲基硅酯(0.104克,0.8 mmol),CuI(0.152g, 0.08 mmol),过氧化叔丁醇(0.154克,1.2 mmol)和N-甲基吡咯烷酮(3 mL),60℃反应;
反应结束后得到的粗产物经柱层析分离(乙酸乙酯:石油醚 = 1:1),得到目标产物(产率85%)。产物的分析数据如下:1H NMR (400 MHz, CDCl3): δ 7.79 – 7.71 (m,4.3H), 7.66 – 7.56 (m, 4.3H), 7.55 – 7.49 (m,4.3H), 7.48 – 7.42 (m, 4.3H),7.39 (dd, J = 7.6, 2.8 Hz, 1.45H), 7.30 (d, J = 8.4 Hz, 0.8H), 7.16 (d, J =8.3 Hz, 0.8H), 7.01 (d, J = 13.6 Hz, 0.4H), 6.62 (d, J = 18.8 Hz, 1H)。
实施例九:(2-(4-氟苯基)-2-硫氰基))乙烯基二苯氧膦的合成
以4-氟苯乙炔、二苯基氧膦作为原料,其反应步骤如下:
在反应瓶中加入4-氟苯乙炔(0.048克,0.4 mmol),二苯氧磷(0.162克,0.8mmol),异硫氰酸三甲基硅酯(0.104克,0.8 mmol),CuI(0.076g, 0.04 mmol),过氧化叔丁醇(0.154克,1.2 mmol)和乙腈(3 mL),70℃反应;
反应结束后得到的粗产物经柱层析分离(乙酸乙酯:石油醚 = 1:1),得到目标产物(产率75%)。产物的分析数据如下:1H NMR (400 MHz, CDCl3): δ 7.82 – 7.71 (m,4H), 7.64 – 7.45 (m, 8H), 7.19 – 7.07 (m, 2H), 6.60 (d, J = 18.9 Hz, 1H)。
实施例十:(2-(4-溴苯基)-2-硫氰基))乙烯基二苯氧膦的合成
以4-溴苯乙炔、二苯基氧膦作为原料,其反应步骤如下:
在反应瓶中加入4-溴苯乙炔(0.072克,0.4 mmol),二苯氧磷(0.081克,0.4mmol),异硫氰酸三甲基硅酯(0.052克,0.4 mmol),CuCl2(0.056g, 0.04 mmol),过氧化叔丁醇(0.154克,1.2 mmol)和乙腈(3 mL),50℃反应;
反应结束后得到的粗产物经柱层析分离(乙酸乙酯:石油醚 = 1:1),得到目标产物(产率72%)。产物的分析数据如下:1H NMR (400 MHz, CDCl3): δ 7.89 – 7.69 (m,5H), 7.66 – 7.30 (m, 16.7H), 7.24 – 7.14 (m, 1.6H), 7.01 (d, J = 13.6 Hz,0.7H) 6.62 (d, J = 18.8 Hz, 1H)。
实施例十一:(2-(4-硝基苯基)-2-硫氰基))乙烯基二苯氧膦的合成
以4-硝基苯乙炔、二苯基氧膦作为原料,其反应步骤如下:
在反应瓶中加入4-硝基苯乙炔(0.059克,0.4 mmol),二苯氧磷(0.243克,1.2mmol),异硫氰酸三甲基硅酯(0.154克,1.2 mmol),CuCl2(0.112g, 0.08 mmol),过氧化叔丁醇(0.154克,1.2 mmol)和乙腈(3 mL),50℃反应;
反应结束后得到的粗产物经柱层析分离(乙酸乙酯:石油醚 = 1:1),得到目标产物(产率70%)。产物的分析数据如下:1H NMR (400 MHz, CDCl3): δ 7.82 – 7.71 (m,4H), 7.64 – 7.45 (m, 8H), 7.19 – 7.07 (m, 2H), 6.60 (d, J = 18.9 Hz, 1H)。
实施例十二:(2-(4-甲氧基羰基苯基)-2-硫氰基))乙烯基二苯氧膦的合成
以4-乙炔基苯甲酸甲酯、二苯基氧膦作为原料,其反应步骤如下:
在反应瓶中加入4-乙炔基苯甲酸甲酯(0.064,0.4 mmol),二苯氧磷(0.243克,1.2 mmol),异硫氰酸三甲基硅酯(0.154克,1.2 mmol),CuCl2(0.056g, 0.04 mmol),过氧化叔丁醇(0.154克,1.2 mmol)和N,N-二甲基甲酰胺(3 mL),50℃反应;
反应结束后得到的粗产物经柱层析分离(乙酸乙酯:石油醚 = 1:1),得到目标产物(产率73%)。产物的分析数据如下: 1H NMR (400 MHz, CDCl3): δ 7.8 – 7.72 (m,4H), 7.60 – 7.48 (m, 8H), 6.95 (d, J = 8.8 Hz, 2H), 6.58 (d, J = 18.9 Hz,1H), 3.89 (s, 3H)。
实施例十三:(1,2-二苯基-2-硫氰基)乙烯基二苯氧膦的合成
以二苯乙炔、二苯基氧膦作为原料,其反应步骤如下:
在反应瓶中加入二苯乙炔(0.071克,0.4 mmol),二苯氧磷(0.243克,1.2mmol),异硫氰酸三甲基硅酯(0.154克,1.2 mmol),CuI2(0.128g, 0.04 mmol),过氧化叔丁醇(0.154克,1.2 mmol)和N,N-二甲基甲酰胺(3 mL),50℃反应;
反应结束后得到的粗产物经柱层析分离(乙酸乙酯:石油醚 = 1:1),得到目标产物(产率82%)。产物的分析数据如下:1H NMR (400 MHz, CDCl3): δ 7.85 – 7.71 (m,8H), 7.67 – 7.39 (m, 12H)。
实施例十四:(1-乙酰基-2-苯基-2-硫氰基)乙烯基二苯氧膦的合成
以1-苯基丁炔-3-酮、二苯基氧膦作为原料,其反应步骤如下:
在反应瓶中加入1-苯基丁炔-3-酮(0.058克,0.4 mmol),二苯氧磷(0.081克,0.4 mmol),异硫氰酸三甲基硅酯(0.052克,0.4 mmol),CuI2(0.256g, 0.08 mmol),过氧化叔丁醇(0.154克,1.2 mmol)和N,N-二甲基甲酰胺(3 mL),50℃反应;
反应结束后得到的粗产物经柱层析分离(乙酸乙酯:石油醚 = 1:1),得到目标产物(产率74%)。产物的分析数据如下:1H NMR (400 MHz, CDCl3): δ 7.91 – 7.82 (m,4H), 7.64 – 7.58 (m, 2H), 7.56 – 7.46 (m, 7H), 7.43 – 7.39 (m, 2H), 1.38 (s,3H)。
实施例十五:(2-(吡啶-2-基)-2-硫氰基)乙烯基二苯氧膦的合成
以2-乙炔基吡啶、二苯基氧磷作为原料,其反应步骤如下:
在反应瓶中加入2-乙炔基吡啶(0.041克,0.4 mmol),,二苯氧磷(0.081克,0.4mmol),异硫氰酸三甲基硅酯(0.052克,0.4 mmol),CuBr2(0.088g, 0.04 mmol),过氧化叔丁醇(0.154克,1.2 mmol)和N-甲基吡咯烷酮(3 mL),40℃反应;
反应结束后得到的粗产物经柱层析分离(乙酸乙酯:石油醚 = 1:1),得到目标产物(产率78%)。产物的分析数据如下:1H NMR (400 MHz, CDCl3): δ 7.88-7.86 (m, 1H),7.78 – 7.72 (m, 5H), 7.53 – 7.36 (m, 8H), 6.55 (d, J = 15.9 Hz, 1H)。
实施例十六:(2-(噻吩-2-基)-2-硫氰基)乙烯基二苯氧膦的合成
以2-乙炔基噻吩、二苯基氧磷作为原料,其反应步骤如下:
在反应瓶中加入2-乙炔基噻吩(0.042克,0.4 mmol),二苯氧磷(0.081克,0.4mmol),异硫氰酸三甲基硅酯(0.052克,0.4 mmol),CuBr2(0.176g, 0.08 mmol),过氧化叔丁醇(0.154克,1.2 mmol)和N-甲基吡咯烷酮(3 mL),40℃反应;
反应结束后得到的粗产物经柱层析分离(乙酸乙酯:石油醚 = 1:1),得到目标产物(产率82%)。产物的分析数据如下:1H NMR (400 MHz, CDCl3): δ 7.78 – 7.72 (m,4H), 7.53 – 7.47 (m, 6H), 7.39-7.37 (m, 1H), 7.01-6.81 (m, 2H), 6.59 (d, J =15.7 Hz, 1H)。
实施例十七:(2-(2-苯基乙基)-2-硫氰基)乙烯基二苯氧膦的合成
以4-苯基丁-1-炔、二苯基氧磷作为原料,其反应步骤如下:
在反应瓶中加入4-苯基丁-1-炔(0.053克,0.4 mmol),二苯氧磷(0.081克,0.4mmol),异硫氰酸三甲基硅酯(0.052克,0.4 mmol),CuBr2(0.088g, 0.04 mmol),过氧化叔丁醇(0.154克,1.2 mmol)和N-甲基吡咯烷酮(3 mL),40℃反应;
反应结束后得到的粗产物经柱层析分离(乙酸乙酯:石油醚 = 1:1),得到目标产物(产率75%)。产物的分析数据如下:1H NMR (400 MHz, CDCl3): δ 7.73 – 7.64 (m,4.3H), 7.61 – 7.39 (m, 10.7H), 7.24 – 7.04 (m,6.4H), 6.49 (d, J = 17.6 Hz,1H), 6.06 (d, J = 19.4 Hz, 0.4H), 3.32 – 3.26 (m, 2.1H), 3.08 – 3.01 (m,2.1H), 2.91 – 2.84 (m, 2.1H)。
实施例十八: (2-(3-苯基丙基)-2-硫氰基)乙烯基二苯氧膦的合成
以5-苯基戊-1-炔、二苯基氧磷作为原料,其反应步骤如下:
在反应瓶中加入5-苯基戊-1-炔(0.058克,0.4 mmol),二苯氧磷(0.081克,0.4mmol),异硫氰酸三甲基硅酯(0.052克,0.4 mmol),CuSCN(0.05克, 0.04 mmol),过氧化叔丁醇(0.154克,1.2 mmol)和N-甲基吡咯烷酮(3 mL),50℃反应;
反应结束后得到的粗产物经柱层析分离(乙酸乙酯:石油醚 = 1:1),得到目标产物(产率77%)。产物的分析数据如下:1H NMR (400 MHz, CDCl3): δ 7.73 – 7.64 (m,2H), 7.61 – 7.39 (m, 9H), 7.24 – 7.04 (m, 4H), 6.49 (d, J = 17.6 Hz, 1H),3.32 – 3.26 (m, 2H), 3.08 – 3.01 (m, 2H), 2.91 – 2.84 (m, 4H)。
实施例十九:(2-正戊基-2-硫氰基)乙烯基二苯氧膦的合成
以庚-1-炔、二苯基氧磷作为原料,其反应步骤如下:
在反应瓶中加入庚-1-炔(0.038克,0.4 mmol),二苯氧磷(0.081克,0.4 mmol),异硫氰酸三甲基硅酯(0.052克,0.4 mmol),CuSCN(0.10克, 0.08 mmol),过氧化叔丁醇(0.154克,1.2 mmol)和丙酮(3 mL),50℃反应;
反应结束后得到的粗产物经柱层析分离(乙酸乙酯:石油醚 = 1:1),得到目标产物(产率81%)。产物的分析数据如下:1H NMR (400 MHz, CDCl3): δ 7.95 – 7.86 (m,0.9H), 7.78 – 7.69 (m, 5.5H), 7.66 – 7.52 (m, 10H), 7.45 – 7.25 (m, 1.8H),7.01 (d, J = 19.9 Hz, 0.8H), 6.89 (d, J = 18.0 Hz, 1H), 2.99 – 2.89 (m, 3H),2.80 – 2.63 (m, 3H), 1.70 – 1.58 (m, 2H), 1.53 – 1.35 (m, 4H), 1.20 – 1.15(m, 4H), 0.89 – 0.72 (dt, J = 43.5, 6.9 Hz, 6H)。
实施例二十:(2-环丙基-2-硫氰基)乙烯基二苯氧膦的合成
以环丙基乙炔、二苯基氧磷作为原料,其反应步骤如下:
在反应瓶中加入环丙基乙炔(0.095克,0.4 mmol),二苯氧磷(0.081克,0.4mmol),异硫氰酸三甲基硅酯(0.052克,0.4 mmol),CuSCN(0.05克, 0.04 mmol),过氧化叔丁醇(0.154克,1.2 mmol)和丙酮(3 mL),60℃反应;
反应结束后得到的粗产物经柱层析分离(乙酸乙酯:石油醚 = 1:1),得到目标产物(产率71%)。产物的分析数据如下:1H NMR (400 MHz, CDCl3): δ 7.73 – 7.64 (m,4H), 7.61 – 7.39 (m, 6H), 6.49 (d, J = 15.6 Hz, 1H), 3.32 – 3.26 (m, 1H),3.08 – 3.01 (m, 2H), 2.91 – 2.84 (m, 2H)。
实施例二十一:(2-苯基-2-硫氰基)乙烯基磷酸二甲酯的合成
以苯乙炔、二甲基亚磷酸酯作为原料,其反应步骤如下:
在反应瓶中加入苯乙炔(0.041克,0.4 mmol),二甲基亚磷酸酯(0.088克,0.8mmol),异硫氰酸三甲基硅酯(0.052克,0.4 mmol),CuSCN(0.05克, 0.04 mmol),过氧化叔丁醇(0.154克,1.2 mmol)和丙酮(3 mL),30℃反应;
反应结束后得到的粗产物经柱层析分离(乙酸乙酯:石油醚 = 1:1),得到目标产物(产率84%)。产物的分析数据如下:1H NMR (400 MHz, CDCl3): δ 7.33-7.17 (m, 5H),6.62 (d, J = 18.1 Hz, 1H), 3.25 (d, J = 7.8 Hz, 6H)。
实施例二十二:(2-苯基-2-硫氰基)乙烯基磷酸二乙酯的合成
以苯乙炔、二乙基亚磷酸酯作为原料,其反应步骤如下:
在反应瓶中加入苯乙炔(0.041克,0.4 mmol),二乙基亚磷酸酯(0.110克,0.8mmol),异硫氰酸三甲基硅酯(0.052克,0.4 mmol),CuSCN(0.05克, 0.04 mmol),过氧化叔丁醇(0.154克,1.2 mmol)和N-甲基吡咯烷酮(3 mL),50℃反应;
反应结束后得到的粗产物经柱层析分离(乙酸乙酯:石油醚 = 1:1),得到目标产物(产率86%)。产物的分析数据如下:1H NMR (400 MHz, CDCl3): δ 7.33-7.17 (m, 5H),6.62 (d, J = 18.1 Hz, 1H), 4.24-4.14 (m, 4H), 1.36 (t, J = 7.5 Hz, 6H)。
实施例二十三:(2-苯基-2-硫氰基))乙烯基二(4-甲氧基苯基)氧膦的合成
以苯乙炔、二苯基氧膦作为原料,其反应步骤如下:
在反应瓶中加入苯乙炔(0.041克,0.4 mmol),二苯氧磷(0.081克,0.4 mmol),异硫氰酸三甲基硅酯(0.052克,0.4 mmol),CuSCN(0.05克, 0.04 mmol),过氧化叔丁醇(0.154克,1.2 mmol)和N-甲基吡咯烷酮(3 mL),50℃反应;
反应结束后得到的粗产物经柱层析分离(乙酸乙酯:石油醚 = 1:1),得到目标产物(产率88%)。产物的分析数据如下:1H NMR (400 MHz, CDCl3): δ 7.79-7.75 (m, 4H),7.33-7.06 (m, 9H), 6.62 (d, J = 19.1 Hz, 1H), 3.81 (s, 6H)。
实施例二十四:2-乙氧基-4-巯基-1-甲基-2-氧代-1H-苯并[1,2]氮杂磷杂环-3-亚磷酸二乙酯(4)的合成
以2-甲胺基苯乙炔、二乙基亚磷酸酯作为原料,其反应步骤如下:
在反应瓶中加入2-甲胺基苯乙炔(0.104克,0.8 mmol),加入二乙基亚磷酸酯(0.110克,0.8 mmol),异硫氰酸三甲基硅酯(0.104克,0.8 mmol),CuSCN(0.10克, 0.08mmol),过氧化叔丁醇(0.154克,1.2 mmol)和N-甲基吡咯烷酮(5 mL),50℃反应;
反应结束后得到的粗产物经柱层析分离(乙酸乙酯:石油醚 = 1:1),得到目标产物24-1(产率81%)。产物的分析数据如下:1H NMR (400 MHz, CDCl3): δ9.81 (s, 1H),7.33-7.17 (m, 5H), 6.62 (d, J = 18.9 Hz, 1H), 4.24-4.14 (m, 4H), 3.86 (s,3H), 1.36 (t, J = 7.5 Hz, 6H);
⑷在反应瓶中加入24-1 (0.978克,3 mmol)和醋酸(30 mL),向其中加入锌粉(3.0克, 45 mmol),再将混合溶液加热回流24 h。硅藻土过滤,滤液浓缩后加入乙醚,水洗两次,无水硫酸钠干燥,浓缩得产物24-2(产率98%)。产物的分析数据如下:1H NMR (300 MHz,CDCl3): δ9.81 (s, 1H), 7.33-7.17 (m, 5H), 4.54 (d, J = 13.9 Hz, 2H), 4.14-4.04 (m, 4H), 3.86 (s, 3H), 1.36 (t, J = 7.5 Hz, 6H);
⑸在反应瓶中加入24-2(0.301克,1 mmol)、三乙基亚磷酸酯(0.498克,7 mmol)、三氟甲磺酸亚铜(0.021克,0.1 mmol)、二叔丁基过氧化物(1.022克,7 mmol)和N,N-二甲基甲酰胺(5 mL),80℃反应至结束。加入20 mL水,乙酸乙酯萃取,干燥,浓缩,粗产物经柱层析分离(乙酸乙酯:石油醚 = 1:1),得到目标化合物3(产率78%)。产物的分析数据如下:1HNMR (300 MHz, CDCl3): δ9.81 (s, 1H), 7.33-7.17 (m, 5H), 4.61 – 4.58 (m, 1H),4.14-4.04 (m, 8H), 3.86 (s, 3H), 1.39 – 1.30 (m, 12H);
(6)在反应瓶中加入乙醇钠溶液(0.2克钠(9 mmol)溶于30 mL乙醇中)和化合物3(1.748克,4 mmol),加热回流15小时后,冷却至室温,加入稀盐酸调节pH至中性,乙酸乙酯萃取,干燥,浓缩,粗产物经柱层析分离(乙酸乙酯:石油醚 = 1:1),得目标化合物4(产率78%)。产物的分析数据如下:1H NMR (400 MHz, CDCl3): δ 7.46 (d, J = 8.4 Hz, 2H),7.84 (d, J = 8.4 Hz, 2H), 4.01 – 3.88 (m, 6H), 3.23 (d, J = 4.7 Hz, 3H), 1.91(d, J = 3.8 Hz, 1H), 1.12 (dt, J = 6.6, 3.6 Hz, 6H), 0.99 (dt, J = 6.6, 3.5Hz, 3H)。
实施例二十五:1-甲基-3-硫代吲哚酮-2,2-二亚磷酸四乙酯(5)的合成
以化合物3作为原料,其反应步骤如下:
(1) 在反应瓶中加入化合物3(0.087克,0.2 mmol)、亚碘酰苯(0.088克, 0.4mmol), 四正丁基碘化胺(0.089克, 0.24 mmol) 和甲苯(1 mL)。室温反应;
(2) TLC跟踪反应直至完全结束;
(3) 反应结束后得到的粗产物经柱层析分离(乙酸乙酯:石油醚 = 1:1),得目标化合物5(产率81%)。产物的分析数据如下:1H NMR (400 MHz, CDCl3): δ 7.42 (d, J =8.1 Hz, 2H), 7.85 (d, J = 8.1 Hz, 2H), 4.01 – 3.84 (m, 8H), 3.14 (d, J = 3.3Hz, 3H), 1.41 – 1.11 (m, 12H)。
实施例二十六:1,1-二(二乙基膦酸酯基)庚硫酮-2(26-3)的合成
以庚炔、二乙基亚磷酸酯作为原料,其反应步骤如下:
在反应瓶中加入庚炔(0.077克,0.8 mmol),加入二乙基亚磷酸酯(0.220克,1.6mmol),异硫氰酸三甲基硅酯(0.208克,1.6 mmol),CuSCN(0.10克, 0.08 mmol),过氧化叔丁醇(0.205克,1.6 mmol)和N-甲基吡咯烷酮(5 mL),50℃反应;
反应结束后得到的粗产物经柱层析分离(乙酸乙酯:石油醚 = 1:1),得到目标产物26-1(产率82%)。产物的分析数据如下:1H NMR (400 MHz, CDCl3): δ 6.43 (d, J =13.9 Hz, 1H), 4.24 – 4.14 (m, 4H), 3.08 (t, J = 4.7 Hz, 2H), 1.41 – 1.30 (m,6H), 1.24 (dd, J = 9.3, 7.6 Hz, 6H), 0.85 (t, J = 6.9 Hz, 3H);
⑷在反应瓶中加入26-1 (0.873克,3 mmol)和醋酸(30 mL),向其中加入锌粉(3.0克, 45 mmol),再将混合溶液加热回流24 h。硅藻土过滤,滤液浓缩后加入乙醚,水洗两次,无水硫酸钠干燥,浓缩得产物26-2(产率95%)。产物的分析数据如下:1H NMR (300 MHz,CDCl3): δ4.24 – 4.14 (m, 4H), 3.34 (d, J = 15.3 Hz, 2H), 3.08 (t, J = 4.7 Hz,2H), 1.41 – 1.30 (m, 6H), 1.24 (dd, J = 9.3, 7.6 Hz, 6H), 0.85 (t, J = 6.9Hz, 3H);
⑸在反应瓶中加入26-2(0.266克,1 mmol)、三乙基亚磷酸酯(0.498克,7 mmol)、三氟甲磺酸亚铜(0.021克,0.1 mmol)、二叔丁基过氧化物(1.022克,7 mmol)和N,N-二甲基甲酰胺(5 mL),80℃反应至结束。加入20 mL水,乙酸乙酯萃取,干燥,浓缩,粗产物经柱层析分离(乙酸乙酯:石油醚 = 1:1),得到目标化合物26-3(产率78%)。产物的分析数据如下:1HNMR (300 MHz, CDCl3): δ 4.24 – 4.14 (m, 8H), 3.34 (d, J = 15.3 Hz, 1H), 3.08(t, J = 4.7 Hz, 2H), 1.41 – 1.30 (m, 6H), 1.34 – 1.01 (m, 12H), 0.85 (t, J =6.9 Hz, 3H)。
Claims (2)
1.一种β-巯基氮杂磷杂环类衍生物的制备方法,包括以下步骤:将炔烃、磷试剂、异硫氰酸三甲基硅酯、铜催化剂和过氧化物溶于溶剂中,于30~70℃下反应,获得β-硫氰基烯基膦酰类衍生物;然后以β-硫氰基烯基膦酰类衍生物为原料,在锌催化剂和醋酸的存在下,制备得到β-硫羰基膦酰类衍生物;然后以β-硫羰基膦酰类衍生物为原料,在亚磷酸酯、三氟甲磺酸亚铜、二叔丁基过氧化物存在下,制备得到β-硫羰基双膦酰类衍生物;最后以β-硫羰基双膦酰类衍生物为原料,在乙醇钠、盐酸存在下,制备得到β-巯基氮杂磷杂环类衍生物;
所述炔烃为2-甲基氨基苯乙炔;
所述磷试剂为二乙基亚磷酸酯;
所述铜催化剂的化学式为CuXn,其中X为Cl、Br、I或SCN中的一种;n为1或2;
所述β-硫氰基烯基膦酰类衍生物的化学结构式如下:
所述β-硫羰基膦酰类衍生物的化学结构式如下:
所述β-硫羰基双膦酰类衍生物的化学结构式如下:
所述β-巯基氮杂磷杂环类衍生物的化学结构式如下:
2.根据权利要求1所述的制备方法,其特征在于:按摩尔比,炔烃∶磷试剂∶异硫氰酸三甲基硅酯∶铜催化剂∶过氧化物为1∶(1~3)∶(1~3)∶(0.1~0.3)∶(1~3);利用薄层层析色谱跟踪反应直至完全结束;反应结束后对产物进行柱层析分离提纯处理;所述溶剂选自乙醇、乙腈、四氢呋喃、丙酮、甲苯、N,N-二甲基甲酰胺或N-甲基吡咯烷酮中的一种;所述过氧化物为过氧化叔丁醇。
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