CN105131014B - 一种螺环羟吲哚咪唑啉并氧氮杂卓化合物及其合成方法 - Google Patents
一种螺环羟吲哚咪唑啉并氧氮杂卓化合物及其合成方法 Download PDFInfo
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Abstract
本发明公开了一种螺环羟吲哚咪唑啉并氧氮杂卓化合物及其合成方法,具体为以重氮羟吲哚与二苯并氧氮杂卓为反应物,在三氟甲磺酸铁(Ⅱ)或者对甲苯磺酸一水合物的催化下,在溶剂中合成得到产物。本发明公开的方法原料简单易得,反应条件温和,后处理简单方便,适用的底物范围广,收率高,非对映选择性高;由此合成得到的产物可用以合成药物和杀虫剂的中间体。
Description
技术领域
本发明涉及螺环羟吲哚咪唑啉类化合物的合成,具体涉及一种螺环羟吲哚咪唑啉并氧氮杂卓化合物及其催化合成方法。
背景技术
螺环羟吲哚咪唑啉类化合物广泛的存在于天然产物中,具有显著的生理和药理活性,如抗病毒、杀菌、抑制酶的活性、抗肿瘤等广泛的生物活性并且广泛的存在于生物碱中。同时也是许多药物分子中不可或缺的重要结构单元,而受到很多科学家的关注。而二苯并氧氮杂卓类化合物也具有很好的生物活性和药用价值,常见于生物碱和抗抑郁症药物中,例如常用的抗抑郁症药物阿莫沙平具有很好的临床药效(式一)。现有技术,未见关于螺环羟吲哚咪唑啉、二苯并氧氮杂卓这两类都具有生物活性和药理作用的结构结合在一起的合成方法的报道。因此,发展高效合成螺环羟吲哚咪唑啉并氧氮杂卓结构化合物的合成方法引起了申请人极大的兴趣。
式一
现有技术中螺环羟吲哚衍生物的合成方法报道很多,但螺环羟吲哚咪唑啉类化合物的合成方法鲜有报道。文献中有报道应用重氮羟吲哚来合成螺环的三元环结构。Muthusamy课题组报道了以Rh2(OAc)4为催化剂,铑金属催化的重氮羟吲哚和三取代苯甲醛的分子间环氧化反应,能够以55%~84%的收率得到重氮羟吲哚环氧化的目标产物,该合成方法使用了金属铑这种贵金属催化剂,价格昂贵。同时反应的温度要求在60℃下进行,反应条件较为苛刻,能量消耗大(Muthusamy, S.; Gunanathan, C.; Nethaji, M.Stereoselective Epoxide Generation with Cyclic Rhodium Carbenoids: A NewAccess to Spiro-indolooxiranes. Synlett. 2004, 639–642.);许课题组报道了三乙胺碱性条件下氯乙酰氯与二苯并氧氮杂卓的Staudinger反应,该方法能以8.2%~89.2%的收率得到二苯并氧氮杂卓并β内酰胺-2-氮杂环丁酮(Qi H. Z., MO S. Y., and Xu J. X.,Highly Stereoselective Synthesis of trans-3-Chloro-b-lactams from Imines andMixed Chloroacetyl and Nitroacetyl Chlorides. Chemical Research In Chinese Universites, 2011,V27 (6): 958-962)。
通过使用催化量的催化剂促进多倍的新物质的生成,是一种最有效、最经济的合成有机化合物的方法。在有机合成研究领域,路易斯酸和布朗斯特酸催化可应用于很多有机物的合成;但是能够通过路易斯酸催化或布朗斯特酸催化,高效合成螺环羟吲哚咪唑啉并氧氮杂卓结构化合物未见文献报道。
发明内容
本发明的目的是提供一种螺环羟吲哚咪唑啉并氧氮杂卓化合物及其催化合成方法。
为达到上述发明目的,本发明采用的技术方案是:一种螺环羟吲哚咪唑啉并氧氮杂卓化合物,其结构式为:
。
上述螺环羟吲哚咪唑啉并氧氮杂卓化合物的合成方法,包括以下步骤,以二苯并氧氮杂卓、重氮羟吲哚为反应物,以布朗斯特酸或者路易斯酸为催化剂,在有机溶剂中,室温下反应得到产物螺环羟吲哚咪唑啉并氧氮杂卓化合物;
所述二苯并氧氮杂卓的化学结构式为,其中R1选自:氯、甲基、叔丁基、氢中的一种;R2选自氯或者氢;
所述重氮羟吲哚的化学结构式为,其中R3为甲基、苄基、苄氧羰基或者叔丁氧羰基;R4为甲基、甲氧基、氯或者溴。
上述技术方案中,所述有机溶剂为醚类溶剂、苯类溶剂或者醇类溶剂;比如二氯甲烷、乙醚、四氢呋喃、甲苯、1,2-二氯乙烷、对二甲苯、间二甲苯、邻二甲苯、1,4-二氧六环、甲基叔丁基醚或者甲醇;优选四氢呋喃。
上述技术方案中,以摩尔量计,所述催化剂的用量为重氮羟吲哚的5~20%;二苯并氧氮杂卓的用量为重氮羟吲哚的2~2.5倍。
优选的技术方案中,以摩尔量计,所述催化剂的用量为重氮羟吲哚的10%;二苯并氧氮杂卓的用量为重氮羟吲哚的2.2倍。
本发明中,催化剂优选为三氟甲磺酸铁(Ⅱ)或者对甲苯磺酸一水合物。
催化剂三氟甲磺酸铁(Ⅱ)的化学结构式为:
催化剂对甲苯磺酸一水合物的化学结构式如下所示:
上述技术方案中,反应过程包括在室温下,向反应瓶中依次加入催化剂、二苯并氧氮杂卓、重氮羟吲哚、溶剂,搅拌(磁力或机械)反应20~25小时,反应结束后,反应液通过简单的柱层析(洗脱剂优选为二氯甲烷∶石油醚=2∶1~1∶1)即可得到目标产物螺环羟吲哚咪唑啉并氧氮杂卓化合物;该类化合物是很多抗菌药物,抗肿瘤、抗人类免疫缺陷病毒、抗病毒剂和酶抑制剂的类似物,有巨大的潜在应用价值。
本发明中,反应体系使用四氢呋喃为溶剂和使用对甲苯磺酸一水合物或者三氟甲磺酸铁(Ⅱ)为催化剂,以提高反应收率,最高可达94% 和91% 的产率。
上述反应过程如下所示:
由于上述技术方案运用,本发明与现有技术相比具有下列优点:
1.本发明首次通过使用三氟甲磺酸铁(Ⅱ)或者对甲苯磺酸一水合物为催化剂,催化重氮羟吲哚与适量二苯并氧氮杂卓的串联反应,以优秀的非对映选择性和高的收率合成了一系列螺环羟吲哚咪唑啉并氧氮杂卓化合物。该化合物结合了具有生物活性和药理作用的螺环羟吲哚咪唑啉、二苯并氧氮杂卓结构的功效,为有机合成、生物医药的发展提供更多选择。
2.本发明公开的合成螺环羟吲哚咪唑啉并氧氮杂卓化合物的反应催化效率高,催化剂用量低,后处理简单,反应属于串联环化反应,体系中没有副产物生成。
3.本发明公开的合成螺环羟吲哚咪唑啉并氧氮杂卓化合物的方法适用底物范围很广,原料均为工业化、廉价易得的产品,无污染;操作简便,收率高,化学选择性择性好;反应条件温和,无需加热或者冷却条件,室内温度即可很好反应,并且官能团兼容性高,非对映选择性优秀,收率高。
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:
反应瓶中依次加入对甲苯磺酸一水合物 (0.95 mg,0.005 mmol)、1a (43.1mg,0.22 mmol),2a (15.9 mg, 0.1 mmol),加入2 mL四氢呋喃,在室温条件下搅拌反应24小时,反应体系通过简单的柱层析(洗脱剂为二氯甲烷:石油醚=2:1)即可得到目标产物3a(收率分别为27.6 mg, 53%),白色固体,非对映选择性>99/1。
反应瓶中依次加入三氟甲磺酸铁(Ⅱ)(1.8 mg,0.005 mmol)、1a (43.1mg, 0.22mmol),2a (15.9 mg, 0.1 mmol),加入2 mL四氢呋喃,在室温条件下搅拌反应24小时,反应体系通过简单的柱层析(洗脱剂为二氯甲烷:石油醚=2:1)即可得到目标产物3a(收率21.3mg, 41% yield),白色固体,非对映选择性>99/1。
反应瓶中依次加入对甲苯磺酸一水合物(1.9 mg,0.01 mmol)或者三氟甲磺酸铁(Ⅱ)(3.5 mg,0.01 mmol)作为催化剂,1a(43.1mg, 0.22 mmol),2a (15.9 mg, 0.1mmol),加入2 mL四氢呋喃,室温条件下搅拌反应24小时,反应体系通过简单的柱层析(洗脱剂为二氯甲烷:石油醚=2:1)即可得到目标产物3a(收率分别为47.4 mg, 91%, 43.2 mg,83% yield),白色固体,非对映选择性>99/1。
反应瓶中依次加入对甲苯磺酸一水合物(3.8 mg,0.02 mmol)或者三氟甲磺酸铁(Ⅱ)(7 mg,0.02mmol)作为催化剂,1a(43.1mg, 0.22 mmol),2a (15.9 mg, 0.1 mmol),加入2 mL四氢呋喃,室温条件下搅拌反应24小时,反应体系通过简单的柱层析(洗脱剂为二氯甲烷:石油醚=2:1)即可得到目标产物3a(收率分别为43.7mg, 84%, 41.6 mg, 80%yield),白色固体,非对映选择性>99/1。
对产物3a进行分析,结果如下: 1H NMR (400 MHz, DMSO) δ 11.21 (s, 1H),7.40 (s, 1H), 7.31 (s, 4H), 7.23 – 6.96 (m, 10H), 6.90 (s, 1H), 6.84 – 6.64(m, 3H), 6.56 (m, 1H), 5.82 (d, J = 7.2 Hz, 1H), 4.97 (s, 1H). 13C NMR (101MHz, DMSO) δ 175.28, 158.48, 155.22, 153.47, 144.57, 140.52, 136.99, 135.11,130.07, 129.50, 129.43, 129.09, 127.63, 126.64, 126.12, 125.69, 125.57,125.46, 124.60, 123.64, 122.81, 122.04, 121.97, 121.91, 121.11, 120.72,120.07, 118.00, 113.62, 109.73, 73.17, 72.29, 71.46. IR (neat, cm-1): 3134,3062, 3033, 2891, 1718, 1600, 1576, 1321. HRMS (ESI): calcd. for C34H23N3O3Na+[M + Na]+ 544.1632; found: 544.1645.以上数据证明目的产物合成成功。
实施例二:
反应瓶中依次加入对甲苯磺酸一水合物 (1.9 mg,0.01 mmol), 1a (43.1mg,0.22 mmol),2b (15.9 mg, 0.1 mmol),加入2 mL四氢呋喃,在室温条件下搅拌反应24小时,反应体系通过简单的柱层析(洗脱剂为二氯甲烷:石油醚=1:1)即可得到目标产物3a(收率为48.4 mg, 93% yield),白色固体,非对映选择性>99/1。
反应瓶中依次加入三氟甲磺酸铁(Ⅱ)(3.5 mg,0.01 mmol), 1a (43.1mg, 0.22mmol),2b (15.9 mg, 0.1 mmol),加入2 mL四氢呋喃,在室温条件下搅拌反应24小时,反应体系通过简单的柱层析(洗脱剂为二氯甲烷:石油醚=1:1)即可得到目标产物3a(收率为45.8 mg, 88% yield),白色固体,非对映选择性>99/1。
对产物3b进行分析,结果如下: 1H NMR (400 MHz, CDCl3) δ 7.42 (dd, J =7.2, 0.8 Hz, 1H), 7.38 (s, 1H), 7.16 – 7.09 (m, 4H), 7.05 (dd, J = 8.0, 1.6Hz, 1H), 7.00 – 6.81 (m, 7H), 6.76 (td, J = 7.6, 0.8 Hz, 1H), 6.73 – 6.63 (m,2H), 6.55 (td, J = 7.6, 1.6 Hz), 6.50 (dd, J = 7.6 1H), 6.44 (td, J = 7.6,1H), 5.56 (dd, J = 8.0, 1.2 Hz, 1H), 5.03 (s, 1H), 3.24 (s, 3H). 13C NMR (101MHz, CDCl3) δ 174.59, 159.03, 155.78, 153.88, 145.33, 141.79, 137.47,135.30,129.92, 129.40, 129.31, 127.63, 126.83, 126.70, 125.79, 125.67, 125.43,125.35, 124.53, 123.34, 123.11, 123.05, 122.23, 121.52, 121.24, 121.12,120.18, 118.43, 113.93, 107.70, 73.71, 73.22, 72.24, 26.79. IR (neat, cm-1):3165, 3065, 3034, 2860, 2819, 1715, 1624, 1455, 1369, 1213, 731.14, 666. HRMS(ESI): calcd. for C35H25N3O3Na+ [M + Na]+ 558.1788; found: 558.1768.以上数据证明目的产物合成成功。
实施例三:
反应瓶中依次加入对甲苯磺酸一水合物 (1.9 mg,0.01 mmol), 1a (43.1mg,0.22 mmol),2c (24.9 mg, 0.1 mmol),加入2 mL乙醚,在室温条件下搅拌反应24小时,反应体系通过简单的柱层析(洗脱剂为二氯甲烷:石油醚=1:1)即可得到目标产物3c(收率为47.9 mg, 92%),白色固体,非对映选择性>99/1。
反应瓶中依次加入三氟甲磺酸铁(Ⅱ)(3.5 mg,0.01 mmol), 1a (43.1mg, 0.22mmol),2c (24.9 mg, 0.1 mmol),加入2 mL四氢呋喃,在室温条件下搅拌反应24小时,反应体系通过简单的柱层析(洗脱剂为二氯甲烷:石油醚=1:1)即可得到目标产物3c(收率为46.3 mg, 89%),白色固体,非对映选择性>99/1。
对产物3c进行分析,结果如下: 1H NMR (400 MHz, CDCl3) δ 7.54 – 7.48 (m,4H), 7.42 – 7.33 (m, 3H), 7.25 – 7.20 (m, 4H), 7.15 (dd, J = 7.6, 1.6 Hz,1H), 7.08 – 6.93 (m, 7H), 6.83 (td, J = 7.6, 0.8 Hz, 1H), 6.78(dd, J = 8.0,1.2 Hz, 1H), 6.66 (d, J = 8.0, 1H), 6.60 (td, J = 7.6, 1.2 Hz, 1H), 6.55 (td,J = 7.6, 1.6 Hz, 1H), 6.48 (td, J = 8.0, 1.6 Hz, 1H), 5.64 (dd, J = 8.0, 1.2Hz, 1H), 5.36 (d, J = 15.2 Hz, 1H), 5.17 (s, 1H), 4.63 (d, J = 14.8 Hz, 1H).13C NMR (101 MHz, CDCl3) δ 174.82, 159.09, 155.79, 153.98, 145.42, 141.32,137.54, 135.55, 135.34, 129.94, 129.35, 129.31, 129.04, 128.89, 128.25,127.93, 126.92, 126.87, 125.70, 125.68, 125.61, 125.38, 124.60, 123.36,123.31, 123.15, 122.22, 121.63, 121.26, 121.14, 120.22, 118.53, 114.58,108.59, 73.63, 73.27, 72.31, 44.89. IR (neat, cm-1): 3063, 3035, 2922, 2848,2803, 2758, 1719, 1599, 1576, 1490, 730, 1030. HRMS (ESI): calcd. forC41H29N3O3Na+ [M + Na]+ 634.2101; found: 634.2129.以上数据证明目的产物合成成功。
实施例四:
反应瓶中依次加入对甲苯磺酸一水合物 (1.9 mg,0.01 mmol)或者三氟甲磺酸铁(Ⅱ)(3.5 mg,0.01 mmol)作为催化剂, 1a (43.1mg, 0.22 mmol),2d (26.3 mg, 0.1mmol),加入2 mL对二甲苯,在室温条件下搅拌反应24小时,反应体系通过简单的柱层析(洗脱剂为二氯甲烷:石油醚=1:1)即可得到目标产物3d (收率分别为47.8 mg, 92 %, 45.3mg, 87% yield),白色固体,非对映选择性>99/1。
对产物3d进行分析,结果如下: 1H NMR (400 MHz, CDCl3) δ 7.79 (d, J = 7.6Hz, 2H), 7.53 (dd, J = 13.6, 7.2 Hz, 2H), 7.44 (d, J = 8.0 Hz, 1H), 7.37 (t,J = 7.6 Hz, 2H), 7.31 (s, 1H), 7.18 – 7.05 (m, 6H), 7.04 – 6.88 (m, 6H), 6.88– 6.69 (m, 4H), 6.59 (t, J = 7.2 Hz, 1H), 6.01 (d, J = 8.0 Hz, 1H), 5.03 (s,1H). 13C NMR (101 MHz, CDCl3) δ 175.42, 168.86, 158.93, 155.66, 153.93,145.78, 138.57, 137.26, 135.57, 133.55, 130.12, 130.05, 129.77, 129.75,129.06, 128.43, 128.00, 127.40, 126.95, 126.91, 125.73, 125.71, 125.52,125.49, 125.45, 124.83, 124.09, 123.26, 122.90, 122.75, 121.58, 121.53,121.22, 120.29, 119.31, 116.09, 114.61, 114.28, 74.47, 74.42, 72.55. IR(neat, cm-1): 3183, 3153, 3079, 3062, 1716, 1621,1498, 1454, 1392, 1368. HRMS(ESI): calcd. for C41H27N3O4Na+ [M + Na]+ 648.1894; found: 648.1924. 以上数据证明目的产物合成成功。
实施例五:
反应瓶中依次加入对甲苯磺酸一水合物 (1.9 mg,0.01 mmol)或者三氟甲磺酸铁(Ⅱ)(3.5 mg,0.01 mmol)作为催化剂, 1a (43.1mg, 0.22 mmol),2e (25.9 mg, 0.1mmol),加入2 mL 1,4-二氧六环,在室温条件下搅拌反应24小时,反应体系通过简单的柱层析(洗脱剂为二氯甲烷:石油醚=1:1)即可得到目标产物3e (收率分别为47.5 mg, 91%,47.1 mg, 90%),白色固体,非对映选择性>99/1。
对产物3e进行分析,结果如下:1H NMR (400 MHz, CDCl3) δ 7.57 – 7.53 (m,2H), 7.44 (s, 1H), 7.25 – 7.10 (m, 6H), 7.09 – 6.98 (m, 5H), 6.97 – 6.91 (m,3H), 6.80 – 6.76 (m, 1H), 6.67 (td, J = 7.6, 1.6 Hz, 1H), 6.56 (td, J = 7.6,1.4 Hz, 1H), 5.70 (dd, J = 8.4, 1.6 Hz, 1H), 5.13 (s, 1H), 1.69 (s, 9H). 13CNMR (101 MHz, CDCl3) δ 173.98, 159.03, 155.88, 153.93, 148.94, 145.42,138.21, 137.26, 134.94, 130.06, 129.69, 129.12, 127.70, 126.88, 126.16,125.93, 125.75, 125.43, 125.36, 124.99, 124.71, 123.47, 122.81, 122.39,121.63, 121.43, 121.20, 120.28, 118.75, 114.45, 114.31, 85.01, 74.41, 74.03,72.41, 28.27. IR (neat, cm-1): 3063, 2961, 2923, 2851, 1772, 1731, 1689, 1600,1490, 1465, 1454. ESI–MS: m/z [M + Na]+ calcd for C39H31N3O5Na+: 644.2156;found: 644.2157.以上数据证明目的产物合成成功。
实施例六:
反应瓶中依次加入对甲苯磺酸一水合物 (1.9 mg,0.01 mmol)或者三氟甲磺酸铁(Ⅱ)(3.5 mg,0.01 mmol)作为催化剂, 1a (49mg, 0.25 mmol),2f (17.3 mg, 0.1mmol),加入2 mL四氢呋喃,在室温条件下搅拌反应24小时,反应体系通过简单的柱层析(洗脱剂为二氯甲烷:石油醚=2:1)即可得到目标产物3f (收率分别为45.8 mg, 88%, 42.2mg, 81%),白色固体,非对映选择性>99/1。
对产物3f进行分析,结果如下:1H NMR (400 MHz, DMSO) δ 11.09 (s, 1H),7.37 (s, 1H), 7.33 – 7.31 (m, 2H), 7.30 – 7.26 (m, 1H), 7.19 (dd, J = 8.0,1.2 Hz, 1H), 7.17 – 7.06 (m, 6H), 7.05 – 7.02 (m, 2H), 6.96 (d, J = 7.2 Hz,1H), 6.90 (td, J = 6.0, 2.0 Hz, 1H), 6.83 (dd, J = 8.0, 0.8 Hz 1H), 6.71 (td,J = 7.6, 1.6 Hz, 1H), 6.58 – 6.54(m, 2H), 5.81 (dd, J = 7.6, 1.2 Hz 1H), 4.93(s, 1H), 2.02 (s, 3H). 13C NMR (101 MHz, DMSO) δ 175.27, 158.51, 155.30,153.49, 144.56, 138.18, 137.05, 135.21, 130.63, 130.11, 129.77, 129.45,129.13, 127.68, 126.78, 126.10, 125.70, 125.59, 125.44, 125.18, 124.60,123.64, 122.93, 122.05, 121.91, 121.06, 120.77, 120.11, 117.99, 113.72,109.51, 73.27, 72.26, 71.46, 20.72.IR (neat, cm-1): 3165, 3065, 3034, 2860,2819, 1715, 1600, 1455, 1320, 1300. ESI–MS: m/z [M + Na]+ calcd forC35H25N3O3Na+: 558.1788; found: 558.1786.以上数据证明目的产物合成成功。
实施例七:
反应瓶中依次加入对甲苯磺酸一水合物 (1.9 mg,0.01 mmol)或者三氟甲磺酸铁(Ⅱ)(3.5 mg,0.01 mmol)作为催化剂, 1a (43.1mg, 0.22 mmol),2f (19.3 mg, 0.1mmol),加入2 mL四氢呋喃,在室温条件下搅拌反应24小时,反应体系通过简单的柱层析(洗脱剂为二氯甲烷:石油醚=2:1)即可得到目标产物3f (收率分别为47.5 mg, 91%, 44.3mg, 85%),白色固体,非对映选择性>99/1。
对产物3g行分析,结果如下:1H NMR (400 MHz, DMSO) δ 11.65 (s, 1H), 7.40(s, 1H), 7.32 (d, J = 3.6 Hz, 2H), 7.28 – 7.25 (m, 1H), 7.21 (dd, J = 7.6,1.2 Hz, 1H), 7.13 – 7.03 (m, 8H), 6.97 – 6.90 (m, 2H), 6.82 – 6.74 (m, 2H),6.58 (t, J = 7.6 Hz, 1H), 5.75 (d, J = 8.4 Hz, 1H), 4.97 (s, 1H). 13C NMR (101MHz, DMSO) δ 175.31, 158.50, 155.28, 153.46, 144.64, 138.13, 136.79, 134.89,130.20, 129.77, 129.47, 128.95, 128.73, 127.50, 126.12, 125.86, 125.65,125.56, 124.77, 123.52, 123.29, 123.11, 122.38, 122.20, 122.07, 121.19,120.76, 120.16, 118.34, 114.22, 113.53, 79.18, 73.78, 72.56, 71.53. 4.98 (s,1H). IR (neat, cm-1): 3065, 3039, 2955, 2817, 2107, 1726, 1619, 1601, 1491,1453, 1387, 1316. ESI–MS: m/z [M + Na]+ calcd for C34H22ClN3O3Na+: 578.1242;found: 578.1244.以上数据证明目的产物合成成功。
实施例八:
反应瓶中依次加入对甲苯磺酸一水合物 (1.9 mg,0.01 mmol)或者三氟甲磺酸铁(Ⅱ)(3.5 mg,0.01 mmol)作为催化剂, 1a (43.1mg, 0.22 mmol),2h (23.6 mg, 0.1mmol),加入2 mL四氢呋喃,在室温条件下搅拌反应24小时,反应体系通过简单的柱层析(洗脱剂为二氯甲烷:石油醚=2:1)即可得到目标产物3h (收率分别为46.9 mg, 90 %, 43.2mg, 83% yield),白色固体,非对映选择性>99/1。
对产物3h进行分析,结果如下: 1H NMR (400 MHz, CDCl3) δ 7.44 (s, 1H),7.38 (d, J = 8.0 Hz, 1H), 7.24 – 7.22 (m, 2H), 7.20 – 7.11 (m, 3H), 7.10 –6.93 (m, 8H), 6.83 – 6.79 (m, 1H), 6.75 (d, J = 1.6 Hz, 1H), 6.63 (td, J =7.2, 1.6 Hz, 1H), 6.58 (td, J = 7.6, 1.6 Hz, 1H), 5.83 (dd, J = 8.0, 1.6 Hz,1H), 5.12 (s, 1H). 13C NMR (101 MHz, CDCl3) δ 177.15, 159.05, 155.83, 154.05,145.54, 140.04, 137.28, 135.22, 130.11, 129.83, 129.22, 127.85, 127.19,126.79, 126.56, 126.49, 125.84, 125.78, 125.52, 124.84, 123.86, 122.96,122.79, 122.54, 121.67, 121.58, 121.21, 120.28, 118.97, 113.97, 113.39,73.89, 73.22, 72.38. IR (neat, cm-1): 3196, 3064, 3037, 2815, 1722, 1606,1576, 1490, 1455, 1315. ESI–MS: m/z [M + Na]+ calcd for C34H22BrN3O3Na+:622.0737; found: 622.0750.以上数据证明目的产物合成成功。
实施例九:
反应瓶中依次加入对甲苯磺酸一水合物 (1.9 mg,0.01 mmol)或者三氟甲磺酸铁(Ⅱ)(3.5 mg,0.01 mmol)作为催化剂, 1a (43.1mg, 0.22 mmol),2i (19.3 mg, 0.1mmol),加入2 mL四氢呋喃,在室温条件下搅拌反应24小时,反应体系通过简单的柱层析(洗脱剂为二氯甲烷:石油醚=2:1)即可得到目标产物3i (收率分别为46.8 mg, 90%, 45.4mg, 87% yield),白色固体,非对映选择性>99/1。
对产物3i进行分析,结果如下: 1H NMR (400 MHz, CDCl3) δ 9.05 (s, 1H),7.43 (d, J = 8.4 Hz, 2H), 7.24 – 7.16 (m, 5H), 7.11 – 6.99 (m, 6H), 6.94 (dd,J = 5.2, 2.4 Hz, 1H), 6.83 – 6.77 (m, 2H), 6.62 – 6.54 (m, 3H), 5.84 (dd, J =8.0, 1.6 Hz, 1H), 5.12 (s, 1H). 13C NMR (101 MHz, CDCl3) δ 177.69, 159.03,155.82, 154.04, 145.54, 139.92, 137.28, 135.25, 135.06, 130.11, 129.81,129.22, 127.81, 126.80, 125.99, 125.84, 125.77, 125.53, 124.84, 123.87,123.56, 122.80, 122.56, 121.66, 121.55, 121.20, 120.27, 118.94, 113.94,110.82, 73.92, 73.27, 72.39. IR (neat, cm-1): 3196, 3064, 3037, 2815, 1722,1606, 1576, 1490, 1455, 1389, 1367, 1315, 1292. ESI–MS: m/z [M + Na]+ calcdfor C34H22ClN3O3Na+: 578.1242; found: 578.1232.以上数据证明目的产物合成成功。
实施例十:
反应瓶中依次加入对甲苯磺酸一水合物 (1.9 mg,0.01 mmol)或者三氟甲磺酸铁(Ⅱ)(3.5 mg,0.01 mmol)作为催化剂, 1a (39.2mg, 0.20 mmol),2j (19.3 mg, 0.1mmol),加入2 mL四氢呋喃,在室温条件下搅拌反应24小时,反应体系通过简单的柱层析(洗脱剂为二氯甲烷:石油醚=2:1)即可得到目标产物3j (收率分别为44.9 mg, 86%, 41.7mg, 80% yield),白色固体,非对映选择性>99/1。
对产物3j进行分析,结果如下: 1H NMR (400 MHz, DMSO) δ 11.36 (s, 1H),7.40 (s, 1H), 7.33 – 7.28 (m, 3H), 7.26 (d, J = 3.6, Hz, 1H), 7.22 (dd, J =7.6, 1.2 Hz, 1H), 7.18 – 7.13 (m, 3H), 7.11 (d, J = 2.0 Hz, 1H), 7.10 (t, J =2.8 Hz, 1H), 7.07 – 7.04 (m, 3H), 6.97 – 6.91 (m, 2H), 6.75 (td, J = 7.7, 9.2Hz, 1H), 6.71 (d, J = 8.4, 1H), 6.59 (td, J = 7.6, 1.2 Hz, 1H), 5.76 (dd, J =8.0, 1.2 Hz, 1H), 4.98 (s, 1H). 13C NMR (101 MHz, DMSO) δ 174.87, 158.52,155.31, 153.49, 144.66, 139.48, 136.72, 134.87, 130.28, 129.79, 129.44,128.99, 128.85, 127.69, 125.94, 125.87, 125.83, 125.67, 125.57, 124.81,124.33, 123.80, 122.40, 122.22, 122.10, 121.20, 120.80, 120.27, 118.40,113.49, 111.40, 73.21, 72.23, 71.45. IR (neat, cm-1): 3164, 3120, 3066, 2850,2821, 1718, 1619, 1490,1455, 1393, 1370, 1320. ESI–MS: m/z [M + Na]+ calcdfor C34H22ClN3O3Na+: 578.1242; found: 578.1240.以上数据证明目的产物合成成功。
实施例十一:
反应瓶中依次加入对甲苯磺酸一水合物 (1.9 mg,0.01 mmol)或者三氟甲磺酸铁(Ⅱ)(3.5 mg,0.01 mmol)作为催化剂, 1a (43.1mg, 0.22 mmol),2k (18.9 mg, 0.1mmol),加入2 mL四氢呋喃,在室温条件下搅拌反应24小时,反应体系通过简单的柱层析(洗脱剂为二氯甲烷:石油醚=1:1)即可得到目标产物3k (收率分别为48.9 mg, 94%, 47.4mg, 91% yield),白色固体,非对映选择性>99/1。
对产物3k进行分析,结果如下: 1H NMR (400 MHz, DMSO) δ 11.03 (s, 1H),7.40 (s, 1H), 7.32 – 7.27 (m, 3H), 7.20 (dd, J = 8.0, 1.6 Hz, 1H), 7.16 –7.09 (m, 5H), 7.06 – 7.03 (m, 2H), 6.99 (d, J = 7.2, 1H), 6.96 (s, 1H), 6.91(td, J = 6.8, 2.0 Hz, 1H), 6.72 (td, J = 5.2, 1.6 Hz, 1H), 6.61(d, J = 1.6Hz,2H), 6.56 (td, J = 8.0, 1.2 Hz, 1H), 5.85 (dd, J = 8.0, 0.8 Hz, 1H), 4.96(s, 1H), 3.51 (s, 3H). 13C NMR (101 MHz, DMSO) δ 174.98, 158.54, 155.30,154.74, 153.54, 144.59, 136.93, 135.06, 133.84, 130.16, 129.51, 129.18,127.96, 127.81, 125.87, 125.74, 125.61, 125.48, 124.63, 123.69, 122.78,122.05, 121.96, 121.15, 120.77, 120.19, 118.04, 114.10, 113.68, 111.40,110.24, 73.37, 72.05, 71.34, 55.11. IR (neat, cm-1): 3165.22, 3132.47,3063.19, 3042.15, 2955.52, 2848.83, 1709.70, 1599.65, 1485.85, 1455.26,1387.44, 1366.57, 1316.20, 1291.06. ESI–MS: m/z [M + Na]+ calcd forC34H22ClN3O3Na+: 578.1242; found: 578.1236.以上数据证明目的产物合成成功。
实施例十二:
反应瓶中依次加入对甲苯磺酸一水合物 (1.9 mg,0.01 mmol)或者三氟甲磺酸铁(Ⅱ)(3.5 mg,0.01 mmol)作为催化剂, 1a (43.1mg, 0.22 mmol),2l (18.7 mg, 0.1mmol),加入2 mL四氢呋喃,在室温条件下搅拌反应24小时,反应体系通过简单的柱层析(洗脱剂为二氯甲烷:石油醚=1:1)即可得到目标产物3l (收率分别为48.5 mg, 93%, 45.8mg, 88% yield),白色固体,非对映选择性>99/1。
对产物3l进行分析,结果如下: 1H NMR (400 MHz, DMSO) δ 11.14 (s, 1H),7.38 (s, 1H), 7.31 – 7.26 (m, 3H), 7.20 (dd, J = 7.6, 1.2 Hz, 1H), 7.15 –7.07 (m, 5H), 7.03 (dd, J = 10.4, 7.2 Hz, 2H), 7.03 – 6.97 (m, 2H), 6.88 (td,J = 8.8, 1.6 Hz, 1H), 6.72 (td, J = 9.2, 1.2 Hz, 1H), 6.65 (s, 1H), 6.56 (t,J = 7.2, 1H), 5.85 (d, J = 7.2 Hz, 1H), 4.94 (s, 1H), 2.06 (s, 3H), 1.98 (s,3H). 13C NMR (101 MHz, DMSO) δ 175.78, 158.49, 155.29, 153.47, 144.52, 137.11,136.75, 135.27, 131.11, 130.45, 130.07, 129.43, 129.17, 127.64, 126.50,126.13, 125.70, 125.55, 125.40, 124.55, 123.27, 122.93, 122.50, 121.99,121.83, 120.97, 120.76, 120.10, 118.64, 117.92, 113.91, 73.61, 72.44, 71.50,20.62, 16.00. IR (neat, cm-1): 3184, 3080, 3039, 2811, 1714, 1629, 1602, 1576,1493, 1455, 1385, 1368, 1316, 1290. ESI–MS: m/z [M + Na]+ calcd forC35H25N3O4Na+: 572.1945; found: 572.1943. 以上数据证明目的产物合成成功。
实施例十三:
反应瓶中依次加入对甲苯磺酸一水合物(1.9 mg,0.01 mmol)或者三氟甲磺酸铁(Ⅱ)(3.5 mg,0.01 mmol)作为催化剂,1b(50.3mg, 0.22 mmol),2a (15.9 mg, 0.1mmol),加入3 mL甲醇,在室温条件下搅拌反应24小时,反应体系通过简单的柱层析(洗脱剂为二氯甲烷:石油醚=2:1)即可得到目标产物3m (收率分别为46.9 mg, 90%, 41.7 mg,82% yield),白色固体,非对映选择性>99/1。
对产物3m进行分析,结果如下: 1H NMR (400 MHz, DMSO) δ 11.35 (s, 1H),7.46 (s, 1H), 7.40 – 7.34 (m, 2H), 7.32-7.26 (m, 3H), 7.24 – 7.18 (m, 2H),7.14 – 7.04 (m, 5H), 6.97 – 6.91 (m, 2H), 6.79 (td, J = 7.6, 0.4 Hz, 1H),6.71 (d, J = 7.6 Hz, 1H), 6.61 (dd, J = 8.4, 2.4 Hz, 1H), 5.77 (d, J = 2.4Hz, 1H), 5.03 (s, 1H). 13C NMR (101 MHz, DMSO) δ 174.54, 158.17, 154.81,152.32, 143.41, 140.59, 138.13, 136.14, 130.52, 130.00, 129.73, 129.45,129.19, 128.45, 127.66, 125.91, 125.58, 124.62, 124.03, 123.48, 122.38,122.28, 121.15, 120.28, 117.46, 113.03, 109.82, 73.05, 71.69, 71.34. IR(neat, cm-1): 3185, 3163, 3142, 3083, 3039, 2837, 1716, 1622, 1597, 1488,1470, 1455, 1415, 1386, 1365, 1313. ESI–MS: m/z [M + Na]+ calcd forC34H21Cl2N3O3Na+: 612.0852; found: 612.0851. 以上数据证明目的产物合成成功。
实施例十四:
反应瓶中依次加入对甲苯磺酸一水合物 (1.9 mg,0.01 mmol)或者三氟甲磺酸铁(Ⅱ)(3.5 mg,0.01 mmol)作为催化剂, 1c (50.3mg, 0.22 mmol),2a (20.9 mg, 0.1mmol),加入2 mL四氢呋喃,在室温条件下搅拌反应24小时,反应体系通过简单的柱层析(洗脱剂为二氯甲烷:石油醚=2:1)即可得到目标产物3n (收率分别为46.9 mg, 90%, 41.7mg, 82% yield),白色固体,非对映选择性>99/1。
对产物3n进行分析,结果如下:1H NMR (400 MHz, DMSO) δ 11.17 (s, 1H),7.33 – 7.26 (m, 4H), 7.15(s, 2H), 7.13 (s, 1H), 7.07 – 7.01 (dd, J = 15.7,7.5 Hz, 4H), 6.95 (s, 2H), 6.90 – 6.86 (m, 1H), 6.83(d, J = 8.0 Hz, 1H), 6.76(t, J = 7.6 Hz, 1H), 6.70 (d, J = 8.0 Hz, 1H), 5.65 (s, 1H), 4.92 (s, 1H),2.10 (s, 3H), 1.86 (s, 3H). 13C NMR (101 MHz, DMSO) δ 175.44, 158.53, 155.49,151.46, 142.63, 140.69, 136.72, 134.84, 134.62, 134.33, 130.02, 129.52,129.33, 127.56, 126.75, 126.10, 125.40, 124.95, 124.65, 123.53, 123.01,122.06, 121.96, 121.70, 121.03, 120.36, 120.02, 118.34, 114.38, 109.51,73.08, 72.36, 71.31, 20.70, 20.59. IR (neat, cm-1): 3156, 3087, 3035, 2834,1716, 1618, 1602, 1503, 1491, 1468, 1456, 1422, 1374, 1320. ESI–MS: m/z [M +H]+ calcd for C36H27N3O3H+: 550.2125; found: 550.2143. 以上数据证明目的产物合成成功。
实施例十五:
反应瓶中依次加入对甲苯磺酸一水合物 (1.9 mg,0.01 mmol)或者三氟甲磺酸铁(Ⅱ)(3.5 mg,0.01 mmol)作为催化剂, 1d (22.9mg, 0.22 mmol),2a (15.9 mg, 0.1mmol),加入2 mL四氢呋喃,在室温条件下搅拌反应24小时,反应体系通过简单的柱层析(洗脱剂为二氯甲烷:石油醚=2:1)即可得到目标产物3o (收率分别为47.7 mg, 91%, 44.3mg, 85% yield),白色固体,非对映选择性>99/1。
对产物3o进行分析,结果如下: 1H NMR (400 MHz, DMSO) δ 11.26 (s, 1H),7.44 (d, J = 7.6 Hz 1H), 7.41 (s, 1H),7.40 – 7.34(m, 3H), 7.29 (d, J = 7.6Hz, 1H), 7.20 (td, J = 7.6, 1.6 Hz, 1H), 7.17 – 7.12 (m, 4H), 7.08 – 7.03 (m,2H), 6.99 – 6.92 (m, 2H), 6.85 (dd, J = 9.2, 2.8 Hz, 1H), 6.78 (t, J = 7.6Hz, 1H), 6.69 (d, J = 7.6 Hz, 1H), 5.76 (d, J = 8.8 Hz, 1H), 5.00 (s, 1H). 13CNMR (101 MHz, DMSO) δ 174.74, 158.06, 154.69, 153.82, 144.77, 140.50, 136.02,134.23, 130.40, 129.76, 129.68, 128.54, 127.87, 127.69, 126.04, 125.98,125.51, 124.53, 124.10, 123.53, 122.43, 122.10, 121.21, 120.73, 120.29,114.56, 109.95, 73.12, 71.86, 71.39. IR (neat, cm-1): 3167, 3138, 3038, 2969,2893, 2846, 1716, 1624, 1602, 1573, 1486, 1470, 1451, 1409, 1388, 1319. ESI–MS: m/z [M + Na]+ calcd for C34H21Cl2N3O3Na+: 612.0852; found: 612.0852. 以上数据证明目的产物合成成功。
实施例十六:
反应瓶中依次加入对甲苯磺酸一水合物 (1.9 mg,0.01 mmol)或者三氟甲磺酸铁(Ⅱ)(3.5 mg,0.01 mmol)作为催化剂, 1e (22.9 mg, 0.22 mmol),2a (15.9 mg, 0.1mmol),加入2 mL四氢呋喃,在室温条件下搅拌反应24小时,反应体系通过简单的柱层析(洗脱剂为二氯甲烷:石油醚=2:1)即可得到目标产物3p (收率分别为47.6 mg, 91%, 43.7mg, 84% yield),白色固体,非对映选择性>99/1。
对产物3p进行分析,结果如下: 1H NMR (400 MHz, DMSO) δ 11.25 (s, 1H),7.50 (d, J = 7.6 Hz, 1H), 7.42 (s, 1H), 7.31 (s, 3H), 7.21 (s, 1H), 7.19 (s,1H), 7.09 (d, J = 6.4 Hz, 4H), 6.92(s,1H), 6.80 (d, J = 9.6 Hz, 2H), 6.71 (d,J = 6.4 Hz, 1H), 6.61 (s, 1H), 5.82 (d, J = 7.6 Hz, 1H), 5.00 (s, 1H). 13C NMR(101 MHz, CDCl3) δ 176.63, 154.27, 153.87, 151.49, 144.39, 138.73, 137.16,135.06, 131.23, 130.49, 130.15, 129.88, 126.99, 126.96, 126.51, 126.26,126.23, 126.05, 126.00, 125.85, 125.46, 125.35, 125.09, 124.03, 123.76,123.53, 121.98, 121.57, 118.81, 114.19, 109.96, 73.96, 72.96, 72.12. IR(neat, cm-1): 3183, 3153, 3079, 3062, 1716, 1621, 1603, 1498, 1467, 1454,1392, 1368, 1322. ESI–MS: m/z [M + Na]+ calcd for C34H21Cl2N3O3Na+: 612.0852;found: 612.0852.以上数据证明目的产物合成成功。
实施例十七:
反应瓶中依次加入对甲苯磺酸一水合物 (1.9 mg,0.01 mmol)或者三氟甲磺酸铁(Ⅱ)(3.5 mg,0.01 mmol)作为催化剂, 1f (20.9 mg, 0.22 mmol),2a (15.9 mg, 0.1mmol),加入2 mL四氢呋喃,在室温条件下搅拌反应24小时,反应体系通过简单的柱层析(洗脱剂为二氯甲烷:石油醚=2:1)即可得到目标产物3q (收率分别为47.6 mg, 91%, 46.5mg, 89% yield),白色固体,非对映选择性>99/1。
对产物3q进行分析,结果如下: 1H NMR (400 MHz, DMSO) δ 11.15 (s, 1H),7.35 – 7.26 (m, 4H), 7.18 – 7.06 (m, 5H), 7.04 – 6.94 (m, 4H), 6.90 – 6.84(m, 2H), 6.75 (t, J = 7.2 Hz, 1H), 6.67 (d, J = 7.6 Hz, 1H), 6.51 (dd, J =8.4, 1.6 Hz, 1H), 5.70 (d, J = 8.4 Hz, 1H), 4.88 (s, 1H), 2.20 (s, 3H), 2.08(s, 3H). 13C NMR (101 MHz, DMSO) δ 175.54, 158.46, 155.31, 153.22, 144.29,140.53, 134.40, 134.16, 132.63, 129.94, 129.40, 129.31, 127.55, 127.09,126.90, 126.16, 125.93, 125.44, 124.60, 123.56, 123.06, 122.43, 121.92,121.36, 121.25, 121.13, 120.05, 113.48, 109.67, 73.12, 72.46, 71.38, 20.32,19.49. IR (neat, cm-1): 3140, 3083, 3036, 2955, 2903, 2847, 1718, 1623, 1509,1486, 1470, 1451, 1366. ESI–MS: m/z [M + Na]+ calcd for C36H27N3O3Na+: 572.1945;found: 572.1937.以上数据证明目的产物合成成功。
实施例十八:
反应瓶中依次加入对甲苯磺酸一水合物 (1.9 mg,0.01 mmol)或者三氟甲磺酸铁(Ⅱ)(3.5 mg,0.01 mmol)作为催化剂, 1g (20.9 mg, 0.22 mmol),2a (15.9 mg, 0.1mmol),加入2 mL四氢呋喃,在室温条件下搅拌反应24小时,反应体系通过简单的柱层析(洗脱剂为二氯甲烷:石油醚=2:1)即可得到目标产物3r (收率分别为45.3 mg, 87%, 41.6mg, 80% yield),白色固体,非对映选择性>99/1。
对产物3r进行分析,结果如下: 1H NMR (400 MHz, DMSO) δ 11.41 (s, 1H),7.55 (dd, J = 8.0, 1.2 Hz, 1H), 7.49 (s, 1H), 7.43 (d, J = 2.4 Hz, 1H), 7.36– 7.22 (m, 5H), 7.18 (d, J = 2.4, 1H), 7.12 (t, J = 7.6 Hz, 1H), 7.06 (d, J =7.8 Hz, 1H), 6.91 (d, J = 6.8 Hz, 1H), 6.84 (t, J = 7.6 Hz, 1H), 6.75 (d, J =8.0 Hz, 1H), 6.67 (dd, J = 8.4, 2.4 Hz, 1H), 5.80 (d, J = 2.4 Hz, 1H), 5.07(s, 1H). 13C NMR (101 MHz, DMSO) δ 174.15, 152.98, 151.87, 150.27, 142.05,140.57, 137.85, 135.82, 130.60, 130.49, 130.34, 130.15, 129.97, 129.89,127.16, 126.65, 125.52, 125.13, 125.05, 124.93, 124.84, 124.77, 124.68,124.55, 124.03, 122.72, 122.53, 122.41, 117.58, 113.22, 110.01, 72.96, 71.38,71.09. IR(neat,cm-1):3190,3154, 3087, 3031, 1722, 1618, 1595, 1492, 1469,1451, 1418, 1385, 1368, 1308. ESI–MS: m/z [M + H]+ calcd for C34H19 Cl4N3O3H+:657.0181; found: 658.0096.以上数据证明目的产物合成成功。
实施例十九:
反应瓶中依次加入对甲苯磺酸一水合物 (1.9 mg,0.01 mmol)或者三氟甲磺酸铁(Ⅱ)(3.5 mg,0.01 mmol)作为催化剂, 1h (24.3 mg, 0.22 mmol),2a (15.9 mg, 0.1mmol),加入2 mL四氢呋喃,在室温条件下搅拌反应24小时,反应体系通过简单的柱层析(洗脱剂为二氯甲烷:石油醚=2:1)即可得到目标产物3s (收率分别为47.4 mg, 91%, 44.3mg, 85% yield),白色固体,非对映选择性>99/1。
对产物3s进行分析,结果如下: 1H NMR (400 MHz, DMSO) δ 11.22 (s, 1H),7.49 (dd, J = 8.0, 1.2 Hz, 1H), 7.35 (s, 1H), 7.30 – 7.25 (m, 2H), 7.21 –7.15 (m, 3H), 7.09 (dd, J = 15.2, 7.6 Hz, 3H), 6.93 – 6.83 (m, 3H), 6.80 (t,J = 7.6 Hz, 1H), 6.72 (d, J = 7.6 Hz, 1H), 6.44 – 6.39 (m, 1H), 5.75 (s, 1H),4.95 (s, 1H), 2.14 (s, 3H), 1.88 (s, 3H). 13C NMR (101 MHz, DMSO) δ 175.04,153.38, 151.10, 150.96, 141.36, 140.68, 136.37, 135.65, 134.98, 134.29,131.36, 130.19, 129.91, 129.82, 126.67, 126.54, 126.27, 125.48, 125.37,125.04, 124.57, 124.35, 122.42, 122.35, 122.13, 120.63, 118.42, 114.49,109.74, 73.00, 72.01, 71.04, 54.90, 20.75, 20.61. IR(neat,cm-1): 3157, 3085,3032, 2914, 2857, 1717, 1618, 1605 1578, 1502 1468, 1453. 1425, 1389, 1369,1319. ESI–MS: m/z [M + Na]+ calcd for C36H25Cl2N3O3Na+: 640.1165; found:640.1175. 以上数据证明目的产物合成成功。
实施例二十:
反应瓶中依次加入对甲苯磺酸一水合物 (1.9 mg,0.01 mmol)或者三氟甲磺酸铁(Ⅱ)(3.5 mg,0.01 mmol)作为催化剂, 1i (28.5 mg, 0.22 mmol),2a (15.9 mg, 0.1mmol),加入2 mL四氢呋喃,在室温条件下搅拌反应24小时,反应体系通过简单的柱层析(洗脱剂为二氯甲烷:石油醚=2:1)即可得到目标产物3t (收率分别为47.9 mg, 92%, 44.3mg, 84% yield),白色固体,非对映选择性>99/1。
对产物3t进行分析,结果如下: 1H NMR (400 MHz, DMSO) δ 11.31 (s, 1H),7.47(d, J = 7.6 Hz, 1H), 7.45 (s,1H),7.30 – 7.27 (m, 2H), 7.20 – 7.04 (m,6H), 7.00 – 6.92 (m, 3H), 6.81 (t, J = 7.2 Hz, 1H), 6.73 (d, J = 7.6 Hz, 1H),6.58 (dd, J = 8.4, 1.6 Hz, 1H), 5.82 (d, J = 1.6 Hz, 1H), 5.01 (s, 1H), 1.07(s, 9H), 0.92 (s, 9H). 13C NMR (101 MHz, Acetone) δ 176.33, 176.22, 155.10,152.44, 152.41, 149.94, 149.57, 142.94, 141.48, 137.46, 135.32, 132.46,130.96, 130.65, 130.43, 128.16, 127.69, 127.20, 126.97, 126.73, 126.55,126.06, 125.95, 125.02, 123.25, 122.91, 122.02, 121.32, 120.37, 115.82,113.41, 110.66, 110.61, 74.46, 73.60, 72.68, 35.27, 35.04, 31.45, 31.31. IR(neat,cm-1): 3195, 3164, 3075, 3031, 2959, 2922, 2850, 1721, 1617, 1605, 1505,1468, 1456, 1446, 1418, 1383, 1360, 1309. ESI–MS: m/z [M + H]+ calcd forC42H37Cl2N3O3H+: 702.2285; found: 702.2275. 以上数据证明目的产物合成成功。
实施例二十一:
反应瓶中依次加入对甲苯磺酸一水合物 (1.9 mg,0.01 mmol)或者三氟甲磺酸铁(Ⅱ)(3.5 mg,0.01 mmol)作为催化剂, 1j (24.3 mg, 0.22 mmol),2a (15.9 mg, 0.1mmol),加入2 mL四氢呋喃,在室温条件下搅拌反应24小时,反应体系通过简单的柱层析(洗脱剂为二氯甲烷:石油醚=2:1)即可得到目标产物3u (收率分别为47.5 mg, 91%, 44.3mg, 86% yield),白色固体,非对映选择性>99/1。
对产物3u进行分析,结果如下: 1H NMR (400 MHz, DMSO) δ 11.19 (s, 1H),7.48 (d, J = 7.6 Hz, 1H), 7.31 – 7.25 (m, 3H), 7.19 (t, J = 8.0 Hz, 1H), 7.13– 7.05 (m, 5H), 6.91 (s, 1H) , 6.90 (s, 2H), 6.80 (t, J = 7.2 Hz, 1H), 6.70(d, J = 7.6 Hz, 1H), 6.58 (d, J = 8.0 Hz, 1H), 5.72 (d, J = 8.4 Hz, 1H), 4.91(s, 1H), 2.23 (s, 3H), 2.09 (s, 3H). 13C NMR (101 MHz, DMSO) δ 175.14, 153.34,152.90, 150.79, 143.07, 140.54, 134.66, 134.08, 132.30, 131.35, 130.11,129.80,127.18, 126.67, 126.57, 126.52, 126.43, 125.53, 125.41, 125.10,124.58, 124.51, 124.35, 123.03,122.08, 121.76, 121.48, 113.67, 109.89, 73.05,72.13, 71.10, 67.01, 25.12, 20.37, 19.54. IR(neat,cm-1): 3178, 3139, 3084,3039, 2850, 1718 , 1626, 1509, 1469, 1455, 1448, 1387, 1364, 1314. ESI–MS: m/z [M + Na]+ calcd for C36H25Cl2N3O3Na+: 640.1165; found: 640.1170. 以上数据证明目的产物合成成功。
Claims (8)
1.一种螺环羟吲哚咪唑啉并氧氮杂卓化合物的合成方法,其特征在于,包括以下步骤:以二苯并氧氮杂卓和重氮羟吲哚为反应物,以布朗斯特酸或者路易斯酸为催化剂,在有机溶剂中,室温下反应得到螺环羟吲哚咪唑啉并氧氮杂卓化合物;
所述二苯并氧氮杂卓的化学结构式为,其中R1选自:氯、甲基、叔丁基、氢中的一种;R2选自氯或者氢;
所述重氮羟吲哚的化学结构式为,其中R3为甲基、苄基、苄氧羰基或者叔丁氧羰基;R4为甲基、甲氧基、氯或者溴;
所述螺环羟吲哚咪唑啉并氧氮杂卓化合物的结构式为:
其中R1选自:氯、甲基、叔丁基、氢中的一种;R2选自氯或者氢;R3为甲基、苄基、苄氧羰基或者叔丁氧羰基;R4为甲基、甲氧基、氯或者溴。
2.根据权利要求1所述螺环羟吲哚咪唑啉并氧氮杂卓化合物的合成方法,其特征在于:所述有机溶剂为二氯甲烷、乙醚、四氢呋喃、甲苯、1,2-二氯乙烷、对二甲苯、间二甲苯、邻二甲苯、1,4-二氧六环、甲基叔丁基醚或者甲醇。
3.根据权利要求2所述螺环羟吲哚咪唑啉并氧氮杂卓化合物的合成方法,其特征在于:所述有机溶剂为四氢呋喃。
4.根据权利要求1所述螺环羟吲哚咪唑啉并氧氮杂卓化合物的合成方法,其特征在于:以摩尔量计,所述催化剂的用量为重氮羟吲哚的5~20%,二苯并氧氮杂卓的用量为重氮羟吲哚的2~2.5倍。
5.根据权利要求4所述螺环羟吲哚咪唑啉并氧氮杂卓化合物的合成方法,其特征在于:以摩尔量计,所述催化剂的用量为重氮羟吲哚的10%,二苯并氧氮杂卓的用量为重氮羟吲哚的2.2倍。
6.根据权利要求1所述螺环羟吲哚咪唑啉并氧氮杂卓化合物的合成方法,其特征在于:所述催化剂为三氟甲磺酸铁(Ⅱ)或者对甲苯磺酸一水合物。
7.根据权利要求1所述螺环羟吲哚咪唑啉并氧氮杂卓化合物的合成方法,其特征在于:反应过程包括在室温下,向反应器中依次加入催化剂、二苯并氧氮杂卓、重氮羟吲哚、溶剂,搅拌反应20~25小时。
8.根据权利要求1所述螺环羟吲哚咪唑啉并氧氮杂卓化合物的合成方法,其特征在于:反应结束后,反应液通过柱层析即可得到目标产物螺环羟吲哚咪唑啉并氧氮杂卓化合物。
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