三氟甲基取代二氢菲类化合物的合成方法与流程

1.本发明涉及有机合成技术领域，具体涉及三氟甲基取代二氢菲类化合物的合成方法。


背景技术：

2.二氢菲类化合物可通过抑制nf
‑
κb等通路有效地抑制炎症因子的产生，这类化合物结构存在于多种抗炎药物中，该类结构同时也具有良好的抗癌活性。而三氟甲基是一种有强吸电子性、强亲脂性的含氟基团，三氟甲基的引入经常可以增强药物分子的药物活性。
3.目前对于二氢菲类化合物研究开发相对并不充分，因此，开发三氟甲基取代二氢菲类化合物的高效合成方法对于药物先导化合物的筛选具有重要作用。


技术实现要素：

4.为了克服上述技术缺陷，本发明提供了一种三氟甲基取代二氢菲类化合物及其制备方法和应用。本发明中，所述化合物结构新颖，具体结构为在铑催化剂存在下，以2
‑
联苯硼酸类化合物和α,β
‑
不饱和酮化合物为起始原料，一步即可完成上述化合物合成，高产率得到三氟甲基取代二氢菲类化合物，合成方法目前尚未有报道。该方法具有如下优势：反应条件温和，成本低，反应收率高，产生的副产物少、反应路径合理，可高效制备该类型的化合物。
5.本发明所述一种三氟甲基取代二氢菲类化合物，具体结构如下：
[0006][0007]
其中：r1选自c1
‑
c6烷基、卤素、c1
‑
c6烷氧基、三氟甲基、硝基、腈基、c1
‑
c4烷氧羰基中的一种或多种；r2选自苯基或取代苯基、萘基或取代萘基、噻吩基或取代噻吩基、呋喃基或取代呋喃基，取代基为c1
‑
c6烷基、卤素、c1
‑
c6烷氧基、三氟甲基、硝基、腈基、c1
‑
c4烷磺酰基、c1
‑
c4烷氧羰基中的一种或多种。
[0008]
b结构中，表示
[0009]
本发明还提供了上述结构化合物的合成方法，包括如下步骤：以2
‑
联苯硼酸类化合物1和α,β
‑
不饱和酮化合物2a或2b为起始原料，在过渡金属铑催化剂和银盐氧化剂作用下，有机溶剂中加热反应分别得到三氟甲基取代二氢菲类化合物3a或3b。
[0010]
反应方程式表示如下：
[0011][0012]
其中：r1选自c1
‑
c6烷基、卤素、c1
‑
c6烷氧基、三氟甲基、硝基、腈基、c1
‑
c4烷氧羰基中的一种或多种；r2选自苯基或取代苯基、萘基或取代萘基、噻吩基或取代噻吩基、呋喃基或取代呋喃基，取代基为c1
‑
c6烷基、卤素、c1
‑
c6烷氧基、三氟甲基、硝基、腈基、c1
‑
c4烷磺酰基、c1
‑
c4烷氧羰基中的一种或多种；2b选自
[0013]
进一步地，在上述技术方案中，所述铑催化剂为[cp
tbu
rhi2]2或[cp
*
rhcl2]2。
[0014]
进一步地，在上述技术方案中，所述银盐氧化剂为醋酸银、碳酸银、氧化银中的一种或多种。
[0015]
进一步地，在上述技术方案中，所述化合物1、化合物2、铑催化剂与银盐氧化剂摩尔比为1.0
‑
1.5:1.0:0.04
‑
0.10:1.0
‑
2.0。
[0016]
进一步地，在上述技术方案中，有机溶剂选自饱和烃类酯，例如乙酸乙酯、甲基叔丁酯、甲酸乙酯或苯甲酸叔丁酯等，优选溶剂为乙酸乙酯。
[0017]
进一步地，在上述技术方案中，所述加热反应温度为60
‑
90℃。
[0018]
进一步地，在上述技术方案中，反应无需惰性气体保护，可在空气中直接进行。
[0019]
进一步地，在上述技术方案中，得到的产物进一步衍生如下(以3aa为例)：
[0020][0021]
为了对反应机理进行研究，做了如下对比试验，结果如下：
[0022][0023]
根据以上对比试验结果，推测的可能反应机理如下：
[0024][0025]
本发明在得到上述化合物3最优条件下，2
‑
联苯硼酸与活泼烯烃偶联反应得到环化产物和桥环化合物，具体如下：
[0026][0027]
发明有益效果
[0028]
本发明可高选择性合成三氟甲基取代二氢菲类化合物，本发明的优势在于：首次合成此类化合物，反应条件温和，效率高，反应路径合理，后处理简单。
具体实施方式
[0029]
以下通过实施例对本发明的上述内容做进一步详细说明，但不应该将此理解为本发明上述主题的范围仅限于以下的实施例，凡基于本发明上述内容实现的技术均属于本发明的范围。
[0030]
反应条件优化试验：
[0031]
反应条件探索试验：(以1a和2a在铑催化下生成3aa为例)典型操作为：将化合物1a(0.12mmol,1.2eq)、[cp
tbu
rhi2]2(4.0mol％)、化合物2a(0.1mmol,1.0eq)和agoac(0.025mmol)、ag2o(0.1mmol)、乙酸乙酯(1.0ml)混合后，反应管密封，升温至80℃反应，薄层板(tlc)监测原料2a完全消失(12h)；旋干溶剂，柱层析分离(石油醚/乙酸乙酯体积比15:1)，得到白色固体3aa。
[0032]
反应方程式如下：
[0033]
[0034][0035]
a
反应条件:1a(0.1mmol),2a(0.1mmol),[cp
tbu
rhi2]2(4mol％),氧化剂(x eq),溶剂(1ml),60℃,空气条件下反应12h,分离收率.
b
[cp
*
rhcl2]2(4mol％)替代[cp
tbu
rhi2]2.
c
括号内收率为非环化的1,4
‑
加成副产物的收率.
d
80℃.
e
1a(0.12mmol).
f
无[cp
tbu
rhi2]2.
[0036]
如表所示，对反应的边界条件进行了探索，发现其他可能的反应条件下均以不同的收率得到目标产物。最终确定最佳反应条件为：在乙酸乙酯(ea)溶剂中，采用[cp
tbu
rhi2]2为催化剂，在agoac和ag2o存在下原料1a和2a以最优收率得到3aa。
[0037]
在以上优化试验基础上，三氟甲基取代二氢菲类化合物3通用合成方法，典型操作如下：
[0038][0039]
在反应试管中，加入化合物1、化合物2(化合物1与化合物2摩尔比1.5
‑
1.0:1.0)和[cp
tbu
rhi2]2(1
‑
10mol％)，在空气条件下，再加入有机溶剂，密封真空封管，置于80℃油浴中，搅拌至反应完毕。加水淬灭，乙醚萃取，合并乙醚层，减压除去有机溶剂得到粗产物，pe/ea硅胶柱层析纯化，得到化合物3。
[0040]
实施例1
[0041][0042]
在25ml耐压管中，依次加入2
‑
联苯硼酸(0.12mmol,24mg)、4,4,4
‑
三氟
‑1‑
(对甲苯
基)丁
‑2‑
烯
‑1‑
酮(0.1mmol,21.4mg)、[cp
tbu
rhi2]2(0.004mmol,4.9mg)、agoac(0.025mmol,4.2mg)、ag2o(0.1mmol,23.2mg)和ea(1.0ml),反应管密封，然后将该混合物于80℃加热搅拌反应12h。反应完成后，待反应完全后冷却到室温，旋干溶剂。加入去离子水与乙酸乙酯，水相萃取三次，合并有机相，用饱和食盐水反萃一次，无水硫酸钠干燥。旋干用柱层析分离(石油醚/乙酸乙酯＝15:1)，得白色固体3aa(34.2mg,94％)。该化合物的表征数据如下：1h nmr(600mhz,cdcl3)δ7.80
–
7.73(m,4h),7.34
–
7.31(m,1h),7.28
–
7.25(m,1h),7.19(d,j＝8.0hz,2h),7.17
–
7.08(m,4h),5.08(s,1h),3.84(q,j＝9.4hz,1h),2.32(s,3h).
13
c nmr(100mhz,cdcl3)δ196.0,144.6,134.9,134.3,132.6,131.3,130.7,129.8,129.7,129.6,128.9,128.7,128.3,128.0,126.4(d,j＝1.0hz,1c),126.3(q,j＝281.8hz,1c),124.2,124.1,45.9(d,j＝1.1hz,1c),45.7(q,j＝27.3hz,1c),21.8.
19
f nmr(376mhz,cdcl3)δ
‑
70.09(d).hrms(esi
‑
tof)m/z:[m na]

calcd for c
23
h
17
f3nao

389.1124,found:389.1124.
[0043]
实施例2
[0044]
采用按实施例1所述方法，得白色固体3ab(23.0mg,55％,m.p.114
‑
116℃).
[0045]
该化合物表征数据如下：1h nmr(400mhz,cdcl3)δ7.86(d,j＝8.1hz,2h),7.72
–
7.67(m,2h),7.27(d,j＝8.0hz,2h),7.18(d,j＝8.8hz,1h),7.13(d,j＝7.8hz,1h),6.96(m,2h),5.10(s,1h),3.82(q,j＝9.4hz,1h),2.40(s,3h),2.28(s,3h),2.27(s,3h).
13
c nmr(100mhz,cdcl3)δ196.1,144.5,137.7,137.4,132.5,132.3,131.9,131.8,130.5,130.4,130.1,129.8,129.4,129.0,126.4(q,j＝281.9hz,1c),125.8,123.7,123.7,45.84,45.83(q,j＝27.1hz,1c),21.8,21.2,21.1.
19
f nmr(376mhz,cdcl3)δ
‑
70.06(d).[m na]

calcd for c
25
h
21
f3nao

417.1437,found:417.1437.
[0046]
实施例3
[0047]
采用按实施例1所述方法，得白色固体3ac(29.3mg,61％,m.p.105
‑
106℃).
[0048]
该化合物表征数据如下：1h nmr(400mhz,cdcl3)δ7.88(d,j＝8.1hz,2h),7.77(d,j＝8.3hz,1h),7.74(d,j＝8.3hz,1h),7.43(dd,j＝8.3,1.9hz,1h),7.35(dd,j＝8.2,1.9hz,1h),7.31(d,j＝8.0hz,2h),7.19(s,1h),7.13(d,j＝1.7hz,1h),
5.14(s,1h),3.91(q,j＝9.5hz,1h),2.44(s,3h),1.31(s,9h),1.26(s,9h).
13
c nmr(100mhz,cdcl3)δ196.5,150.8,150.6,144.3,132.9,132.0,131.5,130.0,129.7,129.0,128.3,126.7,126.6,126.5(q,j＝281.8hz,1c),125.7,125.6,123.5,123.4,45.9(q,j＝26.8hz,1c),46.5,34.6,31.4,31.3,21.8.
19
f nmr(565mhz,cdcl3)δ
‑
70.19(d).[m na]

calcd for c
31
h
33
f3nao

501.2376,found:501.2373.
[0049]
实施例4
[0050]
采用按实施例1所述方法，得白色固体3ad(25.1mg,29％,m.p.146
‑
147℃).
[0051]
该化合物表征数据如下：1h nmr(600mhz,cdcl3)δ7.87(d,j＝8.2hz,2h),7.71(d,j＝8.7hz,1h),7.69(d,j＝8.7hz,1h),7.31(d,j＝8.0hz,2h),6.95(dd,j＝8.7,2.7hz,1h),6.88(dd,j＝8.6,2.6hz,1h),6.73(d,j＝2.3hz,1h),6.72(d,j＝2.6hz,1h),5.09(s,1h),3.85(q,j＝9.4hz,1h),3.79(s,3h),3.76(s,3h),2.44(s,3h).
13
c nmr(100mhz,cdcl3)δ196.0,158.9,158.7,144.6,132.6,131.3,129.8,129.0,127.7,127.3,127.0(d,j＝0.9hz,1c),126.3(q,j＝282.2hz,1c),124.7,124.6,116.7,115.19,115.16,113.9,55.42,55.35,46.2,46.0(q,j＝26.8hz,1c),21.8.
19
f nmr(376mhz,cdcl3)δ
‑
70.02(d).[m na]

calcd for c
25
h
21
f3nao

449.1335,found:449.1331.
[0052]
实施例5
[0053]
采用按实施例1所述方法，得白色固体3ab(32.6mg,83％,m.p.133
‑
134℃).
[0054]
该化合物表征数据如下：1h nmr(600mhz,cdcl3)δ7.88(d,j＝8.2hz,2h),7.71(s,1h),7.69(s,1h),7.31(d,j＝8.0hz,2h),7.12
–
7.05(m,4h),5.15(s,1h),3.90(q,j＝9.4hz,1h),2.44(s,3h),2.43(s,3h),2.42(s,3h).
13
c nmr(100mhz,cdcl3)δ196.3,144.4,139.4,138.2,134.7,134.2,132.6,131.1,129.7,129.4,129.0,128.9,128.8,127.8,126.4(q,j＝281.7hz,1c),124.9,124.8,123.6,45.6,45.4(q,j＝27.1hz,1c),21.8,21.7,21.6.
19
f nmr(565mhz,cdcl3)δ
‑
70.23(d).[m na]

calcd for c
25
h
21
f3nao

417.1437,found:417.1432.
[0055]
实施例6
[0056]
采用按实施例1所述方法，得白色固体3af(16.3mg,37％,m.p.140
‑
141℃).
[0057]
该化合物表征数据如下：1h nmr(400mhz,cdcl3)δ7.84(d,j＝8.2hz,2h),7.80(d,j＝2.0hz,1h),7.78(d,j＝2.0hz,1h),7.32(d,j＝8.1hz,2h),7.28
–
7.23(m,2h),7.17
–
7.14(m,2h),5.15(s,1h),3.91(q,j＝9.2hz,1h),2.45(s,3h).
13
c nmr(100mhz,cdcl3)δ195.4,145.1,136.1,135.5,135.0,134.8,132.6,132.1,130.9,130.0,129.3,128.9,128.7,125.9(q,j＝281.1hz,1c),124.9,124.6,124.5,45.23,45.20(q,j＝27.8hz,1c),21.9.
19
f nmr(376mhz,cdcl3)δ
‑
70.22(d).[m na]

calcd for c
23
h
15
cl2f3nao

457.0344,found:457.0341.
[0058]
实施例7
[0059]
采用按实施例1所述方法，得白色固体3ag(14.4mg,29％,m.p.130
‑
131℃).
[0060]
该化合物表征数据如下：1h nmr(600mhz,cdcl3)δ8.12(s,2h),8.09(s,1h),7.85(d,j＝8.1hz,2h),7.58(d,j＝7.8hz,1h),7.55(d,j＝7.8hz,1h),7.41
–
7.36(m,2h),7.34(d,j＝8.0hz,2h),5.28(s,1h),4.02(q,j＝9.1hz,1h),2.45(s,3h).
13
c nmr(150mhz,cdcl3)δ194.8,145.4,134.8,134.5,134.0,132.4(q,j＝32.7hz,1c),132.1,131.8,131.4(q,j＝32.6hz,1c),130.3,130.2,130.1,129.0,126.7,125.8(q,j＝3.5hz,1c),125.6(q,j＝3.8hz,1c),124.0(q,j＝272.4hz,1c),123.9(q,j＝273.1hz,1c),121.3(q,j＝3.9hz,1c),121.2(q,j＝3.9hz,1c),45.52,45.52(q,j＝27.7hz,1c),21.9.
19
f nmr(376mhz,cdcl3)δ
‑
62.80(d),
‑
70.16(d).[m na]

calcd for c
25
h
15
f9nao

525.0871,found:525.0871.
[0061]
实施例8
[0062]
采用按实施例1所述方法，得白色固体3ah(25.1mg,38％,m.p.76
‑
77℃).
[0063]
该化合物表征数据如下：1h nmr(400mhz,cdcl3)δ7.72(d,j＝8.2hz,2h),7.24
–
7.19(m,4h),7.13(d,j＝9.9hz,1h),7.08(d,j＝10.1hz,1h),7.04(m,1h),6.97(d,j＝7.4hz,1h),5.07(s,1h),3.93(q,j＝9.2hz,1h),2.36(s,3h).
13
c nmr(100mhz,cdcl3)δ195.0,159.8(d,j＝249.3hz,1c),159.6(d,j＝246.8hz,1c),144.8,134.5(d,j＝3.8hz,1c),132.4,130.3,129.94(d,j＝9.2hz,1c),129.85,129.6(d,j＝9.0hz,1c),128.8,126.5(d,j＝2.8hz,1c),125.7(q,j＝281.6hz,1c),124.9(d,j＝2.8hz,1c),119.7(d,j＝15.3hz,1c),119.4(d,j＝14.9hz,1c),117.8(d,j＝23.5hz,1c),116.8(d,j＝23.7hz,1c),47.0,46.3(q,j＝26.0hz,1c),21.8.
19
f nmr(376mhz,cdcl3)δ
‑
69.19(d),
‑
104.97/
‑
105.01(m),
‑
105.25/
‑
105.30(m),
‑
105.90/
‑
105.94(m),
‑
106.18/
‑
106.22(m).[m na]

calcd for c
23
h
15
f5nao

425.0935,found:425.0936.
[0064]
实施例9
[0065]
采用按实施例1所述方法，得白色固体3ai(11.1mg,26％,m.p.111
‑
112℃).
[0066]
该化合物表征数据如下：1h nmr(600mhz,cdcl3)δ7.86(d,j＝8.2hz,2h),7.71(d,j＝8.7hz,1h),7.68(d,j＝8.7hz,1h),7.30(d,j＝8.1hz,2h),6.95(dd,j＝8.7,2.6hz,1h),6.87(dd,j＝8.6,2.7hz,1h),6.72(d,j＝2.4hz,1h),6.71(d,j＝2.6hz,1h),5.09(s,1h),3.84(q,j＝9.6hz,1h),3.79(s,3h),3.76(s,3h),2.44(s,3h).
13
c nmr(150mhz,cdcl3)δ196.0,158.9,158.7,144.6,132.6,131.3,129.8,129.0,127.9,127.7,127.3,127.0,126.3(q,j＝281.7hz,1c),124.7,124.6,116.7,115.19,115.16,114.3,113.9,55.44,55.37,46.2,46.1(q,j＝27.1hz,1c),21.8.
19
f nmr(376mhz,cdcl3)δ
‑
70.04(d).[m na]

calcd for c
25
h
21
f3na o
3
449.1335,found:449.1330.
[0067]
实施例10
[0068]
采用按实施例1所述方法，得白色固体3ba(36.6mg,99％,m.p.93
‑
94℃).
[0069]
该化合物表征数据如下：1h nmr(400mhz,cdcl3)δ7.95
–
7.91(m,2h),7.85
–
7.80(m,2h),7.42
–
7.38(m,1h),7.36
–
7.32(m,1h),7.24
–
7.18(m,3h),7.17
–
7.10(m,3h),5.09(s,1h),3.88(q,j＝9.3hz,1h).
13
c nmr(100mhz,cdcl3)δ194.9,166.0(d,j＝256.0hz,1c),134.7,131.6(d,j＝3.0hz,1c),131.5(d,j＝9.4hz,2c),134.3,131.3,130.3,129.9,129.6,128.9,128.4,128.2,126.3(q,j＝1.0hz,1c),126.2(q,j＝281.8hz,1c),124.3,124.1,116.4,116.3(d,j＝21.9hz,2c),116.2,46.1,45.6(q,j＝27.4hz,1c).
19
f nmr(376mhz,cdcl3)δ
‑
70.13(d),
‑
104.17/
‑
104.24(m).[m na] calcd for c22h14f4nao 393.0873,found:393.0872.
[0070]
实施例11
[0071]
采用按实施例1所述方法，得白色固体3ca(33.5mg,87％,m.p.120
‑
121℃).
[0072]
该化合物的表征数据如下：1h nmr(400mhz,cdcl3)δ7.93
–
7.89(m,4h),7.57
–
7.46(m,3h),7.45
–
7.41(m,1h),7.35
–
7.27(m,3h),7.23(dd,j＝7.5,1.3hz,1h),5.16(s,1h),3.97(q,j＝9.4hz,1h).
13
c nmr(150mhz,cdcl3)δ195.4,140.1,134.7,134.3,133.6,131.3,130.2,130.1,129.9,129.7,129.4,128.9,128.4,128.2,126.4,126.2(q,j＝281.7hz,1c),124.3,124.2,46.2(s,1h),45.5(q,j＝27.3hz,1c).
19
f nmr(376mhz,cdcl3)δ
‑
70.12(d).[m na]

calcd for c
22
h
14
f3clnao

409.0577,found:406.0572.
[0073]
实施例12
[0074]
采用按实施例1所述方法，得白色固体3da(42.3mg,98％,m.p.123
‑
125℃).
[0075]
该化合物的表征数据如下：1h nmr(400mhz,cdcl3)δ7.77(m,2h),7.69(d,j＝8.6hz,2h),7.54(d,j＝8.6hz,2h),7.35
–
7.33(m,1h),7.287.31
–
7.26(m,1h),7.21
–
7.13(m,3h),7.09(d,j＝7.4hz,1h),5.01(s,1h),3.83(q,j＝9.3hz,1h).
13
c nmr(150mhz,cdcl3)δ195.6,134.7,134.3,134.1,132.4,131.3,130.2,130.1,129.9,129.7,128.9,128.8,128.4,128.2,126.4,126.2(q,j＝281.6hz,1c),124.3,124.1,46.2,45.5(q,
j＝27.4hz,1c).
19
f nmr(376mhz,cdcl3)δ
‑
70.06(d).[m na]

calcd for c
22
h
14
f3brnao

453.0072,found:453.0066.
[0076]
实施例13
[0077]
采用按实施例1所述方法，得白色固体3ea(33.9mg,89％,m.p.165
‑
167℃).
[0078]
该化合物表征数据如下：1h nmr(600mhz,cdcl3)δ7.96(d,j＝8.7hz,2h),7.87(d,j＝7.9hz,1h),7.84(d,j＝7.9hz,1h),7.43
–
7.41(m,1h),7.37
–
7.34(m,1h),7.25
–
7.21(m,2h),7.19(,2h),6.97(d,j＝8.7hz,2h),5.15(s,1h),3.92
–
3.86(m,4h).
13
c nmr(100mhz,cdcl3)δ194.8,164.0,134.9,134.4,131.3,131.2,131.0,129.8,129.5,128.7,128.3,128.0,127.8,126.4,126.3(q,j＝281.6hz,1c),124.2,124.1,114.3,55.7,45.9(q,j＝27.2hz,1c),45.5.
19
f nmr(565mhz,cdcl3)δ
‑
70.21(d).[m na]

calcd for c
23
h
17
f3nao
2
405.1073,found:405.1066.
[0079]
实施例14
[0080]
采用按实施例1所述方法，得白色固体3fa(38.5mg,92％,m.p.95
‑
97℃).
[0081]
该化合物表征数据如下：1h nmr(400mhz,cdcl3)δ7.91(d,j＝8.2hz,2h),7.84
–
7.76(m,2h),7.69(d,j＝8.2hz,2h),7.43
–
7.36(m,1h),7.34
–
7.31(m,1h),7.25
–
7.15(m,3h),7.12(d,j＝7.4hz,1h),5.06(s,1h),3.89(q,j＝9.3hz,1h).
13
c nmr(150mhz,cdcl3)δ196.0,138.5,134.8(q,j＝33.0hz,1c),134.6,134.3,131.3,129.9,129.8,129.6,129.1,129.0,128.5,128.3,126.2(d,j＝281.9hz,1c),126.1(q,j＝4.0hz,2c),124.4,124.2,123.6(q,j＝272.8hz,1c),46.9,45.3(q,j＝27.5hz,1c).
19
f nmr(376mhz,cdcl3)δ
‑
63.18,
‑
70.04(d).[m na] calcd for c
23
h
14
f6nao

443.0841,found:443.0834.
[0082]
实施例15
[0083]
采用按实施例1所述方法，得白色固体3ga(14.7mg,35％,m.p.124
‑
126℃).
[0084]
该化合物表征数据如下：1h nmr(400mhz,cdcl3)δ8.30(d,j＝8.7hz,2h),7.96(d,j＝8.7hz,2h),7.88
–
7.82(m,2h),7.49
–
7.44(m,1h),7.41
–
7.36(m,1h),7.34
–
7.27(m,2h),7.25
–
7.21(m,1h),7.17(d,j＝7.5hz,1h),5.07(s,1h),3.98(q,j＝9.3hz,1h).
13
c nmr(100mhz,cdcl3)δ195.8,150.4,140.8,134.3,134.2,131.3,130.0,129.5,129.3,129.0,128.6,128.5,126.5,126.1(q,j＝281.5hz,1c),124.6,124.2,124.1,47.4(d,j＝1.2hz,1c),45.1(q,j＝27.5hz,1c).
19
f nmr(376mhz,cdcl3)δ
‑
69.94(d).[m na]

calcd for c
22
h
14
f3nao
3
420.0818,found:420.0816.
[0085]
实施例16
[0086]
采用按实施例1所述方法，得白色固体3ha(28.9mg,67％,m.p.150
‑
151℃).
[0087]
该化合物表征数据如下：1h nmr(400mhz,cdcl3)δ8.05(d,j＝8.5hz,2h),7.98(d,j＝8.5hz,2h),7.87
–
7.83(m,2h),7.48
–
7.44(m,1h),7.40
–
7.36(m,1h),7.33
–
7.29(m,2h),7.25
–
7.21(m,1h),7.18
–
7.16(m,1h),5.08(s,1h),3.97(q,j＝9.3hz,1h),3.08(s,3h).
13
c nmr(100mhz,cdcl3)δ196.0,144.4,140.2,134.4,134.2,131.3,130.0,129.4,129.2,129.2,128.6,128.4,128.1,126.5,126.1(q,j＝281.8hz,1c),124.5,124.2,47.3,45.1(q,j＝27.5hz,1c),44.4.
19
f nmr(376mhz,cdcl3)δ
‑
69.94(d).[m na]

calcd for c
23
h
17
f3nao3s

453.0743,found:453.0741.
[0088]
实施例17
[0089]
采用按实施例1所述方法，得白色固体3ia(18.4mg,47％,m.p.80
‑
81℃).
[0090]
该化合物表征数据如下：1h nmr(600mhz,cdcl3)δ7.86(d,j＝7.8hz,1h),7.81(d,j＝7.7hz,1h),7.48
–
7.43(m,2h),7.39
–
7.30(m,4h),7.28
–
7.26(m,1h),7.17
–
7.15(m,1h),7.12(d,j＝7.6hz,1h),7.02(d,j＝7.4hz,1h),4.79(s,1h),4.15(q,j＝9.6hz,1h),1.81(s,3h).
13
c nmr(100mhz,cdcl3)δ201.5,137.9,137.0,134.4,133.9,131.4,130.6,130.6,129.7,128.7,128.3,128.2,127.5(d,j＝1.1hz,1c),126.4(q,j＝281.3hz,1c),126.2,125.4,124.1,124.0,50.6(d,j＝1.1hz,1c),44.4(q,j＝27.5hz,1c),
19.3.
19
f nmr(376mhz,cdcl3)δ
‑
69.80(d).[m na]

calcd for c
23
h
17
f3nao

389.1124,found:389.1125.
[0091]
实施例18
[0092]
采用按实施例1所述方法，得白色固体3ja(33.7mg,91％,m.p.113
‑
115℃).
[0093]
该化合物表征数据如下：1h nmr(400mhz,cdcl3)δ7.95
–
7.91(m,2h),7.85
–
7.80(m,2h),7.42
–
7.38(m,1h),7.36
–
7.32(m,1h),7.24
–
7.17(m,3h),7.15
–
7.11(m,3h),5.09(s,1h),3.87(q,j＝9.3hz,1h).
13
c nmr(150mhz,cdcl3)δ197.5,195.0,166.1(d,j＝255.6hz,1c),134.7,134.3,131.6(d,j＝3.1hz,1c),131.5(d,j＝9.6hz,1c),131.3,130.3,129.9,129.6,128.9,128.4,128.2,126.3,126.2(q,j＝281.5hz,1c),124.3,124.1,116.3(d,j＝21.9hz,1c),46.1,45.6(q,j＝27.4hz,1c).
19
f nmr(376mhz,cdcl3)δ
‑
70.13(d),
‑
104.17/
‑
104.24(m).[m na]

calcd for c
22
h
14
f4nao

393.0873,found:393.0874.
[0094]
实施例19
[0095]
采用按实施例1所述方法，得无色油状液体3ka(20.8mg,47％).
[0096]
该化合物表征数据如下：1h nmr(400mhz,cdcl3)δ7.85(d,j＝7.9hz,1h),7.78(d,j＝7.5hz,1h),7.63(d,j＝7.9hz,1h),7.49
–
7.42(m,3h),7.38
–
7.34(m,2h),7.33
–
7.28(m,1h),7.08
–
7.04(m,1h),6.90(d,j＝7.4hz,1h),6.74(d,j＝7.7hz,1h),4.64(s,1h),4.30(q,j＝9.7hz,1h).
13
c nmr(100mhz,cdcl3)δ200.3,137.6(q,j＝2.1hz,1c),134.0,133.9,131.7,131.3,130.8,130.0,129.7,129.0,128.9,128.5,128.2,127.7(q,j＝1.0hz,1c),127.3,126.9(q,j＝32.1hz,1c),126.6(q,j＝4.6hz,1c),126.4(q,j＝281.2hz,1h),124.13,124.11,123.6(q,j＝273.8hz,1c),51.9,43.7(q,j＝27.6hz,1c).
19
f nmr(376mhz,cdcl3)δ
‑
57.93,
‑
69.89(d).[m na]

calcd for c
23
h
14
f6nao

443.0841,found:443.0844.
[0097]
实施例20
[0098]
采用按实施例1所述的方法，得白色固体3la(36.2mg,99％,m.p.90
‑
92℃).
[0099]
该化合物表征数据如下：1h nmr(400mhz,cdcl3)δ7.80
–
7.75(m,2h),7.68(d,j＝6.7hz,1h),7.62(s,1h),7.37
–
7.26(m,4h),7.20
–
7.10(m,4h),5.09(s,1h),3.86(q,j＝9.4hz,1h),2.32(s,3h).
13
c nmr(100mhz,cdcl3)δ196.7,139.0,135.3,134.8,134.4,131.3,130.6,129.8,129.6,129.4,128.9,128.7,128.3,128.1,126.4,126.3(q,j＝281.9hz,1c),125.9,124.2,124.1,46.1(d,j＝1.1hz,1c),45.6(q,j＝27.2hz,1c),21.5.
19
f nmr(376mhz,cdcl3)δ
‑
70.11(d).[m na]

calcd for c
23
h
17
f3nao

389.1124,found:389.1123.
[0100]
实施例21
[0101]
采用按实施例1所述方法，得白色固体3ma(34.4mg,93％,m.p.72
‑
74℃).
[0102]
该化合物表征数据如下：1h nmr(400mhz,cdcl3)δ7.89
–
7.80(m,2h),7.76
–
7.71(m,1h),7.55
–
7.52(m,1h),7.51
–
7.40(m,2h),7.39
–
7.34(m,1h),7.31
–
7.20(m,4h),7.17(dd,j＝7.6,1.3hz,1h),5.09(s,1h),3.92(q,j＝9.3hz,1h).
13
c nmr(150mhz,cdcl3)δ195.4(d,j＝1.6hz,1c),163.1(d,j＝249.4hz,1c),137.5(d,j＝6.2hz,1c),134.7,134.3,131.3,130.7(d,j＝7.7hz,1c),130.0,129.9,129.7,129.0,128.4,128.2,126.2(q,j＝281.8hz,1c),124.4,124.3(d,j＝3.3hz,1c),124.2,120.6(d,j＝21.7hz,1c),115.7(d,j＝22.2hz,1c),46.5,45.4(q,j＝27.3hz,1c).
19
f nmr(376mhz,cdcl3)δ
‑
70.07(d),
‑
110.66/
‑
110.73(m).[m na]

calcd for c
22
h
14
f4nao

393.0873,found:393.0873.
[0103]
实施例22
[0104]
采用按实施例1所述方法，得淡黄色液体3na(27.5mg,71％).
[0105]
该化合物表征数据如下：1h nmr(600mhz,cdcl3)δ7.86
–
7.83(m,3h),7.79(d,j＝7.8hz,1h),7.55(d,j＝6.3hz,1h),7.45
–
7.41(m,2h),7.38
–
7.35(m,1h),7.29
–
7.26(m,1h),7.24
–
7.22(m,2h),7.17(d,j＝7.4hz,1h),5.08(s,1h),3.92(q,j＝9.3hz,1h).
13
c nmr(100mhz,cdcl3)δ195.4,137.0,135.5,134.6,134.3,133.5,131.3,
130.3,129.9,129.7,129.0,128.9,128.5,128.2,126.7,126.4(d,j＝1.1hz,1c),126.2(q,j＝281.8hz,1c),124.4,124.2,46.5(d,j＝1.1hz,1c),45.4(q,j＝27.5hz,1c).
19
f nmr(376mhz,cdcl3)δ
‑
70.03(d).[m na]

calcd for c
22
h
14
clf3nao

409.0577,found:409.0577.
[0106]
实施例23
[0107]
采用按实施例1所述方法，得白色固体3oa(38.0mg,88％,m.p.130
‑
131℃).
[0108]
该化合物表征数据如下：1h nmr(400mhz,cdcl3)δ7.99
–
7.98(m,1h),7.87
–
7.83(m,3h),7.71(d,j＝8.1hz,1h),7.46
–
7.42(m,1h),7.39
–
7.35(m,2h),7.30
–
7.21(m,3h),7.18(d,j＝7.4hz,1h),5.07(s,1h),3.92(q,j＝9.3hz,1h).
13
c nmr(10mhz,cdcl3)δ195.3,137.2,136.4,134.6,134.3,131.8,131.3,130.6,129.9,129.84,129.75,129.0,128.5,128.3,127.1,126.4(d,j＝1.1hz,1c),126.2(q,j＝281.9hz,1c),124.4,124.2,123.5,46.5(d,j＝1.1hz,1c),45.4(q,j＝27.4hz,1c).
19
f nmr(376mhz,cdcl3)δ
‑
70.14(d).[m na]

calcd for c
22
h
14
brf3nao

453.0072,found:453.0072.
[0109]
实施例24
[0110]
采用按实施例1所述方法，得无色油状液体3pa(32.0mg,76％).
[0111]
该化合物表征数据如下：1h nmr(600mhz,cdcl3)δ8.14(s,1h),8.10(d,j＝7.9hz,1h),7.88(d,j＝7.6hz,1h),7.87
–
7.84(m,2h),7.66
–
7.63(m,1h),7.48
–
7.45(m,1h),7.41
–
7.38(m,1h),7.33
–
7.30(m,1h),7.29
–
7.27(m,1h),7.26
–
7.24(m,1h),7.20(dd,j＝7.5,1.1hz,1h),5.14(s,1h),3.96(q,j＝9.3hz,1h).
13
c nmr(150mhz,cdcl3)δ195.4,136.1,134.6,134.3,131.73,131.72(q,j＝33.1hz,1c),131.4,129.91,129.88(q,j＝3.4hz,1c),129.8,129.72,129.65,129.1,128.5,128.3,126.4,126.2(q,j＝281.7hz,1c),125.6(q,j＝3.5hz,1c),124.5,124.2,123.6(q,j＝272.6hz,1c),46.6,45.3(q,j＝27.5hz,1c).
19
f nmr(565mhz,cdcl3)δ
‑
62.92,
‑
70.07(d).[m na]

calcd for c
23
h
14
f6nao

443.0841,found:443.0841.
[0112]
实施例25
[0113]
采用按实施例1所述方法，得白色固体3qa(30.0mg,73％,
m.p.158
‑
159℃).
[0114]
该化合物表征数据如下：1h nmr(600mhz,cdcl3)δ7.81(d,j＝7.8hz,1h),7.79(d,j＝7.8hz,1h),7.68(dd,j＝8.4,1.9hz,1h),7.38
–
7.35(m,1h),7.34(d,j＝1.9hz,1h),7.31
–
7.29(m,1h),7.21
–
7.17(m,2h),7.17
–
7.14(m,1h),7.13(d,j＝7.7hz,1h),6.90(d,j＝8.4hz,1h),5.11(s,1h),3.90(s,3h),3.87
–
3.82(m,1h),3.77(s,3h).
13
c nmr(100mhz,cdcl3)δ194.9,153.8,149.6,134.9,134.4,131.4,131.0,129.8,129.5,128.7,128.3,128.0,127.9,126.4,126.3(q,j＝281.8hz,1c),124.2,124.1,123.2,111.2,110.3,56.3,56.0,46.0(q,j＝27.2hz,1c),45.3(s,1h).
19
f nmr(376mhz,cdcl3)δ
‑
70.22(d).[m na]

calcd for c
24
h
19
f3nao
3
435.1178,found:435.1169.
[0115]
实施例26
[0116]
采用按实施例1所述方法，得白色固体3ra(33.4mg,83％,m.p.114
‑
115℃).
[0117]
该化合物表征数据如下：1h nmr(400mhz,cdcl3)δ8.52(s,1h),7.99(d,j＝7.8hz,1h),7.95
–
7.83(m,5h),7.65
–
7.54(m,2h),7.45
–
7.41(m,1h),7.39
–
7.32(m,1h),7.27
–
7.19(m,4h),5.34(s,1h),4.01(q,j＝9.4hz,1h).
13
c nmr(100mhz,cdcl3)δ196.4,135.8,134.8,134.4,132.6,132.5,131.4,130.6,130.4,129.8,129.7,129.1,129.0,128.8,128.4,128.1,128.0,127.2,126.5,126.4(q,j＝281.7hz,1c),124.5,124.3,124.1,46.2,45.8(q,j＝27.2hz,1c).
19
f nmr(376mhz,cdcl3)δ
‑
70.09(d).[m na]

calcd for c
26
h
17
f3nao

425.1124,found:425.1117.
[0118]
实施例27
[0119]
采用按实施例1所述方法，得黄色油状液体3sa(33.8mg,99％).
[0120]
该化合物表征数据如下：1h nmr(600mhz,cdcl3)δ7.88
–
7.82(m,2h),7.66(d,j＝1.1hz,1h),7.45
–
7.37(m,3h),7.34
–
7.26(m,3h),7.11(d,j＝3.5hz,1h),6.54(dd,j＝3.6,1.7hz,1h),4.98(s,1h),4.00(q,j＝9.4hz,1h).
13
c nmr(100mhz,cdcl3)δ185.1,151.2,146.9,134.6,134.3,131.3,,130.01,129.95,129.6,128.9,128.3,128.2,127.2(d,j＝1.0hz,1c),126.2(q,j＝281.5hz,1c),124.3,124.1,118.9,113.0,46.8,45.2
(q,j＝27.4hz,1c).
19
f nmr(376mhz,cdcl3)δ
‑
70.11(d).[m na]

calcd for c
20
h
13
f3nao
2
365.0760,found:365.0760.
[0121]
实施例28
[0122]
采用按实施例1所述方法，得黄色油状液体3ta(4.0mg,16％).
[0123]
该化合物表征数据如下：1h nmr(400mhz,cdcl3)δ7.84(d,j＝7.6hz,1h),7.79(d,j＝7.6hz,1h),7.41
–
7.20(m,5h),6.98(d,j＝7.6hz,1h),3.93(d,j＝5.6hz,1h),3.34
–
3.25(m,1h),2.60
–
2.55(m,1h),2.46
–
2.42(m,1h),2.04
–
1.99(m,1h),1.94
–
1.82(m,2h),1.81
–
1.75(m,1h).
13
c nmr(100mhz,cdcl3)δ212.6,138.0,133.6,133.0,132.5,128.4,128.3,128.0,127.8,127.7,127.6,124.3,124.1,54.7,43.7,39.2,28.1,25.6.[m na]

calcd for c
18
h
16
nao

271.1093,found:271.1093.
[0124]
实施例29
[0125]
采用按实施例1所方法，得白色固体3ua(7.8mg,30％,m.p.166
‑
167℃).
[0126]
该化合物表征数据如下：1h nmr(600mhz,cdcl3)δ7.92(d,j＝7.8hz,2h),7.74(d,j＝7.4hz,2h),7.43
–
7.33(m,4h),4.36(s,2h),3.00(s,3h).
13
c nmr(150mhz,cdcl3)δ177.3,131.2,130.1,128.8,128.5,127.0,123.5,43.4,25.7.[m na]

calcd for c
17
h
13
nnao
2
286.0838,found:286.0830.
[0127]
实施例30
[0128]
采用按实施例1所述方法，得白色固体3va(17.3mg,73％).
[0129]
该化合物表征数据如下：1h nmr(400mhz,cdcl3)δ7.71(d,j＝7.6hz,1h),7.58(d,j＝16.3hz,1h),7.47
–
7.38(m,6h),7.35
–
7.30(m,2h),6.67(d,j＝16.3hz,1h),2.56(q,j＝7.3hz,2h),1.10(t,j＝7.3hz,3h).
13
c nmr(150mhz,cdcl3)δ201.3,143.2,141.8,140.1,132.9,130.6,130.1,130.0,128.4,127.9,127.8,127.6,126.9,33.4,8.3.[m na]

calcd for c
17
h
16
nao

259.1093,found:259.1093.
[0130]
实施例31
[0131]
采用按实施例1所述方法，得白色固体3wa(24.3mg,93％,m.p.133
‑
135℃).
[0132]
该化合物表征数据如下：1h nmr(600mhz,cdcl3)δ7.66
–
7.61(m,2h),7.43
–
7.39(m,4h),7.31
–
7.27(m,2h),4.12(t,j＝6.0hz,2h),3.15(dd,j＝18.6,5.3hz,2h),3.00(dd,j＝18.9,6.9hz,2h).
13
c nmr(150mhz,cdcl3)δ205.8,203.5,137.3,135.0,132.5,129.7,129.1,128.5,53.4,46.8.[m na]

calcd for c
18
h
14
nao
2
285.0886,found:285.0881.
[0133]
实施例32
[0134]
采用按实施例1所述方法，得黄色固体3xa(17.8mg,64％,m.p.139
‑
140℃).
[0135]
该化合物表征数据如下：1h nmr(400mhz,cdcl3)δ7.69
–
7.61(m,2h),7.45
–
7.38(m,4h),7.34
–
7.26(m,2h),4.18
–
4.17(m,1h),3.54(d,j＝8.0hz,1h),3.25(dd,j＝19.1,3.1hz,1h),3.21
–
3.13(m,1h),3.03(dd,j＝19.1,6.4hz,1h),1.13(d,j＝6.8hz,3h).
13
c nmr(150mhz,cdcl3)δ207.7,203.4,137.4,137.0,136.0,134.3,132.6,132.3,130.2,129.7,129.3,128.8,128.7,128.1,62.0,54.0,48.7,47.7,14.3.[m na]

calcd for c
19
h
16
nao
2
299.1043,found:299.1038.
[0136]
实施例33
[0137]
采用按实施例1所述方法，得黄色固体3ya(7.9mg,25％,m.p.136
‑
137℃).
[0138]
该化合物表征数据如下：1h nmr(400mhz,cdcl3)δ9.46
–
9.35(m,1h),8.89(d,j＝8.4hz,1h),8.74
–
8.70(m,2h),7.81
–
7.69(m,4h),6.78(s,1h),1.45(s,9h).
13
c nmr(150mhz,cdcl3)δ190.7,189.2,158.5,134.3,133.5,133.0,132.8,129.5,129.22,129.17,128.7,128.4,128.1,127.0,126.8,123.0,122.8,35.6,29.6.[m na]

calcd for c
22
h
18
nao
2
337.1199,found:337.1196.
[0139]
实施例34
[0140]
反应采用扩大规模试验，参考实施例1反应条件，仅仅反应规模扩大，结果如下：
[0141][0142]
实施例35
[0143]
化合物3aa到4衍生化操作步骤：
[0144]
将3aa(36.6mg，0.1mmol)和mcpba(83.0mg，0.5mmol)溶解于ch2cl2(1.0ml)中，然后加入磷酸盐缓冲液(ph＝7，0.4ml)和hfip(1.0ml)，并在室温下剧烈搅拌36h。饱和硫代硫酸钠溶液(3.0ml)淬灭，二氯甲烷萃取，无水硫酸钠干燥，旋蒸后柱层析得到14.1mg黄色油状液体4，收率37％。1h nmr(600mhz,cdcl3)δ7.94(d,j＝7.8hz,1h),7.89(d,j＝7.8hz,1h),7.65(d,j＝8.2hz,2h),7.61(d,j＝7.5hz,1h),7.53
–
7.47(m,2h),7.41
–
7.34(m,3h),7.09(d,j＝8.2hz,2h),6.52(d,j＝1.2hz,1h),3.99(q,j＝9.1hz,1h),2.32(s,3h).
13
c nmr(150mhz,cdcl3)δ165.7,144.1,134.2,134.1,131.7,131.0,130.6,130.4,129.9,129.7,129.1,128.5,128.3,127.0,126.9(q,j＝281.3hz,1c),126.4,124.3,124.0,68.3(q,j＝1.9hz,1c),48.1(q,j＝26.6hz,1c),21.8.
19
f nmr(565mhz,cdcl3)δ
‑
68.58(d).[m na]

calcd for c
16
h
10
f3nao
2
405.1073,found:405.1073.
[0145]
化合物3aa到6衍生化操作步骤：
[0146]
将3aa(36.6mg，0.1mmol)溶解于干dcm(2.0ml)中，添加lialh4(29.0mg，0.1mmol)，并在80℃下搅拌反应4h，然后通过缓慢添加水(2.0ml)淬灭。用二氯甲烷萃取，无水硫酸钠干燥，旋蒸后柱层析得到中间产物5 5'。5 5'(35.6mg，0.1mmol)溶解于干dcm中，然后沿管壁缓慢加入三氟磺酸(15.0mg，0.1mmol)。反应在80℃下加热并搅拌12小时，然后冷却至室温。旋蒸后柱层析得到29.3mg黄色油状液体6，收率84％。1h nmr(600mhz,cdcl3)δ8.75(d,j＝8.0hz,1h),8.73(d,j＝8.3hz,1h),8.36(d,j＝8.2hz,1h),8.10(d,j＝8.4hz,1h),7.74
–
7.66(m,3h),7.55
–
7.52(m,1h),7.08(d,j＝8.0hz,2h),7.03(d,j＝8.0hz,2h),4.75(s,2h),2.31(s,3h).
13
c nmr(150mhz,cdcl3)δ137.0,136.2,135.6,131.9,131.0,130.6,129.4,128.6,127.89,127.86,127.6,127.3,127.1,127.0,126.03(q,j＝5.2hz,1c),125.97(q,j＝277.8hz,1c),124.5(q,j＝27.6hz,1c),123.03,123.00,35.7(q,j＝4.8hz,1c),21.1.
19
f nmr(56c5 mhz,cdcl3)δ
‑
50.56.[m na]

calcd for c
16
h
10
f3na

373.1175,found:373.1177.
[0147]
化合物3aa到7衍生化操作步骤：
[0148]
在惰性气体条件下，向甲基三苯基溴化膦(124.0mg，0.4mmol)、叔丁醇钾(44.9mg，0.4mmol)和thf(2.0ml)组成溶液中加入3aa(36.6mg，0.1mmol)。反应在30℃下加热并搅拌12小时，然后冷却至室温。乙酸乙酯萃取，无水硫酸钠干燥，旋蒸后柱层析得到29.2mg无色油状液体7，收率80％。1h nmr(400mhz,cdcl3)δ7.92
–
7.90(m,2h),7.50
–
7.48(m,2h),7.41
–
7.37(m,1h),7.36
–
7.31(m,2h),7.31
–
7.28(m,2h),7.28
–
7.25(m,2h),7.12(d,j＝7.5hz,1h),5.14(s,1h),4.59(s,1h),4.39
–
4.34(m,1h),3.53(q,j＝9.8hz,1h),2.45(s,3h).
13
c nmr(150mhz,cdcl3)δ148.1,137.9,137.3,135.0,134.9,134.1,131.8,129.9,129.6,
129.4,128.5,128.2,127.9,127.1,126.7,126.6(q,j＝282.2hz,1c),124.0,123.8,116.8,46.7(q,j＝26.2hz,1c),42.6,21.3.
19
f nmr(376mhz,cdcl3)δ
‑
69.96(d).[m na]

calcd for c
24
h
19
f3na

387.1331,found:387.1331.
[0149]
上实施例描述了本发明的基本原理、主要特征及优点。本行业的技术人员应该了解，本发明不受上述实施例的限制，上述实施例和说明书中描述的内容只是说明本发明的原理，在不脱离本发明原理的范围下，本发明还会有各种变化和改进，这些变化和改进均落入本发明保护的范围内。