串联的 5-endo 卤代内酰胺化 c-h 键氧化官能团化合成 β -...
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串联的 5-Endo 卤代内酰胺化 C-H 键氧化官能团化合成 β - 卤代吡咯烷酮的新方法. 吕明灿 导师 : Richard P. Hsung 教授 唐宇 副教授 2013.05.23. 1. 背景介绍. 2. 课题设计. 3. 结果与讨论. 4. 结论. 5. 致谢. 5- 羟基吡咯 -2- 酮类化合物 A, 具有广泛的生物活性。 A1, 被证明具有良好的抗肿瘤活性, A2, 抗癌活性. 1. 背景介绍. 1.1 5- 羟基吡咯 -2- 酮类生物活性. 5-Hydroxypyrrol-2(5 H )-ones. - PowerPoint PPT PresentationTRANSCRIPT
串联的 5-Endo 卤代内酰胺化 C-H 键氧化官能团化合成 β-卤代吡咯烷酮的新方法
吕明灿导师 : Richard P. Hsung 教授 唐宇 副教授2013.05.23
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2. 课题设计1. 背景介绍
3. 结果与讨论4. 结论
5. 致谢
3
1. 背景介绍 5- 羟基吡咯 -2- 酮类化合物 A, 具有广泛的生物活性。 A1, 被证明具有良好的抗肿瘤活性, A2, 抗癌活性 .
5-Hydroxypyrrol-2(5H)-ones
N
R2 R3
OR1
HOR4A
N
Br
OMe
HORA1
N
H Me
OH
HOH
A2 (jatropham)
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1.1 5- 羟基吡咯 -2- 酮类生物活性
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N OR1
HO
R2
R3 R4
O
NH
H
OH
O
H
CO2Me
lucilactaene
O
NH
ORO
O
HO
PI-091 R = MePI-090 R = H
NH
HOH2C
O
NO
O
OMe
pukeleimide A
N
H
O
O HO
OH
(+)-amabiline
1.2 5- 羟基吡咯 -2- 酮类化合物的有机应用
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R2
R1 R3
NHR4O
CuX2
N
X R3
OR5
R1
R4X = Cl, Br R2 = H, R5 = OH
R2 = H, R5 = R2
1. 3.1 铜催化的 2,3- 连烯酰胺环合
--Ma, S. M.; Xie H. X. Org. Lett. 2000, 24, 3801
1.3.2 酰基氰类经金属催化的缩合环化
R1 R2
O O RC6H4COCN
[Ni(acac)2]
R1 R2
O O
H2N COC6H4R NH
O
H2N COMe
HO
RC6H4
--Veronese, A. C.; Callegari, R. J. Chem. Soc., Perkin Trans. 1 1994, 1779
1.3 吡咯烷酮类化合物的合成方法
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NH
O
R1
HO
R2
CR1
OR2
Ni(CN)2, NaOH (2.5 N)
KCN, CO (1 atm)
1.3.3 镍催化的 α- 炔酮的氰化
--Arzoumanian, H.; Jean, M.; Nuel, D. Organometallics 1997, 16, 2726.
1.3.4 内酯的氨化
--Farina, F.; Victoria, M. M.; Carmen, P. M. et al. Heterocycles, 1984, 8, 1733.
O
CH3
COOH
O2
CH3OHO
CH3
OH3CO
NH3
NH
CH3
OHO
1.3.5 5-Endo 电环化Ph
HNtBu
O
NISallyl alcohol
N
I
OPh
O
tBu
--Igor, D. J.; Fabien G.; Zard, S. Z. Org. Lett. 2010, 12, 416
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2. 课题设计I
O
NHR
C4H9BEt3 / O2BF3 OEt2
C4H9
O
NHRI
tBuOClI2, rt
N
I
O C4H9
R = H
72 %
NOR = Ph
63 %
C3H7
Ph
2.1 选题依据
--Tang, Y.; Li, C. Z. Org. Lett. 2004, 6, 3229
IO
NHR2
R3BEt3 / O2BF3 OEt2
R3
O
NHR2
IR1 R1
N
R3
OR1
I
R25-endo
N
R1
I
R3O
R2
-elimination
- I
N
R1
O
R2
R3 N
R1
O
R2
R3
tBuOI
R1NHR5R2
R3 OtBuOCl/I2
O NR5
R3
HCl (3.0 N)
reflux O O
R3
R4 R1
R2 R2
R1
R4 R4
CH2Cl2, rt
--Tang, Y.; Li, C. Z. Tetrahedron Lett., 2006, 47, 3823
R1 = Me, R2 = Me, Et R3 = I, COOEt, Me, BuR4 = H, MeR5 = H, Bn, Ph
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Ph
HNtBu
O
NISallyl alcohol
N
I
OPh
O
tBu
--Igor, D. J.; Fabien G.; Zard, S. Z. Org. Lett. 2010, 12, 416
Ph
HNtBu
O
NIS (2 equiv)
N
I
OPh
HO
tBu
HNtBu
O
- H
N
I
O
tBuPh
NIS
N
I
O
tBuPh
IH2O
- HN
I
O
tBuPh
I
HO- HI
Ph I
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R1NH
X OR2
tBuOCl/I2N OR1
HOX
R2
X = Cl, Br, IR1 = alkyl R2 = aryl, alkyl
solvent
NH
R2
O IR1
tBuOCl/I2N
R2
O IR1
4-exo NO
I
R2
R1
- I NO R1
R2
NO R1
R2
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A
B
2.2 研究内容
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3. 结果与讨论NH
OPh
I
2a 3a
N OHO
I
Ph
I+
solvent, rt
entry iodinating reagent (equiv) solvent time(h)
yield (%)
1 I2/Na2CO3 (3) CH3CN/H2O (1:1) 96 -a
2 ICl (3) CH3CN/H2O (1:1) 1 21b
3 BPIT (3) CH3CN/H2O (1:1) 96 trace
4 NIS (2) CH3CN/H2O (1:1) 72 38
5 tBuOCl/I2 (3 / 2) CH3CN/H2O (1:1) 15 58
6 NIS (1) CH3CN/H2O (1:1) 72 trace
7 NIS (4) CH3CN/H2O (1:1) 20 65
8 NIS (6) CH3CN/H2O (1:1) 10 63
9 tBuOCl/I2 (1 / 1) CH3CN/H2O (1:1) 72 19
10 tBuOCl/I2 (1 / 2) CH3CN/H2O (1:1) 72 58
3.1 条件优化
11 tBuOCl/I2 (2 / 3) CH3CN/H2O (1:1) 20 60
12 tBuOCl/I2 (3 / 3) CH3CN/H2O (1:1) 15 67
13 tBuOCl/I2 (3 / 3) H2O 3 -a
14 tBuOCl/I2 (3 / 3) THF 3 16
15 tBuOCl/I2 (3 / 3) CH2Cl2 3 31
16 tBuOCl/I2 (3 / 3) Acetone 3 13
17 tBuOCl/I2 (3 / 3) CH3CN ( 0.08 M ) 3 83
18 NIS (4) CH3CN 96 19
19 tBuOCl/I2 (3 / 3) CH3CN ( 0.04 M) 3 63
20 tBuOCl/I2 (3 / 3) CH3CN ( 0.01 M) 3 58a No desired product was generated. b β-Chloro product was obtained, yield was 34%.
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3.2 .1 β- 碘代 - 吡咯烷酮的合成 a
NH
OR3
IR1
N OR1
HO
I
R3
2 3
A: tBuOCl (3.0 equiv) I2 (3.0 equiv), CH3CN
B: NIS (4.0 equiv) CH3CN/H2O (1/1)R2
R2
entry R1 R2 R3 yield (%)b
1 Me H Ph (a) 83 (65)
2 Me H Bn (b) 65 (80)
3 Me H n-Bu (c) 70 (76)
4 Me H p-OMeC6H4 (d) 45 (58) c
5 Me H p-NO2C6H4 (e) 60 (40)
6 n-Bu H Ph (f) 83 (82)
7 n-Bu H Bn (g) 81 (94)a Method A: Treating substrate 2 (1.0 equiv) with tBuOCl (3.0 equiv) and I2 (3.0 equiv) in acetonitrile at rt, stirring for 4 h. Method B: Treating substrate 2 (1.0 equiv) with NIS (4.0 equaiv ) in acetonitrile-water (1:1) at rt, stirring for 20 h.b The datas in parenthesis were yield derived by using Method B. c The reaction was stirred for 48 h.
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3.2 目标化合物的合成
NH
OR2
XR1
N OR1
HO
X
R2
reagent
solvent, rt
entry R1 R2 X reagent (equiv) yield (%)
1 Me Ph Cl NCS _
2 Ph Ph Cl NCS _
3 Me Bn Br NBS 51a
4 n-Bu Ph Br tBuOCl/I2 41b
5 n-Bu Ph Cl tBuOCl/I2 23c
a The reaction was stirred for 10 h at 50 oC.b 20% of starting materials were recovered, the ratio of β-bromo-pyrrolidinones to β -iodo-pyrrolidinones was 1:6.c 18% of starting materials were recovered , the ratio of β-iodo-pyrrolidinones to β -chloro-pyrrolidinones was 1:3.5.
3.2.2 方法的扩展
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3.2.3 β- 溴代 - 吡咯烷酮的合成 a
NH
OR2
BrR1
N OR1
HO
Br
R2
4 5
NBS (4 equiv) CH3CN/H2O (1/1)
50 oC, 12 h
entry R1 R2 yield (%)
1 n-Bu Ph (a) 40 b
2 Me Ph (b) 36 b,c
3 Me Bn (c) 58
4 Me n-Bu (d) 63
a Treating substrate 4 (1.0 equiv) with NBS (4.0 equiv) in acetonitrile-water (1:1) at 50 oC, stirring for 10 h.b para-bromo-phenyl in product was derived. c 20% of starting materials were recovered
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3.3 其他取代基底物的探索研究 3.3.1
I O
NH2C4H9
tBuOCl/I2
N O
I
I O
NH
C4H9
tBuOCl/I2tBu
HN
OOC3H7
CH3CN/H2Ort, 3 h
76%
N OC4H9
I3l
HO
tBu
tBuI
2m
2l
8
3m
C4H9CH3CN, rt, 4 h 61%
Tianjin University 17--唐宇, [博士学位论文 ],上海;中国科学院上海有机化学研究所, 2005.
3.3.2
O
NH
Ph O
NH
PhC4H9
6 7
R
I O
NH
R = Me, trans-2a C4H9, trans-2f
Ph
底物要求 : β-位烯基碘代或溴代 , Z- 式结构
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3.4 反应机理探究
N O
R2
I O
NH
R1
2
R2 I+I O
NH
R1 R2
I+-H+ I
I
-HI
N O
R2
I
N O
R2
I[O]
+H2O
-H+N OR1
R2
I
HO
3
12 13
1415
R1
R1R1
N O
I
HO
PhN O
Ph
HO
Ph
PhB(OH)2
Pd(OAc)2, Na2CO3EtOH, 55 oC, 4 h
74%3a 9
3.5 方法的可应用性
I
NH
O
OMeOMe
N
MeO
MeO
NIS
86%N
MeO
MeOO
Icrispine A
2n
11
N
MeO
MeOHO
O
I10
CH3CN/H2Ort, 11 h
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4 结论 1. 我们发展了一种以 β- 卤代 -β,γ- 不饱和酰胺为底物,在次氯酸叔丁酯与碘(或者 NIS )的作用下,通过串联的 5-endo 环化, C-H 键氧化官能团化来合成卤代吡咯烷酮类化合物的新方法,这一方法具有重要意义。 2. 用我们发现的方法成功构建了天然产物分 子
Crispine A 的母核结构,证明了我们发现的这一方法具有较高的可实用性。 3. 在温和的条件下完成了 C-H 键氧化官能团化。
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5 致谢 感谢 Richard Hsung 教授对我的支持
感谢唐宇副教授对我的悉心指导和教育 感谢杜云飞、黄剑辉副教授对本实验提出的宝贵意见
感谢冯鹤静、刘小凡、刘丽伟以及本课题组的所有成员 感谢各位答辩委员的莅临指导 感谢我的家人对我学业的支持
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谢谢