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

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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