Aza-Prins Cyclization

陈殿峰

2011.01.15

Contents

♦ Introduction

♦ Catalyzed Aza-Prins

♦ Cascade Reactions

♦ Conclusions

2

Introduction

3

Prins Cyclization

1.Condensation of olefins&aldehydes

2.Kriewitz, 1899

3.Prins, 1917

8.Aza-Prins

7.Homoallylalcohol

6.Diene 5.Substituted olefins4.Simple olefins

E. Arundale; L. A. Mikeska. Chem.Rev. 1952.505-550.David.R. Adams. Synlett. 1977.661-672.

Catayzed Aza-Prins Cyclization

4

Catalysts

Brønsted acids

Lewis acids

HOAcp-TSACSA……

AuFeB……

NX

R

HA

or Lewis acid

NX

R

Nu

NX

HA

or Lewis acidR

NX R

Nu

NX RR'

HA

or Lewis acidN

X RR'

Nu

NR

XR'

HA

or Lewis acid NR

XR'

Nu

A

B

C

D

X= -CH2-, -CO-,-SO2-

General model

Brønsted Acid

NH

R1

+Bronsted acid

CH2Cl2 or CH3CN0oC or rt.

N

R1

R2

+ Nu

Nu

R1= Ts, Boc, Ms, Bn

R R

R2=alkyl, aryl yiled 60-90%

NR1

R

R2

Nu

orR2

O

H

R2

OH

HNH

R1

R+ NH

R1

R

R2

OHH

N

R1

R

R2

OH2H

N

R1

R2

R

N

R1

R2

R Nu

N

R1

R2

NuR

N

R1

R2

R

N

R1

R2

R

pathway 1

pathway 2

NR1

R

R2

Nu

NR1

R

R2

Nu

Ⅰ

Ⅱ

BA: HOAc, CSA,,TsOH p-TSA, PMA

J.S.Yadav. J. Org. Chem. 2010.75. 2081-2084. 6

Brønsted Acid

Aza-Prins or Cope?

Indirect evidence :

N

R1

[3, 3]N

R1

aza-PrinsN

R1

aza-PrinsR2

N

R1

R2

R2

(x ee%)

R2RR R

R

x ee%

＜ x ee%Nu

Nu

Adrian P. Dobbs. Org. Biomol. Chem.,2010,8,1064-1080 7

N

R1

R2

R[3, 3]

N

R1

R2

R

NH

R1

R2

R

aza-Prins

N

R1

R2

R

aza-PrinsNu

N

R1

R2

RNu

2,6-DBP:2,6-di-tert-butylpyridine

Lewis Acid

8Young Ho Rhee. J. Am. Chem. Soc. 2009. 131. 14660-14661.

4b: more electrophilic

Poor conversion:AgBF4

AgOTf

1 、 Au catalysts

1 、 Au catalysts

9Young Ho Rhee. J. Am. Chem. Soc. 2009. 131. 14660-14661.

10

1 、 Au catalysts

Two possible pathways:

slow

Evidence forPathway 2 :

unstable

Young Ho Rhee. J. Am. Chem. Soc. 2009. 131. 14660-14661.

2 、 Fe catalysts

R. P.Hsung .Org.Lett. 2006.8.3837-3840.Juan I. Padron. Eur.J.Org.Chem. 2010. 2304-2313.

Proposed Intermediates

Energy Calculation

11

X=Cl 、 Br 、 I 、 acac

2 、 Fe catalysts

Solvents screen：CH2Cl2 is the best！

12R. P. Hsung .Org.Lett. 2006.8.3837-3840.

3 、 Bi catalysts

R’=alkyl,82-90% ; R’=aryl, ＞ 90%;dr=9:1

M. S. R. Murty. Tetrahedron.Lett. 2008.49.1141-1145.

13

R=alkyl or aryl; Yield 80-92%dr ＞ 96 ： 4

No GaI3, no reaction;Only GaI3, yield 20-35%

S. J. Yadav. Tetrahedron.Lett. 2008. 49. 3330-3334.

4 、 Ga catalysts

Entry p-anisaldehyde(equiv) I2(equiv) yield %

1

2

3

4

56

78

2.3

2.11.0

1.0

1.01.0

1.0

1.0

1.1

0.50.2

0.05

0

HTIB(0.05)DIB(0.10)

TsOH(0.10)

54

71

84

75

—

26

—24

I2 catalysts

J. S. Yadav. Tetrahedron.Lett. 2009.50.2256-2260. 14

HTIB: PhIOH(OTs)DIB :PhI(OAc)2

I2 catalysts

Mechanism：

15

Stereocontrol：

J. S. Yadav. Tetrahedron.Lett. 2009.50.2256-2260.

Other Lewis Acids: Sc 、 In 、 Sn 、 Ti etc. also performed well.

Adrian P. Dobbs. Org.Biomol.Chem.,2010,8,1064-1080

5 、 Boron catalysts

J. S. Yadav. Tetrahedron.Lett. 2010.51.1578-1581. 16

R=aryl, mainly cis productsyield:68-93%

TsHN R1

+ R2CHOHBF4 BEt2

CH2Cl2, 0oC-rt

no produt Substitutedamine failed!

TsHN

+

HBF4 BEt2

CH2Cl2, 0oC-rtCHO

N

Ts

F

N

Ts

F

+

7:3

TsHN

+

HBF4 BEt2

CH2Cl2, 0oC-rtAr

CHO

N

Ts

F

Ar

Cacade Reactions

2 、 Aza-Prins-Pinacol

3 、 Aza-Prins-Friedel-Crafts

17

1 、 Formal double Aza-Prins

4 、 Diels-Alder-Aza-Prins

18

1 、 Formal double Aza-Prins

TsHN

R1

R1=NHTs or OH

+R2 H

O 10mol% Sc(OTf)3

CH2Cl2, 80oCX

NH

H

Ts

R2R2= aryl or alkyl yield 65-80%

TsHN

R1

+R2

10mol% p-TSA

ClCH2CH2Cl, 75oCX

NH

H

Ts

R2H2C

R1=NHTs or OH R2= aryl yield 65-80%

O

J. S. Yadav. Tetrahedron.Lett. 2010.51.3412-3416.J. S. Yadav. J.Org.Chem. 2010.75. 2081-2084.

X= O / NTs

X= O / NTs

Mechanism:

(1)

(2)

19

1 、 Formal double Aza-Prins

Matthew D. Shair. J.Am.Chem.Soc. 2008.130.16864-16866.20

1 、 Formal double Aza-Prins

2 、 Aza-Prins-Pinacol

21

NHP

R3

+

R5R4

O

NP

OR1R3

R5R4

NP

R3

R5 R4

Aza-Prins

NP

R3

R5 R4

O

R1=alkyl; R2=alkyl or H; R3=alkyl, R4=alkyl ,R5=alkyl or H

Pinacol rearrangment

R2=HH shifts

R2=alkylalkyl shifts

N

R1O R2

R3 R2

O

PR4

R5

R1O R2

NP

R3

R5 R4

O

R2

Lary. E. Overman. Org.Lett. 2001.3.1229-1232.

Mechanism:

1 、 preferential cyclization of E-imine2 、 avoid bulky siloxy group

22

2 、 Aza-Prins-Pinacol

Alan. Armstrong. Org.Lett. 2005.7.1335-1338.23

2 、 Aza-Prins-Pinacol

Overman’s conclusion:

1 、 Ts-iminium tends to be trapped by enolate rapidly

2 、 Pathway generally for N-alkyl iminiumⅠ

Armstrong proposed mechanism

L.E. Overman. JACS. 1998.120.4329-4336.

24

2 、 Aza-Prins-Pinacol

Alan. Armstrong. Org.Lett. 2005.7.1335-1338.

3 、 Aza-Prins-Friedel-Crafts Alkylation

25John.A. Porco, Jr. J.Am. Chem. Soc. 2010. 132. 6412-6418.

Energy Calculation

John.A. Porco, Jr. J.Am. Chem. Soc. 2010. 132. 6412-6418.

26

3 、 Aza-Prins-Friedel-Crafts Alkylation

With diene:

27

3 、 Aza-Prins-Friedel-Crafts Alkylation

John.A. Porco, Jr. J.Am. Chem. Soc. 2010. 132. 6412-6418.

4 、 Diels-Alder-Aza-Prins

Clayton H. Heathcock. J. Am. Chem. Soc. 1988. 110,8734-8736. J. Org. Chem. 1992. 57. 2544-2553.K C. Nicolaou. Angrew. Chem. Int. Ed. 2002. 41. 1668-1698 28

Methyl Homosecodaphniphyllate

Polystep Reaction

29

Stephen Hanessian. Org. Lett. 2004. 6. 4683-4686Stephen Hanessian .J. Am. Chem. Soc. 2004. 126. 6064-6071.Stephen Hanessian .J. Org. Chem. 2005. 70, 5070-5085.

Reductive coupling followed by Aza-Prins

1st step: reductive coupling between eneyne

Glenn C. Micalizio. Org.Lett. 2009.11.4982-4985.

Regioselectivity20:1

30

Glenn C. Micalizio. Org.Lett. 2009.11.4982-4985.

Reductive coupling followed by aza-Prins

31

Aza-Prins followed by ElectrocyclicH

H

N H

HNO

Iyconadin A

O

H

H

NHBn

HCHO(aq),AcOH,SiO2

60oC, 81%

H

H

NBn

H

H

NBn

- H

H

H

NBn

H

H2/Pd/C,MeOH

Boc2O, 94%

H

H

NBoc

H

CHBr3, BnNEt3Cl,i-PrOH

NaOH(aq),CH2Cl2,61%

H

H

NBoc

H

BrBr

H

H

NH

H

BrBr

TFA, CH2Cl2

rt

H

H

NH

H

BrBr

Pyridine,reflux

96%, two steps

H

H

NH

H

Br H

H

N H

Br

Iyconadin A

Tohru Fukuyama. J.Am.Chem.Soc. 2010. 32

33

Conclusion

1 、 Aza-Prins cyclization is a classical methodology in synthesis of a lot of natural products, especially alkloids;

2 、 To the best of my knowledge, aza-cope rearrangment is always competing with Aza-Prins ,and there is still no effective solution.

3 、 Few effective catalysts could promot aza-prins crclization behaving in asymmetric ways.

Thank you!

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