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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