boshun wan ( 万伯顺 ) e-mail: [email protected]

Catalytic Heterocycle Synthesis Group http://www.chs.dicp.ac.cn/

Boshun Wan (万伯顺 )

E-mail: [email protected]

Recent Advances for the Selective Synthesis of Heterocycles


Natural products

Chemicals for R&D

Polymer Materials

Heterocycles for Sustainable Chemistry

Heterocycles

Pharmaceuticals


Top 100 Brand Name Drugs by US Retail Sales in 2010

Heterocycles: ~50%; Pyridine/Pyrrole: ~10%

http://cbc.arizona.edu/njardarson/group/top-pharmaceuticals-poster


Overview of My Group

NR

NH

RNH

R

Cycloaddition

Cyclization

etc.

etc.

This reportPyridines

DihydropyridinesPyrroles

EnterpriseSponsoredResearch

GovernmentSponsoredResearch

Projects

(> 4,500,000 RMB/year)

NR

N

NR

NH

R

S

R

etc

973 Project (2010CB833300) NSFC-1 (21172218)

(> 800,000 RMB/year) NSFC-2 (pending)


Why Cycloadditon?

N[2 + 2 + 2]

R2

R1

R4

R3

NR5

Two C-C bonds & One C-N bond simultaneously

High atom efficiency

Advantages:

Regioselectivity

Chemoselectivity

Problems:

N

N

NR'

NR'

H

Me

MeH

Complanadine A

NNR'

H

Me

SiR3desilylation

[2 + 2 + 2] cycloaddition

+

NR'

H

Me

CNNR'

H

Me

CN+

SiR3

SiR3

[2 + 2 + 2] cycloaddition

2

Dionicio Siegel et al. J. Am. Chem. Soc. 2010, 132, 5924.


Generic description of the 6 factors

Metal-catalyzed[2 + 2 + 2]

cycloaddition

Saá, C. Vollhardt

Tanaka, K.

Yamamoto, Y. Saá, C.

Louie, J.Takahashi, T.

Urabe, H.

Zenneck, U. Guerchais, V.

(a) Varela, J. A.; Saá, C. Chem. Rev. 2003, 103, 3787. (b) Chopade, P. R.; Louie, J. Adv. Synth. Catal. 2006, 348, 2307. (c) Heller, B.; Hapke, M. Chem. Soc. Rev. 2007, 36, 1085. (d) Varela, J. A.; Saá, C. Synlett 2008, 2571. (e) Wang, C. X.; Li, X. C.; Xu, F.; Wan, B. S. Prog. Chem. 2010, 22, 610.

N

26FeIron

[Ar]4d65s2

44Ru

Ruthenium[Kr]4d75s1

27CoCobalt[Ar]3d74s2

28Ni

Nickel[Ar]3d84s2

45Rh

Rhodium[Kr]3d85s1

22Ti

Titanium[Ar]3d24s2

“CpCo”

“Rh/P-P”

“Cp*Ru”

“Zr/Ni” “Ni/NHC”

“Ti(OiPr)4/iPrMgCl”

Developed Catalytic Systems

“Fe(0)” “Fe(+I)”


Why Iron?

Iron (0.02 US$/mol)

US

$ pe

r mol

2011

1876Ramsay

HCN (g)

C2H2 (g) hot iron N

HH

HH

H 1996Zenneck

Iron(0) complex

2002Guerchais

Iron(I) complex

Co, Ru, Rh, Ni, Ti, etc....

Cheap Nontoxic Benign Quantity

Fe: 3d64s2


Iron Catalytic System

C N

+

Fe

20 oC, 48~96 h NR1 R2

R1

+

TON(pyridine) : TON(benzene) = 0.24~0.69

R2

CHC

R1

HCC

R1

Two regioisomers

R1

R1

R1

Two regioisomers

PSiMe3

FeNCCH3

NCCH3CH3CN

HC C

N

EtOOC

H3C COOEt

73% yield

2

SolventFe

NH3C

R

RR

Zenneck's Work: Organometallics 1996, 15, 2713

Guerchais's Work:

Organometallics 2002, 21, 2578.

Harsh reaction condition for the formation of iron complexLow chemoselectivity

R = COOEtSolvent = CH3CN

or

R = COOEt, CH2NMe2Solvent = CH2Cl2

R

L1 (5 mol%)Zn (10 mol%)

ZnI2 (10 mol%)

CH3CN, 50 C

RR

R

+

R

R R

11~94% yieldRatio of I:II : 58:42~>99:1

NN

Me

N

NMe

Me

Me

FeCl Cl

L1

Catal. Commun. 2011, 12, 489.Yang's Work:

I II


Problems and Solutions

Three crucial problems:

1. Low-valent metal

2. Substrate Coordination & Product Dissociation

3. Benzene byproducts

MLn

MLn N

CR'

or MLn N

CR'

N

M

R'

M N

R'

"MLn"N

Ln

Ln

insertion

[4+2] cycloaddition

R

R R

R R R R

R

R

R

R

R'

RR

R' C NOxidativeCoupling+

R

Common Mechanism:

Rbenzenes


Fe(L)n

NR2

orOxidative Cyclization

Fe(L)nR1

R1

R1 R1 NR2

R1R1

R1R1

R1 R1

NR2

azaferracyclopentadiene ferracyclopentadiene

benzenes(byproduct)

chemoselectivity

Step 2

Step 3

Simple iron salt

Phosphine ligands

Reductant

Low-valentiron species

High reactivity for chemo- and regioselective

[2 + 2 + 2]

N

R2R1

R1

R1

R1

Iron-catalyzed[2 + 2 + 2] cycloaddition

R1 R1

NR2

in situ

Step 1

Problems and Solutions


Cycloaddition of Diynes and Unactivated Nitriles

N

MeO2C

MeO2C

Ph

3a, 98% (94%)a

N

MeO2C

MeO2C

3b, 96%

N

MeO2C

MeO2C

3c, 62%

N

MeO2C

MeO2C

CH3

3d, 91% (93%)b

N

MeO2C

MeO2C

3e, 48%

N

MeO2C

MeO2C

3f, 96%

N

MeO2C

MeO2C

3g, 96%

PhN

MeO2C

MeO2C

3h, 66%

N

MeO2C

MeO2C

3i, 49%

N

MeO2C

MeO2C

3j, 43%

NN

R3

Ts

3k, R3 = Ph, 98%3l, R3 = Me, 93%

NO

Ph

3m, 98%

N

Et

Et

R3

3n, R3 = Ph, 95%3o, R3 = Me, 85%

ZR1

R2+

10 mol% FeI2/dppp (1:2)

N

R2

R1

ZR3

20 mol% Zn, THF, RT

1 3

R3 CN

2

a 5% catalyst b 5% catalyst, 20 equiv nitrile

10 equiv(unactivated)


Cycloaddition of Diynes and Unactivated Nitriles

(Continued)

NN

R3

Ts

3q, R3 = Ph, 69%3r, R3 = Me, 64%

NO

PhR3

3t, R3 = Ph, 65%3u, R3 = Me, 56%

N

MeO2C

MeO2C

3p, 83%

N

MeO2C

MeO2C

3s, 79%

N

MeO2C

MeO2C

TMSR3

3v, R3 = Ph, 91%3w, R3 = Me, 83%


Cycloaddition of Tetrayne

All-intramolecular Cycloaddition

E

E

N

E

E

10 mol%FeI2/2dppp/Zn

THF, rtN

E

E

EE

(E = CO2Me) 6 (72%)

E

E E

E


THF, rt+ PhCN

N

N

Ph

Ph

E

E

E

E

+N

PhE

E

E

E

(E = CO2Me)

4 (85%)

10 equiv

5 (<5%)


Cycloaddition of Alkynenitrile and Alkyne

N

Ph

Ph

N+ Ph

THF, 48 h N

Ph20 mol%

FeI2/2 dppp/Zn

(3 equiv)

+

7 (39%) 8 (trace)

nPr TMSFor , no reaction.or

XN

R+

R'

R'

10 mol% Fe(OAc)2

Zn, DMF, 85 C

R = H, Me, Et, TMS, PhR' = alky, aryl

NX

RR'

R'

22 examples30-86% yield

NN N

iPr

iPrBnO

iPr

iPr OBn

Louie, J. et al. Org. Lett. 2011, 13, 2936.

13 mol%

(L2)

Louie, J.


Ph + CH3CN(3 equiv)


THF, rt

Ph

Ph

Ph Ph

Ph PhN

Ph

Ph

CH3

N

PhCH3

Ph

10 12

+ + +

9 1148 hours: ND ND ND

96 hours:

8%

ND ND47%7%

(1 equiv)

Ph


THF, rt, 48 h

Ph

Ph

Ph+

Ph

Ph

9 (55%) 10 (trace)

Ph

Ph + CH3CN(5 equiv)

N

Ph

Ph

CH3+

N

PhCH3

Ph

11 (60%) 12 (6%)


THF, rt, 48 h

(1)

(2)

(3)

Control Experiments


RL

RS

R CN[FeLn],

FeN

RL R

RS

Ln

Less bulkyFavorable

N

RL

RS

R

Observed56~91% yield

regioselectivity: >99:1

Zn

19

Pathway B

17

Z

Z

Z

or

FeN

RS R

RL

Ln

18

Z

N

RL

RS

R

Not Observed

Fe

RL

RS

Ln

[FeLn]

N

R

Zn

Fe

RL

RSLn

Fe

RL

RS

Ln

N

R

More bulkyLess favorable

Less favorableintermediate

R CN

R CN

13

14

15

16

Z

Z

Z

Pathway A

Z

Supposed to be favoredbut not observed

More bulkyLess favorable

Possible Pathways to Form Pyridines


FeN

RL R

RS

LnZ

azaferracyclopentadieneintermediate

RL

RS

+N

RS

RL

RR CN

unactivated

10 mol% FeI2/dppp (1:2)

20 mol% Zn, THF, rtZ Z

23 examplesup to 98% isolated yield

With Wang, C. X. Angew. Chem. Int. Ed. 2011, 50, 7162

Iron-Catalyzed Cycloaddition


Cycloaddition of Alkynes and Nitriles in Water

+N

R1

R1

R2

[2 + 2 + 2]cycloaddition

H2O

R2

R1 R1

R1

R1

N

Problems:

[M], Substrates

H2O

poor solubility

R2 N

R2 NH2

O

H2O hydrolysis

1) 2)

H2O/Organic Solventh or

water-soluble catalyst

water-soluble substrates

Previous Work: Our Work:

in situgenerated catalyst

pure water(no organic solvent)

+Solutions:


With Xu, F. ChemSusChem. 2012, 5, 854 (IF 6.325)

Ruthenium-catalyzed [2+2+2] Cycloaddition in Pure Water

up to 87% yield

XR1

R2+

N

R2

R1

XR

R CNCp*Ru(COD)Cl, tppts

H2O, 50 oC


Entry R1 R2 R3 Yield (%)

1 C6H5 C6H5 4-MeC6H4 97

2 3-MeC6H4 C6H5 4-MeC6H4 67

3 4-MeC6H4 C6H5 4-MeC6H4 89

4 4-FC6H4 C6H5 4-MeC6H4 97

5 2-CF3C6H4 C6H5 4-MeC6H4 82

6 2-ClC6H4 C6H5 4-MeC6H4 98

7 2-BrC6H4 C6H5 4-MeC6H4 96

8 C6H5 4-MeC6H4 4-MeC6H4 93

9 C6H5 4-FC6H4 4-MeC6H4 96

10 4-FC6H4 C6H5 C6H5 94

11 2-BrC6H4 C6H5 C6H5 95

12 C6H5 C6H5 4-MeC6H4 98

R2

R1 NSO2R3

CO2Me

CO2Me

NH

CO2Me

CO2Me

R1

DMF

140 °C, 6 h

R3O2S

R2

"" Migration

20 21

Synthesis of Pyrroles via Cyclization


Entry R1 R2 R3 Yield (%)

1 C6H5 C6H5 4-MeC6H4 97

2 3-MeC6H4 C6H5 4-MeC6H4 82

3 4-MeC6H4 C6H5 4-MeC6H4 95

4 4-FC6H4 C6H5 4-MeC6H4 94

5 2-CF3C6H4 C6H5 4-MeC6H4 94

6 2-ClC6H4 C6H5 4-MeC6H4 93

7 2-BrC6H4 C6H5 4-MeC6H4 90

8 C6H5 4-MeC6H4 4-MeC6H4 92

9 C6H5 4-FC6H4 4-MeC6H4 94

10 4-FC6H4 C6H5 C6H5 95

11 2-BrC6H4 C6H5 C6H5 88

12 C6H5 C6H5 4-MeC6H4 84

R2

R1 NSO2R3

CO2Me

CO2Me

"" MigrationN

CO2Me

CO2MeR1

H

R2

R3O2S

DMF, 80 C, 4 h

Cs2CO3 (10 mol%)

20 22

Synthesis of Pyrroles via Cyclization


Mechanism Study

"α" Migration

R2

R1

CO2Me

CO2MeNSO OR3

N

CO2Me

CO2Me

R2

R1

SOR3

ON

CO2Me

CO2Me

R2

R1

S OOR3

N

CO2Me

CO2Me

S

R2

R1

OOR3

26

R2

R1 NSO2R3

CO2Me

CO2Me

20

Aza-Claisen Rearrangement

23 24

25

NH

CO2Me

CO2Me

R2

R1

S OOR3

22

Ion-Pair


Crossover Experiment

Mechanism Study

N

CO2Me

CO2Me

Ph

PhO2S H

F

N

CO2Me

CO2Me

Ph

PhO2S HBrN

CO2Me

CO2Me

Ph

TolO2S H

F

N

CO2Me

CO2Me

Ph

TolO2S HBr

CO2MeNSO2Ph

Ph

CO2Me

F

CO2MeNSO2Tol

Ph

CO2Me

Br

DMF140 oC

21j 21g 21d 21k

20j 20g

41% 47% 46% 52%

anticipated products new products


"β" MigrationMechanism Study

CO2MeN

TsPh

CO2MeH

F

N

CO2Me

CO2MePh

H

TsCs2CO3

DMF, 80 oC, 4 h

F

22i28i

CO2MeNTs

Ph

CO2Me

F

Cs2CO3

94%

20i

DMF, 80 oC, 4 h

94%

R1 N CO2Me

CO2Me

S OOR3

HR2

SO

O

R3

N

CO2Me

CO2MeR1

R2

N CO2Me

CO2Me

R1

31

R2

SO

OR3

N

CO2Me

CO2MeR1

R2

S OOR3

28 29

30

R2

R1 NSO2R3

CO2Me

CO2Me

20

NH

CO2Me

CO2Me

R1

22

R2

SO

OR3

Ion-Pair

Base

H

R1 N CO2Me

CO2Me

S OOR3

R2

27

H Base


Crossover Experiment

Competition Experiment

DMF, 80 oC

Cs2CO3 (10 mol%)

N

CO2Me

CO2Me

H

Ph

FN

CO2Me

CO2Me

H

Ph

FN

CO2Me

CO2Me

H

Ph

N

CO2Me

CO2Me

HBr

PhO2S TolO2S PhO2STolO2S

Br

22j, 40%

CO2MeNSO2Ph

Ph

CO2Me

F

CO2MeNSO2Tol

Ph

CO2Me

Br

20j 20gPh

22g, 47% 22d, 43% 22k, 38%

DMF, 80 oC

Cs2CO3 (10 mol%)

CO2MeNSO2Ph

Ph

CO2Me

Br

TolSO2Na+(1 equiv.) N

CO2Me

CO2Me

H

PhPhO2S

Br

N

CO2Me

CO2Me

H

Ph

Br

TolO2S

+

20k 22k, 36% 22g, 59%

CO2MeNSO2Tol

Ph

CO2Me

Br

PhSO2Na+

(1 equiv.) N

CO2Me

CO2Me

H

PhPhO2S

Br

N

CO2Me

CO2Me

H

Ph

Br

TolO2S

+

20g 22k, 36%22g, 60%

DMF, 80 oC

Cs2CO3 (10 mol%)


Highly Regioselective Sulfonyl-Group Migration Reactions

With Xin, X. Y. Angew. Chem. Int. Ed. 2012, 51, 1693.

R2

R1 N CO2Me

CO2Me

SO2R3

NH

CO2Me

CO2Me

R2

R1

R3O2S

NH

CO2Me

CO2Me

R1

R2

R3O2S

DMF, 140 oC

DMF, 80 oC

Cs2CO3 (10 mol %)

"β " MigrationUp to 97% yield

Up to 98% yield

"α " Migration


Summary

R1 R1

NR2

N

R3

OH

N

R1

R1

R2R1

R1

[Ru][2]

in water

[Fe][1]

r.t.

[1] Angew. Chem. Int. Ed. 2011, 50, 7162.[2] ChemSusChem 2012, 5, 854.

[2+2+2]

[Rh][3] N H

XRR

Me

R4

NR4

X

R

R

Me[4]or

R2

R1 NS

CO2R4

CO2R4

OOR3

N

CO2Me

CO2Me

R2

R1

R3O2S

N CO2Me

CO2Me

R1

R2

R3O2S

140 oC

DMF, 80 oC

Cs2CO3 (10 mol %)

DMF

Highly Regioselective Sulfonyl-Group Migration

H

H Versatle Building Block

N

R3

R1

CO2Me

CO2MeSO2R2

N

R3

CO2Me

CO2MeR1

[5] Angew. Chem. Int. Ed. 2012, 51, 1693

[6] To be submitted

[7] To be submitted

[3] To be submitted.[4] Unpublished results.


N

O+ S

HN O

OH2N

R N

O RPdCl2(CH3CN)2 (5 mol %)

Phen.•H2O (6 mol%)Cu(OAc)2 (6 equiv.)Na2CO3 (1.5 equiv.)

100 °C, 4.5h

N

O

92%N

O

N

O

N

O

N

O

N

O

N

O

N

O

N

O

84%86% 67%[b]

90% 47%

Cl

72%

CF3

70%

CF3

87%

N

OF

92%N

OOMe

77%

N

Ot-Bu

73%

苯并恶唑与不同磺酰肼的氧化偶联


苯并恶唑与不同磺酰肼的氧化偶联N

X

X= O, S, NCH3

+ SHN O

OH2NR

N

XR

PdCl2(CH3CN)2 (5 mol %)Phen•H2O (6 mol%)

Cu(OAc)2 (6 equiv.)Na2CO3 (1.5 equiv.)

100 °C, 4.5h

N

O

90%N

O

89%N

O

92%N

O

88%

N

O

OEt

O

91%

N

OPh

84%N

O

MeO

78%

N

O

Cl85%

N

S

87%N

S

71%

N

S

86%N

S

43%

N

SAcO

78%

N

S

71%N

SO2N

54%

N

N N

NO

O93%

boshun wan ( 万伯顺 ) e-mail: [email protected]

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