Presentaci¾n Proyecto Pirroles definitiva

8/11/2019 Presentacin Proyecto Pirroles definitiva

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Modular Three-ComponentOrganocatalytic Synthesis of

3,4-Disubstituted Pyrroles by aOne-Pot Domino Reaction

Carlos Jarava

Barrera

COMMUNICATIONS


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COMMUNICATIONS1.Introduction

Pyrroles represent one of the most widely used heterocycles due to theirpresence in several natural and non- natural products.

Pyrrole itself is readiliy available commercially, and is manufactured by

alumina-catalysed gas-phase interaction of furan and ammonia.

Degradation of the blood respiratory pigment haem, and chlorophyll, ledto the formation of mixtures of alkylpyrroles.

N

H


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NH

H2N

CO 2HCO 2H

Phorphobilinogen(living cell)

Vitamin B 12

Chlorophyll

Haem
http://upload.wikimedia.org/wikipedia/commons/b/be/Heme_b.svg


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NN

Alkyl Me

Tetrapyrroles asChromophores

NH

Ar COAr

NR

Ar N

Ar

XN

(Antifungal Activity)

N

N

OHR1 R2

OHR2R2

IV Halitulin R 1=H, R 2=OHV Isohalitulin R 1=OH, R 2=H

I

II (COX inhibitors) III

3,4.disubstituted pyrroles represent important building blocks forthe synthesis of tetraporphyrines and several bioactive compounds


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COMMUNICATIONS1. Introduction

Tetrapyrroles as chromophores inthe plant photoreceptorphytochrome

U. Robben, I. Lindner, W. Grtner J. Am. Chem. Soc. 2008 , 130 , 11304


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L. Knorr Ber. Dtsch. Chem. Ges. 1884 , 17 , 1635

Knorr synthesis


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Paal-Knorr synthesis

C. Pall Ber. Dtsch. Chem. Ges. 1885 , 18 , 367

O

O

ammonia,benzenereflux

90%

RN
http://en.wikipedia.org/wiki/File:PKP_mechanism.svg


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Hantzsch synthesis

R1

NH O

R3

O

R4

O R 2

R1

NH2 O

O R 2

NH

R1

O

OR 2

R3

R4

R1

O

OOR2

NH3

R1

N

O

O

R2

R3R4

Cl

Cl

A. Hantzsch Ber. Dtsch. Chem. Ges. 1890 , 23 , 1474


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COMMUNICATIONS2.Disadvantages

Most of the syntheses for pyrroles are methods that involve multi-steproutes, expensive reagents, and rarely provide the 3,4-substitution pattern.

For these reasons, it would be highly desirable to develop a Lego methodthat could start from three different components, with each oneincorporating a desired substitution: one for 3-position, another for the 4-position, and finally the N-substitution.

We present a new catalytic method for the synthesis of 3,4-disubstitutedpyrroles.


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COMMUNICATIONS3.Objective

It would be highly desirableto have an alternativemethod for the synthesis of

3-4-pyrroles

N

R1 R2

R3


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COMMUNICATIONS4. Lego Method

ChemCatChem 2012 , DOI: cctc.201200104


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COMMUNICATIONS5. Screening

CHO1 Cat (mol%)

NO 2Ph

Br

+N

i- Pr Ph

N

HNH

NH

O

NH

CO 2H

1a 1b 1c 1d

Bn

CH 2Cl2

CHO

PhNO 2

Br

BnNH 2

(no isolated)Entry Catalyst Time (h) Conversion Yield (%)

1 1a (20 mol%) 24 20 -

2 1b (20 mol%) 1.5 50 -

3 1c (20 mol%) 1.5 100 65

4 1d (20 mol%) 1.5 70 -

5 1c (10 mol%) 1.5 100 90

6 1c (5 mol%) 1.5 100 88

7 1c (1 mol%) 24 100 72

8 1c (5 mol%) b 8 100 57

[a] All the reactions were carried out with 0.44 mmol of nitroalkene 3a , 0.88mmol of aldehyde 2a and 1.0 mmol of BnNH 2 in 0.9 mL of CH 2Cl2. [b] Inthis case the amount of aldehyde was reduce to 0.53 mmol.


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COMMUNICATIONS6. Kinetic studies

CHO(5 mol%)

NO 2Ph+

CH 2Cl2

CHO

Ph NO 2

Conversion:>99%

NH

CHO (5 mol%)

NO 2Ph+

NH

CH 2Cl2

CHO

Ph NO 2

Conversion:30%

Nitrostyrene preferspirrolidine


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COMMUNICATIONS6. Kinetic studies

Br-Nitrostyrene preferspiperidine

CHO(5 mol%)

NO 2

Ph+

NH

CH2Cl

2

CHO

Ph NO 2

Conversion: 89 %

Br

Br

CHO (5 mol%)

NO 2Ph

Br

+

NH

CH 2Cl2

CHO

Ph NO 2

Br Conversion: 58 %


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COMMUNICATIONS7. Scope

(88%) (76%) (85%) (large scale)

NBn

Ph

NBn

NBn

(62%) (20 mol% catalyst)

NBn

O

N

Bn

Cl

(58%)(57 %)

N

Bn

F


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(45%) (20 mol% catalyst) (79%)

NBn

NBn

Ph

(65%) (61%)

NBn

Ph

NBn

Bn Ph


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(88%) (90%) (>99%) (55%) (52%)

When R 3 = H, there is no reaction.

N

Ph

N

Ph

N

Ph

Ph

N

Ph

N


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COMMUNICATIONS8. Non racemization

PhNH2

CO 2Me

NO 2Ph

Br a) 1c (5 mol%)

b)CHO N

CO 2MePh

Ph

ee>98%(Yield= 72%) ee=96%

H


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COMMUNICATIONS9. Complex molecules

NH2

NHBoc

NHBoc

N

CHONO 2

Ph

Br

b)

a) 1c (5 mol%)

Ph

(61%) yield

a) TFA

b)

CHONO 2

Ph

Br a) 1c (5 mol%)

CHO

PhNO 2

Br

N

N

Ph

Ph

(36%) yield

( )2

( )3


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COMMUNICATIONS10. Mechanism

First stage

NH

N

H

N

H

NR1

H

R1CH 2CHO

R1

R1

R2 NO 2

Br

R2O2N

Br

OR1

H

R2O2N

Br


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COMMUNICATIONS10. Mechanism

Second stage

< >

NO 2Br

Br-nitrostyrene acts as a

tripositive synthon

R3-NH2

"One pot addition"

N

R1 H

R2O2N

Br

R3

HN

R1H

R3

Br NO 2

R2

NR3

N

R2 R 1

O

O

HNR3

R2 R 1

I

II

III

syn-elimination

OR1 H

R2O 2N

Br


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COMMUNICATIONS11. Conclusions

The use of trans -bromonitrostyrenes under enamine catalysis with theunexpensive piperidine, allows 1,4-Michael adduct intermediates which

are treated with the desired amine (R 3-NH2), and trigger the dominoreaction to the obtention of the final 3,4-disubstituted pyrrole derivative.


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COMMUNICATIONS12. Other Projects

Trienamine Catalysis

O

H

NH

Ph

OTMSPh

NO 2HOOC

CHCl 3

NO 2

40 C

O2N

CHO

N

HPh

OTMSPh

Chen et al. ACIE 2011


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Trienamine Catalysis

OHC

H

O

R1

R3X

H

O

MeO 2CCO 2Me

H

OEt

O

O

O

NO 2

Br


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Dienamine Catalysis of Ketones

O NO 2

Br

Chincona (10 mol%)

OFBA (20 mol%)Toluene 0,2M

40 C48h

O

NO 2

Br

Ph

NO

O

O

O

H OEt

O

O

OEt

O

NOH

Ph


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Cycloaddition [2+2]

Ph

O

NO 2Br

Ph PhPh

Br

NO 2OHC

CH 2Cl2

BifunctionalSquaramide

DEA (1eq)

NO

Catalyst

Problem: Derivation

COMMUNICATIONS13 C t P j t


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COMMUNICATIONS13. Current Project

Synthesis of 1,2-dihydronaphtho[2,1-]furanes

Entry Reaction Base Co-catalyst(mol%)

Conversion(%) (ee%)

ReactionTime

1 CJ88 DIPEA 20 31 24 h 2 CJ89:A Et3N 10 30 24h 3 CJ89:B NaOAc 10 26 24h 4 CJ89:C K2CO 3 10 12 24h 5 CJ89:D Pyridine 10 8 (66) 24h 6 CJ89:E NaHCO 3 10 0 24h 7 CJ89:F DMAP 10 37 4d 8 CJ89:G DBU 10 32 4d 9 CJ89:H Dimethylaniline 10 22 4d 10 CJ89:D Pyridine 10 41 4d

11 CJ90A Et 3N 100 100 (xx) 3d 12 CJ90B NaOAc 100 81 (xx) 3d 13 CJ91A DMAP 50 67 (xx) 3d 14 CJ91:B DBU 50 77 (xx) 3d 15 CJ91:C DIPEA 50 78 (xx) 3d 16

CJ94A Methilimidazole 10 27 24h

17 CJ94B DABCO 10 56 (xx) 24h 18 CJ94C Diethylamine 10 29 24h 19 CJ94D TMEDA 10 27 24h


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Presentaci¾n Proyecto Pirroles definitiva

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