Synthesis of meso-substituted porphyrins

Mariusz Tasior

Rothemund method – in 1935...

Rothemund, P., J. Am. Chem. Soc. 1935, 57, 2010.

HN

CH3CHOconditions

N HN

NH N

H3C

CH3

CH3

CH3

conditions: 140°C, 24hr, pyridine, followed by slow cooling

sealed tube was employed to avoid loss of the volatile aldehydes

Rothemund method – in 1935...

First report about effects of metals in pyrrole-aldehyde condensation: Ball, R. H. et al. J. Am. Chem. Soc. 1946, 68, 2278.

HN

RCHOconditions

N HN

NH N

R

R

R

R

conditions = 90 - 220°C, 24 - 48hr, solvent: MeOH, pyridine

high concentration of starting materials (0.5M), no oxidant

R = H, CH3, C4H9, C6H5 etc

yields: porphine was isolated in 0.9% yield, TMP 1% yield, products were contaminated with 10-20% of chlorin

improved procedure for TPP published in 1941 (7.5-9% yield)

Some general considerations...HN

CHO

conditions

HO

HN NH HN NH HN

HN

Some general considerations...

NH HN

NH HN

NH HN

NH HN

OHN HN

NH N

high dilution oxidant !!!

Adler method

Adler, A.D.; Longo, F. R.; Shergalis, W., J. Am. Chem. Soc. 1964, 86, 3145.

HN conditions

N HN

NH N

Ph

Ph

Ph

Ph

conditions: acetic acid or benzene + chloroacetic acid, Dean-Stark trap, air, reflux, 36hr, or propionic acid (bp 141°C), reflux, 30 min.

lower yield in presence of metal salts

yields: TPP was isolated in 30-40% yield, products were contaminated with 2-10% of chlorin which can be easly removed by treatment with DDQ in refluxing toluene.

CHO

Air!!! Reagents concentration 0.02M!!!

Scope of Adler method

low yields <10%, some anomalus products are observed (o-acetoxybenzaldehyde)

CHO

R

CHO

OH

CHO

OAc

some functional groups must be protected

D2O TPP-d8OO

OHN relux

1h, no air

benzaldehyde

air

Scope of Adler method

HN conditions

N HN

NH N

R

R

R

R

CHORLi

HN

OH

R

HN

RCHNconditions

N HN

NH N

R

R

R

R

Mixed-aldehyde condensation

N HN

NH N

A

A

A

A

N HN

NH N

A

A

B

A

N HN

NH N

A

A

B

B

N HN

NH N

B

B

B

B

N HN

NH N

A

B

B

B

N HN

NH N

A

B

A

B

6.25% 25% 25%

12.5%25%6.25%

Mixed-aldehyde condensation

N HN

NH N

4.5% yield

O

O

CHO HO

pyrrole, tolualdehyde, propionic acid

Dont event think about condensation of 3 aldehydes, few examples in the literature, 0.7% max

Leznoff, C. C.; Svirskaya, P.I, Angew. Chem. In. Ed. 1978, 12, 947.

Lindsey method 1979-...

Lindsey, J. S., Hsu, H. C., Schreiman, I. C. Tetrahedron Lett. 1986, 27, 4969.Lindsey, J. S., Schreiman, I. C., Hsu, H. C., Kearney, P. C., Marguerettaz, A. M.

Tetrahedron Lett. 1986, 27, 4969.Acid cocatalysis, salt effect: Lindsey et al. JPP, 2001, 5, 681

HN

RCHOconditions

N HN

NH N

R

R

R

R

conditions: catalyst - TFA or BF3-etherate, DCM, rt, 30-60 minlow concentration of starting materials (0.01M), addition of DDQ or p-chloranil in the second step

Reaction is vey sensitive to changes in reagents and catalyst concentrationDDQ reacts 5500 times more rapidly than p-chloranil in the dehydrogenation of 1,2-dihydronaphthalene

yields: up to 50%

Ethanol as cocatalyst in TMP synthesis

Scope of Lindsey methodmight be a problem

N

CHO

CHO

OH

CHO

OAc

some functional groups must be protected

O

O

CHO competitive Michael addition

CHO

Comparison of synthetic methodsRothemund Adler Lindsey

Solvent Pyridine Propionic acid

Acetic acid

RCOOH+benzene

DCM

Chloroform

Temperature 140-220ºC 141ºC 25ºC

Catalyst - Same as solvent TFA

BF3-etherate

Clays, other acids

Concentration 0.4-3.6M 0.3-0.1M 0.1-0.001M

Reaction time 24-48hr 1hr 1hr

Workup Separate crystals Filter crystals Chromatography

Yield <10% ~20% ~ 40%

Scope very narrow modest broad

Routes to specific classes of meso-substituted porphyrins

N HN

NH N

TMS CHO

TMS

TMS

TMS

TMS

1. pyrrole, BF3-etherate2. DDQ, 14%

N HN

NH N

C12H25O CHOCo2(CO)8, THF

C12H25O

(CO)3Co

Co(CO)3

CHO

OC12H25

OC12H25

OC12H25

C12H25O

1. pyrrole, BF3-etherate

2. DDQ

3. Fe(ClO4)3, MeOH

Trans-A2B2-porphyrins

HN

1. TFAN HN

NH N

A A

NH

2. p-chloranilA

B

B

aldehyde + pyrrole

MgBr2 or InCl3

CHOB

For dipyrromethane synthesis: Lindsey, J. S. et al. Org. Process Res. Dev. 2003, 7, 799.For condensation conidtions and scrambling: Lindsey, J. S. et al. J. Org. Chem. 1999, 8, 2864

Scrambling

NH HN

NH HN

B

A

A

H+

NH+ HN

NH HN

B

A

A

H

NH

NH

HN

HN

A

B A

NH +HN

NH HN

B

A

A

Porphyrins bearing up to 4 different meso substituents

NH

EtMgBr, THF

HN

A

NSB

O

NH HN

A

OB

1. EtMgBr, THF

2. CROCl

NH HN

A

OB

OC

NaBH4, MeOH

NH HN

A

OHB

HOC

NH

1. TFA, DCM

HN

D

NH HN

A

OHB

HOC

N HN

NH N2. DDQ

B

A

C

D

Thank you...