Reaction of pyrrole with aldehydes – a mysterious

story Daniel T. Gryko

Institute of Organic Chemistry of the Polish Academy of Sciences

Warsaw, Poland

NH

N

HN

HNA A

B

Ehrlich reagent NH

N

HN

HNA A

B

NH

+ H+

CHO

NMe2

NH

NMe2

N

NMe2

H

Variety of products NH

N

HN

HNA A

B

NH

N

NH N

HNR R

R

R

R

NH

N

HN

HNR R

N

NH

NH

N

N

N

R

R

R

RR

R

RCHO+

NNH

HNN

NNH

HNN

N

NH

N

HNR R

R

R

at least 11 distinct macrocyclic species

Complexity NH

N

HN

HNA A

B

Fig. 1 A representative LD-MS spectrum from a crude oxidized reaction mixture of pyrrole + benzaldehyde (100 mM pyrrole + benzaldehyde, 10 mM BF3–Et2O, CH2Cl2, room temperature, 2 min). The oligomer length (n) is given by the number above the symbol. The yield of TPP (UV–Vis) is noted.

Rothemund NH

N

HN

HNA A

B

P. Rothemund J. Am. Chem. Soc. 1935, 57, 2010.P. Rothemund J. Am. Chem. Soc. 1936, 58, 625.P. Rothemund J. Am. Chem. Soc. 1939, 61, 2912.P. Rothemund, A. R. Menotti J. Am. Chem. Soc. 1941, 63, 267.

N

NH N

HN

R

R

R

RRCHO NH

+neat, pyridinesealed ampule

1-9%

Adler NH

N

HN

HNA A

B

A. D. Adler, F. R. Longo, W. Shergalis J. Am. Chem. Soc. 1964, 86, 3145.A. D. Adler, F. R. Longo and co-workers J. Org. Chem. 1967, 32, 476.

N

NH N

HN

Ar

Ar

Ar

ArArCHO NH

+C2H5COOH

reflux, air

~20%

Zn(OAc)2 in HOAc

Zn(OAc)2 in MeOH

ClCH2COOH, benzene

H3PO4, benzene

Lindsey NH

N

HN

HNA A

B

J. S. Lindsey, I. C. Schreiman, H. C. Hsu, P. C. Kearney et al J. Org. Chem. 1987, 52, 827.G. R. Geier III, J. A. Riggs, J. S. Lindsey JPP 2001, 5,681.

N

NH N

HN

Ar

Ar

Ar

ArArCHO NH

+

1. TFA or BF3.Et2O, CH2Cl2 10-40%2. DDQ or p-chloranil

1. TFA and BF3.Et2O, CH2Cl2

2. DDQ or p-chloranil~50%

Lindsey NH

N

HN

HNA A

B

J. S. Lindsey, I. C. Schreiman, H. C. Hsu, P. C. Kearney et al J. Org. Chem. 1987, 52, 827.

Lindsey-salts NH

N

HN

HNA A

B

F. Li, K. Yang, J. S. Tyhonas, K. A. MacCrum, J. S. Lindsey Tetrahedron 1997, 53, 12339.

N

NH N

HN

Ar

Ar

Ar

ArArCHO NH

+1. BF3

.Et2O, salts

6-61%

2. DDQ or p-chloranil

1. No correlation with cations.2. No correlation with desiccative power.3. Reversible or not???

Lindsey-salts NH

N

HN

HNA A

B

F. Li, K. Yang, J. S. Tyhonas, K. A. MacCrum, J. S. Lindsey Tetrahedron 1997, 53, 12339.

Lindsey-deep NH

N

HN

HNA A

B

G. R

. Gei

er II

I, J.

S. L

inds

ey O

rg. L

ett.

2000

, 2, 1

745.

Lindsey-st. hind. NH

N

HN

HNA A

B

1. TFA or BF3.Et2O, CH2Cl2

2. DDQ or p-chloranil

CHO

N

NH N

HNNH

+

0%

30%1. BF3.Et2O, CHCl3

2. DDQ or p-chloranil

0.75% ethanol

J. S. Lindsey, R. W. Wagner J. Org. Chem. 1989, 54, 828.

Trans-A2B2-porphyrins NH

N

HN

HNA A

B

J. S. Lindsey, R. W. Wagner J. Org. Chem. 1999, 64, 2864.D. T. Gryko, M. Tasior, Tetrahedron Lett. 2003, 44, 3317.

1. TFA, CH2Cl22. DDQ, toluene

N

NH N

HN

20-30%

1. BF3.Et2O, MeCN, NH4Cl, 0 C

2. DDQ or p-chloranil

NH HN

NH HN CHO

R

NH HN

R

R

+

N

CHO

+1. TFA (4 eq.), CH2Cl22. DDQ, dioxane

~10%

20-40%

Gas phase NH

N

HN

HNA A

B

C. M. Drain, X. Gong Chem. Commun. 1997, 2117.

N

NH N

HN

Ar

Ar

Ar

ArArCHO NH

+

1-23%

200 C, gas phase

Gas phase-2 NH

N

HN

HNA A

B

C. M. Drain, et al. J. Porphyrins Phthalocyanines. 2010, 14, 621.

N

NH N

HN

Ar

Ar

Ar

ArNH

+

10%

200 C, Zn(OAc)2

N

CHO

Oxidative Lewis Acids NH

N

HN

HNA A

B

E. F. LLama and co-workers J. Chem. Soc. Perkin 1 1995, 2611.

N

NH N

HN

Ar

Ar

Ar

ArArCHO NH

+

40-65%

VOCl3 or TiCl4CH2Cl2

In phenols NH

N

HN

HNA A

B

G. A. Mirafzal, H. M. Bosse, J. M. Summer Tetrahedron Lett. 1999, 40, 623.

N

N N

N

Ar

Ar

Ar

ArArCHO NH

+2,4,6-trichlorophenol

MnCl2, reflux, air

20-70%

Mn

In micelles NH

N

HN

HNA A

B

R. P. Bonar-Law J. Org. Chem 1996, 61, 3623.

N

NH N

HN

Ar

Ar

Ar

ArArCHO NH

+1. SDS, H2O, HCl2. p-chloranil, THF

HO

HO

OHOOC

COOH

43%

40%

0%

18%

Rocha-Gonzalves NH

N

HN

HNA A

B

M. d’A. Rocha Gonzalves and co-workers J. Het. Chem. 1985, 22, 931.

N

NH N

HN

Alk

Alk

Alk

AlkAlkCH(OMe)2 NH

+1. TFA, CCl4, 60 C2.DDQ or p-chloranil

18%

Rocha-Gonzalves NH

N

HN

HNA A

B

M. d’A. Rocha Gonzalves and co-workers Heterocycles 1996, 43, 1423.M. d’A. Rocha Gonzalves and co-workers JPP, 2007, 11, 77-84.

N

NH N

HN

Ar

Ar

Ar

Ar

ArCHO NH

+

HOAc, nitrobenzenereflux

5-78%

1. BF3.Et2O, CHCl32.H2O2, HOAc

12-40%

propionic acid, nitrobenzene, MW 4-25%

Sharghi NH

N

HN

HNA A

B

H. Sharghi, A. H. Nejad Helv. Chim. Acta 2003, 86, 408.H. Sharghi, A. H. Nejad Tetrahedron 2004, 60, 1863.

N

NH N

HN

Ar

Ar

Ar

ArArCHO NH

+1. PCl5 or CF3SO2Cl

30-65%

2. O2

Krausz NH

N

HN

HNA A

B

P. Krausz et al. J. Porphyrins Pkthalocyanines 2006, 10, 937.P. Krausz et al. Tetrahedron Lett. 2008, 49, 5537.

N

NH N

HN

Ar

Ar

Ar

ArArCHO NH

+1. activated charcoal

~40%

2. 1 h, 200 oC

N

NH N

HN

Ar

Ar

Ar

ArArCHO NH

+1. I2, CH2CL2, MW

30-40%

2. p-chloranil, MW

Furuta/Lotos NH

N

HN

HNA A

B

L. Latos-Grażyński and co-workers Angew. Chem. Int. Ed.. 1994, 33, 779.H. Furuta, H. Osano, T. Ogawa J. Am. Chem. Soc. 1994, 116, 767.

N

NH

N

HN

Ar

Ar

Ar

Ar

NH

+

1. BF3.Et2O

4-7%

2. p-chloranil

CHO

CHO

HBr, t-BuOH, CH2Cl2

NH

+

4 : 7

1 : 1

Lindsey N-confused NH

N

HN

HNA A

B

G. R. Geier III, J. S. Lindsey J. Org. Chem. 1999, 64, 1596.J. S. Lindsey, K. A. MacCrum, J. S. Tyhonas, Y.-Y. Chuang J. Org. Chem. 1994, 59,579.G. R. Geier III, D. M. Haynes, J. S. Lindsey Org. Lett. 1999, 1, 1455.

N

NH

N

HN

Ar

Ar

Ar

Ar

NH

+

1. CH3SO3H

40%

2. p-chloranil

CHO

CHO

1. TFA or BF3.Et2O

NH

+

2. DDQ or p-chloranil

ubiquitous product

Lindsey N-confused NH

N

HN

HNA A

B

G. R. Geier III, D. M. Haynes, J. S. Lindsey Org. Lett. 1999, 1, 1455.

Cavaleiro NH

N

HN

HNA A

B

J. A. S. Cavaleiro and coworkers Chem. Commun. 1999, 385.

NH

+

CHOF

FF

F

F AcOH, PhNO2

N

NH N

HNC6F5 C6F5

C6F5

C6F5

+NH N

HNNC6F5C6F5

R C6F5

C6F5C6F5

N

N

15% 1%

Cavaleiro NH

N

HN

HNA A

B

J. A. S. Cavaleiro and coworkers Chem. Commun. 1999, 385.

NH N

HNNC6F5C6F5

C6H5 C6F5

C6F5C6F5

N

N

HNNH

NH HNC6F5 C6F5

C6H5C6F5

C6F5 C6F5

N

N

Osuka-1 NH

N

HN

HNA A

B

J.-Y. Shin, H. Furuta, K. Yoza, S. Igarashi, A. Osuka J. Am. Chem. Soc. 2001, 123, 7190.

NH N

NH N

HNC6F5 C6F5

C6F5

C6F5

+

CHOF

FF

F

F

N

NH N

HNC6F5 C6F5

C6F5

C6F5 n = 2-9

12 + 15 + 20 + 5 + 6 + 3 = 61%

1. BF3.Et2O, CH2Cl22. DDQ

+

Osuka-2 NH

N

HN

HNA A

B

J.-Y. Shin, H. Furuta, K. Yoza, S. Igarashi, A. Osuka J. Am. Chem. Soc. 2001, 123, 7190.S. Shimizu, J.-H. Shin, H. Furuta, R. Ismael, A. Osuka Angew. Chem. Int. Ed.. 2003, 42, 78.

Who was first? NH

N

HN

HNA A

B

N. M. Loim and co-workers Izv. Akad. Nauk. Ser. Khim. 1994, 5, 925.E. Rose and co-workers J. Am. Chem. Soc. 1996, 118, 1567.L. Latos-Grażyński and co-workers New J. Chem. 1997, 21, 691.

NH

+ 1. BF3.Et2O

2. DDQ, ?%

R

NH

N

HN

HNR R

CHONO2O2N

But

MoOC COCO

CHO

CHO

HOAc

4%

1. ??

2. ???

No catalyst… NH

N

HN

HNA A

B

G. I. Zhungietu, F. N. Chukhrii Zh. Vses. Khim. Obshchest. 1970, 15, 586.T. Severin, I. Ipach Chem. Ber. 1975, 108, 1768.S. P. Ivonin, A. V. Lapandin, A. A. Anishchenko Synth. Comm. 2004, 34, 451.

N

+CHO

O

NOH

Obenzene, RT, 2h

67%

NH

1.benzene, rflx, 2h2. NaIO4 N

HCHOOHC

NH

benzene, rflx, 2hNH OH

O

78%

21%

With base… NH

N

HN

HNA A

B

S. Taniguchi and co-workers Synlett 1999, 73.

NH

(CH2O) aq, K2CO3

NH OH

86%

5 C, 7dHO

Summary NH

N

HN

HNA A

B

• We utilize the reaction which we do not understand

• More accidental than rational development

• Probably still at the early stage