Microwave-Assisted Synthesis and Reactivity of Porphyrins

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Current Organic Synthesis, 2014, 11, 89-109 89 Microwave-Assisted Synthesis and Reactivity of Porphyrins

Marta Pineiro*

Departamento de Química, Universidade de Coimbra, Rua Larga 3004-535 Coimbra, Portugal

Abstract: This paper describes past and current microwave-assisted methodologies for the synthesis of porphryins and porphyrin derivatives, including porphyrin precursors such as dipyrromethanes. The review is organized in two main topics, porphyrin synthesis and porphyrin reactivity under microwave irradiation and covers solventless and solution reactions.

Keywords: Hydroporphyrin, metalloporphyrin, microwave irradiation, microwave synthesis, porphyrin, tetrapyrrolic macrocycles.

1. INTRODUCTION stituted beta-porphyrins were obtained via cyclisation of linear The acknowledgement that porphyrins and related compounds tetrapyrroles, b-bilenes and a,c-biladienes [15] could be referred. had essential functionalities in nature prompted the interest in mul- Microwave-assisted organic chemistry has grown in the last tiple scientific domains, from the deeper comprehension of those decades as a valuable and versatile tool for organic chemists [16]. functions to the investigation of new applications which comprise In general, compared to conventional heating methods, microwave several analytical uses [1], dye-sensitised solar cells [2], molecular heating has been shown to drastically reduce reaction times, in- electronics and non-linear optics [3], sensors of small molecules crease reaction yields and enhance product selectivity, mostly re- such as O2, NO, NH3 or phosphines [4], catalysts in oxidation and ducing undesirable side reaction products. Microwave irradiation is, photo-oxidation reactions [5], and several biological applications in our days, fully recognized as a useful tool for organic synthesis such as photodynamic therapy of cancer, imaging and boron neu- used in multi-step total synthesis [17], medicinal chemistry and tron-capture therapy [6]. drug discovery [18], polymer synthesis [19], material science [20], nanotechnology [21] and biochemical processes [22]. The use of The remarkable popularity and versatility of porphyrins and microwave irradiation for the synthesis and derivatization of por- their derivatives relies in a great length, on the development and phyrins is reviewed herein. improvement of synthetic strategies over the years that make possible the huge availability of these compounds. Since Rothemund’s report on the one-pot synthesis of meso-substituted porphyrins [7] 2. SYNTHESIS OF PORPHYRINS AND RELATED COM- several simple one-step or two-step approaches have been devel- POUNDS oped for the preparation of these compounds. Adler and Longo used equimolar quantities of pyrrole and benzaldehyde in refluxing 2.1. Solventless Reaction Conditions propionic acid [8]. Rocha Gonsalves and co-workers obtained The preparation of porphyrins under microwave (MW) activa- meso-tetraalkylporphyrins in a two-step procedure starting from tion was firstly described by Loupy and co-workers in 1992 [23]. pyrrole and the methyl acetal of the corresponding aliphatic alde- Irradiation of a mixture of pyrrole (1) and benzaldehyde (2) pre- hyde in refluxing carbon tetrachloride to prepare the corresponding adsorbed on the surface of silicon dioxide for 10 minutes, using a porphyrinogen followed by photo-oxidation or chemical oxidation microwave digester and open-vessel conditions, afforded with quinones [9]. Lindsey and co-workers followed a similar two- 5,10,15,20-tetraphenylporphyrin (3) in 9.5% yield (Scheme 1). One step strategy for the synthesis of meso-tetraarylporphyrins, the por- decade after the report by Loupy this procedure was adapted for phyrinogen is formed, from pyrrole and aldehyde, in dichloro- undergraduate experimental teaching [24]. methane doped with acid at room temperature, followed by oxida- The research group of Raghavan [25] published a solvent-free tion with quinone [10]. Using acetic or propionic acid as solvent microwave-promoted synthesis of three porphyrins 3 and 4a,b in and nitrobenzene as solvent and oxidant, Rocha Gonsalves and co- 2004. The reactions were carried out in a domestic microwave ap- workers synthesized aryl and alkyl meso substituted porphyrins via paratus operating at 1200 W during 12 minutes, using HZSM-5 a simple one step procedure [11]. zeolites or Al-MCM-41 mesoporous molecular sieves as solid More complex multi-step protocols, which involve the prepara- acidic catalysts, the latter exhibiting a better performance (Scheme tion of multi-substituted pyrrolic precursors, were used to prepare 2). Porphyrin yields fell to a negligible level when the surface of the porphyrins substituted at the beta position. In order to typify the catalyst was doped with tetraethoxy silane and also when the reac- diverse strategies the MacDonald methodology [12], also known as tion was performed with solvents. Starting from pyrrole and alkyl [2+2] strategy indicating the condensation of two dipyrromethanes, ketones and under the same reaction conditions, calix(4)pyrroles was used to prepare beta-substituted porphyrins with or without 6a-6d were synthesized in good yields, (Scheme 3). additional substituents at the meso-position; the “head to tail” con- Following this study Raghavan and co-workers [24] reported densation of four molecules of pyrrole under acidic reaction condi- the one-step reaction and separation of porphyrins and tions [13]; the [3+1] condensation between diformyl pyrrole and calix(4)pyrroles, i.e. porphyrinogen on a single thin layer chroma- tripyrrane affords beta-substituted porphyrins and was also applied tography (TLC) plate. The reaction of pyrrole and aromatic alde- for the synthesis of expanded porphyrins [14]; unsymmetrical sub- hydes or ketones over zeolite based molecular sieve catalysts as sorbents in TLC under microwave heating allows in situ synthesis and evaluation of the reaction products. The best results were ob- *Address correspondence to this author at the Departamento de Química, Universidade de Coimbra, Rua Larga 3004-535 Coimbra, Portugal; Tel: +351239854479; tained using Al-MCM-41 as solid support, yielding 56.5% and Fax: +351239852080; E-mail: [email protected] 79.1% of porphyrin 3 and porphyrinogen 6a, respectively. The

CHO NH N 1a SiO2 + MW (135 W, 10 min) N HN

N H 2 3 9.5 %

Scheme 1. Ar Ar CHO

1a Ar = C6H5 1b Ar = 4-CH OC H 3 6 4 NH N 1c Ar = 4-CH3C6H4 Al-MCM-41 (0.5 g) + Ar Ar MW (12 min) N HN

N H 2 Ar

3 Ar = C6H5 23.5% 4a Ar = 4-CH3OC6H4 16.0% 4b Ar = 4-CH3C6H4 40.1%

Scheme 2.

R1 R2

1 2 NH 6a R = R = CH3 1 2 O 1 HN 1 5a R = R = CH3 Al-MCM-41 (0.5 g) R R 6b R1 = CH ; R2 = CH CH 1 2 3 2 3 5b R = CH3; R = CH2CH3 + 6c R1 = R2 = CH CH 1 2 1 2 2 2 2 3 5c R = R = CH2CH3 R R N MW ( 12 min) R R 1 - 2 H NH HN 6d R = -(CH2)4 R 5d R1 = -(CH ) - R2 2 4 2

R1 R2 Scheme 3. process could have a possible application in high throughput paral- methyl 4-formylbenzoate, 3-hydroxybenzaldehyde and pyrrole, pre- lel synthesis and screening on a single micro plate employing mi- adsorbed on the surface of silica gel, heated for 12 minutes at 450 crowave irradiation in combinatorial chemistry. W, in a domestic oven with temperature and power control, the 5,10,15,20-Tetrakis(4-tert-butylphenyl)porphyrin (8a) and desired unsymmetrically substituted porphyrin 12a and the symmet- 5,10,15,20-tetrakis(4-hydroxyphenyl)porphyrin (8b) were obtained rical meso-substituted porphyrin 12b were obtained with 13% and in good yields, heating the corresponding aldehyde and pyrrole 38% isolated yield, respectively. These unsymmetrical porphyrins under microwave irradiation in a domestic oven at 240 W during 5 were typically synthesized in reflux of propionic acid for 3 h with min without solvent or solid support. As described previously by relatively poor yields (~ 10%) [28]. Zn(II) and Cu(II) complexes 13 and 14 of unsymmetrical meso-substituted porphyrins were synthe- Hu and co-workers [26], using the porphyrins, MgCl2 and 1,8- diazabicyclo[5.4.0]undec-7-ene (DBU) as starting materials, the sized by heating the same reagent mixture, the corresponding di- magnesium porphyrinates 9a,b were synthesized under microwave chloride salt and 1 mL of 2,6-dimethylpyridine in silica gel under irradiation in 5 minutes in yields up to 72%. Tetraperylene substi- microwave irradiation [29]. A similar procedure was used to syn- tuted porphyrin 10 was obtained in 59% yield from the reaction of thesize Cu(II)-5-(2-hydroxyphenyl)-10,15,20-tris(4-carboxymethyl- hydroxyporphyrin 8b and a perylene derivative in DMF with phenyl)porphyrinate 15a and Zn(II)-5-(2-hydroxyphenyl)-10,15,20- tris(4-carboxymethylphenyl)porphyrinate 15b with 40% and 38% K2CO3 under microwave irradiation at 240 W during 30 min, (Scheme 4) [27]. yield, respectively. The symmetrically substituted porphyrinates of Cu(II) and Zn(II) were obtained in the same reaction with yields of Unsymmetrical meso-substituted porphyrins bearing two differ- about 55% [30], (Scheme 5). ent aryl groups at the methylene positions in a 3:1 proportion (A3B type) were prepared under microwave heating using solid-supported Ni (II) 5,10,15,20-tetraphenylporphyrinate 16 was prepared in a and open-vessel reaction conditions. Using 3:1:4 molar ratio of two-step procedure, with first the porphyrin 3 being synthesized Microwave-Assisted Synthesis and Reactivity of Porphyrins Current Organic Synthesis, 2014, Vol. 11, No. 1 91

Ar Ar

N H NH N N N 2 MgCl2, DBU Ar Mg Ar + Ar Ar MW ( 240 W, 5 min) MW ( 240 W, 5 min) N N Ar CHO N HN

7a Ar = 4-tBuC6H4 7b Ar = 4-HOC6H4 Ar Ar 8a Ar = 4-tBuC6H4 44% 9a Ar = 4-tBuC H 72% 8b Ar = 4-HOC H 48% 6 4 6 4 9b Ar = 4-HOC H 68% RO OR 6 4

9b K2CO3 DMF RBr N MW (240 W, 30 min) N Mg N

N O O

N N R =

RO 10 OR O O Scheme 4.

1 11a Ar = 4-CH3CO2C6H4 2 1 2 11b Ar =3-HOC6H4 Ar CHO + Ar CHO + 2 7b Ar = 4-HOC6H4 N 2 H 11d Ar = 2-HOC6H4 2

11a:11b:2 (3:1:4) 11a:11c:2 (3:1:4) 11a:11c:2 (3:1:4) 11a:11d:2 (3:1:4) SiO2, ZnCl2 SiO , CuCl SiO2, MCl2 SiO2 (10 g) 2 2 2,6-dimethylpyridine 2,6-dimethylpyridine 2,6-dimethylpyridine MW ( 450 W, 12 min) MW(175 °C, 450 W, 10 min) MW(180 °C, 475 W, 8 min) MW(180 °C, 475 W, 10 min)

Ar1 Ar1 Ar1 Ar1

NH N N N N N N N 1 1 1 Ar2 Ar Ar2 Zn Ar Ar2 Cu Ar Ar2 M Ar1 N HN N N N N N N

Ar1 Ar1 Ar1 Ar1 12a Ar1 = 4-CH O CC H ; 1 1 1 3 2 6 4 13 Ar = 4-CH3O2CC6H4; 14 Ar = 4-CH3O2CC6H4; 15a M = Cu; Ar = 4-CH3O2CC6H4; Ar2 =3-HOC H 13% 2 2 2 6 4 Ar =4-HOC6H4 48% Ar =4-HOC6H4 52% Ar =2-HOC6H4 38% 12b Ar1 = Ar2 = 4-CH O CC H 38% 1 3 2 6 4 15b M = Zn; Ar = 4-CH3O2CC6H4; 2 Ar =2-HOC6H4 40%

Scheme 5. under microwave irradiation using silica gel as solid support in 67% intervals in between [31], (Scheme 6). Without DBU, this reaction yield, and in the second step, porphyrin 3 reacts with an excess of does not proceed, the mechanism has been reported, explaining the NiCl2 in DBU under microwave irradiation in a domestic oven at essential role of DBU in the conversion of metal-free porphyrins 750 W for 6 min yielding 57% of the metalloporphyrin, i.e. in an into metalloporphyrins [32]. overall yields of 38%. The same compound was prepared, in 60% Yaseen and colleagues [33] reported the solid-supported syn- yield, in a one-pot reaction starting from pyrrole, benzaldehyde and thesis of two meso-tetraarylporphyrins under microwave heating NiCl ground together and poured into DBU, the mixture was 2 using as solid support silica gel, previously acidified with propanoic stirred for 10-15 minutes and irradiated in a microwave domestic acid and dried in an oven at 50 °C for 12 h. Porphyrins 18a and 18b oven at 500 W in a silica gel bath for 8 minutes with two-minute 92 Current Organic Synthesis, 2014, Vol. 11, No. 1 Marta Pineiro

Ar Ar

NH N N N SiO2 DBU, NiCl2 Ar CHO + Ar Ar Ar Ni Ar N MW (500 W, 5 min) MW (750 W, 6 min) N 1a Ar = C6H5 H N HN N

2 Ar Ar

16 Ar = C6H5 57-60% 3 Ar = C6H5 67%

DBU, NiCl2

MW (500 W, 8 min)

Scheme 6. Ar Ar

N N N + NH N H SiO2/H SiO2, M(OAc)2 2 Ar Ar Ar M Ar + MW MW N HN N N (100 ˚C, 200 W, 5 min) (111 ˚C, 250 W, 6 min) Ar CHO

17a Ar = 4-(CH3)2CH2C6H4 Ar Ar 17b Ar = 3,5-tBuC H 6 3 19a M = Ni; Ar = 4 (CH3)2CH2C6H4 90% 18a Ar = 4-(CH3)2CH2C6H4 19b M = Ni; Ar = 3,5-tBuC6H3 92% 18b Ar = 3,5-tBuC6H3 19c M = Cu; Ar = 4 (CH3)2CH2C6H4 94% 19d M = Cu; Ar = 3,5-tBuC6H3 93% Scheme 7. Ar MW C.H.

1a Ar = C H 6 5 3 Ar = C6H5 41% 29% 1b Ar = 4-CH OC H 3 6 4 Ar CHO NH N 4b Ar = 4-CH3OC6H4 15% 9% 20a Ar = 2-CH OC H Propionic acid (5 mL) 3 6 4 21a Ar = 2-CH3OC6H4 43% 27% 20b Ar = 4-O NC H Ar Ar 2 6 4 + 21b Ar = 4-O2NC6H4 28% 6% 20c Ar = 2-O NC H MW (3-5 min) 2 6 4 N HN 21c Ar = 2-O2NC6H4 25% 5% 20d Ar = 2,4,6-CH C H 3 6 2 21d Ar = 2,4,6-CH3C6H2 19% 13% 20e Ar = 4-ClC H 6 4 N 21e Ar = 4-ClC6H4 7% 3% 20f Ar = 3-ClC H H 6 4 2 21f Ar = 3-ClC6H4 4% trace Ar Scheme 8. were synthesized after 10 minutes under microwave irradiation at heating (C. H.) using 160 mL of propionic acid, all porphyrins were 100 °C in 37% and 32% yield respectively, (Scheme 7). The crude obtained with higher isolated yields under microwave irradiation, reaction from the porphyrin synthesis was used, after washed with a (Scheme 8). saturated solution of copper or nickel acetate in methanol, to trans- Recently, Mikus and co-workers [35] reviewed this method in form the porphyrins into the corresponding metal complexes 19a-d, an attempt to optimize the microwave-assisted synthesis of meso- under microwave irradiation during 6 minutes, yields up to 94% tetraphenylporphyrin. Using a concentration of 4.0 M of the rea- being obtained, (Scheme 7). gents, in the reaction carried out at 120 °C during 30 min in the presence of p-chloranil as external oxidant, porphyrin 3 was ob- 2.2. Synthesis in Solution tained in 30% yield. Chauhan and co-workers [34] reported in 2001, the condensa- Hu and co-workers [26] used the method described by Chau- tion of equimolar amounts of a series of aryl aldehydes and pyrrole man for the synthesis of 5,10,15,20-tetrakis(4-tbutylphenyl)por- in an open vessel, employing propionic acid as solvent and making phyrin (8a) in 56% yield. This porphyrin was transformed into the use of a microwave domestic oven in an adaptation of the classical corresponding Mg(II), Zn(II), Cu(II), In(III) and Al(III) complexes Adler method. Although the authors used a domestic oven (power under microwave irradiation using DBU as catalyst in high yields, not disclosed) microwave irradiation for 3 to 5 minutes, followed (Scheme 9). by cooling to room temperature, and further purification, the target meso-substituted porphyrins 3, 4b and 21a-f were obtained with A series of resorcin[4]arene cavitand-capped porphyrin cap- poor to moderate isolated yields. Nevertheless, comparing micro- sules 24a-f were synthesized in moderate yields (around 10%) from wave irradiation using 5 mL of propionic acid with conventional an equimolar mixture of pyrrole and aldehydes 23a-f in propionic Microwave-Assisted Synthesis and Reactivity of Porphyrins Current Organic Synthesis, 2014, Vol. 11, No. 1 93

N N MCl2,DBU Ar M Ar MW (240 W, 5 min) N N Ar

NH N Ar = 4-tBuC6H4 Propionic acid 9a M = Mg 72% Ar CHO + Ar Ar 22a M = Zn 65% N MW (560W, 5 min) 22b M = Cu 77% H N HN 7a Ar = 4-tBuC6H4 2 Ar Ar

N Cl N 8a Ar = 4-tBuC6H4 56% MCl ,DBU 3 Ar M Ar MW (240 W, 5 min) N N

Ar = 4-tBuC6H4 22c M = In 71% 22d M = Al 68% Scheme 9.

R R

R R R R O O R R O O O O O O O O (CH2)n O O O O O O (CH2)n O O O O O O O O n(H2C) n(H C) (CH2)n O 2 O Pyrrole, Propionic acid O n(H C) 2 n(H2C) (CH2)n O O O MW (160 ˚C, 5 min) OHC O O NH N OHC N HN OHC OHC

23a R = C5H11; n = 4 24a R = C5H11; n = 4 10% 23b R = C5H11; n = 3 24b R = C5H11; n = 3 10% 23c R = C5H11; n = 2 24c R = C5H11; n = 2 17% 23d R = CH2CH2C6H5; n = 4 24d R = CH2CH2C6H5; n = 4 8% 23e R = CH2CH2C6H5; n = 3 24e R = CH2CH2C6H5; n = 3 13% 23f R = CH2CH2C6H5; n = 2 24f R = CH2CH2C6H5; n = 2 18% Scheme 10. acid, under microwave irradiation in a Liberty microwave peptide (terpyridinyl)phenyl]porphyrin was obtained in 12% yield from synthesizer from CEM company using sealed borosilicate tubes. pyrrole and aldehyde in propionic acid under microwave irradiation The use of longer reaction times, lower and higher temperatures do in a domestic oven during 10 min. This porphyrin was further de- not afforded better reaction yields, (Scheme 10)[36]. rivatized into the ruthenium complexes 27a,b through the reaction Propionic acid was also used as solvent in the microwave- with 4 equiv. of the paramagnetic [4’-tolylterpyridine]Ru(III) assisted synthesis of 5,10,15,20-tetrakis[4’-(terpyridinyl)phenyl] adduct in ethylene glycol under microwave irradiation [37], porphyrin and its Ru(II) complexes. 5,10,15,20-Tetrakis[4’- (Scheme 11). 94 Current Organic Synthesis, 2014, Vol. 11, No. 1 Marta Pineiro

N N N

CHO

N N N + H NH N 2 Propionic acid N N MW (400 W, 10 min) N HN N N N

N 25 N

N 26 N N

N N N N Ru Ru N N N N N R

Ethylene glycol MW (450 W, 20 min)

N N N N NH N Ru R R N Ru N N N N HN N N N N

N N N Ru N N N

27a R = CH3 27b R = OC10H21

R Scheme 11. Microwave-Assisted Synthesis and Reactivity of Porphyrins Current Organic Synthesis, 2014, Vol. 11, No. 1 95

(640 W, (200 ˚C, 5 min) 5 min) Ar 3 Ar = C H 20% 46% 1a Ar = C6H5 6 5 29a Ar = 2-ClC H 8% 28a Ar = 2-ClC6H4 6 4 21e Ar = 4-ClC H 21% 20e Ar = 4-ClC6H4 6 4 Ar CHO NH N 29b Ar = 2,6-Cl C H 4% 5% 28b Ar = 2,6-Cl2C6H3 2 6 3 Propionic acid/Nitrobenzene 29c Ar = 2-BrC H 5.5% 28c Ar = 2-BrC6H4 Ar Ar 6 4 + 29d Ar = 4-BrC H 12% 30% 28d Ar = 4-BrC6H4 6 4 MW N HN 29e Ar = 3-O NC H 8% 28e Ar = 3-O2NC6H4 2 6 4 29f Ar = 3-CH OC H 15% 10% 28f Ar = 3-CH3OC6H4 3 6 4 N 4a Ar = 4-CH OC H 15% 50% 1b Ar = 4-CH3OC6H4 H 3 6 4 8a Ar = 4-tBuC H 25% 55% 7a Ar = 4-tBuC6H4 2 6 4 - Ar 29g Ar = 2,4,6-(CH ) C H 1.5% 28g Ar = 2,4,6 (CH3)3C6H2 3 3 6 2 - 29h Ar = 2,4,6-(CH O) C H 13% 28h Ar = 2,4,6 (CH3O)3C6H2 3 3 6 2 29i Ar = 3-HOC H 12% 36% 11b Ar = 3-HOC6H4 6 4

Scheme 12.

Ar Ar

NH N NH N M = Zn Cu Ni Co Mn DMF, M(OAc)2.nH2O Ar Ar Ar Ar 30a-e 95% 83% 74% 73% 88% MW(480 W, 3 min) 30f-j 96% 89% 78% 78% 90% 3 Ar = C H N HN 6 5 N HN 30k-n 95% 92% 92% -- 91% 21e Ar = 4-ClC6H4 29i Ar = 3-HOC6H4

Ar Ar Scheme 13.

Ar1

1 1 2 1a Ar = C6H5 1) CH2Cl2, I2 3 Ar = Ar = C6H5 47% 1 NH N 1b Ar2 =4-CH OC H Ar CHO 1 2 3 6 4 MW(100 W, 30 °C, 20 min) 31a Ar = C6H5; Ar = 4-CH3OC6H4 11% 2 2 1 1 2 11a Ar =4-CH3O2CC6H4 + + Ar Ar 31b Ar = C6H5; Ar = 4-CH3O2CC6H4 27% 2 1 2 7b Ar = 4-HOC6H4 N 2) p-Chloranil 31c Ar = C H ; Ar = 4-HOC H 8% Ar2 CHO H N HN 6 5 6 4 20b Ar2 = 4-O NC H 31d Ar1 = C H ; Ar2 = 4-O NC H 22% 2 6 4 2 MW(100 W, 30 ˚C, 1 min) 6 5 2 6 4 2 1 2 20e Ar = 4-ClC6H4 31e Ar = C6H5; Ar = 4-ClC6H4 15% Ar1 Scheme 14.

The adaptation of the classical Rocha Gonsalves one-step syn- Zerrouki and co-workers described a microwave-assisted, io- thesis of meso-tetrarylporphyrins to microwave technology was dine-catalysed, one-pot-two-step synthesis of 5,10,15,20-tetraphe- reported by Pineiro and Gonsalves in 2007 [38]. Irradiation of nylporphyin (3) in 2008 [41]. First, pyrrole, benzaldehyde, di- stoichiometric quantities of one of 13 different aryl aldehydes and chloromethane and a 10% molar equivalent of molecular iodine pyrrole in a mixture of propionic acid and nitrobenzene for 5 min- were activated under microwave irradiation (100 W, 30 °C), then p- utes, using a domestic microwave equipment set at 640 W, pro- chloranil was added and a second period of microwave irradiation vided the corresponding porphyrins 3, 4a, 8a, 21e and 29a-i with was performed (100 W, 30 °C). An isolated yield of 47% was low to moderate isolated yields. As in the original method, chroma- achieved after chromatographic work-up. The same authors subse- tographic purification procedures were avoided in some cases. The quently employed this microwave-activated synthetic approach to kinetic study of this methodology performed by Cavaleiro and co- the preparation of some A3B unsymmetrical meso-tetraarylpor- workers for the synthesis of meso-tetraphenylporphyrin under mi- phyrins, 31a-e, in moderate yields [42], (Scheme 14). crowave irradiation concludes that the conditions firstly reported were the ones that afford better yields [39]. Pineiro and Gonsalves Metalloporphyrins have been synthesized in 1,3-dialkylimi- revisited their methodology using a single-mode microwave reactor dazolium ionic liquids under microwave irradiation. meso- instead of the domestic microwave oven previously utilized [40]. tetraphenylporphyrin (3) mixed with the corresponding chloride salt The selected aryl aldehyde and pyrrole were added to propionic was converted into Zn(II), Cu(II), Co(II), Fe(III) and Mn(III) metal- acid (3.5 mL) and nitrobenzene (1.5 mL) thoroughly mixed and loporphyrins in 1-butyl-3-methylimidazolium tetrafluoroborate heated at 200 °C for 5 min under focused microwave with an initial ([bmin][BF4]) under microwave irradiation in high yields. The power setting of 250 W. Seven porphyrins were obtained in 5 min manganese complexes 33b-f were also sucessfully obtained using reactions, with improved yields ranging from 5% to 55%, affording this method [43], (Scheme 15). The reaction of Pd(II) and Pt(II) from 0.5 to 1.1 gram of product, (Scheme 12). salts of meso-tetraphenylporphyrin and its -octabromine derivative Porphyrins 3, 21e and 29i were transformed into the corre- in 1-butyl-3-methylimidazolium bromide under microwave irradia- sponding metalloporphyrins 30a-n in high yields under microwave tion afforded the corresponding metalloporphyrins in high yields irradiation mixing the porphyrin with Zn(II), Cu(II), Ni(II), Co(II) and reaction times 10-20 times shorter than the required using con- or Mn(III) acetate in dimethylformamide DMF [38] (Scheme 13). ventional methods [44]. 96 Current Organic Synthesis, 2014, Vol. 11, No. 1 Marta Pineiro

Ar Ar 30a M = Zn; Ar = C6H5 96% 30b M = Cu; Ar = C6H5 98% N N 30d M = Co; Ar = C6H5 75% NH N 30e M = Mn; Ar = C H 83% [bmin][BF4], MCl2.nH2O 6 5 M Ar Ar Ar Ar 33a M = Fe; Ar = C6H5 74% MW(320 W, 5 min) 33b M = Mn; Ar = 4-ClC6H4 76% 3 Ar = C H N N 6 5 N HN 33c M = Mn; Ar = 2,6-Cl2C6H4 71% 21b Ar = 4-O NC H 2 6 4 33d M = Mn; Ar = 4-O2NC6H4 74% 21e Ar = 4-ClC H - 6 4 33e M = Mn; Ar = 2,4,6 (CH3)3C6H2 72% 25b Ar = 2,6-Cl2C6H4 33f M = Mn; Ar = C F 71%* - Ar 6 5 25g Ar = 2,4,6 (CH3)3C6H2 Ar *reaction time: 10 min 32 Ar = C6F5

Scheme 15. Ph Ph

N N NH N MX (3 equiv.) 30c M = Ni; X = OAc. R. conditions : Pyridine MW (180 °C, 15 min) 2 Ph M Ph Ar Ph 34a M = Pd; X = acac. R. conditions: Pyridine MW(180 °C, 15 min) 34b M = Pt; X = acac. R. conditions: PhCN MW(250 °C, 15 min) MW N N N HN

Ph Ph 3

Ph OH Ph OH

OH OH NH N N N MX2 (3 equiv.) 36a M = Ni; X = OAc. R. conditions : Pyridine MW (180 °C, 15 min) 70% Ph Ph Ph M Ph 36b M = Pd; X = acac. R. conditions: Pyridine MW(180 °C, 15 min) 50% MW N HN N N

Ph 35 Ph

Ph O Ph O

O O NH N N N MX2 (3 equiv.) 38a M = Ni; X = OAc. R. conditions : Pyridine MW (180 °C, 15 min) 70% Ph Ph Ph M Ph 38b M = Pd; X = acac. R. conditions: Pyridine MW(180 °C, 15 min) 50% MW 38c M = Pt; X = acac. R. conditions: PhCN MW(250 °C, 20 min) N HN N N

Ph 37 Ph

Scheme 16.

Leadbeater and co-workers systematically tested the suitability specific influence of the microwave irradiation which enhances the of microwave heating as a tool for inserting Group 10 metal ions, reaction allowing the synthesis of lanthanide complexes of porphy- Ni(II), Pd(II) and Pt(II), into meso-tetraphenylporphyrins and chlorins 40a,b with moderate yields (around 30%) within 3 min instead rins [45]. meso-Tetraphenylporphyrin (3) and porpholactone 37 of 10 h for classical heating [47], (Scheme 17). were converted into Ni(II), Pd(II) and Pt(II) complexes 30c, 34a,b Porphine (42a), the structural simplest porphyrin, was synthe- and 38a-c, respectively in quantitative yields. In order to obtain the sized as the Mg(II) complex through microwave-assisted self- Pt(II) complexes it was necessary to use more drastic conditions, condensation of 1-acyldipyrromethane (41a) in toluene with 10 heating at 250 °C for 15 min or 20 min under microwave irradia- equiv. of DBU and 3 equiv. of MgBr in 45 minutes with 37% tion. In the case of chlorin 35 the reaction yields for the formation 2 yield, a notably short reaction time when compared with the 19 h of Ni(II) and Pd(II) complexes 36a,b decrease due to the formation necessary to obtain porphine in 40% yield under classical heating of secondary products related to the oxidation of the diol moiety, conditions [48]. Using this approach and starting from 1-acyl-5- (Scheme 16). aryl-dipyrromethanes, Mg(II) complexes of A2B2 type meso- The enhancement of the rate of porphyrin metallation by Cu2+ tetraarylporphyrins 42a-j were obtained in low to moderate yield in the presence of Li+ observed in dichloromethane [46] was studied [49], (Scheme 18). on the metallation of 5-(4-hydroxyphenyl)-10,15,20-tris(4-methyl- phenyl)porphyrin (39) with the lanthanides erbium and gadolinium Using the same nonacidic magnesium mediated reaction condi- in dimethylacetamide. The effect is concentration-dependent, with a tions, and two non-identical 1-acyldipyrromethanes bearing pyridyl Microwave-Assisted Synthesis and Reactivity of Porphyrins Current Organic Synthesis, 2014, Vol. 11, No. 1 97

Ar1 O

Ln O Ar1 NH N Ln(acac)3, DMA, LiCl Ar2 Ar1 N N MW(165 W, 3 min, 150 °C) Ar2 Ar1 N HN N N

39 Ar1 Ar1 1 1 2 Ar = 4-HOC6H4; 40a M = Er; Ar = 4-HOC6H4; Ar =4-CH3C6H4 2 1 2 Ar =4-CH3C6H4 40b M = Gd; Ar = 4-HOC6H4; Ar =4-CH3C6H4

Scheme 17.

Ar2 Ar2

N N MgBr2, DBU, Toluene NH N Ar1 Mg Ar1 Ar1 MW (300 W, 45 min) N N O MW C.H. 1 2 41a Ar = Ar = H Ar2 42a Ar1 = Ar2 = H 37% 40% 1 2 41b Ar = 2-Pyridyl; Ar = 4-CH3C6H4 42b Ar1 = 2-Pyridyl; Ar2 = 4-CH C H Trace 6% 1 2 3 6 4 41c Ar = C6F5; Ar = 4-CH3C6H4 42c Ar1 = C F ; Ar2 = 4-CH C H 1% 2% 1 2 6 5 3 6 4 41d Ar = H; Ar = 4-CH3C6H4 42d Ar1 = H; Ar2 = 4-CH C H 19% 39% 1 2 3 6 4 41e Ar = 4-CH3C6H4; Ar = H 42e Ar1 = 4-CH C H ; Ar2 = H 0% Trace 1 2 3 6 4 41f Ar = 2-Pyridyl; Ar = 2-Pyridyl 42f Ar1 = 2-Pyridyl; Ar2 = 2-Pyridyl 61% Trace 1 2 41g Ar = 4-Pyridyl; Ar = 4-Pyridyl 42g Ar1 = 4-Pyridyl; Ar2 = 4-Pyridyl 47% Trace 1 2 41h Ar = 4-Pyridyl; Ar = 2-Pyridyl 42h Ar1 = 4-Pyridyl; Ar2 = 2-Pyridyl 21% 3% 1 2 41i Ar = H; Ar = 3-Pyridyl 42i Ar1 = H; Ar2 = 3-Pyridyl 4% Trace 1 2 41j Ar = H; Ar = CO2CH2CH3 1 2 42j Ar = H; Ar = CO2CH2CH3 13% 0%

Scheme 18.

2 2 Ar Ar2 Ar

NH N NH N 1)MgBr2, DBU, Toluene NH N O MW (300 W, 45 min) 1 Ar1 1 + Ar1 R Ar Ar R O 2) Demetalation N HN N HN N HN

2 R Ar 45 R 44 41a R = H R = H R = Pentyl 41f Ar1 = 2-Pyridyl; Ar2 = 2-Pyridyl 43a Ar1 = 3-Pyridyl; Ar2 = 3-Pyridyl 42f/45a Ar1 = 2-Pyridyl; Ar2 = 2-Pyridyl 13/12 7/10 41g Ar1 = 4-Pyridyl; Ar2 = 4-Pyridyl 44a/45b Ar1 = 3-Pyridyl; Ar2 = 3-Pyridyl 28/3 17/23 43b Ar1 = 2-Pyridyl; Ar2 = 3-Pyridyl 42g/45c Ar1 = 4-Pyridyl; Ar2 = 4-Pyridyl 27/14 26/12 43c Ar1 = 4-Pyridyl; Ar2 = 3-Pyridyl 44b/45d Ar1 = 2-Pyridyl; Ar2 = 3-Pyridyl 9/11 12/14 43d Ar1 = 2-Pyridyl; Ar2 = 4-Pyridyl 44c/45e Ar1 = 4-Pyridyl; Ar2 = 3-Pyridyl 14/-- 16/5 43e Ar1 = H; Ar2 = 3-Pyridyl 44d/45f Ar1 = 2-Pyridyl; Ar2 = 4-Pyridyl 0/11 22/15 43f Ar1 = H; Ar2 = 4-Pyridyl 44e/45g Ar1 = H; Ar2 = 3-Pyridyl 32/Trace 43g R = Pentyl 44f/45h Ar1 = H; Ar2 = 4-Pyridyl 21/11

Scheme 19. or alkyl substituents at the 5-position, followed by demet- The Zn(II) complex of chlorin 48 was synthesized through in allation, Lindsey and co-workers synthesized unsymmetrical situ cyclization, oxidation and metallation under microwave irradia- substituted meso-porphyrins 42f, 42g, 44a-f and 45a-h [49], tion with 5% yield, while the yield under conventional heating (Scheme 19). (C.H.) did not exceed 2% [50], (Scheme 20). 98 Current Organic Synthesis, 2014, Vol. 11, No. 1 Marta Pineiro

Si Si

O 1)TsOH.H2O CH2Cl2/MeOH HN Room Temperature, 30 min N N NH + 2) AgOTf, Zn(OAc) Zn HN 2 2,2,6,6-tetramethylpiperidine N N N CH3CN Br MW (300 W, 45 min, 81˚C) Br 47 Br 46 48

Scheme 20.

OH 1) CH2Cl2, I2 NH N MW (100 W, 20 min, 30 °C) + 3 + 4 OH N 2) p-Chloranil H N HN CHO CHO MW (100 W, 3 min, 30˚C) 2 7b 1a

N N 49 8% BocHN N N NH H 50 CO2Me K2CO3, DMF MW( 300W, 15 min, 120 ˚C) NH N O

N HN N N NH

N CO2Me HN

51 88% NHBoc

Scheme 21.

The microwave-assisted, iodine-catalysed, one-pot-two-step rylmethanes 52a-e from pyrrole and benzeldehyde in a (1:10) molar synthesis described by Zorruuki and co-workers was applied to the ratio in dicloromethane [52], (Scheme 22). synthesis of A3B type porphyrin 49 with 8% yield, a slight im- Preparation of tri-, tetra- and penta- unsubstituted pyrranes (54- provement from the 7% yield obtained under conventional heating 56), was also achieved in moderate yields and short reaction time conditions. Boc-protected pseudo meso-tetraarylporphyrin-based by microwave-assisted one-step condensation of aqueous formalde- amino-acid 51, suitable for the generation of a large range of pep- hyde with pyrrole [53], (Scheme 23). tidic porphyrin derivatives, was synthesized in 88% yield by se- quential addition of triazine 50 with an excess of K2CO3 in DMF under microwave irradiation [51], (Scheme 21). 3. PORPHYRIN REACTIVITY UNDER MICROWAVE IRRADIATION Some porphyrin precursors such as dipyrrylmethanes were synthesized under microwave irradiation. Zerrouki and co-workers Besides the synthesis of porphyrin macrocycles and metal inser- used molecular iodine as catalyst for the synthesis of dipyr- tion reactions, microwave irradiation was also applied for the Microwave-Assisted Synthesis and Reactivity of Porphyrins Current Organic Synthesis, 2014, Vol. 11, No. 1 99

Reduction of a series of tetraarylporphyrins with diimide, gen- Ar erated in situ from the reaction of p-toluenesulphonylhydrazine and N potassium carbonate in 1,4-dioxane, under microwave irradiation H 2 during 25 minutes, afforded bacteriochlorins 57a-g with high CH2Cl2, I2 + NH HN yields. The oxidation of those bacteriochlorins with MnO2 in 1,4- MW (100 W, 30 ˚C, 1 min) dioxane under microwave irradiation at 90 °C for 2 minutes af- 52a Ar = C6H5 60% Ar CHO forded the corresponding chlorins 58a-g with yields ranging from 52b Ar = 4-CH3OC6H4 90% 65 to 90% and recovered mass up to 85 % [40], (Scheme 24). 52c Ar = 4-CH3O2CC6H4 90% 1a Ar = C6H5 52d Ar = 4-HOC6H4 55% Chlorins 59 and 60 were synthesized with 83% and 23% yields, 1b Ar = 4-CH3OC6H4 52e Ar = 4-O2NC6H4 84% respectively, via microwave-assisted Diels-Alder reaction of pen- 11a Ar = 4-CH3O2CC6H4 7b Ar = 4-HOC H tafluorophenylporphyrin 32 with pentacene and naphthacene in 6 4 dichlorobenzene. The reaction of chlorin 59 with pentacene under 20b Ar = 4-O2NC6H4 microwave irradiation at 200 °C for 20 minutes afforded bisaducts Scheme 22. 61 and 62 as a mixture with 7 % yield, Although the yields are low, this is significant because these compounds are not available by conventional heating conditions. Chlorin 60 was obtained as a mix- H CO 2 (37% sol in H2O) + ture of isomers 60a and 60b in a 3:2 ratio [54], (Scheme 25). N 53 H 2 Porphyrins 63a,b in DMSO, subjected to microwave irradiation for 4 minutes at 250 °C, gave via retro Diels-Alder reaction, por- MW (240 W, 40 s) phyrins 64a,b in quantitative yield [55], (Scheme 26). Synthesis of chlorins 67a,g was achieved by [8 + 2] cycloaddition of diazafulvenium methide 66 with meso-tetraarylporphyrins. The reduced macrocycles were obtained in moderate yields after 20 NH NH HN NH HN HN min under microwave irradiation at 250 °C in 1,2,4- + + trichlorobenzene (1,2,4-TCB), (Scheme 27). The same reaction conditions applied to 5,15-diarylporphyrins 68a,c afforded a mix- HN NH HN NH HN ture of regioisomeric chlorins 69a,c and 70a,c, also in moderate yields [56], (Scheme 28). The microwave irradiation of 5,10,15,20-tetrakis(2,6- 54 11% 55 17% dichlorophenyl)porphyrin (25b) with montmorillonite K-10 and NH concentrated nitric acid for 1.5 minutes gave the -heptanitro de- 56 19% rivative (72) in 72 % yield. The use of a mixture of montmorillonite K-10 and Cu(NO3)2 as a mild nitrating agent, and the increase of SScheme 23. the reaction time to 2 minutes slightly increases the yield of the modification of the porphyrin core, synthesizing chlorins and bacte- heptanitro compound and decrease the degradation of the reagent. riochlorins, to introduce subtituents in the porphyrin periphery or to Similar yields and selectivity were obtained by performing the reac- modify these substituents in order to increase the variability of tion over the Zn(II) and Cu(II) complex of porphyrin 25b [57], functionalization. (Scheme 29).

Ar Ar recovered mass(63/64 ratio)

57a Ar = C6H5 90%(75/25) p-toluenesulphonylhydrazide NH N NH N 57b Ar = 2,6-Cl2C6H3 92%(85/15) K2CO3, 1,4-Dioxane 57c Ar = 3-CH OC H 95%(85/15) Ar 3 6 4 Ar Ar Ar 57d Ar = 3-HOC6H4 93%(80/20) MW (120 ˚C, 25 min) 57e Ar = 4-CH OC H 95%(65/35) N HN N HN 3 6 4 57f Ar = 4-BrC6H4 92%(65/35) 57g Ar = 4-tBuC6H4 90%(45/30/25)* * 63/64/porphyrin Ar Ar MnO 3 Ar = C H 2 6 5 1,4-Dioxane 29b Ar = 2,6-Cl2C6H3 MW (90 ˚C, 3 min) 29f Ar = 3-CH3OC6H4 29i Ar = 3-HOC6H4 4a Ar = 4-CH3OC6H4 Ar 29d Ar = 4-BrC6H4 recovered mass(63/porphyrin ratio) 8a Ar = 4-tBuC6H4 58a Ar = C H 92%(80/20) NH N 6 5 58b Ar = 2,6-Cl2C6H3 85%(75/25) Ar Ar 58c Ar = 3-CH3OC6H4 93%(90/10) 58d Ar = 3-HOC6H4 88%(65/35) N HN 58e Ar = 4-CH3OC6H4 90%(90/10) 58f Ar = 4-BrC6H4 88%(85/15) 58g Ar = 4-tBuC6H4 86%(70/30) Ar Scheme 24. 100 Current Organic Synthesis, 2014, Vol. 11, No. 1 Marta Pineiro

NH N

Ar Ar Ar Ar N HN

NH N NH N 60a Ar = C6F5 Ar Ar Ar Ar Ar DCB N HN DCB N HN MW (200 °C, 30 min) MW (180 °C, 45 min)

Ar Ar Ar

59 Ar = C6F5 83% 32 Ar = C6F5 NH N

Ar Ar DCB MW (200 °C, 20 min) N HN

60b Ar = C6F5

Ar Ar

NH N NH N

Ar Ar Ar Ar N HN N HN

Ar Ar

61 Ar = C6F5 62 Ar = C6F5

Scheme 25.

OMe MeO OMe MeO

Ar Ar OMe MeO MeO OMe

NH N NH N DMSO Ar Ar MeO Ar Ar OMe MW (250 ˚C, 4 min) N HN N HN MeO OMe Ar Ar MeO OMe OMe MeO 63a Ar = H - 64a Ar = H 63b Ar = 2,4,6 (CH3)3C6H2 - 64b Ar = 2,4,6 (CH3)3C6H2

Scheme 26. Microwave-Assisted Synthesis and Reactivity of Porphyrins Current Organic Synthesis, 2014, Vol. 11, No. 1 101

MeO2C CO2Me CO2Me MeO2C Ar Ar N N N N 66 O S NH N 2 NH N 21e Ar = 4-ClC H 1,2,4-trichlorobenzene 6 5 Ar Ar 67a Ar = 4-ClC6H5 30% 3 Ar = C H Ar Ar 6 5 67b Ar = C6H5 31% 29i Ar = 4-CH C H MW (250 °C, 20 min) 3 6 4 N HN N HN 67c Ar = 4-CH3C6H4 26% 4a Ar = 4-CH OC H 3 6 4 67d Ar = 4-CH3OC6H4 20% 65 Ar = 4-FC H 6 4 67e Ar = 4-FC6H4 10% 29f Ar = 3-CH OC H 3 6 4 67f Ar = 3-CH3OC6H4 13% 29b Ar = 2,6-Cl C H Ar Ar 2 6 3 67g Ar = 2,6-Cl2C6H3 13%

Scheme 27.

MeO C 2 CO Me CO Me CO2Me 2 2 N MeO2C Ar Ar N Ar N N CO2Me N N

NH N O2S 72 NH N NH N 1,2,4-TCB Ar Ar + Ar Ar N HN MW (250 °C, 20 min) N HN N HN

68a Ar = 4-ClC H 6 5 69a Ar = 4-ClC6H5 8% 70a Ar = 4-ClC6H5 12% Ar 68b Ar = C H Ar Ar 6 5 69b Ar = C6H5 13% 70b Ar = C6H5 13% 68c Ar = 4-CH OC H 3 6 4 69c Ar = 4-CH3OC6H4 16% 70c Ar = 4-CH3OC6H4 12%

Scheme 28.

Ar O2N Ar NO2

O2N NO2 N N N N K10,Cu(NO3)2 72a M = 2H; Ar = 2,6-Cl C H 84% Ar Ar M Ar 2 6 3 Ar M 72b M = Zn; Ar = 2,6-Cl C H 95% MW (240 W, 2 min) 2 6 3 N N 72c M = Cu; Ar = 2,6-Cl C H 87% 25b M = 2H; Ar = 2,6-Cl2C6H3 N N 2 6 3 71a M = Zn; Ar = 2,6-Cl2C6H3 O2N NO2 71b M = Cu; Ar = 2,6-Cl2C6H3 Ar Ar NO2 Scheme 29.

meso-Bromoporphyrins 73a,b were transformed into meso- The microwave-assisted condensation reaction of acetylchlorin aminoporphyrins 74a,h through bromine displacement with primary 77 gave chlorins 79a, b,e with high yields, (Scheme 33) [60], while amines, without metal catalyst, under microwave irradiation in formylbacteriochlorin 80a reacted with hydroxylamine hydrochlo- short reaction times and good yields. Porphyrins with bromine at ride and pyridine in absolute ethanol under microwave irradiation to the beta position do not react in these reaction conditions even upon afforded oxime 81 in 48% yield and with semicarbazide hydrochlo- prolonged heating or microwave irradiation [58], (Scheme 30). ride and sodium acetate, also in absolute ethanol, to gave the corre- The selective displacement of the fluorine atom at the para po- sponding semicarbazone 82 in 36% yield [61]. Under the same reac- sition of the phenyl ring in tetrakis-5,10,15,20-pentafluorophenyl- tion conditions reaction of bisacetyl derivative 80b with aryl alde- porphyrin (32) with primary amines was achieved in an efficient hydes 78a-e, in basic ethanolic solution at 80°C for 40 minutes, af- manner under microwave irradiation, the reaction product obtained forded bacterioclorins 83a-e in low to moderate yields, (Scheme 34). in high yields and short reaction times specially when compared The Wittig condensation of triphenyl[(porphyrin-2-yl)methyl] with the 20 h -2 days necessary to obtain the desired porphyrin, phosphonium chloride 84 with aldehyde 85 in the presence chloro- 75a-c, in moderate yield under conventional heating [59], (Scheme form and an excess of DBU under focused microwave irradiation at 31). 60 W for 10 minutes gave porphyrin 86 with 40% yield and a com- Urotropine and metalloporphyrins 19a-d powdered together in plete trans stereoselectivity [62], (Scheme 35). an agate mortar, were doped on H2SO4/silica gel and introduced in The microwave-assisted Kabachnick-Fields reaction of formyl an open quartz flask having an outer solvent circulating jacket for and acetyl natural porphyrins with tert-butyl amine and diethyl- the control of temperature, and heated under microwave irradiation phosphite in dichloroethane for 2 minutes afforded the - to afford formyl nickel(II) and Cu(II) porphyrinates 76 with good aminophosphonates derivatives 87, 88, 89a-c and 90 in very high yields [33], (Scheme 32). yields [63], (Fig. 1). 102 Current Organic Synthesis, 2014, Vol. 11, No. 1 Marta Pineiro

Br NHR

74a R = CH3CH2CH2; Ar = C6H5 75% NH N NH N 74b R = CH3CH2CH2CH2; Ar = C6H5 95% R-NH2 74c R = C6H5CH2; Ar = C6H5 99% Ar Ar Ar Ar 74d R = 4-CH3OC6H4CH2; Ar = C6H5 77% 74e R = 4-FC H CH ; Ar = C H 89% N HN MW (150-300 W, 2-16 min) N HN 6 4 2 6 5 74f R = C6H5CH2; Ar = 3,5-tBuC6H3 89% 74g R = NH2CH2CH2; Ar = 3,5-tBuC6H3 47% 74h R = HOCH2CH2; Ar = 3,5-tBuC6H3 10% H H 73a Ar = C6H5 73b Ar = 3,5-tBuC6H3 Scheme 30. Ar NHR F F

NH N F F Ar Ar R-NH2 (10 equiv.), NMP HN N F F F F MW (1100 W, 10-30 min) NH N RHN NHR Ar 32 Ar = C6F5 N HN O H F F F F N 75a Ar = N O 94% H F F H3COOC O H N 75b Ar = N 77% F F H H H N O O N O NHR 75c Ar = O 94% O Scheme 31.

Ar Ar O

N N H N N SiO2, Urotropine Ar M Ar Ar M Ar MW (111 ˚C, 200 W, 18 min) N N N N 19a M = Ni; Ar = 4 (CH ) CH C H 3 2 2 6 4 76a M = Ni; Ar = 4 (CH3)2CH2C6H4 54% 19b M = Ni; Ar = 3,5-tBuC H 6 3 76b M = Ni; Ar = 3,5-tBuC6H3 50% 19c M = Cu; Ar = 4 (CH ) CH C H 3 2 2 6 4 76c M = Cu; Ar = 4 (CH3)2CH2C6H4 54% Ar 19d M = Cu; Ar = 3,5-tBuC H Ar 6 3 76d M = Cu; Ar = 3,5-tBuC6H3 51% Scheme 32.

NH N NH N Aldehyde 78a,b,e NaOH, EtOH MW (40 min, 80°C) HN 3 N HN N 79a R = C6H5 92% 3 - 79b R = C6H5-CH=CH 90% Aldehydes 3 78a C6H5-CHO 79e R = 53% 78b C6H5-CH=CH-CHO 77 O O 78c 3,5-MOMOC6H3-CHO - 78d 4 (CH3)2NC6H4-CHO R3

78e OHC

Scheme 33. Microwave-Assisted Synthesis and Reactivity of Porphyrins Current Organic Synthesis, 2014, Vol. 11, No. 1 103

O HO NH 1 2 N 2 R = R = H R1 H O N H O N

NH-NH R1 = R2 = H H2N 2 NH N NH N NaOAc, Ethanol H2NOH.HCl, Py, Ethanol NH N MW (300 W, 20 min, 100°C) MW (300 W, 20 min, 100˚C) N HN N HN N HN

2 81 1 2 R 82 80a R = R = H 1 2 80b R = CH3; R = COCH3 Aldehydes 1 2 R = CH3; R = COCH3 78a C6H5-CHO Aldehyde 78a-e 78b C6H5-CH=CH-CHO 78c 3,5-MOMOC6H3-CHO NaOH, EtOH - 78d 4 (CH3)2NC6H4-CHO MW (40 min, 80˚C) 3 83a R = C6H5 58% O 3 - CHO 83b R = C6H5-CH=CH 57% 3 - 83c R = 3,5-MOMOC6H3 24% 3 - - 78e N HN 83d R = 4 (CH3)2NC6H4 17% R3 83e R3 = 9% O NH N

Scheme 34.

Ar N

Ar Ar NH N N

Ar Ar + DBU, CHCl3 NH HN N HN N N MW(60 W, 10 min) 85 N Ar Ar N O Ar + P (Ph)3 H 86 Ar = C6H5 40% 84 Ar = C6H5 Scheme 35.

O O BuHtN P(OEt)2 O BuHtN (EtO)2 P P NHtBu R1 (OEt) H OH 2 NHtBu H R2 H HO P O NH N NH N NH N NH N (EtO)2

N HN N HN N HN N HN

MeO C CO2Me 2 R2

1 2 CO Me 89a R = H; R = H 89% CO2Me MeO C 2 MeO2C CO2Me 2 89b R1 = H; R2 = CO Me 87% MeO2C 2 1 2 87 95% 88 93% 89c R = CH3; R = H 91% 90 90% Fig. (1). Porphyrins and chlorins bearing -aminophosphonates synthesized under microwave irradiation. 104 Current Organic Synthesis, 2014, Vol. 11, No. 1 Marta Pineiro

N Ar NH2 Ar HN R1 N N R2 Pd(OAc)2, XPhos N Ar Ni Ar + O KOtBu, toluene N R3 N Ar Ni Ar N N MW (800 W, 2 min R4 + 500 W, 30 min) N N 92a R1 = R3 = R4 = H; R2 = I Ar 92b R1 = R3 = H; R2 = R4 = Br 1 3 2 4 Ar 91 Ar = C6H5 92c R = R = Br; R = R = H 93 Ar = C6H5 32% O O N N

Ar HN NH Ar Ar HN HN Ar

N N N N N N N N Ni Ni Ni Ar Ar Ar Ar Ni Ar Ar Ar Ar N N N N N N N N

Ar Ar Ar 95 Ar = C H 63% Ar 94 Ar = C6H5 41% 6 5 Scheme 36.

CO2CH3

O O N O

Ar CO2CH3 O O O N O NH N Ar O N N HN O CO2CH3 CO2CH3 O N O Ar CO CH 2 3 THF 96 MW (80-220W, 180 °C, 2h) + Ar Ar O O N O O CO CH NH N 2 3 NH N N Ar N Ar N HN N HN O O O CO2CH3 Ar 97 Ar = C6H5 Ar 98 Ar = C6H5 38% Scheme 37. Porphyrin indolin-2-one conjugates 93-95 were obtained Microwave-assisted coupling of porphyrin 96 and dimer 97 in using the Buchwald-Hartwig palladium-catalyzed amination reac- dry THF for 2 h gave bis-porphyrin tweezer 98 by alkene plus tion of iodinated and dibrominated indolin-2-one derivatives 92a-c cyclobutane epoxide (ACE) reaction with 38% yield. The reaction and Ni(II) porphyrinate 91 under microwave irradiation [64], time short when compared with the 90 h required for the reaction (Scheme 36). using conventional heating [65], (Scheme 37). Microwave-Assisted Synthesis and Reactivity of Porphyrins Current Organic Synthesis, 2014, Vol. 11, No. 1 105

O N N O Ru+ N NH2 NH NH N N 1) Ru(DMSO)4Cl2 (1 equiv.), DMF Ar Ar NH N - MW (200 W, 20 min) PF6 N HN Ar Ar 2) 2,2'-bipyridine (2 equiv.), DMF MW (200 W, 20 min) N HN Ar 100 Ar = C H 21% Ar 6 5 99 Ar = C6H5 Scheme 38. OR

N N Zn OR 101b R = Propargyl 101a R = CH CH CH N N N 2 2 2 3 CuSO4, Sodium L-ascorbate CuCl, 102a or b 102c,d, e or 102f Toluene THF/tBuOH/H2O MW (80W, 20 min, 140 °C) MW (80W, 3 min, 85 °C) Ar Ar

N N OR N N Zn Ar 101a R = CH2CH2CH2N3 Zn Ar 101b R = Propargyl N N N N

Ar Ar AcO OAc 104c Ar = C6H4O OAc AcO N N OAc 57% 103a Ar = C6H4O O N O N N OAc 65% OAc N O AcO OAc OAc 104d Ar = C6H4O AcO N N 103b Ar = C H O OAc 45% 6 4 N O OAc N O OAc 68% N OAc N O AcO OAc OAc 104e Ar = C6H4O O OAc N N O 80% N O OAc OAc OAc OAc OAc OAc AcO O AcO O O AcO O AcO AcO AcO O AcO O AcO O AcO O OAc AcO AcO OAc AcO N3 102c 102d O OAc 102b O N3 102a 102e N3 O

Scheme 39. 106 Current Organic Synthesis, 2014, Vol. 11, No. 1 Marta Pineiro

CuI, Na ascorbate, Ar TBTA CHO DMSO:H2O (9:1) OHC N N 106 Ar Zn N N N MW(50 W, 2h, 80°C) N N

R1 R2 105a Ar 107 Ar = 3,5-tBuC6H3 84%

CuI, Na ascorbate, Ar CHO DMSO:H2O (9:1)

OHC N3 NN N N 108 105b N Ar Zn Ar Ar Zn N N N N MW(50 W, 30 min, 80°C) N N

Ar Ar

1 2 105a R = N3; R = H; Ar = 3,5-tBuC6H3 109 Ar = 3,5-tBuC6H3 quantitative yield 1 2 105b R = ethynyl; R = H; Ar = 3,5-tBuC6H3 1 2 105c R = H; R = ethynyl; Ar = 3,5-tBuC6H3 CHO CuI, Na ascorbate, Ar DMSO:H2O (9:1) N 105c N3 N OHC N N N 110 Ar Zn MW(50 W, 30 min, 80°C) N N

Ar 111 Ar = 3,5-tBuC6H3 29% Scheme 40.

O O CO H CO2Me 2 113a R = C6F5 112a R = C6F5 113b R = 3,5-(CF3)2C6H3 112b R = 3,5-(CF ) C H 3 2 6 3 NHN NHN 113c R = 4-C(CH3)C6H4 112c R = 4-C(CH3)C6H4 NaOH (6 N), THF 113d R = 2,4,6-(CH3)3C6H2 R R 112d R = 2,4,6-(CH3)3C6H2 R R 113e R = 4-CH3OC6H3 112e R = 4-CH3OC6H3 MW (75 ˚C, 10 min) 113f R = Butyl N NH N 112f R = Butyl NH 113g R = H 112g R = H

R R Scheme 41.

Porphyrin-polypyridine ruthenium complexes 100 were synthe- cycloadditions (Click reaction) following two different strategies: sized under microwave irradiation in a two step procedure. In the coupling of azidoporphyrin 101a with propargyl glycosides 102a,b first step porphyrin 99 and ruthenium complex (Ru(DMSO)4Cl2) in the presence of CuCl2 in toluene or, condensation of propargyl- react at reflux in dimethylformamide for 20 minutes under micro- porphyrin 101b with azidoglycosides 102c-d in the presence of wave irradiation; in the second step, 2 equivalents of 2,2’- CuSO4/L-ascorbate as catalytic system. Following the second strat- bipyridine in DMF were added and the final complex was formed egy better yields of porphyrin glycoconjugates 104a-d (45-80%) after 20 minutes under microwave irradiation, [66] (Scheme 38). were obtained [67], (Scheme 39). Glycoconjugated porphyrins 103a,b and 104a-d were synthe- Microwave-assisted synthesis was used to promote click chem- sized using the microwave-assisted copper-catalyzed azide-alkyne istry between azidoporphyrin 105a and propargyl aldehyde 106 in Microwave-Assisted Synthesis and Reactivity of Porphyrins Current Organic Synthesis, 2014, Vol. 11, No. 1 107

OH OR

114a Ar = C6H; R = Ethyl 73% 114b Ar = C H; R = Buthyl 73% N HN Alkyl halide NHN 6 114c Ar = C H; R = 1-Brbuthyl 73% K2CO3, DMF 6 Ar Ar Ar Ar 114d Ar = C6H; R = Penthyl 70% MW (300 W, 3-8 min) 114e Ar = C6H; R = Hepthyl 73% N NH N NH 114f Ar = C6H; R = Dodecyl 73% 114g Ar = C6H; R = tetradecanyl 67% 114h Ar = C6H; R = iso-Propyl 70% Ar Ar 31c Ar = C6H5 Scheme 42.

O2N Ar1 Ar1 O

S NO2 O Cl NHN 1 2 3 4 NHN 116a Ar = 4-SAMC6H4; Ar = Ar = Ar = C6H5 70% CHCl /Pyridine 1 2 3 4 3 Ar4 Ar2 116b Ar = Ar = 4-SAMC6H4; Ar = Ar = C6H5 57% 4 Ar2 1 3 2 4 Ar 116c Ar = Ar = 4-SAMC6H4; Ar = Ar = C6H5 81% MW (300 W, 25 min, 120 ˚C) NH N NH N O2N

Ar3 SAM = HNO S NO Ar3 2 2 1 2 3 4 115a Ar = 4-H2NC6H4; Ar = Ar = Ar = C6H5 1 2 3 4 115b Ar = Ar = 4-H2NC6H4; Ar = Ar = C6H5 1 3 2 4 115c Ar = Ar = 4-H2NC6H4; Ar = Ar = C6H5

Scheme 43. the presence of tris(benzyltriazolylmethyl)amine (TBTA), after 90 CONFLICT OF INTEREST minutes the reaction product 107 was obtained in 84% yield. In a different strategy, the authors heat azide aldehydes 108 and 110 and The author confirms that this article content has no conflict of propargyl porphyrins 105b,c under microwave irradiation to afford interest. the expected click chemistry products 109 and 111, in the absence of TBTA, with moderate to high yields [68], (Scheme 40). ACKNOWLEDGEMENTS Hangman porphyrin-xanthenes with carboxylic acid moiety Author thanks to Fundação para a Ciência e Tecnologia (Pest- 113a-g were obtained in quantitative yield by base catalyzed hy- C/QUI/UI0313/2011) and Ciência Viva (PEC62) for financial drolysis of the corresponding methyl ester 112a-g after microwave support. irradiation for 4 h [69], (Scheme 41). Alkyloxy porphyrins 114a-h have been prepared by direct cou- REFERENCES pling of unsymmetrical meso-substituted porphyrin 31c and alkyl [1] Biesaga, M.; Pyrzynska, K.; Trojanowicz, M. Porphyrins in analytical chem- halides under microwave irradiation. Using potassium carbonate istry. A review. Talanta, 2000, 51, 209-224. [2] (a) Campbell, W.M.; Burrell, A.K.; Officer, D.L.; Jolley, K.W. Porphyrins as and DMF as solvent alkyloxy porphyrins were obtained after 3 to 8 light harvesters in the dye-sensitised TiO2 solar cell. Coord. Chem. Rev., minutes in yields of up to 67%, the exception being the reaction 2004, 248, 1363-1379; (b) Lia, L.-L.; Diau, E. W.-G. Porphyrin-sensitized with chlorohexane that affords 70% of the desired porphyrin after solar cells. Chem. Soc. Rev., 2013, 42, 291-304; (c) Waltera, M.G.; Rudine, 85 minutes at 500 W [70], (Scheme 42). A.B.; Wamser, C.C. Porphyrins and phthalocyanines in solar photovoltaic cells. J. Porphyrins Phthalocyanines, 2010, 14, 759-792. Dissolution of unsymmetrically meso-substituted amino por- [3] (a) Jurow, M.; Schuckman, A.E.; Batteas, J.D.; Drain, C.M. Porphyrins as phyrins 115a-c and an excess of 2,4-dinitrobenzenesuphonyl chlo- molecular electronic components of functional devices. Coord. Chem. Rev., ride in a mixture of chloroform with pyridine followed by micro- 2010, 254, 2297-2310; (b) Calvete, M.; Yang, G.Y.; Hanack, M. Porphyrins and phthalocyanines as materials for optical limiting. Synth. Met., 2004, 141, wave irradiation at 120 °C for 25 minutes gave mono and di- 231-243; (c) Calvete, M.J.F. Near infra-red absorbing materials with nonlin- sulfonamidophenylporphyrins 116a-c in high yields [71], (Scheme ear transmission properties. Int. Rev. Phys. Chem., 2012, 31, 319-366. 43). [4] (a) Suslick, K.S.; Rakow, N.A.; Kosal, M.E.; Chou, J.-H. The materials chemistry of porphyrins and metalloporphyrins. J. Porphyrin Phthalo- cyanines, 2000, 4, 407-413; (b) Malinski, T. In: The Porphyrin Handbook; CONCLUSION Kadish, K. M., Smith, K. M., Guilard, R., Eds.; Academic Press: San Diego, 2000; Vol. 6, pp 231-256; (c) Di Natale, C.; Monti, D.; Paolesse, R. Chemi- Microwave-assisted synthesis has been successfully applied for cal sensitivity of porphyrin assemblies - Review article. Mater. Today, 2010, the synthesis of porphyrin macrocycles and metal insertion reac- 13, 46-52. tions. Microwave irradiation was also applied for the modification [5] (a) Aida, T.; Inoue, S. In: The Porphyrin Handbook; Kadish, K.M., Smith, K. M., Guilard, R., Eds.; Academic Press: San Diego, 2000; Vol. 6, pp. 133- of the porphyrin core, synthesize chlorins and bacteriochlorins, to 156; (b) Lissi, E.A.; Encinas, M.V.; Lemp, E.; Rubio, M.A. Singlet oxygen 1 introduce substituents in the porphyrin periphery or to modify these O2( Dg) Bimolecular processes. Solvent and compartmentalization effects. substituents in order to increase the variability of functionalization. Chem. Rev., 1993, 93, 699-723. 108 Current Organic Synthesis, 2014, Vol. 11, No. 1 Marta Pineiro

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Received: September 12, 2013 Revised: October 09, 2013 Accepted: October 10, 2013