De novo synthesis of long-Wavelength absorbing chlorin-13,15-dicarboximides

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De Novo Synthesis of Long-Wavelength Absorbing

Chlorin-13,15-dicarboximides

ꢀ

Marcin Ptaszek, Dorothee Lahaye, Michael Krayer, Chinnasamy Muthiah, and

Jonathan S. Lindsey*

Department of Chemistry, North Carolina State University, Raleigh, North Carolina 27695-8204

jlindsey@ncsu.edu

Received December 14, 2009

Chlorins bearing a six-membered imide ring spanning positions 13-15, commonly referred to as

purpurinimides, exhibit long-wavelength absorption yet have heretofore only been available via

semisynthesis from naturally occurring chlorophylls. A concise route to synthetic chlorins, which

bear a geminal dimethyl group in the pyrroline ring, has been extended to provide access to chlorin-

13,15-dicarboximides. The new route entails (i) synthesis of a 13-bromochlorin, (ii) palladium-

catalyzed carbamoylation at the 13-position, (iii) regioselective 15-bromination under acidic condi-

tions, and (iv) one-flask palladium-mediated carbonylation and ring closure to form the imide. In

some cases the ring closure reaction afforded the isomeric (and readily separable) chlorin-isoimide in

addition to the chlorin-imide. The resulting chlorin-imides and chlorin-isoimides exhibit long-

wavelength absorption (679-715 nm) and emission (683-720 nm) in the far-red and near-infrared

spectral region. The absorption of the chlorin-(iso)imides fills the spectral window between that of

analogous synthetic chlorins and 13¹-oxophorbines (603-687 nm) and bacteriochlorins (707-792 nm).

The synthetic versatility of the de novo route complements the existing semisynthetic route from

chlorophylls and should enable fundamental spectroscopic studies and photochemical applications.

Introduction

isocyclic ring can be used to modify the spectral and

excited-state properties of the chlorophyll molecules.

Chlorophylls possess a five-membered exocyclic ring

spanning the 13- and 15-positions. The exocyclic ring con-

tains an oxo moiety at the 13¹-position and a methoxy-

carbonyl substituent at the 13²-position. The electron-with-

drawing 13-keto group embedded in the exocyclic ring

(termed the isocyclic ring) is conjugated with the macrocyclic

π-system, and causes a significant hyperchromic and bath-

ochromic shift of the long-wavelength absorption band. The

position and strength of the long-wavelength absorption

band not only affect the spectral coverage but also are key

determinants of the energy and properties of the excited

singlet state. Thus, alteration of the keto group in the

Synthetic manipulation of chlorophylls;both early degra-

dative methods as well as constructive modifications that

continue in the present era;have focused on alteration of the

isocyclic ring.^1,2Conant and Moyer first reported that treat-

ment of methyl pheophorbide a in ether with methanolic KOH

afforded a series of chlorins, of which two purplish brown

substances were isolated and termed “phaeopurpurins 7 and

18”.³Fischer identified the respective compounds as origi-

nating from oxidative opening of the isocyclic ring⁴to

give a chlorin-13,15-dicarboxylic acid and a chlorin bearing a

(2) Pavlov, V. Y.; Ponomarev, G. V. Chem. Heterocycl. Compd. 2004, 40,

393–425.

(3) Conant, J. B.; Moyer, W. W. J. Am. Chem. Soc. 1930, 52, 3013–3023.

€

(4) Fischer, H.; Moldenhauer, O.; Sus, O. Liebigs Ann. Chem. 1931, 486,

107–177.

(1) (a) Hynninen, P. H. In Chlorophylls; Scheer, H., Ed.; CRC Press: Boca

Raton, FL, 1991; pp 145-209. (b) Hyvarinen, K.; Hynninen, P. H. Res. Adv. Org.

Bioorg. Chem. 2001, 1, 1–19.

DOI: 10.1021/jo902649d

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2010 American Chemical Society

Ptaszek et al.

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six-membered anhydride ring.^4,5Fischer further constructed

the six-membered imide ring from the chlorin-anhydride

“purpurin-18” and its methyl ester^6,7to give the corres-

ponding purpurinimide^8,9(hereafter referred to as a chlorin-

imide¹⁰).

SCHEME 1

In the 1990s, Smith carried out a variety of modifications

to purpurin-18 as well as the related chlorin-e₆and chlorin-p₆

analogues (Scheme 1).^11,12He also showed that the N-alkyl

chlorin-imide derivative exhibited the long-wavelength

absorption band at 706 nm, a position bathochromically

shifted with respect to that of the parent chlorophyll macro-

cycle.¹²The shift of the absorption band in the chlorin-

imide to longer wavelength made the compounds attractive

for a number of reasons, particularly as photosensitizers in

photodynamic therapy (PDT). In PDT, the use of light

sources with wavelengths in the red or near-infrared region

enables deep penetration of tissue,¹³which in turn places

a premium on photosensitizers that are active in the red

or near-infrared spectral region. In more recent years, the

groups of Mironov and of Pandey have significantly expan-

ded the scope of chlorin-imides,^14-27including extension

(5) Fischer, H.; Filser, L; Hagert, W.; Moldenhauer, O. Liebigs Ann.

Chem. 1931, 490, 1–38.

(6) Fischer, H.; Gibian, H. Liebigs Ann. Chem. 1941, 547, 216–233.

(7) Fischer, H.; Gibian, H. Liebigs Ann. Chem. 1942, 550, 208–251.

(8) Fischer, H. Chem. Rev. 1937, 20, 41–68.

(9) Treibs, A. Das Leben und Wirken von Hans Fischer; Hans Fischer-

€

Gesellschaft: Munchen, Germany, 1971; pp 342-349 and 372-378.

(10) The term purpurin, first used to name the madder dye 1,2,4-trihy-

droxyanthraquinone (Thomson, R. H. Naturally Occurring Quinones, 2nd

ed.; Academic Press: London, UK, 1971; pp 407-408), has since been

applied to describe diverse chlorins wherein the isocyclic ring has been

modified in a variety of ways.^1,8,9Given the diffuse usage of purpurins and

purpurinimides, we restrict the nomenclature for the de novo synthesized

macrocycles herein to the formal terms chlorin-13,15-dicarboxylic anhy-

dride, chlorin-13,15-dicarboximide, and chlorin-13,15-dicarboxisoimide.

(11) Pandey, R. K.; Bellnier, D. A.; Smith, K. M.; Dougherty, T. J.

Photochem. Photobiol. 1991, 53, 65–72.

(12) Lee, S.-J. H.; Jagerovic, N.; Smith, K. M. J. Chem. Soc., Perkin

Trans. 1 1993, 2369–2377.

(13) Dawson, J. B.; Barker, D. J.; Ellis, D. J.; Grassam, E.; Cotterill, J. A.;

Fisher, G. W.; Feather, J. W. Phys. Med. Biol. 1980, 25, 695–709.

(14) Mironov, A. F.; Lebedeva, V. S.; Yakubovskaya, R. I.; Kazachkina,

N. I.; Fomina, G. I. Proc. SPIE 1999, 3563, 59–67.

(15) Mironov, A. F.; Lebedeva, V. S. Tetrahedron Lett. 1998, 39, 905–908.

(16) Mironov, A. F.; Grin, M. A.; Nochovny, S. A.; Toukach, P. V.

Mendeleev Commun. 2003, 13, 156–157.

to bacteriochlorin-imides derived from bacteriochloro-

phyll a.^28-34The chlorin-imides have been used chiefly as

photosensitizers in PDT^18,35,36although several studies have

been carried out related to artificial photosynthesis.^20,22-24,37

Limited spectroscopic studies to date suggest that the presence

(17) Mironov, A. F.; Ruziev, R. D.; Lebedeva, V. S. Russ. J. Bioorg.

Chem. 2004, 30, 466–476.

(18) Nazarova, A. I.; Feofanov, A. V.; Karmakova, T. A.; Sharonov,

G. V.; Plyutinskaya, A. D.; Yakubovskaya, R. I.; Lebedeva, V. S.; Mironov,

A. F.; Maurizot, J.-C.; Vigny, P. Russ. J. Bioorg. Chem. 2005, 31, 482–494.

(19) Nechaev, A. V.; Mironov, A. F. Russ. J. Bioorg. Chem. 2008, 34, 245–

251.

(28) Mironov, A. F.; Grin, M. A.; Tsyprovskiy, A. G. J. Porphyrins

Phthalocyanines 2002, 6, 358–361.

(29) Mironov, A. F.; Grin, M. A.; Tsiprovskiy, A. G.; Kachala, V. V.;

Karmakova, T. A.; Plyutinskaya, A. D.; Yakubovskaya, R. I. J. Porphyrins

Phthalocyanines 2003, 7, 725–730.

(20) Zheng, G.; Dougherty, T. J.; Pandey, R. K. Chem. Commun. 1999,

24, 2469–2470.

(21) Zheng, G.; Potter, W. R.; Camacho, S. H.; Missert, J. R.; Wang, G.;

Bellnier, D. A.; Henderson, B. W.; Rodgers, M. A. J.; Dougherty, T. J.;

Pandey, R. K. J. Med. Chem. 2001, 44, 1540–1559.

(30) Mironov, A. F.; Grin, M. A.; Tsiprovskii, A. G.; Segenevich, A. V.;

Dzardanov, D. V.; Golovin, K. V.; Tsygnkov, A. A.; Shim, Y. K. Russ. J.

Bioorg. Chem. 2003, 29, 190–197.

(22) Fukuzumi, S.; Ohkubo, K.; Imahori, H.; Shao, J.; Ou, Z.; Zheng, G.;

Chen, Y.; Pandey, R. K.; Fujitsuka, M.; Ito, O.; Kadish, K. M. J. Am. Chem.

Soc. 2001, 123, 10676–10683.

(23) Ohkubo, K.; Imahori, H.; Shao, J.; Ou, Z.; Kadish, K. M.; Chen, Y.;

Zheng, G.; Pandey, R. K.; Fujitsuka, M.; Ito, O.; Fukuzumi, S. J. Phys.

Chem. A 2002, 106, 10991–10998.

(24) Li, G.; Dobhal, M. P.; Shibata, M.; Pandey, R. K. Org. Lett. 2004, 6,

2393–2396.

(25) Gryshuk, A.; Chen, Y.; Goswami, L. N.; Pandey, S.; Missert, J. R.;

Ohulchanskyy, T.; Potter, W.; Prasad, P. N.; Oseroff, A.; Pandey, R. K.

J. Med. Chem. 2007, 50, 1754–1767.

(26) Pandey, S. K.; Zheng, X.; Morgan, J.; Missert, J. R.; Liu, T.-H.;

Shibata, M.; Bellnier, D. A.; Oseroff, A. R.; Henderson, B. W.; Dougherty,

T. J.; Pandey, R. K. Mol. Pharm. 2007, 4, 448–464.

(27) Goswami, L.N.;Ethirajan,M.;Dobhal, M. P.; Zhang, M.; Missert, J. R.;

Shibata, M.; Kadish, K. M.; Pandey, R. K. J. Org. Chem. 2009, 74, 568–579.

(31) Mironov, A. F.; Grin, M. A.; Tsiprovskii, A. G.; Titeev, R. A.;

Nizhnik, E. A.; Lonin, I. S. Mendeleev Commun. 2004, 14, 204–207.

(32) Chen, Y.; Graham, A.; Potter, W.; Morgan, J.; Vaughan, L.;

Bellnier, D. A.; Henderson, B. W.; Oseroff, A.; Dougherty, T. J.; Pandey,

R. K. J. Med. Chem. 2002, 45, 255–258.

(33) Kozyrev, A. N.; Chen, Y.; Goswami, L. N.; Tabaczynski, W. A.;

Pandey, R. K. J. Org. Chem. 2006, 71, 1949–1960.

(34) Goswami, L. N.; Chen, Y.; Missert, J.; Li, G.; Pallenberg, A.;

Pandey, R. K. Heterocycles 2007, 71, 1929–1949.

(35) Nazarova, A.;Ignatova, A.;Feofanov, A.;Karmakova, T.; Pljutinskaya,

A.; Mass, O.; Grin, M.; Yakubovskaya, R.; Mironov, A.; Maurizot, J.-C.

Photochem. Photobiol. Sci. 2007, 6, 1184–1196.

(36) Pandey, R. K.; Goswami, L. N.; Chen, Y.; Gryshuk, A.; Missert,

J. R.; Oseroff, A.; Dougherty, T. J. Lasers Surg. Med. 2006, 38, 445–467.

(37) Tamiaki, H.; Shimamura, Y.; Yoshimura, H.; Pandey, S. K.;

Pandey, R. K. Chem. Lett. 2005, 34, 1344–1345.

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of the six-membered imide ring does not significantly alter the

excited-state lifetime of the chlorin.³⁸

SCHEME 2

A chief attraction of chlorin-imides is the ability to

introduce diverse groups at the nitrogen of the imide ring.

In addition, the presence of the second carbonyl group (at the

15-position) further stabilizes the macrocycle toward routine

handling as evidenced by the variety of reported imidation

reactions and subsequent applications. Thus, the ready

availability of purpurin-18 from chlorophyll a, the bath-

ochromic shift and stability upon imide formation, and the

diverse imide N-substituents that can be introduced together

render such chlorin-imides quite attractive for a number of

applications.

On the other hand, the only methods for the synthesis have

relied on the modification of naturally occurring chloro-

phylls. The modification of the isocyclic ring usually entails

(1) base-promoted, oxidative ring-opening (allomerization)

to produce the corresponding diacid and (2) conversion of

the resulting diacid (or diester) to the anhydride or imide.

The chief limitation of this method stems not from the

transformation of the isocyclic ring itself, but rather the

constraints imposed by the nearly full complement of sub-

stituents at the β-pyrrolic positions of the naturally occurring

macrocycles. To our knowledge there are no reports con-

cerning the de novo synthesis of chlorin-imides.³⁹To fulfill

the potential of chlorin-imides in applications as diverse as

solar energy conversion, PDT, and fluorescence bioimaging

requires the ability to tailor the macrocycle at will without

constraints imposed by the substituents present in the parent

chlorophyll structure.

Here we report a de novo synthesis of chlorin-imides. The

synthetic route builds from the strategies we have developed

over the years for the de novo synthesis^40-42of chlorins and

their subsequent elaboration.^43-46The chlorins bear a gem-

inal dimethyl group in the pyrroline ring to stabilize the

macrocycle toward adventitious dehydrogenation. The new

synthetic route entails the Pd-mediated derivatization of

13-bromochlorins to introduce the methoxycarbonyl or

carbamoyl group, (2) regioselective 15-bromination of the

resulting 13-substituted chlorins, and (3) a one-flask Pd-

mediated carbonylation followed by ring closure. The result-

ing chlorin-imides bear 0 or 1 β-pyrrolic substituents and

hence constitute sparsely substituted analogues of the natur-

ally derived “purpurinimides” described above. This simple

route to tailorable chlorin-imides should allow systematic

studies of their fundamental spectroscopic and photochemi-

cal properties.

Results and Discussion

(38) Kuz’mitskii, V. A.; Knyukshto, V. N.; Gael, V. I.; Zen’kevich, E. I.;

Sagun, E. I.; Pukhlikova, N. A.; Lebedeva, V. S.; Mironov, A. F. J. Appl.

Spectrosc. 2003, 70, 43–53.

(39) Galezowski, M.; Gryko, D. T. Curr. Org. Chem. 2007, 11, 1310–

1338.

(40) Strachan, J.-P.; O’Shea, D. F.; Balasubramanian, T.; Lindsey, J. S.

J. Org. Chem. 2000, 65, 3160–3172.

(41) Taniguchi, M.; Ra, D.; Mo, G.; Balasubramanian, T.; Lindsey, J. S.

J. Org. Chem. 2001, 66, 7342–7354.

(42) Ptaszek, M.; McDowell, B. E.; Taniguchi, M.; Kim, H.-J.; Lindsey,

J. S. Tetrahedron 2007, 63, 3826–3839.

(43) (a) Laha, J. K.; Muthiah, C.; Taniguchi, M.; McDowell, B. E.;

Ptaszek, M.; Lindsey, J. S. J. Org. Chem. 2006, 71, 4092–4102. (b) Laha,

J. K.; Muthiah, C.; Taniguchi, M.; McDowell, B. E.; Ptaszek, M.; Lindsey,

J. S. J. Org. Chem. 2009, 74, 5122.

(44) Laha, J. K.; Muthiah, C.; Taniguchi, M.; Lindsey, J. S. J. Org. Chem.

2006, 71, 7049–7052.

(45) Taniguchi, M.; Ptaszek, M.; McDowell, B. E.; Lindsey, J. S. Tetra-

hedron 2007, 63, 3840–3849.

I. Retrosynthetic Analysis. A retrosynthetic approach to

chlorin-13,15-dicarboximides is outlined in Scheme 2. The

route to 3,13-disubstituted chlorins relies on the known

reaction of Western and Eastern halves.⁴²Very recently we

also developed a method for regioselective 15-bromination

of the chlorin.⁴⁶Thus, the key issues for extension of estab-

lished routes to the chlorin-imides concern the nature

and order of the carbonylative reactions at the 13- and

15-positions. In initial studies we intended to prepare the

chlorin bearing alkoxycarbonyl substituents at both the 13- and

15-positions of the macrocycle, and build the six-membered

imide ring from the corresponding diacid following saponifica-

tion of the ester groups. Eventually, we settled on a one-flask

Pd-catalyzed carbonylation of the 13-carbamoyl-15-bromo-

substituted chlorin to form the imide ring. The latter approach

(46) Muthiah, C.; Lahaye, D.; Taniguchi, M.; Ptaszek, M.; Lindsey, J. S.

J. Org. Chem. 2009, 74, 3237–3247.

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proved to be more efficient and afforded the expected product

in fewer steps.

SCHEME 3

II. Synthesis. A. Alkoxycarbonylation of Chlorins. One

starting chlorin contains the 18,18-dimethyl group, a 10-mesityl

group, and a 13-bromo group; this chlorin is denoted FbC-

M¹⁰Br¹³. A second chlorin contains in addition a 3-bromo

substituent and is denoted FbC-M¹⁰Br^3,13. Streamlined meth-

ods^42,47were applied to gain access to substantial quantities of

the known⁴⁶bromo-chlorin FbC-M¹⁰Br¹³(in 38% yield from

1.0 mmol of 1⁴⁸and 2⁴³) and the new dibromochlorin FbC-

M¹⁰Br^3,13(in 25% yield from 0.5 mmol of 1-Br⁴⁹and 2). The

starting 3-bromo- or 3,13-dibromo-substituted chlorin was

subjected to Pd-mediated carbonylation with use of CO

and Pd(PPh₃)₄in DMF/toluene followed by addition of

NaOMe to give the corresponding 3-methoxycarbonyl or

3,13-bis(methoxycarbonyl)chlorin (Scheme 3). In this manner,

chlorin-13-monoester FbC-M¹⁰Es¹³and chlorin-3,13-diester

FbC-M¹⁰Es^3,13were obtained in 66% and 83% yield, respec-

tively.

Prior studies of the regioselectivity of bromination of

chlorins showed an overlay of steric effects of substituents

at specific sites on the intrinsic electronic reactivity of the

chlorin.⁴⁶Thus, under neutral conditions, 13-unsubstituted

chlorins undergo bromination regioselectively at the 15-posi-

tion, whereas 10,13-substituted chlorins undergo bromina-

tion preferentially at the 7-position. On the other hand,

acidic conditions suppress reaction at the 7-position, and

the 10,13-substituted chlorin undergoes bromination regio-

selectively at the 15-position.⁴⁶Such studies were performed

with chlorins bearing 13-acetyl or 13-bromo substituents.

Here, treatment of 13-ester-substituted chlorins FbC-

M¹⁰Es¹³and FbC-M¹⁰Es^3,13with NBS in acidified CH₂Cl₂

also afforded regioselective 15-bromination to give FbC-

M¹⁰Es¹³Br¹⁵(78%) and FbC-M¹⁰Es^3,13Br¹⁵(72%) (Scheme 3).

One-flask palladium-catalyzed reactions that form cyclic

imides from the corresponding haloesters,^50-52dibromo

compounds,^53,54or even monoesters⁵⁵have been described.

Initially, we investigated this general approach to install the

six-membered imide ring. Thus, formation of the imide ring

was attempted by reaction of FbC-M¹⁰Es¹³Br¹⁵with CO and

benzylamine (or propylamine) under various conditions

[e.g., Pd(PPh₃)₄in toluene/DMF; Pd(OAc)₂/Xantphos/

Et₃N in toluene; Pd(OAc)₂/PPh₃/Cs₂CO₃in toluene]. This

approach proved to be fruitful in certain cases (see below).

Attempts at a one-flask installation of the imide ring on

dibromochlorin⁴⁶FbC-M¹⁰Br^13,15were unsuccessful (see the

Supporting Information). Accordingly, we pursued other

approaches for installing the imide ring on 3-unsubstituted

chlorins, as described in the next sections.

B. Chlorin-Diester and Chlorin-Anhydride Formation.

The chlorin-13,15-diester FbC-M¹⁰Es^13,15was sought as an

intermediate to introduce the imide unit. After investigation

of a number of conditions, we found that reaction of mono-

bromo/monoester chlorin FbC-M¹⁰Es¹³Br¹⁵with CO in

THF/MeOH containing Pd(PPh₃)₄and K₂CO₃afforded

the desired diester FbC-M¹⁰Es^13,15(Scheme 4). Efforts to

hydrolyze both methoxycarbonyl groups were unsuccessful;

however, one ester was hydrolyzed, and upon coupling with

a primary amine, yielded the corresponding chlorin-imide

(see the Supporting Information for exploratory studies and

data). Although the stepwise route to the chlorin-diester

FbC-M¹⁰Es^13,15did not provide a viable route to the chlorin-

imide, the chlorin-diester FbC-M¹⁰Es^13,15was quite attractive

for spectroscopic examination.

(47) Mass, O.; Ptaszek, M.; Taniguchi, M.; Diers, J. R.; Kee, H. L.;

Bocian, D. F.; Holten, D.; Lindsey, J. S. J. Org. Chem. 2009, 74, 5276–5289.

(48) Ptaszek, M.; Bhaumik, J.; Kim, H.-J.; Taniguchi, M.; Lindsey, J. S.

Org. Process Res. Dev. 2005, 9, 651–659.

ꢀ

The synthesis of chlorin-13,15-dicarboxylic anhydride

also was pursued. Thus, monoester chlorin FbC-Es¹³Br¹⁵

was subjected to carbonylation with CO in the presence of a

stoichiometric amount of Pd(PPh₃)₄in DMF/toluene. Sub-

sequent treatment of the resulting acylpalladium intermedi-

ate with aqueous NaOH afforded chlorin-anhydride FbC-

M¹⁰An in 21% yield (Scheme 4). Alternatively the chlorin-

anhydride FbC-M¹⁰An was obtained in 21% yield together

with a large amount of debrominated starting material

(49) Krayer, M.; Balasubramanian, T.; Ruzie, C.; Ptaszek, M.; Cramer,

D. L.; Taniguchi, M.; Lindsey, J. S. J. Porphyrins Phthalocyanines 2009, 13,

1098–1110.

(50) Martinelli, J. R.; Watson, D. A.; Freckmann, D. M. M.; Barder,

T. E.; Buchwald, S. L. J. Org. Chem. 2008, 73, 7102–7107.

(51) Worlikar, S. A.; Larock, R. C. J. Org. Chem. 2008, 73, 7175–7180.

(52) Begouin, A.; Queiroz, M.-J. R. P. Eur. J. Org. Chem. 2009, 2820–

2827.

(53) Perry, R. J.; Turner, S. R. J. Org. Chem. 1991, 56, 6573–6579.

(54) Takacs, A.; Acs, P.; Kollar, L. Tetrahedron 2008, 64, 983–987.

(55) Inoue, S.; Shiota, H.; Fukumoto, Y.; Chatani, N. J. Am. Chem. Soc.

2009, 131, 6898–6899.

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SCHEME 4

SCHEME 5

(66%) with use of CO, a stoichiometric amount of Pd(PPh₃-

)₄, Cs₂CO₃, and H₂O (2 equiv) in THF. The chlorin-

anhydride FbC-M¹⁰An provides a valuable benchmark for

spectroscopic comparison with the previously described anhy-

dride (i.e., purpurin-18) derived from chlorophyll a. However,

with the goal of forming the corresponding chlorin-imides, we

sought a more direct approach for installing the imide ring.

Thus, we turned to the corresponding 13-carbamoyl-substi-

tuted chlorins rather than 13-ester substituents.

was a significant drawback; therefore, we explored different

conditions for the carbamoylation process.

C. Carbamoylation of Chlorins. The starting 3-bromo- or

3,13-dibromo-substituted chlorin also was subjected to Pd-

mediated reaction in the presence of CO and a primary amine

to introduce the carbamoyl unit. Recently, we employed

analogous palladium-catalyzed carbamoylation to tailor

the perimeter of synthetic bacteriochlorins.⁵⁶This method

requires a stoichiometric amount of palladium. Upon appli-

cation to the chlorins here, satisfactory results were obtained

in some cases, but in other cases double carbonylation

(yielding an oxalamide moiety) as well as multiple products

were observed. For example, treatment of the 13-bromo-

chlorin FbC-M¹⁰Br¹³to the Pd-mediated carbonylation

conditions in the absence of an amine followed by propyl-

amine afforded the double-carbonylated, oxalamide-substi-

tuted chlorin FbC-M¹⁰(COCmPr)¹³in 38% yield (eq 1).

While this result illustrates the richness of this chemistry,

the requirement for a stoichiometric amount of palladium

Numerous conditions and catalytic systems have been

reported for Pd-catalyzed alkoxycarbonylation or carba-

moylation,^50-55,57-59although few are applicable for a low

(atmospheric) pressure of CO. In addition, Pd-mediated cou-

pling reactions with tetrapyrrole macrocycles typically are carried

out in quite dilute solution.^60,61We found modified Buchwald

(57) Mori, M. In Handbook of Organopalladium Chemistry for Organic

Synthesis; Negishi, E., Ed.; Wiley-Interscience; New York, 2002; pp 2313-2332.

(58) Barnard, C. F. J. Organometallics 2008, 27, 5402–5422.

€

(59) Brennfuhrer, A.; Neumann, H.; Beller, M. Angew. Chem., Int. Ed.

2009, 48, 4114–4133.

(60) Wagner, R. W.; Johnson, T. E.; Li, F.; Lindsey, J. S. J. Org. Chem.

1995, 60, 5266–5273.

ꢀ

(56) Ruzie, C.; Krayer, M.; Balasubramanian, T.; Lindsey, J. S. J. Org.

Chem. 2008, 73, 5806–5820.

(61) Wagner, R. W.; Ciringh, Y.; Clausen, C.; Lindsey, J. S. Chem. Mater.

1999, 11, 2974–2983.

J. Org. Chem. Vol. 75, No. 5, 2010 1663

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TABLE 1. Carbonylation-Intramolecular Amidation To Give Chlorin-Imides and/or Chlorin-Isoimides

reaction products (% yield)

chlorin-isoimide

reaction

conditions^a

entry

starting material

chlorin-imide

other

c

b

-

1

2

3

4

5

6

FbC-M¹⁰(CmBn)¹³Br¹⁵(R³= H, R = Bn)

FbC-M¹⁰(CmPh)¹³Br¹⁵(R³= H, R = Ph)

FbC-M¹⁰(CmBn)^3,13Br¹⁵(R³= CONHBn, R = Bn)

FbC-M¹⁰(CmPh)^3,13Br¹⁵(R³= CONHPh, R = Ph)

A

B

C

B

FbC-M¹⁰I-Bn 50%

FbC-M¹⁰I-Bn Trace

FbC-M¹⁰I-Ph Trace

FbC-M¹⁰I-Ph 45%

-

FbC-M¹⁰Iso-Bn 55%

FbC-M¹⁰Iso-Ph 59%

-

b

-

b

-

d

-

FbC-(CmBn)³M¹⁰I-Bn 32% FbC-(CmBn)³M¹⁰Iso-Bn 26%

b

-

b

FbC-(CmPh)³M¹⁰I-Ph 72%

^aReaction conditions: (A) Pd(PPh₃)₄(1 equiv), CO, toluene/DMF (1:1), no base. (B) Pd(PPh₃)₄(1 equiv), CO, toluene, Cs₂CO₃(3 equiv). (C) Pd-

(PPh₃)₄(20 mol %), CO, toluene, Cs₂CO₃(3 equiv). ^bNot observed. ^cDebrominated starting material (FbC-M¹⁰(CmBn)¹³) was observed in 50% yield.

^dTraces of unreacted starting material and debrominated starting material (FbC-M¹⁰(CmPh)¹³) also were observed.

conditions⁵⁰[CO balloon pressure, Pd(OAc)₂(15-30 mol %),

Xantphos (15-30 mol %), Et₃N or Cs₂CO₃(3-6 mol equiv),

and 2-4 equiv of amine in toluene] to be successful. Thus, the

reaction of FbC-M¹⁰Br¹³or FbC-M¹⁰Br^3,13with benzylamine

gave the corresponding 3-N-benzylcarbamoylchlorin FbC-

M¹⁰(CmBn)¹³or 3,13-bis(N-benzylcarbamoyl)chlorin FbC-

M¹⁰(CmBn)^3,13in 84% or 58% yield, respectively (Scheme 5).

Similarly, the reaction of FbC-M¹⁰Br¹³with aniline gave FbC-

M¹⁰(CmPh)¹³in 64% yield. The reaction of FbC-M¹⁰Br^3,13

with aniline under similar conditions resulted in a low yield

(25%), whereas the reaction in toluene/DMF (1:1) gave FbC-

M¹⁰(CmPh)^3,13in 44% yield. In each case, examination of the

reaction course (TLC and UV-vis) revealed the formation and

subsequent disappearance of unknown intermediates, and the

reaction mixture typically contained a small amount of uni-

dentified byproducts. Regardless, the target chlorins were

obtained in reasonable yield and in satisfactory purity.

The four 13-carbamoylchlorins were subjected to bromi-

nation under acidic conditions,⁴⁶which suppress bromination

in ring B (i.e., the 7- and 8-positions) and thereby direct

bromination to the 15-position (Scheme 5). Thus, treatment

of the chlorin with 1 equiv of NBS in CH₂Cl₂/TFA solution

afforded the corresponding 15-bromochlorin in satisfactory

yield, together with a small amount of dibromo or monobromo

side products. In each case the product was purified upon

column chromatography.

D. Ring Closure. The four chlorins bearing 13-carbamoyl

and 15-bromo substituents were subjected to a Pd-mediated

domino carbonylation-intramolecular amidation reaction.

Thus, the reaction of FbC-M¹⁰(CmBn)¹³Br¹⁵with CO in the

presence of a stoichiometric amount of Pd(PPh₃)₄in DMF/

toluene (1:1) afforded chlorin-imide FbC-M¹⁰I-Bn in

50% yield, together with the corresponding debromi-

nated starting material FbC-M¹⁰(CmBn)¹³also in 50% yield

(Table 1, entry 1). However, the same reaction of FbC-M¹⁰-

(CmBn)¹³Br¹⁵in toluene alone but with Cs₂CO₃afforded the

chlorin-isoimide FbC-M¹⁰Iso-Bn as the major product with

only trace amounts of the desired chlorin-imide FbC-M¹⁰I-

Bn (entry 2). Similarly, treatment of FbC-M¹⁰(CmPh)¹³Br¹⁵

with CO in the presence of a stoichiometric amount of

Pd(PPh₃)₄in toluene afforded chlorin-isoimide FbC-

M¹⁰Iso-Ph in 59% yield (entry 3), together with a trace

amount of the desired chlorin-imide FbC-M¹⁰I-Ph. In con-

trast, use of a catalytic amount of Pd(PPh₃)₄afforded

chiefly the desired chlorin-imide without observable

amounts of the chlorin-isoimide (entry 4). The reaction of

3,13-bis(carbamoyl)chlorin FbC-M¹⁰(CmBn)^3,13Br¹⁵in the

presence of a stoichiometric amount of Pd(PPh₃)₄in toluene

afforded both the desired chlorin-imide (32%) and the

chorin-isoimide (26%) (entry 5). However, the same con-

ditions applied to 3,13-bis(carbamoyl)chlorin FbC-M¹⁰-

(CmPh)^3,13Br¹⁵afforded the chlorin-imide as the only ob-

servable product in 72% yield (entry 6). Finally, we note that

in some cases, particularly with stoichiometric amounts of

the palladium reagent, the crude reaction mixture showed

trace amounts of palladium chelated chlorin (upon LD-MS

analysis), which could be separated from the free base

chlorins by column chromatography and was not further

analyzed.

In summary, the Pd-mediated carbonylative ring closure

tends to afford a mixture of the chlorin-imide and chlor-

in-isoimide in unpredictable ratio. While methods for the

conversion of isoimides into imides are known,^21,33,62most

employ strong base, which we sought to avoid. One attempt

to convert the chlorin-isoimide FbC-(CmBn)³M¹⁰Iso-Bn

into the corresponding chlorin-imide FbC-(CmBn)³-

M¹⁰I-Bn via C-N rearrrangement upon refluxing in tolu-

ene did not result in any noticeable isomerization. The

formation of the 6-membered isoimide ring apparently stems

from nucleophilic attack of the carbonyl oxygen on the

intermediate acyl-palladium species. Such transformations

(62) Kozyrev, A. N.; Zheng, G.; Zhu, C.; Dougherty, T. J.; Smith, K. M.;

Pandey, R. K. Tetrahedron Lett. 1996, 37, 6431–6434.

1664 J. Org. Chem. Vol. 75, No. 5, 2010

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are precedented in palladium-catalyzed reactions as well as

in reaction of carboxylic acid derivatives of chlorophylls with

amines.²¹Key spectral features for distinguishing the iso-

mers are described below.

SCHEME 6

E. Chlorin-Imide with a Distinct 3-Substituent. The afore-

mentioned methods afford the chlorin-imide lacking a

3-substituent or bearing a 3-carbamoyl substituent. In the

latter case, the 3-carbamoyl substituent is identical with that

initially employed at the 13-position to construct the imide

ring. Here we sought to prepare a chlorin-imide bearing a

different auxochrome at the 3-position, namely a 3-methoxy-

carbonyl group. Thus, the 3,13-bis(methoxycarbonyl)chlorin

bearing a 15-bromo group (FbC-M¹⁰Es^3,13Br¹⁵) was subjected

to Pd-mediated carbamoylation with benzylamine in THF

containing Pd(PPh₃)₄and Cs₂CO₃. Under these conditions

the corresponding chlorin-imide FbC-Es³M¹⁰I-Bn was ob-

tained in 57% yield (Scheme 6). Attempted imide formation

with benzylamine with use of Pd(OAc)₂, 1,3-bis(diphenyl-

phosphino)propane, and Cs₂CO₃in toluene (or Pd(PPh₃)₄

and Et₃N in DMF/toluene) resulted mainly in the corres-

ponding debrominated starting material (FbC-M¹⁰Es^3,13). No

chlorin-isoimide was observed.

III. Characterization. The new chlorin-anhydride, chlorin-

imides, and chlorin-isoimides were characterized by ¹H NMR

(and in some cases ¹³C NMR and 2D NOESY) spectroscopy,

mass spectrometry (ESI-MS and/or LD-MS), and UV-vis

absorption and emission spectroscopy. To obtain absolute

proof of the putative chlorin-imide and chlorin-isoimide

structures, a number of samples (including free base and zinc

chelates) were examined under different conditions to obtain

suitable crystals for X-ray analysis. X-ray crystal structures

were obtained for the free base chlorin-isoimides FbC-M¹⁰Iso-

Bn and FbC-M¹⁰Iso-Ph, and the zinc chelate chlorin-imide

ZnC-M¹⁰I-Ph [obtained by the reaction of FbC-M¹⁰I-Ph with

Zn(OAc)₂]. In each case the X-ray data confirmed the proposed

structures for the chlorin-imide and chlorin-isoimides (see

the Supporting Information). The X-ray crystal structure of

FbC-M¹⁰Iso-Bn revealed Z stereochemistry of the isoimide

moiety, as has been reported for other (nonchlorin) isoimides.⁶³

We are not aware of prior single-crystal X-ray data to establish

the structure of chlorin-imides versus chlorin-isoimides.

While X-ray characterization was unambiguous, a more acces-

sible method for distinguishing the isomers was sought, as

described in the next section.

quite complex and there were no sharp distinctions in the IR

spectra of the two compounds (see spectra in the Supporting

Information).

The chlorin-imide and chlorin-isoimide isomeric pairs

exhibited quite similar ¹H NMR spectra; however, one key

distinction was evident in each pair examined: the chemical

shifts of the two pyrrolic N-H protons for the chlor-

in-imide resonate further downfield (δ 0.58 to 0.08 ppm)

compared to those of the corresponding chlorin-isoimide

(0.07 to -0.41 ppm). In other words, the chemical shift of the

pyrrolic N-H protons for the chlorin-imides is not shifted

upfield to the extent typical of chlorins. Typically, the

pyrrolic N-H chemical shifts for synthetic chlorins without

an exocyclic ring range from -2.0 to -1.0 ppm with a sepa-

ration (Δδ) of the two resonances for the distinct N-H

protons (for all chlorins where substituents give rise to C_s

symmetry) ranging from 0 to 0.4 ppm. For comparison,

the chemical shifts for the two pyrrolic NH protons of the

13¹-oxophorbine FbOP-M¹⁰(a synthetic chlorin containing

a 5-membered isocyclic ring spanning positions 13 and 15,

vide infra)⁴⁶are quite far apart (-1.41 and 1.13 ppm; Δδ =

2.54 ppm). The results demonstrate the effect of a given

exocyclic ring spanning positions 13 and 15 on the ring

current of the chlorin macrocycle. The chemical shifts and

differences in chemical shifts for the pyrrolic NH protons of

the chlorin-imides, chlorin-isoimides, nonbrominated pre-

cursors and the previously reported 13¹-oxophorbine FbOP-

M¹⁰are listed in Table 2.

A. Chlorin-Imide versus Chlorin-Isoimide. Three pairs of

isomers (chlorin-imide and chlorin-isoimide) were exam-

ined to identify simple means of spectroscopic distinction

(Chart 1). The UV-vis absorption spectra of the three pairs

of isomers are shown in Figure 1. The long wavelength

Q_yabsorption band of the chlorin-imides (blue) and the

chlorin-isoimides (magenta) varies only slightly for a given

pair of isomers. However, the ratio of the peak intensity of

the Q_yand the B band maximum (I_Q/I_B) is greater for the

y

chlorin-isoimides (0.61-0.68) versus that of the chlorin-

imides (0.43-0.56). Such a distinction, while apparently

consistent, is insufficient for reliable structural identifica-

tion. Attempts to differentiate between the chlorin-imide

FbC-M¹⁰I-Bn and the chlorin-isoimide FbC-M¹⁰Iso-Bn by

using IR spectroscopy were inconclusive, as the spectra were

A literature search did not provide any precedence for such a

direct comparison of chlorin-imide and chlorin-isoimide iso-

mers. However, a similar downfield shift of the resonance

of the N-H protons was reported for a bacteriochlorin-imide

versus that of the bacteriochlorin-isoimide,³³as well as for a

(63) Corrie, J. E. T.; Moore, M. H.; Wilson, G. D. J. Chem. Soc., Perkin

Trans. 1 1996, 777–781.

J. Org. Chem. Vol. 75, No. 5, 2010 1665

Ptaszek et al.

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CHART 1. Chlorin-Imide and Chlorin-Isoimide Isomeric

Pairs

porphyrin-imide versus that of the corresponding porphyr-

in-isoimide.⁶⁴(¹H NMR spectroscopy has also been used to

assign the structures of two bacteriochlorin-isoimide

isomers.³³) In general, naturally derived chlorin-imides have

been reported to show chemical shifts for the two N-H protons

in the range of -0.69 to 1.04 ppm.^{12,15-17,21-23,25,26}For the

most part, the Δδof the resonances for the two N-H protons in

a given chlorin-imide was <∼0.2 ppm (and in some cases only

a single peak was noted^{15,17,21,22,25,26}).

In summary, the most accessible operational means of

distinguishing chlorin-imide and chlorin-isoimide isomers

appears to be the difference in chemical shifts of the reso-

nances due to the pyrrolic NH protons. In the case of the

N-benzyl isomers, the chemical shift of the benzylic -CH₂-

protons provides a further distinction: the resonance occurs

at ∼5.6 ppm for the chlorin-imides FbC-M¹⁰I-Bn and

FbC-(CmBn)³M¹⁰I-Bn versus ∼5.2 ppm for the correspond-

ing chlorin-isoimides FbC-M¹⁰Iso-Bn and FbC-(CmBn)³-

M¹⁰Iso-Bn. On the other hand, other regions of the ¹H NMR

spectra, as well as the ¹³C NMR spectra vary only slightly

and inconsistently for the corresponding pairs of isomers,

and thus do not provide diagnostic tools for their distinction.

FIGURE 1. Absorption spectral features of chlorin-imides versus

chlorin-isoimides (in toluene at room temperature, normalized at

the B bands): (A) FbC-M¹⁰I-Bn (blue), FbC-M¹⁰Iso-Bn (magenta);

(B) FbC-M¹⁰I-Ph (blue), FbC-M¹⁰Iso-Ph (magenta); and (C) FbC-

(CmBn)³M¹⁰I-Bn (blue), FbC-(CmBn)³M¹⁰Iso-Bn (magenta).

B. Absorption Spectral Properties. The chlorin-imides

exhibit many absorption spectral features typical of chlorins,

with strong absorption in the blue region (B band) and a mode-

rately strong long-wavelength absorption band (Q_yband) in the

red region. The long-wavelength absorption band is relatively

sharp with a full-width-at-half-maximum (fwhm) of 15-18 nm.

The emission spectra of this class of compounds mirror the

long-wavelength absorption band, with a narrow Q_y(0,0) band

(fwhm17-18 nm) and a comparatively weak Q_y(0,1) transition.

The Stokes shifts range from 5 to 8 nm (see spectra in the

(64) Kozyrev, A. N.; Zheng, G.; Lazarou, E.; Dougherty, T. J.; Smith,

K. M.; Pandey, R. K. Tetrahedron Lett. 1997, 38, 3335–3338.

1666 J. Org. Chem. Vol. 75, No. 5, 2010

Ptaszek et al.

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TABLE 2. Comparison of Pyrrolic NH ¹H NMR Chemical Shifts of

Chlorin Derivatives^a

TABLE 3. Absorption and Emission Spectral Properties of Chlorins

with 3- and/or 13-Substituents^a

compd

pyrrolic ΝH δ (ppm)

Δδ (ppm)

compd

λ

_{Q (0,0)}(fwhm)/nm I_Q/I_B

λ_em(fwhm)/nm

y

FbC-M¹⁰A¹³

659 (12)

653 (11)

652 (13)

654 (14)

671 (19)

687 (16)

677 (14)

669 (18)

673 (21)

0.50

0.51

0.46

0.48

0.61

0.76

0.77

0.55

0.59

662 (13)

656 (12)

656 (13)

658 (15)

677 (19)

693 (17)

681 (14)

675 (17)

681 (16)

FbC-M¹⁰Es¹³

chlorin precursors

FbC-M¹⁰(CmBn)¹³

FbC-M¹⁰(CmPh)¹³

FbC-M¹⁰(CmBn)^3,13

FbC-M¹⁰(CmPh)^3,13

-1.74, -1.44

-1.67, -1.35

-1.42

0.30

0.32

0

FbC-M¹⁰(CmBn)¹³

FbC-M¹⁰(CmPh)¹³

FbC-M¹⁰(COCmPr)¹³

FbC-M¹⁰A^3,13

-1.48

0

FbC-M¹⁰Es^3,13

chlorin-imides

0.08, 0.43

0.15, 0.58

FbC-M¹⁰(CmBn)^3,13

FbC-M¹⁰I-Bn

0.35

0.43

0.20

0.23

FbC-M¹⁰(CmPh)^3,13

FbC-M¹⁰I-Ph

^aIn toluene at room temperature.

FbC-(CmBn)³M¹⁰I-Bn

FbC-(CmBn)³M¹⁰I-Ph

0.09, 0.29

0.19, 0.42

that of the 13-unsubstituted chlorin FbC-M¹⁰(λ_Qy

=

chlorin-isoimides

-0.55, -0.12

-0.41, 0.07

FbC-M¹⁰Iso-Bn

0.43

0.48

0.26

637 nm).⁶⁷The bathochromic shift increases in the series

carbamide < ester < ketone < oxalamide (Figure 2A). The

bathochromic shift is accompanied by a relative increase of the

FbC-M¹⁰Iso-Ph

FbC-(CmBn)³M¹⁰Iso-Bn

-0.41, -0.15

13¹-oxophorbine

-1.41, 1.13

^aAll spectra were obtained in CDCl₃.

peak intensity of the Q_yversus B band ratio (I_Q/I_B). (2)

Substitution at the 3-position causes an increase in the I_Q/I_B

y

FbOP-M¹⁰

2.54

y

ratio for the same substituents. (3) The installation of substi-

tuents at the 3-position causes an additional bathochromic shift

of 390, 542, or 618 cm^-1for the carbamide, ester, or ketone,

respectively. (4) The magnitude of the bathochromic shift

reflects the electron-withdrawing ability of the group attached

to the carbonyl moiety in substituents at the 13-position

(amino < alkoxy < alkyl < carbamide).

Supporting Information). The sharp absorption band renders

these compounds well suited for use in energy-transfer cas-

cades,⁶⁵where a series of chromophores with distinct energy

levels can be constructed, or polychromatic flow cytometry,⁶⁶

where a palette of spectrally distinct absorbers/emitters is de-

sired. A key requirement for such applications is the ability to

tune the position of the long-wavelength absorption band in a

systematic manner. Here we first consider the spectral effects

caused by placement of various carbonyl substituents at the 3-

and/or 13-positions of the chlorin, and then consider the spectra

of chlorins bearing various exocyclic rings. The 13-acetylchlor-

in⁴⁶FbC-M¹⁰A¹³, 3,13-diacetylchlorin⁶⁷FbC-M¹⁰A^3,13, and 13¹-

oxophorbine⁴⁶FbOP-M¹⁰are included for comparison.

The introduction of an ester substituent at the 15-position

(FbC-M¹⁰Es^13,15) has a negligible effect (bathochromic shift

of only 70 cm^-1) on the position of the Q_yband versus the

corresponding 15-unsubstituted chlorin FbC-M¹⁰Es¹³, but

does significantly diminish the relative intensity of the Q_y

band (Figure 2B). On the other hand, ring closure to give the

chlorin-anhydride FbC-M¹⁰An causes a significant bath-

ochromic shift (538 cm^-1) versus the corresponding chlor-

in-diester FbC-M¹⁰Es^13,15. This observation illustrates the

effect of the spatial arrangement and electron-withdrawing

features of the carbonyl groups at the 13- and 15-positions in

determining the spectroscopic properties of the chlorin.

2. Nature of the Exocyclic Ring. The availability of the

chlorin-anhydride, chlorin-imides, and chlorin-isoimides

enables a systematic comparison of the effects of various

exocyclic rings on the position of the long-wavelength ab-

sorption band. The spectral properties of FbC-M¹⁰An and

three pairs of chlorin-imides and chlorin-isoimides are

listed in Table 4 (see the Supporting Information for spectra).

A set of compounds with common substituents (10-mesityl and

a geminal dimethyl group in the pyrroline ring) but with various

exocyclic rings includes the oxophorbine (656 nm), chlorin-

anhydride (680 nm), N-phenyl chlorin-imide (685 nm), and

N-phenyl chlorin-isoimide (687 nm). Thus, the presence of the

imide or isoimide ring causes a substantial bathochromic shift

versus that of the oxophorbine. It is noteworthy that N-hydroxy

chlorin-imides (derivatives of chlorophylls) have been reported

to give a further ∼9-nm bathochromic shift versus the N-H

analogue.⁶⁸

1. Effects of Carbonyl Substituents. The spectral properties

of the 13- and 3,13-substituted chlorins are listed in Table 3.

Several comparisons concerning the effects of various carbonyl

substituents at the 13- or 3,13-positions of the chlorins are as

follows: (1) The introduction of a carbonyl substituent at the

13-position results in a bathochromic shift of the Q_yband versus

(65) (a) Kee, H. L.; Nothdurft, R.; Muthiah, C.; Diers, J. R.; Fan, D.;

Ptaszek, M.; Bocian, D. F.; Lindsey, J. S.; Culver, J. P.; Holten, D.

Photochem. Photobiol. 2008, 84, 1061–1072. (b) Kee, H. L.; Diers, J. R.;

Ptaszek, M.; Muthiah, C.; Fan, D.; Lindsey, J. S.; Bocian, D. F.; Holten, D.

Photochem. Photobiol. 2009, 85, 909–920.

3. Outlook. The position of the long-wavelength absorp-

tion band of a photochemically active species is of utmost

importance, defining not only a spectral region where ab-

sorption occurs but also the energy level of the initially

(66) De Rosa, S. C.; Brenchley, J. M.; Roederer, M. Nature Med. 2003, 9,

112–117.

(67) Kee, H. L.; Kirmaier, C.; Tang, Q.; Diers, J. R.; Muthiah, C.;

Taniguchi, M.; Laha, J. K.; Ptaszek, M.; Lindsey, J. S.; Bocian, D. F.;

Holten, D. Photochem. Photobiol. 2007, 83, 1110–1124.

(68) Mezentseva, A. A.; Burlyaeva, E. V.; Mironov, A. F. Russ. J. Phys.

Chem. B 2008, 2, 525–530.

J. Org. Chem. Vol. 75, No. 5, 2010 1667

Ptaszek et al.

JOCArticle

TABLE 4. Absorption and Emission Spectral Properties of Chlorins

Bearing Various Exocyclic Rings^a

compd

λ

_{Q (0,0)}(fwhm)/nm I_Q/I_B

λ_em(fwhm)/nm

y

FbOP-M¹⁰

656 (11)

679 (13)

680 (15)

685 (14)

686 (15)

687 (17)

699 (18)

708 (19)

709 (19)

715 (17)

0.63

0.61

0.49

0.44

0.43

0.65

0.67

0.56

0.60

0.69

660 (12)

683 (15)

685 (17)

690 (17)

691 (16)

693 (17)

705 (17)

713 (19)

716 (19)

720 (18)

FbC-M¹⁰Iso-Bn

FbC-M¹⁰An

FbC-M¹⁰I-Ph

FbC-M¹⁰I-Bn

FbC-M¹⁰Iso-Ph

FbC-(CmBn)³M¹⁰Iso-Bn

FbC-(CmBn)³M¹⁰I-Bn

FbC-(CmPh)³M¹⁰I-Ph

FbC-Es³M¹⁰I-Bn

^aIn toluene at room temperature.

has not yet revealed design strategies for pushing the Q_y

absorption band into the near-infrared region.

On the other hand, the position of the long-wavelength

absorption band in synthetic bacteriochlorins ranges from

717 nm for the bacteriochlorin FbBC lacking any β-pyrrolic

or meso substituents⁷⁴to 785-792 nm for 3,13-bis(chalcone)-

substituted bacteriochlorin analogues thereof.⁷³As with

chlorins, the presence of a variety of auxochromes at the

β-pyrrolic (2,3,12,13) or 5,15 (meso) positions enables tuning of

the Q_yband with few-nanometer precision within this spectral

region.^56,73-77Recently, the introduction of methoxy substitu-

ents at the 5- and 15-positions (FbBC-OMe^5,15) was found to

cause a hypsochromic shift of the Q_yband, giving absorption at

707 nm.⁷⁸

FIGURE 2. Absorption spectra of chlorins (in toluene at room

temperature, normalized at the B bands). (A) Comparison of 3- and

3,13-substituted chlorins: FbC-M¹⁰(CmBn)¹³(black, a), FbC-M¹⁰

-

Es¹³(magenta, b), FbC-M¹⁰(CmBn)^3,13(blue, c), FbC-M¹⁰(CO-

CmPr)¹³(orange, d), and FbC-M¹⁰Es^13,15(green, e). (B) Comparison

of carbonyl-substituted chlorins: monoester-chlorin FbC-M¹⁰Es¹³

(blue, a), diester-chlorin FbC-M¹⁰Es^13,15(magenta, b), and chlorin-

anhydride FbC-M¹⁰An (green, c).

formed excited state. In this regard, the chlorin-imides and

chlorin-isoimides fill a crucial window in the far-red/near-

infrared spectral region. Prior studies with synthetic chlorins

have shown that the position of the long-wavelength

Q_yabsorption band could be shifted from 603 nm (for the

zinc complex of the chlorin lacking any β-pyrrolic or meso

substituents)⁴²to 687 nm (for FbC-M¹⁰A^3,13).⁶⁷By varying

the number and position of substituents at the perimeter of

the synthetic chlorins, the absorption spectral properties

could be tuned within that spectral region with few-nan-

ometer precision.^{43,47,67,69-73}Although the presence of the

Thus, the present spectral region that is accessible via de

novo synthesized bacteriochlorins is 707-792 nm. The spec-

tral region left untouched by prior chlorins or bacteriochlo-

rins (687-707 nm) is nicely matched by the chlorin-(iso)-

imides, which absorb strongly in the region 686-715 nm.

Thus, the chlorin-(iso)imides fill a spectral window that lies

between that of simple chlorins and bacteriochlorins (Figure 3).

In this regard, a series of synthetic tetrapyrrole pigments is

now available that affords tunable absorption spanning the red

and near-infrared region from 600 to 800 nm.

isocyclic ring (e.g., FbOP-M¹⁰, λ_{Q (0,0)}=656 nm) afforded a

y

substantial bathochromic shift relative to that of the unsub-

stituted chlorin,⁴⁶investigation of a wide variety of substituents

Experimental Section

I. Streamlined Synthesis of 13-Bromo-17,18-dihydro-10-mesi-

tyl-18,18-dimethylporphyrin (FbC-M¹⁰Br¹³). A mixture of 2,3,

4,5-tetrahydro-1,3,3-trimethyldipyrrin (1, 0.19 g, 1.0 mmol) and

(69) Taniguchi, M.; Kim, H.-J.; Ra, D.; Schwartz, J. K.; Kirmaier, C.;

Hindin, E.; Diers, J. R.; Prathapan, S.; Bocian, D. F.; Holten, D.; Lindsey,

J. S. J. Org. Chem. 2002, 67, 7329–7342.

(70) Taniguchi, M.; Ptaszek, M.; McDowell, B. E.; Boyle, P. D.; Lindsey,

J. S. Tetrahedron 2007, 63, 3850–3863.

(71) Kee, H. L.; Kirmaier, C.; Tang, Q.; Diers, J. R.; Muthiah, C.;

Taniguchi, M.; Laha, J. K.; Ptaszek, M.; Lindsey, J. S.; Bocian, D. F.;

Holten, D. Photochem. Photobiol. 2007, 83, 1125–1143.

(74) Taniguchi, M.; Cramer, D. L.; Bhise, A. D.; Kee, H. L.; Bocian,

D. F.; Holten, D.; Lindsey, J. S. New J. Chem. 2008, 32, 947–958.

(75) Kim, H.-J.; Lindsey, J. S. J. Org. Chem. 2005, 70, 5475–5486.

(76) Fan, D.; Taniguchi, M.; Lindsey, J. S. J. Org. Chem. 2007, 72, 5350–

5357.

ꢀ

(77) Borbas, K. E.; Ruzie, C.; Lindsey, J. S. Org. Lett. 2008, 10, 1931–

(72) Muthiah, C.; Ptaszek, M.; Nguyen, T. M.; Flack, K. M.; Lindsey,

J. S. J. Org. Chem. 2007, 72, 7736–7749.

ꢀ

(73) Ruzie, C.; Krayer, M.; Lindsey, J. S. Org. Lett. 2009, 11, 1761–1764.

1934.

(78) Krayer, M.; Ptaszek, M.; Kim, H.-J.; Meneely, K. R.; Fan, D.; Secor,

K.; Lindsey, J. S. J. Org. Chem. 2010, 75, DOI: 10.1021/jo9025572.

1668 J. Org. Chem. Vol. 75, No. 5, 2010

Ptaszek et al.

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4.63 (s, 2H), 7.25 (s, 2H), 8.41 (d, J=4.4 Hz, 1H), 8.63 (s, 1H), 8.75

(s, 1H), 8.90 (d, J=4.4 Hz, 1H), 8.94 (s, 1H), 9.08 (s, 1H), 9.83 (s,

1H); LD-MS obsd 614.0; FAB-MS obsd 615.0759, calcd 615.0753

[(Mþ H)^þ, M=C₃₁H₂₈Br₂N₂]; λ_abs399, 413, 504, 651 nm.

II. General Procedure for the Palladium-Catalyzed Carbonyl-

ation. Unless noted otherwise, all palladium-catalyzed carbonyl-

ation reactions were carried out following the general procedure

described below. The solid materials were placed in a Schlenk

flask, and the flask was capped with a septum. The flask was

evacuated, purged with argon (3 times), and subsequently

evacuated and purged with carbon monoxide (3 times). The

solvent was purged with argon (∼30 min) and subsequently

with carbon monoxide (∼30 min). The required amount of

solvent was then transferred via syringe to the reaction flask,

following by any required liquid reagents. The reaction flask

was placed in a preheated oil bath. For the reactions of

duration less than ∼2 h, a slow flow of carbon monoxide

was maintained by a long needle (the end of which was placed

∼2-3 mm above the solvent level) and a vented needle was also

provided. For reactions of longer duration, a balloon of

carbon monoxide was attached in a similar manner but without

a vented needle.

FIGURE 3. Comparison of Q_yregion absorption bands of chlo-

rins, chlorin-(iso)imides, and bacteriochlorins. The chlorin-(iso)-

imides fill a spectral window defined by chlorins and bacteriochlorins.

The colors and labels are as follows: chlorin-anhydride FbC-M¹⁰An

(orange, a); chlorin-(iso)imides FbC-M¹⁰I-Bn (magenta, b), FbC-

(CmBn)³M¹⁰Iso-Bn (black, c), FbC-(CmBn)³M¹⁰I-Bn (blue, d), and

FbC-Es³M¹⁰I-Bn (green, e). Spectra are in toluene at room tempe-

rature.

The workup procedure and purification entailed chromato-

graphy. In some cases the crude reaction mixture showed trace

amounts of palladium-chelated chlorin (upon LD-MS analysis),

which could be separated from the free base chlorin target

compound as a fast-running component upon chromatography.

In each case where a chlorin-imide and chlorin-isoimide were

observed, the former eluted prior to the latter.

Caution: Carbon monoxide is toxic. All handling of carbon

monoxide should be carried out in a well-vented fume hood. Use

of carbon monoxide sensors in the laboratory workspace is

advised.

8,9-dibromo-1-formyl-5-mesityldipyrromethane (2, 0.42 g, 0.93

mmol) in CH₂Cl₂(30 mL) was treated with a solution of

TsOH H₂O (0.95 g, 5.0 mmol) in MeOH (10 mL). The resulting

3

mixture was stirred at room temperature for 30 min. A sample of

2,2,6,6-tetramethylpiperidine (5.0 mL, 29 mmol) was added, and

the reaction mixture was concentrated. The resulting yellow-red

solid was suspended in CH₃CN (100 mL), to which samples of

2,2,6,6-tetramethylpiperidine (5.1 mL, 30 mmol), anhydrous Zn-

(OAc)₂(2.75 g, 15.0 mmol), and AgOTf (0.771 g, 3.00 mmol) were

added. The resulting mixture was refluxed for 18 h exposed to air,

and then concentrated and filtered through silica (CH₂Cl₂). Frac-

tions containing chlorin were collected and concentrated. The

resulting blue-green solid was dissolved in CH₂Cl₂(10 mL), treated

with TFA (0.875 mL, 11.4 mmol), and stirred for 4 h. The reaction

mixture was treated with saturated aqueous NaHCO₃and stirred

vigorously for 5 min. The organic phase was separated, washed

(water and brine), dried (Na₂SO₄), and concentrated. Column

chromatography [silica, hexanes/CH₂Cl₂(2:1)] afforded a green

solid (0.19 g, 38%). The characterization data (¹H NMR, absorp-

tion, LD-MS, FAB-MS) were consistent with those reported

previously.⁴⁶

17,18-Dihydro-10-mesityl-13-methoxycarbonyl-18,18-dimethyl-

porphyrin (FbC-M¹⁰Es¹³). Samples of FbC-M¹⁰Br¹³(41.0 mg,

0.0763 mmol) and Pd(PPh₃)₄(88.1 mg, 0.0763 mmol) were reacted

in toluene/DMF [7.6 mL, (1:1)] for 2 h at 80 °C under an atmo-

sphere of CO as described in the General Procedure. A sample of

MeONa (0.14 mL, 30% in MeOH, ∼10 equiv) was added. The

resulting deep-green mixture was allowed to cool to room tempera-

ture and poured into saturated aqueous NH₄Cl. The resulting

purple-brown mixture was extracted with CH₂Cl₂. The organic

extract was washed (water and brine), dried (Na₂SO₄), and con-

centrated. Column chromatography afforded a trace of des-bromo

chlorin (FbC-M¹⁰, first fraction, green) and the title compound

(second fraction, violet-purple) as a violet solid (26.1 mg, 66%): ¹H

NMR δ-1.48 (br s, 1H), -1.18 (br s, 1H), 1.88 (s, 6H), 2.05 (s, 6H),

2.64 (s, 3H), 4.24 (s, 3H), 4.63 (s, 2H), 7.28 (s, 2H), 8.43 (d, J =

4.4 Hz, 1H), 8.76 (d, J=4.4 Hz, 1H, partially overlapped), 8.77 (s,

1H, overlapped), 8.87 (d, J=4.7 Hz, 1H), 9.08 (s, 1H), 9.11 (d, J=

4.7 Hz, 1H), 9.59 (s, 1H), 10.02 (s, 1H); ¹³C NMR (75 MHz) δ 21.5,

31.1, 46.9, 51.9, 52.2, 94.6, 96.6, 106.3, 121.6, 123.5, 125.3, 128.0,

129.5, 129.7, 130.9, 132.7, 136.5, 137.6, 137.8, 138.0, 139.2, 142.8,

152.5, 153.8, 163.8, 166.4, 178.0; LD-MS obsd 516.3; ESI-MS obsd

517.2593, calcd 517.2598 [(M þH)^þ, M=C₃₃H₃₂N₄O₂]; λ_abs367,

405, 508, 653 nm.

3,13-Dibromo-17,18-dihydro-10-mesityl-18,18-dimethylporphyrin

(FbC-M¹⁰Br^3,13). A mixture of 8-bromo-2,3,4,5-tetrahydro-1,3,3-

trimethyldipyrrin (1-Br, 0.134 g, 0.500 mmol) and 2 (0.220 g, 0.500

mmol) in CH₂Cl₂(15 mL) was treated with a solution of

TsOH H₂O (0.475 g, 2.5 mmol) in MeOH (5 mL). The resulting

3

mixture was stirred at room temperature for 30 min, treated with

2,2,6,6-tetramethylpiperidine (2.5 mL, 14 mmol), and concentrated.

The resulting solid was suspended in CH₃CN (50 mL), to which

samples of 2,2,6,6-tetramethylpiperidine (2.5 mL, 14 mmol), anhy-

drous Zn(OAc)₂(1.35 g, 7.50 mmol), and AgOTf (0.385 g, 1.50

mmol) were added. The resulting mixture was refluxed for 18 h

exposed to air. The reaction mixture was concentrated and filtered

through silica (CH₂Cl₂). Fractions containing chlorin were col-

lected, concentrated, and demetalated with use of TFA as described

for FbC-M¹⁰Br¹³. Column chromatography [silica, hexanes/

CH₂Cl₂(1:1)] afforded a greenish solid (75.5 mg, 25%): ¹H

NMR δ -1.78 (br s, 2H), 1.85 (s, 6H), 2.04 (s, 6H), 2.61 (s, 3H),

17,18-Dihydro-10-mesityl-3,13-bis(methoxycarbonyl)-18,18-

dimethylporphyrin (FbC-M¹⁰Es^3,13). Samples of FbC-M¹⁰Br^3,13

(123 mg, 0.200 mmol) and Pd(PPh₃)₄(463 mg, 0.400 mmol) were

reacted in DMF/toluene [20 mL, (1:1)] at 80 °C for 2 h under an

atmosphere of CO as described in the General Procedure. After 2 h,

excess NaOMe (216 mg, 4.00 mmol) in MeOH (10 mL) was added

to the reaction mixture. The latter was stirred at 80 °C for 5 min

before being cooled to room temperature. A saturated aqueous

solution of NH₄Cl (100 mL) was added, and the mixture was

extracted with CH₂Cl₂. The organic layer was separated, filtered

through Celite (CH₂Cl₂), and concentrated. Column chromato-

graphy [silica, hexanes/CH₂Cl₂(1:2)] affordedapurplesolid(95mg,

J. Org. Chem. Vol. 75, No. 5, 2010 1669

Ptaszek et al.

JOCArticle

83%): ¹H NMR δ -1.47 (br s, 2H), 1.84 (s, 6H), 2.04 (s, 6H), 2.62

(s, 3H), 4.22 (s, 3H), 4.35 (s, 3H), 4.63 (s, 2H), 7.24 (s, 2H), 8.40 (d,

J=4.4 Hz, 1H), 8.85 (s, 1H), 8.90 (d, J=4.4 Hz, 1H), 9.10 (s, 1H),

9.43 (s, 1H), 10.04 (s, 1H), 10.61 (s, 1H); ESI-MS obsd 575.2653,

calcd 575.2653 [(M þH)^þ, M=C₃₅H₃₄N₄O₄]; λ_abs(CH₂Cl₂) 379,

413, 518, 550, 618, 675 nm.

data (¹H NMR, absorption, LD-MS) were consistent with those

reported above.

13,15-Bis(methoxycarbonyl)-17,18-dihydro-10-mesityl-18,18-

dimethylporphyrin (FbC-M¹⁰Es^13,15). Samples of FbC-M¹⁰Es¹³Br¹⁵

(16 mg, 0.026 mmol), Pd(PPh₃)₄(6.1 mg, 5.3 μmol), and K₂CO₃

(36 mg, 0.011 mmol) in THF/MeOH [1.6 mL, (1:1)] were reacted

under an atmosphere of CO for 24 h at 85 °C as described in the

General Procedure. The reaction mixture was filtered through

Celite (CH₂Cl₂) and concentrated. Column chromatography

[silica, hexanes/CH₂Cl₂(3:1 to 1:2)] provided starting material,

debrominated starting material (FbC-M¹⁰Es¹³), and the title pro-

duct (purple fraction), which upon concentration afforded a purple

solid (11 mg, 73%): ¹H NMR δ -0.67 (br s, 2H), 1.84 (s, 6H), 1.98

(s, 6H), 2.60 (s, 3H), 4.12 (s, 3H), 4.15 (s, 3H), 4.67 (s, 2H), 7.22 (s,

2H), 8.28 (d, J=4.5 Hz, 1H), 8.62 (m, 2H), 8.75 (m, 2H), 9.00 (d,

J=4.8 Hz, 1H), 9.41 (s, 1H); LD-MS obsd 574.5; FAB-MS obsd

575.26528, calcd 575.26583 [(M þ H)^þ, M = C₃₅H₃₄N₄O₄]; λ_abs

361, 404, 506, 535, 602, 654 nm.

17,18-Dihydro-10-mesityl-18,18-dimethyl-13-[2-(N-propylamino)-

1,2-dioxoethyl]porphyrin (FbC-M¹⁰(COCmPr)¹³). Samples of

FbC-M¹⁰Br¹³(25 mg, 0.046 mmol) and Pd(PPh₃)₄(54 mg,

0.046 mmol) were reacted in toluene/DMF [3 mL, (1:1)] for 3 h

at 100 °Cunder an atmosphere of CO as described in the General

Procedure. The reaction mixture was cooled to ∼60 °C, where-

upon excess propylamine (0.50 mL) was added. Upon cooling to

room temperature, the green-brown mixture was diluted with

CH₂Cl₂, filtered through Celite (CH₂Cl₂), and concentrated.

Column chromatography (silica, CH₂Cl₂) afforded a green solid

15-Bromo-17,18-dihydro-10-mesityl-13-methoxycarbonyl-18,18-

dimethylporphyrin (FbC-M¹⁰Es¹³Br¹⁵). A solution of FbC-M¹⁰Es¹³

(29.9 mg, 0.0579 mmol) in CH₂Cl₂/TFA [29 mL, (10:1)] was treated

with NBS (0.580 mL, 0.10 M in CH₂Cl₂, 0.058 mmol). The deep-

green mixture was stirred at room temperature for 30 min. Saturated

aqueous NaHCO₃was slowly added, and the resulting mixture was

stirred for 5 min. The organic layer was separated, washed (water,

brine), dried (Na₂SO₄), and concentrated. Column chromatogra-

phy [silica, hexanes/CH₂Cl₂, (1:1)] afforded small amounts of uni-

dentified chlorins (first fraction, pink; second fraction, purple) and

the product (third fraction, purple), which upon concentration

afforded a purple solid (27.0 mg, 78%): ¹H NMR δ -1.40 (br s,

2H), 1.84 (s, 6H), 2.03 (s, 6H), 2.61 (s, 3H), 4.20 (s, 3H), 4.58 (s, 2H),

7.23 (s, 2H), 8.39 (d, J = 4.4 Hz, 1H), 8.64 (s, 1H), 8.71 (s, 1H,

overlapped), 8.72 (d, J=4.4 Hz, 1H, partially overlapped), 8.84 (d,

J=4.8 Hz, 1H), 9.08 (d, J=4.8 Hz, 1H), 9.52 (s, 1H); LD-MS obsd

594.9, ESI-MS obsd 595.1706, calcd 595.1703 [(M þ H)^þ, M =

C₃₃H₃₁BrN₄O₂); λ_abs365, 405, 509, 535, 598, 649 nm.

15-Bromo-17,18-dihydro-10-mesityl-3,13-bis(methoxycarbonyl)-

18,18-dimethylporphyrin (FbC-M¹⁰Es^3,13Br¹⁵). A solution of FbC-

M¹⁰Es^3,13(100 mg, 0.174 mmol) in CH₂Cl₂/TFA [70 mL, (10:1)]

was treated with NBS (1.74 mL, 0.10 M in CH₂Cl₂, 0.174 mmol).

The deep-green solution was stirred at room temperature for 1 h.

Saturated aqueous NaHCO₃was slowly added, and the resulting

mixture was stirred for 5 min. The organic layer was separated,

dried (Na₂SO₄), and concentrated. Column chromatography

(silica, CH₂Cl₂) afforded a purple solid (83 mg, 72%): ¹H NMR

δ-1.55 (br s, 2 H), 1.82 (s, 6 H), 2.03 (s, 6 H), 2.59 (s, 3 H), 4.20 (s, 3

H), 4.33 (s, 3 H), 4.60 (s, 2 H), 7.23 (s, 2 H), 8.39 (d, J=4.4 Hz,

1 H), 8.70 (s, 1 H), 8.81 (s, 1 H), 8.86 (d, J=4.4 Hz, 1 H), 9.41 (s,

1 H), 10.53 (s, 1 H); ESI-MS obsd 653.1761, calcd 653.1763 [(Mþ

H)^þ, M=C₃₅H₃₃BrN₄O₄]; λ_abs(CH₂Cl₂) 378, 414, 520, 551, 615,

671 nm.

17,18-Dihydro-10-mesityl-18,18-dimethylporphyrin-13,15-di-

carboxylic Anhydride (FbC-M¹⁰An). Samples of FbC-M¹⁰Es¹³-

Br¹⁵(16.4 mg, 0.0275 mmol) and Pd(PPh₃)₄(3.6 mg, 0.017

mmol) in DMF/toluene [2.75 mL, (1:1)] were reacted at 70 °C

for 2 h under an atmosphere of CO as described in the General

Procedure. After 2 h, a 2 M aqueous solution of NaOMe (120 μL)

was added to the reaction mixture. The latter was stirred at 70 °C

for 30 min before being allowed to cool to room temperature.

Saturated aqueous NH₄Cl was added, and the mixture was

extracted with CH₂Cl₂. The organic layer was separated, filtered

through Celite (CH₂Cl₂), and concentrated. Column chroma-

tography (silica, CH₂Cl₂) gave four fractions; the first fraction

consisted of debrominated starting material, the second and

third fractions contained unidentified chlorins, and the fourth

fraction afforded the title compound as a purple solid (3.1 mg,

21%): ¹H NMR δ 0.19 (br s, 1H), 0.76 (br s, 1H), 1.86 (s, 6H),

1.98 (s, 6H), 2.58 (s, 3H), 4.80 (s, 2H), 7.22 (s, 2H), 8.21-8.32 (m,

1H), 8.53 (d, J = 6.33 Hz, 2H), 8.65-8.74 (m, 1H), 8.92-9.02

(m, 2H), 9.32 (s, 1H); LD-MS obsd 528.3; ESI-MS obsd

529.2242; calcd 529.2234 [(M þ H)^þ, M = C₃₃H₂₈N₄O₃]; λ_abs

414, 549, 680 nm. The same compound was prepared upon

reaction of FbC-M¹⁰Es¹³Br¹⁵(24.5 mg, 0.0411 mmol), Pd-

(PPh₃)₄(47.5 mg, 0.0411 mmol), Cs₂CO₃(39.8 mg, 0.124 mmol),

and H₂O (1.4 μL, 0.078 mmol) in THF (5.0 mL) at 80 °C for 16 h

under an atmosphere of CO as described in the General Proce-

dure. The reaction mixture was filtered through Celite (CH₂Cl₂)

and concentrated. Column chromatography (silica, CH₂Cl₂)

provided debrominated starting material (first fraction) and the

title compound (second fraction, 2.1 mg, 10%). Characterization

1

(10 mg, 38%): H NMR δ -0.89 (br s, 1H), -0.54 (br s, 1H),

1.08 (t, J=7.4 Hz, 3H), 1.73-1.80 (m, 2H), 1.87 (s, 6H), 2.01 (s,

6H), 2.59 (s, 3H), 3.50 (app q, J=6.8 Hz, 2H), 4.54 (s, 2H), 7.21

(s, 2H), 7.71 (app t, J=5.8 Hz, 1H), 8.33 (d, J=4.4 Hz, 1H), 8.63

(s, 1H), 8.66 (d, J=4.4 Hz, 1H), 8.78 (d, J=4.7 Hz, 1H), 9.02 (d,

J=4.7 Hz, 1H), 9.44 (s, 1H), 9.87 (s, 1H), 9.93 (s, 1H); ¹³C NMR

δ 11.5, 21.3, 21.5, 22.8, 30.7, 41.3, 46.6, 51.6, 94.3, 96.7, 106.3,

123.2, 125.3, 125.5, 127.9, 129.8, 131.2, 132.5, 133.1, 133.6,

136.8, 136.9, 152.6, 154.4, 162.4, 164.7, 178.8, 184.7; LD-MS

obsd 571.2; ESI-MS obsd 572.3020, calcd 572.3020 [(M þ H)^þ,

M =C₃₆H₃₇N₅O₂]; λ_abs347, 376, 427, 518, 553, 615, 671 nm.

13-(N-Benzylcarbamoyl)-17,18-dihydro-10-mesityl-18,18-di-

methylporphyrin (FbC-M¹⁰(CmBn)¹³). Samples of FbC-M¹⁰Br¹³

(40.0 mg, 0.0744 mmol), Pd(OAc)₂(2.5 mg, 0.011 mmol),

Xantphos (6.5 mg, 0.011 mmol), Cs₂CO₃(72.7 mg, 0.223 mmol),

and benzylamine (16 μL, 0.15 mmol) were reacted in toluene

(3.0 mL) for 12 h at 80 °C under an atmosphere of CO as des-

cribed in the General Procedure. The reaction mixture was

concentrated and chromatographed (silica, CH₂Cl₂) to afford

a green solid (37.1 mg, 84%): ¹H NMR δ -1.74 (br s, 1H), -1.44

(br s, 1H), 1.85 (s, 6H), 2.04 (s, 6H), 2.61 (s, 3H), 4.63 (s, 2H),

4.97 (d, J=5.6 Hz, 2H), 7.04 (app t, J=5.6 Hz, 1H), 7.25 (s, 2H),

7.34-7.38 (m, 1H), 7.42-7.46 (m, 2H), 7.60-7.62 (m, 2H), 8.40

(d, J=4.3 Hz, 1H), 8.71 (s, 1H), 8.81 (d, J=4.4 Hz, 1H), 8.83 (s,

1H), 8.91 (d, J=4.7 Hz, 1H), 9.15 (d, J=4.6 1H), 9.65 (s, 1H),

10.09 (s, 1H); ¹³C NMR δ 21.5, 21.7, 31.2, 44.4, 46.6, 52.0, 94.8,

97.2, 106.3, 122.0, 124.3, 125.0, 126.1, 127.9, 128.0, 128.5, 129.1,

129.2, 131.0, 132.3, 132.9, 136.1, 137.4, 137.7, 138.0, 138.7,

139.3, 142.3, 152.5, 153.3, 163.7, 166.1, 177.4; LD-MS obsd

591.5; ESI-MS obsd 592.3064, calcd 592.3071 [(M þ H)^þ, M =

C₃₉H₃₇N₅O]; λ_abs368, 405, 416, 508, 535, 600, 654 nm.

13-(N-Phenylcarbamoyl)-17,18-dihydro-10-mesityl-18,18-di-

methylporphyrin (FbC-M¹⁰(CmPh)¹³). Samples of FbC-M¹⁰Br¹³

(40.0 mg, 0.0744 mmol), Pd(OAc)₂(2.5 mg, 0.011 mmol),

Xantphos (6.5 mg, 0.011 mmol), Et₃N (31 μL, 0.22 mmol),

and aniline (14 μL, 0.15 mmol) in toluene (3 mL) were reacted

for 20 h at 80 °C under an atmosphere of CO as described in the

General Procedure. The reaction mixture was concentrated and

chromatographed (silica, CH₂Cl₂) to afford a green solid (27.5 mg,

64%): ¹H NMR δ -1.67 (br s, 1H), -1.35 (br s, 1H), 1.88 (s, 6H),

1670 J. Org. Chem. Vol. 75, No. 5, 2010

Ptaszek et al.

JOCArticle

2.04 (s, 6H), 2.63 (s, 3H), 4.60 (s, 2H), 7.23-7.25 (m, 1H,

partially overlapped with CHCl₃signal), 7.29 (s, 2H), 7.47-

7.51 (m, 2H), 7.90 (app d, J=8.0 Hz, 2H), 8.41 (s, 1H, partially

overlapped), 8.42 (d, J = 4.4 Hz, 1H, partially overlapped),

8.80-8.82 (m, 3H, three overlapped signals), 8.99 (d, J=4.8 Hz,

1H), 9.15 (d, J=4.8 Hz, 1H), 9.6 (s, 1H), 10.0 (s, 1H); ¹³C NMR

(75 MHz) δ 21.6, 21.7, 31.1, 46.9, 51.9, 94.8, 97.0, 106.3, 120.8,

122.3, 124.2, 124.8, 125.2, 126.3, 128.1, 129.4, 131.0, 132.5,

133.0, 136.4, 137.4, 137.7, 138.1, 138.4, 139.4, 142.5, 152.6,

153.6, 163.8, 164.4, 177.7 (signal of one carbon is not visible);

LD-MS obsd 577.7; ESI-MS obsd 578.2912, calcd 578.2914

[(MþH)^þ, M=C₃₈H₃₅N₅O]; λ_abs368, 405, 416, 508, 535, 600,

654 nm.

compound (purple fraction); concentration of the latter affor-

ded a purple solid (24.5 mg, 71%): ¹H NMR δ -1.60 (br s, 2H),

1.83 (s, 6H), 2.03 (s, 6H), 2.62 (s, 3H), 4.60 (s, 2H), 4.92 (d, J=

5.4 Hz, 2H), 6.59 (t, J=5.4 Hz, 1H), 7.24 (s, 2H), 7.31-7.36 (m,

1H), 7.39-7.43 (m, 2H), 7.56-7.58 (m, 2H), 8.40-8.41 (m, 1H),

8.64 (s, 1H), 8.74-8.76 (m, 1H, partially overlapped), 8.76 (s,

1H, partially overlapped), 8.87 (d, J=4.7 Hz, 1H), 9.11 (d, J=

4.7 Hz, 1H), 9.57 (s, 1H) (signal of one N-H proton is not

visible); LD-MS obsd 590.5 (M - Br)^þ; ESI-MS obsd 670.2166,

calcd 670.2176 [(M þ H)^þ, M = C₃₉H₃₆BrN₅O]; λ_abs364, 405,

509, 534, 596, 648 nm.

15-Bromo-13-(N-phenylcarbamoyl)-17,18-dihydro-10-mesityl-

18,18-dimethylporphyrin (FbC-M¹⁰(CmPh)¹³Br¹⁵). A solution

of FbC-M¹⁰(CmPh)¹³(27.0 mg, 0.0467 mmol) in CH₂Cl₂/TFA

[18.6 mL, (10:1)] was treated with NBS (0.47 mL, 0.10 M in

CH₂Cl₂, 0.047 mmol). The deep-green reaction mixture was

stirred at room temperature for 45 min. Saturated aqueous

NaHCO₃was slowly added, and the resulting mixture was

vigorously stirred for 5 min. The organic layer was separated,

washed (water, brine), dried (Na₂SO₄), and concentrated. Col-

umn chromatography [silica, hexanes/CH₂Cl₂(1:3)] gave four

fractions; the first purple fraction was an unidentified chlorin,

the second greenish fraction was unreacted starting material, the

third fraction was an unidentified chlorin, and the fourth frac-

tion afforded the title compound as a purple solid (18.7 mg,

3,13-Bis(N-benzylcarbamoyl)-17,18-dihydro-10-mesityl-18,18-

dimethylporphyrin (FbC-M¹⁰(CmBn)^3,13). Samples of FbC-

M¹⁰Br^3,13(32.9 mg, 0.0533 mmol), Pd(OAc)₂(3.6 mg, 0.017

mmol), Xantphos (9.2 mg, 0.016 mmol), benzylamine (24 μL,

0.21 mmol), and Cs₂CO₃(52.1 mg, 0.160 mmol) in toluene

(2.1 mL) were reacted at 80 °C for 14 h under an atmosphere

of CO as described in the General Procedure. The pink reaction

mixture was concentrated under high vacuum, and the resulting

solid was dissolved in CH₂Cl₂and poured on a short silica

column (CH₂Cl₂). Column chromatography [silica, hexanes/

CH₂Cl₂/ethyl acetate (5:10:1)] afforded a pink solid (20.9 mg,

1

54%): H NMR δ -1.42 (br s, 2H), 1.82 (s, 6H), 2.01 (s, 6H),

1

61%): H NMR δ -1.51 (br s, 2H), 1.84 (s, 6H), 2.04 (s, 6H),

2.60 (s, 3H), 4.61 (s, 2H), 4.96 (d, J = 5.8 Hz, 2H), 5.07 (d, J=

5.7 Hz, 2H), 6.99-7.02 (m, 1H), 7.19-7.15 (m, 1H), 7.24 (s, 2H),

7.34-7.50 (m, 6H), 7.58-7.66 (m, 4H), 8.35 (d, J=4.4 Hz, 1H),

8.70 (s, 1H), 8.79 (s, 1H), 8.88 (d, J=4.4 Hz, 1H), 9.07 (s, 1H),

10.06 (s, 1H), 10.62 (s, 1H); LD-MS obsd 724.9; ESI-MS obsd

725.3587, calcd 725.3599 [(M þ H)^þ, M = C₄₇H₄₄N₆O₂]; λ_abs

375, 410, 515, 545, 613, 669 nm. The same compound was

prepared upon replacement of Cs₂CO₃with Et₃N: Samples of

FbC-M¹⁰Br^3,13(61.6 mg, 0.100 mmol), Pd(OAc)₂(6.7 mg, 0.033

mmol), Xantphos (17.3 mg, 0.033 mmol), benzylamine (44 μL,

0.40 mmol), and Et₃N (84 μL, 0.60 mmol) in toluene (4 mL) were

reacted under an atmosphere of CO at 80 °C for 3 h, affording

upon analogous workup a pink-purple solid (41.8 mg, 58%).

Characterization data (¹H NMR, absorption, LD-MS, ESI-

MS) were consistent with those reported above.

2.59 (s, 3H), 4.59 (s, 2H), 7.21-7.24 (m, 1H, partially overlap-

ped), 7.22 (s, 2H), 7.44-7.48 (m 2H), 7.84 (app d, J = 7.7 Hz,

2H), 7.99 (s, 1H), 8.41 (d, J=4.4 Hz, 1H); 8.70 (s, 1H), 8.75 (d,

J = 4.4 Hz, partially overlapped), 8.76 (s, 1H), 8.90 (d, J =

4.4 Hz, 1H), 9.12 (d, J=4.4 Hz, 1H), 9.57 (s, 1H); ESI-MS obsd

656.2015, calcd 656.2025 [(M þ H)^þ, M = C₃₈H₃₄BrN₅O]; λ_abs

365, 405, 509, 534, 596, 649 nm.

15-Bromo-3,13-bis(N-benzylcarbamoyl)-17,18-dihydro-10-mesityl-

18,18-dimethylporphyrin (FbC-M¹⁰(CmBn)^3,13Br¹⁵). A solution

of FbC-M¹⁰(CmBn)^3,13(20.5 mg, 0.0283 mmol) in CH₂Cl₂/TFA

[11.3 mL, (10:1)] was treated with NBS (0.283 mL, 0.10 M in

CH₂Cl₂, 0.028 mmol). The resulting deep-green mixture was

stirred at room temperature for 40 min, whereupon another

batch of NBS (0.056 mL, 0.0056 mmol) was added, and the

reaction mixture was stirred for an additional 30 min. Saturated

aqueous NaHCO₃was added slowly, and the resulting mixture

was stirred vigorously for 5 min. The organic layer was sepa-

rated, washed (water and brine), dried (Na₂SO₄), and concen-

trated. The resulting purple solid was dissolved in CH₂Cl₂(with

the aid of sonication) and chromatographed [silica, hexanes/

CH₂Cl₂/ethyl acetate (5:10:1)] to afford traces of unknown

substances, unreacted starting material (highly fluorescent,

purple fraction), and the expected product; concentration of

3,13-Bis(N-phenylcarbamoyl)-17,18-dihydro-10-mesityl-18,18-

dimethylporphyrin (FbC-M¹⁰(CmPh)^3,13). Samples of FbC-M¹⁰-

Br^3,13(100. mg, 0.162 mmol), Pd(OAc)₂(11.1 mg, 0.0487 mmol),

Xantphos (28.3 mg, 0.0487 mmol), Cs₂CO₃(316 mg, 0.973

mmol), and aniline (60 μL, 0.65 mmol) were reacted in DMF/

toluene [6.6 mL, (1:1)] for 20 h at 80 °C under an atmosphere of

CO as described in the General Procedure. The reaction mixture

was filtered through Celite (ethyl acetate) and concentrated.

Column chromatography on a short silica column (CH₂Cl₂)

afforded a red-brown solid (50 mg, 44%): ¹H NMR δ -1.48 (br

s, 2H), 1.87 (s, 6H), 2.00 (s, 6H), 2.62 (s, 3H), 4.58 (s, 2H),

7.18-7.25 (m, 1H), 7.28 (s, 2H), 7.27-7.33 (m, 1H), 7.46-7.55

(m, 4H), 7.90 (d, J=7.7 Hz, 2H), 7.98 (d, J=7.7 Hz, 2H), 8.38

(d, J = 4.4 Hz, 1H), 8.42 (s, 1H), 8.66 (s, 1H), 8.83 (s, 1H),

8.86 (s, 1H), 8.89 (d, J=4.40 Hz, 1H), 9.21 (s, 1H), 10.02 (s, 1H),

10.61 (s, 1H); ESI-MS obsd 697.3283, calcd 697.3286 [(MþH)^þ,

M= C₄₅H₄₀N₆O₂]; λ_abs(CH₂Cl₂) 412, 515, 548, 615, 671 nm.

13-(N-Benzylcarbamoyl)-15-bromo-17,18-dihydro-10-mesityl-

18,18-dimethylporphyrin (FbC-M¹⁰(CmBn)¹³Br¹⁵). A solution

of FbC-M¹⁰(CmBn)¹³(30.5 mg, 0.0515 mmol) in CH₂Cl₂/TFA

[20.6 mL, (10:1)] was treated with NBS (0.52 mL, 0.10 M in

CH₂Cl₂, 0.052 mmol). The deep-green solution was stirred at

room temperature for 1 h. Saturated aqueous NaHCO₃was

slowly added, and the resulting mixture was stirred for 5 min.

The organic layer was separated, dried (Na₂SO₄), and concen-

trated. Column chromatography (silica, CH₂Cl₂) provided an

unidentified first fraction (pink), starting material (second

fraction), an unidentified fraction (third, pink), and the title

1

the latter afforded a violet solid (16.2 mg, 71%): H NMR δ

-1.65 (br s, 1H), 1.80 (s, 6H), 1.88 (s, 6H), 2.60 (s, 3H), 4.49 (s,

2H), 4.91 (d, J=5.6 Hz, 2H), 5.05 (d, J=5.6 Hz, 2H), 6.59 (t, J=

5.6 Hz, 1H), 7.23 (s, 2H), 7.26 (1H, overlapped with CHCl₃

signal), 7.34-7.48 (m, 6H), 7.56-7.64 (m, 4H), 8.36 (d, J =

4.4 Hz, 1H), 8.62 (s, 1H), 8.65 (s, 1H), 8.83 (d, J=4.4 Hz, 1H),

9.05 (s, 1H), 10.56 (s, 1H) (signal of one N-H proton is not

visible); LD-MS obsd 723.4 (M - Br)^þ; ESI-MS obsd 803.2698,

calcd 803.2704 [(M þ H)^þ, M = C₄₇H₄₃BrN₆O₂]; λ_abs374, 411,

517, 547, 611, 666 nm.

15-Bromo-3,13-bis(N-phenylcarbamoyl)-17,18-dihydro-10-mesityl-

18,18-dimethylporphyrin (FbC-M¹⁰(CmPh)^3,13Br¹⁵). A solution

of FbC-M¹⁰(CmPh)^3,13(50 mg, 0.072 mmol) in CH₂Cl₂/TFA

[30 mL, (10:1)] was treated with NBS (0.72 mL, 0.10 M in

CH₂Cl₂, 0.072 mmol). The deep-green solution was stirred at

room temperature for 1 h. Saturated aqueous NaHCO₃was

slowly added, and the resulting mixture was stirred for 5 min.

The organic layer was separated, dried (Na₂SO₄), and concen-

trated. Column chromatography on a short silica column

J. Org. Chem. Vol. 75, No. 5, 2010 1671

Ptaszek et al.

JOCArticle

(CH₂Cl₂) afforded a red-brown solid (41 mg, 74%): ¹H NMR δ

-1.55 (br s, 2H), 1.84 (s, 6H), 1.98 (s, 6H), 2.59 (s, 3H), 4.56 (s,

2H), 7.23 (s, 2H), 7.29-7.34 (m, 2H), 7.48 (t, J = 7.8 Hz, 2H),

7.55 (t, J=7.8 Hz, 2H), 7.85 (d, J=7.7 Hz, 2H), 7.98 (d, J=7.7

Hz, 2H), 8.02 (s, 1H), 8.39 (d, J=4.4 Hz, 1H), 8.64 (s, 1H), 8.75

(s, 1H), 8.77 (s, 1H), 8.85 (d, J=4.4 Hz, 1H), 9.20 (s, 1H), 10.55

(s, 1H); ESI-MS obsd 775.2393, calcd 775.2391 [(MþH)^þ, M=

C₄₅H₃₉BrN₆O₂]; λ_abs(CH₂Cl₂) 412, 518, 549, 614, 668 nm.

13²-N-Benzyl-17,18-dihydro-10-mesityl-18,18-dimethylporphy-

rin-13,15-dicarboximide (FbC-M¹⁰I-Bn). Samples of FbC-M¹⁰-

(CmBn)¹³Br¹⁵(15.2 mg, 0.0226 mmol) and Pd(PPh₃)₄(26.1 mg,

0.0226 mmol) were reacted in toluene/DMF [1.5 mL, (1:1)] at

80 °C for 2 h under an atmosphere of CO as described in the

General Procedure. The flow of CO was then stopped, and the

reaction mixture was kept at 80 °C for 1 h. The reaction mixture

was filtered through Celite (CH₂Cl₂) and concentrated. Column

chromatography (silica, CH₂Cl₂) provided the title compound

(first fraction, purple) and debrominated starting material

(second fraction, 6.5 mg). Data for the title compound: purple

solid (7 mg, 50%): ¹H NMR δ 0.08 (br s, 1H), 0.43 (br s, 1H),

1.86 (s, 6H), 1.95 (s, 6H), 2.58 (s, 3H), 4.82 (s, 2H), 5.67 (s, 2H),

7.20 (s, 2H), 7.24-7.28 (m, 1H, partially overlapped with

residual CHCl₃), 7.34-7.39 (m, 2H), 7.74-7.76 (m, 2H), 8.26

(d, J = 4.4 Hz, 1H), 8.53 (s, 1H), 8.53 (d, partially overlapped

with singlet), 8.66 (d, J=4.8 Hz, 1H), 8.94 (d, J=4.8 Hz, 1H),

8.99 (s, 1H), 9.32 (s, 1H); ¹³C NMR (75 MHz) δ 21.4, 21.6, 31.5,

46.4, 51.4, 54.0, 93.7, 96.1, 110.2, 119.7, 123.9, 125.9, 127.1,

128.3, 128.5, 128.7, 128.8, 131.1, 133.2, 133.7, 136.6, 137.1,

138.4, 138.6, 138.7, 140.3, 144.5, 147.3, 153.2, 154.2, 164.5,

171.9, 180.9; LD-MS obsd 618.0; ESI-MS obsd 618.2866, calcd

618.2864 [(M þ H)^þ, M = C₄₀H₃₅N₅O₂]; λ_abs363, 420, 553,

686 nm.

Hz, 1H), 8.55 (s, 1H, overlapped with doublet), 8.68 (d, J=4.8 Hz,

1H), 8.97 (d, J = 4.8 Hz, 1H), 9.03 (s, 1H), 9.34 (s, 1H); LD-MS

obsd 603.8; ESI-MS obsd 604.2712, calcd 604.2707 [(MþH)^þ, M=

C₃₉H₃₃N₅O₂]; λ_abs364, 419, 551, 685 nm.

13¹-N-Phenylimino-17,18-dihydro-10-mesityl-18,18-dimethyl-

porphyrin-13,15-dicarboxisoimide (FbC-M¹⁰Iso-Ph). Samples of

FbC-M¹⁰(CmPh)¹³Br¹⁵(23.5 mg, 0.0358 mmol), Pd(PPh₃)₄

(41.3 mg, 0.0358 mg), and Cs₂CO₃(35.0 mg, 0.107 mmol) were

reacted in toluene (1.4 mL) at 80 °C for 2 h under an atmosphere

of CO as described in the General Procedure. The resulting

mixture was diluted with CH₂Cl₂, filtered through Celite, and

concentrated. Column chromatography [silica, hexanes/CH₂-

1

Cl₂(1:3)] afforded a purple solid (12.8 mg, 59%): H NMR δ

-0.41 (br s, 1H), 0.07 (br s, 1H); 1.90 (s, 6H), 2.00 (s, 6H), 2.59 (s,

3H), 4.87 (s, 2H), 7.24 (s, 2H), 7.23-7.24 (m, 1H, overlapped

with singlet), 7.47-7.51 (m, 2H), 7.53-7.56 (m, 2H), 8.33 (d, J=

4.4 Hz, 1H), 8.65 (d, J=4.4 Hz, 1H), 8.68 (s, 1H), 8.76 (d, J=

4.7 Hz, 1H), 9.05 (d, J=4.7 Hz, 1H), 9.13 (s, 1H), 9.49 (s, 1H);

¹³C NMR δ 21.1, 21.4, 31.2, 46.2, 53.7, 93.5, 95.9, 109.9, 119.3,

123.7, 124.1, 124.8, 126.0, 128.1, 128.6, 128.9, 131.1, 133.0,

133.2, 133.6, 136.3, 137.2, 138.3, 138.5, 144.7, 145.4, 145.7,

153.0, 154.3, 164.0, 172.0, 181.2 (signal of one carbon is not

visible); ESI-MS obsd 604.2711, calcd 604.2707 [(MþH)^þ, M=

C₃₉H₃₃N₅O₂]; λ_abs367, 418, 512, 550, 634, 687 nm.

13²-N-Benzyl-3-(N-benzylcarbamoyl)-17,18-dihydro-10-mesityl-

18,18-dimethylporphyrin-13,15-dicarboximide (FbC-(CmBn)³M¹⁰I-

Bn). Samples of FbC-M¹⁰(CmBn)^3,13Br¹⁵(20.5 mg, 0.0255 mmol),

Pd(PPh₃)₄(29.5 mg, 0.0255 mmol), and Cs₂CO₃(25 mg, 0.077

mmol) were reacted in toluene (4.0 mL) at 80 °C for 20 h under an

atmosphere of CO as described in the General Procedure. The

reaction mixture was filtered through Celite (ethyl acetate) and

concentrated. Column chromatography (silica, CH₂Cl₂) gave two

fractions; the first fraction afforded the title compound as a purple

solid (6.1 mg, 32%); the second fraction afforded the chlorin-

isoimide FbC-(CmBn)³M¹⁰Iso-Bn as a purple solid (5.0 mg, 26%).

Data for FbC-(CmBn)³M¹⁰I-Bn:¹HNMRδ0.11 (br s, 1H), 0.29 (br

s, 1H), 1.85 (s, 6H), 1.92 (s, 6H), 2.58 (s, 3H), 4.82 (s, 2H), 5.01 (d,

J = 5.8 Hz, 2H), 5.66 (s, 2H), 7.21 (s, 2H), 7.32-7.44 (m, 3H),

7.43-7.52 (m, 2H), 7.55-7.64 (m, 2H), 7.66-7.79 (m, 3H), 8.25 (d,

J=4.4 Hz, 1H), 8.53 (s, 1H), 8.65 (d, J=4.7 Hz, 1H), 8.85 (s, 1H),

9.05 (s, 1H), 10.34 (s, 1H); ESI-MS obsd 751.3392, calcd 751.3391

[(MþH)^þ, M=C₄₈H₄₂N₆O₃]; λ_abs378, 424, 564, 708 nm. Data for

FbC-(CmBn)³M¹⁰Iso-Bn: ¹H NMR δ -0.42 (br s, 1H), -0.14 (br s,

1H), 1.83 (s, 6H), 1.97 (s, 6H), 2.57 (s, 3H), 4.90 (s, 2H), 5.03 (d, J=

5.6 Hz, 2H), 5.23 (s, 2H), 7.20 (s, 2H), 7.43 (m, 5 H), 7.57-7.67 (m,

3H), 7.67-7.80 (m, 2H), 8.26 (d, J=4.4 Hz, 1H), 8.66 (s, 1H), 8.74

(d, J=4.4 Hz, 1H), 8.93 (s, 1H), 9.06 (s, 1H), 10.52 (s, 1H); ESI-MS

obsd 751.3393, calcd 751.3391 [(M þH)^þ, M=C₄₈H₄₂N₆O₃]; λ_abs

418, 555, 699 nm.

13¹-N-Benzylimino-17,18-dihydro-10-mesityl-18,18-dimethyl-

porphyrin-13,15-dicarboxisoimide (FbC-M¹⁰Iso-Bn). Samples of

FbC-M¹⁰(CmBn)¹³Br¹⁵(24.3 mg, 0.0362 mmol), Pd(PPh₃)₄

(41.8 mg, 0.0362 mmol), and Cs₂CO₃(35.7 mg, 0.109 mmol)

were reacted in toluene (1.5 mL) at 80 °C for 2 h under an

atmosphere of CO as described in the General Procedure. The

resulting mixture was diluted with CH₂Cl₂, filtered through

Celite, and concentrated. Column chromatography (silica,

CH₂Cl₂) afforded a trace of FbC-M¹⁰I-Bn (first fraction, purple)

and the title compound (second fraction, purple), which upon

concentration afforded a purple solid (12.2 mg, 55%): ¹H NMR

δ - 0.55 (br s, 1H), - 0.12 (br s, 1H), 1.84 (s, 6H), 2.02 (s, 6H),

2.57 (s, 3H), 4.92 (s, 2H), 5.24 (s, 2H), 7.20 (s, 2H), 7.30-7.33 (m,

1H), 7.40-7.45 (m, 2H), 7.64-7.67 (m, 2H), 8.30 (d, J=4.4 Hz,

1H), 8.65 (d, J=4.4 Hz, 1H), 8.70 (s, 1H), 8.77 (d, J=4.8 Hz,

1H), 9.04 (s, 1H), 9.06 (d, J = 4.8 Hz, 1H), 9.51 (s, 1H); ¹³C

NMR (75 MHz) δ 21.1, 21.4, 31.3, 46.2, 51.2, 53.8, 53.5, 95.8,

110.0, 119.5, 123.7, 125.7, 126.9, 128.0, 128.3, 128.5, 128.6,

130.9, 132.9, 130.0, 133.5, 136.4, 136.9, 138.2, 138.35, 138.44,

140.1, 144.3, 147.0, 152.9, 153.9, 164.2, 171.7, 180.7; LD-MS

obsd 617.8, 526.7 (M - Bn)^þ; ESI-MS obsd 618.2857, calcd

618.2864 [(MþH)^þ, M=C₄₀H₃₅N₅O₂]; λ_abs363, 414, 507, 544,

625, 679 nm.

13²-N-Phenyl-3-(N-phenylcarbamoyl)-17,18-dihydro-10-mesityl-

18,18-dimethylporphyrin-13,15-dicarboximide (FbC-(CmPh)³M¹⁰I-

Ph). Samples of FbC-M¹⁰(CmPh)^3,13Br¹⁵(10.0 mg, 0.0129 mmol),

Pd(PPh₃)₄(14.8 mg, 0.0129 mmol), and Cs₂CO₃(12.6 mg, 0.0387

mmol) were reacted in toluene (2.0 mL) at 80 °C for 20 h under

an atmosphere of CO as described in the General Procedure.

The reaction mixture was filtered through Celite (ethyl acetate)

and concentrated. Column chromatography on a short silica

column (CH₂Cl₂) afforded a purple-green solid (6.7 mg, 72%):

¹H NMR δ 0.19 (br s, 1H), 0.42 (br s, 1H), 1.87 (s, 6H), 1.92

(s, 6H), 2.58 (s, 3H), 4.80 (s, 2H), 7.22 (s, 2H), 7.53 (m, 6H), 7.64 (d,

J = 7.4 Hz, 2H), 7.93 (d, J = 7.7 Hz, 2H), 8.25 (d, J = 4.4 Hz,

1H), 8.55 (s, 1H), 8.60 (s, 1H), 8.66 (d, J = 4.7 Hz, 1H), 8.98 (s,

1H), 9.11 (s, 1H), 10.35 (s, 1H); ESI-MS obsd 723.3076, calcd

723.3078 [(M þ H)^þ, M = C₄₆H₃₈N₆O₃]; λ_abs(CH₂Cl₂) 422, 565,

660, 710 nm.

13²-N-Phenyl-17,18-dihydro-10-mesityl-18,18-dimethylpor-

phyrin-13,15-dicarboximide (FbC-M¹⁰I-Ph). Samples of FbC-

M¹⁰(CmPh)¹³Br¹⁵(7.0 mg, 0.011 mmol), Pd(PPh₃)₄(2.5 mg,

0.0022 mmol), and Cs₂CO₃(10.7 mg, 0.033 mmol) were reacted

in toluene (1 mL) at 80 °C for 14 h under an atmosphere of CO as

described in the General Procedure. The reaction mixture was

diluted with CH₂Cl₂, filtered through Celite, and chromato-

graphed [silica, hexanes/CH₂Cl₂, (1:1 to 3:1)] to afford a trace of

debrominated starting material (first fraction), unreacted starting

material (second fraction), and the title compound (third fraction,

3 mg, 45%): ¹HNMRδ0.15 (br s, 1H), 0.58 (br s, 1H), 1.88 (s, 6H),

1.93 (s, 6H), 2.58 (s, 3H), 4.79 (s, 2H), 7.21 (s, 2H), 7.56-7.58 (m,

3H), 7.63-7.68 (m, 2H), 8.26 (d, J=4.4 Hz, 1H), 8.55 (d, J=4.4

13²-N-Benzyl-3-methoxycarbonyl-17,18-dihydro-10-mesityl-18,18-

dimethylporphyrin-13,15-dicarboximide (FbC-Es³M¹⁰I-Bn). Samples

of FbC-M¹⁰Es^3,13Br¹⁵(35.5 mg, 0.0543 mmol), Pd(PPh₃)₄(63.0 mg,

1672 J. Org. Chem. Vol. 75, No. 5, 2010

Ptaszek et al.

JOCArticle

0.0543 mmol), Cs₂CO₃(54 mg, 0.16 mmol), and benzylamine (12 μL,

0.11 mmol) were reacted in THF (3.6 mL) at 80 °C for 20 h under an

atmosphere of CO as described in the General Procedure. The

reaction mixture was filtered through Celite (ethyl acetate) and

concentrated. Column chromatography (silica, CH₂Cl₂) afforded a

green solid (21 mg, 57%): ¹H NMR δ 0.19 (br s, 1H) (a signal for

one NH proton was not visible), 1.85 (s, 6H), 1.95 (s, 6H), 2.58

(s,3H),4.32(s,3H),4.84(s,2H),5.67(s,2H),7.21(s,2H),7.34-7.39

(m, 3H), 7.74 (d, J = 6.9 Hz, 2H), 8.27 (d, J = 4.4 Hz, 1H), 8.63

(s, 1H), 8.69 (d, J = 4.4 Hz, 1H), 9.07 (s, 1H), 9.23 (s, 1H), 10.35

(s, 1H); ESI-MS obsd 676.2922, calcd 676.2918 [(M þ H)^þ, M=

C₄₂H₃₇N₅O₄]; λ_abs(CH₂Cl₂) 379, 424, 568, 659, 715 nm.

666.1849, calcd 666.1842 [(M þ H)^þ, M = C₃₉H₃₁N₅O₂]; λ_abs

425, 558, 615, 661 nm.

Acknowledgment. This work was supported by a grant

from the Division of Chemical Sciences, Office of Basic

Energy Sciences, Office of Energy Research, U.S. Depart-

ment of Energy (DE-FG02-96ER14632). Mass spectra were

obtained at the Mass Spectrometry Laboratory for Biotech-

nology at North Carolina State University. Partial funding

for the Facility was obtained from the North Carolina

Biotechnology Center and the National Science Foundation.

The Department of Chemistry of North Carolina State

University and the State of North Carolina provided funds

to purchase the Apex2 diffractometer.

Zn(II)-13²-N-Phenyl-17,18-dihydro-10-mesityl-18,18-di-

methylporphyrin-13,15-dicarboximide (ZnC-M¹⁰I-Ph). A solu-

tion of FbC-M¹⁰I-Ph (2.0 mg, 0.033 mmol) in CH₂Cl₂(1.0 mL)

was treated with 0.1 mL of methanolic Zn(OAc)₂2H₂O (37 mg,

3

0.17 mmol), and the reaction mixture was stirred at room

temperature for 16 h. Standard workup and chromatogra-

phy (silica, CH₂Cl₂) gave the title compound (2 mg, 90%):

¹H NMR δ 1.89 (s, 6H), 1.89 (s, 6H), 2.56 (s, 3H), 4.73

(s, 2H), 7.18 (s, 2H), 7.45-7.57 (m, 3H), 7.58-7.67 (m, 2H),

8.13-8.20 (m, 1H), 8.23-8.29 (m, 1H), 8.44-8.52 (m, 2H),

8.78-8.88 (m, 1H), 8.96 (s, 1H), 9.12 (s, 1H); ESI-MS obsd

Supporting Information Available: Spectral data (¹H NMR

and ¹³C NMR) for all new chlorins including spectral assign-

ments; exploratory studies concerning routes to chlorin-imides;

additional information concerning experimental procedures;

X-ray data for FbC-M¹⁰Iso-Bn, FbC-M¹⁰Iso-Ph, and ZnC-

M¹⁰I-Ph. This material is available free of charge via the Internet

at http://pubs.acs.org.

J. Org. Chem. Vol. 75, No. 5, 2010 1673

Article Doi

De novo synthesis of long-Wavelength absorbing chlorin-13,15-dicarboximides

DOI: 10.1021/jo902649d

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Article abstract of DOI:10.1021/jo902649d

Full text of DOI:10.1021/jo902649d

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