Rational Syntheses of Porphyrins Bearing up to Four Different Meso Substituents

J . Org. Chem. 2000, 65, 7323-7344

7323

Ra tion a l Syn th eses of P or p h yr in s Bea r in g u p to F ou r Differ en t

Meso Su bstitu en ts

Polisetti Dharma Rao, Savithri Dhanalekshmi, Benjamin J . Littler, and J onathan S. Lindsey*

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

jlindsey@ncsu.edu

Received J une 9, 2000

Porphyrins bearing specific patterns of substituents are crucial building blocks in biomimetic and

materials chemistry. We have developed methodology that avoids statistical reactions, employs

minimal chromatography, and affords up to gram quantities of regioisomerically pure porphyrins

bearing predesignated patterns of up to four different meso substituents. The methodology is based

upon the availability of multigram quantities of dipyrromethanes. A procedure for the diacylation

of dipyrromethanes using EtMgBr and an acid chloride has been refined. A new procedure for the

preparation of unsymmetrical diacyl dipyrromethanes has been developed that involves (1)

monoacylation with EtMgBr and a pyridyl benzothioate followed by (2) introduction of the second

acyl unit upon reaction with EtMgBr and an acid chloride. The scope of these acylation methods

has been examined by preparing multigram quantities of diacyl dipyrromethanes bearing a variety

of substituents. Reduction of the diacyl dipyrromethane to the corresponding dipyrromethane-

dicarbinol is achieved with NaBH₄in methanolic THF. Porphyrin formation involves the acid-

catalyzed condensation of a dipyrromethane-dicarbinol and a dipyrromethane followed by oxidation

with DDQ. Optimal conditions for the condensation were identified after examining various reaction

parameters (solvent, temperature, acid, concentration, time). The conditions identified (2.5 mM

reactants in acetonitrile containing 30 mM TFA at room temperature for <7 min) provided reaction

without detectable scrambling (LD-MS) for aryl-substituted dipyrromethanes, and trace scrambling

for alkyl-substituted dipyrromethanes. The desired porphyrins were obtained in 14-40% yield.

The synthesis is compatible with diverse functionalities: amide, aldehyde, carboxylic acid, ester,

nitrile, ether, bromo, iodo, ethyne, TMS-ethyne, TIPS-ethyne, perfluoroarene. In total 30 porphyrins

of the types A₃B, trans-A₂B₂, trans-AB₂C, cis-A₂B₂, cis-A₂BC, and ABCD were prepared, including

>1-g quantities of three porphyrins.

In tr od u ction

uents. The routes employed generally become more

elaborate as the number of different substituents in-

creases. The best methods to prepare each of the seven

classes of meso-substituted porphyrins (lacking â-sub-

stituents) are summarized as follows:

(1) A₄-porphyrins are readily synthesized under mild

conditions and at high concentration in the one-flask

reaction of pyrrole and the corresponding aldehyde.³

(2) A₃B-porphyrins have been prepared by reaction of

pyrrole and two aldehydes, affording a statistical mixture

of all six substituted products, which were then separated

by chromatography.^2,4The chromatographic separation

was generally lengthy and afforded only small quantities

(typically <100 mg) of the desired porphyrin.

(3) trans-A₂B₂-porphyrins have been typically prepared

by reaction of an aldehyde and a dipyrromethane. In any

acid-catalyzed reaction involving polypyrromethanes,

acid-catalyzed fragmentation followed by an alternate

recombination is an ever-present possibility. These pro-

cesses ultimately scramble the meso-substituents and

result in a mixture of porphyrins.⁵We readily identified

conditions that afford trans-A₂B₂-porphyrins without

Meso-substituted porphyrins bearing specific patterns

of functional groups are valuable components in the

synthesis of porphyrin-based biomimetic systems and

molecular materials. Indeed, the level of architectural

sophistication that can be achieved in such systems is

closely tied to the availability of suitable porphyrin

building blocks. As a result, we have devoted considerable

effort to the development of methodologies for the syn-

thesis of diverse porphyrin building blocks.^1,2

The seven types of meso-substituted porphyrins are

shown in Chart 1. Our goals in developing syntheses of

these classes of porphyrins are as follows: (1) achieve

broad scope, (2) employ minimal chromatography, and

(3) obtain up to 1-g quantities of porphyrin. The objective

of broad scope has motivated the use of mild reaction

conditions, while the desire to avoid chromatography and

to work on a reasonable scale has prompted the develop-

ment of rational approaches that do not require the

separation of a mixture of porphyrins.

The strategy for the synthesis of meso-substituted

porphyrins depends on the pattern of different substit-

(3) Lindsey, J . S.; MacCrum, K. A.; Tyhonas, J . S.; Chuang, Y.-Y.

J . Org. Chem. 1994, 59, 579-587.

(1) Lindsey, J . S. In Metalloporphyrin-Catalyzed Oxidations; Mon-

tanari, F., Casella, L. Eds.; Kluwer Academic Publishers: Dordrecht,

The Netherlands, 1994; pp 49-86.

(2) Lindsey, J . S. In The Porphyrin Handbook; Kadish, K. M., Smith,

K. M., Guilard, R., Eds.; Academic Press: San Diego, CA, 2000; Vol.

1, pp 45-118.

(4) (a) Little, R. G.; Anton, J . A.; Loach, P. A.; Ibers, J . A. J .

Heterocycl. Chem. 1975, 12, 343-349. (b) Little, R. G. J . Heterocycl.

Chem. 1981, 18, 129-133.

(5) Littler, B. J .; Ciringh, Y.; Lindsey, J . S. J . Org. Chem. 1999, 64,

2864-2872.

Published on Web 09/27/2000

7324 J . Org. Chem., Vol. 65, No. 22, 2000

Rao et al.

Ch a r t 1

(5) trans-AB₂C-porphyrins have been prepared by

statistical reaction of a dipyrromethane and two alde-

hydes, or of two dipyrromethanes and one aldehyde. In

each case the resulting three porphyrins (assuming no

acidolytic scrambling) are then separated chromato-

graphically. In pursuit of rational routes to trans-AB₂C-

porphyrins, we have previously reported methods for

diacylation of dipyrromethanes and reduction of the

resulting diacyl dipyrromethanes to the corresponding

dipyrromethane-dicarbinol.⁹However, the lack of suitable

conditions for performing the dipyrromethane-dicarbinol

+ dipyrromethane reaction stymied the implementation

of this rational route (as also occurred with ABCD-

porphyrins, vide infra). An alternative route to this class

of porphyrins involves treating a 5,15-disubstituted por-

phyrin with an organolithium reagent, quenching with

water, and then treating with an alkyl iodide followed

by oxidation.¹⁰

(6) cis-A₂BC-porphyrins have not been prepared via

rational routes.

(7) ABCD-porphyrins have been prepared in small

amounts by a rational approach involving sequential

introduction of acyl groups (or their equiv) onto the

dipyrromethane nucleus, followed by reduction to the

dipyrromethane-dicarbinol, and then condensation of the

dipyrromethane-dicarbinol with a dipyrromethane.⁹The

methods for monoacylation or diacylation were only

partially selective, in each case affording a mixture of

unreacted, monoacylated, and diacylated species which

were separated by chromatography. The condensation

conditions for the dipyrromethane-dicarbinol + dipyr-

romethane reaction afforded regioisomerically pure por-

phyrin in low yield (<10%). The limitations in dipyr-

romethane chemistry and the low yield of porphyrin

formation limited the scale to milligram quantities of

porphyrins. All acid catalysis conditions examined that

gave higher yields of porphyrins also resulted in scram-

bling. Scrambling must be avoided altogether in the

synthesis of porphyrins bearing three or four different

substituents due to the large number of possible products.

This route to ABCD-porphyrins in principle encompasses

the syntheses of porphyrins bearing two or three different

substituents; however, the low yield, small scale, and

prohibitive levels of chromatography have effectively

limited the applications of this approach. Other routes

to ABCD-porphyrins have also been plagued by one or

more of these problems.¹¹

In this paper, we describe methods for the synthesis

of the five types of meso-substituted porphyrins (A₃B,

trans-AB₂C, cis-A₂B₂, cis-A₂BC, and ABCD) that previ-

ously have been inaccessible by rational routes on a

reasonable scale (up to 1 g) with minimal chromatogra-

phy. Dipyrromethanes provide the starting point for each

porphyrin target. We describe refined conditions for the

diacylation of dipyrromethanes, essential precursors to

A₃B- and trans-AB₂C-porphyrins. Then we build on our

recent method for selective monoacylation of a dipyr-

romethane to achieve sequential acylation, thereby pro-

viding the unsymmetrical diacyl dipyrromethane pre-

scrambling from the condensation of a dipyrromethane

bearing a sterically hindered substituent, such as a

mesityl group, at the 5-position with an aldehyde. A high

level of scrambling is observed under the same conditions

with a dipyrromethane bearing a sterically unhindered

substituent. After an extensive study, we identified

conditions that minimized scrambling for sterically un-

hindered dipyrromethanes, but the porphyrin yield was

poor. Recently we showed that the self-condensation of

a dipyrromethane-monocarbinol (derived from a mono-

acyl dipyrromethane) provides a general method for the

rational synthesis of trans-A₂B₂-porphyrins in good yield

without scrambling.⁶The greater reactivity of the dipyr-

romethane-monocarbinol compared with the dipyrro-

methane + aldehyde condensation enables reaction under

mild acid conditions without scrambling.

(4) cis-A₂B₂-porphyrins have been prepared rationally

in milligram quantities by reaction of a tripyrrane with

a pyrrole-dicarbinol.⁷Statistical syntheses requiring

extensive chromatographic separation have involved

mixed condensations of two aldehydes and pyrrole,^2,4or

a linked dialdehyde, an aldehyde, and pyrrole.⁸

(8) Hwang, K. C.; Mauzerall, D.; Wagner, R. W.; Lindsey, J . S.

Photochem. Photobiol. 1994, 59, 145-151.

(9) Lee, C.-H.; Li, F.; Iwamoto, K.; Dadok, J .; Bothner-By, A. A.;

Lindsey, J . S. Tetrahedron 1995, 51, 11645-11672.

(10) Feng, X.; Senge, M. O. Tetrahedron 2000, 56, 587-590.

(11) Wallace, D. M.; Leung, S. H.; Senge, M. O.; Smith, K. M. J .

Org. Chem. 1993, 58, 7245-7257.

(6) Rao, P. D.; Littler, B. J .; Geier III, G. R.; Lindsey, J . S. J . Org.

Chem. 2000, 65, 1084-1092.

(7) Heo, P.-Y.; Lee, C.-H. Bull. Korean Chem. Soc. 1996, 17, 515-

520.

Rational Syntheses of Porphyrins

J . Org. Chem., Vol. 65, No. 22, 2000 7325

cursors to cis-A₂B₂-, cis-A₂BC-, and ABCD-porphyrins.

Conditions also have been refined for the reduction of

diacyl dipyrromethanes to the corresponding dipyr-

romethane-dicarbinols. A lengthy study has been per-

formed of the acid-catalyzed condensation of a dipyr-

romethane-dicarbinol and a dipyrromethane in order to

achieve the highest possible yield without detectable

scrambling.¹²These routes have proved successful in the

majority of cases examined and broaden the scope of

accessible porphyrin model systems.

methanol afforded dipyrromethane 2o in 92% yield (eq

3). The availability of pure dipyrromethanes in gram

quantities forms the foundation of our rational routes to

meso-substituted porphyrins.

Resu lts a n d Discu ssion

I. Meth od ology for P r ep a r in g P or p h yr in P r ecu r -

sor s

Syn th esis of Dipyr r om eth an es. The dipyrromethanes

were prepared by a one-flask reaction of an aldehyde with

pyrrole.^13,14Aldehydes were obtained commercially (1a -

d , 1f-k ), prepared as described in the literature (1l),¹⁵

or obtained via the Pd-mediated coupling¹⁶of 4-bro-

mobenzaldehyde with trimethylsilylacetylene and triiso-

propylsilylacetylene, respectively (1e and 1m ). According

to a refined procedure,¹³each aldehyde was dissolved in

excess pyrrole at room temperature, treated with TFA

for a few min, and the resulting dipyrromethane was

purified either by bulb-to-bulb distillation followed by

recrystallization or filtration through a pad of silica

followed by recrystallization (eq 1). Distillation (or filtra-

Dia cyla tion of Dip yr r om eth a n es. Dipyrromethanes

with identical acyl groups at the 1- and 9-positions are

key precursors to A₃B-, trans-A₂B₂-, and trans-AB₂C-

porphyrins. An early study showed that treatment of a

dipyrromethane with excess EtMgBr in THF followed by

excess acid chloride produced both the diacylated dipyr-

romethane and monoacylated dipyrromethane.^9,17The

following section summarizes a lengthy series of studies

that attempted to produce the diacyl dipyrromethane as

the sole product. The best conditions identified were then

applied to a variety of dipyrromethanes and acid chlo-

rides. The acid chlorides employed were commercially

available, except for acid chloride 3. The Pd-catalyzed

coupling of ethyl 4-iodobenzoate with triisopropylsily-

lacetylene followed by saponification according to a

procedure¹⁸for the preparation of 4-ethynylbenzoic acid

afforded the required carboxylic acid. Subsequent reac-

tion with thionyl chloride gave acid chloride 3 (eq 4).

(i) Op tim iza tion of Rea ction Con d ition s. For the

optimization study we chose the reaction of 5-phenyl-

(12) The limit of detection of scrambled porphyrins by laser-

desorption mass spectrometry (LD-MS) is approximately 1 part in 100.

Thus, for a porphyrin yield of 25%, any putative single scrambled

(nonisomeric) porphyrin would be present in no greater than 0.25%

yield. Note that the MS method cannot exclude scrambling leading

exclusively to isomeric porphyrins (e.g., trans to cis). However, rear-

rangement processes leading to isomers would be expected to form a

distribution of porphyrin products, including those of other masses.

See ref 6.

(13) Littler, B. J .; Miller, M. A.; Hung, C.-H.; Wagner, R. W.; O’Shea,

D. F.; Boyle, P. D.; Lindsey, J . S. J . Org. Chem. 1999, 64, 1391-1396.

(14) Lee, C. H.; Lindsey, J . S. Tetrahedron 1994, 50, 11427-11440.

(15) Lindsey, J . S.; Prathapan, S.; J ohnson, T. E.; Wagner, R. W.

Tetrahedron 1994, 50, 8941-8968.

(16) Takahashi, S.; Kuroyama, Y.; Sonogashira, K.; Hagihara, N.

Synthesis 1980, 627-628.

tion through silica) removes most higher molecular

weight oligomers and recrystallization removes N-con-

fused dipyrromethane. In this manner, dipyrromethanes

2a -d ,¹³2e,¹⁷2f,¹⁴2g,⁶2h ,¹³and 2l⁶prepared previously

and new dipyrromethanes 2i-k ,m were obtained on a

multigram scale in analytically pure form. Reduction of

2j with DIBAL-H afforded dipyrromethane 2n in 47%

yield (eq 2). Treatment of 2e with K₂CO₃in THF/

7326 J . Org. Chem., Vol. 65, No. 22, 2000

Rao et al.

dipyrromethane (2a ) with EtMgBr and p-toluoyl chloride

as our model system. This reaction affords diacylated

dipyrromethane 4a and monoacylated dipyrromethane

5a (R¹) phenyl, R²) p-tolyl) as shown in eq 5. To

improve the yield of the diacylated compound we altered

the reaction solvent, solvent for EtMgBr, temperature,

concentration, and ratio of dipyrromethane:EtMgBr:acid

chloride. The chelating agent TMEDA was also added to

some reactions. The ratio of 4a :5a in the crude reaction

product was determined with ¹H NMR spectroscopy by

integration of the peaks due to the pyrrolic NH (monoacyl

at δ 8.25, 9.65 ppm; diacyl at δ 11.60 ppm) and/or the

meso CH (monoacyl at δ 5.60 ppm; diacyl at δ 5.72 ppm)

of the acyl dipyrromethanes. A detailed description of

these studies is included in the Supporting Information.

Our major findings are as follows: (1) The best results

were obtained with 0.05 M dipyrromethane and a 1:5:

2.2 molar ratio of dipyrromethane:EtMgBr:acid chloride

in toluene (rather than THF) at room temperature for

10 min. These conditions afford the diacylated and

monoacylated dipyrromethanes (4a , 5a ) in a typical ratio

of 5:1. (2) A decrease in the amount of EtMgBr (2 mol

equiv) caused a substantial decline in diacylated product.

(3) A larger excess of p-toluoyl chloride did not further

increase the amount of diacylated product. (4) Reaction

in toluene was superior to reaction in THF, with no

greater than a 2:1 ratio of diacylated:monoacylated

species obtained in THF. (5) The reaction could be

performed at 6-fold higher concentration (0.3 M dipyr-

romethane) while maintaining the same 1:5:2.2 ratio of

dipyrromethane:EtMgBr:RCOClwithout significant change

in the diacylated:monoacylated ratio (∼4:1). Although

these refined conditions do not afford the diacylated

product exclusively, the higher ratio of diacylated:monoa-

cylated species facilitates purification compared to previ-

ous methods. Note that pure diacyl dipyrromethanes are

essential for the success of these rational routes.¹⁹

(ii) Scop e of th e Refin ed Dia cyla tion P r oced u r e.

The refined procedure was applied to a variety of dipyr-

(17) Cho, W.-S.; Kim, H.-J .; Littler, B. J .; Miller, M. A.; Lee, C.-H.;

Lindsey, J . S. J . Org. Chem. 1999, 64, 7890-7901.

(18) Yashima, E.; Matsushima, T.; Okamoto, Y. J . Am. Chem. Soc.

1997, 119, 6345-6359.

(19) A monoacyl dipyrromethane yields a dipyrromethane-mono-

carbinol on reduction that readily undergoes self-condensation yielding

the corresponding trans-A₂B₂-porphyrin.⁶Thus, the presence of a

monoacyl dipyrromethane impurity in a diacyl dipyrromethane (de-

rived from an intermediate in the diacylation of a dipyrromethane, or

the starting material in the acylation of a monoacyl dipyrromethane)

will likely lead to an unwanted porphyrin contaminant. The success

of the rational syntheses relies on the use of pure dipyrromethanes

and diacyl dipyrromethanes.

Rational Syntheses of Porphyrins

J . Org. Chem., Vol. 65, No. 22, 2000 7327

Ta ble 1. Op tim iza tion of Rea ction Con d ition s for

Acyla tion of Mon oa cyl Dip yr r om eth a n es^a

p-toluoyl

product:

substrate^bsolvent EtMgBr^cchloride

substrate

entry

(mmol)

(2 mL)

(mmol)

(7a :5b)^d

1

2

3

4

5

6

0.50

THF

1.25

1.50

2.00

2.50

3.00

0.75

1.00

1.50

2.00

1.50

1.0:1.0

1.5:1.0

1.8:1.0

2.3:1.0

19:1.0

toluene

>20:1^e

a

b

All reactions were performed at room temperature. 1-Ben-

zoyl-5-(4-methoxyphenyl)dipyrromethane (5b). ^cEtMgBr was used

as a 1.0 M solution in THF. The ratio was determined by ¹H

d

NMR spectroscopic analysis of crude reaction samples. ^eNo un-

reacted substrate could be detected by ¹H NMR spectroscopy.

romethanes (1-15 mmol) and acid chlorides (eq 5). In

each case the crude reaction product was examined by

¹H NMR spectroscopy. The ratio of diacylated and

monoacylated products generally ranged from 1:1 to 5:1

(see Experimental Section). In most cases purification

was achieved by column chromatography followed by

precipitation from boiling aqueous 2-propanol. In some

cases further purification was required, which was

achieved by a second crystallization from CH₂Cl₂-hex-

anes or methanol. The reaction readily afforded reason-

able yields of diacyl dipyrromethanes in most cases, with

the following noticeable exceptions: (1) Reaction with

pentafluorobenzoyl chloride gave low yields (4c, 4e). Our

attempts to improve the yield of 4e by varying the

amounts of EtMgBr, lowering the temperature, or using

sequential addition of EtMgBr and the acid chloride were

unsuccessful. (2) Reactions involving 5-(4-iodophenyl)-

dipyrromethane required two chromatographic columns

followed by recrystallization to obtain pure samples of

compounds 4m , 4o, and 4p . (3) The diacylation with 3,5-

di-tert-butylbenzoyl chloride afforded a rather low yield

of the desired compound 4o. (4) A₃B-porphyrins in which

A is mesityl and B incorporates a synthetic handle have

proved to be very useful building blocks in materials

chemistry.^15,20Diacylation of 5-mesityldipyrromethane

with mesitoyl chloride furnished the corresponding diacyl

dipyrromethane 4q in only 19% yield.

Sequ en tia l Acyla tion of Dip yr r om eth a n es. Dipyr-

romethanes bearing two different acyl groups at the 1-

and 9-positions are required precursors to cis-A₂B₂-, cis-

A₂BC- and ABCD-porphyrins.^9,11We recently reported

that treatment of a dipyrromethane with EtMgBr fol-

lowed by an S-2-pyridyl-substituted benzothioate (6) is

an efficient procedure for the preparation of 1-acyl

dipyrromethanes (5) in multigram quantities.^6,21Our

previous approach toward unsymmetrical diacyl dipyr-

romethanes involved alkylation of a 1-acyldipyrromethane

at the 9-position with a benzoxathiolium tetrafluorobo-

rate, but this route entailed preparation of the benzoxa-

thiolium derivative and then oxidative hydrolysis of the

1-acyl-9-alkyldipyrromethane in order to unveil the 9-acyl

moiety.⁹For a more simple procedure, we envisioned that

further treatment of the 1-acyldipyrromethane with

EtMgBr followed by an acid chloride should enable the

introduction of a second acyl group at the 9-position.

(20) Lammi, R. K.; Ambroise, A.; Balasubramanian, T.; Wagner, R.

W.; Bocian, D. F.; Holten, D.; Lindsey, J . S. J . Am. Chem. Soc. 2000,

122, 7579-7591.

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

J . S. J . Org. Chem. 2000, 65, 3160-3172.

(i) P r ep a r a t ion of Mon oa cyl Dip yr r om et h a n es.

S-2-Pyridyl-substituted benzothioates 6a -c were pre-

7328 J . Org. Chem., Vol. 65, No. 22, 2000

Rao et al.

pared as reported from the corresponding acid chlorides

and 2-mercaptopyridine (eq 6).⁶Thioesters 6d and 6e

were prepared in the same manner in 77% and 88%

yields, respectively. Thioester 6f was synthesized by

coupling thioester 6c with trimethylsilylacetylene using

Pd₂(dba)₃and TEA (instead of Pd(PPh₃)₂Cl₂and N,N-

diisopropylethylamine) (eq 7). These conditions gave an

improved yield and a shorter reaction time.⁶Monoacyl

dipyrromethanes 5b,⁶5c,⁶5h ,²¹and 5d -g were synthe-

sized from the corresponding dipyrromethanes and

thioesters (eq 8).

EtMgBr followed by 3 equiv of acid chloride is referred

to as procedure A.

(iii) Scop e of Acyla t ion of Mon oa cyl Dip yr -

r om eth a n es. The monoacyl dipyrromethanes 5b-e were

converted to diacyl dipyrromethanes 7a -e using proce-

dure A (eq 9). Treatment of monoacyl dipyrromethane

5b with EtMgBr followed by pentafluorobenzoyl chloride

furnished a 1:10 mixture of 5b and 7b. Column chroma-

tography afforded 7b in 49% yield. Similarly, 5c was

treated with p-anisoyl chloride to obtain 7c in 58% yield.

In contrast, treatment of monoacyl dipyrromethanes 5d

or 5e with EtMgBr followed by 4-iodobenzoyl chloride

produced a complex mixture. The desired products 7e and

7d were isolated in about 50% yield from the crude

mixture via column chromatography, but the difficulty

of these separations prompted us to develop a modified

procedure.

(ii) Mod el Acyla tion Stu d y. We chose the reaction

of 1-benzoyl-5-(4-methoxyphenyl)dipyrromethane⁶(5b)

and p-toluoyl chloride as a model system for optimization

of conditions. Thus, a solution of 5b (0.50 mmol) in THF

(2 mL, 0.25 M) at room temperature was treated with

EtMgBr (1.25 mmol) followed by p-toluoyl chloride (0.75

1

To minimize the amount of free EtMgBr present at any

time, we added small portions of the EtMgBr (2, 2, 1

equiv) and acid chloride (1, 1, 0.5 equiv) sequentially and

repeatedly at 10 min intervals (procedure B) rather than

the entire amounts all-at-once (procedure A). Analytically

pure diacyl dipyrromethanes 7e-i were prepared via

procedure B in good yields and substantial quantities

(2-5 g) in a straightforward manner. In the preparation

of diacyl dipyrromethane 7j, the ¹H NMR spectrum of

the product initially isolated indicated the presence of

up to 20% of an unidentified product. Recrystallization

from methanol afforded pure 7j in 22% yield.

mmol) (eq 9). TLC and H NMR analysis indicated the

presence of equal amounts of the desired diacyl dipyr-

romethane 7a and the starting monoacyl dipyrromethane

(entry 1, Table 1). The use of toluene rather than THF

as solvent improved conversion to the diacyl dipyr-

romethane (entry 2). In toluene, as the amount of

EtMgBr and acid chloride increased, so did the consump-

tion of starting material (entries 3-6). Complete con-

sumption of the monoacyl dipyrromethane was achieved

upon treatment of 5b with 6 equiv of EtMgBr and 3 equiv

of p-toluoyl chloride (entry 6). The desired diacyl dipyr-

romethane 7a was isolated in 66% yield after column

chromatography. This procedure where the monoacyl

dipyrromethane is treated all-at-once with 6 equiv of

Red u ction of Dia cyl Dip yr r om eth a n es. The reduc-

tion of diacyl dipyrromethanes can be achieved with

Rational Syntheses of Porphyrins

J . Org. Chem., Vol. 65, No. 22, 2000 7329

excess NaBH₄(50 molar equiv) in THF/methanol (3:1)

as shown in eq 10.^9,17This method (reduction method 1)

worked well in all cases examined with the exception of

7d , where partial cleavage of the trimethylsilyl group

occurred. (It is noteworthy that the TMS-ethynylphenyl

group at the 5-position of diacyl dipyrromethanes 4i and

4j was compatible with such reduction conditions.)

Deprotection of a TMS-ethynyl group has been reported

using NaBH(OMe)₃,²²a likely species in the reaction mix-

ture. As a model study, we examined a variety of con-

ditions for cleanly reducing the TMS-ethyne substituted

monoacyl dipyrromethane 5d (excess NaBH₄in diglyme,

2-propanol/THF or 2-propanol instead of THF/methanol)

but without success. The reduction of 5d was finally

accomplished with the TMS-ethyne group intact with a

10:1 mixture of anhydrous THF/methanol and only 10

molar equiv of NaBH₄. Application of this procedure

(reduction method 2) to diacyl dipyrromethane 7f (1 mmol

scale, 0.75 g) using 20 mmol of NaBH₄afforded the

corresponding dicarbinol with the TMS-ethyne group

intact. In summary, method 1 uses a large amount of

NaBH₄(50 molar equiv) in reagent grade THF/methanol

(3:1). Method 2 uses a smaller excess of NaBH₄(20 molar

equiv) in anhydrous THF/methanol (10:1). The latter

method is attractive because (1) less NaBH₄is used and

(2) TMS-ethyne groups remain intact. Method 2 was

developed during the course of this work and has been

used exclusively for all subsequent reductions.

Attempted reduction of 1,9-dimesitoyl-5-mesityldipyr-

romethane (4q) to the corresponding dicarbinol was

unsuccessful with either method or with a variety of other

hydride reducing agents (NaBH₄-CeCl₃, BH₃-THF, Li-

AlH₄, NaAlH₄, LiBH₄). Thus at present, mesityl groups

cannot be introduced into the porphyrin nucleus via

acylation of a dipyrromethane.

II. Non scr a m blin g Con d ition s for th e Con d en sa -

tion of a Dip yr r om eth a n e-Dica r bin ol a n d a Dip yr -

r om eth a n e

The development of nonscrambling conditions is es-

sential for the rational synthesis of porphyrins in con-

densations employing dipyrromethanes. We readily iden-

tified conditions for the nonscrambling condensation of

a sterically hindered dipyrromethane and an aldehyde,

but identification of nonscrambling conditions for the

condensation of a sterically unhindered dipyrromethane

and an aldehyde proved more difficult.⁵We eventually

identified conditions that gave little or no scrambling for

the latter reaction, albeit in less than 10% yield: con-

densation at 10 mM in acetonitrile at 0 °C with BF₃‚Et₂O

in the presence of NH₄Cl, followed by DDQ oxidation.⁵

We applied these conditions to the reaction of a dipyr-

romethane-dicarbinol and a dipyrromethane (10 mM

each), and also to the reaction of heteroatom-substituted

substrates (a furylpyrromethane-dicarbinol or thienylpyr-

romethane-dicarbinol) leading to the corresponding het-

eroatom-substituted (N₃O, N₃S) porphyrins.¹⁷Compared

to the dipyrromethane + aldehyde condensation, the

dipyrromethane-dicarbinol + dipyrromethane condensa-

tion proceeded much more rapidly, gave higher yields and

produced no detectable scrambled byproducts.¹²However,

the elimination of scrambling was critically dependent

on using a minimum amount of acid. With 1 mM BF₃‚

Et₂O, capricious variations in the reaction rate and

isolated yield of porphyrin were observed. Increasing the

acid concentration to 2 mM overcame some of the

variability, but increasing the BF₃‚Et₂O concentration to

5 mM resulted in the production of scrambled byproducts.

For the rational syntheses described herein, we un-

dertook a detailed study aimed at refining the low-

scrambling reaction conditions for the dipyrromethane-

dicarbinol + dipyrromethane condensation. This study

had two principal aims: (1) maximize the yield with no

scrambling; (2) find conditions that produce consistent

kinetics and yields. We employed a model system em-

ploying dipyrromethane 2a and the dipyrromethane-

dicarbinol derived from 4a to obtain trans-A₂B₂-porphyrin

(22) Myers, A. G.; Harrington, P. M.; Kuo, E. Y. J . Am. Chem. Soc.

1991, 113, 694-695.

7330 J . Org. Chem., Vol. 65, No. 22, 2000

Rao et al.

F igu r e 2. Effect of the TFA concentration on the porphyrin

yield. Reactions were performed with 2.5 mM dipyrromethane-

dicarbinol (derived from 4a ) and 2.5 mM dipyrromethane (2a )

in acetonitrile at room temperature. The yield of porphyrin

8a was determined spectroscopically upon oxidation of reaction

aliquots with DDQ. No scrambling was detected at any

concentration. Legend: b 1.00 mM TFA; O 3.16 mM TFA; 1

10.0 mM TFA; 3 31.6 mM TFA; 9 100 mM TFA.

F igu r e 1. Effect of the reaction solvent on the porphyrin yield.

Reactions were performed with 2.5 mM dipyrromethane-

dicarbinol (derived from 4a ) and 2.5 mM dipyrromethane (2a )

at room-temperature catalyzed by 20 mM TFA. The yield of

porphyrin 8a was determined spectroscopically upon oxidation

of reaction aliquots with DDQ. See text for results of the

scrambling assay. Legend: O nitromethane; b acetonitrile; 4

CH₂Cl₂; 2 CHCl₃; 9 toluene; 0 DMF; [ ethyl acetate; ]

DMSO; 1 diethyl ether; 3 THF.

∼10% porphyrin yield with no scrambling. From 1 to 30

min the porphyrin yield continued to increase, but the

improvement in yield was outweighed by the production

of scrambled porphyrins. After 30 min in CH₂Cl₂and

toluene, severe scrambling had occurred, but in CHCl₃

only a small amount of the scrambled products was

detected. (3) CH₃CN and CH₃NO₂gave the highest yields.

Reaction in acetonitrile was complete within 1 min and

showed no increase in yield up to 30 min, and no

scrambling was detected by LD-MS at all timepoints. In

contrast, reaction in nitromethane produced a small

increase in yield from 1 to 30 min, but this was ac-

companied by the production of small amounts of

scrambled byproducts. Therefore, acetonitrile was the

solvent used in the subsequent studies.

Acid Con cen tr a tion . The effect of the concentration

of TFA (1.00 mM to 100 mM) was examined on the yield

and extent of scrambling in acetonitrile at room temper-

ature. Figure 2 shows that an increase in the amount of

acid led to an increase in the porphyrin yield. No

scrambling was detected by LD-MS at all timepoints,

even at 100 mM TFA.

Con cen tr ation of Dipyr r om eth an e-Dicar bin ol an d

Dip yr r om eth a n e. Large volumes of solvent are required

for preparative-scale syntheses if the reaction is per-

formed with the dipyrromethane-dicarbinol and dipyr-

romethane at 2.5 mM. Therefore, we studied whether the

reaction could be performed at a 4-fold higher concentra-

tion. The reactions were performed in acetonitrile at room

temperature and over a TFA concentration range from

10.0 mM to 316 mM. As shown in Figure 3, reaction at

10 mM dipyrromethane-dicarbinol and dipyrromethane

resulted in a lower yield of porphyrin compared with

reaction at 2.5 mM. The higher acid concentration

employed at higher reactant concentration also resulted

in scrambling at long reaction times. No scrambling was

detected at 1 min over the range of TFA concentration

studied. At 30 min the reactions catalyzed by 10.0 mM

and 31.6 mM showed no scrambling, but the reactions

8a (eq 11). In this system, the combination of phenyl and

p-tolyl substituents allows resolution of scrambled por-

phyrins in the LD-MS spectrum while minimizing steric

and electronic differences.

Acid Ca ta lyst. Both BF₃‚Et₂O/NH₄Cl and TFA af-

forded trans-porphyrins with minimal scrambling from

the dipyrromethane + aldehyde condensation. We de-

cided to focus on TFA for two reasons: (1) BF₃‚Et₂O/

NH₄Cl afforded capricious results in the dipyrromethane-

dicarbinol + dipyrromethane condensations in the het-

eroatom porphyrin study,¹⁷and (2) a detailed study into

the pyrrole + aldehyde condensation showed that reac-

tions performed with TFA produced more consistent

reaction kinetics and porphyrin yields compared to those

performed using the BF₃‚Et₂O/NH₄Cl catalyst system.⁵

Because the pyrrole + aldehyde and dipyrromethane +

aldehyde condensations catalyzed by TFA in previous

studies showed little or no salt effect, all reactions were

performed with no added salts. (See the Supporting

Information of ref 5 for a thorough description of studies

comparing TFA and BF₃‚Et₂O in the dipyrromethane +

aldehyde reaction.)

Solven t. We examined the dipyrromethane-dicarbinol

+ dipyrromethane condensation in 10 different solvents.

The reaction conditions chosen were based on the optimal

conditions for the pyrrole + aldehyde condensation under

TFA catalysis; 10 mM pyrrole, 10 mM aldehyde, and 20

mM TFA. Because the dipyrromethane building blocks

each contain two pyrrole units, 2.5 mM dipyrromethane-

dicarbinol and 2.5 mM dipyrromethane were used to

maintain an overall “pyrrole” and “aldehyde” concentra-

tion of 10 mM. The solvents examined fell into three

major categories (Figure 1). (1) DMF, ethyl acetate,

DMSO, diethyl ether, and THF gave a reaction that was

complete within 1 min and afforded the porphyrin in poor

yield (<6%) but with no scrambling at all times. (2)

CH₂Cl₂, CHCl₃(containing 0.75% ethanol), and toluene

gave an initial fast reaction within 1 min that afforded

Rational Syntheses of Porphyrins

J . Org. Chem., Vol. 65, No. 22, 2000 7331

decline in yield was only pronounced when the solvent

was cooled close to its freezing point.

Op tim a l Rea ction Con d ition s. From the data pre-

sented above we conclude that the optimal condensation

conditions are 2.5 mM dipyrromethane-dicarbinol and 2.5

mM dipyrromethane with 31.6 mM TFA in acetonitrile

at room temperature. The reaction is complete within 1

min and proceeds with no detectable scrambling. For

convenience we have employed 30 mM TFA for all

synthetic applications. The significant advantages of the

optimized conditions compared to those previously em-

ployed in the heteroatom porphyrin study (10 mM

dipyrromethane-dicarbinol and 10 mM dipyrromethane

catalyzed by 1.0 mM BF₃‚Et₂O in acetonitrile at 0 °C in

the presence of 100 mM NH₄Cl)¹⁷are as follows: (1)

higher yield (30% vs 15%); (2) the reaction rate, porphyrin

yield, and extent of scrambling are less sensitive to the

exact amount of acid catalyst added; (3) reaction condi-

tions are more simple (no added salt, no cooling in an

ice-bath). These refined conditions have already proved

effective in several applications.^21,23,24

F igu r e 3. Effect of a higher concentration of reactants on the

porphyrin yield. Reactions were performed with dipyrrometh-

ane-dicarbinol (derived from 4a ) and dipyrromethane (2a ) (10

mM each) in acetonitrile at room temperature. The yield of

porphyrin 8a was determined spectroscopically upon oxidation

of reaction aliquots with DDQ. See text for results of the

scrambling assay. Legend: b 10.0 mM TFA; 9 31.6 mM TFA;

2 100 mM TFA; [ 316 mM TFA. (0 Calibration reaction

performed with 2.5 mM dipyrromethane-dicarbinol, 2.5 mM

dipyrromethane, and 31.6 mM TFA.)

III. Syn th esis of P or p h yr in s

To prepare the target porphyrins, the desired diacyl

dipyrromethane was reduced to the corresponding di-

carbinol (using method 1 or 2; see Experimental Section),

and then immediately condensed with the desired dipyr-

romethane under the optimal conditions delineated above

(2.5 mM of each dipyrromethane species in acetonitrile

containing 30 mM TFA at room temperature, followed

within a few minutes by oxidation with DDQ). A sample

from each porphyrin-forming reaction was analyzed by

LD-MS to examine for the presence of scrambled por-

phyrin products. The porphyrins were isolated by a

simple process involving the following steps: (1) filtration

through a pad of alumina to remove quinone species, (2)

removal of solvent under reduced pressure, (3) one silica

gel chromatography procedure, and (4) recrystallization,

trituration of a suspension in hot alcohol, or sonication

of a suspension in alcohol.

Tr a n s-A₂B₂-p or p h yr in s. The best syntheses of trans-

A₂B₂-porphyrins employ condensation of a dipyrromethane

+ aldehyde⁵or self-condensation of a dipyrromethane-

monocarbinol.⁶While the synthesis of a trans-A₂B₂-

porphyrin by the condensation of an A-dipyrromethane

and a BAB-dipyrromethane-dicarbinol²⁵has little pre-

parative merit, this route is useful for studies of scram-

bling and examination of substituent effects. Thus,

porphyrin 8a (eq 11) was prepared for scrambling studies,

and porphyrin 8b (Scheme 1) was prepared in order to

examine the effect of the strongly electron-withdrawing

pentafluorophenyl group (vide infra).

A₃B-p or p h yr in s. A₃B-porphyrins can be prepared in

two different ways, involving either an A₃-dipyrromethane-

dicarbinol + B-dipyrromethane, or an ABA-dipyrrometh-

ane-dicarbinol + A-dipyrromethane (Scheme 1). The

former route was followed for porphyrins 9a -i, while the

latter was employed for porphyrin 9j. The efficacy of the

reaction was slightly different with aryl versus alkyl

substituted dipyrromethanes.

F igu r e 4. Effect of temperature on the porphyrin yield.

Reactions were performed with 2.5 mM dipyrromethane-

dicarbinol (derived from 4a ) and 2.5 mM dipyrromethane (2a )

in acetonitrile catalyzed by 31.6 mM TFA. The yield of

porphyrin 8a was determined spectroscopically upon oxidation

of reaction aliquots with DDQ. Legend: b -20 °C to -30 °C;

9 0 °C; 2 room temperature; [ 40 °C.

catalyzed by 100 mM and 316 mM TFA produced

scrambled products that were detected by LD-MS. The

extent of scrambling was related to the acid concentration

because trace scrambling was observed with 100 mM

TFA, but severe scrambling was seen with 316 mM TFA.

(23) Miller, M. A.; Lammi, R. K.; Prathapan, S.; Holten, D.; Lindsey,

J . S. J . Org. Chem. 2000, 65, 6634-6649.

Rea ction Tem p er a tu r e. Finally, we studied the

effect of different reaction temperatures on the porphyrin

yield for the condensation of 2.5 mM dipyrromethane-

dicarbinol and dipyrromethane in acetonitrile catalyzed

by 31.6 mM TFA. As shown in Figure 4, the porphyrin

yield decreased at lower reaction temperatures, but the

(24) (a) Clausen, C.; Gryko, D. T.; Yasseri, A. A.; Diers, J . R.; Bocian,

D. F.; Kuhr, W. G.; Lindsey, J . S. J . Org. Chem. 2000, 65, 7371-7378.

(b) Li, J .; Gryko, D.; Dabke, R. B.; Diers, J . R.; Bocian, D. F.; Kuhr, W.

G.; Lindsey, J . S. J . Org. Chem. 2000, 65, 7379-7390.

(25) In the term XYZ-dipyrromethane-dicarbinol, the X, Y, and Z

refer to the 1-, 5-, and 9-positions, respectively.

7332 J . Org. Chem., Vol. 65, No. 22, 2000

Rao et al.

A₃B-porphyrins (A ) aryl): The diacyl dipyrromethanes

4f and 4e were reduced using NaBH₄and the resulting

dicarbinols were condensed with 5-phenyldipyrromethane

(2a ) to give porphyrins 9a and 9b in 27% and 18% yields,

respectively. In the case of 9b (A ) pentafluorophenyl),

further column chromatography was required to obtain

the pure porphyrin. The porphyrins 9c and 9d were

prepared in 25% and 18% yields by reducing 4n followed

by condensation with 2h and 2i, respectively. The di-

carbinol obtained after the reduction of 4i when con-

densed with 5-(4-tert-butylphenyl)dipyrromethane (2g)

afforded the porphyrin 9j in 27% yield. LD-MS analysis

of crude reaction samples showed no scrambling during

the synthesis of these porphyrins.

A₃B-porphyrins (A ) pentyl): Porphyrins 9e-i were

prepared by the condensation of the tripentyldipyr-

romethane-dicarbinol derived from 4k with various meso-

substituted dipyrromethanes (Scheme 1). The LD-MS

analysis of crude reaction samples revealed no scram-

bling during the formation of porphyrins 9g and 9i, but

low levels of scrambling were detected in the formation

of porphyrins 9e, 9f, and 9h . In the latter cases, purifica-

tion by column chromatography on silica followed by

trituration with refluxing ethanol furnished the pure

porphyrin products. The synthesis of porphyrins 9e-i

show that electron-donating groups at the 5-position of

the dipyrromethane increase the yield of the porphyrin

during the condensation. The yields range from 35% (4-

acetamidophenyl) to 14% (pentafluorophenyl).

porphyrins is shown in Scheme 2. The diacyl dipyr-

romethanes 7h and 7i were reduced to the corresponding

dicarbinols and condensed with dipyrromethanes 2h and

2m to afford porphyrins 11a (1.18 g) and 11b (0.53 g),

respectively. The diacyl dipyrromethane 7j (bearing two

pentafluorophenyl groups) on reduction followed by

condensation with 2h furnished a mixture of products

along with desired porphyrin 11c. LD-MS analysis of this

sample gave a peak consistent with the corresponding

mono-pentafluorophenyl-substituted corrole in addition

to the desired porphyrin which could not be obtained in

pure form. Corrole formation is known to be favored with

electron-withdrawing substituents.²⁶LD-MS analysis of

the crude reaction samples showed no scrambling during

the synthesis of the other porphyrins in this set.

Cis-A₂BC-p or p h yr in s. The synthesis of a cis-A₂BC-

porphyrin requires an unsymmetrical diacyl dipyrro-

methane. One approach involves an ABC-dipyrromethane-

dicarbinol + A-dipyrromethane, while an alternative

approach employs an AAB-dipyrromethane-dicarbinol +

C-dipyrromethane. Porphyrins 12a -c were prepared via

the former route in yields of 16-29%. Reduction method

2 was employed with diacyl dipyrromethanes bearing

TMS or TIPS-ethyne groups (7f, 7g). Porphyrin 12d was

prepared following the second route from diacyl dipyr-

romethane 7h and dipyrromethane 2e in 26% yield

(Scheme 2). LD-MS analysis of the crude reaction samples

showed no scrambling during the synthesis of these

porphyrins.

Tr a n s-AB₂C-p or p h yr in s. Retrosynthetic analysis of

trans-AB₂C-porphyrins reveals two distinct approaches

involving either a BAB-dipyrromethane-dicarbinol +

C-dipyrromethane (Scheme 1) or an ABC-dipyrromethane-

dicarbinol + B-dipyrromethane (Scheme 2). The former

route is more efficient as only one diacylation procedure

is required, while the latter route requires sequential

introduction of the two acyl units. Several noteworthy

observations were made during the course of these

syntheses. (1) Porphyrin 10a was prepared from 4d and

2a in 36% yield, consistent with other reactions (vide

infra) in which a pentafluorophenyl group in the 5-posi-

tion of the dipyrromethane-dicarbinol increased the por-

phyrin yield. (2) The synthesis of porphyrin-carboxalde-

hyde 10d from 4o and formyl-substituted dipyrromethane

2n illustrates the high chemoselectivity of the condensa-

tion. Reaction occurs much faster at the carbinol than

at the formyl group, affording the intact porphyrin-

carboxaldehyde 10d in 17% yield as the only porphyrin

product. (3) A 0.9-g batch (22% yield) of porphyrin 10e

was prepared from 4p and the ester-substituted dipyr-

romethane (2l). (4) Since the mesitoyl group could not

be reduced to the corresponding carbinol, we used an

ABC-dipyrromethane-dicarbinol + B-dipyrromethane to

prepare the desired trans-AB₂C-porphyrin 10f, where B

) mesityl (Scheme 2). This route requires synthesis of

the unsymmetrical diacyl dipyrromethane but provides

the only rational route at present to obtain the desired

porphyrin with mesityl groups occupying trans-positions.

(5) No scrambling was detected upon LD-MS analysis of

the crude reaction samples during the synthesis of any

of these trans-AB₂C-porphyrins.

ABCD-p or p h yr in s. Five ABCD-porphyrins were pre-

pared as shown in Scheme 2. Noteworthy observations

from this set are as follows. (1) Reduction of diacyl

dipyrromethane 7e (method 1) and reaction with dipyr-

romethane 2m resulted in a 1:1 mixture of desired

porphyrin 13b and desilylated porphyrin (loss of TMS)

in 25% total yield. Upon application of reduction method

2, porphyrin 13b was obtained in good yield (1.05 g, 27%)

without loss of the TMS group and with no detectable

scrambling. (2) Porphyrins 13b and 13d each bear three

functional groups that can be selectively manipulated and

are potential building blocks for the construction of “T-

shaped” porphyrin architectures. The former contains one

iodo group and two protected ethynes, while the latter

contains three ethynes that can be reacted sequentially

(unprotected, TMS-protected, and TIPS-protected). (3)

Porphyrin 13e, prepared in >1-g quantity, bears four

different functional groups for sequential elaboration via

Pd coupling reactions. LD-MS analysis of the crude

reaction samples indicated no detectable scrambling in

any of these reactions.

(IV) Ta ctica l Con sid er a tion s

The rational routes to porphyrins described herein are

compatible with diverse functionalities: amide, aldehyde,

carboxylic acid, ester, nitrile, ether, bromo, iodo, ethyne,

TMS-ethyne, TIPS-ethyne, and perfluoroarene. The suc-

cessful formation of the porphyrin in optimal yield

requires appropriate placement of substituents in the

dipyrromethane precursors, taking into consideration

electronic effects, steric effects, and functional group

reactivity.

Effect of Su bstitu en ts on th e Dip yr r om eth a n e-

Dica r bin ol + Dip yr r om eth a n e Con d en sa tion . The

reactions of a number of the dipyrromethanes and

Cis-A₂B₂-p or p h yr in s. Retrosynthetic analysis reveals

that regardless of the disconnection, the dipyrromethane

must be sequentially acylated with two different groups,

one of which introduces the same substituent that is

present at the 5-position. The synthesis of three cis-A₂B₂-

(26) Gross, Z.; Galili, N.; Saltsman, I. Angew. Chem., Int. Ed. 1999,

38, 1427-1429.

Rational Syntheses of Porphyrins

J . Org. Chem., Vol. 65, No. 22, 2000 7333

Sch em e 1

7334 J . Org. Chem., Vol. 65, No. 22, 2000

Rao et al.

Sch em e 2

Rational Syntheses of Porphyrins

J . Org. Chem., Vol. 65, No. 22, 2000 7335

dipyrromethane-dicarbinols provide insight into the elec-

tronic effects of substituents. The outcome is quite

different for the 5-position of a dipyrromethane and the

5-position of a dipyrromethane-dicarbinol. For substitu-

ents at the 5-position of a dipyrromethane, the yield

increases with electron-releasing strength. A clear trend

is seen in the formation of porphyrins 9e-i, where the

yield increases from 14% (pentafluorophenyl) to 35% (4-

acetamidophenyl). Conversely, for substituents at the

5-position of a dipyrromethane-dicarbinol, a higher yield

is obtained with pentafluorophenyl (13c, 40%) than with

mesityl (13b, 27%). In general, the presence of a pen-

tafluorophenyl group at the 5-position of a dipyr-

romethane-dicarbinol affords high yields, as observed

with porphyrins 10a (36%) and 12a (formed from 7c +

2a ; 29% yield). These results are consistent with those

observed during the self-condensation of dipyrromethane-

monocarbinols.⁶

The final condensation is quite tolerant of the substit-

uents in the dipyrromethane-dicarbinol or dipyrromethane.

Significant problems have been encountered in only a few

cases. (1) Dipyrromethane-dicarbinols bearing two or

three pentafluorophenyl groups can give side reactions.

With one pentafluorophenyl group at either the 5-position

(10a , 12a from 7c + 2a , 13c) or at one of the carbinol

positions (12a from 7b + 2a ), the reaction proceeded

smoothly and gave porphyrin in yields of 20-40%. With

pentafluorophenyl groups at both of the carbinol positions

(8b), reaction also proceeded smoothly (24%). However,

with pentafluorophenyl groups at the 5-position and one

(11c) or both of the carbinol positions (9b), the reaction

was not clean and further purification was required to

obtain the desired porphyrin. (2) The tripentyl-substi-

tuted dipyrromethane-dicarbinol reacts poorly. A low

level of scrambling was observed in the syntheses of

porphyrins 9e, 9f, and 9h , though in each case the target

porphyrin could be purified by chromatography. (3)

Dipyrromethanes bearing heterocyclic substituents (e.g.,

pyridyl) react very poorly under these conditions but can

be reacted with dipyrromethane-dicarbinols without

scrambling under modified condensation conditions.²⁷

A striking example of the selective and mild nature of

the dipyrromethane-dicarbinol + dipyrromethane con-

densation is provided by the formation of the porphyrin-

carboxaldehyde 10d . The direct synthesis of 10d without

using an aldehyde protecting group was prompted by our

observation that the reaction of a dipyrromethane-

carbinol is much faster than the reaction of a dipyr-

romethane and an aldehyde.²⁸(This observation under-

pinned the development of the nonscrambling synthesis

of trans-A₂B₂-porphyrins by the self-condensation of a

sterically unhindered dipyrromethane-monocarbinol.⁶)

Porphyrin-carboxaldehydes are useful building blocks but

have formerly only been prepared with the aldehyde in

masked form. This direct synthesis of a porphyrin-

carboxaldehyde suggests the possibility of incorporating

a variety of very sensitive, unprotected groups in the

dipyrromethane unit with subsequent conversion to the

corresponding porphyrin.

the use of EtMgBr and acid chlorides, the scope of

compatible functional groups (e.g., alkyl, bromophenyl,

iodophenyl, methoxyphenyl, TMS-ethynylphenyl, TIPS-

ethynylphenyl, pentafluorophenyl) incorporated into di-

acyl dipyrromethanes is substantial. The broad compat-

ibility likely reflects the rapid formation of the pyrrolic

magnesium bromide derivative of the dipyrromethane,

which is substantially less reactive than EtMgBr. Evi-

dence of such diminished reactivity stems from the ability

to introduce a second acyl unit into a monoacyl dipyr-

romethane (by treatment with EtMgBr followed by an

acid chloride) without significant attack on the first acyl

unit. Still, the reaction conditions required to convert a

dipyrromethane to a dipyrromethane-dicarbinol are far

more demanding than those in forming the dipyr-

romethane itself. Given these different reaction condi-

tions, and the fact that up to four different groups can

be incorporated in the meso-substituted porphyrin, the

issue arises as to the optimal order and components in

which the groups should be introduced.²⁹In exploring the

generality of these routes, involving the preparation of

27 diacyl dipyrromethanes and 30 porphyrins, the fol-

lowing heuristics have emerged concerning the order of

introduction of various groups (precursors to the porphy-

rin meso substituents).

(1) A substituent that is vulnerable to attack by

EtMgBr or reduction by NaBH₄[e.g., acetamide (9i),

terminal ethyne (13d ), aldehyde (10d ), carboxylic acid

(9d ), ester (10e), nitrile (9g)] should be introduced during

the final condensation through the incoming dipyr-

romethane.

(2) The dipyrromethane to be acylated should carry the

most resistant of the required groups at the 5-position

(e.g., 13d ).

(3) In successive acylation yielding an unsymmetrical

diacyl dipyrromethane, the group that is more resistant

to attack by EtMgBr should be introduced in the first

acylation via the thioester reagent (e.g., 7d , 7e, 7g, 7h ).

(4) The inability to reduce a mesitoyl-substituted

dipyrromethane requires that mesityl groups be intro-

duced at the 5-position of a dipyrromethane or dipyr-

romethane-dicarbinol (e.g., 10f, 13b, 13d ).

Con clu sion

The synthesis of porphyrins bearing different meso

substituents has presented a number of challenges.

Porphyrins bearing two different substituents (A₃B,

trans-A₂B₂, cis-A₂B₂) have been available via a statistical

condensation of pyrrole with two aldehydes, albeit in

small quantities following extensive chromatography.

Porphyrins with three (cis-A₂BC, trans-AB₂C) or four

(ABCD) different substituents require rational syntheses.

The success of rational syntheses requires the absence

of acidolytic scrambling of the location of substituents

at all stages of the synthesis. As such, the rational

synthesis of substituted porphyrins involves methodology

at the other extreme from the one-flask pyrrole-aldehyde

condensation leading to A₄-porphyrins. The rational

(ii) Or d er of In tr od u ction of Gr ou p s. The rational

routes to the porphyrins described herein rely on the

preparation of diacyl dipyrromethanes and their subse-

quent reduction to the corresponding dicarbinol. Despite

(29) For a given ABCD-porphyrin, there are four possible dipyr-

romethane-dicarbinol + dipyrromethane condensations, and two pos-

sible orderings for introducing the two acyl units into each of the

corresponding diacyl dipyrromethanes. Thus there are eight possible

routes for preparing a given ABCD-porphyrin. Note that this is an

ordering issue and does not involve isomers of the given ABCD-

porphyrin. See Supporting Information for consideration of routes to

the other classes of meso-substituted porphyrins.

(27) Gryko, D.; Lindsey, J . S. J . Org. Chem. 2000, 65, 2249-2252.

(28) Geier, G. R., III.; Lindsey, J . S. Manuscripts in preparation.

7336 J . Org. Chem., Vol. 65, No. 22, 2000

Rao et al.

reaction mixture was determined as described previously.^5,31

In some cases, the final step in purification involved a

procedure in which the porphyrin product was suspended in

alcohol and the suspension was sonicated for a few minutes

in a standard benchtop ultrasonic cleaning bath, followed by

filtration.

Aldehydes 1a -d and 1f-k were obtained commercially. The

following compounds were prepared as described in the

literature: aldehyde 1l;¹⁵dipyrromethanes 2a -d ,¹³2e,¹⁷2f,¹⁴

2g,⁶2h ,¹³and 2l;⁶monoacyl dipyrromethanes 5b, 5c, and 5h ;⁶

S-2-pyridyl benzothioates 6a -c.⁶

Stu d ies of th e Dip yr r om eth a n e-Dica r bin ol + Dip yr -

r om et h a n e Con d en sa t ion . A sample of 4a (275 mg, 0.60

mmol) was reduced by NaBH₄(1.13 g, 30.0 mmol) in THF/

methanol (3:1, 40 mL) to afford upon workup the corresponding

dipyrromethane-dicarbinol as a foamlike solid (reduction

method 1). Due to the limited stability of the dipyrromethane-

dicarbinol, 60 mL of acetonitrile was immediately added, and

a 10-mL portion of the dipyrromethane-dicarbinol was placed

in each of five separate reaction flasks (10 mmol each). For

the study examining the effect of the reaction solvent, the

acetonitrile was then removed under vacuum, and the solvent

of interest was added. For all other reactions additional

acetonitrile was added if required to give the desired reagent

concentration, and then 2a was added. The reactions were then

performed in sets of five, starting one reaction every 6 min by

the addition of TFA. The reaction yield and extent of scram-

bling were determined at 1, 5, 15, and 30 min by UV-vis

spectroscopy and LD-MS, respectively, as described previ-

ously.⁵

methodology developed herein has four stages: (1) a one-

flask synthesis of dipyrromethanes, (2) preparation of a

symmetrical diacyl dipyrromethane by diacylation or an

unsymmetrical diacyl dipyrromethane by sequential acy-

lation, (3) reduction of the diacyl dipyrromethane to the

dipyrromethane-dicarbinol, and (4) nonscrambling con-

densation of a dipyrromethane-dicarbinol + dipyr-

romethane followed by oxidation to give the porphyrin.

Refinement has been made to steps 2-4 in order to

achieve broad scope, minimal chromatography, and ease

of implementation. The diacyl dipyrromethanes are

analytically pure and are available in multigram quanti-

ties. Although the yields of the dipyrromethane-di-

carbinol + dipyrromethane reaction range from only 14

to 40%, the absence of detectable scrambling in almost

all cases greatly diminishes the chromatography required

for purification. In general, we find that with the

requisite starting materials (pyrrole- and carbonyl-

containing compounds) in hand, 0.1-1 g quantities of a

porphyrin can be prepared in a straightforward manner

in about one week. The rational routes described encom-

pass A₃B-, trans-AB₂C-, cis-A₂B₂-, cis-A₂BC-, and ABCD-

porphyrins. The ability to prepare significant quantities

of such porphyrins in pure form may prove useful in a

variety of biomimetic and materials applications.

Exp er im en ta l Section

4-[2-(Tr im eth ylsilyl)eth yn yl]ben za ld eh yd e (1e).³²Pre-

pared by an improved procedure (see Supporting Information).

4-[2-(Tr iisop r op ylsilyl)et h yn yl]b en za ld eh yd e (1m ).

4-Bromobenzaldehyde (4.62 g, 25.0 mmol), Pd(PPh₃)₂Cl₂(0.105

g, 0.15 mmol), and CuI (0.57 g, 3.0 mmol) were placed in a

Schlenk flask which was thoroughly flushed with argon. Then

degassed triethylamine (50 mL) followed by triisopropylsilyl-

acetylene (5.47 g, 30.0 mmol) were introduced, and the flask

was sealed. The contents of the flask were stirred at 80 °C for

12 h. Then the reaction mixture was cooled to room temper-

ature, the solids were removed by filtration, and the filtrate

was concentrated. The crude brown oil was bulb-to-bulb

distilled (130-140 °C at 0.02 mmHg) to obtain a colorless

liquid (6.05 g, 84%). ¹H NMR δ 1.14 (m, 21H), 7.61 (d, J ) 8.1

Hz, 2H), 7.82 (d, J ) 8.1 Hz, 2H), 10.00 (s, 1H); ¹³C NMR δ

11.4, 18.8, 95.9, 106.1, 129.6, 129.9, 132.7, 135.6, 191.6. Anal.

Calcd for C₁₈H₂₆OSi: C, 75.46; H, 9.15. Found: C, 75.37; H,

9.09.

5-(4-Ca r boxyp h en yl)d ip yr r om eth a n e (2i). Following a

general procedure,¹³a mixture of pyrrole (60 mL, 0.86 mol)

and 4-carboxybenzaldehyde (2.60 g, 17.3 mmol) was flushed

with argon for 5 min and treated with TFA (0.133 mL, 1.73

mmol), and the mixture was stirred for 5 min. 0.1 M aq NaOH

(50 mL) and ethyl acetate (100 mL) were added, and the layers

were separated. The aqueous layer was acidified with dil HCl

solution and extracted again with ethyl acetate. The combined

organic layers were washed with brine, dried (Na₂SO₄), and

concentrated to remove the excess pyrrole. Column chroma-

tography [silica, CH₂Cl₂/ethyl acetate (3:1)] afforded a pale

brown oil which was dissolved in a 1:20 mixture of water and

ethanol and was allowed to crystallize at 0 °C overnight,

affording a blue solid that was filtered and dried in vacuo (2.35

g, 51%). mp 149-150 °C; ¹H NMR (acetone-d₆) δ 5.55 (s, 1H),

5.76 (m, 2H), 6.05 (m, 2H), 6.70 (m, 2H), 7.34 (d, J ) 8.1 Hz,

2H), 7.96 (d, J ) 8.1 Hz, 2H), 9.75 (br, 2H) (acid hydrogen not

observed); ¹³C NMR δ 44.9, 107.7, 108.3, 118.2, 129.4, 129.6,

130.5, 133.3, 149.9, 167.9. Anal. Calcd for C₁₆H₁₄N₂O₂: C,

72.16; H, 5.30; N, 10.52. Found: C, 71.50; H, 5.38; N, 10.25.

Gen er a l. ¹H (300 MHz) and ¹³C (75 MHz) NMR spectra

were obtained in CDCl₃unless noted otherwise. Absorption

spectra were collected routinely. Elemental analyses were

performed by Atlantic Microlab, Inc. Melting points are

uncorrected. Bulb-to-bulb distillations were performed using

a standard-size Kugelrohr short path distillation apparatus

(Aldrich). Silica gel (Baker, 40 µm average particle size) and

alumina (Fisher, 80-200 mesh) were used for column chro-

matography. The CHCl₃was reagent grade and contained

0.75% ethanol. Dipyrromethanes were prepared as described

previously and analyzed for purity by gas chromatography.⁹

The dipyrromethanes, diacyl dipyrromethanes, and dipyr-

romethane-dicarbinols were easily detected in TLC upon

exposure to Br₂vapor.

The acylations with acid chlorides were performed in freshly

distilled toluene (from CaH₂). The acid chlorides were of

reagent grade and were used as obtained. In all acylation pro-

cedures involving EtMgBr and an acid chloride, TLC analysis

indicated the presence of fast-migrating dark impurities (not

characterized) which were readily removed during chromato-

graphic purification. Purification of the diacyl dipyrromethanes

was increasingly difficult with the presence of increased

amounts of unreacted monoacyl dipyrromethane. Isolation of

the diacyl dipyrromethanes following column chromatography

generally was achieved by (a) slow precipitation from hot

2-propanol/water, or (b) slow precipitation from CH₂Cl₂/hex-

anes (or in other solvents as specified) at room temperature

with slow evaporation of the solvent on standing. In general,

the diacyl dipyrromethanes were obtained as amorphous pale

brown solids rather than crystalline materials.

The reduction of the diacyl dipyrromethanes were performed

in THF/methanol. In method 1, the THF and methanol were

of reagent grade (A.C.S.). In method 2, the THF was freshly

distilled from Na/benzophenone and anhydrous methanol was

used as received from Aldrich.

Porphyrin-forming reactions were performed in reagent-

grade (A.C.S.) acetonitrile obtained from Fisher (used without

any further purification). Porphyrins (from reaction samples

or following purification) were analyzed by laser desorption

ionization mass spectrometry (LD-MS) without a matrix.³⁰The

progress of the porphyrin-forming reactions was monitored

spectroscopically and the extent of scrambling in the crude

(30) (a) Fenyo, D.; Chait, B. T.; J ohnson, T. E.; Lindsey, J . S. J .

Porphyrins Phthalocyanines 1997, 1, 93-99. (b) Srinivasan, N.; Haney,

C. A.; Lindsey, J . S.; Zhang, W.; Chait, B. T. J . Porphyrins Phthalo-

cyanines 1999, 3, 283-291.

(31) Lindsey, J . S.; Schreiman, I. C.; Hsu, H. C.; Kearney, P. C.;

Marguerettaz, A. M. J . Org. Chem. 1987, 52, 827-836.

Rational Syntheses of Porphyrins

J . Org. Chem., Vol. 65, No. 22, 2000 7337

5-(4-Cya n op h en yl)d ip yr r om eth a n e (2j). A sample of

4-cyanobenzaldehyde (3.8 g, 29 mmol) was reacted with excess

pyrrole following the reported procedure.¹³After preliminary

workup (wash with 0.1 M aq NaOH, remove pyrrole by rotary

evaporation), the crude product was purified by column

chromatography [silica, CH₂Cl₂/ethyl acetate (1:1)] to obtain

a pale yellow oil which was recrystallized from hot ethyl

acetate. The white needles thus obtained were filtered and

dried in vacuo (5.1 g, 50%). ¹H NMR (acetone-d₆) δ 5.58 (s,

1H), 5.77 (m, 2H), 6.02 (AB quartet, J ) 3.0 Hz, 2H), 6.72 (AB

quartet, J ) 3.0 Hz, 2H), 7.38 (d, J ) 8.1 Hz, 2H), 7.64-7.68

(m, 2H), 9.77 (br, 2H). Other analytical data (mp, ¹³C NMR)

are consistent with literature values.³³

5-(4-Aceta m id op h en yl)d ip yr r om eth a n e (2k ). A sample

of 4-acetamidobenzaldehyde (4.0 g, 25 mmol) was reacted with

excess pyrrole following the general procedure.¹³After pre-

liminary workup (wash with 0.1 M aq NaOH, remove pyrrole

by rotary evaporation), the crude product was purified by

column chromatography [silica, CH₂Cl₂/ethyl acetate (4:1)] to

obtain a yellow oil which was dissolved in a 1:20 mixture of

water and ethanol. The resulting yellow solid was filtered and

dried in vacuo (4.0 g, 58%). mp 158-160 °C; ¹H NMR (acetone-

d₆) δ 2.04 (s, 3H), 5.39 (s, 1H), 5.72 (m, 2H), 5.97 (m, 2H), 6.66

(m, 2H), 7.10 (m, 2H), 7.52 (d, J ) 7.8 Hz, 2H), 9.13 (br, 1H),

9.65 (br, 2H); ¹³C NMR (acetone-d₆) δ 24.4, 44.6, 107.5, 108.3,

117.9, 120.0, 129.7, 134.4, 138.9, 139.6. Anal. Calcd for

NMR δ 3.08 (s, 1H), 5.46 (s, 1H), 5.91 (s, 2H), 6.18 (m, 2H),

6.70 (s, 2H), 7.18 (d, J ) 8.1 Hz, 2H), 7.47 (d, J ) 8.1 Hz, 2H),

7.89 (br, 2H); ¹³C NMR δ 44.4, 78.0, 84.1, 108.1, 109.2, 118.2,

121.3, 129.1, 132.5, 133.0. Anal. Calcd for C₁₇H₁₄N₂: C, 82.90;

H, 5.73; N, 11.37. Found: C, 82.66; H, 5.72; N, 11.39.

4-[2-(Tr iisop r op ylsilyl)eth yn yl]ben zoyl Ch lor id e (3).

Ethyl 4-iodobenzoate (13.8 g, 50.0 mmol), Pd(PPh₃)₂Cl₂(0.21

g, 0.30 mmol), and CuI (0.57 g, 3.0 mmol) were placed in a

Schlenk flask, and the flask was thoroughly flushed with

argon. Then degassed triethylamine (100 mL) followed by

triisopropylsilylacetylene (10.94 g, 60.00 mmol) were intro-

duced, and the flask was sealed. The contents of the flask were

stirred at 50 °C for 1 h and then at room temperature for a

further 12 h. The solids were filtered and the filtrate was

concentrated. The crude brown oil was dissolved in ethanol

(500 mL), and aq NaOH (2 M, 100 mL) was added. The

homogeneous reaction mixture was stirred for 12 h at room

temperature. Then the reaction mixture was diluted with

water (400 mL) and washed with ether. The aqueous layer

was acidified with concentrated HCl and extracted with ether.

The combined ether layers were dried (Na₂SO₄) and concen-

trated. The faintly colored oil was dissolved in hexanes and

allowed to crystallize, affording colorless crystals (12.15 g,

81%). mp 93-94 °C; ¹H NMR δ 1.14 (m, 21H), 7.56 (d, J ) 8.1

Hz, 2H), 8.04 (d, J ) 8.1 Hz, 2H) (acid hydrogen not observed);

¹³C NMR δ 11.4, 18.8, 95.2, 106.2, 128.8, 129.3, 130.2, 132.2,

172.0. Anal. Calcd for C₁₈H₂₆O₂Si: C, 71.47; H, 8.66. Found:

C, 71.48; H, 8.66. The acid (10.57 g, 35.00 mmol) was dissolved

in benzene (25 mL), thionyl chloride (12.8 mL, 175 mmol) was

added, and the mixture was refluxed for 36 h. The volatile

components were removed by vacuum evaporation (water

aspirator), and the faintly colored oil was bulb-to-bulb distilled

(150-160 °C at 0.02 mmHg) to afford a pale yellow liquid (9.56

g, 85%). ¹H NMR δ 1.17 (m, 21H), 7.60 (d, J ) 8.1 Hz, 2H),

8.07 (d, J ) 8.1 Hz, 2H); ¹³C NMR δ 11.4, 18.8, 97.4, 105.5,

C

₁₇H₁₇N₃O: C, 73.10; H, 6.13; N, 15.04. Found: C, 73.08; H,

6.17; N, 15.06.

5-{4-[2-(Tr iisop r op ylsilyl)e t h yn yl]p h e n yl}d ip yr r o-

m eth a n e (2m ). A sample of 1m (5.72 g, 20.0 mmol) was

reacted with excess pyrrole following the general procedure.¹³

After preliminary workup (wash with 0.1 M aq NaOH, remove

pyrrole by rotary evaporation), the crude oil was bulb-to-bulb

distilled (180-190 °C at 0.02 mmHg) to obtain a pale yellow

oil which was dissolved in a 1:20 mixture of water and meth-

anol and was allowed to crystallize at 0 °C overnight. The

resulting grayish amorphous solid was filtered and dried in

130.9, 131.3, 132.4, 132.5, 167.8. Anal. Calcd for C₁₈H₂₅

ClOSi: C, 67.36; H, 7.85. Found: C, 67.37; H, 7.87.

-

1

vacuo (4.15 g, 51%). mp 80-81 °C; H NMR δ 1.12 (m, 21H),

Gen er a l P r oced u r e for Dia cyla tion , Exem p lified for

1,9-Bis(4-m eth ylben zoyl)-5-p h en yld ip yr r om eth a n e (4a ).

A solution of EtMgBr (25.0 mL, 25.0 mmol) was added slowly

to a stirred, tap-water-cooled flask containing a solution of

5-phenyldipyrromethane (2a , 1.11 g, 5.00 mmol) in toluene

(100 mL) under an Ar atmosphere. An exothermic reaction

with gas evolution ensued. The resulting brown solution was

stirred for 30 min at room temperature. Then a solution of

p-toluoyl chloride (1.65 mL, 12.5 mmol) in toluene (12.5 mL)

was added over 10 min. The solution darkened, and the

mixture was stirred for an additional 10 min. The reaction

was quenched by adding satd aq NH₄Cl (75 mL). Ethyl acetate

(100 mL) was then added. The organic phase was washed

successively with water and brine and then dried (MgSO₄).

The solvent was removed under reduced pressure to afford a

brown oil. ¹H NMR analysis of the crude reaction mixture

indicated a 4.4:1 product ratio (diacyl dipyrromethane versus

monoacyl dipyrromethane). The crude product was then puri-

fied by column chromatography [silica, CH₂Cl₂/ethyl acetate

(95:5)], and the main fractions containing the desired diacyl

dipyrromethane were collected. Removal of solvent afforded a

yellow foam which was dissolved in hot 2-propanol (25 mL).

Precipitation with water (1-2 mL) afforded an amorphous

solid. Recrystallization from CH₂Cl₂/hexanes afforded pure 4a

(1.61 g, 70%). Analytical data are consistent with literature

values.¹⁷

5.46 (s, 1H), 5.89 (m, 2H), 6.15 (m, 2H), 6.69 (m, 2H), 7.14 (m,

2H), 7.43 (m, 2H), 7.91 (br, 2H); ¹³C NMR δ 11.4, 18.7, 43.8,

90.7, 106.9, 107.5, 108.5, 117.5, 128.3, 132.14, 132.3, 142.4.

Anal. Calcd for C₂₆H₃₄N₂Si: C, 77.56; H, 8.51; N, 6.96. Found:

C, 77.44; H, 8.54; N, 6.94.

5-(4-F or m ylp h en yl)d ip yr r om eth a n e (2n ). A solution of

2j (1.0 g, 4.0 mmol) in CH₂Cl₂(22 mL) was treated dropwise

with a solution of DIBAL-H (1 M in hexanes, 8.0 mL, 8.0 mmol)

at room temperature. The reaction mixture was stirred at room

temperature for about 3 h and then quenched with 100 mL of

satd aq NH₄Cl and stirred for a further 2 h. More CH₂Cl₂(50

mL) was added, and the aqueous layer was removed. The

organic layer appeared as an emulsion, to which 10% aq NaOH

(100 mL) was added. The aqueous phase was extracted with

CH₂Cl₂. The combined organic layers were washed with brine,

dried (Na₂SO₄), and concentrated to dryness. The light brown

residue was purified by column chromatography (silica, CH₂-

Cl₂) to afford a pale yellow solid (0.47 g, 47%). mp 117-118

1

°C; H NMR δ 5.55 (s, 1H), 5.90 (s, 2H), 6.17-6.20 (m, 2H),

6.73-6.75 (m, 2H), 7.34 (d, J ) 7.8 Hz, 2H), 7.80 (d, J ) 8.1

Hz, 2H), 8.04 (br, 2H), 9.96 (s, 1H); ¹³C NMR δ 44.3, 107.9,

108.8, 118.0, 129.3, 130.3, 131.6, 135.4, 149.5, 192.3. Anal.

Calcd for C₁₆H₁₄N₂O: C, 76.78; H, 5.64; N, 11.19. Found: C,

76.73; H, 5.65; N, 11.08.

5-(4-Eth yn ylp h en yl)d ip yr r om eth a n e (2o). Solid K₂CO₃

(0.35 g) was added to a solution of dipyrromethane 2e (0.96 g,

3.0 mmol) in THF/methanol (25 mL, 4:1). The mixture was

stirred for 40 min at room temperature and then concentrated.

The residue was dissolved in CH₂Cl₂and washed with water

and brine. The organic layer was dried (Na₂SO₄) and filtered

through a bed of silica. Recrystallization from CH₂Cl₂/hexanes

1,9-Bis(4-m et h oxyb en zoyl)-5-p h en yld ip yr r om et h a n e

(4b). Following the general diacylation procedure, reaction of

2a (0.67 g, 3.0 mmol) and p-anisoyl chloride (1.28 g, 7.50 mmol)

afforded a 3.3:1 product ratio; column chromatography [silica,

hexanes/ethyl acetate (13:7)] followed by precipitation from

2-propanol/water gave an amorphous solid (0.97 g, 66%). mp

120-121 °C; ¹H NMR δ 3.84 (s, 6H), 5.65 (s, 1H), 5.92 (m, 2H),

6.51 (m, 2H), 6.89 (d, J ) 8.7 Hz, 4H), 7.33-7.42 (m, 3H), 7.53

(d, J ) 7.2 Hz, 2H), 7.78 (d, J ) 8.7 Hz, 4H), 11.46 (br, 2H);

¹³C NMR δ 45.4, 55.7, 111.3, 113.6, 120.4, 127.7, 129.1, 129.2,

131.3, 131.4, 132.1, 140.9, 162.7, 183.7; FAB-MS obsd 490.1916,

1

afforded colorless needles (0.68 g, 92%). mp 109-110 °C; H

(32) Ravikanth, M.; Strachan, J .-P.; Li, F.; Lindsey, J . S. Tetrahe-

dron 1998, 54, 7721-7734.

(33) Vigmond, S. J .; Chang, M. C.; Kallury, K. M. R.; Thompson,

M. Tetrahedron Lett. 1994, 35, 2455-2458.

7338 J . Org. Chem., Vol. 65, No. 22, 2000

Rao et al.

calcd 490.1893 (C₃₁H₂₆N₂O₄). Anal. Calcd for C₃₁H₂₆N₂O₄: C,

75.90; H, 5.34; N, 5.71. Found: C, 75.48; H, 5.48; N, 5.60.

1,9-Bis(p e n t a flu or ob e n zoyl)-5-p h e n yld ip yr r om e t h -

a n e (4c). Following the general diacylation procedure, reaction

of 2a (0.45 g, 2.0 mmol) and pentafluorobenzoyl chloride (0.72

mL, 5.0 mmol) afforded a 5.3:1 product ratio; column chroma-

tography [silica, hexanes/ethyl acetate (17:3)] followed by slow

precipitation from CH₂Cl₂/hexanes gave an amorphous solid

110.3, 120.5, 124.9, 129.1, 130.3, 130.4, 133.0, 135.6, 137.5,

139.4, 154.9, 183.7; FAB-MS obsd 584.3409, calcd 584.3403

(C₄₀H₄₄N₂O₂). Anal. Calcd for C₄₀H₄₄N₂O₂: C, 82.15; H, 7.58;

N, 4.79. Found: C, 82.09; H, 7.64; N, 4.80.

1,9-Bis(4-iod oben zoyl)-5-m esityld ip yr r om eth a n e (4h ).

Following the general diacylation procedure, reaction of 2d

(1.32 g, 5.00 mmol) with p-iodobenzoyl chloride (2.93 g, 12.5

mmol) afforded a 1.7:1 product ratio; column chromatography

[silica, hexanes/ethyl acetate (17:3)] followed by slow precipita-

tion from CH₂Cl₂/hexanes gave an amorphous solid (2.14 g,

59%). mp > 225 °C (dec); ¹H NMR δ 2.22 (s, 6H), 2.32 (s, 3H),

5.96 (m, 2H), 6.19 (s, 1H), 6.58 (m, 2H), 6.93 (s, 2H), 7.40 (d,

J ) 8.1 Hz, 4H), 7.74 (d, J ) 8.1 Hz, 4H), 11.34 (br, 2H); ¹³C

NMR δ 20.8, 39.2, 98.9, 110.7, 121.0, 129.9, 130.4, 130.7, 132.7,

137.2, 137.4, 140.3, 182.7; FAB-MS obsd 724.0080, calcd

724.0084 (C₃₂H₂₆I₂N₂O₂). Anal. Calcd for C₃₂H₂₆I₂N₂O₂: C,

53.06; H, 3.62; N, 3.87. Found: C, 53.10; H, 3.61; N, 3.81.

1,9-Bis(4-ter t-b u t ylb en zoyl)-5-{4-[2-(t r im et h ylsilyl)-

eth yn yl]p h en yl}d ip yr r om eth a n e (4i). Following the gen-

eral diacylation procedure, reaction of 2e (1.59 g, 5.00 mmol)

with 4-tert-butylbenzoyl chloride (2.15 mL, 12.5 mmol) afforded

a 3:1 product ratio; column chromatography [silica, hexanes/

ethyl acetate (17:3)] followed by slow precipitation from

hexanes gave an amorphous solid (2.09 g, 65%). mp 178-180

°C; ¹H NMR δ 0.31 (s, 9H), 1.36 (s, 18H), 5.67 (s, 1H), 5.92 (m,

2H), 6.55 (m, 2H), 7.42 (d, J ) 7.8 Hz, 4H), 7.48 (s, 4H), 7.70

(d, J ) 7.8 Hz, 4H), 11.60 (br, 2H); ¹³C NMR δ -0.06, 31.1,

34.9, 44.9, 94.3, 104.9, 111.0, 120.6, 122.0, 124.9, 128.7, 129.5,

131.1, 132.4, 135.5, 140.2, 140.9, 155.1, 184.4; FAB-MS obsd

638.3355, calcd 638.3329 (C₄₂H₄₆N₂O₂Si). Anal. Calcd for

1

(0.35 g, 29%). mp 150-151 °C; H NMR δ 5.66 (s, 1H), 6.15

(m, 2H), 6.70 (m, 2H), 7.22-7.48 (m, 5H), 9.62 (br, 2H); ¹³C

NMR δ 44.4, 112.0, 122.4, 128.2, 128.3, 129.3, 131.4, 138.0,

142.3, 172.2; FAB-MS obsd 610.0773, calcd 610.0739 (C₂₉H₁₂

₁₀N₂O₂). Anal. Calcd for C₂₉H₁₂F₁₀N₂O₂: C, 57.06; H, 1.98;

N, 4.59. Found: C, 58.18; H, 2.46; N, 4.37.

-

F

1,9-Bis(4-m eth ylben zoyl)-5-(p en ta flu or op h en yl)d ip yr -

r om eth a n e (4d ). Following the general diacylation procedure,

reaction of 2b (0.62 g, 2.0 mmol) with p-toluoyl chloride (0.66

mL, 5.0 mmol) afforded a 1.9:1 product ratio; column chroma-

tography [silica, CH₂Cl₂/ethyl acetate (19:1)] followed by slow

precipitation from CH₂Cl₂/hexanes gave an amorphous solid

1

(0.56 g, 51%). mp 155-156 °C; H NMR δ 2.38 (s, 6H), 6.06

(m, 2H), 6.16 (s, 1H), 6.61(m, 2H), 7.22 (d, J ) 8.1 Hz, 4H),

7.70 (d, J ) 8.1 Hz, 4H), 11.49 (br, 2H); ¹³C NMR δ 22.0, 33.9,

110.9, 120.5, 129.3, 130.1, 131.9, 135.7, 136.2, 143.1, 184.8;

FAB-MS obsd 548.1518, calcd 548.1523 (C₃₁H₂₁F₅N₂O₂). Anal.

Calcd for C₃₁H₂₁F₅N₂O₂: C, 67.88; H, 3.86; N, 5.11. Found: C,

68.16; H, 3.85; N, 5.08.

1,9-Bis(p en t a flu or ob en zoyl)-5-(p en t a flu or op h en yl)-

d ip yr r om eth a n e (4e). Following the general diacylation

procedure, reaction of 2b (0.31 g, 1.0 mmol) and pentafluo-

robenzoyl chloride (0.36 mL, 2.5 mmol) afforded a product ratio

of <0.9:1 (estimated, due to overlapping peaks); column

chromatography [silica, CH₂Cl₂/ethyl acetate (49:1)] followed

by slow precipitation from CH₂Cl₂/hexanes gave an amorphous

solid (0.18 g, 25%). mp > 225 °C (dec); ¹H NMR (DMSO-d₆) δ

6.01 (d, J ) 3.9 Hz, 2H), 6.04 (s, 1H), 6.87 (d, J ) 3.9 Hz, 2H),

12.69 (br, 2H); FAB-MS obsd 700.0307, calcd 700.0268

(C₂₉H₇F₁₅N₂O₂). Anal. Calcd for C₂₉H₇F₁₅N₂O₂: C, 53.77; H,

1.89; N, 4.05. Found: C, 48.84; H, 1.06; N, 4.14 (4e did not

furnish satisfactory elemental analysis data). Alternatively,

4e was obtained by stepwise addition of acylating reagents.

Thus a solution of 2b (0.94 g, 3.0 mmol) in toluene (60 mL)

was treated with a solution of EtMgBr (6.0 mL, 6.0 mmol) and

a solution of pentafluorobenzoyl chloride (0.43 mL, 3.0 mmol)

in toluene. After 10 min, the addition of EtMgBr (6.0 mL, 6.0

mmol) and acid chloride (0.43 mL, 3.0 mmol) was repeated.

After a further 10 min, the remaining portions of EtMgBr (3.0

mL, 3.0 mmol) and acid chloride (0.21 mL, 1.5 mmol) were

added. After reaction for 10 min, the reaction mixture was

quenched. Purification of the crude product was performed as

before, affording 4e (0.51 g, 24%) with the same purity as

above.

C

₄₂H₄₆N₂O₂Si: C, 78.95; H, 7.26; N, 4.38; Found: C, 78.78; H,

7.21; N, 4.43.

1,9-Bis(4-m eth ylben zoyl)-5-{4-[2-(tr im eth ylsilyl)eth yn yl]-

p h en yl}d ip yr r om eth a n e (4j). Following the general diacy-

lation procedure, reaction of 2e (1.59 g, 5.00 mmol) with

p-toluoyl chloride (1.65 mL, 12.5 mmol) afforded a 1.8:1 product

ratio; column chromatography [silica, hexanes/ethyl acetate

(8:2)] followed by slow precipitation from 2-propanol gave an

amorphous solid (1.11 g, 40%). Analytical data are consistent

with literature values.¹⁷

1,9-Dih exa n oyl-5-p en tyld ip yr r om eth a n e (4k ). Follow-

ing the general diacylation procedure, reaction of 2f (1.08 g,

5.00 mmol) with hexanoyl chloride (1.74 mL, 12.5 mmol)

resulted in no detectable monoacyl compound; column chro-

matography [silica, hexanes/ethyl acetate (9:1)] followed by

recrystallization from 2-propanol/water gave yellow crystals

1

(1.24 g, 60%). mp 128-129 °C; H NMR δ 0.85 (m, 9H), 1.31

(m, 14H), 1.69 (m, 4H), 2.09 (m, 2H), 2.76 (t, J ) 7.2 Hz, 4H),

4.18 (t, J ) 8.1 Hz, 1H), 6.09 (m, 2H), 6.85 (m, 2H), 10.79 (br,

2H); ¹³C NMR δ 13.8, 13.9, 22.4, 25.3, 27.4, 31.5, 31.6, 33.1,

37.7, 38.0, 107.7, 117.9, 131.3, 141.9, 191.3; FAB-MS obsd

413.3171, calcd 413.3168 (C₂₆H₄₀N₂O₂). Anal. Calcd for

1,9-Bis(4-m eth oxyben zoyl)-5-(4-m eth oxyp h en yl)d ip yr -

r om eth a n e (4f). Following the general diacylation procedure,

reaction of 2c (0.63 g, 2.5 mmol) with p-anisoyl chloride (1.06

g, 6.25 mmol) afforded a 2.5:1 product ratio; column chroma-

tography [silica, CH₂Cl₂/ethyl acetate (3:1)] followed by slow

precipitation from CH₂Cl₂/hexanes gave an amorphous solid

(0.89 g, 69%). mp 109-110 °C; ¹H NMR δ 3.82 (s, 3H), 3.85 (s,

6H), 5.58 (s, 1H), 5.96 (m, 2H), 6.57 (m, 2H), 6.92 (m, 6H),

7.40 (d, J ) 8.7 Hz, 2H), 7.81 (d, J ) 8.7 Hz, 4H), 11.00 (br,

2H); ¹³C NMR δ 44.3, 55.5, 55.6, 110.9, 113.5, 114.5, 120.1,

130.0, 131.2, 131.7, 140.6, 162.7, 183.5; FAB-MS obsd 520.2012,

calcd 520.1998 (C₃₂H₂₈N₂O₅). Anal. Calcd for C₃₂H₂₈N₂O₅: C,

73.83; H, 5.42; N, 5.38. Found: C, 73.53; H, 5.46; N, 5.32.

1,9-Bis(4-t er t -b u t ylb e n zoyl)-5-m e sit yld ip yr r om e t h -

a n e (4g). Following the general diacylation procedure, reaction

of 2d (1.32 g, 5.00 mmol) with 4-tert-butylbenzoyl chloride (2.44

mL, 12.5 mmol) resulted in no detectable monoacyl compound;

column chromatography [silica, hexanes/ethyl acetate (8:2)]

followed by slow precipitation from hexanes gave an amor-

phous solid (2.42 g, 83%). mp 144-145 °C; ¹H NMR δ 1.34 (s,

18H), 2.21 (s, 6H), 2.32 (s, 3H), 6.08 (m, 2H), 6.14 (s, 1H), 6.75

(m, 2H), 6.93 (s, 2H), 7.43 (d, J ) 8.1 Hz, 4H), 7.74 (d, J ) 8.1

Hz, 4H), 10.43 (br, 2H); ¹³C NMR δ 20.8, 20.9, 31.1, 34.9, 39.1,

C₂₆H₄₀N₂O₂: C, 75.68; H, 9.77; N, 6.79. Found: C, 75.95; H,

9.74; N, 6.82.

1,9-Bis{4-[2-(t r iisop r op ylsilyl)et h yn yl]b en zoyl}-5-(4-

ter t-bu tylp h en yl)d ip yr r om eth a n e (4l). Following the gen-

eral diacylation procedure, reaction of 2g (1.39 g, 5.00 mmol)

in toluene (100 mL) with 3 (4.01 g, 12.5 mmol) afforded a 2:1

product ratio; column chromatography [silica, CH₂Cl₂/ethyl

acetate (60:1)] followed by slow precipitation from 2-propanol/

water gave an amorphous solid (1.61 g, 38%). mp 151-152

°C; ¹H NMR δ 1.13 (s, 42H), 1.34 (s, 9H), 5.61 (s, 1H), 6.00 (m,

2H), 6.56 (m, 2H), 7.39 (m, 4H), 7.49 (d, J ) 8.1 Hz, 4H), 7.71

(d, J ) 8.1 Hz, 4H), 11.07 (br, 2H); ¹³C NMR δ 11.6, 18.9, 31.7,

34.9, 44.8, 94.1, 106.6, 111.7, 121.0, 126.2, 127.2, 128.7, 129.7,

131.9, 137.1, 137.8, 141.6, 150.8, 183.7; FAB-MS obsd 846.5005,

calcd 846.4976 (C₅₅H₇₀N₂O₂Si₂). Anal. Calcd for C₅₅H₇₀N₂O₂-

Si₂: C, 77.96; H, 8.33; N, 3.31. Found: C, 77.78; H, 8.33; N,

3.34.

1,9-Bis{4-[2-(tr iisop r op ylsilyl)eth yn yl]ben zoyl}-5-(4-io-

d op h en yl)d ip yr r om eth a n e (4m ). Following the general

diacylation procedure, reaction of 2h (0.35 g, 1.0 mmol) with

3 (0.80 g, 2.5 mmol) resulted in no detectable monoacyl

compound; column chromatography [silica, CH₂Cl₂/ethyl ac-

etate (9:1)] followed by slow precipitation from ethanol gave

Rational Syntheses of Porphyrins

J . Org. Chem., Vol. 65, No. 22, 2000 7339

an amorphous solid (0.36 g, 39%). mp 212-214 °C; ¹H NMR δ

1.17 (s, 42H), 5.64 (s, 1H), 5.97 (m, 2H), 6.49 (m, 2H), 7.38 (d,

J ) 8.1 Hz, 2H), 7.52 (d, J ) 8.7 Hz, 4H), 7.69 (d, J ) 8.7 Hz,

4H), 7.76 (d, J ) 8.1 Hz, 2H), 11.75 (br, 2H); ¹³C NMR δ 11.2,

18.6, 44.7, 93.2, 94.0, 106.2, 111.6, 120.9, 127.0, 129.5, 130.9,

131.0, 131.6, 137.2, 138.0, 140.0, 140.7, 183.5; FAB-MS obsd

916.3311, calcd 916.3316 (C₅₁H₆₁IN₂O₂Si₂). Anal. Calcd for

with brine, dried (Na₂SO₄), and concentrated. Column chro-

matography [silica, CH₂Cl₂f CH₂Cl₂/ethyl acetate (95:5)]

afforded a foamlike solid. Recrystallization from hexanes

provided a yellowish amorphous solid (3.92 g, 84%). mp 131-

132 °C; ¹H NMR δ 0.26 (s, 9H), 2.08 (s, 6H), 2.29 (s, 3H), 5.94

(s, 1H), 6.12 (m, 2H), 6.21 (m, 1H), 6.68 (m, 1H), 6.79 (m, 1H),

6.89 (s, 2H), 7.53 (d, J ) 8.1 Hz, 2H), 7.79 (d, J ) 8.1 Hz, 2H),

7.85 (br, 1H), 9.24 (br, 1H); ¹³C NMR δ 0.03, 20.8, 20.9, 38.7,

97.2, 104.4, 107.3, 109.0, 110.3, 117.1, 120.7, 126.6, 128.8,

129.1, 129.8, 130.7, 131.9, 133.1, 137.3, 137.5, 138.1, 141.4,

183.2. Anal. Calcd for C₃₀H₃₂N₂OSi: C, 77.54; H, 6.94; N, 6.03.

Found: C, 77.47; H, 6.94; N, 6.03.

1-{4-[2-(Tr im eth ylsilyl)eth yn yl]ben zoyl}-5-(p en ta flu o-

r op h en yl)d ip yr r om et h a n e (5e). Following the general

monoacylation procedure, reaction of 2b (2.81 g, 9.00 mmol)

and 6f (2.80 g, 9.00 mmol) followed by column chromatography

[silica, CH₂Cl₂/ethyl acetate (98:2)] and then crystallization

from methanol afforded pale yellow needles (2.85 g, 62%). mp

167 °C; ¹H NMR δ 0.28 (s, 9H), 5.93 (s, 1H), 6.07 (m, 2H), 6.13

(m, 1H), 6.69 (m, 1H), 6.77 (m, 1H), 7.55 (d, J ) 8.1 Hz, 2H),

7.77 (d, J ) 8.1 Hz, 2H), 8.49 (br, 1H), 10.38 (br, 1H); ¹³C NMR

δ 0.00, 33.4, 97.8, 104.2, 108.5, 109.0, 110.6, 114.9, 118.8, 120.9,

126.6, 127.2, 129.1, 131.0, 132.0, 137.5, 138.3, 143.4, 184.1.

Anal. Calcd for C₂₇H₂₁F₅N₂OSi: C, 63.27; H, 4.13; N, 5.47.

Found: C, 63.27; H, 4.14; N, 5.42.

C

₅₁H₆₁IN₂O₂Si₂: C, 66.79; H, 6.70; N, 3.05. Found: C, 66.70;

H, 6.80; N, 3.01.

1,9-Bis(4-ter t-bu tylben zoyl)-5-(4-ter t-bu tylph en yl)dipyr -

r om eth a n e (4n ). Following the general diacylation procedure,

reaction of 2g (4.17 g, 15.0 mmol) in toluene (300 mL) with

4-tert-butylbenzoyl chloride (7.30 mL, 37.5 mmol) afforded a

1.9:1 product ratio; column chromatography [silica, CH₂Cl₂/

ethyl acetate (10:1)] followed by slow precipitation from

2-propanol/water gave an amorphous solid (5.21 g, 58%). mp

1

140-142 °C; H NMR δ 1.34 (s, 9H), 1.36 (m, 18H), 5.61 (s,

1H), 6.09 (m, 2H), 6.77 (m, 2H), 7.28 (d, J ) 7.2 Hz, 2H), 7.39

(d, J ) 8.1 Hz, 2H), 7.46 (d, J ) 7.2 Hz, 4H), 7.77 (d, J ) 8.1

Hz, 4H), 10.09 (br, 2H); ¹³C NMR δ 31.4, 31.6, 34.8, 35.2, 44.5,

111.1, 120.6, 125.3, 126.1, 128.5, 129.5, 131.2, 135.8, 140.7,

150.6, 155.4, 184.5; FAB-MS obsd 598.3544, calcd 598.3559

(C₄₁H₄₆N₂O₂). Anal. Calcd for C₄₁H₄₆N₂O₂: C, 82.24; H, 7.74;

N, 4.68. Found: C, 81.91; H, 7.69; N, 4.77.

1,9-Bis(3,5-di-ter t-bu tylben zoyl)-5-(4-iodoph en yl)dipyr -

r om eth a n e (4o). Following the general diacylation procedure,

reaction of 2h (1.04 g, 3.00 mmol) with 3,5-di-tert-butylbenzoyl

chloride (1.90 g, 7.50 mmol) afforded a 0.7:1 product ratio;

column chromatography [silica, CH₂Cl₂/ethyl acetate (15:1)]

followed by slow precipitation from 2-propanol/water gave an

amorphous solid (0.56 g, 24%). mp 172-175 °C; ¹H NMR δ

1.05 (s, 36H), 5.47 (s, 1H), 5.70 (m, 2H), 6.25 (m, 2H), 7.24 (m,

8H), 7.47 (d, J ) 7.8 Hz, 2H), 12.18 (br, 2H); ¹³C NMR δ 31.6,

35.2, 45.3, 93.1, 111.4, 121.3, 124.5, 125.8, 131.4, 131.5, 138.1,

138.3, 140.7, 150.6, 185.8; FAB-MS obsd 780.3184, calcd

780.3152 (C₄₅H₅₃IN₂O₂). Anal. Calcd for C₄₅H₅₃IN₂O₂: C, 69.22;

H, 6.84; N, 3.59. Found: C, 68.82; H, 6.74; N, 3.63.

1,9-Bis(4-t er t -b u t ylb e n zoyl)-5-(4-iod op h e n yl)d ip yr -

r om eth a n e (4p ). Following the general diacylation procedure,

reaction of 2h (3.48 g, 10.0 mmol) with 4-tert-butylbenzoyl

chloride (5.90 mL, 25.0 mmol) afforded a 1.6:1 product ratio;

column chromatography [silica, CH₂Cl₂/ethyl acetate (10:1)]

followed by slow precipitation from 2-propanol/water gave an

amorphous solid (2.93 g, 44%). mp 168-169 °C; ¹H NMR δ

1.26 (s, 18H), 5.61 (s, 1H), 5.88 (m, 2H), 6.78 (m, 2H), 7.15 (d,

J ) 8.1 Hz, 2H), 7.24 (d, J ) 8.5 Hz, 4H), 7.50 (m, 6H), 11.83

(br, 2H); ¹³C NMR δ 32.7, 46.1, 94.4, 112.5, 122.2, 126.5, 131.1,

132.4, 132.7, 137.0, 139.3, 141.8, 141.9, 156.6, 185.9; FAB-MS

obsd 668.1917, calcd 668.1900 (C₃₇H₃₇IN₂O₂). Anal. Calcd for

1-(4-Br om ob en zoyl)-5-{4-[2-(t r im et h ylsilyl)et h yn yl]-

p h en yl}d ip yr r om eth a n e (5f). Following the general mono-

acylation procedure, reaction of 2e (4.77 g, 15.0 mmol) and

6d (4.41 g, 15.0 mmol) followed by column chromatography

[silica, CH₂Cl₂/ethyl acetate (98:2)] and then slow precipitation

from CH₂Cl₂/hexanes afforded a pale yellow amorphous powder

1

(5.81 g, 77%). mp 151-152 °C (dec); H NMR δ 0.25 (s, 9H),

5.54 (s, 1H), 5.97 (br, 1H), 6.06 (m, 1H), 6.17 (m, 1H), 6.69 (m,

1H), 6.78 (m, 1H), 7.12 (d, J ) 8.1 Hz, 2H), 7.38 (d, J ) 8.1

Hz, 2H) 7.58-7.68 (m, 4H), 8.20 (br, 1H), 9.83 (br, 1H); ¹³C

NMR δ 0.68, 44.5, 105.3, 108.7, 109.1, 111.8, 118.7, 122.2,

127.4, 128.8, 131.0, 131.2, 132.2, 132.8, 137.6, 141.8, 142.9,

184.2. Anal. Calcd for C₂₇H₂₅BrN₂OSi: C, 64.67; H, 5.02; N,

5.59. Found: C, 64.92; H, 5.21; N, 5.39.

1-(4-ter t-Bu t ylb en zoyl)-5-(4-ter t-b u t ylp h en yl)d ip yr -

r om eth a n e (5g). Following the general monoacylation pro-

cedure, reaction of 2g (5.56 g, 20.0 mmol) and 6e (5.43 g, 20.0

mmol) followed by column chromatography [silica, CH₂Cl₂/

ethyl acetate (98:2)] and then slow precipitation from hexanes/

CH₂Cl₂afforded colorless amorphous granules (7.11 g, 81%).

1

mp 198-200 °C; H NMR δ 1.29 (s, 9H), 1.37 (s, 9H), 5.55 (s,

1H), 6.02 (br, 1H), 6.12 (m, 1H), 6.16 (m, 1H), 6.67 (m, 1H),

6.83 (m, 1H), 7.14 (m, 2H), 7.31 (m, 2H), 7.48 (m, 2H), 7.75

(m, 2H), 8.34 (br, 1H), 9.93 (br, 1H); ¹³C NMR δ 31.3, 31.4,

34.5, 35.1, 43.7, 107.7, 108.2, 110.7, 117.9, 121.5, 125.3, 125.6,

128.0, 129.1, 130.9, 131.6, 135.8, 138.0, 142.5, 149.9, 155.4,

184.8. Anal. Calcd for C₃₀H₃₄N₂O: C, 82.15; H, 7.81; N, 6.39.

Found: C, 81.98; H, 8.07; N, 6.13.

C

₃₇H₃₇IN₂O₂: C, 66.47; H, 5.58; N, 4.19. Found: C, 66.42; H,

5.64; N, 4.11.

1,9-Dim esitoyl-5-m esityld ip yr r om eth a n e (4q). Follow-

ing the general diacylation procedure, reaction of 2d (0.53 g,

2.0 mmol) in toluene (40 mL) with mesitoyl chloride (0.83 mL

g, 5.0 mmol), followed by column chromatography [silica, CH₂-

Cl₂/ethyl acetate (98:2)] and recrystallization from CH₂Cl₂/hex-

anes gave yellowish plates (0.23 g, 19%). (A ratio of monoacyl

and diacyl dipyrromethanes could not be determined by ¹H

NMR analysis of the crude reaction mixture.) mp 159-161 °C;

¹H NMR 2.08 and 2.15 (2s, 18H), 2.28, 2.29 and 2.30 (3s, 9H),

5.88 (s, 1H), 6.11 (m, 1H), 6.41 (s, 1H), 6.58 (s, 1H), 6.83 (s,

2H), 6.85 (s, 2H), 6.87 (m, 1H), 6.90 (s, 2H), 8.19 (br, 1H), 9.02

(br, 1H). Anal. Calcd for C₃₈H₄₀N₂O₂: C, 81.98; H, 7.24; N, 5.03.

Found: C, 81.78; H, 7.41; N, 5.01.

Gen er a l Mon oa cyla tion P r oced u r e, Exem p lified for

1-{4-[2-(Tr im eth ylsilyl)eth yn yl]ben zoyl}-5-m esityld ip yr -

r om eth a n e (5d ). A solution of EtMgBr in THF (25 mL, 25

mmol, 1 M) was added to a solution of 5-mesityldipyr-

romethane (2d , 2.64 g, 10.0 mmol) in dry THF (10 mL) at room

temperature. After stirring for 10 min, the flask was cooled to

-78 °C, and a solution of S-2-pyridyl 4-[2-(trimethylsilyl)-

ethynyl]benzothioate (6f, 3.11 g, 10.0 mmol) in THF (10 mL)

was added. Then the cooling bath was removed, the mixture

was stirred for 30 min, and then the reaction mixture was

quenched with satd aq NH₄Cl. The organic layer was washed

S-2-P yr id yl 4-br om oben zoth ioa te (6d ). Treatment of

2-mercaptopyridine (7.18 g, 64.6 mmol) with 4-bromobenzoyl

chloride (14.17 g, 64.6 mmol) in CH₂Cl₂(300 mL) according to

the reported procedure,⁶followed by recrystallization from

ethyl acetate/hexanes, afforded colorless needles (14.62 g,

1

77%). mp 132-133 °C; H NMR δ 7.29-7.33 (m, 1H), 7.59-

7.62 (m, 2H), 7.67-7.78 (m, 2H), 7.83-7.87 (m, 2H), 8.64-

8.66 (m, 1H); ¹³C NMR δ 124.5, 129.6, 129.7, 131.5, 132.8,

135.9, 137.9, 151.1, 151.2, 189.0. Anal. Calcd for C₁₂H₈-

BrNOS: C, 49.00; H, 2.74; N, 4.76. Found: C, 49.26; H, 2.76;

N, 4.77.

S-2-P yr id yl 4-ter t-bu tylben zoth ioa te (6e). Treatment of

2-mercaptopyridine (4.44 g, 40.0 mmol) with 4-tert-butylben-

zoyl chloride (7.86 g, 40.0 mmol) in CH₂Cl₂(200 mL) according

to the reported procedure,⁶followed by recrystallization from

hexanes, afforded colorless flakes (9.56 g, 88%). mp 91-92 °C;

¹H NMR δ 1.35 (s, 9H), 7.30-7.35 (m, 1H), 7.50 (m, 2H), 7.72-

7.79 (m, 2H), 7.96 (m, 2H), 8.67 (m, 1H); ¹³C NMR δ 31.7, 35.9,

124.2, 126.5, 128.2, 131.5, 134.5, 137.7, 151.1, 152.2, 158.4,

189.4. Anal. Calcd for C₁₆H₁₇NOS: C, 70.81; H, 6.31; N, 5.16.

Found: C, 70.97; H, 6.38; N, 5.16.

7340 J . Org. Chem., Vol. 65, No. 22, 2000

Rao et al.

S-2-P yr id yl 4-[2-(tr im eth ylsilyl)eth yn yl]ben zoth ioa te

(6f). The following is a refined procedure. A mixture of 6c

(10.23 g, 30.0 mmol), Pd₂(dba)₃(0.46 g, 0.50 mmol), PPh₃(1.05

g, 4.00 mmol), and CuI (0.57 mg, 3.0 mmol) was placed in a

Schlenk flask. The flask was pump-filled with Ar three times,

and then a degassed (argon) mixture of THF (60 mL) and

triethylamine (20 mL) was introduced followed by trimethyl-

silylacetylene (4.24 mL, 36.0 mmol). The flask was sealed

tightly, and the contents were stirred for 1 h at 50 °C and 12

h at room temperature. The solid was filtered off, and the

filtrate was concentrated. Flash column chromatography

[silica, hexanes/ethyl acetate (4:1)] afforded a brown solid.

Recrystallization (ethyl acetate) afforded pale yellow crystals

(6.54 g, 70%). Analytical data are consistent with literature

values.⁶

P r oced u r e A for Acyla tion of Mon oa cyl Dip yr r o-

m eth a n es, Exem p lified for 1-Ben zoyl-5-(4-m eth oxyp h en -

yl)-9-(4-m eth ylben zoyl)d ip yr r om eth a n e (7a ). 1-Benzoyl-

5-(4-methoxyphenyl)dipyrromethane (5b, 0.18 mg, 0.50 mmol)

was dissolved in dry toluene (2 mL). To this solution, EtMgBr

(3.0 mL, 3.0 mmol, 1.0 M solution in THF) was slowly added

at room temperature under argon. After stirring for 10 min,

p-toluoyl chloride (0.20 mL, 1.5 mmol) was added, and stirring

was continued for 30 min. Then satd aq NH₄Cl (10 mL) and

ethyl acetate (10 mL) were added. The organic layer was

separated, dried (Na₂SO₄), and concentrated. Column chro-

matography of the residue [silica, CH₂Cl₂/ethyl acetate (95:

5)] afforded 0.16 g (66%) of a yellow amorphous powder. ¹H

NMR δ 2.38 (s, 3H), 3.81 (s, 3H), 5.62 (s, 1H), 5.96 (m, 2H),

6.53 (m, 2H), 6.90 (m, 2H), 7.18 (d, J ) 8.1 Hz, 2H), 7.35-

7.48 (m, 5H), 7.67 (d, J ) 8.1 Hz, 2H), 7.75 (m, 2H), 11.48 (br,

2H); ¹³C NMR δ 24.2, 46.8, 57.9, 113.6, 113.7, 116.8, 123.1,

123.5, 130.6, 131.3, 132.2, 132.3, 132.5, 133.5, 133.7, 134.1,

135.1, 138.2, 140.9, 143.6, 144.1, 144.7, 161.5, 186.9, 187.1.

Anal. Calcd for C₃₁H₂₆N₂O₃: C, 78.46; H, 5.52; N, 5.90.

Found: C, 78.10; H, 5.62; N, 5.77.

P r oced u r e

B

for Acyla tion of Mon oa cyl Dip yr r o-

m eth a n es, Exem p lified for 1-(4-Iod oben zoyl)-5-m esityl-

9-{4-[2-(t r im et h ylsilyl)et h yn yl]b en zoyl}d ip yr r om et h -

a n e (7e). To a stirred solution of monoacyl dipyrromethane

5d (2.32 g, 5.00 mmol) in dry toluene (20 mL) at room

temperature was added EtMgBr (10 mL, 10 mmol, 1 M in

THF) slowly under argon, and the mixture was stirred for 5

min. To the resulting mixture was added 4-iodobenzoyl

chloride (1.33 g, 5.00 mmol). After 10 min, the same process

was repeated once. After stirring for 10 min (TLC indicated

incomplete but relatively clean reaction), the mixture was

treated with additional EtMgBr (5.0 mL, 5.0 mmol, 1 M in

THF) followed by 4-iodobenzoyl chloride (0.67 g, 2.5 mmol).

After stirring the contents for 20 min, satd aq NH₄Cl and ethyl

acetate were added. The organic layer was separated, dried

(Na₂SO₄), and concentrated. Purification by column chroma-

tography [silica, CH₂Cl₂/ethyl acetate (98:2)] followed by slow

precipitation from CH₂Cl₂/methanol afforded a pink amor-

phous solid (2.36 g, 68%). mp 147-148 °C; ¹H NMR δ 0.27 (s,

9H), 2.25 (s, 6H), 2.33 (s, 3H), 5.94 (m, 2H), 6.21 (s, 1H), 6.58

(m, 2H), 6.94 (s, 2H), 7.40 (d, J ) 7.8 Hz, 2H), 7.46 (d, J ) 8.1

Hz, 2H), 7.63 (d, J ) 7.8 Hz, 2H), 7.73 (d, J ) 8.1 Hz, 2H),

11.42 (br, 2H); ¹³C NMR δ 0.7, 21.8, 40.1, 99.7, 105.2, 111.6,

122.0, 127.2, 130.0, 130.8, 131.1, 131.2, 131.7, 132.4, 133.8,

138.0, 138.1, 138.3, 138.5, 141.1, 141.4, 183.5. Anal. Calcd for

C

₃₇H₃₅IN₂O₂Si: C, 63.97; H, 5.08; N, 4.03. Found: C, 63.85;

H, 5.06; N, 3.91.

1-{4-[2-(Tr iisop r op ylsilyl)e t h yn yl]b e n zoyl}-5-m e s-

it y l-9-{4-[2-(t r im e t h y ls ily l)e t h y n y l]b e n zo y l}d ip y r -

r om eth a n e (7f). Following acylation procedure B, reaction

of 5d (2.32 g, 5.00 mmol) and 3 (4.00 g, 12.5 mmol) followed

by column chromatography [silica, CH₂Cl₂/ethyl acetate (98:

2)] and slow precipitation from 2-propanol afforded a brown

amorphous solid (2.45 g, 65%). mp 148-150 °C; ¹H NMR δ

0.30 (s, 9H), 1.18 (s, 21H), 2.33 (s, 6H), 2.37 (s, 3H), 5.94-

5.95 (m, 2H), 6.32 (s, 1H), 6.58 (s, 2H), 6.98 (s, 2H), 7.49-7.52

(m, 4H), 7.66 (m, 4H), 11.93 (br, 2H); ¹³C NMR δ 0.06, 11.4,

18.8, 21.1, 39.5, 93.6, 97.1, 104.4, 104.5, 106.6, 110.9, 121.4,

121.5, 126.4, 126.7, 129.4, 130.4, 131.7, 131.7, 133.4, 137.1,

137.7, 137.8, 137.9, 140.8, 182.8. Anal. Calcd for C₄₈H₅₆N₂O₂-

Si₂: C, 76.96; H, 7.53; N, 3.74. Found: C, 76.68; H, 7.57; N,

3.60.

1-(4-Br om ob en zoyl)-5-{4-[2-(t r im et h ylsilyl)et h yn yl]-

p h en yl}-9-(4-iod oben zoyl)d ip yr r om eth a n e (7g). Monoacyl

dipyrromethane 5f (4.51 g, 9.00 mmol) and 4-iodobenzoyl

chloride (6.00 g, 22.5 mmol) were reacted following acylation

procedure B. TLC analysis indicated the presence of a trace

amount of monoacyl dipyrromethane. Column chromatography

[silica, CH₂Cl₂/ethyl acetate (95:5)] followed by slow precipita-

tion from ethanol afforded a pink amorphous solid (4.61 g,

69%). mp > 225 °C; ¹H NMR δ 0.25 (s, 9H), 5.63 (s, 1H), 5.91

(m, 2H), 6.46 (m, 2H), 7.42 (d, J ) 8.1 Hz, 2H), 7.48 (s, 4H),

7.55 (m, 4H), 7.74 (d, J ) 8.1 Hz, 2H), 11.77 (br, 2H); ¹³C NMR

δ 0.19, 45.1, 94.9, 99.5, 104.8, 111.8, 121.1, 122.6, 126.9, 128.9,

130.9, 131.4, 131.5, 132.6, 136.7, 137.3, 137.4, 140.7, 141.3,

183.4, 183.6. Anal. Calcd for C₃₄H₂₈BrIN₂O₂Si: C, 55.83; H,

3.86; N, 3.83. Found: C, 55.53; H, 3.84; N, 3.73.

1-(4-ter t-Bu t ylb en zoyl)-5-(4-ter t-b u t ylp h en yl)-9-(4-io-

doben zoyl)dipyr r om eth an e (7h ). Monoacyl dipyrromethane

5g (4.39 g, 10.0 mmol) and 4-iodobenzoyl chloride (6.65 g, 25.0

mmol) were reacted following acylation procedure B. TLC

analysis indicated the presence of a trace amount of monoacyl

dipyrromethane. Column chromatography [silica, CH₂Cl₂/ethyl

acetate (95:5)] followed by slow precipitation from CH₂Cl₂/

methanol afforded a brown amorphous solid (5.12 g, 76%). mp

158-160 °C; ¹H NMR δ 1.35 (s, 18H), 5.64 (s, 1H), 5.98-6.03

(m, 2H), 6.57 (m, 1H), 6.63 (m, 1H), 7.39 (m, 4H), 7.42 (m,

2H), 7.50 (m, 2H), 7.71-7.78 (m, 4H), 11.13 (br, 2H); ¹³C NMR

δ 31.8, 32.0, 35.2, 35.6, 45.1, 99.6, 111.7, 112.0, 121.1, 121.5,

125.6, 126.4, 129.0, 130.1, 131.2, 131.7, 136.1, 137.6, 137.9,

1-Ben zoyl-5-(4-m eth oxyph en yl)-9-(pen taflu or oben zoyl)-

d ip yr r om eth a n e (7b). Following acylation procedure A,

reaction of 5b (0.23 g, 0.65 mmol) and pentafluorobenzoyl

chloride (0.29 mL, 2.0 mmol) followed by column chromatog-

raphy [silica, CH₂Cl₂/ethyl acetate (95:5)] and recrystallization

from ether/hexanes afforded colorless needles (0.18 g, 49%).

mp 123-124 °C; ¹H NMR δ 3.76 (s, 3H), 5.68 (s, 1H), 6.07 (m,

2H), 6.61 (m, 1H), 6.77 (m, 3H), 7.11 (m, 2H), 7.40-7.55 (m,

3H), 7.76-7.79 (m, 2H), 10.45 and 10.72 (br, 2H); ¹³C NMR δ

43.6, 55.3, 110.9, 112.0, 114.3, 121.4, 122.7, 128.3, 129.2, 129.6,

131.1, 131.3, 132.0, 138.3, 140.7, 144.4, 159.1, 171.9, 185.1.

Anal. Calcd for C₃₀H₁₉F₅N₂O₃: C, 65.46; H, 3.48; N, 5.09.

Found: C, 65.57; H, 3.51; N, 4.93.

1-Ben zoyl-5-(pen taflu or oph en yl)-9-(4-m eth oxyben zoyl)-

d ip yr r om eth a n e (7c). Following acylation procedure A,

reaction of 5c (0.21 g, 0.50 mmol) and p-anisoyl chloride (0.20

mL, 1.5 mmol) followed by column chromatography [silica,

CH₂Cl₂/ethyl acetate (95:5)] and recrystallization from ether/

hexanes afforded colorless needles (0.16 g, 58%). mp 124-125

1

°C; H NMR δ 3.87 (s, 3H), 6.11 (m, 3H), 6.68 (m, 2H), 6.93

(m, 2H), 7.41-7.54 (m, 3H), 7.79-7.85 (m, 4H), 10.68 (br, 2H);

¹³C NMR δ 33.7, 55.5, 110.6, 110.7, 113.6, 119.7, 120.6, 128.3,

129.6, 129.9, 130.6, 131.4, 131.5, 131.9, 132.0, 135.6, 136.5,

138.1, 139.3, 139.6, 143.5, 146.9, 162.9, 183.5, 184.7. Anal.

Calcd for C₃₀H₁₉F₅N₂O₃: C, 65.46; H, 3.48; N, 5.09. Found: C,

65.40; H, 3.56; N, 5.07.

1-(4-Iod ob en zoyl)-5-(p en t a flu or op h en yl)-9-{4-[2-(t r i-

m eth ylsilyl)eth yn yl]ben zoyl}d ip yr r om eth a n e (7d ). Fol-

lowing acylation procedure A, reaction of 5e (2.05 g, 4.00 mmol)

and 4-iodobenzoyl chloride (3.19 g, 12.0 mmol) followed by

column chromatography [silica, hexanes/2-propanol (9:1)] and

slow precipitation from ethanol furnished a pink amorphous

1

solid (1.48 g, 50%). mp 135-136 °C; H NMR δ 0.26 (s, 9H),

6.07 (m, 2H), 6.13 (s, 1H), 6.59 (m, 2H), 7.47-7.52 (m, 4H),

7.70-7.80 (m, 4H), 11.05 (br, 2H); ¹³C NMR δ -0.1, 33.5, 97.5,

99.4, 104.1, 110.7, 113.6, 120.4, 126.9, 127.9, 129.3, 130.9,

131.1, 131.6, 136.2, 136.5, 136.9, 137.1, 137.4, 138.9, 143.5,

146.2, 183.3. Anal. Calcd for C₃₄H₂₄F₅IN₂O₂Si: C, 54.99; H,

3.26; N, 3.77. Found: C, 55.19; H, 3.39; N, 3.62.

138.2, 141.4, 142.5, 150.9, 155.8, 184.0. Anal. Calcd for C₃₇H₃₇

IN₂O₂: C, 66.47; H, 5.58; N, 4.19. Found: C, 66.81; H, 5.70;

N, 4.08.

1-(4-ter t-Bu t ylb en zoyl)-5-(4-ter t-b u t ylp h en yl)-9-{4-[2-

(tr iisop r op ylsilyl)eth yn yl]ben zoyl}d ip yr r om eth a n e (7i).

-

Rational Syntheses of Porphyrins

J . Org. Chem., Vol. 65, No. 22, 2000 7341

Following acylation procedure B, reaction of 5g (2.19 g, 5.00

mmol) and 3 (4.00 g, 12.5 mmol) followed by column chroma-

tography [silica, CH₂Cl₂/ethyl acetate (95:5)] and slow precipi-

tation from ethanol afforded a brown amorphous solid (2.42

pressure yielded the dicarbinol as a foamlike solid. To the 2-L

flask containing the dipyrromethane-dicarbinol (3.6 mmol

assuming quantitative reduction) was added dipyrromethane

2m (1.45 g, 3.60 mmol) followed by reagent grade (A.C.S.)

acetonitrile (1.44 L). The mixture was stirred for 5 min to

achieve dissolution, and then TFA (3.33 mL, 43.2 mmol, 30

mM) was added in a steady slow stream over the course of 1

min with efficient stirring. The reaction was monitored by

absorption spectroscopy after a total elapsed time of 1 and 2.5

min following the completion of TFA addition. [Reaction

monitoring was performed by injecting a 25 µL reaction aliquot

into a solution of DDQ (300 µL, 0.01 M in toluene); then 25

µL of the resulting oxidized mixture was dissolved in CH₂Cl₂/

EtOH (3:1, 3 mL), and the absorption spectrum was re-

corded.^5,31] The yield of porphyrin was about the same at the

first (1 min) and second timepoints (2.5 min), indicating the

dipyrromethane-dicarbinol + dipyrromethane condensation

was complete. Then (elapsed time of 3.5 min after the addition

of TFA) DDQ (2.45 g, 10.8 mmol) was added, and the mixture

was stirred at room temperature for 1 h. Then triethylamine

(6.02 mL, 43.2 mmol) was added, and the entire reaction

mixture was filtered (to remove quinone species) through a

pad of alumina (7.5 × 15 cm) and eluted with CH₂Cl₂(∼2 L)

until the eluant was no longer dark. The resulting porphyrin-

containing solution was concentrated by rotary evaporation

to give a dark solid. The solid was redissolved in CH₂Cl₂(100

mL) and passed through a pad of silica (7.5 × 20 cm) with

CH₂Cl₂elution to remove non-porphyrin products. Fractions

were collected to obtain the porphyrin (fast-eluting) free of non-

porphyrinic materials (slow-eluting). The purple fractions were

combined and concentrated by rotary evaporation to give a

purple solid. Recrystallization from CH₂Cl₂/methanol afforded

1

g, 67%). mp 148-151 °C (dec); H NMR δ 1.12 (s, 21H), 1.35

(s, 18H), 5.62 (s, 1H), 6.03 (m, 2H), 6.61-6.67 (m, 2H), 7.34-

7.53 (m, 8H), 7.75 (d, J ) 9.0 Hz, 4H), 10.73 (br, 2H); ¹³C NMR

δ 11.9, 19.3, 31.8, 32.0, 35.2, 35.6, 45.1, 94.3, 107.0, 111.7,

112.0, 121.2, 121.4, 121.5, 125.6, 126.4, 127.4, 129.1, 130.1,

130.2, 131.5, 131.8, 132.2, 136.2, 137.7, 138.4, 141.5, 150.9,

155.7, 184.1, 185.0. Anal. Calcd for C₄₈H₅₈N₂O₂Si: C, 79.73;

H, 8.09; N, 3.87. Found: C, 79.69; H, 8.13; N, 3.73.

1-(4-Iod oben zoyl)-5-(p en ta flu or op h en yl)-9-(p en ta flu o-

r oben zoyl)d ip yr r om eth a n e (7j). Monoacyl dipyrromethane

5h (2.53 g, 5.00 mmol) and 4-iodobenzoyl chloride (1.33 g, 5.0

mmol) were reacted following acylation procedure B. TLC

analysis indicated the presence of a considerable amount of

monoacyl dipyrromethane. Then additional EtMgBr (5.0 mL,

5.0 mmol, 1.0 M) followed by 4-iodobenzoyl chloride (0.67 g,

2.5 mmol) were added. Column chromatography [silica, CH₂-

Cl₂/ethyl acetate (95:5)] followed by slow precipitation from

hexanes afforded a pink amorphous solid which was found to

be a mixture of two compounds (¹H NMR analysis). The desired

compound was obtained as a cotton-like solid (0.81 g, 22%)

after recrystallization from methanol. ¹H NMR δ 6.06 (s, 1H),

6.18 (m, 2H), 6.65 (m, 1H), 6.76 (m, 1H), 7.54 (m, 2H), 7.82

(m, 2H), 10.27 (br, 2H); FAB-MS obsd 735.9728, calcd 735.9706.

Anal. Calcd for C₂₉H₁₁F₁₀IN₂O₂: C, 47.31; H, 1.51; N, 3.80.

Found: C, 45.99; H, 1.81; N, 3.63.

Gen er a l P r oced u r es for P or p h yr in F or m a tion : Re-

du ction of Diacyl Dipyr r om eth an es. Meth od 1.¹⁷A sample

of NaBH₄(50 mmol, 50 mol equiv) was added in small portions

(every 5 min) to a stirred solution of a diacyl dipyrromethane

(4 or 7, 1.0 mmol) in THF/methanol (3:1, 80 mL) in a round-

bottomed flask open to the atmosphere. A significant evolution

of gas occurred throughout the course of this reaction. The

progress of the reduction was monitored by TLC [alumina,

CH₂Cl₂/ethyl acetate]. After the reaction was complete (about

40 min), the reaction mixture was quenched with water (20

mL) and poured into CH₂Cl₂(100 mL). The organic phase was

isolated, washed with water (2 × 100 mL), and dried (K₂CO₃).

Removal of solvent afforded the dicarbinol as a foamlike solid.

Meth od 2. A sample of NaBH₄(20 mmol, 20 mol equiv) was

added in small portions (every 2 min) to a stirred solution of

a diacyl dipyrromethane (4 or 7, 1.0 mmol) in dry THF/

methanol (10:1, 44 mL) in a round-bottomed flask. The flask,

fitted with a vented rubber septum and flooded with argon,

was opened as needed to add the NaBH₄. A modest evolution

of gas occurred throughout the course of this reaction. The

progress of the reduction was monitored by TLC [alumina,

CH₂Cl₂/ethyl acetate]. After the reaction was complete (about

40 min), the reaction mixture was poured into a stirred

mixture of satd aq NH₄Cl (100 mL) and CH₂Cl₂(100 mL). The

satd aq NH₄Cl is essential to buffer the solution (e.g., thereby

avoiding cleavage of TMS groups). The organic phase was iso-

lated, washed with water (2 × 100 mL), and dried (Na₂SO₄).

Removal of solvent afforded the dicarbinol as a foamlike solid.

Exem p la r y La r ge-sca le P r oced u r e, Given for 5-(4-

Iod op h en yl)-10-m esityl-15-{4-[2-(tr im eth ylsilyl)eth yn yl]-

p h e n yl}-20-{4-[2-(t r iisop r op ylsilyl)e t h yn yl]p h e n yl}-

p or p h yr in (13b). A sample of diacyl dipyrromethane 7e (2.50

g, 3.60 mmol) was dissolved in dry THF/methanol (10:1, 160

mL) at room temperature in a 500-mL round-bottomed flask

fitted with a vented rubber septum and flooded with argon.

The septum was removed as needed to add NaBH₄(2.72 g,

72.0 mmol, 20 mol equiv) in small portions (∼0.5 g, every 2

min) with rapid stirring (reduction method 2). The progress

of the reduction was monitored by TLC analysis [alumina, CH₂-

Cl₂/ethyl acetate (3:2)] of reaction aliquots. After the reaction

was complete (about 40 min), the reaction mixture was poured

into a stirred mixture of satd aq NH₄Cl (200 mL) and CH₂Cl₂

(400 mL) in a 1-L beaker. The organic phase was removed in

a 1-L separatory funnel, washed with water (2 × 200 mL),

dried (Na₂SO₄), and placed in a 2-L round-bottomed flask.

Removal of solvent on a rotary evaporator under reduced

1

a crystalline purple solid (1.05 g, 27%). H NMR δ -2.71 (br,

2H), 0.41 (s, 9H), 1.29 (s, 21H), 1.86 (s, 6H), 2.65 (s, 3H), 7.31

(s, 2H), 7.91 (m, 4H), 7.96 (d, J ) 8.1 Hz, 2H), 8.10 (d, J ) 8.1

Hz, 2H), 8.18 (apparent t, J ) 8.1 Hz, 4H), 8.74-8.86 (m, 8H);

LD-MS obsd 1060.31; FAB-MS obsd 1058.3601, calcd 1058.3636

(C₆₃H₆₃IN₄Si₂).

Exem p la r y Sm a ll-sca le P r oced u r e, Given for 5,15-

Dip h en yl-10,20-bis(p en ta flu or op h en yl)p or p h yr in (8b). A

solution of diacyl dipyrromethane 4c (0.18 g, 0.30 mmol) in

dry THF/methanol (10:1, 13.2 mL) in a 50-mL round-bottomed

flask (fitted with a rubber septum and flooded with argon) was

reduced by adding portions of NaBH₄(total amount 0.23 g,

6.0 mmol) (reduction method 2). After the reduction was

complete (TLC monitoring as for 13b), the reaction mixture

was poured into satd aq NH₄Cl (20 mL) and CH₂Cl₂(40 mL)

in a 200-mL beaker. The organic layer was separated in a

separatory funnel, washed twice with water, dried (Na₂SO₄),

and placed in a 250-mL round-bottomed flask. Removal of the

solvent by rotary evaporation under vacuum yielded the

dicarbinol as a foamlike solid. Then 5-phenyldipyrromethane

(2a , 67 mg, 0.30 mmol) and reagent-grade (A.C.S.) acetonitrile

(120 mL) were added, and the mixture was stirred to achieve

a homogeneous solution. Then TFA (0.280 mL, 3.65 mmol) was

added in a slow steady stream over 5-10 s with rapid stirring.

Reaction monitoring (as described for 13b) showed rapid

reaction, and after 5 min of elapsed time, DDQ (0.20 g, 0.90

mmol) was added. After stirring for 1 h at room temperature,

triethylamine (0.507 mL, 3.65 mmol) was added, and the entire

reaction mixture was filtered through a pad of alumina (4 ×

8 cm) and eluted with CH₂Cl₂(∼150 mL) until the eluant was

no longer dark. The resulting porphyrin solution was concen-

trated, redissolved in CH₂Cl₂(30 mL), and passed through a

pad of silica (4 × 8 cm) with CH₂Cl₂elution to remove non-

porphyrinic pigments. The purple fractions were combined and

concentrated to give a purple solid which was recrystallized

from CH₂Cl₂/methanol (58 mg, 24% from 4c). ¹H NMR δ -2.83

(br, 2H), 7.78-7.84 (m, 6H), 8.20-8.25 (m, 4H), 8.80 (d, J )

4.5 Hz, 4H), 8.95 (d, J ) 4.5 Hz, 4H); LD-MS obsd 796.50;

FAB-MS obsd 794.1514, calcd 794.1528 (C₄₄H₂₀F₁₀N₄).

Notes Con cer n in g th e P or p h yr in -F or m in g Rea ction .

(1) The condensation was monitored by absorption spectros-

copy in order to add DDQ at the appropriate time (i.e., after

condensation has leveled off). Samples were removed for

7342 J . Org. Chem., Vol. 65, No. 22, 2000

Rao et al.

spectroscopic monitoring (DDQ oxidation and absorption

spectroscopy) after 1 min, 2.5 min, 4 min, etc. If the yield was

essentially the same for two successive timepoints, bulk

oxidation was performed by adding DDQ to the reaction

mixture. This generally occurred for the first and second

timepoints (indicating the reaction was complete in e1 min);

given manual constraints in experimentation the bulk oxida-

tion was then generally started at ∼3.5 min following the

completion of the addition of TFA. In the following procedures,

the times given for DDQ oxidation reflect the number of

timepoints collected [always 2 (addition of DDQ after 3-5

min), sometimes 3 (addition of DDQ after 5-7 min)] in

spectroscopic yield monitoring of porphyrin formation. (2) The

last sample obtained in spectroscopic yield monitoring also was

examined by LD-MS to check for the presence of scrambled

porphyrin products. (3) In the following procedures, “standard

workup” refers to the following sequence of steps: (i) treatment

with a sufficient amount of triethylamine to neutralize the

TFA, (ii) filtration through alumina, (iii) evaporation of the

solvent, (iv) dissolution in CH₂Cl₂followed by column chro-

matography on silica, (v) evaporation of the solvent to obtain

the porphyrin as a purple solid. Any further purification

procedures are specified in individual preparations.

5.1 Hz, 2H), 9.52-9.54 (m, 4H); LD-MS obsd 597.28; FAB-MS

obsd 596.3887, calcd 596.3879 (C₄₁H₄₈N₄).

5,10,15-Tr ip en tyl-20-(4-m eth oxyp h en yl)p or p h yr in (9f).

Reduction (method 1) of 4k (0.25 g, 0.60 mmol) followed by

condensation with 2c (0.15 g, 0.60 mmol) for 4 min, oxidation

with DDQ (0.41 g, 1.8 mmol), and standard workup gave a

purple solid which was suspended in boiling ethanol for a few

min, cooled, filtered, and dried (0.11 g, 28% from 4k ). ¹H NMR

δ -2.78 (br, 2H), 0.94-1.02 (m, 9H), 1.49-1.60 (m, 6H), 1.75-

1.80 (m, 6H), 2.49-2.50 (m, 6H), 4.21 (s, 3H), 4.91-5.01 (m,

6H), 7.27 (m, 2H), 8.07 (m, 2H), 8.83 (d, J ) 5.1 Hz, 2H), 9.37

(d, J ) 4.5 Hz, 2H), 9.49-9.53 (m, 4H); LD-MS obsd 626.24;

FAB-MS obsd 626.3969, calcd 626.3985 (C₄₂H₅₀N₄O).

5,10,15-Tr ip en tyl-20-(4-cya n op h en yl)p or p h yr in (9g).

Reduction (method 1) of 4k (0.25 g, 0.60 mmol) followed by

condensation with 2j (0.15 g, 0.60 mmol) for 5 min, oxidation

with DDQ (0.41 g, 1.8 mmol), and standard workup gave a

purple solid which was suspended in boiling ethanol for a few

min, cooled, filtered, and dried (68 mg, 18% from 4k ). ¹H NMR

δ -2.75 (br, 2H), 0.94-1.02 (m, 9H), 1.49-1.58 (m, 6H), 1.74-

1.82 (m, 6H), 2.47-2.55 (m, 6H), 4.90-4.97 (m, 6H), 8.03.(d,

J ) 7.2 Hz, 2H), 8.26 (d, J ) 8.1 Hz, 2H), 8.66 (d, J ) 4.5 Hz,

2H), 9.38 (d, J ) 5.1 Hz, 2H), 9.49-9.54 (m, 4H); LD-MS obsd

623.76; FAB-MS obsd 621.3830, calcd 621.3831 (C₄₂H₄₇N₅).

5,10,15-Tr ipen tyl-20-(pen taflu or oph en yl)por ph yr in (9h ).

Reduction (method 1) of 4k (0.25 g, 0.60 mmol) followed by

condensation with 2b (0.19 g, 0.60 mmol) for 4 min, oxidation

with DDQ (0.41 g, 1.8 mmol), and standard workup gave a

purple solid which was suspended in boiling ethanol for a few

min, cooled, filtered, and dried (57 mg, 14% from 4k ). ¹H NMR

δ -2.65 (br, 2H), 0.95-1.02 (m, 9H), 1.48-1.60 (m, 6H), 1.73-

1.83 (m, 6H), 2.47-2.56 (m, 6H), 4.94-5.15 (m, 6H), 8.71 (d,

J ) 4.2 Hz, 2H), 9.45 (d, J ) 5.1 Hz, 2H), 9.48 (d, J ) 5.1 Hz,

2H), 9.54 (d, J ) 4.5 Hz, 2H); LD-MS obsd 686.83; FAB-MS

obsd 686.3410, calcd 686.3408 (C₄₁H₄₃F₅N₄).

5,10,15-Tr is(4-m eth oxyph en yl)-20-ph en ylpor ph yr in (9a).

Reduction (method 2) of 4f (0.26 g, 0.50 mmol) followed by

condensation with 2a (0.11 g, 0.50 mmol) for 4 min, oxidation

with DDQ (0.34 g, 1.5 mmol), and standard workup and recrys-

tallization from CH₂Cl₂/methanol furnished a purple solid (94

mg, 27% from 4f). ¹H NMR δ -2.76 (br, 2H), 4.09 (s, 9H), 7.28

(d, J ) 7.8 Hz, 6H), 7.74-7.76 (m, 3H), 8.12 (d, J ) 7.8 Hz,

6H), 8.20-8.23 (m, 2H), 8.82-8.87 (m, 8H); LD-MS obsd

705.01; FAB-MS obsd 704.2780, calcd 704.2787 (C₄₇H₃₆N₄O₃).

5,10,15-Tr is(p en ta flu or op h en yl)-20-p h en ylp or p h yr in

(9b). Reduction (method 2) of 4e (0.21 g, 0.30 mmol) followed

by condensation with 2a (67 mg, 0.30 mmol) for 6 min,

oxidation with DDQ (0.20 g, 0.90 mmol), and standard workup

with an additional gravity column chromatography [silica,

CHCl₃/hexanes (1:2)] furnished a purple solid (47 mg, 18% from

5,10,15-Tr ipen tyl-20-(4-acetam idoph en yl)por ph yr in (9i).

Reduction (method 1) of 4k (0.25 g, 0.60 mmol) followed by

condensation with 2k (0.17 g, 0.60 mmol) for 7 min, oxidation

with DDQ (0.41 g, 1.8 mmol), and standard workup gave a

purple solid which was suspended in boiling ethanol for a few

min, cooled, filtered, and dried (0.14 g, 35% from 4k ). ¹H NMR

δ -2.77 (br, 2H), 0.94-1.02 (m, 9H), 1.46-1.61 (m, 6H), 1.71-

1.85 (m, 6H), 2.35 (s, 3H), 2.45-2.59 (m, 6H), 4.89-5.10 (m,

6H), 7.49 (s, 1H), 7.86 (d, J ) 8.1 Hz, 2H), 8.11 (d, J ) 8.1 Hz,

2H), 8.80 (d, J ) 4.5 Hz, 2H), 9.36 (d, J ) 5.1 Hz, 2H), 9.49-

9.54 (m, 4H); LD-MS obsd 653.98; FAB-MS obsd 653.4130,

calcd 653.4094 (C₄₃H₅₁N₅O).

1

4e). H NMR δ -2.85 (br, 2H), 7.76-7.84 (m, 3H), 8.19-8.23

(m, 2H), 8.81 (d, J ) 4.5 Hz, 2H), 8.89 (m, 4H), 8.96 (d, J )

4.5 Hz, 2H); LD-MS obsd 885.83; FAB-MS obsd 884.1083, calcd

884.1057 (C₄₄H₁₅F₁₅N₄).

5,10,15-Tr is(4-ter t-bu tylp h en yl)-20-(4-iod op h en yl)p or -

p h yr in (9c). Reduction (method 2) of 4n (2.56 g, 4.30 mmol)

followed by condensation with 2h (1.50 g, 4.30 mmol) for 4

min, oxidation with DDQ (2.92 g, 13.0 mmol), and standard

workup furnished a purple solid which was suspended in

methanol, sonicated for 5 min, filtered, and dried (0.98 g, 25%

5,10,15-Tr is(4-ter t-bu tylph en yl)-20-{4-[2-(tr im eth ylsilyl)-

eth yn yl]p h en yl}p or p h yr in (9j). Reduction (method 1) of 4i

(0.45 g, 0.70 mmol) followed by condensation with 2g (0.19 g,

0.70 mmol) for 5 min, oxidation with DDQ (0.48 g, 2.1 mmol),

and standard workup furnished a purple solid which was

suspended in ethanol, sonicated for 5 min, filtered, and dried

1

from 4n ). H NMR δ -2.78 (br, 2H), 1.61 (s, 27H), 7.75 (d, J

) 8.1 Hz, 6H), 7.94 (d, J ) 8.1 Hz, 2H), 8.09 (d, J ) 8.1 Hz,

2H), 8.13 (d, J ) 8.1 Hz, 4H), 8.14 (d, J ) 8.1 Hz, 2H), 8.79 (d,

J ) 4.5 Hz, 2H), 8.88-8.91 (m, 6H); LD-MS obsd 908.96; FAB-

MS obsd 908.3301, calcd 908.3315 (C₅₆H₅₃IN₄).

1

5,10,15-Tr is(4-ter t-bu tylp h en yl)-20-(4-ca r boxyp h en yl)-

p or p h yr in (9d ). Reduction (method 2) of 4n (0.18 g, 0.30

mmol) followed by condensation with 2i (80 mg, 0.30 mmol)

for 5 min, oxidation with DDQ (0.20 g, 0.90 mmol), and use of

polar solvents in the standard workup (alumina, THF/acetic

acid (10:1); silica, CH₂Cl₂/methanol (10:1)) furnished a purple

solid which was suspended in methanol, sonicated for 5 min,

filtered, and dried (44 mg, 18% from 4n ). ¹H NMR δ -2.55

(br, 2H), 1.64 (s, 27H), 7.79 (d, J ) 7.8 Hz, 6H), 8.17 (d, J )

8.1 Hz, 6H), 8.38 (d, J ) 8.7 Hz, 2H), 8.54 (d, J ) 8.1 Hz, 2H),

8.81 (d, J ) 4.5 Hz, 2H), 8.91-8.95 (m, 6H) (acid hydrogen

not observed); LD-MS obsd 828.19; FAB-MS obsd 826.4264,

calcd 826.4247 (C₅₇H₅₄N₄O₂).

5,10,15-Tr ip en tyl-20-p h en ylp or p h yr in (9e). Reduction

(method 1) of 4k (0.25 g, 0.60 mmol) followed by condensation

with 2a (0.13 g, 0.60 mmol) for 6 min, oxidation with DDQ

(0.41 g, 1.8 mmol), and standard workup gave a purple solid

which was suspended in boiling ethanol for a few min, cooled,

filtered, and dried (78 mg, 22% from 4k ). ¹H NMR δ -2.71

(br, 2H), 0.96-1.04 (m, 9H), 1.48-1.62 (m, 6H), 1.72-1.85 (m,

6H), 2.57-4.45 (m, 6H), 4.90-5.12 (m, 6H), 7.75-7.78 (m, 3H),

8.19 (d, J ) 7.2 Hz, 2H), 8.81 (d, J ) 5.1 Hz, 2H), 9.39 (d, J )

(0.17 g, 27% from 4i). H NMR δ -2.75 (br, 2H), 0.37 (s, 9H),

1.60 (s, 27H), 7.75 (d, J ) 8.1 Hz, 6H), 7.87 (d, J ) 8.1 Hz,

2H), 8.12-8.18 (m, 8H), 8.78 (d, J ) 4.5 Hz, 2H), 8.80-8.90

(m, 6H); LD-MS obsd 880.73; FAB-MS obsd 878.4782, calcd

878.4744 (C₆₁H₆₂N₄Si).

5-P h en yl-15-(p en t a flu or op h en yl)-10,20-b is(4-m et h yl-

p h en yl)p or p h yr in (10a ). Reduction (method 2) of 4d (0.22

g, 0.40 mmol) followed by condensation with 2a (0.89 g, 0.40

mmol) for 4 min, oxidation with DDQ (0.27 g, 1.2 mmol), and

standard workup furnished a purple solid which was recrys-

tallized from CH₂Cl₂/methanol (0.11 g, 36% from 4d ). ¹H NMR

δ -2.75 (br, 2H), 2.73 (s, 6H), 7.57 (d, J ) 7.2 Hz, 4H), 7.76-

7.80 (m, 3H), 8.10 (d, J ) 7.2 Hz, 4H), 8.21-8.24 (m, 2H), 8.76

(d, J ) 5.1 Hz, 2H), 8.85 (d, J ) 4.2 Hz, 2H), 8.88 (d, J ) 5.1

Hz, 2H), 8.97 (d, J ) 5.1 Hz, 2H); LD-MS obsd 732.89; FAB-

MS obsd 732.2294, calcd 732.2312 (C₄₆H₂₉F₅N₄).

5-(4-Iod op h en yl)-15-p h en yl-10,20-bis(4-m eth ylp h en yl)-

p or p h yr in (10b). Reduction (method 1) of 4a (0.23 g, 0.50

mmol) followed by condensation with 2h (0.17 g, 50 mmol) for

5 min, oxidation with DDQ (0.34 g, 1.5 mmol), and standard

workup gave a purple solid which was suspended in boiling

ethanol for a few min, cooled, filtered, and dried (82 mg, 21%

Rational Syntheses of Porphyrins

J . Org. Chem., Vol. 65, No. 22, 2000 7343

1

from 4a ). H NMR δ -2.78 (br, 2H), 2.73 (s, 6H), 7.55 (d, J )

5-(4-Met h oxyp h en yl)-10-(p en t a flu or op h en yl)-15,20-

d ip h en ylp or p h yr in (12a ). Reduction (method 2) of 7b (0.11

g, 0.20 mmol) followed by condensation with 2a (44 mg, 0.20

mmol) for 3.5 min, oxidation with DDQ (136 mg, 0.60 mmol),

and standard workup including recrystallization from CH₂-

Cl₂/methanol afforded a crystalline purple solid (28 mg, 20%).

¹H NMR δ -2.70 (br, 2H), 4.10 (s, 3H), 7.26-7.32 (m, 2H),

7.76-7.81 (m, 6H), 8.13-8.26 (m, 6H), 8.80-9.02 (m, 8H); LD-

MS obsd 734.56; FAB-MS obsd 734.2146, calcd 734.2105

(C₄₅H₂₇F₅N₄O). Alternatively, reduction (method 2) of 7c (0.14

g, 0.25 mmol) followed by reaction with 2a (56 mg, 0.25 mmol)

afforded porphyrin 12a (54 mg, 29%).

8.1 Hz, 4H), 7.74-7.76 (m, 3H), 7.93-7.96 (m, 8H), 8.09 (d, J

) 8.1 Hz, 6H), 8.20-8.22 (m, 2H), 8.80-8.90 (m, 4H); LD-MS

obsd 770.50; FAB-MS obsd 768.1749, calcd 768.1750 (C₄₆H₃₃

IN₄).

5-(4-Iod op h e n yl)-15-{4-[2-(t r im e t h ylsilyl)e t h yn yl]-

p h en yl}-10,20-bis(4-m eth ylp h en yl)p or p h yr in (10c). Re-

duction (method 1) of 4j (0.83 g, 1.5 mmol) followed by

condensation with 2h (0.52 g, 1.5 mmol) for 5 min, oxidation

with DDQ (1.02 g, 4.5 mmol), and standard workup furnished

a purple solid which was suspended in methanol, sonicated

-

1

for 5 min, filtered, and dried (0.34 g, 26% from 4j). H NMR δ

-2.82 (br, 2H), 0.40 (s, 9H), 2.70 (s, 6H), 7.55 (d, J ) 8.1 Hz,

4H), 7.85-7.87 (m, 2H), 7.92-7.95 (m, 2H), 8.06-8.10 (m, 6H),

8.13-8.16 (m, 2H), 8.80 (apparent t, J ) 5.0 Hz, 4H), 8.86-

8.88 (m, 4H); LD-MS obsd 866.22; FAB-MS obsd 864.2137,

calcd 864.2145 (C₅₁H₄₁IN₄Si).

5-(4-F or m ylp h en yl)-15-(4-iod op h en yl)-10,20-bis(3,5-d i-

ter t-bu tylp h en yl)p or p h yr in (10d ). Reduction (method 2) of

4o (0.13 g, 0.17 mmol) followed by condensation with 2n (43

mg, 0.17 mmol) for 5 min, oxidation with DDQ (0.12 g, 0.50

mmol), and standard workup furnished a brown solid which

was suspended in methanol, sonicated for 5 min, filtered and

dried (29 mg, 17% from 4o). ¹H NMR δ -2.81 (br, 2H), 1.48

(s, 36H), 7.76-7.77 (m, 2H), 7.90-7.93 (m, 2H), 8.00-8.07 (m,

6H), 8.22 (d, J ) 8.1 Hz, 2H), 8.36 (d, J ) 8.1 Hz, 2H), 8.72 (d,

J ) 4.5 Hz, 2H), 8.78 (d, J ) 5.1 Hz, 2H), 8.85-8.88 (m, 4H),

10.34 (s, 1H); LD-MS obsd 993.43; FAB-MS obsd 992.3922,

calcd 992.3890 (C₆₁H₆₁IN₄O).

5-Mesityl-10,15-bis{4-[2-(tr im eth ylsilyl)eth yn yl]ph en yl}-

20-{4-[2-(tr iisopr opylsilyl)eth yn yl]ph en yl}por ph yr in (12b).

Reduction (method 2) of 7f (0.38 g, 0.50 mmol) followed by

condensation with 2e (0.18 g, 0.50 mmol) for 3.5 min, oxidation

with DDQ (0.34 g, 1.5 mmol), and standard workup furnished

a purple solid (82 mg, 16%). ¹H NMR δ -2.75 (br, 2H), 0.42

(s, 18H), 1.29 (s, 21H), 1.87 (s, 6H), 2.66 (s, 3H), 7.32 (s, 2H),

7.90-7.92 (m, 6H), 8.17-8.21 (m, 6H), 8.75-8.89 (m, 8H); LD-

MS obsd 1029.35; FAB-MS obsd 1028.5092, calcd 1028.5065

(C₆₈H₇₂N₄Si₃).

5-(4-Br om op h en yl)-10-{4-[2-(t r im et h ylsilyl)et h yn yl]-

p h en yl}-15,20-bis(4-iod op h en yl)p or p h yr in (12c). Reduc-

tion (method 2) of 7g (0.73 g, 1.0 mmol) followed by conden-

sation with 2h (0.35 g, 1.0 mmol) for 3.5 min, oxidation with

DDQ (0.68 g, 3.0 mmol), and standard workup furnished a

1

purple solid (0.22 g, 21%). H NMR δ -2.83 (br, 2H), 0.42 (s,

9H), 7.90 (m, 8H), 8.07 (m, 6H), 8.16 (m, 2H), 8.85 (s, 8H);

LD-MS obsd 1043.99; FAB-MS obsd 1039.9875, calcd 1039.9904

(C₄₉H₃₅BrI₂N₄Si).

5-{4-[2-(Tr im eth ylsilyl)eth oxyca r bon yl]p h en yl}-15-(4-

iodoph en yl)-10,20-bis(4-ter t-bu tylph en yl)por ph yr in (10e).

Reduction (method 2) of 4p (2.73 g, 4.0 mmol) followed by

condensation with 2l (1.47 g, 4.0 mmol) for 5 min, oxidation

with DDQ (2.72 g, 12.0 mmol), and standard workup furnished

a purple solid which was suspended in methanol, sonicated

5,10-Bis(4-ter t-bu tylp h en yl)-15-(4-iod op h en yl)-20-{4-[2-

(tr im eth ylsilyl)eth yn yl]p h en yl}p or p h yr in (12d ). Reduc-

tion (method 2) of 7h (0.67 g, 1.0 mmol) followed by conden-

sation with 2e (0.32 g, 1.0 mmol) for 3.5 min, oxidation with

DDQ (0.68 g, 3.0 mmol), and standard workup furnished a

1

for 5 min, filtered, and dried (0.90 g, 22% from 4p ). H NMR

δ -2.77 (br, 2H), 0.21 (s, 9H), 1.27-1.37 (m, 2H), 1.64 (s, 18H),

4.60-4.68 (m, 2H), 7.79 (d, J ) 8.7 Hz, 4H), 7.98 (d, J ) 8.7

Hz, 2H), 8.12 (d, J ) 8.1 Hz, 2H), 8.16 (d, J ) 8.1 Hz, 4H),

8.33 (d, J ) 8.7 Hz, 2H), 8.46 (d, J ) 8.1 Hz, 2H), 8.81 (d, J )

5.1 Hz, 2H), 8.84 (d, J ) 4.5 Hz, 2H), 8.94 (d, J ) 4.5 Hz, 4H);

LD-MS obsd 997.65; FAB-MS obsd 996.3288, calcd 996.3296

(C₅₈H₅₇IN₄O₂Si).

1

purple solid (0.25 g, 26%). H NMR δ -2.78 (br, 2H), 0.40 (s,

9H), 1.63 (s, 18H), 7.79 (d, J ) 7.2 Hz, 4H), 7.89 (d, J ) 8.1

Hz, 2H), 7.97 (d, J ) 8.1 Hz, 2H), 8.12 (d, J ) 8.1 Hz, 2H),

8.16 (d, J ) 8.1 Hz, 2H), 8.18 (d, J ) 7.2 Hz, 4H), 8.81-8.93

(m, 8H); LD-MS obsd 950.77; FAB-MS obsd 948.3074, calcd

948.3084 (C₅₇H₅₃IN₄Si).

5-(4-ter t-Bu tylp h en yl)-10-(4-m eth ylp h en yl)-15-(4-m eth -

oxyp h en yl)-20-p h en ylp or p h yr in (13a ). Reduction (method

1) of 7a (0.16 g, 0.33 mmol) followed by condensation with 2g

(0.094 g, 0.33 mmol) for 3.5 min, oxidation with DDQ (0.227

g, 1.00 mmol), and standard workup furnished a purple solid

which was suspended in ethanol, sonicated for 5 min, filtered,

and dried (51 mg, 21%). ¹H NMR δ -2.76 (br, 2H), 1.60 (s,

9H), 2.70 (s, 3H), 4.08 (s, 3H), 7.28 (m, 2H), 7.55 (d, J ) 8.1

Hz, 2H), 7.75 (m, 5H), 8.13 (m, 6H), 8.20-8.23 (m, 2H), 8.81-

8.88 (m, 8H); LD-MS obsd 715.55; FAB-MS obsd 714.3346,

calcd 714.3359 (C₅₀H₄₂N₄O).

5,15-Dim e sit yl-10-{4-[2-(t r iisop r op ylsilyl)e t h yn yl]-

p h e n y l}-20-{4-[2-(t r i m e t h y ls i ly l)e t h y n y l]p h e n y l}-

p or p h yr in (10f). Reduction (method 2) of 7f (0.75 g, 1.0 mmol)

followed by condensation with 2d (0.26 g, 1.0 mmol) for 3.5

min, oxidation with DDQ (0.68 g, 3.0 mmol), and standard

workup furnished a purple solid (0.24 g, 24%). ¹H NMR δ -2.62

(br, 2H), 0.40 (s, 9H), 1.28 (s, 21H), 1.85 (s, 12H), 2.65 (s, 6H),

7.30 (s, 4H), 7.88 (d, J ) 8.1 Hz, 2H), 7.89 (d, J ) 8.1 Hz, 2H),

8.19 (d, J ) 8.1 Hz, 4H), 8.72 (d, J ) 5.4 Hz, 4H), 8.77-8.82

(m, 4H); LD-MS obsd 976.64; FAB-MS obsd 974.5164, calcd

974.5139 (C₆₆H₇₀N₄Si₂).

5-(4-Iod op h en yl)-10-(p en ta flu or op h en yl)-15-{4-[2-(tr i-

m eth ylsilyl)eth yn yl]p h en yl}-20-{4-[2-(tr iisop r op ylsilyl)-

eth yn yl]p h en yl}p or p h yr in (13c). Reduction (method 2) of

7d (0.74 g, 1.0 mmol) followed by condensation with 2m (0.40

g, 1.0 mmol) for 3.5 min, oxidation with DDQ (0.68 g, 3.0

mmol), and standard purification furnished a brown solid

which was suspended in methanol, sonicated for 5 min, filtered

and dried to give a reddish-brown solid (0.44 g, 40%). ¹H NMR

δ -2.82 (br, 2H), 0.38 (s, 9H), 1.26 (s, 21H), 7.88-7.96 (m, 6H),

8.11-8.17 (m, 6H), 8.78-8.92 (m, 8H); LD-MS obsd 1108.58;

FAB-MS obsd 1106.2678, calcd 1106.2695 (C₆₀H₅₂F₅IN₄Si₂).

5-(4-Eth yn ylph en yl)-10-{4-[2-(tr iisopr opylsilyl)eth yn yl]-

p h e n yl}-15-m e sit yl-20-{4-[2-(t r im e t h ylsilyl)e t h yn yl]-

p h en yl}p or p h yr in (13d ). Reduction (method 2) of 7f (0.75

g, 1.0 mmol) followed by condensation with 2o (0.25 g, 1.0

mmol) for 3.5 min, oxidation with DDQ (0.68 g, 3.0 mmol),

and standard workup including recrystallization from CH₂-

Cl₂/methanol afforded a crystalline purple solid (0.25 g, 26%).

¹H NMR δ -2.67 (br, 2H), 0.43 (s, 9H), 1.30 (s, 21H), 1.88 (s,

6H), 2.67 (s, 3H), 3.35 (s, 1H), 7.32 (s, 2H), 7.92 (d, J ) 8.1

Hz, 2H), 7.93 (d, J ) 8.1 Hz, 4H), 8.21 (d, J ) 8.1 Hz, 6H),

5,10-Bis(4-ter t-b u t ylp h en yl)-15,20-b is(4-iod op h en yl)-

p or p h yr in (11a ). Reduction (method 2) of 7h (3.34 g, 5.00

mmol) followed by condensation with 2h (1.74 g, 5.00 mmol)

for 3.5 min, oxidation with DDQ (3.40 g, 15.0 mmol), and

standard workup furnished a purple solid which was sus-

pended in methanol, sonicated for 5 min, filtered, and dried

1

(1.18 g, 24%). H NMR δ -2.81 (br, 2H), 1.61 (s, 18H), 7.77 (d,

J ) 8.1 Hz, 4H), 7.95 (d, J ) 8.1 Hz, 4H), 8.08-8.14 (m, 8H),

8.81-8.90 (m, 8H); LD-MS obsd 979.82; FAB-MS obsd 978.1697,

calcd 978.1656 (C₅₂H₄₄I₂N₄).

5,10-B is(4-t er t -b u t y lp h e n y l)-15,20-b is {4-[2-(t r iiso-

p r op ylsilyl)eth yn yl]p h en yl}p or p h yr in (11b). Reduction

(method 2) of 7i (1.44 g, 2.00 mmol) followed by condensation

with 2m (0.800 g, 2.00 mmol) for 3.5 min, oxidation with DDQ

(1.36 g, 6.00 mmol), and standard workup including recrys-

tallization from CH₂Cl₂/methanol afforded a crystalline purple

solid (0.53 g, 24%). ¹H NMR δ -2.77 (br, 2H), 1.27 (s, 42H),

1.62 (s, 18H), 7.78 (d, J ) 8.1 Hz, 4H), 7.90 (d, J ) 8.1 Hz,

4H), 8.15 (d, J ) 8.1 Hz, 4H), 8.18 (d, J ) 8.1 Hz, 4H), 8.83-

8.92 (m, 8H); LD-MS obsd 1090.30; FAB-MS obsd 1086.6432,

calcd 1086.6391 (C₇₄H₈₆N₄Si₂).

7344 J . Org. Chem., Vol. 65, No. 22, 2000

Rao et al.

8.76-8.89 (m, 8H); LD-MS obsd 958.27; FAB-MS obsd 956.4665,

calcd 956.4670 (C₆₅H₆₄N₄Si₂).

Mass Spectrometry Laboratory for Biotechnology. Par-

tial funding for the Facility was obtained from the North

Carolina Biotechnology Center and the National Science

Foundation.

5-(4-Br om op h en yl)-10-{4-[2-(tr iisop r op ylsilyl)eth yn yl]-

ph en yl}-15-(4-iodoph en yl)-20-{4-[2-(tr im eth ylsilyl)eth yn yl]-

p h en yl}p or p h yr in (13e). Reduction (method 2) of 7g (2.92

g, 4.00 mmol) followed by condensation with 2m (1.62 g, 4.00

mmol) for 3.5 min, oxidation with DDQ (2.72 g, 12.0 mmol),

and standard workup including recrystallization from CH₂-

Su p p or tin g In for m a tion Ava ila ble: ¹H NMR and LD-

MS spectra for all new porphyrins; improved experimental

procedure for synthesis of 1e; procedures and tables of data

for refinement of the procedure giving symmetrical diacyl

dipyrromethanes; and complete retrosynthetic analyses for the

five types of porphyrins. This material is available free of

charge via the Internet at http://pubs.acs.org.

1

Cl₂/methanol afforded a purple solid (1.12 g, 25%). H NMR δ

-2.82 (br, 2H), 0.41 (s, 9H), 1.28 (s, 21H), 7.89-7.97 (m, 8H),

8.08-8.18 (m, 8H), 8.85 (m, 8H); LD-MS obsd 1098.02; FAB-

MS obsd 1094.2288, calcd 1094.2272 (C₆₀H₅₆BrIN₄Si₂).

Ack n ow led gm en t. This work was funded by the

NIH (GM36238). Mass spectra were obtained at the

J O000882K

Article Doi

Rational Syntheses of Porphyrins Bearing up to Four Different Meso Substituents

DOI: 10.1021/jo000882k

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Article abstract of DOI:10.1021/jo000882k

Full text of DOI:10.1021/jo000882k

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