Efficient synthesis of monoacyl dipyrromethanes and their use in the preparation of sterically unhindered trans-porphyrins

Article abstract of DOI:10.1021/jo9915473

The condensation of an aldehyde with a dipyrromethane bearing a sterically unhindered aryl substituent at the 5-position typically results in low yield and a mixture of porphyrin products derived from acidolytic scrambling. We have developed a concise nonscrambling synthesis of such trans-porphyrins that takes advantage of the availability of multigram quantities of dipyrromethanes. This route involves the selective monoacylation of the dipyrromethanes with a pyridyl thioester, reduction of the monoacyl dipyrromethane to the corresponding carbinol, and self- condensation of the carbinol to form the porphyrin. The monoacylation procedure has wide scope as demonstrated by the preparation of a set of 15 diverse monoacyl dipyrromethanes in good yield at the multigram scale. The dipyrromethanecarbinol self-condensation reaction is extremely rapid (<3 min) under mild room-temperature conditions and affords the trans-porphyrin in 16- 28% yield. Analysis by laser-desorption mass spectrometry (LD-MS) of samples from the crude reaction mixture revealed no scrambling within the limit of detection (1 part in 100). The self-condensation is compatible with a range of electron-withdrawing or -releasing substituents as well as substituents for building block applications (TMS-ethyne, ethyne, iodo, ester). The absence of any detectable scrambling in the self-condensation enables a simple purification. The synthesis readily affords gram quantities of pure, sterically unhindered trans-porphyrins in a process involving minimal chromatography.

Full text of DOI:10.1021/jo9915473

1084
J . Org. Chem. 2000, 65, 1084-1092
Efficien t Syn th esis of Mon oa cyl Dip yr r om eth a n es a n d Th eir Use
in th e P r ep a r a tion of Ster ica lly Un h in d er ed tr a n s-P or p h yr in s
Polisetti Dharma Rao, Benjamin J . Littler, G. Richard Geier III, and J onathan S. Lindsey*
Department of Chemistry, North Carolina State University, Raleigh, North Carolina 27695-8204
Received October 5, 1999
The condensation of an aldehyde with a dipyrromethane bearing a sterically unhindered aryl
substituent at the 5-position typically results in low yield and a mixture of porphyrin products
derived from acidolytic scrambling. We have developed a concise nonscrambling synthesis of such
trans-porphyrins that takes advantage of the availability of multigram quantities of dipyrro-
methanes. This route involves the selective monoacylation of the dipyrromethanes with a pyridyl
thioester, reduction of the monoacyl dipyrromethane to the corresponding carbinol, and self-
condensation of the carbinol to form the porphyrin. The monoacylation procedure has wide scope
as demonstrated by the preparation of a set of 15 diverse monoacyl dipyrromethanes in good yield
at the multigram scale. The dipyrromethanecarbinol self-condensation reaction is extremely rapid
(<3 min) under mild room-temperature conditions and affords the trans-porphyrin in 16-28% yield.
Analysis by laser-desorption mass spectrometry (LD-MS) of samples from the crude reaction mixture
revealed no scrambling within the limit of detection (1 part in 100). The self-condensation is
compatible with a range of electron-withdrawing or -releasing substituents as well as substituents
for building block applications (TMS-ethyne, ethyne, iodo, ester). The absence of any detectable
scrambling in the self-condensation enables a simple purification. The synthesis readily affords
gram quantities of pure, sterically unhindered trans-porphyrins in a process involving minimal
chromatography.
In tr od u ction
An alternative route to the synthesis of trans-por-
phyrins bearing sterically unhindered substituents is the
self-condensation of a dipyrromethanecarbinol (Scheme
1). Implementation of this promising methodology has
been limited to the preparation of three trans-porphyrins
(up to 75 mg scale). Despite the forcing reaction condi-
tions (hot propionic acid in air), this approach was
reported to provide less scrambling than analogous
dipyrromethane-aldehyde condensations.4 A fuller ex-
amination of this promising methodology, including a
thorough investigation of mild reaction conditions, has
been hampered by the lack of a simple method for
preparing multigram batches of dipyrromethanecarbinols.
Recently, we reported an efficient synthesis of analyti-
cally pure 5-substituted dipyrromethanes in multigram
batches,5 providing the critical first step in a route to
dipyrromethanecarbinols. We also have developed pro-
cedures for the acylation of dipyrromethanes involving
treatment of the dipyrromethane with ethylmagnesium
bromide followed by an acid chloride.6,7 Although various
ratios of dipyrromethane/ethylmagnesium bromide/acid
chloride could be employed to favor either the monoacyl-
or diacyldipyrromethane, a mixture of the monoacyl and
diacyl compounds was always produced. Quite tedious
column chromatography was required to give the pure
monoacyldipyrromethane.6 We have reexamined the
Meso-substituted trans-porphyrins are key structural
components found in a wide range of model systems in
biomimetic and materials chemistry.1,2 An attractive
route for the synthesis of these valuable compounds
involves the condensation of a dipyrromethane with an
aldehyde, but this approach is often stymied by acid-
catalyzed scrambling processes that give rise to undesired
porphyrin byproducts.2 We recently reported a detailed
study into the reaction conditions of the dipyrromethane-
aldehyde condensation with the aim of preventing the
acid-catalyzed scrambling processes.3 We discovered
reaction conditions that eliminated scrambling for con-
densations involving sterically hindered dipyrromethanes,
such as 5-mesityldipyrromethane, allowing preparation
of the pure trans-porphyrins in good yield with minimal
chromatography. Examination of a wide range of reaction
conditions for condensations involving sterically unhin-
dered dipyrromethanes, such as 5-phenyldipyrromethane,
showed that scrambling was very difficult to suppress
for these cases. We identified reaction conditions that
dramatically reduced the amount of scrambling, but the
persistence of low levels of scrambling as well as the poor
yields (<10% in all cases) sharply limited the quality and
quantity of material available.
(1) Lindsey, J . S. In Metalloporphyrin-Catalyzed Oxidations; Mon-
tanari, F., Casella, L. Eds.; Kluwer Academic Publishers: The Neth-
erlands, 1994; pp 49-86.
(4) Wallace, D. M.; Leung, S. H.; Senge, M. O.; Smith, K. M. J . Org.
Chem. 1993, 58, 7245-7257.
(5) 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.
(6) 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.
(2) Lindsey, J . S. In The Porphyrin Handbook; Kadish, K. M., Smith,
K., Guilard, R., Eds.; Academic Press: San Diego, CA 1999; Vol. 1, pp
45-118.
(3) Littler, B. J .; Ciringh, Y.; Lindsey, J . S. J . Org. Chem. 1999, 64,
2864-2872.
(7) Lee, C.-H.; Li, F.; Iwamoto, K.; Dadok, J .; Bothner-By, A. A.;
Lindsey, J . S. Tetrahedron 1995, 51, 11645-11672.
10.1021/jo9915473 CCC: $19.00 © 2000 American Chemical Society
Published on Web 01/28/2000

Synthesis of Monoacyl Dipyrromethanes
J . Org. Chem., Vol. 65, No. 4, 2000 1085
Sch em e 1
m eth a n es. Dipyrromethanes 1a -f were prepared by
condensation of the aldehyde in neat excess pyrrole (eq
1).5 Dipyrromethanes 1a -d were purified by bulb-to-bulb
distillation in order to remove the higher oligomers.
Dipyrromethane 1e was highly crystalline and was
purified by precipitation from the crude reaction mixture
without distillation. Distillation or direct crystallization
of dipyrromethane 1f was not possible. Therefore, puri-
fication was achieved by column chromatography to
remove most of the higher weight oligomers, followed by
precipitation of the dipyrromethane. Finally, all of the
dipyrromethanes (1a -f) were recrystallized affording
multigram batches of pure dipyrromethane.
P r ep a r a tion of P yr id yl Th ioester s. The majority of
our target thioesters (2a -f) were readily prepared in high
yields by condensing commercially available acid chlo-
rides with 2-mercaptopyridine (eq 2). In three cases, the
monoacylation of dipyrromethanes by employing 2-
pyridyl thioesters8 instead of acid chlorides, as such
thioesters have been reported to be superior for the
acylation of pyrrolemagnesium bromide.9 This approach
has provided an efficient, selective procedure for monoa-
cylation of dipyrromethanes, affording the direct precur-
sor to the desired dipyrromethanecarbinols on the gram
scale.
In this paper, we describe the monoacylation procedure
and demonstrate its wide scope by the preparation of
diverse monoacyl dipyrromethanes. Reduction using
NaBH4 in methanol/THF provides the corresponding
dipyrromethanecarbinols on a multigram scale. Studies
of the dipyrromethanecarbinol self-condensation have
shown that porphyrin formation is extremely rapid and
proceeds with no detectable scrambling. The scope of the
synthesis has been investigated by examining the effects
on yield of electron-withdrawing or releasing substituents
and by preparing a set of porphyrin building blocks for
use in the synthesis of multiporphyrin arrays. A key
objective has been to minimize chromatography in all
aspects of this synthetic route to trans-porphyrins.
requisite acid chlorides were not commercially available.
Thus, the TMS-protected ethynylthioester 2g was pre-
pared from 2f and trimethylsilylacetylene via a Pd-
mediated coupling reaction (eq 3).10 The reaction of
2,2′-dipyridyl disulfide with 4-ethynylbenzoic acid or
Resu lts a n d Discu ssion
1. Mon oa cyla tion of Dip yr r om eth a n es a n d Re-
d u ction to th e Ca r bin ol. P r ep a r a tion of Dip yr r o-
(8) Araki, M.; Sakata, S.; Takei, H.; Mukaiyama, T. Bull. Chem. Soc.
J pn. 1974, 47, 1777-1780.
(9) Nicolaou, K. C.; Claremon, D. A.; Papahatjis, D. P. Tetrahedron
Lett. 1981, 22, 4647-4650.
(10) Li, J .; Ambroise, A.; Yang, S. I.; Diers, J . R.; Seth, J .; Wack, C.
R.; Bocian, D. F.; Holten, D.; Lindsey, J . S. J . Am. Chem. Soc. 1999,
121, 8927-8940.

1086 J . Org. Chem., Vol. 65, No. 4, 2000
Rao et al.
Ta ble 1. Op tim iza tion of th e Mon oa cyla tion Rea ction
thioester
dipyrromethane EtMgBra
(2a )a
yieldb
(%)
entry
(1a )
(equiv)
(equiv)
solvent
1
2
3
4
5
0.10 M, 1.0 equiv
0.30 M, 1.0 equiv
0.05 M, 1.0 equiv
1.00 M, 1.0 equiv
1.00 M, 1.0 equiv
2.0
2.0
2.0
2.0
2.5
2.5
1.0
1.0
1.0
1.0
toluene
toluene
THF
THF
THF
c
71
69
73
82
a
Molar equivalents. b Isolated yield of monoacyl dipyrromethane
3a . c Yield not determined due to the difficulty of separating 3a
from unreacted 2a .
Use of a stoichiometric amount of 2a in toluene gave
monoacyl dipyrromethane 3a in good yield with complete
consumption of the thioester (entry 2). Purification of 3a
from the product mixture by column chromatography was
straightforward because the other compounds present
[unreacted 1a and 1-(p-tolyl)propan-1-one] eluted much
more readily than the desired product. Therefore, an
important feature of an effective monoacylation proce-
dure must be the complete consumption of the pyridyl
thioester.
4-acetamidobenzoic acid afforded the unprotected ethynyl-
thioester 2h or acetamidothioester 2i, respectively (eq 4).9
Many pyridyl thioesters have poor solubility in toluene,
so we examined the use of THF as an alternate reaction
solvent. THF provided effective reaction of pyridyl
thioesters and Grignard reagents leading to ketones.8 The
reaction was performed at modest concentration (entry
3) or at 1 M (entry 4). Though the yield of monoacylation
was good in both cases, the solvent change resulted in
incomplete consumption of thioester 2a even after 2 h at
room temperature. Subsequent addition of a further
aliquot of EtMgBr (2.0 molar equiv) removed 2a without
attacking the ketone in the monoacyl compound. The
requirement to add a second aliquot of EtMgBr was easily
avoided by initially adding a slightly larger excess of
EtMgBr (2.5 molar equiv) to the dipyrromethane at high
concentration in THF (entry 5). These optimized reaction
conditions afforded monoacyl dipyrromethane 3a in
excellent yield and purity after straightforward column
chromatography.
Develop m en t of a Selective Mon oa cyla tion P r o-
ced u r e. The model system shown in eq 5 was used to
examine acylation conditions using the pyridyl thioester.
The results of this study, which involve variation in ratios
and overall concentrations, are presented in Table 1.
Scop e of th e Mon oa cyla tion P r oced u r e. The mono-
acylation procedure (entry 5) was applied to a wide
variety of substrates (eq 6). In each case, no diacylation
was observed, and the monoacyl product was readily
isolated in good yield after straightforward column chro-
matography. Although the batches of monoacyldipyrro-
methane produced by this method were faintly colored,
all were analytically pure (1H NMR, TLC, elemental
analysis). The reaction has wide scope, tolerating a
variety of functional groups in the 1- and 5-positions,
including the protected carboxylic acid present in dipyrro-
methane 1f. The only failure occurred when 5-phenyl-
dipyrromethane (1a ) was treated with the acetamido-
substituted pyridyl thioester 2i. Presumably, the Grig-
nard reagent is incompatible with the acidic NH group.
Redu ction Affor din g th e Dipyr r om eth an ecar bin ol.
We recently discovered that diacyldipyrromethanes are
readily reduced to dipyrromethanediols by a large excess
of NaBH4 in a mixture of THF and methanol.6 Applica-
tion of these reaction conditions to the reduction of
monoacyl dipyrromethane 3a gave carbinol 3a -OH.
Carbinol 3a -OH decomposed when stored, so further
characterization was not attempted and the carbinol was
used directly in the self-condensation. This same ap-
proach was applied successfully with the other monoacyl
dipyrromethanes (3h -o).
Treatment of 5-phenyldipyrromethane (1a ) at 0.1 M with
EtMgBr (2.0 molar equiv) followed by pyridyl thioester
2a (2.5 molar equiv) gave a product mixture composed
principally of monoacyl dipyrromethane 3a and unre-
acted pyridyl thioester 2a (entry 1). Most importantly,
1
no other acylated products were detected by TLC or H
NMR spectroscopy. However, the yield could not be
determined because separation of monoacyl dipyrro-
methane 3a from pyridyl thioester 2a was extremely
difficult by column chromatography or crystallization.

Synthesis of Monoacyl Dipyrromethanes
J . Org. Chem., Vol. 65, No. 4, 2000 1087
Sch em e 2
difference so that any scrambling will be readily detected
by LD-MS.3 The selection of phenyl and p-tolyl substit-
uents also allowed direct comparison with data obtained
in our previous study of the dipyrromethane-aldehyde
condensation where the same substituents were em-
ployed.3
Self-condensation of carbinol 3a -OH was performed
using reaction conditions (5 mM carbinol in acetonitrile
containing 30 mM TFA at room temperature) that were
developed during a study of the condensation of a
dipyrromethanediol and a dipyrromethane.11 The reac-
tion was monitored by treatment of reaction aliquots with
DDQ followed by absorption spectroscopic determination
of the yield of porphyrin.12 Spectroscopic monitoring in
this manner revealed the self-condensation to be com-
plete within 1 min with a 26% yield of porphyrin. LD-
MS analysis of the crude reaction mixture showed a
single porphyrin peak with no detectable scrambled
porphyrin byproducts.13 Therefore, this self-condensation
reaction was superior to the dipyrromethane-aldehyde
condensation performed under low-scrambling conditions
(e.g., catalysis with BF3-etherate and NH4Cl in aceto-
nitrile at 0 °C)3 for the following reasons: (1) Scrambling
was reduced from a trace level to a level below the LD-
MS detection limit (Figure 1). (2) The spectroscopic
2. Self-Con d en sa tion of Ca r bin ols. Mod el Stu d y.
The self-condensation of carbinol 3a -OH leading to 5,15-
di-p-tolyl-10,20-diphenylporphyrin (4a ) was employed as
a model for exploring appropriate reaction conditions
(Scheme 2). This combination of substituents minimized
steric and electronic differences while providing a mass
(11) Rao, P. D.; Dhanalekshmi, S.; Littler, B. J .; Lindsey, J . S.
Manuscript in preparation.
(12) Lindsey, J . S.; Schreiman, I. C.; Hsu, H. C.; Kearney, P. C.;
Marguerettaz, A. M. J . Org. Chem. 1987, 52, 827-836.

1088 J . Org. Chem., Vol. 65, No. 4, 2000
Rao et al.
F igu r e 1. Comparison of the crude porphyrin product distri-
bution formed in the preparation of porphyrin 4a (m/z ) 642).
(a) Condensation of 5-phenyldipyrromethane and p-tolualde-
hyde under standard porphyrin-forming conditions (10 mM
dipyrromethane and 10 mM aldehyde in CH2Cl2 at room
temperature catalyzed by 17.8 mM TFA); extensive scram-
bling. (b) Condensation of 5-phenyldipyrromethane and p-
tolualdehyde under low-scrambling conditions;3 trace scram-
bling. (c) Self-condensation of carbinol 3a -OH; no detectable
scrambling.
porphyrin yield increased from 9% to 26%. (3) The
reaction time decreased from ∼4 h to a few min.
Effect of th e Electr on ic Na tu r e of th e Su bstitu -
en ts. To examine the effect of electron-releasing and
electron-withdrawing substituents on the yield and ex-
tent of scrambling in the self-condensation reaction,
monoacyldipyrromethanes 3h -k were each reduced then
immediately self-condensed as described above (eq 7).
Despite p-anisyl and pentafluorophenyl being extreme
examples of electron-releasing and electron-withdrawing
groups, respectively, spectroscopic monitoring showed
rapid reaction for all cases, and LD-MS analysis of each
crude reaction mixture showed a single porphyrin peak,
i.e., no scrambling. The byproducts in these reactions
were easily removed by filtration first through a pad of
alumina then through a pad of silica. This straightfor-
ward purification procedure afforded pure samples of
porphyrins 4b-d in 16-28% yield.
releasing groups in the 5-position and electron-withdraw-
ing groups at the carbinol position. This effect is consistent
with the nucleophilic character of the 9-position (R-
pyrrole) and the electrophilic character of the carbinol
position, which give rise to self-condensation. The effect
is clearly illustrated in the self-condensation reactions
of 3h -OH and 3k -OH. The p-anisyl and pentafluoro-
phenyl substituents of 3h -OH are positioned to enhance
the reactivity at both sites engaged in the self-condensa-
tion, whereas the same substituents are reversed in 3k -
OH. Both dipyrromethanecarbinols afford the same
porphyrin (4b), but 3h -OH gave a yield of 28% compared
to 16% for 3k -OH. The impact on yield of substituent
placement in the dipyrromethanecarbinol is modest with
the presence of one electronically neutral substituent
(phenylcarbinol, 3i, 26% yield of 4c) or misplaced sub-
stituent (pentafluorophenyl at the 5-position, 3j, 22%
yield of 4d ). These results suggest that attention paid to
placement of substituents in the dipyrromethanecarbinols
is important for achieving optimal yields of trans-por-
phyrins, but at least within the scope defined by the
extreme cases examined, the level of any scrambling is
insignificant regardless of choice of substituent place-
ment.
The data obtained for the four combinations of sub-
stituents (3h -k ) reveal higher yields with electron-
(13) The limit of detection of scrambled porphyrins by LD-MS is
approximately 1 part in 100 (see the Experimental Section). Thus, for
a trans-porphyrin yield of 25%, any putative single scrambled por-
phyrin (except the cis-porphyrin) would be present in no greater than
0.25% yield. Note that the MS method cannot exclude scrambling
leading exclusively to the cis-porphyrin. However, rearrangement
processes leading to such an isomer would be expected to form a
distribution of porphyrin products, including those of other masses.
See ref 3.

Synthesis of Monoacyl Dipyrromethanes
J . Org. Chem., Vol. 65, No. 4, 2000 1089
Gr a m -Sca le P r ep a r a tion of P or p h yr in s. To estab-
lish the preparative value of the self-condensation meth-
odology, we performed the self-condensation on a 20.0
mmol scale using carbinol 3a -OH derived from monoacyl
dipyrromethane 3a . At this larger scale scrambling was
still absent, and filtration of the crude product mixture
first through a pad of alumina then through a pad of
silica afforded 1.28 g (20% yield) of pure porphyrin 4a .
The utility of this method has been further explored
by the preparation of four trans-porphyrins (4e-h , eq 7)
that are useful building blocks in the construction of
multiporphyrin arrays.14-16 In each case, no scrambling
was observed, and 0.2-1.2 g batches of the pure por-
phyrins were readily isolated in 20-25% yield after
minimal chromatography. One slight limitation in scope
was observed with the TMS-ethyne-substituted monoacyl
dipyrromethane 3n . 1H NMR and LD-MS analysis of the
corresponding porphyrin showed loss of some of the TMS
protecting groups (presumably during the reduction to
give the dipyrromethanecarbinol) and that the initial
porphyrin product consisted of a mixture of fully depro-
tected, partially deprotected, and fully protected por-
phyrins. Treatment of this mixture with Bu4NF in THF
removed the remaining TMS groups, affording the pure
fully deprotected porphyrin 4g.
A good illustration of the versatility of this methodology
is afforded by the synthesis of porphyrin 4h . This
porphyrin bears two free ethynes and two TMS-protected
esters; the desire to perform selective chemistry at the
ethynes required these groups to be prepared without the
typical use of TMS protection. The reaction of dipyrro-
methane 1f under our standard conditions with the
4-ethynylbenzothioate 2h did not afford the desired
monoacyl dipyrromethane 3o. However, the reaction
using only 2 mol of ethylmagnesium bromide per mol of
dipyrromethane afforded the desired monoacyl dipyrro-
methane 3o in 66% yield. The monoacyldipyrromethane
underwent reduction and self-condensation in the stand-
ard way to afford the diethynyl diester porphyrin 4h in
20% yield.
enables the preparation of sterically unhindered trans-
porphyrins with no detectable scrambling. The methodol-
ogy entails a concise series of reactions (dipyrromethane
preparation, monoacylation, reduction to the carbinol,
and self-condensation of the dipyrromethanecarbinol)
that can be implemented to give gram quantities of the
desired porphyrin. This approach now completes a set of
synthetic methods that should allow the preparation of
a wide variety of meso-substituted trans-porphyrins via
straightforward synthetic methods that require minimal
chromatography.
Exp er im en ta l Section
Gen er a l Meth od s. 1H (300 MHz, CDCl3) and absorption
spectra were collected routinely. Elemental analyses were
performed by Atlantic MicroLab, Inc. Melting points are
uncorrected. Bulb-to-bulb distillation was performed using a
standard-size Kugelrohr short-path distillation apparatus
(Aldrich). Dipyrromethanes 1a -d were prepared as described
previously.5 Column chromatography was performed on silica
(Baker, 40 µm average particle size) and alumina (Fisher, 80-
200 mesh). The dipyrromethanes were examined by GC
analysis as described previously.5
For monoacylation and Pd-coupling reactions, THF was
distilled from Na/benzophenone. All other chemicals are
reagent grade and were used as obtained. Unless otherwise
indicated, all reagents were obtained from Aldrich Chemical
Co., and all solvents were obtained from Fisher Scientific. The
dipyrromethanes, monoacyldipyrromethanes, and their cor-
responding carbinols were easily visualized upon exposure of
TLC plates to Br2 vapor.
Porphyrins (from crude reaction mixtures, or following
purification) were analyzed by laser desorption ionization mass
spectrometry (LD-MS) without a matrix17 using a Bruker
Proflex II spectrometer. The progress of the porphyrin forming
reactions was monitored spectroscopically, and the extent of
scrambling in the crude reaction mixture determined as
described previously.3
Deter m in a tion of Lim it of Detection of Scr a m bled
P or p h yr in s by LD-MS An a lysis. Various ratios (300:1, 100:
1, 30:1, 10:1, 3:1, 1:1, 1:3, 1:10, 1:30, 1:100, 1:300) of tetra-
phenylporphyrin (TPP) and tetra-p-tolylporphyrin (TTP) were
prepared by mixing appropriate quantities of each porphyrin.
Porphyrin solutions of 1 or 0.01 mM in CH2Cl2 were used. The
TPP/TTP mixtures were analyzed by LD-MS as described
above (see the Supporting Information).
Con clu sion
Methods for the synthesis of trans-porphyrins have
evolved from the use of statistical condensations of
pyrrole and two aldehydes affording a mixture of six
porphyrins, to the more recent condensations of one
dipyrromethane and one aldehyde. The latter route has
been plagued by acid-catalyzed scrambling affording a
mixture of porphyrins, from which small quantities of
porphyrins are typically obtained by elaborate chroma-
tography. Recently identified nonscrambling condensa-
tion conditions suitable for dipyrromethanes bearing a
sterically hindered aryl group (e.g., mesityl) afford gram
quantities of trans-porphyrins with minimal chromatog-
raphy, but dipyrromethanes bearing an unhindered aryl
group give low yields (<10%) and some scrambling under
these conditions. The methodology described herein
5-(4-ter t-Bu tylp h en yl)d ip yr r om eth a n e (1e). A sample
of TFA (1.61 mL, 20.8 mmol) was added to a stirred solution
of 4-tert-butylbenzaldehyde (33.8 g, 208 mmol) in pyrrole (362
mL, 5.21 mol) under Ar. The solution was stirred for 5 min,
and then 0.1 M NaOH was added. The mixture was then
poured into brine and ethyl acetate. The organic phase was
isolated, washed with water, and then dried (Na2SO4) and the
solvent removed to afford a brown solid. Trituration of the solid
with hexanes followed by filtration afforded a colorless powder.
Recrystallization [ethanol/water (20:1)] afforded colorless crys-
tals (22.0 g, 38%): mp 160 °C; 1H NMR δ 1.30 (s, 9 H), 5.45 (s,
1 H), 5.94 (m, 2 H), 6.15 (q, J ) 2.9 Hz, 2 H), 6.68 (m, 2 H),
7.14 (m, 2 H), 7.33 (m, 2 H), 7.90 (br s, 2 H). Anal. Calcd for
C
19H22N2: C, 81.97; H, 7.97; N, 10.06. Found: C, 81.80; H,
7.99; N, 10.04.
5-[4-[2-(Tr im e t h ylsilyl)e t h oxyca r b on yl]p h e n yl]d i-
p yr r om eth a n e (1f). A sample of TFA (154 µL, 2.00 mmol)
was added to a stirred solution of 4-[2-(trimethylsilyl)ethoxy-
carbonyl]benzaldehyde14 (5.0 g, 20 mmol) in pyrrole (35 mL,
0.50 mol) under Ar. The solution was stirred for 5 min, and
then 0.1 M NaOH, ethyl acetate, and brine were added. The
(14) Lindsey, J . S.; Prathapan, S.; J ohnson, T. E.; Wagner, R. W.
Tetrahedron 1994, 50, 8941-8968.
(15) Ravikanth, M.; Strachan, J .-P.; Li, F.; Lindsey, J . S. Tetrahe-
dron 1998, 54, 7721-7734.
(16) Wagner, R. W.; J ohnson, T. E.; Lindsey, J . S. J . Am. Chem.
Soc. 1996, 118, 11166-11180. Lindsey, J . S. In Modular Chemistry;
Michl, J ., Ed.; NATO ASI Series C: Mathematical and Physical
Sciences, Vol. 499; Kluwer Academic Publishers: Dordrecht, 1997; pp
517-528.
(17) (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.

1090 J . Org. Chem., Vol. 65, No. 4, 2000
Rao et al.
organic phase was washed with water and then dried (Na2SO4)
and the solvent removed. The residue was dissolved in CH2Cl2
and filtered through a pad of silica gel (CH2Cl2) to remove
higher weight oligomers. Recrystallization (CH2Cl2/hexanes)
of the resulting tan solid afforded colorless crystals (4.11 g,
flask was sealed tightly and then heated for 24 h at 60 °C.
After being cooled to room temperature, the solution was
gravity filtered, and the solid residue was washed with CH2Cl2.
The filtrate was washed with water and dried (Na2SO4) and
the solvent removed. Purification by flash column chromatog-
raphy [silica; hexanes/ethyl acetate (4:1)] afforded pale yellow
crystals. Recrystallization (ethyl acetate) afforded colorless
1
56%): mp 108 °C; H NMR δ 0.06 (s, 9 H), 1.12 (dd, J ) 9.0,
7.8 Hz, 2 H), 4.40 (m, 2 H), 5.53 (s, 1 H), 5.89 (m, 2 H), 6.16
(m, 2 H), 6.72 (m, 2 H), 7.28 (d, J ) 8.1 Hz, 2 H), 7.98 (d, J )
8.1 Hz, 2 H), 7.98 (br s, 2 H). Anal. Calcd for C21H26N2O2Si:
C, 68.81; H, 7.15; N, 7.64. Found: C, 68.70; H, 7.20; N, 7.68.
Gen er a l P r oced u r e for th e P r ep a r a tion of a n S-
P yr id yl Th ioester fr om 2-Mer ca p top yr id in e a n d a n Acid
Ch lor id e. S-2-P yr id yl 4-m eth ylben zoth ioa te (2a ). A solu-
tion of p-toluoyl chloride (6.61 mL, 50.0 mmol) in CH2Cl2 (100
mL) was added over 10 min to a stirred solution of 2-mercap-
topyridine (5.56 g, 50.0 mmol) in CH2Cl2 (250 mL). After a
further 60 min, 2 N NaOH was added. The organic phase was
isolated, washed with water, and then dried (Na2SO4) and the
solvent removed to afford a yellow oil. The oil was dissolved
in a minimum volume of ethyl acetate and precipitated with
hexanes. Filtration afforded colorless crystals (8.34 g, 73%):
mp 62 °C; 1H NMR δ 2.44 (s, 3 H), 7.26-7.35 (m, 3 H), 7.73-
7.79 (m, 2 H), 7.91 (d, J ) 8.1 Hz, 2 H), 8.67 (m, 1 H). Anal.
Calcd for C13H11NOS: C, 68.10; H, 4.84; N, 6.11. Found: C,
68.16; H, 4.83; N, 6.16.
1
crystals (3.53 g, 57%): mp 105 °C; H NMR δ 0.25 (s, 9 H),
7.34 (m, 1 H), 7.56 (d, J ) 8.1 Hz, 2 H), 7.70-7.82 (m, 2 H),
7.95 (d, J ) 8.1 Hz, 2 H), 8.68 (m, 1 H). Anal. Calcd for C17H17
-
NOSSi: C, 65.55; H, 5.50; N, 4.50. Found: C, 65.48; H, 5.44;
N, 4.50.
S-2-P yr id yl 4-Eth yn ylben zoth ioa te (2h ). A solution of
4-ethynylbenzoic acid20 (1.11 g, 7.50 mmol), 2,2′-dipyridyl
disulfide (3.30 g, 15.0 mmol), and triphenylphosphine (3.93 g,
15.0 mmol) in anhydrous THF (20 mL) was stirred for 24 h at
room temperature under Ar. Removal of the solvent followed
by purification by column chromatography [silica; ethyl acetate/
hexanes (1:3)] afforded colorless crystals (1.2 g, 67%): mp 102
°C; 1H NMR δ 3.28 (s, 1H), 7.35 (m, 1H), 7.59 (m, 2 H), 7.71-
7.83 (m, 2 H), 7.97 (m, 2 H), 7.69 (m, 1 H). Anal. Calcd for
C14H9NOS: C, 70.27; H, 3.79; N, 5.85. Found: C, 69.82; H,
3.87; N, 5.82.
S-2-P yr id yl 4-Aceta m id oben zoth ioa te (2i). A suspension
of 4-acetamidobenzoic acid (3.58 g, 20.0 mmol), 2,2′-dipyridyl
disulfide (6.60 g, 30.0 mmol), and triphenylphosphine (7.87 g,
30.0 mmol) in anhydrous THF (100 mL) was stirred for 24 h
at room temperature under Ar. Removal of the solvent followed
by purification by column chromatography [silica; CH2Cl2/
methanol (20:1)] afforded colorless needles (3.78 g, 65%): mp
155 °C; 1H NMR δ 2.21 (s, 3 H), 7.34 (m, 1 H), 7.63 (d, J ) 8.1
Hz, 2 H), 7.63 (br s, 1 H), 7.70-7.82 (m, 2 H), 7.97 (d, J ) 8.1
Hz, 2 H), 8.67 (m, 1 H). Anal. Calcd for C14H12N2O2S: C, 61.75;
H, 4.44; N, 10.29. Found: C, 61.77; H, 4.40; N, 10.22.
S-2-P yr id yl 4-ben zoth ioa te (2b). Condensation of benzoyl
chloride (5.60 g, 40.0 mmol) and 2-mercaptopyridine (4.44 g,
40.0 mmol) as described for 2a afforded colorless crystals (6.45
g, 75%). Spectral data of 2b were identical to those reported.8,18
S-2-P yr id yl P en ta flu or oben zoth ioa te (2c). Condensa-
tion of pentafluorobenzoyl chloride (1.3 mL, 9.0 mmol) and
2-mercaptopyridine (1.0 g, 9.0 mmol) as described for 2a gave
a pale yellow solid that turned brown when stored above 0
°C. Recrystallization from hexanes gave brown crystals (2.07
1
g, 75%): mp 48-51 °C; H NMR δ 7.36-7.40 (m, 1 H), 7.74-
Gen er a l P r oced u r e for th e Mon oa cyla tion of Dip yr -
r om eth a n es. 1-(p-Tolu oyl)-5-p h en yld ip yr r om eth a n e (3a ).
A solution of EtMgBr (25 mL, 25 mmol, 1.0 M in THF) was
carefully added via syringe to a stirred solution of 5-phenyl-
dipyrromethane (1a ) (2.22 g, 10.0 mmol) in THF (10 mL) under
Ar. The mixture was stirred at room temperature for 10 min
and then cooled to -78 °C. A solution of (p-toluoyl)pyridyl
thioester (2a ) (2.29 g, 10.0 mmol) in THF (10 mL) was then
added over 1 min. The solution was maintained at -78 °C for
10 min, and then the cooling bath was removed. TLC [silica;
CH2Cl2/ethyl acetate (25:1)] showed complete consumption of
the pyridyl thioester after 15 min, so the reaction was
quenched with saturated aqueous NH4Cl. The mixture was
allowed to warm to room temperature, poured into CH2Cl2,
washed with water, and then dried (Na2SO4) and the solvent
removed to afford a dark foam. Purification by flash column
chromatography [silica; neat CH2Cl2 to CH2Cl2/ethyl acetate
(100:3)] afforded a golden amorphous solid (2.79 g, 82%).
Analytical data were identical to those previously reported.6
1-(4-Iod oben zoyl)-5-p h en yld ip yr r om eth a n e (3b). A so-
lution of 1a (1.11 g, 5.00 mmol) in THF (80 mL) was treated
with EtMgBr (10 mL, 10 mmol, 1.0 M in THF) and a solution
of 2f (1.70 g, 5.00 mmol) in THF (10 mL) as described for 3a .
The reaction was quenched for 1 h after removal of the cooling
bath. Purification by flash column chromatography [silica;
ethyl acetate/:hexanes (1:4)] followed by precipitation from
ether/hexanes afforded a tan solid (1.70 g, 74%): mp 138 °C;
1H NMR δ 5.54 (s, 1 H), 5.98 (m, 1 H), 6.09 (m, 1 H), 6.15 (m,
1 H), 6.67 (m, 1 H), 6.76 (m, 1 H), 7.18-7.33 (m, 5 H), 7.51 (d,
J ) 9.0 Hz, 2 H), 7.80 (d, J ) 9.0 Hz, 2 H), 8.14 (br s, 1 H),
9.76 (br s, 1 H). Anal. Calcd for C22H17IN2O: C, 58.42; H, 3.79;
N, 6.19. Found: C, 58.56; H, 3.77; N, 6.14.
7.85 (m, 2 H), 8.67-8.69 (m, 1 H). Anal. Calcd for C12H4F5-
NOS: C, 47.22; H, 1.32; N, 4.59. Found: C, 47.22; H, 1.34; N,
4.51.
S-2-P yr id yl 4-Meth oxyben zoth ioa te (2d ). Condensation
of 4-methoxybenzoyl chloride (6.82 g, 40.0 mmol) and 2-mer-
captopyridine (4.44 g, 40.0 mmol) as described for 2a , except
that recrystallization was from ether/hexanes, afforded color-
less crystals (7.06 g, 72%): mp 73 °C; 1H NMR δ 3.87 (s, 3 H),
6.97 (m, 2 H), 7.33 (m, 1 H), 7.76 (m, 2 H), 8.00 (m, 2 H), 8.67
(d, J ) 2.7 Hz, 1 H). Anal. Calcd for C13H11NO2S: C, 63.65; H,
4.52; N, 5.71. Found: C, 63.81; H, 4.42; N, 5.66.
S-2-P yr id yl 3-Iod oben zoth ioa te (2e). Condensation of
3-iodobenzoyl chloride19 (10.6 g, 40.0 mmol) and 2-mercapto-
pyridine (4.44 g, 40.0 mmol) as described for 2a , except that
recrystallization was from ether/hexanes, afforded colorless
needles (11.6 g, 85%): mp 55 °C; 1H NMR δ 7.24 (m, 1 H),
7.33-7.38 (m, 1 H), 7.69-7.72 (m, 1 H), 7.77-7.83 (m, 1 H),
7.93-8.00 (m, 2 H), 8.32 (m, 1 H), 8.68 (m, 1 H). Anal. Calcd
for C13H11NO2S: C, 42.25; H, 2.36; N, 4.11. Found: C, 42.24;
H, 2.36; N, 4.17.
S-2-P yr id yl 4-Iod oben zoth ioa te (2f). Condensation of
4-iodobenzoyl chloride (2.66 g, 10.0 mmol) and 2-mercapto-
pyridine (1.11 g, 10.0 mmol) as described for 2a , except that
recrystallization was from ether/hexanes, afforded colorless
needles (3.10 g, 91%): mp 128 °C; 1H NMR δ 7.33-7.37 (m, 1
H), 7.70-7.88 (m, 6 H), 8.68 (m, 1 H). Anal. Calcd for C13H11
-
NO2S: C, 42.25; H, 2.36; N, 4.11. Found: C, 42.23; H, 2.35;
N, 4.12.
S-2-P yr id yl 4-[2-(Tr im eth ylsilyl)eth yn yl]ben zoth ioa te
(2g). A mixture of 2f (6.82 g, 20.0 mmol), Pd(PPh3)2Cl2 (0.42
g, 0.60 mmol, 3 mol %), and CuI (380 mg, 2.00 mmol, 10 mol
%) was placed in a Schlenk flask. The flask was pump-filled
with Ar three times, and then a degassed mixture of THF (60
mL) and N,N-diisopropylethylamine (20 mL) was added fol-
lowed by trimethylsilylacetylene (4.24 mL, 30.0 mmol). The
1-(4-Iod ob en zoyl)-5-(4-m et h oxyp h en yl)d ip yr r om et h -
a n e (3c). A solution of 1b (1.26 g, 5.00 mmol) in THF (80 mL)
was treated with EtMgBr (10 mL, 10 mmol, 1.0 M in THF)
and a solution of 2f (1.70 g, 5.00 mmol) in THF (10 mL) as
described for 3a . The reaction was quenched for 1 h after
(18) Beckwith, A. L. J .; Duggan, S. A. M. J . Chem. Soc., Perkin
Trans. 2 1994, 1509-1518
(19) Norris, J . F.; Young, H. H., J r. J . Am. Chem. Soc. 1935, 57,
1420-1424.
(20) Yashima, E.; Matsushima, T.; Okamoto, Y. J . Am. Chem. Soc.
1997, 119, 6345-6359.

Synthesis of Monoacyl Dipyrromethanes
J . Org. Chem., Vol. 65, No. 4, 2000 1091
removal of the cooling bath. Purification by flash column
chromatography [silica; ethyl acetate/hexanes (1:4)] afforded
a pale brown foamlike solid (1.82 g, 75%): mp 68 °C; 1H NMR
δ 3.79 (s, 3 H), 5.48 (s, 1 H), 5.97 (m, 1 H), 6.08 (m, 1 H), 6.17
(m, 1 H), 6.70 (m, 1 H), 6.76 (m, 1 H), 6.85 (m, 2 H), 7.12 (m,
2 H), 7.55 (m, 2 H), 7.81 (m, 2 H), 8.04 (br s, 1 H), 9.50 (br s,
1 H). Anal. Calcd for C22H17IN2O: C, 57.28; H, 3.97; N, 5.81.
Found: C, 57.16; H, 3.96; N, 5.75.
1-(4-Iod oben zoyl)-5-(p en ta flu or op h en yl)d ip yr r om eth -
a n e (3d ). A solution of 1c (0.94 g, 3.0 mmol) in THF (50 mL)
was treated with EtMgBr (6.0 mL, 6.0 mmol, 1.0 M in THF)
and a solution of 2f (1.02 g, 3.00 mmol) in THF (6 mL) as
described for 3a . The reaction was quenched for 1 h after
removal of the cooling bath. Purification by flash column
chromatography [silica; ethyl acetate/hexanes (1:4)] afforded
a tan solid (1.14 g, 70%): mp 208 °C; 1H NMR δ 5.92 (s, 1 H),
6.18 (m, 1 H), 6.20-6.25 (m, 2 H), 6.76-6.80 (m, 2 H), 7.58
(m, 2 H), 7.84 (m, 2 H), 8.25 (br s, 1 H), 9.33 (br s, 1 H). Anal.
Calcd for C22H12F5IN2O: C, 48.73; H, 2.23; N, 5.17. Found:
C, 49.15; H, 2.45; N, 5.04.
1-(4-Iod oben zoyl)-5-m esityld ip yr r om eth a n e (3e). A so-
lution of 1d (0.79 g, 3.0 mmol) in THF (50 mL) was treated
with EtMgBr (6.0 mL, 6.0 mmol, 1.0 M in THF) and a solution
of 2f (1.02 g, 3.00 mmol) in THF (6 mL) as described for 3a .
The reaction was quenched for 1 h after removal of the cooling
bath. Purification by flash column chromatography [silica;
ethyl acetate/hexanes (1:4)] afforded an off-white solid (1.12
g, 71%): mp 163 °C; 1H NMR δ 2.08 (s, 6 H), 2.29 (s, 3 H),
5.94 (s, 1 H), 6.13 (m, 2 H), 6.69 (m, 1 H), 6.79 (m, 1 H), 6.89
(s, 2 H), 7.57 (m, 2 H), 7.83 (m, 3 H), 9.25 (br s, 1 H). Anal.
Calcd for C25H23IN2O: C, 60.74; H, 4.69; N, 5.67. Found: C,
60.43; H, 4.53; N, 5.42.
with EtMgBr (12.5 mL, 12.5 mmol, 1.0 M in THF) and a
solution of 2b (1.08 g, 5.00 mmol) in THF (5 mL) as described
for 3a . The reaction was quenched for 30 min after removal of
the cooling bath. Purification by flash column chromatography
[silica; ethyl acetate/hexanes (1:3)] afforded a pink amorphous
1
solid (1.26 g, 76%): mp 147 °C dec; H NMR δ 3.75 (s, 3 H),
5.53 (s, 1 H), 5.99 (m, 1 H), 6.13 (m, 2 H), 6.63 (m, 1 H), 6.76
(d, J ) 8.1 Hz, 2 H), 6.81 (m, 1 H), 7.08 (d, J ) 8.1 Hz, 2 H),
7.43-7.55 (m, 3 H), 7.78 (m, 2 H), 8.57 (br s, 1 H), 10.43 (br s,
1 H). Anal. Calcd for C23H20N2O2: C, 77.51; H, 5.66; N, 7.86.
Found: C, 77.79; H, 5.65; N, 7.92.
1-Ben zoyl-5-(p en ta flu or op h en yl)d ip yr r om eth a n e (3j).
A solution of 1c (1.28 g, 4.00 mmol) in THF (4 mL) was treated
with EtMgBr (10 mL, 10 mmol, 1.0 M in THF) and a solution
of 2b (0.86 g, 4.0 mmol) in THF (4 mL) as described for 3a .
The reaction was quenched for 30 min after removal of the
cooling bath. Purification by flash column chromatography
[silica; ethyl acetate/hexanes (1:3)] followed by precipitation
from ether/hexanes afforded a brown amorphous solid (1.26
g, 71%): mp 148 °C; 1H NMR δ 5.93 (s, 1 H), 6.06-6.07 (m, 2
H), 6.12 (m, 1 H), 6.67 (m, 1 H), 6.79 (m, 1 H), 7.43-7.58 (m,
3 H), 7.82 (d, J ) 6.3 Hz, 2 H), 8.51 (br s, 1 H), 10.31 (br s, 1
H). Anal. Calcd for C22H13F5N2O: C, 63.47; H, 3.15; N, 6.73.
Found: C, 63.62; H, 3.15; N, 6.68.
1-(4-Me t h oxyb e n zoyl)-5-(p e n t a flu or op h e n yl)d ip yr -
r om eth a n e (3k ). A solution of 1c (1.28 g, 4.00 mmol) in THF
(4 mL) was treated with EtMgBr (10 mL, 10 mmol, 1.0 M in
THF) and a solution of 2d (1.0 g, 4.0 mmol) in THF (4 mL) as
described for 3a . The reaction was quenched for 30 min after
removal of the cooling bath. Purification by flash column
chromatography [silica; ethyl acetate/hexanes (1:4)] afforded
1
a pink amorphous solid (1.30 g, 73%): mp 67 °C; H NMR δ
1-[4-[2-(Tr im eth ylsilyl)eth yn yl]ben zoyl]-5-ph en yldipyr -
r om eth a n e (3f). A solution of 1a (0.89 g, 4.0 mmol) in THF
(65 mL) was treated with EtMgBr (8.0 mL, 8.0 mmol, 1.0 M
in THF) and a solution of 2g (1.25 g, 4.00 mmol) in THF (8
mL) as described for 3a . The reaction was quenched for 1 h
after removal of the cooling bath. Purification by flash column
chromatography [silica; ethyl acetate/hexanes (1:4)] followed
by precipitation from ether/hexanes afforded a yellowish
foamlike solid (1.10 g, 65%): mp 168 °C; 1H NMR δ 0.26 (s, 9
H), 5.54 (s, 1 H), 5.98 (m, 1 H), 6.08 (m, 1 H), 6.15 (m, 1 H),
6.70 (m, 1 H), 6.77 (m, 1 H), 7.20-7.35 (m, 5 H), 7.53 (d, J )
8.1 Hz, 2 H), 7.76 (d, J ) 8.1 Hz, 2 H), 8.05 (br s, 1 H), 9.45
(br s, 1 H). Anal. Calcd for C27H26N2OSi: C, 76.74; H, 6.20; N,
6.63. Found: C, 76.73; H, 6.23; N, 6.65.
3.87 (s, 3 H), 5.92 (s, 1 H), 6.04-6.15 (m, 3 H), 6.70 (m, 1 H),
6.78 (m, 1 H), 6.97 (m, 2 H), 7.87 (m, 2 H), 8.48 (br s, 1 H),
10.23 (br s, 1 H). Anal. Calcd for C23H15F5N2O2: C, 61.89; H,
3.39; N, 6.28. Found: C, 61.60; H, 3.41; N, 6.26.
1-(3-I o d o b e n zo y l)-5-(4-t er t -b u t y lp h e n y l)d ip y r r o -
m eth a n e (3l). A solution of 1e (279 mg, 1.00 mmol) in THF
(1.0 mL) was treated with EtMgBr (2.5 mL, 2.5 mmol, 1.0 M
in THF) and a solution of 2e (341 mg, 1.00 mmol) in THF (1.0
mL) as described for 3a . The reaction was quenched for 20
min after removal of the cooling bath. Purification of the crude
reaction product by flash column chromatography [silica;
CH2Cl2/hexanes (2:1) to neat CH2Cl2] afforded a pale yellow
amorphous solid (360 mg, 71%): mp 79 °C dec; 1H NMR δ 1.30
(s, 9 H), 5.52 (s, 1 H), 6.01 (m, 1 H), 6.12 (m, 1 H), 6.17 (q, J
) 2.9 Hz, 1 H), 6.71 (m, 1 H), 6.78 (dd, J ) 3.7 and 2.2 Hz, 1
H), 7.13 (d, J ) 8.1 Hz, 2 H), 7.17-7.22 (m, 1 H), 7.33 (d, J )
8.1 Hz, 2 H), 7.76 (m, 1 H), 7.86 (m, 1 H), 8.08 (br s, 1 H), 8.14
(m, 1 H), 9.57 (br s, 1 H). Anal. Calcd for C26H25IN2O: C, 61.42;
H, 4.96; N, 5.51. Found: C, 61.35; H, 4.93; N, 5.43.
1-(3-Iod ob en zoyl)-5-[4-[2-(t r im et h ylsilyl)et h oxyca r -
bon yl]p h en yl]d ip yr r om eth a n e (3m ). A solution of 1f (3.66
g, 10.0 mmol) in THF (10 mL) was treated with EtMgBr (25
mL, 25 mmol, 1.0 M in THF) and a solution of 2e (3.41 g, 10.0
mmol) in THF (15 mL) as described for 3a . The reaction was
quenched for 30 min after removal of the cooling bath.
Purification by flash column chromatography [silica; ethyl
acetate/hexanes (1:3)] followed by precipitation from ether/
hexanes afforded a tan solid (4.05 g, 68%): mp 146-147 °C;
1H NMR δ 0.08 (s, 9 H), 1.12 (t, J ) 9.0 Hz, 2 H), 4.41 (m, 2
H), 5.59 (s, 1 H), 5.97 (m, 1 H), 6.06 (m, 1 H), 6.18 (m, 1 H),
6.74 (m, 1 H), 6.79 (m, 1 H), 7.18-7.30 (m, 3 H), 7.78 (d, J )
8.1 Hz, 1 H), 7.87 (d, J ) 8.1 Hz, 1 H), 8.00 (d, J ) 8.1 Hz, 2
H), 8.10 (br s, 1 H), 8.15 (s, 1 H), 9.51 (br m, 1 H). Anal. Calcd
for C28H29IN2O3Si: C, 56.38; H, 4.90; N, 4.70. Found: C, 56.33;
H, 4.86; N, 4.84.
1-[4-[2-(Tr im eth ylsilyl)eth yn yl]ben zoyl]-5-(4-m eth oxy-
p h en yl)d ip yr r om eth a n e (3g). A solution of 1b (1.0 g, 4.0
mmol) in THF (65 mL) was treated with EtMgBr (8.0 mL, 8.0
mmol, 1.0 M in THF) and a solution of 2g (1.25 g, 4.00 mmol)
in THF (8 mL) as described for 3a . The reaction was quenched
for 1 h after removal of the cooling bath. Purification by flash
column chromatography [silica; ethyl acetate/hexanes (1:4)]
1
afforded a yellow solid (1.31 g, 72%): mp 150 °C; H NMR δ
0.26 (s, 9 H), 3.79 (s, 3 H), 5.49 (s, 1 H), 5.97 (s, 1 H), 6.07 (m,
1 H), 6.17 (m, 1 H), 6.71 (m, 1 H), 6.77 (m, 1 H), 6.87 (m, 2 H),
7.13 (m, 2 H), 7.53 (d, J ) 8.1 Hz, 2 H), 7.77 (d, J ) 8.1 Hz, 2
H), 8.01 (br s, 1 H), 9.45 (br s, 1 H). Anal. Calcd for C28H28N2O2-
Si: C, 74.30; H, 6.24; N, 6.19. Found: C, 74.36; H, 6.28; N,
6.18.
1-(P e n t a flu or ob e n zoyl)-5-(4-m e t h oxyp h e n yl)d ip yr -
r om eth a n e (3h ). A solution of 1b (1.0 g, 4.0 mmol) in THF
(4 mL) was treated with EtMgBr (10 mL, 10 mmol, 1.0 M in
THF) and a solution of 2c (1.22 g, 4.00 mmol) in THF (4 mL)
as described for 3a . The reaction was quenched for 30 min after
removal of the cooling bath. Purification by flash column
chromatography [silica; ethyl acetate/hexanes (1:4)] afforded
an off-white amorphous solid (0.80 g, 65%): mp 50 °C; 1H NMR
δ 3.79 (s, 3 H), 5.49 (s, 1 H), 5.98 (m, 1 H), 6.10 (m, 1 H), 6.17
(m, 1 H), 6.64 (m, 1 H), 6.72 (m, 1 H), 6.86 (d, J ) 8.1 Hz, 2
H), 7.10 (d, J ) 8.1 Hz, 2 H), 8.04 (br s, 1 H), 9.64 (br s, 1 H).
Anal. Calcd for C23H15F5N2O2: C, 61.89; H, 3.39; N, 6.28.
Found: C, 62.17; H, 3.63; N, 6.17.
1-[4-[2-(Tr im et h ylsilyl)et h yn yl]b en zoyl]-5-(4-ter t-b u -
tylp h en yl)d ip yr r om eth a n e (3n ). A solution of 1e (2.79 g,
10.0 mmol) in THF (10 mL) was treated with EtMgBr (25.0
mL, 25.0 mmol, 1.0 M in THF) and a solution of 2g (3.11 g,
10.0 mmol) in THF (10 mL, 1.0 M) as described for 3a . The
reaction was quenched for 5 min after removal of the cooling
bath. Purification of the crude reaction product by flash column
chromatography [silica; CH2Cl2 (neat)] a pale yellow amor-
1-Ben zoyl-5-(4-m eth oxyp h en yl)d ip yr r om eth a n e (3i). A
solution of 1b (1.26 g, 5.00 mmol) in THF (5 mL) was treated

1092 J . Org. Chem., Vol. 65, No. 4, 2000
Rao et al.
phous solid (3.63 g, 76%): mp 99 °C dec; 1H NMR δ 0.27 (s, 9
H), 1.30 (s, 9 H), 5.52 (s, 1 H), 6.00 (m, 1 H), 6.12 (m, 1 H),
6.16 (m, 1 H), 6.68 (m, 1 H), 6.77 (m, 1 H), 7.12 (d, J ) 8.1 Hz,
2 H), 7.32 (d, J ) 8.1 Hz, 2 H), 7.53 (d, J ) 8.1 Hz, 2 H), 7.74
(d, J ) 8.1 Hz, 2 H), 8.16 (br s, 1 H), 9.73 (br m, 1 H). Anal.
Calcd for C31H34N2OSi: C, 77.78; H, 7.16; N, 5.85. Found: C,
77.83; H, 7.16; N, 5.92.
afford a purple solid (43 mg, 22%): 1H NMR δ -2.84 (br s, 2
H), 7.80 (m, 6 H), 8.21 (dd, J ) 7.2 and 1.5 Hz, 4 H), 8.80 (d,
J ) 4.5 Hz, 4 H), 8.95 (d, J ) 4.5 Hz, 4 H); C44H20F10N4 calcd
mass 794.2, obsd 794.5 (LD-MS); calcd exact mass 795.1607
(MH+), obsd 795.1627 (MH+) (FAB-MS).
5,15-Bis(4-ter t-b u t ylp h en yl)-10,20-b is(3-iod op h en yl)-
p or p h yr in (4e). Monoacyldipyrromethane 3l (5.08 g, 10.0
mmol) was reduced and then self-condensed as described for
4a to afford a purple solid (1.21 g, 25%): 1H NMR δ -2.80 (br
s, 2 H), 1.63 (s, 18 H), 7.48-7.53 (m, 2 H), 7.79 (d, J ) 8.1 Hz,
4 H), 8.13-8.22 (m, 8 H), 8.61 (m, 2 H), 8.83 (m, 4 H), 8.93
(m, 4 H); C52H44I2N4 calcd mass 978.2, obsd 980.5 (LD-MS);
calcd exact mass 979.1734 (MH+), obsd 979.1734 (MH+) (FAB-
MS).
5,15-Bis(3-iod op h en yl)-10,20-bis[4-[2-(tr im eth ylsilyl)-
eth oxyca r bon yl]p h en yl]p or p h yr in (4f). Monoacyldipyrro-
methane 3m (3.9 g, 6.5 mmol) was reduced and then self-
condensed as described for 4a to afford a purple solid (0.90 g,
24%): 1H NMR δ -2.86 (br s, 2 H), 0.18 (s, 18 H), 1.30 (t, J )
7.8 Hz, 4 H), 4.61 (t, J ) 7.8 Hz, 4 H), 7.49 (m, 2 H), 8.15 (m,
4 H), 8.28 (d, J ) 7.8 Hz, 4 H), 8.45 (d, J ) 7.8 Hz, 4 H), 8.58
(s, 2 H), 8.84 (m, 8 H); C56H52I2N4O4Si2 calcd mass 1154.2, obsd
1157.9 (LD-MS); calcd exact mass 1155.1695 (MH+), obsd
1155.1699 (MH+) (FAB-MS).
1-(4-E t h yn ylb en zoyl)-5-{4-[2-(t r im et h ylsilyl)et h oxy-
ca r bon yl]p h en yl}d ip yr r om eth a n e (3o). A solution of 1f
(1.46 g, 3.98 mmol) in THF (10 mL) was treated with EtMgBr
(8.0 mL, 8.0 mmol, 1.0 M in THF) and a solution of 2h (0.96
g, 4.0 mmol) in THF (4 mL, 1.0 M) as described for 3a . The
reaction was quenched for 30 min after removal of the cooling
bath. Purification of the crude reaction product by flash column
chromatography [silica; ethyl acetate/hexanes (1:4)] furnished
1
a grayish amorphous solid (1.3 g, 66%): mp 173-174 °C; H
NMR δ 0.08 (s, 9H), 1.13 (m, 2 H), 3.22 (s, 1 H), 4.41 (t, J )
8.1 Hz, 2 H), 5.59 (s, 1 H), 5.97 (m, 1 H), 6.05 (m, 1 H), 6.18
(m, 1 H), 6.73 (m, 1 H), 6.79 (m, 1 H), 7.28 (d, J ) 8.1 Hz, 2
H), 7.57 (d, J ) 8.1 Hz, 2 H), 7.78 (m, 2 H), 7.99 (m, 2 H), 8.09
(br s, 1 H), 9.55 (br s, 1 H). Anal. Calcd for C30H30N2O3Si: C,
72.84; H, 6.11; N, 5.66. Found: C, 72.79; H, 6.11; N, 5.53.
Gen er a l P r oced u r e for P or p h yr in F or m a tion : 5,15-
Di-p-tolyl-10,20-diph en ylpor ph yr in (4a). A sample of NaBH4
(18.9 g total, 0.50 mol, 25 molar equiv) was carefully added in
small portions (∼5 g each every 5 min) to a stirred solution of
1-(p-toluoyl)-5-phenyldipyrromethane (3a , 6.81 g, 20.0 mmol)
in THF/methanol (3:1, 400 mL). The progress of the reduction
was followed by TLC [alumina, hexanes/ethyl acetate (9:1)].
The reaction was complete after 20 min, so the reaction
mixture was quenched with water (800 mL) and then poured
into CH2Cl2 (800 mL). The organic phase was isolated, washed
with water (2 × 800 mL), and then dried (K2CO3) and the
solvent removed to afford the carbinol as an orange oil.
The carbinol (∼20.0 mmol) was immediately dissolved in
4.00 L of acetonitrile, and TFA (9.24 mL, 120 mmol, 30 mM)
was added. The solution instantly darkened and the reaction
was monitored by UV spectroscopy. After 3 min, the spectro-
scopic yield of porphyrin had essentially leveled off, and then
DDQ (9.08 g, 40.0 mmol) was added and the mixture stirred
at room temperature for 1 h. Then triethylamine (16.7 mL,
120 mmol) was added, and the entire reaction mixture was
then filtered through a pad of alumina (eluted with CH2Cl2)
until the eluant was no longer dark. Removal of the solvent
gave a dark solid that was fully redissolved in CH2Cl2 (∼500
mL) and filtered through a pad of silica (eluted with CH2Cl2)
to afford a purple solid (1.28 g, 20% from 3a ): C46H34N4 calcd
mass 642.3, obsd 643.8 (LD-MS). 1H NMR data were identical
to those previously reported.3
5,15-Bis(4-ter t-bu tylph en yl)-10,20-bis(4-eth yn ylph en yl)-
p or p h yr in (4g). Monoacyldipyrromethane 3n (3.83 g, 8.00
mmol) was reduced and then self-condensed as described for
1
4a to afford a purple solid (0.80 g). The H NMR spectrum of
the porphyrin product indicated partial loss of the TMS group.
Consequently, the sample was suspended in THF (600 mL)
and treated with Bu4NF on silica (1.5 g) overnight to com-
pletely deprotect the ethynyl moieties. The suspension was
suction-filtered, and the residue was washed with CHCl3 (300
mL). The filtrate was concentrated to dryness, and the residue
was suspended in ethyl alcohol (50 mL). After 5 min of
sonication, the suspension was filtered to obtain 4g as a bright
purple solid (0.63 g, 20% overall yield): 1H NMR δ -2.79 (s, 2
H), 1.55 (s, 18 H), 3.32 (s, 2 H), 7.76 (d, J ) 7.8 Hz, 4 H), 7.89
(d, J ) 8.1 Hz, 4 H), 8.13 (d, J ) 8.1 Hz, 4 H), 8.18 (d, J ) 7.8
Hz, 4 H), 8.80 (d, J ) 4.5 Hz, 4 H), 8.90 (d, J ) 4.5 Hz, 4 H);
C
56H46N4 requires 774.9, obsd 775.7 (LD-MS), calcd exact mass
774.3722 (M+), obsd 774.3693 (M+) (FAB-MS).
5,15-Bis(4-et h yn ylp h en yl)-10,20-b is[4-(2-(t r im et h yl-
silyl)eth oxyca r bon yl)p h en yl]p or p h yr in (4h ). Monoacyl-
dipyrromethane 3o (1.30 g, 2.63 mmol) was reduced and then
self-condensed as described for 4a to afford 4h as a purple solid
(0.245 g, 20%): 1H NMR δ -2.85 (s, 2 H), 0.18 (s, 18 H), 1.29
(t, J ) 8.1 Hz, 4 H), 3.32 (s, 2 H), 4.61 (t, J ) 8.1 Hz, 4 H),
7.90 (d, J ) 8.1 Hz, 4 H), 8.17 (d, J ) 8.1 Hz, 4 H), 8.29 (d, J
) 8.1 Hz, 4 H), 8.44 (d, J ) 8.1 Hz, 4 H), 8.83 (m, 8 H);
5,10-Bis(4-m eth oxyp h en yl)-10,20-bis(p en ta flu or op h en -
yl)p or p h yr in (4b). Monoacyldipyrromethane 3h (223 mg,
0.499 mmol) was reduced and then self-condensed as described
for 4a to afford a purple solid (60 mg, 28%): 1H NMR δ -2.81
(br s, 2 H), 4.10 (s, 6 H), 7.31 (d, J ) 8.7 Hz, 4 H), 8.13 (d, J
) 8.7 Hz, 4 H), 8.79 (d, J ) 5.1 Hz, 4 H), 8.92 (d, J ) 5.1 Hz,
4 H); C46H24F10N4O2 calcd mass 854.2, obsd 854.9 (LD-MS);
calcd exact mass 855.1818 (MH+), obsd 855.1794 (MH+) (FAB-
MS). Similarly, monoacyl dipyrromethane 3k (223 mg, 0.499
mmol) afforded 4b (33 mg, 16%).
5,10-Bis(4-m et h oxyp h en yl)-10,20-d ip h en ylp or p h yr in
(4c). Monoacyldipyrromethane 3i (0.18 g, 0.50 mmol) was
reduced and then self-condensed as described for 4a to afford
a purple solid (41 mg, 26%): 1H NMR δ -2.76 (br s, 2 H), 4.09
(s, 6 H), 7.28 (d, J ) 8.7 Hz, 4 H), 7.72-7.78 (m, 6 H), 8.13 (d,
J ) 8.7 Hz, 4 H), 8.21 (m, 4 H), 8.85 (m, 8 H); C46H34N4O2
calcd mass 674.3, obsd 674.7 (LD-MS); calcd exact mass
675.2760 (MH+), obsd 675.2768 (MH+) (FAB-MS).
C
60H54N4O4Si2 requires 951.2, obsd 953.4 (LD-MS), calcd exact
mass 950.3684 (M+), obsd 950.3705 (M+) (FAB-MS).
Ack n ow led gm en t. This work was funded by the
NIH (GM36238). Mass spectra were obtained at the
Mass Spectrometry Laboratory for Biotechnology. Par-
tial funding for the Facility was obtained from the North
Carolina Biotechnology Center and the National Science
Foundation. We thank Dr. Daniel Gryko for preparation
of 1f and Dr. J on-Paul Strachan for the preparation of
2a and 2c.
Su p p or tin g In for m a tion Ava ila ble: The determination
of the limits of detection of scrambled porphyrins by LD-MS
1
analysis; H NMR spectra and LD-MS spectra of porphyrins
4a -h . This material is available free of charge via the Internet
at http://pubs.acs.org.
5,10-Bis(p en t a flu or op h en yl)-10,20-d ip h en ylp or p h y-
r in (4d ). Monoacyldipyrromethane 3j (208 mg, 0.500 mmol)
was reduced and then self-condensed as described for 4a to
J O9915473