A Tin-Complexation Strategy for Use with Diverse Acylation Methods in the Preparation of 1,9-Diacyldipyrromethanes

Article abstract of DOI:10.1021/jo035622s

The acylation of dipyrromethanes to form 1,9-diacyldipyrromethanes is an essential step in the rational synthesis of porphyrins. Although several methods for acylation are available, purification is difficult because 1,9-diacyldipyrromethanes typically st

Full text of DOI:10.1021/jo035622s

A Tin -Com p lexa tion Str a tegy for Use w ith Diver se Acyla tion
Meth od s in th e P r ep a r a tion of 1,9-Dia cyld ip yr r om eth a n es
Shun-ichi Tamaru, Lianhe Yu, W. J ustin Youngblood, Kannan Muthukumaran,
Masahiko Taniguchi, and J onathan S. Lindsey*
Department of Chemistry, North Carolina State University, Raleigh, North Carolina 27695-8204
jlindsey@ncsu.edu
Received November 4, 2003
The acylation of dipyrromethanes to form 1,9-diacyldipyrromethanes is an essential step in the
rational synthesis of porphyrins. Although several methods for acylation are available, purification
is difficult because 1,9-diacyldipyrromethanes typically streak extensively upon chromatography
and give amorphous powders upon attempted crystallization. A solution to this problem has been
achieved by reacting the 1,9-diacyldipyrromethane with Bu2SnCl2 to give the corresponding dibutyl-
(5,10-dihydrodipyrrinato)tin(IV) complex. The reaction is selective for dipyrromethanes that bear
acyl groups at both the 1- and 9-positions but otherwise is quite tolerant of diverse substituents.
The diacyldipyrromethane-tin complexes are stable to air and water, are highly soluble in common
organic solvents, crystallize readily, and chromatograph without streaking. Four methods (Friedel-
Crafts, Grignard, Vilsmeier, benzoxathiolium salt) were examined for the direct 1,9-diacylation of
a dipyrromethane or the 9-acylation of a 1-acyldipyrromethane. In each case, treatment of the
crude reaction mixture with Bu2SnCl2 and TEA at room temperature enabled facile isolation of
multigram quantities of the 1,9-diacyldipyrromethane-tin complex. The diacyldipyrromethane-
tin complexes could be decomplexed with TFA in nearly quantitative yield. Alternatively, use of a
diacyldipyrromethane-tin complex in a porphyrin-forming reaction (reduction with NaBH4, acid-
catalyzed condensation with a dipyrromethane, DDQ oxidation) afforded the desired free base
porphyrin in yield comparable to that obtained from the uncomplexed diacyldipyrromethane. The
acylation/tin-complexation strategy has been applied to a bis(dipyrromethane) and a porphyrin-
dipyrromethane. In summary, the tin-complexation strategy has broad scope, is compatible with
diverse acylation methods, and greatly facilitates access to 1,9-diacyldipyrromethanes.
In tr od u ction
and 9-positions. The first step entails reaction of the
dipyrromethane with EtMgBr followed by a 2-S-pyridyl
benzothioate, which gives the 1-acyldipyrromethane (2).2
The subsequent acylation of 2 affords the 1,9-diacyldipyr-
romethane (3).1 Both the direct diacylation process and
the second acylation of the sequential acylation process
typically afford mixtures of products that are separated
with difficulty. Such limitations occur regardless of the
acylation method that is employed.
The methods that have been employed for the acylation
of meso-substituted, â-unsubstituted dipyrromethanes
were originally developed for the acylation of pyrrole
(Table 1). Friedel-Crafts acylation of pyrrole3 with a
Lewis acid and an acid chloride has been extended to
core-modified dipyrromethanes4-6 and N-confused dipyr-
romethanes.7 Acylation of the “pyrrole Grignard reagent”3
Diacyldipyrromethanes are critical intermediates in
porphyrin synthesis.1 The reduction of a 1,9-diacyldipyr-
romethane affords the corresponding diol, which can be
reacted with a dipyrromethane to give the meso-substi-
tuted porphyrin. Diacyldipyrromethanes with identical
substituents at the 1- and 9-positions can be used in the
synthesis of A3B-, trans-A2B2-, and trans-AB2C-porphy-
rins, while diacyldipyrromethanes with different substit-
uents at the 1- and 9-positions serve as precursors to cis-
A2B2-, cis-AB2C-, and ABCD-porphyrins. Thus, the
preparation of porphyrins bearing distinct patterns of
substituents requires effective procedures for the diacy-
lation of dipyrromethanes. To carry out porphyrin syn-
theses at reasonable scale also requires acylation meth-
ods that can be implemented with limited reliance on
chromatographic separation procedures.
(2) Rao, P. D.; Littler, B. J .; Geier, G. R., III; Lindsey, J . S. J . Org.
Chem. 2000, 65, 1084-1092.
(3) Anderson, H. J .; Loader, C. E. In Pyrroles. Part I; J ones, R. A.;
Ed., J ohn Wiley & Sons: New York, 1990; pp 397-497.
(4) Cho, W.-S.; Lee, C.-H. Bull. Korean Chem. Soc. 1998, 19, 314-
319.
(5) Lee, C.-H.; Cho, W.-S. Tetrahedron Lett. 1999, 40, 8879-8882.
(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.
(7) Maeda, H.; Osuka, A.; Ishikawa, Y.; Aritome, I.; Hisaeda, Y.;
Furuta, H. Org. Lett. 2003, 5, 1293-1296.
Two distinct acylation strategies have been developed
(Scheme 1). The direct diacylation approach introduces
identical groups at the 1- and 9-positions in a one-flask
reaction with a dipyrromethane (1). The sequential
acylation process introduces different groups at the 1-
(1) Rao, P. D.; Dhanalekshmi, S.; Littler, B. J .; Lindsey, J . S. J . Org.
Chem. 2000, 65, 7323-7344.
10.1021/jo035622s CCC: $27.50 © 2004 American Chemical Society
Published on Web 01/13/2004
J . Org. Chem. 2004, 69, 765-777
765

Tamaru et al.
TABLE 1. Acyla tion Meth od s for P r ep a r in g 1,9-Dia cyld ip yr r om eth a n esa
a
Methods for the direct diacylation of a dipyrromethane or the acylation of a 1-acyldipyrromethane (step 2 in the sequential acylation
process). Acylation is achieved via a two-step process of alkylation followed by oxidative hydrolysis. c Vilsmeier formylation is achieved
b
with DMF and POCl3. Results described herein. e Reagent for oxidative hydrolysis following alkylation. f Each method produces polar
d
byproducts of unknown composition. The byproducts listed are those known to interfere with purification of the 1,9-diacyldipyrromethane.
g
A significant quantity of nonpolar byproducts also is formed.
dipyrromethanes.8,11 Vilsmeier aroylation of pyrrole using
SCHEME 1
N-acyl morpholides12,13 has been extended to dipyr-
romethanes13,14 (and also to bipyrroles15). Vilsmeier for-
mylation of pyrrole using DMF/POCl3 has been extended
to dipyrromethanes.16,17 Related substituents (nitrile,18
amide19) have also been introduced at the 1- and 9-posi-
tions of dipyrromethanes.
Although the methods of acylation for dipyrromethanes
are analogous to those for pyrrole, the acylation chem-
istry of dipyrromethanes is distinct from that of simple
pyrroles in the following ways. (1) A dipyrromethane is
more sensitive toward acid than pyrrole owing to the
facile acidolysis of the pyrrole-meso-carbon bond. (2) A
dipyrromethane is susceptible to dehydrogenation yield-
ing the corresponding dipyrrin. (3) 1,9-Diacyldipyr-
romethanes are quite difficult to purify, generally giving
amorphous powders upon attempted crystallization and
extensive streaking upon chromatography. Indeed, the
challenge of purifying a diacyldipyrromethane by column
chromatography-typically a laborious process that con-
sumes extensive amounts of solvent and chromatographic
media-is one of the chief impediments to the implemen-
tation of rational syntheses of meso-substituted porphy-
rins.
Regardless of acylation strategy and acylation method,
there remains a need for improvements in the synthesis
(9) (a) Cadamuro, S.; Degani, I.; Fochi, R.; Gatti, A.; Regondi, V.
Synthesis 1987, 311-314. (b) Barbero, M.; Cadamuro, S.; Degani, I.;
Fochi, R.; Gatti, A.; Regondi, V. J . Org. Chem. 1988, 53, 2245-2250.
(10) (a) Degani, I.; Fochi, R. J . Chem. Soc., Perkin Trans. 1 1976,
323-325. (b) Barbero, M.; Cadamuro, S.; Degani, I.; Fochi, R.; Gatti,
A.; Regondi, V. Synthesis 1986, 1074-1076.
(11) Brin˜as, R. P.; Bru¨ckner, C. Tetrahedron 2002, 58, 4375-4381.
(12) White, J .; McGillivray, G. J . Org. Chem. 1977, 42, 4248-4251.
(13) Wallace, D. M.; Leung, S. H.; Senge, M. O.; Smith, K. M. J .
Org. Chem. 1993, 58, 7245-7257.
(14) Gryko, D. T.; Tasior, M.; Koszarna, B. J . Porphyrins Phthalo-
cyanines 2003, 7, 239-248.
(15) Bro¨ring, M. Synthesis 2000, 1291-1294.
(16) Khoury, R. G.; J aquinod, L.; Aoyagi, K.; Olmstead, M. M.;
Fisher, A. J .; Smith, K. M. Angew. Chem., Int. Ed. Engl. 1997, 36,
(formed by reaction of pyrrole with EtMgBr) has been
2497-2500.
used extensively with dipyrromethanes.1,8 The alkylation
(17) Bru¨ckner, C.; Posakony, J . J .; J ohnson, C. K.; Boyle, R. W.;
of pyrrole9 with a benzoxathiolium tetrafluoroborate10
followed by oxidative hydrolysis has been extended to
J ames, B. R.; Dolphin, D. J . Porphyrins Phthalocyanines 1998, 2, 455-
465.
(18) Boyle, R. W.; Karunaratne, V.; J asat, A.; Mar, E. K.; Dolphin,
D. Synlett 1994, 939-940.
(8) Lee, C.-H.; Li, F.; Iwamoto, K.; Dadok, J .; Bothner-By, A. A.;
Lindsey, J . S. Tetrahedron 1995, 51, 11645-11672.
(19) Depraetere, S.; Dehaen, W. Tetrahedron Lett. 2003, 44, 345-
347.
766 J . Org. Chem., Vol. 69, No. 3, 2004

Preparation of 1,9-Diacyldipyrromethanes
and purification of diacyldipyrromethanes. Kitamura and
Yamashita recently reported the reaction of 1,9-dicar-
bomethoxy-3,7-dibromodipyrromethane (4) and dibutyltin
dichloride (Bu2SnCl2) in the presence of TEA at room
temperature to give the corresponding N,N-dibutyltin
complex 5 in 93% yield (eq 1).20 The complex was stable
To explore the selectivity of tin complexation with
various dipyrromethane species expected to be present
in crude acylation mixtures, a set of control experiments
was carried out (Scheme 2). A tin complex was not
obtained upon treatment with Bu2SnCl2 and TEA in CH2-
Cl2 of a dipyrromethane (1a ), 1-acyldipyrromethane (2a ),
1,8-diacyldipyrromethane (7), or 1,9-diacyldipyrrin (8).
Treatment of a mixture (1:1 molar ratio) of the dipyr-
romethane 1a and the diacyldipyrromethane 3a under
the same conditions gave exclusively the diacyldipyr-
romethane-tin complex 6a . The successful and highly
selective complexation of a 1,9-diacyldipyrromethane
indicated that tin complexation could form the basis for
a purification procedure.
Scop e w ith 1,9-Dia cyld ip yr r om eth a n es. We exam-
ined the generality of the tin complexation with 1,9-
diacyldipyrromethanes bearing different substituents
(eq 2). In each case, the tin complex was relatively
to routine handling. Treatment of 5 with TFA regener-
ated the dipyrromethane 4 in high yield. We felt that this
complexation/decomplexation chemistry might be ex-
ploited to facilitate isolation and purification of 1,9-
diacyldipyrromethanes.
In this paper, we describe the use of tin complexation
for the isolation and purification of 1,9-diacyldipyr-
romethanes. We characterize the selectivity of complex-
ation of a variety of dipyrromethane species and the scope
of complexation with a family of 1,9-diacyldipyrrometh-
anes. Next, we investigate the use of tin complexation
as a purification aid with four acylation methods (A-D,
Table 1) applied to the 1,9-diacylation of a dipyrro-
methane and the 9-acylation of a 1-acyldipyrromethane.
As part of this work, we have investigated refined
methods for the Friedel-Crafts and for the benzoxathio-
lium procedures. An overarching objective has been to
perform reactions at high concentration and with mini-
mal solvent usage during purification. Taken together,
this work dramatically simplifies the preparation and
isolation of 1,9-diacyldipyrromethanes.
Resu lts a n d Discu ssion
1. Tin Com p lexa tion Stu d ies. Su bstr a te Selectiv-
ity. We applied the tin-complexation reaction described
by Kitamura and Yamashita with 1,9-bis(4-methylben-
zoyl)-5-phenyldipyrromethane (3a ). Thus, the reaction of
3a and Bu2SnCl2 in CH2Cl2 containing TEA at room
temperature afforded the corresponding tin complex 6a
in 90% yield (Scheme 2). The tin complex was readily
isolated by filtration over a pad of silica, was easily
crystallized from ethyl ether or precipitated from ethyl
ether/methanol, and gave satisfactory purity upon el-
emental analysis.
(20) Kitamura, C.; Yamashita, Y. J . Chem. Soc., Perkin Trans. 1
1997, 1443-1447.
J . Org. Chem, Vol. 69, No. 3, 2004 767

Tamaru et al.
SCHEME 2
hydrophobic and was readily isolated by filtration over
a pad of silica. The corresponding tin complex was
typically obtained in good yield (74-93%). One exception
was observed with diacyldipyrromethane 3i (CF3CO
groups), which gave the tin complex in 42% yield but
slowly decomposed upon storage at room temperature.
Otherwise, the tin complexation works well regardless
of the nature of the substituents at the 1,9-positions,
including unhindered (formyl, 3b), sterically hindered
(mesitoyl, 3c), alkanoyl (3f), electron-releasing (4-meth-
oxybenzoyl, 3g) and electron-withdrawing (pentafluo-
robenzoyl, 3h ) substituents. Substituents located at the
meso (5-) position have little effect on the tin complex-
ation, though a slightly lower yield (74%) was observed
with the meso-unsubstituted diformyldipyrromethane
(3d ).
complex 9a or 9b in 91% or 88% yield, respectively (eq
3). These results illustrate the generality of the tin-
complexation process. From a practical standpoint, it is
noteworthy that while most of the dibutyltin complexes
were solids and gave large crystals, the diphenyltin
complex gave a powder, and the dioctyltin complex was
an oil.
Ch ar acter ization . The diacyldipyrromethane-tin com-
plexes are stable to water and routine handling. The
stability to water distinguishes these complexes from
trialkyltin-pyrroles such as N-(tributylstannyl)pyrrole,
which decompose upon exposure to water or alcohols.21
Unlike diacyldipyrromethanes, the diacyldipyrrometh-
ane-tin complexes can easily be precipitated/crystallized
The reaction of diacyldipyrromethane 3a with diphen-
yltin dichloride or dioctyltin dichloride afforded the
(21) Pommier, J . C.; Lucas, D. J . Organomet. Chem. 1973, 57, 139-
153.
768 J . Org. Chem., Vol. 69, No. 3, 2004

Preparation of 1,9-Diacyldipyrromethanes
from ethyl ether/methanol and afford satisfactory el-
emental analysis results.
The spectral changes upon tin complexation include
disappearance of the IR stretch owing to the N-H bonds
(3236 cm-1) and the absence of the characteristic stretch
in the region expected for typical CdO bonds (1614, 1599
1
cm-1). The H NMR spectra show the disappearance of
the NH resonances and a ∼0.5 ppm downfield shift of
the resonances of the H2/H8 protons (∼7.0 ppm). The
butyl groups attached to the tin atom give two triplets
for the terminal methyl groups as well as two sets of 13
C
signals for diacyldipyrromethanes that bear two different
meso substituents, owing to the different magnetic
environment of the two butyl groups (syn or anti with
respect to the meso substituent). The 119Sn NMR spectra
of selected 1,9-diacyldipyrromethane-tin complexes (6a ,
6b, 6e, 6f, 6p , 6q) showed only one singlet for each
complex, ranging from -242 ppm for the diformyl species
6b to -282 ppm for 6a . In general, the diacyldipyr-
romethane-tin complexes afford very clean 1H NMR
spectra.
X-ray structural analyses were performed on 6a and
6b (Figure 1). Selected bond lengths and angles for the
two structures are shown in Supporting Information. The
tin atom in both structures adopts a highly distorted
pseudo-octahedral geometry. The Sn-O bond lengths in
both 6a [2.461(2), 2.488(2) Å] and 6b [2.515(2), 2.548(2)
Å] are 0.1-0.2 Å shorter than the Sn-O bond lengths
[2.519(5), 2.629(5) Å] of 5.20 The C-O bond length was
longer in both 6a [1.254, 1.259 Å] and 6b [1.248, 1.249
Å] than for that in 2-benzoylpyrrole (1.234(4) Å).22 In each
structure, the two pyrrole units, two carbonyl groups, and
the tin atom are nearly coplanar. Coordination of the two
carbonyl groups and the two pyrrolic nitrogen atoms to
the central tin atom effectively masks four groups that
can engage in hydrogen bonding. The diminished con-
formational freedom and ensheathed R-acylpyrrole motifs
are the source of the striking change in physical proper-
ties (polarity, crystallinity) upon conversion of a 1,9-
diacyldipyrromethane to the corresponding tin complex.
The facile reaction of 4 with dibutyltin dichloride in
the presence of a mild base to give tin complex 5 (eq 1)
F IGURE 1. ORTEP drawings of a representative molecule
in the crystal structure of 6a (top) and 6b (bottom). All
hydrogens have been omitted for clarity.
was attributed to the increased acidity of the pyrrolic
N-H groups caused by the presence of two electron-
withdrawing groups per pyrrole unit.20 Even a single acyl
unit increases the N-H acidity significantly (pyrrole-2-
carboxaldehyde has pKa ∼15,23 compared with a value
of 17.5 for pyrrole24), thereby increasing the reactivity of
the diacyldipyrromethane. On the other hand, the forma-
tion of stable tin complexes requires the appropriate
coordination geometry for the central tin atom. Given
that a stable tin complex was not obtained with the 1,8-
diacyldipyrromethane 7 but was obtained with each 1,9-
diacyldipyrromethane examined herein, including 3a (an
isomer of 7), the structural requisites to give a stable
complex appear to be the presence of one acyl unit at each
R-position for coordination to the tin atom.
2. Tin Com p lexa tion a s a n Aid for P u r ifica tion
of 1,9-Dia cyld ip yr r om eth a n es. Prior to examination
of the various acylation methods, a process for using tin
complexation as a means of purifying 1,9-diacyldipyr-
romethanes was established (Scheme 3). A crude reaction
mixture obtained from the attempted diacylation of
5-phenyldipyrromethane (1a ) using SbCl5 and p-toluoyl
chloride (method A, Table 1) was quenched with aqueous
NaHCO3, and the organic layer was separated, dried, and
(23) Limage, M.-H.; Lautie´, A.; Novak, A. C. R. Acad. Sci., Ser. B
1975, 280, 601-603.
(24) Yagil, G. Tetrahedron 1967, 23, 2855-2861.
(22) English, R. B.; McGillivray, G.; Smal, E. Acta Crystallogr. 1980,
B36, 1136-1141.
J . Org. Chem, Vol. 69, No. 3, 2004 769

Tamaru et al.
SCHEME 3
Crafts acylation has not been used previously with
dipyrromethanes. For method A, the best conditions
entail use of SnCl4 (equimolar with the acid chloride) in
1,2-dichloroethane or CH2Cl2 at room temperature with
500 mM dipyrromethane for 10 min or analogous condi-
tions using SbCl5 with 50 mM dipyrromethane for 5 min.
For method C, the alkylation conditions entail 4 molar
equiv of the benzoxathiolium tetrafluoroborate per dipyr-
romethane (a 2-fold excess) in THF and 4 molar equiv of
DBU with 300 mM dipyrromethane at room temperature.
The hydrolysis conditions entail HgO and aqueous HBF4.
Methods B (Grignard)1 and D (Vilsmeier)14 have been
used as described previously.
Dir ect 1,9-Dia cyla tion . The results of the direct 1,9-
diacylation of a dipyrromethane followed by tin complex-
ation are shown in Table 2. Each method (A-D) was
applied to the synthesis of diacyldipyrromethane-tin
complex 6a (entry 1). The tin complex was obtained with
the simple purification process outlined in Scheme 3
(except for method C, which required a silica pad filtra-
tion prior to tin complexation), despite the different types
of byproducts that are characteristic of the different
acylation methods (Table 1). Friedel-Crafts acylation
(method A) also was applied with the dipyrromethane
(1b) bearing an ester substituent to give 6l, a compound
unavailable via the Grignard method. Application of
method A to dipyrromethane (1c) and p-toluoyl chloride
resulted in substantial decomposition, while the Grignard
method (B) afforded 6e in 54% yield. A similar reactivity
profile was observed with p-iodobenzoyl chloride, where
the Grignard method afforded the desired diacyldipyr-
romethane-tin complex 6m in 32% yield. Regardless of
the acylation method, application of the tin complexation
method greatly facilitated the purification process. In-
deed, the synthesis of 6a was readily scaled (method B)
with little change in yield to give 20 g of product.
Sequ en tia l 1,9-Acyla tion . 1-Acyldipyrromethanes
2a -d were prepared following the general procedure
described in the literature2 with only slight modification
of the workup method. The 9-acylation of a 1-acyldipyr-
romethane has been achieved by methods B (Grignard)1
and C (benzoxathiolium),9 but no prior examples of
method A (Friedel-Crafts) have been reported. Ap-
propriate conditions for the Friedel-Crafts acylation
entail use of SbCl5 (2 equiv) and the acid chloride (1.5
equiv) with a 1-acyldipyrromethane (50 mM) in 1,2-
dichloroethane at room temperature for 5 min (see
Supporting Information). The concentration of acid cata-
lyst is greater than that for direct 1,9-diacylation; the
higher level of acid is tolerable owing to the greater
stability toward acid of the 1-acyldipyrromethane versus
the dipyrromethane.
CHART 1
concentrated. The residue was dissolved in CH2Cl2 or
ClCH2CH2Cl and treated with TEA and Bu2SnCl2 at
room temperature. Prior to tin complexation, the diacyl-
dipyrromethane streaked [Rf ) 0.5-0.3, CH2Cl2/ethyl
acetate (7:1) on silica] and overlapped with some byprod-
ucts on TLC analysis. After complexation, the diacyl-
dipyrromethane-tin complex was the least polar com-
pound (Rf ) 0.7, CH2Cl2 on silica) among the major
products while the byproducts gave Rf e 0.2. Filtration
over a silica pad (6 cm × 10 cm) gave the diacyldipyr-
romethane-tin complex (1.1 g) with a modest amount of
solvent (300 mL) in a short period (30 min). (By contrast,
isolation of a similar amount of 1,9-diacyldipyrromethane
by chromatography typically consumes 1.2 L of solvent
with a larger silica column (6 cm × 18 cm) over 3-4 h.)
The product was dissolved in ethyl ether and precipitated
upon addition of methanol, affording the diacyldipyr-
romethane-tin complex as a pale yellow solid in 58%
yield. In a few instances, the diacyldipyrromethane-tin
complex underwent decomplexation during filtration over
silica, which appeared to be due to a given batch of silica
gel rather than characteristic substituents on the diacyl-
dipyrromethane. Regardless, the problem of decomplex-
ation was easily avoided by using a basic eluant [e.g.,
CH2Cl2/hexanes (1:1) containing 1% of TEA] or by using
alumina in place of silica.
We investigated the various methods for 9-acylation
in conjunction with tin complexation. In method A, the
reaction of 2a with p-toluoyl chloride gave the desired
diacyldipyrromethane 3a (∼70% yield) as well as an
isomeric 1,8-diacyldipyrromethane 7 (∼10% yield; see
Supporting Information for characterization). The 1,9-
diacyldipyrromethane-tin complex 6a was obtained
selectively in 66% yield. Application of method B or C
gave 6a in 56 or 46% yield, respectively (Table 3, entry
1). Method A was applied to acylation of 2b-d , affording
the corresponding diacyldipyrromethane-tin complexes
6n -p in 52-72% yield (entries 2-4). Note that the
3. Acyla tion of Dip yr r om eth a n es. Meth od s. The
four acylation approaches listed in Table 1 were applied
to the direct 1,9-diacylation of a dipyrromethane and the
9-acylation of a 1-acyldipyrromethane. The reactants
(10a -d ) for introducing acyl units are shown in Chart
1. Methods A (Friedel-Crafts) and C (benzoxathiolium)
were studied extensively to develop suitable reaction
conditions (see Supporting Information). Indeed, Friedel-
770 J . Org. Chem., Vol. 69, No. 3, 2004

Preparation of 1,9-Diacyldipyrromethanes
TABLE 2. 1,9-Dia cyla tion of Dip yr r om eth a n es
a
The methods differ only in the conditions for acylation, and each method employed the same procedure for tin complexation (approximate
concentrations given). Method A: 50 mM 1, 100 mM acid chloride, 100 mM SbCl5 in ClCH2CH2Cl. Method B: 100 mM 1, 250 mM acid
chloride, 500 mM EtMgBr in toluene/THF. Method C: (1) 300 mM 1, 1.2 M benzoxathiolium tetrafluoroborate salt, 1.2 M DBU in THF;
b
(2) 1.2 M HgO, 2.4 M HBF4 (aq). Method D: 167 mM 1, 667 mM N-acyl morpholide, 1.33 M POCl3 in ClCH2CH2Cl. The high concentration
conditions (250 mM 1, 750 mM acid chloride, 500 mM SnCl4 in ClCH2CH2Cl) gave 39% yield. c The formation of a corresponding
diacyldipyrromethane 3m was not observed by TLC analysis.
acylation of 2d with p-iodobenzoyl chloride followed by
tin complexation afforded the desired 6p in fair yield
(Table 3, entry 4), whereas the direct 1,9-diacylation of
a dipyrromethane with p-iodobenzoyl chloride was not
successful (Table 2, entry 4). Treatment of 2a with
modified conditions for Vilsmeier formylation (DMF and
p-toluoyl chloride)11,25 afforded the corresponding 9-formyl
product, which gave the tin complex 6q in 58% yield
(Table 3, entry 5). An alternative synthesis of an ana-
logue proceeded via 9-alkylation of a 1-formyldipyr-
romethane with a benzoxathiolium tetrafluoroborate
followed by oxidative hydrolysis.11
4. Decom p lexa tion of 1,9-Dia cyld ip yr r om eth a n e-
Tin Com p lexes. The diacyldipyrromethane-tin com-
plexes were readily isolated and were stable on storage
for months. Treatment of the diacyldipyrromethane-tin
complexes with TFA afforded the corresponding uncom-
plexed diacyldipyrromethanes in high yields (eq 4).
5. Ap p lica tion s. Tetr a a cyla tion of a Bis(d ip yr -
r om eth a n e). 1,4-Bis(dipyrromethan-5-yl)benzene (11)26
is readily available by reaction of terephthalaldehyde
with excess pyrrole.27 Such bis(dipyrromethanes) joined
by a p-phenylene linker are potentially valuable inter-
mediates in the synthesis of p-phenylene-linked multi-
(25) (a) Finkbeiner, H. J . Org. Chem. 1965, 30, 2861-2862. (b)
porphyrin arrays.28,29 However, the poor solubility of 11
and derivatives therefrom presents a major limitation to
their use. Our prior attempts to prepare the tetraacyl
Chong, R.; Clezy, P. S.; Liepa, A. J .; Nichol, A. W. Aust. J . Chem. 1969,
22, 229-238.
(26) Bennis, V.; Gallagher, J . F. Acta Crystallogr. 1998, C54, 130-
132.
(27) Lee, C.-H.; Lindsey, J . S. Tetrahedron 1994, 50, 11427-11440.
derivative of 11 encountered intractable separations
J . Org. Chem, Vol. 69, No. 3, 2004 771

Tamaru et al.
TABLE 3. 9-Acyla tion of 1-Acyld ip yr r om eth a n es
a
The methods differ only in the conditions for acylation; each method employed the same procedure for tin complexation (approximate
concentrations given). Method A: 50 mM 2, 75 mM acid chloride, 100 mM SbCl5 in CH2Cl2. Method B: 250 mM 2, 1.5 M EtMgBr (1.0 M
solution in THF), 750 mM acid chloride in toluene. Method C: (1) 500 mM 2, 1.0 M benzoxathiolium tetrafluoroborate salt, 1.0 M DBU;
b
(2) 1.0 M HgO, 2.0 M HBF4 (aq). The high concentration conditions (500 mM 2, 750 mM acid chloride, 1.0 mM SnCl4 in CH2Cl2 or
ClCH2CH2Cl) gave 60% yield. c A Vilsmeier formylation using 3.0 M 2, 12 M N,N-dimethylformamide, and 4.5 M p-toluoyl chloride in
ClCH2CH2Cl.
owing to the incomplete acylation and very poor solubility
of the acylated products.
We addressed the separation and solubility problems
through use of tin complexation (eq 5). Thus, a suspen-
sion of 11 in toluene was treated with EtMgBr followed
by acid chloride 10e (method B), affording several reac-
tion products upon TLC analysis. Workup followed by tin
complexation, filtration through a silica pad, and pre-
cipitation afforded the target compound 12 in 20% yield.
This compound is quite soluble in organic solvents and
can be used in the synthesis of p-phenylene-linked
multiporphyrin arrays.
Dia cyla tion of a P or p h yr in -Dip yr r om eth a n e. We
recently described the synthesis of p-phenylene-linked
triads of porphyrins wherein the three porphyrins are
present in distinct metalation states (Mg, Zn, free base).29
The synthesis of the triads relied on the condensation of
a porphyrin-dipyrromethane and a porphyrin-dipyr-
(28) (a) Khoury, R. G.; J aquinod, L.; Paolesse, R.; Smith, K. M.
Tetrahedron 1999, 55, 6713-6732. (b) Paolesse, R.; Pandey, R. K.;
Forsyth, T. P.; J aquinod, L.; Gerzevske, K. R.; Nurco, D. J .; Senge, M.
O.; Licoccia, S.; Boschi, T.; Smith, K. M. J . Am. Chem. Soc. 1996, 118,
3869-3882. (c) Helms, A.; Heiler, D.; McLendon, G. J . Am. Chem. Soc.
1992, 114, 6227-6238. (d) Sessler, J . L.; J ohnson, M. R.; Creager, S.
E.; Fettinger, J . C.; Ibers, J . A. J . Am. Chem. Soc. 1990, 112, 9310-
9329. (e) Sessler, J . L.; J ohnson, M. R. Angew. Chem., Int. Ed. Engl.
1987, 26, 678-680.
(29) Speckbacher, M.; Yu, L.; Lindsey, J . S. Inorg. Chem. 2003, 42,
4322-4337.
772 J . Org. Chem., Vol. 69, No. 3, 2004

Preparation of 1,9-Diacyldipyrromethanes
SCHEME 4
romethane-dicarbinol. Substantial difficulty was encoun-
tered in preparing the porphyrin-diacyldipyrromethane,
which served as the precursor to the porphyrin-dipyr-
romethane-dicarbinol. We examined the applicability of
the tin chemistry to the purification of the porphyrin-
diacyldipyrromethane obtained upon direct 1,9-diacyla-
tion of the corresponding porphyrin-dipyrromethane (eq
6). Free base porphyrin 13 was reacted with benzoxathio-
d iol (resulting from the direct reduction of 3a ) and 1a
was performed for comparison. The progress of the
condensation was assessed by removing a reaction aliquot
and oxidizing with DDQ, followed by UV-vis spectro-
scopic analysis to determine the yield of porphyrin
(Figure 2). The key results are as follows. (1) In both
cases, the yield of porphyrin peaked at ∼15 min (27-
29%) and remained nearly constant up to 30 min. (2) No
scrambled porphyrin products (derived from acidolysis
of dipyrromethane species) were observed upon analysis
of each crude reaction mixture by laser-desorption mass
spectrometry (LD-MS). (3) No tin porphyrin was observed
upon analysis of the crude reaction mixture (absence of
m/z ) 759.5, Sn -15: C46H32N4Sn) by LD-MS or of the
isolated porphyrin product by 1H NMR, UV-vis, fluo-
rescence and LD-MS analysis. (4) The isolated yield of
porphyrin 15 (from 6a and 1a ) was 28%, which was
consistent with the yield observed spectroscopically.
6. Sa fety Con sid er a tion s. We sought to determine
the nature of the tin species formed during decomplex-
ation or reduction of the diacyldipyrromethane-tin com-
plexes. The crude reaction mixture obtained upon TFA
decomplexation of 6a (in CH2Cl2) was examined by 119Sn
NMR spectroscopy (standard; Me4Sn ) 0.00 ppm). Four
peaks were obtained (-196.3, -174.5, -169.8, and -167.0
ppm). The peak at -196.3 ppm is attributed to Bu2Sn-
(O2CCF3)2 [-195 ppm is reported31 for Bu2Sn(OAc)2],
while the remaining three peaks likely stem from stan-
noxane oligomers of type (Bu2SnO)n (-177 ppm31). The
lium salt 10c (method C) followed by oxidative hydrolysis
to give the porphyrin-diacyldipyrromethane. Multiple
porphyrin products were obtained. Treatment to the tin
complexation chemistry afforded a new, more mobile
species that was readily isolated. The desired tin complex
14 was obtained in low yield (17%) but in exceptional
purity. The high purity and facile isolation sets this
synthesis apart from the previously reported preparation
of the uncomplexed diacyldipyrromethane-porphyrin.29
Dir ect Syn th esis of P or p h yr in s fr om a Dia cyl-
d ip yr r om eth a n e-Tin Com p lex. It occurred to us that
the diacyldipyrromethane-tin complexes might be used
as precursors in the synthesis of porphyrins. Thus,
diacyldipyrromethane-tin complex 6a was reduced to the
putative dicarbinol derivative (3a -d iol) following a stan-
dard method1 for the reduction of diacyldipyrromethanes
using NaBH4 (Scheme 4). Reduction of 6a to the putative
dipyrromethane-dicarbinol 3a -d iol took longer (3.5-4 h)
than the corresponding reduction of 3a to 3a -d iol (40 min
to 1 h) as observed by TLC analysis. Condensation of 3a -
d iol (obtained from the reduction of 6a ) with 1a was
carried out using a literature procedure:30 Yb(OTf)3 (3.2
mM) in CH2Cl2 (2.5 mM) at room temperature followed
by oxidation with DDQ. The similar condensation of 3a -
(30) Geier, G. R., III; Callinan, J . B.; Rao, P. D.; Lindsey, J . S. J .
Porphyrins Phthalocyanines 2001, 5, 810-823.
(31) Davis, A. G. Organotin Chemistry; VCH: Weinheim, 1997; pp
18-24.
J . Org. Chem, Vol. 69, No. 3, 2004 773

Tamaru et al.
hydrides react slowly in water to form gels, presumably
of the corresponding stannoxane (R2SnO)n.37 Taken to-
gether, the use of tin reagents in diacyldipyrromethane
chemistry as described herein would not appear to
warrant any extraordinary safety precautions.
Ou tlook
The previous difficulty in purifying 1,9-diacyldipyr-
romethanes has been overcome by conversion of the
diacyldipyrromethane to the corresponding dialkyltin
complex. Selective complexation of 1,9-diacyldipyrro-
methanes versus other dipyrromethane species originates
in the requirement for acyl groups at both the 1- and
9-positions to give a stable coordination complex. The tin
complexation process is tolerant of diverse substituents
and can be used in conjunction with a variety of acylation
methods. Formation of the tin complex alters the struc-
ture of the diacyldipyrromethane in two ways: (1)
blocking of the pyrrolic nitrogen and carbonyl oxygen
atoms, thereby ensheathing all sites that can engage in
hydrogen bonding, and (2) enforcing a rigid structure
with essentially coplanar pyrrole units. The resulting
diacyldipyrromethane-tin complex is typically less polar
than the corresponding diacyldipyrromethane, has high
solubility in organic solvents, chromatographs as a sharp
band, and crystallizes readily. The simplicity of the
complexation/decomplexation process suggests the use of
a catch-and-release strategy, where the tin-dichloride
reagent is incorporated in an insoluble polymeric resin.
Examples of resins are known where the tin-dichloride
unit is located on a pendant group on a cross-linked
polymer such as polystyrene.38 In summary, although
further improvements in acylation methods are still
needed, the simplified isolation, purification, and han-
dling of 1,9-diacyldipyrromethanes via the tin-complex-
ation strategy described herein should help broaden the
scope of porphyrin synthesis.
F IGURE 2. Comparison of the yield of porphyrin as a function
of time upon reaction of dipyrromethane-dicarbinol 3a -d iol +
dipyrromethane 1a , where the 3a -d iol species was derived
from the corresponding diacyldipyrromethane 3a (b) or the
diacyldipyrromethane-tin complex 6a (9). The reaction was
performed with catalysis by Yb(OTf)3 in CH2Cl2 (the concen-
tration of each reactant is 2.5 mM, the concentration of the
catalyst is 3.2 mM) and oxidation by DDQ. Each data point is
the average from duplicate reactions.
crude mixture obtained upon NaBH4 reduction of 6a (to
give 3a -d iol) also was examined by 119Sn NMR spectros-
copy (in THF/MeOH (10/1)). A signal at -203.4 ppm was
observed, which is consistent with dibutyltin dihydride
(Bu2SnH2, -205 ppm31). Therefore, no species other than
dibutyltin compounds were formed during decomplex-
ation or reduction of the diacyldipyrromethane-tin com-
plexes.
Organotin compounds are widely perceived to be quite
toxic. In fact, the toxicity of organotin compounds varies
substantially depending on the number and size of
hydrocarbon substituents at the tin atom. Although
trialkyltin and triaryltin compounds have been employed
as biocides32 and cause damage to the central nervous
system of laboratory animals,33 dialkyltin compounds are
not useful as biocides and do not cause such damage in
similar studies. Among dialkyltin compounds, dibutyltin
compounds are less harmful than dimethyl- and dieth-
yltin compounds as a result of their lower propensity for
absorption into biological tissues.32 Indeed, food-grade
plastics incorporate dioctyltin compounds, which are
considered practically nontoxic because of their low level
of leaching into food materials and extremely poor
biological uptake.33,34 There is also no indication that
dialkyltin compounds have any carcinogenic effect.35 The
acute toxicity of dibutyltin dichloride (LD50 ) 100 mg/
kg) is relatively low, and polymeric stannoxanes such as
(Bu2SnO)n are generally much less toxic (LD50 ) 600-
800 mg/kg).36 Although little information is available
regarding the toxicity of dialkyltin hydrides, dialkyltin
Exp er im en ta l Section
Non com m er cia l Com p ou n d s. The dipyrromethanes 1a -
c,e-g39 and 1d 1 were prepared as described in the literature.39
The known 1-acyldipyrromethanes 2a ,2 2c1, 2d ,1 diacyldipyr-
romethanes 3a ,c,f-h ,k ,q,1 3b,30 3j40 and 3d ;41,17 acylating
reagents 10c,10 10d ,14,42 10e,43 10f,10 and 10g;10 bis(dipyr-
romethane) 11;27 and porphyrin 1329 were prepared as de-
scribed.
(36) Neumann, W. P. The Organic Chemistry of Tin; J ohn Wiley &
Sons: London, 1970; pp 230-237.
(37) (a) Ingham, R. K.; Rosenberg, S. D.; Gilman, H. Chem. Rev.
1960, 60, 459-539. (b) Finholt, A. E.; Bond, A. C., J r.; Wilzback, K.
E.; Schlesinger, H. I. J . Am. Chem. Soc. 1947, 69, 2692-2696.
(38) (a) Weinshenker, N. M.; Crosby, G. A.; Wong, J . Y. J . Org.
Chem. 1975, 40, 1966-1971. (b) Mercier, F. A. G.; Biesemans, M.;
Altmann, R.; Willem, R.; Pintelon, R.; Schoukens, J .; Delmond, B.;
Dumartin, G. Organometallics 2001, 20, 958-962.
(39) 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.
(40) Tomizaki, K.-y.; Yu, L.; Wei, L.; Bocian, D. F.; Lindsey, J . S. J .
Org. Chem. 2003, 68, 8199-8207.
(41) (a) Honeybourne, C. L.; J ackson, J . T.; Simmonds, D. J .; J ones,
O. T. G. Tetrahedron 1980, 36, 1833-1838. (b) Chang, C. K. J . Org.
Chem. 1981, 46, 4610-4612. (c) Wickramasinghe, A.; J aquinod, L.;
Nurco, D. J .; Smith, K. M. Tetrahedron 2001, 57, 4261-4269.
(42) Buhleier, E.; Wehner, W.; Vo¨gtle, F. Chem. Ber. 1979, 112, 559-
566.
(32) (a) Tin and Organotin Compounds, A Preliminary Review;
World Health Organization: Geneva, 1980. (b) Cooney, J . J . Helgol.
Meeresunters. 1995, 49, 663-677.
(33) Boyer, I. J . Toxicology 1989, 55, 253-298.
(34) (a) Barnes, J . M.; Stoner, H. B. Br. J . Ind. Med. 1958, 15, 15-
22. (b) Klimmer, O. R. Arzneim.-Forsch. 1969, 19, 934-939.
(35) U. S. National Cancer Institute TR-183; Bioassay of Dibutyltin
Diacetate for Possible Carcinogenicity, DHEW Publication 79-1739;
National Cancer Institute:Washington, DC, 1979.
(43) Korshunov, M. A.; Bodnaryuk, F. N.; Fershtut, E. V. Zh. Org.
Khim. 1967, 3, 140-143.
774 J . Org. Chem., Vol. 69, No. 3, 2004

Preparation of 1,9-Diacyldipyrromethanes
Tin Com p lexa tion of a 1,9-Dia cyld ip yr r om eth a n e,
Exem p lified for Dibu tyl[5,10-d ih yd r o-1,9-bis(4-m eth yl-
ben zoyl)-5-p h en yld ip yr r in a to]tin (IV) (6a ). A sample of 3a
(916 mg, 2.00 mmol) was treated with TEA (814 µL, 6.00
mmol) and Bu2SnCl2 (608 mg, 2.00 mmol) in CH2Cl2 (4 mL)
at room temperature for 1 h. The mixture was filtered over a
pad of silica (CH2Cl2). The eluant was concentrated to dryness.
The resulting residue (often slightly brown) was dissolved in
a minimum amount of diethyl ether. Then methanol was
added, yielding a precipitate, which upon filtration afforded a
colorless solid (1.25 g, 90%): mp 155-157 °C (dec); 1H NMR δ
0.68 (t, J ) 7.2 Hz, 3H), 0.73 (t, J ) 7.2 Hz, 3H), 1.06-1.53
(m, 10H), 1.64-1.71 (m, 2H), 2.44 (s, 6H), 5.59 (s, 1H), 6.18
(d, J ) 3.6 Hz, 2H), 7.08 (d, J ) 3.6 Hz, 2H), 7.16-7.32 (m,
9H), 7.82 (d, J ) 8.0 Hz, 4H); 13C NMR δ 13.83, 13.84, 21.8,
24.2, 25.0, 26.21, 26.52, 27.44, 27.50, 45.9, 115.3, 123.9, 126.9,
128.38, 128.84, 129.30, 129.36, 135.2, 136.0, 142.4, 144.5,
151.7, 184.7; 119Sn NMR δ -282.3; FAB-MS obsd 691.2374,
calcd 691.2347 (C39H42N2O2Sn). Anal. Calcd for C39H42N2O2-
Sn: C, 67.94; H, 6.14; N, 4.06. Found: C, 68.00; H, 6.15; N,
4.07. Alternatively, the reaction could be carried out at the
concentration of 100 or 50 mM (1,9-diacyldipyrromethane) with
comparable results.
satisfactory analytical data (mp, 1H NMR spectrum, and
elemental analysis).
Meth od B a t La r ge Sca le. A solution of EtMgBr (375 mL,
375 mmol, 1.0 M solution in THF) was added slowly to a tap-
water-cooled flask containing a solution of 1a (16.8 g, 75.0
mmol) in toluene (750 mL) under argon. An exothermic
reaction with gas evolution ensued. The resulting mixture was
stirred at room temperature for 30 min. A solution of p-toluoyl
chloride (24.8 mL, 188 mmol) in toluene (188 mL) was added
over 30 min, and the resulting solution was stirred for 30 min.
The reaction mixture was poured into saturated aqueous NH4-
Cl (1.50 L) and ethyl acetate (1.50 L). The organic layer was
washed [water (2 × 1 L) and brine (2 × 1 L)], dried (Na2SO4),
and filtered. The filtrate was concentrated to dryness. The
residue was treated with TEA (31.4 mL, 225 mmol) and Bu2-
SnCl2 (22.8 g, 75.0 mmol) in CH2Cl2 (300 mL) at room
temperature for 30 min followed by a slight modification of
the silica-pad purification technique [silica, 6 × 27 cm; CH2-
Cl2/hexanes (1/1) with 1% TEA; total amount of eluant ) 2.3
L, ∼1.5 h]. The eluant was concentrated to dryness. The
residue was dissolved in diethyl ether, and then methanol was
added, yielding a precipitate. Filtration afforded a pale yellow
solid (20.3 g, 39%) that exhibited satisfactory analytical data
1
(mp, H NMR spectrum, and elemental analysis).
Dir ect 1,9-Dia cyla tion of Dip yr r om eth a n es w ith Su b-
sequ en t Tin Com p lexa tion , Exem p lified for 6a . Meth od
A (SbCl5 Ca ta lysis). A solution of 1a (1.11 g, 5.00 mmol) and
p-toluoyl chloride (1.32 mL, 10.0 mmol) in ClCH2CH2Cl (100
mL) was treated with SbCl5 (1.34 mL, 10.0 mmol) at room
temperature for 5 min. The reaction mixture was poured into
saturated aqueous NaHCO3 (50 mL) and stirred vigorously for
30 min. The organic layer was collected, washed (water and
brine), dried (Na2SO4), and filtered. The filtrate was concen-
trated to dryness. The residue (typically blue or green) was
treated with TEA (2.10 mL, 15.0 mmol) and Bu2SnCl2 (1.52 g,
5.00 mmol) in CH2Cl2 (10 mL) at room temperature for 30 min.
The mixture was filtered over a silica pad (CH2Cl2). The eluant
was concentrated to dryness. The residue was dissolved in a
minimum amount of diethyl ether. Then methanol was added,
yielding a precipitate, which upon filtration afforded a pale
yellow solid (2.00 g, 58%) with satisfactory analytical data (mp,
1H NMR spectrum, and elemental analysis).
Meth od C (Ben zoxa th ioliu m Sa lt Dia lk yla tion /Hy-
d r olysis). A solution of benzoxathiolium salt 10c (6.28 g, 20.0
mmol) in THF (13 mL) was treated with DBU (3.04 g, 20.0
mmol) at room temperature for 3 min in a sealed round-bottom
flask. A solution of dipyrromethane 1a (1.11 g, 5.00 mmol) in
THF (4 mL) was injected into the reaction mixture, and the
resulting mixture was stirred for 5 min. HgO (4.34 g, 20.0
mmol) and aqueous HBF4 (5.23 mL of 48 wt % solution, 40.0
mmol) were added to the mixture. The mixture was stirred at
room temperature for 3 h, and then 2 M aqueous NaOH (5
mL) was added. The mixture was poured into saturated
aqueous NH4Cl and CH2Cl2. The organic layer was washed
(water and brine), dried (Na2SO4), and filtered. The filtrate
was concentrated to dryness. The residue was filtered through
a pad of silica with CH2Cl2, followed by CH2Cl2 with 10% ethyl
acetate. The eluant was concentrated. Treatment of the residue
with TEA (2.10 mL, 15.0 mmol) and Bu2SnCl2 (1.53 g, 5.00
mmol) in CH2Cl2 (10 mL) at room temperature for 1 h followed
by the standard purification technique (described in method
A) afforded a colorless solid (1.29 g, 37%) with satisfactory
analytical data (mp, 1H NMR spectrum, and elemental analy-
sis).
Meth od D (Vilsm eier ). A mixture of 10d (8.21 g, 40.0
mmol) and POCl3 (7.46 mL, 80 mmol) was stirred under argon
at 65 °C for 3 h and then was cooled to room temperature.
The reaction mixture was dissolved in ClCH2CH2Cl (60 mL)
and was treated with 1a (2.22 g, 10.0 mmol) under reflux for
2 h. The reaction mixture was poured into saturated aqueous
CH3CO2Na (60 mL) followed by heating at 65 °C for 1 h. The
organic layer was collected, and the aqueous layer was
extracted with CH2Cl2. The initial organic layer and the eluant
were combined, washed (water and brine), dried (Na2SO4), and
filtered. The filtrate was concentrated to dryness. Treatment
of the residue with TEA (4.20 mL, 30.0 mmol) and Bu2SnCl2
(3.04 g, 10.0 mmol) in CH2Cl2 (20 mL) at room temperature
for 15 min followed by the standard purification technique
(described in method A) afforded a pale yellow solid (4.34 g,
63%) with satisfactory analytical data (mp, 1H NMR spectrum,
and elemental analysis).
Meth od A a t High Con cen tr a tion (Sn Cl4 Ca ta lysis). A
solution of 1a (2.22 g, 10.0 mmol) and p-toluoyl chloride (4.00
mL, 30.0 mmol) in ClCH2CH2Cl (20 mL) was treated with
SnCl4 (2.30 mL, 20.0 mmol) at room temperature for 5 min.
The reaction mixture was poured into saturated aqueous
NaHCO3 (50 mL) and stirred vigorously for 30 min. The
organic layer was washed (water and brine), dried (Na2SO4),
and filtered. The filtrate was concentrated to dryness. Treat-
ment of the residue with TEA (4.18 mL, 30.0 mmol) and Bu2-
SnCl2 (3.04 g, 10.0 mmol) in ClCH2CH2Cl (10 mL) at room
temperature for 30 min followed by the standard purification
technique as described in method A afforded pale yellow
crystals (2.62 g, 39%) with satisfactory analytical data (mp,
1H NMR spectrum, and elemental analysis).
Meth od B (Gr ign a r d ). A solution of EtMgBr (50 mL, 50.0
mmol, 1.0 M solution in THF) was added slowly to a tap-water-
cooled flask containing a solution of 1a (2.22 g, 10.0 mmol) in
toluene (200 mL) under argon. An exothermic reaction with
gas evolution ensued. The resulting mixture was stirred at
room temperature for 30 min. A solution of p-toluoyl chloride
(3.31 mL, 25.0 mmol) in toluene (25 mL) was added over 10
min, and the resulting solution was stirred for 10 min. The
reaction mixture was poured into saturated aqueous NH4Cl
(200 mL) and ethyl acetate (150 mL). The organic layer was
washed (water and brine), dried (Na2SO4), and filtered. The
filtrate was concentrated to dryness. Treatment of the residue
with TEA (4.18 mL, 30.0 mmol) and Bu2SnCl2 (3.04 g, 10.0
mmol) in CH2Cl2 (40 mL) at room temperature for 30 min
followed by the standard purification technique (described in
method A) afforded a pale yellow solid (3.17 g, 46%) with
Syn th esis of 1-Acyld ip yr r om eth a n es, Exem p lified for
1-(4-Meth ylben zoyl)-5-p h en yld ip yr r om eth a n e (2a ).2
A
solution of EtMgBr (50.0 mL, 50.0 mmol, 1.0 M in THF) was
added slowly to a solution of 1a (4.44 g, 20.0 mmol) in THF
(20 mL) under argon. The resulting mixture was stirred at
room temperature for 10 min and then cooled to -78 °C. A
solution of S-2-pyridyl 4-methylbenzothioate (4.58 g, 20.0
mmol) in THF (20 mL) was added. The mixture was stirred
at -78 °C for 10 min and then warmed to room temperature.
J . Org. Chem, Vol. 69, No. 3, 2004 775

Tamaru et al.
The reaction mixture was poured into saturated aqueous NH4-
Cl (150 mL) and THF (10 mL). The organic layer was washed
(water and brine), dried (Na2SO4), and filtered. The filtrate
was chromatographed [silica (10 × 24 cm), CH2Cl2 (2.3 L)],
affording a golden amorphous solid (5.82 g, 86%) with satisfac-
tory analytical data (mp, 1H NMR spectrum, and elemental
analysis).
followed by the standard purification technique (as described
in method A) afforded a colorless solid (2.10 g, 37%) with
satisfactory analytical data (mp, 1H NMR spectrum, and
elemental analysis).
Meth od D (Mod ified Vilsm eier F or m yla tion ), Affor d -
in g Dibu tyl[5,10-d ih yd r o-1-for m yl-9-(4-m eth ylben zoyl)-
5-p h en yld ip yr r in a to]tin (IV) (6q). A mixture of 2a (1.02 g,
3.00 mmol) and DMF (929 µL, 12.0 mmol) in ClCH2CH2Cl (1
mL) was treated with p-toluoyl chloride (595 µL, 4.50 mmol)
at room temperature under argon. The mixture was heated
at reflux for 45 min and then cooled to room temperature. The
reaction mixture was poured into saturated aqueous Na2CO3.
The organic layer was collected, and the aqueous layer was
extracted with CH2Cl2. The initial organic layer and the eluant
were combined, washed (water and brine), dried (Na2SO4), and
filtered. The filtrate was concentrated to dryness. Treatment
of the residue with TEA (1.25 mL, 9.00 mmol) and Bu2SnCl2
(912 mg, 3.00 mmol) in CH2Cl2 (12 mL) at room temperature
for 25 min followed by chromatography (silica, CH2Cl2) af-
forded an orange oil (1.04 g, 58%): 1H NMR δ 0.67-0.78 (m,
6H), 1.08-1.36 (m, 6H), 1.38-1.72 (m, 6H), 2.43 (s, 3H), 5.56
(s, 1H), 6.12 (d, J ) 4.0 Hz, 1H), 6.21 (d, J ) 4.0 Hz, 1H), 7.05
(d, J ) 4.0 Hz, 1H), 7.12 (d, J ) 4.0 Hz, 1H), 7.14-7.22 (m,
3H), 7.26-7.32 (m, 4H), 7.81 (d, J ) 8.0 Hz, 2H), 9.19 (s, 1H);
13C NMR δ 13.60, 13.64, 21.7, 23.9, 24.5, 26.04, 26.35, 27.2,
45.5, 114.7, 115.9, 123.88, 123.92, 126.8, 128.1, 128.7, 129.23,
129.26, 134.4, 135.5, 138.1, 142.6, 144.0, 151.5, 152.0, 178.7,
184.3; 119Sn NMR δ -257.0; FAB-MS obsd 601.1906 [(M +
Acyla tion of 1-Acyld ip yr r om eth a n es w ith Su bsequ en t
Tin Com p lexa tion , Exem p lified for 6a . Meth od A (SbCl5
Ca ta lysis). A solution of 2a (1.70 g, 5.00 mmol) and p-toluoyl
chloride (0.990 mL, 7.50 mmol) in CH2Cl2 (100 mL) was treated
with SbCl5 (1.28 mL, 10.0 mmol) at room temperature for 10
min. The reaction mixture was poured into saturated aqueous
NaHCO3 (100 mL) and stirred vigorously for 30 min. The
organic layer was washed (water and brine), dried (Na2SO4),
and filtered. The filtrate was concentrated to dryness. The
residue was treated with TEA (2.10 mL, 15.0 mmol) and Bu2-
SnCl2 (1.52 g, 5.00 mmol) in CH2Cl2 (10 mL) at room temper-
ature for 15 min. The mixture was filtered over a silica pad
(CH2Cl2). The eluant was concentrated to dryness. The residue
was dissolved in a minimum amount of diethyl ether. Then
methanol was added, yielding a precipitate, which upon
filtration afforded a pale yellow solid (2.26 g, 66%) with
satisfactory analytical data (mp, 1H NMR spectrum, and
elemental analysis).
Meth od A a t High Con cen tr a tion (Sn Cl4 Ca ta lysis). A
solution of 2a (1.70 g, 5.00 mmol) and p-toluoyl chloride (0.990
mL, 7.50 mmol) in ClCH2CH2Cl (10 mL) was treated with
SnCl4 (1.17 mL, 10.0 mmol) at room temperature for 10 min.
The reaction mixture was poured into saturated aqueous
NaHCO3 (100 mL) and CH2Cl2 (50 mL) and stirred vigorously
for 30 min. The organic layer was washed (water and brine),
dried (Na2SO4), and filtered. The filtrate was concentrated to
dryness. Treatment of the residue with TEA (2.10 mL, 15.0
mmol) and Bu2SnCl2 (1.52 g, 5.00 mmol) in CH2Cl2 (20 mL) at
room temperature for 15 min followed by the standard
purification technique (as described in method A) afforded a
pale yellow solid (2.10 g, 60%) with satisfactory analytical data
H)+], calcd 601.1879 (C32H36N2O2Sn). Anal. Calcd for C32H36
-
N2O2Sn: C, 64.13; H, 6.05; N, 4.67. Found: C, 64.03; H, 6.04;
N, 4.67.
Decom p lexa tion of a 1,9-Dia cyld ip yr r om eth a n e-Tin
Com p lex, 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 (3a ). A solution of 6a (345 mg, 0.500
mmol) in CH2Cl2 (5 mL) was treated with TFA (116 µL, 1.50
mmol) at room temperature for 10 min. The mixture was
filtered through a pad of silica [hexanes/ethyl acetate (2:1)].
The eluant was concentrated to dryness. The residue was
dissolved in diethyl ether, and then hexanes was added,
causing formation of a precipitate. Filtration afforded a
colorless solid (218 mg, 95%) with satisfactory analytical data
(mp, 1H NMR spectrum, and elemental analysis). In some
cases (depending on substituents), the residue obtained from
the silica-pad filtration could be washed with an organic
solvent to obtain the product.
1
(mp, H NMR spectrum, and elemental analysis).
Meth od B (Gr ign a r d ). A solution of EtMgBr (30.0 mL,
30.0 mmol, 1.0 M solution in THF) was added slowly to a
solution of 2a (1.70 g, 5.00 mmol) in toluene (20 mL) under
argon. The resulting mixture was stirred at room temperature
for 10 min. A sample of p-toluoyl chloride (2.00 mL, 15.0 mmol)
was added, and the mixture was stirred for 30 min. The
reaction mixture was poured into saturated aqueous NH4Cl
(100 mL) and ethyl acetate (100 mL). The organic layer was
washed (water and brine), dried (Na2SO4), and filtered. The
filtrate was concentrated to dryness. Treatment of the residue
with TEA (2.10 mL, 15.0 mmol) and Bu2SnCl2 (1.52 g, 5.00
mmol) in CH2Cl2 (10 mL) at room temperature for 15 min
followed by the standard purification technique (as described
in method A) afforded a pale yellow solid (1.93 g, 56%) with
satisfactory analytical data (mp, 1H NMR spectrum, and
elemental analysis).
Meth od C (Ben zoxa th ioliu m Sa lt Alk yla tion /Hyd r oly-
sis). A solution of 10c (3.14 g, 10.0 mmol) in THF (8 mL) was
treated with DBU (1.52 g, 10.0 mmol) at room temperature
for 3 min in a well-sealed round-bottom flask. A solution of
2a (1.70 g, 5.00 mmol) in THF (4 mL) was injected into the
reaction mixture, and the resulting mixture was stirred for
30 min. HgO (2.17 g, 10.0 mmol) and aqueous HBF4 (2.61 mL
of 48 wt% solution, 20.0 mmol) were added. The mixture was
stirred at room temperature for 3 h, and then 2 M aqueous
NaOH (5 mL) was added. The mixture was poured into
saturated aqueous NH4Cl, and CH2Cl2 was added. The organic
layer was washed (water and brine), dried (Na2SO4), and
filtered. The filtrate was concentrated to dryness. The residue
was filtered through a pad of silica [CH2Cl2, then CH2Cl2/ethyl
acetate (9:1)]. The eluant was concentrated. Treatment of the
residue with TEA (2.10 mL, 15.0 mmol) and Bu2SnCl2 (1.53
g, 5.00 mmol) in CH2Cl2 (10 mL) at room temperature for 1 h
Syn th esis of 1,4-Bis[d ibu tyl(5,10-d ih yd r o-1,9-(3,5-d i-
ter t-bu tylben zoyl)-5-d ip yr r in a to)tin (IV)]ben zen e (12). A
solution of EtMgBr (5.00 mL, 5.00 mmol, 1.0 M in THF) was
added slowly to a tap-water-cooled flask containing a suspen-
sion of 11 (183 mg, 0.500 mmol) in toluene (30 mL) under
argon. The resulting mixture was stirred at room temperature
for 30 min. A solution of 10e (632 mg, 2.50 mmol) in toluene
(3.0 mL) was added over 5 min, and the mixture was stirred
for 10 min. The reaction mixture was poured into saturated
aqueous NH4Cl (50 mL) and ethyl acetate (50 mL). The organic
layer was washed (water and brine), dried (Na2SO4), and
filtered. The filtrate was concentrated to dryness. Treatment
of the residue with TEA (367 µL, 2.63 mmol) and Bu2SnCl2
(303 mg, 1.00 mmol) in CH2Cl2 (20 mL) at room temperature
for 30 min followed by the standard purification (as described
in method A) afforded a pale blue solid (165 mg, 20%): mp >
1
270 °C; H NMR δ 0.66-0.76 (m, 12H), 1.04-1.76 (m, 96H),
5.55 (s, 2H), 6.19 (d, J ) 3.9 Hz, 4H), 7.01 (d, J ) 3.9 Hz, 4H),
7.14 (s, 4H), 7.59-7.62 (m, 4H), 7.69-7.72 (m, 8H); 13C NMR
δ 13.8, 13.9, 24.1, 25.4, 26.3, 26.5, 27.4, 27.5, 31.6, 35.2, 45.4,
115.3, 123.5, 124.0, 126.0, 128.5, 136.4, 137.3, 142.7, 151.1,
151.4, 185.9; FAB-MS obsd 1694.38, calcd 1694.84 (C100H134
-
N4O4Sn2). Anal. Calcd for C100H134N4O4Sn2: C, 70.92; H, 7.98;
N, 3.31. Found: C, 70.97; H, 7.98; N, 3.33.
Dibu tyl[5,10-d ih yd r o-1,9-bis(p-tolu oyl)-5-(4-(10,20-bis-
(3,5-d i-ter t-bu tylp h en yl)-15-m esityl)p or p h in -5-yl)p h en yl-
d ip yr r in a to]tin (IV) (14). A sample of 10c (66 mg, 0.21 mmol)
776 J . Org. Chem., Vol. 69, No. 3, 2004

Preparation of 1,9-Diacyldipyrromethanes
was added to a 5-mL round-bottomed flask containing a
magnetic stirring bar. The flask was sealed with a septum and
vented with a needle. Dry THF (1.0 mL) and DBU (32 mg,
0.21 mmol) were added, and then the venting needle was
removed. The solution was stirred at room temperature for 3
min, during which time the benzoxathiolium salt dissolved and
the solution turned pale yellow. A solution of 13 (54 mg, 53
µmol) in dry THF (1.0 mL) was injected into the reaction
vessel. After 1 h, the reaction vessel was opened to the
atmosphere, HgO (46 mg, 0.21 mmol) and aqueous HBF4 (55
µL of 48 wt% solution 0.42 mmol) were added, and the vessel
was sealed again. After 1 h, CH2Cl2 (3 mL) was added, the
mixture was transferred into a 20-mL vial, saturated aqueous
NH4Cl (4 mL) was added. The organic layer was separated
and washed with water, washed with brine, dried (Na2SO4),
and filtered. The filtrate was concentrated to dryness. The
residue was redissolved in CH2Cl2 (0.5 mL), and TEA (21 µL,
0.15 mmol) was added. A solution of Bu2SnCl2 (16 mg, 52 µmol)
in 0.5 mL of CH2Cl2 was added, and the mixture was stirred
for 2.5 h. The solution was diluted with hexanes (2 mL) and
chromatographed (silica, hexanes/CH2Cl2 containing 1% TEA).
The desired compound eluted as the second red band, yielding
10 mg of a purple solid. Fractions containing the impure
product were rechromatographed under the same conditions,
yielding an additional 3 mg of the pure title compound (total
equiv) in small portions with rapid stirring at room temper-
ature. TLC analysis after 2 h [silica, hexanes/ethyl acetate (3/
1)] indicated incomplete reduction. Therefore, an additional
amount of NaBH4 (303 mg, 8.00 mmol) was added in the same
manner. After another 2 h, TLC analysis showed complete
reduction of 6a . The reaction was quenched by slow addition
of saturated aqueous NH4Cl. The reaction mixture was
extracted with CH2Cl2, dried (K2CO3) and concentrated, af-
fording 3a -d iol as a slightly yellow foamlike solid. The freshly
prepared 3a -d iol was condensed with 1a (89 mg, 0.40 mmol)
in CH2Cl2 (160 mL) under catalysis with Yb(OTf)3 (317 mg,
0.512 mmol, 3.2 mM) at room temperature for 30 min. DDQ
(272 mg, 1.20 mmol) was added, and the reaction mixture was
stirred for 1 h at room temperature. The reaction mixture was
then neutralized with TEA and filtered through a pad of silica
(eluted with CH2Cl2). The first fraction was collected and
concentrated. The residue was suspended in methanol. The
suspension was sonicated and then filtered, affording a purple
solid (75 mg, 29%) with satisfactory analytical data (1H NMR
spectrum, UV-vis, LD-MS, fluorescence). The duplicate reac-
tion afforded a similar result (71 mg, 28%).
Ack n ow led gm en t. We thank Ms. Andrea Naranjo,
Mr. George Vandeveer, and Mr. Tashi Herzmark for
early technical assistance. This work was supported by
the NIH (GM36238). Mass spectra were obtained at the
Mass Spectrometry Laboratory for Biotechnology at
North Carolina State University. Partial funding for the
facility was obtained from the North Carolina Biotech-
nology Center and the NSF.
1
yield ) 13 mg, 17%); mp 230-232 °C (dec); H NMR δ -2.67
(s, 2H), 0.70-0.77 (m, 6H), 1.14-1.31 (m, 4H), 1.35-1.62 (m,
42H), 1.73-1.82 (m, 2H), 1.86 (s, 6H), 2.47 (s, 6H), 2.62 (s,
3H), 5.93 (s, 1H), 6.52 (d, J ) 3.9 Hz, 2H), 7.24-7.27 (m, 4H),
7.34 (d, J ) 8.0 Hz, 4H), 7.58 (d, J ) 8.4 Hz, 2H), 7.77-7.79
(m, 2H), 7.90 (d, J ) 8.0 Hz, 4H), 8.08-8.09 (m, 4H), 8.14 (d,
J ) 8.4 Hz, 2H), 8.69 (d, J ) 4.8 Hz, 2H), 8.83-8.86 (m, 6H);
13C NMR δ 13.9, 21.70, 21.89, 21.97, 24.23, 25.14, 26.29, 26.5,
27.6, 32.0, 35.3, 45.9, 115.6, 118.2, 119.7, 121.14, 121.29, 124.0,
126.7, 127.9, 129.36, 129.45, 130.28, 135.04, 135.28, 136.32,
137.83, 138.83, 139.62, 141.11, 141.27, 142.5, 143.9, 148.9,
151.7, 184.9; LD-MS obsd 1492.1; FAB-MS obsd 1493.7029 [(M
+ H)+], calcd 1493.7321 (C96H104N6O2Sn); λmax (toluene) 422,
486, 517, 550, 592, 649 nm.
Su p p or tin g In for m a tion Ava ila ble: A complete descrip-
tion of studies of improved methods for acylation of dipyr-
romethanes (Friedel-Crafts, benzoxathiolium); complete ex-
perimental section including characterization data for all new
compounds; X-ray data for 6a and 6b; and 1H NMR spectra
for selected compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
Dir ect P or p h yr in F or m a tion fr om 6a , Yield in g 5,15-
J O035622S
Bis(4-m eth ylp h en yl)-10,20-d ip h en ylp or p h yr in (15).44
A
solution of 6a (276 mg, 0.400 mmol) in dry THF/MeOH (15
mL, 10:1) was treated with NaBH4 (303 mg, 8.00 mmol, 20
(44) Littler, B. J .; Ciringh, Y.; Lindsey, J . S. J . Org. Chem. 1999,
64, 2864-2872.
J . Org. Chem, Vol. 69, No. 3, 2004 777