Masked imidazolyl-dipyrromethanes in the synthesis of imidazole-substituted porphyrins

Article abstract of DOI:10.1021/jo061461r

Imidazole-substituted metalloporphyrins are valuable for studies of self-assembly and for applications where water solubility is required. Rational syntheses of porphyrins bearing one or two imidazol-2-yl or imidazol-4-yl groups at the meso positions have been developed. The syntheses employ dipyrromethanes, 1-acyldipyrromethanes, and 1,9-diacyldipyrromethanes bearing an imidazole group at the 5-position. The polar, reactive imidazole unit was successfully masked by use of (1) the 2-(trimethylsilyl)ethoxymethyl (SEM) group at the imidazole pyrrolic nitrogen, and (2) a dialkylboron motif bound to the pyrrole of the dipyrromethane and coordinated to the imidazole imino nitrogen. The nonpolar nature of such doubly masked imidazolyl-dipyrromethanes facilitated handling. Selected masked dipyrromethanes were characterized by ¹¹B and ¹⁵N NMR spectroscopy. Five distinct methods were examined to obtain trans-A₂B₂-, trans-AB₂C-, and trans-AB-porphyrins. Each porphyrin contained one or two SEM-protected imidazole units. The SEM group could be removed with TBAF or HCl. Two zinc(II) porphyrins and a palladium(II) porphyrin bearing a single imidazole moiety were prepared and subjected to alkylation (with ethyl iodide, 1,3-propane sultone, or 1,4-butane sultone) to give water-soluble imidazolium-porphyrins. This work establishes the foundation for the rational synthesis of a variety of porphyrins containing imidazole units.

Full text of DOI:10.1021/jo061461r

Masked Imidazolyl-Dipyrromethanes in the Synthesis of
Imidazole-Substituted Porphyrins
Jayeeta Bhaumik, Zhen Yao, K. Eszter Borbas, Masahiko Taniguchi, and
Jonathan S. Lindsey*
Department of Chemistry, North Carolina State UniVersity, Raleigh, North Carolina 27695-8204
jlindsey@ncsu.edu
ReceiVed July 13, 2006
Imidazole-substituted metalloporphyrins are valuable for studies of self-assembly and for applications
where water solubility is required. Rational syntheses of porphyrins bearing one or two imidazol-2-yl or
imidazol-4-yl groups at the meso positions have been developed. The syntheses employ dipyrromethanes,
1-acyldipyrromethanes, and 1,9-diacyldipyrromethanes bearing an imidazole group at the 5-position. The
polar, reactive imidazole unit was successfully masked by use of (1) the 2-(trimethylsilyl)ethoxymethyl
(SEM) group at the imidazole pyrrolic nitrogen, and (2) a dialkylboron motif bound to the pyrrole of the
dipyrromethane and coordinated to the imidazole imino nitrogen. The nonpolar nature of such doubly
masked imidazolyl-dipyrromethanes facilitated handling. Selected masked dipyrromethanes were
characterized by 11B and 15N NMR spectroscopy. Five distinct methods were examined to obtain trans-
A2B2-, trans-AB2C-, and trans-AB-porphyrins. Each porphyrin contained one or two SEM-protected
imidazole units. The SEM group could be removed with TBAF or HCl. Two zinc(II) porphyrins and a
palladium(II) porphyrin bearing a single imidazole moiety were prepared and subjected to alkylation
(with ethyl iodide, 1,3-propane sultone, or 1,4-butane sultone) to give water-soluble imidazolium-
porphyrins. This work establishes the foundation for the rational synthesis of a variety of porphyrins
containing imidazole units.
Introduction
behavior3-5 and for DNA binding.6 Despite these promising
attributes, the methods for preparing imidazolyl porphyrins
remain poorly developed.
Porphyrins bearing four meso-imidazolyl groups have been
prepared by condensation of an imidazolecarboxaldehyde with
pyrrole via the Adler method.7,8 The similar reaction with
Imidazolyl-porphyrins are of widespread interest in materials
chemistry and the life sciences. An early impetus for preparing
imidazolyl-porphyrins stemmed from biomimicry studies of
hemoglobin,1 where an imidazole group occupies the apical site
of an iron porphyrin. Since then, a large number of porphyrins
have been prepared bearing imidazole units directly attached
to the porphyrin macrocycle. In the latter cases, the imidazole
group provides the basis for controlled self-assembly to give
multimeric architectures for use in light-harvesting studies.2
Alternatively, derivatization yields water-soluble imidazolium-
porphyrins that have been investigated for superoxide dismutase
(3) Kachadourian, R.; Menzeleev, R.; Agha, B.; Bocckino, S. B.; Day,
B. J. J. Chromatogr. B 2002, 767, 61-67.
(4) Kachadourian, R.; Johnson, C. A.; Min, E.; Spasojevic, I.; Day, B.
J. Biochem. Pharmacol. 2004, 67, 77-85.
(5) Batinic-Haberle, I.; Spasojevic, I.; Stevens, R. D.; Hambright, P.;
Neta, P.; Okado-Matsumoto, A.; Fridovich, I. Dalton Trans. 2004, 1696-
1702.
(6) Yamamoto, T.; Tjahjono, D. H.; Yoshioka, N.; Inoue, H. Bull. Chem.
Soc. Jpn. 2003, 76, 1947-1955.
(7) Milgrom, L. R.; Dempsey, P. J. F.; Yahioglu, G. Tetrahedron 1996,
52, 9877-9890.
(1) Collman, J. P. Acc. Chem. Res. 1977, 10, 265-272.
(2) Furutsu, D.; Satake, A.; Kobuke, Y. Inorg. Chem. 2005, 44, 4460-
4462.
10.1021/jo061461r CCC: $33.50 © 2006 American Chemical Society
Published on Web 10/20/2006
J. Org. Chem. 2006, 71, 8807-8817
8807

Bhaumik et al.
inclusion of a second aldehyde has been used in a statistical
synthesis of an A3B-porphyrin bearing one imidazole group.2,9
trans-AB-Porphyrins10 and trans-AB2C-porphyrins11-18 have
been prepared in a statistical approach by reaction of a
dipyrromethane, an imidazolecarboxaldehyde, and a second
aldehyde. The synthesis of trans-A2B2-porphyrins has been
achieved in a rational manner by reaction of a dipyrromethane
and an imidazolecarboxaldehyde.19-22 However, the yields of
trans-A2B2-porphyrins are typically quite low (in most cases
∼2%).19,20
imidazole-substituted A4-porphyrins, Milgrom investigated ben-
zyl or p-methoxybenzyl protecting groups for the imidazole
pyrrolic nitrogen.7 While promising, some difficulties were
encountered in deprotecting the corresponding porphyrins.
Despite the well-developed use of imidazole protecting groups
in protein chemistry (to protect the imidazole moiety of
histidine),27 the use of imidazole protecting groups has not been
further investigated in porphyrin chemistry.
In this paper, we report our studies aimed at developing
improved methods for manipulating imidazolyl-dipyrromethanes.
The SEM group has been examined to protect the imidazole
pyrrolic nitrogen, whereas dialkylboron complexes of imida-
zolyl-dipyrromethanes were investigated for masking the imino
nitrogen atom. The resulting masked dipyrromethanes and
1-acyldipyrromethanes have been used in five distinct routes
to porphyrins. Taken together, this work provides a substantial
improvement in methods for preparing porphyrins bearing one
or two imidazole units.
Several years ago we began studies aimed at the rational
synthesis of porphyrins bearing one nitrogen heterocyclic group
at the meso position. A given heterocyclic aldehyde (2-, 3-,
4-pyridinecarboxaldehyde, quinoline-3-carboxaldehyde, imida-
zole-2-carboxaldehyde, or uracil-5-carboxaldehyde) was con-
densed with pyrrole to afford the corresponding dipyrromethane,
which upon reaction with a dipyrromethane-dicarbinol gave
the respective A3B-porphyrin bearing a single heterocyclic
group. The yield of the imidazolyl-porphyrin was unacceptably
low (1.5%), whereas the other porphyrins (e.g., pyridyl, quinolyl,
uracil) were obtained in yields of 5-20%.23 Similarly, the
reaction of an imidazolyl-dipyrromethane and an aldehyde to
give a trans-A2B2-porphyrin also proceeded in low yield (3%).24
The incorporation of the imidazole unit in porphyrins presents
the following challenges: (1) imidazole-containing compounds
are polar and streak upon chromatography, and (2) the imidazole
nitrogens provide sites that function as a weak acid (pyrrolic
nitrogen) and weak base or nucleophile (imino nitrogen). Indeed,
the imidazole group in a dipyrromethane interferes with
1-acylation, thereby preventing access to dipyrromethane-1-
carbinols (which are valuable precursors to trans-A2B2-porphy-
rins).25,26 More generally, imidazolyl-dipyrromethanes afford
low yields of porphyrin upon reaction with a dipyrromethane-
1,9-dicarbinol. We considered that these problems might be
mitigated by use of protecting groups for the imidazole
nitrogens. In one of the earliest studies of the synthesis of
Results and Discussion
1. Development of Masked Imidazol-2-yl Compounds for
Use in Porphyrin Synthesis. A. Protecting the Imidazole
Pyrrolic Nitrogen. 5-(Imidazol-2-yl)dipyrromethane (1) has
been prepared by the solventless condensation of imidazole-2-
carboxaldehyde in pyrrole under reflux.23 However, the yield
was low (14%), and 1 was incompatible with subsequent
Grignard-mediated acylation of the dipyrromethane. The dif-
ficulties presented by the synthesis and derivatization of 1
prompted investigation of a variety of protecting group strate-
gies.
(8) Amaravathi, M.; Murthy, K. S. K.; Rao, M. K.; Reddy, B. S.
Tetrahedron Lett. 2001, 42, 6745-6747.
The imidazole protecting groups employed in peptide chem-
istry and related fields include trityl,28 2,4-dimethylpent-3-
yloxycarbonyl,29 2-adamantyloxymethyl,27 p-tosyl,30 and SEM31
groups. We considered the following in selecting a protecting
group: (1) methods of introduction and removal, (2) compat-
ibility with conditions employed in dipyrromethane preparation
and derivatization, (3) compatibility with conditions employed
in porphyrin formation, and (4) ease of purification via
crystallization or chromatography. The p-tosyl group appeared
attractive, but exploratory work indicated the p-tosyl-protected
imidazole-2-carboxaldehyde required extensive chromatography
for purification. Eventually we settled on use of the SEM group.
To mask the imidazole pyrrolic nitrogen with the SEM
group,31 we treated imidazole-2-carboxaldehyde with NaH
followed by SEMCl, which afforded the SEM-protected alde-
hyde 2 in 82% yield (Scheme 1). The condensation of aldehyde
2 with excess pyrrole at room temperature in the presence of
(9) Inaba, Y.; Kobuke, Y. Tetrahedron 2004, 60, 3097-3107.
(10) Yao, M.; Irie, T.; Ishida, N.; Inoue, H.; Yoshioka, N. Synth. Metals
2003, 137, 917-918.
(11) Nomoto, A.; Kobuke, Y. Chem. Commun. 2000, 1104-1105.
(12) Takahashi, R.; Kobuke, Y. J. Am. Chem. Soc. 2003, 125, 2372-
2373.
(13) Ikeda, C.; Satake, A.; Kobuke, Y. Org. Lett. 2003, 5, 4935-4938.
(14) Morikawa, S.; Ikeda, C.; Ogawa, K.; Kobuke, Y. Lett. Org. Chem.
2004, 1, 6-11.
(15) Kuramochi, Y.; Satake, A.; Kobuke, Y. J. Am. Chem. Soc. 2004,
126, 8668-8669.
(16) Kameyama, K.; Satake, A.; Kobuke, Y. Tetrahedron Lett. 2004,
45, 7617-7620.
(17) Ozeki, H.; Nomoto, A.; Ogawa, K.; Kobuke, Y.; Murakami, M.;
Hosoda, K.; Ohtani, M.; Nakashima, S.; Miyasaka, H.; Okada, T. Chem.s
Eur. J. 2004, 10, 6393-6401.
(18) Takahashi, R.; Kobuke, Y. J. Org. Chem. 2005, 70, 2745-2753.
(19) Kobuke, Y.; Miyaji, H. J. Am. Chem. Soc. 1994, 116, 4111-4112.
(20) Kobuke, Y.; Miyaji, H. Bull. Chem. Soc. Jpn. 1996, 69, 3563-
3569.
(21) Tjahjono, D. H.; Yamamoto, T.; Ichimoto, S.; Yoshioka, N.; Inoue,
H. J. Chem. Soc., Perkin Trans. 1 2000, 3077-3081.
(22) Ikeda, C.; Fujiwara, E.; Satake, A.; Kobuke, Y. Chem. Commun.
2003, 616-617.
(23) Gryko, D.; Lindsey, J. S. J. Org. Chem. 2000, 65, 2249-2252.
(24) Nagata, N.; Kugimiya, S.-I.; Kobuke, Y. Chem. Commun. 2000,
1389-1390.
(25) Geier, G. R., III; Callinan, J. B.; Rao, P. D.; Lindsey, J. S. J.
Porphyrins Phthalocyanines 2001, 5, 810-823.
(26) Rao, P. D.; Littler, B. J.; Geier, G. R., III; Lindsey, J. S. J. Org.
Chem. 2000, 65, 1084-1092.
(27) Okada, Y.; Wang, J.; Yamamoto, T.; Takashi, Y; Mu, Y. Chem.
Pharm. Bull. 1997, 45, 452-456.
(28) Eichholtz, T.; de Bont, D. B. A.; de Widt, J.; Liskamp, R. M. J.;
Ploegh, H. L. J. Biol. Chem. 1993, 268, 1982-1986.
(29) Karlstro¨m, A.; Unde´n, A. Chem. Commun. 1996, 959-960.
(30) Beltra´n, M.; Pedroso, E.; Grandas, A. Tetrahedron Lett. 1998, 39,
4115-4118.
(31) Whitten, J. P.; Matthews, D. P.; McCarthy, J. R. J. Org. Chem.
1986, 51, 1891-1894.
8808 J. Org. Chem., Vol. 71, No. 23, 2006

Masked Imidazolyl Dipyrromethanes
SCHEME 1
SCHEME 2
MgBr2 (0.5 equiv)32 afforded the protected imidazolyl-dipyr-
romethane 3 as a sticky solid in 30% yield following chroma-
tography. The catalyst InCl3 (0.3 equiv) also could be employed,
but MgBr2 afforded a cleaner reaction mixture.
B. Masking the Imidazole Imino Nitrogen by Dialkylboron
Complexation. The imidazolyl-dipyrromethane 3 streaks upon
chromatographic purification. Earlier we found that 1-acyl-
dipyrromethanes, which also streak on chromatographic media,
react with dialkylboron triflates to form dialkylboron complexes
that are hydrophobic and are readily handled.33 With the same
objective of achieving a hydrophobic complex, we treated
dipyrromethane 3 with excess Bu2B-OTf, which afforded the
dibutylboron complex Bu2B-3 as a viscous oil in 81% yield
(Scheme 1). Similarly, treatment of 3 with 9-BBN-OTf afforded
9-BBN-3 as a dark red solid in 58% yield. In these complexes,
the boron is presumably bonded to the pyrrole and coordinated
to the imidazole imino nitrogen. Owing to both the dialkylboron
complex and the SEM group, the two imidazole nitrogens are
fully masked. As expected, Bu2B-3 and 9-BBN-3 proved to be
of low polarity and chromatographed without streaking near the
solvent front.
9-BBN-OTf was unsuccessful. The streamlined synthesis pro-
vides ready access to Bu2B-3.
The standard method for 1-acylation entails treatment of a
dipyrromethane with EtMgBr followed by reaction with a
2-pyridyl thioester (Mukaiyama reagent). Application of this
approach with dipyrromethane 3 and Mukaiyama reagent 434
afforded a crude mixture of the 1-acyldipyrromethane. However,
the resulting 1-acyldipyrromethane (5) was very polar and
streaked extensively upon attempted chromatography. Treatment
of the crude mixture with 9-BBN-OTf (2 equiv) afforded (9-
BBN)2-5 as a nonpolar, crystalline solid in 25% yield (Scheme
2).
A similar synthesis using Bu2B-OTf gave the dibutylboron
complex (Bu2B)2-5 in 23% yield, which also was nonpolar and
readily isolated. An alternative route to (Bu2B)2-5 from 3
entailed reversal of the order of acylation and dialkylboron
complexation. Thus, a sample of the dibutylboron complex of
Bu2B-3 was treated with EtMgBr (2 equiv) and Mukaiyama
reagent 4 followed by TEA and Bu2B-OTf (2 equiv). The
desired bis(dibutylboron) complex (Bu2B)2-5 was obtained in
11% yield (Scheme 2).
We also investigated dialkylboron complexation as a means
of purifying the crude reaction mixture upon dipyrromethane
formation. After the reaction of 2 and pyrrole in the presence
of MgBr2 (0.5 equiv), the crude reaction mixture was freed of
pyrrole and then treated with TEA and Bu2B-OTf (3 equiv),
affording Bu2B-3 in 30% overall yield. The similar use of
The dibutylboron complex (9-BBN)2-5 was characterized in
detail. According to 1H NMR spectroscopy, FAB-MS, and
elemental analysis, the product contains two 9-BBN moieties.
Confirmation of the structure was achieved by X-ray structural
(32) Laha, J. K.; Dhanalekshmi, S.; Taniguchi, M.; Ambroise, A.;
Lindsey, J. S. Org. Proc. Res. DeV. 2003, 7, 799-812.
(33) Muthukumaran, K.; Ptaszek, M.; Noll, B.; Scheidt, W. R.; Lindsey,
J. S. J. Org. Chem. 2004, 69, 5354-5364.
(34) Zaidi, S. H. H.; Muthukumaran, K.; Tamaru, S.-I.; Lindsey, J. S. J.
Org. Chem. 2004, 69, 8356-8365.
J. Org. Chem, Vol. 71, No. 23, 2006 8809

Bhaumik et al.
SCHEME 3
analysis (see Supporting Information). One 9-BBN unit is bound
to the pyrrolic nitrogen atom and coordinated to the R-carbonyl
moiety, forming a cyclic coplanar array of five atoms. The
second 9-BBN unit is bound to the other pyrrolic nitrogen atom
and coordinated to the pyridyl nitrogen of the imidazole unit,
forming a cyclic array of six atoms. The C-O bond (1.302 Å)
is longer than that in 2-benzoylpyrrole (1.234 Å),35 suggesting
some enolate character, whereas the C-C bond between the
carbonyl carbon and the R-carbon of the acylpyrrole (1.404 Å)
is significantly shorter than that in 2-benzoylpyrrole (1.446 Å),35
suggesting partial multiple bond character. The B-N coordinate
bond length (1.640 Å) is longer than the B-O coordinate bond
length (1.557 Å). The presence of the three protecting groups
effectively masks all polar and/or hydrogen-bonding sites and
thereby renders the imidazolyl-dipyrromethane a rather hy-
drophobic complex.
2. Synthesis of Imidazol-2-yl Porphyrins. A. trans-A2B2-
Porphyrin Containing Two Imidazole Groups. Our goal was
to employ the boron complex of 1-acyldipyrromethane (R2B)2-5
in the synthesis of trans-A2B2 imidazolyl-porphyrin (SEM)2-
6. The established methods33 for working with dialkylboron
complexes of acyldipyrromethanes entail (1) decomplexation
in refluxing 1-pentanol to give the acyldipyrromethane, which
is then reduced with NaBH4 to give the corresponding dipyr-
romethanecarbinol, or (2) direct reduction of the acyldipyr-
romethane-dialkylboron complex with NaBH4, whereupon
decomplexation occurs in situ yielding the dipyrromethan-
ecarbinol.
SCHEME 4
Attempts to reduce dibutylboron-complex (Bu2B)2-5 with
NaBH4, even with 100 equiv for ∼5 h, were not successful.
Alternatively, (Bu2B)2-5 was subjected to refluxing 1-pentanol
for 7 h followed by reduction with NaBH4, and the crude
mixture was employed under conditions for porphyrin formation,
but porphyrin (SEM)2-6 was not observed. However, reduction
of (9-BBN)2-5 with excess NaBH4 (50 equiv) afforded the
corresponding carbinol. The carbinol was then treated with Yb-
(OTf)3 (3.2 mM) to carry out the self-condensation. Subsequent
oxidation with DDQ afforded (SEM)2-6 in 12% yield (Scheme
3). Laser desorption mass spectrometry (LD-MS) analysis of
the crude reaction mixture did not show any porphyrins derived
from scrambling processes. TLC analysis of the product
(SEM)2-6 showed two porphyrin components, as expected for
the two atropisomers. After column chromatography, only the
more polar atropisomer was isolated in pure form. In accord
with the literature,19 the more polar atropisomer was assigned
the cis-configuration, where both SEM groups are positioned
on the same plane of the porphyrin.
B. trans-AB2C-Porphyrin Containing One Imidazole Group.
A trans-AB2C-porphyrin bearing one imidazole group was
prepared as shown in Scheme 4. The tin complex of a 1,9-
diacyldipyrromethane (7)36 was reduced using NaBH4 to give
the corresponding dicarbinol, which was condensed with imi-
dazol-2-yl dipyrromethane 3 in the presence of Yb(OTf)3. The
progress of the reaction was monitored by absorption spectros-
copy. After 1 h, DDQ was added to give porphyrin SEM-8 in
17% yield.
owing to their compact size.37 Two trans-AB-porphyrins were
sought, one bearing an imidazole unit and a bioconjugatable
handle, and a benchmark compound bearing an imidazole unit
and a phenyl substituent. A new synthetic route to trans-AB-
C. trans-AB-Porphyrins Containing One Imidazole Group.
trans-AB-Porphyrins are valuable for life sciences applications
(35) English, R. B.; McGillivray, G.; Smal, E. Acta Crystallogr. 1980,
B36, 1136-1141.
(36) Tamaru, S.-I.; Yu, L.; Youngblood, W. J.; Muthukumaran, K.;
Taniguchi, M.; Lindsey, J. S. J. Org. Chem. 2004, 69, 765-777.
(37) Borbas, K. E.; Mroz, P.; Hamblin, M. R.; Lindsey, J. S. Bioconjugate
Chem. 2006, 17, 638-653.
8810 J. Org. Chem., Vol. 71, No. 23, 2006

Masked Imidazolyl Dipyrromethanes
porphyrins relies on access to 1,9-diformyldipyrromethanes.38
The required dipyrromethane 10a32 or 10b (a known com-
pound39 with limited characterization data) was prepared by
reaction of excess pyrrole with the respective aldehyde 9a or
9b (a known compound39 with limited characterization data;
see Supporting Information for a new preparation). Vilsmeier
formylation of the dipyrromethanes gave 11a40 and 11b. The
reaction of 1,9-diformyldipyrromethane 11a with n-propylamine
in THF gave the corresponding bis(iminomethyl)dipyrromethane.
The latter was combined with imidazolyl-dipyrromethane 3
in ethanol containing Zn(OAc)2, which upon refluxing in the
presence of air for 13 h afforded a mixture of porphyrin and
chlorin species. Treatment of the mixture with DDQ (1.5 equiv)
at room temperature converted chlorin to porphyrin, affording
SEM-Zn12 in 28% overall yield (Scheme 5). Similar treatment
of 1,9-diformyldipyrromethane 11b and 3 in hot toluene (85
°C) rather than refluxing ethanol gave porphyrin SEM-Zn13
in 23% yield.
SCHEME 5
D. Palladium Porphyrin (trans-AB) Containing One Imi-
dazole Group. Palladium porphyrins are valuable as phospho-
rescent markers41 and for photodynamic therapy applications.42
Following a new route to palladium porphyrins,43 a mixture of
1,9-diformyldipyrromethane 11a, dipyrromethane 3, KOH, and
Pd(CH3CN)2Cl2 in EtOH was heated at reflux exposed to air
for 2 h. Removal of the solvent followed by chromatography
afforded the compact trans-AB palladium porphyrin SEM-Pd12
in 32% yield (Scheme 6).
3. Development and Application of Masked Imidazol-4-
yl Compounds in the Synthesis of Imidazol-4-yl Porphyrins.
Treatment of 4(5)-imidazolecarboxaldehyde with NaH followed
1
by SEMCl afforded a mixture of two isomers (1:1 ratio by H
NMR analysis) of the SEM-protected imidazolecarboxaldehyde
14 (14a and 14b) in 88% overall yield (Scheme 7). The mixture
of isomers of 14 was reacted with excess pyrrole in the presence
of InCl3. With 0.1 equiv of InCl3, a mixture of a dipyrromethane
and an unreacted aldehyde (by TLC and 1H NMR analysis) was
obtained, which was difficult to separate. In the presence of
1.0 equiv of InCl3, a mixture of two isomers of the protected
imidazolyl-dipyrromethane (15a, 15b) was obtained. Two
approaches were investigated to handle this mixture. (1)
Chromatography afforded the less polar isomer (15a) in 16%
yield upon small-scale reaction (on the basis of the 1:1 mixture
of 14a:14b), or 8% yield at larger scale. The chromatography
was difficult because 15a and 15b each streaked and exhibited
similar chromatographic retention factors. The more polar
regioisomer was not isolated in pure form. (2) Alternatively,
the mixture of 15a and 15b (from the dipyrromethane synthesis
without purification) was treated with dibutylboron triflate in
the presence of TEA. The dibutylboron complex Bu2B-15a was
obtained in 5% yield from aldehyde 14a (two steps: dipyr-
romethane synthesis and boron complexation), whereas attempts
to use 9-BBN-OTf resulted in decomposition of the correspond-
ing 9-BBN complex upon chromatography.
Dipyrromethane 15a was treated with EtMgBr followed by
Mukaiyama reagent 4 in the standard approach for 1-acylation.
The crude mixture was treated directly with TEA and 9-BBN-
OTf33 to give (9-BBN)2-16 in 34% yield (Scheme 8). Reduction
of (9-BBN)2-16 with NaBH4 gave the corresponding carbinol,
which underwent self-condensation upon exposure to Yb(OTf)3.
Subsequent oxidation with DDQ afforded (SEM)2-17 in 15%
yield. LD-MS analysis of the crude reaction mixture did not
show the presence of any scrambled porphyrins. Alternatively,
Bu2B-15a was condensed with p-tolualdehyde in the presence
of TFA to yield the bis(SEM-imidazolyl)porphyrin (SEM)2-
17, which requires in situ decomplexation of the dibutylboron
(38) Taniguchi, M.; Balakumar, A.; Fan, D.; McDowell, B. E.; Lindsey,
J. S. J. Porphyrins Phthalocyanines 2005, 9, 554-574.
(39) Marecek, V.; Janchenova, H.; Stibor, I.; Budka, J. J. Electroanal.
Chem. 2005, 575, 293-299.
(40) Bru¨ckner, C.; Posakony, J. J.; Johnson, C. K.; Boyle, R. W.; James,
B. R.; Dolphin, D. J. Porphyrins Phthalocyanines 1998, 2, 455-465.
(41) Papkovsky, D. B.; O’Riordan, T.; Soini, A. Biochem. Soc. Trans.
2000, 28, 74-77.
(42) Wiehe, A.; Stollberg, H.; Runge, S.; Paul, A.; Senge, M. O.; Ro¨der,
B. J. Porphyrins Phthalocyanines 2001, 5, 853-860.
(43) Sharada, D. S.; Muresan, A. Z.; Muthukumaran, K.; Lindsey, J. S.
J. Org. Chem. 2005, 70, 3500-3510.
J. Org. Chem, Vol. 71, No. 23, 2006 8811

Bhaumik et al.
SCHEME 6
SCHEME 8
SCHEME 7
romethanes prepared herein. The results are summarized in
Table 1. The assignments are summarized in the Supporting
Information.
Proton-coupled gHMBC (gradient heteronuclear multiple
bond correlation) analysis for SEM-protected imidazole-2-
carboxaldehyde 2 showed two peaks (-84.3 and -195.0 ppm)
corresponding to the imidazole imino nitrogen and SEM-
protected imidazole pyrrolic nitrogen, respectively. Upon proton-
coupled gHSQC (gradient heteronuclear single quantum coher-
ence) analysis, dipyrromethane 3 showed a single peak at
-227.7 ppm corresponding to the two identical pyrrolic
nitrogens. Proton-coupled gHMBC analysis for dipyrromethane
3 showed peaks at -119.2, -205.3, and -227.7 ppm, attributed
motif. A small amount of scrambling (Level 1)44 was observed
upon examination of the crude reaction mixture. The pure trans-
A2B2-porphyrin (SEM)2-17 was isolated by chromatography in
26% yield.
4. 15N NMR and 11B NMR Spectroscopic Studies. Thomp-
son and co-workers recently described the use of 15N NMR
spectroscopy for the identification of dipyrromethane com-
pounds.45 We utilized this powerful method to characterize the
imidazolyl and pyrrolic nitrogen atoms in the various dipyr-
(44) Littler, B. J.; Ciringh, Y.; Lindsey, J. S. J. Org. Chem. 1999, 64,
2864-2872.
(45) Wood, T. E.; Berno, B.; Beshara, C. S.; Thompson, A. J. Org. Chem.
2006, 71, 2964-2971.
8812 J. Org. Chem., Vol. 71, No. 23, 2006

Masked Imidazolyl Dipyrromethanes
TABLE 1. 15N NMR Spectroscopic Data for Imidazole-Containing
Compoundsa
TABLE 2. 11B NMR Spectroscopic Data for Boron Complexes of
Dipyrromethanesa
δ
15N NMR Resonances (ppm)b
gHMBC
δ
11B NMR Resonances (ppm)
compound
gHSQC
compound
N-BR2
O-BR2
2
3
c
-227.7
-226.4
-227.7
c
-84.3, -195.0
Bu2B-3
9-BBN-3
(9-BBN)2-5
(Bu2B)2-5
(9-BBN)2-16b
1.94
1.93
-0.04
1.08
-119.2, -205.3, -227.7
9-BBN-3d
Bu2B-3
-162.1, -193.0, -199.4, -226.4
-167.9, -198.5, -202.5, -227.7
-146.8, -160.5, -193.7, -199.5
-154.0, -167.2, -200.3, -202.3
-165.1, -197.2, -228.5
12.65
13.24
12.06
(9-BBN)2-5d
(Bu2B)2-5
Bu2B-15ae
(9-BBN)2-16
1.44
c
a 11B NMR spectroscopy was performed in THF-d8 at 50 °C. b Data were
obtained at room temperature.
-228.4
c
-146.1, -160.5, -194.9, -198.5
a 15N NMR spectroscopic data were collected with 0.2 M samples in
THF-d8 at room temperature. b Chemical shifts were standardized with
respect to 1.0 M MeNO2 (δ 0.0 ppm). c Not applicable. d A 0.1 M sample
was used. e The resonance from the boron-complexed pyrrolic nitrogen was
not observed.
Table 2. In general, imidazole coordination results in an upfield
resonance near that of the standard BF3‚O(Et)2, whereas acyl
oxygen coordination results in a slight downfield shift near 12-
13 ppm.
5. Metalation of Imidazole-Substituted Porphyrins. We
examined the synthesis of chelates of imidazolyl-porphyrins
containing magnesium(II), zinc(II), palladium(II), and indium-
(III), all of which are of potential interest for photodynamic
therapeutic applications. In addition, imidazolyl-porphyrins are
known to form diverse assemblies upon chelation of metals that
accept a fifth ligand (e.g., zinc, magnesium).48 The chelates were
formed either by metalation of a free base imidazolyl-porphyrin
or by formation of the metalloporphyrin in the porphyrin-
forming process. Regardless of method, each imidazole unit was
masked with an SEM group. Zinc insertion was achieved by
treatment of an SEM-protected imidazolyl-porphyrin with zinc
acetate (Schemes 4 and 8).49 Metalation as part of the porphyrin-
forming process was achieved in refluxing ethanol with zinc
acetate (Scheme 5) or PdCl2(CH3CN)2 (Scheme 6). Metalation
with magnesium (MgI2/N,N-diisopropylethylamine)50 or indium
(InCl3) was carried out at the microscale level with selected
porphyrins, affording metalloporphyrins for exploratory studies
(Supporting Information).
In our studies, each zinc chelate gave an aggregated sample
in a nonpolar solvent, such as CH2Cl2 [trans-A2B2-porphyrin
(SEM)2-Zn17; trans-AB2C-porphyrin SEM-Zn8; and trans-
AB-porphyrins SEM-Zn12 and SEM-Zn13]. The hallmark of
aggregation in each case was the presence of a split Soret band
(415 ( 5, 434 ( 5 nm). Each such zinc porphyrin gave a single
sharp Soret band (∼425 nm) in a polar solvent, such as
methanol. By contrast, palladium porphyrin SEM-Pd12 showed
a sharp Soret band regardless of solvent polarity, as expected
due to the lack of interaction between the tetracoordinated
palladium and imidazole species.
to the imidazole imino nitrogen, SEM-protected imidazole
pyrrolic nitrogen, and the pyrrole nitrogen, respectively.46
The dialkylboron-complexed imidazolyl-dipyrromethane
Bu2B-3, Bu2B-15a, or 9-BBN-3 also showed only one peak in
the gHSQC experiment, owing to the single NH in each
molecule. The dialkylboron-complexed dipyrromethanes 9-BBN-3
and Bu2B-3 each showed four peaks upon gHMBC analysis.
(Compound Bu2B-15a exhibited only three peaks as the
resonance from the boron-complexed pyrrole nitrogen was not
observed.) For example, 9-BBN-3 revealed four resonances at
distinct chemical shifts (-162.1, -193.0, -199.4, -226.4 ppm)
as expected owing to the distinct environment of the imidazole
imino nitrogen, the boron-complexed pyrrole nitrogen, the SEM-
protected imidazole pyrrolic nitrogen, and the free pyrrole
nitrogen, respectively. In general, dialkylboron complexation
of the imidazole imino nitrogen caused an upfield chemical shift
(∆δ ) -43 ppm for 9-BBN; -49 ppm for Bu2B) with respect
to dipyrromethane 3 (-119.2 ppm). On the other hand,
dialkylborylation of the pyrrole nitrogen caused deshielding (∆δ
) 35 ppm for 9-BBN; 29 ppm for Bu2B) compared to the free
pyrrole nitrogen in 3 (-227.7 ppm).
The bis(dialkylboron) complexes of 1-acyl-5-imidazolyl-
dipyrromethanes [(9-BBN)2-5, (Bu2B)2-5, and (9-BBN)2-16]
typically exhibited four distinct resonances. Examination of the
spectra indicate a downfield chemical shift (∆δ ) 74-82 ppm)
for the pyrrole nitrogen complexed by an oxygen-coordinated
boron moiety versus that of dipyrromethane 3 (-227.7 ppm),
which can be attributed to the combined electron-withdrawing
effect of the alkylboron moiety and the acyl group. In summary,
15N NMR chemical shift values were quite useful for structural
comparison of compounds with multiple nitrogen atoms.
We also carried out 11B NMR studies of selected dialkylboron
complexes of the dipyrromethanes. 11B NMR spectroscopy of
(9-BBN)2-5 showed two peaks (δ 12.65 and -0.04 ppm) for
the two boron moieties relative to the 11B standard (BF3‚O(Et)2
at 0 ppm). The two peaks are consistent with coordination of
one boron atom to the carbonyl oxygen and the other boron
atom to the imidazole imino nitrogen, respectively. By com-
parison, Bu2B-3 gave only one peak (1.94 ppm), to be compared
with N-(9-borabicyclo[3.3.1]non-9-yl)pyrrole, which lacks in-
tramolecular coordination and resonates downfield at 59.9
ppm.47 The results of the 11B NMR studies are summarized in
6. Synthesis of Water-Soluble trans-AB Imidazolium-
Porphyrins. Dialkylation of an imidazole unit forms a charged
species, which provides an attractive means for imparting water
solubility to imidazolyl-porphyrins for life sciences applica-
tions. Conditions for the dialkylation were surveyed using
porphyrins bearing a single imidazole motif. The porphyrins
examined were Zn12, Pd12, and 13, prepared from SEM-Pd12,
SEM-Zn12, and SEM-Zn13, respectively, upon treatment with
(47) Wrackmeyer, B.; Schwarze, B. J. Organomet. Chem. 1997, 534,
207-211.
(48) (a) Satake, A.; Kobuke, Y. Tetrahedron 2005, 61, 13-41. (b)
Kobuke, Y.; Ogawa, K. Bull. Chem. Soc. Jpn. 2003, 76, 689-708.
(49) Carcel, C. M.; Laha, J. K.; Loewe, R. S.; Thamyongkit, P.;
Schweikart, K.-H.; Misra, V.; Bocian, D. F.; Lindsey, J. S. J. Org. Chem.
2004, 69, 6739-6750.
(46) Berger, S.; Braun, S.; Kalinowski, H.-O. NMR Spectroscopy of the
Non-Metallic Elements; John Wiley & Sons Ltd.: Toronto, 1997; pp 111-
318.
(50) O’Shea, D. F.; Miller, M. A.; Matsueda, H.; Lindsey, J. S. Inorg.
Chem. 1996, 35, 7325-7338.
J. Org. Chem, Vol. 71, No. 23, 2006 8813

Bhaumik et al.
TBAF in refluxing THF or concentrated HCl in refluxing EtOH.
Porphyrin 13 containing a carboxylate ester was metalated
affording Zn13. Derivatives of Zn12 and Pd12 can serve as
benchmark molecules to determine the hydrophilicity imparted
upon the core porphyrin by dialkylation and as models for the
optimization of the alkylation conditions. Zn13 can also be
utilized in the synthesis of water-soluble derivatives and, upon
hydrolysis of the carboxylate ester group, attached to biomol-
ecules for life sciences applications.
Supporting Information). Porphyrin Zn12-Et2 was only weakly
soluble in water (10-4 M), whereas Zn12-S2 displayed excellent
water solubility (∼5 mM). It is noteworthy that both Zn12-Et2
and Zn12-S2 were soluble and gave sharp absorption bands in
CH2Cl2, a solvent where the presence of a free imidazole
nitrogen results in aggregation of the zinc porphyrin. The
aqueous solubility of Zn12-S2 is only slightly lower than that
of Zn18a or Zn18b (∼10 to 20 mM).37 Replacement of the
alkylsulfonate units with more stable analogues (e.g., quaternary
amines) may result in the retention of the aqueous solubility
while eliminating the problem caused by the hydrolysis of the
alkylsulfonate moiety, thus giving porphyrins that are potentially
useful for life sciences applications.
Conditions for the alkylation were surveyed by scanning
various alkylating agents (ethyl iodide, 1,3-propane sultone, 1,4-
butane sultone), bases (NaOMe, NaH), solvents (methanol,
DMF, acetone, neat), reaction temperatures (ambient, g80 °C,
microwave), and reaction times (5 min to 3 days). Key results
of the alkylation optimization study are provided below, and
additional information is provided in the Supporting Information.
Alkylations carried out with ethyl iodide on Zn12, Pd12, or
Zn13 in each case resulted in good yields of the dialkylated
product Zn12-Et2, Pd12-Et2, or Zn13-Et2, which was easily
purified upon silica column chromatography. The identity of
the pure material was validated by mass spectrometry (LD-MS,
FAB-MS), 1H NMR spectroscopy, and absorption spectroscopy.
Alkylation of Zn12 with 1,4-butane sultone gave a mixture of
mono- and dialkylated products (Zn12-S and Zn12-S2, respec-
tively), along with large amounts of the sultone reagent.
Conventional aqueous-organic workup (water/ethyl acetate)
yielded the monoalkylated Zn12-S in the organic layer (as
shown by 1H NMR spectroscopy, ESI-MS, and reversed-phase
HPLC). Concentration of the aqueous layer and purification of
the residue with preparative reversed-phase chromatography
yielded the dialkylated porphyrin Zn12-S2 devoid of 1,4-butane
sultone reagent. Porphyrin Zn12-S2 was unstable in aqueous
solution and rapidly dealkylated to give Zn12-S as shown by
reversed-phase HPLC and ESI-MS. The instability is presum-
ably caused by intramolecular nucleophilic attack of the
sulfonate on the methylene unit attached to the imidazolium-
nitrogen (an analogous process has been reported with free
nucleophiles and alkylimidazoles51). The instability of the
alkylsulfonates is easily rationalized, but nonetheless was
somewhat surprising, given that N-sulfobutyl imidazolium
species have been prepared for studies as ionic liquids.52 The
motivation for preparing the alkylsulfonic acid derivatives came
from our prior studies of swallowtail porphyrins (e.g., Zn18)
wherein the termini of the swallowtail motif bear ionizable
groups.37 Such porphyrins have high solubility in water.
Outlook
Imidazolyl-porphyrins containing one or two imidazole units
have been prepared by employing two masking agents for the
imidazole nitrogens. The SEM group blocks the imidazole
pyrrolic nitrogen, whereas the dialkylboron group blocks the
imidazole imino nitrogen, thereby affording nonpolar imidazole
species that are readily handled. The use of masked imidazole
species (versus the unprotected imidazole unit) enables the
rational synthesis of imidazolyl-porphyrins with yields more
comparable to those where simple aryl substituents are em-
ployed. Five distinct routes have been successfully employed
for forming imidazolyl-porphyrins. The zinc(II) and palladium-
(II) chelates of imidazolium-porphyrins may facilitate com-
parative studies of efficacy in photodynamic therapy. Taken
together, facile access to imidazolyl porphyrins and imidazolium
porphyrins should facilitate the design of porphyrin-based
molecular architectures for various applications in supramo-
lecular chemistry and the life sciences.
Experimental Section
Synthesis of an SEM-Protected Imidazolecarboxaldehyde:
1-[2-(Trimethylsilyl)ethoxymethyl]imidazole-2-carboxalde-
hyde (2).31 Following a general procedure,31 a sample of NaH (60%
dispersion in mineral oil, 0.800 g, 20 mmol) was washed with
hexanes (2 × 25 mL) under argon. The flask was charged with
dry DMF (30 mL), and 2-imidazolecarboxaldehyde (1.92 g, 20.0
mmol) was added in small portions. After stirring at room
temperature for 1.5 h, the reaction mixture was treated dropwise
with SEMCl (3.53 g, 21.2 mmol). The reaction mixture became
slightly warm upon addition of SEMCl. After stirring for 2.5 h,
the reaction mixture was quenched with water and extracted with
ethyl acetate. The organic extract was washed, dried (Na2SO4), and
1
concentrated to give a yellow oil (3.7 g, 82%): H NMR (300 MHz)
δ -0.12 (s, 9H), 0.83 (t, J ) 8.4 Hz, 2H), 3.48 (t, J ) 8.4 Hz,
2H), 5.70 (s, 2H), 7.26-7.28 (m, 1H), 7.32-7.34 (m, 1H), 9.75
(s, 1H); 13C NMR δ -1.4, 17.8, 66.9, 75.7, 125.5, 132.0, 143.5,
182.3; 15N NMR δ -84.3, -195.0 (gHMBC); FAB-MS obsd
227.1221, calcd 227.1216 [(M + H)+, M ) C10H18N2O2Si].
Synthesis of an SEM-Protected Imidazolyl-Dipyrrometh-
ane: 5-[1-(2-(Trimethylsilyl)ethoxymethyl)imidazol-2-yl]dipyr-
romethane (3). Following a general procedure32 with modification,
a mixture of pyrrole (104 mL, 1.50 mol) and aldehyde 2 (3.39 g,
15.0 mmol) was stirred and degassed with argon for 10 min. A
sample of MgBr2 (1.38 g, 7.50 mmol) was added, and the mixture
was stirred under argon at room temperature for 1.5 h. The resulting
dark yellow mixture was treated with NaOH (3.00 g, 75.0 mmol,
20-40 mesh beads). After stirring for 45 min, the resulting light
brown mixture was filtered. The filtrate was concentrated under
The solubility of the dialkylated imidazolium-porphyrins was
assessed in water (Table 3) and in four organic solvents (see
(51) Glenn, A. G.; Jones, P. B. Tetrahedron Lett. 2004, 45, 6967-6969.
(52) (a) Yoshizawa, M.; Ohno, H. Ionics 2002, 8, 267-271. (b) Cole,
A. C.; Jensen, J. L.; Ntai, I.; Tran, K. L. T.; Weaver, K. J.; Forbes, D. C.;
Davis, J. H., Jr. J. Am. Chem. Soc. 2002, 124, 5962-5963. (c) Yoshizawa,
M.; Hirao, M.; Ito-Akita, K.; Ohno, H. J. Mater. Chem. 2001, 11, 1057-
1062.
8814 J. Org. Chem., Vol. 71, No. 23, 2006

Masked Imidazolyl Dipyrromethanes
TABLE 3. Dialkylation of Imidazolyl Porphyrins
a The sample exhibited a split Soret band indicative of aggregation.
vacuum (0.2 mmHg). Traces of pyrrole were removed by thrice
treatment of the crude viscous residue in the evaporation flask with
hexanes (50 mL) followed by removal of the volatile components.
The resulting light brown viscous liquid was purified by column
chromatography [silica, CH2Cl2 f CH2Cl2/ethyl acetate (4:1)] to
afford a brown viscous liquid (1.55 g, 30.2%): 1H NMR δ -0.03
(s, 9H), 0.89 (t, J ) 8.0 Hz, 2H), 3.45 (t, J ) 8.0 Hz, 2H), 5.27 (s,
2H), 5.73 (s, 1H), 5.96-6.00 (m, 2H), 6.09-6.11 (m, 2H), 6.66-
6.70 (m, 2H), 6.92-6.98 (m, 1H), 7.03-7.05 (m, 1H), 9.14-9.24
(br, 2H); 13C NMR δ -1.4, 17.9, 35.4, 66.5, 75.1. 106.2, 108.2,
117.7, 119.9, 127.6, 129.9, 148.0; 15N NMR δ -227.7 (gHSQC);
-119.2, -205.3, -227.7 (gHMBC); FAB-MS obsd 343.1960, calcd
343.1954 [(M + H)+, M ) C18H26N4OSi].
Boron Complexation of an Imidazolyl-Dipyrromethane: 10-
(Dibutylboryl)-5-[1-(2-(trimethylsilyl)ethoxymethyl)imidazol-2-
yl]dipyrromethane (Bu2B-3). A solution of 3 (0.22 g, 0.64 mmol)
in CH2Cl2 (1.3 mL) was treated with TEA (0.22 mL, 1.6 mmol)
and Bu2B-OTf (1.3 mL, 1.3 mmol, 1.0 M in CH2Cl2). After stirring
for 1 h at room temperature, the mixture was poured onto a pad of
silica, which was eluted with CH2Cl2. The product eluted as a fast
moving red band, which upon concentration afforded a dark red
viscous liquid (0.24 g, 81%): 1H NMR δ -0.03 (s, 9H), 0.41-
0.52 (m, 4H), 0.71-0.76 (m, 16H), 3.41-3.50 (m, 2H), 5.21 (d, J
) 10.0 Hz, 1H), 5.45 (d, J ) 10.0 Hz, 1H), 5.79 (s, 1H), 5.94-
5.98 (m, 1H), 6.01-6.03 (m, 1H), 6.07-6.09 (m, 1H), 6.23-6.25
(m, 1H), 6.61-6.63 (m, 1H), 6.76-6.78 (m, 1H), 7.11-7.13 (m,
2H), 7.94-8.10 (br, 1H); 13C NMR δ -1.1, 14.3, 18.0, 26.45, 26.60,
27.4, 28.7, 33.9, 67.4, 76.3, 104.6, 106.3, 107.9, 108.6, 118.4, 120.3,
121.2, 121.7, 144.9, resonances were not observed from two of
the quaternary carbons in the pyrrolic rings and two of the carbon
atoms adjacent to the boron atoms; 11B NMR δ 1.94; 15N NMR δ
-227.7 (gHSQC); δ -167.9, -198.5, -202.5, -227.7 (gHMBC);
FAB-MS obsd 467.3377, calcd 467.3372 [(M + H)+, M ) C26H43-
BN4OSi].
Boron Complexation as a Purification Aid for Imidazolyl-
Dipyrromethanes: Direct Conversion of 2 f Bu2B-3. Following
general procedures32,33 with modification, a degassed mixture of
pyrrole (10.5 mL, 0.151 mol) and aldehyde 2 (0.34 g, 1.5 mmol)
was treated with MgBr2 (0.14 g, 0.76 mmol). The mixture was
stirred under argon at room temperature for 1.5 h. NaOH (0.30 g,
7.5 mmol, 20-40 mesh beads) was added to quench the reaction.
Stirring for 1 h afforded a light brown mixture. The mixture was
filtered. The filtrate was concentrated. Traces of pyrrole were
removed by thrice treatment of the crude viscous residue in the
evaporation flask with hexanes (50 mL) followed by removal of
the volatile components. The resulting crude dipyrromethane was
dissolved in CH2Cl2 (3.0 mL) and treated with TEA (0.76 mL, 5.4
mmol) and Bu2B-OTf (4.5 mL, 4.5 mmol, 1.0 M in CH2Cl2). The
mixture was stirred at room temperature. After 1 h, the mixture
was poured onto a pad of silica, which was eluted with CH2Cl2.
The product eluted as a fast moving red band, which upon
concentration afforded a dark red viscous solid (0.21 g, 30%).
Characterization data (1H NMR, 13C NMR, UV-vis) were con-
sistent with the values reported above.
Boron Complexation of
a 1-Acyl-5-imidazolyl-dipyr-
romethane: 10,11-Bis(9-borabicyclo[3.3.1]non-9-yl)-1-(4-meth-
ylbenzoyl)-5-[1-(2-(trimethylsilyl)ethoxymethyl)imidazol-2-yl]-
dipyrromethane [(9-BBN)2-5]. Following a general procedure33
with slight modification, a solution of EtMgBr (9.50 mL, 9.5 mmol,
1.0 M in THF) was added slowly to a solution of 3 (1.63 g, 4.75
mmol) in THF (4.8 mL) under argon. The resulting mixture was
stirred at room temperature for 10 min and then cooled to -78 °C.
J. Org. Chem, Vol. 71, No. 23, 2006 8815

Bhaumik et al.
A solution of 4 (1.09 g, 4.75 mmol) in THF (4.8 mL) was added.
The reaction mixture was stirred at -78 °C for 10 min and then
allowed to warm to room temperature over the course of 1.5 h.
The reaction was quenched by addition of saturated aqueous NH4-
Cl (20 mL). The mixture was extracted with ethyl acetate. The
organic layer was washed (water and brine), dried (Na2SO4), and
filtered. The filtrate was concentrated. The crude product (a reddish
orange oil) thus obtained was dissolved in CH2Cl2 (9.5 mL) and
treated with TEA (1.59 mL, 11.4 mmol) and 9-BBN-OTf (19 mL,
10 mmol, 0.5 M in hexanes) with stirring at room temperature.
After 1 h, the mixture was poured onto a pad of silica (3 × 15
cm), which was eluted with CH2Cl2. The fast moving yellow band
was concentrated. Further chromatography [silica, hexanes/CH2-
Cl2 (1:1)] afforded a yellow solid (846 mg, 25%): mp 170-172
°C; 1H NMR δ -0.07 (s, 9H), 0.74-0.93 (m, 6H), 1.50-2.43 (m,
24H), 2.52 (s, 3H), 3.16-3.27 (m, 2H), 4.35 (d, J ) 10.0 Hz, 1H),
4.62 (d, J ) 10.0 Hz, 1H), 5.57 (s, 1H), 6.01-6.04 (m, 1H), 6.21-
6.26 (m, 1H), 6.52-6.55 (m, 1H), 7.01-7.06 (m, 1H), 7.34-7.37
(m, 1H), 7.41-7.43 (m, 3H), 7.66-7.69 (m, 1H), 8.19 (d, J ) 8.4
Hz, 2H); 13C NMR δ -1.5, 18.1, 21.5, 22.1, 23.47, 23.63, 23.8,
25.0, 25.7, 26.2, 30.1, 31.01, 31.05, 31.7, 34.2, 34.41, 34.44, 34.8,
39.8, 67.2, 77.2 (overlapped with CHCl3), 105.8, 107.4, 117.3,
118.1, 121.3, 124.3, 124.5, 127.7, 129.95, 130.09, 130.13, 134.7,
145.9, 146.4, 147.4, 175.7, resonances from the two of the
bridgehead carbons in the 9-BBN rings were not observed; 11B
NMR δ -0.04, 12.65; 15N NMR δ -146.8, -160.5, -193.7,
-199.5 (gHMBC). Anal. Calcd for C42H58B2N4O2Si: C, 72.00; H
8.34; N, 8.00. Found: C, 71.97; H, 8.32; N, 7.90; FAB-MS obsd
700.4572, calcd 700.4515 (C42H58B2N4O2Si); λabs (THF) 297, 369
nm.
The entire reaction mixture was filtered through a pad of alumina
[5 × 10 cm, CH2Cl2/MeOH (19:1 f 9:1)] until the eluent was no
longer dark. Removal of solvent gave a dark solid, which upon
column chromatography [silica, 3 × 20 cm, CH2Cl2/ethyl acetate
(9:1 f 1:1)] gave a purple solid (24 mg, 12%): 1H NMR (300
MHz) δ -2.86 to -2.78 (br, 2H), -0.42 (s, 9H), -0.38 (s, 9H),
0.35-0.45 (m, 4H), 2.72 (s, 6H), 2.84-2.96 (m, 4H), 5.40 (s, 2H),
5.11 (s, 2H), 7.58 (d, J ) 8.1 Hz, 4H), 7.66-7.77 (m, 4H), 8.00-
8.16 (m, 4H), 8.77-8.85 (m, 4H), 8.92 (d, J ) 4.5 Hz, 4H); LD-
MS obsd 883.0; FAB-MS obsd 883.4335, calcd 883.4300 [(M +
H)+, M ) C52H58N8O2Si2]; λabs 419, 516, 552, 589 nm; λem 655,
720 nm.
Synthesis of
a trans-AB2C-Porphyrin (One Imidazole
Group): 5,15-Bis(4-methylphenyl)-10-[1-(2-(trimethylsilyl)-
ethoxymethyl)imidazol-2-yl]porphyrin (SEM-8). Following gen-
eral procedures25 for the condensation of a dipyrromethane and a
dipyrromethane-1,9-dicarbinol with slight modification, a sample
of NaBH4 (0.568 g, 15.0 mmol, 50 molar equiv) was slowly added
in small portions to a stirred solution of 7 (0.184 g, 0.300 mmol)
in THF/MeOH (5:1, 12 mL). The reaction was monitored by TLC
analysis (silica, CH2Cl2). After 4.5 h, the reaction was quenched
by slow addition of saturated aqueous NH4Cl (60 mL). The reaction
mixture was extracted with CH2Cl2, and the organic layer was dried
(K2CO3) and concentrated to afford the dicarbinol. The dicarbinol
(∼0.3 mmol) was immediately dissolved in CH2Cl2 (120 mL), then
3 (103 mg, 0.300 mmol) and Yb(OTf)3 (0.242 g, 0.390 mmol, 3.2
mM) were added. The mixture slowly darkened. After 1 h, the
spectroscopic yield of porphyrin had essentially leveled off,
whereupon DDQ (0.204 g, 0.900 mmol) was added. The mixture
was stirred at room temperature for 1 h. TEA (0.11 mL, 0.78 mmol)
was added, and the entire reaction mixture was concentrated. The
residue was chromatographed [silica, 3 × 18 cm, CH2Cl2/ethyl
acetate (1:1) containing 1% TEA] to give a purple solid (35 mg,
17%): 1H NMR δ -3.01 to -2.99 (br, 2H), -0.41 (s, 9H), -0.39
(t, J ) 8.0 Hz, 2H), 2.72 (s, 6H), 2.86 (t, J ) 8.0 Hz, 2H), 5.04 (s,
2H), 7.59 (d, J ) 8.0 Hz, 4H), 7.68-7.69 (m, 1H), 7.72-7.73 (m,
1H), 8.08-8.15 (m, 4H), 8.81 (d, J ) 8.0 Hz, 2H), 8.97 (d, J )
4.8 Hz, 2H), 9.05 (d, J ) 4.8 Hz, 2H), 9.35 (d, J ) 4.8 Hz, 2H),
10.28 (s, 1H); LD-MS obsd 686.8; FAB-MS obsd 687.3288, calcd
687.3268 [(M + H)+, M ) C43H42N6OSi]; λabs 414, 510, 582 nm;
λem 645, 710 nm.
Synthesis of a Zinc(II)-trans-AB-Porphyrin (One Imidazole
Group): Zn(II)-5-Phenyl-10-[1-(2-(trimethylsilyl)ethoxymethyl)-
imidazol-2-yl]porphyrin (SEM-Zn12). Following a general
procedure38 with slight modification, a solution of 1,9-diformyl-
dipyrromethane 11a (56 mg, 0.20 mmol) and n-propylamine (0.04
mL, 0.5 mmol) in THF (1 mL) was stirred at room temperature for
1 h. After removal of the excess n-propylamine and THF under
vacuum, the residue and dipyrromethane 3 (69 mg, 0.20 mmol)
were dissolved in ethanol (20 mL). The mixture was then treated
with Zn(OAc)2 (0.367 g, 2.00 mmol) and refluxed open to the air
for 13 h. After removing the solvent, the residue was chromato-
graphed [silica, CH2Cl2 f CH2Cl2/ethyl acetate (4:1)] to afford a
dark purple solid (24 mg, 19%): 1H NMR (300 MHz, CD2Cl2) δ
-0.81 (s, 9H), -0.40 (t, J ) 7.8 Hz, 2H), 1.55-1.61 (m, 2H),
1.91 (s, 1H), 3.16 (s, 2H), 5.54 (d, J ) 3.9 Hz, 2H), 5.76 (s, 1H),
7.86-8.02 (m, 3H), 8.27 (d, J ) 6.9 Hz, 1H), 8.77 (d, J ) 6.9 Hz,
1H), 8.83 (d, J ) 3.9 Hz, 2H), 9.24 (d, J ) 3.9 Hz, 2H), 9.51 (d,
J ) 3.9 Hz, 2H), 10.23 (s, 2H); 13C NMR (CD2Cl2, 300 MHz) δ
-2.3, 16.8, 65.8, 74.7, 106.3, 116.3, 121.9, 126.7, 126.9, 127.6,
131.4, 132.5, 132.9 (a resonance from one of the â-carbons was
overlapped), 135.1, 135.3, 143.7, 145.5, 149.2, 149.6, 149.9. 150.3;
LD-MS obsd 644.3; FAB-MS obsd 644.1725, calcd 644.1698
(C35H32N6OSiZn); λabs 402, 422, 551 nm; λem 595, 645 nm.
Synthesis of a Palladium(II)-trans-AB-Porphyrin (One Imi-
dazole Group): Pd(II)-5-Phenyl-10-[1-(2-(trimethylsilyl)ethoxy-
methyl)imidazol-2-yl]porphyrin (SEM-Pd12). Following a gen-
eral procedure,43 samples of 1,9-diformyldipyrromethane 11a (14
mg, 0.050 mmol), dipyrromethane 3 (17 mg, 0.049 mmol), KOH
1-Acylation of an Imidazolyl-Dipyrromethane Boron Com-
plex: Bu2B-3 f (Bu2B)25. Following a general procedure,33
a
solution of EtMgBr (1.40 mL, 1.40 mmol, 1.0 M in THF) was added
slowly to a solution of Bu2B-3 (0.25 g, 0.54 mmol) in THF (0.60
mL) under argon. The resulting mixture was stirred at room
temperature for 10 min and then cooled to -78 °C. A solution of
4 (0.15 g, 0.65 mmol) in THF (0.60 mL) was added. The reaction
mixture was stirred at -78 °C for 10 min and then allowed to warm
to room temperature with stirring for 3 h. The reaction mixture
was treated with half-saturated aqueous NH4Cl and ethyl acetate.
The organic extract was washed (saturated aqueous NaHCO3 and
brine), dried (Na2SO4), and filtered. The filtrate was concentrated.
The crude product thus obtained was dissolved in CH2Cl2 (1.1 mL)
and treated with TEA (0.18 mL, 1.3 mmol) and Bu2B-OTf (1.1
mL, 1.1 mmol, 1.0 M in CH2Cl2) with stirring at room temperature.
After 1 h, the mixture was concentrated and chromatographed
[silica, hexanes/CH2Cl2 (1:1) f CH2Cl2] affording a reddish orange
viscous liquid (42 mg, 11%). Characterization data (1H NMR, 13
C
NMR) were consistent with the values reported in the Supporting
Information.
Synthesis of
a trans-A2B2-Porphyrin (Two Imidazole
Groups): 5,15-Bis(4-methylphenyl)-10,20-bis[1-(2-(trimethyl-
silyl)ethoxymethyl)imidazol-2-yl]porphyrin [(SEM)2-6]. Follow-
ing general procedures25,33 for the self-condensation of
a
dipyrromethane-1-carbinol with slight modification, a sample of
NaBH4 (0.95 g, 25 mmol, 50 molar equiv) was slowly added in
small portions to a stirred solution of (9-BBN)2-5 (0.35 g, 0.50
mmol) at 0 °C in THF/MeOH (3:1, 20 mL). The reaction was
monitored by TLC analysis (silica, CH2Cl2). After 1.5 h, the reaction
mixture was poured into a stirred solution of saturated aqueous
NH4Cl and ethyl acetate (1:1, 100 mL). The organic layer was
washed with water, dried (Na2SO4), and concentrated to afford the
carbinol as an orange oil. The carbinol (∼0.5 mmol) was im-
mediately dissolved in CH2Cl2 (100 mL), and Yb(OTf)3 (0.20 g,
0.32 mmol, 3.2 mM) was added. The mixture slowly darkened,
and the reaction was monitored by absorption spectroscopy. After
4 h, the spectroscopic yield of porphyrin had essentially leveled
off, whereupon DDQ (0.17 g, 0.75 mmol) was added. After stirring
at room temperature for 1 h, TEA (89 µL, 0.64 mmol) was added.
8816 J. Org. Chem., Vol. 71, No. 23, 2006

Masked Imidazolyl Dipyrromethanes
(14 mg, 0.25 mmol), and Pd(CH3CN)2Cl2 (8.0 mg, 0.031 mmol)
were placed in a flask fitted with a condenser exposed to air. Ethanol
(0.5 mL) was added, and the mixture was stirred and heated to
reflux for 2 h. The solvent was evaporated. The residue was
chromatographed [silica, toluene/THF (1:1)] to afford an orange
solid (11 mg, 32%): 1H NMR (CD2Cl2, 300 MHz) δ -0.38 (s,
9H), 0.40 (t, J ) 8.1 Hz, 2H), 2.99 (t, J ) 8.1 Hz, 2H), 5.10 (s,
2H), 7.70-7.74 (m, 2H), 7.76-7.85 (m, 3H), 8.10-8.23 (m, 2H),
8.93 (d, J ) 4.8 Hz, 2H), 9.00 (d, J ) 4.8 Hz, 2H), 9.31 (d, J )
4.8 Hz, 2H), 9.36 (d, J ) 4.8 Hz, 2H), 10.32 (s, 2H); LD-MS obsd
686.0; FAB-MS obsd 686.1476, calcd 686.1442 (C35H32N6OSiPd);
λabs (toluene) 405, 515, 547 nm; λem (toluene) 550, 600 nm.
Dialkylation of an Imidazolyl-Metalloporphyrin: Zn(II)-5-
(1,3-Diethylimidazol-2-ium)-10-phenylporphyrin (Zn12-Et2). Fol-
lowing a general procedure,31 porphyrin SEM-Zn12 (26 mg, 0.040
mmol) was treated with TBAF (1.0 mL, 1.0 mmol, 1.0 M in THF),
and the reaction mixture was heated to reflux for 26 h. Porphyrin
Zn12 had poor solubility in organic solvents (e.g., CH2Cl2, ethyl
acetate, THF, and DMF). The porphyrin residue showed a single
component by TLC and the expected molecule ion peak by LD-
Zinc Metalation of an Imidazolyl-Porphyrin: Zn(II)-5,15-
Bis(4-methylphenyl)-10,20-bis[1-(2-(trimethylsilyl)ethoxymeth-
yl)imidazol-4-yl]porphyrin [(SEM)2-Zn17]. Following a general
procedure,49 a solution of porphyrin (SEM)2-17 (12 mg, 14 µmol)
in CHCl3/MeOH (4 mL, 3:1) was treated with Zn(OAc)2‚2H2O (77
mg, 0.35 mmol, 25 equiv). The reaction mixture was stirred at room
temperature for 12 h. The reaction was quenched with water and
extracted with ethyl acetate. The organic layer was dried (Na2SO4),
concentrated, and chromatographed [silica, CH2Cl2 f CH2Cl2/ethyl
acetate (1:1)] to afford a greenish purple solid (12 mg, 91%): 1H
NMR (300 MHz) δ -0.13 (s, 9H), 0.17 (s, 9H), 0.56 (t, J ) 7.8
Hz, 2H), 1.17 (t, J ) 7.8 Hz, 2H), 2.49 (s, 1H), 2.64 (t, J ) 7.8
Hz, 2H), 2.85 (s, 6H), 3.93 (t, J ) 7.8 Hz, 2H), 4.27 (s, 2H), 5.67
(s, 1H), 5.72 (s, 2H), 5.91 (d, J ) 4.2 Hz, 2H), 7.55 (d, J ) 6.9
Hz, 2H), 7.71 (d, J ) 6.9 Hz, 2H), 7.88 (s, 1H), 7.99 (d, J ) 6.9
Hz, 2H), 8.22 (s, 1H), 8.30 (d, J ) 4.2 Hz, 2H), 8.57 (d, J ) 6.9
Hz, 2H), 9.02 (d, J ) 4.2 Hz, 2H), 9.22-9.34 (d, J ) 4.2 Hz, 2H);
LD-MS obsd 945.2; FAB-MS obsd 944.3358, calcd 944.3356
(C52H56N8O2Si2Zn); λabs (THF) 417, 433, 572 nm; λem (CH2Cl2)
620, 675 nm.
1
MS analysis, but did not afford a satisfactory H NMR spectrum
(CD3OD, DMF-d7). The sample was washed repeatedly with water
to remove excess TBAF and then used directly in derivatization
reactions. The entire sample of Zn12 (∼0.04 mmol) was treated
with EtI (0.100 mL, 1.25 mmol) in DMF (0.4 mL), and the reaction
mixture was heated at 60 °C for 2 days. Because LD-MS of the
crude sample showed the formation of the demetalated species along
with the desired product Zn12-Et2, the crude material was treated
with Zn(OAc)2‚2H2O (0.22 g, 1.0 mmol). The resulting mixture
was heated at 60 °C for 12 h. After removal of DMF under high
vacuum, the crude mixture was purified by column chromatography
[silica, CH2Cl2/MeOH (99:1 f 3:1)] to afford a purple solid (10
mg, 36%, assuming an iodide counterion): 1H NMR (300 MHz,
CD3OD) δ 0.90 (t, J ) 6.6 Hz, 6H), 3.96-4.01 (m, 4H), 7.71-
7.73 (m, 3H), 8.12 (d, J ) 6.6 Hz, 2H), 8.26-8.30 (m, 2H), 8.72
(d, J ) 4.5 Hz, 2H), 8.94 (d, J ) 4.5 Hz, 2H), 9.35 (d, J ) 4.5 Hz,
2H), 9.52 (d, J ) 4.5 Hz, 2H), 10.33 (s, 2H); LD-MS obsd 571.0;
FAB-MS obsd 571.1609, calcd 571.1589 (C33H27N6Zn, lacking
counterion); λabs (MeOH) 413, 544, 578 nm; λabs (water at pH 8)
408, 540, 574 nm; λem (MeOH) 540, 640 nm.
Acknowledgment. This work was supported by the NIH
(GM36238). Mass spectra were obtained at the Mass Spec-
trometry Laboratory for Biotechnology at North Carolina State
University. Partial funding for the facility was obtained from
the North Carolina Biotechnology Center and the NSF. We
thank the State of North Carolina for funding the purchase of
the Apex2 diffractometer, and the NSF for funding the purchase
of the NMR spectrometers.
Supporting Information Available: Survey of conditions for
dialkylation of imidazole-substituted porphyrins; solubility test for
imidazolium-porphyrins; experimental section; description of NMR
studies; X-ray data for (9-BBN)2-5; and spectral data for selected
compounds. This material is available free of charge via the Internet
at http://pubs.acs.org.
JO061461R
J. Org. Chem, Vol. 71, No. 23, 2006 8817