Investigation of the scope of a new route to ABCD-bilanes and ABCD-porphyrins

Article abstract of DOI:10.1021/jo8010396

(Chemical Equation Presented) A new route to bilanes and porphyrins bearing four distinct meso substituents has been studied to elucidate the scope and gain entry to previously inaccessible compounds. The route entails (i) synthesis of a 1-bromo-19-acylbi

Full text of DOI:10.1021/jo8010396

Investigation of the Scope of a New Route to ABCD-Bilanes and
ABCD-Porphyrins
Dilek Kiper Dogutan and Jonathan S. Lindsey*
Department of Chemistry, North Carolina State UniVersity, Raleigh, North Carolina 27695-8204
jlindsey@ncsu.edu
ReceiVed May 14, 2008
A new route to bilanes and porphyrins bearing four distinct meso substituents has been studied to elucidate
the scope and gain entry to previously inaccessible compounds. The route entails (i) synthesis of a 1-bromo-
19-acylbilane by acid-catalyzed condensation of a 1-acyldipyrromethane and a 9-bromodipyrromethane-
1-carbinol and (ii) intramolecular cyclization of the 1-bromo-19-acylbilane in the presence of a metal
salt (MgBr2, 3 mol equiv) and a non-nucleophilic base (DBU, 10 mol equiv) in a noncoordinating solvent
(toluene) at 115 °C exposed to air to afford the corresponding magnesium(II) porphyrin. In this study,
two sets of bilanes were initially prepared to explore substituent effects. In the first set, all bilanes vary
only in the nature of the substituent at the 10-position. In the second set, all bilanes vary only in the
nature of the substituent attached to the acyl unit (the 20-position). The substituents examined at the 10-
and 20-positions include alkyl, aryl (electron-rich, electron-deficient, hindered), heteroaryl, ester, or no
substituent (-H). The bilanes were obtained in 35-87% yield, and the target porphyrins in up to 60%
yield. Further study of the scope focused on bilanes and porphyrins bearing three heterocyclic substituents
(o-, m-, p-pyridyl) or four alkyl groups (ethyl, propyl, butyl, pentyl), in which case microwave irradiation
was used for the porphyrin-forming step. Altogether, 17 bilanes and 19 porphyrins were prepared and
characterized. In summary, the new route provides access to meso-substituted bilanes and porphyrins for
which access is limited via other methods.
Introduction
fragments thereof to form undesired macrocycles containing
distinct patterns or combinations of substituents.4–8) The chief
limitations of this “2 + 2” method reside in the macrocycle-
forming step: the reaction is carried out in dilute solution
(2.5-25 mM reactants), the yield is low (20-30%), dichlo-
romethane is typically used as the solvent, and an added
chemical oxidant (DDQ) is employed for conversion of the
porphyrinogen to the porphyrin. In addition, certain types of
substituents afford poor results (e.g., alkyl,2 heterocyclic,2 no
Porphyrins bearing multiple substituents in distinct patterns
are valuable constituents in biomimetic and materials chemistry.
One route to porphyrins bearing four different meso substituents
(i.e., ABCD-porphyrins) relies on the condensation of an ABC-
dipyrromethane-1,9-dicarbinol and a D-dipyrromethane followed
by oxidation of the resulting porphyrinogen.1–3 The reaction is
compatible with a variety of substituents, and proceeds without
detectable scrambling in many cases. (Scrambling refers to the
cleavage of pyrromethane moieties and recombination of
(4) Littler, B. J.; Ciringh, Y.; Lindsey, J. S. J. Org. Chem. 1999, 64, 2864–
2872.
(5) Geier, G. R., III; Littler, B. J.; Lindsey, J. S. J. Chem. Soc., Perkin Trans.
2 2001, 701–711.
(6) Geier, G. R., III; Littler, B. J.; Lindsey, J. S. J. Chem. Soc., Perkin Trans.
2 2001, 712–718.
(7) Geier, G. R., III; Callinan, J. B.; Rao, P. D.; Lindsey, J. S. J. Porphyrins
Phthalocyanines 2001, 5, 810–823.
(8) Geier, G. R., III; Lindsey, J. S. Tetrahedron 2004, 60, 11435–11444.
(1) Lee, C.-H.; Li, F.; Iwamoto, K.; Dadok, J.; Bothner-By, A. A.; Lindsey,
J. S. Tetrahedron 1995, 51, 11645–11672.
(2) Rao, P. D.; Dhanalekshmi, S.; Littler, B. J.; Lindsey, J. S. J. Org. Chem.
2000, 65, 7323–7344.
(3) Zaidi, S. H. H.; Fico, R. M., Jr.; Lindsey, J. S. Org. Process Res. DeV.
2006, 10, 118–134.
6728 J. Org. Chem. 2008, 73, 6728–6742
10.1021/jo8010396 CCC: $40.75 2008 American Chemical Society
Published on Web 08/07/2008

ABCD-Bilanes and ABCD-Porphyrins
substituent9,10). An alternative route relies on treatment of an
intact porphyrin with nucleophiles (e.g., organolithiums) fol-
lowed by oxidation to form the porphyrin bearing distinct
patterns of substituents.11
SCHEME 1
We recently developed a new strategy for the synthesis of
ABCD-porphyrins that relies on two key reactions: (1) acid-
catalyzed condensation of an AB-substituted 1-bromo-dipyr-
romethane-9-carbinol (I) and a CD-substituted 1-acyldipyr-
romethane (II) to give the corresponding 19-acyl-1-bromobilane
(III), and (2) cyclization of the bilane (III) in the presence of
a non-nucleophilic base (DBU), a noncoordinating solvent
(toluene), and a metal reagent (MgBr2) at 115 °C exposed to
air. In the one case examined, cyclization to give the ABCD-
porphyrin IV proceeded in 65% yield (Scheme 1).12
The “porphyrins via bilanes” strategy has several attractive
features: (i) no detectable scrambling at any stage of the
synthesis, (ii) good yield (up to 60%) at high concentration (100
mM) for the macrocycle-forming step, (iii) synthesis of the
porphyrin in a relatively short period of time (e.g., <1 week),
(iv) no added chemical oxidant for porphyrin formation, (v)
magnesium porphyrins as the products, which easily undergo
demetalation, and (vi) facile chromatographic purification. Our
chief focus in developing this approach has been to broaden
access to porphyrins, yet the accompanying entre´e to meso-
substituted bilanes may be of comparable value.
The reaction conditions for the intramolecular cyclization of
a 19-acyl-1-bromobilane also have been applied to the conden-
sation of two 1-acyldipyrromethane molecules to give the
corresponding trans-A2B2-porphyrin without formation of an
isolable bilane (Scheme 2). Upon examination of a wide variety
of 1-acyldipyrromethanes,13 the reaction conditions were found
to be particularly well-suited to the synthesis of porphyrins that
bear less than four meso substituents (e.g., trans-A2-porphyrins).
The limiting example of such sparsely substituted porphyrins
entails the condensation of two 1-formyldipyrromethane mol-
ecules to give porphine (all meso-substituents ) H).14 The
reaction conditions also were well-suited to the presence of
pyridyl groups, which enabled the synthesis of a variety of novel
porphyrins bearing pyridyl groups via rational (e.g., trans-A2B2-,
trans-A2-porphyrin) or statistical (e.g., cis-A2-, cis-AB-, A-
porphyrin) approaches. Greater structural diversity was not
achievable owing to the use of 1-acyldipyrromethanes (i.e.,
ABCD-porphyrins were not accessible), however, and the
reaction conditions were poorly compatible with alkyl substit-
uents (e.g., trans-A2B2-porphyrins bearing four alkyl groups
could not be prepared).
SCHEME 2
The prior study of the new methodology for the intramo-
lecular cyclization of a 19-acyl-1-bromobilane did not examine
the scope of application.12 In the study described herein, we
investigated the scope of substituents that can be introduced to
ABCD-bilanes and the corresponding ABCD-porphyrins. The
groups of interest include alkyl chains, aryl units with electron-
withdrawing or electron-releasing groups, bulky substituents,
heterocycles, and no substituent (-H). Elucidating the type of
substituents that could be tolerated at the 10- and 20-positions
(R10, R20) was of most immediate interest because such sites
engage in reaction to form the bilane and porphyrin, respectively.
The R10 substituent derives from the 1-bromodipyrromethane-
9-carbinol (I); this substituent must tolerate acylation of the
dipyrromethane, reduction to the R-carbinol, and acid-catalyzed
condensation to give the bilane. The R20 substituent is not
involved in bilane formation but resides at the R-position where
carbon-carbon bond formation must occur in the cyclization
(9) Fan, D.; Taniguchi, M.; Yao, Z.; Dhanalekshmi, S.; Lindsey, J. S.
Tetrahedron 2005, 61, 10291–10302.
(10) Taniguchi, M.; Balakumar, A.; Fan, D.; McDowell, B. E.; Lindsey, J. S.
J. Porphyrins Phthalocyanines 2005, 9, 554–574.
(11) Senge, M. O. Acc. Chem. Res. 2005, 38, 733–743.
(12) Dogutan, D. K.; Zaidi, S. H. H.; Thamyongkit, P.; Lindsey, J. S. J.
Org. Chem. 2007, 72, 7701–7714.
(13) Dogutan, D. K.; Ptaszek, M.; Lindsey, J. S. J. Org. Chem. 2008, 73,
6187–6201.
(14) Dogutan, D. K.; Ptaszek, M.; Lindsey, J. S. J. Org. Chem. 2007, 72,
5008–5011.
J. Org. Chem. Vol. 73, No. 17, 2008 6729

Dogutan and Lindsey
CHART 1
to give the porphyrin (IV) under magnesium-mediated, oxidative
conditions. The substituents at positions 5 and 15 (R5, R15) are
also of interest; however, studies of numerous porphyrin-forming
reactions indicate that there is greater latitude for diverse
substituents at the center of dipyrromethane moieties than at
the reacting R-positions.2
The paper is divided into three parts. In part I, we describe
the synthesis of 1-bromo-9-acyldipyrromethanes and 1-acyl-
dipyrromethanes, and their elaboration to the corresponding
bilanes under acid-catalyzed condensation. Part II describes the
one-flask conversion of the 1-bromo-19-acylbilanes to the
corresponding ABCD-porphyrins. In part III, the findings from
the prior sections are applied in the synthesis of two types of
porphyrins: (i) porphyrins bearing three pyridyl groups and (ii)
tetraalkylporphyrins. The study reveals information concerning
the types of meso-substituted bilanes and porphyrins that can
be synthesized via this new methodology.
Results and Discussion
I. Synthesis of Bilanes. The groups chosen to explore the
scope of the methodology include alkyl (pentyl), electron-
withdrawing (pentafluorophenyl), electron-releasing (4-meth-
oxyphenyl), heterocyclic (4-pyridyl), bulky (mesityl), alkyl ester
(3-methoxy-3-oxopropyl), and no substituent (-H). In this study,
two sets of bilanes were prepared. In the first set, all bilanes
vary only at the 10-position, whereas in the second set, all
bilanes vary only at the 20-position. Such variation is achieved
by condensation of a series of 1-bromodipyrromethane-9-
carbinols with a 1-acyldipyrromethane. The invariant (5-, 15-)
substituents are identical with that of the benchmark bilane 1a
(vide infra), namely phenyl and 4-tert-butylphenyl, whereas
4-methylphenyl (10-position) or 4-ethylphenyl (20-position) is
swapped out in bilane set 1 or 2, respectively. The two sets of
bilanes (1, 2) and the corresponding magnesium porphyrins
(MgP-1, MgP-2) are shown in Chart 1.
A. Preparation of Dipyrromethane Species. Established
routes were followed to obtain the dipyrromethane species
required herein, a sizable number of which are known com-
pounds. Multigram quantities of 5-phenyldipyrromethane 3a15
and 5-(4-tert-butylphenyl)dipyrromethane 3b12 were synthesized
by condensation of the corresponding aldehyde with excess
pyrrole.15 Dipyrromethane 3a was acylated16 with known
Mukaiyama reagents (4a,17 4b,13 4c,17 4d,17 4e,13 4f13) to give
the corresponding 1-acyldipyrromethanes 5a-f in 71-93%
yield (Table 1, entries 1-6), of which 5a,16 5b-d,18 and 5e7
are known compounds (5b-e were prepared previously by a
different route). The acylation17 of 3a with 2,4,6-trimethylben-
zoyl chloride (4g) afforded the corresponding 1-acyldipyr-
romethane 5g18 in 21% yield (entry 7). Formylation14 of 3a
with the Vilsmeier reagent (4h) afforded 5h19 in 43% yield
(entry 8). The 1-acyldipyrromethanes 5a-h were subjected to
regioselective R-bromination20,21 with NBS to give 1-bromo-
9-acyldipyrromethanes 5a-h-Br in 54-92% yield (Table 1,
entries 1-8), of which 5a-Br18 is a known compound. The
variation in yield is believed to stem from differences in stability
and ease of purification of each product. The resulting 1-bromo-
9-acyldipyrromethanes constitute precursors for the AB-half of
each bilane.
The precursors for the CD-half of each bilane were derived
by acylation of dipyrromethane 3b in the same manner as for
dipyrromethane 3a. The acylations entailed use of Mukaiyama
reagents 4i12 (Table 2, entry 1) and 4b-f (entries 2-6), 2,4,6-
trimethylbenzoyl chloride (entry 7), and the Vilsmeier reagent
(entry 8). In so doing, new 1-acyldipyrromethanes 6a-h were
obtained in 27-66% yield.
B. Bilane Formation. We followed the protocol12 employed
previously for the synthesis of the target bilanes: (i) each
1-bromo-9-acyldipyrromethane (5a-h-Br) was reduced to the
corresponding carbinol (5a-h-Br-OH) in THF/MeOH (3:1)
with NaBH4. Each crude carbinol (5a-h-Br-OH, 0.5 M) was
condensed with a 1-acyldipyrromethane (6a-h, 0.5 M) in
CH3CN/MeOH (3:1) containing Yb(OTf)3 (3.3 mM) at room
temperature. In most cases, after 2 h of condensation, TLC
analysis of the crude reaction mixture revealed complete
consumption of the carbinol, a trace of unreacted 1-acyldipyr-
romethane (6a-h), and the corresponding bilane (1a-h).
Workup entailed quenching with excess triethylamine followed
by column chromatography. For the preparation of bilane set 1
(R10 variation), 1-acyldipyrromethane 6a was condensed with
each of the 1-bromodipyrromethane-9-carbinols 5a-h-Br-OH
to give bilanes 1a-h. For set 2 (R20 variation), each of the
1-acyldipyrromethanes 6b-h was condensed with 1-bromo-
dipyrromethane-9-carbinol 5a-Br-OH to give bilanes 2b-h.
(15) Laha, J. K.; Dhanalekshmi, S.; Taniguchi, M.; Ambroise, A.; Lindsey,
J. S. Org. Process Res. DeV. 2003, 7, 799–812.
(16) Rao, P. D.; Littler, B. J.; Geier, G. R., III; Lindsey, J. S. J. Org. Chem.
2000, 65, 1084–1092.
(17) Zaidi, S. H. H.; Muthukumaran, K.; Tamaru, S.-I.; Lindsey, J. S. J.
Org. Chem. 2004, 69, 8356–8365.
(18) Sharada, D. S.; Muresan, A. Z.; Muthukumaran, K.; Lindsey, J. S. J.
Org. Chem. 2005, 70, 3500–3510.
(19) Ptaszek, M.; McDowell, B. E.; Lindsey, J. S. J. Org. Chem. 2006, 71,
4328–4331.
(20) Strachan, J.-P.; O’Shea, D. F.; Balasubramanian, T.; Lindsey, J. S. J.
Org. Chem. 2000, 65, 3160–3172.
(21) Ptaszek, M.; McDowell, B. E.; Taniguchi, M.; Kim, H.-J.; Lindsey, J. S.
Tetrahedron 2007, 3826–3839.
6730 J. Org. Chem. Vol. 73, No. 17, 2008

ABCD-Bilanes and ABCD-Porphyrins
TABLE 1. Synthesis of 1-Bromo-9-acyldipyrromethanes
a Reference 16. b Reference 18. c Inseparable mixture of 1-bromo and 2-bromo-9-acyldipyrromethanes. d Acylation was performed with
2,4,6-trimethylbenzoyl chloride.17 e Via Vilsmeier formylation.14
The results are displayed in Table 3. Application of the
standard method only worked well in the first set of bilanes
(entries 1-8) in three cases (1a, 1b, 1d), but afforded good
yields for all members of the second set of bilanes (2b-h;
entries 9-15). In the first set of bilanes, the R10 substituent
is varied, and reaction must occur at this (carbinol) site for
bilane formation. By contrast, in the second set of bilanes,
the R20 substituent is varied, which does not participate in
bilane formation. Modified conditions for bilane formation
were investigated where reaction failed as described in the
following.
of acid to 230 mM in acetonitrile in the absence of methanol,
reaction proceeded in 3 h to give bilane 1e together with two
more polar, unidentified products. MALDI-MS analysis revealed
the molecule ion peak expected for bilane 1e together with
multiple peaks, none of which was consistent with any
scrambling processes. The standard workup and purification with
column chromatography afforded the target bilane 1e in 36%
yield (Table 3, entry 5).
Because the incorporation of heterocyclic substituents in
distinct patterns has presented notorious difficulties in porphyrin
synthesis,2,13,22–24 we also examined several other mild Lewis
acid catalysts [Zn(OTf)2, InCl3, Er(OTf)3, and Bi(OTf)3] over
a range of concentrations (3.30, 23.0, and 230 mM) in neat
acetonitrile for the synthesis of 1e. Zn(OTf)2 gave no product
even after overnight stirring at room temperature. InCl3,
Er(OTf)3, and Bi(OTf)3 at 230 mM each afforded the target
bilane upon 6-8 h of reaction. The cleanest reaction was
(i) R10 ) Pentafluorophenyl (1c). Only a trace of 1c was
observed after 8 h under the standard conditions. Upon
increasing the concentration of Yb(OTf)3 to 23 mM (while
maintaining the 3:1 ratio of CH3CN/MeOH), after 30 min the
resulting heterogeneous reaction mixture contained the bilane
1c, a trace amount of unreacted 6a, and a polar unidentified
component (TLC analysis). Alternatively, the concentration of
Yb(OTf)3 was maintained at 3.3 mM while carrying out the
reaction in acetonitrile in the absence of methanol. After 5 h,
TLC analysis revealed complete consumption of 5-c-Br-OH, a
trace amount of 6a, and bilane 1c. Subsequent workup afforded
bilane 1c in 87% yield (Table 3, entry 3).
(22) Gryko, D.; Lindsey, J. S. J. Org. Chem. 2000, 65, 2249–2252.
(23) Gryko, D. T.; Tasior, M. Tetrahedron Lett. 2003, 44, 3317–3321.
(24) (a) Andrews, K.; McMillin, D. R. Biochemistry 2008, 47, 1117–1125.
(b) Shelton, A. H.; Rodger, A.; McMillin, D. R. Biochemistry 2007, 46, 9143–
9154. (c) Gonc¸alves, D. P. N.; Sanders, J. K. M. Synlett 2007, 591–594. (d)
Gonc¸alves, D. P. N.; Ladame, S.; Balasubramanian, S.; Sanders, J. K. M. Org.
Biomol. Chem. 2006, 4, 3337–3342. (e) Wu, S.; Li, Z.; Ren, L. G.; Chen, B.;
Liang, F.; Zhou, X.; Jia, T.; Cao, X. P. Bioorg. Med. Chem. 2006, 14, 2956–
2965. (f) Bejune, S. A.; Shelton, A. H.; McMillin, D. R. Inorg. Chem. 2003, 42,
8465–8475. (g) Gerasimchuk, N. N.; Mokhir, A. A.; Rodgers, K. R. Inorg. Chem.
1998, 37, 5641–5650.
(ii) R10 ) 4-Pyridyl (1e). No bilane was observed after 5 h
under the standard conditions, or upon increasing the concentra-
tion of Yb(OTf)3 to 23 mM. Upon increasing the concentration
J. Org. Chem. Vol. 73, No. 17, 2008 6731

Dogutan and Lindsey
TABLE 2. Synthesis of 1-Acyldipyrromethanes
In summary, modified acid-catalysis conditions proved useful
for dipyrromethane-carbinols bearing pentafluorophenyl or
p-pyridyl groups at the carbinol site. The origin of use of the
mixed solvent CH3CN/MeOH (3:1) stemmed from use of the
acid in a stock solution of methanol, which afforded higher
solubility of the acid than neat acetonitrile.12 Neat acetonitrile
was employed here to avoid competition of the acid for the
hydroxy group of methanol versus the hydroxy group of the
dipyrromethane-carbinol. [Note that in the absence of methanol,
the acid catalyst is not entirely dissolved (the reaction mixture
is heterogeneous), yet we maintain use of the concentration term
(e.g., 230 mM) for consistency and purposes of comparison.]
Regardless of solvent, bilanes bearing a 10-mesityl group or
no substituent (R10 ) H) cannot be prepared via this approach.
The bilanes were characterized by NMR spectroscopy (1H, 13C)
and mass spectrometry (MALDI-MS, ESI-MS).
II. Synthesis of Metalloporphyrins from Bilanes. The
synthesis of ABCD-porphyrins was carried out by using bilanes
that possess a variety of substituents at the 10-position (set 1:
1a-e) and 20-position (set 2: 2b-h). The standard protocol12
entails the bilane (100 mM) in toluene (115 °C) containing DBU
(10 mol equiv versus the bilane) and MgBr2 (3 mol equiv versus
the bilane) with exposure to air. The results are displayed in
Table 3. Of 11 new trials (MgP-1a12 was made previously),
nine ABCD-porphyrins were obtained in yields of 17-60% in
2-4 h.
The standard reaction with bilane 2h to obtain ABC-porphyrin
MgP-2h (which contains one unsubstituted meso position)
afforded an inseparable mixture of porphyrin and chlorin as
evidenced by absorption spectroscopy (λabs ) 624 nm, consistent
with expectation for a magnesium-triarylchlorin26,27) and laser-
desorption mass spectrometry (LD-MS) in the absence of a
matrix28 (Table 3, entry 15). A traditional method for handling
such mixtures entails DDQ-mediated oxidation to convert
chlorin to porphyrin;29–31 however, treatment of the mixture gave
an unknown byproduct in low yield rather than the desired
porphyrin. Meso-unsubstituted porphyrins are known to be
susceptible to reactions at the unsubstituted meso site, particu-
larly upon oxidation to give meso,meso-linked dimers.32 Given
that magnesium porphyrins are more susceptible to one-electron
oxidation than zinc porphyrins,33 and zinc reagents have been
employed in place of MgBr2 in the conversion of bilane to
porphyrin,12 we carried out the macrocycle-forming reaction in
the presence of Zn(OAc)2. The use of Zn(OAc)2 with bilane
2h afforded a lesser amount of chlorin (λabs ) 620 nm), and
upon oxidation with DDQ, the target zinc ABC-porphyrin ZnP-
2h was obtained in 25% yield.
a Ref 12. b Acylation was performed with 2,4,6-trimethylbenzoyl
chloride. c Via Vilsmeier formylation.
observed with InCl3 (no starting materials remained). The
success of these reaction conditions augurs well for the synthesis
of elaborate bilanes bearing heterocyclic substituents.
(iii) R10 ) 3-Methoxy-3-oxopropyl (1f). The reduction of
the ketone in 5f-Br to give 5f-Br-OH proceeded smoothly;
however, the standard condensation protocol afforded three new
components, but no bilane was detected by MALDI-MS or by
1H NMR spectroscopy (entry 6). The origin of this surprising
failure is not known, but may stem from chelation of magnesium
by the ester and the R-carbinol moieties.
An alternative approach to prepare ABC-porphyrins was
investigated by the reaction of 1-formyl-9-bromodipyrromethane
5h-Br (without reduction) and 1-acyldipyrromethane 6a to give
the bilene-b intermediate. This approach was pursued because
(iv) R10 ) Mesityl (1g). All attempts to reduce the mesitoyl
group of 5g-Br failed to give the corresponding carbinol 5g-
Br-OH (entry 7). The conditions examined include use of excess
NaBH4 (100 mol equiv versus 5g-Br, 8.25 mM) in anhydrous
THF/MeOH (2:1),25 twice this amount of NaBH4, or LiBH4.
(v) R10 ) H (1h). The reaction of 5h-Br-OH and 6a under
standard conditions afforded three components (a streaking
component, unreacted 6a, and a polar material). Standard
workup gave mostly decomposition products rather than the
desired bilane (entry 8).
(26) Taniguchi, M.; Kim, M. N.; Ra, D.; Lindsey, J. S. J. Org. Chem. 2005,
70, 275–285.
(27) Taniguchi, M.; Ptaszek, M.; McDowell, B. E.; Boyle, P. D.; Lindsey,
J. S. Tetrahedron 2007, 63, 3850–3863.
(28) Srinivasan, N.; Haney, C. A.; Lindsey, J. S.; Zhang, W.; Chait, B. T. J.
Porphyrins Phthalocyanines 1999, 3, 283–291.
(29) Barnett, G. H.; Hudson, M. F.; Smith, K. M. Tetrahedron Lett. 1973,
14, 2887–2888.
(30) Rousseau, K.; Dolphin, D. Tetrahedron Lett. 1974, 15, 4251–4254.
(31) Barnett, G. H.; Hudson, M. F.; Smith, K. M. J. Chem. Soc., Perkin
Trans. 1 1975, 1401–1403.
(32) Kamo, M.; Tsuda, A.; Nakamura, Y.; Aratani, N.; Furukawa, K.; Kato,
T.; Osuka, A. Org. Lett. 2003, 5, 2079–2082.
(33) Fuhrhop, J.-H.; Mauzerall, D. J. Am. Chem. Soc. 1969, 91, 4174–4181.
(25) Decre´au, R. A.; Collman, J. P. Tetrahedron Lett. 2003, 44, 3323–3327.
6732 J. Org. Chem. Vol. 73, No. 17, 2008

ABCD-Bilanes and ABCD-Porphyrins
TABLE 3. Synthesis of Bilanes (1, 2) and ABCD-Porphyrins (MgP-1, MgP-2)
J. Org. Chem. Vol. 73, No. 17, 2008 6733

Dogutan and Lindsey
TABLE 3. Continued
a The bilanes were prepared with 1 or 0.5 mmol of each reactant in CH3CN/MeOH (3:1) containing Yb(OTf)3 (3.3 mM) in 2-5 h at room
temperature (Method 3). b Each porphyrin was prepared by reaction of a bilane in toluene containing MgBr2 and DBU exposed to air under conventional
heating (Method 4). c Reference 12. d Performed in CH3CN without MeOH. e A more polar porphyrin, a putative covalent adduct with DBU, was
isolated in ∼6% yield. f Perfomed with 230 mM Yb(OTf)3. g The reduction of 5g-Br was not successful. h 5h-Br-OH decomposed during bilane
formation (Method 1). i The free base porphyrin bearing a carboxylic acid (rather than an ester). j Performed with 23 mM Yb(OTf)3 at 55 °C. k An
inseparable mixture of porphyrin and chlorin was obtained. l Performed with Zn(OAc)2 in place of MgBr2.
SCHEME 3
(i) chlorin contaminants are believed to derive upon tautomeric
rearrangement of polypyrromethane precursors (e.g., porphy-
rinogens),34 (ii) we felt that preformation of the unsaturated unit
at the position lacking an aryl substituent (i.e., the 10-position)
would thereby avoid tautomeric rearrangement at this apparently
problematic site, and (iii) the requisite 1-bromo-9-formyldipyr-
romethanes have been used successfully in analogous condensa-
tions in chlorin chemistry.21,35 The reaction with the standard
acid-catalysis conditions with Yb(OTf)3 was sluggish and
required mild heating (55 °C) for 2 h to give the bilene (λmax
)
490 nm), whereas the same reaction could be carried out in 30
min with p-toluenesulfonic acid at room temperature. Subse-
quent treatment of the bilene to the porphyrin-forming conditions
indeed gave MgP-2i in 11% yield (Scheme 3). On the other
hand, prolonged heating of the reaction mixture in air gave the
corresponding meso,meso-linked porphyrin dimer.
III. Applications. The scope was explored further by
preparation of bilanes and porphyrins bearing three pyridyl
groups or four alkyl groups. In this study, the substituent
variation was focused at the R5, R15, and R20 sites while
maintaining the R10 substituent of a type that is known to afford
successful reaction in bilane formation.
A. Porphyrins Bearing Three Pyridyl Substituents. (i)
Bilane Synthesis. We investigated the synthesis of target
molecules bearing three heterocyclic substituents (o-, m-,
p-pyridyl). In each target bilane, the R5 substituent was
m-pyridyl, the R10 substituent was 4-ethylphenyl, and the 15-
and 20-positions were varied (o-, m-, p-pyridyl). The synthesis
of each bilane employed 1-bromodipyrromethane-9-carbinol
7-Br-OH, which was prepared as shown in Scheme 4. The
dipyrromethane bearing a m-pyridyl group (3c)22 was treated
with Mukaiyama reagent 4i to give the corresponding 1-acyl-
dipyrromethane 7 in 42% yield. R-Bromination20,21 of the latter
afforded 1-acyl-9-bromodipyrromethane 7-Br in 79% yield.
Reduction with NaBH4 gave 7-Br-OH, which constitutes the
precursor for the AB-half of each bilane, in clean fashion (one
new component by TLC analysis).
The bilane synthesis entailed condensation of the carbinol
7-Br-OH with a 1-acyldipyrromethane (0.5 M each) in neat
acetonitrile (without methanol) containing Yb(OTf)3 (230 mM).
The rationale for the use of neat acetonitrile stemmed from our
findings that bilanes that contain a heterocyclic group (1e,
p-pyridyl) or a bulky electron-withdrawing substituent (1c,
pentafluorophenyl) at the 10-position are formed faster and in
higher yield upon reaction in neat acetonitrile. Each of the four
1-acyldipyrromethanes (8a-d) employed bears two pyridyl
groups and is a known compound13 (Table 4).
NMR spectroscopy showed the presence of the target bilane
and an unidentified impurity. Although the 1-acyldipyr-
romethane generally was not detected, its presence was
ostensibly revealed upon subsequent porphyrin formation.
Our prior studies have shown that prolonged chromatographic
purification of a bilane results in formation of a green
byproduct, presumably owing to oxidation.12 Accordingly,
in each case the crude bilane was carried on to the porphyrin-
forming reaction without further purification.
(ii) Porphyrin Synthesis. Microwave irradiation can provide
a superior method versus conventional heating for the synthesis
of porphyrins bearing heterocyclic substituents.13 Accordingly,
in each case the crude bilane was subjected to the porphyrin-
In each bilane-forming reaction, chromatographic purifica-
tion proved difficult given the tendency of the tripyridyl-
substituted bilanes to streak. In each case, TLC analysis of
1
the purified fraction revealed one component; however, H
(34) Dolphin, D. J. Heterocycl. Chem. 1970, 7, 275–283.
(35) Laha, J. K.; Muthiah, C.; Taniguchi, M.; McDowell, B. E.; Ptaszek,
M.; Lindsey, J. S. J. Org. Chem. 2006, 71, 4092–4102.
6734 J. Org. Chem. Vol. 73, No. 17, 2008

ABCD-Bilanes and ABCD-Porphyrins
TABLE 4. Porphyrins Bearing Three Pyridyl Substituentsa
a The bilane and the porphyrin were prepared following Method 5 (see text). Microwave irradiation was used in each porphyrin-forming reaction.
b Demetalation was performed.
SCHEME 4
and a trans-A2B2-porphyrin. The trans-A2B2-porphyrin is
believed to derive from the condensation of unreacted 1-acyl-
dipyrromethane (8) that was present as a contaminant in the
crude bilane.
The results are shown in Table 4. Porphyrin MgP-9a contains
an o-pyridyl group flanked by two m-pyridyl groups (trans-
AB2C-porphyrin) and was isolated in 12% yield. Porphyrin
MgP-9b contains three m-pyridyl groups (A3B-porphyrin) and
was obtained in 8% yield upon alumina column chromatogra-
phy. In each case, a trace of the trans-A2B2-porphyrin (MgP-
10a, MgP-10b) also was isolated.
The chromatographic purification of the magnesium porphyrin
was not successful in the case of putative MgP-9c and MgP-
9d, each of which bears one p-pyridyl group and two other
pyridyl groups. Hence, demetalation was performed and the
target porphyrin was isolated as the free base. Thus, free base
porphyrin P-9c contains a sequence of m-, p-, and m-pyridyl
groups (trans-AB2C-porphyrin) and was isolated in 17% yield
accompanied by the free base trans-A2B2-porphyrin P-10c in
7% yield. (For comparison, the yield of each porphyrin P-9c
and P-10c is based on the theoretical yield of the target bilane.)
Similarly, free base porphyrin P-9d, which contains a sequence
of m-, o-, and p-pyridyl groups (ABCD-porphyrin), was isolated
in 25% yield accompanied by the free base trans-A2B2-
porphyrin P-10d in 15% yield. The synthetic approach affords
the desired pyridyl-porphyrins in low yield but provides a viable
complement to existing rational methods2,13,22–24 for preparing
porphyrins bearing distinct patterns of pyridyl substituents.
B. Tetraalkylporphyrins. The synthesis of porphyrins bear-
ing four meso-alkyl groups also was examined. A variety of
meso-alkyl/aryl-porphyrins have been prepared;7,36–38 however,
forming conditions [DBU (10 mol equiv) and MgBr2 (3 mol
equiv) in toluene] via microwave irradiation. In each case, the
TLC and LD-MS analyses of the crude reaction mixture revealed
the presence of two porphyrin products, the target porphyrin
J. Org. Chem. Vol. 73, No. 17, 2008 6735

Dogutan and Lindsey
TABLE 5. Synthesis of Alkyl-Substituted 1-Acyldipyrromethanes
a Reference 13. b Reference 46.
CHART 2
All of the dipyrromethanes are known compounds; those
bearing the meso substituent H (3d),15 ethyl (3e),13 propyl (3f),13
and pentyl (3h)15 were prepared previously by condensation with
pyrrole in the presence of InCl3. 5-Butyldipyrromethane (3g),
previously described without complete characterization,44,45 was
prepared herein by reaction with pyrrole containing InCl3. A
new Mukaiyama reagent, S-2-pyridyl butanothioate (4k), was
prepared by reaction of 2-mercaptopyridine and butyryl chloride.
A series of 1-acyldipyrromethanes was prepared as shown
in Table 5. The reaction of dipyrromethanes 3d-h with the
Mukaiyama reagents 4b, 4j,13 4k, and 4l13 following the
standard acylation procedure16 afforded the target 1-acyldipyr-
romethanes in 42-79% yields, of which 11b,13 11e,13 and 11h46
are known compounds. 1-Acyldipyrromethanes 11b-d and 11h
were subjected to regioselective R-bromination20,21 with NBS
to afford the corresponding 1-bromo-9-acyldipyrromethanes
(Table 5). Compound 11c-Br was very unstable and underwent
discoloration upon warming a stored sample above -4 °C.
Surprisingly, the analogous compound 11d-Br was sufficiently
stable to obtain full characterization data (1H NMR and 13C
NMR spectra in THF-d8, ESI-MS, and elemental analysis).
the most elaborate meso-tetraalkylporphyrins prepared to date
apparently are limited to A4-39–42 and A3B-substituent43patterns.
The dipyrromethanes used are shown in Chart 2.
(36) Atamian, M.; Wagner, R. W.; Lindsey, J. S.; Bocian, D. F. Inorg. Chem.
1988, 27, 1510–1512.
6736 J. Org. Chem. Vol. 73, No. 17, 2008

ABCD-Bilanes and ABCD-Porphyrins
TABLE 6. Bilanes and Porphyrins Bearing Alkyl Substituentsa
a The bilane was prepared in CH3CN containing Yb(OTf)3 (3.3 mM) for 30 min at room temperature (Method 6). Each porphyrin was prepared by
reaction of a bilane in toluene containing MgBr2 and DBU exposed to air under microwave irradiation unless noted otherwise. b By use of conventional
heating (Method 4; no demetalation, giving the magnesium chelate). c No porphyrin was obtained upon conventional heating.
The bilane synthesis was performed under conditions slightly
modified from the standard protocol given that all of the dialkyl
1-bromo-9-acyldipyrromethane-carbinols were found to be
unstable in the solid form. Reduction of a dialkyl 1-bromo-9-
acyldipyrromethane (11b-Br, 11c-Br, 11d-Br, 11h-Br) was
carried out in the standard way with excess NaBH4 to give the
corresponding carbinol. The modifications to the procedure were
as follows: (i) the dipyrromethane-carbinol was concentrated
in a mixture of ethyl ether/acetonitrile (1:5) until most of the
ether was removed, (ii) the resulting carbinol was used directly
in the bilane-forming reaction, and (iii) acid-catalyzed conden-
sation was carried out at 0.05 M (rather than 0.5 M) in
acetonitrile containing Yb(OTf)3. Acetonitrile was used alone
(without methanol) in conjunction with the lower reaction
concentration, and in preliminary experiments with alkyl-
substituted substrates was found to support reactions with good
yields. In this manner, the subsequent standard workup with
chromatography afforded the target tetraalkylbilanes in 62-86%
yields (Table 6).
Treatment of tetraalkyl-substituted bilane 12a to the reaction
conditions (including conventional heating for 8 h) gave the
target cis-A2B2-porphyrin MgP-12a in 16% yield. However,
attempts to perform the reaction of bilane 12b or 12c under
conventional heating gave no porphyrin. The promising results
obtained for the synthesis of porphyrins bearing heterocyclic
substituents under microwave irradiation13 encouraged the
analogous synthesis of tetraalkylporphyrins. Thus, a given bilane
(12c-f) was treated with DBU (10 mol equiv) and MgBr2 (3
mol equiv) in toluene (Table 6). The reaction mixture was
subjected to microwave irradiation for 30 min. In each case,
examination of the crude reaction mixture by absorption
spectroscopy showed the characteristic porphyrin Soret band
and two broad peaks (303 and 525 nm; unassigned origin). TLC
analysis showed consumption of the bilane, formation of the
porphyrin, and a polar tailing component. Microwave irradiation
was continued (typically 36 h) until TLC analysis and absorption
spectroscopy did not show any intermediate. The crude reac-
tion mixture was subjected to demetalation followed by column
chromatography. In each case, the porphyrin was obtained in
yields ranging from 16% to 24%. The resulting porphyrins
include two ABCD-porphyrins (P-12e, P-12f), each of which
contains an ethyl, propyl, butyl, and pentyl group (and hence
are isomers), and one trans-AB2C-porphyrin (P-12d).
(37) Ohashi, A.; Satake, A.; Kobuke, Y. Bull. Chem. Soc. Jpn. 2004, 77,
365–374.
(38) Lindsey, J. S. In The Porphyrin Handbook; Kadish, K. M., Smith, K. M.,
Guilard, R., Eds.; Academic Press: San Diego, CA, 2000; Vol. 1, pp 45-118.
(39) Lindsey, J. S.; Schreiman, I. C.; Hsu, H. C.; Kearney, P. C.; Marguer-
ettaz, A. M. J. Org. Chem. 1987, 52, 827–836.
(40) Thamyongkit, P.; Speckbacher, M.; Diers, J. R.; Kee, H. L.; Kirmaier,
C.; Holten, D.; Bocian, D. F.; Lindsey, J. S. J. Org. Chem. 2004, 69, 3700–
3710.
(41) Thamyongkit, P.; Lindsey, J. S. J. Org. Chem. 2004, 69, 5796–5799.
(42) Borbas, K. E.; Mroz, P.; Hamblin, M. R.; Lindsey, J. S. Bioconj. Chem.
2006, 17, 638–653.
(43) Gryko, D.; Li, J.; Diers, J. R.; Roth, K. M.; Bocian, D. F.; Kuhr, W. G.;
Lindsey, J. S. J. Mater. Chem. 2001, 11, 1162–1180.
¨
(44) Senge, M. O.; Hatscher, S.; Okten, Z.; Speck, M. Tetrahedron Lett.
2003, 44, 4463–4466.
(45) Rucareanu, S.; Mongin, O.; Schuwey, A.; Hoyler, N.; Gossauer, A.;
Amrein, W.; Hediger, H.-U. J. Org. Chem. 2001, 66, 4973–4988.
(46) Muthukumaran, K.; Ptaszek, M.; Noll, B.; Scheidt, W. R.; Lindsey, J. S.
J. Org. Chem. 2004, 69, 5354–5364.
J. Org. Chem. Vol. 73, No. 17, 2008 6737

Dogutan and Lindsey
Outlook
The data obtained herein provide extensive information
concerning the scope of the route to ABCD-bilanes and ABCD-
porphyrins. The key findings are as follows:
(1) The pentyl unit gave better yields at the 20- versus 10-
position in both bilane and porphyrin formation (Table 3, entries
2 and 9).
(2) The pentafluorophenyl unit at the 10- versus 20-position
of the bilane gave somewhat better yields upon bilane formation
(Table 3, entries 3 and 10), but the reverse was observed in
porphyrin formation.
(3) The 4-methoxyphenyl group at the 20- versus 10-position
of the bilane resulted in a higher yield in the porphyrin-forming
reaction (Table 3, entries 4 and 11).
(4) No significant difference in porphyrin yield was observed
by having the 4-pyridyl group at the 10- or 20-position of the
bilane (Table 3, entries 5 and 12).
(5) An alkyl ester unit can be introduced to the porphyrin
macrocycle via the 20- but not the 10-position of the bilane
(Table 3, entries 6 and 13).
(6) A mesityl group cannot be introduced at the 10-position of
the bilane, and a 20-mesityl-substituted bilane does not give
significant amounts of the porphyrin (Table 3, entries 7 and 14).
(7) A 10-unsubstituted porphyrin can be prepared via a
bilene-b (but not a bilane) because a dipyrromethane containing
a primary carbinol does not give the bilane (Table 3, entry 8;
Scheme 3).
for macrocycle formation. The conditions support reaction in
the presence of alkyl and pyridyl substituents without detectable
scrambling. Thus, the new capabilities with pyridyl and alkyl
groups fill longstanding lacunae in porphyrin chemistry.
The scope demonstrated herein is quite promising for a
number of applications. The applications for the porphyrins are
manifold, yet the bilanes may prove equally versatile. Almost
all prior studies of bilanes have focused on naturally occurring
analogues, which bear ꢀ-pyrrole substituents and lack meso
substituents.47–56 The bilanes (and their various oxidized
analogues: bilenes, biladienes, and bilatrienes) may prove very
attractive in studies of coordination chemistry, supramolecular
chemistry, redox chemistry, materials chemistry, and photo-
chemistry (as phytochrome or phycobilin analogues). Regardless
of application, significant features of the route will require
further development. One limitation is the necessity for elevated
temperature to achieve macrocycle formation: the reaction
proceeds well at ∼115 °C but poorly at lower temperatures.
Much about scope remains to be determined, including the
effects of ortho and meta substituents on meso-aryl groups, and
the effects of diverse substituents at the 5- and 15-positions of
the bilane and porphyrin. Much about the mechanism of
macrocycle formation also remains unknown, particularly the
nature of the reactive end groups (acylpyrrole and bromopyrrole)
upon carbon-carbon bond formation, the nature of any metal-
coordination complexes (i.e., templating), the course of oxidation
prior to or following macrocycle formation, and the relative
reactivity of the different (up to eight) stereoisomeric forms of
the bilane. We note that while the reaction conditions and
substrate in the macrocyclization are highly suggestive of metal
templating, and the strategy was conceived with the notion that
metal templating would facilitate macrocyclization, the reaction
conditions also support facile metal (magnesium, zinc) insertion
of free base porphyrins;13,57 hence, the isolation of the metal-
loporphyrin is alone insufficient proof of metal templating.
Gaining a deeper understanding of such mechanistic aspects of
the reaction may lead to milder conditions for macrocycle
formation and thereby further broaden the scope of application.
(8) A 20-unsubstituted porphyrin can be prepared as the zinc
but not the magnesium chelate (Table 3, entry 15).
(9) The synthesis of sparsely substituted alkylporphyrins via
conventional heating was rather unsuccessful but could be
achieved via microwave irradiation (Table 6, entries 2 and 3).
(10) Bilanes and porphyrins bearing up to three different
pyridyl groups in distinct arrangements can be prepared (Table
4). A change in the ratio of reagents was not necessary for
successful reaction despite the presence of three alternative
coordination sites (in addition to the acyl moiety) for the acid
catalyst or MgBr2 in the reacting species.
(11) Bilanes and porphyrins bearing up to four different alkyl
groups can be prepared (Table 6).
Experimental Section
5-Butyldipyrromethane (3g). Following a reported procedure,15
a solution of valeraldehyde (5.31 mL, 50.0 mmol) in pyrrole (347
mL, 5.00 mol) at room temperature under argon was treated with
(12) The 1-bromo-19-acylbilanes bearing aryl or heteroaryl
substituents were stable to routine handling on the open benchtop
and upon prolonged storage at -4 °C. By contrast, the analogous
bilanes bearing alkyl substituents were rather unstable and were
used shortly after preparation (see Supporting Information).
Alkyl and pyridyl groups were of particular interest in this
study because both types of groups have afforded poor results
with the standard dipyrromethane + dipyrromethane-dicarbinol
route to ABCD-porphyrins.2 The alkyl-substituted dipyr-
romethanes give rise to multiple porphyrin products (owing to
acidolytic scrambling), whereas the pyridyl groups tend to
complex with the acid catalysts and thereby impede the reaction.
Extensive efforts have been devoted to the challenge of
synthesizing porphyrins bearing distinct patterns of pyridyl
substituents.13,22–24 The new method for condensation of a
1-acyldipyrromethane (Scheme 2) to give trans-A2B2-porphyrins
is broadly compatible with pyridyl substituents but only
marginally so with alkyl groups; regardless, the route does not
provide access to ABCD patterns for porphyrins, and offers no
access to bilanes at all.13 The conditions employed herein rely
on (i) a mild Lewis acid in a polar medium [e.g., Yb(OTf)3 in
acetonitrile] for bilane formation and (ii) nonacidic conditions
(47) Gossauer, A.; Engel, J. In The Porphyrins; Dolphin, D. , Ed.; Academic
Press: New York, 1978;Vol. 2, pp 197-253.
(48) Falk, H. The Chemistry of Linear Oligopyrroles and Bile Pigments;
Springer-Verlag: Wien, Austria, 1989.
(49) Boiadjiev, S. E.; Lightner, D. A. Synlett 1994, 777–785.
(50) Terry, M. J. In Heme, Chlorophyll, and Bilins: Methods and Protocols;
Smith, A. G., Witty, M., Eds.; Humana Press: Totowa, NJ, 2002; pp 273-291.
(51) McDowell, M. T.; Lagarias, J. C. In Heme, Chlorophyll, and Bilins:
Methods and Protocols; Smith, A. G., Witty, M., Eds.; Humana Press: Totowa,
NJ, 2002; pp 293-309.
(52) Gossauer, A. In The Porphyrin Handbook; Kadish, K. M., Smith, K. M.,
Guilard, R., Eds.; Academic Press: San Diego, CA, 2003; Vol. 13, pp 237-
274.
(53) Mizutani, T.; Yagi, S. J. Porphyrins Phthalocyanines 2004, 8, 226–
237.
(54) Jacobi, P. A.; Odeh, I. M. A.; Buddhu, S. C.; Cai, G.; Rajeswari, S.;
Fry, D.; Zheng, W.; DeSimone, R. W.; Guo, J.; Coutts, L. D.; Hauck, S. I.;
Leung, S. H.; Ghosh, I.; Pippin, D. Synlett 2005, 2861–2885.
(55) Chepelev, L. L.; Beshara, C. S.; MacLean, P. D.; Hatfield, G. L.; Rand,
A. A.; Thompson, A.; Wright, J. S.; Barclay, L. R. C. J. Org. Chem. 2006, 71,
22–30.
(56) Mu¨ller, T.; Ulrich, M.; Ongania, K.-H.; Kra¨utler, B. Angew. Chem.,
Int. Ed. 2007, 46, 8699–8702.
(57) Lindsey, J. S.; Woodford, J. N. Inorg. Chem. 1995, 34, 1063–1069.
6738 J. Org. Chem. Vol. 73, No. 17, 2008

ABCD-Bilanes and ABCD-Porphyrins
InCl3 (1.11 g, 5.00 mmol) for 1.5 h. Powdered NaOH (6.00 g, 150
mmol) was added. After being stirred for 1 h, the mixture was
suction filtered. Excess pyrrole was removed from the filtrate under
high vacuum, leaving a brown oil. Chromatography of the latter
[silica, hexanes/CH2Cl2 (1:1) f (2:3)] afforded a yellow liquid (4.26
g, 42%): 1H NMR δ 0.87 (t, J ) 7.2 Hz, 3H), 1.25-1.33 (m, 4H),
1.91 (app q, J ) 7.2 Hz, 2H), 3.90 (t, J ) 7.6 Hz, 1H), 6.06-6.09
(m, 2H), 6.11-6.16 (m, 2H), 6.54-6.56 (m, 2H), 7.54-7.58 (br,
2H); 13C NMR δ 14.3, 22.9, 30.0, 34.5, 37.8, 105.5, 108.2, 117.3,
133.7; ESI-MS obsd 202.14735, calcd 202.14700 (C13H18N2). Anal.
Calcd for C13H18N2: C, 77.18; H, 8.97; N, 13.85. Found: C, 77.29;
H, 8.99; N, 13.60.
S-2-Pyridyl Butanothioate (4k). Following a reported proce-
dure,17 a solution of 2-mercaptopyridine (5.55 g, 50.0 mmol) in
THF (50.0 mL) was treated slowly with butyryl chloride (5.33 g,
50.0 mmol). The resulting reaction mixture was stirred for 30 min.
The reaction mixture was added to a biphasic solution of saturated
aqueous NaHCO3 (100 mL) and diethyl ether (100 mL). The
mixture was stirred until the foaming subsided. The organic layer
was extracted with diethyl ether. The organic extract was washed
(water, brine), dried (Na2SO4), and concentrated to afford a yellow
oil (8.066 g, 89%): 1H NMR δ 0.99 (t, J ) 7.4 Hz, 3H), 1.73-1.78
(m, 2H), 2.68 (t, J ) 7.4 Hz, 2H), 7.26-7.29 (m, 1H), 7.61 (d, J
) 7.4 Hz, 1H), 7.71-7.75 (m, 1H), 8.60-8.61 (m, 1H); 13C NMR
δ 13.7, 19.2, 46.2, 123.6, 130.3, 137.3, 150.6, 151.8, 196.6; ESI-
MS obsd 181.05612, calcd 181.05613 (C9H11NOS). Anal. Calcd
for C9H11NOS: C, 59.64; H, 6.12; N, 7.73. Found: C, 59.69; H,
6.10; N, 7.63.
General Protocol for the Synthesis of 1-Acyldipyrromethanes
(Method 1). Following the standard procedure,16 a solution of
EtMgBr (19.0 mL, 19 mmol, 1.0 M in THF) was added slowly to
a solution of a dipyrromethane (3a-i, 7.50 mmol) in THF (15.0
mL) under argon. The resulting mixture was stirred at room
temperature for 10 min, and then cooled to -78 °C. A solution of
a Mukaiyama reagent (4a-d,4f,4i-l, 7.50 mmol) in THF (15.0
mL) was added to the reaction mixture (4e134 was added as a solid).
The solution was stirred at -78 °C for 10 min, and then allowed
to warm to room temperature. The reaction mixture was quenched
by the addition of saturated aqueous NH4Cl. The mixture was
extracted with ethyl acetate. The organic layer was washed (water,
brine), dried (Na2SO4), and filtered. The filtrate was concentrated.
Column chromatography [silica, CH2Cl2 (until all the unreacted
dipyrromethane was eluted) f hexanes/ethyl acetate (3:1)] afforded
the corresponding 1-acyldipyrromethane.
1-(4-Ethylbenzoyl)-5-(3-pyridyl)dipyrromethane (7). Follow-
ing Method 1, a solution of EtMgBr (10.0 mL, 10. mmol, 1.0 M in
THF) was added to a solution of 3c (0.893 g, 4.00 mmol) in THF
(8.0 mL). A solution of 4i (0.973 g, 4.00 mmol) in THF (8.0 mL)
was added to the reaction mixture. The resulting crude product was
chromatographed [silica, CH2Cl2/ethyl acetate (3:2) f CH2Cl2/ethyl
acetate (1:1) f ethyl acetate] to afford a light-brown foam (0.594
g, 42%): mp 68-70 °C; 1H NMR δ 1.27 (t, J ) 7.6 Hz, 3H), 2.72
(q, J ) 7.6 Hz, 2H), 5.57 (s, 1H), 5.93-5.96 (m, 1H), 6.07-6.09
(m, 1H), 6.12-6.14 (m, 1H), 6.69-6.70 (m, 1H), 6.79-6.81 (m,
1H), 7.12-7.16 (m, 1H), 7.28 (d, J ) 7.8 Hz, 2H), 7.47-7.49 (m,
1H), 7.72 (d, J ) 7.8 Hz, 2H), 8.39-8.42 (m, 2H), 9.22-9.41 (br,
1H), 10.55-10.62 (br, 1H); 13C NMR δ 15.5, 29.1, 42.0, 108.4,
108.5, 110.9, 118.7, 121.3, 123.6, 128.1, 129.5, 130.3, 131.3, 135.8,
136.1, 137.1, 140.9, 148.5, 149.1, 149.8, 185.1; ESI-MS obsd
356.1756, calcd 356.1757 [(M + H)+, M ) C23H21N3O]. Anal.
Calcd for C23H21N3O: C, 77.72; H, 5.96; N, 11.82. Found: C, 77.88;
H, 5.97; N, 11.48.
were added, and the reaction mixture was allowed to warm to room
temperature. Ethyl acetate was added. The organic phase was
washed (water, brine), dried (K2CO3), and concentrated under
reduced pressure without heating. The crude product was purified
by column chromatography [silica, hexanes/ethyl acetate (3:1)] to
afford the corresponding 1-acyl-9-bromodipyrromethane.
1-Bromo-9-hexanoyl-5-phenyldipyrromethane (5b-Br). Fol-
lowing Method 2, a solution of 5b (1.728 g, 5.40 mmol) in THF
(54.0 mL) was treated with NBS (0.961 g, 5.40 mmol) to afford a
brown paste (1.36 g, 63%): 1H NMR δ 0.87-0.90 (m, 3H),
1.31-1.33 (m, 4H), 1.61-1.65 (m, 2H), 2.52-2.69 (m, 2H), 5.45
(s, 1H), 5.89-5.91 (m, 1H), 6.04-6.07 (m, 2H), 6.82-6.84 (m,
1H), 7.12-7.14 (m, 2H), 7.25-7.30 (m, 3H), 8.52-8.66 (br, 1H),
9.72-9.92 (br, 1H); 13C NMR δ 14.2, 22.7, 25.5, 31.9, 37.9, 44.3,
98.0, 109.9, 110.56, 110.6, 117.7, 127.6, 128.4, 128.9, 131.9, 132.7,
140.2, 140.4, 191.8; FAB-MS obsd 399.1073, calcd 399.1072 [(M
+ H)+, M ) C21H23BrN2O]. Anal. Calcd for C21H23BrN2O: C,
63.16; H, 5.81; N, 7.02. Found: C, 62.94; H, 5.88; N, 6.85.
1-Bromo-9-(pentafluorobenzoyl)-5-phenyldipyrromethane (5c-
Br). Following Method 2, a solution of 5c (0.833, 2.00 mmol) in
THF (20.0 mL) was treated with NBS (0.354 g, 2.00 mmol) at
-78 °C to afford a brown foam (0.686 g, 69%): mp 85-87 °C; 1H
NMR δ 5.49 (s, 1H), 5.86-5.96 (m, 1H), 6.09-6.11 (m, 2H),
6.62-6.72 (m, 1H), 7.16-7.22 (m, 2H), 7.31-7.37 (m, 3H),
8.02-8.22 (br, 1H), 9.68-9.84 (br, 1H); 13C NMR (THF-d8) δ 45.3,
98.3, 110.3, 110.4, 110.5, 112.0, 112.2, 122.5, 127.8, 128.0, 129.6,
132.6, 134.4, 137.4, 139.9, 141.7, 142.1, 143.7, 144.3, 145.8, 146.2,
171.7; ESI-MS obsd 495.01176, calcd 495.01259 [(M + H)+, M
) C22H12BrF5N2O]. Anal. Calcd for C22H12BrF5N2O: C, 53.36; H,
2.44; N, 5.66. Found: C, 53.28; H, 2.16; N, 6.02.
General Protocol for the Synthesis of Bilanes (Method 3).
Following the published procedure,12 a solution of a 1-bromo-9-
acyldipyrromethane (5a-h-Br) in dry THF/MeOH (3:1, 0.0125 M)
under argon at room temperature was treated with NaBH4 (25.0
mol equiv versus 5a-h-Br) in small portions with rapid stirring.
The progress of the reaction was monitored by TLC analysis [silica,
hexanes/ethyl acetate (3:1)]. The reaction was complete in ∼30
min. The reaction mixture was poured into a mixture of saturated
aqueous NH4Cl (25 mL) and ethyl ether (25 mL). The organic phase
was separated, washed (water, brine), dried (K2CO3), and concen-
trated under reduced pressure at ambient temperature to yield the
corresponding dipyrromethane-carbinol (5a-h-Br-OH) as a yellow-
orange paste. The resulting product was transferred to an oven-
dried round-bottomed flask with diethyl ether (10.0 mL). The diethyl
ether solution of the dipyrromethane-carbinol was concentrated to
give an orange paste. For improved stability, the dipyrromethane-
carbinol was handled as a paste containing residual diethyl ether
rather than as a dry solid. A sample of a 1-acyldipyrromethane
6a-h (1.00 mmol, 0.5 M) was added. A septum was fitted to the
flask, and anhydrous acetonitrile was added under a slow argon
flow. The resulting reaction mixture was stirred for 1 min,
whereupon Yb(OTf)3 (as a 10 mM stock solution in methanol, or
as a solid, to give a final acid concentration of 3.3-230 mM) was
slowly added. The reaction mixture darkened. The reaction mixture
was stirred until all of the dipyrromethane-carbinol was consumed
[0.5-5 h; TLC analysis: silica, hexanes/ethyl acetate (3:1)]. An
aliquot was removed from the reaction mixture and checked by
MALDI-MS (POPOP). No detectable scrambling was observed.
The reaction mixture was neutralized by the addition of triethyl-
amine [10 mol equiv versus Yb(OTf)3]. The reaction mixture turned
light brown. The resulting mixture was diluted with diethyl ether
(∼50 mL), washed (water, brine), dried (K2CO3), and concentrated
to afford a light-brown foam. The crude product was chromato-
graphed to afford the bilane as a light-brown foam, presumably as
a mixture of stereoisomers.
General Protocol for the Bromination of 1-Acyldipyr-
romethanes (Method 2). Following a general procedure,20,21
a
solution of 1-acyldipyrromethane (5a-h, 11b-d, 11h; 1.00-5.40
mmol, 0.1 M) in dry THF (10.0-54.0 mL) was cooled to -78 °C
under argon. A solid sample of NBS (1.00-5.40 mmol) was added
to give a concentration of 0.1 M, and the reaction mixture was
stirred at -78 °C for 1 h. Hexanes (20.0 mL) and water (20.0 mL)
1-Bromo-15-(4-tert-butylphenyl)-19-(isonicotinoyl)-10-(4-me-
thylphenyl)-5-phenylbilane (2e). Following Method 3, a solution
of 5a-Br (0.105 g, 0.250 mmol) in dry THF/MeOH (20.0 mL, 3:1)
was treated with NaBH4 (0.236 g, 6.25 mmol). The resulting
J. Org. Chem. Vol. 73, No. 17, 2008 6739

Dogutan and Lindsey
carbinol 5a-Br-OH in dry acetonitrile (0.340 mL) was treated with
6e (0.096 g, 0.25 mmol) and Yb(OTf)3 (0.160 mL of a 10.0 mM
stock solution in anhydrous MeOH). The resulting reaction mixture
was stirred at room temperature for 4 h. The standard workup and
column chromatography [silica, hexanes/ethyl acetate (1:4)] afforded
a brown foam (0.119 g, 61%), presumably as a mixture of 8
temperature. On the basis of TLC analysis of the crude reaction
mixture (silica, ethyl acetate) the reaction was complete in ∼30
min. The reaction mixture was poured into a mixture of saturated
aqueous NH4Cl (∼10 mL) and diethyl ether (∼10 mL). The organic
phase was separated, washed (water, brine), dried (K2CO3), and
concentrated until some diethyl ether (∼5 mL) remained. The
resulting orange-yellow solution (7-Br-OH) was transferred to an
oven-dried round-bottomed flask (25 mL). A sample of 1-acyl-
dipyrromethane (0.164 g, 0.500 mmol) was added followed by
anhydrous acetonitrile (1 mL) under a slow flow of argon. The
resulting solution was concentrated under low pressure with a rotary
evaporator (ambient temperature) to largely remove the ethyl ether
and give a volume of ∼1 mL (predominantly acetonitrile). The
resulting orange-red solution was stirred for 1 min, whereupon
Yb(OTf)3 (0.142 g, 0.230 mmol) was added. The reaction mixture
immediately turned dark red-orange. An aliquot was removed from
the reaction mixture at various times and checked by TLC analysis
(silica, ethyl acetate). Up to four components were observed [trace
of unreacted 1-acyldipyrromethane, target bilane, unknown streaking
red component, and the carbinol (Rf 0.19, 0.39, 0.58, and 0.81,
respectively), which upon exposure to bromine were orange, dark
brown, dark pink, and dark red, respectively]. The reaction mixture
was stirred until all of the carbinol was consumed. MALDI-MS
(POPOP) analysis of the crude reaction mixture gave a peak (m/z
745.9) consistent with the target bilane. The reaction was neutralized
by the addition of triethylamine (0.020 mL). The resulting mixture
was diluted with ethyl acetate (∼30 mL) and washed with water
and brine. The organic layer was dried (K2CO3) and concentrated
to afford a dark red-brown paste.
(ii) Porphyrin Formation under Microwave Conditions. The
crude bilane was transferred to a 10-mL glass tubular reaction vessel
containing a magnetic stir bar and toluene (5 mL). The headspace
contained air. A sample of DBU (0.750 mL, 5.00 mmol) was added
via syringe. The vessel was sealed with a septum. The resulting
mixture was stirred for 5 min at room temperature. The reaction
mixture darkened. The septum was removed and MgBr2 (0.276 g,
1.50 mmol) was added all-at-once. The vessel was sealed with a
septum and the resulting heterogeneous reaction mixture was stirred
at room temperature for 1 min. The vessel was subjected to
microwave irradiation at 100 W. The protocol was as follows: (1)
heat from room temperature to 115 °C (irradiate for 2 min), (2)
hold at 115 °C (irradiate for 15 min; the temperature typically
overshot to 135 °C and then stabilized after 2 min), (3) allow to
cool to room temperature (∼1 min), (4) check the reaction mixture
by TLC analysis and absorption spectroscopy, (5) repeat steps 1-3
until porphyrin formation is complete (typically 3-4 h overall).
After porphyrin formation was complete, the crude reaction mixture
was dissolved in THF (HPLC-grade and stabilizer-free). The
solution was concentrated and chromatographed [alumina, THF
(HPLC-grade and stabilizer-free) f THF/MeOH (10:1)]. (The use
of solvent containing the stabilizer 2,6-di-tert-butyl-4-methylphenol
resulted in contamination of the porphyrin with the stabilizer
following chromatography.) The porphyrin-containing fraction was
concentrated. The resulting porphyrin was suspended in methanol
(5 mL). The suspension was sonicated for ∼1 min, centrifuged,
and decanted to obtain the magnesium porphyrin. In some cases,
purification of the crude reaction mixture by alumina column
chromatography [alumina, CH2Cl2 f THF f THF/MeOH (10:1)]
was not successful due to extensive streaking of the magnesium
porphyrin. In such cases, the porphyrin-containing fractions were
combined, subjected to demetalation, and the product was purified
as the free base porphyrin.
1
stereoisomers: mp 92-95 °C; H NMR (THF-d8) δ 1.29 (s, 9H),
2.27 (s, 3H), 5.22-5.25 (m, 1H), 5.27-5.29 (m, 1H), 5.41-5.45
(m, 1H), 5.49-5.56 (m, 5H), 5.85-5.89 (m, 1H), 5.91-5.95 (m,
1H), 6.71-6.74 (m, 1H), 7.01-7.06 (m, 4H), 7.09-7.14 (m, 5H),
7.19-7.21 (m, 2H), 7.29-7.31 (m, 2H), 7.61-7.62 (m, 2H), 8.68
(m, 2H), 9.54-9.61 (br, 1H), 9.66-9.69 (br, 1H), 10.31-10.42
(br, 1H), 11.18-11.26 (br, 1H); 13C NMR (THF-d8) δ 21.3, 31.9,
35.2, 44.8, 45.0, 45.4, 97.2, 107.7, 107.9, 109.8, 110.1, 111.3, 120.9,
123.2, 125.9, 127.2, 128.9, 129.4, 129.5, 129.53, 131.2, 132.3,
132.4, 132.44, 133.1, 133.2, 134.3, 134.4, 134.5, 134.9, 134.93,
135.0, 136.3, 136.4, 140.5, 141.9, 144.1, 144.2, 145.1, 146.7, 150.2,
151.1, 182.5; MALDI-MS (POPOP) obsd 782.1, 783.1, 784.1,
785.1, 786.1, 787.1, 788.1, 789.1, calcd 785.27292 (C48H44BrN5O);
ESI-MS obsd 786.2777, calcd 786.2801 [(M + H)+, M )
C48H44BrN5O].
General Protocol for the Synthesis of Porphyrins (Method
4). Following the reported procedure,12 an oven-dried one-necked
round-bottomed flask (10 mL) containing a dry stir bar and fitted
with a vented Teflon septum was treated successively with a sample
of a bilane (1b-e, 0.300 mmol) and dry toluene (3.00 mL). DBU
(0.450 mL, 3.00 mmol, 10.0 mol equiv versus the bilane) was added
dropwise at room temperature. The reaction mixture darkened with
stirring over the course of 5 min. A sample of MgBr2 (0.166 g,
0.900 mmol, 3.00 mol equiv versus the bilane) was added in one
portion under vigorous stirring. (Note that a dry flask is essential,
as is vigorous stirring, so that MgBr2 does not clump as a solid on
the bottom of the flask, which typically lowers the yield of
porphyrin.) The reaction mixture was stirred for 1 min at room
temperature. The flask was fitted with a reflux condenser (4 cm
diameter × 30 cm) having the top end open to the atmosphere,
and the flask was placed in an oil bath preheated to 115 °C. The
reaction mixture (heterogeneous) was stirred at 115 °C. The crude
reaction mixture was checked by absorption spectroscopy and TLC
analysis (silica CH2Cl2). In most cases the formation of porphyrin
was complete in 2-3 h. The crude reaction mixture was checked
by LD-MS analysis for possible scrambling. The crude reaction
mixture was concentrated and then chromatographed [alumina,
CH2Cl2 f CH2Cl2/ethyl acetate (4:1) f (2:1)]. The porphyrin-
containing fraction was concentrated to afford a purple solid.
20-(4-tert-Butylphenyl)-15-(4-methylphenyl)-10-phenyl-5-(4-
pyridyl)porphinatomagnesium(II) (MgP-2e). Application of Method
4 with 2e (0.059 g, 0.075 mmol), DBU (0.113 mL, 0.750 mmol),
and MgBr2 (0.042 g, 0.25 mmol) in toluene (0.750 mL) with
chromatographic workup [alumina, CH2Cl2 f CH2Cl2/ethyl acetate
f (3:1) f (2:1) f ethyl acetate/MeOH (30:1)] afforded a solid.
The resulting product was washed with hexanes (3 × 5 mL) to
afford a purple solid (0.029 g, 54%): 1H NMR δ 1.64 (s, 9H), 2.69
(s, 3H), 7.59 (m, 2H), 7.74-7.76 (m, 3H), 7.83-7.86 (m, 2H),
8.08-8.20 (m, 8H), 8.75-8.80 (m, 2H), 8.83-8.85 (m, 8H); LD-
MS obsd 708.2; ESI-MS obsd 707.2893, calcd 707.2901
(C48H37MgN5); λabs (toluene) 407, 427, 564, 604 nm.
General Protocol for the Synthesis of Porphyrins Bearing
Three Pyridyl Substituents (Method 5). The procedure differed
from Method 4 in the following ways: (1) Bilane formation was
carried out in neat acetonitrile (no methanol). (2) The bilane was
not readily purified and hence was used in crude form, whereupon
a small amount of unreacted 1-acyldipyrromethane gave the
corresponding trans-A2B2-porphyrin. (3) Porphyrin formation was
carried out under microwave irradiation. (4) The magnesium
porphyrin was demetalated and the free base porphyrin was isolated.
(i) Bilane formation. A sample of 7-Br (0.217 g, 0.500 mmol)
in dry THF/MeOH (40.0 mL, 3:1) was treated all-at-once with
NaBH4 (0.473 g, 12.5 mmol, 25.0 mol equiv) under argon at room
(iii) Demetalation. The crude magnesium porphyrin was dis-
solved in CH2Cl2 (5 mL) and demetalated by the addition of TFA
(0.030 mL). The reaction mixture was stirred for 1 h, whereupon
a sample of triethylamine was added (0.020 mL). The crude reaction
mixture was washed (water, brine), dried (Na2SO4), and concen-
trated. The resulting product was chromatographed [silica, CH2Cl2
6740 J. Org. Chem. Vol. 73, No. 17, 2008

ABCD-Bilanes and ABCD-Porphyrins
f CH2Cl2/THF (1:10) f THF]. The porphyrin-containing fractions
were concentrated and combined to afford the free base porphyrin.
10-(4-Ethylphenyl)-5,15-di-3-pyridyl-20-(2-pyridyl)porphi-
natomagnesium(II) (MgP-9a). Following Method 5, 7-Br (0.217
g, 0.500 mmol) and 8a (0.164 g, 0.500 mmol) gave a red-brown
paste. The crude bilane was treated with DBU (0.750 mL, 5.00
mmol) and MgBr2 (0.276 g, 1.50 mmol) in toluene (5 mL) under
microwave conditions followed by standard workup to afford a
to 135 °C and then stabilized after 2 min), (3) allow to cool to
room temperature (∼1 min), (4) check the reaction mixture by TLC
analysis [silica, CH2Cl2, a streaking red-brown unidentified product
and a magnesium porphyrin typically were observed] and absorption
spectroscopy (3 bands were observed at 303, 425, and 525 nm),
(5) repeat steps 1-4 until the intermediate was largely consumed.
Most reactions were quite sluggish, in which case the reaction flask
was treated with microwave irradiation for a longer period of time
(∼6 h) prior to analysis. The total overall microwave irradiation
time typically was ∼24 h. The crude reaction mixture was
transferred to a round-bottomed flask with THF (HPLC-grade and
lacking stabilizer) and concentrated. The crude product was washed
(water, brine), dried (Na2SO4), and concentrated.
(iii) Demetalation. The procedure was identical to Method 5.
1-Bromo-15-butyl-5-ethyl-19-hexanoyl-10-propylbilane (12f).
Following Method 6, a solution of 11c-Br (0.242 g, 0.750 mmol)
in dry THF/MeOH (60.0 mL, 3:1) was treated with NaBH4 (0.708
g, 18.8 mmol). The standard workup procedure was followed. A
solution of 11g (0.225 g, 0.750 mmol) in acetonitrile (15.0 mL)
was added to the carbinol solution in ethyl ether (∼45.0 mL). The
ether was removed under reduced presssure, and Yb(OTf)3 (31.0
mg, 0.0495 mmol, 3.30 mM) was added. The reaction mixture was
stirred for 30 min at room temperature. The standard workup and
column chromatography afforded a brown paste (0.370 g, 81%),
presumably as a mixture of 8 stereoisomers: 1H NMR (THF-d8) δ
0.81-0.92 (m, 12H), 1.28-1.34 (m, 8H), 1.59-1.66 (m, 4H),
1.83-1.93 (m, 6H), 2.64 (t, J ) 7.2 Hz, 2H), 3.67 (t, J ) 7.6 Hz,
1H), 3.79 (t, J ) 7.6 Hz, 1H), 3.89 (t, J ) 7.8 Hz, 1H), 5.67-5.69
(m, 3H), 5.73-5.74 (m, 2H), 5.85-5.87 (m, 2H), 6.72-6.75 (m,
1H), 9.01-9.08 (br, 1H), 9.16-9.24 (m, 1H), 10.04-10.16 (br,
1H), 10.42-10.54 (br, 1H); 13C NMR (THF-d8) δ 22.6, 24.2, 24.3,
31.5, 33.3, 33.4, 38.9, 40.8, 42.5, 45.7, 45.72, 47.9, 48.2, 48.3, 48.6,
49.0, 50.8, 105.9, 115.1, 115.3, 117.2, 117.6, 119.8, 126.5, 141.9,
142.4, 142.5, 143.1, 143.8, 143.9, 144.1, 144.2, 146.9, 153.6; ESI-
MS obsd 606.29350, calcd 606.29333 (C34H47BrN4O).
1
purple solid (39 mg, 12%): H NMR (DMSO-d6) δ 1.44 (t, J )
7.6 Hz, 3H), 2.93 (q, J ) 7.6 Hz, 2H), 7.59 (d, J ) 7.0 Hz, 2H),
7.76-7.84 (m, 3H), 8.05-8.06 (m, 2H), 8.18-8.19 (m, 1H),
8.24-8.26 (m, 1H), 8.56 (d, J ) 7.0 Hz, 2H), 8.68-8.72 (m, 6H),
8.78 (d, J ) 4.6 Hz, 2H), 8.96 (d, J ) 4.6 Hz, 2H), 9.01 (d, J )
4.6 Hz, 1H), 9.28-9.36 (m, 2H); LD-MS obsd 667.4; ESI-MS obsd
667.2339, calcd 667.2335 [(M + H)+, M ) C43H29MgN7]; λabs
(THF) 409, 430, 571, 612 nm.
General Protocol for the Synthesis of Bilanes and
Porphyrins Bearing Alkyl Substituents (Method 6). The proce-
dure differs from Method 4 in the following ways: (1) The
1-acyldipyrromethane (typically a paste) was handled as a solution
in acetonitrile. (2) Bilane formation was carried out in neat
acetonitrile (no methanol) and at 50 mM instead of 500 mM. (3)
Porphyrin formation was carried out under microwave irradiation.
(4) The magnesium porphyrin was demetalated and the free base
porphyrin was isolated.
(i) Bilane Formation. A sample of 9-bromo-1-acyldipyr-
romethane 11-Br (0.250 mmol) in dry THF/MeOH (20.0 mL, 3:1)
was treated with NaBH4 (0.236 g, 6.25 mmol, 25.0 mol equiv versus
11-Br) to give the carbinol. On the basis of TLC analysis of the
crude reaction mixture [silica, hexanes/ethyl acetate (3:1)] the
reaction was complete in ∼30 min. The reaction mixture was poured
into a mixture of saturated aqueous NH4Cl in diethyl ether (∼40
mL). The organic phase was extracted with diethyl ether, washed
(water, brine), dried (K2CO3) and transferred to a round-bottomed
flask. A solution of 1-acyldipyrromethane 11 in acetonitrile (5 mL)
was transferred to the resulting carbinol solution via syringe. (Note
that alkyl-substituted 1-acyldipyrromethanes typically exist as a
paste at room temperature; therefore, the 1-acyldipyrromethane was
weighed in a vial and transferred as a solution). The resulting
solution was concentrated under low pressure with a rotary
evaporator (ambient temperature) to largely remove the ethyl ether
and give a volume of ∼5 mL (predominantly acetonitrile). The
resulting orange-red solution (containing a residual amount of ethyl
ether) was treated with Yb(OTf)3 (10.0 mg, 0.0165 mmol, ∼3.3
mM) under a slow flow of argon. An aliquot was removed from
the reaction mixture after 30 min and checked by TLC analysis
[silica, hexanes/ethyl acetate (3:1)]. A trace amount of unreacted
11 and bilane 12 were observed. Exposure of the TLC plate to
bromine further identified the components by the characteristic
orange spot and dark brown spot, respectively. The reaction was
neutralized with triethylamine [0.0250 mL, 0.165 mmol, 10 mol
equiv versus Yb(OTf)3]. The resulting mixture was diluted with
ethyl acetate (∼30 mL) and washed with water and brine. The
organic layer was dried (K2CO3) and concentrated to afford a dark
brown paste. The resulting crude product was chromatographed
[silica, hexanes/ethyl acetate (3:1)] to afford a brown paste.
(ii) Porphyrin Formation under Microwave Conditions. A
sample of bilane 12 (0.10 mmol) was transferred to a 10 mL glass
reaction vessel containing a magnetic stir bar and toluene (1 mL).
The headspace contained air. A sample of DBU (0.15 mL, 1.0
mmol) was added via syringe. The vessel was sealed with a septum.
The resulting mixture was stirred for 5 min at room temperature.
The reaction mixture darkened. The septum was removed, and
MgBr2 (0.055 g, 0.30 mmol) was added. The vessel was sealed
with a septum, and the resulting heterogeneous reaction mixture
was stirred at room temperature for 1 min. The vessel was subjected
to microwave irradiation at 100 W. The protocol was as follows:
(1) heat from room temperature to 115 °C (irradiate for 2 min), (2)
hold at 115 °C (irradiate for 30 min; temperature typically overshot
5-Butyl-15-ethyl-10-pentyl-20-propylporphyrin (P-12f). Ap-
plication of Method 6 with 12f (0.122 g, 0.200 mmol), DBU (0.300
mL, 2.00 mmol), and MgBr2 (0.111 g, 0.600 mmol) in toluene (2.0
mL) afforded a crude product. Demetalation of the crude product
was followed by chromatographic workup [silica, hexanes/CH2Cl2
1
(1:1)] to afford a purple solid (0.025 g, 24%): H NMR δ -2.68
(s, 2H), 0.98 (t, J ) 7.4 Hz, 3H), 1.13 (t, J ) 7.4 Hz, 3H), 1.32 (t,
J ) 7.4 Hz, 3H), 1.51-1.57 (m, 2H), 1.76-1.84 (m, 4H), 2.11 (t,
J ) 7.4 Hz, 3H), 2.48-2.56 (m, 6H), 4.87-4.99 (m, 8H),
9.45-9.46 (m, 8H); 13C NMR δ 14.4, 14.6, 15.2, 22.9, 23.0, 23.9,
29.0, 31.8, 32.9, 35.5, 35.7, 37.6, 38.6, 41.0, 118.3, 118.6, 118.7,
119.9, 127.2-129.3 (br); MALDI-FT-ICR-MS obsd 507.35271,
calcd 507.34877 [(M + H)+, M ) C34H42N4]; λabs (toluene) 419,
521, 554, 602, 662 nm.
Porphyrin Formation via a Bilene: 20-(4-tert-Butylphenyl)-
5-(4-ethylphenyl)-10-phenylporphinatomagnesium(II) (MgP-2i).
Bilene formation was accomplished with catalysis either by (i)
Yb(OTf)3 or (ii) p-toluenesulfonic acid followed by (iii) porphyrin
formation. (i) Yb(OTf)3 catalysis: A solution of 5h-Br (0.105 g,
0.250 mmol) in acetonitrile (2.35 mL) was treated with Yb(OTf)3
(1.15 mL, 0.0115 mmol, from a 10.0 mM stock solution in CH3CN/
MeOH (3:1)). The reaction mixture was stirred for 5 min and 6a
(0.106 g, 0.250 mmol) was added. The resulting heterogeneous
mixture was stirred at room temperature for 30 min. No product
was observed. A sample of Yb(OTf)3 (0.0420 g, 0.0682 mmol, total
acid concentration 23.0 mM) was added. The resulting heteroge-
neous mixture was stirred at room temperature for 2 h. On the basis
of TLC analysis [silica, hexanes/ethyl acetate (3:1)] only a trace
amount of product was observed. The reaction mixture was placed
in an oil bath preheated to 55 °C. The reaction mixture became
homogeneous in 10 min, and was maintained at 55 °C for 2 h. The
TLC analysis revealed the presence of a streaking component and
a trace amount of unreacted 6a. The reaction mixture was
concentrated. The resulting crude product was washed (water,
J. Org. Chem. Vol. 73, No. 17, 2008 6741

Dogutan and Lindsey
brine), dried (Na2SO4), and concentrated to give the crude bilene-
b. (ii) p-Toluenesulfonic acid catalysis: A solution of 5h-Br (0.052
g, 0.13 mmol) in CH2Cl2 (0.600 mL) was treated with p-
toluenesulfonic acid monohydrate solution [0.0285 g, 0.150 mmol
in CH2Cl2/MeOH (0.625 mL, 24:1)]. The reaction mixture was
stirred for 5 min and 6a (0.051 g, 0.13 mmol) was added. The
resulting heterogeneous mixture was stirred at room temperature
for 30 min. TLC analysis (silica, CH2Cl2) revealed the presence of
a streaking component. A sample of triethylamine (0.020 mL) was
added. The resulting crude product was washed (water, brine), dried
(Na2SO4), and concentrated to give the crude bilene-b. (iii) The
crude bilene-b (here reported from Yb(OTf)3 catalysis) was
dissolved in toluene (2.5 mL) and treated with DBU (0.375 mL,
2.50 mmol) and MgBr2 (0.138 g, 0.750 mmol) at 115 °C with
exposure to air for ∼4-6 h. Column chromatography [silica,
CH2Cl2 f CH2Cl2/ethyl acetate (4:1) f (2:1)] afforded 5,15-bis(4-
tert-butylphenyl)-10,20-bis(4-ethylphenyl)porphinatomagne-
sium(II) (<2% yield on the basis of absorption spectroscopy with
an assumed molar absorption coefficient at the Soret band of
500 000 M-1cm-1) followed by the title compound. Fractions
containing the latter were concentrated to give a purple solid (0.016
phyrin-forming reaction was carried out for 15 h, the product was
the singly fused porphyrin dimer, which was isolated following
column chromatography [silica, CH2Cl2 f CH2Cl2/ethyl acetate
(4:1) f (2:1)] as a purple solid (0.013 g, 8%). Data for the singly
fused porphyrin dimer of unknown stereochemical configuration
1
(MgP-2i-dimer): H NMR δ 1.52-1.59 (m, 24H), 3.05 (q, J )
9.6 Hz, 4H), 7.59-7.63 (m, 16H), 7.94-8.21 (m, 4H), 8.12-8.15
(m, 4H), 8.21-8.23 (m, 6H), 8.52-8.59 (m, 4H), 8.88-8.97 (m,
8H); 13C NMR δ 15.9, 29.1, 31.9, 35.0, 121.2, 122.2, 122.5, 122.7,
123.3, 126.0, 126.4, 127.1, 131.5, 131.6, 131.8, 131.9, 132.1, 132.2,
134.2, 134.6, 134.9, 135.0, 140.8, 141.3, 143.2, 144.0, 149.6, 149.8,
149.9, 150.1, 150.2, 150.4, 150.7, 155.2, 155.3; LD-MS obsd
1286.9, FAB-MS obsd 1286.5554, calcd 1286.5424 (C88H70Mg2N8);
λabs (toluene) 427 (br), 465 (br), 577 (br), 620 nm.
Acknowledgment. This work was funded 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 National Science
Foundation.
1
g, 11%): H NMR δ 1.54 (t, J ) 7.6 Hz, 3H), 1.63 (s, 9H), 2.99
(q, J ) 7.6 Hz, 2H), 7.54 (d, J ) 7.6 Hz, 2H), 7.74-7.76 (m, 5H),
8.10-8.16 (m, 4H), 8.22-8.23 (m, 2H), 8.89-8.95 (m, 4H),
8.98-9.04 (m, 2H), 9.29 (s, 2H), 10.12 (s, 1H); 13C NMR δ 15.9,
29.0, 32.0, 35.1, 106.3, 121.0, 121.5, 122.3, 123.5, 125.9, 126.5,
127.2, 131.6, 131.7, 132.1, 132.2, 132.5, 132.8, 134.8, 134.82,
134.9, 135.0, 140.8, 141.3, 143.1, 143.9, 149.8, 149.9, 150.0, 150.2;
LD-MS obsd 644.5, ESI-MS obsd 644.2784, calcd 644.2792
(C44H36MgN4); λabs (toluene) 422, 558, 597 nm. When the por-
Supporting Information Available: Stability information
about bilanes; procedures for preparing compounds; Experi-
mental Section; and spectral data for selected compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
JO8010396
6742 J. Org. Chem. Vol. 73, No. 17, 2008