Synthesis, structural characterization, aromatic characteristics, and metalation of neo-confused porphyrins, a newly discovered class of porphyrin isomers

Article abstract of DOI:10.1021/jo500580e

Neo-confused porphyrins represent a unique family of porphyrin isomers that retain overall aromatic characteristics by virtue of a 17-atom 18π electron delocalization pathway. These porphyrin analogues have a pyrrolic subunit linked in a 1,3-fashion so that a nitrogen atom is directly connected to a meso-bridging carbon. Pyrrole-3-carbaldehydes were shown to react with sodium hydride and 5-acetoxymethylpyrrole-2-carbaldehydes in DMF to give the crucial neo-confused dipyrrolic dialdehyde intermediates. MacDonald "2 + 2" condensation of the dialdehydes with a dipyrrylmethane afforded a dihydroporphyrinoid, and subsequent oxidation with 0.2% aqueous ferric chloride generated a series of fully conjugated neo-confused porphyrins. Unusual dihydroporphyrin byproducts were also identified. Reaction of neo-confused porphyrins with nickel(II) or palladium(II) acetate in refluxing acetonitrile gave excellent yields of the corresponding organometallic derivatives. Proton NMR spectroscopy demonstrates that the diatropic character of this system is diminished compared to regular porphyrins, although neo-confused porphyrins retain porphyrin-like UV-vis spectra. Protonation led to the sequential formation of mono- and dicationic species. Proton NMR spectra for the dications showed the presence of enhanced diamagnetic ring currents.

Full text of DOI:10.1021/jo500580e

Article
pubs.acs.org/joc
Synthesis, Structural Characterization, Aromatic Characteristics, and
Metalation of Neo-Confused Porphyrins, a Newly Discovered Class of
Porphyrin Isomers
Ruoshi Li, Aaron D. Lammer, Gregory M. Ferrence, and Timothy D. Lash*
Department of Chemistry, Illinois State University, Normal, Illinois 61790-4160, United States
*
S Supporting Information
ABSTRACT: Neo-confused porphyrins represent a unique family of porphyrin isomers that retain overall aromatic
characteristics by virtue of a 17-atom 18π electron delocalization pathway. These porphyrin analogues have a pyrrolic subunit
linked in a 1,3-fashion so that a nitrogen atom is directly connected to a meso-bridging carbon. Pyrrole-3-carbaldehydes were
shown to react with sodium hydride and 5-acetoxymethylpyrrole-2-carbaldehydes in DMF to give the crucial neo-confused
dipyrrolic dialdehyde intermediates. MacDonald “2 + 2” condensation of the dialdehydes with a dipyrrylmethane afforded a
dihydroporphyrinoid, and subsequent oxidation with 0.2% aqueous ferric chloride generated a series of fully conjugated neo-
confused porphyrins. Unusual dihydroporphyrin byproducts were also identified. Reaction of neo-confused porphyrins with
nickel(II) or palladium(II) acetate in refluxing acetonitrile gave excellent yields of the corresponding organometallic derivatives.
Proton NMR spectroscopy demonstrates that the diatropic character of this system is diminished compared to regular
porphyrins, although neo-confused porphyrins retain porphyrin-like UV−vis spectra. Protonation led to the sequential formation
of mono- and dicationic species. Proton NMR spectra for the dications showed the presence of enhanced diamagnetic ring
currents.
INTRODUCTION
common with the porphyrin macrocycle, consists of four
pyrrolic rings connected by a total of four methine units.
However, in porphycene there are two direct connections
between pyrrole moieties, while the remaining linkages consist
of two carbon units. Porphycene is also fully aromatic and
possesses 18π electron pathways that are similar to those found
■
The porphyrin macrocycle is one of the best studied of all
1
chemical systems. Initially, much of the work in this area was
directed at the structure elucidation and synthesis of naturally
occurring porphyrins and related species such as the
2
,3
chlorophylls.
However, porphyrins have properties that
1
7
in porphyrin. Subsequently, several other examples of
make them superior ligands for transition metal ions, and the
inorganic and catalytic chemistry of these structures has
attracted considerable attention. Furthermore, porphyrins
18
constitutional isomers of this type were synthesized. In
4
1994, two groups reported a different type of porphyrin isomer
2
where one of the pyrrolic units had been inverted, and this
have found applications in diverse areas that include medicine
1
9,20
5
system was named N-confused porphyrin.
Although
(
e.g., as photosensitizers in photodynamic therapy), optical
6
7
speculations on the possible formation of N-confused
materials, and nanotechnology. In addition, porphyrins
exhibit unusual nonbenzenoid aromatic character over the
entire macrocycle, and this is often attributed to the presence of
21,22
porphyrins had been published more than 50 years earlier,
the 1994 discoveries were unexpected and opened up an
2
3,24
8
exciting new area of research.
N-Confused porphyrins exist
an 18π electron circuit (Scheme 1, shown in bold). Given the
in two major tautomeric forms, 2a and 2b, and form diverse
remarkably large number of studies that have been carried out
on the porphyrins, it is not surprising that investigations into
related macrocyclic systems have been increasingly pur-
11
coordination complexes. Tautomer 2a is fully aromatic due to
the presence of the 18π electron pathway, but 2b is cross-
conjugated and exhibits substantially reduced diatropic
9
−11
12
sued.
This includes work on expanded porphyrins,
1
3
14
contracted porphyrins, heteroanalogues, and carbaporphyr-
1
5
ins. In 1986, Vogel reported the synthesis of porphycene (1),
Received: March 11, 2014
Published: April 3, 2014
16
the first example of a porphyrin isomer. Porphycene, in
©
2014 American Chemical Society
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Scheme 1
Scheme 2
2
5
26
the benzo-unit fell below 9 ppm. These values do not compare
character. As is the case for carbaporphyrinoid systems, N-
confused porphyrins form organometallic derivatives under
mild conditions, and the rich chemistry of this system has led to
the formation of porphyrinoid structures such as N-fused
to the downfield resonances for meso-protons in true
31
porphyrins, which commonly show up near 10 ppm. Neo-
confused porphyrin 4a was shown to react with nickel(II)
acetate in refluxing acetonitrile to give the corresponding
1
1
porphyrins. Moreover, doubly N-confused porphyrins with
two inverted pyrrole rings have also been reported.
A third type of porphyrin isomer 3 was recently postulated
where one of the pyrrole rings is linked to a bridging methine
carbon (meso-carbon) via a nitrogen atom, and this new
27
28
metallo-derivative 8a in 90% yield. However, in the original
study, the corresponding palladium(II) complex 8b could not
be isolated in pure form.
To extend our studies into this fascinating new porphyrin
isomer system, we explored the synthesis of neo-confused
porphyrins without fused benzene units. This approach would
enable the properties of “true” neo-confused porphyrins to be
assessed rather than those of the benzo-fused structures. In
addition, it is anticipated that the properties of this system will
differ as significantly from porphyrins as the intensively
explored N-confused porphyrins do, and far more in-depth
investigations are required. In this paper, full details on the
synthesis, structural characterization, and metalation of neo-
confused porphyrins are reported, and the aromatic character-
istics of these porphyrinoids are explored by spectroscopic
28,29
isomeric form was called neo-confused porphyrin.
This
system can potentially take on aromatic characteristics due to
the presence of a 17-atom 18π electron delocalization pathway.
DFT studies showed that the neo-confused system will be near
planar, although NICS calculations indicate that the diatropic
character will be somewhat reduced compared to true
porphyrins. Examples of benzo-fused neo-confused porphyr-
ins 4 were prepared by using the MacDonald “2 + 2”
condensation pathway (Scheme 2). Indole-3-carbaldehyde
reacted with acetoxymethylpyrrole 5 in the presence of sodium
hydride to give N-pyrrolylmethylindole 6a in good yields.
Treatment of 6a with TFA, followed by the addition of
trimethyl orthoformate at 0 °C, afforded the related dialdehyde
b. The dialdehyde was reacted with dipyrrylmethanes 7 in
the presence of p-toluenesulfonic acid and following oxidation
with DDQ, benzo-neo-confused porphyrins were isolated in
3
0
28
28
3
2,33
methods.
This work provides a framework for future
investigations into neo-confused porphyrinoid systems.
2
8
6
RESULTS AND DISCUSSION
■
Synthesis of Neo-Confused Porphyrins. A “2 + 2”
synthetic route to neo-confused porphyrins was investigated.
Retrosynthetically, neo-confused dipyrrylmethanes 10 were
required as pivotal intermediates, and it was anticipated that
these might be obtained in turn from pyrrole aldehydes 11 and
acetoxymethylpyrrole 5 (Scheme 3). This approach parallels
2
8
2
4−25% yield. The UV−vis spectra for 4a and 4b were
remarkably porphyrin-like, showing a strong Soret band at 407
nm and a series of Q bands between 503 and 615 nm. These
porphyrin analogues also exhibited significant diatropic
character and the proton NMR spectrum for 4a showed the
internal CH and NH resonances at upfield values of −0.33 and
28
our earlier synthesis of benzo-neo-confused porphyrins 4.
28
34
−
0.74 ppm, respectively. Nevertheless, these shifts are
Pyrrole-3-carbaldehyde (11a) was dissolved in THF and
treated with sodium hydride. The mixture was then refluxed
relatively small compared to those observed for porphyrins
and carbaporphyrins. The external meso-protons for 4a were
similarly shifted downfield to give four 1H singlets at 8.91, 8.96,
35
with acetoxymethylpyrrole 5 in an attempt to generate the
corresponding dipyrrolic product 13a (Scheme 4). These
conditions gave 13a in up to 36% yield, together with varying
9
.68, and 9.99 ppm, although only the meso-protons adjacent to
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1
5,37
Scheme 3
condensation.
This approach requires the availability of
suitable tripyrrolic intermediates, and the synthesis of neo-
confused porphyrins would necessitate the production of
modified tripyrranes such as 15 (Scheme 5). With this in
Scheme 5
Scheme 4
mind, dipyrrole aldehydes 13a and 13b were reduced with
sodium borohydride to give the corresponding carbinols 16 in
good yields (Scheme 5). Similarly, 6a was reduced to give the
related indole carbinol 17 (Scheme 6). Carbinols 16a and 16b
Scheme 6
were reacted with α-unsubstituted pyrrole 18 under mildly
acidic conditions, but this failed to give the expected
condensation to form neo-confused tripyrranes 15a or 15b
(Scheme 5). Extensive decomposition occurred under strongly
acidic conditions, and no identifiable products could be
detected by proton NMR spectroscopy. In the indole carbinol
case, however, 17 reacted with 18 in refluxing ethyl acetate
containing 5% acetic acid to give the tripyrrane analogue 19 in
93% yield (Scheme 6). Unfortunately, attempts to cleave the
tert-butyl esters with TFA led to decomposition. During the
course of these studies, attempts were made to purify carbinol
17 by column chromatography on silica gel. However, instead
of eluting the purified carbinol, a bilane analogue 20 was
isolated instead in 76% yield (Scheme 7). The formation of the
doubly neo-confused bilane can be rationalized as follows:
Protonation of 17, followed by loss of water, would afford the
azafulvene cation 21, and this can react with a second molecule
of 17 to give 22. Subsequent elimination of formaldehyde and
loss of a proton would then lead to the observed product
(Scheme 7). Although the bilane analogue might be used to
prepare doubly neo-confused porphyrins, attempts to cleave the
tert-butyl esters resulted in decomposition.
amounts of the tripyrrolic byproduct 14. The byproduct
resulted from deprotonation of 13a, and further reaction with
acetoxymethylpyrrole 5 generated the second nitrogen−carbon
bond. The lack of selectivity was a cause for concern, but the
problem was easily overcome by carrying out the reaction in
DMF at 100 °C. Under these conditions, 13a was generated in
80% yield, and only a small amount of 14 was observed. Methyl
36
4
-formylpyrrole-2-carboxylate (11b) reacted with sodium
hydride in THF to give the related dipyrrolic product 13b in
7% yield (Scheme 4). The higher selectivity in this case was
7
attributed to the anticipated increased acidity of the NH in 11b
due to stabilization of the conjugate base by the presence of
two electron-withdrawing carbonyl moieties. However, at-
tempts to convert 13a and 13b into the corresponding
dialdehydes 10a and 10b were unsuccessful. When dipyrroles
13a or 13b were treated with TFA, complete degradation took
place. Although this approach had been successfully applied to
the preparation of 6b, we recognized that self-condensation
reactions could potentially occur under these reaction
conditions. For this reason, alternative strategies for synthesiz-
ing neo-confused porphyrins were considered.
Many examples of carbaporphyrinoid systems have been
prepared using the “3 + 1” variant on the MacDonald
Given the difficulties encountered in these studies, our
attention returned to the “2 + 2” route to neo-confused
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Scheme 7
Scheme 9
Scheme 10
porphyrins. As the principle impediment to using this strategy
was the problem in converting the formylpyrroylmethylpyrrole
esters 13 into the corresponding dialdehydes, attempts were
made to circumnavigate the issue by introducing the required
aldehyde moiety at an earlier stage in the synthesis. In order to
do this, acetoxymethylpyrrole aldehydes 12 were required.
Attempts to react pyrrole aldehyde 23 with lead tetraacetate led
to decomposition, even though related pyrrole esters react
under these conditions to give acetoxymethylpyrroles. An
example of an acetoxymethylpyrrole aldehyde was previously
prepared by chlorination of a 5-methylpyrrole-2-carbaldehyde
with tert-butyl hypochlorite in carbon tetrachloride, followed by
treatment of the intermediary chloromethylpyrrole with sodium
monoalcohol 26 would be expected to occur more readily than
a second reduction to dialcohol 28, as the aldehyde moiety in
2
6 would be expected to have significantly reduced reactivity
(
Scheme 9). In order to apply this approach, significant
quantities of dialdehydes 25 were required. It has been reported
that pyrrole dialdehydes 25 can be prepared by reacting 3,4-
dialkylpyrrole-2-carboxylic acids (e.g., 29a) with TFA and
39
triethyl orthoformate (Scheme 11). However, in our hands,
Scheme 11
38
acetate in acetic acid. Hence, 23 was reacted with t-BuOCl to
give the chloromethyl derivative 24, and subsequent treatment
with NaOAc-AcOH afforded acetoxymethylpyrrole 12a
(
Scheme 8). Even so, the desired acetate 12a was only isolated
in 25% yield.
Scheme 8
this procedure has given variable results. Although excellent
yields were obtained in some experiments, little or no
dialdehyde was generated in other cases. The original paper
did not specify precise conditions, and it became necessary to
optimize the reaction conditions for these procedures. These
reactions were found to be very temperature sensitive. When
dimethylpyrrole 29a was reacted with TFA−CH(OEt) at 10
3
°
C, dialdehyde 25a was isolated in 71% yield, a significant
improvement over the previously reported 49% yield. The first
step in the reaction involved decarboxylation of the pyrrole
carboxylic acid, and for this reason, α-unsubstituted pyrroles
such as 29b can also be used in this chemistry. Under
optimized conditions, 29b was converted into the correspond-
ing 3,4-diethylpyrrole dialdehyde in 61% yield, a considerable
improvement over the earlier report, but the reaction was again
very sensitive to variations in temperature. Reduction of 25a or
25b with 0.25 equiv sodium borohydride in methanol at 0 °C
proved to be highly selective, and the corresponding carbinols
26 were isolated in excellent yields (Scheme 9). Nevertheless,
A different strategy was required to prepare these critical
intermediates. We speculated that pyrrole dialdehydes 25 might
be selectively reduced with sodium borohydride to give the
corresponding monoalcohols 26 and that subsequent acetyla-
tion would afford the required acetates 12 (Scheme 9). Pyrrole
aldehydes 27 have considerably reduced reactivity compared to
aromatic aldehydes, such as benzaldehyde, due to a favored
dipolar resonance contributor 27′ (in essence, they behave like
vinylogous amides) (Scheme 10). However, this effect is
diminished in pyrrole dialdehydes 25 because the nitrogen
cannot interact as effectively with both aldehyde units. Hence,
the initial reaction with sodium borohydride to give the
excess NaBH rapidly produced the related dicarbinols 29.
4
Subsequent reaction with acetic anhydride and pyridine then
gave the acetoxymethylpyrroles 12. At room temperature, the
yields were relatively poor, but much better results were
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obtained when the reactions were conducted at 5 °C. Optimal
results were achieved when the reactions were carried out at −3
MS showed that the byproduct has the molecular formula
C H N O , while the NMR data suggested that the structure
45
48
6
6
°
C for 1 h, and excellent yields of the acetate derivatives were
incorporated one dipyrrylmethane unit from 7a and two neo-
confused components from 10c. In the 500 MHz proton NMR
spectrum, six methyl units were identified as singlets between
1.88 and 2.01 ppm, and two additional methyl groups were
identified as two long-range coupled quartets at 1.44 and 1.85
ppm. Two aldehyde moieties were evident (two 1H singlets at
9.30 and 9.63 ppm), as well as two 3H singlets at 3.72 and 3.80
ppm, corresponding to methoxy resonances. Two 1H doublets
at 4.23 and 5.72 ppm gave a coupling constant J = 14.0 Hz, and
isolated (Scheme 9). Nevertheless, when the reaction time was
increased, the yields for the acetate product deteriorated.
Methyl 4-formylpyrrole-2-carboxylate (11b) was reacted with
sodium hydride and 12b in DMF. When the reaction was
carried out at 22 °C for 18 h, the ratio of starting material
(
11b) to product (10c) was 1:2.2. At 40 °C, the ratio improved
slightly to 1:2.8, but at 80 °C the starting material/product ratio
was 1:1. Unexpectedly, when the reaction was conducted at 30
1
1
°C, the starting material to product ratio was a greatly
H− H COSY allowed these resonances to be assigned as being
improved 1:14. Clearly, this chemistry is again very sensitive to
variations in temperature. Under the optimized reaction
conditions, dipyrrolic dialdehyde 10c was isolated in 75%
yield (Scheme 4). Similarly, 11b reacted with 12c to afford the
related dialdehyde 10d. However, when 3-pyrrolecarbaldehyde
due to a geminally coupled diastereotopic methylene unit. Four
doublets were noted at 6.69, 7.19, 7.91, and 8.39 ppm (J = 1.8
Hz), corresponding to CH protons on two separate pyrrolic
subunits. Four 1H singlets were observed at 4.90, 5.58, 6.19,
and 6.96 ppm, and the HSQC spectrum demonstrated that the
2
(
11a) was reacted with sodium hydride and 12b, very poor
first three singlets corresponded to sp carbon atoms, while the
3
yields of the related neo-confused dipyrrole 10e were obtained.
Dialdehyde 10c was reacted with dipyrrylmethane 7a at
room temperature for 16 h in methanol-dichloromethane in the
presence of p-toluenesulfonic acid (Scheme 12). If the reaction
furthest downfield of these signals corresponded to an sp
hybridized CH, which correlated with a resonance in the
carbon-13 NMR spectrum at 50.7 ppm. There is clearly no
indication of macrocyclic aromatic character, a result that is
consistent with an open-chain structure or a macrocycle with
interrupted conjugation. The UV−vis spectrum gave a
moderately strong band at 385 nm and two broad absorptions
at 644 and 709 nm. Addition of trace amounts of TFA gave rise
to a new species with an absorption at 390 nm and
bathochromically shifted broad bands at 717 and 791 nm. At
higher concentrations of TFA, a third species evolved showing
a strong absorption at 428 nm and broad peaks above 700 nm.
These results indicate that the green byproduct undergoes two
sequential protonation steps to afford a dication, and this
suggests that two basic nitrogens are available in the original
molecule. The identity of the byproduct was firmly established
by X-ray crystallography, which demonstrated that it is a
dihydroporphyrin 31 with two appended pyrrolic units that are
trans to one another (Scheme 12). Full details of the
crystallographic data were presented in the preliminary
Scheme 12
32
communication and are not repeated herein. The core 5,6-
dihydroporphyrin system found in 31 is unusual, but similar
species have previously been obtained by cyclizing a,c-
4
0,41
biladienes.
On the other hand, the generation of this type
of hexapyrrolic product in a MacDonald condensation reaction
is totally unprecedented. The formation of 31 can be
rationalized by the mechanism shown in Scheme 13. Initial
condensation between 7a and neo-confused dipyrrylmethane
dialdehyde 10 would afford the bilene intermediate 32, and
subsequent cyclization would yield the observed phlorin 30a.
However, reaction with a second molecule of 10c would give an
open-chain hexapyrrolic intermediate 33a. Subsequent depro-
tonation could produce an enamine-type structure 34a, and
subsequent cyclization would then lead to a tetrahydroporphyr-
in 35a. This species is presumably then oxidized to give the
observed byproduct 31. Diethyl neo-confused dipyrrylmethane
dialdehyde 10d was similarly reacted with 7a in the presence of
p-toluenesulfonic acid, and following oxidation with 0.2%
aqueous ferric chloride gave neo-confused porphyrin 9b in 42%
yield. The oxidation appeared to occur slightly more slowly in
this case, and treatment with ferric chloride was extended to 25
min. A similar green byproduct was also generated. In some
reactions, two green bands were observed. One of these
corresponded to dihydroporphyrin 31b, but the second
compound gave proton NMR spectra that were consistent
mixture was purified by column chromatography without
carrying out an oxidation step, a bright blue fraction
corresponding to neo-confused phlorin 30a was collected.
The phlorin is somewhat unstable, and exposure to air led to
the gradual formation of neo-confused porphyrin 9a. Attempts
to oxidize the crude reaction mixture with DDQ led to
decomposition rather than the formation of 9a. However, when
the reaction mixture was shaken with a 0.2% aqueous solution
of ferric chloride for 20 min, the phlorin was smoothly
converted into the neo-confused porphyrin. Following
extraction, column chromatography, and recrystallization from
chloroform−hexanes, 9a was isolated in 55% yield. The neo-
confused porphyrin eluted from an alumina column as a purple
fraction, but this was followed by a green colored band.
Following recrystallization from chloroform−hexanes, the
byproduct was isolated as a green powder in 26% yield. HR
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Scheme 13
external proton on the neo-confused ring. This resonance is
coupled to the interior CH, which shows up as a broadened
peak at 1.32 ppm; the internal NH was observed at 1.78 ppm.
Again, the upfield shifts for the inner protons are substantially
smaller than those seen for porphyrins or carbaporphyrins. In
porphyrins, methyl substituents commonly show up at 3.6 ppm
due to the strong deshielding influence of the aromatic system,
but the methyl substituents for 9b appear as two 3H singlets at
2
.95 and 3.08 ppm, values that again confirm the reduced
diatropicity of neo-confused porphyrins. The diatropicity of 9b
is also slightly diminished compared to benzo-neo-confused
porphyrins 4, which shows the interior CH and NH resonances
2
8
at −0.74 and −0.33 ppm, respectively. Neo-confused
porphyrins have an 18π electron delocalization pathway that
includes the pair of electrons on the neo-confused nitrogen
atom. In porphyrinoids 9, the presence of the electron-
withdrawing ester unit is likely to disrupt this pathway due to
the presence of cross-conjugated dipolar canonical forms such a
9x (Scheme 14), and this may be responsible for the reduced
Scheme 14
with the reduced species 35b. Tetrahydroporphyrin 35b was
too unstable to isolate, and prolonged oxidation afforded a
single green fraction corresponding to 31b in 10−18% yield.
Finally, MacDonald condensation of 7a with dialdehyde 10e
was carried out in an attempt to prepare a porphyrinoid 9c with
an unsubstituted neo-confused ring. Unfortunately, no trace of
porphyrinoid product was observed, and this system has not
been further pursued due to the difficulties encountered in
preparing intermediate 10e. The failure of this chemistry may
be due to the intermediates taking on a conformation that is
incompatible with macrocycle formation.
Spectroscopic Characterization of Neo-Confused
Porphyrins. The spectroscopic data for neo-confused
porphyrins 9a and 9b were consistent with an aromatic system,
although they exhibit diminished aromatic character compared
to true porphyrins. The proton NMR spectrum for 9b in
diatropic character of 9 compared to 4. In addition, the 17-
atom delocalization pathway found in 4 and 9 appears to be less
effective than the 18-atom delocalization pathways found in
porphyrins and carbaporphyrins, and this observation is
supported by nucleus independent chemical shift calculations.
Neo-confused porphyrin 9a gave a similar proton NMR
30
CDCl showed the presence of a moderate diamagnetic ring
spectrum in CDCl . The carbon-13 NMR spectra of 9a and
3
3
current, and the meso-protons were observed as four 1H
singlets at 8.29, 8.33, 8.77, and 10.70 ppm (Figure 1). One of
these resonances is substantially deshielded, but this is due to
the proximity of the CH to the carbonyl moiety. As the meso-
protons in porphyrins show up near 10 ppm, the deshielding
effect due to macrocyclic conjugation in 9b is much smaller. A
doublet was also observed at 8.64 ppm (J = 1.8 Hz) for the
9b confirmed the absence of symmetry within the macrocycle
and showed the internal CH at 124.9 ppm. For 9b, the meso-
carbons furthest removed from the neo-confused unit appeared
at 93.2 and 93.7 ppm, while the C-5 and C-20 resonances were
identified at 113.5 and 113.8 ppm, respectively. The inner NH
proton could reside on any one of the three internal nitrogens,
but the data does not allow the identification of specific
tautomers. However, DFT calculations have demonstrated that
the depicted tautomer is favored, and in any case, this species
has less steric hindrance within the macrocyclic cavity and can
30
take part in favorable hydrogen bonding interactions.
Addition of TFA to 9b in CDCl afforded the corresponding
3
dication 9bH22+ (Scheme 15), and this species showed a
significantly enhanced diatropic ring current. The proton NMR
spectrum showed the internal CH resonance shifted upfield to
−
1.21 ppm, while the meso-protons were shifted downfield to
give four 1H singlets at 8.84, 8.89, 9.58, and 11.14 ppm (Figure
). The methyl substituents gave rise to two 3H singlets at 3.12
2
and 3.19 ppm, values that reflect further deshielding due to the
aromatic ring current. The dication is stabilized by charge
2
+
delocalization due to resonance contributors, such as 9′H
,
2
that possess 18-atom aromatic delocalization pathways
(Scheme 15), and these are presumably responsible for the
observed increase in diatropicity. The same type of resonance
Figure 1. The 500 MHz proton NMR spectrum of neo-confused
porphyrin 9b in CDCl3.
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was assigned to the dication 9H 2+. Similar results were
Scheme 15
2
obtained for 9b (Figure 3).
Figure 3. UV−vis spectra of neo-confused porphyrin 9b. Red line: free
+
base in dichloromethane. Blue line: monocation 9bH in CH Cl with
2
2
equiv TFA. Purple line: dication 9bH22 in 1% TFA-CH Cl .
+
5
2 2
Metalation of Neo-Confused Porphyrins. The metal-
ation of neo-confused porphyrin 9a was also investigated.
Reaction of 9a with nickel(II) acetate in refluxing acetonitrile
afforded the corresponding nickel(II) complex 36a as orange
crystals in 68% yield (Scheme 16) following purification by
Scheme 16
column chromatography and recrystallization from chloro-
form−hexanes. The proton NMR spectrum for 36a showed
that the diatropic characteristics for the metal complex are
slightly increased compared to the free base form 9a, and the
meso-protons are shifted downfield to give four 1H singlets at
8
.47, 8.69, 8.87, and 10.85 ppm. The β-pyrrolic proton now
shows up as a singlet at 8.63 ppm. The UV−vis spectrum for
6a was markedly different from 9a, showing two Soret-like
bands at 334 and 385 nm and several Q bands between 500 and
00 nm (Figure 4). The related palladium(II) complex 36b was
Figure 2. The 500 MHz proton NMR spectrum of neo-confused
porphyrin dication 9aH22 in TFA-CDCl3.
3
+
7
contributor can be written for the free base porphyrinoid, but
this is disfavored due to the associated charge separation. The
2
+
carbon-13 NMR spectrum of 9bH2 in TFA-CDCl showed
3
the internal CH at 111.0 ppm, while the meso-carbons gave
resonances at 94.4 (15-CH), 95.5 (10-CH), 117.5 (20-CH),
and 119.1 ppm (5-CH).
The UV−vis spectrum for 9a was porphyrin-like, showing a
Soret band at 390 nm and a series of Q bands at 525, 549, 562,
and 604 nm. However, the intensity of the Soret band is
somewhat reduced compared to true porphyrins. Addition of
1
−5 equiv of TFA resulted in the formation of a new species
+
that was attributed to a monocation 9H (Scheme 15). The
Soret band shifted to 396 nm, and the Q bands were
bathochromically shifted to give absorptions at 511, 550, 584,
Figure 4. UV−vis spectra of metallo-neo-confused porphyrins in
dichloromethane. Red line: nickel complex 36a. Blue line: palladium
complex 36b.
6
14, and 662 nm. At higher concentrations of TFA, a third
species was generated with a Soret band at 409 nm, and this
4
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Article
prepared by reacting 9a with palladium(II) acetate in refluxing
acetonitrile (Scheme 16). Following column chromatography
on alumina and recrystallization from chloroform−hexanes,
36b was isolated in 78% yield as dark green crystals. The
diatropic character for the palladium complex was slightly
enhanced compared to 36a, and in the proton NMR spectrum,
the meso-protons appeared as four 1H singlets at 8.58, 8.79,
9.01, and 10.97 ppm, while the external pyrrolic proton gave a
singlet at 8.70 ppm (Figure 5). The UV−vis spectrum of 36b
was quite different from 36a and showed three Soret bands at
333, 384, and 414 nm, together with Q bands at 501, 534, 583,
and 628 nm (Figure 4).
Figure 7. Color POV-Ray rendered ORTEP III drawing (50%
probability level, hydrogen atoms drawn arbitrarily small) of
palladium(II) complex 36b. Selected bond lengths (Å): Pd−N(24),
2
.002(2); Pd−N(23), 2.046(3); Pd−N(22), 2.031(2); Pd−C(21),
Figure 5. The 500 MHz proton NMR spectrum of palladium complex
1.958(3). Selected bond angles (deg): C(21)−Pd−N(24), 90.4(1);
C(21)−Pd−N(22), 89.6(1); N(24)−Pd−N(22), 179.8(1); C(21)−
Pd−N(23), 179.3 (1); N(24)−Pd−N(23), 90.0(1); N(22)−Pd−
N(23), 90.0(1).
3
6b in CDCl3.
Crystals of 36a and 36b that were suitable for X-ray
diffraction analysis were obtained by vapor diffusion of hexanes
into chloroform solutions, and the results confirm both the
presence of the coordinated metal cations and the neo-
confused moieties (Figures 6 and 7). The asymmetry provided
by the ethyl substituents provided well-ordered structures
where the neo-confused nitrogen atom could easily be
identified. For nickel(II) complex 36a, two crystallographically
independent species were identified in the X-ray structure, the
bond lengths and angles of which are indistinguishable. There
are subtle variations in torsions, and the primary difference
between the two molecules is that one presents the two ethyl
substituents on the same face of the macrocycle and the other
has the ethyl groups directed toward opposing faces. This is
presumably attributable to nothing more than subtle packing
forces. In addition to the well-behaved displacement parame-
ters, the structure shows that the macrocycle is rather planar, as
evidenced by the 0.046 Å rms distance the framework atoms lie
from the plane defined by Ni, C(21), N(22), N(23), and
N(24). The largest deviations from the plane are C(10)
(
0.096(9) Å), C(3) (0.088(8) Å), and C(12) (0.081(7) Å). Of
the 24 framework atoms, only six deviate more than 0.05 Å
from the aforementioned plane. The structure exhibits
framework bond distances consistent with a generally localized
π-bonding model. The metal coordination environment of 36a
is essentially a four-coordinate square planar geometry about
the Ni(II) metal center. The coordination sphere bond lengths
and angles are essentially indistinguishable from the related
NCP complexes Ni(2-(2-bromoethyl)NCTPP), Ni(2-(3-
phenoxypropyl)NCTPP), Ni(2-CH C H NCTPP), and
Ni(2-(4-MeO CC H CH )NCTPP), although 36a is more
4
2
4
3
44
2
6
5
45
2
6
4
2
rigorously planar than these NCP complexes. Similar values
46
were also obtained for a nickel(II) azuliporphyrin complex. In
6a, the 1.915(2) Å Ni−C(21) distance is significantly shorter
Figure 6. Color POV-Ray rendered ORTEP III drawing (50%
probability level, hydrogen atoms drawn arbitrarily small) of one of the
two crystallographically independent residues of nickel neo-confused
porphyrin 36a. Selected bond lengths (Å): Ni−N(24), 1.931(2); Ni−
N(23), 1.969(2); Ni−N(22), 1.968(2); Ni−C(21), 1.915(2). Selected
bond angles (deg): C(21)−Ni−N(24), 90.10(7); C(21)−Ni−N(22),
3
than the 1.969(2) Å Ni−N(23) distance, which is consistent
with the greater basicity of the carbanion ligand. The X-ray
crystal structure of palladium complex 36b also showed that the
macrocycle is remarkably planar, as evidenced by the 0.032 Å
rms distance the framework atoms lie from the plane defined by
Pd, C(21), N(22), N(23), and N(24) (Figure 7). The largest
deviations from the plane are C(2) (−0.067(5) Å) and C(20)
8
1
9
9.53(7); N(24)−Ni−N(22), 179.47(6); C(21)−Ni−N(23),
79.32(7); N(24)−Ni−N(23), 90.21(6); N(22)−Ni−N(23),
0.16(6).
4
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−0.095(9) Å), and only two of the 24 framework atoms
Article
(
under reflux with palladium(II) acetate in acetonitrile. Attempts
to purify the crude product by column chromatography on
silica led to a considerable amount of decomposition, and only
impure samples of 8b could be isolated. However, when the
purification was carried out on a neutral grade 3 alumina
column, the metalated derivative was isolated in pure form.
Following recrystallization from chloroform−hexanes, 8b was
isolated as dark green crystals in 92% yield. The meso-protons
in the proton NMR spectrum of 8b showed up at 9.09, 9.33,
9.83, and 9.91 ppm, values that are very similar to those
observed for the free base neo-confused porphyrin 4a and
slightly further downfield compared to the corresponding
nickel(II) complex 8a. Hence, the diatropic character of 8b
appears to be comparable to 4a but slightly enhanced compared
to nickel(II) complex 8a. The nickel(II) complex may be less
planar in solution as porphyrinoids often have to ruffle to
accommodate the smaller nickel(II) cation, and this factor
may explain the observed differences. The UV−vis spectrum of
palladium(II) complex 8b is very different from the related
nickel(II) complex, as was the case for metalloporphyrinoids
36a and 36b. Complex 8b gave three Soret-like bands at 335,
390, and 421 nm, together with four Q bands at 504, 533, 553,
and 595 nm. This contrasts to the UV−vis spectrum for
nickel(II) derivative 8a, which shows a single Soret band at 390
nm and two Q absorptions at 514 and 623 nm.
deviate by more than 0.05 Å from the aforementioned plane.
The structure again exhibits framework bond distances
consistent with a generally localized π-bonding model. The
metal coordination environment of 36b is essentially a four-
coordinate square planar geometry about the Pd(II) metal
center. The planarity and coordination sphere metrics are
similar to the related NCP complexes Pd(2-
4
3
ethoxycarbonylmethyl)NCTPP)
and Pd(2-CH C H )-
2 6 5
47
4
4
NCTPP), as well as a palladium(II) azuliporphyrin and a
48
palladium(II) pyrazoloporphyrin. As expected, the 1.958(3) Å
Pd−C(21) distance is significantly shorter than the 2.046(3) Å
Pd−N(23) distance due to the greater basicity of the carbanion
ligand.
Improved Synthesis, Structural Characterization, and
Metalation of Benzo-Neo-Confused Porphyrins. As
efficient syntheses of neo-confused porphyrins have been
developed, we sought to apply the same principles to the
preparation of benzo-neo-confused porphyrins. Specifically, in
the earlier study the yields for dialdehyde intermediate 6b were
moderate, and the MacDonald condensation leading to
porphyrinoids 4 only gave yields in the range of 24−25%
4
9
(
Scheme 2). Hence, we investigated a more direct synthesis of a
suitable dialdehyde intermediate. Indole-3-carbaldehyde was
reacted with sodium hydride and acetoxymethylpyrrole
aldehyde 12b in DMF at 30 °C. This directly afforded the
related dialdehyde 37 in 58% yield. MacDonald “2 + 2”
condensation of 37 with 7a in the presence of p-toluenesulfonic
acid, followed by oxidation with a 0.2% aqueous ferric chloride
solution, gave the new benzo-fused neo-confused porphyrin 38
in 45% yield (Scheme 17). The benzoporphyrinoid had similar
In the initial report on benzo-neo-confused porphyrins, X-ray
diffraction analysis was performed on the nickel(II) complex 8a
but not for the free base structure 4a. We subsequently
obtained crystals of 4a that were suitable for analysis and the
results confirm the presence of the neo-confused moiety
(Figure 8). The well-ordered structure allowed the neo-
confused nitrogen atom to be easily identified, and the X-ray
structural data clearly places the internal hydrogen atoms
attached to the C(21) internal carbon and the N(23) nitrogen
atom opposite to it. This confirms predictions based on DFT
Scheme 17
3
0
studies that this tautomer would be favored. In addition to
the well-behaved displacement parameters, the structure shows
that the macrocycle is nearly planar, as evidenced by the 0.055
Å rms distance the framework atoms lie from the plane defined
by C(21), N(22), N(23), and N(24). The largest deviations
from the plane are C(13) (−0.099(10) Å), C(20) (0.096(9)
Å), and C(8) (0.095(9) Å), and only six of the 24 framework
atoms deviate more than 0.07 Å from the aforementioned
plane. The X-ray crystal structure of palladium complex 8b was
also obtained (Figure 9), and this confirms the presence of the
palladium cation. The structure shows that the macrocycle is
remarkably planar, as evidenced by the 0.030 Å rms distance
the framework atoms lie from the plane defined by Pd, C(21),
N(22), N(23), and N(24), and the largest deviations from the
plane are C(13) (−0.072(4) Å) and C(20) (−0.061(4) Å). In
fact, only two of the 24 framework atoms deviate by more than
spectroscopic properties to the previously prepared benzo-neo-
confused porphyrins 4a and 4b. The UV−vis spectrum gave a
strong Soret band at 408 nm, and four Q bands were evident
between 500 and 625 nm. The yield in the macrocycle
formation step was clearly much improved compared to the
original synthesis where DDQ was used as the oxidant. For this
reason, the synthesis of 4a was repeated using the new
conditions. With this approach, dialdehyde 6b reacted with 7a
to give benzoporphyrinoid 4a in 40% yield, a significant
0
.05 Å from the plane. Again, the structure exhibits framework
bond distances consistent with a generally localized π-bonding
model, and the metal coordination environment of 8b is
essentially a four-coordinate square planar geometry about the
Pd(II) metal center. As was the case for 36b, the Pd−C(21)
distance (1.964(5) Å) is significantly shorter than the 2.048(4)
Å Pd−N(23) distance due to the greater basicity of the
carbanion ligand.
28
improvement over the 25% yield reported previously.
Previously, 4a was shown to give the related nickel(II)
complex 8a in excellent yields, but attempts to isolate the
related palladium(II) complex 8b had been unsuccessful
CONCLUSIONS
Efficient syntheses of neo-confused porphyrins without fused
benzo-units have been developed for the first time. Neo-
■
(
Scheme 2). The palladation of 4a was reinvestigated following
the procedure used to prepare 36b. Hence, 4a was heated
4
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The Journal of Organic Chemistry
Article
are significantly reduced. Nevertheless, neo-confused porphyr-
ins retain aromatic characteristics by virtue of a 17-atom 18π
electron delocalization pathway. Protonation studies were
performed, and mono- and dicationic species can be discerned
2
+
by UV−vis spectroscopy. The dicationic species 9H showed
2
increased aromatic character due to the presence of resonance
contributors that possess diaza[18]annulene π-delocalization
pathways. Neo-confused porphyrins were readily converted
into stable nickel(II) and palladium(II) organometallic
derivatives that also exhibited significant diatropic character.
Improved syntheses of benzo-neo-confused porphyrins were
also developed. Three metal complexes and the free base form
of a benzo-neo-confused porphyrin were characterized by X-ray
diffraction analysis, the results of which demonstrate that the
system exhibits localized π-bonding consistent with a macro-
cycle that possesses reduced aromatic character. These results
provide the foundations for future studies into this new family
of porphyrin isomers.
Figure 8. Color POV-Ray rendered ORTEP III drawing (50%
probability level, hydrogen atoms drawn arbitrarily small) of benzo-
neo-confused porphyrin 4a. Selected bond lengths (Å): N(1)−C(2),
EXPERIMENTAL SECTION
Melting points are uncorrected. NMR spectra were recorded using a
00 or 500 MHz NMR spectrometer. H NMR values are reported as
chemical shifts δ, relative integral, multiplicity (s, singlet; d, doublet; t,
■
1
4
1
1
.422 (2); C(2)−C(3), 1.401(2); C(3)−C(4), 1.452(3); C(4)−C(5),
.413(3); C(4)−C(21), 1.373(3); C(21)−N(1), 1.374(2); C(5)−
triplet; q, quartet; m, multiplet; br, broad peak), and coupling constant
C(6), 1.372(3); C(6)−C(7), 1.465(2); C(7)−C(8), 1.355(3); C(8)−
C(9), 1.471(2); C(9)−C(10), 1.410(2); C(10)−C(11), 1.381(2);
C(11)−C(12), 1.448(2); C(12)−C(13), 1.366(3); C(13)−C(14),
(
J). Chemical shifts are reported in parts per million (ppm) relative to
1
13
CDCl ( H residual CHCl δ 7.26, C CDCl triplet δ 77.23) or
3
3
3
1
13
DMSO-d ( H residual DMSO-d pentet δ 2.49 ppm, C DMSO-d6
6
5
1
.443(3); C(14)−C(15), 1.377(2); C(15)−C(16), 1.408(3); C(16)−
septet δ 39.7 ppm), and coupling constants were taken directly from
C(17), 1.466(2); C(17)−C(18), 1.357(3); C(18)−C(19), 1.469(2);
C(19)−C(20), 1.365(3); C(20)−N(1), 1.374(2); C(6)−N(22),
1
1
the spectra. NMR assignments were made with the aid of H− H
COSY, HSQC, DEPT-135, and NOE difference proton NMR
spectroscopy. Standard software was used to perform 2D experiments.
High-resolution mass spectra (HRMS) were carried out by using a
double focusing magnetic sector instrument. H and C NMR spectra
for all new compounds are reported in Supporting Information.
tert-Butyl 4-Ethyl-5(3-formyl-1-pyrrolylmethyl)-3-methyl-
pyrrole-2-carboxylate (13a). Sodium hydride (60% dispersion in
mineral oil, 169 mg) was added to 3-pyrrolecarbaldehyde (300 mg,
1
.382(2); N(22)−C(9), 1.346(2); C(11)−N(23), 1.373(2); N(23)−
C(14), 1.379(2); C(16)−N(24), 1.344(2); N(24)−C(19), 1.379(2).
1
13
3
.16 mmol) in DMF (50 mL), and the mixture was stirred at room
temperature under anhydrous conditions for 30 min. tert-Butyl 5-
acetoxymethyl-4-ethyl-3-methylpyrrole-2-carboxylate (1.012 g, 3.60
mmol) was dissolved in DMF (25 mL) and added dropwise over 20
min. The solution was stirred at 100 °C for 16 h, diluted with ether,
and washed with water, back extracting with ether. The combined
organic layers were washed with brine and dried over sodium sulfate,
filtered, and evaporated under reduced pressure. The residue was
purified on a silica gel column, eluting initially with chloroform and
then with 1% methanol−chloroform. A tripyrrolic byproduct 14 eluted
initially, followed by dipyrrole 13a. Recrystallization from ethanol−
water gave the neo-confused dipyrrole (798 mg, 2.525 mmol, 80%) as
1
a white powder, mp 139−140 °C: H NMR (500 MHz, CDCl ) δ 1.00
3
(
3H, t, J = 7.6 Hz, CH CH ), 1.54 (9H, s, t-Bu), 2.26 (3H, s, 3-CH ),
2
3
3
2
.42 (2H, q, J = 7.6 Hz, 4-CH ), 5.02 (2H, s, bridge-CH ), 6.60 (1H,
2 2
Figure 9. Color POV-Ray rendered ORTEP III drawing (50%
probability level, hydrogen atoms drawn arbitrarily small) of
compound 8b. Selected bond lengths (Å): Pd−N(24), 2.009(4);
Pd−N(23), 2.048(4); Pd−N(22), 2.022(4); Pd−C(21), 1.964(5).
Selected bond angles (deg): C(21)−Pd−N(24), 90.6(2); C(21)−Pd−
N(22), 89.5(2); N(24)−Pd−N(22), 179.9(2); C(21)−Pd−N(23),
dd, J = 1.7, 3.0 Hz, 4′-H), 6.64 (1H, t, J = 2.6 Hz, 5′-H), 7.18 (1H, t, J
13
= 1.9 Hz, 2′-H), 9.07 (1H, br s, NH), 9.66 (1H, s, CHO); C NMR
(CDCl ) δ 10.6 (3-CH ), 15.7 (CH CH ), 17.4 (4-CH ), 28.7
3
3
2
3
2
(C(CH ) ), 45.2 (bridge-CH ), 81.2 (C(CH ) ), 109.1 (4′-CH),
3
3
2
3 3
121.1, 123.2 (5′-CH), 124.7, 125.9, 126.6, 127.1, 128.5 (2′-CH), 161.5
(ester CO), 185.6 (CHO); HR MS (EI) calcd for C H N O ,
316.1787; found, 316.1769. Anal. Calcd for C H N O : C, 68.33; H,
18 24 2 3
1
8
24
2
3
179.3(2); N(24)−Pd−N(23), 89.8(2); N(22)−Pd−N(23), 90.2(1).
7
.65; N, 8.85. Found: C, 68.19; H, 7.62; N, 8.70.
tert-Butyl 1(5-tert-Butoxycarbonyl-3-ethyl-4-methyl-2-pyr-
rolylmethyl)-4-ethyl-5(3-formyl-1-pyrrolylmethyl)-3-methyl-
confused porphyrins represent an important new class of
porphyrin isomers, and this study has allowed the properties of
this system to be investigated. Although neo-confused
porphyrins retain UV−vis spectra that resemble true porphyr-
ins, albeit with Soret bands of diminished intensity, the
diatropic ring currents observed in their proton NMR spectra
pyrrole-2-carboxylate (14). Recrystallization of the tripyrrolic
byproduct from the previous reaction using chloroform−hexane gave
1
1
4 (65 mg, 0.12 mmol, 6.7%) as a white powder, mp 80−81 °C: H
NMR (500 MHz, CDCl ) δ 0.97 (3H, t, J = 7.6 Hz, 4-CH CH ), 1.01
3
2
3
(3H, t, J = 7.5 Hz, 3′-CH CH ), 1.53 (9H, s, 5′-CO t-Bu), 1.61 (9H, s,
2
3
2
2-CO t-Bu), 2.20 (3H, s, 4′-CH ), 2.27 (3H, s, 3-CH ), 2.34 (2H, q, J
2
3
3
4
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The Journal of Organic Chemistry
Article
=
7.6 Hz, 3′-CH ), 2.40 (2H, q, J = 7.5 Hz, 4-CH ), 4.96 (2H, s, N−
NMR (CDCl ) δ 10.4 (4′-CH ), 16.1 (CH CH ), 17.4 (3′-CH ), 28.6
2
2
3
3
2
3
2
CH −C5), 5.13 (2H, s, N−CH −C2′), 6.53 (1H, t, J = 2.5 Hz, 5″-H),
(t-Bu), 43.0 (bridge-CH ), 51.7 (OCH ), 58.4 (OCH ), 80.5
2
2
2 3 2
6
.60 (1H, dd, J = 1.7, 3.0 Hz, 4″-H), 6.85 (1H, t, J = 1.9 Hz), 9.24
(C(CH ) ), 117.9 (3-CH), 120.2, 121.9, 124.3, 125.2, 125.3, 127.31
3 3
13
(
1H, br, NH), 9.61 (1H, s, CHO); C NMR (CDCl ) δ 10.6 (4′-
(5-CH), 127.35, 161.1 (CO), 162.8 (CO); HR MS (ESI) calcd
3
CH ), 11.7 (3-CH ), 15.8 (4-CH CH ), 16.0 (3′-CH CH ), 17.6
(
(
1
1
5
for C H N O + H, 377.2076; found, 377.2073.
3
3
2
3
2
3
20 28
2
5
3′,4-CH ), 28.70 (t-Bu), 28.75 (t-Bu), 40.5 (N−CH −C2′), 42.8
1(5-tert-Butoxycarbonyl-3-ethyl-4-methyl-2-pyrrolylmeth-
yl)-3-hydroxymethylindole (17). 1(5-tert-Butoxycarbonyl-3-ethyl-
4-methyl-2-pyrrolylmethyl)indole-3-carbaldehyde (6a, 1.00 g, 2.52
mmol) was dissolved in ethanol (100 mL), and sodium borohydride
(300 mg, 7.89 mmol) was added to the stirred solution. The reaction
was allowed to mix for 16 h; then, water (50 mL) was added and
ethanol was removed under reduced pressure. The water layer was
extracted twice with chloroform, and the combined organic layers were
dried over sodium sulfate, filtered, and evaporated under reduced
pressure. The resulting residue was recrystallized from chloroform−
2
2
N−CH −C5), 80.5, 82.1, 109.0 (4″-CH), 120.4, 122.7 (5″-CH),
2
23.1, 123.7, 125.4, 126.6, 127.0, 127.5, 127.8 (2″-CH), 161.3, 162.5,
85.4 (CHO); HR MS (EI) calcd for C H N O , 537.3203; found,
31
43
3
5
37.3203.
Methyl 1(5-tert-Butoxycarbonyl-3-ethyl-4-methyl-2-pyrro-
lylmethyl)-4-formylpyrrole-2-carboxylate (13b). Methyl 4-for-
mylpyrrole-2-carboxylate (120 mg, 0.78 mmol) and sodium hydride
(
35 mg, 60% dispersion in mineral oil, 0.88 mmol) were dissolved in
freshly distilled THF (20 mL) and mixed for 30 min. tert-Butyl 5-
acetoxymethyl-4-ethyl-3-methylpyrrole-2-carboxylate (246 mg, 0.88
mmol) in THF (5 mL) was added dropwise to the solution. The
reaction mixture was refluxed overnight under anhydrous conditions.
The solution was then washed with water, back extracting with ether,
and the combined organic layers were washed with brine, dried over
sodium sulfate, filtered, and evaporated under reduced pressure to give
hexanes to give the carbinol (750 mg, 2.03 mmol, 81%) as a white
1
powder, mp 140−141 °C: H NMR (500 MHz, CDCl ) δ 1.06 (3H, t,
3
J = 7.6 Hz, CH CH ), 1.52 (9H, s, t-Bu), 1.60 (1H, br, OH), 2.26 (3H,
2
3
s, 4′-CH ), 2.48 (2H, q, J = 7.6 Hz, 3′-CH ), 4.84 (2H, s, OCH ), 5.17
3
2
2
(2H, s, bridge-CH ), 6.99 (1H, s, 2-H), 7.15−7.18 (1H, m, 5-H),
2
7.23−7.26 (1H, m, 6-H), 7.32 (1H, d, J = 8.2 Hz, 7-H), 7.73 (1H, d, J
= 7.8 Hz, 4-H), 8.48 (1H, br, NH); 13C NMR (CDCl ) δ 10.6 (4′-
the product (225 mg, 0.60 mmol, 77%) as a white powder, mp 128−
3
1
129 °C: H NMR (500 MHz, CDCl ) δ 1.07 (3H, t, J = 7.6 Hz,
CH
CH
3
), 15.8 (CH
), 57.4 (OCH
2
CH
), 81.0 (C(CH ) ), 109.5 (7-CH), 116.2, 119.7 (4-
3 3
3
), 17.5 (3′-CH ), 28.7 (t-Bu), 41.6 (bridge-
2
3
CH CH ), 1.55 (9H, s, t-Bu), 2.25 (3H, s, 4′-CH ), 2.51 (2H, q, J =
2
2
2
3
3
7
.6 Hz, 3′-CH ), 3.91 (3H, s, OCH ), 5.41 (2H, s, bridge-CH ), 7.36
CH), 120.2 (5-CH), 120.6, 122.7 (6-CH), 125.6, 125.8, 126.20 (2-
CH), 126.24, 127.6, 137.0, 161.4 (CO); HR MS (ESI) calcd for
C H N O + H, 369.2178; found, 369.2169.
22 28 2 3
2
3
2
(
1H, d, J = 1.9 Hz, 3-H), 7.39 (1H, d, J = 1.9 Hz, 5-H), 9.45 (1H, br,
13
NH), 9.73 (1H, s, CHO); C NMR (CDCl ) δ 10.5 (4-CH ), 16.0
3
3
(
(
1
CH CH ), 17.6 (3′-CH ), 28.7 (t-Bu), 44.1 (bridge-CH ), 52.2
1,3-Bis(5-tert-butoxycarbonyl-3-ethyl-4-methyl-2-
2
3
2
2
OCH ), 80.8 (C(CH ) ), 118.5 (3-CH), 120.9, 124.1, 125.44, 125.46,
pyrrolymethyl)indole (19). Carbinol 17 (108 mg, 0.29 mmol) and
tert-butyl 4-ethyl-3-methyl-pyrrole-2-carboxylate (18, 66 mg, 0.31
mmol) were dissolved in a solution of ethyl acetate (10 mL) and acetic
acid (0.5 mL). The solution was refluxed under nitrogen for 5 h, and
the ethyl acetate was removed under reduced pressure. The remaining
solution was diluted with chloroform and washed with water, back
extracting with chloroform. The combined organic layers were washed
with saturated sodium bicarbonate solution, dried over sodium sulfate,
and filtered, and the solvent was removed under reduced pressure. The
residue was purified by column chromatography on silica, eluting with
50:50 dichloromethane−hexanes and recrystallized from chloroform−
3
3 3
25.50, 126.2, 132.6 (5-CH), 161.1, 162.5, 185.2 (CHO); HR MS
(
EI) calcd for C H N O , 374.1842; found, 374.1838. Anal. Calcd
20 26 2 5
for C H N O : C, 64.15; H, 7.00; N, 7.48. Found: C, 63.98; H, 7.04;
N, 7.30.
20
26
2
5
tert-Butyl 4-Ethyl-5(3-hydroxymethyl-1-pyrrolymethyl)-3-
methylpyrrole-2-carboxylate (16a). 1(5-tert-Butoxycarbonyl-3-
ethyl-4-methyl-2-pyrrolylmethyl)pyrrole-3-carbaldehyde (13a, 100
mg, 0.32 mmol) and sodium borohydride (12 mg, 0.32 mmol) were
stirred in ethanol (25 mL) at room temperature for 16 h. The solvent
was removed under reduced pressure, and the residue was taken up in
chloroform. The solution was washed with water and back extracted
with chloroform. The combined organic fractions were dried over
sodium sulfate and filtered, and the excess solvent was removed under
reduced pressure. The residue was recrystallized from chloroform−
hexanes to give the tripyrrane analogue (149 mg, 0.27 mmol, 93%) as
1
a white powder, mp 176−177 °C: H NMR (500 MHz, CDCl
) δ 1.04
), 1.49 (9H,
s), 1.51 (9H, s) (2 × t-Bu), 2.26 (3H, s), 2.27 (3H, s) (2 × pyrrole-
CH ), 2.44−2.50 (4H, m, CH CH ), 4.00 (2H, s3-CH ), 5.16 (2H, s,
N−CH ), 6.78 (1H, s, 2-H), 7.11 (1H, t, J = 7.5 Hz, 5-H), 7.22 (1H, t,
J = 7.6 Hz, 6-H) 7.30 (1H, d, J = 8.2 Hz, 7-H), 7.48 (1H, d, J = 7.9 Hz,
3
(3H, t, J = 7.5 Hz), 1.08 (3H, t, J = 7.5 Hz) (2 × CH CH
2 3
hexanes to give the alcohol (100 mg, 0.31 mmol, 98%) as a white
powder, mp 86−87 °C: H NMR (500 MHz, CDCl ) δ 1.04 (3H, t, J
=
3
2
3
2
1
3
2
7.6 Hz, CH CH ), 1.55 (9H, s, t-Bu), 1.60 (1H, br, OH), 2.25 (3H,
2 3
13
s, 3-CH ), 2.44 (2H, q, J = 7.6 Hz, CH CH ), 4.52 (2H, s, OCH ),
4-H), 8.34 (1H, br), 8.43 (1H, br) (2 × NH); C NMR (CDCl
10.6, 10.7 (2 × pyrrole-CH ), 15.7 (2 × CH CH ), 17.49, 17.53 (2 ×
CH CH ), 22.2 (3-CH ), 28.69, 28.75 (2 × t-Bu), 41.7 (N−CH ),
3
) δ
3
2
3
2
4
.94 (2H, s, bridge-CH ), 6.18 (1H, br t, J = 2.2 Hz, 4′-H), 6.58 (1H,
3
2
3
2
13
t, J = 2.5 Hz, 5′-H), 6.62 (1H, br, 2′-H), 8.47 (1H, br, NH); C NMR
2
3
2
2
(
500 MHz, CDCl ) δ 10.6 (3-CH ), 15.8 (CH CH ), 17.4 (4-CH ),
80.2, 80.8, 109.5 (7-CH), 112.5, 118.6, 119.3 (4-CH), 120.0 (5-CH),
120.4, 122.7 (6-CH), 123.5, 125.4, 125.86, 125.89 (2-CH), 126.0,
126.5, 128.2, 131.2, 137.0, 161.3, 161.5 (2 × CO); HR MS (EI)
3
3
2
3
2
28.7 (t-Bu), 44.7 (bridge-CH ), 59.0 (OCH ), 80.9 (C(CH ) ), 108.9
2 2 3 3
(
4′-CH), 119.3 (2′-CH), 120.5, 121.4 (5′-CH), 125.1, 125.5, 125.7,
1
3
3
26.6, 161.4 (CO); HR MS (ESI) calcd for C H N O + Na,
calcd for C34H N O , 559.3410; found, 559.3416. Anal. Calcd for
45 3 4
18
26
2
3
41.1841; found, 341.1835. HR MS (FAB): calcd for C H N O ,
18.1943; found, 318.1951.
C H N O : C, 72.96; H, 8.10; N, 7.51. Found: C, 72.62; H, 8.13; N,
34 45 3 4
18
26
2
3
7.39.
Methyl 1(5-tert-Butoxycarbonyl-3-ethyl-4-methyl-2-pyrro-
1,1′-Bis(5-tert-butoxycarbonyl-3-ethyl-4-methyl-2-pyrrolyl-
methyl)-3,3′-diindolylmethane (20). To purify crude carbinol 17
(1.68 g, 4.57 mmol), a solution in dichloromethane was loaded onto a
silica gel column and then eluted with dichloromethane. A doubly neo-
confused bilane was collected, the solvent was removed under reduced
pressure, and the residue was recrystallized from ethanol to give the
lylmethyl)-4-hydroxymethylpyrrole-2-carboxylate (16b). Di-
pyrrole aldehyde 13b (1.345 g, 3.60 mmol) and sodium borohydride
(
275 mg, 7.27 mmol) were dissolved in ethanol (200 mL) and stirred
for 5 h. Solvent was removed under reduced pressure. The resulting
residue was taken up in chloroform and washed with water, back
extracting with chloroform. The combined organic layers were dried
over sodium sulfate and filtered, and excess solvent was removed
under reduced pressure. The residue was dried in vacuo to give the
tetrapyrrole (1.49 g, 2.16 mmol, 76%) as a white powder, mp 97−99
1
°C: H NMR (500 MHz, CDCl
) δ 1.01 (6H, t, J = 7.6 Hz, 2 ×
3
CH
2.44 (4H, q, J = 7.6 Hz, 2 × CH
(4H, s, 2 × N−CH ), 6.79 (2H, br s, 21,22-H), 7.08 (2H, t, J = 7.5 Hz,
CH
), 1.49 (18H, s, 2 × t-Bu), 2.24 (6H, s, 2 × pyrrole-CH
),
2
3
3
carbinol (1.330 g, 3.53 mmol, 98%) as an orange tar that solidified
2
CH ), 4.20 (2H, s, bridge-CH ), 5.14
3
2
1
upon standing, mp 82−87 °C: H NMR (500 MHz, CDCl ) δ 1.08
2
3
2
2
2
2
(
2
3H, t, J = 7.6 Hz, CH CH ), 1.54 (9H, s, t-Bu), 1.67 (1H, br, OH),
8 ,12 -H), 7.19 (2H, t, J = 7.5 Hz, 7 ,13 -H), 7.26 (2H, d, J = 8.2 Hz,
2
3
1
1
1
1
.24 (3H, s, 4′-CH ), 2.51 (2H, q, J = 7.6 Hz, 3′-CH ), 3.86 (3H, s,
7 ,13 -H), 7.59 (2H, d, J = 7.9 Hz, 8 ,12 -H), 8.39 (2H, br, 2 × NH);
13
3
2
OCH ), 4.47 (2H, s, OCH ), 5.31 (2H, s, bridge-CH ), 6.86 (1H, d, J
C NMR (CDCl
): δ 10.6 (2,18-CH ), 15.7 (2 × CH CH ), 17.5
3 3 2 3
3
2
2
13
=
1.9 Hz, 5-H), 6.92 (1H, d, J = 1.9 Hz, 3-H), 9.59 (1H, br, NH); C
(3,17-CH ), 21.3 (bridge-CH ), 28.7 (2 × t-Bu), 41.7 (2 × N−CH ),
2
2
2
4
088
dx.doi.org/10.1021/jo500580e | J. Org. Chem. 2014, 79, 4078−4093

The Journal of Organic Chemistry
Article
1
1
2
2
1
1
8
1
1
6
6
7
0.7, 109.3 (7 ,13 -CH), 115.6, 119.5 (8 ,12 -CH), 119.8 (8 ,12 -CH),
residue was recrystallized from ethyl acetate−hexanes to give the
2
2
20.1, 122.2 (7 ,13 -CH), 124.9, 125.8, 125.9, 127.1, 128.7, 137.0,
monoaldehyde (385 mg, 2.13 mmol, 84%) as a white solid, mp 65−66
1
61.3 (2 × CO); HR MS (ESI) calcd for C H N O + H,
°C: H NMR (500 MHz, DMSO-d ) δ 1.04 (3H, t, J = 7.5 Hz), 1.10
43
52
4
4
6
89.4067; found, 689.4045. HR MS (EI): calcd for C H N O ,
(3H, t, J = 7.5 Hz) (2 × CH CH ), 2.39 (2H, q, J = 7.5 Hz, 4-CH ),
43
52
4
4
2
3
2
88.3988; found, 688.3982. Anal. Calcd for C H N O : C, 74.97; H,
.61; N, 8.13. Found: C, 74.80; H, 7.63; N, 7.99.
,4-Dimethyl-2,5-pyrroledicarbaldehyde (25a). 3,4-Dimethyl-
pyrrole-2-carboxylic acid (29a, 2.00 g) was dissolved in TFA (30 mL)
under N in the dark for 5 min while cooling the flask in a salt−ice
2.65 (2H, q, J = 7.5 Hz, 3-CH ), 4.40 (2H, s, OCH ), 5.00 (1H, br, s,
43
52
4
4
2
2
13
OH), 9.50 (1H, s, CHO), 11.41 (1H, br, NH); C NMR (DMSO-d6)
δ 16.4, 16.5, 16.8, 17.4, 54.6, 123.6, 127.1, 135.8, 137.9, 177.3. Anal.
Calcd for C H NO : C, 66.27; H, 8.34; N, 7.73. Found: C, 66.11; H,
3
10
15
2
2
8.34; N, 7.59.
bath. When the temperature of the reaction reached −5 °C, triethyl
orthoformate (32 mL) was added quickly, maintaining the temper-
ature below 10 °C. The mixture was allowed to stir for 1 h at 10 °C
and was then poured into 100 mL of water. Aqueous sodium
hydroxide solution (20%) was added dropwise to neutralize the
solution to litmus paper. The mixture was extracted with dichloro-
methane (×4), and the combined organic layers were washed with
brine and dried over magnesium sulfate. The solvent was removed
under reduced pressure, and the residue was recrystallized from
chloroform−hexanes to give a purple-brown solid (1.57 g, 10.4 mmol,
5-Acetoxymethyl-3,4-dimethylpyrrole-2-carbaldehyde
(12b). Acetic anhydride (7.5 mL) was added to a solution of pyrrole
carbinol 26a (350 mg, 2.28 mmol) in pyridine (7.5 mL) at −3 °C
using a salt−ice bath, and the mixture was stirred for 1 h. The mixture
was dispersed between dichloromethane and water, and the organic
layer was separated. The aqueous layer was further extracted with
dichloromethane (×3), and the combined organic solutions were dried
over sodium sulfate. The solvent was removed under reduced pressure,
and the dark brown residue was recrystallized from chloroform−
hexane to give the acetoxymethylpyrrole (380 mg, 1.94 mmol, 85%
39
1
1
7
2%), mp 156−158 °C (lit. mp 157−158 °C): H NMR (400 MHz,
yield) as a light brown solid, mp 121−122 °C: H NMR (500 MHz,
CDCl ) δ 2.31 (6H, s, 2 × CH ), 9.89 (2H, s, 2 × CHO), 9.98 (1H,
3
3
CDCl ) δ 2.01 (3H, s, 4-CH ), 2.08 (3H, s, OCOCH ), 2.26 (3H, s, 3-
3
3
3
13
br, NH); C NMR (100 MHz, CDCl ) δ 8.3, 129.6, 131.9, 180.3.
3
CH ), 5.04 (2H, s, 5-CH ), 9.17 (1H, br s, NH), 9.62 (1H, s, CHO);
3 2
C NMR (125 MHz, CDCl ) δ 8.5 (4-CH ), 8.9 (3-CH ), 21.0
3,4-Diethyl-2,5-pyrroledicarbaldehyde (25b). TFA (6 mL)
13
3
3
3
was placed in a foil-covered, three-neck, round-bottom flask equipped
with a thermometer and a pressure-equalized additional funnel. The
flask was cooled in an ice bath, and 3,4-diethylpyrrole (29b, 1.00 g)
was added under nitrogen. The addition was exothermic. When the
temperature of the reaction mixture had dropped to 12 °C, freshly
distilled triethyl orthoformate (26 mL) was added quickly, and the
temperature was allowed to rise to room temperature (22 °C). Stirring
was continued for 1 h, and the mixture was then poured into water
(
OCOCH ), 57.2 (5-CH ), 120.4, 129.3, 131.0, 131.3, 171.4 (acetate
3 2
CO), 177.7 (CHO); EI MS (70 eV) m/z (% relative intensity) 195
+
+
(
31, M ), 153 (28, [M − CH CO] ), 136 (100, [M −
2
+
C H O ] ); HR MS (EI) calcd for C H NO , 195.0895; found,
2
3
2
10 13
3
1
95.0893.
-Acetoxymethyl-3,4-diethylpyrrole-2-carbaldehyde (12c).
Acetic anhydride (4.0 mL) was added to a solution of pyrrole carbinol
6b (190 mg, 1.05 mmol) in pyridine (4.0 mL) at −3 °C using a salt−
5
2
(
100 mL). Sodium hydroxide solution (20%) was added to neutralize
ice bath, and the mixture was stirred for 1 h. The mixture was
dispersed between dichloromethane and water, and the organic layer
was separated. The aqueous layer was further extracted with
dichloromethane (×3), and the combined organic solutions were
dried over sodium sulfate. The solvent was removed under reduced
pressure, and the dark brown residue was recrystallized from
chloroform−hexane to give the acetoxymethylpyrrole (160 mg, 0.72
mmol, 68%) as a brown solid, mp 74−76 °C: H NMR (400 MHz,
DMSO-d ) δ 1.02 (3H, t, J = 7.5 Hz, 4-CH CH ), 1.12 (3H, t, J = 7.5
Hz, 3-CH CH ), 2.01 (3H, s, C(O)CH ), 2.39 (2H, q, J = 7.5 Hz, 4-
CH ), 2.66 (2H, q, J = 7.5 Hz, 3-CH ), 4.98 (2H, s, OCH ), 9.56 (1H,
the solution, and the mixture was exhaustively extracted with ethyl
acetate. The organic layers were combined and dried over magnesium
sulfate. The solvent was removed under reduced pressure, and the
residue recrystallized from ethyl acetate−hexanes. The dialdehyde
(
1
1
0.873 g, 4.87 mmol, 61%) was obtained as a pale yellow solid, mp
39
1
04−107 °C (lit mp 105−107 °C): H NMR (400 MHz, CDCl ) δ
3
.25 (6H, t, J = 7.6 Hz, 2 × CH CH ), 2.77 (4H, q, J = 7.6 Hz, 2 ×
2
3
1
13
CH ), 9.74 (1H, br, NH), 9.88 (2H, s, 2 × CHO); C NMR (100
MHz, CDCl ) δ 16.8, 17.5, 131.6, 135.9, 180.3.
2
6
2
3
3
2
3
3
5
-Hydroxymethyl-3,4-dimethylpyrrole-2-carbaldehyde
(
26a). A solution of 25a (564 mg, 3.73 mmol) in methanol (18 mL)
2
2
2
13
s, CHO), 11.75 (1H, br, NH); C NMR (100 MHz, DMSO-d ) δ
1
2
was cooled to 0 °C with the aid of a salt−ice bath. Sodium
borohydride (36 mg, 0.93 mmol) was then added, and the mixture was
stirred for 10 min. Brine (21 mL) was added, and stirring was
continued for an additional 15 min. The mixture was exhaustively
extracted with ethyl acetate, and the combined organic phases were
dried over magnesium sulfate. The drying reagent was removed by
suction filtration, and the solvent was evaporated under reduced
pressure. The solid residue was recrystallized from chloroform−
hexanes to give the monoaldehyde (560 mg, 3.66 mmol, 98% yield) as
a brown solid, mp 118−128 °C. The product was approximately 97%
pure by proton NMR spectroscopy. Further purification by column
chromatography on grade 3 alumina, eluting with 20% chloroform−
6
6.3 (4-CH ), 16.5 (4-CH CH ), 16.7 (3-CH ), 17.4 (3-CH CH ),
2 2 3 2 2 3
0.8 (C(O)CH ), 56.8 (OCH ), 125.6, 128.2, 131.2, 135.6, 170.3
3
2
(
acetate CO), 178.1 (CO); HR MS (ESI) calcd for C H NO +
12 17
3
H, 224.1287; found, 224.1286.
Methyl 4,5′-Diformyl-3′,4′-dimethyl-1,2′-dipyrrylmethane-
2
0
-carboxylate (10c). Sodium hydride (60% in mineral oil, 48 mg,
.50 mmol) was added to a solution of methyl 4-formylpyrrole-2-
carboxylate (144 mg, 0.94 mmol) in DMF (30 mL), and the mixture
was stirred at room temperature for 30 min. A solution of
acetoxymethylpyrrole 12b (171 mg, 0.94 mmol) in DMF (15 mL)
was then added dropwise over 10 min, and the resulting mixture was
stirred for 18 h at 30 °C. The mixture was diluted with ether and
washed with water, and the aqueous solution was back extracted with
ether (×3). The combined organic phases were dried over sodium
sulfate, and the solvent was removed under reduced pressure.
Recrystallization from ethanol gave the neo-confused dipyrrylmethane
hexanes, gave an analytical sample as a yellow-brown solid, mp 125−
1
1
(
26 °C: H NMR (500 MHz, CDCl ) δ 1.95 (3H, s, 4-CH ), 2.25
3
3
3H, s, 3-CH ), 3.90 (1H, br, OH), 4.73 (2H, s, OCH ), 9.42 (1H, s,
CHO), 10.40 (1H, br, NH); C NMR (125 MHz, CDCl ) δ 8.4, 9.0,
3
2
13
3
5
6.6, 117.7, 128.5, 133.7, 139.0, 176.9. Anal. Calcd for C H NO : C,
8 11 2
1
6
2.73; H, 7.24; N, 9.14. Found: C, 63.16; H, 6.99; N, 9.14.
-Hydroxymethyl-3,4-diethylpyrrole-2-carbaldehyde (26b).
(205 mg, 0.71 mmol, 75%) as a white solid, mp 194 °C, dec: H NMR
5
(500 MHz, CDCl
(3H, s, OCH ), 5.46 (2H, s, bridge-CH
H), 7.43 (1H, d, J = 1.8 Hz, 3-H), 9.60 (1H, s, 5′-CHO), 9.64 (1H, br
s, NH), 9.74 (1H, s, 4-CHO); 13C NMR (125 MHz, CDCl
) δ 8.8 (3′-
CH ), 44.0 (bridge-CH ), 52.4 (OCH ), 118.5 (3-CH),
3
) δ 2.08 (3H, s, 3′-CH
3
), 2.25 (3H, s, 4′-CH
3
), 3.91
A solution of 25b (450 mg, 2.52 mmol) in methanol (15 mL) was
cooled to 0 °C with the aid of a salt−ice bath. Sodium borohydride
3
2
), 7.36 (1H, d, J = 1.8 Hz, 5-
(
38.1 mg, 0.40 equiv, 1.02 mmol) was then added, and the mixture was
3
stirred for 10 min. Brine (17 mL) was added, and stirring was
continued for an additional 15 min. The mixture was extracted with
ethyl acetate (×3), and the combined organic phases were dried over
magnesium sulfate. The drying agent was removed by suction
filtration, and the solvent was removed under reduced pressure. The
), 9.0 (4′-CH
3
3
2
3
119.9, 124.1, 125.5, 129.3, 130.98, 131.02, 132.5 (5-CH), 162.4 (ester
CO), 177.8 (5′-CHO), 185.3 (4-CHO); EI MS (70 eV) m/z (%
+
+
relative intensity) 288 (18, M ), 256 (28, [M − CH OH] ), 227 (25),
3
+
213 (31), 153 (10), 136 (100, [C H NO] ); HR MS (EI) calcd for
8
10
4
089
dx.doi.org/10.1021/jo500580e | J. Org. Chem. 2014, 79, 4078−4093

The Journal of Organic Chemistry
Article
C H N O , 288.1110; found, 288.1106. Anal. Calcd for C H N O :
C, 62.49; H, 5.59; N, 9.72. Found: C, 62.13; H, 5.51; N, 9.58.
mg, 0.055 mmol, 55%) as a purple powder, mp >300 °C. The green
fraction was recrystallized from chloroform−hexane to give 31a (10.0
mg, 0.013 mmol, 26%) as a green powder, mp >300 °C: UV−vis (1%
Et N−CH Cl ) λ (log ε) 329 (4.46), 390 (4.72), 486 (sh, 3.63),
15
16
2
4
15 16
2
4
Methyl 4,5′-Diformyl-3′,4′-diethyl-1,2′-dipyrrylmethane-2-
carboxylate (10d). Sodium hydride (60% in mineral oil, 16.2 mg,
3
2
2
max
0.17 mmol) was added to a solution of methyl 4-formylpyrrole-2-
525 (sh, 3.85), 549 (3.98), 562 (sh, 3.96), 604 nm (3.75); UV−vis (3
carboxylate (51 mg, 0.33 mmol) in DMF (10 mL), and the mixture
was stirred at room temperature for 30 min. A solution of
acetoxymethylpyrrole 12c (77 mg, 0.33 mmol) in DMF (10 mL)
was then added dropwise over 10 min, and the resulting mixture was
stirred for 18 h at 30 °C. The mixture was diluted with ether and
washed with water, and the aqueous solution was back extracted with
ether (×3). The combined organic phases were dried over sodium
sulfate, and the solvent was removed under reduced pressure.
equiv TFA-CH Cl ) λ (log ε) 298 (4.34), 396 (4.72), 511 (3.67),
2
2
max
550 (3.82), 584 (3.90), 614 (3.99), 662 nm (3.96); UV−vis (1% TFA-
CH Cl ) λ (log ε) 302 (4.31), 357 (sh, 4.50), 409 (4.81), 528
2
2
max
1
(3.73), 571 (3.77), 619 (sh, 3.84), 669 nm (3.94); H NMR (500
MHz, CDCl ) δ 1.23 (1H, s, 21-H), 1.56 (3H, t, J = 7.6 Hz, 8-
3
CH CH ), 1.61 (3H, t, J = 7.6 Hz, 12-CH CH ), 1.69 (1H, br s, NH),
2
3
2
3
2.87 (3H, s, 17-CH ), 2.95 (6H, s, 7,18-CH ), 3.04 (3H, s, 13-CH ),
3
3
3
3.38 (2H, q, J = 7.6 Hz, 8-CH ), 3.51 (2H, q, J = 7.6 Hz, 12-CH ),
2
2
Recrystallization from ethanol gave the neo-confused dipyrrylmethane
4.17 (3H, s, OCH ), 8.20 (1H, s, 15-H), 8.30 (1H, s, 10-H), 8.60 (1H,
3
1
1
(
(
(
(
46 mg, 0.15 mmol, 45%) as white solid, mp 130.5−131 °C: H NMR
d, J = 1.6 Hz, 3-H), 8.74 (1H, s, 5-H), 10.57 (1H, s, 20-H); H NMR
(dication 9aH22 , 500 MHz, TFA-CDCl ) δ −0.66 (1H, s, 21-H), 1.51
+
400 MHz, DMSO-d ) δ 0.85 (3H, t, J = 7.5 Hz, 3′-CH CH ), 1.12
6
2
3
3
3H, t, J = 7.5 Hz, 4′-CH CH ), 2.34 (2H, q, J = 7.5 Hz, 3′-CH ), 2.66
(3H, t, J = 7.6 Hz), 1.53 (3H, t, J = 7.6 Hz) (8,12-CH CH ), 3.04 (3H,
2
3
2
2
3
2H, q, J = 7.5 Hz, 4′-CH ), 3.79 (3H, s, OCH ), 5.56 (2H, s, bridge-
s, 17-CH ), 3.06 (3H, s, 13-CH ), 3.14 (3H, s, 7-CH ), 3.17 (3H, s,
2
3
3 3 3
CH ), 7.25 (1H, d, J = 1.9 Hz, 3-H), 7.71 (1H, d, J = 1.9 Hz, 5-H),
18-CH ), 3.49−3.54 (4H, 2 overlapping quartets, 8,12-CH ), 4.16
2
3
2
1
9
.58 (1H, s, 5′-CHO), 9.69 (1H, s, 4-CHO), 11.73 (1H, br, NH); H
(3H, s, OCH ), 8.25 (1H, d, J = 1.5 Hz, 3-H), 8.69 (1H, s, 15-H), 8.75
3
1
3
NMR (500 MHz, CDCl ) δ 1.10 (3H, t, J = 7.6 Hz, 3′-CH CH ), 1.23
(1H, s, 10-H), 9.44 (1H, s, 5-H), 10.99 (1H, s, 20-H); C NMR
3
2
3
(
(
3H, t, J = 7.6 Hz, 4′-CH CH ), 2.53 (2H, q, J = 7.6 Hz, 3′-CH ), 2.72
(CDCl ) δ 10.8 (13-CH ), 10.9, 11.03, 11.05, 16.6 (12-CH CH ), 16.8
2
3
2
3
3
2
3
2H, q, J = 7.6 Hz, 4′-CH ), 3.91 (3H, s, OCH ), 5.49 (2H, s, bridge-
(8-CH ), 19.2 (12-CH ), 19.3 (8-CH CH ), 52.1 (OCH ), 93.0 (15-
2
3
2 2 2 3 3
CH ), 7.37 (1H, d, J = 1.9 Hz, 3-H), 7.43 (1H, d, J = 1.9 Hz, 5-H),
CH), 93.7 (10-CH), 113.4 (20-CH), 113.5 (5-CH), 121.0, 124.9,
2
13
9
.60 (1H, s, 5′-CHO), 9.73 (1H, s, 4-CHO), 9.84 (1H, br, NH);
C
125.7, 127.2 (3-CH), 134.2, 135.3, 140.1, 141.4, 142.0, 142.6, 142.9,
144.4, 145.3, 154.7, 162.0, 162.6, 163.2; 13C NMR (dication 9aH2
2+
,
NMR (CDCl ) δ 16.5 (3′-CH CH ), 17.1 (3′-CH ), 17.3 (4′-CH ),
3
2
3
2
2
1
1
7.8 (4′-CH CH ), 44.0 (bridge-CH ), 52.3 (OCH ), 118.5 (3-CH),
TFA-CDCl ) δ 11.0, 11.2, 11.3 (7-CH ), 11.7 (18-CH ), 15.7 (2 ×
2
3
2
3
3
3
3
24.2, 125.5, 125.9, 128.8, 130.8, 132.6 (5-CH), 137.3, 162.3 (ester
CH CH ), 19.3, 19.5, 53.0 (OCH ), 93.4 (15-CH), 95.1 (10-CH),
2 3 3
CO), 177.9 (5′-CHO), 185.3 (4-CHO); HR MS (EI) calcd for
112.7, 116.9 (20-CH), 118.5 (5-CH), 122.5, 122.9 (3-CH), 126.0,
134.0, 135.3, 139.3, 141.5, 142.4, 143.3, 145.7, 146.6, 149.8, 152.1,
152.7, 156.0, 161.0; HR MS (EI) calcd for C H N O , 480.2525;
C H N O , 316.1423; found, 316.1430. Anal. Calcd for C H N O :
17
20
2
4
17 20
2
4
C, 64.54; H, 6.37; N, 8.86. Found: C, 64.62; H, 6.45; N, 8.89.
(5-Formyl-3,4-dimethyl-2-pyrrolymethyl)indole-3-carbal-
30
32
4
2
1
found, 480.2521. Anal. Calcd for C H N O : C, 74.97; H, 6.71; N,
30 32 4 2
dehyde (37). Sodium hydride (60% in mineral oil, 24 mg, 0.25
mmol) was added to a solution of 3-indolecarbaldehyde (68 mg, 0.47
mmol) in DMF (30 mL), and the mixture was stirred at room
temperature for 30 min. A solution of acetoxymethylpyrrole 12b (85.5
mg, 0.47 mmol) in DMF (15 mL) was then added dropwise over 10
min, and the resulting mixture was stirred for 18 h at 30 °C. The
mixture was diluted with ether and washed with water, and the
aqueous solution was back extracted with ether (×3). The combined
organic phases were dried over sodium sulfate, and the solvent was
removed under reduced pressure. Recrystallization from ethanol gave
1
1.66. Found: C, 74.50; H, 6.71; N, 11.34.
3,17-Diethyl-5(4-formyl-2-methoxycarbonyl-1-pyrrolyl)-
1
7(4-formyl-2-methoxycarbonyl-1-pyrrolylmethyl)-
2,3,7,8,12,18-hexamethyl-5,6-dihydroporphyrin (31a). UV−vis
(1% Et N−CH Cl ): λ (log ε) 334 (4.35), 385 (4.58), 472 (sh,
3
2
2
max
3.80), 644 (3.81), 709 nm (3.90); UV−vis (5 equiv TFA-CH Cl ):
2
2
λ
(log ε) 390 (4.66), 642 (sh, 3.71), 717 (3.98), 791 nm (4.00);
max
UV−vis (5% TFA-CH Cl ): λ (log ε) 428 (4.84), 732 (sh, 3.55),
826 nm (3.88); H NMR (500 MHz, CDCl ): δ 1.09 (3H, t, J = 7.6
Hz, 17-CH CH ), 1.16 (3H, t, J = 7.6 Hz, 13-CH CH ), 1.44 (3H, br
q, J = 1.0 Hz, 8-CH ), 1.85 (3H, br q, J = 1.0 Hz, 7-CH ), 1.88 (3H,
s, 3-CH ), 1.91 (3H, s, 12-CH ), 1.92 (3H, s, 2-CH ), 2.01 (3H, s, 18-
3 3 3
CH ), 2.35−2.46 (4H, m, 2 × CH CH ), 3.80 (3H, s, 6-pyrrole-
CO CH ), 3.88 (5-pyrrole-CO CH ), 4.30 (1H, d, J = 14.0 Hz, 6-
2
2
max
1
3
2
3
2
3
5
5
the neo-confused dipyrrylmethane (75.1 mg, 0.26 mmol, 55%) as a
3
3
1
light yellow solid, mp 212−213 °C: H NMR (400 MHz, DMSO-d )
6
1
.90 (3H, s, 3′-CH ), 2.17 (3H, s, 4′-CH ), 5.43 (2H, s, bridge-CH ),
.24 (1H, t, J = 7.5 Hz, 5-H), 7.30 (1H, t, J = 7.7 Hz, 6-H), 7.66 (1H,
3
3
2
3
2
3
7
2 3 2 3
d, J = 8.1 Hz, 7-H), 8.09 (1H, d, J = 7.5 Hz, 4-H), 8.27 (1H, s, 2-H),
CH ), 4.90 (1H, s, 10-H), 5.58 (1H, s, 15-H), 5.79 (1H, d, J = 14.0
2
13
9
.56 (1H, s, 5′-CHO), 9.91 (1H, s, 3-CHO), 11.91 (1H, br, NH);
C
Hz, 6-CH ), 6.19 (1H, s, 20-H), 6.96 (1H, s, 5-H), 7.04 (1H, d, J = 1.8
2
NMR (100 MHz, DMSO-d ) δ 8.4 (3-CH ), 8.8 (4-CH ), 41.7
Hz, 6-pyrrole 3-H), 7.26 (1H, d, J = 1.8 Hz, 5-pyrrole 3-H), 7.99 (1H,
d, J = 1.8 Hz, 6-pyrrole 5-H), 8.46 (1H, d, J = 1.8 Hz, 5-pyrrole 5-H),
6
3
3
(
bridge-CH ), 111.3, 117.4 (7-CH), 119.4, 121.2 (4-CH), 122.8 (5-
2
CH), 123.8 (6-CH), 124.9, 128.9, 131.4, 137.1, 140.7 (2-CH), 178.0
9.37 (1H, s, 6-pyrrole-CHO), 9.71 (1H, s, 5-pyrrole-CHO), 13.37
1
13
(
7
5′-CHO), 185.0 (3-CHO). Anal. Calcd for C H N O · / H O: C,
(2H, br s, 2 × NH); C NMR (125 MHz, CDCl ): δ 8.8, 9.2, 9.4, 9.6,
1
7
16
2
2
5
2
3
1.91; H, 5.82; N, 9.87. Found: C, 71.97; H, 5.77; N, 9.76.
9.8, 11.5, 14.9, 15.2, 17.6, 17.9, 50.7, 51.6, 52.0 (2), 87.0, 87.1, 95.6,
115.0, 115.8, 116.3, 121.6, 122.8, 124.3, 124.5, 124.6, 128.6, 131.6,
133.1, 136.05, 136.07, 136.6, 138.1, 139.7, 141.8, 148.2, 150.5, 152.0,
154.3, 161.7, 162.0, 175.1, 185.0, 185.6; HR MS (ESI) calcd for
C H N O + H, 769.3714; found, 769.3707.
8
,12-Diethyl-2-methoxycarbonyl-7,13,17,18-tetramethyl-1-
aza-21-carbaporphyrin (9a). p-Toluenesulfonic acid (56 mg) in
methanol (6 mL) was added dropwise to a stirred mixture of
dialdehyde 10c (29 mg, 0.10 mmol) and dipyrrylmethane dicarboxylic
acid 7a (31 mg, 0.10 mmol) in dichloromethane (50 mL) and
methanol (6 mL). The resulting mixture was allowed to stir for 16 h at
room temperature. The solution was shaken with a 0.2% aqueous ferric
chloride solution for 20 min to oxidize the phlorin intermediate. The
organic phase was separated, and the aqueous solution was back
extracted with dichloromethane. The combined organic solutions were
washed with water and 5% aqueous sodium bicarbonate solution, and
the solvent was removed under reduced pressure. The residue was
purified by column chromatography on grade 3 alumina, eluting with
dichloromethane and hexane (1:1 to 3:1). The neo-confused
porphyrin was collected as a pink-purple fraction, followed by a
green band corresponding to dihydroporphyrin 31a. Recrystallization
from chloroform−hexanes gave the neo-confused porphyrin 9a (26.4
45
48
6
6
8,12-Diethyl-2-methoxycarbonyl-7,13,17,18-tetramethyl-1-
aza-21-carbaporphyrin (neo-confused phlorin 30a). p-Toluene-
sulfonic acid (56 mg) in methanol (6 mL) was added dropwise to a
stirred mixture of dialdehyde 10c (29 mg, 0.10 mmol) and
dipyrrylmethane dicarboxylic acid 7a (31 mg, 0.10 mmol) in
dichloromethane (50 mL) and methanol (6 mL). The resulting
mixture was allowed to stir for 16 h at room temperature. The solution
was washed with water and 5% aqueous sodium bicarbonate solution,
and the solvent was removed under reduced pressure. The residue was
purified by column chromatography on grade 3 alumina, eluting with
chloroform and hexane (1:1), and a deep blue fraction was collected.
The solvent was evaporated under reduced pressure to give the neo-
confused phlorin (31.1 mg, 0.069 mmol, 69%) as a purple powder, mp
4
090
dx.doi.org/10.1021/jo500580e | J. Org. Chem. 2014, 79, 4078−4093

The Journal of Organic Chemistry
Article
>
300 °C: UV−vis (1% Et N−CH Cl ) λ (log ε) 368 (4.53), 562
1.10 (3H, t, J = 7.6 Hz), 1.17 (3H, t, J = 7.6 Hz), 1.94 (3H, s), 2.00
(3H, s), 2.06−2.26 (4H, m), 2.32 (2H, q, J = 7.6 Hz), 2.37−2.47 (4H,
m), 2.62−2.70 (2H, m), 3.81 (3H, s), 3.87 (1H, d, J = 14.0 Hz), 3.89
(3H, s), 5.01 (1H, s), 5.60 (1H, s), 6.04 (1H, d, J = 14.0 Hz), 6.08
(1H, s), 6.97 (1H, d, J = 1.8 Hz), 7.06 (1H, s), 7.25 (1H, d, J = 1.8
Hz), 8.15 (1H, d, J = 1.8 Hz), 8.23 (1H, d, J = 1.8 Hz), 9.27 (1H, s),
3
2
2
max
(4.15), 598 nm (4.15); UV−vis (1% TFA-CH Cl ) λ (log ε) 327
(4.38), 392 (4.54), 552 (sh, 3.97), 600 (4.19), 669 nm (4.05); H
2
2
max
1
NMR (500 MHz, CDCl ) δ 1.21 (3H, t, J = 7.6 Hz, 12-CH CH ), 1.28
3
2
3
(
3H, t, J = 7.6 Hz, 8-CH CH ), 2.27 (3H, s, 7-CH ), 2.30 (3H, s, 13-
2 3 3
CH ), 2.32 (3H, s, 17-CH ), 2.35 (3H, s, 18-CH ), 2.68 (2H, q, J = 7.6
Hz, 12-CH ), 2.72 (2H, q, J = 7.6 Hz, 8-CH ), 3.84 (3H, s, OCH ),
3
3
3
9.68 (1H, s), 13.18 (1H, br); 13C NMR (125 MHz, CDCl ) δ 9.3, 9.6,
2
2
3
3
5
.56 (1H, d, J = 1.8 Hz, 21-H), 5.68 (2H, s, 20-CH ), 6.06 (1H, s, 10-
13.2, 13.9, 14.9, 15.2, 16.1, 16.6, 16.7, 17.4, 17.59, 17.63, 17.9, 18.9,
50.8, 51.6, 52.0, 52.5, 87.1, 88.2, 95.6, 114.8, 115.9, 116.3, 122.9, 123.8,
124.5, 124.8, 127.3, 133.0, 136.26, 136.31, 138.0, 141.7, 142.3, 148.0,
161.8, 162.0, 185.1, 185.5; HR MS (ESI) calcd for C H N O + H,
2
H), 6.39 (1H, s, 5-H), 6.98 (1H, s, 15-H), 7.04 (1H, d, J = 1.8 Hz, 3-
H), 7.67 (1H, br s), 8.27 (1H, v br) (2 × NH); C NMR (125 MHz,
CDCl ) δ 9.3, 9.7, 10.0, 10.2, 15.0, 15.5, 18.0, 18.5, 44.2, 51.5, 86.1,
13
3
49 56
6
6
9
1
8.5, 109.0, 118.2, 118.5, 120.4, 121.6, 122.5, 124.5, 127.2, 129.4,
33.0, 138.83, 138.85, 139.4, 143.9, 149.2, 150.8, 161.9, 165.8; HR MS
825.4333; found, 825.4340.
8,12-Diethyl-7,13,17,18-tetramethylbenzo[b]-1-aza-21-
carba-1H,23H-porphyrin (38). p-Toluenesulfonic acid (56 mg) in
methanol (6 mL) was added dropwise to a stirred mixture of
dialdehyde 37 (28 mg, 0.10 mmol) and dipyrrylmethane dicarboxylic
acid 7a (31 mg, 0.10 mmol) in dichloromethane (50 mL) and
methanol (6 mL). The resulting mixture was allowed to stir for 16 h at
room temperature. The solution was washed with water and 5%
aqueous sodium bicarbonate solution, and the solvent was removed
under reduced pressure. The residue was purified by column
chromatography on grade 3 alumina, eluting with dichloromethane
and hexanes (2:3), and a dark purple fraction was collected. The
solvent was evaporated under reduced pressure, and the residue
recrystallized from chloroform−hexanes to give the neo-confused
porphyrin (20.9 mg, 0.044 mmol, 44%) as purple crystals, mp >300
(
EI) calcd for C H N O , 482.2682; found, 482.2673.
30 34 4 2
8
,12,17,18-Tetraethyl-2-methoxycarbonyl-7,13-dimethyl-1-
aza-21-carbaporphyrin (9b). p-Toluenesulfonic acid (56 mg) in
methanol (6 mL) was added dropwise to a stirred mixture of
dialdehyde 10d (30 mg, 0.10 mmol) and dipyrrylmethane dicarboxylic
acid 7a (31 mg, 0.10 mmol) in dichloromethane (50 mL) and
methanol (6 mL). The resulting mixture was allowed to stir for 16 h at
room temperature. The solution was shaken with a 0.2% aqueous ferric
chloride solution for 20 min to oxidize the phlorin intermediate. The
organic phase was separated, and the aqueous solution back extracted
with dichloromethane. The combined organic solutions were washed
with water and 5% aqueous sodium bicarbonate solution, and the
solvent was removed under reduced pressure. The residue was purified
by column chromatography on grade 3 alumina, eluting with
dichloromethane and hexanes (2:3), and the neo-confused porphyrin
eluted as a purple band. Recrystallization from chloroform−hexanes
gave 9b (20.1 mg, 0.041 mmol, 44%) as a purple powder, mp >300
°C: UV−vis (1% TEA-CH
503 (3.90), 536 (4.06), 569 (3.85), 615 nm (3.88); UV−vis (1% TFA-
CH Cl ) λmax (log ε) 297 (4.31), 397 (4.69), 615 (3.90), 662 nm
(3.94); H NMR (500 MHz, CDCl
(1H, br, NH), 1.68 (3H, t, J = 7.7 Hz, 8-CH
Hz, 12-CH CH ), 3.13 (3H, s, 17-CH ), 3.19 (3H, s, 18-CH
(3H, s, 7-CH ), 3.31 (3H, s, 13-CH ), 3.63 (2H, q, J = 7.7 Hz, 8-CH
3.78 (2H, q, J = 7.7 Hz, 12-CH ), 7.79−7.84 (2H, m, 2 ,3 -H), 8.71−
1
Cl ) λmax (log ε) 348 (4.40), 408 (4.92),
2
2
2
2
1
) δ −0.76 (1H, s, 21-H), −0.32
CH ), 1.72 (3H, t, J = 7.7
), 3.24
),
3
°C: UV−vis (CH Cl ) λ (log ε) 330 (4.52), 390 (4.78), 524 (3.88),
2
3
2
2
max
5
λ
6
4
49 (4.04), 562 (4.01), 603 (3.82); UV−vis (5 equiv TFA-CH Cl )
2
3
3
3
2
2
(log ε) 396 (4.81), 510 (3.70), 550 (3.85), 584 (3.96), 614 (4.08),
3
3
2
max
2
2
62 (4.06); UV−vis (1% TFA-CH Cl ) λ (log ε) 357 (sh, 4.61),
2
2
2
max
1
1
10 (4.92), 529 (3.75), 573 (3.85), 618 (sh, 3.91), 668 (4.03); H
8.74 (1H, m, 2 -H), 8.85−8.87 (1H, m, 3 -H), 8.88 (1H, s, 15-H),
1
NMR (500 MHz, CDCl ) δ 1.32 (1H, br d, 21-H), 1.57 (3H, t, J = 7.6
Hz), 1.61 (3H, t, J = 7.6 Hz), 1.62 (3H, t, J = 7.6 Hz), 1.66 (3H, t, J =
7
8.96 (1H, s, 10-H), 9.66 (1H, s, 5-H), 9.95 (1H, s, 20-H); H NMR
3
2
+
(500 MHz, TFA-CDCl , dication 38H ) δ −2.84 (1H, s, 21-H),
3 2
.7 Hz) (4 × CH CH ), 1.78 (1H, br, NH), 2.95 (3H, s, 7-CH ), 3.08
1.60−1.64 (6H, 2 overlapping triplets, 2 × CH
2
CH
), 3.39 (3H, s, 18-CH
), 3.78 (4H, q, J = 7.7 Hz, 2 × CH CH
3
), 3.29 (3H, s, 17-
), 3.40 (3H, s, 7-
2
3
3
(
3
4
3H, s, 13-CH ), 3.35−3.40 (4H, 2 overlapping quartets, 8,17-CH ),
CH
3
), 3.31 (3H, s, 13-CH
3
3
3
2
.44 (2H, q, J = 7.6 Hz, 18-CH ), 3.54 (2H, q, J = 7.7 Hz, 12-CH ),
CH
3
2
3
), 7.88−7.92 (2H, m,
2
2
2
2
1
1
.18 (3H, s, OCH ), 8.29 (1H, s, 15-H), 8.33 (1H, s, 10-H), 8.64 (1H,
2 ,3 -H), 8.62−8.65 (1H, m, 2 -H), 8.65−8.68 (1H, m, 3 -H), 9.42
(1H, s, 15-H), 9.49 (1H, s, 10-H), 10.22 (1H, s, 5-H), 10.54 (1H, s,
3
1
d, J = 1.8 Hz, 3-H), 8.77 (1H, s, 5-H), 10.70 (1H, s, 20-H); H NMR
2+
13
(
1
500 MHz, TFA-CDCl , dication 9bH2 ) δ −1.21 (1H, br, 21-H),
20-H); C NMR (CDCl
3
) δ 11.2 (17-CH
3
), 11.38, 11.40, 11.43, 17.0
3
.53−1.57 (6H, 2 overlapping triplets), 1.59 (3H, t, J = 7.7 Hz) (3 ×
(12-CH
2
CH
3
), 17.4 (8-CH CH ), 19.5 (12-CH
2
3
2
), 19.7 (8-CH ), 93.6
2
1
CH CH ), 1.70 (3H, t, J = 7.7 Hz, 18-CH CH ), 3.12 (3H, s, 13-
(15-CH), 94.1 (10-CH), 107.7 (20-CH), 108.9 (15-CH), 112.2 (2 -
CH), 119.2, 120.7 (3 -CH), 124.4 (21-CH), 125.2, 125.5, 132.9,
2
3
2
3
1
CH ), 3.19 (3H, s, 7-CH ), 3.53−3.59 (6H, m, 3 × CH CH ), 3.67
3
3
2
3
(
2H, q, J = 7.7 Hz, 18-CH ), 4.19 (3H, s, OCH ), 8.32 (1H, d, J = 1.5
133.8, 135.8, 139.7, 140.0, 140.9, 141.0, 141.9, 143.1, 143.9, 154.0,
2
3
159.1, 159.8; 13C NMR (TFA-CDCl
, dication 38H
2+
) δ 11.5, 11.6,
Hz, 3-H), 8.84 (1H, s, 15-H), 8.89 (1H, s, 10-H), 9.58 (1H, s), 5-H,
1
CH ), 16.6, 16.8, 17.3, 18.1 (18-CH CH ), 19.1, 19.21, 19.28, 19.32
(
1
1
1
3
2
1.14 (1H, s, 20-H); 13C NMR (CDCl ): δ 10.91 (13-CH ), 10.96 (7-
11.7, 11.9, 16.2, 19.8, 19.9, 95.2 (15-CH), 95.7 (10-CH), 110.0 (20-
3
3
1
1
CH), 112.5 (5-CH), 114.4 (2 -CH), 117.6 (21-H), 122.4 (3 -CH),
123.3, 128.4, 128.8, 129.2, 133.2, 135.6, 138.4, 139.8, 140.7, 141.6,
142.1, 142.6, 145.6, 146.8, 147.8, 148.8, 151.4; HR-MS (EI) calcd for
3
2
3
18-CH ), 52.2 (OCH ), 93.2 (15-CH), 93.7 (10-CH), 113.5 (5-CH),
2 3
13.8 (20-CH), 121.1, 124.8 (21-H), 125.8, 127.3 (3-CH), 134.2,
40.2, 141.1, 141.4, 142.6, 143.0, 143.9, 144.4, 148.2, 154.8, 162.0,
C
H
N
, 472.2635; found, 472.2626.
8,12,18-Triethyl-7,13,17-trimethylbenzo[b]-1-aza-21-carba-
H,23H-porphyrin (4a). A solution of p-toluenesulfonic acid
32
32
4
62.6, 162.7; 13C NMR (TFA-CDCl , dication 9bH2 ) δ 11.3 (7-
2+
3
1
CH ), 11.4 (13-CH ), 15.55, 15.56, 16.3, 17.0 (18-CH CH ), 19.0,
3
3
2
3
monohydrate (56 mg) in methanol (6 mL) was added to a stirred
solution of dialdehyde 6b (30 mg, 0.10 mmol) and dipyrrylmethane
dicarboxylic acid 7a (31 mg, 0.10 mmol) in dichloromethane (50 mL)
and methanol (6 mL), and the resulting mixture was stirred for 16 h at
room temperature. The solution gradually turned a dark red color. The
solution was shaken with 0.2% aqueous ferric chloride for 20 min to
oxidize the phlorin intermediate. The organic phase was separated, and
the aqueous solution was back extracted with dichloromethane. The
combined organic solutions were washed with water and 5% aqueous
sodium bicarbonate solution. The solvent was removed under reduced
pressure, and the residue was purified on a grade 3 alumina column,
eluting with dichloromethane−hexanes. A purple fraction was
collected and recrystallized from chloroform−hexanes to yield the
neo-confused porphyrin (20.1 mg, 0.041 mmol, 40%) as dark purple
1
9.3, 19.6, 19.8 (18-CH ), 18.82, 22.9, 31.2, 53.3 (OCH ), 94.4 (15-
2
3
CH), 95.5 (10-CH), 111.0 (21-CH), 117.5 (20-CH), 117.9, 119.1 (5-
CH), 123.0, 123.21 (3-CH), 123.23, 126.5, 132.6, 140.1, 141.3, 142.5,
1
42.6, 144.7, 147.4, 149.4, 151.6, 152.8, 155.2, 161.2; HR MS (EI)
calcd for C H N O , 508.2832; found, 508.2838.
32
36
4
2
1
2,18-Dimethyl-5(4-formyl-2-methoxycarbonyl-1-pyrrolyl)-
7
2
(4-formyl-2-methoxycarbonyl-1-pyrrolylmethyl)-
,3,7,8,13,17-hexaethyl-5,6-dihydroporphyrin (31b). A later
green band was also collected and recrystallized from chloroform−
heptane to afford dihydroporphyrin 31b (8.3−15.2 mg, 0.010−0.018
mmol, 10.1−18.3%) as a green powder, mp >300 °C: UV−vis
(
(
(
(
CH Cl ) λ (log ε) 389 (4.52), 653 (3.78), 714 nm (3.85); UV−vis
2
2
max
5% TFA-CH Cl ) λ (log ε) 430 (4.68), 729 (sh, 3.62), 819 nm
2
2
max
1
3.87); H NMR (500 MHz, CDCl ) δ 0.51 (3H, t, J = 7.6 Hz), 0.66
3H, t, J = 7.6 Hz), 1.03 (3H, t, J = 7.5 Hz), 1.06 (3H, t, J = 7.6 Hz),
3
2
8
1
crystals, mp >300 °C (lit. mp >300 °C): H NMR (500 MHz,
4
091
dx.doi.org/10.1021/jo500580e | J. Org. Chem. 2014, 79, 4078−4093

The Journal of Organic Chemistry
Article
1
2
2
CDCl ) δ −0.84 (1H, s), −0.36 (1H, br s), 1.68 (3H, t, J = 7.6 Hz),
(3 -CH), 120.6, 124.5 (2 -CH), 125.9 (3 -CH), 133.1, 133.6, 134.9,
135.4, 135.5, 139.6, 140.1, 143.0, 143.4, 144.1, 144.6, 145.0, 147.0,
147.4; HR MS (EI) calcd for C H N Pd, 590.1661; found, 590.1671.
3
1
.71−1.74 (6H, two overlapping triplets), 3.17 (3H, s), 3.24 (3H, s),
3.32 (3H, s), 3.64 (2H, q, J = 7.7 Hz), 3.68 (2H, q, J = 7.7 Hz), 3.79
33
32
4
(
8
2H, q, J = 7.7 Hz), 7.82−7.85 (2H, m), 8.75−8.79 (1H, m), 8.86−
.90 (1H, m), 8.95 (1H, s), 8.98 (1H, s), 9.70 (1H, s), 10.03 (1H, s).
ASSOCIATED CONTENT
Supporting Information
■
(
8,12-Diethyl-2-methoxycarbonyl-7,13,17,18-tetramethyl-1-
*
S
aza-21-carbaporphyrinato)nickel(II) (36a). Neo-confused por-
phyrin 9a (15.0 mg, 0.031 mmol) and nickel(II) acetate hexahydrate
(
1
Experimental for the crystallographic studies and selected H
1
1
13
NMR, H− H COSY, HMQC, C NMR, MS, and UV−vis
spectra. This material is available free of charge via the Internet
at http://pubs.acs.org.
15.0 mg) were dissolved in acetonitrile (15 mL) and the mixture was
stirred under reflux for 3 h. The mixture was diluted with
dichloromethane and washed with water, and the organic solution
was evaporated under reduced pressure. The residue was purified by
column chromatography on grade 3 alumina eluting with chloroform.
Recrystallization from chloroform−hexanes gave the nickel neo-
confused porphyrin (11.3 mg, 0.021 mmol, 68%) as orange crystals,
mp >300 °C: UV−vis (CH Cl ) λ (log ε) 334 (4.60), 385 (4.74),
28 (sh, 4.22), 534 (3.85), 608 (3.49), 657 (3.64); H NMR (500
MHz, CDCl ) δ 1.59 (3H, t, J = 7.7 Hz, 8-CH CH ), 1.62 (3H, t, J =
.7 Hz, 12-CH CH ), 2.88 (3H, s, 17-CH ), 2.95 (3H, s, 18-CH ),
AUTHOR INFORMATION
Corresponding Author
E-mail: tdlash@ilstu.edu
■
*
2
2
max
1
4
Notes
3
2
3
The authors declare no competing financial interest.
7
2 3 3 3
2
.99 (3H, s, 13-CH ), 3.02 (3H, s, 7-CH ), 3.49 (4H, q, J = 7.7 Hz, 2
3
3
ACKNOWLEDGMENTS
■
×
CH CH ), 4.16 (3H, s, OCH ), 8.47 (1H, s, 15-H), 8.63 (1H, s, 3-
2 3 3
13
This work was supported by the National Science Foundation
under Grant No. CHE-1212691, and the Petroleum Research
Fund, administered by the American Chemical Society. The
authors also thank the National Science Foundation (Grant No.
CHE-1039689) for providing funding for the X-ray diffrac-
tometer.
H), 8.69 (1H, s, 10-H), 8.87 (1H, s, 5-H), 10.85 (1H, s, 20-H);
C
NMR (CDCl ) δ 10.9 (18-CH ), 11.0, 11.1, 16.9, 19.4, 19.5, 51.9
3
3
(
OCH ), 94.8 (15-CH), 96.3 (10-CH), 113.2 (5-CH and 20-CH),
3
1
1
24.9, 129.9, 131.2 (3-CH), 134.3, 134.6, 136.90, 136.92, 138.2, 140.0,
40.8, 142.7, 145.3, 148.1, 150.62, 150.69, 152.5, 162.1 (CO); HR
MS (EI) calcd for C H N NiO , 536.1722; found, 536.1715.
30
30
4
2
(
8,12-Diethyl-2-methoxycarbonyl-7,13,17,18-tetramethyl-1-
aza-21-carbaporphyrinato)palladium(II) (36b). A mixture of neo-
confused porphyrin 9a (20.0 mg, 0.041 mmol) and palladium(II)
acetate (20 mg) in acetonitrile (10 mL) was stirred under reflux for 3
h. The mixture was diluted with dichloromethane and washed with
water. The organic solution was evaporated under reduced pressure,
and the residue was purified by column chromatography on grade 3
alumina, eluting with chloroform. Recrystallization from chloroform−
hexanes gave the palladium neo-confused porphyrin (19.2 mg, 0.032
mmol, 78%) as purple green crystals, mp >300 °C: UV−vis (CH Cl )
REFERENCES
■
(
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2
2
λ
5
1
(log ε) 333 (4.56), 384 (4.66), 414 (4.55), 467 (3.56), 501 (3.66),
max
1
34 (4.01), 583 (3.70), 628 (3.91); H NMR (500 MHz, CDCl ) δ
3
.63−1.68 (6H, 2 overlapping triplets, 2 × CH CH ), 2.98 (3H, s, 17-
̈
(3) Willstatter, R.; Stoll, A. Investigations on Chlorophyll; Science
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2
3
CH ), 3.05 (3H, s, 18-CH ), 3.06 (3H, s, 13-CH ), 3.12 (3H, s, 7-
3
3
3
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3
2
3
(
3H, s, OCH ), 8.58 (1H, s, 15-CH), 8.70 (1H, s, 3-CH), 8.79 (1H, s,
3
13
1
0-CH), 9.01 (1H, s, 5-CH), 10.97 (1H, s, 20-CH); C NMR
(
CDCl ) δ 10.8, 10.99, 11.03, 11.2 (17-CH ), 16.95, 16.99, 19.4, 19.6,
3
3
5
2.0 (OCH ), 95.4 (15-CH), 97.1 (10-CH), 115.1 (20-CH), 115.3
3
(
1
15-CH), 121.3, 129.2, 131.5 (3-CH), 133.7, 135.1, 136.0, 136.8,
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30
30
4
2
(
8,12,18-Triethyl-7,13,17-trimethylbenzo[b]-1-aza-21-
carbaporphyrinato)palladium(II) (8b). Neo-confused porphyrin 4a
10.0 mg, 0.020 mmol) and palladium(II) acetate (10.0 mg) were
(
dissolved in acetonitrile (10 mL) and heated under reflux for 3 h. The
solution was cooled to room temperature, diluted with dichloro-
methane, washed with water, and evaporated under reduced pressure.
The residue was chromatographed on a neutral grade 3 alumina
column, eluting with dichloromethane. Recrystallization from chloro-
form−hexanes gave the palladium(II) complex (10.0 mg, 0.0185
mmol, 92%) as dark green crystals, mp >300 °C: UV−vis (CH Cl )
2
2
λ
5
(log ε) 335 (4.40), 390 (4.79), 421 (4.76), 504 (3.83), 533 (3.82),
max
1
53 (3.75), 595 nm (4.26); H NMR (500 MHz, CDCl ) δ 1.69 (3H,
3
t, J = 7.7 Hz, 18-CH CH ), 1.78 (6H, t, J = 7.7 Hz, 8,12-CH CH ),
2
3
2
3
3
.18 (3H, s, 17-CH ), 3.25 (3H, s, 13-CH ), 3.36 (3H, s, 7-CH ), 3.57
3 3 3
(
7
2H, q, J = 7.7 Hz, 18-CH ), 3.76 (2H, q, J = 7.7 Hz), 3.81 (2H, q, J =
2
2
.7 Hz) (8,12-CH ), 7.64 (1H, t, J = 7.5 Hz, 2 -H), 7.71 (1H, t, J = 7.3
2
2
1
1
Hz, 3 -H), 8.45 (1H, d, J = 7.8 Hz, 2 -H), 8.66 (1H, d, J = 7.4 Hz, 3 -
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H), 9.09 (1H, s, 15-H), 9.33 (1H, s, 10-H), 9.83 (1H, s, 5-H), 9.91
(
1H, s, 20-H); 13C NMR (CDCl ) δ 11.18, 11.24, 11.4 (7-CH ), 17.2,
3
3
1
9
7.39, 17.46 (18-CH CH ), 19.3 (18-CH ), 19.7, 19.9, 96.1 (15-CH),
2 3 2
8.1 (10-CH), 108.5 (5-CH), 110.4 (20-CH), 111.2 (2 -CH), 119.3
1
4
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(
8
(
5
(
(
(
(
4
093
dx.doi.org/10.1021/jo500580e | J. Org. Chem. 2014, 79, 4078−4093