Porphyrins with exocyclic rings. Part 25: synthesis of porphyrins with a fused cyclic ether subunit from tetrahydro-4H-pyan-4-one

Article abstract of DOI:10.1016/j.tet.2010.04.069

A novel porphyrin system with a fused dihydropyran ring has been synthesized from commercially available 4-oxotetrahydropyran. The cyclic ketone reacted with oximes derived from acetoacetate esters in the presence of zinc dust, sodium propionate, and propionic acid at 150-155 °C to give good yields of 5-oxatetrahydroindoles. A low yield of a benzo-fused analog was also obtained using 4-oxochromanone as the starting reagent. Reaction of the b-annelated pyrroles with N-chlorosuccinimide gave the 7-chloro-derivatives and these underwent an acid catalyzed condensation with α-unsubstituted pyrroles to give dipyrrolic products linked by a dihydropyran moiety. Hydrogenolysis of a dipyrrole dibenzyl ester gave the corresponding dicarboxylic acid and this was converted into a dialdehyde by treatment with TFA-CH(OMe)₃. MacDonald '2+2' condensation with two different dipyrrylmethanes under optimized conditions afforded the porphyrin ethers in 30-36% yield. This approach provides a pilot study for the synthesis of porphyrin crown ether structures. In addition, insightful results on the conformations of dihydropyran-linked dipyrroles were obtained by careful examination of their proton NMR spectra in CDCl₃ and DMSO-d₆.

Full text of DOI:10.1016/j.tet.2010.04.069

Tetrahedron 66 (2010) 4413e4422
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Porphyrins with exocyclic rings. Part 25: synthesis of porphyrins with a fused
cyclic ether subunit from tetrahydro-4H-pyan-4-oneq
*
Breland E. Smith, Timothy D. Lash
Department of Chemistry, Illinois State University, Normal, IL 61790-4160, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel porphyrin system with a fused dihydropyran ring has been synthesized from commercially
available 4-oxotetrahydropyran. The cyclic ketone reacted with oximes derived from acetoacetate esters
in the presence of zinc dust, sodium propionate, and propionic acid at 150e155 ꢀC to give good yields of
5-oxatetrahydroindoles. A low yield of a benzo-fused analog was also obtained using 4-oxochromanone
as the starting reagent. Reaction of the b-annelated pyrroles with N-chlorosuccinimide gave the
Received 23 February 2010
Received in revised form 15 April 2010
Accepted 16 April 2010
Available online 21 April 2010
7-chloro-derivatives and these underwent an acid catalyzed condensation with a-unsubstituted pyrroles
Keywords:
Porphyrins
Crown ethers
Conformational analysis
Knorr pyrrole Synthesis
MacDonald condensation
to give dipyrrolic products linked by a dihydropyran moiety. Hydrogenolysis of a dipyrrole dibenzyl ester
gave the corresponding dicarboxylic acid and this was converted into a dialdehyde by treatment with
TFAeCH(OMe)3. MacDonald ‘2þ2’ condensation with two different dipyrrylmethanes under optimized
conditions afforded the porphyrin ethers in 30e36% yield. This approach provides a pilot study for the
synthesis of porphyrin crown ether structures. In addition, insightful results on the conformations of
dihydropyran-linked dipyrroles were obtained by careful examination of their proton NMR spectra in
CDCl3 and DMSO-d6.
Ó 2010 Published by Elsevier Ltd.
1. Introduction
acetic acid reacted with phenylhydrazones 3, or the related oximes,
in the presence of zinc powder to give tetrahydroindoles 4 (Scheme
Porphyrins with fused carbocyclic rings are widely found in
petroleum, oil shales, and other organic-rich sedimentary mate-
rials.1,2 Cycloalkanoporphyrins 1 with fused five-, six- or seven-
membered rings have been identified and these geoporphyrins
provide insights into the origins of fossil fuels.3,4 These porphyrins
are commonly present in metalated forms, usually as the nickel(II)
or vanadyl derivatives, and in most cases appear to be derived from
the chlorophylls that were associated with organisms (mostly algae
or photosynthetic bacteria) that were present at the time these
sediments were initially laid down.1,2 Analytical methods have
been developed to examine and contrast the porphyrins present in
sedimentary materials5 and these can potentially lead to applica-
tions in environmental monitoring, specifically in the analysis of tar
balls resulting from oil spills.6e8 In order to provide reliable stan-
dards for these investigations, synthetic methods have been
developed for the synthesis CAPs with 5-, 6-, 7- or larger exocyclic
rings.9e17 We have previously reported on the synthesis of CAPs
from cycloalka[b]pyrroles 2, which in turn could be obtained from
readily available cyclic ketones.13e17 For instance, cyclohexanone in
2),16 and similar cycloalka[b]pyrroles can be obtained by applica-
tion of the same Knorr-type chemistry.13e18 Tetrahydroindoles 4
were regioselectively oxidized with lead tetraacetate to afford the
7-acetoxy derivatives 5 and these in turn could be reacted with
a
-unsubstituted pyrroles 6 in the presence of p-toluenesulfonic acid
to give dipyrroles 7.16 Deprotection of the ester moieties and further
reaction (e.g., with dipyrrylmethane dialdehydes) gave meso,
b
-propanoporphyrins 8 (CAP6) in good overall yields (Scheme 2).16
The same approach can be applied to the synthesis of CAPs with
virtually any size exocyclic ring component.13e17 The six-membered
ring intermediates were particularly versatile and have allowed the
straightforward synthesis of porphyrins 9 with four exocyclic rings
(Scheme 3).15a To date, this synthetic methodology had only been
applied to the preparation of porphyrins with fused carbocyclic
rings, but in principle the same concepts could be applied to the
synthesis of porphyrins with fused heterocyclic systems.
Porphyrins with appended crown ethers have been widely
investigated and have properties that are desirable for sensor
development and molecular recognition studies.19 Naturally, the
porphyrin macrocycle retains the ability to form coordination
complexes while the crown ether units can also strongly bind with
alkaline metal cations.19e21 However, few examples of porphyrins
with fused crown ether units have been reported.21 Murashima
et al. reported an interesting series of porphyrin fused crown ethers
q
For part 24 in the series, see: Gandhi, V.; Thompson, M. L.; Lash, T. D. Tetra-
hedron 2010, 66, 1787e1799.
* Corresponding author. Fax: þ309 438 5538; e-mail address: tdlash@ilstu.edu
(T.D. Lash).
0040-4020/$ e see front matter Ó 2010 Published by Elsevier Ltd.
doi:10.1016/j.tet.2010.04.069

4414
B.E. Smith, T.D. Lash / Tetrahedron 66 (2010) 4413e4422
10 where the oxygens are directly connected to the
b-pyrrolic
R
R
carbons.21 We speculated that crown ether analogs of CAPs 1 would
also have useful properties. Specifically, porphyrin crown ethers 11
might induce a sufficiently large conformational change on binding
metal cations that they would distort the porphyrin macrocycle and
thereby provide a potential avenue for detector development based
on changes in the visible absorption spectrum or in fluorescence
emission intensity. Therefore, we set out to explore the synthesis of
porphyrins with a fused ether subunit as a model for the
development of structures like 11. It was anticipated that the
strategies we had previously developed for synthesizing CAPs 1
could be adapted to prepare these porphyrin ethers. In this paper,
we report the synthesis of porphyrins with a fused dihydropyran
moieties using this approach (Scheme 1).22
Me
Me
Me
Me
N
NH
N
HN
Et
O
12
2. Results and discussion
In this study, meso,
-(2-oxapropano)porphyrins 12 (R¼Et or
b
CH2CH2CO2Me) were targeted for investigation. This system is the
dihydropyran analog of cycloalkanoporphyrins 8, which were
ultimately synthesized from cyclohexanone. Therefore, it was
anticipated that the porphyrin ether system could be obtained
starting from tetrahydropyran-4-one 13. In the earlier studies,
tetrahydroindoles 4 were prepared using classical Knorr-type
conditions by reacting phenylhydrazones 3 with cyclohexanone
and zinc dust in acetic acid at 110 ꢀC.15,16,18,23 In most Knorr-type
reactions, oximes are used instead of phenylhydrazones but better
results were generally obtained for cyclic ketones using phenyl-
hydrazones.15e17 Most Knorr reactions are also conducted at lower
temperatures (70e80 ꢀC) and yields plummet if the temperature of
the exothermic reaction goes too high. However, much higher
temperatures are necessary for the synthesis of many cycloalka[b]
pyrroles and in the case of larger rings virtually no product is
obtained unless the reaction temperature is raised to >140 ꢀC.17 In
those reactions, propionic acid was substituted for acetic acid as the
reaction solvent. Reactions with cyclopentanone necessitated
temperatures >150 ꢀC,14b and these temperatures were obtained by
dissolving substantial amount of sodium propionate in the reaction
solvent. Reactions with 13 were attempted using oximes 1414b or
phenylhydrazones 315a in acetic acid under the conditions used to
prepare tetrahydroindoles 4, but very low yields of the desired
dihydropyranopyrrole or 5-oxotetrahydroindole product 15 were
obtained (Scheme 4). Following a series of attempts, the best results
were obtained using oximes 14 at reaction temperatures of
150e155 ꢀC in mixtures of sodium propionate and propionic acid.
The chemistry was accomplished by heating a stirred mixture of 13,
sodium propionate, and propionic acid to 150 ꢀC and then adding
a solution of the oxime 14 in propionic acid while simultaneously
adding small portions of zinc dust over a period of ca. 30 min. After
the addition was completed, the mixture was stirred for a further
1 h. These conditions gave good yields for ethyl ester 15a and
benzyl ester 15b, but poor results were still obtained for the related
tert-butyl ester 15c. However, we observed that reactions with
oxime 14c darkened considerably when they were heated for 1 h
after the addition of the reactants had been completed. As it was
unclear how long the reaction mixture needed to be heated, the
reaction time following the addition was reduced to 5 min and the
reaction mixture was rapidly quenched by pouring it into ice-water.
This modification raised the yield of 15c to 20%; however, reducing
the reaction time for esters 15a and 15b had little or no effect on the
observed yields. Dihydropyrano[3,4-b]pyrroles 15 are novel
CO2R
HN
N
NH
N
AcO
HN
(CH2)n
2
(CH2)n
(CH2)n
H2C
1
CAPs
CH2
O
Scheme 1.
O
N
Me
CH3
Zn
CO2R1
CO2R1
O
CH3CO2H
N
H
X
NHPh
3
4 X = H
Pb(OAc)4
5 X = OAc
H+
CO2R1
Me
R2O2C
Me
R
Me
HN
NH
R2O2C
H
N
H
R
6
7
Et
Et
Me
Me
Me
N
NH
N
HN
Me
R
8
CAP6
Scheme 2.
O
n
O
n
O
O
O
O
O
R
O
R
O
N
NH
N
R
1. NaOH/H2O
Δ
NH
N
N
N
NH
N
CO2Et
2. AcOH
Δ
HN
N
H
AcO
K3Fe(CN)6
HN
HN
R
O
O
R = Me, Et, Pr, iPr or Ph
O
O
O
O
O
R
O
9
O
O
n
n
n
11
Scheme 3.
10

B.E. Smith, T.D. Lash / Tetrahedron 66 (2010) 4413e4422
4415
O
using ethyl ester 18a in an attempt to prepare the tetraoxa-analog
of these unusual porphyrins. The ester was saponified in refluxing
sodium hydroxide, and the crude product was treated with potas-
sium ferricyanide in refluxing acetic acid. Unfortunately, this pro-
cedure afforded no trace of porphyrin products and attempts to
prepare symmetrical porphyrin ethers were abandoned. The failure
of this chemistry was attributed to the poor stability of the in-
termediates and the reduced reactivity of the bicyclic pyrrolic unit
caused by the presence of a nearby electronegative oxygen atom.
Me
CO2R
O
Me
O
Zn
CH3CH2CO2H
20-50%
N
H
O
CO2R
N
OH
15 a. R = Et;
b. R = Bn; c. R = t-Bu
13
14
NCS CCl4
Et
Me
CO2R
Me
BnO2C
Me
BnO2C
19
H
HN
NH
N
H
Me
CO2R
O
Benzyl ester 18b was reacted with an a-unsubstituted pyrrole 19
in acetic acid, using p-toluenesulfonic acid as a catalyst, and this
afforded a dipyrrole 20a that was linked via the dihydropyran unit
(Scheme 4). The benzyl ester protective groups were cleaved by
hydrogenolysis over 10% Pd/C to give the corresponding di-
carboxylic acid 21 in quantitative yield. The dicarboxylic acid could
be isolated in pure form, but had to be handled with care or partial
decomposition ensued. The related dialdehyde 22 was also re-
quired and this was generated by treating 21 with TFA and then
adding trimethyl orthoformate while maintaining the temperature
at 25 ꢀC, followed by stirring the reaction for 10 min at 40 ꢀC. The
outcome of this reaction was somewhat sensitive and higher or
lower temperatures gave poor results. In our studies, we commonly
isolate dipyrrole dicarboxylic acids by carefully precipitating the
products from an aqueous ammonia solution by acidification with
acetic acid at 5 ꢀC, followed by suction filtration, exhaustive
washing with water, and drying in vacuo.16,17 However, material
obtained this way gave variable results and better results were
generally obtained when the dicarboxylic acid was taken on with
a minimum of handling following the hydrogenolysis step. The
synthesis of a dipyrrole 20b with mixed ester units was also
investigated. Pyrrole 15c was reacted with NCS in carbon tetra-
chloride but gave relatively poor results. Although the chloro-de-
rivative 18c was generated, the reaction had to be stopped before
going to completion to avoid decomposition. The product was then
reacted with 19 and p-toluenesulfonic acid in acetic acid to form the
required dipyrrole. This compound was isolated following column
chromatography as an oil and used directly to generate a dipyrrole
aldehyde 23. The oil was stirred with TFA at room temperature for
10 min and treated with trimethyl orthoformate. Following chro-
matography and recrystallization, aldehyde 23 was obtained in 17%
yield. The chemistry observed for dihydropyranopyrroles is
significantly modified by the 5-oxa substitution compared to tet-
rahydroindoles. The oxygen appears to exert enough of an electron-
withdrawing effect to reduce the reactivity of the 7-position
towards reactions with lead tetraacetate or NCS. In addition, it is far
less straightforward to convert dipyrrolic intermediates in the
dihydropyran series into the corresponding aldehydes. Neverthe-
less, dipyrroles 20a, 21, and 22 could all be isolated in good to
excellent yields under optimized conditions.
R = Bn or t-Bu
p-TSA
54% from 15b
Et
N
H
O
Cl
20
a. R = Bn; b. R = t-Bu
18
a. R = Et
b. R = Bn
c. R = t-Bu
H2
Pd/C
99%
R = t-Bu
TFA
CH(OMe)3
17%
BnO2C
Me
R = Bn
CO2H
Me
HO2C
Me
CHO
Me
HN
NH
HN
NH
Et
Et
O
21
O
23
80%
TFA
CH(OMe)3
CHO
Me
OHC
Me
HN
O
NH
Et
22
Scheme 4.
heterocyclic compounds and are obtained in a very simple fashion
using the Knorr approach. In fact, this is the first time that Knorr-
type chemistry has been used to prepare pyrroles with fused
heterocyclic rings. Therefore, we speculated that other heterocyclic
systems could be obtained using the same methodology. With this
in mind, 4-chromanone (16) was reacted with oxime 14a and zinc
dust in an attempt to prepare the pyrrolic tricycle 17 (Scheme 5).
Again, the best results were obtained at 150e155 ꢀC in mixtures of
sodium propionate and propionic acid, but in this case yields of 17
were relatively low (ca. 6%). Although this chemistry allows for
a remarkably direct synthesis of this novel chromanopyrrole
system, it is clearly not practical. As the structure of 17 is not
compatible with porphyrin synthesis, this tricyclic system was not
further investigated.
O
Me
CO2Et
O
Me
Zn
O
O
CH3CH2CO2H
CH3CH2CO2Na
150-155 oC
N
H
N
CO2Et
The NMR properties for dihydropyranopyrroles 15, and the
solvent dependent results for dipyrroles 20a and 22, were suffi-
ciently unusual to warrant further discussion. In the monopyrroles
(e.g.,15a; Fig.1), the isolated 4-CH2 group gave a downfield signal at
4.6 ppm, while the resonances for the 6- and 7-methylene units
showed up at 3.9 and 2.7 ppm, respectively. Although these shifts
are to be expected, the 4-CH2 unit gave a broadened long range
coupled triplet (J¼1.2 Hz), while the 7-CH2 gave a broadened triplet
that showed indications of long range coupling as well. This degree
16
17
OH
14a
Scheme 5.
In order to utilize dihydropyrano[3,4-b]pyrroles 15, it was nec-
essary to introduce a leaving group on the -methylene unit. Tet-
a
rahydroindoles 4 react with lead tetraacetate in acetic acid to give
the related acetoxy compounds 5 (Scheme 2),15,16 but the dihy-
dropyranopyrroles gave no isolatable products with this reagent.
Instead, 15a and 15b were reacted with N-chlorosuccinimide (NCS)
in carbon tetrachloride in the presence of a strong lamp (Scheme 4).
The chemistry was somewhat sluggish, taking several hours to
reach completion, but the reaction could easily be monitored by
proton NMR spectroscopy. The resulting chloro-derivatives 18 were
somewhat unstable and were taken on in crude form. Tetrahy-
droindoles had been used to prepare porphyrins 9 with four exo-
cyclic rings (Scheme 3),15a and this chemistry was also investigated
5
of JHH coupling interaction across the pyrrolic unit is somewhat
unexpected and is analogous to homoallylic coupling in olefinic
systems. The interaction was confirmed using 1He1H COSY NMR
spectroscopy. Long range coupling of this type was weak in dipyr-
roles 20e22, and while the interactions gave rise to some peak
broadening, only weak correlations could be seen by COSY NMR
spectroscopy. However, the proton NMR data for the dipyrroles
provides some important information on the conformations of

4416
B.E. Smith, T.D. Lash / Tetrahedron 66 (2010) 4413e4422
corresponding to the 4- and 6-methylenes were shifted upfield by
4
5 O
Me
0.1e0.2 ppm, while the ethyl CH2 gave rise to two widely separated
multiplets at 1.9 and 2.1 ppm (Fig. 3). The upfield shift and
increased resolution of this diastereotopic methylene indicates that
3
6
CO2Et
2
7
N
H
the ethyl group is held under the p-system of the adjacent pyrrole
15a
unit, and this geometry presumably results from favorable hydro-
gen bonding interactions with the DMSO solvent (Fig. 4). The up-
field shift of the ethyl CH3 resonance from 1.10 ppm in CDCl3 to
0.77 ppm in DMSO-d6 also supports this conjecture. Nevertheless,
4.64
2.76 2.74 2.72
ppm
ppm
O
Hx
Ha
4.6 4.5 4.4 4.3 4.2 4.1 4.0 3.9 3.8 3.7 3.6 3.5 3.4 3.3 3.2 3.1 3.0 2.9
ppm
N
N
H
H
Ha
O
Hx
Figure 1. Partial 500 MHz proton NMR spectrum of 5-oxatetrahydroindole 15a in
CDCl3 showing the unusual 5J coupling between the 4- and 7-CH2 protons at 2.72 and
4.63 ppm, respectively.
Hb
Hb
H
N
H
N
these intermediates. At 500 MHz, the three protons at positions 6
and 7 on the dihydropyran unit of 20a are sufficiently well resolved
to represent an AMX system (Fig. 2). In addition, the protons
corresponding to the 4-CH2 moiety gave an AB quartet (J¼13.5 Hz)
at 4.7 ppm. The ethyl CH2 was also diastereotopic and gave rise to
a multiplet centered on 2.47 ppm. In DMSO-d6, significant changes
were observed in these proton NMR resonances (Fig. 3). The peaks
Conformation B
Conformation A
(favored for 22 in CDCl3)
Ha
Hb
N
H
O
Hx
H
O
H
C
H
N
CD3
S
CH3
CD3
4-CH2
diastereotopic CH2
Conformation (type A) of dihydropyran-linked dipyrroles in d6-DMSO
showing the diastereotopic CH2 protons for the ethyl moiety.
Figure 4. Proposed equilibrium of conformations A and B for dihydropyran-linked
dipyrroles. Substituents are not shown for the sake of clarity. Hydrogen bonding to
DMSO favors a type A conformation but holds the ethyl substituent in a specific ori-
entation relative to the adjacent pyrrole ring.
2.50
ppm
2.45
ppm
4.75
4.70
the 3J coupling constants for the two protons at position 6 and the
adjacent 7-CH fell into the range of 5.0 to 7.1 Hz in both solvents
(Table 1), values that are consistent with the 60ꢀ dihedral angles in
conformation A (Fig. 4). The proton NMR spectrum for dialdehyde
22 in DMSO-d6 showed similar coupling interactions for the CHCH2
unit with vicinal coupling constants of 5.3 and 6.8 Hz, values that
again suggest that conformation A is favored, and the ethyl CH2 also
shows an upfield shift and strongly diastereotopic characteristics.
However, the proton NMR spectrum of 22 in CDCl3 showed sig-
nificant differences in the coupling for the CH2CH unit. In this case,
the 6-CH2 resonances are significantly shifted upfield and show
vicinal coupling constants with the 7-CH of 5.7 and 9.5 Hz (Table 1).
This coupling interaction is not consistent with conformation A and
suggests that the alternative conformation B is more favored in this
case (Fig. 4). Conformation B has dihedral angles of 60 and 180ꢀ
between the CH2 protons and the Karplus correlation is therefore
far closer to the observed coupling constants. The proton NMR
spectrum for monoaldehyde 23 in CDCl3 shows intermediary vici-
nal coupling constants for the CHCH2 unit (J¼5.3 and 8.0 Hz),
indicating that conformation B is somewhat favored in this case as
well. In all of these spectra, the geminal coupling for the 6-CH2 is ca.
11 Hz. However, all three dipyrroles are drawn into a conformation
of type A by strong hydrogen bonding interactions. These hydrogen
bonding interactions are also evident from the downfield shifts for
the two NH resonances in DMSO-d6, showing values of 10.88 and
11.35 ppm for 20a, 11.03 and 11.58 ppm for 23, and 11.21 and
11.65 ppm for 22. The increased deshielding observed for the
dialdehyde is due to the increased electron-withdrawing charac-
teristics of the formyl moieties compared to the ester units. Hence,
the NMR data provides important insights into the factors that
influence the favored conformations of dipyrrolic intermediates. As
the dibenzyl ester 20a appears to favor a different conformation to
dialdehyde 22, placement of the formyl units may affect the efficacy
4.25
4.20
4.15
4.10
4.05
4.00
3.95
3.90
3.85
3.80
ppm
Figure 2. Partial 500 MHz proton NMR spectrum of dipyrrole 20a in CDCl3 showing an
AB quartet at 4.7 ppm for the 4-CH2 and a multiplet for the diastereotopic ethyl CH2 at
2.43e2.51 ppm. The AB quartet is slightly broadened due to long range coupling ef-
fects. The region between 3.70 and 4.25 ppm corresponds to the CHCH2 unit of the
dihydropyran ring and the J values for this system are consistent with conformation A.
4-CH2
diastereotopic CH2
4.60
ppm
2.2
2.1
2.0
ppm
4.25 4.20 4.15 4.10 4.05 4.00 3.95 3.90 3.85 3.80 3.75 3.70
ppm
Figure 3. Partial 500 MHz proton NMR spectrum of dipyrrole 20a in DMSO-d6
showing an AB quartet at 4.5 ppm for the 4-CH2 and two well resolved 1H multiplets
for the diastereotopic ethyl CH2 at 1.9 and 2.1 ppm. The region between 3.65 and
4.25 ppm corresponds to the CHCH2 unit of the dihydropyran ring and the J values for
this system are again consistent with conformation A.

B.E. Smith, T.D. Lash / Tetrahedron 66 (2010) 4413e4422
4417
Table 1
Chemical shifts and coupling constants for the CHCH2 system in dipyrroles 20a, 22, and 23 in CDCl3 or DMSO-d6. The triplets observed in some cases for the 7-CHx are un-
resolved doublets of doublets and the reported J values fall between the coupling constants for HaeHx and HbeHx
Dipyrrole (solvent)
6-CHa (multiplicity, J Hz)
6-CHb (multiplicity, J Hz)
7-CH (multiplicity, J Hz)
20a (CDCl3)
20a (DMSO-d6)
22 (CDCl3)
22 (DMSO-d6)
23 (CDCl3)
3.78 (dd, 7.1, 11.0 Hz)
3.69 (dd, 6.3, 11.0 Hz)
3.74 (dd, 9.5, 10.9 Hz)
3.70 (dd, 6.8, 11.1 Hz)
3.75 (dd, 8.0, 11.1 Hz)
3.67 (dd, 7.5, 11.1 Hz)
4.08 (dd, 5.0, 11.0 Hz)
3.92 (dd, 5.2, 11.0 Hz)
4.14 (dd, 5.7, 10.9 Hz)
3.96 (dd, 5.3, 11.1 Hz)
4.09 (dd, 5.3, 11.1 Hz)
3.93 (dd, 5.5, 11.1 Hz)
4.21 (br t, 5.9 Hz)
4.24 (t, 5.6 Hz)
4.34 (dd, 5.7, 9.5 Hz)
4.25 (t, 5.8 Hz)
4.25 (dd, 5.5, 8.0 Hz)
4.28 (br t, 6.5 Hz)
23 (DMSO-d6)
of macrocycle formation.15e17 In earlier investigations, Gossauer
demonstrated that a tripyrrane dialdehyde reacted with a dipyr-
rylmethane under acid catalyzed conditions to give pentaphyrin,
but reaction of a dipyrrylmethane dialdehyde with a tripyrrane
gave no pentapyrrolic product and only porphyrin by-products
were noted.24 No explanation was offered for this observation and
in fact the result does not seem to be consistent with the
tetrapyrrolic macrocycle as
undergoes slow air oxidation in the presence of excess zinc acetate.
Although these conditions gave good yields for meso, -prop-
a
porphodimethene 25, but this
b
anoporphyrins 9, very little of the porphyrin ether product 12a was
formed. Dropwise addition of the dipyrrolic reactants toa solution of
p-toluenesulfonic acid in methanoledichloromethane showed
some improvement but the yield was only raised to 9%. Slow addi-
tion of the reactants to the acid catalyst allows the effective con-
centration of reactants to be minimized at any given time and this
may facilitate cyclization reactions. However, this approach must be
used with caution as acid catalyzed fragmentationerecombination
processes may occur that can produce mixtures of porphyrin prod-
ucts.26 The NMR data for the isolated product was consistent with
a single isomer27 and the slow addition method does not lead to
undue difficulties in this case. However, the yields were still un-
acceptably low and further modifications were necessary. We
speculated that the electron-withdrawing effect of the dihy-
dropyran oxygen exerted a deleterious effect by deactivating the
nearby pyrrolic unit towards electrophilic substitution. This factor
had also lead to problems with the synthesis of dipyrroles 20 and the
formylation of this system to give dialdehyde 22 also required the
use of higher temperatures than were usually necessary. It is also
possible that the conformation of the dipyrrolic intermediates was
not conducive to macrocycle formation, but this factor is more dif-
ficult to address. If the electronic factor is primarily responsible for
the low yields, better results would be expected using dialdehyde 22
and dipyrrylmethane 26a. As dipyrrole 22 already has the required
carbonecarbon bonds, it only remains for the more reactive dipyr-
role 26a to undergo electrophilic substitution to assemble the por-
phyrin macrocycle. Dipyrroles 22 and 26a were condensed under
the slow addition MacDonald ‘2þ2’ conditions and then air oxidized
for 2 days in the presence of zinc acetate (Scheme 6). Following
extraction, demetalation, chromatography and recrystallization
fromchloroformemethanol, the newporphyrin systemwas isolated
in 36% yield. Dialdehyde 22 was also reacted with dipyrrylmethane
26b under these conditions to give the related porphyrin diester 12b
in 30% yield. Although the successful synthetic route to porphyrins
12a and 12b is based on earlier work, various steps had to be
considerably modified to overcome the deleterious effects due tothe
presence of an oxygen atom. Porphyrin synthesis is generally reliant
on the electron-rich characteristics of the pyrrolic precursors, and
electron-withdrawing groups can severely inhibit the necessary
electrophilic substitution processes that lead to macrocycle forma-
tion. The observations and solutions to the issues that arose in the
synthesis of dihydropyran-fused porphyrins have potential value in
the synthesis of other porphyrins with electron-withdrawing
groupings.
Ha
Hn
Hm
O
Hb
5
6
4
Et
Hx
7
Me
Me
3
HN
NH
2
X
X
Dipyrroles 20a, 22 and 23
X = CO2Bn or CHO
mechanism for the reaction. Initial condensation would be expec-
ted to give the same open-chain pentapyrrolic intermediate, so why
should be the final outcome be different? Clearly, our results offer
a possible answer if the conformations of the intermediates are
altered when the formyl moieties are present on different re-
actants. Importantly, if the placement of formyl groups on a dipyr-
rolic fragment significantly alters the conformations, it may be
possible to make use of this effect in directing macrocycle
formation.
Initially, the synthesis of porphyrin 12a was attempted using
conventional MacDonald ‘2þ2’ condensation conditions25 by
reacting dipyrrole dicarboxylic acid 21 with dipyrrylmethane
dialdehyde 24 in the presence of p-toluenesulfonic acid in meth-
anoledichloromethane (Scheme 6). The reaction generates the
R
R
24 R = Et, Y = CHO
26 Y = CO2H
Me
Me
Me
Me
HN
NH
NH
a. R = Et; b. R = PMe
Y
X
Y
X
H
R
R
HN
O
Me
Me
Me
N
N
N
Et
H H
H
H
N
21 X = CO2H; 22 X = CHO
Me
R
R
Et
25 (porphodimethene)
O
Me
Me
Me
Me
N
NH
N
[O]
The UVevis spectrum for porphyrin 12a (Fig. 5) was very similar
to the spectrum previously reported for 9 and gave a Soret band at
404 nm together with four Q bands in the visible region (phyllo-
type pattern28). Addition of TFA to solutions of 12a gave the related
dication 12aH22þ, and this afforded a much stronger and sharper
Soret absorption at 411 nm. The proton NMR spectrum of 12a in
CDCl3 showed typical porphyrin-type aromatic characteristics29
where the three external meso-protons gave rise to three 1H
30-36% from 22
HN
PMe = CH2CH2CO2Me
Et
O
12 a. R = Et; b. R = PMe
Scheme 6.

4418
B.E. Smith, T.D. Lash / Tetrahedron 66 (2010) 4413e4422
similar UV and proton NMR data. Porphyrins 12a and 12b were also
characterized by carbon-13 NMR spectroscopy, mass spectrometry,
and combustion analysis.
3. Conclusions
Knorr-type reactions of tetrahydropyran-4-one with oximes
derived from esters of acetoacetic acid in the presence of zinc dust
and sodium propionate in propionic acid at 150e155 ꢀC gave good
yields of pyrroles with fused dihydropyran rings. These fused ring
pyrroles exhibit unusual 5J homonuclear coupling in their proton
NMR spectra that are analogous to homoallylic coupling in olefinic
systems. The dihydropyanopyrroles reacted with N-chloro-
succinimide in CCl4 to give unstable 7-chloro-derivatives and these
further condensed with an
a-unsubstituted pyrrole under acid
Figure 5. UVevis spectra of porphyrin 12a in 1% Et3Nechloroform (free base; blue
line) and 1% TFAechloroform (dication 12aH22þ; red line). The insert shows details of
the Q band region.
catalyzed conditions to give dipyrroles incorporating the dihy-
dropyran unit. Cleavage of the protective ester groups gave a di-
carboxylic acid, and subsequent treatment with TFA and trimethyl
orthoformate afforded the related dialdehyde. The proton NMR
spectra for the dihydropyran-linked dipyrroles demonstrated that
significant conformational changes occur due to solvent in-
teractions (DMSO vs CHCl3) and the introduction of electron-
withdrawing formyl moieties. The dihydropyran-linked dipyrrole
dialdehyde was condensed with dipyrrylmethanes in the presence
of p-toluenesulfonic acid, and following air oxidation in the pres-
ence of zinc acetate, the corresponding porphyrin ethers could be
isolated in 30e36% yield. The formation of this unique porphyrin
system suggests that related crown ether structures might also be
obtained by using a similar synthetic strategy. This could poten-
tially be achieved by using acyclic ketones with suitably placed
methoxy groups as the precursors to pyrrolic intermediates.
Alternatively, previously reported crown ether/cyclic ketone
hydrids30 could be used to directly synthesize pyrroles with fused
crown ether units.
singlets near 10 ppm, while the internal NHs gave two separate NH
resonances at ca. 3.5 ppm. The appearance of two separate NH
peaks indicates that a single tautomeric species is favored for 12a,
and that NH exchange is relatively slow. The resonances were
somewhat concentration dependent and the meso-protons shifted
upfield by approx. 0.1 ppm in more concentrated solutions. The
exocyclic ring gave rise to two singlets at 5.87 and 6.86 ppm, which
correspond to the pyrrole CH2 and meso-CH2 components,
respectively. These large downfield shifts are consistent with the
expected porphyrin diamagnetic ring current. The corresponding
dication 12aH22þ in TFAeCDCl3 showed the meso-protons further
downfield near 10.5 ppm, while up to four different NH resonances
could be seen upfield between ꢁ2.5 and ꢁ3.7 ppm (Fig. 6). The
singlets for the exocyclic ring were shifted slightly downfield by
0.1e0.2 ppm, and are now observed at 5.99 and 7.05 ppm. The
resonances for the porphyrin methyls and the methylenes of the
ethyl groups are also mostly shifted downfield, and taken together
these data indicate that the dication has a slightly larger diatropic
ring current than the free base porphyrin. Porphyrin 12b gave
4. Experimental
4.1. General
Et
Et
15
Benzyl acetoacetate, tert-butyl acetoacetate, ethyl acetoacetate,
tetrahydro-4H-pyan-4-one, 4-chromanone, N-chlorosuccinimide,
p-toluenesulfonic acid, and 10% palladium/charcoal were
purchased from Aldrich or Acros, and were used without further
purification. Chromatography was performed using grade three
neutral alumina or 70e230 mesh silica gel. Melting points were
determined in open capillary tubes using a Mel-Temp apparatus
and are uncorrected. UVevis absorption spectra were run on
a Varian Cary Spectrophotometer. Proton and carbon-13 NMR data
were obtained on a Varian Gemini 400 MHz FT NMR spectrometer
or a 500 MHz Bruker NMR Avance III spectrometer. Mass spectral
determinations were conducted at the Mass Spectral Laboratory,
School of Chemical Sciences, University of Illinois at Urbana-
Champaign, and elemental analyses were obtained from the
School of Chemical Sciences Microanalysis Laboratory at the
University of Illinois.
Me
Me
N
N
N
H
H
H
H
20
10
1
N
2 Me
Me
4
3
5
31
Et
51
O
2+
12H2
-2.5
-3.0
ppm
4.2. Synthetic procedures
4.2.1. Benzyl
3-methyldihydropyrano[4,3-b]pyrrole-2-carboxylate
(15b). Tetrahydro-4H-pyran-4-one (1.00 g, 10 mmol) and sodium
propionate (13.4 g, 0.14 mol) were allowed to dissolve in propionic
acid (224 mL) while heating to 150 ꢀC. A solution of benzyl ester
oxime 14b14b (2.43 g, 11 mmol) in propionic acid (45 mL) was then
added dropwise while simultaneously adding zinc dust (4.0 g,
61 mmol) in small portions, keeping the reaction mixture at
10.5
7.0
6.5
ppm
ppm
Figure 6. Partial 500 MHz proton NMR spectrum of porphyrin dication 12aH22þ in
TFAeCDCl3 showing the downfield and upfield regions. The four internal NH protons
give rise to four separate upfield resonances between ꢁ2.5 and ꢁ3.7 ppm.
a
temperature between 150e155 ꢀC. Once the addition was

B.E. Smith, T.D. Lash / Tetrahedron 66 (2010) 4413e4422
4419
completed, the resulting mixture was allowed to stir for 1 h while
gradually cooling to 140 ꢀC. The resulting orange mixture was
cooled to 70 ꢀC, then poured into ice-water (600 mL) and allowed
to stand overnight. The precipitate was suction filtered and
recrystallized from ethanol to give the dihydropyranopyrrole
(797 mg, 2.94 mmol) as a tan powder, mp 123e125 ꢀC. The aqueous
filtrate was extracted with dichloromethane, washed with water
and 10% aqueous sodium bicarbonate, and dried over sodium
sulfate. The residue was combined with the filtrate from the
recrystallization and purified by flash chromatography on silica,
eluting with a 50:50 mixture of dichloromethane and chloroform.
The product containing fractions were identified by TLC, combined,
and rotary evaporated. The resulting solid was crystallized from
ethanol to give the product (545 mg, 2.01 mmol, combined yield
solvent was removed under reduced pressure, and the residue was
chromatographed on silica, eluting with 50:50 dichloro-
a
methaneechloroform. The product containing fractions were
identified by TLC, combined, and evaporated. The resulting solid
was further recrystallized from ethanol to give the tert-butyl ester
(471 mg, 1.99 mmol, 20%) as pale yellow crystals, mp 185e186 ꢀC;
IR (Nujol):
(500 MHz, CDCl3):
n
3308 (NH str.), 1663 cmꢁ1 (C]O str.); 1H NMR
d
1.56 (9H, s), 2.17 (3H, s), 2.69 (2H, t, J¼5.6 Hz),
3.92 (2H, t, J¼5.6 Hz), 4.60 (2H, t, J¼1.1 Hz), 8.71 (1H, br s); 13C NMR
(CDCl3):
d 10.6, 24.0, 28.7, 64.4, 64.7, 80.6, 117.9, 119.3, 122.5, 128.1,
161.8. Anal. Calcd for C13H19NO3: C, 65.80; H, 8.07; N, 5.90. Found: C,
65.55; H, 8.21; N, 5.97.
4.2.4. Ethyl 3-methylchromano[4,3-b]pyrrole-2-carboxylate (17). A
mixture of 4-chromanone (1.85 g, 12.5 mmol) and sodium pro-
pionate (16.8 g, 0.175 mmol) in propionic acid (56 mL) was pre-
pared and heated while stirring to 150 ꢀC. A solution of ethyl ester
oxime 14a14b (2.17 g,13.6 mmol) in propionic acid (56 mL) was then
added dropwise while zinc dust (5.0 g, 76 mmol) was simulta-
neously added in small portions, maintaining the reaction mixture
at a temperature between 150 ꢀC and 155 ꢀC. Once the addition was
completed, the resulting mixture was allowed to stir for 10 min
while maintaining the temperature between 150 ꢀC and 155 ꢀC. The
resulting mixture was further cooled to 70 ꢀC, then poured into
a beaker of ice-water and allowed to stand overnight for full pre-
cipitation. The mixture was filtered, and the solid was recrystallized
from 100% ethanol to give the chromanopyrrole (160 mg,
0.623 mmol) as an off-white solid, mp 184e185 ꢀC. The aqueous
solution was also extracted with dichloromethane and washed
with saturated aqueous sodium bicarbonate. The extract was then
combined with the filtrate from the recrystallization and chroma-
tographed on flash silica, eluting with dichloromethane. The
product containing fractions were evaporated under reduced
pressure and the residue recrystallized from ethanol to gave the
tricyclic pyrrole (15 mg, 0.058 mmol) (overall yield 5.5%) as a white
50%) as pale yellow crystals, mp 124.5e125.5 ꢀC; IR (Nujol):
n
3304
2.22
(NH str.), 1672 cmꢁ1 (C]O str.); 1H NMR (500 MHz, CDCl3):
d
(3H, s), 2.67 (2H, t, J¼5.6 Hz), 3.92 (2H, t, J¼5.6 Hz), 4.60 (2H, br t,
J¼1.1 Hz), 5.31 (2H, s), 7.30e7.43 (5H, m), 8.87 (1H, br s); 13C NMR
(CDCl3): d 10.6, 23.9, 64.3, 64.6, 65.8, 117.7, 118.2, 124.0, 128.2, 128.3,
128.7, 129.1, 136.7, 161.7. Anal. Calcd for C16H17NO3: C, 70.83; H,
6.31; N, 5.16. Found: C, 70.66; H, 6.35; N, 5.23.
4.2.2. Ethyl
3-methyldihydropyrano[4,3-b]pyrrole-2-carboxylate
(15a). Tetrahydro-4H-pyran-4-one (2.50 g, 25 mmol) and sodium
propionate (33.6 g, 0.35 mol) were allowed to dissolve in propionic
acid (112 mL) upon heating to 150 ꢀC. A solution of ethyl ester
oxime 14a14b (4.35 g, 27 mmol) in propionic acid (112 mL) was then
added dropwise to the solution while small portions of zinc dust
(10 g, 0.15 mol) were added simultaneously, maintaining the re-
action mixture at a temperature between 150 ꢀC and 155 ꢀC. Once
the addition was completed, the mixture was stirred for 1 h while
allowing it to gradually cool to 110 ꢀC. The resulting orange mixture
was cooled to 70 ꢀC, then poured into a 2 L beaker of ice-water
(1.8 L) and allowed to stand overnight. The aqueous solution was
saturated with sodium chloride and filtered. The resulting solid was
chromatographed on flash silica, eluting with a 50:50 mixture of
dichloromethane and chloroform. The product containing fractions
were identified by TLC, combined, and evaporated under reduced
pressure. Recrystallization from ethanol gave dihydropyr-
anopyrrole 15a (1.77 g, 8.47 mmol, 34%) as an off white solid, mp
solid, mp 184e185 ꢀC; IR (Nujol):
n
3287 (NH str.), 1660 cmꢁ1 (C]O
1.40 (3H, t, J¼7.1 Hz), 2.27 (3H, s),
str.); 1H NMR (500 MHz, CDCl3):
d
4.38 (2H, q, J¼7.1 Hz), 5.26 (2H, s), 6.91e6.95 (2H, m), 7.13 (1H, td,
J¼1.5, 7.7 Hz), 7.36 (1H, d, J¼7.7 Hz), 9.40 (1H, br s); 13C NMR
(CDCl3):
d 10.7, 14.8, 60.5, 65.0, 116.1, 117.1, 117.3, 120.6, 120.7, 121.6,
145e146 ꢀC; IR (Nujol):
n
3306, 3263 (NH str.), 1654 cmꢁ1 (C]O
123.7, 127.2, 129.1, 153.9, 162.2. Anal. Calcd for C15H15NO3: C, 70.02;
H, 5.88; N, 5.44. Found: C, 69.88; H, 5.86; N, 5.52.
str.); 1H NMR (500 MHz, CDCl3):
d
1.35 (3H, t, J¼7.1 Hz), 2.20 (3H, s),
2.70 (2H, tt, J¼1.2, 5.5 Hz), 3.93 (2H, t, J¼5.5 Hz), 4.30 (2H, q,
J¼7.1 Hz), 4.60 (2H, t, J¼1.2 Hz), 8.60 (1H, br s); 1H NMR (500 MHz,
4.2.5. Benzyl 7(5-benzyloxycarbonyl-3-ethyl-4-methyl-2-pyrrolyl)-
3-methyldihydropyrano[4,3-b]pyrrole-2-carboxylate (20a). Benzyl
ester 15b (200 mg, 0.738 mmol) was dissolved in carbon tetra-
chloride (20 mL), N-chlorosuccinimide (100 mg, 0.749 mmol) was
added, and the mixture was stirred under a 250 W lamp for 2.5 h.
The resulting solution was diluted with dichloromethane, washed
with water, and 5% aqueous sodium bicarbonate, and the organic
layer dried over sodium sulfate and rotary evaporated to give the
crude chlorinated derivative 18b as an orange oil. The crude oil was
DMSO-d6):
d
1.25 (3H, t, J¼7.1 Hz), 2.09 (3H, s), 2.56 (2H, br t,
J¼5.6 Hz), 3.77 (2H, t, J¼5.6 Hz), 4.18 (2H, q, J¼7.1 Hz), 4.46 (2H, br t,
J¼1.2 Hz), 11.18 (1H, br s); 13C NMR (CDCl3):
d 10.5, 14.7, 23.9, 60.0,
64.3, 64.6, 118.05, 118.06, 123.4, 128.8, 162.2. Anal. Calcd for
C11H15NO3: C, 63.14; H, 7.22; N, 6.69. Found: C, 62.96; H, 7.28; N,
6.67.
4.2.3. tert-Butyl 3-methyldihydropyrano[4,3-b]pyrrole-2-carboxylate
(15c). Tetrahydro-4H-pyran-4-one (1.00 g, 10 mmol) and sodium
propionate (13.4 g, 0.14 mol) were allowed to dissolve in propionic
acid (112 mL) while heating to 150 ꢀC. A solution of tert-butyl ester
oxime 14c14b (2.06 g,11 mmol) in propionic acid (45 mL) was added
dropwise while zinc dust (4.0 g, 61 mmol) was added simulta-
neously in small portions, and the reaction mixture was maintained
at a temperature between 150e155 ꢀC. Once the addition was
complete, the mixture was allowed to stir for 10 min while main-
taining the temperature between 150e155 ꢀC. The resulting orange
mixture was cooled to 70 ꢀC, then poured into 600 mL of ice-water
and allowed to stand overnight. The aqueous solution was extrac-
ted with dichloromethane (ꢂ3), and the combined organic solu-
tions were washed with water and saturated aqueous sodium
bicarbonate solution, and then dried over sodium sulfate. The
dissolved in acetic acid (7 mL) along with
a
-free pyrrole 1931,32
(162 mg, 0.667 mmol) and allowed to stir for 2 h in the presence
of p-toluenesulfonic acid monohydrate (19 mg, 0.10 mmol). The
solution was diluted with dichloromethane, washed with water
and 5% aqueous sodium bicarbonate, and dried over sodium sulfate.
The organic solvent was then removed under reduced pressure and
the residue chromatographed on a silica column, eluting with
chloroform. The product fractions were identified by TLC, com-
bined, and rotary evaporated. Further purification by re-
crystallization from ethanol gave the title dipyrrole (185 mg,
0.36 mmol, 54%) as a white powder, mp 189e190 ꢀC; IR (Nujol):
3293, 3227 (NH str.), 1672, 1655 cmꢁ1 (C]O str.); 1H NMR
(500 MHz, CDCl3):
1.10 (3H, t, J¼7.5 Hz), 2.21 (3H, s), 2.27 (3H, s),
2.42e2.51 (2H, m), 3.78 (1H, dd, J¼7.1, 11.0 Hz), 4.08 (1H, dd, J¼5.0,
n
d

4420
B.E. Smith, T.D. Lash / Tetrahedron 66 (2010) 4413e4422
11.0 Hz), 4.21 (1H, br t, J¼5.9 Hz), 4.66e4.75 (2H, AB quartet,
J¼13.5 Hz), 5.12e5.19 (2H, m), 5.26 (1H, s), 5.28 (1H, s), 7.28e7.39
(10H, m), 9.26 (1H, br s), 9.35 (1H, br s); 1H NMR (500 MHz, DMSO-
d
0.86 (3H, t, J¼7.4 Hz), 2.02e2.12 (1H, m), 2.14e2.28 (1H, m), 2.200
(3H, s), 2.203 (3H, s), 3.31 (3H, s), 3.70 (1H, dd, J¼6.8, 11.1 Hz), 3.96
(1H, dd, J¼5.3, 11.1 Hz), 4.25 (1H, t, J¼5.8 Hz), 4.61 (2H, s), 9.50 (1H,
d6):
d
0.77 (3H, t, J¼7.3 Hz), 1.86e1.95 (1H, m), 2.07e2.16 (1H, m),
s), 9.52 (1H, s),11.21 (1H, s),11.62 (1H, s); 13C NMR (CDCl3):
d 9.0, 9.1,
2.15 (3H, s), 2.16 (3H, s), 3.69 (1H, dd, J¼6.3, 11.0 Hz), 3.92 (1H, dd,
J¼5.2, 11.0 Hz), 4.23 (1H, t, J¼5.6 Hz), 4.53e4.61 (2H, AB quartet,
J¼13.8 Hz), 5.21e5.28 (4H, m), 7.27e7.42 (10H, m), 10.88 (1H, s),
15.7, 17.1, 33.4, 64.3, 69.3, 119.9, 126.9, 127.2, 129.2, 129.3, 131.0,
135.5, 135.7, 176.0, 176.3. HRMS (EI), m/z calcd for C17H20N2O3:
300.1474. Found: 300.1470. Anal. Calcd for C17H20N2O3$¼H2O: C,
66.98; H, 6.78; N, 9.19. Found: C, 66.92; H, 6.66; N, 9.08.
11.35 (1H, s); 13C NMR (CDCl3):
d 10.96, 10.99, 16.8, 17.6, 33.2, 64.8,
65.9, 66.0, 70.4, 118.4, 118.56, 118.65, 123.0, 125.3, 126.4, 128.0,
128.18, 128.23, 128.71, 128.73, 130.5, 130.8, 136.3, 136.4, 162.1, 162.2.
HRMS (EI), m/z calcd for C31H32N2O5: 512.2311. Found: 512.2314.
Anal. Calcd for C31H32N2O5$½H2O: C, 71.38; H, 6.37; N, 5.37. Found:
C, 71.35; H, 6.33; N, 5.32.
4.2.8. 7(5-Benzyloxycarbonyl-3-ethyl-4-methyl-2-pyrrolyl)-3-meth-
yldihydropyrano[4,3-b]pyrrole-2-carbaldehyde (23). tert-Butyl ester
15b (200 mg, 0.844 mmol) was dissolved in carbon tetrachloride
(16 mL) along with N-chlorosuccinimide (113 mg, 0.844 mmol),
and stirred under a 250 W lamp for 200 min. The solution was
diluted with dichloromethane, washed with water and 5% aqueous
sodium bicarbonate, dried over sodium sulfate, and rotary evapo-
rated to give the crude chlorinated derivative 18c as a red-orange
4.2.6. 7(5-Carboxy-3-ethyl-4-methyl-2-pyrrolyl)-3-methyldihy-
dropyrano[4,3-b]pyrrole-2-carboxylic acid (21). Dibenzyl ester 20a
(500 mg, 0.977 mmol), reagent grade acetone (150 mL), methanol
(20 mL), and triethylamine (20 drops) were added to a hydrogena-
tion vessel. Palladium of 10% on activated charcoal (200 mg) was
added to the vessel under nitrogen, and the mixture was allowed to
shake under a hydrogen atmosphere (40 psi) overnight. The
palladium catalyst was then removed by suction filtration and the
solution was rotary evaporated. The resulting oil was dissolved in
5% aqueous ammonia and then enough water was added to the
solution to give a total volume of 40 mL. This aqueous solution was
then cooled to <5 ꢀC in a salteice bath and neutralized to litmus
with glacial acetic acid while maintaining the temperature <5 ꢀC.
The resulting cloudy solution was allowed to stand at below 5 ꢀC to
allow full precipitation, then suction filtered, washed repeatedly
with water, and vacuum dried to give the dicarboxylic acid (323 mg,
0.973 mmol, 99%) as a pale purple solid, mp 162 ꢀC, dec; 1H NMR
oil. The oil was dissolved in acetic acid (7 mL) along with a-free
pyrrole 1931,32 (161 mg, 0.66 mmol) and allowed to stir for 2 h in
the presence of p-toluenesulfonic acid (11 mg, 0.06 mmol). The
resulting solution was diluted with dichloromethane, washed with
water and 5% aqueous sodium bicarbonate, and dried over sodium
sulfate. The organic solvent was then evaporated under reduced
pressure and the residue was chromatographed on a silica column,
eluting with a 50:50 mixture of dichloromethane and chloroform.
The product fractions were rotary evaporated to give crude dipyr-
role 20b (316 mg, 0.66 mmol) as a dark red oil that was used
without further purification. The oil was dissolved in trifluoroacetic
acid (5 mL) and stirred for 1 h at room temperature. Trimethyl
orthoformate (1.0 mL, 9.1 mmol) was added dropwise to the solu-
tion while maintaining the temperature below 30 ꢀC and allowed to
stir at room temperature for 1 h. The solution was poured into
a beaker of ice-water (40 mL) and concentrated aqueous ammonia
(5 mL) was added. The mixture was suction filtered to give a solid
that was purified by silica column chromatography, eluting with
10% ethyl acetateetoluene. The product fractions were combined,
and the solvent was evaporated under reduced pressure to give an
oil. Crystallization from ethyl acetateehexanes gave the aldehyde
(DMSO-d6):
d
0.82 (3H, t, J¼7.4 Hz), 1.93e2.02 (1H, m), 2.10e2.22
(1H, m), 2.14 (3H, s), 2.15 (3H, s), 3.70 (1H, dd, J¼6.0, 11.0 Hz), 3.88
(1H, dd, J¼5.0, 11.0 Hz), 4.15 (1H, br t, J¼5.4 Hz), 4.52e4.61 (2H, AB
quartet, J¼13.3 Hz), 10.43 (1H, br s), 11.08 (1H, br s), 11.91 (2H, br s);
13C NMR (DMSO-d6):
d 10.3, 10.5, 15.6, 16.7, 32.9, 63.8, 69.9, 117.44,
117.49, 118.3, 121.4, 123.3, 125.5, 129.5, 131.9, 162.6, 162.7. Anal.
Calcd for C17H20N2O5$¼H2O: C, 60.61; H, 6.13; N, 8.32. Found: C,
60.70; H, 6.14; N, 8.18.
(46 mg, 0.113 mmol, 17%) as a tan solid, mp 90 ꢀC, dec; IR (Nujol):
n
3237 (NH str.), 1668, 1627 cmꢁ1 (C]O str.); 1H NMR (CDCl3):
d
1.12
4.2.7. 7(3-Ethyl-5-formyl-4-methyl-2-pyrrolyl)-3-methyldihydropyr-
ano[4,3-b]pyrrole-2-carbaldehyde (22). Dibenzyl ester 20a (250 mg,
0.488 mmol) was hydrogenated under the foregoing conditions,
the catalyst was suction filtered and the solvent evaporated on
a rotary evaporator. The residue was dried overnight under vacuum
and gave the dicarboxylic acid 21 (165 mg) as an off-white solid in
quantitative yield. This was dissolved in TFA (3 mL) and stirred at
room temperature for 2 min. Trimethyl orthoformate (0.60 mL,
5.5 mmol) was added dropwise while maintaining the temperature
at 25 ꢀC (ꢃ2 ꢀC), and then allowed to stir for an additional 10 min
on a preheated water bath at 40 ꢀC. The solution was then poured
into ice-water (80 mL), and neutralized with aqueous ammonia.
The resulting mixture was extracted with dichloromethane, dried
over sodium sulfate, and evaporated under reduced pressure. The
dark residue was purified by column chromatography on silica,
eluting with 20e30% ethyl acetate in toluene. The product fractions
were combined, and the solvent was evaporated under reduced
pressure to give the dialdehyde as a brown solid (117.8 mg,
0.393 mmol, 80%). Recrystallization from ethyl acetateehexanes
gave dipyrrole dialdehyde (89.3 mg, 0.298 mmol, 61%) as an off-
(3H, t, J¼7.6 Hz), 2.22 (3H, s), 2.28 (3H, s), 2.47 (2H, q, J¼7.6 Hz), 3.75
(1H, dd, J¼8.0, 11.1 Hz), 4.09 (1H, dd, J¼5.3, 11.1 Hz), 4.25 (1H, dd,
J¼5.5, 8.0 Hz), 4.70 (2H, s), 5.12 (1H, d, J¼12.6 Hz), 5.26 (1H, d,
J¼12.6 Hz), 7.29e7.38 (5H, m), 9.27 (1H, s), 9.45 (1H, br s), 9.91 (1H,
s); 1H NMR (DMSO-d6):
d
0.78 (3H, t, J¼7.5 Hz), 1.92e2.00 (1H, m),
2.10e2.17 (1H, m), 2.16 (3H, s), 2.19 (3H, s), 3.67 (1H, dd, J¼7.5,
11.1 Hz), 3.93 (1H, dd, J¼5.5, 11.1 Hz), 4.28 (1H, br t, J¼6.5 Hz),
4.56e4.63 (2H, AB quartet, J¼13.8 Hz), 5.22e5.28 (2H, AB quartet,
J¼12.8 Hz), 7.30e7.42 (5H, m), 9.50 (1H, s), 11.03 (1H, br s), 11.58
(1H, s); 13C NMR (CDCl3):
d 9.1, 11.0, 16.4, 17.5, 33.3, 64.4, 66.0, 69.9,
118.5,119.4,125.9,126.1,127.5,127.9,128.2,128.7,129.2,130.4,135.6,
136.3, 162.3, 176.3. HRMS (EI), m/z calcd for C24H26N2O4: 406.1893.
Found: 406.1891.
4.2.9. 7,13,17-Triethyl-2,8,12,18-tetramethyl-3,5-(2-oxapropano)por-
phyrin (12a). A solution of p-toluenesulfonic acid monohydrate
(80 mg, 0.42 mmol) in dichloromethane (30 mL) and methanol
(6 mL) was prepared in a 250 mL round bottom flask that was
wrapped in foil. Dipyrrole dialdehyde 22 (39.1 mg, 0.13 mmol) and
dipyrrole dicarboxylic acid 26a33 (43.6 mg, 0.137 mmol) were dis-
solved in dichloromethane (24 mL) and methanol (1.5 mL), and this
solution was added slowly dropwise to the reaction flask over 1 h.
The solution was allowed to stir overnight in the dark, then a sat-
urated solution of zinc acetate in methanol (2 mL) was added, and
the reaction was allowed to stir for a further 2 days open to the air
for oxidation. The resulting solution was washed with water and
white solid, mp 177 ꢀC, dec; IR (Nujol):
n
3215 (NH str.), 1634 cmꢁ1
(C]O str.); 1H NMR (500 MHz, CDCl3):
d
1.16 (3H, t, J¼7.6 Hz), 2.24
(3H, s), 2.29 (3H, s), 2.47 (2H, q, J¼7.6 Hz), 3.74 (1H, dd, J¼9.5,
10.9 Hz), 4.14 (1H, dd, J¼5.7, 10.9 Hz), 4.34 (1H, dd, J¼5.7, 9.5 Hz),
4.65e4.75 (2H, AB quartet, J¼13.5 Hz), 9.09 (1H, s), 9.11 (1H, s),
10.46 (1H, br s), 10.89 (1H, br s); 1H NMR (500 MHz, DMSO-d6):

B.E. Smith, T.D. Lash / Tetrahedron 66 (2010) 4413e4422
4421
carefully back extracted with chloroform. The organic solvent was
then evaporated, and the residue was dissolved in trifluoroacetic
acid (5 mL), diluted with chloroform, and washed with water and
5% aqueous sodium bicarbonate. The solvent was removed via ro-
tary evaporation and the residue was chromatographed on grade 3
neutral alumina, eluting with dichloromethane. The product frac-
tions were combined and rotary evaporated, and subsequent re-
crystallization from chloroform and methanol gave the porphyrin
six-membered cyclic ether (23.2 mg, 0.047 mmol, 36%) as a dark
purple powder, mp 250 ꢀC, dec; UVevis (1% Et3NeCHCl3): lmax
(log10 e) 404 (5.23), 502 (4.14), 537 (3.71), 569 (3.78), 622 nm
(3.45); UVevis (1% TFAeCHCl3): lmax (log10 e) 411 (5.53), 554 (4.18),
a 500 MHz NMR spectrometer was provided by the National Sci-
ence Foundation under grant no. CHE-0722385.
Supplementary data
Supplementary data associated with this article can be found in
online version at doi:10.1016/j.tet.2010.04.069.
References and notes
1. Baker, E. W.; Palmer, S. E. In The Porphyrins; Dolphin, D., Ed.; Academic: New
York, NY, 1978; Vol. 1, pp 486e552.
597 nm (3.67); 1H NMR (500 MHz, CDCl3):
d
ꢁ3.60 (1H, br s), -3.46
2. (a) Filby, R. H.; Van Berkel, G. J. In Metal Complexes in Fossil Fuels. Geochemistry,
Characterization, and Processing; Filby, R. H., Branthaver, J. F., Eds.; American
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J.; Ocampo, R. In The Porphyrin Handbook; Kadish, K. M., Smith, K. M., Guilard, R.,
Eds.; Academic: San Diego, 2000; Vol. 1, pp 349e398; (d) Czernuszewicz, R. S.
J. Porphyrins Phthalocyanines 2000, 4, 426.
(1H, br s), 1.77 (3H, t, J¼7.7 Hz), 1.86 (3H, t, J¼7.7 Hz), 1.88 (3H, t,
J¼7.7 Hz), 3.48 (3H, s), 3.56 (3H, s), 3.60 (3H, s), 3.64 (3H, s), 3.90
(2H, q, J¼7.7 Hz), 4.00 (2H, q, J¼7.7 Hz), 4.11 (2H, q, J¼7.7 Hz), 5.87
(2H, s), 6.86 (2H, s), 9.95 (1H, s), 9.98 (1H, s), 10.04 (1H, s); 1H NMR
(500 MHz, TFAeCDCl3):
d
ꢁ3.56 (1H, br s), ꢁ3.53 (1H, br s), ꢁ3.16
3. (a) Chicarelli, M. I.; Kaur, S.; Maxwell, J. R. In Metal Complexes in Fossil Fuels.
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American Chemical Society: Washington, DC, 1987; pp 40e67; (b) Ocampo, R.;
Callot, H. J.; Albrecht, P. In Metal Complexes in Fossil Fuels. Geochemistry, Char-
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27, 5257; (c) Smith, N. W.; Smith, K. M. Energy Fuels 1990, 4, 675.
13. (a) Lash, T. D. In Advances in Nitrogen Heterocycles; Moody, C. J., Ed.; JAI:
Greenwich, Connecticut, 1995; Vol. 1, pp 19e51; (b) Lash, T. D. Org. Geochem.
1989, 14, 213; (c) Lash, T. D.; Balasubramaniam, R. P.; Catarello, J. J.; Johnson, M.
C.; May, D. A., Jr.; Bladel, K. A.; Feeley, J. M.; Hoehner, M. C.; Marron, T. G.;
Nguyen, T. H.; Perun, T. J., Jr.; Quizon, D. M.; Shiner, C. M.; Watson, A. Energy
Fuels 1990, 4, 668.
14. (a) Lash, T. D.; Catarello, J. J. Tetrahedron 1993, 49, 4159; (b) Quizon-Colquitt, D.
M.; Lash, T. D. J. Heterocycl. Chem. 1993, 30, 477; (c) Li, W.; Lash, T. D. Tetrahedron
Lett. 1998, 39, 8571; (d) Lash, T. D.; Quizon-Colquitt, D. M.; Shiner, C. M.;
Nguyen, T. H.; Hu, Z. Energy Fuels 1993, 4, 668; (e) Zhang, B.; Lash, T. D. Tet-
rahedron Lett. 2003, 44, 7253; (f) Lash, T. D.; Li, W.; Quizon-Colquitt, D. M.
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(1H, br s), ꢁ2.51 (1H, br s), 1.70 (3H, t, J¼7.9 Hz), 1.75 (3H, t,
J¼7.9 Hz), 1.78 (3H, t, J¼7.7 Hz), 3.55 (3H, s), 3.56 (3H, s), 3.62 (3H,
s), 3.63 (3H, s), 3.91 (2H, q, J¼7.7 Hz), 4.09 (2H, q, J¼7.9 Hz), 4.11
(2H, q, J¼7.9 Hz), 5.99 (2H, s), 7.05 (2H, s),10.44 (1H, s),10.49 (1H, s),
10.57 (1H, s); 13C NMR (CDCl3):
d 11.6, 11.77, 11.80, 11.9, 16.6, 17.7,
18.0, 19.9, 20.1, 22.2, 66.9, 69.1, 95.8, 96.8, 97.1, 112.7, 112.7, 132.5,
133.4, 135.5, 135.6, 138.1, 138.2, 140.1, 144.5; 13C NMR (TFAeCDCl3):
d
11.8, 11.9, 12.0, 15.9, 16.47, 16.52, 20.24, 20.29, 21.7, 65.1, 69.4, 97.3,
98.4, 99.9, 132.4, 135.9, 137.0, 138.0, 138.5, 138.8, 139.0, 141.0, 141.4,
141.7, 142.6, 142.9, 143.0, 143.1, 144.1, 145.0. HRMS (EI), m/z calcd for
C32H36N4O: 492.2889. Found: 492.2887. Anal. Calcd for
C32H36N4O$1/20CHCl3: C, 77.20; H, 7.29; N, 11.24. Found: C, 77.44; H,
7.46; N, 11.14.
4.2.10. 7-Ethyl-13,17-di(2-methoxycarbonylethyl)-2,8,12,18-tetra-
methyl-3,5-(2-oxapropano)
porphyrin
(12b). Dialdehyde 22
(39.1 mg, 0.13 mmol) and dipyrrole dicarboxylic acid 26b33
(60.0 mg, 0.14 mmol) were reacted under the foregoing condi-
tions. Following purification of a grade 3 alumina column, eluting
with dichloromethane, the product was recrystallized from chlor-
oformemethanol to give the diester (23.8 mg, 0.039 mmol, 30%) as
a purple solid, mp 258e259 ꢀC; UVevis (1% Et3NeCHCl3): lmax
(log10 e) 405 (5.29), 503 (4.20), 537 (3.81), 570 (3.87), 623 nm
(3.61); UVevis (1% TFAeCHCl3): lmax (log10 e) 412 (5.53), 555 (4.22),
597 nm (3.76); 1H NMR (500 MHz, CDCl3):
d
ꢁ3.59 (1H, s), ꢁ3.44
(1H, s), 1.78 (3H, t, J¼7.7 Hz), 3.24e3.32 (4H, m), 3.49 (3H, s), 3.58
(3H, s), 3.63 (3H, s), 3.66 (3H, s), 3.67 (3H, s), 3.69 (3H, s), 3.94 (2H,
q, J¼7.7 Hz), 4.33 (2H, t, J¼7.9 Hz), 4.44 (2H, t, J¼7.8 Hz), 5.90 (2H, s),
6.90 (2H, s), 9.96 (1H, s), 10.01 (1H, s), 10.06 (1H, s); 1H NMR
(500 MHz, TFAeCDCl3):
d
ꢁ3.42 (1H, s), ꢁ3.40 (1H, br s), ꢁ3.00 (1H,
s), ꢁ2.41 (1H, br s), 1.77 (3H, t, J¼7.7 Hz), 3.12 (2H, t, J¼7.5 Hz), 3.18
(2H, t, J¼7.5 Hz), 3.54 (3H, s), 3.56 (3H, s), 3.580 (3H, s), 3.581 (3H,
s), 3.64 (3H, s), 3.65 (3H, s), 3.90 (2H, q, J¼7.7 Hz), 4.41e4.47 (4H,
m), 5.98 (2H, s), 7.04 (2H, s),10.49 (1H, s),10.57 (1H, s),10.79 (1H, s);
13C NMR (TFAeCDCl3):
d 11.8, 12.0, 12.2, 15.9, 21.67, 21.74, 21.80,
35.57, 35.61, 52.5, 65.0, 67.5, 98.43, 98.47, 100.0, 115.7, 132.1, 136.0,
137.6, 138.4, 138.7, 139.1, 139.6, 139.8, 140.7, 141.1, 141.2, 141.4, 142.4,
142.7, 142.9, 143.0, 174.2. HRMS (EI), m/z calcd for C36H40N4O5:
608.2999. Found: 608.3013. Anal. Calcd for C36H40N4O5: C, 71.03; H,
6.62; N, 9.20. Found: C, 70.71; H, 6.91; N, 8.82.
15. (a) Lash, T. D.; Bladel, K. A.; Johnson, M. C. Tetrahedron Lett. 1987, 28, 1135; (b)
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54, 359.
17. (a) Lash, T. D.; Johnson, M. C. Tetrahedron Lett. 1989, 30, 5697; (b) Lash, T. D.;
Perun, T. J., Jr. Tetrahedron Lett. 1987, 28, 6265; (c) Lash, T. D.; Nguyen, T. H.; Hu,
Z. Synlett 1994, 905; (d) Hu, Z.; Lash, T. D. Synlett 1994, 909; (e) Bastian, J. A.;
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Marron, T. G.; Bastian, J. A. Tetrahedron 2007, 63, 12343.
Acknowledgements
This work was supported by the National Science Foundation
under grant nos. CHE-0616555 and CHE-0911699, and the Petro-
leum Research Fund, administered by the American Chemical So-
ciety. B.E.S. also acknowledges support from Pfizer, Inc. Funding for
18. Gribble, G. W. Knorr and PaaleKnorr pyrrole syntheses. In Name Reactions in
Heterocyclic Chemistry; Li, J. J., Ed.; Wiley: Hoboken, NJ, 2005; pp 79e88.

4422
B.E. Smith, T.D. Lash / Tetrahedron 66 (2010) 4413e4422
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