Porphyrins with exocyclic rings. Part 21: Influence of pyrrolic and carbocyclic ring alkyl substituents on the synthesis of porphyrins bearing six-membered exocyclic rings

Article abstract of DOI:10.1016/j.tet.2005.10.019

A series of 5-substituted 4,5,6,7-tetrahydroindoles were prepared by reacting 4-substituted cyclohexanones with phenylhydrazones derived from esters of acetoacetic acid under Knorr-type reaction conditions. Related 6,6-dimethyltetrahydroindoles were also

Full text of DOI:10.1016/j.tet.2005.10.019

Tetrahedron 61 (2005) 11628–11640
Porphyrins with exocyclic rings. Part 21: Influence of pyrrolic
and carbocyclic ring alkyl substituents on the synthesis
of porphyrins bearing six-membered exocyclic rings*
*
Craig M. Shiner and Timothy D. Lash
Department of Chemistry, Illinois State University, Normal, IL 61790-4160, USA
Received 29 July 2005; revised 29 September 2005; accepted 10 October 2005
Abstract—A series of 5-substituted 4,5,6,7-tetrahydroindoles were prepared by reacting 4-substituted cyclohexanones with
phenylhydrazones derived from esters of acetoacetic acid under Knorr-type reaction conditions. Related 6,6-dimethyltetrahydroindoles
were also prepared by reacting dimedone with oximes by the Knorr pyrrole syntheses, followed by selective reduction of the remaining
ketone moiety with diborane. The substituted tetrahydroindoles were regioselectively oxidized with lead tetraacetate to give the related
7-acetoxy derivatives, and these reacted with 5-unsubstituted pyrrole esters to give pyrrolyltetrahydroindoles. In one case, a bromo
substituent was used to protect the b-position of the pyrrole reactant. Cleavage of the benzyl ester protective groups with hydrogen over Pd/C,
which also removes the bromo-protective group, gave four dipyrrole carboxylic acids. These were condensed with a dipyrrylmethane
dialdehyde using the MacDonald ‘2C2’ condensation to give substituted porphyrins with six-membered exocyclic rings. These structures
are useful for comparison to porphyrin samples found in organic-rich sediments such as oil shales and petroleum. The presence of methyl
substituents on the six-membered ring for the tetrahydroindole precursors slightly decreases the yields for porphyrin synthesis, and this effect
is enhanced when the system becomes more sterically crowded due to the presence of an ethyl group of the adjacent pyrrole ring. 5-Alkyl
substituted tetrahydroindoles were also converted to tetrapropanoporphyrins via a cyclotetramerization procedure. The alkyl substituents
again decreased the yields, although 5-alkyl substituents were found to have a far less deleterious effect than 6-alkyl groups. In addition to
providing samples to help assign the vibrational spectra of geoporphyrin samples, these results demonstrate that highly substituted porphyrin
systems can be prepared from tetrahydroindole derivatives.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
environment in the water column.6 Furthermore, the
modifications that these structures undergo can be related
to the thermal maturity of the sediments and may provide
additional information on the conditions leading to fossil fuel
formation.7 Petroporphyrins also provide a unique finger-
print for petroleum resources that can find application in
environmental monitoring, for example, for oil spills.8 The
most abundant of the sedimentary cycloalkanoporphyrins
(CAPs) is deoxophylloerythoroetioporphyrin (DPEP; 1,
RZR1ZEt, R2ZR3ZH) but a large number of related
DPEP-type petroporphyrins have been identified, including
porphyrins with substituted cycloalkano-rings (1; R2 or
R3ZMe).1–5 Methyl substituted CAPs 2a,b with six-
membered exocyclic rings are also known,9,10 as well as a
related hydroxymethyl-CAPs 2c and 2d.11 In order to
provide standards for the analysis of petroporphyrins, we
have developed synthetic routes to CAPs starting from cyclic
ketones.12–17 For instance, meso,b-propanoporphyrins 4
were synthesized using the MacDonald ‘2C2’ condensation
(Scheme 1).17b,c Cyclohexanone reacts with oximes or
phenylhydrazones 5 in the presence of zinc and acetic acid
Metalloporphyrins with five-, six- or seven-membered
exocyclic rings (1–3, Chart 1) are commonly found in
organic-rich sediments such as oil shales and petroleum,
usually in the form of nickel(II) or vanadyl complexes.1–5
These materials are believed to be derived from the
photosynthetic pigments associated with algae or bacteria
and can be considered to be molecular fossils of the
chlorophylls from which they are derived.1 The structures of
these porphyrins give insights into the environment that
existed at that time; for instance, the presence of
bacteriopetroporphyrins derived from the Chlorobiaceae
or brown sulfur bacteria provides evidence for an anoxic
* For part 20 in the series, see: Cillo, C. M.; Lash, T. D. Tetrahedron 2005,
61, 11615–11627.
Keywords: Petroporphyrins; 4,5,6,7-Tetrahydroindoles; MacDonald ‘2C2’
condensation; Cycloalkanoporphyrins; Pyrrole chemistry.
Corresponding author. Tel.: C1 309 438 8554; fax: C1 309 438 5538;
e-mail: tdlash@ilstu.edu
*
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.10.019

C. M. Shiner, T. D. Lash / Tetrahedron 61 (2005) 11628–11640
11629
the synthesis of porphyrins with five-, six-, seven-, and
eight-membered exocyclic rings.14,15,17 In addition, the
dipyrrolic intermediates have been utilized in stepwise
syntheses of naturally occurring petroporphyrins.14e,f,15a,17a
Furthermore, 7-acetoxy-4,5,6,7-tetrahydroindoles 7 can be
hydrolyzed to give hydroxy carboxylic acids 11, and these
undergo cyclotetramerization with potassium ferricyanide in
refluxing acetic acid to give the unusual tetrapropano-
porphyrins 12 in moderate yields (Scheme 2).16 Ring size
greatly effects the efficiency of these syntheses, probably by
altering the conformation of intermediary tetrapyrroles prior
to macrocycle formation.12 Less work has been conducted on
the synthesis of porphyrins bearing substituents on the
exocyclic rings. For the cyclotetramerization chemistry
shown in Scheme 2, the presence of a methyl group at
position 6 on the tetrahydroindole intermediate 11g greatly
decreases the yield of tetrapropanoporphyrin, while no
product at all is formed for the 6,6-dimethyl substituted
structures 11h and 11i.16 In an attempt to more fully explore
the versatility of this chemistry, and to provide samples for
structurally characterizing geoporphyrins using resonance
Raman spectroscopy,18–26 the dimethylpropanoporphyrins
13a–d were targeted for synthesis. In addition, the influence
of 5-alkyl substitutents on the cyclotetramerization
chemistry was also investigated.
Me
Me
R
R
Et
Et
Me
Me
Me
N
N
N
N
N
N
N
N
M
M
Me
Me
Me
R1
H
R2
R3
R1
1
2
a. M = VO; R = Et; R1 = Me
b. M = VO; R = R1 = Me
c. M = Ni; R = Et; R1 = CH2OH
d. M = Ni; R = H; R1 = CH2OH
M = Ni or VO
R = H, Me or Et
R1 = H, Me, Et or Pr
R2,R3 = H or Me
Et
Et
Me
R
Me
Me
Me
Me
Et
Me
NH
N
N
N
N
N
N
M
HN
Me
Me
R
R3
H
2 R3
1 R
R
13
3
a. R = Et; R1 = R2 = Me; R3 = H
b. R = R3 = H; R1 = R2 = Me
c. R = Et; R1 = R2 = H; R3 = Et
d. R = R1 = R2 = H; R3 = Me
M = Ni or VO
R = H, Me or Et
4
5
R
R1
3
6
2
7
R2
HO
Chart 1.
CO2H
N1
H
R
O
R
11
AcOH ∆
Zn
K3Fe(CN)6
AcOH
CO2R1
N
CO2R1
O
N
R1
X
H
X
R2
R
5
6 X = H
Pb(OAc)4
R2
R1
7 X = OAc
R3
R
R2
R3
Me
NH
N
N
R
Me
p-TSA
R1
NH
N
N
CO2R2
AcOH
H
N
HN
H
8
HN
R
Me
Me
1. p-TSA
2. [O]
R2
R1
R3
R
R4
R4
OHC
Me
4
12
R
Me
a. R = Me; R1 = R2 = H (15%)
b. R = Et; R = R = H (14%)
c. R = Pr; R = R = H (12%)
d. R = Ph; R = R = H (1%)
e. R = i-Pr; R = R = H (trace)
f. R = t-Bu; R = R = H (0%)
g. R = R = Me; R = H (3%)
h. R = R = R = Me (0%)
CHO
Me
NH HN
R1O2C
1
2
CO2R2
NH HN
1
2
9
1
2
R4
For R1,R2 = Bn
R1 = R2 = H
R4
H2
Pd/C
10
1
2
1
2
1
2
Scheme 1.
1
2
to give 4,5,6,7-tetrahydroindoles 616,17 and these react with
lead tetraacetate in acetic acid to regioselectively afford the
acetoxy derivatives 7.16,17 These undergo acid catalyzed
condensations with a-unsubstituted pyrroles 8 to give
dipyrroles 9.17 Deprotection of the terminal ester groups
gives the corresponding dicarboxylic acids and these react
with dipyrrylmethane dialdehydes 10 in the presence of
p-toluenesulfonic acid to give, following the addition of zinc
acetate and air oxidation, O20% yield of the propano-
porphyrins 4.17 This chemistry has been applied to
1
2
i. R = R = R = Me (0%)
Scheme 2.
2. Results and discussion
In order to synthesize porphyrins with substituted six-
membered exocyclic rings, it was first necessary to prepare a
series of previously unknown 5- and 6-substituted tetra-
hydroindole (THI) derivatives. THIs 6 were easily prepared

11630
C. M. Shiner, T. D. Lash / Tetrahedron 61 (2005) 11628–11640
by a modified Knorr-type pyrrole condensation from
cyclohexanone (Scheme 1),16,17 and this approach is well
suited for the synthesis of 5-substituted systems (Scheme 3).
Reaction of phenylhydrazones 15a–c with 4,4-dimethyl-
cyclohexanone (16a) in the presence of zinc dust and
sodium acetate in acetic acid gave the required THIs 14a–c.
The zinc initially reduces the imine unit and cleaves aniline
to generate an a-aminoketone, and this condenses and
cyclizes onto the cyclic ketone to generate the pyrrolic
products. Phenylhydrazone 15b similarly reacted with
4-methylcyclohexanone (16b) or 4-tert-butylcyclohexanone
(16c) to give THIs 14d and 14e, respectively. Treatment of
14a–e with lead tetraacetate in acetic acid gave the
7-acetoxy derivatives 17a–e in excellent yields, although
it is worth noting that 17d and 17e were obtained as a
mixture of two diastereomers.
O
O
Me
O
AcOH
Zn
Me
CO2R4
Me
Me
O
Me
Me
CO2R4
N
N
H
OH
19
Me
CO2R4
B2H6
Me
Me
N
H
AcO
Me
CO2R4
20
Me
Me
Pb(OAc)4
N
H
a. R = Bn
b. R = t-Bu
18
Scheme 4.
R2
R2
R1
for the analysis of vibrational spectra for geochemical
samples, porphyrins with an ethyl or a hydrogen next to the
exocyclic ring were required. The ethyl substituted
dipyrroles 22a and 22c were obtained by condensing
acetoxyTHIs 14a and 20a with 5-unsubstituted pyrrole
21a in the presence of p-toluenesulfonic acid in acetic acid.
Similarly, 20b reacted with the 4,5-unsubstituted pyrrole
ester 21b to give the corresponding pyrrolyltetrahydro-
indole 22d in 38% yield (Scheme 5). However, attempts to
react acetoxyTHI 14a with 21b failed to give more than
trace amounts of the required dipyrrolic product. This
problem had been encountered previously when two
adjacent a and b sites are unsubstituted on the pyrrole
nucleus.17a,27 The absence of an electron-donating
b-substituent decreases the reactivity of the pyrrole, and it
is also possible that substitution could occur at both
positions. These problems were overcome by using a
4-bromo-protected pyrrole 21c instead of 21b.17a The
reaction of 20b with 21c did not work well with the usual
conditions but when zinc chloride was used as the catalyst in
dichloromethane, the bromo-substituted dipyrrole 22d was
isolated in 39% yield. Hydrogenolysis of 22a–d over 10%
palladium–charcoal with trace amounts of triethylamine in
acetone or ethanol gave the corresponding carboxylic acids
23a–c (Scheme 6) in high yields. As expected, treatment of
R
O
Zn
R1
O
AcOH
R
CO2R4
N
NH
Ph
O
O
16
CO2R4
H2N
a. R1 = R2 = Me
15
b. R1 = Me; R2 = H
c. R1 = t-Bu; R2 = H
a. R = Me; R4 = Bn
b. R = Me; R4 = Et
c. R = Et; R4 = Me
R2
R2
R1
R1
O
R
R
35-49%
CO2R4
N
H
CO2R4
N
H
14
Pb(OAc)4
R2
For tetrahydroindoles 14 and 17:
a. R = R1 = R2 = Me; R4 = Bn
b. R = R1 = R2 = Me; R4 = Et
c. R = Et; R1 = R2 = R4 = Me
d. R = R1 = Me; R2 = H; R4 = Et
R1
R
CO2R4
N
AcO
H
17
e. R = Me; R1 = t-Bu; R2 = H; R4 = Et
Scheme 3.
Due to the symmetry of ketones 16a–c, the required
5-substituted THIs 14 are generated in isomerically pure
form. However, 6-alkyl substituted THIs 18 cannot be
prepared in this fashion as 3-substituted cyclohexanones
would generate mixtures of 4- and 6-substituted products.
The problem can be overcome by using substituted
1,3-cyclohexanones to direct the chemistry,16,17 followed
by reduction of the superfluous carbonyl grouping.
Dimedone reacts with oximes under conventional Knorr
pyrrole condensation conditions to give 4-oxoTHI 19 with
the correct substitution pattern (Scheme 4). Hence, benzyl
or tert-butyl acetoacetate were reacted with nitrous acid to
give the corresponding oximes and these in turn were
condensed with dimedone in the presence of zinc dust in
acetic acid to give 19a and 19b, respectively. The ketone
moiety was then selectively reduced with diborane to afford
the required 6,6-dimethylTHIs in good yields. These were
again selectively oxidized with lead tetraacetate to give the
acetoxy derivatives 20.
R1
R2
Me
CO2Bn
R
Me
R4O2C
R3
R3
H
N
N
H
H
OAc
21
a. R = Et
b. R = H
c. R = Br
p-TSA
AcOH
R2
R1
R3
R3
R
Me
Me
NH HN
CO2Bn
R4O2C
22
a. R = Et; R1 = R2 = Me; R3 = H; R4 = Bn
b. R = Br; R1 = R2 = Me; R3 = H; R4 = Bn
c. R = Et; R1 = R2 = H; R3 = Me; R4 = Bn
d. R = H; R1 = R2 = H; R3 = Me; R4 = t-Bu
In order to assess how steric factors affect the yields in
porphyrin synthesis, as well as to provide standards suitable
Scheme 5.

C. M. Shiner, T. D. Lash / Tetrahedron 61 (2005) 11628–11640
11631
Et
Et
Et
Et
Me
Me
OHC
Me
Me
Me
NH HN
NH
N
N
CHO
1. p-TSA
24
R4O2C
Me
2. O2-Zn(OAc)2
CO2H
HN
NH HN
Me
Me
R
R3
R3
R
R3
R3
R1 R2
1 R2
13
23
R
a. R = Et; R1 = R2 = Me; R3 = H
b. R = R3 = H; R1 = R2 = Me
c. R = Et; R1 = R2 = H; R3 = Me
d. R = R1 = R2 = H; R3 = Me
a. R = Et; R1 = R2 = Me; R3 = R4 = H
b. R = R3 = R4 = H; R1 = R2 = Me
c. R = Et; R1 = R2 = R4 = H; R3 = Me
d. R = R1 = R2 = H; R3 = Me; R4 = t-Bu
Et
Et
Me
Me
Me
N
H
N
N
H
H
H
N
Me
R
R3
R3
R1
R2
25 (porphodimethene)
Scheme 6.
the bromo-dipyrrole 22b with hydrogen and trace triethyl-
amine in methanol led to reductive cleavage of both the
bromo-substituent and the benzyl ester moiety to afford the
b-unsubstituted dipyrrole 23b.
changed to an ethyl, the yield drops to 14%. Placement of
the gem-dimethyl unit next to the meso-carbon increases
potential steric interactions and even when the pyrrolic
substituent is H, the yield dropped to 10%. Moreover, when
the ethyl group is present next to the methyls in 13c, the
yield was only 3.5–7%. The MacDonald condensation takes
place via porphodimethene intermediates that still retain an
sp3 carbon at the bridge incorporating the exocyclic ring.
This relieves some of the steric congestion that results in the
more planar aromatic porphyrin structures 13. Once
the macrocycle has been generated, slow air oxidation
gives the porphyrin product. The decreased yields probably
result from the dipyrrolic intermediates taking on confor-
mations due to these steric interactions that are not favorable
for macrocycle formation, and further condensation would
then lead to oligopyrrolic products. Although the yields for
13a, 13b and 13d could be raised to 28–39% by using
dilution techniques, this approach must be handled with
some caution. The pyrrolic intermediates can undergo
acidolysis reactions followed by random recombinations
that can give rise to mixtures of porphyrin products,30 and
attempts to improve the yield of 13c gave material that
showed additional resonances in the porphyrin’s proton
NMR spectrum. Nonetheless, pure porphyrin can be
obtained under conventional conditions, and these results
provide some insights into the limitations of this
methodology.
Dipyrroles 23a–d were the final precursors for porphyrin
synthesis (Scheme 6). Although several routes for
synthesizing porphyrins with exocyclic rings have been
explored previously,12,28 including cyclizations of
a,c-biladienes,15a,17 the MacDonald condensation29 had
been found to be the most versatile route for preparing
cycloalkanoporphyrins. This ‘2C2’ methodology requires
that one of the two condensing dipyrrolic reactants is
symmetrical or two porphyrin isomers will be formed.29 As
we planned to use the symmetrical dialdehyde 24 in our
studies, this methodology was the best suited for our
purposes. MacDonald condensations of 23a–c were
conducted under conventional conditions29b by reacting
the dicarboxylic acids with dipyrrylmethane dialdehyde 24
in the presence of p-toluenesulfonic acid. The intermediary
porphodimethenes 25 were treated with a solution of zinc
acetate in methanol and air oxidized for 1–3 days17c to give
the dimethylpropanoporphyrins 13a–c. Dipyrrole tert-butyl
ester 23d was first treated with TFA to cleave the protective
group and then reacted with 24 under the same conditions.
The yields in each case were lower than had been
observed for unsubstituted meso,b-propanoporphyrins 4
(Scheme 1).17 However, the yields correlate well with the
steric factors involved. The best yield (16%) was obtained
for porphyrin 13b where the gem-dimethyl unit is placed at
the second carbon of the propano chain and the adjacent
b-pyrrolic site is unsubstituted. When the b-substituent is
The UV–vis spectra for 13a, 13b and 13d in chloroform
showed strong Soret bands at 405 nm and the usual series of
four smaller Q bands through the visible region. The Q
bands are generally labeled I–IV, with the longest

11632
C. M. Shiner, T. D. Lash / Tetrahedron 61 (2005) 11628–11640
R1
wavelength band being designated I and the shortest
wavelength absorption labeled IV. These bands showed a
phyllo type pattern31 where the relative intensities of the
absorptions were IVOIIOIIIOI. The sterically congested
porphyrin 13c showed a slightly red shifted Soret band at
409 nm, and the Q bands were also slightly shifted to longer
wavelengths. In 1% TFA–chloroform, the corresponding
dications 13H22C for 13a, 13b and 13d gave reddish-pink
solutions with intensified Soret bands at 411–412 nm and
two relatively weak Q bands at 553–556 and 594–601 nm.
However, 13cH22C afforded green solutions that gave a
bathochromically shifted Soret band at 418 nm and Q bands
at 564 and 610 nm. This result suggests that the dication
exhibits further distortion due to a combination of the
peripheral steric crowding and the presence of 4 internal
NHs. The proton NMR spectra for porphyrin 13a, 13b and
13d showed typical shifts due to the presence of a powerful
diatropic ring current. Three 1H singlets for the meso-
protons were observed in each case between 9.88 and
10.07 ppm, while the four methyl substituents gave rise to
several singlets between 3.53 and 3.77 ppm. Small
differences were noted for the highly crowded propano-
porphyrin 13c, where one of the meso-protons was slightly
shifted upfield to a value of 9.74 ppm, but most of the
remaining resonances fell into the same general range. The
CH2 on the exocyclic ring connected to the b-pyrrolic
carbon gave a singlet near 3.7 ppm for 13a and 13b, while
the corresponding triplet for this unit in 13c and 13d was
observed at 3.88 and 3.86 ppm, respectively. The exocyclic
ring CH2 connected to the meso-carbon in 13a and 13b was
further deshielded to 4.91 or 4.80 ppm, respectively. The
gem-dimethyl groups on porphyrins 13a and 13b gave rise
to a 6H singlet near 1.5 ppm, while the corresponding
resonances in 13c and 13d were further deshielded and gave
the 6H singlet at 2.5 ppm, as expected given the relative
proximity of the methyl groups to the porphyrin macro-
cycle. It is also notable that for 13c, one of the ethyl triplets
was shifted upfield to 1.24 ppm compared to typical values
of 1.7–1.9 ppm. In the presence of TFA, the corresponding
dications for 13a, 13b and 13d showed the presence of four
internal NH resonances that fell into the range of K2.8 to
K4.0 ppm. The relatively large separation between the
individual NH resonances indicates a large degree of
asymmetry within the porphyrin cavity. The proton NMR
spectrum of 13cH22C in TFA–CDCl3 also showed four NH
peaks but these were shifted downfield to a range of K1.9 to
K3.4 ppm. The external meso-protons were all shifted to
values above 10 ppm, although these shifts were slightly
smaller for 13cH22C. The decreased ring current was also
evident from the chemical shifts for the methyl resonances
of 13cH22C, which gave values of 3.14, 3.35, 3.45 and
3.47 ppm compared to chemical shifts of 3.54–3.74 ppm for
the other three porphyrin dications. The exocyclic ring for
13cH22C also showed evidence for crowding where the
resonances for the two CH2 units appeared as broadened
triplets at 2.20 and 3.77 ppm; at 25 8C the latter resonance
was very broad but this resolved into a broadened triplet at
50 8C. Finally, the ethyl unit adjacent to the exocyclic ring
in 13cH22C, gave a triplet that was abnormally shifted
upfield to 0.53 ppm. This unit appears slightly upfield in the
free base 13c but the effect is far more apparent in the
dication. Presumably this is due to the highly distorted
R2
R
1. NaOH
R
R2
R1
14
NH
N
2. AcOH ∆
K3Fe(CN)6
R1
R2
HN
N
R
R
26
a. R = R1 = Me, R2 = H
1
1 R2
R
2
b. R = Me, R = t-Bu, R = H
1
2
c. R = R = R = Me
1
2
d. R = Et, R = R = Me
Scheme 7.
macrocycle of 13cH22C, and to a lesser extent for free base
13c, placing this ethyl unit over the porphyrin p-system.
Porphyrins with four six-membered exocyclic rings have been
prepared previously, but the presence of alkyl substitutents at
position 6 of the THI precursors (Scheme 2) had a strongly
deleterious effect on this chemistry. Given the results that we
had obtained for the MacDonald condensation, it seemed
likely that tetrapropanoporphyrins could be obtained more
readily from 5-substituted THIs. AcetoxyTHIs 17b–e were
hydrolysed with sodium hydroxide and the resulting hydroxy
carboxylic acids were heated under reflux in acetic acid with
potassium ferricyanide. Following purification by column
chromatography and recrystallization from chloroform–
methanol, the new tetrapropanoporphyrins 26 were isolated
in moderate yield (Scheme 7). The 5-methyl substituted THI
17d gave the porphyrin product 26a in 10.4% yield, although
the 5-tert-butyl substituted THI 17e gave porphyrin 26b in
only 2.5% yield. The gem-dimethyl THIs 17b and 17c gave
intermediary results affording porphyrins 26c and 26d,
respectively, in 6–8% yields. Again, the presence of 5-alkyl
substituents decreases the yields but to a far lesser extent than
for 6-alkyl substituted THIs. In addition, the presence of two
substituents exerts a larger detrimental influence that is further
exacerbated for the tert-butyl THI 14e. Porphyrins 26a and
26b gave complex NMR spectra that were consistent with the
presence of diastereomers. The gem-dimethyl porphyrins 26c
and 26d have no chiral centers and are therefore generated as
single isomers. However, they are virtually insoluble in
chloroform and only dissolved sufficiently well in
TFA–CDCl3 to give NMR data. Even then the signals were
somewhat broadened. This broadening was temperature
dependent and indicates that the gem-dimethyl units introduce
constraints to the mobility of the exocyclic rings. The gem-
dimethyl units for 26c gave a very broad peak at 1.1 ppm,
while the CH2 units of the exocyclic rings afforded broad
singlets at 3.5 and 4.8 ppm. The methyl substituents were
noted at 3.3 ppm, while the NH resonance was observed at
K2.5 ppm, confirming that most of the diatropic character for
the crowded porphyrin system has been retained.32 The
carbon-13 NMR spectrum of 26c in TFA–CDCl3 showed five
resonancesinthe aliphaticregionbetween 14and 45 ppm, and
five aromatic resonances between 115 and 142 nm for the 44
carbon structure, confirming the expected high degree of
symmetry for this porphyrin. Similar results were obtained for
the tetraethylporphyrin 26d. The UV–vis spectra for these

C. M. Shiner, T. D. Lash / Tetrahedron 61 (2005) 11628–11640
11633
compounds also suggest that 26c and 26d are more
conformationally distorted. The UV–vis spectra for 26a and
26b are very similar, showing Soret bands at 418 or 419 nm
and a series of Q bands at 518, 550, 591 and 647 nm (phyllo-
type spectrum; IVOIIOIIIOI). However, the Soret band
shifts to 422 nm for 26c, while all of the bands are further red
shifted to values of 425, 523, 558, 597 and 654 nm for 26d.
Bathochromic shifts of this type are commonly associated
with distorted nonplanar porphyrin systems.33
The catalyst was removed by suction filtration and the
solvent evaporated under reduced pressure to give the crude
cyclic ketone (25.0 g; quantitative) as colorless glacial
crystals. 1H NMR (CDCl3): d 1.09 (6H, s), 1.66 (4H, t, JZ
6.8 Hz), 2.34 (4H, t, JZ6.8 Hz); 13C NMR (CDCl3): d 27.6,
29.9, 38.1, 39.2, 212.6.
4.2.2. Benzyl 3,5,5-trimethyl-4,5,6,7-tetrahydro-1H-
indole-2-carboxylate (14a). A mixture of 4,4-dimethyl-
cyclohexanone (6.35 g), sodium acetate (71.19 g) and
glacial acetic acid (475 mL) were placed in a 1 L
Erlenmeyer flask and the stirred mixture was heated on a
oil bath to 120 8C. A mixture of phenylhydrazone 15a17c
(14.92 g) and zinc dust (30 g) was added in small portions to
the flask, while maintaining the temperature of reaction
between 125–130 8C. After the addition was complete, the
reaction mixture was stirred at 110 8C for 1 h. The mixture
was then cooled to 70 8C and the solution decanted into
ice/water. The resulting precipitate was filtered, washed
thoroughly with water and recrystallized from ethanol to
give white crystals (5.33 g; 35%), mp 134–135 8C. IR
(Nujol mull): n 3287 (NH str.), 1670 cmK1 (C]O str.); 1H
NMR (CDCl3): d 0.97 (6H, s), 1.53 (2H, t, JZ6.5 Hz), 2.17
(2H, s), 2.23 (3H, s), 2.52 (2H, t, JZ6.5 Hz), 5.29 (2H, s),
7.25–7.43 (5H, m), 8.78 (1H, br s); 13C NMR (CDCl3):
d 10.4, 20.1, 28.1, 30.1, 35.1, 35.7, 65.3, 117.2, 119.4,
126.7, 128.0, 128.5, 131.5, 136.8, 161.6. Anal. Calcd for
C19H23NO2: C, 76.73; H, 7.79; N, 4.71. Found: C, 76.62;
H, 7.63; N, 4.67.
3. Conclusions
Porphyrins with six-membered exocyclic rings have
previously been synthesized from tetrahydroindoles, and
the new results demonstrate that this approach can also be
applied to the synthesis of porphyrins with substituted
exocyclic rings. Tetrahydroindoles bearing two 5- or 6-alkyl
substituents were prepared and used to generate dipyrrolic
precursors to dimethylpropanoporphyrins needed in the
assignment of vibrational spectra for petroporphyrin
samples. The alkyl groups had a deleterious effect on the
yields, which increased with the degree of steric crowding,
but the methodology still allows the synthesis of diverse
porphyrin structures. Cyclotetramerization of 5-alkyl or
5,5-dimethyl tetrahydroindoles gave four examples of
substituted tetrapropanoporphyrins. Although this
chemistry can only be applied to porphyrins with four six-
membered exocyclic rings, these new examples extend this
class of crowded porphyrin systems.
4.2.3. Ethyl 3,5-dimethyl-4,5,6,7-tetrahydro-1H-indole-
2-carboxylate (14d). A mixture of 4-methylcyclohexanone
(5.60 g), sodium acetate (12.50 g) and acetic acid (75 mL)
were placed in a 500 mL Erlenmeyer flask and heated to
70 8C on a water bath. A solution of phenylhydrazone
15b16b (12.00 g) in acetic acid (75 mL) was added to the
mixture while simultaneously adding zinc dust (35 g) in
small portions and maintaining the temperature of the
reaction between 90–100 8C. Once the addition was
complete, the mixture was stirred for 1 h on a boiling
water bath. The mixture was cooled to 70 8C and poured into
ice/water (2 L). The precipitate was filtered, washed with
water and recrystallized from ethanol–water to give the title
compound (5.46 g; 49%) as off-white crystals, mp
94.5–95.5 8C. IR (Nujol mull): n 3310 (NH str.),
4. Experimental
4.1. General
Ethyl acetoacetate, tert-butyl acetoacetate, dimedone,
4-methylcyclohexanone, 4-tert-butylcyclohexanone, 4,4-
dimethyl-2-cyclohexenone, lead tetraacetate, 10% wt %
palladium on activated carbon, triethylamine, and p-tolue-
nesulfonic acid were purchased from Aldrich or Acros, and
were used without further purification. Benzyl acetoacetate
was purchased from TCI America. Chromatography was
performed using grade III neutral alumina or 70–230 mesh
silica gel. Melting points were determined in open capillary
tubes on a Mel-Temp apparatus and are uncorrected.
UV–vis absorption spectra were run on a Beckmann
DU-40 spectrophotometer or a Varian Cary Spectrophoto-
meter. Proton and carbon-13 NMR data were obtained on a
Varian Gemini 300 or 400 MHz FT NMR 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 Micro-Analysis, Inc.,
Wilmington, DE 19808 or the School of Chemical Sciences
Microanalysis Laboratory at the University of Illinois.
1
1656 cmK1 (C]O str.); H NMR (CDCl3): d 1.07 (3H, d,
JZ6.5 Hz), 1.34 (3H, t, JZ7.1 Hz), 1.4 (1H, m), 1.67–2.02
(3H, m), 2.22 (3H, s), 2.45–2.65 (3H, m), 4.29 (2H, q,
JZ7.1 Hz), 8.59 (1H, br s); 13C NMR (CDCl3): d 10.2, 14.6,
21.7, 22.5, 29.6, 31.2, 59.5, 117.5, 119.8, 125.7, 132.0,
162.0. Anal. Calcd for C13H19NO2: C, 70.54; H, 8.67; N,
6.33. Found: C, 70.70; H, 8.45; N, 6.14.
4.2.4. Ethyl 5-tert-butyl-3-methyl-4,5,6,7-tetrahydro-1H-
indole-2-carboxylate (14e). Prepared from 4-tert-butyl-
cyclohexanone (7.70 g) and phenylhydrazone 15b16b
(11.70 g) by the previous procedure, except that the
temperature during the initial addition was maintained at
130 8C. Recrystallization from methanol gave the title
pyrrole (5.95 g; 45%) as small white flakes, mp
173–173.5 8C. IR (Nujol mull): n 3293 (NH str.),
4.2. Synthetic procedures
4.2.1. 4,4-Dimethylcyclohexanone. A solution of 4,4-
dimethyl-2-cyclohexenone (25.0 g) in acetone (75 mL)
was shaken with 10% palladium–charcoal under a hydrogen
atmosphere at room temperature and 30 psi for 90 min.
1
1666 cmK1 (C]O str.); H NMR (CDCl3): d 0.96 (9H, s),
1.33 (3H, t), 1.3–1.4 (1H, m), 1.99–2.18 (2H, m), 2.25

11634
C. M. Shiner, T. D. Lash / Tetrahedron 61 (2005) 11628–11640
(3H, s), 2.48–2.71 (4H, m), 4.31 (2H, q), 8.88 (1H, br s);
13C NMR (CDCl3): d 10.4, 14.7, 22.5, 23.7, 24.6, 27.6, 32.7,
45.6, 59.7, 117.7, 120.3, 126.3, 132.8, 162.4. Anal. Calcd
for C16H25NO2: C, 72.96; H, 9.57; N, 5.32. Found: C, 72.60;
H, 9.57; N, 5.16.
give the title compound (15.43 g; 54%) as an off-white
powder, mp 162.5–162.5 8C; IR (Nujol mull): n 3206 (NH
1
str.), 1712, 1689 cmK1 (2!C]O str); H NMR (CDCl3):
d 1.07 (6H, s), 2.32 (2H, s), 2.61 (3H, s), 2.62 (2H, s), 5.32
(2H, s), 7.27–7.47 (5H, m), 9.28 (1H, br s); 13C NMR
(CDCl3): d 11.6, 28.5, 35.2, 37.0, 53.0, 68.2, 119.4, 119.6,
128.1, 128.7, 129.0, 136.0, 144.4, 161.7, 194.6. Anal. Calcd
for C19H21NO3: C, 73.28; H, 6.81; N, 4.50. Found: C, 73.13;
H, 6.70; N, 4.60.
4.2.5. Ethyl 3,5,5-trimethyl-4,5,6,7-tetrahydro-1H-
indole-2-carboxylate (14b). Prepared by the previous
procedure from 4,4-dimethylcyclohexanone (6.30 g) and
phenylhydrazone 15b16b (11.70 g). Recrystallization from
ethanol gave the tetrahydroindole (5.76 g; 49%) as small
white needles, mp 117.5–119.5 8C. Further crystallization
from ethanol gave an analytical sample as white crystals,
mp 119.5–120 8C. IR (Nujol mull): n 3303 (NH str.),
4.2.8. tert-Butyl 3,6,6-trimethyl-4-oxo-4,5,6,7-tetra-
hydro-1H-indole-2-carboxylate (19b). tert-Butyl aceto-
acetate (31.64 g) was dissolved in acetic acid (62 mL) and
cooled to 10 8C in a ice-salt bath. A solution of sodium
nitrite (22.0 g) in water (62 mL) was added dropwise to the
stirred mixture, while maintaining the temperature below
15 8C. After the addition was complete, the resulting oxime
solution was allowed to stir at room temperature for 1 h.
1
1671 cmK1 (C]O str.); H NMR (CDCl3): d 0.98 (6H, s),
1.34 (3H, t, JZ7.2 Hz), 1.55 (2H, t, JZ6.5 Hz), 2.18 (2H, br
s), 2.21 (3H, s), 2.56 (2H, t, JZ6.5 Hz), 4.29 (2H, q,
JZ7.2 Hz), 8.70 (1H, br s); 13C NMR (CDCl3): d 10.3, 14.7,
20.2, 28.2, 30.2, 35.2, 35.9, 59.7, 117.9, 119.6, 126.4, 131.3,
162.3. Anal. Calcd for C14H21NO2: C, 71.45; H, 8.99; N,
5.95. Found: C, 71.43; H, 9.12; N, 5.87.
A solution of sodium acetate (20.00 g) and dimedone
(28.04 g) were added to glacial acetic acid (200 mL) and
heated on a water bath to 60 8C. The crude oxime solution
was added dropwise to the stirred mixture, while simul-
taneously adding zinc dust (40 g) and maintaining the
reaction at 80 8C. After the addition was complete, the
mixture was heated on a boiling water bath for 1 h, cooled to
70 8C and poured into ice/water. The resulting precipitate
was filtered, washed thoroughly with water to remove traces
of acetic acid and recrystallized from methanol to give the
required tetrahydroindole (10.35 g; 19%) as a white powder,
mp 207–209 8C. IR (Nujol mull): n 3292 (NH str.),
4.2.6. Methyl 3-ethyl-5,5-dimethyl-4,5,6,7-tetrahydro-
1H-indole-2-carboxylate (14c). Prepared by the previous
procedure from 4,4-dimethylcyclohexanone (6.30 g) and
phenylhydrazone 15c16b (11.70 g). Recrystallization from
ethanol gave the title pyrrole (4.21 g; 36%) as small white
chunky needles, mp 153–154 8C. Further crystallization
from ethanol gave an analytical sample as white crystals,
mp 154–154.5 8C. IR (Nujol mull): n 3310 (NH str.),
1
1662 cmK1 (C]O str.); H NMR (CDCl3): d 0.98 (6H, s),
1.10 (3H, t, JZ7.5 Hz), 1.56 (2H, t, JZ6.3 Hz), 2.21 (2H, br
s), 2.56 (2H, t, JZ6.6 Hz), 2.69 (2H, q, JZ7.5 Hz), 3.82
(3H, s), 8.60 (1H, br s); 13C NMR (CDCl3): d 15.1, 18.4,
20.2, 28.1, 30.3, 35.2, 35.8, 51.0, 116.9, 118.9, 131.5, 133.4,
162.4. Anal. Calcd for C14H21NO2: C, 71.45; H, 8.99;
N, 5.95. Found: C, 71.42; H, 9.26; N, 5.79.
1
1655 cmK1 (C]O str.); H NMR (CDCl3): d 1.10 (6H, s),
1.59 (9H, s), 2.34 (2H, s), 2.58 (3H, s), 2.67 (2H, s), 9.51
(1H, br s); 13C NMR (CDCl3): d 11.5, 28.5, 35.2, 37.1, 53.0,
81.5, 118.9, 120.8, 127.4, 143.9, 161.7, 194.8. Anal. Calcd
for C16H23NO3: C, 69.27; H, 8.37; N, 5.05. Found: C, 68.82;
H, 8.09; N, 4.98.
4.2.7. Benzyl 3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-
1H-indole-2-carboxylate (19a). Benzyl acetoacetate
(38.44 g) was dissolved in acetic acid (62 mL) and cooled
to 10 8C in a ice-salt bath. A solution of sodium nitrite
(22.00 g) in water (62 mL) was added dropwise to the
stirred mixture, maintaining the reaction temperature below
15 8C throughout. After stirring for 1 h at room temperature,
the mixture was extracted with dichloromethane
(3!50 mL) and the combined organic solutions washed
with water, 10% NaHCO3 solution and water. The solution
was dried over Na2SO4, filtered and the solvent evaporated.
The resulting oxime was obtained as a yellow oil (43.03 g;
97%) and was used without further purification.
4.2.9. Benzyl 3,6,6-trimethyl-4,5,6,7-tetrahydro-1H-
indole-2-carboxylate (18a). Sodium borohydride (5.72 g)
was dissolved in anhydrous THF (130 mL) and placed in a
500 mL 3-neck flask equipped with a nitrogen flow inlet,
addition funnel, a condenser and a thermometer.
4-Oxotetrahydroindole 19a (11.85 g) in anhydrous THF
(230 mL) was added and the mixture was cooled to K5 8C
in an ice/salt bath. The system was purged with nitrogen and
the slow addition of boron trifluoride etherate (26.7 mL)
was initiated, while maintaining a temperature below 0 8C.
After the addition was complete, the mixture was allowed to
stir at room temperature for 2 h. The mixture was poured
into ice/water and the resulting precipitate filtered off,
washed well with warm water and recrystallized from
dichloromethane–hexane to give the tetrahydroindole
(7.63 g; 67%) as a white powder, mp 142.5–143 8C. IR
(Nujol mull): n 3295 (NH str.), 1664 cmK1 (C]O str.); 1H
NMR (CDCl3): d 0.97 (6H, s), 1.52 (2H, t, JZ6.5 Hz), 2.17
(2H, s), 2.23 (3H, s), 2.50 (2H, t, JZ6.5 Hz), 5.29 (2H, s),
7.23–7.45 (5H, m), 8.90 (1H, br s); 13C NMR (CDCl3):
d 10.4, 20.1, 28.1, 30.1, 35.1, 35.7, 65.3, 117.3, 119.4,
126.7, 128.0, 128.5, 131.7, 136.8, 161.7. Anal. Calcd for
C19H23NO2: C, 76.72; H, 7.81; N, 4.71. Found: C, 76.46;
H, 7.65; N, 4.76.
Anhydrous sodium acetate (10.0 g) and dimedone (11.20 g)
were added to glacial acetic acid (100 mL) and heated on a
water bath to 70 8C. A solution of the foregoing oxime
(19.20 g) in acetic acid (50 mL) was added dropwise to the
stirred mixture, while simultaneously adding zinc dust
(30 g) and maintaining the reaction temperature at
85–90 8C. After the addition was complete, the mixture
was heated on a boiling water bath for 1 h, cooled to 70 8C
and poured into ice/water. The resulting precipitate was
filtered, washed thoroughly with water to remove traces of
acetic acid and recrystallized from chloroform–hexanes to

C. M. Shiner, T. D. Lash / Tetrahedron 61 (2005) 11628–11640
11635
4.2.10. tert-Butyl 3,6,6-trimethyl-4,5,6,7-tetrahydro-1H-
indole-2-carboxylate (18b). Using the procedure described
above, 19b (7.45 g) afforded the title compound (4.95 g;
70%) after recrystallization from methanol as white crystals,
mp 150.5–151.5 8C. IR (Nujol mull): n 3304 (NH str.),
31.8, 33.9, 65.5, 72.4, 119.1, 120.8, 125.0, 128.0, 128.1,
128.5, 129.6, 136.6, 161.3, 172.4. Anal. Calcd for
C21H25NO4: C, 70.96; H, 7.09; N, 3.94. Found: C, 70.99;
H, 7.02; N, 4.01.
1
1654 cmK1 (C]O str.); H NMR (CDCl3): d 0.98 (6H, s),
4.2.14. Ethyl 7-acetoxy-3,5-dimethyl-4,5,6,7-tetrahydro-
1H-indole-2-carboxylate (17d). Lead tetraacetate (4.21 g)
was added in one portion to a stirred solution of ethyl
3,5-dimethyl-4,5,6,7-tetrahydro-1H-indole-2-carboxylate
(14d; 2.00 g) in acetic acid (18 mL) and acetic anhydride
(2 mL). The mixture was stirred for 3 h at room
temperature, extracted with dichloromethane and washed
with water, 5% sodium bicarbonate solution and water. The
acetoxy derivative was obtained as a pale brown oil (2.42 g;
96%) and used without further purification. Crystallization
from hexanes gave an analytical sample as white crystals,
mp 120–121 8C; IR (Nujol mull): n 3313 (NH str.), 1729
1.51 (2H, t, JZ6.4 Hz), 1.56 (9H, s), 2.21 (3H, s), 2.33 (2H,
s), 2.38 (2H, t, JZ6.4 Hz), 8.67 (1H, br s); 13C NMR
(CDCl3): d 10.5, 18.5, 28.0, 28.6, 30.5, 36.3, 36.8, 79.9,
117.9, 118.7, 124.8, 131.5, 161.6. Anal. Calcd for
C16H25NO2: C, 72.95; H, 9.59; N, 5.32. Found: C, 72.82;
H, 9.29; N, 5.34.
4.2.11. tert-Butyl 7-acetoxy-3,6,6,-trimethyl-4,5,6,7-
tetrahydro-1H-indole-2-carboxylate (20b). Lead tetra-
acetate (5.31 g) was added in one portion to a stirred
solution of 18b (5.31 g) in acetic acid (57 mL) and acetic
anhydride (3 mL). The mixture was stirred for 2.5 h at room
temperature, extracted with dichloromethane and washed
with water, 5% sodium bicarbonate solution and water. The
organic layer was dried over sodium sulfate and evaporated
under reduced pressure to give the desired acetoxy
compound as a yellow oil (quantitative). Crystallization
from hexane gave the 7-acetoxytetrahydroindole (2.36 g;
64.5%) as white crystals, mp 137.5–138.5 8C. IR (Nujol
mull): n 3300 (NH str.), 1715 (acetoxy C]O str.),
1
(acetoxy C]O str.), 1662 cmK1 (pyrrole C]O str.); H
NMR (CDCl3): d 1.12 (3H, d, JZ6.7 Hz) 1.34 (3H, t,
JZ7.2 Hz), 1.61 (1H, m), 1.81–2.17 (3H, m), 2.05 (3H, s),
2.23 (3H, s), 2.60 (1H, dd), 4.30 (2H, m), 5.65 (1H, m) 9.06
(1H, br s); 13C NMR (CDCl3): d 10.0, 14.5, 21.2, 21.4, 21.6,
25.6, 29.4, 29.6, 37.3, 59.7, 65.4, 67.7, 119.4, 119.5, 122.5,
122.8, 124.2, 128.5, 129.5, 161.4, 172.3. Anal. Calcd for
C13H19NO4: C, 64.50; H, 7.56; N, 5.01. Found: C, 64.46; H,
7.56; N, 5.03.
1
1699 cmK1 (pyrrole C]O str.); H NMR (CDCl3): d 0.93
(3H, s), 1.06 (3H, s), 1.55 (9H, s), 1.43–1.62 (1H, m) 1.83
(1H, m), 2.06 (3H, s), 2.20 (3H, s), 2.25–2.53 (2H, m), 5.21
(1H, s), 8.91 (1H, br s); 13C NMR (CDCl3): d 10.2, 18.2,
21.1, 23.9, 25.6, 28.5, 31.9, 33.9, 72.5, 80.4, 120.6, 120.7,
123.6, 128.6, 161.1, 172.3. Anal. Calcd for C18H27NO4:
C, 67.26; H, 8.47; N, 4.36. Found: C, 67.85; H, 8.70;
N, 4.37.
4.2.15. Ethyl 7-acetoxy-5-tert-butyl-3-methyl-4,5,6,7-
tetrahydro-1H-indole-2-carboxylate (17e). Prepared
from 14e (1.00 g) by the procedure detailed above. The
acetoxy derivative was obtained as a yellow oil (1.08 g;
88%), which was used without further purification. An
analytical sample was obtained as white crystals by
recrystallization from hexane, mp 121–123 8C. IR (Nujol
mull): n 3279 (NH str.), 1734 (acetoxy C]O str.),
1
1674 cmK1 (pyrrole C]O str.); H NMR (CDCl3): d 0.98
4.2.12. Benzyl 7-acetoxy-3,5,5-trimethyl-4,5,6,7-tetra-
hydro-1H-indole-2-carboxylate (17a). Prepared by the
previous procedure from 14a (3.00 g). The 7-acetoxy-
tetrahydroindole was recrystallized from hexane to give
off-white crystals (2.83 g; 79%), mp 88.5–90.5 8C. IR
(Nujol mull): n 3302 (NH str.), 1729 (acetoxy C]O str.),
(9H, s), 1.35 (3H, t, JZ7.1 Hz), 1.62 (1H, m), 1.78 (1H, m),
1.92–2.21 (2H, m), 2.05 (3H, s), 2.24 (3H, s), 2.57 (1H, dd),
4.30 (2H, m), 5.67 (1H, m), 9.06 (1H, br s); 13C NMR
(CDCl3): d 10.0, 14.5, 21.2, 22.3, 27.4, 30.5, 33.4, 40.3,
59.8, 65.5, 119.6, 123.0, 124.7, 128.5, 161.5, 172.4. Anal.
Calcd for C18H27NO4: C, 67.25; H, 8.48; N, 4.36. Found: C,
66.96; H, 8.18; N, 4.36.
1
1686 cmK1 (pyrrole C]O str.); H NMR (CDCl3): d 1.01
(3H, s), 1.09 (3H, s), 1.71–1.95 (2H, m), 2.08 (3H, s),
2.12–2.35 (2H, AB quartet), 2.22 (3H, s), 5.24–5.38
(2H, AB quartet), 5.69 (1H, t, JZ5.9 Hz), 7.26–7.46 (5H,
m), 9.10 (1H, br s); 13C NMR (CDCl3): d 10.3, 21.3, 28.4,
29.0, 31.6, 35.1, 41.8, 65.6, 66.2, 119.4, 122.1, 125.4, 128.0,
128.5, 136.5, 161.3, 172.4. Anal. Calcd for C21H25NO4: C,
70.96; H, 7.09; N, 3.94. Found: C, 71.15; H, 7.25; N, 3.97.
4.2.16. Ethyl 7-acetoxy-3,5,5-trimethyl-4,5,6,7-tetra-
hydro-1H-indole-2-carboxylate (17b). Following the
foregoing procedure, 14b (2.00 g) and lead tetraacetate
(4.00 g) gave the title compound as a pale yellow oil (2.48 g,
quantitative). An analytical sample was obtained by slow
crystallization from hexane as white crystals, mp 81–82 8C.
IR (Nujol mull): n 3310 (NH str.), 1734 (acetoxy C]O str.),
4.2.13. Benzyl 7-acetoxy-3,6,6-trimethyl-4,5,6,7-tetra-
hydro-1H-indole-2-carboxylate (20a). Prepared from 19a
(1.00 g) by the procedure detailed for 20b. The 7-acetoxy-
tetrahydroindole was obtained as a pale yellow oil (1.16 g;
97%) and was used without further purification. An
analytical sample was obtained by recrystallization from
hexanes as off-white crystals, mp 75.5–76.5 8C. IR (Nujol
mull): n 3452 (NH str.), 1710 (acetoxy C]O str.),
1
1662 cmK1 (pyrrole-C]O str.); H NMR (CDCl3): d 1.01
(3H, s), 1.09 (3H, s), 1.34 (3H, t, JZ6.9 Hz), 1.73–1.80 (1H,
dd, JZ13.8, 5.7 Hz), 1.88–1.94 (1H, dd, JZ13.6, 6.1 Hz),
2.09 (3H, s), 2.16–2.33 (2H, AB quartet, JZ15.3 Hz), 2.21
(3H, s), 4.22–4.37 (2H, m), 5.68 (1H, t, JZ5.8 Hz), 9.01
(1H, br s); 13C NMR (CDCl3): d 10.2, 14.6, 21.4, 28.6, 29.0,
31.7, 35.2, 41.9, 60.0, 66.4, 120.0, 122.2, 125.3, 128.4,
161.9, 172.9. Anal. Calcd for C16H23NO4: C, 65.51; H, 7.90;
N, 4.77. Found: C, 65.58; H, 7.85; N, 4.56.
1
1667 cmK1 (pyrrole C]O str.); H NMR (CDCl3): d 0.92
(3H, s), 1.06 (3H, s), 1.44–1.56 (1H, m), 1.77–1.91 (1H, m),
2.05 (3H, s), 2.22 (3H, s), 2.38–2.65 (2H, m), 5.20 (1H, s),
5.23–5.38 (2H, AB quartet), 7.28–7.46 (5H, m), 8.89 (1H, br
s); 13C NMR (CDCl3): d 10.3, 18.2, 21.1, 23.9, 25.6, 26.0,
4.2.17. Methyl 7-acetoxy-3-ethyl-5,5-dimethyl-4,5,6,7-
tetrahydro-1H-indole-2-carboxylate (17c). Prepared by

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C. M. Shiner, T. D. Lash / Tetrahedron 61 (2005) 11628–11640
the foregoing procedure from 14c (2.00 g) and lead
tetraacetate (4.00 g). Recrystallization from hexane gave
the acetoxy derivative (1.93 g; 77%) as white crystals, mp
93–94 8C. IR (Nujol mull): n 3300 (NH str.), 1731 (acetoxy
C]O str.), 1676 cmK1 (pyrrole-C]O str.); 1H NMR
(CDCl3): d 1.01 (3H, s), 1.09 (6H, overlapping triplet and
singlet), 1.74–1.81 (1H, dd, JZ13.9, 5.5 Hz), 1.88–1.95
(1H, dd, JZ13.8, 6.3 Hz), 2.09 (3H, s), 2.19–2.36 (2H, AB
quartet, JZ15.4 Hz), 2.66–2.74 (2H, m), 3.82 (3H, s), 5.68
(1H, t, JZ5.8 Hz), 9.03 (1H, br s); 13C NMR (CDCl3):
d 15.1, 18.2, 21.4, 28.5, 29.0, 31.7, 35.2, 41.8, 51.1, 66.5,
119.0, 121.6, 128.5, 132.2, 161.9, 173.0. Anal. Calcd for
C16H23NO4: C, 65.51; H, 7.90; N, 4.77. Found: C, 65.41;
H, 7.99; N, 4.70.
the method described previously for 22c. The residue was
chromatographed on silica eluting with 10% ethyl acetate/
dichloromethane and recrystallized from ethanol to give the
title dipyrrole as a light yellow solid (1.36 g; 46%), mp
157.5–159.5 8C. IR (Nujol mull): n 3283 (NH str.), 1679,
1
1655 cmK1 (C]O str.); H NMR (CDCl3): d 0.79 (3H, s),
1.02 (3H, s), 1.48–1.75 (2H, m), 1.52 (9H, s), 2.22 (3H, s),
2.29 (3H, s), 2.45 (2H, m), 3.65 (1H, s), 5.23 (2H, AB
quartet), 5.80 (1H, m), 7.26–7.44 (5H, m), 8.87 (1H, br s),
9.09 (1H, br s); 13C NMR (CDCl3): d 10.5, 13.2, 18.4, 29.3,
28.5, 28.6, 34.7, 36.2, 45.4, 65.7, 80.2, 113.5, 118.2, 119.1,
120.0, 124.1, 128.0, 128.4, 128.5, 131.0, 135.3, 136.5,
161.6. Anal. Calcd for C29H36N2O4: C, 73.08; H, 7.61; N,
5.88. Found: C, 72.70; H, 7.45; N, 5.68.
4.2.18. Benzyl 7-(5-benzyloxycarbonyl-3-ethyl-4-methyl-
2-pyrrolyl)-3,6,6-trimethyl-4,5,6,7-tetrahydro-1H-indole-
2-carboxylate (22c). Benzyl 4-ethyl-3-methylpyrrole-2-car-
boxylate34 (21a) (0.81 g) and p-toluenesulfonic acid (36 mg)
were dissolved in acetic acid (14 mL) and placed in a 50 mL
Erlenmeyer flask. A solution of benzyl 7-acetoxy-
3,6,6-trimethyl-4,5,6,7-tetrahydro-1H-indole-2-carboxylate
(20a) (1.18 g) in acetic acid (20 mL) was slowly added over
30 min to the stirred reactants and the mixture was then
allowed to stir for a further 3 h at room temperature. The
solution was extracted with dichloromethane and washed with
water, saturated sodium bicarbonate solution and water, and
dried over sodium sulfate. The solvent was removed under
reduced pressure and the residue chromatographed on silica,
eluting with dichloromethane. Recrystallization with ethanol
gave the title dipyrrole (0.71 g; 40%) as a white powder, mp
136.5–137.5 8C.IR(Nujolmull):n3282(NHstr.), 1678 cmK1
(C]O str.) cm; 1H NMR (CDCl3):d 0.90(3H, s), 1.03(3H, s),
1.14 (3H, t, JZ7 Hz), 1.69 (2H, m), 2.25 (3H, s), 2.31 (3H, s),
2.48(4H, m), 3.85(1H,s), 5.11–5.29(4H,twooverlappingAB
quartets), 7.25–7.45 (10H, m), 8.75 (2H, br); 13C NMR
(CDCl3): d 10.7, 11.1, 15.4, 17.7, 18.4, 22.7, 29.1, 35.4, 37.1,
42.8, 65.5, 65.6, 118.3, 119.4, 125.6, 126.4, 126.6, 127.9,
128.5, 130.7, 132.7, 136.6, 136.6, 161.6. Anal. Calcd for
C34H38N2O4$1/2H2O: C, 74.56; N, 7.18; N, 5.11. Found: C,
74.39; H, 7.04; N, 5.02.
4.2.21. Benzyl 7-(5-benzyloxycarbonyl-3-bromo-4-
methyl-2-pyrrolyl)-3,5,5-trimethyl-4,5,6,7-tetrahydro-
1H-indole-2-carboxylate (22b). Benzyl 4-bromo-3-
methylpyrrole-2-carboxylate17a (21c; 0.42 g) and zinc
chloride (0.103 g) were dissolved in dichloromethane
(20 mL) and cooled to below 0 8C. Benzyl 7-acetoxy-3,5,5
trimethyl-4,5,6,7-tetrahydro-1H-indole-2-carboxylate (17a;
0.51 g) was dissolved in dichloromethane (20 mL) and
placed in an addition funnel. The acetoxy mixture was
slowly added over 40 min while maintaining the tempera-
ture below 0 8C. The mixture was allowed to stir at 0 8C for
a further 2 h and then at room temperature overnight. The
solution was washed successively with 3 M hydrochloric
acid, water, 5% sodium bicarbonate solution and water, and
dried over sodium sulfate. The solvent was removed under
reduced pressure. The residue was then purified by flash
chromatography, eluting with 8.5% ethyl acetate/hexane
and recrystallized from ethanol to give the title dipyrrole as
a light pink solid (0.325 g; 39%), mp 115–118 8C. IR (Nujol
1
mull): n 3256 (NH str.), 1676 cmK1 (C]O str.); H NMR
(CDCl3): d 1.04 (3H, s), 1.13 (3H, s), 1.59 (1H, t, JZ
12.4 Hz), 1.88 (1H, dd), 2.18 (3H, s), 2.25 (3H, s), 2.31 (2H,
m), 4.26 (1H, dd), 4.86–5.39 (4H, two overlapping AB
quartets), 7.27–7.48 (10H, m), 10.63 (2H, br); 13C NMR
(CDCl3): d 10.9, 12.2, 24.7, 31.1, 31.4, 31.8, 35.6, 43.6,
65.9, 66.3, 100.5, 117.7, 118.5, 120.3, 125.3, 126.5, 127.7,
127.8, 128.1, 128.4, 128.5, 131.2, 135.9, 136.5, 136.8,
161.6, 162.6. Anal. Calcd for C32H33N2O4Br$1/4H2O: C,
64.70; H, 5.68; N, 4.72. Found: C, 64.70; H, 5.56; N, 4.72.
4.2.19. Benzyl 7-(5-benzyloxycarbonyl-3-ethyl-4-methyl-
2-pyrrolyl)-3,5,5-trimethyl-4,5,6,7-tetrahydro-1H-indole-
2-carboxylate (22a). Prepared by the procedure detailed
above from 17a (0.80 g) and 21a (0.52 g). The residue was
chromatographed on silica eluting with dichloromethane, to
give the title dipyrrole as a yellow oil (0.44 g; 38%) that
solidifiedonstanding. Attemptstorecrystallizethiscompound
were unsuccessful. IR (Nujol mull): n 3264 (NH str.),
4.2.22. 7-(5-Carboxy-3-ethyl-4-methyl-2-pyrrolyl)-3,6,6-
trimethyl-4,5,6,7-tetrahydro-1H-indole-2-carboxylic
acid (23c). Dipyrrole 22c (1.00 g) was dissolved in acetone
(150 mL) and placed in a hydrogenation vessel. Triethyl-
amine (20 drops) was added to the solution, the vessel
purged with nitrogen and 10% palladium–charcoal
(200 mg) was added. The mixture was shaken under an
atmosphere of hydrogen (40 psi) at room temperature
overnight. The solution was filtered to remove the catalyst
and the solvent removed under reduced pressure. The
residue was taken up in a 5% aqueous ammonia solution and
cooled to 5 8C. Glacial acetic acid was added to neutralize
the solution, while maintaining temperature at 0–5 8C. The
resulting precipitate was filtered, washed with water to
remove all traces of acid and dried in vacuo overnight. The
dicarboxylic acid (548 mg; 82%) was obtained as a pale
purple powder, mp 173 8C dec. IR (Nujol mull): n 3306 (NH
1
1674 cmK1 (C]O str.); H NMR (CDCl3): d 1.00 (3H, s),
1.10 (3H, s), 1.11 (3H, t), 1.70 (2H, m), 2.21 (3H, s), 2.27 (3H,
s), 2.22–2.34 (2H, m), 2.46 (2H, m), 4.06 (1H, t), 5.01–5.34
(4H, two overlapping AB quartets), 7.24–7.45 (10H, m), 9.59
(2H, br s); 13C NMR (CDCl3): d 10.8, 16.3, 17.4, 24.8, 30.4,
31.2, 31.8, 35.3, 45.5, 65.5, 117.7, 118.4, 120.3, 124.3, 125.9,
126.5, 127.8, 127.9, 128.1, 128.5, 131.6, 134.5, 136.5, 161.8,
162.0.
4.2.20. tert-Butyl 7-(5-benzyloxycarbonyl-4-methyl-2-
pyrrolyl)-3,6,6-trimethyl-4,5,6,7-tetrahydro-1H-indole-
2-carboxylate (22d). Prepared from 20b (2.00 g) and
benzyl 3-methylpyrrole-2-carboxylate35 (21b; 1.34 g) by
1
str.), 1655 cmK1 (C]O str.); H NMR (CDCl3): d 0.86

C. M. Shiner, T. D. Lash / Tetrahedron 61 (2005) 11628–11640
11637
(3H, s), 1.02 (3H, s), 1.11 (3H, t, JZ6.8 Hz), 1.68 (2H, m),
2.26 (3H, s), 2.38 (3H, s), 2.48 (4H, m), 3.85 (1H, s), 8.24
(2H, br). Anal. Calcd for C20H26N2O4: C, 67.02; H, 7.31; N,
7.81. Found: C, 67.35; H, 7.64; N, 7.78.
412 (5.53), 556 (4.28), 599 nm (3.95); 1H NMR (CDCl3): d
K3.28 (2H, br s), 1.45 (6H, s), 1.79–1.88 (9H, three
overlapping triplets), 3.53 (3H, s), 3.58 (3H, s), 3.64 (3H, s),
3.66 (5H, s), 4.01 (2H, q), 4.05–4.12 (4H, two overlapping
quartets), 4.91 (2H, s), 9.88 (1H, s), 10.02 (1H, s), 10.07
(1H, s); 1H NMR (TFA–CDCl3): d K3.76 (1H, br s), K3.56
(1H, s), K3.54 (1H, br s), K2.96 (1H, br s), 1.29 (6H, s),
1.69 (3H, t, JZ7.8 Hz), 1.74 (6H, t, JZ7.6 Hz), 3.48 (3H,
s), 3.52 (3H, s), 3.59 (3H, s), 3.60 (3H, s), 3.75 (2H, s), 3.89
(2H, q, JZ7.6 Hz), 4.02–4.11 (4H, two overlapping
quartets), 5.05 (2H, s), 10.35 (1H, s), 10.43 (1H, s), 10.51
(1H, s); 13C NMR (TFA–CDCl3): d 11.7, 11.9, 15.9, 16.4,
16.5, 20.2 (2), 21.6, 28.6, 37.3, 37.8, 44.8, 96.2, 97.6, 99.4,
118.7, 135.5, 137.7, 138.2, 138.7, 140.3, 140.4, 140.9,
141.0, 141.2, 142.5, 142.9, 143.3, 143.4, 144.5; EIMS: m/z
(rel int.) 518 (100, MC), 503 (8, [MKCH3]C); HRMS:
Calcd for C35H42N4: 518.3412. Found: 518.3404. Anal.
Calcd for C35H42N4$1/4H2O: C, 80.34; H, 8.19; N, 10.71.
Found: C, 80.14; H, 8.26; N, 10.48. Method B. A solution of
24 (80 mg) and 23a (100 mg) in methanol (2 mL) and
dichloromethane (40 mL) was added dropwise to a stirred
solution of p-toluenesulfonic acid (80 mg) in methanol
(2 mL) and dichloromethane (40 mL) under nitrogen over a
period of 1 h. The resulting mixture was allowed to stir in
the dark open to the air overnight, and then further reacted
under the conditions described for method A. Recrystalliza-
tion from chloroform–methanol gave the title porphyrin
(53 mg, 37%) as dark maroon crystals, mp O 300 8C.
4.2.23. 7-(5-Carboxy-3-ethyl-4-methyl-2-pyrrolyl)-3,5,5-
trimethyl-4,5,6,7-tetrahydro-1H-indole-2-carboxylic
acid (23a). Prepared from 22a (435 mg) by the procedure
detailed above. The dicarboxylic acid powder (256 mg;
88%) was obtained as a pale greyish-purple powder, mp
208–212 8C dec. IR (Nujol mull): n 3307 (NH str.), 1645
1
cmK1 (C]O str.); H NMR (d6-DMSO): d 0.88 (6H, s),
1.04 (3H, t), 1.64 (2H, m), 2.09 (2H, m), 2.15 (3H, s), 2.18
(3H, s), 2.23 (2H, m), 4.05 (1H, m), 10.38 (1H, br s), 10.74
(1H, br s), 11.77 (2H, br). Anal. Calcd for C20H26N2O4: C,
67.02; H, 7.31; N, 7.81. Found: C, 67.41; H, 7.40; N, 7.31.
4.2.24. tert-Butyl 7-(5-carboxy-4-methyl-2-pyrrolyl)-
3,6,6-trimethyl-4,5,6,7-tetrahydro-1H-indole-2-carbo-
xylate (23d). Prepared from 22d (500 mg) by the procedure
described for 23c but using ethanol as the solvent. The
carboxylic acid was obtained as a white solid (344 mg;
85%), mp 158–163 8C. IR (Nujol mull): n 3218 (NH str.),
1
1672 cmK1 (C]O str.); H NMR (d6-DMSO): d 0.72 (3H,
s), 0.92 (3H, s), 1.09–1.17 (1H, m), 1.58–1.75 (1H, m), 1.48
(9H, s), 2.14 (3H, s), 2.15 (3H, s), 2.20–2.48 (2H, m), 3.67
(1H, s), 10.61 (1H, br s), 11.10 (1H, br s), 11.85 (1H, br).
Anal. Calcd for C22H30N2O4: C, 68.37; H, 7.82; N, 7.25.
Found: C, 68.39; H, 7.80; N, 7.26.
4.2.27. 7,13,17-Triethyl-2,8,12,18-tetramethyl-3,5-(3,3-
dimethylpropano)porphyrin (13c). Prepared from 24
(120 mg) and 23c (150 mg) in 30 mL of CH2Cl2 and 3 mL
of methanol using method A as detailed above. Recrystalli-
zation from dichloromethane–methanol gave the porphyrin
(16 mg; 7%) as small lustrous purple needles, mp
256–257 8C; UV–vis (1% Et3N–CHCl3): lmax (log10 3)
409 (5.17), 509 (4.15), 543 (3.84), 578 (3.85), 628 nm
(3.66); UV–vis (1% TFA–CHCl3): lmax (log10 3) 397 (sh,
4.81), 418 (5.35), 564 (4.18), 610 nm (4.13); 1H NMR
(CDCl3): d K2.74 (2H, br s), 1.24 (3H, t, JZ7.6 Hz),
1.80–1.86 (6H, two overlapping triplets), 2.45 (2H, t, JZ
6.4 Hz), 2.51 (6H, s), 3.54 (3H, s), 3.57 (3H, s), 3.58 (3H, s),
3.59 (3H, s), 3.88 (2H, t, JZ6 Hz), 3.94–4.04 (4H, two
overlapping quartets), 4.30 (2H, q, JZ7.6 Hz), 9.74 (1H, s),
9.91 (1H, s), 10.06 (1H, s); 1H NMR (TFA–CDCl3): d
K3.39 (1H, s), K2.99 (1H, s), K2.43 (1H, s), K1.90 (1H,
s), 0.53 (3H, t, JZ7.6 Hz), 1.66 (3H, t, JZ7.8 Hz), 1.70
(3H, t, JZ7.8 Hz), 2.20 (2H, br t), 2.54 (6H, s), 3.14 (3H, s),
3.35 (3H, s), 3.45 (3H, s), 3.47 (3H, s), 3.77 (2H, br),
3.87–3.99 (6H, m), 10.01 (1H, s), 10.06 (1H, s), 10.29 (1H,
s); 13C NMR (TFA–CDCl3): d 11.5, 11.6, 11.8 (2), 14.8,
16.2, 20.0, 20.1, 20.8, 22.8, 31.5, 39.1, 46.1, 95.4, 95.7,
102.3, 128.5, 132.6, 133.7, 135.2, 137.8, 138.9, 139.5,
140.6, 140.8, 141.3, 142.6, 142.8, 143.6, 143.8, 145.1;
EIMS: m/z (rel int.) 518 (100, MC), 503 (64, [MKCH3]C);
HRMS: Calcd for C35H42N4: 518.3412. Found: 518.3393.
Anal. Calcd for C35H42N4$1/2H2O: C, 79.65; H, 8.21; N,
10.62. Found: C, 79.64; H, 8.28; N, 10.47.
4.2.25. 7-(5-Carboxy-4-methyl-2-pyrrolyl)-3,5,5-tri-
methyl-4,5,6,7-tetrahydro-1H-indole-2-carboxylic acid
(23b). Prepared from bromo-dipyrrole 22b (500 mg) by
the procedure detailed for 23c, except that methanol was
used as the solvent. The title carboxylic acid (227 mg; 81%)
was obtained as a light tan solid, mp 198–202 8C dec. IR
(Nujol mull): n 3305 (NH str.), 1646 cmK1 (C]O str.); 1H
NMR (d6-DMSO): d 0.86 (3H, s), 1.05 (3H, s), 1.71 (2H, m),
2.12 (3H, s), 2.19 (3H, s), 2.15 (2H, m), 3.91 (1H, m), 5.67
(1H, s), 10.36 (1H, br s), 11.26 (1H, br s). Anal. Calcd for
C18H22N2O4: C, 65.44; H, 6.71; N, 8.48. Found: C, 65.60;
H, 6.95; N, 8.06.
4.2.26. 7,13,17-Triethyl-2,8,12,18-tetramethyl-3,5-(2,2-
dimethylpropano)porphyrin (13a). Method A. A solution
of p-toluenesulfonic acid (80 mg) in methanol (1.4 mL) was
added in one portion to a stirred mixture of 2417c (80 mg)
and 23a (100 mg) in dichloromethane (10 mL). The mixture
was allowed to stir in the dark overnight. A saturated
solution of zinc acetate in methanol (1.6 mL) was added and
the mixture was again allowed to stir in the dark overnight.
The solution was washed with water, 5% HCl, 5% aqueous
ammonia and water, and dried over anhydrous sodium
sulfate. The solvent was removed under reduced pressure
and the residue chromatographed on alumina eluting with
dichloromethane. The red fractions were combined,
evaporated and rechromatographed on alumina eluting
with toluene. The fractions containing porphyrin were
evaporated and recrystallized from dichloromethane–
methanol to give dark maroon crystals (20 mg; 14%), mp
O300 8C; UV–vis (1% Et3N–CHCl3): lmax (log10 3) 405
(5.22), 504 (4.20), 538 (3.83), 571 (3.88), 625 nm (3.61);
UV–vis (1% TFA–CHCl3): lmax (log10 3) 391 (sh, 4.85),
4.2.28. 13,17-Diethyl-2,8,12,18-tetramethyl-3,5-(2,2-
dimethylpropano)porphyrin (13b). The title porphyrin
was prepared using method A, as detailed for porphyrin 13a,
from 24 (87 mg) and 23b (100 mg). The residue was

11638
C. M. Shiner, T. D. Lash / Tetrahedron 61 (2005) 11628–11640
chromatographed on silica eluting with dichloromethane.
The red fractions were combined, evaporated and crystal-
lized from dichloromethane–methanol to give the
cycloalkanoporphyrin (24 mg; 16%) as deep purple crystals,
mp O300 8C. Under the conditions described in method B
for 13a, the yield was raised to 39%. UV–vis (1%
Et3N–CHCl3): lmax (log10 3) 405 (5.25), 502 (4.19), 537
(3.80), 571 (3.86), 625 nm (3.53); UV–vis (1%
TFA–CHCl3): lmax (log10 3) 390 (sh, 4.86), 411 (5.56),
553 (4.32), 594 nm (3.72); 1H NMR (CDCl3): d K3.37 (2H,
br s), 1.52 (6H, s), 1.85–1.89 (6H, two overlapping triplets),
3.55 (3H, s), 3.60 (3H, s), 3.62 (3H, s), 3.69 (2H, s), 3.77
(3H, s), 4.02–4.11 (4H, two overlapping quartets), 4.80 (2H,
s), 9.26 (1H, s), 9.94 (1H, s), 9.99 (1H, s), 10.06 (1H, s); 1H
NMR (TFA–CDCl3): d K3.98 (1H, br s), K3.92 (1H, br s),
K3.88 (1H, br s), K3.70 (1H, br s), 1.55 (6H, s), 1.70–1.77
(6H, two overlapping triplets), 3.61 (3H, s), 3.65 (3H, s),
3.66 (3H, s), 3.74 (3H, s), 3.81 (2H, s), 4.10–4.16 (4H, two
overlapping quartets), 4.94 (2H, s), 9.46 (1H, s), 10.54 (1H,
s), 10.58 (1H, s), 10.68 (1H, s); 13C NMR (TFA–CDCl3): d
11.7, 11.8, 14.0, 16.4, 20.2, 20.3, 28.6, 36.3, 38.0, 44.7,
97.2, 98.2, 100.1, 118.1, 125.7, 136.2, 138.8, 139.4, 140.2,
140.9, 141.2, 141.8, 141.9, 142.1, 142.6, 142.9, 143.0,
143.6, 144.4, 145.1; EIMS: m/z (rel int.) 490 (100, MC), 475
(13, [MKCH3]C); HRMS: Calcd for C33H38N4: 490.3099.
Found: 490.3108. Anal. Calcd for C33H38N4$1/8CHCl3: C,
78.69; H, 7.60; N, 11.08. Found: C, 78.67; H, 7.78; N, 10.92.
(1H, br s), K3.35 (1H, br s), K3.03 (1H, br s), K2.83 (1H,
br s), 1.69–1.76 (6H, two overlapping triplets), 2.54 (6H, s),
2.74 (2H, t, JZ6.4 Hz), 3.54 (3H, s), 3.55 (3H, s), 3.58 (3H,
s), 3.60 (3H, s), 3.94 (2H, t, JZ6.2 Hz), 4.01–4.10 (4H, two
overlapping quartets), 9.26 (1H, s), 10.33 (1H, s), 10.38 (1H,
s), 10.50 (1H, s); 13C NMR (TFA–CDCl3): d 11.7, 11.8,
14.0, 16.4, 20.2, 20.3, 28.6, 36.3, 38.0, 44.7, 97.2, 98.2,
100.1, 118.1, 125.7, 136.2, 138.8, 139.4, 140.2, 140.9,
141.2, 141.8, 141.9, 142.1, 142.6, 142.9, 143.0, 143.6,
144.4, 145.1; EIMS: m/z (rel int.) 490 (100, MC), 475 (55,
[MKCH3]C); HRMS: Calcd for C33H38N4: 490.3099.
Found: 490.3118. Anal. Calcd for C33H38N4$1/8CHCl3: C,
78.69; H, 7.60; N, 11.08. Found: C, 78.73; H, 7.66; N, 11.00.
4.2.30.
2,7,12,17-Tetramethyl-3,5:8,10:13,15:18,20-
tetrakis(2-methylpropano)porphyrin (26a). Pyrrole 17d
(2.40 g) in methanol (4.5 mL) was added to a solution of
KOH (3.27 g) in water (10.9 mL) and methanol (10.9 mL),
and the mixture refluxed for 2 h on a hot water bath. The
mixture was cooled to 0 8C in an ice-salt bath and carefully
neutralized with 6 M HCl, while maintaining a temperature
below 5 8C. The mixture was extracted with chloroform, dried
over magnesium sulfate and the solvent evaporated under
reduced pressure while maintaining the temperature below
30 8C. Acetic acid (7.6 mL) and potassium ferricyanide
(0.185 g) were added to the residual solid, and the mixture
was heated on a boiling water bath for 1 h. The mixture was
partitioned between dichloromethane and water, and the
organic phase washed with water, 5% aqueous ammonia
solution and water, and dried over anhydrous sodium sulfate.
The solvent was removed under reduced pressure and the
residue chromatographed on grade III alumina eluting with
dichloromethane. The red fractions were combined, evapor-
ated under reduced pressure and rechromatographed on grade
III alumina eluting with toluene. The fractions containing
porphyrin were evaporated and recrystallized from dichloro-
methane–methanol to give deep purple crystals (131 mg;
10.4%), mp O300 8C; UV–vis (CHCl3): lmax (log10 3)
419 (5.29), 518 (4.12), 550 (3.61), 591 (3.62),
647 nm (3.43); 1H NMR (CDCl3): d K2.78 (2H, br s), 1.38–
1.72 (12H, m), 2.14–2.97 (4H, m), 3.43 (12H, s), 3.13–3.98
(8H, m), 4.25–5.29 (8H, m); FABMS: m/z (rel int.) 583 (100)
[MCH]C.
4.2.29. 13,17-Diethyl-2,8,12,18-tetramethyl-3,5-(3,3-
dimethylpropano)porphyrin (13d). Dipyrrole tert-butyl
ester 23d (250 mg) was dissolved in trifluoroacetic acid
(9.5 mL) and allowed to stir for 15 min. The mixture was
diluted with dichloromethane (40 mL) and washed with
water (95 mL), 5% sodium bicarbonate solution (95 mL)
and water (95 mL), and dried over anhydrous potassium
carbonate. The solvent was removed under reduced pressure
keeping the temperature below 40 8C. The residue was
dissolved in dichloromethane (25 mL) and diformyl-
dipyrrylmethane 24 (185 mg) was added. A solution of
p-toluenesulfonic acid (185 mg) in methanol (3.5 mL) was
added in one portion and the mixture allowed to stir in the
dark overnight. A saturated solution of zinc acetate in
methanol (3.6 mL) was added and the mixture was again
allowed to stir in the dark overnight. The solution was
washed with water, 5% HCl, 5% aqueous ammonia and
water, and dried over anhydrous sodium sulfate. The solvent
was removed under reduced pressure and the residue was
chromatographed on alumina eluting with dichloromethane.
The fractions containing porphyrin were evaporated and
recrystallized from dichloromethane–methanol to give deep
purple crystals (32 mg; 10%), mp 281–282 8C. Alterna-
tively, following deprotection of the tert-butyl ester 23d, the
conditions described in method B for 13a gave porphyrin
13d in 28% yield. UV–vis (1% Et3N–CHCl3): lmax (log10 3)
405 (5.05), 504 (4.02), 539 (3.69), 573 (3.72), 625 nm
(3.48); UV–vis (1% TFA–CHCl3): lmax (log10 3) 392 (sh,
4.70), 412 (5.33), 555 (4.13), 601 nm (3.90); 1H NMR
(CDCl3): d K3.28 (1H, br s), K3.15 (1H, br s), 1.85 (3H, t,
JZ7.8 Hz), 1.86 (3H, t, JZ7.6 Hz), 2.50 (6H, s), 2.72 (2H,
t, JZ6.4 Hz), 3.56 (3H, s), 3.60 (3H, s), 3.61 (3H, s), 3.74
(3H, s), 3.86 (2H, t, JZ6.2 Hz), 4.00–4.08 (4H, two
overlapping quartets), 9.47 (1H, s), 9.88 (1H, s), 10.00
4.2.31.
2,7,12,17-Tetramethyl-3,5:8,10:13,15:18,20-
tetrakis(2-tert-butylpropano)porphyrin (26b). Prepared
by the previous procedure from 17e (2.40 g). The title
porphyrin (35 mg; 2.5%) was obtained as deep purple crystals,
mp O300 8C; UV–vis (CHCl3): lmax (log10 3) 419 (5.29), 518
(4.12), 550 (3.61), 591 (3.62), 647 nm (3.43); lmax (log10 3)
418 (5.36), 518 (4.16), 552 (3.66), 591 (3.66), 647 nm (3.60);
1H NMR (CDCl3): d K2.94 (1H, br s), K2.82 (1H, br s),
1.34–1.48 (36H, m), 2.14–2.96 (4H, m), 3.16–4.21 (20H, m),
4.35–4.66 (4H, m), 5.09–5.51 (4H, m); FABMS: m/z (rel int.)
751 (100) [MCH]C, 693 (27).
4.2.32. 2,7,12,17-Tetramethyl-3,5:8,10:13,15:18,20-
tetrakis(2,2-dimethylpropano)-porphyrin (26c). The
title porphyrin was obtained from 17b in 8% yield as deep
purple crystals, mp O300 8C; UV–vis (CHCl3): lmax
(log10 3) 422 (5.33), 520 (4.20), 552 (3.83), 592 (3.88),
646 nm (3.79); UV–vis (1% TFA–CHCl3): lmax (log10 3)
430 (5.43), 584 (4.00), 634 nm (4.19); 1H NMR
1
(1H, s), 10.07 (1H, s); H NMR (TFA–CDCl3): d K3.42

C. M. Shiner, T. D. Lash / Tetrahedron 61 (2005) 11628–11640
11639
Wolff, G. A.; Chicarelli, M. I.; Shaw, G. J.; Evershed, R. P.;
Quirke, J. M. E.; Maxwell, J. R. Tetrahedron 1984, 40, 3777.
4. (a) Callot, H. J.; Ocampo, R.; Albrecht, P. Energy Fuels 1990,
4, 635. (b) Verne-Mismer, J.; Ocampo, R.; Bauder, C.; Callot,
H. J.; Albrecht, P. Energy Fuels 1990, 4, 639. (c) Keely, B. J.;
Prowse, W. G.; Maxwell, J. R. Energy Fuels 1990, 4, 628. (d)
Eckardt, C. B.; Keely, B. J.; Waring, J. R.; Chicarelli, M. I.;
Maxwell, J. R. Philos. Trans. R. Soc. London, Ser. B 1991,
333, 339. (e) Ocampo, R.; Bauder, C.; Callot, H. J.; Albrecht,
P. Geochim. Cosmochim. Acta 1992, 56, 745.
(TFA–CDCl3; 17 8C): d K2.47 (4H, s), 1.12 (24H, br s),
3.34 (12H, s), 3.54 (8H, br s), 4.77 (8H, s); 13C NMR
(TFA–CDCl3): d 14.6, 28.6 (br), 36.1, 37.5, 44.7, 115.3,
133.3, 138.2, 139.2, 141.6; EIMS: m/z (rel int.) 638 (100),
637 (23), 636 (38), 621 (25); HRMS: Calcd for C44H54N4:
638.4322. Found: 638.4325.
4.2.33. 2,7,12,17-Tetraethyl-3,5:8,10:13,15:18,20-tetra-
kis(2,2-dimethylpropano)porphyrin (26d). The title
porphyrin was obtained from 17c in 6% yield as deep
purple crystals, mp O300 8C; UV–vis (1% Et3N–CHCl3):
lmax (log10 3) 425 (5.34), 523 (4.21), 558 (3.81), 597 (3.80),
654 nm (3.64); UV–vis (1% TFA–CHCl3): lmax (log10 3)
432 (5.46), 588 (4.08), 638 nm (4.34); 1H NMR
(TFA–CDCl3; 45 8C): d K2.14 (4H, s), 1.10 (24H, br s),
1.63 (12H, t, JZ7.5 Hz), 3.51 (8H, br s), 3.73 (8H, q,
JZ7.5 Hz), 4.78 (8H, br s); 13C NMR (TFA–CDCl3): d
15.6, 21.2, 28.5 (v br), 36.1, 37.3, 44.2, 115.4, 138.6, 139.3,
139.7, 140.9; EIMS: m/z (rel int.) 694 (100), 693 (8), 692
(10), 677 (3); HRMS: Calcd for C48H62N4: 694.4974.
Found: 694.4975.
5. For meso,b-butanoporphyrins 3, see: Wolff, G. A.; Murray,
M.; Maxwell, J. R.; Hunter, B. K.; Sander, J. K. M. J. Chem.
Soc., Chem. Commun. 1983, 922. Fookes, C. J. R. J. Chem.
Soc., Chem. Commun. 1983, 1474.
6. (a) Ocampo, R.; Callot, H. J.; Albrecht, P. J. Chem. Soc.,
Chem. Commun. 1985, 200. (b) Gibbison, R.; Peakman, T. M.;
Maxwell, J. R. Tetrahedron Lett. 1995, 46, 9057.
7. Barwise, A. J. G. In Metal Complexes in Fossil Fuels.
Geochemistry, Characterization, and Processing; Filby, R. H.,
Branthaver, J. F., Eds.; American Chemical Society:
Washington, DC, 1987; pp 100–109.
´
´
8. Cantu, R.; Stencel, J. R.; Czernuszewicz, R. S.; Jaffe, P. R.;
Lash, T. D. Environ. Sci. Technol. 2000, 34, 192.
9. For the isolation and characterization of methylpropano-
porphyrins 2a and 2b, see: Chicarelli, M. I.; Wolff, G. A.;
Murray, M.; Maxwell, J. R. Tetrahedron 1984, 40, 4033.
10. The free bases of methylpropanoporphyrins 2a and 2b were
reported to be racemic modifications. In addition, the vanadyl
complex of 2a has been shown to be present in the Serpiano
Oil Shale as a mixture of diastereomers: Boreham, C. J.;
Clezy, P. S.; Robertson, G. B. Energy Fuels 1990, 4, 661.
11. Prowse, W. G.; Maxwell, J. R. Geochim. Cosmochim. Acta
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Acknowledgements
This work was supported by the National Science
Foundation under Grant no. CHE-0134472, and the
Petroleum Research Fund, administered by the American
Chemical Society.
12. Lash, T. D. In Moody, C. J., Ed.; Advances in Nitrogen
Heterocycles; JAI Press, 1995; Vol. 1, pp 19–51.
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