Oxidation of 2-methylpyrroles with perchlorinated iron(III) metalloporphyrin catalysts: A versatile synthesis of symmetric and asymmetric dipyrromethanes

Article abstract of DOI:10.1139/v98-190

Abstract: A variety of substituted 2-methylpyrroles (3-8) were oxidized using the metalloporphyrin catalysts iron(III) meso-tetra(2,6-dichloro-3- sulphonatophenyl)-β-octachloroporphyrin chloride 1 and iron(III) meso- tetra(2,6-dichlorophenyl)-β-octachloro

Full text of DOI:10.1139/v98-190

Color profile: Disabled
Composite Default screen
1467
Oxidation of 2-methylpyrroles with
perchlorinated iron(III) metalloporphyrin
catalysts: a versatile synthesis of symmetric and
asymmetric dipyrromethanes
Veranja Karunaratne and David Dolphin
Abstract: A variety of substituted 2-methylpyrroles (3–8) were oxidized using the metalloporphyrin catalysts iron(III)
meso-tetra(2,6-dichloro-3-sulphonatophenyl)-β-octachloroporphyrin chloride 1 and iron(III) meso-tetra(2,6-dichlorophenyl)-
β-octachloroporphyrin chloride 2 under very mild conditions. Treatment of the resulting allylic alcohols 3a–8a with
α-free pyrroles 9 and 10 resulted in a very efficient synthesis of the corresponding dipyrromethanes 3b–8b and 3c–8c.
Furthermore, the above allylic alcohols when treated with furfurylamine produced the novel (2-furylmethyl)-2-
pyrrolylmethylamines 3d–8d.
Key words: catalytic oxidation, metalloporphyrins, pyrroles, dipyrromethanes, polyhalogenated porphyrins.
Résumé : Opérant dans des conditions très douces, on a oxydé divers 2-méthylpyrroles substitués (3–8) à l’aide de
catalyseurs métalloporphyrines, le chlorure de la méso-tétra(2,6-dichloro-3-sulfonatophényl)-β-octachloroporphyrine
fer(III), 1 et le chlorure de la méso-tétra(2,6-dichlorophényl)-β-octachloroporphyrine fer(III), 2. Le traitement des
alcools allyliques obtenus (3a–8a) avec les pyrroles 9 et 10 dont les positions α sont libres permet de réaliser une
synthèse très efficace des dipyrrométhanes correspondants, 3b–8b et 3c–8c. De plus, la réaction de ces alcools
allyliques avec de la furfurylamine conduit à de nouvelles (2-furfurylméthyl)-2-pyrrolylméthylamines 3d–8d.
Mots clés : oxydation catalytique, métalloporphyrines, pyrroles, dipyrrométhanes, porphyrines polyhalogénées.
[Traduit par la Rédaction] Karunaratne and Dolphin 1473
Some of the most interesting and widely studied heme
proteins are cytochromes P-450 (1). Activation of dioxygen
by such monooxygenase enzymes involves insertion of one
of the atoms of O2 into the organic substrate while the other
is reduced to water in the presence of an electron donor.
Studies to unravel the cytochrome P-450 monooxygenase
activity are complicated by the protein. Since much of the
oxidation chemistry occurs at the iron porphyrin, in vitro
biomimetic studies have been focused on synthetic metal-
loporphyrins. As such, meso-tetraphenylporphyrins (2),
which are readily synthesized, are commonly used as mim-
ics of the natural systems.
In 1979, Groves et al. (3) first reported the cytochrome P-
450 monooxygenase-like activity in a model system using
iron(III) meso-tetraphenylporphyrin and iodosylbenzene
(PhIO) as a co-oxidant. Several other metalloporphyrins were
also shown to catalyze both alkene epoxidations (4) and
hydroxylation of unactivated hydrocarbons (1, 5) mimicking
the natural system. However, the utility of these catalysts in
organic synthesis has been limited. While the first-generation
H
R
H
Cl
Cl
X
X
X
X
Cl
H
R
Cl
N
N
N
N
H
H
Cl
X
R
Cl
X
H
X
X
Cl
H
Cl
R
Received February 27, 1998.
V. Karunaratne and D. Dolphin.1 Department of Chemistry,
University of British Columbia, 2036 Main Mall, Vancouver,
BC V6T 1Z1, Canada.
H
1 R = SO3H
2 R = H
2a R = H
X = Cl
X = Cl
X = Br
1Author to whom correspondence may be addressed.
Telephone: (604) 822-4571. Fax: (604) 822-9678.
E-mail: david@dolphin.chem.ubc.ca
Can. J. Chem. 76: 1467–1473 (1998)
© 1998 NRC Canada
I:\cjc\cjc76\cjc-10\OctCHEM-D.vp
Wednesday, January 06, 1999 10:03:51 AM

Color profile: Disabled
Composite Default screen
1468
Can. J. Chem. Vol. 76, 1998
Scheme 1.
catalysts qualitatively exhibited cytochrome P-450 reactions,
loporphyrin and the co-oxidant.
their catalytic activity was rapidly lost by destruction of the
metalloporphyrin. Firstly, these catalysts were improved by
introduction of halogens at the ortho-positions of the phenyl
groups (6). Halogenation imparts steric protection and elec-
tronic activation of the metalloporphyrin. Secondly, further
halogenation of the β-positions has given the full benefit of
such a dual effect, producing more robust catalysts with ad-
ditional resistance to oxidative catalyst destruction (7). For
example, Mansuy and Battioni (8) have shown that when
iron(III) meso-tetra(2,6-dichlorophenyl)-β-octachloroporphyrin
chloride (2) (ClFeTPPCl8βCl8) and the corresponding β-
octabromo substituted porphyrin catalyst, iron(III) meso-
tetra(2,6-dichlorophenyl)-β-octabromoporphyrin chloride (2a)
(ClFeTPPBr8βBr8), were used in the hydroxylation of hep-
tane the total yield of heptanols produced was increased.
Furthermore, the polyhalometalloporphyrin catalysts showed
greater chemoselectivity for alkane hydroxylation over
alkene epoxidation. Such perhalogenated metalloporphyrins
can be rendered water soluble by sulphonation of the meta-
positions of the phenyl ring (9). All of the available evi-
dence from model studies suggest the OϭFeIVPor+·
(porphyrin π-cation radical) (9) formulation for the oxidiz-
ing intermediate, although the exact nature of this high-
valent oxo-metal complex will depend on both the metal-
In continuation of our efforts in the area of polyhalo-
porphyrin catalysts (10), we report herein a straightforward
and efficient oxidation of substituted 2-methylpyrroles (for a
preliminary account of the work described see ref. 11) using
both iron(III) meso-tetra(2,6-dichloro-3-sulphonatophenyl)-
β-octachloroporphyrin chloride (1) (ClFeTPPCl8S4βCl8) and
iron(III) meso-tetra(2,6-dichlorophenyl)-β-octachloroporphyrin
chloride (2) (ClFeTPPCl8βCl8).
Specifically, when a cold (0°C) solution of 2-methyl-
pyrrole (3, 0.2 mmol) in 3 mL of HCl–CH3CN (1:1 v͞v)
containing a catalytic amount of the catalyst 1 (0.0009 mmol)
in the presence of PhIO (1 equiv.) was allowed to react for
10 min, the crude allylic alcohol 3a was obtained (Scheme 1).
1
The H NMR spectrum of crude 3a was clean with no trace
of starting material and showed a singlet (2H) at δ 4.58 cor-
responding to the allylic methylene group. The 1H NMR and
the high resolution mass spectra of 3a were in full accord
with the assigned structure. Purification of this compound
was not attempted due to its known instability. Furthermore,
its IR spectrum exhibited an absorption at 3300 cm–1 due to
the allylic alcohol moiety while the low-resolution mass
spectrum gave a peak at m͞z 225 (M+ – H2O). Importantly,
compound 3a underwent coupling to the α-free pyrrole, 2-
benzyloxycarbonyl-3,4-dimethylpyrrole (9) under very mild
© 1998 NRC Canada
I:\cjc\cjc76\cjc-10\OctCHEM-D.vp
Wednesday, January 06, 1999 10:03:58 AM

Color profile: Disabled
Composite Default screen
Karunaratne and Dolphin
Scheme 2.
1469
R2
R1
N
H
3-7
O
NH
RO2C
3d-7d
conditions (CH2Cl2, rt) to provide the dipyrromethane 3b in
42% yield (from 3). In a similar fashion pyrroles 4–8 were
oxidized and coupled as before to provide the dipyr-
romethanes 4b–8b. In a control experiment, a solution
(HCl–CH3CN, 1:1 v͞v) of pyrrole 3 was treated with PhIO
in the absence of the catalyst 1, and the resulting crude mix-
ture was treated with 2-benzyloxycarbonyl-3,4-dimethyl-
pyrrole. The yield of the dipyrromethane 3b isolated varied
between 5–15%. Upon further investigation of the effect of
PhIO alone on several other 2-methylpyrroles, it became ev-
ident that the yields of the dipyrromethanes produced were
without exception substantially lower than in the presence of
the catalyst. Interestingly, the HCl–CH3CN combination was
found to be crucial for the effective oxidation of the sub-
strates. For example, the oxidation in the H2O–CH3CN me-
dium was very sluggish, clearly indicating the necessity of
an acidic medium for the success of the reaction.
In contrast to Pb(OAc)4 which is the only other reliable
oxidant of 2-methylpyrroles, the ease of oxidation with both
catalysts 1 and 2 stands out as a clear advantage. Further-
more, the sequence of Pb(OAc)4 oxidation(HOAc, Ac2O,
80°C, 24h) followed by dipyrromethane formation (conc.
HCl, reflux) employs considerably harsher conditions and
longer reaction times and leads only to symmetric dipyr-
romethanes. To assess the coupling ability of 2-acetoxypyr-
roles with an α-free pyrrole under our reaction conditions, 2-
acetoxymethyl-5-benzyloxycarbonyl-3-ethyl-4-methylpyrrole
was treated overnight at room temperature with 2-benzyl-
1
oxycarbonyl-3,5-dimethylpyrrole in CH2Cl2. The H NMR
spectrum of the crude reaction mixture indicated only 15%
conversion to the dipyrromethane 4b. On the other hand, di-
rect generation of allylic alcohols by our method allows
ready manipulation of pyrrole units with diverse substitution
patterns and facile generation of synthetically and bio-
synthetically important dipyrromethane units.
Next, we turned our attention to the utilization of catalyst
2 in the same oxidation reaction. More explicitly, when a
TFA–CH2Cl2 (1:9) solution of pyrrole 3 (0.194 mmol) was
treated with the catalyst 2 (0.0015 mmol) and PhIO
(1 equiv.), oxidation of the 2-methyl group occurred within
5 min. As was the case with the catalyst 1, an acidic medium
was also found to be necessary for clean and effective oxida-
tion with the catalyst 2. Neither p-toluenesulphonic acid nor
acetic acid were suitable for this purpose, presumably due to
the acids themselves undergoing oxidation along with the
substrates. However, trifluoroacetic acid proved to be an ex-
cellent reagent. Thus, addition of 2-benzyloxycarbonyl-3,4-
dimethylpyrrole (9) into the same reaction mixture resulted
in an in situ coupling to provide (after neutralization of the
mixture with NaHCO3 followed by chromatography) the
corresponding dipyrromethane 3b in 62% yield. In a differ-
ent run, when 2-ethoxycarbonyl-4-ethyl-3-methylpyrrole
(10) was added to the reaction mixture obtained after the ini-
tial oxidation, the dipyrromethane 3c was obtained in 60%
yield. In a similar fashion, the dipyrromethanes 4c–8c were
prepared from pyrroles 4–8. Thus, by using the appropriate
monopyrrole unit it is possible to synthesize 1,9-dioxycarbo-
nyldipyrromethanes with either symmetric (8b, 3c, 6c) or
asymmetric (3b–7b, 4c, 5c, 7c, 8c) substitution patterns. To
the best of our knowledge, this is the first report of a one-pot
synthesis of dipyrromethanes starting from the correspond-
ing monopyrrole units. Catalyst 1, due its insolubility in or-
ganic solvents, is not suitable for use under these conditions.
On the other hand, when the same one-pot procedure was at-
tempted with catalyst 1 in aqueous acidic medium (HCl–
CH3CN), the reaction was less clean, and the yields of the
dipyrromethanes obtained were substantially lower than with
catalyst 2.
As a further example of the applicability of our oxidation
protocol, the reaction of allylic alcohols (3a–7a) with furfur-
ylamine was examined. Thus, when a solution of compound
3a in CH2Cl2 was allowed to react with an excess of furfury-
lamine, the novel (2-furylmethyl)-2-pyrrolylmethylamine (3d)
was obtained in 36% yield (from 3). Similarly, the furan de-
rivatives 4d–7d were prepared from their corresponding al-
lylic alcohols (Scheme 2).
Aromatic macrocyclic molecules capable of absorbing in
the far red or near infrared region are now finding applica-
tions in biomedical research, specifically as photosensitizers
for use in photodynamic therapy (PDT) of hyperproliferative
diseases such as cancer and psoriasis (12, 13). Substituted
dipyrromethanes which are functionalized with 1,9-diester
groups are precursors in the preparation of the correspond-
ing 1,9-dicyanodipyrromethanes (14). These dicyano com-
pounds have been successfully employed in the synthesis of
porphocyanins, a new class of expanded porphyrins (15, 16).
These compounds due to their long wavelength absorptions
in the visible-near infrared region, and their ability to make
singlet oxygen makes them potential candidates for PDT.
Thus, the methodology described above provides access to a
large library of symmetrical and unsymmetrical 1,9-diacyldi-
pyrromethanes as key intermediates in the synthesis of
porphocyanins and other polypyrrolic macrocyclic systems.
Proton nuclear magnetic resonance (1H NMR) spectra
were obtained from samples dissolved in CDCl3 on a Bruker
AC-200 (200 MHz) or a Bruker WH-400 (400 MHz). Low-
and high-resolution electron impact (EI) mass spectra were
© 1998 NRC Canada
I:\cjc\cjc76\cjc-10\OctCHEM-D.vp
Wednesday, January 06, 1999 10:04:00 AM

Color profile: Disabled
Composite Default screen
1470
Can. J. Chem. Vol. 76, 1998
recorded on a Kratos͞AEI MS-902 spectrometer. Micro-
lyst 1 (0.0015 g, 0.0009 mmol). The crude material isolated
exhibited H NMR (200 MHz), δ: 1.10 (t, 3H, J = 7.5 Hz),
2.30 (s, 3H), 2.44 (q, 2H, J = 7.5 Hz), 4.58 (s, 2H), 5.30 (s,
2H), 7.20–7.41 (m, 5H), 9.00 (br s, 1H); LREIMS (m͞z):
255 (M+ – 18).
1
analyses was carried out using a Carlo Erba Elemental Ana-
lyzer 1106. Flash chromatography was performed on silica
gel 60 (70–230 mesh supplied by E. Merck Co.). All chemi-
cal and solvents were reagent grade.
Oxidation of 2-methylpyrroles with
2-[(5-Benzyloxycarbonyl-3,4-dimethylpyrrole-2-
yl)methyl]-5′-benzyloxycarbonyl-3′-ethyl-4′-methylpyrrole
(3b)
PhIO ClFeTPPCl8S4βCl8 (1). General procedure A
To a cold (0°C) solution of the pyrrole in CH3CN – 3 N
HCl (1:1, v͞v, 2.5 mL͞mmol) was added the catalyst 1
(0.0009 mmol) in one portion. To the resulting light yellow–
brown solution was added PhIO (1 equiv.) in one portion.
After stirring the resulting mixture (all of the PhIO dissolves
rapidly) at 0°C for 10 min, CH2Cl2 (10 mL͞mmol) was
added followed by water (5 mL͞mmol). The layers were
separated, and the organic layer was dried (MgSO4) and
evaporated to provide the corresponding allylic alcohol as a
yellow oily substance which was used immediately in the
next step.
The crude material obtained from the above reaction was
treated with the pyrrole (general procedure B) to provide the
crude dipyrromethane 3a. This material was flash chroma-
tographed on silica gel (1 g, CH2Cl2) to provide the pure
compound (0.039 g, 42% from pyrrole 3) as a pale white
1
solid which exhibited H NMR (400 MHz), δ: 1.04 (t, 3H, J
= 8 Hz), 1.95 (s, 3H), 2.24 (s, 3H), 2.29 (s, 3H), 2.40 (q, 2H,
J = 8 Hz), 3.80 (s, 2H), 5.25 (s, 4H), 7.23–7.45 (m, 10H),
8.95, 8.97 (pair of overlapping s, 1H each). Exact mass
calcd. for C30H32O4N2: 484.2362; found: 484.2359.
Coupling of 2-benzyloxycarbonyl-3,4-dimethyl pyrrole
with the allylic alcohols 3a–8a. General procedure B
To a solution of the allylic alcohol obtained in the above
reaction in CH2Cl2 (2 mL͞mmol) was added 2-benzyloxy-
carbonyl-3,4-dimethylpyrrole (9) or 2-ethoxycarbonyl-4-
ethyl-3-methylpyrrole (10) (1.5 equiv.) The resulting mix-
ture was stirred at rt for 3 h. The solvent was evaporated,
and the resulting yellow oil was subjected to column chro-
matography on silica gel to afford the pure dipyrromethane.
Allylic alcohol 4a
This material was prepared according to the general pro-
cedure A, by treatment of the pyrrole 4 (0.05 g, 0.158 mmol)
with PhIO (0.34 g, 0.158 mmol) and the catalyst 1
(0.0015 g, 0.0009 mmol). The crude substance 4a obtained
1
showed H NMR (200 MHz), δ: 2.29 (s, 3H), 2.50 (t, 2H, J
= 6 Hz), 2.78 (t, 2H, J = 6 Hz), 3.68 (s, 3H), 4.63 (s, 2H),
5.30 (s, 2H), 7.22–7.43 (m, 5H), 8.98 (br s, 1H); LRFABMS
(m͞z): 314 (M+ – H2O + H).
Preparation of 2(furylmethyl)-2-pyrrolylmethylamines
3c–7c. General procedure C
2-[(5-Benzyloxycarbonyl-3,4-dimethylpyrrole-2-
yl)methyl]-5′-benzyloxycarbonyl-3′(carbomethoxyeth-2-
yl)-4′-methylpyrrole 4b
To a solution of the crude allylic alcohol (obtained in the
general procedure A) in CH2Cl2 (3 mL͞mmol) was added
furfurylamine (3 mmol) in one portion. The resultant solu-
tion was stirred at rt for 6 h. Evaporation of the solvent
afforded the crude product as a yellow oil. Flash chromatog-
raphy of the crude material on silica gel afforded the pure
2(furylmethyl)-2-pyrrolylmethylamines.
The crude material obtained from the above reaction was
treated with 2-benzyloxycarbonyl-3,4-dimethylpyrrole (9)
(general procedure B) to provide the crude dipyrromethane
4b. This material was flash chromatographed on silica gel
(1 g, CH2Cl2͞EtOAc, 95:5) to provide the pure compound
1
(0.033 g, 38% from pyrrole 5) as a white solid ; H NMR
(400 MHz), δ: 2.00 (s, 3H), 2.25 (s, 3H), 2.27 (s, 3H), 2.45
(t, 2H, J = 7.5 Hz), 2.72 (t, 2H, J = 7.5 Hz), 3.57 (s, 3H),
3.90 (s, 2H), 5.25 (s, 2H), 5.27 (s, 2H), 7.27–7.40 (m, 10H),
8.55 (s, 1H), 9.08 (s, 1H). Exact mass calcd. for
C32H34O6N2: 542.2417; found: 542.2427.
Oxidation of 2-methylpyrroles with
PhIO ClFeTPPCl8βCl8 (2). One-pot synthesis of
dipyrromethanes. General procedure D
To a cold (0°C) solution of the pyrrole in CH2Cl2–TFA
(9:1, v͞v, 1.5 mL͞mmol) containing the catalyst
2
(0.0009 mmol) was added PhIO (1 equiv.) in one portion.
After ~5 min (when all the solids had dissolved) was added
the appropriate α-free pyrrole (1.5 equiv.). The slightly red-
dish-orange solution obtained was stirred at 0°C for 1.5 h.
Water (5 mL͞mmol) was added and the layers were sepa-
rated. The organic phase was washed with saturated
NaHCO3 until the aqueous phase was basic to litmus. The
organic layer was separated, dried (MgSO4), and evaporated
to afford the crude dipyrromethane as a yellow oil. The
crude material was separated by flash chromatography on
silica gel to afford the pure dipyrromethane.
Allylic alcohol 5a
This compound was obtained according to the procedure
A, by treatment of the pyrrole 5 (0.05 g, 0.146 mmol) with
PhIO (0.032 g, 0.146 mmol) and the catalyst 1 (0.0015 g,
0.0009 mmol). The crude material exhibited 1H NMR
(200 MHz), δ: 0.89 (br t, 3H, J = ~7 Hz), 1.40–1.50 (m,
10H), 2.30 (s, 3H), 2.40 (t, 2H, J = 8 Hz), 4.50 (s, 2H), 5.30
(s, 2H), 7.20–7.50 (m, 5H), 9.30 (br s, 1H); LREIMS (m͞e):
339 (M+ – 18).
2-[(5-Benzyloxycarbonyl-3,4-dimethylpyrrole-2-
yl)methyl]-5′-benzyloxycarbonyl-3′-octyl-4′-methylpyrrole
(5b)
Allylic alcohol 3a
The pyrrole 3 (0.05 g, 0.193 mmol) was converted into
the allylic alcohol 3a according to the general procedure A,
by treatment with PhIO (0.042 g, 0.193 mmol) and the cata-
The crude material obtained from the above reaction was
treated with 2-benzyloxycarbonyl-3,4-dimethylpyrrole (9)
(general procedure B) to provide the crude dipyrromethane
© 1998 NRC Canada
I:\cjc\cjc76\cjc-10\OctCHEM-D.vp
Wednesday, January 06, 1999 10:04:02 AM

Color profile: Disabled
Composite Default screen
Karunaratne and Dolphin
1471
5b. This material was flash chromatographed on silica gel
Allylic alcohol 8a
(1 g, CH2Cl2) to provide the pure compound (0.033 g, 40%
This substance was prepared according to the procedure
A, by treatment of the pyrrole (0.05 g, 0.276 mmol) with
PhIO (0.06 g, 0.276 mmol) and the catalyst 1 (0.0015 g,
1
from pyrrole 5) as a white solid; H NMR (400 MHz), δ:
0.87 (t, 3H, J = 8 Hz), 1.10–1.40 (m, 10H), 1.93 (s, 3H),
2.25 (s, 3H), 2.27 (s, 3H), 2.33 (t, 2H, J = 8 Hz), 3.30 (s,
2H), 5.25 (s, 4H), 7.25–7.40 (m, 10H), 8.25, 8.28 (pair of
overlapping s, 1H each). Exact mass calcd. for C36H44O4N2:
568.3300; found: 568.3309.
0.0009 mmol). The crude material obtained exhibited
1H
NMR (200 MHz), δ: 1.25 (t, 3H, J = 8 Hz), 2.20 (s, 3H),
2.22 (s, 3H), 4.24 (q, 2H, J = 8 Hz), 4.40 (s, 2H), 8.83 (br s,
1H); LREIMS (m/e): 179 (M+ – 18).
2-[(5-Benzyloxycarbonyl-3,4-dimethylpyrrole-2-
Allylic alcohol 6a
yl)methyl]-5′-ethoxycarbonyl-3′,4′-dimethylpyrrole (8b)
The crude material obtained from the above reaction was
treated with the pyrrole (general procedure B) to provide the
crude dipyrromethane 8b. This material was flash chroma-
tographed on silica gel (1 g, CH2Cl2/EtOAc, 95:5) to pro-
vide the pure compound (0.029 g, 25% from pyrrole 8) as a
The pyrrole 6 (0.05 g, 0.256 mmol) was treated with PhIO
(0.056 g, 0.256 mmol) and the catalyst 1 (0.0015 g,
0.0009 mmol), according to the general procedure A, to
1
yield the crude compound; H NMR (200 MHz), δ: 1.00 (t,
3H, J = 8 Hz), 1.22 (t, 3H, J = 8 Hz), 2.00 (s, 3H), 2.40 (q,
2H, J = 8 Hz), 4.22 (q, 2H, J = 8 Hz), 4.45 (s, 2H), 8.80
(br s, 1H); LREIMS (m͞e): 193 (M+ – 18).
1
white solid; H NMR (400 MHz) δ: 1.31 (t, 3H, J = 8 Hz),
1.92 (s, 3H), 1.94 (s, 3H), 2.22 (s, 3H), 2.25 (s, 3H), 3.32 (s,
2H), 4.25 (q, 2H, J = 8 Hz), 5.25 (s, 2H), 7.30–7.41 (m, 5H),
8.65 (br s, 2H). Exact mass calcd. for C24H28O4N2:
408.2449; found: 408.2049. Anal. calcd. for C24H28O4N2: C
70.60, H 6.91, N 6.86; found: C 70.66, H 6.95, N 6.84.
2-[(5-Benzyloxycarbonyl-3,4-dimethylpyrrole-2-
yl)methyl]-5′-ethoxycarbonyl-3′-ethyl-4′-methylpyrrole
(6b)
The crude material obtained from the above reaction was
treated with 2-benzyloxycarbonyl-3,4-dimethylpyrrole (9)
(general procedure B) to provide the crude dipyrromethane
6b. This material was flash chromatographed on silica gel
(1 g, CH2Cl2͞EtOAc, 95:5) to provide the pure compound
2-(Furylmethyl)-2(5-benzyloxycarbonyl-3-ethyl-4-
methyl)pyrrolylmethylamine (3d)
The pyrrole 3 (0.05 g, 0.194 mmol) was transformed into
compound 3d by treatment with furfurylamine (0.05 g,
0.582 mmol) (general procedure C). The crude product was
purified by flash chromatography on silica gel (1 g, CH2Cl2)
and yielded the pure compound (0.025 g, 36% from pyrrole
1
(0.035 g, 32% from pyrrole 6) as a white solid; H NMR
(400 MHz), δ: 1.01 (t, 3H, J = 8 Hz), 1.29 (t, 3H, J = 8 Hz),
1.95 (s, 3H), 2.24 (s, 3H), 2.26 (s, 3H), 2.40 (q, 2H, J =
8 Hz), 3.32 (s, 2H), 4.22 (q, 2H, J = 8 Hz), 5.24 (s, 2H),
7.24–7.34 (m, 5H), 9.15, 9.17 (pair of overlapping s, 1H
each). Exact mass calcd. for C25H30O4N2: 422.2205; found:
422.2206. Anal. calcd. for C25H30O4N2: C 71.11, H 7.15, N
6.63; found: C 71.15, H 7.19, N 6.59.
1
3) as a colorless oil; H NMR (400 MHz) δ: 1.02 (t, 3H, J =
7.5 Hz), 2.29 (s, 3H), 2.36 (q, 2H, J = 7.5 Hz), 3.71 (s, 2H),
3.75 (s, 2H), 5.30 (s, 2H), 6.15 (d, 1H, J = -2 Hz), 6.31 (d,
1H, J = -2 Hz), 7.30–7.45 (m, 6H), 9.07 (br s, 1H). Exact
mass calcd. for C21H24O3N2: 352.1786; found: 352.1795.
2-(Furylmethyl)-2[5-benzyloxycarbonyl-
3(carbomethoxyeth-2-yl)]4-methyl)pyrroloylmethylamine
(4d)
Allylic alcohol 7a
This material was prepared according to the general pro-
cedure A, by treatment of the pyrrole 7 (0.05 g, 0.239 mmol)
with PhIO (0.052 g, 0.239 mmol) and the catalyst 1
(0.0015 g, 0.0009 mmol). The crude material obtained
The pyrrole 4 (0.05 g, 0.158 mmol) was transformed into
compound 4d by treatment with furfurylamine (0.045 g,
0.474 mmol) (general procedure C). The crude product, pu-
rified by flash chromatography on silica gel (1 g, CH2Cl2),
yielded the pure compound (0.21 g, 32% from pyrrole 4) as
1
showed H NMR (200 MHz), δ: 1.00–1.20 (two overlapped
q, 6H, J = 8 Hz each), 1.32 (t, 3H, J = 8 Hz), 2.41 (q, 2H, J
= 8 Hz), 2.68 (q, 2H, J = 8 Hz), 4.25 (q, 2H, J = 8 Hz), 4.60
(s, 2H), 9.00 (br s, 1H); LREIMS (m͞e): 207 (M+ – 18).
1
a colorless oil; H NMR (400 MHz), δ: 2.44 (s, 3H), 2.58 (t,
2H, J = 6.5 Hz), 2.85 (t, 2H, J = 6.5 Hz), 3.79 (s, 3H), 3.89
(s, 2H), 3.91 (s, 2H), 5.45 (s, 2H), 6.33 (d, 1H, J = -2 Hz),
6.74 (d, 1H, J = -2 Hz), 7.46–7.60 (m, 6H), 9.30 (br s, 1H).
Exact mass calcd. for C22H26O5N2: 410.1841; found:
410.1839. Anal. calcd. for C23H26O5N2: C 67.34, H 6.38, N
6.82; found: C 67.38, H 6.41, N 6.79.
2-[(5-Benzyloxycarbonyl-3,4-dimethylpyrrole-2-
yl)methyl]-5′-ethoxycarbonyl-3′,4′-diethylpyrrole (7b)
The crude material obtained from the above reaction was
treated with 2-benzyloxycarbonyl-3,4-dimethylpyrrole (9)
(general procedure B) to provide the crude dipyrromethane
7b. This material was flash chromatographed on silica gel
(1 g, CH2Cl2͞EtOAc, 95:5) to provide the pure compound
2-(Furylmethyl)-2-(5-benzyloxycarbonyl-4-methyl-3-
octyl) pyrrolylmethylamine (5d)
1
(0.036 g, 35% from pyrrole 7) as a white solid; H NMR
The pyrrole 5 (0.05 g, 0.146 mmol) was transformed into
compound 5d by treatment with furfurylamine (0.042 g,
0.438 mmol) (general procedure C). The crude product, pu-
rified by flash chromatography on silica gel (1 g, CH2Cl2),
yielded the pure compound (0.019 g, 30%) as a colorless oil;
1H NMR (400 MHz), δ: 0.79 (t, 3H, J = 7 Hz), 1.10–1.32
(m, 12H), 2.19 (s, 3H), 2.25 (t, 2H, J = 7 Hz), 3.63 (s, 2H),
(400 MHz), δ: 1.05 (t, 3H, J = 8 Hz), 1.14 (t, 3H, J = 8 Hz),
1.29 (t, 3H, J = 7.5 Hz), 1.95 (s, 3H), 2.25 (s, 3H), 2.41 (q,
2H, J = 8 Hz), 2.71 (q, 2H, J = 8 Hz), 3.34 (s, 2H), 4.25 (q,
2H, J = 7.5 Hz), 5.26 (s, 2H), 7.27–7.38 (m, 5H), 8.78 (br s,
2H). Exact mass calcd. for C26H32O4N2: 436.2362; found:
436.2371.
© 1998 NRC Canada
I:\cjc\cjc76\cjc-10\OctCHEM-D.vp
Wednesday, January 06, 1999 10:04:04 AM

Color profile: Disabled
Composite Default screen
1472
Can. J. Chem. Vol. 76, 1998
3.68 (s, 2H), 5.21 (s, 2H), 6.09 (d, 1H, J = -2 Hz), 6.23 (d,
1H, J = -2 Hz), 7.23–7.36 (m, 6H), 9.00 (br s, 1H). Exact
mass calcd. for C27H36O3N2: 436.2725; found: 436.2717.
7.5 Hz), 2.27 (s, 6H), 2.43 (partially buried t, 2H, J =
6.5 Hz), 2.46 (overlapping q, 2H, J = 7 Hz), 2.23 (q, 2H, J =
6.5), 3.67 (s, 3H), 3.91 (s, 2H), 4.25 (q, 2H, J = 7.5 Hz),
5.24 (s, 2H), 7.28–7.39 (m, 5H), 8.68 (br s, 1H), 9.08 (br s,
1H). Exact mass calcd. for C28H34O6N2: 294.5929; found:
494.5932. Anal. calcd. for C28H34O6N2: C 67.99, H 6.92, N
5.66; found: C 68.02, H 6.96, N 5.61.
2-(Furylmethyl)-2-(5-ethoxycarbonyl-3-ethyl-4-methyl)
pyrrolylmethylamine (6d)
The pyrrole 6 (0.05 g, 0.256 mmol) was transformed into
compound 6d by treatment with furfurylamine (0.074 g,
0.768 mmol) (general procedure C). The crude product puri-
fied by flash chromatography on silica gel (1 g, CH2Cl2)
yielded the pure compound (0.021 g, 28%) as a colorless oil;
1H NMR (400 MHz) δ: 1.03 (t, 3H, J = 7 Hz), 1.35 (t, 3H, J
= 7.5 Hz), 2.28 (s, 3H), 2.37 (q, 2H, J = 7 Hz), 3.22 (s, 2H),
3.28 (s, 2H), 4.29 (q, 2H, J = 7.5 Hz), 6.18 (d, 1H, J =
-2 Hz), 6.34 (d, 1H, J = -2, Hz), 7.39 (d, 1H, J = 1 Hz),
8.96 (br s, 1H). Exact mass calcd. for C16H22O3N2:
290.1630; found: 290.1659.
2-[(5-Benzyloxycarbonyl-4-methyl-3-octylylpyrrole-2-
yl)methyl]-5′-ethoxycarbonyl-3′-ethyl-4′-methylpyrrole
(5c)
The pyrrole 5 (0.05 g, 0.146 mmol) was converted into
the dipyrromethane 5c according to the general procedure D
by treatment with PhIO (0.032 g, 1 equiv.), the catalyst 2
(0.002 g, 0.0015 mmol) and 2-ethoxycarbonyl-4-ethyl-3-
methyl-pyrrole (10). Flash chromatography of the crude ma-
terial on silica gel (1 g, CH2Cl2/EtOAc 95:5) provided the
1
dipyrromethane (0.042 g, 55%) as a white solid; H NMR
2-(Furylmethyl)-2-(5-ethoxycarbonyl-3,4-diethyl)
pyrrolylmethylamine (7d)
(400 MHz), δ: 0.88 (t, 3H, J = 6.5 Hz), 1.03 (t, 3H, J =
7.5 Hz), 1.20–1.36 (m, 17H), 2.25 (s, 6H), 2.37 (t, 2H, J =
6.5 Hz), 3.83 (s, 2H), 4.24 (q, 2H, J = 7.5 Hz), 5.25 (s, 2H),
7.28–7.40 (m, 5H), 8.74, 8.80 (pair of overlapping s, 1H
each). Exact mass calcd. for C32H44O4N2: 520.3300; found:
520.3304.
The pyrrole 7 (0.05 g, 0.239 mmol) was transformed into
compound 7d by treatment with furfurylamine (0.069 g,
0.717 mmol) (general procedure C). The crude product was
purified by flash chromatography on silica gel (1 g, CH2Cl2)
and yielded the pure compound (0.023 g, 32%) as a color-
1
less oil; H NMR (400 MHz), δ: 1.21 (t, 3H, J = 7 Hz), 1.33
2-[(5-Ethoxycarbonyl-3-ethyl-4-methylpyrrole-2-
yl)methyl]-5′-ethoxycarbonyl-3′-ethyl-4′-methylpyrrole
(6c)
(t, 3H, J = 8 Hz), 1.53 (t, 3H, J = 7.5 Hz), 2.55 (q, 2H, J =
7 Hz), 2.90 (q, 2H, J = 8 Hz), 3.91 (s, 2H), 3.95 (s, 2H),
3.47 (q, 2H, J = 7.5 Hz), 6.37 (d, 1H, J = -2 Hz), 6.51 (d,
1H, J = 2. Hz), 7.58 (d, 1H, J = 1 Hz), 9.21 (br s, 1H). Exact
mass calcd. for C17H24O3N2: 304.1768; found: 304.1786.
Anal. calcd. for C17H24O3N2: C 67.12, H 7.94, N 9.20;
found: C 67.15, H 7.98, N 8.89.
The pyrrole 6 (0.05 g, 0.256 mmol) was converted into
the dipyrromethane 6c according to the general procedure D
by treatment with PhIO (0.056 g, 1 equiv.), the catalyst 1
(0.002 g, 0.0015 mmol) 3-ethoxycarbonyl-3-ethyl-4-methyl-
pyrrole (10). Flash chromatography of the crude material on
silica gel (1 g, CH2Cl2/EtOAc 95:5) provided the
1
2-[(5′-Ethoxycarbonyl-3′-ethyl-4′-methylpyrrole-2-yl)methyl-
5-benzyloxycarbonyl-3-ethyl-4-methylpyrrole (3c)
The pyrrole 3 (0.05 g, 0.194 mmol) was converted into
the dipyrromethane 3c according to the general D by treat-
ment with PhIO (0.42 g, 1 equiv.), the catalyst 2 (0.002 g,
0.0015 mmol), and 2-ethoxycarbonyl-4-ethyl-3-methyl-
pyrrole (10). Flash chromatography of the crude material on
silica gel (1 g, CH2Cl2/EtOAc 95:5) provided the dipyrro-
methane (0.05 g, 60%) as a pale white solid; 1H NMR
(400 MHz), δ: 1.02 (pair of overlapping t, 3H each, J =
-7 Hz each), 1.27 (t, 3H, J = 7.5 Hz), 2.25 (s, 3H), 2.26
(partially buried q, 2H, J = -7 Hz), 2.28 (s, 3H), 2.41 (q,
2H, J = 7 Hz), 3.84 (s, 2H), 4.20 (q, 2H, J = 7.5 Hz), 5.20
(s, 2H), 7.24–7.35 (m, 5H), 8.98, 9.00 (pair of overlapping s,
1H each). Exact mass calcd. for C26H32O4N2: 436.2362;
found: 436.2378.
dipyrromethane (0.042 g, 44%) as a white solid; H NMR
(400 MHz), δ: 1.04 (t, 6H, J = 8 Hz), 1.32 (t, 6H, J = 8 Hz),
2.28 (s, 6H), 2.41 (q, 4H, J = 8 Hz), 3.86 (s, 2H), 4.27 (q,
4H, J = 8 Hz), 8.61 (br s, 2H). Exact mass calcd. for
C21H30O4N2: 374.4842; found: 374.4851. Anal. calcd. for
C21H30O4N2: C 67.35, H 8.07; N 7.47; found: C 67.38, H
8.09, N 7.42.
2-[(5-Ethoxycarbonyl-3,4-diethylpyrrole-2-yl)methyl]-5′-
ethoxycarbonyl-3′-ethyl-4′-methylpyrrole (7c)
The pyrrole 7 (0.05 g, 0.293 mmol) was converted into
the dipyrromethane 7c according to the general procedure D
by treatment with PhIO (0.052 g, 1 equiv.), the catalyst 1
(0.002 g, 0.0015 mmol), and 2-ethoxycarbonyl-4-ethyl-3-
methyl-pyrrole (10). Flash chromatography of the crude ma-
terial on silica gel (1 g, CH2Cl2/EtOAc 95:5) provided the
1
dipyrromethane (0.048 g, 52%) as a white solid; H NMR
2-[(5-Benzyloxycarbonyl-3(carbomethoxyeth-2-yl)-4-
methylpyrrole-2-yl)methyl]-5′-ethoxycarbonyl-3′-ethyl-4′-
methylpyrrole (4c)
(400 MHz), δ: 1.02, 1.05 (pair of overlapping t, 3H, J =
-7 Hz each), 1.15 (t, 3H, J = 7.5 Hz), 1.30 (t, 6H, J = 8 Hz),
2.25 (s, 3H), 2.38–2.47 (m, 4H), 2.70 (q, 2H, J = 7.5 Hz),
3.78 (s, 2H), 4.24 (q, 4H, J = 8 Hz), 8.90 (br s, 2H). Exact
mass calcd. for C22H32O4N2: 388.2362; found: 388.2359.
The pyrrole 4 (0.05 g, 0.158 mmol) was converted into
the dipyrromethane 4c according to the general procedure D
by treatment with PhIO (0.34 g, 1 equiv.), catalyst 2
(0.002 g, 0.0015 mmol), and 2-ethoxycarbonyl-4-ethyl-3-
methyl-pyrrole (10). Flash chromatography of the crude ma-
terial on silica gel (1 g, CH2Cl2/EtOAc 90:10) provided the
2-[(5-Ethoxycarbonyl-3,4-dimethylpyrrole-2-yl)methyl]-
5′-ethoxycarbonyl-3′-ethyl-4′-methylpyrrole (8c)
The pyrrole 8 (0.05 g, 0.276 mmol) was converted into
the dipyrromethane 8c according to the general procedure D
by treatment with PhIO (0.060 g, 1 equiv.), the catalyst 1
1
dipyrromethane (0.038 g, 48%) as a white solid; H NMR
(400 MHz), δ: 1.05 (t, 3H, J = 7 Hz), 1.30 (t, 3H, J =
© 1998 NRC Canada
I:\cjc\cjc76\cjc-10\OctCHEM-D.vp
Wednesday, January 06, 1999 10:04:07 AM

Color profile: Disabled
Composite Default screen
Karunaratne and Dolphin
1473
(0.002 g, 0.0015 mmol) 2-ethoxycarbonyl-4-ethyl-3-methyl-
pyrrole (10). Flash chromatography of the crude material on
silica gel (1 g, CH2Cl2/EtOAc 95:5) provided the
gel (1 g, CH2Cl2/EtOAc, 95:5) was identical in all respects
to that prepared via the general procedure B.
1
dipyrromethane (0.039 g, 39%) as a white solid; H NMR
2-[(5-Benzyloxycarbonyl-3,4-dimethylpyrrole-2-
(400 MHz), δ: 1,05 (t, 3H, J = 7.5 Hz), 1.28 (br t, 6H, J =
-8 Hz), 1.96 (s, 3H), 2.23 (s, 3H), 2.27 (s, 3H), 2.40 (q, 2H,
J = 7.5 Hz), 3.87 (s, 2H), 4.22 (br q, 4H, J = -8 Hz),
9.11,9.15 (pair of overlapping s, 1H each). Exact mass
calcd. for C20H28O4N2: 360.2049; found: 360.2053. Anal.
calcd. for C20H28O4N2: C 66.68, H 7.83, 7.77; found: C
66.71, H 7.88, N 7.72.
yl)methyl]-5′-ethoxycarbonyl-3′,4′-dimethylpyrrole (8b)
This material was prepared from the pyrrole 8 (0.05 g,
0.276 mmol) according to the general procedure D. Pure 8b
(0.053 g, 47%) obtained after flash chromatography on silica
gel (1 g, CH2Cl2/EtOAc, 95:5) was identical in all respects
to that prepared via the general procedure B.
2-[(5-Benzyloxycarbonyl-3,4-dimethylpyrrole-2-
yl)methyl]-5′-benzyloxycarbonyl-3′-ethyl-4′-methylpyrrole
(3b)
This work was supported by the Natural Sciences and En-
gineering Research Council of Canada.
This material was prepared from the pyrrole 3 (0.05 g,
0.193 mmol) according to the general procedure D. Pure 3b
(0.058 g, 55%) obtained after flash chromatography on silica
gel (1 g, CH2Cl2) was identical in all respects to that pre-
pared via the general procedure B.
1. P.R. Ortiz de Montellano (Editor). Cytochrome P-450: struc-
ture, mechanism and biochemistry. 2nd ed. Plenum Press, New
York. 1995.
2. J.S. Lindsey, I.C. Schreimann, H.C. Hsu, D.C. Keanney, and
A.M. Marguerettuz. J. Am. Chem. Soc. 52, 827 (1987).
3. J.T. Groves, T.E. Nemo, and R.S. Myers. J. Am. Chem. Soc.
101, 1032 (1979).
4. H. Minoun. J. Mol. Catal. 7, 1 (1980); R.A. Sheldon. J. Mol.
Catal. 7, 107 (1980); K.B. Sharpless and T.R. Verhoeven.
Aldrichim. Acta, 12, 63 (1979); R.A. Sheldon and J.K. Kochi.
Metal catalyzed oxidations of organic compounds. Academic
Press, New York. 1981; K.A. Jorgensen. Chem. Rev. 89, 431
(1989).
2-[(5-Benzyloxycarbonyl-3,4-dimethylpyrrole-2-
yl)methyl]-5′-benzyloxycarbonyl-3′(carbomethoxyeth-2-
yl)-4′-methylpyrrole (4b)
This material was prepared from the pyrrole 4 (0.05 g,
0.158 mmol) according to the general procedure D. Pure 4b
(0.047 g, 62%) obtained after flash chromatography on silica
gel (1 g, CH2Cl2/EtOAc, 95:5) was identical in all respects
to that prepared via the general procedure B.
5. C.K. Chang and F. Ebina. J. Chem. Soc. Chem. Commun. 778
(1981).
6. P.S. Traylor, D. Dolphin, and T.G. Traylor. J. Chem. Soc.
Chem. Commun. 279 (1984).
7. T.P. Wijesekara, A. Matsumoto, and D. Dolphin. Angew.
Chem. Int. Ed. Engl. 29, 1028 (1990); T.G. Traylor and S.
Tsuchia. Inorg. Chem. 26, 1338 (1987).
8. D. Mansuy and P. Battioni. In Metalloporphyrins in catalytic
oxidations. Edited by R.A. Sheldon. Marcel Dekker, New
York. 1994. pp. 99–132.
9. T. Nakano, T.P. Wijesekera, D. Dolphin, T.K. Maion, T.K.
Kirk, and R.L. Farrel. U.S. Patent No. 4892241. 1989; L.
Barloy, J.P. Lallier, P. Battioni, D. Mansuy, Y. Piffard, M.
Tournoux, J.B. Valim, and W. Jones. New J. Chem. 61, 71
(1992).
10. D. Dolphin, T.G. Traylor, and L.Y. Xie. Acc. Chem. Res. 251
(1997).
11. V. Karunaratne and D. Dolphin, J. Chem. Soc. Chem.
Commun. 2105 (1995).
12. R. Bonnet. Chem. Soc. Rev. 19 (1995).
13. (a) E. Sternberg, C. Bruckner, and D. Dolphin. Tet. Rep. 54,
4151 (1998); (b) E. Sternberg and D. Dolphin. Curr. Med.
Chem. 3, 293 (1996).
2-[(5-Benzyloxycarbonyl-3,4-dimethylpyrrole-2-
yl)methyl]-5′-benzyloxycarbonyl-3′-octyl-4′-methylpyrrole
(5b)
This material was prepared from the pyrrole 5 (0.05 g,
0.146 mmol) according to the general procedure D. Pure 5b
(0.042 g, 62%) obtained after flash chromatography on silica
gel (1 g, CH2Cl2) was identical in all respects to that pre-
pared via the general procedure B.
2-[(5-Benzyloxycarbonyl-3,4-dimethylpyrrole-2-
yl)methyl]-5′-Ethoxycarbonyl-3′-ethyl-4′-methylpyrrole
(6b)
This material was prepared from the pyrrole 6 (0.05 g,
0.256 mmol) according to the general procedure D. Pure 6b
(0.062 g, 57%) obtained after flash chromatography on silica
gel (1 g, CH2Cl2/EtOAc, 95:5) was identical in all respects
to that prepared via the general procedure B.
14. R.W. Boyle, V. Karunaratne, A. Jasat, and E.K. Mar. Synlett.
11, 939 (1994).
15. D. Dolphin, S.J. Rettig, H. Tang, T. Wijesekara, and L.Y. Xie.
J. Am. Chem. Soc. 115, 9301 (1993).
16. L.Y. Xie, R.W. Boyle, and D. Dolphin. J. Am. Chem. Soc. 118,
4853 (1996).
2-[(5-Benzyloxycarbonyl-3,4-dimethylpyrrole-2-
yl)methyl]-5′-ethoxycarbonyl-3′,4′-diethylpyrrole (7b)
This material was prepared from the pyrrole 7 (0.05 g,
0.239 mmol) according to the general procedure D. Pure 7b
(0.046 g, 44%) obtained after flash chromatography on silica
© 1998 NRC Canada
I:\cjc\cjc76\cjc-10\OctCHEM-D.vp
Wednesday, January 06, 1999 10:04:08 AM