Facile iodination of the vinyl groups in protoporphyrin IX dimethyl ester and subsequent transformation of the iodinated moieties

Article abstract of DOI:10.1016/j.tet.2018.05.040

Iodination of protoporphyrin IX dimethyl ester using phenyliodine bis(trifluoroacetate) (PIFA) and I₂ was studied. Iodine added to both the C3- and C8-vinyl groups equally to afford the iodohydrin or iodoether in the presence of water or alcohol, respectively. Any meso-hydrogen atom was not substituted by an iodine atom under these conditions, although both the vinyl group and one of the meso positions of methyl pyropheophorbide-a bearing a chlorin π-system, a chlorophyll-a derivative, was modified with PIFA and I₂. The reaction intermediates derived from the porphyrin were more reactive than those from the chlorin and liable to form intermolecular linkages. The obtained 2-iodo-1-hydroxyethyl group was transformed into a formyl group by a mild treatment. The corresponding iodoether moiety was readily converted into the acetyl group under basic conditions. These transformations were also applicable to smaller olefins such as styrene.

Full text of DOI:10.1016/j.tet.2018.05.040

Tetrahedron xxx (2018) 1e5
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Tetrahedron
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Facile iodination of the vinyl groups in protoporphyrin IX dimethyl
ester and subsequent transformation of the iodinated moieties
Kota Miyata a, Satoru Yasuda a, Takuto Masuya a, Satoshi Ito a, Yusuke Kinoshita b,
,
*
Hitoshi Tamiaki b, Toru Oba a
a Department of Material and Environmental Chemistry, Graduate School of Engineering, Utsunomiya University, Utsunomiya, Tochigi 321-8585, Japan
b Graduate School of Life Sciences, Ritsumeikan University, Kusatsu, Shiga 525-8577, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Iodination of protoporphyrin IX dimethyl ester using phenyliodine bis(trifluoroacetate) (PIFA) and I2 was
studied. Iodine added to both the C3- and C8-vinyl groups equally to afford the iodohydrin or iodoether
in the presence of water or alcohol, respectively. Any meso-hydrogen atom was not substituted by an
iodine atom under these conditions, although both the vinyl group and one of the meso positions of
Received 18 April 2018
Received in revised form
10 May 2018
Accepted 15 May 2018
Available online xxx
methyl pyropheophorbide-a bearing a chlorin
p-system, a chlorophyll-a derivative, was modified with
PIFA and I2. The reaction intermediates derived from the porphyrin were more reactive than those from
the chlorin and liable to form intermolecular linkages. The obtained 2-iodo-1-hydroxyethyl group was
transformed into a formyl group by a mild treatment. The corresponding iodoether moiety was readily
converted into the acetyl group under basic conditions. These transformations were also applicable to
smaller olefins such as styrene.
Keywords:
Acetylation
Chlorophyll-a
Iodination
© 2018 Published by Elsevier Ltd.
Iodoether
Protoporphyrin-IX
1. Introduction
iodinated porphyrin in mice were reported in 1960,29 details of the
pigment were not provided.
Iodination is a key reaction in organic synthesis and medicinal
chemistry. Organoiodine compounds are employed in various re-
actions, including substitution and cross-coupling reactions.1e3
Furthermore, ioversol, which contains a triiodophenyl group, is
used as an X-ray contrast agent for computed tomography. Thyroid
hormones thyroxine and triiodothyronine also contain iodophenyl
groups. Consequently, new iodination methods with improved
applicability, efficiency, and green chemistry are still extensively
researched.4e13
Wang et al. reported that the C20 position (one of the meso
positions) of Chl derivative 1 (Scheme 1) was iodinated using
phenyliodine bis(trifluoroacetate) (PIFA) and I2 while leaving the
C3-vinyl group unreacted.30 Furthermore, there are no reports on
the transformation of the peripheral iodinated groups derived from
natural tetrapyrroles except for our late observation.
We have recently published some reports on the iodination of
Chl derivative 1 (Scheme 1).31e33 It was demonstrated that an
iodine atom was selectively introduced at the C3-vinyl group or the
C20 position of 1 by simply changing the reaction stoichiometry of
PIFA and I2. Furthermore, iodohydrin 4 was transformed to the
epoxide 5 by treatment with ethylenediamine, and 5 was reacted
with an acid and NaIO4 to afford 3-formyl-chlorin 6. Interestingly,
the treatment of iodoether 7 with a base converted to 8 bearing the
C3-acetyl group, which had, to the best of our knowledge, not been
previously reported. These are useful alternatives to previous
synthetic routes. For examples, hazardous OsO4 was previously
required to prepare 6 from 134; direct epoxidation of 1 to 5 with
mCPBA is impossible, so the synthesis of 5 was accomplished using
the Corey-Chaykovsky reaction of 635; and tetrapropylammonium
perruthenate (TPAP) was required for oxidation of the 1-
Natural tetrapyrroles such as chlorophylls (Chls), protoporphy-
rin IX (PP-IX), and their derivatives have been studied as photo-
sensitizers
for
photodynamic
therapy,14e16
artificial
photosynthesis, and dye-sensitized solar cells.17e21 Alteration of the
C3-vinyl group in Chls is of considerable interest because this group
has great influence on the photophysical properties of Chls.22e28
However, there are few reports on the iodination of the vinyl
groups of these tetrapyrroles. Although introduction of 131I to the
C32 and C82 positions of PP-IX and the pharmacokinetics of this
* Corresponding author.
E-mail address: tob_p206@cc.utsunomiya-u.ac.jp (T. Oba).
https://doi.org/10.1016/j.tet.2018.05.040
0040-4020/© 2018 Published by Elsevier Ltd.
Please cite this article in press as: Miyata K, et al., Facile iodination of the vinyl groups in protoporphyrin IX dimethyl ester and subsequent
transformation of the iodinated moieties, Tetrahedron (2018), https://doi.org/10.1016/j.tet.2018.05.040

2
K. Miyata et al. / Tetrahedron xxx (2018) 1e5
the scope of these reactions, and a possible mechanism of the
acetylation via the iodoether is also discussed.
2. Results and discussion
First, we investigated the iodoetherification of the vinyl groups
in PP-IX dimethyl ester (9) using the homogeneous conditions
under which chlorin 1 was found to be iodinated efficiently
(Table S1). Accordingly, compound 9 was stirred with PIFA (0.5 eq.)
and I2 (1 eq.) in 1,2-dichloroethane for 1 h at room temperature.
Ethanol (EtOH) was then added, and the mixture was additionally
stirred for 2 h at room temperature. Unexpectedly, whereas chlorin
1 was successfully iodinated under these conditions, we obtained
very little of the iodinated porphyrins 10, 11, or 12. The 1H NMR
signals of the products were too broad to be resolved, suggesting
oligomerization of 9. Matrix-assisted laser desorption ionization-
time of flight mass spectrometry (MALDI-TOF-MS) analysis indi-
cated the presence of some iodinated porphyrins (m/z ¼ 763 and
935) as well as iodinated dimeric and trimeric components (e.g. m/
z ¼ 1526, 1698, 2288, and 2461; Fig. S1). Interestingly, the reaction
of 1 did not give dimers and trimers under the same conditions.
We assumed that the iodonium intermediates derived from
porphyrin 9 are more reactive than those from chlorin 1. Conse-
quently, we reacted 9 in the presence of EtOH to immediately trap
the unstable intermediates and suppress the oligomerization. The
reaction mixture was purified using silica gel column chromatog-
raphy. The MS spectrum of the black products clearly showed ion
peaks with m/z increments of 172 and 344 units, indicating addition
of 1 and 2 eq. of EtOI to 9, respectively. Reaction with double the
amount of reagents (1 eq. of PIFA and 2 eq. of I2) and EtOH afforded
the 3,8-di(1-ethoxy-2-iodoethyl) derivative 10 in 80% isolated yield
after purification with chromatography.
Scheme 1. Conversions of the vinyl group in chlorophyll derivative 1. (a) PIFA (0.5 eq.),
I
2 (1 eq.), 1,2-dichloroethane, r.t.; (b) EtOH, r.t.; (c) morpholine, r.t.; (d) ethylene glycol,
r.t.; (e) (i) NaOH, THF/H2O, r.t., (ii) H2SO4/MeOH, r.t.; (f) ethylenediamine, 1,2-
dichloroethane, r.t.; (g) TsOH, NaIO4, THF/H2O, r.t.
hydroxyethyl derivative obtained by hydrobromination and sub-
sequent hydration of 1 to prepare 8.36
Despite the fact that the iodination of the two vinyl groups in
PP-IX would potentially widen the application of cyclic tetrapyr-
roles and their related compounds, very little has been published
on such a transformation. Furthermore, derivatization of the
resultant peripheral iodinated groups has not been explored. Based
on their structural similarities, we expect that PP-IX would undergo
the same reactions that Chl derivatives did. Although their re-
activities are not the same. Consequently, herein we report our
findings on the iodination of a PP-IX derivative 9 (Scheme 2) as well
as the subsequent epoxidation, formylation, and acetylation of the
product. Visible absorption and fluorescence spectra of the iodin-
ated porphyrin are presented. Styrene was employed to investigate
Fig. 1 shows the 1H NMR spectra of these samples, thus obtained
di-iodinated compound 10 and the mixture of 10 and the mono-
iodinated porphyrins 11 and 12. The spectrum for 10 lacks the vi-
nyl proton signals observed for 9, around 6.15e6.40 (C32 and C82)
and 8.20e8.30 ppm (C31 and C81), while the broadened proton
signal at 6.13 ppm (2H) is assignable to the C31 and C81 protons in
1-ethoxy-2-iodoethyl group. The two multiplets at 4.10 and
Scheme 2. Iodoetherification of protoporphyrin-IX dimethyl ester (9). PIFA (0.5 eq.), I2
(1.0 eq.), EtOH/1,2-dichloroethane.
Fig. 1. 1H NMR spectra of (a) 10 and (b) a mixture of 10, 11 and 12. The expanded
portions show the vinyl proton signals for 11 and 12 in CDCl3.
Please cite this article in press as: Miyata K, et al., Facile iodination of the vinyl groups in protoporphyrin IX dimethyl ester and subsequent
transformation of the iodinated moieties, Tetrahedron (2018), https://doi.org/10.1016/j.tet.2018.05.040

K. Miyata et al. / Tetrahedron xxx (2018) 1e5
3
4.35 ppm originate from the C32eH2 and C82eH2 protons, respec-
tively, and the latter overlaps the 13/17-CH2 proton signals as
demonstrated by H,HeCOSY analysis. The 1H NMR signals for the
ethoxy groups (1.41 and 3.88 ppm) appear somewhat broadened
and have complicated fine structures suggesting the sample being a
mixture of the C31 and C81 epimers. Fig. 1b shows the characteristic
resonances from the vinyl groups in the range of 6.10e8.40 ppm
accompanied by the proton signals for the 1-ethoxy-2-iodoethyl
groups at 4.10, 4.35, and 6.13 ppm. Their peak areas indicate
virtually equal yields of regioisomers 11 and 12. It is also demon-
strated that the ratio of the di-iodinated (10) to mono-iodinated
products (11 and 12) in this mixture is roughly 1:1. These results
indicate that the reactivities of the C3- and C8-vinyl groups are
roughly equal.
Interestingly, the conditions examined in this study afforded no
meso-iodinated product from 9. Even though compound 9 was
reacted with 3 eq. of PIFA and I2, the meso-positions remained
intact. This is in clear contrast to chlorin 1, which underwent
iodination at the C20 position with 1 eq. of PIFA and 2 eq. of I2. This
different reactivity may arise from steric hindrance from the C18-
methyl groups as well as electronic effects at the C20 posi-
tion.37,38 It is also noted that neither compound 10 nor hemato-
porphyrin dimethyl ester lacking vinyl groups oligomerized when
they were reacted with PIFA and I2. These results indicate that the
oligomerization of 9 occurs primarily through the C3- and C8-vinyl
moieties. Fig. S2 shows examples of possible dimeric and trimeric
structures assignable to the aforementioned MALDI-TOF-MS peaks.
The analysis indicates the reaction of an unreacted vinyl group and
an iodonium ion at the early stage of the reaction, to form inter-
molecular linkages between the C3/8 moieties. The fact that
porphyrin 9 afforded oligomers but chlorin 1 did not indicates a
difference in the reactivities of the vinyl groups and/or iodonium
ions of these tetrapyrroles. These presumed dimers and trimers
may have photodynamic activity based on their structural simi-
larity to Photofrin.
Fig. 2 shows the UVeVis absorption spectrum of the di-
iodinated porphyrin 10. The Soret absorption of 10 presents a
broad band peaking at 405 nm, while those of the substrate 9 and
hematoporphyrin, a 3,8-devinyl derivative of 9, are at 407 and
405 nm, respectively. The Q absorption bands are observed at 502,
536, 571, and 624 nm, similar to those of hematoporphyrin (503,
537, 573 and 626 nm), and exhibit blue-shifts of 4e5 nm from those
of 9. The relative intensities of the Q bands are similar to those of 9
and hematoporphyrin.
Fig. 3. Fluorescence emission spectra of hematoporphyrin dimethyl ester (dotted line),
9 (broken line) and 10 (solid line) CHCl3 at room temperature (10 mM): excited at each
Soret maximum.
The fluorescence spectrum of 10 is shown in Fig. 3. The fluo-
rescence maximum for 10 is observed at 628 nm, while that for 9
and hematoporphyrin are at 635 and 631 nm, respectively. The
Stokes shifts are 125 (9), 102 (10), and 127 cmꢀ1 (hematopor-
phyrin). The band-widths (full width at half maximum) are 388
(9), 332 (10), and 389 cmꢀ1 (hematoporphyrin). The fluorescence
intensity of 10 is approximately one-tenth those of 9 and
hematoporphyrin.
The iodoether-type porphyrin can be converted into the acetyl-
porphyrin in the same way as chlorin 1 to 8 via 7 (Scheme 1). As 10
was obtained by the reaction with EtOH, 13 was afforded by the
reaction with ethylene glycol (in 84% yield). Reaction of 13 with
aqueous NaOH (Scheme 3) transformed both the iodoether moi-
eties into acetyl groups with simultaneous hydrolysis of the pro-
pionic esters at the C13 and C17 positions to give 3,8-diacetyl-3,8-
devinyl-protoporphyrin. Treatment of this acid with trimethylsilyl-
diazomethane affords 14 in 41% yield. It is well known that com-
pound 14 can be prepared from 9 via hematoporphyrin.39 The
multi-step reaction for this preparation includes addition of HBr to
the vinyl groups, hydrolysis of the bromoethyl groups, and Ley-
Fig. 2. UVeVis absorption spectra of hematoporphyrin dimethyl ester (dotted line), 9
(broken line) and 10 (solid line) recorded in CHCl3 at room temperature: normalized at
the Soret peaks.
Scheme 3. Conversion of the vinyl groups of porphyrin 9. (a) Ethylene glycol, PIFA (1
eq.), I2 (2 eq.), 1,2-dichloroethane, r.t.; (b) (i) NaOH, THF/H2O, r.t., (ii) TMS-CHN2, MeOH,
CHCl3, r.t.; (c) PIFA (2 eq.), I2 (1 eq.), THF/H2O, r.t.; (d) ethylenediami-ne, 1,2-
dichloroethane, 50 ꢁC; (e) TsOH, NaIO4, THF/H2O, r.t.
Please cite this article in press as: Miyata K, et al., Facile iodination of the vinyl groups in protoporphyrin IX dimethyl ester and subsequent
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4
K. Miyata et al. / Tetrahedron xxx (2018) 1e5
Scheme 5. Possible mechanism for acetylation of the iodoether.
t
t
by refluxing with BuOK in BuOH. These results demonstrate that
this acetylation is not restricted to porphyrins and chlorins but is
also applicable to the standard olefins. We speculate that the
acetylation proceeds via the enolether (Scheme 5). Abstraction of
the benzyl proton triggers elimination of an iodide ion, and hy-
drolysis of the resulting enolether gives an acetyl group.
Scheme 4. Conversion of styrene through iodination of the vinyl group. (a) (i) PIFA (0.5
eq.), I2 (1 eq.), 1,2-dichloroethane, r.t., (ii) EtOH; (b) PIFA (0.5 eq.), I2 (1 eq.), 1,2-
dichloroethane, r.t., (iii) ethylene glycol; (c) PIFA (0.5 eq.), I2 (1 eq.), THF/H2O, r.t.; (d)
ethylenediamine, 1,2-dichloroethane, 50 ꢁC; (e) NaOH, THF/H2O, reflux or tBuOK,
tBuOH, reflux.
3. Conclusion
The vinyl groups of PP-IX dimethyl ester were iodinated with
PIFA and I2 to yield iodoethers and iodohydrins. The reactivities of
the C3- and C8-vinyl groups were equal. The meso-hydrogen atoms
of the porphyrin were not substituted by iodine atoms, while both
the vinyl groups and the meso (C20) position of the chlorin reacted
under similar conditions. The reaction intermediates of the
porphyrin were more reactive than those of the chlorin, which
afforded intermolecularly linked porphyrins. These results
demonstrate the differences in the reactivities of the vinyl groups,
the meso positions, and/or the iodination intermediates of these
tetrapyrroles. The obtained iodohydrin and iodoether moieties of
the porphyrin were readily converted into epoxy, formyl, or acetyl
groups. Styrene was transformed into styrene oxide, benzaldehyde,
or acetophenone without aromatic substitution nor oligomeriza-
tion via similar procedures. This study demonstrates the unique-
ness of porphyrins and the versatility of the reactions presented,
and may facilitate the development of new strategies for the
application of tetrapyrroles.
Griffith oxidation using TPAP. Our new protocol is an inexpensive
alternative to this popular sequence.
Like the transformation of chlorin 1 to 6 via 4 (Scheme 1),
porphyrin 9 can be transformed into the 3,8-diformyl derivative
17 via iodination (Scheme 3). However, the procedure for the
porphyrin required some tuning. Although the vinyl group of
chlorin 1 was successfully converted into a 1-hydroxy-2-iodoethyl
group by treatment of the iodonium intermediate with morpho-
line in 1,2-dichloroethane, iodohydrin 15 was not obtained from
porphyrin 9 under the same conditions. Addition of water (20 vol
%) to the system did not result in this conversion but gave oligo-
merization of 9. However, when the solvent was replaced with
aqueous THF, 15 was successfully produced, as confirmed from 1H
NMR and MS spectra. Mixing obtained 15 with ethylenediamine in
1,2-dichloroethane, followed by stirring at room temperature
gave the di-epoxy derivative 16 accompanied by intermediates
that contained both epoxy and 1-hydroxy-2-iodoethyl moieties.
Raising the reaction temperature to 50 ꢁC accelerated the reaction
to afford 16 as the major product. Since compound 16 was not
sufficiently stable to be isolated using column chromatography,
crude 16 was used without purification in the reaction with p-
toluenesulfonic acid (TsOH) and NaIO4. Compound 17 is success-
fully obtained by this greener method without using OsO4 pre-
viously reported.40,41
As shown in Scheme 4, the present vinyl group iodination
protocol as well as the conversions via this iodination are also
applicable to smaller olefins such as styrene (18).6e11 Compound
18 was dissolved in 1,2-dichloroethane and stirred with 0.5 eq. of
PIFA and 1.0 eq. of I2 for 1 h at room temperature. To this system
was added alcohol, and the mixture was stirred for additional 2 h.
This procedure effected iodoetherification of 18 in 80% and 77%
yields for EtOH (19) and ethylene glycol (20), respectively. Neither
oligomerization nor substitution at the aromatic ring were
observed. Essentially the same procedure in aqueous THF gave
iodohydrin 21, and subsequent treatment with ethylenediamine
afforded styrene oxide (23, 72%). Benzaldehyde can be prepared
from styrene oxide by reaction with TsOH and NaIO4.42 These
reactions are also applicable to 1-allyl-4-methoxybenzene (data
not shown).
4. Experimental
4.1. General
Chl-a was extracted from Spirulina and used as a material to
prepare compound 1 as described previously.43,44 The other re-
agents were purchased from Kanto Chemical Co., Inc., Tokyo
Chemical Industry Co., Ltd., or Wako Pure Chemical Industries Ltd.,
and used as provided. 1H NMR (500 MHz) and 13C NMR (125 MHz)
spectra were recorded on a Varian VNMR-500. Chemical shifts are
reported in ppm with reference to tetramethylsilane. MALDI-TOF-
MS and high-resolution mass spectrometry-atmospheric-
pressure chemical ionization (HRMS-APCI) spectra were
measured using a Bruker autoflex II and a Bruker micrOTOF II,
respectively.
Synthesis of new compounds 10 and 13 were shown below and
please see the preparation of known compounds 9, 14, 17, 19, 20, 22
and 23 in supporting information.
4.2. Synthetic procedure
4.2.1. 3,8-Di(1-ethoxy-2-iodoethyl)deuteroporphyrin IX dimethyl
ester (10)
The iodoether moieties obtained from styrene can also be con-
verted into acetyl groups. Iodoether 20 was dissolved in aqueous
THF, followed by addition of aqueous NaOH. The reaction mixture
was refluxed for 4 h to give acetophenone (22) in 86% yield, while
19 remains unreacted after stirring with aqueous NaOH overnight
at room temperature. Both 19 and 20 were also converted into 22
Compound
9 (250 mmol, 148 mg) was dissolved in 1,2-
dichloroethane (100 mL), followed by addition of EtOH (10 mL).
PIFA (1 eq., 108 mg) and I2 (2 eq., 127 mg) were added to the solu-
tion, and the mixture was stirred for 2 h at room temperature. The
mixture was washed with 10 wt% Na2S2O3 aq. and brine. The
Please cite this article in press as: Miyata K, et al., Facile iodination of the vinyl groups in protoporphyrin IX dimethyl ester and subsequent
transformation of the iodinated moieties, Tetrahedron (2018), https://doi.org/10.1016/j.tet.2018.05.040

K. Miyata et al. / Tetrahedron xxx (2018) 1e5
5
organic phase was dried over Na2SO4, followed by evaporation to
Appendix A. Supplementary data
dryness. The residue was purified by silica gel column chroma-
tography (CHCl3/ethyl acetate, 10:1) to isolate 10 in 80% yield
Supplementary data related to this article can be found at
https://doi.org/10.1016/j.tet.2018.05.040.
(200
500 MHz)
m
mol, 187 mg): 1H NMR (the C31, C81-epimeric mixture, CDCl3,
d
10.57, 10.52, 10.12, 10.07 (4s, 4H, meso), 6.15e6.09 (m,
2H, CHe31, 81), 4.44e4.35 (2 m, 4H, CH2e131, 171), 4.40e4.30,
4.13e4.05 (2 m, 4H, CH2e32, 82), 3.93e3.82 (m, 4H, OCH2CH3),
3.73e3.61 (6s, 18H, CH3e21, 71, 121, 181, COOCH3), 3.33e3.24 (2 m,
4H, CH2e132, 172), 1.44e1.38 (m, 6H, OCH2CH3), ꢀ3.67 (br s, 2H,
NH); 13C NMR (the C31, C81-epimeric mixture, CDCl3, 125 MHz)
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dichloroethane (100 mL). Ethyleneglycol (10 mL), PIFA (1 eq.,
108 mg) and I2 (2 eq., 127 mg) were added to the solution. The
mixture was stirred for 2 h at room temperature. The mixture was
then washed with 10 wt% Na2S2O3 aq. and brine. The organic phase
was dried over Na2SO4, and the solvent was removed in vacuo. The
residue was purified by silica gel column chromatography (1,2-
dichloroethane/acetone, 10:1). Yield, 84% (210
m
mol, 203 mg); 1H
10.48,
NMR (the C31, C81-epimeric mixture, CDCl3, 500 MHz)
d
10.42, 10.10, 10.06 (4s, 4H, meso), 6.21e6.14 (m, 2H, CHe31, 81),
4.44e4.37 (2 m, 4H, CH2e131, 171), 4.39e4.32, 4.10e4.03 (2 m, 4H,
CH2e32, 82), 4.00e3.86 (m, 8H, OCH2CH2OH), 3.73e3.61 (s, 18H,
CH3e21, 71, 121, 181, COOCH3), 3.31e3.24 (2 m, 4H, CH2e132,
172), ꢀ3.67 (br s, 2H, NH); 13C NMR (the C31, C81-epimeric mixture,
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Acknowledgments
This work was partially supported by Grants-in-Aid for Scientific
Research (C) (Nos. 25410082 and 16k05740) from the Japan Society
of the Promotion of Science, and by a research project of Utsuno-
miya University Center for Optical Research & Education.
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Please cite this article in press as: Miyata K, et al., Facile iodination of the vinyl groups in protoporphyrin IX dimethyl ester and subsequent
transformation of the iodinated moieties, Tetrahedron (2018), https://doi.org/10.1016/j.tet.2018.05.040