Ene-thiol reaction of C3-vinylated chlorophyll derivatives in the presence of oxygen: Synthesis of C3-formyl-chlorins under mild conditions

Article abstract of DOI:10.1142/S1088424613500983

Reactions of thiol with the C3-vinyl group of various chlorophyll (Chl) derivatives were examined. The reactions resemble thiol-olefin co-oxidation, except that the vinyl C=C double bond was cleaved to afford a formyl group without any transition metal catalyst, and that the simple anti-Markovnikov adduct of thiol to olefin was obtained as a minor product. Peripheral substituents of Chl derivatives little affected the reaction, while the central metal atom of the chlorin macrocycle influenced the composition of the products. Oxygen and acid dissolved in the reaction mixture can facilitate the oxidation. Sufficiently mild conditions in this regioselective oxidation at the C3 ¹-position are significant in bioorganic chemistry.

Full text of DOI:10.1142/S1088424613500983

Journal of Porphyrins and Phthalocyanines
J. Porphyrins Phthalocyanines 2013; 17: 1188–1195
DOI: 10.1142/S1088424613500983
Published at http://www.worldscinet.com/jpp/
Ene-thiol reaction of C3-vinylated chlorophyll derivatives
in the presence of oxygen: synthesis of C3-formyl-chlorins
under mild conditions
Takanori Fukusumia◊◊, Natsuki Takeia, Yubi Tatenoa, Takuya Aokia, Ai Andoa,
Kouhei Kozakaia, Hiroko Shimaa, Tadashi Mizoguchib, Satoshi Itoa,
Tsukasa Ikedaa, Hitoshi Tamiaki*b◊ and 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
Received 20 June 2013
Accepted 29 July 2013
ABSTRACT: Reactions of thiol with the C3-vinyl group of various chlorophyll (Chl) derivatives were
examined. The reactions resemble thiol-olefin co-oxidation, except that the vinyl C=C double bond
was cleaved to afford a formyl group without any transition metal catalyst, and that the simple anti-
Markovnikov adduct of thiol to olefin was obtained as a minor product. Peripheral substituents of Chl
derivatives little affected the reaction, while the central metal atom of the chlorin macrocycle influenced
the composition of the products. Oxygen and acid dissolved in the reaction mixture can facilitate the
oxidation. Sufficiently mild conditions in this regioselective oxidation at the C31-position are significant
in bioorganic chemistry.
KEYWORDS: aldehyde, chlorophyll, co-oxidation, olefin, thiol.
co-oxidation (TOCO reaction) has long been studied in
INTRODUCTION
relation to hydrocarbon fuel instability [5, 6]. Styrene
Ene-thiol reactions are classically found in chemistry
(PhCH=CH2) for instance reacted with thiophenol (PhSH)
but have recently been reevaluated. Electrophilic
and oxygen (O2) to give 1-phenyl-2-(phenylsulfinyl)-
addition, Michael addition, and radical addition of thiol
ethanol, PhCH(OH)CH2S(O)Ph. Thiyl radical (PhS·)
across a double bond are well known. Michael reaction
and molecular oxygen add to the double bond to afford
between a cysteine thiol and a maleimide proceeds even
a sulfanyl hydroperoxide [PhCH(O–O·)CH2SPh] in
in water, and the reaction is widely used for cross-linking
the early step of the co-oxidation. The unstable hydro-
and labeling of proteins [1]. Very recently, such ene-thiol
peroxide transforms into the more stable sulfinyl
reactions have been reinvestigated and highlighted as
ethanol. In contrast, Szmant and co-workers studied the
useful click-reactions beneficial for bio-conjugation and
mechanism of the reaction by NMR, and proposed that
facile synthesis of supramolecules [2–4].
not a thiyl radical but a charge transfer complex formed
When oxygen is introduced into a system involving
by the thiol and the olefin played an essential role in the
thiol and olefin, oxidation of the olefin takes place
early step [7].
besides the formation of simple adducts. This thiol-olefin
In the presence of oxygen, addition of a thiol across
an ene double bond (Ca=Cb) is accompanied by
oxidation of the a-carbon atom and the sulfur atom at
◊SPP full and ◊◊student member in good standing
the b-position. The conventional TOCO reaction does
not, however, involve cleavage of the double bond. The
double bond cleavage, leading to formation of aldehydes
*Correspondence to: Hitoshi Tamiaki, fax: +81 77-561-2659,
email: tamiaki@fc.ritsumei.ac.jp; Toru Oba, tel/fax: +81 28-
689-6147, email: tob_p206@cc.utsunomiya-u.ac.jp
Copyright © 2013 World Scientific Publishing Company

ENE-THIOL REACTION OF C3-VINYLATED CHLOROPHYLL DERIVATIVES IN THE PRESENCE OF OXYGEN 1189
Scheme 1. In vitro conversion of Chl-a (1a) into Chl-d (1b)
using thiophenol and acetic acid
temperature. Because Chl-a, which is labile to strong
oxidants, oxygen, and acids, was readily transformed
into Chl-d in one-step under such mild conditions, we
assume it to be a model reaction of Chl-d biosynthesis.
Very recently, Belykh and Ashikhmina reported that a
catalytic amount of alkyl thiol and oxygen gas enabled
formylation of 2a and chlorin-e6 derivatives [12].
Molecular oxygen attracts much attention as an ideal
oxidant due to its abundance, low cost, and safety, all
of which benefit us from the viewpoint of green and
Fig. 1. Molecular structures of natural chlorophylls and their
sustainable chemistry. N-Hydroxyphthalimide is one of
the catalysts that facilitate oxidation of organic substrates
using molecular oxygen as an oxidant [13, 14]. Attack of
phthalimide N-oxyl radical on an olefin and subsequent
decomposition of the peroxide intermediate are assumed
to be involved in the mechanism that converts olefins
into ketones or aldehydes. Living organisms also use
molecular oxygen in their metabolic processes, for
instance, by using cytochrome P450 as a catalyst.
Molecular oxygen coordinates to the heme iron of P450
to form the ferric peroxide [Fe(III)–OOH], followed by
transformation into the oxo ferryl species [Fe(IV)=O]
that oxidizes the substrates [15]. Thiol in the oxidation
shown in Scheme 1 may also function as a catalyst to
harness molecular oxygen. It is intriguing that no metal
catalyst is needed to cleave the double bond of the vinyl
group of Chl-a. This ene-thiol chemistry is worthy of
investigation from the aspects of bioorganic chemistry as
well as green chemistry.
derivatives 1a–10a possessing the C3-vinyl group as the
substrates of the present oxidation
or ketones, requires transition metal complexes such
as Mn salen [8] and Fe porphyrin [9] in addition to the
thiol and oxygen. b-Sulfanyl hydroperoxides were also
assumed to be intermediates of these catalytic oxidations.
We have found that in the presence of a thiol the
peripheral vinyl groups of chlorophyll-a (Chl-a, 1a,
see Fig. 1) and methyl pyropheophorbide-a (2a) were
selectively converted into the formyl groups to afford
Chl-d (1b) and methyl pyropheophorbide-d (2b),
respectively, in substantial yields without aid of any metal
catalysts (Schemes 1 and 2), which were preliminary
reported [10, 11]. The reaction was carried out by simply
mixing the pigments, thiophenol, and acetic acid in THF,
followed by stirring the solution for several hours at room
Scheme 2. Reaction of the C3-vinyl double bond of Chl-a derivative 2a with a thiol to give 2b–2e. The values in parenthesis indicate
the yields of 2b–2e (using 10 mmol of 2a, see Experimental section for the reaction conditions)
Copyright © 2013 World Scientific Publishing Company
J. Porphyrins Phthalocyanines 2013; 17: 1189–1195

1190 T. FUKUSUMI ET AL.
Here we report the effects of vinylated chlorin
(7a), were similarly transformed to give the corresponding
C3,7-diformyl-chlorins 6b and 7b, respectively, under the
above conditions. 1H NMR spectrum of 6b clearly showed
two formyl proton signals at 11.37 and 11.43 ppm [16],
demonstrating that the C7-formyl group was kept intact
during the oxidation. The C7-formyl group retarded the
oxidation: Chl-b (6a) took 7 h to complete the reaction,
while the formylation of Chl-a (1a) was completed within
4 h, indicating that the C7-formyl-chlorins were less
reactive for the present oxidation than the C7-methylated
pigments. This tendency is consistent with the fact that
demetallation of Zn-chlorins is retarded by electronic
effects of the C7-formyl group [17].
substrates, oxygen molecule, and additional acid species
on the ene-thiol reaction, as a model for the enzymatic
conversionofChl-aintoChl-d.Assubstrates,weexamined
ten pigments including natural Chls and their synthetic
derivatives with different peripheral substituents and
central metals. All the substrates successfully underwent
the oxidation of the vinyl group to give the corresponding
aldehydes. The reaction also gave sulfanyl-adducts, but
simple anti-Markovnikov-type adducts were obtained in
lower yields. Thus, this reaction is in sharp contrast to the
traditional TOCO reaction.
The central metal atom of the chlorin macrocycles
greatly influenced their reactivity to this oxidation. Nickel
and zinc atoms were inserted into the central cavity of the
free base 2a in a conventional way [18], and the obtained
Ni- 9a and Zn-complexes 10a were subjected to the
oxidation reaction as mentioned above. The Ni-complex
9a also afforded the corresponding Ni-formyl-chlorin
9b (35%). The value was comparable to those of Mg
complex 1a to 1b and its free base 2a to 2b. On the other
hand, the C=C double bond cleavage at the C3-moiety
was strongly inhibited in the case of Zn-complex 10a and
C3-formyl-chlorin 10b was obtained in only 9% yield.
The suppression may arise from the difference in the
redox property of the substrates.
RESULTS
When Chl-a (1a), AcOH (1 equiv.), and PhSH (5 equiv.)
were dissolved in THF, followed by stirring overnight in
the air at room temperature, 1a was converted into Chl-d
(1b) successfully (Table 1). When 2a was reacted under the
same conditions, 2a was fully consumed within 5 h and
C3-formyl-chlorin 2b was obtained in the same yield as that
of 1a to 1b. Other natural and synthetic chlorins 3a–8a (see
Fig. 1) also gave their corresponding C3-formyl-chlorins
3b–8b (see Table 1). The reaction proceeded smoothly,
regardless of the esterifying group of the C17-propionate
and the substituents at the C131- and C132-positions. During
the oxidation, the major products were free from any
degradation including hydrogen abstraction at peripheral
substituents, ester hydrolysis, thioacetal formation,
demetallation, and ring opening. The C3-vinyl groups of
C7-formyl-chlorins, Chl-b (6a) and its free base Pheo-b
Table 1 also shows the Qy absorption maxima of na
and nb. Compounds 2a–5a possess the same p-system
and gave the Qy peaks at 667–668 nm. Conversion of the
vinyl group to the formyl group induced large red-shift
of these bands to 691–698 nm. The other substrates also
experienced comparable red-shift by the conversion.
The reaction of 2a afforded two other major products
after purification with reversed-phase HPLC: retention
time (tR) = 21 and 30 min. The slowly eluting (tR = 30
min) and less polar species is assigned to C3-[1-oxo-2-
(phenylsulfanyl)ethyl] derivative 2c (Scheme 2) from
Table 1. Oxidation of C3-vinylated Chl derivatives na to
C3-formyl-chlorins nba
Substrate
lmax
1a (Chl-a) 666
2a 668
3a (Pheo-a) 668
Yield (%)
Product
1
its H NMR [d = 4.86 ppm for singlet CH2-32], visible
lmax Dl (DE)c
b
b
(lmax = 687 nm for Qy peak), and MS data (m/z = 672
for [M]+) [10]. The fast eluting (tR = 21 min) and more
polar species is assignable to a 31-epimeric mixture (1:1)
of C3-[1-hydroxy-2-(phenylsulfanyl)ethyl] form 2d:
lmax = 664 nm for Qy peak and m/z = 674 for [M]+. The
molecular structure of alcohol 2d was also confirmed by
the authentic sample prepared by reduction of ketone 2c
31
31
22
17
25
32
24
26
35
9
1b (Chl-d) [11] 684 18 (395)
2b
697 29 (623)
691 23 (498)
691 24 (521)
698 30 (643)
667 20 (463)
678 28 (635)
667 19 (440)
680 28 (632)
688 29 (640)
3b (Pheo-d)
4a
5a
667
668
4b
5b
6b
7b
8b
9b
10b
t
6a (Chl-b) 647
7a (Pheo-b) 650
with BuNH2BH3 in CH2Cl2. It is noted that the simple
anti-Markovnikov-type adduct, C3-[2-(phenylsulfanyl)-
ethyl] form 2e, was obtained in a lower yield (8%). This
is in sharp contrast to the fact that conventional TOCO
reaction simultaneously gave simple anti-Markovnikov-
type adducts in substantial yields. The typical reaction
of styrene with p-chlorothiophenol at 30 °C afforded
both the sulfinyl alcohol (31%) and the simple adduct
(69%) [7]. This is one of the characteristics of the
present reaction of Chl derivatives. The reaction
conditions employed seemed to be very oxidative for Chl
8a
9a
648
652
659
10a
a
Basic reaction conditions: 3-vinyl-chlorin (10 mmol), AcOH
(1 equiv.), and PhSH (5 equiv.) in THF (3 mL), in the air, at
1
room temperature. The yields were determined by H NMR
spectral analysis (see Experimental section). b In nm in CHCl3.
c Dl in nm and DEin cm-1.
Copyright © 2013 World Scientific Publishing Company
J. Porphyrins Phthalocyanines 2013; 17: 1190–1195

ENE-THIOL REACTION OF C3-VINYLATED CHLOROPHYLL DERIVATIVES IN THE PRESENCE OF OXYGEN 1191
Table 2. Composition of the products of 2a dependent upon the reaction conditionsa
Atmosphere
Yield, %
SPh
SPh
SPh
O
HO
O
a
b
3
3
d
c
e
3
3
3
Air
0
0
6
0
20
13
27
19
14
47
9
9
O2
43
31
25
0
3
6
Ar
16
Air (no AcOH)b
35
a Basic reaction conditions: 3-vinyl-chlorin 2a (100 mmol), AcOH (1 equiv.), and
PhSH (5 equiv.) in THF (10 mL), in the air, at room temperature. b 2a (10 mmol).
derivatives, in spite of lacking any catalyst and flushing
peroxide could lead to the formation of sulfanyl alcohol
nd. Sulfanyl ketone nc could be obtained by additional
abstraction of a hydrogen atom at the C31-position. It is
proposed that the C3-formyl-chlorin nb is also derived
from the peroxide intermediate. The reaction conditions
are sufficiently oxidative even without flushing oxygen
gas through the system. Attack of molecular oxygen to the
C31-carbon centered radical (C3-CH·–CH2SPh) would be
much faster than abstraction of hydrogen from thiophenol
that should provide the simple anti-Markovnikov adduct.
After our preliminary report [10], the formylation
of 2a and chlorin-e6 derivatives (ca. 50% yields) using
a catalytic amount of alkyl thiol (5~7 mole%) and
oxygen gas (4~5 L/h, 1 h) was described [12]. We could
not obtain such C3-formyl-chlorins in the presence of
an alkyl thiol under the atmospheric conditions where
Chl-d biosynthesis took place [10]. A large amount of
oxygen in the system may activate reactivity of alkyl
thiol and successfully enable the formylation. The fact
that such an alkyl thiol catalyzes the formylation might
suggest that the thiol moiety of cysteine residue can
participate in the enzymatic transformation from Chl-a
to Chl-d. We speculate that a postulated Chl-d synthase
facilitates monooxygenation using molecular oxygen and
preferentially decomposes the peroxide intermediate into
the formyl-chlorin.
oxygen. A Markovnikov-type adduct was detected using
p-toluenesulfonic acid as a coexisting acid [10], but was
not obtained under the present conditions employing
lower acidic AcOH. Preliminary analysis demonstrated
essentially the same tendency for the composition of the
reaction products nb–ne obtained from the other chlorin
substrates 1a and 3a–9a (see Table S1).
Oxygen gas had an additional effect on the
composition of the products (see Table 2). Introduction
of oxygen into the reaction mixture of 2a enhanced the
two-fold formation of 2b and 2c, while production of 2d
was greatly inhibited. When Ar gas was bubbled into the
solution before the reaction, a small amount of substrate
2a remained unreacted even after stirring for 24 h.
DISCUSSION
The present oxidation reaction (Scheme 2) resembles
a traditional TOCO reaction, but clear differences were
noted: (1) the vinyl C=C double bond was cleaved to afford
a formyl group without any transition metal catalysts
or bubbling of oxygen gas, and (2) the simple anti-
Markovnikov adduct ne (C3-CH2CH2SPh) was obtained
in a lower yield. Compound 2a is a good representative
to examine reactivity of these Chl derivatives, because
essentially the same major products were obtained as
in the other derivatives. The vinyl group was selectively
transformed, andlessdegradationofthepigmentsincluding
hydrolysis of esters, demetalation, and ring opening was
observed. The modification at the sole C3-vinyl group
under sufficiently mild reaction conditions offers the
possibility of wider application in organic synthesis and
of the unveiling of unidentified reactions in bioorganic
chemistry including Chl-d biosynthesis.
Not only formyl-chlorins [19, 20] but sulfanylated
chlorins await future application. Supramolecular devices
including artificial photosynthesis may be fabricated by
conjugation of a pigment with a biomolecule by formation
of a thioether linkage between a thiol and a vinyl group.
It is also expected that the sulfanylated chlorins function
as photosensitizing drugs of photodynamic therapy and
as their synthetic intermediates.
EXPERIMENTAL
We assume that the oxidation examined here proceeds
through a peroxide intermediate (Scheme 3) as in a
TOCO reaction [10, 11]. Sequential addition of thiol and
molecular oxygen to the C3-vinyl group of na can afford
a peroxide species. Loss of an oxygen atom from the
Chl-a (1a) and Chl-b (6a) were extracted from
Spirulina and spinach, respectively, and were used as
materials to prepare compounds 2a–5a and 7a–10a
as described previously [18, 21–23]. Reagents were
Copyright © 2013 World Scientific Publishing Company
J. Porphyrins Phthalocyanines 2013; 17: 1191–1195

1192 T. FUKUSUMI ET AL.
Scheme 3. Hypothetical synthetic pathway of the reaction of the C3-vinyl double bond of Chl derivatives na with a thiol. A
thiyl radical (PhS•) attacked the C3-vinyl group, followed by addition of a molecular oxygen. The resulting hydroperoxide
oxidatively decomposed into C3-formyl-chlorins nb, C3-[1-oxo-2-(phenylsulfanyl)ethyl] derivatives nc, and the C3-[1-hydroxy-2-
(phenylsulfanyl)ethyl] derivatives nd, and C3-[2-(phenylsulfanyl)ethyl] derivatives ne
purchased from Kanto Chemical Co., Inc., and were used
as provided. The oxidation reactions of the 3-vinylated
Chl derivatives were carried out as reported earlier [10,
11]. The typical reaction of 2a is described below.
Compound 2a (10 mmol) was dissolved in dry
tetrahydrofuran (THF, 3 mL) and the solution was chilled
in an ice water bath. Thiophenol (PhSH, 5 equiv.) was
added to this solution and stirred for 45 min. Then, acetic
acid (AcOH, 1 equiv.) was added to the mixture, and
stirred for 24 h at room temperature. The mixture was
neutralized by 5% aq. NaHCO3, and the pigments were
extracted with CHCl3. The organic layer was washed
with brine, dried over Na2SO4, and evaporated to dryness.
1
The residue was analyzed by H NMR (Varian VNMR-
500), MALDI-TOF-MS (Bruker autoflex II), and UV-vis
Fig. 2. A partial 1H NMR spectrum of a reaction mixture
recorded after 24-h oxidation. Compound 2a was fully
consumed and products 2b–2e were observed. Characteristic
signals of the respective products are indicated
(JASCOV-550). The composition of 2a–2e in the reaction
1
mixture was calculated based on the H NMR data
(Fig. 2). Areas of proton signals specific for respective
compounds (C3-moieties, CH-5, CH-10, and CH-20)
were divided by the total area of the C132-protons and the
results were averaged from triplicate experiments.
analogs (e.g. C3-acetyl, C3-hyrdoxymethyl, and C3-ethyl
chlorins) [21, 23, 24], and were listed below.
The major products (2b, 37 min; 2c, 30 min; 2d, 21
min) were isolated from the mixtures using a reversed-
phase HPLC [column, Nomura Chemical Develosil
ODS-HG5 (20f × 150 mm); eluent, methanol; pump,
JASCO PU-2089; detector, JASCO MD-2018; flow rate,
3 mL/min; room temperature] and analyzed by their
1H NMR, HRMS (Bruker micrOTOF II), and UV-vis
spectra. The data of 2b were identical to the reported
data [10, 21]. The NMR and UV-vis spectra of novel
compounds 2c, 2d and 2e were similar to those of known
Since the introduction of oxygen or argon gas into
the above reaction mixture involving 10 mmol of 2a
gave scattered results for the composition of products,
the gases were bubbled into a relatively large scale of 2a
(100 mmol and THF, 10 mL) before 24-h stirring to give
less variable data.
Methyl 3-devinyl-3-[1-oxo-2-(phenylsulfanyl)ethyl]-
pyropheophorbide-a (2c). UV-vis (CHCl3): lmax, nm
687 (relative intensity, 0.53), 628 (0.08), 550 (0.12),
Copyright © 2013 World Scientific Publishing Company
J. Porphyrins Phthalocyanines 2013; 17: 1192–1195

ENE-THIOL REACTION OF C3-VINYLATED CHLOROPHYLL DERIVATIVES IN THE PRESENCE OF OXYGEN 1193
1
516 (0.12), 419 (1.00), 390 (0.87). H NMR (500 MHz;
complexes 1, 9 and 10 were measured in CDCl3 containing
10% CD3OD to prevent aggregation. H NMR, HRMS,
1
CDCl3; Me4Si): dH, ppm -2.03 (1H, s, pyrrole-NH)
(another NH was too broad to be observed), 1.71 (3H,
t, J = 8 Hz, CH3-82), 1.84 (3H, d, J = 7 Hz, CH3-181),
2.26–2.36, 2.52–2.79 (4H, m, CH2-171, 172), 3.18 (3H, s,
CH3-71), 3.56 (3H, s, CH3-21), 3.61 (3H, s, CH3-175), 3.71
(3H, s, CH3-121), 3.72 (2H, q, J = 8 Hz, CH2-81), 4.37
(1H, dt, J = 8, 2 Hz, CH-17), 4.56 (1H, dq, J = 2, 7 Hz,
CH-18), 4.86 (2H, s, CH2-32), 5.18, 5.33 (2H, 2d, J = 20
Hz, CH2-132), 7.18–7.22 (3H, m, CH-3′, 4′, 5′ of phenyl),
7.38–7.42 (2H, m, CH-2′, 6′ of phenyl), 8.75 (1H, s,
CH-20), 9.60 (1H, s, CH-10), 9.67 (1H, s, CH-5). HRMS
(APCI): m/z 673.2846 (calcd. for [M + H]+ 673.2849).
Methyl 3-devinyl-3-[1-hydroxy-2-(phenylsulfanyl)-
and UV-vis data of novel compounds 4b, 7b and 8b were
analyzed based on spectral data of known analogs [10,
11, 16, 21–34], and are listed below. Spectral data of
the other products are listed in Supplementary material.
Preparation of 3-vinyl-chlorins 1a–3a [25, 26], 4a [27],
5a–6a [25, 26], 7a [26], 8a [23, 28], 9a [29], and 10a
[30] as well as 3-formyl-chlorins 1b [11, 31], 2b [10, 21],
3b [31], 5b [32, 33], 6b [16], 9b [29], and 10b [34] were
confirmed by the literature data.
Pyropheophytin-d (4b). Compound 4a (10 mmol) was
reacted with PhSH (5 equiv.) and AcOH (1 equiv.) in dry
THF (3 mL) for 24 h at room temperature, as mentioned
above. The desired product 4b was isolated from the
ethyl]pyropheophorbide-a (2d). UV-vis (CHCl3): lmax
nm 664 (relative intensity, 0.51), 608 (0.09), 540 (0.10),
508 (0.10), 412 (1.00). H NMR (500 MHz; CDCl3;
,
reaction mixture using a normal-phase HPLC (tR =
1
15.5 min; column, Senshu-Pak 5251N (20f × 250 mm);
eluent, hexane/2-propanol/methanol = 100/8/4; pump,
JASCO PU-2089; detector, JASCO MD-2018; flow rate,
5 mL/min; room temperature) and analyzed by 1H NMR,
HRMS, and UV-vis spectroscopies. UV-vis (CHCl3):
Me4Si): dH, ppm -1.83 (1H, s, pyrrole-NH) (another NH
was too broad to be observed), 1.70 (3H, t, J = 8 Hz, CH3-
82), 1.80/1.81 (3H, d, J = 7 Hz, CH3-181), 2.22–2.36, 2.52–
2.75 (4H, m, CH2-171, 172), 3.13/3.14 (3H, s, CH3-71),
3.36/3.38 (3H, s, CH3-21), 3.61 (3H, s, CH3-175), 3.68 (3H,
s, CH3-121), 3.68 (2H, q, J = 8 Hz, CH2-81), 3.78–3.94 (2H,
m, CH2-32), 4.30 (1H, m, CH-17), 4.48 (1H, br-q, J = 7 Hz,
CH-18), 5.12, 5.27 (2H, 2d, J = 20 Hz, CH2-132), 6.24 (1H,
m, CH-31), 7.32–7.37 (1H, m, CH-4′ of phenyl), 7.40–7.44
(2H, m, CH-3′, 5′ of phenyl), 7.62–7.66 (2H, m, CH-2′,
6′ of phenyl), 8.53/8.54 (1H, s, CH-20), 9.44/9.46 (1H,
s, CH-5), 9.54 (1H, s, CH-10) (the 31-OH signal was not
detected due to proton exchange with trace water). HRMS
(APCI): m/z 675.3001 (calcd. for [M + H]+ 675.3006).
Alternative preparation of 2d was conducted by reduction
of compound 2c using tert-butylamine borane complex in
the previously described manner [16, 17].
l
max, nm 691 (relative intensity, 0.76), 629 (0.07), 549
(0.14), 517 (0.15), 420 (1.00), 385 (0.84). 1H NMR (500
MHz; CDCl3; Me4Si): dH, ppm -2.02 (1H, s, pyrrole-NH)
(another NH was too broad to be observed). 0.77, 0.78
(6H, 2d, J = 7 Hz, P15-(CH3)2), 0.84 (6H, d, J = 7 Hz, P7,
P11-CH3), 1.62 (3H, s, P3-CH3), 1.74 (3H, t, J = 8 Hz,
CH3-82), 1.84 (3H, d, J = 7 Hz, CH3-181), 2.2–2.8 (4H,
m, CH2-171, 172), 3.76 (2H, q, J = 8 Hz, CH2-81), 3.35,
3.74, 3.79 (9H, 3s, CH3-21, 71, 121), 4.39 (1H, m, CH-17),
4.48–4.62 (3H, m, P1-H2 + CH-18), 5.21 (1H, t, J = 6
Hz, P2-H), 5.19, 5.35 (2H, 2d, J = 20 Hz, CH2-132), 8.85
(1H, s, CH-20), 9.65, 10.35 (2H, 2s, CH-5, 10), 11.58
(1H, s, CHO-31). (Some protons of phytyl group were not
clearly assigned.) HRMS (APCI): m/z 815.5473 (calcd.
for [M + H]+ 815.5475).
Methyl 3-devinyl-3-[2-(phenylsulfanyl)ethyl]pyro-
pheophorbide-a (2e). UV-vis (CHCl3): lmax, nm 661
(relative intensity, 0.48), 605 (0.08), 537 (0.09), 505
3-Devinyl-3-formyl-pheophytin-b (7b). Compound
7a (10 mmol) was reacted with PhSH (5 equiv.) and
AcOH (1 equiv.) in dry THF (3 mL) for 24 h at room
temperature, as mentioned above. The desired product 7b
was isolated from the reaction mixture using a normal-
phase HPLC (tR = 30.0 min; column, Senshu-Pak 5251N
(20f × 250 mm); eluent, hexane/2-propanol/methanol =
100/8/4; pump, JASCO PU-2089; detector, JASCO
MD-2018; flow rate, 5 mL/min; room temperature) and
analyzed by 1H NMR, HRMS, and UV-vis spectroscopies.
UV-vis (CHCl3): lmax, nm 678 (relative intensity, 0.29),
1
(0.09), 412 (1.00). H NMR (500 MHz; CDCl3; Me4Si):
dH, ppm -1.70, 0.49 (2H, 2s, pyrrole-NH × 2), 1.70 (3H,
t, J = 8 Hz, CH3-82), 1.80 (3H, d, J = 7 Hz, CH3-181),
2.22–2.36, 2.51–2.73 (4H, m, CH2-171, 172), 3.19 (3H,
s, CH3-71), 3.29 (3H, s, CH3-21), 3.60 (3H, s, CH3-175),
3.68 (3H, s, CH3-121), 3.70 (2H, q, J = 8 Hz, CH2-81),
3.64, 4.14 (4H, m, CH2-31, 32), 4.28 (1H, dt, J = 7, 2 Hz,
CH-17), 4.47 (1H, dq, J = 2, 7 Hz, CH-18), 5.10, 5.30
(2H, 2d, J = 20 Hz, CH2-132), 7.36 (1H, t, J = 7 Hz, CH-4′
of phenyl), 7.42 (2H, t, J = 7 Hz, CH-3′, 5′ of phenyl),
7.64 (2H, d, J = 7 Hz, CH-2′, 6′ of phenyl), 8.48 (1H, s,
CH-20), 9.10 (1H, s, CH-5), 9.51 (1H, s, CH-10). HRMS
(APCI): m/z 659.3078 (calcd. for [M + H]+ 659.3056).
Alternatively, 2e was synthesized by radical addition of
PhSH initiated by AIBN; detail of this reaction will be
presented elsewhere carriage return.
1
536 (0.11), 454 (1.00). H NMR (500 MHz; CDCl3;
Me4Si): dH, ppm -1.87 (1H, s, pyrrole-NH) (another NH
was too broad to be observed). 0.78, 0.80 (6H, 2d, J = 6
Hz, P15-(CH3)2), 0.84 (6H, d, J = 6 Hz, P7, P11-CH3),
1.58 (1H, m, P15-H), 1.58 (3H, s, P3-CH3), 1.84–1.90
(6H, m, CH3-82, 181), 2.2–2.7 (4H, m, CH2-171, 172),
3.76, 3.76, 3.93 (9H, 3s, CH3-21, 121, 132-COOCH3),
4.15 (2H, q, J = 8 Hz, CH2-81), 4.29 (1H, m, CH-17), 4.55
(1H, dq, J = 2, 8 Hz, CH-18), 4.40–4.53 (2H, m, P1-H2),
5.14 (1H, t, J = 7 Hz, P2-H), 6.32 (1H, s, CH-132), 9.82
The other 3-formyl-chlorins 1b and 3b–10b were
prepared similarly as mentioned above. NMR spectra of
trace compounds were obtained by liquid MAS technique
using the “Nano probe” (Varian). NMR spectra of metal
Copyright © 2013 World Scientific Publishing Company
J. Porphyrins Phthalocyanines 2013; 17: 1193–1195

1194 T. FUKUSUMI ET AL.
(1H, s, CH-20), 9.85, 10.99 (2H, 2s, CH-5, 10), 11.27,
11.67 (2H, 2s, CHO-31, 71). (Some protons of phytyl
group were not clearly assigned.) HRMS (APCI): m/z
887.5377 (calcd. for [M + H]+ 887.5323).
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Methyl 131-deoxo-mesopyropheophorbide-d (8b).
Compound 8a (10 mmol) was reacted with PhSH (5 equiv.)
and AcOH (1 equiv.) in dry THF (3 mL) for 24 h at room
temperature, as mentioned above. The desired product
8b was isolated from the reaction mixture by silica-gel
column chromatography (dichloroethane/diethyl ether =
1
100/3) and analyzed by H NMR, HRMS, and UV-vis
spectroscopies. UV-vis (CHCl3): lmax, nm 667 (relative
intensity, 0.34), 612 (0.06), 552 (0.08), 515 (0.12), 419
(1.00), 334 (0.26), 311 (0.24). 1H NMR (500 MHz; CDCl3;
Me4Si): dH, ppm -2.62, -1.15 (2H, 2s, pyrrole-NH × 2),
1.74 (3H, t, J = 8 Hz, CH3-82), 1.84 (3H, d, J = 8 Hz, CH3-
181), 2.22–2.36, 2.58–2.84 (4H, m, CH2-171, 172), 3.42,
3.46, 3.59, 3.84 (12H, 4s, CH3-21, 71, 121, 175), 3.81 (2H,
q, J = 8 Hz, CH2-81), 3.98–4.11 (2H, m, CH2-131), 4.44
(1H, dt, J = 8, 2 Hz, CH-17), 4.60 (1H, dq, J = 2, 8 Hz,
CH-18), 4.78, 4.90 (2H, ddd, J = 3, 7, 16 Hz, CH2-132),
8.96 (1H, s, CH-20), 9.39, 10.47 (2H, 2s, CH-5, 10), 11.66
(1H, s, CHO-31). HRMS (APCI): m/z 537.2874 (calcd. for
[M + H]+ 537.2866).
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Acknowledgements
This work was partially supported by a research
project (to TO) of Utsunomiya University Center for
Optical Research & Education, and by Grants-in-Aid for
Scientific Research (C) (Nos. 21510132 and 25410082 to
TO) and (A) (No. 2245030 to HT) from Japan Society of
the Promotion of Science (JSPS). We also thank for Mr.
Kinoshita (Ritsumeikan University) and Mr. Roppongi
(Collaboration Center for Research and Development of
Utsunomiya University) for their help with experiments.
Supporting information
Spectral data of by-products are given in the
supplementary material. This material is available free of
charge via the Internet at http://www.worldscinet.com/
jpp/jpp.shtml.
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