Functionalization of Deutero- and Protoporphyrin IX Dimethyl Esters via Palladium-Catalyzed Coupling Reactions

Article abstract of DOI:10.1021/acs.joc.9b00350

Herein, we report the functionalization of the β-positions of deutero- and protoporphyrin IX dimethyl esters. Initial halogenations were carried out on both deutero- and protoporphyrin IX dimethyl esters. Although previously reported, vastly optimized yields with respect to deuteroporphyrin halogenation were obtained. Methods were developed for the bromination of the vinyl groups of protoporphyin IX dimethyl ester. Subsequent palladium-catalyzed coupling reactions were utilized to modify the periphery of these naturally occurring porphyrin derivatives with a variety of functionalities. The described Suzuki, Sonogashira, and "Click" reactions demonstrate the ease at which these porphyrins may be manipulated and even interchangeable, as will be discussed for one example. X-ray crystallographic analysis successfully determined the structure of two derivatives synthesized. Results identified a unique head-to-tail stacking pattern for 3,8-diphenyldeuteroporphyrin IX dimethyl ester, most likely due to the presence of additional aromatic moieties on the periphery of the porphyrin.

Full text of DOI:10.1021/acs.joc.9b00350

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Article
Functionalization of Deutero- and Protoporphyrin IX
Dimethyl Ester via Palladium-catalyzed Coupling Reactions
Jessica M. O'Brien, Elisabeth Sitte, Keith J. Flanagan, Hannes
Kühner, Lukas J. Hallen, Dáire Gibbons, and Mathias O. Senge
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b00350 • Publication Date (Web): 16 Apr 2019
Downloaded from http://pubs.acs.org on April 16, 2019
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Functionalization of Deutero- and Protoporphyrin IX
Dimethyl Ester via Palladium-catalyzed Coupling
Reactions
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§
§
Jessica M. O’Brien, Elisabeth Sitte, Keith J. Flanagan, Hannes Kühner, Lukas J. Hallen, Dáire
Gibbons, and Mathias O. Senge*
School of Chemistry, SFI Tetrapyrrole Laboratory, Trinity Biomedical Sciences Institute, 152–
1
60 Pearse Street, Trinity College Dublin, The University of Dublin, Dublin 2, Ireland
H
N
R
Suzuki-Miyuara
Sonogashira
R
NH
N
N
HN
N
N
N
Br, I
Halogenation
O
O
Click Reaction
Br
O
O
Deuteroporphyrin IX dimethyl ester, R = H
Protoporphyrin IX dimethyl ester, R = vinyl
ABSTRACT Herein, we report the functionalization of the β-positions of deutero- and
protoporphyrin IX dimethyl ester. Initial halogenations were carried out on both deutero- and
protoporphyrin IX dimethyl ester. While previously reported, vastly optimized yields with
respect to deuteroporphyrin halogenation were obtained. Methods were developed for the
bromination of the vinyl groups of protoporphyin IX dimethyl ester. Subsequent palladium-
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catalyzed coupling reactions were utilized to modify the periphery of these naturally occurring
porphyrin derivatives with a variety of functionalities. The described Suzuki, Sonogashira, as
well as “Click” reactions demonstrate the ease at which these porphyrins may be manipulated
and even interchangeable, as will be discussed for one example. X-ray crystallographic analysis
successfully determined the structure of two derivatives synthesized. Results identified a unique
head-to-tail stacking pattern for 3,8-diphenyldeuteroporphyrin IX dimethyl ester, most likely due
to the presence of additional aromatic moieties on the periphery of the porphyrin.
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INTRODUCTION
Deuteroporphyrin IX and protoporphyrin IX, both non-natural and natural porphyrin
derivatives, respectively, were initially synthesized as intermediates in the form of their dimethyl
1
ester counterparts (1 and 2, Figure 1) during Hans Fischer’s total synthesis of hemin in 1929. As
shown in Figure 1, both deutero- and protoporphyrin IX offer multiple points of
functionalization, be it the vinyl groups of the latter or the free β-positions of the former, as well
as the protected carboxylic acid moieties of each, all of which can be manipulated to tune
properties such as cellular uptake, aqueous solubility, and optical imaging capabilities.
H
H
NH
N
N
NH
N
N
HN
HN
O
O
O
O
O
O
O
O
1
2
Figure 1. Individually addressable functionalization points in deuteroporphyrin IX dimethyl
ester 1 (left) and protoporphyrin IX dimethyl ester 2 (right).
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Various functionalization routes have been reported, such as Pd-catalyzed Heck coupling
reactions utilizing a derivative of 1 and methyl acrylate, performed by Smith and Langry in
2
1983. Smith et al. later demonstrated both Heck and Stille couplings at the β-positions,
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synthesizing a variety of alkenyl- and styryl-substituted deutero- and protoporphyrin IX
3
4
derivatives. Numerous Heck couplings have been reported since, as well as Sonogashira
5
couplings more recently. The vinyl groups of both 2 and the corresponding zinc derivative have
been directly functionalized via a Heck reaction by Castella et al., yielding mixtures of four
4
d
regioisomers. Olefin cross-metathesis reactions have been investigated for several derivatives
of protoporphyrin IX and found to give high yields for electron-rich substrates, whilst being less
efficient for electron-deficient alkenes.6
Though much progress has been made with regards to the functionalization of 1, the previously
described couplings have proceeded through mercurated β-positions, which for any biological
studies is far from optimal.2a,3b Additionally, previous endeavors to modify 1 and 2 have been
limited by the availability of halogenated precursors, coupling substrate scope and/or formation
of product mixtures. Thus, we have developed more efficient methods for the halogenation of 1
and 2. This enabled our investigation into an efficient and versatile method for peripheral
functionalization of these natural type IX substituted porphyrin derivatives – most notably the
development of methods for application of the highly versatile Suzuki-Miyaura cross-coupling.7,8
It is hoped that these derivatives may prove to be useful biologically active candidates for
9
treatments such as photodynamic therapy (PDT), as are their parent compounds. The use of
10
protoporphyrin-containing nanomaterials as photosensitizers evokes the demand for methods of
covalent conjugation of these compounds, e.g. via newly introduced functional groups. In
addition, derivatives of 1 and 2 could serve as bactericidal agents against heme-iron dependent
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pathogenic bacteria such as Mycobacterium tuberculosis, Staphylococcus aureus and
Porphyromonas gingivalis, either by disruption of the heme uptake pathway or by delivery of a
1
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drug and analogs of the natural tetrapyrroles are important tools for the elucidation of their
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biosynthetic pathways. Furthermore, protoporphyrin IX and its derivatives promise usefulness
as parts of sensors for toxins and volatile organic compounds (VOCs), e.g., for food safety
1
3
control. The tuning of properties such as solubility could broaden the porphyrins’ spectrum of
applicability in this field.
RESULTS AND DISCUSSION
The β-halogenation of 1 began with the bromination, which followed an adapted literature
14
procedure (Scheme 1, a). The product was obtained in a 92% yield, an improvement on both
procedures referenced, which reported yields of 45% and 40%, respectively. Amalgamation of
both procedures, utilizing NBS as brominating agent, and a temperature of 0 °C for the course of
the reaction and work-up markedly enhanced the efficiency of the reaction. Additionally, in both
reported procedures purification via column chromatography was required, whereas in the
synthesis reported a washing step followed by recrystallization from MeOH afforded 3 not only
in high yield but also high purity. The iodination followed, although reaction conditions were
altered considerably to afford the diiodinated product. Literature procedures were explored.15
However, the best results were obtained upon treatment with NIS with reflux at 80 °C for 48 h,
giving 4 in a yield of 76%.
X
(
a) NBS (4.2 equiv.),
CHCl3, pyridine,
X
NH
N
N
NH
N
N
0
°C, 5 min
HN
HN
(
b) NIS (4.2 equiv.),
CHCl3, pyridine,
80 °C, 35 h
O
O
O
O
O
O
O
O
1
3 X = Br 92%
X = I 79%
4
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Scheme 1. Halogenation of deuteroporphyrin IX dimethylester 1.
The Suzuki-Miyaura Pd-catalyzed coupling reaction was chosen for our initial investigations.8
The first attempt at the Suzuki coupling of 3 and phenylboronic acid (Scheme 2) followed one
reported previously by us16a in which the porphyrin is reacted with 10 equiv. of the boronic acid
in THF with 20 equiv. of K PO and 10 mol% Pd(PPh ) at 60 °C. In this case, the procedure
1
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4
3 4
was unsuccessful in synthesizing the desired product. A second procedure16b was followed which
utilized 10 equiv. of boronic acid per position to be substituted, 20 equiv. of Cs CO and 40
2
3
mol% Pd(dppf)Cl in THF at 80 °C. 5 was obtained in a 60% yield after recrystallization from
2
1
MeOH and confirmed via H NMR and mass spectrometry analysis.
As the formyl functional group is one of the most important for further porphyrin modification
17
and functionalization, the coupling of 3 and 4-formylphenylboronic acid was chosen to be
optimized to establish the best-yielding conditions for future Suzuki-Miyaura coupling reactions.
Initially, identical conditions to those which gave a 60% yield of the diphenyl-substituted
product (5) were utilized (Table 1). This afforded the desired product (6) in a 60% yield after
recrystallization from MeOH. To improve upon this, and to reduce the amount of catalyst
loading, the amount of Pd(dppf)Cl was decreased from 40 mol% to 20 mol% (entry 2), yielding
2
6 in 61%. The reaction conditions were revisited, retaining a catalyst loading of 20 mol% in each
case. Concentration effects were explored, with any reduction in the amount of solvent resulting
in a detrimental effect to the yield of the reaction (entries 3 and 4). Thus, the volume of solvent
was kept at 10 mL for 20–25 mg scale reactions, and investigations moved to the catalyst. Both
PEPPSI-iPr and Pd(dppe)Cl were employed in 20 mol% (entries 5 and 6). However, as neither
2
catalyst demonstrated even close comparability in efficiency to earlier attempts, Pd(dppf)Cl was
2
employed as the catalyst for future coupling reactions. As optimization attempts were
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unsuccessful in achieving higher yields than that of the earlier entries, the conditions detailed in
entry 2 were chosen as optimal for future Suzuki-Miyaura couplings.
Table 1. Optimization of Suzuki-Miyaura coupling reaction (reactions carried out on a 20 mg
scale of 3).
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Entry
Pd
catalyst Base
Solvent
(mL)
Temp
(˚C)
Yield
(%)
(mol%)
(equiv.)
1
2
Pd(dppf)Cl2
40)
Cs CO
(20)
THF
(10)
80
60
2
3
(
Pd(dppf)Cl2
20)
“
“
“
61
(
3
4
“
“
“
“
THF (5)
“
“
35
37
THF
(7.5)
5
6
PEPPSI-iPr
“
“
THF
(10)
“
“
–a
(20)
Pd(dppe)Cl2
“
46
(20)
Reaction conditions: All reactions were performed utilizing 10 equiv. of 4-
formylphenylboronic acid under argon for 18 h. Yields were determined after recrystallization
a
from MeOH. Indicates starting material collected only. “ Indicates “same as above”.
The coupling reaction was repeated using a wide variety of substrates to demonstrate the facile
way the deuteroporphyrin periphery can be manipulated (Scheme 2). The dibrominated
derivative 3 was compared with the diiodinated derivative 4 as a coupling partner. Notably, the
coupling reaction between 4 and 4-formylphenylboronic acid afforded 6 in 79% yield, and higher
yields were observed across the board for all couplings. This indicated that iodinated derivative
was a more efficient coupling partner in these syntheses, and so 4 was used for future reactions.
Aryl couplings tended to give higher yields than those with amine or alkenyl substituents. To
compare the effects of various aromatic systems, coupling of 4 with 9-anthraceneboronic acid,
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N-methylindolylboronic acid, 4-tolylboronic acid and biphenylboronic acid gave 7, 8, 9, and 10
in yields of 53% to 87% (Scheme 2). Higher yields were obtained with less bulky aromatic
substituents, with that of 7 being the lowest, possibly due to the large bulk of the anthracene
moiety so close to the porphyrin macrocycle. Amine couplings were by far the poorest yielding.
Coupling of 4 with 3-aminophenylboronic acid and 4-dimethylaminophenylboronic acid gave 11
and 12 in yields of 25% and 23%, respectively. A Suzuki coupling between 4 and vinylboronic
acid pinacol ester led to the synthesis of protoporphyrin IX dimethyl ester 2 in a yield of 38%.
This reaction demonstrated the ease at which 1 can be transformed into another of the natural
porphyrin derivatives via the use of standard Pd-catalyzed coupling chemistry, albeit if slightly
less cost-efficient. In addition, a coupling with allylboronic acid pinacol ester gave 13 in 34%
yield. An alkyl coupling was also attempted, using butylboronic acid. However, only mono-
substitution and partial dehalogenation occurred, the products of which were determined to be a
mixture of mono-β-substituted dehalogenated deuteroporphyrin, the isomers of which have
proven to be inseparable.
1
1
1
1
1
1
1
1
1
1
2
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X
R
R-B(OH)2 or R-Bpin (20 equiv.),
Cs2CO3 (20 equiv.),
Pd(dppf)Cl2 (20 mol%),
anhydrous THF,
X
R
NH
N
N
NH
N
N
HN
HN
80 °C, 18 h
O
O
O
O
O
O
O
O
3
4
X = Br
X = I
2, 513
O
R =
H
N
5
6
7
8
9
(
from 3) 60%
(
from 4) 70%
(from 3) 61%
(from 4) 79%
(from 3) 31%
(from 4) 53%
(from 3) 57%
(from 4) 72%
(from 4) 77%
N
NH2
10
11
12
13
2
(
from 4) 87%
(from 4) 25%
(from 4) 23%
(from 4) 34% (from 4) 38%
Scheme 2. Suzuki-Miyaura coupling reactions between 3 or 4 and a variety of boronic acids and
boronic acid pinacol esters (2, 5–13).
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Sonogashira coupling reactions were investigated using both 1 and 2 in order to optimize
procedures for more complex synthetic targets, broaden the scope of known derivatives, and
compare with other Pd-catalyzed coupling reactions. No coupling was observed when 3 was
employed as the coupling partner, consistent with the results reported by Brunner and
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b
Schellerer. However, a 14% yield was obtained upon reaction of 4 and trimethylsilylacetylene.
Further investigation found that carrying out the reaction at room temperature, instead of 70 °C,
gave a considerably higher yield of 14, 57% (Scheme 3). Deprotection via TBAF gave 15 in
8
7%.
I
R
(i) CuI (0.30 equiv.),
PPh3 (1.2 equiv.),
Pd(PPh3)Cl2 (10 mol%),
Trimethylsilylacetylene (8.0 equiv.),
TEA, rt, 18 h
I
R
NH
N
N
NH
N
N
HN
HN
(ii) TBAF (2.2 equiv.),
CH2Cl2,
rt, 20 min
O
O
O
O
O
O
O
O
1
4
5
R =
Si
57%
87%
4
1
R =
Scheme 3. Sonogashira coupling of diiododeuteroporphyrin dimethyl ester 4 and subsequent
deprotection to give 15.
Following β-functionalization of 1, the scope of palladium-catalyzed coupling reactions was
expanded to 2. While C-H bond halogenations of chlorin vinyl groups have been reported
1
8
previously, equivalent bromovinyl or iodovinyl derivatives of protoporphyrin IX have been
unknown so far. Attempts to iodinate the vinyl moieties of 2 using either NIS or I and PIFA did
2
not yield the desired product. Conversely, bromination with NBS in DCE at 84 °C afforded the
dibrominated product 18 in 9% (Scheme 4, Table 2, entry 1). Various reaction conditions were
screened for the bromination of 2. As a general trend, it was ascertained that a decrease in
reaction time reduced decomposition of the porphyrin and the use of a minimal amount of NBS
lowered the formation of side products with multiply brominated vinyl groups (entry 2–4). A
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yield of 40% was the highest obtained when 2 was reacted with 2.2 equiv. NBS in DCE at 84 °C
for 2.5 h. Change of solvent to DCM and decrease in the reaction temperature to 40 °C resulted
in no product formation at all (entry 5). Finally, pyridinium bromide perbromide (PBPB) was
1
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1
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2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
employed as a brominating agent (2.2 equivalents) and the reaction was carried out in CHCl at
3
6
1 °C for 3 h and formation of the desired product increased significantly giving 84% yield
(entry 6).
Br
Br
reagent
NH
N
N
NH
N
N
solvent, temp., time
984%
HN
HN
O
O
O
O
O
O
O
O
2
16
Scheme 4. Bromination of the vinyl groups of 2. Reaction conditions used are given in Table 2.
Table 2. Optimization of protoporphyrin IX dimethyl ester (2) bromination to yield 16.
Entry
Brominating agent Reaction time (h) Solvent
(equiv.)
Temp. (˚C) Yield (%)
1
2
3
4
5
6
NBS (2.2)
NBS (3.0)
“
18
5.5
3
DCE
84
“
9
“
22
25
40
–
“
“
NBS (2.2)
“
2.5
5
“
“
DCM
CHCl3
40
61
PBPB (2.2)
3
84
“ Indicates “same as above”
– Indicates no product formation.
With an efficient procedure for the synthesis of precursor 16 at hand, we sought to devise
protocols for Suzuki-Miyaura cross coupling reactions at the vinyl positions. After obtaining
good results for the respective reactions at the β-positions of 1 using a modified literature
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1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
procedure,16b similar reaction conditions were applied for Suzuki-Miyaura coupling reactions of
1
6 with different substrates to afford 17–23 (Scheme 5). 16 was reacted with 20 equiv. of aryl
boronic acid or boronic acid pinacol ester in THF at 66 °C, with Pd(dppf)Cl employed as the
2
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
catalyst and Cs CO as the base (Scheme 5, a). A notable high yield of 86% was obtained in the
2
3
coupling reaction with 4-tolylboronic acid to give 17. Usage of substrates with functional groups
such as 4-methoxyphenyl- and 4-formylphenylboronic acid decreased the product yields (18 and
1
9) to 63% and 67%, respectively. Methyl benzoate substituted porphyrin 20 was isolated in
4
9% yield which was mainly attributed to the low solubility of the boronate ester used, thus
incomplete conversion of the starting material. An anthracene substituent could be introduced in
a moderate yield of 59% (21) whereas coupling reactions with other bulky units such as 1-
methylindole and a BODIPY dye afforded 22 and 23 in only 30% and 24% yield, respectively.
Different coupling conditions were employed for the reaction of 16 with 4-
[(trimethylsilyl)ethynyl]phenylboronic acid pinacol ester. In order to preserve the silyl protecting
groups, thereby preventing side reactions and allowing full characterization of the material, the
base was changed to K PO (20 equiv.) and Pd(PPh ) (10 mol%) was used as a catalyst (Scheme
3
4
3 4
5
, b). Subsequent deprotection with TBAF gave 24 in 32% overall yield.
Br
R
(a) R-B(OH)2 or R-Bpin
Br
(4.020 equiv.),
R
Pd(dppf)Cl2 (20 mol%),
Cs2CO3 (13-20 equiv.),
THF, 66 °C, 1563 h
NH
N
N
NH
N
N
HN
(b) 1. R-Bpin2 (10 equiv.),
Pd(PPh3)4 (10 mol%),
K2PO4 (20 equiv.),
THF, 66 °C, 15 h
HN
2. TBAF (1.7 equiv.),
DCM, rt, 15 min
O
O
O
O
O
O
O
O
16
1724
O
H
O
R =
O
O
1
7
18
19
20
49%
86%
63%
67%
N
F
N
B
N
F
2
1
22
30%
24
23
4%
32% (in 2 steps)
59%
2
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Scheme 5. Suzuki-Miyaura coupling reactions of 16 with different boronic acids and boronic
acid pinacol esters to yield 17–24.
A Masuda borylation19a of 16 using pinacolborane was carried out adapting a procedure by
Hyslop et al.19b which uses Pd(PPh ) Cl (10 mol%) as a catalyst and TEA (20 equiv.) as a base
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
3
2
2
(Scheme 6). The reaction yielded the bisborylated porphyrin (25) in a yield of 48%, as well as
observed but unisolated monoborylated products and recovered starting material.
O
O
Br
B
O
Br
B
HBpin(20.0 equiv.),
Pd(PPh3)2Cl2 (20 mol%),
TEA (20.0 equiv.),
DCE, 84 °C, 3 h
O
NH
N
N
NH
N
N
HN
HN
48%
O
O
O
O
O
O
O
O
16
25
Scheme 6. Masuda borylation of 16 to give 25.
After the promising results obtained from Suzuki-Miyaura coupling on 16, further
investigations in the reactivity of protoporphyrin IX dimethyl ester derivatives were made by
testing the utility of the reversed coupling reaction using 25. Establishing procedures for Suzuki-
Miyaura reactions on protoporphyrin IX dimethyl ester using both reactant combinations would
broaden the range of possible coupling substrates. Exploratory reactions of 25 with 4-
bromotoluene were carried out with optimization of the procedure being attempted (Scheme 7).
Based on a method by Bakar et al.20a that was applied for coupling reactions with meso-
borylated porphyrins, 20 mol% of catalyst Pd(PPh ) and 4.0 equiv. of Cs CO were used in THF
3
4
2
3
(Table 3, entry 1). Coupling product 17 was obtained in only 16% yield. Another procedure was
employed that had been reported by Hata et al.20b for coupling reactions with β-borylated
porphyrins. Use of 10 mol% of Pd (dba) , 0.40 equiv. of PPh and 3.0 equiv. of Cs CO in a
2
3
3
2
3
toluene/DMSO 2:1 mixture led to complete decomposition of the porphyrin within 2 h (entry 2).
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1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
The conditions that had previously been applied for Suzuki-Miyaura coupling reactions with
brominated protoporphyrin IX derivative 16, using 20 mol% of Pd(dppf)Cl and 20 equiv. of
2
Cs CO , yielded compound 17 in 25% (entry 3), a low figure compared to the 86% yield when
2
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
7 was prepared from 16. Clearly, dibrominated precursor 16 proved to be more useful for
Suzuki-Miyaura coupling reactions than diborylated precursor 25.
O
O
B
O
B
4-bromotoluene (2.54.0 equiv)
Pd catalyst
O
base
NH
N
N
NH
N
N
solvent, temp., time
HN
1625%
HN
O
O
O
O
O
O
O
O
25
17
Scheme 7. Suzuki-Miyaura cross-coupling reactions of 25 with 4-bromotoluene to give 17.
Reaction conditions used are given in Table 3.
Table 3. Optimization of Suzuki-Miyaura cross-coupling reactions with borylated
protoporphyrin IX dimethyl ester (25).
Entry Reagents (equiv.)
Time (h) Solvent
THF
Temp. (˚C)
Yield (%)
16
1
2
4-bromotoluene (2.5) 17
Pd(PPh ) (0.20)
66
3
4
Cs CO (4.0)
2
3
4-bromotoluene (4.0) 2
Pd (dba) (0.10)
Toluene/DMSO 80
:1
–
2
2
3
PPh (0.40)
3
Cs CO (3.0)
2
3
3
4-bromotoluene (4.0) 16
THF
66
25
Pd(dppf)Cl (0.20)
2
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Cs CO (20)
2
3
–
Indicates no product formation.
Following the study of the scope of Suzuki-Miyaura reactions, Sonogashira couplings using 16
were investigated as well. No product formation in a coupling with trimethylsilylacetylene was
observed when copper-free conditions were applied. However, use of Pd(PPh ) Cl (10 mol%)
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
3
2
2
with CuI (20 mol%) as a co-catalyst in THF/TEA following a procedure by Fujimoto et al.21
afforded acetylene-appended porphyrin 26 in 98% yield (Scheme 8). A similarly high yield of
9
7% was obtained when phenylacetylene was used as a coupling partner to form 27. Conversely,
reaction with the more electron-deficient methyl 4-ethynylbenzoate did not lead to complete
conversion to the disubstituted product 28, resulting in only 35% yield of desired compound and
a significant amount of recovered starting material. An interchanging cationic and anionic
pathway of the Sonogashira reaction mediated by the electron-rich or electron-poor nature of the
22
alkyne was proposed by Ljungdahl et al. The reaction conditions applied in our studies may
promote the cationic pathway, thereby disfavoring the reaction with electron-poor substrates.
The removal of the trimethylsilyl protection groups of 26 using TBAF proceeded in 86% yield.
R
Br
R
(4.0 equiv.),
R
Br
Pd(PPh3)2Cl2 (10 mol%),
CuI (20 mol%),
THF/TEA 1:1,
NH
N
N
NH
N
N
2540 °C, 1622 h
HN
HN
O
O
O
O
O
O
O
O
16
R = Si
26
2628
CO2Me
27
28
35%
98%
97%
Si
Si
TBAF (2.2 equiv.),
CH2Cl2, rt, 20 min
NH
N
NH
N
N
N
HN
86%
HN
O
O
O
O
O
O
O
O
26
29
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1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Scheme 8. Sonogashira coupling reactions between 16 and different ethynyl substrates to give
2
6–28 and deprotection of 26 with TBAF to give 29.
The ease of appending 16 with an acetylene moiety delivers a readily available starting
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
material for cycloaddition reactions, such as copper-catalyzed 1,3-dipolar cycloadditions of
23
azides and alkynes (“Click reaction”). The feasibility of this reaction for acetylene-appended
protoporphyrin IX derivatives was tested after insertion of zinc(II) in 26 and subsequent TMS-
deprotection to yield 31 (Scheme 9). This was followed by cycloaddition of 31 with 1-azido-3-
bromobenzene (4.0 equiv.) using CuSO ∙5 H O (2.2 equiv.) and sodium ascorbate (4.0 equiv.) in
4
2
DMF to obtain 32 in 28% yield. The meta-bromophenyl substituent introduced to the porphyrin
can be used as a synthetic handle for further arm extensions. This provides acetylene-appended
protoporphyrin IX derivatives as new compounds for Click reactions, possibly adding to the
recently investigated applications of protoporphyrin IX in bioactive materials, biorthogonal
reactions and drug delivery systems.10a,24
Si
Si
Si
Si
Zn(OAc)2·2 H2O (4.0 equiv.),
CH2Cl2/MeOH 3:1,
40 °C, 2.5 h
NH
N
N
N
N
N
N
Zn
HN
74%
O
O
O
O
O
O
O
O
26
30
TBAF (2.4 equiv.),
CH2Cl2, rt, 50 min
Br
Br
98%
N
N
N3
N
(4.0 equiv.),
Br
N
N
N
CuSO4·5 H2O (2.0 equiv.),
sodium ascorbate (4.0 equiv.),
DMF, 100 °C, 5 h
N
N
N
N
N
N
N
Zn
Zn
2
8%
N
O
O
O
O
O
O
O
O
32
31
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Scheme 9. Functionalization of a protoporphyrin IX derivative (31) by azide-alkyne 1,3-dipolar
cycloaddition to give 32.
The optical properties of synthesized porphyrin derivatives studied were in range of expected
parameters. Appending protoporphyrin IX dimethyl ester with aromatic moieties generally led to
a 8–10 nm shift of the last Q band absorption maximum. Ethynyl-substituted free base
derivatives 26–29 showed slightly higher shifts of 9–13 nm, the porphyrin with the largest
change being 28. While the ethynyl moiety extends the conjugation of the porphyrin macrocycle,
the electron-withdrawing carbonyl group in 28 also contributes to the bathochromic shift in
absorption.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
X-ray crystallographic analyses were undertaken on suitable crystals of 5 and 13, the structures
of which were confirmed via single crystal X-ray diffraction (Figure 2). Both structures consist
of a flat macrocycle with an average atom deviation from the least-squares plane (LSP) of the
2
4-atom ring of 0.062 Å (5) and 0.035 Å (13), respectively. This is comparable to literary
examples of deuteroporphyrin IX samples (Figure 3), in which the atom deviation from the LSP
of the macrocycle ranges from 0.029–0.086 Å.25
(
A)
(B)
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1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Figure 2. The molecular structure of compounds 5 (A) and 13 (B). Thermal displacement is
given at 50% probability.
NC
NC
CN
O
CN
O
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
CN
NO2
NH
N
NH
N
N
NH
N
N
N
N
N
N
NC
Ni
N
HN
HN
HN
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
GOTJEE
MESPME
NPRPME
NADPOR
Figure 3. Literary samples of deuteroporphyrin IX dimethyl ester derivatives obtained from the
CCDC database (updated August 2018).25e
The structure of 5 illustrates two packing patterns; the first is the offset head-to-head stacking
pattern, aided by a C–H···O interaction between the methyl ester moiety at O1···H17C and
O1···H13F at a distance of 2.764(8) and 2.664(7) Å, respectively (Figure 4A). The second
packing motif is the head-to-tail overlap caused by interaction of the methyl ester moiety with
the phenyl hydrogen atoms (O3···H36) at a distance of 2.606(8) Å (Figure 4B). This results in
the zig-zag pattern observed for the packing of compound 5 (Figure 5).
(
A)
(B)
Figure 4. Molecular structure of compound 5 showing the head-to-head stacking pattern (A) and
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the head-to-tail stacking pattern (B). O···H interactions are indicated by the red dashed lines.
Thermal displacement is given at 50% probability.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Figure 5. Crystal packing of compound 5 looking down the a-axis. Thermal displacement is
given at 50% probability.
Compound 13 exhibits a head-to-head interaction between the methyl ester moieties,
connected by C–H···O short contacts between O1···H17C and O1···H13C at distances of
2
.649(3) and 2.606(4) Å, respectively (Figure 6). Additionally, a head-to-head overlap aided by a
C–H···O short contact between the methyl ester moieties (O1···H17E) is observed, at a distance
of 2.425(3) Å (Figure 7). This results in the stepwise packing pattern, as illustrated in Figure 8.
The introduction of the carbon between the vinyl group and the β-carbon of the porphyrin
scaffold perturbs the side chain more out-of-plane than that of the naturally occurring
protoporphyrin IX dimethyl ester.26
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1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Figure 6. Molecular structure of compound 13 showing the head-to-head interaction between the
methyl ester moieties. O···H interactions are indicated by the red dashed lines. Thermal
displacement is given at 50% probability.
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Figure 7. Molecular structure of compound 13 showing the head-to-head stacking pattern. O···H
interactions are indicated by the red dashed lines. Thermal displacement is given at 50%
probability.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
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3
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4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
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7
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Figure 8. Crystal packing of compound 13 looking down the a-axis. Thermal displacement is
given at 50% probability.
In comparison to the aforementioned literary samples (Figure 3), the head-to-head stacking and
overlap is the most common packing motif formed. Thus, the head-to-tail stacking featured in 5
is unique, and most likely a result of the additional aromatic ring present.
CONCLUSIONS In conclusion, we have demonstrated the ease at which deutero- and
protoporphyrin IX dimethyl ester can be functionalized via the use of classical palladium-
catalyzed coupling reactions. The optimized conditions will allow further manipulation of optical
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properties, due to the scope of functionalities introduced. The porphyrin derivatives synthesized
herein are promising candidates for apoprotein reconstitution studies to investigate cofactor
2
7
binding and possible enhancement of the catalytic activity of enzymes. Furthermore, it was
shown that the devised reaction procedures enable the facile attachment of functional molecules
such as fluorophores to the porphyrin periphery. In future, this methodology may also be applied
for the introduction of linker groups to produce useful bio-probes.
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EXPERIMENTAL SECTION
General Information. Deuteroporphyrin IX dimethyl ester was purchased from InoChem Ltd.
and used as received. All other reagents were obtained from commercial sources and used as
received, apart from pyrrole which was filtered through a plug of silica before use. All air and/or
water-sensitive materials were handled using standard high vac. procedures. Anhydrous THF
was obtained via passing through alumina under N (g) in a solvent purification system and then
2
further dried over activated molecular sieves. Reactions at elevated temperatures were carried
out using a hot plate with oil bath as a heat source. Flash chromatography was carried out using
either silica gel Florisil (200 mesh; Aldrich) or ALOX (neutral, particle size 0.05–0.15 mm;
Aldrich), as indicated for each synthesis. ALOX was treated by addition of 6% water prior to use
to obtain Brockmann activity grade III. Preparative thin layer chromatography was performed on
precoated preparative Uniplates (silica, 2000 μm, 20 × 20 cm, Analtech). Analytical thin-layer
chromatography was carried out either on precoated 60 F254 silica plates (0.2 mm thick, 20 × 20
cm) or precoated 60 F254 (neutral) ALOX plates and visualized by UV irradiation on a
1
Shimadadzu Multispec-1501. Bruker DPX 400 and Agilent 400 were used to obtain H (400.13
1
3
19
11
MHz), C{H} (100.61 MHz), F{H} (376.60 MHz) and B (128.40 MHz) NMR spectra and a
1
13
Bruker AV 600 was employed for H (600.13 MHz) and C{H} (150.90 MHz) NMR spectra.
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NMR spectroscopy was carried out at room temperature using deuterated solvent, as indicated
for each synthesis. All melting points are uncorrected and determined with a Digital Stuart
SMP10 melting point apparatus. UV/Vis spectra were recorded in solutions using a Specord 250
spectrophotometer from Analytik Jena (1 cm path length quartz cell). Mass spectrometry
analysis (HRMS) was performed with a Q-Tof Premier Waters MALDI quadrupole time-of-
flight (Q-TOF) mass spectrometer equipped with Z-spray electrospray ionization (ESI) and
matrix assisted laser desorption ionization (MALDI) sources in positive mode with trans-2-[3-
1
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0
(4-tert-butylphenyl)-2-methyl-2-propenylidene]malononitrile as the matrix.
General procedure A: Compound 3 or 4 (1.0 equiv.), the appropriate boronic acid or boronic
acid pinacol ester (20 equiv.), Cs CO (20 equiv.), and Pd(dppf)Cl (20 mol%) were dried under
2
3
2
high vac. for 1 h. Anhydrous THF was added under Ar and the solution was degassed via three
(g)
freeze-pump-thaw cycles. The reaction mixture was then heated to 80 °C for 18 h. The solvent
was removed in vacuo and the residue redissolved in CH Cl . This was washed sequentially with
2
2
saturated aqueous NaHCO solution, deionized H O, and brine. The organic layer was dried over
3
2
MgSO , the solvent removed in vacuo and the residue recrystallized from MeOH.
4
General Procedure B: Compound 16 and Cs CO (13–20 equiv.) were dried under high vac.
2
3
for 1 h. Anhydrous THF was added under Ar and the solution was purged with Ar for 20
(g)
(g)
min. The appropriate boronic acid or boronic acid pinacol ester (4.0–20 equiv.) and Pd(dppf)Cl2
20 mol%) were added and the mixture was purged with Ar for another 5 min. The reaction
(
(g)
mixture was then heated to 66 °C for 15–63 h. The solvent was removed in vacuo and the residue
redissolved in CH Cl . This was washed sequentially with saturated aqueous NaHCO solution,
2
2
3
deionized H O, and brine. The organic layer was dried over MgSO , the solvent was removed in
2
4
vacuo and the residue was purified as indicated in the respective section.
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General Procedure C: Compound 16, Pd(PPh ) Cl (10 mol%), CuI (20 mol%) and, if solid,
3
2
2
the ethynyl substrate (4.0 equiv.) were dried under high vac. for 30 min. To a separate sealed
tube, anhydrous THF and anhydrous TEA were added in a 1:1 ratio under Ar , followed by, if
(g)
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0
liquid, the ethynyl substrate (4.0 equiv.). The mixture was purged with Ar for 15 min and then
(g)
transferred to the reaction vessel via a syringe. The reaction was then stirred at 25–40 °C for 16
h. The solvent was removed in vacuo and the residue was purified as indicated in the respective
section.
3
,8-Dibromo-deuteroporphyrin IX dimethyl ester (3) Compound 1 (100 mg, 0.186 mmol) was
dissolved in CHCl (20 mL) and the solution was cooled to 0 °C in an ice-bath. NBS (130 mg,
3
0.730 mmol, 4.2 equiv.) and pyridine (0.20 mL) were added over 2 min, with the reaction
mixture being stirred vigorously at 0 °C for a total of 5 min. The reaction was quenched with
acetone (12 mL), with stirring continued for 5 min. Deionized H O (25 mL) was added, with
2
stirring for a further 5 min at 0 °C. The organic layer was extracted with CHCl and washed
3
twice with deionized H O. The organic layer was dried over MgSO , the solvent removed in
2
4
vacuo, and the residue recrystallized from MeOH to yield a purple crystalline solid (118 mg,
2
8
1
0
.169 mmol, 91%). M.p. = 270–272 °C (lit. 274–277 °C) ; R = 0.73 (ALOX, CH Cl ); H NMR
f 2 2
(
400 MHz, CDCl ): δ = –4.40 (s, 2H, NH), 3.23–3.26 (m, 4H, CH ), 3.56 (s, 3H, CH ), 3.57 (s,
3
2
3
3
H, CH ), 3.58 (s, 3H, CH ), 3.60 (s, 3H, CH ), 3.63 (s, 3H, CH ), 3.64 (s, 3H, CH ), 4.36–4.39
3 3 3 3 3
(
m, 4H, CH ), 9.83 (s, 1H, meso H), 9.91 (s, 1H, meso H), 9.92 (s, 1H, meso H) and 9.99 (s, 1H,
2
1
3
meso H) ppm; C NMR (600 MHz, CDCl ): δ = 11.8, 13.3, 13.3, 21.9, 36.9, 36.9, 51.9, 97.1,
3
9
7.7, 98.1, 98.5 and 173.6 ppm; UV-vis (CH Cl ) λ (log ε) = 402 (5.62), 504 (5.70), 536
max
2
2
+
(
5.73), 572 (5.78) and 625 nm (5.79); HRMS (MALDI) [C H N O Br ] [M] : m/z calcd.
3
2
32
4
4
2
694.0790; found 694.0817.
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,8-Diiodo-deuteroporphyrin IX dimethyl ester (4) Compound 1 (250 mg, 0.463 mmol), NIS
(
440 mg, 1.945 mmol) and pyridine (0.5 mL) were added to CHCl (50 mL) and the reaction
3
mixture was heated to reflux at 80 °C for 48 h. The reaction was quenched with acetone (50 mL),
1
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and deionized H O (50 mL) was added, with the resulting mixture stirred for 5 min. The organic
2
layer was extracted with CHCl and washed twice with deionized H O. The organic layer was
3
2
dried over MgSO , the solvent removed in vacuo, and the residue recrystallized from MeOH to
4
2
8
yield a purple crystalline solid (279 mg, 0.352 mmol, 76%). M.p. = 236 °C (lit. 238 °C) ; R =
f
1
0
.66 (ALOX, CH Cl ); H NMR (400 MHz, CDCl ): δ = –4.07 (s, 2H, NH), 3.24–3.28 (m, 4H,
2
2
3
CH ), 3.59 (s, 3H, CH ), 3.64 (s, 3H, CH ), 3.65 (s, 6H, CH ), 3.67 (s, 3H, CH ), 3.68 (s, 3H,
2
3
3
3
3
CH ), 4.37–4.41 (m, 4H, CH ), 9.95 (s, 1H, meso H), 9.99 (s, 1H, meso H), 10.02 (s, 1H, meso
3
2
13
H) and 10.04 (s, 1H, meso H) ppm; C NMR (600 MHz, CDCl ): δ = 11.7, 11.8, 16.1, 16.2,
3
2
1.9, 36.0, 51.9, 96.6, 97.1, 100.0, 100.4 and 173.6 ppm; UV-vis (CH Cl ) λ (log ε) = 404
2 2 max
(5.46), 504 (5.56), 538 (5.59), 573 (5.62) and 626 nm (5.65); HRMS (MALDI) [C H N O I ]
3
2
32
4
4 2
+
[
M] : m/z calcd. 790.0542; found 790.0513.
,8-Diphenyl-deuteroporphyrin IX dimethyl ester (5) Compound 5 was synthesized in
accordance with general procedure A, utilizing 3 (25 mg, 0.0359 mmol), phenylboronic acid
3
(
88 mg, 0.722 mmol), Cs CO (234 mg, 0.718 mmol) and Pd(dppf)Cl (10.5 mg, 0.0144 mmol,
2 3 2
4
0 mol%) in anhydrous THF (10 mL) to yield large purple crystals (15 mg, 0.0217 mmol, 60%).
Compound 5 was also synthesized from 4 in accordance with general procedure A, utilizing 4
(20 mg, 0.0253 mmol), phenylboronic acid (62 mg, 0.506 mmol), Cs CO (165 mg, 0.506 mmol)
2
3
-3
and Pd(dppf)Cl (4 mg, 5.06 × 10 mmol) in anhydrous THF (10 mL) to yield large purple
2
1
crystals (12.3 mg, 0.0178 mmol, 70%). M.p. = 226 °C; R = 0.77 (ALOX, CH Cl ); H NMR
f
2
2
(400 MHz, CDCl ): δ = –3.58 (s, 2H, NH), 3.27–3.34 (m, 4H, CH ), 3.51 (s, 3H, CH ), 3.56 (s,
3
2
3
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3
H, CH ), 3.66 (s, 3H, CH ), 3.67 (s, 3H, CH ), 3.70 (s, 3H, CH ), 3.73(s, 3H, CH ), 4.40–4.48
3
3
3
3
3
(m, 4H, CH ), 7.70–7.75 (m, 2H, Ar-H), 7.83–7.89 (m, 4H, Ar-H), 8.17 (d, 2H, Ar-H, J = 7.2
2
Hz), 8.22 (d, 2H, Ar-H, J = 7.2 Hz), 10.06 (s, 1H, meso H), 10.15 (s, 1H, meso H), 10.16 (s, 1H,
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13
meso H) and 10.27 (s, 1H, meso H) ppm; C NMR (100 MHz, CDCl ): δ = 11.7, 11.8, 12.3,
3
1
1
5
6
2.4, 21.4, 36.9, 37.0, 51.8, 96.3, 97.3, 99.3, 100.0, 105.0, 127.5, 128.7, 128.7, 132.3, 132.4,
36.1, 173.6 and 173.7 ppm; UV-vis (CH Cl ) λ (log ε) = 403 (5.85), 502 (4.75), 536 (4.63),
2
2
max
+
70 (4.47) and 623 nm (4.31); HRMS (MALDI) [C H N O ] [M] : m/z calcd. 690.3206; found
4
4
42
4
4
90.3207.
,8-Bis(4-formylphenyl)-deuteroporphyrin IX dimethyl ester (6) Compound 6 was synthesized
3
in accordance with general procedure A, utilizing 3 (20 mg, 0.0287 mmol), 4-
formylphenylboronic acid (86 mg, 0.574 mmol), Cs CO (187 mg, 0.574 mmol) and Pd(dppf)Cl
2
2
3
-3
(4.2 mg, 5.74 × 10 mmol) in anhydrous THF (10 mL) to yield a purple crystalline solid (13 mg,
0.0174 mmol, 61%). Compound 6 was also synthesized from 4 in accordance with general
procedure A, utilizing 4 (20 mg, 0.0253 mmol), 4-formylphenylboronic acid (76 mg, 0.506
-3
mmol), Cs CO (165 mg, 0.506 mmol) and Pd(dppf)Cl (4 mg, 5.06 × 10 mmol) in anhydrous
2
3
2
THF (10 mL) to yield a purple crystalline solid (15 mg, 0.0201 mmol, 81%). M.p. = 262 °C; R =
f
1
0
.35 (ALOX, CH Cl ); H NMR (400 MHz, CDCl ): δ = –3.50 (br s, 2H, NH), 3.50 (s, 3H,
2
2
3
CH ), 3.67 (s, 3H, CH ), 3.70 (s, 3H, CH ), 3.75 (s, 3H, CH ), 3.57 (s, 3H, CH ), 3.66 (s, 3H,
3
3
3
3
3
CH ), 3.28–3.35 (m, 4H, CH ), 4.40–4.48 (m, 4H, CH ), 8.31–8.39 (m, 8H, Ar-H), 9.96 (s, 1H,
3
2
2
meso H), 10.07 (s, 1H, meso H), 10.17 (s, 1H, meso H), 10.26 (s, 1H, meso H), 10.35 (s, 1H,
13
CHO) and 10.36 (s, 1H, CHO) ppm; C NMR (100 MHZ, CDCl ): δ = 11.7, 11.8, 12.4, 12.5,
3
2
1.8, 21.9, 36.8, 36.9, 51.8, 96.7, 97.7, 98.9, 99.8, 128.0, 130.1, 130.4, 132.8, 132.9, 135.4,
173.5, 173.5 and 192.3 ppm; UV-vis (CH Cl ) λ (log ε) = 411 (5.11), 505 (4.05), 539 (3.94),
2
2
max
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73 (3.74) and 626 nm (3.60); HRMS (MALDI) [C H N O ] [M] : m/z calcd. 746.3104; found
46 42 4 6
46.3134.
3,8-Bis(9-anthracenyl)-deuteroporphyrin IX dimethyl ester (7) Compound 7 was synthesized
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
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4
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9
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1
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3
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7
8
9
0
in accordance with general procedure A, utilizing 3 (21.5 mg, 0.0309 mmol), 9-
anthraceneboronic acid (160 mg, 0.721 mmol), Cs CO (238 mg, 0.730 mmol) and Pd(dppf)Cl
2
2
3
-3
(
5 mg, 7.02 × 10 mmol) in anhydrous THF (10 mL) to yield a purple crystalline solid (8.4 mg,
.00943 mmol, 31%). Compound 7 was also synthesized from 4 in accordance with general
procedure A, utilizing 4 (20 mg, 0.0253 mmol), 9-anthraceneboronic acid (112 mg, 0.506 mmol),
0
-3
Cs CO (165 mg, 0.506 mmol) and Pd(dppf)Cl (4 mg, 5.06 × 10 mmol) in anhydrous THF (10
2
3
2
mL) to yield a purple crystalline solid (12 mg, 0.0135 mmol, 53%). M.p. = 267 °C; R = 0.75
f
1
(
ALOX, CH Cl ); H NMR (400 MHz, CDCl ): δ = –3.25 (s, 2H, NH), 3.44 (s, 3H, CH ), 3.75
2
2
3
3
(
s, 9H, CH ), 3.63 (s, 3H, CH ), 3.19–3.25 (m, 2H, CH ), 4.34–4.39 (m, 4H, CH ), 3.67 (s, 3H,
3
3
2
2
CH ), 3.07–3.35 (m, 2H, CH ), 4.44–4.49 (m, 2H, CH ), 7.09–7.13 (m, 2H, Ar-H), 7.47–7.53 (m,
3
2
2
2
H, Ar-H), 7.65 (d, 2H, Ar-H, J = 8.4 Hz), 8.25 (d, 2H, Ar-H, J = 8.4 Hz), 8.82 (s, 1H, Ar-H),
.22–7.24 (m, 2H, Ar-H), 7.51–7.57 (m, 2H, Ar-H), 7.84 (d, 2H, Ar-H, J = 9.1 Hz), 8.30 (d, 2H,
7
Ar-H, J = 9.1 Hz), 8.88 (s, 1H, Ar-H), 9.40 (s, 1H, meso H), 9.63 (s, 1H, meso H), 10.14 (s, 1H,
1
3
meso H) and 10.39 (s, 1H, meso H) ppm; C NMR (100 MHz, CDCl ): δ = 11.5, 11.8, 12.2,
3
1
1
2.5, 36.8, 37.0, 40.0, 41.5, 51.7, 51.8, 96.4, 97.5, 98.5, 99.4, 100.1, 125.3, 125.4, 125.6, 125.8,
27.5, 127.6, 128.6, 128.7, 131.6, 131.7, 132.6, 132.7, 173.5 and 173.6 ppm; UV-vis (CH Cl )
2
2
λmax (log ε) = 407 (5.86), 504 (5.95), 538 (5.98), 571 (5.01) and 624 nm (5.05); HRMS:
+
(
MALDI) [C H N O ] [M] : m/z calcd. 890.3832; found 890.3801.
6
0
50
4
4
3
,8-Bis(N-methylindolyl)-deuteroporphyrin IX dimethyl ester (8) Compound 8 was synthesized
in accordance with general procedure A, utilizing 3 (20 mg, 0.0287 mmol), 1-methylindole-5-
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boronic acid pinacol ester (148 mg, 0.574 mmol), Cs CO (187 mg, 0.574 mmol) and
2
3
-3
Pd(dppf)Cl (4.2 mg, 5.74 × 10 mmol) in anhydrous THF (10 mL) to yield a purple crystalline
2
solid (13 mg, 0.0163 mmol, 57%). Compound 8 was also synthesized from 4 in accordance with
general procedure A, utilizing 4 (20 mg, 0.0253 mmol), 1-methylindole-5-boronic acid pinacol
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6
7
8
9
0
-3
ester (130 mg, 0.506 mmol), Cs CO (165 mg, 0.506 mmol) and Pd(dppf)Cl (4 mg, 5.06 × 10
2
3
2
mmol) in anhydrous THF (10 mL) to yield a purple crystalline solid (14.5 mg, 0.0182 mmol,
1
7
2%). M.p. >300 °C; R = 0.54 (ALOX, CH Cl ); H NMR (400 MHz, CDCl ): δ = –3.53 (s, 2H,
f
2
2
3
NH), 3.47 (s, 3H, CH ), 3.68 (s, 3H, CH ), 3.71 (s, 3H, CH ), 3.74 (s, 3H, CH ), 3.52 (s, 3H,
3
3
3
3
CH ), 3.66 (s, 3H, CH ), 3.27–3.35 (m, 4H, CH ), 4.40–4.49 (m, 4H, CH ), 4.05 (s, 3H, N-CH ),
3
3
2
2
3
4.06 (s, 3H, N-CH ), 6.78 (d, 1H, Ar-H, J = 3.0 Hz), 7.29–7.31 (m, 2H, Ar-H), 7.76–7.79 (m,
3
1
7
H, Ar-H), 7.99–8.03 (m, 1H, Ar-H), 8.35 (s, 1H, Ar-H), 6.80 (d, 1H, Ar-H, J = 2.9 Hz), 7.81–
.89 (m, 1H, Ar-H), 8.05–8.10 (m, 1H, Ar-H), 8.42 (s, 1H, Ar-H), 10.10 (s, 1H, meso H), 10.12
1
3
(s, 1H, meso H), 10.22 (s, 1H, meso H) and 10.25 (s, 1H, meso H) ppm; C NMR (100 MHz,
CDCl ): δ = 11.7, 11.8, 12.4, 12.5, 24.9, 33.2, 37.0, 37.1, 51.7, 95.9, 97.0, 99.7, 100.4, 101.5,
3
1
09.3, 109.4, 124.6, 124.7, 126.3, 126.4, 128.9, 130.0, 129.6, 136.4 and 173.7 ppm; UV-vis
(
(
CH Cl ) λ (log ε) = 403 (5.86), 504 (5.96), 539 (5.99), 570 (5.01) and 624 nm (5.05); HRMS:
2
2
max
+
ESI) [C H N O ] [M] : m/z calcd. 796.3737; found 796.3745.
5
0
48
6
4
3
,8-Bis(4-methylphenyl)-deuteroporphyrin IX dimethyl ester (9) Compound 9 was synthesized
in accordance with general procedure A, utilizing 4 (20 mg, 0.0253 mmol), 4-tolylboronic acid
-3
(69 mg, 0.506 mmol), Cs CO (165 mg, 0.506 mmol) and Pd(dppf)Cl (4 mg, 5.06 × 10 mmol)
2
3
2
in anhydrous THF (10 mL) to yield a purple crystalline solid (14 mg, 0.0195 mmol, 77%). M.p.
1
>
300 °C; R = 0.80 (ALOX, CH Cl ); H NMR (400 MHz, CDCl ): δ = –3.57 (s, 2H, NH), 2.68
f
2
2
3
(s, 3H, CH ), 2.69 (s, 3H, CH ), 3.27–3.34 (m, 4H, CH ), 3.52 (s, 3H, CH ), 3.55 (s, 3H, CH ),
3
3
2
3
3
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9
3
.66 (s, 3H, CH ), 3.67 (s, 3H, CH ), 3.70 (s, 3H, CH ), 3.72 (s, 3H, CH ), 4.40–4.48 (m, 4H,
3
3
3
3
CH ), 7.67 (t, 4H, J = 8.03 Hz, Ar-H), 8.04 (d, 2H, J = 8.03 Hz, Ar-H), 8.08 (d, 2H, J = 8.03 Hz,
2
Ar-H), 10.04 (s, 1H, meso H), 10.12 (s, 1H, meso H), 10.13 (s, 1H, meso H) and 10.23 (s, 1H,
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
13
meso H) ppm; C NMR (100 MHz, CDCl ): δ = 11.7, 11.8, 12.3, 12.4, 21.5, 21.6, 21.9, 22.0,
3
3
1
5
7
6.9, 37.0, 51.7, 51.8, 96.1, 97.2, 99.3, 100.0, 129.4, 129.5, 129.6, 132.1, 132.1, 132.2, 137.1,
37.2, 173.6 and 173.7 ppm; UV-vis (CH Cl ) λ (log ε) = 404 (5.03), 503 (3.89), 538 (3.78),
2
2
max
+
71 (3.65) and 625 nm (3.43); HRMS: (MALDI) [C H N O ] [M] : m/z calcd. 718.3519; found
4
6
46
4
4
18.3493.
,8-Bis(4-biphenyl)-deuteroporphyrin IX dimethyl ester (10) Compound 10 was synthesized in
3
accordance with general procedure A, utilizing 4 (20 mg, 0.0253 mmol), 4-biphenylboronic acid
-3
(100 mg, 0.506 mmol), Cs CO (165 mg, 0.506 mmol) and Pd(dppf)Cl (4 mg, 5.06 × 10
2
3
2
mmol) in anhydrous THF (10 mL) to yield a purple solid (18.5 mg, 0.0219 mmol, 87%). M.p.
1
>300 °C; R = 0.81 (ALOX, CH Cl ); H NMR (400 MHz, CDCl ): δ = –3.54 (br s, 2H, NH),
f
2
2
3
3
.27–3.34 (m, 4H, CH ), 3.53 (s, 3H, CH ), 3.62 (s, 3H, CH ), 3.67 (s, 3H, CH ), 3.68 (s, 3H,
2 3 3 3
CH ), 3.69 (s, 3H, CH ), 3.77 (s, 3H, CH ), 4.40–4.47 (m, 4H, CH ), 7.47–7.61 (m, 4H, Ar-H),
3
3
3
2
7
.60–7.72 (m, 4H, Ar-H), 7.92 (t, 4H, J = 7.08 Hz, Ar-H), 8.08–8.12 (m, 4H, Ar-H), 8.24 (d, 2H,
J = 7.86 Hz, Ar-H), 8.29 (d, 2H, J = 7.86 Hz), 10.08 (s, 1H, meso H), 10.13 (s, 1H, meso H),
1
3
1
1
0.20 (s, 1H, meso H) and 10.24 (s, 1H, meso H) ppm; C NMR (100 MHz, CDCl ): δ = 11.6,
3
1.7, 11.7, 21.9, 30.8, 36.6, 36.9, 37.0, 51.6, 51.7, 53.4, 96.3, 96.8, 97.0, 97.2, 115.8, 137.9,
173.6 and 206.8 ppm; UV-vis (CH Cl ) λ (log ε) = 406 (4.98), 504 (3.84), 539 (3.74), 572
2
2
max
+
(3.59) and 626 nm (3.35); HRMS: (MALDI) [C H N O ] [M] : m/z calcd. 842.3832; found
56 50 4 4
8
42.3803.
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1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
3
,8-Bis(3-aminophenyl)-deuteroporphyrin IX dimethyl ester (11) Compound 11 was
synthesized in accordance with general procedure A, utilizing 4 (21.3 mg, 0.0269 mmol), 3-
aminophenylboronic acid pinacol ester (111 mg, 0.506 mmol), Cs CO (165 mg, 0.506 mmol)
2
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
-3
and Pd(dppf)Cl (4 mg, 5.06 × 10 mmol) in anhydrous THF (10 mL). Work-up procedures
2
were followed as previously described, however, column chromatography on Grade III neutral
-3
ALOX (CH Cl /n-hexane, 7:3, v/v) was required to yield a purple solid (4.8 mg, 6.66 × 10
2
2
1
mmol, 25%). M.p. >300 °C; R = 0.88 (ALOX, CH Cl ); H NMR (400 MHz, CDCl ): δ = –3.59
f
2
2
3
(
s, 2H, NH), 3.27–3.34 (m, 4H, CH ), 3.52 (s, 3H, CH ), 3.56 (s, 3H, CH ), 3.66 (s, 3H, CH ),
2 3 3 3
3
.67 (s, 3H, CH ), 3.69 (s, 3H, CH ), 3.72 (s, 3H, CH ), 3.99–4.01 (m, 4H, NH ), 4.40–4.48 (m,
3 3 3 2
4H, CH ), 7.02–7.06 (m, 2H, Ar-H), 7.43–7.49 (m, 2H, Ar-H), 7.52–7.66 (m, 6H, Ar-H), 10.06
2
(
s, 1H, meso H), 10.12 (s, 1H, meso H), 10.16 (s, 1H, meso H) and 10.22 (s, 1H, meso H) ppm;
1
3
C NMR (100 MHz, CDCl ): δ = 14.1, 19.7, 21.9, 22.7, 24.6, 24.8, 29.4, 29.7, 30.3, 31.9, 33.2,
3
37.0, 40.1, 40.7, 40.8, 51.7, 53.4, 83.2, 111.2, 112.7, 112.9, 113.1, 118.5, 125.5, 126.9, 129.4,
1
5
7
33.1, 136.1, 201.7, 205.1 and 212.7 ppm; UV-vis (CH Cl ) λ (log ε) = 401 (5.10), 507 (5.20),
2 2 max
+
46 (5.23), 572 (5.30) and 627 nm (5.29); HRMS: (MALDI) [C H N O ] [M] : m/z calcd.
4
4
44
6
4
20.3424; found 720.3441.
,8-Bis(4-dimethylaminophenyl)-deuteroporphyrin IX dimethyl ester (12) Compound 12 was
synthesized in accordance with general procedure A, utilizing 4 (18.5 mg, 0.0234 mmol), 4-
N,N-dimethylamino)phenylboronic acid (83 mg, 0.505 mmol), Cs CO (165 mg, 0.506 mmol)
3
(
2
3
-3
and Pd(dppf)Cl (4 mg, 5.06 × 10 mmol) in anhydrous THF (10 mL). Work-up procedures
2
were followed as previously described, however, column chromatography on Grade III neutral
-3
ALOX (CH Cl /n-hexane, 7:3, v/v) was required to yield a purple solid (4.1 mg, 5.28 × 10
2
2
1
mmol, 23%). M.p. >300 °C; R = 0.66 (ALOX, CH Cl ); H NMR (400 MHz, CDCl ): δ = –3.74
f
2
2
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(
br s, 2H, NH), 3.31–3.34 (m, 4H, CH ), 3.52 (s, 3H, CH ), 3.55 (s, 6H, CH ), 3.65 (s, 6H, CH ),
2
3
3
3
3
.67 (s, 3H, CH ), 3.70 (s, 3H, CH ), 3.82 (s, 3H, CH ), 3.99 (s, 3H, CH ), 4.39–4.42 (m, 4H,
3 3 3 3
CH ), 7.79–7.84 (m, 4H, Ar-H), 7.64–7.69 (m, 4H, Ar-H), 10.08 (s, 1H, meso H), 10.09 (s, 1H,
2
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
13
meso H), 10.14 (s, 1H, meso H) and 10.17 (s, 1H, meso H) ppm; C NMR (100 MHz, CDCl ): δ
3
=
11.7, 11.7, 12.3, 12.4, 14.1, 21.9, 22.7, 24.8, 29.1, 29.7, 30.0, 31.9, 36.9, 37.0, 37.1, 51.7, 69.7,
3.3, 96.0, 97.0, 99.3, 99.9, 114.1, 115.4, 115.4, 115.5, 126.1, 127.3, 129.7, 131.4, 133.2, 133.2,
33.3, 136.4, 145.8, 145.9, 149.3, 173.6 and 174.7 ppm; UV-vis (CH Cl ) λ (log ε) = 401
8
1
2
2
max
(5.79), 505 (5.89), 538 (5.92), 570 (5.95) and 625 nm (5.99); HRMS: (MALDI) [C H N O ]
48 52 6 4
+
[M] : m/z calcd. 776.4050; found 776.4073.
3,8-Diallyl-deuteroporphyrin IX dimethyl ester (13) Compound 13 was synthesized in
accordance with general procedure A, utilizing 4 (15 mg, 0.0190 mmol), allylboronic acid
pinacol ester (0.07 mL, 63 mg, 0.375 mmol), Cs CO (122 mg, 0.375 mmol) and Pd(dppf)Cl (3
2
3
2
-3
mg, 3.75 × 10 mmol) in anhydrous THF (10 mL) to yield a purple crystalline solid (4 mg, 6.46
-3
1
×
=
10 mmol, 34%). M.p. = 196 °C; R = 0.91 (ALOX, CH Cl ); H NMR (400 MHz, CDCl ): δ
f 2 2 3
–3.71 (s, 2H, NH), 3.28–3.31 (m, 4H, CH ), 3.60 (s, 3H, CH ), 3.62 (s, 3H, CH ), 3.63 (s, 3H,
2
3
3
CH ), 3.65 (s, 3H, CH ), 3.66 (s, 6H, CH ), 4.41–4.46 (m, 4H, CH ), 4.83–4.85 (m, 4H, CH ),
3
3
3
2
2
5
5
1
.23–5.25 (m, 1H, CH2(trans)), 5.31–5.34 (m, 1H, CH2(cis)), 5.26–5.28 (m, 1H, CH2(trans)), 5.35–
.37 (m, 1H, CH2(cis)), 6.54–6.65 (m, 2H, CH ), 10.09 (s, 1H, meso H), 10.10 (s, 1H, meso H),
2
1
3
0.11 (s, 1H, meso H) and 10.12 (s, 1H, meso H) ppm; C NMR (100 MHz, CDCl ): δ = 11.6,
3
11.7, 11.7, 21.9, 30.8, 36.6, 36.9, 37.0, 51.6, 51.7, 53.4, 96.3, 96.8, 97.0, 97.2, 115.8, 137.9,
73.6 and 206.8 ppm; UV-vis (CH Cl ) λ (log ε) = 400 (5.69), 500 (5.79), 534 (5.82), 569
1
2
2
max
+
(5.85) and 622 nm (5.89); HRMS: (MALDI) [C H N O ] [M] : m/z calcd. 618.3206; found
38 42 4 4
618.3224.
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