Reductive Amination-A convenient method for generating diverse, mono-functionalised 5,10,15,20-tetraphenyl porphyrins

Article abstract of DOI:10.1055/s-0028-1083335

Formylation followed by reductive amination of 5,10,15,20-tetraphenyl porphyrin (TPP) is shown to be a versatile synthetic procedure for monosubstitution of the porphyrin core re-giospecifically at one β-position. A diverse range of substituents can be introduced in this way in good yields, including cyclen aza-crown macrocycles. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0028-1083335

PAPER
551
Reductive Amination – A Convenient Method for Generating Diverse,
Mono-Functionalised 5,10,15,20-Tetraphenyl Porphyrins
R
eductive Amina
h
tion to Gene
r
rate
M
on
i
o-Func
s
tionalised Porph
W
yrins elch, Stephen J. Archibald,* Ross W. Boyle*
Department of Chemistry, University of Hull, Kingston-upon-Hull, East Yorkshire, HU6 7RX, UK
Fax +44(1482)466410; E-mail: r.w.boyle@hull.ac.uk
Received 11 August 2008; revised 1 October 2008
ble exception to this list of difficulties related to porphyrin
substitution is the Vilsmeier–Haack formylation reaction
which, due to the formation of a highly electron-with-
drawing iminium salt intermediate that must be hydroly-
Abstract: Formylation followed by reductive amination of
5,10,15,20-tetraphenyl porphyrin (TPP) is shown to be a versatile
synthetic procedure for monosubstitution of the porphyrin core re-
giospecifically at one b-position. A diverse range of substituents
can be introduced in this way in good yields, including cyclen aza- sed to give the formyl-substituted product, only results in
crown macrocycles.
the introduction of more than one formyl group under ex-
treme forcing conditions. For the reasons described, Vils-
meier–Haack formylation is widely used in porphyrin
synthetic chemistry, and the synthesis of monoformyl
5,10,15,20-tetraphenyl porphyrin (1; Scheme 1) has been
refined and optimised by Crossley and Officer,8 who also
used it as a key intermediate for generating other mono-
substituted porphyrins by reduction, halogenation and
Wittig-type reactions. In view of the fact that monoformyl
TPP can be accessed in excellent yield (>90%) it seemed
ideal for generating diversity via a common reaction. Re-
ductive amination using sodium cyanoborohydride is a
well-understood reaction,9 but seemed to us to have been
somewhat neglected in porphyrin synthetic chemistry. We
therefore undertook a study to investigate the applicability
of this method for generating a diverse set of monosubsti-
tuted TPPs via the readily accessible formyl derivative.
Key words: porphyrin, substitution, cyclen, amination, regioselec-
tive
Porphyrins are aromatic tetrapyrrolic macrocycles, which
are found widely in nature where they play vital roles in
photosynthesis, cellular respiration, oxygen transport and
storage, and as components of metalloenzymes.1 The
functions performed by porphyrins in nature have driven
research into the use of synthetic porphyrins in many
areas including artificial photosynthetic systems,2 as oxi-
dation catalysts3 and in photodynamic therapy of cancer.4
In order to integrate porphyrins into biomimetic systems
and fine-tune their optical and redox properties for these
applications, efficient methods for functionalising the
porphyrin core are constantly under investigation.5 One
area that proves particularly troublesome is the regiose-
lective mono-functionalisation of porphyrins. Synthetic
methods leading to porphyrins bearing single functional
groups can be roughly divided into two categories: firstly,
methods that incorporate a substituent into one of the units
used to form the porphyrin, followed by a ‘mixed conden-
sation’ of this precursor with other unsubstituted units.
However, this approach then requires tedious isolation of
the monosubstituted product from unsubstituted and high-
er substituted contaminants, usually by exhaustive chro-
matography. A second option is to take advantage of the
aromatic nature of the porphyrin to perform electrophilic
substitution reactions on the core. Several reactions of this
type are often used including nitration6 and halogenation,7
however, careful control of reaction conditions is often re-
quired in order to prevent contamination with di- or higher
substituted products. Many electrophilic reactions com-
monly performed on other aromatic systems also fail on
the porphyrins, perhaps the most notable of these being
the otherwise ubiquitous Friedel–Crafts alkylation and
acylation reactions, thus further limiting the usefulness of
electrophilic substitution in porphyrin chemistry. A nota-
R
N
N
N
N
M
M = H2, R = H
(i)
M = Cu, R = H (90%)
M = H2, R = CHO (74%) 1
(ii)
Scheme 1 Reagents and conditions: (i) Cu(OAc)2, MeOH–CHCl3,
D; (ii) (a) POCl3, DMF–DCE; (b) H2SO4; (c) NaOH.
A small set of aliphatic and aromatic amines (Scheme 2)
were selected in order to initially test the applicability of
the reductive amination reaction. The results suggested
that the reaction works well, except for amines which in-
corporate a free carboxyl group in the structure (both 5-
aminopentanoic acid and 4-carboxyaniline failed to give
any product); however, the success of the reaction for the
4-carboethoxyaniline, which gave a 74% yield of the ex-
pected product 2, suggested that carboxyl derivatives can
be accessed via the ester derivatives. Aniline gave the ex-
SYNTHESIS 2009, No. 4, pp 0551–0556
x
x
.
x
x
.2
0
0
9
Advanced online publication: 27.01.2009
DOI: 10.1055/s-0028-1083335; Art ID: P08308SS
© Georg Thieme Verlag Stuttgart · New York

552
C. Welch et al.
PAPER
CHO
CHO
N
N
NH
N
NH
N
HN
HN
(i)
(i)
R
NH
N
N
NH
NH
HN
HN
N
N
(80%) 3
R = PhNH (77%) 3
(ii)
4-(EtOOC)PhNH (72%) 2
O
Ot-Bu O
Ot-Bu
OMe
OH
N
N
N
O
(61%) 4
(75%) 5
O
NH
NH
N
NO2
NO2
N
O
Ot-Bu
O
Ot-Bu O
Ot-Bu
N
NH
N
N
N
N
N
(52%) 7
HN
O
Ot-Bu O
Ot-Bu
(52%) 8
HN
N
N
N
O
Ot-Bu
HN
(20%) 6
N
Scheme 3 Reagents and conditions: (i) (a) aniline, AcOH (cat.),
toluene; (b) NaBH3CN, MeOH; (ii) (a) 1,4-di(1-bromomethyl)ben-
zene, Et3N, CH2Cl2; (b) 1,4,7-tris(tert-butoxycarbonylmethyl)-
1,4,7,10-tetraazacyclododecane, Et3N.
O
O
Ot-Bu
Scheme 2 Reagents and conditions: (i) (a) AcOH (cat.), toluene–
THF, D; (b) NaBH3CN, MeOH.
methyl ester of 4-(2-amino-2¢-carbomethoxy)ethyl nitro-
benzene gave the expected product 4 in 61% yield, to our
surprise however, the analogous compound bearing a free
carboxyl group also underwent reaction to give the de-
sired product 5 in a higher yield of 75%. The latter result
suggests that carboxyl groups per se do not universally
preclude reaction under these conditions.
pected secondary amine 3 in the highest yield (77%) of the
four amines tested.
In order to further explore the reaction, two substrates
were next selected that bore two different functional
groups, nitro and carboxyl or ester-protected carboxyl, in
addition to the amine required for attachment to the por-
phyrin. Such compounds seemed to offer the possibility of
introducing two points for further diversification. The
A number of important metalloenzymes contain two or
more complexed metal ions which are integral to the func-
tion they perform; notable examples being nitrite reduc-
Synthesis 2009, No. 4, 551–556 © Thieme Stuttgart · New York

PAPER
Reductive Amination to Generate Mono-Functionalised Porphyrins
553
tase,10 and superoxide dismutase.11 Dinucleating ligands
formed with porphyrins and aza-crown macrocycles are
of particular relevance to modelling the active site of cy-
tochrome c oxidase.12,13
in anhydrous toluene (50 mL) was heated under reflux conditions,
using a Dean–Stark head to remove H2O from the reaction. The re-
action was monitored using TLC (silica; CH2Cl2) until no further re-
action change was observed (24 h). After cooling, NaBH3CN (0.02
g, 0.32 mmol) and MeOH (10 mL) were added and the mixture was
stirred for 2 h. H2O (100 mL) was added and the organic layer was
separated, washed with brine (100 mL) and dried (MgSO4). After
removal of solvent in vacuo, the purple solid residue was adsorbed
onto silica and separated using gravity column chromatography (sil-
ica; CH2Cl2). Relevant fractions were identified by TLC (silica;
CH2Cl2), collected and concentrated to yield the product.
Methods for the construction of linked aza-crown–
porphyrin compounds are therefore of great interest in
relation to producing biomimetic systems.14,15 The com-
pounds would also be of interest for use in the construc-
tion of agents for detecting tumours using computed
tomography or magnetic resonance imaging.16,17 Bearing
this in mind, we chose to next determine whether the re-
ductive amination procedure could be used to conjugate a
second macrocyclic ligand system to the porphyrin. Two
1,4,7,10-tetraazacyclodecane (cyclen) based ligands with
single amino-presenting side arms were selected for the
study, which differed in the linker through which the ami-
no side arm was attached to the cyclen macrocycle. The
first of these, in which the linking group was an amide,
gave the desired product 6, but in a rather disappointing
yield of 20%. Nevertheless, given the simplicity of the re-
action and steric bulk of the porphyrin and cyclen macro-
cycles, this still represents a convenient method with
which to access a relatively complex molecular system.
Repeating the reaction with an analogous cyclen, in which
the carbonyl of the amide linker was replaced with a satu-
rated carbon, resulted in a dramatic increase in the yield of
product 7 to 52%, suggesting that the method is generally
useful for the formation of this type of bulky porphyrin–
cyclen dimer.
Yield: 0.17g (77%); purple solid; mp >350 °C (dec.); Rf = 0.28 (sil-
ica; CH2Cl2).
1H NMR (400 MHz, CDCl3): d = –2.84 (br s, 2 H, NH), 4.15 (br s,
1 H, PhNH), 4.43 (s, 2 H, CH2NH), 6.46 (d, 3J = 7.8 Hz, 2 H, HN-
3
Ar-2,6-H), 6.63 (t, 3J = 7.8 Hz, 1 H, HN-Ar-4-H), 7.05 (t, J = 7.8
Hz, 2 H, HN-Ar-3,5-H), 7.57–7.72 (m, 12 H, 5,10,15,20-Ar-3,4,5-
H), 8.03–8.07 and 8.11–8.16 (m, 8 H, 5,10,15,20-Ar-2,6-H), 8.57
(d, 3J = 4.8 Hz, 1 H, b-H), 8.68–8.79 (m, 5 H, b-H).
13C NMR (100 MHz, CDCl3): d = 44.2, 113.3, 117.6, 119.3, 119.4,
120.3, 120.6, 126.6, 126.7, 127.3, 127.6, 127.7, 128.5, 129.0, 133.2,
134.5, 134.6, 134.7, 141.9, 142.0, 142.2, 142.3, 148.1.
UV/Vis (CH2Cl2): lmax = 419, 515, 549, 590, 645 nm.
MS (ESI): m/z = 720 [M + H]+.
HRMS: m/z calcd for C51H38N5: 720.3122; found: 720.3109.
Ethyl 4-[(5,10,15,20-Tetraphenylporphyrin-2-ylmethyl)ami-
no]benzoate (2)
A mixture of 5,10,15,20-tetraphenylporphyrin-2-carbaldehyde8
(0.13 g, 0.2 mmol), ethyl 4-aminobenzoate (0.033 g, 0.2 mmol) and
AcOH (2 drops) in toluene (50 mL) was heated under reflux condi-
tions, using a Dean–Stark head to remove H2O from the reaction.
The reaction was monitored using TLC (silica; CH2Cl2–MeOH,
249:1) until no further reaction change was observed (30 h). After
cooling, NaBH3CN (0.02 g, 0.32 mmol) and MeOH (10 mL) were
added and the mixture was stirred for 2 h. H2O (100 mL) was added
and the organic layer was separated, washed with brine (100 mL)
and dried (MgSO4). After removal of solvent in vacuo, the purple
solid residue was adsorbed onto silica and separated using gravity
column chromatography (silica; CH2Cl2–MeOH, 249:1). Relevant
fractions were identified by TLC (silica; CH2Cl2–MeOH, 249:1),
collected and concentrated to yield the product.
Finally, encouraged by the success of the majority of re-
actions attempted, we decided to examine the possibility
of further diversifying the porphyrin by reaction of the
secondary amine generated by the reductive amination re-
action. Mono-formyl TPP was therefore reacted with
aniline under the optimised conditions to give 80% of the
N-phenyl-N¢-methylporphyrinato amine 3, which was
subsequently reacted with 1,4-di(1-bromomethyl)ben-
zene and N,N¢,N¢¢-tris(tert-butoxycarbonylmethyl)cyclen
to yield the expected product 8 in 52% yield (Scheme 3).
Given the extreme steric crowding in this system, the suc-
cess of this reaction was extremely encouraging and sug-
gests the method described here has potential for the
construction of relatively complex multifunctional, bis-
macrocylic systems.
Yield: 0.115g (72%); purple solid; mp >350 °C (dec.); Rf = 0.32
(silica; CH2Cl2–MeOH, 249:1).
1H NMR (400 MHz, CDCl3): d = –2.84 (br s, 2 H, NH), 1.37 (t,
3J = 7.2 Hz, 3 H, CH3), 4.33 (q, 3J = 7.2 Hz, 2 H, CH2CH3), 4.51 (br
3
d, 3J = 4.8 Hz, 2 H, CH2NH), 4.58 (br t, J = 4.8 Hz, 1 H, PhNH),
6.46 (d, 3J = 8.8 Hz, 2 H, HN-Ar-2,6-H), 7.65–7.78 (m, 12 H,
5,10,15,20-Ar-3,4,5-H), 7.83 (d, 3J = 8.8 Hz, 2 H, Ar-3,5-H), 8.10–
8.13 and 8.20–8.23 (m, 8 H, 5,10,15,20-Ar-2,6-H), 8.66 (d, 3J = 4.8
Hz, 1 H, b-H), 8.74 (s, 1 H, b-H), 8.78–8.87 (m, 5 H, b-H).
All reagents were purchased from Lancaster Synthesis or Sigma
Aldrich and used without further purification. NMR spectra were
obtained on a Jeol JNM-ECP 400 MHz FT-NMR spectrometer,
with chemical shifts reported in ppm relative to the residual solvent
peak. UV/vis absorption spectra were recorded on an Agilent 8453
spectrometer. Analytical TLC was carried out using aluminium-
backed silica gel 60 F254 and visualised using UV light (254/365
nm) or iodine vapour. Column chromatography was performed us-
ing ICN silica 32-63, 60 Å. Mass spectrometric analyses (ESI) were
made using a Waters ZQ-4000 instrument.
13C NMR (100 MHz, CDCl3): d = 14.6, 43.6, 60.3, 111.9, 118.9,
119.3, 119.5, 120.3, 120.7, 126.6, 126.7, 126.8, 127.2, 127.7, 127.8,
128.6, 131.3, 133.2, 134.5, 134.6, 141.8, 141.9, 142.1, 142.2, 151.7,
166.9.
UV/Vis (CH2Cl2): lmax = 420, 516, 550, 590, 646 nm.
MS (ESI): m/z = 792 [M + H]+.
HRMS: m/z calcd for C54H42N5O2: 792.3333; found: 792.3321.
Methyl 3-(4-Nitrophenyl)-2-[(5,10,15,20-tetraphenylporphy-
rin-2-ylmethyl)amino]propionate (4)
Phenyl(5,10,15,20-tetraphenylporphyrin-2-ylmethyl)amine (3)
A mixture of 5,10,15,20-tetraphenylporphyrin-2-carbaldehyde8
(0.2 g, 0.3 mmol), aniline (0.03 g, 0.3 mmol) and AcOH (2 drops)
To
a stirred solution of 5,10,15,20-tetraphenylporphyrin-2-
carbaldehyde8 (0.16 g, 0.25 mmol) and methyl (S)-2-amino-3-(4-ni-
Synthesis 2009, No. 4, 551–556 © Thieme Stuttgart · New York

554
C. Welch et al.
PAPER
trophenyl)propanoate18 (0.056 g, 0.25 mmol) in a mixture of toluene
(100 mL) and MeOH (30 mL), was added AcOH (0.25 mL). The
dark coloured solution was heated under reflux conditions and, after
1 h, NaBH3CN (0.2 g, 3 mmol) was added and heating was contin-
ued for 48 h. The reaction was monitored by TLC (silica; CH2Cl2)
and, after complete consumption of starting materials, the solvent
was removed in vacuo. The dark solid residue was partitioned be-
tween CH2Cl2 (50 mL) and H2O (50 mL) and the organic layer was
separated and dried over MgSO4. After removal of solvents in vac-
uo, the product was isolated by column chromatography (silica;
CH2Cl2).
urated with toluene (2 × 10 mL). To the dark solid residue was add-
ed a solution of 1,4,7-tris(tert-butoxycarbonylmethyl)-1,4,7,10-
tetraazacyclododecane hydrobromide salt19 (0.2 g, 0.4 mmol) in an-
hydrous CH2Cl2 (25 mL) and Et3N (0.1 mL). The reaction mixture
was stirred at r.t. for 8 h under an argon atmosphere. After removal
of solvent in vacuo, the crude residue was taken into CH2Cl2 (100
mL) and washed with H2O (2 × 50 mL). The organic layer was sep-
arated, dried over MgSO4, concentrated to a volume of ~10 mL and
purified by gravity column chromatography (silica; CH2Cl2–
MeOH, 97:3). Relevant fractions were identified by TLC (silica;
CH2Cl2–MeOH, 97:3), collected and concentrated to yield the title
compound.
Yield: 0.13g (61%); purple solid.
Yield: 0.14 g (54%); yellow oil.
1H NMR (400 MHz, CDCl3): d = –2.79 (br s, 2 H, NH), 3.01 (m,
2 H, NHCH2), 3.48 (ABX, dd, 3JX–A = 7.0 Hz, 3JX–B = 6.7 Hz, 1 H),
1H NMR (400 MHz, CD2Cl2): d = 1.31 [s, 9 H, (CH3)3], 1.35 [s, 9 H,
(CH3)3], 1.38 [s, 9 H, (CH3)3], 2.63 (m, 8 H, 4 × NCH2), 2.78 (t,
3J = 6.7 Hz, 2 H, NCH2), 2.89 (m, 2 H, NCH2), 2.92 [s, 2 H,
2
3.56 (s, 3 H, COOCH3), 3.84 (ABX, br d, JA–B = 16.2 Hz, 1 H),
3.98 (ABX, br d, 2JB–A = 16.2 Hz, 1 H), 7.22 (d, 3J = 8.7 Hz, O2N-
Ar-3,5-H, 2 H), 7.75–7.78 (m, 12 H, 5,10,15,20-Ar-3,4,5-H), 7.99
(m, 4 H, O2N-Ar-2,6-H, 5-Ar-2,6-H), 8.18–8.20 (m, 6 H, 10,15,20-
Ar-2,6-H), 8.57 (d, 3J = 4.5 Hz, 1 H, b-H), 8.76–8.84 (m, 6 H, b-H).
3
CH2C(O)], 3.21 [s, 4 H, 2 × CH2C(O)], 3.52 (t, J = 6.7 Hz, 2 H,
NCH2), 3.67 (t, 3J = 5.0 Hz, 2 H, NCH2), 7.51 (d, 3J = 8.9 Hz, 2 H,
O2N-Ar-2,6-H), 8.15 (d, 3J = 8.9 Hz, 2 H, O2N-Ar-3,5-H).
13C NMR (100 MHz, CDCl3): d = 39.3, 47.2, 51.8, 61.8, 119.1,
119.2, 120.3, 120.6, 123.4, 126.6, 126.7, 126.9, 127.0, 127.7, 127.8,
128.3, 130.1, 133.2, 133.4, 134.5, 134.6, 141.9, 142.1, 142.2, 142.6,
145.2, 146.8, 174.3.
13C NMR (100 MHz, CD2Cl2): d = 28.2, 28.3, 45.1, 49.3, 52.4, 52.8,
52.9, 53.3, 53.5, 53.5, 54.9, 55.5, 58.6, 81.0, 124.0, 128.0, 144.5,
148.2, 169.7, 170.8, 171.0.
MS (ESI): m/z = 664 [M + H]+, 686 [M + Na]+.
UV/Vis (CH2Cl2): lmax = 420, 517, 549, 583, 646 nm.
MS (ESI): m/z = 851 [M + H]+.
tert-Butyl [4-(4-Aminobenzoyl)-7,10-bis-tert-butoxycarbonyl-
methyl-1,4,7,10-tetraazacyclododec-1-yl]acetate
HRMS: m/z calcd for C55H43N6O4: 851.3340; found: 851.3329.
To a solution of tert-butyl [4,7-bis-tert-butoxycarbonylmethyl-10-
(4-nitrobenzoyl)-1,4,7,10-tetraazacyclododec-1-yl]acetate (0.5 g,
0.75 mmol) in EtOH (25 mL) was added 5% wt Pd/C (0.1 g) and the
mixture was stirred at r.t. under an H2 atmosphere. After 2 h, TLC
(silica; CH2Cl2–MeOH, 9:1) showed complete consumption of the
starting material, and the catalyst was removed by filtration. After
the solvent was concentrated in vacuo to a volume of ~5 mL, the
crude mixture was separated by gravity column chromatography
(silica; CH2Cl2–MeOH, 97:3→93:7). Relevant fractions were iden-
tified by TLC (silica; CH2Cl2–MeOH, 97:3), collected and concen-
trated to yield the title compound.
3-(4-Nitrophenyl)-2-[(5,10,15,20-tetraphenylporphyrin-2-yl-
methyl)amino]propionic Acid (5)
To a solution of 5,10,15,20-tetraphenylporphyrin-2-carbaldehyde8
(0.75 g, 1.2 mmol) and (S)-4-nitrophenylalanine (0.2 g, 0.9 mmol)
in THF (100 mL) was added a solution of NaBH3CN (0.11 g, 1.8
mmol) in MeOH (50 mL) and the mixture was heated under reflux
conditions. The reaction was monitored by TLC (silica; CH2Cl2–
MeOH, 95:5) until no further change was discernable (24 h). Sol-
vent was removed in vacuo and the residue was partitioned between
H2O (50 mL) and CH2Cl2 (50 mL). The organic layer was separated,
washed with brine (2 × 30 mL) and dried over MgSO4. After re-
moval of solvent, the product was isolated using column chroma-
tography (silica; CH2Cl2–MeOH, 97:3).
Yield: 0.34 g (71%); yellow solid.
1H NMR (400 MHz, CD2Cl2): d = 1.36 [s, 27 H, (CH3)3], 2.64 (m,
8 H, 4 × NCH2), 2.87 (br s, 4 H, 2 × NCH2), 3.22 (br s, 4 H, 2 ×
NCH2), 3.56 [br s, 4 H, 2 × CH2C(O)], 3.91 [br s, 2 H, CH2C(O)],
6.52 (d, 3J = 8.4 Hz, 2 H, O2N-Ar-2,6-H), 7.07 (d, 3J = 8.4 Hz, 2 H,
O2N-Ar-3,5-H).
13C NMR (100 MHz, CD2Cl2): d = 23.9, 24.0, 52.0 (br), 52.7 (br),
55.2, 57.8 (br), 76.6, 109.9, 122.9, 124.3, 144.0, 166.8, 167.9.
Yield: 0.55 g (75%); purple solid.
1H NMR (400 MHz, CDCl3): d = –2.79 (br s, 2 H, NH), 3.01 (m,
2 H, NHCH2), 3.48 (ABX, dd, 3JX–A = 7.0 Hz, 3JX–B = 6.7 Hz, 1 H),
2
3.56 (s, 3 H, COOCH3), 3.84 (ABX, br d, JA–B = 16.2 Hz, 1 H),
2
3
3.98 (ABX, br d, JB–A = 16.2 Hz, 1 H), 7.22 (d, J = 8.7 Hz, 2 H,
O2N-Ar-3,5-H), 7.75–7.78 (m, 12 H, 5,10,15,20-Ar-3,4,5-H), 7.99
tert-Butyl (4,7-Bis-tert-butoxycarbonylmethyl-10-{4-
[(5,10,15,20-tetraphenylporphyrin-2-ylmethyl)amino]benzoyl}-
1,4,7,10-tetraazacyclododec-1-yl)acetate (6)
3
(m, J = 8.7 Hz, 4 H, O2N-Ar-2,6-H, 5-Ar-2,6-H), 8.18–8.20 (m,
6 H, 10,15,20-Ar-2,6-H), 8.57 (d, 3J = 4.5 Hz, 1 H, b-H), 8.76–8.84
(m, 6 H, b-H).
To
a heated solution of 5,10,15,20-tetraphenylporphyrin-2-
13C NMR (100 MHz, CDCl3): d = 39.3, 47.2, 51.8, 61.8, 119.1,
119.2, 120.3, 120.6, 123.4, 126.6, 126.7, 126.9, 127.0, 127.7, 127.8,
128.3, 130.1, 133.2, 133.4, 134.5, 134.6, 141.9, 142.1, 142.2, 142.6,
145.2, 146.8, 174.3.
carbaldehyde8 (0.20 g, 0.31 mmol) and tert-butyl [4-(4-aminoben-
zoyl)-7,10-bis-tert-butoxycarbonylmethyl-1,4,7,10-tetraazacyclo-
dodec-1-yl]acetate (0.17 g, 0.27 mmol) in THF (30 mL), was added
AcOH (0.1 mL) followed by a solution of NaBH3CN (0.1 g, 1.5
mmol) in MeOH (10 mL). The mixture was heated under reflux
conditions and monitored by TLC (silica; CH2Cl2–MeOH, 9:1) until
all the starting material had been consumed (3 d). The solvent was
removed in vacuo and CH2Cl2 (100 mL) was added to the dark solid
residue. After washing with H2O (100 mL), the organic layer was
dried over MgSO4 and the volume reduced to ~10 mL. The crude
mixture was separated by gravity column chromatography (silica;
CH2Cl2–MeOH, 97:3→9:1). Relevant fractions were identified by
TLC (silica; CH2Cl2–MeOH, 97:3), collected and concentrated to
yield the desired product.
UV/Vis (CH2Cl2): lmax = 420, 517, 549, 583, 646 nm.
MS (ESI): m/z = 851 [M + H]+.
HRMS: m/z calcd for C55H43N6O4: 851.3340; found: 851.3329.
tert-Butyl [4,7-Bis-tert-butoxycarbonylmethyl-10-(4-nitroben-
zoyl)-1,4,7,10-tetraazacyclododec-1-yl]acetate
To 4-nitrobenzoic acid (0.07 g, 0.4 mmol) was added SOCl2 (10
mL) and the mixture was stirred at r.t. for 1 h, followed by 5 h heat-
ing under reflux conditions. When the evolution of acidic gas had
finished, the SOCl2 was removed in vacuo and the residue was trit-
Synthesis 2009, No. 4, 551–556 © Thieme Stuttgart · New York

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Reductive Amination to Generate Mono-Functionalised Porphyrins
555
Yield: 0.07 g (20%); purple solid.
gravity column chromatography (silica; CH2Cl2–MeOH, 9:1). Rel-
evant fractions were identified by TLC (silica; CH2Cl2–MeOH,
9:1), collected and concentrated to yield compound 8.
1H NMR (400 MHz, CD2Cl2): d = –2.91 (br s, 2 H, NH), 1.35 [s,
27 H, (CH3)3], 2.61–3.28 [m, 18 H, 8 × NCH2, CH2C(O)], 3.51 [br
s, 4 H, 2 × CH2C(O)], 4.38 (s, 2 H, CH2NHPh), 6.38 (d, 3J = 8.3 Hz,
2 H, O2N-Ar-3,5-H), 7.06 (d, 3J = 8.3 Hz, 2 H, O2N-Ar-2,6-H),
Yield: 0.044 g (52%); purple solid; mp >350 °C; Rf = 0.44 (silica;
CH2Cl2–MeOH, 9:1).
3
7.61–7.68 (m, 12 H, 5,10,15,20-Ar-3,4,5-H), 8.03 (d, J = 7.9 Hz,
1H NMR (400 MHz, CDCl3): d = –3.05 (br s, 2 H, NH), 1.48 [s, 9 H,
C(CH3)3], 1.49 [s, 18 H, C(CH3)3], 2.80–2.94 (m, 12 H,
NCH2CH2N), 3.01–3.10 (m, 4 H, NCH2CH2N), 3.29 [s, 2 H,
(CH2COOt-Bu)], 3.38 [s, 4 H (CH2COOt-Bu)], 3.42 (s, 2 H, NCH2-
Ph), 4.46 (s, 2 H, NCH2-Ph), 4.59 (s, 2 H, CH2NPh), 6.38 (d,
3J = 7.9 Hz, 2 H, CH2-Ar-H), 6.83–6.89 (m, 1 H, N-Ar-4-H), 6.90–
6.99 (m, 4 H, N-Ar-2,6-H and CH2-Ar-H), 7.24–7.31 (m, 2 H, N-
Ar-3,5-H), 7.68–7.84 (m, 12 H, 5,10,15,20-Ar-3,4,5-H), 8.00–8.04
and 8.05–8.10 (m, 4 H, Ar-2,6-H), 8.14–8.20 (m, 4 H, Ar-2,6-H),
4 H, 5,10-Ar-2,6-H), 8.10 (m, 4 H, 15,20-Ar-2,6-H), 8.56 (d,
3J = 4.8 Hz, 1 H, b-H), 8.70–8.77 (m, 6 H, b-H).
13C NMR (100 MHz, CD2Cl2): d = 28.2, 28.3, 43.8, 52.0, 54.1, 55.2,
81.1, 112.5, 119.8, 121.1, 127.1, 127.2, 127.7, 128.1, 128.7, 133.6,
134.9, 134.9, 135.0, 142.2, 142.3, 142.5, 142.7, 171.0.
MS (ESI): m/z (%) = 1260 [M + H]+, 1282 (100) [M + Na]+.
UV/Vis (CH2Cl2): lmax = 419, 515, 549, 592, 646 nm.
3
8.62 (d, J = 4.8 Hz, 1 H, b-H), 8.71 (s, 1 H, b-H), 8.75–8.80 (m,
2 H, b-H), 8.83 (d, 3J = 4.8 Hz, 1 H, b-H), 8.89–8.91 (m, 2 H, b-H).
tert-Butyl (4,7-Bis-tert-butoxycarbonylmethyl-10-{4-
[(5,10,15,20-tetraphenylporphyrin-2-ylmethyl)amino]benzyl}-
1,4,7,10-tetraazacyclododec-1-yl)acetate (7)
13C NMR (100 MHz, CDCl3): d = 28.13, 28.17, 47.4, 48.8 (br), 49.1,
49.7, 51.2, 52.2, 53.4, 55.1, 58.0, 58.4, 81.6, 81.7, 113.5, 117.9,
119.4, 120.3, 120.7, 124.4, 126.7, 126.8, 126.9, 127.4, 128.0, 128.8,
128.9, 129.2, 130.9, 133.1, 134.3, 134.4, 134.5, 141.0, 141.3, 141.6,
141.8, 150.3, 169.6, 170.5.
To
a heated solution of 5,10,15,20-tetraphenylporphyrin-2-
carbaldehyde8 (0.23 g, 0.36 mmol) and 1,4,7-tris(tert-butoxycarbo-
nylmethyl)-10-(4-aminobenzyl)-1,4,7,10-tetraazacyclododecane20
(0.20 g, 0.32 mmol) in THF (50 mL) under an inert (N2) atmo-
sphere, was added AcOH (0.1 mL) followed by a solution of
NaBH3CN (0.05 g, 0.8 mmol) in MeOH (20 mL). The mixture was
heated under reflux conditions and monitored by TLC (silica;
CH2Cl2–MeOH, 95:5) until all the starting material had been con-
sumed (5 d). The solvent was removed in vacuo and CH2Cl2 (100
mL) added to the dark solid residue. After washing with H2O (100
mL) the organic layer was separated and dried over MgSO4 and the
volume reduced to ~10 mL. The crude mixture was separated by
gravity column chromatography (silica; CH2Cl2–MeOH,
99:1→95:5). Relevant fractions were identified by TLC (silica;
CH2Cl2–MeOH, 95:5), collected and concentrated to yield the de-
sired product.
UV/Vis (CH2Cl2): lmax = 420, 516, 551, 589, 646 nm.
MS (ESI): m/z = 1337 [M + H]+.
Acknowledgment
C.W. thanks the University of Hull Clinical Biosciences Institute
for a PhD studentship. The authors would like to thank the EPSRC
National Mass Spectrometry Service Centre, Swansea for analyses.
References
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Yield: 0.21 g (52%); purple solid.
1H NMR (400 MHz, CDCl3): d = –2.77 (br s, 2 H, NH), 1.45 [s,
27 H, (CH3)3], 2.08–2.80 (m, 16 H, 8 × NCH2), 2.93–3.05 [m, 4 H,
2 × CH2C(O)], 3.18 (s, 2 H, NCH2Ph), 3.25–3.35 [m, 2 H,
CH2C(O)], 4.47 (s, 2 H, CH2NHPh), 6.47 (d, 3J = 8.3 Hz, 2 H, HN-
Ar-3,5-H), 7.18 (d, 3J = 8.3 Hz, 2 H, HN-Ar-2,6-H), 7.65–7.82 (m,
12 H, 5,10,15,20-Ar-3,4,5-H), 8.10–8.16 (m, 4 H, 5,10-Ar-2,6-H),
8.17–8.27 (m, 4 H, 15,20-Ar-2,6-H), 8.66 (d, J = 4.8 Hz, 1 H, b-
H), 8.76–8.88 (m, 6 H, b-H).
13C NMR (100 MHz, CDCl3): d = 27.9, 27.9, 44.1, 49.4, 55.7, 55.9,
56.0, 58.9, 82.1, 82.5, 113.3, 119.2, 119.3, 120.4, 120.8, 126.1,
126.6, 126.7, 126.8, 127.2, 127.6, 127.8, 128.4, 130.9, 133.3, 134.5,
134.6, 141.8, 142.1, 142.5, 147.5, 172.6, 173.5.
3
MS (ESI): m/z = 1246 [M + H]+.
UV/Vis (CH2Cl2): lmax = 419, 516, 549, 593, 646 nm.
tert-Butyl [4,7-Bis-tert-butoxycarbonylmethyl-10-(4-{[phe-
nyl(5,10,15,20-tetraphenylporphyrin-2-ylmethyl)amino]meth-
yl}benzyl)-1,4,7,10-tetraazacyclododec-1-yl]acetate (8)
To a solution of compound 3 (0.05 g, 0.07 mmol) in CH2Cl2 (5 mL)
was added Et3N (2 drops) and a,a-dibromoxylene (0.018 g, 0.07
mmol), and the mixture was stirred at r.t. Monitoring of the reaction
mixture by TLC (silica; CH2Cl2) showed consumption of the a,a-di-
bromoxylene after 4 h. A solution of tert-butyl (4,7-bis-tert-but-
oxycarbonylmethyl-1,4,7,10-tetraazacyclododec-1-yl)acetate (0.035
g, 0.07 mmol) in CH2Cl2 (5 mL) was added. After heating under re-
flux conditions for a further 3 d, TLC (silica; CH2Cl2–MeOH, 9:1)
showed consumption of starting compound 3. CH2Cl2 (100 mL) was
added, the solution was washed with H2O (100 mL) and the organic
layer was collected and dried (MgSO4). Following filtration, the so-
lution was concentrated to a small volume (~10 mL) and purified by
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Synthesis 2009, No. 4, 551–556 © Thieme Stuttgart · New York