A highly efficient biomimetic aromatization of Hantzsch-1,4-dihydropyridines with t-butylhydroperoxide, catalysed by iron(III) phthalocyanine chloride

Article abstract of DOI:10.1016/j.bmc.2008.09.004

Rapid aromatization of Hantzsch-1,4-DHPs with t-butylhydroperoxide catalysed by iron(III) phthalocyanine chloride is described. The reaction proceeds smoothly at room temperature within 1-35 min and the products of high purity were isolated in excellent yields. To explain the reactivity of this catalytical system plausible mechanism have been proposed to involve formation of high-valent oxoferryl species as in cytochrome P450 itself.

Full text of DOI:10.1016/j.bmc.2008.09.004

Bioorganic & Medicinal Chemistry 16 (2008) 9276–9282
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Bioorganic & Medicinal Chemistry
journal homepage: www.elsevier.com/locate/bmc
A highly efficient biomimetic aromatization of Hantzsch-1,4-dihydropyridines
with t-butylhydroperoxide, catalysed by iron(III) phthalocyanine chloride
a
a,
b
*
´
´
´
Mirela Filipan-Litvic , Mladen Litvic , Vladimir Vinkovic
a BELUPO Pharmaceuticals, Inc., R&D, Danica 5, 48000 Koprivnica, Croatia
Institute Ruder Boškovi´c, Bijenicka c. 54, 10002 Zagreb, Croatia
b
ˇ
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 18 July 2008
Revised 11 August 2008
Accepted 2 September 2008
Available online 5 September 2008
Rapid aromatization of Hantzsch-1,4-DHPs with t-butylhydroperoxide catalysed by iron(III) phthalocya-
nine chloride is described. The reaction proceeds smoothly at room temperature within 1–35 min and the
products of high purity were isolated in excellent yields. To explain the reactivity of this catalytical sys-
tem plausible mechanism have been proposed to involve formation of high-valent oxoferryl species as in
cytochrome P450 itself.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
1,4-Dihydropyridines
Aromatization
Catalytic
Iron(III) phthalocyanine chloride
t-Butylhydroperoxide
1. Introduction
these biological processes, as well as to develop a practical
synthetic methods for the preparation of polysubstituted pyri-
The first generation of 1,4-dihydropyridines (1,4-DHPs) synthes-
ised more than 30 years ago possess valuable pharmacological activ-
ity as calcium antagonists and found application in drugs for the
treatment of hypertension and atherosclerosis.1 On the molecular
level 1,4-DHP compounds cause vasorelaxation by blocking volt-
age-operated calcium channel in smooth muscle cells and also by
increasing NO release from intact endothelium.2 One of the repre-
sentative, amlodipine (Fig. 1) is one of the best selling drug in phar-
maceutical industry. Although there is still attempts to improve
pharmacological characteristics of 1,4-DHPs such as better bioavail-
ability, activity, and solubility,3 much attention have been devoted
toimprove theirrecentlydiscoveredpharmacological activities such
as antitumor,4 bronchodilating,5 antidiabetic,6 antiviral7 and antian-
ginal.8 Moreover, 1,4-DHP motif present in coenzymes NADH (Fig. 1)
and NADPH mediates hydrogen transfer reactions in biological sys-
tems.9 The oxidation (aromatization) of 1,4-DHPs into correspond-
ing pyridines is the first step of the metabolism of these drugs and
is catalysed by the cytochrome P450 (CYP) 3A4 isoform.10,11 The ac-
tive site of all cytochrome family contain iron ion surrounded with
heme ligand (Fig. 1) which interconverts between several oxidation
states (+2, +3, +4 and +6).
dines, the aromatization of 1,4-DHP derivatives has received con-
siderable attention from synthetic chemists and plethora of
reagents have been used for that purpose such as nitric acid,10,12
CONH2
N
H
CH2
O
O
H
H
H
O
O
P+ O-
Cl
NH2
OH OH
N
O
MeO2C
H3C
CO2Et
N
P+ O-
O
N
H
NH2
N
N
O
CH2
O
H
H
Amlodipine
H
H
OH OH
NADH
CH3
H3C
N
N
Fe
N
N
Thus, cytochrome is capable of performing many oxidation and
reduction reactions in biological systems. In order to understand
CH3
H3C
COOH
COOH
Heme b
* Corresponding author. Tel.: +385 48 652 457; fax: +385 48 652 461.
E-mail address: mladen.litvic@belupo.hr (M. Litvic´).
Figure 1. Chemical structures of amlodipine, NADH and Heme b.
0968-0896/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2008.09.004

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M. Filipan-Litvic et al. / Bioorg. Med. Chem. 16 (2008) 9276–9282
nitrous acid,13 metallic nitrates,14 chromium(VI) oxidants,15
Ph
Ph
CrO2,16 KMnO4,17 BaMnO4,18 MnO2,19 Mn(OAc)3,20 FeCl3Á6H2O,21
K3[Fe(CN)6],22 Hg(II) and Tl(III) salts,23 SnCl4,24 Pb(OAc)4,25 SbCl5,26
I2,27 SeO2,28 H2O2 in ionic liquid29 amongst many others.30 The cat-
alytical oxidations of 1,4-DHPs have recently been developed such
as RuCl3/O2,31 activated charcoal/O2,32 Co(OAc)2/H2O2,33 I2/urea
hydrogen peroxide adduct34 and others.35 Most of the methods
including oxidation with stoichiometric oxidants as well as catalyt-
ical versions use toxic solvents, suffer from low selectivity, harsh
reaction condition, and cumbersome work-up and thus develop-
ment of mild, more selective and practical method is still de-
manded. Moreover, methods published as the biomimetic version
of 1,4-DHPs aromatization were performed with Mn cata-
MeO2C
H3C
CO2Me
CH3
MeO2C
H3C
CO2Me
CH3
a
N
H
6
N
7
Scheme 1. Reagents: (a) t-BuOOH (2 equiv), catalyst 1 - 5, AcOH, rt.
phthalocyanine chloride (1, Entry 1) toward all tested catalysts.
Moreover, iron catalysts (Entries 1–4) in general possess higher
catalytical activity than corresponding copper(II) phthalocya-
nines 4 and 5 (Entries 5 and 6). The complete consumption
of starting 1,4-DHP 6 with anhydrous FeCl3 as catalyst (Entry
4) has been observed after 4 days at room temperature indi-
cating increased reactivity of complexed iron(III) with
phthalocyanine ligands.
37
lysts35f,35g,35i,36 and Ph2S2 but catalysts containing iron ion as in
Heme b (Fig. 1) have not been tested so far. Metalloporphyrins in
oxidation of substrates with various single-oxygen atom donors
have had a major role for understanding of biological related
reaction of cytochrome P-450, where oxo-metalloporphyrins are
accepted as reactive intermediate. There is stark contrast between
state of art porphyrin and phthalocyanine oxidation chemistry.
Although phthalocyanine complexes with a similar planar struc-
ture to the porphyrins have been actively investigated as oxidation
catalysts their catalytic chemistry is practically not developed in
terms of mechanisms and active species involved in these catalytic
oxidations. Therefore, we concentrated our efforts on the develop-
ment of catalytic methods for aromatization of 1,4-DHP com-
pounds employing phthalocyanine catalysts as well as to
investigate the mechanism and active species involved in these
oxidations.
This is also the case with K3[Fe(CN)6],22 as stoichiometric oxi-
dant which shows higher reactivity than noncomplexed iron(III)
salts. An interesting result has been obtained with Fe(II)
phthalocyanine (2, Entry 2) which is almost four times less active
than the corresponding iron(III) complex 1.
Probably, the main reason for that difference in reactivity is the
presence of chloride ion which mimics aminoacid ligand present in
cytochrome active site.
The electron-withdrawing chlorine atoms in Fe(II) 1,2,3,4,8,
9,10,11,15,16,17,18,22,23,24,25-hexadecachloro-29H,31H-phthalo-
cyanine (3) drastically decrease speed of aromatization suggesting
that e-reach phthalocyanine ligand as in complex 1 plays crucial
role of its reactivity. From the solvent screening (Table 2) acetic
acid emerged as the most convenient (Entry 3) due to the fact that
the product was isolated in almost quantitative yield in shortest
reaction time.
The other tested solvents required prolonged stirring to reach
satisfactory conversion (Entry 1) or reaction was not selective
(Entry 5). Beside t-butylhydroperoxide as stoichiometric oxidant
used in preliminary studies, sodium perborate and percarbonate
were also tested (Table 3). However, the reactions were sluggish
and the products were isolated in only 50 and 30%, respectively.
The reaction with urea–hydrogen peroxide adduct did not give a
trace of the product (Entry 4) due to rapid decomposition of the
hydrogen peroxide in acetic acid.
2. Results and discussion
Herein, we would like to report a first biomimetic aromati-
zation of 1,4-DHPs employing t-butylhydroperoxide as stoichi-
ometric oxidant catalysed by iron(III) phthalocyanine chloride
as effective catalyst.38 We began our studies with several iro-
n(II, III) and copper(II) phthalocyanine complexes 1–5 (Fig. 2).
From our previous experience in aromatization of 1,4-
DHPs25,26,34 we have chosen 1,4-DHP 6 as model compound.
The reaction was initially tested in acetic acid as solvent due
to the best solubility of catalysts (Scheme 1). The obtained re-
sults which are outlined in Table 1 show superiority of iron(III)
N
N
N
N
N
N
Fe
N
N
Fe
N
N
N
N
N
N
N
N
2
Cl
1
Cl
Cl
Cl
Cl
Cl
Cl
Cl
N
N
N
N
Cl
Cl
Cl
N
N
Cu
N
N
N
Fe
N
N
N
N
N
Cl
N
N
Cl
Cl
Cl
Cl
Cl
3
4
SO3Na
NaO3S
N
N
N
Cu
N
N
N
N
N
SO3Na
NaO3S
5
Figure 2. Phthalocyanine complexes.

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M. Filipan-Litvic et al. / Bioorg. Med. Chem. 16 (2008) 9276–9282
Table 1
Table 5
Aromatization of 6 with phthalocyanine catalysts
Optimization of the amount of the catalyst 1
Entry Catalysta
Timeb
Entry
5 (mol%)
0.1
1
2
5
10
Time (min)
Yield (%)
1
2
3
Fe(III) phthalocyanine chloride (1)
Fe(II) phthalocyanine (2)
Fe(II) 1,2,3,4,8,9,10,11,15,16,17,18,22,23,24,25-hexadecachloro- 12 h
20 min
75 min
1
7440
1218
20
2
1
96
97
99
99
98
2
3
4
5
29H,31H-phthalocyanine (3)
4
5
6
FeCl3
4 days
15 days
15 days
Cu(II) phthalocyanine (4)
Cu(II) phthalocyanine-tetrasulfonic acid, tetrasodium salt (5)
a
2 mol%.
results are shown in Table 6. The obtained results indicate high
efficacy of the new catalytical system. The reactions proceeded at
room temperature and were completed within 1–35 min. To our
knowledge this is one of the fastest oxidation system used so far
for the aromatization of 1,4-DHPs at room temperature. The char-
acteristics of the reaction are high selectivity and tolerance to
many functional groups present on 1,4-DHP ring. The yields of
the products were high-to-excellent and were ranged between
88 and 99%. Although, the reaction was very fast, a still slight dif-
ference in reactivity between aryl substituted 1,4-DHPs having
electron donating and withdrawing substituents was observed.
When methyl ester group (Entry 8) in molecule was replaced with
more hydrophobic ethyl, isopropyl and t-butyl groups (Entries 27–
29), a drastical shortening of reaction time was observed. This fact
increases the value of our method due to the fact that most of the
published methods were tested on 1,4-DHPs having ethyl ester
groups rather than less reactive dimethyl ester groups as in our
work. Moreover, the 1,4-DHP 36 having n-propyl groups on posi-
tions 2 and 6 instead of the methyl groups was slower oxidized
suggesting that lipophilicity on that positions decrease the reaction
speed.
b
Complete conversion of starting material.
Table 2
Aromatization of 6 in different solvents
Entry
Solvent
Time (h)
Yield (%)
1
2
3
4
5
6
7
CHCl3
1
93
50
99
CH2Cl2
CH3COOH
CH3CN
DMF
Acetone
Toluene
24
0.3
43
24
43
24
a
—
—
—
b
a
60
a
Low chemoselectivity.
Low conversion (<10%).
b
Table 3
Aromatization of 6 with different oxidants
Entry
Oxidant
Time (h)
Yield (%)
1
2
3
4
t-BuOOH
0.3
99
50
30
0
Based on this observations as well as similarity to cytochrome
promoted aromatization of 1,4-DHP drugs, we have concluded that
from the obtained results speed of metabolism for newly synthes-
ised generation of 1,4-DHPs could be predicted, Figure 3. This as-
pect is very important during the drug design.
NaBO3Á4H2O
Na2CO3Á1.5H2O2
CO(NH2)2ÁH2O2
120a
120a
24
a
Low chemoselectivity.
The 1,4-DHPs having alkyl substituents on position 4 (Entries 1–
7) were almost instantly oxidized with expected results, extrusion
of alkyl radicals affording unsubstituted pyridine derivative 37.
This phenomena is typical for the aromatization with metallic
salts15,20,21,24–26 as well as for cytochrome P450.39 This findings
demonstrate that our catalytical system behaves as cytochrome.
Unexpectedly, 4-n-propyl derivatives 38–40 afforded nondealky-
lated products (Entries 5–7) in high yields. However, pyridine
derivative 38 was isolated as a mixture with a small amount (4%)
of 37 as product of dealkylation. The dealkylation of 4-benzyl-
1,4-DHP 10 afforded benzaldehyde as side-product which was iso-
lated during the chromatographic purification of crude product 37.
In our recent paper, employing I2/urea hydrogen peroxide adduct34
as oxidant, we have described formation of benzyl iodide as deal-
kylation side product which suggests that conditions employing
catalytical system t-BuOOH/iron(III) phthalocyanine chloride
might cause overoxidation of benzylalcohol to benzaldehyde. To
prove this hypothesis, we performed the oxidation of benzylalco-
hol in conditions employed for the aromatization of 1,4-DHPs,
Scheme 2. To our surprise, the reaction was selective using stoichi-
ometric amount of oxidant and was completed within one hour.
The product was isolated in 90% yield.
Table 4
Optimization of the amount of oxidant
Entry
t-BuOOH (equiv)
Time (min)
Yield (%)
1
2
3
4
1
2
3
5
180
20
20
97
99
99
99
15
The optimization of the amount of the oxidant (Table 4) did not
give significant difference in selectivity and the yield of the product
was almost quantitative.
However, the reaction with 2 equiv of t-butylhydroperoxide ap-
peared to be optimal due to the fact that the reaction is much faster
compared to stoichiometric amount and similar to incremental
amount of the oxidant. The last parameter tested for the optimiza-
tion of the reaction was the amount of the catalyst. The results pre-
sented in Table 5 show shortening of the reaction time as the
amount of catalyst increased. Although 0.1 mol% and 1 mol% of
the catalyst gave complete conversion of the starting 1,4-DHP 6,
the reaction with 2 mol% was significantly faster. The 5 and 10
mol% of the catalyst gave almost instant reaction but slightly less
selective than 2 mol%.
The further examination of this catalytical system for the selec-
tive oxidation of alcohols to aldehydes and ketones is beyond the
scope of this article and the obtained results will be published in
due course.
Plausible mechanism of the Fe(III) phthalocyanine chloride-cat-
alysed aromatization of 1,4-DHPs with t-BuOOH is outlined in
Scheme 3 using the reaction with model 1,4-DHP 6 as a represen-
tative. As already mentioned, less catalytical activity of anhydrous
With optimized condition in hand, we have decided to explore
the scope and limitation of this new catalytic method. The series of
substituted 1,4-DHPs was subjected to reaction and the obtained

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M. Filipan-Litvic et al. / Bioorg. Med. Chem. 16 (2008) 9276–9282
Table 6
Aromatization of substituted 1,4-DHPs with t-BuOOH (2 equiv) catalysed by iron(III) phthalocyanine chloride 1 (2 mol%) in acetic acid at rt
R
R4
R1O2C
R3
CO2R2
R3
R1O2C
R3
CO2R2
R3
t-BuOOH, catalyst 1
AcOH, rt
N
H
N
7, 37 - 62
R4
6, 8 - 36
Entry
1,4-DHP
R
R1;R2;R3
Product
37
Time (min)
Yielda (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
8
9
H
i-Pr
CH2Ph
Et
n-Pr
n-Pr
n-Pr
Ph
o-ClC6H4
m-ClC6H4
p-ClC6H4
o-NO2C6H4
m-NO2C6H4
p-NO2C6H4
m-NO2C6H4
o-CH3C6H4
m-CH3C6H4
p-CH3C6H4
Me; Me; Me
Me; Me; Me
Me; Me; Me
Me; Me; Me
Me; Me; Me
Et; Et; Me
H
H
H
H
2
3
3
3
3
3
3
20
5
30
20
5
35
20
4
5
5
7
9
94
94
90
92
91c
94
92
99
96
96
99
96
93
96
90
89
93
92
91
89
94
97
89
88
92
93
95
99
97
91
37
37b
37
38
39
40
7
10
11
12
13
14
6
n-Pr
n-Pr
n-Pr
i-Pr; i-Pr; Me
Me; Me; Me
Me; Me; Me
Me; Me; Me
Me; Me; Me
Me; Me; Me
Me; Me; Me
Me; Me; Me
Me; Et; Me
Me; Me; Me
Me; Me; Me
Me; Me; Me
Me; Me; Me
Me; Me; Me
Me; Me; Me
Me; Me; Me
Me; Me; Me
Me; Me; Me
Me; Me; Me
Me; Me; Me
Et; Et; Me
Ph
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
61
62
o-ClC6H4
m-ClC6H4
p-ClC6H4
o-NO2C6H4
m-NO2C6H4
p-NO2C6H4
m-NO2C6H4
o-CH3C6H4
m-CH3C6H4
p-CH3C6H4
2,4-(CH3)2C6H4
o-CH3OC6H4
m-CH3OC6H4
p-CH3OC6H4
2-Thienyl
2-(5-Br-thienyl)
2-Furyl
2,4-(CH3)2C6H4
o-CH3OC6H4
m-CH3OC6H4
p-CH3OC6H4
2-Thienyl
2-(5-Br-thienyl)
2-Furyl
17
10
7
3d
22d
8d
30
3
p-Ph-C6H4
Ph
Ph
Ph
Ph
p-Ph-C6H4
Ph
i-Pr; i-Pr; Me
t-Bu; t-Bu; Me
Et; Et; n-Pr
Ph
Ph
Ph
1
1
30
a
Isolated yields. All products were identified by comparison with authentic samples (mp, IR, 1H and 13C NMR).
Benzaldehyde was isolated as a side-product.
According to HPLC analysis the crude product contains 4% of dealkylated product 37.
3 equiv of t-BuOOH was used.
b
c
d
son why cytochrome P450 is capable of reacting with chemically
nonreactive compounds such as alkanes (for example, oxidation
of cholesterol).40 Therefore, the mechanism of iron(III) phthalocya-
nine chloride catalysed aromatization of 1,4-DHPs is probably very
similar to cytochrome promoted oxidations in biological systems.
As proposed in Scheme 3 the catalytical cycle begins with dissolu-
tion of the catalyst 1 in acetic acid. Good solubility of the catalyst is
a result of coordination of one molecule of the solvent on free coor-
dination place of iron to form complex 63. In the next step the
replacement of the solvent with t-BuOOH takes place affording
64 which upon oxidative cleavage followed by elimination of
t-butanol give oxoferryl radical cation 65. This type of the reactive
intermediates is proposed and evidenced in cytochrome promoted
oxidations,41 although there are still controversies of its exi-
stance.42 Due to the fact that oxoferryl radical cation in cytochrome
promoted reaction is equally formed by the action of any oxygen
donor (molecular oxygen or peroxides), we have proposed its for-
mation in our reaction. The next step of the cytochrome-promoted
hydroxylations of alkanes is oxygen insertion to form correspond-
ing alcohols. According to some authors this process takes place in
two steps via alkyl radical.43 Thus, the formation of radical cation
67 with subsequent protonation of the catalyst to form hydroxyfer-
ryl complex 66 is the first step in aromatization of 1,4-DHP 6. By
this process the iron(IV) does not change its oxidation state but
free oxygen radical is paired and stabilized. The radical cation 67
R
R1OOC
R2
COOR1
R2
N
H
R = Electronic nature of substituents slightly influence aromatization speed
R1 = More lipophyllic substituents accelerate the reaction
R2 = More lipophylllic substituents decelerate reaction
Figure 3. The influence of substituents on aromatization speed.
CHO
CH2OH
a
71
Scheme 2. Reagents: (a) t-BuOOH, catalyst 1, AcOH, rt.
70
FeCl3 compared to iron(III) phthalocyanine chloride (1) suggests
formation of active species of higher oxidation states of iron,
formed by the action of t-butylhydroperoxide. This is the main rea-

´
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M. Filipan-Litvic et al. / Bioorg. Med. Chem. 16 (2008) 9276–9282
Ph
Ph
H3COOC
H3C
COOCH3
CH3
H3COOC
H3C
COOCH3
CH3
- H+
N
N
N
H
N
N
Fe3+
Cl
=
Fe
N
N
N
N
N
69
7
Cl
1
HOAc
Ph
- e-
+ H+
OH
Fe4+
H3COOC
H3C
COOCH3
CH3
- H2O
O
N
H
H
H3C
O
Fe3+
Cl
63
68
- H+
Cl
66
Ph
H
H3COOC
H3C
COOCH3
CH3
+ t-BuOOH
- HOAc
N
H
- e-
+ H+
67
O
(H3C)3C O
H
O
Ph
H
- t-BuOH
H3COOC
H3C
COOCH3
CH3
Fe4+
Cl
65
Fe3+
+
N
H
Cl
64
6
Scheme 3. Plausible mechanism for the iron(III) phthalocyanine chloride (1) catalysed aromatization of 1,4-DHPs.
3. Conclusions
H CH2Ph
MeO2C
H3C
CO2Me
In summary, this paper describes a new biomimetic aromatiza-
H
.
tion of substituted 1,4-DHPs employing 2 mol% of iron(III) phthalo-
cyanine chloride as catalyst and t-butylhydroperoxide as
stoichiometric oxidant. This catalytic system is superior over liter-
ature employed methods concerning reaction speed and catalyst
activity. The reaction is carried out at room temperature in acetic
acid as solvent and the products, substitute pyridines, were iso-
lated in high purity and excellent yield. The obtained results
showed that the model is behaved as enzyme cytochrome P450.
+
N
CH3
MeO2C
H3C
CO2Me
CH3
H
72
N
- H+
CH2
37
CH2OH
CHO
65
t-BuOOH
4. Experimental
4.1. General
73
70
71
Scheme 4. Plausible mechanism for the oxidative rearrangement of radical cation
72 affording product of dealkylation 37 and benzaldehyde (71).
IR spectra were recorded on a Perkin-Elmer Spectrum One spec-
trometer. 1H NMR and 13C NMR were recorded on a Bruker 600 for
CDCl3 solutions, shifts are given in ppm downfield from TMS as an
internal standard. HPLC analyses for determination of the amount
of dealkylation product 37 were performed with a Thermo Separa-
tion Products (San Jose, USA) instrument equipped with vacuum
degasser SCM 1000, quaternary gradient pump P 4000, autosampler
AS 3000, scanning UV/vis detector UV 3000 HR and ChromQuest 251
software. TLC analyses were performed on Merck’s (Darmstadt, Ger-
many) DC-alufolien with Kieselgel 60254. Melting points were deter-
mined using a Büchi B540 instrument. The 1,4-DHPs were prepared
by modified Hantzsch procedures38,44,45 and fully characterized
(mp, IR, 1H, 13C NMR spectra and elemental analysis) in our recent
paper.34 The literature known aromatization products were charac-
terized by a comparison with authentic samples (melting point) and
their NMR (1H, 13C) and IR spectra.15e,15l,15n,25,27a,29,34
rearranges to more stable benzylic radical with elimination of pro-
ton similarly to mechanism of Mn(OAc)3 promoted aromatization
of 1,4-DHPs.20 The second electron transfer leads to formation of
protonated pyridine 69 which after deprotonation gives the prod-
uct of aromatization 7. The catalyst 1 is regenerated by reductive
elimination of water molecule and thus closing the catalytic cycle.
The mechanism for the oxidative dealkylation of 4-benzyl-1,4-
DHP 10 is outlined in Scheme 4.
The radical cation 72 obtained by one electron transfer to oxo-
ferryl specie 65, rearranges followed by deprotonation to form
dealkylation product 37 and benzyl radical 73 which is instantly
quenched by the oxidant to furnish benzylalcohol 70. The latter
is further oxidized probably by oxoferryl radical cation 65 (Scheme
3) to give benzaldehyde 71 as final product.
We believe that this catalytic system better describes cyto-
chrome P450 than any of published in the literature due to the fact
that iron(III) phthalocyanine chloride is a few times more active
catalyst and contain iron ion surrounded with phthalocyanine
ligand of planar structure as heme ligand.
4.2. General procedure for the aromatization of 1,4-DHPs
To a solution of corresponding 1,4-DHP (1.0 mmol) in AcOH
(10 mL), Fe(III) phthalocyanine chloride
1 (12 mg, 2.0 mol%,

´
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M. Filipan-Litvic et al. / Bioorg. Med. Chem. 16 (2008) 9276–9282
Synth. Commun. 2000, 30, 1661; (g) Vanden Eynde, J. J.; Mayence, A.;
Maquestiau, A. Tetrahedron 1992, 48, 463; (h) Hashemi, M. M.; Balalaie, S. J.
Sci. I. R. Iran 1997, 8, 161; (i) Wang, B.; Hu, Y.; Hu, H. Synth. Commun. 1999, 29,
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Choghamarani, A. G.; Taqian-Nasab, A. Asian J. Chem. 2001, 13, 887; (k)
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Ghorbani-Choghamarani, A.; Safaiee, M.; Shahamirian, M. Synth. Commun.
2007, 37, 1817.
0.02 mmol) was added at once and after that to the resulting solu-
tion t-butylhydroperoxide (0.36 mL, 5.5 M in decane, 2.0 mmol)
was added dropwise. Reaction mixture was stirred at rt during
the time indicated in Table 6. After that to the reaction mixture
water (20 mL) and dichloromethane (10 mL) were added. The pH
was adjusted to seven with solid NaHCO3, organic extract was sep-
arated and water layer was additionally extracted with dichloro-
methane (2Â 10 mL). Combined organic extracts were dried over
anhydrous Na2SO4, filtered and evaporated. The crude product
was purified by column chromatography on silica gel (CH2Cl2/
EtOAc, 9:1) to yield the product of purity >98%. The identities of
products were confirmed by mp, IR, 1H, and 13C NMR spectral data.
16. Ko, K. J.; Kim, J. Y. Tetrahedron Lett. 1999, 40, 3207.
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Acknowledgments
The authors express their gratitude to the Belupo Pharmaceuti-
cals Inc. for financial support of this research.
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