Rapid, efficient, room temperature aromatization of Hantzsch-1,4-dihydropyridines with vanadium(V) salts: superiority of classical technique versus microwave promoted reaction

Article abstract of DOI:10.1016/j.tet.2008.08.103

The aromatization of 1,4-dihydropyridines (1,4-DHPs) employing group 4 (Zr and Hf) and 5 (V, Nb, Ta) elements of periodic system has been studied. The reaction with VOCl₃ in dichloromethane at room temperature afforded products, substituted pyridines, in high-to-excellent yield. For the first time, the formation of charge-transfer complexes (CTCs) has been evidenced in preorganization step between 1,4-DHP and oxidant before electron transfer. The CTC has been formed only in neutral solvents such as dichloromethane and is characterized by intensive coloration. The aromatization of 1,4-DHP with V₂O₅ in refluxing acetic acid has found to be superior over microwave promoted reaction in solventless media. The only reasonable explanation was found in polymeric structure of V₂O₅, which slowly transfer energy of microwaves needed for the activation of the reactants. The solvent polarity dependent oxidative dealkylation of 4-n-propyl-1,4-DHP has been discovered. Unexpectedly, the reaction in acetic acid afforded only 33% of dealkylated product compared to 91% obtained in dichloromethane under the same reaction conditions.

Full text of DOI:10.1016/j.tet.2008.08.103

Tetrahedron 64 (2008) 10912–10918
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Rapid, efficient, room temperature aromatization of Hantzsch-1,4-
dihydropyridines with vanadium(V) salts: superiority of classical
technique versus microwave promoted reaction
a
a,
b
*
´
´
´
Mirela Filipan-Litvic , Mladen Litvic , Vladimir Vinkovic
a BELUPO Pharmaceuticals, Inc., R&D, Danica 5, 48000 Koprivnica, Croatia
b
ˇ
ˇ
Institute RuCer Boskovi´c, Bijenicka c. 54, 10002 Zagreb, Croatia
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 25 July 2008
Received in revised form 12 August 2008
Accepted 27 August 2008
Available online 17 September 2008
The aromatization of 1,4-dihydropyridines (1,4-DHPs) employing group 4 (Zr and Hf) and 5 (V, Nb, Ta)
elements of periodic system has been studied. The reaction with VOCl3 in dichloromethane at room
temperature afforded products, substituted pyridines, in high-to-excellent yield. For the first time, the
formation of charge-transfer complexes (CTCs) has been evidenced in preorganization step between 1,4-
DHP and oxidant before electron transfer. The CTC has been formed only in neutral solvents such as
dichloromethane and is characterized by intensive coloration. The aromatization of 1,4-DHP with V2O5 in
refluxing acetic acid has found to be superior over microwave promoted reaction in solventless media.
The only reasonable explanation was found in polymeric structure of V2O5, which slowly transfer energy
of microwaves needed for the activation of the reactants. The solvent polarity dependent oxidative
dealkylation of 4-n-propyl-1,4-DHP has been discovered. Unexpectedly, the reaction in acetic acid af-
forded only 33% of dealkylated product compared to 91% obtained in dichloromethane under the same
reaction conditions.
Keywords:
1,4-Dihydropyridines
Aromatization
Vanadium(V) salts
NbCl5
TaCl5
Microwave irradiation
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
Additionally, during the storage of drugs containing 1,4-DHPs slow
oxidation takes pace by the action of air oxygen or UV irradi-
Described more than one century ago by Arthur Hantzsch,1 1,4-
dihydropyridines (1,4-DHPs) have now been recognized as valuable
drugs for the treatment of hypertension and other coronary
deseases.2 On the molecular level 1,4-DHP compounds cause vas-
orelaxation by blocking voltage-operated calcium channel in
smooth muscle cells and also by increasing NO release from intact
endothelium.3 Newly synthesized generation of substituted 1,4-
DHPs posses other pharmacological activities such as antitumor,4
bronchodilating,5 antidiabetic,6 neurotropic,7 antianginal8 amongst
others.9 Some of the representatives such as nifedipine,10 nicardi-
pine,11 felodipine (1),12 and amlodipine (2)13 are today some of the
best selling drugs used for treatment of hypertension, Figure 1. In
recent years Bo¨cker and co-workers have studied the metabolism of
Hantzsch-1,4-DHPs and shown that first metabolic step includes
aromatization to corresponding pyridine derivatives,14 which have
found its application for the treatment of atherosclerosis and other
coronary deseases.15 The main representative of such type of
compounds is cerivastatin (3).15 The metabolism of 1,4-DHPs is
catalyzed by the cytochrome P450 (CYP) 3A4 isoform.14,16
atiaon.17 In order to understand this processes the aromatization of
1,4-DHPs has attracted considerable attention from synthetic
chemists.
Cl
Cl
Cl
MeO2C
Me
CO2Et MeO2C
CO2Et
O
Me
N
H
Me
NH2
N
H
2
1
F
OH OH
COOH
MeO
N
3
* Corresponding author. Tel.: þ385 48 652 457; fax: þ385 48 652 461.
´
Figure 1.
E-mail address: mladen.litvic@belupo.hr (M. Litvic).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.08.103

M. Filipan-Litvic´ et al. / Tetrahedron 64 (2008) 10912–10918
10913
Numerous methods for the aromatization of 1,4-DHPs have been
developed for that purpose including the use of metallic salts,18
non-metallic reagents,19 catalytic methods20 among others.21 Re-
cently, microwave irradiation has been used to accelerate the re-
action in solventless media.22 However, despite a plethora of
reagents used for the aromatization of 1,4-DHPs most of them
suffer from low selectivity, the use of harsh reaction condition,
a lack of selectivity, production of toxic water waste, cumbersome
work-up, etc. Moreover, a detailed study of 1,4-DHP aromatization
employing high-valent salts of transition metals lack in the
literature.
In continuation of our program toward development of milder
and more selective methods for the aromatization of 1,4-DHPs,18t,u
we wish to report a comprehensive study with group 4 (Ti(IV),
Zr(IV), Hf(IV)) and 5 (V(V), Nb(V) and Ta(V)) elements of the peri-
odic table.
with stoichiometric amount of ZrCl4 in chloroform as a solvent
(entry 2) proceeded selectively at room temperature affording
substituted pyridine 5 in almost quantitative yield. In other sol-
vents (entries 3–5) the reaction was also selective suggesting that
Zr(IV) is the real oxidant in method employing Zr(NO3)4 as re-
agent.23 As expected the reaction with TiCl4 did not give a trace of
the product even at the higher temperatures (reflux). Similar to
zirconium(IV), HfCl4 selectively afforded product 5. However, due
to its higher molecular weight the reaction with ZrCl4 has greater
preparative value. The stoichiometry of the reactions with ZrCl4 and
HfCl4 show that the metals are reduced from oxidation states þ4 to
þ2, which is in agreement with the chemistry of these two
metals.24
From the fifth group of elements Vanadium(V) salts such as
VOF3 and VOCl3 efficiently and selectively oxidized 1,4-DHP 4 at
room temperature in chloroform as solvent. The product was
isolated in almost quantitative yield (entries 10–12). Unlike their
oxohalides V2O5 and NH4VO3 as less corrosive V(V) salts were less
effective in neutral solvents. However, in acetic acid NH4VO3 se-
lectively aromatized 1,4-DHP 4 to give product in excellent yield.
The complete conversion of starting material at room tempera-
ture employing V(V) salts as oxidants was obtained with 2 equiv
suggesting reduction of oxidant to þ4 oxidation state. In-
terestingly, if the reaction was carried out at reflux temperature
(chloroform) only 1 equiv was required to reach complete con-
version of 1,4-DHP 4. These findings indicate that V4þ is strong
enough oxidant at elevated temperature. In comparison to V(V)
salts, NbCl5 and TaCl5 showed much lower reactivity and reaction
slowly proceeded only in acetic acid as solvent. The conversions
of 83 and 87% were obtained in 72 and 96 h, respectively (entries
20 and 23). In acetonitrile both salts afforded less polar side-
product isolated after extractive work-up in 5% yield. The struc-
ture according to NMR spectra (1H and 13C NMR, COSY, NOESY,
HETCOR, APT) was proved to be methyl-trans-cinnamate 6,
Scheme 1.
2. Results and discussion
We began our research with several higher valent metallic salts
of groups 4 and 5 elements of the periodic system. In the literature
only Zr(NO3)4 has been used23 for the aromatization of 1,4-DHPs
but from the results it was not clear whether the aromatization
took place by the action of Zr(IV) or an equilibrium amount of nitric
acid formed by hydrolysis of the salt. Thus, we have decided to test
salts with non-oxidizing anions such as ZrCl4, TiCl4, and HfCl4 from
the same group of the elements as well as vanadium(V) oxy-
trichloride (VOCl3), NbCl5, and TaCl5 from group 5 of the periodic
table. The 1,4-DHP 4 was used as a model compound in reactions.
The preliminary results outlined in Table 1 showed that reaction
Table 1
Aromatization of 1,4-DHP 5 by different metallic oxidants in various solvents at rt
Ph
Ph
CO2Me
CH3
MeO2C
H3C
MeO2C
H3C
CO2Me
CH3
[O]
N
H
N
Ph
MeO2C
H3C
CO2Me
CH3
H
NbCl5 or TaCl5
MeCN, rt
4
5
H
CO2Me
N
H
Entry
Oxidant
Solvent
Time (h)
Conv. (%)
1
2
3
4
5
6
7
8
TiCl4
CHCl3
CHCl3
CH3CN
EtOH
CH3COOH
CHCl3
CH3CN
CH3COOH
CH3COOH
CHCl3
CHCl3
CHCl3
CH3CN
CH3COOH
CH3COOH
EtOH
CH3COOH
CHCl3
CH3CN
CH3COOH
CHCl3
CH3CN
CH3COOH
24a
72
24
192
24
168
216
24
0
4
6
ZrCl4
ZrCl4
ZrCl4
ZrCl4
HfCl4
HfCl4
HfCl4
HfO2
VOCl3
VOCl3
VOF3
V2O5
100 (96)b
Scheme 1.
98
100 (94)b
To our knowledge, this type of hydrolysis of 1,4-DHPs has not
been described in the literature so far. The formation of 6 probably
takes place in coordination sphere of metals, which was concluded
from the observation that brown precipitate was formed on treat-
ment of acetonitrile solutions of 1,4-DHP with NbCl5 and TaCl5,
Scheme 2. The evolution of hydrogen chloride was observed upon
stirring the reaction mixture for several hours. The formation of
exclusively methyl-trans-cinnamate 6, without a trace of corre-
sponding cis-isomer probably takes place within the complex 7
95
100 (91)b
93
88
90
9
72
10
11
12
13
14
15
16
17
18
19
20
21
22
23
29c
24a,d
29
100 (99)b
98 (90)b
100 (97)b
960
168
24a
24
40
84
V2O5
V2O5
100 (95)b
NH4VO3
NH4VO3
NbCl5
NbCl5
NbCl5
TaCl5
TaCl5
TaCl5
0
24
100 (96)b
960
504
72
48
312
96
de
df
83
0
Ph
Ph
N
MeO2C
H3C
CO2Me
CH3
MeO2C
H3C
CO2Me
CH3
NbCl5, MeCN
df
87
N
H
H
Cl
Cl
Cl
a
The reaction was carried out at reflux temperature.
Isolated yield.
Two equivalents of oxidant were used.
One equivalent of oxidant was used.
The reaction was not selective.
Nb
Cl
7
b
c
d
e
f
Cl
4
Methyl-trans-cinnamate 6 was formed.
Scheme 2.

10914
M. Filipan-Litvic´ et al. / Tetrahedron 64 (2008) 10912–10918
with equatorial position of phenyl ring. Usually, due to the lower
energy of the 1,4-DHP 4 the phenyl ring predominantly occupy
axial position which is not a favorable position when sterically
demanded metal halogenides are present such as in complex 7.
Of all the salts tested from the groups 4 and 5 periodic system,
due to its low molecular weight and high reactivity, VOCl3 was
chosen for further investigation on series of substituted 1,4-DHPs.
The preliminary results on the model 1,4-DHP 4 showed that re-
action with 2 equiv of VOCl3 is, at the beginning of the reaction,
very fast and 90% conversion was reached within 1 h. However, the
complete conversion was obtained after only 29 h. If the same re-
action was carried out with 2.1 equiv of oxidant in dichloromethane
as solvent at room temperature 100% conversion was reached
within 60 min and the product was isolated in excellent yield. The
results outlined in Table 2 indicate that reaction is generally very
fast (1–115 min) for all substituted 1,4-DHPs. The yields of crude
products of high purity obtained after simple extractive work-up
ranged between 88 and 99%. Interestingly, the method is not sen-
sitive to electronic nature and sterical hindrances of substituents
present on aromatic ring. Moreover, the compound 19 (entry 13)
was almost instantly oxidized to yield product in 94% yield. The
derivatives having thienyl, bromothienyl, and furyl substituents,
usually poorly reactive 1,4-DHPs and acid sensitive compounds
were effectively aromatized to yield products in good yields (en-
tries 19–21). As expected the aromatization of 4-alkyl-1,4-DHPs 9
and 11 having ethyl and isopropyl substituents afforded deal-
kylation product 29 in almost quantitative yield. Unexpectedly, 4-
benzyl-1,4-DHP 10 afforded product of dealkylation contaminated
with 2.5% of nondealkylated pyridine 30. Recently, we have de-
scribed this phenomena employing SbCl5 as oxidant.18u However,
the two electron transfer proposed to explain this observation
could not be applied in this case due to the fact that V(V) is reduced
to V(IV) by one electron transfer. Moreover, the aromatization of 4-
n-propyl-1,4-DHP 12 (entry 5) afforded 9% of nondealkylated and
91% dealkylated product. If the reaction was performed in acetic
acid as solvent instead of dichloromethane a mixture of 67% of 31
and 31% of 29 was obtained. These findings indicate that generally
accepted theory of complete dealkylation of 4-alkyl-1,4-DHP
employing strong metallic oxidants is no longer acceptable. Our
results have was clearly shown that even a polarity of solvent de-
termine the ratio of dealkylation and nondealkylation. In order to
explain the obtained results further investigation is required in-
cluding reexamination of published methods employing metallic
oxidants. A detailed and comprehensive study of this work is be-
yond the scope of this article and will be published in due course.
Although the method employing VOCl3 as oxidant is valuable
addition to published methods for the aromatization of 1,4-DHPs
due to the fact that substituted pyridines were prepared in mild
condition and excellent yield, we have decided to explore V2O5 as
less corrosive vanadium(V) salt. Moreover, the regeneration of V2O5
is much easier to accomplish in comparison to VOCl3. The pre-
liminary results showed that reaction in refluxing acetic acid as
solvent gave a product in almost quantitative yield. Therefore, we
expected similar results in much shorter reaction times employing
microwave irradiation in solventless media.
From the literature, microwave irradiation has intensively
studied as effective promoter for the aromatization of 1,4-DHPs22 as
well as many other organic transformations.25 The reactions were
usually completed within a few minutes compared to the several
hours needed when conventional heating is employed.22 Beside
V2O5 as oxidant other metallic oxides were tested such as MoO3,
GeO2, HfO2, and CeO2, which respective halides or nitrates are ca-
pable of reacting with 1,4-DHPs to furnish aromatization products
in high yields.18d,26 The initial experiments on model 1,4-DHP 4
were carried out at 100 ꢀC and power of 150 W under conditions
employed for the microwave promoted aromatization of 1,4-DHPs
by MnO2.18m Interestingly, even a trace of the product 5 was not
obtained with any of oxidants whilst reaction with MnO2 afforded
product in quantitative yield. Under very harsh reaction conditions
(180 ꢀC and power of 1000 W) the oxidation with V2O5 reached 90%
conversion within 30 min (Table 3, entry 3). Under the same re-
action conditions MoO3 gave only 10% of the product (entry 5),
whilst GeO2, CeO2, and HfO2 did not react (entries 7–9). Prolonged
irradiation caused formation of decomposition products without
improvement in the yield. These results clearly indicate that mi-
crowave promoted aromatization of 1,4-DHPs compared to con-
ventional heating has no practical value due to lower selectivity and
very harsh reaction condition employed to initiate the reaction. The
low reactivity of CeO2, GeO2, and HfO2 is probably caused by their
polymeric structures.24 The layered structures of MoO3 and V2O5
allow limited contact between 1,4-DHP molecule and metal cation
needed for oxidation process. Contrary to metallic oxides, a high
Table 2
Aromatization of substituted 1,4-DHPs with VOCl3 (2.1 equiv) in CH2Cl2 at rt
R1
R
MeO2C
H3C
CO2Me
CH3
MeO2C
H3C
CO2Me
CH3
VOCl3 (2.1 equiv.)
CH2Cl2, rt
N
H
N
4, 8-28
5, 29-47
Entry 1,4-DHP
R
Product R1
Time (min) Yield (%)
1
2
3
4
5
6
7
8
8
9
10
11
12
4
H
i-Pr
CH2Ph
Et
n-Pr
Ph
o-ClC6H4
m-ClC6H4
p-ClC6H4
o-NO2C6H4
m-NO2C6H4
p-NO2C6H4
o-CH3C6H4
m-CH3C6H4
p-CH3C6H4
29
29
29/30
29
29/31
5
32
33
34
35
H
H
1
1
98
96
99
97
95
97
95
90
92
0d
89
91
94
94
90
95
91
89
88
92
89
92
H/CH2Pha
H
60
52
32
60
80
80
60
10
70
85
1
85
90
50
75
60
60
H/n-Prb,c
Ph
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
o-ClC6H4
m-ClC6H4
p-ClC6H4
9
10
11
12
13
14
15
16
17
18
19
20
21
22
o-NO2C6H4
m-NO2C6H4
p-NO2C6H4
o-CH3C6H4
m-CH3C6H4
p-CH3C6H4
2,4-(CH3)2C6H3
m-CH3OC6H4
p-CH3OC6H4
2-Thienyl
36
37
38
39
Table 3
40
The aromatization of 1,4-DHP 4 by different metallic oxides under microwave
2,4-(CH3)2C6H3 41
irradiationa
m-CH3OC6H4
p-CH3OC6H4
2-Thienyl
2-(5-Br-thienyl) 45
2-Furyl
42
43
44
Entry
Metallic oxidant
Time (min)
Conv. (%)
1
2
3
4
5
6
7
8
9
V2O5
V2O5
V2O5
MoO3
MoO3
MoO3
GeO2
CeO2
HfO2
10
20
30
10
20
30
30
30
30
10
40
90
0
5
10
0
2-(5-Br-thienyl) 115
2-Furyl
p-Ph–C6H4
46
47
60
85
p-Ph–C6H4
a
According to HPLC a mixture of dealkylated and nondealkylated pyridines was
obtained (98.5:2.5).
b
According to HPLC a mixture of dealkylated and nondealkylated pyridines was
0
0
obtained (91.0:9.0).
c
The reaction in acetic acid afforded a mixture of 29 and 31 in ratio of 33.0:67.0.
Decomposition of starting material observed.
a
d
At 180 ꢀC and power of 1000 W.

M. Filipan-Litvic´ et al. / Tetrahedron 64 (2008) 10912–10918
10915
The ultrasound irradiation accelerates formation of the complex
and the intensive red color was obtained almost instantly, Figure 2.
Interestingly, the color immediately disappeared upon treat-
ment of solution B (Fig. 2) with a drop of polar solvents such as
ethanol or acetic acid. This finding explains why coloration was not
observed in chloroform as a solvent although its polarity is similar
to dichloromethane. The commercial chloroform contains up to 1%
of ethanol as stabilizer and thus formation of charge-transfer
complex has been prevented. In order to characterize the complex
by UV–vis spectrophotometry incremental concentrations of
complex have been prepared according to the literature method.27
Unfortunately, all attempts to record the spectra failed due to the
fact that precipitation of red solid occurred upon standing the
‘solution’ of complex at room temperature. These findings indicate
that in diluted media very small particles of CTC was formed rather
than a real solution. In concentrated media the colored precipitate
was released from the solvent within a few seconds. Thus formed,
the red solid was filtered and its IR spectra were recorded. Un-
fortunately, fast decomposition of the complex was observed and
therefore no significant difference in absorption frequencies was
noticed. Despite the inability to spectroscopically characterize the
CTC it is undoubtly formed by mixing the solution of 1,4-DHP in
dichloromethane and solid TaCl5. Similarly to TaCl5, under the same
condition NbCl5 afforded a yellow-to-green dichloromethane so-
lution with the same characteristics as complex with TaCl5. Owing
to their slower reactivity (Table 1, entries 18 and 21) the formation
of complexes with TaCl5 and NbCl5 were easily noticed. More re-
active oxidants such as VOCl3, ZrCl4, and HfCl4 afforded immediate
colorations that disappeared within a second or changed to colors
characteristic of complex salts. Moreover, even non-metallic oxi-
dants such as molecular iodine and 1,1,2,2-tetracyanoethylene gave
characteristic colors due to formation of a CTC with 1,4-DHPs. All of
these findings encouraged us to conclude that the first step of the
mechanism of aromatization of 1,4-DHP is not, as according to ar-
ticles dealing with mechanism of 1,4-DHP oxidation, an electron
transfer to oxidant but preequilibrium formation of metastable CTC
according to Scheme 3. Thus, the CTC is decomposed via three
possible paths to give corresponding intermediates, which are in
the next steps subsequently transformed to the substituted pyri-
dine product. According to path a one electron transfer (OET) from
1,4-DHP 48 to oxidant 49 takes place to give radical cation 50. This
type of the mechanism is characteristic for metallic salts such as
CAN,18d Mn(OAc)3,18q FeCl3,18r,s etc. According to path b aminyl
radical 51 is formed by homolytic cleavage of N-nitroso21a or
N-iodo20g intermediates. And finally, path c includes direct hydride
abstraction from 1,4-DHP ring to give substituted pyridine in
Figure 2. (A) The solution of 1,4-DHP 8 in dichloromethane; (B) charge transfer
complex formed upon treatment of solution A with solid TaCl5 under ultrasound; (C)
suspension of TaCl5 in dichloromethane.
reactivity of VOCl3 is determined by its monomeric structure,
which easily complexes a 1,4-DHP molecule.
Our results have shown that oxidation reactions under micro-
wave irradiation employing metallic oxides as oxidants is not al-
ways an alternative to classical technique although the redox
potential of metal cations are high enough to initiate the reaction.
The structure of oxidant must always be taken into consideration
before the reaction is performed in practice.
During the preliminary studies of the 1,4-DHP aromatization
employing metallic halides as oxidants the color changes have been
observed at the beginning and during the reaction. This was
explained by the formation of colored complexes characteristic for
the salts of the transition metals and organic ligands. However, the
treatment of the dichloromethane solution of 1,4-DHP 4 with solid
TaCl5 afforded an orange-to-red coloration after several minutes.
Interestingly, the formation of color was not observed if chloro-
form, acetonitrile, and acetic acid were used as solvent. The solvent
polarity dependent coloration is not characteristic of metallic
complexes with organic ligands. The only reasonable explanation is
formation of charge-transfer complex (CTC) between 1,4-DHP and
TaCl5. This type of species is well described if electron rich and
electron poor organic compounds are mixed in nonpolar solvents
such as, for example, 1,2,3,4,5,6-hexamethylbenzene and 1,1,2,2-
tetracyanoethylene in dichloromethane solution.27 Recently, this
type of precomplex has been evidenced in the preorganization step
of reactants to form products in well-known reactions such as
electrophilic aromatic substitution (halogenation, nitration, etc.).28
Taking into account the stability of CTC and prediction that it was
formed between TaCl5 and 1,4-DHP ring rather than phenyl sub-
stituents as in 4 we have performed further testings with non-
substituted 1,4-DHP 8 in freshly prepared dry dichloromethane.
The intensive orange coloration appeared within a few minutes
upon addition of solid TaCl5 to solution of 8 in dichloromethane.
R
MeO2C
H3C
CO2Me
CH3
+
N
H
50
a
R
R
MeO2C
H3C
CO2Me
CH3
MeO2C
H3C
CO2Me
+ OXIDANT
CH3
CHARGE
TRANSFER
COMPLEX
b
c
N
.
N
H
51
48
49
R
MeO2C
H3C
CO2Me
CH3
a - one electron transfer
b - homolytic cleavage
c - hydride abstraction
+
N
H
52
Scheme 3.

10916
M. Filipan-Litvic´ et al. / Tetrahedron 64 (2008) 10912–10918
protonated form 52. This is actually two electron transfer to oxidant
49 and is characteristic for electron deficient organic compounds as
oxidants such as DDQ21b and chloranil. As one could predict the
mechanism of VOCl3 promoted aromatization of 1,4-DHPs takes
place exclusively according to path a, via OET as other metallic salts.
However, the results obtained with 4-n-propyl-1,4-DHP 12 are not
easily explained by this mechanism especially the solvent polarity
dependent dealkylation/nondealkylation ratio. In order to explain
H
H
MeO2C
H3C
CO2Me
- H+
MeO2C
H3C
CO2Me
CH3
+
N
CH3
N
H
56
57
- CH3CH2CH2
- CH3CH2CH2
- H+
VOCl3
H
H
H
MeO2C
H3C
CO2Me
CH3
MeO2C
H3C
CO2Me
H
intramolecular
one electron transfer
CH3
MeO2C
H3C
CO2Me
CH3
MeO2C
H3C
CO2Me
.
+
N
N
+
N
N
CH3
Cl
Cl
V+5 Cl
OH
Cl
Cl
V+4 Cl
29
58
OH
54
53
- H+
H
MeO2C
H3C
CO2Me
CH3
MeO2C
H3C
CO2Me
CH3
+
- CH3CH2CH2
N
N
Cl
Cl
V+4 Cl
OH
31
55
Scheme 5.
Scheme 4.
the results obtained in dichloromethane as solvent formation of
vanadium complex 53 (Scheme 4) is proposed. This type of vana-
dium complex with nitrogen ligands is well known in the chemistry
of its oxohalides.24 By intramolecular OET 53 is transformed to
radical cation 54 and further rearranged to pyridinium salt 55 with
subsequent loss of n-propyl radical. In case of 4-aryl-substituted
1,4-DHPs a more stable benzylic radical is produced upon rear-
rangement and deprotonation of corresponding nitrogen radical
instantly oxidized to give nitrogen cation 58, which upon second
deprotonation produces nondealkylated product 31.
3. Conclusions
Vanadium oxytrichloride acts as an efficient and selective oxi-
dant for room temperature aromatization of substituted 1,4-DHPs.
The products of high purity were isolated in high-to-excellent yield.
For the first time it was shown that aromatization of 1,4-DHPs with
V2O5 in refluxing acetic acid is more efficient method versus mi-
crowave promoted reaction in solventless media. The red colora-
tion obtained upon addition of solid TaCl5 to dichloromethane
solution of 1,4-DHP 8 have been explained by charge-transfer
complex (CTC) formed in preorganization step prior to electron
transfer to oxidant. Beside TaCl5 the formation of CTCs have also
been noticed employing other metallic salts such as NbCl5, HfCl4,
ZrCl4, etc. The influence of solvent polarity on dealkylation/non-
dealkylation of 4-n-propyl-1,4-DHP 12 has been described. The
possible explanation of the results has been provided by study of
reaction mechanism and includes rapid oxidation of aminyl radical
57 formed by equilibrium deprotonation of radical cation 56 prior
to its rearrangement and loss of alkyl substituents.
18q
18t
cation similar to Mn(OAc)3
and Pb(OAc)4 promoted aromati-
zation of 1,4-DHPs. However, the presented mechanism is charac-
teristic only for the reaction in aprotic solvents (Scheme 4) and is
not applicable for the aromatization of 1,4-DHP 12 in acetic acid
mostly that explains formation of exclusively dealkylation product,
which is not in agreement with experimental results (Table 2, entry
5).
The rapid complexation of VOCl3 by acetic acid rather than 1,4-
DHP 12 is the main reason why complex 53 is not formed in that
solvent. Thus, more likely radical cation 56 but not 54 is formed by
bimolecular contact via OET from 1,4-DHP 12 to oxidant. Further-
more, equilibrium deprotonation of 56 to give radical 57 followed
by its rapid quenching with a second equivalent of oxidant yields
unstable nitrogen cation 58, which after deprotonation gives ex-
clusively nondealkylated pyridine 31, Scheme 5. The dealkylation
process takes place either by direct homolytic rearrangement of
radical cation 56 or aminyl radical 57 according to the literature.21a
However, our recent results employing urea hydrogen peroxide
adduct as oxidant catalyzed by molecular iodine have shown that
corresponding aminyl radical is selectively oxidized to product
without the loss of n-propyl group.20g Therefore, the rearrange-
ment of 56 is the main pathway to dealkylation product 29.
The aminyl radical as reactive intermediate has not been pro-
posed so far in the literature for the aromatization of 1,4-DHP by
metallic salts probably due to the fact that radical cation obtained in
the first step is rapidly decomposed to more stable benzylic radical
prior to its deprotonation. In case of strong oxidants such as VOCl3
the equilibrium amount of 57 produced by deprotonation is
4. Experimental section
4.1. General
All IR spectra were recorded on a Perkin–Elmer Spectrum One
spectrometer. 1H NMR and 13C NMR were recorded on a Bruker 600
for CDCl3 solutions, and shifts are given in parts per million
downfield from TMS as an internal standard. HPLC analyses were
performed with a Thermo Separation Products (San Jose, USA) in-
strument 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, Germany) DC-alufolien

M. Filipan-Litvic´ et al. / Tetrahedron 64 (2008) 10912–10918
10917
with Kieselgel 60254. Melting points were determined using a Bu¨chi
B540 instrument. Elemental analyses were performed at the Cen-
microwave oven (180 ꢀC and power of 1000 W) for the times in-
dicated in Table 3. The product was extracted with dichloro-
methane (3ꢁ20 mL) and analyzed by HPLC to determine the
conversion of the reaction.
ˇ
´
tral Analytical Service (CAS) at RuCer Boskovic Institute. Microwave
irradiation promoted reactions were carried out in Milestone MLS-
1200 pyro oven. All chemicals and solvents were purchased from
Aldrich and Merck-Darmstadt. The 1,4-DHPs have been prepared
according to modified Hantzsch methods.20g,18t,29–31 All products of
aromatization are known in the literature and were fully charac-
terized by a comparison with authentic samples (melting point)
and their NMR (1H, 13C) and IR spectra.20g
4.5. Charge-transfer probes
To a solution of corresponding 1,4-DHPs in dry dichloro-
methane27,28 metallic halide was added (TaCl5, NbCl5, HfCl4, ZrCl4)
at once. The suspension was stirred at room temperature to furnish
characteristic coloration. The same test was performed under ul-
trasound sonification to yield more intensive colors in shorter time
(Fig. 2).
4.2. Reaction of 2,6-dimethyl-3,5-dimethoxy-carbonyl-1,4-
dihydropyridine (4) with NbCl5 in acetonitrile at room
temperature
Acknowledgements
To a solution of 1,4-DHP (12, 6 mmol; 1,86 g) in acetonitrile
(30 mL) at room temperature, NbCl5 (6 mmol, 1.62 g) was added at
once. The resulting suspension was stirred at room temperature for
18 days. After that to the reaction mixture were added water
(30 mL) and dichloromethane (30 mL). The phases were separated
and the aqueous phase was additionally extracted with dichloro-
methane (3ꢁ20 mL). The combined organic layers were dried over
Na2SO4, filtered, and evaporated to dryness. The residue was trit-
urated with diisopropylether (50 mL), stirred at room temperature
for 24 h, and filtered. The brown crystals were washed with two
portions of diisopropylether (2ꢁ5 mL). The mother liquor was
evaporated to dryness and the residue was suspended in n-hexane
(50 mL) and stirred at room temperature for 12 h. The inorganic
crystals were filtered and washed with n-hexane (2ꢁ5 mL). The
organic extracts were gathered and evaporated to dryness. The oily
residue was purified by PTLC on silica gel plates using dichloro-
methane as eluent. The fraction with Rf¼0.55 was extracted with
dichloromethane (50 mL) and evaporated to dryness to give 6;
The authors wish to express their gratitude to the Belupo
Pharmaceuticals Inc. for financial support of this research.
References and notes
1. Hantzsch, A. Chem. Ber. 1881, 14, 1637–1638.
2. (a) Gru¨ n, G.; Fleckenstein, A. Arzneim.-Forsch. (Drug Res.) 1972, 22, 334–344; (b)
Bossert, F.; Meyer, H.; Wehinger, E. Angew. Chem. 1981, 93, 755–763; (c) Janis, R.
A.; Triggle, D. J. J. Med. Chem. 1983, 26, 775–785.
3. Berkels, B.; Roesen, R.; Dhein, S.; Fricke, U.; Klaus, W. Cardiovasc. Drug Rev. 1999,
17, 179–186.
4. Tsuruo, T.; Iida, H.; Nojiri, M.; Tsukagoshi, S.; Sakurai, Y. Cancer Res. 1983, 43,
2905–2910.
5. Chapman, R. W.; Danko, G.; Siegels, M. I. Pharmacology 1984, 29, 282–291.
6. Malaise, W. J.; Mathias, P. C. F. Diabetologia 1985, 28, 153–156.
7. Krauze, A.; Germane, S.; Eberlins, O.; Sturms, I.; Klusa, V.; Duburs, G. Eur. J. Med.
Chem. 1999, 34, 301–310.
8. Peri, R.; Padmanabhan, S.; Singh, S.; Rutledge, A.; Triggle, D. J. J. Med. Chem.
2000, 43, 2906–2914.
9. Zhou, X.; Zhang, L.; Tseng, E.; Scott-Ramsay, E.; Schentag, J. J.; Coburn, R. A.;
Morris, M. E. Drug Metab. Dispos. 2005, 33, 321–328.
50 mg (5.2%) as yellow oil. IR (KBr):
1496, 1451, 1440, 1332, 1283, 1260, 1185, 1074, 1039, 1029,
1016 cmꢂ1; 1H NMR (CDCl3):
¼3.81 (t, 3H, OCH3), 6.45 (d, 1H, CH,
n
¼3028, 2991, 2947, 1698, 1679,
10. The Merck Index,12th ed.;Merck Research Laboratories: New Jersey, NJ,1996; p 1121.
11. Iwanami, M.; Shibanuma, T.; Fujimoto, M.; Kawai, R.; Tamazawa, K.; Takenaka,
T.; Takahashi, K.; Murakami, M. Chem. Pharm. Bull. 1979, 27, 1426–1440.
12. Bostro¨m, S. L.; Ljung, B.; Mårdh, S.; Forsen, S.; Thulin, E. Nature 1981, 292,
777–778.
13. Arrowsmith, J. E.; Campbell, S. F.; Cross, P. E.; Stubbs, J. K.; Burges, R. A.;
Gardiner, D. G.; Blackburn, K. J. J. Med. Chem. 1986, 29, 1696–1702.
14. Bo¨cker, R. H.; Guengerich, F. P. J. Med. Chem. 1986, 28, 1596–1603.
15. Bischhoff, H.; Angerbauer, R.; Bender, J.; Bischoff, E.; Faggiotto, A.; Petzinna, D.;
Pfitzner, J.; Porter, M. C.; Schmidt, D.; Thomas, G. Atherosclerosis 1997, 135,
119–130.
d
J¼16.0 Hz), 7.38–7.39 (m, 3H, arom.), 7.51–7.53 (m, 2H, arom.), 7.70
(d, 1H, CH, J¼16.0 Hz); 13C NMR (CDCl3):
¼51.6, 117.8, 128.0, 128.8,
d
130.2, 134.3, 144.8, 167.3. Anal. Calcd for C10H10O2: C, 74.06; H, 6.21.
Found: C, 74.2; H, 6.4.
4.3. General procedure for the aromatization of 1,4-DHPs by
VOCl3 in dichloromethane at room temperature
16. Kudo, S.; Okumura, H.; Miyamoto, G.; Ishizaki, T. Drug Metab. Dispos. 1999, 27,
303–308.
17. Memarian, H. R.; Abdoli-Senejani, M.; Tangestaninejad, S. J. Iran. Chem. Soc.
2006, 3, 285–292.
To a solution of 1,4-DHP derivatives (4, 8–28, 1 mmol) in
dichloromethane (10 mL) VOCl3 was added at once (2.1 mL,
2.1 mmol, 1 M solution in dichloromethane). The reaction mixture
was stirred at room temperature for the time indicated in Table 2.
After that to the reaction mixture was added water (15 mL) and the
pH of water layer was adjusted to 7 with solid NaHCO3. The phases
were separated and the aqueous phase was additionally extracted
with dichloromethane (2ꢁ10 mL). The combined organic layers
were dried over Na2SO4, filtered, and evaporated to dryness. The
crude products were chromatographed on silica gel column eluting
with dichloromethane/ethyl acetate (9:1) to give products of purity
>99%.
18. (a) Khadilkar, B.; Jaisinghani, H.; Khare, A. Ind. J. Chem. 1998, 37B, 817–818; (b)
Meyer, H.; Wehinger, E.; Bossert, F.; Scherling, D. Arzneim.-Forsch. (Drug Res.)
1983, 33, 106–112; (c) Sugiyama, N.; Kubota, K.; Inouye, G. Bull. Chem. Soc. Jpn.
1964, 37, 637–639; (d) Pfister, J. R. Synthesis 1990, 689–690; (e) Vanden Eynde,
J. J.; D’Ozario, R.; Van Haverbeke, Y. Tetrahedron 1994, 50, 2479–2484; (f)
Choudary, B. M.; Valli, V. L. K.; Durga Prasad, A. Synth. Commun. 1991, 21, 2007–
2013; (g) Karami, B.; Montazerozohori, M.; Habibi, M. H.; Zolfigol, M. A. Het-
erocycl. Commun. 2006, 11, 513–516; (h) Memarian, H. R.; Sadeghi, M. M.;
Momeni, A. R. Synth. Commun. 2001, 31, 2241–2244; (i) Vanden Eynde, J. J.;
Delfosse, F.; Mayence, A.; Van Haverbeke, Y. Tetrahedron 1995, 51, 6511–6516; (j)
Katsuyama, I.; Ogawa, S.; Nakamura, H.; Yamaguchi, Y.; Funabiki, K.; Matsui, M.;
Muramatsu, H.; Shibata, K. Heterocycles 1998, 48, 779–785; (k) Kuno, A.; Sakai,
H.; Ohkubo, M.; Takasugi, H. Chem. Pharm. Bull. 1993, 41, 156–162; (l) Kuno, A.;
Sakai, H.; Ohkubo, M.; Takasugi, H. Chem. Pharm. Bull. 1993, 41, 163–170; (m)
Bagley, M. C.; Lubinu, M. C. Synthesis 2006, 1283–1288; (n) Alvarez, C.; Delgado,
F.; Garcı´a, O.; Medina, S.; Ma´rquez, C. Synth. Commun. 1991, 21, 619–624; (o)
´
´
Delgado, F.; Alvarez, C.; Garcıa, O.; Penieres, G.; Marquez, C. Synth. Commun.
1991, 21, 2137–2141; (p) Heravi, M. M.; ShMoosavi, F. S.; ShBeheshtiha, Y.;
Ghassemzadeh, M. Heterocycl. Commun. 2004, 10, 415–418; (q) Varma, R. S.;
Kumar, D. Tetrahedron Lett. 1999, 40, 21–24; (r) Lu, J.; Bai, Y.; Wang, Z.; Yang, B.;
Li, W. Synth. Commun. 2001, 31, 2625–2630; (s) Lu, J.; Bai, Y.-J.; Yang, B.-Q.; Ma,
4.4. General procedure for the aromatization of 1,4-DHPs
with metallic oxides under microwave irradiation
To a solution of 1,4-DHP 4 (1.50 g, 5 mmol) in dichloromethane
(20 mL) was added the corresponding metallic oxide (10 mmol,
V2O5; 5 mmol, MoO3; 10 mmol, CeO2; 5 mmol, HfO2; 5 mmol,
GeO2). After stirring at room temperature for 15 min, the suspen-
sion was evaporated to dryness and dried in vacuum to constant
weight. Thus obtained adsorbed 1,4-DHP was irradiated in
´
H.-R. Chin. J. Org. Chem. 2000, 20, 514–517; (t) Litvic, M.; Cepanec, I.; Filipan, M.;
ˇ ´
ˇ
´
´
Kos, K.; Bartolincic, A.; Druskovic, V.; Tibi, M. M.; Vinkovic, V. Heterocycles 2005,
´
´
´
65, 23–35; (u) Filipan-Litvic, M.; Litvic, M.; Cepanec, I.; Vinkovic, V. ARKIVOC
2008, xi, 96–103.
19. (a) Mohr, E.; Schneider, W. J. Prakt. Chem. 1904, 69, 245–264; (b) Kro¨hnke, F.;
Ahrenhok, G. M.; Gross, K. F. J. Prakt. Chem. 1960, 11, 256–264; (c) Go¨rlitzer, K.;
Buß, D. Arch. Pharm. (Weinheim, Ger.) 1981, 314, 949–954; (d) Zolfigol, M. A.;

10918
M. Filipan-Litvic´ et al. / Tetrahedron 64 (2008) 10912–10918
Kiany-Borazjani, M.; Sadeghi, M. M.; Memarian, H. R.; Mohammadpoor-Baltork,
8158–8163; (c) Zolfigol, M. A.; Zebarjadian, M. H.; Sadegh, M. M.; Mo-
hammadpoor-Baltork, I.; Memarian, H. R.; Shamsipur, M. Synth. Commun. 2001,
31, 929–934; (d) Mashraqui, S. H.; Karnik, M. A. Synthesis 1998, 713–714; (e)
Khadilkar, B.; Borkar, S. Synth. Commun. 1998, 28, 207–212; (f) Balogh, M.;
Hermecz, I.; Me´sza´ros, Z.; Laszlo, P. Helv. Chim. Acta 1984, 67, 2270–2272; (g) Ko,
K. J.; Kim, J. Y. Tetrahedron Lett. 1999, 40, 3207–3208; (h) Nasr-Esfahani, M.;
Moghadam, M.; Tangestaninejad, S.; Mirkhani, V. Bioorg. Med. Chem. Lett. 2005,
15, 3276–3278; (i) Moghadam, M.; Nasr-Esfahani, M.; Tangestaninejad, S.;
Mirkhani, V. Bioorg. Med. Chem. Lett. 2006, 16, 2026–2030; (j) Moghadam, M.;
Nasr-Esfahani, M.; Tangestaninejad, S.; Mirkhani, V.; Zolfigol, M. A. Can. J. Chem.
2006, 84, 1–4; (k) Karami, B.; Montazerozohori, M.; Nasr-Esfahani, M. Hetero-
cycles 2005, 65, 2181–2188; (l) Hashemi, M. M.; Beni, Y. A. J. Sci. I.R. Iran 1998, 9,
237–239; (m) Chavan, S. P.; Kharul, R. K.; Kalkote, U. R.; Shivakumar, I. Synth.
Commun. 2003, 33, 1333–1340; (n) Hashemi, M. M.; Ahmadibeni, Y.; Ghafuri, H.
Monatsh. Chem. 2003, 134, 107–110.
I. Synth. Commun. 2000, 30, 2945–2950; (e) Zolfigol, M. A.; Kiany-Borazjani, M.;
Sadeghi, M. M.; Mohammadpoor-Baltork, I.; Memarian, H. R. Synth. Commun.
2000, 30, 3919–3923; (f) Zolfigol, M. A.; Kiany-Borazjani, M.; Sadeghi, M. M.;
Mohammadpoor-Baltork, I.; Memarian, H. R. Synth. Commun. 2000, 30, 551–
558; (g) Niknam, K.; Zolfigol, M. A.; Razavian, S. M.; Mohammadpoor-Baltork, I.
Heterocycles 2005, 65, 657–660; (h) Zolfigol, M. A.; Shirini, F.; Choghamarani,
A. G.; Mohammadpoor-Baltork, I. Phosphorus Sulfur Silicon 2003, 178, 1709–
1715; (i) Zolfigol, M. A.; Choghamarani, A. G.; Dialameh, S.; Sadeghi, M. M.;
Mohammadpoor-Baltork, I.; Memarian, H. R. J. Chem. Res., Synop. 2003, 18–20;
(j) Hashemi, M. M.; Ghafuri, H.; Karimi-Jaberi, Z. Monatsch. Chem. 2006, 134,
197–200; (k) Zolfigol, M. A.; Bagherzadeh, M.; Niknam, K.; Shirini, F.; Mo-
hammadpoor-Baltork, I.; Choghamarani, A. G.; Baghbanzadeh, M. J. Iran. Chem.
Soc. 2006, 3, 73–80; (l) Niknam, K.; Zolfigol, M. A.; Razavian, S. M.; Mo-
hammadpoor-Baltork, I. J. Heterocycl. Chem. 2006, 43, 199–202; (m) Varma,
R. S.; Kumar, D. J. Chem. Soc., Perkin Trans. 1 1999, 1755–1757; (n) Chavan, S. P.;
Dantale, S. W.; Kalkote, U. R.; Jyothirmai, V. S.; Kharul, R. K. Synth. Commun.
1998, 28, 2789–2792; (o) Zeynizadeh, B.; Dilmaghani, K. A.; Roozijoy, A. J. Chin.
Chem. Soc. 2005, 52, 1001–1004; (p) Yadav, J. S.; Reddy, B. S.; Sabitha, G.; Reddy,
G. S. K. K. Synthesis 2000, 1532–1534; (q) Yadav, J. S.; Reddy, B. V. S.; Basak, A. K.;
Baishya, G.; Venkat Narsaiah, A. Synthesis 2006, 451–454; (r) Chai, L.; Zhao, Y.;
Sheng, Q.; Liu, Z.-Q. Tetrahedron Lett. 2006, 9283–9285; (s) Cai, X.-h.; Yang,
H.-j.; Zhang, G.-l. Can. J. Chem. 2005, 83, 273–275; (t) Panchgalle, S. P.;
Choudhary, S. M.; Chavan, S. P.; Kalkote, U. R. J. Chem. Res., Synop. 2004, 550–551.
20. (a) Mashraqui, S. H.; Karnik, M. A. Tetrahedron Lett. 1998, 39, 4896–4898; (b)
Heravi, M. M.; Behbahani, F. K.; Oskooie, H. A.; Shoar, R. H. Tetrahedron Lett.
2005, 46, 2775–2777; (c) Kamal, A.; Ahmad, M.; Mohd, N.; Hamid, A. M. Bull.
Chem. Soc. Jpn. 1964, 37, 610–612; (d) Nakamichi, N.; Kawashita, Y.; Hayashi, M.
Org. Lett. 2002, 4, 3955–3957; (e) Misner, R. E. Diss. Abstr. 1969, 29B 2817; (f)
Nakamichi, N.; Kawashita, Y.; Hayashi, M. Synthesis 2004, 1015–1020; (g) Fili-
22. Vanden Eynde, J. J.; Mayence, A. Molecules 2003, 8, 381–391.
23. Sabitha, G.; Kiran Kumar Reddy, G. S.; Reddy, Ch. S.; Fatima, N.; Yadav, J. S.
Synthesis 2003, 1267–1271.
24. Cotton, F. A.; Wilkinson, G. Advanced Inorganic Chemistry, 5th ed.; John Wiley &
Sons: New York, NY, 1988.
25. Lidstro¨m, P.; Tierney, J.; Wathey, B.; Westman, J. Tetrahedron 2001, 57, 9225–
9283.
26. Filipan-Litvic´, M.; Litvic´, M.; Cepanec, I.; Pogorelic´, I.; Vinkovic´, V. XX Croatian
Meeting of Chemists and Chemical Engineers, Zagreb, 2007.
27. (a) Rathore, R.; Hubig, S. M.; Kochi, J. K. J. Am. Chem. Soc. 1997, 119, 11468–11480;
(b) Rathore, R.; Lindeman, S. V.; Kochi, J. K. J. Am. Chem. Soc. 1997, 119, 9393–
9404.
28. (a) Rosokha, S. V.; Kochi, J. K. J. Org. Chem. 2002, 67, 1727–1737; (b) Rosokha,
S. V.; Lindeman, S. V.; Rathore, R.; Kochi, J. K. J. Org. Chem. 2003, 68, 3947–
3957.
´
´
´
´
pan-Litvic, M.; Litvic, M.; Vinkovic, V. Tetrahedron 2008, 64, 5649–5656; (h)
Filipan-Litvic´, M.; Litvic´, M.; Vinkovic´, V. Bioorg. Med. Chem., in press. doi:10.
1016/j.bmc.2008.09.004
29. Filipan-Litvic, M. Aromatization of 1,4-Dihydropyridine Derivatives, Doctoral
Thesis, University of Zagreb, 2006; p 190.
30. Litvic´, M.; Cepanec, I.; Vinkovic´, V. Heterocycl. Commun. 2003, 9, 385–390.
31. Litvic´, M.; Filipan, M.; Pogorelic´, I.; Cepanec, I. Green Chem. 2005, 7, 771–
774.
21. (a) Itoh, T.; Nagata, K.; Matsuya, Y.; Miyazaki, M.; Ohsawa, A. J. Org. Chem. 1997,
62, 3582–3585; (b) Zhu, X. Q.; Zhao, B. J.; Cheng, J. P. J. Org. Chem. 2000, 65,