Formation of novel 1,3-thiazole- and 1,2-thiazole-fused aporphines and study on the simultaneously occurring benzothiazole-benzisothiazole-type isomerization

Article abstract of DOI:10.1007/s00706-008-0038-x

The synthesis and acid-catalyzed rearrangement of novel thiazolomorphinandienes have been presented. An isomerization was observed simultaneously with the backbone transformation. An extensive study was performed to determine the major effects of the isom

Full text of DOI:10.1007/s00706-008-0038-x

Monatsh Chem (2009) 140:387–396
DOI 10.1007/s00706-008-0038-x
ORIGINAL PAPER
Formation of novel 1,3-thiazole- and 1,2-thiazole-fused aporphines
and study on the simultaneously occurring benzothiazole–
benzisothiazole-type isomerization
´
´
Attila Sipos Æ Sandor Berenyi
Received: 9 May 2008 / Accepted: 4 July 2008 / Published online: 3 September 2008
Ó Springer-Verlag 2008
Abstract The synthesis and acid-catalyzed rearrange-
ment of novel thiazolomorphinandienes have been pre-
sented. An isomerization was observed simultaneously
with the backbone transformation. An extensive study was
performed to determine the major effects of the isomeri-
zation of 20-alkyl- and aryl-substituted thiazoloapocodeines
into 30-alkyl- and arylisothiazoloapocodeines. The obtained
results provided another practical example of the reversible
benzisothiazole–benzothiazole-type isomerization empha-
sizing the determining role of the thermal effects in the
occurrence of these isomerization products. The obtained
experimental results and the proposed mechanism were in
agreement with the calculated DFT data.
excited singlet state of a molecule is populated, the mole-
cule can convert into the corresponding triplet state or into
the corresponding Dewar isomer (Scheme 2, first inter-
mediate of Mechanism I). The efficiency of these processes
will depend on energetic factors.
If the Dewar isomer is formed, the isomeric product is
obtained. If the triplet state is formed, cleavage of the X–Ca
bond can occur to give ring-opening products, decompo-
sition products or ring contraction products. However, if
the radical formed after the X–Ca cleavage shows a higher
energy than the triplet state, the triplet state will not be able
to give the biradical with high efficiency, and, then, it will
be quenched in radiative and not radiative processes. In this
case, the Dewar isomer could be responsible for the
isomerization reaction, but the isomerized product will
probably be produced in very low quantum yields.
Keywords Alkaloids ꢀ Photochemistry ꢀ
Density functional calculations ꢀ Heterocycles
Introduction
N
N
hv
In 1969 Lablache-Combier et al. [1] found that 1,2-thiazole
(henceforth referred as isothiazole) photoisomerizes to 1,3-
thiazole (henceforth referred as thiazole) in the presence of
primary amines (Scheme 1).
S
(RNH2)
S
1,2-thiazole
(isothiazole)
1,3-thiazole
In the last decades the photoisomerization of thiazole
moiety into isothiazoles [2–7] and isothiazoles to thiazole
structures [8–12] became a widely studied area using dif-
ferent substitution patterns of these five-membered rings.
A general observation regarding the photoisomerization
of pentaatomic aromatic heterocycles states that if the first
Scheme 1
N
N
S
hν
N
I
Ph
Ph
S
S
N
S
Ph
Ph
S
N
S
N
hν
N
Ph
S
II
´
A. Sipos (&) ꢀ S. Berenyi
Ph
Department of Organic Chemistry, University of Debrecen,
P.O. Box 20, 4010 Debrecen, Hungary
e-mail: asipos@puma.unideb.hu
Ph
Scheme 2
123

´
A. Sipos, S. Berenyi
388
Scheme 3
N
O
N
N
S
O
hv /
hv /
∆
N
N
N
Cl
N
H
N
Cl
∆
H
ziprasidone
photochallenge product of ziprasidone
S
this step; furthermore, it is also stressed that the complete
isomerization process showed a significant thermal de-
pendence. This conclusion was based on experimental
results on photoconversion of a large scale of ziprasidone
into the isomerization product. According to their obser-
vations, conversion was higher at elevated temperatures.
N
N
S
hv /
hv
∆
hv
hv
N
S
S
azirine-type
intermediate
benzothiazole
benzisothiazole
Scheme 4
Results and discussion
In connection with the photo-induced isomerization of
2-phenylthiazole [2f] it was concluded that the singlet
excited state could evolve, giving the Dewar thiazole (and
then isothiazole according to Scheme 2, I. route), while the
corresponding excited triplet state can be obtained. Fur-
thermore, the triplet state cannot be converted into the
biradical intermediates (Scheme 2, II. route) because these
intermediates show a higher energy than the triplet state,
thus preventing the formation of the cyclopropenyl
derivatives.
Synthesis
In one of our recent publications, we reported the synthesis
of 20-substituted thiazolomorphinandienes [15]. In the first
step, thebaine (1) was converted into 14b-bromocodeinone
(2) in a reaction with N-bromosuccinimide [16]. A
Hantzsch-type thiazole synthesis was carried out to yield
the aimed 20-substituted thiazolomorphinandienes 3–5
(Scheme 5).
A practical appearance of the isomerization of benz-
isothiazole moiety into the benzothiazole system was
described by industrial researchers [13]. Sharp and col-
leagues investigated the photoisomerization of ziprasidone,
an antipsychotic drug substance, and they observed the
occurrence of a new compound having identical mass
spectra with the one for the original compound. It was then
proved that this phenomenon was caused by the photo-
isomerization of the benzisothiazole portion of ziprasidone
(Scheme 3).
The morphinandiene structure of products 3–5 offered
the possibility of rearrangement into compounds with
aporphine backbone. This type of morphinandiene rear-
rangement has been studied in our laboratory for over
20 years [17–19], and it has been concluded that this
reaction produces apocodeine derivatives almost quantita-
tively. In the acid-catalyzed rearrangement of compounds
3–5, we observed different behaviour for compound 5, and
compounds 3, 4 in point of the obtained products
(Scheme 6).
After the demonstration of the decisive role of benz-
isothiazole moiety in the formation of the photoisomer-
ization product, the research group described a potential
mechanism for the isomerization based on the pertinent
literature [14] (Scheme 4).
In case of 20-amino congener, the expected one-com-
ponent crude product was obtained; however, in case of 20-
methyl and 20-phenyl analogues, two-component reaction
mixtures were found with components in approximately
1
The major step of this mechanism is the formation of an
azirine. Sharp et al. emphasized the thermal dependence of
1:1 ratio. After isolation and full H- and 13C- resonance
assignments (obtained from COSY, TOCSY, HSQC and
R
S
7
N
6
O
O
8
S
CH3
CH3
R
Br
14
RC
5
9
N
N
NBS
N
3
CH3
Ph
NH2
H3C
H3C
H3C
O
O
O
4
5
10
DMF, reflux
NH2
3
CH3
CH3
1
O
O
O
2
1
3-5
2
Scheme 5
123

Formation of novel 1,3-thiazole- and 1,2-thiazole-fused aporphines
389
R
N
R
3
3
4
4
R
N
S
S
S
5
2
4a
2
N
O
3, 6, 9
4, 7, 10
5, 8
CH3
Ph
6
R
5a
1a
7
CH3SO2OH
90-95 oC
N
H
N
H
1
1
7a
NH2
N
+
H3C
H3C
H3C
12
OH
OH
O
8
11
9
CH3
CH3
CH3
O
O
10
3-5
9, 10
6-8
Scheme 6
significant change in the ratio of thiazolo- and isothiazolo-
type products. In view of the above experimental results,
our group decided to initiate an extensive study of the
isomerization of 20-phenylthiazoloapocodeine (7) into 30-
phenylisothiazoloapocodeine (10) to explore the photolytic
and thermal dependences of this rearrangement. We aimed
to investigate either the photoisomerization of the thiaz-
oloapocodeine-type product in a variety of media or the
effect of the application of different reaction conditions
(i.e., application of microwave initiation) in comparison to
the literature method for acid-catalyzed rearrangement1
[20].
NH
NH
NH2
N
S
S
N
H
N
H3C
H
H3C
OH
O
OH
CH3
CH3
O
8
Fig. 1 Tautomer forms of 20-aminothiazoloapocodeine (8)
HMBC spectra) of the products, it was revealed that in case
of compounds 3 and 4 isothiazole-type apocodeines 9, 10
were formed, beside the previously expected thiazoloa-
porphines 6, 7.
For rapid and accurate quantification of thiazolo- and
isothiazoloapocodeines, a HPLC method was established
on the basis methods for apomorphine. Aporphines were
isolated from 0.5 ml of photoisomerization sample using a
liquid–liquid extraction with diethyl ether. Analytes were
separated on a 5-lm C18 Aquasil column (150 mm 9
4.6 mm). The elution was achieved isocratically with a
mobile phase of 2 mMꢀNH4COOH buffer pH 3.8/acetoni-
trile (50/50, vol/vol) at a flow rate of 500 ll/min with UV
detection at 254 nm. The average retention times for
compounds 7 and 10 were found to be 5.9 and 6.6 min,
respectively. The method was appropriately tested for
specificity and accuracy prior to use for the analysis of
different isomerization samples. After performing the
irradiation of the samples, tests were carried out to deter-
mine the extent of decomposition and to demonstrate the
appearance of the isothiazolo products. Representative
chromatograms for the Et2O extracts of two media (blank)
and two photoisomerization samples are presented in
Fig. 2.
The explanation for the occurrence of isothiazoloa-
porphines 9, 10 (‘thiazoloaporphine’ and ‘isothiazoloapor-
phine’ are used for simplification, for IUPAC names refer to
the Experimental section) is an isomerization reaction that is
simultaneous with the acid-catalysed rearrangement. The
applied conditions for the acid-catalyzed rearrangement of
the morphinandienes 3, 4 were the following: 90–95 °C,
polar solvent with strongly acidic character and no protection
from light. These conditions are not in contradiction with
those used by either Sharp et al. in their photoisomerization
tests or other scientists studying photoisomerization of thi-
azoles and isothiazoles.
The reason for the difference in the behaviour of amino-
derivative and its methyl- and phenyl-congeners could be
justified via the significant willingness of 2-amino-benzo-
thiazole moiety for tautomerization (Fig. 1).
The appearance of this imine-type tautomer means an
extra stabilization for benzothiazole structure against
benzisothiazole and may be an inhibitory effect of the
isomerization.
1
Provided the fundamental experimental method for the study of
photoisomerization. Japanese scientists applied a Riko UVL-100HP
(100 W) high-pressure mercury vapour lamp operated at wavelengths
between 180 and 420 nm with a peak at 366 nm. Duration of the
irradiation was 42 h. It means a total of 4,200 Wh of irradiation. In
our photoisomerization studies the same quantity of irradiation was
used.
Systematic study of isomerization
Initially, acid-catalysed rearrangement was repeated in
inert atmosphere (nitrogen gas), but there was no
123

´
A. Sipos, S. Berenyi
390
2'-Ph-thiazoloapocodeine
100
95
Average %
2'-Ph-thiazoloapocodeine
__
>
3'-P_h-_isothiazoloapocodeine
>
90
pH 1.2 medium extracted with Et O
2
pH 1.2 sample extracted with Et O
2
85
pH 4.5 medium extracted with Et O
2
80
pH 1.2
pH 3.0
pH 7.4
pH 10.0 MeOH:H2O
pH 4.5 sample extracted with Et O
2
Studied media
3'-Ph-isothiazoloapocodeine
5.0
5.5
6.0
6.5
7.0
7.5
8.0
Time (min)
2.0
1.5
1.0
0.5
0.0
Fig. 2 Representative chromatograms for photoisomerization media
and samples at pH 1.2 and 4.5
Average %
The first set of photoisomerization experiments was
carried out in different media2 with respect to their pH
ranging from 1.2 to 10.0 at constant ambient temperature at
an initial concentration of 0.5 mmol/l (the same as in
Sharp’s studies). We also applied the photoisomerization
medium used by Sharp et al. (methanol:water = 3:2,
pH = 5.5). The applied media was checked for interfering
absorbancies in the range of the elution of the studied
compounds, and there were no disturbing effects observed.
The following graphs present the average results of three
consecutive samplings and measurements (Fig. 3).
pH 1.2
pH 3.0
pH 7.4
pH 10.0 MeOH:H2O
Studied media
Other decomposition products
20
15
10
5
Average %
In the second step, we chose pH = 1.2 as a medium for
the study of the thermal dependence of the isomerization.
The reason for this decision was that the highest extent of
isomerisation was observed at this pH, and the level of
other decomposition products remained in an acceptable
range. The elevated, constant temperature rearrangement
studies of 20-phenylthiazoloapocodeine (7) were performed
at 35 and 50 °C (Fig. 4).
0
pH 1.2
pH 3.0
pH 7.4
pH 10.0 MeOH:H2O
To protect reaction mixture from disturbing effects (i.e.,
atmospheric oxygen, sunshine, large amounts of heat), a
novel method was developed involving microwave-initiated
acid catalysis. Sample preparation was performed under
inert atmosphere and protected from light. The microwave
reactor maintained these conditions. The product mixture
Studied media
Fig. 3 Photoisomerization results in media with pH ranging from 1.2
to 10.0
was allowed to cool in the dark cavity. The workup was also
performed in a dark place as much as possible.
2
Applied media are commonly used in the pharmaceutical industry
Microwave-promotion was performed with three differ-
ent settings. In the first experiment the target temperature
was set to 90 °C with 5 min hold time. The observed ratio
of thiazole-type vs. isothiazole-type products changed from
approximately 1:1 to 3:2. The second set of reactions was
performed under 70 °C target temperature with 10 min hold
for dissolution tests, and their quality is in agreement with pharma-
ceutical requirements: pH = 1.2—0.1 N hydrochloride solution.
pH = 3.0—0.05 M sodium chloride solution adjusted to pH 3.0 with
hydrochloride solution. pH = 4.5, 6.8 and 7.4—0.05 M sodium
dihydrogen phosphate buffer adjusted to the target pH with sodium
hydroxide solution. pH = 10.0—0.05 M ammonium chloride solu-
tion adjusted to pH 10.0 with ammonia solution.
123

Formation of novel 1,3-thiazole- and 1,2-thiazole-fused aporphines
391
2'-Ph-thiazoloapocodeine
MW rearrangements of
100
2'-Me-thiazolomorphinanediene
75
50
25
0
Average %
90
80
70
60
Ambient temperature
35 °C
50 °C
1. run
2. run
3. run
Applied temperature
MW rearrangements of
2'-Ph-thiazolomorphinanediene
3'-Ph-isothiazoloapocodeine
15
10
5
Average %
75
50
25
0
0
Ambient temperature
35 °C
50 °C
1. run
2. run
3. run
Applied temperature
Content data are averages of 3 runs
Other decomposition products
Average %
Unreacted diene
15
10
5
Benzisothiazole product
Benzothiazole product
Fig. 5 Graphs presenting the contents of the product mixture of
microwave-promoted rearrangements
Computational details
All the results presented in this work were obtained with
ab initio DFT theory using the Gaussian 98 program3 [21]
with the standard 6-31G* basis set, as the electron corre-
lation was expected to be critical in order to evaluate the
reaction profile properly, we carried out these calculations
by means of the hybrid functional developed by Becke and
also Lee, Yang and Parr, which is customarily denoted as
B3LYP [22–25]. Stationary points were characterised by
frequency calculations [26]. All intermediates and products
0
Ambient temperature
35 °C
50 °C
Applied temperature
Fig. 4 Graphs presenting the thermal dependence of the isomer-
ization
time. The amount of unreacted thiazolomorphinandienes
increased to 10%. The ratio of two isomer products
remained the same as in the first experiment. The third set of
microwave-promoted rearrangements was carried out at
65 °C target temperature for 3 min of hold time. The
amount of unreacted dienes increased up to 50%; however,
a remarkable change in the product ratio was observed.
The amount of benzisothiazole-type product dropped to
5% (Fig. 5).
3
The model for thebaine (1) obtained at the B3LYP/6-31G* level
was very much in accord with X-ray data (ref.: Mahler CH, Stevens
ED, Tundell M-L, Nolan SP (1996) Acta Crystallogr C 52:3193) for
compound 1. All computations were performed using a dual-core
Intel Xeon 5130 processor at 2.0 GHz. The CPU times for the
geometry optimization steps were in the range of 4,812–7,332 s. The
total time for geometry steps was 321 h.
123

´
A. Sipos, S. Berenyi
392
have positive Hessian matrices. Transition structures show
only one negative Eigenvalue in their diagonalized force
constant matrices, and their associated eigenvectors were
confirmed to correspond to the motion along the reaction
coordinate under consideration. Several reaction paths
were checked by intrinsic reaction coordinate (IRC) cal-
culations [27–29].
clearly deformed in both cases. Both S0 and T1 states of 2-
phenylthiazole and compound 7 are planar.
D’Auria reported that the triplet excited 2-phenylthiaz-
ole was found to be a p, p* triplet; however, the biradical
transition state structures were p, p triplets. The calculated
energy levels for LSOMOs and HSOMOs (lowest and
highest singly occupied molecular orbitals, respectively)
suggested that the biradicals are very similar to the triplet
species.
The triplet state of 20-phenylthiazoloapocodeine (7)
shows a p, p* character with the LSOMO at -6.37 eV and
the HSOMO at -4.92 eV. The 1,2 biradical is a p, p triplet
with the LSOMO at -6.69 eV and the HSOMO at
-4.87 eV. The 1,5 biradical is a p, p triplet with the
LSOMO at -5.24 eV and the HSOMO at -4.82 eV. It is
clear from the energy diagram (Fig. 6) that the formation
of the triplet species is significantly favoured over the
formation of the Dewar isomer; furthermore, the formation
of the 1,2-biradical is strongly favoured with respect to the
formation of the 1,5-biradical, and this drives the reaction
towards the formation of the isothiazole-type product 10.
The reactions have all been carried out in protic sol-
vents, which will favour acid–base equilibria and could
stabilize the intermediates involved.
Both isomerization routes described in Scheme 2 were
evaluated in DFT calculations by following the steps of
the mechanisms by IRC calculations. There were several
differences found in comparison to D’Auria’s results
regarding the photoisomerization of 2-phenylthiazole [2f].
Structures referring to the 20-phenylthiazoloapocodeine
(7) are illustrated in Fig. 6; the relative energy profile
referring to these structures is reported in Fig. 7 presenting
the proposed sequence of chemical changes; energy values
and geometrical data (bond lengths and angles) are repor-
ted in Tables 1, 2 and 3.
In the ground state, the substrate shows bond lengths in
agreement with the aromatic character of the molecule. For
2-phenylthiazole in the ground state, the calculated bond
angles and distances predict a partial dienic character. This
difference is clearly assigned to the presence of the fused
aromatic system in compound 7. The triplet states were
Fig. 6 Structures participating
in the benzothiazole-
benzisothiazole
photoisomerization
123

Formation of novel 1,3-thiazole- and 1,2-thiazole-fused aporphines
393
Fig. 7 Calculated relative
energies and proposed sequence
of isomerization-related
structures
150
II
XII
S1
S1
100
50
o
III
IV
XI
X
S0
S0
IX
T1
V
T1
T1
VII
T1
VI
VIII
S0
T1
T1
10
7
S0
S0
reaction co-ordinate
Table 1 Bond lengths and energies for five-membered structures
˚
Bond length (A)
Structure
Electronic
state
Rel. energy
(Kcal mol-1
)
3–4
2–3
1a–2
1a–4a
4–4a
PTA (7)
S0
T1
T1
T1
T1
1.7503
1.7878
1.3267
1.4234
1.4349
1.4287
1.4765
1.4020
1.3121
1.3045
1.3111
1.4610
1.4369
1.4545
1.4579
1.4544
1.4287
1.6873
1.7124
1.7101
0
54
46
66
52
PTA (IV)
PTA biradical 1,2 (VI)
PTA biradical 1,5 (V)
1.7842
PITA biradical 1,2
(VIII)
1.7018
PITA biradical 1,5 (IX)
PITA (X)
T1
T1
S0
1.6634
1.6507
1.6411
1.4810
1.4167
1.3235
1.4669
1.4023
1.4677
1.4356
1.4319
1.4254
77
57
9
1.7054
1.6954
PITA (10)
PTA Phenylthiazoloapocodeine; PITA phenylisothiazoloapocodeine
Table 2 Bond and dihedral angles for five-membered structures
Structure
Bond angle (°)
Dihedral angle (°)
2–3–4
1a–2–3
2–1a–4a
1a–4a–4
3–4–4a
4–3–10
(3–2–10)
2–3–10
(1a–2–10)
1–10–2–3
5a–4a–1a–2
PTA (7)
109.78
109.94
109.79
109.72
111.39
111.21
111.45
115.10
117.94
115.67
115.03
113.99
114.00
114.01
114.63
111.56
114.67
114.53
110.03
109.98
109.93
109.63
109.83
109.72
109.55
107.87
107.92
107.64
90.87
90.70
91.43
90.79
96.71
96.44
96.77
119.24
121.02
119.11
119.28
123.23
123.23
123.39
125.67
130.80
125.68
125.69
122.78
122.77
122.60
180.00
179.79
179.58
179.48
179.24
179.59
180.00
180.00
178.77
179.32
179.61
178.88
178.62
180.00
PTA (IV)
PTA biradical 1,2 (VI)
PTA biradical 1,5 (V)
PITA biradical 1,2 (VIII)
PITA biradical 1,5 (IX)
PITA (10)
PTA Phenylthiazoloapocodeine; PITA phenylisothiazoloapocodeine
With respect to the study of the thermal dependence, the
above-presented results confirmed the determining role of
the thermal effects in this type of isomerization reactions
(in accordance with the comment of Sharp et al. regarding
the photoisomerization of ziprasidone). On the basis of
both the experimental results and the calculated data, we
concluded that in the presented mechanism (Fig. 7,
Scheme 7) the energy-demanding VI?VII and VIII?VII
(i.e., the aziridine-formation) steps bore the thermal de-
pending-character.
Conclusion
An extensive photoisomerization study was performed
both by experimental and DFT (density functional theory)
123

´
A. Sipos, S. Berenyi
394
Table 3 Structural properties and energies of three- and four-membered structures
˚
Bond length (A)
Structure
Electronic
state
Bond angle (°)
Dihedral angle (°)
Rel. energy
(Kcal mol-1
)
PTA dewar (III)
S0
1a-N
N-3
1.3332
1-1a-N
4a-S-3
S-3-N
138.57
1-1a-4a-3
1-1a-4a-S
5a-4a-1a-N
1-1a-N-3
5a-4a-3-N
5a-4a-S-3
169.13
89
1.5619
1.5058
1.4794
1.9075
1.9854
51.19
109.61
70.06
58.75
87.15
89.23
81.64
97.42
63.90
65.48
148.14
146.39
130.33
144.34
165.41
121.11
123.92
4a-3
1a-3a
3-S
S-3-4a
S-4a-3
1a-N-3
4a-3-N
1a-4a-3
4a-1a-N
1a-N-3
N-3-1a
N-2-S
4a-S
Aziridine intermediate (VII)
S0
1a-N
N-3
1.7021
1.2723
1.4802
1.4534
1.7217
1.3799
1.5063
1.5187
1.4834
1.9964
1.9045
1-2-3-S
173.23
141.57
144.07
160.38
158.15
162.79
138.27
143.02
5.00
49
91
4a-3-2-N
1a-1-2-N
4a-3-2-20
1a-1-2-20
1-1a-4a-N
1-1a-4a-S
5a-4a-1a-3
3-1a-3a-N
3-1a-4a-S
1-1a-3-N
1a-3a-N-S
1a-3
1a-4a
4a-S
4a-3
3-N
1a-3-S
PITA dewar (XI)
S0
1-1a-3
3-S-N
145.88
50.77
63.79
112.30
104.92
65.44
94.53
112.49
91.18
N-4a
1a-4a
N-S
S-3-N
S-3-2
S-N-3
53.94
4a-S
1a-N-S
1a-3-N
1a-3a-N
4a-1a-3
155.87
117.13
PTA Phenylthiazoloapocodeine; PITA phenylisothiazoloapocodeine
C
N
N
S
S
S
S
S
N
N
C
N
∆
N
H
h
/
hν
N
hν
hν / ∆
ν
∆
N
H
N
N
H
H
C
H
C
3
H
C
3
H
C
3
3
H
C
3
H
H
∆
OH
O
OH
OH
OH
OH
CH
CH
CH
3
CH
3
3
3
CH
3
O
O
O
O
VII
VIII
VI
10
7
Scheme 7
calculations to determine the fundamental mechanism and
determining factors of the unexpected benzothiazole–
benzisothiazole-type isomerization explored during the
formation of aporphine backbone. The experimental
results from either reactions with modified parameters or
target-specific photoisomerization studies and additional
DFT calculation data revealed the main reasons respon-
sible for this isomerization and provided further insight
into the mechanism of long-studied thiazole-isothiazole
rearrangement. Simultaneously with the presented study
of the observed isomerization, we accomplished the
O-demethylation of apocodeines 6–10 to obtain apomor-
phines with potential affinity to dopamine receptors. The
pharmacological evaluation of these products will be
published in due course.
Experimental
Melting points were determined with a Kofler hot-stage
apparatus. Thin-layer chromatography was performed on
pre-coated Merck 5554 Kieselgel 60 F254 foils using
chloroform: methanol = 8:2 mobile phase. The spots were
1
visualized with Dragendorff’s reagent. H and 13C NMR
spectra were recorded on a Bruker AM 360 spectrometer,
chemical shifts are reported in ppm (d) from internal TMS,
123

Formation of novel 1,3-thiazole- and 1,2-thiazole-fused aporphines
395
Off-white plate shape crystals, Rf (chloroform:metha-
nol = 8:2) 0.59; m.p. 162–164 °C; yield: 188 mg (39%);
[a]D25 –206 cm2 g-1 (c 0.1, chloroform); HR-MS (ESI) m/
z (%) found: 415.1479 (M++1, 100), calculated: 415.1484
and coupling constants (J) are measured in Hz. Signal
assignments were based on standard APT, DEPT, HSQC,
HMQC, 1H–1H COSY and NOESY experiments. High-
resolution mass spectral measurements were performed
with a Bruker micrOTOF-Q instrument in the ESI (elec-
trospray ionization) mode. Optical rotation was determined
with a Perkin Elmer Model 241 polarimeter. Elemental
analyses (C, H, N, S) were conducted using the Elemental
Analyser Carlo Erba 1106; their results were found to be in
good agreement ( 0.2%) with the calculated values.
The microwave-induced reactions were carried out in a
Discover model microwave reactor manufactured by CEM
Corporation. Controlled temperature, power, pressure and
time settings were used for all reactions.
1
(M++1); H NMR (360 MHz, CDCl3): d = 7.91 (s, H1),
7.77–7.19 (m, 5H, 3-Ph), 6.68 (2d, J9–10 7.7 Hz, H9, H10),
6.12 (br s, 12-OH), 3.83 (s, 11-OCH3), 3.09–2.41 (m, H5a,
H6a, H6b, H7a), 2.38 (s, NCH3), 2.30–2.07 (m, H5b, H8a,
H8b) ppm; 13C NMR (90 MHz, CDCl3): d = 166.7 (C3),
154.2 (C10), 149.1 (C11), 142.7 (C12), 135.4–112.1 (Ar,
15C), 59.0 (OCH3), 56.5 (C7a), 52.8 (C6), 41.2 (NCH3),
35.1 (C8), 27.4 (C5) ppm.
(7aR)-3-Amino-12-hydroxy-11-methoxy-thiazolo[4,5-k]-5,
6, 7a, 8-tetrahydro-4H-dibenzo [de,g]quinoline (8)
(20-aminothiazolo-apocodeine)
Acid-catalyzed rearrangement of morphinandienes
(general procedure)
Pale yellow cubic crystals were obtained by the recrystal-
lization of crude apocodeine from anhydrous ether; m.p.
25
109–111 °C (ether); yield: 488 mg (89%); [a]D
A mixture of the diene (1 g) and methanesulfonic acid
(5 cm3) was stirred for 20 min at 0 °C. Then the reaction
mixture was heated at 90–95 °C for 30 min. After cooling
to room temperature, the product mixture was added
dropwise, with stirring and external ice-cooling, to a
solution of potassium hydrogen carbonate (10 g) in water
(50 cm3). After extraction with chloroform (3 9 15 cm3),
the combined extracts were washed with saturated brine,
dried (MgSO4), and concentrated in vacuum. In case of
necessity, the residue was submitted to purification by
means of column chromatography (Kieselgel 40, chloro-
form:methanol = 1:1) to yield appropriate apocodeines.
-203 cm2 g-1 (c 0.1, methanol); HR-MS (ESI) m/z (%)
found: 354.1261 (M++1, 100), calculated: 354.1274
(M++1); 1H NMR (360 MHz, DMSO-d6): d = 8.87 (s,
12-OH), 8.29 (s, H1), 7.41 (s, 3-NH2), 6.82 (2d, J9-10
8.4 Hz, H9, H10), 3.84 (s, 11-OCH3), 3.31-2.78 (m, H5a,
H6a, H6b, H7a), 2.47 (s, NCH3), 2.66–2.09 (m, H5b, H8a,
H8b) ppm; 13C NMR (90 MHz, DMSO-d6): d = 162.9
(C3), 148.3 (C10), 148.1 (C11), 143.4 (C12), 135.2–114.5
(Ar, 9C), 60.3 (C7a), 56.4 (OCH3), 52.4 (C6), 42.4 (NCH3),
35.8 (C8), 28.8 (C5) ppm.
(7aR)-12-Hydroxy-2-methyl-11-methoxy-isothiazolo[4,5-
k]-5, 6, 7a, 8-tetrahydro-4H-dibenzo [de,g]quinoline (9)
(30-methylisothiazolo-apocodeine)
(7aR)-12-Hydroxy-3-methyl-11-methoxy-thiazolo[4,5-k]-5,
6, 7a, 8-tetrahydro-4H-dibenzo [de,g]quinoline (6)
(20-methylthiazolo-apocodeine)
Column chromatography was applied to separate com-
pounds 6 and 9. Compound 9 was the second eluted
fraction. Grey plate shape crystals, Rf (chloroform:meth-
anol = 8:2) 0.44; m.p. 142–147 °C, yield: 167 mg (44%);
Column chromatography was applied to separate com-
pounds 6 and 9. Compound 6 was the first eluted fraction.
Grey plate shape crystals; Rf (chloroform:methanol = 8:2)
25
[a]D +16 cm2 g-1 (c 0.1, chloroform); HR-MS (ESI)
25
0.67; m.p. 170–173 °C; yield: 216 mg (44%); [a]D
m/z (%) found: 353.1315 (M++1, 100), calculated:
353.1321 (M++1); 1H NMR (360 MHz, CDCl3):
d = 7.98 (s, H1), 6.77 (2d, J9–10 7.9 Hz, H9, H10), 6.44
(br s, 12-OH), 3.92 (s, 11-OCH3), 3.52–2.83 (m, H5a,
H5b, H6b, H7a, H8b), 2.60 (s, 2-CH3), 2.55 (m, H8a), 2.51
(s, NCH3), 2.41 (m, H6a) ppm; 13C NMR (90 MHz,
CDCl3): d = 158.7 (C2), 147.9 (C11), 142.9 (C12), 142.7
(C5a), 138.2 (C4a), 133.8–114.6 (Ar, 8C), 60.6 (C7a), 56.4
(OCH3), 52.1 (C6), 41.2 (NCH3), 34.0 (C8), 23.8 (C5),
19.5 (C-CH3) ppm.
–109 cm2 g-1 (c 0.1, chloroform); HR-MS (ESI) m/z (%)
found: 353.1309 (M++1, 100), calculated: 353.1321
(M++1); H NMR (360 MHz, CDCl3): d = 7.95 (s, H1),
1
6.77 (2d, J9–10 7.2 Hz, H9, H10), 6.71 (br s, 12-OH), 3.92
(s, 11-OCH3), 3.52-2.92 (m, H5a, H6a, H6b, H7a), 2.85 (s,
3-CH3), 2.81–2.51 (m, H5b, H8a, H8b, NCH3) ppm; 13C
NMR (90 MHz, CDCl3): d = 169.6 (C3), 152.9 (C10),
148.5 (C11), 142.6 (C12), 136.7–114.4 (Ar, 9C), 60.4
(OCH3), 58.6 (C7a), 53.1 (C6), 40.7 (NCH3), 35.1 (C8),
24.2 (C5), 22.2 (C-CH3) ppm.
(7aR)-12-Hydroxy-11-methoxy-3-phenyl-isothiazolo
[4,5-k]-5, 6, 7a, 8-tetrahydro-4H-dibenzo [de,g]
quinoline (10) (20-phenylisothiazolo-apocodeine)
Column chromatography was applied to separate com-
pounds 7 and 10. Compound 10 was the second eluted
(7aR)-12-Hydroxy-11-methoxy-3-phenyl-thiazolo[4,5-k]-5,
6, 7a, 8-tetrahydro-4H-dibenzo [de,g]quinoline
(7) (20-phenylthiazolo-apocodeine)
Column chromatography was applied to separate com-
pounds 7 and 10. Compound 7 was the first eluted fraction.
123

´
A. Sipos, S. Berenyi
396
fraction. White plate shape crystals; Rf (chloroform:meth-
anol = 8:2) 0.43; m.p. 179–183 °C, yield: 159 mg (33%);
[a]D25 +15 cm2 g-1 (c 0.1, chloroform); HR-MS (ESI) m/z
(%) found: 415.1499 (M++1, 100), calculated: 415.1485
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(M++1); H NMR (360 MHz, CDCl3): d = 8.23 (s, H1),
8.11–7.43 (m, 5H, 2-Ph), 6.70 (2d, J9–10 7.9 Hz, H9, H10),
3.59 (s, 11-OCH3), 3.31–2.77 (m, H5a, H5b, H6b, H7a,
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protected from sunlight under nitrogen atmosphere. The
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wave reactor, irradiated at the pre-set target temperature for
the previously set hold time and subsequently cooled by
rapid gas-jet cooling. The product mixture was allowed to
cool to room temperature in the microwave cavity; the
following workup procedure was the same as in case of
thermal activation.
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Conditions for photoisomerization studies
Compound 7 (20.7 mg; 0.5 mmol/dm3) was dissolved in
the corresponding medium4 (100 cm3) and outgassed with
helium for 1 h. The solution was irradiated with a 125 W
high-pressure mercury-arc (Helios-Italquartz, Milan) sur-
rounded by a Pyrex water jacket. After previously
determined irradiation time mixture5 was analyzed by the
described HPLC method in order to determine the extent of
isomerization.
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´
Acknowledgments The authors are grateful to Prof. Sandor Antus
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25. Vosko SH, Wilk L, Nusair M (1980) Can J Phys 58:1200
26. McIver JW, Komornicki AK J Am Chem Soc 94: 2625
for substantial discussions and to the National Science Foundation
(Grant OTKA reg. No. T049436 and NI61336) for the financial
´
´
´
support. We thank the Peter Pazmany Programme (NKTH, RET006/
2004) for allowing us to use the microwave reactor and to Szabolcs
Fekete for the valuable technical help.
´
27. Gonzalez C, Schlegel HB (1989) J Chem Phys 90:2154
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28. Gonzalez C, Schlegel HB (1990) J Phys Chem 94:5523
29. Fukui K (1981) Acc Chem Res 14:363
4
See Footnote 2.
5
See Footnote 1.
123