Formation of novel thiazolomorphinans and thiazoloaporphines

Article abstract of DOI:10.1016/j.tet.2008.08.069

A novel strategy has been developed for the synthesis of ring A fused thiazolomorphinans and ring D fused thiazoloaporphines offering the possibility of formation of regioisomeric products. The conventional thermal thiazole-forming reaction was replaced with microwave initiation and a detailed discussion has been presented on the proposed mechanism of the ring closure.

Full text of DOI:10.1016/j.tet.2008.08.069

Tetrahedron 64 (2008) 10388–10394
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Formation of novel thiazolomorphinans and thiazoloaporphines
*
´
´
´
Levente Giran, Sandor Berenyi, Attila Sipos
Department of Organic Chemistry, University of Debrecen, PO Box 20, H-4010 Debrecen, Hungary
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 2 June 2008
Received in revised form 3 August 2008
Accepted 21 August 2008
Available online 28 August 2008
A novel strategy has been developed for the synthesis of ring A fused thiazolomorphinans and ring D
fused thiazoloaporphines offering the possibility of formation of regioisomeric products. The conven-
tional thermal thiazole-forming reaction was replaced with microwave initiation and a detailed dis-
cussion has been presented on the proposed mechanism of the ring closure.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
Morphinandiene
Aporphine
Acid-catalyzed rearrangement
Kaufmann-type thiazole formation
Microwave promotion
DFT calculations
1. Introduction
substituted natural origin aporphines, such as boldine and pre-
dicentrine.6 The other procedure started with the acid-catalyzed
Thiazole ring systems are widely used structural elements in
medicinal chemistry. This structure, especially in the case of
2-amino substitution, has been applied in the development of the
treatment of allergies, hypertension, inflammation, schizophrenia,
bacterial and HIV infections.1 Go¨rlitzer and Schumann2a and our
research group2b prepared thiazole-fused morphinans at their ring
C in order to test the effect of this novel moiety on the affinity at
opioid receptors (Fig. 1). Recently, Neumeyer’s group3 synthesized
ring A fused 20-aminothiazole derivatives of benzomorphans and
morphinans to study their opioid agonist properties (Fig. 1). The
affinity of these novel series was somewhat reduced from that of
their phenol prototypes, one compound has been identified as
rearrangement of the derivatives of natural morphine yielding
R-aporphinoids and then applied a racemization/resolution se-
quence.7 They found the presence of H-bond donor/acceptor 9-OH
or H-bond acceptor 9-OCH3 groups (substituted boldines/pre-
dicentrines) besides 8-halo/amino and 10/11-OCH3 functions
favourable. Generally, aporphine backbones with highly function-
alized D-rings and substituents having the ability to form H-bonds
are considered a promising starting point of the development of
D1-active ligands.
Ring D fused thiazoloaporphines were also synthesized by our
group targeting primarily the D2-receptor subtypes.2b
In the light of these studies on both thiazolomorphinans and
dopaminergic thiazolocompounds wedecidedto form A-andD-ring
fused (morphinan and aporphine backbone, respectively) de-
rivatives retaining the free phenolic hydroxyl function of the alkaloid
skeletons.
possessing high affinity and selectivity at the
k receptor.
The 2-aminothiazole functionality has been successfully applied
as a heterocyclic bioisostere of the phenol moiety also in dopamine
agonists such as B-HT 920,4a PD 1184401d and pramipexole4b
resulting in improved pharmacological properties (Fig. 1).
In the last two decades considerable amount of research activity
was devoted to the synthesis and pharmacological evaluation of
molecules possessing significant D-1 receptor activity with antag-
onistic character.5 Regarding new aporphinoids developed for this
neuropharmacological field two different approaches were applied
for the formation of these compounds. One of them utilized and
2. Results and discussion
Our attention turned to the formation of ring A fused thiazolo-
morphinans after the successful application of the Hantzsch-type
thiazole synthesis for the introduction of this moiety to the ring C of
morphinans.2b We aimed the development of a novel heteroring-
forming methodology retaining the highly important pharmaco-
phore 3-OH group8 in order to obtain new, potentially opioid-active
compounds with interesting substitution pattern on ring A. The
structure of these compounds also offers the opportunity for the
* Corresponding author. Tel.: þ36 52512900; fax: þ36 52512836.
E-mail address: asipos@puma.unideb.hu (A. Sipos).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.08.069

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L. Giran et al. / Tetrahedron 64 (2008) 10388–10394
10389
NH2
N
OH
OH
OH
N
S
S
H
H
H
H2N
N
N
N
N
H3C
H3C
H3C
O
O
O
C-ring fused aminothiazolo-
morphinandiene
N
N
H3C
H3C
B-HT 920
O
OH
OH
OH
S
NH2
NO2
2
N
N
OCH3
OH
H2N
N
H2N
H2N
S
H
PD 118440
A-ring fused aminothiazolo-
O
H
morphinan
N
S
N
N
N
H
N
H
N
H
H3C
H3C
S
H3C
Pramipexole
NH2
OH
OH
OH
OH
OH
OH
Figure 1. Opioid- and dopamine-active compounds bearing aminothiazole moiety.
S
N
NO2
NH2
H2N
well-known acid-catalyzed rearrangement of the morphinan
skeleton resulting in substituted aporphines with highly active
pharmacophores at ring D according to recent findings on D1-ac-
tive aporphines.2c
4
Scheme 2. Retrosynthesis of the procedure based on 2-nitromorphine (2).
catalyzed rearrangement, we had to work towards the aimed
aminothiazole derivative on very sensitive catechol-containing
aporphines. Although we finally resolved this problem with the
application of immediate salt formation after each step, signifi-
cantly lower overall yield was observed due to the oxidation sen-
sitivity of the catechol motif. This fact particularly emphasized the
importance of the alternative route building up the thiazole ring on
the morphinan skeleton.
In the first stage we identified the Kaufmann-type amino-
thiazole formation9 as a good choice to base the functionalization of
ring D on. The reason for this was not only the fact that it was
successfully applied on morphinan backbone earlier, but also the
facile availability of the starting nitro-derivatives.
We found two alternative routes to form morphinan and apor-
phine backbones fused with aminothiazole moiety at rings A and D,
respectively. One of them was initiated from 1-nitromorphinan
yielding aminothiazoloapocodeine 3 as the final product (Scheme
1), whereas the second alternative was based on 2-nitromorphinan
and led to aminothiazolo-apomorphine 4 (Scheme 2). The two
main routes could be subdivided with respect to the target skeleton
of the Kaufmann-type thiazole formation. It offered the chance of
performing the heteroring formation in both cases on morphinans
or aporphines.
The synthesis and structure elucidation of 1- and 2-nitro-
morphinans10 were started in 1851 and were undoubtedly clarified
in 1963.11 We applied these historical methods for the synthesis of
the 1-nitrocodeine (1)10c and 2-nitromorphine (2).10d
2-Nitromorphine (2) was found to be the only practicable choice
as a starting product for the procedure initiated from 2-nitro-
morphinan. As a consequence of that, after performing the acid-
In order to develop an easy and reliable analytical procedure for
verifying the actual position of the nitro-group of the starting
compounds 1 and 2 instead of the complex and time-consuming
procedures described in the literature,11 we examined the possi-
bilities offered by modern structural analysis and found the in-
vestigation of Nuclear Overhauser Effect (NOE) a good solution due
to the easily identifiable 1-H, 2-H and 10-H protons (Fig. 2).
The observed NOEs were in accordance with the distances
presented on the structures of 1 and 2 optimized at the B3LYP/6-
31þG* level12 in Figure 2 for 1-nitrocodeine (1) there was no NOE
correlation between distant 2-H and 10
2-nitromorphine (2) we found moderate correlation between 1-H
and 10 -H nuclei.
b-H protons; however, for
b
2.1. Reductions and rearrangements
7
OH
OH
OH
8
After obtaining and characterizing nitro-compounds 1 and 2 we
looked for an appropriate reduction procedure to turn them into
the corresponding amino-derivatives. The conventional procedure
utilizes tin–hydrochloric acid reagents,11 however, the product is
formed in tin-salt form, from which the base could be liberated by
H
H
H
14
5
N
N
N
H3C
H3C
H3C
O
O
O
10
1
3
H2N
OCH3
O2N
OCH3
OCH3
N
2
1
S
H2N
3
4
6a
2
5
N
H
N
H
N
H
1
H3C
H3C
H3C
12a
7a
7b
12
7
OH
OH
OH
11
OCH3
O2N
OCH3
H2N
OCH3
8
10a
10
N
S
9
H2N
3
Figure 2. Important distances presented on the structures of 1 and 2 optimized at the
Scheme 1. Retrosynthesis of the procedure based on 1-nitrocodeine (1).
*
B3LYP/6-31þG
level.

´
L. Giran et al. / Tetrahedron 64 (2008) 10388–10394
10390
hydrogen sulfide gas. Owing to environmental and health issues
regarding this procedure we started looking for an alternative
method. After several unsuccessful runs with iron chips in hydro-
chloric acid, zinc in sodium hydroxide solution, ammonium for-
mate and Raney-Ni catalyst in methanol13 (poor conversion or
difficulties during work-up procedure), the procedure applying
formamidinesulfinic acid (FSA) in sodium hydroxide solution was
adapted for both morphinan and aporphine backbones successfully
(Scheme 3).14
140
120
100
80
Temperature (°C)
Pressure (PSI)
Power (W)
60
40
As it was emphasized in the synthesis plans and Scheme 3, the
acid-catalyzed rearrangement15 is a determining procedure in the
formation of the targeted aminothiazoloaporphines 3 and 4. It was
also presented in the retrosyntheses that these methodologies offer
the opportunity of backbone-transformation in each step from
morphinans to aporphines. Generally, in the acid-catalyzed rear-
rangements of 1-substituted codeines 1 and 5 we received the
expected 8-nitro- and 8-aminoapocodeines (7 and 9) in excellent
yields (Scheme 3, panel A). These apocodeines were found to be
stable in free base form without any further transformation.
The rearrangement of 2-substituted morphines 2 and 6 (Scheme
3, panel B) gave 9-nitro- and 9-aminoapomorphines (8 and 10) in
high yield, however, these compounds were found to be even more
sensitive to oxidation in free base form than apomorphines without
a substituent in positions 8 or 9, therefore immediate formation of
the air-stable HCl salts was more significant.
20
0
1
101 201 301 401 501 601 701 801
time (s)
Figure 3. Typical run for the MW-assisted thiazole formation.
instead of conventional thermal effect. Obtained results were in
line with our expectations; the isolated yields were higher in this
pressurized vessel method. Exploiting the freedom of choice of
parameters offered by CEM Discover apparatus, we kept the max-
imal power permitted by the system for such an ionic-polar solu-
tion and applied 130 ꢀC as target temperature with 15 min hold
time. It was found that high temperature was favourable for thi-
azole formation. In Figure 3 a typical run is presented showing
consistent controlled temperature and non-controlled pressure.
As it was mentioned, the optimization of the formation of
2-aminothiazole ringwas performedon1-aminocodeine (5, Scheme
3, panel A). The developed methodology was found to be applicable
and practicable for 2-aminomorphine (6) and corresponding apor-
phines 9 and 10 without major modification (Scheme 4).
2.2. Formation of the 2-aminothiazole ring
The optimization of the heteroring formation procedure was
started on 1-aminocodeine (5) with the application of the con-
ventional method of Kaufmann described in 19289 and adopted for
morphinans by Neumeyer’s group.3 Amine 5 was treated with
potassium thiocyanate and bromine in acetic acid and refluxed
without protection from light. After several optimization steps in-
cluding changes in the reaction time, the target temperature and
the intensity of the lighting (application of outer exposition) there
was no significant increase in the conversion, the isolated yield
remained at a level of 20%. According to the literature, microwave
induction (MW) has been applied successfully for the development
of reactions taking place via a radical intermediate.16 At this point it
should be clarified that no mechanistic explanation is available for
the Kaufmann-type reaction, however, all available experimental
data point to the fact that the role of a radical intermediate is
a reasonable assumption.
2.3. Study on the mechanism of the thiazole formation
The above-presented thiazole formation has been applied fre-
quently for the synthesis of pharmacologically active compounds.17
After an extensive literature search it was found that there is no
unambiguous explanation available for the mechanism of this im-
portant heteroring-forming reaction. Maggiolo presumed the or-
tho-thiocyanation of the ring as a starting step,18 while Trapani et al.
state that the main step is the reaction between in situ formed
(SCN)2 and substituted anilines.19
In accordance with this conclusion further optimization of the
reaction was performed with the application of MW initiation
We have carried out a detailed study based on DFT (Density
Functional Theory) calculations using the Gaussian 98 program
OH
OH
OH
OH
A
B
H
H
H
H
N
N
N
N
H3C
FSA
NaOH
H3C
H3C
FSA
NaOH
H3C
O
O
O
O
O2N
OCH3
H2N
OCH3
OH
OH
1
5
NO2
2
NH2
6
CH3SO2OH
CH3SO2OH
CH3SO2OH
CH3SO2OH
N
N
N
N
H3C
H3C
H3C
H3C
FSA
NaOH
FSA
NaOH
OH
OH
OH
OH
OH
OH
O2N
OCH3
H2N
OCH3
7
9
NO2
8
NH2
10
Scheme 3. Reduction and rearrangement sequences A and B starting from nitromorphinans 1 and 2, respectively.

´
L. Giran et al. / Tetrahedron 64 (2008) 10388–10394
10391
OH
KSCN, Br2 H3C
AcOH
MW
OCH3
OH
OH
KSCN, Br2
OH
A
B
H
H
H
H
S
N
N
N
N
H3C
H3C
H3C
O
O
O
O
AcOH
MW
H2N
OCH3
OH
OH
N
S
11
N
5
NH2
6
H2N
H2N
12
CH3SO2OH
CH3SO2OH
CH3SO2OH
CH3SO2OH
N
N
N
N
KSCN, Br2
KSCN, Br2
H3C
H3C
H3C
H3C
AcOH
MW
AcOH
MW
OH
OH
OH
OH
OH
H2N
OCH3
OH
OCH3
N
S
9
S
3
NH2
10
N
4
H2N
H2N
Scheme 4. Heteroring formation and rearrangement sequences A and B starting from aminomorphinans 5 and 6, respectively.
with the standard 6-31þG
*
basis set, as the electron correlation was
The formation of HSCN from KSCN was also described by Kla-
son.23 In order to confirm the general presumption on the role of
radical species we performed the MW-promoted heteroring for-
mation of 5 in the absence of bromine and in the presence of
expected to be critical in order to evaluate the reaction profile
properly.12 The hybrid functional B3LYP developed by Becke and
also Lee, Yang and Parr was applied throughout this study as we
received satisfactory control data at this level.20 Stationary points
were characterised by frequency calculations.21 All intermediates
and products have positive Hessian matrices. Transition structures
show only one negative eigenvalue in their diagonalized force
constant matrices, and their associated eigenvectors were con-
firmed to correspond to the motion along the reaction coordinate
under consideration. Several reaction paths were checked by in-
trinsic reaction coordinate (IRC) calculations.22
bromine and a-tocopherol, a free radical scavenger. The analysis of
both product mixtures showed the absence of product 11, fur-
thermore we were able to identify the similar side-products.
The t1/11t conversion was submitted for further study to
identify the energetic and steric character of the participating
species (Fig. 4 and Table 1).
In accordance with the calculated geometry data the radical-
containing thiourea moiety migrates from the energetically
Maggiolo’s interpretation was interpreted in the form of a nu-
cleophile radical substitution on aromatic system, however, our
calculations do not support this alternative as the energetic and
steric parameters of the involved intermediates were found to be
highly unfavourable.
favourable t1 conformation to the s-complex structure. Simulta-
neously the electron distribution of the aromatic ring changes and
the C2–H bond elongates.
3. Conclusions
Kaufmann examined the potential reactive species of the thi-
azole formation and presented proofs on the presence of in situ
formed (SCN)2 and HSCN.9 Our calculations pointed to the fact that
in acetic acid medium it is HSCN that performs the thiourea for-
mation of substituted anilines (Scheme 5).
We have presented a novel strategy for the synthesis of ring A
fused thiazolomorphinans and ring D fused thiazoloaporphines
offering the possibility of formation of regioisomeric products. In
the key step of the synthesis routes the conventional thermal
KSCN
+
HOAc
HSCN
OH
+ KOAc
OH
OH
H
N
H
H
N
N
[ HSCN]
H3C
H3C
Br2
H3C
O
O
O
HN
S
OCH3
i1
HN
HS
OCH3
H2N
OCH3
5
i2
NH2
NH
OH
OH
OH
H
H
H
N
N
N
H3C
H3C
H3C
O
O
O
OCH3
OCH3
N
HN
HN
HN
S
OCH3
S
S
NH
H2N
t1
11t
11
Scheme 5. Proposed mechanism for the thiazole formation on compound 5.

´
L. Giran et al. / Tetrahedron 64 (2008) 10388–10394
10392
(5 mL). A solution of NaOH (0.72 g, 18 mmol) in H2O (10 mL) was
made up and 5 mL portion of this was added to the suspension. FSA
(0.97 g, 8.7 mmol) was dissolved in the remaining 5 mL of NaOH
solution and transferred to the alkaline solution of the nitro-de-
rivative. The reaction mixture was heated with stirring on an oil
bath at 90 ꢀC under N2 for 1 h. After a few minutes the nitro-
compound completely dissolved. The product mixture was allowed
to cool to room temperature, the organic solvent was evaporated in
vacuo, the aqueous solution was extracted with CHCl3/MeOH¼2/1
mixture, the organic layer was washed with brine, dried over
MgSO4, filtered and concentrated to afford the amino-compound.
Method B for thiazole ring closure. Aminomorphinan (0.32 mmol)
and KSCN (130 mg, 1.34 mmol) were dissolved in glacial acetic acid
(3 mL) in a 10 mL glass tube and one drop of bromine was added.
The reaction was carried out in MW reactor for 15 min at 130 ꢀC
with 60 W of maximum power, under pressure in a sealed vial.
After cooling, the reaction mixture was poured on to ice water and
the pH was adjusted to 9 by adding concentrated ammonia solution
in the presence of ice. The mixture was extracted with ethylacetate,
the organic layer was washed with brine, dried over MgSO4, filtered
and concentrated in vacuo to afford the appropriate aminothiazole
derivative.
σ-complex
t1
11t
Reaction co-ordinate
Method C for acid-catalyzed rearrangement. A mixture of the
morphinan (0.32 mmol) and methanesulfonic acid (5 mL) was
stirred for 25 min at 90 ꢀC. Then the reaction mixture was poured
on to ice water and the pH was adjusted to 9 by adding concen-
trated ammonia solution with constant ice cooling. The mixture
was extracted with ethylacetate, the organic layer was washed with
brine, dried over MgSO4, filtered and concentrated in vacuo to yield
the appropriate aporphine.
Figure 4. Calculated relative energies and structures of participating species optimized
at the B3LYP/6-31þG level.
*
thiazole-forming reaction was replaced with microwave initiation.
A detailed study has been presented on the proposed mechanism of
the ring closure including experimental proofs and DFTcalculations.
4. Experimental part
4.1. General details
4.2.1. 1-Nitrocodeine (1)
Compound 1 was prepared according to the previously de-
scribed method.10c All the physical properties are in line with
reported data.10 HRMS (ESI) m/z (%) found: 345.1456 (MþþH, 43),
calculated for C18H21N2O5þ: 345.1445 (MþþH); nmax (KBr disc) broad
Melting points were determined with a Kofler hot-stage appa-
ratus and are uncorrected. Thin layer chromatography was per-
formed on pre-coated Merck 5554 Kieselgel 60 F254 foils using
chloroform/methanol¼8/2 mobile phase. The spots were visualized
with Dragendorff’s reagent. 1H and 13C NMR spectra were recorded
on a Bruker AM 360 spectrometer, chemical shifts are reported in
band 3200 (OH), 1520 (NO2) cmꢂ1 1H NMR (360 MHz, CDCl3)
;
d
¼7.30 (s,1H, H2), 5.63, 5.47 (2d, 2H, H7–H8, J7–8 5.2), 4.25–4.05 (m,
2H, H5a, H6a), 3.89 (s, 3H, OCH3), 3.22–2.62 (m, 4H, H9b, H10a, H10b,
H14b), 2.46–2.12 (m, 6H, NCH3, H15b, H16a, H16b), 2.04 (dt, 1H,
H15a, J15a–15b;16a–16b 11.6, J15a–15b 4.7); 13C NMR (360 MHz, CDCl3)
parts per million (d) from internal TMS and coupling constants (J)
d
¼149.14 (C4), 146.27 (C3), 140.43 (C1), 133.21, 131.69, 128.01,
are measured in hertz. High resolution mass spectral measure-
ments were performed with a Bruker micrOTOF-Q instrument in
the ESI mode. Optical rotation was determined with a Perkin–Elmer
Model 241 polarimeter. IR spectra were recorded on Perkin–Elmer
283 B spectrometer.
The MW-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.
114.82, 108.12 (5C), 93.11 (C5), 70.72 (C6), 58.84 (C9), 56.34 (OCH3),
53.11 (C16), 43.11, 41.55, 38.77 (C13, C14, NCH3), 35.74 (C15), 29.18
(C10).
4.2.2. 1-Aminocodeine (5)
Compound 5 was prepared according to general method A. All
the physical properties are in line with reported data.10 Yield:
620 mg (68%); HRMS (ESI) m/z (%) found: 315.1712 (MþþH, 100),
calculated for C18H23N2O3þ: 315.1703 (MþþH); nmax (KBr disc) 3450,
For test reactions regarding mechanistic studies we used
3350 (NH2), broad band 3200 (OH) cmꢂ1 1H NMR (360 MHz,
;
(ꢁ)a-tocopherol, Ph. Eur. grade.
CDCl3)
d
¼6.23 (s, 1H, H2), 5.71, 5.54 (2d, 2H, H7–H8, J7–8 5.7), 5.10
(br s, 2H, NH2), 4.40 (d, 1H, H5a, J5a–6a 7.6), 4.14–4.07 (m, 1H, H6a),
3.73 (s, 3H, OCH3), 3.34–2.48 (m, 4H, H9b, H10a, H10b, H14b), 2.39–
2.01 (m, 7H, NCH3, H15a, H15b, H16a, H16b); 13C NMR (360 MHz,
4.2. Synthesis route starting from 1-nitrocodeine (1)
Method A for reduction of nitro-compounds. The nitro-derivative
(3.2 mmol) was suspended in a mixture of EtOH (15 mL) and water
CDCl3)
d
¼147.24 (C3), 138.19 (C1), 134.58, 131.29, 128.63, 127.77,
111.93, 109.66 (6C), 92.87 (C5), 70.34 (C6), 58.08 (C9), 56.31 (OCH3),
53.28 (C16), 43.19, 40.93, 39.48 (C13, C14, NCH3), 35.63 (C15), 27.11
(C10).
Table 1
Important parameters of involved species
Species
Distance (Å)
N30/C2 S/C2 C2–H C1–N–C–N C1–N–C–S
Dihedral angle (ꢀ)
Rel energy
(kcal molꢂ1
4.2.3. 20-Aminothiazole-(4,5:2,1)-codeine (11)
)
Compound 11 was prepared according to general method B.
t1
3.143
5.414
2.359
1.705
1.123
1.475
d
27.61
58.55
ꢂ177.96
156.28
84.31
6.06
0
34
ꢂ4
Yield: 62 mg (54%). Colourless crystals; Rf (chloroform/meth-
25
s-Complex 4.324
anol¼1/1) 0.33; mp: 164–166 ꢀC; [
a
]
D
ꢂ83 (c 0.10, methanol);
11t
3.812
HRMS (ESI) m/z (%) found: 372.1388 (MþþH, 100), calculated for

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L. Giran et al. / Tetrahedron 64 (2008) 10388–10394
10393
C19H22N3O3Sþ: 372.1376 (MþþH); nmax (KBr disc) 3450, 3350 (NH2),
(7C), 93.31 (C5), 70.56 (C6), 59.81 (C9), 53.39 (C16), 43.56, 40.99,
39.79 (C13, C14, NCH3), 35.19 (C15), 32.18 (C10).
broad band 3200 (OH) cmꢂ1
;
1H NMR (360 MHz, CDCl3)
d
¼5.61,
5.55 (m, 2H, H7–H8), 5.11 (br s, 2H, NH2), 4.11–3.89 (m, 5H, H5a,
H6a, OCH3), 3.32–2.57 (m, 4H, H9b, H10a, H10b, H14b), 2.41–1.69 (m,
7H, NCH3, H15a, H15b, H16a, H16b); 13C NMR (90 MHz, CDCl3)
4.3.2. 2-Aminomorphine (6)
Compound 6 was prepared according to general method A.
d
¼168.25 (C20), 139.25, 136.29, 131.47, 126.38, 126.11, 119.72, 113.48,
Yield: 510 mg (55%). All the physical and spectral data were in line
25
105.62 (8C), 94.41 (C5), 74.23 (C6), 60.11 (C9), 56.17 (OCH3), 49.49
(C16), 43.28, 41.64, 39.94 (C13, C14, NCH3), 38.87 (C15), 27.21 (C10).
with previously published data.14 Mp: >250 ꢀC; [
a]
ꢂ187 (c 0.10,
D
methanol); HRMS (ESI) m/z (%) found: 301.1561 (MþþH, 100), cal-
culated for C17H21N2O3þ: 301.1547 (MþþH); nmax (KBr disc) 3350
4.2.4. 9-Amino-12-hydroxy-6-methyl-11-methoxythiazolo[4,5-
k]5,6,6a,7-tetrahydro-4H-dibenzo[de,g]quinoline (3)
Compound 3 was prepared according to general method B in
a yield of 72 mg (60%) and was prepared according to general
(NH2), broad band 3200 (OH) cmꢂ1 1H NMR (360 MHz, CDCl3)
;
d
¼7.11 (s,1H, H1), 6.04 (br s,1H, 3-OH), 5.74, 5.69 (2d, 2H, H7, H8, J7–
6.2), 5.56 (br s, 2H, NH2), 4.11–4.03 (m, 2H, H5a, H6a), 3.45–2.65
8
(m, 4H, H9b, H10a, H10b, H14b), 2.38–2.09 (m, 6H, NCH3, H15b, H16a,
method C in a yield of 465 mg (49%). Colourless crystals; Rf (chlo-
H16b), 2.01 (dt, 1H, H15a, J15a–15b;16a–16b 10.0, J15a–15b 5.4); 13C NMR
25
roform/methanol¼4/1) 0.38; mp: 163–165 ꢀC; [
a]
ꢂ209 (c 0.10,
(360 MHz, CDCl3)
126.27, 120.86, 114.67 (7C), 94.69 (C5), 71.16 (C6), 60.38 (C9), 52.88
(C16), 44.01, 42.38, 40.23 (C13, C14, NCH3), 35.39 (C15), 31.80 (C10).
d
¼145.11 (C4), 136.11, 131.85, 131.09, 128.60,
D
methanol); HRMS (ESI) m/z (%) found: 354.1271 (MþþH, 100), cal-
culated for C19H20N3O2Sþ: 354.1249 (MþþH); nmax (KBr disc) 3450,
3350 (NH2), broad band 3200 (OH) cmꢂ1 1H NMR (360 MHz,
;
CDCl3)
3.83 (m, 4H, H6a, 10-OCH3), 3.21–2.42 (m, 9H, H4a, H4b, H5a, H5b,
H7a, H7b, NCH3); 13C NMR (90 MHz, CDCl3)
d¼7.21–6.92 (m, 3H, H1, H2, H3), 5.48 (br s, 2H, NH2), 4.11–
4.3.3. 20-Aminohtiazole-(4,5:1,2)-morphine hydrochloride (12$HCl)
Compound 12$HCl was prepared according to general method B.
Yield: 64 mg (51%). Colourless crystals; Rf (chloroform/meth-
d¼169.71 (C9), 143.21,
25
138.45, 135.48, 133.39, 128.68, 124.54, 119.90, 117.72, 112.82, 110.02,
109.56, 108.75 (12C), 64.48 (C6), 56.12 (OCH3), 49.82 (C5), 41.12
(NCH3), 33.31 (C7), 25.74 (C4).
anol¼4/1) 0.41; mp: >250 ꢀC; [
a
]
ꢂ35 (c 0.10, methanol); HRMS
D
(ESI) m/z (%) found: 358.1243 (MþþH, 100), calculated for
C
19H20N3O2Sþ: 358.1220 (MþþH); nmax (KBr disc) 3450, 3350 (NH2),
broad band 3200 (OH) cmꢂ1; 1H NMR (360 MHz, DMSO-d6)
d
¼6.64
4.2.5. 8-Nitroapocodeine (7)
(br s, 1H, 3-OH), 6.11–5.92 (m, 2H, H7, H8), 5.33 (s, 2H, NH2), 4.27–
4.01 (m, 2H, H5a, H6a), 3.27–2.52 (m, 4H, H9b, H10a, H10b, H14b),
2.39–1.68 (m, 7H, NCH3, H15a, H15b, H16a, H16b); 13C NMR (90 MHz,
Compound 7 was prepared according to general method C.
25
Yield: 831 mg (87%). Orange crystals; mp: 128–130 ꢀC; [
a
]
D
ꢂ704
(c 0.10, chloroform); HRMS (ESI) m/z (%) found: 327.1344 (MþþH,
13), calculated for C19H20N3O2Sþ: 327.1339 (MþþH); nmax (KBr disc)
broad band 3200 (OH),1540 (NO2) cmꢂ1; 1H NMR (360 MHz, CDCl3)
DMSO-d6)
d
¼168.44 (C20), 142.21, 135.70, 129.44, 126.71, 122.10,
115.34, 114.97, 113.12 (8C), 93.37 (C5), 67.72 (C6), 59.21 (C9), 51.11
(C16), 43.11, 41.65, 38.77 (C13, C14, NCH3), 32.77 (C15), 29.18 (C10).
d
¼7.52 (s, 1H, H9), 7.11–6.84 (m, 3H, H1, H2, H3), 6.13 (s, 1H, 11-OH),
4.01–3.89 (m, 4H, H6a, 10-OCH3), 3.18–2.44 (m, 9H, H4a, H4b, H5a,
H5b, H7a, H7b, NCH3); 13C NMR (90 MHz, CDCl3)
146.78 (C11), 141.23 (C8), 137.45, 134.71, 132.29, 130.88, 127.76,
123.40, 113.71, 111.65, 109.35 (9C), 60.48 (C6), 56.34 (OCH3), 52.82
(C5), 41.12 (NCH3), 33.24 (C7), 25.22 (C4).
4.3.4. 9-Amino-11,12-dihydroxy-6-methylthiazolo[5,4-k]5,6,6a,7-
tetrahydro-4H-dibenzo[de,g]quinoline hydrochloride (4$HCl)
Compound 4$HCl was prepared according to general method B
in a yield of 88 mg (72%) and was prepared according to general
d¼151.48 (C10),
method C in a yield of 96 mg (68%). Colourless crystals; Rf (chlo-
25
roform/methanol¼1/3) 0.22; mp: >250 ꢀC; [
a
]
D
ꢂ68 (c 0.10,
4.2.6. 8-Aminoapocodeine hydrochloride (9$HCl)
methanol); HRMS (ESI) m/z (%) found: 340.1128 (MþþH, 100), cal-
culated for C18H18N3O2Sþ: 340.1114 (MþþH); nmax (KBr disc) 3450,
Compound 9$HCl was prepared according to general method A
in a yield of 510 mg (56%) and was prepared according to general
3350 (NH2), broad band 3200 (OH) cmꢂ1 1H NMR (360 MHz,
;
method C in a yield of 360 mg (34%). Grey crystals; mp: 178–180 ꢀC;
DMSO-d6)
d
¼7.42–7.02 (m, 3H, H1, H2, H3), 6.58–6.39 (br s, 2H, 2-
25
[
a]
ꢂ421 (c 0.10, methanol); HRMS (ESI) m/z (%) found: 297.1584
OH), 5.22 (s, 2H, NH2), 4.14 (dd, 1H, H6a, J6a–7a 9.2, J6a–7b 3.1), 3.21–
D
(MþþH, 100), calculated for C18H21N2Oþ2 : 297.1598 (MþþH); nmax
2.48 (m, 9H, H4a, H4b,H5a, H5b, H7a, H7b, NCH3); 13C NMR (90 MHz,
(KBr disc) 3450, 3350 (NH2), broad band 3200 (OH) cmꢂ1; 1H NMR
DMSO-d6)
d
¼171.17 (C20), 142.61, 139.70, 136.33, 131.27, 128.18,
(360 MHz, CDCl3 from free base)
d
¼6.99–6.74 (m, 4H, H1, H2, H3,
126.61,122.10,119.76,115.44,113.69,111.07,110.88 (12C), 60.88 (C6),
53.17 (C5), 40.88 (NCH3), 30.44 (C7), 28.12 (C4).
H9), 6.31 (s, 1H, 11-OH), 5.24 (br s, 2H, NH2), 4.08–3.92 (m, 4H, H6a,
10-OCH3), 3.37–2.57 (m, 9H, H4a, H4b, H5a, H5b, H7a, H7b, NCH3);
13C NMR (90 MHz, CDCl3 from free base)
d
¼149.72 (C11), 137.87,
4.3.5. 9-Nitroapomorphine hydrochloride (8$HCl)
135.61, 134.67, 131.01, 127.08, 126.83, 123.29, 123.11, 118.70, 115.44,
113.35 (11C), 60.34 (C6), 56.32 (OCH3), 54.11 (C5), 41.17 (NCH3),
33.78 (C7), 27.24 (C4).
Compound 8$HCl was prepared according to general method C.
25
Yield: 520 mg (49%). Yellow crystals; mp: >250 ꢀC; [
a]
ꢂ221 (c
D
0.10, methanol); HRMS (ESI) m/z (%) found: 313.1189 (MþþH, 56),
calculated for C17H17N3O4þ: 313.1183 (MþþH); nmax (KBr disc) broad
4.3. Synthesis route starting from 2-nitromorphine (2)
band 3200 (OH), 1540 (NO2) cmꢂ1 1H NMR (360 MHz, DMSO-d6)
;
d
¼7.40 (s, 1H, H8), 7.21–7.01 (m, 3H, H1, H2, H3), 6.42 (br s, 2H, 10-
4.3.1. 2-Nitromorphine (2)
OH, 11-OH), 4.14, 4.08 (2d, 1H, H6a, J6a–7a 11.0, J6a–7b 3.2), 3.18–2.27
Compound 2 was prepared according to the previously de-
scribed method.11 All the physical properties are in line with
reported data.11 HRMS (ESI) m/z (%) found: 331.1303 (MþþH, 26),
calculated for C18H21N2O5þ: 331.1288 (MþþH); nmax (KBr disc) broad
(m, 9H, H4a, H4b, H5a, H5b, H7a, H7b, NCH3); 13C NMR (90 MHz,
DMSO-d6)
d
¼145.75 (C11), 136.35, 132.22, 130.08, 127.73, 125.21,
119.40, 117.69, 116.18, 115.33, 115.01, 113.78 (11C), 60.34 (C6), 52.33
(C5), 43.13 (NCH3), 33.72 (C7), 26.45 (C4).
band 3200 (OH), 1510 (NO2) cmꢂ1 1H NMR (360 MHz, CDCl3)
;
d
¼7.33 (s, 1H, H1), 6.14 (br s, 1H, 3-OH), 5.68, 5.65 (2d, 2H, H7, H8,
4.3.6. 9-Aminoapomorphine hydrochloride (10$HCl)
J7–8 5.8), 4.28–4.16 (m, 2H, H5a, H6a), 3.27–2.61 (m, 4H, H9b, H10a,
H10b, H14b), 2.44–2.19 (m, 6H, NCH3, H15b, H16a, H16b), 1.99 (dt,1H,
H15a, J15a–15b;16a–16b 10.1, J15a–15b 4.9); 13C NMR (360 MHz, CDCl3)
Compound 10$HCl was prepared according to general method A
in a yield of 575 mg (59%) and was prepared according to general
method C in a yield of 480 mg (49%). All the physical properties are
in line with previously reported data.10e HRMS (ESI) m/z (%) found:
d¼145.63 (C4), 137.78, 134.80, 130.09, 126.47, 123.78, 119.81, 118.12

´
L. Giran et al. / Tetrahedron 64 (2008) 10388–10394
10394
283.1457 (MþþH, 100), calculated for C17H19N2Oþ2 : 283.1441
(MþþH); nmax (KBr disc) 3450, 3350 (NH2), broad band 3200 (OH)
Lajiness, M. E.; Huff, R. M. Eur. J. Pharmacol. 1995, 290, 29; Schneider, C. S.;
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H. J. Med. Chem. 2000, 43, 3549.
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Mierau, J. J. Med. Chem. 1987, 30, 494; van Vliet, A. L.; Rodenhuis, N.; Wikstro
cmꢂ1
;
1H NMR (360 MHz, DMSO-d6)
d
¼7.03–6.88 (m, 4H, H1, H2,
H3, H9), 6.31 (br s, 2H, 2ꢃ –OH), 5.22 (br s, 2H, NH2), 4.08 (dd, 1H,
H6a, J6a–7a 9.1, J6a–7b 3.1), 3.37–2.59 (m, 9H, H4a, H4b, H5a, H5b, H7a,
´
6. (a) Sobarzo-Sanchez, E. M.; Arbaoui, J.; Protais, P.; Cassels, B. K. J. Nat. Prod.
H7b, NCH3); 13C NMR (90 MHz, DMSO-d6)
131.56, 130.45, 127.48, 123.30, 121.67, 120.93, 117.63, 116.49, 115.91,
115.78 (11C), 63.28 (C6), 52.92 (C5), 43.43(NCH3),33.28(C7),25.79(C4).
d
¼145.53 (C11), 134.39,
2000, 63, 480; (b) Asencio, M.; Hurtado-Guzma´n, C.; Lo´pez, J. J.; Cassels, B. K.;
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4.4. Computational procedure
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1911, 382, 306; (c) Ochiai, E.; Nakamura, T. Proced. Imp. Acad. 1938, 14, 13; (d)
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We have carried out the geometry optimization at Becke’s three-
parameter hybrid (B3LYP)20 levels in the DFT with the basis set
6-31G
using Gaussian 98.12 The solvent effect was not considered.
*
´
´
11. Ochiai, E.; Nakamura, T. Chem. Ber. 1939, 72, 684; Bognar, R.; Gaal, D. Gy. Magy.
Ke´m. Foly. 1963, 69, 17; Chem. Abstr. 1963, 59, 1969b.
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Burant, J. C.; Dapprich, S.; Millam, J. M.; Daniels, A. D.; Kudin, K. N.; Strain, M. C.;
Farkas, O.; Tomasi, J.; Barone, V.; Cossi, M.; Cammi, R.; Mennucci, B.; Pomelli, C.;
Adamo, C.; Clifford, S.; Ochterski, J.; Petersson, G. A.; Ayala, P. Y.; Cui, Q.; Mo-
rokuma, K.; Malick, D. K.; Rabuck, A. D.; Raghavachari, K.; Foresman, J. B.;
Cioslowski, J.; Ortiz, J. V.; Stefanov, B. B.; Liu, G.; Liashenko, A.; Piskorz, P.;
Komaromi, I.; Gomperts, R.; Martin, R. L.; Fox, D. J.; Keith, T.; Al-Laham, M. A.;
Peng, C. Y.; Nanayakkara, A.; Gonzalez, C.; Challacombe, M.; Gill, P. M. W.;
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M.; Replogle, E. S.; Pople, J. A. Gaussian 98, Revision A.3; Gaussian: Pittsburgh,
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Acknowledgements
The authors are grateful to the National Science Foundation
(Grant OTKA reg. nos. T049436 and NI61336) for the financial
support. We thank Peter Pazmany Programme (NKTH, RET006/
2004) to allow us the use of microwave reactor and Szabolcs Fekete
for the valuable technical help.
´
´
´
References and notes
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*
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