Efficient catalyst-free tricomponent synthesis of new spiro[cyclohexane-1,4′-pyrazolo[3,4-e][1, 4]thiazepin]-7′(6′H)-ones

Article abstract of DOI:10.1080/00397911.2018.1554143

A series of spirocyclohexane-1,4′-pyrazolothiazepinones were synthesized by one-pot multicomponent cyclocondensation reactions between 5-amino-1-arylpyrazoles, cyclohexanone and mercaptoacetic acid with good yields and easy purification protocols. Some control experiments involving isolation of reaction intermediates were performed leading to the proposal of three alternative mechanistic pathways conducting to the named spiroheterocycles. All target molecules were fully characterized by IR, NMR, melting point and HRMS.

Full text of DOI:10.1080/00397911.2018.1554143

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: http://www.tandfonline.com/loi/lsyc20
Efficient catalyst-free tricomponent synthesis
of new spiro[cyclohexane-1,4′-pyrazolo[3,4-e][1,
4]thiazepin]-7′(6′H)-ones
Christian Becerra-Rivas, Paola Cuervo-Prado & Fabian Orozco-Lopez
To cite this article: Christian Becerra-Rivas, Paola Cuervo-Prado & Fabian Orozco-Lopez (2019):
Efficient catalyst-free tricomponent synthesis of new spiro[cyclohexane-1,4′-pyrazolo[3,4-e][1,
4]thiazepin]-7′(6′H)-ones, Synthetic Communications, DOI: 10.1080/00397911.2018.1554143
To link to this article: https://doi.org/10.1080/00397911.2018.1554143
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https://doi.org/10.1080/00397911.2018.1554143
Efficient catalyst-free tricomponent synthesis of new
0
spiro[cyclohexane-1,4 -pyrazolo[3,4-e][1, 4]thiazepin]-
0
0
7
(6 H)-ones
Christian Becerra-Rivas, Paola Cuervo-Prado, and Fabian Orozco-Lopez
Group of Studies in Synthesis and Applications of Heterocyclic Compounds, Universidad Nacional
de Colombia, Bogot ꢀa , Colombia
ABSTRACT
ARTICLE HISTORY
Received 24 September 2018
Accepted 22 November 2018
0
A series of spirocyclohexane-1,4 -pyrazolothiazepinones were synthe-
sized by one-pot multicomponent cyclocondensation reactions
between 5-amino-1-arylpyrazoles, cyclohexanone and mercaptoacetic
acid with good yields and easy purification protocols. Some control
experiments involving isolation of reaction intermediates were per-
formed leading to the proposal of three alternative mechanistic
pathways conducting to the named spiroheterocycles. All target mol-
ecules were fully characterized by IR, NMR, melting point and HRMS.
KEYWORDS
Spiroheterocycles; 1,4-
thiazepin-3-ones; aminopyr-
azoles; tricomponent
reaction; catalyst-free
GRAPHICAL ABSTRACT
Introduction
It is well known that seven-membered heterocycles are valuable scaffolds in search for
new drug-like molecules; examples of this are the azepines, oxazepines, and benzodiaze-
pines as modulators of central nervous system (CNS) diseases like psychosis, depression
[
1]
[2–8]
and epilepsy. In addition to CNS activities,
some sulfur and nitrogen derivatives
[
9,10]
[11,12]
have diverse biological desirable effects as antidiabetes;
antiproliferatives
and
CONTACT Fabian Orozco-Lopez
forozcol@unal.edu.co
Group of Studies in Synthesis and Applications of
Heterocyclic Compounds, Universidad Nacional de Colombia, Ciudad Universitaria, Bogot ꢀa A.A.14490, Colombia.
Supplemental data for this article can be accessed publisher’s website.
ß 2019 Taylor & Francis Group, LLC

2
C. BECERRA-RIVAS ET AL.
R
R
H N
2
1
, 3
R
1
. HCl conc
+
a
H
H N
2
b
c
d
e
Cl
2
. NH OH
N
4
HN
N
OMe
F
N
NH2
NO2
1
a-e
2
3a-e, 72-83%
Scheme 1. Synthesis of aminopyrazole precursors.
R
R
O
O
O
H
H N
2
HS
N
N
N
OH
N +
N
Various solvents
S
3a-e
4a-e
Scheme 2. Synthesis of spirocyclohexane-1, 4ꢀ -pyrazolothiazepinones 4a–e.
[
13]
antimicrobials.
Besides, pyrazole-fused thiazepines have been tested recently with
[
14]
[15]
promising results as cytotoxic
and antiparasitic agents.
Multicomponent reactions (MCRs) are efficient and versatile tools to obtain diverse
bioactive compounds in few steps and purifications in comparison to multistep strat-
[
16]
egies.
This approach makes possible to build relatively easy and quick, libraries of
[
17]
complex organic compounds,
although with the difficulty of establishing mechanistic
pathways leading to the target molecule.
Considering that construction of seven-member rings is not the most favored route
[
18]
by Baldwin’s rules,
it is a true synthetic challenge to obtain this type of heterocycles
in relatively simple conditions and without the addition of catalysts. In this work, we
present an easy, accessible and simple-purification protocol to synthesize some novel
0
spirofused cyclohexane-1,4 -pyrazolothiazepinones. Additionally, three possible mecha-
nisms were studied through control experiments involving the isolation of key reaction
intermediates conducting to above-mentioned spirothiazaheterocycles.
Discussion
The synthesis of spirothiazepinones started by the preparation of 1-aryl-3-methyl-5-ami-
nopyrazole derivatives 3a–e with different substitution pattern in 4-position of aryl moi-
ety, by classic cyclocondensation reaction of arylhydrazines 1a–e with 3-
[
19–21]
aminocrotononitrile 2 in acid media (Scheme 1).
Compound 3a was used as scoping substrate in reaction with cyclohexanone and
mercaptoacetic acid (MAA) in equimolar quantities in various solvents to obtain spiro-
0
cyclohexane-1,4 -pyrazolothiazepinones (Scheme 2), where benzene gave rise to the best
results thus allowing to optimize the reaction (Table 1).

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3
Table 1. Scoping conditions for synthesis of compound 4a.
ꢀ
b
Entry
Solvent
Temperature ( C)
Time (h).
Yield of 4a (%)
c
1
2
3
4
5
6
7
8
9
a
MeCN
MeCN /4.0 A MS
THF
Toluene
Toluene
DMF
DMF
Benzene
Solvent-free
Reflux
Reflux
Refluxa
Reflux
48
20
>90
72
72
2
10
72
0.033
NR
5
NR
c
6
NR
Deg
NR
a
c
70
d
100
70 a
c
Reflux
Fussion
15
Deg
d
Dean-Stark apparatus was used.
b
c
Reaction conditions: 0.5 mmol of 3a, equimolar quantities of cyclohexanone and MAA, 5 mL of each solvent.
No reaction observed.
d
Compound 3a was degraded.
Table 2. Stoichiometric scoping of reaction.
Molar relation
cyclohexanone
ꢁ
ꢁ
a
Entry
Molar relation MAA
Time (h).
Yield of 4a (%)
1
2
3
4
5
6
1
1
2
2
2
3
1
2
2
3
4
3
72
60
60
24
60
36
15
18
24
74
50
25
ꢁ
Related to 3a.
a
Reaction conditions: 0.5 mmol of 3a, 5 mL of benzene, water removed by using Dean-Stark apparatus.
In solvent scoping, polar solvents such as DMF and MeCN, did not yield target mol-
ecule or exhibited lower yields in comparison to benzene or toluene with Dean-Stark
apparatus to azeotropically remove water formed during the reaction; and it is also
important to note that the product was not soluble in benzene, which is why turned
out as the best option in terms of isolation and purification of 4a.
The low yield obtained with these above-mentioned attempts of reaction, suggested
us a dependence of product formation with respect to the amount of MAA, making us
consider if such reagent was also acting as an internal catalyst. According to this, an
optimization of stoichiometric relation of cyclohexanone and MAA was necessary to
improve yield of 4a (Table 2).
In the stoichiometric study is clear that reaction proceeds optimally with two equiva-
lents of cyclohexanone and three of MAA, reducing time and getting remarkable
improvement in the yield of product 4a, thus confirming that this reactant exerts action
as an internal catalyst in the reaction. In addition, a higher amount of this reagent
interfered with nucleophilicity of aminopyrazole, decreasing this way the overall yield of
final product.
With this optimal conditions, compounds 3b–d were then converted successfully to
products 4b–d with good yields (Table 3); however, 3e did not afford expected product,
giving rise to cyclohexenylpyrazole derivative 5e instead (Scheme 3).
Complementary reaction studies and mechanistic proposals
Obtaining compound 5e instead of expected spirothiazepinone gave us an idea of the
reaction mechanism followed by substrates during transformation into final products

4
C. BECERRA-RIVAS ET AL.
Table 3. Yields of compounds 4a–d and 5e.
b
b
Entry
–R
Time (h)
Yield of 4 (%)
Yield of 5 (%)
a
b
c
d
e
–H
–Cl
–OMe
–F
–NO
24
25
20
24
36
74
70
76
66
–
–
–
–
67
a
2
–
a
Not observed.
Yields of isolated compounds.
b
R
3a-d
O
H
R
N
N
4a-d
N
S
O
O
H N
2
HS
N
O N
2
OH
N +
PhH, �,
Dean-Stark
N
N
3a-e
5e
3e
H N
2
Scheme 3. Optimized reaction for synthesis of 4a–d and 5e.
4a–d, assuming that such compound could be considered an intermediate by itself or
just a dehydrated by-product of the true intermediate in a key mechanistic pathway
(Scheme 4).
Looking to define the route followed during the formation of the final products, the
synthesis of intermediates 5a and 6a were attempted under the general conditions used
in the tricomponent reaction, giving rise only to the compound 5a (Scheme 5).
These results gave us an idea of the high tendency of 6a to undergo dehydration
under the studied conditions; besides, compound 5a was tried to react with MAA with-
out success (Scheme 5), thus implying that this by-product does not take part in the
formation of 4a, discarding pathway B described in scheme 4.
The pathway A then seems to involve intermediate 6a which successfully provides the
electrophilic center for the nucleophilic attack of the MAA, to end up with the expected
cyclocondensation to the spirothiazepinone ring 4a (Scheme 6).
The instability of 6a (tendency to dehydrate) and the fact that 5a did not react with
MAA, questioned both pathways (A y B) in the general reaction mechanism, although
previous reports described the participation of such type of intermediates in cyclocon-
[
22]
densation reactions.
For this reason, other possible intermediates were proposed con-
sidering the tricomponent approach used in the main reaction (Scheme 7); which
makes possible that cyclohexanone and MAA could react first, giving rise to a spirooxa-
thiolanone derivative 7, which should be reactively enough to interact with aminopyra-
zole to produce the expected spiroheterocycle 4a (Pathway C, Scheme 7).

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5
NO2
N N
NH2
OH
Pathway A
HSCH CO H
NO2
6
e
NO2
2
2
O
N N
NH
+
-
H O
2
O
N
NH2
N
NO2
S
4e
HSCH CO H
2
2
3
e
Pathway B
N N
NH2
5e
Scheme 4. Possible routes to the final product involving the generation of compound 5e.
N N
R
NH2 Not observed
OH
N N
6a
NH
O
O
+
-
H O
2
S
N
NH2
4a
N
HSCH CO H
2
2
N N
3
a
NH2
5a
Scheme 5. Control experiment performed to study the potential participation of 5a and 6a in the
general reaction.
Aiming to prove the reactivity and participation of intermediate 7 in the aforemen-
tioned mechanistic route of the main tricomponent reaction; such intermediate was syn-
[
23]
thesized by a methodology previously reported,
isolated and then allowed to react
under the main reaction conditions with aminopyrazole 3a, yielding the expected seven-
member spiroheterocycle 4a, as single product (Scheme 8).
Given that 7 conducted successfully to product 4a, it is reasonable to establish a reac-
tion mechanism that involves this intermediate as shown in Scheme 7, but during our
study of the tricomponent reaction we realized that there is another alternative route

6
C. BECERRA-RIVAS ET AL.
H N
2
3a
N
H N
H N
H N
N
2
N
2
2
O
H
O
N
N
HO
N
HO
N
H O
2
N
H+
- H+
H+
6a
OH
-
H O
2
O
HS
O
NH
N
OH
O
H N
H
N
H N
HO
2
2
N
N
HO
N
N
H+
-
S
N
N
S
N
S
-
H O
2
4a
Scheme 6. Plausible mechanism of formation of 4a via intermediate 6a.
O
OH
S
O
O
NH2
O
S
OH
HS
CO H
2
N
-
H O
2
N
3a
7
H N
H
N
N
2
H N
N
2
N
HO
N
O
N
N
O
H
S
S
-
H O
2
O
O
S
4a
Scheme 7. Alternative pathway C proposed to explain the formation 4a.
O
N N
O
O
S
H N
NH
2
N
N
S
O
3
a
PhH,
Δ
+
O
PhH,
Δ
Dean - Stark
Ref [23].
Dean - Stark
HO
SH
4a
7
, 95%
Scheme 8. Control experiment to determine the plausibility of proposed pathway C.
consisting in the reaction of aminopyrazole with MAA by an acyl nucleophilic substitution,
to produce a 2-sulfanyl acetamide intermediate 8, which also seems to participate in the
main reaction in the presence of cyclohexanone to yield also 4a (Pathway D, Scheme 9).

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7
O
H
N
N
N
N
N
N
N
N
-
H
2
O
N+
H
N+
HN
HN
C-
H
H
OH
SH
O
8
O
H
O
O
SH -O
SH
HS
+
H O
3
HS
O
OH
N
O
N
S
N
N
N
NH2
a
N
HN
3
+
N
H
1
1)
3
- H O
HS
O
H O
2
4a
Scheme 9. Alternative pathway D proposed to get 4a in tricomponent reaction.
O
N
N
N
N
N
PhH,
Δ
N
HS
OH
H N
2
HN
O
Cyclohexanone
Dean-Stark
PhH / Dean-Stark
HN
3a
Δ
S
O
SH
8
4a
Not isolated
Scheme 10. Control experiment to determine the plausibility of proposed pathway D.
Once again, a control experiment was performed to determine the plausibility of pro-
posed mechanism; this time, a third component approximation was used. Putting in
reaction two of the three reactants until complete transformation, and then adding the
missing one. In this case, 3a and MAA were reacted until consumption of aminopyra-
zole, and then cyclohexanone was added dropwise to the mixture and the reaction was
continued until this last component was completely consumed. This experiment yielded
spirothiazepinone 4a as expected (Scheme 10).
These control experiments lead us to propose three different mechanistic pathways
(A, C and D) conducting to 4a under the general conditions used in the tricompo-
nent approach.
Spectroscopic discussion of synthesized
spirocyclohexanepyrazolo[1,4]thiazepin-7-ones (4a–d)
1
Compounds 4a–d exhibited diagnostic signals in H-NMR spectra, such as a singlet cor-
responding to a-carbonyl CH in d = 3.18–3.23 ppm and aliphatic signals (four multip-
2
lets) assigned to CH of cyclohexane in 1.24–2.21 ppm. Additionally, pyrazolic CH
2
3
protons appeared as a singlet at 2.47–2.51 ppm while in the low field region of spectra
around 7.24 ppm a broad singlet was assigned as the lactam N–H proton (also con-
13
firmed through chemical exchange experiments with D O). Regarding C-NMR and
2
DEPT-135 spectra, signal count corresponded to the number of carbon atoms expected
for title compounds. CH appeared as one signal in the range d = 16.80–16.95 ppm
3

8
C. BECERRA-RIVAS ET AL.
while CH in cyclohexane fragment were observed as three negative phase signals in
2
DEPT-135 spectra around 22.07, 25.38, and 30.94 ppm. Spiranic quaternary carbon
atom appeared at d = 49.43–49.56 ppm, and a-carbonyl CH was observed around 36.9
2
ppm. Aromatic region of spectra displayed signals according to the substitution patterns
of aromatic rings in each molecule.
Finally, the purity of all the obtained compounds was confirmed by means of HRMS-
ESI (except in the case of intermediates 5a and 5e which were confirmed by CHNS
þ
elemental analysis), where the corresponding [M þ 1] peak was observed and com-
pared to the calculated value in all cases.
Conclusion
In summary, an easy purification protocol without external catalyst was developed for
0
the synthesis of spirofused cyclohexane-1,4 -pyrazolothiazepinones with good yields.
Mechanism of this tricomponent reaction was studied by control experiments leading to
three possible routes, two of which involve non-obvious intermediates such as spirooxa-
thiolanone and sulfanyl acetamide. This observation allowed us to open the discussion
to unexpected borders on the mechanism of a seemingly simple reaction.
Is important to state that due to the presence of interesting pharmacophoric cores in
all the spiroheterocycles obtained, they could be considered as promising molecular
hybrids in terms of potential bioactivity, and all of them will be evaluated against differ-
ent targets as part of further studies.
Experimental
0
Typical procedure for the synthesis of spiro[cyclohexane-1,4 -pyrazolo
0
[
3,4-e][1,4]thiazepin]-7(6 H)-ones (4a–d)
3.0 mmol of the corresponding aminopyrazoles (3a–d) were mixed with 6.0 mmol of
cyclohexanone and 9.0 mmol of mercaptoacetic acid in 20 mL of dry benzene. The
resulting mixture was heated to reflux with Dean–Stark trap for 12 h until reaction was
ꢀ
completed. The crude was cooled to room temperature and then was left at 4 C over-
night. The resulting solid was filtered and washed with cold benzene and water yielding
the spirothiazepin-7-ones 4a–d.
3
’-Methyl-1’-phenyl-1’,8’-dihydrospiro[cyclohexane-1,4’-pyrazolo
3,4-e][1,4]thiazepin]-7’(6’H)-one (4a)
[
ꢀ
ꢂ1
White solid (74%, 726 mg); mp: 257-258 C; IR (ꢀ
cm ): 3075, 2927, 2854, 1679,
max
1
7
67. H-NMR (400 MHz, CDCl ): d 1.29 (qt, J = 12.8, 3.7 Hz, 1H), 1.65 (dd, J = 13.7,
3
3
.2 Hz, 2H), 1.81 (m, 3H), 2.15 (m, 4H), 2.51 (s, 3H), 3.23 (s, 2H), 7.25 (s, 1H), 7.41
1
3
(m, 3H), 7.50 (m, 2H). C-NMR (100 MHz, CDCl ): d 16.9, 22.1, 25.4, 31.0, 37.1, 49.5,
3
þ
1
15.4, 125.4, 128.7, 129.8, 133.4, 137.2, 146.3, 171.3. HRMS (ESI) m/z: [M þ H] Calc.
for C H N OS: 328.1478; found: 328.1515.
1
8
21 3

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9
Funding
Authors wish to credit Universidad Nacional de Colombia for the financial support given for
this work.
References
0
[
[
[
1] Beale, J. M.; Block, J. H. Wilson and Gisvold s Textbook of Organic and Medicinal and
Pharmaceutical Chemistry, Lippincott Williams & Wilkins – Wolters Kluwer Health:
Philadelphia, 2011; pp 466–468.
2] Xiao, J.; Free, R. B.; Barnaeva, E.; Conroy, J. L.; Doyle, T.; Miller, B.; Bryant-Genevier, M.;
Taylor, M. K.; Hu, X.; Dulcey, A. J. Med. Chem. 2014, 57, 3450–3463. DOI: 10.1021/
jm500126s.
3] Kiec-Kononowicz, K.; Karolak-Wojciechowska, J.; Michalak, B.; Pekala, E.; Schumacher,
B.; Muller, C. E. Eur. J. Med. Chem. 2004, 39, 205–218. DOI: 10.1016/
j.ejmech.2003.11.009.
[4] Ambrogi, V.; Grandolini, G.; Perioli, L.; Giusti, L.; Lucacchini, A.; Martini, C. Eur. J. Med.
Chem. 1995, 30, 429–437. DOI: 10.1016/0223-5234(96)88253-5.
[
5] Campiani, G.; Butini, S.; Fattorusso, C.; Trotta, F.; Gemma, S.; Catalanotti, B.; Nacci, V.;
Fiorini, I.; Cagnotto, A.; Mereghetti, I. J. Med. Chem. 2005, 48, 1705–1708. DOI: 10.1021/
jm049629t.
[
6] Martinez-Sanz, F. J.; Lajarin-Cuesta, R.; Gonzalez-Lafuente, L.; Moreno-Ortega, A. J.;
Punz oꢀ n, E.; Cano-Abad, M. F.; De los Rios, C. Eur. J. Med. Chem. 2016, 109, 114–123.
DOI: 10.1016/j.ejmech.2015.12.043.
[
7] Warawa, E.; Migler, B. M.; Ohnmacht, C. J.; Needles, A. L.; Gatos, G. C.; McLaren, F. M.;
Nelson, C. L.; Kirkland, K. M. J. Med. Chem. 2001, 44, 372–389. DOI: 10.1021/jm000242+
8] Petterson, H.; B u€ low, A.; Ek, F.; Jensen, J.; Ottesen, L. K.; Fejzic, A.; Ma, J.-N.; Del
Tredici, A. L.; Currier, E. A.; Gardell, L. R.; et al. J. Med. Chem. 2009, 52, 1975–1982.
DOI: 10.1021/jm801534c.
[
[9] Wu, Y.; Aquino, C. J.; Cowan, D. J.; Anderson, D. L.; Ambroso, J. L.; Bishop, M. J.;
Boros, E. E.; Chen, L.; Cunningham, A.; Dobbins, R. L.; et al. J. Med. Chem. 2013, 56,
5094–5114. DOI: 10.1021/jm400459m.
[
10] Sauerberg, P.; Pettersson, I.; Jeppesen, L.; Bury, P. S.; Mogensen, J. P.; Wassermann, K.;
Brand, C. L.; Sturis, J.; W o€ ldike, H. F.; Fleckner, J.; Andersen, A.-S. T.; et al. J. Med.
Chem. 2002, 45, 789–804. DOI: 10.1021/jm010964g.
[
11] Binaschi, M.; Boldetti, A.; Gianni, M.; Maggi, C. A.; Gensini, M.; Bigioni, M.; Parlani, M.;
Giolitti, A.; Fratelli, M.; Valli, C.; et al. ACS Med. Chem. Lett. 2010, 1, 411–415. DOI:
1
0.1021/ml1001163.
12] Laconde, G.; Depreux, P.; Berthelot, P.; Pommery, N.; H ꢀe nichart, J. P. Eur. J. Med. Chem.
005, 40, 167–172. DOI: 10.1016/j.ejmech.2004.10.008.
13] Ambrogi, V.; Furlani, A.; Grandolini, G.; Papaioannou, A.; Perioli, L.; Scarcia, V.;
Tuttobello, L. Eur. J. Med. Chem 1993, 28, 659–667. DOI: 10.1016/0223-5234(93)90024-9.
14] Srikanth, A.; Sarveswari, S.; Vijayakumar, V.; Gridharan, P.; Karthikeyan, S. Med. Chem.
Res. 2015, 24, 553–562. DOI: 10.1007/s00044-014-1153-3.
15] Ferreira de Almeida, L.; Brandao, R.; Simoes-Silva, M. R.; Bernardino da Silva, P.; Jaen,
D.; Franca da Silva, C.; Silva da Gama, A. N.; Krishna, T. R. Correia, M. Eur. J. Med.
Chem. 2018, 149, 257–268. DOI: 10.1016/j.ejmech.2018.02.020.
[
[
[
[
2
[
16] Armstrong, R. W.; Combs, A. P.; Tempest, P. A.; Brown, D.; Keating, T. A. Acc. Chem.
Res. 1996, 29, 123–131. DOI: 10.1021/ar9502083.
[
[
17] Orru, R. V. A.; De Greef, M. Synthesis 2003, 1471–1499. DOI: 10.1055/s-2003-40507.
18] Clayden, J.; Greeves, N.; Warren, S. Organic Chemistry. Oxford Press: New York, 2001; pp
1140–1144.

1
0
C. BECERRA-RIVAS ET AL.
[
19] Nam, N. L.; Grandberg, I. I.; Sorokin, V. I. Chem. Heterocycl. Compd. 2000, 36, 281–283.
DOI: 10.1007/BF02256864.
[
20] Vicentini, C. B.; Manfrini, M.; Mazzanti, M.; Scatturin, A.; Romagnoli, C.; Mares, D. Arch.
Pharm. (Weinheim) 1999, 332, 337–342. PMID: 10575365. DOI: 10.1002/(SICI)1521-
4
184(199910)332:10<337::AID-ARDP337>3.0.CO;2-P
21] Grandberg, I. I.; Klyuchko, G. V. Zh. Obshch. Khim. 1962, 32, 1898. Chem. Abstr. 1963,
8, p4537f.
[
5
[
[
22] Chen, H.; Shi, D. Tetrahedron 2011, 67, 5686–5692. DOI: 10.1016/j.tet.2011.05.069.
23] El-Zohry, M. F.; Awad, I. M. A.; Abdel-Hafez, A. A. Arch. Pharm. Pharm. Med. Chem.
1
993, 326, 115–118. DOI: 10.1002/ardp.19933260209