Synthetic Communications

An International Journal for Rapid Communication of Synthetic Organic

Chemistry

ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: https://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, 49:3, 367-376, DOI:
10.1080/00397911.2018.1554143

To link to this article: https://doi.org/10.1080/00397911.2018.1554143

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Published online: 17 Jan 2019.

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SYNTHETIC COMMUNICATIONSV
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2019, VOL. 49, NO. 3, 367–376

https://doi.org/10.1080/00397911.2018.1554143

Efficient catalyst-free tricomponent synthesis of new

spiro[cyclohexane-1,40 -pyrazolo[3,4-e][1, 4]thiazepin]-
70 (60 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

A series of spirocyclohexane-1,40 -pyrazolothiazepinones were synthe- Received 24 September 2018
sized by one-pot multicomponent cyclocondensation reactions Accepted 22 November 2018
between 5-amino-1-arylpyrazoles, cyclohexanone and mercaptoacetic
KEYWORDS
acid with good yields and easy purification protocols. Some control
Spiroheterocycles; 1,4-
experiments involving isolation of reaction intermediates were per- thiazepin-3-ones; aminopyr-
formed leading to the proposal of three alternative mechanistic azoles; tricomponent
pathways conducting to the named spiroheterocycles. All target mol- reaction; catalyst-free
ecules were fully characterized by IR, NMR, melting point and HRMS.

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
and epilepsy.[1] In addition to CNS activities,[2–8] some sulfur and nitrogen derivatives
have diverse biological desirable effects as antidiabetes;[9,10] antiproliferatives[11,12] 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
368 C. BECERRA-RIVAS ET AL.

R
R
H2N 1, 3 R
+ 1. HCl conc a H
2. NH4OH H2N N b Cl
HN N c OMe
NH2 N
d F
e NO2
1a-e 2 3a-e, 72-83%
Scheme 1. Synthesis of aminopyrazole precursors.

R R

O O O H
H2N HS N N
N
OH
N + N
Various solvents S

3a-e 4a-e
Scheme 2. Synthesis of spirocyclohexane-1,4
-pyrazolothiazepinones 4a–e.

antimicrobials.[13] Besides, pyrazole-fused thiazepines have been tested recently with

promising results as cytotoxic[14] and antiparasitic agents.[15]
Multicomponent reactions (MCRs) are efficient and versatile tools to obtain diverse
bioactive compounds in few steps and purifications in comparison to multistep strat-
egies.[16] This approach makes possible to build relatively easy and quick, libraries of
complex organic compounds,[17] 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
by Baldwin’s rules,[18] 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
spirofused cyclohexane-1,40 -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-
aminocrotononitrile 2 in acid media (Scheme 1).[19–21]
Compound 3a was used as scoping substrate in reaction with cyclohexanone and
mercaptoacetic acid (MAA) in equimolar quantities in various solvents to obtain spiro-
cyclohexane-1,40 -pyrazolothiazepinones (Scheme 2), where benzene gave rise to the best
results thus allowing to optimize the reaction (Table 1).
 SYNTHETIC COMMUNICATIONSV
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Table 1. Scoping conditions for synthesis of compound 4a.

Entry Solvent Temperature ( C) Time (h). Yield of 4a (%)b
1 MeCN Reflux 48 NRc
2 MeCN /4.0 A MS Reflux 20 5
3 THF Reflux >90 NRc
4 Toluene Refluxa 72 6
5 Toluene 70a 72 NRc
6 DMF 100 2 Degd
7 DMF 70 10 NRc
8 Benzene Refluxa 72 15
9 Solvent-free Fussion 0.033 Degd
a
Dean-Stark apparatus was used.
b
Reaction conditions: 0.5 mmol of 3a, equimolar quantities of cyclohexanone and MAA, 5 mL of each solvent.
c
No reaction observed.
d
Compound 3a was degraded.

Table 2. Stoichiometric scoping of reaction.

Molar relation
Entry cyclohexanone Molar relation MAA Time (h). Yield of 4a (%)a
1 1 1 72 15
2 1 2 60 18
3 2 2 60 24
4 2 3 24 74
5 2 4 60 50
6 3 3 36 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
370 C. BECERRA-RIVAS ET AL.

Table 3. Yields of compounds 4a–d and 5e.

Entry –R Time (h) Yield of 4 (%)b Yield of 5 (%)b
a –H 24 74 –
b –Cl 25 70 –
c –OMe 20 76 –
d –F 24 66 –
e –NO2 36 –a 67
a
Not observed.
b
Yields of isolated compounds.

3a-d O H
R N N
4a-d
N
S
O O
H2N N HS O2N
OH
N +
PhH, ,
Dean-Stark
N N
3a-e 3e 5e
H2N

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-
densation reactions.[22] 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).
 SYNTHETIC COMMUNICATIONSV
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NO2

N N
NH2
OH
Pathway A NO2

NO2 6e
HSCH2CO2H
O
N N

+ NH
- H2O O
N NH2
N NO2 S
HSCH2CO2H 4e
3e

N N Pathway B

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

O 6a NH
O
+ - H2O S
N NH2 4a
N

N N HSCH2CO2H
3a
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-
thesized by a methodology previously reported,[23] 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
372 C. BECERRA-RIVAS ET AL.

H2N N 3a
H O N H2N N H2N H2N
O N N
HO N HO N + H2O N
+ H
H+ -H

6a
OH
- H2O
O

HS
O
NH OH H O
N HO N HO H2N H2N N
N N
S N - H+
S N S N N
- H2O

4a

Scheme 6. Plausible mechanism of formation of 4a via intermediate 6a.

O OH O
O
NH2
S O S
HS CO2H OH
- H2O N
N
3a
7

H N N H2N
N N HO H2N N O N
O H
S S N
- H2O O O
S
4a
Scheme 7. Alternative pathway C proposed to explain the formation 4a.

O
O N N O
H2N NH
S O N
PhH, Δ 3a
+ S N
O Dean - Stark PhH, Δ
Ref [23]. Dean - Stark
HO SH 7, 95% 4a

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).
 SYNTHETIC COMMUNICATIONSV
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N N O H N N
N N - H2O N N
H N+
+
HN HN N C-
H OH O H
8 O H
O O -
SH O
SH HS SH

H3O+
HS

O OH N N O
N NH2 N N
N
HN
11) 3a +
- H3O HS
N
H
O
S H2O
4a

Scheme 9. Alternative pathway D proposed to get 4a in tricomponent reaction.

O
N N N
N N PhH, Δ N
HS OH
H2N PhH / Dean-Stark HN Cyclohexanone
HN
3a Δ
Dean-Stark
S
O O
8 SH 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)
Compounds 4a–d exhibited diagnostic signals in 1H-NMR spectra, such as a singlet cor-
responding to a-carbonyl CH2 in d = 3.18–3.23 ppm and aliphatic signals (four multip-
lets) assigned to CH2 of cyclohexane in 1.24–2.21 ppm. Additionally, pyrazolic CH3
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-
firmed through chemical exchange experiments with D2O). Regarding 13C-NMR and
DEPT-135 spectra, signal count corresponded to the number of carbon atoms expected
for title compounds. CH3 appeared as one signal in the range d = 16.80–16.95 ppm
374 C. BECERRA-RIVAS ET AL.

while CH2 in cyclohexane fragment were observed as three negative phase signals in
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 CH2 was observed around 36.9
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
elemental analysis), where the corresponding [M þ 1]þ 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
the synthesis of spirofused cyclohexane-1,40 -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
Typical procedure for the synthesis of spiro[cyclohexane-1,40 -pyrazolo
[3,4-e][1,4]thiazepin]-7(60 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)
White solid (74%, 726 mg); mp: 257-258  C; IR ( max cm1): 3075, 2927, 2854, 1679,
767. 1H-NMR (400 MHz, CDCl3): d 1.29 (qt, J = 12.8, 3.7 Hz, 1H), 1.65 (dd, J = 13.7,
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
(m, 3H), 7.50 (m, 2H). 13C-NMR (100 MHz, CDCl3): d 16.9, 22.1, 25.4, 31.0, 37.1, 49.5,
115.4, 125.4, 128.7, 129.8, 133.4, 137.2, 146.3, 171.3. HRMS (ESI) m/z: [M þ H]þ Calc.
for C18H21N3OS: 328.1478; found: 328.1515.
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Funding
Authors wish to credit Universidad Nacional de Colombia for the financial support given for
this work.

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