Diastereoselective Synthesis of Pyrazolines by Metal-Free Rearrangement of Bicyclic Triazolines

Article abstract of DOI:10.1055/s-0040-1707173

The metal-free preparation of diazoalkanes through the ring rearrangement of bicyclic triazolines is reported here. Their use in 1,3-dipolar cycloaddition reactions with electron-withdrawing alkenes was investigated. This synthetic procedure allows differently substituted pyrazolines to be obtained in few steps and with high atom economy.

Full text of DOI:10.1055/s-0040-1707173

SYNTHESIS
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
©
Georg Thieme Verlag Stuttgart · New York
2020, 52, A–G
paper
A
en
Synthesis
R. Bucci et al.
Paper
Diastereoselective Synthesis of Pyrazolines by Metal-Free
Rearrangement of Bicyclic Triazolines
Raffaella Bucci
EWG
R
Francesca Clerici
O
H
N
N2
N
EWG
Sara Pellegrino*
Emanuela Erba*
Et O
N
N
R
N
2
H
+
+ ArSO2N3
rt
N
N
CH2Cl2
rt
X
N
SO2
Ar
N
SO2Ar
X
N
N SO2Ar
DISFARM-Dipartimento di Scienze Farmaceutiche,
Università degli Studi di Milano, via Venezian 21,
Milano 20133, Italy
X = O, NCH Bn
R = alkyl, CO2Et
EWG = CO2R', CONR'2, CN
2
X
X
one-pot procedure
11 examples
sara.pellegrino@unimi.it
emanuela.erba@unimi.it
62–85% yield
Received: 16.04.2020
Accepted after revision: 02.06.2020
Published online: 09.07.2020
methodologies have been developed so far. In most cases
the diazoalkanes are generated ‘in situ’ from variously sub-
stituted hydrazones (Scheme 1) under different conditions.
DOI: 10.1055/s-0040-1707173; Art ID: ss-2020-f0203-op
7
8
Barluenga and Bi used inorganic bases and high tempera-
Abstract The metal-free preparation of diazoalkanes through the ring
rearrangement of bicyclic triazolines is reported here. Their use in 1,3-
dipolar cycloaddition reactions with electron-withdrawing alkenes was
investigated. This synthetic procedure allows differently substituted
pyrazolines to be obtained in few steps and with high atom economy.
tures, while Myers9 and Charette10 employed oxidizing
agents. Conversely, Brewer 11 reported the preparation of
stable diazo compounds via dehydrogenation of hydrazones
in DMSO.
Key words diazoalkanes, pyrazolines, amidines, 1,3-dipolar cycloaddi-
tion, triazoline rearrangement, metal-free reactions, diastereoselectivi-
ty, atom economy
Bi (2017)
Nos
N
N
H
R1 R2
Barluenga (2013)
Myers (2004)
Tos
N
b
Pyrazoline is a versatile molecule, which has found ap-
plications in a wide range of fields, spanning from material
science to organic electronics, pharmacology, and agro-
TBS
N
N
H
N
H
a
R1 R2
N2
c
R2
R1
R2
1
R1
chemistry. The most common synthetic protocol leading to
this privileged scaffold is the reaction of , unsaturated al-
dehydes or ketones with hydrazine reagents. Hydrazones
e
d
2
NH2
NH2
N
N
are formed as intermediates, which then usually cyclize to
form pyrazolines under acidic or alkaline conditions. A very
efficient and widely exploited alternative strategy for the
synthesis of pyrazolines is represented by the 1,3-dipolar
cycloaddition reaction between diazo compounds and ole-
R1 R2
Brewer (2007)
R1 R2
Charette (2019)
Scheme 1 Examples of diazoalkane synthesis reported in the litera-
ture. Reagents and conditions: a) K CO , 110 °C; b) NaH, AgOTf, 40 °C;
c) PhIF , 2-chloropyridine; d) PhOI, –20 °C; e) oxalyl chloride, DMSO,
2
3
2
3
finic dipolarophiles. This reaction is highly regioselective,
–
78 °C.
with the terminal nitrogen of the diazoalkane attacking the
-carbon. Diazo compounds stabilized by an electron-with-
drawing group (CO or TMS) are normally employed, al-
though Lewis acid catalysis is often needed. Non-stabilized
Our research group reported the formation of diazoal-
kanes through the ring rearrangement of bicyclic triazo-
4
12
diazoalkanes are more reactive, but they are usually highly
unstable and prone to detonation, and, as a consequence,
more difficult to handle. On the other hand, considering the
paramount importance of diazoalkanes in organic synthe-
lines 1 at room temperature in CH Cl . The initial breaking
2 2
2
3
of the N –N bond, followed by amidine bond formation
3a
6a
and the simultaneous breaking of the C –C bond led to
diazo compounds 2 that, in turn, easily reacted with acid
compounds leading to differently functionalized alkyl ami-
5
sis, from click reactions to carbene generation and nucleo-
6
12,13
philic addition, it is not surprising that various synthetic
dines 3 (Scheme 2).
©
2020. Thieme. All rights reserved. Synthesis 2020, 52, A–G
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
Synthesis
R. Bucci et al.
Paper
R
solution quickly rearranged to diazo derivative 2a. The ad-
dition of acrylate 5 (3 equiv) to a solution of 2a in CH Cl led
to the formation of 1H-pyrazoline 4a in 65% yield.
N2
R = halogen,
ester,
N
N
CH2Cl2
i
2
2
R1
amino ester,
peptide
N
N
rt
N
N
R2 SO2
R1
2
SO Ar
R1
N
SO2Ar
N
Encouraged by this result, we tested the reaction be-
tween 2a and different substrates (Table 1). A series of elec-
tron-withdrawing alkenes were used and the desired dihy-
dropyrazoles 4a–g were produced in good yields. The cyc-
loaddition reaction was regiospecific, leading to only one
Ar
R2
3 R2
1
2
i) HX, carboxylic acid, amino acid, peptide acid
Scheme 2 Synthesis of diazoalkanes by ring rearrangement of bicyclic
triazolines
3
regioisomer, as already observed in similar reactions. In-
Diazoalkanes 2 are surprisingly stable and storable at
room temperature and, thus, in this work, we envisaged
their application in 1,3-dipolar cycloaddition reactions
with electron-withdrawing alkenes to obtain differently
substituted pyrazolines 4.
terestingly, the reaction is also diastereoselective. When -
substituted acrylates were used, the corresponding prod-
ucts 4d and 4e were obtained as single diastereomers.
NOESY correlation spectra allowed us to define the trans re-
lationship between the substituents on C4 and C5 of the
pyrazoline ring for both compounds. This trans stereoselec-
tivity is probably ascribable to steric factors that drive the
attack on the  carbon of the diazo compound.
The synthesis of triazolines 1 takes advantage of a mul-
ticomponent click reaction between cyclopentanone, a sec-
12
ondary amine, and sulfonyl azides. When cyclopentanone,
morpholine, and tosyl azide were used in diethyl ether at
room temperature, compound 1a was obtained in 95% yield
The reaction was then tested on cyclic alkenes. When
the reaction was performed on a five-membered cyclic
alkene, 4,5-dihydro-3H-pyrazole 4f was obtained (Table 1).
In this product, the signal corresponding to the NH was
missing and a remarkable number of JCH couplings was ob-
served and have been useful in defining the structure. COSY
experiments clearly showed the couplings between the H3,
(Scheme 3). As already observed with similar compounds,
triazoline 1a was stable if stored at 5 °C as a solid, but in
O
O
Et2O
rt
N
N
CH2Cl2
rt
+
+
TosN3
N
N
N
3
H4, and H5 atoms. In particular, the J coupling constant of
H
Tos
O
H3 was 2.1 Hz, indicating a W-coupling due to the strained
bicyclic structure. On the other hand, when a six-mem-
bered ring was used, 1H-pyrazoline 4g was the only prod-
uct, as observed for acyclic dipolarophiles (Table 1). The dif-
ferent results are probably due to ring torsional strains that
favor the formation of 4,5-dihydro-3H-pyrazole in the case
of the five-membered-ring dipolarophile. In all cases, the
reactions were trans diastereoselective.
1a
CO2Me
N2
CO2Me
N
N
5
H
N
Tos
CH2Cl2
rt
N
N
N Tos
2a
O
4a
O
Scheme 3 Synthesis of pyrazoline 4a
CO2Me
N2
N
N
SO2N3
O
CO2Me
H
O
Et2O
Ph
N
+
+
N
Dansyl
N
CH2Cl2
N
N Dansyl
H
N
O
2b
4h
85%
O
O
N
CH2Cl2
Ph
O
O
N
O
N
N
N
N Dansyl
4
i
O
60%
Scheme 4 Synthesis of Dansyl pyrazolines 4h,i (Method B, 1 mmol scale)
©
2020. Thieme. All rights reserved. Synthesis 2020, 52, A–G

C
Synthesis
R. Bucci et al.
Paper
To reduce the number of synthetic steps, a one-pot pro-
cedure was then developed (Table 2). In this case, the addi-
tion of the dipolarophile was performed without isolation
of the diazoalkane intermediate, being added directly to the
reaction mixture (see Method B in experimental proce-
dures). In this case, also, it was possible to obtain the de-
sired pyrazolines 4 in good yields and with the same stereo-
chemical outcome.
Table 1 (continued)
Dipolarophile
Product 4
Yield (%)
CO2Me
N
MeO2C
*
*
N
CO2Me
H
4
e
65
MeO C
2
N
N Tos
O
Table 1 Synthesis of Pyrazolines 4a–g (Method A)a
O
O
N
R2
*
R1
*
*
*
*
N
N
N2
O
O
N
4f
67
R2
H
R1
N
N
N
Tos
N
Tos
N
N Tos
CH2Cl2
rt
O
O
O
O
*
2a
4a–g
O
N
Dipolarophile
Product 4
Yield (%)
*
O
O
N
H
4
g
62
CO2Me
N
N
N
Tos
N
H
CO2Me
4
a
65
O
a
Synthesis on 1 mmol scale.
N
N
Tos
O
CN
N
Table 2 One-Pot Synthesis of Pyrazolines 4a,h–m (Method B)
N
H
CN
4
b
68
65
68
Amine
Azide
TosN
Dipolarophile
Product 4 Yield (%)
N
N
Tos
O
O
CO2Me
3
4a
4h
73
85
O
N
H
H
N
SO2N3
SO2N3
O
N
CO2Me
N
H
N
H
CONHiPr
4c
N
N
O
N Tos
O
Ph
O
N
4
i
60
O
N
H
CO2Me
N
N
*
*
N
Ph
Ph
H
N
CO2Me
4d
TosN
3
3
CO2Me
4l
62
62
N
H
N
N
Tos
O
N
TosN
CO2Me
4m
N
H
Thieme. All rights reserved. Synthesis 2020, 52, A–G

D
Synthesis
R. Bucci et al.
Paper
The possibility to introduce different substituents on di-
azoalkanes 2 and their effect on the 1,3-dipolar cycloaddi-
tion were also investigated (Table 2). Compound 2b, con-
taining the fluorescent dansyl moiety instead of the tosyl
group, was prepared from the multicomponent reaction of
cyclopentanone, morpholine, and dansyl azide (Scheme 4).
The solution of 2b was then directly used in the reaction
with methyl acrylate or N-benzylmaleimide to produce 1H-
pyrazoline 4h or 4,5-dihydro-3H-pyrazole 4i. This last re-
sult is a further confirmation that when a five-membered-
ring dipolarophile is used, the favored product is the 4,5-di-
hydro-3H-pyrazole.
The use of mono-functionalized piperazine as partner
instead of morpholine could pave the way to a further func-
tionalization of the obtained molecules (Table 2, Scheme 5).
By using benzyl-protected piperazine and cyclopentanone,
whose corresponding enamine rapidly reacted with tosyl
azide in diethyl ether, diazoalkane 2c was synthesized. The
solution of compound 2c was directly treated with the ap-
propriate dipolarophile, affording compounds 4l,m
In conclusion, we have developed a synthetic methodol-
ogy to obtain substituted diazoalkanes, which can be used
in a 1,3-dipolar cycloaddition reaction with electron-with-
drawing alkenes, leading to different substituted dihydro-
pyrazoles. This multicomponent synthesis of pyrazolines is
very versatile, allowing the insertion of fluorescent substit-
uents or further derivatization with moieties such as piper-
azine.
All the commercially available chemicals were purchased from com-
mercial sources without any further purification. Melting points were
obtained on a Stuart ScientificSMP3 digital melting point apparatus
and are uncorrected. ESI-MS spectra were recorded on an LCQ-Advan-
1
13
tage mass spectrometer from Thermo Finnigan. H and C NMR spec-
tra were recorded on Bruker Avance 300 MHz and Gemini 300 MHz
Varian spectrometers. All NMR signals are recorded using TMS as ex-
ternal standard.
4-(3-Tosyl-3,3a,4,5,6,6a-hexahydrocyclopenta[d][1.2.3]triazol-3a-
yl)morpholine (1a)
(
Scheme 5). Compound 4m can be easily debenzylated with
To a solution of 1-morpholinocyclopentene (0.1 g, 0.65 mmol) in Et
O
2
(10 mL), tosyl azide (0.128 g, 0.65 mmol) was added. The mixture was
H and Pd/C, affording free amine 6 in quantitative yield
(
2
stirred for 30 min and a white precipitate started to form. It was fil-
Scheme 6).
tered and abundantly washed with Et O.
2
R2
Yield: 0.21 g, 95%; white powder; mp 88 °C.
N2
R1
1
H NMR (300 MHz, C D ):  = 0.75–1.52 (m, 6 H), 1,74 (s, 3 H), 2.38–
R2
*
*
N
6
6
R
O
R1
N
2.45 (m, 4 H), 3.24–3.44 (m, 4 H), 4.12–4.16 (m, 1 H), 6.62–6.65 (d, J =
8.1 Hz, 2 H), 7.97–7.95 (d, J = 8.1 Hz, 2 H).
N
N
H
Et2O
TosN3
N
Tos
+
+
N
H
N
N Tos
N
N-(5-Diazo-1-morpholinopentylidene)tosylamide (2a)
Bn
2c
4l, m
N
R
A solution of 1a (0.02 g in 1 mL of C D ) was left at rt for 30 min and
6
6
1
13
then the H and C NMR spectra were recorded.
1
CO2Me
CO2Me
N
H NMR (300 MHz, C D ):  = 1.47–1.98 (m, 4 H), 1.87 (s, 3 H), 2.68–
.84 (m, 2 H), 2.89–3.25 (m, 9 H), 6.83–6.90 (m, 2 H), 8.09–8.12 (m, 2
6
6
2
H).
N
*
*
N
H
N
H
13
C NMR (75 MHz, C D ):  = 20.9 (CH ), 23.1 (CH ), 26.3 (CH ), 29.8
6
6
3
2
2
(
6
CH ), 35.1 (CH, very broad signal), 44.3 (CH ), 46.0 (CH ), 65.7 (CH ),
2
2
2
2
N
N
Tos
N
N Tos
6.1 (CH ), 126.6 (CH), 129.1 (CH), 141.6 (C), 142.6 (C), 166.7 (C).
2
N
N
4l
4m
62%
62%
Sequential Cycloaddition Reaction (Method A); General Procedure
Ph
Ph
To a solution of diazoalkane 2a (1 mmol) in CH Cl (5 mL), the appro-
2
2
Scheme 5 Synthesis of piperazine derivatives (Method B, 1 mmol
scale)
priate dipolarophile (3 mmol) was added. The solution was stirred for
h at rt and monitored by TLC (EtOAc/hexane 3:2). The solution was
1
concentrated under reduced pressure and the crude was purified by
column chromatography (silica gel, EtOAc/hexane gradient from 50%
to 90%).
CO2Me
CO2Me
*
*
N
*
*
N
N
N
H
H2
H
One-Pot Cycloaddition Reaction (Method B); General Procedure
Pd/C
To a solution of amine (1 mmol) dissolved in Et O (10 mL), cyclopen-
tanone (1 mmol) and 4 Å MS (4 g) were added; the reaction mixture
2
N
N
Tos
N
N
Tos
was stirred at rt. After 1 h, the azide (1 mmol) in CH Cl (2 mL) was
N
Bn
2
2
4m
N
6
H
added and, after 15 min, the dipolarophile (5 mmol) was also added.
The solution was stirred for 1 h at rt and monitored by TLC (EtOAc/
hexane 3:2). The solution was filtered and concentrated under re-
duced pressure. The crude was purified by column chromatography
Scheme 6 Debenzylation of compound 4m
(silica gel, EtOAc/hexane gradient from 50% to 90%).
©
2020. Thieme. All rights reserved. Synthesis 2020, 52, A–G

E
Synthesis
R. Bucci et al.
Paper
13
Methyl 5-[4-Morpholino-4-(tosylimino)butyl]-4,5-dihydro-1H-
C NMR (75 MHz, CDCl ):  = 17.0 (CH ), 21.4 (CH ), 22.9 (CH ), 30.0
3
3
3
2
pyrazole-3-carboxylate (4a)
(CH ), 33.7 (CH ), 44.1 (CH), 44.7 (CH ), 46.6 (CH ), 51.8 (CH ), 66.3
2 2 2 2 3
(
CH ), 66.6 (CH ), 67.9 (CH), 126.2 (CH), 129.2 (CH), 140.9 (C), 142.2
2 2
Yield (method A): 0.28 g, 65%; yield (method B): 0.32 g, 73%; white
(C), 144.3 (C), 163.3 (C), 166.9 (C).
solid; mp 73 °C (Et O).
2
ESI-MS: m/z = 450.0 [M + H]–.
1
H NMR (300 MHz, CDCl ):  = 1.65–1.83 (m, 4 H), 2.42 (s, 3 H), 2.57–
3
2.62 (m, 1 H), 2.72–2.83 (m, 1 H), 2.99–3.19 (m, 2 H), 3.51–3.72 (m, 8
Anal. Calcd for C21H30N O S: C, 55.98; H, 6.71; N, 12.44. Found: C,
4
5
H), 3.84 (s, 3 H), 4.01–4.11 (m, 1 H), 6.68 (very br s, 1 H), 7.27 (d, J =
55.79; H, 6.89; N, 12.31.
8.2 Hz, 2 H), 7.81 (d, J = 8.2 Hz, 2 H).
13
C NMR (75 MHz, CDCl ):  = 21.4 (CH ), 23.3 (CH ), 29.9 (CH ), 34.5
Dimethyl 5-[4-Morpholino-4-(tosylimino)butyl]-4,5-dihydro-1H-
3
3
2
2
(
(
(
CH ), 36.4 (CH ), 44.8 (CH ), 46.6 (CH ), 52.0 (CH ), 60.7 (CH), 66.3
pyrazole-3,4-dicarboxylate (4e)
2
2
2
2
3
CH ), 66.6 (CH ), 126.2 (CH), 129.2 (CH), 140.8 (C), 141.7 (C), 142.3
2
2
Yield (method A): 0.33g, 65%; white solid; mp 68 °C (Et O).
2
C), 163.3 (C), 166.9 (C).
1
H NMR (300 MHz, CDCl ):  = 1.65–1.94 (m, 4 H), 2.41 (s, 3 H), 2.75–
3
ESI-MS: m/z = 435.35 [M + H]–.
2.88 (m, 1 H), 3.08–3.20 (m, 1 H), 3.45–3.56 (m, 2 H), 3.62–3.79 (m, 7
Anal. Calcd for C20H28N O S: C, 55.03; H, 6.47; N, 12.83. Found: C,
H), 3.77 (s, 3 H), 3.83 (s, 3 H), 4.22–4.34 (m, 1 H), 7.08 (br s, 1 H), 7.28
4
5
54.98; H, 6.60; N, 12.71.
(d, J =8.1 Hz, 2 H), 7.80 (d, J = 8.1 Hz, 2 H).
13
C NMR (75 MHz, CDCl ):  = 21.4 (CH ), 22.8 (CH ), 29.7 (CH ), 34.1
3
3
2
2
N-[4-(3-Cyano-4,5-dihydro-1H-pyrazol-5-yl)-1-morpholino-
(CH ), 44.8 (CH ), 46.7 (CH ), 52.2 (CH ), 52.7 (CH ), 54.8 (CH), 65.7
2 2 2 3 3
butylidene]tosylamide (4b)
(CH), 66.3 (CH ), 66.6 (CH ), 126.1 (CH), 129.2 (CH), 137.9 (C), 140.8
2 2
(
C), 142.3 (C), 162.6 (C), 166.7 (C), 171.0 (C).
Yield (method A): 0.27 g, 68%; white solid; mp 148 °C (Et O).
2
–
+
1
ESI-MS: m/z = 493 [M ], 517 [M + Na].
H NMR (300 MHz, CDCl ):  = 1.62–1.89 (m, 4 H), 2.43 (s, 3 H), 2.45–
3
2.62 (m, 1 H), 2.72–2.86 (m, 1 H), 2.96–3.10 (m, 1 H), 3.10–3.22 (m, 1
Anal. Calcd for C22H30N O S: C, 53.43; H, 6.11; N, 11.33. Found: C,
4
7
H), 3.48–3.57 (m, 2 H), 3.62–3.78 (m, 6 H), 4.08–4.22 (m, 1 H), 7.09 (br
53.24; H, 6.24; N, 11.21
s, 1 H), 7.28 (d, J = 8.2 Hz, 2 H), 7.79 (d, J = 8.2 Hz, 2 H).
1
3
C NMR (75 MHz, CDCl )  = 21.4 (CH ), 23.7 (CH ), 29.7 (CH ), 34.0
4-Methyl-N-{1-morpholino-4-[(3S,3aS,6aR)-6-oxo-3a,4,6,6a-tetra-
hydro-3H-furo[3,4-c]pyrazol-3-yl]butylidene}benzenesulfon-
amide (4f)
3
3
2
2
(CH ), 38.7 (CH ), 44.8 (CH ), 46.7 (CH ), 60.1 (CH), 66.3 (CH ), 66.6
2 2 2 2 2
(CH ), 115.1 (C), 122.4 (C), 126.4 (CH), 129.2 (CH), 140.7 (C), 142.4 (C),
2
1
66.8 (C).
Yield (method A): 0.35 g, 67%; white powder; mp 155–156 °C (Et O).
2
ESI-MS: m/z = 402.4 [M + H]–.
1
H NMR (300 MHz, CDCl ):  = 1.84–2.25 (m, 4 H), 2.43 (s, 3 H), 2.72–
3
Anal. Calcd for C19H25N O S: C, 56.56; H, 6.25; N, 17.36. Found: C,
2.94 (m, 1 H), 2.94–3.08 (m, 1 H), 3.18–3.34 (m, 1 H), 3.51–3.85 (m, 8
H), 3.98–4.08 (m, 1 H), 4.60–4.69 (m, 1 H), 4.92–5.02 (m, 1 H), 5.64–
5
3
56.39; H, 6.40; N, 17.20.
5.70 (m, 1 H), 7.28 (d, J = 8.2 Hz, 2 H), 7.81 (d, J = 8.2 Hz, 2 H).
1
3
N-Isopropyl-5-[4-morpholino-4-(tosylimino)butyl]-4,5-dihydro-
H-pyrazole-3-carboxamide (4c)
C NMR (75 MHz, CDCl ):  = 21.4 (CH ) 23.6 (CH ), 30.1 (CH ), 32.4
3
3
2
2
1
(CH ), 37.1 (CH), 44.8 (CH ), 46.7 (CH ), 66.3 (CH ), 66.6 (CH ), 72.7
2 2 2 2 2
(
CH ), 92.8 (CH), 98.6 (CH), 126.1 (CH), 129.2 (CH), 140.8 (C), 142.3
Yield (method A): 0.32 g, 65%; white powder; mp 62 °C (Et O).
2
2
(C), 166.6 (C), 168.5 (C).
1
H NMR (300 MHz, CDCl ):  = 1.17 (d, J = 6.6 Hz, 6 H), 1.68–1.85 (m, 4
3
+
ESI-MS: m/z = 457.7 [M + Na].
H), 2.41 (s, 3 H), 2.45–2.58 (m, 1 H), 2.76–2.89 (m, 1 H), 3.01- 3.19 (m,
2 H), 3.48–3.57 (m, 2 H), 3.62–3.78 (m, 6 H), 3.92–4.08 (m, 1 H), 4.08–
4.18 (m, 1 H), 6.30–6.65 (2br s, 2 H), 7.28(d, J = 8.1 Hz, 2 H), 7.80 (d, J =
8.1 Hz, 2 H).
Anal. Calcd for C20H26N O S: C, 55.28; H, 6.03; N, 12.89. Found: C,
55.17; H, 6.22; N, 12.77.
4
5
1
3
C NMR (75 MHz, CDCl ):  = 21.4 (CH ), 22.7 (CH ), 23.6 (CH ), 29.9
4-Methyl-N-{1-morpholino-4-[(3S,3aS)-7-oxo-2,3,3a,4,5,7-hexahy-
dropyrano[3,4-c]pyrazol-3-yl]butylidene}benzensulfonamide (4g)
3
3
3
2
(
(
(
CH ), 34.5 (CH ), 36.4 (CH ), 41.1 (CH ), 44.8 (CH), 46.6 (CH ), 60.5
CH), 66.3 (CH ), 66.6 (CH ), 126.2 (CH), 129.2 (CH), 140.9 (C), 142.2
C), 147.5 (C), 161.5 (C), 167.0 (C).
2 2 2 2 2
2
2
Yield (method A): 0.27g, 62%; glassy solid.
1
H NMR (300 MHz, CDCl ):  = 1.74–2.20 (m, 6 H), 2.41 (s, 3 H), 2.77–
3
ESI-MS: m/z = 487.8 [M + Na]+.
2.87 (m, 1 H), 2.96–3.06 (m 1 H), 3.12–3.22 (m, 1 H), 3.53–3.72 (m, 8
Anal. Calcd for C22H33N O S C, 57.00; H, 7.17; N, 15.11. Found: C,
H), 3.91–4.03 (m, 1 H), 4.33–4.41 (m, 1 H), 4.43–4.55 (m, 1 H), 7.27 (d,
5
4
56.92; H, 7.32; N, 14.98
J = 8.2 Hz, 2 H), 7.29 (br s, 1 H), 7.79 (d, J = 8.2 Hz, 2 H).
13
C NMR (75 MHz, CDCl ):  = 21.5 (CH ), 23.9 (CH ), 27.9 (CH ), 30.0
3
3
2
2
Methyl (4R,5R)-4-Methyl-5-[4-morpholino-4-(tosylimino)butyl]-
,5-dihydro-1H-pyrazol-3-carboxylate (4d)
(CH ), 33.0 (CH ), 44.8 (CH ), 46.7 (CH ), 47.2 (CH), 66.3 (CH ), 66.6
(CH ), 69.1 (CH ), 69.9 (CH),126.1 (CH), 129.2 (CH), 140.7 (C), 142.0
2 2
2 2 2 2 2
4
(
C), 142.3 (C), 160.1 (C), 166.9 (C).
Yield (method A): 0.30 g, 68%; white powder; mp 143 °C (Et O).
2
–
+
1
ESI-MS: m/z = 448.7 [M ], 471.12 [M + Na].
H NMR (300 MHz, CDCl ):  = 1.27 (d, J =7.8 Hz, 3 H), 1.59–1.90 (m, 4
3
H), 2.41 (s, 3 H), 2.52–2.57 (m, 1 H), 2.57–2.95 (m, 1 H), 3.10–3.25 (m,
Anal. Calcd for C21H28N O S: C, 56.23; H, 6.29; N, 12.48. Found: C,
4
5
1
H), 3.48–3.55 (m, 2 H), 3.55–3.62 (m, 1 H), 3.62–3.80 (m, 6 H), 3.83
56.08; H, 6.33; N, 12.34.
(s, 3 H), 6.75 (br s, 1 H), 7.27(d, J = 8.1 Hz, 2 H), 7.80 (d, J =8.1 Hz, 2 H).
©
2020. Thieme. All rights reserved. Synthesis 2020, 52, A–G

F
Synthesis
R. Bucci et al.
Paper
1
Methyl 5-[4-({[5-(Dimethylamino)naphthalen-1-yl]sulfonyl}imi-
H NMR (300 MHz, CDCl ):  = 1.22–134 (m, 3 H), 1.54–1.95 (m, 2 H),
3
no)-4-morpholinobutyl]-4-5-dihydro-1H-pyrazole-3-carboxylate
2.28–2.60 (m, 4 H), 2.26 (s, 3 H), 2.68–3.22 (m, 3 H), 3.48–3.95 (m, 9
(
4h)
H), 3.78 (s, 3 H), 6.77 (br s, 1 H), 7.25–7.33 (m, 7 H), 7.79–7.81 (m, 2
H).
Yield (method B): 0.46 g, 85%; yellowish powder; mp 86–87 °C (Et O).
1
2
13
C NMR (75 MHz, CDCl ):  = 17.0 (CH ), 21.5 (CH ), 23.0 (CH ), 30.2
3 3 3 2
H NMR (300 MHz, CDCl ):  = 1.62–1.80 (m, 4 H), 2.50–2.65 (m, 1 H),
3
(
(
(
CH ), 33.7 (CH ), 44.1 (CH), 44.4 (CH ), 46.3 (CH ), 51.8 (CH ), 52.1
2
.65–2.70 (m, 1 H), 2.88 (s, 6 H), 2.72–3.24 m, 3 H), 3.42–3.75 (m, 7
H), 3.84 (s, 3 H), 4.02–4.08 (m, 1 H), 6.75 (br s, 1 H), 7.20 (d, J = 7.2 Hz,
H), 7.47–7.54 (m, 2 H), 8.27(d, J = 7.2 Hz, 1 H), 8.35 (d, J = 8.5 Hz, 1
H), 8.49 (d, J = 8.5 Hz, 1 H).
2 2 2 2 3
CH ), 53.0 (CH ), 62.5 (CH ), 67.9 (CH), 126.2 (CH), 127.5 (CH), 128.4
2
2
2
CH), 129.1 (CH), 136.9 (C), 141.0 (CH), 142.1 (C), 144.5 (C), 163.3 (C),
66.6 (C).
1
1
ESI-MS: m/z = 540.0 [M + H]+.
1
3
C NMR (75 MHz, CDCl ):  = 23.3 (CH ), 30.0 (CH ), 34.5 (CH ), 36.4
3
2
2
2
(
CH ), 44.9 (CH ), 45.4 (CH ), 46.8 (CH ), 52.0 (CH ), 60.8 (CH), 66.3
Anal. Calcd for C28H37N O S: C, 62.32; H, 6.91; N, 12.98. Found: C,
2
2
3
2
3
5
4
(
CH ), 66.6 (CH ), 114.8 (CH), 120.6 (CH), 123.2 (CH), 126.6 (CH),
62.19; H, 7.03; N, 12.81.
2
2
127.3 (CH), 129.4 (C), 129.9 (C), 139.0 (C), 141.6 (C), 151.5 (C), 163.3
(
C), 166.9 (C).
Methyl (4R,5R)-5-[4-Piperazin-1-yl-4-(tosylimino)butyl]-4-meth-
yl-4,5-dihydro-1H-pyrazole-3-carboxylate (6)
+
ESI-MS: m/z = 538.2 [M + Na].
Anal. Calcd for C25H33N O S: C, 58.23; H, 6.45; N, 13.58. Found: C,
To a solution of 4m (0.4 g, 0.74 mmol) in MeOH (10 mL), Pd/C (0.4 g,
5
5
58.11; H, 6.61; N, 13.43.
10%) was added. The solution was stirred under a H atmosphere (1
2
atm) for 12 h at 25 °C. The solution obtained after filtration through a
Celite pad was concentrated under reduced pressure. The crude was
dissolved CH Cl and extracted with water; the aqueous layer was ba-
N-[4-(5-Benzyl-4,6-dioxo-3,3a,4,5,6,6a-hexahydropyrrolo[3,4-
c]pyrazol-3-yl)-1-morpholinobutylidene]-5-(dimethylamino)-
naphthalene-1-sulfonamide (4i)
2
2
sified with NaHCO3 until pH 8 and then extracted with EtOAc. The
solution was dried over Na SO and evaporated under reduced pres-
2
4
Yield (method B): 0.41 g, 65%; glassy solid.
sure, providing compound 6.
1
H NMR (300 MHz, CDCl ):  = 1.65–1.78 (m, 3 H), 1.80–2.14 (m, 1 H),
3
Yield: 0.25 g (80%); white oil.
2.87 (s, 6 H), 2.89–3.09 (m, 2 H), 3.46–3.71 (m, 9 H), 4.57 (s, 2 H),
4.95–5.01 (m, 1 H), 5.78–5.81 (m, 1 H), 7.15 (d, J = 7.2 Hz, 1 H), 7.28–
7.30 (m, 5 H), 7.35–7.52 (m, 2 H), 8.29 (d, J = 7.3 Hz, 1 H), 8.38 (d, J =
8.5 Hz, 1 H), 8.52 (d, J = 8.5 Hz, 1 H).
1
H NMR (300 MHz, CDCl ):  = 1.24 (d, J = 7.6 Hz, 3 H), 1.55–1.83 (m, 4
3
H), 2.39 (s, 3 H), 2.70–3.15 (m, 5 H), 3.42–3.90 (m, 8 H), 3.91 (s, 3 H),
6.81 (br s, 1 H), 7.25 (d, J = 8.2 Hz, 2 H), 7.76 ( d, J = 8.2 Hz, 2 H).
13
13
C NMR (75 MHz, CDCl ):  = 15.2 (CH ), 21.4 (CH ), 22.9 (CH ), 30.1
3 3 3 2
C NMR (75 MHz, CDCl ):  = 23.3 (CH ), 29.7 (CH ), 32.8 (CH ), 42.7
3
2
2
2
(
(
(
CH ), 33.8 (CH ), 44.0 (CH), 45.1 (CH ), 45.2 (CH ), 46.2 (CH ), 47.1
(
(
(
(
CH ), 42.8(CH), 44.9 (CH ), 45.4 (CH), 46.8 (CH ), 66.3 (CH ), 66.7
2 2 2 2 2
2
2
2
2
CH ), 51.8 (CH ), 68.0 (CH), 126.1 (CH), 129.2 (CH), 141.0 (C), 142.1
CH ), 92.9 (CH), 93.3 (CH), 114.8 (CH), 120.5 (CH), 123.2 (CH), 126.7
2
3
2
C), 144.2 (C), 163.3 (C), 166.8 (C).
CH), 127.4 (CH), 128.3 (CH), 128.7 (CH), 128.8 (CH), 129.4 (CH), 129.9
C), 134.8 (C), 139.0 (C), 151.5 (C), 166.6 (C), 168.9 (C), 175.0 (C).
ESI-MS: m/z = 450.1 [M + H]+.
+
ESI-MS: m/z = 638.8 [M + Na].
Anal. Calcd for C21H31N O S: C, 56.10; H, 6.95; N, 15.58. Found: C,
5
4
55.97; H, 7.08; N, 15.29
Anal. Calcd for C32H36N O S: C, 62.32; H, 5.88; N, 13.63. Found: C,
6
5
62.26; H, 5.97; N, 13.58.
Supporting Information
Methyl 5-[4-(4-Benzylpiperazin-1-yl)-4-(tosylimino)butyl]-4,5-di-
hydro-1H-pyrazole-3-carboxylate (4l)
Supporting information for this article is available online at
Yield (method B): 0.32 g, 61%; glassy solid.
https://doi.org/10.1055/s-0040-1707173.
S
u
p
p
orit
n
g Inform ati
o
n
S
u
p
p
orit
n
g Inform ati
o
n
1
H NMR (300 MHz, CDCl ):  = 1.62–1.89 (m, 4 H), 2.40 (s, 3 H), 2.41–
3
2.61 (m, 3 H), 2.72–2.85 (m, 1 H), 2.99–3.18 (m, 2 H), 3.50–3.80 (m, 6
H), 3.59 (s, 2 H), 3.83 (s, 3 H), 4.01–4.12 (m, 1 H), 6.87 (br s, 1 H), 7.27
References
(d, J = 8.1 Hz, 2 H), 7.28–7.37 (m, 5 H), 7.78 (d, J = 8.1 Hz, 2 H).
1
3
(1) (a) Zhang, Y.; Zheng, X.; Zhang, L.; Yang, Z.; Chen, L.; Wang, L.;
Liu, S.; Xie, Z. Org. Biomol. Chem. 2020, 18, 707. (b) Locarno, S.;
Eleta-Lopez, A.; Lupo, M. G.; Gelmi, M. L.; Clerici, F.; Bittner, A.
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Suliman, F. O.; Al-Kindya, S. M. Z. RSC Adv. 2017, 7, 46999.
C NMR (75 MHz, CDCl ):  = 21.4 (CH ), 23,4 (CH ), 30.1 (CH ), 34.4
3
3
2
2
(
(
(
CH ), 36.4 (CH ), 44.24 (CH ), 46.1 (CH ), 52.0 (CH ), 52.0 (CH ), 52.9
CH ), 60.8 (CH), 62.4 (CH ), 126.1 (CH), 127.7 (CH), 128.5 (CH), 129.2
CH), 129.3 (CH), 141.0 (C) , 141.6 (C), 142.1 (C), 161 (C), 163.3 (C),
66.6 (C).
2 2 2 2 3 2
2
2
1
(d) Faria, J. V.; Fazolin, V. P.; Carvalho, M. A. G.; dos Santos, M. S.;
ESI-MS: m/z = 525.0 [M + H]–.
Boechat, N.; Bernardino, R. A. M. Bioorg. Med. Chem. 2017, 25,
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Anal. Calcd for C27H35N O S: C, 61.69; H, 6.71; N, 13.32. Found: C,
6
5
4
1.49; H, 6.84; N, 13.27.
(
f) Havrylyuk, D.; Roman, A.; Lesyk, R. Eur. J. Med. Chem. 2016,
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1
Methyl (4R,5R)-5-[4-(4-Benzylpiperazin-1-yl)-4-(tosylimino)-
butyl]-4-methyl-4,5-dihydro-1H-pyrazole-3-carboxylate (4m)
(
(
Yield (method B): 0.32 g, 62%; glassy solid.
Lett. 2008, 2377. (c) Fustero, S.; Simon-Fuentes, A.; Sanz-Cer-
vera, J. F. Org. Prep. Proced. Int. 2009, 41, 253.
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2020. Thieme. All rights reserved. Synthesis 2020, 52, A–G

G
Synthesis
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3) (a) Nájera, C.; Sansano, J. M.; Yus, M. Org. Biomol. Chem. 2015,
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(
4) Fegheh-Hassanpour, Y.; Ebrahim, F.; Arif, T.; Sintim, H. O.;
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(
©
2020. Thieme. All rights reserved. Synthesis 2020, 52, A–G