Organocatalytic Enantioselective Aminoalkylation of 5-Aminopyrazole Derivatives with Cyclic Imines

Article abstract of DOI:10.1002/ejoc.202001314

In this communication, an efficient asymmetric aminoalkylation of 5-aminopyrazole derivatives with cyclic benzoxathiazine 2,2-dioxides catalyzed by a quinine-derived squaramide in dichloromethane has been established. This is the first example of 5-aminopyrazole derivatives in asymmetric catalysis. A variety of chiral sulfamidates bearing an aminopyrazole moiety were obtained in good yields (up to 98 %) and moderate to excellent enantioselectivities (up to 99 %ee).

Full text of DOI:10.1002/ejoc.202001314

European Journal of Organic Chemistry
Accepted Article
Accepted Article
Title: Organocatalytic Enantioselective Aminoalkylation of 5-
Aminopyrazole derivatives with Cyclic Imines
Authors: Laura Carceller-Ferrer, Aleix González del Campo, Carlos
Vila, Gonzalo Blay, M. Carmen Muñoz, and Jose R. Pedro
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.202001314
Link to VoR: https://doi.org/10.1002/ejoc.202001314
01/2020

10.1002/ejoc.202001314
European Journal of Organic Chemistry
COMMUNICATION
Organocatalytic Enantioselective Aminoalkylation of 5-
Aminopyrazole derivatives with Cyclic Imines
Laura Carceller-Ferrer,[a] Aleix González del Campo,[a] Carlos Vila,[a] Gonzalo Blay,*[a] M. Carmen
Muñoz[b] and José R. Pedro*[a]
Abstract: In this communication, an efficient asymmetric
catalysis. It is noteworthy that the development of such
enantioselective functionalization of this pyrazole derivative could
be interesting for pharmaceutical and medicinal chemistry.
aminoalkylation of 5-aminopyrazole derivatives with cyclic
benzoxathiazine 2,2-dioxides catalyzed by
a
quinine-derived
squaramide in dichoromethane has been established. This is the first
example of 5-aminopyrazole derivatives in asymmetric catalysis. A
variety of chiral sulfamidates bearing an aminopyrazole moiety were
obtained in good yields (up to 98%) and moderate to excellent
enantioselectivities (up to 99%ee).
Cl
CF3
A
H2N
O
tBu
Me
N
H2N
N
N
Cl
N
N
O
Cl
N
Me
NHPh
antifungal
N
N
NH2
H2N
SMe
Introduction
Cl
N
N
p56 Lck inhibitor
H2N
antibacterial
CH3
Heterocycles are fundamental in chemistry and have received the
attention of the synthetic community for many decades, because
they exhibit a wide range of applications in pharmaceutical,
medicinal and agrochemical chemistry as well as in material
science. In this context, nitrogen heterocycles[1] are the most
common and important class of heterocycles, present in
uncountable biologically active compounds and are very
important for drug design in pharmaceutical industry. For example,
in the FDA data base, 60% of small-molecule drugs contain a
nitrogen heterocycle.[2] In this regard, pyrazole derivatives
represent one of the most important nitrogen heterocycles
existing in blockbuster drugs, and consequently their derivatives
have been studied extensively for the last decades.[3] For example,
5-aminopyrazoles have recently gained widespread attention and
occupies a great position because of its biological and medicinal
features as well as its synthetic versatility.[4] This kind of scaffold
is present in several compounds with biological activities such as
antifungal,[5] antibacterial[6] among others[7] (Figure 1A). The
synthetic versatility of 5-aminopyrazoles is very remarkable,
because of the presence of several nucleophilic positions, making
them a synthetic challenge in order to obtain regioselectivity. The
versatility of 5-aminopyrazoles has made them very interesting
scaffolds for the synthetic community and medicinal chemistry,
and several reports have been described showing their
electrophilic functionalization.[4] Despite of this, to the best of our
knowledge, the catalytic enantioselective functionalization of 5-
aminopyrazoles is unknown. Therefore, as a part of our ongoing
interest in organocatalytic enantioselective functionalization of
nitrogen heterocycles,[8] we become interested in study the use of
this kind of nitrogen heterocycles as nucleophiles in asymmetric
OMe
O
NH2
GABA inhibitor
Versatility of 5-aminopyrazole derivatives
B
two nucleophilic positions
R1
HN
Nucleophilic
positions
R2
high substitution diversity
N
N
catalytic enantioselective
functionalization unknown
R3
Figure 1. A) Some biologically active molecules containing 5-aminopyrazole
moiety. B) Versatility of 5-aminopyrazole derivatives.
Herein, we report the organocatalytic enantioselective
aminoalkylation of 1-substituted-1H-pyrazol-5-amines using
benzoxathiazine 2,2-dioxides as electrophiles. Recently, this
class of cyclic imines have attracted attention in asymmetric
catalysis,[9,10] because these compounds have been proved to be
powerful building blocks for the synthesis of chiral
benzosulfamidate heterocycles. In this context, several
sulfamidates have shown important biological activities[11] and
several examples of enantioselective reactions have been
described using these cyclic imines as electrophiles.
Results and Discussion
We chose the aminoalkylation reaction between benzoxathiazine
2,2-dioxides (1a) and 3-methyl-1-phenyl-1H-pyrazol-5-amine (2)
for the optimization studies in the presence of cinchona alkaloid-
derived squaramide organocatalysts (Table 1).[12,13] When the
quinine-derived squaramide A was used as a catalyst we
observed a promising enantioselectivity (49% ee, entry 1). When
B, the quinine-derived squaramide bearing a benzyl group, was
used product 3aa was obtained with an improvement on the
enantiomeric excess to 62% (entry 2). However, when the
quinine-derived squaramide C or D were used, we observed a
decrease on the enantiomeric excess of pyrazole derivative 3aa
[a]
L. Carceller-Ferrer, A. González del Campo, Dr. C. Vila, Prof. Dr. G.
Blay, Prof. Dr. J. R. Pedro
Departament de Química Orgànica, Facultat de Química, Universitat
de València, Dr. Moliner 50, 46100 Burjassot, València (Spain)
E-mail: gonzalo.blay@uv.es; jose.r.pedro@uv.es
Prof. Dr. M. C. Muñoz
[b]
Departament de Física Aplicada, Universitat Politècnica de
València, Camino de Vera s/n, 46022 València (Spain)
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
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10.1002/ejoc.202001314
European Journal of Organic Chemistry
COMMUNICATION
(40% ee and 45% ee, entry 3 and 4). Squaramide E, with a tert-
butyl group, yield a slightly increase on the enantioselectivity of
the reaction (entry 5), obtaining the corresponding chiral
sulfamidate with 83% yield and 65% ee. Cinchonidine-derived
squaramide F, afford the product 3aa with good yield but lower
enantioselectivity. Lastly, when catalyst G, the dihydroquinine-
derived squaramide, was used we observed also lower
enantiomeric excess for the chiral product 3aa (48% ee, entry 6).
Therefore, we chose catalyst E to continue the optimization
process of the reaction conditions, including solvents or
temperatures. Different solvents were then tested (Table 1,
entries 8-13), however we could not improve the results obtained
when CH2Cl2 was used as a solvent (entry 5). Finally, different
temperatures were tested. By lowering the reaction temperature
to 4ꢀ°C (entry 14), the enantioselectivity of the reaction decreased
to 51% ee with a moderate yield (56%). While increasing the
temperature of the reaction to 30 °C, also decreased the
enantiomeric excess of 3aa.
14[d]
15[e]
E (5 mol %)
E (5 mol %)
CH2Cl2
CH2Cl2
24
2
56
99
51
56
[a] Reaction conditions: 1a (0.1 mmol), 2a (0.1 mmol) and catalyst (5 mol%)
in 1 mL of solvent at 20 °C. [b] Isolated yield after column chromatography.
[c] Determined by HPLC using chiral stationary phase. [d] The reaction was
performed at 4 °C. [e] The reaction was performed at 30 °C. DCE=
ClCH2CH2Cl.
At this point of the optimization, we evaluate the substitution
pattern of the 5-aminopyrazole 2 to study the effect of the groups
on the reactivity and enantioselectivity of the reaction (Table 2).
We observed that when we use the 5-aminopyrazole 2b, bearing
a phenyl group at 3 position, we observed a decreased in the
reactivity (93% yield, after 6 days) and a reduction in the
enantioselectivity (27% ee). At this point we decide to study the
effect of the substitution of the amine in the aminoalkylation
reaction. N-benzyl-3-methyl-1-phenyl-1H-pyrazol-5-amine 2c,
gave the chiral sulfamidate 3ac with excellent yield (97%) but
lower enantioselectivity (59% ee). In contrast, 3-methyl-N,1-
diphenyl-1H-pyrazol-5-amine 2d bearing a phenyl protecting
group at the nitrogen of the amine, gave better enantiomeric
excess (83% ee), and good yield (83%) but with 6 days of reaction
time. Finally, when N,1,3-triphenyl-1H-pyrazol-5-amine 2e the
corresponding product was obtained with very low yield (16%),
after 10 days, and low enantioselectivity (32% ee). Therefore, we
decide to continue the optimization process using 5-amino-
pyrazole derivative 2d, that gave the best results in terms of yield
and enantioselectivity. We decide to increase the catalyst loading
to 10 mol% (entry 6), but unfortunately lower enantiomeric excess
for product 3ad was observed.
Table 1. Optimization of the reaction conditions.
O
O
O
O
NH2
Catalyst
(5 mol%)
S
S
O
NH
NH2
O
N
+
Ph
N
N
solvent, rt
Ph
N
N
Me
Me
1a
2a
3aa
CF3
CF3
N
B
, R =
NHR
O
H
A
, R =
N
CF3
MeO
CF3
Ph
Ph
O
C
, R =
D
E
, R =
, R =
N
N
HN
O
H
N
HN
H
N
N
CF3
MeO
O
O
O
CF3
Table 2. Optimization of the reaction conditions.
N
F
G
N
O
O
R2
O
O
HN
E
(5 mol%)
S
R2
S
NH
O
HN
N
O
+
Entry[a]
Catalyst
Solvent
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
DCE
t (h)
Yield (%)[b]
ee (%) [c]
49
Ph
N
20 ºC
Ph
N
N
N
CH2Cl2,
R1
R1
1
A (5 mol %)
B (5 mol %)
C (5 mol %)
D (5 mol %)
E (5 mol %)
F (5 mol %)
G (5 mol %)
E (5 mol %)
E (5 mol %)
E (5 mol %)
E (5 mol %)
E (5 mol %)
E (5 mol %)
5
86
95
70
95
83
80
88
96
96
83
73
73
76
1a
2
3
2
12
24
5
62
Entry[a]
R1
R2
H
2
t (d)
3
Yield (%)[b]
Ee (%) [d]
3
40
1
2
3
4
5
6
Me
Ph
Me
Me
Ph
Me
2a
2b
2c
2d
2e
2d
0.5
6
3aa
3ab
3ac
3ad
3ae
3ad
83
93
97
83
16
84
65
27
59
83
32
76
4
45
H
5
12
24
24
5
65
CH2Ph
Ph
4
6
46
6
7
48
Ph
10
6
8
57
Ph
9
CHCl3
toluene
Et2O
5
50
10
11
12
13
5
20
[a] Reaction conditions: 1a (0.1 mmol), 2a (0.1 mmol) and catalyst (5 mol%)
in 1 mL of CH2Cl2 at 20 °C. [b] Isolated yield after column chromatography.
[c] Determined by HPLC using chiral stationary phase. [d] The reaction was
performed with 10 mol% of E.
5
10
EtOAc
CCl4
5
33
4
10
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10.1002/ejoc.202001314
European Journal of Organic Chemistry
COMMUNICATION
Scheme 1. Scope of the aminoalkylation of 5-aminopyrazoles 2 with cyclic
imines 1. Reaction conditions: 1 (0.1 mmol), 2 (0.1 mmol) and E (5 mol%) in 1
mL of CH2Cl2 at 20 °C for 6 days. Isolated yield after column chromatography.
Enantiomeric excess determined by HPLC using chiral stationary phase.
With the optimized reaction conditions in hand, the scope of
the aminoalkylation reaction was studied (Scheme 1). First, we
evaluate the versatility of the benzoxathiazine 2,2-dioxides with 5-
amino-pyrazole 2d. Various substituents in the 6‐position in the
phenyl ring of the cyclic imines 1, such as Me, MeO, Br or NO2,
were well tolerated under the reaction conditions, and the
corresponding chiral sulfamidates 3 were obtained with good
yields (74–99ꢀ%) and in general high enantioselectivities (83–
99ꢀ%), although the presence of a NO2 group decreases the
enantiomeric excess to 41% ee. A cyclic imine bearing a
substituent in the 8 position gave product 3fd in 52% yield and
86% ee. However, the presence of a methoxy group in the 5
position led to a high decrease in the reactivity (29% yield), but
with good enantioselectivity (79% ee). Furthermore, cyclic imines
(1h-1i) with two substituents that provide steric hindrance, were
tested in the amino alkylation reaction. The presence of highly
steric groups such as tBu group reduces the reactivity (15% yield)
maintaining the enantioselectivity, however if the groups are
chlorine atoms the product 3id is obtained with good yield (75%)
but lower enantiomeric excess (68ꢀ%ꢀee).
We next turned our attention to further investigate the
substrate scope with respect to the 5-aminopyrazoles 2. First we
evaluate the effect of the substituents at the aromatic ring N-1 of
the 5-aminopyrazoles (3af-3ah). The reaction proceeded with
good yields and good enantioselectivities when the substituents
at the aromatic ring of N-1 are Me or Cl. However, the presence
of a MeO group at the aromatic ring of N-1 had a strong influence
obtaining the product as a racemic mixture. 1,3-dimethyl-N-
phenyl-1H-pyrazol-5-amine could be used as nucleophile,
although with moderate levels of enantioselectivity. Other alkyl
groups than Me are tolerated at the 3 position of the 5-
aminopyrazoles (3aj-3ak). Finally, we evaluate the effect of the
substituents at the exocyclic nitrogen. The presence of electron-
donating groups Me or MeO) decreases the enantioselectivity
maintaining good yields, while electron-withdrawing groups (Cl)
increases the enantiomeric excess (91% ee) although the
conversion is low.
O
O
R4
O
O
HN
E
(5 mol%)
20 ºC
S
R4
S
O
NH
HN
Furthermore,
we
performed
several
synthetic
O
N
+
R3
N
transformations with the chiral aminopyrazoles 3 (Scheme 4). We
carried out the reduction of the sulfamidate moiety[11p] of
compound 3ad using LiAlH4 obtaining the corresponding chiral
amine bearing a phenol and aminopyrazole moieties, which was
protected in situ as its Boc derivative 4, with good yield (62%) and
preserving the enantiomeric excess of compound 3ad (83% ee).
Finally, treatment of compounds 3aa and 3ad with
paraformaldehyde under acidic conditions led the formation of
aminopyrazole-sulfamidate fused tetracyclic compounds 5a and
5d with good yields and maintaining the enantiomeric excess
(Scheme 2).
R3
R1
N
N
N
CH2Cl2,
R1
R2
R2
1
2
3
benzoxathiazine 2,2-dioxide derivatives
O
O
O
O
O
O
S
S
Ph
S
Ph
O
NH
HN
O
NH
HN
Ph
O
NH
HN
Ph
Ph
N
N
N
N
Ph
N
N
Me
OMe
3cd
Me
Me
Me
3bd
O
3ad
, 83%, 83% ee
, 74%, 91% ee
, 77%, 99% ee
O
O
O
O
O
S
S
Ph
Ph
S
O
NH
HN
O
NH
HN
Ph
O
NH
HN
Me
Ph
Ph
N
N
N
N
Ph
N
N
Me
Me
Me
3fd
, 52%, 86% ee
Br
3dd
NO2
, 77%, 98% ee
O
3ed
, 99%, 41% ee
O
O
O
O
O
O
Boc
S
Boc
Ph
O
THF
Ph
HN
Me
S
NH
O
O
S
HN
HN
LiAlH4,
Ph
Ph
O
NH
HN
S
O
NH
HN
NH
O
Cl
tBu
HN Ph
Ph
Ph
N
N
N
Ph
Ph
N
N
N
N
then (Boc)2O
N
Ph
N
Me
OMe
N
Me
Me
Me
Cl
tBu
3hd
3ad
, 83% ee
4
, 62% yield, 83% ee
3id
, 29%, 79% ee
, 15%, 92% ee
, 75%, 68% ee
3gd
5-aminopyrazole derivatives
O
O
O
O
O
O
O
O
O
O
S
S
S
R
N
S
S
Me
Ph
Ph
NH
R
O
NH
O
Ph
HN
H
CH3CO2
HN
HN
NH
HN
O
NH
O
N
N
O
n
+
(HCHO)
Me
OMe
Cl
N
N
N
N
Ph
N
N
Ph
CH2Cl
N
N
2,0ºC to rt
Me
Me
3af
N
Me
3ah
Me
Me
, 77%, 74% ee
3ag
, 68%, 0% ee
, 60%, 80% ee
3aa
3ad
, R= H, 65% ee
, R= Ph, 83% ee
5a
5d
, R= H, 49% yield, 59% ee
, R= Ph, 84% yield, 84% ee
O
O
S
O
S
O
O O
S
Ph
Ph
Ph
NH
HN
O
NH
HN
O
NH
HN
O
Cl
Ph
N
N
Me
N
N
N
Scheme 2. Synthetic transformations of chiral 5-aminopyrazoles.
N
Me
Pr
3ai
, 60%, 61% ee
O
3aj
3ak
, 77%, 78% ee
,
37%, 70% ee
O
O
O
O
O
Br
OMe
The absolute configuration of the stereogenic centre in
compound 3ad was determined to be (S) on the basis of X-ray
crystallographic analysis (Scheme 3); the configurations of the
rest of the products 3 were assigned on the assumption of a
uniform mechanistic pathway.[14] A plausible transition-state
model is depicted in Scheme 5. The chiral squaramide acts as
Me
S
S
S
O
NH
HN
O
NH
O
NH
HN
HN
Cl
Ph
N
N
Ph
N
N
N
N
Me
3an
Me
Me
,
28%, 91% ee
3lk
3am
, 67%, 18% ee
, 99%, 66% ee
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10.1002/ejoc.202001314
European Journal of Organic Chemistry
COMMUNICATION
[2]
[3]
E. Vitaku, D. T. Smith, J. T. Njardarson, J. Med. Chem. 2014, 57, 10257-
10274.
bifunctional organocatalyst responsible for the preorientation and
the activation of the substrates. While the benzoxathiazine is
activated upon formation of hydrogen bonds between the nitrogen
and one oxygen of the cyclic imine and the squaramide,[15] the 5-
aminopyrazole undergoes nucleophilic activation by hydrogen
bonding with the quinuclidine moiety of the catalyst. The
nucleophilic attack of the 5-aminopyrazole will be directed to the
Si-face of the cyclic imine, thus accounting for the observed
enantioselectivity. The low conformational mobility and the
impossibility of E/Z isomerization of the double bond of the imine
1 is very important for the enantioselectivity of the reaction. When
the reaction was performed with N-tosylimine prepared from
benzaldehyde the reaction took place with good yield (72%) but
as a racemic mixture after 2 days of reaction.
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N
O
O
OMe
H
Ph
N
H
tBu
H
O
S
O
N
NH
HN
N
[7]
Ph
H
N
O
H
O
O
N
N
N
Ph
Ph
S
H
O
Me
N
Me
N
Si-face attack
Scheme 3. X-ray structure of 3ad and plausible transition-state model.
Conclusions
In conclusion, we have successfully developed an organocatalytic
enantioselective aminoalkylation of 5-aminopyrazole derivatives
[8]
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Eur. J. Org. Chem. 2019, 3040-3044.
with cyclic imines using
a
quinine-derived squaramide
organocatalyst, obtaining the corresponding chiral sulfamidates
bearing a 5-aminopyrazole moiety with good yields (up to 97%)
and moderate to excellent enantioselectivities (up to 99% ee)
under mild reaction conditions. Studies to further extend the
scope of this reaction are currently underway in our laboratory.
[9]
L. De Munck, C. Vila, J. R. Pedro, in Targets in Heterocyclic Chemistry,
Ed. O. A. Attanasi, P. Merino and D. Spinelli, Società Chimica Italiana,
2017, p. 137.
Acknowledgements
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Financial support from the Agencia Estatal de Investigación (AEI,
Spanish Government) and Fondo Europeo de Desarrollo
Regional (FEDER, European Union) (CTQ2017-84900-P) is
acknowledged. L. C. thanks the Universitat de València for a
predoctoral grant. C.V. thanks the Spanish Government for RyC
contract (RYC-2016-20187). Access to NMR, MS and X-ray
facilities from the Servei Central de Suport a la Investigació
Experimental (SCSIE)-UV is also acknowledged.
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Keywords: asymmetric catalysis • nitrogen heterocycles •
pyrazoles • organocatalysis • cyclic imines
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10.1002/ejoc.202001314
European Journal of Organic Chemistry
COMMUNICATION
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[14] CCDC 2024661 (3ad) contains the supplementary crystallographic data
for this paper. These data can be obtained free of charge from The
Cambridge
Crystallographic
Data
Centre via www.ccdc.cam.ac.uk/data_request/cif.
[15] Benzoxathiazine can also make different hydrogen bonds with the chiral
bifunctional organocatalyst, however we have hypothesized the cyclic
transition state-model that have been previously described in the
literature, see references: 11k, 11n and 11q.
[12] For further optimization of organocatalyst see the supporting information.
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10.1002/ejoc.202001314
European Journal of Organic Chemistry
COMMUNICATION
Entry for the Table of Contents (Please choose one layout)
Layout 2:
COMMUNICATION
Organocatalytic Enantioselective
Aminoalkylation of 5-Aminopyrazole
derivatives with Cyclic Imines
O
O
chiral squaramide
R4
O
O
HN
S
R4
S
NH
O
HN
N
O
(5 mol%)
+
R3
N
20 ºC
R3
Laura Carceller-Ferrer,[a] Aleix González
del Campo,[a] Carlos Vila,[a] Gonzalo
Blay,*[a] M. Carmen Muñoz[b] and José
R. Pedro*[a]
R1
N
N
N
CH2Cl2,
R1
R2
R2
22 examples
good yields (up to 99%)
high ee (up to 99%)
5-aminopyrazole as nucleophile
in asymmetric catalysis
Text for Table of Contents
Page No. – Page No.
The first enantioselective alkylation of 5-aminopyrazoles is described with good results. The
organocatalytic alkylation of 5-aminopyrazoles have been acomplished using benzoxathiazine 2,2-
dioxides as electrophiles and a bifunctional squaramide organocatalyst.
*one or two words that highlight the emphasis of the paper or the field of the study: Organocatalysis
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