Dihydropyrrolo[1,2-b]pyrazoles: Withasomnine and related compounds

Article abstract of DOI:10.1016/j.tet.2013.06.009

In the paper we indicate the increasing importance of derivatives containing a dihydropyrrolo[1,2-b]pyrazole (DPP) core. We try to show our synthetic approach based on an improved Kulinkovich method as well as our new synthetic pathway. A complex methodology involving the preparation of substituted DPPs focuses on withasomnine and the synthesis of several structurally related compounds. The developed reaction protocols enable the preparation of the mentioned bicyclic system with broadly diverse substitution. Thus, we are able to prepare systems with aliphatic, aromatic, polyaromatic, heteroaromatic, TMS, and even adamantane substitution with known biologically active properties. The reaction protocol, consisting of two multi-step synthetic pathways, includes Sonogashira and Suzuki-Miyaura cross-coupling reactions, allenyl synthon formation, Kulinkovich cyclopropanation, ring transformations, and nonsymmetrical homoallenyl azines cycloadditions. Moreover, we prepared compounds with a resemblance to other bioactive species: fadrozole, nagstatine, an antitumor agent LY2109761 and a mixed lineage kinase 7 inhibitor DHP-2.

Full text of DOI:10.1016/j.tet.2013.06.009

Accepted Manuscript
Dihydropyrrolo[1,2-b]pyrazoles: withasomnine and related compounds
Juraj Galeta, Luká š Tenora, Stanislav Man, Milan Potá ček
PII:
S0040-4020(13)00927-7
10.1016/j.tet.2013.06.009
TET 24485
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 7 March 2013
Revised Date: 22 May 2013
Accepted Date: 3 June 2013
Please cite this article as: Galeta J, Tenora L, Man S, Potá ček M, Dihydropyrrolo[1,2-b]pyrazoles:
withasomnine and related compounds, Tetrahedron (2013), doi: 10.1016/j.tet.2013.06.009.
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withasomnine and related compounds
Juraj Galeta, Lukáš Tenora, Stanislav Man and Milan Potáček*
Department of Chemistry, Faculty of Science, Masaryk University, Kotlářská 2, 611 37 Brno, Czech Republic

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1
Tetrahedron
journal homepage: www.elsevier.com
Dihydropyrrolo[1,2-b]pyrazoles: withasomnine and related compounds
Juraj Galeta, Lukáš Tenora, Stanislav Man and Milan Potáček*
Department of Chemistry, Faculty of Science, Masaryk University, Kotlářská 2, 611 37 Brno, Czech Republic
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
In the paper we indicate the increasing importance of derivatives containing a
dihydropyrrolo[1,2-b]pyrazole (DPP) core. We try to show our synthetic approach based on an
improved Kulinkovich method as well as our new synthetic pathway. A complex methodology
involving the preparation of substituted DPPs focuses on withasomnine and the synthesis of
several structurally related compounds. The developed reaction protocols enable the preparation
of the mentioned bicyclic system with broadly diverse substitution. Thus, we are able to prepare
systems with aliphatic, aromatic, polyaromatic, heteroaromatic, TMS, and even adamantane
substitution with known biologically active properties. The reaction protocol, consisting of two
multi-step synthetic pathways, includes Sonogashira and Suzuki-Miyaura cross-coupling
reactions, allenyl synthon formation, Kulinkovich cyclopropanation, ring transformations, and
nonsymmetrical homoallenyl azines cycloadditions. Moreover, we prepared compounds with a
resemblance to other bioactive species: fadrozole, nagstatine, an antitumor agent LY2109761
and a mixed lineage kinase 7 inhibitor DHP-2.
Available online
Keywords:
allenyl azine
withasomnine
cycloaddition
dihydropyrrolo[1,2-b]pyrazole
Kulinkovich
2
009 Elsevier Ltd. All rights reserved.
1. Introduction
The preparation and investigation of the reactivity of
nonsymmetrical and symmetrical allenyl azines 1 and 2 have a
tradition in our laboratory (Fig. 1). The presence of a dipole and
Small biologically active molecules that mimic natural
2
products are nowadays being produced and tested by many
research groups. This has led to the concept of function-oriented
synthesis introduced recently by Paul Wender, who simplified
analogues of biologically active natural products by means of
dipolarophile within one molecule is a very potent combination
for heterocyclic chemistry. Thus, during our research we have
published papers dealing with the first example of the
intramolecular criss-cross cycloaddition of symmetrical azines 2
leading to products 5 with four fused centrally connected five-
1
step-economy synthesis. These products exhibited preserved or
even superior activities to those of the natural products. In this
regard we have investigated a comprehensive methodology for
the synthesis of dihydropyrrolo[1,2-b]pyrazoles (DPP) consisting
of two multi-step reaction pathways. One of them is based on the
application of the allene synthon.
3a
membered rings , as well as criss-cross cycloaddition reactions
of nonsymmetrical azines
1 with various dipolarophiles,
3b
combining both an intra- and intermolecular approach. The
latter resulted in heterocycles 4 with three fused five-membered
rings. Moreover, in some cases we were even able to isolate
3
b-d
stable bicyclic systems 3 with a DPP core,
identical to that of
naturally occurring plant alkaloid withasomnine 6 (Fig. 2).
Fig. 2. Bioactive withasomnine 6, fadrozole 7 and nagstatine 8.
Compound 6 was originally isolated in 1966 from the root
bark of Withania Somnifera (Solanaceae). It exhibited a
depression of the CNS and circulatory systems, a mild analgesic
effect, narcosis in higher doses, and the inhibition of
4
Fig. 1. Thermally initiated cycloadditions of homoallenyl azines 1 and 2
leading to bi-, tri- and tetracyclic heterocycles.
cyclooxygenase 1 and 2 (COX-1 and COX-2) and leukotriene B
4
—
——
5
6
(
LTB ) metabolism. There are several reports on the synthesis
4
*
Corresponding author: Tel.: +420 549 496 615; fax: +420 549 492 688; e-
7a
of 6 and, recently, Ichikawa with co-workers applied several
mail address: potacek@mail.muni.cz
synthetic steps including a regioselective Claisen rearrangement

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2
Tetrahedron 7c
of their prepared 4-O-allyl-4-hydroxy-1H-pyrazoles in very
paper, where bromine was used in 80 % aq. iPrOH, did not
work. We observed just traces of the desired product only with
the majority of 11. Product 12 was not purified and treatment
with TEA (2 eq.) afforded 6-chlorohex-1-en-3-one (14) in an
almost quantitative yield (2 h). Using less than 2 eq. of TEA led
to a significantly increased reaction time (>10 h). After vacuum
distillation of 14 we isolated a colorless liquid in 78 % yield with
respect to 9. The following 3-substituted pyrazole ring formation
(15) and its intramolecular cyclization afforded under basic
conditions a key non-substituted intermediate 16 – 5,6-dihydro-
4H-pyrrolo[1,2-b]pyrazole. Although the bromination of such a
7b
good overall yields. Foster et al. reported the divergent
synthesis of 6 via sydnone-alkynylboronate cycloaddition. More
7
c
than 15 years ago, Kulinkovich published a synthetic protocol
but without any experimental evidence or spectroscopic
characterizations of synthesized compounds. Thus, we decided to
re-examine and improve this synthesis with full identifications of
intermediates and products. Fadrazole 7 appeared as another
biologically active compound, which is a potent, selective,
nonsteroidal aromatase inhibitor (type II). It suppresses estrogen
production when administered orally and in this way works as a
suitable candidate for testing as a potential aromatase inhibitor in
structure in position 3 is described with Br
2
/ NaOAc in 60 %
8
7c
estrogen-dependent diseases, including breast cancer. Moreover,
AcOH, we successfuly utilized NBS (1 eq.) in CHCl at room
3
a
further similarity was found with the imidazole-sugar
temperature and after 5 min we observed the formation of a pure
light yellow solid 17 in 77 % yield with respect to 14. The overall
yield of this six-step synthesis is 60 % (see Experimental
Section) with a significantly reduced reaction time compared to a
9
nagstatine 8 (a natural product and a very potent inhibitor of
some glucosaminidases) and similar compounds. An alicyclic
side chain fused to the nitrogen-containing heterocycle is also
known from the chemistry of cannabinoid antagonist analogues.
In view of the beneficial pharmacological properties of CB
10
11
7c
published procedure.
1
receptor ligands (G-protein-coupled membrane receptors
primarily present in the central nervous system) in the treatment
1
2
of a number of diseases, a major aim in medicinal chemistry is
the development of novel CB cannabinoid receptor ligands
1
exhibiting more favorable pharmacological features. It is worth
noting that the 2012 Nobel Prize in Chemistry was awarded for
work on G-protein-coupled receptors.
1
1
N
N
N
N
2
N
2
N
3
3
O
N
N
N
O
LY2109761
DHP-2
F
NH2
Fig. 3. Bioactive compounds LY2109761 and DHP-2 with DPP core.
One can find several other papers dealing with bioactive
1
3
molecules containing a DPP core. We chose two potent
1
3f,g
13c
examples, LY2109761
(an antitumor agent) and DHP-2
(
7
Fig. 3) as a selective inhibitor of MLK7 (mixed lineage kinase
), which is a mitogen-activated protein kinase (MAPK).
14
Scheme 1. Six synthetic steps to brominated heterocycle 17
from ester 9 in 60 % overall yield. Scheme also includes
trasformations of γ-butyrolactone 18 into pyrazole
MAPKs are a highly conserved family of signal transduction
molecules that transmit extracellular signals from the membrane
to the nucleus. Such small molecules deserve attention, especially
with respect to recognizing and specifying their potential
intermediate 15. Reagents and conditions: (i) Ti(iPrO)
eq.), EtMgBr (2 eq.), Et O, r.t., overnight; (ii) few days
standing at the room temperature; (iii) Br (1.1 eq.), K CO
(1.2 eq.), DCM, 0 °C, 1.5 h; (iv) N .H O (2 eq.), DCM,
reflux, 4 h, 70 % from 9; (v) Et N (2 eq.), Et O, r.t., 2 h, 78 %
from 9; (vi) 1. KBr (1.1 eq.), 80 % iPrOH, 0 °C, 1 h; 2.
.H O (5 eq.), 80 % iPrOH, r.t., overnight; (vii) KOH (1.1
eq.), 80 % iPrOH, reflux, 4 h; (viii) NBS (1.1 eq.), CHCl , r.t.,
5 min, 77 % from 14; (ix) SOCl (2.5 eq.), ZnCl (0.08 eq.),
5 °C, 20 h, 75 %; (x) vinylMgBr (1 eq.), THF, -78 °C, 3 h
4
(0.1
1
6
2
applications and benefits.
2
2
3
2. Results and discussion
2
H
4
2
3
2
In this paper, we present two approaches to a series of
3
variously substituted DPPs. The first pathway is represented by a
modified Kulinkovich procedure consisting of
cyclopropanation / ring transformation / aromatization / bicyclic
N
2
H
4
2
a
3
7
c
2
2
skeleton formation in the reaction cascade (Scheme 1). We
investigated this convenient synthetic procedure more deeply and
made several changes and improvements. The first and a key step
5
2
and then SOCl ; (xi) 19 (1.1 eq.), DMF (1.2 eq.), vinylMgBr
(1 eq.), PhCH , -5 °C, 4 h; (xii) ethynylMgBr (1 eq.), CuI
3
1
7
in the method is the Kulinkovich reaction (cyclopropanation) of
ester 9 in the presence of EtMgBr with 10 mol% of Ti(iPrO) in
Et O. However, cyclopropanol 10 was unstable, even in
(
0.08 eq.), THF, 0 °C, 2 h, 52 %; (xiii) Br
2
(1 eq.), CCl
4
, r.t.,
4
3
7
0 min, 93 %; (xiv) N H .H O (5 eq.), 80 % iPrOH, r.t., 14 h,
0 %.
2
4
2
2
refrigerated conditions, and within several hours the formation of
stable ketone 11 was observed. This transformation took several
days at room temperature to be completed. Therefore, compound
Another source for the synthesis of the required compound 14
is the inexpensive compound γ-butyrolactone (18) via 4-
chlorobutanoyl chloride (19) by means of ring opening by
10 was immediately used in the following reaction step without
purification. Here, the ring opening step proceeds with bromine
19
SOCl2 and a subsequent reaction with vinyl magnesium
1
8
2 3
in the presence of K CO in DCM (retro-Barbier fragmentation )
bromide. Because the same ring opening leading to 14 by a
affording a brownish liquid 12 – 1-bromo-6-chlorohexan-3-one.
It is worth noting that the reaction protocol from the original
20
Grignard reagent is described in the literature, we utilized

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3
vinylmagnesium bromide with the idea of simplifying the whole
procedure. However, several attempts to perform this reaction
failed. A different situation occured with ethynylmagnesium
bromide, where, surprisingly, the reaction worked and 6-
chlorohex-1-yn-3-one (20) was isolated in 52 % yield. Following
this, an almost quantitative addition of bromine to the triple bond
was performed affording dibromo derivative 21 in 30 min. Both,
cis and trans isomers in the ratio ~ 3 : 7 were isolated. Our
intention to synthesize substituted pyrazole 22 bearing bromine
at the desired position by the reaction with hydrazine hydrate
failed and, surprisingly, we obtained only non-brominated
pyrazole 15 (70 %). Nevertheless, we have already described its
cyclization to compound 16 and transformation to 3-brominated
DPP 17. The final step to obtaining withasomnine 6 was a Suzuki
– Miyaura coupling reaction of brominated pyrazole 17 with
substituted boronic acids (Table 1).
Table 1. Overview of optimization conditions used in Suzuki–Miyaura coupling reactions of brominated heterocycle 17*
Reaction time Conversion
Yield
[mg (%)]
Biphenyl
[mg]
Entry
R
Solvent
T [°C]
Catalyst
Mol%
[
h]
[%]
1
2
3
4
5
6
7
8
9
.
.
.
.
.
.
.
.
.
Ph
MeOH
THF
reflux
reflux
110
reflux
110
110
110
110
110
110
110
110
110
110
110
90
PdCl
PdCl
PdCl
PdCl
2
2
2
2
(PPh
(PPh
(PPh
(PPh
3
3
3
3
)
)
)
)
2
2
2
2
5
5
5
5
5
2
1
5
5
5
5
2
2
2
5
20
4
NR
NR
50
-
-
-
Ph
24
5
-
Ph
PhCH
3
-
-
Ph
Ph
Xylene
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
2.5
0.25
1
100
100
100
<80
100
<50
<50
NR
100
100
100
NR
NR
53 (57)
28
11
11
-
Pd(PPh
Pd(PPh
Pd(PPh
Pd(dppf)Cl
Pd(OAc)
Pd(dba)
NiCl (PPh
3
)
4
59 (64)
Ph
3
)
4
58 (63)
Ph
3
)
4
6
-
Ph
2
2.5
6
41 (45)
6
Ph
2
-
-
1
1
1
1
1
1
1
0.
1.
2.
3.
4.
5.
6.
Ph
2
6
-
-
Ph
2
3
)
2
7
-
60 (55)
72 (79)
107 (70)
-
-
4-Cl-Ph
4-Pyridine
1-Pyrenyl
Cyclohexyl
Pd(PPh
Pd(PPh
Pd(PPh
3
3
3
)
4
4
4
1.5
1
10
8
)
)
1
20
-
Pd(PPh
3
)
4
3
Cyclohexyl Dioxane
Pd(dppf)Cl
2
24
-
-
*
2
reactant 17 (0.5 mmol), RB(OH) (0.75 mmol), 5 ml of solvent, preheated oil bath; NR = no reaction.
2
1
Initially, we utilized conditions from literature , in which
we tested several palladium catalysts in different loadings (2–5
mol%). Later, we made some corrections to make this reaction
applicable for all the used boronic acids. Reaction with
phenylboronic acid (entries 1–11; Table 1) served as a model
reaction. During testing, our attention was devoted to the
solvent (DMF, xylene, dioxane, THF, methanol), the
temperature, and the reaction time (0.25–24 h). Full conversion
the cyclohexyl substitution to our skeleton failed (entries 15,
16). Moreover, along with the Suzuki product we observed the
characteristic formation of side biphenyl compounds arising
from boronic acid and a phenyl group from the catalyst
(biphenyl, 4-chlorobiphenyl, etc). These structures were
confirmed by NMR and GC–MS after separation.
We have already mentioned two examples of potent
bioactive compounds (Fig. 3) with a DPP core. The aim is to
broaden this area and to continue in successfully utilizing small
was observed with three Pd-catalysts
Pd(dppf)Cl and Pd(PPh in 45–64 % yield within 0.25–2.5 h.
The remaining catalysts (Pd(OAc) , Pd(dba) ) showed lower
– PdCl (PPh ) ,
2 3 2
2
3
)
4
22
molecules, such as dorsomorphin. Thus, beside withasomnine
2
2
6
and its analogues (23a-c), we examined the preparation of
conversions and NiCl
on the performed reactions, we chose as optimal conditions 2
mol% Pd(PPh in DMF at 110 °C. These conditions were
succesfully applied with other boronic acids – 4-chlorophenyl
2 3 2
(PPh ) did not react at all. Thus, based
similar bicyclic compounds bearing two methyl groups at C5
and various substitutions at C2 and C4 (aliphatic, aromatic,
polyaromatic, heteroaromatic, TMS, 1-adamantyl). These
derivatives 25 were prepared by the thermally initiated
intramolecular cycloaddition of nonsymmetrical homoallenyl
3 2
)
(
(
(
entry 12, 55 %), 4-pyridine (entry 13, 79 %) and 1-pyrene
entry 14, 70 %). The reaction time did not exceed 90 min
Table 1). When the concentration of catalyst was increased to
23
azines 24 (Scheme 2).
5
mol%, the reaction worked four times faster but with the
same result (compare entry 5 vs 6). Moreover, several attempts
at using microwave irradiation yielded much lower
conversions than the reactions with conventional heating. After
9
0 min with 5 mol% of Pd(PPh ) we isolated just 37 % of
3 4
Scheme 2. Intramolecular cycloaddition of nonsymmetrical
homoallenyl azines 24 to 2,4-disubstituted-3,3-dimethyl-
desired product 6, and a prolongation of the reaction time led
to unspecified slow decomposition. Any attempt to introduce
5
,6-dihydro-4H-pyrrolo[1,2-b]pyrazoles 25.

ACCEPTED MANUSCRIPT
4
Tetrahedron
Their formation was observed for the first time by Man et
3
b
al. during his work on combined intra-intermolecular criss-
cross cycloadditions of azines 24 with PhNCO. In summary,
we prepared in this way a library of 49 such structures (Table
2)
with full identification and characterization (see
Supplementary Information). The products 25aa-ae with
aliphatic substitution afforded the lowest yields because of
their difficult purification connected with their liquid character
and non-absorbing (254 nm) properties. Products 25ao-bc are
illustrative examples suggesting a general trend in the
reactivities of homoallenyl azines 24. In other words, the
substitution at the allene moiety (R) plays a crucial role, and
methyl (or ethyl)-substituted compounds, compared to non-
substituted ones, react much faster and almost always in higher
yields (25ao in 59 %; 25ap in 82 %). The purity of the starting
material also has a significant influence upon the results.
Differential scanning calorimetry identified the most effective
temperature for each of the derivatives with different p-
substitution. The ideal temperature for this kind of
cycloaddition was around 180 °C; however, for nitro-
derivatives, it was less than 150 °C. This fact is reflected in
much shorter reaction times (25ao in 9 h; 25bb in 30 min). An
analogous conclusion can be found for 2-thiophenyl (25bd,be),
Scheme 3. Proposed mechanism for the formation of
unexpected product 25al via proton migration and
aromatization after amine elimination. The same
transformation was observed with the morpholinomethyl
substitution.
2
(
-furyl (25bg,bh), 1-naphthyl (25bj,bk) and 9-anthryl
25bm,bn) substitutions. In addition, anthryl analogues possess
a very intensive fluorescence (Fig. 4), which can be utilized in
A considerable decomposition was observed along the
formation
of
derivatives
containing
TMS
group
(
25bf,bi,bl,bo). Thus, these reactions were carried out at a
2
4
fluorescent labeling as a fluorescence probe. After the
incorporation of hydroxymethyl or a similar substitution on the
alicyclic side chain, we plan to test its ability as a DNA-
lower temperature (110 °C), which was reflected in the time
prolongation (7.5 – 10 h); however, still low yields were
produced (up to 29 % for 25bf). Bromination with NBS carried
out on selected dimethylated 25ap and 25ba afforded
brominated products 25bx and 25by in high yields. Subsequent
application of optimized conditions for Suzuki coupling (Table
2
5
intercalator.
1) was examined on 25by and again we obtained the desired
product 25bz in very good yield. The structure of such systems
was demonstrated by several crystallographic analyses (Fig. 4
and 5 and Supplementary Information).
Fig. 4. ORTEP representation and fluorescence of 25bm at 366 nm.
Since we are also interested in the chemistry of adamantane,
we decided to combine its characteristic features with
heterocyclic compounds in an attempt to achieve biologically
potent systems. Adamantane has interested chemists for almost
2
6
80
years
and its derivatives have found numerous
27 28
applications in medicinal and material sciences. Since the
discovery of the potent inhibitory properties of
Fig. 5. ORTEP illustrations of 25aj and 25bd crystal structures.
3. Conclusions
2
9
amantadin against several types of viruses in the early 1960s,
a large number of investigations have been initiated. In the
light of these, we prepared new adamantane-containing
heterocycles 25af-am, which appeared as colorless solids.
Moreover, the reaction leading to products 25aj and 25ak
afforded an unexpected bicyclic compound 25al with an
exocyclic double bond at C4 (Scheme 3). To explain its
formation, we propose a mechanism in which we assume that
the dipolar intermediate can be transformed via two pathways.
Here, the formation of 25al may be explained by an
intramolecular attack of a nitrogen atom from the azine
skeleton on the allenyl group producing a bicyclic 1,3-dipole.
However, the electronegative nitrogen atom of pyrrolidine
promotes a 1,5-proton shift followed by aromatization after
amine elimination. This assumption is strongly supported by
We investigated two reaction pathways leading to a library of
58 dihydro-4H-pyrrolo[1,2-b]pyrazole target compounds. With
the utilization of the improved Kulinkovich protocol, the first
path yielded the withasomnine alkaloid (6) and three related
structures (23a-c). We optimized this synthesis and fully
characterized both the isolated intermediates and final
compounds. We are able to synthesize 3-bromo-5,6-dihydro-
4
H-pyrrolo[1,2-b]pyrazole (17) from cheap and accessible
ethyl 4-chlorobutyrate (9) in less than 48 hours in 60 % overall
yield. This means an almost 92 % average yield for all six
steps. Optimized conditions for Suzuki-Miyaura coupling
reactions now enable us to prepare the desired substituted
withasomnines in up to 90 minutes. Another reaction pathway
allowed us to produce analogous dimethylated compounds by
the intramolecular cycloaddition of nonsymmetrical
homoallenyl azines 24. The broad usefulness of such a reaction
is supported by the diverse substitution of the formed products.
We demonstrated possible applications of molecules bearing
polycyclic aromatic system in fluorescent labeling and even as
the experiment with D O, and similar products have also been
2
2
c
isolated during our previous work. The second pathway leads
3
d
to the expected products and is shown elsewhere.

ACCEPTED MANUSCRIPT
5
DNA-intercalators. We showed even biologically active
molecules with DPP core, which is another promising area of
continuing research. Nowadays, small molecules are being
intensively developed in many research groups and our method
is undoubtedly one of the most simple and accessible. We
hope that small molecules will one day bring answers to many
prominent questions.
Table 2. A comprehensive view of all prepared heterocyclic derivatives containing a DPP core with isolated yields and
corresponding CCDC numbers.
Isolated dihydropyrrolo[1,2-b]pyrazoles
N
N
17
Br
(77 % over 3 steps)
N
N
25bm (77 %)
CCDC 908401
N
N
NO2
N
O
25bw (84 %)
a
3d
Those two structures in rectangles have been published

ACCEPTED MANUSCRIPT
6
Tetrahedron
4
. Experimental section
monitored by TLC (DCM). The reaction was finished by the
addition of saturated aq Na (50 mL, gently exothermic)
and water (200 mL). The organic layer was separated and
washed with saturated aq Na (100 mL) and water (100
mL), dried over MgSO and concentrated in vacuo. The dark
red product (28.4 g) was used without further purification. H
NMR: δ = 3.51–3.63 (m, 4H, 2×CH ), 2.97–3.08 (m, 2H, CH ),
.59–2.70 (m, 2H, CH ), 2.01–2.14 (m, 2H, CH ); C NMR: δ
206.4 (C=O), 45.2 (CH ), 44.4 (CH ), 39.8 (CH ), 26.1
CH ), 25.4 (CH ); GC-MS m/z (%): 213 (M , < 1), 123 (16),
2 2 3
S O
4.1. General
2 2 3
S O
All reagents were purchased from commercial suppliers and
4
used as received. Diethylether and THF were distilled from
sodium/benzophenone before use. Chloroform was dried and
distilled from CaCl
1
2
2
2
and P
2
O
5
and stored over 4Å molecular
13
2
=
(
2
2
sieves. Xylene (mixture of isomers) was dried and distilled
from sodium/benzophenone and stored over dry 4Å molecular
sieves. All reactions were carried out under a dry argon
atmosphere and were monitored by TLC (Merck F254 silica
gel). Products were separated by preparative TLC or by liquid
chromatography on a Horizon HPFC System (Biotage, Inc.)
with Biotage Si 12+M and Si 25+M columns. Melting points
were determined on a MPV-HV2 melting point meter in open
capillaries. FT-IR spectra were recorded with a MIDAC
Corporation Spectrafile IR apparatus or with a GENESIS ATI
2
2
2
+
2
2
1
2
1
2
05 (63), 72 (46), 57 (47), 43 (100), 41 (63); FTIR (film):
966, 2924, 1719 (C=O), 1609, 1443, 1414, 1376, 1308, 1265,
212, 1095, 1012. HRMS m/z calcd. for
12.9676. Found: 212.9670.
6
C H10OClBr:
6-Chlorohex-1-en-3-one 14: Dry Et
35.0 mL) was added to compound 12 (0.127 mol, 27.0 g)
dissolved in dry Et O (250 mL) over the course of 30 min at
room temperature. The reaction mixture was stirred for 150
min and monitored by TLC (DCM). The precipitate was
3
N (0.254 mol, 25.4 g,
2
1
13
(
Unicam) spectrometer. H and C spectra were recorded
using a Bruker Avance 300 spectrometer operating at 300.13
MHz ( H) and 75.47 MHz ( C) with CDCl
Tetramethylsilane (δ 0.00 ppm) or residual protons (δ 7.27
ppm) served as internal standards for H NMR and CDCl
1
13
3
as solvent.
filtered and washed with Et
phases were washed with water (300 mL), brine (100 mL) and
again water (200 mL), dried over MgSO and concentrated in
2
O (100 mL). Combined organic
1
3
(δ
4
13
77.23 ppm) for C NMR spectra. GC-MS data were obtained
vacuo. The crude product was distilled with Kugelrohr
apparatus (55–60 °C, ~0.5 mbar) yielding a colorless liquid
(15.4 g, 78 % over 3 steps). H NMR: 6.22–6.33 (m, 1H,
=CH), 6.34 (d, J = 10.1, 1H, =CH
=CH
2.05–2.16 (m, 2H, CH
(=CH), 128.4 (=CH ), 44.4 (CH
MS m/z (%): 133 (M , 5), 97 (15), 70 (34), 55 (100), 41 (20);
FTIR (film): 2961, 2922, 1679 (C=O), 1617, 1443, 1406, 1267,
on a Shimadzu GCMS-QP2010 at 70 eV in the electron impact
mode. MS data were obtained on a Fisons Instruments TRIO
1
2
2
1000 spectrometer at 70 eV in the electron impact mode and by
2
), 5.86 (d, J = 10.1, 1H,
3
3
thermal desorption. Elemental analyses were performed with a
Perkin-Elmer CHN 2400 apparatus. High-resolution mass
spectra (HRMS) were recorded on a Q-TOF Micro micromass
instrument in the positive ESI (CV = 30 V) mode. X-ray
diffraction data were collected on a Kuma KM-4 four-circle
CCD diffractometer and corrected for Lorentz and polarization
effects. The structures were resolved by direct methods and
refined by full-matrix least-squares methods using the
2
), 3.61 (t, J = 6.3, 2H, CH
2
), 2.80 (t, J = 7.0, 2H, CH
2
),
1
3
2
); C NMR: δ = 199.4 (C=O), 136.5
), 36.2 (CH ), 26.5 (CH ); GC-
2
2
2
2
+
6 9
1210, 1098, 964. HRMS m/z calcd. for C H OCl: 133.0415.
Found: 133.0419.
3
0,31
3-(3-Chloropropyl)-1H-pyrazole 15: Compound 14 (0.115
mol, 15.3 g) was dissolved in a mixture of 2-propanol (400
mL) and water (20 mL). The reaction mixture was cooled
down to 0 °C by a water-ice-NaCl bath and a freshly prepared
SHELXTL program package.
in calculated idealized positions.
Hydrogen atoms were placed
1
-(3-Chloropropyl)cyclopropanol 10: Ethyl 4-chlorobutyrate
(0.166 mol, 25.0 g, 23.3 mL) was dissolved in dry Et O (100
(0.02 mol, 5.80 g, 6.04 mL) was added by
syringe over a period of 1 min. EtMgBr (0.349 mol, 46.5 g) in
Et O (120 mL) was added dropwise over the course of 70 min.
9
2
3
solution of KBr (0.127 mol, 35.4 g) in water (80 mL) – 1.15
mL) and Ti(Oi-Pr)
4
eq. of KBr and 1.1 eq. of bromine in water (~60 mL for 0.1
mol KBr) mixed for 30 minutes – was added over a period of
45 minutes. The reaction was left stirring at 0 °C for 1 h and
then allowed to warm up to ambient temperature over a period
of 1 h. Hydrazine monohydrate (0.577 mol, 28.9 g, 28.1 mL)
was slowly added (~15 min) and the reaction mixture was
stirred overnight (12 h). The solvent was removed under
reduced pressure and the residue was diluted with DCM (300
2
The reaction mixture was stirred at room temperature
overnight (17 h). The reaction was quenched by the slow
addition of saturated NH Cl (100 mL). The organic layer was
4
decanted and the solid residue was dissolved in a mixture of
water (200 mL) and 1M HCl (100 mL). Then it was extracted
by Et
by 300 mL of saturated NaCl, dried over MgSO
concentrated in vacuo. The crude product - bright yellow liquid
2
O (2 × 100 mL). Combined organic phases were washed
mL). The organic phase was washed with saturated Na
(60 mL), brine (60 mL) and water (60 mL), dried over MgSO
2
S
2
O
3
4
and
4
and concentrated in vacuo. The bright yellow liquid (16.5 g)
1
1
(
3
2
21.3 g) was used without further purification. H NMR: δ =
was used without further purification. H NMR: δ = 11.68 (bs,
3
3
3
.63 (t, J = 6.6, 2H, CH
2
Cl), 3.39 (bs, 1H, OH), 1.95–2.09 (m,
1H, NH), 7.52 (d, J = 1.8, 1H, CH), 6.12 (d, J = 1.8, 1H,
3
3
3
H, CH
2
CH
2
Cl), 1.68 (t, J = 7.0, 2H, CH
2
CH
-cp), 0.46 (t, J = 6.7, 2H, CH
), 35.4 (CH ), 29.3 (CH
); GC-MS m/z (%): 134 (M , < 1), 105 (87), 88 (100),
7 (26), 60 (33), 41 (68); FTIR (film): 3404, 3333, 3000, 2953,
2
CH
2
Cl), 0.72 (t,
CH), 3.56 (t, J = 6.4, 2H, CH
2.05–2.20 (m, 2H, CH
103.9 (CH), 44.3 (CH
(%): 145 (M , 5), 82 (100), 41 (12); FTIR (film): 2960, 2936,
2855, 2221, 1644, 1536, 1469, 1443, 1383, 1297, 1266, 1100,
2
), 2.88 (t, J = 7.4, 2H, CH
); C NMR: δ = 147.4 (C), 133.8 (CH),
2
),
3
3
13
13
J = 6.7, 2H, CH
2
2
-cp);
C
2
NMR: δ = 54.6 (C), 45.1 (CH
2×CH
2
2
2
), 13.3
2
), 32.4 (CH
2
), 24.3 (CH
2
); GC-MS m/z
+
+
(
7
2
2
850, 1451, 1381, 1295, 1246, 1142, 1106, 1011, 948, 931.
6 9 2
1050, 911. HRMS m/z calcd. for C H N Cl: 145.0527. Found:
145.0528.
1-Bromo-6-chlorohexan-3-one 12: Compound 10 (0.149 mol,
2
0.0 g) was dissolved in DCM (300 mL) and powdered K
2
CO
3
5,6-Dihydro-4H-pyrrolo[1,2-b]pyrazole 16: Compound 15
(0.111 mol, 16.0 g) was dissolved in a mixture of 2-propanol
(240 mL) and water (30 mL) and KOH (0.122 mol, 6.80 g) in
water (30 mL) was added. The reaction mixture was heated to
reflux for 4 h, then the solution was concentrated and the
residue was diluted by 50 ml of water. This suspension was
(
0.178 mol, 24.6 g) was added. The reaction mixture was
cooled down to 0 °C in a water-ice-NaCl bath. The solution of
bromine (0.163 mol, 26.1 g, 8.37 mL) in DCM (75 mL) was
added dropwise over the course of 80 min and the solution was
stirred at 0 °C for another 90 min. The reaction process was

ACCEPTED MANUSCRIPT
7
extracted with DCM (4 × 75 mL); the combined organic
extracts were dried over MgSO and concentrated under
1357, 1265, 1161, 1093, 1013; HRMS m/z calcd. for
35
4
C
12
H
12 ClN
2
: 219.0689. Found: 219.0687.
reduced pressure. The crude product (10.9 g of a light yellow
1
3-(Pyridin-4-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole
liquid) was used without further purification. H NMR: δ =
3
23b: 72 mg (79 %) of a white crystalline solid in 1 h; MP
1 3
7
.49 (s, 1H, CH), 5.94 (s, 1H, CH), 4.12 (t, J = 7.2, 2H,
1
02.9–104.5 °C; H NMR: δ = 8.53 (d, J = 6.2, 2H, Py), 7.90
NCH
NCH
2
), 2.84–2.92 (m, 2H, =C-CH
2
), 2.53–2.65 (m, 2H,
3
3
13
(s, 1H, N=CH), 7.31 (d, J = 6.2, 2H, Py), 4.20 (t, J = 7.3, 2H,
NCH ), 3.11–3.16 (m, 2H, =C-CH ), 2.69–2.77 (m, 2H,
NCH ); C NMR: δ = 150.4 (2×CH), 144.3 (N-C), 141.6
N=CH), 141.1 (C), 119.5 (2×CH), 113.1 (C-Py), 47.9 (CH ),
); GC-MS m/z (%): 185 (M , 100), 76
2
CH
2
); C NMR: δ = 145.7 (C), 143.8 (CH), 98.7 (CH),
+
2
2
4
1
1
1
7.6 (CH
2
), 26.6 (CH
2
), 23.0 (CH
2
); GC-MS m/z (%): 108 (M ,
13
2
CH
2
00), 80 (35), 52 (32); FTIR (film): 2954, 2920, 1614, 1453,
410, 1323, 1174, 1033, 943. HRMS m/z calcd. for C
09.0760. Found: 109.0765.
(
2
2
6
H
9
N
2
:
+
2 2
6.5 (CH ), 24.3 (CH
(
10); FTIR (KCl): 3051, 2981, 2927, 2902, 1545, 1494, 1469,
1439, 1408, 1364, 1315, 1221, 1158; HRMS m/z calcd. for
: 186.1031. Found: 186.1027.
3-Bromo-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole 17: The
bicyclic compound 16 (9 mmol, 973 mg) was dissolved in dry
CHCl (40 mL) and NBS (10 mmol, 1.73 g) was added. The
bright red reaction mixture was stirred for 30 minutes at room
temperature. The mixture was diluted in CHCl (20 mL),
washed with water (3 × 50 mL), dried over MgSO and
concentrated in vacuo. The crude brown solid was dissolved in
Et O and filtered through a thin layer of silica gel. Evaporation
11 12 3
C H N
3
3
1
1
-(Pyren-1-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole 23c:
07 mg (70 %) of a yellow crystalline solid in 1 h; MP 181.9–
3
1
3
82.6 °C; H NMR: δ = 8.29 (d, J = 9.2, 1H, Ar), 8.13–8.18
4
3
(
m, 3H, Ar), 8.04–8.08 (m, 3H, Ar), 7.99 (t, J = 7.6, 1H, Ar),
3
3
7
.94 (d, J = 7.8, 1H, Ar), 7.88 (s, 1H, N=CH), 4.30 (t, J = 7.3,
H, NCH ), 2.94–2.99 (m, 2H, =C-CH ), 2.66–2.74 (m, 2H,
CH ); C NMR: δ = 144.8 (N-C), 144.2 (N=CH), 131.7
C), 131.3 (C), 130.3 (2×C), 129.2 (C), 128.7 (C), 127.6
(3×CH), 127.3 (CH), 126.2 (CH), 125.4 (CH), 125.4 (C), 125.2
CH), 125.0 (CH), 124.9 (CH), 114.9 (C-Ar), 48.3 (CH ), 26.7
); GC-MS m/z (%): 312 (M , 100), 252 (11);
2
2
2
2
of the solvent afforded a light yellow crystalline product (1.43
g) in 77 % yield (MP 82.6–84.0 °C) from 14. It became dark
after standing at room temperature and at a lower temperature.
13
NCH
(
2
2
1
3
M.p. : 82.6–84.0 °C; H NMR: δ = 7.43 (s, 1H, CH), 4.16 (t, J
7.3, 2H, NCH ), 2.82–2.87 (m, 2H, =C-CH ), 2.58–2.66 (m,
); C NMR: δ = 144.8 (C), 143.9 (CH), 86.7 (C-
), 26.2 (CH ), 22.6 (CH ); GC-MS m/z (%): 188
M +1, 64), 186 (63), 107 (93), 80 (49), 51 (100); FTIR (KCl):
(
2
=
2
2
+
1
3
2 2
(CH ), 23.8 (CH
2
H, NCH
2 2
CH
FTIR (KCl): 3042, 2953, 2922, 2892, 1601, 1560, 1489, 1454,
1407, 1349, 1319, 1294, 1243, 1185, 1043; HRMS m/z calcd.
for C22H N : 309.1392. Found: 309.1381.
17 2
Br), 49.0 (CH
(
2
2
2
+
2
9
1
962, 2922, 2854, 1706, 1641, 1452, 1318, 1226, 1156, 1013,
86. HRMS m/z calcd. for C H N Br: 186.9871. Found:
6 8 2
86.9873.
Acknowledgements
4
.2. General procedure for the Suzuki-Miyaura coupling
This work was financially supported by the Grant Agency
of the Czech Republic (grant No. 203/09/1345). We are
grateful to Marek Nečas, Peter Bartoš, Gabriel Demo, Luboš
Prokeš and Lukáš Maier for crystallographic, GC-MS and
NMR measurements.
reactions
Compound 17 (0.50 mmol, 94 mg), the corresponding boronic
acid (0.75 mmol), and 2 mol% of Pd(PPh
mg) were dissolved in DMF (5 mL) and K
07 mg) in water (0.8 mL) was added. The reaction mixture
3
)
4
(0.010 mmol, 11
2
CO (1.50 mmol,
3
2
Supplementary data
was heated at 110 °C and monitored by TLC (AcOEt). The
mixture was filtered, diluted with 20 mL of DCM and
extracted with 10 mL of water. The organic phase was
The rest of experimental procedures and crystal structures,
1
13
full spectral characterizations, copies of H NMR and
C
separated, dried over MgSO
crude products were purified by column chromatography
AcOEt and AcOEt/MeOH = 3 : 1 for 23b).
4
and concentrated in vacuo. The
NMR spectra. Supplementary data related to this article can be
found at http://dx.doi.org/10.1016/j.tet.xxx
(
3-Phenyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole 6: 58 mg
References and notes
(
°
7
2
63 %) of a off-white crystalline solid in 1 h; MP 116.3–116.4
1
1
2
.
.
Wender, P. A.; Verma, V. A.; Paxton, T. J.; Pillow, T. H. Acc.
Chem. Res. 2008, 41, 40.
C; H NMR: δ = 7.81 (s, 1H, N=CH), 7.41–7.48 (m, 2H, Ph),
3
.31–7.40 (m, 2H, Ph), 7.15–7.22 (m, 1H, Ph), 4.17 (t, J = 7.3,
H, NCH ), 3.06–3.13 (m, 2H, =C-CH ), 2.62–2.74 (m, 2H,
CH ); C NMR: δ = 142.8 (N-C), 141.2 (N=CH), 133.7
C), 129.0 (2×CH), 125.9 (CH), 125.3 (2×CH), 115.6 (C-Ph),
(a) Zachová, H.; Man, S.; Nečas, M.; Potáček, M. Eur. J. Org.
Chem. 2005, 2548; (b) Man, S.; Nečas, M.; Bouillon, J.-P.;
Baillia, H.; Harakat, D., Potáček, M. Tetrahedron 2005, 61,
2387; (c) Galeta, J.; Man, S.; Bouillon, J.-P.; Potáček, M. Eur.
J. Org. Chem. 2011, 392.
(a) Potáček, M.; Marek, R.; Žák, Z.; Trottier, J.; Janoušek, Z.;
Viehe, H. G. Tetrahedron Lett. 1993, 34, 8341; (b) Man, S.;
Kulhánek, P.; Potáček, M.; Nečas, M. Tetrahedron Lett. 2002,
2
2
13
NCH
(
4
1
2
2
+
7.8 (CH
2 2 2
), 26.7 (CH ), 24.1 (CH ); GC-MS m/z (%): 184 (M ,
3
.
00), 156 (21), 148 (28), 115 (17), 102 (21), 77 (17); FTIR
KCl): 3054, 2986, 1608, 1422, 1266; HRMS m/z calcd. for
: 185.1079. Found: 185.1080.
(
12 13 2
C H N
4
3, 6431; (c) Man, S.; Nečas, M.; Bouillon, J.-P.; Portella, C.;
Potáček, M. Eur. J. Org. Chem. 2006, 3473; (d) Galeta, J.;
Man, S.; Potáček, M. Arkivoc 2009, Part (vi), 245.
Schröter, H.-B.; Neumann, D.; Katritzky, A. R.; Swinbourne, F.
J. Tetrahedron 1966, 22, 2895.
(a) Hueller, H.; Peters, R.; Scheler, W.; Schmidt, D.; Stremmel,
D. Pharmazie 1971, 26, 361; (b) Wube, A. A.; Wenzig, E.-M.;
Gibbons, S.; Asres, K.; Bauer, R.; Bucar, F. Phytochemistry
3
-(4-Chlorophenyl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole
23a: 60 mg (55 %) of a bright yellow crystalline solid in 1 h;
4
5
.
.
1
MP 111.3–113.2 °C; H NMR: δ = 7.77 (s, 1H, N=CH), 7.35
3
3
3
(
d, J = 8.5, 2H, Ar), 7.31 (d, J = 8.5, 2H, Ar), 4.17 (t, J =
7
2
1
.3, 2H, NCH
H, NCH CH
32.2 (C), 131.4 (C), 129.1 (2×CH), 126.4 (2×CH), 114.5 (C-
), 26.6 (CH ), 24.0 (CH ); GC-MS m/z (%): 218
M , 100), 127 (17), 77 (10); FTIR (KCl): 3051, 2976, 2962,
2
), 3.03–3.09 (m, 2H, =C-CH
); C NMR: δ = 142.8 (N-C), 141.0 (N=CH),
2
), 2.64–2.72 (m,
13
2
2
2
008, 69, 982.
6
.
(a) Onaka, T. Tetrahedron Lett. 1968, 9, 5711; (b) Takano, S.;
Imamura, Y.; Ogasawara, K. Heterocycles 1982, 19, 1223; (c)
Ranganathan, D.; Bamezai, S. Synth. Commun. 1985, 15, 259;
Ar), 47.8 (CH
(
2
2
2
+
(
d) Guzmán-Pérez, A.; Maldonado, L. A. Synth. Commun.
2930, 2897, 2874, 2858, 1603, 1560, 1491, 1456, 1421, 1396,

ACCEPTED MANUSCRIPT
8
Tetrahedron
1
991, 21, 1667; (e) Allin, S. M.; Barton, W. R. S.; Bowman,
17. (a) Kulinkovich, O. G.; Sviridov, S. V.; Vasilevskii, D. A.;
Pritytskaya, T. S. Zh. Org. Khim. 1989, 25, 2244; (b)
Kulinkovich, O. G.; de Meijere, A. Chem. Rev. 2000, 100,
2789.
18. Zhang, W.-C.; Li, C.-J. J. Org. Chem. 2000, 65, 5831.
19. Tran, J. A.; Chen, C. W.; Tucci, F. C.; Jiang, W.; Fleck, B. A.;
Chen, C. Bioorg. Med. Chem. Lett. 2008, 18, 1124.
20. (a) Yang, S.-B.; Gan, F.-F.; Chen, G.-J.; Xu, P.-F. Synlett 2008,
2532; (b) Cai, X.-C.; Wu, X.; Snider, B. B. Org. Lett. 2010, 12,
1600.
21. (a) Miyaura, N.; Yamada, K.; Suzuki, A. Tetrahedron Lett.
1979, 20, 3437; (b) Miyaura, N.; Suzuki, A. Chem. Rev. 1995,
95, 2457; (c) Jana, R.; Pathak, T. P.; Sigman, M. S. Chem. Rev.
2011, 111, 1417; (d) Anderson, E. D.; Boger, D. L. J. Am.
Chem. Soc. 2011, 133, 12285.
22. (a) Zhou, G.; Myers, R.; Li, Y.; Chen, Y.; Shen, X.; Fenyk-
Melody, J.; Wu, M.; Ventre, J.; Doebber, T.; Fujii, N.; Musi,
N.; Hirshman, M. F.; Goodyear, L. J.; Moller, D. E. J. Clin.
Invest. 2001, 108, 1167; (b) Gao, Y.; Zhou, Y.; Xu, A.; Wu, D.
Biol. Pharm. Bull. 2008, 31, 1716; (c) Hao, J.; Ho, J. N.; Lewis,
J. A.; Karim, K. A.; Daniels, R. N.; Gentry, P. R.; Hopkins, C.
R.; Lindsley, C. W.; Hong, C. C. ACS Chem. Biol. 2010, 5, 245;
(d) Cross, E. E.; Thomason, R. T.; Martinez, M.; Hopkins, C.
R.; Hong, C. C.; Bader, D. M. ACS Chem. Biol. 2011, 6, 952;
(e) Hao, J.; Daleo, M. A.; Murphy, C. K.; Yu, P. B.; Ho, J. N.;
Hu, J.; Peterson, R. T.; Hatzopoulos, A. K.; Hong, C. C. PLoS
One 2008, 3, e2904.
W. R.; McInally, T. Tetrahedron Lett. 2002, 43, 4191.
(a) Ichikawa, H.; Watanabe, R.; Fujino, Y.; Usami, Y.
Tetrahedron Lett. 2011, 52, 4448; (b) Foster, R. S.; Huang, J.;
Vivat, J. F.; Browne, D. L.; Harrity, J. P. A. Org. Biomol.
Chem. 2009, 7, 4052; (c) Kulinkovich, O.; Masalov, N.;
Tyvorskii, V.; De Kimpe, N.; Keppens, M. Tetrahedron Lett.
7
8
.
.
1
996, 37, 1095.
(a) Browne, L. J.; Gude, C.; Rodriguez, H.; Steele, R. E. J.
Med. Chem. 1991, 34, 725; (b) Dowsett, M.; Smithers, D.;
Moore, J.; Trunet, P. F.; Coombes, R. C.; Powles, T. J.; Rubens,
R.; Smith, I. E. Eur. J. Cancer 1994, 30, 1453; (c) Buzdar, A.
U.; Smith, R.; Vogel, C.; Bonomi, P.; Keller, A. M.; Favis, G.;
Mulagha, M.; Cooper, J. Cancer 1996, 77, 2503; (d)
Villeneuve, D. L.; Larkin, P.; Knoebl, I.; Miracle, A. L.; Kahl,
M. D.; Jensen, K. M.; Makynen, E. A.; Durhan, E. J.; Carter, B.
J.; Denslow, N. D.; Ankley, G. T. Environ. Sci. Technol. 2007,
4
1, 321; (e) Langlois, V. S.; Duarte-Guterman, P.; Ing, S.;
Pauli, B. D.; Cooke, G. M.; Trudeau, V. L. Gen. Comp.
Endocrinol. 2010, 166, 417; (f) Roumen, L.; Peeters, J. W.;
Emmen, J. M. A.; Beugels, I. P. E.; Custers, E. M. G.; de
Gooyer, M.; Plate, R.; Pieterse, K.; Hilbers, P. A. J.; Smits, J. F.
M.; Vekemans, J. A. J.; Leysen, D.; Ottenheijm, H. C. J.;
Janssen, H. M.; Hermans, J. J. R. J. Med. Chem. 2010, 53,
1
712.
9
1
.
(a) Aoyagi, T.; Suda, H.; Uotani, K.; Kojima, F.; Aoyama, T.;
Horiguchi, K.; Hamada, M.; Takeuchi, T. J. Antibiot. 1992, 45,
1
404; (b) Aoyama, T.; Naganawa, H.; Suda, H.; Uotani, K.;
Aoyagi, T.; Takeuchi, T. J. Antibiot. 1992, 45, 1557.
23. Galeta, J.; Man, S.; Valoušková, A.; Potáček, M. Chem. Pap.
2013, 67, 40.
24. Sinkeldam, R. W.; Greco, N. J.; Tor, Y. Chem. Rev. 2010, 110,
0. (a) Lillelund, V. H.; Jensen, H. H.; Liang, X.; Bols, M. Chem.
Rev. 2002, 102, 515; (b) Tschamber, T.; Gessier, F.; Dubost, E.;
Newsome, J.; Tarnus, C.; Kohler, J.; Neuburger, M.; Streith, J.
Bioorg. Med. Chem. 2003, 11, 3559; (c) Paz, N. R.; Santana, A.
G.; Francisco, C. G.; Suárez, E.; González, C. C. Org. Lett.
2579.
25. (a) Rescifina, A.; Chiacchio, M. A.; Corsaro, A.; de Clercq, E.;
Iannazzo, D.; Mastino, A.; Piperno, A.; Romeo, G.; Romeo, R.;
Valveri, V. J. Med. Chem. 2006, 49, 709; (b) Liu, H.-K.;
Sadler, P. J. Acc. Chem. Res. 2011, 44, 349.
2
012, 14, 3388.
1
1
1. (a) Murineddu, G.; Ruiu, S.; Loriga, G.; Manca, I.; Lazzari, P.;
26. Landa, S.; Macháček, V. Collect. Czech. Chem. Commun. 1933,
5, 1.
Reali, R.; Pani, L.; Toma, L.; Pinna, G. A. J. Med. Chem. 2005,
4
8, 7351; (b) Murineddu, G.; Lazzari, P.; Ruiu, S.; Sanna, A.;
27. (a) Henkel, J. G.; Hane, J. T.; Gianutsos, G. J. Med. Chem.
1982, 25, 51; (b) Zah, J.; Terre'Blanche, G.; Erasmus, E.;
Malan, S. F. Bioorg. Med. Chem. 2003, 11, 3569; (c) Blanpied,
T. A.; Clarke, R. J.; Johnson, J. W. J. Neurosci. 2005, 25, 3312;
(d) Furber, M.; Alcaraz, L.; Bent, J. E.; Beyerbach, A.; Bowers,
K.; Braddock, M.; Caffrey, M. V.; Cladingboel, D.; Collington,
J.; Donald, D. K.; Fagura, M.; Ince, F.; Kinchin, E. C.; Laurent,
C.; Lawson, M.; Luker, T. J.; Mortimore, M. M. P.; Pimm, A.
D.; Riley, R. J.; Roberts, N.; Robertson, M.; Theaker, J.;
Thorne, P. V.; Weaver, R.; Webborn, P.; Willis, P. J. Med.
Chem. 2007, 50, 5882; (e) Miyazaki, A.; Tsuda, Y.; Fukushima,
S.; Yokoi, T.; Vántus, T.; Bökönyi, G.; Szabó, E.; Horváth, A.;
Kéri, G.; Okada, Y. J. Med. Chem. 2008, 51, 5121; (f) Cady, S.
D.; Wang, J.; Wu, Y.; DeGrado, W. F.; Hong, M. J. Am. Chem.
Soc. 2011, 133, 4274.
28. (a) Fort, R. C.; Schleyer, P. von R. Chem. Rev. 1964, 64, 277;
(b) van Bommel, K. J. C.; Metselaar, G. A.; Verboom, W.;
Reinhoudt, D. N. J. Org. Chem. 2001, 66, 5405; (c) Jeong, H.
Y. Thin Solid Films 2002, 417, 171; (d) Morcombe, C. R.;
Zilm, K. W. J. Magn. Reson. 2003, 162, 479; (e) Lenzke, K.;
Landt, L.; Hoener, M.; Thomas, H.; Dahl, J. E.; Liu, S. G.;
Carlson, R. M. K.; Möller, T.; Bostedt, C. J. Chem. Phys. 2007,
127, 084320; (f) Tominaga, M.; Masu, H.; Azumaya, I. J. Org.
Chem. 2009, 74, 8754; (g) Lim, H.; Chang, J. Y.
Loriga, G.; Manca, I.; Falzoi, M.; Dessì, C.; Curzu, M. M.;
Chelucci, G.; Pani, L.; Pinna, G. A. J. Med. Chem. 2006, 49,
7
502.
2. (a) Hall, W. Drug Alcohol Rev. 1998, 17, 433; (b) Pertwee, R.
G. Addict. Biol. 2000, 5, 37; (c) Pertwee, R. G. Gut 2001, 48,
8
1
59; (d) Adam, J.; Cowley, P. Expert. Opin. Ther. Pat. 2002,
2, 1475; (e) Gomez, R.; Navarro, M.; Ferrer, B.; Trigo, J. M.;
Bilbao, A.; Del Arco, I.; Cippitelli, A.; Nava, F.; Pomelli, D.;
de Fonseca, F. R. J. Neurosci. 2002, 22, 9612; (f) Hungund, B.
L.; Basavarajappa, B. S.; Vadasz, C.; Kunos, G.; de Fonseca, F.
R.; Colombo, G.; Serra, S.; Pearson, L.; Koob, G. F. Alcohol
Clin. Exp. Res. 2002, 26, 565; (g) Casu, M. A.; Porcella, A.;
Ruiu, S.; Saba, P.; Marchese, G.; Carai, M. A. M.; Reali, R.;
Gessa, G. L.; Pani, L. Eur. J. Pharmacol. 2003, 459, 97.
3. (a) Tabei, K.; Feng, X.; Venkatesan, A. M.; Abe, T.; Hideki,
U.; Mansour, T. S.; Siegel, M. M. J. Med. Chem. 2004, 47,
1
3
674; (b) Peng, S.-B.; Yan, L.; Xia, X.; Watkins, S. A.; Brooks,
H. B.; Beight, D.; Herron, D. K.; Jones, M. L.; Lampe, J. W.;
McMillen, W. T.; Mort, N.; Sawyer, J. S.; Yingling, J. M.
Biochemistry 2005, 44, 2293; c) Wang, X.; Mader, M. M.;
Toth, J. E.; Yu, X.; Jin, N.; Campbell, R. M.; Smallwood, J. K.;
Christe, M. E.; Chatterjee, A.; Goodson Jr. T.; Vlahos, C. J.;
Matter, W. F.; Bloem, L. J. J. Biol. Chem. 2005, 280, 19298;
(
d) Li, H.; Wang, Y.; Heap, C. R.; King, C.-H. R.; Mundla, S.
Macromolecules 2010, 43, 6943; (h) Tiwari, R. N.; Tiwari, J.
R.; Voss, M.; Clawson, D. K.; Yan, L.; Campbell, R. M.;
Anderson, B. D.; Wagner, J. R.; Britt, K.; Lu, K. X.; McMillen,
W. T.; Yingling, J. M. J. Med. Chem. 2006, 49, 2138; (e) Li,
H.; Wang, Y.; McMillen, W. T.; Chatterjee, A.; Toth, J. E.;
Mundla, S. R.; Voss, M.; Boyer, R. D.; Sawyer, J. S.
Tetrahedron 2007, 63, 11763; (f) Li, H.; McMillen, W. T.;
Heap, C. R.; McCann, D. J.; Yan, L.; Campbell, R. M.; Mundla,
S. R.; King, C.-H. R.; Dierks, E. A.; Anderson, B. D.; Britt, K.
S.; Huss, K. L.; Voss, M. D.; Wang, Y.; Clawson, D. K.;
Yingling, J. M.; Sawyer, J. S. J. Med. Chem. 2008, 51, 2302;
N.; Chang, L. Chem. Eng. J. 2010, 158, 641.
29. (a) Du Pont, Chem. Eng. News Archive 1966, 44, 26; (b)
Vernier, V. G.; Harmon, J. B.; Stump, J. M.; Lynes, T. E.;
Marvel, J. P.; Smith, D. H. Toxicol. Appl. Pharmacol. 1969, 15,
642; (c) Aldrich, P. A.; Hermann, E. C.; Meier, W. E.;
Paulshock, M.; Prichard, W. W.; Snyder, J. A.; Watts, J. C. J.
Med. Chem. 1971, 14, 535; (d) Leonov, H.; Astrahan, P.;
Krugliak, M.; Arkin, I. T. J. Am. Chem. Soc. 2011, 133, 9903.
30. SHELXTL, Version 5.10; Bruker AXS Inc.: Madison, WI,
USA, 1997.
(
g) Wan, X.; Li, Z.-G.; Yingling, J. M.; Yang, J.; Starbuck, M.
31. The crystal structures of compounds
W.; Ravoori, M. K.; Kundra, V.; Vazquez, E.; Navone, N. M.
Bone 2012, 50, 695.
4. Stadheim, T. A.; Kucera, G. L. Leuk. Res. 2002, 26, 55.
5. Speirs, A. L. Lancet 1962, 1, 303.
25af,ah,aj,an,ba,bd,bj,bm and 25bp have been deposited at
the Cambridge Crystallographic Data Centre and allocated the
deposition numbers CCDC 908394–908402.
1
1
1
6. Sakata, T.; Chen, J. K. Chem. Soc. Rev. 2011, 40, 4318.

ACCEPTED MANUSCRIPT
Supporting Information
Dihydropyrrolo[1,2-b]pyrazoles: withasomnine and related
compounds
Juraj Galeta, Lukáš Tenora, Stanislav Man and Milan Potáček*
Department of Chemistry, Faculty of Science, Masaryk University, Kotlářská 2, 611 37 Brno, Czech Republic
potacek@chemi.muni.cz

ACCEPTED MANUSCRIPT
Table of Contents
1
2
3
4
5
6
7
. Side products NMR characterizations
3
. Preparation of ynone 20 and dibromo derivative 21
3
. Dihydropyrrolo[1,2-b]pyrazoles synthesis by cycloaddition reaction
. Bromination of dimethylated dihydropyrrolo[1,2-b]pyrazoles 25as and 25ax with NBS
. Suzuki–Miyaura cross-coupling product 25ca
4
20
21
22
84
1
13
. H and C NMR spectra of all intermediates and final products
. Crystal structures of 25af,ah,an,ba,bj,bp
1
13
Note: NMR measurements were recorded at 300.13 MHz ( H) and 75.47 MHz ( C) in CDCl
3
2

ACCEPTED MANUSCRIPT
. Side products NMR characterizations
1
6
-Chlorohexan-3-one (11)
1
3
3
3
H NMR 3.58 (t, J = 6.3, 2H, CH
2
Cl), 2.61 (t, J = 7.0, 2H, CH
2
CH
2
CH
2
Cl), 2.46 (q, J =
3
7
.3, 2H, CH CH
2 3
), 1.98-2.10 (m, 2H, CH
2
CH
2
Cl), 1.06 (t, J = 7.3, 3H, CH
2 3
CH ).
13
C NMR 210.3 (C=O), 44.6 (CH
2
), 38.9 (CH
2
), 36.1 (CH
2
), 26.4 (CH
2
), 7.8 (CH ).
3
3
-(3-Chloropropyl)-4,5-dihydro-1H-pyrazole (13)
1
3
H NMR 6.62 (s, 1H, NH), 3.57–3.64 (m, 2H, CH
2
), 3.39 (t, J = 9.3, 2H, CH
2
), 2.65 (t,
3
J = 9.3, 2H, CH
2
), 2.40–2.54 (m, 2H, CH
2
), 2.00–2.15 (m, 2H, CH
2
).
13
C NMR 158.0 (C), 46.6 (CH
2
), 44.4 (CH
2
), 35.4 (CH ), 29.0 (CH ), 27.2 (CH ).
2
2
2
2. Preparation of ynone 20 and dibromo derivative 21
6
-Chlorohex-1-yn-3-one (20)
-chlorobutanoic chloride (19) (0.025 mol, 3.52 g) and CuI (0.002 mol, 0.38 g) were
O (30 mL) under argon atmosphere. The reaction
4
dissolved in freshly distilled Et
2
mixture was cooled down to 0 °C and the solution (0.5 M) of ethynylmagnesium
bromide (0.025 mol, 3.23 g) in THF (50 mL) was added dropwise over the course of 40 min. After 30
min it was warmed up to the room temperature. The reaction was quenched with saturated aq NH
30 mL), the organic phase was decanted and the inorganic one was washed with Et O (30 mL). The
combined organic fractions were washed with water (60 mL), brine (60 mL) and water (60 mL), dried
over MgSO and concentrated in vacuo. The crude product was distilled at Kugelrohr apparatus (1
mbar, 90 °C) giving 1.63 g of a colorless liquid (52 %).
4
Cl
(
2
4
1
3
3
H NMR 3.59 (t, J = 6.3, 2H, CH
2
Cl), 3.27 (s, 1H, CH), 2.82 (t, J = 7.1, 2H, CH
2 2 2
CH CH Cl), 2.06–2.19
(m, 2H, CH
2
CH Cl).
2
13
C NMR 186.0 (C=O), 81.4 ( C-), 79.1 ( CH), 43.9 (CH
2
), 42.5 (CH
2
), 26.4 (CH ).
2
+
GC-MS m/z (%): 130 (M , 5), 68 (100), 53 (88), 41 (22).
FTIR (film): 2963, 2926, 2855, 2095 (C C), 1684 (C=O), 1447, 1267, 1107, 1031.
1
,2-Dibromo-6-chlorohex-1-en-3-one (21)
The compound 20 (2.6 mmol, 338 mg) was dissolved in CCl
solution of bromine (2.6 mmol, 414 mg) in CCl (3 mL) was added during 10
min at the room temperature. The mixture was stirred for 20 min and then the
4
(5 mL) and the
4
3

ACCEPTED MANUSCRIPT
solvent was removed under reduced pressure. The crude product was purified by a column
chromatography (AcOEt/PE = 1:4) giving 698 mg (93 %) of a bright yellow liquid - cis and trans
isomers in ratio 3:7.
1
3
3
3
H NMR 8.18 (s, 1H, HC=C), 3.61 (t, J = 5.8, 2H, CH
2
Cl), 3.03 (t, J = 6.8, 2H, CH CH CH Cl), 2.13 (dt, J
2
2
2
3
=
12.7, J = 6.3, 2H, CH
2
CH Cl).
2
13
C NMR 191.7 (C=O), 131.5 (C), 126.2 (CH), 44.2 (CH
2
), 36.6 (CH
2
), 27.0 (CH ).
2
+
GC-MS m/z (%): 290 (M , 5), 228 (51), 213 (45), 185 (14), 105 (100), 77 (40), 53 (42), 41 (95).
FTIR (film): 2961, 2922, 2853, 1694 (C=O), 1553, 1450, 1312, 1237, 1126, 1030.
3. Dihydropyrrolo[1,2-b]pyrazoles synthesis by cycloaddition reaction
General procedure. An appropriate allenyl azine (250 mg) was dissolved in dry xylene (10 mL) and
the resulting mixture was heated to reflux under an argon atmosphere. Reactions were monitored by
TLC and purified by a column chromatography or by a preparative TLC.
5
,5-Dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole (25aa)
Yield: 75 mg (30 %), yellowish oil.
Reaction time and purification: 6 h, HPFC (AcOEt/PE = 1:1).
1
H NMR 7.48 (bs, 1H, N=CH), 5.93 (bs, 1H, C=CH), 3.87 (s, 2H, N-CH
2
), 2.67 (s, 2H, =C-CH ), 1.28 (s, 6H,
2
2
3
×CH ).
13
C NMR 144.9 (N-C), 143.1 (N=CH), 99.3 (C=CH), 61.0 (N-CH ), 43.5 (CH -C-CH ), 38.8 (=C-CH ), 28.4
2
3
3
2
(
2×CH ).
3
+
GC-MS m/z (%): 136 (M , 100), 121 (86), 109 (17), 95 (49), 81 (94), 67 (14), 52 (16), 41 (27).
FTIR (film): 2963, 2929, 2889, 2871 1539, 1462, 1405, 1386, 1325, 1260, 1169, 1116, 1033.
HRMS Calcd. for C
8
H
13
N : 137.1079. Found: 137.1054.
2
4
,5,5-Trimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole (25ab)
Yield: 88 mg (35 %), yellowish oil.
Reaction time and purification: 5 h, HPFC (AcOEt/PE = 1:3).
1
3
H NMR 7.46 (bs, 1H, N=CH), 5.92 (bs, 1H, C=CH), 3.80–3.90 (m, 2H, N-CH
2
), 2.86 (q, J = 7.3, 1H, HC-
3
CH
3
), 1.23 (s, 3H, CH
3 3
), 1.16 (d, J = 7.3, 3H, HC-CH ), 1.05 (s, 3H, CH
3
).
13
C NMR 150.0 (N-C), 142.7 (N=CH), 98.4 (C=CH), 60.9 (N-CH
2
), 46.4 (CH
3
-C-CH
3
), 41.9 (HC-CH ), 26.9
3
(CH
3
), 22.7 (CH
3
), 13.1 (HC-CH ).
3
+
GC-MS m/z (%): 150 (M , 14), 135 (14), 95 (100), 83 (19), 41 (18).
FTIR (film): 2965, 2936, 2873, 1536, 1485, 1464, 1389, 1372, 1341, 1171, 940.
HRMS Calcd. for C : 151.1235. Found: 151.1221.
H N
9 15 2
4

ACCEPTED MANUSCRIPT
2
,4,5,5-Tetramethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole (25ac)
Yield: 125 mg (50 %), yellowish oil.
Reaction time and purification: 5 h, HPFC (AcOEt/PE = 1:4).
1
3
H NMR 5.60 (bs, 1H, =CH), 3.62–3.73 (m, 2H, N-CH ), 2.70 (q, J = 7.3, 1H, HC-CH ), 2.16 (s, 3H, =C-
2
3
3
CH
3
), 1.11 (s, 3H, CH
3
), 1.03 (d, J = 7.3, 3H, HC-CH
3
), 0.94 (s, 3H, CH ).
3
13
C NMR 151.8 (N=C), 150.6 (N-C), 97.6 (=CH), 60.4 (N-CH
2
), 45.5 (CH
3
-C-CH
3
), 41.8 (HC-CH ), 26.6
3
(CH
3
), 22.4 (CH
3
), 14.0 (=C-CH
3
), 12.8 (HC-CH ).
3
+
GC-MS m/z (%): 164 (M , 27), 149 (27), 123 (25), 109 (100) 79 (15).
FTIR (film): 2960, 2927, 2872, 1543, 1444, 1369, 1313, 1163, 1009.
HRMS Calcd. for C10
H
17
N : 165.1392. Found: 165.1375.
2
2
-Ethyl-5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole (25ad)
Yield: 113 mg (45 %), yellowish oil.
Reaction time and purification: 22 h, HPFC (1. AcOEt/PE = 3:1; 2. AcOEt/DCM = 1:2).
1
3
H NMR 5.73 (bs, 1H, =CH), 3.80 (s, 2H, N-CH
2
), 2.63 (q, J = 7.6, 2H, CH
2
CH
3
), 2.62 (s, 2H, =C-CH ),
2
3
1
3
.26 (s, 6H, 2×CH ), 1.24 (t, J = 7.6, 3H, CH
2 3
CH ).
13
C NMR 158.7 (N=C), 145.2 (N-C), 97.0 (=CH), 60.7 (N-CH
2
), 42.7 (CH
3
-C-CH
3
), 38.8 (=C-CH ), 28.2
2
3 2 3
(2×CH ), 22.1 (CH CH ), 13.9 (CH
2
CH ).
3
+
GC-MS m/z (%): 164 (M , 100), 149 (98), 135 (20), 123 (28), 109 (45), 77 (14), 41 (22).
FTIR (film): 2962, 2936, 2875, 1542, 1464, 1443, 1377, 1318, 1265, 1179, 1056.
HRMS Calcd. for C10
H
17
N : 165.1392. Found: 165.1379.
2
5
,5-Dimethyl-2-(prop-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole (25ae)
Yield: 43 mg (17 %), yellowish oil.
Reaction time and purification: 22 h, HPFC (1. AcOEt/PE = 3:1; 2. AcOEt/DCM = 1:4).
1
3
H NMR 5.74 (bs, 1H, =CH), 3.81 (s, 2H, N-CH
2
), 2.94 (sep, J = 6.9, 1H, -CH), 2.63 (s, 2H, =C-CH ), 1.25
2
3
(s, 6H, 2×CH
3
), 1.24 (d, J = 6.9, 6H, HC(CH
)
3 2
).
13
C NMR 163.6 (N=C), 145.3 (N-C), 95.8 (=CH), 60.9 (N-CH
2
), 42.9 (CH
3
-C-CH
3
), 39.1 (=C-CH ), 28.6 (-
2
CH), 28.4 (2×CH
3
), 23.1 (2×CH ).
3
+
GC-MS m/z (%): 178 (M , 29), 163 (100), 121 (24), 107 (35), 41 (15).
FTIR (film): 2960, 2928, 2872, 1540, 1462, 1380, 1371, 1321, 1295, 1184.
HRMS Calcd. for C11 : 179.1548. Found: 179.1537.
H N
19 2
2
-(1-Adamantyl)-5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole (25af)
Yield: 198 mg (79 %), white solid. MP 106.5–107.5 °C.
Reaction time and purification: 15 h, HPFC (AcOEt/PE = 1:4).
1
H NMR 5.76 (s, 1H, =CH), 3.83 (s, 2H, N-CH
2
), 2.64 (s, 2H, =C-CH
2
), 2.02–2.06 (m, 3H, CH, Ad), 1.93–
).
1
.96 (m, 6H, CH , Ad), 1.75–1.78 (m, 6H, CH , Ad), 1.27 (s, 6H, 2×CH
2
2
3
5

ACCEPTED MANUSCRIPT
1
3
C NMR 167.2 (N=C), 145.0 (N-C), 94.8 (=CH), 61.1 (N-CH
2
), 43.2 (CH
).
2
, Ad), 42.9 (CH
3
-C-CH ), 39.2
3
(=C-CH
2 2
), 37.2 (CH , Ad), 34.6 (C, Ad), 29.0 (CH, Ad), 28.6 (2×CH
3
+
GC-MS m/z (%): 270 (M , 100), 213 (31), 85 (36), 83 (52), 45 (19).
FTIR (KBr): 2955, 2905, 2847, 1545, 1472, 1451, 1358, 1310, 1179, 1101, 1056.
HRMS Calcd. for C18 : 271.2174. Found: 271.2162.
Anal. Calcd. for C18 : C, 79.95; H, 9.69; N, 10.36. Found: C, 79.39; H, 9.89; N, 10.24.
H N
27 2
H N
26 2
2
-(1-Adamantyl)-4,5,5-trimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole (25ag)
Yield: 215 mg (86 %), white solid. MP 124.0–126.0 °C.
Reaction time and purification: 5 h, HPFC (AcOEt/PE = 1:4).
1
3
3
3
H NMR 5.76 (s, 1H, =CH), 3.83 (d, J = 10.3, 1H, N-CH
2
), 3.80 (d, J = 10.3, 1H, N-CH
2
), 2.83 (q, J = 7.2,
, Ad), 1.22
1
H, HC-CH
3
), 2.02–2.06 (m, 3H, CH, Ad), 1.93–1.96 (m, 6H, CH
2
, Ad), 1.74–1.78 (m, 6H, CH
2
3
(s, 3H, CH ), 1.15 (d, J = 7.2, 3H, HC-CH
3
3
), 1.05 (s, 3H, CH ).
3
1
3
C NMR 166.7 (N=C), 150.1 (N-C), 93.8 (=CH), 61.0 (N-CH
HC-CH ), 37.2 (CH , Ad), 34.7 (C, Ad), 29.0 (CH, Ad), 27.0 (CH
2
), 45.9 (CH
), 22.9 (CH
3
-C-CH
3
), 43.2 (CH
).
2
, Ad), 42.2
(
3
2
3
3
), 13.1 (HC-CH
3
+
GC-MS m/z (%): 284 (M , 100), 227 (23).
FTIR (KBr): 2959, 2904, 2847, 1542, 1451, 1357, 1308, 1236, 1165, 1050.
HRMS Calcd. for C19 : 285.2331. Found: 285.2329.
Anal. Calcd. for C19 : C, 80.23; H, 9.92; N, 9.85. Found: C, 80.00; H, 9.90; N, 9.83.
H N
29 2
H N
28 2
2
,4-Di-(1-adamantyl)-5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole (25ah)
Yield: 53 mg (21 %), white solid. MP 179.0–179.5 °C.
Reaction time and purification: 6.5 h, recrystallization (PE).
1
2
2
H NMR 5.83 (s, 1H, =CH), 3.76 (d, J = 10.2, 1H, N-CH
2
), 3.65 (d, J = 10.2, 1H, N-CH
2
), 2.43 (s, 1H, HC-
),
Ad),1.90–2.07 (m, 12H, CH
.26 (s, 3H, CH ).
2
, Ad), 1.84 (bs, 3H, CH, Ad), 1.65–1.82 (m, 12H, CH
2
, Ad), 1.33 (s, 3H, CH
3
1
3
1
3
C NMR 166.0 (N=C), 146.7 (N-C), 97.4 (=CH), 62.5 (N-CH
Ad), 41.1 (CH , Ad), 37.3 (CH , Ad), 37.2 (CH , Ad), 36.6 (C, Ad), 34.6 (C, Ad), 30.0 (CH
8.9 (CH, Ad), 25.1 (CH
2
), 59.5 (HC-Ad), 48.1 (CH
3
-C-CH
3
), 43.2 (CH ,
2
2
2
2
3
), 29.0 (CH, Ad),
2
3
).
+
GC-MS m/z (%): 404 (M , 14), 135 (100), 49 (14).
FTIR (KBr): 2983, 2908, 2849, 1713, 1606, 1451, 1234, 1090, 1031.
41 2
HRMS Calcd. for C28H N : 405.3270. Found: 405.3257.
40 2
Anal. Calcd. for C28H N : C, 83.11; H, 9.96; N, 6.92. Found: C, 82.95; H, 10.21; N, 6.70.
4
-(1-Adamantyl)-5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole (25ai)
Yield: 213 g (85 %), white solid. MP 121.0–121.9 °C.
Reaction time and purification: 4 h, HPFC (DCM).
6

ACCEPTED MANUSCRIPT
1
2
2
H NMR 7.46 (s, 1H, N=CH), 6.01 (s, 1H, N-C=CH), 3.83 (d, J = 10.4, 1H, N-CH
2
), 3.68 (d, J = 10.4, 1H,
N-CH
2
), 2.44 (s, 1H, HC-Ad), 1.97 (bs, 3H, CH
).
2
, Ad), 1.60–1.92 (m, 12H, CH
2
, Ad), 1.36 (s, 3H, CH
3
), 1.25
(s, 3H, CH
3
1
3
C NMR 146.5 (N-C), 141.9 (N=CH), 102.0 (N-C=CH), 62.1 (N-CH
2
), 59.0 (HC-Ad), 48.5 (CH
).
3
-C-CH ),
3
4
0.8 (CH , Ad), 37.1 (CH , Ad), 36.7 (C, Ad), 30.3 (CH ), 28.7 (CH, Ad), 24.9 (CH
2
2
3
3
+
GC-MS m/z (%): 270 (M , 24), 255 (41), 135 (100), 107 (15), 93 (19), 79 (17), 49 (14).
FTIR (KBr): 2883, 2845, 2677, 1515, 1449, 1395, 1364, 1344, 1319, 1176, 1141, 1099, 1049.
27 2
HRMS Calcd. for C18H N : 271.2174. Found: 271.2166.
26 2
Anal. Calcd. for C18H N : C, 79.95; H, 9.69; N, 10.36. Found: C, 79.87; H, 9.77; N, 10.11.
2
-(1-Adamantyl)-5,5-dimethyl-4-pyrrolidinomethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole (25aj)
Yield: 45 mg (18 %), white solid. MP 142.0–143.5 °C.
Reaction time and purification: 4 h, HPFC (AcOEt).
1
H NMR 5.82 (s, 1H, =CH), 3.81 (bs, 2H, N-CH
2
), 2.94–3.00 (m, 1H, HC-CH
), 2.46–2.58 (m, 4H, N-CH CH ), 2.04 (bs, 3H, CH, Ad), 1.93–
, Ad), 1.70–1.83 (bs, 6H, CH , Ad), 1.76 (bs, 4H, N-CH CH ), 1.31 (s,
), 1.11 (s, 3H, CH ).
2
), 2.65–
2
1
3
.69 (m, 2H, HC-CH
.98 (bs, 6H, CH
H, CH
2
2
2
2
2
2
2
3
3
1
3
C NMR 166.5 (N=C), 148.0 (N-C), 95.0 (=CH), 61.7 (N-CH
HC-CH ), 45.9 (CH -C-CH ), 43.1 (CH , Ad), 37.1 (CH , Ad), 34.6 (C, Ad), 28.9 (CH, Ad), 27.2 (CH
2×N-CH CH ), 22.8 (CH ).
2
), 55.0 (HC-CH
2
), 54.4 (2×N-CH
2
CH
2
), 46.3
), 23.8
(
(
2
3
3
2
2
3
2
2
3
+
GC-MS m/z (%): 355 (M +1, 13), 166 (20), 137 (37), 123 (31), 109 (33), 96 (100), 79 (26), 67 (53), 53
25), 41 (50).
(
FTIR (KBr): 2959, 2905, 2846, 2781, 1715, 1537, 1486, 1451, 1364, 1323, 1151, 1064.
HRMS Calcd. for C23 : 354.2909. Found: 354.2904.
Anal. Calcd. for C23 : C, 78.14; H, 9.98; N, 11.89. Found: C, 78.16; H, 10.08; N, 11.90.
H N
36 3
H N
35 3
2
-(1-Adamantyl)-5,5-dimethyl-4-morpholinomethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole (25ak)
Yield: 118 mg (47 %), white solid. MP 130.0–131.0 °C.
Reaction time and purification: 6 h, HPFC (AcOEt/PE = 1:4).
1
3
3
H NMR 5.81 (s, 1H, =CH), 3.84 (d, J = 10.3, 1H, N-CH
2
), 3.81 (d, J = 10.3, 1H, N-
3
CH
CH
1
2
), 3.71–3.75 (m, 4H, O-CH
2
), 3.02 (t, J = 7.7, 1H, HC-CH
), 2.04 (bs, 3H, CH, Ad), 1.92–1.96 (m, 6H, CH
), 1.11 (s, 3H, CH ).
2
), 2.44–2.58 (m, 6H,
, Ad), 1.74–1.78 (m, 6H, CH , Ad),
2
2
2
.32 (s, 3H, CH
3
3
13
C NMR 166.7 (N=C), 147.6 (N-C), 95.0 (=CH), 67.3 (2×O-CH
2
), 61.8 (N-CH
2
2
), 57.7 (HC-CH ), 54.1 (2×N-
CH
CH
2
), 45.8 (CH
), 23.0 (CH
3
-C-CH
).
3
), 44.0 (HC-CH
2
), 43.2 (CH
2
, Ad), 37.2 (CH , Ad), 34.6 (C, Ad), 29.0 (CH, Ad), 27.3
2
(
3
3
+
GC-MS m/z (%): 369 (M , 1), 100 (100).
FTIR (KBr): 2961, 2850, 2814, 1793, 1752, 1663, 1537, 1453, 1374, 1312, 1141, 1117, 1035, 1010.
HRMS Calcd. for C23 O: 370.2858. Found: 370.2855.
Anal. Calcd. for C23 O: C, 74.75; H, 9.55; N, 11.37. Found: C, 74.85; H, 9.74; N, 11.39.
H N
36 3
H N
35 3
7

ACCEPTED MANUSCRIPT
2
-(1-Adamantyl)-5,5-dimethyl-4-methylene-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole (25al)
Yield: 23 mg (9 %), colorless oil.
Reaction time and purification: 4 h, HPFC (Et O/PE = 2:1).
2
1
H NMR 6.06 (s, 1H, =CH), 5.29 (s, 1H, =CH ), 4.96 (s, 1H, =CH ), 3.97 (s, 2H, N-CH ),
2
2
2
2
.06 (bs, 3H, CH, Ad), 1.93–1.99 (m, 6H, CH
2
, Ad), 1.73–1.80 (m, 6H, CH
2
, Ad), 1.34 (s, 6H, 2×CH ).
3
1
3
C NMR 168.2 (N=C), 147.5 (N-C), 145.4 (C=CH
2
), 103.6 (=CH
2
), 92.9 (=CH), 61.3 (N-CH
).
2
), 46.3 (CH -C-
3
CH
3
), 43.1 (CH
2
, Ad), 37.1 (CH
2
, Ad), 34.7 (C, Ad), 28.9 (CH, Ad), 28.7 (2×CH
3
+
GC-MS m/z (%): 284 (M +1, 100), 227 (19), 171 (28), 79 (14), 41 (13).
FTIR (film): 2962, 2900, 2848, 1658, 1453, 1384, 1366, 1355, 1312, 1163, 1102, 1056.
HRMS Calcd. for C19 : 283.2174. Found: 283.2161.
H N
27 2
2
-(1-Adamantyl)-5,5-dimethyl-4-phenyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole (25am)
Yield: 193 mg (77 %), white solid. MP 138.0–139.0 °C.
Reaction time and purification: 1.5 h, HPFC (AcOEt/PE = 1:5).
1
2
H NMR 7.06–7.36 (m, 5H, Ph), 5.80 (s, 1H, =CH), 4.00 (s, 1H, HC-Ph), 3.98 (d, J =
2
1
6
0.3, 1H, N-CH
2
), 3.91 (d, J = 10.3, 1H, N-CH
), 0.73 (s, 3H, CH
2
), 2.05 (bs, 3H, CH, Ad), 1.99 (bs, 6H, CH
).
2
, Ad), 1.77 (bs,
H, CH , Ad), 1.33 (s, 3H, CH
2
3
3
1
3
C NMR 166.8 (N=C), 147.2 (N-C), 138.1 (C), 128.7 (2×CH), 128.2 (2×CH), 127.2 (CH), 95.4 (=CH), 60.7
N-CH ), 54.2 (HC-Ph), 47.5 (CH -C-CH ), 43.0 (CH , Ad), 37.0 (CH , Ad), 34.5 (C, Ad), 28.8 (CH, Ad),
7.4 (CH ), 24.2 (CH ).
(
2
2
3
3
2
2
3
3
+
GC-MS m/z (%): 346 (M , 100), 305 (13), 291 (88), 135 (13).
FTIR (KBr): 2957, 2907, 2849, 1602, 1537, 1495, 1454, 1370, 1312, 1217, 1156, 1102.
HRMS Calcd. for C24 : 347.2487. Found: 347.2489.
Anal. Calcd. for C24 : C, 83.19; H, 8.73; N, 8.08. Found: C, 83.10; H, 8.93; N, 7.87.
H N
31 2
H N
30 2
5
,5-Dimethyl-2,4-diphenyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole (25an)
Yield: 210 mg (84 %), white solid. MP 97.5–98.5 °C.
Reaction time and purification: 6 h, HPFC (AcOEt/PE = 1:4).
1
3
H NMR 7.81 (d, J = 8.3, 2H, Ph), 7.15–7.40 (m, 8H, Ph), 6.31 (s, 1H, =CH), 4.07 (s, 1H, HC-Ph), 4.05 (d,
2
2
J = 10.3, 1H, N-CH
2
), 4.00 (d, J = 10.3, 1H, N-CH
2
), 1.38 (s, 3H, CH
3
), 0.78 (s, 3H, CH ).
3
1
3
C NMR 155.6 (N=C), 148.9 (N-C), 137.9 (C), 134.4 (C), 128.8 (2×CH), 128.7 (2×CH), 128.5 (2×CH),
), 54.4 (HC-Ph), 47.9 (CH -C-CH ), 27.6
1
27.6 (CH), 127.5 (CH), 125.5 (2×CH), 97.4 (=CH), 61.0 (N-CH
), 24.3 (CH ).
2
3
3
(CH
3
3
+
GC-MS m/z (%): 288 (M , 5), 247 (20), 233 (100), 202 (20), 130 (20) 102 (50), 77 (20).
FTIR (KBr): 2960, 2925, 2871, 1650, 1602, 1538, 1450, 1430, 1389, 1076, 1029.
Anal. Calcd. for C20
H
20
N : C, 83.30; H, 6.99; N, 9.71. Found: C, 83.40; H, 7.02; N, 9.66.
2
8

ACCEPTED MANUSCRIPT
2
-(4-Methoxyphenyl)-5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole (25ao)
Yield: 148 mg (59 %), white solid. MP 106.5–108.0 °C.
Reaction time and purification: 9 h, preparative TLC (AcOEt/PE = 2:8).
1
3
3
H NMR 7.70 (d, J = 8.8, 2H, Ar), 6.91 (d, J = 8.8, 2H, Ar), 6.18 (s, 1H, =CH), 3.90 (s, 2H, N-CH ), 3.81
2
(s, 3H, OCH
3
), 2.69 (s, 2H, =C-CH
2
), 1.29 (s, 6H, 2×CH
3
).
13
C NMR 159.2 (C), 155.5 (N=C), 146.3 (N-C), 127.3 (C), 126.7 (2×CH), 114.1 (2×CH), 96.1 (=CH), 61.2
(
N-CH
2
), 55.4 (OCH
3
), 43.1 (H
3
C-C-CH
3
), 39.0 (=C-CH
2
), 28.4 (2×CH ).
3
+
GC-MS m/z (%): 242 (M , 100), 227 (44), 142 (16), 115 (15).
FTIR (KBr): 2959, 2938, 2872, 1611, 1520, 1428, 1244, 1173, 1029.
Anal. Calcd. for C15 O: C, 74.35; H, 7.49; N, 11.56. Found: C, 74.58; H, 7.56; N, 11.48.
H N
18 2
2
-(4-Methoxyphenyl)-4,5,5-trimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole (25ap)
Yield: 205 mg (82 %), white solid. MP 74.5–75.5 °C.
Reaction time and purification: 3 h, preparative TLC (AcOEt/PE = 2:8).
1
3
3
H NMR 7.71 (d, J = 8.8, 2H, Ar), 6.90 (d, J = 8.8, 2H, Ar), 6.18 (s, 1H, =CH),
2
2
3
3
.91 (d, J = 10.7, 1H, N-CH
2
), 3.87 (d, J = 10.7, 1H, N-CH
), 1.19 (d, J = 7.2, 3H, HC-CH
2
), 3.80 (s, 3H, OCH
).
3
), 2.88 (q, J = 7.2, 1H,
3
HC-CH
3
), 1.24 (s, 3H, CH
3
3
), 1.08 (s, 3H, CH
3
13
C NMR 159.1 (C), 155.0 (N=C), 151.3 (N-C), 127.3 (C), 126.6 (2×CH), 114.0 (2×CH), 95.1 (=CH), 61.0
(
N-CH
2
), 55.3 (OCH
3
), 46.0 (H
3
C-C-CH
3
), 42.1 (HC-CH
3
), 26.9 (CH
3
), 22.7 (CH
3
), 13.0 (HC-CH ).
3
+
GC-MS m/z (%): 256 (M , 100), 241 (32), 201 (41), 172 (31), 128 (18).
FTIR (KBr): 2962, 2873, 2838, 1610, 1519, 1427, 1244, 1174, 1030.
Anal. Calcd. for C16
H
20
N O: C, 74.97; H, 7.86; N, 10.93. Found: C, 74.97; H, 7.64; N, 11.19.
2
4
-Ethyl-2-(4-methoxyphenyl)-5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole (25aq)
Yield: 195 mg (78 %), colorless oil.
Reaction time and purification: 3 h, preparative TLC (AcOEt/PE = 2:8).
1
3
3
H NMR 7.63 (d, J = 8.6, 2H, Ar), 6.84 (d, J = 8.6, 2H, Ar), 6.17 (s, 1H, =CH),
2
2
3
3
3
4
7
.82 (d, J = 10.6, 1H, N-CH
.6, 1H, HC-Et), 1.54–1.74 (m, 1H, CH
.4, 3H, CH CH ), 1.05 (s, 3H, CH ).
2
), 3.77 (d, J = 10.6, 1H, N-CH
2
), 3.75 (s, 3H, OCH
3
), 2.57 (dd, J = 10.6, J =
3
2
CH
3
), 1.20–1.41 (m, 1H, CH
2
CH ), 1.18 (s, 3H, CH ), 1.05 (t, J =
3
3
2
3
3
13
C NMR 159.3 (C), 154.9 (N=C), 150.1 (N-C), 127.4 (C), 126.7 (2×CH), 114.2 (2×CH), 96.5 (=CH), 61.1
(
N-CH
2
), 55.5 (OCH
).
3
), 50.0 (HC-Et), 46.1 (H
3
C-C-CH
3
), 27.9 (CH
3
), 22.9 (CH
3
), 21.8 (CH
2
CH ), 13.0
3
(CH CH
2
3
+
GC-MS m/z (%): 270 (M , 100), 241 (43), 215 (24), 171 (51).
FTIR (film): 2962, 2873, 2836, 1613, 1522, 1433, 1246, 1173, 1032.
Anal. Calcd. for C H N O: C, 75.52; H, 8.20; N, 10.36. Found: C, 75.29; H, 7.92; N, 10.41.
17
22
2
9

ACCEPTED MANUSCRIPT
5
,5-Dimethyl-2-(4-methylphenyl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole (25ar)
Yield: 193 mg (77 %), white solid. MP 101.0–103.0 °C.
Reaction time and purification: 9 h, preparative TLC (AcOEt/PE = 2:8).
1
3
3
H NMR 7.66 (d, J = 8.1, 2H, Ar), 7.17 (d, J = 8.1, 2H, Ar), 6.22 (s, 1H, =CH), 3.90 (s, 2H, N-CH ), 2.68
2
(
1
s, 2H, =C-CH
3
2
), 2.34 (s, 3H, Ph-CH
C NMR 155.6 (N=C), 146.2 (N-C), 137.1 (C), 131.6 (C), 129.4 (2×CH), 125.3 (2×CH), 96.3 (=CH), 61.1
N-CH ), 43.1 (H C-C-CH ), 39.0 (=C-CH ), 28.4 (2×CH ), 21.4 (Ph-CH ).
3
), 1.28 (s, 6H, 2×CH
3
).
(
2
3
3
2
3
3
+
GC-MS m/z (%): 226 (M , 100), 211 (25), 171 (16), 141 (20), 115 (15).
FTIR (KBr): 2957, 2924, 2871, 1572, 1527, 1472, 1432, 1318, 1195.
Anal. Calcd. for C15
H
18
N : C, 79.61; H, 8.02; N, 12.38. Found: C, 79.65; H, 8.07; N, 12.25.
2
4
,5,5-Trimethyl-2-(4-methylphenyl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole (25as)
Yield: 223 mg (89 %), white solid. MP 84.5–85.5 °C.
Reaction time and purification: 3 h, preparative TLC (AcOEt/PE = 2:8).
1
3
3
H NMR 7.67 (d, J = 8.0, 2H, Ar), 7.17 (d, J = 8.0, 2H, Ar), 6.22 (s, 1H, =CH),
2
2
3
3
.90 (d, J = 10.8, 1H, N-CH
2
), 3.86 (d, J = 10.8, 1H, N-CH
), 1.18 (d, J = 7.2, 3H, HC-CH
2
), 2.87 (q, J = 7.2, 1H, HC-CH
3
), 2.34 (s, 3H,
3
Ph-CH
3
), 1.23 (s, 3H, CH
3
3
), 1.07 (s, 3H, CH ).
3
1
3
C NMR 155.2 (N=C), 151.3 (N-C), 137.0 (C), 131.6 (C), 129.3 (2×CH), 125.2 (2×CH), 95.4 (=CH), 61.0
N-CH ), 45.9 (H C-C-CH ), 42.0 (HC-CH ), 26.8 (CH ), 22.6 (CH ), 21.3 (Ph-CH ), 13.0 (HC-CH ).
(
2
3
3
3
3
3
3
3
+
GC-MS m/z (%): 240 (M , 100), 225 (36), 185 (81), 156 (29), 141 (17), 115 (15).
FTIR (KBr): 2965, 2926, 2865, 1623, 1466, 1430, 1309, 1189.
Anal. Calcd. for C16
H
20
N : C, 79.96; H, 8.39; N, 11.66. Found: C, 80.10; H, 8.46; N, 11.57.
2
4
-Ethyl-5,5-dimethyl-2-(4-methylphenyl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole (25at)
Yield: 205 mg (82 %), colorless oil.
Reaction time and purification: 3 h, preparative TLC (AcOEt/PE = 2:8).
1
3
3
H NMR 7.67 (d, J = 7.9, 2H, Ar), 7.17 (d, J = 7.9, 2H, Ar), 6.28 (s, 1H, =CH),
2
2
3
3
1
1
.90 (d, J = 10.6, 1H, N-CH
0.7, J = 4.5, 1H, HC-Et), 2.34 (s, 3H, Ph-CH
2
), 3.85 (d, J = 10.6, 1H, N-CH
2
), 2.64 (dd, J =
3
3
), 1.56–1.73 (m, 1H, CH
), 1.12 (s, 3H, CH ).
CH
2 3
), 1.35–1.55 (m, 1H, CH
2
CH ),
3
3
.25 (s, 3H, CH
3
), 1.12 (t, J = 7.4, 3H, CH
2
CH
3
3
1
3
C NMR 155.2 (N=C), 150.1 (N-C), 137.1 (C), 131.7 (C), 129.4 (2×CH), 125.4 (2×CH), 96.8 (=CH), 61.2
N-CH ), 50.0 (HC-Et), 46.1 (H C-C-CH ), 27.9 (CH ), 22.9 (CH ), 21.8 (CH CH ), 21.4 (Ph-CH ), 13.0
CH CH ).
(
(
2
3
3
3
3
2
3
3
2
3
+
GC-MS m/z (%): 254 (M , 100), 239 (25), 225 (62), 193 (34), 155 (56).
FTIR (film): 2963, 2932, 2873, 1523, 1459, 1434, 1325, 1192.
Anal. Calcd. for C H N : C, 80.27; H, 8.72; N, 11.01. Found: C, 80.53; H, 8.73; N, 11.06.
17
22
2
1
0

ACCEPTED MANUSCRIPT
5
,5-Dimethyl-2-phenyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole (25au)
Yield: 195 mg (78 %), white solid. MP 89.0–91.5 °C.
Reaction time and purification: 9 h, preparative TLC (AcOEt/PE = 2:8).
1
H NMR 7.76–7.78 (m, 2H, Ph), 7.22–7.40 (m, 3H, Ph), 6.26 (s, 1H, =CH), 3.92 (s, 2H, N-CH ), 2.71 (s,
2
2
H, =C-CH
2
), 1.31 (s, 6H, 2×CH
C NMR 155.7 (N=C), 146.4 (N-C), 134.5 (C), 128.7 (CH), 127.5 (2×CH), 125.5 (2×CH), 96.7 (=CH), 61.3
N-CH ), 43.2 (H C-C-CH ), 39.1 (=C-CH ), 28.5 (2×CH ).
3
).
13
(
2
3
3
2
3
+
GC-MS m/z (%): 212 (M , 100), 197 (38), 171 (34), 157 (28), 128 (34).
FTIR (KBr): 2965, 2933, 2904, 2873, 1606, 1541, 1450, 1429, 1316, 1201.
Anal. Calcd. for C14
H
16
N : C, 79.21; H, 7.60; N, 13.20. Found: C, 78.81; H, 7.65; N, 13.08.
2
4
,5,5-Trimethyl-2-phenyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole (25av)
Yield: 198 mg (79 %), colorless oil.
Reaction time and purification: 3 h, preparative TLC (AcOEt/PE = 2:8).
1
2
H NMR 7.79–7.86 (m, 2H, Ph), 7.23–7.44 (m, 3H, Ph), 6.30 (s, 1H, =CH), 3.96 (d, J = 10.8, 1H, N-CH
2
),
2
3
3
3
2 3
.92 (d, J = 10.8, 1H, N-CH ), 2.93 (q, J = 7.2, 1H, HC-CH ), 1.29 (s, 3H, CH
3
), 1.23 (d, J = 7.2, 3H, HC-
CH
3
), 1.12 (s, 3H, CH
C NMR 155.2 (N=C), 151.4 (N-C), 134.5 (C), 128.7 (CH), 127.4 (2×CH), 125.5 (2×CH), 95.7 (=CH), 61.1
N-CH ), 46.0 (H C-C-CH ), 42.2 (HC-CH ), 26.9 (CH ), 22.7 (CH ), 13.1 (HC-CH ).
3
).
13
(
2
3
3
3
3
3
3
+
GC-MS m/z (%): 226 (M , 100), 211 (43), 185 (32), 171 (98), 141 (43), 102 (20).
FTIR (film): 2964, 2932, 2873, 1605, 1541, 1455, 1430, 1316, 1293.
HRMS Calcd. for C15
H
19
N : 227.1548. Found: 227.1557.
2
4
-Ethyl-5,5-dimethyl-2-phenyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole (25aw)
Yield: 195 mg (78 %), colorless oil.
Reaction time and purification: 3 h, preparative TLC (AcOEt/PE = 2:8).
1
H NMR 7.76–7.81 (m, 2H, Ph), 7.24–7.40 (m, 3H, Ph), 6.32 (s, 1H, =CH), 3.91 (d,
2
2
3
3
J = 10.7, 1H, N-CH
m, 1H, CH CH
2
), 3.87 (d, J = 10.7, 1H, N-CH
2
), 2.66 (dd, J = 10.6, J = 4.6, 1H, HC-Et), 1.58–1.72
3
(
2
3
), 1.39–1.52 (m, 1H, CH
2 3
CH ), 1.26 (s, 3H, CH
3
), 1.14 (t, J = 7.3, 3H, CH
2
CH ), 1.12 (s,
3
3
H, CH
3
).
13
C NMR 155.1 (N=C), 150.2 (N-C), 134.5 (C), 128.7 (2×CH), 127.5 (CH), 125.5 (2×CH), 97.1 (=CH), 61.2
(
N-CH
2
3 3
), 49.9 (HC-Et), 46.1 (H C-C-CH ), 27.8 (CH
3
), 22.9 (CH
3
), 21.8 (CH
2
CH
3
), 13.0 (CH
2
CH ).
3
+
GC-MS m/z (%): 240 (M , 100), 225 (31), 211 (67), 185 (41), 141 (52).
FTIR (film): 2963, 2933, 2873, 1605, 1537, 1460, 1431, 1324, 1194.
HRMS Calcd. for C16
H
21
N : 241.1705. Found: 241.1697.
2
1
1

ACCEPTED MANUSCRIPT
2
-(4-Chlorophenyl)-5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole (25ax)
Yield: 193 mg (77 %), white solid. MP 109.0–110.0 °C.
Reaction time and purification: 9 h, preparative TLC (AcOEt/PE = 2:8).
1
3
3
H NMR 7.70 (d, J = 8.5, 2H, Ar), 7.33 (d, J = 8.5, 2H, Ar), 6.22 (s, 1H, =CH), 3.90 (s, 2H, N-CH ), 2.70
2
(
1
s, 2H, =C-CH
3
2
), 1.29 (s, 6H, 2×CH
C NMR 154.4 (N=C), 146.6 (N-C), 133.1 (C), 133.0 (C), 128.8 (2×CH), 126.7 (2×CH), 96.7 (=CH), 61.2
N-CH ), 43.2 (H C-C-CH ), 39.0 (=C-CH ), 28.3 (2×CH ).
3
).
(
2
3
3
2
3
+
GC-MS m/z (%): 246 (M , 100), 231 (32), 205 (26), 191 (20), 127 (24).
FTIR (KBr): 2956, 2926, 2866, 1506, 1431, 1320, 1199, 1086.
Anal. Calcd. for C14
H
15ClN : C, 68.15; H, 6.13; N, 11.35. Found: C, 68.02; H, 6.16; N, 11.06.
2
2
-(4-Chlorophenyl)-4,5,5-trimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole (25ay)
Yield: 213 mg (85 %), white solid. MP 59.0–61.5 °C.
Reaction time and purification: 3 h, preparative TLC (AcOEt/PE = 2:8).
1
3
3
H NMR 7.70 (d, J = 8.5, 2H, Ar), 7.32 (d, J = 8.5, 2H, Ar), 6.22 (s, 1H, =CH),
2
2
3
3
CH
.91 (d, J = 10.9, 1H, N-CH
2
), 3.87 (d, J = 10.9, 1H, N-CH
2
), 2.88 (q, J = 7.2, 1H, HC-CH
3
), 1.24 (s, 3H,
3
3
), 1.18 (d, J = 7.2, 3H, HC-CH
3
), 1.07 (s, 3H, CH ).
3
13
C NMR 153.9 (N=C), 151.6 (N-C), 133.0 (2×C), 128.8 (2×CH), 126.6 (2×CH), 95.8 (=CH), 61.0 (N-CH ),
2
4
6.0 (H
3 3 3
C-C-CH ), 42.0 (HC-CH ), 26.8 (CH
3
), 22.6 (CH
3
), 13.0 (HC-CH ).
3
+
GC-MS m/z (%): 260 (M , 100), 245 (45), 205 (94), 176 (24), 141 (28).
FTIR (KBr): 2966, 2932, 2865, 1506, 1432, 1340, 1191, 1087.
Anal. Calcd. for C15
H
17ClN : C, 69.09; H, 6.57; N, 10.74. Found: C, 69.29; H, 6.66; N, 10.68.
2
4
-Ethyl-2-(4-chlorophenyl)-5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole (25az)
Yield: 190 mg (76 %), colorless oil.
Reaction time and purification: 3 h, preparative TLC (AcOEt/PE = 2:8).
1
3
3
H NMR 7.71 (d, J = 8.3, 2H, Ar), 7.33 (d, J = 8.3, 2H, Ar), 6.29 (s, 1H, =CH),
2
2
3
3
3
1
1
.89 (d, J = 10.8, 1H, N-CH
.54–1.75 (m, 1H, CH
.11 (s, 3H, CH ).
2
), 3.85 (d, J = 10.8, 1H, N-CH
), 1.31–1.53 (m, 1H, CH
2
), 2.65 (dd, J = 10.7, J = 4.5, 1H, HC-Et),
3
2
CH
3
2 3
CH ), 1.25 (s, 3H, CH
3
), 1.11 (t, J = 7.4, 3H, CH
2
CH ),
3
3
13
C NMR 153.8 (N=C), 150.3 (N-C), 133.0 (C), 132.9 (C), 128.8 (2×CH), 126.6 (2×CH), 97.1 (=CH), 61.1
(
N-CH
2
3 3
), 49.8 (HC-Et), 46.1 (H C-C-CH ), 27.7 (CH
3
), 22.8 (CH
3
), 21.7 (CH
2
CH
3
), 12.9 (CH
2
CH ).
3
+
GC-MS m/z (%): 274 (M , 100), 245 (70), 219 (52), 175 (51).
FTIR (film): 2964, 2933, 2874, 1506, 1432, 1324, 1194, 1091.
Anal. Calcd. for C16 : C, 69.93; H, 6.97; N, 10.19. Found: C, 70.16; H, 6.81; N, 10.17.
H19ClN
2
1
2

ACCEPTED MANUSCRIPT
5
,5-Dimethyl-2-(4-nitrophenyl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole (25ba)
Yield: 178 mg (71 %), yellow solid. MP 176.5–178.5 °C.
Reaction time and purification: 3 h, preparative TLC (AcOEt/PE = 2:8).
1
3
3
H NMR 8.21 (d, J = 8.9, 2H, Ar), 7.89 (d, J = 8.9, 2H, Ar), 6.36 (s, 1H, =CH), 3.95 (s, 2H, N-CH ), 2.74
2
(
1
s, 2H, =C-CH
3
2
), 1.33 (s, 6H, 2×CH
C NMR 153.0 (N=C), 147.1 (N-C), 146.8 (C), 140.7 (C), 125.7 (2×CH), 124.2 (2×CH), 97.9 (=CH), 61.3
N-CH ), 43.3 (H C-C-CH ), 38.9 (=C-CH ), 28.3 (2×CH ).
3
).
(
2
3
3
2
3
+
GC-MS m/z (%): 257 (M , 100), 242 (38), 216 (18), 202 (21).
FTIR (KBr): 2964, 2939, 2874, 1600, 1511, 1344, 1314, 1107.
Anal. Calcd. for C14
H
15
N
3
O : C, 65.35; H, 5.88; N, 16.33. Found: C, 65.28; H, 5.78; N, 16.40.
2
4
,5,5-Trimethyl-2-(4-nitrophenyl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole (25bb)
Yield: 223 mg (89 %), yellow solid. MP 154.0–155.5 °C.
Reaction time and purification: 0.5 h, preparative TLC (AcOEt/PE = 2:8).
1
3
3
H NMR 8.20 (d, J = 8.6, 2H, Ar), 7.90 (d, J = 8.6, 2H, Ar), 6.35 (s, 1H,
2
2
3
=
CH), 3.94 (d, J = 10.9, 1H, N-CH
2
), 3.92 (d, J = 10.9, 1H, N-CH
2
), 2.94 (q, J = 7.3, 1H, HC-CH
3
), 1.28
3
(s, 3H, CH
3
), 1.23 (d, J = 7.3, 3H, HC-CH
3
), 1.11 (s, 3H, CH ).
3
1
3
C NMR 152.6 (N=C), 152.1 (N-C), 146.8 (C), 140.8 (C), 125.6 (2×CH), 124.2 (2×CH), 97.0 (=CH), 61.2
N-CH ), 46.2 (H C-C-CH ), 42.1 (HC-CH ), 26.7 (CH ), 22.6 (CH ), 12.9 (HC-CH ).
(
2
3
3
3
3
3
3
+
GC-MS m/z (%): 271 (M , 84), 256 (46), 216 (100), 170 (38), 115 (21).
FTIR (KBr): 2967, 2933, 2875, 1599, 1513, 1344, 1310, 1106.
Anal. Calcd. for C15
H
17
N
3
O : C, 66.40; H, 6.32; N, 15.49. Found: C, 66.51; H, 6.28; N, 15.56.
2
4
-Ethyl-5,5-dimethyl-2-(4-nitrophenyl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole (25bc)
Yield: 218 mg (87 %), yellow solid. MP 99.5–101.0 °C.
Reaction time and purification: 0.5 h, preparative TLC (AcOEt/PE = 2:8).
1
3
3
H NMR 8.23 (d, J = 9.0, 2H, Ar), 7.92 (d, J = 9.0, 2H, Ar), 6.42 (s, 1H,
2
2
=
CH), 3.94 (d, J = 10.9, 1H, N-CH
2
), 3.90 (d, J = 10.9, 1H, N-CH
2
), 2.69
), 1.33–1.55 (m, 1H, CH
3
3
(dd, J = 10.7, J = 4.5, 1H, HC-Et), 1.58–1.79 (m, 1H, CH
2
CH
3
2
CH ), 1.28 (s, 3H,
3
3
CH
3
), 1.15 (t, J = 7.3, 3H, CH
2
CH
3
), 1.15 (s, 3H, CH
3
).
13
C NMR 152.6 (N=C), 150.8 (N-C), 146.9 (C), 140.8 (C), 125.7 (2×CH), 124.3 (2×CH), 98.3 (=CH), 61.3
(
N-CH
2
3 3
), 49.9 (HC-Et), 46.3 (H C-C-CH ), 27.7 (CH
3
), 22.8 (CH
3
), 21.7 (CH
2
CH
3
), 12.9 (CH
2
CH ).
3
+
GC-MS m/z (%): 285 (M , 100), 270 (42), 256 (86), 230 (62), 186 (45), 140 (31).
FTIR (KBr): 2965, 2935, 2874, 2847, 1602, 1507, 1349, 1317, 1109.
Anal. Calcd. for C16
H
19
N
3
O : C, 67.35; H, 6.71; N, 14.73. Found: C, 67.36; H, 6.68; N, 14.57.
2
1
3

ACCEPTED MANUSCRIPT
5
,5-Dimethyl-2-(thiofen-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole (25bd)
Yield: 110 mg (44 %), yellow solid. MP 84.9–85.9 °C.
Reaction time and purification: 7 h, HPFC (DCM).
1
3
3
H NMR 7.26 (d, J = 2.6, 1H, Ar), 7.18 (d, J = 4.7, 1H, Ar), 6.98–7.03 (m, 1H, Ar), 6.16 (s, 1H, =CH),
.88 (s, 2H, N-CH ), 2.67 (s, 2H, =C-CH ), 1.28 (s, 6H, 2×CH ).
3
2
2
3
13
C NMR 150.6 (N=C), 146.3 (N-C), 137.8 (C), 127.4 (CH), 123.9 (CH), 123.0 (CH), 96.7 (=CH), 61.2 (N-
CH
2
), 43.2 (H
3
C-C-CH
3
), 38.9 (=C-CH
2
), 28.3 (2×CH ).
3
+
GC-MS m/z (%): 218 (M , 100), 203 (23), 177 (17), 134 (25).
FTIR (KBr): 2956, 2925, 2859, 1593, 1526, 1461, 1433, 1385, 1320, 1265, 1219, 1186, 1118, 1047.
HRMS Calcd. for C12
H
15
N S: 219.0956. Found: 219.0941.
2
4
,5,5-Trimethyl-2-(thiofen-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole (25be)
Yield: 203 mg (81 %), yellowish oil.
Reaction time and purification: 3 h, HPFC (DCM).
1
3
4
3
4
3
3
H NMR 7.26 (dd, J = 3.6, J = 1.1, 1H, Ar), 7.16 (dd, J = 5.1, J = 1.1, 1H, Ar), 7.00 (dd, J = 5.1, J = 3.6,
2
2
3
1
1
H, Ar), 6.14 (s, 1H, =CH), 3.87 (d, J = 10.7, 1H, N-CH
2
), 3.83 (d, J = 10.7, 1H, N-CH
2
), 2.85 (q, J = 7.2,
3
H, HC-CH
3
), 1.21 (s, 3H, CH
3
), 1.16 (d, J = 7.2, 3H, HC-CH
3
), 1.05 (s, 3H, CH ).
3
13
C NMR 151.4 (N=C), 150.0 (N-C), 137.8 (C), 127.3 (CH), 123.7 (CH), 122.8 (CH), 95.7 (=CH), 60.9 (N-
CH
2
), 45.9 (H
3
C-C-CH
3
), 41.9 (HC-CH
3
), 26.7 (CH
3
), 22.5 (CH
3
), 12.9 (HC-CH ).
3
+
GC-MS m/z (%): 232 (M , 100), 217 (27), 191 (15), 177 (53), 147 (32), 108 (18).
FTIR (film): 2964, 2932, 2872, 1560, 1531, 1465, 1394, 1329, 1313, 1222, 1188, 1173, 1095, 1051.
HRMS Calcd. for C13
H
17
N S: 233.1112. Found: 233.1116.
2
5
,5-Dimethyl-2-(thiofen-2-yl)-4-trimethylsilyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole (25bf)
Yield: 73 mg (29 %), yellow oil.
Reaction time and purification: 7.5 h at 110 °C, HPFC (DCM).
1
3
3
3
3
H NMR 7.28 (d, J = 3.6, 1H, Ar), 7.18 (d, J = 5.0, 1H, Ar), 7.02 (dd, J = 5.0, J =
.6, 1H, Ar), 6.07 (s, 1H, =CH), 3.83 (bs, 2H, N-CH ), 2.20 (s, 1H, HC-TMS), 1.31 (s, 3H, CH
CH ), 0.15 (s, 9H, TMS).
3
2
3
), 1.30 (s, 3H,
3
13
C NMR 150.2 (N=C), 149.5 (N-C), 138.0 (C), 127.5 (CH), 123.9 (CH), 123.0 (CH), 96.1 (=CH), 62.0 (N-
CH
2
), 47.1 (H
3
3
C-C-CH ), 40.1 (HC-TMS), 30.3 (CH
3
), 26.5 (CH ), -0.8 (TMS).
3
+
GC-MS m/z (%): 290 (M , 31), 275 (100), 73 (94), 45 (15).
FTIR (film): 2961, 2932, 2893, 2877, 1558, 1514, 1466, 1392, 1372, 1326, 1252, 1221, 1120, 1053.
HRMS Calcd. for C15 SSi: 291.1351. Found: 291.1349.
H N
23 2
2
-(Furan-2-yl)-5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole (25bg)
Yield: 153 mg (61 %), colorless oil.
Reaction time and purification: 6 h, HPFC (DCM/Et O = 7:1).
2
1
4

ACCEPTED MANUSCRIPT
1
3
H NMR 7.39 (bs, 1H, Ar), 6.59 (d, J = 2.6, 1H, Ar), 6.41 (bs, 1H, Ar), 6.17 (s, 1H, =CH), 3.86 (s, 2H, N-
CH
2
), 2.65 (s, 2H, =C-CH
2
), 1.25 (s, 6H, 2×CH
3
).
13
C NMR 149.6 (N=C), 147.5 (N-C), 145.8 (C), 141.2 (CH), 111.1 (CH), 104.7 (CH), 96.4 (=CH), 60.9 (N-
CH
2
), 43.1 (H
3
C-C-CH
3
), 38.6 (=C-CH
2
), 28.0 (2×CH ).
3
+
GC-MS m/z (%): 202 (M , 100), 187 (19), 161 (17), 147 (15), 118 (18), 89 (15).
FTIR (film): 2959, 2872, 1538, 1485, 1466, 1441, 1376, 1352, 1323, 1264, 1202, 1149, 1078, 1010.
HRMS Calcd. for C12
H
15
N O: 203.1184. Found: 203.1167.
2
2
-(Furan-2-yl)-4,5,5-trimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole (25bh)
Yield: 238 mg (95 %), yellow oil.
Reaction time and purification: 3 h, HPFC (DCM/AcOEt = 10:1).
1
3
3
H NMR 7.38 (bs, 1H, Ar), 6.59 (d, J = 3.3, 1H, Ar), 6.40 (d, J = 3.3, 1H, Ar), 6.16
2
2
3
(s, 1H, =CH), 3.85 (d, J = 10.7, 1H, N-CH
2
), 3.82 (d, J = 10.7, 1H, N-CH
), 2.83 (q, J = 7.2, 1H, HC-CH
2
3
),
3
1
.19 (s, 3H, CH
3
), 1.13 (d, J = 7.2, 3H, HC-CH
3
), 1.02 (s, 3H, CH
3
).
13
C NMR 150.7 (N=C), 149.5 (N-C), 147.0 (C), 141.0 (CH), 110.9 (CH), 104.4 (CH), 95.3 (=CH), 60.5 (N-
CH
2
), 45.8 (H
3
C-C-CH
3
), 41.6 (HC-CH
3
), 26.3 (CH
3
), 22.1 (CH
3
), 12.5 (HC-CH ).
3
+
GC-MS m/z (%): 216 (M , 100), 201 (25), 175 (16), 161 (52), 132 (39), 92 (16), 78 (16).
FTIR (film): 2964, 2934, 2872, 1540, 1483, 1469, 1455, 1375, 1338, 1316, 1197, 1149, 1079, 1009.
HRMS Calcd. for C13
H
17
N O: 217.1341. Found: 217.1334.
2
2
-(Furan-2-yl)-5,5-dimethyl-4-trimethylsilyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole (25bi)
Yield: 63 mg (25 %), yellow oil.
Reaction time and purification: 10 h at 110 °C, HPFC (DCM/AcOEt = 15:1).
1
3
3
H NMR 7.40 (bs, 1H, Ar), 6.61 (d, J = 3.3, 1H, Ar), 6.43 (d, J = 3.3, 1H, Ar), 6.10
2
2
(s, 1H, =CH), 3.84 (d, J = 10.7, 1H, N-CH ), 3.81 (d, J = 10.7, 1H, N-CH ), 2.20 (s, 1H, HC-TMS), 1.30 (s,
2
2
3
H, CH
3
), 1.29 (s, 3H, CH
3
), 0.15 (s, 9H, TMS).
13
C NMR 149.9 (N=C), 149.1 (N-C), 147.3 (C), 141.4 (CH), 111.3 (CH), 104.8 (CH), 96.0 (=CH), 61.9 (N-
CH
2
), 47.2 (H
3
3
C-C-CH ), 40.0 (HC-TMS), 30.2 (CH
3
), 26.5 (CH ), -0.8 (TMS).
3
+
GC-MS m/z (%): 274 (M , 25), 259 (86), 73 (100), 45 (17).
FTIR (film): 2960, 2876, 1524, 1464, 1425, 1374, 1322, 1251, 1196, 1120, 1078, 1009.
HRMS Calcd. for C15 OSi: 275.1580. Found: 275.1584.
H N
23 2
5
,5-Dimethyl-2-(naphthalen-1-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole (25bj)
Yield: 200 mg (80 %), white solid. MP 101.7–101.8 °C.
Reaction time and purification: 7 h, HPFC (AcOEt/PE = 1:4).
1
3
3
3
H NMR 8.58 (d, J = 8.8, 1H, Ar), 7.85 (d, J = 8.9, 1H, Ar), 7.81 (d, J = 8.2, 1H,
3
Ar), 7.68 (d, J = 7.1, 1H, Ar), 7.42–7.52 (m, 3H, Ar), 6.25 (s, 1H, =CH), 3.99 (s,
H, N-CH ), 2.76 (s, 2H, =C-CH ), 1.33 (s, 6H, 2×CH ).
2
2
2
3
1
5

ACCEPTED MANUSCRIPT
13
C NMR 155.2 (N=C), 145.5 (N-C), 134.1 (C), 132.7 (C), 131.6 (C), 128.4 (CH), 128.1 (CH), 127.0 (CH),
1
26.5 (CH), 126.3 (CH), 125.8 (CH), 125.5 (CH), 100.5 (=CH), 61.4 (N-CH
2
), 43.2 (CH
3
-C-CH ), 39.2 (=C-
3
CH ), 28.5 (2×CH ).
2
3
+
GC-MS m/z (%): 262 (M , 100), 230 (13), 178 (14), 152 (11).
FTIR (KBr): 3051, 2957, 2925, 2882, 1591, 1544, 1485, 1464, 1378, 1314, 1259, 1215, 1179, 1013.
Anal. Calcd. for C18 : C, 82.41; H, 6.92; N, 10.68. Found: C, 82.73; H, 6.96; N, 10.90.
H N
18 2
4
,5,5-Trimethyl-2-(naphthalen-1-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole (25bk)
Yield: 230 mg (92 %), colorless oil.
Reaction time and purification: 4 h, HPFC (DCM).
1
3
H NMR 8.67 (d, J = 8.3, 1H, Ar), 7.66–7.83 (m, 3H, Ar), 7.36–7.50 (m, 3H, Ar),
2
2
6
2
.21 (s, 1H, =CH), 3.90 (d, J = 10.6, 1H, N-CH
.80 (q, J = 7.2, 1H, HC-CH
2
), 3.85 (d, J = 10.6, 1H, N-CH
2
),
3
3
3
), 1.12 (s, 3H, CH
3
), 1.10 (d, J = 7.2, 3H, HC-CH
3
), 0.99 (s, 3H, CH ).
3
1
3
C NMR 154.4 (N=C), 150.3 (N-C), 133.9 (C), 132.5 (C), 131.3 (C), 128.1 (CH), 127.8 (CH), 126.7 (CH),
26.4 (CH), 125.9 (CH), 125.5 (CH), 125.2 (CH), 99.3 (=CH), 60.9 (N-CH ), 45.7 (CH -C-CH ), 41.8 (HC-
1
2
3
3
CH
3
), 26.5 (CH
3
), 22.4 (CH
3
), 12.8 (HC-CH ).
3
+
GC-MS m/z (%): 276 (M , 100), 261 (14), 221 (38), 191 (22), 152 (20).
FTIR (film): 3049, 2964, 2933, 2871, 1592, 1540, 1461, 1378, 1359, 1312, 1261, 1219, 1162, 1012.
HRMS Calcd. for C19 : 277.1705. Found: 277.1690.
H N
21 2
5
,5-Dimethyl-2-(naphthalen-1-yl)-4-trimethylsilyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole (25bl)
Yield: 53 mg (21 %), yellow oil.
Reaction time and purification: 7.5 h at 110 °C, HPFC (DCM).
1
3
3
3
H NMR 8.60 (d, J = 8.1, 1H, Ar), 7.86 (d, J = 8.3, 1H, Ar), 7.81 (d, J = 8.2, 1H,
3
2
Ar), 7.70 (d, J = 7.0, 1H, Ar), 7.44–7.52 (m, 3H, Ar), 6.17 (s, 1H, =CH), 3.94 (d, J
=
9
2
10.5, 1H, N-CH
H, TMS).
2
), 3.92 (d, J = 10.5, 1H, N-CH
2
), 2.29 (s, 1H, HC-TMS), 1.36 (bs, 6H, 2×CH ), 0.18 (s,
3
1
3
C NMR 154.7 (N=C), 148.5 (N-C), 134.2 (C), 132.7 (C), 131.7 (C), 128.4 (CH), 128.1 (CH), 127.0 (CH),
26.6 (CH), 126.3 (CH), 125.7 (CH), 125.5 (CH), 100.0 (=CH), 62.2 (N-CH ), 47.2 (CH -C-CH ), 40.2 (HC-
1
2
3
3
TMS), 30.2 (CH
3
), 26.7 (CH ), -0.7 (TMS).
3
+
GC-MS m/z (%): 334 (M , 29), 319 (100), 73 (65), 45 (12).
FTIR (film): 3072, 2961, 2930, 2877, 1525, 1466, 1379, 1360, 1323, 1252, 1221, 1198, 1121, 1015.
HRMS Calcd. for C21 Si: 335.1944. Found: 335.1940.
H N
27 2
2
-(Anthracen-9-yl)-5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole (25bm)
Yield: 193 mg (77 %), yellow solid. MP 157.0–158.0 °C.
Reaction time and purification: 7 h, HPFC (AcOEt/PE = 1:4).
1
3
3
H NMR 8.47 (s, 1H, Ar), 8.04 (d, J = 8.8, 2H, Ar), 8.00 (d, J = 8.3, 2H, Ar), 7.43
3
3
(t, J = 7.0, 2H, Ar), 7.41 (t, J = 7.1, 2H, Ar), 6.20 (s, 1H, =CH), 4.08 (s, 2H, N-
CH ), 2.88 (s, 2H, =C-CH ), 1.43 (s, 6H, 2×CH ).
2
2
3
1
6

ACCEPTED MANUSCRIPT
13
C NMR 152.6 (N=C), 145.7 (N-C), 131.6 (2×C), 131.4 (2×C), 130.1 (C), 128.4 (2×CH), 127.4 (CH), 127.2
(
2×CH), 125.6 (2×CH), 125.2 (2×CH), 103.0 (=CH), 61.5 (N-CH
2
), 43.5 (CH
3
-C-CH
3
), 39.4 (=C-CH ), 28.6
2
(2×CH ).
3
+
GC-MS m/z (%): 312 (M , 100).
FTIR (KBr): 3049, 2961, 2928, 2881, 1601, 1539, 1463, 1370, 1318, 1266, 1233.
HRMS Calcd. for C22 : 313.1705. Found: 313.1698.
H N
21 2
2
-(Anthracen-9-yl)-4,5,5-trimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole (25bn)
Yield: 230 mg (92 %), yellow solid. MP 117.9–118.4 °C.
Reaction time and purification: 3.5 h, HPFC (AcOEt/PE = 1:4).
1
H NMR 8.49 (s, 1H, Ar), 7.98–8.06 (m, 4H, Ar), 7.35–7.50 (m, 4H, Ar), 6.21 (s,
3
1
1
H, =CH), 4.09 (bs, 2H, N-CH
2
), 3.11 (q, J = 7.2, 1H, HC-CH
3
), 1.40 (s, 3H, CH ),
3
3
.33 (d, J = 7.2, 3H, HC-CH
3
), 1.24 (s, 3H, CH
C NMR 152.1 (N=C), 150.8 (N-C), 131.6 (2×C), 131.5 (2×C), 130.2 (C), 128.4 (2×CH), 127.3 (CH), 127.2
2×CH), 125.6 (2×CH), 125.2 (2×CH), 102.1 (=CH), 61.4 (N-CH ), 46.5 (CH -C-CH ), 42.5 (HC-CH ), 27.0
3
).
13
(
(
2
3
3
3
CH
3
), 22.9 (CH
3
) 13.2 (HC-CH ).
3
+
GC-MS m/z (%): 327 (M , 100), 241 (11), 202 (12).
FTIR (KBr): 3051, 2966, 2935, 2875, 1537, 1467, 1379, 1315, 1172, 1096, 911.
Anal. Calcd. for C23 : C, 84.63; H, 6.79; N, 8.58. Found: C, 84.18; H, 7.00; N, 8.25.
H N
22 2
2
-(Anthracen-9-yl)-5,5-dimethyl-4-trimethylsilyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole (25bo)
Yield: 58 mg (23 %), yellow oil.
Reaction time and purification: 8 h at 110 °C, HPFC (DCM/hexane = 3:1).
1
3
3
H NMR 8.50 (s, 1H, Ar), 8.06 (d, J = 8.6, 2H, Ar), 8.02 (d, J = 8.6, 2H, Ar),
2
7
.40–7.52 (m, 4H, Ar), 6.17 (s, 1H, =CH), 4.07 (d, J = 10.5, 1H, N-CH
2
), 4.04 (d,
2
J = 10.5, 1H, N-CH
.25 (s, 9H, TMS).
2
), 2.42 (s, 1H, HC-TMS), 1.47 (s, 3H, CH
3
), 1.46 (s, 3H, CH ),
3
0
1
3
C NMR 152.0 (N=C), 148.7 (N-C), 131.6 (2×C), 131.4 (2×C), 130.2 (C), 128.4 (2×CH), 127.3 (CH), 127.1
2×CH), 125.6 (2×CH), 125.2 (2×CH), 102.5 (=CH), 62.2 (N-CH ), 47.4 (CH -C-CH ), 40.3 (HC-TMS), 30.5
(
(
2
3
3
CH
3
), 26.8 (CH
3
), -0.7 (TMS).
+
GC-MS m/z (%): 384 (M , 100), 369 (99), 73 (94), 45 (12).
FTIR (film): 3051, 2959, 2874, 1522, 1447, 1347, 1315, 1251, 1118, 1013.
HRMS Calcd. for C25 Si: 385.2100. Found: 385.2108.
H N
29 2
5
,5-Dimethyl-2-(4-dimethylaminophenyl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole (25bp)
Yield: 200 mg (80 %), orange solid. MP 136.1–137.0 °C.
Reaction time and purification: 7 h, HPFC (DCM /AcOEt = 1:1).
1
3
3
H NMR 7.65 (d, J = 8.8, 2H, Ar), 6.73 (d, J = 8.8, 2H, Ar), 6.15 (s, 1H, =CH), 3.89 (s, 2H, N-CH
s, 6H, N(CH ), 2.68 (s, 2H, =C-CH ), 1.29 (s, 6H, 2×CH ).
2
), 2.95
(
3
)
2
2
3
1
7

ACCEPTED MANUSCRIPT
13
C NMR 156.2 (N=C), 150.2 (C), 146.1 (N-C), 126.4 (2×CH), 123.2 (C), 112.7 (2×CH), 95.6 (=CH), 61.2
(
N-CH
GC-MS m/z (%): 255 (M , 100).
FTIR (KBr): 2952, 2922, 2899, 2884, 2866, 2809, 1614, 1529, 1434, 1360, 1320, 1230, 1203, 1167.
HRMS Calcd. for C16 : 256.1814. Found: 256.1806.
2
), 43.1 (H
3
C-C-CH
3
), 40.7 (N(CH
3
)
2
), 39.1 (=C-CH
2
), 28.5 (2×CH
3
).
+
22
H N
3
2
-Ethyl-4-(4-methoxyphenyl)-5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole (25bq)
Yield: 208 mg (83 %), colorless oil.
Reaction time and purification: 5 h, HPFC (DCM/AcOEt = 5:1).
1
3
3
H NMR 7.04 (d, J = 8.5, 2H, Ar), 6.85 (d, J = 8.5, 2H, Ar), 5.76 (s, 1H, =CH), 3.96 (s,
2
2
1
OCH
H, HC-Ar), 3.94 (d, J = 10.4, 1H, N-CH
2
), 3.88 (d, J = 10.4, 1H, N-CH
), 1.33 (s, 3H, CH
2
), 3.78 (s, 3H,
CH ),
3
3
), 2.68 (q, J = 7.6, 2H, CH
2
CH
3
3
), 1.27 (t, J = 7.6, 3H, CH
2
3
3
0
.74 (s, 3H, CH
3
).
C NMR 158.9 (N=C), 158.8 (C), 148.2 (N-C), 130.1 (C), 129.6 (2×CH), 113.7 (2×CH), 97.9 (=CH), 60.6
N-CH ), 55.3 (HC-Ar), 53.5 (OCH ), 47.6 (CH -C-CH ), 27.4 (CH ), 24.2 (CH ), 22.3 (CH CH ), 14.0
CH CH ).
13
(
(
2
3
3
3
3
3
2
3
2
3
+
GC-MS m/z (%): 270 (M , 43), 215 (100), 199 (23), 171 (15), 159 (17), 128 (20).
FTIR (film): 3025, 2958, 2932, 2874, 2835, 1612, 1513, 1461, 1248, 1178, 1032.
HRMS Calcd. for C17 O: 271.1810. Found: 271.1808.
H N
23 2
2
-Benzyl-4-(4-methoxyphenyl)-5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole (25br)
Yield: 208 mg (83 %), colorless oil.
Reaction time and purification: 5 h, HPFC (DCM/AcOEt = 6:1).
1
3
H NMR 7.26–7.31 (m, 4H, Ph), 7.13–7.21 (m, 1H, Ph), 7.01 (d, J = 8.7, 2H, Ar),
3
2
6
1
3
.83 (d, J = 8.7, 2H, Ar), 5.70 (s, 1H, =CH), 4.00 (bs, 2H, N-CH
2
), 3.96 (d, J =
2
0.4, 1H, CH
2
-Ph), 3.94 (s, 1H, HC-Ar), 3.89 (d, J = 10.4, 1H, CH
2
-Ph), 3.78 (s,
H, OCH ), 1.32 (s, 3H, CH
3
3
), 0.74 (s, 3H, CH ).
3
1
3
C NMR 159.0 (C), 156.1 (N=C), 148.6 (N-C), 140.5 (C), 130.0 (C), 129.8 (2×CH), 129.0 (2×CH), 128.6
2×CH), 126.2 (CH), 113.9 (2×CH), 99.3 (=CH), 60.8 (N-CH ), 55.4 (HC-Ar), 53.7 (OCH ), 47.8 (CH -C-
(
2
3
3
CH
3
), 35.8 (CH
2
-Ph), 27.5 (CH
3
), 24.3 (CH ).
3
+
GC-MS m/z (%): 332 (M , 41), 277 (100), 199 (17), 185 (20), 91 (33).
FTIR (film): 3027, 2958, 2931, 2873, 2836, 1612, 1511, 1463, 1247, 1178, 1033.
HRMS Calcd. for C22
H
25
2
N O: 333.1967. Found: 333.1951.
2
-Ethyl-5,5-dimethyl-4-phenyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole (25bs)
Yield: 228 mg (91 %), colorless oil.
Reaction time and purification: 5 h, HPFC (AcOEt/PE = 1:3).
1
3
H NMR 7.23–7.36 (m, 3H, Ph), 7.12 (d, J = 6.9, 2H, Ph), 5.78 (s, 1H, =CH), 4.01 (s,
2
2
3
1
1
H, HC-Ph), 3.96 (d, J = 10.4, 1H, N-CH
2
), 3.91 (d, J = 10.4, 1H, N-CH
2
), 2.69 (q, J = 7.6, 2H, CH
2
CH ),
3
3
.36 (s, 3H, CH
3
), 1.27 (t, J = 7.6, 3H, CH
2
CH
3
), 0.75 (s, 3H, CH ).
3
1
8

ACCEPTED MANUSCRIPT
13
C NMR 159.1 (N=C), 148.1 (N-C), 138.3 (C), 128.8 (2×CH), 128.5 (2×CH), 127.4 (CH), 98.1 (=CH), 60.8
(
N-CH
2
), 54.4 (HC-Ph), 47.8 (CH
3
-C-CH
3
), 27.7 (CH
3
), 24.4 (CH
3
), 22.5 (CH CH
2 3
), 14.1 (CH
2
CH ).
3
+
GC-MS m/z (%): 240 (M , 52), 199 (21), 185 (100), 115 (18).
FTIR (film): 3062, 3029, 2964, 2873, 1949, 1729, 1602, 1536, 1494, 1465, 1382, 1309, 1143, 1076.
HRMS Calcd. for C16 : 241.1705. Found: 241.1688.
H N
21 2
5
,5-Dimethyl-4-phenyl-2-propyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole (25bt)
Yield: 205 mg (82 %), colorless oil.
Reaction time and purification: 5 h, HPFC (AcOEt/PE = 1:3).
1
2
H NMR 7.27–7.34 (m, 3H, Ph), 7.10–7.14 (m, 2H, Ph), 5.77 (s, 1H, =CH), 4.02 (s, 1H, HC-Ph), 3.95 (d, J
2
=
10.4, 1H, N-CH
2
), 3.91 (d, J = 10.4, 1H, N-CH
2
), 2.60–2.65 (m, 2H, CH
2
CH
2
CH ), 1.64–1.75 (m, 2H,
3
3
CH CH ), 1.36 (s, 3H, CH
2
3
3
), 0.98 (t, J = 7.4, 3H, CH CH ), 0.74 (s, 3H, CH ).
2
3
3
1
3
C NMR 157.7 (N=C), 148.0 (N-C), 138.3 (C), 128.8 (2×CH), 128.5 (2×CH), 127.4 (CH), 98.7 (=CH), 60.8
N-CH ), 54.4 (HC-Ph), 47.8 (CH -C-CH ), 31.4 (CH CH CH ), 27.7 (CH ), 24.4 (CH ), 23.2 (CH CH ), 14.2
CH CH ).
(
(
2
3
3
2
2
3
3
3
2
3
2
3
+
GC-MS m/z (%): 254 (M , 24), 226 (100), 213 (23), 199 (91), 115 (31), 59 (17), 45 (20).
FTIR (film): 3027, 2962, 2925, 2871, 1947, 1731, 1652, 1536, 1494, 1456, 1382, 1076.
HRMS Calcd. for C17
H
23
N : 255.1861. Found: 255.1845.
2
5
,5-Dimethyl-4-(4-nitrophenyl)-2-(prop-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole (25bu)
Yield: 220 mg (88 %), yellow oil.
Reaction time and purification: 5 h, HPFC (AcOEt/PE = 1:3).
1
3
3
H NMR 8.20 (d, J = 8.6, 2H, Ar), 7.31 (d, J = 8.6, 2H, Ar), 5.79 (s, 1H, =CH), 4.13
2
2
(s, 1H, HC-Ph), 3.99 (d, J = 10.6, 1H, N-CH
2
), 3.96 (d, J = 10.6, 1H, N-CH
2
), 3.00
),
3
3
(
0
sep, J = 6.9, 1H, HC-(CH
.77 (s, 3H, CH ).
3
)
2
), 1.40 (s, 3H, CH
3
), 1.29 (d, J = 6.9, 6H, HC-(CH
3 2
)
3
13
C NMR 164.3 (N=C), 147.6 (C), 146.5 (C), 146.2 (C), 129.7 (2×CH), 123.8 (2×CH), 97.0 (=CH), 60.7 (N-
CH
2 3 3
), 54.2 (HC-Ar), 48.2 (CH -C-CH ), 28.8 (HC-(CH
3
2
) ), 27.8 (CH
3
), 24.5 (CH
3
), 23.2 (CH
3
), 23.1 (CH ).
3
+
GC-MS m/z (%): 299 (M , 51), 284 (37), 258 (42), 244 (100), 163 (21), 151 (23), 129 (20), 43 (31).
FTIR (film): 2362, 2338, 1642, 1597, 1516, 1388, 1343, 1088.
HRMS Calcd. for C17
H
22
N
3
O : 300.1712. Found: 300.1721.
2
2
-Benzyl-5,5-dimethyl-4-(4-nitrophenyl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole (25bv)
Yield: 205 mg (82 %), yellow oil.
Reaction time and purification: 5 h, HPFC (AcOEt/PE = 1:3).
1
3
H NMR 8.17 (d, J = 8.7, 2H, Ar), 7.25–7.30 (m, 6H, Ar+Ph), 7.17–7.22 (m,
1
H, Ph), 5.72 (s, 1H, =CH), 4.11 (s, 1H, HC-Ar), 3.97–4.02 (m, 4H, N-CH
2
+ CH -
2
Ph), 1.39 (s, 3H, CH ), 0.76 (s, 3H, CH ).
3
3
1
9

ACCEPTED MANUSCRIPT
13
C NMR 156.8 (N=C), 147.5 (C), 146.9 (C), 145.9 (N-C), 140.2 (C), 129.6 (2×CH), 129.0 (2×CH), 128.7
(
2×CH), 126.4 (CH), 123.8 (2×CH), 99.5 (=CH), 60.8 (N-CH
2
), 54.2 (HC-Ar), 48.2 (CH
3
-C-CH
3
), 35.8 (CH -
2
Ph), 27.7 (CH ), 24.4 (CH ).
3
3
+
GC-MS m/z (%): 347 (M , 91), 321 (20), 306 (21), 292 (100), 256 (27), 246 (22), 214 (34), 184 (31), 168
23), 128 (20), 115 (30), 91 (57), 65 (22).
(
FTIR (film): 3029, 2971, 2925, 2873, 1660, 1600, 1517, 1444, 1346, 1106, 1014.
HRMS Calcd. for C21 : 348.1712. Found: 348.1692.
H
22
N
3
O
2
5
,5-Dimethyl-4-(4-morpholinomethyl)-2-(4-nitrophenyl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole
(
25bw)
Yield: 210 mg (84 %), orange solid. MP 194.2–194.4 °C.
Reaction time and purification: 2 h, recrystallization (Et O).
2
1
3
3
H NMR 8.23 (d, J = 8.6, 2H, Ar), 7.92 (d, J = 8.6, 2H, Ar), 6.44 (s, 1H,
3
=
CH), 3.95 (bs, 2H, N-CH
2
), 3.73–3.80 (m, 4H, O-CH
2
), 3.11 (t, J = 7.6, 1H,
).
HC-CH ), 2.41–2.67 (m, 6H, N-CH
2
2
), 1.38 (s, 3H, CH ), 1.16 (s, 3H, CH
3
3
13
C NMR 152.9 (N=C), 149.8 (N-C), 147.0 (C), 140.8 (C), 125.8 (2×CH), 124.3 (2×CH), 98.5 (=CH), 67.3
(
2
2×O-CH
2.9 (CH
2
), 62.0 (N-N-CH
).
2
), 57.5 (HC-CH
2
), 54.2 (2×N-CH
2
), 46.1 (H
3
C-C-CH
3
), 44.1 (HC-CH
2
), 27.3 (CH ),
3
3
+
GC-MS m/z (%): 355 (M , 5), 213 (31), 207 (27), 166 (21), 137 (33), 123 (29), 109 (36), 97 (100), 81
(
27), 67 (44), 43 (36), 41 (59).
FTIR (KBr): 2968, 2923, 1652, 1601, 1514, 1455, 1418, 1344, 1263, 1114.
HRMS Calcd. for C19 : 357.1927. Found: 357.1937.
H
25
N
4
O
4
4. Bromination of dimethylated dihydropyrrolo[1,2-b]pyrazoles with NBS
The bicyclic compound 25as or 25ax (200 mg) was dissolved in chloroform (10 mL) and 1.05 eq NBS
was added. The mixture was stirred at room temperature, diluted with CHCl (10 mL), washed with
and concentrated in vacuo. Brown solids were purified by a
3
water (3×15 mL), dried over MgSO
4
column chromatography.
3
-Bromo-2-(4-methoxyphenyl)-4,5,5-trimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole (25bx)
Yield: 230 mg (83 %), white solid. MP 45.4–45.5 °C.
Reaction time and purification: 90 min, HPFC (DCM/AcOEt = 40:1).
1
3
3
2
H NMR 7.81 (d, J = 8.8, 2H, Ar), 6.94 (d, J = 8.8, 2H, Ar), 3.90 (d, J = 10.6,
2
3
3
1
H, N-CH
2
), 3.85 (d, J = 10.6, 1H, N-CH
2
), 3.81 (s, 3H, OCH
3
), 2.91 (q, J = 7.3, 1H, HC-CH
3
), 1.26 (d, J =
7
3
.3, 3H, HC-CH ), 1.24 (s, 3H, CH
3
), 1.12 (s, 3H, CH
3
).
13
C NMR 159.5 (C), 151.8 (N=C), 148.8 (C), 128.9 (2×CH), 125.7 (C), 113.8 (2×CH), 85.2 (C-Br), 61.5 (N-
CH
2
), 55.3 (OCH
3
), 45.6 (H
3
C-C-CH
3
), 42.6 (HC-CH
3
), 27.4 (CH
3
), 22.5 (CH
3
), 12.2 (HC-CH ).
3
+
GC-MS m/z (%): 336 (M +1, 100), 334 (100), 279 (13), 255 (17), 171 (91), 128 (31).
2
0