A cascade reaction of cinnamyl azides with vinyl sulfones directly generates dihydro-pyrrolo-pyrazole heterocycles

Article abstract of DOI:10.1016/j.tetlet.2021.152860

This report describes the direct synthesis of dihydro-pyrrolo-pyrazole heterocycles from allylic azides and methyl vinyl sulfone. The product results from a complex cascade reaction that is operationally straightforward, with aromatization being the result of a concomitant elimination step. A variety of azides could participate in this reaction (12 examples) and the isolated yields of the desired product ranged from 51%?72%. Lastly the ethylene sulfone group could be removed by heating the product in pyrrolidine.

Full text of DOI:10.1016/j.tetlet.2021.152860

Tetrahedron Letters 67 (2021) 152860
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A cascade reaction of cinnamyl azides with vinyl sulfones directly
generates dihydro-pyrrolo-pyrazole heterocycles
⇑
Angela S. Carlson, Alexandru M. Petre, Joseph J. Topczewski
Department of Chemistry, University of Minnesota Twin Cities, Minneapolis, MN 55455, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
This report describes the direct synthesis of dihydro-pyrrolo-pyrazole heterocycles from allylic azides
and methyl vinyl sulfone. The product results from a complex cascade reaction that is operationally
straightforward, with aromatization being the result of a concomitant elimination step. A variety of
azides could participate in this reaction (12 examples) and the isolated yields of the desired product ran-
ged from 51%À72%. Lastly the ethylene sulfone group could be removed by heating the product in
pyrrolidine.
Received 26 October 2020
Revised 5 January 2021
Accepted 13 January 2021
Available online 3 February 2021
Keywords:
Azide
Ó 2021 Elsevier Ltd. All rights reserved.
Vinyl sulfone
Pyrrolidine
Pyrazole
Cascade reaction
Many pharmaceuticals, agrochemicals, and natural products
contain one or more nitrogen heterocycles.[1,2] Both aromatic
and saturated nitrogen heterocycles are prevalent in these soci-
etally important molecules. Thus, developing and manufacturing
novel agents often requires efficient and robust synthetic access
to differentially substituted N-heterocycles. While a plethora of
synthetic routes are available for some of the most common N-
heterocycles, more complex fused systems often lack expedient
and direct access.
The dihydro-pyrrolo-pyrazole ring system is a fused N-hetero-
cyclic framework featuring an aromatic pyrazole ring fused to a
pyrrolidine (Fig. 1). This fused ring system is a key substructure
in omarigliptin, which is an approved treatment for type 2 dia-
betes,[3] and danusertib, which entered clinical trials to treat
chronic myelogenous leukemia (Fig. 1).[4,5] The dihydro-pyrrolo-
pyrazole substructure also appears in a glycine transporter-1 inhi-
bitor, a P21-activated kinase inhibitor, and elsewhere.[6,7] Versa-
tile synthetic routes to dihydro-pyrrolo-pyrazole heterocycles are
lacking, which is surprising in light of the stated utility. Current
methods to synthesize dihydro-pyrrolo-pyrazoles are primarily
based on carbonyl condensation with hydrazine (Scheme 1).
Exposing 1,3-diketones or b-keto-nitriles to hydrazine can gener-
ate the pyrazole (Scheme 1a).[8] Other prefunctionalized ketones
can condense with hydrazine (Scheme 1b).[3,8,9] Alternatively,
an intramolecular dipolar cycloaddition is possible (Scheme 1c).
[10,11] While effective, these approaches require preformation of
the substrate. Ideally, there would be a divergent method to gener-
ate a wide variety of these heterocycles directly from simple start-
ing materials.
We envisioned accessing dihydro-pyrrolo-pyrazole heterocy-
cles from allylic azides. Previously, we reported a cascade reaction
between cinnamyl azides and commodity acrylates to form
tetrahydro-pyrrolo-pyrazoles (Scheme 2).[12] The proposed mech-
anism for this cascade reaction begins with a (3 + 2)-cycloaddition
between the azide and electron deficient alkene to generate triazo-
line 3.[13–19] This triazoline can equilibrate to the corresponding
diazo species 4 and amine bases can facilitate this equilibrium.
[18,20] Diazo 4 can undergo an intramolecular (3 + 2)-cycloaddi-
tion to generate tetrahydro-pyrrolo-pyrazole 5.[21,22] Tautomer-
ization to the conjugated isomer (6) generated the product
previously reported.[21,22] This reaction was remarkably effective
at generating a diverse family of complex heterocycles from a vari-
ety of Michael acceptors.
Conceivably, by using a Michael acceptor that could subse-
quently eliminate, the cascade reaction could be extended a step
further to aromatization (Scheme 2, step v). This would result in
a dihydro-pyrrolo-pyrazole ring system (7). To explore this possi-
bility, our previous reaction conditions were screened against a
variety of Michael acceptors. Gratifyingly, when vinyl methyl sul-
fone was utilized, the reaction afforded the desired dihydro-pyr-
rolo-pyrazole. However, in the presence of excess methyl vinyl
sulfone, the amine underwent a conjugate addition to generate
compound 2. A detailed analysis of this reaction mixture also
⇑
Corresponding author.
E-mail address: jtopczew@umn.edu (J.J. Topczewski).
https://doi.org/10.1016/j.tetlet.2021.152860
040-4039/Ó 2021 Elsevier Ltd. All rights reserved.
0

A.S. Carlson, A.M. Petre and J.J. Topczewski
Tetrahedron Letters 67 (2021) 152860
Table 1
Reaction Optimization with Methyl Vinyl Sulfone.
entry
solvent
base
equiv MVS
1aa (%)
2aa (%)
1
2
3
4
5
6
7
8
9
C
6
H
6
TEA
TEA
TEA
TEA
TEA
TEA
DIPEA
DIPA
TEA
TEA
TEA
3
3
3
3
3
3
3
3
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
52
65
58
68
57
54
72
28
64
32
57
70
MeCN
IPA
MeOH
DCE
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Fig. 1. Select Biologically Active Molecules Containing a Dihydro-pyrrolo-pyrazole.
1.2
2
4
1
1
0
1
30
n.d.
a
Reactions were conducted with azide 1b (70 mmol), methyl vinyl sulfone (84,
40, 210, or 280 mmol), and base (35 mmol) in solvent (0.2 M) at 70 °C for 48 h.
Conversion and yield were determined by H NMR analysis with dibenzylether as
the internal standard. Not determined = n.d. MVS = methyl vinyl sulfone.
1
1
The equivalents of methyl vinyl sulfone were reduced in an
attempt to prevent the conjugate addition and isolate the free
amine (Table 1, entries 9–10). Unfortunately, reducing the equiv-
alents simply led to low conversion. The eliminated sulfinic acid
could consume an equivalent of methyl vinyl sulfone, with the
dimer being isolated as a side product (shown in header). This
prevented reducing the equivalents of methyl vinyl sulfone
below three equivalents. Conveniently, this side product is fairly
insoluble and can be removed by filtration. Three equivalents of
methyl vinyl sulfone in dioxane with TEA (entry 6) were taken
as optimal.
Scheme 1. Prior Syntheses of Dihydro-pyrrolo-pyrazoles.
Using the optimized conditions, the model substrate (1a) was
isolated in 72% yield (Table 2). Ethyl vinyl sulfone and phenyl vinyl
sulfone were also competent in the reaction (2b and 2c).
The cascade reaction was performed with a variety of cinnamyl
azides (Table 3). The reaction can tolerate electron donating and
electron withdrawing substituents on the arene (2d–2g). Also, the
benzene ring could be replaced by a thiophene (2h), benzothiophene
(2i), or furan (2j). Substrates with electron neutral arenes generally
performed worse and were difficult to isolate (not shown). However,
when substituents were added onto the azide carbon, the reaction
proceeded well (2k–2l). Only substrates with an aryl group were
examined in this reaction because alkyl allylic azides undergo the
Winstein rearrangement.[23–25] This rearrangement generally
causes the starting allylic azide to exist as a mixture of equilibrating
isomers and complicates the reaction mixture. Installing an aryl
Scheme 2. Cascade Reaction with Allylic Azides.
Table 2
Scope of vinyl sulfones.
revealed that some of the triazoline had undergone premature
elimination to generate the N-substituted 1,2,3-triazole (8).
The cascade reaction was subjected to a systematic optimiza-
tion (Table 1). The reaction tolerated a range of solvents (entries
1
–6), as might be expected for a cycloaddition sequence. Dioxane
proved optimal for the dihydro-pyrrolo-pyrazole product. As previ-
ously mentioned, premature elimination to the triazole is one of
the primary side products. Because of this, alternate amine bases
were screened with the hope of slowing the rate of triazole forma-
tion. The use of TEA afforded the highest yield (Table 1).
Yields are reported for isolated and purified products. Yield values reflect the
average of duplicate trials. See Supporting Information for details.
2

A.S. Carlson, A.M. Petre and J.J. Topczewski
Tetrahedron Letters 67 (2021) 152860
group biases the equilibrium so that only one azide isomer is
observed and provides some polarization to the alkene.
During the course of these studies, dynamic NMR behavior was
frequently observed. This was attributed to the two different NH
tautomers that are possible on the pyrazole ring. The tautomeriza-
tion often resulted in significant broadening of the resonances in
1
13
Scheme 3. Removing the protecting group.
both the H and C NMR. This was true in many common NMR sol-
vents including CDCl , CD Cl , MeOD, DMSO, and MeCN. It was
3
2
2
Declaration of Competing Interest
found that in AcOD, both tautomers were independently visible
for some compounds. The optimal NMR solvent was substrate
dependent, but a mixture of MeCN and AcOD frequently limited
the broadening and easily dissolved the compounds. Compounds
The authors declare that they have no known competing finan-
cial interests or personal relationships that could have appeared
to influence the work reported in this paper.
2
c and 2g were crystallized and analyzed by X-ray diffraction
(Fig. 2). Interestingly, the diffraction pattern was most consistent
with each being a different tautomer, which supports a dynamic
equilibrium. The location of the NH has been arbitrarily drawn
through this report.
Acknowledgements
En-chih Liu, Margaret Clapham, and Dr. Victor Young Jr. are
thanked for their assistance with X-ray crystallography. This
research was supported by the National Institute of General Med-
ical Sciences of the National Institutes of Health under Award
Number R35GM124718. We also acknowledge NIH Shared Instru-
mentation Grant #S10OD011952. A.S.C. gratefully acknowledges
support from the Wayland E. Noland Fellowship and UMN Doctoral
Dissertation Fellowship.
The ethyl sulfone group attached to the pyrrolidine nitrogen
could be useful in its own right or potentially viewed as a protect-
ing group. This group was easily removed by simply heating the
compound in pyrrolidine (Scheme 3). Presumably, this is a retro-
aza-Michael addition followed by an aza-Michael addition with
excess pyrrolidine.
In conclusion a new cascade reaction has been developed to
generate dihydro-pyrrolo-pyrazoles directly from cinnamyl azides
and vinyl sulfones. The yields for this cascade reaction are modest,
but acceptable given the large increase in molecular complexity
and number of competing reaction pathways. Removal of the ethy-
lene sulfone group can be easily accomplished.
Appendix A. Supplementary data
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tetlet.2021.152860.
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