Vinylation of α-Aminoazoles with Triethylamine: A General Strategy to Construct Azolo[1,5-a]pyrimidines with a Nonsubstituted Ethylidene Fragment

Article abstract of DOI:10.1021/acs.orglett.1c00571

A new general synthesis of pharmaceutically important azolo[1,5-a]pyrimidines starting from widely available 3(5)-aminoazoles, aldehydes, and triethylamine is developed. The key is to enable the vinylation reaction that allows the in situ generation of elusive acyclic enamines and the subsequent annulation reaction to occur. This direct and practical strategy is capable of constructing a range of 5,6-unsubstituted pyrazolo[1,5-a]pyrimidines and [1,2,4]triazolo[1,5-a]pyrimidines. More importantly, this protocol provides a concise synthetic route to prepare the clinically used zaleplon.

Full text of DOI:10.1021/acs.orglett.1c00571

pubs.acs.org/OrgLett
Letter
Vinylation of α‑Aminoazoles with Triethylamine: A General Strategy
to Construct Azolo[1,5‑a]pyrimidines with a Nonsubstituted
Ethylidene Fragment
Qinghe Gao,∥ Zhenhua Sun,∥ Qinfei Xia,∥ Ruonan Li, Wenlong Wang, Siwei Ma, Yixin Chai,
́
̋
Manman Wu, Wei Hu, Péter Abrányi-Balogh, György M. Keseru, and Xinya Han*
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ABSTRACT: A new general synthesis of pharmaceutically important azolo[1,5-a]pyrimidines starting from widely available 3(5)-
aminoazoles, aldehydes, and triethylamine is developed. The key is to enable the vinylation reaction that allows the in situ generation
of elusive acyclic enamines and the subsequent annulation reaction to occur. This direct and practical strategy is capable of
constructing a range of 5,6-unsubstituted pyrazolo[1,5-a]pyrimidines and [1,2,4]triazolo[1,5-a]pyrimidines. More importantly, this
protocol provides a concise synthetic route to prepare the clinically used zaleplon.
he development of highly efficient and new routes to
Tfused-ring skeletons has been among the most active
areas of research in synthetic chemistry.1 Especially attractive
in this area are annulation reactions that employ readily
available feedstock materials as C2 building blocks for the
assembly of polycyclic (hetero)aromatic scaffolds.2 Despite
their significance, most of these reactions cannot install a
nonsubstituted vinylene fragment, which significantly restricts
the practical value of these methods in medicinal and
pharmaceutical chemistry.3 Although acetylene represents the
simplest and inexpensive C2 unit, the methods of acetylene
annulation are still quite limited.4 This might stem from safety
concerns about operating with the gas-phase reactant.
Therefore, new acetylene surrogates have been explored for
the construction of nonsubstituted vinylene-fused compounds.
Early in 2014, Raw and coworkers described the rhodium-
catalyzed annulation for the synthesis of 3,4-unsubstituted
isoquinolones using vinyl acetate as a safe alternative to
acetylene.5 Similarly, the Cheng team successfully synthesized
3,4-unsubstituted isoquinolines from vinyl acetate and
ketoximes in the rhodium-catalyzed reaction systems.6 In
2019, N-vinyl formamide as an acetylene surrogate was applied
to form 3,4-unsubstituted isoquinolones by the Chen group.7
Furthermore, You realized a rhodium-catalyzed three-compo-
nent approach to ring-fused pyridiniums, wherein 1,2-
dichloroethane served as a vinyl equivalent to generate N-
vinylpyridiniums.8 Most recently, Miura et al. used vinylene
carbonate as a vinylene transfer agent to achieve the assembly
of a nonsubstituted vinylene-fused scaffold.9 Obviously, there
is a continuous need for new reagents that could be used as a
C2 building block in the vinylene annulation protocol. Herein
we report a novel vinylation reaction of α-aminoazoles with
triethylamine, enabling the regioselective synthesis of 5,6-
unsubstituted azolo[1,5-a]pyrimidines with wide substrate
scopes.
Heterocycle-fused pyrimidine represents one of the most
privileged motifs across pharmaceuticals.10 Among them all,
pyrazolo[1,5-a]pyridine derivatives that possess a broad
spectrum of potential biological activities may become a vital
building block in drug discovery.11 Several approved drugs,
Received: February 17, 2021
Published: March 18, 2021
https://doi.org/10.1021/acs.orglett.1c00571
© 2021 American Chemical Society
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a
namely, zaleplon, indiplon, lorediplon, and ocinaplon, which
belong to nonbenzodiazepine sedative and hypnotic agents, are
used in clinical practice. These marketed drugs and other
bioactive molecules with pyrazolo[1,5-a]pyrimidines share
common structural features, including 5,6-unsubstitution and
diverse (hetero)aryl groups at the C-7 position (Scheme 1a).12
Table 1. Optimization of the Reaction Conditions
b
entry
[I]
oxidant
solvent
temp. (°C)
yield (%)
Scheme 1. Selected Examples of Bioactive Pyrazolo[1,5-
a]pyridines and Methods for the Synthesis of Pyrazolo[1,5-
a]pyridines
1
2
3
4
5
6
7
8
NH4I
NIS
I2
DTBP
DTBP
DTBP
DTBP
DTBP
TBHP
DCP
BPO
TBPB
CHP
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
dioxane
CH3CN
DCE
DMF
DMSO
THF
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
130
130
130
130
130
130
130
130
130
130
130
130
130
130
130
130
130
130
130
140
120
110
130
130
130
130
83
69
70
trace
74
trace
81
trace
trace
trace
0
trace
62
63
24
34
30
57
87
87
76
62
KI
TBAI
NH4I
NH4I
NH4I
NH4I
NH4I
NH4I
NH4I
NH4I
NH4I
NH4I
NH4I
NH4I
NH4I
NH4I
NH4I
NH4I
NH4I
NH4I
NH4I
NH4I
NH4I
9
10
11
12
13
14
15
16
17
18
19
20
21
22
H2O2
air
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
c
23
24
25
26
68
87
67
65
d
e
f
a
Reaction conditions: 1a (0.5 mmol), 2a (0.5 mmol), 3a (1.5 mmol),
[I] (0.5 mmol), oxidant (1.5 mmol), solvent (2 mL) for 10 h.
b
c
d
Isolated yields. NH4I (0.1 mmol, 20 mol %). NH4I (0.5 mmol)
e
f
and 3a (1.0 mmol). NH4I (0.5 mmol) and 3a (0.5 mmol). 1a (10
mmol), 2a (10 mmol), and 3a (20 mmol).
However, to date, access to 5,6-unsubstituted pyrazolo[1,5-
a]pyrimidines generally relies on the cyclocondensation
reaction of 3(5)-aminoazoles with β-enaminones, but this
method has poor regioselectivity and requires the preliminary
preparation of β-enaminones (Scheme 1b). In 2018, Ellman
disclosed formyl sulfoxonium ylide as a potential C2 building
block to obtain pyrazolo[1,5-a]pyrimidines possessing no
substitution at the C-6 and C-7 positions with opposite
regioselectivities (Scheme 1c).13 Driven by these studies, we
present the first direct vinylation of 3(5)-aminoazoles with
triethylamine to provide a new general route to 5,6-
unsubstituted 7-arylpyrazolo[1,5-a]pyrimidines (Scheme 1d).
Moreover, the vinyl reaction is superior to the rapid
background reaction from the condensation between 3(5)-
aminoazoles and aldehydes to form terminal enamines. This
transformation enriches the synthesis of the important drug-
like scaffolds in a simple, efficient, and practical process.
Initially, commercially accessible benzaldehyde (1a), ethyl 3-
amino-1H-pyrazole-4-carboxylate (2a), and triethylamine (3a)
were selected as the model substrates to commence our
investigation (Table 1). The reaction was performed using
NH4I and DTBP in PhCl at 130 °C when the desired product
ethyl 7-phenylpyrazolo[1,5-a]pyrimidine-3-carboxylate (4aa)
was obtained in 83% yield (Table 1, entry 1). It is noteworthy
that only isomer 4aa was gained under this condition. In
contrast, the present reaction did not work when KI was used
instead of NH4I (Table 1, entry 4). Then, we found that the
selection of peroxide was important for this annulation
reaction. DTBP was the best oxidant, followed by DCP, and
other peroxide oxidants, such as TBHP, BPO, TBPB, CHP,
and H2O2, were all ineffective (Table 1, entries 6−11).
Notably, a trace amount of 4aa was produced in the absence of
an additional oxidant (Table 1, entry 12). To obtain higher
yields, we next conducted a survey of several solvents.
Unfortunately, most of the tested solvents including dioxane,
acetonitrile, 1,2-dichloroethane, DMF, DMSO, and THF could
not increase the yield of this transformation (Table 1, entries
13−18). Delightedly, the yield of 4aa could be slightly
increased to 87% in toluene (Table 1, entry 19). In addition,
reducing the reaction temperature and the amount of NH4I
had an adverse influence on the reaction (Table 1, entries 21−
23). Finally, the reaction using 2.0 equiv of 3a provided a
uniform result. Significantly, the efficiency and selectivity were
not affected when the transformation was carried out on a
gram scale (Table 1, entry 26).
With the optimized reaction conditions in hand, we further
examined several cyclic and acyclic ethyl amines (3b−3k) as
the C2 building block to react with benzaldehyde and ethyl 3-
amino-1H-pyrazole-4-carboxylate for the preparation of 5,6-
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unsubstituted pyrazolo[1,5-a]pyrimidines (Scheme 2).
Although N,N-diisopropylethylamine (3e), N,N-dimethyle-
compatible with this annulation reaction and provided the
desired product 4ma in 47% yield. Further investigation
manifested that other aromatic aldehydes such as 2-
naphthaldehyde, 1-naphthaldehyde, pyridine-3-carbaldehyde,
formylthiophene, and indole-3-carboxaldehyde were at least
moderately favorable to this transformation and gave rise to
the target products 4na−4ra in 42−82% yields. It is notable
that no formation of a 5-arylpyrazolo[1,5-a]pyrimidine side
product was observed in any example. Astonishingly, aliphatic
aldehydes that are liable to intervene in iminium from 3a could
also deliver the corresponding alkylated pyrazolo[1,5-a]-
pyrimidines (4sa and 4ta), albeit in lower yields (32−34%).
We next evaluated the scope of α-aminoazoles (Scheme 4).
In the case of 3-aminopyrazoles, a number of electron-deficient
Scheme 2. Representative Ethyl Amines
Scheme 4. Substrate Scope of α-Aminoazoles, Tertiary
Alkylamines, and Aldehydes
thanamine (3f), and diethylamine (3j) gave 4aa in yields of
37, 61, and 85%, respectively, the ethyl groups installed on
other amines were not amenable to this transformation.
Next, we investigate the compatibility of this novel
annulation process with a wide range of aldehydes (Scheme
3). Benzaldehydes with a methyl at the para and meta positions
Scheme 3. Substrate Scope of Aldehydes
functionalities such as ester (73%, 4ab), amide (83%, 4ac),
nitrile (81%, 4ad), and phenyl (84%, 4ae) were tolerated in
this present NH4I-based reaction system. In contrast, 5-methyl-
1H-pyrazol-3-amine was not an effective substrate, as an
inseparable mixture was formed. Meanwhile, 5-aminopyrazoles
as substrates also tolerated this transformation well and
displayed similar reactivities as 3-aminopyrazoles. Tripropyl-
amine could also be subjected to the annulation reaction to
produce a 6-methylpyrazolo[1,5-a]pyrimidine derivative in
satisfactory yield (84%, 4af). Intriguingly, the versatility of this
protocol was further mirrored by the successfully used 3(5)-
amino-1,2,4-triazole, which provided a robust access to a series
of [1,2,4]triazolo[1,5-a]pyrimidines (74−80%, 4ag−4ai). In
fact, it is well known that [1,2,4]triazolo[1,5-a]pyrimidine
widely occurs in bioactive compounds.14 Recent drug
discovery efforts with [1,2,4]triazolo[1,5-a]pyrimidine deriva-
tives have focused on anti-influenza,15 anti-Alzheimer’s
disease,16 and anticancer therapeutics.17 Hence, several
(het)arylaldehydes and 3(5)-amino-1,2,4-triazole smoothly
furnished the desired bicyclic-fused pyrimidines in good yields
(75−85%, 4ba and 4ca), whereas only a 50% yield of 4da was
obtained from ortho-methylbenzaldehyde. These results
demonstrated that the position of the substituent could affect
the reaction yield. Other substituents such as tert-butyl (91%,
4ea), methoxy (89%, 4fa), fluoro (87%, 4ia), chloro (84%,
4ja), bromo (80%, 4ka), and trifluoromethyl (90%, 4la) at the
para position were all compatible, and multisubstituted
aldehydes also efficiently reacted to afford the final products
4ga and 4ha in 74−81% yields. Remarkably, a substrate
bearing the strongly electron-withdrawing nitro group was still
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underwent this procedure with complete regioselectivity,
leading to the corresponding products (4aj−4aq) in 47−
84% yields.
To further explore the practical utility of this annulation
strategy in medicinal chemistry settings, this approach was
applied for the concise synthesis of the clinically used hypnotic
drug zaleplon (Scheme 5). Starting from commercially
pyrimidine rings are derived from triethylamine. We then
attempted to add radical scavengers TEMPO and BHT to stop
the reaction; however, the reaction could still proceed normally
(Scheme 6b). These findings support the notion that the
present process may not involve a radical intermediate.
Although the treatment of cinnamaldehyde (7) with 3-
aminopyrazole (2a) generated the desired pyrazolo[1,5-
a]pyrimidine in 80% yield (Scheme 6c), it was not considered
to be the intermediate because cinnamaldehyde was barely
detected when benzaldehyde (1a) reacted with acetaldehyde
under the standard conditions in the absence of 2a (Scheme
6d). It is known that triethylamine could also generate N,N-
diethylethenamine;18 however, this was not the case for this
reaction because the reaction performed with enamine (8) did
not occur (Scheme 6e). Furthermore, we analyzed the mixture
after 30 min of reaction, in which the vinylation product of 3-
aminopyrazole was clearly detected by HRMS. (See the
Supporting Information.) This observation indicates that 3-
aminopyrazole prefers to capture imine intermediates
produced by Et3N. In addition, aerial oxygen and NH4I were
identified as indispensable for the preparation of 4aa (Scheme
6f,g).
Scheme 5. Concise Strategy for the Synthesis of Zaleplon
available 3-nitrobenzaldehyde (1m), 3-amino-4-cyanopyrrole
(2d), and triethylamine (3a), the three-component annulation
protocol proceeded smoothly and gave the precursor 5 in 86%
yield. The desired zaleplon 6 was subsequently obtained in
70% yield (overall yield for two steps) from 5 via hydro-
genation−acetylation followed by ethylation. Thus the syn-
thesis of zaleplon can now be accomplished in only three steps
and in good overall yield.
To gain better insight into this transformation mechanism,
the present annulation with 3a-D15 was investigated, and the
target deuterated product 4aa-Dn was obtained in 89% yield
(Scheme 6a). This result reveals that the two carbons of the
On the basis of the above results and previous reports,19
a
plausible mechanism has been proposed (Scheme 7). The heat
Scheme 7. Plausible Mechanism
Scheme 6. Control Experiments
splits NH4I, which is believed to be the initial step. This
produces HI followed by further rapid oxidation to generate I2.
Then, the oxidation of Et3N with elemental iodine and DTBP
results in the formation of the iminium intermediate B, which
proceeds through the nucleophilic addition of 3-aminopyrazole
(2a) to afford the intermediate C. Next, the key vinylation
product D is formed from C through the elimination of
Et2NH. Significantly, the aldehyde can react with intermediate
D to render intermediate F. Then, intermediate F undergoes
direct pericyclic sigmatropic cyclization followed by hydrogen
and double-bond shifts leading to dihydropyrazolo[1,5-a]-
pyrimidine H. Finally, H translates into product 4aa through
oxidative aromatization.
In summary, we have developed a new general strategy for
the regioselective synthesis of a wide range of 5,6-
unsubstituted pyrazolo[1,5-a]pyrimidine and [1,2,4]triazolo-
[1,5-a]pyrimidine derivatives from commercially available
building blocks by using an appropriate combination of
NH4I and DTBP with aerial oxygen. The unique nature of
this reaction was that the undesired condensation, a prevalent
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Notes
reaction from 3(5)-aminoazoles and aldehydes, was prevented
by the direct vinylation reaction. Notably, the reaction is
enabled by an NH4I-based reaction system that allows the in
situ generation of acyclic enamines that act as nucleophiles in
this annulation process. The synthetic utility of this reaction is
further demonstrated by the concise synthesis of the clinically
used hypnotic drug zaleplon.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful to the National Key R&D Program of China
(no. 2017YFE0118200), the Anhui Key Research and
Development Program (no. 201904b11020025), the Natural
Science Foundation of Anhui Province (no. 1908085MB35),
and the China-Hungary Cooperation Committee Regular
Meeting Exchange Project (nos. 2018-II-2 and 2018-2.1.14-
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c00571.
́
TET-CN-2018-00013) for financial support.
General experimental procedures and spectroscopic data
for the corresponding products (PDF)
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AUTHOR INFORMATION
Corresponding Author
■
Xinya Han − School of Chemistry and Chemical Engineering,
Anhui University of Technology, Maanshan, Anhui 243002,
P. R. China; Email: xinyahan@ahut.edu.cn
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Qinghe Gao − School of Pharmacy, Xinxiang Medical
University, Xinxiang, Henan 453003, P. R. China;
orcid.org/0000-0002-6207-8933
Zhenhua Sun − School of Pharmacy, Xinxiang Medical
University, Xinxiang, Henan 453003, P. R. China
Qinfei Xia − School of Chemistry and Chemical Engineering,
Anhui University of Technology, Maanshan, Anhui 243002,
P. R. China
Ruonan Li − School of Pharmacy, Xinxiang Medical
University, Xinxiang, Henan 453003, P. R. China
Wenlong Wang − School of Pharmacy, Xinxiang Medical
University, Xinxiang, Henan 453003, P. R. China
Siwei Ma − School of Pharmacy, Xinxiang Medical University,
Xinxiang, Henan 453003, P. R. China
Yixin Chai − School of Pharmacy, Xinxiang Medical
University, Xinxiang, Henan 453003, P. R. China
Manman Wu − School of Pharmacy, Xinxiang Medical
University, Xinxiang, Henan 453003, P. R. China
Wei Hu − School of Chemistry and Chemical Engineering,
Anhui University of Technology, Maanshan, Anhui 243002,
P. R. China
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Péter Abrányi-Balogh − Medicinal Chemistry Research
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György M. Keseru − Medicinal Chemistry Research Group,
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Complete contact information is available at:
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(7) Sun, R.; Yang, X.; Li, Q.; Xu, K.; Tang, J.; Zheng, X.; Yuan, M.;
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Author Contributions
∥Q.G., Z.S., and Q.X. contributed equally.
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