A convenient one-pot two-step synthesis of pyrazolylphosphonates from ethynylphosphonate

Article abstract of DOI:10.1016/j.mencom.2021.07.033

A convenient one-pot preparation of pyrazol-3-ylphosphonates involves Cu-catalyzed cross-coupling of acyl chlorides with diethyl ethynylphosphonate followed by heterocyclization with hydrazine.

Full text of DOI:10.1016/j.mencom.2021.07.033

Mendeleev
Communications
Mendeleev Commun., 2021, 31, 536–537
A convenient one-pot two-step synthesis
of pyrazolylphosphonates from ethynylphosphonate
Alexander Yu. Mitrofanov* and Irina P. Beletskaya*
Department of Chemistry, M. V. Lomonosov Moscow State University, 119991 Moscow, Russian Federation.
Fax: +7 495 939 1139; e-mail: mitrofanov@org.chem.msu.ru, beletska@org.chem.msu.ru
DOI: 10.1016/j.mencom.2021.07.033
2. Nꢃ2Nꢃ2
O
R
PꢁOꢂꢁOEtꢂ2
ꢄ2ꢅꢆꢇꢈ
10 eꢉamꢊles
R ꢋ Arꢌ Alk
ꢃN
A convenient one-pot preparation of pyrazol-3-ylphospho-
nates involves Cu-catalyzed cross-coupling of acyl chlorides
with diethyl ethynylphosphonate followed by hetero-
cyclization with hydrazine.
N
R
Cl
1.
ꢀ
PꢁOꢂꢁOEtꢂ2
CuIꢌ DIPEA
Cꢃ2Cl2
Keywords: ynones, cross-coupling, pyrazoles, phosphonates, copper catalysis.
The pyrazole ring is a constituent of various biologically active
compoundsusedasdrugs, pesticides, etc. Hence, thedevelopment
of new methods for their synthesis is an urgent problem.1
Phosphorus-containing pyrazoles obtained recently2–10 are also
of interest due to their biological activity (for examples, see
Online Supplementary Materials, Figure S1).
Conjugated ynones are actively used in the synthesis of
numerous heterocyclic compounds, including pyrazoles.11 They
can react with nucleophiles according to 1,2- or 1,4-addition
mechanism, which in the case of binucleophiles would lead to
heterocyclic compounds in general as two regioisomers, while
often this addition proceeds selectively.Ynones can also undergo
various cycloaddition reactions. In general, ynones were used in
the synthesis of pyrazoles, pyrimidines, pyridines, quinolines,
benzodiazepines, triazoles, etc.11–13Among them, conjugated
ynones bearing phosphoryl group are hardly investigated due to
their low availability based on existing methods.14–16
During our work on the development of syntheses of new
heterocyclic phosphonates,17–20 we proposed that conjugated
ynones of (3-oxoprop-1-yn-1-yl)phosphonate type could be
convenient starting compounds to access various heterocyclic
phosphonates, including pyrazoles. In this work, we have
developed a new convenient method for the preparation of
(3-oxoprop-1-yn-1-yl)phosphonates using Cu-catalyzed cross-
coupling of available acyl chlorides and diethyl ethynyl-
phosphonate, and utilized it for the one-pot synthesis of
pyrazolylphosphonates.
First, we optimized the conditions for the preparation of
(3-oxoprop-1-yn-1-yl)phosphonates using model benzoyl
chloride 1a and diethyl ethynylphosphonate 2 (Scheme 1). When
CuI is used as the precatalyst in the presence of ligands (Table 1,
entries 1–3), the reaction proceeds in CH2Cl2 at room temperature
giving diethyl (3-oxo-3-phenylprop-1-yn-1-yl)phosphonate 3a
only in moderate yields, with significant formation of oxidative
homocoupling product. However, in the absence of ligands
homocoupling did not occur, and the desired phosphonate 3a
was formed in 90% analytical yield (31P NMR) and was isolated
in 80% yield (entry 4). Interestingly, inorganic bases were found
to be ineffective (entries 5, 6), while DIPEA was the best choice
of base. Among solvents, dichloromethane proved to be the most
suitable one (entries 7–9).
The conditions developed for 3a were used for the synthesis
of a series of phosphoryl-substituted ynones 3b–k (see
Scheme 1). The benzoyl chlorides containing either electron
donating or electron withdrawing group reacted with
ethynylphosphonate 2 providing the corresponding ynones 3b–h
in good yields. The best yields were observed in the cases of
R
O
O
i
+
R
P(O)(OEt)2
P(O)(OEt)2
3a–k
Cl
1a–k
2
R = Ph, 80%
R = 4-MeOC6H4, 71%
R = 2-MeOC6H4, 71%
R = 4-MeC6H4, 73%
e R = 4-FC6H4, 70%
R = 4-ClC6H4, 81%
R = 4-BrC6H4, 79%
R = 4-F3CC6H4, 75%
R = But, 90%
R = adamantan-1-yl, 90%
R = Me, 24%
a
b
c
g
h
i
j
k
d
f
Scheme 1 Reagents and conditions: i, 1/2/DIPEA (1:1:1 molar ratio),
CuI (10 mol%), CH2Cl2 (4 ml mmol–1), room temperature, 16 h. Yields are
given for 0.25 mmol scale, the yield for 3a in 6 mmol scale was 83%.
Table 1 Optimization of conditions for the reaction between diethyl
ethynylphosphonate 2 and benzoyl chloride 1a.a
Entry
Ligand (mol%)
Solvent
Base
Yieldb (%)
1
2
3
4
5
6
7
8
9
phen (10)
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
toluene
THF
DIPEA
DIPEA
DIPEA
DIPEA
Cs2CO3
K2CO3
DIPEA
DIPEA
DIPEA
45
TMEDA (10)
50
PPh3 (20)
63
–
–
–
–
–
–
90 (80)
0
0
15
34
MeCN
25
aReaction conditions: CuI (4.8 mg, 0.025 mmol), ligand (0.025–0.05 mmol),
ethynylphosphonate 2 (40.5 mg, 0.25 mmol), benzoyl chloride 1a (32 µl,
0.25 mmol), base (0.25 mmol), solvent (1 ml), room temperature, 16 h.
b From 31P NMR data, isolated yield is given in parentheses.
© 2021 Mendeleev Communications. Published by ELSEVIER B.V.
on behalf of the N. D. Zelinsky Institute of Organic Chemistry of the
Russian Academy of Sciences.
– 536 –

Mendeleev Commun., 2021, 31, 536–537
P(O)(OEt)2
This work was supported by the Russian Science Foundation
(grant no. 19-73-00168, synthesis of compounds 3a–k, and grant
no. 19-13-00223, one-pot synthesis of compounds 4a–j).
O
i
ii
N
+
R
P(O)(OEt)2
[3a–j]
R
N
H
Cl
1a–j
2
4a–j
Online Supplementary Materials
Supplementary data associated with this article can be found
in the online version at doi: 10.1016/j.mencom.2021.07.033.
R = Ph, 80%
R = 4-ClC6H4, 78%
R = 4-BrC6H4, 73%
R = 4-F3CC6H4, 73%
R = But, 89%
f
a
b
c
d
e
R = 4-MeOC6H4, 74%
R = 2-MeOC6H4, 73%
R = 4-MeC6H4, 72%
R = 4-FC6H4, 72%
g
h
i
References
R = adamantan-1-yl, 85%
j
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aliphatic acyl chlorides 1i,j. However, acetyl chloride 1k gave
the corresponding product 3k only in 24% yield. Importantly, the
procedure was good for scaling up as ynone 3a was obtained by
application of 24-fold amount of reactants in 83% yield (1.32 g).
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developed for the synthesis of (3-oxoprop-1-yn-1-yl)-
phosphonates 3, in the synthesis of phosphonylpyrazoles without
preliminary isolation. In fact, when the reaction between acyl
chlorides 1a–j and diethyl ethynylphosphonate 2 was complete,
the futher addition of hydrazine hydrate to the reaction mixture
provided quantitative (31P NMR data) formation of the
corresponding pyrazoles 4a–j (Scheme 2).†
In conclusion, a convenient procedure for the preparation of
(3-oxoprop-1-yn-1-yl)phosphonates by the Cu-catalyzed cross-
coupling of acyl chlorides with diethyl ethynylphosphonate was
developed. On this basis, a one-pot two-step synthesis of pyrazol-
3-ylphosphonates has been proposed. Further study of the
possibility of the application of (3-oxoprop-1-yn-1-yl)-
phosphonates to the synthesis of other heterocyclic phosphonates
is now underway.
†
General procedure for the synthesis of (3-oxoprop-1-yn-1-yl)-
phosphonates 3a–k and pyrazol-3-ylphosphonates 4a–j. A 8 ml glass
vial was charged with diethyl ethynylphosphonate
2 (40.5 mg,
0.25 mmol), CuI (4.8 mg, 0.025 mmol), DIPEA (40 µl, 0.25 mmol), dry
dichloromethane (1 ml) and acyl chloride 1a–k (0.25 mmol) under Ar.
The vial was closed with Teflon cap, and the mixture was stirred at room
temperature for 16 h. For the preparation of 3a–k, the mixture was
evaporated, and the residue was purified by column chromatography on
silica gel using EtOAc–hexane as the eluent. For the preparation of 4a–j,
when the first reaction was complete (16 h), hydrazine hydrate (18 µl,
0.375 mmol) was added, and the mixture was stirred for more 1 h. The
solvent was evaporated, and the residue was purified by column
chromatography on silica gel using CH2Cl2–MeOH as the eluent. Known
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data being in agreement with previously reported ones. New compounds
were fully characterized (see Online Supplementary Materials).
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Received: 22nd March 2021; Com. 21/6500
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