Nef-isocyanide-Perkow access to novel pyrazolone derivations containing a cyclic ketene dithioacetal moiety

Article abstract of DOI:10.1080/00397911.2018.1560474

Alkyl (E)-2-(3-Alkyl-5-oxo-1-phenyl-1,5-dihydro-4H-pyrazol-4-ylidene)-5-(alkylamino)-1,3-dithiole-4-carboxylates have been obtained by condensation of 2-pyrazolin-5-ones with carbon disulfide followed by ring formation with phosphorylated hydroxyketenimin

Full text of DOI:10.1080/00397911.2018.1560474

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Nef-isocyanide-Perkow access to novel pyrazolone
derivations containing a cyclic ketene dithioacetal
moiety
Issa Yavari, Jamil Sheykhahmadi, Hamed Saffarian & Mohammad Reza
Halvagar
To cite this article: Issa Yavari, Jamil Sheykhahmadi, Hamed Saffarian & Mohammad Reza
Halvagar (2019): Nef-isocyanide-Perkow access to novel pyrazolone derivations containing a cyclic
ketene dithioacetal moiety, Synthetic Communications, DOI: 10.1080/00397911.2018.1560474
To link to this article: https://doi.org/10.1080/00397911.2018.1560474
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https://doi.org/10.1080/00397911.2018.1560474
Nef-isocyanide-Perkow access to novel pyrazolone
derivations containing a cyclic ketene dithioacetal moiety
Issa Yavaria, Jamil Sheykhahmadia, Hamed Saffariana, and Mohammad
Reza Halvagarb
b
aDepartment of Chemistry, Tarbiat Modares University, Tehran, Iran; Department of Inorganic
Chemistry, Chemistry and Chemical Engineering Research Centre of Iran, Tehran, Iran
ABSTRACT
ARTICLE HISTORY
Received 10 November 2018
Alkyl (E)-2-(3-Alkyl-5-oxo-1-phenyl-1,5-dihydro-4H-pyrazol-4-ylidene)-
5-(alkylamino)-1,3-dithiole-4-carboxylates have been obtained by
condensation of 2-pyrazolin-5-ones with carbon disulfide followed by
ring formation with phosphorylated hydroxyketenimines [generated
in situ from Nef-isocyanide-Perkow reaction] in the presence of Et3N.
The structure of target compounds was confirmed by X-ray diffrac-
tion study. The good yields of the products, diastereoselectivity, and
lack of activators or metal promoters are the main advantages of
this method.
KEYWORDS
Pyrazolone; Nef-isocyanide-
Perkow reaction; cyclic
ketene dithioacetal; carbon
disulfide; polarized
double bond
GRAPHICAL ABSTRACT
Introduction
Pyrazolone compounds are privileged scaffolds in organic synthesis by virtue of their
potential biological activities and wide-ranging utility as synthetic intermediates.
Bioactive compounds bearing a pyrazolone systems have attracted much interest in
medicinal chemistry.[1–3] Recently, the construction of structurally diverse pyrazolone
derivatives has attracted the research interests of synthetic chemists.[4–8] As part of our
current studies on developments of new applications of pyrazolone derivatives in het-
erocyclic synthesis,[9–12] we now report the formation of novel cyclic ketene dithioace-
tals containing a pyrazolone motif from the reaction between 2-pyrazolin-5-ones-CS2
adduct and phosphorylated hydroxyketenimines [generated in situ from Nef-isocyanide-
Perkow reaction], in the presence of Et3N, at room temperature. Ketene dithioacetals
CONTACT Issa Yavari
yavarisa@modares.ac.ir
Department of Chemistry, Tarbiat Modares University, PO Box
14115-175, Tehran, Iran.
Supplemental data for this article can be accessed on the publisher’s website.
ß 2019 Taylor & Francis Group, LLC

2
I. YAVARI ET AL.
are versatile intermediates in organic synthesis,[13–15] and extensive research has given
rise to new prospects in their chemistry.[16,17]
Recently, we reported on the synthesis of new types of ketene dithioacetals through
the reaction between phosphorylated hydroxyketenimines, 1,3-dicarbonyl compounds,
and carbon disulfide at room temperature.[18]
a-Ketoimidoyl chlorides, generated in situ from acyl chlorides and isocyanides,[19] are
trapped by trialkyl phosphites via a Perkow-type reaction leading to phosphorylated
hydroxyketenimine 1 (Scheme 1).[20] The Nef-isocyanide reaction is performed under
solvent-free conditions, and the Perkow reaction is carried out at room temperature.[21]
Results and discussion
Initially, adduct 4a, obtained from methyl 2-(5-oxo-1-phenyl-4,5-dihydro-1H-pyrazol-3-
yl) acetate (2a) and carbon disulfide, was treated with methyl 3-(tert-butylimino)-2-
[(diethoxyphosphoryl)oxy]acrylate (1a) at room temperature in different solvents. As
shown in Table 1 (Entry 1), the reaction proceeded in EtOH to afford methyl 5-(tert-
butylamino)-2-(3-methyl-5-oxo-1-phenyl-1,5-dihydro-4H-pyrazol-4-ylidene)-1,3-dithiole-
4-carboxylate (3a) in 20% yield. Using CH2Cl2 or acetone (Entries 2 and 3) led to
slightly better yields. The use of MeCN as solvent and Et3N as a base, afforded product
NR2
NR2
O
EtO
EtO
Nef
R3
CO2
O
C
P(OEt)3
R2 NC
P
Cl
R3
CO2
Cl
R3
CO2
O
O
1
Scheme 1. Formation of phosphorylated hydroxyketenimine 1 by a Nef-Perkow sequence.
Table 1. Optimization of reaction conditions for the formation of product 3a from ketenimine 1a,
pyrazolone 2a, and carbon disulfidea.
NtBu
Et3NH
EtO
EtO
MeO
O
C
O
O
O
P
Ph
Ph
Ph
S
S
S
O
H
S
C
S
N
N
N
N
N
N
Me
CO2
O
1a
N
MeCN, Et3
SH
N
tBu
4a
3a
2a
Entry
Solvent
Base (x eq.)
Yield (%)b
1
2
3
4
5
6
7
EtOH
DBU (1)
DBU (1)
DBU (1)
NaH (1)
DABCO (1)
Et3N (1)
Et3N (2)
20
30
45
50
73
80
87
CH2Cl2
Acetone
MeCN
MeCN
MeCN
MeCN
aReaction conditions: (i) 1a (1.1 mmol); (ii) 2a (1 mmol), CS2 (1.2 mmol) and base at r.t., 12 h.
bIsolated yield.

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3
3a in 80% yield (Entry 6). The conversion proceeded in an improved yield (87%) with 2
equivalents of Et3N (Entry 7) in 12 h at room temperature.
With the suitable reaction conditions in hand, we next explored the protocol with phos-
phorylated hydroxyketenimines 1, pyrazolone derivatives 2, and CS2 in the presence of
Et3N. As shown in Table 2, these reactions led to the formation of alkyl 5-(alkylamino)-2-
(3-alkyl-5-oxo-1-phenyl-1,5-dihydro-4H-pyrazol-4-ylidene)-1,3-dithiole-4-carboxylates 3a–j,
in 68–87% yields.
1
The structures of compounds 3a-j were confirmed using IR, H NMR, and 13C NMR
1
spectral data and single-crystal X-ray analyses. For example, the H NMR spectrum of
3a showed singlets at 1.53, 2.60, and 3.86 ppm for tert-Bu, Me, and MeO protons,
1
respectively. The NH proton appears as a fairly broad singlet at 8.61 ppm. The H-
decoupled 13C NMR spectrum of 3a exhibited 18 signals in agreement with the pro-
posed structure.
There is the possibility of geometrical isomerism about the central alkene linkage in
compounds 3. Thus, two geometrical isomers, namely (E)-3 and (Z)-3, are possible.
Unequivocal evidences for the structure and geometry of the central alkene linkage of
compound 3f were obtained from single-crystal X-ray analyses. According to the
ORTEP diagram of 3f, shown in Figure 1, the preferred geometry of the central alkene
linkage is (E). The same structures were assumed for the other derivatives on the basis
of their NMR spectroscopic similarities.
A mechanistic rationalization for the formation of products 3 is shown in Scheme 2.
The Nef-isocyanide reaction leads to the formation of imidoyl chlorides, which can later
be treated with triethyl phosphite to afford ketenimine 1 in a Perkow-type reaction.
Subsequent reaction of triethyl ammonium salt of 4 with 1 afford intermediate 5, which
is converted to 6 by proton transfer reaction. Intermediate 6 undergoes elimination of
Table 2. Synthesis of products 3a–ja.
NR2
Et3NH
S
EtO
EtO
R3
O
O
C
O
O
O
P
Ph
Ph
Ph
S
C
S
S
S
O
H
R3
CO2
N
N
N
MeCN, Et3
N
N
N
N
O
1
+
SH
N
R1
R1
R1
R2
4
3
2
Entry
R1
R2
R3
Product
Yield (%)b
1
2
3
4
5
6
7
8
Me
Me
Me
Me
tBu
tBu
Me
Et
Me
Et
Me
Et
Me
Et
3a
3b
3c
3d
3e
3f
3g
3h
3i
70
77
75
73
68
87
80
86
73
77
Cyclohexyl
Cyclohexyl
tBu
CH2CO2Me
CH2CO2Me
CH2CO2Me
CH2CO2Me
CH2CO2Et
CH2CO2Et
tBu
Cyclohexyl
Cyclohexyl
tBu
9
10
Et
Et
Cyclohexyl
3j
aReaction conditions: (i) 1 (1.1 mmol); (ii) 2 (1 mmol), CS2 (1.2 mmol), at r.t., 12 h.
bIsolated yield.

4
I. YAVARI ET AL.
Figure 1. An ORTEP diagram of 3f. The thermal ellipsoids are drawn at the 40% probability level.
Ph
N
N
Et3NH
O
S
O
OP(O)(OEt)2
R3
O
R1
Ph
SH
S
Et3NH
Ph
S
CO2
N
N
+
N
N
1
-Et3N
Et3N
S
N
+
2
CS2
(EtO)2(O)PO
MeCN
N
SH
R1
R2
R1
R2
R3O2C
5
4
6
OR3
OR3
O
O
Ph
Ph
Imine-enamine
tautomerism
S
S
O
O
N
N
-HOP(O)(OEt)2
-Et3N
N
N
H
S
S
N
N
R1
R2
R1
R2
3
7
Scheme 2. Proposed mechanism for the formation of products 3.
diethyl hydrogen phosphate to afford intermediate 7, which is converted to product 3
by imine-enamine tautomerization reaction.
In summary, we have developed a simple synthesis of novel pyrazolones containing a
cyclic ketene dithioacetal moiety by condensation of 2-pyrazolin-5-ones-CS2 adduct
with phosphorylated hydroxyketenimines, in the presence of Et3N, at room temperature.
This protocol provides fast access to a variety of structurally diverse pyrazolones. The
structure of a typical product was confirmed using X-ray crystallography. The mild and
simple reaction conditions of this protocol make it suitable for the generation of such
derivatives.

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Experimental
Materials
All purchased solvents and chemicals were of analytical grade and used without further
purification. Melting points and IR spectra of all compounds were measured on an
Electrothermal 9100 apparatus and a Shimadzu IR-460 spectrometer, respectively. The
1H and 13C NMR spectra were obtained with a BRUKER DRX-500 AVANCE instru-
ment using CDCl3 as applied solvent and TMS as internal standard at 500 or 300 and
125 or 75 MHz, respectively. The abbreviations used for NMR signals: s ¼ singlet,
d ¼ doublet, t ¼ triplet, and m ¼ multiplet. Mass spectra were recorded on
a
FINNIGAN-MAT 8430 mass spectrometer operating at an ionization potential of 70 eV.
Elemental analyses for C, H, and N were performed using a Heraeus CHN-O-
Rapid analyzer.
General procedure for the synthesis of compounds 3
A mixture of 2-pyrazolin-5-ones (1 mmol) with carbon disulfide (0.091 g, 1.2 mmol) and
Et3N (0.202 g, 2 mmol) in MeCN (4 mL) was stirred for 30 min at room temperature.
Then, a solution of the appropriate ketenimine 1 (1 mmol) in MeCN (2 mL) was added.
After 12 h, the solvent was removed under reduced pressure and the residue was puri-
fied using preparative TLC (SiO2; AcOEt/n-hexane 1:3).
Ethyl (E)-5-(tert-butylamino)-2-(3-(2-methoxy-2-oxoethyl)-5-oxo-1-phenyl-1,5-dihydro-
4H-pyrazol-4-ylidene)-1,3-dithiole-4-carboxylate (3f): Yellow crystals. Mp 160–162 ꢀC;
yield: 0.41 g (87%); IR (KBr)ꢀꢀ cmꢁ1: 3451 (N–H), 1738 (C ¼ O), 1654 (C ¼ O), 1566,
1
1497, 1432, 1265 (C–O). H NMR (CDCl3) d (ppm) 1.32 (t, J ¼ 7.2 Hz, 3H), 1.52 (s,
9H), 3.78 (s, 3H), 3.91 (s, 2H), 4.31 (q, J ¼ 7.2 Hz, 2H), 7.16 (t, J ¼ 7.3 Hz, 1H), 7.39 (t,
J ¼ 7.4 Hz, 2H), 8.01 (d, J ¼ 7.2 Hz, 2H), 8.58 (br s, 1H). 13C NMR (CDCl3) 14.4 (Me),
29.3 (C(Me)3), 36.1 (CH2), 52.4 (MeO), 54.4 (C(Me)3), 61.2 (CH2O), 101.1 (C), 118.8 (2
CH), 123.1 (C), 124.6 (CH), 128.7 (2 CH), 133.7 (C), 138.7 (C), 142.5 (C), 155.3 (C),
162.5 (C ¼ O), 167.3 (C ¼ O), 169.2 (C ¼ O). EI-MS: m/z (%) 475 (8, Mþ), 306 (4), 279
(8), 246 (10), 215 (3), 187 (12), 169 (18), 149 (60), 111 (15), 83 (32), 57 (100), 41 (80).
Anal. Calcd for C22H25N3O5S2 (475.12.): C 55.56, H 5.30, N 8.84. Found: C 55.91, H
5.32, N 8.87%.
X-ray crystal-structure determination of 3f
The X-ray diffraction measurements were carried out on STOE IPDS 2T diffractometer
with graphite-monochromated MoKa radiation. All single crystals were obtained from
DMF solution and mounted on a glass fiber and used for data collection. Cell constants
and orientation matrixes for data collection were obtained by least-square refinement of
the diffraction data from 7488 for compound 3f. Diffraction data were collected in a
series of x scans in 1ꢀ oscillations and integrated using the Stoe X-AREA software
package. The structures were solved by direct methods and subsequent difference
Fourier maps and then refined on F2 by a full-matrix least-squares procedure using
anisotropic displacement parameters. Atomic factors are from the International Tables

6
I. YAVARI ET AL.
for X-ray Crystallography. All non-hydrogen atoms were refined with anisotropic dis-
placement parameters. Hydrogen atoms were placed in ideal positions and refined as
riding atoms with relative isotropic displacement parameters. All refinements were per-
formed using the X-STEP32, SHELXL-2014 and WinGX-2013.3 programs.[22–24
]
CCDC-1815485 contains the supplementary crystallographic data for compound 3f.
These data can be obtained free of charge from The Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif.
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