Synthesis of some novel α-cyanoketene-n, s-acetals derived from secondary aliphatic amines and their use in pyrazole synthesis

Article abstract of DOI:10.1080/00397911.2013.774019

New α-cyanoketene-N,S-acetals 2(a-g) and β-dialkylamine-α- cyanoacrylates 3(g-i) were synthesized in good to excellent yields by the reaction of ethyl 2-cyano-3, 3-bis(methylthio)acrylate 1 with secondary aliphatic amines (i.e., N-methylalkyl- and N-ethyl

Full text of DOI:10.1080/00397911.2013.774019

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Synthesis of Some Novel α -Cyanoketene-N,S-acetals
Derived From Secondary Aliphatic Amines and Their
Use in Pyrazole Synthesis
Wedad M. Al-Adiwish a , M. I. M. Tahir b & W. A. Yaacob a
a School of Chemical Sciences and Food Technology , UniversitiKebangsaan Malaysia , Bangi ,
Selangor , Malaysia
b Department of Chemistry, Faculty of Science , University Putra Malaysia , UPM Serdang ,
Selangor , Malaysia
Accepted author version posted online: 03 Jul 2013.
To cite this article: Synthetic Communications (2013): Synthesis of Some Novel α -Cyanoketene-N,S-acetals Derived From
Secondary Aliphatic Amines and Their Use in Pyrazole Synthesis, Synthetic Communications: An International Journal for
Rapid Communication of Synthetic Organic Chemistry, DOI: 10.1080/00397911.2013.774019
To link to this article: http://dx.doi.org/10.1080/00397911.2013.774019
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Synthesis of Some Novel α-Cyanoketene-N,S-acetals Derived From Secondary
Aliphatic Amines and Their Use in Pyrazole Synthesis
Wedad M. Al-Adiwish1,, M. I. M. Tahir2, W.A. Yaacob1
1School of Chemical Sciences and Food Technology, UniversitiKebangsaan Malaysia,
Bangi, Selangor, Malaysia,
2Department of Chemistry, Faculty of Science, University Putra Malaysia, UPM Serdang,
Selangor, Malaysia
Author to whom correspondence should be addressed: , , Tel.: +60 12 942 7918. E-Mail:
we80dad@yahoo.com;
Abstract
New α-cyanoketene-N,S-acetals2(a-g) and β-dialkylamine-α-cyanoacrylates 3(g-i) were
synthesized in good to excellent yields by the reaction of ethyl 2-cyano-3,3-
bis(methylthio)acrylate 1 with secondary aliphatic amines, i.e. N-methylalkyl- and N-
ethylalkylamines, and pyrrolidine, in the presence of triethylamine, under reflux in
ethanol, for 1–16 h, depending on the amine used. Five N-methylalkyl amines and
pyrrolidine yielded exclusively mono-substituted N,S-acetals2(a-f) in high yields. On the
other hand, N-ethylbenzylamine gave a mixture of mono-substituted products including
N,S-acetal2g in 35% yield and the unexpected product ethyl 3-[benzyl(ethyl)amino]-2-
cyanoacrylate 3g in50% yield. N-ethylcyclohexylamine and N-ethylbutylamine did not
produce N,S-acetals and gave only the unexpected products ethyl 2-cyano-3-
[cyclohexyl(ethyl)amino]acrylate 3h and ethyl 3-[butyl(ethyl)amino]-2-cyanoacrylate 3i
in good yields. The α-cyanoketene-N,S-acetals2(a-f), 2j, and 2k underwent cyclization
with the binucleophile hydrazine in ethanol under reflux to afford substituted
pyrazoles4(a-f), 4j, and 4k in high yields.
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[Supplementary materials are available for this article. Go to the publisher’s online
edition of Synthetic Communications® for the following free supplemental resource(s):
Full experimental and spectral details.]
KEYWORDS: α-Cyanoketene-N,S-acetals; secondary aliphatic amines; pyrazole
derivatives.
INTRODUCTION
The synthesis of α-cyanoketene-N,S-acetals has been a subject of great interest because of
their wide applications. For example, they are important and versatile reagents in organic
synthesis, and have been used in particularfor the synthesis of
polyfunctionalizedheterocycles.[1–9] The synthesis of α-cyanoketene-N,S-acetals has been
reported by other research groups from α-cyanoketene-S,S-acetals through addition–
elimination reactions with strong nucleophiles such as alkylamines or weaker
nucleophiles such as arylamines, under gentle or powerful conditions, in various
solvents.[10–15] However, the α-cyanoketene-S,S-acetals have received much more
attention regarding their reaction with primary amines than regarding their reaction with
secondary amines. In this paper we report the synthesis of new α-cyanoketene-N,S-acetals
2(a-g) and an unexpected β-dialkylamine-α-cyanoacrylates 3(g-i) derived from secondary
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aliphatic amines of N-methylalkyl- and N-ethylalkylamines, and pyrrolidinefrom ethyl 2-
cyano-3,3-bis(methylthio)acrylate 1 asa starting material (Scheme 1, Table 1).
Furthermore, forseveral years, pyrazoles and their derivatives began to attract wide
attention as one of the most active classes of compounds possessing a broad spectrum of
biological activities and pharmacological properties including antibacterial[10]
,
antifungal[11], and insecticidal activity[12]. As a result, many research groups have
reported the synthesis of pyrazole derivatives from α-cyanoketene-N,S-acetals[16–19]. In
our work, we used the α-cyanoketene-N,S-acetals2(a-f), 2j, and 2k to synthesize a new
series of pyrazole derivatives 4(a-f), 4j, and 4k by displacing both the methylthio and
ethoxy groups in the α-cyanoketene-N,S-acetals with the hydrazine binucleophile
(Scheme 2, Table 2). The structures of the obtained compounds were established on the
basis of elemental analysis, FT-IR spectra, 1H-NMR spectra, 13C-NMR spectra, mass
spectra, and X-ray crystallography.
RESULTS AND DISCUSSION
The method for preparing the α-cyanoketene-N,S-acetals2(a-g) and the β-dialkylamine-α-
cyanoacrylates 3(g-i) is presented in Scheme 1. The starting material ethyl-2-cyano-3,3-
bis(methylthio)acrylate 1 was obtained easily in high yield, as reported in the
literature.[23] It was prepared in onepot from the reaction ofethyl 2-cyanoacetate with
carbon disulfide in the presence of potassium carbonate followed by alkylation with
methyl iodide. Compound 1 (1.08 g, 5 mmol) was reacted with nine secondary aliphatic
amines (5 mmol) in the presence of TEA in ethanol (20 mL) under reflux for a few hours,
depending on the amine used. The solvent was evaporated in a vacuum to afford an oily
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viscous crude product that was purified by performing column chromatography with an
ethyl acetate and hexane (1:1) eluent. Five N-methylalkyl amines (entries 1–5) and
pyrrolidine (entry 6) gave exclusively mono-substituted N,S-acetal products 2(a-f) in high
yields (78%–98%). The yields of these products are influenced by the alkyls in the N-
methylalkyl amines. Compared to alkyls with secondary α-carbons, the alkyls with
primary α-carbons (entries 1–4) have less steric crowding, making the N-methylalkyl
amines react much faster with compound 1 (entry 5). This is clearly demonstrated by the
fact that the N-methylalkyl amines in entries 1–4 gave higher yields of 86%–98% than
did the amine in entry 5 (78%). However, pyrrolidine (entry 6), which has a dimethylene
ring residue on two α-carbons, produced an excellent yield of 98% because it has less
steric crowding around its nitrogen facing toward compound 1. The formation of N,S-
acetals2(a-f)begins with a nucleophilic attack by the –NH of the amines on the ethylenic
double bond of compound 1 and concluded with the elimination of methanethiol. A
similar reaction of compound 1 with the N-ethylalkylamine counterpart of N-
ethylbenzylamine (entry 7) gave a mixture of N,S-acetal(2Z)-ethyl3-
[benzyl(ethyl)amino]-2-cyano-3-(methylthio)acrylate 2g, which was obtained in a
relatively low yield (35%) because some of it was converted to the unexpected (2E)-ethyl
3-[benzyl(ethyl)amino]-2-cyanoacrylate product 3g (50%). In contrast, the N-
methylbenzylamine (entry 4), which is less crowded than the N-ethylbenzylamine (entry
7) gave the N,S-acetal of (2Z)-ethyl3-[benzyl(methyl)amino]-2-cyano-3-
(methylthio)acrylate 2d as the only product,with no unexpected products. The low yield
of the N,S-acetal2g is due to the stronger steric push from the N-ethy in N-
ethylbenzylamine than from the N-methyl in N-methylbenzylamine on the big sulfur of
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the C–S bond. This steric push results in the expulsion of the methylthio group as a cation
(CH3S+), where the incipient carbon ion abstracts a proton from ethanol to form
compound 3g in 50% yield. For N-ethylcyclohexylamine (entry 8) and N-ethylbutylamine
(entry 9), the initially formed N,S-acetals are converted completely to (2E)-ethyl-2-
cyano-3-[cyclohexyl(ethyl)amino]acrylate 3h and (2E)-ethyl-3-[butyl(ethyl)amino]-2-
cyanoacrylate 3i in good yields of 77% and 69%, as shown in Table 1.
The structures of the α-cyanoketene-N,S-acetals2(a-g)andtheβ-dialkylamine-α-
cyanoacrylates 3(g-i) were established on the basis of their elemental analyses and
spectral data. The experimental C, H, and N elemental analysis results were in good
agreement with the theoretical values based on the suggested formulas. The characteristic
absorption band in the IR spectra of α-cyanoketene-N,S-acetals2(a-g) is at ν = 1027–1099
cm-1 for C−N stretching vibrations. This means that the amine is attached to the carbon
replaced with a methylthio group (SMe) of ketene-S,S-acetal1 to form N,S-acetal2(a-g).
Bands appeared at ν =911–938 cm-1 and851–898 cm-1 for the asymmetrical and
symmetrical stretching vibrations of the =C−S group, respectively. These bands
disappeared in compounds 3(g-i), which means that they did not form the expected N,S-
acetals. The absorption bands appearing in the range ν = 1664–1747 cm-1 for the C=O
group of compounds 2(a-g) and 3(a-g) and in the range ν = 1514–1607 cm-1 for the C=C
group are significantly shifted from the typical C=O and C=C absorption bands of esters
(1750 cm-1) and alkenes(1600-1660 cm-1). These bands are shifted to lower frequencies
because of the conjugation of the C=O bond with a C=C bond in the α,β-unsaturated
esters. The 1H NMR spectra showed quarter signals at δ 3.93–4.37 ppm corresponding to
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the CH2−O group for all the synthesized compounds. The singlet resonances appearing at
δ 2.84–3.09 ppm are due to the methyl proton attached to the nitrogen (CH3−N) in
compounds 2(a-e). The triplet signals appearing at δ 3.46–3.69 ppm represent CH2−N
groups in compounds 2b, c,and f, whereas the corresponding CH2−N group appeared as
quarter signals at δ 3.40–3.69 ppm for the compounds 2a, 2g, and 3(g-i). Triplet signals
occur at δ 4.35 and δ 4.34 ppm for the CH−N groups of compounds 2e and 3h. The
downfield shifts of these protons are due to the electron-withdrawing effect of the
nitrogen, which reduces the electron density of the proton attached to the carbon and thus
deshields the proton. Signals appeared in the region of δ 6.05–7.34 ppm represent
aromatic protons of compounds 2d, 2g, and 3g. Single signals occur at δ 2.40–2.67 ppm
for the methylthio groups (MeS) of compounds 2(a-g), and these signals disappeared for
compounds 3(g-i). Triplet and multiplet signals appearing between δ 0.66-1.33 and 1.08-
1.89 ppm represent CH2 and CH3 groups. The 13C spectra of all synthesized compounds
showed the expected carbon signals for all types and numbers of carbons in the various
groups. The signals appearing downfield in the region of δ 174.3–179.2ppm are due to
the carbon attached to the sulfide atom (S−C−N) in compounds 2(a-g), and this signal
disappears for compounds 3(g-i), which means that they did not form N,S-acetals. The
most characteristicsignals were atδ 156.2, 153.9, and 153.7 ppm for compounds 3g,
3h,and 3i, respectively, corresponding to the carbon attached to nitrogen (=CH−N). The
signals appearing in the regions of δ 165.9–163.1 ppm and δ 118.4–120.3ppm are
assignable to the carbons in the carbonyl (C=O) and cyano(C≡N) groups, respectively.
The aromatic carbons for compounds 2d, 2g, and 3g occur at δ 126.6–135.3ppm. The
signals observed in the regions of δ67.6–71.8ppm, δ 59.2–61.8 ppm, and δ 43.0–59.0
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ppm are due to the carbons attached to the cyano group (C−CN), oxygen (CH2−O), and
nitrogen (CH2−N), respectively. The signals occurring at higher fields of δ 64.4 and δ
67.8 ppm are due to the carbon attached to nitrogen (CH−N) in compounds 2e and 3h.
The chemical shifts of the carbons in CH2 and CH3 are observed in the ranges of δ 19.5–
32.8ppm and δ 13.3–15.1 ppm, respectively. The structures of the isolated products were
supported by their electrospray ionization mass spectrometry (ESIMS) and direct infusion
mass spectrometry (DIMS) results, which showed molecular ions corresponding to the
molecular formula. For example, the DIMS of compound 2e showed a molecular ion at
m/z = 282.40, which corresponds to the molecular formula C14H22N2O2S (282.41). The
stereochemistry of 3h was established by performing a NOESY experiment (Scheme 2).
The NOESY spectrum suggested a weak cross-peak between the hydrogen of the methyl
Ha fragment and the vinylic hydrogen Hc, which indicated that Ha and Hc are located on
the same side of the molecule, as in the E geometric isomer. Similar results were
observed for 3g and 3i.
The structure of(2Z)-ethyl 2-cyano-3-(methylthio)-3-(pyrrolidin-1-yl)acrylate2f was
further identified by performing X-ray diffraction analysis.[21] The crystal data and
structure refinement results for compound 2f are given in Table 2. The ORTEP plot of
compound 2f and the numbering scheme are presented in Figure 1. The compound
adopted a Z configuration with respect to the C=C bond. Compound 2fcrystallized in an
orthorhombic system with space group P21212. Selected bond distances, bond angles,
and torsion angles are given in Table 3. The bond lengths and angles in the pyrrolidine
ring of compound 2f are within in the normal range Allen et al. 1987.[22] The C2−N3
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bond length is 1.316(3) Å, which is shorter than normal for C−N bonds (1.47 Å). As a
result, the C2=C8 bond length of 1.421(3) Å becomes longer than the normal value of
1.34 Å and closer to that of a C−C single bond (1.54 Å). This is due to the strength of the
π-delocalization between the carbon atom C2 and the nitrogen atom N3.
The mean planes for compound 2f were observed in the pyrrolidine ring
N3/C4/C5/C6/C7, N10/C2/C8/C9/C11 fragment, and O12/O15/C8/C11/C13 fragment;
the maximum deviation was 0.238(2)º at the C14 atom. The dihedral angle between the
pyrrolidine ring and the N10/C2/C8/C9/C11 fragment is 57.58(11)º, and the pyrrolidine
ring makes a dihedral angle of 62.36 (11)º with theO12/O15/C8/C11/C13 fragment. The
methylthio group is twisted out of the mean planes, as can be seen in the value of the
C16−S1−C2−N3 torsion angle, 153.02(14)º(see Electronic Supplementary
Information[21]).
Our work was also extended to the synthesis of a series of pyrazole derivatives that
contain N-methylalkyls, pyrrolidine, piperidine, and morpholine substituents, i.e.,
compounds 4(a-f), 4j, and 4k. These pyrazoles were conveniently prepared by reacting
the N,S-acetals2(a-f) synthesized here and N,S-acetals2j and 2k (first prepared in 1965 by
Yoshikataet al.[23]) with excess amounts of hydrazine (mole ratio 1:5) in ethanol under
reflux, as shown in Scheme 3. These pyrazoles were obtained in good yields of 75–97%
after solvent evaporation, washing with ethanol, and drying followed by recrystallization
from methanol, as shown in Table 4.
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The proposed mechanism for the formation of pyrazoles4(a-f), 4j, and 4k is assumed to
proceed via a nucleophilic attack of the NH2 of hydrazine on the ethylenic bond in
acyclic α-cyanoketene-N,S-acetals 2(a-f), 2j, and 2k to form an intermediate adduct A.
This reaction is followed by elimination of methanethiol to give a neutral intermediate B.
Then, subsequent intramolecularcyclizations occur to give an intermediate adduct C,
followed by expulsion of ethanol to afford products 4(a-f), 4j, and 4k, as shown in
Scheme 4.
The structures of pyrazoles4(a-f), 4j, and 4k were proven by performing elemental
analysis and obtaining spectral data. The elemental analysis and mass spectra for each
compound correspond to the molecular formula. The most important bands in the IR
spectra of the synthesized compounds 4(a-f), 4j, and 4k appeared at υ= 3031–3275 cm-1,
from the stretching vibrations of NH groups. These bands are broad because of Fermi
resonance overtones (overlapping with other fundamental vibrations of the NH bending
band at 1550 cm-1) and strong hydrogen bonding. In addition, the IR spectrum showed
broad absorptions at υ = 1601–1674 cm-1 and at υ = 1504–1614 cm-1 arising from the
stretching vibrations of C=O and C=C, respectively, and these bands overlap with the
N−H bending bands. These bands appeared at lowfrequencies because of the formation of
hydrogen bonds in the molecule. The 1H NMR spectra of 4(a-f), 4j, and 4k showed the
disappearance of the methylthio group (MeS) and ethoxy group (OCH2CH3); this means
that the methylthio group in the N,S-acetals was displaced with hydrazine hydrate and
cyclization bonds to form pyrazoles, after which the ethoxy group was eliminated. For
most of the pyrazoles, we were not able to reveal any clear signal of the NH group
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because of the strength and symmetry of the intramolecular hydrogen bond, which
resulted in a weak dipole and exchange with the solvent in the range at 3.76-4.31 ppm. In
the case of pyrazoles4c, 4f, and 4j, the strongly deshielded signals of the amine proton
appeared at δ 10.29, 10.07, and 10.97 ppm due to the intramolecular hydrogen bonding
between NH and C=O. The 13C NMR spectra showed characteristic peaks of the carbon
attached to the nitrogen (C−NH) at δ 165.2–168.0 ppm and of the carbon of the carbonyl
group (C=O) in the pyrazole rings at δ 155.9–157.4 ppm. Signals due to the carbon in the
cyano groups (CN) also appeared at δ 116.9–117.9 ppm. The signals in the region of
60.8–62.2 ppm are due to the carbons attached to the cyano groups (C−CN).
The structure of 5-[butyl(methyl)amino]-3-oxo-2,3-dihydro-1H-pyrazole-4-carbonitrile
4b was further confirmed by performing X-ray diffraction analysis. Suitable crystals were
grown during slow evaporation of a methanol solution of the compound. The molecular
structure and numbering schemeforcompound 4b are presented in Figure 2. The crystal
data and structure refinement results for compound 2f are given in Table 5 Compound
4b crystallized in an orthorhombic crystal system with space group P212121.[24] Selected
bond distances, bond angles, and torsion angles are given in Table 6. The bond lengths
and angles in the N-ethylmethyl amino group in 4b are in the normal ranges Allen et al.
1987[22]. In 4b, the C5=C6 bond length is 1.406(2) Å, which is longer than the average
(1.34 Å) and indicates single C−C bond character (1.45 Å).In addition, the C5−N9
[1.3330(19)Å], C5−N4 [1.3586(18) Å], and C2−N3 [1.3707(18)Å] bond lengths are
shorter than normal (1.47 Å). These bond lengths confirm the partial double bond
character arising from electron-donating effects of the amino groups. The mean plane of
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the pyrazole4b O1/N9/N3/N8/C10/C5/C6/C2/C7 fragment is planar with a maximum
deviation of -0.052(1)º for the C5 atom. The mean plane forms a dihedral angle of
88.25(17)º with the N1/C10/C11/C12/C14 fragment corresponding to the ethyl amino
group (see Electronic Supplementary Information[24]).
EXPERIMENTAL
Melting points were determined using a hot stage Gallenkamp melting point apparatus.
Infrared spectra were recorded onFT-IR 8300 Shimadzu spectrometer. 1H-NMR and 13C-
NMR spectra were recorded on FT-NMR 400 MHz Joel, ECP, JNM-ECX 500 MHz, Joel
and FT-NMR 600 MHz Bruker, AVANCE III spectrometer operating at 400 MHz, 500
MHz and 600 MHz for 1H-NMR and 100, 125 and 150 MHz for13C-NMR in CDCl3,
CD3OD and DMSO-d6as solvents and using TMS as internal standard; chemical shifts are
reported in δ(ppm). ESIMS spectra were recorded on Dionex, Bruker, and MicroTof Q
apparatus. DIMS spectra were recorded on QP5050A Shimadzu apparatus. Elemental
analyses of all new compounds were performed on Thermo Finnigan EA1112. X-ray
diffraction (XR-D) data were collected at room temperature with Bruker APEXII CCD a
spectrometer. TLC analysis was carried out on silica gel of Merck No. 5545 to monitor
completion of reactions, in which ethyl acetate-hexane (1:1) was used as eluent. Column
chromatography was performed using silica gel of Merck No. 9385.
Synthesis Of Starting Material (1)
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Ethyl-2-cyano-3,3-bis(methylthio)acrylate 1 was prepared in onepot from the reaction
ofethyl 2-cyanoacetate with carbon disulfide in the presence of potassium carbonate
followed by alkylation with methyl iodide, according to literature[20]
.
General Method For Synthesis Of Α-Cyanoketene-N,S-Acetals 2(A-G) And
Compounds 3(G-I)
A mixtureof ethyl 2-cyano-3,3-bis(methylthio)acrylate 1 (1.09 g, 5 mmol), secondary
aliphatic amine (5 mmol), and 3 drops of triethylamine was dissolvedin ethanol (20 mL).
The reaction mixture was reflux for several hours based on the amine used. The solvent
was concentrated in vacuum to afford an oily viscous crude product which was purified
by column chromatography using SiO2 (Merck 9385). Elution with ethyl acetate and
hexane (1:1) furnished compounds 2(a-g)and 3(g-i).
Supporting Information: Full experimental detail, IR, 1H and 13C NMR spectra, analytical
data, HPLC traces, DIMS, ESIMS and X-ray data of new compounds. This material can
be found via the “Supplementary Content” section of this article’s webpage.
Selected Data
(2Z)-Ethyl 3-[Ethyl(Methyl)Amino]-2-Cyano-3- (Methylthio)Acrylate (2a)
Yellow viscous liquid; IR (neat, cm-1) ν:2195 (CN), 1681 (C=O), 1532 (C=C), 1062,
1031 (C−N), 938, 861 (=C−S); 1H NMR (500 MHz, DMSO-d6) δ 1.06 (t, 3H, NCH2CH3,
J = 6.9 Hz), 1.08 (t, 3H, OCH2CH3, J = 7.2 Hz), 2.43 (s, 3H, SCH3), 2.95 (s, 3H, NCH3),
3.54 (q, 2H, NCH2CH3, J = 6.9 Hz), 3.94 (q, 2H, OCH2CH3, J = 7.2 Hz); 13C NMR (125
MHz, DMSO-d6) δ: 13.3 (NCH2CH3), 14.4 (OCH2CH3), 18.1 (SCH3), 42.9 (NCH3), 51.1
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(NCH2), 59.4 (OCH2), 70.1 (C−CN), 119.8 (CN), 163.1 (C=O), 177.3 (S−C−N); ESIMS
found [M+H]+: 229.1063 (calc. for C10H16N2O2S, M+ requires 228.3152); Anal. Calcd.
for C10H16N2O2S: C 52.61, H 7.06, N 12.27%; Found: C 53.01, H 7.08, N 12.12%.
Synthesis Of (2Z)-Ethyl 2-Cyano-3-(Methylthio)-3-Morpholinoacrylate 2j And (2Z)-
Ethyl 2-Cyano-3-(Methylthio)-3-(Piperidin-1-Yl)Acrylate 2k
These compounds 2j and 2kprepared according to Yoshikata et al.’s procedure[23] from
the reaction of compound 1 withmorpholine and pipyridine under reflux in ethanol.
General Method For The Synthesis Of Pyrazoles 4(A-F), 4j And 4k
A suspension of α-cyanoketene-N,S-acetals 2(a-f), 2j and 2k (4 mmol) in hydrazine
hydrate (1g, 20 mmol) was refluxed on water-bath for 2 hours. Then ethanol (20 mL) was
added and the reaction mixture was refluxed further for 2 hours. The solvent was
evaporated and the product was collected, washed with ethanol, dried and recrystallize
from methanol to give pure products of 4(a-f), 4j and 4k.
Supporting Information: Full experimental detail, IR, 1H and 13C NMR spectra, analytical
data, HPLC traces, DIMS, ESIMS and X-ray data of new all pyrazoles. This material can
be found via the “Supplementary Content” section of this article’s webpage
Spectral Data
5-[Ethyl(Methyl)Amino]-3-Oxo-2,3-Dihydro-1H-Pyrazole-4-Carbonitrile (4a).
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Colorless peal crystal; FT-IR (KBr, cm-1) ν: 3150, 3068 (NH), 2210 (CN), 1607 (C=O),
1516 (C=C); 1H NMR (400 MHz, DMSO-d6) δ: 1.08 (t, 3H, NCH2CH3, J = 7.0 Hz), 2.92
(s, 3H, NCH3), 3.39 (q, 2H, NCH2, J = 7.0 Hz), 3.85 (br s, 2H, 2NH,DMSO
exchangeable); 13C NMR (100 MHz, DMSO-d6) δ: 12.6 (NCH2CH3), 36.3 (NCH3), 39.1
(NCH2), 61.2 (C−CN), 117.2 (CN), 157.0 (C=O), 167.7 (C−NH); DIMS found m/z:
166.10 (calc. for C7H10N4O M+ requires 166.18); Anal. Calcd. for C7H10N4O: C 50.59, H
6.07, N 33.71%; Found: C 50.58, H 6.09, N 34.11%.
4. CONCLUSIONS
In summary, we have successfully demonstrated the synthesis of new α-cyanoketene-N,S-
acetals derived only from secondary aliphatic amines. We further carried out their
reactions with hydrazine to produce pyrazoles that have never been reported before. This
method is highly appealing because of its simple procedure and mild conditions and
because the reactions gave high yields and utilize readily available various secondary
aliphatic amines as starting materials. A new feature arises in the preparation of the α-
cyanoketene-N,S-acetals, where noncyclic N-ethylalkylamines yield products of types
which are not obtained using noncyclic N-methylalkylamines. Finally, these α-
cyanoketene-N,S-acetals can be used as intermediates for the synthesis of many other
heterocyclic compounds.
ACKNOWLEDGMENTS
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The authors thank the Ministry of Higher Education Malaysia and UniversitiKebangsaan
Malaysia for research grant UKM-GGPM-KPB-098-2010. A scholarship from the Libyan
government to WMA is greatly appreciated.
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from ketene-N,S-acetals. Tetrahedron. 2003, 59, 1557.
21. CCDC 917655 contains the supplementary crystallographic data for this paper.
Sommen, G.; Comel, A.; Kirsch, G. Preparation of thieno[2,3-b]pyrroles starting
These data can be obtained free of charge via www.ccdc.cam.ac.uk/conts/retrieving.html
(or from the CCDC, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033;
e-mail: deposit@ccdc.cam.ac.uk).
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Allen, F. H.; Kennard, O.; Watson, D. G.; Brammer, L.; Orpen, A. G.; Taylor, R.
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lengths in organic. Compounds. Chem. Soc. Perkin Trans. 2. 1987, S1±S19.
23.
amines and active methylene compounds. J. Pharm. Soc. Jpn. 1965, 85(5), 387–90.
24. CCDC 917654 contains the supplementary crystallographic data for this paper.
Yoshikata, K.; Seigo, K. Reactions of ketenethioacetals. I. Its reaction with some
These data can be obtained free of charge via www.ccdc.cam.ac.uk/conts/retrieving.html
(or from the CCDC, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033;
e-mail: deposit@ccdc.cam.ac.uk).
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Table 1. Preparation of α-cyanoketene-N,S-acetals2(a-g)and compounds 3(g-i).
Entr NHR1R2
y
Time α-Cyanoketene-N,S-
β-dialkylamine-α-
Yield
%
(h)
1h
acetals 2a-g
cyanoacrylates 3g-i
1
2
3
R1 = Me, R2 = Et
2a: R1 = Me, R2 = Et
2b:R1 = Me, R2 = n-Bu
2c:R1 = Me, R2 = n-
hexyl
-
-
92
R1 = Me, R2 = n-Bu
R1 = Me, R2 = n-
hexyl
6h
4h
86
-
86
4
5
R1 = Me, R2 =
benzyl
6h
1h
2d: R1 = Me, R2 =
benzyl
-
-
-
98
78
R1 = Me, R2 =
cyclohexyl
2e:R1 = Me, R2 =
cyclohexyl
6
7
R1, R2 = pyrrolidine
R1 = Et, R2 = benzyl
1h
2f: R1, R2 = pyrrolidine
98
11h
2g: R1 = Et, R2 = benzyl 3g: R1 = Et, R2 =
2g:35,
3g:50
77
benzyl
8
9
R1 = Et, R2 =
cyclohexyl
1h
-
-
3h: R1 = Et, R2 =
cyclohexyl
R1 = Et, R2 = n-Bu
16h
3i:R1 = Et, R2 = n-
Bu
69
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Table 2. Crystal data and structure refinement for compound 2f.
Chemical
formula
C11H16N2O2S1
Absorption coefficient
2.338 mm-1
Formula weight 240.33 g mol-1
F(000)
512.0
Colour
Colorless
Theta range for data
collection
5.0-71.2 (º)
Crystal shape
Size
Prismatic
Reflections collected /
unique
4425, 2240, Rint = 0.020
0.10 x 0.18 x 0.23
Completeness to theta =
25.00
0.991
mm
Temperature
Wavelength
Crystal system
100 K
Max. and min.
transmission
Tmin = 0.837,Tmax =
1.000
1.54180 Å
Refinement method
Full-matrix least-
squares on F2
2231/0/145
orthorhombic
Data/ restraints/
parameters
Space group
a,b,c (Å); α, β, γ
( )º
P21212 (No. 19)
6.7899(3),
Goodness-of-fit on F2
Final R indices [I>2 σ
(I)]
0.730
R = 0.0327,wR = 0.0841
9.9302(4),
17.5667(7); 90, 90,
90
Cell volume
Z
1184.44(9)Å3
Largest diff. peak and
hole
-0.27 & 0.39 e Å−3
4
Calculated density
1.348 g.cm-3
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Table 3. Selected bond lengths (Å), angles and torsion angles (º) for 2f.
Bond
Bond
Bond
Bond angle
(º)
Bond
torsion angles
(º)
length (Å)
1.7646(19)
103.86(10)
142.19(19)
S(1)−C(2)
C(2)−S(1)−C(16)
C(11)−O(12)−C(1
3)
N(3)−C(2)−C(8)−C(9)
C(8)−C(2)−N(3)−C(4)
1.807(2)
1.362(2)
1.452(2)
1.212(2)
115.73(16)
123.66(17)
114.56(15)
121.24(15)
179.64(18)
-29.85(18)
175.06(17
-13.9(3)
S(1)−C(16)
O(12)−C(1
1)
C(2)−N(3)−C(4)
C(16)−S(1)−C(2)−C(8)
C(2)−C(8)−C(11)−O(12)
C(8)−C(2)−N(3)−C(7)
O(12)−C(1
3)
S(1)−C(2)−N(3)
S(1) −C(2)−C(8)
O(15)−C(1
1)
1.316(3)
1.156(3)
1.421(3)
117.66(17)
122.62(17)
110.78(17)
(2) 34.7-
169.64 (19)
163.10(14)
N(3)−C(2)
N(10)−C(9)
C(2)−C(8)
C(2)−C(8)−C(9)
C(2)−C(8)−C(11)
C(14)−C(13)−O(1
2)
S(1)−C(2)−C(8)−C(9)
C(9)−C(8)−C(11)−O(15)
S(1)− C(2)−N(3)− C(7)
1.424(3)
1.453(3)
177.4(2)
153.02(14)
C(8)−C(9)
N(10)−(C9)−C(8)
O(12)−C(11)−O(1
5)
C(16)−S(1)−C(2)−N(3)
O(12)−C(11)−C(8)−C(9)
123.33(18)
- 4.7(2)
C(8)−C(11)
1.527(3)
124.47(17)
1.5 (3)
C(5)−C(4)
C(2)−N(3)−C(7)
O(15)−C(11)−O(12)−C(1
3)
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Table 4. The structures, yields and melting points of pyrazoles4(a-f), 4j and 4k.
Entry
N,S-acetals 2a-f, 2j and Pyrazoles 4a-f, 4j and 4k
Yield %
Melting point
(ºC)
2k
1
2
3
4
5
2a
2b
4a:R1 = Me, R2 = Et
4b:R1 = Me, R2 = n-Bu
4c:R1 = Me, R2 = n-hexyl
4d: R1 = Me, R2 = benzyl
4e: R1 = Me, R2 =
88
75
95
97
80
228-230
197-198
176-178
230-231
> 310
2c
2d
2e
cyclohexyl
6
7
8
2f
2j
2k
4f: R1, R2 = pyrrolidine
4j: R1, R2 = morpholine
4k: R1, R2 = piperidine
91
94
88
> 300
181-183
> 350
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Table 5. Crystal data and structure refinement for 4b.
Chemical
formula
Formula
weight
C9H14N4O
Absorption
coefficient
F(000)
0.719mm-1
416
194.24 g mol-1
Colorless
Colour
Theta range for data 5.4–71.2(º)
collection
Crystal shape Block
Reflections collected / 11181, 1929, Rint =
unique
0.028
Size
0.13 x 0.17 x 0.26
mm
Temperature 150 K
Completeness to
theta = 25.00
Max. and min.
transmission
Refinement method
1.66/0.99
T
min = 0.885,Tmax =
0.911
Wavelength
1.54184 Å
Full-matrix least-
squares on F2
1921/0/128
Crystal
Orthorhombic
Data/ restraints/
parameters
system
Space group
P212121 (No. 19)
Goodness-of-fit on F2 0.99
a,b,c (Å); α, β, 7.52407(17),8.2298(2), Final R indices [I>2 σ R = 0.035,wR =
γ ( )º
16.2919(4); 90, 90, 90 (I)]
0.0874
Cell volume
1008.82(4) Å3
4
Largest diff. peak
-0.20 &, 0.15 (e Å−3)
and hole
Z
Calculated density
1.279 (g.cm-3)
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Table 6. Selected bond lengths [Å], angles [º] and torsion angles [º] for 4b.
Bond
Bond length
(Å)
Bond
Bond angle
(º)
Bond
torsion angles
(º)
1.2394(18)
C5—N4—N3 108.74(11)
-4.8(3)
O1−C2
C10−N9−C5−C
6
C5—N9
1.3330(19)
1.4660(18)
C2—N3—N4 108.86(11)
10.42(16)
C5−N4−N3−C2
N3−N4−C5−N9
N9—C10
C5—N9—
C10
121.90(1
171.24(13)
N9—C14
C5—N4
1.459(2)
C5—N4—N3 108.74(11)
C2—N3—N4 108.86(11)
N9—C5—N4 120.16(13)
N9—C5—C6 132.01(13)
N4—C5—C6 107.82(12)
C7—C6—C5 130.33(13)
C7—C6—C2 122.00(13)
C5—C6—C2 107.49(12)
-8.04(16)
171.81(13)
-176.69(15)
-8.27(15)
-176.25(16)
8.6(3)
N3−N4−C5−C6
N4−N3−C2−O1
C5−C6−C2−O1
N4−N3−C2−C6
N9−C5−C6−C2
N9−C5−C6−C7
C7−C6−C2−O1
C7−C6−C2−N3
1.3586(18)
1.4053(17)
1.3707(18)
1.519(2)
N4—N3
C2—N3
C11—C12
C10—C11
C12—C13
C5−C6
1.523(2)
1.523(2)
-1.1(2)
1.406(2)
179.02(13)
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Scheme 1. Synthesis of α-cyanoketene-N,S-acetals 2(a-g) and compounds 3(g-i).
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Scheme 2. Selected NOESY correlation for compound (3h).
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Scheme 3. Synthesis of substituted pyrazoles 4(a-f), 4j and 4k.
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Scheme 4. Proposed mechanism for the formation of pyrazoles 4(a-f), 4j and 4k.
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Figure 1. The structure of compound (2f) showing the atom numbering scheme with
ellipsoids drawn at the 50% probability level.
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