Divergent Reactivity in the Reaction of β-Oxodithioesters and Hydroxylamine: Access to β-Ketonitriles and Isoxazoles

Article abstract of DOI:10.1021/acs.joc.5b01869

Starting from β-oxodithioesters and hydroxylamine, two completely different transformations afford either β-ketonitriles or isoxazoles with high chemoselectivity depending on the reaction conditions. The reaction of β-oxodithioesters with hydroxylamine in EtOH at room temperature in daylight gave β-ketonitriles in high yields. On the other hand, 3-methylthio-isoxazoles were efficiently obtained as the final products by heating the mixture of β-oxodithioesters and hydroxylamine in HOAc at 90 °C.

Full text of DOI:10.1021/acs.joc.5b01869

Note
pubs.acs.org/joc
Divergent Reactivity in the Reaction of β‑Oxodithioesters and
Hydroxylamine: Access to β‑Ketonitriles and Isoxazoles
Jiaheng Li,† Wei Ma,† Wenbo Ming,† Cong Xu,† Na Wei,† and Mang Wang*,†,‡
†Department of Chemistry, Northeast Normal University, Changchun 130024, P. R. China
‡State Key Laboratory of Polymer Physics and Chemistry, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences,
Changchun 130022, P. R. China
S
* Supporting Information
ABSTRACT: Starting from β-oxodithioesters and hydroxylamine,
two completely different transformations afford either β-ketonitriles or
isoxazoles with high chemoselectivity depending on the reaction
conditions. The reaction of β-oxodithioesters with hydroxylamine in
EtOH at room temperature in daylight gave β-ketonitriles in high
yields. On the other hand, 3-methylthio-isoxazoles were efficiently
obtained as the final products by heating the mixture of β-
oxodithioesters and hydroxylamine in HOAc at 90 °C.
Scheme 1. Reactions of β-Oxodithioesters and
Hydroxylamine
he achievement of complete chemoselectivity in the
Treactions of multifunctional molecules is a major issue in
synthetic organic chemistry.1 β-Oxodithioesters are a kind of
important organic intermediate, having polyfunctional groups
with multireactive sites.2 They have been widely applied in the
construction of various classes of heterocycles with interesting
properties,3−7 for example, in the synthesis of thiophenes,3
pyrroles,4 thiazoles,5 1,2,3-thiadiazoles,6 dihydropyrimidones,7
as well as chromene-2-thiones.8 Taking advantage of easy
preparation, versatile reactivity, and high efficiency in the
applications of organic synthesis and drug design,2−8 the
synthetic utilization of β-oxodithioesters is still an important
task, and those selective transformations based on them are
especially desired. Herein, we disclose two completely different
transformations of β-oxodithioesters with hydroxylamine which
chemoselectively furnish β-ketonitriles and isoxazoles, respec-
tively, under different reaction conditions (Scheme 1A).
During our continuing efforts on the investigations of
heterocycle construction from thioorganic intermediates,
mainly by using of ketene dithioacetals,9,10 we were aware
that the synthesis of isoxazoles by the reaction of β-
oxodithioesters and hydroxylamine was possible and might be
similar to the reactions with α-oxo ketene dithioacetals and
hydroxylamine.11 However, to our surprise, there is no report
for this application until 2013 when Singh and co-workers
developed a straightforward and regioselective synthesis of 3-
aminoisoxazoles12 by multicomponent reactions of β-oxodi-
thioesters, primary (and secondary) amines, and hydroxyl-
amine. In their work, β-oxo thioamide intermediates were
proven to be involved to take part in the cyclocondensation
with hydroxylamine in EtOH (Scheme 1B).
derivative was isolated, but an unprecedented product, 3-oxo-3-
phenylpropanenitrile 2a, was obtained in 65% isolated yield
(Table 1, entry 1). Other tertiary amines, organic or inorganic
bases, including DABCO, DBU, tBuOK, NaOH, NaOAc,
K2CO3, and NaH (entries 2−8), were selected toward the
process during screening the reaction conditions. All the
reactions afforded 2a in good yields. Among them, NaOH was
the best one. Higher temperature (50 °C) made the reaction
messy, and 2a was obtained only in 25% yield (entry 9). Other
solvents were also investigated (entries 1, 10−14), and EtOH
was proven to be super.
Interestingly, when we treated methyl 3-oxo-3-phenyl-
propanedithioate 1a (1.0 equiv) with hydroxylamine hydro-
chloride (1.2 equiv) and tertiary amine (Et3N, 1.2 equiv) in
EtOH (4.0 mL) at room temperature for 7 h, no isoxazole
Received: August 12, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.joc.5b01869
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The Journal of Organic Chemistry
Note
Table 1. Optimization for the Conversion of β-
Oxodithioesters into β-Ketonitriles
Table 2. Synthesis of β-Ketonitriles by the Reaction of β-
Oxodithioesters with Hydroxylamine
a
a
b
entry
base
Et3N
T (°C)
solvent
time (h)
yield (%)
1
rt
rt
rt
rt
rt
rt
rt
rt
50
rt
rt
rt
rt
rt
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
DMF
7
5
65
68
65
73
82
72
73
76
2
DABCO
DBU
3
7
4
tBuOK
NaOH
NaOAc
K2CO3
NaH
4
5
0.8
5.5
5
6
7
8
4
c
9
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
0.5
10
11
10
12
10
25
10
11
12
13
14
61
67
48
62
THF
CH2Cl2
MeCN
d
c
H2O
42
a
Reaction conditions: 1a (0.5 mmol), NH2OH·HCl (0.6 mmol), base
b
c
d
(0.6 mmol), solvent (4 mL). Isolated yields. Messy. 0.1 equiv
TBAB was added.
a
Reaction conditions: 1 (0.5 mmol), NH2OH·HCl (0.6 mmol),
NaOH (0.6 mmol), EtOH (4 mL), rt. Isolated yields.
β-Ketonitriles are versatile synthetic intermediates13 which
have been widely applied in the synthesis of various useful
heterocycles.14 The above reaction sequence indicates for the
first time that the reaction of β-oxodithioesters with hydroxyl-
amine may serve as an efficient route to β-ketonitriles.13,15
Thus, the scope of the reaction was investigated by choosing β-
oxodithioesters 1b−i with different aryl substituents as
substrates under the optimized conditions (Table 1, entry 5).
As shown in Table 2, the selected substrates 1 bearing both
electron-donating and electron-withdrawing aryl groups could
efficiently afford the corresponding β-ketonitrile products 2b−h
at room temperature in good yields. By comparison, β-
oxodithioester with a strong electron-withdrawing CN at
phenyl ring gave 2i in low yield even by prolonging reaction
time. Complex mixture was often obtained when S-methyl 3-
oxo-3-(pyridin-4-yl)propanethioate was selected toward the
identical reaction conditions.
Different from Singh’s work, in which primary or secondary
amines took part in the multicomponent reactions,12 tertiary
amines were only used as the base in our experiments to
neutralize NH2OH·HCl for the reaction with β-oxodithioesters.
It was reported that nitriles could be produced from
thiohydroxamic acids by a thermodynamic dehydrosulfuriza-
tion.16,17 Based on these results, the conversion of 1 into 2 may
involve a thiohydroxamic acid intermediate A and then A′,
which was generated from the nucleophilic substitution of 1 by
NH2OH (Scheme 2, path a). Compared to the work on the
decomposition of thiohydroxamic acids into nitriles which
usually occurred at high temperature,16 A′ easily afforded
nitriles 2 at ambient conditions in our work. Accordingly, a
photolytic process was supposed and has been proven by a
controlled experiment in which no 2a was detected when the
reaction of 1a and NH2OH was performed in dark under the
standard conditions. The suspended sulfur could be observed
during the reaction. Additionally, a route involving thiazirene
intermediate C via B was not ruled out at the present (Scheme
2, path a′).
Further studies on the influence of the wavelength and
intensity of the light and the concentration on the process were
carried out. Although no photocatalyst was used, the wave-
length of the light was proven to be key to the transformation
of β-oxodithioesters into β-ketonitrile. Upon treatment of 1f
with hydroxylamine under the irradiation of blue light (450−
480 nm), no desired β-ketonitrile 2f was detected after 2.5 h
along with the recovery of 1f in 82% yield. On the contrary, 2f
could be isolated in good yield when the reaction was exposed
to green, red, as well as white light. Green light showed a
slightly higher efficiency. In addition, the intensity of the light
made no difference to the reaction, but dilute solution gave
inferior results (for details, see SI).
As described in Scheme 2, the reaction path b also presents a
reasonable route for the synthesis of isoxazoles from β-
oxodithioesters and hydroxylamine as we initially expected.11,12
Aiming to investigate the possibility of path b, we further
screened the reaction conditions including base, temperature,
and solvent for the reaction. To our delight, 3-(methylthio)-5-
phenylisoxazole 3a could be isolated in 17% yield (Scheme 3,
entry 1) when treating methyl 3-oxo-3-phenylpropanedithioate
1a with neutral hydroxylamine (1.2 equiv, preneutralized by
NaOAc (1.2 equiv) in water) in HOAc at room temperature.
The yield of 3a was able to be dramatically increased to 84%
yield by heating the reaction mixture at 90 °C (entry 3).
NH4OAc was also proved to be an efficient base for the
preneutralization of hydroxylamine hydrochloride (entry 4). It
was found that the pretreatment of hydroxylamine hydro-
chloride with a base was required and that no reaction occurred
without this neutralization (entry 5). Moreover, we did not
detect isoxazole isomer which resulted from the reaction of 1a
with hydroxylamine by primary attack of hydroxylamine at its
oxo moiety. It should be due to the predominant attack of
softer nucleophilic nitrogen of hydroxylamine at softer
electrophilic thiocarbonyl of 1a.
B
DOI: 10.1021/acs.joc.5b01869
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The Journal of Organic Chemistry
Note
Scheme 2. Proposed Reaction Mechanism
suitable for the reaction, providing the corresponding isoxazole
derivatives 3i−l in 63−89% yields. However, β-oxodithioester
bearing CN at phenyl ring gave 3m in 27% yield.
Scheme 3. Optimization for Preparing Corresponding
Isoxazoles
In conclusion, two well-controlled transformations of β-
oxodithioesters with hydroxylamine are described to afford β-
ketonitriles and isoxazoles, respectively, under different reaction
conditions. The reaction of β-oxodithioesters with hydroxyl-
amine in EtOH at room temperature in daylight gave β-
ketonitriles in high yields via thiohydroxamic acid intermediate
followed by homolysis. On the other hand, 3-methylthio-
isoxazoles were efficiently obtained through a cyclocondensa-
tion of β-oxodithioesters and hydroxylamine by heating the
mixture in HOAc at 90 °C. The simple execution, readily
available substrates, mild conditions, good yields, and, in
particular, the good chemoselectivity of the reactions make the
protocol very attractive for practical applications.
Isoxazoles are one of classes of heterocyclic compounds with
widely biological and pharmacological activities and agro-
chemical properties.18 Functionalized isoxazoles have also been
demonstrated to be versatile building blocks in organic
synthesis.19 Thus, the scope of the above reaction was
investigated. As described in Table 3, this reaction could be
carried with a series of substituted β-oxodithioesters affording
the corresponding products 3. 1 with both electron-donating
and electron-withdrawing groups can afford isoxazoles 3a−h in
good yields. Those substrates containing heteroaryls are also
EXPERIMENTAL SECTION
■
General. All commercially available compounds were used as
received unless otherwise noted. Reactions were monitored through
thin layer chromatography (TLC, silica gel 60 F254). Subsequent to
elution, spots were visualized using UV radiation (254 nm). Flash
column chromatography was performed on silica gel 60 (particle size
200−400 mesh). 1H NMR and 13C NMR were recorded at 25 °C on a
a
Table 3. Substrate Scope for the Synthesis of Isoxazoles
a
Reaction conditions: 1 (0.5 mmol), NH2OH·HCl (0.6 mmol), NaOAc (0.6 mmol), H2O (0.5 mL), HOAc (4 mL), 90 °C. Isolated yields.
C
DOI: 10.1021/acs.joc.5b01869
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The Journal of Organic Chemistry
Note
500 and 125 MHz spectrometer, respectively, by using TMS as
internal standard. High-resolution mass spectra (HRMS) were
obtained using a microTOF II focus spectrometer (ESI). Melting
points were uncorrected. β-Oxodithioesters 1 were prepared by the
method reported in the literature.20
General Procedure for the Synthesis of 2 (2a was selected
as an example). Hydroxylamine hydrochloride (0.6 mmol) was
stirred with NaOH (0.6 mmol) in 4 mL of EtOH for 10 min at room
temperature. Then, 3-oxo-3-phenylpropanedithioate 1a (0.5 mmol)
was added, and the reaction mixture was stirred at ambient conditions
for 50 min to consume 1a (monitored by TLC). The reaction was
quenched by saturated aqueous NaCl, and extracted with dichloro-
methane (10 mL × 3). The combined organic layer was dried over
anhydrous MgSO4 and evaporated to afford the crude product, which
was purified by column chromatography on silica gel (eluent,
petroleum ether/ethyl acetate, 9:1) to give β-ketonitrile 2a (59.5
mg, 82%) as a white solid.
General Procedure for the Synthesis of 3 (3a was selected
as an example). Hydroxylamine hydrochloride (0.6 mmol) was first
preneutralized by NaOAc (0.6 mmol) in 0.5 mL of water. Then,
HOAc (4 mL) and 3-oxo-3-phenylpropanedithioate 1a (0.5 mmol)
were added to the above mixture (0.6 mmol). After stirring at 90 °C
for 5 h to consume 1a (monitored by TLC), the reaction was
quenched by saturated aqueous NaCl, neutralized by aqueous
NaHCO3, and extracted with dichloromethane (10 mL × 3). The
combined organic layer was dried over anhydrous MgSO4 and
evaporated to afford the crude product, which was purified by column
chromatography on silica gel (eluent, petroleum ether/ethyl acetate,
20:1) to give isoxazole 3a (80.3 mg, 84%) as a white solid.
CDCl3): δ 28.8, 113.3, 113.3, 119.3, 147.7, 150.4, 175.7. HRMS (ESI-
TOF): Calcd for [M + H]+ C7H6NO2, 136.0393; found, 136.0398.
3-Oxo-3-(thiophen-2-yl)propanenitrile (2h). White solid (52.9 mg,
70%). Mp 130−131 °C (lit.15b Mp 124−126 °C). H NMR (500
1
MHz, CDCl3): δ 4.03 (s, 2H), 7.21 (t, J = 4.5 Hz, 1H), 7.80 (dd, J =
5.0, 7.0 Hz, 2H). 13C NMR (125 MHz, CDCl3): δ 29.5, 113.4, 128.7,
133.7, 136.2, 140.8, 179.5. HRMS (ESI-TOF): Calcd for [M + H]+
C7H6NOS, 152.0165; found, 152.0166.
3-(2-Cyanoacetyl)benzonitrile (2i). Light yellow solid (13.3 mg,
26%). Mp 189−190 °C. 1H NMR (400 MHz, CDCl3): δ 4.12 (s, 2H),
7.71 (dd, J = 7.6, 8 Hz, 1H), 7.96 (d, J = 7.6 Hz, 1H), 8.17 (d, J = 8
Hz, 1H), 8.22 (s, 1H); 13C NMR (100 MHz, CDCl3): δ 29.5, 112.8,
113.9, 117.2, 130.2, 132.0, 132.2, 134.9, 137.4, 185.3. HRMS (ESI-
TOF): Calcd for [M + H]+ C10H7N2O, 171.0553; found, 171.0565.
3-(Methylthio)-5-phenylisoxazole (3a). White solid (80.3 mg,
84%). Mp 51−52 °C (lit.11 Mp 56−57 °C). H NMR (500 MHz,
1
CDCl3): δ 2.55 (s, 3H), 6.32 (s, 1H), 7.35−7.38 (m, 3H), 7.64−7.66
(m, 2H). 13C NMR (125 MHz, CDCl3): δ 13.8, 99.0, 125.7 (2C),
127.1, 128.9 (2C), 130.2, 160.9, 169.8. HRMS (ESI-TOF): Calcd for
[M + H]+ C10H10NOS, 192.0478; found, 192.0478.
3-(Methylthio)-5-(p-tolyl)isoxazole (3b). Yellow solid (79.0 mg,
77%). Mp 65−66 °C (lit.11 Mp 64−65 °C). H NMR (500 MHz,
1
CDCl3): δ 2.32 (s, 3H), 2.55 (s, 3H), 6.27 (s, 1H), 7.18 (d, J = 8.0 Hz,
2H), 7.55 (d, J = 8.0 Hz, 2H). 13C NMR (125 MHz, CDCl3): δ 13.9,
21.5, 98.4, 124.4, 125.7 (2C), 129.6 (2C), 140.6, 160.8, 170.1. HRMS
(ESI-TOF): Calcd for [M + H]+ C11H12NOS, 206.0634; found,
206.0633.
5-(4-Methoxyphenyl)-3-(methylthio)isoxazole (3c). White solid
(79.7 mg, 72%). Mp 88−89 °C (lit.11 Mp 74−75 °C). 1H NMR (500
MHz, CDCl3): δ 2.62 (s, 3H), 3.84 (s, 3H), 6.28 (s, 1H), 6.95 (d, J =
12.0 Hz, 2H), 7.63 (d, J = 12.0 Hz, 2H). 13C NMR (125 MHz,
CDCl3): δ 13.9, 55.4, 97.7, 114.3 (2C), 119.9, 127.4 (2C), 160.8,
161.2, 169.9. HRMS (ESI-TOF): Calcd for [M + H]+ C11H12NO2S,
222.0583; found, 222.0585.
5-(3-Methoxyphenyl)-3-(methylthio)isoxazole (3d). White solid
(83.0 mg, 75%). Mp 80−81 °C. 1H NMR (500 MHz, CDCl3): δ 2.63
(s, 3H), 3.86 (s, 3H), 6.40 (s, 1H), 6.98 (dd, J = 1.5, 8.5 Hz, 1H), 7.27
(d, J = 1.5 Hz, 1H), 7.31 (d, J = 8.0 Hz, 1H), 7.37 (t, J = 8.0 Hz, 1H).
13C NMR (125 MHz, CDCl3): δ 13.9, 55.4, 99.3, 110.9, 116.2, 118.3,
128.3, 130.1, 159.9.1, 160.9, 169.7. HRMS (ESI-TOF): Calcd for [M +
H]+ C11H12NO2S, 222.0583; found, 222.0588.
3-Oxo-3-phenylpropanenitrile (2a). White solid (59.5 mg, 82%).
Mp 87−88 °C (lit.15a Mp 81 °C). H NMR (500 MHz, CDCl3): δ
1
4.11 (s, 2H), 7.54 (t, J = 7.5 Hz, 2H), 7.67 (d, J = 7.5 Hz, 1H), 7.93 (d,
J = 7.5 Hz, 2H). 13C NMR (125 MHz, CDCl3): δ 29.4, 113.8, 128.4
(2C), 129.1 (2C), 134.2, 134.8, 187.1. HRMS (ESI-TOF): Calcd for
[M + Na]+ C9H7NNaO, 168.0420; found, 168.0426.
3-Oxo-3-(p-tolyl)propanenitrile (2b). White solid (62.1 mg, 78%).
Mp 103−105 °C (lit.15b Mp 94−96 °C). 1H NMR (500 MHz,
CDCl3): δ 2.44 (s, 3H), 4.09 (s, 2H), 7.32 (d, J = 8.0 Hz, 2H), 7.81 (d,
J = 8.0 Hz, 2H). 13C NMR (125 MHz, CDCl3): δ 21.8, 29.3, 114.1,
128.6 (2C), 129.8 (2C), 131.8, 146.0, 186.8. HRMS (ESI-TOF):
Calcd for [M + H]+ C10H10NO, 160.0757; found, 160.0759.
3-(4-Methoxyphenyl)-3-oxopropanenitrile (2c). White solid (62.2
5-(2-Chlorophenyl)-3-(methylthio)isoxazole (3e). Yellow semi-
mg, 71%). Mp 132−133 °C (lit.14c Mp 132−137 °C). H NMR (500
1
1
solid (93.7 mg, 83%). H NMR (500 MHz, CDCl3): δ 2.64 (s, 3H),
MHz, CDCl3): δ 3.90 (s, 3H), 4.05 (s, 2H), 6.98 (dd, J = 1.5, 7.0 Hz,
2H), 7.90 (dd, J = 2.0, 7.0 Hz, 2H). 13C NMR (125 MHz, CDCl3): δ
29.0, 55.6, 114.1 (2C), 114.3, 127.2, 130.9 (2C), 164.7, 185.5. HRMS
(ESI-TOF): Calcd for [M + H]+ C10H10NO2, 176.0706; found,
176.0710.
6.83 (s, 1H), 7.36−7.38 (m, 2H), 7.49 (dd, J = 2.0, 7.0 Hz, 1H), 7.89−
7.91 (m, 1H). 13C NMR (125 MHz, CDCl3): δ 13.9, 103.9, 125.9,
127.2, 129.4, 130.8, 130.9, 131.7, 160.9, 166.0. HRMS (ESI-TOF):
Calcd for [M + H]+ C10H9ClNOS, 226.0088; found, 226.0092.
5-(3-Chlorophenyl)-3-(methylthio)isoxazole (3f). White solid
1
3-(3-Methoxyphenyl)-3-oxopropanenitrile (2d). White solid (66.6
mg, 76%). Mp 127−128 °C. 1H NMR (500 MHz, CDCl3): δ 3.86 (s,
3H), 4.10 (s, 2H), 7.19−7.21 (m, 1H), 7.41−7.48 (m, 3H). 13C NMR
(125 MHz, CDCl3): δ 29.4, 55.4, 112.4, 113.6, 120.8, 121.1, 123.0,
135.3, 159.9, 186.8. HRMS (ESI-TOF): Calcd for [M + H]+
C10H10NO2, 176.0706; found, 176.0716.
(89.1 mg, 79%). Mp 89−90 °C. H NMR (500 MHz, CDCl3): δ
2.64 (s, 3H), 6.43 (s, 1H), 7.27−7.41 (m, 2H), 7.61−7.63 (m, 1H),
7.72 (t, J = 1.0 Hz, 1H). 13C NMR (125 MHz, CDCl3): δ 13.9, 99.8,
123.9, 125.8, 128.7, 130.3, 130.3, 135.0, 161.1, 168.3. HRMS (ESI-
TOF): Calcd for [M + H]+ C10H9ClNOS, 226.0088; found, 226.0090.
5-(4-Chlorophenyl)-3-(methylthio)isoxazole (3g). White solid
(101.6 mg, 90%). Mp 111−112 °C (lit.11 Mp 107−108 °C). 1H
NMR (500 MHz, CDCl3): δ 2.63 (s, 3H), 6.40 (s, 1H), 7.44 (d, J =
8.5 Hz, 2H), 7.67 (d, J = 8.5 Hz, 2H). 13C NMR (125 MHz, CDCl3):
δ 13.9, 99.3, 125.5, 128.0 (2C), 129.3 (2C), 136.4, 161.1, 168.7.
HRMS (ESI-TOF): Calcd for [M + H]+ C10H9ClNOS, 226.0088;
found, 226.0094.
3-(4-Chlorophenyl)-3-oxopropanenitrile (2e).14b White solid (77.2
mg, 86%). Mp 138−139 °C. 1H NMR (500 MHz, CDCl3): δ 4.06 (s,
2H), 7.52 (d, J = 8.5 Hz, 2H), 7.88 (d, J = 8.5 Hz, 2H). 13C NMR (125
MHz, CDCl3): δ 29.4, 113.4, 129.6 (2C), 129.8 (2C), 132.5, 141.5,
185.9. HRMS (ESI-TOF): Calcd for [M + H]+ C9H7ClNO, 180.0211;
found, 180.0213.
3-(2-Bromophenyl)-3-oxopropanenitrile (2f). Light yellow oil
(70.6 mg, 63%). 1H NMR (500 MHz, CDCl3): δ 4.14 (s, 2H),
7.41−7.47 (m, 2H), 7.53 (dd, J = 1.5, 7.5 Hz, 1H), 7.67 (dd, J = 1.0,
7.5 Hz, 1H). 13C NMR (125 MHz, CDCl3): δ 32.2, 113.1, 119.0,
127.7, 129.5, 133.2, 133.9, 137.644, 190.2. HRMS (ESI-TOF): Calcd
for [M + H]+ C9H7BrNO, 223.9706; found, 223.9686.
5-(2-Bromophenyl)-3-(methylthio)isoxazole (3h). Light yellow
semisolid (113.5 mg, 84%). H NMR (500 MHz, CDCl3): δ 2.55
(s, 3H), 6.76 (s, 1H), 7.18 (t, J = 8.0 Hz, 1H), 7.32 (t, J = 7.5 Hz, 1H),
7.59 (d, J = 8.0 Hz, 1H), 7.72 (d, J = 8.0 Hz, 1H). 13C NMR (125
MHz, CDCl3): δ 13.9, 103.8, 121.1, 127.7, 128.0, 130.0, 131.1, 134.1,
160.6, 167.4. HRMS (ESI-TOF): Calcd for [M + H]+ C10H9BrNOS,
269.9583; found, 269.9596.
1
3-(Furan-2-yl)-3-oxopropanenitrile (2g). White solid (52.0 mg,
77%). Mp 91−92 °C (lit.15b Mp 76−78 °C). H NMR (500 MHz,
5-(Furan-2-yl)-3-(methylthio)isoxazole (3i). Yellow solid (70.7 mg,
1
78%). Mp 55−56 °C (lit.11 Mp 56−57 °C). H NMR (500 MHz,
1
CDCl3): δ 3.98 (s, 2H), 6.65 (dd, J = 1.5, 3.5 Hz, 1H), 7.40 (d, J = 1.0
Hz, 1H), 7.67 (dd, J = 1.0, 1.0 Hz, 1H). 13C NMR (125 MHz,
CDCl3): δ 2.62 (s, 3H), 6.33 (s, 1H), 6.53 (dd, J = 1.5, 3.5 Hz, 1H),
D
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The Journal of Organic Chemistry
Note
6.89 (d, J = 8.5 Hz, 1H), 7.53 (s, 1H). 13C NMR (125 MHz, CDCl3):
δ 13.9, 98.5, 110.7, 111.8, 142.8, 144.1, 160.7, 161.5. HRMS (ESI-
TOF): Calcd for [M + H]+ C8H8NO2S, 182.0270; found, 182.0271.
3-(Methylthio)-5-(thiophen-2-yl)isoxazole (3j). Yellow solid (62.1
(5) (a) Rahman, A.; Ila, H.; Junjappa, H. Synthesis 1984, 1984, 250.
(b) Chandrasekharam, M.; Singh, O. M.; Ila, H.; Junjappa, H. Synth.
Commun. 1998, 28, 3073.
(6) (a) Nagaraju, A.; Ramulu, B. J.; Shukla, G.; Srivastava, A.; Verma,
G. K.; Raghuvanshi, K.; Singh, M. S. Tetrahedron Lett. 2014, 55, 2430.
(b) Singh, M. S.; Nagaraju, A.; Verma, G. K.; Shukla, G.; Verma, R. K.;
Srivastava, A.; Raghuvanshi, K. Green Chem. 2013, 15, 954.
(7) (a) Singh, O. M.; Devi, N. S. J. Org. Chem. 2009, 74, 3141.
(b) Nandi, G. C.; Samai, S.; Singh, M. S. J. Org. Chem. 2010, 75, 7785.
(8) (a) Verma, R. K.; Verma, G. K.; Raghuvanshi, K.; Singh, M. S.
Tetrahedron 2011, 67, 584. (b) Singh, O. M.; Devi, N. S.; Thokchom,
D. S.; Sharma, G. J. Eur. J. Med. Chem. 2010, 45, 2250.
(9) For recent reviews, see: (a) Pan, L.; Bi, X.; Liu, Q. Chem. Soc. Rev.
2013, 42, 1251. (b) Pan, L.; Liu, Q. Synlett 2011, 2011, 1073.
(10) For selected work in our group on the synthesis of heterocycles
from ketene dithioacetals, see: (a) Dong, Y.; Liu, B.; Chen, P.; Liu, Q.;
Wang, M. Angew. Chem., Int. Ed. 2014, 53, 3442. (b) Dong, Y.; Guo,
Y.; Liu, J.; Zheng, G.; Wang, M. Eur. J. Org. Chem. 2014, 2014, 797.
(c) Liu, Y.; Liu, J.; Wang, M.; Liu, J.; Liu, Q. Adv. Synth. Catal. 2012,
354, 2678. (d) Liu, Y.; Wang, M.; Yuan, H.; Liu, Q. Adv. Synth. Catal.
2010, 352, 884. (e) Liang, D.; Wang, M.; Bekturhun, B.; Xiong, B.;
Liu, Q. Adv. Synth. Catal. 2010, 352, 1593.
1
mg, 63%). Mp 65−66 °C. H NMR (500 MHz, CDCl3): δ 2.62 (s,
3H), 6.28 (s, 1H), 7.12 (dd, J = 4.0, 5.0 Hz, 1H), 7.46 (dd, J = 1.0, 5.0
Hz, 1H), 7.49 (d, J = 1.0, 3.5 Hz, 1H). 13C NMR (125 MHz, CDCl3):
δ 13.9, 98.7, 127.2, 128.0, 128.2, 128.8, 161.0, 164.8. HRMS (ESI-
TOF): Calcd for [M + H]+ C8H8NOS2, 198.0042; found, 198.0044.
3-(Methylthio)-5-(pyridin-3-yl)isoxazole (3k). Yellow solid (85.5
mg, 89%). Mp 107−108 °C. 1H NMR (500 MHz, CDCl3): δ 2.65 (s,
3H), 6.51 (s, 1H), 7.42 (dd, J = 1.0, 5.0 Hz, 1H), 8.05 (d, J = 8.0 Hz,
1H), 8.68 (dd, J = 1.5, 4.5 Hz, 1H), 8.99 (d, J = 2.5 Hz, 1H). 13C
NMR (125 MHz, CDCl3): δ 13.9, 100.0, 123.4, 123.7, 132.9, 147.0,
151.0, 161.3, 167.0. HRMS (ESI-TOF): Calcd for [M + H]+
C9H9N2OS, 193.0430; found, 193.0435.
3-(Methylthio)-5-(pyridin-4-yl)isoxazole (3l). White solid (77.9 mg,
81%). Mp 108−109 °C (lit.11 Mp 96−97 °C). H NMR (500 MHz,
1
CDCl3): δ 2.65 (s, 3H), 6.59 (s, 1H), 7.60 (dd, J = 1.5, 4.5 Hz, 2H),
8.75 (t, J = 1.0, 5.0 Hz, 2H). 13C NMR (125 MHz, CDCl3): δ 13.9,
101.6, 119.4 (2C), 133.8, 150.7 (2C), 161.4, 167.1. HRMS (ESI-
TOF): Calcd for [M + H]+ C9H9N2OS, 193.0430; found, 193.0432.
3-(3-(Methylthio)isoxazol-5-yl)benzonitrile (3m). White solid
(11) (a) Purkayastha, M.; Ila, H.; Junjappa, H. Synthesis 1989, 1989,
20. (b) Dieter, R. K.; Chang, H. J. J. Org. Chem. 1989, 54, 1088.
(12) Samai, S.; Chanda, T.; Ila, H.; Singh, M. S. Eur. J. Org. Chem.
2013, 2013, 4026.
1
(17.5 mg, 27%). Mp: 141−142 °C; H NMR (500 MHz, CDCl3): δ
2.65 (s, 3H), 6.50 (s, 1H), 7.61 (t, J = 6.0 Hz, 1H), 7.73 (d, J = 6.4 Hz,
1H), 7.97 (d, J = 6.4 Hz, 1H), 8.02 (s, 1H); 13C NMR (125 MHz,
CDCl3): δ 13.9, 100.5, 113.6, 117.9, 128.4, 129.2, 129.7, 130.0, 133.4,
161.4, 167.3. HRMS (ESI-TOF): Calcd for [M + H]+ C11H9N2OS,
217.0430; found, 217.0441.
(13) Elnagdi, M. H.; Elgemeie, G. E. H. Synthesis 1984, 1984, 1.
(14) Selected applications, see: (a) Bera, H.; Ojha, P. K.; Tan, B. J.;
Sun, L.; Dolzhenko, A. V.; Chui, W.-K.; Chiu, G. N. C. Eur. J. Med.
Chem. 2014, 78, 294. (b) Hu, J.; Wei, Y.; Tong, X. Org. Lett. 2011, 13,
3068. (c) Danence, L. J. T.; Gao, Y.; Li, M.; Huang, Y.; Wang, J. Chem.
- Eur. J. 2011, 17, 3584. (d) Aggarwal, R.; Kumar, V.; Kumar, R.;
Singh, S. P. Beilstein J. Org. Chem. 2011, 7, 179. (e) Moe, S. T.;
Thompson, A. B.; Smith, G. M.; Fredenburg, R. A.; Stein, R. L.;
Jacobson, A. R. Bioorg. Med. Chem. 2009, 17, 3072. (f) James, M. L.;
Fulton, R. R.; Henderson, D. J.; Eberl, S.; Meikle, S. R.; Thomson, S.;
Allan, R. D.; Dolle, F.; Fulham, M. J.; Kassiou, M. Bioorg. Med. Chem.
2005, 13, 6188. (g) Ranatunge, R. R.; Garvey, D. S.; Janero, D. R.;
Letts, L. G.; Martino, A. M.; Murty, M. G.; Richardson, S. K.; Young,
D. V.; Zemetseva, I. S. Bioorg. Med. Chem. 2004, 12, 1357. (h) Laufer,
S. A.; Zimmermann, W.; Ruff, K. J. J. Med. Chem. 2004, 47, 6311.
(15) Representative methods for the synthesis of β-ketonitriles, see:
(a) Park, A.; Lee, S. Org. Lett. 2012, 14, 1118. (b) Levchenko, K. S.;
Semenova, I. S.; Yarovenko, V. N.; Shmelin, P. S.; Krayushkin, M. M.
Tetrahedron Lett. 2012, 53, 3630. (c) Zhang, Z.; Wang, Z.; Zhang, R.;
Ding, K. Angew. Chem., Int. Ed. 2010, 49, 6746. (d) Anbarasan, P.;
Neumann, H.; Beller, M. Chem. - Eur. J. 2010, 16, 4725. (e) Ji, Y.;
Trenkle, W. C.; Vowles, J. V. Org. Lett. 2006, 8, 1161. (f) Kamila, S.;
Zhu, D.; Biehl, E. R.; Hua, L. Org. Lett. 2006, 8, 4429. (g) Yoo, B. W.;
Hwang, S. K.; Kim, D. Y.; Choi, J. W.; Ko, J. J.; Choi, K. I.; Kim, J. H.
Tetrahedron Lett. 2002, 43, 4813. (h) Sim, M. M.; Lee, C. L.; Ganesan,
A. Tetrahedron Lett. 1998, 39, 2195. (i) Kahne, D.; Collum, D. B.
Tetrahedron Lett. 1981, 22, 5011.
(16) (a) Walter, W.; Schaumann, E. Synthesis 1971, 1971, 111.
(b) Ettlinger, M. G.; Lundeen, A. J. J. Am. Chem. Soc. 1957, 79, 1764.
(17) Primary thioamides were also reported to be able to afford
nitriles by the oxidative dehydrosulfurization, see: Yamaguchi, K.;
Yajima, K.; Mizuno, N. Chem. Commun. 2012, 48, 11247.
(18) For selected recent reviews, see, (a) Giomi, D.; Cordero, F.;
Machetti, F. In Comprehensive Heterocyclic Chemistry III; Katritzky, A.,
Ramsden, C., Scriven, E., Taylor, R., Joule, J., Eds.; Elsevier: Oxford,
U.K., 2008, Vol. 4, p 365. (b) Sperry, J. B.; Wright, D. L. Curr. Opin.
Drug Discovery Devel. 2005, 8, 723. (c) Cicchi, S.; Cordero, F. M.;
Giomi, D. Prog. Heterocycl. Chem. 2003, 15, 261.
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.5b01869.
Study on the influence of the light on the formation of β-
ketonitriles, study on the influence of the concentration
1
on the formation of β-ketonitriles, and copies of H
NMR and 13C NMR spectra of all compounds (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: wangm452@nenu.edu.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We gratefully acknowledge National Natural Sciences Founda-
tion of China (21172031 and 21372040) and National Natural
Science Foundation of Jilin (20140101113JC) for financial
support.
REFERENCES
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DOI: 10.1021/acs.joc.5b01869
J. Org. Chem. XXXX, XXX, XXX−XXX