Lewis Base/Br?nsted Acid Cocatalysis for Thiocyanation of Amides and Thioamides

Article abstract of DOI:10.1021/acs.joc.9b03275

Lewis base/Br?nsted acid cocatalysis for electrophilic thiocyanation of olefins is reported. Using a combination of triphenylphosphine selenide and diphenyl phosphate as a catalyst, a wide range of unsaturated amides and thioamides underwent thiocyanation to furnish thiocyanated thiazoline and oxazoline derivatives in high yields (up to 97%).

Full text of DOI:10.1021/acs.joc.9b03275

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Lewis Base/Brønsted Acid Cocatalysis for Thiocyanation of Amides
and Thioamides
Qumruddeen, Arun Yadav, Ruchir Kant, and Chandra Bhushan Tripathi*
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ABSTRACT: Lewis base/Brønsted acid cocatalysis for electro-
philic thiocyanation of olefins is reported. Using a combination of
triphenylphosphine selenide and diphenyl phosphate as a catalyst,
a wide range of unsaturated amides and thioamides underwent
thiocyanation to furnish thiocyanated thiazoline and oxazoline
derivatives in high yields (up to 97%).
atalytic olefin functionalization is a proven and widely
emerged.10 In 2018, N-thiocyanatosaccharin was developed
for the thiocyanation of indoles, aromatic ketones, oxindoles,
and β-ketocarbonyl compounds.10e TMSCl-catalyzed electro-
philic thiocyano-oxy fuctionalization of olefins was reported by
Chen et al.10d Very recently, through the same mechanistic
concept, they have reported the semipinacol rearrangement of
allylic alcohols.10a Zhao et al. also revealed an elegant report on
selenide-catalyzed thiocyanoaminocyclization of olefins.10b
Notwithstanding these developments, thiocyanation of un-
saturated amides and thioamides remains elusive. Herein we
present a Lewis base/Brønsted acid-cocatalyzed thiocyanation
of unsaturated thioamides and amides.
C
applicable tool to attain molecular diversity.1 Amid
several modes of olefin functionalizations, the applications of
Lewis base catalysis are noteworthy.2 Denmark et al. elegantly
utilized Lewis base catalysis for enantioselective olefin
functionalizations.3 Similarly, Lewis base-catalyzed halofunc-
tionalization4 and trifluoromethylthiolation of olefins are also
reported.5 Despite these developments, Lewis base-catalyzed
thiocyanation reactions remain underexplored. We unveil here
a Lewis base/Brønsted acid-cocatalyzed thiocyanation of
unsaturated amides and thioamides (Scheme 1a). Thiocya-
At the outset, thioamide 1a was chosen as a model substrate
for the reaction conditions optimization (Table 1). Thio-
amides are an intrinsically challenging substrate for electro-
philic olefin functionalization. The substrate−electrophile
interaction poses major resistance to catalysis, and often
complex background reactions are observed. We also noticed
complete decomposition of the starting material in the absence
of any catalyst (entry 1). Contemplating that a Lewis base can
catalyze the reaction via activation of a thiocyanating reagent
(2), different Lewis bases were screened (entries 2−6). The
reaction was indeed catalyzed by dibenzyl selenium; however,
3a was obtained in only 28% yield (entry 2). Screening of
diphenyl selenide yielded 3a in 45% yield (entry 3). Shifting to
a stronger Lewis base, triphenylphosphine selenide improved
the reaction yield to 54% (entry 4). It is important to note that
triphenylphosphine selenide outperformed the corresponding
oxide and sulfide derivatives (entries 5 and 6). These results
validate the importance of Lewis base activation of a
thiocyanating reagent. Attempts to further improve the
reaction yield by modulating the thiocyanating reagent,
Scheme 1. Lewis Base-Catalyzed Olefin Functionalizations
and Thiocyanate in Natural Products
nates are important intermediates for the synthesis of a broad
array of sulfur-containing compounds.6 Natural products
containing a thiocyanate group are also known (Scheme 1b).
Their utility has prompted the development of several methods
for thiocyanation.7 The reaction of aromatic and hetero-
aromatic arenes with nucleophilic thiocyanates (MSCN, M =
8
+
K, NH4 , etc.) via a thiocyano radical is broadly studied.
Received: December 5, 2019
Visible-light-mediated thiocyanation of arenes, heteroarenes,
and the addition of N-thiocyanatosulfoximines to styrene is
also reported.9 More recently, an inclination toward the
development of electrophilic thiocyanating reagents has
https://dx.doi.org/10.1021/acs.joc.9b03275
© XXXX American Chemical Society
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Table 1. Reaction Conditions Optimization for
Thiocyanation of β,γ-Unsaturated Thioamide 1a
Table 2. Substrate Scope for the Thiocyanation of
Unsaturated Thioamides 1
a
a
b
entry
Lewis base
Brønsted acid
t (h)
yield (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
16
8
8
8
8
8
8
8
16
16
16
16
16
16
8
8
1
2
<10
28
45
54
37
42
32
58
64
60
38
30
12
9
Bn2Se
Ph2Se
Ph3PSe
Ph3PO
Ph3PS
CF3CO2H
CF3CO2H
CF3CO2H
CF3CO2H
CF3CO2H
CF3CO2H
CF3CO2H
CF3CO2H
CH3SO3H
CH3CO2H
(C6H5O)2P(O)OH
(C6H5O)2P(O)OH
Ph3PSe
Ph3PSe
Ph3PSe
Ph3PSe
Ph3PSe
Ph3PSe
Ph3PSe
Ph3PSe
Ph3PSe
Ph3PSe
Ph3PSe
d
e
f
g
h
14
15
16
17
18
47
60
73
c
92 (71)
a
Reaction conditions: 1a (0.1 mmol, 1.0 equiv), 2 (0.15 mmol, 1.5
equiv), Lewis base (0.01 mmol, 0.1 equiv), and Brønsted acid (0.01
b
c
d
mmol, 0.1 equiv). 1H NMR yield. Isolated yield. Solvent: CHCl3.
e
f
g
Solvent: CH3CN. Solvent: (CH3)2CO. Solvent: C6H5CH3.
h
Solvent: DMF.
concentration, and temperature were futile. Inspired by
Denmark’s work on cooperative Lewis base/Brønsted acid
catalysis for enantioselective bromoetherification,11 we inferred
that the addition of Brønsted acid cocatalyst might be helpful.
The catalytic combination of triphenylphosphine selenide and
trifluoroacetic acid (TFA) moderately improved the reaction
yield to 58% (entry 8). At this point, the effects of different
solvents (entries 9−14) such as chloroform, acetonitrile,
acetone, toluene, and N,N-dimethylformamide (DMF) were
examined; however, dichloromethane remained the solvent of
choice (entry 9). Screening of methanesulfonic acid and acetic
acid could not render significant enhancement in the reaction
yield (entries 15 and 16). The major influence of Lewis base/
Brønsted acid cocatalysis was realized with the combination of
triphenylphosphine selenide and diphenyl phosphate (entries
17 and 18). The reaction was adeptly catalyzed, and 3a was
obtained in a 92% 1H NMR yield (71% isolated yield) after 2 h
(entry 18).
a
Reaction conditions: 1 (0.1 mmol, 1.0 equiv), 2 (0.15 mmol, 1.5
equiv), Ph3PSe (0.01 mmol, 0.1 equiv), and (C6H5O)2P(O)OH (0.01
mmol, 0.1 equiv). Isolated yield. The reaction was carried out for 4
h.
b
c
also applied to the optimized reaction conditions. The reaction
proceeded through 5-exo-trig cyclization, furnishing 5 as a
major product in a good yield (Scheme 2). The structure and
relative configuration of 5 was confirmed through an X-ray
Scheme 2. Reaction with 1,2-Disubstituted Olefin
With the optimized reaction conditions in hand (Table 1,
entry 18), the generality of this thiocyanation reaction was
explored. As summarized in Table 2, a broad range of β,γ-
unsaturated thioamides underwent thiocyanation by Lewis
base/Brønsted acid cocatalysis (Table 2). Both electron-rich
and electron-deficient aryl substitutions were well tolerated.
With heteroaryl substituted unsaturated thioamides, the
reaction took longer than usual, after the reaction time of 4
h, the product 3h was obtained in 63% yield. It is noteworthy
that substrates bearing cyano and keto functional groups were
well tolerated (3f and 3g). Besides, aliphatic substitution on
olefin worked exceedingly well furnishing 3k and 3l in good
yields. Thioamide 4, comprising 1,2-disubstituted olefin, was
a
Reaction conditions: 4 (0.1 mmol, 1.0 equiv), 2 (0.15 mmol, 1.5
equiv), Ph3PSe (0.01 mmol, 0.1 equiv), and (C6H5O)2P(O)OH (0.01
mmol, 0.1 equiv). Isolated yield.
b
B
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structure analysis of 5a.12 The structure and relative
configuration of 5b and 5c were assigned in analogy to 5a.
After successfully exploring the substrate scope for
thiocyanation of unsaturated thioamides, we attempted the
thiocyanation of unsaturated amides. The optimization of
reaction conditions was carried out with 6a as a model
substrate (Table 3). The absence of any background reaction
Table 4. Substrate Scope for Thiocyanation of Unsaturated
Amides 6
a
Table 3. Reaction Conditions Optimization for the
a
Thiocyanation of β,γ-Unsaturated Amide 6a
b
entry
Lewis base
Brønsted acid
[+SCN]
yield (%)
1
2
3
2
2
7
7
<5
46
71
82
Ph3PSe
Ph3PSe
Ph3PSe
(C6H5O)2P(O)OH
(C6H5O)2P(O)OH
(C6H5O)2P(O)OH
c
4
a
Reaction conditions: 6a (0.1 mmol, 1.0 equiv), thiocyanating reagent
(0.15 mmol, 1.5 equiv), Lewis base (0.01 mmol, 0.1 equiv), and
b
c
Brønsted acid (0.01 mmol, 0.1 equiv). Isolated yield. Reaction was
carried over 1 h with 2.0 equiv of 7.
paved the way for catalyst screening (entry 1). Even after an
extended reaction time of 16 h, the conditions optimized for
thiocyanation of 1a (Table 1, entry 18) yielded 8a in only 46%
yield (Table 3, entry 2). However, tweaking the reaction
conditions via altering the thiocyanating reagent from 2 to 7
improved the yield to 71% (entry 3). Finally, by using 2.0
equiv of thiocyanating reagent 7, the product 8a was obtained
in 82% yield (entry 4). It is worth mentioning that the
instability of reagent 7 engendered a serious hurdle, which was
surmounted by the in situ generation of 7 from N-
chlorophthalimide and ammonium thiocyanate.
a
The optimum reaction conditions for thiocyanation of
unsaturated amides (Table 3, entry 4) were applied to different
substrates (Table 4). β,γ-Unsaturated amides (6) bearing
substituents of diverse steric and electronic nature underwent
cyclization to afford thiocyanated oxazoline derivatives 8a−8f
in good yields (Table 4A). Although the reactivity profile
relied upon the electronic nature of the substrates, with
electron-donating aryl and heteroaromatic substituents on the
amide end, the reaction proceeded slowly, but after 3 h, 8b and
8f were obtained in good yield. The electron-deficient
substituents on aryl rings such as chloro, cyano, and keto
were particularly suitable for this reaction, and thiocyanated
oxazoline derivatives 8c−8e were obtained in an excellent
yield. The viability of accessing thiocyanated benzo[d][1,3]-
oxazine derivatives was also probed (Table 4B). With
unsaturated benzamides 9a, 9b, and 9c, the reaction proceeded
smoothly to provide 10a, 10b, and 10c in 88, 91, and 84%
yields , respectively. The scalability of the protocol was tested
with β,γ-unsaturated amide 6d on a 1 mmol scale (Table 4C).
No detrimental effect of scale-up was observed, and 8d was
obtained in an 84% yield. Efforts to develop an asymmetric
variant of this thiocyanation reaction with chiral phosphoric
acids yielded racemic products.12
Reaction conditions: 6 (0.1 mmol, 1.0 equiv), 7 (0.2 mmol, 2.0
equiv), Ph3PSe (0.01 mmol, 0.1 equiv), and (C6H5O)2P(O)OH (0.01
b
c
mmol, 0.1 equiv). Isolated yield. Reaction was carried for 3 h.
Scheme 3. Synthetic Transformations of 3a and the
Influence of the Radical Quencher
of a radical pathway. To demonstrate synthetic utility, the
thiocyanated product 3a was subjected to Grignard addition,
which furnished corresponding thiosulfides (Scheme 3B). The
thiosulfides are an important class of compounds with several
applications in pharmaceutics and biology.13 Thiocyanated
thiazoline 3a reacted efficiently with phenyl and cyclohexyl
Grignard reagents to, respectively, furnish thiosulfides 11 and
12.
For further understanding, the reaction was carried out in
the presence of radical quencher butylated hydroxytoluene
(BHT) (Scheme 3A). Even though the reaction proceeded
with a diminished yield of 3a (56%), it disfavors the possibility
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Note
21.7. HRMS (ESI+): calcd for C18H17N2S2 ([M + H]+), 325.0833;
found, 325.0818.
In summary, a Lewis Base/Brønsted acid-cocatalyzed
thiocyanation of unsaturated amides and thioamides is
developed. A broad range of substrates reacted with electro-
philic thiocyanating reagents to provide thiocyanated thiazo-
line and oxazoline derivatives in high yields. Given the
synthetic and biological relevance of these scaffolds, this
method will find broad applications in multiple disciplines.
2-(4-Methoxyphenyl)-5-phenyl-5-(thiocyanatomethyl)-4,5-
dihydrothiazole (3c). Light yellow oil (25 mg, 0.073 mmol, 73%
yield). Compound 3c was purified over neutral alumina using 10:90
EtOAc/petroleum ether as an eluent. FT-IR (thin film): 2163 (w),
1606 (w), 1509 (w). 1H NMR (400 MHz, CDCl3): δ 7.84−7.75 (m,
2H), 7.46−7.33 (m, 5H), 6.98−6.90 (m, 2H), 4.87 (d, J = 15.9 Hz,
1H), 4.52 (d, J = 15.9 Hz, 1H), 3.86 (s, 3H), 3.69 (d, J = 13.2 Hz,
1H), 3.63 (d, J = 13.2 Hz, 1H). 13C{1H} NMR (100 MHz, CDCl3): δ
166.8, 162.6, 139.0, 130.1, 129.3, 128.7, 127.3, 125.6, 114.2, 111.8,
73.3, 69.3, 55.6, 47.0. HRMS (ESI+): calcd for C18H17N2OS2 ([M +
H]+), 341.0782; found, 341.0778.
EXPERIMENTAL SECTION
■
General Information. Infrared (FT-IR) spectra were recorded on
a Bruker-Alpha Spectrometer with νmax in cm−1. Bands are
characterized as broad (br), strong (s), medium (m), and weak
2-(2-Fluorophenyl)-5-phenyl-5-(thiocyanatomethyl)-4,5-di-
hydrothiazole (3d). Light yellow oil (30 mg, 0.092 mmol, 92%
yield). Compound 3d was purified over neutral alumina using 4:96
EtOAc/petroleum ether as an eluent. FT-IR (thin film): 2157 (w),
1
(w). H NMR spectra were recorded on a BRUKER-AV400 (400
MHz) spectrometer. Chemical shifts are reported in ppm from
tetramethylsilane with the solvent resonance as the internal standard
(CDCl3: δ 7.26). Data are reported as follows: chemical shift,
multiciplity (s = singlet, d = doublet, dd = doublet of doublet, t =
triplet, q = quartet, br = broad, m = multiplet), coupling constants
(Hz), and integration. 13C{1H} NMR spectra were recorded on a
BRUKER-AV400 (100 MHz) spectrometer with complete proton
decoupling. Chemical shifts are reported in ppm from tetramethylsi-
lane with the solvent resonance as the internal standard (CDCl3: δ
77.16). Mass spectra were measured with a Q-TOF micro-
spectrometer.
1
1596 (w). H NMR (400 MHz, CDCl3): δ 7.91 (td, J = 7.6, 1.8 Hz,
1H), 7.51−7.33 (m, 6H), 7.25−7.13 (m, 2H), 4.90 (dd, J = 16.6, 1.2
Hz, 1H), 4.52 (d, J = 16.6 Hz, 1H), 3.70 (d, J = 13.3 Hz, 1H), 3.63
(d, J = 13.3 Hz, 1H). 13C{1H} NMR (100 MHz, CDCl3): δ 162.5,
160.7 (d, J = 254 Hz), 138.9, 133.2 (d, J = 8.7 Hz), 130.4, 129.4,
128.8, 127.3, 124.6, 120.9 (d, J = 10.8 Hz), 116.7 (d, J = 22.2 Hz),
111.7, 72.3, 68.8, 46.9. 19F NMR (376 MHz, CDCl3): δ 110.6.
HRMS (ESI+): calcd for C17H14FN2S2 ([M + H]+), 329.0582; found,
329.0574.
Unless otherwise noted, all reactions have been carried out with
dried and distilled solvents under an atmosphere of argon. Oven-dried
(120 °C) glassware with standard vacuum line techniques were used.
All work up and purification were carried out with reagent grade
solvents in air. Thin-layer chromatography was performed using
Merck silica gel 60 F254 precoated plates (0.25 mm). Column
chromatography was performed using silica gel (230−400 mesh) and
neutral alumina. The heating reactions were carried out by using a
heating stirrer and an oil bath over it. The thiocyanated products are
unstable in nature. Thus, quick purification and storage at −20 °C are
recommended.
2-(2-Chlorophenyl)-5-phenyl-5-(thiocyanatomethyl)-4,5-di-
hydrothiazole (3e). Light yellow oil (26 mg, 0.075 mmol, 75%
yield). Compound 3e was purified over neutral alumina using 10:90
EtOAc/petroleum ether as an eluent. FT-IR (thin film): 3019 (w),
1
2157 (w). H NMR (400 MHz, CDCl3): δ 7.66 (dd, J = 7.7, 1.8 Hz,
1H), 7.52−7.29 (m, 8H), 4.92 (d, J = 16.0 Hz, 1H), 4.55 (d, J = 16.0
Hz, 1H), 3.75 (d, J = 13.2 Hz, 1H), 3.67 (d, J = 13.2 Hz, 1H).
13C{1H} NMR (100 MHz, CDCl3): δ 165.8, 138.7, 132.7, 132.4,
131.7, 130.74, 130.70, 129.4, 128.9, 127.3, 127.1, 111.7, 72.7, 70.3,
46.8. HRMS (ESI+): calcd for C17H14ClN2S2 ([M + H]+), 345.0287;
found, 345.0279.
General Procedure for Thiocyanation of Unsaturated
Thioamides. In an oven-dried 15 mL Schlenk tube, 2 (36.0 mg,
0.15 mmol, 1.5 equiv) was added. The reaction flask was degassed in
vacuo, and DCM (0.5 mL) was added. Subsequently, a solution of
triphenylphosphine selenide (3.4 mg, 0.01 mmol, 0.1 equiv) and
diphenyl phosphate (2.5 mg, 0.01 mmol, 0.1 equiv) in DCM (0.5
mL) was added. To the resulting mixture, a solution of 1 (0.1 mmol,
1.0 equiv) in DCM (0.5 mL) was added. The reaction mixture was
stirred at 25 °C for 2 h. The reaction was monitored by TLC and
diluted with H2O (5 mL). The aqueous layer was extracted with
CH2Cl2 (3 × 10 mL). The combined organic layers were dried over
anhydrous Na2SO4 and concentrated under reduced pressure. The
crude product was purified by column chromatography over neutral
alumina to afford 3.
1-(4-(5-Phenyl-5-(thiocyanatomethyl)-4,5-dihydrothiazol-2-
yl)phenyl)ethan-1-one (3f). Light yellow oil (19 mg, 0.054 mmol,
54% yield). Compound 3f was purified over neutral alumina using
10:90 EtOAc/petroleum ether as an eluent. FT-IR (thin film): 2163
(w), 1685 (m). 1H NMR (400 MHz, CDCl3): δ 8.04−7.98 (m, 2H),
7.96−7.90 (m, 2H), 7.48−7.33 (m, 5H), 4.95 (d, J = 16.4 Hz, 1H),
4.59 (d, J = 16.4 Hz, 1H), 3.70 (d, J = 13.3 Hz, 1H), 3.64 (d, J = 13.3
Hz, 1H), 2.64 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ 197.4,
166.7, 139.4, 138.8, 136.6, 129.4, 128.9, 128.7, 128.6, 127.2, 111.7,
73.7, 69.9, 47.0, 26.9. HRMS (ESI+): calcd for C19H17N2OS2 ([M +
H]+), 353.0782; found, 353.0772.
4-(5-Phenyl-5-(thiocyanatomethyl)-4,5-dihydrothiazol-2-
yl)benzonitrile (3g). Light yellow oil (29 mg, 0.086 mmol, 86%
yield). Compound 3g was purified over neutral alumina using 10:90
EtOAc/petroleum ether as an eluent. FT-IR (thin film): 2231 (w),
2156 (w), 1600 (w). 1H NMR (400 MHz, CDCl3): δ 7.99−7.92 (m,
2H), 7.78−7.71 (m, 2H), 7.48−7.32 (m, 5H), 4.96 (d, J = 16.5 Hz,
1H), 4.60 (d, J = 16.5 Hz, 1H), 3.68 (d, J = 13.4 Hz, 1H), 3.63 (d, J =
13.4 Hz, 1H). 13C{1H} NMR (100 MHz, CDCl3): δ 165.8, 138.5,
136.4, 132.5, 129.3, 128.9, 128.8, 127.0, 118.0, 115.2, 111.5, 73.6,
70.3, 46.8. HRMS (ESI+): calcd for C18H14N3S2 ([M + H]+),
336.0629; found, 336.0621.
2,5-Diphenyl-5-(thiocyanatomethyl)-4,5-dihydrothiazole
(3a). Light yellow oil (22 mg, 0.071 mmol, 71% yield). Compound 3a
was purified over neutral alumina using 4:96 EtOAc/petroleum ether
1
as an eluent. FT-IR (thin film): 3019 (br), 2400 (w), 2163 (w). H
NMR (400 MHz, CDCl3): δ 7.89−7.82 (m, 2H), 7.55−7.34 (m, 8H),
4.92 (d, J = 16.2 Hz, 1H), 4.55 (d, J = 16.2 Hz, 1H), 3.70 (d, J = 13.2
Hz, 1H), 3.64 (d, J = 13.2 Hz, 1H). 13C{1H} NMR (100 MHz,
CDCl3): δ 167.5, 138.9, 132.8, 131.9, 129.3, 128.8, 128.7, 128.4,
127.3, 111.7, 73.5, 69.4, 47.0. HRMS (ESI+): calcd for C17H15N2S2
([M + H]+), 311.0677; found, 311.0670.
5-Phenyl-5-(thiocyanatomethyl)-2-(p-tolyl)-4,5-dihydro-
thiazole (3b). Light yellow oil (29 mg, 0.089 mmol, 89% yield).
Compound 3b was purified over neutral alumina using 6:94 EtOAc/
petroleum ether as an eluent. FT-IR (thin film): 3019 (w), 2163 (w),
1541 (w). 1H NMR (400 MHz, CDCl3): δ 7.77−7.70 (m, 2H), 7.47−
7.32 (m, 5H), 7.27−7.21 (m, 2H), 4.88 (d, J = 16.3 Hz, 1H), 4.53 (d,
J = 16.3 Hz, 1H), 3.69 (d, J = 13.4 Hz, 1H), 3.63 (d, J = 13.4 Hz, 1H),
2.40 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ 167.4, 142.5,
139.0, 130.1, 129.5, 129.3, 128.7, 128.3, 127.3, 111.8, 73.4, 69.2, 47.0,
5-Phenyl-5-(thiocyanatomethyl)-2-(thiophen-3-yl)-4,5-dihy-
drothiazole (3h). White solid (20 mg, 0.063 mmol, 63% yield).
Compound 3h was purified over 230−400 silica gel mesh using 10:90
EtOAc/petroleum ether as an eluent. The reaction was carried over 4
h. The product obtained from column chromatography was
recrystallized twice in CH2Cl2/hexane mixture. FT-IR (thin film):
1
2157 (w), 1652 (w). H NMR (400 MHz, CDCl3): δ 7.81 (dd, J =
3.96, 1.8 Hz, 1H), 7.52 (dd, J = 6.3, 3.8 Hz, 1H), 7.45−7.34 (m, 6H),
4.85 (d, J = 16.0 Hz, 1H), 4.49 (d, J = 16.0 Hz, 1H), 3.69 (d, J = 13.3
Hz, 1H), 3.64 (d, J = 13.3 Hz, 1H). 13C{1H} NMR (100 MHz,
CDCl3): δ 161.8, 138.9, 135.6, 129.4, 129.2, 128.8, 127.3, 126.9,
D
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126.7, 111.7, 73.3, 69.8, 47.0. HRMS (ESI+): calcd for C15H13N2S3
([M + H]+), 317.0241; found, 317.0226.
75% yield, dr: >20:1). Compound 5c was purified over 230−400 silica
gel mesh using 10:90 EtOAc/petroleum ether as an eluent. FT-IR
1
5-(3-Chlorophenyl)-2-phenyl-5-(thiocyanatomethyl)-4,5-di-
hydrothiazole (3i). Light yellow oil (25 mg, 0.072 mmol, 72%
yield). Compound 3i was purified over 100−200 silica gel mesh using
6:94 EtOAc/petroleum ether as an eluent. FT-IR (thin film): 3019
(thin film): 2230 (m), 2153 (m), 1716 (m). H NMR (400 MHz,
CDCl3): δ 7.83−7.78 (m, 2H), 7.68−7.64 (m, 2H), 7.43−7.32 (m,
5H), 4.86 (dd, J = 16.4, 3.9 Hz, 1H), 4.82−4.76 (m, 1H), 4.65 (dd, J
= 16.4, 7.9 Hz, 1H), 4.29 (d, J = 10.3 Hz, 1H). 13C{1H} NMR (100
MHz, CDCl3): δ 165.4, 137.5, 136.4, 132.5, 129.7, 129.4, 128.9,
127.7, 118.1, 115.0, 110.1, 68.7, 56.5, 55.5. HRMS (ESI+): calcd for
C18H14N3S2 ([M + H]+), 336.0629; found, 336.0629.
1
(w), 2157 (w). H NMR (400 MHz, CDCl3): δ 7.87−7.81 (m, 2H),
7.55−7.41 (m, 3H), 7.41−7.34 (m, 3H), 7.27−7.24 (m, 1H), 4.88 (d,
J = 16.2 Hz, 1H), 4.54 (d, J = 16.2 Hz, 1H), 3.68 (d, J = 13.4 Hz, 1H),
3.63 (d, J = 13.4 Hz, 1H). 13C{1H} NMR (100 MHz, CDCl3): δ
167.3, 141.1, 135.4, 132.6, 132.1, 130.6, 129.0, 128.9, 128.4, 127.6,
125.5, 111.5, 73.7, 69.0, 46.7. HRMS (ESI+): calcd for C17H14ClN2S2
([M + H]+), 345.0287; found, 345.0284.
General Procedure for Thiocyanation of Unsaturated
Amides. In an oven-dried 15 mL Schlenk tube, N-chlorophthalimide
(36.0 mg, 0.2 mmol, 2.0 equiv) and ammonium thiocyanate (15.0 mg,
0.2 mmol, 2.0 equiv) were taken. The reaction flask was degassed in
vacuo, and DCM (1.0 mL) was added. The resulting mixture was
stirred at 25 °C for 0.5 h. Subsequently, a solution of
triphenylphosphine selenide (3.4 mg, 0.01 mmol, 0.1 equiv) and
diphenyl phosphate (2.5 mg, 0.01 mmol, 0.1 equiv) in DCM (0.5
mL) was added. To the resulting mixture, a solution of 6 (0.1 mmol,
1.0 equiv) in DCM (0.5 mL) was added. The reaction mixture was
stirred at 25 °C for 1 h. The reaction was monitored by TLC, and
H2O (5 mL) was added. The aqueous layer was extracted with
CH2Cl2 (3 × 10 mL). The combined organic layers were dried over
anhydrous Na2SO4 and concentrated under reduced pressure. The
crude product was purified by column chromatography over 100−200
silica gel mesh to afford 8.
2,5-Diphenyl-5-(thiocyanatomethyl)-4,5-dihydrooxazole
(8a). Yellow oil (24 mg, 0.082 mmol, 82% yield). Compound 8a was
purified over 230−400 silica gel mesh using 15:85 EtOAc/petroleum
ether as an eluent. FT-IR (thin film): 2158 (w), 1653 (m). 1H NMR
(400 MHz, CDCl3): δ 8.13−8.05 (m, 2H), 7.54−7.34 (m, 8H), 4.42
(d, J = 15.1 Hz, 1H), 4.31 (d, J = 15.1 Hz, 1H), 3.57 (s, 2H). 13C{1H}
NMR (100 MHz, CDCl3): δ 163.1, 141.2, 132.1, 129.2, 128.9, 128.8,
128.7, 128.6, 124.8, 111.9, 87.4, 66.9, 44.8. HRMS (ESI+): calcd for
C17H15N2OS ([M + H]+), 295.0905; found, 295.0893.
5-(4-Chlorophenyl)-2-phenyl-5-(thiocyanatomethyl)-4,5-di-
hydrothiazole (3j). Light yellow oil (29 mg, 0.084 mmol, 84%
yield). Compound 3j was purified over 100−200 silica gel mesh using
6:94 EtOAc/petroleum ether as an eluent. FT-IR (thin film): 2157
1
(w), 1492 (w). H NMR (400 MHz, CDCl3): δ 7.86−7.81 (m, 2H),
7.54−7.37 (m, 5H), 7.36−7.28 (m, 2H), 4.87 (d, J = 16.2 Hz, 1H),
4.52 (d, J = 16.2 Hz, 1H), 3.68 (d, J = 13.4 Hz, 1H), 3.63 (d, J = 13.4
Hz, 1H). 13C{1H} NMR (100 MHz, CDCl3): δ 167.4, 137.6, 134.9,
132.7, 132.1, 129.5, 128.8, 128.7, 128.4, 111.6, 73.8, 68.9, 46.7.
HRMS (ESI+): calcd for C17H14ClN2S2 ([M + H]+), 345.0287;
found, 345.0284.
5-Methyl-2-phenyl-5-(thiocyanatomethyl)-4,5-dihydrothia-
zole (3k). Colorless oil (24 mg, 0.097 mmol, 97% yield). Compound
3k was purified over neutral alumina using 6:94 EtOAc/petroleum
1
ether as an eluent. FT-IR (thin film): 2158 (w), 1604 (w). H NMR
(400 MHz, CDCl3): δ 7.82−7.73 (m, 2H), 7.52−7.36 (m, 3H), 4.45
(d, J = 16.3 Hz, 1H), 4.14 (d, J = 16.3 Hz, 1H), 3.42 (d, J = 13.4 Hz,
1H), 3.35 (d, J = 13.4 Hz, 1H), 1.78 (s, 3H). 13C{1H} NMR (100
MHz, CDCl3): δ 167.6, 133.0, 131.8, 128.8, 128.3, 112.6, 74.6, 62.6,
45.7, 24.8. HRMS (ESI+): calcd for C12H13N2S2 ([M + H]+),
249.0520; found, 249.0507.
4-(5-Methyl-5-(thiocyanatomethyl)-4,5-dihydrothiazol-2-
yl)benzonitrile (3l). Light yellow oil (22 mg, 0.08 mmol, 80% yield).
Compound 3l was purified over neutral alumina using 6:94 EtOAc/
petroleum ether as an eluent. FT-IR (thin film): 2216 (w), 2158 (w),
1604 (w). 1H NMR (400 MHz, CDCl3): δ 7.88−7.86 (m, 2H), 7.72−
7.70 (m, 2H), 4.50 (d, J = 16.7 Hz, 1H), 4.19 (d, J = 16.7 Hz, 1H),
3.40 (d, J = 13.6 Hz, 1H), 3.35 (d, J = 13.7 Hz, 1H), 1.78 (s, 3H).
13C{1H} NMR (100 MHz, CDCl3): δ 166.0, 136.7, 132.5, 128.9,
2-(4-Methoxyphenyl)-5-phenyl-5-(thiocyanatomethyl)-4,5-
dihydrooxazole (8b). Light yellow oil (28 mg, 0.086 mmol, 86%
yield). Compound 8b was purified over 100−200 silica gel mesh using
14:86 EtOAc/petroleum ether as an eluent. FT-IR (thin film): 2157
(w), 1651 (m), 1609 (m). 1H NMR (400 MHz, CDCl3): δ 8.05−7.98
(m, 2H), 7.48−7.32 (m, 5H), 7.01−6.93 (m, 2H), 4.38 (d, J = 14.8
Hz, 1H), 4.28 (d, J = 14.8 Hz, 1H), 3.87 (s, 3H), 3.56 (s, 2H).
13C{1H} NMR (100 MHz, CDCl3): δ 162.9, 162.7, 141.3, 130.4,
118.2, 115.1, 112.3, 74.8, 63.6, 45.5, 24.9. HRMS (ESI+): calcd for
129.2, 128.7, 124.8, 119.4, 114.1, 112.0, 87.1, 66.9, 55.5, 44.8. HRMS
(ESI+): calcd for C18H17N2O2S ([M + H]+), 325.1011; found,
325.1007.
C13H12N3S2 ([M + H]+), 274.0473; found, 274.0472.
(R*)-2-Phenyl-5-((S*)-phenyl(thiocyanato)methyl)-4,5-dihy-
drothiazole (5a). Light yellow oil (24 mg, 0.077 mmol, 77% yield,
dr: >20:1). Compound 5a was purified over 230−400 silica gel mesh
using 6:94 EtOAc/petroleum ether as an eluent. FT-IR (thin film):
2361 (w), 2157 (w). 1H NMR (400 MHz, CDCl3): δ 7.75−7.68 (m,
2H), 7.50−7.32 (m, 8H), 4.84 (dd, J = 16.1, 3.4 Hz, 1H), 4.75−4.67
(m, 1H), 4.61 (dd, J = 16.1, 8.0 Hz, 1H), 4.28 (d, J = 10.5 Hz, 1H).
13C{1H} NMR (100 MHz, CDCl3): δ 167.0, 137.9, 132.7, 131.7,
129.5, 129.3, 128.7, 128.4, 127.8, 110.3, 68.5, 56.7, 54.7. HRMS (ESI
+): calcd for C17H15N2S2 ([M + H]+), 311.0677; found, 311.0670.
Recrystallization from the CH2Cl2/hexane mixture yielded diffraction
quality crystals.
2-(4-Chlorophenyl)-5-phenyl-5-(thiocyanatomethyl)-4,5-di-
hydrooxazole (8c). Light yellow oil (30 mg, 0.091 mmol, 91%
yield). Compound 8c was purified over 100−200 silica gel mesh using
8:92 EtOAc/petroleum ether as an eluent. FT-IR (thin film): 2157
1
(w), 1655 (w). H NMR (400 MHz, CDCl3): δ 8.04−8.00 (m, 2H),
7.88−7.85 (m, 1H), 7.77−7.73 (m, 1H), 7.46−7.41 (m, 4H), 7.39−
7.27 (m, 2H), 4.42 (d, J = 15.2 Hz, 1H), 4.32 (d, J = 15.2 Hz, 1H),
3.55 (s, 2H). 13C{1H} NMR (100 MHz, CDCl3): δ 168.2, 162.2,
141.0, 138.4, 134.4, 132.8, 129.9, 129.2, 129.0, 128.9, 125.4, 124.8,
124.6, 123.7, 111.9, 87.7, 66.8, 44.8. HRMS (ESI+): calcd for
C17H14ClN2OS ([M + H]+), 329.0515; found, 329.0508.
(R*)-2-(4-Methoxyphenyl)-5-((S*)-phenyl(thiocyanato)-
methyl)-4,5-dihydrothiazole (5b). Light yellow oil (28 mg, 0.082
mmol, 82% yield, dr: >20:1). Compound 5b was purified over 230−
400 silica gel mesh using 10:90 EtOAc/petroleum ether as an eluent.
4-(5-Phenyl-5-(thiocyanatomethyl)-4,5-dihydrooxazol-2-
yl)benzonitrile (8d). Light yellow oil (27 mg, 0.085 mmol, 85%
yield). Compound 8d was purified over 100−200 silica gel mesh using
12:88 EtOAc/petroleum ether as an eluent. FT-IR (thin film): 2231
(w), 2157 (w), 1656 (w). 1H NMR (400 MHz, CDCl3): δ 8.22−8.17
(m, 2H), 7.80−7.73 (m, 2H), 7.48−7.35 (m, 5H), 4.46 (d, J = 15.8
Hz, 1H), 4.36 (d, J = 15.8 Hz, 1H), 3.57 (d, J = 14.1 Hz, 1H), 3.52
(d, J = 14.1 Hz, 1H). 13C{1H} NMR (100 MHz, CDCl3): δ 161.7,
140.8, 132.5, 130.9, 129.3, 129.2, 129.0, 124.7, 118.2, 115.5, 111.8,
88.3, 66.9, 44.7. HRMS (ESI+): calcd for C18H14N3OS ([M + H]+,
320.0858; found, 320.0853. On a 1 mmol scale, 8d was obtained in
84% yield (270 mg, 0.84 mmol)
1
FT-IR (thin film): 2157 (w), 1606 (m), 1509 (w). H NMR (400
MHz, CDCl3): δ 7.70−7.61 (m, 2H), 7.44−7.33 (m, 5H), 6.90−6.84
(m, 2H), 4.83 (dd, J = 15.8, 3.6 Hz, 1H), 4.72−4.65 (m, 1H), 4.57
(dd, J = 16.1, 7.9 Hz, 1H), 4.28 (d, J = 10.5 Hz, 1H), 3.83 (s, 3H).
13C{1H} NMR (100 MHz, CDCl3): δ 166.5, 162.4, 138.0, 130.1,
129.5, 129.3, 127.8, 125.4, 114.0, 110.3, 68.3, 56.6, 55.5, 54.7. HRMS
(ESI+): calcd for C18H17N2OS2 ([M + H]+), 341.0782; found,
341.0780.
4-((R*)-5-((S*)-Phenyl(thiocyanato)methyl)-4,5-dihydrothia-
zol-2-yl)benzonitrile (5c). Light yellow oil (25 mg, 0.075 mmol,
1-(4-(5-Phenyl-5-(thiocyanatomethyl)-4,5-dihydrooxazol-2-
yl)phenyl)ethan-1-one (8e). Light yellow oil (31 mg, 0.092 mmol,
E
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Note
92% yield). Compound 8e was purified over 100−200 silica gel mesh
using 12:88 EtOAc/petroleum ether as an eluent. FT-IR (thin film):
2157 (w), 1686 (w), 1654 (w). H NMR (400 MHz, CDCl3): δ
petroleum ether as an eluent to yield 8d (270 mg, 0.84 mmol, 84%
yield).
1
General Procedure for Grignard Addition to 3a. In an oven-
dried 15 mL Schlenk tube, 3a (1.0 equiv) was taken. The reaction
flask was degassed in vacuo, and THF (2.0 mL) was added.
Subsequently, the corresponding Grignard reagent (2.0 equiv) was
added. The reaction mixture was stirred at 25 °C for 16 h. The
reaction was monitored by TLC, and NH4Cl (5 mL) was added. The
aqueous layer was extracted with ethyl acetate (3 × 10 mL). The
combined organic layers were dried over anhydrous Na2SO4 and
concentrated under reduced pressure. The crude product was purified
by column chromatography over 230−400 silica gel mesh to afford
corresponding thiosulfides.
2,5-Diphenyl-5-((phenylthio)methyl)-4,5-dihydrothiazole
(11). The reaction was done with 0.07 mmol of 3a. Colorless oil (24
mg, 0.066 mmol, 95% yield). Compound 12 was purified over 230−
400 silica gel mesh using 2:98 EtOAc/petroleum ether as an eluent.
FT-IR (thin film): 3019 (m), 2407 (w). 1H NMR (400 MHz,
CDCl3): δ 7.87−7.80 (m, 2H), 7.52−7.09 (m, 13H), 4.93 (d, J = 16.0
Hz, 1H), 4.56 (d, J = 16.0 Hz, 1H), 3.73 (d, J = 13.0 Hz, 1H), 3.67
(d, J = 13.0 Hz, 1H). 13C{1H} NMR (100 MHz, CDCl3): δ 168.0,
141.4, 136.7, 133.4, 131.5, 130.3, 128.9, 128.7, 128.3, 127.8, 127.3,
126.6, 73.8, 69.9, 47.8. HRMS (ESI+): calcd for C22H20NS2 ([M +
H]+), 362.1037; found, 362.1026.
5-((Cyclohexylthio)methyl)-2,5-diphenyl-4,5-dihydrothia-
zole (12). The reaction was done with 0.1 mmol of 3a. White solid
(16 mg, 0.041 mmol, 41% yield). Compound 12 was purified over
230−400 silica gel mesh using 1:99 EtOAc/petroleum ether as an
eluent. FT-IR (thin film): 3019 (m), 2361 (w). 1H NMR (400 MHz,
CDCl3): δ 7.88−7.82 (m, 2H), 7.51−7.27 (m, 8H), 4.95 (d, J = 15.8
Hz, 1H), 4.51 (d, J = 15.8 Hz, 1H), 3.29 (d, J = 13.1 Hz, 1H), 3.20
(d, J = 13.1 Hz, 1H), 2.19−2.09 (m, 1H), 1.86−1.58 (m, 6H), 1.19−
1.06 (m, 4H). 13C{1H} NMR (100 MHz, CDCl3): δ 168.2, 142.0,
133.4, 131.4, 128.6, 128.5, 128.2, 127.6, 127.3, 73.4, 70.1, 45.3, 43.0,
33.7, 33.6, 26.2, 26.1, 25.7. HRMS (ESI+): calcd for C22H26NS2 ([M
+ H]+), 368.1507; found, 368.1500.
8.22−8.15 (m, 2H), 8.08−7.99 (m, 2H), 7.50−7.32 (m, 5H), 4.46 (d,
J = 15.4 Hz, 1H), 4.36 (d, J = 15.4 Hz, 1H), 3.59 (d, J = 14.1 Hz, 1H),
3.55 (d, J = 14.1 Hz, 1H), 2.65 (s, 3H). 13C{1H} NMR (100 MHz,
CDCl3): δ 197.6, 162.3, 140.9, 139.6, 130.9, 130.4, 129.3, 128.9,
128.6, 128.3, 124.7, 111.9, 84.9, 66.9, 44.7, 26.9. HRMS (ESI+): calcd
for C19H17N2O2S ([M + H]+), 337.1011; found, 337.1010.
5-Phenyl-5-(thiocyanatomethyl)-2-(thiophen-3-yl)-4,5-dihy-
drooxazole (8f). Light yellow oil (23 mg, 0.077 mmol, 77% yield).
Compound 8f was purified over 100−200 silica gel mesh using 12:88
EtOAc/petroleum ether as an eluent. FT-IR (thin film): 2163 (w),
1657 (m). 1H NMR (400 MHz, CDCl3): δ 8.10 (dd, J = 2.8, 1.1 Hz,
1H), 7.59 (dd, J = 5.1, 1.1 Hz, 1H), 7.47−7.33 (m, 6H), 4.37 (d, J =
15.0 Hz, 1H), 4.28 (d, J = 15.0 Hz, 1H), 3.57 (d, J = 13.9 Hz, 1H),
3.52 (d, J = 13.9 Hz, 1H). 13C{1H} NMR (100 MHz, CDCl3): δ
159.9, 141.1, 130.0, 129.2, 129.1, 128.8, 127.3, 126.7, 124.8, 112.0,
87.3, 66.9, 44.7. HRMS (ESI+): calcd for C15H13N2OS2 ([M + H]+),
301.0469; found, 301.0465.
4-Methyl-2-phenyl-4-(thiocyanatomethyl)-4H-benzo[d]-
[1,3]oxazine (10a). Light yellow oil (26 mg, 0.088 mmol, 88%
yield). Compound 10a was purified over 100−200 silica gel mesh
using 3:97 EtOAc/petroleum ether as an eluent. FT-IR (thin film):
2163 (w), 1626 (w). 1H NMR (400 MHz, CDCl3): δ 8.19−8.13 (m,
2H), 7.55−7.33 (m, 5H), 7.28−7.23 (m, 1H), 7.14 (dd, J = 7.5, 1.1
Hz, 1H), 3.59 (d, J = 13.9 Hz, 1H), 3.45 (d, J = 13.9 Hz, 1H), 1.92 (s,
3H). 13C{1H} NMR (100 MHz, CDCl3): δ 155.5, 138.8, 132.0, 131.9,
130.1, 128.5, 128.1, 127.4, 126.5, 126.1, 123.0, 112.3, 79.0, 44.6, 25.9.
HRMS (ESI+): calcd for C17H15N2OS ([M + H]+), 295.0905; found,
295.0897.
2-(4-Chlorophenyl)-4-methyl-4-(thiocyanatomethyl)-4H-
benzo[d][1,3]oxazine (10b). Light yellow oil (30 mg, 0.091 mmol,
91% yield). Compound 10b was purified over 230−400 silica gel
mesh using 4:96 EtOAc/petroleum ether as an eluent. FT-IR (thin
1
film): 3019 (w), 2407 (w). H NMR (400 MHz, CDCl3): δ 8.14−
8.06 (m, 2H), 7.46−7.25 (m, 5H), 7.13 (dd, J = 7.7, 1.2 Hz, 1H), 3.58
(d, J = 13.9 Hz, 1H), 3.44 (d, J = 13.9 Hz, 1H), 1.91 (s, 3H). 13C{1H}
NMR (100 MHz, CDCl3): δ 154.3, 138.6, 138.2, 130.5, 130.2, 129.4,
128.8, 127.6, 126.4, 126.2, 123.0, 112.2, 79.3, 44.6, 26.0. HRMS (ESI
+): calcd for C17H14ClN2OS ([M + H]+), 329.0515; found, 329.0506.
2-(4-Fluorophenyl)-4-methyl-4-(thiocyanatomethyl)-4H-
benzo[d][1,3]oxazine (10c). Light yellow oil (25 mg, 0.080 mmol,
80% yield). Compound 10c was purified over 230−400 silica gel
mesh using 1.5:98.5 EtOAc/petroleum ether as an eluent. FT-IR (thin
film): 2163 (w), 1508 (w), 1214 (s). 1H NMR (400 MHz, CDCl3): δ
8.20−8.15 (m, 2H), 7.44−7.31 (m, 2H), 7.28−7.24 (m, 1H), 7.17−
7.09 (m, 3H), 3.58 (d, J = 13.9 Hz, 1H), 3.44 (d, J = 13.9 Hz, 1H),
1.91 (s, 3H).13C{1H} NMR (100 MHz, CDCl3): δ 165.3 (d, J = 251.2
Hz), 154.6, 138.7, 130.4 (d, J = 8.9 Hz), 130.1, 128.2 (d, J = 3.1 Hz)
127.4, 126.3, 126.0, 123.0, 115.7, 115.5, 112.2, 79.2, 44.6, 26.0. 19F
NMR (376 MHz, CDCl3): δ −107.6. HRMS (ESI+): calcd for
C17H14FN2OS ([M + H]+), 313.0811; found, 313.0806.
General Procedure for Thiocyanation of Unsaturated
Amide 6d at 1 mmol Scale. In an oven-dried 50 mL round-
bottom flask, N-chlorophthalimide(363.0 mg, 2.0 mmol, 2.0 equiv)
and ammonium thiocyanate (150.0 mg, 2.0 mmol, 2.0 equiv) were
taken. The reaction flask was degassed in vacuo, and DCM (8.0 mL)
was added. The resulting mixture was stirred at 25 °C for 0.5 h.
Subsequently, a solution of triphenylphosphine selenide (34.0 mg, 0.1
mmol, 0.1 equiv) and diphenyl phosphate (25.0 mg, 0.1 mmol, 0.1
equiv) in DCM (2.0 mL) was added. To the resulting mixture, a
solution of 6d (1.0 mmol, 1.0 equiv) in DCM (5.0 mL) was added.
The reaction mixture was stirred at 25 °C for 1 h. The reaction was
monitored by TLC, and H2O (15 mL) was added. The aqueous layer
was extracted with CH2Cl2 (2 × 30 mL). The combined organic
layers were dried over anhydrous Na2SO4 and concentrated under
reduced pressure. The crude product was purified by column
chromatography over 100−200 silica gel mesh using 8:92 EtOAc/
Thiocyanation of 6a with Chiral Phosphoric Acid Deriva-
tives. General Procedure. In an oven-dried 15 mL Schlenk tube, N-
chlorophthalimide (27.0 mg, 0.15 mmol, 1.5 equiv) and ammonium
thiocyanate (11.4 mg, 0.15 mmol, 1.5 equiv) were taken. The reaction
flask was degassed in vacuo, and DCM (1.0 mL) was added. The
resulting mixture was stirred at 25 °C for 0.5 h. The resultant mixture
was cooled to −78 °C. Subsequently, a solution of chiral phosphoric
acid (8.6 mg, 0.01 mmol, 0.1 equiv) in DCM (0.2 mL) was added. To
the resulting mixture, a solution of 6a (23.7 mg, 0.1 mmol, 1.0 equiv)
in DCM (0.8 mL) was added. The reaction mixture was stirred at
−78 °C for 48 h. The reaction was monitored by TLC, and H2O (5
mL) was added. The aqueous layer was extracted with CH2Cl2 (3 ×
10 mL). The combined organic layers were dried over anhydrous
Na2SO4 and concentrated under reduced pressure. The conversion
and er of product 8a were determined. The enantiomeric ratio was
determined by HPLC analysis using a Daicel Chiralpak AD-H column
(IPA/n-hexane 10:90, 1.0 mL/min, 20 °C, 254 nm, τ = 14.9 and 15.1
min).12
Synthesis of Unsaturated Amides and Thioamides. Unsatu-
rated Amides. The unsaturated amides 6 and 9 were prepared by
following the reported procedure, and the spectral data are in
accordance with the literature.14 The spectral data for previously
unreported unsaturated amides 6e and 6f are given below.
1-(4-Acetylphenyl)-2-((1-phenylvinyl)amino)ethan-1-one (6e).
White solid (472 mg, 1.69 mmol, 45% yield). Compound 6e was
purified over 100−200 silica gel mesh using 4:96 EtOAc/petroleum
ether as an eluent. FT-IR (thin film): 2919 (w), 1683 (s), 1664 (s).
1H NMR (400 MHz, CDCl3): δ 7.93 (d, J = 8.4 Hz, 2H), 7.78 (d, J =
8.4 Hz, 2H), 7.47−7.45 (m, 2H), 7.36−7.29 (m, 3H), 6.46 (br s, 1H),
5.52 (s, 1H), 5.31 (s, 1H), 4.53 (d, J = 5.4 Hz, 2H). 13C{1H} NMR
(100 MHz, CDCl3): δ 197.5, 166.6, 144.1, 139.3, 138.4, 138.3, 128.7,
128.6, 128.3, 127.4, 126.2, 114.3, 44.0, 26.9. HRMS (ESI+): calcd for
C18H18NO2 ([M + H]+), 280.1338; found, 280.1328.
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Note
2-((1-Phenylvinyl)amino)-1-(thiophen-3-yl)ethan-1-one (6f).
White solid (600 mg, 2.47 mmol, 65% yield). Compound 6f was
purified over 230−400 silica gel mesh using 7:93 EtOAc/petroleum
ether as an eluent. FT-IR (thin film): 1629 (s). 1H NMR (400 MHz,
CDCl3): δ 7.81−7.80 (m, 1H), 7.48−7.45 (m, 2H), 7.37−7.28 (m,
5H), 6.07 (br s, 1H), 5.51 (s, 1H), 5.31 (s, 1H), 4.5 (d, J = 5.68 Hz,
2H). 13C{1H} NMR (100 MHz, CDCl3): δ 163.0, 144.3, 138.4, 137.5,
128.8, 128.3, 128.2, 126.7, 126.2, 126.1, 114.2, 43.6. HRMS (ESI+):
calcd for C14H14NOS ([M + H]+), 244.0796; found, 244.0788.
Unsaturated Thioamides. In an oven-dried flask, 4 (1.0 equiv),
THF (2.0 mL/mmol), and Lawesson reagent (1.5 equiv) were taken.
The mixture was heated at 60 °C for 4 h. The reaction was
concentrated in vacuo, and the oil was purified by column
chromatography on neutral alumina to obtain unsaturated thioamides.
N-(2-Phenylallyl)benzothioamide (1a). Yellow oil (120 mg, 0.45
mmol, 45% yield). Compound 1a was purified over neutral alumina
using 2:98 EtOAc/petroleum ether as an eluent. FT-IR (thin film):
3020 (w), 1511 (w). 1H NMR (400 MHz, CDCl3): δ 7.64−7.59 (m,
2H), 7.51−7.47 (m, 2H), 7.45−7.31 (m, 6H), 5.63 (s, 1H), 5.40 (s,
1H), 4.90 (dd, J = 5.1, 0.7 Hz, 2H). 13C{1H} NMR (100 MHz,
CDCl3): δ 199.4, 142.7, 141.9, 137.7, 131.2, 129.2, 128.9, 128.6,
126.7, 126.2, 116.0, 50.9. HRMS (ESI+): calcd for C16H16NS ([M +
H]+), 254.1003; found, 254.0996.
126.1, 116.1, 50.8, 26.8. HRMS (ESI+): calcd for C18H18NOS ([M +
H]+), 296.1109; found, 296.1103.
4-Cyano-N-(2-phenylallyl)benzothioamide (1g). Yellow oil (60
mg, 0.21 mmol, 43% yield). Compound 1g was purified over neutral
alumina using 10:90 EtOAc/petroleum ether as an eluent. FT-IR
1
(thin film): 3019 (w), 2232 (w). H NMR (400 MHz, CDCl3): δ
7.68−7.63 (m, 3H), 7.60−7.56 (m, 2H), 7.49−7.44 (m, 2H), 7.39−
7.35 (m, 2H), 5.63 (s, 1H), 5.39 (s, 1H), 4.87 (dd, J = 5.3, 0.7 Hz,
2H). 13C{1H} NMR (100 MHz, CDCl3): δ 197.0, 145.3, 142.2, 137.5,
132.4, 128.9, 128.7, 127.4, 126.1, 118.1, 116.3, 114.4, 50.9. HRMS
(ESI+): calcd for C17H15N2S ([M + H]+), 279.0956; found, 279.0951.
N-(2-Phenylallyl)thiophene-3-carbothioamide (1h). Yellow oil
(49 mg, 0.19 mmol, 23% yield). Compound 1h was purified over
neutral alumina using 2:98 EtOAc/petroleum ether as an eluent. FT-
IR (thin film): 3019 (w), 1670 (w). 1H NMR (400 MHz, CDCl3): δ
7.69 (dd, J = 3.0, 1.3 Hz, 1H), 7.52 (br s, 1H), 7.49−7.43 (m, 1H),
7.39−7.30 (m, 4H), 7.25−7.19 (m, 1H), 5.59 (s, 1H), 5.34 (s, 1H),
4.85 (dd, J = 5.1, 0.6 Hz, 2H). 13C{1H} NMR (100 MHz, CDCl3): δ
191.7, 143.5, 142.5, 137.7, 128.8, 128.5, 126.6, 126.4, 126.3, 126.1,
115.6, 50.1. HRMS (ESI+): calcd for C14H14NS2 ([M + H]+),
260.0568; found, 260.0557.
N-(2-(3-Chlorophenyl)allyl)benzothioamide (1i). Yellow oil (75
mg, 0.26 mmol, 32% yield). Compound 1i was purified over neutral
alumina using 2:98 EtOAc/petroleum ether as an eluent. FT-IR (thin
4-Methyl-N-(2-phenylallyl)benzothioamide (1b). Yellow oil (105
mg, 0.34 mmol, 39% yield). Compound 1b was purified over neutral
alumina using 4:96 EtOAc/petroleum ether as an eluent. FT-IR (thin
1
film): 3019 (w), 1507 (w). H NMR (400 MHz, CDCl3): δ 7.68−
7.61 (m, 2H), 7.55 (br s, 1H), 7.50−7.28 (m, 7H), 5.61 (s, 1H), 5.42,
(s, 1H), 4.87 (d, J = 5.1 Hz, 2H). 13C{1H} NMR (100 MHz, CDCl3):
δ 199.7, 141.8, 141.7, 139.8, 134.9, 131.3, 130.1, 128.7, 128.6, 126.7,
126.4, 124.3, 116.8, 50.4. HRMS (ESI+): calcd for C16H15ClNS ([M
+ H]+), 288.0614; found, 288.0605.
1
film): 3021 (w), 1497 (w). H NMR (400 MHz, CDCl3): δ 7.56−
7.47 (m, 4H), 7.41−7.30 (m, 3H), 7.13 (d, J = 8.1 Hz, 2H), 5.62 (s,
1H), 5.39 (s, 1H), 4.89 (d, J = 5.1 Hz, 2H), 2.34 (s, 3H). 13C{1H}
NMR (100 MHz, CDCl3): δ 199.1, 142.7, 141.8, 139.0, 137.8, 129.2,
128.9, 128.6, 126.7, 126.2, 115.8, 50.8, 21.4. HRMS (ESI+): calcd for
C17H18NS ([M + H]+), 268.1160; found, 268.1153.
N-2-(4-Chlorophenyl)allyl)benzothioamide (1j). Yellow oil (40
mg, 0.14 mmol, 16% yield). Compound 1j was purified over neutral
alumina using 2:98 EtOAc/petroleum ether as an eluent. FT-IR (thin
4-Methoxy-N-(2-phenylallyl)benzothioamide (1c). Yellow oil (66
mg, 0.23 mmol, 25% yield). Compound 1c was purified over neutral
alumina using 3:97 EtOAc/petroleum ether as an eluent. FT-IR (thin
1
film): 3018 (w), 1493 (m). H NMR (400 MHz, CDCl3): δ 7.64−
7.59 (m, 2H), 7.59 (br s, 1H), 7.44−7.38 (m, 3H), 7.35−7.29 (m,
4H), 5.59 (s, 1H), 5.38 (s, 1H), 4.86 (d, J = 5.0 Hz, 2H). 13C{1H}
NMR (100 MHz, CDCl3): δ 199.5, 141.7, 136.2, 134.5, 131.3, 129.0,
128.8, 128.6, 127.5, 126.7, 116.2, 50.5. HRMS (ESI+): calcd for
C16H15ClNS ([M + H]+), 288.0614; found, 288.0607.
1
film): 1623 (m), 1489 (m). H NMR (400 MHz, CDCl3): δ 7.66−
7.60 (m, 2H), 7.51−7.46 (m, 2H), 7.41−7.30 (m, 3H), 6.85−6.79
(m, 2H), 5.62 (s, 1H), 5.39 (s, 1H), 4.89 (dd, J = 5.1, 0.7 Hz, 2H),
3.81 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ 198.2, 162.3,
142.8, 137.8, 134.1, 128.9, 128.6, 126.2, 115.8, 113.8, 55.6, 50.8.
HRMS (ESI+): calcd for C17H18NOS ([M + H]+), 284.1109; found,
284.1101.
N-(2-Methylallyl)benzothioamide (1k). Yellow oil (35 mg, 0.18
mmol, 15% yield). Compound 1k was purified over neutral alumina
using 2:98 EtOAc/petroleum ether as an eluent. 1H NMR (400 MHz,
CDCl3): δ 7.78−7.70 (m, 3H), 7.51−7.41 (m, 1H), 7.40−7.33 (m,
2H), 4.96 (s, 1H), 4.93 (s, 1H), 4.40 (d, J = 5.8 Hz, 2H), 1.83 (s,
3H). 13C{1H} NMR (100 MHz, CDCl3): δ 199.7, 141.9, 140.1, 131.2,
128.6, 126.7, 112.6, 52.0, 20.9. HRMS (ESI+): calcd for C11H14NS
([M + H]+), 192.0847; found, 192.0839.
4-Cyano-N-(2-methylallyl)benzothioamide (1l). Yellow oil (35
mg, 0.18 mmol, 15% yield). Compound 1l was purified over neutral
alumina using 4:96 EtOAc/petroleum ether as an eluent. FT-IR (thin
film): 3020 (w), 2233 (w), 1519(w). 1H NMR (400 MHz, CDCl3): δ
7.84−7.73 (m, 3H), 7.66 (d, J = 7.8 Hz, 2H), 4.99 (s, 1H), 4.95 (s,
1H), 4.40 (d, J = 4.4 Hz, 2H), 1.84 (s, 3H). 13C{1H} NMR (100
MHz, CDCl3): δ 197.4, 145.4, 139.7, 132.3, 127.3, 118.0, 114.3,
113.0, 52.1, 20.8. HRMS (ESI+): calcd for C12H13N2S ([M + H]+),
217.0799; found, 217.0788.
2-Fluoro-N-(2-phenylallyl)benzothioamide (1d). Yellow oil (125
mg, 0.46 mmol, 59% yield). Compound 1d was purified over neutral
alumina using 2:98 EtOAc/petroleum ether as an eluent. FT-IR (thin
film): 3049 (m), 1541 (m). 1H NMR (400 MHz, CDCl3): δ 8.10 (td,
J = 16.0, 1.8 Hz, 1H), 7.94 (br s, 1H), 7.51−7.45 (m, 2H), 7.41−7.30
(m, 4H), 7.21−7.15 (m, 1H), 7.01 (m, 1H), 5.61 (s, 1H), 5.41 (s,
1H), 4.92 (d, J = 5.1 Hz, 2H). 13C{1H} NMR (100 MHz, CDCl3): δ
193.6, 157.8 (d, J = 246.8 Hz), 142.4, 137.9, 133.5, 132.5 (d, J = 9.0
Hz), 128.8, 128.5, 126.2, 124.7, 116.0 (d, J = 23.6 Hz), 115.7, 51.0.
HRMS (ESI+): calcd for C16H15FNS ([M + H]+), 272.0909; found,
272.0902.
2-Chloro-N-(2-phenylallyl)benzothioamide (1e). Yellow oil (35
mg, 0.12 mmol, 33% yield). Compound 1e was purified over neutral
alumina using 1.5:98.5 EtOAc/petroleum ether as an eluent. FT-IR
1
(thin film): 3019 (m), 1516 (m). H NMR (400 MHz, CDCl3): δ
N-Cinnamylbenzothioamide (4a). Yellow oil (150 mg, 0.59
mmol, 56% yield). Compound 4a was purified over neutral alumina
using 4:96 EtOAc/petroleum ether as an eluent. FT-IR (thin film):
7.43−7.38 (m, 3H), 7.33−7.12 (m, 7H), 5.54 (s, 1H), 5.35 (s, 1H),
4.80 (dd, J = 5.2, 0.7 Hz, 2H). 13C{1H} NMR (100 MHz, CDCl3): δ
197.4, 142.3, 141.9, 137.7, 130.5, 130.1, 130.0, 128.8, 128.6, 127.0,
126.3, 116.3, 50.6. HRMS (ESI+): calcd for C16H15ClNS ([M + H]+),
288.0614; found, 288.0601.
4-Acetyl-N-(2-phenylallyl)benzothioamide (1f). Yellow oil (60
mg, 0.20 mmol, 30% yield). Compound 1f was purified over neutral
alumina using 2:98 EtOAc/petroleum ether as an eluent. FT-IR (thin
film): 3019 (w), 1684 (w). 1H NMR (400 MHz, CDCl3): δ 7.84 (d, J
= 8.4 Hz, 2H), 7.69 (br s, 1H), 7.64 (d, J = 8.4 Hz, 2H), 7.50−7.44
(m, 2H), 7.41−7.30 (m, 3H), 5.62 (s, 1H), 5.39 (s, 1H), 4.89 (d, J =
4.8 Hz, 2H), 2.54 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ
198.0, 197.4, 145.4, 142.4, 138.6, 137.6, 128.9, 128.7, 128.5, 126.9,
1
3273 (s), 1651 (m). H NMR (400 MHz, CDCl3): δ 7.81−7.74 (m,
2H), 7.68 (br s, 1H), 7.49−7.44 (m, 1H), 7.42−7.26 (m, 7H), 6.70
(d, J = 15.7 Hz, 1H), 6.37 (dt, J = 15.7, 6.4 Hz, 1H), 4.63 (t, J = 6.4
Hz, 2H). 13C{1H} NMR (100 MHz, CDCl3): δ 199.3, 141.8, 136.2,
134.7, 131.3, 128.8, 128.7, 128.3, 126.8, 126.6, 123.0, 48.98. HRMS
(ESI+): calcd for C16H16NS ([M + H]+), 254.1003; found, 254.0994.
N-Cinnamyl-4-methoxybenzothioamide (4b). Yellow oil (78 mg,
0.275 mmol, 28% yield). Compound 4b was purified over neutral
alumina using 2:98 EtOAc/petroleum ether as an eluent. FT-IR (thin
film): 3021 (w), 1605 (w). 1H NMR (400 MHz, CDCl3): δ 7.67 (d, J
= 8.3 Hz, 2H), 7.29−7.13 (m, 5H), 6.73 (d, J = 8.2 Hz, 2H), 6.52 (d,
G
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J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
pubs.acs.org/joc
Note
J = 15.7 Hz, 1H), 6.26−6.17 (m, 1H), 4.46 (m, 3H), 3.69 (s, 3H).
13C{1H} NMR (100 MHz, CDCl3): δ 197.8, 162.2, 136.3, 134.1,
133.8, 128.7, 128.0, 126.5, 123.2, 113.6, 55.5, 48.8. HRMS (ESI+):
calcd for C17H18NOS ([M + H]+), 284.1109; found, 284.1095.
N-Cinnamyl-4-cyanobenzothioamide (4c). Yellow oil (88 mg,
0.32 mmol, 32% yield). Compound 4c was purified over neutral
alumina using 5:95 EtOAc/petroleum ether as an eluent. FT-IR (thin
film): 2232 (w), 1652 (m). 1H NMR (400 MHz, CDCl3): δ 8.03 (br
s, 1H) 7.68 (d, J = 7.4 Hz, 2H), 7.45 (d, J = 7.0 Hz, 2H), 7.29−7.13
(m, 5H), 6.55 (d, J = 15.8 Hz, 1H), 6.27−6.17 (m, 1H), 4.45 (s, 2H).
13C{1H} NMR (100 MHz, CDCl3): δ 196.6, 145.0, 136.0, 134.7,
132.2, 128.7, 128.2, 127.5, 126.5, 122.3, 118.1, 113.9, 49.0. HRMS
(ESI+): calcd for C17H15N2S ([M + H]+), 279.0956; found, 279.0952.
Olefins: Creating a Hybrid, Chiral Bioisostere of the Trifluoromethyl
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.9b03275.
■
sı
Spectral data of new compounds and X-ray analysis
(PDF)
X-ray crystallography data for compound 5a (CIF)
AUTHOR INFORMATION
Corresponding Author
■
Chandra Bhushan Tripathi − CSIR-Central Drug
Research Institute, Lucknow, India, and Academy of
Scientific and Innovative Research, New Delhi, India;
orcid.org/0000-0001-7154-242X;
Email: chandra.tripathi@cdri.res.in
Other Authors
Qumruddeen − CSIR-Central Drug Research Institute,
Lucknow, India, and Academy of Scientific and Innovative
Research, New Delhi, India
Arun Yadav − CSIR-Central Drug Research Institute,
Lucknow, India, and Academy of Scientific and Innovative
Research, New Delhi, India
Ruchir Kant − CSIR-Central Drug Research Institute,
Lucknow, India
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.9b03275
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support is provided by SERB, New Delhi, through
the Early Career Research Award (grant no. ECR/2018/
001910). Analytical support from the SAIF division of CSIR-
CDRI is gratefully acknowledged. Qumruddeen thank DST-
Inspire and Arun Yadav acknowledges CSIR, New Delhi, for a
doctoral fellowship. We thank Dr. Tejender S. Thakur of
Molecular and Structural Biology Division, CSIR-Central Drug
Research Institute for supervising the X-ray Data collection
and structure determination of compound 5a. CDRI
Communication No: 10029.
(5) For selected examples, see: (a) Luo, J.; Cao, Q.; Cao, X.; Zhao,
X. Selenide-catalyzed enantioselective synthesis of trifluoromethylth-
iolated tetrahydronaphthalenes by merging desymmetrization and
trifluoromethylthiolation. Nat. Commun. 2018, 9, 527. (b) Liu, X.;
Liang, Y.; Ji, J.; Luo, J.; Zhao, X. Chiral Selenide-Catalyzed
Enantioselective Allylic Reaction and Intermolecular Difunctionaliza-
tion of Alkenes: Efficient Construction of C-SCF3 Stereogenic
Molecules. J. Am. Chem. Soc. 2018, 140, 4782−4786. (c) Guo, R.;
Huang, J.; Zhao, X. Organoselenium-Catalyzed Oxidative Allylic
Fluorination with Electrophilic N-F Reagent. ACS Catal. 2018, 8,
926−930. (d) Liu, X.; An, R.; Zhang, X.; Luo, J.; Zhao, X.
Enantioselective Trifluoromethylthiolating Lactonization Catalyzed
by an Indane-Based Chiral Sulfide. Angew. Chem., Int. Ed. 2016, 55,
5846−5850.
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