Direct C–S Bond Functionalization of Benzyl Mercaptan

Article abstract of DOI:10.1002/ejoc.202000521

Cleavage of a C–S bond of benzyl mercaptan led to formation of a new C–C bond during (Z)-selective alkenylation of nitriles using 1,10-phenanthroline as organocatalyst and tBuOK as a base. Furthermore, we have shown that the cascaded functionalization of benzylic C–S and aryl–halide bonds could be done in one pot. ¹H NMR study and kinetic experiments also helped to establish the mechanism of the reaction.

Full text of DOI:10.1002/ejoc.202000521

European Journal of Organic Chemistry
Accepted Article
Accepted Article
Title: Direct C-S Bond Functionalization of Benzyl Mercaptan
Authors: Khokan Choudhuri, Milan Pramanik, and Prasenjit Mal
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.202000521
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01/2020

10.1002/ejoc.202000521
European Journal of Organic Chemistry
FULL PAPER
Direct C-S Bond Functionalization of Benzyl Mercaptan
Khokan Choudhuri,[a] Milan Pramanik[a] and Prasenjit Mal*[a]
[a]
Mr. K. Choudhuri, Mr. M. Pramanik, Dr. P. Mal
School of Chemical Sciences, National Institute of Science Education and Research (NISER), HBNI, Bhubaneswar, PO Bhimpur-Padanpur, Via Jatni,
District Khurda, Odisha 752050, India
E-mail: pmal@niser.ac.in
https://www.niser.ac.in/users/pmal#profile-main
Supporting information for this article is given via a link at the end of the document
Abstract: Cleavage of a C-S bond of benzyl mercaptan led to
formation of a new C-C bond during (Z)-selective alkenylation of
nitriles using 1,10-phenanthroline as organocatalyst and tBuOK as a
base. Also, we have shown that the cascaded functionalization of
benzylic C-S and aryl-halide bonds could be done in one pot. 1H
NMR study and kinetic experiments also helped to establish the
mechanism of the reaction.
no report is available in the literature for the synthesis of
stereoselective α,β-unsaturated diphenylacrylonitrile derivatives
from mercaptan as benzyl synthon source via C-S bond
cleavage. In addition, cascaded C-S and C-X (X= Cl, F) bond
functionalization led to thiolated-diphenylacrylonitrile derivatives.
These compounds are mostly used as radiation curing
photosensitive initiator. The C-F bond is relatively less reactive
nature and therefore difficult to functionalize due to high bond
energy.[20] So, development of cascaded C-S and C-X (X = F, Cl)
bond functionalization might be helpful in organic synthesis.
Introduction
α,β-Unsaturated diphenylacrylonitrile skeleton is present in
central cores of many drug molecules,[1] and found to have
potent activities like anticancer,[2] antimicrobial,[3] antioxidant,[4]
antitumor,[5] spasmolytic,[6] cytotoxic,[7] etc. They are also used
as organic lighting-emitting diodes (OLEDs)[8] and provide key
building block in many synthetic transformations.[9] The classical
approach
for
the
synthesis
of
α,β-unsaturated
diphenylacrylonitrile from benzyl alcohol and benzyl cyanide
involves metal catalysis (Figure 1a),[10] which makes the process
unappealing in medicinal or pharmaceutical industries due to
high toxicity issues and formation of unwanted side product.
Functionalization of more than one kind of bonds in one pot
can be the state of art practice in synthetic organic chemistry.
The chemical transformations via multiple bond functionalization
in a cascaded manner can thus be important to mimic multistep
reactions.[11] Among the functionalization of benzylic C-S and
aryl-halide bonds, C-S bond functionalization is an important
aspects in biological systems because, breaking of C-S bonds is
well known in the replication of DNA.[12] Sulfur center in
mercaptan can acts as either nucleophile or electrophile
depending upon reaction environment. In addition, mercaptans
are prone to get oxidized to disulfides.[13] Moreover, the
mercaptans are readily accessible to be utilized as thiyl source
for the formation of various kinds of C-S bonds.[14] The C-S bond
cleavage of unbiased benzyl mercaptans and the utilization of
them as benzyl synthon is extremely challenging and remain
possibly unexplored in organic synthesis. Few examples on C-
C,[15] C- Si,[16] C-O,[17] C-B[18] bond formation reactions are
documented in literature via breaking of the respective pre-
functionalized C-S bonds. In general, UV light[17] or metal
catalysts like Rh[19] and Pd[18] are used to functionalize the C-S
bond on pre-functionalized mercaptans. Herein, the approach
towards metal free base mediated alkenylation of nitrile via C-S
bond functionalization of benzyl mercaptan (Figure 1b) can have
potential application in the pharmaceutical industry or in the
green synthesis of fine chemicals. To the best of our knowledge,
Figure 1. a) Known approach for α‑olefination of nitriles using benzyl alcohol
b) Our approach for alkenylation of nitrile through the breaking and reforming
of C-S bond from benzyl mercaptan.
Results and Discussion
Before aryl-halide bond activations reactions, we have optimized
the reaction sequence for the synthesis of diphenylacrylonitrile
from benzyl cyanide (1a) and benzyl mercaptan (2a) using
tBuOK and 1,10-phenanthroline (1,10-phen) (Table 1). The
reactions were performed at 120 ºC and under open atmosphere.
The compounds 1a and 2a smoothly reacted to afford the
t
diphenylacrylonitrile (3aa) in 90% yield in presence of BuOK
and 1,10-phen within 24 h in benzene (entry 1). Varying the ratio
t
of BuOK and 1,10-phen led to inferior results (entries 2-3). Use
t
of bases other than BuOK was also not giving encouraging
results (entries 4-6). This can be attributed to strong σ-donor
and π-accepter ability of 1,10-phen,[21] to bind potassium(I) ion.
Solvents other than toluene were also ineffective to have better
yield of 3aa (entries 7-12). Notablely, yield was reduced to 62 %
when 1.5 equiv of benzyl mercaptan was used (entry 13). Upon
lowering temperature than 120 ºC did not have any better impact
(entry 14). Very poor yield 3aa (28%) was observed in absence
1
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10.1002/ejoc.202000521
European Journal of Organic Chemistry
FULL PAPER
of 1,10-phen (entry 15). However, no product could be detected
in absence of BuOK (entry 16) and in inert atmosphere (entry
17). However 82% yield of 3aa was observed when reaction
using heterocyclic coupling partners (both in aryl mercaptan and
nitrile substrates). 2-Furfurylthiol reacted with substituted phenyl
acetonitrile to produce 3hf, 3df and 3kf in 82%, 94% and 81%
yields, respectively. Similarly, 2-thenylmercaptan led to 3dg and
t
time was reduced to 18 h (entry 18). Finally, the most suitable
t
condition was found to be using BuOK (2 equiv) and 1,10-phen
3kg
in
76%
and
74%
yields,
respectively.
2-
(0.2 equiv) in toluene (entry 10).
Thiopheneacetonitrile also reacted with benzyl cyanide and
yielded 3ka in 85% yield. Likewise, we have extended our
methodology towards in situ cascaded C-S and C-X (X = Cl, F)
bond functionalization reaction via ipso substitution having halo
substituted benzyl mercaptans (Figure 3). Under the standard
condition benzyl mercaptan containing halides (X = -F, -Cl) at
para position, selectively resulted in (Z)-selective thiolated-
diphenylacrylonitrile derivatives. Fluorine substituted benzyl
mercaptans also led to the products 4bh, 4dh and 4kh, in good
yields (73%, 67% and 50%, respectively) via C-F bond
activation.[22] In addition, chloro substituted benzyl mercaptan
provided 4ae and 4ge, in 65% and 74% yield, respectively.
Mixture of products 3be and 4be was obtained in (3:4) ratio with
36% and 48% yield, respectively, when p-tolylacetonitrile was
taken as one of the coupling partners. However, 2-chloro-4-
fluoro phenylacetonitrile mainly delivered the para selective C-F
bond activated product 4lc in 36% yield.
Table 1. Optimization Method.a
entry
base (equiv)
1,10-phen
(mol %)
solvent
yield
(%)a
1
tBuOK (2.0)
tBuOK (1.0)
tBuOK (2.0)
tBuOLi (2.0)
tBuONa (2.0)
KOH (2.0)
tBuOK (2.0)
tBuOK (2.0)
tBuOK (2.0)
tBuOK (2.0)
tBuOK (2.0)
tBuOK (2.0)
tBuOK (2.0)
tBuOK (2.0)
tBuOK (2.0)
--
0.2
0.2
0.1
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
--
benzene
benzene
benzene
benzene
benzene
benzene
DMF
90
75
40
12
38
0
2
3
4
5
6
7
17
15
50
96
--
8
DCE
9
EtOH
10
11
12
13
14
15
16
17
18
toluene
DMSO
xylene
91
62b
67c
28
0
toluene
toluene
toluene
toluene
toluene
toluene
0.2
0.2
0.2
tBuOK (2.0)
tBuOK (2.0)
0d
82e
Reaction Condition: 1a (0.517 mmol), 2a (1.034 mmol), 1,10-Phenanthroline
t
(0.103 mmol), BuOK (1.034 mmol) in toluene for 24 h. aIsolated yield; b1.5
equiv 2a was used; c100 ºC, 24 h, dN2 atmosphere, eAfter 18 h.
Figure 2. Substrate scope for the substituted 1,2-diphenylacrylonitrile
synthesis. a) C-C Coupling reaction using different kinds of benzyl cyanides
and mercaptans. b) C-C bond synthesis using heterocyclic coupling partner.
3ca: CCDC 1956045.
Using the optimized reaction condition, substrate scope for the
synthesis of α,β-diphenylacrylonitrile derivatives are shown in
Figure 2. Reactions involving both electron donating (-Me, -OMe,
-napthyl) and halide groups (-Cl, -F, -Br) at phenyl acetonitriles
led to excellent yields (80-96%) of the products 3aa-3ha.
Similarly, 3db, 3cc, 3fc, 3dc and 3dd were isolated in 82%,
84%, 71%, 95% and 93% yields, respectively. However, no
product formation was observed with nitrile derivatives with
electron withdrawing -NO2 or -CN substituted phenyl groups (3ic,
3jc). Possibly, after proton abstraction, phenyl acetonitrile led to
benzylic anion intermediate which was not nucleophilic enough
for condensation reaction due to –R effect of the -NO2 or –CN
groups. Furthermore, the versatility of the reaction was explored
Next, we have investigated the mechanism of the reaction using
the support from control experiments shown in Figure 4. Radical
pathway
was
initially
anticipated,[23]
because
1,10-
phenanthroline and tBuOK are known to produce tBuO. via single
electron transfer pathway.[24] However, the use of stoichiometric
amount of radical scavengers like 2,2,6,6-tetramethyl-1-
piperidinyloxy (TEMPO) or butylated hydroxytoluene (BHT)
during the reaction under standard condition shown to have non-
involvement of any radical pathway (Figure 4a). In presence of
2
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10.1002/ejoc.202000521
European Journal of Organic Chemistry
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t
base, the benzyl mercaptan generally produces 1,2-
dibenzyldisulfane. As expected, 85% yield of 3aa was isolated,
when 1,2-dibenzyldisulfane was employed under optimized
formation of complex 5 (Figure 6) from 1,10-phen and BuOK in
toluene-d8 (Figure 6b). A new peak at 5.1 ppm suggested a
strong H-bonding between C(sp3)-H of toluene and oxygen atom
of tBuOK.
condition (Figure 4b).
A kinetic isotopic effect was also
measured and found to be KH/KD = 3.75 (Figure 4c). This
indicates that the benzylic C(sp3)–H bond was actively
participating to form a stable benzyl carbanionic intermediate
during the reaction. Contrastingly, 2-phenylethane-1-thiol and
phenyl acetonitrile under standard condition did not furnish any
products (Figure 4d). This result indicated that stability of
benzylic carbanion is an important factor for the reactions to
proceed. In addition, reaction of 3de with 2h led to the formation
of 4dh in 68 % yield (Figure 4e). This fact confirms that the α,β-
diphenylacrylonitrile might be the intermediate for the formation
of ipso substituted product 4dh via cascaded C-S and C-X bond
functionalization reaction. Also, in absence of phenyl acetonitile,
87% yield of 1,2 dibenzyldisulfane was isolated (Figure 4f).[25]
4dh: CCDC 1956046.
Figure 4. Control experiments.
Figure 3. Scope of cascaded C-S and C-X (X = -F, -Cl) bond activation
reaction.
A plausible mechanism for the cascaded benzylic C-S and aryl-
halide bond functionalization has been proposed in Figure 5.
Literature report[26] suggested that K+ ion from inorganic salt
tBuOK and 1,10-phen might have a reliable interaction with
toluene via π-π stacking and cation-π interaction[27] to form a
t
stable complex 5 in which the counter anion of BuOK could be
available for acidic H-abstraction (Figure 5a). Following,
complex 5 under the treatment with 2a in presence of aerial
dioxygen led to intermediate 2aa. Further, with the help of
complex 5, disulfides expected to get converted to a stable
benzyl carbanion intermediate 2aa’ (Figure 5c). Under standard
condition, benzyl carbanion intermediate 2aa’ is expected to
produce thiobenzaldehyde[28] 6 and the intermediate 7 (Figure
5c). Following, carbanion intermediate 1a’ generated from
phenyl acetonitrile 1a (Figure 5b) was coupled with
thiobenzaldehyde 6 to provide intermediate 8. Finally, release of
H2S (turned the led-acetate paper into black, supporting
information, Scheme S2) from 8 could lead to formation of 3aa
through E2 elimination. On the other hand compound 9 having
F/Cl atom underwent ipso substitution by benzyl thiolate to
produce compound 4ah. 1H NMR studies also supported for the
Figure 5. Plausible mechanism of the reaction. a) Activation of base by 1,10-
phen. b) Generation of benzyl carbocation intermediate from disulfane. c) C-C
bond formation reaction. d) Ipso-substitution and C-S coupling reaction.
The cascaded C-S and C-X (X = Cl, F) bond functionalization
reactions were truly controlled by electronic effect. For aromatic
3
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10.1002/ejoc.202000521
European Journal of Organic Chemistry
FULL PAPER
13C) and DMSO-d6 (2.50 for 1H and 39.520 ppm for 13C). Infrared (IR)
spectra were recorded in wave number (cm-1). Digital melting point
apparatus were used to record the melting point of the compound. High
resolution mass spectroscopy (HR-ESIMS) was recorded on ESI-TOF
(Time-of-flight) mass spectroscopy.
nucleophilic substitution reactions, stability of the sigma
complexes are crucial. Therefore, fluorine substituted phenyl
acetonitrile derivatives were unable to results in ipso substitution
of C-F bonds and 2-(4-fluorophenyl)acetonitrile led to the
formation of 3ea. However, methyl group is an electron donating
group due to hyperconjugation effect which may cause
destabilization of the sigma complexes. Hence, mixture of
products 3be and 4be was obtained in (3:4) ratio with 36% and
48% yield for the p-tolylacetonitrile system. On the other hand,
for 2-(4-chlorophenyl)acetonitrile the –R effect by the Cl group
operative and 4ae was obtained as the only product.
Synthesis
General procedure for the preparation of diphenylacrylonitrile. To a
t
stirred solution of 1,10-Phenanthroline (19 mg, 0.103 mmol) and BuOK
(116 mg, 1.034 mmol) in toluene, benzyl cyanide (60 μL, 0.517 mmol)
and benzyl mercaptan (121 μL, 1.034 mmol) were added. Then the
resulting mixture was allowed to stir at 120 oC for 24 h under open
atmosphere. After that the solution was concentrated under vacuum,
diluted with CH2Cl2 and washed with brine solution. Then the organic
layer was dried over anhydrous sodium sulphate and purified through
silica gel column chromatography using n-hexane and ethyl acetate
solvent mixture as an eluent to afford the product.
KIE Experiment. To a stirred solution of 1,10-phenanthroline (0.021 mg,
0.114 mmol) and tBuOK (0.129 mg, 1.150 mmol) in toluene, benzyl
cyanide (0.076 mg, 0.574 mmol), 1,2-dibenzyldisulfane (0.070 mg, 0.287
mmol) and 1,2-bis(phenylmethyl-d2)disulfane (0.071 mg, 0.287 mmol)
were added. Then the resulting mixture was allowed to stir at 120 oC for
24 h under open atmosphere. After that the solution was concentrated
under vacuum, diluted with CH2Cl2 and washed with brine solution. Then
the organic layer was dried over anhydrous sodium sulfate and purified
through silica gel column chromatography using n-hexane and ethyl
acetate solvent mixture as an eluent to afford the mixture of (3aa and
3aa’) product. After that, KH / KD ratio was calculated from NMR analysis
and found to be KH / KD 3.75.
Figure 6. Possible interaction between the phenanthroline, tBuOK and the
solvent molecule. a) 1H-NMR spectra of 1,10-phenanthroline and tBuOK in
t
toluene-d8 after 0 min. b) 1H-NMR spectra of 1,10-Phenanthroline and BuOK
after 15 min heating at 120 ºC.
Preparation of 1,2-bis(phenylmethyl-d2)disulfane.
We prepared the 1,2-bis(phenylmethyl-d2)disulfane using the standard
procedure[29] by the two step sequence described in details.
Conclusion
Preparation of 1,1-[D2]Phenylmethanethiol acetate. Thioacetic acid
(12.03 mmol) and ZnI2 (2.405 mmol) were added to a solution of
phenylmethan-d2-ol (4.81 mmol) in dichloroethane. Then the solution
was refluxed for 1 h to complete the reaction. After that the resulting
solution was diluted with CH2Cl2 and washed with water, purified over
silica-gel column chromatography to afford 13 as yellow color oil. 1H NMR
(400 MHz, CDCl3) δ 7.62 – 6.93 (m, 5H), 2.35 (s, 3H).
In conclusion, we have shown that using 1,10-phenanthroline as
organocatalyst and tBuOK as base, cascaded activation of
multiple bonds like benzylic C-S and aryl-halide could be
possible in one pot. Overall, by the cleavage of C-S bond of
benzyl mercaptans resulted in the formation of (Z)-selective α,β-
unsaturated diphenylacrylonitriles in presence of phenyl
acetonitriles. Also, synthesis of thiolated diphenylacrylonitriles
derivatives were achieved from the same reaction pot by ipso
substitution in diphenylacrylonitriles when para substituted
Preparation of Di-(1,1-[D2]Phenylmethyl) disulfide: To
a room
temperature solution of 13 in methanol, 0.25 mL conc. HCl was added
and the resulting solution was refluxed for 14 h. After that, the solution
was cooled to room temperature. Following, 5% solution of I2 in methanol
was added and stirred for 30 min. After completion of the reaction,
saturated Na2S2O3 was added to remove the excess amount of I2 and the
organic layer was separated. Then the crude mixture was purified over
silica gel column chromatography using n-hexane and ethyl acetate
solvent mixture to afford the product 14. 1H NMR (400 MHz, CDCl3) δ
7.36 – 7.26 (m, 8H), 7.25 – 7.24 (m, 1H), 7.24 – 7.22 (m, 1H).
halogen containing benzyl mercaptans were used.
Thus
expected that the current methodology will be highly appealing
in organic synthesis, pharmaceutical chemistry and drug
discovery.
Experimental Section
(Z)-2,3-Diphenylacrylonitrile (3aa). Rf = 0.6 (5% ethyl acetate in
hexane); White solid; yield 96% (102 mg); mp 80 - 82 ºC (lit.[30] 86-87 ºC);
1H NMR (700 MHz, DMSO-d6) δ 8.05 (s, 1H), 7.94 (d, J = 7.6 Hz, 2H),
Instrumentation and Chemicals
All the chemicals were purchase from the commercially available source
and used as received. All the reactions were carried out at 120 oC in
open atmosphere. Column chromatography purification was performed
using silica gel (Mesh 230-400) and ethyl acetate/hexane as an eluent
unless otherwise specified. TLC was performed on Merck silica gel 60
F254 aluminum plate and visualized with UV lamp. 1H and 13C NMR
spectra of the compounds were recorded on 400 and 700 MHz
spectrometer at 25 oC. The chemical shift value (δ, ppm) were reported
with respect to the residual chloroform (7.26 for 1H and 77.16 ppm for
7.77 (d, J = 7.6 Hz, 2H), 7.57 – 7.49 (m, 5H), 7.46 (t, J = 7.2 Hz, 1H); 13
C
NMR (175 MHz, DMSO) δ 143.1, 133.8, 133.79, 130.7, 129.4, 129.3,
129.2, 129.0, 125.9, 118.0, 110.4.
(Z)-3-Phenyl-2-(p-tolyl)acrylonitrile (3ba). Rf = 0.62 (5% ethyl acetate
in hexane); White solid; yield 84% (84 mg); mp 62 - 64 ºC (lit.[31] 73-74
ºC); 1H NMR (400 MHz, CDCl3) δ 7.88 (d, J = 7.0 Hz, 2H), 7.58 (d, J =
8.2 Hz, 2H), 7.50 (s, 1H), 7.49 – 7.40 (m, 3H), 7.25 (d, J = 8.2 Hz, 2H),
4
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10.1002/ejoc.202000521
European Journal of Organic Chemistry
FULL PAPER
2.40 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 141.4, 139.6, 134.0, 131.8,
130.5, 129.9, 129.3, 129.1, 126.0, 118.2, 111.8, 21.4.
(Z)-3-(4-Chlorophenyl)-2-(p-tolyl)acrylonitrile (3be). Rf = 0.4 (5% ethyl
acetate in hexane); Off white solid; yield 36% (40 mg); mp 118-120 ºC
(lit.[36] 119-120 ºC); 1H NMR (700 MHz, DMSO) δ 8.01 (s, 1H), 7.94 (d, J
= 8.6 Hz, 2H), 7.66 (d, J = 8.2 Hz, 2H), 7.62 (d, J = 8.6 Hz, 2H), 7.33 (d, J
= 8.2 Hz, 2H), 2.36 (s, 3H); 13C NMR (175 MHz, DMSO) δ 140.4, 139.3,
134.9, 132.7, 130.8, 130.7, 129.8, 129.1, 125.7, 117.7, 110.9, 20.8.
(Z)-2-(4-Bromophenyl)-3-phenylacrylonitrile (3ca). Rf = 0.6 (5% ethyl
acetate in hexane); White solid; yield 96% (84 mg); mp 105-107 ºC (lit.[32]
135-137 ºC); 1H NMR (400 MHz, CDCl3) δ 7.92 – 7.85 (m, 2H), 7.60 –
7.52 (m, 5H), 7.51 – 7.44 (m, 3H); 13C NMR (100 MHz, CDCl3) δ 142.8,
133.6, 133.6, 132.4, 131.0, 129.5, 129.2, 127.6, 123.6, 117.8, 110.8.
(Z)-3-(2-Chlorophenyl)-2-(4-chlorophenyl)acrylonitrile (3dd). Rf = 0.5
(5% ethyl acetate in hexane); White solid; yield 93% (110 mg); mp 110-
112 ºC (lit.[37] 109-110 ºC); 1H NMR (700 MHz, DMSO) δ 8.13 (s, 1H),
7.96 (dd, J = 7.0, 1.8 Hz, 1H), 7.81 (d, J = 8.6 Hz, 2H), 7.67 – 7.63 (m,
1H), 7.61 (d, J = 8.6 Hz, 2H), 7.57 – 7.51 (m, 2H); 13C NMR (175 MHz,
DMSO) δ 140.2, 134.5, 133.4, 132.3, 131.9, 131.8, 129.8, 129.8, 129.4,
127.9, 127.6, 116.7, 113.8.
(Z)-2-(4-Chlorophenyl)-3-phenylacrylonitrile (3da). Rf = 0.5 (5% ethyl
acetate in hexane); White solid; yield 92% (110 mg); mp 117-119 ºC
(lit.[33] 121-122 ºC); 1H NMR (400 MHz, CDCl3) δ 7.93 – 7.85 (m, 2H),
7.61 (d, J = 8.6 Hz, 2H), 7.52 (s, 1H), 7.50 – 7.44 (m, 3H), 7.42 (d, J =
8.6 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 142.7, 135.4, 133.6, 133.1,
130.9, 129.5, 129.4, 129.2, 127.4, 117.8, 110.7.
(Z)-2-Mesityl-3-(4-methoxyphenyl)acrylonitrile (3fc). Rf = 0.15 (5%
ethyl acetate in hexane); Colorless liquid; yield 71% (74 mg); 1H NMR
(400 MHz, CDCl3) δ 7.32 (s, 1H), 6.94 (s, 2H), 6.93 – 6.88 (m, 2H), 6.71
(d, J = 8.8 Hz, 2H), 3.76 (s, 3H), 2.33 (s, 3H), 2.20 (s, 6H); 13C NMR (100
MHz, CDCl3) δ 161.1, 144.9, 138.8, 136.3, 131.2, 129.2, 128.9, 127.0,
120.0, 114.2, 109.1, 55.3, 21.2, 19.7; IR (KBr) ῡ = 2961, 2811, 2248,
1931, 1661, 1154 cm-1; HRMS (ESI-TOF) calcd for C19H19NO (M +H)+
278.1539, found 278.1548.
(Z)-2-(4-Fluorophenyl)-3-phenylacrylonitrile (3ea). Rf = 0.48 (5% ethyl
acetate in hexane); White solid; yield 80% (89 mg); mp 85-87 ºC (lit.[34]
88-89 ºC);1H NMR (400 MHz, CDCl3) δ 7.91 – 7.84 (m, 2H), 7.66 (dd, J =
8.8, 5.2 Hz, 2H), 7.52 – 7.42 (m, 4H), 7.15 (t, J = 8.6 Hz, 2H); 13C NMR
(100 MHz, CDCl3) δ 163.4 (d, JCF = 248 Hz), 142.3 (d, JCF = 1.8 Hz),
133.7, 130.84, 130.78, 129.3 (d, 2JCF = 21.2 Hz), 128.0 (d, 3JCF = 8.3 Hz),
118.0, 116.4, 116.2, 110.8.
1
4
(Z)-2-(4-Chlorophenyl)-3-(4-methoxyphenyl) acrylonitrile (3dc). Rf =
0.2 (5% ethyl acetate in hexane); Off white solid; yield 95% (100 mg); mp
118-120 ºC (lit.[33] 128-129 ºC); 1H NMR (400 MHz, CDCl3) δ 7.88 (d, J =
8.8 Hz, 2H), 7.58 (d, J = 8.6 Hz, 2H), 7.44 (s, 1H), 7.40 (d, J = 8.6 Hz,
2H), 6.99 (d, J = 8.8 Hz, 2H), 3.88 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
161.6, 142.2, 134.7, 133.4, 131.3, 129.2, 127.0, 126.3, 118.2, 114.5,
107.5, 55.5.
(Z)-2-Mesityl-3-phenylacrylonitrile (3fa). Rf = 0.4 (5% ethyl acetate in
hexane); Colorless liquid; yield 84% (78 mg); H NMR (400 MHz, CDCl3)
1
δ 7.38 (s, 1H), 7.32 – 7.25 (m, 1H), 7.19 (t, J = 7.6 Hz, 2H), 6.99 (d, J =
7.6 Hz, 2H), 6.94 (s, 2H), 2.33 (s, 3H), 2.20 (s, 6H); 13C NMR (100 MHz,
CDCl3) δ 147.6, 145.6, 139.1, 136.2, 134.2, 130.4, 129.5, 129.3, 128.9,
119.7, 112.2, 21.3, 19.8; IR (KBr) ῡ = 3017, 2921, 2205, 1610, 1448,
1217 cm-1; HRMS (ESI-TOF) calcd for C18H17N (M +H)+ 248.1434, found
248.1415.
(Z)-3-(Furan-2-yl)-2-(naphthalen-1-yl)acrylonitrile (3hf): Rf = 0.4 (5%
1
(Z)-2-(3,5-dimethoxyphenyl)-3-phenylacrylonitrile (3ga).[35] Rf = 0.2
(5% ethyl acetate in hexane); Off white solid; yield 94% (84 mg); mp 68-
70. 1H NMR (400 MHz, CDCl3) δ 7.88 (d, J = 6.8 Hz, 2H), 7.53 (s, 1H),
7.51 – 7.41 (m, 3H), 6.81 (d, J = 2.2 Hz, 2H), 6.50 (t, J = 2.2 Hz, 1H),
3.85 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 161.2, 142.7, 136.5, 133.6,
130.6, 129.4, 129.0, 118.0, 111.6, 104.3, 101.3, 55.6; HRMS (ESI-TOF)
calcd for C17H15NO2 (M +H)+ 266.1176, found 266.1185.
ethyl acetate in hexane); Yellow color liquid; yield 82% (72 mg); H NMR
(400 MHz, CDCl3) δ 8.20 (d, J = 8.2 Hz, 1H), 7.91 (d, J = 7.6 Hz, 2H),
7.64 (d, J = 1.2 Hz, 1H), 7.62 – 7.46 (m, 4H), 7.24 (d, J = 3.6 Hz, 1H),
7.21 (s, 1H), 6.62 (dd, J = 3.4, 1.6 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ
150.1, 145.1, 134.1, 134.0, 132.9, 130.9, 130.0, 128.9, 127.4, 127.2,
126.6, 125.5, 124.7, 118.7, 115.5, 112.9, 106.3; IR (KBr) ῡ = 3141, 3058,
2924, 2207, 1614, 1471, 1248 cm-1; HRMS (ESI-TOF) calcd for
C17H11NO (M +Na)+ 268.0733, found 268.0732.
(Z)-2-(Naphthalen-1-yl)-3-phenylacrylonitrile (3ha).[10a] Rf = 0.2 (5%
ethyl acetate in hexane); Colorless liquid; yield 94% (86 mg); 1H NMR
(400 MHz, CDCl3) δ 8.20 (d, J = 8.0 Hz, 1H), 7.97 (d, J = 7.6 Hz, 2H),
7.93 (d, J = 8.2 Hz, 2H), 7.63 – 7.56 (m, 3H), 7.55 – 7.50 (m, 4H), 7.36 (s,
1H); 13C NMR (100 MHz, CDCl3) δ 148.0, 134.0, 133.8, 133.7, 130.9,
130.9, 130.0, 129.4, 129.2, 128.9, 127.4, 127.2, 126.6, 125.5, 124.7,
118.7, 110.0.
(Z)-2-(4-Chlorophenyl)-3-(furan-2-yl)acrylonitrile (3df). Rf = 0.25 (5%
ethyl acetate in hexane); Brown solid; yield 94% (85 mg); mp 74-76 ºC
(lit.[33] 80-88 ºC); 1H NMR (400 MHz, CDCl3) δ 7.61 (d, J = 1.6 Hz, 1H),
7.57 (d, J = 8.6 Hz, 2H), 7.40 (d, J = 8.6 Hz, 2H), 7.36 (s, 1H), 7.21 (d, J
= 3.6 Hz, 1H), 6.59 (dd, J = 3.6, 1.6 Hz, 1H); 13C NMR (100 MHz, CDCl3)
δ 149.9, 145.2, 135.1, 132.2, 129.3, 128.2, 126.8, 117.5, 115.7, 112.9,
106.4.
(Z)-3-(4-(tert-Butyl)phenyl)-2-(4-chlorophenyl) acrylonitrile (3db). Rf =
0.65 (5% ethyl acetate in hexane); Light yellow solid; yield 82% (95 mg);
mp 182-184 ºC; 1H NMR (400 MHz, CDCl3) δ 7.84 (d, J = 8.6 Hz, 2H),
7.60 (d, J = 8.6 Hz, 2H), 7.52 – 7.46 (m, 3H), 7.41 (d, J = 8.6 Hz, 2H),
1.35 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 154.7, 142.6, 135.2, 133.3,
130.9, 129.4 (x2), 127.3, 126.2, 118.1, 109.6, 35.2, 31.3; IR (KBr) ῡ =
2976, 2958, 2359, 2339, 2220, 1402 cm-1; HRMS (ESI-TOF) calcd for
C19H18NCl (M +Na)+ 318.1020, found 318.1005.
(E)-3-Phenyl-2-(thiophen-2-yl)acrylonitrile (3ka). Rf = 0.4 (5% ethyl
acetate in hexane); Yellow solid; yield 85% (100 mg); mp 78-80 ºC (lit.[38]
1
76-77 ºC); H NMR (400 MHz, CDCl3) δ 7.85 (d, J = 6.4 Hz, 2H), 7.49 –
7.42 (m, 3H), 7.40 – 7.37 (m, 2H), 7.31 (d, J = 5.2 Hz, 1H), 7.08 (dd, J =
5.2, 3.8 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 139.8, 139.3, 133.5,
130.7, 129.3, 129.1, 128.3, 127.4, 126.4, 117.0, 106.3.
(E)-3-(Furan-2-yl)-2-(thiophen-2-yl)acrylonitrile (3kf): Rf = 0.4 (5%
ethyl acetate in hexane); Yellow solid; yield 81% (92 mg); mp 84-86 ºC;
1H NMR (400 MHz, CDCl3) δ 7.59 (d, J = 1.2 Hz, 1H), 7.35 (d, J = 3.6 Hz,
1H), 7.29 (d, J = 5.2 Hz, 1H), 7.19 (s, 1H), 7.10 (d, J = 3.6 Hz, 1H), 7.06
(dd, J = 5.2, 3.6 Hz, 1H), 6.57 (dd, J = 3.6, 1.6 Hz, 1H); 13C NMR (100
MHz, CDCl3) δ 149.8, 145.1, 138.8, 128.4, 127.2, 126.2, 125.9, 116.8,
115.3, 113.0, 102.6; IR (KBr) ῡ = 3115, 2923, 2853, 2216, 1609, 1468,
1225, 745; HRMS (ESI-TOF) calcd for C11H17NOS (M +H)+ 202.0321,
found 202.0332.
(Z)-2-(4-Bromophenyl)-3-(4-methoxyphenyl) acrylonitrile (3cc). Rf =
0.35 (5% ethyl acetate in hexane); Light yellow solid; yield 84% (81 mg);
mp 128-130 ºC; 1H NMR (700 MHz, CDCl3) δ 7.88 (d, J = 8.8 Hz, 2H),
7.56 (d, J = 8.6 Hz, 2H), 7.52 (d, J = 8.6 Hz, 2H), 7.45 (s, 1H), 6.98 (d, J
= 8.6 Hz, 2H), 3.88 (s, 3H); 13C NMR (175 MHz, CDCl3) δ 161.8, 142.4,
134.0, 132.3, 131.5, 127.4, 126.4, 123.0, 118.3, 114.6, 107.7, 55.6; IR
(KBr) ῡ = 2923, 2852, 2359, 2214, 1511, 1273; HRMS (ESI-TOF) calcd
for C16H12NOBr (M +Na)+ 335.9994, found 335.9995.
5
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202000521
European Journal of Organic Chemistry
FULL PAPER
(Z)-2-(4-Chlorophenyl)-3-(thiophen-2-yl)acrylonitrile (3dg). Rf = 0.4
(5% ethyl acetate in hexane); Yellow solid; yield 76% (80 mg); mp 115-
117 ºC (lit.[33] 135-136 ºC); 1H NMR (700 MHz, DMSO-d6) δ 8.36 (s, 1H),
7.95 (d, J = 4.8 Hz, 1H), 7.78 (d, J = 3.4 Hz, 1H), 7.75 (d, J = 8.6 Hz, 2H),
7.58 (d, J = 8.6 Hz, 2H), 7.28 (dd, J = 4.9, 3.8 Hz, 1H); 13C NMR (175
MHz, DMSO-d6) δ 137.4, 136.3, 135.0, 133.5, 132.3, 132.0, 129.2, 128.1,
127.2, 117.8, 104.9.
125.7, 118.1, 109.2, 34.7; IR (KBr) ῡ = 2954, 2923, 2853, 2185, 1605,
1409, 697; HRMS (ESI-TOF) calcd for C22H16NSCl (M)+ 361.0686, found
361.0717.
(E)-3-(4-((4-Fluorobenzyl)thio)phenyl)-2-(thiophen-2-yl)acrylonitrile
(4kh). Rf = 0.2 (5% ethyl acetate in hexane); Yellow solid; yield 50% (98
mg); mp 90-92 ºC; 1H NMR (400 MHz, CDCl3) δ 7.75 (d, J = 8.4 Hz, 2H),
7.37 (d, J = 3.5 Hz, 1H), 7.35 – 7.26 (m, 6H), 7.10 – 7.04 (m, 1H), 7.00 (t,
J = 8.6 Hz, 2H), 4.17 (s, 2H); 13C NMR (175 MHz, CDCl3) δ 162.3 (d, 1JCF
(E)-2,3-Di(thiophen-2-yl)acrylonitrile (3kg). Rf = 0.35 (5% ethyl acetate
in hexane); Yellow solid; yield 74% (90 mg); mp 130-132 ºC (lit.[38] 130-
131 ºC); 1H NMR (700 MHz, DMSO-d6) δ 8.04 (s, 1H), 7.90 (d, J = 5.0 Hz,
1H), 7.75 (d, J = 3.5 Hz, 1H), 7.66 (dd, J = 5.0, 0.9 Hz, 1H), 7.39 (dd, J =
3.5, 0.8 Hz, 1H), 7.25 (dd, J = 5.0, 3.8 Hz, 1H), 7.16 (dd, J = 5.0, 3.8 Hz,
1H); 13C NMR (100 MHz, CDCl3) δ 138.7, 137.6, 132.1, 132.1, 130.0,
128.2, 127.9, 127.0, 125.9, 117.0, 103.2; IR (KBr) ῡ = 3097, 3081, 2185,
1545, 1430, 750, 713; HRMS (ESI-TOF) calcd for C11H7NS2 (M +Na)+
239.9912, found 239.9916.
4
= 246.2 Hz), 142.8, 140.4, 139.4, 138.9, 132.4 (d, JCF = 3.2 Hz), 131.0
3
(s), 130.5 (d, JCF = 8.1 Hz), 129.6, 128.5, 128.3, 127.3, 126.3, 117.1,
2
115.7 (d, JCF = 21.6 Hz), 105.6, 37.2; IR (KBr) ῡ = 2923, 2853, 2216,
1583, 1507, 1275, 848, 751 cm-1; HRMS (ESI-TOF) calcd for C20H14NS2F
(M +H)+ 352.0624, found 352.0612.
(Z)-2-(2-Chloro-4-((4-methoxybenzyl)thio)phenyl)-3-(4-
methoxyphenyl)acrylonitrile (4ic). Rf
=
0.2 (5% ethyl acetate in
1
hexane); Light yellow solid; yield 36% (54 mg); mp 108-110 ºC; H NMR
(400 MHz, CDCl3) δ 7.83 (d, J = 8.8 Hz, 2H), 7.31 (d, J = 1.6 Hz, 1H),
7.27 – 7.19 (m, 3H), 7.17 – 7.09 (m, 2H), 6.93 (d, J = 8.8 Hz, 2H), 6.81 (d,
J = 8.8 Hz, 2H), 4.09 (s, 2H), 3.83 (s, 3H), 3.76 (s, 3H); 13C NMR (100
MHz, CDCl3) δ 161.8, 159.1, 147.6, 140.0, 133.3, 132.0, 131.3, 130.8,
130.0, 129.6, 128.2, 127.2, 126.0, 117.9, 114.4, 114.1, 105.4, 55.5, 55.3,
37.6; IR (KBr) ῡ = 2954, 2925, 2853, 2125, 1608, 1250, 1177, 738 cm-1;
HRMS (ESI-TOF) calcd for C24H20NO2SCl (M +Na)+ 444.0795, found
444.0798.
(Z)-3-(4-((4-Chlorobenzyl)thio)phenyl)-2-(p-tolyl) acrylonitrile (4be).
Rf = 0.3 (5% ethyl acetate in hexane); White solid; yield 48% (80 mg); mp
114-116 ºC; 1H NMR (700 MHz, DMSO-d6) δ 7.92 (s, 1H), 7.85 (d, J =
8.2 Hz, 2H), 7.63 (d, J = 8.0 Hz, 2H), 7.47 (d, J = 8.2 Hz, 2H), 7.44 (d, J =
8.2 Hz, 2H), 7.37 (d, J = 8.2 Hz, 2H), 7.32 (d, J = 8.0 Hz, 2H), 4.36 (s,
2H), 2.35 (s, 3H); 13C NMR (175 MHz, DMSO-d6) δ 141.0, 139.6, 138.9,
136.3, 131.8, 131.1, 130.9, 130.7, 129.7, 129.5, 128.4, 127.3, 125.6,
118.1, 109.2, 34.7, 20.7; IR (KBr) ῡ = 3026, 2923, 2853, 2212, 1588,
1512, 1491, 746 cm-1; HRMS (ESI-TOF) calcd for C23H18NSCl (M +Na)+
398.0741, found 398.0731.
Acknowledgements
(Z)-3-(4-((4-Fluorobenzyl)thio)phenyl)-2-(p-tolyl) acrylonitrile (4bh).
Rf = 0.3 (5% ethyl acetate in hexane); Off white solid; yield 73% (115
mg); mp 120-122 ºC; H NMR (700 MHz, DMSO-d6) δ 7.91 (s, 1H), 7.85
1
We thank CSIR for funding (Project No. 02(0338)/18/EMR-II
dated 24-04-2018). K.C. and M.P. thank NISER for fellowship.
(d, J = 8.4 Hz, 2H), 7.63 (d, J = 8.0 Hz, 2H), 7.49 – 7.42 (m, 4H), 7.31 (d,
J = 8.0 Hz, 2H), 7.14 (t, J = 8.8 Hz, 2H), 4.35 (s, 2H), 2.35 (s, 3H); 13C
1
NMR (175 MHz, DMSO-d6) δ 161.3 (d, JCF = 243.3 Hz), 141.0, 139.9,
Keywords: Benzylic C-S bond functionalization • Cascaded
Reactions • Organocatalysis • 1,10-Phenanthroline-tBuOK • (Z)-
Selective alkenylation
138.9, 133.3 (d, 4JCF = 2.9 Hz), 131.1, 130.8, 130.8, 129.7, 129.5, 127.3,
2
125.5, 118.1, 115.2 (d, JCF = 21.3 Hz), 109.1, 34.7, 20.7; IR (KBr) ῡ =
2923, 2853, 2211, 1600, 1510, 754; HRMS (ESI-TOF) calcd for
C23H18NSF (M +Na)+ 382.1036, found 382.1034.
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(Z)-3-(4-((4-Chlorobenzyl)thio)phenyl)-2-(3,5-
[2]
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dimethoxyphenyl)acrylonitrile (4ge). Rf = 0.15 (5% ethyl acetate in
hexane); Light yellow solid; yield 74% (106 mg); mp 98-104 ºC; H NMR
1
(400 MHz, CDCl3) δ 7.76 (d, J = 8.4 Hz, 2H), 7.41 (s, 1H), 7.30 (d, J = 8.4
Hz, 2H), 7.26 (s, 3H), 7.24 (s, 1H), 6.76 (d, J = 2.2 Hz, 2H), 6.46 (t, J =
2.1 Hz, 1H), 4.13 (s, 2H), 3.82 (s, 6H); 13C NMR (100 MHz, CDCl3) δ
161.4, 141.8, 140.3, 136.6, 135.3, 133.4, 131.3, 130.2, 129.9, 129.0,
128.5, 118.2, 111.1, 104.4, 101.4, 55.7, 37.3; IR (KBr) ῡ = 2925, 2852,
2211, 1598, 1491, 1206, 737 cm-1; HRMS (ESI-TOF) calcd for
C24H20NO2SCl (M +Na)+ 444.0795, found 444.0770.
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M. De Rosa, L. Lu, E. Zamaratski, N. Szałaj, S. Cao, H. Wadensten, L.
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M. Hranjec, G. Pavlović, M. Marjanović, M. Kralj, G. Karminski-Zamola,
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(Z)-2-(4-Chlorophenyl)-3-(4-((4-fluorobenzyl)thio)phenyl)acrylonitrile
F. Sa̧ czewski, P. Reszka, M. Gdaniec, R. Grünert, P. J. Bednarski, J.
(4dh). Rf = 0.3 (5% ethyl acetate in hexane); Light yellow solid; yield 67%
Med. Chem. 2004, 47, 3438-3449.
1
(100 mg); mp 160-162 ºC; H NMR (400 MHz, CDCl3) δ 7.78 (d, J = 8.4
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Hz, 2H), 7.59 (d, J = 8.4 Hz, 2H), 7.45 – 7.39 (m, 3H), 7.37 – 7.27 (m,
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1
4
162.2 (d, JCF = 246.2 Hz), 141.6, 140.7, 135.2, 133.0, 132.2 (d, JCF
=
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3.2 Hz), 130.9, 130.4 (d, 3JCF = 8.1 Hz), 129.7, 129.3, 128.3, 127.2, 117.8,
2
115.6 (d, JCF = 21.6 Hz), 109.7, 37.0; 19F NMR (376 MHz, CDCl3) δ -
114.8; IR (KBr) ῡ = 3049, 2922, 2853, 2210, 1697, 1592, 755; HRMS
(ESI-TOF) calcd for C22H15NSClF (M +Na)+ 402.0490, found 402.0484.
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= 0.3 (5% ethyl acetate in hexane); Yellow solid; yield 65% (120 mg); mp
1
109-111 ºC; H NMR (400 MHz, CDCl3) δ 7.79 (d, J = 8.4 Hz, 2H), 7.66
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(d, J = 7.4 Hz, 2H), 7.48 – 7.38 (m, 4H), 7.33 (d, J = 8.4 Hz, 2H), 7.29 –
7.26 (m, 4H), 4.16 (s, 2H); 13C NMR (175 MHz, DMSO-d6) δ 142.2, 139.9,
136.3, 133.9, 131.8, 130.8, 130.7, 129.6, 129.2, 129.2, 128.5, 127.3,
6
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202000521
European Journal of Organic Chemistry
FULL PAPER
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10.1002/ejoc.202000521
European Journal of Organic Chemistry
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C-S Bond Activation
Using 1,10-phenanthroline as organocatalyst and tBuOK as base, cascaded activation of three different bonds like C(sp3)-H, benzylic
C-S and aryl-halide could be achievable in one pot.
8
This article is protected by copyright. All rights reserved.