Transition metal-free synthesis of sterically hindered allylarenes from 5-hexene-2-one

Article abstract of DOI:10.1039/d0ob01318h

A simple, efficient and transition metal-free strategy was established for the synthesis of highly functionalized, sterically hindered allylarenes (6, 7 & 8) by base-mediated ring transformation of 2-oxo-6-aryl-4-(methylthio/sec-amino)-2H-pyran-3-carbonit

Full text of DOI:10.1039/d0ob01318h

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DOI: 10.1039/D0OB01318H.
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ARTICLE
Transition metal free synthesis of sterically hindered allylarenes
from 5-hexene-2-one
Received 00th January 20xx,
Accepted 00th January 20xx
Ranjay Shaw,a Ismail Althagafi,b Amr Elagamy,a Reeta Rai,c Chandan Shah,a VIshal Nemaysh,a
Harpreet Singhd and Ramendra Pratapa,*
DOI: 10.1039/x0xx00000x
A simple, efficient and transition metal-free strategy was established for the synthesis of highly functionalized, sterically
hindered allylarenes (6,7 & 8) by base mediated ring transformation of 2-oxo-6-aryl-4-(methylthio/sec.amino)-2H-pyran-3-
carbonitriles (3/4) with 5-hexene-2-one (5). This provides a method for the synthesis of allylarenes functionalized with
different electron donating and withdrawing groups in one pot. The structures of isolated products 6c and 7a were
ascertained by spectroscopic and single crystal X-ray diffraction analyses. In addition, we have performed a molecular
docking study to predict the biological activity of synthesized molecules as estrogen receptor alpha (ERα)and estrogen
receptor beta (ERβ).
www.rsc.org/
et al. separately reported the Suzuki–Miyaura aryl-allyl
coupling to afford allylarenes.8
Introduction
Allylarenes are present as core or sub-structure in various
naturally abundant compounds throughout the plant kingdom
and serve to all aspects of plant responses toward abiotic and
biotic stimuli and defend against herbivores and pathogens.1
Ortho and meta substituted allylarenes are significantly used in
flavour and perfume industry, pharmacological, cosmetic,
material chemistry and also used as synthetic precursors or
intermediates or catalysts for the synthesis of complex
products.1,2 Allylarenes are also used as chain-transfer agents
in radical polymerization reactions due to presence of labile C-
H bond at the α-position relative to the allylic double bond.3
Regioselective allylation of multifunctional arenes by Friedel-
Craft reaction could not be a good choice due to poor
selectivity between ortho- and para- position.4 In addition,
over allylation and good reactivity of double bond also cannot
be ignored.5 Recently, various metal catalyzed cross coupling
strategy for allyl-aryl bond formation have used to afford
various substituted allylbenzene. Palladium and iron catalyzed
synthesis of allylarenes by using Grignard reagents are well
studied among them,6 but very high nucleophilicity of Grignard
reagents limits the utility of this method. Kaufman’s group
Scheme 1. Earlier approaches versus our approach for the synthesis of
allylarenes.
Previous works
H
(a)
H
+
Pd, Cu, Au or Fe
Catalyst
R
M/X
X/M
R
+
R
M = MgX, SnR3, B (OR)2
X = halide, SO3R, OTf
Pd Catalyst
Ac2O, NEt3
(b)
(c)
O
R
R
R
DMPU
110 oC, 15 h
OH
RO
O
Au NPs, H2 (1 atm)
R
O
O
toluene
80 oC, 12 h
This work
R2
O
O
Ar
R2
LiOH, DMSO
30 oC, 12 h
R1
R1
+
synthesized
allylarenes
via
Stille
coupling
of
allyltributylstannane and aryl halide.7 Varma et al. and Gerbino
Ar
a. Department of Chemistry, University of Delhi, North Campus, Delhi-110007 India.
E-mail: rpratap@chemistry.du.ac.in; ramendrapratap@gmail.com; Tel: +91
1127666646
Recently, rhodium catalyzed C-H bond activation strategy was
used for the synthesis of alkenylarenes.9 Noujima et al.
prepared allylarenes by Au/HT catalyzed hydrogenolysis of 3-
arylallylic carbonates in toluene at 60 oC under 1 atm. pressure
of H2.10 Chatterjee et al. reported the synthesis of allylarenes
by palladium catalyzed decarbonylative dehydration of 4-
b. Department of Chemistry, Umm Al-Qura University, Makkah, Saudi Arabia
c. Department of Biochemistry, All India Institute of Medical Sciences, Ansari Nagar,
New Delhi-110029, India
d. Indian Council of Medical Research, Ansari Nagar, New Delhi-110029
† Footnotes relating to the title and/or authors should appear here.
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
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arylbutanoic acid.11 Although excellent yield was observed, the reflux of obtained 2H-pyranone (3) with different secondary
View Article Online
DOI: 10.1039/D0OB01318H
requirement of transition metal catalyst and specific allyl amines in ethanol (see SI).
carbonate substrates limits the scope of this method. In 2-Oxo-4-(piperidin-1-yl)-6-(phenyl)-2H-pyran-3-carbonitrile
addition, most of the reported metal catalyzed protocols till (4a) and 5-hexene-2-one (5) was chosen as model substrates
date require special reaction conditions and expensive and for optimization of reaction condition to afford functionalized
toxic reagents to afford less hindered allylarenes. Herein, we allylarenes. We commenced the optimization by using KOH in
o
wish to report a transition metal free, base mediate ring DMF at 30 C and 58% of product 6a was obtained after 12
transformation strategy for the synthesis of highly hindered hours (Table 1, entry 1).
allylarenes from easily accessible suitably functionalized 2H-
pyran-2-ones and 5-hexene-2-one.
Scheme 2.Synthesis of various functionalized allylarenes 6.
R
R
O
CN
CN
O
LiOH, DMSO
30oC, 10 h
Result and discussion
Ar
Ar
O
Suitably functionalized 2H-pyran-2-ones and ketene
dithioacetals have been widely explored for the assembly of
several important moieties.12 Therefore, based on our past
research experience, we planned to synthesize 3-allyl-4-aryl-2-
methyl-6-(sec.amine)-benzonitriles (6) via 1,6-conjugate
addition of thermally stable enolate of 5-hexene-2-one (5) on
R = sec. amines
R
R
CN
CN
Table 1. Optimization of the reaction conditions 4a
6c
6c; R=Piperidin-1-yl; 71%
6d; R= Morpholin-1-yl; 75%
6a; R=Piperidin-1-yl; 74%
6b; R= Pyrrolidin-1-yl; 70%
N
N
O
CN
O
N
Base, Solvent
Temp., Time
CN
O
R
CN
R
O
CN
CN
O
6a
4a
5
X
O
Temp.(oC)
Time (h)
Yield
6h; R=Piperidin-1-yl; X = F; 61%
6i; R= Piperidin-1-yl; X = Br; 69%
6j; R=Morpholin-1-yl; X = NO2, 39%
Entry
Base
Solvent
(%)b
6e; R=Piperdin-1-yl; 72%
6f; R= Pyrrolidin-1-yl; 66%
6g; 55%
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
KOH
NaH
NaNH2
Cs2CO3
LiOH
NaOH
t-BuOK
LiOH
NaOH
LiOH
DMF
DMF
DMF
DMF
DMF
30
30
30
30
30
30
30
30
30
30
30
70
70
60
0
12
12
12
15
12
12
12
12
12
12
12
12
12
8
58
54
51
32c
67
61
59
74
65
N
N
N
CN
CN
CN
Br
DMF
DMF
Br
DMSO
DMSO
MeCN
THF
EtOH
EGe
6l; 59%
6m; 65%
6k; 63%
R
43
CN
N
LiOH
LiOH
LiOH
LiOH
34c
Mix.d
Mix.d
67
N
CN
CN
S
DMSO
DMSO
O
52c
6o; R=Piperidin-1-yl; 70%
6p; R=Pyrrolidin-1-yl; 68%
6q; R=Morpholin-1-yl;73%
LiOH
12
6r; 62%
6n; 67%
(a) All reactions were carried out by stirring 4a (0.5 mmol) and 5-hexen-1-one (5,
0.75 mmol, 1.5 equiv.); (b) Isolated yield after purification by column
chromatography; (c) Incomplete reaction; (d) Mix. stands for inseparable mixture
of several products and starting materials; (e) EG stands for Ethylene Glycol.
Further, several other bases were screened for the
optimization of reaction condition. Stronger bases NaH and
NaNH2 provided lower yield of desired product, while weaker
base like Cs2CO3 was not able to complete the reaction even in
15 hours (Table 1, entries 2-4). The reaction was further
carried out in DMF using NaOH, LiOH and t-BuOK as a base and
the combination of LiOH/DMF was found to be the best (Table
1, entries 5-7). Different solvents were also screened using
2-oxo-6-aryl-4-(sec.amino)-2H-pyran-3-carbonitriles
(4)
followed by intramolecular decarboxylative cyclization. The
required precursor 4 was synthesized by reaction of methyl 2-
cyano/carbomethoxy-3,3-bis(methylthio)acrylates (1) and aryl
methyl ketones (2) in DMSO under basic condition followed by
2 | J. Name., 2012, 00, 1-3
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LiOH as a base and DMSO was found as the best solvent carbomethoxy-6-aryl-4-methylsulfanyl-2H-pyran-2-ones, which
View Article Online
DOI: 10.1039/D0OB01318H
amongst them (Table 1, entry 8). Use of acetonitrile and THF resulted up to 44-57% yield of allylarenes (7e-f).
gives lower yield of the product (Table 1, entries 10-11). Other To explore the efficacy of present protocol, 3,4-disubstituted
solvents like ethanol and ethylene glycol were inefficient for 5,6-dihydro-2H-benzo[h]chromen-2-one (4s) were treated with
this reaction and inseparable mixture of several products 5-hexene-2-one. Surprisingly, two inseparable isomeric
formed (Table 1, entries 12-13). The structures of the products 8 (40%) and 9 (27%) were obtained. We proposed
compounds were confirmed by 1H and 13C NMR and mass that C-10b position of 4s is relatively more hindered due to
spectrometry data. Structure of compound 6c is also restricted rotation of bridge phenyl group, which reduce the
confirmed by single crystal X-ray.13
possibility of nucleophilic attack of larger nucleophile at C-10b
The substrate scope was explored and presented in scheme 2, position. Compound 5 can provides two enolates from either
where various 2H-pyran-2-ones 4 were efficiently converted side of carbon of carbonyl group and two different products
into desired products 6a-r in good yield. Synthesis of halide may be isolated with different chemoselectivity based on the
bearing allylarenes via regioselective cross coupling reaction is size of nucleophiles (1o versus 2o carbanion) and reaction
always an issue for synthetic chemists. However, we have condition. The polarity difference between products are not
successfully afforded halogen bearing allylarenes 6h, 6i, 6k and enough to separate them, however their structure and yield
6l in good yield without any difficulties. The halide group was were assigned by proton NMR of mixture (see ESI).
well tolerated under optimized reaction condition and Mechanistically, base could generate two carbanion 5a and 5b
complex allylarene can be afforded.
as kinetic and thermodynamic controlled enolates. If the
reaction is initiated by attack of thermodynamically stable
enolate (5b) at C-6/C-10b position of 2-pyranones/2H-
chromene-2-one (3 and 4), it forms new C-C bond though
Michael addition. This leads decarboxylative ring opening
followed by protonation to afford intermediate C. Further, in
presence of excess of base, intermediate C undergoes
intramolecular cyclization to afford D. At last, a base promoted
elimination of water provides aromatization to generate the
product 6.
Scheme 3. Synthesis of –SMe bearing allylarenes 7.
S
S
O
CN/COOMe
CN/COOMe
O
LiOH, DMSO
30 oC, 8 h
Ar
Ar
O
3
5
7
S
S
CN
CN
=
In case of 5,6-dihydro-2H-benzo[h]chromone 4s, the reaction
involves both kinetic as well as thermodynamic controlled
enolates (5a & 5b). When reaction is initiated from kinetically
controlled carbanion 5a, it provides intermediate A by Michael
O
7a, 44%
S
7b, 48%
S
S
CN
addition followed by decarboxylation. Intermediate
A
COOMe
COOMe
undergoes cyclization by involving C-3 of chromene-2-ones
and carbonyl carbon of ketone to afford intermediate B, which
produces the compound 9 after aromatization. The reaction of
4s and 5b results the product 8 by following the similar
reaction pathway as for 6a.
S
Br
7c, 45%
S
7d, 57%
7e, 54%
COOMe
S
Scheme
4.
Reaction
of
2-oxo-4-(piperidin-1-yl)-5,6-dihydro-2H-
benzo[h]chromene-3-carbonitrile (4s) with 5-hexene-2-one.
7f, 53%
N
N
N
O
CN
CN
O
CN
The electronic nature of aryl or heteroaryls group present at C-
6 of 2H-pyran-2-ones did not affect the yield of the product
significantly, while strong electron withdrawing group like –
NO2 (6j) significantly lower the yield. In addition, presence of
sterically hindered aryl group slightly lower the yield (entry 6g
and 6l), whereas different sec.amine substituents at C-4
position of the pyran ring had negligible effect on the yield.
This synthetic methodology shows great functional group
tolerance like amine, aryl, haloaryl and heteroaryl etc.
In the continuation, we also explored this method for the
synthesis of -SMe bearing allylarenes (7a-f) by using 4-
(methylthio)-2H-pyran-2-ones 3. Structure of compound 7a
was confirmed by single crystal X-ray.13 In addition, the
feasibility of the reaction was also examined with 3-
LiOH, DMSO
30 oC, 12 h
+
+
O
4s
5
8,
9,
27%
40%
These synthesized allylarenes contain different synthetically
important functional groups such as nitrile, ester, aromatic
halides and thiomethyl groups. These groups can be further
modified to attain other important products which are
demonstrated in scheme 7. An intramolecular Heck reaction of
6l
provided
84%
of
1,9-dimethyl-3-(piperidin-1-yl)-
phenanthrene-2-carbonitrile (10) in presence of Pd(OAc)2 and
Cs2CO3 in toluene. In order to, synthesize phenanthrene by
dehydrogenative coupling, compound 6d was treated with
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Pd(OAc)2, PhI(AcO)2 and K3PO4 in toluene at 60 oC for 12 hours was also reported by heating with alcoholic soVieluwtAiortincle oOfnlinte-
but this reaction provides isomerized product 3,4'-dimethyl-5- BuOK.14 As reported, treatment of alDlyOlaI:r1e0n.1e0396/dD0wOBit0h13118.H5
o
morpholino-2-(prop-1-en-1-yl)-[1,1'-biphenyl]-4-carbonitrile
equivalent of t-BuOK in t-BuOH for 12 hours at 90 C provides
(11) in excellent yield. Isomerization of allylarenes to styrenes
Scheme 5. Plausible mechanism for the synthesis of 6 and 9.
X
X
N
N
C
N
N
C
N
O
O
N
O
C
O
H
H
O
O
Ar
O
4
O
OH
HO
O
Ar
4s
5b
5a
5
O
-CO2
X
N
N
C
N
CN
O
O
Ar
H OH
O
H
O
-CO2
X
N
X
N
X
N
OH
N
CN
H OH
CN
H
CN
CN
H OH
Ar
Ar
Ar
O
H
O
OH
H
OH
C
6
D
OH
N
N
N
CN
H
CN
CN
H OH
OH
O
H
9
B
A
OH
isomerized analogous 11 in 78% yields. However, 4 equivalent observed selective oxidation of thioether to corresponding
o
of t-BuOK in t-BuOH at 110 C concurrently attack on nitrile sulfoxide to afford 2-allyl-5-methanesulfinyl-3-methyl-biaryls
group to convert them into corresponding amide (12a-b) in 13a-c in excellent yield.
good yield. The oxidation of thioethers and alkene to
corresponding sulfoxides and epoxides are well known with m-
Scheme 6. Synthetic utility of multi-substituted allylarenes
CPBA. H2O2 was often used for selective oxidation of thioethers
in presence of C-C double bond.15 However, the
chemoselectivity of m-CPBA in presence of both functional
group thioether and alkene were unmapped. Herein, we
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Cyclization and aromatization
bond interactions with His524, and Leu525 and 7d is stabilized
with three H-bond interactions with His475, Leu476, and
View Article Online
DOI: 10.1039/D0OB01318H
Thr299. Along with these interactions, the Phe404 and Phe356
established π-π interaction with thienyl ring of 7f at the 3.2 Å
and 2.9 Å distance, while Phe404 and Phe356 stacked against
N
N
Pd(OAc)2 (0.05 equiv.)
Cs2CO3 (1.2 equiv.)
CN
CN
Br
toluene
90 oC, 12 h
10, 84%
6l
Isomerisation
O
N
Method A
O
Pd(OAc)2 (0.05 equiv.),
PhI(AcO)2 (1.2 equiv.),
K3PO4 (1.2 equiv.),
toluene, 60 oC, 12 h.
N
CN
CN
Method B
t-BuOK (1.5 equiv.),
t-BuOH, 90 oC, 12 h
11
6d
Method A - 95%;
Method B- 78%
Amidation and isomerisation
N
O
N
t-BuOH (4 equiv.)
t-BuOH
CN
NH2
Figure 1. Docking analysis into ERα and ERβ: (A) docking of 7f (pink) into ERα; (B)
docking of 7f (pink) into ERβ; (C) docking of 7d (green) into ERα; (D) docking of
7d (green) into ERβ. The residues are shown with sticks and compound 7f and 7d
is shown in ball and stick model. Hydrogen bonds are shown as broken lines
(red).
110 oC, 24 h.
Ar
Ar
12a
12b
; Ar = 4-Br.C6H4; 71%
; Ar = 2-thienyl; 74%
phenyl ring of 7d showing favourable π-π interaction at 3.1 Å
and 2.7Å in ERα and ERβ respectively (Figure. 1). Binding site
residues Thr347, Ala350, Glu353, Arg394, Phe404, Met421,
Phe425, Gly521, His524 and Leu525 are involved in
hydrophobic interactions with active compounds in ERα and
Thr299, Ala302, Glu305, Arg346, Phe356, Met294, Phe377,
Gly472, His475 and Leu476 are involve in ERβ respectively.
The in silico study confirm that compound 7f and 7d are
strongly interacting and shows the same interactions in the
binding sites with significant binding affinities for both ERs
subtypes. These results suggest that these molecules may be
further studied as estrogen receptor alpha (ERα) and estrogen
receptor beta (ERβ). These molecules are under investigation
for further results.
Selective oxidation of thioether
O
S
S
R"
R"
m-CPBA (1.5 equiv.),
Ar
Ar
DCM,
30 oC, 4 h
13a;
13b;
13c;
Ar = C6H5; Y = CN; 98%
Ar = 4-OMe.C6H5; Y = CN; 96%
Ar = 2-thienyl; Y = COOMe; 93%
These class of compounds known to exhibit the estrogen
receptor alpha (ERα) and estrogen receptor beta (ERβ) binding
affinity depending on the substitution pattern.16,17
Molecular docking methods are mainly applied to predict the
binding affinity between the ligand and target protein through
the identification of precise conformation of ligands in the
binding pocket of any protein.18
Conclusions
A simple, base mediate strategy was developed for the
synthesis of highly functionalized sterically hindered
allylarenes by ring transformation of 2-oxo-6-aryl-4-
To elucidate the binding mechanism of newly synthesized
compounds with ERα (PDB ID: 2I0J) and ERβ (PDB ID: 2I0G), a
molecular docking simulation was performed using GLIDE
module. The binding interaction of most active compound 7f
and 7d showed that both fits well in the binding pockets of
crystal structures of ER subtypes. The results clearly indicate
that the compounds 7f and 7d exhibited significant binding
affinities towards ERα (Glide energy -55.11 kcal mol-1 and -
52.21 kcal mol-1) and ERβ (Glide energy -58.95 kcal mol-1 and -
57.14 kcal mol-1) respectively (see SI; Table S2). The best
binding mode of 7f in the binding site is stabilized with two H-
(methylthio/sec.amino)-2H-pyran-3-carbonitriles
with
5-
hexene-2-one. Interestingly, ring transformation of 2-oxo-5,6-
dihydro-2H-benzo[h]chromene-3-carbonitrile with 5-hexene-2-
one provides mixture of allylated 9,10-dihydrophenanthrene
and (but-3-en-1-yl)-9,10-dihydrophenanthrene under the
similar reaction conditions. These reactions suggest that
reactivity of 5-hexene-2-one is also dependent on the nature
of substrates used. This reaction had very good functional
group tolerance, which is limitation for metal catalyzed
approaches. In addition, this method is superior over other
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methods as sterically hindered allylarenes are afforded under 26.2, 24.1, 18.4; IR (cm-1): 2932, 2856, 2807, 2217 (CN), 1642,
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+
mild reaction conditions. The synthesized compounds have 1588, 1454, 997, 916; Calculated MaDssOI:(M10.+10H3)9:/D30O17B0.21301182H,
further synthetic potential and explored to achieve other Observed Mass for (C22H25N2)+: 317.2001.
important molecules. We have successfully achieved the
functionalized phenanthrenes by intramolecular Heck 6b.
2-Allyl-3-methyl-5-(pyrrolidin-1-yl)-[1,1'-biphenyl]-4-
cyclization. Other functional group modification was also carbonitrile:Yield: 70%; 0.35 Rf (5% ethylacetate in hexane),
carried out successfully, which enhances the importance of Cream coloured solid; mp. 100-102 oC;1H-NMR (400 MHz,
synthesized molecules.
CDCl3) δ 7.39 (dd, J = 11.9, 5.2 Hz, 3H, Ar-H), 7.29 (dd, J = 5.4,
We also performed the molecular docking study of synthesized 2.1 Hz, 2H, Ar-H), 6.45 (s, 1H, Ar-H), 5.83 (dq, J = 22.3, 5.2 Hz,
molecules and found that they exhibit good estrogen receptor 1H, -C=C-H), 5.03 (dd, J = 10.2, 1.2 Hz, 1H, -C=C-H), 4.78 (dd, J =
alpha (ERα) and estrogen receptor beta (ERβ) binding affinity.
17.2, 1.5 Hz, 1H, -C=C-H), 3.60 (t, J = 6.4 Hz, 4H, -CH2), 3.20 (t, J
= 2.5 Hz, 2H, -CH2), 2.51 (s, 3H, -CH3), 2.00-1.97 (m, 4H, -CH2);
13C-NMR (100 MHz, CDCl3) δ 149.5, 147.8, 142.9, 141.7, 136.6,
128.7, 128.4, 127.9, 127.2, 123.7, 120.3, 115.1, 113.5, 96.6,
50.2, 33.7, 25.7, 18.4; IR (cm-1): 2925, 2857, 2211 (CN), 1718,
1594, 1462, 1027, 915; Calculated Mass (M+H)+: 303.1856,
Observed Mass for (C21H23N2)+: 303.1876.
Experimental
General
We used commercially available reagents and solvents from
Alfa Aesar, Spectrochem, Sigma Aldrich, Fischer Scientific and
6c. 2-Allyl-3,4'-dimethyl-5-(piperidin-1-yl)-[1,1'-biphenyl]-4-
carbonitrile: Yield: 71%; 0.35 Rf (5% ethylacetate in hexane),
Cream coloured solid; mp. 90-92 oC; 1H-NMR (400 MHz, CDCl3)
δ 7.20 (d, J = 8.2 Hz, 2H, Ar-H), 7.16 (d, J = 8.2 Hz, 2H, Ar-H),
6.72 (s, 1H, Ar-H), 5.88-5.78 (m, 1H, -C=C-H), 5.04 (dd, J = 10.1,
1.8 Hz, 1H, -C=C-H), 4.76 (dd, J = 17.2, 1.6 Hz, 1H, -C=C-H), 3.24
(d, J = 5.0 Hz, 2H, -CH2), 3.10 (t, J = 5.3 Hz, 4H, -CH2), 2.51 (s,
3H, -CH3), 2.40 (s, 3H, -CH3), 1.80-1.74 (m, 4H, -CH2), 1.57 (t, J =
5.5 Hz, 2H, -CH2); 13C-NMR (100 MHz, CDCl3) δ 155.4, 147.8,
142.8, 138.5, 137.3, 136.3, 129.1, 128.7, 128.4, 118.3, 118.1,
115.6, 107.1, 53.5, 34.0, 26.2, 24.1, 21.2, 18.4; IR (cm-1): 2931,
2858, 2216 (CN), 1638, 1590, 1456, 1003, 915; Calculated Mass
(M+H)+: 331.2169, Observed Mass for (C23H27N2)+: 331.2167.
1
TCI without any further purification. H and 13C NMR spectra
were recorded by using a 400 MHz and 100 MHz NMR
spectrometer respectively, and CDCl3 (from Eurisotop) was
used as solvent. Chemical shifts for all the compounds are
reported in parts per million (ppm). One singlet at δ 7.26 ppm
1
of H and a triplet at 77.00 ppm of 13C NMR for CDCl3 were
taken as an internal standard. Signal patterns are mentioned
as s, singlet; d, doublet; dd, double doublet; t, triplet; m,
multiplet; bs, broad singlet and bm, broad multiplet. Coupling
constant (J) for protons are reported in hertz (Hz). Infrared (IR)
spectra was recorded on
a
Perkine Elmer AX-1
spectrophotometer and reported in wave number (cm-1).
HRMS of compounds are reported as (M+H)+ using Agilent
G6530AA (LC-HRMS-Q-TOF) spectrometer. The yields of the
products are reported after chromatographic purification.
6d.
2-Allyl-3,4'-dimethyl-5-morpholino-[1,1'-biphenyl]-4-
carbonitrile: Yield: 75%; 0.25 Rf (5% ethylacetate in hexane),
Cream coloured solid; mp. 108-110 oC; 1H-NMR (400 MHz,
CDCl3) δ 7.21 (d, J = 7.8 Hz, 2H, Ar-H), 7.16 (d, J = 8.2 Hz, 2H,
Ar-H), 6.73 (s, 1H, Ar-H), 5.88-5.78 (m, 1H, -C=C-H), 5.05 (dd, J
= 10.1, 1.8 Hz, 1H, -C=C-H), 4.76 (dd, J = 16.9, 1.8 Hz, 1H, -C=C-
H), 3.90 (t, J = 4.6 Hz, 4H, -CH2), 3.26 (td, J = 3.7, 1.5 Hz, 2H, -
CH2), 3.16 (t, J = 4.6 Hz, 4H, -CH2), 2.53 (s, 3H, -CH3), 2.41 (s,
3H, -CH3); 13C-NMR (100 MHz, CDCl3) δ 153.8, 148.1, 143.2,
138.2, 137.5, 136.0, 130.2, 128.8, 128.3, 127.1, 118.2, 115.7,
107.1, 67.0, 52.2, 34.0, 21.2, 18.5; IR (cm-1): 2921, 2857, 2217
(CN), 1636, 1590, 1449, 1008, 921; Calculated Mass (M+H)+:
333.1961, Observed Mass for (C22H25N2O)+: 333.1959.
General protocol for the synthesis of allylarenes (6a-r)
To a vacuum dried screw capped vial, a mixture of 6-aryl-3-
cyano-4-sec.amino-2H-pyran-2-ones (4; 0.5 mmol) and 5-
o
hexen-2-one (5; 0.6 mmol) was stirred at 30 C in presence of
powdered LiOH (1.0 mmol) in DMSO (4 mL). TLC was used to
monitor the completion of reaction. After completion of
reaction, mixture was poured onto crushed ice water with
constant stirring followed by neutralization with 10% solution
of HCl. The crude solid obtained was filtered, dried and
purified by silica gel column chromatography using
ethylacetate/hexane (1:19) as an eluent.
6e.
2-Allyl-4'-methoxy-3-methyl-5-(piperidin-1-yl)-[1,1'-
biphenyl]-4-carbonitrile: Yield: 72%; 0.30 Rf (5% ethylacetate
in hexane), Cream coloured solid; mp. 108-110 oC; 1H-NMR
(400 MHz, CDCl3) δ 7.20 (d, J = 8.2 Hz, 2H, Ar-H), 6.92 (d, J = 8.2
Hz, 2H, Ar-H), 6.72 (s, 1H, Ar-H), 5.89-5.78 (m, 1H, -C=C-H),
5.04 (dd, J = 10.3, 1.6 Hz, 1H, -C=C-H), 4.76 (dd, J = 16.9, 1.8 Hz,
1H, -C=C-H), 3.85 (s, 3H, -CH3), 3.25 (t, J = 2.5 Hz, 2H, -CH2),
3.10 (t, J = 5.3 Hz, 4H, -CH2), 2.51 (s, 3H, -CH3), 1.80-1.75 (m,
4H, -CH2), 1.60-1.55 (m, 2H, -CH2); 13C-NMR (100 MHz, CDCl3) δ
159.1, 155.4, 147.5, 142.8, 136.3, 133.8, 131.2, 130.2, 129.7,
129.2, 118.4, 118.1, 115.6, 113.5, 107.0, 55.3, 53.5, 34.0, 26.2,
6a.
2-Allyl-3-methyl-5-(piperidin-1-yl)-[1,1'-biphenyl]-4-
carbonitrile: Yield: 74%; 0.35 Rf (5% ethylacetate in hexane),
Cream coloured solid; mp. 96-98 oC; 1H-NMR (400 MHz, CDCl3)
δ 7.41-7.35 (m, 3H, Ar-H), 7.27 (d, J = 5.3 Hz, 2H, Ar-H), 6.73 (s,
1H, Ar-H), 5.82 (dq, J = 10.9, 5.5 Hz, 1H, -C=C-H), 5.03 (d, J = 9.9
Hz, 1H, -C=C-H), 4.75 (d, J = 17.5 Hz, 1H, -C=C-H), 3.23 (d, J =
3.8 Hz, 2H, -CH2), 3.11 (t, J = 5.0 Hz, 4H, -CH2), 2.52 (s, 3H, -
CH3), 1.78 (t, J = 5.0 Hz, 4H, -CH2), 1.58 (s, 2H, -CH2); 13C-NMR
(100 MHz, CDCl3) δ 155.4, 147.7, 142.9, 141.4, 136.2, 129.0,
128.5, 128.0, 127.5, 118.2, 118.1, 115.6, 107.2, 53.5, 34.0,
6 | J. Name., 2012, 00, 1-3
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24.1, 18.5; IR (cm-1): 2926, 2856, 2210 (CN), 1741, 1602, 1464, 140.3, 136.0, 131.2, 130.2, 128.7, 121.8, 118.0, 117.9, 115.8,
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-1
1034, 926; Calculated Mass (M+H)+: 347.2118, Observed Mass 107.6, 53.5, 33.9, 26.2, 24.1, 18.4; IR (cm ): 2934, 2856, 2217
DOI: 10.1039/D0OB01318H
for (C23H27N2O)+: 347.2117.
(CN), 1730, 1641, 1594, 1455, 1008, 918; Calculated Mass
(M+H)+: 395.1117, Observed Mass for (C22H24BrN2)+: 395. 1119.
6f. 2-Allyl-4'-methoxy-3-methyl-5-(pyrrolidin-1-yl)-[1,1'-
biphenyl]-4-carbonitrile: Yield: 66%; 0.30 Rf (5% ethylacetate 6j. 2-Allyl-3-methyl-5-morpholino-4'-nitro-[1,1'-biphenyl]-4-
in hexane), Cream coloured solid; mp. 110-112 oC; 1H-NMR carbonitrile: Yield: 39%; 0.30 Rf (5% ethylacetate in hexane),
(400 MHz, CDCl3) δ 7.21 (d, J = 8.8 Hz, 2H, Ar-H), 6.91 (d, J = 8.7 Cream coloured solid; mp. 162-164 oC; 1H-NMR (400 MHz,
Hz, 2H, Ar-H), 6.41 (s, 1H, Ar-H), 5.88-5.79 (m, 1H, -C=C-H), CDCl3) δ 8.63 (d, J = 8.8 Hz, 2H, Ar-H), 7.82 (d, J = 8.8 Hz, 2H,
5.02 (dd, J = 10.2, 1.8 Hz, 1H, -C=C-H), 4.77 (dd, J = 17.2, 1.9 Hz, Ar-H), 7.05 (s, 1H, Ar-H), 6.23-6.14 (m, 1H, -C=C-H), 5.45 (dd, J
1H, -C=C-H), 3.85 (s, 3H, -CH3), 3.57 (t, J = 6.6 Hz, 4H, -CH2), = 10.2, 1.5 Hz, 1H, -C=C-H), 5.08 (dd, J = 17.2, 1.5 Hz, 1H, -C=C-
3.20 (dd, J = 3.2, 2.1 Hz, 2H, -CH2), 2.48 (s, 3H, -CH3), 1.99-1.96 H), 4.26 (t, J = 4.6 Hz, 4H, -CH2), 3.56-3.53 (m, 6H, -CH2), 2.90
(m, 4H, -CH2); 13C-NMR (100 MHz, CDCl3) δ 158.9, 149.7, 147.5, (s, 3H, -CH3); 13C-NMR (100 MHz, CDCl3) δ 154.0, 147.7, 147.4,
143.0, 136.8, 134.2, 129.6, 124.1, 120.4, 115.2, 113.8, 113.3, 145.6, 143.8, 135.4, 129.5, 123.4, 117.4, 116.3, 108.2, 66.9,
96.5, 55.3, 50.2, 33.8, 25.8, 18.5; IR (cm-1): 2931, 2856, 2217 52.0, 33.9, 18.4; IR (cm-1): 2927, 2858, 2221 (CN), 1744, 1593,
(CN), 1713, 1598, 1459, 1021, 918; Calculated Mass (M+H)+: 1457, 991, 922; Calculated Mass (M+H)+: 364.1656, Observed
333.1961, Observed Mass for (C22H25N2O)+: 333.1949.
Mass for (C21H22N3O3)+: 364.1667.
6g. 2-Allyl-2'-methoxy-3-methyl-5-morpholino-[1,1'- 6k.
2-Allyl-3'-bromo-3-methyl-5-(pyrrolidin-1-yl)-[1,1'-
biphenyl]-4-carbonitrile: Yield: 55%; 0.30 Rf (5% ethylacetate biphenyl]-4-carbonitrile: Yield: 63%; 0.35 Rf (5% ethylacetate
in hexane), Cream coloured solid; mp. 122-124 oC; 1H-NMR in hexane), Cream coloured solid; mp. 126-128 oC; 1H-NMR
(400 MHz, CDCl3) δ 7.40-7.35 (m, 1H, Ar-H), 7.08 (dd, J = 7.4, (400 MHz, CDCl3) δ 7.50-7.47 (m, 1H, Ar-H), 7.42 (t, J = 1.6 Hz,
1.8 Hz, 1H, Ar-H), 7.02-6.96 (m, 2H, Ar-H), 6.71 (s, 1H, Ar-H), 1H, Ar-H), 7.26-7.22 (m, 1H, Ar-H), 7.20 (dt, J = 7.6, 1.4 Hz, 1H,
5.72-5.62 (m, 1H, -C=C-H), 4.93 (dd, J = 10.2, 1.6 Hz, 1H, -C=C- Ar-H), 6.36 (s, 1H, Ar-H), 5.85-5.76 (m, 1H, -C=C-H), 5.03 (dd, J
H), 4.73 (dd, J = 17.2, 1.8 Hz, 1H, -C=C-H), 3.89 (t, J = 4.5 Hz, 4H, = 10.2, 1.7 Hz, 1H, -C=C-H), 4.74 (dd, J = 17.2, 1.8 Hz, 1H, -C=C-
-CH2), 3.74 (s, 3H, -CH3), 3.25-3.09 (m, 6H, -CH2), 2.54 (s, 3H, - H), 3.57 (t, J = 6.5 Hz, 4H, -CH2), 3.15 (dd, J = 3.0, 2.1 Hz, 2H, -
CH3); 13C-NMR (100 MHz, CDCl3) δ 155.9, 153.7, 144.6, 142.6, CH2), 2.47 (s, 3H, -CH3), 1.99-1.96 (m, 4H, -CH2); 13C-NMR (100
135.5, 131.4, 130.4, 129.6, 129.3, 120.3, 118.4, 117.9, 115.3, MHz, CDCl3) δ 149.6, 146.2, 143.8, 143.3, 136.4, 131.5, 130.4,
110.7, 107.3, 67.3, 55.3, 52.1, 34.3, 18.4; IR (cm-1) : 2926, 2857, 129.5, 127.1, 123.5, 122.0, 120.2, 115.4, 113.4, 97.0, 50.3,
2216 (CN), 1735, 1591, 1459, 1018, 921; Calculated Mass 33.7, 25.8, 18.5; IR (cm-1): 2927, 2857, 2212 (CN), 1726, 1594,
(M+H)+: 349.1911, Observed Mass for (C22H25N2O2)+: 349.1913. 1465, 995, 919; Calculated Mass (M+H)+: 381.0961, Observed
Mass for (C21H22BrN2)+: 381.0960.
6h.
2-Allyl-4'-fluoro-3-methyl-5-(piperidin-1-yl)-[1,1'-
biphenyl]-4-carbonitrile: Yield: 61%; 0.30 Rf (5% ethylacetate 6l.
2-Allyl-2'-bromo-3-methyl-5-(piperidin-1-yl)-[1,1'-
in hexane), Cream coloured solid; mp. 158-160 oC; 1H-NMR biphenyl]-4-carbonitrile: Yield: 59%; 0.35 Rf (5% ethylacetate
(400 MHz, CDCl3) δ 7.23 (dd, J = 8.2, 5.5 Hz, 2H, Ar-H), 7.08 (t, J in hexane), Cream coloured solid; mp. 114-116 oC; 1H-NMR
= 8.7 Hz, 2H, Ar-H), 6.69 (s, 1H, Ar-H), 5.82 (dq, J = 22.4, 5.2 Hz, (400 MHz, CDCl3) δ 7.65 (d, J = 7.8 Hz, 1H, Ar-H), 7.33 (t, J = 7.6
1H, -C=C-H), 5.04 (d, J = 9.2 Hz, 1H, -C=C-H), 4.74 (d, J = 17.4 Hz, 1H, Ar-H), 7.24 (t, J = 6.9 Hz, 1H, Ar-H), 7.18 (d, J = 7.3 Hz,
Hz, 1H, -C=C-H), 3.21 (t, J = 2.5 Hz, 2H, -CH2), 3.11 (t, J = 5.3 Hz, 1H, Ar-H), 6.64 (s, 1H, Ar-H), 5.67 (d, J = 6.0 Hz, 1H, -C=C-H),
4H, -CH2), 2.51 (s, 3H, -CH3), 1.81-1.75 (m, 4H, -CH2), 1.61-1.55 4.94 (d, J = 10.1 Hz, 1H, -C=C-H), 4.70 (d, J = 16.9 Hz, 1H, -C=C-
(m, 2H, -CH2); 13C-NMR (100 MHz, CDCl3) δ 163.4 & 160.9 (J = H), 3.24 (dd, J = 16.3, 5.7 Hz, 1H, -CH2), 3.10 (q, J = 5.5 Hz, 4H, -
245.3 Hz), 155.3, 146.6, 142.9, 137.2 & 137.2 (J = 2.8 Hz), CH2), 3.01 (dd, J = 16.5, 5.5 Hz, 1H, -CH2), 2.53 (s, 3H, -CH3),
136.0, 130.1 & 130.0 (J = 8.6 Hz), 128.9, 118.2, 117.9, 115.6 1.77 (q, J = 5.6 Hz, 4H, -CH2), 1.60-1.56 (m, 2H, -CH2); 13C-NMR
&115.0 (J = 65.1 Hz), 114.8, 107.3, 53.4, 33.8, 26.1, 24.0, 18.3; (100 MHz, CDCl3) δ 155.4, 146.1, 142.8, 141.7, 135.2, 132.6,
IR (cm-1) : 2933, 2856, 2218 (CN), 1738, 1595, 1455, 1228, 130.5, 129.3, 129.2, 127.0, 123.0, 118.1, 117.9, 115.6, 107.8,
1001, 918; Calculated Mass (M+H)+: 335.1918, Observed Mass 53.5, 34.1, 26.2, 24.1, 18.4; IR (cm-1): 2932, 2856, 2219 (CN),
for (C22H24FN2)+: 335.1948.
1738, 1590, 1452, 1034, 916; Calculated Mass (M+H)+:
395.1117, Observed Mass for (C22H24BrN2)+: 395.1115.
6i.
biphenyl]-4-carbonitrile: Yield: 69%; 0.35 Rf (5% ethylacetate 6m.
in hexane), Cream coloured solid; mp. 136-138 oC; 1H-NMR yl)benzonitrile: Yield: 65%; 0.35 Rf (5% ethylacetate in
2-Allyl-4'-bromo-3-methyl-5-(piperidin-1-yl)-[1,1'-
3-Allyl-2-methyl-4-(naphthalen-2-yl)-6-(piperidin-1-
o
1
(400 MHz, CDCl3) δ 7.52 (d, J = 8.2 Hz, 2H, Ar-H), 7.14 (d, J = 8.2 hexane), Cream coloured solid; mp. 154-156 C; H-NMR (400
Hz, 2H, Ar-H), 6.67 (s, 1H, Ar-H), 5.86-5.77 (m, 1H, -C=C-H), MHz, CDCl3) δ 7.91-7.84 (m, 3H, Ar-H), 7.76 (s, 1H, Ar-H), 7.54-
5.04 (dd, J = 10.1, 1.8 Hz, 1H, -C=C-H), 4.73 (dd, J = 17.2, 1.6 Hz, 7.52 (m, 2H, Ar-H), 7.42 (dd, J = 8.4, 1.6 Hz, 1H, Ar-H), 6.83 (s,
1H, -C=C-H), 3.21-3.19 (m, 2H, -CH2), 3.10 (t, J = 5.5 Hz, 4H, - 1H, Ar-H), 5.90-5.80 (m, 1H, -C=C-H), 5.08 (dd, J = 10.2, 1.7 Hz,
CH2), 2.51 (s, 3H, -CH3), 1.80-1.75 (m, 4H, -CH2), 1.61-1.55 (m, 1H, -C=C-H), 4.81 (dd, J = 17.2, 1.6 Hz, 1H, -C=C-H), 3.28 (dd, J =
2H, -CH2); 13C-NMR (100 MHz, CDCl3) δ 155.5, 146.4, 143.1, 3.3, 2.1 Hz, 2H, -CH2), 3.14 (t, J = 5.4 Hz, 4H, -CH2), 2.56 (s, 3H, -
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CH3), 1.83-1.77 (m, 4H, -CH2), 1.62-1.56 (m, 2H, -CH2); 13C-NMR 1H, -C=C-H), 3.90 (t, J = 4.5 Hz, 4H, -CH2), 3.40 (t, JV=iew2A.5rticHlezO, n2liHne,
13
(100 MHz, CDCl3) δ 155.4, 147.6, 142.9, 138.9, 136.1, 132.9, -CH2), 3.17 (t, J = 4.5 Hz, 4H, -CH2), 2.53 D(sO,I3: 1H0,.1-0C3H9/3D);0OBC0-1N3M18HR
132.5, 129.1, 128.0, 127.7, 127.6, 127.2, 126.8, 126.4, 126.2, (100 MHz, CDCl3) δ 153.6, 143.6, 141.5, 140.2, 136.0, 130.8,
118.4, 118.1, 115.7, 107.3, 53.5, 34.1, 26.2, 24.0, 18.4; IR (cm- 127.2, 127.0, 126.1, 119.0, 117.6, 115.9, 107.7, 66.9, 52.0,
1) : 2925, 2854, 2215 (CN), 1741, 1587, 1453, 997, 913; 34.1, 18.5; IR (cm-1): 2926, 2857, 2216 (CN), 1630, 1590, 1470,
Calculated Mass (M+H)+: 367.2169, Observed Mass for 1009, 920; Calculated Mass (M+H)+: 325.1369, Observed Mass
(C26H27N2)+: 367.2169.
for (C19H21N2OS)+: 325.1383.
6n. 3-Allyl-4-(furan-2-yl)-2-methyl-6-(piperidin-1- 6r. 2-Allyl-3,6-dimethyl-5-(piperidin-1-yl)-[1,1'-biphenyl]-4-
yl)benzonitrile: Yield: 67%; 0.35 Rf (5% ethylacetate in carbonitrile: Yield: 62%; 0.40 Rf (5% ethylacetate in hexane),
hexane), Cream coloured solid; mp. 96-98 oC; 1H-NMR (400 Cream coloured solid; mp. 118-120 oC; 1H-NMR (400 MHz,
MHz, CDCl3) δ 7.52 (d, J = 1.8 Hz, 1H, Ar-H), 7.15 (s, 1H, Ar-H), CDCl3) δ 7.42-7.35 (m, 3H, Ar-H), 7.06-7.04 (m, 2H, Ar-H), 5.72-
6.62 (d, J = 3.4 Hz, 1H, Ar-H), 6.48 (q, J = 1.7 Hz, 1H, Ar-H), 5.62 (m, 1H, -C=C-H), 4.94 (dd, J = 10.2, 1.7 Hz, 1H, -C=C-H),
6.04-5.94 (m, 1H, -C=C-H), 5.09 (dd, J = 10.3, 1.8 Hz, 1H, -C=C- 4.67 (dd, J = 17.2, 1.8 Hz, 1H, -C=C-H), 3.35 (s, 2H, -CH2), 3.06
H), 4.83 (dd, J = 17.2, 1.7 Hz, 1H, -C=C-H), 3.51-3.49 (m, 2H, - (td, J = 3.6, 1.7 Hz, 4H, -CH2), 2.47 (s, 3H, -CH3), 1.90 (s, 3H, -
CH2), 3.13 (t, J = 5.4 Hz, 4H, -CH2), 2.51 (s, 3H, -CH3), 1.81-1.76 CH3), 1.73-1.59 (m, 6H, -CH2); 13C-NMR (100 MHz, CDCl3) δ
(m, 4H, -CH2), 1.60 (td, J = 11.9, 5.9 Hz, 2H, -CH2); 13C-NMR 152.9, 148.1, 140.6, 139.4, 135.6, 133.3, 132.5, 128.4, 128.3,
(100 MHz, CDCl3) δ 155.5, 152.0, 143.3, 142.7, 135.4, 128.0, 127.1, 118.7, 115.4, 110.7, 51.7, 35.0, 26.9, 24.2, 17.8, 16.5; IR
117.9, 117.2, 116.0, 115.8, 111.5, 110.2, 107.5, 53.4, 34.0, (cm-1): 2928, 2855, 2219 (CN), 1563, 1445, 1025, 916;
26.1, 24.0, 18.3; IR (cm-1): 2931, 2857, 2217 (CN), 1733, 1595, Calculated Mass (M+H)+: 331.2169, Observed Mass for
1456, 998, 919; Calculated Mass (M+H)+: 307.1805, Observed (C23H27N2)+ : 331.2181.
Mass for (C20H23N2O)+: 307.1820.
General protocol for the synthesis of methylthio substituted
6o.
3-Allyl-2-methyl-6-(piperidin-1-yl)-4-(thiophen-2- allylarenes (7a-f): A mixture of 6-aryl-4-(methylthio)-2-oxo-2H-
yl)benzonitrile: Yield: 70%; 0.35 Rf (5% ethylacetate in pyran-3-carbonitrile (3; 0.5 mmol) and 5-hexen-2-ones (5; 0.75
o
hexane), Cream coloured solid; mp. 92-94 oC; 1H-NMR (400 mmol) was stirred at 30 C in presence of powdered LiOH (1.0
MHz, CDCl3) δ 7.36 (d, J = 4.6 Hz, 1H, Ar-H), 7.06 (t, J = 4.1 Hz, mmol) In DMSO (4 mL). TLC was used to monitor the
2H, Ar-H), 6.89 (s, 1H, Ar-H), 5.93 (dq, J = 22.1, 5.1 Hz, 1H, - completion of reaction. After completion of reaction, mixture
C=C-H), 5.09 (d, J = 10.1 Hz, 1H, -C=C-H), 4.79 (d, J = 17.4 Hz, was poured onto crushed ice with constant stirring and
1H, -C=C-H), 3.39 (t, J = 2.5 Hz, 2H, -CH2), 3.12 (t, J = 5.3 Hz, 4H, neutralized with 10% solution of HCl. Obtained solid
-CH2), 2.51 (s, 3H, -CH3), 1.81-1.75 (m, 4H, -CH2), 1.62-1.56 (m, precipitate was filtered, dried and purified by silica gel column
2H, -CH2); 13C-NMR (100 MHz, CDCl3) δ 155.3, 143.2, 142.0, chromatography using ethyl acetate/hexane (1:19) as an
139.9, 136.2, 129.7, 127.1, 126.9, 125.9, 119.2, 117.9, 115.8, eluent.
107.8, 53.4, 34.1, 26.2, 24.1, 18.5; IR (cm-1): 2932, 2854, 2216
(CN), 1639, 1587, 1447, 996, 918; Calculated Mass (M+H)+: 7a.
323.1576, Observed Mass for (C20H23N2S)+: 323.1584.
2-Allyl-3-methyl-5-(methylthio)-[1,1'-biphenyl]-4-
carbonitrile: Yield: 44%; 0.40 Rf (5% ethylacetate in hexane),
Cream coloured solid; mp. 84-86 oC; 1H-NMR (400 MHz, CDCl3)
6p.
3-Allyl-2-methyl-6-(pyrrolidin-1-yl)-4-(thiophen-2- δ 7.42-7.38 (m, 3H, Ar-H), 7.27-7.24 (m, 2H, Ar-H), 6.99 (s, 1H,
yl)benzonitrile: Yield: 68%; 0.35 Rf (5% ethylacetate in Ar-H), 5.86-5.76 (m, 1H, -C=C-H), 5.05 (dd, J = 10.3, 1.6 Hz, 1H,
hexane), Cream coloured solid; mp. 92-94 oC; 1H-NMR (400 -C=C-H), 4.73 (dd, J = 17.3, 1.6 Hz, 1H, -C=C-H), 3.26-3.24 (m,
MHz, CDCl3) δ 7.24 (d, J = 5.0 Hz, 1H, Ar-H), 6.99-6.95 (m, 2H, 2H, -CH2), 2.53 (s, 3H, - CH3), 2.50 (s, 3H, -CH3); 13C-NMR (100
Ar-H), 6.52 (s, 1H, Ar-H), 5.83 (dq, J = 22.3, 5.1 Hz, 1H, -C=C-H), MHz, CDCl3) δ 147.4, 142.8, 140.8, 140.6, 135.5, 133.0, 128.4,
4.98 (dd, J = 10.3, 1.6 Hz, 1H, -C=C-H), 4.72 (dd, J = 17.2, 1.6 Hz, 128.2, 127.8, 125.3, 116.6, 116.0, 111.8, 34.1, 18.4, 15.8; IR
1H, -C=C-H), 3.50 (t, J = 6.6 Hz, 4H, -CH2), 3.25 (t, J = 2.5 Hz, 2H, (cm-1): 2926, 2858, 2219 (CN), 1736, 1645, 1588, 1451, 1035,
- CH2), 2.41 (s, 3H, -CH3), 1.92-1.87 (m, 4H, -CH2); 13C-NMR (100 919; Calculated Mass (M+H)+: 280.1154, Observed Mass for
MHz, CDCl3) δ 149.5, 143.4, 142.4, 139.9, 136.8, 127.0, 126.7, (C18H18NS)+: 280.1155.
125.6, 124.4, 120.2, 115.4, 114.6, 97.2, 50.3, 33.9, 25.8, 18.6;
IR (cm-1): 2924, 2854, 2206 (CN), 1739, 1590, 1446, 996, 916; 7b.
2-Allyl-4'-methoxy-3-methyl-5-(methylthio)-[1,1'-
Calculated Mass (M+H)+: 309.1420, Observed Mass for biphenyl]-4-carbonitrile: Yield: 48%; 0.40 Rf (5% ethylacetate
o
1
(C19H21N2S)+: 309.1420.
in hexane), Cream coloured solid; mp. 94-96 C; H-NMR (400
MHz, CDCl3) δ 7.21 (d, J = 8.8 Hz, 2H, Ar-H), 7.00 (s, 1H, Ar-H),
6q.
3-Allyl-2-methyl-6-morpholino-4-(thiophen-2- 6.94 (d, J = 8.8 Hz, 2H, Ar-H), 5.90-5.80 (m, 1H, -C=C-H), 5.07
yl)benzonitrile: Yield: 73%; 0.25 Rf (5% ethylacetate in (dd, J = 10.3, 1.6 Hz, 1H, -C=C-H), 4.75 (dd, J = 17.2, 1.6 Hz, 1H,
o
1
hexane), Cream coloured solid; mp. 104-106 C; H-NMR (400 -C=C-H), 3.85 (s, 3H, - CH3), 3.28 (dd, J = 2.9, 2.2 Hz, 2H, -CH2),
MHz, CDCl3) δ 7.37 (d, J = 4.7 Hz, 1H, Ar-H), 7.08 (dd, J = 9.1, 2.52 (d, J = 7.0 Hz, 6H, -CH2); 13C-NMR (100 MHz, CDCl3) δ
3.9 Hz, 2H, Ar-H), 6.90 (s, 1H, Ar-H), 5.98-5.88 (m, 1H, -C=C-H), 159.2, 147.1, 142.7, 140.6, 135.6, 133.1, 132.8, 129.6, 125.4,
5.10 (dd, J = 10.2, 1.5 Hz, 1H, -C=C-H), 4.78 (dd, J = 17.2, 1.6 Hz, 116.6, 115.9, 113.5, 111.4, 55.2, 34.0, 18.3, 15.7; IR (cm-1):
8 | J. Name., 2012, 00, 1-3
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2927, 2845, 2219 (CN), 1609, 1577, 1442, 1034, 920; General protocol for the synthesis of 4-allyVl-ie3w-mArteictlehOynl-li1ne-
Calculated Mass (M+H)+: 310.1260, Observed Mass for (piperidin-1-yl)-9,10-dihydrophenanthrene-2-carbonitrile (8)
DOI: 10.1039/D0OB01318H
(C19H20NOS)+: 310.1265.
and
dihydrophenanthrene-2-carbonitrile (9): To
3-Allyl-2-methyl-6-(methylthio)-4-(thiophen-2- mixture of 4-sec.amino-2-oxo-5,6-dihydro-2H-benzo[h]-
3-(but-3-en-1-yl)-1-(piperidin-1-yl)-9,10-
a
dried vial,
7c.
yl)benzonitrile: Yield: 45%; 0.35 Rf (5% ethylacetate in chromene-3-carbonitriles (4b; 0.5 mmol) and 5-hexen-2-ones
hexane), Cream coloured solid; mp. 78-80 oC; 1H-NMR (400 (5; 0.75 mmol) in DMSO (4.0 mL) was added followed by
MHz, CDCl3) δ 7.39 (dd, J = 4.9, 1.4 Hz, 1H, Ar-H), 7.16 (s, 1H, addition of powdered LiOH (1.0 mmol). The reaction mixture
Ar-H), 7.11-7.07 (m, 2H, Ar-H), 5.98-5.89 (m, 1H, -C=C-H), 5.11 was stirred at 30 oC till completion of reaction. After
(dd, J = 10.3, 1.6 Hz, 1H, -C=C-H), 4.77 (dd, J = 17.2, 1.6 Hz, 1H, completion, reaction mixture was poured onto crushed ice
-C=C-H), 3.44-3.41 (m, 2H, -CH2), 2.54 (s, 6H, -CH3); 13C-NMR with constant stirring and neutralized with 10% solution of
(100 MHz, CDCl3) δ 143.1, 141.0, 140.9, 139.7, 135.6, 133.8, HCl. Obtained solid precipitate was filtered and purified by
127.3, 126.4, 126.1, 116.5, 116.2, 116.1, 112.2, 77.3, 77.0, silica gel column chromatography using ethyl acetate/hexane
76.7, 34.2, 18.4, 15.8; IR (cm-1): 2923, 2855, 2218 (CN), 1733, (1:19) as an eluent.
1577, 1434, 1026, 918; Calculated Mass (M+H)+: 286.0719,
Observed Mass for (C16H16NS2)+: 286.0724.
Yield: 67% (8a: 40% & 9a: 27%) ; 0.40 Rf (5% ethylacetate in
hexane), Cream coloured solid; H-NMR (400 MHz, CDCl3) δ
1
7.70-7.66 (m, 2H, Ar-H), 7.40 (s, 1H, Ar-H), 7.32-7.23 (m, 6H,
Ar-H), 6.22-6.13 (m, 1H, -C=C-H), 5.96-5.86 (m, 1H, -C=C-H),
5.29 (dd, J = 10.3, 1.9 Hz, 1H, -C=C-H), 5.10 (dd, J = 17.5, 1.5 Hz,
1H, -C=C-H), 5.04 (d, J = 9.9 Hz, 1H, -C=C-H), 4.98 (dd, J = 17.2,
1.9 Hz, 1H, -C=C-H), 3.55 (t, J = 2.3 Hz, 2H, -CH2), 3.23 (bs, 7H, -
CH2), 2.95 (t, J = 8.0 Hz, 2H, -CH2), 2.86 (t, J = 3.8 Hz, 2H, -CH2),
2.81 (t, J = 3.8 Hz, 2H, -CH2), 2.79-2.75 (m, 2H, -CH2), 2.66 (t, J =
6.5 Hz, 2H, -CH2), 2.51 (s, 3H, -CH3), 2.47 (t, J = 7.6 Hz, 2H, -
CH2), 1.73 (s, 7H, -CH2), 1.65 (s, 3H, -CH2); 13C-NMR (100 MHz,
CDCl3) δ 154.1, 151.5, 144.9, 141.6, 141.4, 140.0, 139.6, 137.9,
137.2, 136.8, 135.6, 134.2, 133.9, 133.2, 130.0, 128.4, 128.0,
127.9, 127.8, 127.1, 127.0, 125.8, 124.5, 120.7, 118.9, 118.2,
116.6, 115.6, 109.2, 107.8, 52.2, 52.0, 35.8, 34.7, 34.1, 29.6,
28.6, 26.8, 25.4, 24.2, 24.2, 23.2, 18.2; IR (cm-1): 2935, 2851,
2221 (CN), 1646, 1594, 1431, 994, 916;Calculated Mass
(M+H)+: 343.1856, Observed Mass for (C24H27N2)+: 343.1857.
7d. Methyl 2-allyl-3-methyl-5-(methylthio)-[1,1'-biphenyl]-4-
carboxylate: Yield: 57%; 0.35 Rf (5% ethylacetate in hexane),
Cream coloured solid; mp. 98-100 oC; 1H-NMR (400 MHz,
CDCl3) δ 7.42-7.37 (m, 3H, Ar-H), 7.30-7.28 (m, 2H, Ar-H), 7.12
(s, 1H, Ar-H), 5.88-5.79 (m, 1H, -C=C-H), 5.04 (d, J = 10.3 Hz,
1H, -C=C-H), 4.80 (dd, J = 17.2, 1.7 Hz, 1H, -C=C-H), 3.98 (s, 3H,
-CH3), 3.29-3.27 (m, 2H, -CH2), 2.45 (s, 3H, -CH3), 2.29 (s, 3H, -
CH3); 13C-NMR (100 MHz, CDCl3) δ 169.6, 144.5, 141.3, 135.9,
134.6, 133.7, 132.3, 128.7, 127.9, 127.8, 127.2, 127.1, 115.7,
52.1, 34.1, 17.6, 16.8; IR (cm-1): 2924, 2854, 1731(s, C=O,
ester), 1638, 1582, 1436, 997, 918; Calculated Mass (M+H)+:
313.1257, Observed Mass for (C19H21O2S)+: 313.1276.
7e. Methyl 2-allyl-4'-bromo-3-methyl-5-(methylthio)-[1,1'-
biphenyl]-4-carboxylate: Yield: 54%; 0.35 Rf (5% ethylacetate
in hexane), Cream coloured solid; mp. 116-118 oC; 1H-NMR
(400 MHz, CDCl3) δ 7.52 (dd, J = 6.6, 1.8 Hz, 2H, Ar-H), 7.15 (dd,
J = 6.5, 1.9 Hz, 2H, Ar-H), 7.05 (s, 1H, Ar-H), 5.86-5.77 (m, 1H, -
C=C-H), 5.04 (dd, J = 10.3, 1.6 Hz, 1H, -C=C-H), 4.76 (dd, J =
17.2, 1.7 Hz, 1H, -C=C-H), 3.96 (s, 3H, -CH3), 3.24 (dt, J = 4.8,
2.0 Hz, 2H, -CH2), 2.44 (s, 3H, -CH3), 2.26 (s, 3H, -CH3); 13C-NMR
(100 MHz, CDCl3) δ 169.5, 143.3, 140.2, 135.8, 135.4, 134.9,
133.7, 132.6, 131.2, 130.5, 127.6, 121.6, 115.9, 52.3, 34.1,
17.7, 16.8; IR (cm-1): 2928, 2855, 1732 (s, C=O, ester), 1588,
1436, 1018, 920; Calculated Mass (M+H)+: 391.0362, Observed
Mass for (C19H20BrO2S)+: 391.0368.
Synthesis of 1,9-dimethyl-3-(piperidin-1-yl)phenanthrene-2
carbonitrile (10): A mixture of 2-allyl-2'-bromo-3-methyl-5-
(piperidin-1-yl)-[1,1'-biphenyl]-4-carbonitrile (6l, 0.2 mmol)
was added to a nitrogen flushed air tight vial. Palladium (II)
acetate (0.01 mmol, 5 mol %), Cs2CO3 (0.25 mmol) and of dry
toluene (1.5 mL) was added to it and again purged with
o
nitrogen gas. Then, the reaction mixture was stirred at 90 C
12-15 hours. After completion, excess of solvent was removed
under vacuum and purified by column chromatography using
DCM/hexane (1: 9) mixture.
Yield: 84%; 0.45 Rf (5% ethylacetate in hexane), White
crystalline solid; mp. 86-88 oC; 1H-NMR (400 MHz, CDCl3) δ
8.64 (d, J = 8.7 Hz, 1H, Ar-H), 8.05 (d, J = 6.9 Hz, 2H, Ar-H), 7.72
(s, 1H, Ar-H), 7.70-7.65 (m, 2H, Ar-H), 3.25 (t, J = 5.0 Hz, 4H, -
CH2), 2.95 (s, 3H, -CH3), 2.75 (s, 3H, -CH3), 1.91-1.85 (m, 4H, -
CH2), 1.69-1.63 (m, 2H, -CH2); 13C-NMR (100 MHz, CDCl3) δ
152.9, 141.6, 132.9, 132.7, 131.7, 129.6, 127.7, 126.4, 125.6,
124.8, 123.7, 122.2, 118.1, 109.5, 108.5, 54.0, 26.3, 24.2, 20.3,
18.4; IR (cm-1): 2935, 2855, 2218 (CN), 1592, 1453, 999, 756;
Calculated Mass (M+H)+: 315.1856, Observed Mass for
(C19H20NOS)+: 315.1856.
7f. Methyl 3-allyl-2-methyl-6-(methylthio)-4-(thiophen-2-
yl)benzoate: Yield: 53%; 0.35 Rf (5% ethylacetate in hexane),
Cream coloured solid; mp. 90-92 oC; 1H-NMR (400 MHz, CDCl3)
δ 7.32-7.30 (m, 1H, Ar-H), 7.24 (d, J = 3.6 Hz, 1H, Ar-H), 7.04-
7.03 (m, 2H, Ar-H), 5.94-5.85 (m, 1H, -C=C-H), 5.05 (dd, J =
10.2, 1.7 Hz, 1H, -C=C-H), 4.79 (dd, J = 17.3, 1.6 Hz, 1H, -C=C-
H), 3.93 (s, 3H, -CH3), 3.39-3.38 (m, 2H, -CH2), 2.43 (s, 3H, -
CH3), 2.24 (s, 3H, -CH2); 13C-NMR (100 MHz, CDCl3) δ 169.4,
141.9, 136.7, 136.0, 134.9, 132.5, 129.0, 127.0, 125.6, 124.6,
124.0, 115.9, 115.3, 52.2, 34.3, 17.7, 16.9; IR (cm-1): 2923,
2853, 1729 (s, C=O, ester), 1640, 1593, 1433, 998, 916;
Calculated Mass (M+H)+: 319.0821, Observed Mass for
(C17H19O2S2)+: 319.0849.
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Journal Name
CH3), 1.57-1.52 (m, 2H, -CH2); 13C-NMR (100 MHz, CDCl3) δ
172.4, 144.2, 141.3, 135.7, 132.4, 131.5, 131.0, 129.7, 129.3,
General protocol for the synthesis of 3,4'-dimethyl-5-morpholino-
2-(prop-1-en-1-yl)-[1,1'-biphenyl]-4-carbonitrile(11):
View Article Online
DOI: 10.1039/D0OB01318H
127.8, 125.9, 118.4, 112.1, 54.1, 29.7, 26.7, 24.1, 22.7, 18.7; IR
(cm-1): 3357 (NH), 2941, 2850, 1662 (C=O, amide), 1638, 1563,
1471, 1440, 989, 911; Calculated Mass (M+H)+: 413.1223,
Observed Mass for (C22H26BrN2O)+: 413.1226.
Method A: A mixture of of 2-methyl-6-morpholino-3-(allyl)-4-
(p-tolyl)benzonitriles (6d, 0.3 mmol) was taken in air tight vial
followed by addition of PhI(AcO)2 (0.36 mmol), Pd(OAc)2
(0.015 mmol) and K3PO4 (0.36 mmol). To the vial, toluene (1.5
mL) was added and reaction mixture was flushed with nitrogen
o
12b.
2-Methyl-6-(piperidin-1-yl)-3-(prop-1-en-1-yl)-4-
and sealed. Then reaction mixture was heated at 60 C for 12
(thiophen-2-yl)benzamide: Yield: 74%; 0.25 Rf (15%
ethylacetate in hexane), Cream coloured solid; mp. 158-160
oC; 1H-NMR (400 MHz, CDCl3) δ 7.31 (dd, J = 5.1, 1.2 Hz, 1H, Ar-
H), 7.09 (dd, J = 3.6, 1.1 Hz, 1H, Ar-H), 7.04 (dd, J = 5.1, 3.6 Hz,
1H, Ar-H), 6.99 (s, 1H, Ar-H), 6.40 (s, 1H, -NH2), 6.25 (dd, J =
16.1, 1.6 Hz, 1H, -C=C-H), 5.91 (s, 1H, -NH2), 5.62-5.53 (m, 1H, -
C=C-H), 2.98 (t, J = 5.1 Hz, 4H, -CH2), 2.39 (s, 3H, -CH3), 1.80
(dd, J = 6.5, 1.7 Hz, 3H, -CH3), 1.71-1.65 (m, 4H, -CH2), 1.56-
1.50 (m, 2H, -CH2); 13C-NMR (100 MHz, CDCl3) δ 172.4, 149.2,
143.6, 135.8, 135.0, 132.6, 132.1, 131.3, 128.3, 127.2, 126.7,
125.6, 118.6, 54.1, 26.7, 24.1, 18.7; IR (cm-1): 3361 (NH), 2936,
2853, 1659 (C=O, amide), 1633, 1561, 1456, 1426, 994, 913;
Calculated Mass (M+H)+: 341.1682, Observed Mass for
(C20H25N2OS)+: 341.1694.
hours. After complete conversion, the excess of solvent as
removed followed by addition of water (15 mL). The reaction
mixture was neutralized with 10% of HCl and extracted with
ethyl acetate (10 mLx2). The organic layer was separated and
dried over anhydrous sodium sulphate. The product was
purified by column chromatography using DCM/hexane (1:9)
mixture as an eluent.
Method B: To a vacuum dried vial 2-methyl-6-morpholino-3-
(allyl)-4-(p-tolyl)benzonitriles (6d, 0.2 mmol) was taken. To the
vial further t-BuOK (0.3 mmol) and t-BuOH (3.0 mL) was added
o
and stirred for 12 hours at 90 C. After complete conversion,
the excess of solvent was removed followed by addition of
water (15 mL). The reaction mixture was neutralized with 10%
of HCl and extracted with ethyl acetate (10mLx2). The organic
layer was separated and dried over anhydrous sodium
sulphate. The product was purified by column chromatography
using DCM/hexane (1:9) mixture as an eluent.
General protocol for the synthesis of compound 13a-c: To a
vacuum dried vial, 2-methyl-6-(methylthio)-3-(allyl)-4-
(aryl)benzonitriles (7, 0.2 mmol) and m-CPBA (55-75% assay)
(1.8 mmol) was added followed by addition of DCM (2 mL) and
Yield: 95% in method A and 78% in method B; 0.25 Rf (5%
o
1
ethylacetate in hexane), White solid; mp. 126-128 C; H-NMR
(400 MHz, CDCl3) δ 7.18 (dd, J = 10.8, 8.5 Hz, 4H, Ar-H), 6.75 (s,
1H, Ar-H), 6.09 (dd, J = 16.0, 1.4 Hz, 1H, -C=C-H), 5.48-5.39 (m,
1H, -C=C-H), 3.90 (t, J = 4.6 Hz, 4H, -CH2), 3.17 (t, J = 4.4 Hz, 4H,
-CH2), 2.56 (s, 3H, -CH3), 2.39 (s, 3H, -CH3), 1.70 (dd, J = 6.6, 1.6
Hz, 3H, -CH3); 13C-NMR (100 MHz, CDCl3) δ 154.0, 146.3, 142.0,
138.3, 137.1, 132.7, 131.7, 129.4, 128.7, 127.2, 118.0, 117.9,
106.8, 67.0, 52.1, 21.2, 19.9, 18.7; IR (cm-1): 2928, 2855,
2217(CN), 1636, 1558, 1491, 1443, 994, 907; Calculated Mass
(M+H)+: 333.1961, Observed Mass for (C22H25N2O)+: 333.1956.
o
stirred for 5 hours at 30 C. After completion, the reaction
mixture was diluted with DCM (10 mL) and extracted with 10%
aqueous solution of Na2CO3 (15 mLx3). Then, organic layer was
separated and dried over sodium sulphate and purified by
column chromatography using ethyl acetate/hexane (1:9)
mixture as an eluent.
13a.
2-Allyl-3-methyl-5-(methylsulfinyl)-[1,1'-biphenyl]-4-
carbonitrile: Yield: 98%; 0.35 Rf (10% ethylacetate in hexane),
White crystalline solid; mp 98-100 oC; 1H-NMR (400 MHz,
CDCl3) δ 7.81 (s, 1H, Ar-H), 7.43-7.40 (m, 3H, Ar-H), 7.30-7.26
(m, 2H, Ar-H), 5.90-5.80 (m, 1H, -C=C-H), 5.11 (dd, J = 10.3, 1.5
Hz, 1H, -C=C-H), 4.76 (dd, J = 17.2, 1.4 Hz, 1H, -C=C-H), 3.41-
3.39 (m, 2H, -CH2), 2.91 (s, 3H, -CH3), 2.61 (s, 3H, -CH3); 13C-
NMR (100 MHz, CDCl3) δ 148.8, 146.7, 143.4, 139.6, 139.5,
134.8, 128.4, 128.3, 128.2, 123.7, 116.6, 114.8, 107.8, 42.8,
34.5, 18.2; IR (cm-1): 2933, 2855, 2216 (CN), 1592, 1501, 1451,
1064 (s, S=O, sulfoxide), 1021, 918; Calculated Mass (M+H)+:
296.1104, Observed Mass for (C18H18NOS)+: 296.1115.
General protocol for the synthesis of compound 12a and 12b:
To a vacuum dried vial 2-methyl-6-(sec.amino)-3-(allyl)-4-
(aryl)benzonitriles (6i or 6o, 0.2 mmol) was heated with t-
BuOK (0.8 mmol) in t-BuOH (3 mL) for 24 hours at 110 oC. After
complete conversion, the excess of solvent was removed
followed by addition of water (15 mL). The reaction mixture
was neutralized with 10% of HCl and extracted with ethyl
acetate (10mLx2). The organic layer was separated and dried
over anhydrous sodium sulphate. The product was purified by
column chromatography using ethyl acetate/hexane (1:9) as
an eluent.
13b.
2-Allyl-4'-methoxy-3-methyl-5-(methylsulfinyl)-[1,1'-
biphenyl]-4-carbonitrile: Yield: 96%; 0.35 Rf (10% ethylacetate
o
1
12a. 4'-Bromo-3-methyl-5-(piperidin-1-yl)-2-(prop-1-en-1-yl)- in hexane), White crystalline solid; mp. 110-112 C; H-NMR
(400 MHz, CDCl3) δ 7.80 (s, 1H, Ar-H), 7.24 (d, J = 8.7 Hz, 2H,
Ar-H), 6.94 (d, J = 8.7 Hz, 2H, Ar-H), 5.88 (dq, J = 22.4, 5.2 Hz,
1H, -C=C-H), 5.12 (dd, J = 10.2, 1.2 Hz, 1H, -C=C-H), 4.77 (dd, J =
17.2, 1.3 Hz, 1H, -C=C-H), 3.85 (s, 3H, -CH3), 3.41 (dd, J = 4.9,
1.8 Hz, 2H, -CH2), 2.89 (s, 3H, -CH3), 2.60 (s, 3H, -CH3); 13C-NMR
(100 MHz, CDCl3) δ 159.6, 148.5, 146.7, 143.4, 139.5, 135.0,
131.9, 129.7, 123.8, 116.5, 114.9, 113.7, 107.4, 55.3, 42.8,
[1,1'-biphenyl]-4-carboxamide:
Yield: 71%; 0.25 Rf (15% ethylacetate in hexane), Cream
o
1
coloured solid; mp. 180-182 C; H-NMR (400 MHz, CDCl3) δ
7.47 (d, J = 8.2 Hz, 2H, Ar-H), 7.15 (d, J = 8.2 Hz, 2H, Ar-H), 6.77
(s, 1H, Ar-H), 6.41 (s, 1H, -NH2), 6.12 (d, J = 16.0 Hz, 1H, -C=C-
H), 5.94 (s, 1H, -NH2), 5.38-5.29 (m, 1H, -C=C-H), 2.96 (t, J = 4.8
Hz, 4H, -CH2), 2.38 (s, 3H, -CH3), 1.68 (q, J = 6.3 Hz, 7H, -CH2 & -
10 | J. Name., 2012, 00, 1-3
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Journal Name
ARTICLE
34.6, 18.2; IR (cm-1): 2922, 2853, 2220 (CN), 1606, 1513, 1458,
1066 (s, S=O, sulfoxide), 1030, 915; Calculated Mass (M+H)+:
326.1209, Observed Mass for (C19H20NO2S)+: 326.1194.
10. (a) Y. Uozumi and T. Osako, Synfacts, 2012, 8, 1039; (b) A.
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R. Jensen, ACS Catal., 2017, 7, 2543.
13c. Methyl 3-allyl-2-methyl-6-(methylsulfinyl)-4-(thiophen-
2-yl)benzoate: Yield: 93%; 0.35 Rf (10% ethylacetate in
hexane), White crystalline solid; mp. 104-106 oC; 1H-NMR (400
MHz, CDCl3) δ 7.96 (s, 1H, Ar-H), 7.37 (d, J = 5.1 Hz, 1H, Ar-H),
7.11 (dd, J = 3.4, 1.1 Hz, 1H, Ar-H), 7.06 (dd, J = 5.0, 3.5 Hz, 1H,
Ar-H), 5.99-5.90 (m, 1H, -C=C-H), 5.12 (dd, J = 10.3, 1.5 Hz, 1H,
-C=C-H), 4.80 (dd, J = 17.3, 1.5 Hz, 1H, -C=C-H), 3.94 (s, 3H, -
CH3), 3.53 (t, J = 2.5 Hz, 2H, -CH2), 2.84 (s, 3H, -CH3), 2.38 (s,
3H, -CH3); 13C-NMR (100 MHz, CDCl3) δ 167.6, 143.1, 140.9,
140.4, 138.8, 137.0, 135.5, 129.7, 127.4, 127.1, 126.4, 123.7,
116.4, 52.5, 44.3, 34.8, 17.1; IR (cm-1): 2929, 2851, 1728 (CO,
Ester), 1598, 1513, 1448, 1058 (S=O, sulfoxide), 999, 910;
Calculated Mass (M+H)+: 302.0668, Observed Mass for
(C16H16NOS2)+: 302.0659.
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Acknowledgements
RS thanks CSIR for providing research fellowship. RP thanks
CSIR for providing financial assistance to perform research. VN
thanks ICMR, New Delhi for providing RAship. CS thank UGC
New Delhi for providing research fellowship. RR thanks DHR,
ICMR New Delhi for providing Women’s Scientist fellowship.
Conflicts of interest
There are no conflicts to declare.
18. N. Lal, V. Nemaysh, P. M. Luthra, Toxicology and Applied
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Organic & Biomolecular Chemistry
Page 12 of 12
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DOI: 10.1039/D0OB01318H
Graphical Abstract
Transition metal free synthesis of sterically hindered allylarenes from 5-hexene-2-
one
Ranjay Shaw, Ismail Althagafi, Amr Elagamy, Reeta Rai, Chandan Shah, Vishal Nemaysh, Harpreet
Singh and Ramendra Pratap*
Sterically hindered allylarenes have been synthesized by ring transformation of 2-pyranones with
5-hexene-2-one.
R
CN/COOMe
O
R
O
CN/COOMe
CH3
Ar
O
LiOH/DMSO
Ar
Sterically hindered allylarenes
Wide functional group tolerance
Good yield
Good synthetic precursor
1