Regioselective synthesis of 1,2,4-trisubstituted imidazole from a mechanistic and synthetic prospective

Article abstract of DOI:10.1080/00397911.2020.1712608

The highly substituted 1,2,4-trisubtituted imidazole was regioselectively synthesized via base mediated domino reaction of amidine scaffold with phenacyl bromide followed by in situ N-alkylation of imidazole. The reaction conditions were optimized in orde

Full text of DOI:10.1080/00397911.2020.1712608

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: https://www.tandfonline.com/loi/lsyc20
Regioselective synthesis of 1,2,4-trisubstituted
imidazole from a mechanistic and synthetic
prospective
Suman Punia, Vikas Verma, Devinder Kumar, Gurjaspreet Singh & Subash C.
Sahoo
To cite this article: Suman Punia, Vikas Verma, Devinder Kumar, Gurjaspreet Singh & Subash C.
Sahoo (2020): Regioselective synthesis of 1,2,4-trisubstituted imidazole from a mechanistic and
synthetic prospective, Synthetic Communications, DOI: 10.1080/00397911.2020.1712608
To link to this article: https://doi.org/10.1080/00397911.2020.1712608
View supplementary material
Published online: 20 Jan 2020.
Submit your article to this journal
Article views: 22
View related articles
View Crossmark data
Full Terms & Conditions of access and use can be found at
https://www.tandfonline.com/action/journalInformation?journalCode=lsyc20

V
R
SYNTHETIC COMMUNICATIONS
https://doi.org/10.1080/00397911.2020.1712608
Regioselective synthesis of 1,2,4-trisubstituted imidazole
from a mechanistic and synthetic prospective
a
a
a
b
Suman Punia , Vikas Verma , Devinder Kumar , Gurjaspreet Singh , and
b
Subash C. Sahoo
a
Department of Chemistry, Guru Jambheshwar University of Science and Technology, Hisar, India;
Department of Chemistry, Panjab University, Chandigarh, India
b
ABSTRACT
ARTICLE HISTORY
The highly substituted 1,2,4-trisubtituted imidazole was regioselec-
tively synthesized via base mediated domino reaction of amidine
scaffold with phenacyl bromide followed by in situ N-alkylation of
imidazole. The reaction conditions were optimized in order to access
three phenomenon (neutralization, condensation, and N-alkylation)
in a single pot. A mechanism for the formation of N–H imidazole
and its subsequent N-alkylation is depicted by isolation of reaction
of intermediates. Electron donating group facilitate N-alkylation,
whereas no N-alkylation was observed in the presence of electron
Received 10 October 2019
KEYWORDS
Domino reaction; imidazole;
pseudo-multicomponent;
regioselectivity
withdrawing (NO ) group. The synthesized compounds and reaction
2
intermediate were characterized using NMR, FTIR, and HRMS. Exact
orientation of various aromatic rings in regioselective N-alkylated
product was confirmed using single crystal X-ray analysis.
GRAPHICAL ABSTRACT
Introduction
[
1]
Imidazole is a vital subunit of many natural products, as well as synthetic bioactive
[
2]
compounds. Many synthetic compounds, containing imidazole unit, showed excellent
[
3]
[4]
[5]
[6]
[7]
antifungal, anticancer, anti-inflammatory, antioxidant, antiepilestic, and anti-
[
8]
[9]
bacterial activity. In addition, inhibition of hNaV1.2 sodium channels by 2, 4(5)-
diarylimidazole and selective inhibition of COX-2
[
10]
by 1,5-disubstituted imidazole has
been reported. Pyrazole containing heterocyclic compounds represent one of the bio-
logical active class of compounds and possess a broad range of pharmaceutical activ-
[
11]
ities.
Several drugs have been designed from pyrazole derivatives, e.g., rimonabant
CONTACT Vikas Verma
vikas_chem_pu@yahoo.com
Department of Chemistry, Guru Jambheshwar University of
Science and Technology, Hisar 125001, India.
Color versions of one or more of the figures in the article can be found online at www.tandfonline.com/lsyc.
Supplemental data for this article can be accessed on the publisher’s website.
ß 2020 Taylor & Francis Group, LLC

2
S. PUNIA ET AL.
functions as a cannabinoid receptor and is utilized to treat obesity; sildenafil inhibits
phosphodiesterase; celecoxib demonstrates anti-inflammatory effects and inhibits COX-
[
12]
2
; fomepizole inhibits alcohol dehydrogenase.
The development of new approaches for chemical transformation toward imidazole
continues to attract attention in contemporary synthetic chemistry. A series of Cu, Fe,
Ag catalyzed methods of imidazole derivatives has been developed recently by the group
[
13]
[14]
[15]
of Li,
Chen,
and Neuville.
Moreover, transition metal-catalyzed direct N–H
functionalization provide a powerful tool for the synthesis of substituted imidazole.
Metal-free multicomponent reactions for building the heterocyclic core are advanta-
geous because of complicated purifying procedure to remove the metal residue in reac-
[
16]
tions. Wang and coworkers
reported an elegant method for imidazole synthesis by
reaction of in situ generated diketone from bromoacetylene with amidine. The virtue of
[
17–20]
simple handling of amidine salt and its reactivity with different electrophiles
vates to synthesize imidazole on amidine scaffold.
moti-
In light of the significance of pyrazole and imidazole in medicinal chemistry, the pre-
sent study focuses on the regioselective synthesis of imidazole containing pyrazole deriv-
atives via base mediated pseudo-multicomponent domino reaction of amidine scaffold
with phenacyl bromide including mechanistic studies.
Results and discussion
Amidines are more nucleophilic than their corresponding salts. Hence, 1H-pyrazole-1-
carboximidamide hydrochloride (1a) was neutralized with different base to generate free
amidine, and the resulted free amidine was reacted with equimolar amount of phenacyl
bromide (2a–2c) under different reaction conditions (Scheme 1). Microwave irradiation
of 1a, 2a–2c and diisoprppylethyamine (DIPEA) as base without solvent and with etha-
nol as solvent does not yield 3a–3c (Entries 1 and 2, Table 1). Refluxing reactants 1,
2
a–2c and DIPEA in ethanol also do not yield 3a–3c (Entry 3). Further, when DIPEA
was changed to Et N, the pyrazolylimidazoles 3a–3c were formed but the yield was very
3
low (Entry 4). Refluxing in another polar immiscible solvent system (CHCl /H O) with
3
2
Et N and K CO also did not yield 3a–3c (Entries 5 and 6, Table 1). Further refluxing
3
2
3
Scheme 1. Synthesis of compound 3.

V
R
SYNTHETIC COMMUNICATIONS
3
Table 1. Optimization of reaction conditions.
Entry
1
Compound
Solvent
Base
Base equivalent
Time (in h)
0.50
% Yield
NR
a
3a
–
DIPEA (MW)
20
3
3
b
c
a
2
3
4
5
6
7
8
3a
Ethanol
Ethanol
Ethanol
DIPEA (MW)
DIPEA
20
0.83
24
NR
NR
3
3
b
c
a
3a
20
3
3
b
c
b
3a
Et
Et
3
N
N
5.0
24
6
5
3
3
3
b
c
3a
CHCl
CHCl
3
/H
/H
2
O
O
3
2.0
2.0
72
NR
3
3
b
c
3a
3
2
K CO
2 3
72
NR
3
3
b
c
b
3a
THF/H
THF/H
2
O
O
NaHCO
3
2.0
36
16
8
7
39
15
14
3
3
b
c
b
3a
2
K CO
2 3
2.0
36
3
3
b
c
a: mmol; b: mol%; NR: no reaction.
of 1a and 2a–2c in miscible polar solvent system (THF/H O) with NaHCO or K CO
3
2
3
2
as base yield 3 (Entries 7 and 8, Table 1). Hence, THF/H O and K CO are the opti-
2
2
3
mized solvent system and base for Scheme 1.
However, the reaction of 1 with 1.2/2.5 equivalent of 2 in the presence of 2.5 equiva-
lent of K CO yields compound 3 and then regioselectively compound 4 instead of 5
2
3
(Scheme 2). When 1.2 equivalent of phenacyl bromide (2a–2c) is reacted with 1.0
equivalent of 1a, N–H imidazole (3a–3c) is isolated, whereas 2.5 equivalent (one equiva-
lent added after 36 h) of corresponding phenacyl bromide (2a–2c) furnished N-alkylated
imidazole (4a–4c). Phenacyl bromides 2d–2f give N-alkylated product predominantly
(4d–4f, 4k–4m) by reacting with 1 whether it is taken 1.2 or 2.5 equivalent. N-alkylated
product is not obtained with phenacyl bromide containing a strong electron withdraw-
ing group (2g) even with 2.5 equivalent of it is used. Further with phenacyl bromide
(
4
2a–2f) N-alkylated product 4 is obtained instead of 5 (Scheme 2). Isolation of 4d and
k even with 1.0 equivalent of 4-methoxyphenacyl bromide and 3g and 3n with 2.0
equivalent of 2g establish that electronic factor is more important than solvation and
[
21]
steric hindrance of amidine.
Mechanism of reaction
A plausible mechanism for the formation of N–H imidazole and its subsequent N-alkyl-
ation is depicted in Scheme 3. The free amidine (8), generated from its salt, reacts as a
binucleophile with phenacyl bromide (2) through SN2 approach to give initially mono-
alkylated intermediate (9) which on intramolecular cyclocondensation furnished 4-H
imidazole (10) via path A. Subsequent dehydration to gain aromaticity affords imidazole

4
S. PUNIA ET AL.
Scheme 2. Reaction Conditions: (i) amidine (1 equiv.), phenacyl bromide (1.2 equiv.), K CO (2.5
2
3
equiv.), THF:H O (5:1), refluxing. (ii) phenacyl bromide (1.2 equiv.) more added in same port after 36 h
2
of step (i). (iii) amidine (1 equiv.), phenacyl bromide (2.5 equiv.), K CO3 (2.5 equiv.), THF:H2O
2
((5:1), refluxing.
(3i) that is N-alkylated with phenacyl bromide in situ to afford 1,2,4-trisubstituted imid-
azole (4) in a regioselective manner instead of 5. Isolation of 3,5-dimethyl-1-(5-(p-
tolyl)-1H-imidazol-2-yl)-1H-pyrazole (3i) when 2-bromo-1-(p-tolyl)ethanone (2b) was
used as a phenacyl bromide support that reaction proceed via path A rather than litera-
[
18]
ture
assumed path B involving the intermediacy of 13 and 14, albeit isolated N-alky-
lated product (4i) through both the pathways can be obtained. However, path B cannot
be completely ruled out as reaction was not spectroscopically monitored.
Scaffold 8, generated by neutralization of corresponding amidine salt, is labile to
decompose into 15 and 16 (Scheme 3) which then may compete for phenacyl bromide.

V
R
SYNTHETIC COMMUNICATIONS
5
Scheme 3. Mechanism of the reaction.
To study this possibility, 3,5-dimethyl-1H-pyrazole-1-carboximidamide nitrate was
treated with two equivalent of 2-bromo-1-(4-tolyl)ethanone in refluxing THF/H O solv-
2
ent system. The workup of the reaction mixture afforded the crude product that showed
ꢀ1
ꢀ1
the appearance of two weak bands at 2351.23 cm and 2326.15 cm in infrared spec-
trum besides other bands thereby suggesting the possibility decomposition of amidine
scaffold into cynamide and 3,5-dimethyl-1H-pyrazole as shown in Scheme 3. The crude
product was separated into different components using column chromatography (silica
mesh 60–120) using ethylacetate/hexane (10:90 v/v) to elute the imidazole product (3i)
followed using ethylacetate/hexane (30:70 v/v) to elute N-alkylated imidazole (4i) and

6
S. PUNIA ET AL.
1
13
Figure 1. H NMR and C NMR of compound 4d and COSY correlation.
N-alkylated pyrazole (18) products. The structure of isolated components was confirmed
1
13
using spectroscopic analysis, including IR, H and C NMR, and mass spectral analysis.
Isolation of n-alkylated pyrazole compound (18) confirmed the decomposition and
account for low yield of n-alkylated imidazole products.
Compound 1a was reacted with p-methoxyphenacyl bromide (2d) to give regioselec-
tively N-alkylated product 4d instead of 5 and N–H imidazole product 3d. A detailed
study of 1D and 2D NMR, HRMS, and FTIR spectra of purified product, indicated that
1-(4-methoxyphenyl)-2-(4-(4-methoxyphenyl)-2-(1H-pyrazol-1-yl)-1H-imidazol-1-yl)e-
thanone (4d) compound has been formed. Regioselectivity of N-alkylated product 4b
[
22]
has been confirmed using single crystal X-ray analysis.
1
H NMR spectra of the representative molecule 4d (Fig. 1) indicate the presence of 20
protons. Protons with coupling constant 1.2–2.4 Hz shows the presence of pyrazole ring
in the molecule. Singlet at d 7.53 with integration of one proton might be due to imid-
azole ring proton as another singlet due to methylene protons appears with the integra-
tion of two proton (d ¼ 5.89). In 2D-NMR, e.g., COSY (Correlation spectroscopy): d 7.53
does not correlate with any other proton showing that it is the proton of imidazole ring
and the signal at d 6.49 (t, J ¼ 2.0, 2.4 Hz) correlate with d 8.33 and 7.64 justifying that it
is due C –H of pyrazole ring. Consequently, the protons at d 6.49, 8.33, and 7.64 are the
4
protons of pyrazole ring. Mutual correlation of signal at d 7.70 with signal at 6.98 and d
7.99 with 7.10 along with J value in phenyl ring range support our assignment of these
signals to the phenyl ring. Due to anisotropy and electron withdrawing ability of carbonyl
group, protons of N-alkylated benzene ring appears at higher chemical shift.
1
3
13
C NMR of 4d (Fig. 1) indicated the presence of 18 signals. DEPT135 C NMR
spectrum (Supplementary information) clearly show the presence of 8 tertiary, 2 pri-
mary and 1 secondary carbon thereby suggesting that the remaining 7 signals were due
to quaternary carbons. In order to establish the assignment of each carbon HSQC
(Heteronuclear Single-Quantum Coherence Spectroscopy) and HMBC (Heteronuclear
Multiple Bond Correlation Spectroscopy), 2D NMR (Supplementary information) was
scanned. HSQC revealed the assignment of primary, secondary and tertiary carbons at d
142.09, 130.99, 130.80, 125.93, 117.35, 114.69, 114.54, 107.57, 56.13, 55.56, and 53.88.

V
R
SYNTHETIC COMMUNICATIONS
7
Figure 2. ORTEP drawing compound 4b.
These were assigned on the basis of key correlation found in HSQC spectra as follow; d
8
1
.33 fi 130.99, 7.99 fi 130.80, 7.70 fi 125.93, 7.64 fi 142.09, 7.53!117.35, 7.10 !
14.69, 6.98 ! 114.54, 6.49 ! 107.57, 5.89 ! 53.88, 3.87 ! 56.13, and 3.79 ! 55.56.
HMBC experiment established the assignment of quaternary carbon signals through two
bond correlations at 191.40, 164.18, 158.70, 140.64, 137.30, 127.52, and 126.80. The
above assignment was confirmed through the correlation of signals at d 8.33 ! 142.09
and 107.57; 7.99 ! 191.40, 164.18 and 130.80; 7.70 ! 158.70, 125.93 and 137.30; 7.53
!
140.64 and 137.30; 7.10 ! 164.18, 127.52 and 114.69; 6.98 ! 158.70, 126.80 and
1
14.54; 5.89 ! 191.40, 117.35 and 140.64; 3.86 ! 164.18 and 3.78 ! 158.70.
Recrystallization of the 2-(2-(1H-pyrazol-1-yl)-4-(p-tolyl)-1H-imidazol-1-yl)-1-(p-tolyl)
ethanone (4b) from methanol afforded crystal of suitable size and quality for single-crystal
X-ray diffraction analysis. The X-ray crystallography of 4b (Fig. 2) confirmed the formation
of 4 rather than 5. Bond angles C C C ¼ 129.9(3), N C N ¼ 124.1(2) and C N C
2
0
19 11
21 17 22
17 21 9
ꢁ
¼
129.7(2)/ are typical of 4b. The selected crystal structure data are presented in
Supplementary information.
Conclusion
Imidazole hybrids were efficiently synthesized via pseudo-multicomponent reaction in
one pot utilizing amidine and phenacyl bromide followed by in situ N-alkylation of
imidazole. Out of two possible regioisomers 4 and 5, product 4 is obtained exclusively
whose structure has been confirmed by 2 D NMR spectroscopy and single crystal X-ray
analysis. Reaction proceed via monoalkylation of in situ generated free amidine and
then cyclization leading to formation of 1H-imidazole. Electronic influence of the sub-
stituent, present on imidazole ring accomplish that N-alkylation is followed by cycliza-
tion facilitating a two-step process in single pot.

8
S. PUNIA ET AL.
Experimental section
Procedure for synthesis of compound 2-(2-(3,5-Dimethyl-1H-pyrazol-1-yl)-4-(4-
methoxyphenyl)-1H-imidazol-1-yl)-1-(4-methoxy pheyl)ethanone (4k)
A two neck 100 ml round bottom flask, equipped with reflux condenser and pressure
equalizing funnel is charged with 3,5-dimethyl-1-(5-phenyl-1H-imidazol-2-yl)-1H-pyra-
zole (1 mmol) in 10 ml of THF:H O (5:1) solvent. Then, slow and portion wise addition
2
of potassium carbonate (2.5 mmol) with vigorous refluxing is carried out. A solution of
2-bromo-1-(p-tolyl)ethan-1-one (2.2 mmol) in THF is constantly added drop wise via
pressure equalizing funnel over a period of 20 min while refluxing. The progress of reac-
tion is monitored using thin layer chromatography (TLC). After completion of the reac-
tion, THF is removed under reduced pressure using rotatory evaporator. Crude product
is filtered and transferred to a 100 ml round bottom flask and stirred in 50 ml of hexane
for one hour. Isolated product is purified by column chromatography (60–120 mesh
silica, hexane/ethylacetate 90/10).
ꢁ
1
Buff colored solid. mp: 210–212 C. H NMR (400 MHz, DMSO) d ¼ 7.93
d, J ¼ 8.8 Hz, 2 H, imidazole N -aryl C -H, C –H), 7.68 (d, J ¼ 8.8 Hz, 2H, imidazole 4-
(
1
2
6
methoxyphenyl C –H, C –H), 7.56 (s, 1H, imidazole H), 7.07 (d, J ¼ 8.8 Hz, 2H, imid-
2
6
azole N -aryl C –H, C –H), 6.97 (d, J ¼ 8.4 Hz, 1H, imidazole 4-methoxyphenyl C –H,
1
3
5
3
C –H), 6.00 (s, 1H, pyrazole C –H), 5.60 (s, 2H, CH ), 3.86 (s, 3H, OCH ), 3.78 (s, 3H,
5
4
2
3
13
OCH ), 2.34 (s, 3H, CH ), 1.97 (s, 3H, CH ). C NMR (100 MHz, DMSO) d ¼ 191.40,
3
3
3
1
1
2
64.20, 158.83, 149.70, 142.70, 140.08, 137.65, 130.68, 127.83, 127.22, 125.99, 116.94,
ꢀ
1
14.66, 106.98, 79.55, 56.11, 55.67, 52.70, 13.44, 11.87. IR (KBr, ꢀmax/cm ): 3001.24,
þ
939.52, 2853.36, 1685.79, 1598.99, 1550.77, 1242.16. HRMS: m/z Cacld. (M þ H) for
C H N O : 417.1921 found 417.1900.
2
4
26 4 3
Additional Supporting information may be found online in the supporting informa-
tion tab for this article.
Acknowledgments
Authors are highly thankful to DST-PURSE (SR/PURSE Phase 2/40(G)), New Delhi and Dr. APJ
Abdul Kalam CIL, GJUS&T, Hisar.
References
[1] Groziak, M. P.; Ding, H. Acta Chim. Slov. 2000, 47, 1–18.
[2] Peng, X. M.; Cai, G. X.; Zhou, C. H. Curr. Top. Med. Chem. 2013, 13, 1963–2010. DOI:
10.2174/15680266113139990125.
[
3] Song, Z.; Zhang, W.; Jiang, M.; Sung, H. H. Y.; Kwok, R. T. K.; Nie, H.; William, I. D.;
Liu, B.; Tang, B. Z. Adv. Funct. Mater. 2016, 26, 824–832. DOI: 10.1002/adfm.201670035.
4] (a) Yue, W.; Wang, H. Monatsh. Chem. 2015, 146, 2079–2086. DOI: 10.1007/s00706-
[
015-1513-9. (b) Bistrovi, A.; Krstulovi, L.; Harej, A.; Grbcic, P.; Sedic, M.; Kostrun, S.;
Pavelic, S. K.; Bajic, M.; Malic, S. R. Eur. J. Med. Chem. 2018, 143, 1–19. (c)
Demirayak, S.; Kayagil, I.; Yurttas, L. Eur. J. Med. Chem. 2011, 46, 411–416. DOI: 10.
1
016/j.ejmech.2010.11.007. (d) Wang, X.-Q.; Liu, L.-X.; Li, Y.; Sun, C.-J.; Chen, W.;
Li, L.; Zhang, H.-B.; Yang, X.-D. Eur. J. Med. Chem. 2013, 62, 111–121. DOI: 10.
016/j.ejmech.2012.12.040.
1

V
R
SYNTHETIC COMMUNICATIONS
9
[
[
5] (a) Tripathy, H.; Krishnanand, S. T.; Adhikary, L.; Chandrashekar, J. Res. J. Pharm. Biol.
Chem. Sci. 2010, 1, 31–44. (b) Assadieskandar, A.; Amini, M.; Salehi, M.; Sadeghian, H.;
Alimardani, M.; Sakhteman, A.; Nadri, H.; Shafiee, A. Bioorg. Med. Chem. 2012, 20,
7160–7166. DOI: 10.1016/j.bmc.2012.09.050. (c) Gaonkar, S. L.; Rai, K. L.; Shetty, N. S.
Med. Chem. Res. 2009, 18, 221–230. DOI: 10.1007/s00044-008-9121-4.
6] (a) Abdel-Wahab, B. F.; Awad, G. E.; Badria, F. A. Eur. J. Med. Chem. 2011, 46,
1505–1511. DOI: 10.1016/j.ejmech.2011.01.062. (b) Salerno, L.; Modica, M. N.; Romeo, G.;
Pittal ꢀa , V.; Siracusa, M. A.; Amato, M. E.; Acquaviva, R.; Giacomo, C. D.; Sorrenti, V.
Eur. J. Med. Chem. 2012, 49, 118–126. DOI: 10.1016/j.ejmech.2012.01.002. (c) Neochoritis,
C. G.; Zarganes-Tzitzikas, T.; Tsoleridis, C. A.; Stephanidou-Stephanatou, J.; Kontogiorgis,
C. A.; Hadjipavlou-Litina, D. J.; Choli-Papadopoulou, T. Eur. J. Med Chem. 2011, 46,
2
97–306. DOI: 10.1016/j.ejmech.2010.11.018.
7] (a) Mishra, R.; Ganguly, S. Med. Chem. Res. 2012, 21, 3929–3939. DOI: 10.1007/s00044-
12-9972-6. (b) Mawasi, H.; Bibi, D.; Bialer, M. Bioorg. Med. Chem. 2016, 24, 4246–4253.
[
[
[
0
DOI: 10.1016/j.bmc.2016.07.018.
8] (a) Desai, N. C.; Maheta, A. S.; Rajpara, K. M.; Joshi, V. V.; Vaghani, H. V.; Satodiya,
H. M. J. Saudi. Chem. Soc. 2014, 18, 963–971. DOI: 10.1016/j.jscs.2011.11.021. (b)
Ghasemi, B.; Beyzaei, H.; Hashemi, S. H.; Majidiani, H. J. Med. Bacteriol. 2015, 4, 7–12.
9] Fantini, M.; Rivara, M.; Zuliani, V.; Kalmar, C. L.; Vacondio, F.; Silva, C.; Baheti, A. R.;
Singh, N.; Merrick, E. C.; Katari, R. S.; et al. Bioorg. Med. Chem. 2009, 17, 3642–3648.;
DOI: 10.1016/j.bmc.2009.03.067.
[
10] Almansa, C.; Alfon, J.; de Arriba, A. F.; Cavalcanti, F. L.; Escamilla, I.; Gomez, L. A.;
Miralles, A.; Soliva, R.; Bartrolı, J.; Carceller, E.; et al. J. Med. Chem. 2003, 46, 3463–3475.
DOI: 10.1021/jm030765s.
[
11] (a) Ansari, A.; Ali, A.; Asif, M.; Shamsuzzaman, S. New J. Chem. 2017, 41, 16–41. DOI:
10.1039/C6NJ03181A. (b) Chandna, N.; Kapoor, J. K.; Grover, J.; Bairwa, K.; Goyal, V.;
Jachak, S. M. New J. Chem. 2014, 38, 3662–3672. DOI: 10.1039/C4NJ00226A. (c) Ali, A.
R.; El-Bendary, E. R.; Ghaly, M. A.; Shehata, I. A. Eur. J. Med. Chem. 2014, 75, 492–500.
DOI: 10.1016/j.ejmech.2013.12.010. (d) Tanitame, A.; Oyamada, Y.; Ofuji, K.; Fujimoto,
M.; Iwai, N.; Hiyama, Y.; Suzuki, K.; Ito, H.; Terauchi, H.; Kawasaki, M.; et al. J. Med.
Chem. 2004, 47, 3693–3696. DOI: 10.1021/jm030394f. (e) Chauhan, S.; Verma, V.; Kumar,
D.; Kumar, A. Synth. Commun. 2019, 49, 1427–1435. DOI: 10.1080/00397911.2019.
1
600192.
12] Mert, S.; Kasımo ꢁg ulları, R.; I c¸ a, T.; C¸ olak, F.; Altun, A.; Ok, S. Eur. J. Med. Chem. 2014,
8, 86–96. DOI: 10.1016/j.ejmech.2014.03.033.
_
[
[
[
7
13] Zhu, Y.; Li, C.; Zhang, J.; She, M.; Sun, W.; Wan, K.; Wang, Y.; Yin, B.; Liu, P.; Li, J. J.
Org. Lett. 2015, 17, 3872–3875. DOI: 10.1021/acs.orglett.5b01854.
14] (a) Wang, C.; Wang, E.; Chen, W.; Zhang, L.; Zhan, H.; Wu, Y.; Cao, H. J. Org. Chem.
2
017, 82, 9144–9153. DOI: 10.1021/acs.joc.7b01781. (b) Wu, P.; Zhang, L.; Zhang, X.;
Guo, X.; Chen, B. Chin. J. Chem. 2016, 34, 363–367. DOI: 10.1002/cjoc.201500759. (c)
Qu, J.; Wu, P.; Tang, D.; Meng, X.; Chen, Y.; Guo, S.; Chen, B. New J. Chem. 2015, 39,
4235–4239. DOI: 10.1039/C5NJ00910C.
[
[
15] Li, J.; Neuville, L. Org. Lett. 2013, 15, 1752–1755. DOI: 10.1021/ol400560m.
16] Chen, C. Y.; Hu, W. P.; Yan, P. C.; Senadi, G. C.; Wang, J. J. Org. Lett. 2013, 15,
6116–6119. DOI: 10.1021/ol402892z.
[
17] (a) Tang, D.; Wu, P.; Liu, X.; Chen, Y. X.; Guo, S. B.; Chen, W. L.; Li, J.-G.; Chen, B. H.
J. Org. Chem. 2013, 78, 2746–2750. DOI: 10.1021/jo302555z. (b) Kumar, T.; Verma, D.;
Menna-Barreto, R. F. S.; Valen c¸ a, W. O.; da Silva J uꢂ nior, E. N.; Namboothiria, I. N. N.
Org. Biomol. Chem. 2012, 00, 1–3. DOI: 10.1039/C4OB02561J. (c) Jagadhane, P. B.;
Telveka, V. N. Synlett 2014, 25, 2636–2638. DOI: 10.1055/s-0034-1379185. (d) Wu, Z.;
Pan, Y.; Zhou, X. Synthesis 2011, 14, 2255–2260. DOI: 10.1055/s-0030-1260669.
[
[
18] Wang, Y.; Frett, B.; Li, H. Y. Org. Lett. 2014, 16, 3016–3019. DOI: 10.1021/ol501136e.
19] Li, B.; Chiu, C. K. F.; Hank, R. F.; Murry, J.; Roth, J.; Tobiassen, H. Org. Process Res. Dev.
2
002, 6, 682–683. DOI: 10.1021/op025552b.

1
0
S. PUNIA ET AL.
[
[
[
20] Tiwari, K.; Verma, P. K.; Singh, S. B.; Singh, J. Synth. Commun. 2012, 42, 3021–3030.
DOI: 10.1080/00397911.2011.574329.
21] Elejalde, N. R.; Mac ꢂı as, M.; Castillo, J. C.; Sortino, M.; Svetaz, L.; Zacchino, S.; Portilla, J.
Chem. Select 2018, 3, 5220–5227. DOI: 10.1002/slct.201801238.
22]
CCDC 1917074 (4b) contains the supplementary crystallographic data for the paper.
Crysatallographic details for this compound are included in supplementary information.