Synthesis, antimicrobial, and brine shrimps lethality assays of 3,3-diaryl-4-(1-methyl-1H-indol-3-yl)azetidin-2-ones

Article abstract of DOI:10.1002/jhet.2057

The paper describes the synthesis, characterization data, and biological activity (antibacterial, antifungal, and brine shrimps lethality) of new azetidin-2-ones. The compounds have been synthesized by the reaction of diarylketenes, generated in situ from

Full text of DOI:10.1002/jhet.2057

Month 2014
Synthesis, Antimicrobial, and Brine Shrimps Lethality Assays of 3,
3-Diaryl-4-(1-methyl-1H-indol-3-yl)azetidin-2-ones
a
b
a
c
*
Girija S. Singh, Yasser M. S. A. Al-kahraman, Disah Mpadi, and Masoom Yasinzai
aDepartment of Chemistry, University of Botswana, Private Bag: 0022, Gaborone, Botswana
bInstitute of Biochemistry, University of Balochistan, Quetta, Pakistan
cVice Chancellor's office, Quaid-i-Azam University, Islamabad, Pakistan
*
E-mail: singhgs@mopipi.ub.bw
Received April 3, 2013
DOI 10.1002/jhet.2057
Published online 00 Month 2014 in Wiley Online Library (wileyonlinelibrary.com).
The paper describes the synthesis, characterization data, and biological activity (antibacterial, antifungal,
and brine shrimps lethality) of new azetidin-2-ones. The compounds have been synthesized by the reaction
of diarylketenes, generated in situ from thermal decomposition of the 2-diazo-1,2-diarylethanones, with
N-(1-methyl-1H-indol-3-yl)methyleneamines. The compounds have been characterized by elemental
analysis and spectral (IR, 1H and 13C NMR, and MS) data. The paper also reports the results of antibacterial,
antifungal, and brine shrimps lethality assays of these compounds. Some of the compounds exhibited
significant biological activity.
J. Heterocyclic Chem., 00, 00 (2014).
INTRODUCTION
diazo-1,2-diarylethanones to generate diarylketenes in
situ as a clean and convenient method requiring no base
or any special reaction condition [16–19].
Azetidin-2-ones, commonly known as β-lactams, are
well-known heterocyclic compounds of biological interest
[1]. The potential antibacterial activity of the β-lactam group
of antibiotics such as penicillins, cephalosporins, and
carbapenems is attributed to the presence of azetidin-2-one
ring in them. The growing concern about development of
resistant pathogens due to β-lactamase enzyme led to
extensive investigation on the isolation of β-lactams from
natural resources, and design and synthesis of natural prod-
ucts-inspired β-lactams [1–3]. Once again, it was a β-lactam
clavulanic acid that offered the major relief as a β-lactamase
inhibitor. A monocyclic azetidin-2-one ezetimibe is now in
clinical use as cholesterol absorption inhibitor [4]. Apart
from these three main biological activities, studies are also
in progress to synthesize new β-lactams and explore their
anticancer activity, hypoglycemic activity, antileishmanial
activity, antiplasmodial activity [5–7], and so forth.
The synthesis of β-lactams involves different types of
cycloaddition reactions and cyclization reactions involving
β-amino acids or β-amino esters [1]. The Staudinger's
ketene–imine cycloaddition is one of the most common
cycloaddition reactions that is used for the synthesis of
β-lactams [8]. This method, which involves generation
of ketenes from acid chlorides in the presence of a tertiary base
or directly from carboxylic acid employing an acid activator
and a tertiary bases, has been used recently by several groups
for the synthesis of diverse types of azetidin-2-ones [5–7,9–
15]. Our group has been using thermal decomposition of 2-
We have recently reported the synthesis and antileishmanial
activity of new natural product-inspired azetidin-2-ones
synthesized by the reaction of N-(1-methyl-1H-indol-3-yl)
methyleneamines with 2-diazo-1,2-diarylethanones under
thermal conditions as a short communication [20]. The present
paper reports the full characterization data and results of
antibacterial, antifungal, and brine shrimps lethality assays
of these compounds. The brine shrimps lethality assay
nowadays is commonly used as a quick and simple method
to know the general toxicity and as a guide to determine the
antitumor activity of the compounds [21,22].
RESULTS AND DISCUSSION
Chemistry. The reaction of 2-diazo-1,2-diarylethanones
1 with N-(1-methyl-1H-indol-3-yl)methyleneamines 4 by
refluxing in dry benzene for 8 h afforded white crystalline
compounds characterized as 3,3-diaryl-4-(1-methyl-1H-
indol-3-yl)azetidin-2-ones 6 (Scheme 1) on the basis of
satisfactory elemental analysis and spectral data. The IR
spectra of the products showed the strong absorption band at
1733 6 cmÀ1 corresponding to the azetidin-2-one carbonyl
group. The 1H NMR spectral spectra showed two
characteristic singlet signals at around δ 3.4 ppm (three
protons) and 6.0 ppm (one proton) corresponding to the
N-methyl protons and β-lactam ring proton besides other
© 2014 HeteroCorporation

G. S. Singh, Y. M. S. A. Al-kahraman, D. Mpadi, and M. Yasinzai
Vol 000
Scheme 1
protons. The 13C NMR spectra showed the carbonyl carbon
around δ 167 ppm.
significant activity on all the strains except F. solani in
which the compounds show good to moderate activity. The
results of antifungal bioassay (Table 2) indicate significant
activity of the compounds 6a, 6e, 6f, and 6h against
C. albicans. The compounds 6b and 6c exhibit good activity
against this fungus, whereas 6d, 6g, and 6i show moderate
activity toward same fungus.
The compounds 6e, 6f, and 6h also show significant
activity against M. canis. The compounds 6a, 6c, and 6d
show good activity against this fungus, and compound 6b
shows moderate activity.
The formation of products is explained by the reaction of
diarylketenes 3, generated in situ by thermal decomposition
of the 2-diazo-1,2-diarylethanones 1 followed by the Wolff
rearrangement of the resulting α-ketocarbenes 2 [23], with
the nitrogen atom of azomethine linkage in 4 leading to the
formation of a zwitterionic intermediates 5 that cyclize to
form the azetidin-2-ones 6. The formation of the zwitterionic
intermediate in the reaction of ketenes with imines has been
evidenced earlier [24].
Against F. solani, two azetidin-2-ones 6e and 6h exhibit
good activity and three azetidin-2-ones 6a, 6c, and 6f
exhibit moderate activity. Azetidin-2-ones 6f and 6h
exhibit significant activity against C. glabrata. The com-
pounds 6c and 6g exhibit good activity against this strain,
whereas the compounds 6a, 6d, 6e, and 6f exhibit only
moderate activity.
Pharmacology. Antibacterial activity. The compounds
were screened for their in vitro antibacterial activity
against three Gram-(+) strains: Staphylococcus aureus,
Bacillus subtilis, and Micrococcus luteus, and two Gram-
(À) strains: Enterobacter aerogenes and Escherichia coli
by disk diffusion method (Kirby-Bauer method) using
cefixime as the standard drug. In general, the compounds
showed much better activity against the Gram-(+) strains
in comparison to Gram-(–) strains (Table 1). The
compound 6a having unsubstituted phenyl rings showed
significant activity against all three Gram-(+) strains. Its
minimum inhibitory concentration (MIC) was determined
as 125 μg/mL against B. subtilis and S. aureus, and 500 μg/
mL against M. luteus. Azetidin-2-ones 6d and 6g also
showed significant activity on B. subtilis whereas 6c and
6g showed significant activity on M. luteus.
Brine shrimps lethality assay.
According to the data
shown for brine shrimps lethality assays (Table 3), five
compounds exhibit more cytotoxicity than the standard
drug MS-222. In general, azetidin-2-ones 6e–h bearing
two p-tolyl groups on C-4 position were observed more
toxic in comparison with those with unsubstituted phenyl
rings on this position. Among the azetidine-2-ones 6a–d
obtained from the reaction of diphenylketene with imines,
compound 6c with a 4-ethoxyphenyl group on N-1
position of the azetidine-2-one ring was the most
cytotoxic followed by 6b containing a 4-methylphenyl
group on N-1 position of azetidine-2-one ring. Among
the azetidin-2-ones 6e–h from dip-tolyl series, the
compound 6h bearing a 4-chlorophenyl group on the N-1
position of the azetidine-2-one ring was the most toxic.
Antifungal activity.
The antifungal bioassay was
performed by the agar tube dilution method using
miconazole as the reference drug, in which the test
compounds were screened for activity against Candida
albicans, Microsporum canis, Fusarium solani, and
Candida glabrata. Some compounds of the series exhibited
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2014
Synthesis, Antimicrobial, and Brine Shrimps Lethality Assays of 3,3-Diaryl-4-(1-
methyl-1H-indol-3-yl)azetidin-2-ones
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

G. S. Singh, Y. M. S. A. Al-kahraman, D. Mpadi, and M. Yasinzai
Vol 000
Table 3
Cytotoxicity dataa of compounds 6a–h.
No. of shrimps killed out of 30 per dilution
No.
1000 μg/mL
100 μg/mL
10 μg/mL
LD50
6a
6b
6c
6d
6e
6f
21
25
30
24
30
24
28
30
0
20
23
26
19
26
20
25
27
0
11
17
23
12
22
16
21
24
0
33.61
3.01
0.95
27.18
1.60
6.37
0.85
0.56
6g
6h
Vehicle control
aThe data are based on mean value of three replicates each of 10, 100, and 1000 μg/mL compared with the standard drug MS-222 (LD50 = 4.30 μg/mL).
7.59 (dd, J = 7.5, 1.2 Hz, 2H), 7.49 (m, 3H), 7.32 (m, 7H),
CONCLUSIONS
7.10 (m, 4H), 6.57 (s, 1H), 6.23 (s, 1H), 3.56 (s, 3H); 13C
In conclusion, the paper reports synthesis and character-
ization data of some new natural product-inspired azetidin-
2-ones. The evaluation of compounds for their
antibacterial, antifungal, and cytotoxicity activity led to
discovery of some significantly bioactive azetidin-2-ones.
The compound 6h, bearing two p-tolyl groups on C-3
and a 4-chlorophenyl group on the ring nitrogen, exhibited
highly significant cytotoxicity. This study opens avenue for
further investigation on azetidin-2-ones bearing diverse
types of indole rings in order to develop potential
antitumor compounds.
NMR (CDCl3, δ ppm): 167.6, 141.3, 138.5, 137.8, 136.9,
129.0, 128.9, 128.6, 128.2, 127.7, 127.4, 127.3, 127.2,
126.8, 124.0, 121.9, 119.8, 118.6, 117.7, 109.7, 108.5, 72.3,
61.1, 32.8; MS m/z (%): 428 (M+, 20), 234 (72), 194 (100),
77 (30). Anal. calcd for C30H24N2O: C, 84.08; H, 5.65; N
6.54. Found: C, 83.73; H, 5.97; N, 6.55.
4-(1-Methyl-1H-indol-3-yl)-3,3-diphenyl-1-(p-tolyl)azetidin-
2-one (6b). Yield 88%; mp 152–154°C; IR (KBr, cmÀ1): 1736,
1511, 1372, 739; 1H NMR (CDCl3, δ ppm): 7.6 (m, 3H),
7.25 (m, 4H), 7.10 (m, 6H), 6.88 (m, 4H), 6.35 (s, 1H),
5.98 (s, 1H), 3.35 (s, 3H), 2.11 (s, 3H); 13C NMR (CDCl3,
δ ppm): 167.3, 141.4, 138.6, 136.9, 135.3, 133.5, 129.5,
128.9, 128.6, 128.3, 127.7, 127.4, 127.3, 126.3, 121.9,
119.8, 118.6, 117.6, 109.6, 108.7, 72.2, 61.1, 32.8, 21.0;
MS m/z (%): 442 (M+, 16), 248 (65), 194 (100), 91 (25).
Anal. calcd for C31H26N2O: C, 84.13; H, 5.92; N 6.33.
EXPERIMENTAL
Found: C, 83.86; H, 6.20; N, 6.28.
Chemistry.
Melting points have been recorded on a Stuart
1 - (4 - Ethoxyphenyl) -4- (1 - methyl -1H-indol-3-yl)-3,3-
Scientific melting point apparatus and are uncorrected. The IR
diphenylazetidin-2-one (6c). Yield 71%; mp 222–224°C; IR
(KBr, cmÀ1): 1735; 1510, 1241, 744; 1H NMR (CDCl3, δ
ppm): 7.77 (t, J = 7.5 Hz, 3H), 7.45 (m, 4H), 7.29 (m, 6H), 7.03
(m, 3H), 6.79 (d, J = 9.0 Hz, 2H), 6.51 (s, 1H), 6.11 (s, 1H),
3.97 (q, J = 7.0 Hz, 2H), 3.58 (s, 3H), 1.39 (t, J = 7 Hz, 3H); 13C
NMR (CDCl3, δ ppm): 166.8, 155.4, 141.3, 138.5, 136.8,
131.1, 128.8, 128.6, 128.2, 127.7, 127.3, 127.2, 126.7, 121.8,
119.7, 118.9, 118.5, 114.8, 109.6, 108.5, 72.1, 63.6, 61.0, 32.8,
14.0; MS (m/z, r. i.): 472 (M+, 100). Anal. calcd for
C32H28N2O2: C, 81.87; H, 5.97; N, 5.93. Found: C, 81.52; H,
spectra were recorded on a Perkin-Elmer-781 IR spectrophotometer
1
using KBr disc of the sample. The H and 13C NMR spectra were
recorded in a CDCl3 solution at 300 MHz and 75.4 MHz,
respectively, on a Brucker™ 300 MHz spectrometer. The
mass spectra were recorded on a Finnigan LCQ Deca mass
spectrometer by electrospray ionization. N-methylindole-3-
carboxaldehyde and amines used in the study were Aldrich
products. The imines of N-methylindole-3-carboxaldehyde
were prepared by refluxing it with appropriate amine in ethanol for
2–6 ([A-Za-z0-9,2–6 h [20]. 2-Diazo-1,2-diphenylethanones were
prepared by oxidation of appropriate benzyl monohydrazone with
bis(acetylacetonato)copper(II) according to the reported method [25].
General procedure for the synthesis of azetidin-2-ones
6.25; N, 5.85.
1- (4 - Chlorophenyl) - 4 - (1 - methyl -1H-indol-3-yl)-3,3-
diphenylazetidin-2-one (6d). Yield 62%; mp 109–112°C; IR
1
(KBr, cmÀ1): 1739, 1490, 1373, 739; H NMR (CDCl3, δ ppm):
7.73 (d, J = 7.5 Hz, 3H), 7.35 (m, 12H), 7.05 (m, 3H), 6.53
(s, 1H), 6.11 (s, 1H), 3.60 (s, 3H); 13C NMR (CDCl3, δ ppm):
167.5, 141.1, 138.2, 136.9, 136.2, 129.1, 128.9, 128.6, 128.1,
127.8, 127.5, 127.2, 127.1, 126.9, 122.0, 119.9, 118.9, 118.5,
109.7, 108.1, 72.5, 61.2, 32.9; MS (m/z, r. i.): 462 (M+, 100).
Anal. calcd for C30H23ClN2O: C, 77.83; H, 5.01; N, 6.05.
(6a–j).
An equimolar amount of an appropriate 2-diazo-1,2-
diarylethanone 2a or 2b and appropriate imine 1 mmol of each in
8 mL of dry benzene was refluxed for 8 h under an atmosphere of
N2. The reaction mixture was allowed to stand overnight at room
temperature. The solvent was evaporated under reduced pressure
and residue was triturated with ethanol to afford the white
crystalline product that was recrystallized with ethanol. The
Found: C, 77.35; H, 5.40; N, 5.80.
4-(1-Methyl-1H-indol-3-yl)-1-phenyl-3,3-dip-tolylazetidin-2-
characterization data of the products are as follows.
4-(1-Methyl-1H-indol-3-yl)-1,3,3-triphenylazetidin-2-one
one (6e). Yield 67%; mp 182–184°C, IR (KBr (cmÀ1): 1732,
(6a).
Yield 82%; mp 108–110°C; IR (KBr, cmÀ1): 1737,
1
1498, 1370, 746; H NMR (CDCl3, δ ppm): 7.66 (d, J = 7.8 Hz,
1493, 1376, 739; 1H NMR (CDCl3, δ ppm): 7.84 (m, 3H),
1H), 7.48 (d, J = 8.1 Hz, 2H), 7.37 (dd, J = 7.8, 0.9 Hz, 2H), 7.1
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2014
Synthesis, Antimicrobial, and Brine Shrimps Lethality Assays of 3,3-Diaryl-4-(1-
methyl-1H-indol-3-yl)azetidin-2-ones
(m, 7H), 6.98 (d, J = 8.1 Hz, 2H), 6.90 (t, J = 7.5 Hz, 1H), 6.70 (d,
J = 8.1 Hz, 2H), 6.37 (s, 1H, CH), 5.97 (s, 1H, CH), 3.42 (s, 3H),
2.23 (s, 3H), 2.03 (s, 3H); 13C NMR (CDCl3, δ ppm): 167.9,
138.6, 137.8, 136.9, 136.8, 136.2, 135.6, 129.5, 128.9, 128.6,
128.4, 128.0, 127.3, 127.1, 123.8, 121.8, 119.7, 118.5, 117.6,
109.6, 108.6, 71.7, 61.0, 32.0, 21.1, 20.9; MS (m/z, r. i.): 456
(M+, 100). Anal. calcd for C32H28N2O: C, 84.18; H, 6.18; N,
6.14.; Found: C, 83.80; H, 6.35; N, 5.96.
plates were incubated at 37°C for 24 h. After 24 h of incubation,
the radius of the clear zone showing no bacterial growth was
measured around each well. The zone of inhibition (mm) was
calculated and compared with the standard drug cefixime.
In vitro antifungal assay.
The antifungal activity was
evaluated by the Agar tube dilution method [27] against
C. albican, M. canis, F. solani, and C. glabrata. The concentration
of the test compounds was 200 μg/mL of DMSO. A reference
antifungal standard drug miconazole and DMSO were used as
positive and negative controls, respectively. Incubation
temperature was maintained at 27°C for 7 days. The inculcation
of fungus was carried out with a 4.0 mm diameter piece of
fungus removed from a seven-days-old culture. The growth in the
compound-amended media was determined by measuring linear
growth (mm) and growth inhibition calculated with reference to
the negative control and % inhibition is reported.
Brine shrimps lethality assay. The cytotoxicity was studied
by the brine-shrimps bioassay lethality method [28]. Brine
shrimp (Artemia salina) larvae, used as test organisms, were
hatched at 37°C in artificial seawater prepared by dissolving
commercial sea salt (28 g) in distilled water (1.0 L). For each
sample, the test was performed in three replicates at 10, 100,
and 1000 μg/mL concentrations in DMSO. The survival rate of
the larvae was observed against all concentrations of test
compounds. For this purpose, 0.5 mL sample of each
compound was taken and the solvent from each vial was
evaporated followed by an addition of 2 mL of artificial
seawater. Thirty shrimps were transferred to each vial and the
final volume was adjusted to 5 mL by artificial seawater. The
uncovered vials were placed under florescence light at 25°C
for 24 h after which the number of survivors were counted and
recorded. The data were analyzed with the Finney computer
program (Finney, 1971) for probit analysis to determine the
LD50 values with 95% confidence intervals.
4-(1-Methyl-1H-indol-3-yl)-1,3,3-trip-tolylazetidin-2-one
(6f). Yield 72%; mp 197–198°C; IR (KBr, cmÀ1): 1731, 1511,
1
1371, 741; H NMR (CDCl3, δ ppm): 7.66 (d, J = 7.8 Hz, 1H),
7.48 (d, J= 8.1 Hz, 2H), 7.26 (d, J= 8.4 Hz, 2H), 7.10 (m, 5H), 6.98
(d, J= 8.4 Hz, 2H), 6.92 (d, J= 8.4 Hz, 2H), 6.70 (d, J= 8.1 Hz, 2H),
6.37 (s, 1H, CH), 5.94 (s, 1H, CH), 3.44 (s, 3H), 2.24 (s, 3H),
2.15 (s, 3H), 2.05 (s, 3H); 13C NMR (CDCl3, δ ppm): 167.6,
138.6, 136.9, 136.1, 135.6, 135.3, 133.3, 129.41, 129.39,
128.6, 128.4, 128.1, 127.3, 127.1, 121.7, 119.7, 118.5, 117.6,
109.5, 108.7, 71.6, 61.0, 32.8, 21.0, 20.9; MS (m/z, r. i.): 470
(M+, 100). Anal. calcd for C33H30N2O: C, 84.22; H, 6.43; N,
5.95. Found: C, 84.25; H, 6.40; N, 5.65.
1-(4-Ethoxyphenyl)-4-(1-methyl-1H-indol-3-yl)-3,3-dip-tolylazetidin-
2-one (6g). Yield 76%; mp 128–130°C; IR (KBr, cmÀ1): 1728, 1506,
1231, 749; 1H NMR (CDCl3, δ ppm): 7.66 (d, J = 7 Hz,
1H), 7.48 (d, J = 8.1 Hz, 2H), 7.30 (dd, J = 6.9, 2.1 Hz, 2H),
7.18–7.05 (m, 5H), 6.99 (d, J = 8.1 Hz, 2H), 6.71 (dd,
J = 8.1, 2.2 Hz, 2H), 6.65 (dd, J = 7.1, 2.0 Hz, 2H), 6.37
(s, 1H), 5.93 (s, 1H), 3.84 (q, J = 6.9 Hz, 2H), 3.45 (s, 3H),
2.25 (s, 3H), 2.05 (s, 3H), 1.26 (t, J = 7.1 Hz, 3H); 13C
NMR (CDCl3, δ ppm): 167.2, 155.3, 138.7, 136.8, 136.1,
135.7, 131.3, 129.4, 128.6, 128.4, 128.0, 127.3, 127.1,
121.7, 119.7, 118.9, 118.5, 114.8, 109.5, 108.7, 71.6, 63.7,
61.1, 32.8, 21.1, 20.9, 14.8; MS (m/z, r. i.): 500 (M+, 100).
Anal. calcd for C34H32N2O2: C, 81.57; H, 6.44; N, 5.60.
Found: C, 81.22; H, 6.76; N, 5.80.
1-(4-Chlorophenyl)-4-(1-methyl-1H-indol-3-yl)- 3,3-dip-
tolylazetidin-2-one (6h). Yield 70%; mp 216–218°C; IR (KBr,
cmÀ1): 1731, 1491, 1370, 747; H NMR (CDCl3, δ ppm): 7.63
1
Acknowledgments. We are grateful to the Chemistry Department,
University of Botswana, and Institute of Biochemistry, University
of Balochistan for providing the necessary research facilities.
(d, J = 7 Hz, 1H), 7.48 (d, J = 8.1 Hz), 7.31 (m, 2H), 7.1 (m, 7H),
6.96 (d, J = 8.1Hz, 2H), 6.70 (d, J = 7.8 Hz, 2H), 6.37 (s, 1H),
5.95 (s, 1H), 3.47 (s, 3H), 2.25 (s, 3H), 2.01 (s, 3H); 13C NMR
(CDCl3, δ ppm): 167.8, 138.4, 137.1, 136.9, 136.3, 135.4, 129.5,
129.0, 128.9, 128.5, 128.4, 127.9, 127.2, 127.0, 121.9, 119.8,
118.8, 118.5, 109.6, 108.2, 72.0, 61.2, 32.8, 21.1, 20.9; MS (m/z,
r. i.): 504 (M+, 100). Anal. calcd for C32H27ClN2O: C, 78.27; H,
5.54; N, 5.71. Found: C, 78.30; H, 5.40; N, 5.40.
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In vitro antibacterial activity
was assayed by disc diffusion method [26] against three Gram
(+) strains: S. aureus, B. subtilis, and M. luteus, and two Gram
(À) strains: E. aerogenes and E. coli. Each test compound
(1 mg) was dissolved in 1 mL of dimethyl sulfoxide (DMSO).
The bacterial cultures were prepared fresh in the nutrient broth
medium over 24 h. In order to compare the turbidity of bacterial
culture, the McFarland 0.5% barium sulfate solution was used
(as turbidity standard). To perform the antibacterial assay,
nutrient agar Petri plates were prepared with sterile cotton
swabs; respective bacterial colony lawns were prepared with
sterile cork-borer (4 mm). Using a micropipette, 30 μL of test
solution was poured into the respective wells and the Petri
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

G. S. Singh, Y. M. S. A. Al-kahraman, D. Mpadi, and M. Yasinzai
Vol 000
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet