I2/KI-Catalyzed synthesis of 5-trifluoromethylated 1,2,4,6-tetrazepine-3-thiones by annulation of trifluoroacetimidoyl chlorides and thiosemicarbazones

Article abstract of DOI:10.1007/s00706-020-02703-5

Abstract: An efficient and simple protocol for the synthesis of trifluoromethylated 1,2,4,6-tetrazepines by intramolecular cross-coupling of C(sp²)–H and N–H bonds using I₂/KI catalyst under aerobic oxidative has been demonstrated. T

Full text of DOI:10.1007/s00706-020-02703-5

Monatshefte für Chemie - Chemical Monthly
https://doi.org/10.1007/s00706-020-02703-5
ORIGINAL PAPER
I2/KI‑Catalyzed synthesis of 5‑trifuoromethylated 1,2,4,6‑
tetrazepine‑3‑thiones by annulation of trifuoroacetimidoyl chlorides
and thiosemicarbazones
Ali Darehkordi1 · Farzaneh Nejad Khorasani1 · Marziyeh Mohammadi1 · Elham Kazemi1
Received: 21 March 2020 / Accepted: 22 October 2020
© Springer-Verlag GmbH Austria, part of Springer Nature 2020
Abstract
An efcient and simple protocol for the synthesis of trifuoromethylated 1,2,4,6-tetrazepines by intramolecular cross-
coupling of C(sp2)–H and N–H bonds using I2/KI catalyst under aerobic oxidative has been demonstrated. This research
exhibited a nucleophilic substitution reaction and then oxidative cyclization between trifuoroacetimidoyl chlorides and
thiosemicarbazones.
Graphic abstract
Keywords 5-Trifuoromethylated 1,2,4,6-tetrazepine-3-thiones · Trifuoroacetimidoyl chlorides · Thiosemicarbazones ·
C–N bond formation
Introduction
been paid recently. For example, copper(II)-catalyzed enantiose-
lective 1,3-dipolar [3+4] cycloaddition of azomethine imines
with in situ-formed azoalkenes [3], transformations of [1,2,4]-
triazolo[4,3-b][1,2,4,5]tetrazines by action of C nucleophiles have
been established, that these reactions are initiated by nucleophilic
attack at the ring nitrogen atom, the ring opening of the tetrazine
ring followed by recyclization provide new opportunities for con-
struction of [1,2,4]triazolo[4,3-b][1,2,4,6]-tetrazepines [4], reac-
tion of 4-amino-6-benzyl-3-hydrazinyl-1,2,4-triazin-5(4H)-one
with isatin in DMF and/or absolute ethanol in the presence of few
drops of piperidine and then ring closure of 4-amino-6-benzyl-3-
[(2-hydroxy-3H-indol-3-ylidene)hydrazono]-3,4-dihydro-1,2,4-
triazin-5(2H)-one [5] and reaction of 1,2-dialkyldiaziridines with
benzoyl isothiocyanate at the room temperature in the presence
of ionic liquids [emim][BF4] and [emim][PF6] by the cleavage
of the C–N and of the N–N bonds of the diaziridine ring [6] are
some of the important methods for synthesis of these compounds.
Tetrazepine derivatives are important seven-membered aza-
heterocyclic compounds that occupy a signifcant position
in medicinal and pesticide chemistry [1].
Although tetrazepine derivatives are very interesting for
chemists and pharmacists, there are limited methods for synthesis
of these compounds. Due to the importance of tetrazepine in the
pharmaceutical and wide range of applications [1, 2], synthesis
of new tetrazepines and also new methods, much attention has
Electronic supplementary material The online version of this
article (https://doi.org/10.1007/s00706-020-02703-5) contains
supplementary material, which is available to authorized users.
* Ali Darehkordi
darehkordi@vru.ac.ir; adarehkordi@yahoo.com
1
Department of Chemistry, Vali-e-Asr University,
Rafsanjan 77176, Iran
Vol.:(0123456789)
1 3

A. Darehkordi et al.
The trifuoromethyl group (CF3) is one of the most com-
mon fuorinated substituents in medicinal, agricultural, and
material sciences [7] as it ofers simultaneously high lipo-
philicity, an elevated electron density and a steric demand
similar to that of the isopropyl group [8]. Among the tri-
fuoromethylated compounds, N-aryltrifuoroacetimidoyl
halides, because having potentially active sites, are the most
useful trifuoromethylated synthetic blocks. CF3-containing
heterocylic compounds have more attention, because of their
physical and pharmaceutical properties, and use in industry,
medicinal, and agriculture [9].
Work-up and distillation of the mixture reaction produced
the target imidoyl chlorides in good to excellent yields
(Scheme 2) [8]. As well as, the thiosemicarbazone deriva-
tives 2 were prepared using benzaldehyde derivatives
and thiosemicarbazide in the presence of sodium acetate
(Scheme 3) [11].
First, we selected N-(p-methoxyphenyl)acetimidoyl
chloride 1a and thiosemicarbazone 2a as the model reac-
tion for our investigation. Various solvents such as THF,
CH3CN, toluene, DMF, and DMSO, and also diferent bases
such as Et3N, NaH, K2CO3, and Cs2CO3 were used in the
presence of KI/I2 at room temperature, 50 °C, 100 °C, and
refux conditions. When trifuoromethylimidoyl chlorides 1
reacted with thiosemicarbazone derivatives 2 using I2/KI as
catalyst and K2CO3 in DMSO at 100 °C, the corresponding
7-(4-methoxyphenyl)-6-(p-tolyl)-5-(trifuoromethyl)-2,6-di-
hydro-3H-1,2,4,6 tetrazepine-3-thione (3a) was produced in
the best yield (80%). All of the reactions were performed in
these conditions to produce the corresponding trifuorometh-
ylated tetrazepine-3-thiones 3a–3e in good yields (Table 1).
To investigate the efects of electronics on the reaction
time and yield, several imidoyl chlorides and thiosemicarba-
zones containing electron-withdrawing and electron-releasing
groups were used (Table 1). The reaction proceeds without
signifcant diferences in reaction time or yield. Due to the
steric hindrance efect of substituents in ortho- or meta posi-
tion of thiosemicarbazones, we did not obtain any product.
The structures of products were confrmed by IR, 1H NMR,
13C NMR, and 19F NMR. For example, the IR spectrum of
7-(4-methoxyphenyl)-6-(p-tolyl)-5-(trifuoromethyl)-2,6-dihy-
Also, C–N bond formation is considered as an impor-
tant phenomenon in synthetic organic chemistry because of
the ubiquitous nature of C–N bonds in various biologically
active molecules [10]. Herein, we wish to report a highly
efcient method for synthesis of CF3-containing tetrazepine-
3-thione derivatives by formation of a new C–N bond of
Csp2–H thiosemicarbazone and NH of trifuoroacetimi-
doyl chlorides section in the presence of I2/KI oxidant
(Scheme 1). It is noteworthy that we did not see any report
about the synthesis of trifuoromethylated 1,2,4,6-tetraze-
pine-3-thione derivatives in the literature.
Results and discussion
To initiate our study, trifuoromethylimidoyl chloride 1 was
prepared according to the procedure which was reported by
reaction of trifuoroacetic acid, primary arylamines, and tri-
phenylphosphine in CCl4 in the presence of triethylamine.
Scheme 1
Scheme 2
Scheme 3
Scheme 1
1 3

I2/KI‑Catalyzed synthesis of 5‑trifuoromethylated 1,2,4,6‑tetrazepine‑3‑thiones by…
Table 1 Synthesis
of 6,7-diphenyl-5-
(trifuoromethyl)-2,6-dihydro-
3H-1,2,4,6-tetrazepine-3-thione
derivatives 3a–3e
Conditions: KI (0.5 mmol), I2 (0.5 mmol), K2CO3 (1.5 mmol), 1 (0.5 mmol), 2 (1 mmol) in DMSO at
100 °C.
dro-3H-1,2,4,6-tetrazepine-3-thione (3a) displayed character-
istic NH and C=S vibrations at 3441 and 1056 cm−1 , respec-
tively. The 1H NMR spectrum of 3a presented two singlets at
2.37 and 3.73 ppm for the protons CH3 and OCH3 and four
doublets at 6.93, 7.34, 7.35, and 7.46 ppm were assigned to
the proton’s aryl rings. Also, NH proton appeared at 7.35 ppm.
The 13C NMR spectrum of 3a displayed a quartet signal at
δ=123.0 ppm for CF3 with a coupling constant 266.4 Hz, and
formation reaction of Csp2–H thiosemicarbazone and NH tri-
fuoroacetimidoylchlorides bonds.
Experimental
All chemicals and solvents were purchased from commercial
sources and used without further purifcation unless oth-
erwise stated. Melting points were determined on a Melt-
Tem II melting point apparatus. IR spectra (KBr, neat) were
obtained on a Thermo Scientifc, Nicolet iS10 Fourier trans-
form IR spectrometer (Thermo Fisher Scientifc, Waltham,
MA, USA). Peaks are reported in wave numbers (cm−1).
All of the NMR spectra were recorded on a Varian model
UNITY Inova 500 MHz (1H: 500 MHz, 13C: 125 MHz, 19F:
470.3 MHz) NMR spectrometer. Chemical shifts of 1H, 13C,
and 19F NMR are reported in parts per million (ppm) from
tetramethylsilane (TMS) as an internal standard in DMSO-
d6 as a solvent.
151.1 ppm for C–CF3 with a coupling constant 35.9 Hz. 19
F
NMR spectrum of 3a displayed a signal at δ=−60.39 ppm
for CF3.
A possible mechanism for this reaction is proposed in
Scheme 4 [12]. The initial reaction of 1 with 2 under basic
conditions gives an imine intermediate A, which this inter-
mediate reacts with iodine-mediated and after that iodocy-
clization generates a species containing a new C–N bond B.
Finally, by tautomerization produce structures 3 (Scheme 4).
Conclusion
General procedure for the synthesis
of trifuoromethylated tetrazepine derivatives 3
In conclusion, we have successfully designed and synthesized
a new series of 1,2,4,6-tetrazepine derivatives which contain a
trifuoromethyl group in good yields via oxidative C–N bond
To a clean 10-cm3 Schlenk flask, molecular iodine
(0.5 mmol), potassium iodide (0.5 mmol), 4 cm3 DMSO
1 3

A. Darehkordi et al.
Scheme 4
130.2, 140.2, 145.5, 150.5, 154.5, 166.6 (q, 2JCF =35.7 Hz,
C–CF3), 171.8 (C=S) ppm; 19F NMR (470.33 MHz, DMSO-
d6): δ=−73.45 ppm.
were added and the resulting mixture was stirred for 10 min
at room temperature. To the resulting solution, trifuoro-
methylimidoyl chloride (0.5 mmol), thiosemicarbazones
(1 mmol), and potassium carbonate (1 mmol) were added
and then stirred for additional 6 h at 100 °C. Upon comple-
tion, the reaction mixture was cooled to room temperature
then quenched with 10 cm3 saturated sodium thiosulfate
solution. The aqueous layer was extracted with ethyl acetate
(3×15 cm3) and dried over anhydrous magnesium sulfate.
Combined organic layer was concentrated and the residue
was purifed by silica gel column chromatography to aford
the corresponding product.
7‑(4‑Bromophenyl)‑6‑(p‑tolyl)‑5‑(trifuoromethyl)‑2,6‑dihy‑
dro‑3H‑1,2,4,6‑tetrazepine‑3‑thione (C17H12BrF3N4S) Red
1
oil; yield: 78%; IR (KBr): ꢀ = 3442, 1056 cm−1; H NMR
(500 MHz, DMSO-d6): δ = 2.36 (s, 3H, CH3), 7.33 (bs,
1H, Ar–H), 7.34 (bs, 2H, Ar–H), 7.35 (bs, 1H, NH), 7.36
3
(bs, 1H, Ar–H), 7.47 (d, JHH = 8.3 Hz, 2H, Ar–H), 7.61
3
(d, JHH = 8.3 Hz, 2H, Ar–H) ppm; 13C NMR (125 MHz,
DMSO-d6): δ=21.2 (CH3), 117.3 (q, 1JCF =186.6 Hz, CF3),
124.8, 125.1, 128.0, 130.3, 130.7, 131.2, 132.2, 135.0,
141.1, 149.2 (q, 2JCF =33.9 Hz, C–CF3), 156.3 (C=S) ppm;
19F NMR (470.33 MHz, DMSO-d6): δ=−60.42 ppm.
7‑(4‑Methoxyphenyl)‑6‑(p‑tolyl)‑5‑(trifluorometh‑
yl)‑2,6‑dihydro‑3H‑1,2,4,6‑tetrazepine‑3‑thione (3a,
C18H15F3N4OS) Red oil; yield: 85%; IR (KBr): ꢀ = 3441,
1
1056 cm−1; H NMR (500 MHz, DMSO-d6): δ = 2.37 (s,
6‑(2‑Chlorophenyl)‑7‑(p‑tolyl)‑5‑(trifuoromethyl)‑2,6‑dihy‑
dro‑3H‑1,2,4,6‑tetrazepine‑3‑thione (C17H12ClF3N4S) Red
3H, CH3), 3.73 (s, 3H, OCH3), 6.93 (d, 3JHH =8.9 Hz, 2H,
Ar–H), 7.34 (d, 3JHH =8.4 Hz, 2H, Ar–H), 7.35 (bs, 1H, NH),
7.36 (d, 3JHH =8.9 Hz, 2H, Ar–H), 7.46 (d, 3JHH =8.4 Hz,
2H, Ar–H) ppm; 13C NMR (125 MHz, DMSO-d6): δ=21.2
(CH3), 55.7 (OCH3), 114.6, 118.0, 123.0 (q, 1JCF =266.4 Hz,
CF3), 128.1, 130.7, 141.0, 145.4, 151.1 (q, 2JCF =35.9 Hz,
C–CF3), 156.9, 161.2, 176.0 (C=S) ppm; 19F NMR
(470.33 MHz, DMSO-d6): δ=−60.39 ppm.
1
oil; yield: 80%; IR (KBr): ꢀ = 3440, 1057 cm−1; H NMR
(500 MHz, DMSO-d6): δ = 2.36 (s, 3H, CH3), 7.34 (d,
3JHH =8.3 Hz, 2H, Ar–H), 7.43 (d, 3JHH =8.7 Hz, 2H, Ar–H),
7.47 (d, 3JHH =8.7 Hz, 2H, Ar–H), 7.48 (d, 3JHH =8.3 Hz,
2H, Ar–H) ppm; 13C NMR (125 MHz, DMSO-d6): δ=21.2
(CH3), 119.68 (q, 1JCF =223.3 Hz, CF3), 124.8, 128.0, 128.4,
128.6, 129.2, 129.8, 130.3, 130.7, 131.0, 136.0, 141.1, 145.0
(q, 2JCF =37.9 Hz, C–CF3), 156.18 (C=S) ppm; 19F NMR
(470.33 MHz, DMSO-d6): δ=−60.43 ppm.
7‑(4‑Chlorophenyl)‑6‑(p‑tolyl)‑5‑(trifuoromethyl)‑2,6‑dihy‑
dro‑3H‑1,2,4,6‑tetrazepine‑3‑thione (3b, C17H12ClF3N4S) Red
1
oil; yield: 75%; IR (KBr): ꢀ = 3442, 1056 cm−1; H NMR
6 , 7 ‑ D i ‑ ( p ‑ t o l y l ) ‑ 5 ‑ ( t r i f l u o r o m e t h y l ) ‑ 2 , 6 ‑ d i h y ‑
(500 MHz, DMSO-d6): δ = 2.32 (s, 3H, CH3), 7.22 (d,
dro‑3H‑1,2,4,6‑tetrazepine‑3‑thione (C18H15F3N4S) Red
3
3JHH = 8.1 Hz, 2H, Ar–H), 7.29 (d, JHH = 8.1 Hz, 2H,
oil; yield: 79%; IR (KBr): ꢀ = 3439, 1055 cm−1 1H
;
Ar–H), 7.69 (d, 3JHH = 8.1 Hz, 4H, Ar–H), 11.36 (bs, 1H,
NH) ppm; 13C NMR (125 MHz, DMSO-d6): δ=21.5 (CH3),
123.7 (q, 1JCF =238.8 Hz, CF3), 126.9, 127.4, 128.8, 129.7,
NMR (500 MHz, DMSO-d6): δ = 2.26 (s, 3H, CH3), 2.36
3
(s, 3H, CH3), 7.17 (d, JHH = 8.0 Hz, 2H, Ar–H), 7.30
1 3

I2/KI‑Catalyzed synthesis of 5‑trifuoromethylated 1,2,4,6‑tetrazepine‑3‑thiones by…
3
3
3. Wei L, Wang ZF, Yao L, Qiu G, Tao H, Li H, Wang CJ (2016)
Adv Synth Catal 358:3955
(d, JHH = 8.2 Hz, 2H, Ar–H), 7.32 (d, JHH = 8.0 Hz,
2H, Ar–H), 7.45 (d, JHH = 8.2 Hz, 2H, Ar–H) ppm; 13C
3
4. Ganebnykh IN, Tolshchina SG, Ishmetova RI, Ignatenko NK,
Slepukhin PA, Rusinov GL, Charushin VN (2011) Eur J Org
Chem 2011:2309
NMR (125 MHz, DMSO-d6): δ = 21.2 (CH3), 117.3 (q,
1JCF = 186.6 Hz, CF3), 21.3, 29.4 (2 CH3), 118.8 (q,
1JCF = 230.0 Hz, CF3), 123.0, 129.0, 129.6, 130.6, 140.9,
141.0, 148.6, 151.3 (q, 2JCF =29.9 Hz, C–CF3), 157.1, 162.0,
168.8 (C=S) ppm; 19F NMR (470.33 MHz, DMSO-d6):
δ=−62.21 ppm.
5. Hamama WS, El-Bana GG, Shaaban S, Zoorob HH (2018) J Het-
erocycl Chem 55:971
6. Shevtsov AV, Kuznetsov VV, Lyssenko KA, Belyakov PA, Mak-
hova NN (2006) Mendeleev Commun 4:218
7. Rahmani F, Darehkordi A (2017) Synlett 28:1224
8. Darehkordi A, Kazemi E (2020) Mol Divers 24:131
9. Darehkordi A, Rahmani F, Hashemi V (2013) Tetrahedron Lett
54:4689
Acknowledgments We gratefully acknowledge the Vail-e-Asr Univer-
sity of Rafsanjan Faculty Research Grant for fnancial support.
10. Badigenchala S, Sekar G (2017) J Org Chem 82:7657
11. Wang D, Hong RY, Guo M, Liu Y, Chen N, Li X, Kong DX (2019)
Molecules 24:4003
12. Hu S, Yang Z, Chen Z, Wu X-F (2019) Adv Synth Catal 361:1
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