One-pot three-component route for the synthesis of S-trifluoromethyl dithiocarbamates using Togni's reagent

Article abstract of DOI:10.3762/bjoc.13.247

A one-pot three-component route for the synthesis of S-trifluoromethyl dithiocarbamates by the reaction of secondary amines, carbon disulfide and Togni's reagent is described. The reactions proceed in moderate to good yields. A similar reaction using a primary aliphatic amine afforded the corresponding isothiocyanate in high yield. A variable temperature NMR study revealed a rotational barrier of 14.6, 18.8, and 15.9 kcal/mol for the C-N bond in the dithiocarbamate moiety of piperidine, pyrrolidine, and diethylamine adducts, respectively. In addition, the calculated barriers of rotation are in reasonable agreement with the experiments.

Full text of DOI:10.3762/bjoc.13.247

One-pot three-component route for the synthesis of
S-trifluoromethyl dithiocarbamates using Togni’s reagent
Azim Ziyaei Halimehjani*1, Martin Dračínský2 and Petr Beier*2
Letter
Open Access
Address:
Beilstein J. Org. Chem. 2017, 13, 2502–2508.
1Faculty of Chemistry, Kharazmi University, P. O. Box 15719-14911,
49 Mofateh St., Tehran, Iran and 2The Institute of Organic Chemistry
and Biochemistry of the Czech Academy of Sciences, Flemingovo
namestí 2, 166 10 Prague 6, Czech Republic
doi:10.3762/bjoc.13.247
Received: 29 September 2017
Accepted: 16 November 2017
Published: 24 November 2017
Email:
Azim Ziyaei Halimehjani* - ziyaei@khu.ac.ir; Petr Beier* -
beier@uochb.cas.cz
This article is part of the Thematic Series "Organo-fluorine chemistry IV".
Guest Editor: D. O'Hagan
* Corresponding author
© 2017 Halimehjani et al.; licensee Beilstein-Institut.
License and terms: see end of document.
Keywords:
dithiocarbamates; electrophilic trifluoromethylation; Togni reagents
Abstract
A one-pot three-component route for the synthesis of S-trifluoromethyl dithiocarbamates by the reaction of secondary amines, car-
bon disulfide and Togni’s reagent is described. The reactions proceed in moderate to good yields. A similar reaction using a prima-
ry aliphatic amine afforded the corresponding isothiocyanate in high yield. A variable temperature NMR study revealed a rota-
tional barrier of 14.6, 18.8, and 15.9 kcal/mol for the C–N bond in the dithiocarbamate moiety of piperidine, pyrrolidine, and
diethylamine adducts, respectively. In addition, the calculated barriers of rotation are in reasonable agreement with the experiments.
Introduction
Dithiocarbamates are well known for their manifold applica- were applied for the synthesis of novel dithiocarbamates.
tions as pesticides, fungicides and crop protection agents in Nevertheless, new synthetic methods towards dithiocarbamates
agriculture [1-3], as intermediates in synthetic organic chem- are sought after and research in this area is still intense.
istry [4-12], radical chain transfer agents in RAFT polymeriza-
tion [13], sulfur vulcanization agents in rubber manufacturing The introduction of a trifluoromethyl group into organic com-
[14] and valuable pharmacophores in medicine [15-17]. Beside pounds is a very productive strategy of modification of mole-
traditional methods, a recent synthesis of dithiocarbamates via a cules for various applications in the fields of pharmaceuticals,
one-pot reaction of an amine, CS2 and an electrophile is of great agrochemicals, and materials sciences. The key properties such
interest due to its simplicity and environmental friendly proce- as metabolic and chemical stability, polarity, bioavailability,
dure. Diverse electrophiles including alkyl halides [18], epox- viscosity and lipophilicity can be altered in molecules contain-
ides [19], alkenes [20-22], aldehydes [23], and alcohols [24] ing the CF3 group in comparison with the nonfluorinated ana-
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logues. Numerous methods have been reported to introduce the (2 equiv) and CS2 (3 equiv) a higher yield of 4a was obtained,
trifluoromethyl group in organic structures including nucleo- albeit the product ratio decreased (Table 1, entry 3). By further
philic, electrophilic, radical and transition metal-mediated tri- varying the equivalents of amines and CS2, we found that when
fluoromethylations. Among the electrophilic trifluoromethyla- using 1.5 equivalents of piperidine and CS2 and 1 equivalent of
tion methods, reagents based on hypervalent iodine (Togni's 3 in THF at −78 °C for 1 hour, the yield was improved to 45%
reagents I and II, Scheme 1b) have been used extensively in tri- with a product ratio of 2.5:1 (Table 1, entry 4). Using excess of
fluoromethylations of S-, P-, O-, and C-nucleophilic functional- 2 and 3 with piperidine as the limiting reagent led to significant
ities [25-32]. Although reports exist on the synthesis of fluori- yield reduction (Table 1, entry 5). The use of chloroform,
nated dithiocarbamates [33-35], the direct trifluoromethylation dichloromethane, ethanol or water as solvents afforded the
of dithiocarbamates has not been described. In 2001 Naumann product, albeit in unsatisfactory yield (interestingly, in aqueous
and co-workers [36] have published a reaction of tetraethyl- KOH the 4a:5a ratio was the highest observed, Table 1, entries
thiuram disulfide with perfluoroorganosilver and perfluo- 6–10). In addition, using Togni's reagent II in THF gave low
roorganocadmium reagents proceeding most probably by a yields of 4a (Table 1, entry 11). Using Et3N as base in THF also
radical mechanism (Scheme 1a). This method suffers from afforded unsatisfactory results (Table 1, entry 12). Although
several drawbacks such as extra reaction steps for the prepara- with the potassium salt of piperidine dithiocarbamate in THF,
tion of the thiuram disulfide and the use of expensive and envi- water or DMF the product ratio increased to 5:1 (Table 1,
ronmentally problematic heavy metals. These observations entries 13–15), the yield of 4a remained low compared to our
prompted us to investigate the reaction of in situ prepared one-pot three-component reaction in THF. In summary, stirring
dithiocarbamic acid with Togni's reagents as a new route to piperidine (1.5 equiv) and CS2 (1.5 equiv) in THF at room tem-
S-trifluoromethyl dithiocarbamates (Scheme 1b).
perature for 10 min, followed by cooling to −78 °C, addition of
3 (1 equiv) and additional stirring for one hour at −78 °C were
considered as optimal reaction conditions for further derivatiza-
Results and Discussion
We started our investigation with a one-pot, three-component tion.
reaction of piperidine, CS2, and a cyclic hypervalent iodane
(Togni's reagent I) as a model reaction to find the optimal reac- In order to explore the scope of the reaction under the opti-
tion conditions for the preparation of S-trifluoromethyl dithio- mized reaction conditions, various commercially available sec-
carbamates (Table 1). In the first run, we observed that the reac- ondary amines were investigated and moderate to good yields
tion of piperidine (1 equiv) with CS2 (2 equiv) in THF for of products 4 were obtained (Scheme 2). The products were iso-
10 min followed by the addition of Togni's reagent I (1 equiv) lated from the reaction mixture by extraction with CH2Cl2 and
and stirring for 2 hours at room temperature afforded the corre- purification was carried out by column chromatography on
sponding trifluoromethyl dithiocarbamate 4a in 25% isolated silica gel using CH2Cl2/n-pentane (1:9) as eluent. The structure
yield and the corresponding thiuram disulfide 5a (ratio of 4a:5a of products was confirmed using IR, 1H NMR, 13C NMR, 19F
1.8:1) (Table 1, entry 1). Performing the same reaction at NMR and HRMS analysis. The dithiocarbamate moiety in S-tri-
−78 °C and slow heating to ambient temperature over 2 hours fluoromethyl dithiocarbamates appeared at 180–185 ppm in the
increased the yield of 4a to 35% with an increase in the 4a:5a 13C NMR spectra, while this group usually can be found at
ratio to 2.4:1 (Table 1, entry 2). Using excess of both the amine 190–200 ppm for S-alkyl dithiocarbamates [4-12]. Also the car-
Scheme 1: Synthetic routes for the preparation of trifluoromethyl dithiocarbamates.
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Table 1: Optimization of the reaction conditions.
Entry 1a (equiv)
2 (equiv)
3 (equiv)
Solvent
T (°C)
Time (h)
Yield 4a (%)a
4a:5ab
1
1
2
1
THF
rt
2
2
1
1
1
1
1
2
2
1
1
2
25
35
40
45
22
17
15
13
15
30
10
10
1.8:1
2.4:1
1.75:1
2.5:1
1.6:1
1:1.4
1.6:1
1.1:1
1.7:1
6:1c
2
1
2
1
THF
−78 to rt
−78
3
2
3
1
THF
4
1.5
1
1.5
2
1
THF
−78
5
1.2
1
THF
−78
6
1.5
1
2
CHCl3
CHCl3
CH2Cl2
EtOH
H2O
0-5
7
2
1
rt
8
1.5
1.2
1.5
1.5
1.5
1.5
1.2
1.5
1.5
1.5
1
−78
9
1
−78
10
11
12
1
0 to rt
−78
1
THF
1:1.8d
1:1e
1
THF
−78 to rt
13
14
15
1
1
1
THF
H2O
DMF
−78 to rt
1.5
10
25
12
4:1
5:1
1:1
(1 equiv)
0 to rt
2
(1.5 equiv)
−55 to rt
1.5
(1 equiv)
aIsolated yield of 4a. bThe ratio of 4a:5a was determined by 1H NMR spectroscopy of the crude reaction mixture. cKOH (1.5 equiv) was used. dTogni's
reagent II was used instead of Togni's reagent I (3). eEt3N (1.5 equiv) was used.
bon of the CF3 group was observed at around 128 ppm as Schoenebeck [37] who showed that isothiocyanates are formed
quartet with a coupling constant of ≈308 Hz. In addition, a in reactions of primary amines with the (Me4N)SCF3 salt
singlet at −40 ppm in the 19F NMR spectra was assigned to the (through a different mechanism).
CF3 group.
Interesting differences in the NMR spectra of compounds 4a–i
The one-pot reaction of benzylamine with CS2 and Togni's were observed. The nitrogen–carbon bond in the dithiocarba-
reagent I under optimal reaction conditions was also investigat- mate group [N–C(S)S] has a bond order higher than one leading
ed. Surprisingly, we observed that the corresponding benzyl iso- to nonequivalence of the two alkyl substituents attached to the
thiocyanate was obtained in high yield. This may be attributed nitrogen atom. However, the rotational barrier of the N–C bond
to the low stability of the corresponding S-trifluoromethyl differs significantly for individual compounds and 1H NMR
benzyldithiocarbamate. Alternatively, the iodane 3 can act as an spectra exhibit features of slow to intermediate chemical
oxidant towards the intermediate benzyl dithiocarbamic acid exchange with substantial signal broadening in some cases.
rather than an electrophilic trifluoromethylating reagent Therefore, we performed a variable temperature NMR study to
(Scheme 3). A similar behavior was recently reported by determine rotational barriers of compounds 4a–c, and the exper-
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imental data are compared to and rationalized by DFT calcula-
tions.
Figure 1 depicts variable temperature 1H NMR spectra of com-
pound 4c. The coalescence of the methyl signals can be ob-
served at 308 K, whereas the coalescence of the CH2 signals
would require an even higher temperature than 328 K. Com-
plete lineshape analysis approach (dynamic NMR, dNMR) pro-
vided the rates of rotation around the N–C bond at all tempera-
tures and the Eyring plot (Figure 2) allowed to determine
the enthalpy and entropy of activation. The entropy of activa-
tion is small (−4.2 cal/K) and the free energy of activation
(15.8 kcal/mol at 300 K) is dominated by the enthalpic term
(14.6 kcal/mol). The rate of rotation k at coalescence tempera-
ture can also be determined by applying the equation
k = 2.22Δν, where Δν is the difference between resonance
frequencies of the exchanging signals at slow exchange regime
(at low temperature). The rotational barrier for compound 4c
determined using this approach (15.9 kcal/mol) is almost iden-
tical to that obtained by the dNMR approach and is higher com-
pared to the corresponding nonfluorinated analogue [35,38,39].
Scheme 2: Synthesis of S-trifluoromethyl dithiocarbamates. Isolated
yields are given in parentheses.
Scheme 3: Formation of benzyl isothiocyanate in a reaction with benzylamine.
Figure 1: Variable temperature 1H NMR spectra of compound 4c (CH2 region on the left and CH3 region on the right); the sample was dissolved in
CDCl3.
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The rotational barriers obtained for compounds 4a–c are sum- The rotational barrier in compound 4b is both experimentally
marized in Table 2.
and computationally higher than in the other two compounds
(4a and 4c). This can be explained by the conformational strain
in the five-membered ring in the transition state. In the ground
state, the conformation of the pyrrolidine ring is 4T3 with
limited steric interactions between adjacent CH2 hydrogen
atoms (Figure 3). On the other hand, a 1E conformation is found
in the transition state structure. Hydrogen atoms are close to
unfavorable syn-periplanar arrangement in this conformation,
which leads to an increased energy demand for the pyrrolidine
rotation.
Conclusion
In conclusion, we have reported a novel multicomponent reac-
tion for the synthesis of S-trifluoromethyl dithiocarbamates
from secondary amines, CS2 and Togni's reagent in moderate to
good yields. Under similar conditions, a primary amine afforded
the corresponding isothiocyanate in excellent yield. The pres-
ence of dithiocarbamate and trifluoromethyl groups in a single
structure generates a new family of compounds with potential
application as agrochemicals or in drug design. A variable tem-
perature NMR study allowed the determination of rotational
barriers of 14.6, 18.8, and 15.9 kcal/mol for the C–N bond in
the dithiocarbamate moiety of piperidine, pyrrolidine and
diethylamine adducts, respectively. The results revealed that the
rotational barrier in fluorinated dithiocarbamates is slightly
higher than in the nonfluorinated analogue [35,38,39]. This may
be attributed to a higher electron affinity of the trifluoromethyl
Figure 2: The Eyring plot obtained for the rotation around the N–C
bond in compound 4c.
Table 2: Experimental and calculated (B3LYP/6-31+g**) rotational
barriers (kcal/mol) in compounds 4a–c.
Compound
ΔG#exp
ΔE#calc
4a
4b
4c
14.6
18.8
15.9
14.6
16.3
15.0
The structures of compounds 4a–c was optimized using DFT group and an increased double bond character of the C–N bond.
methods (B3LYP/6-31+g**). In all three cases, the carbon
atoms attached to the nitrogen and the N–C(S)–S–C atoms of
Supporting Information
the dithiocarbamate group are almost in one plane and the
torsion angle S=C–S–CF3 is close to zero in the optimized
Supporting Information File 1
structures. In the transition state corresponding to the rotation
around the N–C bond, the plane with CH2 carbon atoms at-
tached to the nitrogen and the nitrogen atom is almost perpen-
dicular to the N–C(S)–S–C plane. The calculated barriers of
rotation are in reasonable agreement with experimental data
(Table 2).
Experimantal procedures and characterization data of all
products, copies of 1H, 13C, and 19F NMR spectra of all
compounds.
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-13-247-S1.pdf]
Figure 3: The optimized structure of compound 4b (left) and the transition state structure for the rotation around the N–C bond (right).
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Acknowledgements
We are grateful to the faculty of chemistry of Kharazmi Univer-
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ORCID® iDs
Azim Ziyaei Halimehjani - https://orcid.org/0000-0002-0348-8959
Martin Dračínský - https://orcid.org/0000-0002-4495-0070
Petr Beier - https://orcid.org/0000-0002-0888-7465
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