Thiocyanation of N,N-Dialkylhydrazonoyl Bromides: An Entry to Sulfur-Containing 1,2,4-Triazole Derivatives

Article abstract of DOI:10.1002/ejoc.201700819

A simple and practical one-pot protocol involving sequential C–H bromination and thiocyanation of readily available aldehyde-derived N,N-dialkylhydrazones has been established for the synthesis of 5-thioxo-1,2,4-triazolium inner salts. Application of the method toward the synthesis of value-added 3-sulfanyl-1,2,4-triazoles through N→S alkyl group transfer has also been demonstrated.

Full text of DOI:10.1002/ejoc.201700819

DOI: 10.1002/ejoc.201700819
Communication
Thiocyanation
Thiocyanation of N,N-Dialkylhydrazonoyl Bromides: An Entry to
Sulfur-Containing 1,2,4-Triazole Derivatives
Alexis Prieto,[a] Alexandre Uzel,[a] Didier Bouyssi,*[a] and Nuno Monteiro*[a]
Abstract: A simple and practical one-pot protocol involving se- tion of the method toward the synthesis of value-added 3-
quential C–H bromination and thiocyanation of readily available sulfanyl-1,2,4-triazoles through N→S alkyl group transfer has
aldehyde-derived N,N-dialkylhydrazones has been established also been demonstrated.
for the synthesis of 5-thioxo-1,2,4-triazolium inner salts. Applica-
Introduction
Organic thiocyanates (R-SCN) have been implicated as key inter-
mediates in the synthesis of diverse valuable organosulfur com-
pounds. Many synthetic methods have been developed over
the years to access SCN-derived building blocks, notably based
on nucleophilic substitution of the corresponding organic hal-
ides by using thiocyanate salts as thiocyanating agents.[1] Fre-
quently, however, the resulting organic thiocyanates rearrange
to the thermodynamically more stable isothiocyanate deriva-
tives (R-NCS) through 1,3-shift isomerization.[2] This has gener-
ally been the case for acyl (and aroyl) thiocyanates (Ia),[3] with
only few exceptions,[4] as well as for their nitrogen derivatives,
the imidoyl thiocyanates (Ib) (Scheme 1A).[5] This interesting
Scheme 1. Reactions of acid halides and their nitrogen derivatives with thio-
cyanate salts, involving thiocyanate to isothiocyanate rearrangement.
feature has been shown to also have huge synthetic applica-
tions, especially in heterocyclic series,[3] due to the capacity of
the central carbon atom of the N=C=S group to undergo addi-
tion of a large variety of nucleophilic reagents.
of valuable sulfanyltriazoles through intramolecular N→S alkyl
transfer is also discussed.
Given the importance of the hydrazone functional group in
synthetic organic chemistry,[6] we became interested in explor-
ing the thiocyanation of N,N-dialkylhydrazonoyl halides,[7] ex-
pecting the reaction to yield the corresponding hydrazonoyl
isothiocyanates[8] as reactive intermediates with high synthetic
potential.[9] Herein, we demonstrate that thiocyanation of N,N-
dialkylhydrazonoyl bromides leads to the direct formation of
uncommon 5-thioxo-1,2,4-triazolium inner salts (IV), and estab-
lish hydrazonoyl thiocyanates (III) as first-formed intermediates
in this transformation (Scheme 1B). We also propose a simple
and practical one-pot protocol allowing sequential bromination
and thiocyanation of readily available aldehyde-derived hydraz-
ones. Application of the triazolium inner salts to the synthesis
Results and Discussion
Preliminary investigations were conducted starting from
morpholine-derived hydrazone 1a as
a model substrate
(Scheme 2). Pleasingly, the opening bromination step occurred
almost spontaneously (ca. 5 min as indicated by TLC) in MeCN
at room temperature when using N-bromosuccinimide
(1.1 equiv.) as brominating agent.[10] It was therefore decided
to conduct the thiocyanation reaction subsequently within the
same reaction flask without isolation of the hydrazonoyl brom-
ide 2a. An excess of sodium thiocyanate was thus added, and
the reaction mixture was left to stir for 24 h, after which time
analysis of the crude mixture revealed the presence of a single
product. After standard extraction of water-soluble materials,
the product was isolated in pure analytical form by simple crys-
tallization and, to our surprise, its structure was established as
5-thioxo-1,2,4-triazolium inner salt 5a (93 % isolated yield over
two steps). Interestingly, this class of zwitterionic ring com-
pounds, which also include the related 5-oxo and 5-imino deriva-
[a] Institut de Chimie et Biochimie Moléculaires et Supramoléculaires (ICBMS,
CNRS UMR 5246), Univ Lyon,
Université Claude Bernard Lyon 1, 69622 Villeurbanne, France
E-mail: didier.bouyssi@univ-lyon1.fr
nuno.monteiro@univ-lyon1.fr
http://icbms.fr
Supporting information and ORCID(s) from the author(s) for this article are
available on the WWW under https://doi.org/10.1002/ejoc.201700819.
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tives, had only been scarcely documented, and no synthetic utility
of these compounds has been described so far.[11] This prompted
us to investigate this transformation in more details.
Scheme 2. Sequential C–H bromination/thiocyanation of p-nitrobenzalde-
hyde 4-morpholinylhydrazone (1a).
From a mechanistic point of view, formation of the triazolium
inner salt is supposed to proceed first by nucleophilic substitu-
tion of the in situ generated hydrazonoyl bromide 2a by the
thiocyanate ion to give hydrazonoyl thiocyanate 3a. The latter
would isomerize to the corresponding isothiocyanate 4a, which
would then spontaneously ring close to generate the 1,2,4-tri-
azole ring system. It is interesting that terminating the thio-
cyanation step only 15 min after addition of sodium thiocyan-
ate afforded a 4:1 mixture of 3a and 5a (quantitative yield) by
identical workup and purification steps. Furthermore, stirring
this mixture in MeCN for 24 h in the absence of any other
reagents led to the complete conversion into triazolium 5a,
which gives evidence for the proposed sequence of events.
With a practical one-pot procedure established, we began to
gauge the scope of the process (Scheme 3). We first examined
the reactivity of various benzaldehyde-derived 4-morpholinyl
hydrazones. Good to high yields were generally achieved with
various substituents on the aromatic ring regardless of their
electron-donating or electron-withdrawing nature (5a–5g). An
X-ray structure was obtained for 5c.[12] Overall, the reaction dis-
played good tolerance towards a variety of functional groups,
including nitro, cyano, and halide. A pyrazolyl aldehyde hydraz-
one also proved to be a suitable substrate for the transforma-
Scheme 3. One-pot C–H bromination/thiocyanation of N,N-dialkylhydrazones:
Access to 5-thioxo-1,2,4-triazolium inner salts. Reaction conditions:
1
(1.0 mmol), NBS (1.1 mmol) in 5 mL of MeCN at room temp. until complete
conversion (TLC monitoring, < 15 min); then addition of NaSCN (2.0 mmol),
room temp., 24 h. Yields are given for single runs and refer to analytically
pure products isolated by simple crystallization.
Next, we focused our efforts on finding synthetic application
tion (5h). Remarkably, aliphatic aldehyde-derived hydrazones of triazolium derivatives 5. Interestingly, a diversity of sulfur-
may be involved in the reaction, as illustrated with 5i. Next, the substituted 1,2,4-triazole derivatives has been reported to
influence that the terminal amino group of the hydrazone ex- possess important biological properties,[13] and notably non-
erts on the reaction was examined. Hydrazones bearing other nucleoside HIV-1 reverse transcriptase inhibitory activity
cyclic amino groups, i.e., 1,1-dioxido-4-thiomorpholinyl, 4- (NNRTI).[14] It was envisioned that rearrangement of the
methyl-1-piperazinyl, 1-piperidinyl, and 1-homopiperidinyl, also N-spirotriazolium inner salts through intramolecular N-dealkyl-
participated to give the desired products (5j, 5k, 5l, and 5m, ation/S-alkylation steps would possibly open access to value-
respectively) in moderate to good yields. Finally, a N,N-dimeth- added sulfanyltriazoles, i.e., the triazole-fused S-heterocyclic de-
ylhydrazone proved to be a suitable substrate for this transfor- rivatives 7.[15] Gratifyingly, the desired transformation was
mation as well (5n). It is noteworthy that all synthesized zwitter- achieved by simple heating of the triazolium inner salts at 80 °C
ionic compounds were obtained as bench-stable solids after in DMF in the presence of 2 equiv. LiBr (Scheme 4). Various
simple crystallisation.
triazole-fused heterocycles (7a–e) were thus obtained in mod-
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2.0 mmol) was then added and the reaction mixture was left to stir
for 24 h, after which time the reaction mixture was concentrated in
vacuo and diluted with CH2Cl2 (20 mL). The solution was washed
with water (3 × 10 mL), dried with MgSO4, and concentrated in
vacuo to give a solid residue. Crystallization of the residue from an
appropriate mixture of dichloromethane/petroleum ether gave the
triazolium inner salt in analytically pure form.
erate to excellent isolated yields. Interestingly, synthesis of the
known[16] methylthiotriazole 7f demonstrated that external
N→S methyl group transfer is achievable in a totally selective
manner. It is remarkable that all of the N, C, and S atoms of the
original thiocyanate moiety have contributed to these struc-
tures through bond formation.
General Procedure B. Preparation of Sulfanyltriazoles 7: In a
10 mL screw-cap glass tube equipped with a magnetic stir bar, LiBr
(50 mg, 0.6 mmol) was added to a solution of the selected tri-
azolium inner salt (0.3 mmol) in DMF (1.5 mL). Then the reactor was
sealed, and the reaction mixture was stirred at 80 °C for 2 h. The
reaction mixture was then cooled and diluted with CH2Cl2 (10 mL).
The solution was washed with water (3 × 5 mL), dried with MgSO4,
and concentrated in vacuo to give a solid residue. Purification of
the residue by flash chromatography (silica gel, appropriate mixture
of cyclohexane/ethyl acetate) afforded the corresponding sulfanyl-
triazole.
Acknowledgments
This research was assisted financially by a grant to A. P. from
the French Ministry of Higher Education and Research (MESR).
We thank G. Pilet (Laboratoire des multimatériaux et interfaces,
Université Lyon 1) for the X-ray crystallographic analysis.
Keywords: Hydrazones · Cyclization · Rearrangement ·
Zwitterions · Nitrogen heterocycles
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A one-pot, simple, and practical protocol has been established
for the cyclization of aldehyde-derived hydrazones with thio-
cyanate, which involves
SCN→NCS isomerization, and ring closing sequence. The proto-
col provides an efficient synthetic entry into rarely documented
1,2,4-triazolium inner salts, which are key intermediates for
further elaboration into a diversity of value-added 3-sulfanyl-
1,2,4-triazole derivatives. Further studies into the scope and
synthetic applications of this method are currently underway in
our laboratories, and will be reported as events merit.
a
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Experimental Section
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Received: June 9, 2017
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