Letter
Synthesis of 2‑Imino-1,3,4-thiadiazoles from Hydrazides and
Isothiocyanates via Sequential Oxidation and P(NMe2)3‑Mediated
Annulation Reactions
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ABSTRACT: A P(NMe2)3-mediated annulation reaction of N-
acyldiazenes with isothiocyanates, producing 2-imino-1,3,4-thiadia-
zoles, is reported. This reaction proceeds well with crude N-
acyldiazenes derived from the oxidation of hydrazides by iodine
and permits the sequential synthesis of products directly from
hydrazides without purification of the less stable N-acyldiazene
intermediates. The reaction does not require transition metals and
is a simple, scalable operation with broad substrate scope.
Scheme 1. Synthesis of Nitrogen-Containing Heterocyclic
Compounds by Annulation of N-Acyldiazenes and
Isothiocyanates
1,3,4-Thiadiazoles are important heterocyclic compounds with
a wide range of applications in medicinal, agricultural, and
materials chemistry.1 Their derivatives bearing an amino or
imino group display a broad spectrum of pharmaceutical and
biological properties2 including antimicrobial,3 antitubercular,4
anticancer,5 anti-inflammatory/analgesic,6 antidepressant,7 and
antioxidant activities.8 Consequently, much effort has been
devoted to the synthesis of this class of compounds. To date,
however, methods to prepare 2-imino-1,3,4-thiadiazoles still
rely on the reactions of hydrazonoyl halides or cyanides with
sulfur-containing reagents9 such as thioureas, isothiocyanates,
dithiocarbamates, KSCN, 3-thioxo-[1,2,4]-triazepin-5-ones, or
Erlenmeyer thioazlactones. Therefore, new approaches to the
synthesis of 2-imino-1,3,4-thiadiazole derivatives remain highly
desirable and will benefit the drug discovery community.
N-Acyldiazenes are synthons that are useful for the
construction of diverse heterocyclic skeletons in the presence
of N-heterocyclic carbenes (NHC)10 or other catalysts.11
Previously, we reported a practical method for the preparation
of N-acyldiazenes by iodine-mediated oxidation of hydrazides
under basic conditions. The reaction of these N-acyldiazenes
with isothiocyanates leads to 2-imino-1,3,4-oxadiazoline
products via desulfurization of isothiocyanates.12 Continuing
our research in this area, we describe here a new annulation
reaction of N-acyldiazenes and isothiocyanates promoted by
P(NMe2)3 for the synthesis of 2-imino-1,3,4-thiadiazolines via
deoxidization of N-acyldiazenes (Scheme 1).
by X-ray crystallography (see Notes). Solvent screening
(entries 4−11) suggested that toluene (entry 11) was the
optimal medium for this transformation. Complete consump-
tion of the N-acyldiazene (2a) involves at least 2.0 equiv of the
isothiocyanate (3a) and 2.2 equiv of P(NMe2)3 (entry 13 vs
entries 11, 12, 14). Further studies of the reaction showed that
the optimum reaction temperature was 20 °C (entry 13 vs
entries 15−18). Considering the poor stability of the N-
acyldiazene (2a), we sought to probe the feasibility of the
synthesis of 4a from a hydrazide (1a) without purification of
the intermediate (2a). Upon the completion of the first step,
an oxidation, the reaction was quenched, extracted, and
concentrated to give the crude 2a, which was then directly
subjected to the second-step annulation conditions. The
The required N-acyldiazene (2a) was readily obtained by I2-
mediated oxidation of hydrazide 1a according to our previously
reported procedure.12 Among commonly used organophos-
phine (PR3) reagents (entries 1−4, Table 1), P(NMe2)3 is the
most effective one for the annulation of 2a with an
isothiocyanate (3a) to produce the 2-imino-1,3,4-thiadiazoline
(4a) (entry 4). The structure of compound 4a was confirmed
Received: April 22, 2020
© XXXX American Chemical Society
Org. Lett. XXXX, XXX, XXX−XXX
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