Synthesis of Isothiocyanates and Unsymmetrical Thioureas with the Bench-Stable Solid Reagent (Me4N)SCF3

Article abstract of DOI:10.1021/acs.orglett.7b00689

A highly efficient, selective, and rapid transformation of primary amines and diamines to isothiocyanates and cyclic thioureas is disclosed. As opposed to established approaches that employ toxic or volatile electrophilic liquids and require reaction control (i.e., slow addition, cooling), this protocol utilizes the bench-stable, solid reagent (Me₄N)SCF₃ at room temperature. The method is characterized by operational simplicity, high speed, efficiency, high functional group tolerance, and late-stage applicability. The byproducts are solids, allowing isolation of the target compounds by filtration.

Full text of DOI:10.1021/acs.orglett.7b00689

Letter
pubs.acs.org/OrgLett
Synthesis of Isothiocyanates and Unsymmetrical Thioureas with the
Bench-Stable Solid Reagent (Me4N)SCF3
Thomas Scattolin, Alexander Klein, and Franziska Schoenebeck*
Institute of Organic Chemistry, RWTH Aachen University, Landoltweg 1, 52074 Aachen, Germany
S
* Supporting Information
ABSTRACT: A highly efficient, selective, and rapid transformation of
primary amines and diamines to isothiocyanates and cyclic thioureas is
disclosed. As opposed to established approaches that employ toxic or
volatile electrophilic liquids and require reaction control (i.e., slow
addition, cooling), this protocol utilizes the bench-stable, solid reagent
(Me4N)SCF3 at room temperature. The method is characterized by
operational simplicity, high speed, efficiency, high functional group
tolerance, and late-stage applicability. The byproducts are solids, allowing
isolation of the target compounds by filtration.
sothiocyanates are valuable and ubiquitous building blocks in
natural product synthesis, in materials chemistry, in the
By contrast, this report describes the reaction of a solid,
formally nucleophilic “CS” source [i.e., (Me4N)SCF3] with
primary amines to generate a range of isothiocyanates in a
selective manner.
I
pharmaceutical arena, and more generally in synthesis.1
Applications range from synthetic intermediates en route to
heterocycles, to food additives and compounds of medicinal
importance.2 Synthetic access to isothiocyanates is realized
primarily through the reaction of primary amines with a highly
electrophilic “CS” source, such as carbon disulfide,3
thiophosgene,4,5 or related thiocarbonyl transfer agents (see
Figure 1), e.g. thiocarbonyldiimidazole and dipyridylthiono-
The bench-stable and easily accessible (Me4N)SCF3 salt has
recently found widespread applications in the transition-metal-
catalyzed trifluoromethylthiolation of aryl (pseudo)halides.8,9
As part of our activities in this area,9 we recently encountered
the unexpected direct reactivity of secondary amines with
(Me4N)SCF3 to generate thiocarbamoyl fluorides. Capitalizing
on the rapid access to this valuable intermediate, we were able
to generate a range of R2N−CF3 compounds through further
reaction with AgF.10 While our efforts to fully elucidate the
mechanism are still ongoing, a notable reactivity feature of
(Me4N)SCF3 is the unique selectivity pattern for “N−H”
functionality, leaving otherwise more nucleophilic sites, such as,
for example, tertiary amines, heterocycles, or alkoxides, that lack
a proton untouched.10 As this selectivity contrasts the
established nucleophile/electrophile reactivity paradigm, we
envisioned that the (Me4N)SCF3 salt should have wider
synthetic potential, in particular for late-stage synthetic
applications. This report documents our investigation with
primary amines.
We observed that the addition of the solid (Me4N)SCF3 in a
single portion to a solution of aniline and the mild base NEt3 in
DCM at room temperature led to the direct and near-
quantitative formation of isothiocyanate 3 (illustrated in
Scheme 1). Notably, all side species generated in the
transformation were salts (tetramethylammonium bifluoride
and triethylammonium fluoride) and precipitated as solids
upon addition of low polarity solvents (e.g., hexane or pentane)
at the end of the reaction, which allowed the isolation of the
Figure 1. General approaches vs our strategy.
carbonate (DPT).6 Despite the arsenal of available reagents,
challenges still remain. For example, the commonly used
thiophosgene (SCCl2) is a toxic liquid that reacts highly
exothermically, requiring careful control of temperature and
addition rate. Carbon disulfide (CS2), a highly flammable and
volatile liquid, requires stoichiometric coreagents, such as
Boc2O, triphosgene, cyanuric chloride, DCC, strong acids or
bases, or needs an elevated reaction temperature.4,7 Aside from
safety aspects in the general handling of these compounds, their
instability and reactivity patterns can also be disadvantageous.
For example, low functional group tolerance or selectivity issues
may arise as a consequence of their highly electrophilic
properties, particularly when applied to the synthesis of densely
functionalized compounds, i.e. late-stage synthetic applications.
Received: March 8, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b00689
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
substituent. This includes ortho-keto (2), -nitrile (9), and
-methoxy (10) functionalities and even the bulky tert-butyl
group (7). Additional valuable functional groups, such as nitro
(5), thioether (8), halogens (11), ester (16 and 19), and
tertiary amine (15), were also shown to be well tolerated, and
electron-deficient amines that otherwise react sluggishly by
established methods proved to be efficiently transformed also.
Moreover, the heterocyclic isothiocyanates (12 and 13) could
be synthesized in high yields (75% to 99%).
Scheme 1. Scope in the Synthesis of R−NCS
To demonstrate the larger-scale applicability of the method-
ology, we synthesized 16 on a 10 mmol scale (1.78 g). The
solid (Me4N)SCF3 reagent was added in one portion at room
temperature also at larger scale. There was no significant
warming of the mixture and no need for external cooling and
reaction control, as would otherwise be required for alternative
highly electrophilic reagents, such as thiophosgene.
As a further test of the applicability of this methodology in
the synthesis of more complex molecules and pharmaceutical
applications, several important drug molecules and medicinally
privileged heterocycles were also examined (22−25, Figure 2).
a
sConditions: Amine (0.2 mmol), (Me4N)SCF3 (39 mg, 0.22 mmol),
b
Et3N (42 μL, 0.3 mmol), DCM (1.5 mL). Full conversion was
observed in 15 h.
R−NCS upon simple filtration. Our further explorations
showed that not only DCM but also a wide range of alternative
solvents could be utilized for these reactions, such as toluene,
EtOAc, acetone, THF, Me-THF, MeCN, MTBE, and CPME.
The transformations were equally fast and efficient in these
media. As such, the method appears to be highly practical, using
an easy-to-handle solid as the “CS” source, so circumventing
the need for cooling, slow addition, or purification from
stoichiometric coreagents or byproducts. Moreover, the
(Me4N)SCF3 reagent is characterized by high stability. It is
completely stable as a solid and also in solution. Our
preliminary mechanistic data suggest that there is no
spontaneous liberation of the potentially reactive electrophile,
SCF2.11 Instead, our in situ NMR spectroscopic studies
suggest that the reagent remains unchanged in solution until
addition of the reactive “N−H” substrate, which results in the
direct and rapid formation of R−NCS and salt byproducts.
We next set out to explore the full scope of this
transformation. A wide range of aliphatic and aromatic primary
amines were efficiently transformed with (Me4N)SCF3, yielding
the corresponding R−NCS compounds in excellent yields (see
Scheme 1).
Figure 2. Synthesis of pharmaceutical analogues using analogous
conditions to Scheme 1.
Once again, the transformations were found to be highly
effective, regardless of the molecular complexity. Notably, there
was distinct selectivity for the primary amine, leaving sensitive
(dihydropyridine 24) and alternative nucleophilic moieties
(such as pyridazine in 23 and the tertiary amine in 25)
completely untouched.
To further probe the reactivity of (Me4N)SCF3 relative to
established electrophilic “CS” sources, we undertook a
comparative examination of thiophosgene vs (NMe4)SCF3 for
their ability to discriminate between primary and secondary
amine sites by reaction with N-methyl-1,3-diaminopropane (see
Scheme 2). While thiophosgene generated a complex mixture
of polymeric material under analogous conditions, the well-
defined unsymmetrical cyclic thiourea 31 (83%) was formed
with our method. Such cyclic, unsymmetrical thioureas are used
as antiatherosclerotic agents (i.e., for declogging of arteries),12
as crucial synthetic intermediates en route to pharmaceutically
relevant molecules,13 as ligands for metals,14 or as precursors to
access N-heterocyclic carbenes via reduction.15 They are
traditionally made with CS2 under strongly acidic conditions
and/or high temperature.16 Thus, our method constitutes a
significant advance, being mild, safe, and convenient. We
present several more examples in Scheme 2, including five- and
six-membered rings. A notable highlight is the synthesis of 29
in 90% yield, a relative of a key intermediate toward Dabigatran
The protocol proved to be compatible with bulky aliphatic
amines (e.g., adamantyl 17 or tert-butyl 20), electron-rich or
-deficient aromatic amines, and a wide range of functional
groups. The efficiency was not influenced by the relative
positioning of the amine group to additional substituents on the
aromatic ring: ortho-, meta-, and para-substituents were fully
tolerated, regardless of the electronic or steric nature of the
B
DOI: 10.1021/acs.orglett.7b00689
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 2. Scope of Unsymmetrical Cyclic Thioureas (1)
and Test Reaction with Thiophosgene (2)
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Conditions: Diamine (0.2 mmol), (Me4N)SCF3 (39 mg, 0.22 mmol),
Et3N (42 μL, 0.3 mmol), DCM (1.5 mL).
etexilate,17 showcasing the utility of the reagent for the
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In summary, a convenient, operationally simple, and
comparably safe method to access isothiocyanates and
unsymmetrical cyclic thioureas from the bench-stable solid
(Me4N)SCF3 and primary amines has been disclosed herein.
The method is characterized by high speed, selectivity,
generality, functional group tolerance, and ease of purification
(filtration). As opposed to traditional reagents to access these
compound classes, there is no requirement for external cooling
or reaction control (such as slow addition), allowing addition of
the solid reagent (Me4N)SCF3 at room temperature in one
portion, even at larger scale (for up to 10 mmol, >1 g
demonstrated).
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b00689.
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AUTHOR INFORMATION
■
Corresponding Author
*E-mail: franziska.schoenebeck@rwth-aachen.de.
ORCID
(17) Zerban, G.; Schmitt, H.-P. (Boehringer Ingelheim)
EP1609784A1, 2005.
Franziska Schoenebeck: 0000-0003-0047-0929
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We thank the RWTH Aachen University and the MIWF NRW.
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DOI: 10.1021/acs.orglett.7b00689
Org. Lett. XXXX, XXX, XXX−XXX