C-H Functionalization of Benzothiazoles via Thiazol-2-yl-phosphonium Intermediates

Article abstract of DOI:10.1021/acs.orglett.0c00882

Benzothiazoles undergo regioselective C2-H functionalization with triphenylphosphine to form thiazol-2-yl-triphenylphosphonium salts, and these phosphonium salts react with a wide range of O- A nd N-centered nucleophiles to give the corresponding ethers, amines, and C-N biaryls. The reactions proceed under mild conditions and allow for the recovery of triphenylphosphine at the end of the sequence. In the presence of hydroxide, phosphonium salts undergo disproportionation, resulting in the reduction of the benzothiazole, which is useful for specific C2 deuteration of benzothiazoles.

Full text of DOI:10.1021/acs.orglett.0c00882

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Letter
C−H Functionalization of Benzothiazoles via Thiazol-2-yl-
phosphonium Intermediates
̈
You Zi, Fritz Schomberg, Konrad Wagner, and Ivan Vilotijevic*
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ABSTRACT: Benzothiazoles undergo regioselective C2−H func-
tionalization with triphenylphosphine to form thiazol-2-yl-
triphenylphosphonium salts, and these phosphonium salts react
with a wide range of O- and N-centered nucleophiles to give the
corresponding ethers, amines, and C−N biaryls. The reactions
proceed under mild conditions and allow for the recovery of
triphenylphosphine at the end of the sequence. In the presence of
hydroxide, phosphonium salts undergo disproportionation, resulting in the reduction of the benzothiazole, which is useful for specific
C2 deuteration of benzothiazoles.
hosphonium salts are commonly used in organic synthesis
high as 130 °C (Scheme 1c).16 A metal-free pathway for the
C2−H functionalization of benzothiazoles under mild
conditions would be a valuable addition to medicinal chemistry
toolbox and an enabling factor for rapid access to libraries of
small benzothiazole-containing molecules. In his seminal work
on the synthesis of benzothiazol-2-yl-triphenylphosphonium
triflate, Anders showed that the treatment of benzothiazole
with triphenylphosphine in the presence of triflic anhydride
and a base provides direct regioselective access to this salt.11
Here we demonstrate the generality of this process and show
that benzothiazol-2-yl-triphenylphosphonium salts react with a
wide range of O- and N-nucleophiles under mild conditions
and produce C2-substituted benzothiazoles (Scheme 1d). The
two-step sequence constitutes an efficient method for the C2−
H functionalization of benzothiazoles because the phosphine
can be recovered at the end of the sequence.
Encouraged by the early observations of Anders and the later
work of McNally on similar functionalization of pyridines,6,11
our optimization studies focused on the reactions of benzo-
[d]thiazol-2-yltriphenylphosphonium triflate salt 2a with
benzyl alcohol. Activation of the nucleophile with a suitable
base was required. Strong bases like sodium hydride and alkali
hexamethyldisilazide (HMDS) amides performed well, provid-
ing yields of up to 82%. (For details of the optimization
studies, see the SI.) The outcome depended on the quality of
the base used, and some reactions benefited from increasing
the amount of the nucleophile to 1.5 equiv, although a further
P
as reagents in Witting-type olefinations,1 catalysts in
phase-transfer catalysis and related transformations,2 solvents
in processes that rely on the use of ionic liquids,3 and catalytic
intermediates in Lewis-base-catalyzed reactions with phos-
phine catalysts.4 The breadth of their reactivity and the
electrophilic character of the phosphorus atom, in particular,
have driven the recent leaps in the development of synthetic
methods that feature pentavalent phosphorus intermediates
such as biphilic organophosphorus catalysis,5 contractive C−C
coupling via P(V) intermediates,6 and the redox-neutral
organocatalytic Mitsunobu reactions.7 Our interest in
phosphonium ions stems from reactions that use phosphines
as Lewis base catalysts with typical Michael acceptors, which,
in the presence of water and other protic additives, produce
vinylphosphonium intermediates (Scheme 1a).8 We hypothe-
sized that the distinctly different outcomes these reactions have
in the presence of alcohols (oxidation of C3 of the ynone)9
and water (reduction of C3)10 are the consequence of the
differences in the reactivity of the pentavalent phosphorus
intermediates generated in these processes. If this is also
reflected in the reactivity of arylphosphonium salts,11 the easily
accessible heteroarylphosphonium salts would become val-
uable intermediates in the regioselective functionalization of
heterocycles.
Thiazoles and benzothiazoles are the most common five-
membered aromatic N-heterocycles among the FDA-approved
pharmaceuticals,12 and they are present in numerous bio-
logically active molecules (Scheme 1b),13 are important
components of functional materials,14 and are common
intermediates in organic synthesis.15 Although they almost
always feature a heteroatom substituent at C2 in approved
pharmaceuticals, the direct C2−H functionalization of
benzothiazoles remains largely limited to metal-catalyzed
processes that proceed at elevated temperatures, often as
Received: March 9, 2020
https://dx.doi.org/10.1021/acs.orglett.0c00882
© XXXX American Chemical Society
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Scheme 1. Bioactive C2-Substituted Benzothiazoles,
Previous Work on C2−H Functionalization of
Benzothiazoles, and Our Approach Using Phosphonium
Ions
Scheme 2. Scope of the Reaction for O-Nucleophiles
increase had the inverse effect. The reactions proceeded with
high rates at room temperature in THF, with deprotonation of
alcohol usually performed at a low temperature prior to the
addition of the phosphonium triflate.
A range of alcohol nucleophiles were reactive with the
benzothiazol-2-yl-phosphonium salt 2a (Scheme 2). Primary
alcohols, including simple alkyl, benzylic, and propargylic
alcohols, all gave the desired ethers in a yield range of 42−99%
(4a−n). Even electron-poor alcohol proved efficient in a yield
of 84% (4e). Secondary (4i−k) and tertiary aliphatic alcohol
(4l) gave the desired ethers in 72−83% yields and
demonstrated that the reactions tolerate steric hindrance
close to the reactive centers. The reactions performed well
even in the more complex setting, when menthol and
cholesterol were used as the O-nucleophiles (4m and 4n).
Electron-rich phenols performed well in a yield range of 60−
99% (4o−t). When hydroquinone was used, the product of
monosubstitution was produced in 75% yield (4u). Phenols
with an extended conjugated system, a coumarin derivative,
and naphthalen-1-ol were also suitable reaction partners (4v
and 4w). Halogen-substituted phenols were well tolerated in a
yield range of 59−87% (4x−ab). Sterically more demanding
and electron-poor substrates gave slightly lower yields between
59 and 66% (4z−ac). The main side product was
triphenylphosphine, which could be recovered during
purification.
this, secondary amines performed well, with 4ad−af obtained
in 61−81% yield. When acetanilide was used, the product of
amidation could not be isolated, but the product of amide
hydrolysis 4ag was isolated in yields of 30%. Switching to N-
methylbenzamide improved the overall yield to 81%, but a 1:2
mixture of the amide 4ah and the hydrolysis product 4ai was
obtained. A range of N-heterocycles was shown to be reactive
under the same conditions, affording good yields observed for
pyrroles and indoles regardless of their electronic properties
(4aj−ap, Scheme 3). Imidazoles and benzimidazoles were
equally reactive (4aq and 4as), but the yields were lowered by
the increasing steric demand of the nucleophile (4at and 4au).
Encouraged by the good reactivity observed with O-
nucleophiles, the focus was shifted to N-nucleophiles (Scheme
3). NaHMDS performs significantly better than NaH with N-
nucleophiles. The initial attempts with primary amines and
anilines proved futile. Instead of the desired products, the
corresponding iminophosphoranes were isolated. Along with
B
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Scheme 3. Scope of the Reaction for N-Nucleophiles
Scheme 4. Reaction Scope for Substituted Benzothiazoles
Using pyrazole as the nucleophile resulted in the formation of
biaryl 4ar in a yield of 54%.
A set of benzothiazol-2-yl-phosphonium triflates carrying
both electron-donating and electron-withdrawing substituents
in positions five, six, and seven, 2a−j (Scheme 4, Step 1), was
prepared in a yield range of 24−87% following the method
described by Anders. (The mechanistic proposal for the
formation of the phosphonium salts is shown in Scheme 5a.) 4-
Methoxyphenol and 5-nitroindole were used to evaluate the
reactions with substituted salts. Both electron-rich and
electron-poor phosphonium salts performed well, giving the
products of etherification (4av−bd) and amination (4be−bj)
in good yields (Scheme 4, Step 2). No obvious trends for the
electronic effect of the substituents on benzothiazole could be
observed, suggesting the generality of this method. The studies
of scope also established the tolerance for ether, nitro, ester,
nitrile, ketone, alkene, alkyne, aryl halides, and other N-
heterocyclic substituents.
Aniline and other primary amines failed to produce any of
the desired amination products when used in reactions with
thiazol-2-yl-phosphonium salts. Instead, the reduced benzo-
thiazole was isolated alongside the iminophosphorane 5
derived from the amine nucleophile and triphenylphosphine
(Scheme 5b). It is reasonable to propose that the N−P bond is
formed through direct nucleophilic attack of the anilide anion
on the electrophilic phosphonium ion. This would produce the
aminophosphonium intermediate iv via nucleophilic substitu-
tion or the pentavalent phosphorus intermediate i via
nucleophilic addition to phosphorus. Under basic conditions,
i would be deprotonated to form ii, which would, in turn,
fragment to produce the iminophosphorane 5 and the
benzothiazolide anion iii.11b,17 Because both pathways involve
the formation of benzothiazolide iii, we hypothesized that the
use of water as the nucleophile (as hydroxide ion) would also
result in reduction of the benzothiazole and the formation of
phosphine oxide. Experiments using only a slight excess of
sodium deuteride demonstrated that this indeed is the case
(Scheme 5c). The specific C2 deuterium labeling with 97%
yield and >98% deuterium incorporation was observed for 6a.
The process appears general, as benzothiazoles with electron-
donating and -withdrawing substituents both undergo efficient
C2 labeling (6b and 6c).
The proposed direct nucleophilic attack of the nucleophiles
to the phosphorus atom in the phosphonium salt with both
primary amines and water suggests that this process could also
operate in the reactions that result in C2 functionalization of
benzothiazole. If the pentavalent phosphorus intermediate
similar to i is indeed on the reaction path, that would
necessitate a contractive C−O or C−N bond formation from
the same intermediate akin to reductive elimination. Another
possible mechanistic scenario is the simple aromatic
nucleophilic substitution reaction that would see nucleophilic
attack to the C2 position of the benzothiazole. Our current
studies are aiming to decipher the reaction mechanism and
determine the chemical competence of the proposed
C
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Konrad Wagner − Institute of Organic Chemistry and
Macromolecular Chemistry, Friedrich Schiller University, Jena,
07743 Jena, Germany
Scheme 5. Formation of Iminophosphoranes and Phosphine
Oxides with Primary Amines and Water
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c00882
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support from the Carl-Zeiss Foundation (endowed
professorship to I.V.) and Friedrich Schiller University Jena is
gratefully acknowledged. We thank Dr. Peter Bellstedt and Dr.
Nico Ueberschaar (both FSU Jena) for help with NMR and
MS analysis and Dr. Wenxue Huang (FSU Jena, currently
Wanhua Research Institute) for the synthesis of some N-
substituted benzothiazoles.
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ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c00882.
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Detailed experimental procedures, spectral data for all
new compounds, and 1H, 13C, 19F, and 31P spectra
(PDF)
AUTHOR INFORMATION
Corresponding Author
■
Ivan Vilotijevic − Institute of Organic Chemistry and
Macromolecular Chemistry, Friedrich Schiller University, Jena,
07743 Jena, Germany; orcid.org/0000-0001-6199-0632;
Email: ivan.vilotijevic@uni-jena.de
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