Angewandte
Communications
Chemie
report by Suzuki and co-workers in 1998,[10] but, to date, this
À
chemistry could not be extended to the cleavage of CAr
bonds or rearrangement reactions.
O
Herein, we report an NHC-organocatalyzed Truce–Smiles
rearrangement, which operates through an intramolecular
SNAr reaction of a catalytically generated acyl-anion equiv-
alent under mild conditions and with high yields. The
obtained 2-hydroxybenzophenone moiety is present in many
highly important natural products and pharmaceuticals,
including many biologically active and antibiotic compounds
such as pyoluteorin,[11] acremonidin E,[12] the pyrrolomycin
family,[13] the marinopyrrole family,[14] and cercophorin A
(Figure 1).[15] The highly potent glucose-6-phosphate translo-
case inhibitor mumbaistatin[16] and the protein kinase A and
C inhibitor balanol (not shown)[17] also bear the 2-hydroxy-
benzophenone motif.
Figure 1. Members of a large group of biologically active natural
products containing the 2-hydroxybenzophenone moiety. All the com-
pounds shown are antibiotics.
Subjecting salicylaldehyde derivative 1a to NHC catalysis
afforded the rearrangement product 2a under a range of
conditions. The reaction was systematically optimized by
variation of the NHC catalyst, base, solvent, and temperature
by running reactions with substrate 1a on 0.1 mmol scale
Scheme 2. Substrate scope. Yields given are for the isolated products
following column chromatography. 2i and 2an were synthesized on
a 0.3 mmol scale. [a] Reaction at 808C.
1
reactions, with quantification by H NMR spectroscopy and
using CH2Br2 as an internal standard.[18] It was found that the
reaction is most efficient at room temperature in THF with
a weak base (NaOAc) and the use of highly nucleophilic
triazolium-NHC 3, which bears a N-dimethoxyphenyl sub-
stituent,[19] whereas different NHC precursors with less-
electron-donating N substituents or a thiazole or imidazole
core performed significantly worse. Benzophenone product
2a could be isolated from a 0.5 mmol scale reaction in
excellent yield (90%) under optimized conditions.
linker, with the products 2l and 2m obtained in yields of 81%
and 93%, respectively. We next investigated the scope of the
migrating aryl group. The 4-nitro group, which activates the
arene toward SNAr reactions, is also tolerated in the 2-
position (2aa). In addition to this, other electron-withdrawing
groups, such as nitriles and esters, were tolerated in the
reaction with no drop in yield (88% and 91%), however,
these less electron-poor substrates required the reaction be
heated to 808C.
With the optimized conditions in hand, we studied the
scope of the reaction. We first varied the substitution pattern
on the salicylaldehyde portion of the substrate (Scheme 2).
Electron-donating functional groups, such as methyl,
methoxy, ethoxy, and diethylamino (2b–2g), are tolerated,
and provided the products in very high yields of up to 99%.
Reactions of electron-deficient substrates also proceed in
high yields (2h–2j). Changing the benzaldehyde moiety to
naphthaldehyde gives the product 2k in 94% yield.
Next, various heteroarenes were tested in this reaction.
Pyridine derivatives (2ad–2af), as well as pyrazine (2ag),
quinoline (2ah), and isoquinoline (2ai) were all tolerated,
with yields above 90%. Substrates containing benzothiazoles
(2aj and 2ak) and thiazoles (2al and 2am) were tolerated as
well, with excellent yields obtained. Even pyrrole and furan
derivatives, normally highly nucleophilic arenes, could be
employed in this reaction when activated with electron-
À
withdrawing groups (2an and 2ao). Double CAr O bond
À
À
Of particular note is that C S and C N bond cleavage is
also possible when the substrate contains a thioether or amino
cleavage in a pyridine derivative was also achieved, which
afforded 2ap in 82% yield.
2
ꢀ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2017, 56, 1 – 5
These are not the final page numbers!
Janssen-Müller, Daniel
