Angewandte
Communications
Chemie
chemistry laboratory without the need of a flow photoreactor.
like thioethers, ketones and aldehydes give substantially
lower yields.
To evaluate the utility of the metal-free photoreaction we
Using a fused quartz glass vial, a magnetic stirrer and a UV
lamp, yields are only slightly decreased (83% instead of 92%
for 2a), and reaction times increased.
synthesized a range of biaryl pharmacophores found in
important lead compounds and clinically used drugs (Fig-
ure 3B). Biphenylcarboxylic ester 2d and the corresponding
alkoxy-substituted biphenyl 2e, components of a novel anti-
biotic and of a potent histamine H3 receptor antagonist
A-349821, were prepared in 76% and 89% yield, respectively.
The fluorinated biaryl 2 f, an important building block of an
inhibitor of the antiapoptotic protein Bcl-xL, was obtained in
66% yield. Notably, besides biphenylcarboxy esters it is also
possible to synthesize biphenylacetic ester 2g from the
corresponding sulfonamide (48%). Biaryl 2g is a precursor
of the important antiarthritic non-steroidal antiinflammatory
drugs (NSAID) felbinac and xenbucin.
Next, we envisaged the use of the photochemical aryl
coupling method in a total synthesis of cannabinol. Because of
its analgesic and antiemetic properties this non-psychoactive
cannabinoid is a valuable therapeutic, yet it is only produced
in trace amounts by Cannabis.[16] A photosplicing route to the
cannabinol biaryl scaffold required a highly substituted
sulfonamide precursor that was readily accessible starting
from olivetol (see the Supporting Information). Irradiation
provided the corresponding biaryl (2h) in excellent yield
(93%). Subsequent demethylation, nitrile hydrolysis and
lactonization were achieved in a one-pot reaction (67%).
The obtained benzochromenone was quantitatively converted
into cannabinol by reaction with methyllithium.[17]
Finally, we prepared the biaryl pharmacophore of the top-
selling antihypertensive agents (sartans) such as losartan
(Cozaarꢀ), valsartan (Diovanꢀ), and telmisartan (Micar-
disꢀ).[18] According to the patent literature, their synthesis is
based on Pd-catalyzed cross-couplings and subsequent bro-
mination at the benzylic position, followed by nucleophilic
substitution with primary amines or imidazoles.[19] We estab-
lished a metal-free synthesis of the sartane biaryl scaffold by
irradiation of two different o-substituted sulfonamides, yield-
ing nitrile- and carboxymethyl-substituted biphenyl building
blocks (2i and 2j), which represent valuable starting points to
the synthesis of all important sartans. Whereas the tetrazole
substituents are easily accessible by treatment with sodium
azide, hydrolysis leads to the carboxy-substituted sartans
(Figure 3).
These results show that the photoreaction tolerates
a variety of substituents found in biaryls used for the
preparation of pharmaceuticals with good to excellent yields
(Figure 3B). Surprisingly, it is feasible to couple aryls with
multiple ortho-substituents adjacent to the sulfonamide linker
to produce highly substituted biaryls as shown in the
cannabinol route in high yield.
The high regio- and chemoselectivities of the aryl coupling
À
are striking, since previous studies indicated that the S N
bond of sulfonamides can be cleaved homolytically upon
irradiation, followed by formation of carbon-centered radi-
cals.[13] It is also known that the photochemical activation of
aromatic sulfonamides can lead to radical Smiles rearrange-
ments.[12b,14] A photochemical disruption and recombination
is, however, unlikely. Biaryls that would arise from random
radical recombination processes could not be detected in the
reaction mixture. The outstanding regiocontrol can be better
rationalized by an intramolecular reaction that may be
initiated by a photo-induced charge transfer or polarization,
thus leading to a cyclic transition state that would allow
orbital interactions of both aryl residues. The instable five-
membered intermediate would decompose in the fashion of
a retro-[3+2] cycloaddition to yield the coupling product and
the linker-derived N-sulfonylimine (Figure 2D).[15] The latter
would readily fragment into sulfur dioxide, ammonia and
formaldehyde (upon hydrolysis), thus exerting a driving force
of the reaction.
To test this model we analyzed the side products of the
coupling reaction. For the qualitative detection of ammonia
we employed an alkaline solution of potassium
tetraiodomercurate(II) (Nesslerꢀs reagent). Whereas the
negative controls gave colorless solutions, irradiation of the
sulfonamide solution followed by addition of Nesslerꢀs
reagent resulted in a diagnostic orange coloration (Fig-
ure 2E). Sulfur dioxide formation was monitored by head-
space GC-MS analysis. In contrast to the negative controls,
the expected mass m/z = 64 (SO2) was only detected in the
biaryl-containing reaction mixture (Figure 2F). To trap the
predicted formaldehyde we used 2,4-dinitrophenylhydrazine
(Bradyꢀs reagent). By means of HPLC-HRMS we detected
the formaldehyde-derived hydrazone from the photoreaction
mixture. The identity of the product was verified by compar-
ison of UV/Vis spectra, HRMS data, and retention times with
a synthetic reference generated from a formalin-spiked
solution (Figure 2G). Taken together, the photoreaction of
the sulfonamide leads to a traceless cleavage of the linker and
yields the biaryl product by an ipso-ipso substitution with very
high regioselectivity. To validate the concept of ipso-ipso-
substitution, we prepared regioisomeric sulfonamides with
methyl residues in para-, meta- and ortho-position. In all cases
we observed the specific formation of the para-, meta- and
ortho-substituted biaryls (2a, b, c) (Figure 2H).
This clean, metal-free, and highly selective reaction
appeared to be particularly suitable for the synthesis of
pharmaceuticals. Diverse sulfonamides are readily available
by nucleophilic substitution reactions using sulfonyl chlorides
and benzyl amines (Figure 3A). Preliminary experiments
revealed that a broad range of substituents, ranging from
methoxy-, benzyloxy, cyano-, chloro-, fluoro-, carboxyalkyl-,
dimethylamino- and alkyl-, is tolerated by the method. Only
photolabile substituents such as bromide, iodide and nitro
groups give no photoproducts, and photoactive substituents
In conclusion, we present an unprecedented type of
carbon-carbon bond forming reaction via photogenerated
intermediates.[20] With its high regio- and chemoselectivity the
conceptually new photochemical method shares the advan-
tages of metal-catalyzed cross-couplings without the need of
inert conditions, halogenated aromatics, expensive organo-
metallic reagents or toxic transition metals. It is a particularly
valuable alternative for the synthesis of active pharmaceutical
Angew. Chem. Int. Ed. 2018, 57, 1 – 6
ꢀ 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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