10.1002/ejoc.202100652
European Journal of Organic Chemistry
COMMUNICATION
in 38% total yield (Figure 4). These results support that oxidization
of the primary C–H bond is feasible if the hydroxyl group and the
methyl group are in close proximity.
removed. However, longer 1,n-diols (n ≥ 9) were transformed in
good yields to their double-cyclized products (38bb: 24%, 39bb:
24%, 40bb: 55%) in the presence of 2.0 equiv. of oxidant and
20 mol% iodine whereby these were accompanied by their mono-
cyclized products (38ab: 31%, 39ab: 31%, 40ab: 24%). Almost
no double activation was observed, with only one equivalent of
oxidant showing that the first cyclization is preferred over the
second C–H activation.
Figure 4. Derivatization of (+)-menthol (43a).
We have presented the first iodine-catalyzed synthesis for
different substituted tetrahydrofurans through an intramolecular
C(sp3)–H oxidation of non-activated remote C(sp3)–H bonds. The
reaction proceeds under high regioselectivity favoring the
formation of the 5-membered rings over the thermodynamically
more stable 6-membered rings. This method requires only a
single equivalent of oxidant per activated C–H bond, is
operationally simple, and can be initiated either by daylight or a
simple halogen lamp. The proposed reaction mechanism is based
on two intertwined catalytic cycles combining a radical chain
reaction with an iodine(I/III) redox couple. Although involving
radicals, the reaction proceeds under mild conditions and is
therefore of a broad substrate scope tolerating multiple functional
groups that also allow further derivatization of the constructed
THF-containing products. Aliphatic primary and secondary
alcohols can be cyclized and aliphatic 1,n-diols giving access to
molecules with one or two THF moieties. The disclosed method
demonstrates the potential of iodine catalysis as a non-toxic and
powerful alternative for the conventional metal-catalyzed
synthesis of tetrahydrofurans.[19]
Figure 2. Reaction of 1,n-diols (n = 6–12) under light-induced iodine-catalyzed
cyclization reaction conditions: I2 (10 mol%), PhI(m-CBA)2 (1.0 or 2.0 equiv.),
1,2-DCE, 45 °C, 16 h. Yields were determined after purification by column
chromatography on silica gel. The newly formed C–O bonds are highlighted in
red. x = 2–7; nd = not determined. More examples (n = 6, 8) can be found in the
ESI.
Finally, the developed cyclization reaction was applied to
additional steroidal substrates showing that both the C–H-bond of
the C-19 and the C-18 methyl group can be addressed (Figure 3).
This observation was showcased for the highly functionalized
corticosterone 21-acetate giving the corresponding product 41b
in good yields of 47%. We were more than pleased to
functionalize a tertiary C–H-bond of the pregnene-derivative by
taking advantage of the proximity of the produced oxygen radical
at C-18 and the tertiary 20-C–H bond showing that also tertiary
C–H groups are accessible. Noteworthy, the yield could not be
improved by using higher amounts of iodine and/or oxidant - on
the contrary, the product could not be isolated anymore.
Keywords: C–H functionalization • tetrahydrofuran • iodine
catalysis • oxidation • steroids
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Figure 3 Exploitation of the substrate scope towards steroids based on the
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When subjecting (+)-menthol (43a) to the developed reaction
conditions, activation of a primary C–H bond took place, affording
the corresponding diastereomeric products 43b in a 3:1 mixture
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