Organic Letters
Letter
Figure 1. Synthetic strategies for 3-functionalized four-membered heterocycles. (A) Intramolecular cyclization strategy for 3-substituted four-
membered heterocycles. LG: Leaving group; FG: functional group. (B) Our proposal: in situ incorporation of a leaving group followed cyclization.
(C) Fluorocyclization: previous studies. (D) Fluorocyclization of 2-azidoallyl/2-alkoxyallyl alcohols and amines.
azetidine derivatives belong to a class of newly synthesized 3-
fluoro-functionalized four-membered heterocycles that are
inaccessible by other synthetic methods.5d
eventually achieved this and efficiently obtained 3-function-
alized oxetanes from ketones via a cascade alkynylation
hydroazidation and fluorocyclization sequence (Figure 2B).
Both cyclic and acyclic ketones were equally converted into
corresponding 3-functionalized oxetanes. This conversion
integrates the universality of carbonyl compounds with the
3-functionalized oxetanes, which greatly improves the
possibility of its abundant applications in the field of medicinal
chemistry. In addition to the modification of ethisterone, the
late-stage diversification of citronellal 38 was also realized in
66% yield through the sequential three-step operation.
Next, we speculated that such a fluorocyclization strategy
could also be extended to the synthesis of azetidine scaffolds.
While monitoring the fluorocyclization reaction, progress was
sluggish at −45 °C; thus, we performed the reaction at 25 °C.
To our delight, a variety of N-protected (sulfonyl or acyl) 2-
azidoallyl amines was successfully applied in the fluorocycliza-
tion (Figure 2C). Except for the 4-NO2 group (43), the
electronic nature and position of substituents on the benzene
ring nearly did not influence on the efficiency of azetidine
formation (39−50). The azetidine structure was unambigu-
ously confirmed by single-crystal X-ray diffraction analysis of
41 (CCDC No. 1943313). The aryl sulfonyl group could be
replaced with an alkyl sulfonyl group without affecting the
reaction outcome (52, 53). Such an efficient construction of
alkylsulfonyl-protected azetidine represents a possible techni-
que for the synthesis of Olumiant (marketed drug for the
treatment of rheumatoid arthritis).14 Furthermore, the acyl-
protected α-amino vinyl azides also delivered desired products
in good to high yield (54−64, 59−88% yields). Note that the
acyl-protected azetidine structural unit occurs in several
pharmaceuticals, for instance, Cobimetinib, a high-profile
drug for the treatment of melanoma.15 Finally, the reaction
of the amine attached to the secondary or tertiary carbon
proceeded as well and afforded the cyclized products in high
yield (65−67, 82−93% yields).
After careful screening of the reaction conditions (for details,
see Table S1), the conditions (2-azidoallyl alcohols (1.0
equiv), Py·HF (1.5 equiv), PIDA (1.5 equiv), CH2Cl2 (0.1 M)
at −45 °C) were chosen for the substrate scope and functional
group tolerance studies. First, a variety of cyclic alcohols
tethered with different functional groups undergo the desired
fluorocyclization with good to excellent yield (2−11, 80−93%
yields) (Figure 2A). Note that spiro[3.5]- or spiro[3.6]oxetane
motifs represent the core structural units in the inhibitors of β-
secretase and anticancer agents.12 Also, the use of a
tetrahydropyran derivative led to product 12 in a 84% yield.
Furthermore, 7−15-membered macrocyclic compounds were
efficiently converted into the corresponding oxetanes (13−
16). Fluorenone derivatives also participated in this trans-
formation and could convert to the consistent oxetanes in good
yield (17, 18; 82%, 78% yield, respectively). Strikingly, a wide
variety of acyclic alcohols successfully converted into oxetane
derivatives with almost identical efficiency to cyclic alcohols
(19−37). Starting from the simplest acetone structure, the
target product 19 could be obtained in 87% yield. Dialkyl
alcohols were smoothly transferred into oxetanes with 83−96%
yield (20−22). Diaryl groups furnished the 2,2-diaryloxetanes
in good to high yield (23−30, 57−84% yield); note that these
products have a similar quaternary carbon center in
biodegradable insecticide EDO (Figure S1).13 A modest
drop in the yield was observed for the substrates with
electron-withdrawing groups on the benzene ring (25−27, 29,
30). Further, ethisterone could be converted to the
corresponding oxetane derivative 31 in 69% yield via a two-
step operation. Monosubstituted and unsymmetrical aryl
alcohol derivatives also proved to be effective substrates,
although they afforded a diastereomeric mixture of products
(32−37, 77−95% yield, dr = 1.1:1 to 4.9:1).
Aldehydes and ketones are basic organic synthetic feedstock.
We therefore envisage that developing a one-pot multistep
method to prepare 3-functionalized oxetanes directly from
aldehydes and ketones should be feasible and more syntheti-
cally practical. Observing efficient performance in each step, we
Considering the azido group with many possibilities for
further modification and the potency of a fluorine atom to
modulate chemical and biological properties of molecules,16 we
expect such derivatives would constitute a new chemical space
for exploration in the drug discovery. To demonstrate the
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Org. Lett. 2021, 23, 3674−3679