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alcohol substituents from methyl to more substituted
alkyl chains (23–25) led to significant drops in yield.
Aldehyde byproducts were characterized in these
cases, presumably arising from radical α-fragmenta-
tion, which becomes more favorable with greater
substitution. Installation of a gem-dimethyl at the
benzylic position overcame this issue (26–29), which
we hypothesize to be due to enhanced rate of
cyclization via the Thorpe-Ingold effect. A propargyl
alcohol was cyclized to give 30 in 35% yield,
hampered by competitive oxidation due to the more
activated alcohol α-proton. Chiral chromanes could be
synthesized from the corresponding enantioenriched
alcohols with no epimerization, including 2-methyl
chromane 31 in 60% yield, and ester-substituted
chromane 32, albeit in lower 34% yield due to
competitive alcohol oxidation. Alcohols with both cis
Scheme 2. Umpolung CÀ H etherification with substituted are-
nes.
and trans-fused 6- and 7-membered rings cyclized in ester (51) substitution shut down the cyclization event,
good to high yields to give tricyclic chromane resulting in predominantly recovered starting material.
scaffolds 33 and 34, as well as 36–38, which map on Notably, introduction of an electron-donating methoxy
to the carbon skeleton of the cannabinoid family. In group, which is required for prior HVI-mediated
contrast, an analogous cyclopentyl alcohol cyclized to methods, led to formation of numerous byproducts
give 35 in only 17% yield, possibly due to geometric including uncyclized iodonium salt 52, highlighting
constraints preventing proper orbital overlap for cycli- the complimentary reactivity imparted by the umpo-
zation. Finally, functionalization on the alkyl tether lung heteroatom reaction manifold. While these results
was examined. Chromanes 39 and 40 possessing a indicate that arene substitution is not broadly tolerated,
second, geminal, aromatic ring were both formed in this limitation is offset by the direct installation of the
good to excellent yield. It is noteworthy that, in the iodonium functional handle for downstream function-
case of 39, the second phenyl ring did not undergo alization. Furthermore, while the formation of regioiso-
iodonium salt formation, and in the case of 40, meric products may be detrimental to target-oriented
complete chemoselectivity for cyclization onto the synthesis, it would provide one-pot access to analogues
more electron-rich arene was observed. The presence for small molecule library generation.
of an additional free hydroxyl group (41) led to a
In order to demonstrate the synthetic versatility of
decrease in yield, possibly due to detrimental coordina- the obtained iodonium salts, we undertook a series of
tion to the I(III) center, as the corresponding À OAc subsequent derivatizations using 17 as a model
derivative (42) gave a restored yield of 67%. 3- substrate (Scheme 3a). A key challenge when reacting
Fluorochromane (43) was obtained in 58% yield and non-symmetrical iodonium salts is selective functional-
an alkyl boronic ester was also tolerated, giving 44 in ization of the arene of interest. In the case of 17,
26% NMR yield.
functionalization was required on the more electron-
At this stage, substitution on the aromatic ring was rich arene, selectivity that is achieved primarily
considered (Scheme 2). We began with o-methyl through the use of transition metal catalysis.[12] After
derivative 45 and, under slightly modified conditions, screening, it was found that Pd-catalysis was partic-
obtained the desired iodonium chromane in good yield, ularly effective, allowing for a broad range of trans-
but as a 1:2 mixture of regioisomers 46 and 47, which formations including reduction to the aryl iodide (53)
could be separated via crystallization, with the major or CÀ H (54), aryl- and heteroarylation (55–56),
product arising from an apparent skeletal rearrange- carbonylation (57), Sonogashira and Heck couplings
ment. This result raised interesting mechanistic ques- (58–61), and amination (62). In addition, the synthetic
tions regarding the cyclization event that will be utility of the approach was demonstrated through a
discussed subsequently. A screen of the corresponding concise total synthesis of (+/À )-conicol (Scheme 3b).
m- and p-methyl substrates (48, 49) led to complex The key cyclization proceeded smoothly from ketone
mixtures of products. It should be noted that both 48 64 followed by reduction to the aryl iodide to give 65
and 49 did produce cyclized products, however as in 72% over two steps. Iodochromane 65 could then be
inseparable mixtures of multiple regioisomeric chro- advanced to (+/À )-conicol (3) in just three additional
mane iodonium salts (in the case of 48), as well as steps; late-stage installation of the A-ring olefin from
benzylic oxidation of the methyl group and other 66 gave a mixture of three double bond isomers,
unidentified byproducts. Returning to o-substitution, desired (+/À )-conicol (3), along with Δ8,9-conicol (67)
incorporation of electron-withdrawing fluoro (50) or and Δ9,11-conicol (68), in a 1.0:11.2:1.1 ratio. This
Adv. Synth. Catal. 2021, 363, 1–10
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