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to get the free alcohol an additional reduction step is required
hydration methods tested were found to be ineffective.
and reactions are not catalytic.
(+)-3-Carene worked well to provide the alcohol 3ai albeit
with moderate selectivity (dr= 3:1). For (+)-3-carene, estab-
lished methodology (superstoichiometric Fe or Co-catalysis)
again provided a poorer selectivity (dr= 1.5:1).
We next addressed the scope and limitations of the new
hydration method. Various alkenes were reacted with methyl
4-nitrobenzenesulfonate 2a under the optimized conditions
and the scope of the reaction was found to be remarkably
broad (Table 1). Aliphatic terminal alkenes equipped with
various functional groups, for example, aromatic phenol (3b),
amine (3c) amide (3d), silane (3e), bromo substituent (3 f),
and free amine (3g) worked well to provide the secondary
alcohols 3a–3g in moderate to good yields. Ketones, per-
oxides and dimerized compounds, that are usually observed as
side products in oxygen mediated hydration processes[15] were
not formed. Our anaerobic hydration is also effective for b-
substituted terminal alkenes (3i–3o) and tolerates a wide
range of functional groups including O-benzyl, O-silyl, ester,
aliphatic alcohol, ketone, and heterocycles. Of note, sulfonyl
chloride 2m was used for the hydration reaction to form the
alcohols 3g, 3i, and 3j (for details, see Supporting Informa-
tion). Late stage functionalization of more complex alkenes
derived from (À)-isopulegol (3l), rotenone (3m), betulin (3n)
and pentoxifylline (3o) could be achieved to provide the
corresponding tertiary alcohols in good yields. Hydration also
proceeds with internal alkenes (3p–3t) including natural
products such as b-citronellol (3q), phytol (3r, dr= 1:1) and
osthole (3s). Regioselective hydration of (À)-perillyl alcohol
afforded 3u (70%) as major compound along with 5% of the
doubly hydrated product. Notably, the same reaction with
a large excess of reagent 2a (4.0 equivalents) gave a 4:1
mixture of 3u and the corresponding double hydrated product
as an inseparable mixture. Styrene derivatives worked to
provide the benzylic alcohols 3v–3ad with moderate to good
yields. However, conjugated dienes did not engage in this
hydration process (not shown).
Investigations were continued by studying the chemical
modification of bicyclic monoterpene derivatives. Alkene
hydration worked smoothly on (À)-a-pinene (3aj), (À)-trans-
pinocarveol (3ak), (S)-cis-verbenol (3al), the benzoate ester
of (R)-(À)-nopol (3am) and (À)-myrtenyl acetate (3an) to
afford the targeted tertiary alcohols in moderate to good
yields with excellent diastereoselectivities (> 20:1). For 3aj–
3an, nitroarene-mediated oxygenation occurred anti to the
bulky dimethylmethylene bridge, as expected. For all alkenes
of this bicyclic series, significantly lower diastereoselectivity
was noted upon running the radical hydration using known
aerobic protocols (1.3:1 to 5:1). Nitroarene-mediated hydra-
tion of more complex (+)-aromadendrene gave the tertiary
alcohol 3ao with high diastereoselectivity (dr= 9:1) and high
yield. Selectivity could be further improved upon switching
from 2a to the more bulky ortho,ortho’-disubstituted nitro-
arene 2o providing 3ao with a 14:1 diastereoselectivity. A
similar selectivity was also achieved with the ortho-tert-butyl-
nitroarene 2n (see Supporting Information). Again, existing
methodology did not perform well in particular considering
the diastereoselectivity issue. Epoxides are tolerated, as
documented by the successful hydration of natural (À)-
caryophyllene oxide to 3ap, which was isolated in good yield
and excellent diastereoselectivity (> 20:1). In line with all
other transformations, poor diastereoselectivity was achieved
by using aerobic hydration methodology (1.2:1). Steroids
were found to be eligible substrates and hydration of
cholesterol (3aq) as well as cholesteryl chloride (3ar)
occurred in good yields and excellent diastereoselectivity
(> 20:1). The relative configuration of 3aq and 3ar was
unambiguously assigned by X-ray structure analysis.
Next, we focused on diastereoselective hydrations (Ta-
ble 2). In order to document the potential of our process, we
additionally conducted some of these hydrations using exist-
ing aerobic protocols for comparison (methods A–E). Meth-
od E, that we considered as the most general process, was
used in all cases where comparisons have been made.
Hydration applying our protocol proceeds smoothly on (4-
methylenecyclohexyl)benzene to afford 3ae in 74% yield
with a high diastereoselectivity (10:1). Selectivity could be
further improved upon running the radical hydration with the
bulkier nitroarene 2o to afford 3ae with a 14:1 diastereose-
lectivity (67%). Aerobic hydration using Mn- or Co-catalysis
The efficiency of the novel protocol was further demon-
strated for the hydration of acyclic systems, where the control
of the diastereoselectivity is even more challenging
(Scheme 3). We were pleased to find that good to excellent
selectivities can be achieved for the hydration of various b-
disubstituted styrene derivatives. Reaction of a-methyl, b-
phenyl-substituted vinyl pinacolatoborane afforded the tar-
geted benzylic alcohol 3as in 78% yield with 9:1 diastereo-
selectivity and complete regioselectivity. The diastereoselec-
tivity can be understood considering the allylic A[1,3] strain
provided 3ae with similar or significantly lower yield (30– model where the bulky RL moiety steers the nitroarene to
70%) albeit with poor stereoselectivity (dr= 1.5:1 to 1.7:1).
2a-mediated hydration of a-terpineol and (À)-terpinen-4-ol
worked well to afford 3af and 3ag with excellent diastereo-
selectivity (dr> 20:1) without the need of protection of the
free alcohol group. For 3af and 3ag, traces of the other
diastereoisomer were identified by GC but the minor isomer
could not be isolated. Again, only a low diastereoselectivity
(1.7:1 to 2:1) was achieved for hydration of these two terpenes
with existing aerobic hydration methodology. Our reaction
tolerates the phenolic group of (À)-D8-THC to form the
hydrated product 3ah with perfect selectivity (dr> 20:1). For
this phenolic substrate, the traditional Mukaiyama-type
react from the opposite site.[44–46] For the a-ethyl substituted
congener, a 5:1 diastereoselectivity was obtained. 2-Naphthyl
vinyl pinacolatoboranes reacted with nitroarene 2a to 3au
with good yield, excellent regioselectivity and good diaste-
reoselectivity. It is worth noting that the tested aerobic
hydration protocols did not provide the targeted benzylic
alcohols, while the starting materials fully decomposed. The
vinyl boron entity turned out to be incompatible with these
protocols. b-Silyl-substituted styrenes afforded the hydrated
products 3av and 3aw in high yields, with excellent diaste-
reoselectivity besides 15–16% of regioisomeric a-hydrated
product (see Supporting Information). Again, the established
Angew. Chem. Int. Ed. 2021, 60, 8313 –8320
ꢀ 2021 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH
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