Chemoselective Deoxygenation of 2° Benzylic Alcohols through a Sequence of Formylation and B(C6F5)3-Catalyzed Reduction

Article abstract of DOI:10.1002/ejoc.202100148

A sequence of formylation and B(C₆F₅)₃-catalyzed reduction of the resulting formate with Et₃SiH enables the chemoselective deoxygenation of secondary benzylic alcohols. Primary benzylic and tertiary non-benzylic alcohols are not reduced by this protocol. The formyl group fulfills a double role as activator and self-sacrificing protecting group. The deoxygenation of these formates is fast and can be carried out in the presence of other potentially reducible groups. Neighboring-group participation was found in the deoxygenation of certain diol motifs.

Full text of DOI:10.1002/ejoc.202100148

Communications
doi.org/10.1002/ejoc.202100148
°
Chemoselective Deoxygenation of 2 Benzylic Alcohols
through a Sequence of Formylation and B(C6F5)3-Catalyzed
Reduction
Sven C. Richter[a] and Martin Oestreich*[a]
A sequence of formylation and B(C6F5)3-catalyzed reduction of
the resulting formate with Et3SiH enables the chemoselective
deoxygenation of secondary benzylic alcohols. Primary benzylic
and tertiary non-benzylic alcohols are not reduced by this
protocol. The formyl group fulfills a double role as activator and
self-sacrificing protecting group. The deoxygenation of these
formates is fast and can be carried out in the presence of other
potentially reducible groups. Neighboring-group participation
was found in the deoxygenation of certain diol motifs.
Deoxygenation reactions are of growing interest as these play a
key role in the conversion of renewable resources into useful
feedstocks for the chemical industries.[1] In the most straightfor-
ward approach, the deoxygenation of alcohols can be realized
Scheme 1. Chemoselectivity in Lewis acid-mediated deoxygenation of alco-
hols with hydrosilanes (top) and planned formylation-reduction sequence to
with a system consisting of a Lewis acid and a hydrosilane as
the reductant (Scheme 1, top). With conventional Lewis acids
achieve unusual chemoselectivity in the deoxygenation of benzylic alcohols
(bottom).
[2]
such as BF3·OEt2 or indium halides[3] tertiary alcohols are
preferably reduced. This is due to the formation of a stabilized
carbenium-ion intermediate in the course of the reaction. The
opposite chemoselectivity can be achieved with catalytic
amounts of tris(pentafluorophenyl)borane, B(C6F5)3.[4–6] Rather
than interacting with the Lewis-basic substrate, this boron Lewis
acid activates the hydrosilane through an unusual η1-
coordination.[7] This unconventional Lewis pair is attacked at the
silicon atom by the nucleophilic oxygen atom of, e.g., a free
alcohol, silyl ether, or tosylate. The borohydride released as part
of this step then reduces the activated substrate by hydride
transfer. Consequently, B(C6F5)3-catalyzed deoxygenation typi-
cally favors sterically accessible alcohol derivatives.
selectivity in the subsequent B(C6F5)3-catalyzed reduction. We
anticipated the aforementioned change in mechanism from SN2
to SN1 for this reduction with hydrosilanes based on our
previous study on the deoxygenation of benzylic formates in
the context of a formal decarbonylation strategy.[9]
We began our investigation by studying the B(C6F5)3-
catalyzed reduction of selected secondary benzylic alcohol
derivatives with Et3SiH (1a–6a!7a; Table 1). As a general trend,
it was observed that acylated substrates react faster to the
corresponding hydrocarbon 7a than the archetypal triethylsilyl
ether 1a (entry 1 versus entries 2–6). This can be rationalized by
Complementary to these established methods, we envi-
sioned a sequence of reactions through which secondary
benzylic alcohols are selectively deoxygenated in the presence
of tertiary and primary alcohols (Scheme 1, bottom). In analogy
to the widely applied Barton-McCombie reaction,[8] we planned
to modify the hydroxy group in the first step to alter the
Table 1. B(C6F5)3 catalyzed reduction of selected alcohol derivatives with
triethysilane.[a]
[a] S. C. Richter, Prof. Dr. M. Oestreich
Institut für Chemie, Technische Universität Berlin
Strasse des 17. Juni 115, 10623 Berlin, Germany
E-mail: martin.oestreich@tu-berlin.de
Entry
Substrate
PG
Yield [%][b]
1
2
3
4
5
6
1a
2a
3a
4a
5a
6a
SiEt3
40 (47)[c]
97
96
C(O)Me
C(O)tBu
C(O)OMe
C(O)NEt2
C(O)H
http://organometallics.tu-berlin.de
Supporting information for this article is available on the WWW under
https://doi.org/10.1002/ejoc.202100148
99
88
Part of the “Silicon Chemistry in Organic Synthesis” Special Collection.
48 (99)[c]
© 2021 The Authors. European Journal of Organic Chemistry published by
Wiley-VCH GmbH. This is an open access article under the terms of the
Creative Commons Attribution License, which permits use, distribution and
reproduction in any medium, provided the original work is properly cited.
[a] All reactions were performed on a 0.30 mmol scale. [b] Yields were
estimated by GLC analysis using tetracosane as internal standard. [c] Using
3.0 equiv. of Et3SiH.
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the better accessibility of the Lewis basic carbonyl oxygen atom
in these structures. Acetate 2a, pivalate 3a, carbonate 4a and
carbamate 5a were almost quantitatively deoxygenated in the
presence of two equivalents of Et3SiH as reductant within five
minutes at room temperature (entries 2–5).[10] However, in case
of formate 6a three equivalents of the hydrosilane were
necessary to obtain that yield (entry 6). The formyl-derived
byproducts are also reduced under the applied conditions,
consuming a considerable amount of the reductant.
The formylation reaction is chemoselective (Scheme 2). The
primary and secondary benzylic alcohols 8b and 8a underwent
the formylation in high yield whereas 8% yield were obtained
for the tertiary benzylic alcohol 8c. The deoxygenation of the
secondary and tertiary benzylic formates 6a and 6c proceeded
rapidly to cleanly afford the hydrocarbons 7a and 7c.
Conversely, the CÀ O bond in the primary benzylic formate 6b
was not cleaved under these mild reaction conditions. Instead,
the formate group was reduced, eventually yielding the silyl
ether 1b in excellent yield.[11] The formyl group fulfills different
roles in these reactions, either as an activator of secondary and
tertiary benzylic alcohols or as a self-sacrificing protecting
group for primary alcohols. Hence, the reaction sequence of
formylation and B(C6F5)3-catalyzed reduction allows for chemo-
selective deoxygenation of secondary benzylic alcohols.
The above observations reveal a finely balanced chemo-
selectivity in the reduction step. Reasonable reaction pathways
are supported by byproducts detected by 1H NMR spectroscopy
(Scheme 3). The primary formate 6b converts into the silylcarb-
oxonium ion 9b with the borohydride as the counteranion by
the established mechanism.[7] Neither dissociation into the
primary carbenium ion nor SN2 displacement of the silylated
formate occurs. In turn, 9b is reduced to the mixed acetal 10b.
This intermediate was not captured by NMR spectroscopy as it
is further reduced to the silyl ethers 1b and 11. Et3SiOMe (11) is
Scheme 3. Reaction pathways explaining formate reduction and deoxygena-
tion of primary benzylic formates (top) and secondary benzylic formates
(bottom). Reactions performed in either CD2Cl2 or C6D6, and 1H NMR
(500 MHz) data reported for the latter. Ar=naphth-2-yl.
ultimately reduced to methane (12) along with the correspond-
ing disiloxane.[12] The deoxygenation of the secondary formate
6a follows an SN1 mechanism.[9] Silylcarboxonium ion 9a
dissociates into the benzylic carbenium ion 14a and the
silylated formate 13. Hydride transfer from the borohydride to
the carbenium ion affords the hydrocarbon 7a while formate
13 converts further into bis-silyl acetal 15, silylated methanol
11, methane (12), and the disiloxane by B(C6F5)3-catalyzed
hydrosilylation.[12]
The viability of the chemoselective deoxygenation of a
secondary benzylic alcohol in presence of a primary or tertiary
alcohol was demonstrated in intramolecular competition experi-
ments (Scheme 4). Diol 16 containing a secondary and a
primary benzylic hydroxy group was formylated in 90% to yield
the bis-formate 17. The following reduction afforded the
primary alcohol 18 in good isolated yield after cleavage of the
silyl ether. The selectivity of this step is remarkable considering
that diol 16 without modification would have preferentially
afforded the secondary alcohol (see the Supporting Informa-
tion). Diols 19 and 22 with a tertiary alcohol next to the benzylic
secondary hydroxy group were selectively monoformylated in
88% and 87% yield, respectively. However, the tertiary benzylic
alcohol in 20 was also deoxygenated in the reduction step, not
furnishing desired 21 but 1-ethyl-4-isopropylbenzene as the
main product. Conversely, the tertiary aliphatic hydroxy group
Scheme 2. Assessment of the chemoselectivity in the formylation and the
reduction step, respectively. [a] Reactions were performed on a 5.00 mmol
scale. Isolated yields are reported. [b] Reactions were performed on a
0.30 mmol scale. Yields were estimated by 1H NMR spectroscopy using 1,3,5-
trimethoxybenzene as an internal standard. [c] Performed on a 0.20 mmol
scale. Ar=naphth-2-yl.
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Scheme 4. Intramolecular competition experiments. [a] Reactions were performed on a 4.00 mmol scale. Isolated yields are reported. [b] Reactions were
performed on a 0.30 mmol scale. [c] Isolated yields are obtained after treatment with 1 M TBAF solution and flash-column chromatography on silica. [d] The
yield was estimated by 1H NMR spectroscopy using dimethyl terephthalate as an internal standard.
in 23 was perfectly stable; monodeoxygenated 24 was isolated
in 62% yield.
from the B(C6F5)3-catalyzed reduction of complex polyols with
hydrosilanes.[5c,e]
In an attempt to expand the scope to bis-formylated 1,2-
and 1,3-diols 25 and 26, we found that these substrates lead to
a mixture of three products: the targeted silyl ether 27/28, the
cyclic acetal 29/30 and bis-silyl ether 31/32 (Scheme 5, top).
This result can be explained by neighboring-group participation
by the second formate group (33/34!35/36!29/30;
Scheme 5, bottom). Initial silylation of either formate group
would lead to the same products. This phenomenon is known
The functional-group tolerance of the reduction step was
further investigated by subjecting secondary benzylic formates
37a–e with pending reducible groups to the standard
procedure (Scheme 6). When the primary alcohol was protected
by a iPr3Si (TIPS) as in 37a, a tBuMe2Si (TBDMS) as in 37b, or a
tBuPh2Si group (TBDPS) as in 37c, clean cleavage of the formate
was observed in excellent yields. However, with a less bulky
Et3Si (TES) group as in 37d, the desired product 38d was only
obtained as a minor product in 17% yield. The major product of
this reaction was the corresponding bis-silyl ether.[13] Moreover,
an aryl ether as in 37e also engaged in the defunctionalization,
and 38e was formed in mere 14% yield. While the cleavage of
aryl ethers is a common application of B(C6F5)3À hydrosilane
combinations,[5b,14] we had previously accomplished the chemo-
selective reduction of primary tosylates in the presence of
various primary aryl ethers.[5f]
In summary, we have developed a new way for the
chemoselective deoxygenation of secondary benzylic alcohols
Scheme 6. Chemoselective reduction of secondary benzylic formates in the
presence of silyl and aryl ethers. All reactions were performed on a
0.30 mmol scale. Yields were estimated by 1H NMR spectroscopy using
dimethyl terephthalate as an internal standard.
Scheme 5. Attempted chemoselective deoxygenation of bis-formylated 1,n-
diols and mechanistic discussion. Yields were estimated by GLC analysis by
calibration with authentic samples and tetracosane as an internal standard.
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Acknowledgements
S.C.R. thanks the Fonds der Chemischen Industrie for a predoctoral
fellowship (Kekulé scholarship, 2017–2019). M.O. is indebted to the
Einstein Foundation Berlin for an endowed professorship. Open
access funding enabled and organized by Projekt DEAL.
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showed that the reaction is complete within seconds; reactions were
routinely run for five minutes.
[11] The corresponding methyl carbonate and acetate were also tested
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spectroscopy due to overlapping resonance signals.
Conflict of Interest
The authors declare no conflict of interest.
Keywords: Alcohols
Deoxygenation · Silanes
·
Boron
·
Chemoselectivity
·
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Manuscript received: February 7, 2021
Revised manuscript received: March 15, 2021
Accepted manuscript online: March 16, 2021
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