Photocatalytic Reductive Formation of α-Tertiary Ethers from Ketals

Article abstract of DOI:10.1021/acs.orglett.9b02273

A general photocatalytic reductive strategy for the construction of unsymmetrical α-tertiary dialkyl ethers is reported. By merging Lewis acid-mediated ketal activation and visible-light photocatalytic reduction, in situ-generated α-alkoxy radicals were found to engage in addition reactions with a variety of olefinic partners. Good reaction efficiency is demonstrated with a range of ketals of aromatic and aliphatic ketones. Extension to acetal substrates is also described, demonstrating the overall synthetic utility of this methodology for complex ether synthesis.

Full text of DOI:10.1021/acs.orglett.9b02273

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Photocatalytic Reductive Formation of α‑Tertiary Ethers from Ketals
Thomas Rossolini,† Branislav Ferko,†,‡ and Darren J. Dixon*,†
†Department of Chemistry, University of Oxford, Chemistry Research Laboratory, 12 Mansfield Road, Oxford OX1 3TA, U.K.
‡
́
Department of Organic Chemistry, Slovak University of Technology, Radlinskeho 9, 81237 Bratislava, Slovakia
S
* Supporting Information
ABSTRACT: A general photocatalytic reductive strategy for the construction of unsymmetrical α-tertiary dialkyl ethers is
reported. By merging Lewis acid-mediated ketal activation and visible-light photocatalytic reduction, in situ-generated α-alkoxy
radicals were found to engage in addition reactions with a variety of olefinic partners. Good reaction efficiency is demonstrated
with a range of ketals of aromatic and aliphatic ketones. Extension to acetal substrates is also described, demonstrating the
overall synthetic utility of this methodology for complex ether synthesis.
Scheme 1. (a) Reported Methods for the Synthesis of
Aialkyl Ethers and (b) Visible-Light-Mediated Direct
Strategy toward the Formation of α-Tertiary Dialkyl Ethers
from Ketals
espite the widespread relevance of dialkyl ethers in
pharmaceuticals and bioactive compounds,1 several
D
challenges in accessing this structural unit remain. Approaches
based upon the formation of the corresponding C(sp3)−O
bond, such as classical Williamson ether synthesis, are widely
employed to access simple ethers but are far from general for
more complex systems.2 To this end, a number of key advances
exploiting bespoke reagents3 and the intrinsic reactivity of
various coupling partners4 have been made in recent times,
leading to new valuable C−C bond disconnections for ether
construction.
Significant efforts in photoredox catalysis have offered mild
and unique approaches for new reaction discovery via in situ
generation of free radical species that can partake in radical
coupling or transition metal-catalyzed cross-coupling pro-
cesses.5 In the context of ether synthesis, MacMillan and co-
workers have reported an elegant synthetic procedure for the
generation of benzhydryl ethers exploiting a dual photoredox/
organocatalytic strategy via C−H atom abstraction, utilizing
cyanoarenes as coupling partners (Scheme 1a).6
More recently, the Doyle group has reported a powerful
method for forming similar products via a nickel-catalyzed
reductive cross-coupling from acetals of aromatic aldehydes
(Scheme 1a).7 Although the chemistries described above have
advanced carbon−carbon bond-forming ether syntheses,8 new
and general synthetic approaches for accessing α-tertiary alkyl
ethers remain desirable. To this end, and in an effort to expand
the synthetic range of photocatalytic umpolung chemistry,9 we
sought to explore alternative and common functional groups to
engage in radical coupling reactions.10 We envisaged that ketal
activation with a Lewis acid7,11 followed by visible-light-
mediated single-electron transfer (SET) to the resulting
oxocarbenium ion could deliver a putative nucleophilic α-
alkoxy radical intermediate, which could participate in radical
addition chemistry (Scheme 1b). If successful, this mild
generation and controlled coupling of the α-alkoxy radical
could provide direct access to α-tertiary ethers in one step
from readily available starting materials.
Preliminary evaluation of the proposed photocatalytic
reductive coupling process was carried out with 4′-
fluoroacetophenone dimethyl ketal (1a), [Ir(dF(CF3)-
ppy)2(dtbbpy)]PF6, and dehydroalanine (DHA) derivative 2
as a coupling partner10d,12 (Scheme 2). Initial feasibility studies
Received: July 2, 2019
© XXXX American Chemical Society
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DOI: 10.1021/acs.orglett.9b02273
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higher substrate concentration, with DMA proving to be the
most suitable medium (entries 1−3). Notably, and in contrast
to previous reports,7,11 we recognized that trimethylsilyl
chloride (TMSCl) was not an appropriate Lewis acid for
promoting ketal functionalization, as product 3 was afforded in
negligible yield (entry 6). Additionally, Lewis acidic boron
Scheme 2. Reaction Optimization
•
complexes, such as BF3 OEt2, were also found to be ineffective
(entry 7).13
With optimized conditions established, we sought to explore
the scope of this photocatalytic carbon−carbon bond-forming
reductive coupling reaction with respect to the ketal moiety
(Scheme 3A).14 Initially, substitution around the aromatic ring
was investigated (3−8). Efficient reaction outcomes were
observed with electron-releasing functional groups (5 and 6),
supporting a nucleophilic character of the putative α-alkoxy
radical intermediate.12 Conversely, suppressed reactivity was
observed with electron-withdrawing groups; for example, a
bromine atom in the para position afforded product 8 in 33%
yield.
Ketals bearing larger alkyl substituents underwent the
reaction with good yields (9 and 10). The small decrease in
reactivity was consistent with the increasing steric hindrance
compared to that of methyl-substituted 4.15 A chlorine-
containing side chain was also tolerated, and coupled product
11 was delivered in 36% yield. Importantly, the substrate scope
of this transformation was successfully expanded to diethyl and
diisopropyl ketals in moderate to good yields (12 and 13), and
this reactivity represents a significant improvement considering
followed by reaction optimization elucidated that irradiation
under blue light-emitting diode light in DMA, with
trimethylsilyl trifluoromethanesulfonate (TMSOTf) as the
Lewis acid and 4-phenyl Hantzsch ester (HEPh,Et) as the
stoichiometric reductant, provided the desired tertiary methyl
ether 3 in an optimal 78% NMR yield (entry 1).
Observations made during reaction optimization revealed
the importance of concentration and solvent selection on
reaction outcome (see the Supporting Information for more
details). Significant enhancement was achieved employing a
c
Scheme 3. (A) Scope with Respect to the Ketal Substrate and (B) Performance Evaluation of Mixed Ketal Substrate 1s
a
b
c
Reaction time of 5 h. Reaction time of 48 h. Combined isolated yields on a 0.2 mmol scale.
B
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Letter
d
Scheme 4. (A) Scope with Respect to the Alkene Coupling Partner and (B) Plausible Reaction Mechanism
a
b
c
d
Ten equivalents of coupling partner. Reaction performed on a 0.1 mmol scale. Reaction performed without CHD. Combined isolated yields on
a 0.2 mmol scale. CHD = 1,4-cyclohexadiene.
previously reported limitations on acyclic acetals.7 Moreover,
ketals of aliphatic ketones were found to be competent
substrates for radical generation, delivering the corresponding
products in synthetically useful yields after conjugate addition
(14−16), with dimethoxy cyclopentane affording compound
17 in 53% yield. To demonstrate the generality of this
transformation, we looked to expand the scope to include
acetal substrates. Pleasingly, good reaction efficiency was
achieved with both acyclic and cyclic acetals (18 and 19,
respectively), illustrating complementarity with previous
works.7,11b Finally, the role of the alkoxide functionality was
examined with mixed ketal 1s (Scheme 3B). Interestingly,
phenyl ether 14′ was not formed under the reaction
conditions; however, methyl ether 14 was isolated in 38%
yield [comparable to that with dimethoxy propane ketal as the
starting material (Scheme 3A), 14]. This observation could be
attributed to the leaving group ability of the phenoxy group
being better than that of the methoxy group.
reactivity with acrylate-type acceptors, we investigated
alternative reagents to favor radical termination after Giese-
type addition. In contrast to a radical reduction/protonation
mechanism for DHA, a different termination via hydrogen
atom transfer (HAT) has been proposed previously for acrylate
substrates.16 Catalytic methods involving thiols were not found
to be viable for this purpose.16,17 However, H-atom abstraction
from stoichiometric 1,4-cyclohexadiene (CHD) proved to be
beneficial for improving reaction yields (see the Supporting
Information for details).18 Using these modified conditions,
photocatalytic reductive coupling was achieved between 1a,
phenyl methacrylate, and methyl methacrylate to give the
corresponding tertiary methyl ethers in 74% and 62% yields
(20 and 21, respectively). Variations to the α-position of the
acrylate component were found to play a pivotal role in
reactivity. Pleasingly, fluorine incorporation was tolerated;
monofluorinated 22 and trifluoromethylated 23 were both
afforded in synthetically useful yields. No gem-difluoroalkene
adducts were formed under these reaction conditions.11b,19
Unsubstituted phenyl acrylate resulted in suppressed efficiency
even when a large excess of coupling partner was used (24).
We next examined the scope of this reaction with respect to
the acceptor component, using ketal 1a as a model substrate
(Scheme 4A). It should be noted that to further improve
C
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ORCID
Furthermore, coupling with methacryloyloxazolidinone fur-
nished 25 in moderate yield. These results indicate a key
stabilizing captodative effect arising from the α-substituent, a
conclusion further supported by successful coupling with
electron neutral alkenes. In fact, significant efficiency was
observed with diphenylethylene as the acceptor olefin (26).
Under these reaction conditions, reductive allylation of ketal
1a with a sulfone derivative afforded compound 27 in 30%
yield, despite the different reaction mechanism involved with
these coupling partners.9d,e
Thomas Rossolini: 0000-0002-4083-5091
Darren J. Dixon: 0000-0003-2456-5236
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
D.J.D. and T.R. thank Astex Pharmaceuticals, Ltd., for
generous financial support and Dr. Steven Howard (Astex
Pharmaceuticals, Ltd.) and Dr. Rachel Grainger (Astex
Pharmaceuticals, Ltd.) for helpful discussion. B.F. thanks the
Slovak Academic Information Agency (SAIA) for his research
mobility grant. The authors thank Tatiana Rogova (University
of Oxford) for providing computational data and Prof.
Fernanda Duarte (University of Oxford) for advice and
supervision.
Finally, 1a was subjected to reaction conditions without an
acceptor partner, which afforded dimerized aryl methyl ether
28 in 52% yield as a 1:1 mixture of diastereomers. Rueping and
co-workers have reported the reductive dimerization of
aldehydes and ketones via ketyl radical generation under
visible-light irradiation.20 Accordingly, this result supports a
radical pinacol-type dimerization and provides direct access to
ether pinacol adducts from easily accessible starting materials.
Control experiments established the essential role of the
Lewis acid; no conversion of starting material was observed
without TMSOTf (see the Supporting Information for details).
Moreover, none of the desired reactivity was achieved in the
absence of light, photocatalyst, or Hantzsch ester. On the basis
of these results, we propose the following reaction mechanism
(Scheme 4B).13 Initially, ketal 1 is activated by TMSOTf to
form oxocarbenium ion intermediate I as disclosed in previous
reports.7,11 A highly reducing IrII species (E1/2red = −1.37 V vs
SCE in MeCN),5b generated by electron transfer from the
Hantzsch ester following photoexcitation of IrIII, is capable of
reducing I to generate α-alkoxy radical II.21 The key
nucleophilic intermediate (I) can engage in radical addition
with an appropriate acceptor olefin moiety. After this Giese-
type addition, the resulting free radical intermediate (III)
undergoes a reduction/protonation sequence mediated by the
Hantzsch ester (HE•), or HAT termination favored by the
presence of CHD, depending on the nature of the coupling
partner.16
In summary, the photocatalytic reductive coupling of readily
accessible ketals and acceptor olefins has been developed. This
methodology provides a new approach for generating
challenging α-tertiary dialkyl ethers in a single step and is
also amenable to acetal components. Extension to pinacol
coupling adducts via an α-alkoxy radical dimerization process
has been demonstrated, thus providing insight into the
mechanism. We believe that this methodology provides a
complementary new synthetic approach to complex α-tertiary
ether architectures and that the photocatalytic SET reduction
of oxocarbenium ions will provide new opportunities for future
reaction development.
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ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b02273.
Synthetic procedures and full characterization data of
compounds (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: darren.dixon@chem.ox.ac.uk.
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DOI: 10.1021/acs.orglett.9b02273
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
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(21) The TfOH would be neutralized by the Hantzsch pyridine
(HP) generated in the reaction.
F
DOI: 10.1021/acs.orglett.9b02273
Org. Lett. XXXX, XXX, XXX−XXX