Electrochemical Oxidative Aryl(alkyl)trifluoromethylation of Allyl Alcohols via 1,2-Migration

Article abstract of DOI:10.1021/acs.orglett.9b01518

An electrochemical oxidative difunctionalization of allyl alcohols for the synthesis of β-trifluoromethyl ketones is achieved through a 1,2-migration process. A series of β-trifluoromethyl ketones can be facilely obtained utilizing CF₃SO_2<

Full text of DOI:10.1021/acs.orglett.9b01518

Letter
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Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Electrochemical Oxidative Aryl(alkyl)trifluoromethylation of Allyl
Alcohols via 1,2-Migration
Zhipeng Guan,† Huamin Wang,† Yange Huang, Yunkun Wang, Shengchun Wang, and Aiwen Lei*
College of Chemistry and Molecular Sciences, the Institute for Advanced Studies (IAS), Wuhan University, Wuhan, Hubei 430072,
People’s Republic of China
S
* Supporting Information
ABSTRACT: An electrochemical oxidative difunctionaliza-
tion of allyl alcohols for the synthesis of β-trifluoromethyl
ketones is achieved through a 1,2-migration process. A series
of β-trifluoromethyl ketones can be facilely obtained utilizing
CF3SO2Na as a radical source, eliminating the use of metals and sacrificial chemical oxidants. Importantly, this protocol not only
realizes aryl migration but also offers alkyl-migration products. Additionally, an electrochemically catalyzed ring expansion and
gram-scale reaction demonstrated the synthetic usefulness of this protocol.
he trifluoromethyl group has attracted much attention in
pharmaceutical and agrochemical compounds owing to its
meantime, the same group8g,h realized dichlorination and
heterodifunctionalization of alkenes. On the basis of our
research on difunctionalization of alkenes,8i−k we envisioned
that electrochemical oxidative difunctionalization of alkenes is a
worthwhile approach to accessing β-trifluoromethyl ketones.
Herein, we reported an electrochemical oxidative aryl(alkyl)-
trifluoromethylation of allyl alcohols via 1,2-migration to
synthesize β-trifluoromethyl ketones. Not only aryl-migration
products but also alkyl-migration products can be successfully
generated in the absence of sacrificial oxidants and metals at
room temperature (Scheme 1).
T
strongly electron-withdrawing nature, superior lipophilicity,
permeability, and metabolic stability.1 Compared with other
compounds containing a trifluoromethyl group, β-trifluoro-
methyl ketones not only constitute biologically active
intermediates2 but also can be transformed into more complex
compounds owing to the facile transformation of carbonyl group
to other functional groups.3 To date, a few methods for the
synthesis of β-trifluoromethyl ketones have been reported.4 In
2013, copper-catalyzed trifluoromethylation-initiated radical
1,2-aryl migration in α,α-diaryl allyl alcohols has been reported
by Wu et al.4b Afterward, metal-free catalyzed methods have
been reported to prepare β-trifluoromethyl ketones via 1,2-aryl
migration.4d,e Despite the significance of these developments,
expensive and toxic metals, chemical oxidants, and unstable
trifluoromethyl sources were always required in these reactions,
leading to the difficulty of purification from a mass of undesired
products and metal residual. On the other hand, among these
methods, aryl-migration products were only generated and the
goal of synthesizing alkyl-migration products has not been
achieved. Therefore, a green method for preparation of β-
trifluoromethyl ketones with wider applicability is necessary yet
challenging.
Alkenes, which were ubiquitous in natural products,
organisms, and multifunctional materials, were one of the
most valuable structural units.5 Over the past decades,
difunctionalization of alkenes has proven to be a powerful tool
for molecule synthesis, expanding applications of alkenes
enormously.6 Due to many advantages,7 electrochemistry has
become a hot research topic in recent years. Electrochemical
oxidative difunctionalization of alkenes,8 a highly efficient and
environmentally friendly strategy, has been widely used in
organic synthesis. In this field, significant progress has been
made by chemists. In 2017, Lin and co-workers8f described a
metal-catalyzed electrochemical method for diazidation of
alkenes to offer 1,2-diazides. The target products can be further
converted to vicinal diamines under mild conditions. In the
Scheme 1. Electrochemical Oxidative
Aryl(alkyl)trifluoromethylation of Allyl Alcohols via 1,2-
Migration
Initially, 1,1-diphenylprop-2-en-1-ol (1a) and sodium tri-
fluoromethanesulfinate (2a) were chosen as reaction partners.
Encouragingly, utilizing nBu4NBF4 as the electrolyte and
acetonitrile as solvent, 4,4,4-trifluoro-1,2-diphenylbutan-1-one
3a could be obtained in 65% isolated yield with a graphite rod
anode and iron plate cathode (Table S1, entry 1). When
CH3CN/H2O (5:1) was used as cosolvents, the reaction yield
did not change (Table S1, entry 2). However, no target product
was detected when we used water as the solvent (Table S1, entry
4). Other cosolvents, such as CH3CN/HOAc (5:1), decreased
reaction yield slightly (Table S1, entry 3). Subsequently, we
continued to screen various electrode materials. Although a
similar effect was revealed when we used a graphite rod anode
Received: April 30, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b01518
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
and platinum plate cathode, iron was chosen as the cathode
owing to the advantage of being cheap (Table S1, entry 5).
Compared with platinum and iron, the nickel plate cathode
showed poor effect (Table S1, entry 6). Further experiments
have shown that a change of the electrolyte leads to a decrease of
yield significantly (Table S1, entries 7−8). It is noteworthy that
there was no conversion of raw materials under no electric
current conditions (Table S1, entry 9).
Scheme 3. Scope of α-Alkyl-α-aryl Allyl Alcohols and α-Alkyl-
α-alkyl Allyl Alcohols
a
With the optimized conditions in hand, we explored the scope
of symmetrical α,α-diaryl allyl alcohols to achieve aryltrifluor-
omethylation, as shown in Scheme 2. Pleasingly, α,α-diaryl allyl
a
Scheme 2. Scope of α,α-Diaryl Allyl Alcohols
a
n
Standard conditions: 1 (0.3 mmol), 2 (0.5 mmol), Bu4NBF4 (0.25
mmol), MeCN (6.0 mL), C anode, Fe cathode, undivided cell,
constant current = 10 mA, room temperature, N2, 2 h, isolated yield.
such as hydroxyl and iodo groups, were amenable to this 1,2-
migration method (4e and 4f). Surprisingly, we found that aryl
groups and cycloalkyl groups could migrate to get mixtures of
two inseparable isomers (10:1) (4g−i and 4g′−i′). Considering
the nature of the alkyl group, we proceeded to synthesize an
unusual substrate 1j and found that the ratio of alkyl groups
migration exhibited a striking increase (4j and 4j′). It is worth
mentioning that 2-benzyl-1-phenylbut-3-en-2-ol, an α,α-dialkyl
allylic alcohol, was amenable to migrate to prepare 3-benzyl-
5,5,5-trifluoro-1-phenylpentan-2-one in 55% yield (4k). Fur-
thermore, alkyl groups, such as cyclohexyl, n-propyl, and n-
pentyl, also could realize migration for the synthesis of target
products in satisfactory yields (4l−n).
a
n
Standard conditions: 1 (0.3 mmol), 2 (0.5 mmol), Bu4NBF4 (0.25
mmol), MeCN (6.0 mL), C anode, Fe cathode, undivided cell,
constant current = 10 mA, room temperature, N2, 2 h, isolated yield.
Additionally, electrochemically catalyzed ring expansion was
also realized by the migration route. A series of β-trifluoromethyl
cyclic ketones were synthesized with considerable yield in
Scheme 4. It is worth mentioning that an O-heterocycle was well
tolerated in this protocol (5d). Furthermore, alkyl migration
products could be obtained in these reactions (5f−5i).
Importantly, cyclononyl, cyclotridecyl, and cyclocetyl products
were successfully generated under the standard conditions (5g−
5i), which are difficult to synthesize by existing methods. To
further verify the potential application of this protocol, a larger
scale reaction was carried out (Scheme 5). To our delight, the
procedure could proceed smoothly, giving 3a in 62% yield,
demonstrating the potential application of this protocol in
pharmaceutical and synthetic research.
To gain more insight into the reaction mechanism, several
radical trapping experiments were conducted with radical
scavengers (Scheme 6). The reaction was strongly inhibited
when 2,4-ditert-butyl-4-methylphenol (BHT) and 2,2,6,6-
tetramethyl-1-piperidinyloxy (TEMPO) were added to the
system, suggesting that a radical route may be involved in this
transformation (Scheme 6a and 6b). Additionally, no desired
product was detected and the CF3 radical could be trapped to
alcohols bearing electron-donating aryl groups (Me and OMe)
could react smoothly with sodium trifluoromethanesulfinate
(2a) to access corresponding β-trifluoromethyl ketones in
satisfactory yields (3b and 3c). Moreover, halogen groups such
as F, Cl, and Br were well tolerated in this 1,2-migration
protocol. An electron-withdrawing aryl group was also allowed
to offer the desired product (3g and 3g′). Importantly,
disubstituted alkenes were successfully used to generate the
target molecule through 1,2-migration (3h−j). Subsequently,
unsymmetrical α,α-diaryl allyl alcohols were evaluated under the
optimal reaction conditions. As shown in Scheme 1, electronic
characteristics of the aryl group have obvious influence on the
migration. Electron-rich aryl groups migrated more easily than
electron-deficient aryl groups, suggesting that carbon cation
intermediates might exist during the migration process.9
Pleasingly, the reaction was compatible with methyl, methoxy,
and Cl (3k−m).
To our delight, α-alkyl-α-aryl allyl alcohols were found to
exhibit good reactivity with CF3SO2Na (Scheme 3). High
selectivity was observed, and only aryl-migration products were
obtained in moderate yields (4a−f). Active functional groups,
B
DOI: 10.1021/acs.orglett.9b01518
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Scheme 4. Ring Expansion Reaction
Full experimental details and characterization data for all
products (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: aiwenlei@whu.edu.cn.
ORCID
Aiwen Lei: 0000-0001-8417-3061
Author Contributions
†Z.G. and H.W. contributed equally to this work.
Notes
The authors declare no competing financial interest.
a
n
ACKNOWLEDGMENTS
Standard conditions: 1 (0.3 mmol), 2 (0.5 mmol), Bu4NBF4 (0.25
mmol), MeCN (6.0 mL), C anode, Fe cathode, undivided cell,
constant current = 10 mA, room temperature, N2, 2 h, isolated yield.
■
This work was supported by the National Natural Science
Foundation of China (21520102003) and the Hubei Province
Natural Science Foundation of China (2017CFA010). The
Program of Introducing Talents of Discipline to Universities of
China (111 Program) is also appreciated.
b
MeCN (11 mL), H2O (1 mL).
Scheme 5. Reaction Scale-up
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* Supporting Information
■
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DOI: 10.1021/acs.orglett.9b01518
Org. Lett. XXXX, XXX, XXX−XXX