Radical Desulfur-Fragmentation and Reconstruction of Enol Triflates: Facile Access to α-Trifluoromethyl Ketones

Article abstract of DOI:10.1002/anie.201608507

We report an efficient oxidative radical desulfur-fragmentation and reconstruction of enol triflates for the synthesis of α-CF₃ketones. Preliminary mechanistic studies disclosed that oxidative fragmentation to release a CF₃radical fr

Full text of DOI:10.1002/anie.201608507

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Communications
Chemie
International Edition: DOI: 10.1002/anie.201608507
German Edition: DOI: 10.1002/ange.201608507
Radical Fragmentation
Radical Desulfur-Fragmentation and Reconstruction of Enol Triflates:
Facile Access to a-Trifluoromethyl Ketones
Xiaolong Su, Honggui Huang, Yaofeng Yuan,* and Yi Li*
Abstract: We report an efficient oxidative radical desulfur-
fragmentation and reconstruction of enol triflates for the
synthesis of a-CF3 ketones. Preliminary mechanistic studies
disclosed that oxidative fragmentation to release a CF3 radical
from the triflyl group of enol triflate and subsequent addition
of the CF3 radical to another enol triflate form the desired a-
CF3 ketones. This method provides a new approach to a-CF3
ketones, featuring the utilization of catalytic amount of
oxidants, broad substrate scope, and potential to control the
regioselectivity.
addition of a large excess of the trifluoromethylation reagents
or expensive reagents. Therefore, there is still a demand to
develop methods to generate a-CF3 carbonyl compounds with
broad scope under mild conditions.
Enol triflates have become indispensable substrates and
engaged in a broad array of transition-metal-catalyzed cross-
À
coupling processes to give an access to C C bond forma-
tions.[8] Recent progress in the synthesis of well-defined enol
triflate derivatives may allow the scope to be broadened.[9] In
addition, this trifluormethylation starting from enol tiflates
has the advantage of controlling the regioselectivity with the
use of different regioisomers of the enol triflates. Herein, we
envisioned a radical desulfur-fragmentation and reconstruc-
tion of enol triflates which could efficiently generate a-CF3
ketones (Scheme 1b). Through the fragmentation of the enol
triflate, a CF3 radical was released from the triflyl group and
subsequent addition to another enolate eventually formed the
desired product.
T
he introduction of trifluoromethyl group into organic
molecules may have a dramatic effect on their lipophilicity,
electronegativity, metabolic stability, and bioavailability.[1]
Hence, intense interest has been paid to develop efficient
methods for the synthesis of CF3-containing compounds.[2] a-
CF3 carbonyl compounds have drawn special attention as they
serve as valuable building blocks for various CF3-containing
complex moieties.[3] Significant efforts have been made to
develop novel and diverse synthetic tools for the generation
of a-CF3 carbonyl compounds.[4]
As initially reported by Minisic, the combination of AgI
with persulfate yields AgII and the sulfate radical anion which
turns out to be an efficient electron-transfer oxidant.[10]
Notably, Maiti group reported an elegant work of radical
trifluoromethylation of alkenes.[11] With a catalytic amount of
AgNO3/K2S2O8 and air as the oxidant, the CF3 radical was
generated from CF3SO2Na. Thereby, our investigation com-
General strategies to radical trifluoromethylation include
using enolates in reactions with trifluoromethylation reagents,
such as CF3SO2Na(Cl),[5] CF3I,[6] or Togni reagent[7] (Sche-
me 1a). While impressive progress has been made in this area,
many of the reported examples generally required the
Table 1: Optimizations of the reaction conditions.[a,b]
Entry
Oxidant
Solvent
Yield of 2a
1
(NH4)2S2O8
(NH4)2S2O8
(NH4)2S2O8
-
K2S2O8
Na2S2O8
Other oxidants
20 mol% of (NH4)2S2O8, 12 h
(NH4)2S2O8
(NH4)2S2O8
tBuOH
tBuOH
tBuOH
tBuOH
tBuOH
tBuOH
tBuOH
tBuOH
CH3CN
Acetone
95%
2[c]
3[d]
4
no reaction
no reaction
no reaction
55%
66%
no reaction
95%
5
6
Scheme 1. Pathways of trifluoromethylation.
7[e]
8
9
21%
41%
[*] X. Su, H. Huang, Prof. Dr. Y. Yuan, Prof. Dr. Y. Li
Department of Chemistry
10[e]
Fuzhou University
Fuzhou 350116 (China)
E-mail: yaofeng_yuan@fzu.edu.cn
liyi-chem@fzu.edu.cn
[a] Reaction conditions: 1a (0.8 mmol), AgNO3 (0.008 mmol),
(NH4)2S2O8 (0.96 mmol) in mixed solvents (2 mL of solvent and 2 mL of
water) at 308C. [b] Yield was determined by crude 19F NMR using
trifluoromethoxy benzene as the internal standard. [c] Without AgNO3.
[d] tBuOH was used as the sole solvent. [e] See the Supporting
Information for more details of optimizations.
Supporting information for this article can be found under:
http://dx.doi.org/10.1002/anie.201608507.
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menced by subjecting enol triflate 1a to catalytic amounts
of silver along with (NH4)2S2O8 in a co-solvent system of
tBuOH and water at 308C (Table 1, entry 1).
The desired a-CF3 ketone 2a was produced in a 95%
NMR yield. We found that in the absence of silver salt or
(NH4)2S2O8, product 2a was not formed (Table 1, entry 2
t
and 4). It is worth noting that using BuOH as the sole
solvent did not promote the reaction (Table 1, entry 3).
The use of K2S2O8 or Na2S2O8 instead of (NH4)2S2O8
resulted in dramatically diminished yield of 2a (Table 1,
entries 5 and 6), while other commonly used oxidants
afforded no product (Table 1, entry 7, see the Supporting
Information for details). Although (NH4)2S2O8 is inex-
pensive, we sought to render the reaction catalytic which
will endow this methodology with low cost and high
efficiency. Gratifyingly, the amount of oxidant could be
further decreased to 0.2 equivalent with the same effi-
ciency as the use of 1.2 equivalents of oxidant (Table 1,
entry 8). Only a few organic solvents, such as acetonitrile
and acetone, could provide the desired product albeit in
moderate yields (Table 1, entries 9 and 10, see the
Supporting Information for more details).
With a general method in hand, the broad applic-
ability of this new approach for a library of enol triflates
was demonstrated (Scheme 2). The substrate scope with
aliphatic enol triflates was explored. The reactions of
cyclic enol triflates including those of 5-, 6-, 7-, or 8-
membered rings were evaluated under these conditions, and
the desired cyclic a-CF3 ketones were formed efficiently
(Scheme 2, 2a–2d). Substituted cyclic enol triflates are
accommodated as well (Scheme 2, 2e and 2 f). Applications
of linear enol triflates to the optimized conditions would
afford the products successfully, even with sterically demand-
ing substituents such as the adamantly or tert-butyl group
(Scheme 2, 2h and 2i). Linear aliphatic enol triflates with long
Scheme 3. Reactions with aromatic enol triflates. Reaction conditions:
t
1 (0.8 mmol), AgNO3 (0.008 mmol), (NH4)2S2O8 (0.16 mmol) in BuOH
(2 mL) and H2O (2 mL) at 308C. [a] Yield was determined by crude 19F NMR
and isolated yield was given in parentheses.
chains showed equal reactivity to give the corresponding a-
CF3 ketones in good yields (Scheme 2, 2j and 2k). We also
tried to control the regioselectivity by applying these
regioisomers derived from unsymmetrical alphatic ketones.
Gratefully, the corresponding products were generated with
moderate to good yields in
a regioselective manner
(Scheme 2, 2l and 2m).
The results in Scheme 3 reveal that a broad range of
aromatic enol triflates with diverse electronic and steric
properties could readily participate in this new reaction.
Functional groups, such as NO2, CN, and CO2Me were well
tolerated and the corresponding products were generated in
excellent yields (Scheme 3, 2p–2w). Substrates with methyl
or methoxyl groups on aromatic rings produced the ketones
with lower yields (Scheme 3, 2y–2aa). Hydrogen abstraction
À
on the methoxyl or benzylic C H position was probably the
main reason for these low yields. We also tested enol triflates
with di- or tri-substituted aromatic rings and those substrates
reacted efficiently with full conversation into the desired
products (Scheme 3, 2ae–2ag). To our delight, pyridine-motif
was well compatible under these reaction conditions and 2ah
was generated in an isolated yield of 90%. a-Branched
products could also be formed efficiently under these reaction
conditions with good to excellent isolated yields (Scheme 3,
2ai–2ak).
This route also demonstrates applicability to a range of a-
perfluoroalkylation (Scheme 4). We found that cyclic enol
nonaflates, aromatic enol nonaflates and a-branched sub-
strate were all well tolerated under these reaction conditions
and the corresponding a-perfluoroalkyl ketones were gen-
erated in excellent yields.
Scheme 2. Reactions with aliphatic enol triflates. Reaction conditions:
1 (0.8 mmol), AgNO3 (0.008 mmol), (NH4)2S2O8 (0.16 mmol) in
tBuOH (2 mL) and H2O (2 mL) at 308C. [a] Yield was determined by
crude 19F NMR and isolated yield was given in parentheses.
2
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the model reaction system (Scheme 5c). 20% of compound 6
were observed indicating the involvement of free CF3 radical
during the reaction process.
On the basis of the above experiments and literature
survey, a putative set of reaction cycles is depicted in Figure 1.
Scheme 4. Reactions with enol nonaflates. Reaction conditions: 3
(0.8 mmol), AgNO3 (0.008 mmol), (NH4)2S2O8 (0.96 mmol) in tBuOH
(2 mL) and H2O (2 mL) at 308C. [a] Yield was determined by crude
19F NMR and isolated yield was given in parentheses.
To shed light on the mechanism of this transformation,
several control experiments were conducted (Scheme 5).
Firstly, we performed a radical-trapping experiment (Sche-
me 5a). The standard reaction of 1a was thus repeated in the
presence of 2,2,6,6-tetramethyl-1-piperidinyl oxyl (TEMPO,
0.1 equiv), and the formation of the compound 2a was
completely inhibited, suggesting the involvement of a radical
mechanism. The TEMPOOtBu adduct[12] was detected, as
indicated by GC-MS. Insight into the reaction mechanism was
subsequently derived from investigation of the fragmentation
of the enolates (Scheme 5b). The crossover experiment was
carried out by subjecting an equimolar amount of 1ac and 3d
to the standard conditions. As determined by 19F NMR, all
four possible products 2ac, 4 f, 4d, and 2aj were generated in
a ratio of 30:19:30:17. Further investigation was conducted by
introducing an external electron-rich olefin (10 equiv) into
Figure 1. Putative mechanism.
Firstly, sulfate radical ion was produced by the action of AgI
on persulfate. Initial radical reactions occurred between enol
triflate and sulfate radical anion to yield either the inter-
mediate I (path A) or intermediate II (path B). These radical
intermediates (I or II) underwent fragmentations to form
CSO2CF3 (initiation cycle). The CF3 radical was generated
subsequently after expelling SO2. The addition of the CF3
radical to another enol triflate affords the intermediate III.
Radical reconstruction of III would eventually form the
desired product and another CSO2CF3 radical for next reaction
cycle (chain propagation).
In summary, we have developed a new strategy for the
formation of a-CF3 ketones through oxidative radical frag-
mentation and reconstruction of enol triflates. A CF3 group
present in the triflyl group performed as a radical CF3 source
to react efficiently with the enolate. This method utilizes
readily available starting materials, is easy to handle, and
features a wide substrate scope for both aromatic and
aliphatic compounds. Further studies to expand the applic-
ability of the present reaction system and efforts to develop
other multi-component reactions through the radical cross-
over mechanism are currently underway.
Acknowledgements
Financial support from National Natural Science Foundation
of China (21402028) and Fuzhou University (022537) is
gratefully acknowledged.
Conflict of interest
The authors declare no conflict of interest.
Keywords: enol triflates · ketones · radical fragmentation ·
synthetic methods · trifluoromethylation
Scheme 5. Mechanistic study. See text for details.
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Manuscript received: August 31, 2016
Final Article published: && &&, &&&&
4
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Communications
Radical Fragmentation
Reconstruction business: Oxidative frag-
mentation and reconstruction of enol
triflates is a new strategy for the synthesis
of a-CF3 ketones. Preliminary mechanis-
tic studies indicated oxidative fragmen-
tation to release a CF3 radical from the
triflyl group of the enol triflate and
subsequent addition of the CF3 radical to
another enol triflate forms the desired a-
CF3 ketone.
X. Su, H. Huang, Y. Yuan,*
Y. Li*
&&&& — &&&&
Radical Desulfur-Fragmentation and
Reconstruction of Enol Triflates: Facile
Access to a-Trifluoromethyl Ketones
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ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
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These are not the final page numbers!