Electrochemical Difluoromethylation of Electron-Deficient Alkenes

Article abstract of DOI:10.1002/cssc.201803058

Electrochemical 1,2-hydroxydifluoromethylation and C?H difluoromethylation of acrylamides were developed by using CF₂HSO₂NHNHBoc as the source of the CF₂H group. These electricity-powered oxidative alkene functionalization reactions do not need transition-metal catalysts or chemical oxidants. The reaction outcome, 1,2-difuntionalization or C?H functionalization, is determined by the substituents on the amide nitrogen atom of the acrylamides instead of by the reaction conditions.

Full text of DOI:10.1002/cssc.201803058

Accepted Article
Title: Electrochemical Difluoromethylation of Electron-Deficient Alkenes
Authors: He-Huan Xu, Jinshuai Song, and Hai-Chao Xu
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10.1002/cssc.201803058
ChemSusChem
COMMUNICATION
Electrochemical Difluoromethylation of Electron-Deficient
Alkenes
He-Huan Xu, Jinshuai Song and Hai-Chao Xu*
Abstract: Electrochemical 1,2-hydroxydifluoromethylation and C–H
difluoromethylation of acrylamides have been developed using
CF2HSO2NHNHBoc as the source of CF2H group. These electricity-
powered oxidative alkene functionalization reactions do not need
transition metal catalysts and chemical oxidants. The reaction
outcome, 1,2-difuntionalization or C–H functionalization, is
determined by the substituents on the amide nitrogen atom of the
acrylamides instead of reaction conditions.
Alkene functionalization reactions such as the vicinal
difunctionalization[1] and olefinic C–H functionalization[2] are
important synthetic methods that have been under constant
investigation. We have recently reported a one-step synthesis of
an
easily
handled
difluoromethylation
reagent
CF2HSO2NHNHBoc (1) and applied this reagent in radical
difluoromethylation of alkynes and alkenes.[3] With our continued
interest in applying compound 1 in the synthesis of CF2H-
containing organofluorine compounds, we envision alkene 1,2-
hydroxydifluoromethylation and C–H difluoromethylation via
radical-polar crossover reaction (Scheme 1a).[4] Although
several C–H trifluoromethylation reactions of alkenes have been
disclosed,[5] the analogous difluoromethylation have remained
elusive. On the other hand, radical-polar crossover strategy has
been employed in photochemical 1,2-hydroxydifluoromethylation
of electron-rich aryl alkenes using an [Ir]-catalyst and
electrophilic difluoromethylation reagents (Scheme 2b).[4a,b]
Scheme 1. Difluoromethylation of alkenes.
We began our study by optimizing the electrolysis conditions
for the 1,2-hydroxydifluoromethylation of acrylamide 2 using
reagent 1 and H2O as the reagents (Tables 1). Our previously
developed electrocatalytic conditions employing ferrocene as the
redox catalyst did not work for the current reaction probably
because of the relatively low oxidation potential of ferrocene.[3]
Further studies employed direct electrolysis in a three-necked
round-bottomed flask equipped with a reticulated vitreous
carbon (RVC) anode and a Pt plate cathode. The optimal
conditions involved electrolysis at 70 °C using a constant current
of 10 mA in a mixed solvent of acetone/H2O (1:2). Under these
conditions, the desired product 3 was isolated in 72% yield
(entry 1). H2O was essential for the success of the reaction as its
absence resulted in no formation of 3 (entry 2). Reduction of the
concentration of H2O led to reduced current efficiency (entries 3
and 4). Replacing acetone with 2,2,2-trifluoroethanol (TFE) also
led to yield reduction (entry 5). When the reaction was carried
out at RT instead of 70 °C, product 3 was not formed and the
amide 1 was recovered in 84% (entry 6). Heating was needed to
increase the solubility of the organic reactants in the aqueous
solution. Other anode materials such as graphite plate (entry 7)
and glassy carbon plate (entry 8) were inefficient in promoting
the formation of 3 than RVC. The electrochemical alkene
difunctionalization reaction could be carried out on gram scale
with efficiency similar to the mini gram scale reaction (entry 9).
However, application of such
a mechanistic manifold in
functionalization of electron-deficient alkenes has remained to
be challenging because of the unfavored oxidation of the
electron-deficient carbon radical to the corresponding
carbocation.[4k,6]
Organic electrochemistry is a green and enabling synthetic
tool and has been gaining increasing traction.[7] Particularly, the
anode is a powerful electron sink and has been employed for
achieving difficult oxidation reactions.[8,9] We have been
interested in the development of electrochemical methods to
promote oxidative radical reactions.[3,10] Herein we report
electrochemical 1,2-hydroxydifluoromethylation and C–H
difluoromethylation of acrylamides using reagent 1 as CF2H
source. No transition metal catalyts or chemical oxidants are
needed for these electricity-powered reactions.
[a]
H.-H. Xu, Prof. Dr. H.-C. Xu
State Key Laboratory of Physical Chemistry of Solid Surfaces,
College of Chemistry and Chemical Engineering, Xiamen University
Xiamen 361005 (P. R. China)
E-mail: haichao.xu@xmu.edu.cn
Web: http://chem.xmu.edu.cn/groupweb/hcxu/
Dr. J. Song
College of Chemistry and Molecular Engineering,
Zhengzhou University, Zhengzhou 450001 (P. R. China)
Supporting information for this article is given via a link at the end of
the document.
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10.1002/cssc.201803058
ChemSusChem
COMMUNICATION
Table 1. Optimization of reaction conditions.[a]
good yields and stereoselectivity (25–28). The stereochemistry
of the alkene product was determined using nuclear Overhauser
effect (NOE) experiment. Once again, the use of
CF3SO2NHNHBoc instead of 1 led to the formation of CF3-
containing product 29 in 97% yield.[5]
Entry
Deviation from standard conditions
none
Yield [%][b]
1
2
3
4
5
6
7
8
9
72[c]
no H2O
0 (40)
6 (75)
69[c,d]
acetone/H2O (2:1) as solvent
acetone/H2O (1:1.5) as solvent
TFE/H2O (1:2) as solvent
reaction at RT
45[c]
0 (84)
8 (59)
0 (82)
69 [0.91 g]
graphite plate (1 cm x 1 cm)
glass carbon plate (1 cm x 1 cm)
1.0 g (4.5 mmol) of 2
[a] Reaction conditions: RVC anode (1 cm x 1 cm x 1.2 cm), Pt cathode (1 cm
x 1 cm), 2 (0.2 mmol), 1 (0.4 mmol), solvent (6 mL), argon, janode  0.1 mA
cm−2, 2.0 h (3.7 F mol−1 based on 2). [b] Yield determined by 1H-NMR analysis
using 1,3,5-trimethoxybenzene as the internal standard. Unreacted
parenthesis. [c] Isolated yield. [d] Reaction time = 2.8 h.
2 in
We then investigated the substrate scope of the alkene
difunctionalization reaction by varying the substituents of R1 on
the alkene and R2 on the amide nitrogen atom (Scheme 2). The
phenyl ring on the alkene could be substituted at the para
position with electron donating OMe (4) and halogens such as Cl
(5) and Br (6 and 8), but not the highly electron-withdrawing
acetyl group (7). Many other aryl groups such as 1-naphthyl (9),
3-pyridyl (10) and 2-thiophenyl (11) were tolerated at R1 position
but not a Me group (12). Phenyl groups bearing substituents
with diverse electronic properties such as OMe (13), F (14), Cl
(15), CF3 (16), CN (17), and ester (18) were suitable as R2 on
the amide nitrogen. Besides the secondary N-aryl amides, a
primaryl amide also afforded the hydroxydifluoromethylation
product in 50% yield (20). However, a secondary amide bearing
a N-Me group underwent decomposition and failed to afford the
alkene difunctionalization product 21. While an ester reacted to
afford the difunctionalization product (22) in moderate yield
(38%), the corresponding free carboxylic acid failed completely
(23). Hydroxytrifluoromethylation could also be achieved using
CF3SO2NHNHBoc[11] as the CF3 source (24).
Scheme 2. Scope of pyrrolidine synthesis. Reaction conditions: Table 1, entry
1, 1.3–3.6 h (2.4–6.7 F mol−1). [a] Reaction in MeCN/H2O (2 mL/4 mL). [b]
Reaction in TFE/H2O (5 mL/1 mL).
Further investigations revealed that tertiary amides
underwent C–H difluoromethylation to give CF2H-substituted
acrylamines instead of alkene difunctionalization (Scheme 3).
The C–H difluoromethylation reactions were best carried out in
TFE/H2O (5:1) with Et4NOTs as the electrolyte (Table S1). Under
these conditions, tertiary acrylamides with different N-
substituents reacted to afford the desired products with generally
Scheme 3. Scope of C–H difluoromethylation reaction. Reaction conditions:
acrylamide (0.2 mmol), TFE (5 mL), H2O (1 mL), 3.2–5 h (5.9–9.3 F mol−1). [a]
Determined by 1H NMR analysis of crude reaction mixture.
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10.1002/cssc.201803058
ChemSusChem
COMMUNICATION
atom instead of the reaction parameters. The difunctionalization
of 2 in the presence of H218O afforded [18O]-3 in 40% yield (79%
18O).[12] Dehydration of [18O]-3 afforded 30 in 50% yield. These
experiments suggested that the hydroxyl group in compound 3
was originated from H2O.
A
possible
mechanism
for
the
electrochemical
difluoromethylation reaction has been proposed (Scheme 5a).
Anodic oxidation of the reagent 1 on the anode produces
diazene I, which undergoes decomposition to generate
difluoromethyl radical (•CF2H).[3] Radical addition to the
acrylamide followed by one-electron oxidation at the anode
furnishes the α-carbonyl carbocation II. The Ar1 group, which
can stabilize the carbocation, is critical for the oxidation of the
electron-deficient carbon radical I. Depending on the
substituents on the amide nitrogen atom, the carbocation II
either reacts with H2O to afford the alkene difunctionalization
product or undergoes proton elimination to give the C–H
Scheme 4. Mechanistic studies.
functionalization product. The carbocation IIIA bearing
a
secondary amide moiety probably exists in equilibrium with the
aza-oxyallyl cation IV, which is known to favor addition reaction
over proton elimination (Scheme 5b).[13] The proton elimination
reaction of IIIB proceed via the conformation IIIB1 instead of the
more sterically encumbered IIIB2 affording the Z-isomer as the
major product (Scheme 5c).
In summary, we have developed electrochemical
difluoromethylation
reactions
of
acrylamides
using
CF2HSO2NHNHBoc as the difluoromethylation reagent. While
secondary N-aryl acrylamides react to afford α-hydroxy amides
via alkene hydroxydifluoromethylation, tertiary acrylamides
undergo olefinic C–H functionalization.
Acknowledgements
Financial
support
of
this
research
from
MOST
(2016YFA0204100), NSFC (21672178) and the Fundamental
Research Funds for the Central Universities.
Keywords: electrosynthesis • alkene difunctionalization •
difluoromethylation • radicals • C–H functionalization
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10.1002/cssc.201803058
ChemSusChem
COMMUNICATION
COMMUNICATION
Electrochemical 1,2-
He-Huan Xu, Jinshuai Song and Hai-
Chao Xu*
hydroxydifluoromethylation and C–H
difluoromethylation of acrylamides
have been developed using
CF2HSO2NHNHBoc as the source of
CF2H group. These electricity-
powered oxidative alkene
Page No. – Page No.
Electrochemical Difluoromethylation
of Electron-Deficient Alkenes
functionalization reactions do not need
transition metal catalysts and
chemical oxidants.
This article is protected by copyright. All rights reserved.