Electrochemically promoted decarboxylative borylation of alkyl N-hydroxyphthalimide esters

Article abstract of DOI:10.1016/j.cclet.2021.09.011

An electrochemically promoted decarboxylative borylation reaction is reported. The reaction proceeds under mild conditions in an undivided cell without use of transition metal- or photo-catalysts. The key feature of the reaction is the compatibility of di

Full text of DOI:10.1016/j.cclet.2021.09.011

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Electrochemically promoted decarboxylative borylation of alkyl
N-hydroxyphthalimide esters
Jian-Jun Dai , Xin-Xin Teng , Wen Fang , Jun Xu , Hua-Jian Xu
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DOI:
Reference:
S1001-8417(21)00723-3
https://doi.org/10.1016/j.cclet.2021.09.011
CCLET 6723
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1 September 2021
Please cite this article as: Jian-Jun Dai , Xin-Xin Teng , Wen Fang , Jun Xu , Hua-Jian Xu , Electro-
chemically promoted decarboxylative borylation of alkyl N-hydroxyphthalimide esters, Chinese Chem-
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Communication
Electrochemically promoted decarboxylative borylation of alkyl N-
hydroxyphthalimide esters
a,b,*
a
a
a,b
a,b,*1
Jian-Jun Dai , Xin-Xin Teng , Wen Fang , Jun Xu , Hua-Jian Xu
a
School of Food and Biological Engineering, Hefei University of Technology, Hefei 230009, China
Anhui Province Key Laboratory of Advance Catalytic Materials and Reaction Engineering, Hefei University of Technology, Hefei 230009, China
b
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
An electrochemically promoted decarboxylative borylation reaction is reported. The reaction
proceeds under mild conditions in an undivided cell without use of transition metal- or photo-
catalysts. The key feature of the reaction is the compatibility of diboron reagents with the
electrochemical conditions. This reaction exhibits broad substrate scope, good functional group
tolerability, and easy scalability.
Available online
A
Keywords:
Electrochemical
Decarboxylation
Borylation
Alkyl boronic esters
Redox active esters
Graphical Abstract
An electrochemically promoted decarboxylative borylation reaction is reported. The reaction proceeds under mild conditions in
an undivided cell without use of transition metal- or photo-catalysts.
Alkyl boronic acid and esters represent important scaffolds in both organic synthesis and pharmaceuticals [1]. For example, alkyl
3
boronic acid and esters show great value for the construction of C(sp )–rich scaffolds using cross-coupling reactions [2,3]. In addition,
molecules containing alkyl boron structures have been proven to be life-saving drugs such as Velcade [4,5]. Classic methods to
synthesize alkyl boron compounds include hydroboration of alkenes [6–11], borylation of organometallic nucleophiles (e.g., Grignard
and organolithium reagents) [12–14]. However, these methods suffer from harsh reaction conditions and poor functional group
tolerance. Over the past decade, great attention has been directed to the borylation of alkyl halides using transition-metal catalysis
including Cu [15–16], Ni [17,18], Pd [17,19], Zn [20], Fe [21,22], Mn [23] and more recently photo-induced catalysis [24–33]. In
recent years, the use of easily available and stable carboxylic acids redox active esters (RAEs, e.g., N-hydroxyphthalimide esters)
derived from alkyl carboxylic acids as starting materials for decarboxylative transformations is a fast growing research area [34–40]. In
particular, remarkable progresses have been made with regard to decarboxylative borylation of RAEs [41–44]. Baran and co-workers
reported transition-metal catalyzed (i.e. nickel, copper) protocols for the decarboxylative borylation of RAEs with
bis(pinacolato)diboron (B pin ) using excess MeLi and LiOH as the base, respectively [45,46]. Li and co-workers described the
2
2
decarboxylative borylation of RAEs with excess B pin using an Ir-based photoredox catalyst under 45 W CFL irradiation (Scheme 1A)
2
2
—
——
1
*
Corresponding authors.
E-mail address: daijj@hfut.edu.cn (J.J. Dai), hjxu@hfut.edu.cn (H.J. Xu)

[
47]. Aggarwal el al. developed an efficient photo-induced method to achieved the decarboxylative borylation of RAEs with
bis(catecholato)diboron (B cat ) under irradiation with blue LEDs (Scheme 1A) [48]. An important feature to the success of these
2
2
decarboxylative transformations of RAEs is the facile generation of alkyl radical intermediates via single-electron transfer process.
Electro-organic synthesis servers as a powerful and green technique for oxidative and reductive reactions by single-electron transfer
under mild conditions and good functional group tolerance [49–56]. Recently, elegant works on electrochemical reductive
decarboxylative carbon–carbon bond formation using RAEs have been disclosed by Wang [57], Lei [58] and Zeng [59] groups.
In this context, we hypothesized that the electrochemically promoted reductive decarboxylation of RAEs may be compatible with
diboron reagents such as B pin , B cat , thus resulting the decarboxylative borylation reaction. Herein, we report an efficient method
2
2
2
2
for the construction of alkyl boronic esters using an electrochemically promoted decarboxylative borylation of alkyl N-
hydroxyphthalimide esters (Scheme 1B). This reaction exhibits broad substrate scope, good functional group tolerability, and easy
3
scalability, representing an alternative method for the formation of C(sp )–B bond with electrochemical techniques [60,61].
Scheme 1. Radical decarboxylative borylation of RAEs.
We started our investigation with the electrochemical decarboxylative borylation of N-(cyclohexanecarbonyl)phthalimide and B cat
2
2
under constant current electrolysis (CCE) (Table 1). It was found that the desired product 1 can be obtained in 86% yield (76% isolated)
with 10 mA constant current in an undivided cell followed by the treatment of pinacol and Et N (entry 1). The use of other supporting
3
n
electrolytes including Bu NPF , LiClO and NaBF (entries 2–4) gave 1 in slightly lower yields. Increasing or decreasing the electric
4
6
4
4
current delivered diminished yields (entries 5 and 6). It was also found that this reaction was sensitive to air (entry 7). The cathode
materials such as reticulated vitreous carbon (RVC), nickel, copper and iron failed to improve the efficiency of this reaction (entry 8,
please see Supporting information for more details). Also, the use of graphite anode resulted in lower efficiency compared to that of
platinum anode (entry 9). Notably, the solvent is important to the outcome of the reaction: the use of THF gave a decreased yield (entry
1
0), however the performances of other solvents such as MeCN, DMSO and NMP were poorer than that of DMF (entries 11–13).
Additionally, the decarboxylative borylation reaction proceeded well at cathode in a divided cell (entry 14, not optimized). It should be
noted that the reaction can be promoted by light from fume hood white bulb but at a significantly lower rate (entry 15). This result is in
agreement with the previous report by Aggarwal and co-workers [48]. Finally, control experiments showed that a similar positive result
was obtained when the reaction was conducted in dark (entry 16) and a very lower yield of 1 was observed without the use of electric
current (entry 17). These results highlight the crucial role of an electric current in the decarboxylative borylation reaction.
Table 1
a
Screening of reaction conditions.

b
Entry
Changes from standard conditions
none
Yield (%)
86 (76)
76
68
65
35
44
7
45–67
46
75
21
0
53
57
31
77
1
2
3
4
5
6
7
8
9
n
n
Bu
LiClO
NaBF
4
NPF
6
instead of Bu
4
NBF
4
4
n
4
instead of Bu
4
NBF
NBF
n
4
instead of Bu
4
4
20 mA instead of 10 mA, 2 h
5 mA instead of 10 mA, 8 h
air atmosphere
RVC, Ni, Cu, Fe instead of Pt cathode
graphite instead of Pt anode
THF instead of DMF
MeCN instead of DMF
DMSO instead of DMF
NMP instead of DMF
divided cell was used
w/o electric current
1
1
1
1
1
1
1
1
0
1
2
3
4
5
6
7
in dark
in dark w/o electric current
28
a
Standard conditions: NHPI ester (0.6 mmol, 1 equiv.), B cat (2 equiv.), DMF (2 mL), platinum plate anode: (10 mm × 10 mm × 0.2 mm),
platinum plate cathode: (10 mm × 10 mm × 0.2 mm), Bu NBF (0.6 mol/L), constant current: 10 mA, r.t., argon atmosphere, 4 h, undivided
2
2
n
4
4
cell, then pinacol (4 equiv.), Et N (2 mL), r.t., 2 h. Cell voltage: 1.5–4 V.
3
b
GC yield using mesitylene as an internal standard. Isolated yield is shown in parentheses.
With the optimal reaction conditions in hand, the scope of this reaction was then examined with respect to different alkyl carboxylic
acids. As summarized in Scheme 2A, primary N-hydroxyphthalimide esters bearing either electron-donating or electron-withdrawing
groups were smoothly converted to the corresponding alkylboronates in moderate to good yields (39%–62%). It was demonstrated that
halides such as fluoro (14), chloro (3 and 15) and bromo (7 and 16) groups were well compatible with the reaction, thus not only
demonstrating the orthogonal reactivity of this reaction with previously developed transition metal-catalyzed borylation of halides [15–
2
3], but also providing opportunities for further conversions with cross-coupling reactions [3]. Furthermore, N-hydroxyphthalimide
esters possessing terminal olefin (4), ester (5), phenyl (8 and 11), methyl (12), methoxy (9 and 13), thienyl (10) and trifluoromethyl (17)
groups were well tolerated.

Scheme 2. Substrate scope. Reaction conditions: NHPI ester (0.6 mmol, 1 equiv.), B cat (2 equiv.), DMF (2 mL), platinum plate anode: (10
2
2
n
mm × 10 mm × 0.2 mm), platinum plate cathode: (10 mm × 10 mm × 0.2 mm), Bu NBF (0.6 M), constant current: 10 mA, r.t., argon
4
4
a
b
c
atmosphere, 4 h, undivided cell, then pinacol (4 equiv.), Et N (2 mL), r.t., 2 h. Reaction time was 3 h. Reaction time was 6 h. B cat (3
3
2
2
equiv.) was used.
Then, investigation of the substrate scope was focused on secondary and tertiary N-hydroxyphthalimide esters (Scheme 2B). Both
acyclic and cyclic alkyl N-hydroxyphthalimide esters were all suitable for the decarboxylative borylation, yielding the desired
secondary and tertiary alkylboronates in moderate to good yields (31%–80%). For example, cyclohexyl (2, 22 and 28), cyclopentyl
(20), inner olefin (21), cyclopropyl (18, 27 and 29) and adamantyl (30) motifs were tolerated, as was the important heterocycle, Boc-
protected piperidine (23 and 24). The cyclobutyl boronic ester (19) could also be achieved, albeit with a lower yield. Interestingly,
Aggarwal et al. reported tertiary carboxylic acids such as 1-methyl-cyclohexyl carboxylic acid failed to provide the desired
decarboxylative borylation product in photochemical conditions [48]. To our delight, the desired boronic ester (28) can be formed
smoothly under our electrochemical conditions, suggesting that this electrochemical protocol is complementary to that previously
developed photochemical process.
To further expand the substrate scope, we conducted late-stage modifications of amino acids and drug molecules (Scheme 2C).
Specifically, β-amino acid and γ-amino acids (e.g., γ- aminobutyric acid (GABA), gabapentin and pregabalin) were converted into
boronic esters (31–34) in moderate yields. Gemfibrozil, a lipid-lowering drug, gave the corresponding boronic ester 35 in 53% yield.
The reaction was also amenable to scale-up by a one-pot procedure in which cyclohexyl N-(cyclohexanecarbonyl)phthalimide formed
in situ, followed by electrochemically promoted decarboxylative borylation, delivering the corresponding boronic ester 1 in 48% yield
on a 5.0 mmol scale (Scheme 2D).
A series of experiments were conducted to gain more mechanistic insights of the electrochemically promoted decarboxylative
borylation reaction (Scheme 3). In the radical trapping experiment, with the use of 2,2,6,6-tetramethylpiperidine 1-oxyl (TEMPO, 3
equiv.) as a trapping agent under the standard conditions, the formation of 1 was obviously inhibited and the cyclohexyl/TEMPO

adduct 37 was detected in HRMS analysis (Scheme 3A). Further evidence for the radical mechanism was provided by the reaction of
8, where only ring-opening product 4 was obtained without the formation of cyclopropyl-containing 39 (Scheme 3B). Moreover,
3
when the 5-hexenyl radical clock precursor 40 was used, we obtained cyclization reaction product 41 in 17% yield along with linear
1
product 42, the ratio of 41 and 42 was determined by H NMR analysis (Scheme 3B).
Scheme 3 Control experiments and proposed mechanism for the electrochemical decarboxylative borylation reaction.
Based on previous reports of radical borylation [24,30,34] and the above experimental results, we proposed a possible mechanism
for the electrochemically promoted decarboxylative borylation reaction (Scheme 3C). Initially, alkyl N-hydroxyphthalimide ester was
reduced at the cathode to generate radical anion A that underwent decarboxylation to form the corresponding alkyl radical B
intermediacy. Then, alkyl radical B reacts with B cat and DMF to deliver the intermediate C. Subsequently, the cleavage of B–B bond
2
2
of C to generate D and F. Finally, D is converted to product E with the treatment of pinacol/triethylamine. The radical F is eventually
oxidized at the anode yielding G, and reaction of G and NPhth anion to deliver H.
In summary, we have developed an electrochemically promoted decarboxylative borylation reaction. The process shows broad
substrate scope and provides a series of alkyl boronic esters. It is worth noting that the diboron reagents compatible well with
electrochemical reaction conditions, which will provide opportunities for discovering new electrochemical borylation reactions. The
use of electrochemical methods for making other type of organon boron compounds is currently underway in our laboratory.
Acknowledgments
This work was supported by the National Natural Science Foundation of China (Nos. 21871074 and 21971051), the National Key
R&D Program of China (No. 2018YFB1501604), the Fundamental Research Funds for the Central Universities (No.
PA2020GDKC0021) and the Key Research and Development Program Projects in Anhui Province (No. 201904a07020069).
Declaration of Interest Statement
We declare that we have no financial and personal relationships with other people or organizations that can inappropriately influence
our work, there is no professional or other personal interest of any nature or kind in any product, service and/or company that could be
construed as influencing the position presented in, or the review of, the manuscript entitled.

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