Transition-metal free C-C bond cleavage/borylation of cycloketone oxime esters

Article abstract of DOI:10.1039/C8SC03315C

An efficient transition-metal free C-C bond cleavage/borylation of cycloketone oxime esters has been described. In this reaction, the B₂(OH)₄ reagent not only served as the boron source but also acted as an electron donor source through formation of a complex with a DMAc-like Lewis base. This complex could be used as an efficient single electron reductant in other ring-opening transformations of cycloketone oxime esters. Free-radical trapping, radical-clock, and DFT calculations all suggest a radical pathway for this transformation.

Full text of DOI:10.1039/C8SC03315C

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Transition-metal free C–C bond cleavage/
borylation of cycloketone oxime esters†
Cite this: Chem. Sci., 2019, 10, 161
*
All publication charges for this article
have been paid for by the Royal Society
of Chemistry
Jin-Jiang Zhang, Xin-Hua Duan,
Yong Wu, Jun-Cheng Yang and Li-Na Guo
An efficient transition-metal free C–C bond cleavage/borylation of cycloketone oxime esters has been
described. In this reaction, the B2(OH)4 reagent not only served as the boron source but also acted as an
electron donor source through formation of a complex with a DMAc-like Lewis base. This complex
could be used as an efficient single electron reductant in other ring-opening transformations of
cycloketone oxime esters. Free-radical trapping, radical-clock, and DFT calculations all suggest a radical
pathway for this transformation.
Received 26th July 2018
Accepted 28th September 2018
DOI: 10.1039/c8sc03315c
rsc.li/chemical-science
cleavages of cycloketone oxime esters.10 These established
protocols provided efficient approaches to incorporate the
Introduction
versatile cyanoalkyl moieties into structurally diverse mole-
cules, wherein the iminyl radical was the pivotal intermediate.
Although remarkable advances have been made, the C–C bond
cleavage/borylation of cycloketone oxime derivatives remains
unexplored. Very recently, some elegant transition metal-free
borylation reactions have been reported by different research
groups.11 Intriguingly, the diboron species not only served as
a boron source but also acted as an electron donor source to
generate reactive radical intermediates.11,12 Inspired by these
studies and our previous results, we wish to explore a novel
catalytic system to form a reactive iminyl radical and simulta-
neously to construct C(sp3)–B bonds (Fig. 2, route b). Herein, we
report a transition metal free C–C bond cleavage/borylation of
cyclobutanone oxime esters through using a diboron reagent as
the boron source and activator. This protocol provided
a straightforward access to cyanoalkyl boronic esters, a class of
versatile building blocks in organic synthesis,2,13 in good yields.
Alkylboronic esters are very important building blocks in
organic synthesis as well as in medicinal chemistry and mate-
rials science (Fig. 1).1,2 For instance, they have been widely used
in Suzuki–Miyaura coupling reactions.3 Thus, many chemists
have devoted their efforts to develop facile and efficient
methods for the synthesis of alkylborons.4 The classical method
relies on the trapping of highly reactive alkyl-Li or alkyl-Mg
reagents with suitable boron compounds.5 However, this
procedure suffers from strict conditions as well as poor
functional-group tolerance. In recent years, a number of C–B
bond formation reactions, including transition-metal catalyzed
borylation of alkyl halides, decarboxylative borylation of
aliphatic esters,6 hydroboration of alkenes and others have
emerged as attractive alternatives to classical methods.7
Nevertheless, noble metal catalysts, strong bases and ligands
are usually required in these reactions. Therefore, developing
mild borylation reactions to access functionalized alkylboron
compounds is still desirable and highly in demand.4
Since the pioneering work of Zard and Uemura, C–C bond
cleavage of cycloketone oxime derivatives has emerged as an
attractive strategy to construct C–C and C–Y (Y ¼ O, S, Se, Te, or
X) bonds.8–10 Recently, an array of radical C–C bond cleavages of
cycloketone oxime derivatives have been developed under
different catalytic systems including transition-metal catalysis
and visible-light photocatalysis (Fig. 2, route a).9a–h In addition,
the Castle group reported a microwave-promoted C–C bond
cleavage of cycloketone oxime ethers.9i In this regard, our group
presented a series of iron and copper catalyzed C–C bond
Fig.
moieties.
1 Biologically active compounds containing alkylboronic
Department of Chemistry, School of Science, MOE Key Laboratory for Nonequilibrium
Synthesis and Modulation of Condensed Matter, Xi'an Jiaotong University, Xi'an,
Shaanxi, 710049, China. E-mail: guoln81@xjtu.edu.cn
† Electronic supplementary information (ESI) available: Experimental procedures
and characterization of new compounds are provided. See DOI:
10.1039/c8sc03315c
Fig. 2 Transformation of cyclobutanone oxime derivatives.
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solvents such as NMP and DMF were less effective (entries 9
and 10). Additionally, other types of solvents such as DCM,
acetone and MeCN all furnished worse yields (entries 11–13). It
should be noted that the reaction in DCM using 1.0 equiv. of
DMAc as the additive only afforded a trace amount of 2a (entry
14). Finally, other additives such as 4-phenylpyridine, 4-cyano-
pyridine, DMAP and Cs2CO3 were also tested, but none of them
gave better results than DMAc alone (entries 15–18).
With the optimal conditions in hand, the generality and
limitations of cyclobutanone oxime esters were examined
(Table 2). A variety of 3-aryl, benzyl and alkyl substituted oxime
esters were efficiently engaged in this ring-opening/borylation
reaction to provide the corresponding boronic esters 2a–2q in
moderate to good isolated yields. It was found that the nature of
the substituents on the aromatic ring has a signicant effect on
the reaction efficiency (2e–2g vs. 2h and 2i). Satisfactorily,
functional groups including halogen (2d, 2h, 2j), ester (2i, 2o,
2p) and ether (2m, 2q) in the oxime esters were well-tolerated.
Cyclobutanone oxime ester 1r without any substituent fur-
nished the desired product 2r in 85% yield. The 3,3-disubsti-
tuted substrates 1s and 1t also afforded the target products 2s
and 2t in 76% and 34% yields, respectively.
Results and discussion
To test our hypothesis, cyclobutanone oxime ester 1a was
treated with 1.2 equiv. of bis(pinacolato)diboron (B2pin2) in
DMAc at room temperature under the irradiation of a 23 W CFL
bulb. To our delight, the desired pinacol cyanoalkyl boronic
ester 2a was obtained in 7% yield (Table 1, entry 1). When
bis(catecholato)diboron (B2cat2) was used instead of B2pin2, the
yield of 2a was increased to 54% aer workup with pinacol and
NEt3 (entry 2). However, the yield of 2a decreased dramatically
when the reaction was conducted in the dark. Satisfactorily,
tetrahydroxydiboron B2(OH)4 showed better reaction efficiency
and gave the desired product 2a in 61% yield (entry 4).
Surprisingly, it was found that photoactivation was not essential
for the reaction with B2(OH)4. Treatment of 1a with 2.0 equiv. of
B2(OH)4 still resulted in a 60% yield of 2a even in the dark (entry
5). A similar result was also observed under ambient light (entry
6). These results indicated that the reaction was not triggered by
a light source. Notably, increasing the amount of B2(OH)4 to 3.0
equiv. improved the yield of 2a to 77%, while further increasing
the amount of B2(OH)4 did not improve the yields of 2a (entries
7 and 8). Solvent screening indicated that other amide-based
Notably, besides primary boronic esters, this procedure was
also applicable to provide the secondary ones under modied
conditions. The 2,3-disubstituted oxime esters 1u and 1v
underwent the ring-opening/borylation process regioselectively
to afford the desired products 2u and 2v in acceptable yields by
Table 1 Optimization of reaction conditionsa
ꢀ
using 1.2 equiv. of B2cat2 as the boron source at 80 C under
irradiation with 23 W CFL bulbs. It should be noted that the
light irradiation, heating and boron source are all important for
these reactions, implying that direct photolysis of B2Cat2
Boron sources
Entry (equiv.)
Table 2 Scope of cyclobutanone oxime estersa
Solvent
Additives (equiv.)
Yieldb (%)
1
2
3
4
5
6
7
8
B2pin2 (2.0)
B2Cat2 (2.0)
B2Cat2 (2.0)
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
NMP
7c,d
54c
28e
61c
60e
61
77
73
66
52
B2(OH)4 (2.0)
B2(OH)4 (2.0)
B2(OH)4 (2.0)
B2(OH)4 (3.0)
B2(OH)4 (4.0)
B2(OH)4 (3.0)
B2(OH)4 (3.0)
B2(OH)4 (3.0)
B2(OH)4 (3.0)
B2(OH)4 (3.0)
B2(OH)4 (3.0)
B2(OH)4 (3.0)
B2(OH)4 (3.0)
B2(OH)4 (3.0)
B2(OH)4 (3.0)
9
10
11
12
13
14
15
16
17
18
DMF
MeCN
Acetone
DCM
20
15
n.r.f
Trace
DCM
DMAc (1.0)
DMAc
DMAc
DMAc
DMAc
4-Phenylpyridine (1.0) 56
4-Cyanopyridine (1.0)
DMAP (1.0)
Cs2CO3 (1.0)
Traceg
63
26
a
Reaction conditions: 1a (0.20 mmol, 1.0 equiv.), boron sources (2.0–4.0
equiv.), additives (1.0 equiv.), in 2.0 mL of solvent at room temperature
under N2 for 16 h; then pinacol (0.8 mmol, 4.0 equiv.) dissolved in Et3N
b
(0.7 mL) was added to the reaction mixture and stirred for 1 h. NMR
c
yields by using CH2Br2 as the internal standard. Reaction by
irradiation with
a
23
W compact uorescent light (CFL) bulb.
d
e
Without addition of pinacol and Et3N. The reaction was conducted
a
f
g
1 (0.2 mmol), B2(OH)4 (0.6 mmol), DMAc (2 mL) at room temperature
in the dark. n.r. ¼ no reaction. 3-Phenylbutanenitrile was observed
under N2 for 16 h; then workup with pinacol (0.8 mmol) and Et3N (0.7
mL), isolated yields.
as the major product.
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accounts partly for the formation of 2u and 2v (eqn (1) and (2)).
To gain some understanding of the reaction, several control
The tricyclo[5.2.1.0(2,6)]decan-8-one oxime ester 1w also gave experiments were conducted (Fig. 3). When TEMPO, a typical
the anticipated secondary boronic ester 2w as a single diaste- radical scavenger was subjected to the reaction conditions, only
reomer under the modied conditions, albeit in somewhat low trace amount of 2a was observed, along with the cyanoalkyl-
yield (eqn (3)). Unfortunately, the oxime ester derived from TEMPO adduct 5a which was isolated in 50% yield, implying
2-substituted cyclopentanone or cyclohexanone could not that a radical intermediate was involved in this transformation.
afford the desired product under the present conditions.
In contrast, without B2(OH)4 or DMAc, the reaction of 1a with
TEMPO did not take place, suggesting that both the diboron
reagent and amide-based solvent play a critical role in this ring-
opening process (Fig. 3, eqn (4)). Furthermore, the radical-clock
substrates 6a and 6b furnished the cyclized products 7a and 7b
via a ring-opening/cyclization/borylation cascade, wherein no
linear coupling product was detected (Fig. 3, eqn (5) and (6)).
Treatment of 6c under the standard conditions led to the
product 7c in 58% yield as the sole product (Fig. 3, eqn (7)).
These results also support a radical pathway.
Based upon the preliminary results and previous reports,
a possible mechanism was proposed for this reaction with the
further aid of DFT calculation (Scheme 2, for details, see the
ESI†). This borylation reaction probably proceeds through
a radical chain propagation mechanism. First, cyclobutanone
oxime ester 1a gives the DMAc-stabilized radical intermediate I
through thermal cleavage of the B–B bond of B2(OH)4$DMAc
complex.11,12 Second, N–O bond cleavage of radical I affords the
iminyl radical II, which delivers radical III through a b-carbon
elimination process.7–9 Aerward, the alkyl radical III reacts
with DMAc-ligated B2(OH)4 to produce the precursor of the
desired product 2a0 and DMAc-stabilized boryl radical IV.11,12,14
Finally, the resulting boryl radical IV might propagate a radical
chain process. It is worth mentioning that ArCOOB(OH)2 can be
detected by LCMS during the reaction, which also provided
evidence for our proposed catalytic cycle. On the other hand,
based on the above result and UV-vis spectrum of 1u and B2Cat2
in DMAc, direct light-triggered homolysis of B2Cat2 might be
involved in the reaction of 1u with B2Cat2.
(1)
(2)
(3)
Satisfactorily, this metal free C–C cleavage/borylation reac-
tion of cyclobutanone oxime esters could be scaled up. For
instance, the reaction of 1a on a 2.0 mmol scale gave the
product 2a in 67% isolated yield. Furthermore, the product of
this reaction was not limited to pinacol boronic ester. Using
methyl iminodiacetic acid (MIDA) instead of pinacol for the
reaction workup, the corresponding product 3a was obtained in
60% yield. Moreover, the product 2a could be oxidized by H2O2
followed by hydrolysis to deliver the alcohol 4a in 80% yield
(Scheme 1). Finally, treatment of cyanoalkyl boronic ester 2r
with 4-triuoromethylbromobenzene in the presence of
a palladium catalyst afforded the coupling product 4b in 28%
yield (without optimization).
Scheme 1 Synthesis of 2a on a gram scale and derivatization of the
product.
Fig. 3 Control experiments.
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Acknowledgements
Financial support from Natural Science Basic Research Plan in
Shaanxi Province of China (No. 2016JZ002), and the Funda-
mental Research Funds of the Central Universities (No.
zrzd2017001 and xjj2016056) is greatly appreciated. We thank
Prof. Pengfei Li in XJTU for a helpful discussion. We also thank
Miss Lu at the Instrument Analysis Center of Xi'an Jiaotong
University for her assistance with HRMS analysis.
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Fig. 4 Reductive cleavage reactions employing the B2(OH)4/DMAc
system.
Remarkably, this simple B2(OH)4/DMAc system was also
applicable to other C–C bond cleavage/C–C bond formations
(Fig. 4). The reaction of 1a with quinoxalin-2(1H)-one 8a and
quinine 8b also worked smoothly to give the cyanoalkylated
products 9a and 9b in 52% and 32% yields, respectively (without
optimization).10a,b These results suggested that this new tran-
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metal catalytic systems, further indicating their potential
applications in radical chemistry.
Conclusions
In summary, we have demonstrated the rst transition-metal free
C–C bond cleavage/borylation of cyclobutanone oxime esters.
This protocol is amenable to a variety of cyclobutanone oxime
esters, thus providing a facile access to cyanoalkyl boronic esters
in good yields. Primary mechanism studies revealed that B2(OH)4
not only serves as a boron source but also plays a crucial role in
the C–C bond cleavage process. Further studies on the mecha-
nistic details are currently underway in our laboratory.
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