Free Radical Pathway Cleavage of C—O Bonds for the Synthesis of Alkylboron Compounds

Article abstract of DOI:10.1002/cjoc.201800500

We report a silver-catalyzed borylation of alkyl tosylates, which provides a new method for the synthesis of alkylboron compounds with good functional group compatibility and excellent chemoselectivity. The present work added highly polarized alkyl tosylate C—O bonds to the fairly limited number of C—O bonds able to participate in free radical cleavage pathways. The mechanistic studies suggested that in situ-generated silver(0) catalytic species were the active catalytic species and played a key role in the radical pathway cleavage of C—O bonds.

Full text of DOI:10.1002/cjoc.201800500

Free Radical Pathway Cleavage of C-O Bonds for the Synthesis of
Alkylboron Compounds
Xi Lu,a,† Zhen-Qi Zhang,a,† Lu Yu,b,† Ben Zhang,a Bing Wang,a Tian-Jun Gong,a Chang-Lin Tian,a,b,c Bin Xiao,*,a and Yao Fu*,a
ABSTRACT We report a silver-catalyzed borylation of alkyl tosylates which provides a new method for the synthesis of alkylboron compounds with good
functional group compatibility and excellent chemoselectivity. The present work added highly polarized alkyl tosylate C-O bonds to the fairly limited
number of C-O bonds able to participate in free radical cleavage pathways. The mechanistic studies suggested that in situ-generated silver(0) catalytic
species were the active catalytic species and played a key role in the radical pathway cleavage of C-O bonds.
KEYWORDS radical pathway, C-O bonds cleavage, alkylboron compounds, silver-catalyst, alkyl electrophiles
through SN2 pathways.9 In this context, we report a silver catalytic
system for the direct free radical pathway cleavage of C-O bonds
Introduction
As one of the most widely occurring and naturally abundant
(Figure 1c). In a more general sense, the present work added
chemical bonds known, C-O bonds are commonly found in small
highly polarized alkyl tosylate C-O bonds to the fairly limited
organic molecules and biological macromolecules. The conversion
number of C-O bonds able to participate in free radical cleavage
pathways.10
of C-O bonds plays an irreplaceable role in many fundamental
organic transformations and biochemical processes.1 Under the
Alkylboronic acids are a highly versatile synthon in synthetic
promotion of transition metal catalysts, aromatic C-O bond
chemistry, serving as stable organometallic reagents for
activation had enjoyed great success.2 The alkyl variants, relatively,
were lagged far behind and restricted to classic nucleophilic
substitution reactions (i.e. SN1, SN2) (Figure 1a).3 Alkyl sulfonates,
which are easily accessed from alcohols, represent one of the
most ideal and straightforward types of starting material for the
utilization of naturally abundant C(sp³)-O bonds. Over the past
few years, the scope of traditional SN2 reaction of alkyl sulfonates
had been broadened to a more general concept with SN2-like
oxidative addition pathway (Figure 1b).4 For example, Pd,5 Co,6
Ni,7 Cu,8 and so on could accelerate this process.
constructing carbon-heteroatom or carbon-carbon bonds.11 In
addition, they are also commonly applied in cancer treatment
through boron neutron capture therapy or enzyme inhibition.12
Among the methods developed for the synthesis of alkylboronic
acids and their derivatives, the borylation of alkyl electrophiles
with diverse transition metal catalysts has proved to be one of the
most efficient and prevalent approaches.13 Despite great
achievements by Fu,14 Cook,15 Marder,16 Ito,17 etc.,18 a distinctive
method for borylation through direct C-O bond cleavage remained
18b
undiscovered. The early Cu systems17,
provide general and
efficient strategies for the preparation of primary and secondary
alkylboron compounds, but in situ Finklestein with iodine ions was
required for chloride and sulfonate substrates. Although Pd,18a, 18c
Ni,14, 18c Zn,16a Fe15a systems function well with unactivated alkyl
bromides and iodides, only few examples of activated alkyl
chlorides or sulfonates (benzyl or allyl substrates) were reported.
Robust Mn catalyzed borylation15b allows the transformation of
relatively inert unactivated alkyl chlorides, however, still not
include challenging unactivated alkyl sulfonates. Herein, we
realized the borylation of unactivated alkyl tosylates through silver
catalyzed direct cleavage of C-O bonds. This reaction provide a
novel tool for the creation of alkylboron compounds with good
functional group compatibility and excellent chemoselectivity.
Results and Discussion
Our model reaction involved the borylation of a secondary
alkyl tosylate (1). To achieve this transformation, considerable
efforts were required. Fortunately, we found that the more
polarized C-OTs bonds (compared with carbon-halogen bonds)
Figure 1 Reaction pathways for alkyl tosylates. SET = single electron
transfer. Nu = nucleophile.
New bond cleavage pathways would expand our horizons
beyond utilizing those already existing materials to a totally
different strategy. A radical pathway for the activation of alkyl
sulfonates would provide a new route for the utilization of
abundant alcohols and would supplement the obsolete
knowledge that the alkyl sulfonates almost exclusively activated
could be activated by a polarizable silver catalyst. We
systematically screened the effects of different silver catalysts,
solvents, bases and ligands (see the Supporting Information for
more details). As shown in Table 1, the borylation afforded the
highest yields when C2F5COOAg was combined with LiOtBu in
1,4-dioxane (entry 1). A number of silver catalysts were examined:
a Hefei National Laboratory for Physical Sciences at the Microscale, CAS Key
Laboratory of Urban Pollutant Conversion, Anhui Province Key Laboratory of
Biomass Clean Energy, iChEM, University of Science and Technology of China,
Hefei, 230026, China.
c School of Life Sciences, University of Science and Technology of China, Hefei,
230027, China.
† These authors contributed equally.
E-mail: binxiao@ustc.edu.cn; fuyao@ustc.edu.cn.
b High Magnetic Field Laboratory, Chinese Academy of Sciences, Hefei, 230031,
China.
This article has been accepted for publication and undergone full peer review but has not
been through the copyediting, typesetting, pagination and proofreading process, which
may lead to differences between this version and the Version of Record. Please cite this
article as doi: 10.1002/cjoc.201800500
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AgCl provided a slightly decreased yield (entry 2), whereas AgOTs
and AgOAc were much less effective (entries 3-4), and other silver
catalysts provided no borylation products (entries 5-6). The
selection of solvent was also critical: compared to 1,4-dioxane
(which gave the optimal result), all other solvents tested, such as
THF, CH3CN, DMF and tBuOH, were inferior (entries 7-10). After an
exhaustive screening, LiOtBu emerged as the best base for this
borylation, exhibiting greater efficiency than other lithium
alkoxides (entries 11-12), sodium alkoxides (entry 13) and
potassium alkoxides (entry 14).19 Various ligands were also applied
to this transformation; however, all of them had only deleterious
effects (see the Supporting Information for more details). In
addition, we prepared product 3 in gram-scale, obtaining a
satisfactory yield of 74% in the presence of a much lower loading
of silver catalysts (2%).
ether (18). In addition, heterocycles such as dioxolane (19) and
indole (20) also posed no problem during this borylation process.
For benzyl tosylates (21), this reaction only gave out a much lower
yield.
Table 2 Substrate scope of borylation.a
Table 1 Optimization of the reaction conditions.a
Entry
1
Deviation from above
none
Yield (%)a
89, 84b, 74c
2
AgCl, instead of C2F5COOAg
AgOTs, instead of C2F5COOAg
AgOAc, instead of C2F5COOAg
AgBr or AgI, instead of C2F5COOAg
82
35
3
4
47
5
trace
6
Ag2SO4 or Ag3PO4 or Ag2CO3, instead of C2F5COOAg trace
7
THF, instead of 1,4-dioxane
CH3CN, instead of 1,4-dioxane
DMF, instead of 1,4-dioxane
tBuOH, instead of 1,4-dioxane
LiOMe, instead of LiOtBu
15
trace
trace
27
8
9
10
11
12
13
14
38
LiHMDS, instead of LiOtBu
NaOtBu, instead of LiOtBu
trace
66
a
b
Isolated
yield
for
0.25
mmol-scale
reaction.
Bis[(-)-pinanediolato]diboron was used. c Bis(neopentyl glycolato)diboron
was used. d GC yield. Biphenyl as internal standard.
KOtBu, instead of LiOtBu
34
a
b
GC yield. Biphenyl as internal standard. Isolated yield for 0.25
Scheme 1 Borylation of natural product derivatives.a
mmol-scale reaction. c Isolated yield for 5 mmol-scale reaction with 2%
C2F5COOAg. THF tetrahydrofuran. DMF N,N-dimethylformamide.
=
=
LiHMDS = lithium bis(trimethylsilyl)amide. B2pin2 = bis(pinacolato)diboron.
With the optimized reaction conditions, we sought to examine
the scope of this silver-catalyzed Miyaura borylation of C(sp3)-O
bonds. As shown in Table 2, a broad scope of secondary (3) and
primary (4) alkyl sulfonates could be converted to the
corresponding boronates in modest to good isolated yields
(36-84%). Both tosylates and methanesulfonates were viable
substrates (3), and both cyclic (5) and acyclic (6) tosylates were
readily converted. Regarding boron protecting groups, not only
pinacol (7) but also pinanediol (8) and neopentyl glycol (9)
performed well during the transformation. When 4-substituted
cyclohexyl tosylate was subjected to the standard conditions, the
thermodynamically favored trans-1,4-disubstituted cyclohexyl
boronate (10) was formed (trans-/cis- = 4.5:1).20 Due to the mild
a Isolated yield for a 0.25 mmol-scale reaction.
reaction conditions, this reaction tolerated
a variety of
synthetically relevant functional groups, including relatively robust
ones, such as ether (11), trifluoromethyl (12), amide (13),
sulfonamide (14), aryl chloride (15), and intramolecular terminal
or internal alkene groups (16, 17). Furthermore, this reaction
could also proceed smoothly in the presence of base-sensitive silyl
We further utilized this reaction for the modification of
biologically interesting natural products and demonstrated its
good functional group compatibility (Scheme 1). For example,
epiandrosterone (22) and hecogenin (24) derivatives, which
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contain ketone and ketal groups, respectively, were converted to
the corresponding borylated products (23, 25) smoothly in
moderate to good isolated yields. In addition, the formation of
mixtures of two diastereomers while the thermodynamically
favored equatorial one as major product indicated the new
3:1, which indicated a radical cyclization process.26 Furthermore,
with the addition of the radical-trapping reagent
N-methyl-N-phenylmethacrylamide (38) to the standard reaction
conditions, an indolone derivative (39) was formed, which might
be produced through a Giese-type cascade reaction (Scheme
3d).27 We also confirmed the radical nature of this reaction with
ESR (Electron Spin Resonance) spectroscopy (Scheme 3e, see the
Supporting Information for more details). Under the standard
condition, radical species could be produced through a radical
borylation reaction might proceed through
a radical-type
mechanism.21
Scheme 2 Competition experiments.a
cleavage
(5,5-dimethyl-1-pyrroline-N-oxide).28 Additionally, in
inhibition experiment with
pathway
and
captured
by
DMPO
radical
TEMPO
a
(2,2,6,6-tetramethylpiperidinooxy), this reaction was significantly
inhibited (see the Supporting Information for more details).
Collectively, the above results supported a radical-type reaction
mechanism for the activation of C-O bonds.
Scheme 3 Mechanistic studies.a
a Isolated yield for a 0.25 mmol-scale reaction.
Regarding the chemoselectivity, this reaction exhibited
nontrivial results compared to the traditional activation methods
for alkyl tosylates (mainly, through SN2 pathway). In the
intramolecular competition experiment with secondary and
primary alkyl tosylate sites, the former functionality was more
reactive. The borylation of 26 under standard conditions provided
27 as a single product with 65% yield, which appeared to be
consistent with this borylation of C-O bonds proceeding through a
radical pathway (Scheme 2a).22 Above results could rule out the
traditional SN2 pathway and silver involved SN2 process followed
by carbon-silver radical cleavage.6, 8a, 23 A similar observation was
also made for a substrate (28) with both primary alkyl chloride
and secondary alkyl tosylate sites: we obtained 29 as the only
product (Scheme 2b).14 Finally, in the case of a substrate (30) with
both aryl and alkyl tosylate sites, the former moiety survived (31),
thereby providing further opportunities for subsequent
conventional cross-coupling reactions at the remaining C(sp2)
reaction center (Scheme 2c).
The high polarization of the C-O bond facilitates its activation
through SN1, SN2 or SN2-type oxidative addition process.24 We
studied the stereochemistry of this reaction with optically pure
secondary alkyl tosylate (S)-1. Racemic alcohol product (32) was
obtained with 76% yield after the oxidation, which was opposite
to the SN2 pathway (Scheme 3a).25 With careful analysis of the
byproducts, we also ruled out the SN1 reaction mechanism (see
the Supporting Information for more details). In addition, the
treatment of 4-phenyl-1-butene (33) or cyclohexene (34) under
standard condition didn’t provide the desired borylated products,
which could rule out the pathway of base-promoted β-H
elimination and followed by sequential hydroboration (Scheme
3b).17 To clarify the reaction mechanism,
a radical clock
a Isolated yield for a 0.25 mmol-scale reaction. b Yield based on starting
material recovery.
experiment was carried out. Compound 35 containing a terminal
alkene group was used as the radical clock substrate (Scheme 3c).
In this borylation reaction, we obtained a mixture of direct
coupling product (36) and ring-cyclized product (37) in a ratio of
To obtain more insights into the process of this radical
pathway cleavage of C-O bonds, we conducted preliminary studies
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with the unique silver catalytic system (Table 3). In a mercury drop
experiment, the reaction was completely shut down with the
addition of 20 equiv Hg (entry 2), indicating the formation of
elemental silver. Moreover, this borylation could even be
conducted with commercial available silver nanopowder with
suitable particle size (entries 3-5) or recovered solid residues of
the model reaction (entry 6). Additional interesting observations
were obtained with X-ray diffraction and transmission and
scanning electron microscopy analysis (see the Supporting
Information for more details). These recovered solid residues
exhibited a nanoscale (4-20 nm) and regular face-centered cubic
structure. The above observations provided ample mechanistic
evidence for the generation of silver(0) catalytic species.29
Meanwhile, the in situ formation of silver(0) catalytic species led
to the novel activity and selectivity compared to other
homogeneous catalysts.30
Supporting Information
The supporting information for this article is available on the
WWW under https://doi.org/10.1002/cjoc.2018xxxxx.
Acknowledgement
We are grateful for the support from the National Natural
Science Foundation of China (21472181, 21572212, 21502184,
21732006, and 21702200), Major Program of Development
Foundation of Hefei Center for Physical Science and Technology
(2017FXZY001), Ministry of Science and Technology of China
(2017YFA0303502), Youth Innovation Promotion Association of
the Chinese Academy of Sciences (2015371).
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General procedure for borylation. In air, C2F5COOAg (0.025
mmol, 10 mol%) and LiOtBu (0.50 mmol, 2.0 equiv) were added to
a Schlenk tube equipped with a stir bar. The vessel was evacuated
and filled with argon (three cycles). 1,4-Dioxane (1 mL) was added
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Free Radical Pathway Cleavage of C-O
Bonds for the Synthesis of Alkylboron
Compounds
Xi Lu,† Zhen-Qi Zhang,† Lu Yu,† Ben Zhang,
Bing Wang, Tian-Jun Gong, Chang-Lin Tian,
Bin Xiao,* and Yao Fu*
We report a silver-catalyzed borylation of alkyl tosylates for the synthesis of alkylboron compounds
via radical pathway cleavage of C-O bonds.
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