Boryl Radical-Mediated C?H Activation of Inactivated Alkanes for the Synthesis of Internal Alkynes

Article abstract of DOI:10.1002/adsc.202000772

An intriguing pyridine-boryl radical-mediated C?H alkynylation reaction of inactivated alkanes was described. The reaction features mild operation condition and wide substrate scope, and affords the corresponding products in moderate to good yields. Notab

Full text of DOI:10.1002/adsc.202000772

Title: Boryl Radicals-Mediated C−H Activation of Inactivated Alkanes
for the Synthesis of Internal Alkynes
Authors: Jia-Bin Han, Htet San, Ao Guo, Long Wang, and Xiangying
Tang
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.202000772
Link to VoR: https://doi.org/10.1002/adsc.202000772

10.1002/adsc.202000772
Advanced Synthesis & Catalysis
COMMUNICATION
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Boryl Radical-Mediated C−H Activation of Inactivated Alkanes
for the Synthesis of Internal Alkynes
Jia-Bin Han,a Htet Htet San,a,b Ao Guo,a Long Wang, a and Xiang-Ying Tanga,*
a
School of Chemistry and Chemical Engineering and Hubei Key Laboratory of Bioinorganic Chemistry and Materia
Medica, Huazhong University of Science and Technology, 1037 Luoyu Road, Wuhan 430074, People’s Republic of
China
E-mail: xytang@hust.edu.cn.
b
Department of Industrial Chemistry, Yadanabon University, Amarapura Township, Mandalay Region, 05063, People’s
Republic of Myanmar
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
access to NHC (E)-alkenylboranes.[7] Xie and Zhu
disclosed an elegant inverse hydroboration of
imines under photoredox conditions, providing a
Abstract. An intriguing pyridine−boryl radical-mediated
C−H alkynylation reaction of inactivated alkanes was
described. The reaction features mild operation condition
and wide substrate scope, and affords the corresponding
practical protocol towards medically valuable
aminoboranes compounds.[8] Very recently, Xiang,
Chen and Yang reported an photoinduced Single-
Electron Transfer (SET) process for radical
borylation of alkenes with NHC-borane.[9] Despite
these exciting development in amine−,
phosphine−, and NHC−ligated boryl radical
chemistry, however, investigations engaging
electron-deficient boron radicals are still quite
limited.[10]
products in moderate to good yields. Notably, The presence
of 4-cyanopyride N-oxide was key to the success of the
reaction. Cyclohexane are more easily to be functionalized
in this reaction than toluene, which could be rationally
explained by polarity-match principle.
Keywords: pyridine−boryl radical; alkynylation; C−H
functionalization; inactivated alkanes
Ligated boryl radicals (L−BH2•) have raised great
interest during the last decade.[1-3] Pioneer works
by Roberts systematically investigated the
generation and reactivity of amine− and
Scheme 1. Pyridine−boryl radical-mediated C−H
functionalization
phosphine−boryl
radicals.[1d,4]
Meanwhile,
computational studies by Rablen and Zipse
revealed that the BDEs of B−H bonds in amine−
and phosphine−BH3 complexes were generally
reduced to 94−104 kcal/mol.[3a,3e] In addition,
NHC−boryl radicals, pioneered by Fensterbank,
Lacôte, Malacria, Curran,[5a] were demonstrated to
exhibit diverse reactivity in many valuable
transformations,
including
reductions
of
xanthates,[5b] alkyl/aryl halides,[5c-e] ketones,[5f]
and cyanides[5g], addition,[5h,6a-c] and tandem
cyclizations.[6d-6e] Recently, Curran, Taniguchi
and Wang realized challenging radical addition
trans-hydroboration of alkynes with NHC−BH3 in
1
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10.1002/adsc.202000772
Advanced Synthesis & Catalysis
Recently, Li and Zhu disclosed the generation and 0.5 equiv of 4-cyanopyridine was optimal for this
interesting reactivity of pyridine−boryl radicals reaction (Table 1, entry 11-13). Next, several other
from the reaction between 4-cyanopyridine and borates were tested. Bis(neopentyl glycolato)-
B2pin2.[11] Such pyridine−boryl radicals could diboron (B2) was found to be most effective for
easily undergo reduction of azo compounds, this reaction, improving the reaction to 80% yield
quinones, and sulfoxides,[11a] addition/coupling to (Table
1,
entry
14).
Bis(hexylene
aldehydes and ketones,[11b,c] radical borylations of glycolato)diboron (B3) and 2,2’-Bis-1,3,2-
aryl/alkyl halides or carboxylate derivatives[12] or benzodioxaborole (B4) were also suitable boryl
promote homolysis of Rf−X and subsequent radical sources to provide 2a in 65% and 56%
perfluoroalkylative pyridylation of alkenes.11d yield, respectively. While reaction with
Aggarwal,[12a,b] Li,[12c] and Studer[12d-f] also tetrahydroxydiborane (B4) as diborate source
independently reported borylation of carboxylate, produced merely 5% yield of 2a. Notably, such
amine, and alcohol derivatives and alkyl/aryl C(sp3)−H functionalization of cyclohexane is also
iodides under photo-induced conditions. In light effective at room temperature, albeit in moderate
of these reports and that amine−boryl radicals can yield (Table 1, entry 18). Nevertheless, reaction
selectively abstract hydrogen atom from esters and performed under elevated reaction temperature
ketones,[4] our group recently reported the first provided diminished yield (Table 1, entry 19).
pyridine−boryl radicals mediated α-C−H
Table 1. Optimization of the Reaction Conditionsa
functionalization of ethers, DMF, and amines with
the assistance of oxidants (Scheme 1a).[13a]
Meanwhile, an intriguing site-selective α-alkoxyl
alkynation of ethyl acetate was also recently
realized by our group in the presence of
entry x/y/z oxidants B2(OR)4 Yieldb/%
pyridine−boryl radicals and an oxidant (Scheme
1b).[13b] As part of our continuous investigations
1
2
3
4
5
6
7
8
9
2/1/2
2/1/2
2/1/2
2/1/2
2/1/2
2/1/2
2/1/2
2/1/0
2/1/1
42
46
29
58
63
49
12
12
46
52
37
65
45
I
II
III
IV
V
VI
VII
V
V
V
V
V
V
V
V
V
V
V
V
B1
B1
B1
B1
B1
B1
B1
B1
B1
B1
B1
B1
B1
B2
B3
B4
B5
B2
B2
of pyridine−boryl radicals on C−H bond
activation, we wonder if this strategy could be
further applied for the more challenging direct
functionalization of inactivated alkanes.[14] Herein,
we wish to report the pyridine−boryl radicals
mediated C(sp3)−H functionalization of inert
alkanes towards the synthesis of internal alkynes
under ambient conditions (Scheme 1c).
10 2/1/1.5
11 2/0/2
12 2/0.5/2
13 2/1.5/2
14
15
16
17
18
19
We begin our investigations with the reaction of
((phenylethynyl)sulfonyl)benzene
(1a)
and
cyclohexane in the presence of B2pin2 (B1, 2
equiv), 4-cyanopyridine (1 equiv), and pyridine 1-
oxide (I, 2 equiv), providing the desired product
2a in 42% yield (Table 1, entry 1). Among all
oxidants tested, 4-cyanopyridine 1-oxide showed
the highest efficiency to afford 2a in 63% yield
(Table 1, entry 2−6). Inorganic oxidant like
K2S2O8, almost insoluble in the reaction mixture,
gave 2a in only 12% yield (Table 1, entry 7).
Moreover, when the amount of oxidant V was
reduced, the yield of 2a was also deceased
accordingly (Table 1, entry 8-10). It is worth
noting that 12% yield of 2a was produced in the
absence of oxidant, indicating oxygen may also
function as an alternative oxidant for the reaction.
Further tuning of reaction parameters revealed that
2/1/2
2/1/2
2/1/2
2/1/2
2/1/2
2/1/2
80 (79)c
65
56
5
55d
69e
a)
b)
All reactions were carried out on a 0.2 mmol scale.
Yields were determined by gas chromatography using n-
c)
dodecane as an internal standard. The isolated yield is
shown in parentheses. d) Reaction temperature was 25 ℃.
d)
Reaction temperature was 80 ℃. I: pyridine 1-oxide; II: 4-
methylpyridine1-oxide; III: 2,6-dimethylpyridine 1-oxide;
IV: 2,6-dichloropyridine 1-oxide; V: 4-cyanopyridine 1-
oxide; VI: 4-nitropyridine 1-oxide; VII: K2S2O8; B1:
Bis(pinacolato)diboron; B2: Bis(neopentyl glycolato)-
2
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10.1002/adsc.202000772
Advanced Synthesis & Catalysis
diboron; B3: Bis(hexylene glycolato)diboron; B4: 2,2′-Bis-
1,3,2-benzodioxaborole; B5: Tetrahydroxydiborane.
solid alkanes, 10 equiv of alkanes in 0.5 mL of
chlorobenzene solution was taken into reaction.
The ring size of alkanes did not have a significant
effect on the reaction outcomes, the reactions of
cycloalkanes such as cyclopentane, cycloheptane,
cyclooctane, and cyclododecane all went on
smoothly to deliver 3a−3g in 53−84% yields.
Adamantane was a suitable substrate in the
reaction towards alkynylation, giving the desired
product 3h as two isomers in 62% combined yield.
Interestingly, neohexane was almost exclusively
functionalized at tertiary carbon center and
afforded 3i in 64% yield. Reactions in
methylcyclohexane and n-pentane also proceeded
smoothly but provided the corresponding products
as a mixture of regioisomers (Scheme 3, 3j and
3k). Toluene and p-xylene, with more reactive
benzylic C−H bonds, were also compatible under
similar reaction condition but afforded the
corresponding internal alkynes 3l and 3m in only
41% and 37% yields, respectively.
With the optimized reaction condition established,
we sought to explore the substrate scope of the
C(sp3)−H alkynylation with respect to different
alkynyl sulfones (Table 2). Alkynyl sulfones
tethered with para substituents provided the
desired internal alkynes 2a−2l in moderate to good
yields with no significant substitution effect being
observed. Meta- and ortho- substituted alkynyl
sulfones were also suitable substrates under the
optimized reaction conditions, and the
corresponding products 2m−2q were obtained in
66−96% yields. It is noticeable that using a
decreased amount of 4-cyanopyridine provides
even higher yields in the case of 2b. The bulky
naphthyl-substituted alkynyl sulfones went on the
reaction smoothly to deliver 2r in 61% yields.
Moreover, the alkynyl substituent on the phenyl
ring did not affect the reaction outcome and give
terminal alkynyl substituted product 2s in 45%
yield. Heteroaromatic rings were also compatible
in the reactions to give 2t and 2u in 68% and 51%
yields, respectively. It is worth noting that the
reaction could be successfully scaled up to 1 mmol
scale to afford 2a in 71% yield.
Table 3. Pyridine-boryl radicals mediated C(sp3)−H
alkynylation reactions scope with respect to simple alkanes
Table 2. Pyridine-boryl radicals mediated C(sp3)−H
alkynylation reactions scope with respect to alkynyl
sulfones
a) All reactions were carried out on a 0.2 mmol scale in 2
mL of the corresponding alkanes unless otherwise noted. b)
Alkane (10 equiv) in PhCl (0.5 mL). c) Reaction time was
enlonged to 2 days. d) Yields of all isomers.
a) All reactions were carried out on a 0.2 mmol scale in 2 mL
To gain more insight into the reaction mechanism,
a set of control experiments were performed. First,
when 1 and 2 equiv of TEMPO was added into the
reaction mixture, the yield of 2a was drastically
decreased to 44% and 26%, while no product was
detected when 5 equiv of TEMPO was added into
the reaction mixture (Scheme 4a). These results
b)
c)
of EA. Isolated yields. 1 mmol scale. 0.1 equivment of
4-cyanopyridine was used. d) Yields of all isomers.
To further demonstrate the applicability of
pyridine-boryl radical mediated C(sp3)−H
alkynylation reaction, we next sought to evaluate
the scope of unactivated alkanes (Table 3). For
3
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10.1002/adsc.202000772
Advanced Synthesis & Catalysis
suggested that a radical pathway was probably cyclohexane to produce cyclohexyl radical C,
involved in the reaction. Moreover, a distinct which subsequently reacts with 1a to furnish the
kinetic isotopic effect was observed for C(sp3)−H internal alkynes 2a.[16] Significantly, the rapid
bond cleavage (kH/kD = 2.0), indicating that the removal of generated HBnep by adding 4-
C(sp3)−H bond cleavage of inactivated alkanes cyanopyridine 1-oxide (V) provides a driving
was the rate-determining step during the reactions force for the hydrogen abstraction step.
(for details, see Supplementary Information). In
Scheme 3. Plausible mechanism.
addition, two intermolecular competition
reactions in mixed solvents were performed under
standard reaction conditions. As expected, the
reaction in cyclohexane/diethyl ether gave more
etherized product 4, while the reaction in
cyclohexane/toluene merely afford 2a as the only
product (Scheme 2c). These results could be
rationally explained by polarity-match principle
that electrophilic raidals abstract hydrogen more
readily from an electron-rich C–H bond than from
In summary, we have developed an interesting
C−H alkynylation reaction of unactivated alkanes
through
pyridine−boryl
radical-mediated
an electron-deficient one of similar bond
hydrogen abstraction under mild conditions. The
reaction exhibit broad substrate scope and a
variety of functional groups were well tolerated.
The key to the success of the reaction is adding an
appropriate oxidant to quickly remove the highly
reductive HBnep. Moreover, it was interesting to
find that pyridine−boryl radical abstract hydrogen
much more easily from C−H bond of cyclohexane
than the one of toluene, which could be rationally
explained by polarity-match principle. Further
investigations into detailed reaction mechanism
and application of this protocol are currently
ongoing in our lab.
strength.[15]
Scheme 2. Control experiments
Experimental Section
A oven-dried Schlenk tube equipped with an stirring bar was
charged with ((phenylethynyl)sulfonyl)benzene (1a, 48.4
mg, 0.2 mmol), 4-cyanopyridine (10.4 mg, 0.1 mmol), 4-
cyanopyride N-oxide (48 mg, 0.4 mmol), and B2nep2 (90.4
mg, 0.4 mmol). The reaction tube was evacuated for 10 min
and back filled with nitrogen for three times. Then
cyclohexane (2 mL) was added by syringe under nitrogen.
Based on the results of control experiments and
our previous studies, a plausible mechanism was
proposed for the C(sp3)−H bond alkynylation of
inactive alkanes as shown in Scheme 3. First, the
pyridine−boryl radical A was generated upon
treating diborates with 4-cyanopyridines.[10] The
computational calculation revealed B accounts for
the highest ratio among all resonances.[13b]
Distinct from our previous studies, because no
ligating solvents are present in the current reaction
system, thus the highly reactive intermediate B
could directly abstract a hydrogen atom from
o
The resulting mixture was allowed to stir at 50 C for 12 h.
The reaction mixture was concentrated, the residue was
purified by silica gel column chromatography with
petroleum ether as eluent to give the corresponding product.
Acknowledgements
4
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10.1002/adsc.202000772
Advanced Synthesis & Catalysis
We are grateful for the financial support provided by the National
Natural Science Foundation of China (21871100), the
Fundamental Research Funds for the Central Universities
(2017KFYXJJ166, 2019kfyRCPY096), Huazhong University of
Science and Technology (HUST), and the Opening Fund of Hubei
Key Laboratory of Bioinorganic Chemistry and Materia Medica
(No. BCMM201805). We also thank the Analytical and Testing
Center of HUST, Analytical and Testing Center of the School of
Chemistry and Chemical Engineering (HUST) for access to their
facilities.
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Advanced Synthesis & Catalysis
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