Cleavage of C(aryl)?CH3 Bonds in the Absence of Directing Groups under Transition Metal Free Conditions

Article abstract of DOI:10.1002/anie.201901783

Organic chemists now can construct carbon–carbon σ-bonds selectively and sequentially, whereas methods for the selective cleavage of carbon–carbon σ-bonds, especially for unreactive hydrocarbons, remain limited. Activation by ring strain, directing groups, or in the presence of a carbonyl or a cyano group is usually required. In this work, by using a sequential strategy site-selective cleavage and borylation of C(aryl)?CH₃ bonds has been developed under directing group free and transition metal free conditions. Methyl groups of various arenes are selectively cleaved and replaced by boryl groups. Mechanistic analysis suggests that it proceeds by a sequential intermolecular oxidation and coupling of a transient aryl radical, generated by radical decarboxylation, involving a pyridine-stabilized persistent boryl radical.

Full text of DOI:10.1002/anie.201901783

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Accepted Article
Title: Cleavage of C(aryl)-CH3 Bonds in the Absence of Directing
Groups under Transition Metal Free Conditions
Authors: Peng-Fei Dai, Xiao-Shan Ning, Hua Wang, Xian-Chao Cui,
Jie Liu, Jian-Ping Qu, and Yan-Biao Kang
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10.1002/anie.201901783
Angewandte Chemie International Edition
COMMUNICATION
Cleavage of C(aryl)-CH3 Bonds in the Absence of Directing
Groups under Transition Metal Free Conditions
Peng-Fei Dai,1 Xiao-Shan Ning,1 Hua Wang,1 Xian-Chao Cui,1 Jie Liu,1 Jian-Ping Qu,2,* and Yan-Biao
Kang1,*
Abstract: Organic chemists now can construct carbon-carbon σ-
bonds selectively and sequentially, while methods for the selective
cleavage of carbon-carbon σ-bonds, especially in unreactive
of heavy metals avoids metallic impurities which can be directly
harmful for the patient due to their toxicity or can serve as a
catalyst for the degradation of drugs. Herein, we present our latest
hydrocarbons, remain limited. It usually needs activation by ring strain, results in the development of a sequential tandem[9] radical
directing groups, or in the presence of a carbonyl or a cyano group. In
this work, by using a sequential tandem strategy a site-selective
cleavage of C(aryl)-CH3 bonds has been developed under directing
group-free and transition metal-free conditions. Methyl groups of
various arenes could be selectively cleaved and replaced by boryl
groups. Mechanistic analysis suggests that it proceeds via an
intermolecular sequential oxidation and a coupling of a transient aryl
radical generated by radical decarboxylation with a pyridine-stabilized
persistent boryl radical.
demethylation of methyl arenes under transition metal-free
conditions (Scheme 1B).
Organic chemists now can construct carbon-carbon σ-bonds
selectively and sequentially. While the cleavage of such bonds,
especially in unactivated hydrocarbons without directing groups,
in a selective fashion, is an attractive transformation since it holds
the potential to provide a straightforward access to previously
inconceivable targets from readily available chemical feedstocks.
Carbon-carbon σ-bonds are generally unreactive towards the
insertion of metal complexes, but they have been found to be
cleaved by organometallic compounds[1] when activated by ring
strain[2] or directing groups,[3] when there is an attainment of
aromaticity for prearomatic systems,[4] or in the presence of a
carbonyl or a cyano group.[5] For instance, Milstein and coworkers
have first demonstrated that one of three methyl groups attached
Scheme 1. Demethylative C(aryl)-CH3 bond cleavage of methyl arenes.
B2pin2 refers bis(pinacolato)diboron. Bpin refers pinacolatoboryl.
Reaction conditions were first investigated in the presence of
different additives to furnish the sequential tandem and the
selectivity control in the oxidation of methyl over methoxyl.
Compared to the reaction in the absence of additive 1 or other
lithium salts, LiBr can promote the reaction smoothly (Table 1,
entries 4 vs 1-3). LiBr might promote the radical transfer in the
first step, whereas lowering the amount of LiBr from 50 mol% to
20 mol% does not obviously effect the yield (entries 4 vs 5). tert-
Butyl isonicotinate (TBI)[10b] was found to be an irreplaceable
to an aromatic ring can be selectively cleaved using
a
homogeneous rhodium complex though the sp2-sp3 carbon-
carbon bond of methyl arenes remains intact under most
conventional reaction conditions (Scheme 1A).[3a] Nevertheless,
methods for selective cleavage of unactivated carbon-carbon σ-
bonds still remain limited.[6]
promoter for the borylation (entry
6 and see supporting
inforamtion) after screening additive 2. The increase in tert-butyl
isonicotinate induces low yield (entry 7). The reaction is sensitive
to moisture (entry 8) and 4Å molecular sieves (MS) is therefore
necessary. The moderate yield is partially due to the formation of
4-methoxybenzoic acid in the oxidation. The reaction conditions
listed in entry 5 were chosen as the standard conditions for the
further investigation.
Recently, we have reported efficient selectivity controllable
approaches to both aromatic dinitriles and aromatic diketones via
benzyl radicals generated by N-hydroxyphthalimide/tBuONO
system.[7-8] In the pharmaceutical synthesis the noninvolvement
Various methyl arenes bearing different substituents were then
subjected to the standard conditions to evaluate the scope of
substrates (Scheme 2). Either electron rich or electron deficient
arenes can afford the desired borylation products (2-16). In the
case of ortho-substituted methyl arenes, such as 4 and 9, the low
yield is due to a side reaction. Aryl halides can react with B2pin2
under basic conditions, whereas, under our standard conditions,
tolyl halides could be smoothly converted to halophenyl boronates
(10-16) without dehalogenation[11] or substitution of halides. The
C-C bond of 14 between aryl and CF3 was not effected in this
reaction. Other methyl arenes or heteroarenes were also
applicable by this method (17-24). Started from boronate 33 and
34, diboronate 22 and 23 were achieved in 75% and 43% yields,
1
2
P.-F. Dai, X.-S. Ning, H. Wang, X.-C. Cui, J. Liu and Prof. Dr. Y.-B.
Kang
Department of Chemistry
University of Science and Technology of China
Hefei, Anhui 230026, China
E-mail: ybkang@ustc.edu.cn
Prof. Dr. J.-P. Qu
Institute of Advanced Synthesis, School of Chemistry and
Molecular Engineering, Jiangsu National Synergetic Innovation
Center for Advanced Materials, Nanjing Tech University, Nanjing
211816, China
E-mail: ias_jpqu@njtech.edu.cn
Supporting information for experimental details and spectroscopic
data for all products.
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10.1002/anie.201901783
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providing a new approach to such synthons. Diboronate 22 can
also be prepared from para-xylene in 31% of yield via 2 runs
treatment of xylene under standard conditions. Ketone, ester,
cyano, boryl, and halogen can survive, while aldehydes, amines,
and alcohols cannot be tolerated due to the oxidation by tBuONO
and N-hydroxyphthalimide. With respect to the alkyl containing
methyl arenes, both alkyl and methyl can be oxidized; thus the
selectivity could not be controllable.
Table 1. Reaction conditions.
Entry[a]
Additive 1
none
LiCl
x
Additive 2
TBI
y
2[%][b]
47
48
47
61
67
0
1
0
30
30
30
30
30
30
50
30
2
50
50
50
20
20
20
100
TBI
3
LiF
TBI
4
LiBr
TBI
5
LiBr
TBI
6
LiBr
Py or DMAP
TBI
7
LiBr
58
7
8[c]
H2O
TBI
[a] Conditions: 1a (0.5 mmol), (0.5 mmol), N-hydroxyphthalimide (1.0 mmol),
tBuONO (1.5 mmol), additive 1 (x mol%), 4 Å MS (100 mg), MeCN (2.0 mL),
80 °C, N2, 24 h, then B2pin2 (200 mol%), additive 2 (y mol%), PhCF3 (2.0
mL), 110 °C, 15 h. [b] Determined by 1H NMR (400 MHz) using CH3NO2 and
MeOtBu as internal standards. [c] Without 4Å MS.
This demethylative C-C bond cleavage method tolerates
complex methyl arenes. This enables functionalization of
synthetically useful intermediates and biologically active
molecules (25-32). Using standard conditions, synthetic
intermediates (25, 28, 30), adapalene derivative 26), menthol
derivative (27) as well as camphor derivative (29) could be
obtained in good to moderate yields. Cholesterol analogues were
also subjected to standard conditions and the corresponding
boronates (31-32) were achieved in considerable yields. These
examples indicate that this protocol is synthetically practical.
Selectivity control of this demethylative C-C bond cleavage is
also investigated. The mono-/di-selectivity is simply controlled by
the formation of mono- or diboronate intermediates (Scheme 3).
For the synthesis of diboronates besides C-C cleaving borylation
of monoboronates 33 and 34 (Scheme 3, up), the 2 runs of
standard conditions enable a double C-C cleavage of p-xylene
which affords diboronate 22 in 31% (Scheme 3, bottom). Using
current method either monoboronate 33 or diboronate 22 can be
selectively synthesized from the same starting material p-xylene
just by performing one or two runs of the standard conditions. This
provides a useful method to convert inexpensive chemical
feedstock to high value synthetic intermediates.
Scheme 2. Reaction Scope under standard conditions. Reaction conditions:
methyl arene (0.5 mmol), LiBr (0.1 mmol), N-hydroxyphthalimide (1 mmol),
tBuONO (1.5 mmol), 100 mg 4 Å MS, MeCN (2.0 mL), 80 °C, N2, 24 h, then
B2pin2 (1 mmol), tert-butyl isonicotinate (0.15 mmol), PhCF3 (2.0 mL), 110 °C,
15 h. For the case of 22 from p-xylene, two runs of the standard conditions were
performed.
Scheme 3. Synthesis of diborylation products from mono- or di-C-C bond
activation.
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To further investigate the site selectivity of this demethylative
borylation method, the substrates bearing more than one C(sp2)-
C(sp3) bonds were tested under the standard conditions (Scheme
4). First, para-xylene was tested and the monoborylation product
33 was obtained in 51% of yield. Meta- and ortho-xylenes could
afford the corresponding monoborylation product 35 and 36 under
the same reaction conditions ableit with lower yields. Similarly,
methyl biphenyl boronate 34 could also be obtained under the
standard conditions. The low yield of 34 is due to the low yield in
the oxidation step. Carboxyl and cyano groups were previously
reported as leaving groups in C-C cleaving cross coupling
reactions. However, by this method both groups remained
forming the C-C cleaving borylation products (37, 40) in good
yields with para-substitution but moderate yields with meta- and
ortho-substitution (38, 39, 41, 42). This could provide an
opportunity for selective C-C cleaving cross coupling. Other
substituents such as phenyl, CF3, ketone and ester were also
tolerated in this transformation (34, 43-45).
Scheme 5. Divergent transformations using methyl as leaving group.
Standard conditions are shown in Table 1 Entry 5.
N-hydroxyphthalimide-ester 46 could be isolated in 78% of
yield from the first step of standard conditions. A KIE of 2.2 was
established for the oxidation of 1 to 46 (Eq 1). Compound 54 could
not be observed or isolated from the reaction, but 54 could
transform to 46 in 52% of yield (Eq 2). Ester 46 could be converted
to the corresponding boronate
conditions.[10b]
2
under the standard
Scheme 4. Selectivity control of demethylative C-C bond cleavage.
Reaction conditions: methyl arene (0.5 mmol), LiBr (0.1 mmol), N-
hydroxyphthalimide (1 mmol), tBuONO (1.5 mmol), 100 mg 4 Å MS, MeCN (2.0
mL), 80 °C, N2, 24 h, then B2pin2 (1 mmol), tert-butyl isonicotinate (0.15 mmol),
PhCF3 (2.0 mL), 110 °C, 15 h.
Thus we believe the reaction passes through a sequential
radical tandem of demethylative C-C bond cleaving and borylation
(Scheme 6). Methyl arene A is oxidized to N-hydroxyphthalimide-
ester G via benzyl radicals B,[10] D and F with tBuONO as oxidant.
Intermediate G is transformed to aryl boronate K via a
decarboxylative coupling process. Thus the radical sequential
tandem of the oxidation of methyl arenes to aryl N-
hydroxyphthalimide-ester G and the borylation of aromatic N-
hydroxyphthalimide-ester G enables this demethylative borylation
of methyl arenes.[10b]
The potential synthetic application of this method is
demonstrated in Scheme 5. By our method, methyl group of 1 is
first cleaved to afford the corresponding boronate 2. The latter
was then converted to a variety of functionalized products bearing
N3 (47), Ph (48), Cl (49), S-Ph (51), CN (52), and OH (53) in 48-
66% overall yields. The azidation followed by cyclization gives 50
in 62% yield. Methyl group is used as a “leaving group” in these
formal cross coupling transformations.
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In conclusion, we have developed a traceless demethylative
C(aryl)-CH3 bond cleaving borylation of methyl arenes without
directing groups under transition metal-free conditions. This
method presents an endeavor in the inert carbon-carbon bond
activation and provides a straightforward access to synthetically
useful aryl boronates from inexpensive and abundant materials.
Acknowledgements
We thank the National Natural Science Foundation of China
(NSFC 21672196, 21602001, 21831007) and the Strategic
Priority Research Program of the Chinese Academy of Sciences
(XDB20000000) for financial support.
Keywords: unactivated C-C bond cleavage • unstrained
undirected • methyl as traceless leaving group • methyl arene •
metal-free
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COMMUNICATION
Peng-Fei Dai, Xiao-Shan Ning, Hua
Wang, Xian-Chao Cui, Jie Liu, Jian-Ping
Qu,* and Yan-Biao Kang*
Page No. – Page No.
Cleavage of C(aryl)-CH3 Bonds in the
Absence of Directing Groups under
Transition Metal Free Conditions
Using methyl as a traceless leaving group, cleavage of unactivated, unstrained and
undirected C(aryl)-CH3 bonds now can be done by a sequential tandem metal-free
process.
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