Molecular Oxygen-Mediated Minisci-Type Radical Alkylation of Heteroarenes with Boronic Acids

Article abstract of DOI:10.1021/acs.orglett.7b03297

The carbon-carbon bond formation via autoxidation of organoboronic acid using 1 atm of O₂ is achieved in a simple, clean, and green fashion. The approach allows a technically facile and environmentally benign access to structurally diverse heteroaromatics with medicinally privileged scaffolds. The strategy also displays its practicality and sustainability in the resynthesis of marketed drugs Crestor and pyrimethamine.

Full text of DOI:10.1021/acs.orglett.7b03297

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Molecular Oxygen-Mediated Minisci-Type Radical Alkylation of
Heteroarenes with Boronic Acids
Lizhi Zhang‡ and Zhong-Quan Liu*,†,‡
†State Key Laboratory Cultivation Base for TCM Quality and Efficacy, College of Pharmacy, Nanjing University of Chinese Medicine,
Nanjing 210023, China
‡State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou 730000, China
S
* Supporting Information
ABSTRACT: The carbon−carbon bond formation via autoxidation of organoboronic acid using 1 atm of O2 is achieved in a
simple, clean, and green fashion. The approach allows a technically facile and environmentally benign access to structurally
diverse heteroaromatics with medicinally privileged scaffolds. The strategy also displays its practicality and sustainability in the
resynthesis of marketed drugs Crestor and pyrimethamine.
ynthesis of functional compounds such as drugs benefits
quinones with Ar(R)B(OH)2.11 Subsequently, a convenient
Shuman life worldwide but inevitably leads to a fast access to phenanthridines via a Mn(III)-mediated radical cascade
reaction of diaryl isonitriles with boronic acids was reported by
Tobisu and Chatani in 2012.12 One year later, Lei and co-workers
described a Ni(II)/DTBP-promoted effective arylation of
(sp3)C−H using arylboronic acids.13 Recently, Antonchick
developed a facile metal-free arylation of quinoline N-oxides
with aryl boronic acids under hot DMSO.14 In 2016, a
accumulation of pollutants in the environment. The develop-
ment of greener or sustainable synthetic technology has
historically been and remains a central topic of research in
chemistry.1 Organic transformations using molecular oxygen as
the sole oxidant represent the most meaningful explorations
since O2 is the ideal oxidant. Considerable advances in aerobic
oxidation of alcohol, aldehydes, amine, hydrocarbon, and
organometallics, etc. have been made in the past decades.2
However, transition-metal and/or organocatalysts along with
electron-transfer mediators are usually required in most of these
systems. In contrast, although it would be much simpler, cleaner
and waste-minimizing developments on establishing efficient
synthetic methods based upon autoxidation of organic molecules
without any catalysts have remained stagnant.3 Very few
successful organic transformations, for instance, carbon−carbon
bond formation using only O2, have been explored in the past
years.4 Nevertheless, most processes in these cases are very slow
because direct oxidation by molecular oxygen is usually
kinetically unfavored. It seems that the sustainability is
contradictory to the efficiency in these reactions. Hence,
exploration of more efficient and highly chemoselective synthetic
methods on account of autoxidation to solve this contradiction
remains a great challenge.
A historical report on autoxidation of organoboranes by
Frankland can be traced back to 1860.5 One century later,
organoboranes were introduced to studies of free-radical
reactions.6 Since then, together with organotin hydride and/or
AIBN, R3B/O2 has become a powerful initiator system for radical
reactions.7 In comparison with trialkylboranes8 and organo-
trifluoroborates,9 however, organoboronic acids are rarely
utilized as radical precursors to construct C−C bonds.10 In
2010, Baran and co-workers developed an efficient Ag(I)/
S2O82−-promoted arylation/alkylation of heteroaromatics and
convenient Mn(III)-mediated alkylation of arenes with alkylbor-
15
́
onic acids was discovered by Rodriguez et al. Very recently,
Chen explored an elegant Minisci C−H alkylation of N-
heteroarenes with boronic acids via a Ru(II)/hypervalent
iodine-promoted photoredox process.16 Although these proto-
cols allow facile access to diverse C−C bonds using boronic acids
as the radical sources, they suffered from usage of excess metal
and/or nonmetal chemical oxidants. Herein, we report a catalyst
and metal-free C−H alkylation of heteroarenes with boronic
acids using only 1 atm of O2. To the best of our knowledge, this
work represents the first applicable use of autoxidation of
organoboronic acids to form C−C bonds (Scheme 1).
In order to clarify the mechanisms for autoxidation of
organometallic compounds, Davies and Roberts investigated
the reaction of boronic acid with O2 for the first time in 1966.17
Through extensive studies on oxidation of optically pure 1-
phenylethylboronic acid by oxygen leading to racemic peroxides,
they postulated a radical-chain mechanism for the autoxidation of
organoboranes. Fifty years have passed by since the discovery of
autoxidation of organoboronic acid; however, not a single
applicable use of the autoxidation in organic synthesis has been
reported. Of particular interest is the exploration green radical
systems;18 therefore, we began to envision whether the
autoxidation of boronic acids could be utilized to develop
Received: October 23, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b03297
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 1. Radical C−C Bond Formation Using Alkylboronic
Acid as Precursor
Scheme 2. Molecular Oxygen-Mediated Alkylation of
Lepidine with Boronic Acids
a
efficient synthetic methods, for instance, forming C−C bonds.
Initially, a Minisci-type reaction19,20 of 4-methylquinoline with
butylboronic acid under oxygen atmosphere was designed to test
our hypothesis (Table 1). Table 1 shows that addition of acid,
a
Table 1. Optimization of the Reaction Conditions
a
Reaction conditions: 4-methylquinoline (1 equiv, 0.2 mmol), alkyl
boronic acid (5 equiv, 1 mmol), TFA (2 equiv, 0.4 mmol), DCE (0.5
mL), 1 atm of O2 (air bag), 110 °C, 12 h, unless otherwise noted.
b
c
Isolated yields. HOAc/CH3CN (1:1, 0.5 mL) as alternative solvent.
b
entry
additive (equiv)
solvent (mL)
temp (°C)
yield (%)
c
1
TFA (2)
TFA (2)
TFA (2)
TFA (2)
DCE (2)
DCE (2)
CH3CN (2)
DCE (2)
DCE (2)
DCE (5)
DCE (0.5)
90
110
110
110
110
110
110
c
2
25
14
58
10
c
of quinoline and its derivatives were examined first. The expected
alkylated heteroarenes were successfully obtained in moderate to
excellent yields (11−18). It is noteworthy that various sensitive
functional groups can be tolerated in this protocol. For example,
cinchonine gave the corresponding product in 44% isolated
yields with recovery of 50% of starting material (18).
Subsequently, other N-heteroaromatics such as isoquinoline,
pyridine, phenanthridine, and phthalazine were screened (19−
24). Gratifyingly, the alkylated heterocycles were synthesized in
good to nearly quantitative yields. Furthermore, monoalkylation
compounds were isolated as the major products. More
interestingly, 4-tert-butylpyridine and pyridin-4-ylmethanol
afforded the unique monoalkylated pyridines in 91% and 72%
yield, respectively, and no difunctionalized products were
observed (21 and 22). Both benzo[d]imidazole and benzo[d]-
thiazole were also proven to be effective substrates (25−27).
Finally, an array of DNA base analogues were subjected to this
autoxidative alkylation (28−32). To our delight, these bioactive
compounds were found to be amenable to this system. Notably,
pentoxifylline, a medicine primarily used to reduce pain, led to its
alkylated analogue in 40% yield (32). Pyridine 1-oxide was found
to be an effective substrate in this reaction (33). These results
show that this unique alkylation protocol has broad substrate
scope, which could be potentially applied in the synthesis of
pharmaceuticals.
3
4
5
6
7
d
H2SO4 (1)
TFA (2)
TFA (2)
77
a
Reaction conditions: 4-methylquinoline (0.2 mmol, 1 equiv), n-
BuB(OH)2 (1 mmol, 5 equiv), 1 atm of O2 (air bag); 12 h, unless
b
c
d
otherwise noted. Isolated yields. 6 h. 2 M of H2SO4 used.
solvent, and temperature critically affected the efficiency of this
reaction. No reaction occurred at 90 °C or lower (entry 1). By
increasing the temperature to 110 °C, the desired product was
obtained in 25% (entry 2). Acetonitrile as solvent gave lower
yield than dichloroethane (DCE) (entry 3). To our delight, a
58% yield of the expected products was isolated by extension of
reaction time to 12 h (entry 4). H2SO4 as an alternative to TFA
afforded only 10% yield of the product (entry 5). Furthermore,
we evaluated the cage effect of this system (entries 6 and 7, see
also the Supporting Information). We found it is critical for this
process. Finally, this oxygen-promoted alkylation of hetero-
aromatics with boronic acid produced the corresponding product
in good yields under the following conditions: 1 equiv of
heterocycle, 5 equiv of alkylboronic acid, 2 equiv of TFA, 1 atm
O2, 0.5 mL of DCE, 110 °C, refluxing for 12 h.
With the modified conditions in hand, we began to evaluate
the generality of this reaction. As demonstrated in Scheme 2, an
array of alkylboronic acids are compatible with this system.
Acyclic substrates including primary and secondary boronic acids
afforded the desired alkylated heteroarenes in 35%−87% yields
(1−7). It was found that 2° boronic acids gave higher yields than
1°. In addition, cyclic aliphatic boronic acids are also effective
substrates, and led to the products in 50−90% yields (8−10).
Next we turned our attention to a variety of heterocycles that
are extremely valuable for library design and drug discovery.21 As
illustrated in Scheme 3, we discovered that this new autoxidation
method allows facile alkylation of a broad range of hetero-
aromatics by using boronic acids with 1 atm of O2 only. A series
To verify its application in drug synthesis, we synthesized
several drugs using this autoxidative alkylation strategy. Scheme 4
shows a valuable alternative access to a worldwide best-selling
drug, rosuvastatin, commercially named Crestor. Starting from 1-
(4-fluorophenyl)ethan-1-one, the heterocycle ethyl 2-amino-4-
(4-fluorophenyl)pyrimidine-5-carboxylate was obtained by
known processes.22 Subsequently, the unprotected amino-
pyrimidine was directly subjected to our oxygen-mediated
alkylation with isopropyl boronic acid. The core skeleton 34
was smoothly isolated in 62% yield. Followed by known steps,22
the target drug could then be prepared. Compared with previous
approaches to 34, this method would be more sustainable and
represents a valuable alternative route.
B
DOI: 10.1021/acs.orglett.7b03297
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 3. Molecular Oxygen-Mediated Alkylation of
Heterocycles with Boronic Acids
Scheme 5. Synthesis of Pyriethamine Using this O2-Mediated
Alkylation
a
sustainability make this method very attractive to synthetic
organic chemists.
Ultimately, experiments were carried out to investigate the
mechanism for this reaction. No alkylated heterocycle was
detected by addition of TEMPO as a radical scavenger into the
reaction of 4-methylquinoline with cyclohexylboronic acid under
the typical conditions. A radical trapping adduct 1-(cyclo-
hexyloxy)-2,2,6,6-tetramethylpiperidine was obtained in 75%
yield, which indicates that an alkyl radical should be formed in
this process. Furthermore, a large amount of cyclohexanol was
produced that would be due to autoxidation of cyclohexyl radical
by molecular oxygen. In accordance with the widely accepted
mechanism, this autoxidative alkylation of heterocycles by
boronic acids would conduct a radical-chain process.6,17,24
In summary, a catalyst-free facile carbon−carbon bond
formation via autoxidation of organoboronic acid was developed.
It allows efficient alkylation of diverse heterocycles by using
aliphatic boronic acids and 1 atm of oxygen only. In contrast to
the previous Minisci alkylation reactions requiring stoichiometric
chemical oxidants and/or transition-metal salts, the present
method is metal-free, environmentally benign, and tolerates
sensitive functional groups. Additionally, compared with
unstable and potentially explosive trialkylboron, alkylboronic
acid used as radical precursor is far more stable and safe. Finally,
this discovery might open the door to long-desired revolutions in
green and sustainable chemistry by incorporation of organo-
boronic acid autoxidation into synthetic organic chemistry.
a
Reaction conditions: heterocycle (1 equiv, 0.2 mmol), alkyl boronic
acid (5 equiv, 1 mmol), TFA (2 equiv, 0.4 mmol), DCE (0.5 mL), 1
atm of O2 (air bag), 110 °C, 12 h, unless otherwise noted. Isolated
yields. Bis-alkylation product. HOAc/CH3CN (1:1, 0.5 mL) as
alternative solvent.
b
c
d
ASSOCIATED CONTENT
* Supporting Information
Scheme 4. Synthesis of Rosuvastatin Using This Autoxidative
Alkylation Strategy
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.7b03297.
Experimental procedures, mechanistic studies, and char-
acterization and spectral data (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: liuzhq@lzu.edu.cn.
ORCID
Zhong-Quan Liu: 0000-0001-6961-0585
Notes
Another application in the synthesis of pyrimethamine, an
antimalarial drug, further elucidates the reliability and predict-
ability of this method. Direct ethylation of 5-(4-chlorophenyl)-
pyrimidine-2,4-diamine with ethylboronic acid under 1 atm of O2
afforded the desired medicine in 70% yield (Scheme 5). In
contrast to previous methods,23 the present protocol is more
concise and environmentally friendly. Overall, although
arylboronic acids are not compatible with the current conditions,
the features of metal-free, broad substrate scope, and
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This project is supported by the National Natural Science
Foundation of China (Nos. 21672089 and 21472080) and the
Natural Science Foundation of the Jiangsu Higher Education
Institutions of China (No. 17KJA350001). We also thank Prof.
C
DOI: 10.1021/acs.orglett.7b03297
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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R. X. Tan (Nanjing University of Chinese Medicine) for helpful
discussions.
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