Molecular Oxygen-Mediated Radical Alkylation of C(sp3)-H Bonds with Boronic Acids

Article abstract of DOI:10.1021/acs.orglett.1c00948

A direct and site-specific alkylation of (sp3)C-H bond with aliphatic boronic acid was achieved. By simply heating glycinates and amines together with alkylboronic acids under an oxygen atmosphere, a variety of unnatural α-amino acids and peptides could b

Full text of DOI:10.1021/acs.orglett.1c00948

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Letter
3
Molecular Oxygen-Mediated Radical Alkylation of C(sp )−H Bonds
with Boronic Acids
Le Yang, Zhihong Qiu, Jintao Wu, Jianyou Zhao, Tong Shen, Xuan Huang, and Zhong-Quan Liu*
Cite This: Org. Lett. 2021, 23, 3207−3210
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ABSTRACT: A direct and site-specific alkylation of (sp )C−H
bond with aliphatic boronic acid was achieved. By simply heating
glycinates and amines together with alkylboronic acids under an
oxygen atmosphere, a variety of unnatural α-amino acids and
peptides could be obtained in good yields.
rganoboranes are proven to be valuable radical
Scheme 1. Radical C−H Alkylation Using Alkylboronic Acid
as Precursor
O
precursors which have been widely used in synthetic
1
organic chemistry. More interestingly, free-radical-promoted
direct C−H arylation and alkylation with organoboranes have
2
also been achieved in the past two decades, among which the
2
radical C(sp)−H and C(sp )−H bond alkylation via aliphatic
boranes was extensively explored. However, the direct
3
alkylation of the C(sp )−H bond using alkylborane as the
radical precursor has remained undeveloped.
3
Previous studies showed that the C(sp )−H bond adjacent
3
to an N-atom could couple with an alkyl radical. Also, several
methods have been achieved to prepare unnatural amino acids
and their derivatives. For instance, Xu and co-workers
developed a visible-light-driven decarboxylative alkylation of
4
glycine and peptide in 2018. Peroxide-mediated double
3
C(sp )−H bond functionalization was also accomplished by
5
6
3
Yu and Correa. Very recently, Wang et al. achieved C(sp )−
H bond alkylation utilizing peroxide as the alkyl radical
source. However, these systems suffered from prefabrication
7
of the radical precursor, a potentially explosive peroxide, and
relatively hash conditions. Hence, development of more
efficient and greener access to artificial amino acids and
peptides is highly desirable.
from Table 1, factors such as acidic additives, solvent, and
temperature seriously affect the efficiency of the reaction. By
changing the solvent and its volume, we can get a desired yield
Inspired by our original strategy for molecular oxygen-
mediated alkylation of heteroarene and its derivatives with
8
alkylboronic acid, we began to envision whether this method
3
could meet the challenge of C(sp )−H bond alkylation with
Received: March 19, 2021
Published: April 6, 2021
boronic acid. Fortunately, we found an effective alkylation of a
3
C(sp )−H bond with alkylboronic acid by using 1 atm O
2
(
Scheme 1).
Initially, we carried out the reaction of ethyl(4-
methoxyphenyl)glycinate with isopropyl boronic acid as a
model reaction to optimize the conditions (Table 1). As seen
©
2021 American Chemical Society
https://doi.org/10.1021/acs.orglett.1c00948
3
207
Org. Lett. 2021, 23, 3207−3210

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a
Table 1. Optimization of the Reaction Conditions
Moreover, we examined a series of molecules involving the
C(sp )−H bond adjacent to an N-atom (Scheme 3). First, a
3
Scheme 3. Molecular Oxygen-Promoted Alkylation of
3
a
C(sp )−H Bonds with Boronic Acids
b
entry additive (equiv)
solvent (mL)
DCE (2)
DCE (0.5)
T (°C) yield (%)
1
2
3
4
5
6
7
8
TFA (2)
TFA (2)
TFA (2)
TFA (2)
TFA (2)
TFA (2)
TFA (1)
TFA (2)
100
100
100
100
100
90
70
80
35
73
70
64
60
57
CH CN (0.5)
3
HOAc/DCE (0.25/0.25)
EtOH/DCE (0.25/0.25)
DCE (0.5)
DCE (0.5)
DCE (0.5)
100
100
c
a
Reaction conditions: ethyl(4-methoxyphenyl)glycinate (0.2 mmol, 1
equiv), i-PrB(OH) (1 mmol, 5 equiv), 1 atm O (oxygen bag), 10
2
2
b
c
min, unless otherwise noted. Isolated yields. 3 equiv of i-PrB(OH)
used.
2
(80%) while using 0.5 mL of DCE (entries 1−5). When the
temperature was adjusted to 90 °C, the desired product was
obtained in 64% (entry 6). In addition, a 60% yield of product
was afforded when 1 equiv of TFA was added (entry 7).
Finally, a decreased yield of 1 was isolated by utilizing 3 equiv
of boronic acids (entry 8). It is worth noting that all these
reactions were completed within 10 min.
Next, we evaluated the scope of substrates under the typical
conditions (Scheme 2). Also, we found that both linear and
Scheme 2. Molecular Oxygen-Mediated Alkylation of
Ethyl(4-methoxyphenyl)glycinate with Boronic Acids
a
a
b
Typical reaction conditions. Isolated yields.
broad range of N-aryl glycinates were effective substrates (11−
9). Both electron-rich and electron-deficient aryl substituents
1
a
on the N-atom of glycinates gave the corresponding products
in moderate to good yields (11−18). In addition, halogen can
be tolerated (14−16). The products can be easily converted
into the corresponding α-amino acids. Then, we discovered
that various N-aryl tetrahydroisoquinolines were also amenable
to this system (20−23). Also, the alkylation happened
specifically on the C1-position. Additionally, N-benzylanilines
afforded the desired products smoothly (24 and 25). In
addition, quinoxalin-2(1H)-one gave the corresponding
alkylated product in high yields (26). It is noteworthy that
peptides could also be modified by this method (27). These
data indicate that the present method could be potentially
Reaction conditions: ethyl(4-methoxyphenyl)glycinate (1 equiv, 0.2
mmol), alkyl boronic acid (5 equiv, 1 mmol), TFA (2 equiv, 0.4
mmol), DCE (0.5 mL), 1 atm O (oxygen bag), 100 °C, 10 min.
2
b
Isolated yields.
cyclic aliphatic boronic acids are compatible with this reaction.
In addition, the yields were closely related to the stability of the
alkyl radical derived from the corresponding boronic acid. It is
obvious that 2° boronic acids afforded higher yields than 1°
(
1−7). Furthermore, high yields of the alkylated glycinates
were obtained with cyclic boronic acids (8−10).
3
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pubs.acs.org/OrgLett
Letter
applied in the synthesis of unnatural amino acids, pharma-
ceuticals, and peptides.
Ultimately, we designed some experiments to get insight
into the mechanistic details (Scheme 4). As demonstrated in
Nanjing University of Chinese Medicine, Nanjing 210023,
China
Zhihong Qiu − Jiangsu Collaborative Innovation Center of
Chinese Medicinal Resources Industrialization, College of
Pharmacy, Nanjing University of Chinese Medicine, Nanjing
210023, China
Scheme 4. Control Experiments and Suggested Mechanism
Jintao Wu − Jiangsu Collaborative Innovation Center of
Chinese Medicinal Resources Industrialization, College of
Pharmacy, Nanjing University of Chinese Medicine, Nanjing
210023, China
Jianyou Zhao − Jiangsu Collaborative Innovation Center of
Chinese Medicinal Resources Industrialization, College of
Pharmacy, Nanjing University of Chinese Medicine, Nanjing
210023, China
Tong Shen − Jiangsu Collaborative Innovation Center of
Chinese Medicinal Resources Industrialization, College of
Pharmacy, Nanjing University of Chinese Medicine, Nanjing
210023, China
Xuan Huang − Department of Laboratory Medicine, Affiliated
Hospital of Jiangnan University, Wuxi 214122, China
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c00948
Scheme 4a, we did not observe the desired product 1 by
addition of 3 equiv of TEMPO. Also, a radical adduct 28 was
isolated as expected in 70% yield. According to the previous
Notes
The authors declare no competing financial interest.
1
,3,8,9
reports
and the data we got on this system, a possible
ACKNOWLEDGMENTS
mechanism was proposed in Scheme 4b. Autoxidation of
■
glycinate with O would afford peroxide A, and then, it
This project is supported by National Natural Science
Foundation of China (21971116).
2
eliminated H O followed by protonation leading to B. Next,
2
2
the alkyl radical that was generated from autoxidation of
organoboronic acid was added to B, and the corresponding
radical cation C would be formed. Deprotonation of C gave an
N-centered radical D, which abstracted an H-atom from
glycinate to produce the product and glycinate radical E. This
radical intermediate should be relatively stable due to the
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Experimental procedures, mechanistic studies, and
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