TBN as a metal-free reagent initiated sp3 C–H functionalization of glycine esters: Synthesis of quinoline-2-carboxylate esters

Article abstract of DOI:10.1016/j.tetlet.2018.01.003

As a metal-free reagent, tert-butylnitrite (TBN) initiated aerobic sp³ C–H bond oxidation of glycine esters was achieved, providing a series of quinoline-2-carboxylates in good yields. The mechanistic investigation revealed that in the presence

Full text of DOI:10.1016/j.tetlet.2018.01.003

Accepted Manuscript
TBN as a Metal-free Reagent Initiated sp3 C-H Functionalization of Glycine
Esters: Synthesis of Quinoline-2-carboxylate Esters
Xiaofei Liu, Yu Shao, Pengfei Li, Honghe Ji, Yu Yuan, Xiaodong Jia
PII:
S0040-4039(18)30003-0
https://doi.org/10.1016/j.tetlet.2018.01.003
TETL 49590
DOI:
Reference:
Tetrahedron Letters
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Revised Date:
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24 November 2017
29 December 2017
2 January 2018
Please cite this article as: Liu, X., Shao, Y., Li, P., Ji, H., Yuan, Y., Jia, X., TBN as a Metal-free Reagent Initiated
sp3 C-H Functionalization of Glycine Esters: Synthesis of Quinoline-2-carboxylate Esters, Tetrahedron Letters
(2018), doi: https://doi.org/10.1016/j.tetlet.2018.01.003
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Synthesis of Quinoline-2-carboxylate Esters
Xiaofei Liu,a Yu Shao,c Pengfei Li,a Honghe Ji,a Yu Yuanb,* and Xiaodong Jia b,*

1
Tetrahedron Letters
TBN as a Metal-free Reagent Initiated sp3 C-H Functionalization of Glycine
Esters: Synthesis of Quinoline-2-carboxylate Esters
Xiaofei Liu,a Yu Shao,c Pengfei Li,a Honghe Ji,a Yu Yuan b,* and Xiaodong Jia a,b,*
a College of Chemistry and Chemical Engineering, Northwest Normal University, Lanzhou, Gansu 730070, China
b School of Chemistry and Chemical Engineering, Yangzhou University, Yangzhou, Jiangsu 225002, China
c School of Information Engineering, Yangzhou University, Yangzhou, Jiangsu 225127, China
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
As a metal-free reagent, tert-butylnitrite (TBN) initiated aerobic sp3 C-H bond oxidation of
glycine esters was achieved, providing a series of quinoline-2-carboxylates in good yields. The
mechanistic investigation revealed that in the presence of molecular oxygen, TBN derived
radicals were involved in the C-H bond oxidation and the terminal aromatization.
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
C-H functionalization
tert-Butylnitrite
Aerobic oxidation
Glycine ester
Quinoline
Recently, with the development of activation of inert chemical
To solve this problem, milder and greener oxidants were
[5d, f-j, l, m]
[1]
[2]
bonds, such as C−C,
C−N
and C−O [3] bonds, C-H bond
discovered by several research groups.
Mancheño’s
activation has become one of the hottest topic in organic
chemistry, and numerous methods were established for the
synthesis of complex molecules from readily accessible starting
materials. [4] Besides sp2 and sp C-H bond activation, the direct
sp3 C-H bond functionalization might be one of the most
challenging and exciting goals. In particular, the oxidative
functionalization of glycine derivatives has attracted considerable
-amino
group reported an oxidative Povarov reaction of glycine
-
derivatives, using T+BF4 (2,2,6,6-tetramethylpiperidine-1-
oxoammonium tetrafluoroborate) as the stoichiometric oxidant,
constructing quinoline-2-carboxylate skeleton in high efficiency
[6a-b]
(Figure 1, eq 1).
This oxidant exhibited good functional
group tolerance, and could also be applied to arylation of glycine
[5n]
derivatives in the presence of arylboronic acids.
However,
T+BF4 is not commercially available, and needs prepreparation.
In the search of commercially available catalysts, Liu and co-
workers reported that N-hydroxyphthalimide (NHPI) could also
-
acids and related derivatives. [5, 6, 7]
In 2008, the first example of direct sp3 C-H functionalization
of glycine esters with alkynes was reported by Li and co-
workers, in which Cu(I) was employed in the presence of TBHP
as the stoichiometric oxidant. [5a] Since then, various nucleophiles
initiate this oxidative Povarov reaction in the presence of copper
[6c]
and molecular oxygen.
Since 2012, we developed a new
catalyst system to initiate the reaction between glycine
derivatives and styrenes, in which a catalytic amount of
were applied to this reaction, such as carbonyl compounds, [5b-c
]
triarylamine radical cation salt was employed to promote the
[5d-j]
[5a, k-l]
[5n, 6c]
indoles,
-keto esters,
arylboronic acids,
[6d-h]
aerobic oxidation of glycines.
This catalyst can initiate
[5m]
methylquinolines
and so on. Beyond the development of
various sp3 C-H bond functionalization, and exhibited broad
functional group tolerance. However, only one triarylamine
radical cation salt is commercially available (tris(4-
nucleophiles, a large number of oxidation systems were
established to promote this direct functionalization of glycine
derivatives, in which the TBHP/metal catalyst system was widely
bromophenyl)aminium hexachloroantimonate, TBPA+.), and
[5a-c, e,]
employed.
Albeit this catalyst system exhibited wide
[7]
preparation of other analogues needs SbCl6,
which is
applicability and high reaction efficiency, some shortcomings
inevitably exist. For example, in some cases, the C-H
functionalization of glycine amides occurred smoothly, while the
corresponding analogues, glycine esters, were not compatible.
More importantly, the over use of a stoichiometric amount of
TBHP, an explosive peroxide, might cause serious security
issues, especially in large amount.
hygroscopic and toxic. Based on the economical and
environmental issues, the development of more convenient,
efficient, and general oxidants is still highly desirable in the
direct transformations of glycine derivatives. As part of our
continuous interests on direct transformation of C-H bond, the
use of molecular oxygen as a clean source of oxidant was focused
on. Since oxygen itself does not oxidize glycines effectively, the
help of an appropriate catalyst to promote the aerobic oxidation is

2
Tetrahedron
o
d
e
o
generally necessary. Consequently, we hope to find a new
At 40 C; At room temperature; At 80 C; f In the absence of
TBN.
catalyst system to activate dioxygen, achieving more valuable
transformations.
To test the possibility of TBN initiated aerobic oxidation of
glycine derivatives, we commenced our studies by attempting the
glycine ester 1a with styrene 2a under different reaction
conditions, and the results were compiled in Table 1. Fortunately,
in the presence of 20 mol % TBN under molecular oxygen
atmosphere, the expected reaction occurred smoothly, yielding
the desired quinoline 3a in 36% yield (entry 1). Increasing the
amount of TBN lead to higher yields (entries 2-5), and 50 mol %
TBN gave the best result (entry 3). Then the solvent screen were
performed (entries 6-8), and MeCN was identified as the optimal
choice (entry 3). Lewis acid additives proved to be beneficial to
improve the reaction efficiency, providing the desired product in
75% yield (entry 9). Evaluation of the reaction temperature
revealed that increasing and decreasing the temperature reduced
the yields (entries 11-13). It is worth noting that in the absence of
TBN, only trace amount of the quinoline product was detected
(entry 14), implying that dioxygen could not effectively initiate
this sp3 C-H bond oxidation.
Figure 1. Design for TBN-initiated Functionalization of Glycines.
As a metal-free reagent, TBN (tert-butyl nitrite) is inexpensive
and commercially available, possesses good solubility in
common solvents, and is widely applied to organic synthesis.
Generally, it acts as a surrogate of nitric oxide (NO) and nitrous
[8]
acid to participate in nitrosation reactions. In the presence of
Scheme 1. Reaction Scope of Anilines
molecular oxygen, it can also be used as a nitration reagent,
avoiding the use of high acidic and oxidizing reagents, nitric
acid. Recently, several difunctionalization of C=C unsaturated
[9]
bond was achieved by TBN/TEMPO catalyst system (Figure 1,
eq 2). [10] Albeit a great innovation, the report using TBN as an
[11]
oxidant remains rare.
Among these elegant reactions, the
reaction between TBN and dioxygen attracted our attention.
There is ample evidence that TBN can react with molecular
oxygen, giving the peroxynitrite and tert-butoxyl radical
smoothly, [9b-e] and these oxidizing radicals could probably act as
single electron oxidant and radical initiator. So we questioned
whether TBN/O2 could act as a new catalyst system to initiate sp3
C-H bond functionalization of glycine derivatives. Herein, we
report a practical oxidative Povarov reaction using commercially
available TBN and molecular oxygen as oxidant (Figure 1, eq 3).
Table 1. Optimization of Reaction Conditions a
With the best reaction conditions established, the reaction
scope was then investigated. The substituents on aniline was
firstly varied to evaluate the reaction generality, and the results
are displayed in Scheme 1. Both electron-donating methoxy and
ethoxy groups gave the corresponding products 3a and 3b in
good yields. Electron-withdrawing groups, such as 4-F, 4-Cl, and
4-Br, slightly decreased the reaction efficiency, offering the
desired quinoline-2-carboxylates in 41%, 48%, and 38% yield,
respectively. The 2,4-disubstituted substrates with higher steric
hindrance did not exert negative effect on this oxidative Povarov
reaction, giving the desired products in comparable yields (3g-
3i). When 3,4-dimethylaniline derived glycine ester was
involved, the cyclization occurred selectively on the ortho-
position (3j), probably due to the steric reasons. To test the
practical application of this catalyst system, the reaction of 1a
was performed on 10 mmol scale, and the desired 3a was
obtained in 69% yield, suggesting potential in industrial
applications.
TBN
(mol %)
20
30
50
100
150
50
Additive
(10 mol %)
none
none
none
none
none
none
Yield
(%) b
36
52
67
55
55
21
40
Entry
Solvent
1
2
3
4
5
6
MeCN
MeCN
MeCN
MeCN
MeCN
DCE
7
8
50
50
none
none
CHCl3
DCM
17
75
68
9
50
50
50
50
50
0
InCl3
BF3·OEt2
InCl3
InCl3
InCl3
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
10
11
12
13
14
41 c
25 d
45 e
trace f
Next, the scope of this reaction was extended to various
styrenes, which reacted smoothly in the standard conditions
(Scheme 2). Styrenes with electron-donating groups, such as
OMe, Me, gave higher yields than electron-withdrawing groups
(3l to 3n). The acetoxyl group could also be tolerated, providing
the corresponding quinoline 3o in lower yield. Styrenes with
ortho-groups did not decrease the reaction efficiency, and the
desired products 3p and 3q were isolated in 50% and 71% yields,
InCl3
a Unless otherwise specified, the reaction was carried out with
1a (0.1 mmol), 2a (0.2 mmol) in the presence of TBN, and
b
anhydrous solvent (1.0 mL). Determined by crude products1H
c
NMR, using 1,3,5-trimethoxylbenzene as the internal standard;

3
respectively. When -methylstyrene was employed, the highly
substituted quinoline 3r were obtained in 37% yield.
intermediate (calcd for C19H20N2O4 + H+, 341.1496; found,
341.1496) was also detected. This intermediate, which was
derived from N-nitrosation of the corresponding
Scheme 2. Reaction Scope of Styrenes
tetrahydroquinoline, might be involved in the aromatization
process, providing the quinoline product.
Scheme 4. Control Experiments
Although the exact mechanism remains obscure, a possible
reaction pathway was proposed for this TBN/O2 initiated C-H
bond functionalization of glycine esters, based on experimental
[9-10]
evidence and literature precedent (Scheme 5).
Initially, a
Furthermore, glycine derivatives with various ester groups
were also compatible in this reaction (Scheme 3), and in the
presence of sensitive cyclopropyl ring, the reaction efficiency did
not decrease, generating the expected product 3v in good yield.
When cyclopentyl ester existed, the quinoline 3t was obtained in
lower yield, together with isolation of 34% N-nitroso glycine
ester. The intramolecular oxidative Povarov reaction was also
tested, and the desired quinoline-fused lactone 3w was obtained
in 32% yield.
peroxynitrite radical was formed by aerobic cleavage of the N-O
bond of TBN. Then, the glycine ester was oxidized by this
[12]
peroxynitrite radical, generating an imine intermediate A.
In
the presence of Lewis acid InCl3, a classical Povarov cyclization
occurred, affording the tetrahydroquinoline intermedaite B. After
the subsequent N-nitrosation, a N-nitrosotetrahydroquinoline C
was formed. Through further aerobic aromatization, the desired
quinoline 3 was yielded together with the regeneration of the
peroxynitrite radical closing the catalytic cycle.
Scheme 3. Reaction Scope of Esters
Scheme 5. Proposed Mechanism
To probe the reaction mechanism, several control experiments
were carried out under the standard conditions (Scheme 4). In the
absence of molecular oxygen, only trace amount of the product
3a was detected, implying that dioxygen is crucial to initiate this
In summary, we developed a new catalyst system to achieve
the oxidative Povarov reaction of glycine esters, in which TBN
as an efficient organic catalyst exhibits good reactivity. A series
of quinoline-2-carboxylates were synthesized with good
functional group tolerance. Compared with the reported methods
to functionalize glycines, this reaction is featured by accessible
catalyst system, good efficiency, and transition metal free
conditions. More importantly, this work revealed that TBN can
not only be widely applied to tranditional nitrosation and
nitration reactions, but also be used as an efficient organic
oxidant to initiate the aerobic oxidation of C-H bond. Further
applications and more variants of TBN initiated reaction are still
underway in our laboratory.
reaction, and TBN derived peroxynitrite and tert-butoxyl radical,
[9-10]
whose generation is supported by literatures,
might be
involved in the C-H bond oxidation step. Since secondary amines
can readily be transformed to N-nitrosoamines in the presence of
TBN/O2, the reaction of N-nitrosoglycine ester was tested under
the standard reaction conditions. However, no reaction occurred,
which ruled out the participation of N-nitrosoglycine ester as the
reaction intermediate. To detect the active intermediate and gain
more information of the mechanism, a HRMS experiment of the
reaction mixture was performed. To our delight, a glycine imine
intermediate at m/z 208.0963 (calcd for C11H13NO3 + H+,
208.0968) was detected, verifying that the glycine ester was
oxidized by TBN/O2, followed by InCl3 catalyzed Povarov
Acknowledgments
cyclization. Furthermore,
a
N-nitrosotetrahydroquinoline

4
Tetrahedron
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This work was financially supported by National Natural
Science Foundation of China (NNSFC, No. 21362030 and
21562038) for supporting our research. The authors also thank
Jiangsu Provincial Natural Science Foundation (BK20161328)
for financial support.
7.
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Supplementary Material
1
Copies of all H NMR and 13C NMR spectra of the products.

5
1. TBN (tert-butyl nitrite) as commercially
available and green oxidant.
2. Aerobic sp3 C-H oxidation of glycine esters
under metal-free conditions.
3. Efficient synthesis of quinoline-2-carboxylate
esters.