Auto-oxidative coupling of glycine derivatives

Article abstract of DOI:10.1002/anie.201406905

The unprecedented title reaction between glycine derivatives and indoles, as well as the auto-oxidative Povarov/ aromatization tandem reaction of glycine derivatives with olefins are described. The reactions were performed in the absence of redox-active c

Full text of DOI:10.1002/anie.201406905

Angewandte
Chemie
DOI: 10.1002/anie.201406905
Synthetic Methods
Auto-Oxidative Coupling of Glycine Derivatives**
Congde Huo,* Yong Yuan, Mingxia Wu, Xiaodong Jia, Xicun Wang, Fengjuan Chen, and
Jing Tang
Abstract: The unprecedented title reaction between glycine
derivatives and indoles, as well as the auto-oxidative Povarov/
aromatization tandem reaction of glycine derivatives with
olefins are described. The reactions were performed in the
absence of redox-active catalysts and chemical oxidants under
mild reaction conditions. Only simple organic solvents and air
(or O2) were required.
on triarylaminium salt induced transformations,[8] we also
explored a novel aerobic double Friedel–Crafts alkylation
reaction of glycine derivatives.[4l]
Radical-mediated damage to proteins is oxygen-depen-
dent and leads to aging and diseases. In natural systems,
peptide backbone oxidations and fragmentations are involved
in the formation of a-carbon radicals and their subsequently
generated peroxides.[9] We noted that oxalic acid derivatives
and backbone imines were important intermediates of these
auto-oxidative bioprocesses (Scheme 1, top).[9] We became
Oxidation reactions are of fundamental importance in
nature and play a crucial role in organic synthesis, and there is
currently a demand for more sustainable and selective
oxidation methods.[1] In the last decade, oxidative coupling
reactions have become a growing field in organic chemistry.[2]
Among them, the oxidative dehydrogenative coupling of
glycine derivatives has gained significant attention since the
pioneering study of Zhao and Li in 2008.[3] After that, some
progress has been reported in this context.[4] These reactions
were mostly catalyzed by copper[4a–e] or iron salts[4f–i] in
combination with stoichiometric amounts of chemical oxi-
dants such as TBHP, DTBP, DDQ, or TEMPO oxoammo-
nium salt.[4a–i] Dioxygen is an environmentally benign oxidant
and an atom-efficient reagent in synthetic chemistry.[5]
Molecular oxygen activation has been of long-standing
interest owing to its tremendous potential use in organic
chemistry.[6] The oxidative coupling of N-aryl tetrahydroiso-
quinolines has been well developed under aerobic condi-
tions.[7] Nevertheless, the utilization of elemental oxygen as
a terminal oxidant for the oxidative coupling of glycine
derivatives was relatively rare.[4j–n] In 2012, the group of
Rueping reported a relay catalysis protocol for the indolation
of glycine derivatives using a combination of visible-light
photoredox and Lewis acid catalysis under aerobic condi-
tions.[4j] Recently, we discovered for the first time the simple
copper(I) chloride catalyzed oxidative coupling of glycine
derivatives using O2 as the terminal oxidant.[4k] In addition, Jia
et al. developed the synthesis of quinolines from glycine
derivatives with alkenes by a dehydrogenative Povarov/
oxidation process under radical cation salt catalysis in the
presence of a Lewis acid and O2.[4m,n] And during our studies
Scheme 1. Auto-Oxidation of glycine derivatives and peptides.
interested in determining whether it is possible to intercept
the imine intermediates with various nucleophiles, thus
possibly offering an interesting opportunity for selective
carbon–carbon bond formation. To begin research into this
À
area, we conceived of generating new C C bonds by auto-
oxidation of glycine derivatives under simple reaction con-
ditions (Scheme 1, bottom).
Herein we report the realization of the above goal and
demonstrate that it is possible to carry out auto-oxidative
cross-coupling reactions of glycine derivatives in a simple
mixed organic solvent either under oxygen or open to air. We
believe this is an unprecedented and remarkable break-
through of the oxidative coupling reaction because neither of
the commonly used redox-active catalysts nor chemical
oxidants is involved. This primary work represents the
powerful application potential of the auto-oxidation of
glycine derivatives to construct carbon–carbon bonds and
deliver complex organic frameworks. At the same time, it will
be helpful for understanding the reaction mechanism of
aerobic oxidative coupling reactions.
[*] Dr. C. Huo, Y. Yuan, M. Wu, Dr. X. Jia, Dr. X. Wang, F. Chen, J. Tang
Key Laboratory of Eco-Environment-Related Polymer Materials
Ministry of Education; College of Chemistry and Chemical
Engineering, Northwest Normal University
Lanzhou, Gansu 730070 (China)
E-mail: huocongde1978@hotmail.com
During our studies of copper salt[4k] or triarylaminium
salt[4l] catalyzed aerobic oxidative coupling of glycine deriv-
atives, we always kept a small sample solution of glycine
derivatives for monitoring the reactions by TLC, and
unexpectedly we observed transformation into the oxidized
[**] We thank the National Natural Science Foundation of China
(21262029) and the Fok Ying Tong Education Foundation (141116)
for financial support of this work.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201406905.
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Table 1: Auto-oxidation reaction of glycine derivatives and X-ray-derived
ORTEP drawing of compound 2l.
product in low yields within a few weeks in chlorinated
solvents. This means an auto-oxidation reaction occurred.
This interesting result encouraged us to optimize the reaction
conditions. We surprisingly discovered that the reaction was
highly dependent on the solvent choice and found that the
highest reaction rate and full conversion of 1a could be
achieved if a mixed solvent (MeCN/DCE = 5:1) was used
(Table 1, entry 1). Using the optimized reaction conditions, as
shown in Table 1, a series of oxalic acid derivatives were
delivered in moderate yield.[10]
Entry
1
R1
R2
t [h]
2 ([%])[b,c]
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1 f
Me
Me
Me
Me
Me
MeO
Me
Me
OEt
OMe
OnBu
OtBu
OAllyl
OEt
15
18
16
12
24
20
24
48
2a (63)
2b (61)
2c (61)
2d (52)
2e (52)
2 f (50)
2l (58)
2m (38)
Under the above optimized reaction conditions, the
glycine ester 1a and indole (3a) were chosen as model
À
substrates because Csp2(aryl) Csp3 bond-formation reactions
are of fundamental interest in organic synthesis (Table 2).
And additionally, both glycine derivatives and indoles are
very common substructures in natural products and biolog-
ically active compounds.[11] We were pleased to observe that
high yield of the product 4aa was isolated after 15 hours. The
scope and generality of this protocol was then investigated.
Various glycine derivatives and different indoles were all
suitable substrates in this transformation.
1l
1m
NHCH2CO2Et
NHCH2CONHCH2CO2Et
[a] Standard reaction conditions: 1 (1.0 mmol), MeCN/DCE (5:1,
18 mL), O2 (1 atm), 408C. [b] Yields of the isolated products. [c] All
experiments were repeated three times and the mean values are given.
DCE=1,2-dichloroethane. Thermal ellipsoids shown at 50% probability.
To develop a more general and useful method,
we subsequently turned our attention to investigate
the oxidative Povarov/aromatization tandem reac-
tion under the auto-oxidation conditions. This reac-
tion is important because the produced substituted
quinolines are important scaffolds present in many
bioactive natural products and synthetic drugs.[12] In
this auto-oxidation protocol, electron-rich styrenes
reacted with glycine esters and amides to produce
the desired products in moderate yields. As seen
from Table 3, the reactions went to completion but
the self-oxidation side product 2 could not be
avoided.
And to our surprise, as shown in Scheme 2, when
2,3-dihydrofuran (7) was employed as an alkene
counterpart, a ring closing/opening/closing process
occurred and the unexpected and very interesting
quinolone-fused lactone 8[10] was isolated in 42%
yield.
To investigate the mechanism of this transforma-
tion, experiments were carried out. The reaction of
1a with either 3a, 5a, or 7 under an argon
atmosphere resulted in a significant drop in yield,
thus indicating that oxygen is crucial for the reaction
(Table 4, entries 1–3). Radical-trapping experiments
were conducted by employing TEMPO as a radical
scavenger. The desired product was not observed
under the standard reaction conditions (entries 4–6),
thus suggesting that the present reaction includes
a radical process. We also discovered the critical role
of dichloroethane in this reaction. When freshly
distilled DCE was used, the efficiency of the reaction
dramatically decreased, thus providing the desired
product in only trace amounts. After 3 to 5 weeks of
storage of the solvent (DCE) in common Amber
laboratory bottles, the reactions progressed smoothly
and gave reproducible results. We proposed that
Table 2: Auto-oxidation reaction of glycine derivatives with indoles.
Entry
1
R1
R2
3
R3
t [h]
4 ([%])[b,c]
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1 f
Me
Me
Me
Me
Me
MeO
Cl
OEt
OMe
OnBu
OtBu
OAllyl
OEt
OEt
OEt
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OEt
3a
3a
3a
3a
3a
3a
3a
3a
3b
3c
3d
3e
3 f
3g
3h
3i
H
H
H
H
H
H
H
H
15
16
20
24
24
28
40
40
25
30
18
16
6
22
12
6
8
4
15
21
15
18
48
50
48
60
40
20
24
4aa (81)
4ba (75)
4ca (79)
4da (44)
4ea (74)
4 fa (54)
4ga (57)
4ha (39)
4bb (81)
4bc (71)
4bd (70)
4be (72)
4bf (83)
4bg (78)
4bh (56)
4bi (83)
4bj (76)
4af (77)
4cf (76)
4df (46)
4ef (74)
4 ff (66)
4if (37)
1g
1h
1b
1b
1b
1b
1b
1b
1b
1b
1b
1a
1c
1d
1e
1 f
Br
9
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
MeO
H
5-Me
5-Br
5-MeO
2-Me
2-Ph
N-Bn
N-Me
2-(4-FC6H4)
2-(4-ClC6H4)
2-Ph
2-Ph
2-Ph
2-Ph
2-Ph
2-Ph
2-Ph
2-Ph
2-Ph
2-Ph
2-Ph
2-Ph
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
3j
3 f
3 f
3 f
3 f
3 f
3 f
3 f
3 f
3 f
3 f
3 f
3 f
OnBu
OtBu
OAllyl
OEt
OEt
OEt
1i
1g
1h
1j
1k
1l
Cl
Br
Me
Me
Me
Me
4gf (30)
4hf (33)
4jf (56)
4kf (59)
4lf (76)
OEt
NHMe
NHEt
NHCH2CO2Et
NHCH2CO-
NHCH2CO2Et
1m
4mf (46)
[a] Standard reaction conditions: 1 (1.0 mmol), 3 (1.0 mmol), MeCN/DCE (5:1,
18 mL), O2 (1 atm), 408C. [b] Yield of the isolated product. [c] All experiments were
trace amounts of an acidic impurity may be gener- repeated three times and the mean values are given.
2
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Table 3: Auto-oxidation reaction of glycine derivatives with styrenes.
MnO2 was added at the end of the reaction, gas evolved. This
evolution suggests the generation of H2O2 in the reaction
process because manganese dioxide catalyzes the decompo-
sition of hydrogen peroxide into oxygen and water. The
reaction mixtures of 1a with either 3a, 5a, or 7 leads to the
successful preparation of 4aa, 6aa, or 8, respectively, and they
were analyzed by atomic adsorption spectroscopy, thus
revealing no common redox-active transition metals such as
copper and iron above the detection limit of 0.5 ppm.
A plausible mechanism is depicted in Scheme 3. The
glycine ester 1a was first auto-oxidized to give the hydro-
peroxide intermediate A. The iminium ion intermediate B
could then be formed through an acid-catalyzed SN1-type
procedure from A. Subsequently, coupling of B with 3a
results in the desired product 4aa. In addition, a reasonable
mechanism is also illustrated for the reaction of 1a with 2,3-
dihydrofuran (7; Scheme 2).
Entry
1
R1
R2
5
R3
t [h] 6 ([%])[b,c] 2 [%][b]
1
2
3
4
5
6
1a Me
1b Me
1c Me
1d Me
1e Me
OEt
OMe
5a 4-MeOC6H4 20 6aa (53) 22
5a 4-MeOC6H4 40 6ba (51) 29
OnBu 5a 4-MeOC6H4 48 6ca (46) 15
OtBu 5a 4-MeOC6H4 48 6da (33) 28
OAllyl 5a 4-MeOC6H4 12 6ea (40) 26
1 f MeO OEt
5a 4-MeOC6H4 24 6 fa (47)
9
7
7[d]
8
9
1j Me
1a Me
1a Me
NHMe 5a 4-MeOC6H4 40 6ja (28)
OEt
OEt
OEt
5b 4-MeC6H4
5c 4-tBuC6H4
5d C6H5
42 6ab (36) 38
48 6ac (38) 35
600 6ad (35) 40
10[d] 1a Me
[a] Standard reaction conditions: 1 (1.0 mmol), 5 (2.0 mmol), MeCN/
DCE (5:1, 18 mL), air (1 atm), 408C. [b] Yield of the isolated products.
[c] All experiments were repeated three times and the mean values are
given. [d] O2 (1 atm).
Scheme 3. Proposed mechanism of 1a and 3a.
In conclusion, this protocol realizes an unprecedented
aerobic auto-oxidative cross-coupling reaction of glycine
derivatives and short peptides in a simple mixed organic
solvent under mild reaction conditions. Notably, this prelimi-
nary work demonstrates the first example of oxidative cross-
coupling reactions of glycine derivatives without using any
redox-active catalyst and chemical oxidant. This method
represents the powerful potential to construct complex
bioactive and medicinal organic frameworks.
Scheme 2. Auto-oxidation reaction of 1a with 2,3-dihydrofuran (7),
plausible mechanism, and X-ray derived ORTEP drawing of the
compound 8. Thermal ellipsoids shown at 50% probability.
Table 4: Control experiments.
Entry Substrate[a] Conditions[b]
Yield [%][c]
1
2
3
1a, 3a
1a, 5a
1a, 7
1a, 3a
1a, 5a
1a, 7
1a, 3a
1a, 5a
1a, 7
MeCN/DCE (5:1), Ar
MeCN/DCE (5:1), Ar
MeCN/DCE (5:1), Ar
MeCN/DCE (5:1), TEMPO (1 equiv), O2
MeCN/DCE (5:1), TEMPO (1 equiv), O2
MeCN/DCE (5:1), TEMPO (1 equiv), O2
MeCN/DCE (5:1), HCl (0.2 mol%), O2 76
MeCN/DCE (5:1), HCl (0.2 mol%), O2 36
MeCN/DCE (5:1), HCl (0.2 mol%), O2 38
trace
trace
trace
–
–
–
Experimental Section
4[c]
5[c]
6[c]
7[d]
8[d]
9[d]
General procedure for auto-oxidation reaction of glycine derivatives
with indoles or alkenes: Glycine derivatives (1, 1 mmol) and indoles
(3, 1 mmol) or glycine derivatives (1, 1 mmol) and alkenes (5 or 7,
2 mmol) were dissolved in a mixed solvent (MeCN/DCE, 5:1, 18 mL)
at ambient temperature. The reactions were performed either under
an O2 atmosphere (oxygen balloon) or open to air (open flask) at
408C and completed within 4–60 hour as monitored by TLC. The
products were isolated by column chromatographic separation.
[a] 1a, 3a, 5a, 7: 0.1 mmol. [b] Solvent: 2 mL, 408C, 15–20 h. [c] Deter-
mined by NMR spectroscopy. [d] freshly distilled dichloroethane was
used. TEMPO=2,2,6,6-tetramethylpiperidin-1-oxyl.
Received: July 4, 2014
Revised: August 30, 2014
Published online: && &&, &&&&
ated in the process of storage of DCE and might promote this
auto-oxidation reaction. This acidic impurity proves plausible,
since performing the reaction of 1a with either 3a, 5a, or 7 in
the presence of small amounts of hydrochloric acid
(0.2 mol%, 1 molLÀ1) in freshly distilled DCE resulted in
almost identical product yields (entries 7–9). When 1 mol%
Keywords: alkenes · heterocycles · oxidation · oxygen ·
.
synthetic methods
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ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2014, 53, 1 – 5
These are not the final page numbers!

Angewandte
Chemie
Communications
Synthetic Methods
C. Huo,* Y. Yuan, M. Wu, X. Jia, X. Wang,
F. Chen, J. Tang
&&&& — &&&&
Auto-Oxidative Coupling of Glycine
Derivatives
Aired out: The unprecedented title reac-
tion between glycine derivatives and
indoles, as well as the auto-oxidative
Povarov/aromatization tandem reaction
of glycine derivatives with olefins are
described. The reactions were performed
in the absence of redox-active catalysts
and chemical oxidants under mild reac-
tion conditions. Only simple organic
solvents and air (or O2) were required.
Angew. Chem. Int. Ed. 2014, 53, 1 – 5
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!