Gold-Oxazoline Complex-Catalyzed Cross-Dehydrogenative Coupling of Glycine Derivatives and Alkenes

Article abstract of DOI:10.1002/adsc.201601066

A gold-oxazoline complex-catalyzed dehydrogenative Povarov/oxidation tandem reaction for the synthesis of decorated quinolines has been developed from glycine derivatives and alkenes. The reaction performs under mild reaction conditions in the presence of

Full text of DOI:10.1002/adsc.201601066

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DOI: 10.1002/adsc.201601066
Gold-Oxazoline Complex-Catalyzed Cross-Dehydrogenative
Coupling of Glycine Derivatives and Alkenes
Minjie Ni,+a Yan Zhang,+a,* Tingting Gong,a and Bainian Fenga,*
a
School of Pharmaceutical Science, Jiangnan University, Wuxi 214122, Peopleꢀs Republic of China
Fax : (+86)-0510-8519-7052; e-mail: zhangyan@jiangnan.edu.cn or fengbainian@jiangnan.edu.cn
+
These authors contributed equally to this work.
Received: September 29, 2016; Revised: October 19, 2016; Published online: && &&, 0000
Supporting information for this article can be found under: http://dx.doi.org/10.1002/adsc.201601066.
Abstract: A gold-oxazoline complex-catalyzed dehy- a broad substrate scope and excellent functional
drogenative Povarov/oxidation tandem reaction for group tolerance.
the synthesis of decorated quinolines has been devel-
oped from glycine derivatives and alkenes. The reac-
tion performs under mild reaction conditions in the Keywords: C–H activation; cross-coupling; glycine
presence of oxygen as the oxidant and features derivatives; gold; oxidation
Introduction
of glycine derivatives with oxygen as an oxidant has
been described yet.
C–C bond forming reactions are especially useful in
The imino Diels–Alder reaction was first discov-
synthetic chemistry, and have played a vital role in ered by Povarov in the 1960s. Recently, the oxidative
building complicated molecules from simple precur- dehydrogenative coupling of glycine derivatives has
sors.[1] Consequently, much effort has been made to gained significant attention, which relies on the oxida-
establish and improve the methods for constructing tion of the secondary amine substrates.[6] Since the
new C–C bonds in recent decades.[2] Particularly, C–C first one-pot Povarov reaction reported by Garcꢁa
bond formation from different C–H bonds under oxi- MancheÇo using FeCl3 as the catalyst and a 2,2,6,6-
dative conditions, termed cross-dehydrogenative cou- tetramethyl-1-piperidinyloxy (TEMPO) oxoammoni-
pling (CDC), has attracted much attention. The
method greatly increases the overall efficiency and
improves the atom economy.[3] Among them, gold-cat-
[4]
alyzed cross-dehydrogenative coupling has received
special attention, and remarkable progress has been
made in recent years. So far, the inert C–H bonds
have been directly converted into carbon-carbon and
carbon-heteroatom bonds through gold-mediated oxi-
dative cleavage of C–H bonds, hydride shift or C–H
insertion. These reactions were mainly catalyzed by
gold complexes or salts in combination of oxidants
such as TBHP or NBS.[4b,f] Following the principles of
green chemistry, here oxygen as an environmentally
benign oxidant delivers water as the only by-product,
and thus the reaction has gained considerable atten-
tion in modern oxidation chemistry.[5] The oxidation
of N-aryltetrahydroisoquinolines catalyzed by a gold
complex has been well developed under aerobic con-
ditions[4c–e,g,h] (Scheme 1). Nevertheless, to the best of
Scheme 1. Reported oxidation of N-aryltetrahydroisoquino-
our knowledge, no gold-catalyzed oxidative coupling lines catalyzed by gold complex under aerobic conditions.
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um salt as the oxidant in 2011,[7] similar catalytic sys-
tems have also been developed in other reactions.[8]
In 2014, Huo reported the auto-oxidative coupling of
glycine (Scheme 2).[8d]
Table 1. Optimization of conditions for the O2 oxidative Po-
varov/aromatization reaction.[a]
Entry Catalyst (mol%)
Solvent t [h] Yield [%][b]
1
–
CH3CN 600 30
2
3
4
5
6
7
8
9
–
CH3CN 12
CH3CN 12
CH3CN 12
CH3CN 12
CH3CN 12
CH3CN 12
CH3CN 12
CH3CN 12
CH3CN 12
CH3CN 12
CH3CN 8
CH3CN 8
CH3CN 8
CH3CN 8
CH3CN 3
CH3CN 3
CH3CN 8
CH3CN 8
CH3CN 12
CH3CN 12
CH3CN 12
CH3CN 12
CH3CN 12
CH3CN 12
10
18
27
<5
40
18
<5
<5
61
70
58
53
61
53
80
90
75
73
42
50
52
61
20
82
22
33
31
23
83
85
95
85
90
24
<5
93
91
40
CuCl (10)
CuOAc (10)
Cu(MeCN)4PF6 (10)
Fe(ClO4)3 (10)
Fe(OTf)2 (10)
Mg(OTf)2 (10)
Yb(OTf)3 (10)
4a (10)
4b (10)
5a (10)
5b (10)
6 (10)
7 (10)
8a (10)
8b (10)
9 (10)
10 (10)
11a (10)
11b (10)
12 (10)
Scheme 2. Reported auto-oxidation reaction of glycine de-
rivatives with styrenes.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35[c]
However, under these autoxidation conditions, the
dehydrogenative Povarov/aromatization tandem reac-
tion of glycine derivatives with alkenes was limited to
only highly electron-rich alkenes. The reaction of gly-
cine ester 1a and styrene 2a produced only 35% of
the desired product 3a, with 40% of undesired sub-
strate oxidation. The same group also reported that
the transformation can be promoted by CBr4 under
an air atmosphere.[8e] Recently, Liu and co-workers
also reported a copper(II) triflate-catalyzed aerobic
oxidative C–H functionalization of glycine derivatives
with olefins.[8i] Quinoline derivatives, arising from
these tandem reactions, are very important motifs in
a wide array of compounds with activities of rele-
vance to biology or medicinal chemistry.[9] Therefore,
there is a continued strong demand for efficient and
selective syntheses of these heterocycles. As part of
our on-going research interest.[4b,f] herein we report
the achievement of the above goal and demonstrate
that a gold complex can be used as the catalyst for
the oxidative dehydrogenative reaction of glycine de-
rivatives under aerobic conditions.
AuCl3 (10)
PPh3AuCl (10)
(PhO)3PAuCl (10)
(t-BuC6H4O)3PAuCl (10) CH3CN 12
JohnPhosAuCl (10)
JohnPhosAuMe (10)
AuCl (10)
8b (10)
8b (10)
8b (10)
8b (10)
8b (5)
8b (5)
CH3CN 12
CH3CN 12
CH3CN 12
EA
3
3
3
3
3
3
3
3
3
3
xylene
EtOH
DCE
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
36[d] 8b (5)
37[e]
38[f]
39[g]
8b (5)
8b (5)
8b (5)
Results and Discussion
[a]
Reaction conditions: 1a (0.5 mmol), 2a (2 equiv), solvent
(2.0 mL), 1.0 atm of O2, 608C.
Isolated yields.
The reaction was performed under an argon atmosphere
(1.0 atm).
1 equiv H2O2 (30% aqueous) was used as oxidant.
1 equiv. TBHP (5.0–6.0M in decane) was used instead of
O2.
At first, glycine ester 1a and styrene 2a were chosen
as the model substrates, and the reaction optimization
results are summarized in Table 1. A variety of differ-
ent metal salts (10 mol%) were explored to improve
the reaction efficiency under 1 atm of O2 at 608C
(Table 1, entries 3–9). While several additives includ-
ing CuCl, CuOAc, Fe(ClO4)3 and Fe(OTf)2 proved to
be slightly beneficial to improve the efficiency, other
salts like Cu(MeCN)4PF6, Mg(OTf)2 and Yb(OTf)3 in-
[b]
[c]
[d]
[e]
[f]
1 equiv. DTBP was used instead of O2.
1 equiv. BPO was used instead of O2.
[g]
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hibited the reaction. Gold complexes 4a and 4b, lar yields to O2 were obtained with TBHP and DTBP
which were reported as effective catalyst for the oxi- as oxidants. When BPO was tested, the yield of 3a
dation coupling of N-arylisoquinolines,[4] were exam- dropped to 40% (Table 1, entries 36–39). Consequent-
ined in the reaction of 1a and 2a. To our delight, the ly, the optimal reaction conditions include as catalyst
product 3a was, respectively produced in 61% and 5 mol% 8b at 608C in 1 atm of O2.
70% yields in CH3CN, and no self-oxidation side
With the optimal reaction conditions in hand, the
product was observed (Table 1, entries 10 and 11). scope of the coupling reaction of glycine derivatives
Encouraged by this result, the reaction conditions 1 and alkenes 2 was examined (Table 2 and Table 3).
were investigated further in detail. Among the Various glycine esters and glycine amides were
Au(III) catalysts screened (Figure 1), gold-oxazoline smoothly transformed into the desired products. The
complex 8b showed the best catalytic activity effect of the substitution of the aniline was also inves-
tigated. A wide range of electronically varied anilines
1 with different substituents at the para position were
compatible with the oxidation system, providing the
desired quinolines in good yields. No product was
found when o-tolyl glycine ester (1i) and m-tolyl gly-
cine ester (1j) were tested to react with styrene (2a)
under the optimal condition. These results indicated
the importance of the para-substitution at the aryl
moiety. Meanwhile, the scope of this gold-catalyzed
CDC reaction was further expanded to a range of
substituted alkenes. Reactions with different alkenes
including electron-withdrawing and electron-donating
groups generally provided the corresponding quino-
lines in high yields. Alkynes can also serve as dieno-
philes to participate in this reaction, but yields were
lower. When indene was used in this reaction, a com-
plex polycyclic quinoline was obtained.
To gain an insight of the gold-catalyzed oxidative
dehydrogenative Povarov/aromatization tandem reac-
tion of glycine derivatives with alkenes, some control
experiments were carried out to elucidate the mecha-
nism (Scheme 3). Firstly, the reaction of 1a in the ab-
sence of styrene 2 under the standard reaction condi-
tions was investigated (Scheme 3a). Imine 13a and its
dimer 14a were obtained in a low yield. The result in-
Figure 1. Gold complexes 4–12 screened.
dicates that the imine would be an important inter-
mediate in the gold-catalyzed process. Gold catalysis
might not be absolutely necessary for formation of
the imine (Scheme 3a).[10] Secondly, we found that the
(Table 1, entries 12–23). The utilization of Au(I) gold catalyst also played a vital role for a successful
(AuCl, PPh3AuCl, (t-BuC6H4O)3PAuCl, JohnPhos- cyclization of imine 13a and styrene 2a (Scheme 3b).
A
uCl, JohnPhosAuMe) resulted in the formation of Interestingly, O2 was indispensable for the synthesis
the product with low yields except for (PhO)3PAuCl of 3a as shown in Scheme 3b.
(Table 1, entries 24–29). Among the solvents exam-
Based on the control experiments, some conclu-
ined, EtOH was the most effective (Table 1, en- sions could be drawn: (i) imine 13 might be the inter-
tries 30–34), DCE was not crucial for the reaction mediate in the reaction; (ii) gold catalysis 8b might be
yield as reported in auto-oxidation reactions.[8d] Fur- not absolutely necessary for the formation of imine;
ther studies indicated that reducing the catalyst load- (iii) O2 is indispensable for the synthesis of 3a, not
ing of 8b to 5% had little impact at the reaction out- only in the imine formation stage, but also in the nu-
come (Table 1, entry 34). A control experiment dem- cleophilic addition and aromatization; (iv) the role of
onstrated that when the aerobic oxidative reaction gold for activation of the imine is very likely. Accord-
was carried in an argon atmosphere instead of O2, ing to present results and relevant literature,[4,8,13]
a much lower yield was observed (Table 1, entry 35). a possible mechanism was proposed as shown in
In order to explore the role of O2, other oxidants Scheme 4. Firstly, under the O2 atmosphere, the gly-
were tested including H2O2, TBHP, DTBP, BPO. Tar- cine ester 1a was first auto-oxidized to give the hydro-
[11,8d]
geted 3a was not obtained with H2O2 as oxidant. Simi- peroxide intermediate 17
and imine 13. In the
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Table 2. Gold-oxazoline complex catalyzed O2 oxidative Povarov/aromatization reaction of glycine esters with alkenes.[a]
[a]
Reaction conditions: glycine ester (0.5 mmol), alkene (2 equiv.), 5 mol% 8b, alcohol (2.0 mL), 1.0 atm of O2, 608C.
Isolated yields.
Alkynes were used as dienophiles.
[b]
[c]
second part, electron-rich styrene 2a attacked the presence of O2 as the oxidant and features a broad
gold(III)-activated imine intermediate 18, tetrahydro- substrate scope. This work also represents a new ap-
quinoline 16[12] was formed and further oxidized and plication of the gold complex.
aromatized to afford quinoline 3a.
Experimental Section
Conclusions
General Procedure for the O2 Oxidative Povarov/
Aromatization Tandem Reaction of Glycine
Derivatives with Alkenes
In summary, a gold-oxazoline complex-catalyzed de-
hydrogenative Povarov/oxidation tandem reaction for
the synthesis of decorated quinolines has been devel-
oped from glycine derivatives and alkenes. The reac-
tion performs under mild reaction conditions in the added glycine derivative (1) (0.5 mmol), alkene (2)
To a 10-mL vial equipped with an oxygen balloon was
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Table 3. Gold-oxazoline complex-catalyzed O2 oxidative Povarov/aromatization reaction of glycine amides with alkenes.[a]
[a]
Reaction conditions: glycine amide (0.5 mmol), alkene (2 equiv.), 5 mol% 8b, alcohol (2.0 mL), 1.0 atm of O2, 608C.
Isolated yields.
Alkynes were used as dienophiles.
[b]
[c]
(2 equiv.), gold catalyst 8b (5 mol%), and alcohol (2 mL).
Acknowledgements
The mixture was stirred for 3–6 hours at 608C. After the re-
action was completed as indicated via TLC analysis, the re-
action mixture was poured into water and extracted with
EtOAc. The organic layer was separated and the solvent
We thank for the National Natural Science Foundation of
China (No. 21302067), the National Natural Science Founda-
tion of Jiangsu Province (No. BK20130120) and National
Undergraduate Training Programs for Innovation and Entre-
preneurship (201510295049) for financial support.
was evaporated under vacuum. The residue was purified via
column chromatography over silica gel eluting with EtOAc/
PE to give the desired coupling product 3a–3ar.
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Scheme 3. Control experiments.
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Scheme 4. Possible mechanism.
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FULL PAPERS
asc.wiley-vch.de
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an N2 atmosphere, self-cyclization of imine had priority.
However, under the O2 atmosphere, the nucleophilic
addition of gold-activated imine and styrene occurred
exclusively.
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[13] See the Supporting Information: 2 equiv. TEMPO were
added in the reaction of 1a and 2a, no product was ob-
tained and inhibition was also observed in the reaction
of 13 and 2a. The results of TEMPO addition suggest
that the present reaction might include a radical pro-
cess. Oxygen was used as the oxidation reagent in the
reaction. In order to explain the TEMPO effect on the
control experiment, we refer to some other oxygen-oxi-
dative reactions such as that in: Angew. Chem. Int. Ed.
2014, 53, 13544. In this reference, auto-oxidative cou-
pling of glycine derivatives was realized with O2.
TEMPO was added and the experiment was inhibited.
The reason of the inhibition was that TEMPO restrain-
ed the formation of hyperoxide radical anion of glycine
derivative oxidized by O2. In the supporting informa-
tion, we also found the characteristic peak of hyperox-
ide in LC-MS. So in our reaction, a similar inhibition
might also happen when TEMPO was added.
[10] See the Supporting Information: 1a was treated for the
same reaction time under the optimized conditions
except for the gold catalysis 8b. Only 1a was found
through TLC (254 nm) analysis after reaction for 3
hours. However, the characteristic peak of 13 could be
found in LC-MS. This implies that gold catalysis may
be not absolutely necessary for the formation of the
imine intermediate.
[11] See the Supporting Information: the characteristic
peak of glycine ester hyperoxide 17 (M=226) was
found in LC-MS.
[12] See the Supporting Information: imine 13 and styrene
2a were catalyted by gold catalyst 8b under an N2 at-
mosphere. The in situ LC-MS analysis of the resulting
mixture was conducted 3 hours later with gradient elu-
tion. 15 (M=382) and 16 (M=295, 330 nm in UV)
were found in LC-MS. These results imply that under
Adv. Synth. Catal. 0000, 000, 0 – 0
8
ꢂ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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These are not the final page numbers!

FULL PAPERS
Gold-Oxazoline Complex-Catalyzed Cross-Dehydrogenative
Coupling of Glycine Derivatives and Alkenes
9
Adv. Synth. Catal. 2017, 359, 1 – 9
Minjie Ni, Yan Zhang,* Tingting Gong, Bainian Feng*
Adv. Synth. Catal. 0000, 000, 0 – 0
9
ꢂ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÞÞ
These are not the final page numbers!