Functionalization of N-arylglycine esters: Electrocatalytic access to C-C bonds mediated by n-Bu4NI

Article abstract of DOI:10.3762/bjoc.14.35

An efficient electrocatalytic functionalization of N-arylglycine esters is reported. The protocol proceeds in an undivided cell under constant current conditions employing the simple, cheap and readily available n-Bu₄NI as the mediator. In addition, it is demonstrated that the mediated process is superior to the direct electrochemical functionalization.

Full text of DOI:10.3762/bjoc.14.35

Functionalization of N-arylglycine esters: electrocatalytic
access to C–C bonds mediated by n-Bu4NI
Mi-Hai Luo1, Yang-Ye Jiang1, Kun Xu1, Yong-Guo Liu2, Bao-Guo Sun2
and Cheng-Chu Zeng*1
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2018, 14, 499–505.
1Beijing Key Laboratory of Environmental and Viral Oncology, College
of Life Science & Bioengineering, Beijing University of Technology,
Beijing 100124, China and 2Beijing Key Laboratory of Flavor
Chemistry, Beijing Technology and Business University, Beijing
100048, China
doi:10.3762/bjoc.14.35
Received: 17 November 2017
Accepted: 13 February 2018
Published: 22 February 2018
Email:
This article is part of the Thematic Series "Electrosynthesis II".
Guest Editor: S. R. Waldvogel
Cheng-Chu Zeng* - zengcc@bjut.edu.cn
* Corresponding author
© 2018 Luo et al.; licensee Beilstein-Institut.
License and terms: see end of document.
Keywords:
C–C formation; electrochemical oxidative functionalization; n-Bu4NI;
redox catalyst
Abstract
An efficient electrocatalytic functionalization of N-arylglycine esters is reported. The protocol proceeds in an undivided cell under
constant current conditions employing the simple, cheap and readily available n-Bu4NI as the mediator. In addition, it is demon-
strated that the mediated process is superior to the direct electrochemical functionalization.
Introduction
The oxidative cross dehydrogenative coupling (CDC) of two amino acids has always been paid much attention in industrial
C–H bonds has emerged as an versatile and powerful strategy and academic setting and many advances have been made [12-
for forming new C–C bonds in organic chemistry due to its step 17]. Li et al. first reported the functionalization of glycine deriv-
and atom economic characteristic as well as avoiding the atives with malonates using a stoichiometric quantity of
prefunctionalization of substrates [1-5]. Most of the CDC reac- Cu(OAc)2 as catalyst and oxidant [12]. Later on, arylation,
tions occur between the benzylic C–H bonds and α-C–H bonds vinylation and alkynylation of glycine derivatives were also
adjacent to a heteroatom (N or O) [6-10]. However, the oxida- accomplished by the same group (Scheme 1) [13]. Using the
tive C–C formation of secondary amines, especially amino Cu(OAc)2/pyrrolidine dual catalysts system, Huang developed
acids has been more important for studying properties and func- the oxidative cross coupling of glycine derivatives with acetone
tions of natural and non-natural amino acids [11]. Conse- in the presence of TBHP or DDQ as terminal oxidants [14]. The
quently, efficient and selective construction of C–C bonds of protocol was also extended to reactions with 2-alkylquinoline
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Beilstein J. Org. Chem. 2018, 14, 499–505.
Scheme 1: Cross dehydrogenative coupling of N-arylglycine esters with C–H nucleophiles.
[15] and phenols [16] using O2 and di-tert-butyl peroxide vided cell under constant current electrolysis. It was observed
(DTBP) as oxidant, respectively (Scheme 1). A CuCl-catalyzed that n-Bu4NI promotes the reaction dramatically and higher
oxidative cross coupling of glycine derivatives with indoles has yields of α-functionalized products were afforded compared
been developed by Hou et al., wherein simple copper salts were with the direct electrolysis.
used as catalysts and oxygen as the co-oxidant (Scheme 1) [17].
Results and Discussion
Alternatively, photocatalytic versions of CDC reactions of Initially, N-arylglycine ester 1a and C–H nucleophile 1,3,5-
glycine derivatives with C-nucleophiles were also developed trimethoxybenzene (2a) were chosen as model compounds to
[18,19]. For example, combining the visible light catalyst optimize the electrolytic conditions. As shown in Table 1, when
Ru(bpy)3Cl2, and the transition metal catalyst Cu(OTf)2, Wu constant current electrolysis (CCE) of 1a and 2a was per-
and co-workers achieved aerobic oxidative coupling of second- formed in an undivided cell equipped with 0.1 M LiClO4 in
ary amines with β-keto esters to form C(sp3)–C(sp3) bonds CH3CN in the presence of AcOH using two graphite plates as
(Scheme 1) [18].
anode and cathode, the desired product 3aa was isolated in 27%
yield (Table 1, entry 1). Replacing CH3CN by other solvents,
Although much advance has been made for the functionaliza- such as methanol, ethanol or CH2Cl2 failed to improve the reac-
tion of glycine derivatives, most of these strategies mentioned tion efficiency and only trace amounts of 3aa were detected
above require stoichiometric or excess amounts of chemical (Table 1, entries 2–4). Further solvent screening disclosed that a
oxidants and transition metal (photo)catalysts. The utilization of 1:2 ratio of CH3CN and CH2Cl2 was better, giving 3aa in 66%
stoichiometric or excess amounts of chemical oxidants results in yield (Table 1, entries 5 and 6). Exploring the influence of cur-
producing waste, which is not atomic economically and envi- rent density on the CDC reaction indicated that 3 mA/cm2 was
ronmentally benign. In addition, over-oxidation of products suitable; lower or higher current density led to a slightly lower
likely occurs in the presence of excess amounts of oxidant. On yields of 3aa (entry 5, vs entries 7 and 8). It was observed that
the other hand, the toxicity of residual traces of transition metal the additive plays an important role. Among several additives
(photo)catalyst in products is also highly concerned. Conse- examined, AcOH was proved to be the best, although TFA also
quently, metal-free and environmentally friendly oxidative C–C gave comparable yields of 3aa (Table 1, entries 5 and 11–13),
bond formation is highly desired.
whereas, it gave only 38% yield of 3aa when the reaction was
carried out in the absence of AcOH (Table 1, entry 9). Investi-
Electrochemistry has proved to be an environmentally benign gation of the anode proved that graphite was superior to Pt and
method to achieve the formation of a new chemical bond and a DSA (Dimensionally Stable Anode, Table 1, entries 14 and 15).
functional group conversion by using electrons as redox reagent Finally, to further improve the reaction efficiency, several
rather than terminal chemicals [20-27]. In this context, we have halide-containing mediators as redox catalyst were evaluated.
applied simple halide ions as redox catalysts to achieve electro- To our delight, when n-Bu4NI was utilized as a redox catalyst,
chemical C–H bond functionalization, leading to the formation the yield of 3aa increased to 81% (Table 1, entries 16–19).
of new C–C, C–N, C–O and C–S bonds [28-31]. Herein, we
report the electrochemical α-C–H functionalization of N-aryl- On the basis of the screening of reaction conditions, we could
glycine esters with C–H nucleophiles using n-Bu4NI as redox conclude that the electrocatalytic oxidative coupling should be
catalyst (Scheme 1). The chemistry was performed in an undi- performed in a mixed solution of CH3CN and CH2Cl2
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Beilstein J. Org. Chem. 2018, 14, 499–505.
Table 1: Optimization of reaction conditionsa.
entry
solvent
mediator (equiv)
J (mA/cm2)
additive (equiv)
cathode/anode
yield (%)b
1
CH3CN
–c
3
3
3
3
3
3
1
5
3
3
3
3
3
3
3
3
3
3
3
AcOH (0.5)
AcOH (0.5)
AcOH (0.5)
AcOH(0.5)
AcOH (0.5)
AcOH (0.5)
AcOH (0.5)
AcOH (0.5)
AcOH (0.0)
AcOH (1.0)
TFA (0.5)
C/C
C/C
C/C
C/C
C/C
C/C
C/C
C/C
C/C
C/C
C/C
C/C
C/C
C/Pt
C/DSA
C/C
C/C
C/C
C/C
27
2
MeOH
–c
trace
trace
trace
66
3
EtOH
–c
4d
5
CH2Cl2
–c
CH3CN/CH2Cl2 (1:2)
CH3CN/CH2Cl2 (2:1)
CH3CN/CH2Cl2 (1:2)
CH3CN/CH2Cl2(1:2)
CH3CN/CH2Cl2 (1:2)
CH3CN/CH2Cl2 (1:2)
CH3CN/CH2Cl2 (1:2)
CH3CN/CH2Cl2 (1:2)
CH3CN/CH2Cl2 (1:2)
CH3CN/CH2Cl2 (1:2)
CH3CN/CH2Cl2 (1:2)
CH3CN/CH2Cl2 (1:2)
CH3CN/CH2Cl2 (1:2)
CH3CN/CH2Cl2 (1:2)
CH3CN/CH2Cl2 (1:2)
–c
6
–c
56
7
–c
47
8
–c
50
9
–c
38
10
11
12
13
14
15
16
17
18
19
–c
56
–c
60
–c
H2SO4 (0.5)
Na2CO3 (0.5)
AcOH (0.5)
AcOH (0.5)
AcOH (0.5)
AcOH (0.5)
AcOH (0.5)
AcOH (0.5)
13
–c
40
–c
48
–c
41
n-Bu4NI (0.3)
n-Bu4NBr (0.3)
NH4I (0.3)
NH4Br (0.3)
81
48
54
20
aConditions: 1a (1.0 mmol), 2a (1.2 mmol) in 15 mL solution, LiClO4 (0.1 M), room temperature, electrode C represents graphite plate. bIsolated yield.
cWithout mediator. dn-Bu4NBF4 was used as supporting electrolyte.
(v/v = 1:2), in the presence of n-Bu4NI (30 mol %) as the medi- 3ga and 3ha were afforded in 36% and 27% yields, respective-
ator, AcOH (50 mol %) as the additive and using graphite plate ly. However, 3ga and 3ha were isolated in 14% and 11% yields,
as electrodes under constant current at 3 mA/cm2. With the op- respectively, under the direct electrolytic conditions. In the
timized conditions in hand, we then investigated the scope of cases of N-arylglycine methyl ester 1i and N-arylglycine benzyl
N-arylglycine esters in the reaction with 2a. As a comparison, ester 1j, the electrocatalytic functionalization afforded excel-
direct electrochemical coupling of N-arylglycine esters with 2a lent yields of 3ia (76%) and 3ja (84%), whereas, less effi-
was also performed. As shown in Scheme 2, substituents in- ciency (40–43% yields) was observed without the assistance of
cluding either electron-donating groups (such as methyl and n-Bu4NI.
methoxy) or electron-withdrawing groups (Cl, Br and CF3) in
Next, the reactivity of different C–H nucleophiles was also in-
vestigated. As shown in Scheme 3, β-keto ester and malonates
worked well to afford the desired products 3ab–3ad in moder-
ate yields. In addition, naphthanols were also compatible in this
transformation, giving the corresponding products 3ae–3ag in
good yields. Notably, when styrene and 1-ethynylbenzene were
subjected to reaction with 1a under the standard indirect elec-
trolytic conditions, quinoline-2-carboxylate 3ah was isolated in
64% and 58% yield, respectively. Substituted styrenes and
1-ethynylbenzene were also tolerated well, giving correspond-
ing products 3ai–3aj in 45–50% yields. The formations of
the 4-position of the aryl group were tolerated and gave moder-
ate to good yields of 3ba–3ea (61–69% yields), whereas, only
47–58% yields of the desired 3ba–3ea were isolated under the
direct electrolytic conditions. However, 3fa was afforded in
39% and 12% yields, respectively, when the electrochemical
reaction was performed in the presence or absence of n-Bu4NI
as the redox catalyst. The reason for the low yield of 3fa is not
clear yet. Steric factors seem to play an important role in the
electrochemical CDC reaction of N-arylglycine esters with 2a.
When the methyl group was situated at 2- or 3-position of the
aniline, instead of in the 4-position, the corresponding products
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Beilstein J. Org. Chem. 2018, 14, 499–505.
Scheme 2: Electrochemical CDC reaction of 2a and various N-arylglycine esters. Reaction conditions for the indirect electrolysis: 1 (0.5 mmol),
2a (0.6 mmol), n-Bu4NI (30 mol %), 0.1 M LiClO4/CH3CN (5 mL) and CH2Cl2 (10 mL), AcOH (50 mol %), current density (3 mA/cm2), graphite anode
and cathode, at room temperature; reaction conditions for direct electrolysis: 1 (0.5 mmol), 2a (0.6 mmol), 0.1 M LiClO4/CH3CN (5 mL) and CH2Cl2
(10 mL), AcOH (50 mol %), current density (3 mA/cm2), graphite anode and cathode, at room temperature; yields in parenthesis obtained from direct
electrolysis.
3ah–3aj likely derives from an azo-Diels–Alder reaction of which was detected by TLC and GC–MS. Moreover, when
styrene or ethynylbenzene with an imine intermediate, in situ separated synthesized 5 was subjected to react with 2a, the
generated from anodic oxidation of 1a, followed by additional corresponding product 3aa was isolated in 89% yield. These
oxidation [32-36].
control experiments indicate that 5 is a possible reaction inter-
mediate.
To prove the practicability of the protocol, a scaled-up reaction
was also carried out. As illustrated in Scheme 4, when 6 mmol Based on these control experiments described above, as well as
of ethyl p-tolylglycinate (1a) was allowed to react with 1,3,5- related references [4], a plausible mechanism for the electrocat-
trimethoxybenzene (2a) under the standard conditions, adduct alytic cross dehydrogenative coupling of N-arylglycine esters 1
3aa was isolated in a 75% yield, without obvious losing of with C–H nucleophiles 2 is outlined in Scheme 6. The anodic
yield.
oxidation of iodide generates the active species I2 or I+. Fol-
lowed by a homogeneous reaction with N-arylglycine esters,
To better understand the reaction mechanism, control experi- N-iodo intermediate 4 was generated. Eliminating a molecule of
ments were performed. As shown in Scheme 5, the anodic HI affords imine intermediate 5. In the presence of acetic acid,
oxidation of 1a in the absence of a C–H nucleophile under the protonated 5-H+ undergoes nucleophilic addition with C–H
the standard conditions gives imine intermediate product 5, nucleophiles 2 to give the desired products 3.
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Beilstein J. Org. Chem. 2018, 14, 499–505.
Scheme 3: Scope of 2 using n-Bu4NI as mediator. Reaction conditions:1a (0.5 mmol), 2 (0.6 mmol), n-Bu4NI (30 mol %), 0.1 M LiClO4/CH3CN (5 mL)
and CH2Cl2 (10 mL), AcOH (50 mol %), current density (3 mA/cm2), graphite anode and cathode. Isolated yields are given.
Scheme 4: Scaling up.
Conclusion
for the formation of new C–C bonds is still on the way in our
In summary, an efficient electrocatalytic cross dehydrogenative group.
coupling of arylglycine esters with C–H nucleophiles has been
Experimental
developed. This protocol employs simple n-Bu4NI as the redox
catalyst, avoiding utilization of transition metals and excess Instruments and reagents
amounts of external oxidant, thereby providing an environmen- All melting points were measured with an electrothermal
tally benign method to the CDC reaction. In addition, it was ob- melting point apparatus and are uncorrected. NMR spectra were
served that the electrocatalytic process is superior to the direct recorded using a 400 MHz or 300 MHz spectrometer (400 MHz
electrolysis. Further application of this electrochemical protocol 1H frequency, 100 MHz 13C frequency; 300 MHz 1H frequen-
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Beilstein J. Org. Chem. 2018, 14, 499–505.
Scheme 5: Control experiments.
Scheme 6: A plausible mechanism for the electrocatalytic cross dehydrogenative coupling of N-arylglycine esters with C-nucleophiles.
cy, 75 MHz 13C frequency). Chemical shifts are given as pressure. The residue was poured into a saturated aqueous solu-
δ values (internal standard: TMS). Coupling constants are re- tion of Na2S2O3 and the product was then extracted with DCM
ported in Hz. All starting materials and solvents were obtained (3 × 20 mL), dried over Na2SO4, and concentrated in vacuo.
from commercial sources and used without further purification. The residue was purified by column chromatography on silica
Products were purified by chromatography on silica gel (petro- gel using a mixture of petroleum ether/EtOAc (v/v = 3:1) as
leum ether/EtOAc).
eluent to afford the desired pure product.
Typical procedure for the electrocatalytic cross
Typical procedure for the direct electrochemical
dehydrogenative coupling of N-arylglycine ester and cross dehydrogenative coupling of N-arylglycine
C–H nucleophiles ester and C–H nucleophiles
An undivided cell was equipped with a carbon anode The procedure was identical to that of electrocatalytic synthesis,
(2 × 2 cm2) and a carbon cathode (2 × 2 cm2) and connected to but without the addition of n-Bu4NI as the mediator.
a DC regulated power supply. To the cell was added N-aryl-
glycine ester (0.5 mmol), C–H nucleophiles (0.6 mmol),
Supporting Information
n-Bu4NI (0.15 mmol) and 5 mL of 0.1 M LiClO4/CH3CN and
10 mL CH2Cl2. The mixture was electrolyzed using constant
Supporting Information File 1
current conditions (≈3 mA/cm2) at room temperature under
magnetic stirring. When TLC analysis indicated that the elec-
trolysis was complete (witnessed by the disappearance of the
N-arylglycine ester), the solvent was removed under reduced
General procedure and analytical data.
[https://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-14-35-S1.pdf]
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Beilstein J. Org. Chem. 2018, 14, 499–505.
23.Yang, Q.-L.; Li, Y.-Q.; Ma, C.; Fang, P.; Zhang, X.-J.; Mei, T.-S.
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Acknowledgements
This work was supported by grants from the National Natural
Science Foundation of China (No. 21472011, 21272021)
and the National Key Technology R&D Program
(2017YFB0307502, 2011BAD23B01). ZCC also thank finan-
cial support from the Open Project Program of Beijing Key
Laboratory of Flavor Chemistry, Beijing Technology and Busi-
ness University (BTBU).
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ORCID® iDs
Kun Xu - https://orcid.org/0000-0002-0419-8822
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