Electrochemical dehydrogenative cyclization of 1,3-dicarbonyl compounds

Article abstract of DOI:10.1039/c8cc02472c

The intramolecular C(sp³)-H/C(sp²)-H cross-coupling of 1,3-dicarbonyl compounds has been achieved through Cp₂Fe-catalyzed electrochemical oxidation. The key to the success of these dehydrogenative cyclization reactions is

Full text of DOI:10.1039/c8cc02472c

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Electrochemical dehydrogenative cyclization of
1,3-dicarbonyl compounds†
Cite this:DOI: 10.1039/c8cc02472c
Zheng-Jian Wu,‡ Shi-Rui Li,‡ Hao Long and Hai-Chao Xu
*
Received 27th March 2018,
Accepted 12th April 2018
DOI: 10.1039/c8cc02472c
rsc.li/chemcomm
The intramolecular C(sp3)–H/C(sp2)–H cross-coupling of 1,3-dicarbonyl
compounds has been achieved through Cp2Fe-catalyzed electro-
chemical oxidation. The key to the success of these dehydrogenative
cyclization reactions is the selective activation of the acidic a-C–H
bond of the 1,3-dicarbonyl moiety to generate a carbon-centered
radical.
Carbon-centered radicals derived from 1,3-dicarbonyl compounds
are useful synthetic intermediates and have been applied for synth-
esis of several natural products and bioactive compounds.1 These
electrophilic C-centered radicals can be generated through the
oxidative cleavage of the acidic a-C–H bond of the 1,3-dicarbonyl
compounds using stoichiometric metal or organic oxidants2 or
via transition-metal catalyzed aerobic oxidation (Scheme 1a).3
Alternatively, they can be accessed from a-brominated precursors
via reductive cleavage of the C–Br bond (Scheme 1a).4 The
intramolecular cyclization reactions of these C-centered radicals
with arenes have been employed for the synthesis of various cyclic
Scheme 1 Generation and cyclization of C-radicals from 1,3-dicarbonyl
compounds.
Our investigation was started by optimizing the electrolysis
structures including oxindoles and 3,4-dihydro-1H-quinolin-2- conditions for the cyclization of a-methyl-substituted malonate
ones.3,5
amide 1. Our previously established conditions for the cyclization
To reduce the use of chemical oxidants in the oxidative radical of a-fluoromalonate amides were not effective in promoting
chemistry of active methylene compounds, electrochemical recycling the reaction of 1 probably because of the reduced acidity of 1
of Mn(OAc)3 in a divided cell has been investigated.6 We have been compared with its fluoro analogue. After some screening of
involved in the development of electrochemical methods7 for the the reaction parameters, the optimal electrolysis conditions
generation of synthetically useful organic radical intermediates were determined to utilize THF/MeOH (2 : 1) under reflux
from R–H (R = C or heteroatom) precursors8 and recently in the presence of 10 mol% of Cp2Fe,9 10 mol% of Y(OTf)3,
reported radical-mediated dehydrogenative cyclization reactions and 50 mol% of LiOMe (Table 1). The electrolysis employed a
of a-fluoromalonate amides for the synthesis of 3-fluorooxindoles.8a constant current of 7.5 mA and an undivided cell (a three-necked
Herein we report the electrochemical generation of C-centered round bottomed flask) equipped with a reticulated vitreous
radicals from a-alkyl substituted 1,3-dicarbonyl compounds and carbon (RVC) anode and a platinum plate cathode. Under these
their cyclization reactions with arenes (Scheme 1b).
reaction conditions, the desired oxindole product 2 was isolated
in 85% yield after the consumption of 2.5 F molꢀ1 of charge
(entry 1). The reaction could be scaled up to decagram scale
without reduction in the yield (entry 2). A dramatic decrease
in yield was observed when the reaction was carried out at RT
(entry 3) or in the absence of Cp2Fe (entry 4) or Y(OTf)3 (entry 5).
The use of LiOMe as the base was critical for the success of the
reaction as the use of weaker bases such as Cs2CO3 (entry 6),
State Key Laboratory of Physical Chemistry of Solid Surfaces, Key Laboratory of
Chemical Biology of Fujian Province, Innovative Collaboration Center of Chemistry
for Energy Materials, and College of Chemistry and Chemical Engineering,
Xiamen University, Xiamen 361005, P. R. China. E-mail: haichao.xu@xmu.edu.cn
† Electronic supplementary information (ESI) available. See DOI: 10.1039/
c8cc02472c
‡ These authors contributed equally to this work.
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Table 1 Optimization of reaction conditionsa
Entry
Deviation from the standard conditions
Yieldb [%]
1
2
3
4
None
Decagram scale
Reaction at RT
No Cp2Fe
85c
84 (8.47 g)c
33 (38)
5 (48)
5
6
7
8
No Y(OTf)3
26 (47)
23 (70)
0 (95)
15 (46)
0 (82)
45 (12)
63 (18)
42 (28)
66 (12)
75 (14)
65 (7)
Replacing LiOMe with Cs2CO3
Replacing LiOMe with Na2CO3
Replacing LiOMe with K3PO4
Replacing LiOMe with K2HPO4
Replacing Y(OTf)3 with Zn(OTf)2
Replacing Y(OTf)3 with Sc(OTf)3
Replacing Y(OTf)3 with Sm(OTf)3
Replacing Y(OTf)3 with ln(OTf)3
Replacing Y(OTf)3 with Yb(OTf)3
Replacing Y(OTf)3 with La(OTf)3
9
10
11
12
13
14
15
a
Undivided cell, RVC anode (100 PPI, 1 cm ꢁ 1 cm ꢁ 1.2 cm), Pt plate
cathode (1 cm ꢁ 1 cm), constant current = 7.5 mA, 1 (0.3 mmol), solvent
(6 mL), argon, 2.8 h (2.5 F molꢀ1). Determined by 1H NMR analysis
b
using 1,3,5-trimethoxybenzene as the internal standard. Recovered 1 is
c
given in brackets. Isolated yield.
K2CO3 (entry 7), K3PO4 (entry 8), or K2HPO4 (entry 9) led to either
low yield or no product at all. In addition, other metal triflates such
as Zn(OTf)2 (entry 10), Sc(OTf)3 (entry 11), Sm(OTf)3 (entry 12),
In(OTf)3 (entry 13), Yb(OTf)3 (entry 14) or La(OTf)3 (entry 15) were
less effective in promoting the product formation than Y(OTf)3.
The substrate scope for the synthesis of oxindoles was then
explored (Scheme 2). First, the N-phenyl ring could be substituted
at the para-position with electron donating OMe (3), halogens
such as F (4), Cl (5), and Br (6), and electron-withdrawing
substituents such as CF3 (7), OCF3 (8), and CO2Me (9), but not
Scheme 2 Scope of oxindole synthesis. Reaction conditions: undivided
cell, substrate (0.3 mmol), THF (4 mL), MeOH (2 mL), argon, constant
current = 7.5 mA, 2.8–3 h. a Yield of isolated product. b Methyl tert-butyl
ether/MeOH (2 : 1) were used as solvent. PMP = para-methoxyphenyl.
the highly electron-accepting CN (10) or NO2 (11). The decreased electronic properties (28–34). Introduction of a meta-bromo
reaction efficiency for the electron-deficient substrates was group led to the formation of two regioisomers (35 and 350).
probably caused by the difficulty in cyclizing the electrophilic The 3-aminopyridine derived substrate cyclized regioselectively
C-radical onto the N-phenyl ring. An alkynyl group at the para- at the ortho position of the pyridyl nitrogen atom to give 36. tert-
position was tolerated (12). The reaction was also compatible Butyl ester (37) and b-keto ester (38) were also suitable for the
with substitution at the ortho position of the N-phenyl ring with cyclization reaction. Substitution at the a-position of the amide
OMe (13) or a fused ring (14–16). The a-methyl group in the with a methyl group did not affect the electrolysis reaction (39).
substrate could be replaced by functionalized alkyl chains Lastly, the electrochemical conditions could also be employed to
bearing alkenyl (17, 18), alkynyl (19) or phenyl (20) groups. promote the intramolecular dehydrogenative cross-coupling of a
The N-substituent also tolerated variation and was compatible malonic ester with a pyrrole ring to form the 2,3-dihydro-1H-
with nPr (21), Bn (22), allyl (23), and aryl (24, 25) groups. While pyrrolizine 40, which could be converted to the drug ketorolac
the tert-butyl ester (26) cyclized efficiently, the bisamide failed through saponification followed by decarboxylation.1e
to afford the expected product 27 probably because of its
reduced acidity.
Based on the studies in this work and previous investigations by
us8a and others,10 a possible mechanism for the electrochemical
Further investigations revealed that the electrochemical reaction dehydrogenative cyclization reactions was proposed using
could also be employed for the synthesis of the 3,4-dihydro-1H- malonate amide 1 as the substrate (Scheme 4). When electricity
quinolin-2-ones (Scheme 3). The a-alkyl malonic esters are more is passed through the cell, Cp2Fe gets oxidized at the anode to
acidic than the malonate amides and the former cyclized efficiently give Cp2Fe+. Meanwhile, methoxide is generated at the cathode
in the presence of 5 mol% of Cp2Fe and 30 mol% of Na2CO3 through reduction of methanol solvent. The base methoxide
without the need for a Lewis acid or a strong base. Once again, the deprotonates the malonate amide 1 to give its conjugate
N-phenyl ring could accommodate para-substituents with diverse base I with the equilibrium probably lying far to the side of 1.
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This work was supported by Ministry of Science and Technology
(2016YFA0204100), National Natural Science Foundation of China
(21672178), ‘‘Thousand Youth Talents Plan’’, and Fundamental
Research Funds for the Central Universities.
Conflicts of interest
There are no conflicts to declare.
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Cp2Fe+ through single electron transfer (SET) to afford the
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rearomatization of II led to the final oxindole 2. Considering
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is most likely to help drive the acid–base equilibrium to the
side of I. In comparison, these additives are not necessary for
a-alkyl malonic esters (pKa = 13.1 in H2O), which is more
acidic than the malonate amides such as 1 as well as methanol
(pKa = 15.5 in H2O).
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