Visible light-induced intermolecular radical addition: Facile access to γ-ketoesters from alkyl-bromocarboxylates and enamines

Article abstract of DOI:10.1039/c4cc05590j

A highly efficient addition of alkyl α-bromocarboxylates to enamines by visible light-induced photoredox catalysis is reported. Compared with traditional methods, the reaction described here provided an alternative route for the construction of valuable γ-ketoesters in generally good yields.

Full text of DOI:10.1039/c4cc05590j

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Visible light-induced intermolecular radical
addition: facile access to c-ketoesters from
alkyl-bromocarboxylates and enamines†
Cite this: Chem. Commun., 2014,
50, 13547
Received 20th July 2014,
Accepted 1st September 2014
Bei Hu,a Haixia Chen,b Yan Liu,b Wuheng Dong,a Kai Ren,a Xiaomin Xie,a Hao Xub
and Zhaoguo Zhang*a
DOI: 10.1039/c4cc05590j
www.rsc.org/chemcomm
A highly efficient addition of alkyl a-bromocarboxylates to enamines
by visible light-induced photoredox catalysis is reported. Compared
with traditional methods, the reaction described here provided
an alternative route for the construction of valuable c-ketoesters in
generally good yields.
Traditional photo-initiated radical reaction was considered to
be an alternative method in the field of synthetic chemistry.
However, the poor selectivity and the need for specialized UV
reactors considerably limited its application. Visible light serves as
Scheme 1 Addition of radical to the unsaturated compounds.
a new energy source of photo-induced radical reactions and 5 h afforded the target product (Scheme 1b).9 However, it is
photoredox reactions is showing the power of a radical-involving still quite limited because organotin compounds were used as
reaction in organic synthesis. It has attracted considerable atten- either starting material or as a radical initiator, which were not
tion from numerous researchers and has emerged as a growing environment-friendly in the reaction.
field because the C–X bond formation continues to be a demand
A carbon-centered radical added to an unsaturated carbon
in organic synthesis.1 Free radicals, which are generated by photo- atom in an appropriate acceptor, followed by the fragmentation
redox catalysis, can react to construct the bond of C–X (X = C, S, of the adduct radical, is the key chain-extension method for
N, O). Because C–C bond formation has been documented by the the construction of carbon–carbon bonds. The generation of
2
3
4
5
´
groups of Stephenson, Gagne, Reiser and Masson, Xiao et al. carbonyl alkyl radicals is well-known from an alkyl a-bromo-
have also reported the formation of C–O.6 Despite these signifi- carboxylate under visible light catalyzed reactions.10 Lei et al.
cant advances, the exploitation of novel and efficient organic succeeded in the addition of carbonyl alkyl radicals and alkenes
radical precursors and the extension of their application to more to obtain unsaturated ester compounds (Scheme 2, path a). We
reactions remains highly attractive.7
attempted to find an appropriate acceptor to trap the carbon-
g-Ketoesters are important synthetic intermediates in organic centered electron-deficient radical, followed by the transforma-
synthesis. The traditional radical synthetic methods are radicals tion of one electron, to form an iminium cation, and eventually,
that were irradiated by AIBN or organotin reagents. Hosomi et al. g-ketoesters were achieved (Scheme 2, path b). Considering that
have reported the reaction of ethyl 2-bromopropanoate with the a-carbonyl alkyl radical is relatively electrophilic, electron-
tributylstannyl enolate to give g-ketoesters initiated by AIBN in rich alkenes may be beneficial to the reaction.11 Therefore,
benzene at 80 1C (Scheme 1a).8 Kim et al. also reported that the enamines were preferentially chosen to test the reaction.
photo-stimulated reaction of ethyl a-iodoacetate with vinyl-triflate
We initiated our investigation by examining the reaction
and hexamethylditin in benzene under irradiation at 300 nm for of N-(1-styryl)morpholine and ethyl 2-bromopropanoate with
Ru(bpy)3Cl2 (2 mol%) by employing Et3N (40 mol%) in DMF
under a 23 W household fluorescent lamp irradiation (Table 1,
entry 1). Fortunately, the reaction occurred in 16% yield. When
NaHCO3 (1 eq.) was added, the reaction gave a slightly higher
yield (Table 1, entry 2). Na2CO3 was also examined, and a
a School of Chemistry and Chemical Engineering, Shanghai Jiao Tong University,
800 Dongchuan Road, Shanghai 200240, China. E-mail: zhaoguo@sjtu.edu.cn
b Department of Applied Chemistry, College of Science,
Nanjing University of Technology, Nanjing 210009, China
slightly better result was obtained (Table 1, entry 3). When we
changed the base to K2CO3, a higher yield was achieved
† Electronic supplementary information (ESI) available. See DOI: 10.1039/
c4cc05590j
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the solvents in the presence of K2CO3 as the base for the reaction.
Among the tested solvents, DMF was proven to be the best for
this transformation (Table 1, entries 8–13). The reaction proceeded
with the formation of acetophenone as a by-product during the
reactions. Thus, we tried to add some pyridine derivatives (Table 1,
entries 14–19), which were claimed to be beneficial for improving
reactivity in similar reactions.1m,10 When we applied pyridine to the
reaction, the yield was slightly improved (Table 1, entry 14). When
40 mol% of 4-methoxypyridine relative to enamine was added to
the reaction, an 86% isolated yield was obtained with significantly
less by-product (Table 1, entry 15). There is no obvious influence
with slightly less or more 4-methoxypyridine in the reaction
(Table 1, entries 16 and 17). Other pyridine derivatives, such as
DMAP, did not give a satisfactory yield (Table 1, entry 18). Control
experiments showed that both Ru(bpy)3Cl2 and visible light are
essential for this reaction. When the reactions were conducted
without a catalyst or in dark, essentially no products were formed
regardless of the background reaction (Table 1, entries 19 and 20).
When the molar ratio of 1a and 2a was exchanged from 1 : 2 to 2 : 1,
only a 47% yield was obtained (Table 1, entry 21). Moreover, we also
conducted the reaction with an O2 balloon, and only a 35% yield
was obtained, which indicated that a cage effect existed in the
reaction (Table 1, entry 22).12 In the following experiments, different
enamines (1a–1d) of acetophenone were prepared13 to test their
reaction with 2a (Scheme 3). When 1b was employed as the
substrate, the best result (94% yield) was obtained. Other enamines,
such as 1c and 1d, also provided good results.
Scheme 2 Addition of radical to the unsaturated compounds under
visible-light catalyzed reaction.
Table 1 Optimization of the reaction conditionsa
Entry
Base
Solvent
Additive
Yieldb (%)
1
2
3
4
DMF
DMF
DMF
DMF
DMF
DMF
DMF
CH3CN
DMA
DCM
Toluene
NMP
DMSO
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
16
31
55
64
12
4
11
40
37
8
Next, we evaluated the substrate scope of this reaction with
enamines prepared from piperidine and different ketones, and
the results are listed in Table 2.
NaHCO3
Na2CO3
K2CO3
K3PO4
tBuOK
Et3N
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
5
Enamines 1b, 1e–1l derived from aryl methyl ketone provided
good yields of keto esters. A significant electronic effect was
observed in the reactions of 1h and 1i. The presence of an
electron-withdrawing group decreased the reactivity of the enamine,
whereas an electron-donating group increased the reactivity of
enamine. As a result, the reaction of 1h gave 3h in moderate yield
compared with the reaction of 1i, which gave 3i in excellent yield. It
appears that steric hindrance did not have a remarkable effect on
the reaction when 1j was used as the substrate; 3j was obtained in
97% yield. Enamine 1k (E) prepared from propiophenone can react
smoothly to give the desired product in 66% yield. Moreover, the
reaction of enamine of tetralone 1l was also conducted, which gave
the desired product in poor yields (3l, 33% yield).
6
7c
8
9
10
11
12
13
14
15
16e
17 f
18
19g
20h
21i
22 j
5
35
16
74
90 (86d)
87
89
33
0
Pyridine
4-Methoxypyridine
4-Methoxypyridine
4-Methoxypyridine
DMAP
4-Methoxypyridine
4-Methoxypyridine
4-Methoxypyridine
4-Methoxypyridine
10
47
35
In addition, we extended this radical addition reaction to
other a-carbonyl alkyl or benzyl bromides, and similar results
a
Conditions: 1a (0.5 mmol), 2a (1 mmol), Ru(bpy)3Cl2 (0.01 mmol),
Et3N (0.2 mmol), 4-methoxypyridine (0.2 mmol), base (0.5 mmol),
solvent (2 mL), irradiation with a 23 W household light bulb at about
b
35 1C for 24 h. GC yields based on dibenzyl ether as an internal standard.
c
d
e
Et3N (0.75 mmol). Isolated yield. 4-Methoxypyridine (0.1 mmol) was
f
g
h
used. 4-Methoxypyridine (0.4 mmol). Without light. Without catalyst.
i
1a (1 mmol), 2a (0.5 mmol), GC yield based on dibenzyl ether as an
j
internal standard. O2 balloon.
(Table 1, entry 4). However, a poor result was obtained when K3PO4
or tBuOK was added to the reaction (Table 1, entries 5 and 6). We
know that Et3N not only acted as a reductant but also as a base in
the reactions; however, when Et3N (1.5 eq.) was used as the base, an
even worse result was obtained (Table 1, entry 7). We then screened
Scheme 3 Reactions of different enamines (1a–1d) with 2a.
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Table 2 Reactions of enamines with 2aa
Entry
R
R1
Yieldb (%)
1
2
3
4
5
6
7
8
C6H5 (1b)
H
H
H
H
H
H
H
Me
94
92
92
91
78
96
97
66c
4-Me-C6H4 (1e)
4-F-C6H4 (1f)
4-Cl-C6H4 (1g)
4-CF3-C6H4 (1h)
4-MeO-C6H4 (1i)
2-Me-C6H4 (1j)
C6H5 (1k)
a
Conditions: 1b, 1e–1l (0.5 mmol), 2a (1 mmol), Ru(bpy)3Cl2
(0.01 mmol), Et3N (0.2 mmol), 4-methoxypyridine (0.2 mmol), base
(0.5 mmol), DMF (2 mL), irradiation with 23 W household light bulb at
b
c
about 35 1C for 24 h. Isolated yields. dr = 11 : 1.
Scheme 4 Proposed mechanism.
Table 3 Scope of secondary and tertiary a-carbonyl alkyl or aryl bromides
reaction with 1ba
of the metal catalyst under visible light generates the excited
[Ru(bpy)3]2+* species,14 which oxidizes Et3N to give the active single
electron transfer species, [Ru(bpy)3]+, along with the radical cation
of the amine. Then, the electron-rich metal complex [Ru(bpy)3]+
reduces the activated C–Br bond1m,10 to furnish the electron-
deficient radical I and regenerates [Ru(bpy)3]2+. The rapid addition
of radical I to the electron-rich enamine forms radical II, which can
be rapidly oxidized to iminium cation 2 and undergoes single-
electron transfer to give [Ru(bpy)3]2+*,3 and forms the metal
complex [Ru(bpy)3]+ to complete the photoredox catalytic cycle.
Finally, the g-keto ester 3 can be obtained by the hydrolysis of the
iminium cation 2.15
In summary, we developed an efficient visible-light-
mediated photoredox reaction of a-brominated carboxylates
with enamines via an intermolecular radical addition reaction.
This method provided a novel access to various synthetically
important g-ketoesters in good yields under very mild condi-
tions. Further work toward expanding the use of photoredox
catalysis in the context of radical chemistry is undergoing.
This work was financially supported by the National Natural
a
Conditions: 1b (0.5 mmol), 2m–2r (1 mmol), Ru(bpy)3Cl2 (0.01 mmol),
Et3N (0.2 mmol), 4-methoxypyridine (0.2 mmol), base (0.5 mmol), DMF
(2 mL), irradiation with 23 W household light bulb at 35 1C for
24 h. Isolated yields.
b
were obtained (Table 3). Substrates bearing more than one
substituent at the a-position of a-brominated carboxylates and Science Foundation of China. We thank the Instrumental Analysis
ethyl bromoacetate resulted in relatively poor yields (3n–3p) Center of Shanghai Jiao Tong University for microanalysis.
with the formation of acetophenone, which results from the
hydrolysis of enamine. When cinnamyl or allyl a-brominated
carboxylates were employed as substrates, moderate yields were
obtained without an intramolecular cyclization product.
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