Diastereodivergent Synthesis of Bromoiminolactones: Electrochemical and Chemical Bromoiminolactonization of α-Allylmalonamides

Article abstract of DOI:10.1055/s-0037-1611791

A diastereodivergent synthesis of N-substituted iminolactones by bromoiminolactonization of α-substituted α-allylmalonamides is reported. Whereas bromocyclization under conventional chemical conditions provided cis -bromoiminolactones, electrochemical con

Full text of DOI:10.1055/s-0037-1611791

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© Georg Thieme Verlag Stuttgart · New York
2019, 30, A–E
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K. Yamamoto et al.
Cluster
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Diastereodivergent Synthesis of Bromoiminolactones: Electro-
chemical and Chemical Bromoiminolactonization of -Allyl-
malonamides
Kosuke Yamamoto
Keiko Ishimaru
0
0
0
0-0
0
0
2-
8
1
8
9-7
1
4
1
Br
N
R2
R2
O
O
O
O
N
N
Pt(+)
Pt(–)
O
O
R2
R2
R2
R2
Satoshi Mizuta
Et4NBr
N
N
N
N
O
O
R1
R1
H
H
H
R1
H
Chemical
Electrochemical
conditions
Daishirou Minato
Masami Kuriyama
Osamu Onomura*
conditions
0
0
0
0-0
0
0
2-4
8
7
1-
6
2
7
3
Br
Br
up to >99:1 dr
up to 98:2 dr
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• Diastereodivergent synthesis of bromoiminolactones
14 examples
•
•
Excellent yields and diastereoselectivity for both conditions
Graduate School of Biomedical Sciences, Nagasaki University,
1-14 Bunkyo-machi, Nagasaki 852-8521, Japan
onomura@nagasaki-u.ac.jp
Published as part of the Cluster Electrochemical Synthesis and Catalysis
Received: 31.01.2019
Accepted after revision: 24.03.2019
Published online: 18.04.2019
Electrochemical transformations are considered to be
environmentally friendly, and they have attracted much at-
tention in the field of synthetic organic chemistry.8,9 Olefin-
ic carboxylic acids have been widely used in the well-
known Kolbe electrolysis, affording carbocycles as well as
heterocycles.10 Recently, Moeller and co-workers have de-
veloped electrochemical lactonizations of carboxylic acids
or amides bearing an electron-rich alkene moiety through
generation of olefinic radical cations followed by intramo-
lecular coupling with a nucleophilic site.11 Nonactivated
olefins also participate in electrochemical cyclizations with
a halogen cation (Cl+, Br+, or I+) or a selenium cation as a
mediator or reactant to afford various heterocycles, includ-
ing cyclic carbonates,12 oxazolines,13 ethers,14 and amines.15
Although these electrochemical cyclizations proceeded di-
astereoselectively, the selectivity was dominated by the ste-
reochemistry of the substrate. To the best our knowledge,
electrochemical approaches to the synthesis of brominated
iminolactones have not been disclosed, although they
would be synthetically valuable in terms of reactivity and
further derivatization.
In this paper, we report a diastereodivergent synthesis
of bromo-functionalized iminolactones from easily accessi-
ble allylmalonamides under chemical and electrochemical
conditions. Chemically and electrochemically generated
bromo cations promoted the bromocyclization of allyl-
malonamides to give cis- and trans-isomers, respectively,
from the same substrate in excellent yields with high dias-
tereoselectivities.
For the initial screening, we examined the bromoimino-
lactonization of the -allylmalonamide 1a under chemical
and electrochemical conditions (Table 1). The electrochemi-
cal reaction was performed in a beaker-type undivided cell
under a constant-current condition (20 mA). When 1a was
treated with N-bromosuccinimide (NBS) in CH2Cl2, bromo-
iminolactone 2a was obtained in a high yield with high
DOI: 10.1055/s-0037-1611791; Art ID: st-2019-b0057-c
Abstract A diastereodivergent synthesis of N-substituted iminolac-
tones by bromoiminolactonization of -substituted -allylmalonamides
is reported. Whereas bromocyclization under conventional chemical
conditions provided cis-bromoiminolactones, electrochemical condi-
tions exhibited complementary diastereoselectivity to afford the trans-
products. A variety of substituents on the nitrogen atoms and an -po-
sition of the malonamide were tolerated under both sets of conditions
to afford the corresponding iminolactones in excellent yields and high
diastereoselectivities.
Key words diastereodivergent synthesis, electrochemical synthesis,
N-bromosuccinimide, iminolactones, malonamides, bromoiminolac-
tonization
Lactone skeletons are widely found in natural products
and biologically active molecules, and they are also valuable
building blocks in organic synthesis.1,2 Halolactonization of
unsaturated bonds is a fundamental and effective strategy
for the construction of halogenated lactones.3 To date, a
number of enantio- and diastereoselective halolactoniza-
tions have been developed with transition-metal catalysts
or organocatalysts.4 Halocyclization of olefinic amides (ha-
loiminolactonization) is also a useful approach for the syn-
thesis of halolactones. The resulting iminolactones are easi-
ly transformed into the corresponding lactones. Olefinic
amides sometimes gave better yields and stereoselectivities
than those obtained from olefinic acids.5 Although the re-
ported diastereoselective halo(imino)cyclization reactions
provide the desired products with high degrees of selectivi-
ty, modifications of the substrate structure are commonly
required to obtain products with the opposite relative con-
figuration.6,7 Considering the stereodiversity of naturally
occurring lactones, a diastereodivergent synthesis of imino-
lactones from common substrates would be highly valuable.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, A–E

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K. Yamamoto et al.
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diastereoselectivity (Table 1, entry 1). The combination of
NBS and Cu(OTf)2 provided 2a/2a′ in an identical yield with
high selectivity toward 2a (entry 2).16 Whereas the electro-
chemical bromocyclization with Et4NBr as a supporting
electrolyte in CH2Cl2 gave only trace amounts of products,
the use of a copper catalyst and Et4NBr afforded 2a′ in 78%
yield with a diastereomeric ratio of 9:91 (entries 3 and 4).17
As both diastereomers were obtained as crystalline solids,
their relative configurations were unambiguously deter-
mined by X-ray crystal-structure analysis.18 The chemical
conditions predominantly gave the diastereomer with the
cis-configuration between the amide group and the bro-
momethyl group, whereas the electrochemical conditions
provided the trans-isomer predominantly (see Supporting
Information for details).
with a diastereomeric ratio of 94:6 (entry 5). On the basis of
these results, we selected NBS and toluene as the optimal
bromo cation source and solvent, respectively.
Table 2 Diastereoselective Bromoiminolactonization under Chemical
Conditionsa
Ph
Ph
N
O
O
O
O
N
Ph
Ph
Ph
Ph
Br+ source
solvent, rt
N
N
N
N
O
+
O
H
H
H
H
Me
Me
Me
Br
Br
1a
2a
2a'
Entry
Br+ source
(equiv)
Solvent
Time
(min)
Yieldb (%) drc
of 2
(2a/2a′)
1
2
3
4
5
6
7
8
9
NBS (2.0)
Br2 (2.0)
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
toluene
THF
10
10
10
60
30
10
30
30
10
97
99
99
64
99
96
99
93
95
89:11
75:25
85:15
89:11
94:6
Table 1 Initial Screening of the Bromoiminolactonization of 1a
DBDMH (1.0)
NBS (1.0)
NBS (2.0)
NBS (2.0)
NBS (2.0)
NBS (2.0)
NBS (2.0)
Ph
Ph
N
O
O
O
O
N
Ph
Ph
Ph
Ph
conditions
CH2Cl2, rt
N
N
N
N
O
+
O
H
H
H
H
Me
82:18
57:43
48:52
45:55
Me
Me
MeCN
DMSO
MeOH
Br
Br
1a
2a
2a'
Entry Conditions
Yielda (%) of 2 drb (2a/2a′)
a Reaction conditions: 1a (0.5 mmol), Br+ source (1.0 mmol, 2.0 equiv), sol-
vent (6.0 mL), rt.
1c
2c
3d
4d
NBS (2.0 equiv)
97
89:11
84:16
n.d.e
b Combined isolated yield of both diastereomers.
c Ratio of isolated yields of the two diastereomers.
NBS (2.0 equiv), Cu(OTf)2 (10 mol%)
Pt(+)/Pt(–), Et4NBr (2.0 equiv)
97
trace
76
Pt(+)/Pt(–), Et4NBr (2.0 equiv),
Cu(OTf)2 (10 mol%)
9:91
Next, we examined the effects of some metal catalysts
and ligands on the electrochemical bromoiminolactoniza-
tion of 1a (Table 3). Although Mg(OTf)2 did not promote the
cyclization of 1a, Zn(OTf)2 led to an increase in both the
yield and diastereoselectivity toward 2a′ compared with
Cu(OTf)2 (entries 1–3). The use of N,N,N′,N′-tetramethyleth-
ylenediamine (TMEDA) with Zn(OTf)2 afforded 2a/2a′ in
94% yield with a diastereomeric ratio of 6:94, whereas the
use of 2,2′-bipyridine gave 2a′ almost exclusively in 87%
yield (entries 4 and 5). ZnCl2 was ineffective in this reaction,
affording 2a/2a′ in a low yield (entry 6). Zn(OAc)2 promoted
the cyclization of 1a with high efficiency, but a lower dias-
tereoselectivity was observed (entry 7). Thus, the combina-
tion of Zn(OTf)2 and 2,2′-bipyridine was therefore selected
as optimal for the electrochemical bromoiminolactoniza-
tion.
With the optimized conditions for both the chemical
and electrochemical bromoiminolactonization in hand, we
evaluated the scope of the reaction toward the -allyl-
malonamide (Table 4). With respect to the substituent on
the -position of malonamide, alkyl groups (1b and 1c)
were well tolerated in the reaction under chemical and
electrochemical conditions, affording the corresponding
iminolactones in high yields and high diastereoselectivities
(Table 4, entries 1–4). Whereas the -phenyl-substituted
a Combined isolated yield of both diastereomers.
b Ratio of isolated yields of the two diastereomers
c Reaction conditions: 1a (0.5 mmol), NBS (1.0 mmol, 2.0 equiv), Cu(OTf)2
(0–10 mol%), CH2Cl2 (6.0 mL), rt.
d Reaction conditions: 1a (0.5 mmol), Et4NBr (1.0 mmol, 2.0 equiv),
Cu(OTf)2 (0-10 mol%), CH2Cl2 (6.0 mL), beaker-type undivided cell, Pt plate
electrode (1.0 × 2.0 cm2), 20 mA, 4 F/mol, rt.
e n.d. = not determined.
Encouraged by these results, we began an optimization
of both the chemical and electrochemical conditions for the
diastereodivergent synthesis of 2a and 2a′. First, the effects
of the bromo cation source and the solvent on the bromo-
iminolactonization under chemical conditions were investi-
gated (Table 2). Both molecular bromine and 1,3-dibromo-
5,5-dimethylhydantoin (DBDMH) gave 2a/2a′ in excellent
yields, but with lower diastereoselectivities toward 2a (en-
tries 2 and 3). Halving the amount of NBS resulted in a de-
creased yield of 2a/2a′ despite a prolonged reaction time
(entry 4). This reaction proceeded in various solvents to af-
ford 2a/2a′, but the diastereoselectivity depended on the
polarity of the solvent. Whereas polar solvents such as
DMSO or MeOH provided 2a/2a′ with almost no selectivity,
less-polar solvents exhibited better diastereoselectivity to-
ward 2a (entries 5–9). The highest yield and diastereoselec-
tivity were obtained in toluene, affording 2a in 99% yield
© Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, A–E

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K. Yamamoto et al.
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Table 3 Diastereoselective Bromoiminolactonization under Electro-
Table 4 Substrate Scope of the Bromoiminolactonization under
Chemical or Electrochemical Conditionsa
chemical Conditionsa
Ph
Ph
N
O
O
O
O
R2
R2
N
N
O
O
O
O
N
Pt(+)-Pt(–)
R2
R2
R2
R2
Ph
Ph
Ph
Ph
+
conditions A or B
–2e (4 F/mol)
N
N
N
N
N
N
N
N
O
O
H
H
H
O
+
O
H
R1
R1
2b–n
R1
2b'–n'
H
H
H
H
Me
Me
Me
additive (10 mol%)
Et4NBr (2.0 equiv.)
CH2Cl2, rt
Br
Br
Br
Br
1a
2a
2a'
1b–n
conditions A: chemical conditions
conditions B: electrochemical conditions
Entry
Additive(s) (10 mol%)
Yieldb (%) of 2
drc (2a/2a′)
Entry
1
R1
R2
Conditions Yieldb drc
(%) of 2 (2a/2a′)
1
2
3
4
5
6
7
Cu(OTf)2
76
9:91
Mg(OTf)2
trace
89
n.d.d
8:92
1
2
1b
1c
1d
1e
1f
Et
Ph
A
B
A
B
A
B
A
B
A
B
A
B
A
B
A
B
A
B
A
B
A
B
A
B
A
B
98
73
99
90
98
82
98
86
93
79
96
84
97
81
97
90
97
97
90
78
88
77
71
68
89
73
95:5
0.1:99.9
95:5
6:94
93:7
12:88
96:4
2:98
98:2
6:94
98:2
6:94
98:2
4:96
98:2
6:94
95:5
1:99
92:8
5:95
91:9
12:88
93:7
21:79
94:6
8:92
Zn(OTf)2
Zn(OTf)2 + TMEDA
Zn(OTf)2 + 2,2′-bipyridine
ZnCl2 + 2,2′-bipyridine
Zn(OAc)2 + 2,2′-bipyridine
93
6:94
3
Bu
Ph
Bn
Ph
Ph
Ph
87
0.1:99.9
n.d.
4
20
5
99
10:90
6
a Reaction conditions: 1a (0.5 mmol), Et4NBr (1.0 mmol, 2.0 equiv), addi-
tive(s) (10 mol%), CH2Cl2 (6.0 mL), beaker-type undivided cell, Pt plate elec-
7
trode (1.0 × 2.0 cm2), 20 mA, 4 F/mol, rt.
b Combined isolated yield of both diastereomers.
c Ratio of isolated yields of the two diastereomers.
d n.d. = not determined.
8
9
2-methylbenzyl Ph
3-methylbenzyl Ph
10
11
12
13
14
15
16
17
18
19
20
21d
22e
23
24f
25
26
malonamide 1d was transformed into 2d in excellent yield
with high diastereoselectivity under chemical conditions,
the diastereoselectivity toward 2d′ slightly decreased under
electrochemical conditions (entries 5 and 6). Substrates
bearing benzyl groups with electron-neutral (1e), electron-
donating (1f–h), or electron-withdrawing (1i) substituents
were successfully employed under both conditions, afford-
ing the cis- and trans-diastereomers under chemical and
electrochemical conditions, respectively (entries 7–16). The
effects of substituents on the nitrogen atom of the amide
moiety were also examined. Under both sets of conditions,
the p-methoxyaniline-derived malonamide 1j was success-
fully transformed into the corresponding iminolactones
2j/2j′ in excellent yields with over 95:5 selectivity toward
the major diastereomer (entries 17 and 18). Iminolactones
bearing a p-chlorophenyl group (2k/2k′) were also obtained
with high efficiency (entries 19 and 20). Bromoiminolac-
tonization of 1l under chemical conditions was performed
in a mixed solvent because of the low solubility of 1l in tol-
uene, and 2l was obtained in high yield with excellent dia-
stereoselectivity (entry 21). However, the yield and diaste-
reoselectivity toward 2l′ under electrochemical conditions
decreased slightly (entry 22). 2m, containing a sterically
hindered cyclohexyl group was obtained in good yield with
high diastereoselectivity under chemical conditions, but a
lower selectivity was observed under electrochemical con-
ditions (entries 23 and 24). Under the appropriate reaction
conditions, 2n and 2n′ containing a linear alkyl group, were
successfully obtained in high yields and high diastereose-
lectivities (entries 25 and 26).19
1g
1h
1i
3-methoxyben- Ph
zyl
3-chlorobenzyl Ph
1j
Me
Me
Me
Me
Me
4-MeOC6H4
4-ClC6H4
Bn
1k
1l
1m
1n
Cy
(CH2)7Me
a Conditions A: 1a (0.5 mmol), NBS (1.0 mmol, 2.0 equiv), toluene (6.0 mL),
rt.; Conditions B: 1a (0.5 mmol) , Et4NBr (1.0 mmol, 2.0 equiv), Zn(OTf)2 (10
mol%), 2,2′-bipyridine (10 mol%), CH2Cl2 (6.0 mL), beaker-type undivided
cell, Pt plate electrode (1.0 × 2.0 cm2), 20 mA, 4 F/mol, rt.
b Combined isolated yield of both diastereomers.
c Ratio of the isolated yields of the two diastereomers.
d Toluene–CH2Cl2 (5.9:0.1).
e 3 F/mol.
f 2.7 F/mol.
To gain insight into the origin of the diastereodivergen-
cy in these reactions, we examined the effect of Et4NBr on
the chemical bromoiminolactonization. Control experi-
ments were performed according to the same procedure as
used for the chemical bromocyclization, except that two
© Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, A–E

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K. Yamamoto et al.
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equivalents each of Et4NBr and NBS were premixed in CH2-
Cl2 at room temperature before the addition of the sub-
strate. As shown in Scheme 1, substrate 1a was preferen-
tially transformed into the trans-iminolactone 2a′ under
the NBS/Et4NBr conditions. However, the diastereoselectivi-
ties were lower than those observed under the electro-
chemical conditions. Although the actual role of Zn(OTf)2
and 2,2′-bipyridine in the electrochemical bromoiminolac-
tonization remains unclear, these results indicate that com-
plexes of Et4NBr with an electrochemically generated bro-
mo cation might play a crucial role in the selectivity-deter-
mining step.20,21
were accessible in excellent yields with excellent diastereo-
selectivities. Further investigations to gain mechanistic in-
sight into the diastereoselectivity and to develop asymmet-
ric variants of the present reactions are currently underway
in our laboratory.
Funding Information
This research was supported by JSPS KAKENHI (16K08167, 15K07862,
and 17H06961).
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Supporting Information
Ph
Ph
N
O
O
N
O
O
Supporting information for this article is available online at
Ph
Ph
Ph
Ph
https://doi.org/10.1055/s-0037-1611791.
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+
O
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H
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Me
Me
Et4NBr (2.0 equiv)
Br
Br
CH2Cl2, rt
2a (minor)
2a' (major)
1a
References and Notes
2a/2a' : 98% yield (dr = 15:85)
(1) (a) Natural Lactones and Lactams: Synthesis, Occurrence and Bio-
logical Activity, 1st ed; Janecki, T., Ed.; Wiley-VCH: Weinheim,
Germany, 2013. (b) Bandichhor, R.; Nosse, B.; Reiser, O. Top.
Curr. Chem. 2005, 243, 43. (c) Kitson, R. R. A.; Millemaggi, A.;
Taylor, R. J. K. Angew. Chem. Int. Ed. 2009, 48, 9426. (d) Fukuda,
T.; Matsumoto, A.; Takahashi, Y.; Tomoda, H.; Ōmura, S. J. Anti-
biot. 2005, 58, 252.
(2) (a) Hennecke, U.; Wald, T.; Rösner, C.; Robert, T.; Oestreich, M.
In Comprehensive Organic Synthesis, 2nd ed., Vol. 7; Knochel, P.;
Molander, G. A., Ed.; Elsevier: Oxford, 2014, Chap. 7.21 638.
(b) Zhu, J.-B.; Watson, E. M.; Tang, J.; Chen, E. Y.-X. Science 2018,
360, 398.
Scheme 1 Diastereoselective synthesis of bromoiminolactones using
NBS with Et4NBr
Finally, the transformations of the products were exam-
ined to demonstrate the synthetic utility of the present re-
action (Scheme 2). Iminolactones 2a and 2a′ were easily
transformed into the polysubstituted lactones 3a and 3a′ in
high yields by treatment with oxalic acid in THF–H2O at
room temperature [Scheme 2(a)].22 Nucleophilic substitu-
tion of 2a and 2a′ with 4-bromobenzenethiol afforded the
corresponding iminolactones 4a and 4a′ with a thioether
moiety in excellent yields [Scheme 2(b)]
(3) (a) Ranganathan, S.; Muraleedharan, K. M.; Vaish, N. K.;
Jayaraman, N. Tetrahedron 2004, 60, 5273. (b) Cardillo, G.;
Orena, M. Tetrahedron 1990, 46, 3321. (c) Snyder, S. A.; Treitler,
D. S.; Brucks, A. P. Aldrichimica Acta 2011, 44, 27.
(a) Hydrolysis of 2a/2a'
(4) (a) French, A. N.; Bismire, S.; Wirth, T. Chem. Soc. Rev. 2004, 33,
354. (b) Denmark, S. E.; Kuester, W. E.; Burk, M. T. Angew. Chem.
Int. Ed. 2012, 51, 10938. (c) Murai, K.; Fujioka, H. Heterocycles
2013, 87, 763. (d) Nakatsuji, H.; Sawamura, Y.; Sakakura, A.;
Ishihara, K. Angew. Chem. Int. Ed. 2014, 53, 6974. (e) Gieuw, M.
H.; Ke, Z.; Yeung, Y.-Y. Chem. Rec. 2017, 17, 287.
(5) (a) Robin, S.; Rousseau, G. Tetrahedron 1998, 54, 13681.
(b) Lourie, L. F.; Serguchev, Y. A.; Bentya, A. V.; Ponomarenko,
M. V.; Rusanov, E. B.; Vovk, M. V.; Fokin, A. A.; Ignat’ev, N. V.
J. Fluorine Chem. 2015, 179, 42. (c) Zhao, J.-F.; Duan, Z.-H.; Yang,
H.; Guo, L.-N. J. Org. Chem. 2015, 80, 11149. (d) Arai, T.;
Watanabe, O.; Yabe, S.; Yamanaka, M. Angew. Chem. Int. Ed.
2015, 54, 12767. (e) Zhang, Z.-Q.; Liu, F. Org. Biomol. Chem.
2015, 13, 6690. (f) Kuriyama, M.; Yamamoto, K.; Ishimaru, K.;
Fujimura, N.; Minato, D.; Onomura, O. Heterocycles 2018, 97,
744.
O
Ph
O
O
N
Ph
Ph
(COOH)2
N
N
O
O
H
H
Me
Me
THF–H2O (1:1)
rt, 12 h
Br
: 82%)
: 85%
Br
2a (cis)
2a' (trans)
3a (cis, from 2a)
3a' (trans, from 2a')
(b) Nucleophilic substitution of 2a/2a'
Ph
Ph
O
O
N
N
Br
SH
Ph
Ph
N
N
O
O
H
H
Me
Me
K2CO3, DMF
30 °C, 2 h
Br
SAr
Ar = p-bromophenyl
2a (cis)
2a' (trans)
4a (cis, from 2a)
: 91%)
4a' (trans, from 2a') : 92%
Scheme 2 Transformations of iminolactones 2a and 2a′
(6) The diastereoselectivity in halolactonization of olefinic carbox-
ylic acids with substituents on appropriate positions are known
to be controllable under kinetic or thermodynamic reaction
conditions, see: (a) Bartlett, P. A.; Myerson, J. J. Am. Chem. Soc.
1978, 100, 3950. (b) Bartlett, P. A.; Richardson, D. P.; Myerson, J.
Tetrahedron 1984, 40, 2317. (c) Gonzalez, F. B.; Bartlett, P. A.
Org. Synth. Coll. Vol. VII; Wiley: London, 1990, 164.
(7) A bromolactonization of a cyclopropylmethyl diester by using
Lewis basic chalcogenide catalysts was recently disclosed; for
several substrates, a reversal of the diastereoselectivity was
In conclusion, we have successfully developed a diastereo-
divergent synthesis of bromo-substituted iminolactones by
chemical or electrochemical bromoiminolactonization of -
allylmalonamides.23 A variety of malonamides with an alkyl
or an aryl substituent on the nitrogen atom or at an -posi-
tion were tolerated in the reaction. Both diastereomers
© Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, A–E

E
K. Yamamoto et al.
Cluster
Synlett
observed on changing the chalcogenide catalyst; see: Gieuw, M.
H.; Leung, V. M.-Y.; Ke, Z.; Yeung, Y.-Y. Adv. Synth. Catal. 2018,
360, 4306.
1949, 164, 241. (b) Braude, E. A.; Waight, E. S. J. Chem. Soc. 1952,
1116. (c) Finkelstein, M.; Hart, S. A.; Moore, M.; Ross, S. D.;
Eberson, L. J. Org. Chem. 1986, 51, 3548.
(8) For recent reviews on electrochemical synthesis, see: (a) Franke,
R. Beilstein J. Org. Chem. 2014, 10, 2858. (b) Yoshida, J.-i.;
Kataoka, K.; Horcajada, R.; Nagaki, A. Chem. Rev. 2008, 108,
2265. (c) Yan, M.; Kawamata, Y.; Baran, P. S. Chem. Rev. 2017,
117, 13230. (d) Wiebe, A.; Gieshoff, T.; Möhle, S.; Rodrigo, E.;
Zirbes, M.; Waldvogel, S. R. Angew. Chem. Int. Ed. 2018, 57, 5594.
(e) Möhle, S.; Zirbes, M.; Rodrigo, E.; Gieshoff, T.; Wiebe, A.;
Waldvogel, S. R. Angew. Chem. Int. Ed. 2018, 57, 6018. (f) Jiang,
Y.; Xu, K.; Zeng, C. Chem. Rev. 2018, 118, 4485.
(9) For recent examples, see: (a) Zhang, S.; Li, L.; Wang, H.; Li, Q.;
Liu, W.; Xu, K.; Zeng, C. Org. Lett. 2018, 20, 252. (b) Zhang, S.;
Lian, F.; Xue, M.; Qin, T.; Li, L.; Zhang, X.; Xu, K. Org. Lett. 2017,
19, 6622. (c) Gao, W.-C.; Xlong, Z.-Y.; Pirhaghani, S.; Wirth, T.
Synthesis 2019, 51, 276. (d) Barjau, J.; Königs, P.; Kataeva, O.;
Waldvogel, S. R. Synlett 2008, 2309.
(22) Diethyl allyl(methyl)malonate afforded a diastereoisomeric
mixture of the corresponding lactones in moderate yield with
almost no diastereoselectivity under the chemical conditions.
(23) Bromoiminolactonization of Compounds 1; General Proce-
dure under Chemical Conditions
NBS (178 mg, 2.0 equiv) was added to a solution of 1 (0.5 mmol)
in toluene (6 mL), and the mixture was stirred at rt until all the
starting material was consumed (TLC). The reaction was
quenched with sat. aq Na2S2O3, and the resulting mixture was
extracted with EtOAc. The combined organic layers were dried
(MgSO4), filtered, and concentrated under reduced pressure.
The residue was purified by column chromatography [silica gel,
hexane–EtOAc] to afford 2 and 2′.
Bromoiminolactonization of Compounds 1; General Proce-
dure under Electrochemical Conditions
(10) (a) Schäfer, H. J. Top. Curr. Chem. 1990, 152, 91. (b) Torii, S.;
Tanaka, H. In Organic Electrochemistry, 4th ed; Lund, H.;
Hammerich, O., Ed.; Marcel Dekker: New York, 2001, 499.
(11) (a) Brandt, J. D.; Moeller, K. D. Org. Lett. 2005, 7, 3553.
(b) Perkins, R. J.; Xu, H.-C.; Campbell, J. M.; Moeller, K. D. Beil-
stein J. Org. Chem. 2013, 9, 1630.
(12) Gao, X.; Yuan, G.; Chen, H.; Jiang, H.; Li, Y.; Qi, C. Electrochem.
Commun. 2013, 34, 242.
(13) Haupt, J. D.; Berger, M.; Waldvogel, S. R. Org. Lett. 2019, 21, 242.
(14) (a) Röse, P.; Emge, S.; Yoshida, J.-i.; Hilt, G. Beilstein J. Org. Chem.
2015, 11, 174. (b) Shimizu, A.; Hayashi, R.; Ashikari, Y.; Nokami,
T.; Yoshida, J.-i. Beilstein J. Org. Chem. 2015, 11, 242.
In a beaker-type undivided cell, substrate 1 (0.5 mmol), Et4NBr
(322 mg, 2.0 equiv), Zn(OTf)2 (18.2 mg, 10 mol%), and 2,2′-
bipyridine (7.8 mg, 10 mol%) were dissolved in CH2Cl2 (6 mL),
and the mixture was stirred for 20 min. The reaction vessel was
fitted with a Pt plate electrode (1.0 × 2.0 cm2), and 4 F/mol of
electricity was supplied under constant-current conditions (20
mA). The reaction was then quenched with sat. aq Na2S2O3 and
the resulting mixture was extracted with CH2Cl2. The combined
organic layers were dried (MgSO4), filtered, and concentrated
under reduced pressure. The residue was purified by column
chromatography [silica gel, hexane–EtOAc] to afford 2 and 2′.
(cis)-5-(Bromomethyl)-3-ethyl-N-phenyl-2-(phenylim-
ino)tetrahydrofuran-3-carboxamide (2b) (Prepared under
Chemical Conditions)
(15) (a) Liang, S.; Zeng, C.-C.; Luo, X.-G.; Ren, F.-z.; Tian, H.-Y.; Sun,
B.-G.; Little, R. D. Green Chem. 2016, 18, 2222. (b) Ashikari, Y.;
Shimizu, A.; Nokami, T.; Yoshida, J.-i. J. Am. Chem. Soc. 2013,
135, 16070.
Colorless oil; yield: 187 mg (93%). IR (ATR): 692, 756, 1198,
1445, 1487, 1551, 1599, 1686, 3065 cm–1 1H NMR (400 MHz,
.
(16) Cu(OTf)2 is an effective Lewis acid catalyst for nucleophilic addi-
tion of malonates to 3,4-didehydropiperidinium ions; see:
Matsumura, Y.; Minato, D.; Onomura, O. J. Organomet. Chem.
2007, 692, 654.
(17) Applied currents of 10 or 30 mA led to a decrease in the yield of
2; see Supporting Information for details.
CDCl3):  = 10.66 (s, 1 H), 7.59 (dd, J = 8.5, 1.2 Hz, 2 H), 7.39–7.32
(m, 4 H), 7.26–7.24 (m, 2 H), 7.18–7.14 (m, 1 H), 7.13–7.09 (m, 1
H), 4.76–4.69 (m, 1 H), 3.50 (d, J = 5.4 Hz, 2 H), 2.79 (dd, J = 13.9,
8.0 Hz, 1 H), 2.48 (dd, J = 13.7, 6.8 Hz, 1 H), 2.19–2.05 (m, 2 H),
1.10 (t, J = 7.3 Hz, 3 H). 13C NMR (100 MHz, CDCl3):  = 168.2,
163.0, 144.5, 137.8, 128.9, 128.7, 124.8, 124.1, 123.2, 119.5,
78.1, 56.5, 35.0, 34.9, 33.7, 9.25. HRMS (EI): m/z [M]+ calcd for
(18) CCDC 1893915 and 1893916 contain the supplementary crys-
tallographic data for compounds 2a and 2a′. The data can be
obtained free of charge from The Cambridge Crystallographic
Data Centre via www.ccdc.cam.ac.uk/getstructures .
C
20H2181BrN2O2: 402.0766; found: 402.0763.
(trans)-5-(Bromomethyl)-3-ethyl-N-phenyl-2-(phenylim-
ino)tetrahydrofuran-3-carboxamide (2b′) (Prepared under
Electrochemical Conditions)
(19) The symmetrical bisallyl malonamide 1 (R1 = Allyl; R2 = Ph) gave
a complex mixture under both chemical and electrochemical
conditions.
Colorless oil; yield: 146 mg (73%). IR (ATR): 692, 756, 1198,
1443, 1489, 1541, 1599, 1684, 3323 cm–1 1H NMR (400 MHz,
.
(20) Although the combination of NBS and Et4NBr can generate
molecular bromine, molecular bromine itself provided 2a as a
major product (Table 2, entry 2). The use of Cu(OTf)2 with
molecular bromine did not affect the selectivity (99% yield of 2;
2a/2a′ = 73:27).
(21) Braude and Waight have reported the formation of complexes
between tetraalkylammonium salts and NBS, and the formation
of a 1:1 complex between Et4NBr and NBS has been reported by
Finkelstein et al.; see: (a) Braude, E. A.; Waight, E. S. Nature
CDCl3):  = 9.49 (s, 1 H), 7.56 (d, J = 8.3 Hz, 2 H), 7.37–7.33 (m, 4
H), 7.23 (t, J = 9.0 Hz, 2 H), 7.16–7.10 (m, 2 H), 4.62–4.56 (m, 1
H), 3.66 (dd, J = 10.7, 4.8 Hz, 1 H), 3.57 (dd, J = 11.2, 3.9 Hz, 1 H),
3.34 (dd, J = 13.2, 6.3 Hz, 1 H), 2.32–2.22 (m, 1 H), 2.10–1.96 (m,
2 H), 1.05 (t, J = 7.3 Hz, 3 H). 13C NMR (100 MHz, CDCl3):  =
167.0, 163.6, 145.1, 137.7, 129.0, 128.7, 124.6, 124.3, 123.1,
119.3, 78.6, 58.3, 34.0, 33.6, 33.1, 9.5. HRMS (EI): m/z [M]+ calcd
for C20H2181BrN2O2: 402.0766; found: 402.0763.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, A–E