A novel and practical method for the synthesis of dinotefuran through Michael addition of nitromethane to diethyl maleate

Article abstract of DOI:10.1016/j.tet.2017.12.002

A novel and practical synthesis of dinotefuran 1, featuring a new access to it from known key intermediate (tetrahydrofuran-3-yl)-methanamine 5, has been achieved through Michael addition reaction of nitromethane to diethyl maleate in 6 steps with 45.5% total yield. This synthesis is scalable and hence has high potential for application to further synthetic elaboration on such new neonicotinoid insecticide dinotefuran 1.

Full text of DOI:10.1016/j.tet.2017.12.002

Tetrahedron 74 (2018) 336e340
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
A novel and practical method for the synthesis of dinotefuran through
Michael addition of nitromethane to diethyl maleate
Haifeng Li, Lailai Wang*
State Key Laboratory for Oxo Synthesis and Selective Oxidation, Lanzhou Institute of Chemical Physics, Chinese Academy of Sciences, Lanzhou 730000, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel and practical synthesis of dinotefuran 1, featuring a new access to it from known key inter-
mediate (tetrahydrofuran-3-yl)-methanamine 5, has been achieved through Michael addition reaction of
nitromethane to diethyl maleate in 6 steps with 45.5% total yield. This synthesis is scalable and hence has
high potential for application to further synthetic elaboration on such new neonicotinoid insecticide
dinotefuran 1.
Received 10 October 2017
Received in revised form
24 November 2017
Accepted 1 December 2017
Available online 5 December 2017
© 2017 Elsevier Ltd. All rights reserved.
Keywords:
Dinotefuran
Synthesis
Mickael addition
Nitromethane
Diethyl maleate
1. Introduction
crickets, mealybugs, sawfly larvae and cockroaches.2e5,10,15,16
As far as we know, (tetrahydrofuran-3-yl)-methanol and
Dinotefuran
1,
N-methyl-N0-nitro-N’’-(tetrahydro-3-
(tetrahydrofuran-3-yl)-methanamine 5 (Fig. 1) are the two impor-
tant key intermediates in the synthesis of dinotefuran 1.9,16 Over
the past more than ten years, many studies were performed to
synthesize the methanamine 5. Early synthesis of the methan-
amine 5 were mainly prepared from mesylated (tetrahydrofuran-3-
yl)-methanol.11,17,18 Among which, the production technique of
furylmethyl)guanidine, is the most recent synthesized third gen-
eration neonicotinoid insecticide.1e6 It is developed by Mitsui
Chemicals (Tokyo, Japan) and first registered in Japan in 2002, and
is now increasingly utilized in more than 20 countries.7e10 The
structure of the dinotefuran 1 and its analogs (Fig. 1, 2e4) are very
different from the existing nicotine insecticides.3,8,11 They have a
characteristic tetrahydro-3-furylmethyl moiety instead of chloro
thiazole (Fig. 1, Second generation neonicotinoids, such as clothia-
nidin 6 and thiamethoxam 7) and chlorinated pyridine (Fig. 1, First
generation neonicotinoids, such as nitenpyram 8, imidacloprid 9,
acetamiprid 10 and thiacloprid 11) group of other neonicotinoids,
that was previously considered indispensable for insecticidal ac-
tivity of neonicotinoids.3,6e9,11e13 At the same time, the properties
of dinotefuran are different from nicotine, therefore, it will be
known as the “furanicotine”.14
dinotefuran
1 from (tetrahydrofuran-3-yl)-methanol through
alkylation of diethyl malonate and ethyl chloroacetate under
alkaline condition has been industrialized, but the route was
complicated and hard to operate, the yield was low, and the cost
was very high. Liu et al. reported an access to the methanamine 5 in
a total yield of 41.1% in 5 steps, with 2, 3-dihydronfuran and tri-
chloroacetyl chloride as starting materials.19 Chen and Sharpe
developed a method to synthesize the methanamine 5, utilizing Ru/
C catalytic hydrogenation, dehydration-cyclization, chlorination,
nucleophilic substitution and Raney Ni catalytic hydrogenation
from malic acid in an overall yield of 54.7%.20 Very recently, Zhou
et al. described the synthesis of the methanamine 5 through 5 steps
starting from 4, 5-dihydrofuran-3-carboxylic acid with 38.0% yield
by Pd/C catalytic hydrogenation, chlorination, aminolysis, dehy-
dration and hydrogenation.21 However, the above methods need
long steps, and the application of strongly corrosive, highly toxic
and hazardous chemicals would also cause environmental prob-
lems. Furthermore, much noble metal catalysts were used and
Dinotefuran is a useful candidate in public health because it
shows low mammalian toxicity and broad spectrum quick-kill
insecticide which is effective on a wide variety of insect pests
such as aphids, shiteflies, leafhoppers, leafminers, sawflies, mole
* Corresponding author.
E-mail address: wll@licp.cas.cn (L. Wang).
https://doi.org/10.1016/j.tet.2017.12.002
0040-4020/© 2017 Elsevier Ltd. All rights reserved.

H. Li, L. Wang / Tetrahedron 74 (2018) 336e340
337
Fig. 1. Structures of dinotefuran 1, (tetrahydrofuran-3-yl)-methanamine 5, and other neonicotinoid insecticides 2e4 and 6e11.
therefore the cost was high. Thus, it is still imperative to exploit
maleate.
more practical and scalable method to synthesize this methan-
amine 5, which has a tetrahydro-3-furylmethyl moiety of dinote-
furan 1 and its analogs (Fig. 1, 2e4).
2. Results and discussion
In the present work, our interest has been focused on a novel,
practical and scalable method for the synthesis of dinotefuran 1
from (tetrahydrofuran-3-yl)-methanamine 5, which was synthe-
sized through Michael addition reaction of nitromethane to diethyl
Our study was mainly focused on the issue of access to the key
intermediate (tetrahydrofuran-3-yl)methanamine 5, which was
previously prepared through two steps from another useful inter-
mediate, (tetrahydrofuran-3-yl)methanol, for the synthesis of
dinotefuran 1. In fact, the synthesis of the methanamine 5 not only
gave the key intermediate of the third generation neonicotinoid
insecticide dinotefuran 1, but also provided a novel efficient syn-
thesis strategy for the neonicotinoid insecticides which have a
characteristic tetrahydro-3-furylmethyl moiety instead of an aro-
matic heterocyclic ring. As our retrosynthetic analysis outlined in
Scheme 1, dinotefuran 1 could be synthesized from O-methyl-N-
nitroisourea 12 and methanamine 5. The methanamine 5 could be
conceived by catalytic hydrogenation of nitrocompound 13. Next, in
a key step, it was thought that nitrocompound 13 could be provided
by acid-catalyzed dehydrative cyclization of diol 14. Diol 14 could
be achieved from the nitroester 15 by NaBH4 reduction. We envi-
sioned that nitroester 15 may be obtained from Michael addition
reaction of the commercially available nitromethane to diethyl
Scheme 1. Retrosynthetic analysis of dinotefuran 1.
Scheme 2. Synthesis of the key intermediate (tetrahydrofuran-3-yl)-methanamine 5.

338
H. Li, L. Wang / Tetrahedron 74 (2018) 336e340
maleate 16 in the presence of K2CO3. The overall synthetic strategy
would allow very concise syntheses of dinotefuran 1.
added to maintain the pH of the reaction at 7.
Finally, the methylamination of carbamimidate 18 with 40%
CH3NH2 solution in distilled water at room temperature for 3 h
successfully afforded the target dinotefuran 1 in 90% yield. The
melting point (100e101 ꢀC) was in good agreement with the data
reported for the new neonicotinoid insecticide (99.5e100.7 ꢀC) and
the spectral data (1H and 13C NMR) were also in good agreement
with the reported values of the new neonicotinoid insecticide.22e24
Our synthesis commenced with the preparation of (tetrahy-
drofuran-3-yl)-methanamine 5 (Scheme 2). The Michael addition
reaction, which benefits from mild reaction conditions and high
functional group tolerance as well as high conversions and favor-
able reaction rates, is a facile and versatile synthetic methodology
for the efficient coupling of nucleophiles with electron poor olefins
in organic synthesis. Additionally, the Michael addition is one of the
most useful methods for the mild formation of CeC bonds. Ac-
cording to the above synthetic consideration, as shown in Scheme
2, our synthesis relying on a Michael addition of commercially
available nitromethane to diethyl maleate 16 in the presence of
K2CO3 afforded nitroester 15 in an excellent yield (92%) after 12 h at
room temperature. With the required nitroester 15 in hand, the key
ester reduction was then performed in the presence of NaBH4 or
KBH4. To our great surprise, it is not anticipated that nitroester 15
would be impossibly converted into the key intermediate, diol 14,
as a precursor of nitrocompound 13, but converted to the nitro
elimination compound diethyl methylenesuccinate 17 in 100% yield
when we first tried to treat the nitroester 15 with NaBH4 or KBH4 in
methanol at reflux temperature. The formation of 17 can be
3. Conclusion
In summary, we have developed a novel and practical method to
synthesize dinotefuran 1 based on the synthesis of the known key
intermediate (tetrahydrofuran-3-yl)-methanamine 5 using Michael
additions reaction, NaBH4 reduction, dehydration cyclization and
catalytic hydrogenation as the key steps. Notably, the current syn-
thesis gave a 45.5% overall yield in 6 steps and resulted in an effi-
cient, practical, and scalable synthesis of dinotefuran 1 from easily
accessible starting materials. More importantly, this work provided
a new strategy to accomplish other structurally relevant neon-
icotinoid insecticides which has a characteristic tetrahydro-3-
furylmethyl moiety.
explained by the fact that the nitro group at the
b-position of the
electron-withdrawing nitroester 15 was eliminated to give
unsaturated ester 17 on treated with NaBH4 or KBH4 which played a
a, b-
4. Experimental section
role as base in protic solvent. And we found that the nitro group can
be easily removed from the b-position of the nitroester 15. We next
4.1. General
tried to carry out the reduction by adding the solution of nitroester
15 in EtOH dropwise to the suspension of NaBH4 in THF at 15e20 ꢀC,
and then the reaction mixture was stirred at room temperature for
4 h and refluxed at 63 ꢀC for 6 h until there were no H2 bubbles
released. Fortunately, the desired diol 14 was obtained in 76% yield.
The resulted reduction compound diol 14 was converted into
nitrocompound 13 in 85% yield by acid catalyzed dehydration-
cyclization. At first, the reaction mixture was heated in the pres-
ence of p-TsOH at 120e125 ꢀC for 2 h. Then the reaction was cooled
to 80e85 ꢀC and the formed water was removed by distillation for
about 4 h without the use of any organic solvent. Subsequent the
direct hydrogenation of the nitrocompound 13 catalyzed by 10% Pd/
C afforded methanamine 5 in 99% yield.
We further tried to explore the improved protocol to synthesize
the universal precursor 18 of dinotefuran 1 by O-methyl-N-nitro-
isourea 12 and methanamine 5 (Scheme 3). According to the pre-
vious reports, the carbamimidate 18 was synthesized by treating
the methanamine 5 with 36% HCl in distilled water, and then NaCl
and O-methyl-N-nitroisourea 12 were added in subsequent order,
after that, 0.1 N HCl or 0.1 N NaOH was added to adjust the pH of the
reaction to 7.22,23 However, it is noteworthy that the acidity of the
solution is very strong when 1.0 equivalent of 36% HCl was added to
the solution of methanamine 5. Therefore, it was not reasonable to
add 0.1 N HCl or 0.1 N NaOH to adjust the pH to 7 in the reaction. We
thought that 1.0 N NaOH should be added to adjust the pH of the
reaction to 7 when NaCl and O-methyl-N-nitroisourea 12 were
added to the methanamine 5 aqueous solution, which was treated
with 36% HCl. After that, the reaction was stirred at room temper-
ature until the reaction was finished, in which 0.1 N NaOH was
All reagents and solvents purchased from commercial suppliers
were used without further purification unless otherwise specified.
Reactions were monitored by thin layer chromatography (TLC) on
glass plates precoated with silica gel with a fluorescent indicator.
Flash chromatography was performed on silica gel (200e300
mesh) purchased from Qingdao Haiyang Chemical Co. Ltd. 1H NMR
and 13C NMR spectra were collected on a Bruker AVANCE 400 MHz
spectrometer. Chemical shifts (d) are reported in parts per million
(ppm) from tetramethylsilane (TMS) using the residual solvent
resonance. Multiplicities are abbreviated as s (singlet), d (doublet), t
(triplet), q (quartet), and m (multiplet). High resolution mass
spectra (HRMS) were recorded on a Bulker microTOF-QII mass
spectrometer. Fourier transform infrared (FTIR) analysis was per-
formed using the Nicolet iS10 FTIR. All the samples were scanned in
the range from 4000 to 400 cmꢁ1 and 32 scans per sample were
collected by using the KBr pellet technique. Melting-point of solid
samples was measured by X-4 digital melting-point apparatus with
microscope (Beijing Tech Instrument Co. Ltd. is located in Beijing,
China.).
4.2. Synthesis of diethyl 2-(nitromethyl)succinate (15)
A suspension of K2CO3 (10.4 g, 0.075 mol, 0.3 equiv) in CH3NO2
(100 mL) was stirred at room temperature for 30 min, and then
diethyl maleate (16) (43.0 g, 0.25 mmol, 1.0 equiv) was added. The
reaction mixture was stirred for 12 h at room temperature. The
mixture was filtered through a pad of Celite to remove K2CO3, and
the filter cake was washed with CH2Cl2 (50 mL ꢂ 2). The solvent,
including excess CH3NO2, was evaporated to give an orange liquid.
Scheme 3. Synthesis of dinotefuran 1 from (tetrahydrofuran-3-yl)-methanamine 5.

H. Li, L. Wang / Tetrahedron 74 (2018) 336e340
339
The liquid was purified by silica gel column chromatography using
EtOAc/PE (1:8, v/v) as eluent. Diethyl 2-(nitromethyl)succinate (15)
was obtained as a colorless oil (53.6 g, 92% yield). 1H NMR
twice with water (60 mL ꢂ 3). The dichloromethane phase was
dried over Na2SO4, filtered, and concentrated. The residue was
purified by silica gel column chromatography using EtOAc/PE (1:2,
v/v) as eluent. 3-(nitromethyl)tetrahydrofuran (13) was obtained as
a colorless oil (22.3 g, 85% yield). 1H NMR (400 MHz, CDCl3)
(400 MHz, CDCl3)
d
4.82e4.77 (dd, J ¼ 8.0, 4.0 Hz, 1H), 4.71e4.66
(dd, J ¼ 8.0, 4.0 Hz, 1H), 4.21e4.17 (q, J ¼ 4.0 Hz, 2H), 4.16e4.12 (q,
J ¼ 4.0 Hz, 2H), 3.55e3.49 (m, 1H), 2.84e2.79 (dd, J ¼ 4.0, 4.0 Hz,
1H), 2.71e2.65 (dd, J ¼ 8.0, 8.0 Hz, 1H), 1.26e1.22 (t, J ¼ 8.0 Hz, 3H);
d
4.39e4.37 (d, J ¼ 8.0 Hz, 2H), 3.91e3.86 (m, 2H), 3.78e3.72 (q,
J ¼ 8.0 Hz, 1H), 3.59e3.56 (q, J ¼ 8.0 Hz, 1H), 3.05e2.94 (m, 1H),
13C NMR (101 MHz, CDCl3)
d 170.49, 170.23, 74.41, 61.84, 61.16,
2.19e2.11 (m, 1H), 1.69e1.60 (m, 1H); 13C NMR (101 MHz, CDCl3)
39.05, 32.87,14.02,13.88; IR (KBr) nmax 2985, 2940,1736,1558,1379,
1216, 1097, 1065, 1028, 858 cmꢁ1; HRMS (ESI) m/z calcd for
C9H15NNaO6 [M þ Na]þ 256.0804, found 256.0792.
d 77.67, 70.55, 67.36, 37.38, 29.41; IR (KBr) nmax 2977, 2872, 1737,
1553, 1433, 1385, 1244, 1188, 1072, 911 cmꢁ1; HRMS (ESI) m/z calcd
for C5H9NNaO3 [M þ Na]þ 154.0477, found 154.0475.
4.3. Synthesis of diethyl 2-methylenesuccinate (17)
4.6. Synthesis of (tetrahydrofuran-3-yl)methanamine (5)
A solution of nitroester (15) (23.3 g, 0.1 mol) in MeOH (20 mL)
was heated to reflux, and then NaBH4 (6.8 g, 0.18 mol) or KBH4
(9.7 g, 0.18 mol) was portionwise added. Progress of the reaction
was monitored by TLC, and when finished, it was quenched by
addition of saturated aqueous NaCl and extracted with EtOAc. The
combined organic extracts were dried over Na2SO4, filtered, and
evaporated to give diethyl 2-methylenesuccinate (17) as an orange
3-(Nitromethyl)tetrahydrofuran (13) (26.2 g, 0.2 mol) and 10%
Pd/C (2.6 g) in methanol (250 mL) were hydrogenated at 1 atm and
room temperature for 6 h. Then, the mixture was filtered through a
pad of Celite and the solid was washed by methanol (10 mL ꢂ 3).
The filtrate was concentrated in rotary evaporator to give (tetra-
hydrofuran-3-yl)-methanamine (5) in 99% yield as a yellow oil .1H
NMR (400 MHz, CD3OD)
d
3.87e3.82 (q, J ¼ 8.0, 8.0 Hz, 2H),
oil (18.6 g, 100% yield). 1H NMR (400 MHz, CDCl3)
d
6.26 (s, 1H),
3.75e3.70 (q, J ¼ 4.0, 8.0 Hz, 1H), 3.51e3.48 (t, J ¼ 8.0 Hz, 1H),
2.73e2.72 (d, J ¼ 4.0, 2H), 2.40e2.34 (m, 1H), 2.09e2.06 (m, 1H),
5.67e5.66 (d, J ¼ 4.0 Hz, 1H), 4.23e4.16 (m, 2H), 4.15e4.10 (q,
J ¼ 8.0 Hz, 2H), 3.30 (s, 2H), 1.28e1.21 (m, 6H); 13C NMR (101 MHz,
1.66e1.58 (m,1H); 13C NMR (101 MHz, CD3OD)
d 72.24, 68.71, 44.92,
CDCl3)
d
170.63, 166.10, 134.11, 127.95, 60.90, 60.76, 37.74, 14.05,
42.02, 31.05; IR (KBr) nmax 3420, 2868, 1567, 1395, 1062, 904,
819 cmꢁ1; HRMS (ESI) m/z calcd for C5H12NO [M þ H]þ 102.0919,
found 102.0913.
13.93; IR (KBr) nmax 2984, 2939, 1739, 1720, 1640, 1369, 1317, 1194,
1148, 1033, 947, 819 cmꢁ1; HRMS (ESI) m/z calcd for C9H14NaO4
[M þ Na]þ 209.0787, found 209.0784.
4.7. Synthesis of O-methyl-N-nitroisourea (12)
4.4. Synthesis of 2-(nitromethyl)butane-1,4-diol (14)
Dimethyl sulfate (63.1 g, 0.5 mol) was added to urea (30.0 g,
0.5 mol) at room temperature and the mixture was stirred in a few
minutes. The mixture was then stirred at 80 ꢀC for 24 h. After
cooling to room temperature, 98% H2SO4 (109 mL, 2.0 mol) was
added to the mixture. Then the mixture was further cooled to 5 ꢀC
and fuming nitric acid (97%, 64 mL, 1.5 mol) was added dropwise
over 0.5 h while maintaining the internal temperature to below
10 ꢀC. The ice bath was then removed and the temperature was
gradually raised to room temperature. After stirring for total 2 h,
the mixture was poured on crushed ice, neutralized by adding 30%
NaOH and extracted with ethyl acetate (80 mL ꢂ 3). The combined
ethyl acetate phase was dried over Na2SO4, filtered, and concen-
trated. The solid was washed with ethyl ether to obtain 32.2 g (54%)
A suspension of NaBH4 (14.4 g, 0.38 mol, 1.8 equiv) in THF
(200 mL) was cooled to 15e20 ꢀC with ice water. Nitroester (15)
(49.0 g, 0.21 mol) was dissolved in 55 mL of ethanol and added
dropwise to this suspension over 6 h. Once addition was completed,
the reaction mixture was naturally warmed up to room tempera-
ture and stirred for 4 h until there were no H2 bubbles released. The
resulting slurry was then heated under reflux at 63 ꢀC for 6 h as the
slurry thickened. The slurry was cooled to 15e20 ꢀC again with ice
water and 32 mL of 36% HCl was added dropwised to adjust the pH
to 7, and then a large amount of white solid was precipitated from
the reaction mixture. The precipitate was filtered, and the filter
cake was washed with THF (50 mL ꢂ 3). The combined filtrates
were evaporated to remove the solvent and then repeated the
filtration again. The filtrate was concentrated in vacuum to dryness
and the resulting residue was then dissolved in 20 mL of MeOH and
concentrated in vacuum to dryness again. The yellow oil residue
was purified by silica gel column chromatography using EtOAc/PE
(3:1, v/v) as eluent. 2-(nitromethyl)butane-1,4-diol (14) was ob-
tained as a colorless oil (23.8 g, 76% yield). 1H NMR (400 MHz,
of O-methyl-N-nitroisourea (12) as
107e109 ꢀC; 1H NMR (400 MHz, DMSO-d6)
S); 13C NMR (101 MHz, DMSO-d6)
a
white crystal. Mp:
8.88 (2H, s), 3.75 (3H,
d
d
163.31, 55.60; IR (KBr) nmax
3458, 3347, 1619, 1498, 1446, 1383, 1268, 1112, 1072, 788 cmꢁ1
;
HRMS (ESI) m/z calcd for C2H5N3NaO3 [M þ Na]þ 142.0229, found
142.0237.
CD3OD)
d
4.62e4.57 (dd, J ¼ 8.0, 8.0 Hz, 1H), 4.57e4.50 (dd, J ¼ 8.0,
4.8. Synthesis of O-methyl-N0-nitro-N00-[(tetrahydro-3-furanyl)
methyl] carbamimidate (18)
8.0 Hz, 1H), 3.67e3.60 (m, 3H), 3.58e3.53 (dd, J ¼ 8.0, 8.0 Hz, 1H),
2.54e2.46 (m, 1H), 1.72e1.62 (m, 1H), 1.60e1.53 (m, 1H); 13C NMR
(101 MHz, CD3OD)
d
77.79, 62.53, 59.94, 38.33, 32.18; IR (KBr) nmax
A solution of (tetrahydrofuran-3-yl)-methanamine (5) (20.2 g,
0.2 mol) in distilled water (84 mL) was cooled to 0 ꢀC with ice water,
and then 36% HCl (17 mL, 0.2 mol) was added. After the addition
was completed, NaCl (23.4 g, 0.4 mol) and O-methyl-N-nitroisourea
(12) (23.8 g, 0.2 mol) was added and then the pH of the reaction
mixture was adjusted to 7 with 1.0 N NaOH (140 mL, 0.14 mol).
Then the reaction mixture was stirred at room temperature for 18 h.
The pH of the reaction mixture was maintained at 7 with aliquots
0.1 N NaOH in the reaction. After completion of the reaction, the
mixture was extracted with dichloromethane (80 mL ꢂ 3). The
combined organic layer was washed with saturated NaHCO3
(80 mL) and brine (80 mL), and then dried over Na2SO4. After
3373, 2941, 1552, 1435, 1385, 1055 cmꢁ1; HRMS (ESI) m/z calcd for
C5H11NNaO4 [M þ Na]þ 172.0581, found 172.0580.
4.5. Synthesis of 3-(nitromethyl)tetrahydrofuran (13)
Diol (14) (29.8 g, 0.2 mol) was heated at 120e125 ꢀC for 2 h in
the presence of p-TsOH (3.8 g, 0.02mol), then the reaction mixture
was cooled to 80e85 ꢀC and the formed water was removed by
distillation for about 4 h. The reaction mixture was cooled to room
temperature and dissolved in dichloromethane (80 mL). The
organic layer was washed once with saturated NaHCO3 (60 mL) and

340
H. Li, L. Wang / Tetrahedron 74 (2018) 336e340
filtration of the mixture and concentrated, the crude product was
recrystallized from EtOAc/Hex (1:1, v/v) to obtain carbamimidate
(18) as a white crystal (34.9 g, 86% yield). Mp: 62e63 ꢀC; 1H NMR
Acknowledgments
We are grateful to the financial supports granted by the National
Natural Science Foundation of China (No. 21174155) and the Youth
Foundation of Gansu Province (No. 145RJYA263).
(400 MHz, CDCl3)
d 9.20 (1H, s), 3.93 (3H, S), 3.92e3.86 (1H, m),
3.81e3.70 (2H, m), 3.56e3.52(1H, m), 3.39e3.34 (2H, m),
2.56e2.46 (1H, m), 2.10e2.06 (1H, m), 1.64e1.56 (1H, m); 13C NMR
(101 MHz, CDCl3)
d 162.01, 70.77, 67.49, 56.69, 44.27, 38.70, 29.62;
Appendix A. Supplementary data
IR (KBr) nmax 3307, 2969, 2872, 1738, 1615, 1538, 1366, 1228, 1216,
910, 734 cmꢁ1; HRMS (ESI) for m/z calcd C7H13N3NaO4 [M þ Na]þ
226.0808, found 226.0798.
Supplementary data related to this article can be found at
https://doi.org/10.1016/j.tet.2017.12.002.
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4.9. Synthesis of dinotefuran (1)
A solution of carbamimidate (18) (32.5 g, 0.16 mol) in distilled
water (100 mL) was cooled to 0 ꢀC with ice water. Then 40% CH3NH2
(24.8 g, 0.32 mol) was added. After the addition was completed, the
reaction mixture was stirred at room temperature for additional
3 h. After completion of the reaction, the mixture was diluted with
0.1 N HCl to adjust pH to 6e7. Then the reaction mixture was
poured into dichloromethane (100 mL). The organic layer was
separated, and the aqueous layer was washed with dichloro-
methane (80 mL ꢂ 2) and separated. The combined organic layer
was washed with saturated NaHCO3 (100 mL) and brine solution
(100 mL). It was dried over anhydrous sodium sulfate and
concentrated to obtain a pale yellow crude solid, which was
recrystallization from EtOAc/MeOH (50:1, v/v) to give dinotefuran
(1) as a white solid (29.2 g; 90%). Mp: 100e101 ꢀC; 1H NMR
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(400 MHz, CDCl3)
d 9.32 (1H, s), 5.97 (1H, s), 3.92e3.86 (1H, dd,
J ¼ 8.0, 8.0 Hz), 3.77e3.68 (2H, m), 3.63e3.60 (1H, m), 3.33e3.32
(2H, m), 2.95 (3H, d, J ¼ 4.0 Hz), 2.61e2.60 (1H, m), 2.13e2.02 (1H,
m),1.68e1.60 (1H, m); 13C NMR (101 MHz, CDCl3)
d 158.48, 70.94,
67.56, 44.63, 38.25, 29.52, 28.14; IR (KBr) nmax 3339, 3296, 2952,
2879, 1618, 1542, 1317, 1230, 1168, 891, 786 cmꢁ1; HRMS (ESI) m/z
calcd for C7H15N4O3 [M þ H]þ 203.1146, found 203.1139.
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2007.