Safe, Metal-Free, and Direct Synthesis of Dialkyl Acylmethylidenehydrazine-1,1-dicarboxylates from Dimethylsulfoxonium Acylmethylides and Dialkyl Azodicarboxylates

Article abstract of DOI:10.1002/adsc.201900549

N-Acylhydrazones are versatile electrophiles for the synthesis of nitrogen-containing compounds. Dialkyl acylmethylidenehydrazine-1,1-dicarboxylates are a class of N-acylhydrazones and were prepared efficiently from dimethylsulfoxonium acylmethylides and dialkyl azodicarboxylates. The reaction is temperature-controlled, generating tetraalkyl 3,6-diacyl-1,2,4,5-tetrazinane-1,2,4,5-tetracarboxylates as major products accompanied by dialkyl acylmethylidenehydrazine-1,1-dicarboxylates as byproducts at low temperature, or dialkyl acylmethylidenehydrazine-1,1-dicarboxylates only at high temperature. The current direct synthetic method is a safe and transition-metal-free route for the synthesis of dialkyl acylmethylidenehydrazine-1,1-dicarboxylates. (Figure presented.).

Full text of DOI:10.1002/adsc.201900549

Title: Safe, Metal-Free, and Direct Synthesis of Dialkyl
Acylmethylidenehydrazine-1,1-Dicarboxylates from
Dimethylsulfoxonium Acylmethylides and Dialkyl
Azodicarboxylates
Authors: Bingnan Zhou, Jun Dong, and Jiaxi Xu
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10.1002/adsc.201900549
Advanced Synthesis & Catalysis
FULL PAPER
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Safe, Metal-Free, and Direct Synthesis of Dialkyl
Acylmethylidenehydrazine-1,1-dicarboxylates from
Dimethylsulfoxonium Acylmethylides and Dialkyl
Azodicarboxylates
Bingnan Zhoua, Jun Donga and Jiaxi Xua*
a
State Key Laboratory of Chemical Resource Engineering, Department of Organic Chemistry, College of Chemistry,
Beijing University of Chemical Technology, Beijing 100029, P. R. of China
Fax/Tel: +86 10 64435565; E-mail: jxxu@mail.buct.edu.cn
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.
Abstract. N-Acylhydrazones are versatile electrophiles for byproducts at low temperature,
or dialkyl
the synthesis of nitrogen-containing compounds. Dialkyl acylmethylidenehydrazine-1,1-dicarboxylates only at high
acylmethylidenehydrazine-1,1-dicarboxylates are a class of temperature. The current direct synthetic method is a safe
N-acylhydrazones and were prepared efficiently from and transition-metal-free route for the synthesis of dialkyl
dimethylsulfoxonium
acylmethylides
and
dialkyl acylmethylidenehydrazine-1,1-dicarboxylates.
azodicarboxylates. The reaction is temperature-controlled,
generating tetraalkyl 3,6-diacyl-1,2,4,5-tetrazinane-1,2,4,5-
tetracarboxylates as major products accompanied by dialkyl
acylmethylidenehydrazine-1,1-dicarboxylates as
Keywords: hydrazone; azodicarboxylate; sulfoxonium
ylide; tetrazinane; green synthesis.
c).[5] The base possibly limited the method as
Introduction
unsuitable in the preparation of
dialkyl
alkylidenehydrazine-1,1-dicarboxylates. Recently our
N-Acylhydrazones are versatile electrophiles and research group has also worked on sulfur ylide
have been widely applied in the synthesis of nitrogen- chemistry[6] and dialkyl azodicarboxylate chemistry.[7]
containing compounds, for example through reduction, After analysis of the reactivities of sulfur ylides and
the Mannich reaction, alkylation, cyanation, dialkyl azodicarboxylates, we envisioned that the
cycloaddition, radical addition, and phosphonation.[1] direct reaction of sulfur ylides and dialkyl
Dialkyl acylmethylidenehydrazine-1,1-dicarboxylates azodicarboxlyates should be utilized for the synthesis
and 1,1-dicarboxamides are
acylhydrazone derivatives with more functional dicarboxylates efficiently. Herein, we present a safe,
groups. Dialkyl acylmethylidenehydrazine-1,1- metal-free, and direct synthesis of dialkyl
dicarboxylates were first prepared from dangerous acylmethylidenehydrazine-1,1-dicarboxylates from
a
class of
N- of
dialkyl
acylmethylidenehydrazine-1,1-
and toxic diazomethyl ketones or ethyl diazoacetate dimethylsulfoxonium acylmethylides and dialkyl
with dialkyl azodicarboxylates in 1960s (Scheme 1, azodicarboxylates, and the temperature-controlled
a).[2] During the last decade, Nair’s group developed reactions of dimethylsulfoxonium acylmethylides and
Ph3P-mediated synthesis of dialkyl acylmethylidene- dialkyl azodicarboxylates (Scheme 1, d).
and
alkylidenehydrazine-1,1-dicarboxylates,
respectively, from diarylethane-1,2-diones or
diarylmethanones and dialkyl azodicarboxylates with
1.2 to 1.5 equivalents of Ph3P as an activating reagent
(Scheme 1, b).[3] Shi’s group realized a Ph3P-mediated
synthesis of dialkyl alkylidenehydrazine-1,1-
dicarboxylates from acyl cyanides and dialkyl
azodicarboxylates with an equivalent amount of Ph3P
as an activating reagent (Scheme 1, b).[4] Recently,
Jiang’s group prepared various alkylidenehydrazine-
1,1-dicarboxamides through the palladium-catalyzed
reaction of azodicarboxamides and N-tosylhydrazones,
which generated carbenes under the catalysis of
Pd(TFA)2 in the presence of base Cs2CO3 (Scheme 1,
Results and Discussion
The optimization of reaction conditions was
performed
by
using
the
reaction
of
dimethylsulfoxonium benzoylmethylide (1a) and
diethyl azodicarboxylate (2a) as the model reaction.
Initially, the reaction of 1a and 2a was conducted in a
molar ratio of 1:1 in DCE at 20 C for 12 h, affording
3a in 13% yield as minor product and its dimeric
isomeric product 4a in 41% yield as major product
(Table 1, entry 1). When 1a was increased to 3
1
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10.1002/adsc.201900549
Advanced Synthesis & Catalysis
MeCN were screened, but the yield was not further
improved (Table 1, entries 15-18). The results
indicated that the reaction efficiency could be
significantly affected by solvents. DCE was proven to
be the optimal reaction medium among the various
tested solvents. To shorten the reaction time,
microwave heating was also tested in DCE and
chlorobenzene for 0.5 h, affording 3a in 47% and
57% yields, respectively (Table 1, entries 19 and 20).
Thus, the conditions in entry 9 were selected as the
optimal conditions.
Table 1. Optimization of the reaction conditionsa)
Entrya)
Sol.
Temp.
(oC)
Time (h)
Yield
(%)b)
1a:2a
3a 4a
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
1:1
3:1
3:1
3:1
3:1
3:1
1:3
1:3
1:3
1:4
1:2
1:3
1:3
1:3
1:3
1:3
1:3
1:3
1:3
1:3
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
THF
PhCl
PhMe
MeCN
DCE
PhCl
20
20
10
0
12
12
12
12
12
12
12
12
12
12
12
24
6
13
41
67
68
67
25
25
30
14
0
0
0
0
0
0
0
0
0
66
0
0
12
12
13
5
-40
40
40
60
80
80
80
80
80
80
80
80
80
80
80
150
32
45
62
80
74
53
64
70
52
26
36
9
Scheme 1. Synthesis of Alkylidenehydrazine-1,1-
dicarboxylic Acid Derivatives.
4
4
4
4
o
equivalents and the reaction was carried out at 20 C,
10 oC, and 0 oC, the yield of 4a was improved to 67%,
68%, and 67%, respectively, with 3a in 12-13%
yields (Table 1, entries 2-4). Further decreasing the
reaction temperature resulted in obvious loss of the
yields of both 3a (5% yield) and 4a (25% yield)
(Table 1, entry 5). However, when the reaction
4
17
0.5(MW) 47
0.5(MW) 57
20
a)
The reactions were run on a 0.2-mmol scale of 1a (or 2a
b)
for the 3:1 ratio) in reaction tubes. Isolated yields after
column chromatography with petroleum ether and ethyl
acetate (8:1, v/v) as eluent.
o
temperature was raised to 40 C, the yield of 3a
increased to 32% with no change of the yield of 4a
(Table 1, entry 6). The reaction was conducted in a
molar ratio of 1:3 of 1a and 2a, affording 3a in 45%
yield and 4a in 30% yield (Table 1, entry 7). When
With the optimal reaction conditions in hand, the
scope of sulfoxonium ylides 1 was investigated
(Table 2). The reactions of benzoyl sulfoxonium
ylides with electron-donating substituents (1b, 1c, and
1d) gave the desired products 3b, 3c, and 3d in good
yields of 73-91%, probably because the presence of
the electron-donating groups increased the
nucleophilicity of the carbanion in sulfoxonium ylides
1b-d. On the other hand, this methodology was also
successfully applied to sulfoxonium ylides bearing
electron-withdrawing NO2 (1e) and halogen
substituents Br, Cl, and F (1f-k). As expected,
compared with ylides with electron-donating groups,
the yields of ylides with electron-withdrawing groups
o
the reaction temperature was increased to 60 C, the
yield of 3a was improved to 62%, while 4a was
reduced to 14% yield (Table 1, entry 8). Importantly,
the reaction conducted at 80 °C gave 3a in 80% yield
as the sole product without 4a. The results indicated
that raising the reaction temperature promoted the
generation of 3a with decreasing yield of 4a (Table 1,
entries 7-9). Further increasing or decreasing the
equivalent of 2a resulted in decreasing the yield of 3a
(Table 1, entries 10 and 11). Prolonging or shortening
the reaction time gave no further improvement in the
yield of 3a (Table 1, entries 12-14). Some other
solvents, such as THF, chlorobenzene, toluene, and
2
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10.1002/adsc.201900549
Advanced Synthesis & Catalysis
were relatively lower due to their lower
Subsequently, the reactions of different
nucleophilicity, especially for one with the nitro sulfoxonium ylides 1 with diethyl azodicarboxylate 2
o
group (1e). The structure of product 3e was verified were tested at 10 C, giving the desired products 4 in
by X-ray single crystal diffraction analysis (Figure moderate yields of 33-65% (Table 3). It seemed that
1)(CCDC 1895643).[8] It was noted that there was no both electron-rich and electron-poor substrates
obvious influence of the position of substituents on showed similar reactivity to afford the corresponding
the yield of the reaction (3g, 3h, and 3i). In addition, products 4. Product 4a was generated from 1a and 2a
sulfoxonium ylides with naphthalenecarbonyl and in 60% yield as a major product. Sulfoxonium ylide
cinnamonyl groups instead of benzoyl (1l, 1m, and bearing electron-donating group (1c) was attempted,
1n) also gave rise to the desired products 3l-n in affording 4c in 58% yield. Furthermore, ylides with
satisfactory to good yields of 60%-84%.
halo substituents (1f and 1g) were also tested,
Substrate scope of azodicarboxylates 2 was also resulting in the formation of the desired products 4f
examined (Table 2), diisopropyl azodicarboxylate and 4g in 33% and 53% yields, respectively. The
(2b) and dibenzyl azodicarboxylate (2d) were ylides (4i and 4h) with Cl atom on the ortho- and
employed to give products 3ab and 3cd in 73% and meta-positions of their phenyl group were attempted,
72% yields, respectively. It should be mentioned that showing no significant difference compared to the
a low yield was obtained when di-tert-butyl ylide (4g) with Cl on the para-position of the phenyl
azodicarboxylate (2c) was used as a reagent possibly group.
because the steric influence of the tert-butyl group
blocked the migration of the ester group (3cc).
Table 2. Synthesis of dialkyl acylmethylidenehydrazine-
1,1-dicarboxyates 3a)
Figure 1. Single crystal structure of product 3e.
Table 3. Synthesis of tetraalkyl 3,6-diacyl-1,2,4,5-
tetrazinane-1,2,4,5-tetracarboxylates 4a)
a)
All reactions were carried out with 1 (0.20 mmol) and 2
(0.6 mmol) in DCE (2.0 mL) at 80 oC for 12 h. The yields
(0.6 mmol) in DCE (2.0 mL) at 10 oC for 12 h. The yields
are isolated yields by silica gel column chromatography.
a)
All reactions were carried out with 1 (0.20 mmol) and 2
are isolated yields by silica gel column chromatography.
3
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10.1002/adsc.201900549
Advanced Synthesis & Catalysis
According to previous research,[2b] products 4
On the basis of these experimental results and
were proved unstable at room temperature. It was previous literature,[2b] we tentatively proposed the
reported that a thermal balance between 4 and their reaction mechanism as outlined in Scheme 4. At first,
hydrolytic products or two molecules of 1,3- the
zwitterionic intermediates
temperature. They could hydrolyze into the azodicarboxylate
carbanion
existed at room nucleophilically attacks the N=N bond of diethyl
(2a), affording zwitterionic
of
sulfoxonium
ylide
1a
5
corresponding carbonyl compounds 6 and N,N- intermediate A. Product 4a is its dimer after loss of
disubstituted hydrazines 7 (Scheme 2). But this DMSO. Two molecules of intermediate A undergo
phenomenon was not observed in our reaction system intermolecularly double SN2 reactions to afford 4a.
during workup. However, it was observed that 4a Regarding the other product 3a, the amide anion in
could
convert
into more
stable
product intermediate A nucleophilically attacks the carbonyl
acylmethylidenehydrazine-1,1-dicarboxyate 3a when group of the neighboring carbamate group to generate
temperature was increased in our reaction system.
intermediate B, which undergoes an isomerization to
release DMSO, affording final product 3a. The
reaction proceeds via a nitrogen to nitrogen migration
of a carboethoxy group through an intramolecular
aminolysis followed by elimination of DMSO. In
addition, the mechanism on the conversion of 4a into
3a was also proposed. It is probably the
decomposition of 4a that leads to the formation of
1,2-zwitterionic intermediate C, which processes a
similar 1,2-carboxylate group migration to afford
final product 3a (Scheme 4).
Scheme 2. Decomposition of products 4
To test the conditions that caused 4 to convert to
3, several control experiments were conducted
(Scheme 3). First of all, 4a was heated immediately in
DCE at 80 oC after isolation from the reaction system.
As expected, 4a converted into 3a completely without
any other byproducts. The light-protected conditions
were also tested, which showed no difference in the
yields and ratio of 3a and 4a compared to those
produced under standard reaction conditions. Low
temperature conditions were carried out, product 3a
still was detected in the reaction system. Thus, we
hypothesized that high temperature promoted the
conversion of 4a into 3a. To verify the thermal
conversion and to exclude the acidic effect of CDCl3,
pure 4a was dissolved in DMSO-d6 to obtain its pure
NMR spectrum. A mixture of 4a and 3a appeared in
DMSO-d6 along with time. The same results were
observed in DMSO-d6 as those in CDCl3, revealing
that acidity of CDCl3 was not the reason for the
conversion.
Scheme 4. Proposed mechanism.
Scheme 5. 1,3-Dipole intermediate capture experiments.
Scheme 3. Control experiments.
4
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10.1002/adsc.201900549
Advanced Synthesis & Catalysis
We proposed that 4a converted into 1,2- compounds can be obtained chemospecifally under
zwitterionic intermediate C, which undergoes an high temperature conditions. This method is safe,
intramolecular nucleophilic addition followed by metal-free, and convenient. Tetrazinane compounds
elimination, giving rise to 3a through a similar 1,2- decomposed into more stable hydrazones due to their
carboxylate group migration as the intermediate A to instability, indicating that heating is the major factor
3a.
to promote the decomposition of tetrazinane
Scheckenbach and co-workers previously compounds.
assumed that 1,3-zwitterionic intermediate E was an
intermediate in the conversion of 4a to 3a.[2a]
Although our proposed intermediate C and the
Scheckenbach-assumed intermediate E are resonance
forms of each other, our proposed intermediate C
should be more stable and plausible, because its non-
hydrogen atoms all have a full octet of electrons,
whereas intermediate E has a sextet carbocation
adjacent to an electron-withdrawing benzoyl group.
Thus, intermediate E should be less stable.
Experimental Section
General Information. Unless otherwise noted, all
starting materials were purchased from commercial
suppliers. Dichloromethane and 1,2-dichloroethane
were refluxed over CaH2; THF was refluxed over
lithium aluminum hydride. The solvents were freshly
distilled prior to use. Column chromatography was
performed using silica gel (normal phase, 200-300
mesh) from Branch of Qingdao Haiyang Chemical,
To verify the conversion mechanism, the capture
of the zwitterionic intermediates C or E with
nitroolefin 8 as an electrophile was attempted, in the
hope of obtaining adduct 9 (Scheme 5). To this end,
pure 4a and nitroolefin 8 were mixed and stirred at
room temperature. However, no adduct 9 was
observed. Subsequently, the reaction of sulfur ylide
1a, azodicarboxylate 2a, and nitroolefin 8 when
o
with petroleum ether (PE, 6090 C fraction) and
ethyl acetate (EA) as eluent. Reactions were
monitored by thin-layer chromatography on GF254
silica gel plates (0.2 mm) from Institute of Yantai
Chemical Industry. The plates were visualized under
UV light, as well as other TLC stains (10%
phosphomolybdic acid in ethanol; 1% potassium
permanganate in water; 10 g of iodine absorbed on 30
o
stirred in DCE at 15 C was carried out, affording a
mixture of hydrazine 3a and tetrazinane 4a, as well as
in the absence of nitroolefin 8. Under the conditions
at 60 °C, product 3a was generated in 65% yield.
Based on the current results, the possibility of the
reaction passing through zwitterionic intermediates C
and E was not verified, but not excluded either. The
intramolecular nucleophilic addition was possibly too
fast compared to the intermolecular addition with
nitroolefin 8.
1
g of silica gel). H and 13C NMR spectra were
recorded on a Bruker 400 MHz spectrometer, usually
in CDCl3 as an internal standard, and the chemical
shifts (δ) are reported in parts per million (ppm). And
multiplicities are indicated as s (singlet), d (doublet), t
(triplet), q (quartet), dd (double doublet),
m
(multiplet). Coupling constants (J) are reported in
Hertz (Hz). HRMS measurements were carried out on
an Agilent LC/MSD TOF mass spectrometer. Melting
points were obtained on a Yanaco MP-500 melting
point apparatus and are uncorrected.
A larger-scale experiment was conducted with
sulfur ylide 1l and azodicarboxylate 2a, affording
product 3l as white solid 0.87 g, 90% yield (Scheme
6).
General procedure for the synthesis of dialkyl 2-
acylmethylidenehydrazine-1,1-dicarboxylates 3
Sulfoxonium ylide 1 (2.0 mmol) was added into a
flame dried reaction tube. A solution of dialkyl
azodicarboxylate 2 (6 mmol) in freshly distilled DCE
(2 mL) was added. The reaction tube was sealed and
put in an oil bath. The reaction mixture was allowed
to stir overnight at 80 oC. Upon completion of
reaction, the reaction mixture was cooled to room
temperature. After removal of solvent in vacuum, the
residue
was
subjected
directly
to
flash
Scheme 6. Larger-scale experiment.
chromatography on silica gel with petroleum ether
and EtOAc (10:1, v/v) as eluent, affording the
corresponding product 3.
Conclusion
Diethyl (E)-2-(2-oxo-2-phenylethylidene)hydrazine-1,1-
dicarboxylate (3a)
In summary, we have developed the direct
reaction of sulfoxonium ylides and azodicarboxylates,
a new method for the preparation of hydrazone-1,1-
Colorless oil, yield: 46 mg, 80%; Rf = 0.45 (petroleum
1
ether/EtOAc 5:1, v/v). H NMR (400 MHz, CDCl3) δ 8.22
(s, 1H), 8.21 (d, J = 7.7 Hz, 2H), 7.58 (t, J = 7.4 Hz, 1H),
7.46 (t, J = 7.7 Hz, 2H), 4.41 (q, J = 7.1 Hz, 4H), 1.39 (t, J
= 7.1 Hz, 6H). 13C NMR (101 MHz, CDCl3) δ 189.3, 151.2,
dicarboxylates
and
1,2,4,5-tetrazinane-1,2,4,5-
tetracarboxylates without additives or metal-catalysts. 147.2, 135.2, 133.4, 130.6, 128.3, 64.6, 14.1. HRMS (ESI)
+
m/z [M+H]+ calcd for C14H17N2O5 : 293.1132, found:
The major products of the reaction were effectively
293.1140.
controlled by changing reaction temperature.
Tetrazinane compounds were generated as the major
Diethyl (E)-2-(2-(4-methoxyphenyl)-2-
oxoethylidene)hydrazine-1,1-dicarboxylate (3b)
products at room temperature, while hydrazone
5
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10.1002/adsc.201900549
Advanced Synthesis & Catalysis
Colorless oil, petroleum ether:EtOAc (8:1, v/v) as eluent, Colorless oil, yield: 44 mg, 68%; Rf = 0.45 (petroleum
1
yield: 46 mg, 73%; Rf = 0.26 (petroleum ether/EtOAc 5:1, ether/EtOAc 5:1, v/v). H NMR (400 MHz, CDCl3) δ 8.22
1
v/v). H NMR (400 MHz, CDCl3) δ 8.26 (d, J = 9.0 Hz, (s, 1H), 7.43 – 7.37 (m, 2H), 7.36 – 7.28 (m, 2H), 4.34 (q, J
2H), 8.10 (s, 1H), 6.94 (d, J = 9.0 Hz, 2H), 4.40 (q, J = 7.1 = 7.1 Hz, 4H), 1.32 (t, J = 7.1 Hz, 6H). 13C NMR (101
Hz, 4H), 3.87 (s, 3H), 1.39 (t, J = 7.1 Hz, 6H). 13C NMR MHz, CDCl3) δ 192.2, 151.0, 145.4, 136.6, 132.2, 131.7,
(101 MHz, CDCl3) δ 187.4, 164.0, 151.2, 148.4, 133.1, 130.4, 130.0, 126.2, 64.6, 13.9. HRMS (ESI) m/z [M+H]+
+
128.2, 113.7, 64.5, 55.5, 14.1. HRMS (ESI) m/z [M+H]+ calcd for C14H16ClN2O5 : 327.0742, found: 327.0750.
+
calcd for C15H19N2O6 : 323.1238, found: 323.1242.
Diethyl (E)-2-(2-(2-fluorophenyl)-2-
Diethyl (E)-2-(2-oxo-2-(4-methylphenyl)
oxoethylidene)hydrazine-1,1-dicarboxylate (3j)
ethylidene)hydrazine-1,1-dicarboxylate (3c)
Colorless oil, yield: 53 mg, 85%; Rf = 0.45 (petroleum
1
Colorless oil, yield: 55 mg, 90%; Rf = 0.45 (petroleum ether/EtOAc 5:1, v/v). H NMR (400 MHz, CDCl3) δ 8.33
1
ether/EtOAc 5:1, v/v). H NMR (400 MHz, CDCl3) δ 8.21 (d, J = 1.4 Hz, 1H), 7.78 (td, J = 7.7, 1.6 Hz, 1H), 7.64 –
(s, 1H), 8.14 (d, J = 8.2 Hz, 2H), 7.26 (d, J = 8.0 Hz, 2H), 7.49 (m, 1H), 7.38 – 7.25 (m, 1H), 7.20 – 7.12 (m, 1H),
4.41 (q, J = 7.1 Hz, 4H), 2.42 (s, 3H), 1.40 (t, J = 7.1 Hz, 4.41 (q, J = 7.1 Hz, 4H), 1.38 (t, J = 7.1 Hz, 6H). 13C NMR
6H). 13C NMR (101 MHz, CDCl3) δ 188.6, 151.1, 147.7, (101 MHz, CDCl3) δ 189.0, 161.2 (d, J = 255.3 Hz), 151.1,
144.4, 132.6, 130.7, 129.0, 64.5, 21.7, 14.0. HRMS (ESI) 145.7, 134.2 (d, J = 8.8 Hz), 131.4, 125.1 (d, J = 12.9 Hz),
m/z [M+H]+ calcd for C15H19N2O5 : 307.1288, found: 124.0 (d, J = 3.2 Hz), 116.3 (d, J = 22.3 Hz). 64.6, 14.0.
+
+
307.1293.
HRMS (ESI) m/z [M+H]+ calcd for C14H16FN2O5 :
311.1038, found: 311.1044.
Diethyl (E)-2-(2-(4-(tert-butyl)phenyl)-2-
oxoethylidene)hydrazine-1,1-dicarboxylate (3d)
Diethyl (E)-2-(2-(3,4-dichlorophenyl)-2-
Yellow oil, yield: 63 mg, 91%; Rf = 0.50 (petroleum oxoethylidene)hydrazine-1,1-dicarboxylate (3k)
1
ether/EtOAc 5:1, v/v). H NMR (400 MHz, CDCl3) δ 8.23 Colorless oil, yield: 45 mg, 63%; Rf = 0.45 (petroleum
1
(s, 1H), 7.88 (d, J = 8.4 Hz, 2H), 7.53 (d, J = 8.4 Hz, 2H), ether/EtOAc 5:1, v/v). H NMR (400 MHz, CDCl3) δ 8.43
4.26 (q, J = 7.1 Hz, 4H), 1.35 (s, 9H), 1.29 (t, J = 7.1 Hz, (d, J = 1.5 Hz, 1H), 8.16 (s, 1H), 8.08 (dd, J = 8.4, 1.5 Hz,
6H). 13C NMR (101 MHz, CDCl3) δ 186.1, 158.8, 153.7, 1H), 7.54 (d, J = 8.4 Hz, 1H), 4.43 (q, J = 7.1 Hz, 4H), 1.41
151.4, 131.8, 128.9, 126.0, 64.1, 35.4, 31.0, 14.1. HRMS (t, J = 7.1 Hz, 6H). 13C NMR (101 MHz, CDCl3) δ 186.9,
+
(ESI) m/z [M+H]+ calcd for C18H25N2O5 : 349.1758, found: 150.9, 145.6, 138.0, 134.6, 132.8, 132.7, 130.3, 129.7, 64.8,
+
349.1762.
14.0. HRMS (ESI) m/z [M+H]+ calcd for C14H15Cl2N2O5 :
361.0353, found: 361.0357.
Diethyl (E)-2-(2-(4-nitrophenyl)-2-
oxoethylidene)hydrazine-1,1-dicarboxylate (3e)
Diethyl (E)-2-(2-(naphthalen-1-yl)-2-
Colorless solid, yield: 37 mg, 57%; M.p. 104106 °C, Rf = oxoethylidene)hydrazine-1,1-dicarboxylate (3l)
0.34 (petroleum ether/EtOAc 5:1, v/v). 1H NMR (400 MHz, White solid, yield: 57 mg, 84%; M.p. 8081 °C, Rf = 0.45
1
CDCl3) δ 8.38 (d, J = 8.8 Hz, 2H), 8.29 (d, J = 8.8 Hz, 2H), (petroleum ether/EtOAc 5:1, v/v). H NMR (400 MHz,
8.23 (s, 1H), 4.43 (q, J = 7.1 Hz, 4H), 1.41 (t, J = 7.1 Hz, CDCl3) δ 8.47 (d, J = 8.4 Hz, 1H), 8.35 (s, 1H), 8.08 – 7.98
6H). 13C NMR (101 MHz, CDCl3) δ 188.2, 150. 9, 150.2, (m, 2H), 7.89 (d, J = 7.9 Hz, 1H), 7.68 – 7.46 (m, 3H), 4.37
145.2, 140.1, 131.8, 123.2, 64.9, 14.1. HRMS (ESI) m/z (q, J = 7.1 Hz, 4H), 1.34 (t, J = 7.1 Hz, 6H). 13C NMR (101
+
[M+H]+ calcd for C14H16N3O7 : 338.0983, found: 338.0984. MHz, CDCl3) δ 192.4, 151.2, 148.4, 133.8, 133.1, 132.6,
131.2, 131.0, 128.5, 127.9, 126.4, 125.5, 124.1, 64.5, 14.0.
HRMS (ESI) m/z [M+H]+ calcd for C18H19N2O5 : 343.1288,
+
Diethyl (E)-2-(2-(4-bromophenyl)-2-
found: 343.1293.
oxoethylidene)hydrazine-1,1-dicarboxylate (3f)
White solid, yield: 57 mg, 77%; M.p. 9092 °C, Rf = 0.34
1
(petroleum ether/EtOAc 5:1, v/v). H NMR (400 MHz, Diethyl (E)-2-(2-(naphthalen-2-yl)-2-
CDCl3) δ 8.17 (s, 1H), 8.11 (d, J = 8.5 Hz, 2H), 7.60 (d, J = oxoethylidene)hydrazine-1,1-dicarboxylate (3m)
8.5 Hz, 2H), 4.41 (q, J = 7.1 Hz, 4H), 1.40 (t, J = 7.1 Hz, Colorless oil, yield: 41 mg, 60%; Rf = 0.45 (petroleum
6H). 13C NMR (101 MHz, CDCl3) δ 188.3, 151.0, 146.4, ether/EtOAc 5:1, v/v). H NMR (400 MHz, CDCl3) δ 8.89
1
133.9, 132.2, 131.6, 128.8, 64.7, 14.0. HRMS (ESI) m/z (s, 1H), 8.31 (s, 1H), 8.19 (dd, J = 8.7, 1.4 Hz, 1H), 7.97 (d,
[M+H]+ calcd for C14H16BrN2O5 : 371.0237, found: J = 8.1 Hz, 1H), 7.88 (t, J = 8.7 Hz, 2H), 7.61 (t, J = 7.4 Hz,
+
371.0237.
1H), 7.55 (t, J = 7.5 Hz, 1H), 4.44 (q, J = 7.1 Hz, 4H), 1.41
(t, J = 7.1 Hz, 6H). 13C NMR (101 MHz, CDCl3) δ 189.0,
151.3, 147.4, 135.8, 133.4, 132.5, 132.4, 130.0, 128.8,
128.1, 127.8, 126.7, 125.5, 64.7, 14.1. HRMS (ESI) m/z
Diethyl (E)-2-(2-(4-chlorophenyl)-2-
oxoethylidene)hydrazine-1,1-dicarboxylate (3g)
White solid, yield: 47 mg, 70%; M.p. 8082 °C, Rf = 0.34
+
[M+H]+ calcd for C18H19N2O5 : 343.1288, found: 343.1291.
1
(petroleum ether/EtOAc 5:1, v/v). H NMR (400 MHz,
CDCl3) δ 8.20 (d, J = 8.6 Hz, 2H), 8.19 (s, 1H), 7.44 (d, J = Diethyl (E)-2-((E)-2-oxo-4-phenylbut-3-en-1-
8.6 Hz, 2H), 4.42 (q, J = 7.1 Hz, 4H), 1.40 (t, J = 7.1 Hz, ylidene)hydrazine-1,1-dicarboxylate (3n)
6H). 13C NMR (101 MHz, CDCl3) δ 188.1, 151.0, 146.5, Yellow oil, yield: 41 mg, 65%; Rf = 0.45 (petroleum
1
140.0, 133.5, 132.1, 128.6, 64.7, 14.0. HRMS (ESI) m/z ether/EtOAc 5:1, v/v). H NMR (400 MHz, CDCl3) δ 7.94
[M+H]+ calcd for C14H16ClN2O5 : 327.0742, found: (s, 1H), 7.84 (d, J = 16.1 Hz, 1H), 7.67 (d, J = 16.0 Hz, 1H),
+
327.0740.
7.65 – 7.62 (m, 2H), 7.42 – 7.37 (m, 3H), 4.43 (q, J = 7.1
Hz, 4H), 1.41 (t, J = 7.1 Hz, 6H). 13C NMR (101 MHz,
CDCl3) δ 187.5, 151.2, 146.7, 144.5, 134.8, 130.7, 128.9,
128.7, 120.0, 64.6, 14.1. HRMS (ESI) m/z [M+H]+ calcd
Diethyl (E)-2-(2-(3-chlorophenyl)-2-
oxoethylidene)hydrazine-1,1-dicarboxylate (3h)
Colorless oil, yield: 48 mg, 74%; Rf = 0.53 (petroleum
+
for C16H19N2O5 : 319.1288, found: 319.1297.
1
ether/EtOAc 5:1, v/v). H NMR (400 MHz, CDCl3) δ 8.26
(s, 1H), 8.18 (s, 1H), 8.09 (d, J = 7.8 Hz, 1H), 7.54 (d, J = Diisopropyl (E)-2-(2-oxo-2-phenylethylidene)hydrazine-
8.0 Hz, 1H), 7.39 (t, J = 7.9 Hz, 1H), 4.42 (q, J = 7.1 Hz, 1,1-dicarboxylate (3ab)
4H), 1.40 (t, J = 7.1 Hz, 6H). 13C NMR (101 MHz, CDCl3) Colorless oil, yield: 48 mg, 73%; Rf = 0.50 (petroleum
1
δ 187.9, 151.0, 146.0, 136.6, 134.3, 133.1, 130.7, 129.5, ether/EtOAc 5:1, v/v). H NMR (400 MHz, CDCl3) δ 8.24
128.6, 64.7, 14.0. HRMS (ESI) m/z [M+H]+ calcd for (d, J = 7.2 Hz, 2H), 8.16 (s, 1H), 7.57 (t, J = 7.4 Hz, 1H),
+
C14H16ClN2O5 : 327.0742, found: 327.0738.
7.45 (t, J = 7.7 Hz, 2H), 5.16 (hept, J = 6.3 Hz, 2H), 1.38
(d, J = 6.3 Hz, 12H). 13C NMR (101 MHz, CDCl3) δ 189.4,
150.6, 146.0, 135.3, 133.3, 130.7, 128.2, 73.1, 21.6. HRMS
Diethyl (E)-2-(2-(2-chlorophenyl)-2-
oxoethylidene)hydrazine-1,1-dicarboxylate (3i)
(ESI) m/z [M+H]+ calcd for C16H21N2O5 : 321.1445, found:
+
321.1445.
6
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10.1002/adsc.201900549
Advanced Synthesis & Catalysis
Di(tert-butyl) (E)-2-(2-oxo-2-
(d, J = 8.5 Hz, 4H), 7.49 (d, J = 8.5 Hz, 4H), 6.89 (s, 2H),
4.41 (q, J = 7.2 Hz, 2H), 4.40 (q, J = 7.2 Hz, 2H), 4.27 (q, J
phenylethylidene)hydrazine-1,1-dicarboxylate (3cc)
Colorless oil, yield: 41 mg, 56%; Rf = 0.65 (petroleum = 7.0 Hz, 4H), 1.41 (t, J = 7.2 Hz, 6H), 1.21 (t, J = 7.2 Hz,
1
ether/EtOAc 5:1, v/v). H NMR (400 MHz, CDCl3) δ 8.16 6H). 13C NMR (101 MHz, CDCl3) δ 187.6, 159.9, 151.0,
(d, J = 7.7 Hz, 2H), 7.97 (s, 1H), 7.25 (d, J = 7.7 Hz, 2H), 141.2, 131.4, 130.7, 129.3, 87.8, 69.1, 62.9, 14.5, 14.2.
2.41 (s, 3H), 1.58 (s, 18H). 13C NMR (101 MHz, CDCl3) δ HRMS (ESI) m/z [M+H]+ calcd for C28H31Cl2N4O10
189.0, 149.5, 144.13, 144.07, 132.8, 130.7, 128.9, 85.1, 653.1412, found: 653.1422.
27.8, 21.7. HRMS (ESI) m/z [M+H]+ calcd for
:
+
+
C19H27N2O5 : 363.1914, found: 363.1919.
Tetraethyl 3,6-bis(3-chlorobenzoyl)-1,2,4,5-tetrazinane-
1,2,4,5-tetracarboxylate (4h)
Dibenzyl (E)-2-(2-oxo-2-(4-methylphenyl)ethylidene)
Colorless oil, yield: 39 mg, 60%; Rf = 0.35 (petroleum
1
hydrazine-1,1-dicarboxylate (3cd)
ether/EtOAc 3:1, v/v). H NMR (400 MHz, CDCl3) δ 8.05
Colorless oil, yield: 62 mg, 72%; Rf = 0.50 (petroleum (t, J = 1.8 Hz, 2H), 7.97 (d, J = 7.8 Hz, 2H), 7.61 (ddd, J =
1
ether/EtOAc 5:1, v/v). H NMR (400 MHz, CDCl3) δ 8.24 8.0, 2.0, 1.0 Hz, 2H), 7.46 (t, J = 7.9 Hz, 2H), 6.86 (s, 2H),
(s, 1H), 7.73 (d, J = 8.2 Hz, 2H), 7.33 – 7.26 (m, 10H), 4.41 (q, J = 7.2 Hz, 2H), 4.40 (q, J = 7.2 Hz, 2H), 4.26 (q, J
7.19 (d, J = 8.1 Hz, 2H), 5.18 (s, 4H), 2.40 (s, 3H). 13C = 7.2 Hz, 4H), 1.40 (t, J = 7.2 Hz, 6H), 1.28 (t, J = 7.2 Hz,
NMR (101 MHz, CDCl3) δ 186.0, 155.6, 151.0, 145.8, 6H). 13C NMR (101 MHz, CDCl3) δ 187.6, 159.8, 153.1,
134.5, 131.7, 129.6, 129.0, 128.44, 128.41, 128.3, 69.4, 135.3, 134.6, 134.4, 130.2, 129.2, 127.3, 87.8, 69.1, 62.9,
21.8. HRMS (ESI) m/z [M+H]+ calcd for C25H23N2O5 : 14.5, 14.2. HRMS (ESI) m/z [M+H]+ calcd for
+
431.1601, found: 431.1605.
C28H31Cl2N4O10+: 653.1412, found: 653.1422.
General procedure for the synthesis of tetraethyl 3,6- Tetraethyl 3,6-bis(2-chlorobenzoyl)-1,2,4,5-tetrazinane-
dibenzoyl-1,2,4,5-tetrazinane-1,2,4,5-tetracarboxylates
4
1,2,4,5-tetracarboxylate (4i)
Colorless oil, yield: 42 mg, 65%; Rf = 0.35 (petroleum
ether/EtOAc 3:1, v/v). 1H NMR (400 MHz, CDCl3) δ 7.63 –
7.54 (m, 2H), 7.48 – 7.44 (m, 2H), 7.43 – 7.41 (m, 2H),
7.39 – 7.33 (m, 2H), 6.85 (s, 2H), 4.39 (q, J = 7.4 Hz, 2H),
4.38 (q, J = 7.4 Hz, 2H), 4.19 (q, J = 7.4 Hz, 4H), 1.39 (t, J
= 7.4 Hz, 6H), 1.21 (t, J = 7.4 Hz, 6H). 13C NMR (101
MHz, CDCl3) δ 192.5, 159.6, 154.5, 135.0, 133.1, 132.1,
130.5, 130.4, 127.0, 88.8, 69.0, 62.7, 14.4, 14.1. HRMS
(ESI) m/z [M+H]+ calcd for C28H31Cl2N4O10+: 653.1412,
found: 653.1422.
A mixture of sulfoxonium ylide 1 (6.0 mmol) and
dialkyl azodicarboxylate 2 (2 mmol) in freshly
distilled DCE (2 mL) was stirred overnight at room
temperature until the starting material 2 was
completely consumed (monitored by TLC). After
removal of solvent under reduced pressure, the
residue
was
subjected
directly
to
flash
chromatography on silica gel with petroleum ether
and EtOAc (5:1, v/v) as eluent, affording the
corresponding product 4. The NMR analysis of
product 4 must be conducted within one hour,
otherwise decomposition of 4 would occur.
Larger-scale synthesis of diethyl (E)-2-(2-(naphthalen-
1-yl)-2-oxoethylidene)hydrazine-1,1-dicarboxylate (3l)
Sulfoxonum ylide 1l (0.75 g, 3.04 mmol) and diethyl
azodicarboxylate (2a) (1.59 g, 9.14 mmol) were
dissolved in 20 mL of DCE. The mixture was allowed
to stir overnight at 80 oC. Upon completion of
reaction, the reaction mixture was cooled to room
temperature. After removal of solvent in vacuum, the
Tetraethyl 3,6-dibenzoyl-1,2,4,5-tetrazinane-1,2,4,5-
tetracarboxylate (4a)
Colorless oil, yield: 35 mg, 60%; Rf = 0.35 (petroleum
1
ether/EtOAc 3:1, v/v). H NMR (400 MHz, CDCl3) δ 8.11
(d, J = 7.6 Hz, 4H), 7.65 (d, J = 7.4 Hz, 2H), 7.54 (t, J =
7.7 Hz, 4H), 6.96 (s, 2H), 4.42 (q, J = 7.2 Hz, 2H), 4.41 (q,
J = 7.2 Hz, 2H), 4.28 (q, J = 7.1 Hz, 4H), 1.42 (t, J = 7.2
Hz, 6H), 1.29 (t, J = 7.2 Hz, 6H). 13C NMR (101 MHz,
CDCl3) δ 188.5, 159.8, 153.4, 134.4, 133.1, 129.2, 128. 9,
87.9, 69.0, 62.8, 14.5, 14.2. HRMS (ESI) m/z [M+H]+
calcd for C28H33N4O10+: 585.2191, found: 585.2195.
residue
was
subjected
directly
to
flash
chromatography on silica gel with petroleum ether
and EtOAc (8:1, v/v) as eluent, affording the
corresponding product 3l as white solid (0.87 g, 90%).
Acknowledgements
Tetraethyl 3,6-bis(4-methylbenzoyl)-1,2,4,5-tetrazinane-
1,2,4,5-tetracarboxylate (4c)
This work was supported by the National Natural Science
Foundation of China (Nos. 21572017, 21772010, and
21911530099) and the Fundamental Research Funds for the
Central Universities (XK1802-6).
Orange oil, yield: 35.5 mg, 58%; Rf = 0.35 (petroleum
1
ether/EtOAc 3:1, v/v). H NMR (400 MHz, CDCl3) δ 7.98
(d, J = 8.2 Hz, 4H), 7.31 (d, J = 8.1 Hz, 4H), 6.92 (s, 2H),
4.40 (d, J = 7.2 Hz, 2H), 4.39 (d, J = 7.2 Hz, 2H), 4.25 (q, J
= 7.1 Hz, 4H), 2.43 (s, 6H), 1.40 (t, J = 7.1 Hz, 6H), 1.33 –
1.16 (m, 6H). 13C NMR (101 MHz, CDCl3) δ 188.0, 159.8,
154.0, 145.6, 130.6, 129.6, 129.4, 87.8, 68.9, 62.7, 21.8,
14.5, 14.2. HRMS (ESI) m/z [M+H]+ calcd for
C30H37N4O10+: 613.2504, found: 613.2503.
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1
ether/EtOAc 3:1, v/v). H NMR (400 MHz, CDCl3) δ 7.89
(d, J = 6.7 Hz, 4H), 7.60 (d, J = 6.7 Hz, 4H), 6.82 (s, 2H),
4.39 – 4.29 (m, 4H), 4.25 – 4.15 (m, 4H), 1.38 – 1.29 (m,
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C28H31Br2N4O10+: 741.0401, found: 741.0413.
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1,2,4,5-tetracarboxylate (4g)
Colorless oil, yield: 35 mg, 53%; Rf = 0.35 (petroleum
1
ether/EtOAc 3:1, v/v). H NMR (400 MHz, CDCl3) δ 8.05
7
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10.1002/adsc.201900549
Advanced Synthesis & Catalysis
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8
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10.1002/adsc.201900549
Advanced Synthesis & Catalysis
FULL PAPER
Safe, Metal-Free, and Direct Synthesis of
Dialkyl
Acylmethylidenehydrazine-1,1-
Dicarboxylates
from
Dimethylsulfoxonium
Acylmethylides and Dialkyl Azodicarboxylates
Adv. Synth. Catal. 2019, xxx, Page – Page
Bingnan Zhou,a Jun Donga and Jiaxi Xua*
9
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