Cascade nitrosation and addition-elimination of nitroacetanilides for the highly efficient synthesis of 1,4,2,5-dioxadiazine derivatives

Article abstract of DOI:10.1039/c3ob42487a

A domino nitrosation and addition-elimination of nitroacetanilides with NaNO₂ and H₂SO₄ has been developed to synthesize a variety of 1,4,2,5-dioxadiazine-3,6-dicarboxamides in excellent yields. The substrate scope can be extended to aryl nitromethyl ketones. A cascade reaction mechanism is proposed and the conjugated aryl moiety is considered to help stabilize the aci-nitroso species, the key intermediates in the cascade reaction. The methodology is practical and efficient because it avoids the purification of the intermediates. The nitroacetanilides were prepared from nitroacetic acid and various anilines employing DCC-DMAP as coupling reagents, and this protocol also possesses advantages like easy handling and high yields. This journal is the Partner Organisations 2014.

Full text of DOI:10.1039/c3ob42487a

Organic &
Biomolecular Chemistry
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PAPER
Cascade nitrosation and addition–elimination of
nitroacetanilides for the highly efficient synthesis
of 1,4,2,5-dioxadiazine derivatives†
Cite this: Org. Biomol. Chem., 2014,
12, 4192
Shanyan Mo, Peipei Huang and Jiaxi Xu*
A domino nitrosation and addition–elimination of nitroacetanilides with NaNO2 and H2SO4 has been deve-
loped to synthesize a variety of 1,4,2,5-dioxadiazine-3,6-dicarboxamides in excellent yields. The substrate
scope can be extended to aryl nitromethyl ketones. A cascade reaction mechanism is proposed and the
conjugated aryl moiety is considered to help stabilize the aci-nitroso species, the key intermediates in the
cascade reaction. The methodology is practical and efficient because it avoids the purification of the inter-
mediates. The nitroacetanilides were prepared from nitroacetic acid and various anilines employing DCC–
DMAP as coupling reagents, and this protocol also possesses advantages like easy handling and high yields.
Received 12th December 2013,
Accepted 1st April 2014
DOI: 10.1039/c3ob42487a
www.rsc.org/obc
ponding oximes, generated from aldehydes and hydroxylamine
hydrochloride (Scheme 1). Therefore, this method suffers from
Introduction
Scientists have never stopped pursuing maximum efficiency drawbacks such as tedious steps, poor yields, and poor chemo-
during their research. Cascade reactions, being able to selectivity in the dimerization step. Therefore, a novel protocol
proceed two or more consecutive steps of reactions without involving high efficiency in both yield and reaction steps is
purification of the intermediates, have received increasing still required.
interest from the chemical community.1
Although with only rare reports, the elimination of nitrous
1,4,2,5-Dioxadiazine is the key structure of effective explo- acid from nitrooximes can generate 1,4,2,5-dioxadiazines.2,6
sives BNDD [3,6-bis(4-nitro-1,2,5-oxadiazol-3-yl)-1,4,2,5-dioxa- Recently, Kobayashi and co-workers revealed the nitrosation of
diazene] and BADD [3,6-bis(4-amino-1,2,5-oxadiazol-3-yl)- cyanoacetanilides and further use of their products aci-nitroso-
1,4,2,5-dioxadiazene]2 (Fig. 1), and it can be incorporated into cyanoacetanilides to synthesize quinoxalinone-N-oxides.7 We
chelating and bridging ligands.3 Since the first synthesis of hypothesized that nitrosation of nitroacetamides should be
1,4,2,5-dioxadiazenes,4 almost 120 years have passed. However, also achievable, and envisioned that two equivalents of gener-
little progress has been made towards synthetic methods for ated aci-nitrosonitroacetanilides will undergo intermolecular
1,4,2,5-dioxadiazenes. Most of the reported 1,4,2,5-dioxadia- addition–elimination to afford 1,4,2,5-dioxadiazine-3,6-dicar-
zenes were synthesized via the traditional approach: dimeriza- boxamides by loss of two equivalents of nitrous acid.
tion of nitrile oxides.2–5 The nitrile oxides were obtained from
In regard of the synthesis of nitroacetamides, there is no
halogenated oximes, which were prepared from the corres- universal method available. The aminolysis of nitroacetic
Fig. 1 Explosives BNDD and BADD.
State Key Laboratory of Chemical Resource Engineering, Department of Organic
Chemistry, Faculty of Science, Beijing University of Chemical Technology, Beijing
100029, People’s Republic of China. E-mail: jxxu@mail.buct.edu.cn;
Fax: +86 10 64435565
†Electronic supplementary information (ESI) available: Copies of 1H and 13C
NMR spectra of compounds 2, 3, 6, 7a, 8, and 10. See DOI: 10.1039/c3ob42487a
Scheme 1 Synthesis of 1,4,2,5-dioxadiazenes.
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amount of DMAP (4-dimethylaminopyridine, 0.5 equivalent to
DCC) as an additive, affording N-benzyl-2-nitro-N-phenylaceta-
mide (2a) in 43% yield (Table 1, entry 1). Changing the addi-
tive to HOBt (1-hydroxybenzotriazole) did not improve the
yield (Table 1, entry 2). Although it has a similar function in
coupling as DCC, EDC [N-(3-dimethylaminopropyl)-N′-ethylcar-
bodiimide] did not show any coupling performance in the
reaction, even with HOBt as the additive (Table 1, entries
3 and 4). Uronium/aminium salt HBTU [O-(benzotriazol-1-yl)-
N,N,N′,N′-tetramethyluronium hexafluorophosphate] was also
applied but no 2a was generated (Table 1, entry 5). Then the
loading molar ratio of the acid and DCC was further optimized
(Table 1, entries 6–12). When the loading amount of the acid
was increased to 2.0 equivalents and coupling reagent to 1.5
equivalents, the amide was obtained in almost quantitative
yield (Table 1, entry 8). However, considering that the bypro-
duct DCU (1,3-dicyclohexylurea) was a little difficult to entirely
remove, we tried to decrease the excessive loading of DCC
while maintaining the perfect yield. Decreasing the loading
amount of DCC to 1.2 equivalents led to a dropped yield of
51% (Table 1, entry 9), and the yield raised to 84% when
increasing nitroacetic acid to 2.2 equivalents, but dropped to
54% when nitroacetic acid was increased to 2.5 equivalents
(Table 1, entry 11). Thus, we needed to increase the loading
amount of DCC. However, the yield was 85% when 1.4 equiva-
lents of DCC were used (Table 1, entry 11), not as good as
when using 1.5 equivalents. Therefore, 2.0 equivalents of
nitroacetic acid and 1.5 equivalents of DCC were the optimal
loading amounts for the reaction.
Scheme 2 Synthesis of nitroacetamides.
esters is a traditional method to produce the corresponding
amides. The method is very limited because harsh reaction
conditions are needed and the high acidity of the hydrogen
atom on the 2-position carbon in nitroacetic esters would lead
to salt formation with amines.8 Another approach upon
nitration of pre-formed acetamides suffers from unwelcome
use of moisture sensitive base (LDA9 or NaNH2 10), low temp-
erature (−25 °C), and the toxic and explosive reagent (RONO2),
so its application is also rare. The method of conversion of
1-amino-1-methylthio-2-nitroethenes to 2-nitroacetamides is
really special among amide bond formation protocols;
however, highly functionalized precursor 1,2-bismethylthio-2-
nitroethane and poisonous Hg(II) dichloride are indispensable,
so this approach is hardly a general one (Scheme 2).11 Mios-
kowski and Charette accomplished the esterification of nitro-
acetic acid with various alcohols in the presence of DCC (N,N′-
dicyclohexylcarbodiimide).12 Thus, we assumed that the
method can be extended to condense nitroacetic acid and
amines for the synthesis of nitroacetamides.13
With the optimized set of reaction conditions, we next
investigated the scope and limitation of the coupling reaction
with respect to different amines (Table 2). All alkyl aryl amines
worked well in the reaction whether the anilines had electron-
withdrawing or electron-donating aromatic substituents
Table 1 Optimization of coupling reagentsa
Herein, we report an easily accessible protocol to prepare
nitroacetanilides, and then the use of the nitroacetanilides
afforded to develop a highly efficient method to synthesize
1,4,2,5-dioxadiazine-3,6-dicarboxamides via the cascade nitro-
sation and intermolecular addition–elimination. Although the
explosives BNDD and BADD are important 1,4,2,5-dioxadiazine
derivatives, they were not our target molecules due to their
explosive property.
Amine : acid : reagent :
additive (equiv.)
Entry
Reagents
Yieldb (%)
1
2
3
4
5
6
7
8
9
DCC–DMAP
DCC–HOBt
EDC–DMAP
EDC–HOBt
HBTU–TEAc
DCC–DMAP
DCC–DMAP
DCC–DMAP
DCC–DMAP
DCC–DMAP
DCC–DMAP
DCC–DMAP
1.0 : 1.2 : 1.2 : 0.06
1.0 : 1.2 : 1.2 : 1.2
1.0 : 1.2 : 1.2 : 0.06
1.0 : 1.2 : 1.2 : 1.2
1.0 : 1.2 : 1.2 : 2.4
1.0 : 1.5 : 1.2 : 0.06
1.0 : 1.5 : 1.5 : 0.07
1.0 : 2.0 : 1.5 : 0.07
1.0 : 2.0 : 1.2 : 0.06
1.0 : 2.2 : 1.2 : 0.06
1.0 : 2.5 : 1.2 : 0.06
1.0 : 2.2 : 1.4 : 0.07
43
33
0
Trace
0
55
66
99
51
84
54
85
Results and discussion
Synthesis of nitroacetanilides via coupling of nitroacetic acid
10
11
12
and anilines
We first examined the condensation of nitroacetic acid and
a The reactions were performed on a 2 mmol scale in 10 mL of
dichloromethane. b Isolated yield after column chromatography on
N-phenylbenzylamine (1a) using a variety of coupling reagents
(Table 1). DCC was first employed in the reaction with a small silica gel. c The reaction was conducted in CH3CN.
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acidic solvent AcOH, chlorinated solvent DCM and chloroform,
and strongly polar aprotic solvent DMF, seemed to be totally
ineffective for the reaction (Table 3, entries 2–6).
Table 2 Scope and limitation of the coupling reaction of nitroacetic
acid and amines with DCC–DMAP
All the nitroacetanilides (2a–2l) were investigated under the
optimized reaction conditions, and all reactions proceeded
smoothly, although different reaction times were required for
complete consumption of the substrates in each of the cases
(Table 4). Nitroacetanilides 2a,c–f with different N-alkyl groups
were successfully converted into 1,4,2,5-dioxadiazine-3,6-dicar-
boxamides 3a,c–f in good to excellent yields (72–99%) (Table 4,
entries 1, 3–6). However, the reaction of secondary aniline 2b
produced 3b in only 35% yield (Table 4, entry 2), presumably
because the active N-H in the amide would result in the for-
mation of its enolate, which reduces the electrophilicity of the
CvN bond in the oxime, affecting the cyclization. N,N-Diphe-
nyl-nitroacetamide (2g) with two phenyl groups on the nitro-
gen gave rise to N3,N3,N6,N6-tetraphenyl-1,4,2,5-dioxadiazine-
3,6-dicarboxamide (3g) in 83% yield (Table 4, entry 7). Reac-
tions of N-benzyl-nitroacetanilides 2h–j with a substituted elec-
tron-donating methyl group at different positions of the
N-phenyl group were attempted under the optimized reaction
conditions, and all of the reactions gave rise to the corres-
ponding 1,4,2,5-dioxadiazine-3,6-dicarboxamides 3h–j in good
to excellent yields (83%–99%) (Table 4, entries 8–10). Finally,
N-benzyl-nitroacetanilides 2k–l with substituted electron-with-
drawing halogenated groups on the para-position of the
N-phenyl group furnished the desired 1,4,2,5-dioxadiazine-
3,6-dicarboxamides 3k–l as well (Table 4, entries 11–12).
To gain mechanistic insight into the cascade reaction, we
isolated one of the aci-nitrosonitroacetanilide intermediates
(4c) and investigated the reactivity of it. Intermolecular
addition–elimination of 4c proceeded smoothly to give rise to
3c in 92% yield under the same conditions that generated 4c
(Scheme 3).
Entry
R1
R2
Product
Yielda,b (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
Bn
H
Me
n-Pr
i-Pr
4-ClBn
Ph
Bn
Bn
Bn
Bn
Ph
Ph
Ph
Ph
Ph
Ph
Ph
2a
2b
2c
2d
2e
2f
2g
2h
2i
99
70
96
99
83
85
70
75
96
90
79
64
0
2-CH3C6H4
3-CH3C6H4
4-CH3C6H4
4-BrC6H4
4-IC6H4
Bn
2j
2k
2l
Bn
Bn
2m
a The reactions were performed on a 2 mmol scale in 10 mL of solvent.
Amine : acid : DCC (equiv.) = 1.0 : 2.0 : 1.5. b Isolated yield after column
chromatography on silica gel.
(Table 2, entries 1–12). Unfortunately, dibenzylamine, a dialkyl
amine, failed in the coupling reaction (Table 2, entry 13). As a
result, a dozen 2-nitroacetanilides were synthesized in moder-
ate to perfect yields.
Cascade nitrosation and intermolecular addition–elimination
of nitroacetamides
N-Benzyl-nitroacetanilide (2a) was selected as a model sub-
strate for the cascade nitrosation and intermolecular addition–
elimination towards 1,4,2,5-dioxadiazine-3,6-dicarboxamide
(3a). Surprisingly, the victory was won at the first battle. The
target molecule 3a was obtained in a perfect yield using
sodium nitrite as the nitrosation reagent in the presence of
H2SO4 (Table 3, entry 1). During the reaction, an intermediate
aci-nitrosonitroacetanilide was observed could be isolated.
Other solvents, including protic solvent MeOH, protic and
Table 4 Transformation of nitroacetanilides to 1,4,2,5-dioxadiazines via
the cascade reaction
Table 3 Optimization of solvent and reagent for the cascade reactiona
Entry
R1
R2
Product
Time (h)
Yielda,b (%)
1
2
3
4
5
6
7
8
9
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Bn
H
Me
n-Pr
i-Pr
4-ClBn
Ph
Bn
Bn
Bn
Bn
3a
3b
3c
3d
3e
3f
3g
3h
3i
120
48
120
100
48
72
24
120
61
120
24
99
35
92
97
72
85
83
83
97
99
80
87
Entry
Reagent
Solvent
Time (h)
Yieldb (%)
1
2
3
4
5
6
NaNO2–H2SO4
NaNO2–H2SO4
NaNO2–H2SO4
NaNO2–H2SO4
NaNO2–H2SO4
NaNO2–H2SO4
CH3CN
MeOH
CHCl3
CH2Cl2
AcOH
DMF
120
>120
>120
>120
>120
>120
99
No Rxnc
No Rxnc
No Rxnc
No Rxnc
No Rxnc
2-CH3C6H4
3-CH3C6H4
4-CH3C6H4
4-BrC6H4
4-IC6H4
10
11
12
3j
3k
3l
Bn
72
a The reactions were performed on an 80 mg scale of 2a in 4 mL of
solvent. b Isolated yield after column chromatography on silica gel. a The reactions were performed on 80 mg scale of 2 in 4 mL of solvent.
c No Rxn = no reaction occurred.
b Isolated yield after column chromatography on silica gel.
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Scheme 5 Plausible mechanism for the transformation of aci-nitroso-
nitroacetanilides to 1,4,2,5-dioxadiazine-3,6-dicarboxamides in the
absence of NaNO2–H2SO4.
Scheme 3 Transformation of aci-nitrosonitroacetanilide (4c) to 1,4,2,5-
dioxadiazine-3,6-dicarboxamide (3c).
Firstly, the hydroxy group in aci-nitroso species 4 undergoes a
nucleophilic addition to the electron-deficient imine group in
another molecule of 4. Then the protons transfer from the six-
membered ring to the nitro groups, and two molecules of
nitrous acid are eliminated, furnishing 1,4,2,5-dioxadiazines
(Scheme 5). It should be noted that this mechanism can be
involved in the cascade reaction since the conversion of 4c to
3c occurred in similar yields during the same time whether in
the presence or absence of an acid. On the other hand, the
rate determined step should be irrelevant to the acid-partici-
pating steps.
To extend the application and the substrate scope of the
developed cascade reaction, we tested other nitromethylene-
compounds (Scheme 6). First, N,N-dibenzyl-nitroacetamide
(2m), an N,N-dialkyl substituted nitroacetamide, was prepared
by nitration of N,N-dibenzylacetamide (5)9 and subjected to
the optimized reaction conditions. However, no desired
product was generated. Nitroacetophenone (6a) and nitro-
acetone (6b) were synthesized from nitromethane and the
corresponding N-acylimidazoles and subjected to the cascade
reaction. 2-Nitroacetophenone (6a) successfully gave rise to the
corresponding 3,6-dibenzoyl-1,4,2,5-dioxadiazine (7a) in only
9% yield at room temperature for 8 days. However, the yield
was improved to 75% when the reaction was performed under
refluxing conditions for 10 hours. Whereas, nitroacetone (6b)
failed to produce the expected 3,6-diacetyl-1,4,2,5-dioxadiazine
After taking these results into consideration, a plausible
mechanism for the cascade reaction is proposed (Scheme 4).
Initially, the active methylene of 2 reacts with a nitrosyl cation
to generate aci-nitroso species 4 after isomerization. Sub-
sequently, the nitro group is protonated under the acidic con-
ditions, and the hydroxy group in aci-nitroso species 4
undergoes a nucleophilic addition to the electron-deficient
imine group in another molecule of 4. It should be noted that
the nucleophilic additions might take place simultaneously or
asynchronously. After the elimination of two molecules of
nitrous acid and the deprotonation of the oxonium in the six-
membered ring, 1,4,2,5-dioxadiazines are generated. The cycli-
zation can occur smoothly at room temperature because the
imine group shows strong electrophilicity due to its attach-
ment to two electron-withdrawing groups, nitro and amide
groups.
To our surprise, when the intermediate aci-nitrosonitroace-
tanilide 4c was stirred in MeCN in the absence of NaNO2–
H2SO4 at room temperature, the desired product 2c was
obtained as well, though in slightly lower yield than in the
presence of NaNO2–H2SO4 (Scheme 3). This fact indicates that
the cyclization can occur without the participation of the acid.
Thus, we present an alternative plausible mechanism for the
transformation of aci-nitrosonitroacetanilides to 1,4,2,5-dioxa-
diazine-3,6-dicarboxamides in the absence of NaNO2–H2SO4.
Scheme 4 Plausible mechanism for the cascade reaction.
Scheme 6 Extension of the substrate scope.
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(7b). The above experimental results indicate that all substrates DCC (825 mg, 3 mmol) and DMAP (25 mg, 0.2 mmol) in
with conjugated aryl moieties generated the desired 1,4,2,5- CH2Cl2 (5 mL) at 0 °C. The resulting solution was stirred for
dioxadiazine derivatives. On the contrary, no reaction occurred 4 h. During this period white solid DCU was precipitated and
for all the substrates without conjugated aryl moieties. In subsequently removed by filtration. After removal of the
addition, it is noteworthy that for the reactions that succeeded solvent under reduced pressure, the resulting residue was puri-
to produce 1,4,2,5-dioxadiazine derivatives, aci-nitroso species fied by silica gel column chromatography to give the pure
were observed on TLC monitoring. Therefore, we propose that product 2.
the conjugated aryl moiety may have a great impact to stabilize
N-Benzyl-2-nitro-N-phenylacetamide (2a). 267 mg, 99%
the aci-nitroso species, the intermediates for the reaction, yield. Colorless crystals, m.p. 117–118 °C. Rf = 0.39 (silica gel
making the reaction proceed successfully. Furthermore, reac- plate, ethyl acetate–petroleum ether 1 : 3, v/v). 1H NMR
tions with methyl nitroacetate (8) and 1-nitro-4-(nitromethyl)- (400 MHz, CDCl3) δ: 7.39–7.37 (m, 3H, ArH), 7.28–7.26 (m, 3H,
benzene (10) were attempted as well, but failed to produce the ArH), 7.21–7.18 (m, 2H, ArH), 7.03–7.00 (m, 2H, ArH), 4.96 (s,
desired products, possibly the methylene in 10 is not active 2H, CH2NO2), 4.93 (s, 2H, NCH2). 13C NMR (100 MHz, CDCl3)
enough to cause the nitrosation step to proceed, which is a δ: 160.7 (CvO), 139.6 (C), 135.8 (C), 130.2 (CH), 129.4 (CH),
necessary step for the reaction.
129.0 (CH), 128.6 (CH), 128.2 (CH), 127.9 (CH), 77.1 (CH2NO2),
53.6 (NCH2). IR (DCM) ν (cm−1): 1681 (CvO), 1562 (NO2), 1375
(NO2). HRMS (ESI) calcd for C15H15N2O3 [M + H]+ m/z
271.1077, found 271.1081.
2-Nitro-N-phenylacetamide (2b). 115 mg, 64% yield. Color-
less crystals, m.p. 149–151 °C, lit.14 m.p. 136–138 °C. Rf = 0.15
(silica gel plate, ethyl acetate–petroleum ether 1 : 3, v/v).1H
NMR (300 MHz, DMSO-d6) δ: 10.57(s, 1H, NH), 7.57 (d, J = 7.7
Hz, 1H, ArH), 7.35 (t, J = 7.7 Hz, 1H, ArH), 7.12 (t, J = 7.7 Hz,
1H, ArH), 5.54 (s, 2H, CH2). 13C NMR (75 MHz, DMSO-d6) δ:
159.8 (CvO), 129.0 (CH), 137.9 (C), 124.3 (CH), 119.4 (CH),
79.3 (CH2NO2).
N-Methyl-2-nitro-N-phenylacetamide (2c). 186 mg, 96%
yield. Colorless crystals, m.p. 63–65 °C. Rf = 0.43 (silica gel
plate, ethyl acetate–petroleum ether 1 : 3, v/v). 1H NMR
(400 MHz, CDCl3) δ: 7.51–7.42 (m, 3H, ArH), 7.26 (d, J = 7.6 Hz,
2H, ArH), 4.99 (s, 2H, CH2), 3.36 (s, 3H, CH3). 13C NMR
(100 MHz, CDCl3) δ: 160.7 (CvO), 141.4 (C), 130.5 (CH), 129.2
(CH), 127.0 (CH), 76.9 (CH2), 37.8 (CH3). IR (DCM) ν (cm−1):
1661 (CvO), 1595 (NO2), 1356 (NO2). HRMS (ESI) calcd for
C9H10N2NaO3 [M + Na]+ m/z 217.0584, found 217.0588.
Conclusion
In summary, we first developed an effective and practical
method to synthesize nitroacetanilides by coupling nitroacetic
acid and anilines with DCC–DMAP as coupling reagents. Then
we used the nitroacetanilides to exploit a cascade nitrosation
and intermolecular addition–elimination to access 1,4,2,5-
dioxadiazine-3,6-dicarboxamides with NaNO2–H2SO4. The
latter reaction is broad in scope with respect to the nitroaceta-
nilides, with up to 99% yield. The substrate scope can be
extended to aryl nitromethyl ketones. A cascade reaction
mechanism was proposed and the conjugated aryl moiety is
considered to help stabilize the aci-nitroso species, the key
intermediates in the cascade reaction.
Experimental section
General information
2-Nitro-N-phenyl-N-propylacetamide (2d). 115 mg, 52%
yield. Colorless crystals, m.p. 64–65 °C. Rf = 0.39 (silica gel
plate, ethyl acetate–petroleum ether 1 : 3, v/v). 1H NMR
(400 MHz, CDCl3) δ: 7.51–7.42 (m, 3H, ArH), 7.23 (d, J = 6.9 Hz,
2H, ArH), 4.94 (s, 2H, CH2NO2), 3.73 (t, J = 7.6 Hz, 2H, NCH2),
1.58 (sextet, J = 7.6 Hz, 2H, CH2CH3), 0.93 (d, J = 7.6 Hz, 3H,
CH3). 13C NMR (100 MHz, CDCl3) δ: 160.4 (CvO), 140.0 (C),
130.4 (CH), 129.3 (CH), 128.0 (CH), 77.2 (CH2NO2), 51.5
(NCH2), 20.6 (NCH2CH2), 11.1 (CH3). IR (DCM) ν (cm−1): 1681
(CvO), 1557 (NO2), 1373 (NO2). HRMS (ESI) calcd for
C11H15N2O3 [M + H]+ m/z 223.1077, found 223.1081.
N-Isopropyl-2-nitro-N-phenylacetamide (2e). 185 mg, 83%
yield. Colorless crystals, m.p. 90–91 °C. Rf = 0.31 (silica gel
plate, ethyl acetate–petroleum ether 1 : 3, v/v). 1H NMR
(400 MHz, CDCl3) δ: 7.51–7.47 (m, 3H, ArH), 7.20–7.18 (m, 2H,
ArH), 4.98 (hept, J = 6.8 Hz, 1H, CH), 4.83 (s, 2H, CH2), 1.12 (d,
J = 6.8 Hz, 6H, CH3 × 2). 13C NMR (100 MHz, CDCl3) δ: 160.2
(CvO), 136.1 (C), 130.0 (CH), 129.9 (CH), 129.6 (CH), 77.7
(CH2NO2), 47.6 (CH), 20.6 (CH3). IR (DCM) ν (cm−1): 1673
Melting points (m.p.) were determined on
a Yanaco
1
MP-500 melting point apparatus and are uncorrected. H and
13C NMR spectra were recorded on a Brucker 400 NMR spectro-
meter at 400 MHz and 100 MHz, respectively, in CDCl3 with
TMS as the internal standard and chemical shifts are reported
in ppm. IR spectra were taken on a Nicolet AVATAR 330 FT-IR
spectrometer in dichloromethane (DCM). HRMS spectra were
performed on a Brucker LC/MSD TOF mass spectrometer.
Reagents used were obtained from commercial suppliers and
used without purification. Column chromatography was carried
out with silica gel (200–300 mesh) with petroleum ether (PE,
60 °C–90 °C) and ethyl acetate (EA) as the eluent. All reactions
were followed by thin-layer chromatography (TLC) where practi-
cal, using silica gel 60 F254 fluorescent treated silica gel plates,
which were visualised under UV light (250 nm).
General procedure for the preparation of nitroacetanilides
2 using DCC–DMAP as coupling reagents
To a suspension of nitroacetic acid (315 mg, 3 mmol) in (CvO), 1560 (NO2), 1379 (NO2). HRMS (ESI) calcd for
CH2Cl2 (5 mL) was added a solution of amine 1 (2 mmol), C11H15N2O3 [M + H]+ m/z 223.1077, found 223.1084.
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N-(4-Chlorobenzyl)-2-nitro-N-phenylacetamide (2f). 258 mg,
N-Benzyl-N-(4-bromophenyl)-2-nitroacetamide (2k). 274 mg,
85% yield. Colorless crystals, m.p. 95–96 °C. Rf = 0.42 (silica 79% yield. Colorless crystals, m.p. 114–115 °C. Rf = 0.46 (silica
gel plate, ethyl acetate–petroleum ether 1 : 3, v/v). 1H NMR gel plate, ethyl acetate–petroleum ether 1 : 3, v/v). 1H NMR
(400 MHz, CDCl3) δ: 7.42–7.39 (m, 3H, ArH), 7.26 (d, J = 8.0 Hz, (400 MHz, CDCl3) δ: 7.51 (d, J = 8.6 Hz, 2H, ArH), 7.31–7.27 (m,
2H, ArH), 7.14 (d, J = 8.0 Hz, 2H, ArH), 7.04–7.00 (m, 2H, ArH), 3H, ArH), 7.20–7.16 (m, 2H, ArH), 6.89 (d, J = 8.6 Hz, 2H, ArH),
4.96 (s, 2H, CH2NO2), 4.89 (s, 2H, NCH2). 13C NMR (100 MHz, 4.96 (s, 2H, CH2NO2), 4.90 (s, 2H, NCH2). 13C NMR (100 MHz,
CDCl3) δ: 160.8 (CvO), 139.4 (C), 134.3 (C), 133.9 (C), 130.4 CDCl3) δ: 160.5 (CvO), 138.5 (C), 135.4 (C), 133.5 (CH), 129.9
(CH), 130.4 (CH), 129.5 (CH), 128.8 (CH), 128.1 (CH), 77.0 (CH), 129.0 (CH), 128.7 (CH), 128.1 (CH), 123.6 (C), 76.9
(CH2NO2), 53.0 (NCH2). IR (DCM) ν (cm−1): 1681 (CvO), 1557 (CH2NO2), 53.6 (NCH2). IR (DCM) ν (cm−1): 1681 (CvO), 1557
(NO2), 1373 (NO2). HRMS (ESI) calcd for C15H14ClN2O3 (NO2), 1372 (NO2). HRMS (ESI) calcd for C15H14BrN2O3
[M + H]+ m/z 305.0687, found 305.0690.
[M + H]+ m/z 349.0182, found 349.0186.
2-Nitro-N,N-diphenylacetamide (2g). 107 mg, 42% yield.
N-Benzyl-N-(4-iodophenyl)-2-nitroacetamide (2l). 253 mg,
Colorless crystals, m.p. 155–156 °C. Rf = 0.39 (silica gel plate, 64% yield. Colorless crystals, m.p. 124–125 °C. Rf = 0.43 (silica
ethyl acetate–petroleum ether 1 : 3, v/v). 1H NMR (400 MHz, gel plate, ethyl acetate–petroleum ether 1 : 3, v/v). 1H NMR
CDCl3) δ: 7.47–7.23 (m, 10H, ArH), 5.14 (s, 2H, CH2NO2). 13C (400 MHz, CDCl3) δ: 7.71 (d, J = 8.5 Hz, 2H, ArH), 7.30–7.27 (m,
NMR (100 MHz, CDCl3) δ: 160.6 (CvO), 141.1 (C), 140.4 (C), 3H, ArH), 7.19–7.17 (m, 2H, ArH), 6.75 (d, J = 8.5 Hz, 2H, ArH),
130.5 (CH), 129.3 (CH), 129.1 (CH), 128.4 (CH), 127.0 (CH), 4.96 (s, 2H, CH2NO2), 4.90 (s, 2H, NCH2). 13C NMR (100 MHz,
125.7 (CH), 77.7 (CH2NO2). IR (DCM) ν (cm−1): 1682 (CvO), CDCl3) δ: 160.4 (CvO), 139.5 (CH), 139.2 (C), 135.5 (C), 130.1
1559 (NO2), 1364 (NO2). HRMS (ESI) calcd for C14H13N2O3 (CH), 129.0 (CH), 128.7 (CH), 128.1 (CH), 95.2 (C), 76.9
[M + H]+ m/z 257.0921, found 257.0924.
(CH2NO2), 53.6 (NCH2). IR (DCM) ν (cm−1): 1681 (CvO), 1557
N-Benzyl-2-nitro-N-(o-tolyl)acetamide (2h). 213 mg, 75% (NO2), 1374 (NO2). HRMS (ESI) calcd for C15H14IN2O3 [M + H]+
yield. Colorless crystals, m.p. 71–74 °C. Rf = 0.52 (silica gel m/z 397.0044, found 397.0049.
plate, ethyl acetate–petroleum ether 1 : 3, v/v). 1H NMR
Preparation of 2-(hydroxyimino)-N-methyl-2-nitro-N-
phenylacetamide (4c)
(400 MHz, CDCl3) δ: 7.32–7.25 (m, 4H, ArH), 7.20–7.12 (m, 3H,
ArH), 6.78 (d, J = 7.8 Hz, 1H, ArH), 5.27 (d, J = 13.9 Hz, 1H, 1H
in CH2NO2), 4.89 (d, J = 13.7 Hz, 1H in NCH2), 4.75 (d, J = 13.7 To
a mixture of N-methyl-2-nitro-N-phenylacetamide (2c)
Hz, 1H in NCH2), 4.41 (d, J = 13.9 Hz, 1H, 1H in CH2NO2), 2.12 (80 mg, 0.412 mmol) and sodium nitrite (142 mg, 2.06 mmol)
(s, 3H, CH3). 13C NMR (100 MHz, CDCl3) δ: 161.0 (CvO), 137.9 in MeCN (4.0 mL) was added sulfuric acid (206 mg,
(C), 135.9 (C), 135.6 (C), 132.0 (CH), 129.7 (CH), 129.5 (CH), 2.06 mmol) at 0 °C. The mixture was stirred for 2 days (the
129.2 (CH), 128.5 (CH), 128.0 (CH), 127.6 (CH), 77.1 (CH2NO2), reaction was monitored by TLC until complete consumption of
52.7 (NCH2), 17.2 (CH3). IR (DCM) ν (cm−1): 1680 (CvO), 1562 2c), and water (5 mL) was added, followed by addition of
(NO2), 1375 (NO2). HRMS (ESI) calcd for C16H17N2O3 [M + H]+ dichloromethane (5 mL). The organic phase was separated,
m/z 285.1234, found 285.1238.
dried over anhydrous sodium sulfate, and concentrated. The
N-Benzyl-2-nitro-N-(m-tolyl)acetamide (2i). 273 mg, 96% residue was purified by silica gel column chromatography to
yield. Colorless crystals, m.p. 90–91 °C. Rf = 0.46 (silica gel afford the pure product 4c.
plate, ethyl acetate–petroleum ether 1 : 3, v/v). 1H NMR
2-(Hydroxyimino)-N-methyl-2-nitro-N-phenylacetamide (4c).
(400 MHz, CDCl3) δ: 7.31–7.27 (m, 3H, ArH), 7.25 (d, J = 7.1 Hz, 91 mg, 99% yield. Colorless crystals, m.p. 94–95 °C. Rf = 0.35
1H, ArH), 7.22–7.17 (m, 3H, ArH), 6.84 (s, 1H, ArH), 6.77 (d, J = (silica gel plate, ethyl acetate–petroleum ether 1 : 3, v/v). 1H
7.6 Hz, 2H, ArH), 4.97 (s, 2H, CH2NO2), 4.91 (s, 2H, NCH2), NMR (400 MHz, DMSO-d6) δ: 13.96 (s, 1H, OH), 7.49–7.38 (m,
2.32 (s, 3H, CH3). 13C NMR (100 MHz, CDCl3) δ: 160.7 (CvO), 3H, ArH), 7.29–7.27 (m, 2H, ArH), 3.35 (s, 3H, CH3). 13C NMR
140.6 (C), 139.6 (C), 135.9 (C), 130.1 (CH), 129.9 (CH), 129.0 (100 MHz, DMSO-d6) δ: 156.1 (CvO), 154.3 (CvN), 140.0 (C),
(CH), 128.5 (CH), 128.5 (CH), 127.9 (CH), 125.1 (CH), 77.1 129.6 (CH), 129.1 (CH), 126.0 (CH), 35.9 (CH3). IR (DCM) ν
(CH2NO2), 53.6 (NCH2), 21.2 (CH3). IR (DCM) ν (cm−1): 1681 (cm−1): 1633 (CvO), 1590 (CvN), 1549 (NO2), 1338 (NO2).
(CvO), 1562 (NO2), 1374 (NO2). HRMS (ESI) calcd for HRMS (ESI) calcd for C9H10N3O4 [M + H]+ m/z 224.0666, found
C16H17N2O3 [M + H]+ m/z 285.1234, found 285.1237.
224.0671.
N-Benzyl-2-nitro-N-(p-tolyl)acetamide (2j). 256 mg, 90%
yield. Colorless crystals, m.p. 96–97 °C. Rf = 0.46 (silica gel
plate, ethyl acetate–petroleum ether 1 : 3, v/v). 1H NMR
General procedure for the cascade nitrosation and
addition–elimination of nitroacetanilides
(400 MHz, CDCl3) δ: 7.28–7.26 (m, 3H, ArH), 7.21–7.18 (m, 2H, To a mixture of nitroacetamide 2 (80 mg) and sodium nitrite (5
ArH), 7.16 (d, J = 8.0 Hz, 1H, ArH), 6.88 (d, J = 8.0 Hz, 2H, equiv. of 2) in MeCN (4.0 mL) was added sulfuric acid (5 equiv.
ArH), 4.96 (s, 2H, CH2NO2), 4.90 (s, 2H, NCH2), 2.35 (s, 3H, of 2) at 0 °C. The mixture was stirred at rt for 24–120 h, then
CH3). 13C NMR (100 MHz, CDCl3) δ: 160.9 (CvO), 139.5 (C), water (5 mL) was added, followed by addition of dichloro-
136.9 (C), 135.9 (C), 130.8 (CH), 129.0 (CH), 128.5 (CH), 127.9 methane (5 mL). The organic phase was separated, dried over
(CH), 77.1 (CH2NO2), 53.6 (NCH2), 23.7 (CH3). IR (DCM) ν anhydrous sodium sulfate, and concentrated. The residue was
(cm−1): 1675 (CvO), 1559 (NO2), 1374 (NO2). HRMS (ESI) calcd purified by silica gel column chromatography to afford the
for C16H17N2O3 [M + H]+ m/z 285.1234, found 285.1237.
pure product 3.
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N3,N6-Dibenzyl-N3,N6-diphenyl-1,4,2,5-dioxadiazine-3,6-dicar- (CH), 128.9 (CH), 128.6 (CH), 111.8 (CvN), 48.8 (CH), 48.3
boxamide (3a). 73.5 mg, 99% yield. Colorless crystals, (CH), 20.5 (CH3), 20.5 (CH3). IR (DCM) ν (cm−1): 1659 (CvO),
m.p. 154–156 °C. Rf = 0.54 (silica gel plate, ethyl acetate–pet- 1618 (O–CvN). HRMS (ESI) calcd for C22H25N4O4 [M + H]+ m/z
roleum ether 1 : 3, v/v). 1H NMR (400 MHz, CDCl3) δ: 7.34–7.29 409.1870, found 409.1877.
(m, 10H, ArH), 7.24–7.19 (m, 8H, ArH), 7.06–7.03 (m, 2H, ArH),
N3,N6-Bis(4-chlorobenzyl)-N3,N6-diphenyl-1,4,2,5-dioxadiazine-
5.09 (s, 2H, NCH2), 5.07 (s, 2H, NCH2). 13C NMR (100 MHz, 3,6-dicarboxamide (3f). 64 mg, 85% yield. Colorless crystals,
CDCl3) δ: 157.3 (CvO), 155.6 (CvO), 151.3 (CvN), 140.4 (C), m.p. 181–183 °C. Rf = 0.60 (silica gel plate, ethyl acetate–pet-
139.3 (C), 135.5 (C), 135.5 (C), 129.4 (CH), 129.2 (CH), 128.7 roleum ether 1 : 3, v/v). 1H NMR (400 MHz, CDCl3) δ: 7.32–7.17
(CH), 128.6 (CH), 128.6 (CH), 128.5 (CH), 128.4 (CH), 128.2 (m, 16H, ArH), 7.06–7.03 (m, 2H, ArH), 5.04 (s, 2H, NCH2),
(CH), 127.9 (CH), 127.9 (CH), 127.8 (CH), 127.1 (CH), 111.4 5.02 (s, 2H, NCH2). 13C NMR (100 MHz, CDCl3) δ: 157.3
(CvN), 53.9 (NCH2), 53.6 (NCH2). IR (DCM) ν (cm−1): 1659 (CvO), 155.7 (CvO), 151.2 (CvN), 140.2 (C), 139.0 (C), 134.0
(CvO), 1619 (O–CvN). HRMS (ESI) calcd for C30H25N4O4 (CH), 133.9 (C), 133.8 (C), 130.1 (CH), 129.7 (CH), 129.6 (CH),
[M + H]+ m/z 505.1870, found 505.1868.
129.3 (CH), 128.9 (CH), 128.8 (CH), 128.8 (C), 128.7 (C), 127.9
N3,N6-Diphenyl-1,4,2,5-dioxadiazine-3,6-dicarboxamide (3b). (CH), 127.0 (CH), 111.2 (CvN), 53.3 (NCH2), 53.0 (NCH2). IR
25 mg, 35% yield. Colorless crystals, m.p. 185–186 °C. Rf = 0.41 (DCM) ν (cm−1): 1660 (CvO), 1621 (O–CvN). HRMS (ESI)
(silica gel plate, ethyl acetate–petroleum ether 1 : 3, v/v). 1H calcd for C30H22Cl2N4NaO4 [M + Na]+ m/z 595.0910, found
NMR (400 MHz, DMSO-d6) δ: 11.30 (s, 1H, NH), 11.06 (s, 1H, 595.0920.
NH), 7.75 (d, J = 7.8 Hz, 2H, ArH), 7.61 (d, J = 7.7 Hz, 2H, ArH),
N3,N3,N6,N6-Tetraphenyl-1,4,2,5-dioxadiazine-3,6-dicarboxa-
7.42–7.37 (m, 4H, ArH), 7.21–7.16 (m, 2H, ArH). 13C NMR mide (3g). 62 mg, 83% yield. Colorless crystals, m.p.
(100 MHz, DMSO-d6) δ: 154.5 (CvO), 151.6 (CvO), 151.3 187–188 °C. Rf = 0.54 (silica gel plate, ethyl acetate–petroleum
(CvN), 137.4 (C), 137.3 (C), 129.1 (CH), 128.9 (CH), 125.1 ether 1 : 3, v/v). 1H NMR (400 MHz, CDCl3) δ: 7.43–7.27 (m,
(CH), 125.0 (CH), 120.7 (CH), 119.8 (CH), 110.4 (CvN). IR 10H, ArH). 13C NMR (100 MHz, CDCl3) δ: 157.3 (CvO), 155.3
(DCM) ν (cm−1): 1666 (CvO), 1633 (O–CvN). HRMS (ESI) (CvO), 152.1 (CvN), 141.1 (C), 140.0 (C), 129.6 (CH), 129.3
calcd for C16H13N4O4 [M + H]+ m/z 325.0931, found 325.0943.
(CH), 128.5 (CH), 128.1 (CH), 127.6 (CH), 126.1 (CH), 111.6
N3,N6-Dimethyl-N3,N6-diphenyl-1,4,2,5-dioxadiazine-3,6-dicar- (CvN). IR (DCM) ν (cm−1): 1667 (CvO), 1615 (O–CvN).
boxamide (3c). 67 mg, 92% yield. Colorless crystals, m.p. HRMS (ESI) calcd for C28H21N4O4 [M + H]+ m/z 477.1557,
129–130 °C. Rf = 0.43 (silica gel plate, ethyl acetate–petroleum found 477.1567.
ether 1 : 3, v/v). 1H NMR (400 MHz, CDCl3) δ: 7.38–7.26 (m,
N3,N6-Dibenzyl-N3,N6-di(o-tolyl)-1,4,2,5-dioxadiazine-3,6-di-
10H, ArH), 3.50 (s, 3H, CH3), 3.46 (s, 3H, CH3). 13C NMR carboxamide (3h). 62 mg, 83% yield. Colorless crystals, m.p.
(100 MHz, CDCl3) δ: 157.2 (CvO), 155.3 (CvO), 151.4 (CvN), 229–231 °C. Rf = 0.66 (silica gel plate, ethyl acetate–petroleum
142.1 (C), 140.8 (C), 129.6 (CH), 129.3 (CH), 128.4 (CH), 128.3 ether 1 : 3, v/v). 1H NMR (400 MHz, CDCl3) δ: 7.38–7.29 (m,
(CH), 126.9 (CH), 126.1 (CH), 111.2 (CvN), 37.8 (CH3), 37.5 10H, ArH), 7.24–7.05 (m, 5H, ArH), 7.03–6.85 (m, 2H, ArH),
(CH3). IR (DCM) ν (cm−1): 1666 (CvO), 1617 (O–CvN). HRMS 6.73–6.54 (m, 1H, ArH), 5.87–5.19 (m, 2H, NCH2), 4.62–4.17
(ESI) calcd for C18H17N4O4 [M + H]+ m/z 353.1244, found (m, 2H, NCH2), 2.54–2.08 (m, 6H, CH3 × 2). 13C NMR
353.1245.
(100 MHz, CDCl3) δ: 156.8 (CvO), 156.1 (CvO), 150.6 (CvN),
N3,N6-Diphenyl-N3,N6-dipropyl-1,4,2,5-dioxadiazine-3,6-dicar- 136.1 (C), 135.9 (C), 135.4 (C), 135.2 (C), 131.4 (C), 131.3 (C),
boxamide (3d). 71.3 mg, 97% yield. Colorless oil. Rf = 0.64 131.2 (C), 131.2 (C), 130.4 (CH), 129.9 (CH), 129.8 (CH), 129.7
(silica gel plate, ethyl acetate–petroleum ether 1 : 3, v/v). 1H (CH), 129.6 (CH), 129.5 (CH), 129.4 (CH), 129.3 (CH), 129.0
NMR (400 MHz, CDCl3) δ: 7.40–7.26 (m, 10H, ArH), 3.89–3.81 (CH), 129.0 (CH), 128.9 (CH), 128.9 (CH), 128.5 (CH), 128.5
(m, 4H, NCH2 × 2), 1.73–1.61 (m, 4H, CH2CH3 × 2), 0.99 (t, J = (CH), 128.5 (CH), 128.4 (CH), 128.1 (CH), 128.0 (CH), 128.0
7.5 Hz, 3H, CH3), 0.97 (t, J = 7.5 Hz, 3H, CH3). 13C NMR (CH), 127.9 (CH), 126.7 (CH), 126.5 (CH), 126.3 (CH), 126.2
(100 MHz, CDCl3) δ: 157.1 (CvO), 155.2 (CvO), 151.7 (CvN), (CH), 123.9 (CH), 105.0 (CvN), 53.5 (NCH2), 52.8 (NCH2), 52.5
140.7 (C), 139.3 (C), 129.5 (CH), 129.2 (CH), 128.5 (CH), 128.4 (NCH2), 52.3 (NCH2), 18.0 (CH3) 17.8 (CH3), 17.7 (CH3), 17.6
(CH), 127.8 (CH), 127.2 (CH), 111.5 (CvN), 51.7 (NCH2), 51.6 (CH3). IR (DCM) ν (cm−1): 1650 (CvO), 1618 (O–CvN). HRMS
(NCH2), 20.6 (CH2CH3), 20.5 (CH2CH3), 11.1 (CH3), 11.1 (CH3). (ESI) calcd for C32H28N4NaO4 [M + Na]+ m/z 555.2003, found
IR (DCM) ν (cm−1): 1660 (CvO), 1615 (O–CvN). HRMS (ESI) 555.2008.
calcd for C22H25N4O4 [M + H]+ m/z 409.1870, found 409.1867.
N3,N6-Dibenzyl-N3,N6-di(m-tolyl)-1,4,2,5-dioxadiazine-3,6-di-
N3,N6-Diisopropyl-N3,N6-diphenyl-1,4,2,5-dioxadiazine-3,6- carboxamide (3i). 73 mg, 97% yield. Colorless crystals, m.p.
dicarboxamide (3e). 53 mg, 72% yield. Colorless crystals, 132–134 °C. Rf = 0.60 (silica gel plate, ethyl acetate–petroleum
m.p. 169–170 °C. Rf = 0.46 (silica gel plate, ethyl acetate–pet- ether 1 : 3, v/v). 1H NMR (400 MHz, CDCl3) δ: 7.38–7.27 (m, 8H,
roleum ether 1 : 3, v/v). 1H NMR (400 MHz, CDCl3) δ: 7.41–7.39 ArH), 7.12–6.97 (m, 6H, ArH), 6.89–6.80 (m, 2H, ArH), 5.07 (s,
(m, 2H, ArH), 7.34–7.32 (m, 6H, ArH), 7.23–7.21 (m, 2H, ArH), 2H, NCH2), 5.06 (s, 2H, NCH2), 2.23 (s, 3H, CH3), 2.21 (s, 3H,
5.02 (hept, 1H, CH), 4.90 (hept, 1H, CH), 1.22 (d, J = 6.8 Hz, CH3). 13C NMR (100 MHz, CDCl3) δ: 157.2 (CvO), 155.6
6H, CH3 × 2), 1.21 (d, J = 6.8 Hz, 6H, CH3 × 2). 13C NMR (CvO), 151.3 (CvN), 140.4 (C), 139.5 (C), 139.4 (C), 139.2 (C),
(100 MHz, CDCl3) δ: 156.8 (CvO), 155.2 (CvO), 151.5 (CvN), 135.7 (C), 135.6 (C), 129.4 (CH), 129.2 (CH), 129.1 (CH), 128.9
136.7 (C), 135.6 (C), 130.2 (CH), 129.7 (CH), 129.1 (CH), 129.0 (CH), 128.7 (CH), 128.6 (CH), 128.6 (CH), 128.2 (CH), 127.8
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(CH), 127.7 (CH), 127.4 (CH), 125.0 (CH), 124.1 (CH), 111.5 (CvO), 1611 (O–CvN), 1597 (O–CvN). HRMS (ESI) calcd for
(CvN), 53.9 (NCH2), 53.6 (NCH2), 21.2 (CH3), 21.1 (CH3). IR C16H11N2O4 [M + H]+ m/z 295.0713, found 295.0719.
(DCM) ν (cm−1): 1658 (CvO), 1617 (O–CvN). HRMS (ESI)
calcd for C32H29N4O4 [M + H]+ m/z 533.2183, found 533.2194.
Preparation of N,N-dibenzyl-nitroacetamide (2m)
N3,N6-Dibenzyl-N3,N6-di(p-tolyl)-1,4,2,5-dioxadiazine-3,6-di-
To a solution of diisopropylamine (875 mg, 6 mmol) in THF
carboxamide (3j). 73.5 mg, 99% yield. Colorless crystals,
m.p. 124–126 °C. Rf = 0.60 (silica gel plate, ethyl acetate–pet-
roleum ether 1 : 3, v/v). 1H NMR (400 MHz, CDCl3) δ: 7.34–7.27
(m, 10H, ArH), 7.06 (d, J = 8.1 Hz, 2H, ArH), 7.00 (d, J = 8.1 Hz,
2H, ArH), 6.96 (d, J = 8.1 Hz, 2H, ArH), 6.91 (d, J = 8.1 Hz, 2H,
ArH), 5.05 (s, 2H, NCH2), 5.03 (s, 2H, NCH2), 2.27 (s, 3H, CH3),
2.25 (s, 3H, CH3). 13C NMR (100 MHz, CDCl3) δ: 157.3 (CvO),
155.6 (CvO), 151.4 (CvN), 138.6 (C), 138.4 (C), 137.9 (C),
136.7 (C), 135.7 (C), 135.6 (C), 130.0 (CH), 129.7 (CH), 128.7
(CH), 128.6 (CH), 128.6 (CH), 128.3 (CH), 127.8 (CH), 127.7
(CH), 127.7 (CH), 126.9 (CH), 111.5 (CvN), 53.9 (NCH2), 53.6
(NCH2), 21.0 (CH3). IR (DCM) ν (cm−1): 1658 (CvO), 1618
(O–CvN). HRMS (ESI) calcd for C32H29N4O4 [M + H]+ m/z
533.2183, found 533.2191.
(10 mL) was added butyllithium (2.73 mL, 1.6 M in THF,
6 mmol) at −25 °C under nitrogen atmosphere. A solution of
N,N-dibenzyl-acetamide (5) (1.2 g, 5 mmol) in THF (5 mL) was
slowly added via a syringe. After 30 min, the reaction mixture
was allowed to warm to 0 °C, n-C6H13ONO2 (883 mg, 6 mmol)
was added and the resulting mixture was stirred for 2 hours.
The reaction was quenched with aqueous NH4Cl solution, fol-
lowing by extraction with DCM. The organic phase was separ-
ated, dried over anhydrous sodium sulfate, and concentrated.
The residue was purified by silica gel column chromatography
to afford the pure product 2m.
N,N-Dibenzyl-nitroacetamide (2m). 639 mg, 45% yield. Col-
orless crystals, m.p. 94–96 °C. Rf = 0.40 (silica gel plate, ethyl
1
acetate–petroleum ether 1 : 3, v/v). H NMR (400 MHz, CDCl3)
N3,N6-Dibenzyl-N3,N6-bis(4-bromophenyl)-1,4,2,5-dioxadia-
zine-3,6-dicarboxamide (3k). 61 mg, 80% yield. Colorless
crystals, m.p. 143–145 °C. Rf = 0.60 (silica gel plate, ethyl
δ: 7.41–7.30 (m, 6H, ArH), 7.25 (d, J = 7.2 Hz, 2H, ArH), 7.14 (d,
J = 7.2 Hz, 2H, ArH), 5.29 (s, 2H, CH2NO2), 4.67 (s, 2H, NCH2),
4.37 (s, 2H, NCH2). 13C NMR (100 MHz, CDCl3) δ: 161.7
(CvO), 135.7 (C), 134.6 (C), 129.4 (CH), 128.8 (CH), 128.5
(CH), 128.3 (CH), 128.0 (CH), 126.2 (CH), 77.0 (CH2NO2), 50.0
(NCH2), 49.4 (NCH2). IR (DCM) ν (cm−1): 1684 (CvO), 1551
(NO2), 1370 (NO2). HRMS (ESI) calcd for C16H17N2O3 [M + H]+
m/z 285.1234, found 285.1235.
1
acetate–petroleum ether 1 : 3, v/v). H NMR (400 MHz, CDCl3)
δ: 7.38–7.24 (m, 14H, ArH), 7.07 (d, J = 8.3 Hz, 2H, ArH), 6.94
(d, J = 8.3 Hz, 2H, ArH), 5.05 (s, 2H, NCH2), 5.02 (s, 2H, NCH2).
13C NMR (100 MHz, CDCl3) δ: 157.1 (CvO), 155.4 (CvO),
151.1 (CvN), 139.3 (C), 138.1 (C), 135.1 (C), 135.1 (C), 132.7
(CH), 132.4 (CH), 129.7 (CH), 128.9 (CH), 128.8 (CH), 128.8
(CH), 128.7 (CH), 128.3 (CH), 128.2 (CH), 128.0 (CH), 122.8
(CH), 122.7 (CH), 111.1 (CvN), 53.8 (NCH2), 53.5 (NCH2). IR
(DCM) ν (cm−1): 1660 (CvO), 1620 (O–CvN). HRMS (ESI)
calcd for C30H23Br2N4O4 [M + H]+ m/z 661.0081, found
661.0086.
Preparation of nitromethyl compounds (6, 8, and 10)
Nitromethyl ketones 6,15,16 methyl nitroacetate (8),17 and
1-nitro-4-(nitromethyl)benzene (10)18 were prepared following
the literature procedures.
2-Nitro-1-phenylethanone (6a). 1H NMR (400 MHz, CDCl3)
δ: 7.88 (d, J = 7.6 Hz, 2H, ArH), 7.69 (t, J = 7.5 Hz, 1H, ArH),
7.55 (dd, J = 7.6, 7.5 Hz, 2H, ArH), 5.90 (s, 2H, CH2NO2). 13C
NMR (101 MHz, CDCl3) δ: 185.6 (CvO), 135.1 (C), 133.4 (CH),
129.3 (CH), 128.2 (CH), 81.2 (CH2NO2).
N3,N6-Dibenzyl-N3,N6-bis(4-iodophenyl)-1,4,2,5-dioxadiazine-
3,6-dicarboxamide (3l). 66 mg, 87% yield. Colorless crystals,
m.p. 169–171 °C. Rf = 0.57 (silica gel plate, ethyl acetate–pet-
1
roleum ether 1 : 3, v/v). H NMR (400 MHz, CDCl3) δ: 7.57 (d,
Nitroacetone (6b). 1H NMR (400 MHz, CDCl3) δ: 5.31 (s, 2H,
CH2NO2), 2.33 (s, 3H, CH3). 13C NMR (101 MHz, CDCl3) δ:
193.8 (CvO), 83.7 (CH2NO2), 27.4 (CH3).
J = 8.3 Hz, 2H, ArH), 7.50 (d, J = 8.3 Hz, 2H, ArH), 7.37–7.24
(m, 10H, ArH), 6.92 (d, J = 8.3 Hz, 2H, ArH), 6.79 (d, J = 8.3 Hz,
2H, ArH), 5.04 (s, 2H, NCH2), 5.02 (s, 2H, NCH2). 13C NMR
(100 MHz, CDCl3) δ: 157.0 (CvO), 155.3 (CvO), 151.1 (CvN),
140.1 (C), 138.9 (C), 138.7 (CH), 138.4 (CH), 135.1 (C), 135.1
(C), 129.8 (CH), 129.0 (CH), 128.8 (CH), 128.8 (CH), 128.7 (CH),
128.3 (CH), 128.2 (CH), 128.0 (CH), 111.1 (CvN), 94.4 (C), 94.2
(C), 53.8 (NCH2), 53.5 (NCH2). IR (DCM) ν (cm−1): 1655 (CvO),
1618 (O–CvN). HRMS (ESI) calcd for C30H23I2N4O4 [M + H]+
m/z 756.9803, found 756.9812.
Methyl 2-nitroacetate (8). 1H NMR (400 MHz, CDCl3) δ: 5.19
(s, 2H, CH2NO2), 3.88 (s, 3H, OCH3). 13C NMR (101 MHz,
CDCl3) δ: 162.2 (CvO), 76.1 (CH2NO2), 53.6 (OCH3).
1-Nitro-4-(nitromethyl)benzene (10). 1H NMR (400 MHz,
CDCl3) δ: 8.28 (d, J = 8.7 Hz, 2H, ArH), 7.59 (d, J = 8.7 Hz, 2H,
ArH), 5.53 (s, 2H, CH2NO2). 13C NMR (101 MHz, CDCl3) δ:
139.5 (C), 129.9 (C), 129.2 (CH), 124.1 (CH), 72.6 (CH2NO2).
3,6-Dibenzoyl-1,4,2,5-dioxadiazine (7a). 220 mg (1 mmol
scale), 75% yield. Colorless, crystals, m.p. 87–88 °C. Rf = 0.57
(silica gel plate, ethyl acetate–petroleum ether 1 : 3, v/v). 1H
NMR (400 MHz, CDCl3) δ: 8.20 (dd, J = 8.8, 1.6 Hz, 2H, ArH),
Acknowledgements
7.86 (dd, J = 8.8, 1.2 Hz, 2H, ArH), 7.74–7.67 (m, 2H, ArH), This work was supported in part by The National Basic
7.58–7.51 (m, 4H, ArH). 13C NMR (100 MHz, CDCl3) δ: 181.8 Research Program of China (no. 2013CB328905) and the
(CvO), 180.4 (CvO), 154.3 (CvN), 135.4 (CH), 135.3 (CH), National Natural Science Foundation of China (no. 21172017
133.9 (C), 133.8 (C), 130.5 (CH), 129.6 (CH), 129.2 (CH), 129.0 and 20092013). Mr Zhanhui Yang is thanked for his generous
(CH), 111.6 (CvN). IR (DCM) ν (cm−1): 1682 (CvO), 1666 experimental support.
This journal is © The Royal Society of Chemistry 2014
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