A novel heterocyclic system - Dihydro-2H-1,5,2,4-dioxadiazine. 2,4-Dimethyldihydro-2H-1,5,2,4-dioxadiazine hydrochloride: Synthesis and NMR study

Article abstract of DOI:10.1023/B:RUCB.0000042299.54558.80

The first representative of a novel heterocyclic system, namely, 2,4-dimethyldihydro-2H-1,5,2,4-dioxadiazine hydrochloride, was synthesized.

Full text of DOI:10.1023/B:RUCB.0000042299.54558.80

Russian Chemical Bulletin, International Edition, Vol. 53, No. 6, pp. 1349—1350, June, 2004
1349
A novel heterocyclic system — dihydroꢀ2Hꢀ1,5,2,4ꢀdioxadiazine.
2,4ꢀDimethyldihydroꢀ2Hꢀ1,5,2,4ꢀdioxadiazine hydrochloride:
synthesis and NMR study ✾
O. V. Anikin,ꢀ D. L. Lipilin, P. A. Belyakov, V. Yu. Ryabtsev, and V. A. Tartakovsky
N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences,
47 Leninskii prosp., 119991 Moscow, Russian Federation.
Fax: +7 (095) 135 5328. Eꢀmail: anikinOV@ioc.ac.ru
The first representative of a novel heterocyclic system, namely, 2,4ꢀdimethyldihydroꢀ2Hꢀ
1,5,2,4ꢀdioxadiazine hydrochloride, was synthesized.
Key words: bis(aminooxy)methane, bis(tertꢀbutyloxycarbonylaminooxy)methane, 2,4ꢀdiꢀ
methyldihydroꢀ2Hꢀ1,5,2,4ꢀdioxadiazine hydrochloride, alkylation.
Construction of the 1,5,2,4ꢀdioxadiazine ring has been
reported only for two 2,4ꢀdialkylꢀ2Hꢀ1,5,2,4ꢀdioxadiꢀ
azineꢀ3,6(2,4H )ꢀdiones.1 Data for dihydroꢀ2Hꢀ1,5,2,4ꢀ
dioxadiazine or its derivatives have not been documented
to date.
Our approach to the synthesis of the target structure
was as follows (Scheme 1). Bis(aminooxy)methane2—4 (1)
may be regarded as a heteroanalog of 1,3ꢀdiaminopropane,
which is known to form hexahydropyrimidine in the reacꢀ
tion with formaldehyde.5,6 An analogous reaction of
bis(aminooxy)methane should give dihydroꢀ2Hꢀ1,5,2,4ꢀ
dioxadiazine 5. To avoid a possible opening of the ring as
a result of ring—chain tautomerism (as observed for
1,3ꢀdiaminopropane5), bis(aminooxy)methane 1 was reꢀ
placed by its N,N´ꢀdimethyl derivative 4 prepared by
methylation of bis(tertꢀbutyloxycarbonylaminooxy)meꢀ
thane (2). The reaction of salt 4 with paraform affords
2,4ꢀdimethyldihydroꢀ2Hꢀ1,5,2,4ꢀdioxadiazine monoꢀ
hydrochloride (5) in more than 90% yield.
For recording NMR spectra, compound 5 was twice
recrystallized from PriOH.
1
The H NMR spectra of product 5 at 25 °C contain
strongly broadened signals for the CH2 protons at δ ∼4.2
and ∼5.7. At 60 °C, these signals change to instrumentꢀ
width singlets. This broadening can result from both
intraꢀ or intermolecular proton exchange of the acid and
conformation processes (hindered inversion of the N atom
and/or the ring (on the NMR time scale)). The hindered
inversion follows from the presence of both quartets for
the methylene groups upon the binding of the acid proton
by pyridine added to a tube with compound 5.
Scheme 1
Experimental
Mass spectra were recorded on Kratos MSꢀ30 (EI, 70 eV)
and Varian CHꢀ6 instruments (ESI MS). 1H and 13C NMR
spectra were recorded on a Bruker AMꢀ300 spectrometer
(300.13 and 75.5 MHz, respectively). Bis(aminooxy)methane
dihydrochloride was prepared according to a known proꢀ
cedure.2—4
Diꢀtertꢀbutyl N,N´ꢀ(methylenedioxy)dicarbamate (2). Triꢀ
ethylamine (9.2 mL, 66 mmol) and a solution of diꢀtertꢀbutyl
dicarbonate (14.4 g, 66 mmol) in 20 mL of anhydrous CH2Cl2
were added successively at 5—10 °C to a stirred suspension of
dihydrochloride 1 (4.53 g, 30 mmol) in 50 mL of anhydrous
CH2Cl2. The reaction mixture was stirred at 20 °C for 8 h,
allowed to stand for ∼18 h, and then poured into water (200 mL).
The organic layer was separated and dried with Na2SO4 and
the solvent was removed. The residue was recrystallized from
C6H6 to give compound 2 (7.15 g, 86%) as colorless crystals,
m.p. 109—110 °C. Found (%): C, 47.21; H, 7.83; N, 9.91.
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 6, pp. 1295—1297, June, 2004.
1066ꢀ5285/04/5306ꢀ1349 © 2004 Plenum Publishing Corporation

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Russ.Chem.Bull., Int.Ed., Vol. 53, No. 6, June, 2004
Anikin et al.
C11H22N2O6. Calculated (%): C, 47.47; H, 7.97; N, 10.07.
1H NMR (DMSOꢀd6), δ: 1.40 (s, 18 H, CMe3); 4.81 (s, 2 H,
CH2); 9.78 (s, 2 H, NH). 13C NMR (DMSOꢀd6), δ: 27.9
(C(CH3)3); 80.6 (CMe3); 100.6 (CH2); 150.0 (C=O). MS,
m/z: 278 [M]+.
2 H, CH2); 9.50 (br.s, 4 H, NH2+). 13C NMR (DMSOꢀd6), δ:
37.5 (NMe); 96.4 (CH2).
2,4ꢀDimethyldihydroꢀ2Hꢀ1,5,2,4ꢀdioxadiazine hydrochloride
(5). Paraform (0.1 g, 3 mmol) was added to a solution of comꢀ
pound 4 (0.37 g, 2 mmol) in 5 mL of MeOH. The reaction
mixture was stirred for 3 h, the solvent was removed, and the
residue was recrystallized from PriOH to give compound 5
(0.28 g, 91%) as colorless crystals, m.p. 140—141 °C. Found (%):
C, 30.82; H, 7.23; Cl, 23.22; N, 17.90. C4H11ClN2O2. Calcuꢀ
lated (%): C, 31.08; H, 7.17; Cl, 22.93; N, 18.12. 1H NMR
(DMSOꢀd6), 25 °C, δ: 2.73 (s, 6 H, NMe); 4.20 (br.s, 2 H,
NCH2N); 5.67 (br.s, 2 H, OCH2O); 9.91 (s, 1 H, NH+).
1H NMR (DMSOꢀd6), 60 °C, δ: 2.70 (s, 6 H, NMe); 4.00 (s,
2 H, NCH2N); 5.32 (s, 2 H, OCH2O); 9.43 (s, 1 H, NH+).
1H NMR (DMSOꢀd6—Pyꢀd5 (1 : 1)), 25 °C, δ: 2.49 (s, 6 H,
NMe); 3.11 (m, 1 H, NCH2N); 3.94 (m, 1 H, NCH2N); 4.96 (m,
1 H, OCH2O); 5.19 (m, 1 H, OCH2O). 13C NMR (DMSOꢀd6),
δ: 42.4 (Me); 81.1 (NCH2N); 94.5 (OCH2O). MS, m/z: 118
[M – HCl]+.
Diꢀtertꢀbutyl N,N´ꢀdimethylꢀN,N´ꢀ(methylenedioxy)dicarbaꢀ
mate (3). A solution of MeONa (700 mg, 13 mmol) in 10 mL of
anhydrous MeOH was added to a stirred solution of compound 2
(1.39 g, 5 mmol) in 5 mL of anhydrous MeOH. Stirring was
continued for an additional 10 min. Then the solvent was reꢀ
moved and the residue was dried in vacuo and dissolved in 5 mL
of anhydrous DMSO. Methyl iodide (1.5 mL, 25 mmol) was
added at 5 °C to the stirred solution. The reaction mixture was
heated at 60 °C for 1 h, cooled, and poured into water (100 mL).
The product was extracted with C6H6 (3×30 mL). The benzene
extract was washed with aqueous 10% Na2S2O3 and water and
dried with Na2SO4. The solvent was removed and the resulting
oil was dissolved in 50 mL of hexane. The undissolved residue
was filtered off, the solvent was removed, and the product was
dried in vacuo to give compound 3 (1.35 g, 88%) as large transꢀ
parent crystals, m.p. 45—48 °C. Found (%): C, 51.12; H, 8.47;
N, 9.26. C13H26N2O6. Calculated (%): C, 50.97; H, 8.55;
N, 9.14. 1H NMR (DMSOꢀd6), δ: 1.40 (s, 18 H, CMe3); 3.10 (s,
6 H, NMe); 5.05 (s, 2 H, CH2). 13C NMR (DMSOꢀd6), δ: 27.9
(C(CH3)3); 38.4 (NMe); 81.3 (CMe3); 101.8 (CH2); 156.9
(C=O). MS, m/z: 306 [M]+.
2,6ꢀDiazaꢀ3,5ꢀdioxaheptane dihydrochloride (4). Dry HCl
was passed through a solution of compound 3 (1 g, 0.33 mmol)
in 25 mL of anhydrous Et2O for 5 min. The reaction mixture was
left at 20 °C for 4 h. The precipitate that formed was filtered off
and washed with anhydrous Et2O to give compound 4 (0.52 g,
87%) as colorless crystals, m.p. 162—164 °C (from EtOH).
Found (%): C, 20.14; H, 6.82; Cl, 39.41; N, 15.78.
C3H12Cl2N2O2. Calculated (%): C, 20.12; H, 6.76; Cl, 39.60;
N, 15.65. 1H NMR (DMSOꢀd6), δ: 2.83 (s, 6 H, NMe); 5.64 (s,
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Received March 26, 2004