Synthesis of 3,4,5,6-Tetrahydro-2H-1,3,4-oxadiazin-2-ones Employing a Metal Hydride and Diethyl Carbonate: An Alternative Cyclization Method over 1,1′-Carbonyldiimidazole

Article abstract of DOI:10.1081/SCC-120028356

A series of 3,4,5,6-tetrahydro-2H-1,3,4-oxadiazin-2-ones have been synthesized from valine, leucine, ephedrine, and norephedrine. The synthesis is accomplished through a process of nitrosation, reduction, and cyclization. The cyclization protocol employed involves the use of a metal hydride (LiH or NaH) and diethyl carbonate rather than 1,1′-carbonyldiimidazole.

Full text of DOI:10.1081/SCC-120028356

SYNTHETIC COMMUNICATIONSw
Vol. 34, No. 5, pp. 835–843, 2004
Synthesis of 3,4,5,6-Tetrahydro-2H-1,3,4-
oxadiazin-2-ones Employing a Metal
Hydride and Diethyl Carbonate: An
Alternative Cyclization Method over
1,10-Carbonyldiimidazole
David M. Casper, David Kieser, Jennifer R. Blackburn,
*
and Shawn R. Hitchcock
Department of Chemistry, Illinois State University, Normal, Illinois, USA
ABSTRACT
A series of 3,4,5,6-tetrahydro-2H-1,3,4-oxadiazin-2-ones have been
synthesized from valine, leucine, ephedrine, and norephedrine. The
synthesis is accomplished through a process of nitrosation, reduction,
and cyclization. The cyclization protocol employed involves the use of
a metal hydride (LiH or NaH) and diethyl carbonate rather than
1,10-carbonyldiimidazole.
Key Words: 3,4,5,6-Tetrahydro-2H-1,3,4-oxadiazin-2-ones cyclization;
1,10-Diethylcarbonate; b-Amino alcohols; Oxadiazinone.
*
Correspondence: Shawn R. Hitchcock, Department of Chemistry, Illinois State
University, Normal, IL 61790-4160, USA; E-mail: hitchcock@xenon.che.ilstu.edu.
835
DOI: 10.1081/SCC-120028356
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com
Copyright # 2004 by Marcel Dekker, Inc.

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Casper et al.
3,4,5,6-Tetrahydro-2H-1,3,4-oxadiazin-2-ones (Also known as 1,3,4-
oxadiazinan-2-ones. These heterocycles were first disclosed by Trepanier.
Please see Ref.[1].) have been known for more than thirty years but only
recently have been examined in terms of their synthesis,[2] conformational
analysis,[3,4] and asymmetric application.[5] The most prevalent methodology
for the synthesis of these heterocycles is based on cyclization of b-hydrazino
alcohols. Typically, b-amino alcohols are nitrosated at the amino group and
the corresponding N-nitrosamines are reduced with lithium aluminum hydride
to b-hydrazino alcohols. The b-hydrazino alcohols are then cyclized with 1,10-
carbonyldiimidazole to afford the oxadiazinone (Sch. 1).[2,6]
Because of the cost of 1,10-carbonyldiimidazole, we began to explore
different cyclizing agents for the synthesis of oxadiazinones. In the process of
our discovery, we determined that the use of diethyl carbonate in conjunction
with a metal hydride (sodium or lithium) proved to be just as effective as 1,10-
carbonyldiimidazole. A test substrate, the b-hydrazino alcohol derived from
(1R,2S)-ephedrine (4a), was cyclized with diethyl carbonate and lithium
hydride to give the oxadiazinone 1a in 74% yield after recrystallization
(Sch. 2). This is comparable to the yield of 75% reported previously with 1,10-
carbonyldiimidazole.[2] In terms of price, diethyl carbonate has a cost of
$5/mole while CDI has a cost of $234/mol.[7]
We became interested in expanding the scope of the cyclization by
exploring other substrates. We were gratified to learn that the cyclization was
also applicable to the b-hydrazino alcohol of N-neopentyl norephedrine (4b),
which was cyclized to give oxadiazinone 9b in 58% yield. This yield is
nearly comparable to the cyclization of the b-hydrazino alcohol using
Scheme 1. Synthesis of 3,4,5,6-tetrahydro-2H-1,3,4-oxadiazin-2-ones.

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Synthesis of 3,4,5,6-Tetrahydro-2H-1,3,4-oxadiazin-2-ones
837
Scheme 2. Cyclization of the b-hydrazino alcohol derived from ephedrine.
1,10-carbonyldiimidazole (69%).[2] We decided to pursue more examples
derived from the a-amino acids valine and leucine.
Thus, commercially available b-amino alcohols 5a–b were alkylated via
reductive amination with trimethylacetaldehyde and sodium borohydride to
afford the corresponding N-neopentyl-b-amino alcohols 6a–b in high yield
(Sch. 3) (for an excellent discussion on reductive amination methods, please
see Ref.[8]). Subsequent N-nitrosation (NaNO2/HCl) gave the desired
N-neopentyl-N-nitrosamines 7a–b as mixtures of diastereomeric E- and
Z-diastereomers. N-nitrosamines are potentially carcinogenic materials and
should be handled with great care. (Caution. It should be noted that many
N-nitrosamines and their derivatives are potentially dangerous carcinogens
and should be handled with due caution. For more information on N-nitro-
samines see Ref.[9].) For the sake of characterization of 7a–b, the E-diastereo-
mer was determined to be the dominant isomer by 1H NMR spectroscopy.[10]
Scheme 3. Synthesis of oxadiazinones 9a and 9b.

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Casper et al.
Table 1. Synthesis of oxadiazinones 9a and 9b.
Yield (%)
Entry
R
6
7
8
9
a
(CH3)2 CH–
(CH3)2CHCH2–
73
71
65
72
89
87
96
49
b
Reduction of the N-neopentyl-N-nitrosamines was accomplished with lithium
aluminum hydride.[2,11] This process afforded the corresponding b-hydrazino-
alcohols 8a–b.
The cyclization was performed with sodium hydride and diethyl carbon-
ate to give a-amino acid based 3,4,5,6-tetrahydro-2H-1,3,4-oxadiazin-2-ones
9a and 9b in 96% and 49%, respectively (Table 1).
In summary, we have synthesized a series of 3,4,5,6-tetrahydro-2H-1,3,4-
oxadiazin-2-ones using a metal hydride and diethyl carbonate to effect the
cyclization.
EXPERIMENTAL
General Remarks
Tetrahydrofuran and diethyl ether were distilled from a potassium/
sodium alloy with benzophenone ketyl. Methylene chloride was distilled from
calcium hydride. Reactions were run under a nitrogen atmosphere. Flash
chromatography was conducted with silica gel (32–63 mesh). All 1H and 13
C
NMR spectra were recorded at 258C on a Varian spectrometer in
deuteriochloroform operating at 400 and 100 MHz, respectively. Chemical
shifts are reported in parts per million (d scale) relative to tetramethylsilane
(0.00 ppm) or chloroform (7.26 ppm), and coupling constants (J values) are
listed in hertz (Hz). Infrared spectra are reported in reciprocal centimeters
(cm21) and are measured either as a neat liquid or as a potassium bromide
pellet. Melting points were recorded on a Mel-Temp apparatus and are
uncorrected. Gas chromatography was performed on a Hewlett–Packard
Instrument (G1800A/GCD) with an ionization voltage of 70 eV; peaks are
reported as m/z (percentage intensity relative to the base peak). Elemental
analyses were conducted by the Microanalytical Laboratory, School of
Chemical Sciences, University of Illinois, and Urbana-Champaign.

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839
3,4,5,6-Tetrahydro-4,5-dimethyl-6-phenyl-2H-1,3,4-
oxadiazin-2-one: (1a)
Ephedrine hydrazine (24.0 mmol) and freshly distilled hexanes (125 mL)
were combined in a 1 L flask. To this solution was added diethylcarbonate
(60 mmol) and the solution was heated to reflux under nitrogen. To the
reaction mixture was added LiH (25.2 mmol) and allowed to stir for 24 hr. The
mixture was then cooled to room temperature, and the solvent was removed by
rotary evaporation. This solid was extracted with ethyl acetate (3 ꢀ 50 mL),
washed with aqueous saturated solution of sodium bicarbonate (50 mL) then
an aqueous solution of brine (50 mL), dried (Na2SO4) followed by the removal
of solvent by rotary evaporation. This process yielded the title compound as a
white solid in 74% yield. This material was spectroscopically identical to the
previously synthesized material.[3]
3,4,5,6-Tetrahydro-5-methyl-4-(2,2-dimethylpropyl)-6-
phenyl-1,3,4-oxadiazin-2-one (1b)
The title compound was isolated by recrystallization from ethyl acetate
and hexanes (69%). This material was spectroscopically identical to the
previously synthesized material.[2]
General procedure for the preparation of the neopentyl aminoalcohol
derivative 6. In a 1 L round bottom flask was placed the b-amino alcohol
(18.4 g, 178 mmol), ethanol (180 mL), trimethylacetylaldehyde (19.4 mL,
178 mmol) and the reaction mixture was stirred for 1 hr. To the resulting
mixture was added NaBH4 (12.16 g, 321.3 mmol) and it was stirred for 1 hr.
The reaction was then quenched with an aqueous saturated solution of
NaHCO3 and then extracted with CH2Cl2 (3 ꢀ 75 mL), washed with an
aqueous saturated solution of brine (100 mL), dried (Na2SO4) and the solvents
were removed by rotary evaporation.
N-Neopentyl-valinol (6a)
Isolated product recrystallized with ethyl acetate–hexanes (3 : 1) to yield
6a in 73% yield as a clear, colorless oil (the analytical information colected for
this compound was identical to the literature; see Ref.[12]). Rf ¼ 0.40 (ethyl
1
acetate–hexanes, 3 : 7). H NMR: d 0.88 (d, J ¼ 6.6 Hz, 3H,), 0.92 (s, 9H),
0.96 (d, J ¼ 6.6 Hz, 3H), 1.73–1.85 (m, 1H), 2.22 (d, J ¼ 11.0 Hz, 1H), 2.35
(sextet, J ¼ 4.4 Hz, 1H), 2.47 (d, J ¼ 11.0 Hz, 1H), 3.27 (dd, J ¼ 10.3, 7.7 Hz,
1H), 3.58 (dd, 1H, J ¼ 10.3, 4.4 Hz). 13C NMR: d 18.3, 19.5, 27.5, 28.9, 31.5,

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Casper et al.
59.1, 60.2, 64.7. IR (neat): 3383, 2955, 1048 cm21. EI-MS, m/z (%): 174
(Mþ, 34), 142 (100), 130 (51), 116 (66), 72 (80). HRMS Calcd for C10H23NO:
174.1858. Found: 174.1855.
N-Neopentyl-leucinol (6b)
The title compound was recovered in 71% yield as a clear, colorless oil.
1H NMR: d 0.92 (s, 9H), 1.20 (quintet, J ¼ 7.0 Hz, 1H), 1.39 (quintet,
J ¼ 7.7 Hz, 1H), 1.62 (septet, J ¼ 6.6 Hz, 1H), 2.23 (d, J ¼ 11.4 Hz, 1H), 2.47
(d, J ¼ 11.4 Hz, 1H), 2.66 (m, 1H), 3.19 (dd, J ¼ 10.3, 6.6 Hz, 1H), 3.60 (dd,
J ¼ 10.4, 4.4 Hz, 1H). 13C NMR: d 22.6, 22.9, 24.9, 27.6, 31.4, 41.4, 57.1,
58.9 62.9. IR (neat): 3335, 2954, 1054 cm21. EI-MS, m/z (%): 188 (Mþ, 17),
170 (68), 156 (100). HRMS Calcd for C11H25NO: 188.2014. Found: 188.2014.
General Procedure for the Preparation of the
N-Nitrosamines 7
The N-alkylated amino alcohol 6 (124 mmol) and THF (50 mL) were
combined and an aqueous solution of HCl (2.74 M, 143 mmol) was added
followed by the addition of sodium nitrite (143 mmol) in small portions and
then stirred for 24 hr. The cloudy mixture was then diluted with and saturated
aqueous solution of NaHCO3 until it became basic. The reaction mixture was
then extracted with ethyl acetate (3 ꢀ 60 mL) and washed with a saturated
aqueous solution of brine (50 mL). The resulting solution was then dried
(NaSO4) followed by the removal of solvent by rotary evaporation.
N-Neopentyl-N-nitroso-valinol (7a)
This process yielded white crystals that were determined to be ca. 95%
1
pure by the H NMR spectrum. Mp: 78–808C; Rf ¼ 0.60 (ethyl acetate–
hexanes, 1 : 1). Only the major isomer was observed. 1H NMR (CDCl3): 0.93
(s, 9H), 0.98 (d, J ¼ 7.0 Hz, 3H), 1.07 (d, J ¼ 6.6 Hz, 3H), 2.10–2.15 (m, 1H),
2.40–2.44 (m, 1H), 2.72 (d, J ¼ 12.8 Hz, 1H), 3.63–3.68 (m, 1H), 4.13–4.21
(m, 1H), 4.27 (d, J ¼ 13.2 Hz, 1H). 13C NMR: d 19.5, 20.0, 28.6, 31.1, 34.9,
57.9, 62.8, 72.3. IR (KBr): 3346, 2962, 1178 cm21. EI-MS, m/z (%): 203
(Mþ þ H, 1), 116 (32), 71 (57), 57 (100). Anal. Calcd for C10H22N2O2:
C, 59.37; H, 10.96; N, 13.85. Found: C, 59.21; H, 10.98; N, 13.72.

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N-Neopentyl-N-nitroso-leucinol (7b)
841
The N-nitrosamine 7b was recovered as a mixture of E- and Z-rotamers
(10 : 1). Only the major rotamer has been characterized. Rf ¼ 0.52 (ethyl
1
acetate–hexanes, 2 : 3). H NMR: d 0.93 (s, 9H), 0.96 (d, J ¼ 6.2 Hz, 3H),
0.99 (d, J ¼ 6.2 Hz, 3H), 1.64–1.74 (m, 1H), 1.91–1.97 (m, 1H), 3.13 (dd,
J ¼ 13.2, 1.5 Hz, 1H), 3.82 (d, J ¼ 13.2 Hz, 1H), 3.99–4.13 (m, 2H). 13C
NMR: d 22.0, 23.2, 24.9, 28.5, 34.6, 41.0, 57.2, 64.8, 65.1. IR (KBr): 3375,
2961, 1189 cm21. EI-MS, m/z (%): 217 (Mþ, 6), 128 (24), 113 (29), 74 (100),
55 (61). Anal. Calcd for C10H22N2O2: C, 59.37; H, 10.96; N, 13.85. Found:
C, 59.21; H, 10.98; N, 13.72.
General Procedure for the Preparation of Oxadiazinones (9)
In a flame-dried, nitrogen purged 5 L, three-neck round bottom flask fitted
with an addition funnel and a condenser was placed lithium aluminum hydride
(8.72 g, 230 mmol) and freshly distilled tetrahydrofuran (300 mL). The
mixture was then heated to reflux. The b-hydroxy-N-nitrosamine (77 mmol)
was dissolved in freshly distilled tetrahydrafuran (250 mL) and transferred to
the addition funnel. While the mixture was at reflux the N-nitrosamine was
added slowly over a period of 30 min. Once the addition was completed the
reaction mixture remained under reflux for an additional 2 hr. The reaction
mixture was then cooled to room temperature followed by the cautious
addition of sodium hydroxide (6 M). The resulting mixture was diluted with a
saturated aqueous solution of sodium potassium tartrate (200 mL) and stirred
for 45 min. The resulting mixture was then extracted with ethyl acetate
(4 ꢀ 125 mL), washed with a saturated aqueous solution of brine (100 mL),
dried (Na2SO4) followed by the removal of the solvent by rotary evaporation
to give product 8. Due to the ready degradation of the hydrazines, cyclization
was directly carried out to afford the corresponding oxadiazinones.
In a flame-dried, nitrogen purged 500 mL round bottom flask was placed
the b-hydrazino alcohol 8 (26.8 mmol) and freshly distilled hexanes (100 mL).
To this solution was added diethylcarbonate (7.92 g, 67.0 mmol) and the
solution was heated to reflux. To the reaction mixture was added sodium
hydride (1.18 g, 29.5 mmol) and allowed to stir for 2 hr. The mixture was then
cooled to room temperature, and the solvent was removed by rotary evapora-
tion. This solid was suspended in ethyl acetate (50 mL), washed with 1 M
hydrochloric acid (3 ꢀ 50 mL), aqueous saturated solution of sodium bi-
carbonate (50 mL) then an aqueous solution of brine (50 mL), dried (Na2SO4)
followed by the removal of solvent by rotary evaporation.

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Casper et al.
3,4,5,6-Tetrahydro-5-isopropyl-4-neopentyl-2H-1,3,4-
oxadiazin-2-one (9a)
This process yielded a white solid in 96% yield. Mp: 86–888C; Rf ¼ 0.31
1
(ethyl acetate–hexanes, 3 : 7). H NMR: d 0.94 (s, 9H), 0.98 (d, J ¼ 6.6 Hz,
3H). 1.10 (d, J ¼ 6.6 Hz, 3H), 1.84–1.90 (m, 1H), 2.24–27 (m, 1H),
2.45 (d, J ¼ 13.5 Hz, 1H), 2.75 (d, J ¼ 13.5 Hz, 1H), 4.40 (dd, J ¼ 11.3 Hz,
1H), 4.55 (dd, J ¼ 11.3, 3.3 Hz, 1H), 6.31 (bs, 1H). 13C: d 19.5, 20.1, 26.9,
27.7, 32.8, 64.1, 64.9, 72.6, 152.4. IR (KBr): 3244, 2957, 1704, 1301,
1104 cm21. EI-MS, m/z (%): 214 (6, Mþ), 171 (38), 157 (100). Anal. Calcd
for C11H22N2O2: C, 61.65; H, 10.35; N, 13.07. Found: C, 61.78; H, 10.52;
N, 12.99.
3,4,5,6-Tetrahydro-5-isobutyl-4-neopentyl-2H-1,3,4-
oxadiazin-2-one (9b)
This yielded a white solid that was recrystallized from ethyl acetate–
hexanes to afford the title compound in 49% yield. Mp: 84–868C; Rf ¼ 0.39
1
(ethyl acetate–hexanes, 1 : 1). H NMR: d 0.92 (s, 3H), 0.93 (s, 9H), 0.95
(s,3H) 1.16–1.23 (m, 1H), 1.57–1.65 (m, 1H), 1.77–1.87 (m, 1H), 2.45
(d, J ¼ 13.2 Hz, 1H), 2.75 (d, J ¼ 13.2 Hz, 1H), 2.85–2.89 (m, 1H), 4.12 (dd,
J ¼ 11.0, 2.6 Hz, 1H), 4.60 (dd, J ¼ 11.3, 3.7 Hz, 1H), 7.00 (bs, 1H). 13C:
d 22.0, 22.9, 24.4, 27.8, 32.6, 38.8, 56.4, 67.2, 71.6, 152.0. IR (KBr): 3243,
2956, 1704, 1101 cm21. EI-MS, m/z (%): 228 (6, Mþ), 171 (39), 115 (100).
Anal. Calcd for C12H24N2O2: C, 63.12; H, 10.59; N, 12.27. Found: C, 63.51;
H, 11.00; N, 11.77.
ACKNOWLEDGMENT
We gratefully acknowledge the financial support from the department of
chemistry of Illinois State University (ISU). We also acknowledge continued
support from Merck & Co, Inc.
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Harris, J.N. US patent 3,377,345, 1968.

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2. Casper, D.M.; Nora, G.P.; Blackburn, J.R.; Bentley, J.T.; Taylor, D.C.;
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Received in the USA September 3, 2003

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