Organic Process Research & Development
Communication
1
freshly sublimed MTAD. This method provides rapid access to
MTAD and could also find potential applications toward the
preparation of other diverse members in the urazole and
triazolinedione family.
H NMR (D O), yielding near quantitative conversion to the
2
product along with 2.0 equiv of imidazole. The residue solid
was recrystallized from i-PrOH (3.8 L, reflux) and left
overnight at room temperature. The solution was filtered
through a glass frit, and the filter cake was dried on the frit for
EXPERIMENTAL PROCEDURES
2
h with suction, then washed with cold i-PrOH (2 × 300 mL).
■
General Considerations. Tetrahydrofuran (THF), meth-
anol, and i-PrOH were purchased from Fisher and used
without further purification. Ethyl carbazate was purchased
from Alfa Aesar. Carbonyldiimidazole (CDI) was purchased
from Oakwood. Methylamine (40% aq) was purchased from
The mother liquid and filtrates were combined and reduced to
an overall volume of 1.0 L and placed in a freezer (−20 °C) to
recrystallize overnight. The resulting mixture was filtered,
washed with i-PrOH (2 × 100 mL), and dried under vacuum.
Both crops were combined to yield 137.2 g (85%) of 5.
General note: If imidazole is present in a quantity greater than
Sigma-Aldrich. K CO3 (anhydrous) was purchased from
2
1
Fisher. t-BuOCl was prepared according to the known
5% by H NMR, another wash with i-PrOH is required for
adequate reproducibility in the next step.
15
literature procedure. All other reagents were purchased
from commercial suppliers and used without further
purification.
1
H NMR: (500 MHz, D O) δ 4.15 (q, J = 7.1 Hz, 1H), 2.69
2
(s, 2H), 1.23 (t, J = 7.1 Hz, 1H).
1
13
13
H and C NMR spectra were recorded on Varian Unity
C NMR: (126 MHz, D O, CD OD) δ 162.1, 159.8, 63.8,
2
3
1
13
5
00 (500 MHz, H; 126 MHz, C) MHz or Bruker 500 (500
MHz, H; 126 MHz, C) spectrometers. Spectra are
26.9, 14.7.
1
13
IR: 3312 (m, br), 3213 (m,br), 2992 (m, br), 1720 (m),
1706 (m), 1660 (s), 1543 (m), 1278 (s), 1223 (s), 660 (m).
m.p.: 140−144 °C.
referenced to residual chloroform (δ = 7.26 ppm, 1H; 77.16
1
3
1
ppm, C) or residual methanol (δ = 3.31 ppm, H; 49.0 ppm,
1
3
3•+
[M+H] •+
,
C). Chemical shifts are reported in parts per million (ppm).
Multiplicities are indicated by s (singlet), d (doublet), t
triplet), q (quartet), and m (multiplet). Coupling constants J
HRMS: (ESI-TOF, m/z) calcd for C
5
H
N
12
O
3
162.0873 found: 162.0879.
(
The analytical data were in accordance with previously
9
are reported in hertz (Hz). Mass spectrometry (MS) was
performed by the University of Illinois Mass Spectrometry
reported values.
Preparation of 4-Methyl-1,2,4-triazolidine-3,5-dione
(6). To a 2 L round-bottom flask were added 5 (161.6 g, 1 mol,
1.0 equiv) and methanol (1.0 L, 1.0 M), and the mixture was
stirred and cooled in an ice bath for approximately 30 min.
Potassium carbonate (276.4 g, 2 mol, 2.0 equiv) was added in a
single portion, and the flask was equipped with a reflux
condenser and heated to 65 °C under an atmosphere of
nitrogen. After 2 h, stirring halted due to formation of solids,
+
Laboratory. Electron impact (EI ) spectra were performed at
7
0 eV using methane as the carrier gas, with time-of-flight
+
(
TOF) mass analyzer. Chemical ionization (CI ) spectra were
performed with methane reagent gas, with either a double
focusing sector field (DFSF) or time-of-flight (TOF) mass
+
analyzer. Electrospray ionization (ESI ) spectra were per-
formed using a time-of-flight (TOF) mass analyzer. Data are
reported in the form of m/z (intensity relative to the base peak
which was resolved by the addition of H O (100 mL) with
2
=
100). Infrared (IR) spectra were measured neat on a Perkin-
heating continued for an additional 12 h. The reaction mixture
was then cooled to 0 °C before dropwise acidification with
concentrated HCl (400 mL, 12 M aq., 4.0 mol, 4.0 equiv) to a
pH of 1. [Caution! This step is highly exothermic and generates
Elmer spectrum BX FT-IR spectrometer. Peaks are reported in
−
1
cm with indicated relative intensities: s (strong, 0−33% T);
m (medium, 34−66% T), w (weak, 67−100% T), and br
(
broad). Melting points were measured on a Buchi B-540
large quantities of CO .] The solvent was first removed under
2
meting point apparatus and are uncorrected. Optical rotations
were recorded on a Jasco P-2000 polarimeter at 589 nm and
reduced pressure (bath temperature, 40 °C; pressure, 150
mbar), and the bath temperature and pressure were adjusted to
80 °C and 20 mbar, until most of the water was removed, and
the mixture could be scraped into a free-flowing solid. The
solid 6/KCl mixture was then placed under vacuum (<1 mbar)
overnight and then placed in a vacuum desiccator for 2 days
before further use. The solid (25 wt% of 6), was stored until
oxidation to 1 was needed. The yield of this transformation
are reported in units of 10− (deg cm g ). HPLC was
performed on a Shimadzu Prominence HPLC system with an
SPDM20A UV/vis photodiode array detector (220 nm).
Preparation of Ethyl 2-(Methylcarbamoyl)hydrazine-
1
2
−1
1-carboxylate (5). To a three-neck, 2 L round-bottom flask,
equipped with a mechanical stirrer and thermometer, were
added THF (1.0 L, 1.0 M) and ethyl carbazate (104.1 g, 1.0
mol, 1.0 equiv), and the mixture was cooled in an ice bath
under an atmosphere of nitrogen. CDI (162.2 g, 1.0 mol, 1.0
equiv) was added slowly over 15 min, regulating the internal
temperature to remain below 15 °C, and allowed to stir at 0 °C
1
was determined to be 90% by H NMR using dimethyl
malonic acid as an internal standard in D O.
2
1
H NMR: (500 MHz, D O) δ 3.06.
2
13
C NMR: (126 MHz, D O, CH OH) δ 156.6, 25.1.
2
3
IR: 3312 (m, br), 3007 (s, br), 2762 (m, br), 1671 (s), 1491
(s), 1269 (m), 983 (w), 606 (s).
for 2 h. Thereafter, methylamine (40 wt% in H O, 113 mL, 1.3
2
mol, 1.3 equiv) was added in a single portion, and the flask was
removed from the ice bath and allowed to warm up to room
temperature. Full conversion was noted after 4 h (TLC);
however, the solution can be stirred overnight with no
noticeable loss in yield. After completion, the solvent was
removed under reduced pressure (bath temperature: 40 °C,
pressure: 20−45 mbar) until a thick oil formed. The remaining
solvent was removed under vacuum (<1 mbar) with stirring
m.p.: 233−235 °C.
+
HRMS: (ESI-TOF, m/z) calcd for C H N O Na [M
3
5
3
2
+
+Na] , 138.0279 found: 138.0274.
Preparation of 4-Methyl-3H-1,2,4-triazole-3,5(4H)-
dione (1) from 5. To a 500 mL round-bottom flask charged
with 5 (25 g, 155 mmol, 1.0 equiv) and methanol (155 mL, 1.0
M) was added potassium carbonate (42.9 g, 310 mmol, 2.0
equiv) in a single portion. The round-bottom flask was placed
into an oil bath, equipped with a reflux condenser, and heated
to 65 °C under an atmosphere of nitrogen. After 2 h, stirring
(bath temperature: 35 °C, time: 16 h) until the oil solidified.
At this point, the purity of the crude material was analyzed by
D
Org. Process Res. Dev. XXXX, XXX, XXX−XXX