A hydrazine- and phosgene-free synthesis of tetrazinanones, precursors to 1,5-dialkyl-6-oxoverdazyl radicals

Article abstract of DOI:10.1021/jo300027b

A complementary approach to published synthetic methods for tetrazinanones, precursors to verdazyl radicals, is described herein. This approach uses carbohydrazide, a commercially available reagent, as a common starting material. Unlike previous methods d

Full text of DOI:10.1021/jo300027b

Article
pubs.acs.org/joc
A Hydrazine- and Phosgene-Free Synthesis of Tetrazinanones,
Precursors to 1,5-Dialkyl-6-Oxoverdazyl Radicals
Matthew Bancerz, Beom Youn, Matthew V. DaCosta, and Michael K. Georges*
Department of Chemical and Physical Sciences, University of Toronto at Mississauga, 3359 Mississauga Road, Mississauga, Ontario,
Canada, L5L 1C6
S
* Supporting Information
ABSTRACT: A complementary approach to published synthetic
methods for tetrazinanones, precursors to verdazyl radicals, is
described herein. This approach uses carbohydrazide, a
commercially available reagent, as a common starting material.
Unlike previous methods described in the literature, this
synthetic scheme does not rely on phosgene, phosgene
substitutes, or the limited pool of commercially available monosubstituted hydrazines for its execution. A large variety of
alkyl substitution patterns at the N-1 and N-5 positions of verdazyl radicals are possible, including both symmetrically and
unsymmetrically substituted products. An initial condensation reaction of carbohydrazide with a specific aldehyde introduces the
desired C-3 substituent in the final verdazyl radical product and protects the NH2 groups during the subsequent N-1 and N-5
alkylation reactions. A succeeding methanolysis and concomitant ring-closing reaction gives the tetrazinanone. A number of
known oxidation methods can then be employed to form the final verdazyl radical product.
focus for making several classes of heterocycles, including
oxadiazolones,9 pyrazolotriazinones, dihydropyrazolotetrazi-
nones, and tetrahydropyrazolotetrazinones.10 The scope of
this work, to date, has been limited to the 1,5-dimethyl-3-aryl-6-
oxoverdazyl radicals since they were the easiest to make using
previously reported syntheses. The synthetic procedure
reported herein allows the expansion of the substitution
patterns available in these heterocycles by enabling the alkyl
groups at N-1 and N-5 to be varied with relative ease.
The most common procedure used in the preparation of
oxoverdazyl radicals uses either phosgene or the safer
alternative reagent triphosgene, which generates phosgene in
situ, with alkyl or aryl hydrazines, sometimes requiring
protection of the NH2 groups, to provide 1,1′-disubstituted-
carbonic dihydrazides. The dihydrazides are condensed with an
aldehyde to yield tetrazinanones, which are subsequently
oxidized using any one of a number of oxidants, such as
NaIO4, K3Fe(CN)6, PbO2, or Dess−Martin reagent, to afford
the verdazyl radicals.11 This approach is greatly limited by the
choice of commercially available monosubstituted hydrazines
and, in our particular case, is further limited by our inability to
purchase methyl hydrazine because of its restricted sale in
Canada. The method also only provides symmetrically
substituted N-1 and N-5 verdazyl radicals, and even then,
there is a restriction to the steric bulk of the alkyl group that
can be accommodated. When the alkyl group in the alkyl
hydrazine is bulky, phosgene reacts with the NH2 rather than
the desired NH group. As a consequence, the N-1, N-5-
diisopropyl derivative is made using a protecting group
INTRODUCTION
■
Verdazyl radicals, a class of resonance stabilized hydrazyl
radicals, were first reported by Kuhn and Trischmann in 1963.1
They are characterized by a six-membered heterocyclic ring
with four nitrogen atoms and, for the most part, are stable
enough to be isolated and stored at ambient temperature in air
for extended periods of time.2 This remarkable property has
been attributed to the spin delocalization of the single electron
across all four nitrogens. Verdazyl radicals’ innate stability,
without having to rely on sterically bulky substituent groups,
has made them popular spin bearing molecules in the study of
molecular magnets.3 In addition, they have been used as spin
labels in ESR,4 as polymerization inhibitors,5 and as mediators
in living radical polymerizations.6 Only recently have verdazyl
radicals emerged as substrates for organic synthesis,7 an
interesting omission considering the preponderance of
heteroatoms in their structures and, therefore, their potential
as substrates for the synthesis of many new and varied
heterocyclic compounds.
Verdazyl radicals containing a carbon at the 6-position can be
readily categorized into two classes depending on the
hybridization of that carbon. In one class, the carbon is sp3-
hybridized, either CH2 or CHR. In the other class, the carbon is
sp2-hybridized with a carbonyl or thiocarbonyl group, and the
resulting compounds are, respectively, referred to as
oxoverdazyl and thioverdazyl radicals. The C-6 sp3 class of
verdazyl molecules has been synthesized exclusively with aryl
substituents at the N-1 and N-5 positions, whereas the
oxoverdazyl radicals have been made with aryl and alkyl groups
at these same nitrogen positions.
Oxoverdazyl radicals were first reported in 1980 by
Received: January 11, 2012
Published: February 7, 2012
Neugebauer and Umminger8 and have been our group’s
© 2012 American Chemical Society
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Scheme 1. Synthetic Pathway
Table 1. Products and Reaction Yields of Mono- and Dialkylation and Methanolysis and Ring-Closure Reactions
approach, specifically a Boc group, to limit the otherwise
unsubstituted nitrogen’s nucleophilicity, to form the sym-
metrical 1,1′-diisopropyl-carbonic dihydrazide.12
RESULTS AND DISCUSSION
■
Herein, we report an alternative synthesis of symmetrical and
unsymmetrical 2,4-dialkyl-1,2,4,5-tetrazinan-3-ones that avoids
the use of phosgene and alkyl hydrazines. As illustrated in the
examples provided, this synthetic strategy allows the realization
of previously unreported verdazyl radicals specifically based on
the tetrazinanones 15−19 and 23. Scheme 1 illustrates the
general synthetic approach.
The synthesis is initiated with commercially available
carbohydrazide. Condensation with an aryl aldehyde protects
the NH2 groups from the subsequent alkylation reaction while
introducing the desired C-3 aryl substituent in the target
verdazyl radical. N-alkylation is typically accomplished in
anhydrous tetrahydrofuran (THF) with the appropriate
dialkylsulfate and sodium hydride. Although alkyl sulfates are
typically used for consistency, alkyl iodides also work well,
Unsymmetrical N-1-aryl-N-5-alkyl oxoverdazyl radicals have
been prepared by Milcent and co-workers13 with a procedure
subsequently refined by Brook and co-workers.14 A hydrazone,
obtained from a condensation reaction between an aldehyde
and an aryl hydrazine, is reacted with an equivalent of phosgene
in the presence of triethylamine. The intermediate acyl
ammonium ion formed in situ is then reacted with a Boc-
protected alkyl hydrazine. The Boc group is removed by acid
hydrolysis, and a subsequent ring-closing reaction produces the
desired tetrazinanone. While effective, the method still relies on
commercially available aryl hydrazines, as well as the toxic and
expensive triphosgene reagent. To date, unsymmetrically
substituted 1,5-dialkyl-oxoverdazyls have not been made.
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previously synthesized by condensation of carbohydrazide with the
except in cases where their boiling point is inconveniently low.
In the cases where the two alkyl groups differ, alkylation is
performed stepwise with the first step requiring smaller
equivalences of the alkylating agent and sodium hydride.
Fortuitously, the monoalkylated carbohydrazide is less reactive
than carbohydrazide itself, enabling the monoakylation to
proceed in high yield and purity. The reaction to form the
dialkylated product is then accomplished using additional
alkylating agent and NaH. In cases where higher reaction
temperatures are necessary for the second alkylating reaction to
reach completion, anhydrous toluene can be substituted for
THF. The last steps in the reaction sequence, methanolysis and
ring closure, occur concomitantly to produce the tetrazinanone,
which can then be oxidized to the verdazyl radical.
Methanolysis and ring closure is achieved in methanol at
room temperature in 1 h with p-toluenesulfonic acid as an acid
catalyst. One hydrazone group on the starting material
undergoes acid-catalyzed methanolysis and the newly formed
free amine attacks the CN bond of the remaining hydrazone,
resulting in a 6-endotrig cyclization to form the product
tetrazinanone. In our initial studies of this last reaction, it was
appropriate aldehyde. NMR spectra were recorded at 23 °C, operating
1
at 400 MHz for H NMR and 100 MHz for 13C NMR spectroscopy.
Chemical shifts (δ) are reported in parts per million (ppm) referenced
to tetramethylsilane (δ = 0 ppm) for 1H NMR spectra and CDCl3 (δ =
77.0 ppm) for 13C NMR spectroscopy. Coupling constants (J) are
reported in hertz (Hz). Mass spectrometry was performed with an ESI
source, MS/MS, and accurate mass capabilities, associated with a
capillary LC system.
General Methanolysis and Ring-Closure Procedure. Carbo-
di(N′-benzylidene-N-methylhydrazide) (1) (5.00 g, 17 mmol) was
dissolved in 250 mL of methanol. p-Toluenesulfonic acid (4.85 g, 25.5
mmol) and carbohydrazide (2.30 g, 25.5 mmol) were added to the
solution, and the reaction was allowed to stir for 1 h at room
temperature. Once the reaction was complete, as indicated by
disappearance of (1) on TLC, sodium methoxide was added
incrementally until the solution was basic, pH ∼ 10. Following this,
the solvent was evaporated in vacuo and the crude product was filtered
through a short silica gel column using 1:19 methanol in ethyl acetate
as the eluent and recrystallized in 1:2 EtOAc in hexanes to yield white
needle-like crystals (3.07 g, 88%): mp 103−105 °C; FT-IR (ν, cm−1,
KBr) 3254, 3218, 2967, 2938, 2877, 1598, 1506, 1451; 1H NMR (400
MHz, CDCl3) δ 7.55−7.51 (d, J = 7.3 Hz, 2H), 7.42−7.34 (m, 3H),
5.09−5.02 (t, J = 9.9 Hz, 1H), 4.40−4.35 (d, J = 10.0 Hz, 2H), 3.17 (s,
6H); 13C NMR (100 MHz, CDCl3) δ 155.4, 135.2, 128.72, 128.67,
126.5, 69.4, 38.1; HRMS (ESI) m/z [M + H]+ calcd for C10H15N4O,
207.12459; found, 207.12373.
Carbo-di(N′-benzylidene-N-methylhydrazide) (1). Carbo-di-
N-benzylhydrazide (5.10 g, 19.1 mmol) was added to a 500 mL round-
bottom flask and dissolved in 200 mL of dry THF with stirring.
Dimethylsulfate (2.2 equiv, 5.30 g, 3.9 mL, 42.0 mmol) was added,
followed by a slow addition of 3 equiv of sodium hydride (1.38 g, 57
mmol). The solution was brought to reflux and allowed to react for 2
h. The reaction mixture was cooled to 0 °C, and the unreacted sodium
hydride was quenched by the slow addition of methanol until no
effervescence was observed with added methanol. The volume of the
reaction mixture was reduced in vacuo and then taken up in 100 mL of
EtOAc and washed three times with 75 mL of water. The crude extract
was dried over anhydrous sodium sulfate, and the solvent was
evaporated in vacuo. The crude product was filtered through a short
silica gel column (3:2 EtOAc in hexanes as the eluent) and
recrystallized in 1:19 EtOAc in hexanes to yield off-white crystals
(4.73 g, 85%): mp 131−134 °C; FT-IR (ν, cm−1, KBr) 3062, 3030,
2952, 2919, 1656, 1597, 1478; 1H NMR (400 MHz, CDCl3) δ 7.74 (s,
2H), 7.66−7.60 (m, 4H), 7.32−7.27 (m, 6H), 3.49 (s, 6H); 13C NMR
(100 MHz, CDCl3) δ 158.4, 137.7, 135.3, 129.1, 128.6, 127.0, 32.9;
HRMS (ESI) m/z [M + H]+ calcd for C17H19N4O, 295.15589; found,
295.15631.
1
observed by TLC and H NMR that the starting dialkylated
bishydrazone was in equilibrium with the tetrazinanone and the
free aldehyde, preventing the reaction from going beyond
∼50% conversion. Adding carbohydrazide to react with the free
aldehyde to form the corresponding mono- and dihydrazones
resulted in significant increases in the yield of the tetrazinanone.
The hydrazones conveniently precipitated out of solution and
were readily isolated by filtration. They were subsequently used
as starting materials when the reaction scheme was repeated.
Table 1 shows a series of tetrazinanones prepared by this
method as an illustration of the scope of the synthetic
procedure. The alkylation reactions proceed well with primary
alkyl groups; however, secondary groups (i.e., isopropyl,
cyclohexyl) were problematic, which is where Milcent’s
synthesis11 could be applied instead. Also, when thiocarbohy-
drazide was used as a starting material in an attempt to make a
6-thioverdazyl radical, alkylation was observed to occur
selectively on only one nitrogen and on the sulfur, affording
compound 20 in high yield (94%), rather than the desired di-
N-alkylated product. Yields for the alkylation reactions range
from 28 to 91%, and yields for the methanolysis and ring-
closure reactions range from 45 to 91%.
Carbo-di(N′-2-thienylidene-N-methylhydrazide) (2). Carbo-
di-N-2-thienylhydrazide (1.00 g, 3.59 mmol) was added to a 100
mL round-bottom flask and dissolved in 50 mL of dry THF with
stirring. Dimethylsulfate (2.2 equiv, 1.22 g, 0.9 mL, 7.90 mmol) was
added, followed by a slow addition of 3 equiv of sodium hydride (259
mg, 10.8 mmol). The solution was heated at reflux for 2 h. The
reaction mixture was allowed to cool to 0 °C, and the unreacted
sodium hydride was carefully quenched with the slow addition of
methanol. The solution volume was reduced in vacuo and then taken
up in 50 mL of EtOAc and washed three times with 50 mL of water.
The crude extract was dried over anhydrous sodium sulfate, and the
solvent was evaporated in vacuo. The crude product was isolated using
silica gel column chromatography (2:3 EtOAc in hexanes as the
eluent) and recrystallized in 1:4 EtOAc in hexanes to yield white
crystals (613 mg, 56%): mp 160−163 °C; FT-IR (ν, cm−1, KBr) 3086,
3072, 1645, 1587, 1420; 1H NMR (400 MHz, CDCl3) δ 7.90 (s, 2H),
7.24−7.19 (m, 4H), 7.02−6.99 (m, 2H), 3.43 (s, 6H); 13C NMR (100
MHz, CDCl3) δ 157.6, 140.6, 132.8, 127.9, 126.9, 126.7, 33.1; HRMS
(ESI) m/z [M + H]+ calcd for C13H15N4OS2, 307.06873; found,
307.06962.
CONCLUSION
■
To conclude, a synthesis complementary to existing methods to
make tetrazinanones, without the use of phosgene or
hydrazines, that can be oxidized to 1,5-dialkyl-6-oxoverdazyl
radicals, is described. This method, via stepwise alkylation, can
be readily used to generate unsymmetrical substitution patterns
in 1,5-dialkyl-6-oxoverdazyl radicals that have not been
previously reported in the literature. The scope of available
alkyl substituents at these positions is greatly improved over
current methods due to the wider commercial availability of
alkylating agents relative to the monosubstituted hydrazines
used in most of the other previously published procedures.
Both aryl and alkyl groups can be introduced at the C-3
position of the verdazyl radical by using the appropriate
substituted aldehyde during the initial condensation reaction.
EXPERIMENTAL SECTION
General. Silica gel chromatography was performed with silica gel
60 (particle size 40−63 Å). Carbo-di-N-benzylhydrazides were
■
Carbo-di(N′-benzylidene-N-benzylhydrazide) (3). Carbo-di-N-
benzylhydrazide (6.00 g, 22.5 mmol) was added to a 500 mL round-
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bottom flask and dissolved in 150 mL of anhydrous toluene with
stirring. Benzylbromide (2.2 equiv, 8.40 g, 5.9 mL, 49.6 mmol) was
added, followed by the slow addition of 3 equiv of sodium hydride
(1.62 g, 67.6 mmol). The solution was heated at reflux for 24 h. The
reaction mixture was allowed to cool to 0 °C, and the unreacted
sodium hydride was carefully quenched by the slow addition of
methanol. The solution was taken up in 100 mL of EtOAc and washed
three times with 70 mL of water. The crude extract was dried over
anhydrous sodium sulfate, and the solvent was evaporated in vacuo.
The resulting product was filtered through a short silica gel column
(DCM as the eluent) and recrystallized in methanol to yield colorless
granular crystals (9.16 g, 91%): mp 117−120 °C; FT-IR (ν, cm−1,
KBr) 3052, 2972, 2927, 1669, 1602, 1495; 1H NMR (400 MHz,
CDCl3) δ 7.64 (s, 2H), 7.43−7.38 (m, 8H), 7.37−7.32 (m, 4H),
7.29−7.22 (m, 3H), 7.21−7.14 (m, 5H), 5.36 (s, 4H); 13C NMR (100
MHz, CDCl3) δ 158.9, 139.1, 135.9, 134.9, 128.9, 128.7, 128.3, 127.0,
126.9, 126.3, 49.3; HRMS (ESI) m/z [M + H]+ calcd for C29H27N4O,
447.21849; found, 447.21949.
with 50 mL of water. The crude extract was dried over anhydrous
sodium sulfate, and the solvent was evaporated in vacuo. The crude
product was filtered through a short silica gel column (DCM as the
eluent) and recrystallized from methanol to yield off-white crystals
(2.20 g, 88%): mp 97−99 °C; FT-IR (ν, cm−1, KBr) 3061, 3024, 1708,
1
1667, 1604, 1423; H NMR (400 MHz, CDCl3) δ 7.76 (s, 1H), 7.62
(s, 1H), 7.54−7.46 (m, 4H), 7.39−7.30 (m, 4H), 7.28−7.17 (m, 7H),
5.30 (s, 2H), 3.53 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 158.5,
139.1, 137.7, 135.9, 135.1, 134.9, 128.93, 128.90, 128.7, 128.4, 128.3,
127.0, 126.89, 126.86, 126.3, 49.3, 32.7; HRMS (ESI) m/z [M + H]+
calcd for C23H23N4O, 371.18719; found, 371.18559.
Carbo-N′-benzylidene-N-benzylhydrazide(N′-benzylidene-
N-ethylhydrazide) (7). Carbo-N′-benzylidene(N′-benzylidene-N-
benzylhydrazide) (5) (625 mg, 1.75 mmol) was added to a 100 mL
round-bottom flask and dissolved in 20 mL of anhydrous toluene with
stirring. Diethylsulfate (1.2 equiv, 324 mg, 0.27 mL, 2.10 mmol) was
added, followed by a slow addition of 2 equiv of sodium hydride (84
mg, 3.51 mmol). The solution was heated to reflux and allowed to
react for 10 h. The reaction mixture was allowed to cool to 0 °C, the
unreacted sodium hydride was quenched by a slow addition of
methanol, and the solution volume was reduced in vacuo. This
solution was then taken up in 50 mL of EtOAc and washed once with
100 mL of 1 M NaOH(aq) and two more times with 100 mL of water.
The crude extract was dried over anhydrous sodium sulfate, and the
solvent was evaporated in vacuo. The crude product was filtered
through a short silica gel column (DCM as the eluent) to yield an
orange oil (510 mg, 75%): FT-IR (ν, cm−1, KBr) 3061, 3025, 2974,
2933, 1665, 1598, 1426; 1H NMR (400 MHz, CDCl3) δ 7.81 (s, 1H),
7.61 (s, 1H), 7.50−7.42 (m, 4H), 7.39−7.29 (m, 4H), 7.27−7.13 (m,
7H), 5.28 (s, 2H), 4.16−4.04 (q, J = 6.9 Hz, 2H), 1.36−1.29 (t, J = 6.8
Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 158.3, 139.1, 138.6, 136.2,
135.2, 135.1, 129.0, 128.9, 128.8, 128.5, 128.3, 127.05, 126.94, 126.93,
126.4, 49.6, 39.7, 11.2; HRMS (ESI) m/z [M + H]+ calcd for
C24H25N4O, 385.20284; found, 385.20202.
Carbo-di(N′-benzylidene-N-ethylhydrazide) (4). Carbo-di-N-
benzylhydrazide (7.00 g, 26.3 mmol) was added to a 500 mL round-
bottom flask and dissolved in 150 mL of anhydrous toluene with
stirring. Diethylsulfate (2.2 equiv, 8.90 g, 7.4 mL, 57.9 mmol) was
added, followed by a slow addition of 3 equiv of sodium hydride (1.89
g, 78.9 mmol). The solution was brought to reflux and allowed to react
for 24 h. The reaction mixture was allowed to cool to 0 °C, and the
unreacted sodium hydride was quenched by the slow addition of
methanol. The solution was then taken up in 100 mL of EtOAc and
washed three times with 75 mL of water. The crude extract was dried
over anhydrous sodium sulfate, and the solvent was evaporated in
vacuo. The crude product was filtered through a short silica gel column
(1:199 methanol in DCM as the eluent) and recrystallized from 1:19
EtOAc in hexanes to yield off-white crystals (6.95 g, 82%): mp 83−85
°C; FT-IR (ν, cm−1, KBr) 3022, 2978, 2934, 2873, 1659, 1604, 1597,
1
1464; H NMR (400 MHz, CDCl3) δ 7.81 (s, 2H), 7.61−7.56 (m,
Carbo-N′-benzylidene-N-benzylhydrazide(N′-benzylidene-
N-ethylhydrazide) (8). Carbo-di-N-benzylhydrazide (5.00 g, 18.8
mmol) was added to a 500 mL round-bottom flask and dissolved in
250 mL of dried THF with stirring. Diethylsulfate (1.1 equiv, 3.18 g,
2.6 mL, 20.7 mmol) was added, followed by a slow addition of 2 equiv
of sodium hydride (902 mg, 37.6 mmol). The solution was heated to
reflux and allowed to react for 4 h. The reaction mixture was allowed
to cool to 0 °C, and the unreacted sodium hydride was quenched by
the slow addition of methanol. The solution was then taken up in 150
mL of EtOAc and washed three times with 75 mL of water. The crude
extract was dried over anhydrous sodium sulfate, and the solvent was
evaporated in vacuo. The crude product was filtered through a short
silica gel column (1:99 methanol in DCM as the eluent) and
recrystallized from 1:9 EtOAc in hexanes to yield off-white crystals
(4.38 g, 79%): mp 128−130 °C; FT-IR (ν, cm−1, KBr) 3298, 3267,
3018, 2979, 1681, 1516, 1404; 1H NMR (400 MHz, CDCl3) δ 9.85 (s,
1H), 8.07 (s, 1H), 7.78−7.74 (m, 2H), 7.68−7.64 (m, 3H), 7.46−7.33
(m, 6H), 4.13−4.07 (q, J = 7.1 Hz, 2H), 1.24−1.19 (t, J = 7.1 Hz, 3H);
13C NMR (100 MHz, CDCl3) δ 151.7, 145.1, 137.0, 134.3, 134.0,
129.63, 129.61, 128.7, 128.4, 127.2, 126.7, 35.4, 11.0; HRMS (ESI) m/
z [M + H]+ calcd for C18H21N4O, 309.17154; found, 309.17177.
Carbo-N′-benzylidene-N-ethylhydrazide(N′-benzylidene-N-
methylhydrazide) (9). Carbo-N′-benzylidene-N-benzylhydrazide(N′-
benzylidene-N-ethylhydrazide) (8) (4.37 g, 14.8 mmol) was added to
a 500 mL round-bottom flask and dissolved in 200 mL of anhydrous
toluene with stirring. Dimethylsulfate (1.2 equiv, 2.24 g, 1.7 mL, 17.8
mmol) was added, followed by a slow addition of 2 equiv of sodium
hydride (710 mg, 29.6 mmol). The solution was heated to 85 °C and
allowed to react for 2 h. The reaction mixture was allowed to cool to 0
°C, the unreacted sodium hydride was quenched by the slow addition
of methanol, and the solution volume was reduced in vacuo. The
solution was then taken up in 150 mL of EtOAc and washed three
times with 100 mL of water. The crude extract was dried over
anhydrous sodium sulfate, and the solvent was evaporated in vacuo.
The crude product was filtered through a short silica gel column
(1:199 methanol in DCM as the eluent) to yield off-white crystals
4H), 7.28−7.24 (m, 6H), 4.10−4.03 (q, J = 7.1 Hz, 4H), 1.34−1.28 (t,
J = 7.1 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ 157.8, 138.5, 135.2,
128.9, 128.4, 126.8, 39.8, 11.2; HRMS (ESI) m/z [M + H]+ calcd for
C19H23N4O, 323.18719; found, 323.18744.
Carbo-N′-benzylidene(N′-benzylidene-N-benzylhydrazide)
(5). Carbo-di-N-benzylhydrazide (5.00 g, 18.8 mmol) was added to a
500 mL round-bottom flask and dissolved in 250 mL of dried THF
with stirring. Benzylbromide (1.1 equiv, 3.53 g, 2.46 mL, 20.7 mmol)
was added, followed by the slow addition of 2 equiv of sodium hydride
(901 mg, 37.6 mmol). The solution was heated to reflux and allowed
to react for 4 h. The reaction mixture was allowed to cool to 0 °C, and
the unreacted sodium hydride was quenched by the slow addition of
methanol. This solution was then taken up in 150 mL of EtOAc and
washed three times with 100 mL of water. The crude extract was dried
over anhydrous sodium sulfate, and the solvent was evaporated in
vacuo. The crude product was filtered through a short silica gel column
(1:49 methanol in DCM as the eluent) and recrystallized from 1:9
EtOAc in hexanes to yield off-white crystals (5.35 g, 80%): mp 188−
191 °C; FT-IR (ν, cm−1, KBr) 3338, 3029, 1708, 1607, 1498, 1485; 1H
NMR (400 MHz, CDCl3) δ 10.02 (s, 1H), 8.15 (s, 1H), 7.82−7.77
(m, 2H), 7.58−7.51 (m, 3H), 7.42−7.21 (m, 11H), 5.30 (s, 2H); 13C
NMR (100 MHz, CDCl3) δ 152.4, 145.5, 138.8, 135.1, 133.9, 129.8,
129.7, 128.8, 128.6, 128.5, 127.33, 127.29, 126.8, 126.5, 45.3; HRMS
(ESI) m/z [M + H]+ calcd for C22H21N4O, 357.17154; found,
357.17284.
Carbo-N′-benzylidene-N-benzylhydrazide(N′-benzylidene-
N-methylhydrazide) (6). Carbo-N′-benzylidene(N′-benzylidene-N-
benzylhydrazide) (5) (2.40 g, 6.73 mmol) was added to a 250 mL
round-bottom flask and dissolved in 100 mL of anhydrous toluene
with stirring. Dimethylsulfate (1.1 equiv, 934 mg, 0.70 mL, 7.40
mmol) was added, followed by slow a addition of 2 equiv of sodium
hydride (323 mg, 13.5 mmol). The solution was heated to 85 °C and
allowed to react for 2 h. The reaction mixture was allowed to cool to 0
°C, and the unreacted sodium hydride was quenched by the slow
addition of methanol. The solution volume was reduced in vacuo. This
solution was then taken up in 75 mL of EtOAc and washed three times
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(4.02 g, 88%): mp 99−101 °C; FT-IR (ν, cm−1, KBr) 3062, 3023,
8.8 Hz, 1H), 4.58−4.53 (d, J = 8.8 Hz, 2H), 3.15 (s, 6H); 13C NMR
(100 MHz, CDCl3) δ 155.1, 138.1, 127.1, 126.0, 125.8, 66.9, 38.1;
HRMS (ESI) m/z [M + H]+ calcd for C8H13N4OS, 213.08101; found,
213.08115.
1
2980, 2933, 2903, 1651, 1598, 1427; H NMR (400 MHz, CDCl3) δ
7.80 (s, 1H), 7.73 (s, 1H), 7.64−7.58 (m, 4H), 7.31−7.25 (m, 6H),
4.12−4.04 (q, J = 7.1 Hz, 2H), 3.47 (s, 3H), 1.34−1.29 (t, J = 7.0 Hz,
3H); 13C NMR (100 MHz, CDCl3) δ 158.0, 138.5, 137.3, 135.2,
135.1, 129.0, 128.8, 128.41, 128.36, 126.9, 126.8, 39.6, 33.0, 11.1;
HRMS (ESI) m/z [M + H]+ calcd for C18H21N4O, 309.17154; found,
309.17245.
2,4-Dibenzyl-6-phenyl-1,2,4,5-tetrazinan-3-one (14). Carbo-
di(N′-benzylidene-N-benzylhydrazide) (3) (1.50 g) was reacted
according to the general methanolysis and ring-closure procedure to
yield white needle-like crystals (1.09 g, 91%): mp 147−150 °C; FT-IR
1
(ν, cm−1, KBr) 3256, 3249, 3227, 1594, 1501, 1449; H NMR (400
Carbo-N′-benzylidene-N-methylhydrazide(N′-benzylidene-
N-propylhydrazide) (10). Carbo-N′-benzylidene(N′-benzylidene-N-
propylhydrazide) (11) (2.00 g, 6.49 mmol) was added to a 250 mL
round-bottom flask and dissolved in 40 mL of anhydrous toluene with
stirring. Dimethylsulfate (1.4 equiv, 1.15 g, 0.86 mL, 9.08 mmol) was
added, followed by a slow addition of 2.2 equiv of sodium hydride
(340 mg, 14.3 mmol). The solution was heated to 85 °C and allowed
to react for 2 h. The reaction mixture was allowed to cool to 0 °C, the
unreacted sodium hydride was quenched by the slow addition of
methanol, and the solution volume was reduced in vacuo. This
solution was then taken up in 75 mL of EtOAc and washed three times
with 50 mL of water. The crude extract was dried over anhydrous
sodium sulfate, and the solvent was evaporated in vacuo. The crude
product was filtered through a short silica gel column (1:99 methanol
in DCM as the eluent) to yield a light yellow oil (1.67 g, 80%): FT-IR
(ν, cm−1, KBr) 3059, 3027, 2962, 2932, 2874, 1666, 1598, 1572, 1422;
1H NMR (400 MHz, CDCl3) δ 7.74 (s, 1H), 7.65 (s, 1H), 7.63−7.56
MHz, CDCl3) δ 7.45−7.24 (m, 15H), 4.82−4.67 (m, 5H), 4.23−4.17
(d, J = 10.8 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 154.0, 137.6,
134.8, 128.6, 128.4, 128.3, 127.3, 126.1, 69.5, 53.1; HRMS (ESI) m/z
[M + H]+ calcd for C22H23N4O, 359.18719; found, 359.18893.
2,4-Diethyl-6-phenyl-1,2,4,5-tetrazinan-3-one (15). Carbo-di-
(N′-benzylidene-N-ethylhydrazide) (4) (347 mg) was reacted
according to the general methanolysis and ring-closure procedure to
yield white needle-like crystals (252 mg, 82%): mp 70−72 °C; FT-IR
(ν, cm−1, KBr) 3231, 3063, 3034, 2972, 2930, 2868, 1600, 1496, 1452,
1
1421; H NMR (400 MHz, CDCl3) δ 7.56−7.52 (m, 2H), 7.43−7.34
(m, 3H), 4.94−4.86 (t, J = 11.2 Hz, 1H), 4.19−4.13 (d, J = 11.3 Hz,
2H), 3.73−3.63 (sextet, J = 7.0 Hz, 2H), 3.56−3.45 (sextet, J = 7.0 Hz,
2H), 1.23−1.18 (t, J = 7.0 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ
154.4, 135.4, 128.8, 128.7, 126.3, 70.4, 44.6, 12.4; HRMS (ESI) m/z
[M + H]+ calcd for C12H19N4O, 235.15589; found, 235.15581.
2-Benzyl-4-methyl-6-phenyl-1,2,4,5-tetrazinan-3-one (16).
Carbo-N′-benzylidene-N-benzylhydrazide(N′-benzylidene-N-methyl-
hydrazide) (6) (6.10 g) was reacted according to the general
methanolysis and ring-closure procedure to yield white needle-like
crystals (2.11 g, 45%): mp 98−100 °C; FT-IR (ν, cm−1, KBr) 3238,
(m, 4H), 7.24−7.17 (m, 6H), 4.98−4.91 (t, J = 7.4 Hz, 2H), 3.37 (s,
3H), 1.79−1.68 (sextet, J = 7.4 Hz, 2H), 1.00−0.93 (t, J = 7.4 Hz,
3H); 13C NMR (100 MHz, CDCl3) δ 158.2, 138.3, 137.3, 135.3,
135.2, 129.0, 128.8, 128.42, 128.37, 126.89, 126.85, 46.3, 33.0, 19.2,
11.2; HRMS (ESI) m/z [M + H]+ calcd for C19H23N4O, 323.1866;
found, 323.1866.
1
3030, 2909, 1687, 1597, 1514; H NMR (400 MHz, CDCl3) δ 7.48−
7.27 (m, 10H), 4.99−4.92 (t, J = 10.4 Hz, 1H), 4.79−4.73 (d, J = 14.5
Hz, 1H), 4.69−4.63 (d, J = 14.5 Hz, 1H), 4.35−4.30 (d, J = 10.4 Hz,
1H), 4.24−4.19 (d, J = 10.3 Hz, 1H), 3.21 (s, 3H); 13C NMR (100
MHz, CDCl3) δ 154.4, 137.7, 134.9, 128.62, 128.57, 128.5, 128.3,
127.2, 126.2, 69.4, 53.5, 37.9; HRMS (ESI) m/z [M + H]+ calcd for
C16H19N4O, 283.15589; found, 283.15616.
Carbo-N′-benzylidene(N′-benzylidene-N-propylhydrazide)
(11). Carbo-di-N-benzylhydrazide (2.50 g, 9.39 mmol) was added to a
500 mL round-bottom flask and dissolved in 100 mL of dried THF
with stirring. Iodopropane (1.2 equiv, 1.92 g, 1.1 mL, 11.3 mmol) was
added, followed by a slow addition of 2 equiv of sodium hydride (451
mg, 18.8 mmol). The solution was heated to reflux and allowed to
react for 24 h. The reaction mixture was allowed to cool to 0 °C, and
the unreacted sodium hydride was quenched by the slow addition of
methanol. This solution was then taken up in 100 mL of EtOAc and
washed three times with 75 mL of water. The crude extract was dried
over anhydrous sodium sulfate, and the solvent was evaporated in
vacuo. The crude product was filtered through a short silica gel column
(2:98 methanol in DCM as the eluent) and recrystallized from 1:9
EtOAc in hexanes to yield off-white crystals (2.14 g, 74%): mp 114−
116 °C; FT-IR (ν, cm−1, KBr) 3327, 2960, 2937, 2874, 1695, 1608,
1511, 1402; 1H NMR (400 MHz, CDCl3) δ 9.88 (s, 1H), 8.05 (s, 1H),
7.77−7.73 (m, 2H), 7.67−7.63 (m, 2H), 7.61 (s, 1H), 7.45−7.31 (m,
6H), 4.02−3.96 (t, J = 7.5 Hz, 2H), 1.70−1.59 (sextet, J = 7.5 Hz,
2H), 1.00−0.95 (t, J = 7.4 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ
152.1, 145.1, 137.1, 134.2, 134.0, 129.6, 128.7, 128.4, 127.2, 126.7,
42.1, 18.9, 11.0; HRMS (ESI) m/z [M + H]+ calcd for C18H21N4O,
309.17154; found, 309.17177.
2-Benzyl-4-ethyl-6-phenyl-1,2,4,5-tetrazinan-3-one (17).
Carbo-N′-benzylidene-N-benzylhydrazide(N′-benzylidene-N-ethylhy-
drazide) (7) (290 mg) was reacted according to the general
methanolysis and ring-closure procedure to yield an orange oil (154
mg, 69%): FT-IR (ν, cm−1, KBr) 3234, 3062, 3030, 2971, 2927, 1613,
1
1495, 1451; H NMR (400 MHz, CDCl3) δ 7.46−7.20 (m, 10H),
4.82−4.56 (m, 3H), 4.35−4.27 (m, 2H), 3.73−3.62 (sextet, J = 7.0 Hz,
1H), 3.46−3.36 (sextet, J = 7.0 Hz, 1H), 1.19−1.14 (d, J = 7.0 Hz,
3H); 13C NMR (100 MHz, CDCl3) δ 154.0, 137.8, 135.1, 128.5,
128.4, 128.3, 127.2, 126.2, 69.8, 53.5, 44.6, 12.3; HRMS (ESI) m/z [M
+ H]+ calcd for C17H21N4O, 297.17154; found, 297.17162.
2-Ethyl-4-methyl-6-phenyl-1,2,4,5-tetrazinan-3-one (18).
Carbo-N′-benzylidene-N-ethylhydrazide(N′-benzylidene-N-methylhy-
drazide) (9) (200 mg) was reacted according to the general
methanolysis and ring-closure procedure to yield white needle-like
crystals (70 mg, 49%): mp 78−80 °C; FT-IR (ν, cm−1, KBr) 3251,
3226, 2972, 2932, 2871, 1593, 1490, 1450, 1430; 1H NMR (400 MHz,
CDCl3) δ 7.54−7.48 (m, 2H), 7.40−7.28 (m, 3H), 4.89−4.81 (t, J =
10.0 Hz, 1H), 4.78−4.72 (d, J = 10.0 Hz, 1H), 4.64−4.58 (d, J = 10.0
Hz, 1H), 3.75−3.55 (sextet, J = 7.0 Hz, 1H), 3.41−3.30 (sextet, J = 7.0
Hz, 1H), 3.10 (s, 3H), 1.18−1.10 (t, J = 6.9 Hz, 3H); 13C NMR (100
MHz, CDCl3) δ 154.6, 135.3, 128.4, 126.4, 69.7, 44.5, 37.8, 12.4;
HRMS (ESI) m/z [M + H]+ calcd for C11H17N4O, 221.14024; found,
221.13961.
2,4-Dimethyl-6-phenyl-1,2,4,5-tetrazinan-3-one (12). Carbo-
di(N′-benzylidene-N-methylhydrazide) (1) (5.00 g) was reacted
according to the general methanolysis and ring-closure procedure to
yield white needle-like crystals (3.07 g, 88%): mp 103−105 °C; FT-IR
1
(ν, cm−1, KBr) 3254, 3218, 2967, 2938, 2877, 1598, 1506, 1451; H
NMR (400 MHz, CDCl3) δ 7.55−7.51 (d, J = 7.3 Hz, 2H), 7.42−7.34
(m, 3H), 5.09−5.02 (t, J = 9.9 Hz, 1H), 4.40−4.35 (d, J = 10.0 Hz,
2H), 3.17 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 155.4, 135.2,
128.72, 128.67, 126.5, 69.4, 38.1; HRMS (ESI) m/z [M + H]+ calcd
for C10H15N4O, 207.12459; found, 207.12373.
2,4-Dimethyl-6-(thiophen-2-yl)-1,2,4,5-tetrazinan-3-one
(13). Carbo-di(N′-2-thienylidene-N-methylhydrazide) (2) (193 mg)
was reacted according to the general methanolysis and ring-closure
procedure to yield white needle-like crystals (82 mg, 62%): mp 123−
125 °C; FT-IR (ν, cm−1, KBr) 3246, 2970, 2923, 2875, 1602, 1507,
1434; 1H NMR (400 MHz, CDCl3) δ 7.32−7.29 (d, J = 4.9 Hz, 1H),
7.16−7.13 (m, 1H), 7.04−7.00 (t, J = 4.5 Hz, 1H), 5.24−5.18 (t, J =
2-Methyl-6-phenyl-4-propyl-1,2,4,5-tetrazinan-3-one (19).
Carbo-N′-benzylidene-N-methylhydrazide(N′-benzylidene-N-propyl-
hydrazide) (10) (500 mg) was reacted according to the general
methanolysis and ring-closure procedure to yield a yellow-orange oil
(262 mg, 72%): FT-IR (ν, cm−1, KBr) 3235, 3061, 3032, 2961, 2930,
1
2873, 1690, 1616, 1451; H NMR (400 MHz, CDCl3) δ 7.54−7.48
(m, 2H), 7.40−7.28 (m, 3H), 4.92−4.84 (t, J = 9.9 Hz, 1H), 4.77−
4.69 (d, J = 10.1 Hz, 1H), 4.62−4.54 (d, J = 9.9 Hz, 1H), 3.55−3.44
(m, 1H), 3.37−3.26 (m, 1H), 3.11 (s, 3H), 1.68−1.55 (sextet, J = 7.3
Hz, 2H), 0.93−0.84 (t, J = 7.3 Hz, 3H); 13C NMR (100 MHz, CDCl3)
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δ 154.8, 135.5, 128.6, 126.5, 69.7, 51.6, 38.0, 20.7, 11.3; HRMS (ESI)
m/z [M + H]+ calcd for C12H19N4O, 235.1553; found, 235.1558.
Methyl-N′-2-dibenzylidene-1-methylhydrazinecarbohydra-
zonothioate (20). Thiocarbo-di-N-benzylhydrazide (1.00 g, 3.54
mmol) was added to a 250 mL round-bottom flask and dissolved in 75
mL of dried THF with stirring. Dimethylsulfate (2.2 equiv, 0.98 g, 0.7
mL, 7.79 mmol) was added, followed by a slow addition of 3 equiv of
sodium hydride (254 mg, 10.6 mmol). The solution was brought to
reflux and allowed to react for 2 h. The reaction mixture was allowed
to cool to 0 °C, the unreacted sodium hydride was quenched by the
slow addition of methanol, and the solution volume was reduced in
vacuo. This solution was then taken up in 50 mL of EtOAc and
washed three times with 100 mL of water. The extract was dried over
anhydrous sodium sulfate, and the solvent was evaporated in vacuo.
The crude product was recrystallized from 1:9 EtOAc in hexanes to
yield bright yellow crystals (1.03 g, 94%): mp 64−65 °C; FT-IR (ν,
cm−1, KBr) 3055, 3020, 2925, 1593, 1567, 1510, 1406; 1H NMR (400
MHz, CDCl3) δ 8.30 (s, 1H), 7.79−7.73 (m, 2H), 7.70−7.65 (d, J =
7.3 Hz, 2H), 7.62 (s, 1H), 7.42−7.34 (m, 5H), 7.34−7.28 (t, J = 7.2
Hz, 1H), 3.55 (s, 3H), 2.63 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
164.0, 155.7, 136.3, 135.3, 135.1, 129.9, 128.8, 128.6, 128.5, 127.7,
126.6, 33.4, 17.8; HRMS (ESI) m/z [M + H]+ calcd for C17H19N4S,
311.13304; found, 311.13254.
(632 mg, 84%): mp 74−76 °C; FT-IR (ν, cm−1, KBr) 3250.3, 3226.1,
1
3084.0, 3009.3, 2971.4, 2910.4, 1696.4, 1488.8; H NMR (400 MHz,
CDCl3) δ 7.52−7.48 (m, 2H), 7.37−7.27 (m, 3H), 5.89−5.77 (m,
1H), 5.25−5.18 (dd, J = 17.1 Hz, 1.5 Hz, 1H), 5.16−5.11 (dd, J = 10.2
Hz, 1.3 Hz, 1H), 4.92−4.80 (m, 2H), 4.77−4.70 (d, J = 8.9 Hz, 1H),
4.14−4.06 (m, 1H), 4.01−3.93 (m, 1H), 3.09 (s, 3H); 13C NMR (100
MHz, CDCl3) δ 154.4, 135.3, 133.5, 128.4, 126.5, 117.1, 69.5, 52.6,
37.8; HRMS (ESI) m/z [M + H]+ calcd for C12H17N4O, 233.1396;
found, 233.1395.
Carbo-di-(N′-3-phenylpropionyl-N-methylhydrazide) (24).
Carbo-di-N-3-phenylpropionylhydrazide (815 mg, 2.52 mmol) was
added to a 100 mL round-bottom flask and dissolved in 50 mL of
dried THF with stirring. Dimethylsulfate (2.2 equiv, 732 mg, 0.55 mL,
5.79 mmol) was added, followed by a slow addition of 3 equiv of
sodium hydride (0.182 g, 7.58 mmol). The solution was brought to
reflux and allowed to react for 2 h. The reaction mixture was allowed
to cool to 0 °C, the unreacted sodium hydride was quenched by the
slow addition of methanol, and the solution volume was reduced in
vacuo. This solution was then taken up in 100 mL of EtOAc and
washed three times with 75 mL of water. The crude extract was dried
over anhydrous sodium sulfate, and the solvent was evaporated in
vacuo. The crude product was filtered through a short silica gel column
(1:1 EtOAc in hexanes as the eluent) to yield a yellow oil (0.797 g,
90%): FT-IR (ν, cm−1, KBr) 3060, 3025, 2926, 1623, 1479, 1453,
1385, 1334; 1H NMR (400 MHz, CDCl3) δ 7.30−7.26 (m, 4H),
7.22−7.17 (m, 6H), 7.03 (t, 2H), 3.18 (s, 6H), 2.86 (t, 4H), 2.65 (m,
4H); 13C NMR (100 MHz, CDCl3) δ 158.8, 141.1, 140.9, 128.5,
128.4, 126.1, 34.5, 33.4, 33.1; HRMS (ESI) m/z [M + H]+ calcd for
C21H27N4O, 351.21849; found, 351.21844.
2,4-Dimethyl-6-(3-phenyl)propionyl-1,2,4,5-tetrazinan-3-
one (25). Carbo-di(N′-3-phenylpropionyl-N-methylhydrazide) (24)
(0.424 g) was reacted according to the general methanolysis and ring-
closure procedure to yield an off-white solid (130 g, 46%): mp 82−84
°C; FT-IR (ν, cm−1, KBr) 3232, 3205, 2956, 2919, 2869, 1597, 1495,
1439, 1392; 1H NMR (400 MHz, CDCl3) δ 7.32−7.26 (m, 2H),
7.23−7.17 (m, 3H), 4.21−4.12 (d, J = 9.9 Hz, 2H), 3.82−3.69 (m,
1H), 3.07 (s, 6H), 2.81−2.74 (m, 2H), 1.82 (m, 2H); 13C NMR (100
MHz, CDCl3) δ 155.3, 140.7, 128.36, 128.31, 126.0, 67.0, 37.9, 31.7,
31.6.1; HRMS (ESI) m/z [M + H]+ calcd for C10H15N4O, 207.12459;
found, 207.12373.
Carbo-di(N′-paravinylicbenzylidene-N-ethylhydrazide) (26).
Carbo-di-N-paravinylicbenzylhydrazide (1.21 g, 4.53 mmol) was added
to a 100 mL round-bottom flask and dissolved in 50 mL of anhydrous
toluene with stirring. Diethylsulfate (4.0 equiv, 2.79 g, 2.3 mL, 18.1
mmol) was added, followed by a slow addition of 6 equiv of sodium
hydride (0.651 g, 27.1 mmol). The solution was brought to reflux and
allowed to react for 39 h. The reaction mixture was allowed to cool to
0 °C, and the unreacted sodium hydride was quenched by a slow
addition of methanol. The solution was then taken up in 100 mL of
EtOAc and washed three times with 75 mL of water. The crude extract
was dried over anhydrous sodium sulfate, and the solvent was
evaporated in vacuo. The crude product was filtered through a short
silica gel column (1:1 EtOAc in hexanes as the eluent) and
recrystallized from 1:19 EtOAc in hexanes to yield off-yellow solids
(396 mg, 28%): mp 78−81 °C; FT-IR (ν, cm−1, KBr) 3025, 2933,
1666, 1624, 1453, 1385, 1086, 752, 700; 1H NMR (400 MHz, CDCl3)
δ 7.78 (s, 2H), 7.58−7.28 (m, 8H), 6.72−6.61 (dd, J = 10.9 Hz, 6.9
Hz, 2H), 5.76−5.67 (d, J = 17.8 Hz, 2H), 5.27−5.20 (d, J = 11.8 Hz,
2H), 4.09−4.01 (q, J = 6.9 Hz, 4H), 1.34−1.27 (t, J = 7.0 Hz, 6H); 13C
NMR (100 MHz, CDCl3) δ 157.9, 138.3, 138.2, 136.4, 134.9, 127.1,
126.4, 114.3, 39.9, 11.3; HRMS (ESI) m/z [M + H]+ calcd for
C23H27N4O, 375.21849; found, 375.21848.
Carbo-N′-benzylidene(N′-benzylidene-N-allylhydrazide)
(21). Carbo-di-N-benzylhydrazide (2.80 g, 10.5 mmol) was added to a
250 mL round-bottom flask and dissolved in 100 mL of dried THF
with stirring. Allylbromide (5 equiv, 6.36 g, 4.5 mL, 52.5 mmol) was
added, followed by a slow addition of 2 equiv of sodium hydride (876
mg, 21.0 mmol). The solution was heated to reflux and allowed to
react for 24 h. The reaction mixture was allowed to cool to 0 °C, and
the unreacted sodium hydride was quenched by the slow addition of
methanol. This solution was then taken up in 100 mL of EtOAc and
washed three times with 200 mL of water. The extract was dried over
anhydrous sodium sulfate, and the solvent was evaporated in vacuo.
The crude product was filtered through a short silica gel column (1:49
methanol in DCM as the eluent) and recrystallized from 1:9 EtOAc in
hexanes to yield yellow crystals (1.80 g, 56%): mp 43−45 °C; FT-IR
1
(ν, cm−1, KBr) 3347.1, 3060.6, 3024.6, 1678.5, 1510.4, 1486.3; H
NMR (400 MHz, CDCl3) δ 9.95 (s, 1H), 8.08 (s, 1H), 7.78−7.73 (m,
2H), 7.66−7.62 (m, 2H), 7.58 (s, 1H), 7.44−7.32 (m, 6H), 5.84−5.73
(m, 1H), 5.22−5.12 (m, 2H), 4.69−4.65 (m, 2H); 13C NMR (100
MHz, CDCl3) δ 151.9, 145.4, 138.7, 134.1, 134.0, 130.5, 129.71,
129.69, 128.7, 128.4, 127.2, 126.8, 117.0, 43.5; HRMS (ESI) m/z [M +
H]+ calcd for C18H19N4O, 307.1553; found, 307.1558.
Carbo-N′-benzylidene-N-methylhydrazide(N′-benzylidene-
N-allylhydrazide) (22). Carbo-N′-benzylidene(N′-benzylidene-N-al-
lylhydrazide) (11) (1.30 g, 4.24 mmol) was added to a 100 mL round-
bottom flask and dissolved in 50 mL of anhydrous THF with stirring.
Dimethylsulfate (1.2 equiv, 643 mg, 0.48 mL, 5.10 mmol) was added,
followed by a slow addition of 2 equiv of sodium hydride (204 mg,
8.48 mmol). The solution was heated to reflux and allowed to react for
3 h. The reaction mixture was allowed to cool to 0 °C, the unreacted
sodium hydride was quenched by the slow addition of methanol, and
the solution volume was reduced in vacuo. This solution was then
taken up in 75 mL of EtOAc and washed three times with 75 mL of
water. The crude extract was dried over anhydrous sodium sulfate, and
the solvent was evaporated in vacuo. The crude product was filtered
through a short silica gel column (1:99 methanol in DCM eluent) to
yield a light orange oil (1.17 g, 86%): FT-IR (ν, cm−1, KBr) 3060.1,
1
3024.1, 1664.3, 1606.0, 1421.5, 1384.4; H NMR (400 MHz, CDCl3)
δ 7.67 (s, 1H), 7.64 (s, 1H), 7.63−7.55 (m, 4H), 7.22−7.16 (m, 6H),
5.92−5.80 (m, 1H), 5.34−5.26 (d, J = 17.3 Hz, 1H), 5.22−5.16 (d, J =
10.6 Hz, 1H), 4.64−4.60 (m, 2H), 3.37 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 158.0, 138.7, 137.5, 135.3, 135.1, 131.5, 129.0, 128.9, 128.4,
126.93, 126.89, 116.8, 47.2, 32.8; HRMS (ESI) m/z [M + H]+ calcd
for C19H21N4O, 321.1709; found, 321.1710.
2-Methyl-6-phenyl-4-allyl-1,2,4,5-tetrazinan-3-one (23).
Carbo-N′-benzylidene-N-methylhydrazide(N′-benzylidene-N-allylhy-
drazide) (22) (1.04 g, 4.48 mmol) was reacted according to the
general methanolysis and ring-closure procedure to yield white crystals
2,4-Diethyl-6-paravinylphenyl-1,2,4,5-tetrazinan-3-one (27).
Carbo-di(N′-paravinylicbenzylidene-N-ethylhydrazide) (26) (108 mg)
was reacted according to the general methanolysis and ring-closure
procedure to yield a yellow oil (48 mg, 64%): FT-IR (ν, cm−1, KBr)
3233, 2968, 2930, 1609, 1428, 1261, 1126, 1080, 1016; 1H NMR (400
MHz, CDCl3) δ 7.53−7.48 (m, 2H), 7.45−7.40 (m, 2H), 6.77−6.67
(dd, J = 6.8 Hz, 10.9 Hz, 1H), 5.82−5.74 (d, J = 17.8 Hz, 1H), 5.33−
5.26 (d, J = 10.9 Hz, 1H), 4.94−4.85 (t, J = 11.2 Hz, 1H), 4.20−4.11
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dx.doi.org/10.1021/jo300027b | J. Org. Chem. 2012, 77, 2415−2421

The Journal of Organic Chemistry
Article
(d, J = 11.3 Hz, 2H), 3.74−3.62 (sextet, J = 7.0 Hz, 2H), 3.56−3.44
(sextet, J = 7.0 Hz, 2H), 1.24−1.16 (t, J = 7.0 Hz, 6H); 13C NMR (100
MHz, CDCl3) δ 154.4, 138.2, 136.1, 134.6, 126.4, 114.8, 70.1, 44.6,
12.4; HRMS (ESI) m/z [M + H]+ calcd for C14H21N4O, 261.17154;
found, 261.17221.
ASSOCIATED CONTENT
■
S
* Supporting Information
1H and 13C NMR spectra. This material is available free of
charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: michael.georges@utoronto.ca.
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Support was provided by the National Science and Engineering
Research Council of Canada. M.B. gratefully acknowledges a
University of Toronto (UT) fellowship and a Helen Sawyer
Hogg Graduate Admission UT Fellowship.
REFERENCES
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