Verdazyl radicals as substrates for organic synthesis: A synthesis of 3-methyl-5-aryl-1,3,4-oxadiazolones

Article abstract of DOI:10.1021/jo200820g

The synthesis of oxadiazolones under hydrolytic conditions is described for a series of 3-methyl-5-aryl-1,3,4-oxadiazolone compounds. The unique starting materials for the hydrolysis reaction are obtained from efficient 1,3-dipolar cycloaddition reactions

Full text of DOI:10.1021/jo200820g

NOTE
pubs.acs.org/joc
Verdazyl Radicals as Substrates for Organic Synthesis: A Synthesis of
3-Methyl-5-aryl-1,3,4-oxadiazolones
Matthew Bancerz 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
b
ABSTRACT: The synthesis of oxadiazolones under hydrolytic
conditions is described for a series of 3-methyl-5-aryl-1,3,4-
oxadiazolone compounds. The unique starting materials for the
hydrolysis reaction are obtained from efficient 1,3-dipolar
cycloaddition reactions of styrene and azomethine imine di-
poles derived from verdazyl radicals via a disproportionation reaction. A proposed mechanism for the formation of these biologically
relevant oxadiazolones includes an opening of the tetrazinone ring followed by a 5-exo-trig ring closure. In support of the mechanism,
in one case the ring-opened intermediate was isolated and subsequently treated with acid to give the relevant oxadiazolone.
unique and valuable property of heterocyclic compounds is
their ability to undergo a variety of rearrangements in one
Reactions of 1,1-dimethyl-2-substituted hydrazides with acid chlor-
ides provide another general route to these oxadiazolones.13 As well,
oxadiazolones have been made via the rearrangement which occurs
upon methylation of a precursor heterocycle 2-alkoxy-substituted
1,3,4-oxadiazole.14 This latter synthetic route, like the previous
examples, still relies on appropriately substituted hyrazides.15 The
use of verdazyl radicals as starting materials to 1,3,4-oxadiazolones
presents a completely different route to existing methodologies.
Verdazyl radicals have been known for nearly 50 years,16 and the
chemistry of their synthesis has been well studied and for the most
part is very straightforward.17 The synthesis of the verdazyl radicals
required to make the oxadiazolones presented herein all use the
readily available NꢀN building block methyl hydrazine.18
A
step to give new molecular architectures that would otherwise
require a multistep sequence of involved reactions. Considering
that most naturally occurring and synthetic biologically active
compounds are heterocyclic, these rearrangements offer a so-
phisticated opportunity to enable the building of libraries of
compounds with interesting motifs for new drug discoveries
along the lines of the DOS concept.1 We have recently shown
that verdazyl radicals, as a result of their propensity to react with
each other via a disproportionation reaction to form azomethine
imines, can be used as substrates for the synthesis of a variety of
heterocyclic compounds. This application goes beyond their
traditional relevance as spin probes in ESR studies,2 mediators
for living radical polymerizations,3 molecular magnets,4 and
polymerization inhibitors.5 Thus, for example, 1,5-dimethyl-3-
phenyl-6-oxoverdazyl radical has been shown to be a unique
starting material for a series of tetrahydropyrazolotetrazinone
compounds.6 The key step in the reaction sequence is a
regioselective 1,3-dipolar cycloaddition7 of a variety of electron-
deficient dipolarophiles, in particular, acrylates, methacrylates,
acrylonitriles, and the slightly electron-rich styrene, with the
azomethine imine derived from the disproportionation reaction
between two verdazyl radicals. Alkyne dipolarophiles, on the
other hand, provide dihydropyrazolotetrazinones, which upon
heating at 150 °C rearrange in an interesting manner to afford
pyrazolotriazinones.8
It seemed reasonable to assume that exposure of cycloadduct
1, obtained from the 1,3-dipolar cycloaddition reaction between
the azomethine imine, derived from 1,5-dimethyl-3-phenyl-6-
oxoverdazyl radical, with styrene, to acid hydrolysis conditions
would lead at minimum to a ring-opening of the tetrazinone ring.
What would happen after that occupied the realm of wild
speculation. As expected, heating compound 1 in 1:1 THF/3 M
HClaq for 3 days at 60 °C resulted in the complete disappearance
of the starting material, as evidenced by TLC. Fortuitously, the
1
reaction was very clean with a single major product, whose H
NMR showed the presence of a phenyl ring and an N-methyl
group but nothing more. The 13C NMR spectrum added the fact
that there were also two quaternary C’s. Single-crystal X-ray
crystallography provided the complete structure. Since the yield
of the reaction was good (73%) and the reaction itself was simple
and very straightforward, the scope and limitations of the
reaction were investigated using the unique set of previously
unreported cycloadducts 2ꢀ9 and 20, 22, 24, and 26. The results
are summarized in Table 1. Yields of the oxadiazolones ranged
typically from 42 to 79% with the exception of the 2-furyl
Herein, we report a further extension to the synthetic useful-
ness of verdazyl radicals as substrates for organic synthesis,
specifically for the synthesis of 3-methyl-5-aryl-1,3,4-oxadiazo-
lones. 1,3,4-Oxadiazolones have been shown to be important as
ion channel inhibitors9 and drugs for the treatment of malaria10
and tuberculosis.11 A common route for the synthesis of 3-methyl-
5-aryl-1,3,4-oxadiazolones involves the reaction of potassium
salts of substituted hydrazides with phosgene to give 5-aryl sub-
stituted oxadiazolones, which are subsequently N-methylated.12
Received: April 25, 2011
Published: June 27, 2011
r
2011 American Chemical Society
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Table 1. Cycloaddition Precursor Structures, 3-Methyl-5-aryl-1,3,4-oxadiazole Products, And Hydrolysis Reaction Yields
NOTE
derivative 16 that gave only a 7.7% yield. We suspect the lower yield
for 16 is due to furan’s susceptibility to hydrolysis under acidic
conditions. Unexpectedly, the cycloaddition products of 5-alkyl
substituted verdazyl radicals did not provide any oxadiazolones.
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NOTE
Scheme 1. Proposed Mechanism for the Formation of 3-Methyl-5-phenyl-1,3,4-oxadiazolone
A literature search reveals that some of the simple compounds
in Table 1 have not been previously reported, specifically
compounds 14ꢀ18. Due to the biological relevance of these
compounds it would seem that the synthesis of these compounds
would be widespread enough to include these simple examples.
Their absence, especially with those containing heterocycles at
the 5-position, might imply a gap in current methodologies to
make these compounds. Also, the synthesis of 18 from 9
demonstrates that this approach can be used to provide complex
multioxadiazolone architectures that may not be trivial to make
by other methods. Compounds 25 and 27 were synthesized to
demonstrate that this methodology is compatible with substitu-
ents other than methyl at the 3 position.
It was found that using 1:1 THF and 3 M HClaq at 60 °C for
the hydrolysis reaction provides a reasonable balance between
the rate of reaction and mild reaction conditions. At ambient
temperature the reaction proceeds very slowly, requiring a week
for all the starting material to disappear, while at 60 °C the
reaction is complete after 72 h. The exceptions are 14, 24, and 26,
which require a temperature of 100 °C over 3 days to go to
completion. Using these reaction conditions on 4-alkyl- as
opposed to 4-aryl-substituted cycloadducts did not appear to
yield any oxadiazolones. Compound 20 and 22 were subjected to
the acid hydrolysis conditions; however, upon workup numerous
spots were observed on TLC and column chromatography did
not yield the expected products 21 and 23, respectively, shown in
Table 1. This could be due to the lack of conjugation experienced
by the CdN bond in the alkyl case leaving the LUMO too high in
energy for an efficient hydrolysis reaction to occur and leading
instead to several unidentified decomposition products.
protonated by HCl resulting in the formation of an iminium ion
which is subsequently attacked by water. Following a series of
protonation and deprotonation steps compound 19 is formed.
Compound 19 undergoes a 5-exo-trig ring-closing reaction
followed by a fragmentation reaction resulting in the oxadiazo-
lone product. This fragmentation byproduct was never isolated.
We suspect the isolation by our methods may be difficult because
the fragment may break down into volatile compounds in the
reaction or upon workup. In support of this mechanism, a small
amount of compound 19 (16 mg) was able to be isolated from
the hydrolysis reaction mixture of compound 1. Acid hydrolysis
of 19 gave compound 10 as confirmed by TLC and 1H NMR.
In conclusion, a novel synthesis complementary to existing
methodologies has been developed for the synthesis of 3-methyl-
5-aryl-1,3,4-oxadiazol-2(3H)-ones with yields typically ranging
from 42 to 79%. Using appropriately 3-substituted verdazyl
radicals, reacted with the inexpensive and readily available
styrene dipolarophile, 4-aryl-2-methyl-6-phenyl-2,6,7,8-tetrahy-
dro-1H-pyrazolo[1,2-a][1,2,4,5]tetrazin-1-ones are prepared
and subjected to acid hydrolysis conditions yielding 3-methyl-
5-aryl-1,3,4-oxadiazol-2(3H)-ones. A mechanism is proposed,
and as supporting evidence an intermediate was isolated and then
shown to afford the final product when subjected to the hydro-
lytic conditions.
’ EXPERIMENTAL SECTION
General Methods. Silica gel chromatography was performed with
silica gel 60 (particle size 40ꢀ63 μm). Verdazyl radicals were previously
synthesized according to published procedures.16 NMR spectra were
recorded at 23 °C, operating at 400 MHz for 1H NMR and 100 MHz for
13C NMR spectroscopy. Chemical shifts (δ) are reported in parts per
A proposed mechanism for the hydrolysis reaction is provided
in Scheme 1. According to this mechanism, the 4-N position is
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NOTE
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. X-ray data were
collected on a diffractometer using monochromated Mo KR radiation,
and measurements were made using a combination of Φ and ω scans
with k offsets to fill the Ewald sphere. The structure was solved and
refined for full-matrix least-squares refinement that was based on F2. All
H atoms were included in the calculated positions and allowed to refine
in the riding-motion approximation with Uiso tied to the carrier atom.
General Cycloaddition Procedure. 1,5-Dimethyl-3-phenyl-6-
oxoverdazyl (203 mg, 1 mmol) was dissolved in 2 mL of THF in a 10 mL
round-bottom flask. Excess styrene (500 mg, 4.8 mmol) was added, and
the solution was refluxed for 24 h. The reaction solution was cooled to
ambient temperature, and the unreacted styrene was removed in vacuo.
The product was isolated by silica column chromatography (1:2 ethyl
acetate/hexanes).
General Hydrolysis Procedure. The styrene cycloadduct (306 mg,
1 mmol) was dissolved in 5 mL of THF in a 10 mL round-bottom flask
equipped with a condenser. A 5 mL solution of 3 M HClaq was added,
and the reaction was stirred and heated at 60 °C for 3 days. The reaction
mixture was cooled to ambient temperature and extracted with 50 mL
of dichloromethane 3 times. The dichloromethane extracts were com-
bined, dried over sodium sulfate, and evaporated to give an oil. The
product was isolated by silica gel column chromatography (1:2 ethyl
acetate/hexanes).
2-Methyl-4,6-diphenyl-2,6,7,8-tetrahydro-1H-pyrazolo[1,2-a][1,2,-
4,5]tetrazin-1-one (1). 1,5-Dimethyl-3-phenyl-6-oxoverdazyl (203 mg)
was reacted according to the general procedure for cycloaddition yield a
yellow waxy solid (257.3 mg, 84%): FT-IR (ν, cmꢀ1, KBr) 2929, 1675,
1607, 1363, 757, 696; 1H NMR (400 MHz, CDCl3) δ 7.44ꢀ7.40 (d, J =
7.2 Hz, 2H), 7.35ꢀ7.30 (t, J = 7.2 Hz, 1H), 7.27ꢀ7.20 (t, J = 8.0 Hz,
2H), 7.18ꢀ7.12 (m, 3H), 6.93ꢀ6.88 (m, 2H), 4.74ꢀ4.69 (m, 1H),
4.39ꢀ4.30 (m, 1H), 3.67ꢀ3.58 (m, 1H), 3.20 (s, 3H), 2.61ꢀ2.50
(m, 1H), 2.26ꢀ2.14 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 155.0
(C), 147.4 (C), 139.5 (C), 131.6 (C), 130.2 (CH), 128.2 (CH), 128.1
(CH), 127.8 (CH), 127.5 (CH), 127.2 (CH), 66.1 (CH3), 44.8 (CH2),
36.4 (CH), 33.3 (CH2); HRMS (ESI) m/z [M]+ calcd for C18H19N4O
307.15589, found 307.15632.
4-(4-Fluorophenyl)-2-methyl-6-phenyl-2,6,7,8-tetrahydro-1H-
pyrazolo[1,2-a][1,2,4,5]tetrazin-1-one (2). 1,5-Dimethyl-3-(4-fluoro)-
phenyl-6-oxoverdazyl (300 mg) was reacted according to the general
procedure for cycloaddition to yield a yellow waxy solid (311 mg, 71%):
FT-IR (ν, cmꢀ1, KBr) 3541, 3021, 2951, 1691, 1417, 1361; 1H NMR
(400 MHz, CDCl3) δ 7.42ꢀ7.36 (m, 2H), 7.18ꢀ7.12 (m, 3H), 6.92ꢀ
6.86 (m, 4H) 4.79ꢀ4.63 (m, 1H), 4.36ꢀ4.28 (m, 1H), 3.66ꢀ3.57 (m,
1H), 3.20 (s, 3H), 2.59ꢀ2.48 (m, 1H), 2.23ꢀ2.13 (m, 1H); 13C NMR
(100 MHz, CDCl3) δ 164.9ꢀ162.4 (d, J = 249 Hz) (C), 154.9 (C),
146.4 (C), 139.2 (C), 129.4ꢀ129.3 (d, J = 8.6 Hz) (CH), 128.2 (CH),
127.8 (CH), 127.70ꢀ127.67 (d, J = 3 Hz) (C), 127.1 (CH), 115.2ꢀ
114.9 (d, J = 22 Hz), 66.2 (CH), 44.8 (CH2), 36.3 (CH3), 33.3 (CH2);
HRMS (ESI) m/z [M]+ calcd for C18H17N4OF 324.1386, found
324.1390.
127.8 (CH), 127.3 (CH), 124.1 (C), 113.6 (CH), 66.2 (CH), 55.2 (CH3),
44.9 (CH2), 36.4 (CH3), 33.4 (CH2); HRMS (ESI) m/z [M]+ calcd for
C19H20N4O2 336.1586, found 336.1577.
2-Methyl-6-phenyl-4-(3-(trifluoromethyl)phenyl)-2,6,7,8-tetrahy-
dro-1H-pyrazolo[1,2-a][1,2,4,5]tetrazin-1-one (4). 1,5-Dimethyl-3-(3-
trifluoromethylphenyl)-6-oxoverdazyl (700 mg) was reacted according
to the general procedure for cycloaddition yield a yellow waxy solid (612 mg,
63%): FT-IR (ν, cmꢀ1, KBr) 3554, 3478, 2949, 1681, 1617, 1321, 1127; 1H
NMR (400 MHz, CDCl3) δ 7.63ꢀ7.62 (s, 1H), 7.61ꢀ7.58 (d, J = 8 Hz,
1H), 7.54ꢀ7.50 (d, J = 8 Hz, 1H) 7.35ꢀ7.29 (t, J = 8 Hz, 1H), 7.16ꢀ7.09
(m, 3H), 6.91ꢀ6.87 (m, 2H), 4.67ꢀ4.62 (m, 1H), 4.32ꢀ4.24 (m, 1H),
3.75ꢀ3.67 (m, 1H), 3.25 (s, 3H), 2.61ꢀ2.51 (m, 1H), 2.25ꢀ2.14 (m, 1H);
13C NMR (100 MHz, CDCl3) δ 154.9 (C), 145.9 (C), 138.9 (C),
130.9ꢀ129.9 (q, J = 32.4 Hz) (C), 130.4 (C), 128.5 (C), 128.3 (CH),
128.0 (C), 127.6ꢀ119.5 (q, J = 271 Hz) (C), 127.2 (CH), 126.5ꢀ126.4 (q,
J = 3.6 Hz) (CH), 124.3ꢀ124.2 (q, J = 3.8 Hz) (CH), 66.6 (CH3), 45.0
(CH2), 36.6 (CH), 33.4 (CH2); HRMS (ESI) m/z [M + H]+ calcd for
C19H18N4OF3 375.1427, found 375.1423.
2-Methyl-6-phenyl-4-(pyridin-2-yl)-2,6,7,8-tetrahydro-1H-pyrazolo-
[1,2-a][1,2,4,5]tetrazin-1-one (5). 1,5-Dimethyl-3-(2-pyridyl)-6-ox-
overdazyl (800 mg) was reacted according to the general procedure
for cycloaddition to yield a yellow waxy solid (885 mg, 74%); FT-IR
(ν, cmꢀ1, KBr) 3550, 3472, 2946, 1669, 1408, 1194; 1H NMR
(400 MHz, CDCl3) δ 8.59ꢀ8.56 (dq, J = 4.8 Hz, 0.8 Hz, 1H), 7.58ꢀ
7.49 (dt, J = 8 Hz, 1.6 Hz, 1H), 7.48ꢀ7.44 (dt, J = 7.6 Hz, 0.8 Hz, 1H),
7.22ꢀ7.17 (ddd, J = 7.3 Hz, 4.8 Hz, 1.6 Hz, 1H), 7.15ꢀ7.10 (m, 3H),
7.00ꢀ6.95 (m, 2H), 5.30ꢀ5.25 (m, 1H), 4.36ꢀ4.28 (m, 1H),
3.68ꢀ3.55 (m, 1H), 3.25 (s, 3H), 2.69ꢀ2.59 (m, 1H), 2.23ꢀ2.13
(m, 1H); 13C NMR (100 MHz, CDCl3) δ 155.0 (C), 149.9 (C), 148.7
(CH), 145.9 (C), 140.0 (C), 136.1 (CH), 128.2 (CH), 127.6 (CH),
126.8 (CH), 124.1 (CH), 122.4 (CH), 65.3 (CH3), 44.3 (CH2), 36.6
(CH), 33.7 (CH2); HRMS (ESI) m/z [M]+ calcd for C17H17N5O
307.1433, found 307.1445.
4-(1H-Indol-6-yl)-2-methyl-6-phenyl-2,6,7,8-tetrahydro-1H-pyrazolo-
[1,2-a][1,2,4,5]tetrazin-1-one (6). 1,5-Dimethyl-3-(6-indole)-6-oxover-
dazyl (100 mg) was reacted according to the general procedure for
cycloaddition to yield a beige solid (68 mg, 48%): mp 160ꢀ162 °C; FT-
IR (ν, cmꢀ1, KBr) FT-IR (ν, cmꢀ1, KBr) 3049, 3250, 2938, 1652, 1598,
1421, 1168; 1H NMR (400 MHz, CDCl3) δ 8.20ꢀ8.02 (br, 1H),
7.95ꢀ7.91 (d, J = 8 Hz, 1H), 7.34ꢀ7.30 (d, J = 7.6 Hz, 1H), 7.25ꢀ7.13
(m, 5H), 7.10ꢀ7.08 (d, J = 2.8 Hz, 1H), 7.02ꢀ6.98 (m, 2H), 4.79ꢀ4.73
(m, 1H), 4.23ꢀ4.08 (m, 1H), 3.90ꢀ3.82 (m, 1H), 3.25 (s, 1H),
2.61ꢀ2.50 (m, 1H), 2.28ꢀ2.19 (m, 1H); 13C NMR (100 MHz, CDCl3)
δ 155.9 (C), 144.5 (C), 140.5 (C), 136.2 (C), 128.3 (CH), 127.8 (CH),
127.4 (CH), 126.8 (CH), 125.0 (C), 123.0 (CH), 121.3 (CH), 121.2
(CH), 111.1 (CH), 109.2 (C), 66.0 (CH), 45.1 (CH2), 36.7 (CH3), 33.4
(CH2); HRMS (ESI) m/z [M + H]+ calcd for C20H20N5O 346.1662,
found 346.1657.
4-(Furan-2-yl)-2-methyl-6-phenyl-2,6,7,8-tetrahydro-1H-pyrazolo-
[1,2-a][1,2,4,5]tetrazin-1-one (7). 1,5-Dimethyl-3-(2-furyl)-6-oxover-
dazyl (600 mg) was reacted according to the general procedure for
cycloaddition to yield a yellow waxy solid (256 mg, 65%); FT-IR
(ν, cmꢀ1, KBr) 3548, 3475, 2926, 1679, 1375, 1018; 1H NMR (400 MHz,
CDCl3) δ 7.36=7.34 (m, 1H), 7.25ꢀ7.18 (m, 3H), 7.09ꢀ7.05 (m, 2H)
6.45ꢀ6.42 (d, J = 3.2 Hz, 1H), 6.29ꢀ6.26 (m, 1H), 4.90ꢀ4.84 (m, 1H),
4.20ꢀ4.10 (m, 1H), 3.72ꢀ3.62 (m, 1H), 3.21 (s, 3H), 2.60ꢀ2.48 (m,
1H), 2.22ꢀ2.11 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 155.4 (C),
144.6 (C), 143.8 (CH), 139.6 (C), 139.3 (C), 128.2 (CH), 127.7 (CH),
126.7 (CH), 112.6 (CH), 111.2 (CH), 65.7 (CH), 44.5 (CH2), 36.3
(CH3), 33.5 (CH2); HRMS (ESI) m/z [M + H]+ calcd for C16H17N4O2
297.1346, found 297.1348.
4-(4-Methoxyphenyl)-2-methyl-6-phenyl-2,6,7,8-tetrahydro-1H-p-
yrazolo[1,2-a][1,2,4,5]tetrazin-1-one (3). 1,5-Dimethyl-3-(4-methoxy)-
phenyl-6-oxoverdazyl (350 mg) was reacted according to the general
procedure for cycloaddition to yield a yellow waxy solid (302.7 mg, 60%):
1
FT-IR (ν, cmꢀ1, KBr) 2937, 1665, 1607, 1514, 1357, 1252, 1028; H
NMR(400MHz, CDCl3) δ7.38ꢀ7.33 (d, J= 8.8Hz, 2H),7.18ꢀ7.14 (m,
3H), 6.93ꢀ6.88 (m, 4H) 6.78ꢀ6.73 (d, J = 8.8 Hz, 2H), 4.72ꢀ4.67 (m,
1H), 3.39ꢀ3.31 (m, 1H), 3.79 (s, 3H), 3.64ꢀ3.56 (m, 1H), 3.18 (s, 3H),
2.60ꢀ2.50 (m, 1H), 2.25ꢀ2.15 (m, 1H);13C NMR (100 MHz, CDCl3) δ
161.3 (C), 155.3 (C), 147.4 (C), 139.7 (C), 129.1 (CH), 128.3 (CH),
2-Methyl-6-phenyl-4-(thiophene-3-yl)-2,6,7,8-tetrahydro-1H-pyr-
azolo[1,2-a][1,2,4,5]tetrazin-1-one (8). 1,5-Dimethyl-3-(3-thiophene)-
6-oxoverdazyl (100 mg) was reacted according to the general procedure
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NOTE
for cycloaddition yield a yellow waxy solid (34.5 mg, 23%): FT-IR
procedure to yield a white solid (313 mg, 78%): mp 75ꢀ76 °C; FT-
1
1
(ν, cmꢀ1, KBr) 3298, 3102, 2956, 1659, 1595, 1371, 1034; H NMR
IR (ν, cmꢀ1, KBr) 3057, 1774, 1562, 1362, 1247, 1022; H NMR
(400 MHz, CDCl3) δ 7.35ꢀ7.33 (dd, J = 3.2 Hz, 1.2 Hz, 1H), 7.22ꢀ
7.18 (m, 3H), 7.17ꢀ7.14 (dd, J = 4.8 Hz, 3.0 Hz, 1H), 7.06ꢀ7.03 (dd, J =
5.2 Hz, 1.2 Hz, 1H), 7.02ꢀ6.97 (m, 2H), 4.78ꢀ4.72 (m, 1H), 4.25ꢀ
4.17 (m, 1H), 3.75ꢀ3.67 (m, 1H), 3.18 (s, 3H), 2.60ꢀ2.49 (m, 1H),
2.25ꢀ2.15 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 155.1 (C), 143.8
(C), 139.8 (C), 133.8 (C), 128.4 (CH), 128.0 (CH), 127.3 (CH), 126.6
(CH), 126.3 (CH), 125.8 (CH), 66.4 (CH3), 44.9 (CH2), 36.5 (CH),
33.7 (CH2); HRMS (ESI) m/z [M]+ calcd for C16H16N4OS 312.1045,
found 312.1043.
(400 MHz, CDCl3) δ 8.77ꢀ8.73 (d, J = 4.8 Hz, 1H), 7.90ꢀ7.82 (m,
2H) 7.46ꢀ7.43 (m, 1H), 3.56 (s, 3H); 13C NMR (100 MHz, CDCl3)
δ 153.3 (C), 151.9 (C), 150.4 (CH), 142.8 (C), 137.1 (CH), 125.6
(CH), 121.4 (CH), 32.8 (CH3); HRMS (ESI) m/z [M + H]+ calcd
for C8H8N3O2 178.0611, found 178.0610.
5-(1H-Indol-6-yl)-3-methyl-1,3,4-oxadiazol-2(3H)-one (15). Com-
pound 6 (60 mg) was reacted according to the general hydrolysis
procedure to yield a brownish solid (16 mg, 42%): mp 185ꢀ186 °C; FT-
IR (ν, cmꢀ1, KBr) 3551, 3252, 2942, 1764, 1633, 1449, 998; 1H NMR
(400 MHz, CDCl3) δ 8.80ꢀ8.60 (br, NH), 8.12ꢀ8.08 (d, J = 7.6 Hz,
1H) 7.73ꢀ7.72 (d, J = 2.8 Hz, 1H), 8.47ꢀ8.43 (d, J = 7.2 Hz, 1H),
7.34ꢀ7.26 (m, 2H) 3.52 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 153.6
(C), 151.4 (C), 136.1 (C), 126.0 (CH), 123.8 (CH), 123.7 (C), 122.0
(CH), 121.0 (CH), 111.7 (CH), 101.8 (C), 32.7 (CH3); HRMS (ESI)
m/z [M + H]+ calcd for C11H10N3O2 216.0778, found 216.0779.
5-(Furan-2-yl)-3-methyl-1,3,4-oxadiazol-2(3H)-one (16). Com-
pound 7 (256 mg) was reacted according to the general hydrolysis
procedure to yield a white solid (11 mg, 7.7%): mp 91ꢀ93 °C; FT-
4,40-(1,4-Phenylene)bis(2-methyl-6-phenyl-2,6,7,8-tetrahydro-1H-
pyrazolo[1,2-a][1,2,4,5]tetrazin-1-one) (9). 1,4-Bis-(1,5-dimethyl-6-ox-
overdazyl)benzene (200 mg) was reacted according to the general
procedure for cycloaddition to yield a yellow waxy solid (107 mg,
33%): mp 194ꢀ197 °C; FT-IR (ν, cmꢀ1, KBr) 3550, 2941, 1673, 1617,
1
1364; H NMR (400 MHz, CDCl3) δ 7.38ꢀ7.37 (s, 2H), 7.37ꢀ7.36
(s, 2H), 7.22ꢀ7.12 (m, 6H), 6.92ꢀ6.84 (m, 4H), 4.70ꢀ4.66 (m, 2H),
4.46ꢀ4.35 (m, 2H), 3.65ꢀ3.51 (m, 2H), 3.20ꢀ3.19 (s, 3H), 3.19ꢀ3.18
(s, 3H), 2.64ꢀ2.52 (m, 2H), 2.28ꢀ2.16 (m, 2H); 13C NMR (100 MHz,
CDCl3) δ 155.0 (C), 146.35 (C), 146.31 (C), 139.31 (C), 139.27 (C),
133.48 (C), 133.44 (C), 128.4 (CH), 128.3 (CH), 128.1 (CH), 127.32
(CH), 127.28 (CH), 127.25 (CH), 66.32 (CH3), 66.25 (CH3), 45.0
(CH2), 36.6 (CH), 33.22 (CH2), 33.18 (CH2); HRMS (ESI) m/z [M +
H]+ calcd for C30H31N8O2 535.2564, found 535.2561.
1
IR (ν, cmꢀ1, KBr) 3138, 2924, 1779, 1645, 1471, 1225, 1016; H
NMR (400 MHz, CDCl3) δ 7.60ꢀ7.58 (m, 1H), 6.98ꢀ6.96 (d, J =
3.6 Hz, 2H), 6.57ꢀ6.55 (dd, J= 3.6 Hz, 2 Hz 1H) 3.50 (s, 3H); 13
C
NMR (100 MHz, CDCl3) δ 152.8 (C), 146.6 (C), 145.6 (CH),
138.9 (C), 113.5 (CH), 111.9 (CH), 32.9 (CH3); HRMS (ESI) m/z
[M + H]+ calcd for C7H7N2O3 167.0451, found 167.0454.
3-Methyl-5-phenyl-1,3,4-oxadiazol-2(3H)-one (10). Compound 1
(306 mg) was reacted according to the general hydrolysis procedure to
3-Methyl-5-(thiophene-3-yl)-1,3,4-oxadiazol-2(3H)-one (17). Com-
pound 8 (34.5 mg) was reacted according to the general hydrolysis
procedure to yield a white solid (9.2 mg, 46%): mp 68ꢀ70 °C; FT-IR
yield a white solid (129 mg, 73%): mp 64ꢀ65 °C; FT-IR (ν, cmꢀ1
,
KBr) 3068, 1770, 1638, 1455, 1356, 1020; 1H NMR (400 MHz,
CDCl3) δ 7.85ꢀ7.82 (m, 2H), 7.54ꢀ7.44 (m, 3H), 3.51 (s, 3H);
13C NMR (100 MHz, CDCl3) δ 153.7 (C), 153.1 (C), 131.5 (CH),
128.9 (CH), 125.5 (CH), 123.8 (C), 32.7 (CH3); HRMS (ESI) m/z
[M + H]+ calcd for C9H9N2O2 177.0658, found 177.0665.
1
(ν, cmꢀ1, KBr) 3475, 3131, 2922, 1774, 1619, 1310, 1107; H NMR
(400 MHz, CDCl3) δ 7.86ꢀ7.84 (dd, J = 2.8 Hz, 1.2 Hz, 1H),
7.47ꢀ7.45 (dd, J = 5.2 Hz, 1.2 Hz, 1H) 7.44ꢀ7.41 (dd, J = 5.2 Hz,
3.2 Hz, 1H), 3.48 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 153.4 (C),
150.4 (C), 127.5 (CH), 126.7 (CH), 125.3 (C), 124.6 (CH), 32.7
(CH3); HRMS (ESI) m/z [M + H]+ calcd for C7H7N2O2S 183.0222,
found 183.0221.
5-(4-Fluorophenyl)-3-methyl-1,3,4-oxadiazol-2(3H)-one (11).
Compound 2 (311 mg) was reacted according to the general hydrolysis
procedure to yield a white solid (119 mg, 64%): mp 86ꢀ88 °C; FT-IR
1
(ν, cmꢀ1, KBr) 3537, 3086, 1782, 1611, 1508, 1225, 1015; H NMR
5,50-(1,4-Phenylene)bis(3-methyl-1,3,4-oxadiazol-2(3H)-one) (18).
Compound 9 (107 mg) was reacted according to the general hydro-
lysis procedure to yield a white solid (35 mg, 64%): mp 278ꢀ282 °C;
FT-IR (ν, cmꢀ1, KBr) 3548, 3475, 1781, 1617, 1413, 1112; 1H NMR
(400 MHz, CDCl3) δ 7.93 (s, 4H), 3.53 (s, 6H); 13C NMR (100 MHz,
CDCl3) δ 153.4 (C), 152.1 (C), 126.3 (C), 126.1 (CH), 32.9 (CH3);
HRMS (ESI) m/z [M + H]+ calcd for C12H11N4O4 275.0774, found
275.0783.
(400 MHz, CDCl3) δ 7.84ꢀ7.80 (m, 2H), 7.18ꢀ7.13 (m, 2H), 3.50 (s,
3H); 13C NMR(100 MHz, CDCl3) δ165.8 (C), 163.2 (C), 153.5ꢀ152.3
(d, J = 127 Hz) (C), 127.8ꢀ127.7 (d, J = 8.8 Hz) (CH), 120.1ꢀ120.0 (d,
J = 3.2 Hz) (C), 116.4ꢀ116.2 (d, J = 22.2 Hz) (CH), 32.7 (CH3); HRMS
(ESI) m/z [M + H]+ calcd for C9H8N2O2F 195.0564, found 195.0562.
5-(4-Methoxyphenyl)-3-methyl-1,3,4-oxadiazol-2(3H)-one (12).
Compound 3 (303 mg) was reacted according to the general hydrolysis
procedure to yield a white solid (126 mg, 68%): mp 133ꢀ135 °C; FT-IR
N0-Benzoyl-N-methyl-3-phenylpyrazolidine-1-carbohydrazide (19).
Compound 1 (260 mg) was reacted according to the general hydrolysis
procedure to yield a clear oil (19 mg, 7.7%): FT-IR (ν, cmꢀ1, KBr) 3191,
1
(ν, cmꢀ1, KBr) 2976, 2847, 1785, 1618, 1513, 1260, 1021; H NMR
(400 MHz, CDCl3) δ 7.77ꢀ7.72 (d, J = 8.8 Hz, 2H), 6.98ꢀ6.94 (d, J =
8.8 Hz, 2H), 3.86 (s, 3H), 3.47 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
162.1 (C), 153.7 (C), 153.1 (C), 127.2 (CH), 116.1 (C), 114.3 (CH),
55.3 (CH3), 32.5 (CH3); HRMS (ESI) m/z [M + H]+ calcd for
C10H11N2O3 207.0764, found 207.0767.
3-Methyl-5-(3-(trifluoromethyl)phenyl)-1,3,4-oxadiazol-2(3H)-one
(13). Compound 4 (600 mg) was reacted according to the general hy-
drolysis procedure to yield a white solid (310 mg, 79%): mp 38ꢀ39 °C;
FT-IR (ν, cmꢀ1, KBr) 3555, 2950, 1782, 1612, 1577, 1180; 1H NMR
(400 MHz, CDCl3) δ 8.09 (s, 1H), 8.01ꢀ7.97 (d, J = 8 Hz, 1H)
7.78ꢀ7.74 (d, J = 8 Hz, 1H), 7.65ꢀ7.59 (t, J = 8 Hz, 1H) 3.53 (s, 3H);
13C NMR (100 MHz, CDCl3) δ 153.2 (C), 151.7 (C), 132.1ꢀ131.1 (q,
J = 33 Hz) (C), 129.6 (CH), 128.5 (CH), 127.9ꢀ127.8 (q, J = 3.6 Hz)
(CH), 124.7ꢀ119.3 (q, J = 271 Hz) (C), 124.6 (C), 122.4ꢀ122.3 (q, J =
3.9 Hz) (CH), 32.7 (CH3); HRMS (ESI) m/z [M + H]+ calcd for
C10H8N2O2F3 245.0532, found 245.0543.
1
2958, 2872, 1729, 1689, 1620, 1289; H NMR (400 MHz, CDCl3) δ
9.36 (br, 1H), 7.90ꢀ7.84 (d, J = 7.6 Hz, 2H), 7.54ꢀ7.48 (t, J = 7.2 Hz,
1H), 7.33ꢀ7.38 (t, J = 8.0 Hz, 2H), 7.32ꢀ7.22 (m, 5H), 5.00ꢀ4.30 (br,
1H), 4.20ꢀ4.14 (t, J = 7.6 Hz, 1H), 3.84ꢀ3.76 (m, 1H), 3.66ꢀ3.56 (m,
1H), 3.25 (s, 3H), 2.48ꢀ2.37 (m, 1H), 2.14ꢀ2.00 (m, 1H); 13C NMR
(100 MHz, CDCl3) δ 165.4 (C), 161.3 (C), 138.0 (C), 132.1 (C), 131.0
(C), 128.60 (CH), 128.57 (CH), 127.9 (CH), 127.3 (CH), 126.8 (CH),
63.0 (CH3), 47.9 (CH2), 38.3 (CH), 34.0 (CH2); HRMS (ESI) m/z [M
+ H]+ calcd for C18H21N4O2 325.16645, found 325.16524.
4-tert-Butyl-2-methyl-6-phenyl-2,6,7,8-tetrahydro-1H-pyrazolo-
[1,2-a][1,2,4,5]tetrazin-1-one (20). 1,5-Dimethyl-3-(tert-butyl)-6-oxo-
verdazyl (183 mg) was reacted according to the general procedure for
cycloaddition yield a yellow solid (217.1 mg, 76%): FT-IR (ν, cmꢀ1
,
KBr) 3173, 3142, 2988, 2954, 1595, 1351; 1H NMR (400 MHz, CDCl3)
δ 7.33ꢀ7.27 (m, 2H), 7.25ꢀ7.19 (m, 3H), 4.92ꢀ4.86 (m, 1H),
4.10ꢀ4.02 (m, 1H), 3.38ꢀ3.28 (m, 1H), 3.12 (s, 3H), 2.56ꢀ2.45 (m,
1H), 2.07ꢀ1.96 (m, 1H), 1.05 (s, 9H); 13C NMR (100 MHz, CDCl3) δ
3-Methyl-5-(pyridin-2-yl)-1,3,4-oxadiazol-2(3H)-one (14). Com-
pound 5 (700 mg) was reacted according to the general hydrolysis
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dx.doi.org/10.1021/jo200820g |J. Org. Chem. 2011, 76, 6377–6382

The Journal of Organic Chemistry
NOTE
156.9 (C), 156.4 (C), 140.8 (C), 128.4 (CH), 127.6 (CH), 126.4 (CH),
65.6 (CH3), 43.6 (CH2), 36.3 (CH), 35.9 (C), 35.4 (CH2), 28.7 (CH3);
HRMS(ESI) m/z[M]+ calcd for C16H23N4O 287.18719, found 287.18720.
4-Benzhydryl-2-methyl-6-phenyl-2,6,7,8-tetrahydro-1H-pyrazolo-
[1,2-a][1,2,4,5]tetrazin-1-one (22). 1,5-Dimethyl-3-benzhydryl-6-oxo-
verdazyl (110 mg) was reacted according to the general procedure
for cycloaddition yield a yellow solid (96 mg, 65%): mp 144ꢀ146 °C;
FT-IR (ν, cmꢀ1, KBr) 3025, 2901, 1684, 1619, 1493, 1384; 1H NMR
(400 MHz, CDCl3) δ 7.44ꢀ7.25 (m, 10H), 7.15ꢀ7.06 (m, 3H),
6.80ꢀ6.74 (m, 2H), 4.57 (s, 1H), 4.44ꢀ4.37 (t, J = 7.2 Hz, 1H),
3.68ꢀ3.53 (m, 2H), 3.14 (s, 3H), 2.35ꢀ2.25 (m, 1H), 2.04ꢀ1.92 (m,
1H); 13C NMR (100 MHz, CDCl3) δ 157.1 (C), 151.5 (C), 140.6 (C),
139.6 (C), 138.6 (C), 129.07 (CH), 129.06 (CH), 128.81 (CH), 128.76
(CH), 128.2 (CH), 127.7 (CH), 127.3 (CH), 126.4 (CH), 126.1 (CH),
61.7 (CH3), 51.8 (CH), 43.0 (CH2), 36.3 (CH), 35.3 (CH2); HRMS
(ESI) m/z [M + H]+ calcd for C25H25N4O 397.20284, found 397.20295.
2-Isopropyl-4,6-diphenyl-2,6,7,8-tetrahydro-1H-pyrazolo[1,2-a]-
[1,2,4,5]tetrazin-1-one (24): yellow waxy solid; FT-IR (ν, cmꢀ1, KBr)
3062, 3030, 2973, 2933, 1719, 1671, 1450, 1384; 1H NMR (400 MHz,
CDCl3) δ 7.65ꢀ7.59 (t, J = 7.2 Hz, 1H), 7.50- 7.46 (m, 2H), 7.38ꢀ7.33
(t, J = 7.6 Hz, 2H), 7.20ꢀ7.10 (m, 3H), 6.90ꢀ6.85 (d, J = 6.8 Hz, 2H),
4.74ꢀ4.68 (m, 1H), 4.64ꢀ4.47 (m, 2H), 3.56ꢀ3.48 (m, 1H),
2.64ꢀ2.52 (m, 1H), 2.29ꢀ2.20 (m, 1H), 1.21ꢀ1.16 (d, J = 6.8 Hz,
3H), 0.97ꢀ0.93 (d, J = 6.4 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ
154.2 (C), 146.5 (C), 139.3 (C), 133.0 (C), 130.0 (CH), 128.3 (CH),
128.1 (CH), 127.8 (CH), 127.5 (CH), 127.3 (CH), 66.0 (CH3), 47.2
(CH2), 44.8 (CH2), 32.9 (CH2), 19.8 (CH3), 19.6 (CH3); HRMS (ESI)
m/z [M + H]+ calcd for C20H23N4O 335.18719, found 335.18793.
3-Isopropyl-5-phenyl-1,3,4-oxadiazol-2(3H)-one (25). Compound
24 (25 mg) was reacted according to the general hydrolysis procedure
’ AUTHOR INFORMATION
Corresponding Author
*E-mail: michael.georges@utoronto.ca.
’ ACKNOWLEDGMENT
Support was provided by the National Science and Engineer-
ing Research Council of Canada. M.B. gratefully acknowledges a
University of Toronto (UT) fellowship and a Helen Sawyer
Hogg Graduate Admission UT Fellowship. X-ray analysis was
performed by Alan Lough at the University of Toronto.
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to yield a white solid (9.2 mg, 61%): mp 45ꢀ47 °C; FT-IR (ν, cmꢀ1
,
KBr) 2983, 2938, 2877, 1767, 1614, 1356; 1H NMR (400 MHz, CDCl3)
δ 7.88ꢀ7.87 (dd, J = 7.6 Hz, 1.2 Hz, 2H), 7.53ꢀ7.43 (m, 3H),
4.46ꢀ4.35 (sept, J = 6.8 Hz, 1H), 1.46ꢀ1.41 (d, J = 6.8 Hz, 6H); 13C
NMR (100 MHz, CDCl3) δ 153.0 (C), 152.8 (C), 131.2 (CH), 128.7
(CH), 125.5 (CH), 124.0 (C), 48.1 (CH), 20.7 (CH3); HRMS (ESI)
m/z [M + H]+ calcd for C11H13N2O2 205.09770, found 205.09738.
2-Benzyl-4,6-diphenyl-2,6,7,8-tetrahydro-1H-pyrazolo[1,2-a][1,2,-
4,5]tetrazin-1-one (26): yellow solid; mp 99ꢀ101 °C; FT-IR (ν, cmꢀ1
,
KBr) 3060, 3029, 2925, 1674, 1604, 1384; 1H NMR (400 MHz, CDCl3)
δ 7.37ꢀ7.35 (d, J = 7.2 Hz, 2H), 7.34ꢀ7.20 (m, 8H), 7.12ꢀ7.06 (t, J =
7.2 Hz, 1H), 7.01ꢀ7.94 (t, J = 8.0 Hz, 2H), 6.79ꢀ6.75 (d, J = 7.2 Hz, 2H),
4.98ꢀ4.92 (d, J= 14.8 Hz, 1H), 4.74ꢀ4.68 (m, 1H), 4.63ꢀ4.56 (d, J= 15.2
Hz, 1H) 4.49ꢀ4.42 (m, 1H), 3.59ꢀ3.53 (m, 1H), 2.62ꢀ2.51 (m, 1H),
2.23ꢀ2.12 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 154.7 (C), 147.1
(C), 139.4 (C), 137.4 (C), 131.8 (C), 130.2 (CH), 128.25 (CH), 128.19
(CH), 128.17 (CH), 128.1 (CH), 127.7 (CH), 127.5 (CH), 127.1 (CH),
127.0 (CH), 66.3 (CH3), 52.6 (CH2), 44.8 (CH2), 33.5 (CH2); HRMS
(ESI) m/z [M + H]+ calcd for C24H23N4O 383.18719, found 383.18844.
3-Benzyl-5-phenyl-1,3,4-oxadiazol-2(3H)-one (27). Compound 26
(130 mg) was reacted according to the general hydrolysis procedure to
yield a white solid (53.2 mg, 62%): mp 96ꢀ98 °C; FT-IR (ν, cmꢀ1, KBr)
3063, 3032, 2925, 2853, 1767, 1612, 1571; 1H NMR (400 MHz, CDCl3)
δ 7.84ꢀ7.80 (dd, J = 8.0 Hz, 1.2 Hz, 2H), 7.51ꢀ7.30 (m, 8H), 4.95 (s,
2H); 13C NMR (100 MHz, CDCl3) δ 153.4 (C), 153.2 (C), 134.8 (C),
131.4 (CH), 128.8 (CH), 128.7 (CH), 128.23 (CH), 128.17 (CH),
125.6 (CH), 123.7 (C), 49.6 (CH2); HRMS (ESI) m/z [M + H]+ calcd
for C15H13N2O2 253.09770, found 253.09834.
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’ ASSOCIATED CONTENT
Supporting Information. 1H and 13C NMR spectra;
S
b
X-ray data (CIF). This material is available free of charge via
the Internet at http://pubs.acs.org.
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dx.doi.org/10.1021/jo200820g |J. Org. Chem. 2011, 76, 6377–6382