Synthesis of spiro-fused pyrazolidoylisoxazolines

Article abstract of DOI:10.1021/jo200924y

Routes to structurally unique spiro-fused pyrazolidoylisoxazolines are reported. These methods start with monosubstituted hydrazines or hydrazides and utilize the nitrile oxide 1,3-dipolar cycloaddition reaction to generate the targeted spiro-fused bis-he

Full text of DOI:10.1021/jo200924y

ARTICLE
pubs.acs.org/joc
Synthesis of Spiro-Fused Pyrazolidoylisoxazolines
Kathryn G. Guggenheim,† Jeffrey D. Butler,† Phillip P. Painter,† Beth A. Lorsbach,§ Dean J. Tantillo,†
and Mark J. Kurth*,†
†Department of Chemistry, University of California, One Shields Avenue, Davis, California 95616, United States
§Dow AgroSciences, Discovery R&D, 9330 Zionsville Road, Indianapolis, Indiana 46268, United States
S Supporting Information
b
ABSTRACT: Routes to structurally unique spiro-fused pyrazolidoylisox-
azolines are reported. These methods start with monosubstituted hydra-
zines or hydrazides and utilize the nitrile oxide 1,3-dipolar cycloaddition
reaction to generate the targeted spiro-fused bis-heterocycles. Molecular
shape space diversity analyses were performed on these pyrazolidoylisox-
azolines showing that manipulation of the appended R groups significantly
changes the molecular shape.
’ INTRODUCTION
4-chloro-N-hydroxybenzimidoyl chloride (5; prepared in two
steps from 4-chlorobenzaldehyde5) in the presence of triethyla-
mine effected the key 1,3-dipolar cycloaddition and provided the
spirocycle 6 in 70% yield.
The spiro-isoxazoline motif is an important structural feature
found in a number of biologically active natural products.
Examples include 11-deoxyfistularin-3 and 11-oxoaerothionin
(isolated from the Caribbean sponges Aplysina fistularis and
Aplysina lacunosa, respectively; Figure 1a), which exhibit activity
against human breast (cell line MCF-7)1 and human colon (cell
line HCT 116) cancers,2 respectively. Futhermore, three spiro-
cyclic isoxazolines, isolated from the marine sponge Suberea
clavata (aerophobin 1, purealdin L, and aplysinamisine II;
Figure 1b) have been found to inhibit serine protease factors
IXa and FXIa and thus show potential as antithrombotic agents.3
The pyrazolidine moiety is also a feature in many synthetically
designed bioactive compounds showing antihyperglycemic ac-
tivity via inhibition of the serine peptidase dipeptidyl peptidase
IV (DPP-IV).4
Herein, synthetic routes to the unique scaffold comprised of
spiro-fused pyrazolidine and isoxazoline components are pre-
sented (1; Figure 1c). Connecting these two heterocycles
spirocyclically produces a uniquely functionalized molecular
architecture that could find utility as a scaffold for the construc-
tion of probes targeting various biological receptors.
With Lipinski’s Rule of 5 in mind,6 we next set out to prepare
lower molecular weight analogues of 1 (the molecular weight of 6
is 545.3 g/mol) where R1 or R2 would be nonaryl groups.
Attempts to introduce the R2 diversity via direct alkylation of
arylhydrazide 7e (Scheme 2) with low molecular weight alkylat-
ing agents (i.e., methyl iodide) resulted in very low yields
(i.e., ∼5%) of the desired product due to overalkylation.
Reductive amination, a logical alternative, with acetaldehyde
gave ∼10% yield of the desired N0-ethylacylhydrazide; use of
formaldehyde in this type of reductive amination has also been
reported to be ineffective.7,8 Interestingly, hydrazone formation
from 7a,d,e,g with acetone followed by reduction with sodium
cyanoborohydride afforded the N0-isopropylacylhydrazides 8a,d,
e,g in respectable yields (59ꢀ86%) with no chromatographic
purification required (Scheme 2).7 This favorable result could be
due to the purported stability of the disubstituted acylhydrazone
intermediate relative to the mono- and unsubstituted hydra-
zones.7 Indeed, aldehyde/acylhydrazide condensation and sub-
sequent reduction results in cyclic trimerization of the inter-
mediate hydrazone to give a 1,3,5-triazinane as reported by Fox
et al.8 Given these reductive amination results, spiro-fused
analogues where R2 was fixed as isopropyl were prepared using
Method B as delineated in Scheme 2. While the conditions for
pyrazolidine ring formation employed in Method A (Scheme 1)
were unsuccessful (resulted in oligomer formation), we found
that treatment of 8a,d,e,g with sodium hydride in THF afforded
9a,d,e,g in moderate yields (56ꢀ86%). Subsequent 1,3-dipolar
cycloaddition via the nitrile oxide derived from 10 delivered
spirocycles 11aꢀh.
’ RESULTS AND DISCUSSION
Retrosynthetically, the spiro-fused-pyrazolidoylisoxazoline
scaffold 1 can be envisioned as arising from N0-alkylacylhydra-
zide, 3-chloro-2-(chloromethyl)prop-1-ene, and nitrile oxide
building blocks as shown in Figure 1c. As an initial investigation
of this strategy, hydrazide 2 was treated with 3-bromobenzyl
bromide to afford 3 in a 68% yield (requires slow addition of the
alkylating agent to minimize overalkylation; Scheme 1). The
resulting N0-alkylacylhydrazide 3 was then subjected to alkylation
with 3-chloro-2-(chloromethyl)prop-1-ene in K2CO3/NaI/acet-
one to form pyrazolidine 4. Having constructed the requisite
4-methylenepyrazolidine dipolarophile, treatment of 4 with
Received: May 17, 2011
Published: June 08, 2011
r
2011 American Chemical Society
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Scheme 2. Method B Route to Spiro-Fused Pyrazolidoyl-
isoxazolines 11aꢀh
Figure 1. (a) 11-Deoxyfistularin-3 and 11-oxoaerothionin (active
against human breast and colon carcinomas). (b) Aerophobin 1, pure-
aldin L, and aplysinamisine II (serine protease inhibitors). (c) Retro-
synthetic analysis of spiro-fused pyrazolidoylisoxazolines 1.
Scheme 1. Method A Route to Spiro-Fused Pyrazolidoyl-
isoxazoline 6
undesired regioisomer 16 instead of the required hydrazide 17
(Scheme 4). Hydrazinolysis of methyl benzoate with methyl
hydrazine was also unsuccessful in providing N0-methylbenzohy-
drazide 17 (Scheme 4). In contrast, hydrazinolysis of methyl
pyrazine-2-carboxylate (18; Scheme 4) delivered N0-methylpyr-
azine-2-carbohydrazide (19) in excellent yield (90%).10 The
divergent regioselectivities observed with these two methods
can be rationalized on the basis of the mechanistic differences
described by Condon et al.:11 acylation using an anhydride is
governed by the greater nucleophilicity of the substituted
nitrogen, whereas acylation using a simple ester is governed
by steric congestion around the neutral, tetrahedral inter-
mediate.11 With hydrazide 19 in hand, the methods employed
in Schemes 2 and 3 delivered the targeted pyrazolidine, and the
sequence-ending 1,3-dipolar cycloaddition delivered final pro-
duct 20 in 55% yield.
Four spiro-fused pyrazolidoylisoxazolines with the R1 diversity
element of 1 fixed as a methyl substituent were prepared next
using Method C (Scheme 3). Arylhydrazine 12a,c was treated
with acetic anhydride to afford N0-arylacetohydrazide 13a,c in
high yields (>95%) with no purification necessary.9 Employing
the same conditions used in Method B (Scheme 2), these
acetohydrazides were then converted to pyrazolidines 14a,c,
and subsequent 1,3-dipolar cycloaddition delivered spirocycles
15aꢀd.
Finally, acylation of methyl hydrazine with benzoic anhydride
was investigated as an entry point in an attempt to prepare spiro-
fused heterocycle 1 adorned with a methyl group at the R2
position. Unfortunately, this effort resulted in formation of the
A molecular shape space diversity analysis (Figure 2), which
categorizes a compound’s shape as ratios of rod-, disk-, or sphere-
like character,12 was performed on the collection of compounds
reported above as well as on virtual analogues thereof. This
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Scheme 3. Method C Route to Spiro-Fused Pyrazolidoyl-
isoxazolines 15aꢀd
Scheme 4. Method D Route to Spiro-Fused Pyrazolidoyl-
isoxazoline 20
Figure 2. Molecular shape space diversity for (a) virtual library 1 (R1 =
Me, R2 and R3 = substituted phenyl groups); (b) virtual library 2 (R2 =
Me, R1 and R3 = substituted phenyl groups); (c) virtual library 3 (R3 =
Me, R1 and R2 = substituted phenyl groups); (d) virtual library 4 (R1, R2,
and R3 = substituted phenyl groups). Up to 200 conformations within
10 kcal/mol, as estimated by MMFF94,13 are plotted in blue while global
minima for each member of a library is represented by red. Virtual library
constituents and computational methods14 are defined in Supporting
Information.
analysis revealed that manipulation of the various R groups
on the spiro-fused scaffold significantly alters the shape
ratios in the resulting triangle plots. For instance, analysis of
a virtual library showed that if R1 is a methyl substituent,
molecular shapes are localized into the rod-like region
(Figure 2a; calculations included multiple low-energy confor-
mers for each analogue). A methyl group at R2 gives results
much like having large substituents at all three diversity points,
but slightly shifted to the rod-like region (Figure 2b). Placing
a methyl at R3 shifts the shape distribution toward the center
of the plot (“goblet-like” shape, Figure 2c). In contrast, when
all substituents are large (substituted phenyl groups), molec-
ular shapes are widely distributed between the rod- and
disk-like regions and cover a significant amount of shape space
(Figure 2d). These results suggest that shape biasing can
be achieved by manipulating the substituents about the spiro-
fused pyrazolidoylisoxazoline core. Of course, shape control
is an important factor in the rational design of a biological
ligand.
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In conclusion, synthetic entry into the novel spiro-fused
pyrazolidoylisoxazolines has been achieved.15 These spirocycles
(and virtual analogues thereof) were examined computationally
to characterize their overall molecular shapes. The compounds
reported here are currently being evaluated by collaborators at
Dow AgroSciences for pesticidal activity and have been sub-
mitted to the NIH molecular libraries small molecule repository
(MLSMR).
122.8, 55.4; HRMS (ESI) calcd for C14H12BrClN2O
(M + H)+, 338.9895, found 338.9898.
General Procedure for the Preparation of 2-Isopropyl Aryl
Hydrazides (8a,d,e,g): 4-Bromo-N0-isopropylbenzohydra-
zide (8g).
’ EXPERIMENTAL SECTION
Prepared according to literature procedures found in ref 7
yielding a white solid (79 mg, 66% yield): mp 141ꢀ142 °C; IR
(neat) νmax 3306, 3242, 2967, 1638, 1543, 1496, 1379, 1313,
1073, 1012, 894, 842 cmꢀ1; 1H NMR (400 MHz, CDCl3) δ 7.89
(s, 1H), 7.63 (d, J = 8.5 Hz, 2H), 7.57 (d, J = 8.5 Hz, 2H), 4.86 (s,
1H), 3.21 (sept, J = 6.3 Hz, 1H), 1.09 (d, J = 6.3 Hz, 6H); 13C
NMR (100 MHz, CDCl3) δ 166.7, 132.1, 131.8, 128.6, 126.7,
51.5, 21.0; HRMS (ESI) calcd for C10H13BrN2O (M + H)+,
257.0284, found 257.0287.
1. Materials and Methods. All reagents and solvents were
purchased from commercial vendors and used without further purifica-
tion. Concentration of reaction mixtures refers to rotary evaporation
under reduced pressure carried out at 40 °C. Thin layer chromatog-
raphy (TLC) was performed on silica-coated glass plates (silica gel 60
F254, 0.5 mm thickness) and visualized at 254 nm. Silica gel (60 Å
pores, particle size ranging from 32 to 63 μm) was used for all flash
chromatography purification. NMR spectral data was obtained at
1
N0-Isopropylfuran-2-carbohydrazide (8e).
ambient temperature unless otherwise specified. H NMR spectra
were recorded at 300, 400, or 600 MHz in CDCl3. 13C NMR spectra
were recorded at 75, 100, or 150 MHz in CDCl3. δ values are reported
and shown in parts per million (ppm) and referenced against CDCl3
(7.26 ppm for 1H and 77.16 ppm for 13C), and J coupling values are
listed in Hz. Infrared spectral data was obtained on an FT-IR
spectrometer with major peaks listed. LC/MS data was obtained
for mass verification and purity analysis; the specifications of the
instrument are as follows: electrospray (+) ionization, mass range of
150ꢀ1500 Da, 20 V cone voltage, MS C18 column (2.1 mm ꢁ 50 mm ꢁ
3.5 μm), mobile phase consisting of water and acetonitrile with a 0.1% TFA
buffer, and a flow rate of 0.2 mL/min.
Synthesized according to the general procedure for the prepara-
tion of 2-isopropyl aryl hydrazides (8a,d,e,g), which yielded a
white solid (2.248 g, 84% yield): mp 100ꢀ102 °C; IR (neat) νmax
1
3325, 3233, 2977, 1647, 1567, 1489, 1306, 940, 884 cmꢀ1; H
NMR (400 MHz, CDCl3) δ 8.12 (s, 1H), 7.41 (t, J = 0.8 Hz, 1H),
7.10 (d, J = 3.5 Hz, 1H), 6.47 (ddd, J = 3.5, 1.7, and 0.8 Hz, 1H),
4.74 (s, 1H), 3.19 (sept, J = 6.3 Hz, 1H), 1.07 (d, J = 6.3 Hz, 6H);
13C NMR (100 MHz, CDCl3) δ 158.3, 146.9, 144.2, 114.7,
112.1, 51.5, 20.8; HRMS (ESI) calcd for C8H12N2O2 (M + H)+,
169.0972, found 169.0969.
2. Preparation of 2-Substituted Hydrazides (Procedures
and Characterization Data): N0-(3-Bromobenzyl)-4-chloro-
benzohydrazide (3).
4-(tert-Butyl)-N0-isopropylbenzohydrazide (8a).
To a solution of 4-chlorobenzohydrazide (1.50 g, 8.79 mmol)
in N,N-dimethylformamide (15 mL) in a round-bottom flask
equipped with a stir bar was added N,N-diisopropylethyla-
mine (0.919 mL, 5.28 mmol). 3-Bromobenzyl bromide
(439 mg, 1.76 mmol), dissolved in N,N-dimethylformamide
(7 mL), was added to the solution via syringe pump over 12 h
(0.6 mL/h) at room temperature. The reaction mixture
was allowed to stir until TLC indicated the disappearance
of 3-bromobenzyl bromide. The resulting mixture was then
diluted with saturated aqueous ammonium chloride (40 mL)
and extracted with 95:5 ethyl acetate/hexanes (3 ꢁ 40 mL).
The combined organic extracts were washed with brine
(100 mL), dried over sodium sulfate, filtered, and concen-
trated. The crude material was purified by flash chromatogra-
phy (gradient mobile phase: 2:3 EtOAc/hexanes f 1:1
EtOAc/hexanes) yielding 3, a white solid (406 mg, 68%
yield): mp 149 °C; IR (neat) νmax 3303, 3290, 3052, 2913,
2453, 2398, 1625, 1593, 1411, 1384, 1089, 1009, 869,
Synthesized according to the general procedure for the prepara-
tion of 2-isopropyl aryl hydrazides (8a,d,e,g), which yielded a
light pink solid (2.079 g, 85% yield): mp 103ꢀ104 °C; IR (neat)
νmax 3267, 3238, 2961, 2927, 2875, 1648, 1536, 1473, 1310,
849 cmꢀ1; 1H NMR (300 MHz, CDCl3) δ 8.14 (s, 1H), 7.71 (d,
J = 8.4 Hz, 2H), 7.43 (d, J = 8.4 Hz, 2H), 4.92 (s, 1H), 3.22 (sept,
J = 6.3 Hz, 1H), 1.32 (s, 9H), 1.08 (d, J = 6.3 Hz, 6H); 13C NMR
(75 MHz, CDCl3) δ 167.4, 155.3, 130.1, 126.9, 125.6, 51.4, 35.0,
31.2, 20.9; HRMS (ESI) calcd for C14H22N2O (M + H)+,
235.1805, found 235.1807.
N0-Isopropylnicotinohydrazide (8d).
844 cmꢀ1 1H NMR (300 MHz, CDCl3) δ 7.63 (d,
;
Synthesized according to the general procedure for the prepara-
tion of 2-isopropyl aryl hydrazides (8a,d,e,g), which yielded a
white crystalline material (939 mg, 59%): mp 108ꢀ110 °C; IR
(neat) νmax 3269, 3234, 2969, 2870, 1621, 1588, 1544, 1471,
J = 8.4 Hz, 2H), 7.58 (s, 1H), 7.52 (s, 1H), 7.45 ꢀ 7.39
(m, 3H), 7.31 (d, J = 7.6 Hz, 1H), 7.22 (t, J = 7.7 Hz, 1H), 5.14
(s, 1H), 4.06 (s, 2H); 13C NMR (75 MHz, CDCl3) δ 166.8,
140.0, 138.5, 132.1, 131.1, 131.0, 130.3, 129.2, 128.4, 127.7,
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1
1414, 1347, 1320 cmꢀ1; H NMR (400 MHz, CDCl3) δ
pyrazolidine 4, a white solid (84 mg, 18% yield): mp 128ꢀ
129 °C; IR (neat) νmax 2919, 2902, 2850, 1609, 1451, 1432,
1417, 1090, 898, 839 cmꢀ1; 1H NMR (300 MHz, CDCl3) δ 7.52
(s, 1H), 7.40 (t, J = 7.8 Hz, 3H), 7.33 (d, J = 5.6 Hz, 1H), 7.27 (t,
J = 7.3 Hz, 2H), 7.17 (t, J = 7.8 Hz, 1H), 5.27 (s, 1H), 5.21
(s, 1H), 4.25 (s, 2H), 4.18 (s, 2H), 3.79 (s, 2H); 13C NMR (150
MHz, CDCl3) δ 167.8, 143.5, 138.2, 136.5, 133.6, 132.8, 131.1,
130.1, 130.0, 128.0, 127.9, 122.7, 108.4, 60.8, 58.8, 47.8; HRMS
(ESI) calcd for C18H16BrClN2O (M + H)+, 391.0208, found
8.97 (dd, J = 2.2 and 0.8 Hz, 1H), 8.78 (s, 1H), 8.68 (dd,
J = 4.9 and 1.7 Hz, 1H), 8.10 (dt, J = 7.9 and 1.9 Hz, 1H), 7.36
(ddd, J = 7.9, 4.9, and 0.8 Hz, 1H), 4.93 (s, 1H), 3.20 (sept,
J = 6.3 Hz, 1H), 1.07 (d, J = 6.3 Hz, 6H); 13C NMR (100 MHz,
CDCl3) δ 165.6, 152.5, 148.0, 135.3, 129.0, 123.7, 51.5, 20.9;
HRMS (ESI) calcd for C9H13N3O (M + H)+, 180.1132, found
180.1125.
General Procedure for the Preparation of 2-Aryl Acetohy-
drazides (13a,c): N0-(4-Chlorophenyl)acetohydrazide (13a).
391.0212.
General Procedure for the Preparation of 4-Methylene-
pyrazolidines (9a,d,e,g and 14a,c): (4-Bromophenyl)(2-iso-
propyl-4-methylenepyrazolidin-1-yl)methanone (9g).
Prepared according to literature procedures found in ref 9.
Cha0racterization data is in agreement with published values.
N -(3-Chlorophenyl)acetohydrazide (13b).
4-Bromo-N0-isopropylbenzohydrazide (8g; 375 mg, 1.46 mmol)
and 3-chloro-2-(chloromethyl)prop-1-ene (0.768 mL, 7.29
mmol) were combined in a round-bottom flask equipped with
a stir bar and flushed with nitrogen. Dry THF (10 mL) was then
added to the flask, and the contents were cooled in an ice bath.
Sodium hydride (350 mg, 60% dispersion in mineral oil, 8.75
mmol) was added slowly, and the reaction mixture was allowed
to warm to room temperature with stirring under nitrogen
overnight. Water (10 mL) was cautiously added, and the mixture
was concentrated, diluted with a saturated aqueous solution of
NH4Cl (10 mL), and extracted with ethyl acetate (3 ꢁ 10 mL).
The organic extracts were combined, washed with brine (20 mL),
dried over sodium sulfate, filtered, concentrated, and purified by
flash chromatography (1:1 EtOAc/hexane) to afford pyrazoli-
dine 9g as a yellow oil (388 mg, 86% yield): IR (neat) νmax 2969,
Prepared according to the general procedure for the preparation
of 2-aryl acetohydrazides (13a,c). Characterization data is in
agreement with published values.
Procedure for the Preparation of N0-Methylpyrazine-2-
carbohydrazide (19).
2926, 2867, 1619, 1587, 1434, 1414, 1382, 1608, 880, 836 cmꢀ1
;
1H NMR (300 MHz, CDCl3) δ 7.68 (d, J = 8.3 Hz, 2H), 7.43 (d,
J = 8.3 Hz, 2H), 5.13 (d, J = 17.9 Hz, 2H), 4.59 (d, J = 14.6 Hz,
1H), 3.93 (d, J = 14.6 Hz, 1H), 3.61 (d, J = 15.4 Hz, 2H), 2.72 (m,
1H), 0.80 (d, J = 32.0 Hz, 6H); 13C NMR (75 MHz, CDCl3)
δ 167.5, 144.7, 134.1, 131.0, 130.6, 124.5, 106.8, 56.5, 55.2, 48.5,
20.7, 20.2; HRMS (ESI) calcd for C14H17BrN2O (M + H)+,
309.0597, found 309.0598.
Prepared according to literature procedures found in ref 10.
Characterization data is in agreement with published values.
3. Preparation of Pyrazolidine Intermediates (Procedures
and Characterization Data): (2-(3-Bromobenzyl)-4-methyle-
nepyrazolidin-1-yl)(4-chlorophenyl)methanone (4).
Furan-2-yl(2-isopropyl-4-methylenepyrazolidin-1-yl)-
methanone (9e).
To a solution of 3-chloro-2-(chloromethyl)prop-1-ene (630 μL,
5.98 mmol) in acetone (15 mL) in a round-bottom flask with side
arm equipped with a stir bar and reflux condenser were added
potassium carbonate (826 mg, 5.98 mmol) and sodium iodide
(90 mg, 0.598 mmol). The resulting mixture was brought to
reflux and N0-(3-bromobenzyl)-4-chlorobenzohydrazide (3; 406 mg,
1.20 mmol), dissolved in acetone (7 mL), was added via syringe
pump over 12 h. The reaction mixture was subsequently con-
centrated, diluted with a saturated aqueous solution of ammo-
nium chloride (20 mL), and extracted with ethyl acetate (3 ꢁ
15 mL). The organic extracts were combined and washed
with brine (30 mL), dried over sodium sulfate, filtered, concen-
trated, and purified by flash chromatography (gradient mobile
phase: 1:4 EtOAc/hexanes f 2:3 EtOAc/hexanes) to afford
Prepared according to the general procedure for the preparation
of 4-methylenepyrazolidines (9a,d,e,g and 14a,c), which yielded
a yellow oil (828 mg, 64% yield): IR (neat) νmax 3111, 2986,
2973, 2860, 1627, 1563, 1476, 1451, 1424, 1366, 1017,
1
908 cmꢀ1; H NMR (600 MHz, CDCl3) δ 7.39 (s, 1H), 7.36
(d, J = 0.7 Hz, 1H), 6.28 (dd, J = 3.4 and 1.7 Hz, 1H), 5.00 (app
pent, J = 2.1 Hz, 1H), 4.94 (app pent, J = 2.1 Hz, 1H), 4.54 (d, J =
13.1 Hz, 1H), 3.70 (d, J = 13.1 Hz, 1H), 3.40 (d, J = 7.0 Hz, 2H),
2.67 (sept, J = 6.3 Hz, 1H), 0.88 (d, J = 6.3 Hz, 6H); 13C NMR
(150 MHz, CDCl3) δ 159.1, 146.2, 144.4, 144.3, 117.9, 110.9,
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106.3, 56.2, 54.2, 47.7, 20.5, 19.6; HRMS (ESI) calcd for
C12H16N2O2 (M + H)+, 221.1285, found 221.1281.
(4-(tert-Butyl)phenyl)(2-isopropyl-4-methylenepyrazo-
lidin-1-yl)methanone (9a).
20.7; HRMS (ESI) calcd for C12H13ClN2O (M + H)+, 237.0789,
found 237.0789.
1-(2-(4-Chlorophenyl)-4-methylenepyrazolidin-1-yl)-
methanone (14a).
Prepared according to the general procedure for the prepara-
tion of 4-methylenepyrazolidines (9a,d,e,g and 14a,c), which
yielded a yellow oil (966 mg, 62% yield): IR (neat) νmax 2966,
2904, 2866, 1626, 1433, 1416, 1382, 895 cmꢀ1; NMR spectra
obtained at ꢀ30 °C displaying a mixture of rotamers (most
abundant listed) 1H NMR (600 MHz, CDCl3) δ 7.78 (d, J =
8.2 Hz, 2H), 7.34 (d, J = 8.2 Hz, 2H), 5.21 (s, 1H), 5.15 (s,
1H), 4.66 (d, J = 15.9 Hz, 1H), 3.98 (d, J = 15.9 Hz, 1H), 3.73
(d, J = 14.7 Hz, 1H), 3.62 (d, J = 14.7 Hz, 1H), 2.74 (sept, J =
6.1 Hz, 1H), 1.29 (s, 9H), 0.89 (d, J = 6.1 Hz, 3H), 0.78 (d, J =
6.3 Hz, 3H); 13C NMR (150 MHz, CDCl3) δ 168.5, 153.2,
144.9, 132.0, 129.0, 124.4, 106.9, 56.6, 55.1, 48.4, 34.8, 31.2,
20.9, 20.2; HRMS (ESI) calcd for C18H26N2O (M + H)+,
287.2118, found 287.2114.
Prepared according to the general procedure for the preparation
of 4-methylenepyrazolidines (9a,d,e,g and 14a,c), which yielded
a yellow oil (343 mg, 27% yield): IR (neat) νmax 1663, 1486,
1401, 826 cmꢀ1; 1H NMR (600 MHz, CDCl3) δ 7.22 (s, 2H),
6.86 (s, 2H), 5.08 (s, 1H), 5.03 (s, 1H), 4.73 (s, 1H), 4.04 (s,
2H), 3.79 (s, 1H), 2.07 (s, 3H); 13C NMR (150 MHz, CDCl3)
δ 173.1, 149.2, 143.3, 129.4, 127.7, 117.0, 107.1, 60.6, 46.9, 20.7;
HRMS (ESI) calcd for C12H13ClN2O (M + H)+, 237.0789,
found 237.0790.
(2-Methyl-4-methylenepyrazolidin-1-yl)(pyrazin-2-yl)-
methanone.
(2-Isopropyl-4-methylenepyrazolidin-1-yl)(pyridin-3-yl)-
methanone (9d).
Prepared according to the general procedure for the preparation
of 4-methylenepyrazolidines (9a,d,e,g and 14a,c), which yielded
a yellow oil (81 mg, 5% yield): IR (neat) νmax 2959, 2925, 2865,
2794, 1608, 1405, 1319, 1114, 1013 cmꢀ1; 1H NMR (600 MHz,
CDCl3) δ 9.08 (d, J = 1.5 Hz, 1H), 8.49 (dd, J = 2.5 and 1.5 Hz,
1H), 8.45 (d, J = 2.5 Hz, 1H), 5.05 (s, 1H), 5.00 (s, 2H), 4.95 (s,
1H), 3.86 (s, 2H), 2.89 (s, 3H); 13C NMR (150 MHz, CDCl3) δ
147.3, 144.1, 143.8, 143.4, 143.3, 141.2, 112.1, 73.4, 62.6, 48.9;
HRMS (ESI) calcd for C10H12N4O (M + H)+, 205.1084, found
205.1078.
Prepared according to the general procedure for the preparation
of 4-methylenepyrazolidines (9a,d,e,g and 14a,c), which yielded
a yellow oil (688 mg, 56% yield): IR (neat) νmax 2974, 2877,
1625, 1589, 1451, 1410, 888 cmꢀ1; 1H NMR (400 MHz, CDCl3)
δ 8.68 (s, 1H), 8.21 (s, 1H), 7.75 (d, J = 5.9 Hz, 1H), 6.94 ꢀ 6.91
(m, 1H), 4.84 (s, 1H), 4.79 (s, 1H), 4.30 (d, J = 15.3 Hz, 1H),
3.59 (d, J = 15.3 Hz, 1H), 3.31 (d, J = 23.8 Hz, 2H), 2.38 (s, 1H),
0.45 (d, J = 47.5 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ 165.7,
149.9, 149.5, 143.9, 136.1, 130.6, 121.8, 106.3, 56.0, 54.5, 47.6,
20.1, 19.5; HRMS (ESI) calcd for C13H17N3O (M + H)+,
232.1445, found 232.1443.
4. General Procedure for the Preparation of Spiro-Fused
Pyrazolidoylisoxazolines (6, 11aꢀh, 15aꢀd, and 20): (4-
Bromophenyl)(8-isopropyl-3-(2-methoxyphenyl)-1-oxa-2,7,8-
triazaspiro[4.4]non-2-en-7-yl)methanone (11g).
1-(2-(3-Chlorophenyl)-4-methylenepyrazolidin-1-yl)-
ethanone (14c).
To a dichloromethane (5 mL) solution of pyrazolidine 9g (109
mg, 0.35 mmol) under N2 was added triethylamine (122 μL, 0.88
mmol), and the resulting solution was cooled in an ice bath.
Chlorooxime 10 (R3 = o-OMe-C6H4; 131 mg, 0.71 mmol),
dissolved in dichloromethane (5 mL), was added to the solution
via syringe pump over 12 h. The resulting mixture was allowed to
warm to room temperature with stirring over 5 h. Water (10 mL)
was added, and the mixture was subsequently extracted with
dichloromethane (3 ꢁ 10 mL). The combined organic extracts
were washed with saturated ammonium chloride (20 mL) and brine
(20 mL), dried over sodium sulfate, filtered, concentrated by rotary
Prepared according to the general procedure for the preparation
of 4-methylenepyrazolidines (9a,d,e,g and 14a,c), which yielded
a yellow oil (340 mg, 27% yield): IR (neat) νmax 1659, 1590,
1476, 1449, 1397, 897, 853 cmꢀ1; 1H NMR (300 MHz, CDCl3)
δ 7.19 (t, J = 8.1 Hz, 1H), 6.97 ꢀ 6.91 (m, 2H), 6.80 (ddd, J = 8.3,
2.3, and 0.8 Hz, 1H), 5.08 (dt, J = 4.2 and 2.1 Hz, 1H), 5.03 (dt,
J = 4.2 and 2.2 Hz, 1H), 4.73 (s, 1H), 4.08 ꢀ 4.05 (m, 2H), 3.79
(s, 1H), 2.07 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 173.3,
151.8, 143.3, 135.3, 130.5, 122.6, 115.8, 113.8, 107.1, 60.2, 46.9,
5808
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evaporation, and purified by flash chromatograpy (EtOAc/hexane
2:3) to afford spiro-fused pyrazolidoylisoxazoline 11g as a white
solid (101 mg, 62% yield): mp 60ꢀ65 °C; IR (neat) νmax
2971, 2934, 1626, 1599, 1490, 1461, 1433, 1384, 1357, 1252,
93.9, 62.7, 58.0, 54.5, 45.6, 34.9, 31.3, 20.9, 20.5; HRMS (ESI) calcd
for C25H30FN3O2 (M + H)+, 424.2395, found 424.2392.
(4-(tert-Butyl)phenyl)(8-isopropyl-3-(2-(trifluoromethyl)-
phenyl)-1-oxa-2,7,8-triazaspiro[4.4]non-2-en-7-yl)methanone
(11b).
1
1012, 911 cmꢀ1; H NMR (600 MHz, CDCl3) δ 7.76 ꢀ7.64
(m, 3H), 7.48 (d, J = 7.5 Hz, 2H), 7.38 (t, J = 7.0 Hz, 1H), 6.97 (t,
J = 6.5 Hz, 1H), 6.93 (d, J = 7.9 Hz, 1H), 4.43 (s, 1H), 3.91 (d, J =
17.1 Hz, 1H), 3.84 (s, 3H), 3.76 (s, 1H), 3.69 (d, J = 12.6 Hz, 1H),
3.58 (d, J = 17.7 Hz, 1H), 3.37 (s, 1H), 3.15 (d, J = 11.9 Hz, 1H),
0.88 (d, J = 142.8 Hz, 6H); 13C NMR (600 MHz, CDCl3) δ 157.5,
155.8, 134.1, 131.8, 131.0, 130.7, 129.2, 124.8, 121.0, 118.0, 111.5,
93.5, 63.1, 57.4, 55.5, 54.2, 46.5, 21.3, 20.6; HRMS (ESI) calcd for
C22H24BrN3O3 (M + H)+, 458.1074, found 458.1069.
(8-(3-Bromobenzyl)-3-(4-chlorophenyl)-1-oxa-2,7,8-tri-
Prepared according to the general procedure for the preparation
of spiro-fused pyrazolidoylisoxazolines (6, 11aꢀh, 15aꢀd, and
20), which yielded a white solid (104 mg, 63% yield): mp 68 °C;
IR (neat) νmax 2969, 2906, 2876, 1624, 1427, 1314, 1169, 1117,
1075, 1035 cmꢀ1; 1H NMR (600 MHz, CDCl3) δ 7.75 (d, J = 7.7
Hz, 3H), 7.61 (t, J = 7.5 Hz, 1H), 7.56 (t, J = 7.5 Hz, 1H), 7.53
(d, J = 7.3 Hz, 1H), 7.37 (d, J = 8.4 Hz, 2H), 4.46 (s, 1H), 3.99 (s,
1H), 3.74 (d, J = 12.9 Hz, 1H), 3.53 (s, 1H), 3.46ꢀ3.38 (m, 2H),
3.18 (d, J = 11.2 Hz, 1H), 1.32 (s, 9H), 1.06 (s, 3H), 0.88 (s, 3H);
13C NMR (150 MHz, CDCl3) δ 169.3, 156.1, 153.8, 132.2,
130.7, 130.1, 129.1, 128.8 (q, JCF = 31.3 Hz), 128.6, 126.8 (q,
JCF = 5.2 Hz), 124.6, 123.9 (q, JCF = 273.8 Hz) 94.4, 62.5, 57.3,
54.6, 47.3, 34.9, 31.3, 20.9, 20.50; HRMS (ESI) calcd for
C26H30F3N3O2 (M + H)+ 474.2363, found 474.2352.
azaspiro[4.4]non-2-en-7-yl)(4-chlorophenyl)methanone (6).
Prepared according to the general procedure for the preparation
of spiro-fused pyrazolidoylisoxazolines (6, 11aꢀh, 15aꢀd, and
20), which yielded a white solid (77 mg, 70% yield): mp
78ꢀ85 °C; IR (neat) νmax 2446, 2414, 2394, 2355, 1644,
(4-(tert-Butyl)phenyl)(3-(2,4-dichlorophenyl)-8-isopropyl-1-
oxa-2,7,8-triazaspiro[4.4]non-2-en-7-yl)methanone (11c).
1
1595, 1092, 914, 828 cmꢀ1; H NMR (600 MHz, CDCl3)
δ 7.53 (d, J = 8.6 Hz, 2H), 7.50 ꢀ 7.46 (m, 3H), 7.38 (dd, J =
8.0 and 0.7 Hz, 1H), 7.35 (d, J = 8.6 Hz, 2H), 7.30 (d, J = 8.6 Hz,
2H), 7.24 (d, J = 8.0 Hz, 1H), 7.14 (t, J = 7.8 Hz, 1H), 4.31 (d, J =
13.1 Hz, 1H), 4.24 (d, J = 13.1 Hz, 1H), 3.84 (d, J = 11.2 Hz, 1H),
3.60 (d, J = 11.2 Hz, 1H), 3.53 (d, J = 14.7 Hz, 1H), 3.50 (d, J =
14.7 Hz, 1H), 3.42 (d, J = 17.1 Hz, 1H), 3.37 (d, J = 17.1 Hz, 1H);
13C NMR (150 MHz, CDCl3) δ 166.1, 156.3, 139.4, 138.1, 136.6,
132.4, 131.9, 131.1, 130.2, 129.2, 129.0, 128.5, 128.1, 128.1, 127.6,
122.7, 89.7, 61.2, 59.0, 45.9, 41.0; HRMS (ESI) calcd for
C25H20BrCl2N3O2 (M + H)+, 544.0189, found 544.0179.
Prepared according to the general procedure for the preparation
of spiro-fused pyrazolidoylisoxazolines (6, 11aꢀh, 15aꢀd, and
20), which yielded a white solid (93 mg, 56% yield): mp 85 °C;
IR (neat) νmax 2966, 2951, 2903, 2869, 1621, 1586, 1424, 1383,
1363, 1106, 917 cmꢀ1; 1H NMR (600 MHz, CDCl3) δ 7.75 (s,
2H), 7.60 (d, J = 8.4 Hz, 1H), 7.44 (d, J = 1.9 Hz, 1H), 7.36 (d, J =
8.4 Hz, 2H), 7.29 (dd, J = 8.4 and 1.9 Hz, 1H), 4.41 (s, 1H), 3.94
(s, 1H), 3.71 (d, J = 12.9 Hz, 2H), 3.60 (d, J = 17.0 Hz, 1H), 3.36
(s, 1H), 3.20 (d, J = 9.4 Hz, 1H), 1.32 (s, 9H), 0.98 (d, J = 88.4
Hz, 6H); 13C NMR (150 MHz, CDCl3) δ 169.3, 155.3, 153.9,
136.8, 133.7, 132.4, 131.3, 130.6, 129.1, 127.6, 127.3, 124.6, 94.6,
62.4, 57.6, 54.6, 45.9, 34.9, 31.3, 20.9, 20.5; HRMS (ESI) calcd
for C25H29Cl2N3O2 (M + H)+, 474.1710, found 474.1706.
(8-Isopropyl-3-(2-methoxyphenyl)-1-oxa-2,7,8-triazaspiro-
[4.4]non-2-en-7-yl)(pyridin-3-yl)methanone (11d).
(4-(tert-Butyl)phenyl)(3-(2-fluorophenyl)-8-isopropyl-1-
oxa-2,7,8-triazaspiro[4.4]non-2-en-7-yl)methanone (11a).
Prepared according to the general procedure for the preparation of
spiro-fused pyrazolidoylisoxazolines (6, 11aꢀh, 15aꢀd, and 20),
which yielded a white solid (83 mg, 56% yield): mp 69ꢀ71 °C; IR
(neat) νmax 2967, 2903, 2870, 1622, 1452, 1425, 1384, 1362, 1227,
922 cmꢀ1; 1H NMR (600 MHz, CDCl3) δ 7.84 (t, J = 7.0 Hz, 1H),
7.75 (s, 2H), 7.43 ꢀ 7.38 (m, 1H), 7.36 (d, J = 8.4 Hz, 2H), 7.18 (t,
J = 7.6 Hz, 1H), 7.11 (dd, J = 11.0 and 8.6 Hz, 1H), 4.43 (s, 1H),
3.95 (s, 1H), 3.70 (d, J= 12.9 Hz, 2H), 3.56 (d, J= 16.8 Hz, 1H), 3.38
(s, 1H), 3.20 (d, J = 10.1 Hz, 1H), 1.32 (s, 9H), 0.98 (d, J = 95.1 Hz,
6H); 13C NMR (150 MHz, CDCl3) δ 169.3, 161.3, 159.6, 153.8,
152.9 (d, JCF = 2.6 Hz), 132.4, 132.1 (d, JCF = 8.7 Hz), 129.0 (m, 1C),
124.7 (m, 1C), 117.40 (d, JCF = 11.5 Hz), 116.6 (d, JCF = 22.2 Hz),
Prepared according to the general procedure for the preparation of
spiro-fused pyrazolidoylisoxazolines (6, 11aꢀh, 15aꢀd, and 20),
5809
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which yielded a white solid (205 mg, 64% yield): mp 58ꢀ65 °C; IR
(neat) νmax 2971, 2929, 1635, 1589, 1462, 1434, 1408, 1248, 1028,
909, 897 cmꢀ1; 1H NMR (600 MHz, CDCl3) δ 9.02 (s, 1H), 8.59
(s, 1H), 8.07 (d, J = 6.4 Hz, 1H), 7.71 (d, J = 7.1 Hz, 1H), 7.36 (td,
J= 8.4 and 1.6 Hz, 1H), 7.28 (dd, J= 7.1 and 5.1 Hz, 1H), 6.95 (t, J=
7.5 Hz, 1H), 6.91 (d, J = 8.4 Hz, 1H), 4.43 (d, J = 11.0 Hz, 1H),
3.91 ꢀ 3.86 (m, 1H), 3.82 (s, 3H), 3.77 (d, J = 18.7 Hz, 1H), 3.69
(d, J = 13.0 Hz, 1H), 3.57 (d, J = 18.1 Hz, 1H), 3.35 (s, 1H), 3.14 (d,
J = 13.0 Hz, 1H), 0.84 (d, J = 145.4 Hz, 6H); 13C NMR (150 MHz,
CDCl3) δ 166.7, 157.5, 155.8, 150.8, 150.1, 136.9, 131.7, 131.2,
129.2, 122.6, 120.9, 117.9, 111.4, 93.5, 63.1, 57.1, 55.5, 54.2, 46.4,
21.2, 20.6; HRMS (ESI) calcd for C21H24N4O3 (M + H)+,
381.1921, found 381.1929.
128.4, 126.8 (q, JCF = 5.1 Hz), 123.9 (q, JCF = 273.0 Hz), 118.6,
111.2, 94.5, 62.9, 56.5, 53.8, 47.3, 21.3, 20.2; HRMS (ESI) calcd for
C20H20F3N3O3 (M + H)+, 408.1530, found 408.1528.
(4-Bromophenyl)(8-isopropyl-3-(thiophen-2-yl)-1-oxa-2,
7,8-triazaspiro[4.4]non-2-en-7-yl)methanone (11h).
Prepared according to the general procedure for the preparation
of spiro-fused pyrazolidoylisoxazolines (6, 11aꢀh, 15aꢀd, and
20), which yielded a brown solid (51 mg, 76% yield): mp
71ꢀ80 °C; IR (neat) νmax 2973, 2930, 1621, 1588, 1424,
(3-(2-Fluorophenyl)-8-isopropyl-1-oxa-2,7,8-triazaspiro-
[4.4]non-2-en-7-yl)(furan-2-yl)methanone (11e).
1
1383, 1012, 911 cmꢀ1; H NMR (600 MHz, CDCl3) δ 7.70
(d, J = 8.3 Hz, 2H), 7.49 (d, J = 8.3 Hz, 2H), 7.41 (d, J = 5.1 Hz,
1H), 7.20 (d, J = 3.5 Hz, 1H), 7.07 (t, J = 4.6 Hz, 1H), 4.36
(s, 1H), 3.94 (s, 1H), 3.70 (d, J = 11.0 Hz, 1H), 3.60 (d, J = 16.8
Hz, 1H), 3.46 (d, J = 16.8 Hz, 1H), 3.33 (s, 1H), 3.19 (d, J = 11.0
Hz, 1H), 1.00 (s, 3H), 0.86 (s, 3H); 13C NMR (150 MHz,
CDCl3) δ 168.2, 152.0, 134.3, 131.7, 131.0, 131.0, 128.8,
128.7, 127.6, 125.0, 93.9, 63.0, 57.5, 54.7, 44.7, 21.0, 20.6; HRMS
(ESI) calcd for C19H20BrN3O2S (M + H)+, 434.0533, found
434.0532.
Prepared according to the general procedure for the preparation
of spiro-fused pyrazolidoylisoxazolines (6, 11aꢀh, 15aꢀd, and
20), which yielded a yellow solid (179 mg, 68% yield): mp
53ꢀ60 °C; IR (neat) νmax 2975, 2932, 1631, 1473, 1453, 1418,
1-(8-(4-Chlorophenyl)-3-(2-fluorophenyl)-1-oxa-2,7,8-
1
1083, 1050, 1017, 917 cmꢀ1; H NMR (600 MHz, CDCl3)
triazaspiro[4.4]non-2-en-7-yl)ethanone (15a).
δ 7.78 (t, J = 7.3 Hz, 1H), 7.54 (s, 1H), 7.52 (m, 1H), 7.35 (tdd,
J = 7.2, 5.2, and 1.6 Hz, 1H), 7.13 (t, J = 7.6 Hz, 1H), 7.06 (ddd,
J = 11.2, 8.5, and 0.9 Hz, 1H), 6.42 (dd, J = 3.4 and 1.7 Hz, 1H),
4.51 (d, J = 12.2 Hz, 1H), 3.79 (d, J = 11.5 Hz, 1H), 3.66 (t, J =
13.3 Hz, 2H), 3.45 (d, J = 17.9 Hz, 1H), 3.39 (pent, J = 6.0 Hz,
1H), 2.99 (d, J = 13.3 Hz, 1H), 1.17 (d, J = 6.0 Hz, 3H), 1.03 (d,
J = 6.0 Hz, 3H); 13C NMR (150 MHz, CDCl3) δ 160.3 (d, JCF
=
252.8 Hz), 159.9, 152.9, 146.4, 145.0, 132.1, 128.8, 124.6, 118.6,
117.1, 116.5 (d, JCF = 22.2 Hz), 111.2, 94.0, 63.1, 57.0, 53.7, 45.5,
21.3, 20.2; HRMS (ESI) calcd for C19H20FN3O3 (M + H)+,
358.1562, found 358.1563.
Prepared according to the general procedure for the preparation of
spiro-fused pyrazolidoylisoxazolines (6, 11aꢀh, 15aꢀd, and 20),
which yielded a white solid (62 mg, 29% yield): mp 146 °C; IR
(neat) νmax 1660, 1488, 1450, 1405, 919, 828, 818 cmꢀ1; 1H NMR
(600 MHz, CDCl3) δ7.78 (t, J= 7.2 Hz, 1H), 7.41 ꢀ 7.36 (m, 1H),
7.26 (d, J = 8.2 Hz, 2H), 7.15 (t, J = 7.6 Hz, 1H), 7.09 (dd, J = 8.8
and 8.9 Hz, 1H), 6.91 (d, J = 8.2 Hz, 2H), 4.36 (s, 1H), 4.02 (d, J =
12.2 Hz, 1H), 3.82 (s, 1H), 3.60 (s, 1H), 3.47 (s, 2H), 2.09 (s, 3H);
13C NMR (150 MHz, CDCl3) δ 173.6, 160.4 (d, JCF = 252.6 Hz),
152.9, 149.1, 132.2 (d, JCF = 8.8 Hz), 129.5, 128.9 (d, JCF = 2.9 Hz),
127.7, 124.7 (d, JCF = 3.4 Hz), 117.2 (d, JCF = 11.0 Hz), 116.7, 116.5
(d, JCF = 21.8 Hz), 93.4, 66.0, 54.9, 44.0, 20.6; HRMS (ESI) calcd
for C19H17ClFN3O2 (M + H)+, 374.1066, found 374.1069.
Furan-2-yl(8-isopropyl-3-(2-(trifluoromethyl)phenyl)-1-
oxa-2,7,8-triazaspiro[4.4]non-2-en-7-yl)methanone (11f).
Prepared according to the general procedure for the preparation
of spiro-fused pyrazolidoylisoxazolines (6, 11aꢀh, 15aꢀd,
and 20), which yielded a yellow solid (114 mg, 66% yield): mp
130ꢀ137 °C; IR (neat) νmax 2985, 2968, 2934, 2927, 1627, 1418,
1312, 1167, 1115, 1076 cmꢀ1; 1H NMR (600 MHz, CDCl3) δ 7.72
(d, J = 7.7 Hz, 1H), 7.60 ꢀ 7.56 (m, 2H), 7.53 (t, J = 7.5 Hz, 2H),
7.50 (d, J = 7.5 Hz, 1H), 6.44 (dd, J = 3.4 and 1.7 Hz, 1H), 4.54 (d,
J = 12.6 Hz, 1H), 3.85 (d, J = 12.6 Hz, 1H), 3.73 (d, J = 13.1 Hz,
1H), 3.52 (d, J = 17.5 Hz, 1H), 3.42 (pent, J = 6.0 Hz, 1H), 3.35 (d,
J = 17.5 Hz, 1H), 3.00 (d, J = 13.1 Hz, 1H), 1.20 (d, J = 6.0 Hz, 3H),
1.05 (d, J = 6.0 Hz, 3H); 13C NMR (151 MHz, CDCl3) δ 160.0,
156.1, 146.5, 145.1, 132.2, 130.6, 130.1, 128.7 (q, JCF = 31.6 Hz),
5810
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1-(8-(4-Chlorophenyl)-3-(2-(trifluoromethyl)phenyl)-1-
oxa-2,7,8-triazaspiro[4.4]non-2-en-7-yl)ethanone (15b).
Prepared according to the general procedure for the preparation
of spiro-fused pyrazolidoylisoxazolines (6, 11aꢀh, 15aꢀd, and
20), which yielded a white solid (124 mg, 65% yield): mp
157ꢀ158 °C; IR (neat) νmax 1659, 1490, 1407, 1314, 1177,
1110, 1035, 828 cmꢀ1; 1H NMR (600 MHz, CDCl3) δ 7.65 (d,
J = 7.5 Hz, 1H), 7.49 (dt, J = 23.2 and 7.5 Hz, 2H), 7.40 (d, J =
7.5 Hz, 1H), 7.18 (d, J = 8.8 Hz, 2H), 6.84 (d, J = 8.8 Hz, 2H),
4.29 (s, 1H), 3.97 (d, J = 12.0 Hz, 1H), 3.77 (s, 1H), 3.40 (s, 1H),
3.27 (s, 2H), 2.01 (s, 3H); 13C NMR (150 MHz, CDCl3)
δ 173.5, 156.1, 149.0, 132.2, 130.6, 130.1, 129.5, 128.7 (q,
JCF = 31.9 Hz), 128.3, 127.7, 126.8 (q, JCF = 5.0 Hz), 123.9 (q,
JCF = 273.3 Hz), 116.6, 93.7, 65.6, 54.4, 46.0, 20.5; HRMS (ESI)
calcd for C20H17ClF3N3O2 (M + H)+, 424.1034, found 424.1034.
1-(8-(3-Chlorophenyl)-3-(2,4-dichlorophenyl)-1-oxa-2,
7,8-triazaspiro[4.4]non-2-en-7-yl)ethanone (15c).
(ESI) calcd for C20H17ClN4O2 (M + H)+, 381.1113, found
381.1116.
(3-(2-Fluorophenyl)-8-methyl-1-oxa-2,7,8-triazaspiro-
[4.4]non-2-en-7-yl)(pyrazin-2-yl)methanone (20).
Prepared according to the general procedure for the preparation
of spiro-fused pyrazolidoylisoxazolines (6, 11aꢀh, 15aꢀd,
and 20), which yielded a white solid (75 mg, 55% yield): mp
56ꢀ65 °C; IR (neat) νmax 2959, 2928, 1640, 1451, 1433, 1386,
1017, 917 cmꢀ1; 1H NMR (600 MHz, CDCl3) δ 8.85 (s, 1H),
8.62 (d, J = 5.5 Hz, 2H), 7.84 (t, J = 7.1 Hz, 1H), 7.41 (q, J = 5.6
Hz, 1H), 7.19 (t, J = 7.4 Hz, 1H), 7.12 (t, J = 8.5 Hz, 1H), 4.17
(d, J = 12.9 Hz, 1H), 3.75 (d, J = 17.4 Hz, 1H), 3.56 (d, J = 17.4
Hz, 1H), 3.32 (d, J = 13.0 Hz, 1H), 3.13 (d, J = 13.0 Hz, 1H), 2.99
(s, 1H), 2.85 (s, 3H); 13C NMR (150 MHz, CDCl3) δ 166.6,
161.3, 159.6, 152.9, 149.8, 145.4, 143.7 (d, JCF = 41.4 Hz), 132.3
(d, JCF = 8.7 Hz), 128.9, 124.8 (d, JCF = 3.2 Hz), 117.1 (d, JCF
=
11.5 Hz), 116.6 (d, JCF = 22.5 Hz), 93.8, 67.4, 55.8, 45.8, 45.1;
HRMS (ESI) calcd for C17H16FN5O2 (M + H)+, 342.1361,
found 342.1361.
Prepared according to the general procedure for the preparation of
spiro-fused pyrazolidoylisoxazolines (6, 11aꢀh, 15aꢀd, and 20),
which yielded a white solid (128 mg, 72% yield): mp 67ꢀ77 °C; IR
(neat) νmax 1668, 1590, 1476, 1428, 1384, 1339 cmꢀ1; 1H NMR
(600 MHz, CDCl3) δ 7.54 (d, J = 8.2 Hz, 1H), 7.41 (s, 1H), 7.26 ꢀ
7.24 (m, 1H), 7.20 (t, J = 8.2 Hz, 1H), 6.96 (d, J = 6.7 Hz, 2H), 6.83
(d, J = 5.8 Hz, 1H), 4.38 (s, 1H), 4.05 (d, J = 11.5 Hz, 1H), 3.78 (s,
1H), 3.64 (s, 1H), 3.50 (d, J= 32.7 Hz, 2H), 2.08 (s, 3H); 13CNMR
(150 MHz, CDCl3) δ 173.8, 155.4, 151.7, 136.9, 135.5, 133.6,
131.3, 130.6, 127.7, 127.0, 122.6, 115.5, 113.4, 94.1, 65.4, 54.5, 44.4,
20.6; HRMS (ESI) calcd for C19H16Cl3N3O2 (M + H)+, 424.0381,
found 424.0383.
’ ASSOCIATED CONTENT
Supporting Information. Copies of H NMR and 13C
1
S
b
NMR spectra for all new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
*E-mail: mjkurth@ucdavis.edu.
4-(7-Acetyl-8-(3-chlorophenyl)-1-oxa-2,7,8-triazaspiro-
’ ACKNOWLEDGMENT
[4.4]non-2-en-3-yl)benzonitrile (15d).
We thank the National Science Foundation (CHE-0910870)
and the National Institutes of Health (GM089153) for generous
financial support.
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and 20), which yielded a white solid (61 mg, 41% yield): mp
89ꢀ95 °C; IR (neat) νmax 3066, 2955, 2925, 2227, 1667, 1591,
1476, 1430, 1390, 1350, 915, 838 cmꢀ1; 1H NMR (600 MHz,
CDCl3) δ 7.68 (d, J = 2.1 Hz, 4H), 7.23 (t, J = 7.9 Hz, 1H),
7.01 ꢀ 6.95 (m, 2H), 6.85 (d, J = 7.0 Hz, 1H), 4.41 (s, 1H), 4.07
(d, J = 12.2 Hz, 1H), 3.81 (s, 1H), 3.56 (s, 1H), 3.49 (s, 1H),
3.39 (s, 1H), 2.10 (s, 3H); 13C NMR (150 MHz, CDCl3)
δ 173.8, 155.0, 151.6, 135.6, 133.3, 132.7, 130.7, 127.2, 122.8,
118.1, 115.6, 114.2, 113.4, 94.2, 65.9, 54.9, 41.9, 20.6; HRMS
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ARTICLE
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(15) During review of this manuscript, the question was asked if the
methods reported here for the synthesis of spiro-fused pyrazolidoylisox-
azoline 1 could be adapted to a one-pot cascade format. Regrettably,
4-methylenepyrazolidine formation requires the use of excess (we employed
5 equiv; see 3 f 4 in the Experimental Section) 3-chloro-2-(chloro-
methyl)prop-1-ene to minimize the production of unwanted bis-hydrazide
21. Preliminary studies also established that 3-chloro-2-(chloromethyl)-
prop-1-ene reacts with nitrile oxides to give isoxazoline 22, which proved
unreactive in the alkylation of N0-alkylacylhydrazides. Together, these two
observations preclude the feasibility of developing an effective one-pot
cascade route to 1.
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dx.doi.org/10.1021/jo200924y |J. Org. Chem. 2011, 76, 5803–5812