Novel trinitrogen-containing triheterocycles via the intramolecular nitrile oxide cycloaddition reaction

Article abstract of DOI:10.1055/s-0030-1260188

The intramolecular nitrile oxide cycloaddition (INOC) reaction is applied to the synthesis of novel isoxazolooxazepinoindazole, benzoisoxazolodiazepinoindazolone, and spiro[isoxazoloazepine]piperidine heterocycles. Each of these targets incorporates a uni

Full text of DOI:10.1055/s-0030-1260188

PAPER
3241
Novel Trinitrogen-Containing Triheterocycles via the Intramolecular Nitrile
Oxide Cycloaddition Reaction
T
rinitrogen-Contai
n
ning Trihete
d
rocycle
s
rew J. Ferreira, Danielle M. Solano, James S. Oakdale, Mark J. Kurth*
Department of Chemistry, University of California, One Shields Avenue, Davis, CA 95616, USA
E-mail: mjkurth@ucdavis.edu
Received 7 July 2011
spiro[isoxazoloazepine]piperidine 3 heterocycles depict-
Abstract: The intramolecular nitrile oxide cycloaddition (INOC)
reaction is applied to the synthesis of novel isoxazolooxazepinoin-
dazole, benzoisoxazolodiazepinoindazolone, and spiro[isox-
azoloazepine]piperidine heterocycles. Each of these targets
ed in Figure 1. The motivation for addressing these syn-
thetic challenges is underscored by the high biological
activity of the related heterocycles 4–6 presented in
incorporates a unique trinitrogen-containing triheterocyclic frame- Figure 1.
work.
N
Keywords: alkenes, cycloadditions, heterocycles, pericyclic reac-
tions, spiro compounds
O
O
N
Me
N
N
N
O
N
N
Intramolecular nitrile oxide cycloaddition (INOC) reac-
tions offer a vehicle for incorporating fused isoxazoline
N
N
O
O
Boc
O
ring systems into biologically interesting heterocycles.
Our objective, to develop routes to novel isox-
azoloazepine-based heterocycles, is set against a back-
drop of INOC reactions having a rich history in natural
product synthesis. Recent examples of total syntheses uti-
lizing an INOC reaction as the key step include those of
branimycin,1 macrosphelides,2 brefeldin A,3 and calyste-
gines B2.4 Additionally, INOC reactions forming isoxazo-
lines fused to seven-membered rings have been reported
in studies targeting taxanes,5 zoapatanol,6 and the hydra-
zulenone ring system.7
1
2
3
O
O2N
N
HN
O
N
N
O
N
O
4
5
6
Figure 1 Heterocyclic targets: isoxazolooxazepinoindazole 1, ben-
zoisoxazolodiazepinoindazolone 2, and spiro[isoxazoloazepine]pipe-
ridine 3; structural analogues: glycine antagonist 4,14 heterocycle 5
with cytostatic activity against HeLa cells,15 and high affinity and
selective s ligand 616
The utility, but also the efficiency, of the INOC step are
wide-ranging when applied to the synthesis of isoxazo-
lines fused to seven-membered rings. Although good
yields have been observed for some heterocyclizations,5
others are poor,8 and some result in no product formation.9
Achieving the desired product over dimerization can be an
obstacle because of the high reactivity of the nitrile oxide
intermediate as well as the natural propensity for forma-
tion of the 3,5-disubstituted isoxazoline in intermolecular
variants; in contrast, intramolecular variants leading to
medium-sized rings require formation of the 3,4-disubsti-
tuted isoxazoline.10
Because of the ready availability of indazole 9 from a pre-
vious methodology development effort in our laborato-
ries,17 we set oxime 10, and its subsequent INOC to 1, as
our initial objective (Scheme 1). The synthesis of INOC
precursor 10 involved strategic placement of the olefin
and oxime moieties – a process which began with the slow
addition of 7 in tetrahydrofuran to a stirring solution of
base and ethanolamine in tetrahydrofuran. 2-[(2-Ni-
trobenzyl)amino]ethanol (8) was obtained in near quanti-
In the privileged heterocycle quest, the combining of
functional groups and multiple points of diversity is criti-
cal. Moreover, isoxazolines provide added potential in
that they allow synthetic access to g-amino alcohols,11,12
b-hydroxy ketones,11,13 b-hydroxy nitriles/acids/esters,11
and a,b- and b,g-unsaturated oximes.11 Our objective was
to develop routes to the novel isoxazolooxazepinoinda-
zole 1, benzoisoxazolodiazepinoindazolone 2, and
tative yield.
A Davis–Beirut N–N bond-forming
heterocylization reaction18 afforded the targeted indazole
9 in 80% yield. Allyl alcohol was employed as the solvent
(and external nucleophile) for this reaction so as to intro-
duce the requisite INOC dipolarophile. Swern oxidation
of the primary alcohol in 9 and subsequent oxime forma-
tion from the resulting 2-(2H-indazol-2-yl)acetaldehyde
were performed without purification of the aldehyde, be-
cause it tended to decompose upon attempted purification
by silica gel chromatography. Conversion into oxime 10
was accomplished by treatment of the aldehyde with hy-
SYNTHESIS 2011, No. 20, pp 3241–3246
x
x.
x
x
.
2
0
1
1
Advanced online publication: 24.08.2011
DOI: 10.1055/s-0030-1260188; Art ID: M68111SS
© Georg Thieme Verlag Stuttgart · New York

3242
A. J. Ferreira et al.
PAPER
OH
H2N
i-Pr2NEt
NO2
Br
NO2
OH
HO
H
N
THF
96%
KOH, H2O
80%
7
8
HO
N
N
O
HON
9
N
N
NaOCl, Et3N
a) Swern oxidation
N
N
N
CHCl3, 50 °C
73%
b) H2NOH⋅HCl
NaOAc, EtOH
THF, H2O
O
O
O
1
87%
10
Scheme 1 Synthesis of isoxazolooxazepinoindazole 1
droxylamine in ethanol plus sodium acetate, and proceed- This heterocycle, which contains benzo-1,3-oxazine and
ed in 87% yield over the two steps from indazole 9.
2H-indazole substructures, is readily available in one step
from 2-nitrobenzaldehyde.22 Treating benzoxazinoinda-
zole 11 with acetic acid (sealed vessel, MW, 170 °C) ef-
fects ring opening of the benzoxazine heterocycle and
delivers indazolone 12 in 55% yield.
The final step in this sequence, oxime to nitrile oxide con-
version, was effected in situ by using aqueous sodium hy-
pochlorite in a biphasic chloroform system.19 Addition of
catalytic triethylamine was found to improve the reaction
yield. We also found that warming the reaction mixture to With the benzylic alcohol thus protected as an acetate,
50 °C resulted in further yield improvement; this observa- N1-allylation of the indazolone moiety with allyl bromide
tion may reflect the relatively reduced reactivity of the followed by base-mediated hydrolysis of the benzylic
system when confronted with the constraint of giving the acetate gave N1,N2-disubstituted indazolone 13 in 98%
3,4-regioisomer over the 3,5-regioisomer.10,20 Finally, overall yield from 12 (Scheme 2). Oxidation of the thus
high dilution conditions (10–3 M) were employed to max- liberated benzylic alcohol was accomplished best with py-
imize formation of the desired trinitrogen-containing tri- ridinium chlorochromate in dichloromethane, and treating
heterocycle 1 (isolated in 73% yield) over potentially the resulting aldehyde with hydroxylamine hydrochloride
competing oligomeric side products.
proceeded smoothly to deliver oxime 14 (75% overall
yield from 13). Employing high dilution (10–3 M) and
gentle warming (as with 10→1) resulted in the targeted
INOC to produce benzoisoxazolodiazepinoindazolone 2
in good yield (80%).
We set formation of oxime 14, and its subsequent INOC
to 2, as our second objective (Scheme 2). Recent reports
from our laboratory21 concerning the conversion of inda-
zoles into indazolones prompted this effort, which began
with 5H-benzo[4,5][1,3]oxazino[3,2-b]indazole (11).
H
N
N
AcOH
N
N
a)
Br
MW
i-Pr2NEt
CH2Cl2
170 °C
O
O
55%
b) Na2CO3
OAc
EtOH, H2O
11
12
40 °C, 98%
N
N
O
N
O
13
OH
NaOCl, Et3N
N
N
a) PCC, CH2Cl2
N
N
b) H2NOH⋅HCl
NaOAc, EtOH
THF, H2O
75%
CHCl3, 50 °C
80%
O
O
NOH
2
14
Scheme 2 Synthesis of benzoisoxazolodiazepinoindazolone 2
Synthesis 2011, No. 20, 3241–3246 © Thieme Stuttgart · New York

PAPER
Trinitrogen-Containing Triheterocycles
3243
O
N
O
CO2Me
OMe
OH
a) LDA, THF
b)
KOH, 60 °C
THF, MeOH, H2O
92%
Br
N
N
Boc
92%
Boc
Boc
15
16
17
a) oxalyl chloride,
cat. DMF, pyridine
toluene, 0 °C
b) MeHN(CH2)2OH
88%
N
O
NOH
OH
O
O
Me
N
N
N
NaOCl, Et3N
a) Swern oxidation
Me
Me
O
CHCl3, 50 °C
80%
b) H2NOH⋅HCl
NaOAc, EtOH
THF, H2O
64%
N
Boc
N
N
Boc
Boc
3
19
18
Scheme 3 Synthesis of spiro[isoxazoloazepine]piperidine 3
rameters were 5.5 kV spray voltage, capillary temperature of 275 °C
and sheath gas setting of 20 L/min. Spectral data were acquired at a
resolution setting of 100000 FWHM with the lockmass feature.
As our third trinitrogen-containing hetrocyclic target, we
selected spiro-fused isoxazoloazepinylpiperidinone 3
(Scheme 3). The oxime 19 required for this INOC was
prepared starting from commercially available Boc-pro-
tected piperidine-1,4-dicarboxylate 15. Ca-Allylation de-
livered ester 17 in excellent yield (92%). While attempts
at direct ester to amide (16→18) conversion were unsuc-
cessful, ester saponification, activation (oxalyl chloride),
and aminolysis with 2-(methylamino)ethanol gave N-(2-
hydroxyethyl)-N-methylpiperidine-4-carboxamide 18 in
81% overall yield from 16.
Isoxazoles 1–3 by INOC; General Procedure
A 250 mL round-bottom flask containing CHCl3 (40 mL, 0.01 M),
NaOCl (25 mL, 15 mmol), and cat. Et3N (6 mL, 0.05 mmol) was
warmed to 50 °C with vigorous stirring. A 10 mL syringe contain-
ing oxime 10, 14,or 19 (1 mmol) in CHCl3 (10 mL) was affixed to
a syringe pump and added at a rate of 1.5 mL/h. Upon completion
of addition, the mixture was stirred for 6 h, when total consumption
of starting material was observed by TLC. The crude mixture was
added to H2O (30 mL) and extracted with CHCl3 (3 × 30 mL). The
combined organics were washed with brine (30 mL), dried
(Na2SO4), filtered, and concentrated in vacuo. The crude residue
was purified by flash chromatography (silica gel, EtOAc–hexanes,
1:1 to 3:1); this gave cycloaddition products 1–3.
Swern oxidation of 18 gave the corresponding acetalde-
hyde, which reacted with hydroxylamine hydrochloride to
deliver oxime 19 in 64% yield over two steps (Scheme 3).
Employing the same conditions outlined above for the
preparation of 1 and 2 delivered spiro[isoxazolo[3,4-
c]azepine-5,4¢-piperidin]-6(3H)-one 3 in 80% yield.
3,3a,4,12-Tetrahydroisoxazolo[3¢,4¢:5,6][1,3]oxazepino-
[3,2-b]indazole (1)
Clear oil; yield: 167 mg (73%).
IR (neat): 3229, 2974, 2162, 1661, 1483, 1256 cm–1.
1H NMR (600 MHz, CDCl3): d = 7.88 (d, J = 7.6 Hz, 1 H), 7.58 (t,
J = 8.3 Hz, 1 H), 7.26 (t, J = 7.6 Hz, 1 H), 7.19 (d, J = 8.3 Hz, 1 H),
5.40 (d, J = 14.7 Hz, 1 H), 4.72 (dd, J = 9.6, 7.6 Hz, 1 H), 4.31 (dd,
J = 10.6, 6.0 Hz, 1 H), 4.17 (dd, J = 14.7, 1.3 Hz, 1 H), 4.08–3.93
(m, 2 H), 2.92 (t, J = 10.6 Hz, 1 H).
In summary, the intramolecular nitrile oxide cycloaddi-
tion (INOC) reaction has been applied to the synthesis of
novel isoxazolooxazepinoindazole 1, benzoisoxazolodi-
azepinoindazolone 2, and spiro[isoxazoloazepine]piperi-
dine 3 heterocycles. Each of these targets incorporates a
unique trinitrogen-containing triheterocyclic framework.
13C NMR (151 MHz, CDCl3): d = 161.99, 151.79, 149.72, 132.71,
All chemicals were purchased from commercial suppliers and used
without further purification. Analytical TLC was carried out on pre-
coated plates (silica gel 60 F254, 250 mm thickness) and UV light
was used for visualization. Flash chromatography was performed
using 60 Å, 32–63 mm silica gel (Scientific Adsorbents). Concentra-
tion in vacuo refers to rotary evaporation under reduced pressure.
1H NMR spectra were recorded on Mercury (1H 300 MHz; 13C 75
MHz), Inova (1H 400 MHz; 13C 100 MHz) and VNMRS (1H 600
MHz; 13C 125 MHz) spectrometers with CDCl3 or DMSO-d6 as sol-
vents. Chemical shifts are reported relative to the residual solvent
peak. IR spectra were recorded on an ATI-FTIR spectrometer. For
HRMS, samples were analyzed by flow-injection analysis into a
Thermo Fisher Scientific LTQ Orbitrap (San Jose, CA) operated in
the centroided mode. Samples were injected into a mixture of 50%
MeOH and 0.1% aq formic acid at a flow of 200 ml/min. Source pa-
124.67, 123.77, 120.50, 111.86, 71.24, 54.54, 47.14, 40.55.
HRMS (EI): m/z calcd for C12H11N3O2: 229.09; found: 230.0922.
7a,8-Dihydrobenzo[3,4]isoxazolo[3¢,4¢:5,6][1,2]diazepino[1,2-
a]indazol-14(7H)-one (2)
Amber solid; yield: 212 mg (80%); mp 171–173 °C.
IR (neat): 2956, 2926, 2869, 1670, 1614, 1482, 1467, 1315 cm–1.
1H NMR (600 MHz, CDCl3): d = 8.01 (d, J = 7.9 Hz, 1 H), 7.88 (d,
J = 7.9 Hz, 1 H), 7.76 (d, J = 8.2 Hz, 1 H), 7.58 (t, J = 7.8 Hz, 1 H),
7.51 (t, J = 7.8 Hz, 1 H), 7.39 (t, J = 7.6 Hz, 1 H), 7.21 (t, J = 7.6
Hz, 1 H) 7.12 (d, J = 8.2 Hz, 1 H), 4.68 (t, J = 9.5 Hz, 1 H), 4.09–
3.96 (m, 2 H), 3.79 (dd, J = 13.4, 10.0 Hz, 1 H), 3.66–3.60 (m, 1 H).
Synthesis 2011, No. 20, 3241–3246 © Thieme Stuttgart · New York

3244
A. J. Ferreira et al.
PAPER
13C NMR (151 MHz, CDCl3): d = 163.16, 158.10, 150.10, 135.03,
133.65, 131.87, 128.96, 128.77, 128.05, 124.97, 124.86, 123.58,
119.33, 112.01, 72.64, 54.00, 47.19.
13C NMR (101 MHz, CDCl3): d = 164.15, 163.96, 149.27, 146.33,
145.81, 132.79, 129.96, 124.43, 122.65, 120.74, 118.46, 112.05,
52.03, 51.90, 41.73, 37.67.
HRMS (EI): m/z calcd for C17H13N3O2: 291.10; found: 292.1088.
HRMS (EI): m/z calcd for C12H13N3O2: 231.10; found: 232.1078.
tert-Butyl 7-Methyl-6-oxo-3,3a,4,6,7,8-hexahydrospiro[isoxazo-
lo[3,4-c]azepine-5,4¢-piperidine]-1¢-carboxylate (3)
White crystalline solid; yield: 232 mg (80%); mp 180–183 °C.
tert-Butyl 4-Allyl-4-{[2-(hydroxyimino)ethyl](methyl)carbam-
oyl}piperidine-1-carboxylate (19)
White amorphous solid; yield: 108 mg (64% over two steps).
IR (neat): 2974, 2928, 1680, 1628, 1421, 1366, 1247, 1172, 1143,
860 cm–1.
IR (neat): 3329, 2982, 2928, 1679, 1625, 1433, 1260, 1160 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.29 (t, J = 5.5, 0.6 H), 6.62 (t,
J = 4.3, 0.4 H), 5.67–5.54 (m, 1 H), 5.04 (dd, J = 20.5, 13.3 Hz, 2
H), 4.21–3.98 (m, 2 H) 3.78 (br s, 1 H), 3.69 (d, J = 8.8 Hz, 1 H),
3.19 (s, 1 H), 3.12 (s, 3 H), 2.98 (t, J = 11.2 Hz, 2 H), 2.40 (dd,
J = 14.6, 7.2 Hz, 1 H), 2.31 (dd, J = 14.6, 7.2 Hz, 2 H), 2.2 (d, 8.6
Hz, 2 H), 1.42 (s, 9 H), 1.26–1.18 (m, 2 H).
13C NMR (101 MHz, CDCl3): d = 174.10, 155.23, 146.99, 132.83,
118.62, 79.71, 49.22, 46.15, 45.93, 45.79, 42.55, 42.46, 37.59,
36.70, 34.54 (br s), 28.66.
1H NMR (600 MHz, CDCl3): d = 4.61 (t, J = 8.3 Hz, 1 H), 4.46 (dd,
J = 31.4, 16.0 Hz, 1 H), 4.15 (t, J = 13.8 Hz, 1 H), 3.94 (t, J = 9.0
Hz, 1 H), 3.76–3.52 (m, 2 H), 3.51–3.35 (m, 1 H), 3.06 (s, 3 H), 2.98
(t, J = 11.8 Hz, 1 H), 2.24 (t, J = 11.4 Hz, 1 H), 2.17 (dd, J = 14, 2.8
Hz, 1 H), 1.90 (dd, J = 14.0, 5.3 Hz, 1 H), 1.66 (t, J = 13.3 Hz, 2 H),
1.42 (s, 9 H), 1.24 (ddd, J = 25.0, 23.7, 13.7 Hz, 2 H).
13C NMR (151 MHz, CDCl3): d = 174.89, 154.83, 106.06, 79.79,
75.21, 46.54, 45.71, 44.65, 39.45, 38.94, 37.12, 30.74, 28.62.
HRMS (EI): m/z calcd for C17H27N3O4: 337.20; found: 338.12.
HRMS (EI): m/z calcd for C17H29N3O4: 339.21; found: 340.1754.
2-(2-Nitrobenzylamino)ethanol (8)
2-[3-Oxo-1H-indazol-2(3H)-yl]benzyl Acetate (12)
Prepared as reported by Oakdale et al.;17 spectral data are in accord
with literature values.
Indazole 11 (458 mg, 2 mmol) and AcOH (13 mL, 0.15 M) were
added to a 25 mL microwave vial. The soln was stirred for 2 h at
170 °C in the microwave apparatus. The cooled crude mixture was
neutralized to pH 7 with aq NaHCO3, H2O (50 mL) was added, and
the mixture was extracted with EtOAc (3 × 60 mL). The organics
were washed with brine (60 mL), dried (Na2SO4), filtered, and con-
centrated in vacuo. The resulting residue was purified by flash chro-
matography (silica gel, EtOAc–hexanes, 6:4).
2-[3-(Allyloxy)-2H-indazol-2-yl]ethanol (9)
Prepared as reported by Oakdale et al.;17 spectral data are in accord
with literature values.
Oximes 10 and 19; General Procedure
Alcohol 9 or 18 (0.5 mmol) was added to a flame-dried 50 mL
round-bottom flask before the flask was flushed several times with
N2. CH2Cl2 (5 mL, 0.2 M) was added and the reaction flask was
cooled to –78 °C for 15 min. Oxalyl chloride (85 mL, 1 mmol) was
added and the mixture was left to stir for another 15 min before
DMSO (141 mL, 2 mmol) was added. After 20 min, Et3N (269 mL,
2 mmol) was added and the reaction mixture was left to stir for an
additional 20 min before being warmed to 0 °C. The reaction mix-
ture was allowed to stir at 0 °C for 20 min until completion of the
reaction was verified by TLC. The mixture was added to aq NH4Cl
(20 mL) and the resulting mixture was extracted with CH2Cl2 (3 ×
20 mL). The combined organics were washed with brine (30 mL),
dried (Na2SO4), filtered, and concentrated in vacuo. The resulting
aldehyde was used in the next reaction without further purification.
Tan semi-solid; yield: 310 mg (55%).
IR (neat): 3044, 2862, 2839, 3603, 1736, 1637, 1580, 1364, 1325,
1243, 1039 cm–1.
1H NMR (600 MHz, CDCl3): d = 8.5 (br s, 1 H), 7.71 (d, J = 7.8 Hz,
1 H), 7.52 (dd, J = 8.3, 8.3 Hz, 1 H), 7.47 (d, J = 7.5 Hz, 1 H), 7.41–
7.30 (m, 3 H), 7.22–7.16 (m, 2 H), 5.10 (s, 2 H), 1.94 (s, 3 H).
13C NMR (151 MHz, CDCl3): d = 171.2, 162.7, 147.9, 134.8, 134.0,
132.7, 129.5, 129.3, 129.2, 127.7, 124.3, 122.9, 118.2, 112.8, 62.8,
21.1.
HRMS (EI): m/z calcd for C16H14N2O3: 282.10; found: 283.1080.
1-Allyl-2-[2-(hydroxymethyl)phenyl]-1H-indazol-3(2H)-one
(13)
A mixture of H2NOH·HCl (69 mg, 1 mmol) and NaOAc (123 mg,
1.5 mmol) dissolved in EtOH–THF–H2O (5:3:1, 5 mL) was added
to a 50 mL round-bottom flask containing this crude aldehyde (0.5
mmol). The soln was left to stir at 23 °C for 18 h, when total con-
sumption of starting material was observed by TLC. The THF and
EtOH were removed in vacuo, H2O (30 mL) was added, and the
mixture was extracted with EtOAc (3 × 30 mL). The combined or-
ganics were washed with brine (30 mL), dried (Na2SO4), filtered,
and concentrated in vacuo. The residue was purified by flash chro-
matography (silica gel, EtOAc–hexanes, 75:25 to 100:1).
i-Pr2NEt (347 mL, 2 mmol) and allyl bromide (172 mL, 2 mmol)
were added to a 0.2 M soln of 12 (282 mg, 1 mmol) in CH2Cl2 (5
mL) in a dry 100 mL round-bottom flask at 23 °C. TLC indicated
complete consumption of starting material after 18 h. H2O (30 mL)
was added and the mixture was extracted with EtOAc (3 × 30 mL).
The organics were washed with brine (30 mL), dried (Na2SO4), fil-
tered, and concentrated in vacuo. The allylated product was collect-
ed as a deep amber semi-solid in near quantitative yield (448 mg,
98%). The product was used in the next step without further purifi-
cation.
This crude material (322 mg, 1 mmol) was added to a 100 mL
round-bottom flask and dissolved in EtOH–H2O (1:1, 2 mL).
NaHCO3 (168 mg, 2 mmol) was added and the soln was warmed to
50 °C for 48 h. H2O (30 mL) was added and the mixture was ex-
tracted with EtOAc (3 × 30 mL). The organics were washed with
brine (30 mL), dried (Na2SO4), filtered, and concentrated in vacuo.
The alcohol product was collected as a white crystalline solid.
2-[3-(Allyloxy)-2H-indazol-2-yl]acetaldehyde Oxime (10)
Yellow oil; yield: 100 mg (87%).
IR (neat): 3224, 1730, 1657, 1488, 1464, 1262 cm– 1
.
1H NMR (400 MHz, CDCl3): d = 10.56 (s, 0.6 H), 10.15 (s, 0.4 H),
7.81 (dd, J = 7.1, 7.1 Hz, 1 H), 7.47 (dd, J = 14.4, 7.3 Hz, 1 H), 7.33
(t, J = 5.9, 0.6 H), 7.18–7.03 (m, 2 H), 6.66 (t, J = 4.4, 0.4 H), 5.46–
5.25 (m, 1 H), 5.16 (d, J = 17.1 Hz, 1 H), 5.05 (dd, J = 23.1, 10.7
Hz, 1 H), 4.86 (d, J = 4.5 Hz, 1 H), 4.62 (d, J = 6.0 Hz, 1 H), 4.28
(d, J = 6.0 Hz, 2 H).
White crystals; yield: 274 mg (>98%); mp 91.7–92.2 °C.
IR (neat): 3317, 2932, 2858, 1639, 1611, 1492, 1455, 767 cm–1.
Synthesis 2011, No. 20, 3241–3246 © Thieme Stuttgart · New York

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Trinitrogen-Containing Triheterocycles
3245
1H NMR (400 MHz, CDCl3): d = 7.83 (d, J = 7.8 Hz, 1 H), 7.63–
7.53 (m, 2 H), 7.41–7.33 (m, 2 H), 7.26–7.23 (m, 2 H), 7.19 (dd,
J = 7.6, 7.6 Hz, 1 H), 5.50–5.32 (m, 1 H), 5.02 (d, J = 10.2 Hz, 1 H),
4.90 (d, J = 17.1 Hz, 1 H), 4.83 (d, J = 10.5 Hz, 1 H), 4.64 (d,
J = 11.7 Hz, 1 H), 4.38–4.22 (m, 2 H), 3.89 (dd, J = 15.9, 7.6 Hz, 1
H).
13C NMR (101 MHz, CDCl3): d = 164.56, 149.96, 138.75, 133.31,
133.16, 132.19, 130.18, 129.21, 129.17, 126.74, 124.87, 123.19,
121.06, 118.23, 112.38, 62.21, 52.72.
IR (neat): 2962, 2928, 1734, 1689, 1427, 1177 cm–1.
1H NMR (300 MHz, CDCl3): d = 5.70–5.56 (m, 1 H), 5.04 (d,
J = 4.1 Hz, 1 H), 4.99 (d, J = 10.5 Hz, 1 H), 3.81 (d, J = 10.5 Hz, 2
H), 3.66 (d, J = 0.6 Hz, 3 H), 2.85 (t, J = 11.6 Hz, 2 H), 2.23 (d,
J = 7.4 Hz, 2 H), 2.04 (d, J = 13.6 Hz, 2 H), 1.51–1.28 (m, 11 H).
13C NMR (75 MHz, CDCl3): d = 175.73, 155.03, 132.87, 118.62,
79.61, 51.94, 46.22, 44.50, 41.88 (br s), 33.13, 28.62.
HRMS (EI): m/z calcd for C15H25NO4: 283.18; found: 284.1108.
HRMS (EI): m/z calcd for C17H16N2O2: 280.12; found: 281.1286.
4-Allyl-1-(tert-butoxycarbonyl)piperidine-4-carboxylic Acid
(17)
2-[1-Allyl-3(2H)-oxo-2H-indazol-2-yl]benzaldehyde Oxime (14)
PCC (215 mg, 1 mmol) was added to a flame-dried 100 mL round-
bottom flask. Indazole 13 (280 mg, 1 mmol) in CH2Cl2 (5 mL, 0.2
M) was added to a second 50 mL conical flask. Both flasks were
flushed several times with argon. The CH2Cl2 soln of 13 was trans-
ferred by using a cannula to the 100 mL round-bottom flask contain-
ing the PCC, and the soln was stirred at 23 °C for 16 h; TLC
confirmed total consumption of starting material. The crude mixture
was added to sat. aq NH4Cl (30 mL), extracted with CH2Cl2 (3 × 30
mL), and washed with brine (30 mL). The organics were collected,
dried (Na2SO4), filtered, and concentrated in vacuo. The crude prod-
uct was carried forward without further purification.
A soln of 16 (282 mg, 1 mmol) and KOH (560 mg, 10 mmol) in
H2O–THF–MeOH (2:2:1, 50 mL) was added to a 100 mL round-
bottom flask. The reaction mixture was warmed to 65 °C and stirred
for 5.5 h until completion of the reaction was verified by TLC. The
MeOH and THF were removed in vacuo and the mixture was acid-
ified with aqueous citric acid to pH 4; this afforded white crystals,
which were collected by filtration and dried.
White crystals; yield: 247 mg (92%); mp 130–132 °C.
IR (neat): 2985, 1723, 1643, 1450, 1166, 1132, 973, 927, 870 cm–1.
1H NMR (300 MHz, CDCl3): d = 5.59–5.46 (m, 1 H), 5.02–4.74 (m,
2 H), 3.65 (d, J = 13.5 Hz, 2 H), 2.76 (t, J = 10.7 Hz, 2 H), 2.09 (d,
J = 7.3 Hz, 2 H), 1.87 (d, J = 13.5 Hz, 2 H), 1.38–0.95 (m, 11 H).
This crude aldehyde (279 mg, 1 mmol) along with H2NOH·HCl
(138 mg, 2 mmol), NaOAc (246 mg, 3 mmol), and EtOH–THF–
H2O (5:3:1, 5 mL) were added to a 100 mL round-bottom flask. The
mixture was left to stir at 23 °C for 18 h; TLC confirmed total con-
sumption of starting material. The THF and EtOH were removed in
vacuo, H2O (30 mL) was added, and the mixture was extracted with
EtOAc (3 × 30 mL). The combined organics were washed with
brine (30 mL), dried (Na2SO4), filtered, and concentrated in vacuo.
The residue was purified by flash chromatography (silica gel,
EtOAc–hexanes, 85:15 to 100:0).
13C NMR (75 MHz, DMSO-d6): d = 176.80, 154.53, 134.00,
118.85, 79.22, 45.30, 43.74, 41.94, 33.06, 28.74.
HRMS (EI): m/z calcd for C14H23NO4: 269.16; found: 270.1270.
tert-Butyl 4-Allyl-4-[(2-hydroxyethyl)(methyl)carbamoyl]pipe-
ridine-1-carboxylate (18)
A soln of 17 (269 mg, 1 mmol) in toluene (5 mL, 0.2 M) was added
to a flame-dried 100 mL round-bottom flask. DMF (cat., 4 mL), py-
ridine (0.5 mL), and oxalyl chloride (172 mL, 2 mmol) were added
subsequently, and the mixture was stirred at 23 °C. After 2 h, 2-
(methylamino)ethanol (150 mg, 2 mmol) was added and the mix-
ture was left to stir for 18 h. Upon completion of the reaction, the
crude mixture was added to NaHCO3 (50 mL) and the resulting
mixture was extracted with CH2Cl2 (3 × 50 mL). The combined or-
ganics were washed with brine (50 mL), dried (Na2SO4), filtered,
and concentrated in vacuo. The residue was purified by flash chro-
matography (silica gel, EtOAc–hexanes, 9:1 to 1:0).
Light yellow oil; yield: 219 mg (75%).
IR (neat): 2955, 2929, 2857, 1648, 1543, 1319, 981 cm–1.
1H NMR (600 MHz, CDCl3): d = 8.11 (s, 1 H), 7.92 (d, J = 7.8 Hz,
1 H), 7.86 (d, J = 7.8 Hz, 1 H), 7.55 (dd, J = 7.8, 7.8 Hz, 1 H), 7.42
(dd, J = 7.7, 7.7 Hz, 1 H), 7.36–7.30 (m, 2 H), 7.24 (d, J = 8.3 Hz,
1 H), 7.19 (dd, J = 7.5, 7.5 Hz, 1 H), 5.46–5.37 (m, 1 H), 5.05 (d,
J = 10.3 Hz, 1 H), 4.95 (d, J = 16.9 Hz, 1 H), 4.14 (dd, J = 15.5, 5.5
Hz, 1 H), 3.99 (dd, J = 15.5, 7.1 Hz, 1 H).
13C NMR (151 MHz, CDCl3): d = 163.24, 150.17, 147.61, 133.76,
133.67, 133.13, 130.65, 129.94, 128.69, 127.42, 127.12, 125.04,
123.15, 121.39, 118.80, 112.54, 53.11.
Yellow oil; yield: 287 mg (88%).
IR (neat): 3430, 2976, 1680, 1421, 1391, 1365, 1246, 1154, 1048,
973, 9216, 864, 753 cm–1.
1H NMR (600 MHz, CDCl3): d = 5.77–5.61 (m, 1 H), 5.17–4.99 (m,
2 H), 3.84–3.71 (m, 4 H), 3.65–3.61 (m, 1 H), 3.47–3.43 (m, 1 H),
3.21 (s, 3 H), 3.09 (t, J = 11.6 Hz, 1 H), 2.96 (t, J = 11.6 Hz, 1 H),
2.42 (dd, J = 14.3, 7.5 Hz, 1 H), 2.35 (dd, J = 14.3, 7.5 Hz, 1 H),
2.22 (d, J = 14.3 Hz, 2 H), 1.62–1.27 (m, 11 H).
13C NMR (101 MHz, CDCl3): d = 175.84, 155.14, 132.97, 118.51,
79.60, 61.62, 53.84, 53.63, 45.97, 42.50, 37.79, 34.56 (br s), 28.65.
HRMS (EI): m/z calcd for C17H15N3O2: 293.32; found: 294.1238.
1-tert-Butyl 4-Methyl 4-Allylpiperidine-1,4-dicarboxylate (16)
A 100 mL round-bottom flask was flame-dried and flushed several
times with N2. i-Pr2NH (dried over 4 Å MS; 200 mg, 2.75 mmol)
and anhyd THF (3 mL) were added to the round-bottom flask. The
soln was cooled to –70 °C and 2.5 M n-BuLi in hexanes (1 mL, 2.5
mmol) was added. The mixture was left to stir for 45 min. This
freshly prepared soln of LDA was added via cannula to a soln of 15
(219 mg, 2.05 mmol) in anhyd THF (5 mL) cooled in a –70 °C bath.
The reaction mixture was kept between –70 and –60 °C for 1 h be-
fore allyl bromide (297 mg, 2.46 mmol) was added. The mixture
was allowed to warm overnight to ambient temperature. Sat. aq
NH4Cl was added and the mixture was extracted with EtOAc (3 ×
30 mL). The combined organics were washed with brine (30 mL),
dried (Na2SO4), filtered, and concentrated in vacuo. The residue
was purified by flash chromatography (silica gel, EtOAc–hexanes,
10:90 to 25:75).
HRMS (EI): m/z calcd for C17H30N2O4: 326.22; found: 327.1653.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis. Included
are a detailed experimental section and NMR spectra.
Acknowledgment
The authors thank the Tara K. Telford Fund for Cystic Fibrosis Re-
search at UC Davis, the National Institutes of Health (GM0891583),
and the National Science Foundation [CHE-0910870; and CHE-
Clear oil; yield: 534 mg (92%).
Synthesis 2011, No. 20, 3241–3246 © Thieme Stuttgart · New York

3246
A. J. Ferreira et al.
PAPER
(10) Jager, V.; Colinas, P. A. Synthetic Applications of 1,3-
0443516, CHE-0449845, and CHE-9808183 for NMR spectrome-
ters] for their generous support.
Dipolar Cycloaddition Chemistry toward Heterocycles and
Natural Products, In The Chemistry of Heterocyclic
Compounds, Vol. 59; Padwa, A.; Pearson, W. H., Eds.; John
Wiley & Sons: New York, 2002, 361–472.
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Synthesis 2011, No. 20, 3241–3246 © Thieme Stuttgart · New York