Preparation of a spiroisoxazolinopiperidinylbenzamide-based scaffold

Article abstract of DOI:10.1055/s-0029-1218290

A route to spiroisoxazolinopiperidinylbenzamides has been developed. N-Boc-4-piperidone underwent a Wittig olefination and Boc-deprotection followed by a nucleophilic substitution reaction with 4-fluoro-3-nitrobenzoic acid to yield the starting scaffold 3

Full text of DOI:10.1055/s-0029-1218290

LETTER
3019
Preparation of a Spiroisoxazolinopiperidinylbenzamide-Based Scaffold
Preparation of
a
S
p
r
iroisoxa
i
z
olinop
s
iperidiny
t
lbenzam
i
ide-
B
n
ased Scaffold A. Milinkevich, Mark J. Kurth*
Department of Chemistry, University of California, One Shields Avenue, Davis, CA 95616, USA
Fax +1(530)7528995; E-mail: mjkurth@ucdavis.edu
Received 3 July 2009
spiropiperidine substructure is so abundant in biologically
pertinent molecules, it has earned ‘privileged structure’
status.11
Abstract: A route to spiroisoxazolinopiperidinylbenzamides has
been developed. N-Boc-4-piperidone underwent a Wittig olefina-
tion and Boc-deprotection followed by a nucleophilic substitution
reaction with 4-fluoro-3-nitrobenzoic acid to yield the starting scaf-
fold 3 in excellent yields. Diversification of the acid with primary
amines, followed nitrile oxide formation in situ (aryl oximes treated
with bleach) and subsequent 1,3-dipolar cycloaddition to the exo-
methylene moiety delivered the spiroisoxazolinopiperdines. Reduc-
tion of the arylnitro group followed by acylation with acid chlorides
or reductive amination with aldehydes yielded the spiroisoxazoli-
nopiperidinylbenzamide library.
Due to the strong biological activity of each individual
heterocycle and the additional activities when connected
in a spiro fashion, we set out to prepare a library contain-
ing the spiroisoxazolinopiperidine substructure. Although
this substructure is known in the literature,12 here it was
tethered to a diversifiable molecule in order to synthesize
a library containing this moiety. Library synthesis increas-
es the possibility of finding a highly active compound by
creating a target scaffold with diversity elements that
probe chemical space. Often, biological evaluation pro-
duces a hit that can be further refined and improved to a
valuable lead compound.13 We report that the targeted li-
brary (A) can be synthesized from trifunctionalized scaf-
fold 3 (Figure 1).
Key words: nitrile oxide, isoxazolines, nucleophilic substitution,
cycloaddition, piperidines
Small-molecule heterocyclic compounds are attractive
due to their ability to interact with biological systems.
Isoxazoline-containing compounds have been shown to
display a wide range of biological activities, including
herbicidal,1 anti-inflammatory,2 anti-tuberculosis,3 anti-
fungal,4 anti-influenza,5 and antibacterial activities.4 This
moiety, when spiro-connected, is also found in bioactive
natural products, including 11-deoxyfistularin-3 and pu-
realidin Q, which both have anticancer properties, and in
aerothionin, zamamistatin, and agelorin B, which exhibit
antibiotic, antifungal, or antimycobacterial activities.6
Natural products containing this substructure, araplysil-
lins-I and –II as well as purealidin B, have shown antimi-
crobial activities.7
The synthesis of target scaffold 3 began with commercial-
ly available N-Boc-4-piperidone (1; Scheme 1). Subject-
ing 1 to Wittig olefination conditions delivered the
exomethylene moiety in high yield. Exomethylenepiperi-
dine 2 was Boc-deprotected and then treated with 4-fluo-
ro-3-nitrobenzoic acid in the presence of DIPEA to
promote the nucleophilic substitution. It should be noted
that attempts to isolate the neutral amine failed as the
compound proved to be highly water-soluble. Instead, the
TFA salt was neutralized to pH 8 with triethylamine and
then used in the nucleophilic substitution. The carboxylic
acid was treated with base prior to the addition of the exo-
methylenepiperidine and the nucleophilic substitution
then proceeded in high yield (94%) to deliver the targeted
scaffold 3.
Another biologically relevant heterocycle is the piperi-
dine moiety. Compounds containing this heterocycle have
shown antioxidant and anti-inflammatory activity8 as well
as anticoagulant activity.9 It is interesting to note that
when this heterocycle is spiro-connected, various other
activities arise, including antiviral activity.10 In fact, the
Diversification of this trifunctional scaffold (Scheme 2)
began with an EDC-mediated coupling of amine chemset
O
O
N
R1
OH
H
H2N
R1
N
N
O
HN
NO2
R3
N
R2
Cl
O
3
C
A
N+
O–
R2
set I: R3 = C(O)R'
set II: R3 = R'
R3
H
O
or
R3
Figure 1 Spiroisoxazolinopiperidinylbenzamide (A) reagents
SYNLETT 2009, No. 18, pp 3019–3023
x
x
.x
x
.2
0
0
9
Advanced online publication: 13.10.2009
DOI: 10.1055/s-0029-1218290; Art ID: S07509ST
© Georg Thieme Verlag Stuttgart · New York

3020
K. A. Milinkevich, M. J. Kurth
LETTER
O
O
OH
1. TFA, CH2Cl2
PhPMeBr
N
O
KOt-Bu, THF
2.
N
N
88%
NO2
OH
Boc
1
Boc
2
3
F
NO2
DIPEA, CH2Cl2
94%
Scheme 1 Synthesis of the trifunctional scaffold
4 (Figure 2) to carboxylic acid 3, which proceeded in which is generated in situ, reacting with the alkene prefer-
good to excellent yields (78–98%). The route to benz- entially rather than dimerizing.However, changing the or-
amides 5 could also be achieved by amidation of 4-fluoro- der of addition by adding a solution of the oxime to the
3-nitrobenzoic acid followed by the nucleophilic substitu- alkene and bleach increases dipole reaction with the al-
tion with the exomethylenepiperidine, but synthesis of the kene and thus minimizes dimerization. This modified ad-
trifunctional scaffold proved to be more efficient.
dition procedure using aryl oxime chemset 6 (Scheme 2)
delivered the sprioisoxazolinopiperdine 7 in moderate to
good yields (50–89%). It has been demonstrated that the
5,5-disubstituted isoxazoline is the major regioisomer
when reacting a nitrile oxide with a 1,1-disubstituted al-
kene.6,12a,15,16 Comparison of the proton NMR isoxazoline
methylene AB quartet in 7 to similar systems established
that, indeed, the 5,5-disubstituted regioisomer was ob-
tained.12a,16
With benzamide 5 in hand, introduction of the spiroisox-
azoline group proceeded via a nitrile oxide 1,3-dipolar cy-
cloaddition. Initial attempts involved the use of
hydroximoyl chlorides and triethylamine to form the reac-
tive nitrile oxide intermediate. Although product forma-
tion was observed, yields were not consistent. However,
the use of oximes and bleach, which is the most common
source for sodium hypochlorite, proved to be more reli-
able and consistently produced higher yields.
Installation of the final diversity element began with
tin(II) chloride mediated reduction of the arylnitro func-
tional group. Although literature protocols have shown
that treatment of an isoxazoline with metal-based reduc-
ing agents can cleave the N–O bond,17 we have shown the
isoxazoline moiety remains intact under tin(II) chloride
reducing conditions.15 Thus, the reduction of the arylnitro
group was performed in the presence of concentrated hy-
drochloric acid under refluxing conditions to yield the
arylamine in good yields (74–93%).18 The reduction was
sluggish until the addition of hydrochloric acid and, al-
though these conditions appear harsh, NMR revealed that
the isoxazoline and amide moieties remained unaffected.
Most commonly, the biphasic nitrile oxide 1,3-dipolar cy-
cloaddition reaction is performed by addition of bleach to
a solution of the alkene and oxime14 with the nitrile oxide,
4
O
O
R1
R1
NH2
OH
N
H
EDC, HOBt
CH2Cl2–DMF
N
N
NO2
NO2
3
5 {1–2}
O
R1
6
Finally, HOBt-mediated coupling of the aryl amine in 8
with carboxylic acids was attempted, but yields were poor
as this amine is relatively non-nucleophilic and too hin-
dered to attack the activated ester.
N
H
R2
N OH
SnCl2, HCl
MeOH
N
O
NaOCl
CH2Cl2
NO2
N
7 {1–2,1–2}
Fortunately, coupling with acyl chloride chemset 9
(Figure 2) provided amide 10{1–2,1–2,1–9} in good
yields (47–94%). Alternatively, a reductive amination
(Scheme 3) with aldehyde chemset 11 (Figure 3) provid-
ed amine 12{2,1–2,1–4} in moderate yields (48–62%).
Both of these diversification methods led to the targeted
spiroisoxazolinopiperidinylbenzamide library.
R2
O
R1
N
H
O
R1
N
9
O
O
NH2
N
R3
Cl
N
H
In summary, a route to novel spiroisoxazolinopiperidinyl-
benzamides has been developed leading to a 44-member
library.19 Key steps included EDC-mediated coupling of
amines, nitrile oxide 1,3-dipolar cycloaddition, arylnitro
reduction, and either acylation with acid chlorides or re-
ductive amination with aldehydes to give the trifunction-
alized heterocycle. The work presented here is in
R2
pyridine, THF
N
8 {1–2,1–2}
O
HN
O
N
R3
10 {1–2,1–2,1–9}
R2
Scheme 2 Preparation of the spiroisoxazolinopiperidinylbenzamide
library
Synlett 2009, No. 18, 3019–3023 © Thieme Stuttgart · New York

LETTER
Preparation of a Spiroisoxazolinopiperidinylbenzamide-Based Scaffold
3021
O
N
R1
H
N
O
HN
O
N
R3
10 {1–2,1–2,1–9}
R2
R1
R2
R3
//
//
//
//
O
//
Br
{1}
{2}
{1}
{2}
{1}
{4}
{7}
{8}
//
//
Br
//
//
O
//
{2}
{3}
{5}
{6}
Cl
//
//
NO2
Cl
//
Cl
{9}
Figure 2 Diversity inputs for the spiroisoxazolinopiperidinylbenzamide library
O
R1
O
R1
11
R3
O
N
H
N
H
H
N
N
O
O
NaBH3CN
AcOH, CH2Cl2
NH2
HN
N
N
R3
12 {2,1–2,1–4)
R2
R2
8 {2,1–2}
Scheme 3 Preparation of Set II arylamines
O
R1
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
N
H
N
O
HN
N
Acknowledgment
R3
R2
This work was supported by the National Science Foundation
(CHE-0614756) and the National Institute for General Medical Sci-
ences (GM076151). NMR spectrometers were funded in part by the
National Science Foundation (CHE-0443516 and CHE-9808183).
12 {2,1–2,1–4}
R1
{2}
R2
R3
//
//
//
//
References and Notes
Cl
{1}
{2}
{1}
{2}
{3}
{4}
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//
Br //
F
//
O
Figure 3 Additional diversity inputs for the spiroisoxazolinopiperi-
dinylbenzamide library
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ical Sciences (NIGMS) to create pilot-scale diversity li-
braries.
Synlett 2009, No. 18, 3019–3023 © Thieme Stuttgart · New York

3022
K. A. Milinkevich, M. J. Kurth
LETTER
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(19) Procedure for Olefin Synthesis: tert-Butyl 4-
Methylenepiperidine-1-carboxylate (2).
Methyltriphenylphosphonium bromide (35.86 g, 110.4
mmol) was dissolved in anhydrous THF (100 mL) and
cooled in an ice bath. Potassium tert-butoxide (1.0 M in
THF, 105.4 mL, 105.4 mmol) was added and the reaction
mixture was stirred at 0 °C for 30 min, then warmed to room
temperature for 30 min, and warmed to reflux for 1 h.
The reaction mixture was cooled in an ice bath and a solution
of N-Boc-4-piperidone (10.00 g, 50.19 mmol) in anhydrous
THF (50 mL) was added. The mixture was removed from the
ice bath and warmed to reflux until TLC showed the reaction
was complete (~4 h). The reaction mixture was diluted with
water, concentrated by rotary evaporation, and extracted
with EtOAc (3×). The combined organic layers were dried
over MgSO4, filtered, and concentrated by rotary
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evaporation. Purification by flash chromatography (EtOAc–
hexane, 1:9) gave 2 as a colorless oil (8.76 g, 88% yield). IR
(neat): 2977, 2940, 2907, 2865, 1692, 1652, 1416, 1365,
1235, 1165, 1114 cm–1; 1H NMR (300 MHz, CDCl3): d =
4.74 (s, 2 H), 3.42 (t, J = 5.7 Hz, 4 H), 2.18 (t, J = 5.7 Hz,
4 H), 1.47 (s, 9 H); 13C NMR (75 MHz, CDCl3): d = 154.9,
145.5, 109.2, 79.6, 45.5, 34.7, 28.6; MS (ESI): m/z = 198
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Petros, A. M.; Shoemaker, A. R.; Song, X.; Wang, X.;
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+
[C11H20NO2 ]. Purity was determined to be 89% by HPLC
analysis.
Procedure for Scaffold Synthesis: 4-(4-Methylene-
piperidin-1-yl)-3-nitrobenzoic Acid (3). tert-Butyl 4-
methylenepiperidine-1-carboxylate (2; 4.71 g, 23.9 mmol)
was dissolved in CH2Cl2 (50 mL) and trifluoroacetic acid (50
mL) was added. The reaction mixture was stirred at room
temperature for 2 h after which it was concentrated by rotary
evaporation. The residue was dissolved in CH2Cl2 (20 mL)
and triethylamine was added until the solution reached pH 8.
4-Fluoro-3-nitrobenzoic acid (2.21 g, 12.0 mmol) was
dissolved in a separate flask in CH2Cl2 (20 mL) and DIPEA
(8.33 mL, 47.8 mmol) was added at 0 °C. The mixture was
stirred for 30 min at which time the pH 8 solution of
deprotected amine was added dropwise and stirred overnight
while warming to room temperature. The reaction mixture
was concentrated by rotary evaporation, the crude oil was
dissolved in ethyl acetate and water, and the pH was adjusted
to pH ~3 with 1 M HCl. The layers were separated and the
aqueous layer was extracted with EtOAc (2×). The
combined organic layers were dried over MgSO4, filtered,
and concentrated by rotary evaporation. Purification by flash
chromatography (MeOH–CHCl3, 1:9) gave 3 as a bright
orange solid (2.95 g, 94% yield). A small portion of the
product was further purified for analytical purposes; mp
137–138 °C; IR (neat): 2949, 2905, 2854, 2168, 1676, 1600,
1526, 1491, 1428, 1388, 1348, 1293, 1264, 1231, 1206,
1160, 1127, 1065 cm–1; 1H NMR (600 MHz, DMSO-d6): d =
13.08 (s, 1 H), 8.28 (d, J = 1.8 Hz, 1 H), 8.00 (dd, J = 9.0,
1.8 Hz, 1 H), 7.34 (d, J = 9.0 Hz, 1 H), 4.81 (s, 2 H), 3.18 (t,
J = 5.4 Hz, 4 H), 2.32 (t, J = 5.4 Hz, 4 H); 13C NMR (150
MHz, DMSO-d6): d = 165.7, 148.1, 144.1, 139.0, 134.2,
127.8, 121.1, 120.5, 109.6, 51.7, 33.6; MS (ESI): m/z = 263
(15) Dixon, S. M.; Milinkevich, K. A.; Fujii, J.; Liu, R.; Yao, N.;
Lam, K. S.; Kurth, M. J. J. Comb. Chem. 2007, 9, 143.
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N.; Sottocornola, S. Org. Lett. 2006, 8, 4521.
+
[C13H15N2O4 ]. Purity was determined to be ~100% by
HPLC analysis.
Synlett 2009, No. 18, 3019–3023 © Thieme Stuttgart · New York

LETTER
Preparation of a Spiroisoxazolinopiperidinylbenzamide-Based Scaffold
3023
General Procedure for Amine Coupling to 5{1–2}.
The resulting oil was dissolved in CH2Cl2 (10 mL) and water
(10 mL) and the mixture was adjusted to pH ~7 with 1 M
NaOH. The layers were separated and the aqueous layer was
extracted with CH2Cl2 (2×). The combined organic layers
were dried over MgSO4, filtered, and concentrated by rotary
evaporation. Purification by flash chromatography (EtOAc–
hexane) gave 8{1–2,1–2} in 74–93% yield.
Compound 3 (1 equiv), HOBt (1.4 equiv), and EDC (1.4
equiv) were dissolved in a mixture of CH2Cl2–DMF (4:1, 50
mL) at 0 °C and stirred for 30 min. The requisite amine (1.8
equiv) was added dropwise and the solution was stirred
overnight while warming to room temperature. The resulting
solution was concentrated by rotary evaporation and taken
up in EtOAc (50 mL). The solution was then extracted with
saturated aq. NaHCO3 (50 mL), 1 M HCl (50 mL), water (50
mL), and brine (50 mL). The organic layer was dried over
MgSO4, filtered, and concentrated by rotary evaporation.
Purification by flash chromatography (EtOAc–hexane) gave
5{1–2} in 78–98% yield.
General Procedure for Isoxazoline Synthesis to give 7{1–
2,1–2}. Compound 5{1–2} (1 equiv) was dissolved in
CH2Cl2 (5 mL) and bleach (laboratory grade, 5.65%, 4
equiv) was added at 0 °C. A solution of the requisite oxime
6{1–2} (2 equiv) in CH2Cl2 (5 mL) was added via addition
funnel to the reaction mixture. The resulting solution was
stirred overnight. Water (20 mL) and CH2Cl2 (20 mL) were
added and the layers were separated. The organic layer was
extracted with water (2×) and the combined organic layers
were dried over MgSO4, filtered, and concentrated by rotary
evaporation. Purification by flash chromatography (EtOAc–
hexane) gave 7{1–2,1–2} in 50–89% yield.
General Procedure for Acid Chloride Coupling to give
10{1–2,1–2,1–9}. Compound 8{1–2,1–2} (1 equiv) was
dissolved in anhydrous THF (5 mL) and pyridine (1.5 equiv)
was added. The solution was cooled to 0 °C and the requisite
acid chloride (1.2 equiv) was added dropwise. The mixture
was stirred overnight, after which time TLC showed the
reaction was complete. Water (5 mL) and diethyl ether (5
mL) were added and the solution was adjusted to pH ~7 with
1 M NaOH. The layers were separated and the aqueous layer
was extracted with diethyl ether (2×). The combined organic
layers were dried over MgSO4, filtered, and concentrated by
rotary evaporation. Purification by flash chromatography
(EtOAc–hexane) gave 10{1–2,1–2,1–9} in 47–94% yield.
General Procedure for Reductive Amination to give
12{2,1–2,1–4}. Compound 8{2,1–2} (1 equiv) was dissolved
in CH2Cl2 (5 mL) and the requisite aldehyde (1.5 equiv) and
acetic acid (4 equiv) were added. The solution was stirred for
6 h after which time sodium cyanoborohydride (5 equiv) was
added. The mixture was stirred overnight, concentrated by
rotary evaporation, and taken up in ethyl acetate (10 mL).
The organic layer was washed with saturated aq. NaHCO3,
1M HCl, and brine. The organic layer was dried over
MgSO4, filtered, and concentrated by rotary evaporation.
Purification by MPLC gave 12{2,1–2,1–4} in 48–62% yield.
General Procedure for Aryl Nitro Reduction to give 8{1–
2,1–2}. Compound 7{1–2,1–2} (1 equiv) and tin(II) chloride
dihydrate (3 equiv) were dissolved in MeOH (10 mL) and
stirred for 10 min. Concentrated HCl (6 equiv) was added
dropwise and the mixture was warmed to reflux until TLC
showed the reaction was complete. The solution was cooled
to room temperature and concentrated by rotary evaporation.
Synlett 2009, No. 18, 3019–3023 © Thieme Stuttgart · New York

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