Reductive cleavage of isoxazole

Hydroxy ketone
Direct
N–O Cleavage reactions of heterobicycloalkene-fused 2-isoxazolines

Table 3: Effects of bridgehead substitution on Raney Ni/AICI3 mediated cleavage of 7-oxabenzonorbornadiene-fused 3-methyl-2-isoxazolines.

Y Raney Ni/AICI3 Y
\/N OH Me
Y R1 0 51522 THF/MeOH/H20 Y R1
X 0-5 ‘'0 X
10a,f—k 16a,f—k

General Procedures

Cleavage of Symmetrical 2-isoxazolines 10a-e (Table 2, entries 1-5); 17 and 19 (Scheme 4).

In a similar manner to our recent publication,4 methanol (25.0 mL) and distilled water (5.0 mL)

was added to an oven—dried flask containing the isoxazoline (102 mg, 0.5 mmol), and the mixture

was cooled to 0-5 “C. AlCl3 (200 mg, 1.5 mmol) was added to the cold solution in one portion

and maintained for 15 minutes. Raney-nickel (1.2 g) was added and the reaction was stirred for 4

hours. The solution was filtered through Celite, the filter cake was washed with methanol, and

the solvent was then removed by rotary evaporation. The organic mixture was extracted with

dichloromethane, dried over sodium sulphate and reconcentrated. Afier addition of hexanes (3-5

mL), the crude product was allowed to stir at room temperature for 30 minutes and was then

filtered to afford pure B—hydroxyketone (95 mg, 0.465 mmol, 93%) as a white solid.

Cleavage of Unsymmetrical 2-isoxazolines 10f-k (Table 3, entries 2-7); 18a-b (Scheme 4).

Following the above General Procedure, THF was added as a co-solvent of varying quantities:

For every 0.15 mmol of isoxazoline 10f-k, the relative solvent ratio was modified to 515:2

(THF:MeOH:water) using THF (5 mL), MeOH (5 mL), and distilled water (2 mL). For every

0.15 mmol of isoxazolines 18a-b, the solvent ratio was modified to l5:5:2 with THF (15 mL),

MeOH (5 mL) and distilled water (2 mL).

Synthesis of Functionalized Benzopyrans via Intramolecular 1,3-Dipolar Cycloaddition of
Nitrile Oxides

0 O
‘elk (CH1)nCO1MC Rcncy ..*!L(CH2)»1CO2Me
AlCl3 It

R CH3OH—H2O R '

N—O 0 OH
ITIX \ Renev Ni. AICI. X‘XVI

Methyl 15-hydroxy-7,13-dioxo-9,11-ethan0—l5-
R—prostanates (X, XlII—XVl). To a solution of
1mmol of isoxazolinoprostanoid I—IX in 6 ml of a
mixture methanol—water, 5:1, was added by small
portions 600 mg of AlCl3 and 500 mg of Raney Ni.
The suspension was stirred for 24 h. The reaction
mixture was dissolved in a two—fold volume of
chloroform, filtered through a glass frit, then 1/3 of
water volume was added thereto. The methanol and
chloroform were distilled off in a vacuum. The
hydroxyketone was thrice extracted with chloroform
from the water residue, the extract was dried on
MgSO4, the solvent was distilled off in a vacuum.
The residue was subjected to column chromatography
on silica gel at gradient elution with ether—hexane
mixture.

Molybdenum-Mediated One-Pot Synthesis of Pyrazoles from Isoxazoles

Table 1 Optimization of the Mo-Based N—O Bond Cleavage and In Situ

Hydrolysis of the B-Amino Enonea

O—N OH O
\ \ \
[M0]
acid la: Mo(C0)5
lb: Mo(CO)3(CH3CH2CN)3
solvent, T “G Ic: Mo(CO)4(CH3CN)2
15 h Id: Mo(CO)3(cyc|oheptatriene)

13 2a
 Preparation of 3-(4-Isopropylphenyl)pentane-2,4-dione (2a)
A microwave vial equipped with a magnetic bar was charged with
isoxazole 1a (0.5 mmol, 1 equiv), THF/H20 (3:1, 2 mL) and 1 M HCl
(0.75 mmol. 1.5 equiv). [Mo] Id (0.25 mmol, 0.5 equiv) was added and
the vial was sealed. The reaction mixture was vigorously stirred and
heated at 70 °C for 16 h. The reaction mixture was cooled to r.t., and
concentrated under reduced pressure. The crude material was puri-
fied by flash chromatography (KP—Sil, 0-1 0% Et0Ac in heptane) to give
2a.

Reduction of ∆2-Isoxazolines to -HydroxyKetones with Iron and Ammonium Chloride as

Reducing Agent

)NLO%R
2 T»
Fe. NH4C| U
R, EtOHlH2O, so °c R1 R2

General Procedure for the Reduction of A3-Isoxazolines to

,3-Hydroxy Ketones with Fe/NH4Cl as Reducing Agent. To a
stirred solution of A3—isoxazoline la (lb-l, 0.3 mmol) and NH4C|
(161 mg. 3 mmol) in ethanol and water (121. 15 mL) was added
Fe powder (168 mg. 3 mmol). The mixture was heated to 80 °C
and was allowed to stir at this temperature for 6 h. The reaction
mixture was cooled to room temperature. diluted with ethyl acetate.
and filtered through a silica pad. The filtrate was washed with brine.
and the organic layer was separated. dried over MgSO4. and
evaporated in Vacuo. The residue was then purified by flash chro-
matography on silica gel to give the desired product 2a (2b—l).

N–O Cleavage reactions of heterobicycloalkene-fused2-isoxazolines

Table 3: Effects of bridgehead substitution on Raney Ni/AICI3 mediated cleavage of 7-oxabenzonorbornadiene—fused 3-methyl-2-isoxazolines.

X 0 Me X 0 O
Y \ Raney Ni/AICI3 Y

Y 0 /N 5.5.2 THF/MeOH/H20
. .

Y OH Me
X R‘ 0-5 °c X R‘
10a.f—k 16a,f—k
 General Procedures

Cleavage of Symmetrical 2-isoxazolines 10a-e (Table 2, entries 1-5); 17 and 19 (Scheme 4).

In a similar manner to our recent publication,4 methanol (25.0 mL) and distilled water (5.0 mL)

was added to an oven-dried flask containing the isoxazoline (102 mg, 0.5 mmol), and the mixture

was cooled to 0-5 °C. AlCl3 (200 mg, 1.5 mmol) was added to the cold solution in one portion

and maintained for 15 minutes. Raney-nickel (1.2 g) was added and the reaction was stirred for 4

hours. The solution was filtered through Celite, the filter cake was washed with methanol, and

the solvent was then removed by rotary evaporation. The organic mixture was extracted with

dichloromethane, dried over sodium sulphate and reconcentrated. After addition of hexanes (3-5

mL), the crude product was allowed to stir at room temperature for 30 minutes and was then

filtered to afford pure B—hydroxyketone (95 mg, 0.465 mmol, 93%) as a white solid.

Cleavage of Unsymmetrical 2-isoxazolines 10f-k (Table 3, entries 2-7); 18a-b (Scheme 4).

Following the above General Procedure, THF was added as a co-solvent of varying quantities:

For every 0.15 mmol of isoxazoline 10f-k, the relative solvent ratio was modified to 5:522

(THF:MeOH:water) using THF (5 mL), MeOH (5 mL), and distilled water (2 mL). For every

0.15 mmol of isoxazolines 18a-b, the solvent ratio was modified to 152522 with THF (15 mL),

MeOH (5 mL) and distilled water (2 mL).

Methods for the Conversion of Isoxazolines to B-Hydroxy Ketones

 Since a1uminum(III) is known to catalyze imine hydrolysis, and since
aluminum chloride undergoes hydrolysis to release HC1, we have furthermore examined
in greater detail a catalyst system comprised of W—2 Raney nickel and AlCl3
(4 equiv) in methanol and water (5:1) Reduction occurred cleanly and in high
.

yield with all seven isoxazolines displayed in the Table.5 we zthua Auggut that the
pnuemt ccbtalyét ayutcmr would be one as the rum: to be aorbsidmed when the conveluion 05
Lsoxazotiéne to B-hyd/Loxy hetone IA !L€qu»Ul€d.6

Idirect
Reductive Ring Opening of 3,5-Bis(2-arylethenyl)isoxazoles with Molybdenum
Hexacarbonyl: A Novel Route to Symmetrical and Unsymmetrical Curcumin Derivatives

Ar‘ Ar2 c°nc- HC| Ar‘ Al‘2

0 NH2 pH 4-5, 45 °C 0 OH
24 h
1a;Ar1 = CSH5, Ar2 = CGH5, 52%
1b; Ar‘ = 4-OMeC5H4, Ar2 = 4-OMeC5H4, 63%
1c; Ar‘ = 3,4—diOMeC5H3, Ar? = 3,4—diOMeC5H3, 49%
1d; Ar‘ = 4—OMeC6H4, Ar? = C6H5, 48%
1e; Ar‘ = 3,4—diOMeC5H3, Ar2 = CSH5, 51%
1f; Ar‘ = 3,4-diOMeC6H3, Al'2 = 4-OMeC6H4, 52%

Scheme 6:

General procedure for hydrolysis of 5-amino-1 ,7-

diaryl-1,4,6-heptatrien-3-ones 8a-f
To a stirred solution of 5-amino-1-ary|-
1,4—hexadien—3—one (0.1 mmol) in ethanol (1.5 ml)
was added concentrated HCI dropwise to adjust
the pH between 4 and 5. The solution was then
stirred at 50°C. After 24 hours,the reaction mixture
was neutralized with a saturated KZCOS solution.
 The aqueous layer was extracted with diethyl ether
(3 x 25 mL). The combined organic layer was
dried (Na2SO4) and concentrated under reduce
pressure. Purification of the residue using column
chromatography on silica gel with a gradient of
30-50% ethyl acetate/hexane as eluent gave 1-aryl-
5-hydroxy-1,4-hexadien-3-ones 1a-f (48-63%) as
crystalline solids.

Straightforward transformation of isoxazoles into pyrazoles: renewed and improved

amino ketone

Ph Ph
N2H4, Ni _

Ph
/ ,N
\ e»
MeOH, A Ph
NH
2
0 o
68%
1h 3

4.4.1. 3,5-Diphenylpyrazole (2h). 3,5—Diphenylisoxazole

(Ih) (22 mg, 0.1 mmol) and hydrazine hydrate (0.08 mL)
were stirred in MeOH (0.5 mL) in the presence of Raney
nickel (~20 mg). The reaction was slow, so the mixture
was heated to 60 °C for 1 h, which led to complete conver-
sion of the starting material (TLC). The mixture was then
kept at ambient temperature for 3 days, which did not lead
to changes in its composition. Column chromatography
(CH2Cl2 as an eluent) gave 15 mg (68%) of 3-amino-l,3—di—
phenylprop—2—en—l—one (3) as a yellow oil. Rf (3% MeOH/

amino alcohol
Synthesis of Functionalized Benzopyrans via Intramolecular 1,3-Dipolar Cycloaddition of
Nitrile Oxides

N/o NH2 OH NHAc

’ L. Cf]? _<i>-©ffi”oAc
o O O
1 11 12

Scheme 3. Reagents and conditions: (i) LAH, Et3O, A; (ii) A020, 13, rt.
 (4-Amino-2,3-dihydro-4H-benzopyran-3-yl)methanol II

A solution of isoxazoline, l (0.17 g, lmmol), in anhydrous diethyl ether

(7.5 mL) was added drop wise at rt under N2 to lithium aluminium
hydride (LAH) (0.08 g, 2.2 mmol) suspended in 2.5 mL of anhydrous
ether. The mixture was refluxed for 8 h, cooled, and quenched with cone.
sodium sulphate (dropwise). The reaction mixture was extracted with
ether (four times). The organic extracts were combined, dried over
sodium sulphate, and evaporated to yield crude amino alcohol. The pro-
duct was purified by column chromatography on silica gel to afford a
liquid (0.15 g, 84%); IR (CHCI3): u,m,,( 3685, 3345, 3200, 2400, 1216,
771cm-‘= ‘H NMR (300MHz, CDCI3): 5 7.20-7.14 (t, J=8.1Hz,
2H), 6.93-6.88 (t, J: 7Hz, 1H), 6.85-6.82 (d, J: 8.1 Hz, 1H) [4.25—
4.22 (m), 4.13-4.12 (cl, J: 4.2 Hz), 4.07-4.02 (dd, J 3.6Hz, 11Hz), =

4H] 3.88-3.83 (dd, J: 5.1 Hz, 11Hz, 1H), 2.77 (s, 3H), 2.18-2.12 (m,
1H) ppm; “C NMR (75 MHz, CDCI3): 5 153.87, 129.51, 128.65,
126.25, 120.51, 116.75, 63.55, 60.95, 47.28, 39.20 ppm; MS: M+ 179.

A one-pot synthesis of 3-trifluoromethyl 2-isoxazolines from trifluoromethyl aldoxime

_ .....__.........J. _ ._-..__-....-- ._ _.._ ._.

F C/E-3\R NaBH4_ NiC|2 NH2 OH

3 THF/MeOH FaC R
1 -42 “C to rt, 24 h 7

.I....A....a... .........I....A :....I...:....I .

~———a~—u—.:- —-— ---—— ~— ~--—:-av-—~ -———~——~vv—:-—-——:—

General Procedure for the synthesis of amino alcohols:

Synthesis of 4-amino-5,5,5-trifluoro-1-phenylpentan-2-ol 7a: NiClz.6H2O (0.620 g, 2.62 mmol, 3 eq.)

and 5-benzyl-3-(trifluoromethyl)-4,5-dihydroisoxazole (300 mg, 1.31 mmol, 1 eq.) were dissolved in 3:1

mixture of MeOH/ THF at -42°C. After 10 min of stirring, NaBH4 (O.495g, 2.618 mmol, 10 eq.) was upon

with the reaction, the mixture immediately turned black. After 3 days The mixture was concentrated in

vacuo and the residue was purified by flash column chromatography (DCM/MeOH); white solid, 154 mg,

50%, mp 88-90°C; 1H NMR (400 MHz, CDCI3) 5 Syn: 7.34-7.21 (m, 5H), 4.1 (m, 1H), 3.36 (m, 1H), 2.87
(dd, J= 4.0, 12.0 Hz, 1H), 2.74 (dd, J= 8.0, 12.0 Hz, 1H), 1.88 (m, 1H), 1.46 (m, 1H). Anti: 7.3-7.2 (m,

5H), 4.184.15 (m, 1H), 3.55 (m, 1H), 2.81 (d, J: 8.0 Hz, 2H), 1.80 (1H, m), 1.62 (1H, m), BC NMR (100
MHZ, CDCI3) 5 129.6, (129.5), 128.8 (128.6), 126.8 (126.6), 72.9, 68.8, 54.5 (q, J : 30.0 Hz) (50.6 (q, J=
29.4 Hz), 44.3 (44.1), 35.1 (34.2), CF; n.o. . 19F (188 MHz, CDC13) 6 -77.2 (d, J= 7.4 Hz), -77.9 (d, J= 7.1
Hz). Anal. Calcd for C11H]4F3NO: C, 56.65 ; H, 6.05 ; N, 6.01 .Found C, 56.71 1 ; H, 6.12 ; N, 5.95.
A New Method for Stereoselective Homoallylic Amine Synthesis

n‘ n‘
4 5

Wale 1. ate
2-|4Hl

" 9H NH, 9 OH NH,

Ph,P ‘ Pnzp
R’ R’
R‘ n‘

Method for Reduction of 4,5-Di/1ydroisoxaz0Ies.——NaBH4 (5

equiv.) was added portionwise to a stirred solution of the 4,5-
dihydroisoxazole 4 or S (1 equiv.) and NiCl2-6H20 (2 equiv.) in
MeOH (30 cm’ per mol of the 4,5—dihydroisoxazole) at
— 30 °C under N2 or Ar, and the mixture stirred for 5~l0 min.
The Me0l-I was removed under reduced pressure (CARE—it
often bumps) and cone. aqueous NH 3 (d 0.88, 30 cm’ per mmol
of 4,5-dihydroisoxazole) and CHZCIZ (an equal volume) were
added to the residue; the mixture was then stirred exposed to
the air until the organic layer was a pale yel|ow—brown. The
mixture was separated and the aqueous layer extracted with
CH2Clz (3 x the same volume as before). The combined
organic layers were dried (NazSO‘) and evaporated under
reduced pressure to give the crude reaction product.

Enantiomerically Pure Sul phi nyl-4,5-d i hyd roisoxazoles. Part 1 . Stereocontrolled

Synthesis of Optically Active p-Ketols and y-Amino Alcohols
NH 2 OH R2

Me R3

W
H R‘
‘V’ (m—ne)

Nro R2
li).(”) .
9| N| O R’
Me 1 R3 P‘MeC5H,.“:'ls\/S81<R3
H R ' H R

(1)—(5) (70,b)—(l20.b)

0 OH R2

Me R3
1
H R

(13)
 Synthesis of y-Amino Alcohols (l4)—(l6).—Reductions with
LiAlH4 were carried out as described by J5ger,9 with a 3:1
reducing agent: substrate molar ratio in ether. Yields, isomer
ratios and optical rotations are reported in Table 3. Reductions
with zinc or sodium borohydride in the presence of nickel(u)
chloride were carried out as follows. To a methanol (15 ml)
solution of NiCl2-6H2O (0.475 g, 2 mmol) and sulphinyl-
isoxazoline (1 mmol), Zn(BH_,), (0.16 M in ether; 4 mmol, 25 ml)
or NaBH,, (0.190 g, 5 mmol) was added portionwise at —— 30 °C.
After being stirred for 3 h the reaction mixture was concentrated
under reduced pressure. To the resulting residue concentrated
aqueous ammonium hydroxide (20 ml) was added and the
aqueous layer extracted twice with dichloromethane. Evapor-
ation of the organic solvent gave the crude products which were

Chemical Transformations of 9,11-Ethano-13,15-isoxazolinoprostanoids

0
(CH:)nCO3Me

R CH
N—O

FIX Ren
NiSO4—NaBI-I4 '

(CH2)nCO3Mc

NH, OH

Methyl 13-amino-15-hydroxy-7-oxo-9,11-ethano-
15-R—prostanates (XXIV, XXV). To a solution of
0.5 mmol of isoxazoline and 0.5 mmol of NiSO4 in
10 ml of methanol cooled to —25°C was added
2.5 mmol of sodium borohydride. In 15 min the cool-
ing was removed, and the mixture was stirred for 1 h.
Then 10 ml of 25% aqueous ammonia was added, the
product was extracted into ether, the extract was
dried on Na2SO4, the solvent was evaporated, the
residue was subjected to chromatography on plates or
column charged with silica gel, elution with a mixture
chloroform—methanol, 20: 1.

SYNTHESES VIA ISOXAZOLINES III.DIASTEREOSELECTIVE SYNTHESIS OF

T-AMINO-ALCOHOLS WITH 2 AND 3 CHIRAL CENTRES 2
 R201-R3=H Q-I.
Experimental procedure, f- aminoalcohols 5 from isoxazolines 3:
10 mmol ofg in abs. ether are added with stirring to an ice-cold mixture of 10-14 mmol
of LiAll-I4 in ether (30-100 ml total depending on the solubility of E). Complete reaction
(I. e. 3. 5 h of reflux with ff, 8 h at 0°C with 13) is assured by TLC control. Per g of LiAll-I4
used, 1 ml of water, 0. 75 ml of a 20% NaOH solution and 3. 5 ml of water are then added
slowly. The solids are filtered off and washed carefully with ether, then CHCI3 or extraxted
with CHCI3 in a soxhlet apparatus. The organic solutes are combined, dried (Na2SO4) and
evaporated. The residue is distilled or crystallized (from benzene/pentane or cyclohexane/
pentane) and dried (P205). - Aminoalcohols 3 readily absorb CO2; they should further be
stored and handled with exclusion of water and oxygen.

Synthesis of Unsymmetrically 4-Substituted 2,2'-Bipyridines.

\ Fl
38 R = CH3 LiA|H4 N/
3!) R = Ph 11.":
NH2 OH OH

48 R = CH3
4b R = Ph

Scheme 3
21_ Typical procedure: Lithium aluminium hydride (0.77 g. 20 mmol) was suspended in THF (15 ml).
cooled to 0°C. and to this was added dropwise 5-(2-hydroxyethy])-5-methyl-3—(pyrid-2~yl)-A3-
isoxazoline 3a (1.05 g, 5.1 mmol) in THF (15 ml). The reaction mixture was stirred for 4 hr at 0°C and
then allowed to stand overnight at —15°C. Saturated sodium sulphate solution (1.5 ml) was added and
the suspension was filtered. The precipitate was washed with dichloromethane (50 ml) and the com-
bined filtrates were dried (MgSO.) and concentrated under reduced pressure to give a yellow oil. The
crude product was purified by column chromatography on silica using methanol as eluent to give 2-( 1-
amino-3,5-dihydroxy-3-rneKhylpentyl)-pyridine 42 as a pale yellow oil (0.78 g, 74%).

Synthesis of a 1,3-spiro-amino-alcohol-derived chiral auxiliary and its application to Diels–

Alder reactions

-0 H2
/ LiAlH‘, THF, rt 3

H
(zt)-1 0 (:I:)-1 1

3.4. Synthesis of amino alcohol (2)-11

(:t)-10 (1.13 g, 7.45 mmol) in THF (15 ml) was added to

a suspension of LiAlH4 (380 mg, 10.0 mmol) in THF
(15 ml) at 0°C, warmed to 22°C and stirred for 15 h.
The grey suspension was cooled to 0°C and quenched
with NaOH(,,q, (10%, 5 ml). Upon warming to room
temperature, enough NaOH(.,,q, (10%, ~100 ml) was
added to dissolve Al salts. Extraction with Et2O (3x75
ml), washing with brine (75 ml), drying over Na2S04
and concentration in vacuo gave (:)-11 as a white waxy
solid (1.00 g, 6.43 mmol, 86.3%): bp 45°C/0.2 Torr; IR
(film)v,,,,x 3280, 2953, 2865, 1575, 1455, 1377, 1328,
1306, 1157, 1092, 1048, 996, 948, 907, 818 cm“; ‘H
NMR (200 MHz, CDCI3): 5 4.12402 (m, 1H), 3.28 (t,
J=6.3 Hz, 1H), 2.83 (br s, 3H), 2.14-1.21 (m, 12H); “C