Synthesis of Δ2-isoxazoline fatty acid ester heterocycles

Article abstract of DOI:10.1007/s11746-001-0386-9

Fatty ester Δ²-isoxazoline heterocycles were prepared in good yields and excellent regioselectivity from 1,3-dipolar cycloaddition reactions between methyl 10-undecenoate and nitrile oxides. This methodology provides convenient access to the methyl esters of margaric (4b) and stearic (4c) acids in 63-66% yield that contain the isoxazoline heterocycle between C-10 and C-12. These fatty heterocycle compounds are synthesized in a one-pot sequence in which methyl 10-undecenoate is used to trap the reactive nitrile oxide intermediates that are generated by reacting aldoximes with aqueous sodium hypochlorite and a catalytic amount of triethylamine or by directly reacting hydroximic acid chlorides with a stoichiometric amount of base. The fatty ester Δ²-isoxazoline heterocycles represent a versatile synthon that may be useful to obtain oleochemicals with potentially new and interesting properties not easily accessible by other methods.

Full text of DOI:10.1007/s11746-001-0386-9

Synthesis of ∆2-Isoxazoline Fatty Acid Ester Heterocycles
James A. Kenar* and Sevim Z. Erhan
USDA, ARS, NCAUR, Oil Chemical Research, Peoria, Illinois 61604
ABSTRACT: Fatty ester ∆2-isoxazoline heterocycles were pre-
trapped by olefins, and recently a simple procedure was re-
ported in which water-insoluble aldoximes are reacted with
sodium hypochlorite (household bleach) under biphasic con-
ditions (11). This methodology represents a practical entry into
∆2-isoxazolines because the starting materials needed are gen-
erally inexpensive and readily available, and importantly, the
simplicity of the reaction allows it to be readily scaled up.
The straightforward synthesis of ∆2-isoxazolines from ni-
trile oxides and their potentially interesting properties cou-
pled with their synthetic versatility make them an interesting
class of compounds that have potential industrial or biologi-
cal applications. Herein, we now report an initial study fo-
cused on the synthesis of long-chain fatty ester ∆2-isoxazo-
line heterocycles made by reacting methyl 10-undecenoate
with various nitrile oxides generated in situ from readily ob-
tainable aldoxime or hydroximic acid chloride precursors.
pared in good yields and excellent regioselectivity from 1,3-
dipolar cycloaddition reactions between methyl 10-unde-
cenoate and nitrile oxides. This methodology provides conve-
nient access to the methyl esters of margaric (4b) and stearic
(4c) acids in 63–66% yield that contain the isoxazoline hetero-
cycle between C-10 and C-12. These fatty heterocycle com-
pounds are synthesized in a one-pot sequence in which methyl
10-undecenoate is used to trap the reactive nitrile oxide inter-
mediates that are generated by reacting aldoximes with aque-
ous sodium hypochlorite and a catalytic amount of triethyl-
amine or by directly reacting hydroximic acid chlorides with a
stoichiometric amount of base. The fatty ester ∆2-isoxazoline
heterocycles represent a versatile synthon that may be useful to
obtain oleochemicals with potentially new and interesting prop-
erties not easily accessible by other methods.
Paper no. J9890 in JAOCS 78, 1045–1050 (October 2001).
KEY WORDS: Aldoximes, 1,3-dipolar cycloaddition, hydrox-
imic acid chlorides, ∆2-isoxazolines, methyl 10-undecenoate,
nitrile oxides.
EXPERIMENTAL PROCEDURES
Materials. Methyl 10-undecenoate was prepared by the ester-
ification of 10-undecenoic acid (Kodak, Rochester, NY) in
methanol using a catalytic amount of anhydrous HCl and was
purified by Kugelrohr distillation (12). Acetaldoxime (1a)
and syn-benzaldehyde oxime (1e) were purchased from
Aldrich Chemical Co. (Milwaukee, WI). The oximes of hexa-
nal (1b), heptanal (1c), octanal (1d), purchased from Lan-
caster Chemical Co. (Lancaster, PA), and trimethylacetalde-
hyde (1f), Aldrich Chemical Co., were prepared by the
method of Bousquet (13). The oximes were recrystallized
from ethanol/water and were dried in vacuo before use. Ethyl
and methyl chlorooximidoacetates, 6g and 6h, were prepared
according to the method reported by Kozikowski and Adam-
czyk (14). The materials were recrystallized from hexane
dried under vacuum and used directly in the reactions.
Sodium hypochlorite (10–15%) was purchased from Aldrich
Chemical Co. Methylene chloride and chloroform were ob-
tained from EM Science (Gibbstown, NJ). The chloroform
was freshly distilled, to remove traces of H2O, from anhy-
drous potassium carbonate before use. All other solvents were
obtained from Fisher Scientific Co. (Fairlawn, NJ) and were
used without further purification. Unless otherwise noted, all
other chemicals were purchased from Aldrich Chemical Co.
and were used without further purification.
The 1,3-dipolar cycloaddition reaction between nitrile oxides
and alkenes has been known for many years, and it provides
convenient access to the complex five-membered heterocyclic
ring system known as isoxazolines (1, an excellent review of
nitrile oxide chemistry). Recently, interest in ∆2-isoxazolines
has increased markedly because of reports describing their
pharmacological properties (2,3) and because ∆2-isoxazolines
represent a synthetically versatile intermediate that readily
undergoes further transformations, e.g., alkylation (4), dehy-
drogenation to isoxazoles (5), or reductive cleavage to expose
functionality such as β-hydroxy ketones, α,β-unsaturated ke-
tones (6), or γ-amino alcohols (7).
Because nitrile oxides are highly reactive intermediates and
dimerize readily to furoxans, they are usually generated in situ
and trapped in the presence of olefinic substrates. The two
most widely used routes to prepare isoxazolines by trapping
nitrile oxides with alkenes are: (i) the Mukaiyama (8) method
(or a variation thereof) in which primary nitroalkanes are
reacted with a dehydrating agent such as aryl isocyanates and
(ii) dehydrohalogenation of hydroximic acid chlorides ob-
tained by reacting aldoximes with a halogenating agent such
as N-chlorosuccinimide (9) or chlorine (10). The aldoxime
route is a convenient method to generate nitrile oxides to be
Melting points. Melting points were determined on a
Fisher Johns melting point apparatus and are uncorrected.
*To whom correspondence should be addressed at USDA, ARS, NCAUR,
1815 N. University St., Peoria, IL 61604.
E-mail: kenarja@mail.ncaur.usda.gov
Nuclear magnetic resonance (NMR). H NMR and 13C
1
NMR spectra were recorded using a Bruker ARX 400
Copyright © 2001 by AOCS Press
1045
JAOCS, Vol. 78, no. 10 (2001)

1046
J.A. KENAR AND S.Z. ERHAN
spectrometer (Billerica, MA) with a 5-mm dual proton/car- based on its calculated concentration and the equivalents
bon probe (400 MHz 1H/100.61 MHz 13C) using CDCl3 as desired.
the solvent in all experiments.
Representative procedure for the synthesis of ∆2-isoxazo-
Fourier transform infrared. Infrared (IR) spectra were ob- lines from methyl 10-undecenoate and syn-benzaldehyde oxime
tained using a PerkinElmer (Norwalk, CT) Spectrum RX FT- using sodium hypochlorite. To a vigorously stirred mixture of
IR system as either a film on NaCl plates (liquids) or in a KBr methyl 10-undecenoate (3.51 g, 17.7 mmol), triethylamine
matrix (solids).
(250 µL, 1.79 mmol), CH2Cl2 (20 mL), and aqueous sodium
Gas chromatography (GC). GC was performed with a hypochlorite (12.6%, 19.0 mL, 38.6 mmol) at 2°C, a solution
Hewlett-Packard 5890 Series II gas chromatograph (Palo of benzaldehyde oxime (2.28 g; 18.3 mmol) in CH2Cl2 (10 mL)
Alto, CA), equipped with a flame-ionization detector and an was added dropwise (25 min) at a rate to maintain the tempera-
autosampler/injector. Analyses were conducted on an HP- ture below 5°C. The mixture was stirred at <10°C for 2 h and
5MS capillary column, 30 m × 0.25 mm i.d. (Hewlett- then stirred at room temperature (rt) for an additional 2 h. The
Packard). The column flow was 1.0 mL/min with helium head reaction phases were separated, and the aqueous phase was ex-
pressure of 15 psi (776 torrs); split ratio of 75:1; programmed tracted with CH2Cl2 (3 × 20 mL). The combined CH2Cl2 ex-
ramp 100°C, for 2 min, ramp 100–210°C at 20°C/min, 210 to tracts were dried (MgSO4), and the solvent was removed under
250 at 10°C/min, hold 20 min at 250°C; injector and detector reduced pressure to give 5.62 g of a light yellow solid (100%).
temperatures set at 280°C.
One recrystallization from methanol gave 4.24 g of 4e as white
GC/mass spectrometry (MS). GC/MS analyses were con- crystals (75%), m.p.: 59–60°C.
ducted using a Hewlett-Packard 5890 Series II Plus GC [col-
1H NMR of 5-(9-methyl nonanoate)-3-phenyl-∆2-isoxa-
umn: HP-5MS column (30 m × 0.25 mm i.d.); Hewlett- zoline (4e): δ 7.70–7.66 (m, 2H, aromatic H), 7.44–7.40
Packard Co.] coupled with a Hewlett-Packard 5989B mass (m, 3H, aromatic H), 4.75–4.72 (m, 1H, CH2–HC(O)–CH2),
spectrometer using a mass range of 50–550 amu. Electron 3.68 (s, 3H, –OCH3), 3.40 (dd, 1H, J = 16.4 and 10.3
ionization (EI) was performed at 70 eV, while positive chem- Hz, –(O)CH–CH2–C(=N)–), 2.98 (dd, 1H, J = 16.4 and 8.2
ical ionization (CI) used methane as reagent gas. GC condi- Hz, –(O)CH–CH2–C(=N)–), 2.32 (t, 2H, J = 7.5 Hz,
tions: helium head pressure 3 psi (155 torr); injector tempera- CH2–CH2–COOMe), 1.9–1.3 (m, 14H, alkyl chain H). 13C
ture set at 250°C; transfer line temperature set at 280°C; pro- NMR: δ 174.2 (C=O), 156.3 (C=N), 130.0 (aromatic C), 129.8
grammed ramp 100°C for 2 min, 100–210°C at 20°C/min, (aromatic C), 128.6 (aromatic C), 126.6 (aromatic C), 81.4
210–270°C at 10°C/min, hold 20 min at 270°C.
(CH2–HC(O)–CH2), 51.3 (O–CH3), 39.9, 35.3, 34.1, 29.3,
Thin-layer and column chromatography. Analytical thin- 29.3, 29.1, 29.0, 25.5, 24.9. IR (KBr) cm−1: 2922, 2849, 1738,
layer chromatography was carried out on silica gel 60F254 1594, 1567. 5-(9-methyl nonanoate)-3-phenyl-∆2-isoxazoline
(250 µm) purchased from Alltech Associates Inc. (Waukegan, GC retention time 20.2 min. MS (EI): m/z 317 (M+, 1%), 286
IL). Conventional column chromatography was carried out (M+ − CH3O, 2%) and 146 (C9H8NO, 100%). MS (CI): m/z
using silica gel 22 (22–200 mesh) purchased from the Aldrich 318 (MH+, 54%), 346 (M+ + C2H5, 11%), 358 (M+ + C3H5,
Chemical Co. The eluent used for analytical and preparative 3%), 286 (M+ − CH3O, 16%), and 146 (C9H8NO+, 4%).
chromatography was 30:70 ethyl ether/hexane.
The 5-(9-methyl nonanoate)-3-methyl-∆2- isoxazoline (4a)
Determination of aqueous NaOCl concentration. The purified by column chromatography: 1H NMR δ 4.55–4.45 (m,
NaOCl solution used in the reactions was titrated for NaOCl 1H, CH2–HC(O)–CH2), 3.64 (s, 3H, OCH3), 2.94 (dd, 1H, J =
concentration with a solution made from Na2S2O3·5 H2O 16.8 and 10.1 Hz, –(O)CH–CH2–C(=N)–), 2.51 (dd, 1H, J =
(20 g, 80.6 mmol) in 800 mL of deionized water (15). The 16.9 and 8.2 Hz, –(O)CH–CH2–C(=N)–), 2.27 (t, 2H, J = 7.5
Na2S2O3 solution was standardized by titrating a solution Hz, CH2–CH2–COOMe), 1.95 (s, 3H, –CH2–(N=)C–CH3),
of KIO3 (102.8 mg, 0.48 mmol), KI (2 g, 12.0 mmol), 50% 1.75–1.20 (m, 14H, alkyl chain H). 13C NMR: δ 174.3 (C=O),
solution of H2SO4 (5 mL), and water (50 mL). When this 155.2 (C=N), 80.3 (CH2–HC(O)–CH2), 51.4 (O–CH3), 43.7,
purple solution turned yellow, 1% soluble starch solution 35.2, 34.0, 29.3, 29.2, 29.1, 29.0, 25.5, 24.9, 13.3. IR (NaCl)
(1 mL) was added, which reproduced a purple color. Addi- cm−1: 2929, 2856, 1738 (C=O), 1632 (C=N). 5-(9-Methyl
tional Na2S2O3 solution was added until the solution was nonanoate)-3-methyl-∆2-isoxazoline GC retention time 11.3
clear. The concentration of the Na2S2O3 solution was then min. MS (EI): m/z 255 (M+, 0.4%), 224 (M+ − CH3O, 3%),
calculated based on the volume of Na2S2O3 added and the and 84 (C4H6NO+, 100%). MS (CI): m/z 256 (MH+, 100%),
reaction of 1 mol of KIO3 with 6 mol of Na2S2O3. A solution 284 (M+ + C2H5, 25%), 296 (M+ + C3H5, 9%), 224 (M+ −
of aqueous NaOCl (1 mL), KI (2 g, 12.0 mmol), 6 M HCl CH3O, 61%), and 84 (C4H6NO+, 1%).
(2 mL), and deionized water was then titrated with the stan-
The 5-(9-methyl nonanoate)-3-pentyl-∆2-isoxazoline (4b)
dardized Na2S2O3 in the same manner as the KIO3 titration. purified by column chromatography: 1H NMR δ 4.55–4.45 (m,
The NaOCl concentration was determined from the volume 1H, CH2–HC(O)–CH2), 3.67 (s, 3H, OCH3), 2.95 (dd, 1H, J =
of Na2S2O3 added and the reaction of 1 mol of NaOCl with 16.7 and 10.1 Hz, –(O)CH–CH2–C(=N)–), 2.53 (dd, 1H, J =
2 mol of Na2S2O3. The aqueous NaOCl concentration 16.8 and 8.1 Hz, –(O)CH–CH2–C(=N)–), 2.35–2.25 (m, 4H,
(10–15% from Aldrich) was found to be 1.69 M (12.6%). The CH2–CH2–COOMe and –C(=N)–CH2–CH2–), 1.70–1.20 (m,
amount of aqueous NaOCl used in a reaction was determined 20H, alkyl chain H), 0.90 (t, 3H, J = 6.9 Hz, –CH2–CH3). 13
C
JAOCS, Vol. 78, no. 10 (2001)

SYNTHESIS OF ∆2-ISOXAZOLINE FATTY ACID ESTERS
1047
NMR: δ 174.3 (C=O), 158.9 (C=N), 80.0 (CH2–HC(O)–CH2),
Representative procedure for the synthesis of ∆2-isoxazo-
51.4 (O–CH3), 42.1, 35.2, 34.7, 31.7, 29.4, 29.3, 29.1, 28.9, lines from methyl 10-undecenoate and syn-benzaldehyde
27.8, 26.4, 25.5, 24.9, 22.6, 14.0 (–CH3). IR (NaCl) cm−1: oxime using N-chlorosuccinimide (9). To a stirred mixture of
2930, 2857, 1740 (C=O), 1622 (C=N). 5-(9-Methyl N-chlorosuccinimide (NCS; 1.10 g, 8.1 mmol), pyridine (38
nonanoate)-3-pentyl-∆2-isoxazoline GC retention time 15.1 µL, 0.47 mmol), in dry chloroform (7.5 mL) at 24°C was
min. MS (EI): m/z 311 (M+, 2%), 280 (M+ − CH3O, 2%) and added syn-benzaldehyde oxime (1.0 g, 8.2 mmol) in one por-
140 (C8H14NO+, 100%). MS (CI): m/z 312 (MH+, 100%), 340 tion. The mixture was allowed to stir ca. 20 min, after which
(M+ + C2H5, 17%), 352 (M+ + C3H5, 6%), 280 (M+ − CH3O, time the suspended NCS had disappeared. Methyl 10-unde-
11%), and 140 (C8H14NO+, 3%).
cenoate (2.0 g, 10.1 mmol) was added, and the temperature
The 5-(9-methyl nonanoate)-3-hexyl-∆2-isoxazoline (4c) raised to 50°C. Triethylamine (1.17 mL, 8.4 mmol) in CHCl3
purified by column chromatography: 1H NMR δ 4.55–4.45 (2 mL) was added dropwise over 30–35 min, and the reaction
(m, 1H, CH2–HC(O)–CH2), 3.68 (s, 3H, OCH3), 2.96 (dd, solution was then stirred at 50°C for 4.5 h. The reaction solu-
1H, J = 16.7 and 10.1 Hz, –(O)CH–CH2–C(=N)–), 2.54 (dd, tion was cooled, washed with water (2 × 10 mL), dried
1H, J = 16.7 and 8.1 Hz, –(O)CH–CH2–C(=N)–), 2.36–2.28 (MgSO4), and evaporated in vacuo to obtain 3.0 g of a crude
(m, 4H, CH2–CH2–COOMe and –C(=N)–CH2–CH2–), oil. One recrystallization from methanol gave 1.04 g of 4e as
1.70–1.20 (m, 22H, alkyl chain H), 0.90 (t, 3H, J = 6.9 Hz, white crystals (41%), m.p.: 59–60°C.
–CH2–CH3). 13C NMR: δ 174.3 (C=O), 158.9 (C=N), 80.0
Representative procedure for the synthesis of 5-(9-methyl
(CH2–HC(O)–CH2), 51.4 (O–CH3), 42.1, 35.2, 34.1, 31.5, nonanoate)-3-carbalkoxy-∆2-isoxazoline 4g and 4h from
29.4, 29.3, 29.1, 29.1, 28.9, 27.8, 26.4, 25.5, 24.9, 22.5, 14.0 methyl 10-undecenoate and alkylchlorooximidoacetate. To a
(–CH3). IR (NaCl) cm−1: 2930, 2857, 1740 (C=O), 1622 vigorously stirred solution of methyl 10-undecenoate (1.08 g,
(C=N). 5-(9-Methyl nonanoate)-3-hexyl-∆2-isoxazoline GC 5.5 mmol) and ethyl chlorooximidoacetate (763 mg, 5.1
retention time 16.6 min. MS (EI): m/z 325 (M+, 2%), 294 mmol) in ethyl ether (14 mL) was added a solution of triethyl-
(M+ − CH3O, 0.3%), and 154 (C9H16NO+, 100%). MS (CI): amine (700 µL, 5.02 mmol) in ethyl ether (10 mL) dropwise
m/z 326 (MH+, 100%), 354 (M+ + C2H5, 17%), 366 (M+ + at room temperature over 1 h. A white precipitate formed
C3H5, 6%), 294 (M+ − CH3O, 8%), and 154 (C9H16NO+, 3%). upon triethylamine addition. After stirring an additional 2 h,
The 5-(9-methyl nonanoate)-3-heptyl-∆2-isoxazoline (4d) the reaction mixture was taken up in water (10 mL) and ex-
purified by column chromatography: 1H NMR δ 4.51–4.43 (m, tracted with ethyl ether (3 × 30 mL). The combined ether ex-
1H, CH2–HC(O)–CH2), 3.64 (s, 3H, OCH3), 2.92 (dd, 1H, J = tracts were washed with water (10 mL), dried (MgSO4), and
16.7 and 10.1 Hz, –(O)CH–CH2–C(=N)–), 2.50 (dd, 1H, J = concentrated. The crude product was chromatographed on sil-
16.8 and 8.1 Hz, –(O)CH–CH2–C(=N)–), 2.32–2.25 (m, 4H, ica gel as described for the previous isoxazolines. Product 4g
CH2–CH2–COOMe and –C(=N)–CH2–CH2–), 1.75–1.15 (m, (1.1 g, 66%) was obtained as a clear oil.
24H, alkyl chain H), 0.85 (t, 3H, J = 6.9 Hz, –CH2–CH3). 13
C
1H NMR of 5-(9-methyl nonanoate)-3-carbethoxy-∆2-isox-
NMR: δ 174.3 (C=O), 158.9 (C=N), 80.0 (CH2–HC(O)–CH2), azoline (4g): δ 4.70–4.80 (m, 1H, CH2–HC(O)–CH2), 4.30 (q,
51.4 (O–CH3), 42.0, 35.2, 34.1, 31.7, 29.4, 29.3, 29.2, 29.1, 2H, J = 10.71 and 7.1 Hz, –OCH2CH3), 3.62 (s, 3H, OCH3),
29.1, 28.9, 27.8, 26.4, 25.5, 24.9, 22.6, 14.0 (–CH3). IR (KBr) 3.21 (dd, 1H, J = 17.5 and 10.9 Hz, –(O)CH–CH2–C(=N)–),
cm−1: 2926, 2852, 1738 (C=O), 1632 (C=N). 5-(9-Methyl 2.79 (dd, 1H, J = 17.5 and 8.5 Hz, –(O)CH–CH2–C(=N)–), 2.26
nonanoate)-3-heptyl-∆2-isoxazoline GC retention time 18.5 (t, 2H, J = 7.5 Hz, CH2–CH2–COOMe), 1.80–1.10 (m, 17H,
min. MS (EI): m/z 339 (M+, 2%), 308 (M+ − CH3O, 1%) and alkyl chain H and –O–CH2–CH3). 13C NMR: δ 174.1 (C=O,
168 (C10H18NO+, 100%). MS (CI): m/z 340 (MH+, 100%), methyl ester), 160.8 (C=O, ethyl ester), 151.2 (C=N), 84.0
368 (M+ + C2H5, 16%), 380 (M+ + C3H5, 5%), 308 (M+ − (CH2–HC(O)–CH2), 61.9 (–O–CH2CH3), 51.3 (O–CH3), 38.2,
CH3O, 8%), and 168 (C10H18NO+, 4%).
34.9, 33.9, 29.1, 29.1, 28.9, 28.9, 24.9, 24.7, 14.0 (–CH3). IR
The 5-(9-methyl nonanoate)-3-t-butyl-∆2-isoxazoline (4f) (NaCl) cm−1: 2932, 2857, 1739 (C=O), 1721 (C=O), 1587
purified by column chromatography: 1H NMR δ 4.51–4.43 (C=N). 5-(9-Methyl nonanoate)-3-carbethoxy-∆2-isoxazoline
(m, 1H, CH2–HC(O)–CH2), 3.64 (s, 3H, OCH3), 2.97 (dd, GC retention time 14.53 min. MS (EI): m/z 314 (MH+, 2%), 282
1H, J = 16.5 and 10.0 Hz, –(O)CH–CH2–C(=N)–), 2.54 (dd, (M+ − CH3O, 4%), 240 (M+ − C2H5O2, 7%), and 142
1H, J = 16.6 and 8.0 Hz, –(O)CH–CH2–C(=N)–), 2.28 (t, 2H, (C6H8NO3 , 100%). MS (CI): m/z 314 (MH+, 66%), 342 (M+ +
+
J = 7.5 Hz, CH2–CH2–COOMe), 1.75–1.2 (m, 14H, alkyl C2H5, 25%), 354 (M+ + C3H5, 7%), 282 (M+ − CH3O, 100%).
chain H), 1.17 (s, 9H, –C(CH3)3). 13C NMR: δ 174.4 (C=O),
The 5-(9-methyl nonanoate)-3-carbmethoxy-∆2-isoxazo-
1
165.9 (C=N), 80.4 (CH2–HC(O)–CH2), 51.5 (O–CH3), 39.4, line (4h) purified by column chromatography: H NMR
35.2, 34.1, 33.0, 29.4, 29.4, 29.2, 29.1, 28.1, 25.6, 25.0. 5-(9- δ 4.72–4.85 (m, 1H, CH2–HC(O)–CH2), 3.87 (s, 3H, OCH3),
Methyl nonanoate)-3-t-butyl-∆2-isoxazoline GC retention 3.65 (s, 3H, OCH3), 3.23 (dd, 1H, J = 17.5 and 10.9
time 12.7 min. IR (NaCl) cm−1: 2931, 2857, 1740 (C=O), Hz, –(O)CH–CH2–C(=N)–), 2.82 (dd, 1H, J = 17.5 and 8.5
1609 (C=N). MS (EI): m/z 297 (M+, 2%), 240 (M+ − C4H9, Hz, –(O)CH–CH2–C(=N)–), 2.29 (t, 2H, J = 7.5 Hz,
1%), and 126 (C7H12NO+, 100%). MS (CI): m/z 298 (MH+, CH2–CH2–COOMe), 1.90–1.10 (m, 14H, alkyl chain H). 13
C
100%), 326 (M + C2H5, 12%), 338 (M + C3H5, 3%), and 126 NMR: δ 174.2 (C=O, methyl ester), 161.2 (C=O, methyl
(C7H12NO+, 2%).
ester), 151.1 (C=N), 84.2 (CH2–HC(O)–CH2), 52.7 (O–CH3),
JAOCS, Vol. 78, no. 10 (2001)

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J.A. KENAR AND S.Z. ERHAN
51.4 (O–CH3), 38.3, 35.0, 34.0, 29.2, 29.2, 29.0, 29.0, 24.5, fatty ester from the aqueous NaOCl phase. Chlorination of
24.9. IR (KBr) cm−1: 2994, 2914, 2852, 1739 (C=O), 1720 the aldoxime in the aqueous NaOCl followed by HCl elimi-
(C=O), 1582 (C=N). 5-(9-Methyl nonanoate)-3-carbmeth- nation gives the reactive nitrile oxide intermediate in situ. Mi-
oxy-∆2-isoxazoline GC retention time 13.6 min. MS (EI): gration of the nitrile oxide into the methylene chloride phase
m/z 300 (MH+, 1%), 282 (M+ − CH3O, 5%), 240 (M+ − allows it to be trapped by the olefinic substrate. Interestingly,
+
C2H3O2, 4%), and 128 (C5H6NO3 , 100%). MS (CI): m/z 300 when we used acetaldoxime as the nitrile oxide precursor,
(MH+, 26%), 328 (M+ + C2H5, 18%), 340 (M+ + C3H5, 5%), only low yields (23%) of 4a were obtained (Table 1, entry 4a)
and 286 (M+ − CH3O, 100%).
relative to the other nitrile oxide precursors. Presumably, the
high solubility of acetaldoxime and its corresponding nitrile
oxide in the reaction mixture’s aqueous phase prevents effi-
cient partitioning into the organic phase where it can be effi-
RESULTS AND DISCUSSION
Scheme 1 depicts the reaction sequence initially utilized to syn- ciently trapped by the olefinic substrate.
thesize ∆2-isoxazolines by 1,3-dipolar cycloaddition between
To examine if the isoxazoline yields could be improved,
nitrile oxides, 2, and methyl 10-undecenoate, 3. Although two isoxazoline formation was briefly examined by generating ni-
regioisomers, namely, the 3,5-substituted and 3,4-substituted trile oxides from aldoximes under nonaqueous reaction condi-
isoxazolines, 4 and 5, respectively, are possible from the reac- tions using N-chlorosuccinimide at 50°C in anhydrous CHCl3
tion, nitrile oxide cycloadditions to terminal olefins are highly following the procedure of Larsen and Torssell (9). The yields
regioselective and give predominantly 3,5-substituted isoxazo- for the two reactions examined by this method are also shown
lines (1). In this respect, methyl 10-undecenoate behaved as a in Table 1 (yields in parentheses). As can be seen, the yield of
typical monosubstituted olefin and gave 4 as the only observ- 4a improves significantly while the yield for 4c remains ap-
able isoxazoline. These reactions proceed smoothly and repre- proximately equal to the yield obtained by the other method.
sent a convenient way to synthesize fatty compounds contain- The improved yield of 4a obtained from acetaldoxime under
ing the ∆2-isoxazoline ring system. As can be seen in Table 1 these conditions confirms, in part, our earlier suspicions that
(entries 4a–4f), the ∆2-isoxazolines are obtained in good yields acetaldoxime’s hydrophilic nature may have prevented the re-
after purification by silica gel chromatography.
action from taking place in the biphasic reaction conditions.
Because nitrile oxides readily dimerize to furoxans, one
GC and 1H NMR analyses of the crude isoxazoline prod-
uct mixtures obtained from these reactions confirmed that the commonly used technique to slow down the rate of furoxan
cycloaddition reactions gave only one regioisomer. Also tab- formation relative to the desired 1,3-dipolar cycloaddition is
ulated in Table 1 are the 1H NMR chemical shifts for the 4- to use hindered nitrile oxides. The isoxazoline yields reported
and 5-ring hydrogens of compounds 4 (Scheme 1). Compari- in Table 1 support this notion. As can be seen, the yields im-
son of these data obtained for the purified isoxazolines with prove as the steric hindrance of the nitrile oxide increases in
1H NMR data for analogous ∆2-isoxazolines found in the lit- the order, Me < alkyl < phenyl < t-butyl (the R group shown
erature (9) helped establish that the 3,5-substituted regioiso- in Table 1 is derived from the nitrile oxide). Accordingly, the
mer, 4, was formed exclusively.
half-life for acetonitrile oxide (R = Me) has been reported to
In addition to the isoxazolines, unreacted starting olefin, be <1 min (10), benzonitrile oxide’s (R = phenyl) half-life is
easily recovered during silica gel chromatography, is the other 30–60 min (10), and 2,2-dimethylpropanenitrile oxide (R = t-
main material observed from these reactions. Small amounts butyl) has been reported to be 9 d (6). Thus, the longer the ni-
of furoxans, from nitrile oxide dimerization, were also re- trile oxide can persist in solution without undergoing dimer-
trieved by chromatography. Chlorinated olefin and subse- ization, the greater the likelihood that it can be trapped by the
quent chlorhydrin products formed by reaction with NaOCl terminal olefin to produce isoxazolines.
were not observed since the organic phase of the biphasic re-
The only other example we found where nitrile oxides are
action mixture appears to effectively protect the hydrophobic used to make isoxazoline fatty compounds was reported by
SCHEME 1
JAOCS, Vol. 78, no. 10 (2001)

SYNTHESIS OF ∆2-ISOXAZOLINE FATTY ACID ESTERS
1049
TABLE 1
Yields, Melting Points, and 1H NMR Data for ∆2-Isoxazoline (4) Obtained from the Cycloaddition
Between Nitrile Oxides 2 and Methyl 10-Undecenoate
Yielda,b
(%)
m.p.
(°C)
1H NMRc δ, J (Hz)
ring H (5-position)
1H NMRc δ, J (Hz)
ring H (4-position)
∆2-Isoxazolines (4)
4a, R = Me
23 (40)
Oil
4.55–4.45 (m, 1H)
4.55–4.45 (m, 1H)
4.55–4.45 (m, 1H)
4.51-4.43 (m, 1H)
4.75–4.72 (m, 1H)
4.51–4.43 (m, 1H)
4.70–4.80 (m, 1H)
4.72–4.85 (m, 1H)
2.94 (dd, 1H, J = 16.8 and 10.1)
2.51 (dd, 1H, J = 16.9 and 8.2)
4b, R = –(CH2)4CH3
4c, R = –(CH2)5CH3
4d, R = –(CH2)6CH3
4e, R = Phenyl
65
Oil
2.95 (dd, 1H, J = 16.7 and 10.1)
2.53 (dd, 1H, J = 16.8 and 8.1)
63 (66)
64
Melts at rt
29–30
59–60
Melts at rt
Oile
2.96 (dd, 1H, J = 16.7 and 10.1)
2.54 (dd, 1H, J = 16.7 and 8.1)
2.92 (dd, 1H, J = 16.7 and 10.1)
2.50 (dd, 1H, J = 16.8 and 8.1)
74
3.40 (dd, 1H, J = 16.4 and 10.3)
2.98 (dd, 1H, J = 16.4 and 8.2)
4f, R = t-Butyl
85
2.97 (dd, 1H, J = 16.5 and 10.0)
2.54 (dd, 1H, J = 16.6 and 8.0)
4g,d R = –CO2Et
66
3.21 (dd, 1H, J = 17.5 and 10.9)
2.79 (dd, 1H, J = 17.5 and 8.5)
4h,d R = –CO2Me
55
56–58
3.23 (dd, 1H, J = 17.5 and 10.9)
2.82 (dd, 1H, J = 17.5 and 8.5)
aIsolated yields.
bYields in parentheses obtained by reacting aldoximes with N-chlorosuccinimide in CHCl3 at 50°C following the proce-
dure of Larsen and Torssell (9).
cSpectra taken in CDCl3 at 400 MHz. NMR, nuclear magnetic resonance.
dPrepared from the corresponding hydroximic acid chlorides; see Experimental Procedures section.
eAll attempts to recrystallize 4g failed.
Ahmed et al. (16). Interestingly, they reported the 1,3-cycload- ing glycine ester hydrochlorides with sodium nitrite in an
dition between methyl 10-undecenoate and nitrile oxide aqueous HCl solution (14). Both the methyl and ethyl hydrox-
MeOOCC≡N+–O−, obtained from the reaction of methyl imic acid chlorides are crystalline compounds, although the
chlorooximidoacetate with base, gave the 3,4-substituted re- ethyl hydroximic acid chloride was much easier to handle
gioisomer exclusively in 90% yield. These authors may have since the methyl hydroximic acid chloride is very hygroscopic.
inadvertently reported the wrong structure for the isoxazoline
As can be seen from Table 1 (entries 4g and 4h), in our
they prepared. Because their result seemingly contradicts the hands, the isoxazoline yields obtained from these reactions
large body of knowledge regarding nitrile oxide cycloaddi- were somewhat lower than those reported by Ahmed et al. (16),
tions to monosubstituted olefins, we repeated their research by 66% and 55% for 4g and 4h, respectively. We suspect the lower
synthesizing isoxazolines 4g and 4h with both the carb- yields obtained using 6h relative to 6g result from the difficulty
methoxy and carbethoxy functionality substituted at the 3- in handling the hygroscopic reagent. The chemical shifts and
position of the isoxazoline ring. Because the aldehydes needed coupling constants determined from 1H NMR analyses of puri-
to prepare the starting oximes required for the biphasic reac- fied isoxazoline 4h are similar to those reported by Ahmed
tion were not readily available, we opted to generate and trap et al. (16) and to the other isoxazoline ring hydrogens reported
the nitrile oxides by treating their corresponding hydroximic in this work (Table 1). Additionally, the chemical shift, split-
acid chlorides, which were easily prepared, with base in the ting patterns, and coupling constant values for the isoxazoline
presence of methyl 10-undecenoate (Scheme 2).
ring hydrogens of 5h would be substantially different from
Accordingly, the ethyl and methyl hydroximic acid chlo- what was observed. Based on these observations and the
rides, 6g and 6h, were prepared by treating their correspond- known regioselectivity of nitrile oxides toward terminal olefins,
SCHEME 2
JAOCS, Vol. 78, no. 10 (2001)

1050
J.A. KENAR AND S.Z. ERHAN
6. Curran, D.P., S.A. Scanga, and C.J. Fenk, Reduction of ∆2-Isox-
azolines. Synthesis of β-Hydroxy Acid Derivatives, Ibid. 49:
3474–3478 (1984).
7. Confalone, P.N., E.D. Lollar, G. Pizzolato, and M.R.
Uskokovíc, Use of Intramolecular [3+2] Cycloaddition Reac-
tions in the Synthesis of Natural Products. A Stereospcific Syn-
thesis of ( )-Biotin from Cycloheptene, J. Am. Chem. Soc.
100:6291–6292 (1978).
8. Mukaiyama, T., and T. Hoshino, The Reaction of Primary Ni-
troparaffins with Isocyanates, Ibid. 82:5339–5342 (1960).
9. Larsen, K.E., and K.B.G. Torssell, An Improved Procedure for
the Preparation of 2- Isoxazolines, Tetrahedron 40:2985–2988
(1984).
10. Grundmann, C., and P. Grünanger, The Nitrile Oxides, Springer-
Verlag, Berlin, 1971.
11. Lee, G.A., A Simplified Synthesis of Unsaturated Nitrogen-
Heterocycles Using Nitrile Betaines, Synthesis:508–509 (1982).
12. Chang, S.-P., Allyl Esters and Allyl Epoxy Esters from Crambe
Oil, J. Am. Oil Chem. Soc. 56:855–856 (1979).
13. Bousquet, E.W., in Organic Syntheses Collective Volume 2,
edited by A.H. Blatt, John Wiley and Sons, New York, 1943,
pp. 313–315.
it is most likely that 4h, not 5h (Scheme 1, R = CO2R), is the
correct isoxazoline structure obtained from these reactions.
In conclusion, nitrile oxides react readily with the terminal
olefin, methyl 10-undecenoate, to give good yields of 3,5-
substituted ∆2-isoxazolines under mild reaction conditions.
These long-chain fatty ester isoxazolines may have interest-
ing biological and industrial applications, and may also be
used as intermediates to derive new oleochemicals with inter-
esting properties not easily obtainable by other methods.
ACKNOWLEDGMENTS
The authors thank Joneen McElligott for her help in the syntheses of
these compounds, and Dr. David Weisleder for collection of the
NMR data.
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[Received February 8, 2001; accepted August 14, 2001]
JAOCS, Vol. 78, no. 10 (2001)