A versatile entry to 3-unsubstituted 2-isoxazolines

Article abstract of DOI:10.1055/s-2008-1042900

A new catalytic method for the preparation of 3-unsubstituted 2-isoxazolines is reported. The isoxazolines are easily prepared from the aliphatic α,β-unsaturated aldehydes and simple oximes in the presence of an anilinium salt catalyst. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1042900

LETTER
827
A Versatile Entry to 3-Unsubstituted 2-Isoxazolines
Versatile
E
ntr
y
to
n
3-Unsubstitu
t
ted 2-
I
t
iines Pohjakallio, Petri M. Pihko*
Laboratory of Organic Chemistry, Helsinki University of Technology, P.O. Box 6100, 02015 TKK, Espoo, Finland
Fax +358(9)4512538; E-mail: petri.pihko@tkk.fi
Received 20 December 2007
drolysis.9 Table 1 shows the NMR yield of 10 after 3
hours when different combinations of bases and acids
were employed as catalysts. (Figure 1)
Abstract: A new catalytic method for the preparation of 3-unsub-
stituted 2-isoxazolines is reported. The isoxazolines are easily pre-
pared from the aliphatic a,b-unsaturated aldehydes and simple
oximes in the presence of an anilinium salt catalyst.
Screens quickly revealed that the desired reaction could
Key words: aldehydes, oximes, catalysis, heterocycles, isoxazoline indeed be achieved and both the acid and the base played
a significant role in the process. The reaction proceeded
R1
Me
2-Isoxazoline heterocycles are typically and most conve-
niently prepared by the 1,3-dipolar cycloaddition between
alkenes and nitrile oxides.1 Other methods including the
reaction of a,b-unsaturated carbonyl compounds with hy-
droxylamine salts have been employed but with limited
success.2 Due to the lack of good preparative methods, a
very limited range of 3-unsubstituted compounds has
been reported in the literature. The 1,3-cycloadditions of
fulminic acid or silyl nitronates with activated olefins ap-
pear to be the only straightforward methods for the prep-
aration of these compounds.3,4 A single example of a
reaction between hydroxyurea and crotonaldehyde to give
5-methyl-2-isoxazoline has been reported.5 Recently,
Pennicott el al. also disclosed a method for obtaining these
compounds from O-propargylic hydroxylamines.6 Herein
we report a new catalytic method for the preparation of 3-
unsubstituted 2-isoxazolines directly from a,b-unsaturat-
ed aldehydes and oximes. The reaction complements the
existing methods nicely as it allows easy preparation of
compounds bearing a nonstabilizing substituent at the 5-
position of the heterocycle.
O
N
R3
H
t-Bu
N
H
N
N
N
H
Me
R
H
Bn
R2
1
2
3
4
a) R1 = H, R2 = H, R3 = Me
b) R1 = H, R2 = OMe, R3 = Me
c) R1 = H, R2 = CF3, R3 = Me
d) R1 = H, R2 = H, R3 = i-Pr
e) R1 = i-Pr, R2 = i-Pr, R3 = H
O
a) R = CH2Cl
b) R = CHCl2
c) R = CF3
OH
5
O
PhO
MeSO3H
P
PhO
OH
6
7
Figure 1 Selected amines and acids used in the catalyst screening
Table 1 Screen of Different Base and Acid Combinations in the 2-
Isoxazoline Formation a
base + acid
(20 mol%)
HO
Pr
O
O
N
N
+
toluene, r.t.
Pr
H
10
8
9a
Recently, Jørgensen and co-workers published an enan-
tioselective method for conjugate addition of oximes to
a,b-unsaturated aldehydes.7 During our own study of
similar reactions, we encountered problems that arose
from the reversibility of the addition. We anticipated that
these problems could be circumvented by developing a
catalyst that would cyclize the conjugate addition product
directly to a more stable 2-isoxazoline. The work of Jaqui-
er et al.5 and the recent communication by the Dawson
group8 suggested that this could be well achieved using a
suitable amine salt that would be able to catalyze both the
conjugate addition and the cyclization step.
Acid (Yield of 10, %)
Base
1a
1b
1c
1d
1e
2
5a
5b
5c
6
7
8
35
48
42
61
51
69
23
11
57
76
46
45
31
43
16
10
74
38
Initially, we chose to examine the reaction between 2-hex-
enal 8 and acetone oxime 9a in the presence different
amine salts. Acetone oxime was chosen as the oxime part-
ner due to its practical utility and sensitivity towards hy-
3
4
0
29
38
a The reactions were performed by mixing aldehyde (0.24 mmol),
oxime (0.2 mmol), base (0.04 mmol), and acid (0.04 mmol) in toluene
(1 mL) at r.t. NMR yield of 10 after 3 h is given. 4-Bromoanisole or
3,5-bis(trifluoromethyl)bromobenzene were used as internal stan-
dards.
SYNLETT 2008, No. 6, pp 0827–0830
Advanced online publication: 11.03.2008
DOI: 10.1055/s-2008-1042900; Art ID: G37807ST
© Georg Thieme Verlag Stuttgart · New York
x
x.
x
x.
2
0
0
8

828
A. Pohjakallio, P. M. Pihko
LETTER
efficiently only when acids and bases of suitable pKa and The method appears to be fairly general, affording the 2-
pKaH value were employed. Different N-alkylanilines to- isoxazoline products in moderate to good yields. The con-
gether with trifluoroacetic acid or diphenylphosphate ditions are also compatible with more sensitive function-
(DPP) gave the best results. The imidazolidinone base 4 alities (entries 4 and 8) and steric hindrance in the b-
was also very efficient in promoting the reaction with the position is also tolerated (entry 5). However, in common
same acids. However, only racemic products were ob- with other O- and N-additions to unsaturated aldehydes,
tained in these conditions, and as such we decided to focus the method is limited to the use of aliphatic a,b-unsaturat-
on cheaper and simpler alternatives, particularly on the N- ed aldehydes. Substrates with further conjugation in the b-
methylaniline (1a). After solvent screens, toluene position were unreactive. Employing a-acroleins as reac-
emerged as the solvent of choice for the reaction, although tion partners also failed, even when salts of primary amine
other nonpolar solvents, such as chlorinated hydrocarbons 1e were used as catalysts.11
or dioxane may also be used. In temperature screens, run-
ning the reaction at 0 °C gave optimal results.
According to our hypothesis, the reaction mechanism in-
volves an initial iminium-catalyzed conjugate addition of
Selection of the oxime reagent significantly affects the re- oxime to the a,b-unsaturated aldehyde followed by the
action rate. In general, small, low-molecular-weight cyclization step that proceeds through hydrolysis of the
oximes are ideal starting materials, since the parent ketone formed O-alkyloxime. In preliminary NMR studies, we
is easy to separate afterwards from the reaction mixture. have observed that the concentration of the conjugate ad-
Various oximes turned out to be reactive in the conditions dition product rises rapidly and then falls as the concentra-
developed (Table 2). Of the oximes tested, diethylketone tion of the 2-isoxazoline product rises.12 However, the
oxime 9c possessed the best combination of reactivity, other mechanistic pathways, such as an oxime transfer
stability, and practical utility in our conditions. Most between the aldehyde and the oxime, followed by an un-
oximes, excluding the most sterically hindered com- favorable 5-endo-trig cyclization, cannot be ruled out.13
pounds such as 9d, are capable hydroxylamine donors for
Notably, the reaction can also be promoted by acid alone,
the reaction. It should be stressed that acetone oxime and
in which case the reaction proceeds at a comparable rate
acetaldehyde oxime may be viable alternatives when the
to the amine-catalyzed reaction but only after an initial in-
duction period. This behavior indicates that a new cata-
product must be purified by distillation.10
The generality of the reaction was explored with a variety lytic species is generated under these conditions.14 This
of a,b-unsaturated aldehydes (Table 3).
species could also play a role in our difficulties in obtain-
ing enantioenriched products.15
Table 2 Oxime Screen for Isoxazoline Synthesis
In conclusion, we have developed a simple anilinium salt
catalyzed method for the preparation of 5-substituted 2-
isoxazolines from a,b-unsaturated aldehydes and readily
available oximes. Our method complements the existing
methods by enabling the preparation of a variety of 3-un-
substituted 2-isoxazolines, and requires no further stabili-
zation at the 5-position of the heterocycle. Mechanistic
studies to test our mechanistic hypothesis are under way
and will be published later along with the full account of
this work.
O
P
OPh
OPh
Me
N
–O
H
H
OH
R2
O
Pr
N
O
11 (20 mol%)
N
Pr
H
R1
toluene, 0 °C
8
9
10
Oxime
9a
R1
R2
NMR yield (%)a
Me
Me
74
38
78
0
9b
9c
-(CH2)4-
Et
Acknowledgment
Et
Me
Me
H
TEKES and Graduate School of Organic Chemistry and Chemical
Biology are acknowledged for material and financial support. We
thank Dr. Jari Koivisto for NMR assistance.
9d
9e
t-Bu
Ph
4
9f
Me
46
19
22
8
References and Notes
(1) (a) Easton, C. J.; Hughes, C.; Merricc, M.; Savage, G. P.;
Simpson, G. W. Adv. Heterocycl. Chem. 1994, 60, 261. (b)
For examples of the use of 2-isoxazolines in total synthesis
setting, see: Kozikowski, A. P. Acc. Chem. Res. 1984, 17,
410.
(2) Lang, S. A.; Lin, Y.-i. In Comprehensive Heterocyclic
Chemistry, Vol. 6; Katritzky, A. R.; Rees, C. W., Eds.;
Pergamon: Oxford, 1984, 88–98.
9g
Ph
H
9h
9i
4-MeOC6H4
4-NO2C6H4
PhHC=CH
H
H
9j
H
34
a The reactions were performed with aldehyde (0.24 mmol), oxime
(0.2 mmol), and aniline salt 11 (0.04 mmol) in toluene (1 mL) at 0 °C.
NMR yield after 6 h is given.
(3) Huisgen, R.; Christl, M. Chem. Ber. 1973, 106, 3291.
Synlett 2008, No. 6, 827–830 © Thieme Stuttgart · New York

LETTER
Versatile Entry to 3-Unsubstituted 2-Isoxazolines
829
Table 3 Synthesis of 2-Isoxazolines17–21
O
P
OPh
OPh
Me
N
O
H
H
OH
R
O
O
N
11 (20 mol%)
+
N
R
H
toluene, 0 °C
8
9c
10
Entry
1
Aldehyde
Product
Time (h) Yield (%)a
O
O
8a
8b
10a
6
80b
55c
N
H
O
O
2
3
4
5
10b
10c
10d
10e
6.5
N
H
O
H
O
8c
8d
8e
6.5
15.5
6.5
86
63
73
N
O
O
O
N
BnO
BnO
H
O
H
N
O
O
6
7
8f
10f
7
73
N
PMBO
PMBO
O
H
O
O
8g
10g
14.5
83d
N
H
O
O
O
8
9
8h
8i
10h
10i
N
15
73
82
MeO2C
H
MeO2C
O
O
7.5
N
TBDPSO
TBDPSO
H
a Yields refer to isolated and chromatographically purified products.
b NMR yield after 6 h is given.
c The reaction was performed in CHCl3 using 10 mol% of 11 in 20 mmol scale using acetaldehyde oxime 9f as oxime reactant. The yield refers
to distilled product.
d 1:1 mixture of diastereomers.
(4) (a) Torssell, K.; Zeuthen, O. Acta Chem. Scand. Ser. B 1978,
32, 118. (b) Sharma, S. C.; Torssell, K. Acta Chem. Scand.
Ser. B 1979, 33, 379. (c) Das, N. B.; Torssell, K. B. G.
Tetrahedron 1983, 39, 2247.
(5) Jacquier, R.; Olive, J.-L.; Petrus, C.; Petrus, F. Tetrahedron
Lett. 1975, 16, 2337.
(11) Erkkilä, A.; Pihko, P. M.; Clarke, M.-R. Adv. Synth. Catal.
2007, 349, 802.
(12) In control experiments, the reaction products did not
equilibrate to starting materials when exposed to the reaction
conditions [e.g., 3-pentanone (30 mol%), catalyst (50
mol%), r.t., 3 h].
(6) Pennicott, L.; Lindell, S. Synlett 2006, 463.
(7) Bertelsen, S.; Diner, P.; Johansen, R. L.; Jørgensen, K. A.
J. Am. Chem. Soc. 2007, 129, 1536.
(13) A related reaction for the preparation of 3-substituted 2-
isoxazolines from b,g-unsaturated ketones has been
proposed to follow this mechanism. See: Norman, A. L.;
Shurrush, K. A.; Calleroz, A. T.; Mosher, M. D. Tetrahedron
Lett. 2007, 48, 6849.
(8) Dirksen, A.; Hackeng, T. M.; Dawson, P. E. Angew. Chem.
Int. Ed. 2006, 45, 7581.
(9) Acetone oxime has previously been used as a transoximation
reagent. See: Juskowiak, M.; Krzyzanowski, P. J. Prakt.
Chem. 1989, 331, 870.
(10) For the preparation of volatile 10a, the use of acetaldehyde
oxime under modified conditions is recommended. See ref.
21.
(14) We initially believed that this species is hydroxylamine.
However, in control experiments, hydroxylammonium
diphenylphosphate turned out to be relatively poor catalyst
for the reaction, and exhibited a similar induction period
than acid catalysts.
(15) Moderate enantioselectivities (up to 63%) could be obtained
using a chiral imidazolidinone base along with strong acids
Synlett 2008, No. 6, 827–830 © Thieme Stuttgart · New York

830
A. Pohjakallio, P. M. Pihko
LETTER
in colder temperatures. However, in these cases, the reaction
rate and conversion were poor. Attempts to obtain
enantioenriched products in the presence of chiral
phosphoric acids failed. These studies will be reported
separately.
(100 MHz, CDCl3): d = 145.8, 137.8, 128.4, 127.71, 127.67,
77.1, 73.5, 70.7, 37.8. HRMS (ESI+): m/z calcd for
[C11H13NO2 + H]: 192.1025; found: 192.1028.
(20) Analytical Data of Compound 10h
Reaction time: 15 h; yield 0.072 g (73%); eluent: gradient
50–65% MTBE in hexane; Rf = 0.23 (30% MTBE in
hexane). IR (film): 2949, 2862, 2738, 1723, 1690, 1657,
1436, 1273, 1161, 1128, 974 cm–1. 1H NMR (400 MHz,
CDCl3): d = 7.11 (t, 1 H, J = 1.7 Hz), 6.93 (td, 1 H, J1 = 7.0
Hz, J2 = 15.6 Hz), 5.82 (td, 1 H, J1 = 1.6 Hz, J2 = 15.6 Hz),
4.50 (m, 1 H), 3.70 (s, 3 H), 3.05 (ddd, 1 H, J1 = 1.8 Hz,
J2 = 10.5 Hz, J3 = 17.4 Hz), 2.60 (ddd, 1 H, J1 = 1.8 Hz,
J2 = 7.9 Hz, J3 = 17.4 Hz), 2.25 (m, 2 H), 1.72–1.47 (m, 4
H). 13C NMR (100 MHz, CDCl3): d = 166.9, 148.6, 145.8,
121.4, 78.2, 51.4, 40.5, 34.5, 31.8, 24.0. HRMS (ESI+): m/z
calcd for [C10H15NO3 + Na]: 220.0950; found: 220.0946.
(21) Synthesis of Compound 10b
(16) Gibert, J. P.; Jacquier, R.; Pétrus, C. Bull. Soc. Chim. Fr.
1979, 281.
(17) General Procedure for the Preparation of 2-Isoxazolines
Using Diethylketone Oxime
To a solution of amine salt 11 (37.1 mg, 0.1 mmol, 20.7
mol%) in toluene (2.5 mL) at 0 °C was added aldehyde (0.6
mmol, 120 mol%). After 4 min, diethylketone oxime (55 mL,
0.5 mmol, 100 mol%) was added and the mixture was stirred
at 0 °C for the indicated period of time. The reaction mixture
was diluted with Et2O (15 mL), washed with sat. NaHCO3 (5
mL), and 5% oxalic acid (2 × 5 mL). The layers were
separated. The acidic and basic aqueous layers were back-
extracted separately with Et2O (2 × 6 mL and 5 mL,
respectively). The combined organic layers were washed
with brine, dried (Na2SO4), and concentrated to a volume of
1–2 mL. The residue was purified by column
To a solution of salt 11 (0.743 g, 2.08 mmol, 10.4 mol%) in
CHCl3 (50 mL) at 0 °C was added crotonaldehyde (1.99 mL,
24 mmol, 120 mol%). After 6 min, acetaldehyde oxime (1.23
mL, 20 mmol, 100 mol%) was added. The ice bath was
removed and the reaction mixture was stirred at r.t. After 6
h, the reaction mixture was washed with 10% oxalic acid
solution (10 mL) and then with 5% oxalic acid (30 mL, 20
mL). Hexanes (10 mL) was added22 and the layers were
separated. The organic layer was washed with sat. NaHCO3
(20 mL) and both acidic and basic aqueous phases were
back-extracted separately with Et2O (50 mL). The combined
organic phases were dried (Na2SO4) and concentrated by
distillation. The dark brown residue was distilled under
reduced pressure (15 mmHg, water-aspirator vacuum) to
give 0.871 g (51%) of 10b as colorless liquid (purity >95%
by 1H NMR).
chromatography.
(18) Analytical Data of Compound 10c
Reaction time: 6.5 h; yield 0.076 g (86%); eluent: gradient:
10–30% MTBE in hexane; Rf = 0.35 (40% EtOAc in
hexane). IR (film): 3062, 3026, 2924, 2589, 1600, 1495,
1454, 1275, 843 cm–1. 1H NMR (400 MHz, CDCl3): d =
7.31–7.27 (m, 2 H), 7.21–7.18 (m, 3 H), 7.12 (t, 1 H, J = 1.8
Hz), 4.52 (m, 1 H), 3.04 (ddd, 1 H, J1 = 1.8 Hz, J2 = 10.5 Hz,
J3 = 17.4 Hz), 2.80 (ddd, 1 H, J1 = 5.6 Hz, J2 = 9.5 Hz,
J3 = 13.9 Hz), 2.72 (ddd, 1 H, J1 = 6.9 Hz, J2 = 9.3 Hz,
J3 = 13.9 Hz), 2.62 (ddd, 1 H, J1 = 1.8 Hz, J2 = 7.8 Hz,
J3 = 17.4 Hz), 2.01 (dddd, 1 H, J1 = 5.6 Hz, J2 = 7.9 Hz,
J3 = 9.3 Hz, J4 = 13.6 Hz), 1.83 (dddd, 1 H, J1 = 5.2 Hz,
J2 = 6.9 Hz, J3 = 9.5 Hz, J4 = 13.6 Hz). 13C NMR (100 MHz,
CDCl3): 145.9, 141.1, 128.5, 126.0, 77.8, 40.5, 36.9, 31.8.
HRMS (ESI+): m/z calcd for [C11H13NO + H]: 176.1075;
found: 176.1070.
Analytical Data of Compound 10b
Bp 52 °C/15 mmHg (lit. 65 °C/25 mmHg);16 Rf = 0.57 (50%
EtOAc in hexane, KMnO4 stain). IR (film): 2976, 2918,
1680, 1641, 1599, 1438, 1379, 1275, 843 cm–1. 1H NMR
(400 MHz, CDCl3): d = 7.11 (br s, 1 H), 4.71–4.60 (m, 1 H),
3.07 (ddd, 1 H, J1 = 1.8 Hz, J2 = 10.3 Hz, J3 = 17.3 Hz), 2.57
(ddd, 1 H, J1 = 1.8 Hz, J2 = 7.7 Hz, J3 = 17.3 Hz), 1.32 (d, 3
H, J = 6.2 Hz). 13C NMR (100 MHz, CDCl3): d = 145.8,
74.8, 42.0, 20.7. HRMS (ESI+): m/z calcd for [C4H7NO – H]:
84.0449; found: 84.0453.
(19) Analytical Data of Compound 10d
Reaction time: 15.5 h; yield 0.061 g (63%); eluent: 10–30%
MTBE in hexane; Rf = 0.25 (50% EtOAc in hexane). IR
(film): 3419, 3064, 3031, 2918, 2852, 1726, 1602, 1496,
1453, 1367, 1114, 1027, 838 cm–1. 1H NMR (400 MHz,
CDCl3): d = 7.37–7.27 (m, 5 H), 7.12 (t, 1 H, J = 1.8 Hz),
4.71 (dtdd, 1 H, J1 = 0.5 Hz, J2 = 5.0 Hz, J3 = 7.4 Hz,
J4 = 10.7 Hz), 4.58 (s, 2 H), 3.58 (dd, 1 H, J1 = 5.0 Hz,
J2 = 10.4 Hz), 3.52 (dd, 1 H, J1 = 5.0 Hz, J2 = 10.4 Hz), 3.04
(ddd, 1 H, J1 = 1.8 Hz, J2 = 10.7 Hz, J3 = 17.6 Hz), 2.90
(ddd, 1 H, J1 = 1.8 Hz, J2 = 7.4 Hz, J3 = 17.6 Hz). 13C NMR
(22) The catalyst is highly soluble in chlorinated solvents, but
less soluble in hydrocarbons. Addition of hexanes assists in
catalyst removal. The same yield has also been obtained in
50 mmol scale by direct distillation of the reaction mixture,
without attempts to remove the catalyst components.
Synlett 2008, No. 6, 827–830 © Thieme Stuttgart · New York