Substituent effects in isoxazoles: Identification of 4-substituted isoxazoles as Michael acceptors

DOI: 10.1039/b207808b

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Journal of the Chemical Society. Perkin Transactions 2 (2001) p. 2031 - 2038 (2002)

Update date:2022-08-11

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Authors:

Lee, Connie K.Y.

Easton, Christopher J.

Gebara-Coghlan, Mariana

Radom, Leo

Scott, Anthony P.

Simpson, Gregory W.

Willis, Anthony C.

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Article abstract of DOI:10.1039/b207808b

Crystallographic and theoretical studies have been used to investigate substituent effects, which are manifest in electrochemical and yeast-catalysed reactions of 4- and 5-acyl-, alkoxycarbonyl-, cyano- and phenyl-substituted isoxazoles. The results show that isoxazoles substituted at the 4-position with π-electron-withdrawing substituents have enhanced C4-C5 bond polarity and are structurally similar to Michael acceptors. As a consequence there is elongation and weakening of their N-O bonds. By contrast, their 5-substituted regioisomers and isoxazoles substituted at C4 with conjugating, but not π-electron-withdrawing, substituents have diminished C4-C5 bond polarity. This results in the selective electrochemical and yeast-catalysed reduction of 4-substituted isoxazoles, as well as their hydrogenolytic ring cleavage and conjugate reduction with sodium borohydride.

Full text of DOI:10.1039/b207808b

View Article Online / Journal Homepage / Table of Contents for this issue

Substituent eﬀects in isoxazoles: identiﬁcation of 4-substituted

isoxazoles as Michael acceptors

Connie K. Y. Lee,^aChristopher J. Easton,*^aMariana Gebara-Coghlan,^aLeo Radom,^a

Anthony P. Scott,^aGregory W. Simpson^band Anthony C. Willis^a

^aResearch School of Chemistry, Australian National University, Canberra, ACT 0200,

Australia. E-mail: easton@rsc.anu.edu.au

^bCSIRO Molecular Science, Bayview Ave, Clayton, VIC 3168, Australia

Received (in Cambridge, UK) 9th August 2002, Accepted 13th September 2002

First published as an Advance Article on the web 24th October 2002

Crystallographic and theoretical studies have been used to investigate substituent eﬀects, which are manifest in

electrochemical and yeast-catalysed reactions of 4- and 5-acyl-, alkoxycarbonyl-, cyano- and phenyl-substituted

isoxazoles. The results show that isoxazoles substituted at the 4-position with π-electron-withdrawing substituents

have enhanced C4–C5 bond polarity and are structurally similar to Michael acceptors. As a consequence there is

elongation and weakening of their N–O bonds. By contrast, their 5-substituted regioisomers and isoxazoles

substituted at C4 with conjugating, but not π-electron-withdrawing, substituents have diminished C4–C5 bond

polarity. This results in the selective electrochemical and yeast-catalysed reduction of 4-substituted isoxazoles, as

well as their hydrogenolytic ring cleavage and conjugate reduction with sodium borohydride.

reaction of acetonitrile oxide and methyl (Z)-3-iodo-

Introduction

propenoate. Isoxazoles 3c and 4c were obtained via reaction

of 2,4,6-trimethylbenzonitrile oxide with methyl propiolate.

However, as the 5-substituted regioisomer 4c was found to be

not crystalline, compounds 3c and 4c could not be used for

structural studies.

Isoxazoles are aromatic heterocycles but their aromatic rings

are readily disrupted under reducing conditions.¹This occurs

via cleavage of their weak N–O bonds whereby the β-imino

ketone functionality is revealed. Ring-opening is most com-

monly accomplished through hydrogenation with a suitable

catalyst, such as palladium on carbon,²platinum black³or

Raney nickel.⁴Other reducing agents known to eﬀect ring-

cleavage include samarium iodide,⁵molybdenum hexacarbo-

nyl,⁶iron pentacarbonyl⁷and phenylmagnesium bromide.⁸

Previously, we reported ring-opening reactions of isoxazoles via

yeast catalysis⁹and electrolysis,¹⁰to give β-imino ketones as

analogues of the herbicide Grasp^®. Peculiar substituent eﬀects

were observed in these processes. Isoxazoles substituted at the

4-position with π-electron-withdrawing acyl, alkoxycarbonyl

and cyano groups reacted smoothly and eﬃciently, while the

5-substituted regioisomers and 4- and 5-phenylisoxazoles were

either inert or required more vigorous conditions to react, and

then gave complex product mixtures. We have now examined

the basis of these substituent eﬀects, using crystallographic and

theoretical methods, and found that 4-substituted isoxazoles

are polarised in such a way that they behave as Michael

acceptors.

X-Ray crystallographic analysis showed four crystallo-

graphically-independent molecules in the unit cell of 3a

and only one in those of each of 3b and 4a,b. In each case the

methoxycarbonyl group is coplanar with the isoxazole ring. The

carbonyl groups of 3a,b and 4a are s-trans to the C4–C5 bond,

while that of 4b is s-cis. Key bond lengths derived from the

crystallographic analyses of 3a,b and 4a,b are shown in Table 1.

The data obtained for the 3-methylisoxazoles 3b and 4b have

the lowest standard errors and are therefore the most reliable.

They show that relative to the carbonyl group of 4b, that of 3b

is more extensively conjugated to the ring. This is indicated

by elongation of the C41–O41 bond of 3b, compared with the

C51–O51 bond of 4b, and shortening of the C4–C41 bond of

3b, compared with the C5–C51 bond of 4b. This correlates with

the more extensive conjugation of the isoxazole ring oxygen

Results and discussion

Our crystallographic studies involved analyses of bond lengths

in regioisomeric pairs of 4- and 5-substituted isoxazoles. The

solid-state structures of compounds 1a,b and 2a,b had been

reported previously.^11–13The latter two each comprise a unit cell

with two crystallographically-independent molecules, while

those of the former two each exhibit only one, and selected

bond lengths for these structures are shown in Table 1. In

attempts to make further comparisons between regioisomers

and obtain data with lower standard errors, studies of com-

pounds 3a–c and 4a–c were also carried out. The 4- and 5-

methoxycarbonylisoxazoles 3a and 4a were synthesised via

cycloaddition of 2,6-dichlorobenzonitrile oxide with methyl

propiolate, while isoxazoles 3b and 4b were prepared through

DOI: 10.1039/b207808b

J. Chem. Soc., Perkin Trans. 2, 2002, 2031–2038

This journal is © The Royal Society of Chemistry 2002

2031

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Table 1 Selected bond lengths (Å) of acyl- and alkoxycarbonyl-isoxazoles determined through X-ray crystallographic analysis

Compound

O1–N2

C5–O1

C4–C5

C4–C41

C41–O41

C5–C51

C51–O51

1a^a

1b^a

2a^a

1.411(3)

1.426(2)

1.407(7)

1.397(7)

1.391(7)

1.398(7)

1.422(5)

1.423(5)

1.419(5)

1.427(2)

1.400(2)

1.416(2)

1.324(4)

1.320(3)

1.349(8)

1.329(8)

1.322(9)

1.329(9)

1.337(6)

1.339(6)

1.324(6)

1.340(6)

1.331(2)

1.349(2)

1.340(4)

1.330(3)

1.326(8)

1.32(1)

1.445(4)

1.438(3)

—

1.207(4)

1.188(3)

—

1.45(1)

1.461(9)

1.44(1)

1.48(1)

—

1.209(8)

1.188(7)

1.19(3)

1.18(1)

—

2b^a

1.32(1)

—

1.345(7)

1.354(7)

1.350(7)

1.338(7)

1.345(2)

1.337(3)

1.347(2)

1.472(7)

1.462(7)

1.464(7)

1.482(7)

1.459(2)

—

1.196(5)

1.211(5)

1.198(6)

1.204(5)

1.211(2)

—

1.477(3)

1.479(2)

1.203(2)

—

^aData from references 11–13.

Table 2 Calculated bond lengths (Å) for the isoxazole 5

Method

O1–N2

N2–C3

C3–C4

C4–C5

C5–O1

B3-LYP/6-31G*

B3-LYP/6-31ϩG*

B3-LYP/6-311ϩG(3df,2p)

MP2/6-31G*

1.400

1.401

1.394

1.392

1.396

1.400

1.313

1.305

1.328

1.311

1.313

1.424

1.425

1.420

1.414

1.427

1.426

1.360

1.362

1.354

1.364

1.355

1.360

1.345

1.339

1.354

1.349

1.346

CCSD/6-31G*

DRM microwave spectroscopy^a

^aData from reference 18.

with the enoate moiety in 3b than in 4b, as reﬂected in the

longer C5–O1 bond of 4b relative to that of 3b. In turn, this

conjugation of the isoxazole ring oxygen increases the length of

the N–O bond of 3b relative to that of 4b. The data for the

regioisomeric pairs 1a and 2a, 1b and 2b, and 3a and 4a, are

less accurate but seem to follow the same trends, particularly

as regards the N2–O1 and O1–C5 bonds. Thus 4-acyl- and

alkoxycarbonyl-substituted isoxazoles appear to display conju-

gation similar to that seen with α,β-unsaturated ketones and

acrylates, and as a consequence their N–O bonds are elongated

and presumably weakened.

In order to explore these observations, theoretical studies

of variously substituted isoxazoles were also carried out. The

theoretical calculations correspond to isolated gas-phase

molecules, and are thus not aﬀected by the intermolecular

interactions that may distort crystallographic data. The cal-

culations were carried out with standard ab initio and density

functional procedures^14,15using the GAUSSIAN 98 suite of

programs.¹⁶The methods employed for structural predictions

include the B3-LYP hybrid density functional theory approach,

second-order Møller–Plesset perturbation theory (MP2) and

coupled cluster theory (CCSD), with a variety of basis sets.

Conformational energies and electron aﬃnities were calculated

using the high-level G3(MP2)//B3-LYP procedure unless

otherwise noted, and refer to 0 K.¹⁷

The performance of the theoretical methods was ﬁrst evalu-

ated for the parent isoxazole 5. Computed bond lengths for

the minimum energy conformation were compared with those

derived experimentally through double-resonance-modulated

microwave spectroscopy¹⁸(Table 2). All the methods examined

gave reasonable geometries, but particularly good performance

was seen with the computationally eﬃcient B3-LYP/6-31G*

level of theory, where the maximum deviation from the experi-

mental values was found to be 0.002 Å. This method was there-

fore used in further studies of the formyl-, cyano- and vinyl-

substituted isoxazoles 6–11. The formyl group was chosen as

the simplest example of a carbonyl group. The cyano group

was examined as another π-electron-withdrawing substituent.

The vinyl group was investigated as a conjugating but not π-

electron-withdrawing substituent, representative of alkenyl and

aryl groups.

In the minimum energy conformations, the substituents of

the isoxazoles 6–11 are coplanar with the isoxazole rings, due to

conjugation. This gives rise to s-trans and s-cis forms (a and b)

with the formyl- and vinyl-isoxazoles 6, 7, 10 and 11. For

4-formylisoxazole 6, the G3(MP2)//B3-LYP calculations show

that the s-trans conformer 6a is more stable than the s-cis

form 6b by 2.7 kJ mol^Ϫ1, while with the 5-formylisoxazole 7,

the calculated energy diﬀerence between the s-trans and s-cis

conformers 7a and 7b is 6.4 kJ mol^Ϫ1, with the latter being

of lower energy. For the 4- and 5-vinylisoxazoles 10 and 11, the

s-trans forms 10a and 11a are favoured over the s-cis isomers

10b and 11b, by 4.4 and 3.2 kJ mol^Ϫ1, respectively.

Bond lengths derived from the minimum energy conforma-

tions of the isoxazoles 5–11 are shown in Table 3. The observed

trends are independent of the conformations in the cases of

6a,b, 7a,b, 10a,b and 11a,b. These trends for 6a,b and 7a,b are

similar to those discussed above on the basis of the crystallo-

graphic results for 1a,b and 2a,b, and 3a,b and 4a,b. It is

possible to make further comparisons by including the data for

the unsubstituted isoxazole 5. Conjugation of the carbonyl

groups to the rings in 6a,b and 7a,b is reﬂected in the greater

lengths of their C4–C5 bonds relative to that of 5. This

enhances conjugation between O1 and C4–C5 in 6a,b, as indi-

cated by the relative shortness of their C5–O1 bonds, but dis-

rupts conjugation between O1 and C4–C5 in 7a,b, as indicated

by the relatively greater lengths of their C5–O1 bonds. As a

result, the O1–N2 bonds of 6a,b are longer than that of 5, while

those of 7a,b are shorter. The cyano and vinyl substituents are

also conjugated with the isoxazole rings of 8–11, as indicated by

the lengths of their C4–C5 bonds relative to that of 5. Further

analysis of bond lengths shows that when these groups are

located at C5, in 9 and 11a,b, they disrupt conjugation between

O1 and C4–C5 and increase the O1–N2 interaction. The cyano

group at C4 in 8 increases the extent of conjugation between O1

and C4–C5 and decreases the O1–N2 interaction, to a similar

extent to that seen with the formyl substituent in 6a,b. By com-

parison, the vinyl group at C4 of 10a,b has little eﬀect on either

2032

J. Chem. Soc., Perkin Trans. 2, 2002, 2031–2038

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Table 3 Selected bond lengths (Å) of the isoxazoles 5–11 derived for their minimum energy conformations using the B3-LYP/6-31G* method

C41–O41

C41–N41

C41–C42

C51–O51

C51–N51

C51–C52

Compound

O1–N2

C5–O1

C4–C5

C4–C41

C5–C51

1.400

1.415

1.412

1.386

1.387

1.405

1.387

1.402

1.401

1.398

1.394

1.345

1.334

1.332

1.351

1.355

1.334

1.356

1.343

1.341

1.354

1.356

1.360

1.369

1.371

1.369

1.368

1.370

1.367

1.368

1.370

1.371

1.372

—

1.464

1.466

—

1.419

—

1.457

1.460

—

1.217

—

1.163

—

1.339

—

1.472

1.471

—

1.419

—

1.451

1.453

1.212

1.215

—

1.163

—

1.339

10a

10b

11a

11b

—

Table 4 π-Electron densities of the isoxazoles 5–11 derived for their minimum energy conformations using the B3-LYP/6-31G* method

Compound

C41

O41

N41

C42

C51

O51

N51

C52

1.68

1.66

1.67

1.68

1.66

1.68

1.67

1.70

1.69

1.23

1.22

1.23

1.19

1.20

1.22

1.20

1.22

1.23

0.99

0.95

0.97

0.99

0.97

0.98

0.99

1.00

0.99

1.09

1.10

1.05

1.03

1.13

1.05

1.06

1.07

1.10

1.00

0.96

0.94

1.01

1.02

0.97

1.05

1.02

1.01

0.99

—

1.09

—

1.02

—

1.29

1.30

—

1.08

—

0.79

—

0.96

—

1.00

—

1.31

1.32

—

0.80

0.79

—

0.96

—

1.02

1.00

10a

10b

11a

11b

—

0.97

0.99

—

isoxazoles, with their electron-deﬁcient C5 centres. Presumably

these reactions proceed via the corresponding radical anions,

and properties of these species might also be expected to pro-

vide an indication of their ease of formation. However, analysis

of bond lengths (Table 5) and π-electron distributions (Table 6)

in the radical anions of 5–11, and of the electron aﬃnities of

the isoxazoles 5–11 to give the corresponding radical anions

(Table 7) gives no indication of other factors that might con-

tribute to the observed pattern of reactivity. Indeed the electron

aﬃnities of the 5-formyl- and cyano-substituted isoxazoles 7a,b

and 9 are higher than those of the 4-substituted isomers 6a,b

and 8, in contrast to the greater reactivity recorded for com-

pounds of the latter types.

Thus the crystallographic and theoretical studies show a

correlation between the structural eﬀects of the substituents

and the susceptibility of isoxazoles towards electrochemical

and yeast-catalysed reduction. These processes result indirectly

in ring-opening through N–O bond cleavage. To determine if

there would also be a relationship between direct N–O bond

cleavage and the elongation of bonds of this type in isoxazoles

substituted at C4 with π-electron-withdrawing substituents,

pairs of regioisomeric 4- and 5-substituted isoxazoles were sub-

jected to catalytic hydrogenation. Each of the isoxazoles 1a, 2a,

3c and 4c underwent ring-opening on treatment with hydrogen

over palladium on carbon, to give the corresponding imines

12–15. However, in competitive experiments, the 4-carbonyl-

substituted isoxazoles 1a and 3c were more reactive than their

corresponding 5-substituted isomers 2a and 4c. Reaction of

a 1 : 1 mixture of 1a and 2a when stopped part way aﬀorded a

1 : 5 : 6 : 2 mixture of 1a, 2a, 12 and 13, showing that 1a had

reacted approximately six times faster than 2a. A 1 : 1 mixture

of 3c and 4c gave a 10 : 11 : 1 mixture of 4c, 14 and 15, and

there was no evidence of residual 3c, demonstrating that 3c is at

least an order of magnitude more reactive than 4c. It is there-

fore apparent that the elongation of N–O bonds of substituted

isoxazoles results in their weakening and selective cleavage.

Another feature of 4-carbonyl- and cyano-substituted

isoxazoles identiﬁed through the structural studies, and already

mentioned above, is their similarity to Michael acceptors. To see

the O1–C4–C5 or O1–N2 interaction, presumably due to the

non-polar nature of this substituent.

Through their conjugation with the isoxazole rings, the sub-

stituents of compounds 6–11 aﬀect the π-electron distribution

to various degrees (Table 4). The C4–C5 bond of 5 is polarised,

and this is enhanced by the formyl substituent at C4 of 6a,b, but

diminished by that substituent at C5 of 7a,b. The less polar

cyano group has a similar but less marked eﬀect in 8 and 9,

while the non-polar vinyl substituent of 10a,b and 11a,b has

little impact on the electron distribution. It seems likely that this

polarisation is the reason for the facile electrochemical and

yeast-catalysed reduction of 4-carbonyl- and cyano-substituted

J. Chem. Soc., Perkin Trans. 2, 2002, 2031–2038

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Table 5 Selected bond lengths (Å) of the radical anions of the isoxazoles 5–11, determined using the B3-LYP/6-31G* method

Radical

anion

precursor

C41–O41

C41–N41

C41–C42

C51–O51

C51–N51

C51–C52

O1–N2

C5–O1

C4–C5

C4–C41

C5–C51

5^a

5^b

1.470

1.491

1.420

1.416

1.421

1.418

1.434

1.442

1.445

1.427

1.418

1.431

1.426

1.448

1.444

1.422

1.407

1.406

1.398

1.404

1.397

1.385

1.390

1.415

1.409

1.408

1.417

1.404

1.414

1.404

1.390

1.396

1.432

1.400

1.426

1.413

1.420

1.412

1.413

1.408

1.453

1.436

1.419

1.442

1.423

1.432

1.416

—

1.420

1.423

1.421

1.423

—

1.415

1.414

—

1.382

—

1.403

1.402

—

1.265

1.272

1.262

1.266

—

1.264

1.270

—

1.189

—

1.395

1.399

6a^a

6a^b

6b^a

6b^b

7a^b

7b^b

8^a

—

1.396

1.395

—

1.424

1.423

—

1.179

1.182

—

1.378

1.392

1.376

1.384

—

8^b

9^b

10a^a

10a^b

10b^a

10b^b

11a^b

11b^b

—

^aNon-planar conformation (see footnote c). ^bPlanar conformation. ^cThe minimum energy conformations of the radical anions of 7a,b, 9 and 11a,b

are all planar. Those of 5, 6a,b, 8 and 10a,b are non-planar. The planar conformations of the anions of 5, 6a,b, 8 and 10a,b are less stable than the

non-planar forms, by 14.8, 1.7, 1.0, 14.7, 7.5 and 5.6 kJ mol^Ϫ1, respectively (B3-LYP/6-31G*, no ZPVE).

Table 6 π-Electron densities of the planar conformations of the radical anions of the isoxazoles 5–11, determined using the B3-LYP/6-31G*

method

Radical anion

percursor

C41

C51

O41

O51

N41

N51

C42

C52

1.81

1.77

1.75

1.76

1.80

1.79

1.78

1.49

1.28

1.29

1.35

1.36

1.34

1.39

1.30

1.32

1.39

1.18

0.99

1.02

1.06

1.05

1.03

1.07

1.02

1.05

1.06

1.05

1.20

1.11

1.22

1.20

1.23

1.22

1.12

1.11

1.25

1.32

1.27

1.25

1.07

1.22

1.20

1.32

1.28

1.06

1.07

—

1.49

1.50

—

1.28

—

1.30

—

1.34

1.31

—

1.05

—

1.00

—

1.12

1.11

—

1.53

1.51

—

1.05

—

1.03

—

1.16

1.15

10a

10b

11a

11b

—

1.29

1.31

—

Table 7 Electron aﬃnities (eV) of the isoxazoles 5–11, determined

conjugate reduction to give the isoxazoline 16a, in 91% yield.

The generality of these processes was explored using the isoxa-

zoles 3d and 4d, which were obtained by treatment of methyl

(Z)-3-iodopropenoate with decanenitrile oxide. On reaction

with borohydride, 4d gave the isoxazole 17b in 92% yield, while

3d produced the isoxazoline 16b and the isoxazole 18, in yields

of 73 and 18%, respectively. Clearly the 4-substituted isoxazoles

3c,d behave as masked acrylates but this is not observed

with the 5-substituted regioisomers 4c,d. To the best or our

knowledge, there is only one other report of hydride reduction

of isoxazoles to give isoxazolines,¹⁹and in that case it was

shown that 4-carbonyl-substituted isoxazoles did not react in

this manner. This inconsistency may be attributed to the use

of at least a ten-fold excess of sodium borohydride in the

present study, but only stoichiometric quantities in the earlier

work. Brown and Rapoport²⁰have shown that a large excess

of reducing agent is required for conjugate reduction of α,β-

unsaturated esters.

using the G3(MP2)/B3-LYP method

Compound

Electron aﬃnity (eV)

Ϫ1.02

0.15

0.35

0.74

0.75

0.10

0.41

10a

10b

11a

11b

Ϫ0.55

Ϫ0.28

Ϫ0.02

In summary, the present studies show that a conjugating,

π-electron-withdrawing substituent at the 4-position of an

isoxazole elongates the N–O bond, and enhances the C4–C5

bond polarity to a similar extent to that seen with Michael

acceptors. As a result these isoxazoles are susceptible to electro-

chemical and yeast-catalysed reduction and hydrogenolytic

ring cleavage, and they undergo conjugate reduction with boro-

hydride. The latter observation is probably the most important

in terms of synthetic potential, given the versatile functionality

of isoxazoles and their rigidity, which should make them

suitable for exploitation in asymmetric synthesis. To this end

if this would be reﬂected in their reactivity, the isoxazoles 3c

and 4c were treated with an excess of sodium borohydride. With

the 5-methoxycarbonylisoxazole 4c, reaction aﬀorded only the

hydroxymethylisoxazole 17a, which was isolated in 93% yield.

By contrast, the 4-methoxycarbonylisoxazole 3c underwent

2034

J. Chem. Soc., Perkin Trans. 2, 2002, 2031–2038

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PhH), 9.08 (1H, s, H5); δ_C52.1 (CH₃O), 114.2 (C4), 126.8 (C),

127.9 (2 × CH), 132.0 (CH), 135.4 (2 × C), 154.9 (C3), 158.7

(C᎐O), 163.2 (C5); m/z 238, 236 (M^ϩϪ Cl, 51 and 100%), 212

᎐

(22), 198 (13), 184 (8), 171 (6), 157 (5), 148 (8), 136 (4), 109 (7),

100 (3), 75 (5); Found 238.0085. C₁₁H₇³⁷ClNO₃(M^ϩϪ Cl)

requires 238.0085; Found, 236.0112. C₁₁H₇³⁵ClNO₃(M^ϩϪ Cl)

requires 236.0111; and 4a (700 mg, 57%) as a colourless solid,

mp 114–116 ЊC (lit.¹⁰mp 114–116 ЊC); ν_max1736, 1593, 1581,

1459, 1377, 1307, 1232, 1198, 1152, 1100, 1079, 1001, 953, 915,

851, 807, 789, 772, 730, 710 cm^Ϫ1; δ_H4.03 (3H, s, CH₃O), 7.08

(1H, s, H4), 7.27–7.50 (3H, m, 3 × PhH); m/z 277, 275, 273

(M^ϩ, 5, 23 and 46%), 216 (29), 214 (75), 212 (100), 186 (38),

184 (46); the H NMR spectral data of the isoxazole 4a are

consistent with reported values.¹⁰

X-Ray data for 3a. C₁₁H₇Cl₂NO₃, primitive orthorombic,

space group Pna2₁(no. 33), a = 14.7870(2) Å, b = 22.7232(3) Å,

c = 14.1751(2) Å, V = 4763.0(1) Å³, Z = 16, D_calc= 1.518 g cm^Ϫ3

µ = 5.38 cm^Ϫ1. A total of 69227 reﬂections were measured,

corrected for absorption²⁴and merged to yield 5676 unique

reﬂections (R_int= 0.065). Hydrogen atoms were included at

geometrically determined positions. The compound is present

as a racemate within the crystal structure. There are four

independent molecules of C₁₁H₇Cl₂NO₃in the crystallographic

asymmetric unit. The absolute structure of the crystal was

determined by relative reﬁnement. Final agreement factors for

3287 reﬂections with I > 2σ(I) and 612 parameters were R =

0.038, wR = 0.037 and gof = 0.97. CCDC reference number

191571. See http://ww w .rsc.org/suppdata/p2/b2/b207808b/ for

crystallographic ﬁles in .cif or other electronic format.

we intend to investigate reductions and nucleophilic addition

reactions of isoxazoles that are substituted at C4 with chiral

auxiliaries attached via ester linkages.

Experimental

Melting points were determined on

a Koﬂer hot-stage

apparatus under a Reichert microscope and are uncorrected. ¹H

and ¹³C NMR spectra were recorded on either a Varian Gemini

300 or a Varian Mercury 300 spectrometer, as dilute solutions

in CDCl₃. Electron impact mass spectra were recorded on either

a VG Micromass 7070F or an AEI MS-30 spectrometer, operat-

ing at an ionisation potential of 70 eV. IR spectra were recorded

on KBr discs using a Perkin-Elmer 1800 Fourier Transform

Infrared Spectrometer. Elemental analyses were performed by

the Microanalytical Laboratory, Research School of Chemistry,

Australian National University. Chromatography was per-

formed using Merck-Keiselgel 60 (230–400 mesh ASTM). The

ketoisoxazoles 1a and 2a were prepared as reported.¹⁰

X-Ray data for 4a. C₁₁H₇Cl₂NO₃, primitive monoclinic, space

group P2₁/a (no. 14), a = 10.4382(3) Å, b = 10.2875(4) Å, c =

11.4036(5) Å, β = 109.859(2)Њ, V = 1151.73(7) Å³, Z = 4, D_calc

1.569 g cm^Ϫ3, µ = 5.56 cm^Ϫ1. A total of 20168 reﬂections were

measured, corrected for absorption²⁴and merged to yield 2631

unique reﬂections (R_int= 0.058). Hydrogen atom coordinates

were reﬁned. Final agreement factors for 1685 reﬂections with

I > 2σ(I) and 175 parameters were R = 0.033, wR = 0.038

and gof = 0.93. CCDC reference number 191572. See http://

www.rsc.org/suppdata/p2/b2/b207808b/ for crystallographic

ﬁles in .cif or other electronic format.

Single crystal X-ray diﬀraction data were obtained for 3a,b

and 4a,b. A Nonius Kappa CCD diﬀractometer with graphite-

monochromated Mo-Kα radiation (λ = 0.71069 Å) was used for

all crystals. Intensity data were collected at 200 K to 2θ_max= 55Њ

in each case. The structures were solved by direct methods²¹

and reﬁned on F by full-matrix least-squares.²²Non-hydrogen

atoms were reﬁned with anisotropic displacement parameters.

Further speciﬁc details are given under the individual com-

pounds.

3-Methylisoxazole-4-carboxylic acid methyl ester 3b and

3-methylisoxazole-5-carboxylic acid methyl ester 4b

To a stirred mixture of (Z)-3-iodopropenoic acid methyl ester

(11.3 g, 53.4 mmol) and acetohydroximoyl chloride²⁵(620 mg,

6.67 mmol) at 18 ЊC was added over 16 h a solution of triethyl-

amine (1.02 mL, 7.34 mmol) in dry Et₂O (4 mL). After stirring

at 18 ЊC for a further 24 h, the mixture was poured into H₂O

(75 mL) and the layers were separated. The aqueous phase was

extracted with Et₂O (3 × 75 mL) and the combined organic

solutions were washed with brine (1 × 75 mL) and then dried

(anhydrous MgSO₄). The ethereal solvent was distilled oﬀ at

atmospheric pressure and ﬂash column chromatography of

the residue, eluting with hexanes–EtOAc (4 : 1) aﬀorded the

title compounds 3b (197 mg, 21%) as colourless blocks, after

recrystallization from hexanes and Et₂O at 0 ЊC; mp 24–25 ЊC

ν_max1734, 1592, 1491, 1435, 1405, 1299, 1249, 1133, 1109, 805,

772 cm^Ϫ1; δ_H2.50 (3H, s, CH₃), 3.86 (3H, s, CH₃O), 8.84 (1H, s,

H5); δ_C10.1 (CH₃), 51.2 (CH₃O), 112.7 (C4), 158.2 (C3), 161.3

3-(2,6-Dichlorophenyl)isoxazole-4-carboxylic acid methyl ester

3a and 3-(2,6-dichlorophenyl)isoxazole-5-carboxylic acid methyl

ester 4a

Triethylamine (0.70 mL, 5.0 mmol) was added dropwise over

15 min to a stirred mixture of 2,6-dichlorobenzohydroximoyl

chloride²³(1.0 g, 4.5 mmol) and methyl propiolate (0.47 g,

5.6 mmol) in THF (20 mL) at 18 ЊC. After heating the mixture

at reﬂux for 2 days, the solvent was removed under reduced

pressure. The residue was taken up in Et₂O (100 mL) and the

solution was washed with H₂O (2 × 75 mL). The aqueous solu-

tions were extracted with Et₂O (3 × 75 mL). The combined

organic solutions were washed with brine (1 × 50 mL), dried

(anhydrous MgSO₄) and concentrated in vacuo. Flash column

chromatography of the residue, eluting with hexanes–EtOAc

(4 : 1) aﬀorded the title compounds 3a (233 mg, 19%) as colour-

less needles, after recrystallization through vapour diﬀusion

from hexanes and Et₂O at 18 ЊC, mp 85–87 ЊC; ν_max1732, 1576,

1561, 1433, 1395, 1306, 1196, 1148, 1128, 1105, 1075, 1017, 861,

775, 730 cm^Ϫ1; δ_H3.76 (3H, s, CH₃O), 7.34–7.45 (3H, m, 3 ×

(C᎐O), 162.5 (C5); Found 141.0425. C H NO (M^ϩ) requires

᎐

141.0426; and 4b (508 mg, 54%) as colourless plates, after

recrystallization from hexanes and Et₂O at 0 ЊC, mp 94–95 ЊC;

ν_max1731, 1444, 1382, 1299, 1233, 1093, 1004, 932, 900, 851, 771

cm^Ϫ1; δ_H2.38 (3H, s, CH₃), 3.96 (3H, s, CH₃O), 6.80 (1H, s, H4);

δ_C11.3 (CH₃), 52.7 (CH₃O), 110.0 (C4), 157.2 (C3), 159.7 (C5),

160.4 (C᎐O); m/z 141 (M^ϩ, 76%), 115 (6), 110 (23), 102 (10), 91

᎐

(3), 82 (100), 77 (3), 73 (10), 63 (2), 59 (8), 54 (23).

J. Chem. Soc., Perkin Trans. 2, 2002, 2031–2038

2035

View Article Online

X-Ray data for 3b. C₆H₇NO₃, primitive monoclinic, space

group P2₁/c (no. 14), a = 7.8027(3) Å, b = 11.2422(5) Å, c =

iodopropenoic acid methyl ester (4.00 g, 18.9 mmol) and

decylhydroximoyl chloride (prepared from decanaldoxime

and N-chlorosuccinimide) (485 mg, 2.36 mmol) in dry Et₂O

(100 mL) at 18 ЊC. After stirring at 18 ЊC for a further 24 h, the

mixture was poured into H₂O (50 mL). The aqueous layer was

separated and extracted with Et₂O (3 × 100 mL). The combined

organic solutions were washed with brine (1 × 75 mL), dried

(anhydrous MgSO₄) and concentrated in vacuo. Flash column

chromatography of the residue, eluting with hexanes–CH₂Cl₂

(1 : 1) aﬀorded the title compounds 3d (102 mg, 17%) as a

colourless oil (Found: C, 66.62; H, 9.39; N, 5.74. C₁₄H₂₃NO₃

requires C, 66.37; H, 9.15; N, 5.53%); ν_max2926, 2855, 1735,

1586, 1436, 1297, 1245, 1134, 1103, 806, 778 cm^Ϫ1; δ_H0.89 (3H,

t, J 6.7, CH₃CH₂), 1.20–1.45 (12H, m, 6 × CH₂), 1.72 (2H,

quintet, J 7.7, CH₂), 2.92 (2H, t, J 7.7, CH₂), 3.87 (3H, s,

CH₃O), 8.85 (1H, s, H5); δ_C14.1 (CH₃), 22.6 (CH₂), 25.2 (CH₂),

27.6 (CH₂), 29.24 (CH₂), 29.2 (CH₂), 29.3 (CH₂), 29.4 (CH₂),

8.4806(4) Å, β = 111.428(2)Њ, V = 692.49(5) Å³, Z = 4, D_calc

1.354 g cm^Ϫ3, µ = 1.10 cm^Ϫ1. A total of 14023 reﬂections were

measured, corrected for absorption²⁴and merged to yield 1573

unique reﬂections (R_int= 0.059). Hydrogen atom coordinates

and isotropic displacement factors were reﬁned. Final

agreement factors for 904 reﬂections with I > 2σ(I) and 115

parameters were R = 0.036, wR = 0.040 and gof = 1.01. CCDC

reference number 191573. See http://ww w .rsc.org/suppdata/p2/

b2/b207808b/ for crystallographic ﬁles in .cif or other electronic

format.

X-Ray data for 4b. C₆H₇NO₃, primitive monoclinic, space

group P2₁/m (no. 11), a = 5.8086(2) Å, b = 6.3238(3) Å, c =

8.8391(4) Å, β = 92.435(2)Њ, V = 324.39(2) Å³, Z = 2, D_calc

1.445 g cm^Ϫ3, µ = 1.17 cm^Ϫ1. A total of 9358 reﬂections were

measured, corrected for absorption²⁶and merged to yield 752

unique reﬂections (R_int= 0.045). Hydrogen atom coordinates

and isotropic displacement parameters were reﬁned. All non-

hydrogen atoms lie on a crystallographic mirror plane. Final

agreement factors for 693 reﬂections with I > 2σ(I) and 76

parameters were R = 0.035, wR = 0.053 and gof = 2.12. CCDC

reference number 191574. See http://ww w .rsc.org/suppdata/p2/

b2/b207808b/ for crystallographic ﬁles in .cif or other electronic

format.

31.8 (CH ), 51.8 (CH O), 112.7 (C4), 161.7 (C3), 162.5 (C᎐O),

᎐

163.0 (C5); m/z 253 (M^ϩ, 25%), 238 (7), 222 (18), 210 (12), 194

(14), 182 (17), 168 (13), 154 (49), 141 (100), 122 (26), 110 (7),

96 (16), 83 (19), 68 (19); Found 253.1675. C₁₄H₂₃NO₃(M^ϩ

)

requires 253.1678; and 4d (258 mg, 43%) as a colourless solid,

mp 50–52 ЊC (Found: C, 66.28; H, 8.72; N, 5.37. C₁₄H₂₃NO₃

requires C, 66.37; H, 9.15; N, 5.53%); ν_max2953, 2914, 2848,

1731, 1470, 1291, 1274, 1088, 1007, 908, 851, 770, 717 cm^Ϫ1

;

δ_H0.88 (3H, t, J 7.0, CH₃CH₂), 1.28–1.43 (12H, m, 6 × CH₂),

1.67 (2H, quintet, J 7.5, CH₂), 2.72 (2H, t, J 7.5, CH₂), 3.96

(3H, s, CH₃O), 6.81 (1H, s, H4); δ_C14.0 (CH₃), 22.6 (CH₂), 25.9

(CH₂), 28.1 (CH₂), 29.0 (CH₂), 29.2 (2 × CH₂), 29.4 (CH₂), 31.8

3-(2,4,6-Trimethylphenyl)isoxazole-4-carboxylic acid methyl

ester 3c and 3-(2,4,6-trimethylphenyl)isoxazole-5-carboxylic

acid methyl ester 4c

(CH ), 52.7 (CH O), 109.2 (C4), 157.3 (C3), 159.3 (C᎐O), 164.7

᎐

(C5); m/z 253 (M^ϩ, 11%), 238 (6), 224 (3), 210 (5), 194 (58), 182

A mixture of 2,4,6-trimethylbenzonitrile oxide²³(400 mg, 2.48

mmol) and methyl propiolate (208 mg, 2.48 mmol) in THF

(65 mL) was heated at reﬂux for 2 days. After the solvent was

removed under reduced pressure, the residue was taken up in

Et₂O (100 mL) and the solution was washed with H₂O (1 ×

75 mL). The aqueous phase was separated and extracted with

Et₂O (3 × 75 mL). The combined organic solutions were

washed with brine (1 × 75 mL), dried (anhydrous MgSO₄)

and concentrated in vacuo. Flash column chromatography of

the residue, eluting with hexanes–Et₂O (7 : 3) aﬀorded the

title compounds 3c (425 mg, 70%) as colourless blocks, after

recrystallization through vapour diﬀusion from hexanes and

Et₂O at 18 ЊC, mp 75–77 ЊC (Found: C, 68.22; H, 6.03; N, 5.60.

C₁₄H₁₅NO₃requires C, 68.56; H, 6.16; N, 5.71%); ν_max1724,

1610, 1573, 1457, 1394, 1306, 1136, 1018, 839, 407 cm^Ϫ1; δ_H2.05

(6H, s, o,oЈ-MesCH₃), 2.33 (3H, s, p-MesCH₃), 3.73 (3H, s,

CH₃O), 6.94 (2H, s, 2 × MesH), 9.06 (1H, s, H5); δ_C19.8 (2 ×

CH₃), 21.1 (CH₃), 51.7 (CH₃O), 113.7 (C4), 123.7 (C), 128.1

(4), 166 (21), 154 (43), 141 (100), 122 (7), 108 (6), 96 (11), 82

(16), 68 (16); Found 253.1676. C₁₄H₂₃NO₃(M^ϩ) requires

253.1678.

(E )-3-Amino-2-formyl-3-(2,4,6-trimethylphenyl)acrylic acid

methyl ester 14

A solution of 3-(2,4,6-trimethylphenyl)isoxazole-4-carboxylic

acid methyl ester 3c (100 mg, 0.408 mmol) in MeOH (1 mL) was

added to a suspension of 10% palladium on carbon (10 mg) in

MeOH (5 mL) under an atmosphere of hydrogen. After stirring

at 18 ЊC for 24 h, the mixture was ﬁltered through a pad of

Celite^®. The ﬁlter cake was washed with MeOH (5 × 10 mL)

and the combined ﬁltrates were concentrated under reduced

pressure. Flash column chromatography of the residue, eluting

with hexanes–EtOAc (4 : 1) aﬀorded the title compound 14

(99 mg, 98%) as a colourless oil (Found: C, 67.96; H, 6.90; N,

5.62. C₁₄H₁₇NO₃requires C, 68.00; H, 6.93; N, 5.66%); ν_max

3440, 3319, 2948, 2924, 1731, 1600, 1535, 1436, 1270, 1186,

1125 cm^Ϫ1; δ_H2.22 (6H, s, o,oЈ-MesCH₃), 2.30 (3H, s,

p-MesCH₃), 3.76 (3H, s, CH₃O), 5.81 (2H, br s, NH₂), 6.89 (2H,

s, 2 × MesH), 10.2 (1H, s, CHO); δ_C19.0 (2 × CH₃), 21.1 (CH₃),

50.8 (CH₃O), 101.9 (CCO₂CH₃), 128.1 (2 × CH), 133.4 (2 × C),

(2 × CH), 136.8 (2 × C), 138.9 (C), 160.8 (C3 and C᎐O), 163.2

᎐

(C5); m/z 245 (M^ϩ, 100%), 228 (20), 214 (21), 198 (6), 186 (58),

170 (29), 158 (84), 149 (6), 142 (23), 130 (26), 115 (28), 103 (16),

91 (36), 84 (15), 77 (28), 65 (13), 57 (15); Found 245.1053.

C₁₄H₁₅NO₃(M^ϩ) requires 245.1052; and 4c (164 mg, 27%) as

a colourless oil (Found: C, 68.46; H, 6.25; N, 5.58. C₁₄H₁₅NO₃

requires C, 68.56; H, 6.16; N, 5.71%); ν_max2955, 1749, 1653,

1613, 1585, 1505, 1457, 1384, 1305, 1286, 1235, 1221, 1171,

1123, 1002, 852, 770 cm^Ϫ1; δ_H2.13 (6H, s, o,oЈ-MesCH₃), 2.38

(3H, s, p-MesCH₃), 4.01 (3H, s, CH₃O), 6.90 (1H, s, H4), 6.96

(2H, s, 2 × MesH); δ_C20.1 (2 × CH₃), 21.0 (CH₃), 52.7 (CH₃O),

110.9 (C4), 124.7 (C), 128.4 (2 × CH), 137.0 (C), 139.2 (2 × C),

133.9 (C), 138.4 (C), 166.6 (CNH ), 170.8 (C᎐O), 191.9 (CHO);

᎐

m/z 247 (M^ϩ, 8%), 232 (100), 217 (60), 202 (66), 186 (25), 172

(50), 158 (40), 146 (85), 130 (21), 115 (17), 88 (11), 77 (14);

Found 247.1207. C₁₄H₁₇NO₃(M^ϩ) requires 247.1208.

The relative conﬁguration of compound 14 is assumed to be

E, based on the structure of the precursor isoxazole 3c.

157.2 (C3), 159.9 (C᎐O), 162.6 (C5); m/z 245 (M^ϩ, 59%), 214

᎐

(5), 186 (100), 171 (12), 158 (70), 143 (26), 133 (18), 119 (20),

(Z )-2-Hydroxy-4-imino-4-(2,4,6-trimethylphenyl)but-2-enoic

115 (24), 103 (15), 91 (30), 77 (22), 62 (9), 57 (8); Found

acid methyl ester 15

245.1056. C₁₄H₁₅NO₃(M^ϩ) requires 245.1052.

A solution of 3-(2,4,6-trimethylphenyl)isoxazole-5-carboxylic

acid methyl ester 4c (100 mg, 0.408 mmol) in MeOH (1 mL) was

added to a suspension of 10% palladium on carbon (10 mg) in

MeOH (3 mL) under an atmosphere of hydrogen. After stirring

at 18 ЊC for 10 days, the mixture was ﬁltered through a pad of

Celite^®. The ﬁlter cake was washed with MeOH (5 × 10 mL)

3-Nonylisoxazole-4-carboxylic acid methyl ester 3d and

3-nonylisoxazole-5-carboxylic acid methyl ester 4d

A solution of triethylamine (0.37 mL, 2.60 mmol) in Et₂O

(10 mL) was added over 18 h to a stirred solution of (Z)-3-

2036

J. Chem. Soc., Perkin Trans. 2, 2002, 2031–2038

View Article Online

and the combined ﬁltrates were concentrated under reduced

pressure. Flash column chromatography of the residue, eluting

with hexanes–EtOAc (4 : 1) aﬀorded the title compound 15 (99

mg, 98%) as a colourless oil (Found: C, 67.92; H, 6.91; N, 5.63.

C₁₄H₁₇NO₃requires C, 68.00; H, 6.93; N, 5.66%); δ_H2.26 (s, 6H,

o,oЈ-MesCH₃), 2.30 (s, 3H, p-MesCH₃), 3.85 (s, 3H, CH₃O),

5.76 (br s, 1H, NH or OH), 5.90 (s, 1H, CH), 6.90 (s, 2H, 2 ×

MesH), 10.5 (br s, 1H, NH or OH); δ_C19.2 (2 × CH₃), 21.0

(CH₃), 52.6 (CH₃O), 94.4 (CH), 128.3 (2 × CH), 133.5 (C),

5-carboxylic acid methyl ester 4c (80.0 mg, 0.326 mmol) in dry

EtOH (6 mL) at 0–5 ЊC (ice bath). After heating at reﬂux for

24 h, the mixture was cooled to 0–5 ЊC (ice bath) and quenched

by dropwise addition of 1 M HCl (to pH 2). The solvent was

removed under reduced pressure, the residue was taken up

in Et₂O (10 mL) and the solution was washed with H₂O (1 ×

7 mL). The aqueous layer was extracted with Et₂O (3 × 10 mL).

The combined organic solutions were washed with H₂O (1 ×

7 mL), aq. NaHCO₃(1 × 7 mL) and brine (1 × 7 mL), dried

(anhydrous MgSO₄) and concentrated in vacuo. Flash column

chromatography of the residue, eluting with hexanes–EtOAc

(4 : 1) aﬀorded the title compound 17a (66 mg, 93%) as a colour-

less oil (Found: C, 71.63; H, 6.91; N, 6.56. C₁₃H₁₅NO₂requires

C, 71.87; H, 6.96; N, 6.45%); ν_max3382, 2923, 2860, 1612, 1457,

1393, 1363, 1173, 1142, 1076, 1036, 996, 888, 852, 813, 575

cm^Ϫ1; δ_H1.20 (1H, br s, OH), 2.15 (6H, s, oЈ,oЈ-MesCH₃), 2.33

(3H, s, p-MesCH₃), 4.87 (2H, s, CH₂O), 6.21 (1H, s, H4), 6.95

(2H, s, 2 × MesH); δ_C20.1 (2 × CH₃), 21.0 (CH₃), 56.3 (CH₂O),

103.2 (C4), 125.7 (C), 128.3 (2 × CH), 137.0 (2 × C), 138.9 (C),

134.7 (2 × C), 139.0 (C), 164.0 (CCO Me), 168.0 (C᎐NH), 178.4

᎐

(C᎐O); m/z 247 (M^ϩ, 14%), 188 (100), 158 (7), 145 (36), 130

᎐

(23), 115 (9), 105 (6), 91 (8), 77 (6); Found 247.1210. C₁₄H₁₇NO₃

(M^ϩ) requires 247.1208.

The relative conﬁguration of compound 15 is assumed to be

Z, based on the structure of the precursor isoxazole 4c.

Competitive hydrogenation of 3-(2,4,6-trimethylphenyl)isoxa-

zole-4-carboxylic acid methyl ester 3c and 3-(2,4,6-trimethyl-

phenyl)isoxazole-5-carboxylic acid methyl ester 4c

162.1 (C3), 171.7 (C5); m/z 217 (M^ϩ, 64%), 205 (3), 186 (100),

To a mixture of 3-(2,4,6-trimethylphenyl)isoxazole-4-carboxylic

acid methyl ester 3c (50.0 mg, 0.204 mmol) and 3-(2,4,6-tri-

methylphenyl)isoxazole-5-carboxylic acid methyl ester 4c

(50.0 mg, 0.204 mmol) in MeOH (5 mL) was added 10% pal-

ladium on carbon (10 mg) under an atmosphere of hydrogen.

After the suspension was stirred at 18 ЊC for 2 days, the mixture

was ﬁltered through a pad of Celite^®. The ﬁlter cake was

washed with MeOH (5 × 10 mL), and the combined ﬁltrates

171 (13), 143 (26), 131 (17), 119 (22), 115 (21), 103 (12), 91 (30),

77 (19), 65 (9), 53 (6); Found 217.0658. C₁₃H₁₅NO₂(M^ϩ

requires 217.0653.

)

4-Hydroxymethyl-3-nonyl-2-isoxazoline 16b and 4-hydroxy-

methyl-3-nonylisoxazole 18

Sodium borohydride (186 mg, 4.92 mmol) was added over

15 min to a solution of the isoxazole 3d (83.0 mg, 0.328 mmol)

in dry EtOH (17 mL) at 0–5 ЊC (ice bath). After heating at reﬂux

for 24 h, the reaction mixture was cooled to 0–5 ЊC (ice bath)

and quenched by dropwise addition of 1 M HCl (to pH 2). The

solvent was evaporated under reduced pressure, the residue

was taken up in Et₂O (10 mL) and the solution was washed

with H₂O (7 mL). The aqueous phase was extracted with Et₂O

(3 × 10 mL). The combined organic solutions were washed

with H₂O (2 × 7 mL) and brine (1 × 7 mL), dried (anhydrous

MgSO₄) and evaporated in vacuo. Flash column chroma-

tography of the residue, eluting with hexanes–EtOAc (7 : 3)

aﬀorded the title compounds 16b (54 mg, 73%) as a colourless

oil (Found: C, 68.67; H, 11.38; N, 5.85. C₁₃H₂₅NO₂requires C,

68.68; H, 11.08; N, 6.16%); ν_max3400, 2926, 2854, 1466, 1378,

1095, 1043, 929, 873, 722 cm^Ϫ1; δ_H0.88 (3H, t, J 6.7, CH₃CH₂),

1.20–1.40 (10H, m, 5 × CH₂), 1.50–1.71 (5H, m, 2 × CH₂and

OH), 2.26 (1H, m, CH₂), 2.45 (1H, m, CH₂), 3.39 (1H, m, H4),

3.78 (2H, m, CH₂O), 4.26 (2H, m, H5 and H5Ј); δ_C14.1 (CH₃),

22.6 (CH₂), 26.1 (CH₂), 26.5 (CH₂), 29.1 (CH₂), 29.2 (CH₂),

29.3 (CH₂), 29.4 (CH₂), 31.8 (CH₂), 52.4 (C4), 61.0 (CH₂O),

were concentrated under reduced pressure. H NMR analysis

indicated the mixture was composed of (E)-3-amino-2-formyl-

3-(2,4,6-trimethylphenyl)acrylic acid methyl ester 14 (described

above), 3-(2,4,6-trimethylphenyl)isoxazole-5-carboxylic acid

methyl ester 4c (described above) and (Z)-2-hydroxy-4-imino-

4-(2,4,6-trimethylphenyl)but-2-enoic acid methyl ester 15

(described above) in a ratio of 11 : 10 : 1.

4-Hydroxymethyl-3-(2,4,6-trimethylphenyl)-2-isoxazoline 16a

Sodium borohydride (185 mg, 4.89 mmol) was added over 15

min to a stirred solution of 3-(2,4,6-trimethylphenyl)isoxazole-

4-carboxylic acid methyl ester 3c (80.0 mg, 0.326 mmol) in dry

EtOH (5 mL) at 0–5 ЊC (ice bath). After heating at reﬂux for

24 h, the mixture was cooled to 0–5 ЊC (ice bath) and quenched

by dropwise addition of 1 M HCl (to pH 2). The solvent was

evaporated in vacuo, the residue was taken up in Et₂O (10 mL)

and the solution was washed with H₂O (1 × 7 mL). The

aqueous layer was extracted with Et₂O (3 × 7 mL). The com-

bined organic solutions were washed with H₂O (1 × 7 mL), aq.

NaHCO₃(1 × 7 mL) and brine (1 × 7 mL), dried (anhydrous

MgSO₄) and concentrated in vacuo. Flash column chroma-

tography of the residue, eluting with hexanes–EtOAc (4 : 1)

aﬀorded the title compound 16a (65 mg, 91%) as a colourless oil

(Found: C, 71.11; H, 7.71; N, 6.12. C₁₃H₁₇NO₂requires C,

71.21; H, 7.81; N, 6.39%); ν_max3369, 2962, 2922, 2208, 2088,

1612, 1453, 1378, 1313, 1261, 1140, 1102, 975, 852, 733, 573

cm^Ϫ1; δ_H1.55 (1H, br s, OH), 2.28 (6H, s, o,oЈ-MesCH₃), 2.30

(3H, s, p-MesCH₃), 3.69 (2H, m, CH₂O), 3.75 (1H, m, H4), 4.50

(2H, m, H5 and H5Ј), 6.91 (2H, s, 2 × MesH); δ_C20.0 (2 ×

CH₃), 21.1 (CH₃), 54.5 (C4), 61.0 (CH₂O), 71.8 (C5), 124.9 (C),

128.7 (2 × CH), 136.7 (2 × C), 138.8 (C), 158.3 (C3); m/z 219

71.0 (C5), 159.9 (C3); m/z 227 (M^ϩ, 26%), 210 (5), 196 (16), 180

(13), 156 (5), 140 (6), 128 (61), 115 (100), 108 (9), 98 (15), 85

(25), 69 (20), 55 (29); Found 227.1882. C₁₃H₂₅NO₂(M^ϩ

)

requires 227.1885; and 18 (13 mg, 18%) as a colourless oil

(Found: C, 69.68; H, 10.54; N, 6.15. C₁₃H₂₃NO₂requires C,

69.29; H, 10.29; N, 6.22%; ν_max3400, 2926, 2854, 1609, 1465,

1417, 1117, 1020, 873 cm^Ϫ1; δ_H0.88 (3H, t, J 7.0, CH₃CH₂), 1.18

(13H, m, 6 × CH₂and OH), 1.71 (2H, quintet, J 7.7, CH₂), 2.71

(2H, t, J 7.7, CH₂), 4.58 (2H, s, CH₂O), 8.30 (1H, s, H5); δ_C14.1

(CH₃), 22.7 (CH₂), 24.9 (CH₂), 27.7 (CH₂), 29.2 (CH₂), 29.3

(CH₂), 29.5 (CH₂), 29.7 (CH₂), 31.9 (CH₂), 53.9 (CH₂O), 118.4

(C4), 156.1 (C5), 162.0 (C3); m/z 225 (M^ϩ, 4%), 208 (9), 196

(M^ϩ, 100%), 202 (51), 188 (47), 172 (90), 164 (4), 158 (55), 146

(6), 182 (7), 154 (8), 136 (14), 126 (57), 113 (100), 98 (8), 85 (11),

69 (8), 55 (19); Found 225.1727. C₁₃H₂₃NO₂(M^ϩ) requires

(76), 130 (48), 121 (20), 115 (42), 103 (26), 91 (55), 77 (4), 65

(22), 57 (4); Found 219.1258. C₁₃H₁₇NO₂(M^ϩ) requires

225.1729.

219.1259.

The H NMR data of the 2-isoxazoline 16a are fully con-

5-Hydroxymethyl-3-nonylisoxazole 17b

sistent with reported values.²⁷

Using the procedure described above for the reduction of

the isoxazole 3d, reaction of sodium borohydride (224 mg,

5.93 mmol) and 3-nonylisoxazole-5-carboxylic acid methyl

ester 4d (100 mg, 0.395 mmol) followed by ﬂash column

chromatography of the residue, eluting with hexanes–EtOAc

5-Hydroxymethyl-3-(2,4,6-trimethylphenyl)isoxazole 17a

Sodium borohydride (185 mg, 4.89 mmol) was added over 15

min to a stirred solution of 3-(2,4,6-trimethylphenyl)isoxazole-

J. Chem. Soc., Perkin Trans. 2, 2002, 2031–2038

2037

View Article Online

G. W. Simpson and E. R. T. Tiekink, J. Chem. Soc., Chem.

Commun., 1994, 2035.

(7 : 3) aﬀorded the title compound 17b (82 mg, 92%) as a colour-

less solid, mp 34–35 ЊC (Found: C, 69.35; H, 10.01; N, 6.08.

C₁₃H₂₃NO₂requires C, 69.29; H, 10.29; N, 6.22%); ν_max3368,

2928, 2856, 1669, 1134, 1071, 999, 802 cm^Ϫ1; δ_H0.89 (3H, t,

J 6.8, CH₃CH₂), 1.38–1.42 (12H, m, 6 × CH₂), 1.50–1.75 (3H,

m, CH₂and OH), 2.67 (2H, t, J 7.3, CH₂), 4.76 (2H, s, CH₂O),

6.11 (1H, s, H4); δ_C14.0 (CH₃), 22.6 (CH₂), 25.9 (CH₂), 28.2

(CH₂), 29.1 (CH₂), 29.2 (2 × CH₂), 29.4 (CH₂), 31.8 (CH₂), 56.1

10 C. J. Easton, G. A. Heath, C. M. M. Hughes, C. K. Y. Lee,

G. P. Savage, G. W. Simpson, E. R. T. Tiekink, G. J. Vuckovic and

R. D. Webster, J. Chem. Soc., Perkin Trans. 1, 2001, 1168–1174.

11 C. J. Easton, C. M. M. Hughes, E. R. T. Tiekink, C. E. Lubin,

G. P. Savage and G. W. Simpson, Tetrahedron Lett., 1994, 35,

3589–3592.

12 (a) C. J. Easton, C. M. M. Hughes, E. R. T. Tiekink, G. P. Savage

and G. W. Simpson, Z. Kristallogr., 1994, 209, 771–772; (b)

C. J. Easton, C. M. M. Hughes, E. R. T. Tiekink, G. P. Savage and

G. W. Simpson, Z. Kristallogr., 1996, 211, 193–194; (c) C. J. Easton,

C. M. M. Hughes, E. R. T. Tiekink, G. P. Savage and G. W. Simpson,

Z. Kristallogr., 1994, 209, 767–768.

(CH₂O), 101.4 (C4), 164.2 (C3), 171.3 (C5); m/z 225 (M^ϩ, 4%),

194 (34), 182 (6), 168 (7), 154 (3), 140 (5), 126 (44), 96 (13), 82

(11), 68 (11), 55 (20); Found 225.1727. C₁₃H₂₃NO₂(M^ϩ

requires 225.1729.

)

13 C. M. M. Hughes, PhD thesis, University of Adelaide, 1995.

14 W. J. Hehre, L. Radom, P. v. R. Schleyer and J. A. Pople, Ab Initio

Molecular Orbital Theory, Wiley, New York, 1986.

15 F. Jensen, Introduction to Computational Chemistry, Wiley, New

York, 1999.

Acknowledgements

The authors thank G. Vuckovic for the crystallographic

analysis of the isoxazole 4a, and they acknowledge the receipt

of Australian Postgraduate Awards (Industry) by C.K.Y.L

and M.G.-C, ﬁnancial support provided by CSIRO Molecular

Science, Dunlena Pty. Ltd. and the Australian Research

Council, and generous allocations of computing time on the

Compaq Alphaserver of the National Facility of the Australian

Partnership for Advanced Computing and Fujitsu VPP-300

and SGI Power Challenge of the Australian National Uni-

versity Supercomputer Facility.

16 M. J. Frisch, G. W. Trucks, H. B. Schlegel, G. E. Scuseria,

M. A. Robb, J. R. Cheeseman, V. G. Zakrzewski, J. A. Montgomery,

Jr., R. E. Stratmann, J. C. Burant, S. Dapprich, J. M. Millam,

A. D. Daniels, K. N. Kudin, M. C. Strain, O. Farkas, J. Tomasi,

V. Barone, M. Cossi, R. Cammi, B. Mennucci, C. Pomelli,

C. Adamo, S. Cliﬀord, J. Ochterski, G. A. Petersson, P. Y. Ayala,

Q. Cui, K. Morokuma, D. K. Malick, A. D. Rabuck,

K. Raghavachari, J. B. Foresman, J. Cioslowski, J. V. Ortiz,

B. B. Stefanov, G. Liu, A. Liashenko, P. Piskorz, I. Komaromi,

R. Gomperts, R. L. Martin, D. J. Fox, T. Keith, M. A. Al-Laham,

C. Y. Peng, A. Nanayakkara, C. Gonzalez, M. Challacombe,

P. M. W. Gill, B. Johnson, W. Chen, M. W. Wong, J. L. Andres,

C. Gonzalez, M. Head-Gordon, E. S. Replogle and J. A. Pople,

GAUSSIAN 98, Revision A.6, Gaussian Inc., Pittsburgh, PA, 1998.

17 A. G. Baboul, L. A. Curtiss, P. C. Redfern and K. Raghavachari,

J. Chem. Phys., 1999, 110, 7650–7657.

18 O. L. Stiefvater, J. Chem. Phys., 1975, 63, 2560–2569.

19 A. Alberola, A. M. Gonzalez, M. A. Laguna and F. J. Pulido,

Synthesis, 1983, 413–414.

20 M. S. Brown and H. Rapoport, J. Org. Chem., 1963, 28, 3261–3263.

21 A. Altomare, G. Cascarono, C. Giacovazzo, A. Guagliardi,

M. C. Burla, G. Polidori and M. Camalli, SIR92, J. Appl.

Crystallogr., 1994, 27, 435.

References

1 (a) K. B. G. Torssell, Nitrile Oxides, Nitrones and Nitronates in

Organic Synthesis: Novel Strategies in Synthesis, VCH Publishers,

New York, 1988; (b) A. Quilico, G. Speroni, L. C. Behr and

R. L. McKee, Five- and Six-Membered Compounds with Nitrogen

and Oxygen, ed. R. H. Wiley, The Chemistry of Heterocyclic

Compounds series, vol. 17, Interscience Publishers, New York, 1962.

2 H. Uno, M. Kurokawa and H. Nishimura, Chem. Pharm. Bull.,

1976, 24, 644–647.

3 (a) S. De Bernardo and M. Weigele, J. Org. Chem., 1977, 42,

109–112; (b) R. Beugelmans and C. Morin, J. Org. Chem., 1977, 42,

1356–1360.

4 (a) A. Barco, S. Benetti, G. P. Pollini, P. G. Baraldi, M. Guarneri,

D. Simoni and C. Gandolﬁ, J. Org. Chem., 1981, 46, 4518–4524;

(b) P. G. Baraldi, A. Barco, S. Benetti, S. Manfredini, G. P. Pollini

and D. Simoni, Tetrahedron Lett., 1984, 25, 4313–4316.

5 N. R. Natale, Tetrahedron Lett., 1982, 23, 5009–5012.

6 M. Nitta and T. Kobayashi, J. Chem. Soc., Chem. Commun., 1982,

877–878.

22 Molecular Structure Corporation, teXsan: Single Crystal Structure

Analysis Software, MSC, 3200 Research Forest Drive, The

Woodlands, TX 77381, USA, 1992–1997.

23 K.-C. Liu, B. R. Shelton and R. K. Howe, J. Org. Chem., 1980, 45,

3916–3918.

24 (a) R. H. Blessing, Acta Crystallogr., Sect. A, 1995, 51, 33–38;

(b) R. H. Blessing, J. Appl. Crystallogr., 1997, 30, 421–426.

25 J. C. Zhang and D. P. Curran, J. Chem. Soc., Perkin Trans. 1, 1991,

2627–2631.

7 M. Nitta and T. Kobayashi, Tetrahedron Lett., 1982, 23, 3925–3928.

8 N. K. Kochetkov and S. D. Sokolov, Zh. Obshch. Khim., 1963, 33,

1442–1446.

26 Z. Otwinowski and W. Minor, Scalepak, Methods Enzymol., 1997,

276, 307–326.

27 L. Toma, P. Quadrelli, G. Perrini, R. Gandolﬁ, C. Di Valentin,

A. Corsaro and P. Caramella, Tetrahedron, 2000, 56, 4299–4309.

9 C. J. Easton, C. M. M. Hughes, K. D. Kirby, G. P. Savage,

2038

J. Chem. Soc., Perkin Trans. 2, 2002, 2031–2038

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