A single-step synthesis of 4-oxazolin-2-ones and their use in the construction of polycyclic structures bearing quaternary stereocenters

FULL PAPER

DOI: 10.1002/ejoc.200900114

A Single-Step Synthesis of 4-Oxazolin-2-ones and Their Use in the

Construction of Polycyclic Structures Bearing Quaternary Stereocenters

Blanca M. Santoyo,^[a]Carlos González-Romero,^[a,b]Omar Merino,^[a]

Rafael Martínez-Palou,^[a,c]Aydeé Fuentes-Benites,^[a,b]Hugo A. Jiménez-Vázquez,^[a]

Francisco Delgado,^[a]and Joaquín Tamariz*^[a]

Keywords: Heterocycles / Microwaves reactions / Quaternary stereocenters / Michael addition / Domino reactions

A new method for the synthesis of 4-oxazolin-2-ones by a

one-pot MW-promoted condensation of α-ketols and isocyan-

ates is reported. An alternative thermal approach using the

same starting materials is also described. These cyclic en-

amides were efficient nucleophiles, reacting with Michael

acceptors and prenyl bromide to give a variety of polycyclic

structures bearing one or two quaternary stereocenters. The

selectivity of the products depended on the reaction condi-

tions and on the electrophile used.

Germany, 2009)

Introduction

The synthetic potential of substituted 4-oxazolin-2-ones,

2-oxazolidinones, and 4-methylene-2-oxazolidinones as chi-

ral auxiliaries, versatile intermediates, biologically active

compounds, and β-amino alcohols precursors^[1]has at-

tracted special attention, leading to the development of a

large number of synthetic methods for the preparation of

these compounds.^[2]They have also found widespread use

in the fields of agriculture,^[3]industry,^[4]and pharmaceuti-

cals.^[5]4-Oxazolin-2-ones can be considered as ambident

nucleophiles^[6]as they have two potential attacking atoms:

The C-4 and C-5 atoms (Figure 1). The former results from

the fact that it is the terminal carbon of the double bond

of an enol ester moiety and the latter from the fact that it

is the terminal carbon of the double bond of an enamide

moiety.^[7]In principle, under electrophilic conditions, either

one or both centers may attack the electrophile. To the best

of our knowledge, 4-oxazolin-2-ones have been little studied

as nucleophilic species for the synthesis of attractive molec-

ular targets.^[7,8]The reason for this is that enamides have

been regarded as deactivated enamines lacking the nucleo-

philic reactivity characteristic of the latter.

Figure 1. Compounds 1 as potential ambident nucleophiles.

Previously, we designed a regioselective synthesis of N-

substituted 4-oxazolin-2-ones 1 and 4-methylene-2-oxazoli-

dinones 2 starting from α-ketol 3a and isocyanates 4

(Scheme 1).^[9]The one-pot synthesis of 4-methylene-2-oxaz-

olidinones 2 involved a tandem condensation of 3a with a

series of isocyanates 4; the presence of dioxane as solvent

was essential to yield this regioisomer.^[9]In contrast, when

DMF was employed as the solvent, a stereoisomeric mix-

ture of aminals 5 was obtained, which were treated ther-

mally in the presence of DMSO to give a series of thermo-

dynamic isomers of 4-oxazolin-2-ones 1. This methodology

was also efficient for the preparation of the corresponding

3-substituted 4-oxazoline-2-thiones 6 and 4-methylene-1,3-

oxazolidine-2-thiones 7 (Scheme 1).^[10]Although obtained

in lower yields, compounds 6 were also prepared by an al-

ternative single-step reaction by microwave (MW) irradia-

tion of a mixture of 3a and 8.^[10]We also found that com-

pounds 1 behave as neutral nucleophiles in the presence of

a Michael acceptor, leading to the addition product at C-5

with the regioselectivity totally controlled by the enamide

moiety.^[9]

[a] Departamento de Química Orgánica, Escuela Nacional de

Ciencias Biológicas, Instituto Politécnico Nacional,

Prol. Carpio y Plan de Ayala s/n, 11340 México, D. F., Mexico

E-mail: jtamariz@woodward.encb.ipn.mx

[b] Departamento de Química Orgánica, Facultad de Química,

Universidad Autónoma del Estado de México,

Paseo Colón/Paseo Tollocan s/n, 50000 Toluca, Estado de

México, Mexico

As a part of our ongoing research into the synthesis of

4-oxazolin-2-ones and their potential as nucleophiles, we

herein describe a short and efficient method for the synthe-

[c] Programa de Ingeniería Molecular, Instituto Mexicano del

Petroleo,

Eje Lázaro Cárdenas 152, 07730 México, D. F., Mexico

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Scheme 1.

Scheme 2.

Table 1. Yields of compounds 1a–h, 9a–c, and 10a,b obtained by

condensation of α-ketols 3a–c with isocyanates 4.^[a]

sis of these heterocycles as well as their use in the construc-

tion of a variety of substituted bicyclic structures with qua-

ternary stereocenters.^[11]

Entry Ketol

R¹

R²

4 (R³)

Product (% yield)^[b]

1

2

3

4

5

6

7

8

3a

3b

3c

Me

Ph

Me

H

Ph

4a (C₆H₅)

1a (92)

1b (80)

1c (72)

1d (62)

1e (84)

1f (65)

1g (79)

1h (31)

9a (78)

9b (80)

9c (78)

10a (81)

10b (50)

4b (4-MeC₆H₄)

4c (2-OMeC₆H₄)

4d (4-OMeC₆H₄)

4e (4-ClC₆H₄)

4f (3-OMeC₆H₄)

4g (C₆H₅CH₂)

4h (ClCH₂CH₂)

4a (C₆H₅)

Results and Discussion

Following the successful preparation of the 4-oxazoline-

2-thiones 6 by MW irradiation of a mixture of 3a and iso-

thiocyanates 8,^[10]we undertook the synthesis of the 4-ox-

azolin-2-ones 1 by the same methodology, but by using iso-

cyanates 4a–g as the starting materials (Scheme 2). Unlike

compounds 6, which required 2 mol-equiv. of triethylamine,

a number of derivatives 1 were obtained in high yields in

the absence of base (Table 1, entries 1–8). Note that in con-

trast to the previously reported method,^[9]which required

solvent and was carried out in a two-step sequence, this

was a solvent-free single-step procedure. Moreover, this new

9

10

11

12

13

4d (4-OMeC₆H₄)

4i (3-MeC₆H₄)

4a (C₆H₅)

Ph

4h (ClCH₂CH₂)

[a] In the presence of 1:1 mol-equiv. of 3/4; MW irradiation

(200 W), 120 °C, 90 min. [b] Yield after recrystallization or column

chromatography.

The versatility of the method was also tested with α-ke-

method provides, except in the case of 1h, much higher tols 3b and 3c. The reaction of the former with isocyanates

yields (ca. 77%) than the previous one (ca. 58%). In ad- 4a, 4d, and 4i led to the corresponding 3-substituted 1,3-

dition, the isolation procedure was very simple as the crude oxazolin-2-ones 9a–c in good yields (Table 1, entries 9–11).

mixture was dissolved in dichloromethane and then poured Microwave irradiation of mixtures of 3c with isocyanates 4a

into water. The organic layer was then dried, the solvent or 4h gave the expected heterocycles 10a,b in modest-to-

removed, and the solid residue recrystallized. Interestingly, good yields (Table 1, entries 12 and 13). In the case of 10b, a

when the reaction was carried out with benzyl isocyanate small amount (6%) of the 1,3-imidazol-2-one 11b was also

(4g), a second product was isolated in 21% yield, the N,NЈ- isolated (Scheme 3). The structure of 10b was established

disubstituted 1,3-imidazol-2-one 11a (Scheme 3). This was by spectroscopy and confirmed by X-ray crystallography

probably formed as a result of the presence of benzylamine (Figure 2).^[13]The planes of the phenyl groups are almost

in the reaction mixture which adds to 1g.^[4b,12]The amine orthogonal, with the 5-Ph group being close to being copla-

would result from the hydrolysis of the isocyanate by water nar with the heterocycle. This conformation is probably sta-

liberated in the reaction.

bilized by hydrogen-bonding as the ortho proton (C7-H) of

Scheme 3.

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A Single-Step Synthesis of 4-Oxazolin-2-ones

5-Ph points towards the ipso-C of the 4-Ph group, with a

distance between them (2.695 Å) indicative of a CH···π in-

teraction.

Scheme 4.

These results support not only the previously proposed

mechanism for the formation of compounds 1,^[9]but also

the idea that the sequential processes, the cyclization step

of carbamates 12 to hemiaminals 5 and the conversion of

the latter, by dehydration, to the desired 1,3-oxazolin-2-

ones 1, are thermally dependent. Therefore, we investigated

the transformation of a mixture of α-ketols 3 and isocyan-

ates 4 into the desired 4-oxazolin-2-ones 1 under thermal

Figure 2. X-ray structure of 10b (ellipsoids at the 30% probability

level).

In addition, the MW procedure allows the selective for- conditions in the absence of solvent. When α-ketol 3a was

mation of hemiaminals 5 (Scheme 4) as the reaction of 3a treated with 4a at 140 °C for 36 h, the expected 4-oxazolin-

and 4a carried out at a lower temperature (100 °C) fur- 2-one 1a was obtained in excellent yield (Table 2, entry 1).

nished a mixture of the stereoisomeric hemiaminals 5a The reaction with isocyanate 4h furnished the correspond-

(anti/syn, 85:15) in good yield (78%). The structure of the ing heterocycle 1h in moderate yield (Table 2, entry 7). To

major isomer anti-5a was established by NOE experiments shorten the reaction time, triethylamine was added

in which the signal of the 6-Me group is enhanced on irradi- (1.2 mol-equiv.) to the reaction mixture, which gave 1a as

ation of the 5-H signal. When a mixture of α-ketol 3b and the major product in high yield (85%; entry 2). In addition,

4a was allowed to react under the same conditions, hemia- a second product was isolated, which corresponded to the

minal 5b was formed in 80% yield (Scheme 4). It was inter- 4-methylene-2-oxazolidinone 2a, in low yield (12%). In con-

esting to find that no hemiaminals 5a were obtained when trast with the results obtained with isocyanate 4h, in the

the reaction between 3a and 4a was carried out under MW reactions of 3a with isocyanates 4d and 4e, larger amounts

irradiation at a lower temperature (80 °C) and that only car- of the isomers with the exocyclic double bond, 2d and 2e,

bamate 12 was isolated in high yield as colorless crystals were obtained (Table 2, entries 4 and 5). As shown pre-

(Scheme 4).

viously, because the latter isomer is the kinetic product,^[9]it

Table 2. Thermal condensation of α-ketols 3a and 3b with isocyanates 4.^[a]

Entry

3

4 (R³)

Et₃N [mol-equiv.]

T [°C]

t [h]

1 (% yield)^[b]

2 (% yield)^[b]

1

2

3

4

5

6

7

8

3a

3b

4a (C₆H₅)

–

140

130

110

130

110

130

36

24

1a (97)

1a (85)

1b (39)

1d (43)

1e (30)

1f (49)

1h (55)

9a (83)

9a (66)

9c (84)

9c (75)

2a (0)

4a (C₆H₅)

1.2

–

1.2

–

2a (12)

2b (49)

2d (31)

2e (17)

2f (26)

2h (0)

4b (4-MeC₆H₄)

4d (4-OMeC₆H₄)

4e (4-ClC₆H₄)

4f (3-OMeC₆H₄)

4h (ClCH₂CH₂)

4a (C₆H₅)

4i (3-MeC₆H₄)

2a (0)

9

10

11

13a (0)

2h (0)

1.2

13b (0)

[a] In the presence of 1:1.2 mol-equiv. of 3a/4. [b] Yield after recrystallization or column chromatography.

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is expected that decreasing the temperature would increase Table 3. Yields of compounds 14a–c, obtained by condensation of α-

ketol 3d and isocyanates 4.^[a]

the proportion of compounds 2 to the detriment of the

thermodynamic compounds 1. Indeed, although the con-

version of starting materials was not complete, in the reac-

tions of 3a with isocyanates 4b and 4f carried out at 110 °C,

the proportion of isomers 2 was augmented (Table 2, en-

tries 3 and 6). If the temperature was further decreased,

hemiaminals 5 started to appear in the reaction mixtures.

In contrast to this behavior, when α-ketol 3b was submit-

ted to reaction with isocyanates 4a and 4i under both condi-

tions, either with or without triethylamine, only the isomers

with the endocyclic double bond, 9a and 9c, were obtained

(Table 2, entries 8–11), that is, even in the crude mixtures,

4-methylene-2-oxazolidinones 2a, 2h, 13a, and 13b were not

detected.

Entry

4 (R)

14 (% yield)^[b]

1^[c]

2^[d]

3^[d]

4^[e]

4a (C₆H₅)

4d (4-OMeC₆H₄)

4h (ClCH₂CH₂)

14a (67)

14a (86)

14b (92)

14c (53)

[a] In the presence of ca. 1:1.2 mol-equiv. of 3d/4. [b] Yield after

recrystallization or column chromatography. [c] MW irradiation (300 W),

140 °C, 3 h. [d] Carried out at 130 °C, no solvent, 24 h. [e] Carried out

with 1.0 mol-equiv. of Et₃N, at 130 °C, no solvent, 36 h.

Furthermore, this methodology proved to be efficient

with tertiary α-ketol 3d. The reaction between 3d and 4a

led to the 4-methylene-1,3-oxazolidin-2-one 14a in moder-

ate yield (Table 3, entry 1). However, to obtain the latter, reactivity of the enamide scaffold of 1 with other electro-

the power of the MW irradiation, the temperature, and the philes, as well as that of the newly formed exocyclic en-

reaction time had to be increased compared with the reac- amide moiety of 16a. Thus, thermal treatment of a mixture

tions with α-ketols 3a–c. In contrast, 14a was obtained in a of 1a and 15a at 160 °C for 24 h gives rise not only to ad-

higher yield when the condensation reaction was carried out duct 16a in 59% yield, but also to endocyclic diene 19a in

under thermal and solvent-free conditions (Table 3, en- low yield (14%; Scheme 5). The presence of the latter indi-

try 2). These conditions were later extended to the reactions cates that the enamide moiety of 16a is able to add to the

of 3d with isocyanates 4d and 4h, which afforded 4-methyl- carbonyl group intramolecularly through the sequential for-

ene-1,3-oxazolidin-2-ones 14b and 14c, respectively mation of the zwitterionic intermediate 17a and then

(Table 3, entries 3 and 4). X-ray diffraction analysis of 14b alcohol 18a, which undergoes dehydration to diene 19a.

showed a structural pattern (Figure 3)^[13]similar to other

A Lewis acid such as AlCl₃catalyzed the same reaction

analogous heterocycles,^[9,10,14]namely the quasi-orthogonal at a lower temperature (70 °C) to give adduct 16a (42%)

conformation of the aromatic ring attached to the nitrogen and a slightly improved yield of diene 19a (36%). However,

atom with respect to the heterocyclic ring.

when the thermal reaction was carried out at 160 °C in the

Owing to the fact that any methodology that is able to presence of ZnCl₂in acetonitrile, diarylamine 20a was iso-

introduce quaternary stereocenters into the target molecules lated as the main product in low yield (35%; Scheme 5).

attracts great interest in organic synthesis^[15]because of the Compounds 16a and 19a were not observed in the reaction

large incidence of natural products containing this struc- mixture, but unidentified side-products were detected. Di-

tural attribute, it is important that the heterocycles 14 ob- arylamine 20a may arise from decarboxylation and aroma-

tained possess a quaternary stereocenter at C-5 (see below). tization of diene 19a, as has previously been suggested.^[9]

The Michael reaction is a powerful tool for the formation This mechanism is supported by the fact that adduct 16a

of C–C bonds and the β-functionalization of carbonyl com- was converted into diarylamine 20a in 49% yield when it

pounds.^[16]As we have previously shown, 4-oxazolin-2-one was treated under the same conditions.

1a undergoes conjugate addition to methyl vinyl ketone

To improve the selectivity and yields of these processes,

(15a) under thermal conditions (160 °C) to give adduct 16a we investigated the use of MW irradiation in the conjugate

(Scheme 5).^[9]We investigated more drastic thermal condi- addition of 1a to 15a. Thus, after MW irradiation (300 W,

tions and MW irradiation with the aim of evaluating the 140 °C) of a solvent-free mixture of 1a and 15a, adduct 16a

Figure 3. X-ray structure of 14b (ellipsoids at the 30% probability level).

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A Single-Step Synthesis of 4-Oxazolin-2-ones

Scheme 5.

Scheme 6. Reagents and conditions: (i) 1a and 15a, MW (300 W), 140 °C, 6 h: 16a (77%) and 21a (16%); (ii) 1a and 15a, MW (400 W),

160 °C, 6 h: 21a (34%); (iii) 16a and 15a, MW (400 W), 160 °C, 4 h: 21a (34%); (iv) 1a and 15b, MW (200 W), 100 °C, 6 h: 21b (77%);

(v) 1a and 15b, 80 °C, 5 d: 21b (81%); (vi) 9a and 15a, 160 °C, 24 h: 16c (87%); (vii) 9a and 15b, 100 °C, 24 h: 21c (74%).

was obtained in 77% yield, along with the bicyclic dihy- lein (15b). Therefore, when a mixture of the latter was irradi-

dropyran 21a (16%; Scheme 6). When the power of the irra- ated (200 W) at 100 °C for 6 h in the presence of 1a, only

diation and the temperature were increased to 400 W and dihydropyran 21b was observed in good yield (77%;

160 °C, respectively, compound 21a was afforded in a Scheme 6). The structure of 21b was established by spec-

higher yield (34%). Although dihydropyrans can be pre- troscopy and X-ray crystallography (Figure 4).^[13]A similar

pared by concerted hetero-Diels–Alder cycloaddition be- result was obtained when the mixture was heated at 80 °C for

tween enamines and oxabutadienes,^[17]21a can be synthe- 5 d; 21b was obtained in 81% yield. All thermal or MW as-

sized by a stepwise mechanism, as suggested in a previous says carried out to isolate 16b were unsuccessful. This con-

report.^[18]It is well known that MW irradiation promotes trasting behavior of 15b in comparison with 15a indicates that

the activation and stabilization of polar species.^[19]Hence it the reactivity of the zwitterionic species 22b is higher than

could stabilize zwitterionic intermediate 22a to allow cycli- that of 22a, which is probably due to the lower stability of

zation to compound 21a by attack of the charged oxygen the monosubstituted enolate moiety of 22b. This hypothesis

atom on the electrophilic iminium carbon atom (Scheme 6). seems to be supported by the fact that 16c was obtained and

To support this idea, adduct 16a was treated under analo- isolated in high yield (87%) when the reaction between 9a

gous conditions. Thus, MW irradiation (400 W, 160 °C) for and 15a was carried out under thermal conditions (160 °C,

4 h, led to isolation of the dihydropyran 21a in 34% yield.

24 h). Further evidence for this is provided by the thermal

These interesting results prompted us to investigate the ad- reaction of 9a with 15b under less severe conditions, which

dition of 1a to a more reactive Michael acceptor such as acro- gave the dihydropyran 21c in good yield (74%; Scheme 6).

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Scheme 7.

Figure 4. X-ray structure of 21b (ellipsoids at the 30% probability

level).

which activated acrolein (15b) by complexing the oxygen

atom or the double bond as a Lewis acid catalyst, as has

been documented previously.^[20]A similar complexing func-

Although a formal concerted hetero-Diels–Alder ad- tion of iodine with the carbonyl group of intermediate 16b

dition cannot be completely ruled out in the formation of would favor nucleophilic attack of the exocyclic enamide to

dihyropyrans 21, we tried to capture enolate 22b by adding give diene 19b. In fact, a similar outcome resulted when the

a reactive electrophile such as methyl iodide to give 23 addition was carried out in the presence of iodine (5% mol-

(Scheme 6). Thus, when a mixture of 1a and an excess equiv.) at 0 °C for 2.5 h, albeit in low yield (31%). The

(3 mol-equiv.) of 15b was heated in xylene at 160 °C in the structure of 19b was established by spectroscopy and X-ray

presence of 2.0 molequiv. of MeI, diene 19b was isolated as crystallography (Figure 5).^[13]

a single product in 93% yield (Scheme 7). Even when the

It was interesting that other products could be isolated

reaction temperature was decreased (100–120 °C), the depending on the reaction time, the presence of methyl io-

1

methylated quenching product 23 was not detected by H dide, or the number of mol-equiv. of 15b. For example,

NMR measurements of the crude mixture. However, by when further mol-equiv. of 15b were added, aside from

lowering the temperature, the dihydropyran 21b was ob- diene 19b, the major product of the reaction mixture corre-

served in the reaction mixture, which suggests that it corre- sponded to diene 24, which arose from the conjugate ad-

sponds to the kinetic product, whereas the diene 19b corre- dition of diene 19b to a second molecule of 15b (Scheme 7).

sponds to the thermodynamically controlled product.

Moreover, when the reaction without methyl iodide was

To obtain more insight into this reaction, we carried out maintained at 160 °C for 96 h, a different outcome was ob-

the addition reaction of 1a with a large excess (5 mol-equiv.) served as phenyl(tolyl)amine 20b prevailed over diene 19b

of 15b in xylene at 160 °C in the presence of MeI (2.0 mol- and was isolated in good yield (87%). Decarboxylation of

equiv.) for 24 h. Diene 19b was obtained and, in contrast the latter would explain the formation of 20b.

with the reactions shown in Scheme 5 in which aniline 20a

Owing to the softness of the Michael acceptors used as

was isolated as the main product under these conditions, electrophiles, and with the aim of extending the study of

aniline 20b was not detected (Scheme 7). The role that the reactivity of 4-oxazolin-2-ones 1 to diverse substrates,

methyl iodide plays in the reaction is still not clear, but it we explored the reaction of prenyl bromide (25) with 1a

seems to be significant because when the reaction was con- (Scheme 8). Thermal (160 °C) treatment of a mixture of 1a

ducted in the absence of MeI, diene 19b was obtained in and 25 in xylene for 24 h gave, instead of the expected prod-

low yield (30%) or the corresponding aniline 20b was af- uct 28, the fused cyclohexenic oxazolidine 26 in moderate

forded. Probably, methyl iodide was reduced to iodine, yield (53%) as colorless crystals. The structure was assigned

Figure 5. X-ray structure of 19b (ellipsoids at the 30% probability level).

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A Single-Step Synthesis of 4-Oxazolin-2-ones

Scheme 8.

by 1D and 2D NMR measurements and unambiguously observed cyclohexene product 26. At least for the first step,

established by single-crystal X-ray diffraction (Figure 6).^[13]these mechanisms may be supported by the fact that prenyl-

Note that both the fused heterocycle and cyclohexene rings ated product 28 was isolated from the crude mixture in low

adopt a twisted conformation, which allows the angular yield (18%) when the reaction was carried out in xylene at

methyl groups to assume a more stable noneclipsed confor- 100 °C for 36 h.

mation. This could explain why the double bond is selec-

tively formed at the C4–C5 position and not at the C5–C6

of the bicycle 26, which facilitates such a twisted conforma-

tion.

Conclusions

We have described two methods for the one-step synthe-

sis of N-substituted 4-oxazolin-2-ones 1 in high yields that

involve thermal and MW irradiation conditions. These

molecules have also proved to be reactive regioselective nu-

cleophiles with a series of Michael acceptors, for example,

methyl vinyl ketone (15a) and acrolein (15b), and alkyl bro-

mides, such as prenyl bromide (25). Interestingly, and de-

pending on the temperature, most of the reactions led to a

variety of bicyclic molecules as a result of a domino process,

taking advantage of the sequential formation of endo-het-

erocyclic enamides/exo-heterocyclic enamides or endo-

heterocyclic enamides/iminium ions, either as nucleophilic/

nucleophilic or nucleophilic/electrophilic species, respec-

tively. In all cases, the regioselectivity of the reactions was

controlled by the most nucleophilic center C-5 of the double

bond of the 4-oxazolidin-2-ones 1. Therefore these hetero-

cyclic enamides are useful and versatile synthons for the

preparation of a wide variety of functionalized heterocycles

with quaternary carbon centers. Additional studies on the

reactivity of these heterocycles and their application to the

synthesis of complex polycyclic molecules are in progress

and will be reported in due course.

Figure 6. X-ray structure of 26 (ellipsoids at the 30% probability

level).

Two possible domino mechanisms for this reaction can

be proposed, as depicted in Scheme 8. Both involve a first

prenylation reaction at the C-5 carbon atom to afford the

salt 27, which leads to the neutral species 28. The double

bond of the prenyl chain of the latter undergoes proton-

ation to yield carbocation 29, followed by isomerization to

the iminium species 30 and ring closure to the cyclohexene

intermediate 31, and finally isomerization of the double

bond to yield 26. An alternative pathway starts from 28

to give, through isomerization of the double bond, neutral

dialkene 32, which undergoes an intramolecular ene reac-

Experimental Section

General: Melting points (uncorrected) were determined with an

Electrothermal capillary melting point apparatus. IR spectra were

recorded with a Perkin-Elmer 1600 spectrometer. ¹H and ¹³C NMR

spectra were obtained with a Varian Mercury-300 (300 MHz) in-

strument with CDCl₃as the solvent and TMS as the internal stan-

dard. Mass spectra (MS) were recorded, in electron impact mode,

with Hewlett–Packard 5971A and Thermo-Finnigan Polaris Q

tion to yield precursor 31,^[21]and then isomerization to the spectrometers. High-resolution mass spectra (HRMS), in electron

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impact and FAB⁺modes, were obtained with JEOL JSM-GCMat-

eII and JMS-SX 102 spectrometers, respectively. X-ray crystallo-

graphic structures were obtained with Siemens P4 and Oxford Xca-

liburS diffractometers. Microwave (MW) irradiation was performed

by using a SEV/MIC-1 (Mexico) MW reactor.^[22]Microanalyses

were performed by M-H-W Laboratories (Phoenix, AZ). All air-

and moisture-sensitive reactions were carried out under nitrogen

using oven-dried glassware. THF and xylene were freshly distilled

from sodium and dichloromethane and MeCN from calcium hy-

dride prior to use. Li₂CO₃was dried overnight at 120 °C before

use. Et₃N was distilled from NaOH. All other reagents were used

without further purification.

72%) was afforded as colorless crystals (hexane/CH₂Cl₂, 6:1). R_f=

0.28 (hexane/EtOAc, 7:3); m.p. 112–113 °C. ¹H NMR (300 MHz,

CDCl₃): δ = 1.72 (br. s, 3 H, CH₃C-4), 2.09 (br. s, 3 H, CH₃C-5),

3.82 (s, 3 H, MeO), 6.98–7.06 (m, 2 H, Ar-H), 7.21–7.26 (m, 1

H, Ar-H), 7.35–7.42 (m, 1 H, Ar-H) ppm. ¹³C NMR (75.4 MHz,

CDCl₃): δ = 8.0 (CH₃C-4), 10.0 (CH₃C-5), 55.6 (OCH₃), 112.1

(arom. CH), 119.0 (C-4), 120.9 (arom. CH), 122.2 (arom. C), 129.9

(arom. CH), 130.4 (arom. CH), 131.6 (C-5), 154.6 (C-2), 155.6

(arom. C) ppm. IR (film): ν = 1752, 1706, 1601, 1509, 1462, 1383,

˜

1287, 1254, 1020, 985, 755, 697 cm^–1. MS (70 eV): m/z (%) = 219

(34) [M]⁺, 148 (100), 133 (10), 92 (11), 77 (15). C₁₂H₁₃NO₃

(219.24): calcd. C 65.74, H 5.98, N 6.39; found C 66.09, H 6.13, N

6.68.

General Procedures for the Preparation of N-Substituted 4-Oxaz-

olin-2-ones 1a–h, 9a–c, and 10a,b

N-(4-Anisyl)-4,5-dimethyl-4-oxazolin-2-one (1d) and N-(4-Anisyl)-5-

methyl-4-methylene-2-oxazolidinone (2d): Synthesized according to

method A, with 3a (0.88 g) and 4d (1.49 g), 1d (1.36 g, 62%) was

afforded as a white powder. Synthesized according to method C,

with 3a (0.20 g, 2.27 mmol), 4d (0.41 g, 2.72 mmol), and Et₃N

(0.28 g, 2.72 mmol), 1d (0.21 g, 43%) and 2d (0.15 g, 31%) as pale-

yellow powders were afforded. Data for 1d: R_f= 0.40 (hexane/

EtOAc, 7:3); m.p. 76–77 °C (ref.^[9]76–77 °C). Data for 2d: R_f=

0.58 (hexane/EtOAc, 7:3); m.p. 90–91 °C (ref.^[9]77–78 °C).

Method A: A mixture of α-ketol 3 (0.01 mol) and isocyanate 4

(0.01 mol) was placed in a threaded ACE glass pressure tube with

a sealed Teflon screw cap under N₂. The mixture was stirred and

irradiated with MW irradiation (200 W) at 120 °C for 90 min (see

Table 1). The mixture was diluted with CH₂Cl₂(40 mL), poured

into H₂O (100 mL), and stirred for 30 min. The mixture was filtered

and the aqueous layer was washed with CH₂Cl₂(2ϫ40 mL). The

combined organic layers were dried (Na₂SO₄) and the solvent re-

moved under vacuum. The residue was purified by column

chromatography on silica gel (30 g per gram of crude, hexane/

EtOAc, 9:1) to give the corresponding heterocycles 1a–h, 9a–c, or

10a,b.

N-(4-Chlorophenyl)-4,5-dimethyl-4-oxazolin-2-one (1e) and N-(4-

Chlorophenyl)-5-methyl-4-methylene-2-oxazolidinone (2e): Synthe-

sized according to method A, with 3a (0.88 g) and 4e (1.49 g), 1e

(1.87 g, 84%) was afforded as a white powder. Synthesized accord-

ing to method C, with 3a (0.30 g, 3.40 mmol), 4e (0.63 g,

4.08 mmol), and Et₃N (0.41 g, 4.08 mmol), 1e (0.23 g, 30%) and 2e

(0.13 g, 17%) as pale-yellow powders were afforded. Data for 1e:

R_f= 0.32 (hexane/EtOAc, 7:3); m.p. 132–133 °C (ref.^[9]125–

126 °C). Data for 2e: R_f= 0.52 (hexane/EtOAc, 7:3); m.p. 102–

103 °C (ref.^[9]102–103 °C).

Method B: A mixture of α-ketol 3 and isocyanate 4 (1.2 mol-equiv.)

was placed in a threaded ACE glass pressure tube with a sealed

Teflon screw cap under N₂. The mixture was stirred and heated

at 130–140 °C for 24–36 h. The mixture was diluted with CH₂Cl₂

(20 mL), stirred for 30 min, filtered, and the solvent removed under

vacuum. The residue was purified by column chromatography on

silica gel (30 g per gram of crude, hexane/EtOAc, 9:1) to give the

corresponding heterocycles 1, 2, or 9.

N-(3-Anisyl)-4,5-dimethyl-4-oxazolin-2-one (1f) and N-(3-Anisyl)-5-

methyl-4-methylene-2-oxazolidinone (2f): Synthesized according to

method A, with 3a (0.88 g) and 4f (1.49 g), 1f (1.42 g, 65%) was

afforded as a white powder. Synthesized according to method C,

with 3a (0.20 g, 2.27 mmol), 4f (0.28 g, 2.72 mmol), and Et₃N

(0.27 g, 2.72 mmol), 1f (0.14 g, 49%) as a white powder and 2f

(0.077 g, 26%) as a pale-yellow oil were afforded. Data for 1f: R_f

= 0.37 (hexane/EtOAc, 7:3); m.p. 63–64 °C. ¹H NMR (300 MHz,

CDCl₃): δ = 1.86 (br. s, 3 H, CH₃C-4), 2.10 (br. s, 3 H, CH₃C-5),

3.82 (s, 3 H, MeO), 6.82–6.95 (m, 3 H, Ar-H), 7.31–7.39 (m, 2 H,

Ar-H) ppm. ¹³C NMR (75.4 MHz, CDCl₃): δ = 8.7 (CH₃C-4), 9.9

(CH₃C-5), 55.3 (OCH₃), 112.6 (arom. CH), 113.9 (arom. CH),

117.8 (C-4), 119.0 (arom. CH), 130.0 (arom. CH), 132.2, 134.8,

Method C: Following the same procedure as described for method

B with α-ketol 3b and isocyanate 4 (1.2 mol-equiv.), triethylamine

(1.2 mol-equiv.) was added and the corresponding heterocycles 1,

2, or 9 were obtained.

4,5-Dimethyl-N-phenyl-4-oxazolin-2-one (1a) and 5-Methyl-4-meth-

ylene-N-phenyl-2-oxazolidinone (2a): Synthesized according to

method A, with 3a (0.88 g) and 4a (1.19 g), 1a (1.73 g, 92%) was

afforded. Synthesized according to method B, with 3a (0.50 g,

5.67 mmol) and 4a (0.81 g, 6.81 mmol), 1a (1.04 g, 97%) was af-

forded. Synthesized according to method C, with 3a (0.30 g,

3.40 mmol), 4a (0.49 g, 4.09 mmol), and Et₃N (0.41 g, 4.09 mmol),

1a (0.55 g, 85%) as colorless crystals (hexane/CH₂Cl₂, 1:1) and 2a

(0.077 g, 12%) as a pale-yellow powder were afforded. Data for 1a:

R_f= 0.50 (hexane/EtOAc, 7:3); m.p. 79–80 °C (ref.^[9]79–80 °C).

Data for 2a: R_f= 0.65 (hexane/EtOAc, 7:3); m.p. 87–88 °C (ref.^[9]

87–88 °C).

154.4 (C-2), 160.2 (arom. C) ppm. IR (film): ν = 1759, 1708, 1602,

˜

1495, 1460, 1380, 1255, 1158, 1043, 1003 cm^–1. MS (70 eV): m/z

(%) = 219 (10) [M]⁺, 148 (10), 107 (30), 92 (14), 77 (100), 63 (42).

HRMS (FAB): calcd. for C₁₂H₁₃NO₃[M]⁺219.0895; found

219.0895. Data for 2f: R_f= 0.49 (hexane/EtOAc, 7:3). ¹H NMR

(300 MHz, CDCl₃): δ = 1.61 (d, J = 6.6 Hz, 3 H, CH₃C-5), 3.81 (s,

3 H, MeO), 4.08 (dd, J = 2.7, 2.1 Hz, 1 H, CH₂=), 4.23 (t, J =

2.7 Hz, 1 H, CH₂=), 5.20–5.29 (m, 1 H, 5-H), 6.88 (t, J = 2.4 Hz,

1 H, Ar-H), 6.92 (dd, J = 8.0, 2.1 Hz, 2 H, Ar-H), 7.38 (t, J =

8.1 Hz, 1 H, Ar-H) ppm. ¹³C NMR (75.4 MHz, CDCl₃): δ = 21.1

(CH₃C-5), 55.4 (OCH₃), 75.0 (C-5), 82.1 (CH₂=), 112.6 (arom.

CH), 114.2 (arom. CH), 119.1 (arom. CH), 130.3 (arom. CH),

134.8 (arom. C), 147.4 (C-4), 155.2 (C-2), 160.4 (arom. C) ppm. IR

4,5-Dimethyl-N-(4-tolyl)-4-oxazolin-2-one (1b) and 5-Methyl-4-

methylene-N-(4-tolyl)-2-oxazolidinone (2b): Synthesized according

to method A, with 3a (0.88 g) and 4b (1.33 g), 1b (1.62 g, 80%)

was afforded. Synthesized according to method C, with 3a (0.20 g,

2.27 mmol), 4b (0.36 g, 2.72 mmol), and Et₃N (0.28 g, 2.72 mmol),

1b (0.18 g, 39%) as colorless crystals (hexane/CH₂Cl₂, 1:1) and 2b

(0.23 g, 49%) as a pale-yellow powder were afforded. Data for 1b:

R_f= 0.61 (hexane/EtOAc, 7:3); m.p. 67–68 °C (ref.^[9]64–65 °C).

Data for 2b: R_f= 0.67 (hexane/EtOAc, 7:3); m.p. 72–73 °C (ref.^[9]

72–73 °C).

(film): ν = 1762, 1680, 1600, 1492, 1458, 1393, 1323, 1259, 1224,

˜

1164, 1082, 1042, 1002, 866, 814, 783, 699 cm^–1. MS (70 eV): m/z

(%) = 220 (85) [M + 1]⁺, 176 (100), 161 (96), 134 (26), 104 (49), 78

(28), 63 (19). HRMS (EI): calcd. for C₁₂H₁₃NO₃[M]⁺219.0896;

N-(2-Anisyl)-4,5-dimethyl-4-oxazolin-2-one (1c): Synthesized ac-

cording to method A, with 3a (0.88 g) and 4c (1.49 g), 1c (1.58 g, found 219.0896.

2512

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Eur. J. Org. Chem. 2009, 2505–2518

A Single-Step Synthesis of 4-Oxazolin-2-ones

N-(Benzyl)-4,5-dimethyl-4-oxazolin-2-one (1g) and 1,3-Dibenzyl-4,5- to method C, with 3b (0.10 g, 1.34 mmol), 4i (0.22 g, 1.63 mmol),

dimethyl-1H-imidazol-2(3H)-one (11a): Synthesized according to

method A, with 3a (0.88 g) and 4g (1.33 g), 1g (1.61 g, 79%) and

11a (0.615 g, 21%) as white powders were afforded. Data for 1g: R_f

and Et₃N (0.13 g, 1.35 mmol), 9c (0.192 g, 75%) was afforded. R_f

= 0.27 (hexane/EtOAc, 7:3); m.p. 56–57 °C. ¹H NMR (300 MHz,

CDCl₃): δ = 1.90 (d, J = 1.4 Hz, 3 H, CH₃C-4), 2.39 (s, 3 H,

= 0.25 (hexane/EtOAc, 7:3); m.p. 95–96 °C. ¹H NMR (300 MHz, CH₃Ar), 6.70 (q, J = 1.4 Hz, 1 H, 5-H), 7.08 (dm, J = 7.7 Hz, 1

CDCl₃): δ = 1.82 (s, 3 H, CH₃C-4), 2.02 (s, 3 H, CH₃C-5), 4.73

H, Ar-H), 7.13 (br. s, 1 H, Ar-H), 7.21 (br. d, J = 7.7 Hz, 1 H, Ar-

(s, 2 H, PhCH₂N-3), 7.20–7.42 (m, 5 H, Ar-H) ppm. ¹³C NMR H), 7.36 (t, J = 7.7 Hz, 1 H, Ar-H) ppm. ¹³C NMR (75.4 MHz,

(75.4 MHz, CDCl₃): δ = 8.1 (CH₃C-4), 9.8 (CH₃C-5), 45.2

(PhCH₂N-3), 117.2 (C-4), 127.0 (2 C, arom. CH), 127.7 (arom.

CDCl₃): δ = 9.4 (CH₃C-4), 21.2 (CH₃Ar), 123.9 (C-5, arom. CH),

124.6 (C-4), 127.5 (arom. CH), 129.2 (arom. CH), 129.3 (arom.

CH), 128.7 (2 C, arom. CH), 131.5 (C-5), 136.4 (arom. C), 155.9 CH), 133.1 (arom. C), 139.6 (arom. C), 155.1 (C-2) ppm. IR (film):

(C-2) ppm. IR (film): ν = 1745, 1704, 1371, 755 cm^–1. MS (70 eV): ν = 1754, 1608, 1590, 1492, 1439, 1383, 1294, 1201, 1143, 1079,

˜

m/z (%) = 203 (100) [M]⁺, 112 (3), 91 (50), 65 (12). C₁₂H₁₃NO 791, 773, 700 cm^–1. MS (70 eV): m/z (%) = 189 (15) [M]⁺, 132 (26),

(203.24): calcd. C 70.92, H 6.45, N 6.89; found C 71.16, H 6.68, N

91 (100), 65 (75), 63 (20), 51 (12), 39 (65). C₁₁H₁₁NO₂(189.21):

6.97. Data for 11a: R_f= 0.20 (hexane/EtOAc, 7:3); m.p. 122– calcd. C 69.83, H 5.86, N 7.40; found C 69.78, H 5.76, N 7.31.

1

123 °C. H NMR (300 MHz, CDCl₃): δ = 1.85 (s, 6 H, 2 CH₃C),

3,4,5-Triphenyl-4-oxazolin-2-one (10a): Synthesized according to

method A, with 3c (2.12 g) and 4a (1.19 g), 10a (2.53 g, 81%) was

4.87 (s, 4 H, 2 PhCH₂N), 7.20–7.38 (m, 10 H, 2 Ph-H) ppm. ¹³C

NMR (75.4 MHz, CDCl₃): δ = 8.6 (2 CH₃C), 44.6 (2 PhCH₂N),

afforded as a white powder (EtOAc). R_f= 0.50 (hexane/EtOAc,

7:3); m.p. 219–220 °C (ref.^[23]211 °C).

113.4 (C-4, C-5), 127.0 (4 C, arom. CH), 127.2 (2 C, arom. CH),

128.6 (4 C, arom. CH), 138.1 (2 C, arom. C), 153.8 (C-2) ppm. IR

N-(2-Chloroethyl)-4,5-diphenyl-4-oxazolin-2-one (10b) and 1,3-

Bis(2-chloroethyl)-4,5-diphenyl-1H-imidazol-2(3H)-one (11b): Syn-

thesized according to method A, with 3c (2.12 g) and 4h (1.05 g),

10b (1.49 g, 50%) as a white powder and 11b (0.214 g, 6%) as col-

orless crystals were afforded. Data for 10b: R_f= 0.50 (hexane/

EtOAc, 7:3); m.p. 104–105 °C. ¹H NMR (300 MHz, CDCl₃): δ =

3.61 (t, J = 6.2, Hz, 2 H, ClCH₂CH₂N-3), 3.79 (t, J = 6.2, Hz, 2

H, ClCH₂CH₂N-3), 7.18–7.28 (m, 5 H, Ph-H), 7.42–7.48 (m, 2 H,

Ph-H), 7.52–7.59 (m, 3 H, Ph-H) ppm. ¹³C NMR (75.4 MHz,

CDCl₃): δ = 40.2 (ClCH₂CH₂N-3), 43.3 (ClCH₂CH₂N-3), 123.1

(C-4), 124.3 (2 C, arom. CH), 126.6 (arom. C), 127.5 (arom. C),

127.8 (arom. CH), 128.5 (2 C, arom. CH), 129.7 (2 C, arom. CH),

130.4 (arom. CH), 130.7 (2 C, arom. CH), 134.8 (C-5), 154.3 (C-

(film): ν = 2929, 1708, 1654 cm^–1. 1496, 1444, 1356, 1182, 1075,

˜

700 cm^–1. MS (70 eV): m/z (%) = 292 (3) [M]⁺, 92 (8), 91 (100),

65 (15). HRMS (EI): calcd. for C₁₉H₂₀N₂O [M]⁺292.1576; found

292.1584.

N-(2-Chloroethyl)-4,5-dimethyl-4-oxazolin-2-one (1h):^[9]Synthesized

according to method A, with 3a (0.88 g) and 4h (1.05 g), 1e

(0.545 g, 31%) was afforded as a reddish oil. R_f= 0.50 (hexane/

EtOAc, 7:3).

4-Methyl-N-phenyl-4-oxazolin-2-one (9a): Synthesized according to

method A, with 3b (0.74 g) and 4a (1.19 g), 9a (1.365 g, 78%) was

afforded as colorless crystals (hexane/CH₂Cl₂, 1:6). Synthesized ac-

cording to method B, with 3b (0.10 g, 1.34 mmol) and 4a (0.19 g,

1.62 mmol), 9a (0.196 g, 83%) was afforded. Synthesized according

to method C, with 3b (0.10 g, 1.34 mmol), 4a (0.19 g, 1.62 mmol),

and Et₃N (0.13 g, 1.35 mmol), 9a (0.158 g, 66%) was afforded. R_f

= 0.31 (hexane/EtOAc, 7:3); m.p. 58–59 °C. ¹H NMR (300 MHz,

CDCl₃): δ = 1.92 (d, J = 1.5 Hz, 3 H, CH₃C-4), 6.71 (q, J = 1.5 Hz,

1 H, 5-H), 7.30–7.38 (m, 2 H, Ph-H), 7.40–7.55 (m, 3 H, Ph-

H) ppm. ¹³C NMR (75.4 MHz, CDCl₃): δ = 9.5 (CH₃C-4), 124.0

(C-5), 124.5 (C-4), 126.9 (2 C, arom. CH), 128.5 (arom. CH), 129.5

2) ppm. IR (film): ν = 1758, 1445, 1381, 1059, 758, 700 cm^–1. MS

˜

(70 eV): m/z (%) = 300 (1) [M]⁺, 166 (5), 105 (50), 104 (96), 103

(100), 89 (15), 77 (98), 63 (65), 51 (52). C₁₇H₁₄ClNO₂(299.75):

calcd. C 68.12, H 4.71, N 4.67; found C 68.35, H 4.63, N 4.66.

1

Data for 11b: R_f= 0.20 (hexane/EtOAc, 7:3); m.p. 114–115 °C. H

NMR (300 MHz, CDCl₃): δ = 3.62 (t, J = 6.8, Hz, 4 H,

ClCH₂CH₂N-3), 4.00 (t, J = 6.8, Hz, 4 H, ClCH₂CH₂N-3), 7.14–

7.22 (m, 4 H, Ph-H), 7.25–7.36 (m, 6 H, Ph-H) ppm. ¹³C NMR

(75.4 MHz, CDCl₃):

δ = 40.9 (2 ClCH₂CH₂N-3), 43.1 (2

(2 C, arom. CH), 133.3 (arom. C), 155.0 (C-2) ppm. IR (film): ν =

˜

ClCH₂CH₂N-3), 121.2 (C-4, C-5), 128.3 (2 C, arom. C), 128.4 (2

C, arom. CH), 128.6 (4 C, arom. CH), 130.4 (4 C, arom. CH),

1754, 1665, 1597, 1502, 1396, 1385, 1278, 1152, 1076, 966, 762,

694 cm^–1. MS (70 eV): m/z (%) = 175 (46) [M⁺], 118 (100), 103 (40),

91 (3), 77 (44), 52 (20). C₁₀H₉NO₂(175.18): calcd. C 68.56, H 5.18,

N 8.00; found C 68.42, H 4.95, N 8.25.

153.2 (C-2) ppm. IR (film): ν = 3055, 2961, 1687, 1500, 1446, 1397,

˜

1362, 1262, 1017, 760, 705 cm^–1. MS (70 eV): m/z (%) = 364 (18)

[M + 4]⁺, 362 (64) [M + 2]⁺, 360 (100) [M]⁺, 298 (50), 249 (24),

236 (26), 206 (78), 179 (18), 105 (12), 77 (10). C₁₉H₁₈Cl₂N₂O

(361.27): calcd. C 63.17, H 5.02, N 7.75; found C 63.05, H 5.00, N

7.72.

N-(4-Anisyl)-4-methyl-4-oxazolin-2-one (9b): Synthesized according

to method A, with 3b (0.74 g) and 4d (1.49 g), 9b (1.645 g, 80%)

was afforded as a white powder. R_f= 0.40 (hexane/EtOAc, 7:3);

m.p. 103–104 °C. ¹H NMR (300 MHz, CDCl₃): δ = 1.88 (d, J =

1.7 Hz, 3 H, CH₃C-4), 3.84 (s, 3 H, MeO), 6.69 (q, J = 1.7 Hz, 1

H, 5-H), 6.96–7.02 (m, 2 H, Ar-H), 7.20–7.26 (m, 2 H, Ar-H) ppm.

¹³C NMR (75.4 MHz, CDCl₃): δ = 9.4 (CH₃C-4), 55.5 (OMe),

114.7 (2 C, arom. CH), 123.7 (C-5), 124.8 (C-4), 125.8 (arom. C),

128.3 (2 C, arom. CH), 155.4 (C-2), 159.5 (arom. C) ppm. IR (film):

(4R*,5S*)-4-Hydroxy-4,5-dimethyl-N-phenyl-2-oxazolidinone (anti-

5a) and (4R*,5R*)-4-Hydroxy-4,5-dimethyl-N-phenyl-2-oxazolidi-

none (syn-5a): A mixture of 3a (0.88 g, 0.01 mol) and 4a (1.19 g,

0.01 mol) was placed in a threaded ACE glass pressure tube with

a sealed Teflon screw cap under N₂. The mixture was stirred and

irradiated with MW (200 W) at 100 °C for 60 min. The mixture

was diluted in CH₂Cl₂(40 mL), poured into H₂O (100 mL), stirred

for 30 min, and the precipitate filtered. The aqueous layer was

washed with CH₂Cl₂(2ϫ40 mL), the combined organic layers were

dried (Na₂SO₄), and the solvent removed under vacuum. The resi-

ν = 1750, 1515, 1396, 1298, 1251, 1154, 1078, 968, 836 cm^–1. MS

˜

(70 eV): m/z (%) = 205 (10) [M]⁺, 148 (12), 107 (15), 77 (100), 63

(42). C₁₁H₁₁NO₃(205.21): calcd. C 64.38, H 5.40, N 6.83; found C

64.13, H 5.41, N 7.00.

4-Methyl-N-(3-tolyl)-4-oxazolin-2-one (9c): Synthesized according due was purified by column chromatography on silica gel (30 g per

to method A, with 3b (0.74 g) and 4i (1.33 g), 9c (1.47 g, 78%) was

afforded as colorless crystals (hexane/CH₂Cl₂, 1:6). Synthesized ac-

cording to method B, with 3b (0.10 g, 1.34 mmol) and 4i (0.22 g,

1.63 mmol), 9c (0.216 g, 84%) was afforded. Synthesized according

gram of crude, hexane/EtOAc, 9:1) to give a mixture of anti-5a-/

syn-5a (85:15, 1.61 g, 78%), which after recrystallization (hexane/

CH₂Cl₂, 1:1) afforded anti-5a (1.26 g, 61%) as colorless crystals. R_f

= 0.55 (hexane/EtOAc, 1:1); m.p. 102–104 °C (ref.^[9]97–99 °C).

Eur. J. Org. Chem. 2009, 2505–2518

www.eurjoc.org

2513

J. Tamariz et al.

FULL PAPER

4-Hydroxy-4-methyl-N-phenyl-2-oxazolidinone (5b): Synthesized ac-

cording to the method for the preparation of 5a, with 3b (0.74 g,

0.01 mmol) and 4a (1.19 g, 0.01 mmol), 5b (1.55 g, 80%) was af-

forded as colorless crystals. R_f= 0.45 (hexane/EtOAc, 7:3); m.p.

127–128 °C. ¹H NMR (300 MHz, CDCl₃): δ = 1.45 (s, 3 H, CH₃C-

4), 4.26 (d, J = 9.5 Hz, 1 H, 5-H), 4.37 (d, J = 9.5 Hz, 1 H, 5-H),

6.15 (br. s, 1 H, OH), 7.25–7.50 (m, 5 H, Ph-H) ppm. ¹³C NMR

(75.4 MHz, CDCl₃): δ = 24.3 (CH₃C-4), 76.0 (C-5), 87.7 (C-4),

127.0 (2 C, arom. CH), 127.2 (arom. CH), 128.9 (2 C, arom. CH),

C₁₂H₁₃NO₂[M]⁺203.0946; found 203.0948. C₁₂H₁₃NO₂(203.24):

calcd. C 70.92, H 6.45, N, 6.89; found C 71.18, H, 6.54, N, 6.94.

N-(4-Anisyl)-5,5-dimethyl-4-methylene-2-oxazolidinone (14b): Syn-

thesized according to method B, with 3d (0.10 g, 0.98 mmol) and 4d

(0.175 g, 1.176 mmol), 14b (0.21 g, 92%) was afforded as colorless

crystals. R_f= 0.54 (hexane/EtOAc, 7:3); m.p. 101–102 °C. ¹H NMR

(300 MHz, CDCl₃): δ = 1.62 (s, 6 H, 2 CH₃C-5), 3.83 (s, MeO),

4.02 (d, J = 2.9 Hz, 1 H, CH₂=), 4.06 (d, J = 2.9 Hz, 1 H, CH₂=),

6.95–7.01 (m, 2 H, Ar-H), 7.21–7.27 (m, 2 H, Ar-H) ppm. ¹³C

NMR (75.4 MHz, CDCl₃): δ = 28.0 (2 CH₃C-5), 55.5 (CH₃O), 80.9

(CH₂=), 82.4 (C-5), 114.8 (2 C, arom. CH), 126.5 (arom. C), 128.4

134.5 (arom. C), 156.2 (C-2) ppm. IR (film): ν = 3326, 1735, 1502,

˜

1427, 1242, 1153, 1077, 951, 759, 694 cm^–1. MS (70 eV): m/z (%) =

193 (18) [M]⁺, 175 (28), 119 (100), 92 (20), 77 (19). C₁₀H₁₁NO₃

(193.20): calcd. C 62.17, H 5.74, N 7.25; found C 62.08, H 5.88, N

7.44.

(2 C, arom. CH), 154.5 (C-2), 159.3 (arom. C) ppm. IR (film): ν =

˜

1756, 1683, 1644, 1517, 1457, 1404, 1296, 1252, 1189, 825 cm^–1.

MS (70 eV): m/z (%) = 233 (100) [M]⁺, 189 (18), 174 (23), 158 (6),

133 (62), 103 (6). HRMS (EI): calcd. for C₁₃H₁₅NO₃[M]⁺

233.1052; found 233.1049.

3-Oxobutan-2-yl Phenylcarbamate (12): A mixture of 3a (0.88 g,

0.01 mol) and 4a (1.19 g, 0.01 mol) was placed in a threaded ACE

glass pressure tube with a sealed Teflon screw cap under N₂. The

mixture was stirred and irradiated with MW (200 W) at 80 °C for

90 min. The mixture was dissolved in CH₂Cl₂(25 mL) and the sol-

vent removed under vacuum. The residue was crystallized from

hexane/CH₂Cl₂(6:1) to give 12 (1.75 g, 85%) as colorless crystals.

N-(2-Chloroethyl)-5,5-dimethyl-4-methylene-2-oxazolidinone (14c):

Synthesized according to method B, with 3d (0.10 g, 0.98 mmol),

4h (0.123 g, 1.166 mmol), and NEt₃(0.0099 g, 0.098 mmol) and

heating for 36 h, 14c (0.099 g, 53%) was afforded as a white pow-

der. R_f= 0.53 (hexane/EtOAc, 7:3); m.p. 60–61 °C. ¹H NMR

(300 MHz, CDCl₃): δ = 1.53 (s, 6 H, 2 CH₃C-5), 3.66–3.72 (m, 2

H, ClCH₂CH₂N-3), 3.76–3.83 (m, 2 H, ClCH₂CH₂N-3), 4.07 (d, J

= 3.3 Hz, 1 H, CH₂=), 4.17 (d, J = 3.3 Hz, 1 H, CH₂=) ppm. ¹³C

R_f

=

0.40 (hexane/EtOAc, 7:3); m.p. 66–67 °C. ¹H NMR

(300 MHz, CDCl₃): δ = 1.44 (d, J = 7.2 Hz, Me-1), 2.22 (s, Me-4),

5.14 (q, J = 7.2, Hz, 1 H, 2-H), 6.85–6.90 (br. s, 1 H, NH), 7.00–

7.10 (m, 1 H, Ar-H), 7.25–7.40 (m, 4 H, Ar-H) ppm. ¹³C NMR

(75.4 MHz, CDCl₃): δ = 16.1 (CH₃-1), 25.7 (CH₃-4), 75.3 (CH-2),

118.7 (2 C, arom. CH), 123.7 (arom. CH), 129.1 (2 C, arom. CH),

137.3 (arom. C), 152.6 (HNCO), 206.4 (C-3) ppm. MS (70 eV): m/z

(%) = 207 (11) [M]⁺, 189 (23), 116 (60), 118 (100), 103 (6), 92 (22),

77 (70), 65 (24), 58 (33), 51 (30).

NMR (75.4 MHz, CDCl₃):

δ = 27.9 (2 CH₃C-5), 39.2

(ClCH₂CH₂N-3), 42.7 (ClCH₂CH₂N-3), 79.8 (CH₂=), 82.6 (C-5),

150.4 (C-4), 155.3 (C-2) ppm. IR (film): ν = 1750, 1736, 1685, 1637,

˜

1440, 1409, 1372, 1335, 1297, 1267, 1151, 1080, 822 cm^–1. MS

(70 eV): m/z (%) = 191 (24) [M + 2]⁺, 189 (77) [M]⁺, 174 (7), 154

(100), 110 (93), 96 (50), 82 (35), 68 (56), 63 (43), 56 (36).

C₈H₁₂ClNO₂(189.64): calcd. C 50.67, H 6.38, N 7.39; found C

50.42, H 6.56, N 7.18.

General Procedures for the Preparation of N-Substituted 5,5-

Dimethyl-4-methylene-2-oxazolidinones 14a–14c. 5,5-Dimethyl-4-

methylene-N-phenyl-2-oxazolidinone (14a)

General Procedures for the Preparation of 5-Methyl-4-methylene-5-

(3-oxobutyl)-N-phenyl-2-oxazolidinone (16a) and 5,7a-Dimethyl-3-

phenyl-7,7a-dihydro-3H-benzoxazol-2-one (19a)

Method A: A mixture of 3d (1.02 g, 0.01 mol) and 4a (1.19 g,

0.01 mol) was placed in a threaded ACE glass pressure tube with

a sealed Teflon screw cap under N₂. The mixture was stirred and

irradiated with MW (300 W) at 140 °C for 3 h (see Table 3). The

mixture was diluted with CH₂Cl₂(40 mL), poured into H₂O

(40 mL), and stirred for 1 h. The mixture was filtered and the aque-

ous layer was washed with CH₂Cl₂(2ϫ40 mL). The combined or-

ganic layers were dried (Na₂SO₄) and the solvent removed under

vacuum. The residue was purified by column chromatography on

silica gel (30 g per gram of crude, hexane/EtOAc, 8:2) to give 14a

(1.37 g, 67%) as colorless crystals.

Method A: A mixture of 1a (0.945 g, 0.005 mol) and 15a (1.75 g,

0.025 mol) in dry xylene (10 mL) was heated at 160 °C under N₂

for 24 h in an ACE pressure tube sealed with a Teflon screw cap.

The solvent was removed under vacuum and the residue was puri-

fied by column chromatography on silica gel (30 g, hexane/EtOAc,

9:1) to give 16a (0.763 g, 59%) as colorless crystals (hexane/

CH₂Cl₂, 1:1) and 19a (0.164 g, 14%) as a colorless oil.

Method B: A mixture of 1a (0.189 g, 0.001 mol) in dry THF (4 mL)

and 15a (0.35 g, 0.005 mol) in dry HMPA (0.5 mL) was placed in

an ACE pressure tube sealed with a Teflon screw cap under N₂and

in darkness. At 20 °C, AlCl₃(0.147 g, 0.001 mol) was added and

the mixture was heated at 70 °C for 72 h. The residue was poured

into H₂O (50 mL) and extracted with CH₂Cl₂(3ϫ20 mL). The or-

ganic layer was dried (Na₂SO₄), the solvent was removed under

vacuum, and the residue was purified by column chromatography

on silica gel (30 g, hexane/EtOAc, 9:1) to give 16a (0.109 g, 42%)

as colorless crystals (hexane/CH₂Cl₂, 1:1) and 19a (0.087 g, 36%)

as a colorless oil.

Method B: A mixture of 3d (0.10 g, 0.98 mmol) and 4a (0.152 g,

1.277 mmol) was placed in a threaded ACE glass pressure tube

with a sealed Teflon screw cap under N₂. The mixture was stirred

and heated at 130 °C for 24 h. The mixture was diluted with

CH₂Cl₂(10 mL), filtered, and the solvent removed under vacuum.

The residue was purified by column chromatography on silica gel

(30 g per gram of crude, hexane/EtOAc, 8:2) to give 14a (0.171 g,

86%) as colorless crystals. R_f= 0.78 (hexane/EtOAc, 7:3); m.p.

133–135 °C. ¹H NMR (300 MHz, CDCl₃): δ = 1.66 (s, 6 H, 2

CH₃C-5), 4.05 (d, J = 3.0 Hz, 1 H, CH₂=), 4.14 (d, J = 3.0 Hz, 1

Data for 16a: R_f= 0.50 (hexane/EtOAc, 7:3); m.p. 107–108 °C

H, CH₂=), 7.32–7.41 (m, 3 H, Ph-H), 7.45–7.52 (m, 2 H, Ph- (ref.^[9]94–96 °C). Data for 19a: R_f= 0.37 (hexane/EtOAc, 9:1). H

1

H) ppm. ¹³C NMR (75.4 MHz, CDCl₃): δ = 28.1 (2 CH₃C-5), 81.1

(CH₂=), 82.5 (C-5), 127.0 (2 C, arom. CH), 128.3 (arom. CH),

NMR (300 MHz, CDCl₃): δ = 1.49 (s, 3 H, CH₃C-7a), 1.76 (dd, J

= 1.8, 1.5 Hz, 3 H, CH₃C-5), 2.40 (ddd, J = 16.2, 6.3, 0.6 Hz, 1 H,

129.5 (2 C, arom. CH), 134.0 (arom. C), 151.8 (C-4), 154.5 (C- 7-H), 2.56 (t, J = 16.2, 2.7 Hz, 1 H, 7-H), 5.04 (s, 1 H, 4-H), 5.33–

2) ppm. IR (film): ν = 1751, 1653, 1407, 1186, 1081, 836, 762,

5.39 (m, 1 H, 6-H), 7.30–7.38 (m, 1 H, Ph-H), 7.40–7.50 (m, 4 H,

Ph-H) ppm. ¹³C NMR (75.4 MHz, CDCl₃): δ = 21.6 (CH₃), 21.9

(CH₃), 34.3 (C-7), 81.3 (C-7a), 96.7 (C-4), 113.8 (C-6), 125.4 (2 C,

˜

702 cm^–1. MS (70 eV): m/z (%) = 203 (75) [M]⁺, 158 (91), 144 (97),

118 (22), 104 (100), 91 (14), 77 (70), 51 (29). HRMS (EI): calcd. for

2514

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Eur. J. Org. Chem. 2009, 2505–2518

A Single-Step Synthesis of 4-Oxazolin-2-ones

arom. CH), 127.7 (arom. CH), 129.4 (2 C, arom. CH), 132.2 (C-

by column chromatography on silica gel (40 g, hexane/EtOAc, 9:1)

5), 134.1 (arom. C), 142.3 (C-3a), 155.4 (C-2) ppm. IR (film): ν = to give 16a (2.0 g, 77%) as colorless crystals (hexane/CH₂Cl₂, 1:1)

˜

1754, 1675, 1598, 1501, 1406, 1334, 1196, 1072, 1019, 761,

697 cm^–1. MS (70 eV): m/z (%) = 241 (89) [M]⁺, 196 (100). 182 (78),

167 (29), 105 (30), 77 (68), 51 (26). C₁₅H₁₅NO₂(241.29): calcd. C

74.67, H 6.27, N 5.81; found C 74.96, H 6.53, N 5.59.

and 21a (0.41 g, 16%) as a white solid.

Method B: Synthesized according to method A, a mixture of 1a

(0.19 g, 0.001 mol) and 15a (0.35 g, 0.005 mol) was irradiated with

MW (400 W) and heated at 160 °C for 6 h to give 21a (0.088 g,

34%) as a white solid.

General Procedures for the Preparation of 2,5-Dimethyl-N-phenyl-

aniline (20a)

Method C: Synthesized according to method B, a mixture of 16a

(0.10 g, 0.39 mmol) and 15a (0.135 g, 1.9 mmol) was irradiated with

MW (400 W) and heated at 160 °C for 4 h to give 21a (0.09 g, 34%)

as a white solid.

Method A: A mixture of 1a (0.189 g, 0.001 mol), 15a (0.35 g,

0.005 mol) in dry MeCN (10 mL), and ZnCl₂(0.680 g, 0.005 mol)

was heated at 160 °C under N₂and in darkness for 72 h in an ACE

pressure tube sealed with a Teflon screw cap. The residue was ex-

tracted with EtOAc (3ϫ15 mL) and with CH₂Cl₂(3ϫ15 mL). The

solvent was removed under vacuum and the residue was purified

by column chromatography on silica gel (30 g, hexane/EtOAc, 9:1)

to give 20a (0.07 g, 35%) as a pale-pink oil, which quickly dark-

ened.

Data for 16a: R_f= 0.50 (hexane/EtOAc, 7:3); m.p. 95–96 °C (ref.^[9]

94–96 °C). Data for 21a: R_f= 0.30 (hexane/EtOAc, 7:3); m.p. 115–

1

116 °C. H NMR (300 MHz, CDCl₃): δ = 1.49 (s, 3 H, CH₃C-7a),

1.57 (s, 3 H, CH₃C-3a), 1.85 (br. s, 3 H, CH₃C-5), 2.23–2.34 (dm,

J = 16.5 Hz, 1 H, 7-H), 2.47 (dd, J = 16.5, 6.6 Hz, 1 H, 7-H), 4.83–

4.89 (m, 1 H, 6-H), 7.30–7.38 (m, 1 H, Ar-H), 7.40–7.43 (m, 4 H,

Ar-H) ppm. ¹³C NMR (75.4 MHz, CDCl₃): δ = 19.5 (CH₃), 20.9

(CH₃), 24.1 (CH₃C-5), 30.1 (C-7), 84.0 (C-7a), 94.4 (C-3a), 98.0

(C-6), 127.1 (2 C, arom. CH), 127.5 (arom. CH), 129.0 (2 C, arom.

Method B: A mixture of 16a (0.259 g, 0.001 mol) in dry acetonitrile

(5 mL) and ZnCl₂(0.680 g, 0.005 mol) was placed in an ACE pres-

sure tube sealed with a Teflon screw cap under N₂and in darkness,

and heated at 160 °C for 24 h. The residue was suspended in EtOAc

(20 mL) and washed with H₂O (20 mL). The aqueous layer was

washed with EtOAc (2ϫ20 mL) and the combined organic layers

were dried (Na₂SO₄). The solvent was removed under vacuum and

the residue was purified by column chromatography on silica gel

(30 g, hexane/EtOAc, 9:1) to give 20a (0.095 g, 49%) as a pale-pink

oil that quickly darkened. R_f= 0.80 (hexane/EtOAc, 8:2). ¹H NMR

(300 MHz, CDCl₃): δ = 2.22 (s, 3 H, CH₃Ar), 2.27 (s, 3 H, CH₃Ar),

6.75 (br. d, J = 7.4 Hz, 1 H, Ar-H), 6.86–6.99 (m, 3 H, Ph-H), 7.07

(br. s, 1 H, Ar-H), 7.09 (d, J = 7.4 Hz, 1 H, Ar-H), 7.21–7.30 (m,

2 H, Ar-H) ppm. ¹³C NMR (75.4 MHz, CDCl₃): δ = 17.5 (CH₃Ar),

21.1 (CH₃Ar), 117.4 (2 C, arom. CH), 119.3 (arom. CH), 120.3

(arom. CH), 122.7 (arom. CH), 129.3 (2 C, arom. CH), 130.7

(arom. CH), 131.5 (arom. C), 136.4 (arom. C), 144.0 (arom. C),

CH), 134.8 (arom. C), 150.9 (C-5), 155.5 (C-2) ppm. IR (film): ν =

˜

1764, 1713, 1675, 1499, 1395, 1324, 1239, 1170, 1070, 981, 765,

698 cm^–1. MS (70 eV): m/z (%) = 260 (13) [M + 1]⁺, 259 (6) [M]⁺,

241 (8), 197 (16), 189 (100), 144 (12), 118 (55), 77 (15). HRMS

(EI): calcd. for C₁₅H₁₇NO₃[M]⁺259.1208; found 259.1195.

General Procedures for the Preparation of (3aR*,7aS*)-3a,7a-Di-

methyl-3-phenyl-3,3a,7,7a-tetrahydro-2H-pyrano[2,3-d]oxazol-2-

one (21b)

Method A: A mixture of 1a (0.378 g, 0.002 mol) and 15b (0.623 g,

0.011 mol) in dry xylene (4 mL) was heated at 80 °C under N₂and

in darkness in an ACE pressure tube sealed with a Teflon screw

cap for 5 d. The residue was extracted with EtOAc (3ϫ15 mL) and

CH₂Cl₂(3ϫ20 mL). The combined organic layers were filtered, the

solvent was removed under vacuum, and the residue was purified

by column chromatography on silica gel (40 g, hexane/EtOAc, 9:1)

to give 21b (0.402 g, 81%) as colorless crystals (hexane/CH₂Cl₂,

6:1).

149.5 (arom. C) ppm. IR (film): ν = 3381, 2924, 1598, 1497, 1461,

˜

1310, 802, 746 cm^–1. MS (70 eV): m/z (%) = 197 (76) [M]⁺, 120

(34), 91 (42), 77 (100), 51 (90), 39 (53). HRMS (FAB): calcd. for

C₁₄H₁₅N [M]⁺197.1204; found 197.1203.

Method B: A mixture of 1a (0.378 g, 0.002 mol) and 15b (1.12 g,

0.02 mol) was irradiated with MW (200 W) and heated at 100 °C

under N₂in an ACE pressure tube sealed with a Teflon screw cap

for 6 h. The residue was extracted with EtOAc (3ϫ15 mL) and

CH₂Cl₂(3ϫ15 mL). The combined organic layers were filtered, the

solvent was removed under vacuum, and the residue was purified

by column chromatography on silica gel (40 g, hexane/EtOAc, 9:1)

to give 21b (0.378 g, 77%) as colorless crystals (hexane/CH₂Cl₂,

6:1). R_f= 0.37 (hexane/EtOAc, 7:3); m.p. 127–128 °C. ¹H NMR

(300 MHz, CDCl₃): δ = 1.48 (s, 3 H, CH₃C-7a), 1.60 (s, 3 H, CH₃C-

3a), 2.32 (dt, J = 16.8, 2.8 Hz, 1 H, 7-H), 2.53 (dd, J = 16.8, 6.6 Hz,

1 H, 7-H), 5.12–5.19 (m, 1 H, 6-H), 6.51 (dd, J = 5.5, 3.0 Hz, 1 H,

5-H), 7.35–7.45 (m, 5 H, Ar-H) ppm. ¹³C NMR (75.4 MHz,

CDCl₃): δ = 20.9 (CH₃C-7a), 24.5 (CH₃C-3a), 29.5 (C-7), 84.3 (C-

7a), 94.5 (C-3a), 103.9 (C-6), 127.6 (2 C, arom. CH), 127.9 (arom.

CH), 129.1 (2 C, arom. CH), 134.4 (arom. C), 143.0 (C-5), 155.5

2-Methyl-N-phenylaniline (20b): Synthesized according to method

A for the preparation of 20a, a mixture of 1a (0.378 g, 0.002 mol)

and 15b (0.56 g, 0.01 mol) in dry xylene (10 mL) was heated at

160 °C for 96 h to afford 20b (0.32 g, 87%) as a colorless oil that

quickly darkened. R_f= 0.87 (hexane/EtOAc, 7:3). ¹H NMR

(300 MHz, CDCl₃): δ = 2.28 (s, 3 H, CH₃Ar), 5.40 (br. s, 1 H, NH),

6.90–7.05 (m, 4 H, Ar-H), 7.10–7.30 (m, 5 H, Ph-H) ppm. ¹³C

NMR (75.4 MHz, CDCl₃): δ = 17.9 (CH₃Ar), 117.4 (2 C, arom.

CH), 118.7 (arom. CH), 120.4 (arom. CH), 121.9 (arom. CH),

126.7 (arom. CH), 128.2 (arom. C), 129.3 (2 C, arom. CH), 130.9

(arom. CH), 141.2 (arom. C), 143.9 (arom. C) ppm. IR (film): ν =

˜

3380, 2923, 1593, 1498, 1308, 746 cm^–1. MS (70 eV): m/z (%) = 184

(35) [M + 1]⁺, 183 (100), 106 (45), 90 (52), 77 (75), 51 (50). HRMS

(FAB): calcd. for C₁₃H₁₃N [M]⁺183.1048; found 183.1043.

General Procedures for the Preparation of 5-Methyl-4-methylene-5-

(3-oxobutyl)-N-phenyl-2-oxazolidinone (16a) and (3aR*,7aS*)-

3a,5,7a-Trimethyl-3-phenyl-3,3a,7,7a-tetrahydro-2H-pyrano[2,3-d]-

oxazol-2-one (21a)

(C-2) ppm. IR (film): ν = 1760, 1654, 1499, 1386, 1214, 1140, 1052,

˜

758, 698 cm^–1. MS (70 eV): m/z (%) = 245 (3) [M]⁺, 189 (84), 118

(100), 77 (39). C₁₄H₁₅NO₃(245.27): calcd. C 68.56, H 6.16, N 5.71;

found C 68.39, H 5.97, N 5.93.

Method A: A mixture of 1a (1.90 g, 0.01 mol) and 15a (3.50 g,

0.05 mol) was irradiated with MW (300 W) and heated at 140 °C (3aR*,7aS*)-3a-Methyl-3-phenyl-3,3a,7,7a-tetrahydro-2H-pyrano-

in an ACE pressure tube sealed with a Teflon screw cap under N₂

for 6 h. The residue was extracted with EtOAc (3ϫ20 mL), the

solvent was removed under vacuum, and the residue was purified

[2,3-d]oxazol-2-one (21c): Synthesized according to method A for

the preparation of 21b, a mixture of 9a (0.351 g, 0.002 mol) and

15b (0.224 g, 0.004 mol) in dry xylene (4 mL) was heated at 100 °C

Eur. J. Org. Chem. 2009, 2505–2518

www.eurjoc.org

2515

J. Tamariz et al.

FULL PAPER

for 24 h to give 21c (0.34 g, 74%) as a white powder. R_f= 0.35

(hexane/EtOAc, 7:3); m.p. 95–96 °C. ¹H NMR (300 MHz, CDCl₃):

δ = 1.55 (s, 3 H, CH₃C-3a), 2.45 (ddt, J = 17.5, 4.2, 2.6 Hz, 1 H,

arom. CH), 127.6 (arom. CH), 129.4 (2 C, arom. CH), 131.1 (C-

6), 134.1 (arom. C), 140.6 (C-3a), 155.2 (C-2), 201.3 (CHO) ppm.

IR (film): ν = 1770, 1700, 1676, 1600, 1499, 1403, 1335, 1217, 1014,

˜

7-H), 2.58 (ddd, J = 17.5, 6.2, 1.9 Hz, 1 H, 7-H), 4.77–4.82 (m, 1 762, 696 cm^–1. MS (70 eV): m/z (%) = 283 (5) [M]⁺, 239 (20), 196

H, 7a-H), 5.12–5.19 (m, 1 H, 6-H), 6.51 (dd, J = 5.5, 3.0 Hz, 1 H,

(100), 183 (15), 167 (5), 91 (5), 77 (5). HRMS (FAB): calcd. for

5-H), 7.30–7.45 (m, 5 H, Ar-H) ppm. ¹³C NMR (75.4 MHz, C₁₇H₁₈NO₃[M + 1]⁺284.1287; found 284.1295.

CDCl₃): δ = 21.9 (C-7), 23.4 (CH₃C-3a), 78.4 (C-7a), 90.6 (C-3a),

4-Methyl-5-(3-oxobutyl)-N-phenyl-4-oxazolidin-2-one (16c): Synthe-

101.4 (C-6), 127.3 (2 C, arom. CH), 127.8 (arom. CH), 129.1 (2 C,

arom. CH), 134.4 (arom. C), 143.0 (C-5), 155.8 (C-2) ppm. IR

sized according to method A for the preparation of 16a and 19a,

a mixture of 9a (0.351 g, 0.002 mol) and 15a (0.28 g, 0.004 mol)

gave 16c (0.426 g, 87%) as colorless crystals (hexane/CH₂Cl₂, 6:1).

R_f= 0.20 (hexane/EtOAc, 6:4); m.p. 85–86 °C. ¹H NMR

(300 MHz, CDCl₃): δ = 1.90 (s, 3 H, CH₃C-4), 2.19 (s, 3 H,

CH₃CO), 2.67–2.75 (m, 2 H, AcCH₂CH₂C-5), 2.77–2.84 (m, 2 H,

AcCH₂CH₂C-5), 7.26–7.31 (m, 2 H, Ar-H), 7.35–7.41 (m, 1 H, Ar-

H), 7.42–7.50 (m, 2 H, Ar-H) ppm. ¹³C NMR (75.4 MHz, CDCl₃):

δ = 8.7 (CH₃C-4), 18.4 (AcCH₂CH₂C-5), 29.9 (CH₃CO), 40.3

(AcCH₂CH₂C-5), 118.6 (C-4), 126.8 (2 C, arom. CH), 128.2 (arom.

CH), 129.3 (2 C, arom. CH), 133.7 (C-5), 134.4 (arom. C), 154.5

(film): ν = 2924, 1753, 1652, 1597, 1497, 1378, 1198, 1120, 1056,

˜

975, 861, 759, 695 cm^–1. MS (70 eV): m/z (%) = 232 (7) [M + 1]⁺,

231 (3) [M]⁺, 188 (4), 176 (6), 91 (6), 77 (100), 51 (52). HRMS (EI):

calcd. for C₁₃H₁₃NO₃[M]⁺231.0895; found 231.0889.

General Procedures for the Preparation of 7a-Methyl-3-phenyl-7,7a-

dihydro-3H-benzoxazol-2-one (19b) and 3-(7a-Methyl-2-oxo-3-

phenyl-2,3,7,7a-tetrahydrobenzo[d]oxazol-6-yl)propanal (24)

Method A: A mixture of 1a (0.38 g, 0.002 mol), 15b (0.342 g,

0.006 mol) in dry xylene (4 mL), and MeI (0.568 g, 0.004 mol) was

heated at 160 °C under N₂and in darkness in an ACE pressure

tube sealed with a Teflon screw cap for 24 h. The mixture was ex-

tracted with EtOAc (3 ϫ 20 mL) and CH₂Cl₂(3 ϫ 20 mL). The

combined organic layers were filtered, the solvent was removed un-

der vacuum, and the residue was purified by column chromatog-

raphy on silica gel (30 g per 1 g of mixture, hexane/EtOAc, 9:1) to

give 0.42 g (93%) of 19b as colorless crystals.

(C-2), 206.7 (CO) ppm. IR (film): ν = 1754, 1708, 1597, 1498, 1427,

˜

1376, 1246, 1166, 979, 762, 700 cm^–1. MS (70 eV): m/z (%) = 246

(8) [M + 1]⁺, 245 (6) [M]⁺, 188 (22), 144 (22), 128 (12), 118 (33),

77 (100), 51 (48). HRMS (EI): calcd. for C₁₄H₁₅NO₃[M]⁺

245.1052; found 245.1060.

3a,5,7a-Trimethyl-3-phenyl-3a,6,7,7a-tetrahydro-3H-benzoxazol-2-

one (26): A mixture of 1a (0.378 g, 0.002 mol) and 25 (1.49 g,

0.01 mol) in dry xylene (4 mL) was heated at 160 °C under N₂and

in darkness in an ACE pressure tube sealed with a Teflon screw

cap for 24 h. The mixture was extracted with EtOAc (3ϫ15 mL)

and with CH₂Cl₂(3ϫ15 mL). The combined organic layers were

filtered, the solvent was removed under vacuum, and the residue

was purified by column chromatography on silica gel (30 g per 1 g

of mixture, hexane/EtOAc, 9:1), to afford 26 (0.27 g, 53%) as color-

less crystals (hexane/CH₂Cl₂, 6:1). R_f= 0.32 (hexane/EtOAc, 8:2);

m.p. 121–122 °C. ¹H NMR (300 MHz, CDCl₃): δ = 1.20 (s, CH₃C-

3a), 1.49 (s, 3 H, CH₃C-7a), 1.73 (br. s, 3 H, CH₃C-5), 1.75–1.86

(m, 1 H, 7-H), 1.92 (dm, J = 17.3 Hz, 1 H, 6-H), 2.17 (ddd, J =

13.8, 5.1, 4.4 Hz, 1 H, 7-H), 2.25–2.38 (m, 1 H, 6-H), 5.09 (br. s, 1

H, 4-H), 7.20–7.26 (m, 2 H, Ar-H), 7.30–7.44 (m, 3 H, Ar-H) ppm.

¹³C NMR (75.4 MHz, CDCl₃): δ = 21.4 (CH₃C-3a), 21.7 (CH₃C-

7a), 23.4 (CH₃C-5), 26.3 (C-6), 30.9 (C-7), 63.7 (C-3a), 81.6 (C-7a),

122.6 (C-4), 127.7 (arom. CH), 128.9 (2 C, arom. CH), 129.1 (2 C,

arom. CH), 135.4 (C-5), 136.9 (arom. C), 156.6 (C-2) ppm. IR

Method B: Synthesized according to method A, a mixture of 1a

(0.38 g, 0.002 mol), 15b (0.56 g, 0.01 mol) in dry xylene (4 mL), and

MeI (0.568 g, 0.004 mol), was heated at 160 °C for 24 h to give 19b

(0.095 g, 21%) as a white powder and 24 (0.326 g, 58%) as a color-

less oil.

Method C: Compound 1a (0.30 g, 1.59 mmol) in dry CH₂Cl₂

(4 mL) was added to a mixture of 15b (0.356 g, 6.36 mmol) and

iodine (0.08 g, 0.319 mmol) in dry CH₂Cl₂(3.6 mL) and stirred at

0 °C under N₂for 2.5 h. The mixture was diluted with CH₂Cl₂

(20 mL), poured into a 10% aqueous solution of sodium thiosul-

fate (40 mL), and stirred until the red color had disappeared. The

aqueous layer was washed with CH₂Cl₂(2ϫ20 mL), the combined

organic layers were dried (Na₂SO₄), and the solvent was removed

under vacuum. The residue was purified by column chromatog-

raphy on silica gel (30 g per 1 g of mixture, hexane/EtOAc, 9:1) to

afford 19b (0.112 g, 31%) as a white powder.

1

(film): ν = 1748, 1597, 1498, 1446, 1376, 1226, 1153, 1096, 1050,

˜

Data for 19b: R_f= 0.65 (hexane/EtOAc, 7:3); m.p. 103–105 °C. H

969, 764 cm^–1. MS (70 eV): m/z (%) = 258 (26) [M + 1]⁺, 257 (3)

[M]⁺, 121 (10), 118 (10), 105 (45), 95 (45), 93 (86), 91 (42), 81 (64),

77 (100), 67 (39), 65 (25), 51 (32). HRMS (EI): calcd. for

C₁₆H₁₉NO₂[M]⁺257.1416; found 257.1415.

NMR (300 MHz, CDCl₃): δ = 1.51 (s, 3 H, CH₃C-7a), 2.52 (dd, J

= 16.7, 6.2 Hz, 1 H, 7-H), 2.70 (dm, J = 16.7 Hz, 1 H, 7-H), 5.17

(d, J = 5.5 Hz, 1 H, 4-H), 5.64–5.72 (m, 1 H, 6-H), 5.92–6.01 (m,

1 H, 5-H), 7.30–7.54 (m, 5 H, Ar-H) ppm. ¹³C NMR (75.4 MHz,

CDCl₃): δ = 21.8 (CH₃), 34.0 (C-7), 80.9 (C-7a), 93.2 (C-4), 119.4

(C-6), 124.1 (C-5), 125.3 (2 C, arom. CH), 127.6 (arom. CH), 129.4

(2 C, arom. CH), 134.0 (arom. C), 142.0 (C-3a), 155.1 (C-2) ppm.

5-Methyl-5-(3-methylbut-2-enyl)-4-methylene-3-phenyloxazolidin-2-

one (28): A mixture of 1a (0.150 g, 0.795 mmol) and 25 (0.354 g,

2.378 mmol) in dry xylene (1.5 mL) was heated at 100 °C under N₂

and in darkness in an ACE pressure tube sealed with a Teflon screw

cap for 36 h. The mixture was extracted with EtOAc (3ϫ15 mL)

and CH₂Cl₂(3ϫ15 mL), the solvent was removed under vacuum,

and the residue was purified by column chromatography on silica

gel (30 g per 1 g of mixture, hexane/EtOAc, 98:2) to afford 28

IR (film): ν = 1770, 1674, 1499, 1406, 1334, 1201, 1074, 1016 cm^–1.

˜

MS (70 eV): m/z (%) = 227 (5) [M]⁺, 182 (25), 106 (19), 91 (38), 79

(64), 77 (100), 51 (76). HRMS (FAB): calcd. for C₁₄H₁₃NO₂[M]⁺

227.0946; found 227.0945.

1

Data for 24: R_f= 0.27 (hexane/EtOAc, 7:3). H NMR (300 MHz,

CDCl₃): δ = 1.48 (s, 3 H, CH₃C-7a), 2.33 (d, J = 16.0 Hz, 1 H, 7- (0.037 g, 18%) as a pale-yellow oil. R_f= 0.68 (hexane/EtOAc, 7:3).

H), 2.44–2.54 (m, 2 H, OHCCH₂CH₂-6), 2.58–2.66 (m, 2 H,

¹H NMR (300 MHz, CDCl₃): δ = 1.62 (s, 3 H, CH₃C-5), 1.68 (br.

OHCCH₂CH₂-6), 2.74 (dm, J = 16.0 Hz, 1 H, 7-H), 5.14 (d, J = s, 3 H, CH₃CH=), 1.76 (br. s, 3 H, CH₃CH=), 2.44 (dd, J = 14.5,

5.5 Hz, 1 H, 4-H), 5.68–5.74 (m, 1 H, 5-H), 7.30–7.52 (m, 5 H, Ar- 7.8 Hz, 1 H, CH₂CH=), 2.62 (dd, J = 14.5, 7.0 Hz, 1 H, CH₂CH=),

H), 9.79 (t, J = 1.5 Hz, 1 H, CHO) ppm. ¹³C NMR (75.4 MHz,

4.03 (d, J = 2.7 Hz, 1 H, H₂C=), 4.13 (d, J = 2.7 Hz, 1 H, H₂C=),

CDCl₃): δ = 22.0 (CH₃), 29.0 (OHCCH₂CH₂-6), 38.2 (C-7), 41.5 5.19–5.28 (m, 1 H, HC=), 7.25–7.53 (m, 5 H, Ph-H) ppm. ¹³C

(OHCCH₂CH₂-6), 81.1 (C-7a), 93.2 (C-4), 119.1 (C-5), 125.2 (2 C, NMR (75.4 MHz, CDCl₃): δ = 18.2 (CH₃C-5), 26.0 (CH₃CH=),

2516

www.eurjoc.org

Eur. J. Org. Chem. 2009, 2505–2518

A Single-Step Synthesis of 4-Oxazolin-2-ones

Table 4. Crystal data and structure refinement for 10b, 14b, 19b, 21b, and 26.

Structure

10b

14b

19b

21b

26

Empirical formula

Molecular weight

Temperature [K]

Crystal size [mm³]

Crystal system

Space group

a [Å]

b [Å]

c [Å]

α [°]

β [°]

C₁₇H₁₄ClNO₂

299.74

294(2)

0.44ϫ0.30ϫ0.28

monoclinic

Cc

15.648(3)

11.2784(6)

8.4257(5)

90

100.909(5)

90

1460.1(3)

4

C₁₃H₁₅NO₃

233.26

294(2)

0.36ϫ0.22ϫ0.16

monoclinic

P₁21/c₁

14.3453(3)

6.25270(10)

14.6418(3)

90

110.130(2)

90

1233.10(4)

4

1.256

0.090

C₁₄H₁₃NO₂

227.25

294(2)

C₁₄H₁₅NO₃

245.27

294(2)

0.80ϫ0.76ϫ0.48

orthorhombic

Pbca

11.8679(6)

14.1438 (24)

15.1326(11)

90

2540.1(5)

8

1.283

C₁₆H₁₉NO₂

257.32

294(2)

0.40ϫ0.38ϫ0.26

orthorhombic

Pbcn

30.369(2)

11.8433(8)

7.8962(4)

90

2840.0(3)

8

1.204

0.35ϫ0.30ϫ0.25

triclinic

¯

P1

7.9291(3)

9.1092(6)

9.6086(5)

109.688(5)

110.085(4)

100.239(4)

578.92 (7)

2

γ [°]

Volume [Å³]

Z

Density [mg/m³]

1.364

1.304

0.088

Absorption coefficient [mm^–1] 2.345

0.741

0.629

θ range [°]

4.86–56.88

1245

1109

1077

0.0626

0.1509

1.075

2.83–32.56

11607

4067

2660

0.0456

0.1195

1.048

2.50–32.51

8804

3792

2669

0.0418

0.1245

1.148

5.68–57.00

2247

1707

1565

0.0420

0.1044

1.047

4.01–57.04

2597

1928

Reflections collected

Independent reflections

Observed reflections

R₁

1398

0.0918

0.2023

1.034

wR₂

Goodness-of-fit on F²

26.1 (CH₃CH=), 39.7 (CH₂CH=), 81.4 (H₂C=), 84.9 (C-5), 116.3 thank the Universidad Autónoma del Estado de México for its

(HC=), 127.1 (2 C, arom. CH), 128.3 (arom. CH), 129.5 (2 C, financial support and B. M. S., R. M.-P., and O. M. thank CON-

arom. CH), 134.2 (Me₂C=), 137.2 (arom. C), 150.5 (C-4), 156.0 (C- ACYT for scholarships awarded. H. A. J.-V., F. D., and J. T. are

2) ppm. IR (film): ν = 2923, 1772, 1676, 1502, 1454, 1397, 1320,

fellows of the Estímulo al Desempeño de Investigación (EDI) del

IPN and Comisión de Operación y Fomento de Actividades

Académicas del IPN (COFAA-IPN) programs.

˜

1292, 1228, 1147, 1062, 982 cm^–1. HRMS (FAB): calcd. for

C₁₆H₁₉NO₂[M]⁺257.1416; found 257.1422.

Single-Crystal X-ray Crystallography: Single crystals of 10b and

14b were obtained by recrystallization from CH₂Cl₂/hexane (1:1),

compound 21b from CH₂Cl₂/hexane (7:3), and compounds 19b and

26 from CH₂Cl₂/hexane (1:6) as colorless crystals. These were

mounted on glass fibers. Crystallographic measurements were per-

formed using Mo-K_αradiation (graphite crystal monochromator, λ

= 71073 Å) and at room temperature. Three standard reflections

were monitored periodically; they showed no change during data

collection. Unit cell parameters were obtained from least-squares

refinement of 26 reflections in the range 2 Ͻ 2θ Ͻ 20°. Intensities

were corrected for Lorentzian and polarization effects. No absorp-

tion correction was applied. Anisotropic temperature factors were

introduced for all non-hydrogen atoms. Hydrogen atoms were

placed in idealized positions and their atomic coordinates refined.

Unit weights were used in the refinement (Table 4). Structures were

solved by using the SHELXTL,^[24]SHELX97,^[25]or SIR92^[26]pro-

grams as implemented in the WinGX suite^[27]and refined by using

SHELXTL or SHELX97 within WinGX on a personal computer.

In all cases ORTEP and packing diagrams were produced with the

PLATON software package.^[28]

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Acknowledgments

We are grateful to Drs. Gerardo Zepeda, Eleuterio Burgueño, and

Francisco Díaz for their assistance in spectrometric measurements,

and Alan Larsen for reviewing the English in the manuscript. J. T.

acknowledges the Secretaría de Investigación y Posgrado del Insti-

tuto Politécnico Nacional (SIP/IPN; Grants 20040123, 20050151,

20060583, 20070339, 20080527, and 20090519) and the Consejo

Nacional de Ciencia y Tecnología (CONACYT) (Grants 32273-E,

43508-Q, and 83446) for financial support. C. G.-R. and A. F.-B.

Eur. J. Org. Chem. 2009, 2505–2518

www.eurjoc.org

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A single-step synthesis of 4-oxazolin-2-ones and their use in the construction of polycyclic structures bearing quaternary stereocenters

DOI: 10.1002/ejoc.200900114

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