Access to isolable azomethine ylides by photochemical transformation of 2,3-dihydroisoxazoles

FULL PAPER

Access to Isolable Azomethine Ylides by Photochemical Transformation of

2,3-Dihydroisoxazoles

Eloisa Lopez-Calle,^[a][‡]Manfred Keller,^[a][‡‡]and Wolfgang Eberbach*^[a]

Dedicated to Professor Howard E. Zimmerman

Keywords: Azomethine ylides / Isomerization / Nitrogen heterocycles / Photochemistry

Photochemical excitation of the 2,3-dihydroisoxazoles 19−21

resulted in the formation of the stable azomethine ylides 22,

25, and 28, representing the first isolable examples of such

species bearing stabilizing groups only at one end of the 1,3-

dipole. The UV and NMR spectroscopic data of the

photoproducts clearly indicate that the iminium and the an-

ionic parts of the azomethine ylide systems are not planar.

This conclusion is unambiguously confirmed by crystal struc-

the products 33a, 35a−c, and 41, but these are the result not

of an initial 1,3-dipolar cycloaddition but rather of a formal

[4+2] addition with involvement of 34a, 36a−c, and 41 as un-

stable primary products. On heating in refluxing toluene the

azomethine ylides are transformed into annulated pyrrole

systems (42/43, 46/47, 48/49). In contrast to other examples,

the direct thermal transformation of the annulated 2,3-dihy-

droisoxazoles into pyrroles is not successful, but the reaction

ture analysis of 25b, in which a twist angle of 73° was deter- can be achieved by simultaneous thermal and photochemical

mined between the two polar moieties. In the case of 25d the

rotation barrier around the central CN bond amounts to 16

kcal/mol at 333 K. In line with the unusual stability of the

ylides is their low reactivity against dipolarophiles. Only the

highly reactive N-methyltriazolidinedione gives formation of

activation, as shown for the conversion of 19 into the pyrroles

42/43.

( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,

Germany, 2003)

Introduction

for a few compounds formed under mild conditions and

possessing sufficiently high barriers against further trans-

formations.^[13,14]We have recently shown that 2π- and 4π-

substituted 2,3-dihydroisoxazoles can be used as masked

azomethine ylides for subsequent 1,5- and 1,7-dipolar cycli-

zation reactions.^[15]

Azomethine ylides are important building blocks, mostly

used in situ as reactive intermediates, for the construction

of N-heterocyclic compounds.^[1]Among their most success-

ful preparations are: (i) the thermal or photochemical CC-

cleavage of aziridines,^[2,3](ii) the prototropic rearrange-

ments of imines,^[4](iii) the decarboxylative route from am-

ino acids and aldehydes,^[5]and (iv) the widely variable desi-

lylation methods of iminium precursors.^[6,7]In connection

with our ongoing work on novel applications of 1,3-dipoles

in heterocyclic synthesis^[8]we have explored the potential of

2,3-dihydroisoxazoles (type 1) as precursors of stabilized

and possibly isolable azomethine ylides 5. The isolation of

2,3-dihydroisoxazoles is difficult in many cases because of

their lability, and secondary reactions often afford a number

of products.^[9]The most frequently observed transform-

ations are shown in Scheme 1 and include the formation

of pyrroles 6,^[10]2,3-dihydrooxazoles 8,^[9,11]and piperazines

7.^[9,12]The isolation of acyl aziridines 3 has been described

[a]

Institut für Organische Chemie und Biochemie der Universität

Freiburg,

Albertstrasse 21, 79104 Freiburg, Germany

Fax: (internat.) ϩ49-(0)761/203 6085

E-mail: eberbach@organik.chemie.uni-freiburg.de

[‡]

New address: Evotec OAI AG, Schnakenburgallee 114, 22525

Hamburg.

Crystal structure analyses.

[‡‡]

Scheme 1

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 2003 WILEY-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim 1434Ϫ193X/03/0408Ϫ1438 $ 20.00ϩ.50/0 Eur. J. Org. Chem. 2003, 1438Ϫ1453

Azomethine Ylides by Photochemical Transformation of 2,3-Dihydroisoxazoles

FULL PAPER

Generally, azomethine ylides are only isolable under am- the reaction between methyl propiolate and 17 was unsuc-

bient conditions if particular electronic requirements are cessful, affording an unspecific mixture with only traces of

met, as shown with the efficiently stabilized dipoles 9,^[16]21c. As can be seen from the reaction conditions, the cyclo-

10,^[17]11,^[18]12,^[19]13,^[20]and 14^[21]as representative ex- addition reactivity of the piperidino nitrone 15 is signifi-

amples (Scheme 2).^[22,23]

cantly lower than those of 16 and 17.

Table 1. Reaction conditions, yields, and UV data for the 2,3-di-

hydroisoxazoles 19aϪd, 20aϪd, and 21a, 21b, and 21d

Reaction conditions

Yield [%]

λ_max(ε)^[a]

19a

EtOH, 30 min, rfx

EtOH, 10 h, rfx

EtOH, 2 h, rfx

Et₂O, 17 h, room temp.

Et₂O, 20 h, room temp.

Et₂O, 3 h, room temp.

CH₂Cl₂, 24 h, room temp.

CH₂Cl₂, 26 h, room temp.

80

83

59

77

85

83

85

92

85

69

302 (8800)

282 (7500)

269 (5300)

268 (2900)

303 (8000)

285 (8800)

261 (6100)

269 (3800)

289 (8700)

278 (10800)

265 (4400)

19b

19c

19d

20a

20b

20c

20d

Scheme 2

21a^[b]

21b^[b]

21d^[b]

In order to avoid thermally provoked secondary reactions

of the azomethine ylides, the intention in this work was to

induce the transformation 1Ǟ5 by electronic excitation. Al-

though the photochemical behavior of five-membered het-

eroaromatic systems and their dihydro analogues Ϫ includ-

ing isoxazoles and 4,5-dihydroisoxazoles Ϫ has been exten-

sively studied, photochemical experiments with the respect-

ive 2,3-dihydro isomers are still lacking.^[24,25]We now

describe the photochemical transformation of a series of

differently annulated dihydroisoxazoles 19؊21^[26]into the

isolable azomethine ylides 22, 25, and 29, discussion of their

structures, and some investigations of the chemical reactiv-

ity of the dipolar systems.^[27]

[a]

[b]

In CH₃CN.

Treatment of 18a, 18b, and 18d with nitrone 17

prepared in situ.

The wavelengths of the c and d series are slightly red-

shifted (261Ϫ278 nm, see Table 1) relative to the UV ab-

sorption maxima of the dihydroisoxazoles

a and b

(278Ϫ302 nm), thus allowing excitation through the use of

a Vycor filter (λ Ͼ ca. 230 nm) for the c and d compounds

and of a Jenaglass filter (λ Ͼ ca. 280 nm) in the latter case.

Irradiation of a ca. 10^Ϫ3molar solution of 19a in benzene

with a high-pressure mercury lamp (Hanua 150 W) afforded

a main product, identified as the azomethine ylide 22a, in

88% yield (m.p. 133 °C) after complete conversion (36 min)

and subsequent chromatographic purification. Under simi-

lar conditions, the tert-butyl derivative 19b is likewise trans-

formed into 22b (75%, m.p. 104 °C). In the cases of 19c

Results and Discussion

The well established 1,3-dipolar cycloaddition method- and 19d the photolysis was performed in diethyl ether, and

ology was employed for the preparation of the required 2,3- compounds of the dipolar structure 22 were again isolated

dihydroisoxazoles 19Ϫ21.^[28]Treatment of the known nitro- as the major products (c: 25%, d: 58%). The low yields,

nes 15Ϫ17 with the alkynes 18aϪd afforded the cycload- especially of 22c, are mainly due to product loss during the

1

ducts 19aϪd, 20aϪd, and 21a, 21b, and 21d in good yields chromatographic workup; according to H NMR analysis

and with perfect regioselectivities (Scheme 3, Table 1). Only carried out prior to purification, both 22c and 22d had been

Scheme 3

Eur. J. Org. Chem. 2003, 1438Ϫ1453

1439

E. Lopez-Calle, M. Keller, W. Eberbach

FULL PAPER

formed in about 70Ϫ80% yields. Furthermore, careful in- metry-allowed 1,3-N shift 19aǞ23a, which would be con-

1

spection of the H NMR spectra of the a-c series (but not ceivable from the excited singlet state of 19.

d) revealed additional signals compatible with the azabicy-

clo[4.1.0]heptene structure 23, the ratios of 22:23

amounting to approximately 10:1 (a), 60:1 (b), and 6:1 (c).

Unfortunately, all attempts to isolate the bicyclic isomers

have so far failed. The dipolar compounds 22aϪd are the

first representatives of isolable azomethine ylides bearing

stabilizing groups only at one terminus of the 1,3-dipolar

system. The few examples with π-substituents on both sides

are mostly derived from conjugated iminium compounds

such as isoquinolinium or dihydroisoquinolinium yl-

ides.^[16,29,30]

Scheme 5

Further evidence for the intermediacy of aziridines 23

was obtained from independent photolysis experiments.

After irradiation of ca. 10^Ϫ3molar solutions of 22a in ben-

zene for 10 min, the H NMR spectrum of the photolysate

Scheme 4

1

indicated the presence of a ca. 10:1 mixture of 22a and bi-

The structures of the azomethine ylides 22 were deter- cyclic aziridine 23a, the isomer ratio being the same as ob-

mined by spectroscopic/analytical investigations (see Exp. tained from the photoreaction of 19a. This therefore indi-

Section) as well as from some chemical transformations cates that the electronically excited ylide 22a is transformed

(vide infra). In addition to the elemental analyses and/or into the aziridine 23a. In order to slow down or suppress

MS and HRMS data, through which the isomeric natures thermal reactions, the irradiation of a sample of 19a in

of the photoproducts and their starting compounds were CD₃CN was performed in a NMR tube at Ϫ30 °C until

1

established, the IR, UV, and NMR spectroscopic data un- complete conversion. Analysis of the H NMR spectrum

ambiguously support the proposed structures. For 22a, revealed the appearance of two products, 22a and 23a, but

characteristic NMR absorptions are: δ_Hϭ 8.91 (CHO), now in a 2:1 ratio. After the mixture had warmed to room

3.90 (2Ј-H), 2.91 (5Ј-H), 2.34 (6Ј-CH₃); δ_Cϭ 33.4 (C-5Ј), temperature, however, the ratio had again changed to 10:1.

53.7 (C-2Ј), 123.0 (C-2), 140.3 (C-6Ј). Interestingly, the UV From the above results it is concluded that 23a is thermally

absorption bands are at relatively short wavelengths, with converted into the azomethine ylide 22a, whereas the re-

maxima at 333 (ε ϭ 3500) and 280 nm (ε ϭ 13500), which verse reaction takes place on electronic excitation.

is probably due to reduced conjugation between the twisted

The photolysis experiments with the pyrrolo isoxazolines

cyclic and the acyclic parts of the dipole system.^[31]Because 20aϪd (see Table 1 for the UV data) were performed under

all attempts to isolate the bicyclic aziridines 23aϪc were the conditions described for the piperidino derivatives 19.

unsuccessful, their identification had to be performed on Despite the use of light of higher energy (λ Ͼ 230 nm) the

1

the basis of their H NMR spectra: the following signals consumption of 20c and 20d is considerably slower than for

are indicative for 23a/b/c: 2.58/2.41/2.47 (6-CH₃), 3.55/3.57 20a and 20b (λ Ͼ 280 nm). According to the product analy-

(a, c: 5Ј-H), 3.79/3.90 (a, c: 2Ј-H), 9.29/9.70/9.53 (CHO).

ses, one compound Ϫ namely the corresponding azome-

The proposed pathway of the transformation 19Ǟ22/23 thine ylide (25aϪd) Ϫ was formed exclusively or predomi-

is outlined in Scheme 5. It includes the photochemically in- nately in each case (60Ϫ91% yield, see Table 2). There were

duced NO-cleavage to the diradical 24 as first step, followed no indications of the presence of aziridines of type 23, but

by bond reorganization to the bicyclic aziridine 23, which further products were isolated in 8 and 17% yields, respec-

undergoes CC-cleavage to afford the final product 22. To tively, in the cases of 20c and 20d. These similarly turned

examine the multiplicity of the excited state, the irradiation out to be isomeric with the starting dihydrooxazolines and

of 19a was also performed in acetone, both as solvent and were identified as the pyrrolidinylidenemalonates 26c and

as triplet sensitizer (E_Tϭ 80 kcal/mol). Under conditions 26d (Scheme 6).

otherwise analogous to those described for the direct exci-

The NMR spectra of the dipoles 25 agree well with the

tation, a reaction mixture giving an 85% yield of 22a and data for the corresponding piperidino derivatives 22

23a in a 10:1 ratio was obtained after chromatography puri- (Table 3), and the UV absorptions are again, as would be

fication. The almost identical results strengthen the suppo- expected, at shorter wavelengths (Table 2). As already dis-

sition that the reacting species is triplet in nature. In this cussed for the azomethine ylides 22, the non-planarity of

case a two-step mechanism with an intermediate such as 24 the ylide system might be the reason for this. This expla-

should be operative, thus excluding an alternative sym- nation is supported in the case of 25 by the observation that

1440

Eur. J. Org. Chem. 2003, 1438Ϫ1453

Azomethine Ylides by Photochemical Transformation of 2,3-Dihydroisoxazoles

FULL PAPER

hand, the second NϪC bond of the ylide is even shorter

than a pure CϭN bond.

Table 2. Photolysis of 20aϪd

Conditions^[a]

Products^[b]

25 [UV data]^[c]

26

20a

20b

20c

20d

benzene, λ Ͼ 280 nm, 1.5 h

benzene, λ Ͼ 280 nm, 1.7 h

acetonitrile, λ Ͼ 230 nm, 3.7 h

acetonitrile, λ Ͼ 230 nm, 4.5 h

88 [330 (3600), 278 (13400)]

91 [331 (1600), 274 (16600)]

60 [335 (2100), 256 (13700)]

75 [326 (1700), 261 (11800)]

Ϫ

8

17

^[a]1.0 mmol of 20 in 250 mL of solvent. ^[b]Yields in %, after purifi-

[c]

cation. λ_max[nm] (ε), in CH₃CN.

Scheme 6

Figure 1. Crystal structure of the azomethine ylide 25b

(SCHAKAL drawing, hydrogen atoms omitted; the numbering

does not correspond with the correct nomenclature); selected bond

the methylene protons at C-2Ј and C-4Ј give rise to broad-

ened AB signals in the H NMR spectra, thus indicating

˚

lengths [A] and angles [°]: C2ϪN 1.292, NϪC5 1.467, NϪC6 1.445,

1

C2ϪC3 1.491, C3ϪC4 1.531, C4ϪC5 1.541, C6ϪC7 1.429,

C6ϪC12 1.395; C2ϪNϪC5 112.7, C2ϪNϪC6 126.2, C7ϪC6ϪN

116.1, C2ϪNϪC5 112.7, C7ϪC6ϪC12 130.5; angle between the

planes C5ϪNϪC2 and C7ϪC6ϪC12 72.7

their non-equivalence. Because of the bulky substituents at

the azomethine moiety there is obviously no free rotation

around the central CN bond and hence no planarity of the

molecules. A strong indication of a barrier to the geometri-

cal change of the dipole system was provided by dynamic

NMR experiments with 25d. When a sample of 25d was

heated in pentadeuteriobromobenzene, the 19.5 Hz splitting

of the methylene protons at C-4Ј disappeared and the co-

alescence temperature was reached at 333 K, corresponding

to a ∆G^#value of 16 kcal/mol (δ_Aϭ 2.51, δ_Bϭ 2.30, in

C₆D₅Br).

The structural data are in agreement with the other

known X-ray data relating to the isolable azomethine ylides

10,^[17b]11,^[18]12,^[19]and 13^[20](Table 4). With the exceptions

of the symmetric bis-indanedione derivative 12 and the en-

docyclic system 13, there are significant differences between

the CϪN bond lengths, indicating strong bond localization

with high double bond and single bond character, respec-

tively. Whereas the CϪNϪC bond angle in 13 (110°) is con-

sistent with the value for five-membered rings, the corre-

sponding angles in 10؊12 and 25b are in the 121Ϫ134°

range. An important feature of the structures is the ge-

ometry of the dipole unit. The expected planarity of the

1,3-dipole is seen only in 10 (the arrangement is obviously

assisted by a hydrogen bond between the NϪH and the

carbonyl oxygen of the ester function) and in 13 (due to the

endocyclic structure). In contrast, compounds 11 and 12

have twist angles of 30° and 20°, respectively. However,

most striking is the fact that the cyclic immonium and the

anionic parts of 25b are twisted around the NϪC6 bond

with an angle of 73°, the two components being arranged

in an almost orthogonal manner, resulting in significant

charge separation. With this observation in mind, the rela-

Table 3. Selected NMR spectroscopic data (δ-values, in CDCl₃) of

the azomethine ylides 25a, 25b, and 25d

¹H-shift

¹³C-shift

2Ј-H 3Ј-CH₃4Ј-H 5Ј-CH₃C-2 C-2Ј C-3Ј C-4Ј C-5Ј

25a 4.10

4.22

1.32 2.98

1.35

1.29 2.82

1.30 2.98

1.25 2.80

3.00

2.30 116.8 71.7 35.7 52.7 184.9

2.17 115.2 71.5 35.4 52.4 186.4

2.28 101.8 72.1 35.3 50.1 185.4

25b 3.84

4.05

25c 3.85

4.28

25d 4.89

1.29 2.86

3.04

2.33

97.7 72.3 35.5 52.6 171.0

4.20

Final confirmation of the non-planarity of 25b was ob- tively short-wavelength UV absorptions of the azomethine

tained by crystallographic analysis^[32](Figure 1). Among ylides and the signal doubling of the methylene protons of

the various parameters, it is of particular interest that the 25aϪd find a convincing explanation.

˚

NϪC6 bond is significantly longer (1.445 A) than the

In view of the non-planarity of the dipolar system, the

˚

NϪC2 bond of the azomethine ylide system (1.292 A), indi- unexpected stability of the compounds 25 (the same should

cating little or no π-conjugation between the ring nitrogen apply for 22) must be due to a particular electronic stabiliz-

and C6. The former bond length is only slightly shorter ation of the ionic centers, and possibly steric effects. This is

than the average length of a ^(sp3)NϪC^(sp3)bond (1.48 A), a further example of thermodynamic and/or kinetic stabiliz-

˚

compared to 1.35 A for a ^(sp2)NϪC^(sp2)bond. On the other ation of not usually isolable intermediates, such as the Ard-

˚

Eur. J. Org. Chem. 2003, 1438Ϫ1453

1441

E. Lopez-Calle, M. Keller, W. Eberbach

FULL PAPER

Table 4. CϪN distances, CϪNϪC angles, and twist angles in the

dipoles 25b and 10؊13

˚

CϪN [A]

CϪNϪC [°]

twist [°]

25b

1.30/1.44

1.30/1.43

1.32/1.40

1.34/1.35

1.35/1.37

121

134

127

128

110

73

10^[17]

11^[18]

12^[19]

13^[20]

30

20

uengo carbenes^[33]or particularly substituted carbocations,

carbanions, or radicals.^[34]However, it has to be emphasized

that the electronic nature of the original species has signifi-

cantly changed in all those cases. The question therefore

arises of whether the compounds still belong to the respect-

ive parent class of compounds. With regard to the above

discussion, as well as to the chemical experiments with sev-

eral derivatives of the azomethine ylides 22 and 25 (vide

infra), there are at least doubts.

The structure determination of the minor photoproducts

of 20c and 20d, confirmed as isomers by elemental analyses

and MS, raised some problems. Comparison of the NMR

spectra with the data for the dipoles 25c and 25d showed

that there were two main differences: the low-field absorp-

tion of one methyl group (3.06/301 ppm compared to 2.28/

2.33 ppm) and the appearance of the ring methylene pro-

tons as sharp singlets at δ ϭ 3.12/3.4 and 3.09/3.85, respec-

tively. The assignment of the pyrrolidinylidenemalonate

structures 26c and 26d was supported by an X-ray analysis

of 26d^[32](Figure 2). The relatively short NϪC4 bond

Figure 2. Crystal structure of the pyrrolidinylidenemalonate 26d

(SCHAKAL drawing, hydrogen atoms omitted; the numbering

does not correspond with the correct nomenclature); selected bond

˚

lengths [A] and angles [°]:C1ϪC2 1.533, C2ϪC3 1.544, C3ϪC4

1.504, NϪC1 1.474, NϪC4 1.314, C4ϪC5 1.436; NϪC4ϪC3

108.9, NϪC4ϪC5 124.1, C3ϪC4ϪC5 126.9; angle between the

planes NϪC4ϪC3 and C6ϪC5ϪC10 36.0

Scheme 7

˚

(1.309 A) and the unusually long C4ϪC5 bond (1.427 A)

are indications that the dipolar resonance structure of 26d

represents an important contribution to the carbonyl-sub-

stituted enamine system. The exocyclic double bond is not

planar, the twist angle amounting to 36°.

The formation of the enamines 26c and 26d can be ex-

plained by the assumption of an excited state cleavage of

the NO bond as first step, producing the diradical 27 (see

Scheme 7), followed by a 1,2-migration of the methyl group

to afford 26. Although the mechanism seems quite plaus-

ible, we are aware of only one analogous methyl shift, which

is involved, however, during a thermal reaction between bi-

s(trifluoroacetylene) and an aromatic nitrone.^[35]

The photolysis of the oxazolo-dihydroisoxazole deriva-

tives 21a, 21b, and 21d in each case gave only one photo-

isomer, with the structure of the corresponding azomethine

ylide (28a, 28b, and 28d; Scheme 8). As judged from the

NMR spectra of the raw photolysates, the yields of the

products were almost quantitative, the given yields of 89,

60, and 90%, respectively, being due to their partial de-

composition during workup and showing rather the lower

limit. The hindered rotation around the central CN bonds

in compounds 28 is nicely reflected by the appearance of

two NMR singlets for the C-4Ј methyl groups and the AB

Scheme 8

Table 5. Selected NMR spectroscopic data (δ-values in CDCl₃) for

the azomethine ylides 28a, 28b, and 28d

¹H-shift

¹³C-shift

5ЈϪH 2ЈϪCH₃4Ј-CH₃CϪ2 CϪ2Ј CϪ4Ј CϪ5Ј

28a 4.70

2.28

2.15

2.33

1.53

1.57

1.36

1.48

1.52

1.53

108.8 176.8 69.9

110.3 176.6 69.6

89.1 178.1 70.1

82.1

82.0

82.4

28b 4.64

4.62

28d 4.63

4.72

With regard to the chemical reactivity of isolable azome-

patterns for the CϪ5Ј methylene protons in 28b and 28d thine ylides, there are reports of cycloaddition reactions

(Table 5).

with appropriate dipolarophiles under mild conditions,

1442

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Azomethine Ylides by Photochemical Transformation of 2,3-Dihydroisoxazoles

FULL PAPER

such as the formation of 29؊31 from the respective com- hyde proton signal; instead a broad absorption at δ ϭ

pounds 9,^[16]10,^[17]and 12^[19](Scheme 9).

13.5 ppm, which disappeared on addition of D₂O, was a

clear indication of a chelated OH group. Among the other

data, the ¹³C absorptions at δ ϭ 162.4 and 110.8 ppm

should be mentioned; these are caused by the two olefinic

carbon atoms C-5/C-6 (Table 5) and support the proposed

structure 33a.

The formation of 33a cannot be explained by a 1,3-di-

polar cycloaddition, but must rather proceed through a for-

mal [4ϩ2] addition onto the enolate form 22aЈ of the di-

polar system to produce the betaine 34a, which rearranges

to the keto tautomer of 33a by a 1,2-hydride shift (alterna-

tively, a proton transfer to the oxygen to afford 33a would

also be conceivable). This unusual behavior of the azome-

thine ylide moiety must be due to the particular geometry

discussed above, in which the interaction between the two

parts of the molecule is significantly decreased. However,

we have no obvious explanation for the fact that the attack

of MTAD takes place at the carbonyl carbon of 22a.

To the best of our knowledge there is only one previously

described comparable reaction mode for the addition of di-

polarophiles to 1,3-dipoles: the addition of electron-de-

ficient alkynes to phosphanyldiazoalkanes. In this case the

electrophilic attack of the diazaphosphanes produces 1,2,4-

λ⁵-diazophosphanes, probably through the intermediacy of

1,6-dipolar species.^[36]

Scheme 9

In sharp contrast to the above results, all attempts to

achieve such 1,3-dipolar cycloadditions between examples

of the dipolar compounds 22, 25, and 28 and dimethyl ace-

tylenedicarboxylate (DMAD), methyl propiolate (MP), or

Under conditions similar to those described for 22a, the

N-phenyl maleimide (NPMI) as dipolarophiles failed. At reactions between the pyrrolidine derivatives 25aϪc and

ambient temperatures there was no conversion, whereas MTAD proceeded much more slowly and less cleanly. Be-

only complex mixtures containing no separable products cause of the instabilities of the products and the increasing

were obtained in boiling benzene solutions. Treatment of formation of polymeric material, the reactions were stopped

22a with methyltriazolinedione (MTAD) in dichlorometh- after 30 min, a point at which less than 50% conversion had

ane, however, resulted in complete conversion after 10 min been reached. After chromatographic workup two mono-

at 25 °C affording a single crystalline product in 78% yield meric products were isolated: the starting material 25 as the

(m.p. 155 °C). Although the elemental analysis and the MS main component (ca. 40%) and a minor compound

supported the formation of a 1:1 adduct (m/e ϭ 356), the (10Ϫ14%) to which the structure of 35 was assigned

expected structure 32a was inconsistent with the NMR (Scheme 11). Although the compounds are structurally re-

spectroscopic data. Most importantly, there was no alde- lated to 33a, the loss of an oxygen at C-5 is an surprising

Scheme 10

Eur. J. Org. Chem. 2003, 1438Ϫ1453

1443

E. Lopez-Calle, M. Keller, W. Eberbach

FULL PAPER

discrepancy (indicated by the elemental analysis and the cessful. Instead, the hydrolyzed compound 41 was isolated

MS). That difference aside, the NMR spectroscopic data after chromatographic separation (Scheme 12). As in the

are very comparable (see Table 5).

case of 33, but in contrast to that of 35, no reduction pro-

cess is involved in the reaction pathway.

Table 6. Selected NMR spectroscopic data (δ values, in CDCl₃) of

the cycloadducts 33a and 35aϪc

It is generally accepted that the thermal transformation

of 3-alkyl-substituted 2,3-dihydrooxazolines into pyrroles

proceeds through azomethine ylides as intermediates (see

Scheme 1. 1Ǟ5Ǟ6).^[9,10]In order to lend further support

to this assumption, we performed investigations with some

of the dipolar systems described above. Transformations of

the piperidino derivatives 22aϪd were successfully achieved

by heating them at reflux in toluene solutions for 1.5Ϫ6 h.

Depending on the nature of R¹and R², either the two tetra-

hydroindolizines 42 and 43 (a,b) or only one isomer (43c,d)

were isolated (Scheme 13). This result can be explained by

assuming a 1,4-H-shift to the enamine 44 as the first step,

followed by a cyclocondensation process. The observed

chemoselectivity is in agreement with the decreasing reac-

tivity of the carbonyl component in the order CHO Ͼ COR

Ͼ CO₂CH₃.

¹H-shift

¹³C-shift

C-5 C-6 C-8 C-11a^[a]

C-10a^[b]

5-OH^[a]8-H 11-H^[a]11a-CH₃

[a]

[b]

5-H^[b]

10-H^[b]10a-CH₃

33a 13.5 2.70 1.66

3.19 2.70

1.56

1.42

1.35

1.32

162.4 110.8 52.0

125.9 114.7 65.0

125.5 112.3 66.5

117.7 112.6 65.7

76.6

81.7

81.9

82.1

35a 7.32 2.65 2.12

3.36 2.98

35b 7.37 2.59 2.02

3.30 3.06

35c 7.63 2.62 2.07

3.60 3.00

[a]

[b]

33a. 35aϪc.

The transformation of azomethine ylides into annulated

pyrrole derivatives adds a new alternative to the synthesis

of such heterocycles. In this context the question arose of

whether the same result might be achieved by direct trans-

formation of the bicyclic 2,3-dihydroisoxazoles used in this

work. Experiments performed with the piperidino com-

pounds 19aϪd were unsuccessful, however, complex prod-

uct mixtures with only traces of the expected pyrroles 42/43

being detected after toluene solutions of 19 had been heated

at reflux. This failure, though, is probably due to side reac-

tions: if the transformation of 19a is performed under

short-time thermolysis conditions (330 °C/ca. 10 s contact

time), the pyrroles 42a/43a are similarly formed in high

yield.^[37]Interestingly, heating of toluene solutions of 19

with simultaneous irradiation with a daylight 500 W lamp

also resulted in the formation of the indolizines 42/43, albeit

in lower yield (Scheme 14).

The thermal behavior of the pyrrolidine dipoles 25 paral-

lels that of the higher homologues 22, with the exception of

significantly longer reaction times (3 days vs. 1.5Ϫ6 h, in

refluxing toluene), and the additional formation of the en-

amines 45aϪd (Scheme 15). It was shown by independent

experiments that the latter compounds can be transformed

Scheme 11

Mechanistically, the most difficult problem lies in the fact into the pyrrolizidines 46/47 on heating benzene solutions

that a reduction step has to be involved. Because there is of 45 in an autoclave for 12 h at 200 °C. The high thermal

no particular reduction agent present, we tentatively pro- stability of the products follows from the observation that

pose the route outlined in Scheme 12. The pathway includes the yields of the heterocycles are still quite high despite the

a Cannizzaro-type hydride transfer between the dipole 36 harsh conditions (46a/47a: 70%/5%; 46b/47b: 80%/4%; 47c:

and product 38 (keto tautomer), resulting in the formation 60%, 47d: 65%).

of the iminium derivative 37 (which might be responsible

The dihydrooxazole system 28 turned out to be much

for the polymeric material) and the alcohol 39, the direct more stable, and so the thermal reactions of 28a and 28b

precursor of the final products 35aϪc. In view of the 50% were performed with benzene solutions in an autoclave at

loss of starting material by this pathway, the low experimen- 200 °C for 12 and 3 h, respectively. Chromatographic purifi-

tal yield of 35 would find a reasonable explanation.

cation of the reaction mixtures resulted in each case in the

Treatment of the oxazolino derivative 28a with MTAD isolation of three products: the pyrroles 48a/48b (13%, 20%)

at room temperature for 3 days again resulted in a formal and 49a/49b (13%, 13%), as well as the non-cyclic N-formyl

[4ϩ2] addition, but the isolation of the corresponding tri- derivatives 52a/52b (45%, 38%). Whereas the formation of

azine 40, the diaza analogue of an orthoester, was not suc- the two annulated pyrroles follows the same pathway as dis-

1444

Eur. J. Org. Chem. 2003, 1438Ϫ1453

Azomethine Ylides by Photochemical Transformation of 2,3-Dihydroisoxazoles

FULL PAPER

Scheme 12

an intramolecular cleavage of a 1,3-dicarbonyl compound

by a secondary amine, a reaction documented for the bimo-

lecular alternative.^[38]

Scheme 13

Scheme 14

Scheme 16

Conclusion

The aim of this work was to investigate the photochem-

ical behavior of 2,3-dihydroisoxazoles. On irradiation of an-

nulated heterocycles of this type, substituted at C-4 with

keto, aldehyde, or ester functions, transformations to stable

azomethine ylides take place as the main reaction pathway.

For the first time, compounds of this type with stabilizing

groups at only one terminus of the 1,3-dipolar system were

isolated under ambient conditions. On the basis of the

NMR spectroscopic data, and in particular a crystal struc-

Scheme 15

cussed for the related compounds 42/43, the occurrence of ture analysis of 25b, evidence for the non-planarity of the

the major components 52a and 52b is quite unexpected. iminium and the anionic parts of the molecules was ob-

Our tentative explanation includes the hydrolysis of the en- tained. The twist angle in 25b amounts to 73°, a clear indi-

amines 50 by traces of water to afford compounds 51, which cation of almost no conjugative interaction between the po-

undergo rearrangement to the observed products 52 lar centers. In the case of 25d, the rotation barrier around

(Scheme 16). The latter transformation can be regarded as the central CN bond was determined to be 16 kcal/mol at

Eur. J. Org. Chem. 2003, 1438Ϫ1453

1445

E. Lopez-Calle, M. Keller, W. Eberbach

FULL PAPER

2-tert-Butyl-3a-methyl-4,5,6,7-tetrahydro-3aH-isoxazolo[2,3-a]-

pyridine-3-carbaldehyde (19b): Treatment of 15^[39]with 18b (0.78 g,

7.1 mmol) in boiling ethanol (30 mL, 30 min) gave 19b (0.82 g,

83%) as a pale yellow oil after flash chromatography (SiO₂, cyclo-

hexane/ethyl acetate, 15:1). IR (CCl₄): ν˜ ϭ 2960, 2920, 2890, 2840,

1640 (CϭO), 1580, 1460, 1445, 1390, 1365, 1320, 1270, 1125, 1075,

333 K. In view of the significantly reduced electronic inter-

action within the dipolar structures, which is also docu-

mented in the relatively short-wavelength UV absorptions

(λ_maxϽ 335 nm), the unusual stability of the dipolar com-

pounds 22, 25, and 28 is very surprising. Along the same

lines, but in contrast to other isolable azomethine ylides, is

their low reactivity towards dipolarophiles such as dimethyl

acetylenedicarboxylate or N-phenylmaleimide. With N-phe-

nyltriazolinedione, however, formal DielsϪAlder additions

1

950, 790, 745 cm^Ϫ1. H NMR: δ ϭ 1.23 (m, 1 H, 4-H), 1.30 (s, 3

H, CH₃), 1.38 (s, 9 H, tBu), 1.43Ϫ1.73 (m, 4 H, 5-H, 6-H), 2.64

(m, 1 H, 4-H), 2.75 (m, 1 H, 7-H), 3.29 (m, 1 H, 7-H), 10.16 (s, 1

H, CHO). UV (CH₃CN): δ ϭ 233 nm (ε ϭ 4100), 282 nm (ε ϭ

do take place, finally affording the products 33a, 35aϪc, 7500). MS (70 eV, EI): m/z (%) ϭ 224 (6%) [M^ϩϩ 1], 223 (32),

209 (53), 168 (31), 166 (61), 152 (61), 138 (43), 125 (22), 124 (25),

122 (27). HRMS (C₁₃H₂₁NO₂): calcd. 223.1572; found 223.1571.

and 41, respectively.

Although the formation of pyrroles by thermal trans-

formation of simple 2,3-dihydrooxazoles is a well known

procedure, only the methodology involving a photochem-

ical and a thermal step is successful for obtaining annulated

pyrroles such as 42/43, 46/47, and 48/49.

Methyl 3a-Methyl-4,5,6,7-tetrahydro-3aH-isoxazolo[2,3-a]pyridine-

3-carboxylate (19c): Treatment of 15^[39]with 18c (0.50 g, 5.9 mmol)

in boiling ethanol (20 mL, 10 h) gave 19c (0.26 g, 59%) as a yellow

oil after flash chromatography (SiO₂, cyclohexane/ethyl acetate,

15:1). IR (CCl₄): ν˜ ϭ 2960, 2940, 2900, 2850, 1710 (CϭO), 1620,

1605, 1435, 1350, 1335, 1325, 1280, 1150, 1125, 1110, 1090, 1070

Experimental Section

cm^Ϫ^{1 1}H NMR: δ ϭ 1.32 (m, 1 H, 4-H), 1.35 (s, 3 H, CH₃),

.

1.47Ϫ1.75 (m, 4 H, 5-H, 6-H), 2.45 (m, 1 H, 4-H), 2.92 (m, 1 H,

7-H), 3.32 (m, 1 H, 7-H), 3.74 (s, 3 H, OCH₃), 7.36 (s, 1 H, 2-H).

UV (CH₃CN): λ ϭ 269 nm (ε ϭ 5300). MS (70 eV, EI): m/z (%) ϭ

197 (5%) [M^ϩ], 182 (59), 149 (11), 138 (7), 124 (9), 122 (9), 110

(18), 109 (13), 96 (12), 94 (9), 93 (7). HRMS (C₁₀H₁₅NO₃): calcd.

197.1052; found 197.1049.

General: Melting points are uncorrected. IR: PerkinϪElmer 257

Infracord. ¹H NMR: Bruker WM 250 (250 MHz), ¹³C NMR:

Bruker WM 400 (100 MHz). CDCl₃as solvent and TMS as in-

ternal standard. MS: Finnigan MAT 44 S (70 eV) with Datasystem

MAT SS 200. Elemental analyses: PerkinϪElmer Elemental Ana-

lyzer 240. Products were isolated by flash chromatography on silica

gel (Silica 32Ϫ36, ICN Biomedicals) or alumina oxide /Alumina

N, Biomedicals). TLC: SiO₂60 F-254, 0.2 mm (Merck). Irradiation

was performed with a 150 W high-pressure mercury lamp (Hanau

TQ 150) at 20 °C with either a Vycor (λ Ͼ ca. 230 nm) or a Jena

glass filter (λ Ͼ ca. 280 nm) at ca. 20 °C; the solutions were satu-

rated with dry nitrogen before irradiation.

Dimethyl 3a-Methyl-4,5,6,7-tetrahydro-3aH-isoxazolo[2,3-a]pyri-

dine-2,3-dicarboxylate (19d): Treatment of 15^[39](0.50 g, 4.4 mmol)

with dimethyl acetylenedicarboxylate (18d, 0.69 g, 4.9 mmol) in

boiling ethanol (40 mL, 2 h) gave 19d (0.87 g, 77%) as a pale yellow

oil after flash chromatography (SiO₂, cyclohexane/ethyl acetate,

15:1). IR (CCl₄): ν˜ ϭ 2940, 2850, 1760 (CϭO), 1715 (CϭO), 1635,

1450, 1430, 1350, 1330, 1280, 1230, 1200, 1170, 1140, 1090, 1040,

1

1010 cm^Ϫ1. H NMR: δ ϭ 1.31 (m, 1 H, 4-H), 1.40 (s, 3 H, CH₃),

General Procedure for the Preparation of the Dihydrooxazoles 19 by

1,3-Dipolar Cycloaddition: A solution of the nitrone 15 (ca.

5 mmol) and the alkyne derivative 18 (1.1 equivalent) in ethanol

(30Ϫ80 mL) was heated at reflux until complete conversion

(0.5Ϫ2 h). After concentration, the remaining solution was poured

into water (ca. 20 mL) and then extracted with dichloromethane.

The combined organic solutions were washed with brine, dried

(MgSO₄), and concentrated in vacuo. The crude material was puri-

fied by flash chromatography (SiO₂).

1.46Ϫ1.76 (m, 4 H, 5-H, 6-H), 2.40 (m, 1 H, 4-H), 2.64 (m, 1 H,

7-H), 3.38 (m, 1 H, 7-H), 3.77 (s, 3 H, OCH₃), 3.88 (s, 3 H, OCH₃).

UV (CH₃CN): λ ϭ 268 nm (ε ϭ 2900). MS (70 eV, EI): m/z (%) ϭ

255 (5%) [M^ϩ], 241 (6), 240 (52), 196 (38), 164 (14), 154 (26), 108

(11), 96 (42), 82 (25), 81 (16). HRMS (C₁₂H₁₇NO₅): calcd.

255.1107; found 255.1106.

General Procedure for the Preparation of the Dihydrooxazoles 20 by

1,3-Dipolar Cycloaddition: A solution of the alkyne derivative 18

(1.01 equivalent) in diethyl ether (1 mL) was added dropwise under

N₂at room temperature to a stirred solution of 3,3,5-trimethyl-3,4-

dihydro-2H-pyrrole 1-oxide (16)^[40,41](ca. 8 mmol) in pure diethyl

ether (5 mL). The mixture was stirred until complete conversion

and then concentrated in vacuo (removal of the solvent and the

remaining starting materials). The crude material was purified by

flash chromatography (SiO₂).

3a-Methyl-2-phenyl-4,5,6,7-tetrahydro-3aH-isoxazolo[2,3-a]-

pyridine-3-carbaldehyde (19a): Treatment of 6-methyl-2,3,4,5-tetra-

hydropyridine N-oxide (15)^[39](0.70 g, 6.2 mmol) with 18a (0.87 g,

6.7 mmol) in boiling ethanol (30 mL, 30 min) gave 19a (1.20 g,

80%) as a colorless solid after flash chromatography (SiO₂, cyclo-

hexane/ethyl acetate, 25:1) and subsequent recrystallization, m.p.

80 °C (ethyl acetate). IR (CCl₄): ν˜ ϭ 2960, 2940, 2850, 2820, 2740

(OC-H), 1650 (CϭO), 1620, 1590, 1490, 1450, 1440, 1390, 1370,

1350, 1340, 1275, 1115, 1065, 690 cm^Ϫ1. H NMR: δ ϭ 1.32 (m, 1

H, 4-H), 1.46 (s, 3 H, CH₃), 1.58 (m, 2 H, 5-H), 1.72 (m, 2 H, 6-

3a,5,5-Trimethyl-2-phenyl-3a,4,5,6-tetrahydropyrrolo[1,2-b]-

isoxazole-3-carbaldehyde (20a): Treatment of 16^[40,41](1.00 g,

1

H), 2.73 (m, 1 H, 4-H), 2.99 (m, 1 H, 7-H), 3.48 (m, 1 H, 7-H), 7.9 mmol) with 18a (1.04 g, 8.0 mmol) for 17 h gave 20a (1.72 g,

7.45Ϫ7.66 (m, 5 H, Ph-H), 9.80 (s, 1 H, CHO). ¹³C NMR: δ ϭ 85%) as a yellow oil after flash chromatography (SiO₂, cyclohexane/

19.8/22.3 (C-5, C-6), 27.5 (CH₃), 30.8 (C-4), 52.0 (C-7), 69.1 (C-

ethyl acetate, 10:1). IR (CCl₄): ν˜ ϭ 2960, 2930, 2870, 2820/2720

3a), 119.0 (C-3), 127.2 (Ph-C), 128.9 (Ph-C), 129.5 (Ph-C), 132.0 (aldehyde), 1650 (CϭO), 1620 (CϭC), 1595, 1490, 1440, 1390,

1

(Ph-C), 171.3 (C-2), 186.3 (CHO). UV (CH₃CN): λ ϭ 302 nm (ε ϭ 1370, 1340, 1290, 1270, 1125, 1065, 915 cm^Ϫ1. H NMR: δ ϭ 1.12

9200), 252 nm (ε ϭ 7000), 224 nm (ε ϭ 11900). MS (70 ev. EI): (s, 3 H, CH₃), 1.21 (s, 3 H, CH₃), 1.58 (s, 3 H, CH₃), 1.89 (d, 1 H,

m/z (%) ϭ 243 (8%) [M^ϩ], 228 (64), 200 (15), 187 (15), 105 (76),

82 (11), 78 (13), 77 (78), 70 (10), 69 (11), 67 (13). C₁₅H₁₇NO₂

(243.3): calcd. C 74.05, H 7.04, N 5.76; found C 73.83, H 7.04,

N 5.70.

4-H), 2.30 (d, 1 H, 4-H), 3.03 (d, 1 H, 6-H), 3.42 (d, 1 H, 6-H),

7.54 (m, 5 H, Ph-H), 9.72 (s, 1 H, CHO), J_4,4ϭ 13.3, J_6,6ϭ 9.8 Hz.

UV (CH₃CN): λ ϭ 303 nm (ε ϭ 8000), 248 nm (ε ϭ 7200). MS

(70 eV, EI): m/z (%) ϭ 257 (25%) [M^ϩ], 242 (30), 201 (14), 200

1446

Eur. J. Org. Chem. 2003, 1438Ϫ1453

Azomethine Ylides by Photochemical Transformation of 2,3-Dihydroisoxazoles

FULL PAPER

(100), 173 (16), 172 (16), 145 (39), 144 (25), 131 (10), 124 (29).

HRMS (C₁₆H₁₉NO₂): calcd. 257.1416; found 257.1411.

1490, 1390, 1375, 1350, 1260, 1120, 1040, 690 cm^Ϫ1. ¹H NMR: δ ϭ

1.36 (s, 3 H, CH₃), 1.42 (s, 3 H, CH₃), 2.00 [s, 3 H, C(7a)-CH₃),

3.33 (d, 1 H, 2-H), 3.82 (d, 1 H, 2-H), 7.58 (m, 5 H, Ph-H), 9.72

(s, 1 H, CHO); J_2,2ϭ 9.0 Hz. UV (CH₃CN): λ ϭ 289 nm (ε ϭ

8700), 250 nm (ε ϭ 8400). MS (70 eV, EI): m/z (%) ϭ 259 (2%)

[M^ϩ] 244 (8), 229 (3), 228 (37), 200 (4), 188 (13), 187 (32), 186 (16),

158 (7), 145 (3).

2-tert-Butyl-3a,5,5-trimethyl-3a,4,5,6-tetrahydropyrrolo[1,2-b]-

isoxazole-3-carbaldehyde (20b): Treatment of 16 (1.00 g,

7.9 mmol)^[40,41]with 18b (0.88 g, 8.0 mmol) for 17 h gave 20b

(1.55 g, 83%) as pale yellow crystals after flash chromatography

(SiO₂, cyclohexane/ethyl acetate, 10:1) and crystallization, m.p. 55

°C (n-pentane, subl.). IR (CCl₄): ν˜ ϭ 2960, 2920, 2860, 2830/2740

(aldehyde), 1640 (CϭO), 1595 (CϭC), 1460, 1455, 1390, 1360,

6-tert-Butyl-3,3,7a-trimethyl-2,3-dihydro-7aH-[1,3]oxazolo[3,2-b]-

isoxazole-7-carbaldehyde (21b): A reaction mixture of freshly pre-

pared 17 (7.1 mmol),^[42]4,4-dimethyl-2-pentynal (18b, 1.17 g,

10.6 mmol), and triethylamine (0.72 g, 7.1 mmol), stirred for 10 h,

gave 21b (1.16 g, 69%) as a yellow oil after flash chromatography

(SiO₂, cyclohexane/ethyl acetate, 5:1); pale yellow crystals from

cyclohexane/n-pentane, m.p. 59 °C. IR (CCl₄): ν˜ ϭ 2980, 2940,

2900, 2850, 2760 (H-CO), 1660 (CϭO), 1610 (CϭC), 1580, 1470,

1

1325, 1280, 1270, 1140, 1080, 970, 925, 695 cm^Ϫ1. H NMR: δ ϭ

1.07 (s, 3 H, CH₃), 1.15 (s, 3 H, CH₃), 1.37 (s, 9 H, tBu), 1.45 (s,

3 H, CH₃), 1.82 (d, 1 H, 4-H), 2.19 (d, 1 H, 4-H), 2.76 (d, 1 H, 6-

H), 3.30 (d, 1 H, 6-H), 10.07 (s, 1 H, CHO), J_4,4ϭ 13.3, J_6,6

ϭ

9.8 Hz. UV (CH₃CN): λ ϭ 285 nm (ε ϭ 8800), 230 nm (ε ϭ 4200).

C₁₄H₂₃NO₂(237.4): calcd. C 70.85, H 9.77, N 5.90; found C 70.35,

H 9.72, N 6.10.

1390, 1370, 1340, 1300, 1270, 1180, 1140, 1040 cm^Ϫ^{1 1}H NMR

.

(250 MHz. CDCl₃): δ ϭ 1.30 (s, 3 H, CH₃), 1.34 (s, 3 H, CH₃),

1.40 (s, 9 H, tBu), 1.91 [s, 3 H, C(7a)-CH₃), 3.17 (d, 1 H, 2-H),

3.73 (d, 1 H, 2-H), 10.04 (s, 1 H, CHO); J_2,2ϭ 9.0 Hz. UV

(CH₃CN): λ ϭ 278 nm (ε ϭ 10400). C₁₃H₂₁NO₃(239.4): calcd. C

65.25, H 8.85, N 5.85; found C 64.88, H 8.87, N 5.83.

Methyl 3a,5,5-Trimethyl-3a,4,5,6-tetrahydropyrrolo[1,2-b]isoxazole-

3-carboxylate (20c): Treatment of 16^[40,41](1.00 g, 7.9 mmol) with

18c (0.67 g, 8.0 mmol) for 20 h gave 20c (1.41 g, 83%) as colorless

crystals after flash chromatography (SiO₂, cyclohexane/ethyl acet-

ate, 10:1) and crystallization, m.p. 33 °C (n-pentane, subl.). IR

(CCl₄): ν˜ ϭ 2960, 2930, 2860, 1715 (CϭO), 1620 (CϭC), 1470,

1440, 1370, 1350, 1300, 1290, 1220, 1210, 1190, 1110, 1090, 1065

Dimethyl 3,3,7a-Trimethyl-2,3-dihydro-7aH-[1,3]oxazolo[3,2-b]isox-

azole-6,7-dicarboxylate (21d): A reaction mixture of freshly pre-

pared 17 (7.1 mmol),^[42]18d (1.30 g, 9.1 mmol), and triethylamine

(0.72 g, 7.1 mmol), stirred for 5 h, gave 21d (1.32 g, 69%) as a yel-

low oil after flash chromatography (SiO₂, cyclohexane/ethyl acetate,

20:1/10:1).^[22]IR (CCl₄): ν˜ ϭ 2990, 2970, 2950, 2860, 1760 (CϭO),

1720 (CϭO), 1660 (CϭC), 1440, 1380, 1350, 1300, 1270, 1210,

1

cm^Ϫ1. H NMR: δ ϭ 1.10 (s, 3 H, CH₃), 1.17 (s, 3 H, CH₃), 1.50

(s, 3 H, CH₃), 1.79 (d, 1 H, 4-H), 2.18 (d, 1 H, 4-H), 2.88 (d, 1 H,

6-H), 3.35 (d, 1 H, 6-H), 3.74 (s, 3 H, OCH₃), 7.22 (s, 1 H, 2-H),

J_4,4ϭ 13.3, J_6,6ϭ 9.8 Hz. UV (CH₃CN): λ ϭ 261 nm (ε ϭ 6100).

MS (70 eV, EI): m/z (%) ϭ 211 (70%) [M^ϩ], 197(11), 196 (100), 164

(18), 142 (22), 136 (18), 124 (93), 123 (48), 123 (48), 97 (25).

1200, 1170, 1110, 1080, 1040 cm^{Ϫ1 1}H NMR): δ ϭ 1.31 (s, 3 H,

.

CH₃), 1.37 (s, 3 H, CH₃), 1.90 [s, 3 H, C(7a)-CH₃), 3.34 (d, 1 H,

2-H), 3.78 (s, 3 H, OCH₃), 3.79 (d, 1 H, 2-H), 3.92 (s, 3 H, OCH₃);

J_2,2ϭ 9.0 Hz. UV (CH₃CN): λ ϭ 265 nm (ε ϭ 4400). MS 70 eV,

EI): m/z (%) ϭ 271 (4%) [M^ϩ] 256 (24), 200 (19), 183 (18), 182

(100), 170 (14), 150 (64), 125 (13), 112 (14), 83 (13).

Dimethyl

3a,5,5-Trimethyl-3a,4,5,6-tetrahydropyrrolo[1,2-b]isox-

azole-2,3-dicarboxylate (20d): Treatment of 16^[40,41](1.00 g,

7.9 mmol) with 18d (1.14 g, 8.0 mmol) for 3 h gave 20d (1.95 g,

92%) as colorless crystals after flash chromatography (SiO₂, cyclo-

hexane/ethyl acetate, 10:1) and crystallization, m.p. 63 °C (diethyl

ether/n-pentane). IR (CCl₄): ν˜ ϭ 2960, 2930, 2870, 1760 (CϭO),

1715 (CϭO), 1650 (CϭC), 1440, 1370, 1350, 1295, 1280, 1260,

Photolysis of 19a: A solution of 19a (105 mg, 0.43 mmol) in pure

benzene (200 mL, Jena filter) was irradiated until complete conver-

sion (36 min, TLC monitoring). After concentration, a solid crude

1200, 1165, 1120, 1100, 1070 cm^Ϫ^{1 1}H NMR: δ ϭ 1.11 (s, 3 H,

.

CH₃), 1.17 (s, 3 H, CH₃), 1.52 (s, 3 H, CH₃), 1.78 (d, 1 H, 4-H),

2.22 (d, 1 H, 4-H), 2.93 (d, 1 H, 6-H), 3.36 (d, 1 H, 6-H), 3.76 (s,

3 H, OCH₃), 3.90 (s, 3 H, OCH₃); J_4,4ϭ 13.3 Hz; J_6,6ϭ 9.8 Hz.

UV (CH₃CN): λ ϭ 269 nm (ε ϭ 3800). C₁₃H₁₉NO₅(269.3): calcd.

C 57.98, H 7.11, N 5.20; found. C 57.93, H 7.08, N 5.22.

1

material was obtained. According to the H NMR spectrum, this

contained the azomethine ylide 22a and 7-benzoyl-6-methyl-1-aza-

bicyclo[4.1.0]heptane-7-carbaldehyde (23a) in the ratio ca. 10:1.

Crystallization from ethanol/ethyl acetate (1:1) gave 22a (92 mg,

88%) as yellow crystals, m.p.133 °C. IR (CCl₄): ν˜ ϭ 2950, 2850,

1600 (CϭO), 1570 (CϭC), 1510, 1440, 1400, 1340, 1300, 1290,

General Procedure for the Preparation of the Dihydrooxazoles 21

by 1,3-Dipolar Cycloaddition. (a) 2,4,4-Trimethyloxazoline N-Oxide

(17):^[42]A solution of triethyl orthoacetate (1.2 equivalent) in di-

chloromethane (2.5 mL) was added under N₂at room temperature

to a stirred solution of 2-(hydroxyamino)-2-methyl-1-propanol hy-

drochloride (ca. 5 mmol) in pure dichloromethane (2.5 mL).

(b) Compound 21: After 1 h, the above mixture was treated with

pure triethylamine (1 equivalent) and the alkyne derivative 18 (ca.

1.3 equivalent), and stirring was continued until complete conver-

sion. The mixture was concentrated in vacuo (removal of the sol-

vent and the remaining starting materials), and the crude material

was purified by flash chromatography (SiO₂).

1

1270, 1220, 1180, 890, 860 cm^Ϫ1. H NMR: δ ϭ 1.93 (m, 2 H, 3Ј-

H), 2.09 (m, 2 H, 4Ј-H), 2.34 (s, 3 H, CH₃), 2.91 (t, 2 H, 5Ј-H),

3.90 (m, 2 H, 2Ј-H), 7.41 (m, 3 H, Ph-H), 7.58 (m, 2 H, Ph-H),

8.91 (s, 1 H, CHO). ¹³C NMR: δ ϭ 17.6/21.5 (C-3Ј, C-4Ј), 23.8

(CH₃), 33.4 (C-5Ј), 53.7 (C-2Ј), 123.0 (C-2), 128.0 (Ph-C), 128.4

(Ph-C), 129.1 (Ph-C), 129.7 (Ph-C), 140.3 (C-6Ј), 176.7 (CHO),

186.6 (CO). UV (CH₃CN): λ ϭ 333 nm (ε ϭ 3500), 280 nm (ε ϭ

13500). MS (70 eV, EI): m/z (%) ϭ 244 (8%) [M^ϩ] 243 (46), 229

(16), 228 (100), 215 (5), 214 (25), 200 (33), 186 (6), 78 (7), 77 (55),

70 (5). C₁₅H₁₇NO₂(243.3): calcd. C 74.05, H 7.04, N 5.76; found

C 73.98, H 7.07 N 5.71.

Data of 23a: ¹H NMR (taken from the mixture with 22a): δ ϭ 2.56

(s, 3 H, CH₃); 3.55 (m, 2 H, 5-H), 3.80 (m, 2 H, 2-H), 9.29 (s, 1

H, CHO).

3,3,7a-Trimethyl-6-phenyl-2,3-dihydro-7aH-[1,3]oxazolo[3,2-b]-

isoxazole-7-carbaldehyde (21a): A reaction mixture of freshly pre-

pared 17 (5.3 mmol),^[42]3-phenylpropynal (18a, 0.84 g, 6.5 mmol),

and triethylamine (0.74 g, 5.3 mmol), stirred for 24 h, gave 21a

(1.17 g, 85%) as a yellow oil after flash chromatography (SiO₂,

Photolysis of 19b: A solution of 19b (120 mg, 0.54 mmol) in pure

benzene (200 mL, Jena filter) was irradiated until complete conver-

cyclohexane/ethyl acetate, 5:1). IR (CCl₄): ν˜ ϭ 3080, 3060, 2980, sion (46 min, TLC monitoring). After concentration, a solid crude

1

2940, 2850, 2760/2730 (aldehyde), 1665 (CϭO), 1630 (CϭC), 1590,

material was obtained. According to the H NMR spectrum, this

Eur. J. Org. Chem. 2003, 1438Ϫ1453

1447

E. Lopez-Calle, M. Keller, W. Eberbach

FULL PAPER

contained the azomethine ylide 22b and 7-(2,2-dimethylpropanoyl)-

6-methyl-1-aza-bicyclo[4.1.0]heptane-7-carbaldehyde (23b) in the

ratio ca. 60:1. Crystallization from diethyl ether/dichloromethane

gave 22b (90 mg, 75%) as light brown crystals, m.p.104 °C. IR

(KBr): ν˜ ϭ 2960, 2860, 1640, 1590, 1530, 1510, 1480, 1460, 1380,

229 (41), 228 (11), 215 (13), 214 (83), 212 (13), 173 (64), 131 (10),

124 (59). HRMS (C₁₆H₁₉NO₂): calcd. 257.1416; found 257.1413.

C₁₆H₁₉NO₂(257.4): calcd. C 74.68, H 7.44, N 5.44; found C 74.04,

H 7.43, N 5.32.

Photolysis of 20b: A solution of 20b (240 mg, 1.01 mmol) in pure

benzene (200 mL, Jena filter) was irradiated until complete conver-

sion (100 min, TLC monitoring). After concentration, crystalliza-

tion of the solid residue afforded 25b (220 mg, 91%) as yellow, hy-

groscopic crystals, m.p. 109 °C (diethyl ether). IR (CCl₄): ν˜ ϭ 2960,

2860, 2810 (OC-H), 1590 (CϭO), 1510 (CϭC), 1520, 1470, 1460,

1410, 1380, 1360, 1320, 1200, 1180, 1090 cm^Ϫ1. ¹H NMR: δ ϭ 1.29

(s, 3 H, CH₃), 1.30 (s, 3 H, CH₃), 1.31 (s, 9 H, tBu), 2.17 (s, 3 H,

CH₃), 2.82 (m, 1 H, 4Ј-H), 2.98 (m, 1 H, 4Ј-H), 3.84 (m, 1 H, 2Ј-

H), 4.05 (m, 1 H, 2Ј-H), 9.46 (s, 1 H, CHO). ¹³C NMR: δ ϭ 18.1

(CH₃), 26.9 (CH₃), 27.3 (CH₃), 29.5 (tϪBuϪCH₃), 35.4 (C-3Ј), 41.4

(C-2), 52.4 (C-4Ј), 71.5 (C-2Ј), 115.2 (C-4), 173.6 (CHO), 186.4 (C-

5Ј), 194.4 (CϭO). UV (CH₃CN): λ ϭ 331 nm (ε ϭ 1600), 274 nm

(ε ϭ 16600). MS (70 eV, EI): m/z (%) ϭ 237 (22%) [M^ϩ] 222 (14),

194 (20), 181 (12), 180 (100), 162 (10), 153 (14), 152 (89), 138 (12),

136 (12). HRMS (C₁₄H₂₃NO₂): calcd. 237.1729; found 237.1724.

C₁₄H₂₃NO₂(237.4): calcd. C 70.85, H 9.77, N 5.50; found C 69.98,

H 9.56, N 5.68.

1

1310, 1280, 1200, 1140, 1000, 800 cm^Ϫ1. H NMR: δ ϭ 1.31 (s, 9

H, tBu), 1.89 (m, 2 H, 3Ј-H), 2.00 (m, 2 H, 4Ј-H), 2.18 (s, 3 H,

CH₃), 2.81 (m, 2 H, 5Ј-H), 3.67 (m, 2 H, 2Ј-H), 9.41 (s, 1 H, CHO).

UV (CH₃CN): λ ϭ 330 (ε ϭ 1500), 274 nm (ε ϭ 17900). MS (70 eV,

EI): m/z (%) ϭ 224 (3%) [M ϩ 1]^ϩ, 223 (21), 209 (13), 208 (100),

194 (12), 180 (19), 152 (9), 138 (63), 124 (16), 122 (10). HRMS

(C₁₃H₂₁NO₂): Calcd. 223.1571; found. 223.1569. C₁₃H₂₁NO₂

(223.3): calcd. C 69.92, H 9.48, N 6.27; found C 68.97, H 9.48,

N 6.05.

Data of 23b: ¹H NMR (taken from the mixture with 22b): δ ϭ 2.41

(s, 3 H, CH₃), 9.71 (s, 1 H, CHO).

Photolysis of 19c: A solution of 19c (400 mg, 2.0 mmol) in pure

benzene (200 mL, Vycor filter) was irradiated until complete con-

version (170 min, TLC monitoring). After concentration a crude

1

material was obtained. According to the H NMR spectrum, this

contained the azomethine ylide 22c and 7-methoxy-6-methyl-1-aza-

bicyclo[4.1.0]heptan-7-carbaldehyde (23c) in the ratio ca. 6:1. Flash

chromatography (neutral Al₂O₃, activity III, dichloromethane/

methanol, 50:1) gave 22c (100 mg, 25%) as a light brown oil. IR

(CCl₄): ν˜ ϭ 2980, 2930, 1730 (br., CϭO), 1640, 1570, 1530, 1430,

Photolysis of 20c: A solution of 20c (220 mg, 1.04 mmol) in pure

acetonitrile (200 mL, Vycor filter) was irradiated until complete

conversion (220 min, TLC monitoring). After concentration, flash

chromatography of the residue (neutral Al₂O₃, activity III, ethyl

acetate/ethanol, 20:1) gave 25c (132 mg, 60%) and methyl 3-oxo-2-

(1,4,4-trimethyl-2-pyrrolidinylidene)propanoate (26c,18 mg, 8%).

1330, 1295, 1230, 1180, 1130, 1100, 1070, 1030 cm^Ϫ^{1 1}H NMR:

.

δ ϭ 1.88 (m, 2 H, 3Ј-H), 2.02 (m, 2 H, 4Ј-H), 2.32 (s, 3 H, CH₃),

2.80 (m, 1 H, 5Ј-H), 2.89 (m, 1 H, 5Ј-H), 3.70 (s, 3 H, OCH₃), 3.73

(m, 2 H, 2Ј-H), 9.00 (s, 1 H, CHO). MS (70 eV, EI): m/z (%) ϭ 197

(31) [M^ϩ) 182 (100), 138 (37), 136 (14), 110 (29), 108 (36), 100 (12).

Data of 23c: ¹H NMR (taken from the mixture with 22c): δ ϭ 2.47

(s, 3 H, CH₃), 3.57 (m, 2 H, 5-H), 3.90 (m, 2 H, 2-H), 3.74 (s, 3 H,

OCH₃), 9.54 (s, 1 H, CHO).

Data for 25c: Light brown oil. IR (CCl₄): ν˜ ϭ 2960, 2880, 2820

(OC-H), 1655 (CϭO), 1580 (CϭC), 1560, 1440, 1420, 1390, 1350,

1

1330, 1305, 1195, 1135, 1080, 1045, 900 cm^Ϫ1. H NMR: δ ϭ 1.25

(s, 6 H, CH₃), 2.28 (s, 3 H, CH₃), 2.80 (d, br., 1 H, 4Ј-H), 3.00 (d,

br., 1 H, 4Ј-H), 3.70 (s, 3 H, OCH₃), 3.85 (d, br., 1 H, 2Ј-H), 4.28

Photolysis of 19d: A solution of 19d (200 mg, 0.78 mmol) in pure

benzene (200 mL, Vycor filter) was irradiated until complete con-

version (2.5 h, TLC monitoring). After concentration a crude mate-

(d, br., 1 H, 2Ј-H), 9.07 (s, 1 H, CHO), J_4Ј,4Јϭ 20.2 Hz; J_2Ј,2Ј

ϭ

13.3 Hz. ¹³C NMR: δ ϭ 18.9 (CH₃), 26.5 (CH₃), 27.1 (CH₃), 35.3

(C-3Ј), 50.1 (C-4Ј), 52.5 (OCH₃), 72.1 (C-2Ј), 101.8 (C-2), 165.5

(CO₂R), 171.8 (CHO), 185.4 (C-5Ј). UV (CH₃CN): λ ϭ 335 nm

(ε ϭ 2100), 256 nm (ε ϭ 13700). MS (70 eV, EI): m/z (%) ϭ 211

(31%) [M^ϩ] 196 (28), 194 (18), 180 (18), 152 (100), 151 (34), 136

(33), 124 (20), 108 (15), 96 (18). HRMS (C₁₁H₁₇NO₃: calcd.

211.1208; found 211.1202.

1

rial was obtained. According to the H NMR spectrum, this con-

tained the azomethine ylide 22d. Flash chromatography (SiO₂, di-

chloromethane/methanol, 15:1) gave 22d (105 mg, 58%) as a light

brown oil. IR (CCl₄): ν˜ ϭ 2980, 2940, 2860, 1740 (ROCϭO), 1650,

1530, 1430, 1400, 1340, 1280, 1210, 1180, 1140, 1070, 1040, 900

cm^Ϫ1. ¹H NMR: δ ϭ 1.90 (m, 2 H, 3Ј-H), 2.03 (m, 2 H, 4Ј-H), 2.36

(m, 3 H, CH₃), 2.87 (m, 2 H, 5Ј-H), 3.67 (s, 3 H, OCH₃), 3.81 (m,

2 H, 2Ј-H), 3.84 (s, 3 H, OCH₃). MS (70 eV, EI): m/z (%) ϭ 256

(3%) [M ϩ 1]^ϩ, 255 (22), 241 (8), 240 (66), 197 (11), 196 (100),

164 (64), 140 (16), 136 (8), 108 (24). HRMS (C₁₂H₁₇NO₅), calcd.

255.1107; found 255.1108.

Data for 26c: Yellow oil. IR (CCl₄): ν˜ ϭ 2960, 2920, 2860, 2780,

1690 (OCϭO), 1630 (CϭO), 1545, 1450, 1400, 1320, 1290, 1260,

1

1230, 1190, 1120, 1060, 1050, 960 cm^Ϫ1. H NMR: δ ϭ 1.17 (s, 6

H, CH₃), 3.06 (s, 3 H, NCH₃), 3.12 (s, 2 H, 3Ј-H), 3.46 (s, 2 H, 5Ј-

H), 3.75 (s, 3 H, OCH₃), 9.69 (s, 1 H, CHO). MS (70 eV, EI): m/z

(%) ϭ 211 (36%) [M^ϩ] 196 (12), 194 (13), 180 (18), 168 (12), 153

(12), 152 (100).

Photolysis of 20a: A solution of 20a (250 mg, 0.97 mmol) in pure

benzene (200 mL, Jena filter) was irradiated until complete conver-

sion (90 min, TLC monitoring). After concentration, crystallization

of the solid residue afforded 25a (220 mg, 88%) as yellow, hygro-

scopic crystals, m.p. 120 °C (diethyl ether/dichloromethane). IR

(CCl₄): ν˜ ϭ 3050, 2960, 2870/2800 (OC-H), 1600 (CϭO), 1580 (Cϭ

C), 1530, 1420, 1355, 1340, 1300, 1290, 1180, 1080, 1030 cm^Ϫ1. ¹H

NMR: δ ϭ 1.32 (s, 3 H, CH₃), 1.35 (s, 3 H, CH₃), 2.30 (s, 3 H,

CH₃), 2.98 (s, 2 H, 4Ј-H), 4.10 [d (br), 1 H, 2Ј-H], 4.22 [d (br), 1

Photolysis of 20d: A solution of 20d (280 mg, 1.04 mmol) in pure

acetonitrile (200 mL, Vycor filter) was irradiated until complete

conversion (270 min, TLC monitoring). After concentration, flash

chromatography of the residue (SiO₂, ethyl acetate/methanol, 20:1/

10:1) gave 25d (210 mg, 75%) and dimethyl 2-(1,4,4-trimethyl-2-

pyrrolidinylidene)malonate (26d, 48 mg, 17%).

H, 2Ј-H], 7.40 (m, 3 H, Ph-H), 7.58 (m, 2 H, Ph-H), 8.98 (s, 1 H, Data for 25d: Yellow oil. IR (CCl₄): ν˜ ϭ 2960, 2940, 2840, 1740

CHO); J_2Ј,2Јϭ 13.3 Hz. ¹³C NMR: δ ϭ 18.7 (CH₃), 27.0 (CH₃),

(OCϭO), 1660 (OCϭO), 1530, 1440, 1330, 1220, 1195, 1150, 1080,

35.7 (C-3Ј), 52.7 (C-4Ј), 71.7 (C-2Ј), 116.8 (C-2), 127.9 (Ph-C), 1050, 990 cm^Ϫ1. H NMR: δ ϭ 1.29 (s, 6 H, CH₃), 2.33 (s, 3 H,

128.5 (Ph-C), 129.8 (Ph-C), 140.2 (Ph-C), 177.5 (CHO), 184.9 (C- CH₃), 2.86 (d, br., 1 H, 4Ј-H), 3.04 (d, br., 1 H, 4Ј-H), 3.68 (s, 3

1

5Ј), 186.7 (CϭO). UV (CH₃CN): λ ϭ 330 nm (ε ϭ 3600), 278 nm H, OCH₃), 3.85 (s, 3 H, OCH₃), 3.89 (d, br., 1 H, 2Ј-H), 4.20 (d,

(ε ϭ 13400). MS (70 eV, EI): m/z (%) ϭ 257 36%) [M^ϩ] 242 (14), br., 1 H, 2Ј-H); J_4Ј,4Јϭ 19.5 Hz; J_2Ј,2Јϭ 13.3 Hz. ¹³C NMR: δ ϭ

1448

Eur. J. Org. Chem. 2003, 1438Ϫ1453

Azomethine Ylides by Photochemical Transformation of 2,3-Dihydroisoxazoles

18.7 (CH₃), 26.5 (CH₃), 27.8 (CH₃), 35.5 (C-3Ј), 50.6 (OCH₃), 51.8

¹³C NMR: δ ϭ 13.6 (CH₃), 24.6 (CH₃), 25.2 (CH₃), 50.4 (OCH₃),

FULL PAPER

(OCH₃), 52.6 (C-4Ј), 72.3 (C-2Ј), 97.7 (C-2), 163.9 (CO₂R), 168.0 51.7 (OCH₃), 70.1 (C-4Ј), 82.4 (C-5Ј), 89.1 (C-2), 165.4 (CO₂R),

(CO₂R), 171.0 (C-5Ј), 188.2 (CϭO). UV (CH₃CN): λϭ 326 nm 168.4 (CO₂R), 174.1 (CO), 178.1 (C-2Ј). UV (CH₃CN): λ ϭ

(ε ϭ 1700), 261 nm (ε ϭ 11800). MS (70 eV, EI): m/z (%) ϭ 269 261 nm. MS (70 eV, EI): m/z (%) ϭ 272 (3%) [M ϩ 1]^ϩ, 271 (23),

(11%) [M^ϩ], 211 (12), 210 (100), 179 (6), 178 (55), 150 (4). HRMS

(C₁₃H₁₉NO₅): calcd. 269.1263; found. 269.1258.

213 (11), 212 (100), 174 (13), 142 (6), 140 (15), 138 (4), 130 (10),

115 (3). HRMS (C₁₂H₁₇NO₆): calcd. 271.1056; found 271.1047.

Reaction between 22a and Methyltriazolinedione (MTAD): A solu-

tion of MTAD (25 mg, 0.20 mmol) in dichloromethane (2 mL) was

slowly added to a solution of 22a (48 mg, 0.20 mmol) in pure di-

chloromethane (5 mL). The mixture was stirred for 20 min at room

temp. and then concentrated. Flash chromatography of the residue

(SiO₂, cyclohexane/ethyl acetate, 3:2) gave 6-benzoyl-5-hydroxy-

2,11a-dimethyl-9,10,11,11a-tetrahydro-1H,8H-pyrido[2,1-c][1,2,4]-

triazolo[1,2-a][1,2,4]triazine-1,3(2H)-dione (33a, 55 mg, 78%) as

yellow crystals, m.p. 155 °C (cyclohexane/ethyl acetate, 3:2). IR

(KBr): ν˜ ϭ 2940, 1795 (CϭO), 1730 (CϭO), 1720 (CϭO), 1600,

1450, 1440, 1390, 1360, 1320, 1270, 1250, 1220, 1190, 1170, 1120

Data for 26d: Colorless crystals, m.p. 98 °C (diethyl ether/dichloro-

methane). IR (CCl₄): ν˜ ϭ 2940, 2860, 1730, 1690, 1620, 1540, 1460,

1450, 1430, 1400, 1390, 1325, 1290, 1200, 1150, 1130, 1100, 1070,

1000 cm^Ϫ1. ¹H NMR: δ ϭ 1.18 (s, 6 H, CH₃), 3.01 (s, 3 H, NCH₃),

3.09 (s, 2 H, 3-H), 3.52 (s, 2 H, 5-H), 3.68 (s, 3 H, OCH₃), 3.85 (s,

3 H, OCH₃). ¹³C NMR: δ ϭ 26.7 (CH₃), 35.9 (C-4), 40.0 (NCH₃),

50.9 (OCH₃), 51.6 (C-3), 51.9 (OCH₃), 70.4 (C-5), 93.8 (C-1Ј),

167.1 (CO₂R), 167.4 (CO₂R), 176.6 (C-2), 181.4 (CO). UV

(CH₃CN): λ ϭ 315 nm (ε ϭ 12500), 252 nm (ε ϭ 8700). MS (EI):

m/z (%) ϭ 269 (25%) [M^ϩ], 211 (80), 210 (100), 180 (22), 178 (16),

152 (25). C₁₃H₁₉NO₅(269.3): calcd. C 57.98, H 7.11, N 5.20; found

C 57.79, H 7.07, N 5.20.

1

cm^Ϫ1. H NMR: δ ϭ 1.56 (s, 3 H, CH₃), 1.66 (m, 5 H, 9-H, 10-H,

11-H), 2.70 (m, 2 H, 8-H, 11-H), 3.14 (s, 3 H, NCH₃), 3.19 (m, 1

H, 8-H), 7.46 (m, 3 H, Ph-H), 8.22 (m, 2 H, Ph-H), 13.49 (s, 1 H,

OH). ¹³C NMR: δ ϭ 20.1 (C-10), 24.8 (CH₃), 25.3 (CH₃), 25.3 (C-

9), 34.4 (C-11), 52.0 (C-8), 76.6 (C-11a), 110.8 (C-6), 128.2 (Ph-

C), 129.0 (Ph-C), 131.7 (Ph-C), 132.6 (Ph-C), 146.2 (NCO), 148.8

(NCO), 162.4 (C-5), 169.6 (CO). MS (70 eV, EI): m/z (%) ϭ 357

(3%) [M ϩ 1]^ϩ, 356 (15), 341 (5), 243 (6), 242 (33), 214 (5), 167

(4), 149 (10), 105 (100), 82 (3). C₁₈H₂₀N₄O₄(356.4): calcd. C 60.66,

H 5.66, N 15.72; found C 60.51, H 5.62, N 15.58.

Photolysis of 21a: A solution of 21a (1.19 g, 4.6 mmol) in pure ben-

zene (200 mL, Jena filter) was irradiated until complete conversion

(440 min, TLC monitoring). After concentration, crystallization of

the solid residue from diethyl ether/dichloromethane gave 1.06 g

(89%) of the azomethine ylide 28a as yellow crystals, m.p. 135 °C.

IR (CHCl₃): ν˜ ϭ 2960, 2930, 2840, 1640 (CϭO), 1590 (CϭC), 1570,

1530, 1440, 1370, 1360, 1330, 1300, 1280, 980 cm^Ϫ1. ¹H NMR: δ ϭ

1.53 (s, 3 H, CH₃), 1.57 (s, 3 H, CH₃), 2.28 [s, 3 H, C(2Ј)-CH₃),

4.70 (s, 2 H, 5Ј-H), 7.40 (m, 3 H, Ph-H), 7.62 (m, 2 H, Ph-H), 9.08

(s, 1 H, CHO). ¹³C NMR: δ ϭ 13.6 (CH₃), 25.1 (CH₃), 25.2 (CH₃),

69.9 (C-4Ј), 82.1 (C-5Ј), 108.8 (C-2), 128.0 (Ph-C), 128.5 (Ph-C),

129.8 (Ph-C), 140.4 (Ph-C), 176.8 (C-2Ј), 179.3 (CHO), 186.7 (CO).

UV (CH₃CN): λ ϭ 278 nm (ε ϭ 12000). MS (70 eV, EI): m/z (%) ϭ

260 (8%) [M ϩ 1] ^ϩ, 259 (40), 232 (5), 231 (28), 204 (17), 189 (5),

176 (16), 163 (10), 162 (22), 135 (12). C₁₅H₁₇NO₃(259.3): calcd. C

69.48, H 6.61, N 5.40; found C 69.27, H 6.70, N 5.37.

Reaction between 25a and MTDA: A solution of MTAD (45 mg,

0.40 mmol) in dichloromethane (2 mL) was slowly added to a solu-

tion of 25a (100 mg, 0.39 mmol) in pure dichloromethane (5 mL).

The mixture was stirred for 30 min at room temp. and then concen-

trated. Flash chromatography of the residue (neutral Al₂O₃, ac-

tivity III, dichloromethane/ethanol, 10:1) gave 6-benzoyl-2,9,9,10a-

tetramethyl-8,9,10,10a-tetrahydro-1H-pyrrolo[2,1-c][1,2,4]-

triazolo[1,2-a][1,2,4]triazine-1,3(2H)-dione (35a, 20 mg, 14%) as a

yellow oil, and 25a (40 mg, 40%). Data for 35a: IR (CCl₄): ν˜ ϭ

2960, 2930, 2860, 1780, 1730, 1650 (CϭO), 1610 (CϭC), 1455,

Photolysis of 21b: A solution of 21b (1.10 g, 4.6 mmol) in pure ben-

zene (200 mL, Jena filter) was irradiated until complete conversion

(370 min, TLC monitoring). After concentration, flash chromatog-

raphy (basic Al₂O₃, activity III, ethyl acetate) afforded the azome-

thine ylide 28b (0.66 g, 60%) as a yellow, hygroscopic, wax-like

solid. IR (CCl₄): ν˜ ϭ 2980, 2940, 2900, 2880, 1690 (CϭO), 1600

1380, 1290, 1270, 1230, 1180, 1150, 1050, 1010 cm^Ϫ^{1 1}H NMR:

.

δ ϭ 1.12 (s, 3 H, CH₃), 1.20 (s, 3 H, CH₃), 1.42 (s, 3 H, 10a-CH₃),

2.12 (d, 1 H, 10-H), 2.65 (d, 1 H, 8-H), 2.98 (d, 1 H, 10-H), 3.12

(s, 3 H, NCH₃), 3.36 (d, 1 H, 8-H), 7.32 (s, 1 H, 5-H), 7.50 (m, 3

H, Ph-H), 7.75 (m, 2 H, Ph-H); J_10,10ϭ 14.3, J_8,8ϭ 9.3 Hz. ¹³C

NMR: δ ϭ 22.3 (CH₃), 25.4 (NCH₃), 27.1 (CH₃), 28.0 (CH₃), 37.0

(C-9), 50.5 (C-10), 65.0 (C-8), 81.7 (C-10a), 114.7 (C-6), 125.9 (C-

5), 128.3 (Ph-C), 129.0 (Ph-C), 132.1 (Ph-C), 137.8 (Ph-C), 146.8

(N-CO), 153.0 (N-CO), 190.6 (CO). MS (70 eV, EI): m/z (%) ϭ 354

(60%) [M^ϩ] 339 (11), 282 (10), 255 (62), 254 (11), 240 (17), 226

(11), 212 (13), 198 (7), 136 (14). HRMS (C₁₉H₂₂N₄O₃): calcd.

354.1692; found 354.1688.

(CϭC), 1530, 1480, 1460, 1390, 1380, 1310, 1230, 1170, 1050 cm^Ϫ1

.

¹H NMR: δ ϭ 1.34 (s, 9 H, tBu), 1.36 (s, 3 H, CH₃), 1.48 (s, 3 H,

CH₃), 2.15 [s, 3 H, C(2Ј)-CH₃), 4.64/4.62 (AB-d, 2 H, 5Ј-H), 9.47

(s, 1 H, CHO); J_5Ј,5Јϭ 9 Hz. ¹³C NMR (100 MHz. CDCl₃): δ ϭ

13.3 (CH₃), 24.9 (CH₃), 25.2 (CH₃), 29.6 (tBu), 41.4 (C-2), 69.6 (C-

4Ј), 82.0 (C-5Ј), 110.3 (C-4), 175.6 (CHO), 176.6 (C-2Ј), 195.9 (CO).

UV (CH₃CN): λ ϭ 279 nm (ε ϭ 11200). MS (70 eV, EI): m/z (%) ϭ

239 (10%) [M^ϩ] 183 (6), 182 (54), 156 (6), 144 (19), 140 (9), 128

(6), 127 (5), 115 (20), 114 (37), 112 (9).

Reaction between 25b and MTDA: A solution of MTAD (170 mg,

1.50 mmol) in dichloromethane (5 mL) was slowly added to a solu-

tion of 25b (350 mg, 1.47 mmol) in pure dichloromethane (15 mL).

The mixture was stirred for 30 min at room temp. and then concen-

trated. Flash chromatography of the residue (neutral Al₂O₃, ac-

tivity III, dichloromethane/ethanol, 10:1) gave 6-(2,2-dimethylpro-

panoyl)-2,9,9,10a-tetramethyl-8,9,10,10a-tetrahydro-1H-pyrrolo-

Photolysis of 21d: A solution of 21d (0.62 g, 2.3 mmol) in pure

acetonitrile (200 mL, Vycor filter) was irradiated until complete

conversion (8.5 h, TLC monitoring). After concentration, a residue

1

was obtained. According to the H NMR analysis, this contained

the azomethine ylide 28d as the only identifiable compound (ca.

90%, yellow oil). Because of its great instability towards SiO₂and

Al₂O₃the spectroscopic identification of 28d was accomplished

without further purification. IR (CHCl₃): ν˜ ϭ 2980, 2940, 1730

(OCϭO), 1660 (OCϭO), 1630, 1540, 1480, 1440, 1400, 1370, 1345,

[2,1-c][1,2,4]triazolo[1,2-a][1,2,4]-triazine-1,3(2H)-dione

(35b,

70 mg, 14%) as a yellow solid and 25b (165 mg, 47%). Data for

35b: m.p. 124 °C (diethyl ether/n-pentane). IR (CCl₄): ν˜ ϭ 2960,

1320, 1150, 1050, 990, 890 cm^Ϫ1. ¹H NMR: δ ϭ 1.52 (s, 3 H, CH₃), 2940, 2880, 1780, 1730, 1670 (CϭO), 1615 (CϭC), 1460, 1400,

1.53 (s, 3 H, CH₃), 2.33 [s, 3 H, C(2Ј)-CH₃), 3.67 (s, 3 H, OCH₃), 1350, 1300, 1270, 1200, 1150, 1060, 1010 cm^Ϫ1. ¹H NMR: δ ϭ 1.12

3.87 (s, 3 H, OCH₃), 4.63/4.72 (AB-d, 2 H, 5Ј-H); J_5Ј,5Јϭ 9 Hz.

(s, 3 H, CH₃), 1.25 (s, 3 H, CH₃), 1.30 (s, 9 H, tBu), 1.35 (s, 3 H,

Eur. J. Org. Chem. 2003, 1438Ϫ1453

1449

E. Lopez-Calle, M. Keller, W. Eberbach

FULL PAPER

10a-CH₃), 2.02 (d, 1 H, 10-H), 2.59 (d, 1 H, 8-H), 3.06 (d, 1 H, 10-

H), 3.12 (s, 3 H, NCH₃), 3.30 (d, 1 H, 8-H), 7.37 (s, 1 H, 5-H);

Data for 43a: Colorless crystals, m.p. 72 °C (cyclohexane/ethyl acet-

ate, 3:1). IR (CCl₄): ν˜ ϭ 2940, 2840, 1650 (CϭO), 1600, 1505, 1490,

J_10,10ϭ 14.3, J_8,8ϭ 9.3 Hz. ¹³C NMR: δ ϭ 21.9 (CH₃), 25.3 1455, 1440, 1420, 1370, 1350, 1310, 1190, 1125, 1020, 870 cm^Ϫ1

.

(NCH₃), 27.5 (CH₃), 28.2 (tϪBuϪCH₃), 29.0 (CH₃), 36.5 (C-9), ¹H NMR: δ ϭ 1.90 (m, 2 H, 6-H), 2.00 (m, 2 H, 7-H), 3.16 (t, 2

43.9 (tϪBuϪC), 50.2 (C-10), 66.5 (C-8), 81.9 (C-10a), 112.3 (C-6), H, 8-H), 3.99 (t, 2 H, 5-H), 6.56 (s, 1 H, 1-H), 7.34 (m, 5 H, Ph-

125.5 (C-5), 146.9 (N-CO), 153.2 (N-CO), 203.0 (CO). MS 70 eV, H), 9.91 (s, 1 H, CHO), J_5,6ϭ J_7.8ϭ 5.9 Hz. MS (70 eV, EI): m/z

EI): m/z (%) ϭ 335 (13%) [M ϩ 1]^ϩ, 334 (68), 319 (30), 262 (13), (%) ϭ 226 (17%) [M ϩ 1]^ϩ, 225 (100), 224 (65), 210 (8), 196 (20),

236 (12), 235 (92), 220 (25), 137 (25), 136 (38), 82 (16). C₁₇H₂₆N₄O₃115 (9), 105 (7), 77 (11). C₁₅H₁₅NO (225.3): calcd. C 79.97, H 6.71,

(334.5): calcd. C 61.06, H 7.84, N 16.75; found C 60.94, H 7.83,

N 16.51.

N 6.22; found C 79.85, H 6.68, N 6.02.

Thermolysis of 22b: A solution of 22b (480 mg, 2.1 mmol) in tolu-

ene (300 mL) was heated at reflux for 3.5 h. After concentration in

vacuo, the residue was separated by flash chromatography (cyclo-

Reaction between 25c and MTDA: A solution of MTAD (180 mg,

1.59 mmol) in dichloromethane (7 mL) was slowly added to a solu-

tion of 25c (330 mg, 1.56 mmol) in pure dichloromethane (20 mL).

The mixture was stirred for 30 min at room temp. and then concen-

trated. Flash chromatography of the residue (neutral Al₂O₃, ac-

tivity III, cyclohexane/dichloromethane, 1:1; dichloromethane/

ethanol, 10:1) gave methyl 6-[(2,9,9,10a-tetramethyl-1,3-dioxo-

2,3,8,9,10,10a-hexahydro-1H-pyrrolo[2,1-c][1,2,4]triazolo[1,2-a]-

[1,2,4]triazine]carboxylate (35c, 50 mg, 10%) as a yellow oil and

25c (130 mg, 39%). IR (CCl₄): ν˜ ϭ 2960, 2860, 2820, 1780 and 1730

(N-CϭO), 1720 (OCϭO), 1625 (CϭC), 1450, 1430, 1400, 1360,

hexane/ethyl acetate, gradient from 25:1

Ǟ 15:1), affording

2,2-dimethyl-(5,6,7,8-tetrahydroindolizin-3-yl)propan-1-one (42b,

273 mg, 62%) and 2-tert-butyl-5,6,7,8-tetrahydroindolizine-3-carb-

aldehyde (43b, 50 mg, 11%).

Data for 42b: Colorless crystals, m.p. 59 °C (diethyl ether/n-pen-

tane). IR (CCl₄): ν˜ ϭ 2940, 2920, 2900, 2860, 1630 (CϭO), 1485,

1465, 1440, 1425, 1390, 1365, 1345, 1335, 1315, 1305, 1200, 1085

1

cm^Ϫ1. H NMR: δ ϭ 1.36 (s, 9 H, tBu), 1.79 (m, 2 H, 6-H), 1.91

(m, 2 H, 7-H), 2.81 (t, 2 H, 8-H), 4.34 (t, 2 H, 5-H), 5.91 (d, 1 H,

1-H), 7.04 (d, 1 H, 2-H), J_1,2ϭ 4.0, J_5,6ϭ 6.6 Hz. MS (70 eV, EI):

m/z (%) ϭ 205 (12%) [M^ϩ], 149 (10), 148 (100), 120 (6), 118 (4),

106 (6), 93 (4), 79 (5), 78 (5), 77 (5). HRMS (C₁₃H₁₉NO): calcd.

205.1467, found 205.1463. C₁₃H₁₉NO (205.3): calcd. C 76.05, H

9.33, N 6.82; found C 75.83, H 9.48, N 6.79.

1280, 1260, 1185, 1140, 995 cm^Ϫ^{1 1}H NMR: δ ϭ 1.14 (s, 3 H,

.

CH₃), 1.25 (s, 3 H, CH₃), 1.32 (s, 3 H, CH₃), 2.07 (d, 1 H, 10-H),

2.62 (d, 1 H, 8-H), 3.00 (d, 1 H, 10-H), 3.10 (s, 3 H, NCH₃), 3.60

(d, 1 H, 8-H), 3.80 (s, 3 H, OCH₃), 7.63 (s, 1 H, 4-H), J_10,10

ϭ

14.3, J_8,8ϭ 9.3 Hz. ¹³C NMR: δ ϭ 22.2 (CH₃), 25.3 (NCH₃), 27.3

(CH₃), 28.4 (CH₃), 36.8 (C-9), 50.4 (C-10), 51.9 (OCH₃), 65.7 (C-

8), 82.1 (C-10a), 112.6 (C-6), 117.7 (C-5), 146.7 (N-CO), 153.1 (N-

CO), 164.3 (CO). MS (70 eV, EI): m/z (%) ϭ 308 (84%) [M^ϩ], 293

(36), 209 (100), 195 (39), 194 (81), 162 (39).

Data for 43b: Colorless crystals, m.p. 71 °C (diethyl ether/n-pen-

tane). IR (CCl₄): ν˜ ϭ 2940, 2900, 2860, 1670 (CϭO), 1650, 1500,

1460, 1450, 1390, 1360, 1310, 1210, 1135, 1110, 970 cm^Ϫ^{1 1}H

.

NMR: δ ϭ 1.36 (s, 9 H, tBu), 1.86 (m, 2 H, 6-H), 1.95 (m, 2 H, 7-

H), 3.07 (t, 2 H, 8-H), 3.87 (t, 2 H, 5-H), 6.24 (s, 1 H, 1-H), 10.09

(s, 1 H, CHO), J_5,6ϭ J_7,8ϭ 6.6 Hz. MS (70 eV, EI): m/z (%) ϭ

206 (6%) [M ϩ 1]^ϩ, 205 (37), 190 (100), 172 (6), 162 (54), 134 (8),

132 (6), 120 (20), 118 (9), 95 (6), 93 (9). C₁₃H₁₉NO (205.3): calcd.

C 76.05, H 9.33, N 6.82; found C 75.85, H 9.36, N 6.79.

Reaction between 28a and MTAD: A solution of MTAD (235 mg,

2.08 mmol) in dichloromethane (3 mL) was slowly added to a solu-

tion of 28a (215 mg, 0.83 mmol) in pure dichloromethane (5 mL).

The mixture was stirred for 3 days at room temp. and then concen-

trated. Flash chromatography of the residue (SiO₂, ethyl acetate)

gave 2-[(E)-1-benzoyl-2-hydroxy-2-(4-methyl-3,5-dioxo-1,2,4-tria-

zolan-1-yl)ethenyl]amino-2-methylpropyl acetate (41, 114 mg, 35%)

as a yellow foam. IR (CHCl₃): ν˜ ϭ 3340 (br., NϪH, OϪH), 1780

(CϭO), 1730 (br., CϭO), 1650 (CϭO), 1600 (CϭC), 1570, 1450,

Thermolysis of 22c: A solution of 22c (100 mg, 0.51 mmol) in tolu-

ene (80 mL) was heated at reflux for 1.5 h. After concentration in

vacuo, the residue was separated by flash chromatography (cyclo-

hexane/ethyl acetate, 25:1 Ǟ 15:1), affording methyl 5,6,7,8-tetra-

hydroindolizine-3-carboxylate (43c, 59 mg, 65%) as a light yellow

oil. IR (CCl₄): ν˜ ϭ 2940, 2920, 2880, 2850, 1700 (CϭO), 1485,

1470, 1440, 1430, 1425, 1395, 1355, 1320, 1305, 1230, 1180, 1145,

1040 cm^Ϫ1. ¹H NMR: δ ϭ 1.80 (m, 2 H, 6-H), 1.96 (m, 2 H, 7-H),

2.81 (t, 2 H, 8-H), 3.79 (s, 3 H, CH₃), 4.33 (t, 2 H, 5-H), 5.86 (d,

1 H, 1-H), 6.92 (d, 1 H, 2-H), J_1,2ϭ 4.0, J_5,6ϭ J_7,8ϭ 6.6 Hz. MS

(70 eV, EI): m/z (%) ϭ 180 (7%) [M ϩ 1]^ϩ, 179 (64), 164 (14), 148

(47), 146 (9), 121 (17), 120 (100), 119 (12), 118 (19), 106 (20).

HRMS (C₁₀H₁₃NO₂): calcd. 179.0947; found 179.0946.

1

1380, 1360, 1310, 1260, 990 cm^Ϫ1. H NMR: δ ϭ 1.37 (s, 6 H, 2-

CH₃), 2.11 (s, 3 H, COCH₃), 3.08 (s, 3 H, NCH₃), 4.18 (s, 2 H, 1-

H), 5.60 (br. s, 2 H, NH), 7.47 (m, 2 H, Ph-H), 7.59 (m, 1 H, Ph-

H), 8.10 (m, 2 H, Ph-H). MS (CI, isobutane): m/z (%) ϭ 391 (10%)

[M^ϩ] 390 (25), 389 (100), 388 (5), 361 (3), 277 (9), 276 (50), 248

(15).

Thermolysis of 22a: A solution of 22a (80 mg, 0.3 mmol) in toluene

(50 mL) was heated at reflux for 6 h. After concentration in vacuo,

the residue was separated by flash chromatography (cyclohexane/

ethyl acetate, 25:1), affording phenyl-(5,6,7,8-tetrahydroindolizin-3-

yl)methanone (42a, 53 mg, 71%) and 2-phenyl-5,6,7,8-tetrahydroin-

dolizine-3-carbaldehyde (43a, 13 mg, 18%).

Thermolysis of 22d: A solution of 22d (90 mg, 0.35 mmol) in tolu-

ene (50 mL) was heated at reflux for 3 h. After concentration in

vacuo, the residue was separated by flash chromatography (SiO₂,

cyclohexane/ethyl acetate, 10:1), affording dimethyl 5,6,7,8-tetra-

hydroindolizine-2,3-dicarboxylate (43d, 58 mg, 69%) as a yellow oil.

Data for 42a: Colorless crystals, m.p. 83 °C (n-pentane/diethyl

ether). IR (CCl₄): ν˜ ϭ 2950, 2860, 1625 (CϭO), 1600, 1580, 1490,

1470, 1445, 1430, 1390, 1340, 1320, 1310, 1240, 1190, 1170, 1040, IR (CCl₄): ν˜ ϭ 2980, 2930, 1730 (CϭO), 1700 (CϭO), 1480, 1440,

1

1025, 880, 700, 655 cm^Ϫ1. H NMR: δ ϭ 1.86 (m, 2 H, 6-H), 1.99 1430, 1395, 1340, 1310, 1280, 1250, 1200, 1150, 1120, 1060 cm^Ϫ1

.

(m, 2 H, 7-H), 2.87 (t, 2 H, 8-H), 4.50 (t, 2 H, 5-H), 5.93 (d, 1 H,

1-H), 6.71 (d, 1 H, 2-H), 7.44 (m, 3 H, Ph-H), 7.77 (m, 2 H, Ph-

¹H NMR: δ ϭ 1.81 (m, 2 H, 6-H), 1.95 (m, 2 H, 7-H), 2.78 (t, 2

H, 8-H), 3.81 (s, 3 H, OCH₃), 3.84 (s, 3 H, OCH₃), 4.21 (t, 2 H, 5-

H), J_1.2ϭ 4.5 Hz. MS (70 eV, EI): m/z (%) ϭ 226 12%) [M ϩ 1]^ϩH), 6.20 (s, 1 H, 1-H), J_5,6ϭ J_7,8ϭ 6.6 Hz. MS (70 eV, EI): m/z

225 (78), 224 (100), 208 (6), 197 (8), 196 (23), 184 (5), 120 (12), 106

(8), 105 (16). C₁₅H₁₅NO (225.3): calcd. C 79.97, H 6.71, N 6.22; 164 (18), 147 (63), 134 (20), 119 (58), 106 (12). HRMS

(%) ϭ 238 (8%) [M ϩ 1]^ϩ, 237 (62), 206 (97), 205 (69), 176 (16),

found C 79.91, H 6.73, N 6.16.

(C₁₂H₁₅NO₄): calcd. 237.1001; found 237.1003.

1450

Eur. J. Org. Chem. 2003, 1438Ϫ1453

Azomethine Ylides by Photochemical Transformation of 2,3-Dihydroisoxazoles

FULL PAPER

Thermolysis of 25a: A solution of 25a (450 mg, 1.75 mmol) in tolu-

ene (250 mL) was heated at reflux for 3 days. After concentration

in vacuo, the residue was separated by flash chromatography (SiO₂,

cyclohexane/ethyl acetate, 10:1, ethyl acetat/methanol, 20:1), af-

fording (2,2-dimethyl-2,3-dihydro-1H-pyrrolizin-5-yl)(phenyl)me-

1640 (RCϭO), 1600 (CϭC), 1470, 1400, 1370, 1320, 1260, 1170,

1

1150, 1060 cm^Ϫ1. H NMR: δ ϭ 1.22 (s, 15 H, CH₃), 2.89 (m, 2

H, CϭCH₂), 3.22 (s, 2 H, 3Ј-H), 4.21 (s, 2 H, 5Ј-H), 4.80 (d, 1 H,

2-H), 9.30 (d, 1 H, CHO), J_2,CHOϭ 7.5 Hz. ¹³C NMR (100 MHz,

CDCl₃): δ ϭ 26.3 (CH₃), 26.9 (CH₃), 36.3 (C-4Ј), 43.4 (C-4), 44.6

thanone (46a, 264 mg, 63%), 2,2-dimethyl-6-phenyl-2,3-dihydro- (br., ϭCH₂), 50.2 (C-3Ј), 66.3 (C-5Ј), 95.3 (br., C-2), 168.5 (C-2Ј),

1H-pyrrolizine-5-carbaldehyde (47a, 29 mg, 7%), and 2-(4,4-di-

methyl-2-methylene-1-pyrrolidinyl)-3-oxo-3-phenylpropanal (45a,

54 mg, 12%).

187.4 (CHO), 208.0 (CO). MS (70 eV, EI): m/z (%) ϭ 237 (17%)

[M^ϩ], 153 (29), 152 (100), 136 (19), 124 (16), 122 (8), 109 (7), 108

(16), 95 (13), 94 (9). C₁₄H₂₃NO₂(237.4): calcd. C 70.85, H 9.77, N

5.90; found C 70.77, H 9.71, N 5.90.

Data for 46a: Yellow crystals, m.p. 57 °C (diethyl ether/n-pentane).

IR (CCl₄): ν˜ ϭ 3025, 2960, 2860, 1620 (CϭO), 1600 (CϭC), 1460,

Thermolysis of 25c: A solution of 25c (290 mg, 1.37 mmol) in tolu-

ene (175 mL) was heated at reflux for 3 days. After concentration

in vacuo, the residue was separated by flash chromatography (SiO₂,

cyclohexane/ethyl acetate, 5:1, ethyl acetate/methanol, 20:1), afford-

ing methyl 2,2-dimethyl-2,3-dihydro-1H-pyrrolizine-5-carboxylate

(47c, 24 mg, 9%) and methyl 2-(4,4-dimethyl-2-methylene-1-pyrroli-

dinyl)-3-oxopropanoate (45c, 163 mg, 56%).

1430, 1400, 1380, 1300, 1270, 1150, 1040, 1020, 890, 690, 660 cm^Ϫ1

.

¹H NMR: δ ϭ 1.29 (s, 6 H, CH₃), 2.69 (s, 2 H, 1-H), 4.20 (s, 2 H,

3-H), 5.92 (d, 1 H, 7-H), 6.81 (d, 1 H, 6-H), 7.48 (m, 3 H, Ph-H),

7.82 (m, 2 H, Ph-H), J_6,7ϭ 4.5 Hz. MS (70 eV, EI): m/z (%) ϭ 240

(12%) [M ϩ 1]^ϩ, 239 (70), 238 (9), 225 (13), 224 (78), 222 (22), 196

(10), 184 (27), 162 (24), 154 (14). C₁₆H₁₇NO (239.3): calcd. C 80.30,

H 7.16, N 5.85; found C 80.28, H 7.16, N 5.83.

Data for 45c: Light yellow crystals, m.p. 92 °C (diethyl ether/n-

pentane). IR (CCl₄): ν˜ ϭ 2960, 2940, 2880, 2760/2710, 1755 (OCϭ

O), 1650 (HCϭO), 1600 (CϭC), 1550, 1440, 1410, 1370, 1320,

Data for 47a: Yellow crystals, m.p. 145 °C (diethyl ether/n-pentane).

IR (CCl₄): ν˜ ϭ 3030, 2960, 2860, 2800/2730, 1660 (CϭO), 1620

1

(CϭC), 1520, 1460, 1440, 1390, 1370, 1250, 1170 cm^Ϫ1. H NMR:

1260, 1210, 1180, 940 cm^Ϫ^{1 1}H NMR: δ ϭ 1.21 (s, 6 H, CH₃),

.

δ ϭ 1.31 (s, 6 H, CH₃), 2.99 (s, 2 H, 1-H), 3.75 (s, 2 H, 3-H), 6.63

(s, 1 H, 7-H), 7.40 (m, 5 H, Ph-H), 9.94 (s, 1 H, CHO). MS (70 eV,

EI): m/z (%) ϭ 240 (9%) [M ϩ 1]^ϩ, 239 (51), 238 (14), 225 (17),

224 (100), 196 (13), 184 (7), 183 (6), 182 (23), 180 (7). C₁₆H₁₇NO

(239.3): calcd. C 80.30, H 7.16, N 5.85; found C 80.19, H 7.13,

N 5.93.

2.88 (s, br., 2 H, CϭCH₂), 3.31 (s, 2 H, 3Ј-H), 3.77 (s, 3 H, OCH₃),

3.98 (s, 2 H, 5Ј-H), 4.98 (d, 1 H, 2-H), 9.38 (d, 1 H, CHO),

J_2,CHOϭ 7.5 Hz. MS (70 eV, EI): m/z (%) ϭ 211 (40%) [M^ϩ], 196

(46), 194 (28), 183 (13), 152 (100), 136 (26), 124 (46), 108 (25), 96

(13). C₁₁H₁₇NO₃(211.3): calcd. C 62.54, H 8.11, N 6.63; found C

62.50, H 8.02, N 6.66.

Data for 45a: IR (CCl₄): ν˜ ϭ 3060, 2960, 2920, 2760/2710, 1700

(HCϭO), 1640 (RCϭO), 1600 (CϭC), 1550, 1450, 1400, 1340,

Data for 47c: Yellow oil. IR (CCl₄): ν˜ ϭ 2960, 2930, 2900, 2880,

1705 (CϭO), 1490, 1470, 1440, 1330, 1280, 1270, 1260, 1200, 1130,

1320, 1220, 1170, 1155 cm^Ϫ^{1 1}H NMR: δ ϭ 1.25 (s, 6 H, CH₃),

.

1

1110, 1030, 940 cm^Ϫ1. H NMR: δ ϭ 1.25 (s, 6 H, CH₃), 2.65 (s,

2.94 (m, 2 H, ϭCH₂), 3.33 (s, 2 H, 3-H), 4.68 (s, 2 H, 5-H), 4.93

(d (br), 1 H, 2-H), 7.50 (m, 2 H, Ph-H), 7.63 (m, 1 H, Ph-H), 7.92

(m, 2 H, Ph-H), 9.34 (d (br), 1 H, CHO), J_2,CHOϭ 7.5 Hz.

2 H, 1-H), 3.80 (s, 3 H, OCH₃), 4.00 (s, 2 H, 3-H), 5.86 (d, 1 H, 7-

H), 6.91 (d, 1 H, 6-H), J_6,7ϭ 4.5 Hz. MS (70 eV, EI): m/z (%) ϭ

193 (87%) [M^ϩ], 192 (17), 178 (32), 162 (44), 160 (21), 138 (84),

134 (54), 118 (27), 107 (19), 106 (100).

Thermolysis of 25b: A solution of 25b (450 mg, 1.90 mmol) in tolu-

ene (250 mL) was heated at reflux for 3 days. After concentration

in vacuo, the residue was separated by flash chromatography (SiO₂,

cyclohexane/ethyl acetate, 10:1, ethyl acetate/methanol, 30:1), af-

fording (2,2-dimethyl-2,3-dihydro-1H-pyrrolizin-5-yl)-2,2-dimeth-

ylpropan-1-one (46b, 91 mg, 22%), 6-tert-butyl-2,2-dimethyl-2,3-di-

hydro-1H-pyrrolizine-5-carbaldehyde (47b, 5 mg, 1%), and 2-(4,4-

dimethyl-2-methylene-1-pyrrolidinyl)-3-oxo-4,4-dimethylpentanal

(45b, 312 mg, 69%).

Thermolysis of 25d: A solution of 25d (500 mg, 1.86 mmol) in tolu-

ene (250 mL) was heated at reflux for 3 days. After concentration

in vacuo, the residue was separated by flash chromatography (SiO₂,

cyclohexane/ethyl acetate, 3:1, ethyl acetate/methanol, 30:1), afford-

ing dimethyl 2,2-dimethyl-2,3-dihydro-1H-pyrrolizine-5,6-dicar-

boxylate (47d, 84 mg, 18%) and dimethyl 2-(4,4-dimethyl-2-methyl-

ene-1-pyrrolidinyl)-3-oxosuccinate (45d, 300 mg, 60%).

Data for 46b: Light yellow crystals, m.p. 71 °C (diethyl ether/n-

pentane). IR (CCl₄): ν˜ ϭ 2960, 2920, 2900, 2860, 1630 (CϭO),

1460, 1450, 1440, 1430, 1390, 1360, 1300, 1270, 1200, 1160, 1060,

Data for 45d: Yellow crystals, m.p. 128 °C (diethyl ether/n-pentane).

IR (KBr): ν˜ ϭ 3010, 2960, 2880, 1750 (CϭO), 1720 (CϭO), 1630

(CϭC), 1550, 1480, 1420, 1320, 1250, 1220, 1170, 1100, 1050, 980

910 cm^{Ϫ1 1}H NMR: δ ϭ 1.23 (s, 6 H, CH₃), 1.37 (s, 9 H, tBu),

.

cm^Ϫ^{1 1}H NMR: δ ϭ 1.20 (s, 6 H, CH₃), 3.18 (s, 2 H, CϭCH₂),

.

2.61 (s, 2 H, 1-H), 4.09 (s, 2 H, 3-H), 5.87 (d, 1 H, 7-H), 7.02 (d,

1 H, 6-H), J6,7 ϭ 4.5 Hz. MS (70 eV, EI): m/z (%) ϭ 219 (12%)

[M^ϩ], 163 (12), 162 (100), 120 (7), 106 (15), 86 (7), 84 (10), 79/6),

78 (8), 77 (9). C₁₄H₂₁NO (219.4): calcd. C 76.67, H 9.65, N 6.39;

found C 76.40, H 9.60, N 6.25.

3.31 (s, 2 H, 3Ј-H), 3.79 (s, 3 H, OCH₃), 3.81 (s, 3 H, OCH₃), 4.08

(s, 2 H, 5Ј-H), 5.75 (s, 1 H, 2-H). MS (70 eV, EI): m/z (%) ϭ 269

(M^ϩ, 4%), 211 (13), 210 (100), 182 (15), 166 (4), 151 (3), 150 (8),

122 (6), 108 (5). C₁₃H₁₉NO₅(269.3): calcd. C 57.98, H 7.11, N

5.20; found C 57.76, H 6.91, N 5.17.

Data for 47b: Yellow oil. IR (CCl₄): ν˜ ϭ 2960, 2900, 2880, 2820,

2710, 1680 (CϭO), 1650 (CϭC), 1520, 1470, 1440, 1390, 1360,

Data for 47d: Yellow crystals, m.p. 52 °C (diethyl ether/n-pentane).

IR (CCl₄): ν˜ ϭ 2960, 2930, 2900, 2870, 1730 (CϭO), 1705 (CϭO),

1485, 1470, 1450, 1290, 1250, 1200, 1190, 1140, 1120, 1110, 1060

1310, 1220, 1180, 1120 cm^{Ϫ1 1}H NMR: δ ϭ 1.28 (s, 6 H, CH₃),

.

1.37 (s, 9 H, tBu), 2.91 (s, 2 H, 1-H), 3.65 (s, 2 H, 3-H), 6.32 (s, 1

H, 7-H), 9.90 (s, 1 H, CHO). MS (70 eV, EI): m/z (%) ϭ 219 (35%)

[M^ϩ], 205 (17), 204 (100), 190 (9), 177 (14), 176 (59), 120 (13), 91

(14), 86 (11), 84 (17).

1

cm^Ϫ1. H NMR: δ ϭ 1.25 (s, 6 H, CH₃), 2.64 (s, 2 H, 1-H), 3.83

(s, 3 H, OCH₃), 3.86 (s, 3 H, OCH₃), 4.01 (s, 2 H, 3-H), 6.26 (s, 1

H, 7-H). MS (70 eV, EI): m/z (%) ϭ 251 (90%) [M^ϩ], 220 (100),

219 (26), 204 (64), 190 (16), 188 (32), 164 (70), 162 (16), 161 (34),

160 (89). C₁₃H₁₇NO₄(251.3): calcd. C 62.14, H 6.82, N 5.57; found

Data for 45b: Colorless crystals, m.p. 123 °C (diethyl ether/n-pen-

tane). IR (CCl₄): ν˜ ϭ 2960, 2930, 2880, 2750/2710, 1720 (HCϭO), C 61.93, H 6.69, N 5.61.

Eur. J. Org. Chem. 2003, 1438Ϫ1453

1451

E. Lopez-Calle, M. Keller, W. Eberbach

FULL PAPER

Thermolysis of 45a: A solution of 45a (100 mg, 0.39 mmol) in pure

benzene (50 mL) was heated in an autoclave at 200 °C for 12 h.

After concentration of the mixture in vacuo, the residue was sepa-

concentration of the mixture in vacuo, the residue was separated

by flash chromatography (SiO₂, cyclohexane/ethyl acetate, 10:1), af-

fording 1-(3,3-dimethyl-2,3-dihydropyrrolo[2,1-b][1,3]oxazol-5-yl)-

rated by flash chromatography (SiO₂, cyclohexane/ethyl acetate, 2,2-dimethylpropan-1-one (48b, 87 mg, 20%), 6-(tert-butyl)-3,3-di-

10:1), affording 46a (65 mg, 70%) and 47a (5 mg, 5%).

methyl-2,3-dihydropyrrolo[2,1-b][1,3]oxazole-5-carbaldehyde (49b,

55 mg, 13%), and 2-[(3,3-dimethyl-2-oxobutyl)(formyl)amino]-2-

methylpropyl acetate (52b, 189 mg, 38%).

Thermolysis of 45b: A solution of 45b (100 mg, 0.42 mmol) in pure

benzene (50 mL) was heated in an autoclave at 200 °C for 12 h.

After concentration of the mixture in vacuo, the residue was sepa-

Data for 48b: Pale yellow crystals, m.p. 73 °C (diethyl ether/n-pen-

rated by flash chromatography (SiO₂, cyclohexane/ethyl acetate, tane). IR (CCl₄): ν˜ ϭ 2980, 2940, 2900, 2880, 1630 (CϭO), 1570,

10:1), affording 46b (74 mg, 80%) and 47b (4 mg, 4%).

1490, 1480, 1440, 1400, 1350, 1260, 1200, 1130, 1080, 1040, 1000,

910 cm^Ϫ^{1 1}H NMR: δ ϭ 1.37 (s, 9 H, tBu), 1.68 (s, 6 H, CH₃),

4.60 (s, 2 H, 2-H), 5.27 (d, 1 H, 7-H), 7.03 (d, 1 H, 6-H), J_6,7

.

Thermolysis of 45c: A solution of 45c (100 mg, 0.47 mmol) in pure

benzene (50 mL) was heated in an autoclave at 200 °C for 24 h.

After concentration of the mixture in vacuo, the residue was sepa-

rated by flash chromatography (SiO₂, cyclohexane/ethyl acetate,

10:1), affording 47c (55 mg, 60%).

ϭ

4.5 Hz. MS (70 eV, EI): m/z (%) ϭ 222 (5%) [M ϩ 1]^ϩ, 221 (35),

194 (1), 166 (1), 165 (12), 164 (100), 137 (2), 136 (3), 110 (10), 109

(2). C₁₃H₁₉NO₂(221.3): calcd. C 70.56, H 8.65, N 6.33; found C

70.30, H 8.53, N 6.29.

Thermolysis of 45d: A solution of 45d (100 mg, 0.37 mmol) in pure

benzene (50 mL) was heated in an autoclave at 200 °C for 24 h.

After concentration of the mixture in vacuo, the residue was sepa-

rated by flash chromatography (SiO₂, cyclohexane/ethyl acetate,

10:1), affording 47d (61 mg, 65%).

Data for 49b: Yellow oil. IR (CCl₄): ν˜ ϭ 2960, 2900, 2860, 2740/

2720, 1670 (CϭO), 1630 (CϭC), 1550, 1490, 1460, 1410, 1360,

1260, 1230, 1120, 1070, 990, 650 cm^{Ϫ1 1}H NMR: δ ϭ 1.34 (s, 9

.

H, tBu), 1.54 (s, 6 H, CH₃), 4.67 (s, 2 H, 2-H), 5.94 (s, 1 H, 7-H),

9.75 (s, 1 H, CHO). MS (70 eV, EI): m/z (%) ϭ 222 (15%) [M ϩ

1]^ϩ, 221 (97), 207 (14), 206 (100), 180 (6), 179 (33), 178 (43), 166

(6), 164 (13).

Thermolysis of 28a: A solution of 28a (650 mg, 2.51 mmol) in pure

benzene (75 mL) was heated in an autoclave at 200 °C for 3.5 h.

After concentration of the mixture in vacuo, the residue was sepa-

rated by flash chromatography (SiO₂, cyclohexane/ethyl acetate,

10:1), affording (3,3-dimethyl-2,3-dihydropyrrolo[2,1-b][1,3]oxazol-

5-yl)(phenyl)methanone (48a, 79 mg, 13%), 3,3-dimethyl-6-phenyl-

2,3-dihydropyrrolo[2,1-b][1,3]oxazole-5-carbaldehyde (49a, 79 mg,

13%), and 2-[formyl(2-oxo-2-phenylethyl)amino]-2-methylpropyl

acetate (52a, 313 mg, 45%).

Data for 52b: Yellow oil. IR (CCl₄): ν˜ ϭ 2980, 2900, 2870, 1750

(OCϭO), 1730 (RCϭO), 1665 (NCϭO), 1480, 1390, 1380, 1350,

1

1260, 1225, 1190, 1060, 1050, 1000, 950 cm^Ϫ1. H NMR: δ ϭ 1.24

(s, 9 H, tBu), 1.41 (s, 6 H, CH₃), 2.10 (s, 3 H, COCH₃), 4.02 (s, 2

H, CH₂), 4.30 (s, 2 H, OCH₂), 8.47 (s, 1 H, NCHO). MS (CI,

isobutane): m/z (%) ϭ 258 (100%) [M ϩ 1]^ϩ, 257 (2), 230 (3), 216

(3), 200 (3), 198 (2), 160 (3), 115 (2), 100 (2).

Data for 48a: Yellow crystals, m.p. 102 °C (diethyl ether/n-pentane).

IR (CCl₄): ν˜ ϭ 3060, 2960, 2930, 2880, 1620 (CϭO), 1490, 1450,

Acknowledgments

1

1430, 1380, 1340, 1260, 1210, 1030, 1020, 880, 690, 670 cm^Ϫ1. H

NMR: δ ϭ 1.79 (s, 6 H, CH₃), 4.68 (s, 2 H, 2-H), 5.33 (d, 1 H, 7-

This work was supported by the Fonds der Chemischen Industrie.

E. L.-C. gratefully acknowledges the Landesgraduiertenförderung

Baden-Württemberg for a stipend.

H), 6.73 (d, 1 H, 6-H), 7.45 (m, 3 H, Ph-H), 7.73 (m, 2 H, Ph-H),

J

_6,7ϭ 4.5 Hz. MS (70 eV, EI): m/z (%) ϭ 242 (19%) [M ϩ 1]^ϩ, 241

(100), 240 (11), 226 (7), 212 (26), 198 (11), 187 (10), 186 (50), 184

(7), 158 (15). C₁₅H₁₅NO₂(241.3): calcd. C 74.67, H 6.27, N 5.81;

found C 74.55, H 6.22, N 5.72.

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Data for 49a: Yellow crystals, m.p. 132 °C (diethyl ether/n-pentane).

IR (KBr): ν˜ ϭ 3040, 2960, 2920, 2830, 2750, 1650 (CϭO), 1600

(CϭC), 1530, 1490, 1350, 1220, 1200, 970, 930, 860, 770, 700, 660

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(s, 1 H, 7-H), 7.32 (m, 3 H, Ph-H), 7.47 (m, 2 H, Ph-H), 9.70 (s, 1

H, CHO). MS (70 eV, EI): m/z (%) ϭ 242 (19%) [M ϩ 1]^ϩ, 241

(100), 240 (22), 198 (9), 186 (23), 185 (13), 184 (11), 170 (13), 158

(11), 144 (6). C₁₅H₁₅NO₂(241.3): calcd. C 74.67, H 6.27, N 5.81;

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1750, 1710, 1665 (NCϭO), 1590, 1450, 1380, 1350, 1300, 1220,

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1100, 1050, 1000, 960, 910, 690 cm^Ϫ1. H NMR: δ ϭ 1.47 (s, 6 H,

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OCH₂), 7.49 (m, 2 H, Ph-H), 7.61 (m, 1 H, Ph-H), 7.99 (m, 2 H,

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(CH₃), 47.6 (C-1Ј), 57.0 (C-2), 68.9 (C-1), 127.9 (Ph-C), 128.7 (Ph-

C), 133.5 (Ph-C), 135.1 (Ph-C), 162 (NCHO), 170.4 (CO₂R), 193.4

(CO). MS (70 eV, EI), m/z (%) ϭ 277 (7%) [M^ϩ], 205 (5), 204 (40),

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1452

Eur. J. Org. Chem. 2003, 1438Ϫ1453

Azomethine Ylides by Photochemical Transformation of 2,3-Dihydroisoxazoles

FULL PAPER

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Received November 11, 2002

[O02625]

Eur. J. Org. Chem. 2003, 1438Ϫ1453

1453

Article Doi

Access to isolable azomethine ylides by photochemical transformation of 2,3-dihydroisoxazoles

DOI: 10.1002/ejoc.200390203

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Article abstract of DOI:10.1002/ejoc.200390203

Full text of DOI:10.1002/ejoc.200390203

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