The dipolar route to azepin-3-one derivatives by heterocyclization of linear and monocyclic enallenyl nitrones as the key step

FULL PAPER

The Dipolar Route to Azepin-3-one Derivatives by Heterocyclization of

Linear and Monocyclic Enallenyl Nitrones as the Key Step

Karin Knobloch,^[a,b]Joachim Koch,^[a]Manfred Keller,^[a][‡]and and Wolfgang Eberbach*^[a]

Keywords: Azepinones / Allenes / Nitrones / Electrocyclization / Photochemistry

The recently discovered transformation of benzopentenynyl

nitrones into 1,2-dihydrobenz[c]azepin-3-ones has been ex-

tended to the synthesis of structurally different systems in-

cluding the monocyclic derivatives 17 and 18, the bicyclic

azepinones 10a–d, and the tricyclic heterocycles 37–40, 42,

43, 45, 47, and 48. In addition, the applicability of the reac-

tion principle was demonstrated through the preparation of

the benzo-piperidino compound 52 which acts as a model

compound for the alkaloid astrocasine (53). A multistep reac-

tion mechanism is proposed that involves enallenyl nitrones

as precursors of a 1,7-dipolar electrocyclization process fol-

lowed by further bond reorganizations. The occurrence of cy-

clopropanones (type E and H) as intermediates is supported

by the formation of isoindoles (41, 44, and 46) as minor prod-

ucts in some cases. Photochemical studies with selected dihy-

droazepinones gave different results: Whereas the monocy-

clic azepinone 17 reacted under both direct and sensitized

excitation to form the bicyclic diastereomers 20 and 21, the

reactions of the bicyclic compounds 10 were more compli-

cated. Only 10a,b were observed to undergo the 4π-cycliza-

tion reaction upon direct irradiation, resulting, after CO ex-

trusion and hydrolysis, in the formation of the aldehydes

22a,b. Under triplet-sensitized conditions 10b–d undergo a

1,5-phenyl shift to afford the isomers 25b–d.

Germany, 2005)

lene unit in ring-forming procedures,^[8]for example, in

[2+2],^[9,10]Diels–Alder,^[11,12]and 1,3-dipolar cycloaddition

reactions,^[13,14]as well as in palladium-catalyzed transfor-

mations,^[15]Pauson–Khand-type cyclization reactions,^[16]

and metathesis processes.^[17]

Introduction

Owing to the frequently observed biological activity of

seven-membered azaheterocycles their synthesis remains an

ongoing challenge. Of the wide range of structures that are

known, the benzazepin-3-one system deserves particular at-

tention because there are quite a number of its derivatives

that have been used for pharmaceutical purposes, for in-

stance, as adrenaline antagonists,^[1]inflammation inhibi-

tors,^[2]as a drug with cholesterol-lowering properties,^[3]or

as a mediator in cellular adhesion events.^[4]Until now only

a few general syntheses of the system have been available.^[5]

We have previously developed a novel methodology for

the synthesis of this benzazepin-3-one system that is par-

ticularly simple, variable with respect to structural require-

ments, and can be executed under unusually mild condi-

Scheme 1.

As a result of our work on the preparation of 1,2-dihy-

tions.^[6]The procedure is based on the heterocyclization of drobenzazepin-3-ones, it was the aim of this work to

conjugated penta-1,2,4-trienyl nitrones of general type 1 as broaden the scope of the methodology by applying the

the key step leading to intermediate oxazepine derivatives 2 same type of transformation to compounds with an alkeno-

which undergo a multistep rearrangement sequence to af- annulation of the double bond (see structure 9), and also

ford azepin-3-one products

3

in high overall yield to the linear systems 14 and 16.^[18]

To construct the allene unit we took advantage of the

(Scheme 1).^[7]The reaction principle is a further example of

the increasing number of successful applications of an al- base-catalyzed propargyl-allenyl isomerization of an appro-

priate precursor which could proceed by the formal mi-

[‡] Correspondence author for the crystal structure analyses.

[a] Institut für Organische Chemie und Biochemie der Universität

Freiburg,

gration of either an inner or an outer proton, that is, mi-

gration of the type 4 Ǟ 5 or 6 Ǟ 5 (Scheme 2), respectively.

In contrast to our recent investigations^[6,7]we used the latter

alternative to generate an equilibrium concentration of the

allene isomer, which was expected to undergo the required

transformation under the same mild conditions.

Albertstrasse 21, 79104 Freiburg, Germany

Fax: +49-(0)761/203-6085

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

[b] Current address: Siegfried CMS Ltd., 4800 Zofingen, Switzer-

land

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DOI: 10.1002/ejoc.200400922

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experiments, the formation of an allenic compound, sup-

posedly the direct precursor of the 1,7-dipolar cyclization

process, was not observed. The structures of the bicyclic

lactams were unambiguously confirmed by elemental analy-

ses and detailed spectroscopic investigations. Among other

data the strong IR absorptions at 1670/1675 cm^–1as well as

the ¹³C NMR signals at about 166 ppm underline the pres-

ence of the lactam moiety.

Scheme 2.

In order to test the thermodynamic stability of the struc-

tures 10, which contain two exocyclic double bonds that

can be shifted by a sigmatropic 1,5-hydrogen migration to

afford the seemingly more stable isomers 11, the com-

pounds were refluxed in toluene. After 2 h equilibrium con-

centrations were obtained that depend on the size of the

carbocyclic ring: Whereas the ratio of the tautomeric com-

pounds 10 and 11 was unity for derivatives a and b, struc-

ture 10 dominates by a factor of 2.5 in the case of d, with

a ratio of Ͼ50:1 for c. With the exception of the cyclohep-

teno-annulated azepinone system, the thermodynamic sta-

bility of the double-bond isomers is, in contrast to expecta-

tion, not very different. In order to obtain more infor-

mation about these systems, the thermochemical data is

currently being evaluated, including the determination of

the enthalpy of formation and the molecular strain.^[21]

As a further test of the reaction principle of Scheme 1,

the preparation of an analogue of astrocasine, a naturally

occurring euphorbiaceae alkaloid, is described.^[19]In ad-

dition, the photochemical reactivity of some dihydroazepi-

none derivatives will be briefly discussed.

Results and Discussion

Synthesis and Transformation of Cycloalkeno-Annulated

Nitrone Systems

The annulated allene precursors 9 were prepared by fol-

lowing the general protocol applied earlier to related com-

pounds (Scheme 3).^[7]Sonogashira alkynylation of the

known annulated bromo aldehydes 7^[20]produced the pro-

pargyl compounds 8 (89–98%) which were treated with

methylhydroxylamine hydrochloride and sodium acetate in

dichloromethane as solvent to give the conjugated nitrones

9a–d in yields of 57–88% (Scheme 3).

Synthesis and Transformation of Linear Nitrone Systems

After treatment of 0.1 m solutions of the dipolar systems

Following the same procedure as described for the syn-

9 in methanol with 0.5 equiv. of potassium hydroxide at thesis of compounds 9, the linear phenyl-benzyl system 14

room temperature complete consumption of the starting was obtained from (Z)-β-bromocinnamaldehyde (12)^[22,23]

materials was attained after 1.5 h (a, c, d) and 3 h (b). Aque- via 13 in 36 and 86% yields for the two steps, respectively

ous work up and chromatographic purification of the crude (Scheme 4). Dimethyl nitrone 16 was formed in 90% yield

material afforded a crystalline product, which, in each case, from the known 3-methylhexenynal 15.^[24]

had the structure of an annulated dihydroazepinone 10 (a:

Treatment of a methanolic solution of the benzyl deriva-

79%, b: 88%, c: 46%, d: 65%). As found in our previous tive 14 with sodium methoxide at room temperature for

Scheme 3. Reagents and conditions: (i) HCϵCCH₂Ph, PdCl₂(PPh₃)₂, CuI, NEt₃, C₆H₆; (ii) CH₃NHOH·HCl, NaOAc, CH₂Cl₂; (iii) KOH,

MeOH, room temp.

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Dipolar Route to Azepinone Derivatives by Heterocyclization of Enallenyl Nitrones

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Scheme 4. Reagents and conditions: (i) and (ii) as for Scheme 3; (iii) MeONa, MeOH, 30 min, room temp.; (iv) NaH, DMF, 22 h, 60 °C.

30 min gave 17 in almost quantitative yield (94%, m.p. 74– neral case). Cleavage of the notoriously weak NO bond^[25]

76 °C). In contrast, the conditions required for the reaction of C gives the diradical D which rebonds to give the azadi-

of compound 16 with a terminal methyl group turned out enylcyclopropanone E and is followed by a one- or two-step

to be much harsher. Owing to the significantly lower acidity cyclization reaction to produce F.^[7]

of the propargylic proton a stronger base for the induction

of the essential propargyl-allenyl rearrangement was

needed. Even with sodium hydride in DMF and at a tem-

perature of 60 °C the reaction took 22 h for complete con-

Photoreactivity of the Dihydroazepinones 10a–d and 17

version (Scheme 4). It was a pleasant surprise that despite

such conditions the expected dihydroazepinone 18 was

formed at all, albeit in a lower yield (28%). Interestingly,

both dihydroazepinones 17 and 18 have double bonds con-

jugated to the ring nitrogen. Experiments with derivative 17

in boiling toluene revealed the corresponding isomer with

carbonyl and phenyl conjugation (19) to have an equilibra-

tion concentration of less than 3%.

The importance of the base strength on the reactivity of

14 and 16 lends further support to our mechanistic pro-

posal for a multistep rearrangement with the formation of

an allene in the first step (A Ǟ B) and subsequent 1,7-

dipolar cyclization to methyleneoxazepine C (Scheme 5, ge-

The photochemistry of dihydroazepinones (the same is

true for azepinones) has been studied in only a few

cases.^[26,27]In analogy with other 1,3-cycloheptadienes,^[28]

electrocyclic ring closure to the corresponding bicyclic iso-

mers is observed as the main reaction. Owing to the limited

knowledge of the photochemistry of such heterocycles, and

with appropriate systems in hand, we have made some pre-

liminary studies of the photochemistry of the monocyclic

and bicyclic compounds 17 and 10a–d, respectively.

On irradiation of approximately 10^–3m solutions of the

diphenyldihydroazepinone 17 under both direct (diethyl

ether, λ Ͼ 270 nm, 30 min, 70% conversion) and triplet-

sensitized excitation (acetone, λ Ͼ 270 nm, 15 min, 44%

conversion), a bicyclization reaction took place to afford an

approximate 1:1 mixture of the diastereomers 20 and 21

(Scheme 6) in 86 and 62% yields (related to conversion),

respectively, which could be easily separated by flash

chromatography; no other products were detectable. The

structures of the isomers were differentiated on the basis of

the magnitude of the ¹H NMR coupling constant J_4,5

,

which is 10.7 Hz for 20 and 2.7 Hz for 21, which correspond

to dihedral angles of about 0 and 120°, respectively.

In the case of the dihydroazepinones 10 the type of annu-

lation has an important effect on the photochemical behav-

ior. Whereas on direct excitation of 10a,b (ca. 10^–3m in di-

ethyl ether, λ Ͼ 210 nm, 1 h), reaction mixtures were

formed which, after chromatographic work up, gave the

known aldehydes 22a,b^[29]in 80 and 59% yields, no defined

product could be detected after the photolysis of 10c,d. Al-

though there was no direct evidence for the formation of

the tricyclic lactams 23a,b, their intermediate formation

Scheme 5.

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K. Knobloch, J. Koch, M. Keller, W. Eberbach

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the lactam ring. In contrast, the ring protons of the second-

ary product 26c form a three-spin system.

Scheme 6.

through a 4π-cyclization process seems likely (Scheme 7).

Subsequent CO extrusion by a Norrish I reaction would

then lead to the imines 24, which are hydrolyzed during

chromatographic purification.

Scheme 8.

The conversion of the lactam 10 into the isomeric com-

pound 25 is connected with a 1,5-migration of the phenyl

group along the diene system. The spin-correlation effect,

that is, the different result obtained under acetone-sensi-

tized photolysis compared with the direct excitation modus

is an indication of a triplet process and, consequently, not

a concerted sigmatropic shift. If the possible 1,5-hydrogen

migration did not take place, the special migratory ability

of phenyl groups through the formation of bridged species

must be recognized. Although a multistep walk process^[30]

would also be feasible, we prefer a mechanism through a

bridged intermediate like 27 (Scheme 8).

Comparable phenyl migrations are very rare. Besides a

report of the photochemical 1,5-phenyl shift in dibenzoy-

lethenes,^[31]which, however, happens along an ene-carbonyl

unit to an oxygen terminus, we are aware of only the few

examples detected by Uda and co-workers during studies

on the photochemistry of phenyl-substituted oxepinones

and cyclohepta-1,3-dienones.^[32]As in our case, all these

transformations take place from the excited triplet state.

Scheme 7.

The acetone-sensitized photolysis of 10 produced quite

different results. With the exception of the lowest homol-

ogue, 10a, which gave no specific products, the dihy-

droazepinones were transformed upon irradiation (ca.

10^–3m in acetone; λ Ͼ 270 nm; b: 2 h, c: 1 h, d: 0.5 h) into

the isomeric compounds 25b–d in 42, 60 and 62% yields

(Scheme 8). Among the new products, 25c was thermally

labile and rearranged even at room temperature by a 1,5-

hydrogen shift to the isomer 26c which has the double

bonds in the same position as the starting compounds. The

Synthesis and Transformation of Pyrroline N-Oxide

Systems^[33]

structures of the photoproducts are clearly supported by

In order to broaden the scope of the above reaction prin-

1

the spectroscopic data. For example, in the H NMR spec- ciple, the synthesis of pyrrolidino-annulated azepinones

tra of 25b and 25d, the AB pattern of the olefinic protons from the pyrroline N-oxides 34–36 was investigated.^[34]The

at C-4 and C-5 with a coupling constant of J_4,5= 12.2 Hz required dipolar precursors were prepared by following a

and the singlet signals of the benzylic 1-H (4.72/4.92 ppm) procedure which was recently developed for the synthesis of

are convincing evidence for the particular functionalities of 13-azasteroid analogues (see Scheme 9).^[35]Thus, Grignard

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Dipolar Route to Azepinone Derivatives by Heterocyclization of Enallenyl Nitrones

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Scheme 9. Reagents and conditions: (i) vinylmagnesium bromide, THF; (ii) IBX, DMSO, room temp.; (iii) RCH₂NO₂, iPr₂NH, CHCl₃;

(iv) Fe, HCl, EtOH, reflux.

reaction of the aldehydes 8a,b and 28 with vinylmagnesium

bromide gave the allylic alcohols 29a–c (69–90%) and, after

oxidation with IBX (o-iodoxybenzoic acid), the vinyl

ketones 30a–c (ca. 90%). Subsequent Michael addition with

nitromethane, nitroethane, and phenylnitromethane, respec-

tively, afforded the compounds 31a–c, 32c, and 33c (58–

91%), which were transformed into the pyrroline N-oxides

Scheme 10.

34a–c, 35c, and 36c (36–80%) by reductive cyclization with

Fe/HCl, according to a protocol of Black and Strauch.^[36]

The cyclization experiments were typically carried out by

refluxing solutions of the nitrones 34–36 in toluene with atom in the δ position to the dienamide unit. These assign-

potassium hydroxide as base and catalytic amounts of tetra- ments are unambiguously supported by the crystal struc-

n-butylammonium iodide (TBAI) to enhance the propargyl- ture analysis^[37]of 37 which also confirmed the cis arrange-

allene isomerization process (procedure A) or, in some ment of the methyl and phenyl groups (Figure 1).

cases, by stirring methanolic solutions of the nitrones at

room temperature with sodium methoxide as the base (pro- 34b was refluxed in toluene with KOH/TBAI for 1 h to give

cedure B). a mixture of the two diastereomers 39 and 40 in 40 and

In a similar manner, the cyclohexeno-annulated nitrone

The cyclopenteno-annulated nitrone system 34a was re- 16% yield, respectively (Scheme 11). The structural assign-

fluxed in toluene according to procedure (A). After com- ment of the major component to the cis component 39,

plete conversion (1 h, TLC) and work up, a 4:7 mixture of obtained as a colorless solid after flash chromatography of

two products was obtained in 85% yield which could not the reaction mixture and subsequent crystallization of the

be separated by chromatography. However, crystallization main fraction from ethanol, was mainly based on the al-

1

of an ethanolic solution of the mixture gave the major com- most identical H NMR pattern of the 3-H, 6-H, and 7-H

pound in the pure form. According to the analytical data protons of the pyrrolidine-azepinone part of the molecule

the product was identified as an isomer of the starting com- to that of the cyclopenteno derivative 37. In contrast, the

pound 34a, namely, the two-fold annulated dihydroazepi- signals of 6-H and 7-H of 40 are shifted upfield by 0.85 and

none 37. The second product turned out to possess the iso- 0.24 ppm, respectively.

meric structure 38 with the 3-methyl and 6-phenyl groups

in a trans position (Scheme 10).

After the reaction of 34b with sodium methoxide in

methanol for 5 h at room temperature, a mixture of three

The identification of the products was mainly based on compounds was obtained after work up. Besides the 6,7,5-

spectroscopic information, especially the ¹H and ¹³C NMR ring systems 39 and 40, the isomeric 6,5,5-product 41 was

data. In the case of 37, the strong IR absorption at isolated (Scheme 11). The formation of this type of com-

1667 cm^–1and the ¹³C NMR signal at δ = 163 ppm indicate pound was recently observed in an analogous heterocycliz-

the presence of the lactam moiety. Further support for the ation reaction.^[7]Important structural indications are the

1

structure comes from the H NMR signals at δ = 3.48 and ¹H NMR signals of the proton at C-3Ј (m, δ = 5.00 ppm,

5.28 ppm which have been assigned to the protons at C-6 J_3Ј,CH3= 6.5 Hz), the benzylic methylene protons at C-2 (s,

and C-7 (J = 5.2 Hz). The relatively high-field absorption δ = 3.98 ppm), and, in addition, the ¹³C signal at δ =

of the olefinic 7-H is characteristic of an olefinic hydrogen 185 ppm as well as the 1619 cm^–1IR absorption of the keto

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K. Knobloch, J. Koch, M. Keller, W. Eberbach

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form, whereas 42 had to be analyzed as a crystalline mix-

ture with 43.

Figure 1. ORTEP plot of the crystal structure of the bis-annulated

dihydroazepinone 37 (hydrogen atoms omitted for clarity; the num-

bering does not correspond to the correct nomenclature); selected

bond lengths [Å] and torsion angles [°]: C1–C2 1.531, C1–O1 1.223,

C2–C3 1.515, C3–C4 1.341, C4–C5 1.513, C4–C8 1.456, C8–C7

1.520, C8–C9 1.353, C9–N1 1.408, C9–C10 1.508, C12–N1 1.484,

C1–N1 1.371; N1–C1–C2–C3 74.0, C1–C2–C3–C4 –70.4, C2–C3–

C4–C8 6.0, C3–C4–C8–C9 33.2, C4–C8–C9–N1 –1.4, C8–C9–N1–

C1 –26.7.

Scheme 12.

Although much structural information was obtained for

the dihydroazepinones 42 and 43, including the relative ste-

reochemistry at C-3 and C-11b, from inspection of their

NMR spectra, crystallographic analysis of 43 confirmed its

structure and the cis geometry of the methyl group and the

11b-H proton (Figure 2).

With the pyrroline N-oxides 35c and 36c it was shown

that a methyl group in the αЈ-position to the ring nitrogen

of the nitrone systems is not mandatory. Reaction of 35c

according to procedure A resulted in the formation of the

dihydroazepinone 45 (R = H); again, an isoindole (46) was

identified after treatment of a methanolic solution of 35c

with sodium methoxide at room temperature. In contrast,

the reaction of the phenyl-substituted nitrone 36c gave a

3:4 mixture of the 6,7,5-ring isomers 47 and 48 as the only

products under both conditions. It is no surprise that in

Scheme 11.

group. Hence, the compound does not contain an amide the case of the benzo-annulated nitrones (unlike the alkeno-

function. annulated systems, see Schemes 3 and 10) the isolated het-

The base-catalyzed transformation of the benzo-annu- erocycles are those which are formed by a final hydrogen

lated nitrone derivative 34c proceeded in the same general shift, that is, after reestablishment of the aromaticity of the

way generating the corresponding tricyclic heterocycles 42 six-membered rings.

and 43 (Scheme 12) upon application of procedure A, and,

The stereochemical assignment of structure 47 to the

additionally, the isoindole 44 after reacting 34c under con- minor component, isolated as colorless crystals, with trans

ditions B; in both cases overall yields of about 80% were geometry of the phenyl group at C-3 and the 11b-H atom

obtained. Attempts were made to separate the products by was tentatively derived from the fact that 3-H (δ =

flash chromatography and crystallization, however, only 43 5.21 ppm) is coupled with both vicinal protons 2α-H and

(as crystals) and 44 (as an oil) were obtained in their pure 2β-H (J = 7.5 Hz) and not with only one hydrogen as in

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Dipolar Route to Azepinone Derivatives by Heterocyclization of Enallenyl Nitrones

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indole derivatives 41, 44, and 46 (general structure M,

Scheme 13) lends further support to a cyclopropanone of

structure H as a key intermediate within the proposed reac-

tion cascade. Besides the rearrangement of H to a dihy-

droazepinone I by cleavage of bond a, the alternative open-

ing of bond b would lead to an oxallyl species J which, after

nucleophilic attack of the imine nitrogen with formation of

the isomeric dipole K, produces the isoindole M by simple

tautomerization.

Synthesis of Astrocasine Analogue 52

The structure and absolute configuration of the alkaloid

astrocasine (53, Scheme 14), isolated from Astrocasia phyl-

lantoides,^[19]was determined by Silverton and co-workers

by crystallography.^[38]The main part of the molecule con-

Figure 2. ORTEP plot of the crystal structure of the dihydrobenzo-

azepinone 43 (hydrogen atoms omitted for clarity; the numbering

does not correspond to the correct nomenclature); selected bond

lengths [Å] and torsion angles [°]: C2–N1 1.4825, C4–C5 1.5246,

C5–N1 1.4772, C5–C6 1.5222, C6–C11 1.4097, C11–C12 1.4733,

C12–C13 1.3462, C13–C14 1.5134, C14–N1 1.3454, C14–O1

1.2350; N1–C14–C13–C12 –59.16, C14–C13–C12–C11 9.98, C13–

C12–C11–C6 40.74, C12–C11–C6–C5 –2.14, C11–C6–C5–N1 –

66.61, C6–C5–N1–C14 63.52, C5–N1–C14–C13 14.66.

case of the major compound 48 (δ_3-H= 5.37 ppm, J =

7.9 Hz) and the related product 43 with clearly proven ste-

reochemistry. The structure of 47 was later unambiguously

confirmed by crystallography.^[37]

Mechanistically, the formation of the new bis-annulated

dihydroazepinones of type I (Scheme 13) can be explained

by the same general route as sketched in Scheme 5 for the

Scheme 14. Reagents and conditions: (i) BrMg(CH₂)₄Cl, THF,

–40 °C; (ii) IBX, DMSO, room temp.; (iii) NH₂OH·HCl, K₂CO₃,

transformation AǞF. The additional occurrence of the iso- EtOH/H₂O, reflux; (iv) KOH, TBAI, toluene, reflux.

Scheme 13.

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K. Knobloch, J. Koch, M. Keller, W. Eberbach

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room temperature, and then treated with dry triethylamine

(1.1 equiv.). After completion of the reaction (TLC) the red-brown

mixture was filtered and the solution was concentrated in vacuo.

The crude material was purified by flash chromatography on silica

gel.

sists of a benzopiperidinoazepin-3-one system with 6,7,6-

ring annulation, which is homologous to the 6,7,5-systems

42, 43, 45, 47, and 48 described above, and the question

arose as to whether the former system would be available

by the same general route. Therefore preliminary studies

toward the preparation of the azepinone derivative 52, en-

visaged as a model of the naturally occurring compound

53, were made.

2-(3Ј-Phenylprop-1Ј-ynyl)cyclopent-1-ene-1-carbaldehyde

(8a):

Treatment of 7a (880 mg, 5.03 mmol, 4.5 h) according to the gene-

ral procedure, and subsequent purification (cyclohexane/ethyl ace-

tate, 60:1), gave 8a (1.04 g, 98%) as a dark-yellow oil. IR (CCl ): ν

˜

4

The synthesis of the dipolar precursor 51 is shown in

Scheme 14. Grignard reaction of 28 with 4-chlorobutylmag-

nesium bromide, prepared in situ from 4-chlorobutyl bro-

mide and magnesium in THF, afforded the alcohol 49,^[39]

which was transformed into the corresponding ketone 50

by oxidation with IBX. In a variation of the dipole-forming

step, 50 was treated according to a procedure of Brandman

and Conley^[40]with hydroxylamine hydrochloride and po-

tassium carbonate in a 1:1 mixture of ethanol and water to

give the required nitrone 51 in 42% yield. Further transfor-

mation of 51 was accomplished under our standard condi-

tions with potassium hydroxide and TBAI in refluxing tolu-

ene to deliver the desired benzopiperidinoazepinone 52 as

a crystalline compound (52%).

= 3030, 2960, 2820, 2215 (CϵC), 1675 (C=O), 1600 (C=C), 1495,

1

1455, 1355, 1250, 1225, 1030 cm^–1. H NMR (250 MHz): δ = 1.95

3

(dddd, J_{4,3a/3b/5a/5b}= 7.6 Hz, 2 H, 4-H), 2.61 (m_c, 2 H, 3-/5-H),

2.72 (m_c, 2 H, 3-/5-H), 7.27–7.36 (m, 5 H, Ar-H), 10.07 (s, 1 H,

CHO) ppm. ¹³C NMR (100 MHz): δ = 22.1 (C-4), 22.2/29.5 (C-3/-

5), 39.2 (C-3Ј), 76.9 (C-1Ј), 100.0 (C-2Ј), 127.0 (C-Ar), 127.9 (C-

Ar), 128.8 (C-Ar), 135.8 (C-1ЈЈ), 143.9/147.7 (C-1/-2), 189.0

(CHO) ppm. MS (EI, 70 eV): m/z (%) = 210 (91) [M]⁺, 209 (100),

181 (15) [M – CHO]⁺, 165 (29), 153 (25), 115 (16), 91 (11)

[CH₂Ph]⁺, 77 (11) [C₆H₅]⁺. HRMS (C₁₅H₁₄O): calcd. 210.1045;

found 210.1045.

2-(3Ј-Phenylprop-1Ј-ynyl)cyclohex-1-ene-1-carbaldehyde (8b): Treat-

ment of 7b (2.00 g, 10.6 mmol, 4 h) according to the general pro-

cedure, and subsequent purification (cyclohexane/ethyl acetate,

60:1), gave 8b (3.31 g, 97%) as a pale-red oil. IR (CCl ): ν = 3065,

˜

4

3030, 2940, 2865, 2215 (CϵC), 1675 (C=O), 1605 (C=C), 1495,

1455, 1365, 1275, 1230, 1170 cm^–1. H NMR (250 MHz): δ = 1.65

1

Conclusions

(m_c, 4 H, 4-H, 5-H), 2.20–2.29 (m, 2 H, 3-/6-H), 2.38–2.47 (m, 2

H, 3-/6-H), 3.82 (s, 2 H, 3Ј-H), 7.21–7.35 (m, 5 H, Ar-H), 10.21 (s,

1 H, CHO) ppm. ¹³C NMR (100 MHz): δ = 21.2 (C-4/-5), 21.9 (C-

4/-5), 22.0/26.1 (C-3/-6), 32.7 (C-3Ј), 79.9 (C-1Ј), 97.6 (C-2Ј), 126.9

(C-Ar), 127.9 (C-Ar), 128.8 (C-Ar), 136.1 (C_q), 140.6 (C_q), 142.4

(C_q), 193.1 (CHO) ppm. MS (EI, 70 eV): m/z (%) = 224 (82) [M]⁺,

209 (100), 195 (76) [M – CHO]⁺, 181 (49), 167 (73), 163 (43), 153

(41).

The synthetic scope and generality of the recently discov-

ered multistep transformation of benzopentenynyl nitrones

into 1,2-dihydrobenz[c]azepin-3-ones has been extended to

structurally different systems including monocyclic and alk-

eno-annulated systems as well as to dihydrobenzazepinones

with an additional annulation in the 1,2-position. The ap-

plicability of this methodology was further demonstrated

by the preparation of a piperidino derivative of the latter

series, which can be used as a model compound of the alka-

loid astrocasine. Despite the complexity of the overall reac-

tion sequence the transformations take place in mostly

good yields and under unusually mild conditions at room

temperature, albeit boiling toluene is preferable in the syn-

2-(3Ј-Phenylprop-1Ј-ynyl)cyclohept-1-ene-1-carbaldehyde

(8c):

Treatment of 7c (2.21 g, 10.9 mmol, 9 h) according to the general

procedure, and subsequent purification (cyclohexane/ethyl acetate,

60:1), gave 8c (2.30 g, 89%) as a dark-yellow oil. IR (CCl ): ν =

˜

4

2925, 2855, 2205 (CϵC), 1675 (C=O), 1595, 1495, 1455, 1255,

1

1180, 950 cm^–1. H NMR (250 MHz): δ = 1.53–1.71 (m, 4 H, 4-/

5-/6-H), 1.74–1.87 (m, 2 H, 4-/5-/6-H), 2.49 (m_c, 2 H, 3-/7-H), 2.62

thesis of the tricyclic heterocycles. Photochemical studies of (m_c, 2 H, 3-/7-H), 3.85 (s, 2 H, 3Ј-H), 7.19–7.36 (m, 5 H, Ar-H),

10.17 (s, 1 H, CHO) ppm. ¹³C NMR (100 MHz): δ = 24.1/25.7/25.8

(C-4/-5/-6), 26.3/32.2 (C-3/-7), 37.8 (C-3Ј), 81.3 (C-1Ј), 99.4 (C-2Ј),

some azepinone derivatives revealed, among other results,

examples of hitherto rarely observed 1,5-phenyl migration

126.9 (C-Ar), 127.9 (C-Ar), 128.8 (C-Ar), 126.1 (C_q-Ar), 146.4

processes.

(C_q), 148.1 (C_q), 192.5 (CHO) ppm. MS (EI, 70 eV): m/z (%) = 238

(13) [M]⁺, 163 (57), 105 (51), 91 (100) [CH₂Ph]⁺, 77 (45) [C₆H₅]⁺.

2-(3Ј-Phenylprop-1Ј-ynyl)cyclooct-1-ene-1-carbaldehyde (8d): Treat-

ment of 7d (1.30 g, 6.00 mmol, 5 h) according to the general pro-

cedure, and subsequent purification (cyclohexane/ethyl acetate,

Experimental Section

General: Melting points are uncorrected. IR: Perkin–Elmer 257 In-

fracord spectrometer. ¹H NMR: Bruker WM 250 (250 MHz), WM

100:1), gave 8d (1.41 g, 94%) as a dark-yellow oil. IR (CCl ): ν =

˜

4

400 (400 MHz), and DRX 500 (500 MHz) spectrometers. ¹³C

NMR: Bruker WM 400 (100 MHz) and DRX 500 (125 MHz) spec-

trometers. CDCl₃as solvent and TMS as internal standard. MS:

Finnigan MAT 44 S spectrometer (70 eV) with Datasystem MAT

SS 200. Elemental analyses: Perkin–Elmer Elemental Analyzer 240.

Flash chromatography: silica gel (silica 32–36, ICN Biomedicals).

TLC: SiO₂60 F-254, 0.2 mm (Merck).

3030, 2930, 2855, 2215 (CϵC), 1675 (C=O), 1595, 1495, 1455,

1

1300, 1215, 1030 cm^–1. H NMR (250 MHz): δ = 1.42–1.59 (m, 4

H, 5-H, 6-H), 1.72–1.84 (m, 4 H, 4-H, 7-H), 2.45 (m_c, 2 H, 3-/8-

H), 2.59 (m_c, 2 H, 3-/8-H), 7.23–7.36 (m, 5 H, Ar-H), 10.22 (s, 1

H, CHO) ppm. ¹³C NMR (100 MHz): δ = 23.5/26.0/26.2/26.6 (C-

4/-5/-6/-7), 28.9/29.9 (C-3/-8), 34.4 (C-3Ј), 80.4 (C-1Ј), 98.1 (C-2Ј),

126.9 (C-Ar), 127.9 (C-Ar), 128.8 (C-Ar), 136.1 (C-1ЈЈ), 143.6/145.7

(C-1/-2), 192.8 (CHO) ppm. MS (EI, 70 eV): m/z (%) = 252 (30)

[M]⁺, 251 (38), 237 (100), 223 (23) [M – CHO]⁺, 209 (89), 181 (47),

165 (51), 141 (38), 115 (50), 91 (81) [CH₂Ph]⁺. HRMS (C₁₈H₂₀O):

calcd. 252.1514; found 252.1515.

General Procedure for the Sonogashira Reaction of the Bromo Alde-

hydes 7 with 3-Phenylprop-1-yne: A degassed (argon) 0.2 m solution

of 7 in dry benzene was stirred with PdCl₂(PPh₃)₂(5 mol%), CuI

(0.05–0.1 mol%) and 3-phenylprop-1-yne (1.5 equiv.) for 15 min at

2722

www.eurjoc.org

Eur. J. Org. Chem. 2005, 2715–2733

Dipolar Route to Azepinone Derivatives by Heterocyclization of Enallenyl Nitrones

FULL PAPER

General Procedure for Formation of the Nitrones 9: Sodium acetate

(3 equiv.) and, after 15 min, the aldehyde 8 (1 equiv.) were added

to a stirred suspension of N-methylhydroxylamine hydrochloride

(0.25 m, 1.3 equiv.) in dry CH₂Cl₂at room temperature. After com-

pletion of the reaction (TLC), the mixture was hydrolyzed with

water and extracted 2–3 times with CH₂Cl₂. The combined organic

phases were washed with brine, dried (MgSO₄), and concentrated

in vacuo. The crude material was purified by flash chromatography

on silica gel.

2.92 (m_c, 2 H, 8Ј-H), 3.67 (s, 3 H, NCH₃), 3.82 (s, 2 H, 3ЈЈ-H),

7.23–7.37 (m, 5 H, Ar-H), 7.55 (s, 1 H, 1-H) ppm. ¹³C NMR

(125 MHz): δ = 25.3/26.0/26.2/26.5 (C-4Ј/-5Ј/-6Ј/-7Ј), 28.9/30.2 (C-

3Ј/-8Ј), 32.7 (C-3ЈЈ), 54.5 (NCH₃), 82.8 (C-1ЈЈ), 96.0 (C-2ЈЈ), 126.8

(C-Ar), 127.8 (C-Ar), 128.6 (C-Ar), 129.2 (C_q-Ar), 136.8 (C_q),

136.9 (C-1), 138.9 (C_q) ppm. MS (EI, 70 eV): m/z (%) = 281 (39)

[M]⁺, 238 (17), 224 (21), 190 (100) [M – CH₂Ph]⁺, 162 (30), 115

(36), 91 (70) [CH₂Ph]⁺, 77 (19) [C₆H₅]⁺, 42 (59). HRMS

(C₁₉H₂₃NO): calcd. 281.1780; found 281.1780.

Methyl{[2Ј-(3ЈЈ-phenylprop-1ЈЈ-ynyl)cyclopent-1Ј-en-1Ј-yl]methyl- General Procedure for the Base-Catalyzed Transformation of the

ene}amine N-Oxide (9a): Treatment of 8a (710 mg, 3.38 mmol, 6 h) Nitrones 9 into 10: A 0.1 m solution of the nitrone 9 in dry methanol

according to the general procedure, and subsequent purification

(cyclohexane/ethyl acetate, 2:1), gave 9a (700 mg, 88%) as beige

was treated with base (0.5 equiv.) and stirred at room temperature

until completion of the reaction (TLC). The mixture was hy-

drolyzed with water and extracted with CH₂Cl₂. The combined or-

crystals, m.p. 63 °C (ethanol). IR (CCl ): ν = 3025, 2945, 2845,

˜

4

1

1550, 1495, 1415, 1295, 1165 cm^–1. H NMR (250 MHz): δ = 1.92 ganic phases were washed with saturated aqueous NH₄Cl and with

(m_c, 2 H, 4Ј-H), 2.51 (t, ³J_3Ј,4Ј= 7.6 Hz, 2 H, 3Ј-H), 3.16 (m_c, 2 H, brine, dried (MgSO₄), and concentrated in vacuo. The residue was

5Ј-H), 3.70 (s, 3 H, NCH₃), 3.84 (s, 2 H, 3ЈЈ-H), 7.21–7.38 (m, 6 purified by flash chromatography on silica gel.

H, Ar-H, 1-H) ppm. ¹³C NMR (100 MHz): δ = 23.2 (C-4Ј), 26.3/

2-Methyl-4-phenyl-4,6,7,8-tetrahydrocyclopenta[c]azepin-3(2H)-one

33.7 (C-3Ј/-5Ј), 36.8 (C-3ЈЈ), 53.7 (NCH₃), 78.6 (C-1ЈЈ), 98.2 (C-

(10a): Treatment of 9a (155 mg, 0.65 mmol, KOH, 1.5 h) according

2ЈЈ), 126.9 (C-Ar), 127.9 (C-Ar), 128.7 (C-Ar), 129.9 (C_q-Ar), 133.1

to the general procedure, and subsequent purification (cyclohexane/

(C-1), 136.5/140.8 (C-1Ј/-2Ј) ppm. MS (EI, 70 eV): m/z (%) = 239

ethyl acetate, 3:1), gave 10a (123 mg, 79%) as a colorless solid, m.p.

(18) [M]⁺, 148 (66), 120 (32), 103 (23), 91 (43) [CH₂Ph]⁺, 77 (38)

167–168 °C (ethanol). IR (CCl ): ν = 3025, 2960, 2850, 1670

˜

4

[C₆H₅]⁺, 51 (29), 42 (100). HRMS (C₁₆H₁₇NO): calcd. 239.1310;

found 239.1311. C₁₆H₁₇NO (239.3): calcd. C 80.30, H 7.16, N 5.85;

found C 79.78, H 7.31, N 5.80.

(C=O), 1375, 1260, 1220, 1100 cm^–1. ¹H NMR (250 MHz): δ = 1.86

(m_c, 2 H, 7-H), 2.42–2.63 (m, 4 H, 6-H, 8-H), 3.18 (s, 3 H, NCH₃),

3

3.74 (md, J_4,5= 5.5 Hz, 1 H, 4-H), 5.48 (md, J_5,4= 5.5 Hz, 1 H,

Methyl{[2Ј-(3ЈЈ-phenylprop-1ЈЈ-ynyl)cyclohex-1Ј-en-1Ј-yl]methyl- 5-H), 6.11 (s, 1 H, 1-H), 7.23–7.39 (m, 5 H, Ar-H) ppm. ¹³C NMR

ene}amine N-Oxide (9b): Treatment of 8b (4.55 g, 20.3 mmol, 22 h) (125 MHz): δ = 24.7 (C-7), 31.0/31.1 (C-6/-8), 37.0 (NCH₃), 52.9

according to the general procedure, and subsequent purification

(C-4), 118.5/124.3 (C-5/-4Ј), 127.0 (C-1), 128.2 (C-Ar), 129.3 (C-

(cyclohexane/ethyl acetate, 2:1, 1:2), gave 9b (3.73 g, 72%) as a col-

Ar), 130.7 (C_q), 138.7/143.3 (C-5a/-8a), 164.9 (C-3) ppm. UV

orless oil. IR (CCl ): ν = 3030, 2940, 2860, 1535, 1495, 1450, 1420, (CH₃CN): λ_max= 287 nm (ε = 4900 dm³mol^–1cm^–1). MS (EI,

˜

4

1245, 1175, 1160 cm^–1. ¹H NMR (250 MHz): δ = 1.62 (m_c, 4 H, 4Ј-

70 eV): m/z (%) = 239 (100) [M]⁺, 238 (54), 210 (18) [M – NCH₃]

H, 5Ј-H), 2.31 (br. s, 2 H, 3Ј-H), 2.88 (br. s, 2 H, 6Ј-H), 3.66 (s, 3 ⁺, 182 (10) [M – CONCH₃]⁺, 134 (42), 77 (9) [C₆H₅]⁺. C₁₆H₁₇NO

H, NCH₃), 3.81 (s, 2 H, 3ЈЈ-H), 7.22–7.37 (m, 5 H, Ar-H), 7.51 (s,

(239.32): calcd. C 80.30, H 7.16, N 5.85; found C 79.95, H 7.36, N

1 H, 1-H) ppm. ¹³C NMR (100 MHz): δ = 21.7/22.1 (C-4Ј/-5Ј), 5.80.

26.2/26.6 (C-3Ј/-6Ј), 31.6 (C-3ЈЈ), 54.3 (NCH₃), 82.2 (C-1ЈЈ), 95.8

2-Methyl-4-phenyl-2,4,6,7,8,9-hexahydro-3H-2-benzazepin-3-one

(C-2ЈЈ), 125.3 (C_q), 126.9 (C-Ar), 127.9 (C-Ar), 128.7 (C-Ar), 136.4

(C_q), 138.7 (C-1), 138.8 (C_q) ppm. MS (EI, 70 eV): m/z (%) = 253

(46) [M]⁺, 234 (29), 224 (13), 162 (100) [M – CH₂Ph]⁺, 134 (23),

115 (22), 91 (24) [CH₂Ph]⁺, 42 (25). HRMS (C₁₇H₁₉NO): calcd.

253.1467; found 253.1465.

(10b): Treatment of 9b (100 mg, 0.39 mmol, KOH, 3 h) according

to the general procedure, and subsequent purification (cyclohexane/

ethyl acetate, 30:1), gave 10b (88 mg, 88%) as a colorless solid, m.p.

94–95 °C (ethanol). IR (CCl ): ν = 2935, 2860, 1675 (C=O), 1600

˜

4

(C=C), 1445, 1380, 1260, 1220, 1085 cm^–1. ¹H NMR (250 MHz): δ

Methyl{[2Ј-(3ЈЈ-phenylprop-1ЈЈ-ynyl)cyclohept-1Ј-en-1Ј-yl]methyl- = 1.47–1.71 (m, 2 H, 7-/8-H), 1.79–1.96 (m, 2 H, 7-/8-H), 2.18–

ene}amine N-Oxide (9c): Treatment of 8c (500 mg, 2.00 mmol, 7 h)

according to the general procedure, and subsequent purification

(cyclohexane/ethyl acetate, 2:1, 1:2), gave 9c (300 mg, 57%) as a

2.44 (m, 4 H, 6-H, 9-H), 3.13 (s, 3 H, NCH₃), 3.74 (br. s, 1 H, 4-

H), 5.45 (d, ³J_5,4= 6.1 Hz, 1 H, 5-H), 6.01 (s, 1 H, 1-H), 7.23–7.40

(m, 5 H, Ar-H) ppm. ¹³C NMR (125 MHz): δ = 25.9/26.0 (C-7/-8),

31.6/32.1 (C-6/-9), 35.7 (NCH₃), 51.4 (C-4), 123.6 (C-5), 126.0 (C-

Ar), 126.9 (C-Ar), 127.6 (C_q), 128.2 (C-Ar), 129.4 (C-1), 137.2 (C_q),

138.4 (C_q), 167.4 (C-3) ppm. UV (CH₃CN): λ_max= 258 nm (ε =

dark-yellow oil. IR (CCl ): ν = 3025, 2925, 2850, 1550, 1495, 1450,

˜

4

1

1415, 1165, 1130 cm^–1. H NMR (250 MHz): δ = 1.52–1.64 (m, 4

H, 4Ј-/5Ј-/6Ј-H), 1.73–1.84 (m, 2 H, 4Ј-/5Ј-/6Ј-H), 2.49 (m_c, 2 H, 3Ј-

H), 2.97 (m_c, 2 H, 7Ј-H), 3.66 (s, 3 H, NCH₃), 3.81 (s, 2 H, 3ЈЈ- 5090 dm³mol^–1cm^–1). MS (EI, 70 eV): m/z (%) = 253 (100) [M]⁺,

H), 7.22–7.37 (m, 5 H, Ar-H), 7.42 (s, 1 H, 1-H) ppm. ¹³C NMR

224 (25) [(M – NCH₃) + 1]⁺, 196 (23) [(M – CONCH₃) + 1]⁺, 176

(18) [M – C₆H₅]⁺, 148 (40), 115 (27), 77 (16) [C₆H₅]⁺. C₁₇H₁₉NO

(100 MHz): δ = 26.1/26.2/26.3 (C-4Ј/-5Ј/-6Ј), 27.4/32.4 (C-3Ј/-7Ј),

35.6 (C-3ЈЈ), 54.1 (NCH₃), 83.5 (C-1ЈЈ), 97.1 (C-2ЈЈ), 126.8 (C-Ar), (253.34): calcd. C 80.60, H 7.56, N 5.53; found C 80.15, H 7.62, N

127.9 (C-Ar), 128.7 (C-Ar), 132.4 (C_q), 136.9 (C_q), 137.3 (C-1),

142.2 (C_q) ppm. MS (EI, 70 eV): m/z (%) = 267 (10) [M]⁺, 176 (68)

[M – CH₂Ph]⁺, 91 (67) [CH₂Ph]⁺, 77 (26) [C₆H₅]⁺, 65 (27), 57 (27),

42 (100). HRMS (C₁₈H₂₁NO): calcd. 267.1623; found 267.1625.

5.43.

2-Methyl-4-phenyl-4,6,7,8,9,10-hexahydrocyclohepta[c]azepin-

3(2H)-one (10c): Treatment of 9c (105 mg, 0.39 mmol, KOH, 1.5 h)

according to the general procedure, after purification (cyclohexane/

Methyl{[2Ј-(3ЈЈ-phenylprop-1ЈЈ-ynyl)cyclooct-1Ј-en-1Ј-yl]methylene}- ethyl acetate, 2:1) gave 10c (48 mg, 46%) as a colorless solid, m.p.

amine N-Oxide (9d): Treatment of 8d (550 mg, 2.58 mmol, 22 h)

according to the general procedure, and subsequent purification

(cyclohexane/ethyl acetate, 2:1), gave 9d (501 mg, 82%) as a yellow

128–129 °C (ethanol). IR (CCl ): ν = 2925, 2850, 1675 (C=O),

˜

4

1585, 1495, 1455, 1380, 1260, 1115, 1085 cm^–1. ¹H NMR

(250 MHz): δ = 1.47–1.74 (m, 6 H, 7-H, 8-H, 9-H), 2.28–2.51 (m,

3

oil. IR (CCl ): ν = 3025, 2925, 2855, 1550, 1450, 1225, 1165,

4 H, 6-H, 10-H), 3.13 (s, 3 H, NCH₃), 3.56 (d, J_4,5= 6.1 Hz, 1 H,

˜

4

1030 cm^–1. ¹H NMR (250 MHz): δ = 1.40–1.55 (m, 4 H, 4Ј-/5Ј-/6Ј-/ 4-H), 5.53 (d, J_5,4= 6.1 Hz, 1 H, 5-H), 6.13 (s, 1 H, 1-H), 7.28–

7Ј-H), 1.59–1.80 (m, 4 H, 4Ј-/5Ј-/6Ј-/7Ј-H), 2.47 (m_c, 2 H, 3Ј-H), 7.41 (m, 5 H, Ar-H) ppm. ¹³C NMR (100 MHz): δ = 30.0/30.2/31.9

3

Eur. J. Org. Chem. 2005, 2715–2733

www.eurjoc.org

2723

K. Knobloch, J. Koch, M. Keller, W. Eberbach

FULL PAPER

(C-7/-8/-9), 35.2/35.7 (C-6/-10), 35.8 (NCH₃), 51.8 (C-4), 124.4/

toluene (50 mL) was refluxed for 2 h and then concentrated in

127.0 (C-5/-4Ј), 127.5 (C-1), 128.3 (C-Ar), 129.6 (C-Ar), 132.2 (C_q), vacuo. Separation of the isomers by flash chromatography (cyclo-

138.6 (C_q), 142.0 (C_q), 166.9 (C-3) ppm. UV (CH₃CN): λ_max

=

hexane/ethyl acetate, 10:1, 3:1) gave, besides 10d (212 mg, 71%),

266 nm (ε = 5500 dm³mol^–1cm^–1). MS (EI, 70 eV): m/z (%) = 267

11d (85 mg, 28%) as a colorless oil. IR (CCl ): ν = 2925, 2855,

˜

4

(100) [M]⁺, 252 (23) [M – CH₃]⁺, 238 (35) [M – NCH₃]⁺, 210 (11) 1640 (C=O), 1470, 1445, 1395, 1225, 1115, 1005 cm^–1. ¹H NMR

[M – CONCH₃]⁺, 176 (30). C₁₈H₂₁NO (267.37): calcd. C 80.88, H (250 MHz): δ = 1.43–1.76 (m, 8 H, 7-H, 8-H, 9-H, 10-H), 2.30–

7.71, N 5.13; found C 80.86, H 7.92, N 5.24.

2.47 (m, 4 H, 6-H, 11-H), 3.12 (s, 3 H, NCH₃), 3.74 (br. s, 2 H, 1-

H), 6.64 (s, 1 H, 5-H), 7.22–7.39 (m, 3 H, Ar-H), 7.52–7.60 (m, 2

H, Ar-H) ppm. ¹³C NMR (100 MHz): δ = 26.0/26.4/28.6/29.6/31.0/

32.7 (C-6/-7/-8/-9/-10/-11), 35.1 (NCH₃), 53.8 (C-1), 127.5 (C-Ar),

128.1 (C-Ar), 128.2 (C-Ar), 129.6 (C_q), 134.8 (C-5), 136.9 (C_q),

139.0 (C_q), 139.3 (C_q), 167.1 (C-3) ppm. MS (EI, 70 eV):

m/z (%) = 281 (100) [M]⁺, 252 (44) [M – NCH₃]⁺, 224 (37) [M –

CONCH₃]⁺, 190 (32), 91 (23), 42 (34). HRMS (C₁₉H₂₃NO): calcd.

281.1780; found 281.1780.

2-Methyl-4-phenyl-2,4,6,7,8,9,10,11-octahydro-3H-cycloocta[c]-

azepin-3-one (10d): Treatment of 9d (200 mg, 0.71 mmol, KOH,

1.5 h) according to the general procedure, and subsequent purifica-

tion (cyclohexane/ethyl acetate, 20:1), gave 10d (130 mg, 65%) as a

colorless solid, m.p. 121–123 °C (ethanol). IR (CCl ): ν = 2930,

˜

4

2855, 1675 (C=O), 1580, 1455, 1380, 1305, 1260, 1220, 1120,

1

1080 cm^–1. H NMR (250 MHz): δ = 1.14–1.51 (m, 3 H, 8-/9-H),

1.55–1.85 (m, 5 H, 7-/8-/9-/10-H), 2.15–2.29 (m, 2 H, 6-/11-H),

2.41–2.54 (m, 1 H, 6-/11-H), 2.57–2.72 (m, 1 H, 6-/11-H), 3.15 (s,

(Z)-3,6-Diphenylhex-2-en-4-ynal (13): A degassed and stirred solu-

tion of 12 (R¹= Ph) (1.60 g, 7.58 mmol) in dry benzene was treated

with PdCl₂(PPh₃)₂(260 mg, 0.37 mmol), CuI (ca. 10 mg), 3-phen-

ylprop-1-yne (1.15 g, 9.86 mmol) and, after 15 min, with dry trieth-

ylamine (849 mg, 8.34 mmol). The reaction mixture was stirred for

1.5 h under argon at room temperature. After filtration and concen-

tration of the solution in vacuo, purification of the reddish-brown

residue by flash chromatography (cyclohexane/ethyl acetate, 20:1)

3

3 H, NCH₃), 3.49 (d, J_4,5= 6.1 Hz, 1 H, 4-H), 5.53 (d, J_5,4

=

6.1 Hz, 1 H, 5-H), 6.15 (s, 1 H, 1-H), 7.26–7.42 (m, 5 H, Ar-

H) ppm. ¹³C NMR (100 MHz): δ = 25.1/25.7 (C-8/-9), 30.1/31.9

(C-7/-10), 33.1/33.2 (C-6/-11), 35.7 (NCH₃), 51.8 (C-4), 124.6/128.0

(C-5/-4Ј), 127.0 (C-Ar), 128.3 (C-Ar), 129.7 (C-1), 131.0 (C_q-Ar),

138.7 (C_q), 141.6 (C_q), 166.8 (C-3) ppm. UV (CH₃CN): λ_max

=

264 nm (ε = 3830 dm³mol^–1cm^–1). MS (EI, 70 eV): m/z (%) = 281

(100) [M]⁺, 266 (16) [M – CH₃]⁺, 252 (48) [M – NCH₃]⁺, 238 (30),

224 (36) [M – CONCH₃]⁺, 190 (34). C₁₉H₂₃NO (281.40): calcd. C

81.10, H 8.24, N 4.98; found C 80.96, H 8.42, N 4.89.

afforded 13 (668 mg, 36%) as a dark-yellow oil. IR (CCl ): ν =

˜

4

3065, 3030, 2830, 2225 (CϵC), 1675 (C=O), 1565, 1495, 1450,

1340, 1140 cm^–1. ¹H NMR (250 MHz): δ = 3.97 (s, 2 H, 6-H), 6.76

3

2-Methyl-4-phenyl-1,6,7,8-tetrahydrocyclopenta[c]azepin-3(2H)-one

(11a): A solution of 10a (330 mg, 1.38 mmol) in dry toluene

(70 mL) was refluxed for 2 h and then concentrated in vacuo. Sepa-

ration of the isomers by flash chromatography (cyclohexane/ethyl

acetate, 10:1, 3:1) gave, besides 10a (170 mg, 52%), 11a (145 mg,

(d, J_2,1= 7.9 Hz, 1 H, 2-H), 7.26–7.47 (m, 8 H, Ar-H), 7.75–7.81

(m, 2 H, Ar-H), 10.29 (d, ³J_1,2= 7.9 Hz, 1 H, 1-H) ppm. ¹³C NMR

(100 MHz): δ = 26.3 (C-2), 77.8 (C-4), 101.6 (C-5), 127.1 (C-Ar),

127.1 (C-Ar), 128.0 (C-Ar), 128.8 (C-Ar), 128.9 (C-Ar), 131.0 (C-

Ar), 131.5 (C-2), 135.5 (C_q-Ar), 136.0 (C_q-Ar), 142.9 (C-3), 193.4

(C-1) ppm. MS (EI, 70 eV): m/z (%) = 246 (66) [M]⁺, 245

(100), 217 (85) [M – CHO]⁺, 215 (85), 202 (96), 155 (87) [M –

CH₂Ph]⁺, 139 (33), 115 (42). HRMS (C₁₈H₁₄O): calcd. 246.1045;

found 246.1039.

44%) as colorless crystals, m.p. 109–110 °C (ethanol). IR (CCl ): ν

˜

4

=

2960, 2890, 2835, 1630 (C=O), 1440, 1395, 1225, 1160,

1065 cm^–1. ¹H NMR (500 MHz): δ = 2.01 (m_c, 2 H, 7-H), 2.52–

2.58 (m, 2 H, 6-/8-H), 2.61–2.67 (m, 2 H, 6-/8-H), 3.11 (s, 3 H,

NCH₃), 3.78 (s, 2 H, 1-H), 6.69 (s, 1 H, 5-H), 7.26 (m_c, 1 H, Ar-

H), 7.31–7.35 (m, 2 H, Ar-H), 7.52–7.56 (m, 2 H, Ar-H) ppm. ¹³C

NMR (125 MHz): δ = 23.4 (C-7), 34.3/36.2 (C-6/-8), 35.8 (NCH₃),

47.7 (C-1), 127.5 (C-Ar), 128.0 (C-Ar), 128.3 (C-Ar), 128.7 (C-Ar),

139.5 (C_q), 139.6 (C_q), 139.8 (C_q), 142.6 (C_q), 168.2 (C-3) ppm. MS

(EI, 70 eV): m/z (%) = 239 (100) [M]⁺, 210 (33) [M – NCH₃]⁺, 183

(54), 182 (17) [M – CONCH₃]⁺, 134 (29). C₁₆H₁₇NO (239.32):

calcd. C 80.30, H 7.16, N 5.85; found C 79.93, H 7.28, N 5.78.

Methyl{[(Z)-3,6-diphenylhex-2-en-4-ynyl]methylene}amine N-Oxide

(14): Treatment of 13 (668 mg, 2.71 mmol, 8 h) according to the

general procedure, and subsequent purification by flash chromatog-

raphy (cyclohexane/ethyl acetate, 1:2), gave 14 (643 mg, 86%) as a

yellow, viscous oil which was crystallized from ethanol, m.p. 101–

102 °C (ethanol; decomp.). IR (CCl ): ν = 3065, 3025, 2945, 2225

˜

4

(CϵC), 1535, 1495, 1410, 1340, 1170 cm^–1. H NMR (250 MHz):

1

δ = 3.76 (s, 3 H, NCH₃), 3.96 (s, 2 H, 6-H), 7.28–7.45 (m, 8 H, Ar-

2-Methyl-4-phenyl-1,2,6,7,8,9-hexahydro-3H-2-benzazepin-3-one

(11b): A solution of 10b (500 mg, 1.97 mmol) in dry toluene

(100 mL) was refluxed for 2 h and then concentrated in vacuo. Sep-

aration of the isomers by flash chromatography (cyclohexane/ethyl

acetate, 10:1, 3:1) gave, besides 10b (239 mg, 48%), 11b (251 mg,

3

H), 7.60 (d, J_2,1= 10.1 Hz, 1 H, 2-H), 7.70 (d, J_1,2= 10.1 Hz, 1

H, 1-H), 7.75–7.81 (m, 2 H, Ar-H) ppm. ¹³C NMR (125 MHz): δ

= 26.3 (C-6), 52.8 (NCH₃), 79.3 (C-4), 100.0 (C-5), 122.3 (C-Ar),

126.7 (C-Ar), 127.0 (C-Ar/-2), 127.9/128.6/128.8/129.2 (C-Ar/-2),

1 2 8 . 9 ( C_q) , 1 3 6 . 2 ( C_q), 136. 7 (C_q), 136. 9 (C-1) ppm.

MS (EI, 70 eV): m/z (%) = 275 (26) [M]⁺, 202 (26), 184 (100) [M –

50%) as a colorless oil. IR (CCl ): ν = 2935, 2860, 1635 (C=O),

˜

4

1

1440, 1395, 1220, 1145, 1000 cm^–1. H NMR (250 MHz): δ = 1.67

CH₂Ph]⁺115 (62), 91 (62) [CH₂Ph]⁺, 77 (25) [C₆H₅]⁺, 42 (41).

,

(m_c, 4 H, 7-H, 8-H), 2.20 (m_c, 2 H, 6-/9-H), 2.33 (m_c, 2 H, 6-/9-

H), 3.13 (s, 3 H, NCH₃), 3.65 (s, 2 H, 1-H), 6.57 (s, 1 H, 5-H), 7.25–

7.38 (m, 3 H, Ar-H), 7.52–7.58 (m, 2 H, Ar-H) ppm. ¹³C NMR

(100 MHz): δ = 22.3/22.5 (C-7/-8), 28.4/31.0 (C-6/-9), 35.4 (NCH₃),

53.6 (C-1), 127.5 (C-Ar), 128.1 (C-Ar), 128.2 (C-Ar), 133.5 (C_q),

134.2 (C-5), 136.3 (C_q), 138.5 (C_q), 139.3 (C_q), 167.5 (C-3) ppm.

MS (EI, 70 eV): m/z (%) = 253 (100) [M]⁺, 252 (44), 224 (46) [M –

NCH₃]⁺, 197 (20), 196 (54) [M – CONCH₃]⁺, 136 (49), 77 (22)

[C₆H₅]⁺. HRMS (C₁₇H₁₉NO): calcd. 253.1467; found 253.1470.

C₁₇H₁₉NO (253.34): calcd. C 80.60, H 7.56, N 5.53; found C 80.00,

H 7.46, N 5.37.

C₁₉H₁₇NO (275.35): calcd. C 82.88, H 6.22, N 5.09; found C 82.62,

H 5.95, N 4.86.

Methyl{[(Z)-3-methylhex-2-en-4-yn-2-yl]methylene}amine N-Oxide

(16): Treatment of 15^[24](423 mg, 3.91 mmol, 1.5 h) according to

the general procedure, and subsequent purification (cyclohexane/

ethyl acetate, 1:2, ethyl acetate/methanol, 10:1), gave 16 (486 mg,

90%) as a colorless solid, m.p. 95–97 °C (diethyl ether). IR (CCl₄):

ν = 2945, 2920, 1550, 1410, 1325, 1175, 1135, 1030 cm^–1. ¹H NMR

˜

(250 MHz): δ = 2.00 (s, 3 H, 6-H), 2.07 (s, 3 H, 3-CH₃), 3.73 (s, 3 H,

NCH₃), 6.86 (d, ³J_2,1= 9.8 Hz, 1 H, 2-H), 7.44 (d, ³J_1,2= 9.8 Hz, 1

2-Methyl-4-phenyl-1,2,6,7,8,9,10,11-octahydro-3H-cycloocta[c]- H, 1-H) ppm. ¹³C NMR (100 MHz): δ = 4.7 (C-6), 14.8 (3-CH₃),

azepin-3-one (11d): A solution of 10d (300 mg, 1.07 mmol) in dry

52.4 (NCH₃), 78.5 (C-4), 96.3 (C-5), 124.3 (C-2), 128.2 (C-3), 136.2

2724

www.eurjoc.org

Eur. J. Org. Chem. 2005, 2715–2733

Dipolar Route to Azepinone Derivatives by Heterocyclization of Enallenyl Nitrones

FULL PAPER

(C-1) ppm. MS (EI, 70 eV): m/z (%) = 137 (45) [M]⁺, 122 (100)

conditions (Solidex filter, 30 min), 17 (27 mg, 30 %), 20 (27 mg,

[M – CH₃]⁺, 77 (23), 53 (39), 51 (19), 42 (63). C₈H₁₁NO (137.18): 30%), and 21 (27 mg, 30%) were isolated.

calcd. C 70.04, H 8.08, N 10.21; found C 69.99, H 8.17, N 10.12.

Compound 20: Colorless solid, m.p. 172–174 °C (diethyl ether). IR

1-Methyl-3,5-diphenyl-1,3-dihydro-2H-azepin-2-one (17): Treatment

of 14 (100 mg, 0.36 mmol, NaOMe, 30 min) according to the gene-

ral procedure, and subsequent purification (cyclohexane/ethyl ace-

(CCl ): ν = 3060, 3025, 2925, 1700 (C=O), 1490, 1450, 1395, 1220,

˜

4

1175, 1095 cm^–1. ¹H NMR (400 MHz): δ = 3.06 (s, 3 H, NCH₃),

3

4.04 (d, J_4,5= 10.7 Hz, 1 H, 4-H), 4.17 (dd, J_5,4= 10.7, J_5,1

=

3

tate, 10:1), gave 17 (94 mg, 94%) as a yellow solid, m.p. 74–76 °C 4.3 Hz, 1 H, 5-H), 4.39 (d, J_1,5= 4.3 Hz, 1 H, 1-H), 6.76 (s, 1 H,

(diethyl ether). IR (CCl ): ν = 3060, 3035, 2925, 1680 (C=O), 1635, 7-H), 6.77–6.80 (m, 2 H, Ar-H), 6.93–7.06 (m, 8 H, Ar-H) ppm.

˜

4

1585, 1495, 1370, 1265, 1210, 1080 cm^–1. H NMR (250 MHz): δ

¹³C NMR (125 MHz): δ = 28.6 (NCH₃), 44.1 (C-5), 50.7 (C-1),

1

3

= 3.23 (s, 3 H, NCH₃), 3.80 (d, J_3,4= 6.3 Hz, 1 H, 3-H), 5.99 (d, 58.4 (C-4), 125.1 (C-Ar), 126.9 (C-Ar), 127.7 (C-Ar), 128.0 (C-Ar),

³J_4,3= 6.3 Hz, 1 H, 4-H), 6.17 (d, J_6,7= 8.9 Hz, 1 H, 6-H), 6.50

128.1 (C-Ar), 129.9 (C-Ar), 130.5 (C-7), 132.7 (C_q-Ar), 137.4 (C_q-

Ar), 152.1 (C-6), 174.8 (C-3) ppm. MS (EI, 70 eV): m/z (%) = 275

(88) [M]⁺, 274 (100), 204 (27), 202 (22), 196 (39), 170 (32), 144 (37).

3

(d, J_7,6= 8.9 Hz, 1 H, 7-H), 7.28–7.43 (m, 10 H, Ar-H) ppm. ¹³C

3

NMR (125 MHz): δ = 36.3 (C-3), 52.7 (NCH₃), 115.3/124.9/127.3/

127.9/132.6 (C-4/-6/-7/-Ar), 127.1 (C-Ar), 128.4 (C-Ar), 128.5 (C- HRMS (C₁₉H₁₇NO): calcd. 275.1304; found 275.1310.

Ar), 129.7 (C-Ar), 138.1 (C_q), 138.2 (C_q), 138.7 (C_q), 166.7 (C-

Compound 21: Amorphous solid. IR (CCl ): ν = 3060, 3025, 2925,

˜

4

2) ppm. MS (EI, 70 eV): m/z (%) = 275 (77) [M]⁺, 274 (100), 219

(23), 196 (38), 170 (44), 128 (14), 115 (21). HRMS (C₁₉H₁₇NO):

calcd. 275.1310; found 275.1310.

1695 (C=O), 1490, 1450, 1420, 1390, 1295, 1095 cm^–1. ¹H NMR

(400 MHz): δ = 3.01 (s, 3 H, NCH₃), 3.74 (br. s, 1 H, 4-H), 3.79

3

4

(ddd, J_5,1= 4.1, J_5,4= 2.7, J_5,7= 0.6 Hz, 1 H, 5-H), 4.51 (dd,

³J_1,5= 4.1, J_1,4= 1.5 Hz, 1 H, 1-H), 6.71 (d, J_7,5= 0.6 Hz, 1 H,

7-H), 7.26–7.30 (m, 3 H, Ar-H), 7.33–7.40 (m, 7 H, Ar-H) ppm.

¹³C NMR (125 MHz): δ = 28.6 (NCH₃), 46.3 (C-5), 50.9 (C-4),

125.5 (C-Ar), 127.2 (C-Ar), 127.8 (C-Ar), 128.9 (C-Ar), 129.0 (C-

Ar), 129.2 (C-Ar), 129.3 (C-7), 131.9 (C_q-Ar), 141.0 (C_q-Ar), 152.9

(C-6), 175.1 (C-3) ppm. MS (EI, 70 eV): m/z (%) = 275 (56) [M]⁺,

274 (58), 196 (15), 173 (100), 170 (16), 144 (53). HRMS

(C₁₉H₁₇NO): calcd. 275.1310; found 275.1310.

4

1-Methyl-3,5-diphenyl-1,7-dihydro-2H-azepin-2-one (19): A solution

of 17 (62 mg, 0.23 mmol) in dry toluene (4 mL) was refluxed for

6 h and then concentrated in vacuo. Separation of the isomers by

flash chromatography (cyclohexane/ethyl acetate, 5:1, 1:2) gave 17

(58 mg, 97 %) and also 19 (2 mg, 3 %) as a pale-yellow oil. IR

(CCl ): ν = 3060, 3025, 2925, 2855, 1645 (C=O), 1495, 1445, 1395,

˜

4

1205, 1075, 1005 cm^–1

.

¹H NMR (250 MHz): δ = 3.17 (s, 3 H,

3

NCH₃), 3.93 (d, J_7,6= 6.9 Hz, 2 H, 7-H), 6.55 (t, J_6,7= 6.9 Hz,

1 H, 6-H), 7.00 (s, 1 H, 4-H), 7.29–7.46 (m, 8 H, Ar-H), 7.63–7.68

(m, 2 H, Ar-H) ppm. ¹³C NMR (100 MHz): δ = 34.9 (NCH₃), 47.3

(C-7), 125.5/128.2/128.3/130.1 (C-4/-6/-Ar), 126.8 (C-Ar), 128.1 (C-

Ar), 128.4 (C-Ar), 128.7 (C-Ar), 129.6 (C_q), 138.8 (C_q), 142.7 (C_q),

167.3 (C-2) ppm. MS (EI, 70 eV): m/z (%) = 275 (100) [M]⁺, 274

(70), 246 (50) [M – NCH₃]⁺, 196 (49), 170 (64), 158 (60), 77 (35)

[C₆H₅]⁺, 42 (79). HRMS (C₁₉H₁₇NO): calcd. 275.1310; found

275.1307.

Photolysis of 10a (in Diethyl Ether): A degassed (N₂) solution of

10a (30 mg, 0.13 mmol) in diethyl ether (100 mL) was irradiated at

20 °C for 1 h with a high-pressure Hg lamp (Hanau TQ 150,

150 W) using a quartz filter (λ Ͼ 210 nm). Concentration in vacuo

and purification by flash chromatography (cyclohexane/ethyl ace-

tate, 5:1) afforded 2-[(E)-2-phenylvinyl]cyclopent-1-ene-1-carbal-

dehyde (22a) (24 mg, 80%).^[29]

Photolysis of 10b (in Diethyl Ether): A degassed (N₂) solution of

10b (30 mg, 0.12 mmol) in diethyl ether (100 mL) was irradiated at

20 °C for 1 h with a high-pressure Hg lamp (Hanau TQ 150,

150 W) using a quartz filter (λ Ͼ 210 nm). Concentration in vacuo

and purification (cyclohexane/ethyl acetate, 5:1) afforded 2-[(E)-2-

phenylvinyl]cyclohex-1-ene-1-carbaldehyde (22b) (18 mg, 59%).^[29]

1,5-Dimethyl-1,3-dihydro-2H-azepin-2-one (18): A solution of 16

(70 mg, 0.51 mmol) in dry DMF (3 mL) under N₂was treated with

NaH (40 mg, 1.02 mmol, 60% suspension in mineral oil), stirred at

room temperature for 45 min, and then at 60 °C for 22 h. After

cooling an aqueous solution of NH₄Cl (1:1) and then water were

added and the reaction mixture was extracted with dichlorometh-

ane (3×10 mL). The combined organic phases were washed with

saturated NH₄Cl and brine, dried (MgSO₄), and concentrated in

vacuo. Flash chromatography (cyclohexane/ethyl acetate, 10:1) af-

Photolysis of 10b (in Acetone): A degassed (N₂) solution of 10b

(100 mg, 0.39 mmol) in freshly distilled acetone (100 mL) was irra-

diated at 20 °C for 2 h with a high-pressure Hg lamp (Hanau TQ

150, 150 W) using a Solidex filter (λ Ͼ 270 nm). Concentration in

vacuo and purification (cyclohexane/ethyl acetate, 20:1, 10:1, 5:1)

afforded, besides unreacted 10b (6 mg, 6 %), 2-methyl-1-phenyl-

1,2,6,7,8,9-hexahydro-3H-2-benzazepin-3-one (25b) as a colorless

forded 18 (20 mg, 28%) as a colorless oil. IR (CCl ): ν = 3030,

˜

4

2920, 1675 (C=O), 1600, 1425, 1370, 1290, 1270, 1205, 1160,

1

4

1075 cm^–1. H NMR (250 MHz): δ = 1.85 (d, J = 1.2 Hz, 3 H, 5-

3

CH₃), 2.85 (d, J_3,4= 7.0 Hz, 2 H, 3-H), 3.12 (s, 3 H, NCH₃), 5.38

3

amorphous solid (42 mg, 42%). IR (CCl ): ν = 3025, 2935, 2855,

(mt, J_4,3= 7.0 Hz, 1 H, 4-H), 5.70 (d, J_6,7= 9.0 Hz, 1 H, 6-H),

˜

4

1635 (C=O), 1495, 1450, 1395, 1250, 1220 cm^{–1 1}H NMR

.

6.17 (d, J_7,6= 9.0 Hz, 1 H, 7-H) ppm. ¹³C NMR (100 MHz): δ =

3

(250 MHz): δ = 1.67–1.85 (m, 4 H, 7-H, 8-H), 2.14–2.23 (m, 2 H,

20.7 (5-CH₃), 35.5 (C-3), 37.5 (NCH₃), 117.2/118.2 (C-6/-7), 130.6

(C-4), 135.3 (C-5), 167.4 (C-2) ppm. MS (EI, 70 eV): m/z (%) = 137

(100) [M]⁺, 122 (16) [M – CH₃]⁺, 108 (86) [M – NCH₃]⁺, 94 (66).

HRMS (C₈H₁₁NO): calcd. 137.0841; found 137.0841.

6-/9-H), 2.44–2.54 (m, 2 H, 6-/9-H), 3.36 (s, 3 H, NCH₃), 4.72 (s,

3

1 H, 1-H), 5.85 (d, J_4,5= 12.2 Hz, 1 H, 4-H), 5.98 (d, J_5,4

=

12.2 Hz, 1 H, 5-H), 7.04–7.13 (m, 2 H, Ar-H), 7.19–7.25 (m, 3 H,

Ar-H) ppm. ¹³C NMR (125 MHz): δ = 22.3/22.6 (C-7/-8), 23.9/24.0

(C-6/-9), 39.2 (NCH₃), 67.0 (C-1), 125.4 (C-Ar), 126.8 (C-4/-5/-Ar),

127.1/137.5 (C-4/-5/-Ar), 128.1 (C-Ar), 132.2 (C_q), 138.7 (C_q), 140.1

(C_q), 167.4 (C-3) ppm. MS (EI, 70 eV): m/z (%) = 253 (100) [M]⁺,

252 (63), 224 (67) [M – NCH₃]⁺, 176 (23) [M – C₆H₅]⁺, 148 (24),

77 (23) [C₆H₅]⁺. HRMS (C₁₇H₁₉NO): calcd. 253.1567; found

253.1568.

Photolysis of 17: A degassed (N₂) solution of 17 (90 mg,

0.33 mmol) in freshly distilled acetone (100 mL) was irradiated at

20 °C for 15 min with a high-pressure Hg lamp (Hanau TQ 150,

150 W) using a Solidex filter (λ Ͼ 270 nm). Concentration in vacuo

and flash chromatography (cyclohexane/ethyl acetate, 3:1, 2:1) af-

forded, besides unreacted 17 (50 mg, 56%), endo-2-methyl-4,6-di-

phenyl-2-azabicyclo[3.2.0]hept-6-en-3-one (20) (13 mg, 14%) and

exo-2-methyl-4,6-diphenyl-2-azabicyclo[3.2.0]hept-6-en-3-one (21)

(12 mg, 13%). After irradiation in diethyl ether under comparable

Photolysis of 10c (in Acetone): A degassed (N₂) solution of 10c

(50 mg, 0.19 mmol) in freshly distilled acetone (100 mL) was irradi-

Eur. J. Org. Chem. 2005, 2715–2733

www.eurjoc.org

2725

K. Knobloch, J. Koch, M. Keller, W. Eberbach

FULL PAPER

ated at 20 °C for 1 h with a high-pressure Hg lamp (Hanau TQ

150, 150 W) using a Solidex filter (λ Ͼ 270 nm). Concentration in

vacuo and purification (cyclohexane/ethyl acetate, 3:1) afforded a

mixture of 25c/26c (30 mg, 60%) as a colorless oil. Upon standing

the mixture in solution the ratio of the isomers changed rapidly in

favor of 2-methyl-1-phenyl-4,6,7,8,9,10-hexahydrocyclohepta[c]

azepin-3(2H)-one (26c), which can be isolated in the pure form. IR

5Ј), 71.3 (C-1), 78.4 (ϵC), 93.4 (ϵC), 114.9 (C-3), 120.2 (C-2Ј),

126.7 (C-Ar), 127.9 (2 C-Ar), 128.6 (2 C-Ar), 136.8 (C_q-Ar), 138.1

(C-2), 149.6 (C_q-1Ј) ppm. MS (EI, 70 eV): m/z (%) = 239 (4)

[M + 1]⁺, 238 (22) [M]⁺, 237 (24) [M – 1]⁺, 223 (33), 221 (11)

[M – OH]⁺, 220 (9), 219 (13), 211 (7), 210 (23) [M – C₂H₄]⁺, 209

(47), 207 (11), 205 (17), 196 (10) [M – C₃H₆]⁺, 183 (18), 181 (31)

[C₁₄H₁₃]⁺, 167 (53), 165 (55), 161 (10) [M – C₆H₅]⁺, 155 (37)

[C₁₂H₁₁]⁺, 147 (75) [M – PhCH₂]⁺, 134 (53), 133 (26), 115 (60)

(CCl ): ν = 2930, 2855, 1665 (C=O), 1445, 1425, 1380, 1345, 1300,

˜

4

1

1105, 1055 cm^–1. H NMR (400 MHz): δ = 1.45–1.54 (m, 2 H, 8- [C₉H₇]⁺, 91 (100) [PhCH₂]⁺. HRMS (C₁₇H₁₈O): calcd. 238.1358;

H), 1.60–1.71 (m, 2 H, 7-/9-H), 1.72–1.86 (m, 2 H, 7-/9-H), 2.25–

2.37 (m, 3 H, 6-/10-H), 2.44–2.52 (m, 1 H, 6-/10-H), 2.69 (s, 3 H,

found 238.1358.

1-[2Ј-(3ЈЈ-Phenylprop-1ЈЈ-ynyl)cyclohex-1Ј-en-1Ј-yl]prop-2-en-1-ol

(29b): A solution of 8b (1.00 g, 4.46 mmol) in dry THF (50 mL)

under N₂was treated at –78 °C with a 0.9 m solution of vinylmag-

nesium bromide (4.68 mmol, 5.2 mL) in THF. The reaction mixture

was stirred for 30 min and then the solution was warmed to room

temperature, hydrolyzed with saturated NH₄Cl (10 mL), diluted

with water (50 mL), and then extracted with diethyl ether. The

combined organic phases were washed with brine, dried (MgSO₄),

and concentrated in vacuo. Flash chromatography (cyclohexane/

ethyl acetate, 50:1, 30:1) afforded 29b (1.00 g, 90%) as an orange

2

3

NCH₃), 2.77 (dd, J = 12.2, J_4,5= 7.7 Hz, 1 H, 4-H_a), 3.19 (dd,

3

²J = 12.2, J_4,5= 6.0 Hz, 1 H, 4-H_b), 5.66 (m_c, 1 H, 5-H), 7.22–

7.28 (m, 2 H, Ar-H), 7.33 (m_c, 1 H, Ar-H), 7.38 (m_c, 2 H, Ar-

H) ppm. ¹³C NMR (125 MHz): δ = 29.2/31.1/32.0/32.6/34.9 (C-6/-

7/-8/-9/-10), 34.2 (NCH₃), 36.5 (C-4), 121.3 (C-Ar), 127.9 (C-Ar),

128.3 (C-Ar), 130.0 (C-5), 132.9 (C_q), 137.4 (C_q), 137.5 (C_q), 143.6

(C_q), 170.2 (C-3) ppm. MS (EI, 70 eV): m/z (%) = 267 (84) [M]⁺,

266 (80), 252 (18) [M – CH₃]⁺, 210 (20) [M – CONCH₃]⁺, 118

(29), 77 (26) [C₆H₅]⁺. HRMS (C₁₈H₂₁NO): calcd. 267.1623; found

267.1623.

oil. IR (CCl ): ν = 3620 (OH), 3482 (OH, br.), 3088, 3067, 3031,

˜

4

Photolysis of 10d (in Acetone): A degassed (N₂) solution of 10d

(100 mg, 0.35 mmol) in freshly distilled acetone (100 mL) was irra-

diated at 20 °C for 30 min with a high-pressure Hg lamp (Hanau

TQ 150, 150 W) using a Solidex filter (λ Ͼ 270 nm). Concentration

in vacuo and purification (cyclohexane/ethyl acetate, 10:1, 3:1) af-

forded, besides unreacted 10d (16 mg, 16%), 2-methyl-1-phenyl- H, 3_trans-H), 5.38 (br. d, J_1,2= 4.9 Hz, 1 H, 1-H), 5.90 (ddd, J_2,3t

1,2,6,7,8,9,10,11-octahydro-3H-cycloocta[c]azepin-3-one (25d)

(62 mg, 62%) as a colorless solid, m.p. 111–113 °C (diethyl ether).

2935, 2862, 2840, 2217, 1707, 1604, 1495, 1453, 1436, 1418,

1224 cm^–1. ¹H NMR (250 MHz): δ = 1.60 (m_c, 4 H, 4Ј-H, 5Ј-H),

1.82 (1 H, OH), 1.94–2.07 (m, 1 H, 3Ј-/6Ј-H), 2.21 (m_c, 3 H, 3Ј-H,

3

6Ј-H), 3.77 (s, 2 H, 3ЈЈ-H), 5.13 (ddd, J_3c,2= 10.4, J = 1.8, J =

3

1.5 Hz, 1 H, 3_cis-H), 5.28 (ddd, J_3t,2= 17.1, J = 1.8, J = 1.5 Hz, 1

3

= 17.1, J_2,3c= 10.4, J_2,1= 4.9 Hz, 1 H, 2-H), 7.20–7.37 (m, 5 H,

Ar-H) ppm. ¹³C NMR (125 MHz): δ = 22.1/22.4/23.1 (C-4Ј/-5Ј/-6Ј),

25.9/30.6 (C-3Ј/-3ЈЈ), 74.2 (C-1), 81.9 (ϵC), 91.4 (ϵC), 114.4 (C-3),

IR (CCl ): ν = 2930, 2850, 1650 (C=O), 1630 (C=C), 1590, 1470,

˜

4

1445, 1395, 1250, 1010 cm^–1. H NMR (250 MHz): δ = 1.21–1.92 117.0 (C_q-2Ј), 126.6 (C-Ar), 127.9 (2 C-Ar), 128.5 (2 C-Ar), 136.9

1

(m, 8 H, 7-H, 8-H, 9-H, 10-H), 2.07–2.18 (m, 1 H, 6-/11-H), 2.24– (C_q-Ar), 138.2 (C-2), 144.0 (C_q-1Ј) ppm. MS (EI, 70 eV): m/z (%)

2.38 (m, 1 H, 6-/11-H), 2.55–2.69 (m, 1 H, 6-/11-H), 2.73–2.87 (m,

= 253 (2), 252 (13) [M]⁺, 251 (7), 238 (2), 237 (14), 235 (7) [M –

1 H, 6-/11-H), 3.36 (s, 3 H, NCH₃), 4.92 (s, 1 H, 1-H), 5.90 (d, ³J_4,5OH]⁺, 234 (8), 225 (3) [M – C₂H₃]⁺, 224 (5), 223 (15), 221 (12), 219

3

= 12.2 Hz, 1 H, 4-H), 6.03 (d, J_5,4= 12.2 Hz, 1 H, 5-H), 7.08–

(8), 209 (7), 195 (6) [M – C₃H₅O]⁺, 191 (13), 186 (10), 179 (14),

7.14 (m, 2 H, Ar-H), 7.19–7.26 (m, 3 H, Ar-H) ppm. ¹³C NMR 178 (15), 167 (16), 165 (24), 161 (68) [M – C₇H₇]⁺, 155 (12)

(125 MHz): δ = 26.0/26.5/28.9/29.8 (C-7/-8/-9/-10), 32.5/35.3 (C-6/-

[C₁₂H₁₁]⁺, 153 (12), 152 (15), 141 (21), 129 (15), 115 (40) [C₉H₇]⁺,

11), 38.5 (NCH₃), 67.2 (C-1), 125.5 (C-Ar), 127.1 (C-Ar), 128.0 (C- 105 (23), 91 (100) [C₇H₇]⁺. HRMS (C₁₈H₂₀O): calcd. 252.1514;

Ar), 128.2/138.1 (C-4/-5), 135.4 (C_q), 138.6 (C_q), 142.5 (C_q), 167.3

(C-3) ppm. MS (EI, 70 eV): m/z (%) = 281 (100) [M]⁺, 252 (70)

[M – NCH₃]⁺, 224 (35) [M – CONCH₃]⁺, 210 (28), 118 (30), 77

(21) [C₆H₅]⁺. HRMS (C₁₉H₂₃NO): calcd. 281.1780; found

281.1777.

found 252.1512.

1-[2Ј-(3ЈЈ-Phenylprop-1ЈЈ-ynyl)phenyl]prop-2-en-1-ol (29c): A solu-

tion of 28^[7](1.71 g, 7.77 mmol) in dry THF (90 mL) under N₂was

treated at –78 °C with a 0.9 m solution of vinylmagnesium bromide

(8.16 mmol, 9.1 mL) in THF. The reaction mixture was stirred for

2 h, and then the solution was warmed to room temperature, hy-

drolyzed with saturated NH₄Cl (9 mL), diluted with water (90 mL),

and then extracted with diethyl ether. The combined organic phases

were washed with brine, dried (MgSO₄), and concentrated in vacuo.

Flash chromatography (cyclohexane/ethyl acetate, 60:1) afforded

1-[2Ј-(3ЈЈ-Phenylprop-1ЈЈ-ynyl)cyclopent-1Ј-en-1Ј-yl]prop-2-en-1-ol

(29a): A solution of 8a (2.00 g, 9.51 mmol) in dry THF (100 mL)

under N₂was treated at –78 °C with a 0.9 m solution of vinylmag-

nesium bromide (9.99 mmol, 11.1 mL) in THF. The reaction mix-

ture was stirred for 100 min and then the solution was warmed

to room temperature, hydrolyzed with saturated NH₄Cl (10 mL),

diluted with water (100 mL) and then extracted with diethyl ether.

The combined organic phases were washed with brine, dried

(MgSO₄), and concentrated in vacuo. Flash chromatography (cy-

clohexane/ethyl acetate, 60:1, 40:1) afforded 29a (1.57 g, 69%) as

29c (1.86 g, 86%) as a yellow-orange oil. IR (CCl ): ν = 3619 (OH),

3472 (OH), 3067, 3030, 2891, 2228 (CϵC), 1956, 1850, 1707, 1640,

˜

4

1602, 1555, 1495, 1453, 1419, 1336, 1294, 1187, 1129, 1021,

1

995 cm^–1. H NMR (500 MHz): δ = 2.31 (1 H, OH), 3.85 (s, 2 H,

3

2

3ЈЈ-H), 5.13 (td, J_3c,2= 10.5, J_3c,3t= 1.5 Hz, 1 H, 3_cis-H), 5.28

3

2

3

an orange oil. IR (CCl ): ν = 3618 (OH, s), 3418 (OH, br.), 3083,

(td, J_3t,2= 17.2, J_3t,3c= 1.5 Hz, 1 H, 3_trans-H), 5.65 (d, J_1,2

=

˜

4

3

3065, 3028, 2958, 2925, 2851, 1549, 1251, 1216, 1112, 1067, 993,

5.4 Hz, 1 H, 1-H), 6.04 (ddd, J_2,3t= 17.2, J_2,3c= 10.5, J_2,1

1

3

919 cm^–1. H NMR (250 MHz): δ = 1.88 (quint, J = 7.5 Hz, 2 H, 5.4 Hz, 1 H, 2-H), 7.21 (m_c, ³J = 7.7, ³J = 7.4 Hz, 1 H, Ar-H), 7.25

3

4Ј-H), 1.98 (1 H, OH), 2.33–2.41 (m, 1 H, 3Ј-/5Ј-H), 2.48–2.55 (m,

(m_c, J = 7.4 Hz, 1 H, Ar-H), 7.28–7.35 (m, J = 7.4 Hz, 3 H, Ar-

3

³J = 7.5 Hz, 3 H, 3Ј-H, 5Ј-H), 3.78 (s, 2 H, 3ЈЈ-H), 5.13 (td, J_3c,2H), 7.39 (m_c, 2 H, Ar-H), 7.44 (dd, J = 7.7, J = 1.4 Hz, 1 H, Ar-

2

3

= 10.4, J_3c,3t= 1.6 Hz, 1 H, 3_cis-H), 5.17 (td, J_1,2= 5.8, J =

0.7 Hz, 1 H, 1-H), 5.29 (td, ³J_3t,2= 17.2, ²J_3t,3c= 1.6 Hz, 1 H, 3_trans

H), 5.91 (ddd, ³J_2,3t= 17.2, ³J_2,3c= 10.4, ³J_2,1= 5.8 Hz, 1 H, 2-H),

H) ppm. ¹³C NMR (125 MHz): δ = 25.9 (C-3ЈЈ), 73.1 (C-1), 80.5

(ϵC), 92.9 (ϵC), 114.9 (C-3), 121.6 (C_q-Ar), 125.9 (C-Ar), 126.8

(C-Ar), 127.4 (C-Ar), 128.0 (C-Ar), 128.5 (C-Ar), 128.7 (C-Ar),

-

7.22–7.25 (m, 1 H, Ar-H), 7.30–7.36 (m, 4 H, Ar-H) ppm. ¹³C 132.6 (C-Ar), 136.6 (C_q-Ar), 139.3 (C-2), 144.3 (C_q-Ar) ppm. MS

NMR (125 MHz): δ = 22.4 (C-4Ј), 26.1 (C-3ЈЈ), 31.3/37.2 (C-3Ј/-

(EI, 70 eV): m/z (%) = 248 (3) [M]⁺, 231 (7) [M – OH]⁺, 230 (19),

2726

www.eurjoc.org

Eur. J. Org. Chem. 2005, 2715–2733

Dipolar Route to Azepinone Derivatives by Heterocyclization of Enallenyl Nitrones

FULL PAPER

229 (29), 228 (12), 221 (2) [M – C₂H₃]⁺, 219 (31), 215 (41), 203

(24), 191 (20) [M – C₃H₅O]⁺, 189 (31), 171 (2) [M – Ph]⁺, 165 (20),

ane/ethyl acetate, 60:1) afforded 30c (1.32 g, 83%) as a yellow oil.

IR (CCl ): ν = 3067, 3031, 2894, 2235 (CϵC), 1672 (C=O), 1606,

˜

4

157 (68) [M – C₇H₇]⁺, 145 (8) [M – C₈H₇]⁺, 144 (16), 141 (27), 129 1442, 1400, 995, 961 cm^–1. H NMR (500 MHz): δ = 3.82 (s, 2 H,

1

(46), 128 (48), 103 (12) [C₈H₇]⁺, 91 (100) [C₇H₇]⁺. HRMS

(C₁₈H₁₆O): calcd. 248.1201; found 248.1202.

3ЈЈ-H), 5.83 (dd, J_3c,2= 10.5, J_3c,3t= 1.4 Hz, 1 H, 3_cis-H), 6.21

(dd, J_3t,2= 17.4, J_3t,3c= 1.4 Hz, 1 H, 3_trans-H), 6.95 (dd, J_2,3t

3

2

3

2

3

=

3

17.4, J_2,3c= 10.5 Hz, 1 H, 2-H), 7.24 (m_c, 1 H, Ar-H), 7.33 (m_c,

2 H, Ar-H), 7.35–7.37 (m, 3 H, Ar-H), 7.41 (dd, ³J = 7.5, J =

1.4 Hz, 1 H, Ar-H), 7.52 (m_c, ³J = 7.5, J = 1.4 Hz, 2 H, Ar-H) ppm.

¹³C NMR (125 MHz): δ = 26.1 (C-3ЈЈ), 80.9 (ϵC), 93.7 (ϵC), 122.1

(C_q), 126.8 (C-Ar), 127.8 (C-Ar), 128.1 (C-Ar), 128.4 (C-Ar), 128.6

(C-Ar), 130.4 (C-3), 130.7 (C-Ar), 133.4 (C-Ar), 135.8 (C-2), 136.1

(C_q-Ar), 141.2 (C_q-Ar), 194.8 (C=O) ppm. MS (EI, 70 eV): m/z (%)

= 247 (18) [M + 1]⁺, 246 (100) [M]⁺, 245 (53), 231 (10), 219 (3)

[M – C₂H₃]⁺, 217 (22), 215 (28), 204 (64), 191 (9) [M – C₃H₇O]⁺,

190 (12), 189 (42), 165 (15), 115 (14) [C₉H₇]⁺. HRMS (C₁₈H₁₄O):

calcd. 246.1045; found 246.1044.

1-[2Ј-(3ЈЈ-Phenylprop-1ЈЈ-ynyl)cyclopent-1Ј-en-1Ј-yl]prop-2-en-1-one

(30a): o-Iodoxybenzoic acid (IBX, 2.03 g, 7.25 mmol) was added to

a stirred solution of 29a (1.33 g, 5.52 mmol) in dry DMSO

(140 mL) under argon. The mixture was stirred for a further 1.5 h,

and then the solution was cooled in an ice bath and treated with

diethyl ether/water (150 mL, 1:2 mixture). After extraction with di-

ethyl ether the organic phase was washed with saturated NaHCO₃

and brine, dried (MgSO₄), and then concentrated in vacuo. Flash

chromatography (cyclohexane/ethyl acetate, 60:1) gave 30a (1.21 g,

92%) as a yellow oil. IR (CCl ): ν = 3060, 3028, 2959, 2849, 2210

˜

4

(CϵC), 1652 (C=O), 1455, 982 cm^–1. ¹H NMR (500 MHz): δ =

3

4-Nitro-1-[2Ј-(3ЈЈ-phenylprop-1ЈЈ-ynyl)cyclopent-1Ј-en-1Ј-yl]pentan-

1-one (31a): Compound 30a (830 mg, 3.51 mmol) was added to a

solution of nitroethane (5.04 mL, 70.24 mmol), dry diisopro-

pylamine (1.62 mL, 11.90 mmol), and dry chloroform (80 mL) un-

der argon. This solution was stirred for 66 h at room temperature

and then a 1:1 mixture of saturated NH₄Cl and brine (80 mL) was

added. The reaction mixture was extracted with chloroform, and

the organic phases were dried (MgSO₄) and concentrated in vacuo.

Flash chromatography of the residue (cyclohexane/ethyl acetate,

1.89 (quint, J_4Ј,3Ј/5Ј= 7.7 Hz, 2 H, 4Ј-H), 2.75 (m_c, J_3Ј/5Ј,4Ј

=

3

7.7 Hz, 4 H, 3Ј-H, 5Ј-H), 3.86 (s, 2 H, 3ЈЈ-H), 5.56 (dd, J_3c,2

10.5, J_3c,3t= 2.0 Hz, 1 H, 3_cis-H), 6.28 (dd, J_3t,2= 16.9, J_3t,3c

2

3

2

2.0 Hz, 1 H, 3_trans-H), 7.26 (m_c, 1 H, Ar-H), 7.34 (m_c, 4 H, Ar-H),

3

7.45 (dd, J_2,3t= 16.9, J_2,3c= 10.5 Hz, 1 H, 2-H) ppm. ¹³C NMR

(125 MHz): δ = 21.8 (C-4Ј), 26.5 (C-3ЈЈ), 33.4/40.9 (C-3Ј/-5Ј), 79.7

(ϵC), 101.1 (ϵC), 126.9 (C-3), 127.7 (C-Ar), 128.1 (C-Ar), 128.7

(C-Ar), 133.9 (C-2), 134.4 (C_q-2Ј), 135.9 (C_q-Ar), 146.5 (C_q-1Ј),

188.6 (C=O) ppm. MS (EI, 70 eV): m/z (%) = 238 (2), 237 (16) [M

+ 1]⁺, 236 (100) [M]⁺, 221 (11), 207 (12), 193 (7), 179 (18), 178

(25), 166 (11), 165 (30), 152 (15), 115 (5), 91 (9) [PhCH₂]⁺. HRMS

(C₁₇H₁₆O): calcd. 236.1201; found 236.1193.

60:1) gave 31a (663 mg, 60%) as a red-orange oil. IR (CCl ): ν =

˜

4

3028, 2941, 2210 (CϵC), 1654 (C=O), 1590 cm^–1. ¹H NMR

3

(500 MHz): δ = 1.48 (d, J_5,4= 6.8 Hz, 3 H, 5-H), 1.86 (quint,

3

³J_4Ј,3Ј/5Ј= 7.7 Hz, 2 H, 4Ј-H), 2.04–2.11 (m, J_3,2= 4.6 Hz, 1 H, 3-

3

1-[2Ј-(3ЈЈ-Phenylprop-1ЈЈ-ynyl)cyclohex-1Ј-en-1Ј-yl]prop-2-en-1-one

(30b): o-Iodoxybenzoic acid (IBX, 2.74 g, 9.78 mmol) was added to

a stirred solution of 29b (1.90 g, 7.52 mmol) in dry DMSO

(180 mL) under argon. The mixture was stirred for a further 1.5 h,

and then the solution was cooled in an ice bath and treated with

diethyl ether/water (210 mL, 1:2 mixture). After extraction with di-

ethyl ether the organic phase was washed with saturated NaHCO₃

and brine, dried (MgSO₄), and then concentrated. Flash

chromatography (cyclohexane/ethyl acetate, 60:1) gave 30b (1.69 g,

H), 2.16 (m_c, J_3,2= 7.2 Hz, 1 H, 3-H), 2.67 (m_c, J_3Ј/5Ј,4Ј= 7.7,

⁴J_3Ј,5Ј= 2.3 Hz, 2 H, 3Ј-/5Ј-H), 2.72 (m_c, J_3Ј/5Ј,4Ј= 7.7, J_3Ј/5Ј

=

3

4

3

2.3 Hz, 2 H, 3Ј-/5Ј-H), 2.99 (ddd, J_2,3= 7.2, J_2,3= 4.6 Hz, 2 H,

2-H), 3.86 (s, 2 H, 3ЈЈ-H), 4.54 (m_c, ³J_4,5= 6.8 Hz, 1 H, 4-H), 7.25–

7.29 (m, 1 H, Ar-H), 7.34–7.35 (m, 4 H, Ar-H) ppm. ¹³C NMR

(125 MHz): δ = 19.4 (C-5), 21.7 (C-4Ј), 26.4 (C-3ЈЈ), 29.2 (C-3),

32.9/37.1/40.8 (C-2/-3Ј/-5Ј), 79.6 (ϵC), 83.0 (C-4), 102.2 (ϵC),

127.0 (C-Ar), 128.1 (2 C-Ar), 128.8 (2 C-Ar), 134.8 (C_q-2Ј), 135.9

(C_q-Ar), 145.7 (C_q-1Ј), 196.4 (C=O) ppm. MS (EI, 70 eV): m/z (%)

= 311 (33) [M]⁺, 310 (100) [M – 1]⁺, 265 (30) [M – NO₂]⁺, 264 (15),

263 (39), 249 (11), 239 (12), 237 (11), 236 (30), 235 (18), 225 (13),

223 (30) [M – C₃H₆NO₂]⁺, 222 (85), 209 (53) [M – C₄H₈NO₂]⁺,

197 (26) [M – C₉H₇]⁺, 181 (33) [M – C₅H₈NO₃]⁺, 166 (30), 165

(53), 152 (33). HRMS (C₁₉H₂₀NO₃[M – 1]): calcd. 310.1443; found

310.1443.

90%) as a yellow oil. IR (CCl ): ν = 3067, 3031, 2939, 2862, 2210

˜

4

(CϵC), 1662 (C=O), 1601, 1495, 1453, 1433, 1401, 1359, 1275,

1

3

1230, 1197 cm^–1. H NMR (250 MHz): δ = 1.66 (m_c, J = 6.4, J

3

= 5.5 Hz, 4 H, 4Ј-H, 5Ј-H), 2.34 (m_c, J = 6.4, J = 4.9 Hz, 4 H,

3Ј-H, 6Ј-H), 3.73 (s, 2 H, 3ЈЈ-H), 5.62 (dd, J_3c,2= 10.4, J_3c,3t

1.5 Hz, 1 H, 3_cis-H), 6.21 (dd, J_3t,2= 17.1, J_3t,3c= 1.5 Hz, 1 H,

3

2

=

3

2

3

3_trans-H), 6.93 (dd, J_2,3t= 17.1, J_2,3c= 10.4 Hz, 1 H, 2-H), 7.22–

7.32 (m, 5 H, Ar-H) ppm. ¹³C NMR (125 MHz): δ = 21.7/22.0

(C-4Ј/-5Ј), 26.1/26.2 (C-3ЈЈ/-3Ј/-6Ј), 31.9 (C-3Ј/-6Ј), 82.7 (ϵC), 95.8

(ϵC), 125.5 (C_q-2Ј), 126.7 (C-Ar), 128.1 (2 C-Ar), 128.2 (C-3),

128.6 (2 C-Ar), 135.6 (C-2), 136.3 (C_q-Ar), 143.0 (C_q-1Ј), 196.0

(C=O) ppm. MS (EI, 70 eV): m/z (%) = 252 (3), 251 (19), 250 (100)

4-Nitro-1-[2Ј-(3ЈЈ-phenylprop-1ЈЈ-ynyl)cyclohex-1Ј-en-1Ј-yl]pentan-1-

one (31b): Compound 30b (1.69 g, 6.75 mmol) was added to a solu-

tion of nitroethane (9.05 mL, 126.0 mmol), dry diisopropylamine

(3.12 mL, 22.26 mmol), and dry chloroform (130 mL) under argon.

This solution was stirred for 66 h at room temperature and then a

1:1 mixture of saturated NH₄Cl and brine (100 mL) was added.

The reaction mixture was extracted with chloroform and the or-

ganic phases were dried (MgSO₄) and concentrated in vacuo. Flash

chromatography of the residue (cyclohexane/ethyl acetate, 60:1,

[M]⁺, 249 (62), 236 (15) [M

–

CH₂]⁺, 235 (81), 223 (5)

[M – C₂H₃]⁺, 221 (22), 208 (10) [M – C₃H₆]⁺, 207 (34), 195 (13)

[C₁₅H₁₅]⁺, 193 (18), 186 (26), 179 (45), 178 (35), 165 (39), 152 (22),

115 (35) [C₉H₇]⁺, 103 (10) [C₈H₇]⁺, 91 (31) [C₇H₇]⁺. HRMS

(C₁₈H₁₈O): calcd. 250.1358; found 250.1358.

40:1) gave 31b (2.01 g, 91%) as a yellow oil. IR (CCl ): ν = 3066,

˜

4

3028, 2939, 2862, 2210 (CϵC), 1659 (C=O), 1593, 1551, 1494,

1

1-[2Ј-(3ЈЈ-Phenylprop-1ЈЈ-ynyl)phenyl]prop-2-en-1-one

(30c):

o- 1453, 1386, 1354, 1221, 1170 cm^–1. H NMR (500 MHz): δ = 1.47

Iodoxybenzoic acid (IBX, 2.36 g, 8.44 mmol) was added to a stirred

solution of 29c (1.60 g, 6.50 mmol) in dry DMSO (160 mL) under

argon. The mixture was stirred for a further 1.5 h, and then the

solution was cooled in an ice bath and treated with diethyl ether/

(d, ³J_5,4= 6.6 Hz, 3 H, CH₃), 1.62 (m_c, 4 H, 4Ј-H, 5Ј-H), 2.04 (m_c,

3

²J = 14.9, J_3,4= 4.6 Hz, 1 H, 3-H), 2.13 (m_c, ²J = 14.9, J_3,4

=

3

9.1, J_3,2= 6.2 Hz, 1 H, 3-H), 2.29 (m_c, 2 H, 3Ј-/6Ј-H), 2.36 (m_c, 2

3

H, 3Ј-/6Ј-H), 2.96 (m_c, J_2,3= 6.2 Hz, 2 H, 2-H), 3.80 (s, 2 H, 3ЈЈ-

water (180 mL, 1:2 mixture). After extraction with diethyl ether the H), 4.50 (m_c, ³J_4,3= 9.1, ³J_4,5= 6.6, ³J_4,3= 4.6 Hz, 1 H, 4-H), 7.25–

organic phase was washed with saturated NaHCO₃and brine, dried

(MgSO₄), and then concentrated. Flash chromatography (cyclohex-

7.27 (m, 1 H, Ar-H), 7.32–7.35 (m, 4 H, Ar-H) ppm. ¹³C NMR

(125 MHz): δ = 19.4 (C-5), 21.7/21.9 (C-4Ј/-5Ј/-6Ј), 25.7/33.0 (C-

Eur. J. Org. Chem. 2005, 2715–2733

www.eurjoc.org

2727

K. Knobloch, J. Koch, M. Keller, W. Eberbach

3Ј/-6Ј), 26.2 (C-3ЈЈ), 29.4/37.9 (C-3/-2), 82.9 (C-4), 83.1 (ϵC), 97.5 (C-Ar), 128.8 (C-Ar), 131.4 (C-Ar), 134.2 (C-Ar), 136.2 (C_q-Ar),

FULL PAPER

(ϵC), 126.9 (C-Ar), 127.5 (C_q-2Ј/-Ar), 128.1 (2 C-Ar), 128.8 (2 C-

Ar), 136.3 (C_q-2Ј/-Ar), 142.2 (C_q-1Ј), 201.8 (C=O) ppm. MS (EI,

140.5 (C_q-Ar), 201.1 (C=O) ppm. MS (EI, 70 eV): m/z (%) = 307

(19) [M]⁺, 306 (90), 261 (23) [M – NO₂]⁺, 260 (28), 247 (11)

70 eV): m/z (%) = 325 (9) [M]⁺, 324 (28), 295 (32), 280 (14), 279 (62) [M – CH₂NO₂]⁺, 235 (27), 233 (67) [M – C₂H₄NO₂]⁺, 232 (91), 231

[M – NO]⁺, 278 (38), 277 (36), 263 (35), 251 (17) [M – C₂H₄NO₂]⁺, (45), 220 (33), 219 (91) [M – C₃H₆NO₂]⁺, 218 (26), 216 (21)

250 (57), 249 (30), 239 (29), 238 (23), 237 (100) [M – C₃H₆NO₂]⁺,

[M – C₇H₇]⁺, 215 (35), 207 (63), 204 (35) [M – C₈H₇]⁺, 203 (38),

236 (61), 235 (39), 234 (5) [M – C₇H₇]⁺, 224 (14), 223 (60) 202 (51), 192 (10) [C₁₀H₁₀NO₃]⁺, 191 (48), 190 (58), 189 (100), 165

[C₁₆H₁₅O]⁺, 221 (20), 213 (46), 212 (36), 211 (76), 210 (6) (47), 116 (6) [C₄H₆NO₃]⁺, 115 (21) [C₉H₇]⁺, 109 (33), 103 (9)

[C₁₁H₁₆NO₃]⁺, 209 (32), 195 (27) [C₁₅H₁₆]⁺, 194 (16), 183 (20), 179

(36), 178 (34), 167 (37), 166 (24), 165 (57), 153 (33), 152 (40), 141

(38), 129 (22), 115 (55), 105 (18), 91 (86). HRMS (C₂₀H₂₂NO₃[M –

1]): calcd. 324.1600; found 324.1604.

[C₈H₈]⁺, 91 (24) [C₇H₇]⁺, 89 (20) [C₃H₆NO₂]⁺. HRMS (C₁₉H₁₆NO₃

[M – 1]): calcd. 306.1130; found 306.1130.

4-Nitro-4-phenyl-1-[2Ј-(3ЈЈ-phenylprop-1ЈЈ-ynyl)phenyl]butan-1-one

(33c): A solution of phenylnitromethane (1.14 g, 8.34 mmol), dry

diisopropylamine (1.17 mL, 8.34 mmol), and dry chloroform

(110 mL) under argon was treated with a solution of 30c (1.58 g,

6.41 mmol) in chloroform (10 mL). This solution was stirred for

24 h at room temperature and then a 1:1 mixture of saturated

NH₄Cl and brine (120 mL) was added. The reaction mixture was

extracted with chloroform and the organic phases were dried

(MgSO₄) and concentrated in vacuo. Flash chromatography of the

residue (cyclohexane/ethyl acetate, 60:1, 40:1) gave 33c as bright-

4-Nitro-1-[2Ј-(3ЈЈ-phenylprop-1ЈЈ-ynyl)phenyl]pentan-1-one (31c): A

solution of nitroethane (12.5 mL, 174.6 mmol), dry diisopro-

pylamine (4.04 mL, 28.8 mmol), and dry chloroform (190 mL) un-

der argon was treated with a solution of 30c (2.15 g, 8.73 mmol) in

chloroform (10 mL). This solution was stirred for 66 h at room

temperature and then a 1:1 mixture of saturated NH₄Cl and brine

(200 mL) was added. The reaction mixture was extracted with chlo-

roform and the organic phases were dried (MgSO₄) and concen-

trated in vacuo. Flash chromatography of the residue (cyclohexane/

ethyl acetate, 50:1, 30:1) gave 31c (2.53 g, 90%) as a yellow oil. IR

yellow solid (2.19 g, 89%), m.p. 63–64 °C (ethanol). IR (CCl ): ν

˜

4

= 3088, 3067, 3033, 2939, 2902, 2233 (CϵC), 1684 (C=O), 1593,

1

2

3

1360 cm^–1. H NMR (400 MHz): δ = 2.49 (m_c, J_3,3= 7.3, J_3,4

=

(CCl ): ν = 3364, 3066, 3032, 2987, 2939, 2894, 2232 (CϵC), 1695,

˜

4

1684 (C=O), 1388, 1357 cm^–1. ¹H NMR (500 MHz): δ = 1.51 (d,

3

2

3

6.5 Hz, 1 H, 3-H), 2.77 (m_c, J_3,4= 9.0, J_3,3= 7.3, J_3,2= 6.9 Hz,

³J_5,4= 6.6 Hz, 3 H, CH₃), 2.13–2.20 (m, ²J = 14.8, ³J_3,2= 7.3, ³J_3,4

3

1 H, 3-H), 3.13 (dd, J_2,3= 6.9, J = 2.1 Hz, 2 H, 2-H), 3.82 (s, 2

3

= 4.6 Hz, 1 H, 3-H), 2.21–2.29 (m, ²J = 14.8, J_3,4= 9.1, J_3,2

=

H, 3ЈЈ-H), 5.51 (dd, ³J_4,3= 9.0, ³J_4,3= 6.5 Hz, 1 H, 4-H), 7.27 (m_c,

6.2 Hz, 1 H, 3-H), 3.15 (ddd, ³J_2,3= 7.3, ³J_2,3= 6.2, ⁴J_2,4= 2.2 Hz,

3

J = 6.9 Hz, 1 H, Ar-H), 7.34–7.41 (m, 11 H, Ar-H), 7.52 (dd, J =

7.7, J = 1.3 Hz, 1 H, Ar-H), 7.58 (dd, J = 7.7, J = 1.3 Hz, 1 H,

3

2 H, 2-H), 3.88 (s, 2 H, 3ЈЈ-H), 4.57 (m_c, J_4,3= 9.1, J_4,5= 6.6,

³J_4,3= 4.6, J_4,2= 2.2 Hz, 1 H, 4-H), 7.27 (t, J = 7.2 Hz, 1 H, Ar-

4

3

Ar-H) ppm. ¹³C NMR (100 MHz): δ = 26.0 (C-3ЈЈ), 28.3 (C-3),

38.1 (C-2), 81.3 (ϵC), 90.4 (C-4), 94.2 (ϵC), 121.8 (C_q), 126.9 (C-

Ar), 127.8 (C-Ar), 128.0 (C-Ar), 128.1 (C-Ar), 128.2 (C-Ar), 128.8

(C-Ar), 129.1 (C-Ar), 129.9 (C-Ar), 131.4 (C-Ar), 134.2 (C-Ar),

134.4 (C_q), 136.2 (C_q), 140.5 (C_q), 201.1 (C=O) ppm. MS (CI, iso-

butane, 150 eV): m/z (%) = 383 (1) [M]⁺, 339 (11), 338 (29), 337

(100) [M – NO₂]⁺, 319 (7), 247 (4) [M – C₇H₇NO₂]⁺, 233 (9) [M –

C₈H₈NO₂]⁺, 232 (6), 219 (5) [M – C₉H₁₀NO₂]⁺, 191 (3) [C₁₅H₁₁]⁺,

189 (5), 115 (2) [C₉H₇]⁺, 91 (7) [C₇H₇]⁺. C₂₅H₂₁NO₃(383.4): calcd.

C 78.31, H 5.52, N 3.65; found C 78.10, H 5.58, N 3.57.

3

H), 7.35 (t, J = 7.6 Hz, 3 H, Ar-H), 7.42 (m_c, J = 7.6 Hz, 3 H,

3

Ar-H), 7.54 (dd, J = 7.7, J = 0.8 Hz, 1 H, Ar-H), 7.62 (dd, J =

7.7, J = 1 Hz, 1 H, Ar-H) ppm. ¹³C NMR (125 MHz): δ = 19.5/

26.1 (C-3ЈЈ/-5), 29.3/38.0 (C-2/-3), 81.3 (ϵC), 82.8 (C- 4), 94.2

(ϵC), 121.8 (C_q-Ar), 126.9 (C-Ar), 128.1 (C-Ar), 128.2 (C-Ar),

128.8 (C-Ar), 131.3 (C-Ar), 134.2 (C-Ar), 136.3 (C_q-Ar), 140.5 (C_q-

Ar), 201.2 (C=O) ppm. MS (EI, 70 eV): m/z (%) = 321 (6) [M]⁺,

320 (25), 275 (20) [M – NO₂]⁺, 273 (15), 247 (5) [M – C₂H₄NO₂]⁺,

246 (13), 245 (29), 244 (6) [M – C₆H₅]⁺, 235 (27), 233 (26) [M –

C₃H₆NO₂]⁺, 232 (48), 231 (50), 219 (51) [M – C₄H₈NO₂]⁺, 218 (26),

215 (30), 207 (50), 205 (15), 204 (20), 203 (32), 202 (33), 191 (41)

[C₁₅H₁₁]⁺, 190 (44), 189 (100), 165 (39), 115 (11) [C₉H₇]⁺, 109 (20),

105 (11), 103 (7) [C₈H₇]⁺, 91 (12) [C₇H₇]⁺. HRMS (C₂₀H₁₈NO₃

[M – 1]): calcd. 320.1286; found 320.1282.

General Procedure for the Reductive Cyclization of the Nitro Com-

pounds 31a–c, 32c, and 33c: A suspension of the nitro derivative

and hydrogen-reduced iron powder^[36](5 equiv.) in ethanol, ef-

ficiently stirred with a magnet bar, was refluxed and then treated

with 0.5 m HCl (0.5 mL per 1 mmol of nitro compound). Another

portion of reduced iron powder (5 equiv.) was added, and the solu-

tion was refluxed for a further 2.5 h. The mixture was then filtered

and the filter cake carefully washed with dichloromethane; the

combined organic solutions were neutralized with saturated

NaHCO₃and then concentrated in vacuo. Purification was ac-

complished by flash chromatography (ethyl acetate, ethyl acetate/

methanol, 50:1, 20:1).

4-Nitro-1-[2Ј-(3ЈЈ-phenylprop-1ЈЈ-ynyl)phenyl]butan-1-one (32c):

A

solution of nitromethane (9.46 mL, 174.6 mmol), dry diisopro-

pylamine (4.04 mL, 28.8 mmol), and dry chloroform (190 mL) un-

der argon was treated with a solution of 30c (2.15 g, 8.73 mmol) in

chloroform (10 mL). This solution was stirred for 66 h at room

temperature and then triethylamine (4 mL) was added and the solu-

tion stirred for a further 5 h. A 1:1 mixture of saturated NH₄Cl

and brine (200 mL) was added and the reaction mixture was ex-

tracted with chloroform. The organic phases were dried (MgSO₄)

and concentrated in vacuo. Flash chromatography of the residue

(cyclohexane/ethyl acetate, 60:1, 50:1, 30:1) gave 32c (1.57 g, 58%)

2-Methyl-5-[2Ј-(3ЈЈ-phenylprop-1ЈЈ-ynyl)cyclopent-1Ј-en-1Ј-yl]-3,4-

dihydro-2H-pyrrole N-Oxide (34a): According to the general pro-

cedure, treatment of 31a (820 mg, 2.63 mmol) with a total of 1.47 g

(26.3 mmol) of hydrogen-reduced iron powder and 0.5 m HCl

as a yellow oil. IR (PTFE): ν = 3059, 3029, 2925, 2227 (CϵC),

˜

1695, 1684 (C=O), 1555, 1495, 1455 cm^–1. H NMR (500 MHz): δ (1.5 mL) in ethanol (3 mL) gave, after work up, 34a (417 mg, 56%)

1

3

= 2.32 (quint, J_3,2/4= 6.8 Hz, 2 H, 3-H), 3.20 (t, J_2/4,3= 6.8 Hz, as a brown oil. IR (CCl ): ν = 3028, 2971, 2932, 1561, 1453, 1418,

˜

4

2 H, 2-/4-H), 3.97 (s, 2 H, 3ЈЈ-H), 4.35 (t, J_4/2,3= 6.8 Hz, 2 H, 4-/ 1316, 1246, 1221, 1068, 1005, 976 cm^–1. H NMR (500 MHz): δ =

2-H), 7.27 (m_c, 1 H, Ar-H), 7.34–7.41 (m, 5 H, Ar-H), 7.44 (dt, J

3

1

3

2

3

1.43 (d, J_CH3,2= 6.6 Hz, 3 H, CH₃), 1.65 (m_c, J = 12.8, J_3,4=

3

= 7.5, J = 1.4 Hz, 1 H, Ar-H), 7.54 (dd, J = 7.7, J = 1.2 Hz, 1 H,

9.4, J_3,2= 6.9 Hz, 1 H, 3-H), 1.89 (quint, J_4Ј,3Ј/5Ј= 7.7 Hz, 2 H,

Ar-H), 7.63 (dd, J = 7.7, J = 1.2 Hz, 1 H, Ar-H) ppm. ¹³C NMR

4Ј-H), 2.25 (m_c, ²J = 12.8, J_3,4= 4.8 Hz, 1 H, 3-H), 2.54 (t,

3

(125 MHz): δ = 21.8 (C-3), 26.2 (C-3ЈЈ), 38.3/74.7 (C-2/-4), 81.4

(ϵC), 94.3 (ϵC), 121.8 (C_q-Ar), 127.0 (C-Ar), 128.1 (C-Ar), 128.2

³J_3Ј/5Ј,4Ј= 7.7 Hz, 2 H, 3Ј-/5Ј-H), 3.01 (m_c, ²J = 16.6 Hz, 1 H, 4-

2

3

H), 3.14 (m_c, J = 16.6, J_4,3= 9.4, J_4,3= 4.8 Hz, 1 H, 4-H), 3.21

2728

www.eurjoc.org

Eur. J. Org. Chem. 2005, 2715–2733

Dipolar Route to Azepinone Derivatives by Heterocyclization of Enallenyl Nitrones

FULL PAPER

(m_c, ³J_3Ј/5Ј,4Ј= 7.7 Hz, 2 H, 3Ј-/5Ј-H), 3.79 (s, 2 H, 3ЈЈ-H), 4.02 (m,

gave, after work up, 35c (100 mg, 36%) as a red-brown oil. IR

3

³J_2,3= 6.9, J_2,CH3= 6.6 Hz, 1 H, 2-H), 7.23–7.27 (m, 1 H, Ar-H),

(CCl ): ν = 3416, 3066, 3028, 2956, 2878, 2232 (CϵC), 1375,

˜

4

7.31–7.34 (m, 4 H, Ar-H) ppm. ¹³C NMR (125 MHz): δ = 18.6

(CH₃), 23.2 (C-4Ј), 26.0/26.4 (C-3/-4/-3ЈЈ), 29.3/34.1/38.6 (C-3/-4/-

3Ј/-5Ј), 68.9 (C-2), 80.6 (ϵC), 97.7 (ϵC), 126.8 (C-Ar), 127.9 (2 C-

Ar), 128.4 (C_q-5/-Ar), 128.6 (2 C-Ar), 136.3/137.4 (C_q-1Ј/-2Ј), 140.6

(C_q-5/-Ar) ppm. MS (EI, 70 eV): m/z (%) = 280 (12) [M + 1]⁺, 279

1225 cm^–1. H NMR (500 MHz): δ = 2.04 (m_c, J_3,2/4= 7.9 Hz, 2

1

3

4

H, 3-H), 3.22 (m_c, J_2,4= 2.0 Hz, 2 H, 2-/4-H), 3.84 (s, 2 H, 3ЈЈ-

3

4

H), 4.14 (m_c, J_2/4,3= 7.9, J_2,4= 2.0 Hz, 2 H, 2-/4-H), 7.27 (m_c, 1

H, Ar-H), 7.31–7.40 (m, 6 H, Ar-H), 7.52 (dd, ³J = 7.7, J = 1.3 Hz,

1 H, Ar-H), 8.11 (dd, J = 7.9, J = 1.3 Hz, 1 H, Ar-H) ppm. ¹³C

3

(54) [M]⁺, 278 (28), 264 (5) [M – CH₃]⁺, 262 (33), 260 (52), 250 NMR (125 MHz): δ = 17.6/33.0/63.5 (C-2/-3/-4), 26.1 (C-3ЈЈ), 81.4

(31), 236 (12), 220 (15), 202 (8) [M – C₆H₅]⁺, 189 (16), 188 (100),

178 (13), 160 (42), 146 (33), 91 (24). HRMS (C₁₉H₂₁NO): calcd.

279.1623; found 279.1620.

(ϵC), 93.1 (ϵC), 122.5 (C_q-Ar), 126.9 (C-Ar), 127.9 (C-Ar), 128.1

(C-Ar), 128.7 (C-Ar), 128.8 (C-Ar), 129.5 (C-Ar), 131.4 (C_q-Ar),

133.5 (C-Ar), 136.3 (C_q-Ar), 143.6 (C-5) ppm. MS (EI, 70 eV):

m/z (%) = 275 (9) [M]⁺, 274 (22), 259 (19) [M – O]⁺, 258 (63), 247

(15) [M – C₂H₄]⁺, 246 (66), 233 (17) [M – C₃H₆]⁺, 215 (13), 198 (6)

[M – C₆H₅]⁺, 191 (4) [C₁₅H₁₁]⁺, 189 (14), 184 (100) [M – C₇H₇]⁺,

172 (38) [M – C₈H₇]⁺, 157 (18), 156 (81), 129 (56), 128 (52), 116

(22), 115 (26) [C₉H₇]⁺, 103 (20) [C₈H₇]⁺, 91 (17). HRMS

(C₁₉H₁₆NO [M – 1]): calcd. 274.1231; found 274.1230.

2-Methyl-5-[2Ј-(3ЈЈ-phenylprop-1ЈЈ-ynyl)cyclohex-1Ј-en-1Ј-yl]-3,4-

dihydro-2H-pyrrole N-Oxide (34b): According to the general pro-

cedure, treatment of 31b (400 mg, 1.23 mmol) with a total of

686 mg (12.3 mmol) of hydrogen-reduced iron powder and 0.5 m

HCl (0.6 mL) in ethanol (2 mL) gave, after work up, 34b (144 mg,

40%) as an orange oil. IR (PTFE): ν = 3419, 3085, 3061, 3028,

˜

2656, 2216 (CϵC), 1337, 1030 cm^–1. ¹H NMR (500 MHz): δ = 1.39

2-Phenyl-5-[2Ј-(3ЈЈ-phenylprop-1ЈЈ-ynyl)phenyl]-3,4-dihydro-2H-

3

2

3

(d, J_CH3,2= 6.6 Hz, 3 H, CH₃), 1.58 (m_c, J_3,3= 12.8, J_3,4= 9.1, pyrrole N-Oxide (36c): According to the general procedure, treat-

³J_3,2= 6.5, J_3,4= 6.3 Hz, 1 H, 3-H), 1.66 (m_c, 4 H, 4Ј-H, 5Ј-H),

2.19 (m_c, J_3,3= 12.8, J_3,4= 9.0, J_3,2= 8.4, J_3,4= 5.0 Hz, 1 H,

3-H), 2.28 (m_c, 2 H, 3Ј-/6Ј-H), 2.40–2.44 (m, 1 H, 3Ј-/6Ј-H), 2.52–

ment of 33c (1.00 g, 2.61 mmol) with a total of 1.46 g (26.1 mmol)

of hydrogen-reduced iron powder and 0.5 m HCl (1.2 mL) in etha-

nol (5 mL) gave, after flash chromatography (cyclohexane/ethyl

acetate, 5:1, 1:2), 36c (738 mg, 80%) as a green-brown oil. IR

3

2

3

2

3

2.56 (m, 1 H, 3Ј-/6Ј-H), 2.84 (dddd, J_4,4= 17.7, J_4,3= 9.0, J_4,3

4

2

3

= 6.3, J_4,2= 1.7 Hz, 1 H, 4-H), 2.93 (dddd, J_4,4= 17.7, J_4,3

=

(PTFE): ν = 3405, 3059, 3029, 2950, 2227 (CϵC), 1956, 1373,

˜

9.1, ³J_4,3= 5.0, ⁴J_4,2= 2.1 Hz, 1 H, 4-H), 4.06 (m_c, ³J_2,3= 8.4, ³J_2,31029 cm^–1. ¹H NMR (500 MHz): δ = 2.08 (m_c, J_3,3= 13.1, J_3,4

=

2

3

4

3

2

= 6.5, J_2,CH3= 6.6, J_2,4= 2.1, J_2,4= 1.7 Hz, 1 H, 2-H), 7.21– 8.9, J_3,2= 5.4, J_3,4= 4.9 Hz, 1 H, 3-H), 2.54 (m_c, J_3,3= 13.1,

7.25 (m, 1 H, Ar-H), 7.29–7.32 (m, 4 H, Ar-H) ppm. ¹³C NMR ³J_3,4= 9.2, J_3,2= 9.2, J_3,4= 9.1 Hz, 1 H, 3-H), 3.26 (dddd, J_4,4

3

2

(125 MHz): δ = 18.6 (CH₃), 21.6/21.9/25.1/26.1/26.2/29.9/31.1 (C- = 17.9, ³J_4,3= 9.2, ³J_4,3= 4.9, ⁴J_4,2= 1.2 Hz, 1 H, 4-H), 3.38 (dddd,

3

4

3/-3Ј/-3ЈЈ/-4/-4Ј/-5Ј/-6Ј), 68.9 (C-2), 82.7 (ϵC), 93.3 (ϵC), 123.7

(C_q-2Ј), 126.7 (C-Ar), 128.0 (2 C-Ar), 128.6 (2 C-Ar), 134.3 (C_q- (s, 2 H, 3ЈЈ-H), 5.19 (m_c, J_2,3= 9.2, J_2,3= 5.4, J_2,4= 2.0, J_2,4

²J_4,4= 17.9, J_4,3= 9.1, J_4,3= 8.9, J_4,2= 2.0 Hz, 1 H, 4-H), 3.83

3

4

=

1Ј), 136.7 (C_q-Ar), 174.7 (C_q-5) ppm. MS (EI, 60 eV): m/z (%) =

1.2 Hz, 1 H, 2-H), 7.25 (m_c, 1 H, Ar-H), 7.30–7.39 (m, 11 H, Ar-

H), 7.55 (dd, J = 7.9, J = 1.4 Hz, 1 H, Ar-H), 8.31 (dd, J = 7.9, J

293 (46) [M]⁺, 276 (13) [M – O]⁺, 237 (3) [C₁₆H₁₅NO]⁺, 203 (24),

202 (100) [M – C₇H₇]⁺, 192 (19), 186 (11) [C₁₃H₁₇N – 1]⁺, 178 (9) = 1.4 Hz, 1 H, Ar-H) ppm. ¹³C NMR (125 MHz): δ = 26.1 (C-3ЈЈ),

[C₁₁H₁₆NO]⁺, 174 (70), 164 (17) [C₁₁H₁₇N – 1]⁺, 160 (16), 131 (20),

115 (8) [C₉H₇]⁺, 105 (10), 91 (35). HRMS (C₂₀H₂₃NO): calcd. 5), 126.8 (C-Ar), 127.1 (2 C-Ar), 127.9 (C-Ar), 128.1 (C-Ar), 128.3

27.2 (C-3), 31.2 (C-4), 77.9 (C-2), 81.9 (ϵC), 93.1 (ϵC), 122.6 (C_q-

293.1779; found 293.1779.

(C-Ar), 128.7 (C-Ar), 128.8 (2 C-Ar), 128.9 (C-Ar), 129.3 (C-Ar),

131.7 (C-2Ј), 133.6 (C-Ar), 136.2 (C_q-Ar), 138.6 (C-1Ј), 141.9 (C_q-

Ar) ppm. MS (EI, 70 eV): m/z (%) = 351 (18) [M]⁺, 350 (21) [M –

1]⁺, 335 (17) [M – O]⁺, 334 (54), 333 (25), 322 (35), 261 (21), 260

(100) [M – PhCH₂]⁺, 244 (42), 232 (34), 231 (22), 230 (33), 219

(28), 218 (27), 217 (22), 215 (38), 202 (34), 191 (15) [C₁₅H₁₁]⁺, 189

(31), 156 (66), 128 (78), 117 (22), 115 (32) [C₉H₇]⁺, 91 (70)

[PhCH₂]⁺. HRMS (C₂₅H₂₀NO [M – 1]): calcd. 350.1545; found

350.1545.

2-Methyl-5-[2Ј-(3ЈЈ-phenylprop-1ЈЈ-ynyl)phenyl]-3,4-dihydro-2H-

pyrrole N-Oxide (34c): According to the general procedure, treat-

ment of 31c (321 mg, 1.0 mmol) with a total of 558 mg (10.0 mmol)

of hydrogen-reduced iron powder and 0.5 m HCl (0.5 mL) in etha-

nol (2 mL) gave, after work up, 34c (215 mg, 74%) as a red-brown

oil. IR (PTFE): ν = 3416, 3059, 3028, 2971, 2929, 2227 (CϵC)

˜

cm^–1. ¹H NMR (500 MHz): δ = 1.49 (d, J_CH3,2= 6.6 Hz, 3 H,

3

CH₃), 1.67 (m_c, 1 H, 3-/4-H), 2.26 (m_c, 1 H, 3-/4-H), 3.06–3.12 (m,

1 H, 3-/4-H), 3.14–3.21 (m, 1 H, 3-/4-H), 3.83 (s, 2 H, 3ЈЈ-H), 4.19 General Procedure for the Base-Catalyzed Transformations of the

3

(m_c, J_2,CH3= 6.6 Hz, 1 H, 2-H), 7.26 (tt, 1 H, Ar-H), 7.29–7.38

Nitrones 34a–c, 35c, and 36c: Solutions of the nitrones in the re-

(m, 6 H, Ar-H), 7.51 (dd, 1 H, Ar-H), 8.15 (dd, 1 H, Ar-H) ppm. spective solvents were treated with a base, and in some cases tetra-

¹³C NMR (125 MHz): δ = 18.6 (CH₃), 25.9/26.1 (C-3ЈЈ/-3/-4), 30.7 n-butylammonium iodide (TBAI), at the given temperature. Work

(C-3/-4), 69.6 (C-2), 81.6 (ϵC), 92.9 (ϵC), 126.9 (C-Ar), 127.9 (C- up of the reaction mixtures was accomplished by addition of water,

Ar), 128.1 (2 C-Ar), 128.7 (2 C-Ar), 128.9 (C-Ar), 129.3 (C-Ar),

extraction with diethyl ether, washing of the organic phases with

131.9 (C_q-2Ј), 133.5 (C-Ar), 136.4 (C_q-Ar/-1Ј), 141.8 (C_q-Ar/-1Ј), saturated aqueous NH₄Cl and brine, drying (MgSO₄), concentra-

174.2 (C_q-5) ppm. MS (EI, 70 eV): m/z (%) = 289 (9) [M]⁺, 288

(25), 273 (15) [M – O]⁺, 272 (66), 261 (19) [M – C₂H₄]⁺, 260 (100),

247 (21), 233 (3) [M – C₄H₈]⁺, 230 (17), 219 (16), 215 (18), 202

(15), 198 (98) [M – C₇H₇]⁺, 186 (36) [M – C₈H₇]⁺, 168 (23), 156

(64), 153 (21), 129 (23), 128 (56), 115 (20) [C₉H₇]⁺, 103 (14)

[C₈H₇]⁺, 91 (14) [C₇H₇]⁺. HRMS (C₂₀H₁₈NO [M – 1]): calcd.

288.1388; found 288.1396.

tion in vacuo, and flash chromatography of the residue followed by

crystallization (if possible).

cis- and trans-3-Methyl-6-phenyl-2,3,6,8,9,10-hexahydrocyclopenta-

[c]pyrrolo[1,2-a]azepin-5(1H)-one (37 and 38): A stirred mixture of

34a (280 mg, 1.00 mmol) and TBAI (37 mg, 10 mol%) in dry tolu-

ene (5 mL) was treated with KOH (56 mg, 1.00 mmol). After re-

fluxing the resulting suspension for 1 h and work up, flash

N- chromatography (cyclohexane/ethyl acetate, 100:1, 60:1, 40:1) of the

crude material afforded an approximate 1.7:1 mixture of 37 and 38

5-[2Ј-(3ЈЈ-Phenylprop-1ЈЈ-ynyl)phenyl]-3,4-dihydro-2H-pyrrole

Oxide (35c): According to the general procedure, treatment of 32c

(307 mg, 1.0 mmol) with a total of 558 mg (10.0 mmol) of hydro- (238 mg, 85%). Colorless crystals of 37 (68 mg), m.p. 173–175 °C,

gen-reduced iron powder and 0.5 m HCl (0.5 mL) in ethanol (2 mL)

www.eurjoc.org

were obtained from ethanol.

Eur. J. Org. Chem. 2005, 2715–2733

2729

K. Knobloch, J. Koch, M. Keller, W. Eberbach

FULL PAPER

Compound 37:^[37]IR (CCl ): ν = 3064, 3023, 2967, 2925, 2873, 2847,

flash chromatography (cyclohexane/ethyl acetate, 50:1) of the crude

˜

4

1667 (C=O), 1456, 1394, 1328, 1263, 1098, 1067 cm^–1. ¹H NMR material afforded 41 (12 mg, 16%) and a 1.3:1 mixture of 39 and

3

2

(500 MHz): δ = 1.19 (d, J_CH3,3= 6.5 Hz, 3 H, CH₃), 1.66 (m_c, J 40 (33 mg, 44%).

= 12.6, ³J_2,1= 8.9, ³J_2,3= 1.9 Hz, 1 H, 2-H), 1.80 (m_c, ³J = 8.5 Hz,

Compound 41: IR (CCl ): ν = 3031, 2934, 2857, 1619 (C=O), 1550,

˜

4

2

3

1 H, 9-H), 1.92 (m_c, 1 H, 9-H), 2.07 (m_c, J = 12.6, J_2,3= 8.0 Hz,

1 H, 2-H), 2.44–2.52 (m, J = 8.5 Hz, 4 H, 8-H, 10-H), 2.75 (m_c,

1462, 1444, 1404, 1279, 1245, 1049, 879 cm^–1. ¹H NMR (500 MHz):

3

δ = 1.25 (d, J_CH3,3Ј= 6.5 Hz, 3 H, CH₃), 1.72 (2 H)/1.80 (2 H)/

³J_1,2= 8.9 Hz, 2 H, 1-H), 3.48 (m_c, J_6,7= 5.2 Hz, 1 H, 6-H), 4.58

3

2.08 (1 H)/2.44 (2 H)/2.54–2.62 (1 H)/2.65 (1 H)/2.76 (1 H)/2.90 (2

3

(m_c, J_3,2= 8.0, J_3,CH3= 6.5, J_3,2= 1.9 Hz, 1 H, 3-H), 5.28 (d,

³J_7,6= 5.2 Hz, 1 H, 7-H), 7.26–7.31 (m, 3 H, Ar-H), 7.34–7.32 (m,

2 H, Ar-H) ppm. ¹³C NMR (125 MHz): δ = 19.8 (CH₃), 24.4 (C-

9), 28.3 (C-2), 29.2 (C-1), 30.8/32.1 (C-8/-10), 53.1 (C-6), 57.2 (C-

3), 114.1 (C-7), 122.0 (C_q), 126.9 (C-Ar), 128.3 (2 C-Ar), 129.6

(2 C-Ar), 133.1 (C_q), 139.3 (C_q), 143.9 (C_q), 163.4 (C=O) ppm. MS

(EI, 70 eV): m/z (%) = 280 (20) [M + 1]⁺, 279 (100) [M]⁺, 278 (73),

264 (9) [M – CH₃]⁺, 262 (11), 251 (16) [M – C₂H₄]⁺, 250 (12), 237

(8) [M – C₃H₆]⁺, 236 (15), 202 (9) [M – C₆H₅]⁺, 200 (10)

[C₁₃H₁₄NO]⁺, 174 (31), 91 (16), 77 (11). C₁₉H₂₁NO (279.2): calcd.

C 81.68, H 7.58, N 5.01; found C 81.36, H 7.40, N 4.87.

3

H) (1Ј-/2Ј-/6Ј-/7Ј-/8Ј-/9Ј-H), 3.98 (s, 2 H, 2-H), 5.00 (m_c, J_3Ј,CH3

= 6.5 Hz, 1 H, 3Ј-H), 7.20–7.24 (m, 5 H, Ar-H) ppm. ¹³C NMR

(125 MHz): δ = 21.1/21.7/22.9/23.8 (C-6Ј/-7Ј/-8Ј/-9Ј), 21.8/25.8 (C-

1Ј/CH₃), 34.3/46.7/56.4 (C-2Ј/-3Ј/-2), 113.4/141.4 (C-5Јa/-9Јa), 126.5

(C-Ar), 128.5 (2 C-Ar), 129.6 (2 C-Ar), 130.9/132.8/135.9 (C-5Ј/-

5Јa/-9Јb/-Ar), 132.8 (C-5Ј/-9Јb/-Ar), 135.9 (C_q-5Ј/-9Јb/-Ar), 141.4

(C_q-5Јa/-9Јa), 185.8 (C=O) ppm. MS (EI, 70 eV): m/z (%) = 293

(11) [M]⁺, 203 (13), 202 (100) [M – C₇H₇]⁺, 189 (8), 174 (15)

[C₁₂H₁₆N]⁺, 149 (8), 117 (6), 91 (20), 79 (7). HRMS (C₂₀H₂₃NO):

calcd. 293.1780; found 293.1779.

cis- and

trans-3-Methyl-6-phenyl-1,2,3,11b-tetrahydro-5H-pyr-

mixture of 34c

1

Selected ¹H NMR Spectroscopic Data for 38: H NMR (250 MHz,

rolo[2,1-a][2]benzazepin-5-one (42 and 43):

A

taken from the mixture with 37): δ = 1.22 (d, ³J = 6.4 Hz, 3 H,

(385 mg, 1.33 mmol) and TBAI (49 mg, 10 mol%) in dry toluene

(8 mL) was stirred for 5 min, treated with KOH (23 mg, 0.41 mmol)

and then refluxed for 1 h. After work up, flash chromatography

(cyclohexane/ethyl acetate, 30:1, 20:1, 10:1) of the crude material

afforded an approximate 1.45:1 mixture of 42 and 43 (312 mg,

81%), from which, after repeated chromatography and crystalli-

zation (ethanol), fractions of pure 42 (50 mg) and 43 (109 mg) were

isolated.

CH₃), 1.55–1.6 (2 H), 2.4–2.55 (4 H), 2.6–2.65 (2 H), 2.85–2.9 (dd,

3

³J = 4.9, J = 1.6 Hz, 2 H), 3.63–3.68 (m, J = 4.9 Hz, 1 H, 6-H),

4.52–4.64 (1 H, 3-H), 5.55 (s, 1 H, 7-H), ca. 7.2 (3 H, Ar-H), 7.2–

7.25 (2 H, Ar-H) ppm.

cis- and trans-3-Methyl-6-phenyl-1,2,3,6,8,9,10,11-octahydro-5H-

pyrrolo[2,1-a][2]benzazepin-5-one (39 and 40): A stirred mixture of

34b (120 mg, 0.41 mmol) and TBAI (15 mg, 10 mol%) in dry tolu-

ene (3 mL) was treated with KOH (23 mg, 0.41 mmol). After re-

fluxing the resulting suspension for 1 h and work up, flash

chromatography (cyclohexane/ethyl acetate, 10:1) of the crude ma-

terial afforded an approximate 2.5:1 mixture of 39 and 40 (67 mg,

56%). Colorless crystals of 39 (31 mg), m.p. 177–179 °C, were ob-

tained from ethanol.

Compound 42: Colorless crystals, m.p. 103–104 °C (ethanol). ¹H

3

NMR (500 MHz): δ = 1.19 (d, J_CH3,3= 6.2 Hz, 3 H, CH₃), 1.89

(m_c, 1 H, 1-/2-H), 2.32 (m_c, 2 H, 1-/2-H), 2.72–2.77 (m, 1 H, 1-/2-

H), 4.27 (m_c, J = 6.3 Hz, 1 H, 3-H), 4.69 (dd, J = 7.9, J = 7.3 Hz,

1 H, 11b-H), 7.33 (s, 1 H, 7-H), 7.35 (m_c, 1 H, Ar-H), 7.36–7.41

(m, 5 H, Ar-H), 7.45 (d, J = 7.3 Hz, 1 H, Ar-H), 7.66 (dd, J = 7.3,

J = 1.4 Hz, 2 H, Ar-H) ppm. ¹³C NMR (125 MHz): δ = 20.7 (CH₃),

Compound 39: IR (PTFE): ν = 3060, 3023, 2962, 2923, 2855, 2088,

˜

1653 (C=O), 1558, 1456, 1394, 1336, 1215, 1154 cm^–1. ¹H NMR 25.9/32.6 (C-1/-2), 55.3/57.9 (C-3/-11b), 122.0 (C-Ar), 127.5 (C-Ar),

(500 MHz): δ = 1.19 (d, ³J_CH3,3= 6.5 Hz, 3 H, CH₃), 1.58 (m_c, ²J_2,2127.8 (C-Ar), 128.1 (2 C-Ar), 128.8 (2 C-Ar), 128.9 (C-Ar), 130.4

3

= 12.5, J_2,3= 3.4 Hz, 3 H, 2-H, 8-/9-/10-/11-H), 1.85 (m_c, 2 H, 8-/

(C-Ar), 134.2 (C-Ar), 135.9/139.6/140.2 (C_q-6/-7a/-11a/-Ar), 184.6

2

3

9-/10-/11-H), 2.07 (m_c, J_2,2= 12.5, J_2,1= 10.2, J_2,1= 7.8 Hz, 1 (C=O) ppm. C₂₀H₁₉NO (289.2): calcd. C 83.01, H 6.62, N 4.84;

H, 2-H), 2.18–2.29 (m, ²J = 14.3, J = 12.3 Hz, 2 H, 8-/9-/10-/11-

found C 82.23, H 6.71, N 4.71 (crystals contain traces of water).

2

H), 2.38 (m_c, J = 14.3, J = 3.9 Hz, 1 H, 8-/9-/10-/11-H), 2.52 (m_c,

Compound 43:^[37]Colorless crystals, m.p. 108–110 °C (ethanol). IR

J = 3.9 Hz, 1 H, 8-/9-/10-/11-H), 2.67 (m_c, ²J = 16.2, J_1,2

=

3

(CCl ): ν = 3064, 3023, 2967, 2925, 1636 (C=O), 1419 cm^–1. ¹H

˜

4

10.2 Hz, 1 H, 1-H), 2.87 (m_c, ²J = 16.2, J_1,2= 10.2 Hz, 1 H, 1-H),

3

NMR (500 MHz): δ = 1.40 (d, J_CH3,3= 6.3 Hz, 3 H, CH₃), 1.77

3

3.45 (dd, J_6,7= 6.0 Hz, 1 H, 6-H), 4.56 (m_c, J_3,CH3= 6.5, J_3,2

=

(dd, ²J_2α,2β= 12.3, J_2α,1α= 6.2 Hz, 1 H, 2α-H), 2.34 (m_c, ³J_2β,1α

=

3

3.4 Hz, 1 H, 3-H), 5.30 (dd, J_7,6= 6.0 Hz, 1 H, 7-H), 7.26–7.38

(m, 5 H, Ar-H) ppm. ¹³C NMR (125 MHz): δ = 20.6 (CH₃), 25.6/

25.8/29.4/32.7 (C-8/-9/-10/-11), 28.3 (C-1), 28.4 (C-2), 51.8 (C-6),

55.7 (C-3), 119.8 (C_q-11a), 120.9 (C-7), 126.9 (C-Ar), 128.3 (2 C-

Ar), 129.8 (2 C-Ar), 134.1/137.8/138.9 (C_q-7a/-11a/-Ar), 166.7

(C=O) ppm. MS (EI, 70 eV): m/z (%) = 294 (20) [M + 1]⁺, 293

(100) [M]⁺, 292 (94), 278 (13) [M – CH₃]⁺, 264 (12), 216 (14) [M –

C₆H₅]⁺, 202 (23), 188 (16), 115 (9), 91 (17). C₂₀H₂₃NO (293.2):

calcd. C 81.87, H 7.90, N 4.77; found C 81.71, H 7.97, N 4.67.

2

3

14.0, J_2β,2α= 12.3, J_2β,3= 8.1, J_2β,1β= 6.0 Hz, 1 H, 2β-H), 2.49

(m_c, J_1α,2β= 14.0, J_1α,1β= 13.5, J_1α,11b= 7.7, J_1α,2α= 6.2 Hz, 1

H, 1α-H), 2.65 (dd, J_1β,1α= 13.5, J_1β,2β= 6.0 Hz, 1 H, 1β-H),

3

2

3

2

3

4.36 (m_c, J_3,2β= 8.1, J_3,CH3= 6.3 Hz, 1 H, 3-H), 4.77 (d, J_11b,1α

= 7.7 Hz, 1 H, 11b-H), 7.27 (s, 1 H, 7-H), 7.30–7.36 (m, 4 H, Ar-

H), 7.39 (m_c, 3 H, Ar-H), 7.69 (m_c, 2 H, Ar-H) ppm. ¹³C NMR

(125 MHz): δ = 19.4 (CH₃), 25.5/31.1 (C-1/-2), 54.0/57.7 (C-3/-11b),

122.6/127.6/128.0/128.2/128.4/128.6/130.0/131.3 (C-7/-Ar), 136.2/

138.3/139.0/140.8 (C-6/-7a/-11a/-Ar), 164.4 (C=O) ppm. MS (EI,

60 eV): m/z (%) = 304 (5) [M + H₂O]⁺, 289 (9) [M]⁺, 274 (2) [M –

CH₃]⁺, 214 (16), 213 (100), 183 (40), 181 (17), 105 (8). C₂₀H₁₉NO

1

Selected H NMR Spectroscopic Data of 40: H NMR (500 MHz,

taken from the mixture with 39): δ = 1.25 (d, ³J = 6.3 Hz, 3 H,

CH₃), 1.5–1.6 (2 H), 1.6–1.7 (2 H), ca. 1.9–2.0 (2 H), 2.0–2.15 (2 (289.4): calcd. C 83.01, H 6.62, N 4.84; found C 82.37, H 6.69, N

H), 2.3–2.4 (2 H), 2.4–2.45 (1 H), 2.45–2.5 (1 H), 4.30 (s, 1 H, 6- 4.69 (crystals contain water).

3

H), 4.5–4.55 (1 H, 3-H), 5.54 (d, J = 8.0 Hz, 1 H, 7-H), ca. 7.2 (3

H, Ar-H), 7.2–7.25 (2 H, Ar-H) ppm.

1-(3Ј-Methyl-2Ј,3Ј-dihydro-1ЈH-pyrrolo[2Ј,1Ј-a]isoindol-5Ј-yl)-2-

phenylethanone (44): A mixture of 34c (90 mg, 0.315 mmol) in dry

1-(3Ј-Methyl-2Ј,3Ј,6Ј,7Ј,8Ј,9Ј-hexahydro-1ЈH-pyrrolo[2Ј,1Ј-a]iso-

indol-5Ј-yl)-2-phenylethanone (41): mixture of 34b (74 mg,

0.25 mmol) in dry methanol (3 mL) and NaOMe (14 mg,

0.25 mmol) was stirred for 5 h at room temperature. After work up,

methanol (1 mL) and MeONa (17 mg, 0.31 mmol) was stirred for

4 h at room temperature. After work up, flash chromatography (cy-

clohexane/ethyl acetate, 40:1, 30:1, 20:1) of the crude material af-

forded 44 (13 mg, 14%) and a 3:2 mixture of 42 and 43 (29 mg,

A

2730

www.eurjoc.org

Eur. J. Org. Chem. 2005, 2715–2733

Dipolar Route to Azepinone Derivatives by Heterocyclization of Enallenyl Nitrones

FULL PAPER

3

26%). After a reaction time of 90 h, 16 mg (18%) of 44 and 73 mg 5.21 (t, J_3,2= 7.5 Hz, 1 H, 3-H), 6.80 (dd, 2 H, Ar-H), 7.08 (m_c,

1

(66%) of 42/43 (ca. 3:2 mixture) were isolated. H NMR spectro-

3 H, Ar-H), 7.30 (m_c, 1 H, Ar-H), 7.35 (m_c, 2 H, Ar-H), 7.39 (s, 1

H, 7-H), 7.41–7.46 (m, 3 H, Ar-H), 7.53 (m_c, 1 H, Ar-H), 7.66 (dd,

2 H, Ar-H) ppm. ¹³C NMR (125 MHz): δ = 26.6 (C-1), 35.0 (C-2),

58.4 (C-11b), 63.9 (C-3), 122.7 (C-Ar), 125.9 (2 C-Ar), 126.6 (C-

3

scopic data for 44 (250 MHz): δ = 1.41 (d, J_CH3,3Ј= 6.4 Hz, 3 H,

2

3

CH₃), 2.31 (dddd, J = 12.5, J_2Ј,3Ј= 7.3, J_2Ј,1Ј= 2.1, J = 0.9 Hz,

1 H, 2Ј-H), 2.79 (m_c, ²J = 12.5, J_2Ј,1Ј= 10.4 Hz, 1 H, 2Ј-H), 3.07–

3

3.23 (m, J_1Ј,2Ј= 10.4, J_1Ј,2Ј= 2.1 Hz, 2 H, 1Ј-H), 4.34 (d, J = Ar), 127.8 (C-Ar), 127.9 (C-Ar), 128.1 (2 C-Ar), 128.4 (2 C-Ar),

2.1 Hz, 2 H, 2-H), 5.44 (m_c, J_3Ј,2Ј= 7.3, J_3Ј,CH3= 6.4 Hz, 1 H,

3

128.9 (2 C-Ar), 129.2 (C-7/-Ar), 130.9 (C-7/-Ar), 134.9 (C-7/-Ar),

3

3Ј-H), 7.11 (m_c, J = 8.2 Hz, 1 H, 7Ј-/8Ј-H), 7.26 (dd, J = 8.9 Hz, 136.1 (C_q), 139.1 (C_q), 139.5 (C_q), 139.8 (C_q), 142.4 (C_q), 164.7

1 H, 7Ј-/8Ј-H), 7.30–7.36 (m, 5 H, Ar-H), 7.62 (td, J = 8.2, J = (C=O) ppm. MS (EI, 70 eV): m/z (%) = 352 (18) [M + 1]⁺, 351 (64)

3

1.2 Hz, 1 H, 6Ј-/9Ј-H), 7.95 (d, J = 8.9 Hz, 1 H, 6Ј-/9Ј-H) ppm.

[M]⁺, 335 (6) [M – O]⁺, 334 (21), 274 (2) [M – C₆H₅]⁺, 246 (18),

234 (35) [C₁₆H₁₂NO]⁺, 233 (5) [M – C₉H₁₀]⁺, 232 (11), 221 (2)

[C₁₆H₁₅N]⁺, 220 (13), 206 (5) [C₁₅H₁₀O]⁺, 204 (13), 202 (11), 191

(10), 119 (100), 115 (15), 104 (12), 91 (17), 77 (11). C₂₅H₂₁NO

(351.4): calcd. C 85.44, H 6.02, N 3.99; found C 85.14, H 6.13, N

3.98.

6-Phenyl-1,2,3,11b-tetrahydro-5H-pyrrolo[2,1-a][2]benzazepin-5-one

(45): A solution of 35c (100 mg, 0.36 mmol) and TBAI (13 mg,

10 mol%) in dry toluene (2 mL) was stirred for 5 min, treated with

KOH (20 mg, 0.36 mmol), and then refluxed for 0.5 h. After work

up, flash chromatography (cyclohexane/ethyl acetate, 10:1, 5:1, 3:1)

of the crude material afforded 45 (75 mg, 75%) as an amorphous

solid; colorless crystals were obtained from ethanol, m.p. 132–

¹H NMR Spectroscopic Data of 48: ¹H NMR (250 MHz, taken

from the mixture with 47): δ = 1.97 (m_c, 1 H, 1-/2-H), 2.48–2.69

(m, J = 7.9 Hz, 3 H, 1-H, 2-H), 5.06 (d, J = 7.3 Hz, 1 H, 11b-H),

5.37 (d, J = 7.9 Hz, 1 H, 3-H), 7.26–7.28 (m, 1 H, Ar-H), 7.30 (br.

s, 2 H, Ar-H), 7.32–7.34 (m, 2 H, Ar-H), 7.35–7.37 (m, 2 H, Ar-

H), 7.40 (m_c, 5 H, Ar-H), 7.44 (m_c, 1 H, Ar-H), 7.62–7.67 (m, 2

H, Ar-H) ppm.

133 °C. IR (CCl ): ν = 3064, 3023, 2976, 2950, 2930, 2878, 1636

˜

4

(C=O), 1429, 1345 cm^–1. H NMR (400 MHz): δ = 2.13 (m_c, 2 H,

1-/2-/3-H), 2.35 (m_c, 1 H, 1-/2-/3-H), 2.75 (m_c, 1 H, 1-/2-/3-H), 3.59

(m_c, 1 H, 1-/2-/3-H), 3.74 (m_c, 1 H, 1-/2-/3-H), 4.73 (d, ³J = 7.1 Hz,

1 H, 11b-H), 7.32 (m_c, 2 H, Ar-H, 7-H), 7.34–7.44 (m, 6 H, Ar-

H), 7.69 (m_c, 2 H, Ar-H) ppm. ¹³C NMR (100 MHz): δ = 23.6/

27.7/46.6/57.1 (C-1/-2/-3/-11b), 122.4/127.6/128.0/128.3/128.5/

130.4/133.2 (C-Ar), 136.1/138.5/139.2/140.1 (C_q-6/-7a/-11a/-Ar),

164.6 (C=O) ppm. MS (EI, 70 eV): m/z (%) = 275 (54) [M]⁺,

274 (23), 247 (6) [M – C₂H₄]⁺, 246 (23), 218 (16), 198 (5) [M –

C₆H₅]⁺, 189 (9), 170 (19), 158 (100) [C₁₀H₈NO]⁺, 108 (11).

C₁₉H₁₇NO (275.3): calcd. C 82.88, H 6.22, N 5.09; found C 82.31,

H 6.3, N 4.92 (crystals contain traces of water).

1

5-Chloro-1-[2Ј-(3ЈЈ-phenylprop-1ЈЈ-ynyl)phenyl]pentan-1-ol (49):

A

solution of 4-chlorobutylmagnesium bromide, freshly prepared

from 1-bromo-4-chlorobutane (1.26 mL, 11.0 mmol) and magne-

sium turnings (267 mg, 11.0 mmol) in THF (12 mL), was added to

a stirred solution of 28 (2.02 g, 9.17 mmol) in dry THF (12 mL)

at –40 °C under N₂. This mixture was stirred at –40 °C for a further

3 h, and then warmed to room temperature, treated with saturated

NH₄Cl, and extracted with diethyl ether. The combined organic

phases were washed with water, dried (MgSO₄), and concentrated

in vacuo. Flash chromatography (cyclohexane/ethyl acetate, 50:1,

1-(2Ј,3Ј-Dihydro-1ЈH-pyrrolo[2Ј,1Ј-a]isoindol-5Ј-yl)-2-phenyl-

ethanone (46): A mixture of 35c (100 mg, 0.36 mmol) in dry meth-

anol (2 mL) and MeONa (19 mg, 0.36 mmol) was stirred for 24 h

at room temperature. After work up, flash chromatography (cyclo-

hexane/ethyl acetate, 10:1, 5:1, 3:1) of the crude material afforded,

besides 45 (65 mg, 65%), 46 (6 mg, 6%). ¹H NMR (250 MHz): δ =

40:1) afforded 49 (1.07 g, 37%) as a yellow oil. IR (CCl ): ν =

˜

4

3067, 3028, 2939, 1698, 1650, 1453, 1252, 1068, 906 cm^–1. ¹H NMR

(500 MHz): δ = 1.41–1.49 (m, J = 4.9 Hz, 1 H, 2-H), 1.56–1.62 (m,

J = 7.9 Hz, 1 H, 2-H), 1.75 (m_c, J = 6.8 Hz, 4 H, 3-H, 4-H), 3.47

(t, J = 6.8 Hz, 2 H, 5-H), 3.87 (s, 2 H, 3ЈЈ-H), 5.13 (dd, J = 7.9, J

= 4.9 Hz, 1 H, 1-H), 7.21 (dt, J = 7.5, J = 1.4 Hz, 1 H, Ar-H), 7.26

(m_c, 1 H, Ar-H), 7.31 (dd, J = 7.5, J = 1.4 Hz, 1 H, Ar-H), 7.55

(m_c, 2 H, Ar-H), 7.39 (d, J = 0.8 Hz, 1 H, Ar-H), 7.42 (m, 2 H,

Ar-H), 7.47 (m_c, 1 H, Ar-H) ppm. ¹³C NMR (125 MHz): δ = 23.3

(C-3), 26.0 (C-3ЈЈ), 32.4/37.3 (C-2/-4), 44.9 (C-5), 72.1 (C-1), 80.3

(ϵC), 92.9 (ϵC), 120.9 (C-2Ј), 125.2/127.1/128.4/132.4 (C-3Ј/-4Ј/-

5Ј/-6Ј), 126.8 (C-Ar), 127.9 (2 C-Ar), 128.7 (2 C-Ar), 136.6 (C_q-

Ar), 146.4 (C-1Ј) ppm. MS (EI, 70 eV): m/z (%) = 312 (14) [M]⁺,

235 (3) [M – C₃H₆Cl]⁺, 222 (31), 221 (100) [M – C₄H₈Cl]⁺, 204 (9),

203 (14), 193 (10), 191 (6) [C₁₅H₁₁]⁺, 178 (16), 115 (21)

[C₉H₇]⁺, 105 (8), 91 (53). HRMS (C₂₀H₂₁ClO): calcd. 312.1281;

found 312.1282.

3

2.65 (m_c, J = 8.2, J = 7.3 Hz, 2 H, 2Ј-H), 3.18 (t, J = 7.3 Hz, 2

H, 1Ј-/3Ј-H), 4.33 (s, 2 H, 2-H), 4.71 (t, ³J = 8.2 Hz, 2 H, 3Ј-/1Ј-

3

H), 7.12 (m_c, J = 8.2, J = 6.7, J = 0.9 Hz, 1 H, 7Ј-/8Ј-H), 7.31–

7.38 (m, J = 6.7 Hz, 6 H, 7Ј-/8Ј-H, Ar-H), 7.63 (td, J = 8.2, J =

0.9 Hz, 1 H, 6Ј-/9Ј-H), 7.96 (td, J = 8.5, J = 0.9 Hz, 1 H, 6Ј-/9Ј-

3

H) ppm.

3,6-Diphenyl-1,2,3,11b-tetrahydro-5H-pyrrolo[2,1-a][2]benzazepin-5-

one (47 and 48): A solution of 36c (466 mg, 1.33 mmol) and TBAI

(49 mg, 10 mol%) in dry toluene (10 mL) was stirred for 5 min,

treated with KOH (74 mg, 1.33 mmol), and then refluxed for 0.5 h.

After work up, flash chromatography (cyclohexane/ethyl acetate,

50:1, 30:1, 10:1) of the crude material afforded an approximate

0.77:1 mixture of 47 (24%) and 48 (31%) (total yield 260 mg, 55%).

Only the minor component, 47 (see Results and Discussion sec-

tion), was isolated in the pure form. Treatment of a methanolic

solution of 36c with MeONa at room temperature for 4 h gave a

similar result: After work up and purification an approximate

0.73:1 mixture of 47 (22%) and 48 (30%) was obtained.

5-Chloro-1-[2Ј-(3ЈЈ-phenylprop-1Ј-ynyl)phenyl]pentan-1-one

(50):

IBX (1.08 g, 3.86 mmol) was added to a stirred solution of 49

(0.93 g, 2.97 mmol) in dry DMSO (75 mL) under argon. The mix-

ture was stirred for a further 4.5 h and then the solution was cooled

in an ice bath and treated with diethyl ether/water (100 mL, 1:2

mixture). After extraction with diethyl ether, the organic phase was

washed with saturated NaHCO₃and brine, dried (MgSO₄), and

then concentrated. Flash chromatography (cyclohexane/ethyl ace-

Compound 47: Colorless crystals, m.p. 164 °C (ethanol). IR

(PTFE): ν = 3054, 3027, 2977, 2945, 2888, 1949, 1621, 1491, 1414,

˜

1335, 1265, 1249 cm^–1. H NMR (500 MHz): δ = 2.16 (m_c, J_2α,2β

1

2

3

2

= 12.5, J_2α,3= 7.5, J_2α,1β= 3.7 Hz, 1 H, 2α-H), 2.44 (m_c, J_1α,1βtate, 60:1) of the residue gave 50 (769 mg, 83%) as a yellow oil. IR

= 13.2, ³J_1α,11b= 7.7, ³J_1α,2β= 4.2 Hz, 1 H, 1α-H), 2.56 (m_c, ²J_2β,2α

(CCl ): ν = 3060, 3028, 2952, 2230 (CϵC), 1684 (C=O), 1539, 1494,

= 12.5, ³J_2β,3= 7.5, ³J_2β,1β= 7.1, ³J_2β,1α= 4.2 Hz, 1 H, 2β-H), 2.78 1453, 1252, 1221, 1072, 1004, 926 cm^–1. H NMR (500 MHz): δ =

˜

4

1

2

3

(m_c, J_1β,1α= 13.2, J_1β,2β= 7.1, J_1β,2α= 3.7, J_1β,11b= 3.2 Hz, 1

1.70–1.76 (m, J_3,2= 6.9 Hz, 2 H, 3-H), 1.77–1.83 (m, J_4,5=

6.5 Hz, 2 H, 4-H), 3.06 (t, J_2,3= 6.9 Hz, 2 H, 2-H), 3.47 (t, J_5,4

3

H, 1β-H), 4.90 (dd, J_11b,1α= 7.7, J_11b,1β= 3.2 Hz, 1 H, 11b-H),

Eur. J. Org. Chem. 2005, 2715–2733

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2731

K. Knobloch, J. Koch, M. Keller, W. Eberbach

FULL PAPER

= 6.5 Hz, 2 H, 5-H), 3.87 (s, 2 H, 3ЈЈ-H), 7.26 (m_c, J = 7.9 Hz, 1

H, Ar-H), 7.35 (m_c, J = 7.7 Hz, 3 H, Ar-H), 7.39–7.42 (m, J =

7.5 Hz, 3 H, Ar-H), 7.53 (dd, J = 7.7, J = 1.4 Hz, 1 H, Ar-H), 7.58

(d, J = 7.9 Hz, 1 H, Ar-H) ppm. ¹³C NMR (125 MHz): δ = 21.7

(C-3), 26.2 (C-3ЈЈ), 32.1 (C-4), 41.2 (C-2), 44.8 (C-5), 81.4 (ϵC),

93.5 (ϵC), 121.5 (C_q-1), 126.9 (C-Ar), 127.9/128.0/130.9/134.0 (C-

3Ј/-4Ј/-5Ј/-6Ј), 128.1 (2 C-Ar), 128.8 (2 C-Ar), 136.3 (C_q-Ar), 141.5

(C_q-1Ј), 203.3 (C=O) ppm. MS (EI, 70 eV): m/z (%) = 311 (34) [M

+ 1]⁺, 310 (48) [M]⁺, 309 (91), 275 (7) [M – Cl]⁺, 234 (20), 233

(100) [M – C₃H₆Cl]⁺, 232 (14), 219 (42) [C₁₆H₁₁O]⁺, 215 (26), 205

(17), 202 (20), 201 (14), 191 (40), 189 (80), 165 (40), 95 (13). HRMS

(C₂₀H₁₉ClO): calcd. 310.1124; found 310.1125.

Acknowledgments

The technical assistance of Sabine Müller is gratefully acknowl-

edged.

[1]

J. O. Hawthorne, E. L. Mihelic, U.S. Patent 3668232, 1972

[Chem. Abstr. 1972, 77, 101199s]; J. O. Hawthorne, E. L. Mih-

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[2]

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A. A. Pessolano, B. E. Witzel, R. L. Clark, T.-Y. Shen, P. Gra-

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6-[2Ј-(3ЈЈ-Phenylprop-1ЈЈ-ynyl)phenyl]-2,3,4,5-tetrahydropyridine N-

Oxide (51): A mixture of 50 (300 mg, 0.97 mmol), hydroxylamine

hydrochloride (134 mg, 1.93 mmol), and potassium carbonate

(133 mg, 0.97 mmol) in ethanol/water (6 mL, 1:1 mixture) was re-

fluxed for 4 h. This solution was cooled to room temperature, brine

(10 mL) was added, and the solution was extracted with ethyl ace-

tate. The combined organic phases were washed with saturated

NaHCO₃, dried (MgSO₄), and concentrated in vacuo. Purification

by flash chromatography (ethyl acetate/methanol, 50:1, 10:1) af-

a) P. Josee Voorstad, J. M. Chapman, G. H. Cocolas, S. D.

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lander, S. T. Ross, J. M. Samanen, I. N. Uzinskas, J. W. Venslav-

sky, C. C.-K. Yuan, R. C. Haltiwanger, M. Gowen, S.-M.

Hwang, I. E. James, M. W. Lark, D. J. Rieman, G. B. Stroup,

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[4]

forded 51 (119 mg, 42%) as an orange oil. IR (CCl ): ν = 3060,

˜

4

3028, 2952, 2862, 1252, 1068, 1004, 976 cm^–1. ¹H NMR (500 MHz):

δ = 1.66 (m_c, J = 6.2, J = 5.7 Hz, 2 H, 3-/4-H), 1.86 (m_c, J = 6.2,

J = 5.7 Hz, 2 H, 3-/4-H), 2.66 (tt, J = 6.3, J = 1.9 Hz, 2 H, 5-H),

3.81 (s, 2 H, 3ЈЈ-H), 3.86 (tt, J = 6.3, J = 1.9 Hz, 2 H, 2-H), 7.25

(m_c, 1 H, Ar-H), 7.30–7.35 (m, 5 H, Ar-H), 7.38 (m_c, 2 H, Ar-H),

7.52 (m_c, 1 H, Ar-H) ppm. ¹³C NMR (125 MHz): δ = 18.8/23.2 (C-

3/-4), 26.0 (C-3ЈЈ), 30.6 (C-5), 58.9 (C-2), 80.4 (ϵC), 91.6 (ϵC),

121.8 (C_q-2Ј), 126.8 (C-Ar), 127.7/128.2/128.6/132.7 (C-3Ј/-4Ј/-5Ј/-

6Ј), 128.1 (2 C-Ar), 128.7 (2 C-Ar), 136.8/137.9 (C_q-Ar/-1Ј), 145.2

(C_q-6) ppm. MS (EI, 70 eV): m/z (%) = 289 (6) [M]⁺, 273 (13) [M –

O]⁺, 272 (26), 260 (56), 244 (16), 230 (14), 202 (17), 199 (17), 198

(100) [M – C₇H₇]⁺, 189 (22), 186 (45), 170 (44), 168 (31), 158 (20),

153 (40), 143 (23), 128 (41), 115 (37), 103 (21), 91 (16). HRMS

(C₂₀H₁₉NO): calcd. 289.1467; found 289.1469.

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a) Y. Horiguchi, T. Saitoh, T. Kashiwagi, L. Katura, M. Ita-

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[7]

[8]

[9]

For reviews, see: a) D. J. Pasto, Tetrahedron 1984, 40, 2805–

2827; b) H. F. Schuster, G. M. Coppola, Allenes in Organic

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a) H. Hopf in The Chemistry of Allenes (Ed.: S. R. Landor),

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2, pp. 331–337.

7-Phenyl-1,3,4,12b-tetrahydropyrido[2,1-a][2]benzazepin-6(2H)-one

(52): KOH (18 mg, 0.33 mmol) was added to a stirred mixture of

51 (95 mg, 0.33 mmol) and TBAI (12 mg, 10 mol%) in dry toluene

(3 mL). After refluxing the suspension for 1 h, work up was ac-

complished by addition of water (10 mL) and extraction with di-

ethyl ether. The combined organic fractions were washed with satu-

rated NH₄Cl and brine, dried (MgSO₄), and concentrated. Flash

chromatography (cyclohexane/ethyl acetate, 40:1, 20:1, 5:1) of the

crude material afforded 52 (50 mg, 52%); colorless crystals, m.p.

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For selected examples, see: a) R. W. M. Aben, S. Braverman,

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[11]

[12]

W. Carruthers, Cycloaddition Reactions in Organic Synthesis,

Pergamon Press, Oxford, 1990.

155–157 °C, were obtained from ethanol. IR (CCl ): ν = 3068,

˜

4

3023, 2943, 2861, 1634, 1416, 1255, 1232, 1002, 977 cm^–1. ¹H NMR

(500 MHz): δ = 1.65 (m_c, J = 13.2, J = 3.7 Hz, 1 H, 2-/3-/4-H),

1.86 (m_c, J = 13.4 Hz, 1 H, 2-/3-/4-H), 1.93–2.03 (m, 2 H, 2-/3-/4-

For selected examples, see: a) U. Koop, G. Handke, N. Krause,

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2

3

2

H), 2.12 (m_c, J = 14.5, J_1,12b= 6.9 Hz, 1 H, 1-H), 2.47 (m_c, J =

14.5 Hz, 1 H, 1-H), 2.64 (m_c, J = 13.5, J = 3.7 Hz, 1 H, 2-/3-/4-H),

3

[13]

[14]

4.46 (m_c, J = 13.8 Hz, 1 H, 2-/3-/4-H), 4.75 (dd, J_12b,1= 6.9, J =

2.6 Hz, 1 H, 12b-H), 7.27 (br. s, 1 H, 8-H), 7.32–7.45 (m, J = 9.5,

J = 6.8 Hz, 6 H, Ar-H), 7.52 (d, J = 6.8 Hz, 1 H, Ar-H), 7.72 (m_c,

J = 9.5 Hz, 1 H, Ar-H) ppm. ¹³C NMR (125 MHz): δ = 21.1/24.1/

25.4 (C-1/-2/-3), 38.1/52.3 (C-4/-12b), 124.4 (C-Ar), 127.6/128.1/

128.2/130.1 (C-9/-10/-11/-12), 128.4 (2 C-Ar), 130.6 (C-8), 136.2

(C_q), 138.4 (C_q), 139.5 (C_q), 139.7 (C_q), 167.0 (C=O) ppm. MS (EI,

70 eV): m/z (%) = 290 (20) [M + 1]⁺, 289 (100) [M]⁺, 288 (24), 261

(39) [M – C₂H₄]⁺, 260 (33), 233 (5) [M – C₄H₈]⁺, 212 (7) [M –

C₆H₅]⁺, 204 (27), 191 (13), 184 (72), 178 (11) [C₁₀H₁₀]⁺, 172 (65),

159 (2) [C₁₁H₁₃N]⁺, 115 (12), 109 (11), 77 (6). C₂₀H₁₉NO (289.4):

calcd. C 83.01, H 6.62, N 4.84; found C 82.85, H 6.56, N 4.78.

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2732

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Eur. J. Org. Chem. 2005, 2715–2733

Dipolar Route to Azepinone Derivatives by Heterocyclization of Enallenyl Nitrones

FULL PAPER

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Received: December 30, 2004

Eur. J. Org. Chem. 2005, 2715–2733

www.eurjoc.org

2733

Article Doi

The dipolar route to azepin-3-one derivatives by heterocyclization of linear and monocyclic enallenyl nitrones as the key step

DOI: 10.1002/ejoc.200400922

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Article abstract of DOI:10.1002/ejoc.200400922

Full text of DOI:10.1002/ejoc.200400922

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