Substituted 3-hydroxypyrroles from 1-azapenta-1,4-dien-3-ones: The aza-Nazarov reaction - Synthesis and quantum chemical calculations

FULL PAPER

DOI: 10.1002/ejoc.200600602

Substituted 3-Hydroxypyrroles from 1-Azapenta-1,4-dien-3-ones:

The Aza-Nazarov Reaction – Synthesis and Quantum Chemical Calculations

Jürgen Dieker,^[a]Roland Fröhlich,^[a]and Ernst-Ulrich Würthwein*^[a]

Dedicated to Professor Gerhard Erker on the occasion of his 60th birthday

Keywords: Aza-Nazarov reaction / Ring-closure reactions / 3-Hydroxypyrroles / Quantum chemistry / Cations / Ring

contraction

On the basis of quantum chemical calculations, 1-azapenta-

1,4-dien-3-ones were chosen as candidates for a thorough

theoretical and experimental investigation of their electro-

cyclization reactivity upon protonation. According to G3

theory, the O-protonated 1-azapenta-1,4-dien-3-one cyclizes

with high exothermicity and modest activation barrier to give

the corresponding 3-hydroxydihydropyrrolium ion (“aza-

easily prepared from corresponding α-imino-carbonyl com-

pounds 7 and 8 by aldol condensation. Experimentally, as

evidenced by in situ NMR experiments, 1-azapenta-1,4-dien-

3-ones gave dihydropyrrole cations upon protonation at a

low temperature. For preparative purposes, trapping of the

3-hydroxypyrrole intermediates with the use of anhydrides

proved to be advantageous. Thus, a large variety of new,

Nazarov reaction”), whereas the corresponding O-proton- fully substituted 3-hydroxypyrrole derivatives 13–17 have

ated 2-azapenta-1,4-dien-3-one shows endothermicity and a

huge barrier to the electrocyclization reaction. The stereo-

chemistry of the cyclization reaction (torquoselectivity) was

studied in detail theoretically as well as the cyclization prop-

erties of vinylogous system 4, which may give either five- or

seven-membered heterocyclic cations (5 versus 6). 1-Amino-

and 1-alkoxy-1-azapenta-1,4-dien-3-ones 9 and 10 were

become accessible in moderate-to-good yields, including two

bis-pyrrole compounds 17a,b. All new compounds were thor-

oughly characterized, including a number of X-ray diffrac-

tion studies.

Germany, 2006)

With this in mind, we performed quantum chemical cal-

culations in order to identify cationic species suitable for

exothermic ring-closure reactions to yield pyrrole deriva-

tives. Furthermore, we studied the mechanism and the ste-

reochemistry of the cyclization reaction in detail, including

the cyclization of a vinylogous system able to form five-

and/or seven-membered heterocyclic products. In the next

step of the study we synthesized suitable precursors of these

cationic intermediates, which turned out to be promising

candidates for the ring-closure reaction (“aza-Nazarov reac-

tion”). Finally, in a low-temperature NMR study and on

a preparative scale, we investigated the suitability of these

precursors for the preparation of derivatives of various 3-

hydroxypyrroles by the cyclization reaction, including those

that may give either a five- and/or a seven-membered

heterocyclic system upon cyclization.

In the literature, only sparse information concerning such

cyclization reactions is available. Ciufolini and Roschangar

coined, to the best of our knowledge, the term “aza-Naza-

rov”.^[7]They observed that a special quinoline derivative

containing a 1-azadienone subunit reacted upon treatment

with Lewis acids like Yb(fod)₃to give an indolizine deriva-

tive. In the authors opinion, “this interesting reaction…has

Introduction

The Nazarov cyclization reaction [Figure 1, Equation (1)]

is a very valuable method for the synthesis of five-mem-

bered carbocycles.^[1–3]The key step of this pericyclic reac-

tion is a conrotatory 4π electrocyclization of a pentadienyl

cation, which is controlled by the principle of preservation

of orbital symmetry, thus resulting in predictable stereo-

chemistry of the products. The intermediate pentadienyl

cations are usually prepared from penta-1,4-dien-3-ones

with the use of strong Brønsted acids, but Lewis acids might

also be used.

As part of an ongoing project investigating the influence

of heteroatoms on the reactivity of charged polyenyl com-

pounds^[4–6]we were interested in finding out if a Nazarov-

type reaction may also be applied as a general method for

the synthesis of heterocycles, for example, pyrroles.

[a] Organisch-Chemisches Institut, Westfälische Wilhelms-Uni-

versität,

Corrensstraße 40, 48149 Münster, Germany

Fax: +49-251-83-39772

E-mail: wurthwe@uni-muenster.de

Supporting information for this article is available on the

WWW under http://ww w .eurjoc.org or from the author.

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as 2-amino- or 2-alkoxy-2,3-dihydropyrrol-3-ones resulting

from a Beckmann rearrangement and cyclization reaction.

The structures of the products of these cyclization reactions

as formulated by Diels et al. are close, but not identical, to

the correct ones, as we will show in this contribution.

The cationic cyclization reaction presented herein is a

preparatively useful alternative to the anionic cyclization of

2-azapentadienyl metal systems in the synthesis of pyr-

roles.^[13–15]

Results and Discussion

Quantum Chemical Calculations

Starting with the parent Nazarov reaction, that is, the

electrocyclization of the 3-hydroxypentadienylium ion to

give the 2-hydroxycyclopentenylium ion, we examined the

thermodynamics of the cyclization reactions of the U-

shaped 3-hydroxy-1- and -2-azapentadienylium ions to give

the corresponding positively charged azaheterocycles (Fig-

ure 1) in order to learn more about the electronic influence

of nitrogen atoms in such conversions. According to the

calculations, all of the reactions proceed starting from the

U-shaped conformation/configuration in a concerted, peri-

cyclic, conrotatory mode, in which one single transition

state interconnects the starting materials and products.

Whereas the cyclization of the methyl-substituted Naza-

rov system [Figure 1, Equation (1)]^[16–18]is indicated to be

slightly endothermic (3 kcal/mol) with a substantial acti-

vation barrier (19 kcal/mol) (G3^[19]level of theory,

Gaussian 98^[20]and 03^[21]), a nitrogen atom in the 1-position

Figure 1. Cyclization reactions of 3-hydroxypentadienylium and

various aza-3-hydroxypentadienylium systems. Relative energies

[kcal/mol] with respect to the starting material are given for the

transition states and the cyclic products (G3 level of theory).

[3-hydroxy-1-methyl-1-azapentadienylium

ion,

Equa-

tion (2)] results in a very exothermic ring-closure reaction

(ca. –37 kcal/mol) with a reduced activation barrier (8 kcal/

yet to be fully explored, but it already appears to have lim- mol). In contrast, the corresponding cation with a nitrogen

ited scope”. In a study by Matoba and coworkers, a number atom in the 2-position [3-hydroxy-2-azapentadienylium sys-

of heterocyclic chalcones derived from aza-heterocycles tem, Equation (3)] is not expected to form cyclic products

underwent cyclization to the corresponding pyrrole systems because of the positive heat of reaction (ca. 24 kcal/mol)

on treatment with strong acids (HCl, HClO₄).^[8–10]They and the huge activation barrier (29 kcal/mol). In general

also included a vinylogous chalcone in their study. This re- terms, this very strong influence of the position of the nitro-

acted to give a five-membered heterocyclic system, not a gen atom within the unsaturated chain may be attributed to

seven-membered one. Hill et al. reported the photocycliza- the nature of the electronic structure of the open chain cat-

tion of heterocyclic enones giving indolo[1,2-a]quinoxa- ion: a nitrogen atom in an odd position of a positively

lines.^[11]In all these examples, at least one double bond of charged unsaturated chain (1-azaallyl cation substructure

the 1-azadienones was part of an aromatic system.

with some nitrenium character) leads to highly destabilized,

In this work we were interested in studying the scope very reactive systems, whereas a nitrogen atom in an even

and limitations of the aza-Nazarov reaction carried out as position (2-azapropenylium moiety) significantly stabilizes

closely as possible to the parent Nazarov system. Instead of such cations, thus decreasing its reactivity. On the other

cyclopentenones, hydroxypyrroles were the expected prod- hand, the heterocyclic product ion in Equation (2) is

ucts from such cyclization reactions, which have, to the best well stabilized (iminium ion structure), whereas the hetero-

of our knowledge, been described in the literature only cyclic product ion from Equation (3) is highly reactive

once. In 1927, Diels et al. reported in a contribution con- (again a 1-azaallyl cation substructure). The electronic

cerning the Beckmann rearrangement “new transforma- properties of 1-azapentadienylium ions have been discussed

tions and rearrangements of oximes and hydrazones”.^[12]previously.^[22]

They treated oximes, oxime ethers and hydrazones of

From these calculations it is evident that a Nazarov-type

diacetylbenzal with perchloric acid in acetic anhydride to cyclization reaction might only be expected if the more elec-

obtain five-membered ring systems, which they identified tronegative nitrogen atom is located in the 1-position of the

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Hydroxypyrroles from Azapentadienones: The Aza-Nazarov Reaction

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pentadienylium moiety. Therefore, we concentrated our

study on 3-hydroxy-1-azapentadienylium systems. For pre-

parative reasons, however, we have not investigated the im-

ine-derived 3-hydroxy-1-azapentadienylium systems experi-

mentally, but we have instead examined the less reactive 1-

amino- and 1,3-dihydroxy-1-azapentadienylium ions [Equa-

tions (4) and (5)], which were generated by protonation of

the corresponding hydrazones and oximes. Figure 1 clearly

shows the strong influence of these donor groups^[18]on the

general reactivity of the intermediate cationic species, espe-

cially with respect to the reaction enthalpies, but the influ-

ence of the nitrogen atom in the 1-position of the 1-azapen-

tadienylium moiety still dominates and leads to substantial

exothermicity for the reactions of the oxime and hydrazone

with modest activation barriers.

In order to perform quantum chemical calculations of

systems larger than the ones discussed above, we repeated

these calculations at two additional lower levels of theory,

with the use of the recently developed SCS-MP2/6-31G(d)//

RHF/6-31G(d)^[23]method and the B3LYP/6-311+G(d,p)

DFT method. Owing to the excellent performance of SCS-

MP2/6-31G(d)//RHF/6-31G(d) observed here and else-

where,^[24]we used this method to evaluate details of the

reaction mechanism and its stereochemistry. In comparison

to SCS-MP2 (and G3), the reaction enthalpy calculated by

the DFT method for the cyclization reaction was too low

by about 6–9 kcal/mol. By using the classical uncorrected

MP2 method, the heat of the cyclization reaction was calcu-

lated to be about 2–10 kcal/mol more exothermic than that

calculated with the SCS-MP2 method.

Figure 2. Four different modes for the cyclization reaction of 3-

hydroxy-1-methoxy-1-azapentadienylium ion 1 to give 2. Relative

energies were calculated at the SCS-MP2/6-31G(d)//RHF/6-31G(d)

level of theory and are given in kcal/mol.

From a comparison of the out,out to the out,in transition

states on the one hand and of the in,out to the in,in transi-

For a more detailed look at the reaction mechanism of tion states on the other hand, it can be clearly seen that the

the conrotatory, thermally allowed ring-closure reaction orientation of the methyl substituent in the 5-position has

and its stereochemical features, model system 1 leading to only a small effect on the activation barrier. On the other

heterocyclic cation 2, which is similar to some of the experi- hand, the outward or inward position of the methoxy group

mentally studied compounds, was investigated computa- attached to the nitrogen atom in the 1-position of the 1-

tionally in detail [SCS-MP2/6-31G(d)//RHF/6-31G(d)]. The azapentadienylium moiety (out,out versus in,out and out,in

special emphasis of these calculations was the evaluation of versus in,in) leads to considerable differences in the acti-

effects produced by the phenomenon known as torquoselec- vation energy, as described in the literature.^[18]

tivity^[25,26]on pentadienylium systems with electron-donat-

The conrotatory transition states out,out-1-TS and

ing or -withdrawing substituents attached to the 1- and/or out,in-1-TS deviate by 30–35° from planarity and resemble

5-positions (Figure 2).^[27]We were interested to see whether each other closely. The torsional angle of the atoms C3–

3-hydroxy-1-methoxy-1-azapentadienylium ion 1 (with a C2–N1–O(Me) amounts to –166° in both structures, indi-

lone pair of electrons on the N1 atom and the C=N π elec- cating that a simultaneous interaction of the C=N π system

tron system) also shows substantial differences in the acti- and the lone pair of electrons on the nitrogen atom with

vation barriers for inward and outward rotation, as known the carbon atom in the 5-position is important for ring for-

for the Nazarov reaction.^[18]Thus, the four conceivable mation. The partially formed C–N bonds have a length of

transition states with the stereochemical combinations 2.14 or 2.24 Å, indicating an early transition state. Houk et

out,out, in,out, out,in and in,in, where the first descriptor al. reported typical transition state C–C distances for the

refers to the substituent at the nitrogen atom in the 1-posi- forming bond of 1.95–2.28 Å for pericyclic reactions.^[28]

tion, the second to the methyl group attached to the C5

The binding interaction in these transition states is domi-

atom, were calculated for complete analysis of the cycliza- nated by the second highest occupied molecular orbital

tion of molecule 1. In general, the aza-Nazarov cyclization (HOMO-1, see Supporting Information). The electronega-

of 1 is calculated to be a strongly exothermic reaction with tive nitrogen atom causes a shift of the nodal plane of the

a low energy barrier provided that the methoxy group pentadienylium HOMO from the C3 atom into the vicinity

adopts an outward position during the cyclization process. of the C4 atom in 1-azapentadienylium system 1 (HOMO-

In contrast, the corresponding alternative inward position 1).

of the electron-donating substituent during the rotation is

In contrast, the in,out-1-TS and in,in-1-TS transition

kinetically extremely disfavoured by 30–35 kcal/mol.

states are helix-shaped late transition states (1.95 and

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J. Dieker, R. Fröhlich, E.-U. Würthwein

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2.04 Å) with very substantial deviations from planarity (up methanesulfonic acid. In order to understand this selectiv-

to 86°). Here, owing to the steric requirements of the inward ity, the energy hyperfaces of both cyclization modes were

substituents, the cation cannot easily take advantage of or- studied computationally, concentrating on the lowest en-

bital stabilization by delocalization, thus explaining the ergy out,out isomers.

high activation barrier. In addition to this effect, the in,out-

1-TS and in,in-1-TS transition states show a strong anti-

bonding interaction between the free electron pair on the

oxygen atom of the methoxy function and the partially

formed new σ bond (see Supporting Information for a

graphical representation of the relevant orbitals).

The ionic character of these pericyclic reactions is small:

the NBO charge separation between the N1 atom (–0.05e)

and the C5 atom (0.09e) amounts to only 0.14e for out,out-

1-TS, 0.18e for in,out-1-TS (N1: –0.06; C5: 0.12), 0.19e for

in,out-1-TS (N1: –0.17; C5: 0.02) and 0.18e for in,in-1-TS

(N1: –0.16; C5: 0.02).

The NICS^[29,30]values for the four discussed transition

Scheme 1.

states have also been determined with respect to an axis

perpendicular to the centre of the forming heterocycle

[B3LYP/6-311+G(d,p)]. The following maximal NICS

values were found: in,out-1-TS –8.6; out,out-1-TS –8.6;

out,in-1-TS –8.2 and in,in-1-TS –6.1. The value for the

Nazarov reaction itself is 10.4, which is well in line with

these values, clearly indicating aromatic character and un-

derlining the pericyclic nature of these cyclization reactions.

Probably because of strong steric crowding, the NICS value

for the in,in-transition state is somewhat smaller.

The kinetically favoured route to the five-membered ring

involves rotation about the C3–C4 bond of protonated in-

termediate 4 and leads to the corresponding U-shaped iso-

mer U-4. This local minimum structure has the ability to

cyclize in a conrotatory mode via an out,out transition-state

structure to form pentacyclic cation 5. The calculated ener-

gies for this reaction path are shown in Figure 3. As ex-

pected, the thermodynamic and kinetic data for the 1,5-

electrocyclization reaction are comparable to those of the

model systems (compare Figures 1 and 2).

Calculations on Experimentally Studied System 3

The alternative, thermally allowed, disrotatory 6π 1,7-

electrocyclization to give seven-membered ring system 6 is

slightly more exothermic than the 1,5-electrocyclization re-

Five- versus Seven-Membered Ring Formation

Acid-induced cyclization reactions of vinylogous com- action (Figure 1), but requires more C–C bond rotations.

pound 3 allow the possibility of forming either five- (5) or Furthermore, the activation barriers necessary to achieve a

seven-membered (6) ring systems (Scheme 1). Experimen- conformation that allows the transition to a seven-mem-

tally (vide infra), only the formation of the five-membered bered ring are significantly higher and are much larger than

ring is observed upon protonation with the use of trifluoro- that required for the 1,5-electrocyclization.

Figure 3. Energy profiles for the cyclization of cation 4 to form either five-membered heterocyclic system 5 or seven-membered ring

system 6 [SCS-MP2/6-31G(d)//RHF/6-31G(d)].

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Hydroxypyrroles from Azapentadienones: The Aza-Nazarov Reaction

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Experimental Studies

In the case of diacetylhydrazone derivative 7, vinyl moie-

ties were introduced by an aldol condensation giving com-

pounds 9 in 57–76% yields; this approach is, however, ap-

plicable only to nonenolizable aldehydes (Scheme 2). It

proved best to deprotonate α-imino-carbonyl compound 7

first and to then treat it with the aldehyde. The structural

properties of 9a,c were determined by X-ray crystallography

Synthesis of 1-Azapenta-1,4-dien-3-ones 3, 9–11

To synthesize 1-azapenta-1,4-dien-3-ones 3, 9–11, we

took advantage of a procedure published by Diels et al. in

1927.^[12,31]This synthetic route starts from the highly reac-

tive dicarbonyl compound diacetyl. Donor-substituted ni-

trogen functionalities in the 1-position were introduced eas-

ily through condensation reactions with hydrazines and hy-

droxylamines (acetic acid catalysis) following literature pro-

cedures to give corresponding N-methyl-N-phenylhydra-

zone 7^[32]and oxime, respectively. In all the cases studied,

condensation took place only once. The oxime was con-

verted into corresponding oxime ether 8a by benzylation

and to 8b by methylation of the oxime anion.^[33]

Scheme 2.

Scheme 3.

Figure 4. Molecular structures of 9c (left) and 3 (right), as obtained by X-ray diffraction, showing the (E,E) configuration of both

compounds.

Scheme 4.

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J. Dieker, R. Fröhlich, E.-U. Würthwein

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(Figure 4, 9c). In all cases (E)-configured C=C and C=N tem (Scheme 1, vide supra). Figure 5 shows two ¹³C NMR

double bonds were found with adjacent C=O and C=N spectra; the upper spectrum is that of compound 3, the

moieties in the anti positions.

lower spectrum was obtained after the addition of trifluoro-

In a similar manner, oximes 8a,b gave a great variety of methanesulfonic acid to 3, dissolved in CD₂Cl₂, at –60 °C.

1-azapenta-1,4-dien-3-one derivatives 3 and 10 in 44–95% All of the signals could be assigned by using 2D experi-

yields by aldol condensation (Scheme 3), including vinylog- ments (COSY, HMQC and HMBC correlation techniques).

ous systems and those with heterocyclic substituents in the During the addition of the acid, the colour of the solution

5-position of the azadienone. X-ray structures were ob- changed from colourless to intense pink, which indicated

tained for 3 (Figure 4) and 10a,o, again showing (E)-config- the successful protonation of 3 and the formation of a posi-

ured C=C and C=N double bonds with C=O and C=N in tively charged, conjugated π system.

the anti positions.

Each signal that is present in the spectrum of 3 corre-

Bis-aldehydes like terephthalaldehyde or thiophene-2,5- sponds exactly to one new signal in the spectrum of proton-

dicarbaldehyde reacted twice in the aldol condensation of ated compound 5, that is, 1-azadienone 3 reacts completely

8b to give products 11a,b in 91 and 66% yields, respectively to give only one new compound. The signal due to the car-

(Scheme 4).

bonyl group disappeared as a result of proton attack at the

oxygen atom. The large shift of the signal arising from C10

to a high field indicates its rehybridization from sp²to sp³.

Thus, cyclization to form dihydropyrrolium ion 5 takes

place at a low temperature (–60 °C). This is in contrast to

Protonation of Compound 3: In situ NMR Characterization

of the Cation in Acidic Solution

In order to study the course of the protonation reaction the observations of Howell et al.^[34]who only observed the

of compounds 3 and 9–11, experiments in a NMR tube cyclization of the (nitrogen-free) Nazarov system 4-hy-

were first undertaken. For this purpose, compound 3 was droxyhepta-2,4-dien-5-ylium at 20 °C.

treated at –60 °C with an excess of trifluoromethanesulfonic

In order to determine whether a five- or a seven-mem-

acid. Oxime 3 is particularly interesting since it may cyclize bered heterocycle was formed, quantum chemical NMR

to form either a five- or a seven-membered heterocyclic sys- shift calculations for compounds 5 and 6 were performed

Figure 5. ¹³C NMR spectra for the protonation of 3 with numbering scheme for the carbon atoms. Upper spectrum: compound 3 before

addition of trifluoromethanesulfonic acid (room temperature); lower specrum: after addition of the acid to form 5 (CD₂Cl₂, –60 °C,

100 MHz). The signals from CF₃are marked with asterisks.

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at the DFT B3LYP/6-311+G(d,p) level of theory with the 3-hydroxypyrroles in nonpolar solvents exclusively form the

use of the GIAO method as implemented in the Gaussian keto tautomer, whereas in polar solvents like dimethyl sulf-

03 package. According to the calculations for the five-mem- oxide the enol form (like 12a) predominates (up to 85–

bered ring, two groups of signals are expected between δ = 95%).

5 and 6 ppm (for 4-H and 10-H), one between 6 and

6.5 ppm (3-H) and one signal between 7 and 7.5 ppm (9-H)

besides the aromatic signals. These predicted data for the

five-membered ring fit nicely with the experimental spec-

trum, whereas the calculated set of signals for a possible

seven-membered ring system with one group between 4 and

4.5 ppm and three groups between 6.5 and 7.5 ppm dis-

agrees with the experimental spectrum. The ¹³C NMR spec-

troscopic data also fit much better for a five-membered ring

system than for a seven-membered ring (certainty value R²

= 0.9902 versus 0.9792 for a correlation of all signals). Be-

sides the chemical shifts, experimental and calculated coup-

ling constants also confirm the preferred formation of the

five-membered ring system, as predicted by the quantum

chemical calculations (vide supra).

These NMR studies together with the X-ray structure

determinations (see below) clearly show the nature of the

reaction products (1-amino- or 1-alkoxy-3-hydroxypyrrole

derivatives) first isolated by Diels et al.^[12]They further

prove unambiguously that the aza-Nazarov mechanism

postulated in the introduction takes place, instead of a

Beckmann rearrangement, as proposed by Diels et al. Quite

clearly, under the reaction conditions employed (strong acid

at low temperature), protonation of starting materials 3, 9

and 10 takes place mainly at the carbonyl oxygen atom,

thus opening the aza-Nazarov channel, whereas we ob-

served no sign of an oxime oxygen protonation, which

would give rise to Beckmann-type rearrangement products.

Scheme 5.

In order to isolate more stable products in subsequent

experiments, 2.5–3 equiv. of anhydrides were added to the

acidic reaction mixture of 9a at –10 °C without isolation of

presumed intermediate 12b, following a suggestion by Diels

et al.^[12]Then work up with aqueous NaHCO₃was carried

out. Indeed, after column filtration spectroscopically pure

pyrrole 13 was obtained in 97% yield (Scheme 6). This com-

pound is more stable than 12a, but also decomposes within

a couple of days with darkening.

Scheme 6.

Preparation of Pyrroles

In a similar way, oxime derivative 10o was converted into

corresponding N-methoxypyrrolylpyrrole 14 on treatment

with trifluoromethanesulfonic acid and subsequent addition

of acetic anhydride, followed by aqueous work up (58%,

Scheme 7).

The NMR experiments clearly showed that 1-azapenta-

1,4-dien-3-one 3 cyclizes to give the five-membered ring sys-

tems upon protonation by using strong organic acid. Bear-

ing in mind the well-known generally poor thermal stability

of this class of compound, we were interested in developing

a preparative route to 3-hydroxypyrrole derivatives^[35,36]

based on these mechanistic findings.

Thus, at –78 °C a solution of azadienone 9b in anhydrous

dichloromethane was treated with 1.2 equiv. of trifluorome-

thanesulfonic acid. This solution was treated at –78 °C with

a large excess of an aqueous sodium hydrogen carbonate

solution in order to quickly neutralize the crude acidic reac-

tion mixture under mild conditions. Then the reaction mix-

ture was slowly warmed to room temperature. The layers

were separated, followed by very quick work up (drying,

evaporation of the solvent) in order to avoid thermal de-

Scheme 7.

Additional experiments showed that the formation of

composition. NMR spectroscopic data (CDCl₃) suggest the compounds 13 and 14 is an exception. All other in situ pre-

formation of very sensitive 3-hydroxypyrrole 12a pared 3-hydroxypyrroles 12, being very electron-rich aro-

(Scheme 5), which exists in the less polar solvent dichloro- matic compounds, reacted twice with the anhydrides, first

methane at room temperature exclusively as two dia- at the hydroxy group and secondly in the 4-position by elec-

stereomers (resulting from rotation around the N–N bond) trophilic substitution leading to fully substituted com-

of the keto form 12aЈ, equilibrating via 12a. The preference pounds 15 (from hydrazones 9, Scheme 8) and 16 (from ox-

for this tautomer is in accord with the observations by imes 3 and 10, Scheme 9). Generally, acetic anhydride gave

McNab and Monahan.^[35,36]They found that unsubstituted the most stable products. Treatment of the reaction mixture

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with benzoic or propionic anhydride led to pyrroles 15a,c

and 16f,h. Compound 15c is a reddish gum which decom-

poses quickly. Compounds 15a and 16f form mixtures with

another product that lacks the acetyl group in the 4-posi-

tion and could not be separated completely.

Scheme 9.

Scheme 8.

X-ray structure determinations were performed on 16d,e

In general, many different types of azadienones 3, 9 and (Figure 6). Vinylogous compound 1-azahepta-1,4,6-trien-3-

10 were successfully converted into the corresponding 3- one 3 (see above for quantum chemical calculations and

hydroxypyrrole derivatives 15 and 16 without any indication NMR experiments), which has the (hypothetical) possibility

of major side-reactions (e.g., Beckmann-type rearrange- of forming either a five- or a seven-membered ring system,

ments).

exclusively yields pyrrole derivative 16d.

Figure 6. Molecular structures of 16d (left) and 16e (right), as obtained by X-ray crystallography.

Scheme 10.

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Hydroxypyrroles from Azapentadienones: The Aza-Nazarov Reaction

FULL PAPER

tetramethylsilane or solvent as internal reference. CHN elemental

analysis: Elementar Vario El III. Melting points are uncorrected.

All solvents were rigorously dried by standard methods. When nec-

essary, the experiments were carried out with complete exclusion

of moisture (argon atmosphere, septum-syringe technique) in glass-

ware that had been thoroughly dried by repeated heating under an

atmosphere of argon and subsequent evacuation.

Successful cyclization of bis(azadienone)s 11a,b was also

achieved under aza-Nazarov conditions. For these experi-

ments, an excess of 4 equiv. (or more) of the acid was used

before the reaction was quenched with 6 equiv. of acetic

acid anhydride. Both azadienone subunits cyclized simulta-

neously (Scheme 10). Spectroscopically pure compound 17a

was obtained in 95% yield after column filtration (44% af-

ter recrystallization). The structure of this compound was

elucidated by X-ray diffraction (Figure 7). Thiophene deriv-

ative 17b was also obtained, but complete purification was

not possible. Compounds of this type are of interest with

regard to electric conductivity.^[37]

2-Methoxyimino-7-phenylhepta-4,6-dien-3-one (3): 3-Methoxyimi-

nobutan-2-one (8b)^[29](3.0 g, 26.1 mmol) and cinnamaldehyde

(5.6 mL, 5.9 g, 44.6 mmol) were treated with an aqueous solution

of potassium hydroxide (30%, 3 mL) at 0 °C. A yellow precipitate

was formed immediately after addition of the first drop of base.

The reaction mixture was stirred for 1 h at 0 °C and treated with

methanolic potassium hydroxide solution (7 mL) at room tempera-

ture for complete reaction. The resulting solid was filtered off and

recrystallized from methanol. Pale yellow solid, 2.6 g (11.3 mmol,

43.6%), m.p. 94.8 °C, b.p. 145 °C (0.007 mbar, Kugelrohr oven). R_f

(TLC) = 0.35 (silica gel, petroleum ether/TBME, 3:1), R_t(GC) =

1

17.48 min [40–10/min–280(5)]. H NMR (600 MHz, CD₂Cl₂): δ =

2.01 [s, 3 H, H₃CC(N)], 4.11 (s, 3 H, OCH₃), 6.98–7.06 (m, 2 H,

H_olef.), 7.29 (d, ³J = 15.2 Hz, 1 H, H_olef.), 7.34–7.41 (m, 3 H,

H

_arom./olef.), 7.51–7.57 (m, 3

H, H_arom./olef.) ppm. ¹³C NMR

(150 MHz, CD₂Cl₂): δ = 9.04 [H₃CC(N)], 63.17 (OCH₃), 123.35

[HCC(O)], 126.75 (PhCHCH), 127.10 (o-C_arom.), 128.71 (m-C_arom.),

129.09 (p-C_arom.), 135.65 (ipso-C_arom.), 141.69 (Ph-CH), 143.27

Figure 7. Molecular structure of compound 17a, as obtained by X-

ray diffraction.

[CH=CHC(O)], 155.69 (C=N), 186.70 (C=O) ppm. IR (film): ν =

˜

3080 (w, CH_arom.), 3026 (w, CH_arom.), 2978 (w, CH_aliph.), 2936 (s,

CH_aliph.), 2820 (m, CH_aliph.), 2650 (w), 1975 (w), 1956 (w), 1659

(vs, C=O_ketone), 1608 (sh., C=C_olef.), 1587 (vs, br., C=C), 1578 (m,

C=C), 1447 (m, CH_aliph.), 1356 (m, CH), 1317 (s), 1213 (s), 1177

(m), 1051 (vs), 934 (s), 853 (s), 756 (s, CH_arom.), 708 (m), 689 (m,

CH_arom.), 615 (w), 529 (m), 507 (m) cm^–1. GC–MS (70 eV): m/z (%)

= 229 (10) [M]⁺, 198 (16), 170 (14), 157 (45), 129 (80) [Ph-

(CHCH)₂]⁺, 128 (100), 115 (12), 102 (14), 77 (9) [C₆H₅]⁺.

Conclusions

In this report we have shown that the long-known Naza-

rov reaction of 1,4-pentadien-3-ones may successfully be

applied to the corresponding nitrogen derivatives, 1-aza-1,4-

pentadien-3-ones. These precursors give access to highly

substituted 3-hydroxypyrrole derivatives by the aza-Naza- C₁₄H₁₅NO₂(229.27): calcd. C 73.34, H 6.59, N 6.11; found C

73.20, H 6.36, N 6.01.

rov route. By carrying out quantum chemical calculations

we have demonstrated the importance of the position of

the nitrogen atom within the conjugated chain in pericyclic

cyclization reactions. The stereochemical course and the

conrotatory mode of the cyclization reaction have also been

X-ray Crystal Structure Analysis of 3:^[38]Formula C₁₄H₁₅NO₂, M

= 229.27, colourless crystal, 0.50×0.30×0.05 mm, a = 6.860(1), b

= 7.945(1), c = 23.943(2) Å, β = 96.49(1)°, V = 1296.6(3) Å³, ρ_calcd.

= 1.174 gcm^–3, µ = 0.632 mm^–1, empirical absorption correction

studied in detail by quantum chemical methods, including (0.743 Յ T Յ 0.969), Z = 4, monoclinic, space group P2₁/c (No.

14), λ = 1.54178 Å, T = 223 K, ω/2θ scans, 2861 reflections col-

the cyclization of a system that may give either a five- or

seven-membered heterocyclic system. On the basis of the

experiments of Diels et al.,^[12]a number of new precursors

suitable for ring formation were prepared. An in situ NMR

study provided information on the temperature range neces-

sary for the cyclization reaction and strongly indicated the

aza-Nazarov reaction mode rather than a Beckmann-type

rearrangement mechanism as originally proposed by Diels

et al. On a preparative scale, various 1-amino- and 1-alk-

oxy-3-hydroxypyrrole derivatives have been prepared and

fully characterized, including a number of X-ray structure

determinations. Thus, starting with a mechanistic proposal,

we have finally been able to develop a new general pro-

cedure for the synthesis of fully substituted 3-hydroxypyr-

role derivatives.

lected (–h, –k, l), [(sinθ)/λ] = 0.62 Å^–1, 2636 independent (R_int

=

0.021) and 2104 observed reflections [I Ն 2σ(I)], 157 refined param-

eters, R = 0.041, wR₂= 0.130, max. residual electron density 0.17

(–0.14) eÅ^–3, hydrogen atoms calculated and refined as riding

atoms.

Low-Temperature NMR Investigation of the Protonation of 3 to 5:

Under complete exclusion of moisture in an NMR tube that had

been thoroughly dried by repeated heating under an atmosphere of

argon and subsequent evacuation, 3 (55 mg, 0.24 mmol) was dis-

solved in deuteriated dichloromethane (0.2 mL, freshly distilled

from P₂O₅). In a pear-shaped flask under an atmosphere of argon,

trifluoromethanesulfonic acid (0.04 mL, 0.07 g, 0.5 mmol) was dis-

solved in deuteriated dichloromethane (0.6 mL). Both solutions

were vigorously shaken (Vortex) and cooled to –78 °C. The acid

solution was added to the NMR tube with the use of Schlenk tech-

niques. The colour of the reaction mixture changed immediately

from slightly yellow to intense pink. The solution was shaken again

Experimental Section

Materials and Methods: IR: Nicolet 5DXC spectrometer. H- and

1

(Vortex) and H- and ¹³C NMR spectra were measured at –60 °C

(Figure 5). ¹H NMR (600 MHz, –60 °C, CD₂Cl₂): δ = 2.67 (s, 3 H,

H₃C-1), 4.20 (s, 3 H, H₃C-2), 5.71–5.80 (m, 2 H, HC-4, HC-10),

1

¹³C NMR: Bruker WM 300 and Varian Unity 600 spectrometers,

Eur. J. Org. Chem. 2006, 5339–5356

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5347

J. Dieker, R. Fröhlich, E.-U. Würthwein

FULL PAPER

6.28 (s, 1 H, HC-3), 7.09 (d, J = 15.3 Hz, 1 H, HC-9), 7.41–7.49

3

C_aminearom., C=N), 187.7 (C=O) ppm. IR (KBr): ν = 3063 (w,

˜

(m, 5 H, H_arom.), 11.87 (br., OH) ppm. ¹³C NMR (150 MHz, CH_arom.), 3032 (sh., CH_arom.), 2974 (s, CH_aliph.), 2940 (m, CH_aliph.),

–60 °C, CD₂Cl₂): δ = 11.96 (C-1), 67.45 (C-2), 73.07 (C-10), 113.69

(C-4), 115.90 (C-3), 126.76 (2 C, C-5), 128.69 (2 C, C-6), 129.52 (C-

8), 133.69 (C-7), 141.26 (C-12), 147.15 (C-9), 172.78 (C-11) ppm.

2882 (sh., CH_aliph.), 1641 (vs, C=O), 1599 (s, C=C), 1579 (s, C=C),

1556 (s), 1494 (m), 1357 (s, CH_aliph.), 1305 (w), 1294 (m), 1255 (m),

1228 (s), 1110 (w), 1056 (w), 1002 (w), 881 (w), 840 (w), 831 (w),

784 (w), 744 (vs, CH_arom.), 705, 684 (vs, CH_arom.) cm^–1. MS (70 eV):

m/z (%) = 323 (87) [M]⁺, 254 (20), 217 (9), 176 (41), 130 (17), 113

(28), 106 (100) [NPhCH₃]⁺, 102 (18), 77 (25), 57 (9). C₁₈H₁₇N₃O₃

(323.13): calcd. C 66.86, H 5.30, N 13.00; found C 66.65, H 5.20,

N 12.94.

4-(2-Methyl-2-phenylhydrazono)-1-phenylpent-1-en-3-one (9a): 3-(2-

Methyl-2-phenylhydrazono)butan-2-one (7)^[39](5.0 g, 26.3 mmol)

and benzaldehyde (2.9 mL, 3.0 g, 28.3 mmol) were dissolved in

methanol (20 mL). The solution was treated with aqueous NaOH

(40%, 0.5 g) according to a procedure described by Diels et al.^[12,40]

After about 4 h a yellow precipitate was formed. Stirring of the

reaction mixture was continued for 48 h for complete reaction. The

precipitate was filtered off and washed with water until a neutral

reaction was obtained. The product was purified by recrystalli-

zation from ethyl acetate. Yellow solid, 4.8 g (17.2 mmol, 65.6%),

m.p. 139.5 °C (decomp.), 138–139 °C.^[35]R_f(TLC) = 0.35 (silica

gel, petroleum ether/TBME, 3:1), R_t(GC) = 19.43 min [40–10/min–

6-(2-Methyl-2-phenylhydrazono)-1-phenylhepta-1,3-dien-5-one (9c):

3-(2-Methyl-2-phenylhydrazono)butan-2-one (7) (3.6 g, 18.9 mmol)

and cinnamaldehyde (2.4 mL, 2.5 g, 28.0 mmol) were dissolved in

methanol (15 mL) at 0 °C. The solution was treated with a meth-

anolic solution of potassium hydroxide (30%, 5 mL, 27.0 mmol) at

room temperature and stirred for 4 h. The crude product was fil-

tered off by using a glass filter funnel (D3) and washed several

times with cold water. The crude product was recrystallized from

1

280(5)]. H NMR (300 MHz, CDCl₃): δ = 2.11 [s, 3 H, H₃CC(N)],

3.54 (s, 3 H, NCH₃), 7.03–7.09 (m, 1 H, H_arom.), 7.21–7.24 (m, 2 cold ethyl acetate. Orange solid, 3.3 g (10.8 mmol, 57.1%), m.p.

1

H, H_arom.), 7.33–7.42 (m, 5 H, H_arom.), 7.61–7.65 (m, 2 H, H_arom.),

95.5 °C (decomp.). H NMR (300 MHz, CDCl₃): δ = 2.10 [s, 3 H,

H₃CC(N)], 3.51 (s, 3 H, NCH₃), 6.92–7.08 (m, 3 H, H_arom./olef.),

7.20–7.38 (m, 7 H, H_arom./olef.), 7.45–7.57 (m, 4 H, H_arom./olef.) ppm.

3

7.71 [d, J = 16.0 Hz, 1 H, C(O)CH], 8.01 (d, J = 16.0 Hz, 1 H,

PhCH) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 14.8 [CH₃C(N)],

43.8 (NCH₃), 117.7 (o/m-C_arom.), 121.5 (p-C_arom.), 122.8 ¹³C NMR (75 MHz, CDCl₃): δ = 14.8 [H₃CC(N)], 43.7 (NCH₃),

(o/m-C_arom.), 128.3 (o/m-C_arom.), 128.8 (o/m-C_arom.), 129.1

(p-C_arom.), 129.9 (C_olef.), 135.7 (ipso-C_arom.), 141.5 (C_olef.), 149.2,

117.6 (o/m-C_arom.), 122.7 (p-C_arom.), 125.1 (C_olef.), 127.1

(o/m-C_arom.), 127.7 (p-C_arom.), 128.8 (3 C, o/m-C_arom./C_olef.), 129.1

(o/m-C_arom.), 136.5 (ipso-C_arom.), 140.5 (C_olef.), 141.8 (C_olef.), 149.7

149.5 (ipso-C_N–Ph., C=N), 188.5 (C=O) ppm. IR (KBr): ν = 3049

˜

(w, CH_arom.), 3005 (w, sh., CH_arom.), 2968 (w, CH_aliph.), 1647 (vs, [2 C, ipso-C_arom./(C=N)], 188.6 (C=O) ppm. IR (KBr): ν = 3061

˜

C=O), 1607 (s, C=C), 1550 (vs, br., C=C), 1489 (s), 1369 (w, (w, CH_arom.), 3030 (w, CH_arom.), 3011 (sh., CH_arom.), 2910 (s,

CH_aliph.), 1352 (w), 1303 (s), 1281 (m), 1215 (vs), 1176 (w), 1117 CH_aliph.), 1641 (vs, C=O), 1599 (s, C=C), 1580 (s, C=C), 1557 (s),

(m), 1067 (s), 993 (m), 899 (w), 866 (w), 795(w), 762 (m), 752 (s, 1495 (m), 1358 (s, CH_aliph.), 1306 (w), 1296 (m), 1256 (m), 1222 (s),

CH_arom.), 692 (s, CH_arom.) cm^–1. MS (70 eV): m/z (%) = 278 (96)

1177 (w), 1111 (w), 1056 (w), 1005 (w), 883 (w), 841 (w), 831 (w),

[M]⁺, 209 (36), 172 (33), 131 (87) [C₉H₇O]⁺, 106 (100) [C₇H₈N]⁺,

785 (w), 745 (m, CH_arom.), 708 (m), 685 (m, CH_arom.) cm^–1. MS

77 (38) [C₆H₅]⁺. C₁₈H₁₈N₂O (278.35): calcd. C 77.67, H 6.52, N (70 eV): m/z (%) = 304 (68) [M]⁺, 235 (100), 198 (9) [M –

10.06; found C 77.53, H 6.54, N 10.01.

NCH₃Ph]⁺, 157 (53) [Ph(CH)₄CO]⁺, 128 (77), 113 (18), 106 (85)

[NPhCH₃]⁺, 77 (30), 57 (29). C₂₀H₂₀N₂O (304.39): calcd. C 78.92,

H 6.62, N 9.20; found C 78.79, H 6.50, N 9.17.

X-ray Crystal Structure Analysis of 9a:^[38]Formula C₁₈H₁₈N₂O, M

= 278.34, yellow crystal, 0.60×0.10×0.03 mm, a = 31.410(3), b =

13.160(2), c = 7.287(1) Å, β = 92.34(1)°, V = 3009.6(7) Å³, ρ_calcd.

=

X-ray Crystal Structure Analysis of 9c:^[38]Formula C₂₀H₂₀N₂O, M

= 304.38, yellow crystal, 0.60×0.20×0.15 mm, a = 6.236(1), b =

8.618(1), c = 15.923(1) Å, α = 83.95(1), β = 84.48(1), γ = 82.09(1)°,

V = 840.0(2) Å³, ρ_calcd.= 1.203 gcm^–3, µ = 0.586 mm^–1, empirical

absorption correction (0.720 Յ T Յ 0.917), Z = 2, triclinic, space

1.229 gcm^–3, µ = 0.606 mm^–1, empirical absorption correction

(0.713 Յ T Յ 0.982), Z = 8, monoclinic, space group C2/c (No.

15), λ = 1.54178 Å, T = 293 K, ω/2θ scans, 3335 reflections col-

lected ( h, +k, –l), [(sinθ)/λ] = 0.62 Å^–1, 3075 independent (R_int

=

¯

0.037) and 1768 observed reflections [I Ն 2σ(I)], 193 refined param-

eters, R = 0.047, wR₂= 0.122, max. residual electron density 0.17

(–0.17) eÅ^–3, hydrogen atoms calculated and refined as riding

atoms.

group P1 (No. 2), λ = 1.54178 Å, T = 223 K, ω/2θ scans, 3748

reflections collected (+h, k, l), [(sinθ)/λ] = 0.62 Å^–1, 3418 inde-

pendent (R_int= 0.015) and 3018 observed reflections [I Ն 2σ(I)],

211 refined parameters, R = 0.044, wR₂= 0.138, max. residual elec-

tron density 0.23 (–0.15) eÅ^–3, hydrogen atoms calculated and re-

fined as riding atoms.

4-(2-Methyl-2-phenylhydrazono)-1-(4-nitrophenyl)pent-1-ene-3-one

(9b): p-Nitrobenzaldehyde (300 mg, 2.0 mmol) and 3-(2-methyl-2-

phenylhydrazono)butan-2-one (7)^[39](380 mg, 2.0 mmol) were dis-

solved in methanol (4 mL) and cooled to 0 °C. After treatment with

potassium tert-butoxide (224 mg, 2.0 mmol) the colour of the solu-

tion changed from intense yellow to deep red. A precipitate was

formed after about 2 h. Stirring was continued for 8 h for complete

reaction before the precipitate was filtered off and washed with cold

methanol. Red solid, 0.49 g (1.5 mmol, 75.8%), m.p. 123–124 °C

(decomp.). ¹H NMR (300 MHz, CDCl₃): δ = 2.12 [s, 3 H,

4-(Benzyloxyimino)-1-phenylpent-1-en-3-one (10a): 3-(Benzyloxyimi-

no)butan-2-one (8a)^[41](7.5 g, 39.2 mmol) and benzaldehyde

(7.4 mL, 7.8 g, 73.5 mmol) were treated with a methanolic sodium

hydroxide solution (10%, 15 mL, 38.0 mmol) at 0 °C. A colourless

precipitate was formed. The solution was stirred for 2 h for com-

plete reaction before the precipitate was filtered off by using a glass

filter funnel. This crude product was recrystallized from methanol

twice. Colourless solid, 7.6 g (27.2 mmol, 69.7%), m.p. 80.0 °C

H₃CC(N)], 3.61 (s, 3 H, NCH₃), 7.09–7.14 (m, 1 H, H_N–Ph.), 7.23– (80 °C^[12]). R_t(GC): 20.47 min [40–10/min–280(5)]. ¹H NMR

7.26 (m, 2 H, HN_N–Ph.), 7.36–7.41 (m, 2 H, H_N–Ph.), 7.65–7.76 (m, (300 MHz, CDCl₃): δ = 2.06 [s, 3 H, H₃CC(N)], 5.34 (s, 2 H,

3

3 H, H_arom./olef.), 8.11 (d, J = 16.0 Hz, 1 H, H_olef.), 8.22–8.25 (m, OCH₂), 7.33–7.43 (m, 8 H, H_arom./olef.), 7.56–7.75 (m, 4 H,

2

H, H_arom.) ppm. ¹³C NMR (75 MHz, CDCl₃): 14.7 H_arom./olef.) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 9.3 [CH₃C(N)],

δ =

[CH₃C(N)], 43.9 (NCH₃), 118.1 (o/m-C_arom.), 123.4 (p-C_arom.), 77.6 (OCH₂), 120.8 (C_olef.), 128.2 (C_arom.), 128.3 (C_arom.), 128.5

124.1 (o/m-C_arom.), 125.6 (C_olef.), 128.7 (o/m-C_arom.), 129.2 (C_arom.), 128.8 (C_arom.), 130.3 (C_arom.), 135.1 (ipso-C), 137.0 (ipso-

(o/m-C_arom.), 138.0 (C_olef.), 142.0, 147.3 (ipso-C), 148.2, 149.2 (ipso- C), 143.1 (Ph-CH_olef.), 156.4 (C=N), 186.7 (C=O) ppm. IR (KBr):

5348

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Hydroxypyrroles from Azapentadienones: The Aza-Nazarov Reaction

FULL PAPER

ν = 3082 (w), 3065 (w), 3026 (m, CH_arom.), 2974 (w), 2945 (m,

CH_aliph.), 2887, 1666 (vs, C=O), 1608 (br.), 1574 (sh.), 1495 (m),

1450 (m), 1344 (s, CH_aliph.), 1204 (w), 1069 (s), 1016 (vs), 984 (s),

3063 (w, CH_arom.), 3036 (w, CH_arom.), 2964 (m, CH_aliph.), 2947 (m,

CH_aliph.), 2887 (m), 1665 (s, C=O), 1603 (vs), 1468 (m), 1439 (w),

1362 (w), 1337 (s, CH_aliph.), 1283 (w), 1072 (s), 1009 (vs), 982 (s),

˜

953 (m), 893 (m), 867 (w), 759 (s, CH_arom.), 709 (s, CH_arom.), 678 959 (m), 895 (m), 752 (s), 712 (s, CH_arom.), 700 (m, CH_arom.) cm^–1.

(m) cm^–1. MS (70 eV): m/z (%) = 279 (48) [M]⁺, 131 (30) [Ph- MS (70 eV): m/z (%) = 357 (9) [M]⁺, 102 (9), 91 (100) [C₈H₇]⁺.

(CH)₂CO]⁺, 103 (33) [Ph(CH₂)]⁺, 91 (100), 77 (32), 51 (8) cm^–1. MS C₁₈H₁₆BrNO₂(357.04): calcd. C 60.35, H 4.50, N 3.91; found C

(ESI, CHCl₃/CH₃OH with LiClO₄present): m/z (%) = 286.2 (100)

[M + Li]⁺, 302.2 (55) [M + Na]⁺, 318.2 (8) [M + K]⁺, 565.4 (42)

[M₂+ Li]⁺, 581.4 (17) [M₂+ Na]⁺, 844.6 (9) [M₃+ Li]⁺.

C₁₈H₁₇NO₂(279.33): calcd. C 77.40, H 6.13, N 5.01; found C

77.33, H 6.13, N 4.90.

60.28, H 4.41, N 3.75.

2-(Benzyloxyimino)-5-(4-nitrophenyl)pent-4-en-3-one (10d): 3-(Ben-

zyloxyimino)butan-2-one (8a)^[41](3.0 g, 15.7 mmol) and 4-ni-

trobenzaldehyde (2.4 g, 15.9 mmol) were treated with a methanolic

solution of potassium hydroxide (3.6 mL, 30%, 19.2 mmol) at 0 °C.

After addition of the base the aldehyde completely dissolved. A

yellow precipitate was formed from the dark solution after about

12 h. The solid was filtered off and washed with water until neutral.

The crude product was refluxed with boiling methanol to remove

impurities. Filtration gave a yellow solid, 3.5 g (10.8 mmol, 68.7%),

m.p. 131 °C. ¹H NMR (300 MHz, CDCl₃): δ = 2.1 [s, 3 H,

H₃CC(N)], 5.4 (s, 2 H, OCH₂), 7.2–7.8 (m, 9 H, H_arom./olef.), 8.21–

8.22 (m, 2 H, H_nitroarom.) ppm. ¹³C NMR (75 MHz, CDCl₃): δ =

9.3 [CH₃C(N)], 77.8 (OCH₂), 124.1 (o/m-C_arom.), 124.6 (C_olef.),

128.3 (o/m-C_arom.), 128.3 (p-C_arom.), 128.5 (o/m-C_arom.), 128.9 (o/m-

X-ray Crystal Structure Analysis of 10a:^[38]Formula C₁₈H₁₇NO₂,

M = 279.33, light yellow crystal, 0.60×0.50×0.15 mm, a =

23.681(2), b = 7.754(1), c = 17.056(2) Å, β = 106.31(1)°, V =

3005.8(6) Å³, ρ_calcd.= 1.234 gcm^–3, µ = 0.642 mm^–1, empirical ab-

sorption correction (0.700 Յ T Յ 0.910), Z = 8, monoclinic, space

group C2/c (No. 15), λ = 1.54178 Å, T = 223 K, ω/2θ scans, 6120

reflections collected ( h, k, +l), [(sinθ)/λ] = 0.62 Å^–1, 3074 inde-

pendent (R_int= 0.032) and 2784 observed reflections [I Ն 2σ(I)],

192 refined parameters, R = 0.041, wR₂= 0.125, max. residual elec-

tron density 0.23 (–0.16) eÅ^–3, hydrogen atoms calculated and re-

fined as riding atoms.

C_arom.), 136.8 (ipso-C), 139.7 (C_olef.), 141.2 (ipso-C), 148.5 (ipso-C),

156.3 (C=N), 186.1 (C=O) ppm. IR (KBr): ν = 3458 (br.), 3111

˜

4-(Benzyloxyimino)-1-(p-tolyl)pent-1-en-3-one (10b): 3-(Benzyloxy-

imino)butan-2-one (8a)^[41](5.3 g, 27.7 mmol) and p-tolualdehyde

(3.3 mL, 3.4 g, 28.3 mmol) were treated with a methanolic solution

of potassium hydroxide (6 mL, 30%, 32 mmol) at 0 °C. A solid was

formed after about 5 min. The mixture was stirred for 1 h at room

temperature for complete reaction. The solid was then filtered off

and washed with water until neutral. The crude product was recrys-

tallized from methanol. Colourless solid, 6.9 g (23.5 mmol, 83.9%),

(m), 3076 (m), 3034 (w, CH_arom.), 2972 (w), 2937 (m, CH_aliph.), 1668

(s, C=O), 1614 (s), 1597 (sh.), 1512 (vs), 1340 (vs, CH_aliph.), 1109

(w), 1069 (s), 997 (br.), 885 (w), 841 (m), 799 (w), 756 (m), 721 (m),

700 (m, CH_arom.) cm^–1. MS (70 eV): m/z (%) = 324 (11) [M]⁺, 176

(7) [C₉H₆NO₃]⁺, 102 (9), 91 (100) [C₇H₇]⁺. C₁₈H₁₆N₂O₄(324.11):

calcd. C 66.66, H 4.97, N 8.64; found C 66.38, H 4.90, N 8.58.

2-(Benzyloxyimino)-7-phenylhepta-4,6-dien-3-one (10e): 3-(Benzyl-

m.p. 62.4 °C. ¹H NMR (300 MHz, CDCl₃): δ = 2.06 [s, 3 H, oxyimino)butan-2-one (8a)^[41](5.3 g, 27.7 mmol) and cinnamal-

H₃CC(N)], 2.36 (s, 3 H, p-CH₃), 5.33 (s, 2 H, OCH₂), 7.17–7.20 dehyde (5.6 mL, 5.9 g, 44.5 mmol) were treated with a methanolic

(m, 2 H, H_arom./olef.), 7.32–7.42 (m, 5 H, H_arom.), 7.43–7.47 (m, 2

solution of potassium hydroxide (53.5 mmol, 10 mL, 30%) at 0 °C.

A yellow precipitate was formed after about 5 min. For complete

3

H, H_arom./olef.), 7.55–7.72 (m, J = 16.2 Hz, 2 H, H_arom./olef.) ppm.

¹³C NMR (75 MHz, CDCl₃): δ = 9.34 [CH₃C(N)], 21.47 (p-Ph- reaction the mixture was stirred for 1 h at room temperature. The

CH₃), 77.54 (OCH₂), 119.79 (C_olef.), 128.17 (p-C_arom.), 128.28 (o/m-

solid was filtered off and washed with water until neutral. The

C_arom.), 128.49–128.50 (4 C, o/m-C_arom.), 129.56 (o/m-C_arom.), crude product was recrystallized from methanol. Yellow solid, 4.6 g

1

132.36 (ipso-C), 137.00 (ipso-C), 140.75 (ipso-C), 143.17 (C_olef.),

(15.1 mmol, 53.8%), m.p. 90.8 °C. H NMR (400 MHz, CDCl₃): δ

156.38 (C=N), 186.70 (C=O) ppm. IR (KBr): ν = 3063 (w, = 2.04 [s, 3 H, H₃CC(N)], 5.31 (s, 2 H, OCH₂), 6.92–7.52 (m, 14

˜

CH_arom.), 3026 (w, CH_arom.), 2957 (m, CH_aliph.), 2920 (m, CH_aliph.), H, H_arom./olef.) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 9.27

2887 (m), 1659 (s, C=O), 1595 (vs), 1568 (sh.), 1510 (m), 1454 (w), [CH₃C(N)], 77.45 (OCH₂), 124.26 (C_olef.), 127.19 (4 C, o/m-C_arom.),

1410 (w), 1362 (m), 1340 (s, CH_aliph.), 1177 (w), 1070 (s), 1020 (vs), 128.15 (o/m-C_arom.), 128.47 (2 C, p-C_arom.), 128.74 (o/m-C_arom.),

984 (s), 962 (s), 897 (m), 810 (s), 750 (s), 698 (s, CH_arom.), 613

129.01 (C_olef.) ppm. IR (KBr): ν = 3022 (w, CH_arom.), 2931 (m,

˜

(m) cm^–1. MS (70 eV): m/z (%) = 293 (34) [M]⁺, 145 (27) CH_aliph.), 1663 (vs, C=O), 1587 (s), 1495 (m), 1448 (w), 1439 (w),

[C₁₀H₉O]⁺, 117 (16) [C₉H₉]⁺, 91 (100) [C₇H₇]⁺. C₁₉H₁₉NO₂1354 (s, CH_aliph.), 1306 (w), 1207 (m), 1067 (s), 1015 (vs), 986 (s),

(293.14): calcd. C 77.79, H 6.53, N 4.77; found C 77.75, H 6.50, N

4.63.

883 (w), 849 (m), 745 (m, CH_arom.) 696 (m, CH_arom.) cm^–1. MS

(70 eV): m/z (%) = 305 (9) [M]⁺, 214 (9), 157 (19), 128 (31)

[C₁₀H₈]⁺, 91 (100) [C₇H₇]⁺, 57 (10). MS (ESI, CHCl₃/CH₃OH): m/z

(%) = 328.3 (100) [M + Na]⁺. C₂₀H₁₉NO₂(305.37): calcd. C 78.66,

H 6.27, N 4.59; found C 78.64, H 6.09, N 4.53.

2-(Benzyloxyimino)-5-(2-bromophenyl)pent-4-en-3-one (10c): 3-

(Benzyloxyimino)butan-2-one (8a)^[41](3.8 g, 19.9 mmol) and 2-bro-

mobenzaldehyde (4.0 g, 21.6 mmol) were treated with a methanolic

solution of potassium hydroxide (20 mmol, 4.0 mL, 30%) at 0 °C.

The product was immediately formed after addition of the base.

The solid was filtered off and washed with water until neutral. The

crude product was recrystallized twice from methanol. Colourless

solid, 6.0 g (16.7 mmol, 83.7%), m.p. 114.4 °C. ¹H NMR

General Procedure for the Preparation of Compounds 10f–10o: 3-

Methoxyiminobutan-2-one (8b)^[33](2.4 g, 20.8 mmol) was dissolved

in ethanol (5 mL), treated dropwise with an aqueous solution of

potassium hydroxide (10%, 15 mL, 25 mmol) and stirred vigor-

ously at about –10 °C. The aldehyde (20.8 mmol) was dissolved in

(300 MHz, CDCl₃): δ = 2.1 [s, 3 H, H₃CC(N)], 5.3 (s, 2 H, OCH₂), methanol (5 to max. 20 mL, depending on its solubility) and added

7.2–7.4 (m, 7 H, H_arom./olef.), 7.5–7.7 (m, 3 H, H_arom./olef.), 8.1 (d, dropwise to the enolate at –10 °C. The ice bath was removed and

³J = 16 Hz, 1 H, H_olef.) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 9.3 after about 2–4 h a precipitate started to form. If not, the usual

[CH₃C(N)], 77.7 (OCH₂), 123.4 (C_olef.), 125.9 (ipso-C-Br), 127.5 ways to initiate a crystallization were used (addition of a piece of

(C_arom.), 127.9 (C_arom.), 128.2 (3 C, o/m-C_arom., C_arom.), 128.5 (o/m- potassium hydroxide as a seed crystal; rubbing against the wall of

C_arom.), 131.1 (C_arom.), 133.4 (C_arom.), 135.1 (ipso-C), 136.8 (ipso-

the flask, ultrasonification). For complete reaction the mixture was

C), 141.3 (C_olef.), 156.3 (C=N), 186.3 (C=O) ppm. IR (KBr): ν = stirred for 12 h until the reaction mixture became solid. The solid

˜

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5349

J. Dieker, R. Fröhlich, E.-U. Würthwein

FULL PAPER

was filtered off (glass filter funnel D3 or D4) and washed with a

small amount of methanol. The product was recrystallized from

ethyl acetate or methanol. In other cases the product was dried in

vacuo and purified by Kugelrohr distillation.

benzaldehyde (2.8 g, 19.9 mmol). Colourless solid, 4.5 g

(18.9 mmol, 94.7%), m.p. 109.4 °C. H NMR (400 MHz, CDCl₃):

1

δ = 2.02 [s, 3 H, H₃CC(N)], 4.12 (s, 3 H, OCH₃), 7.35–7.37 (m, 2

H, H_arom./olef.), 7.53–7.55 (m, 2 H, H_arom./olef.), 7.64–7.65 (m, 2 H,

H

_arom./olef.) ppm. ¹³C NMR (100 MHz, CDCl₃):

δ = 8.95

4-Methoxyimino-1-phenylpent-1-en-3-one (10f): From 3-methoxy-

iminobutan-2-one (8b)^[33](2.4 g, 20.8 mmol) and benzaldehyde

(2.1 mL, 2.2 g, 20.7 mmol). Colourless solid, 3.6 g (17.7 mmol,

84.3%), m.p. 83.5 °C (82 °C^[29]). ¹H NMR (400 MHz, CDCl₃): δ =

2.03 [s, 3 H, H₃CC(N)], 4.11 (s, 3 H, OCH₃), 7.35–7.41 (m, 3 H,

[CH₃C(N)], 63.24 (OCH₃), 121.06 (C_olef.), 129.07 (o/m-C_arom.),

129.63 (o/m-C_arom.), 133.57 (ipso-C), 136.15 (ipso-C), 141.43 (C_olef.),

155.97 (C=N), 186.36 (C=O) ppm. IR (KBr): ν = 3443 (br.), 3323

˜

(w), 3260 (w), 3032 (w, CH_arom.), 2978 (w, CH_aliph.), 2938 (m,

CH_aliph.), 2822 (m), 1666 (s, C=O), 1605 (vs), 1562 (w), 1489 (w),

1404 (w), 1335 (s, CH_aliph.), 1050 (vs, br.), 1005 (s), 939 (w), 889

(m), 808 (m), 725 (m, CH_arom.) cm^–1. MS (70 eV): m/z (%) = 237

(58) [M]⁺, 206 (11) [M – OCH₃]⁺, 178 (65), 165 (100) [C₉H₆ClO]⁺,

137 (61) [C₈H₆Cl]⁺, 127 (17), 102 (46) [C₈H₆]⁺, 75 (11).

C₁₂H₁₂ClNO₂(237.68): calcd. C 60.64, H 5.09, N 5.89; found C

60.61, H 4.91, N 5.82.

H_arom./olef.), 7.60–7.75 (m,

4

H, H_arom./olef.) ppm. ¹³C NMR

(100 MHz, CDCl₃): δ = 8.95 [CH₃C(N)], 63.17 (OCH₃), 120.64

(C_olef.), 128.51 (o/m-C_arom.), 128.80 (o/m-C_arom.), 130.27 (p-C_arom.),

135.10 (ipso-C), 143.01 (C_olef.), 156.02 (C=N), 186.62 (C=O) ppm.

IR (KBr): ν = 3442 (br.), 3321 (w), 3082 (w, CH_arom.), 3061 (w),

˜

3001 (m, CH_arom.), 2945 (m, CH_aliph.), 2824 (m), 1665 (s, C=O),

1607 (vs), 1574 (m), 1495 (w), 1448 (m), 1339 (s, CH_aliph.), 1200

(m), 1070 (s), 1043 (vs), 984 (s), 932 (m), 887 (m), 862 (m), 764 (s),

706 (s, CH_arom.), 681 (m, CH_arom.) cm^–1. MS (ESI, MicroTOF):

calcd. 226.0838 [M + Na]⁺; found 226.0843 [M + Na]⁺. C₁₂H₁₃NO₂

(203.09): calcd. C 70.92, H 6.45, N 6.89; found C 70.68, H 6.40, N

6.80.

1-(4-Nitrophenyl)-4-methoxyiminopent-1-en-3-one (10j): From 3-

methoxyiminobutan-2-one (8b)^[33](2.3 g, 20.0 mmol) and 4-ni-

trobenzaldehyde (3.0 g, 19.9 mmol). Yellow solid, 4.2 g (16.9 mmol,

84.5%), m.p. 174.5 °C. ¹H NMR (300 MHz, CDCl₃): δ = 1.95 [s, 3

H, H₃CC(N)], 4.06 (s, 3 H, OCH₃), 7.58–7.73 (m, 4 H, H_arom./olef.),

8.15–8.18 (m, 2 H, H_arom./olef.) ppm. ¹³C NMR (75 MHz, CDCl₃):

δ = 8.9 [CH₃C(N)], 63.4 (OCH₃), 124.0 (o/m-C_arom.), 124.4 (C_olef.),

129.0 (o/m-C_arom.), 139.6 (C_olef.), 141.2 (ipso-C), 148.4 (ipso-C),

4-Methoxyimino-1-(p-tolyl)pent-1-en-3-one (10g): From 3-methoxy-

iminobutan-2-one (8b)^[33](2.4 g, 20.8 mmol) and p-tolualdehyde

(2.5 mL, 2.5 g, 20.8 mmol). Colourless solid, 3.1 g (15.3 mmol,

72.6%), m.p. 71 °C, b.p. 120 °C (0.001 mbar). ¹H NMR (400 MHz,

CDCl₃): δ = 2.02 [s, 3 H, H₃CC(N)], 2.37 (s, 3 H, H₃C-Ph), 4.11

(s, 3 H, OCH₃), 7.18–7.20 (m, 2 H, H_arom.), 7.51–7.53 (m, 2 H,

156.0 (C=N), 186.0 (C=O) ppm. IR (KBr): ν = 3113 (w), 3069 (w,

˜

CH_arom.), 2990 (w, CH_aliph.), 2945 (m, CH_aliph.), 2899 (w), 2843 (w),

2816 (w), 1670 (vs, C=O_ketone), 1616 (s, C=C_olef.), 1597 (s, C=C),

1520 (vs, C=C), 1493 (sh.), 1412 (m, CH_aliph.), 1342 (vs, br., CH),

1070 (m), 1042 (s), 986 (m), 893 (m), 843 (w), 843 (m), 802 (w),

756 (w, CH_arom.), 712 (w) cm^–1. MS (70 eV): m/z (%) = 248 (73)

[M]⁺, 189 (69), 176 (100) [C₉H₆NO₃]⁺, 143 (18), 130 (56), 102 (64),

90 (26), 76 (20). C₁₂H₁₂N₂O₄(248.23): calcd. C 58.06, H 4.87, N

11.29; found C 58.11, H 4.81, N 11.29.

3

H_arom.), 7.71 (d, J = 16 Hz, 1 H, H_olef.), 7.62 (d, J = 16 Hz, 1 H,

H_olef.) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 9.00 [CH₃C(N)],

21.47 (H₃C-Ph), 63.15 (OCH₃), 119.63 (C_olef.), 128.55 (o/m-C_arom.),

129.55 (o/m-C_arom.), 132.38 (ipso-C), 140.76 (ipso-C), 143.12 (C_olef.),

156.04 (C=N), 186.68 (C=O) ppm. IR (KBr): ν = 3017 (w,

˜

CH_arom.), 2986 (m, CH_aliph.), 2945 (s, CH_aliph.), 2905 (sh., CH_aliph.),

1665 (vs, C=O), 1603 (s), 1568 (s, C=C), 1510 (m), 1463 (m), 1410

(w), 1337 (s, CH_aliph.), 1178 (m), 1057 (s), 1036 (vs), 986 (s), 935

(m), 889 (m), 816 (s), 762 (m, CH_arom.), 698 (m, CH_arom.), 676 (w,

sh.) cm^–1. MS (70 eV): m/z (%) = 217 (64) [M]⁺, 186 (17) [M –

OCH₃]⁺, 158 (51), 145 (100) [C₁₀H₉O]⁺, 117 (52) [C₉H₉]⁺, 115 (20),

91 (20) [C₇H₇]⁺. C₁₃H₁₅NO₂(217.26): calcd. C 71.87, H 6.96, N

6.45; found C 71.77, H 6.84, N 6.40.

2-Methoxyimino-7-(4-methoxyphenyl)hepta-4,6-dien-3-one

(10k):

From 3-methoxyiminobutan-2-one (8b)^[33](2.3 g, 20.0 mmol) and

4-methoxycinnamaldehyde (3.2 g, 19.7 mmol). After about 20 min

a solid precipitated from the yellow solution. The solid was recrys-

tallized from methanol twice. Intensely yellow solid, 3.1 g

(12.0 mmol; 60.2%), m.p. 139–141 °C, b.p. 185 °C (0.036 mbar). ¹H

NMR (300 MHz, CDCl₃): δ = 2.0 [s, 3 H, H₃CC(N)], 3.8 (s, 3 H,

Ph-OCH₃), 4.1 (s, 3 H, NOCH₃), 6.8–7.0 (m, 4 H, H_arom./olef.), 7.1–

7.3 (m, 1 H, H_arom./olef.), 7.4–7.5 (m, 3 H, H_arom./olef.) ppm. ¹³C

NMR (75 MHz, CDCl₃): δ = 8.9 [CH₃C(N)], 55.3 (Ph-OCH₃), 63.0

(NOCH₃), 114.3 (2 C, HC_arom.-COCH₃), 123.0 (C_olef.), 125.1

(C_olef.), 128.7 (2 C, C_arom.), 129.1 (C_q,arom.), 141.4 (C_olef.), 143.6

(C_olef.), 156.0 (C=N), 160.5 (C_q,_C-OMe), 186.7 (C=O) ppm. IR

1-(2-Bromophenyl)-4-methoxyiminopent-1-en-3-one (10h): From 3-

methoxyiminobutan-2-one (8b)^[33](2.3 g, 20.0 mmol) and 2-bro-

mobenzaldehyde (2.3 mL, 3.7 g, 20.0 mmol). Colourless solid, 4.4 g

(15.6 mmol, 78.0%), m.p. 70–72 °C, b.p. 138–140 °C (0.004 mbar).

¹H NMR (300 MHz, CDCl₃): δ = 2.03 [s, 3 H, H₃CC(N)], 4.11 (s,

3 H, OCH₃), 7.18–7.35 (m, 2 H, H_arom.), 7.55–7.62 (m, 2 H,

3

(KBr): ν = 2999 (w, CH_arom.), 2963 (w, CH_aliph.), 2936 (m, CH_aliph.),

˜

H_arom./olef.), 7.69–7.73 (m, 1 H, H_arom./olef.), 8.08 (d, J = 16 Hz, 1

H, H_olef.) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 9.0 [CH₃C(N)],

63.3 (OCH₃), 123.4 (C_olef.), 126.0 (C-Br), 127.5 (C_arom.), 127.9

(C_arom.), 131.1 (C_arom.), 133.4 (C_arom.), 135.2 (ipso-C-C), 141.4

2837 (w), 2814 (w), 1657 (m, C=O), 1580 (vs), 1510 (m), 1358 (m),

1250 (s, CH_aliph.), 1171 (m), 1065 (sh.), 1047 (vs), 1028 (m), 1013

(m), 932 (w), 847 (s), 721 (w) cm^–1. MS (70 eV): m/z (%) = 259

(100) [M]⁺, 228 (50) [M – OMe]⁺, 200 (48), 187 (64) [C₁₂H₁₁O₂]⁺,

159 (33) [C₁₁H₁₁O]⁺, 144 (37), 127 (33), 105 (26). C₁₅H₁₇NO₃

(259.27): calcd. C 69.48, H 6.61, N 5.40; found C 69.34, H 6.38, N

5.16.

(C_olef.), 156.0 (C=N), 186.2 (C=O) ppm. IR (KBr): ν = 3096 (w,

˜

CH_arom.), 3071 (w, CH_arom.), 2984 (m, CH_aliph.), 2937 (s, CH_aliph.),

2818 (w, CH_aliph.), 1967 (w), 1935 (w), 1668 (vs, C=O), 1601 (s),

1585 (s, sh.), 1560 (m, C=C), 1510 (m), 1462 (m), 1410 (w), 1366

(s, CH_aliph.), 1335 (s), 1279 (w), 1200 (m), 1153 (m), 1070 (s), 1042

(vs), 980 (s), 928 (m), 881 (m), 858 (w, sh.), 762 (m, CH_arom.), 717

(m, CH_arom.), 657 (w) cm^–1. MS (70 eV): m/z (%) = 281 (37) [M]⁺,

222 (18), 202 (71), 181 (37), 143 (12), 127 (17), 102 (100) [C₈H₆]⁺,

75 (13), 57 (11). C₁₂H₁₂BrNO₂(282.13): calcd. C 51.09, H 4.29, N

4.96; found C 51.12, H 4.08, N 4.81.

4-Methoxy-1-(2-pyridyl)iminopent-1-en-3-one (10l): From 3-meth-

oxyiminobutan-2-one (8b)^[33](2.0 g, 17.4 mmol) and pyridine-2-

carbaldehyde (1.7 mL, 1.9 g, 17.0 mmol) by using ethanol as sol-

vent. Yellow solid, 1.4 g (6.9 mmol, 40.3%), m.p. 102–104 °C. ¹H

NMR (300 MHz, CDCl₃): δ = 2.03 [s, 3 H, H₃CC(N)], 4.12 (s, 3

H, H₃CO), 7.22–7.29 (m, 1 H, H_arom.), 7.47–7.50 (m, 1 H, H_arom.),

3

1-(4-Chlorophenyl)-4-methoxyiminopent-1-en-3-one (10i): From 3-

methoxyiminobutan-2-one (8b)^[33](2.3 g, 20.0 mmol) and p-chloro-

7.68–7.74 (m, 1 H, H_arom.), 7.70 (d, J = 15.7 Hz, 1 H, H_olef.), 8.10

3

(d, J = 15.7 Hz, 1 H, H_olef.), 8.66–8.69 (m, 1 H, H_arom.) ppm. ¹³C

5350

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Eur. J. Org. Chem. 2006, 5339–5356

Hydroxypyrroles from Azapentadienones: The Aza-Nazarov Reaction

FULL PAPER

NMR (75 MHz, CDCl₃): δ = 8.9 [H₃CC(N)], 63.3 (OCH₃), 124.1

(C_olef.), 129.5 (ipso-C_pyrrole), 132.9 (C_olef.), 156.1 (C=N), 186.3

(C_arom.), 124.4 (C_arom.), 124.8 (C_olef.), 136.6 (C_arom.), 141.4 (C_arom.), (C=O) ppm. IR (film): ν = 3317 (br., NH_pyrrole), 3121 (w, CH_arom.),

˜

150.1 (C_olef.), 153.5 (C=N), 155.8 (C=N), 186.9 (C=O) ppm. IR

2997 (w, CH_aliph.), 2933 (s, CH_aliph.), 2818 (w, CH), 1651 (vs,

(KBr): ν = 3059 (w), 3003 (w, CH), 2941 (m, CH_aliph.), 2905 (w, C=O_ketone), 1585 (s, C=C_olef.), 1557 (vs, br., C=C), 1539 (m, C=C),

˜

sh.), 1693 (vs, C=O_ketone), 1678 (sh.), 1591 (m, C=C_olef.), 1566 (w),

1475 (m), 1435 (m, CH_aliph.), 1362 (w), 1340 (w, CH), 1315 (w), 1067 (vs), 1034 (s), 989 (s), 931 (m), 868 (s), 856 (m), 737 (s), 662

1070 (sh.), 1045 (vs), 899 (m), 849 (w), 789 (w), 748 (w) cm^–1. MS (m, CH), 600 (s), 536 (m), 446 (m) cm^–1. MS (ESI, CH₃OH): m/z

1435 (m, CH_aliph.), 1337 (m, C–H), 1265 (s), 1202 (m), 1126 (m),

(ESI, CH₃OH/CHCl₃): m/z (%) = 205 (100) [M + H]⁺. C₁₁H₁₂N₂O₂(%) = 193 (80) [M + H]⁺, 215 (42) [M + Na]⁺, 316 (80), 407 (100)

(204.09): calcd. C 64.69, H 5.92, N 13.72; found C 64.52, H 5.91,

N 13.65.

[M₂+ Na]⁺. C₁₀H₁₂N₂O₂(192.21): calcd. C 62.49, H 6.29, N 14.57;

found C 62.41, H 6.20, N 14.56.

4-Methoxyimino-1-(3-thienyl)pent-1-en-3-one (10m): From 3-meth-

oxyiminobutan-2-one (8b)^[33](2.3 g, 20.0 mmol) and thiophene-3-

carbaldehyde (1.8 mL, 2.2 g, 19.6 mmol). The solid was recrys-

tallized from methanol. Pale yellow solid, 3.6 g (17.2 mmol;

86.0%), m.p. 139.5 °C, b.p. 122 °C (0.024 mbar). ¹H NMR

(300 MHz, CDCl₃): δ = 2.02 [s, 3 H, H₃CC(N)], 4.10 (s, 3 H,

X-ray Crystal Structure Analysis of 10o:^[38]Formula C₁₀H₁₂N₂O₂,

M = 192.22, yellow crystal, 0.15×0.10×0.10 mm, a = 5.645(1), b

= 8.433(1), c = 11.434(1) Å, α = 84.26(1), β = 76.72(1), γ =

73.07(1)°, V = 506.5(1) Å³, ρ_calcd.= 1.260 gcm^–3, µ = 0.735 mm^–1,

empirical absorption correction (0.898 Յ T Յ 0.930), Z = 2, tri-

¯

clinic, space group P1 (No. 2), λ = 1.54178 Å, T = 223 K, ω and

OCH₃), 7.33 (dd, J = 2.9 Hz, J = 5.1 Hz, 1 H, H_thiophene), 7.39 (dd, φ scans, 4432 reflections collected ( h, k, l), [(sinθ)/λ] =

J = 1.2 Hz, J = 5.1 Hz, 1 H, H_thiophene), 7.56–7.57 (m, 1 H,

0.59 Å^–1, 1611 independent (R_int= 0.047) and 1299 observed reflec-

H_thiophene), 7.47 (d, ³J = 15.9 Hz, 1 H, H_olef.), 7.71 (d, ³J = 15.9 Hz, tions [I Ն 2σ(I)], 132 refined parameters, R = 0.041, wR₂= 0.125,

1 H, H_olef.) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 9.0 [H₃CC(N)], max. residual electron density 0.17 (–0.14) eÅ^–3, hydrogen atoms

63.1 (OCH₃), 120.4 (C_thiophene), 125.6 (C_thiophene), 126.7 (C_olef.),

calculated and refined as riding atoms.

128.7 (C_thiophene), 136.4 (C_olef.), 138.4 (ipso-C_thiophene), 156.0 (C=N),

1,4-Bis(4-methoxyimino-3-oxopent-1-en-1-yl)benzene (11a): 3-Meth-

oxyiminobutan-2-one (8b)^[33](10.0 g, 86.9 mmol) was treated with

an aqueous solution (10%) of potassium hydroxide (55 mL,

100 mmol) to give the enolate. The enolate was treated dropwise

with a solution of terephthalaldehyde (5.0 g, 37.3 mmol) in ethanol

(20 mL) at 0 °C. The solution was stirred at room temperature for

24 h, resulting in a bright brown solid. The product was filtered off

(glass filter funnel D4) and washed with small amounts of cold

ethanol. The crude product was purified by recrystallization from

methanol. Yellow solid, 11.1 g (33.8 mmol; 90.6%), m.p. 195 °C

(decomp.), b.p. 160–180 °C (0.002 mbar). ¹H NMR (300 MHz,

186.8 (C=O) ppm. IR (KBr): ν = 3094 (m, CH), 3015 (w, CH),

˜

2980 (w, CH_aliph.), 2936 (m, CH_aliph.), 2816 (w, CH_aliph.), 1665 (vs,

C=O_ketone), 1593 (s, C=C_olef.), 1514 (m, C=C), 1437 (w, CH_aliph.),

1329 (m, CH), 1292 (w), 1246 (m), 1067 (s), 1051 (vs), 1003 (m),

934 (m), 872 (m), 822 (m), 802 (s), 777 (w), 662 (m, C–H), 606 (m),

588 (m), 530 (w) cm^–1. MS (70 eV): m/z (%) = 209 (100) [M]⁺, 178

(20) [M – OCH₃]⁺, 150 (48), 137 (96) [C₇H₅OS]⁺, 109 (69)

[C₆H₅S]⁺, 65 (38). C₁₀H₁₁NO₂S (209.26): calcd. C 57.39, H 5.30,

N 6.69; found C 57.31, H 5.16, N 6.63.

1-(3-Bromo-2-thienyl)-4-methoxyiminopent-1-en-3-one (10n): From

3-methoxyiminobutan-2-one (8b)^[33](1.6 g, 13.9 mmol) and 3-bro- CDCl₃): δ = 2.03 [s, 6 H, 2×H₃CC(N)], 4.13 (s, 6 H, 2×OCH₃),

mothiophene-2-carbaldehyde^[42](3.2 g, 16.6 mmol). Yellow solid,

7.64 (s, 4 H, H_olef./_arom.

), 7.70 (s, 4 H, H_olef./arom.) ppm. ¹³C NMR

3.3 g (11.5 mmol, 82.4%), m.p. 123.5 °C, b.p. 165 °C (0.006 mbar). (150 MHz, CD₂Cl₂): δ = 8.97 [CH₃C(N)], 63.55 (OCH₃), 121.87

¹H NMR (400 MHz, CDCl₃): δ = 2.02 [s, 3 H, H₃CC(N)], 4.12 (s, (C_olef.), 129.20 (4 C, C_arom.), 137.20 (ipso-C), 141.76 (C_olef.), 156.24

3

3 H, OCH₃), 7.04 (d, J = 5.3 Hz, 1 H, H_thiophene), 7.34 (dd, J = (C=N), 186.53 (C=O) ppm. IR (KBr): ν = 3316 (w), 3032 (w,

˜

0.7 Hz, J = 5.3 Hz, 1 H, H_thiophene), 7.48 (d, ³J = 15.8 Hz, 1 H, CH_arom.), 2988 (w, CH_aliph.), 2930 (w, C–H_aliph.), 2818 (w, CH_aliph.),

H_olef.), 7.89 (dd, ³J = 15.8, J = 0.9 Hz, 1 H, H_olef.) ppm. ¹³C NMR 2124 (w), 1929 (w), 1663 (vs, C=O_ketone), 1597 (br. s, C=C_olef.), 1510

(100 MHz, CDCl₃): δ = 8.98 [H₃CC(N)], 63.27 (OCH₃), 116.93 (C-

(m, C=C), 1418 (m, CH_aliph.), 1350 (sh.), 1315 (m, CH), 1294 (w),

1196 (m), 1067 (s), 1050 (vs), 1007 (m), 930 (m), 883 (m), 824 (m),

Br), 121.31 (C_thiophene), 127.71 (C_olef.), 131.59 (C_thiophene), 133.40

(C_olef.), 135.26 (ipso-C_thiophene), 155.83 (C=N), 185.98 (C=O) ppm. 783 (w), 689 (s, C–H), 528 (m), 513 (m), 427 (w) cm^–1. MS (70 eV):

IR (KBr): ν = 3445 (br.), 3101 (w), 3084 (m, CH_arom.), 2982 (w), m/z (%) = 328.0 (100) [M]⁺, 297.0 (30), 269.1 (65), 228 (19), 184.0

˜

2939 (w, CH_aliph.), 2828 (w), 1659 (m, C=O), 1585 (br., vs), 1423

(27), 156.0 (55), 128 (63), 100 (20), 72 (22). C₁₈H₂₀N₂O₄(328.36):

(m), 1362 (w), 1325 (s, CH_aliph.), 1240 (w), 1159 (w), 1068 (sh.), calcd. C 65.84, H 6.14, N 8.53; found C 65.86, H 5.95, N 8.47.

1040 (vs), 968 (m), 932 (m), 883 (w), 851 (m), 739 (m), 710 (m),

2,5-Bis(4-methoxyimino-3-oxopent-1-en-1-yl)thiophene (11b): 3-

692 (m) cm^–1. MS (70 eV): m/z (%) = 287 (16) [M]⁺, 256 (12) [M –

Methoxyiminobutan-2-one (8b)^[33](900 mg, 7.8 mmol) was treated

OMe]⁺, 215 (62) [C₇H₄BrOS]⁺, 208 (100) [M – Br]⁺, 187 (28), 159

with an aqueous solution (10%) of potassium hydroxide (6 mL) to

(33) [C₁₁H₁₁O]⁺, 136 (27) [C₇H₄OS]⁺, 108 (87) [C₆H₄S]⁺, 63 (19).

give the enolate. The enolate was treated dropwise with a suspen-

C₁₀H₁₀BrNO₂S (288.16): calcd. C 41.68, H 3.50, N 4.86; found C

sion of thiophene-2,5-dicarbaldehyde (500 mg, 3.6 mmol) in etha-

41.62, H 3.26, N 4.76.

nol (5 mL) at 0 °C. Stirring was continued for 12 h at room tem-

4-Methoxyimino-1-(1H-pyrrol-2-yl)pent-1-en-3-one (10o): From 3-

methoxyiminobutan-2-one (8b)^[33](2.4 g, 20.8 mmol) and pyrrole-

2-carbaldehyde (2.0 g, 21.0 mmol) dissolved in methanol (20 mL).

The colour of the solution turned red. The crude solid was recrys-

tallized from methanol. Yellow solid, 1.9 g (9.9 mmol, 47.1%), m.p.

perature, resulting in an intensely yellow solid. This was filtered off

and washed with small amounts of ethanol. Intensely yellow solid,

790 mg (2.4 mmol, 66.7%), m.p. 176 °C (decomp.). ¹H NMR

(300 MHz, CDCl₃): δ = 2.02 [s, 6 H, 2×H₃CC(N)], 4.13 (s, 6 H,

2×OCH₃), 7.26 (s, 2 H, H_thio.), 7.48 (d, J = 15.6 Hz, 2 H, H_olef.),

7.76 (d, J = 15.7 Hz, 2 H, H_olef.) ppm. ¹³C NMR (75 MHz, CDCl₃):

1

48.5 °C, b.p. 134 °C (0.003 mbar). H NMR (300 MHz, CDCl₃): δ

= 2.0 [s, 3 H, H₃CC(N)], 4.1 (s, 3 H, OCH₃), 6.3 (br. m, 1 H,

δ = 8.99 [CH₃C(N)], 63.32 (OCH₃), 121.17 (C_olef.), 132.51

CH_pyrrole), 6.7 (m, 1 H, CH_pyrrole), 6.9 (m, 1 H, CH_pyrrole), 7.2 (d, (C_thiophene),134.65 (C_olefin.), 143.11 (ipso-C), 156.94 (C=N), 186.0

3

³J = 15.9 Hz, 1 H, H_olef.), 7,7 (d, J = 15.9 Hz, H_olef.), 9.0 (br., 1

H, NH) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 9.1 [H₃CC(N)], (w), 2937 (m, CH_aliph.), 2900 (sh.), 2820 (w, CH_aliph.), 1665 (vs,

63.0 (OCH₃), 111.3 (C_pyrrole), 114.1 (C_pyrrole), 115.6 (C_pyrrole), 122.9 C=O_ketone), 1580 (vs, br., C=C_olef.), 1510 (m, C=C), 1450 (w), 1438

(C=O) ppm. IR (KBr): ν = 3305 (w), 3090 (sh.), 3080 (w), 2974

˜

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5351

J. Dieker, R. Fröhlich, E.-U. Würthwein

FULL PAPER

(w, CH_aliph.), 1377 (w), 1340 (m), 1281 (w), 1231 (m), 1190 (m), NMR spectra of the crude product showed only the signals of the

1067 (s), 1051 (vs), 984 (m), 924 (m), 860 (s), 824 (s), 768 (w), 716 corresponding pyrrole, however, sometimes it decomposed rapidly.

(w), 665 (m), 534 (m) cm^–1. MS (ESI, CHCl₃/MeOH): m/z (%) = When possible the substances were purified by recrystallization or

335 (80) [M + H]⁺. C₁₆H₁₈N₂O₄S (334.10): calcd. C 57.47, H 5.43, column chromatography for CHN analysis.

N 8.38; found C 57.22, H 5.33, N 8.19.

1-(Methylphenylamino)-2-methyl-5-phenyl-1H-pyrrol-3-yl Acetate

1-(Methylphenylamino)-2-methyl-5-(4-nitrophenyl)-1H-pyrrol-3-ol

(12a): 4-(2-Methyl-2-phenylhydrazono)-1-(4-nitrophenyl)pent-1-en-

3-one (9b) (320 mg, 1.0 mmol) was dissolved in dry dichlorometh-

ane (30 mL) and the solution cooled to –78 °C. After dropwise ad-

dition of trifluoromethanesulfonic acid (0.12 mL, 0.18 g, 1.2 mmol)

the solution turned green, but brightened after about 5 min. A sat-

urated sodium hydrogen carbonate solution (4.5 mL) was added

at –78 °C. The solution was warmed to room temperature. The or-

ganic layer was washed with saturated sodium hydrogen carbonate

solution (5 mL) until the aqueous layer became neutral. The or-

ganic layer was washed with water (20 mL), dried with MgSO₄and

50% of the volume of the solvent was evaporated. TBME (20 mL)

was added and the solvent completely removed. The residue was

dried in vacuo. NMR spectroscopy of the crude product showed

signals that we assigned to only two diastereomers (rotamers) of

dihydropyrrole 12aЈ (Scheme 11). The crude product was filtered

through a short column (silica gel; TMBE). During the concentra-

tion of the solution a solid was formed, which was immediately

dissolved in dichloromethane and analyzed by NMR spectroscopy.

¹H NMR (600 MHz, CD₂Cl_2,298 K): δ = 1.54, 1.58 (2×s, 3 H,

CCH_3,slightly broadened), 2.78, 3.07 [2×s, 3 H, N(CH₃)], 3.91,

4.31 (2×s, 1 H, 3-H, br.), 5.61, 5.63 (2×s, 1 H, 4-H), 6.85–6.92 (m,

2 H, 5-H), 7.05–7.06 (m, 1 H, 6-H), 7.26–7.34 (m, 2 H, 7-H), 7.62–

7.74 (m, 2 H, 8-H), 8.17–8.20 (m, 2 H, 9-H).

(13): From trifluoromethanesulfonic acid (0.1 mL) and 4-(2-

methyl-2-phenylhydrazono)-1-phenylpent-1-en-3-one (9a) (500 mg,

1.8 mmol). The reaction mixture was treated with acetic anhydride

(1.9 mL). The crude product was purified by column filtration (sil-

ica gel, TMBE). A small amount of a byproduct (methylaniline;

3.9%) was formed according to GC analysis that couldnЈt be re-

moved. Crude yield 560 mg (1.74 mmol, 96.7%). R_f(TLC) = 0.48

(silica gel, TBME), R_t(GC) = 21.08 min [40–10/min–280(5)], pu-

rity: 96.1 %. ¹H NMR (600 MHz, CDCl₃): δ = 1.88 (s, 3 H,

H₃CCN), 2.26 [s, 3 H, OC(O)CH₃], 3.25 (s, 3 H, NCH₃), 6.26 (s, 1

H, H_pyrrole), 6.47–6.48 (m, 2 H, o-H_arom.), 6.82–6.85 (m, 1 H,

H_{a r o m .}), 7.14–7.17 (m, 1 H, H_{ar om .}), 7.20–7.37 (m, 6 H,

H

_arom.) ppm. ¹³C NMR (150 MHz, CD₂Cl₂): δ = 8.39 (CH₃CN),

20.79 (H₃CCOO), 40.04 (NCH₃), 100.03 (HC_pyrrole), 111.36

(o-C_N–Ph.), 118.83 (C_q), 119.03 (C_arom.), 126.61 (C_arom.), 127.05

(o/m-C_arom.), 128.24 (o/m-C_arom.), 129.43 (o/m-C_arom.), 129.78 (C_q),

131.50 (C_q), 132.94 (C_q), 148.70 (ipso-C_N–Ph.), 169.10 [H₃CC(O)

O] ppm. IR (Film): ν = 3066 (w, CH_arom.), 3031 (w, CH_arom.), 2962

˜

(m, CH_aliph.), 2922 (w, CH_aliph.), 2818 (w, CH_aliph.), 2359 (w), 2251

(w), 1755 (s, C=O), 1598 (s, C=C), 1501 (vs), 1456 (w), 1369 (m),

1307 (w), 1219 (vs), 1146 (m), 1095 (m), 910, 806 (w), 752 (sh.,

CH), 734 (s), 692 (m). GC–MS (70 eV): m/z (%) = 320 (20) [M]⁺,

248 (22), 172 (100) [M – CH₃CO – NMePh]⁺, 107 (85), 106 (64),

77 (80), 51 (27), 43 (71).

1-Methoxy-2-methyl-5-(1H-pyrrol-2-yl)-1H-pyrrol-3-yl Acetate

(14): From trifluoromethanesulfonic acid (0.4 mL, 4.6 mmol) dis-

solved in dry dichloromethane (50 mL) and a solution of 4-meth-

oxyimino-1-(1H-pyrrol-2-yl)pent-1-en-3-one (10o) (790 mg,

4.1 mmol) in dry dichloromethane (5.5 mL). The colour of the

solution changed from yellow to orange to brown. The product was

purified by column chromatography (SiO₂, TBME), resulting in a

spectroscopically pure substance that decomposed rapidly. Brown

gum, rapidly darkening to give a black tar, crude yield 561 mg

1

(2.4 mmol, 58.4%), R_f(TLC) = 0.59 (silica gel, TBME). H NMR

(400 MHz, CDCl₃): δ = 2.08 (s, 3 H, H₃CCN), 2.17 [s, 3 H, OC(O)

CH₃], 3.69 (s, 3 H, OCH₃), 5.85–6.66 (m, 4 H, H_pyrrole), 8.62 (br.,

1 H, NH) ppm. ¹³C NMR (100 MHz, CD₂Cl₂): δ = 7.35 (CH₃CN),

20.73 (H₃CCOO), 65.51 (NOCH₃), 94.26 (C_pyrrole), 100.12

(C_pyrrole), 106.05 (C_pyrrole), 109.21 (C_pyrrole), 117.46 (C_pyrrole), 130.16

(C_pyrrole), 168.47 [H₃CC(O)O] ppm. MS (70 eV): m/z (%) = 234 (26)

[M]⁺, 203 (16) [M – OCH₃]⁺, 161 (100), 91 (23). MS (ESI, CHCl₃/

CH₃OH): m/z (%) = 257 (100) [M + Na]⁺, daughters: 226 (50)

[M – OCH₃+ Na]⁺, 183 (72) [M – OCH₃– H₃CCO + Na]⁺. MS

(MicroTOF): m/z (%): calcd. 257.0897 [M + Na]⁺; found 257.0904

Scheme 11. Numbering of 12aЈ for NMR assignment.

General Procedure for the Cyclization of Azadienones with the Use

of Trifluoromethanesulfonic Acid: A solution of trifluoromethane-

sulfonic acid (0.4 mL) in dry dichloromethane (150 mL) was cooled

to –10 °C. A solution of the 1-azapenta-1,4-dienone (7.5 mmol) in

dry dichloromethane (10 mL) was added dropwise with stirring

(colour change). After complete addition stirring was continued

until completion of the reaction (TLC control, eluent: TBME).

Then the reaction mixture was treated with acetic anhydride

[M + Na]⁺

.

4-Benzoyl-3-benzoyloxy-2-methyl-1-(methylphenylamino)-5-phenyl-

(2 mL). After warming to room temperature and stirring for 10 min 1H-pyrrole (15a): 4-(2-Methyl-2-phenylhydrazono)-1-phenylpent-1-

the solution was again cooled to –10 °C and a saturated solution

of sodium hydrogen carbonate (10 mL) was added carefully. The

added hydrogen carbonate initially solidified, so that the acidic re-

action mixture was neutralized very slowly and in a controlled

manner. The organic layer was washed with saturated sodium hy-

drogen carbonate solution (10 mL) until the aqueous layer became

neutral. Then the organic layer was washed with water (20 mL),

dried with MgSO₄and 50% of the volume of the solvent evapo-

rated. TMBE (20 mL) was added and the solvent was evaporated

completely. The remaining crude product was dried in vacuo. The

en-3-one (9a) (334 mg, 1.2 mmol) was added dropwise to a solution

of trifluoromethanesulfonic acid (0.3 mL, 3.4 mmol) at –78 °C to

give a dark green solution. At the end of the addition the reaction

mixture was slightly green. Stirring at –78 °C was continued for

10 min before the mixture was treated with a solution of benzoic

anhydride (565 mg, 2.5 mmol) in dichloromethane (10 mL). The

colourless solution was warmed to room temperature and stirring

at room temperature was continued for 8 h. The reaction mixture

was then treated with saturated sodium hydrogen carbonate solu-

tion. After aqueous work up the product was purified by column

5352

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Eur. J. Org. Chem. 2006, 5339–5356

Hydroxypyrroles from Azapentadienones: The Aza-Nazarov Reaction

FULL PAPER

chromatography (SiO₂, TBME/pentane = 1:1), but it was not pos-

sible to separate it from the derivative that is unsubstituted in the

4-position. Yellow oil, 88 mg (1.9 mmol, 15.0 %). ¹H NMR

8.97 (C-15), 27.36 (C-14), 35.30 (C-11), 40.46 (NCH₃), 111.24 (C-

18), 114.63 (C_q), 120.06 (C-20), 121.17 (C_q), 122.97 (C-7), 129.56

(C-19), 131.31 (C-6), 131.61 (C_q), 131.73 (C_q), 137.37 (C_q), 147.57

(300 MHz, CDCl₃): δ = 2.04 (s, 3 H, CCH₃), 3.28 (NCH₃), 6.56– (C_q), 147.84 (C_q), 172.70 (C-10), 196.01 (C-13) ppm (Scheme 12).

6.57 (m, 2 H, o-H_N–Ph.), 7.07–7.57 (m, 10 H, H_arom.), 7.64–7.66 (m,

3-Acetoxy-4-acetyl-5-(2-bromophenyl)-1-methoxy-2-methyl-1H-pyr-

2 H, H_arom.), 7.75–7.77 (m, 2 H, H_arom.), 7.84–7.87 (m, 2 H, H_arom.),

role (16a): 1-(2-Bromophenyl)-4-methoxyiminopent-1-en-3-one

8.00–8.03 (m, 2 H, H_arom.) ppm. ¹³C NMR (75 MHz, CDCl₃): δ =

(10h) (2.0 g, 7.1 mmol) was dissolved in dichloromethane (100 mL)

8.46 (CCH₃), 40.44 (NCH₃), 110.46 (C_q), 114.30, 120.23, 127.61–

and added dropwise to a solution of trifluoromethanesulfonic acid

130.11 (C_arom., C_pyrrole), 131.66, 132.13 (C_q), 132.80, 133.34 (C_q),

(4 mL, 48.8 mmol) in dichloromethane (500 mL). The reaction

138.36, 138.73 (C_arom., C_pyrrole), 151.81 (ipso-C_N–Ph.), 164.75

mixture was treated with acetic anhydride (15 mL). After aqueous

(CO₂Ph), 195.11 (PhC=O) ppm.

work up a highly viscous, colourless liquid was obtained. Yield

1.91 g (5.2 mmol, 73.2%). ¹H NMR (300 MHz, CDCl₃): δ = 1.9 (s,

3 H, NCCH₃), 2.3 (s, 3 H, CH₃CO₂), 2.4 [s, 3 H, CH₃C(O)], 3.7 (s,

3 H, OCH₃), 7.51–7.71 (m, 3 H, H_arom.), 7.7–7.8 (m, 1 H,

3-Acetoxy-4-acetyl-2-methyl-1-(methylphenylamino)-5-(4-nitro-

phenyl)-1H-pyrrole (15b): From trifluoromethanesulfonic acid

(0.2 mL, 2.3 mmol) and 4-(2-methyl-2-phenylhydrazono)-1-(4-ni-

trophenyl)pent-1-en-3-one (9b) (507 mg, 1.5 mmol). The crude

product was purified by column chromatography (SiO₂, TBME).

Yellow solid, 474 mg (1.2 mmol, 75.3%), m.p. Ͼ 88 °C (decomp.).

¹H NMR (300 MHz, CDCl₃): δ = 1.9 (s, 3 H, NCCH₃), 2.1 (s, 3

H,H₃CCO), 2.4 (s, 3 H, H₃CCO), 3.2 (s, 3 H, NCH₃), 6.37–6.40

(m, 2 H, o-H_N–Ph.), 6.85–6. 9 (m, 1 H, p-H_N–Ph.), 7.22–7.25 (m, 2

H, m-H_N–Ph.), 7.43–7.45 (m, 2 H, H_nitroarom.), 8.11–8.15 (m, 2 H,

H_nitroarom.) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 8.1 (H₃CCN),

20.6 (H₃CCOO), 30.1 (H₃CC_ketone), 40.5 (NCH₃), 111.3 (o-C_N–Ph.),

114.9 (C_q), 120.1 (p-C_N–Ph.), 121.3 (C_q), 123.0 (2 C, C_nitroarom.),

129.6 (m-C_N–Ph.), 131.5 (2 C; C_nitroarom.), 131.9 (C_q), 132.2 (C_q),

137.2 (C_q), 147.7 (C_q), 147.9 (C_q), 169.13 (O=C_ester), 192.5

(O=C_ketone) ppm. MS (ESI, CHCl₃/CH₃OH, 38 eV): m/z (%) = 430

(100) [M + Na]⁺, 408 (13) [M + H]⁺.

H

_arom.) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 7.39 (H₃CC_pyrrole),

21.12 (H₃CCOO), 29.67 (H₃CCO_ketone), 66.74 (OCH₃), 112.17

(C_pyrrole), 116.81 (C_pyrrole), 126.35 (C_q), 127.76 (CH), 128.62 (C_q),

129.86 (C_q), 131.34 (CH), 131.88 (C_q), 133.34 (2 C, C_arom.), 169.96

(CO₂CH₃), 192.51 (H₃C=O) ppm. MS (ESI, MicroTOF, CH₃OH):

m/z (%) = 366.03 [M + H]⁺, 388.01 (100) [M + Na]⁺. C₁₆H₁₆BrNO₄

(366.21): calcd. C 52.48, H 4.40, N 3.82; found C 53.06, H 5.06, N

3.47.

3-Acetoxy-4-acetyl-5-(4-chlorophenyl)-1-methoxy-2-methyl-1H-pyr-

role (16b): From 1-(4-chlorophenyl)-4-methoxyiminopent-1-en-3-

one (10i) (0.55 g, 2.3 mmol) and a solution of trifluoromethanesul-

fonic acid (0.3 mL) in dichloromethane. The reaction mixture was

treated with acetic anhydride (2 mL) at –78 °C. The reaction mix-

ture was warmed to –10 °C and treated with sodium hydrogen car-

bonate solution followed by aqueous work up. The product was

purified by Kugelrohr distillation. Yellow, very viscous oil, 0.53 g

(1.6 mmol, 71.6%), b.p. 200 °C (0.009 mbar). ¹H NMR (300 MHz,

CDCl₃): δ = 1.95 (s, 3 H, NCCH₃), 2.08 (s, 3 H, CH₃CO₂), 2.25 [s,

3 H, CH₃C(O)], 3.50 (s, 3 H, OCH₃), 7.36 (m, 4 H, H_arom.) ppm.

¹³C NMR (75 MHz, CDCl₃): δ = 7.02 (H₃CC_pyrrole), 20.63

(H₃CCOO), 30.00 (H₃CCO_ketone), 65.85 (OCH₃), 111.74 (C_pyrrole),

116.38 (C_pyrrole), 127.46 (C_pyrrole), 128.05 (C_pyrrole), 128.52

(o/m-C_arom.), 129.53 (ipso-C_arom.), 132.10 (o/m-C_arom.), 135.06 (ipso-

1-(Methylphenylamino)-2-methyl-5-(4-nitrophenyl)-4-propionyl-3-

propionyloxy-1H-pyrrole (15c): From trifluoromethanesulfonic acid

(0.2 mL, 2.3 mmol) and 4-(2-methyl-2-phenylhydrazono)-1-(4-ni-

trophenyl)pent-1-en-3-one (9b) (547 mg, 1.7 mmol). The brown re-

action mixture was stirred for 1 h at –78 °C before being treated

with propionic anhydride (0.5 mL, 0.5 g, 3.9 mmol) to give a green

solution. After work up with sodium hydrogen carbonate and evap-

oration of the solvent the crude product (an orange gum) was puri-

fied by column chromatography (SiO₂, TBME/pentane = 1:2). The

solid decomposed rapidly. The substance was dissolved in chloro-

form and a ¹H NMR spectrum (600 MHz) recorded immediately.

Orange gum, rapidly decomposing, crude yield 303 mg (0.7 mmol,

C_arom.), 169.49 (CO CH ), 192.67 (H C=O) ppm. IR (film): ν =

˜

2

3

3025 (w, CH_arom.), 2941 (m, CH_aliph.), 1764 (vs, C=O), 1658 (vs),

1602 (m), 1522 (s), 1473 (s), 1431 (s), 1410 (s), 1367 (s), 1261 (m),

1206 (vs), 1130 (m), 1111 (m), 1016 (m), 962 (w), 907 (w), 843

(sh.), 814 (vs), 731 (s) cm^–1. MS (ESI, MicroTOF, CH₃OH): calcd.

344.0660 [M + Na]⁺; found 344.0661. C₁₆H₁₆ClNO₄(321.76):

calcd. C 59.73, H 5.01, N 4.35; found C 59.53, H 4.99, N 4.25.

1

41.2%). R_f(TLC) = 0.32 (silica gel, TBME). H NMR (600 MHz,

CDCl₃): δ = 1.00 (t, ³J = 7.3 Hz, 3 H, H₃C-12), 1.31 (t, ³J = 7.5 Hz,

3 H, H₃C-15), 1.89 (s, 3 H, H₃C-9), 2.43 (q, ³J = 7.3 Hz, 2 H, H₂C-

11), 2.68 (q, ³J = 7.5 Hz, 2 H, H₂C-14), 3.18 (s, 3 H, NCH₃), 6.38–

6.39 (m, 2 H, HC-18), 6.87–6.89 (m, 1 H, HC-20), 7.23–7.26 (m, 2

H, HC-19), 7.43–7.44 (m, 2 H, HC-6), 8.11–8.13 (m, 2 H, HC- 3-Acetoxy-4-acetyl-1-methoxy-2-methyl-5-(4-nitrophenyl)-1H-pyr-

7) ppm. ¹³C NMR (150 MHz, CDCl₃): δ = 7.89 (C-9), 8.19 (C-12), role (16c): 1-(4-Nitrophenyl)-4-methoxyiminopent-1-en-3-one (10j)

(0.75 g, 3.0 mmol) was added dropwise to a solution of trifluoro-

methanesulfonic acid (0.5 mL) in dichloromethane. The dark-col-

oured reaction mixture was treated with acetic anhydride (2 mL)

at –78 °C. The reaction mixture was warmed to –10 °C and treated

with sodium hydrogen carbonate solution followed by aqueous

work up. The product was purified by column chromatography

(SiO₂, TBME). Viscous reddish gum, 0.56 g (1.7 mmol, 56.7%). ¹H

NMR (300 MHz, CDCl₃): δ = 2.08 (s, 3 H, NCCH₃), 2.10 (s, 3 H,

CH₃CO₂), 2.26 [s, 3 H, CH₃C(O)], 3.51 (s, 3 H, OCH₃), 7.60–7.64

(m, 2 H, H_arom.), 8.17–8.20 (m, 2 H, H_arom.) ppm. ¹³C NMR

(75 MHz, CDCl₃): δ = 7.17 (H₃CC_pyrrole), 20.52 (H₃CCOO), 30.06

(H₃CCO_ketone), 66.04 (OCH₃), 112.27 (C_pyrrole), 117.47 (C_pyrrole),

123.05 (o/m-C_arom.), 125.94 (C_pyrrole), 129.71 (C_pyrrole), 131.51 (o/m-

C_arom.), 135.28 (ipso-C_arom.), 147.45 (ipso-C_arom.), 169.05

(CO CH ), 192.23 (H C=O) ppm. IR (film): ν = 3098 (w, CH_arom.),

˜

2

3

Scheme 12. Numbering of 15c for NMR assignment.

2988 (m, CH_aliph.), 2941 (w, CH_aliph.), 1771 (s, C=O), 1665 (m),

Eur. J. Org. Chem. 2006, 5339–5356

www.eurjoc.org

5353

J. Dieker, R. Fröhlich, E.-U. Würthwein

FULL PAPER

1601 (m), 1589 (s, C=C), 1474 (w), 1429 (w), 1394 (w), 1346 (vs),

calcd. 316.0614 [M + Na]⁺; found 316.0616. C₁₄H₁₅NO₄S (293.34):

1267 (w), 1202 (s), 1109 (m), 1090 (m), 1045 (w), 1013 (w), 961 (w), calcd. C 57.32, H 5.15, N 4.77; found C 57.07, H 5.00, N 4.86.

903 (w), 858 (m), 833 (s), 733 (m) cm^–1. MS (ESI, MicroTOF):

calcd. 355.0901 [M + Na]⁺; found 355.0909. C₁₆H₁₆N₂O₆(332.31):

calcd. C 57.83, H 4.85, N 8.43; found C 57.98, H 5.09, N 8.57.

X-ray Crystal Structure Analysis of 16e:^[38]Formula C₁₄H₁₅NO₄S,

M = 293.33, colourless crystal, 0.45 × 0.25 × 0.25 mm, a =

10.830(1), b = 8.581(1), c = 15.654(1) Å, β = 100.81(1)°, V =

1428.9(2) Å³, ρ_calcd.= 1.363 gcm^–3, µ = 2.135 mm^–1, empirical ab-

sorption correction (0.447 Յ T Յ 0.617), Z = 4, monoclinic, space

group P2₁/n (No. 14), λ = 1.54178 Å, T = 223 K, ω and φ scans,

8379 reflections collected ( h, k, l), [(sinθ)/λ] = 0.59 Å^–1, 2399

independent (R_int= 0.042) and 2098 observed reflections [I Ն

2σ(I)], 193 refined parameters, R = 0.041, wR₂= 0.124, max. resid-

ual electron density 0.23 (–0.26) eÅ^–3, sulfur atom disordered over

two positions, hydrogen atoms calculated and refined as riding

atoms.

3-Acetoxy-4-acetyl-1-methoxy-2-methyl-5-styryl-1H-pyrrole (16d):

From a solution of trifluoromethanesulfonic acid (0.4 mL,

4.6 mmol) in dry dichloromethane (20 mL) and a solution of 2-

methoxyimino-7-phenylhepta-4,6-dien-3-one (3) (0.63 g, 2.7 mmol)

in dry dichloromethane (10 mL). The resulting reaction mixture

was slowly warmed to –10 °C and treated with acetic anhydride

(2.0 mL). After aqueous work up a yellow precipitate was obtained.

In some experiments no precipitate was formed after evaporation

of the solvent. In such cases the oil was dissolved in chloroform

and the solvent was again removed in vacuo to give a yellow solid

which was recrystallized from methanol. Yellow solid, 0.57 g

4-Benzoyl-3-benzoyloxy-1-benzyloxy-2-methyl-5-phenyl-1H-pyrrole

(16f): 4-(Benzyloxyimino)-1-phenylpent-1-en-3-one (10a) (660 mg,

2.4 mmol) was added dropwise to trifluoromethanesulfonic acid

(0.4 mL, 4.6 mmol) at –78 °C to give an orange solution. At the

end of the addition the reaction mixture turned slightly yellow. Stir-

ring was continued for 10 min at –78 °C before the reaction mixture

was treated with a solution of benzoic anhydride (1.1 g, 4.9 mmol)

in dichloromethane (17 mL). The solution turned colourless. The

mixture was warmed to room temperature and stirred for 1 h. Then

the reaction mixture was again cooled to –10 °C and washed with

sodium hydrogen carbonate solution. After aqueous work upthe

product was purified by column filtration (SiO₂, TBME), but sepa-

ration from a byproduct that was unsubstituted in the 4-position

could not be achieved. Yellow oil, 0.96 g. ¹H NMR (400 MHz,

CDCl₃): δ = 2.11 (s, 3 H, NCCH₃), 4.55 (s, 2 H, PhCH₂), 6.93–

8.06 (m, 20 H, H_arom.) ppm. ¹³C NMR (100 MHz, CDCl₃): δ =

8.60 (CH₃), 81.35 (OCH₂Ph), 111.58 (C_q), 117.86, 125.82, 127.43,

128.30, 128.61, 129.01, 129.32, 129.58, 130.13, 130.57, 130.84,

1

(1.8 mmol, 67.4%), m.p. Ͼ68 °C (decomp.). H NMR (300 MHz,

CDCl₃): δ = 2.15 (s, 3 H, NCCH₃), 2.33 (s, 3 H, O₂CCH₃), 2.37 [s,

3 H, (O)CCH₃], 3.91 (s, 3 H, OCH₃), 7.23–7.37 (m, 3 H, H_arom.),

7.43 (d, J = 16.8 Hz, 1 H, H_olef.), 7.51–7.54 (m, 2 H, H_arom.), 7.69

3

(d, J = 16.8 Hz, 1 H, H_olef.) ppm. ¹³C NMR (75 MHz, CDCl₃): δ

= 7.4 (H₃CCN), 20.7 (H₃CCOO), 30.5 (H₃CCO_ketone), 65.0

(OCH₃), 111.2 (C_pyrrole), 115.6 (C_olef), 117.7 (C_pyrrole), 126.3

(C_pyrrole), 126.6 (o/m-C_arom.), 127.9 (p-C_arom.), 128.6 (o/m-C_arom.),

129.8 (C_pyrrole), 132.3 (C_olef.), 137.6 (ipso-C_arom.), 168.9 (O=C_ester),

192.8 (O=C_ketone) ppm. IR (KBr): ν = 3304, 3022 (w, CH_arom.),

˜

2936 (m, CH_aliph.), 2820 (m, CH_aliph.), 1659 (vs, C=O), 1585 (s, br.,

C=C), 1448 (m), 1356 (s, CH_aliph.), 1317 (w), 1213 (w), 1075 (m,

br.), 915 (m), 853 (m), 756 (vs, CH_arom.), 689 (vs, CH_arom.) cm^–1.

MS (ESI, CHCl₃/CH₃OH, 40 eV): m/z (%) = 649.6 (100) [M₂

+

Na]⁺, 627.6 (18) [M₂+ H]⁺, 336.5 (55) [M + Na]⁺, 314.5 (51) [M

+ H]⁺_.C₁₈H₁₉NO₄(313.35): calcd. C 68.99, H 6.11, N 4.47; found

C 68.12, H 5.90, N 4.29.

131.20, 131.24, 132.21, 133.53, 134.01, 135.24, 139.77 (C_arom.

,

C_pyrrole), 165.65 (CO₂Ph), 191.57 (PhC=O) ppm. MS (ESI,

CH₃OH/CHCl_3,50 eV): m/z (%) = 511 (63) [M + Na]⁺, 489 (100)

[M + H]⁺, 407 (6) [M – PhC=O + Na]⁺, 385 (95) [M – PhC=O +

H]⁺.

X-ray Crystal Structure Analysis of 16d:^[38]Formula C₁₈H₁₉NO₄,

M = 313.34, yellow crystal, 0.60×0.20×0.10 mm, a = 12.863(1), b

= 7.990(2), c = 16.695(2) Å, β = 103.11(1)°, V = 1666.2(5) Å³, ρ_calcd.

= 1.249 gcm^–3, µ = 0.725 mm^–1, empirical absorption correction

(0.670 Յ T Յ 0.931), Z = 4, monoclinic, space group P2₁/n (No.

14), λ = 1.54178 Å, T = 223 K, ω/2θ scans, 3535 reflections col-

4-Acetyl-3-acetoxy-1-benzyloxy-2-methyl-5-phenyl-1H-pyrrole

(16g): 4-(Benzyloxyimino)-1-phenylpent-1-en-3-one (10a) (0.51 g,

1.8 mmol) was added dropwise to trifluoromethanesulfonic acid

(0.3 mL, 3.4 mmol) at –78 °C to give a yellow solution. Stirring at

–78 °C was continued for 10 min and then the reaction mixture

was treated with acetic anhydride (3.5 mL, 3.6 mmol) to give a red

solution. The reaction mixture was warmed to –10 °C and treated

with sodium hydrogen carbonate solution followed by aqueous

work up. The product was purified by column chromatography (sil-

ica gel, TBME) to give a red oil, 0.44 g (1.2 mmol, 67.3%). ¹H

NMR (400 MHz, CDCl₃): δ = 2.00 (s, 3 H, NCCH₃), 2.08 (CH₃),

2.33 (CH₃), 4.60 (s, 2 H, PhCH₂), 6.13–6.92 (m, 2 H, H_arom.), 7.23–

7.34 (m, 3 H, H_arom.), 7.47–7.51 (m, 5 H, H_arom.) ppm. ¹³C NMR

(100 MHz, CDCl₃): δ = 8.60 (CH₃), 20.72 (H₃CCOO), 29.96

(H₃CCO_ketone), 80.70 (OCH₂Ph), 111.67 (C_pyrrole), 116.71 (C_pyrrole),

128.33 (2 C), 128.55 (2 C), 128.97 (p-C_arom.), 129.30 (p-C_arom.),

129.41 (C_q), 129.44 (C_q), 129.62 (2 C), 129.99 (C_q), 131.11 (2 C),

132.76 (C_arom.,C_pyrrole), 169.68 (CO₂CH₃), 193.19 (H₃C=O) ppm.

lected (–h, –k, l), [(sinθ)/λ] = 0.62 Å^–1, 3382 independent (R_int

=

0.016) and 2599 observed reflections [I Ն 2σ(I)], 213 refined param-

eters, R = 0.055, wR₂= 0.172, max. residual electron density 0.55

(–0.48) e Å^–3, hydrogen atoms calculated and refined as riding

atoms.

3-Acetoxy-4-acetyl-1-methoxy-2-methyl-5-(3-thienyl)-1H-pyrrole

(16e): From trifluoromethanesulfonic acid (0.4 mL, 4.6 mmol) and

4-methoxyimino-1-(3-thienyl)pent-1-en-3-one (10m) (0.450 g,

2.1 mmol), resulting in a red solution. The product was separated

by column chromatography (SiO₂, TBME) from a byproduct show-

ing a third acylation on the thiophene moiety. Colourless crystals,

1

0.370 g (1.3 mmol; 60.1%), m.p. 114–115 °C. H NMR (400 MHz,

CDCl₃): δ = 2.05 (s, 3 H, NCCH₃), 2.15 (s, 3 H, O₂CCH₃), 2.34 [s,

3 H, (O)CCH₃], 3.62 (s, 3 H, OCH₃), 7.24 (m, 1 H, H_thiophene),

7.41 (m, 1 H, H_thiophene), 7.55 (m, 1 H, H_thiophene) ppm. ¹³C NMR

(100 MHz, CDCl₃): δ = 6.9 (H₃CCN), 20.6 (H₃CCOO), 29.6

(H₃CCO_ketone), 65.7 (OCH₃), 111.8 (C_pyrrole), 116.3 (C_pyrrole), 124.4

(C_pyrrole), 125.2 (HC_thiophene), 127.0 (HC_thiophene), 128.4 (C_q), 129.3

(HC_thiophene), 129.4 (C_q), 169.6 (O=C_ester), 192.8 (O=C_ketone) ppm.

IR (film): ν = 3065 (w), 3032 (w, CH_arom.), 2955 (sh., CH_aliph.),

˜

2930 (m, CH_aliph.), 1827 (s), 1769 (vs), 1657 (s), 1599 (w), 1526 (w),

1474 (m), 1431 (m), 1402 (s), 1369 (s, CH_aliph.), 1258 (w), 1209 (s,

br.), 1126 (s, br), 1092 (m), 997 (m), 954 (w), 910 (m, br), 770 (sh.),

754 (m, CH_arom.), 702 (s, CH_arom.) cm^–1. MS (ESI, MicroTOF,

CH₃OH): calcd. 386.1363 (C₂₂H₂₁NO₄Na⁺); found 386.1357.

IR (KBr): ν = 3437 (br.), 3097 (m), 2995 (w), 2951 (w, CH_aliph.),

˜

2926 (w), 1759 (m, C=O), 1645 (vs), 1435 (m), 1414 (m), 1367 (m),

1259 (w), 1207 (vs), 1132 (w), 1093 (w), 1013 (w), 978 (m), 932 (m), 1-Methoxy-2-methyl-5-phenyl-4-propionyl-3-(propionyloxy)-1H-pyr-

864 (w), 800 (m), 686 (w) cm^–1. MS (ESI, MicroTOF, CH₃OH): role (16h): 4-Methoxyimino-1-phenylpent-1-en-3-one (10f) (1.0 g,

5354

www.eurjoc.org

Eur. J. Org. Chem. 2006, 5339–5356

Hydroxypyrroles from Azapentadienones: The Aza-Nazarov Reaction

FULL PAPER

4.9 mmol) were added dropwise to trifluoromethanesulfonic acid

(0.5 mL, 5.7 mmol) at –78 °C. The reaction mixture was warmed

to room temperature and again cooled to –78 °C before it was

treated with propionic anhydride (0.6 mL, 0.6 g, 4.9 mmol). The

product was purified by column filtration (silica gel, petroleum

ether/TBME = 5:1). Viscous brown gum, rapidly decomposing.

Crude yield 0.41 g (1.3 mmol, 26.5%). R_f(TLC) 0.10 (silica gel,

phene (11b) (150 mg, 0.4 mmol). Complete purification by various

methods could not be achieved. H NMR (300 MHz, CDCl₃): δ =

1

2.18 [s, 12 H, 4×H₃C, (2 ×CH₃CN, 2×H₃CC_ester)], 2.33 (s, 6 H,

2 × H₃C, H₃CC_ketone), 3.79 (s, 6 H, 2 × OCH₃), 7.36 (s, 2 H,

H

_thiophene) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 7.1 (H₃CCN),

20.6 (H₃CCOO), 29.6 (H₃CC_ketone), 66.1 (OCH₃), 113.0 (C_pyrrole),

117.6 (C_pyrrole), 120.7 (C_q), 129.6 (C_q), 130.5 (HC_thiophene), 131.2

1

3

TBME). H NMR (300 MHz, CDCl₃): δ = 0.91 (t, J = 7.3 Hz, 3 (C_q), 169.3 (OC=O), 192.5 (C=O) ppm. MS (ESI, CHCl₃/CH₃OH,

3

H), 1.29 (t, J = 7.6 Hz, 3 H), 2.15 (s, 3 H, NCCH₃), 2.26 (q, J =

cone 35 eV): m/z (%) = 503 (50) [M + H]⁺, 525 (100) [M + Na]⁺.

7.3 Hz, 2 H, CH₂), 2.64 (q, ³J = 7.6 Hz, 2 H), 2.93 (s, 3 H, OCH₃), MS (MicroTOF): calcd. 525.1296 [M + Na]⁺; found 525.1302 [M

7.42–7.50 (m, 5 H) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 7.06

(CH₃), 8.26 (CH₃), 9.04 (NCCH₃), 27.40 (CH₂), 34.92 (CH₂), 65.77

(OCH₃), 111.47 (C_q), 115.91 (C_q), 128.24 (o/m-C_arom.), 128.8

(p-C_arom.), 129.0 (C_q), 129.4 (C_q), 129.5 (C_q), 130.7 (o/m-C_arom.),

173.1 (O=C_ester), 196.6 (O=C_ketone) ppm. MS (70 eV): m/z (%) =

315 (45) [M]⁺, 286 (3), 259 (100) [M – C₂H₅C(O)]⁺, 228 (99)

[C₁₃H₁₀NO₃]⁺, 210 (31) [C₁₄H₁₂NO]⁺, 199 (16), 182 (19), 159 (13),

141 (24), 129 (33), 57 (67).

+ Na]⁺.

Supporting Information (see footnote on the first page of this arti-

cle): Quantum chemical data for Figure S1 and S2 and graphical

representations of the transition states 1-TS (charge distribution

and relevant orbitals, Figure 2).

Acknowledgments

1,4-Bis[4-acetoxy-3-acetyl-1-methoxy-5-methyl-1H-pyrrol-2-yl]ben-

zene (17a): From a solution of trifluoromethanesulfonic acid

(4.0 mL, 45.8 mmol) in dichloromethane (500 mL) and a solution

of 1,4-bis(4-methoxyimino-3-oxopent-1-en-1-yl)benzene (11a)

(2.0 g, 6.1 mmol) in dichloromethane (100 mL). The reaction mix-

ture was treated with acetic anhydride (20 mL) and neutralized by

addition of a saturated sodium hydrogen carbonate solution

(2×80 mL). After aqueous work up the solvent was completely re-

The authors thank the Deutsche Forschungsgemeinschaft (Euro-

pean Graduate College “Template Directed Chemical Synthesis”)

and the Fonds der Chemischen Industrie (Frankfurt) for financial

support. We thank Dr. K. Bergander, University of Münster, for

helpful discussions.

[1] K. Habermas, S. E. Denmark, Organic Reactions (Ed.: L.A.

Paquette), John Wiley & Sons, Inc, New York, 1994, vol. 45,

pp. 1–158.

[2] M. A. Tius, Eur. J. Org. Chem. 2005, 2193–2206.

[3] M. Harmata, Chemtracts – Organic Chemistry 2004, 17, 416–

435.

1

moved. The H NMR spectrum of the crude product showed only

the signals of the resulting pyrrole. For the elemental analysis the

substance was recrystallized from methanol. Ochre-brown solid,

2.87 g (5.8 mmol, 95%) (crude product), 1.33 g (2.7 mmol, 44%)

1

after second recrystallization, m.p. 216 °C (decomp.). H NMR

[4] S. Klötgen, E.-U. Würthwein, Tetrahedron Lett. 1995, 36,

(400 MHz, CDCl₃): δ = 2.05 (s, 6 H, 2 × H₃C-6), 2.18 (s, 6 H,

2×H₃C-10), 2.34 (s, 6 H, 2×H₃C-13), 3.61 (s, 6 H, 2×OCH₃),

7.60 (s, 4 H, H_arom.) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 7.10

(H₃CCN), 20.70 (H₃CCOO), 29.88 (H₃CC_ketone), 65.77 (OCH₃),

111.90 (C_pyrrole), 116.50 (C_pyrrole), 128.65 (C_q), 129.60 (C_q), 129.72

(C_q), 130.72 (4×C_arom.), 169.58 (OC=O), 192.81 (C=O) ppm. IR

7065–7068.

[5] S. Klötgen, R. Fröhlich, E.-U. Würthwein, Tetrahedron 1996,

52, 14801–14812.

[6] K. Gerdes, P. Sagar, R. Fröhlich, B. Wibbeling, E.-U.

Würthwein, Eur. J. Org. Chem. 2004, 3465–3476.

[7] M. A. Ciufolini, F. Roschangar, Tetrahedron 1997, 53, 11049–

11060.

(KBr): ν = 3022 (sh., CH_arom.), 2995 (s, CH_aliph.), 2939 (m,

˜

[8] K. Matoba, K. Itoh, K. Kondo, T. Yamazaki, M. Nagata,

Chem. Pharm. Bull. 1981, 29, 2442–2450.

CH_aliph.), 2882 (sh., CH_aliph.), 1778 (vs), 1761 (m), 1666 (vs), 1597

(s, C=C), 1544 (m), 1473 (m), 1423 (s, C-H_aliph.), 1396, 1365, 1319

(w), 1253 (m), 1211 (vs), 1132 (w), 1095 (w), 1047 (w), 1012 (s),

966 (w), 906 (s), 864 (s), 827 (m), 810 (m) cm^–1. MS (ESI, CHCl₃/

CH₃OH): m/z (%) = 535 (42) [M + K]⁺, 519 (100) [M + Na]⁺, 497

(50) [M + H]⁺. MS (70 eV): m/z (%) = 496 (50) [M]⁺, 454 (42) [M –

[9] K. Matoba, Y. Miyata, T. Yamazaki, Chem. Pharm. Bull. 1983,

31, 476–481.

[10] K. Matoba, T. Terada, M. Sugiura, T. Yamazaki, Heterocycles

1987, 26, 55–58.

[11] A. Atfah, M. Y. Abu-Shuheil, J. Hill, Tetrahedron 1990, 46,

6483–6500.

[12] O. Diels, O. Buddenberg, S. Wang, Justus Liebigs Ann. Chem.

1927, 451, 223–241.

· +

C₂H₂O]⁺, 423 (27) [C₂₃H₂₃N₂O₆] , 381 (100) [C₂₁H₂₁N₂O₅] , 350

(38), 307 (11), 127 (29), 113 (18), 57 (19). C₂₆H₂₈N₂O₈(496.51):

calcd. C 62.89, H 5.68, N 5.64; found C 62.46, H 5.52, N 5.55.

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Received: July 14, 2006

Published Online: October 5, 2006

5356

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Eur. J. Org. Chem. 2006, 5339–5356

Article Doi

Substituted 3-hydroxypyrroles from 1-azapenta-1,4-dien-3-ones: The aza-Nazarov reaction - Synthesis and quantum chemical calculations

DOI: 10.1002/ejoc.200600602

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