Synthetic studies related to diketopyrrolopyrrole (DPP) pigments. Part 1: The search for alkenyl-DPPs. Unsaturated nitriles in standard DPP syntheses: A novel cyclopenta[c]pyrrolone chromophore

TETRAHEDRON

Pergamon

Tetrahedron 58 (2002) 5547±5565

Synthetic studies related to diketopyrrolopyrrole (DPP) pigments.

Part 1: The search for alkenyl-DPPs.

Unsaturated nitriles in standard DPP syntheses:

a novel cyclopenta[c]pyrrolone chromophore^q

Colin J. H. Morton,^aRyan Gilmour,^aDavid M. Smith,^a,pPhilip Lightfoot,^a

Alexandra M. Z. Slawin^aand Elizabeth J. MacLean^b

^aSchool of Chemistry, University of St Andrews, Purdie Building, St Andrews, Fife, KY16 9STScotland, UK

^bDepartment of Synchrotron Radiation, Daresbury Laboratory, Daresbury, Warrington, Cheshire, WA4 4AD England, UK

Received 10 January 2002; revised 25 March 2002; accepted 18 April 2002

AbstractÐReactions of the anion of ethyl 4,5-dihydro-5-oxo-2-phenylpyrrole-3-carboxylate with the Diels±Alder adducts of acrylonitrile

and various dienes rarely yield the expected DPP derivatives. The reaction with cyclohex-3-enecarbonitrile provides a noteworthy exception:

thermolysis of the resulting cyclohexenyl-DPP gives butadiene and impure 3-ethenyl-6-phenyl-DPP, the latter being thermally unstable.

Michael additions predominate when the above anion reacts with a,b-unsaturated nitriles: acrylonitrile and methacrylonitrile give 4,4-

bis(cyanoethyl) and 4,4-bis(2-cyanopropyl) derivatives, and cinnamonitrile, substituted cinnamonitriles and 3-(2-thienyl)acrylonitrile give

deep red 3-aryl-5-cyano-4-hydroxy-2H-cyclopenta[c]pyrrol-1-ones. These ambident nucleophiles may undergo N- and either O- or

3,6-Disubstituted 2H,5H-pyrrolo[3,4-c]pyrrole-1,4-diones

1, familiarly known as diketopyrrolopyrroles or DPPs, are

currently of considerable commercial importance as `high-

performance' pigments. For example, the 3,6-diaryl

compounds are widely used to provide the colouring matter

for red automotive paints,¹and variation of the substituents

attached to the aryl rings may serve to modify the precise

colour of the pigment.²The success of these compounds as

pigments relies, in part, on their very low solubility in most

common solvents and in the media in which they are

dispersed for commercial applications. This lack of

solubility is presumed to result from extensive inter-

molecular hydrogen bonding in the solid,^1±3and the red

colour as well as the low solubility also derive in part

from p±p stacking, a phenomenon which is obvious from

X-ray crystallography.³

DPP derivatives bearing identical 3- and 6-substituents are

produced commercially by the reaction of a dialkyl (usually

di-t-butyl) succinate with 2 molar equiv. of a nitrile in the

presence of a strong and sterically hindered base, sodium

t-amyloxide being the reagent of choice (Scheme 1).⁴The

®rst step in the process is presumed to lead to the pyrroline-

carboxylate ester 2, and the latter (after deprotonation)

reacts with a second equivalent of the nitrile to yield the

®nal product 1. Evidence for the intermediacy of

Scheme 1.

^qPresented, in part, at the 17th International Congress of Heterocyclic Chemistry, Vienna, August 1999.

Keywords: pigments; pyrrolinones; Diels±Alder reactions; Michael reactions; cyclisations.

Corresponding author; e-mail: dms@st-and.ac.uk

p

PII: S0040-4020(02)00443-X

5548

C. J. H. Morton et al. / Tetrahedron 58 (2002) 5547±5565

Scheme 2.

compounds of type 2 is provided by the independent

synthesis of the ester 3 from ethyl bromoacetate and the

anion of ethyl benzoylacetate, followed by ring closure

using ammonium acetate (Scheme 2); the ester 3 then reacts

further with nitriles to give DPP derivatives 4 in which one

of the 3- and 6-substituents is phenyl but the other may

vary.⁵

carbonitrile 9a (the Diels±Alder adduct of cyclopentadiene

and acrylonitrile) is commercially available, and the furan±

acrylonitrile adduct 9b was obtained by the literature pro-

cedure;⁸both of these are mixtures of exo- and endo-

isomers. The reaction of 2-methylfuran with acrylonitrile

produced a mixture of four isomers, i.e. exo- and endo-

9c±d.⁹These isomer mixtures were used in standard DPP

syntheses with the pyrrolinecarboxylate ester 3 in presence

of sodium t-amyloxide; however, the reactions were

conducted at relatively low temperatures in order to mini-

mise premature retro-Diels±Alder cleavage of the bridged

bicyclic moieties.

Although many DPP derivatives, both symmetrically and

unsymmetrically substituted, have been prepared by one

or other of the above methods, to our knowledge there is

no literature report to date of a DPP derivative in which the

3- and/or 6-substituent contains an alkenic double bond. Of

particular interest to us was the effect on the colour of the

pigment of such a double bond, if it were conjugated with

the chromophoric p-electron system. In addition, the

presence of an alkenic substituent would offer opportunities

for further elaboration of this substituent through functional

group transformations.

Reaction of the oxygen-bridged adduct 9b with the

pyrrolinecarboxylate ester 3 and sodium t-amyloxide gave

a DPP which, surprisingly, was not the expected product 5b

but 3,6-diphenyl-DPP 4a; the isolated yield was 48%. The

corresponding reaction of the mixture 9c and 9d with the

ester 3 similarly gave, in 46% yield, a mixture of two

3-phenyl-6-tolyl-DPPs (presumably the o- and m-tolyl

isomers 4b and 4c). Under similar conditions, the norbor-

nenecarbonitrile 9a failed altogether to react with the ester

The use of an alkenic nitrile directly in one of the standard

DPP syntheses did not at ®rst commend itself to us, for two

main reasons:

1

3, the only product isolated having H NMR and mass

spectra consistent with the indigoid compound 10, an

expected¹⁰product of oxidative dimerisation of compound

3. Reaction of the furan-derived adduct 9b with diethyl

succinate and sodium t-amyloxide also led to 3,6-diphenyl-

DPP 4a and benzonitrile, the latter being identi®ed by GC

and ¹H NMR.

(i) Acrylonitrile itself is liable to undergo anionic

polymerisation in presence of a nucleophilic base,⁶and

indeed a preliminary reaction involving acrylonitrile and

sodium t-amyloxide alone (in the absence of either a

succinate or the ester 3) yielded an intractable colourless

solid which is presumed to be an oligomer or polymer.

(ii) a,b-Unsaturated nitriles are excellent Michael

acceptors⁷Ða fact which we were subsequently able to

demonstrate for ourselves (see below).

Two important questions arise from these results:

(i) Does the aromatisation of the oxygen-bridged bicyclic

system occur prior to, subsequent to, or during, the incor-

poration of the nitrile into a DPP?

(ii) Why does the methylene-bridged bicyclic nitrile 9a

apparently fail to react with the pyrrolinecarboxylate

ester 3?

Accordingly, our initial attempts to synthesize alkenyl-DPPs

sought to use as electrophiles some Diels±Alder adducts of

acrylonitrile, in the hope that a subsequent retro-Diels±

Alder step might release the alkenic functionality after

ring closure to the DPP had been achieved.

The initial synthetic targets were DPP analogues of the

types 5 and 6, the expectation being that a thermal retro-

Diels±Alder procedure might then yield the mono- or di-

alkenyl-DPPs 7 and 8. Of the nitriles required as starting

materials for these syntheses, bicyclo[2.2.1]hept-5-ene-2-

(i) The aromatisation of 7-oxabicyclo[2.2.1]heptenes in

the presence of base has been recorded in a few cases. It is

recorded, for example, that Diels±Alder adducts of furan

with fumaronitrile are aromatised to phthalonitriles by

reaction with lithium hexamethyldisilazide at 2788C,¹¹

C. J. H. Morton et al. / Tetrahedron 58 (2002) 5547±5565

5549

and the 9c±d isomer mixture itself is transformed into a

mixture of o- and m-tolunitriles by reaction with potas-

sium t-butoxide followed by acidi®cation.⁹The failure of

the cyclopentadiene±acrylonitrile adduct 9a to react with

the pyrrolinecarboxylate ester lends weight to the

hypothesis that aromatisation of 9b and 9c±d precedes

their reactions with the ester 3. While, indeed, we have

shown that 7-oxabicyclo[2.2.1]hept-5-ene-2-carbonitrile

9b reacts with sodium t-amyloxide alone, in the absence

of either the ester 3 or diethyl succinate, to give benzo-

nitrile, the conversion is not quantitative; and it thus

appears possible that the aromatisation of the bridged

bicyclic system may occur both before and after reaction

of the nitriles with compound 3.

appear generally to be lower-yielding than those involv-

ing their aromatic counterparts. No reason has evidently

been advanced for this difference, although it is con-

ceivable that any nitrile which contains an a-hydrogen

may be deprotonated by the action of a strong base, and

the electrophilicity of the cyano-carbon thereby reduced.

It is also possible that in some branched-chain aliphatic

nitriles there may be steric hindrance to nucleophilic

attack at the cyano-carbon. Nevertheless we have demon-

strated that isobutyronitrile, cyclohexanecarbonitrile,

diphenylacetonitrile, and even norbornane-2-carbonitrile

react normally with the pyrrolinecarboxylate ester 3 to

give the DPP analogues 4d, 4e, 4f and 4g, respectively,

so steric hindrance may be discounted as the reason for

the failure of the norbornenecarbonitrile 9a to produce a

(ii) Standard DPP syntheses involving aliphatic nitriles

Scheme 3.

5550

C. J. H. Morton et al. / Tetrahedron 58 (2002) 5547±5565

DPP analogue. The possibility of a retro-Diels±Alder

literature,^4abut details of its preparation and characterisa-

tion are lacking; and nothing has hitherto been recorded

about the corresponding di-(3-furyl) compound 17, nor

about 3-(2- or 3-furyl)-6-phenyl-DPPs 18a and 18b.

Compounds 16 and 18a were obtained by standard DPP

syntheses using, respectively, diethyl succinate and the

pyrrolinecarboxylate ester 3 in reactions with 2-furonitrile

and sodium t-amyloxide. The corresponding reactions with

3-furonitrile yielded compounds 17 and 18b, the 3-furo-

nitrile itself being prepared from 3-furoic acid by reaction

with 1,3-dicyanobenzene according to the procedure of

Garst and Wilson.¹⁵

process in competition with nucleophilic addition may

also be ruled out since the nitrile 9a is largely recoverable

from the reaction mixture. However, the acidity of the

a-hydrogen of the nitrile 9a relative to these other

secondary nitriles remains an open question, even

although intuitively it appears that diphenylacetonitrile

ought to be the most acidic of this whole series.

Cyclohexene-3-carbonitrile 11 (formally the Diels±Alder

adduct of butadiene and acrylonitrile) was obtained from

the corresponding aldehyde (which is commercially avail-

able) by way of the oxime 12 (Scheme 3),¹²and this nitrile

also reacts normally with the pyrrolinecarboxylate ester 3 to

produce the cyclohex-3-enyl-DPP 13 (Scheme 3).

Compound 13, which was fully characterised as its N,N⁰-

bis-(t-butoxycarbonyl) derivative 14 (see below), is not only

an alkenyl-DPP in its own right, and thus the ®rst fully

authenticated representative of this class of DPP analogues,

but it also undergoes retro-Diels±Alder cleavage on ¯ash

vacuum pyrolysis at 7008C, yielding butadiene, identi®ed

1

by H NMR, and (presumably) 3-ethenyl-6-phenyl-DPP 7,

although the latter was not obtained pure, possibly because

of a tendency to undergo polymerisation at the elevated

temperature of the furnace outlet at which it was deposited.

Nevertheless, the concept of using a Diels±Alder/retro-

Diels±Alder sequence in order to generate alkenyl-DPPs

is now established.

A recurring problem in the syntheses of DPP analogues

arises as a result of their very low solubility in most

common solvents, and impurities trapped within the pre-

cipitated solid cannot therefore be removed easily by recrys-

tallisation; for the purposes of complete characterisation

conversion of these compounds into N,N⁰-diacyl [e.g.

bis(t-butoxycarbonyl)] derivatives is often necessary.¹³We

sought to obviate the synthetic problem by using an

N-protected pyrrolinone ester as a starting compound in

the standard synthetic sequence, since N,N⁰-disubstituted

DPPs are generally amenable to recrystallisation; but acyl-

ation of 2-pyrrolinones tends to occur at oxygen rather than

nitrogen, to give 2-acyloxypyrroles,¹⁴and in accordance

with this precedent, reaction of the pyrrolinecarboxylate

ester 3 with di-t-butyl dicarbonate gave ethyl 5-(t-butoxy-

The compounds 16, 18a and 18b were fully characterised as

their N,N⁰-bis-(t-butoxycarbonyl) derivatives, and 18a was

also converted, by reaction with methyl toluene-p-sulfonate

and base, into its N,N⁰-dimethyl derivative 18c which

formed crystals suitable for X-ray analysis (see below).

In the crystals of 18c, whereas the phenyl substituent is

tilted out of this plane by approximately 308, the furan

and DPP ring systems are coplanar. This indicates the

possibility of conjugation between the p-electrons of these

two systems, although there is no clear evidence for such

conjugation in the crystalline state, since the interannular

bond is only marginally shorter than that between the phenyl

group and the DPP ring (see below); however it is still

carbonyloxy)-2-phenylpyrrole-3-carboxylate

15.

The

potentially carbanionic centre in the ring is lost on formation

of the delocalised 6p-system, and this synthetic approach to

DPPs has not therefore been further explored.

Ê

signi®cantly shorter (by approximately 0.05 A) than the

interannular bond in biphenyl.¹⁶

Disappointingly none of the four compounds 16, 17, 18a or

18b showed any tendency to undergo Diels±Alder reactions

at atmospheric pressure, either with dimethyl acetylene±

dicarboxylate or with phenylacetylene, under a variety of

experimental conditions. This is not perhaps entirely

surprising in the case of the 2-furyl and di-(2-furyl)

compounds, since any conjugation between the adjacent

p-electron systems in these compounds would be inter-

rupted by the cycloaddition; and 2-phenylfuran derivatives,

where a similar effect may be expected to operate, have

been described as `notoriously poor' dienes in Diels±

Alder reactions.¹⁷In the 3-furyl series, however, the

A second synthetic approach to alkenyl- and (substituted

aryl)-DPPs employing Diels±Alder and retro-Diels±Alder

reactions involved the use of furyl-substituted DPPs as inter-

mediates, and their subsequent reactions with dienophiles.

3,6-Di-(2-furyl)-DPP 16 has been mentioned in patent

C. J. H. Morton et al. / Tetrahedron 58 (2002) 5547±5565

5551

Scheme 4.

formation of a Diels±Alder adduct would still allow a

degree of conjugation between the two ring systems, and

relative to the 2-furyl series, any steric hindrance to the

approach of the diene and dienophile ought also to be

reduced.

crystallography (Fig. 4) to have the structure 19b, and the

former was accordingly assigned the corresponding

structure 19a (Scheme 4).

The ¹H NMR spectrum of compound 19a is complicated, on

account of the diastereotopicity of the methylene hydro-

gens: the three signals in the region d 2±3 (ratio of integrals

1:2:1) all approximate to double triplets. In the case of

compound 19b, the additional complexity observed in the

¹H NMR spectrum is consistent (a) with the presence of two

diastereomers in unequal proportions, a conclusion which is

reinforced by the appearance of `major' and `minor' signals

in the ¹³C NMR spectrum, and (b) with the two 2-cyano-

propyl substituents being differently oriented in space with

respect to the ring, resulting in the non-equivalence of the

The limited success of the Diels±Alder/retro-Diels±Alder

approach led us to explore the other possible route to these

compounds, viz. the direct reaction of ethyl 4,5-dihydro-5-

oxo-2-phenylpyrrole-3-carboxylate 3 with a,b-unsaturated

nitriles and sodium t-amyloxide (cf. Scheme 2), although

we recognised the possibility of conjugate addition as a

competing process (see above). In the event, the reactions

of the anion of compound 3 with acrylonitrile and metha-

crylonitrile gave 1:2 adducts; the latter was shown by X-ray

Scheme 5.

5552

C. J. H. Morton et al. / Tetrahedron 58 (2002) 5547±5565

Figure 1. X-ray structure (simpli®ed) of compound 14.

Ê

Selected bond lengths (A): C(1)-O(1) 1.211(5); C(1)-N(2) 1.446(5); N(2)-C(3) 1.414(5); C(3)-C(3A) 1.352(5); C(3A)-C(3AA) 1.432(6); N(2)-C(31) 1.407(6);

C(31)-O(21) 1.291(7); C(21)-C(22) 1.447(11); C(3AA)-C(1) 1.455(6); C(3)-C(11) 1.476(5); C(22)-C(23) 1.46(2); C(23)-C(24) 1.42(2); C(24)-C(25)

1.348(14); C(25)-C(26) 1.481(15).

Selected interbond angles (8): N(2)-C(1)-C(3AA) 102.9(3); C(1)-C(3AA)-C(3A) 108.2(4); C(3)-C(3A)-C(3AA) 110.3(4); N(2)-C(3)-C(3A) 107.3(3); C(1)-

N(2)-C(3) 111.1(3); C(21)-C(22)-C(23) 117.8(11); C(22)-C(23)-(C24) 114.8(10); C(23)-C(24)-C(25) 123.3(8); C(24)-C(25)-C(26) 122.2(7); C(25)-C(26)-

(C21) 112.8(8); C(26)-C(21)-C(22) 115.8(8).

Selected torsion angles (8): C(1)-C(2)-C(3)-C(3A) 2.0(4); C(1)-C(2)-C(3)-C(11) 177.2(3); C(3A)-C(3)-C(11)-C(12) 126.1(5); C(2)-C(3)-C(11)-C(12)

248.1(6); C(3)-C(2)-C(1)-O(1) 175.0(4); C(21)-C(22)-C(23)-C(24) 23(2); C(22)-C(23)-C(24)-C(25) 2(2); C(23)-C(24)-C(25)-C(26) 27(2); C(24)-C(25)-

C(26)-C(21) 213(2); C(26)-C(21)-C(22)-C(23) 43.3(14).

corresponding carbons in these two substituents. The crystal

of 19b selected for X-ray analysis was that of the (racemic)

diastereomer in which both 2-cyanopropyl substituents have

the same absolute con®guration, and the reference molecule

shown in Fig. 4 is, arbitrarily, the (S,S) enantiomer (see

below). No cyclised product was detected in these reactions.

highly insoluble, acidic product was clearly not the expected

phenyl-styryl-DPP 21a, since its infra-red spectrum showed

retention of the cyano group; nor was it a simple 1:1 adduct,

since the ester carbonyl absorption was missing. Further-

more, it was not an isomer of compound 21a

(C₂₀H₁₄N₂O₂), since the molecular ion in its mass spectrum

corresponds to the formula C₂₀H₁₂N₂O₂. The corresponding

reactions of the anion of 3 with the substituted cinnamo-

nitriles 20b±d, 20f and 20h, and with 3-(2-thienyl)acrylo-

The reaction of compound 3 with cinnamonitrile, 20a, and

sodium t-amyloxide took a different course. The dark red,

Figure 2. X-ray structure (slightly simpli®ed) of compound 15.

Ê

Selected bond lengths (A): C(1)-C(2) 1.379(7); C(2)-C(3) 1.423(7); C(3)-C(4) 1.331(8); C(4)-N(1) 1.375(7); N(1)-C(1) 1.371(7); C(2)-C(11) 1.462(7); C(11)-

O(1) 1.217(6); C(1)-C(5) 1.479(7); C(4)-O(5) 1.393(6).

Selected interbond angles (8): C(1)-N(1)-C(4) 108.0(5); N(1)-C(4)-C(3) 110.9(5); C(2)-C(3)-C(4) 105.8(5); C(1)-C(2)-C(3) 108.4(5); N(1)-C(1)-C(2)

107.0(5).

Selected torsion angles (8): N(1)-C(1)-C(2)-C(3) 0.0(7); C(2)-C(3)-C(4)-N(1) 20.3(8); N(1)-C(1)-C(2)-C(11) 2175.5(6); C(1)-C(2)-C(11)-O(1) 2176.9(7);

N(1)-C(1)-C(5)-C(6) 47.0(8).

C. J. H. Morton et al. / Tetrahedron 58 (2002) 5547±5565

5553

Figure 3. X-ray structure of compound 18c.

Ê

Selected bond lengths (A): N(1)-C(1) 1.382(5); C(1)-C(2) 1.371(6); C(2)-C(5) 1.405(5); C(5)-C(6) 1.454(6); C(6)-N(1) 1.407(5); C(2)-C(3) 1.450(6); C(3)-

N(2) 1.429(5); N(2)-C(4) 1.382(5); C(4)-C(5) 1.366(5); C(4)-C(13) 1.470(6); C(6)-O(2) 1.224(5); C(3)-O(1) 1.208(5); C(1)-C(9) 1.442(6); C(9)-O(3)

1.383(5); O(3)-C(10) 1.367(5); C(10)-C(11) 1.328(7); C(11)-C(12) 1.430(7); C(12)-C(9) 1.355(6).

Selected interbond angles (8): N(1)-C(1)-C(2) 107.8(3); C(1)-C(2)-C(5) 109.2(4); C(2)-C(5)-C(6) 107.7(4); C(5)-C(6)-N(1) 104.0(3); C(6)-N(1)-C(1)

111.2(3); C(2)-C(3)-N(2) 102.8(3); C(3)-N(2)-C(4) 111.7(3); N(2)-C(4)-C(5) 107.4(3); C(4)-C(5)-C(2) 109.5(4); C(5)-C(2)-C(3) 108.6(4).

Selected torsion angles (8): N(1)-C(1)-C(2)-C(5) 0.3(5); C(1)-C(2)-C(5)-C(6) 20.7(5); C(2)-C(5)-C(6)-O(2) 178.6(5); C(2)-C(3)-N(2)-C(4) 0.8(5); C(3)-C(2)-

C(5)-C(4) 1.2(5); C(5)-C(2)-C(3)-O(1) 2178.3(5); C(5)-C(4)-C(13)-C(14) 2147.3(5); C(2)-C(1)-C(9)-C(12) 21.2(8).

nitrile 20i gave analogous products. The reaction with

p-(dimethylamino)cinnamonitrile 20g gave a purple±red

product with the expected H NMR and mass spectra, but

dimethylation of the dianion 25d, was con®rmed by X-ray

crystallography (Fig. 5).

1

in an impure state and in low yield; and the reaction with

p-nitrocinnamonitrile 20e gave only an intractable light

brown solid which could not readily be characterised.

When methylation of the dianion 25a was attempted using

iodomethane, however, the alkylation took a different

course. This gave ®rst an orange monomethyl derivative,

1

the H NMR spectrum of which showed a 3-proton signal

Given the retention of the cyano function and the disappear-

ance of the ester group during the reaction, the most

plausible course of events was as shown in Scheme 5.

Conjugate addition of the anion of 3 to the cinnamonitrile

20 followed by nucleophilic attack on the carbonyl group of

the ester would lead to the dihydro-intermediate 22, and

dehydrogenation of the latter, giving 23 and thence its

enol tautomer 24, would result in considerably increased

conjugation. In each case the deep red colour of the product,

and that of its derived dianion 25, were consistent with the

presence of such a conjugated p-electron system, which is

similar to that of diaryl-DPP derivatives. Additionally, the

¹H NMR spectra of the compounds were more in accord

with the enolic structure 24 than the ketonic tautomer 23,

since no signal corresponding to a tertiary hydrogen at C-5

was discernible.

Although all these new compounds were somewhat more

soluble in organic solvents than diaryl-DPP derivatives, and

most had measurable melting (decomposition) points and

NMR spectra, none could be recrystallised satisfactorily,

and as with diaryl-DPPs, it was rarely possible to obtain

analytically pure samples. Attempts to form derivatives of

24a by direct alkylation or acylation, in order to provide

de®nitive proof of its structure, met with little success.

However, the dianion 25a, which is the initially obtained

product of the reaction of 3 with 20a, underwent dimethyl-

ation and diethylation in situ by treatment with the

Figure 4. X-ray structure of compound 19b.

Ê

Selected bond lengths (A): N(1)-C(1) 1.40(1); C(1)-C(2) 1.36(1); C(2)-C(3)

1.51(1); C(3)-C(4) 1.55(1); C(4)-N(1) 1.36(1); C(4)-O(1) 1.21(1); C(2)-

C(11) 1.45(1); C(11)-O(2) 1.23(1); C(1)-C(5) 1.44(1); C(3)-C(14)

1.57(1); C(3)-C(18) 1.52(2); C(21)-N(3) 1.14(2).

Selected torsion angles (8): C(2)-C(1)-N(1)-C(4) 21(1); C(1)-C(2)-C(3)-

C(4) 25(1); C(2)-C(1)-C(5)-C(10) 2130(1); C(1)-C(2)-C(11)-O(3)

211(2); C(1)-C(2)-C(11)-O(2) 170(1); C(2)-C(3)-C(18)-C(19) 256(1);

C(2)-C(3)-C(14)-C(15) 32(1).

1

appropriate alkyl toluene-p-sulfonate, the H NMR spectra

of the orange±red products being consistent with the N,O-

dialkylated compounds (26a and 27a, respectively). The

structure of compound 26d, obtained in similar fashion by

5554

C. J. H. Morton et al. / Tetrahedron 58 (2002) 5547±5565

Figure 5. (a) X-ray structure and (b) crystal packing of compound 26d.

Ê

Selected bond lengths (A): C(1)-C(2) 1.381(4); C(2)-N(3) 1.376(3); N(3)-C(4) 1.435(4); C(4)-C(5) 1.446(4); C(5)-C(6) 1.378(4); C(6)-C(7) 1.454(4); C(7)-

C(8) 1.413(4); C(8)-C(1) 1.430(4); C(1)-C(5) 1.419(4); C(4)-O(16) 1.212(3); C(8)-O(27) 1.324(3); C(2)-C(9) 1.471(4); C(6)-C(17) 1.468(4).

Selected interbond angles (8): C(1)-C(2)-N(3) 107.5(2); C(2)-N(3)-C(4) 111.1(2); N(3)-C(4)-C(5) 104.3(2); C(4)-C(5)-C(1) 107.3(3); C(5)-C(1)-C(2)

109.8(2); C(1)-C(5)-C(6) 110.4(2); C(5)-C(6)-C(7) 106.4(2); C(6)-C(7)-C(8) 108.7(3); C(7)-C(8)-C(1) 107.0(2); C(8)-C(1)-C(5) 107.4(2).

Selected torsion angles (8): C(1)-C(2)-N(3)-C(4) 0.2(3); C(2)-N(3)-C(4)-C(5) 21.1(3); C(2)-C(1)-C(5)-C(6) 178.1(2); C(6)-C(7)-C(8)-C(1) 20.8(3); C(1)-

C(2)-C9-C(14) 138.4(3); C(5)-C(6)-C(17)-C(18) 33.5(8); C(5)-C(1)-C(8)-O(27) 178.9(3); C(2)-N(3)-C(4)-O(16) 178.8(3); O(16)-C(4)-C(5)-C(6) 2.1(7).

(d 1.90) which was consistent with the C-methyl structure

28a; prolonged exposure to the methylating agent produced

a bright orange dimethyl derivative, with methyl resonances

in the H NMR spectrum corresponding to those of a C,N-

dimethyl derivative. The structure of this compound, viz.

29a, was also con®rmed by X-ray crystallography (Fig. 6).

more complicated, since the spatial requirements of the

phenyl and cyclohex-3-enyl groups in the crystal are suf®-

ciently similar that they occupy the same site in the asym-

metric unit, and since the t-butoxycarbonyl moiety is also

disordered unequally over two sites. However, all the

disorder may be successfully modelled, and it can be

demonstrated that the double bond in the cyclohexenyl

moiety has not migrated in the strongly basic medium in

which it is formed. The re®ned structure and the most

signi®cant structural data are shown in Fig. 1.

1

1. X-Ray crystallography

Of the six compounds, viz. 14, 15, 18c, 19b, 26d and 29a,

the structures of which were determined by X-ray crystal-

lography, analysis of 15 and 18c is straightforward, despite

some disorder in the t-butoxycarbonyloxy-substituent in

compound 15. The structures and the most signi®cant data

for these compounds are shown in Figs. 2 and 3. The crystal

structure of compound 14 (Fig. 1), however, is considerably

Apart from the coplanarity of the furan and DPP ring

systems, the most striking structural feature of compound

18c is the very short central bond [C(2)±C(5) in Fig. 3]. The

same is true of 3,6-diphenyl-DPP 4a itself and its N,N⁰-

dimethyl derivative,³although apparently this has not

previously attracted comment. It implies considerable

C. J. H. Morton et al. / Tetrahedron 58 (2002) 5547±5565

5555

Figure 6. X-ray structure (simpli®ed) of compound 29a.

Ê

Selected bond lengths (A): N(1)-C(2) 1.414(4); C(2)-C(3) 1.508(4); C(3)-C(4) 1.369(4); C(4)-C(5) 1.506(5); C(5)-C(6) 1.586(4); C(6)-C(7) 1.414(4); C(7)-

C(8) 1.397(4); C(8)-N(1) 1.397(4); C(3)-C(7) 1.447(4); C(2)-O(2) 1.232(4); C(6)-O(6) 1.196(4); C(8)-C(9) 1.501(4); C(4)-C(15) 1.474(3).

Selected interbond angles (8): C(8)-N(1)-C(2) 110.7(2); N(1)-C(2)-C(3) 104.9(2); C(2)-C(3)-C(7) 105.5(2); C(3)-C(7)-C(8) 109.2(3); C(7)-C(8)-N(1)

108.5(3); C(3)-C(4)-C(5) 106.1(3); C(4)-C(5)-C(6) 106.7(2); C(5)-C(6)-C(7) 103.5(3); C(6)-C(7)-C(3) 110.5(2); C(7)-C(3)-C(4) 113.1(2).

Selected torsion angles (8): N(1)-C(2)-C(3)-C(7) 8.4(5); C(2)-C(3)-C(7)-C(6) 172.3(4); C(4)-C(3)-C(7)-C(8) 2172.0(4); C(3)-C(4)-C(15)-C(16) 22.2(6);

C(4)-C(5)-C(6)-C(7) 3.0(5); C(7)-C(8)-C(9)-C(10) 243.1(6); C(1)-N(1)-C(2)-C(3) 179.4(5); O(2)-C(2)-N(1)-C(8) 2178.5(5); C(3)-C(7)-C(6)-O(6)

2178.3(6); O(6)-C(6)-C(7)-C(8) 29.0(12).

delocalisation within the diene moiety, something which

may perhaps be achieved at the expense of conjugation

involving the carbonyl groups, since the bonds joining the

latter to the diene [C(2)±C(3) and C(5)±C(6)] are in fact the

longest within the ring systems.

the mean planes of adjacent molecules is approximately

Ê

3.6 A.

In the crystals of compound 29a, there is some disorder at

the tetrahedral carbon, C(5), in the ring; Fig. 6 is a simpli®ed

version of the structure showing the major occupancies of

the substituents at this carbon. For clarity the minor

occupancies, i.e. C(22B) and N(21B), are not shown in

this ®gure. The cyclopentapyrrolone ring system is again

essentially planar, although interestingly in this particular

case the 6-phenyl substituent [C(15)±C(20) in Fig. 6] also

lies in this same plane.

A view of the structure of compound 19b is shown in Fig. 4.

This shows clearly the spatial non-equivalence of the two

2-cyanopropyl substituents attached to the planar pyrroli-

none ring. In the ®gure, one of the two cyano groups

(C(21)±N(3)) appears below, and apparently almost

orthogonal to, the carbonyl group of the ester. There is

some disorder in the other 2-cyanopropyl group, the cyano

group of which [C(16)±N(2)] appears to lie across the

pyrrolinone carbonyl group. The torsion angles C(2)±

C(3)±C(14)±C(15) and C(2)±C(3)±C(18)±C(19) are also

remarkably different [32(1) and 56(1)8, respectively]:

whereas the latter represents a normal staggered conforma-

tion along the C(3)±C(18) bond, it appears as if the other

cyano group is being pulled `inwards' by the pyrrolinone

oxygen, although the C(16)±O(1) distance is still relatively

long.

2. Conclusion

In the reaction of the anion of compound 3 with a,b-

unsaturated nitriles, conjugate addition occurs in preference

to direct attack on the cyano-carbon; the products are either

bis-(cyanoalkyl) adducts, or else cyclopenta[c]pyrrolones,

24, and not the expected alkenyl-DPPs. These cyclopenta-

pyrrolones are, however, structurally related to DPPs, and

have similar solubilities and chromophoric characteristics.

The largest crystals of compound 26d which could be

readily obtained were still too small to be examined by

normal X-ray methods. However the structure of 26d was

obtained using the microcrystal diffraction facility at the UK

National Synchrotron Radiation Service at the CLRC

Laboratory, Daresbury: this showed [Fig. 5(a)] that, as in

DPP derivatives, the two aryl substituents are not coplanar

with the central heterocyclic ring system, although unlike

DPPs, these aryl substituents do not lie in parallel planes.

The packing diagram [Fig. 5(b)] shows that the molecules

show a degree of p±p stacking in the crystal, although

alternate molecules are orientated at 1808 to one another,

so that the `stack' is only approximate: the distance between

The synthesis of alkenyl-DPPs by

retro-Diels±Alder sequence appears to be of very little

generality.

a Diels±Alder/

3. Experimental

3.1. General

FT-IR spectra of solids were recorded for Nujol mulls, and

those of liquids were recorded for thin ®lms, and are

expressed in cm²¹. Unless otherwise indicated, UV±visible

spectra were recorded (wavelengths expressed in nm) for

5556

C. J. H. Morton et al. / Tetrahedron 58 (2002) 5547±5565

1

solutions in acetonitrile or dimethyl sulfoxide, and H and

¹³C NMR spectra were obtained at 300 and 75.4 MHz,

respectively, for solutions in d₆-dimethyl sulfoxide. Chemi-

cal shifts (d) are expressed relative to SiMe₄(d_Hd_C0)

and coupling constants (J) in Hz. Mass spectra and accurate

mass measurements were obtained using electron impact

ionisation at 70 eV. Flash chromatography was carried out

on silica gel grade H. Organic extracts were dried over

sodium sulfate or magnesium sulfate. `Ether' refers to

diethyl ether and `petrol' to the fraction of bp 40±608C.

`Boc't-butoxycarbonyl, Me₃C±O±CO±; DMAP4-

(N,N-dimethylamino)pyridine.

water; lit.,²²197±1998C, 200±2018C²⁴). d_H(isomer

mixture: CDCl₃, 200 MHz) E-isomer: 6.06 (1H, d,

J17.5 Hz, CHCN), 7.64 (2H, m, J8.8 Hz, Ar-H-2 and

-6), 7.48 (1H, d, J17.5 Hz, CHCHCN), 8.29 (2H, m, Ar

H-3 and -5). Z isomer: 5.72 (1H, d, J12.0 Hz, CHCN),

7.25 (1H, d, J12.0 Hz, CHCHCN), 7.95 (2H, J8.8 Hz,

Ar H-2 and -6), 8.32 (2H, d, Ar H-3 and -5). E/Z

ratio2.5:1. n_max2218 (CuN), 1630 (CvC), 1602, 1526

and 1333 (NO₂).

3.1.4. p-Fluorocinnamonitrile 20f. As provided, was a

semi-solid distillate (bp 1108C/3 mmHg) containing crystals

(of the E-isomer) with mp 62±668C (lit.,^21,2264±668C, 64±

658C²⁵). d_H(isomer mixture) (CDCl₃; 200 MHz) E-isomer:

5.82 (1H, d, J16.7 Hz, CHCN), 7.11 (2H, t, J8.6 Hz, Ar

H-3 and -5), 7.37 (1H, d, J16.7 Hz, CHCHCN), 7.46 (2H,

dd, J8.6 (H,H) and 5.4 (H,F) Hz, Ar H-2 and -6). Z-

isomer: 5.44 (1H, d, J12.0 Hz, CHCN), 7.82 (2H, dd,

J8.6 and 5.4 Hz, Ar H-2 and -6); other resonances

obscured by those of the E-isomer. E/Z ratio14:1. n_max

2205 (CuN), 1620 and 1600 (CvC).

2-Methylbutan-2-ol (t-amyl alcohol) was dried by heating

under re¯ux with sodium metal for several hours followed

Ê

by distillation on to 4 A molecular sieves. Sodium t-amyl-

oxide solution was obtained by dissolving the appropriate

quantity of sodium, cut into small pieces, in boiling t-amyl

alcohol under nitrogen: this process normally required

several hours but could be accelerated by the addition of a

catalytic amount of anhydrous iron(III) chloride. Ethyl 4,5-

dihydro-5-oxo-2-phenylpyrrole-3-carboxylate

3

was

obtained, according to the patent procedure,⁵from diethyl

benzoylsuccinate¹⁸(10.0 g, 0.036 mol) and ammonium

acetate (28.07 g, 0.36 mol) in acetic acid (50 cm³) at 70±

808C. Yield 6.35 g (76%), mp 172.5±173.58C (from propan-

2-ol: lit.,⁵1748C).

3.1.5. p-(Dimethylamino)cinnamonitrile 20g. Yield 63%,

mp 158±1608C (lit.,²⁶163.58C) d_H(CDCl₃): E isomer: 3.03

[6H, s, N(CH₃)₂], 5.58 (1H, d, J17.6 Hz, CHCN), 6.66

(2H, d, J8.8 Hz, Ar H-3 and -5), 7.28 (1H, d, CHCHCN),

7.32 (2H, d, Ar H-2 and -6); Z isomer: 3.04 (6H, s,

N(CH₃)₂), 5.09 (1H, d, J12.1 Hz, CHCN), 6.68 (2H, d,

Ar H-3 and -5), 6.94 (1H, d, J12.1 Hz, CHCHCN), 7.75

(2H, d, J9.1 Hz, Ar-H-2 and -6). E/Z ratio3.6:1. n_max

2181 (CuN), 1600 (CvC).

Acrylonitrile, methacrylonitrile, cinnamonitrile and

p-methoxycinnamonitrile were commercial samples, and

samples of p-¯uorocinnamonitrile, 3-(3,4-methylenedioxy-

phenyl)acrylonitrile and 3-(2-thienyl)acrylonitrile were

kindly donated by our colleague Dr R. A. Aitken; these

last four were mixtures of E- and Z-isomers, the former

predominating, and were generally used without further

puri®cation. These and the other substituted cinnamonitriles

may be prepared by a variant of the Horner±Wadsworth±

Emmons reaction,¹⁹from the overnight reaction at room

temperature of equimolar quantities of diethyl cyano-

methylphosphonate, the appropriate aldehyde and sodium

hydride in tetrahydrofuran.

3.1.6. 3-(3,4-Methylenedioxyphenyl)acrylonitrile 20h. As

provided, mp 76±898C (lit.,²¹91±928C, 948C,²³888C²⁷). d_H

(CDCl₃; 200 MHz) E-isomer: 5.67 (1H, d, J16.6 Hz,

CHCN), 6.03 (2H, s, CH₂), 6.82 (1H, d, J8.4 Hz, Ar H-

6), 6.90±7.00 (2H, m, Ar H-2 and -5), 7.28 (1H, d,

J16.6 Hz, CHCHCN). Z-isomer: 5.30 (1H, d,

J12.0 Hz, CHCN); other resonances obscured by those

of the E-isomer. E/Z ratio9:1. n_max2220 (CuN), 1620

and 1600 (CvC).

3.1.1. p-Methylcinnamonitrile 20b. Yield 92%, mp 71±

738C (lit.,²⁰70±718C, 71±728C²¹, 73±748C²²). d_H(CDCl₃,

200 MHz) E isomer: 2.39 (3H, s, Ar-CH₃), 5.82 (1H, d,

J16.7 Hz, CHCN), 7.21 (2H, d, J8.1 Hz, Ar H-3 and -

5), 7.32 (1H, d, CHCHCN), 7.37 (2H, d, Ar H-2 and -6). Z

isomer: 5.36 (1H, d, J12.0 Hz, CHCN), 7.08 (1H, d,

J12.0 Hz, CHCHCN); other resonances obscured by

those of the E-isomer. E/Z ratio10:1. n_max2215 (CuN),

1618 (CvC).

3.1.7. 3-(2-Thienyl)acrylonitrile 20i. Puri®ed by

Kugelrohr distillation, this had bp (bulb temp.) 1208C/

0.6 mmHg (lit.,²⁸(E) 1048C/1 mmHg; (Z) 768C/0.2 mmHg).

d_H(CDCl₃; 200 MHz) E-isomer: 5.65 (1H, d, J16.3 Hz,

CHCN), 7.10 (1H, dd, J4.8 and 3.7 Hz, Th H-4), 7.23 (1H,

d, J4.7 Hz, Th H-5), 7.43 (1H, d, J3.7 Hz, Th H-3), 7.48

(1H, d, J16.3 Hz, CHCHCN); Z-isomer: 5.31 (1H, d,

J11.7 Hz, CHCN), 7.56 (1H, d, J3.9 Hz, Th H-3),

other resonances obscured by those of the E-isomer. E/Z

ratio4.5:1. n_max2215 (CuN), 1670 and 1605 (CvC).

3.1.2. p-Chlorocinnamonitrile 20c. Yield 66%, mp 85±

868C (from propan-2-ol; lit.,²¹84±868C, 84±878C²³). d_H

(CDCl₃) E isomer: 5.86 (1H, d, J16.4 Hz, CHCN), 7.36

(1H, d, CHCHCN), 7.37±7.46 (4H, m, Ar-H); Z isomer:

5.48 (1H, d, J11.8 Hz, CHCN), 7.09 (1H, d, J11.8 Hz,

CHCHCN), 7.45 (2H, d, Ar H-3 and -5), 7.75 (2H, d,

J8.0 Hz, Ar H-2 and -6). E/Z ratio5:1. n_max2217

(CuN), 1625 (CvC), 1591.

The other nitriles used in this study were prepared as given

below.

3.1.8. 7-Oxabicyclo[2.2.1]hept-5-ene-2-carbonitrile 9b.⁸

A mixture of furan (10.05 g, 0.148 mol), acrylonitrile

(6.62 g, 0.125 mol) and zinc iodide (2.0 g, 6.3 mmol) was

stirred at 40±608C for 48 h. The light brown mixture was

then diluted with ethyl acetate, washed with 0.1 M sodium

thiosulfate (2£10 cm³) and concentrated under reduced

pressure. Column chromatography of the residue [silica

3.1.3. p-Nitrocinnamonitrile 20e. Yield 56%: recrystallisa-

tion gave the E-isomer, mp 200±2028C (from ethanol±

C. J. H. Morton et al. / Tetrahedron 58 (2002) 5547±5565

5557

gel, 30±70 grade; eluent, petrol/ethyl acetate (2:1)] yielded

the adduct 9b (5.36 g, 35%), bp 110±1158C/0.3 mmHg, as

an exo/endo mixture. n_max2244 (CuN). d_H(CDCl₃;

assigned with aid of COSY): exo adduct: 1.77 (1H, dd,

J8.5 and 11.5 Hz, H-3), 2.14 (1H, m, H-3⁰), 2.41 (1H,

dd, J4.0 and 8.4 Hz, H-2), 5.19 and 5.24 (1H, m, H-1 or

4), 6.32 (1H, dd, H-5 or 6), 6.44 (1H, dd, J_1,61.7 Hz and

J_5,65.8 Hz, H-5 or 6). endo Adduct: d_H1.56 (1H, dd,

J3.6 and 11.5 Hz, H-3), 2.31 (1H, m, H-3⁰), 2.94 (1H,

dt, J4.0 and 9.6 Hz, H-2), 5.15 (1H, m, H-1 or 4), 5.24

(1H, m, H-1 or 4), 6.50 (1H, dd, H-5 or 6), 6.58 (1H, dd,

J_1,61.7 Hz and J_5,65.8 Hz, H-5 or 6). The exo:endo ratio

is approximately 4:3, and the spectra are in broad agreement

with the published data.²⁹

and dried (Na₂SO₄). The solution was concentrated to small

volume; ¯ash chromatography of the residue (silica gel H;

eluent, dichloromethane) yielded a colourless oil (12.74 g,

64%) which was used without further puri®cation. n_max

2240 (CuN), 1654 (CvC). d_H(CDCl₃; 200 MHz) 1.86±

2.30 (4H, m, 2£CH₂), 2.31±2.45 (2H, m, CH₂), 2.76±2.89

(1H, m, CHCN), 5.59±5.79 (2H, m, HCvCH).

3.1.12. 3-Furonitrile. A mixture of 3-furoic acid (3.61 g,

32.2 mmol) and 1,3-dicyanobenzene (10.74 g, 83.8 mmol)

was heated gradually to 290±3008C in a distillation

apparatus ®tted with a fractionating column. The colourless

distillate [2.47 g, 82%; bp 159±1628C (lit.³¹1518C)] solidi-

®ed on standing (mp 23.5±24.58C). n_max2247 (CuN). d_H

(CDCl₃) 6.64±6.65 (1H, m, H-4), 7.51±7.52 (1H, m, H-5),

7.97 (1H, d, J0.8 Hz, H-2).

3.1.9. Diels±Alder adducts of 2-methylfuran and acrylo-

nitrile (9c/d).⁹A mixture of 2-methylfuran (10.0 g,

0.122 mol), acrylonitrile (12.93 g, 0.244 mol) and zinc

iodide (2.02 g, 0.0063 mol) was stirred at 508C for 9 h,

then at 258C for 5 days. The light brown mixture was then

diluted with ethyl acetate, washed with 0.1 M sodium thio-

sulfate then water, dried and concentrated under reduced

pressure (crude yield 9.86 g, 60%). Column chromato-

graphy of a small portion (silica gel; eluent, petrol/ethyl

acetate) yielded pure adducts: n_max2250 (CuN). The

product was a mixture of 2 constitutional isomers 9c and

9d, each consisting of an exo/endo mixture. A complete

assignment was not possible due to the complexity of the

isomer mixture, but the alkenic protons H-5 and H-6

provided limited information, con®rming the presence of

4 isomers: d_H(CDCl₃) 1.61±1.69 (m), 1.76 (s), 1.81 (s),

1.83±1.92 (m), 1.97±2.04 (m), 2.20±2.29 (m), 2.39±2.52

(m), 2.63 (dd, J3.7 and 9.4 Hz), 3.04±3.10 (m), 5.01±5.07

(m), 5.12±5.14 (m), 6.11 (d), 6.25 (d), 6.30 (d), 6.38 (d,

J5.6 Hz), 6.42 (dd), 6.47 (dd), 6.55 (dd, J1.6 and

3.1.13. 3,6-Diphenyl-DPP 4a. (a) Benzonitrile (0.23 g,

2.2 mol) then the pyrrolinecarboxylate ester 3 (0.37 g,

1.6 mmol) were added successively, with stirring and

under nitrogen, to a solution of sodium t-amyloxide [from

sodium (0.14 g, 6.1 mmol)] in dry t-amyl alcohol (15 cm³),

whereupon a red precipitate rapidly formed. The mixture

was heated under re¯ux for 2 h, cooled and added portion-

wise to an ice-cooled mixture of methanol (5 cm³) and

concentrated hydrochloric acid (1 cm³). The bright red

precipitate was ®ltered off, washed thoroughly with

methanol and water then dried in vacuo. Yield 0.24 g (52%).

(b) Benzonitrile (2.24 g, 21.7 mmol) was added, with stir-

ring and under nitrogen, to a solution of sodium t-amyloxide

[from sodium (0.5 g, 21.7 mmol)] in dry t-amyl alcohol

(45 cm³) Diethyl succinate (1.89 g, 10.8 mmol) was then

added portionwise over 4 h and heating continued for a

further 1 h. The mixture was stirred for 16 h at 258C, then

added to an ice-cooled mixture of concentrated hydrochloric

acid (2.2 cm³) and methanol (20 cm³). The bright red pre-

cipitate was ®ltered off, washed with methanol and dried in

1

5.8 Hz). The complete H NMR spectra are reproduced

pictorially in Ref. 9.

1

3.1.10. Norbornane-2-carbonitrile. Magnesium (5.17 g,

213 mmol) was added to a mixture of 5-norbornene-2-

carbonitrile 9a (5.0 g, 42 mmol), methanol (100 cm³) and

5% palladium on charcoal (0.4 g). After a brief induction

period, the reaction proceeded with brisk evolution of gas.

When the magnesium had been consumed, the mixture was

added to ice-cooled 30% hydrochloric acid, extracted with

an ethyl acetate/ether mixture, dried (Na₂SO₄) then concen-

trated. Kugelrohr distillation (bulb temp. 90±1008C/

1 mmHg) yielded a colourless oil (2.30 g, 45%) which

solidi®ed upon standing (lit. bp,³⁰628C/7 Torr; no mp

reported). d_H(CDCl₃) 1.19±2.03 (8H, m), 2.34±2.72 (3H, m).

vacuo. Yield 0.11 g (31%). The ®ltrate was shown by H

NMR to contain unreacted benzonitrile and diethyl succi-

nate.

n_max3070 and 3160 (N±H), 1640 (CvO), 1600 (N±H

bending or Ar-CvC stretch). m/z 288.0909 (M^1z, 100%;

C₁₈H₁₂N₂O₂requires 288.0899), 258 (25), 230 (41), 104

(72), 77 (63).

The 2,5-bis-(t-butoxycarbonyl) derivative^13bwas prepared

by stirring a mixture of compound 4a (0.49 g, 1.7 mmol),

tetrahydrofuran (25 cm³), DMAP (0.08 g, 0.7 mmol) and

Boc₂O (1.23 g, 5.6 mmol) at room temperature for 24 h.

Further Boc₂O (0.4 g, 1.8 mmol) was then added and stir-

ring continued for 2.5 h. The reaction mixture was concen-

trated, the residual moist brown solid mixed with methanol

(1 cm³), ®ltered off and washed with methanol (2 cm³). The

light yellow product (0.69 g, 83%) was dried in vacuo. The

product decomposed without melting over the range 185±

2368C (by DSC). l_max424 (1 10625). d_H(CDCl₃;

200 MHz) 1.38 [18H, s, C(CH₃)₃], 7.46±7.51 (6H, m, m-/

p-Ar-H), 7.72±7.76 (4H, m, o-Ar-H). d_C27.4 (OC(CH₃)₃),

85.2 (OC(CH₃)₃), 112.3, 112.4 (C-3 and quat. Ar-C), 128.5,

128.6 (o-/m-Ar-C), 131.6 (p-Ar-C), 146.4, 148.2 (C-1 and

3a), 159.5 (COC(CH₃)₃).

3.1.11. Cyclohexene-3-carbonitrile 11. The literature

method¹²was adapted as follows: Triethylamine (20.70 g,

0.205 mol) was added to a stirred mixture of 1,2,4,6-tetra-

hydro-benzaldehyde (20.50 g, 0.186 mol), hydroxylamine

hydrochloride (19.80 g, 0.285 mol) and dried acetonitrile

(160 cm³) under nitrogen, and the mixture was then heated

to re¯ux (808C). Phthalic anhydride (30.41 g, 0.205 mol)

was then added portionwise during 3 h, heating was

continued for a further 2 h, and the mixture was stirred at

258C for 16 h then evaporated to dryness, extracted with

dichloromethane, the colourless precipitate ®ltered off and

the combined ®ltrates washed with 10% aqueous ammonia

5558

C. J. H. Morton et al. / Tetrahedron 58 (2002) 5547±5565

3.1.14. Reaction of nitrile 9b with the pyrrolinecar-

boxylate ester 3. The ester 3 (1.57 g, 6.8 mmol) and the

nitrile 9b (0.94 g, 7.8 mmol) were added successively

under nitrogen to a solution of sodium t-amyloxide [from

sodium (0.46 g, 20 mmol)] in dry t-amyl alcohol (25 cm³) at

408C, and the mixture was stirred at 258C for 3.5 days. A

bright red precipitate gradually formed. The mixture was

then added to an ice-cooled mixture of methanol and

concentrated hydrochloric acid (2 cm³). The red precipitate

was ®ltered off, washed with methanol then water, and dried

in vacuo, to give 3,6-diphenyl-DPP (1.0 g, 48%), spectro-

scopically identical with an authentic sample.

[from sodium, 3.55 g (154 mmol)] in dried t-amyl alcohol

(150 cm³). The mixture was stirred at 258C for 6 days, then

added to a mixture of water (100 cm³) and methanol (5 cm³)

and acidi®ed dropwise with concentrated hydrochloric acid

(15 cm³). The organic extracts were dried (Na₂SO₄) and

concentrated. Flash chromatography (silica gel H; eluent,

petrol/ethyl acetate (2/1), then ethyl acetate and methanol)

yielded four fractions:

1. yellow oil (5.0 g). ¹H NMR and infra-red spectra showed

predominantly nitrile 9a, with a small amount of alkenic

material with d_H5.58 (dd, J2.2 and 5.7 Hz).

2. beige solid (0.38 g). The ¹H NMR and mass spectra were

consistent with ester 3.

3.1.15. Reaction of the nitrile mixture 9c/d with the

pyrrolinecarboxylate ester 3. The ester 3 (4.04 g,

17.5 mmol) then the nitrile 9c/d (3.00 g, 22.2 mmol) were

added, at 65±708C and under nitrogen, to a solution of

sodium t-amyloxide [from sodium, 1.38 g (60 mmol)] in

dry t-amyl alcohol (125 cm³). The mixture was stirred at

85±908C for 3.5 h, then added to an ice-cooled mixture of

methanol (50 cm³) and concentrated hydrochloric acid

(6 cm³). The bright red precipitate was ®ltered off, washed

with methanol then water, and dried in vacuo. Yield 2.42 g

(46%). For the mixture of isomers 4b and 4c, d_H(200 MHz)

2.28 and 2.38 (s, 2£CH₃), 7.34±8.51 (m, Ar-H), 10.90±

11.30 (4H, m, NH, removed upon D₂O exchange). m/z

302 (M^1z, 100%), 288 (7), 91 (49).

1

3. brown solid (4.56 g), with H NMR and mass spectra

again consistent with ester 3.

4. purple solid (3.88 g): ¹H NMR (DMSO-d₆) spectrum was

consistent with the structure 10. d_H(200 MHz) 1.06 (6H,

t, J7.1 Hz, 2£OCH₂CH₃), 3.97 (4H, q, 2£OCH₂CH₃),

7.42±7.45 (6H, m, Ar-H), 7.54±7.59 (4H, m, Ar-H),

10.65 (2H, br. s, NH). m/z 458 (M^1z, 5%), 341 (5), 231

(20), 105 (58), 71 (100).

3.1.19. 3-Isopropyl-6-phenyl-DPP 4d. The pyrroline-

carboxylate ester 3 (2.0 g, 8.6 mmol) and isobutyronitrile

(0.69 g, 11.0 mmol) were added successively at 80±908C

under nitrogen, to sodium t-amyloxide [from sodium,

0.63 g (27.4 mmol)] in dried t-amyl alcohol (30 cm³). Stir-

ring was continued for 1 h, and the mixture was then heated

under re¯ux for 2 h. Further isobutyronitrile (0.67 g,

9.7 mmol) was added, and stirring continued for 1.5 h at

re¯ux and a further 15 h at 258C. The mixture was then

added to an ice-cooled mixture of methanol (20 cm³),

water (30 cm³) and concentrated hydrochloric acid

(3 cm³). The yellow precipitate was ®ltered off, washed

with methanol then water, and dried in vacuo. Yield

0.65 g (31%), mp 306±3078C. (Found: C, 71.1; H, 5.5; N,

10.6. C₁₅H₁₄N₂O₂requires C, 70.9, H, 5.6; N, 11.0%). n_max

3140 (N±H), 1654 (CvO). d_H1.29 (6H, d, J6.9 Hz,

CH(CH₃)₂), 2.91 (1H, septet, J6.9 Hz, CHCH₃), 7.51±

7.53 (3H, m, m-/p-Ar-H), 8.33±8.37 (2H, m, o-Ar-H),

10.59 and 10.85 (each 1H, s, NH, reduced on D₂O

exchange). l_max(DMSO) 437 (1 12872).

3.1.16. Reaction of the nitrile 9b with diethyl succinate. A

mixture of the nitrile 9b (1.96 g, 16.2 mmol) and diethyl

succinate (2.82 g, 16.2 mmol) was added, portionwise and

under nitrogen, over 1 h to a solution of sodium t-amyloxide

(from sodium, 1.12 g) in dry t-amyl alcohol (125 cm³).

Stirring was continued for 2 h at re¯ux, then for 16 h at

258C. The mixture was added to an ice-cooled mixture of

methanol (30 cm³) and concentrated hydrochloric acid

(4.5 cm³). The red precipitate was ®ltered off, washed

with methanol then water and dried in vacuo; yield 2.62 g.

The product was spectroscopically identical with an

authentic sample of 4a, but elemental analysis indicated

1

traces of inorganic impurity. GC and H NMR analysis of

the concentrated ®ltrate con®rmed the presence of benzo-

nitrile.

3.1.17. Reaction of the nitrile 9b with sodium t-amyl-

oxide. The nitrile 9b (1.0 g, 8.3 mmol) was added, under

nitrogen, to a boiling solution of sodium t-amyloxide (from

sodium, 0.56 g) in t-amyl alcohol (50 cm³). A white pre-

cipitate quickly formed. Stirring was continued at re¯ux

for 4 h, then the mixture was acidi®ed with concentrated

hydrochloric acid (3 cm³). The light yellow solution

containing a white precipitate was concentrated, washed

with water (whereupon the precipitate dissolved), extracted

with ether, dried and concentrated to give a small amount of

white intractable solid and a colourless oil (ca. 50 mg) with

the pungent odour of benzonitrile. ¹H and ¹³C NMR

con®rmed the presence of benzonitrile and a small amount

of nitrile 9b.

The following analogues of 4d were prepared similarly.

3.1.20. 3-Cyclohexyl-6-phenyl-DPP 4e. This was obtained

from the pyrrolinecarboxylate ester 3 (2.0 g, 8.6 mmol),

cyclohexanecarbonitrile (1.16 g, 10.6 mmol), and sodium

t-amyloxide [from sodium, 0.64 g (27.8 mmol)] in dried

t-amyl alcohol (40 cm³) at 80±908C. After 1 h at re¯ux,

further cyclohexanecarbonitrile (1.20 g, 11.0 mmol) was

added, and stirring continued at re¯ux for 2 h, then at

258C for 14 h. Yellow precipitate, yield 0.28 g (11%);

sublimes without melting at .4008C. (Found: C, 72.6; H,

6.0; N, 9.1. C₁₈H₁₈N₂O₂requires C, 73.5, H, 6.2; N, 9.5%).

n_max3143 (N±H), 1648 (CvO), 1609. d_H1.10±1.31 (4H,

m, cyclohexyl H), 1.65±1.89 (6H, m, cyclohexyl H), 2.50±

2.65 (1H, m, H-1⁰), 7.43±7.56 (3H, m, m-/p-Ar-H), 8.34±

8.37 (2H, m, o-Ar-H), 10.56 and 10.87 (each 1H, s, NH,

reduced on D₂O exchange). l_max(DMSO) 439 (1 16006),

460 (15350).

3.1.18. Attempted reaction of the ester 3 with the nitrile

9a. The pyrrolinecarboxylate ester 3 (10.06 g, 43.5 mmol)

and 5-norbornene-2-carbonitrile 9a (7.74 g, 64.9 mmol)

were added at 258C under nitrogen to sodium t-amyloxide

C. J. H. Morton et al. / Tetrahedron 58 (2002) 5547±5565

5559

3.1.21. 3-Diphenylmethyl-6-phenyl-DPP 4f. This was

prepared from the pyrrolinecarboxylate ester 3 (2.01 g,

8.7 mmol), diphenylacetonitrile (1.73 g, 9.0 mmol), and

sodium t-amyloxide (from sodium, 0.69 g (30.0 mmol) in

dried t-amyl alcohol (40 cm³), the mixture being heated

under re¯ux for 3.5 h, then stirred at 258C for 18 h. Yellow

precipitate, yield 0.95 g (29%), mp 295±2968C. (Found: C,

79.0; H, 4.6; N, 7.4. C₂₅H₁₈N₂O₂requires C, 79.4, H, 4.8; N,

7.4%). n_max3138 (N±H), 1679 (CvO), 1645. d_H5.58 (1H,

s, Ar-CH), 7.27±7.40 (10H, m, CH-Ar-H), 7.53±7.55 (3H,

m, m-/p-Ar-H), 8.36±8.38 (2H, m, o-Ar-H), 10.82 and 10.95

(each 1H, s, NH, reduced on D₂O exchange). l_max(DMSO)

443 (1 17940), 466 (17284).

(C-3a), 148.1 and 148.5 (C-1 and -4), 157.0 (C-6a), 158.8

and 159.2 (CO(CH₃)₃).

Single crystals suitable for X-ray analysis were prepared by

recrystallisation from an ethanol±tetrahydrofuran mixture.

3.1.25. Flash vacuum pyrolysis of 3,6-diphenyl-DPP 4a.

3,6-Diphenyl-DPP 4a was heated under ¯ash vacuum

pyrolysis conditions to a temperature of 7008C under a

pressure of 7£10²²Torr. A red solid was collected at the

furnace outlet. The infra-red spectrum was identical with

that of an authentic sample of diphenyl-DPP 4a.

3.1.26. Flash vacuum pyrolysis of DPP 13. The DPP

derivative 13 was heated under ¯ash vacuum pyrolysis

conditions, with a pressure of 8£10²³Torr and a furnace

inlet temperature of 300±3308C. In each case a 100 mg

sample (^10 mg) was used. The furnace temperature and

results were as follows:

3.1.22. 3-(Norborn-2-yl)-6-phenyl-DPP 4g. This was

prepared from the pyrrolinecarboxylate ester 3 (3.18 g,

13.8 mmol), norbornane-2-carbonitrile (2.00 g, 16.5 mmol)

and sodium t-amyloxide (from sodium, 1.16 g (50.4 mmol))

in dried t-amyl alcohol (30 cm³) at 100±1108C for 3 h.

Yellow±brown precipitate, yield 0.62 g (15%); subl.

.4008C. Elemental analysis shows slight impurity

(Found: C, 73.3; H, 5.8; N, 8.6. C₁₉H₁₈N₂O₂requires C,

74.5; H, 5.9; N, 9.1%). d_H1.14±1.31 (3H, m, norbornyl

H), 1.42±1.60 (4H, m, norbornyl H), 2.28±2.29 (2H, m,

norbornyl H), 2.58±2.61 (2H, m, norbornyl H), 7.44±7.51

(3H, m, m-/p-Ar-H), 8.36±8.37 (2H, m, o-Ar-H), 10.60 and

10.91 (each 1H, s, NH, reduced on D₂O exchange). l_max

(DMSO) 430 (1 17381), 449 (17371).

Temperature

Products

500 and 6008C A yellow-orange solid was collected at

the furnace outlet. The H NMR was

1

identical with that of starting material

13. The contents of the cold-trap were

rinsed out with CDCl₃, but no products

were detected by ¹H NMR other than a

trace amount of benzene

3.1.23. 3-(Cyclohex-3-enyl)-6-phenyl-DPP 13. This was

prepared from the pyrrolinecarboxylate ester 3 (5.02 g,

21.7 mmol), cyclohexene-3-carbonitrile 11 (2.33 g,

21.7 mmol), and sodium t-amyloxide [from sodium, 1.76 g

(77.9 mmol)] in dried t-amyl alcohol (35 cm³), the

mixture being heated under re¯ux for 6.5 h. Yellow-brown

precipitate, yield 2.66 g (42%), mp 358±3608C with colour

change to orange-red. (Found: C, 73.1; H, 5.3; N, 9.3.

C₁₈H₁₆N₂O₂requires C, 74.0; H, 5.5; N, 9.6%). d_H1.82±

2.89 (7H, m, cyclohexenyl H-1⁰and 3£CH₂), 5.65±5.78

(2H, m, H-3⁰and -4⁰), 7.50±7.53 (3H, m, m-/p-Ar-H),

8.34±8.36 (2H, m, o-Ar-H), 10.61 (1H, s, NH), 10.88 (1H,

s, NH).

7008C

A ¯uorescent orange solid was

collected at the furnace outlet. d_H

(DMSO-d₆) 5.74±5.94 (m, alkenic H),

6.61±6.65 (m, alkenic H), 7.27±7.48

(m, Ar-H), 7.56±7.83 (m, Ar-H), 8.32±

8.60 (m, Ar-H), 10.63, 10.93, 10.97,

11.18, 11.19 and 11.36 (s, NH). The

contents of the cold-trap, dissolved in

CDCl₃, contained butadiene: d_H

(CDCl₃) 5.07±5.24 (4H, m, CH₂vCH),

6.23±6.40 (2H, m, CH₂vCH; identical

with the published spectrum³²), and

benzene [trace amount, d_H7.34 (s)]

3.1.24. 2,5-Bis-(t-butoxycarbonyl)-3-(cyclohex-3-enyl)-6-

phenyl-DPP 14. A mixture of 3-cyclohex-3-enyl-6-phenyl-

DPP 13 (0.39 g, 13 mmol), DMAP (0.02 g, 0.16 mmol),

di-t-butyl dicarbonate (1.02 g, 47 mmol), triethylamine

(0.42 g, 42 mmol) and tetrahydrofuran (30 cm³) was stirred

with exclusion of moisture for 8 h, then concentrated to

small volume. The residue was mixed with methanol

(2 cm³), the mixture ®ltered and the ¯uorescent yellow

residue then washed with methanol and dried in vacuo.

Yield 0.12 g (19%); decomposes without melting. (Found:

C, 68.7; H, 6.8; N, 5.6. C₂₈H₃₂N₂O₆requires C, 68.3; H, 6.6;

N, 5.7%). d_H(CDCl₃) 1.38 (9H, s, OC(CH₃)₃), 1.58 (9H, s,

OC(CH₃)₃), 1.98±2.10 (1H, m, CH₂), 2.19±2.33 (4H, m,

2£CH₂), 2.73±2.83 (1H, m, CH₂), 3.23±3.32 (1H, m,

HCCH₂), 5.71±5.82 (2H, m, HCvCH), 7.30±7.48 (3H,

m, m-/p-Ar-H), 7.67±7.76 (2H, m, o-Ar-H). d_C

(50.3 MHz) 25.1, 26.4, 27.4, 27.8, 29.1 and 34.8

(2£OC(CH₃)₃, C-1⁰, -2⁰, -5⁰and -6⁰), 85.0 and 85.4

(OC(CH₃)₃), 110.4 and 111.3 (C-3 and -6), 125.3, 126.4,

128.1, 128.3, 128.4 and 131.1 (Ar-C, C-3⁰and -4⁰), 144.9

3.1.27. Ethyl 5-t-butoxycarbonyloxy-2-phenylpyrrole-3-

carboxylate 15. A mixture of the ester 3 (0.37 g,

1.6 mmol), DMAP (0.05 g, 0.4 mmol), Boc₂O (0.39 g,

1.8 mmol) and tetrahydrofuran (25 cm³) was stirred at

258C for 24 h and the solvent then evaporated under reduced

pressure to give an orange oil. Flash chromatography [silica

gel H; eluent petrol/ethyl acetate (2:1)] yielded ester 3 and a

colourless solid (0.08 g, 15%), mp 125±1268C (from 70:30

ethanol±water). (Found: C, 65.3; H, 6.5; N, 4.2. C₁₈H₂₁NO₅

requires C, 65.3; H, 6.4; N, 4.2%). d_H(CDCl₃) 1.25 (3H, t,

J7.1 Hz, OCH₂CH₃), 1.57 (9H, s, C(CH₃)₃), 4.21 (2H, q,

J7.1 Hz, OCH₂CH₃), 6.30 (1H, s, pyrrole H), 7.35±7.43

(3H, m, m-/p-Ar-H), 7.58±7.61 (2H, m, o-Ar-H), 8.74 (1H,

br.s, NH).

3.1.28. 3-(2-Furyl)-6-phenyl-DPP 18a. This was prepared,

as described above for compound 4d, from the pyrroline-

carboxylate ester 3 (1.24 g, 5.4 mmol), 2-furonitrile

(0.54 g, 5.8 mol), and sodium t-amyloxide [from

sodium, 0.39 g (17 mmol)] in boiling dry t-amyl alcohol

5560

C. J. H. Morton et al. / Tetrahedron 58 (2002) 5547±5565

(30 cm³) for 3 h at 100±1108C, then for 16 h at 258C.

Red precipitate, yield 1.05 g (70%), mp .4008C.

(Found: C, 69.1; H, 3.5; N, 9.8. C₁₆H₁₀N₂O₃requires

C, 69.1, H, 3.6; N, 10.1%). d_H6.85 (1H, dd, J1.8 and

3.6 Hz, furyl H-4), 7.52±7.56 (3H, m, m-/p-Ar-H), 7.75

(1H, d, furyl H-3), 8.08 (1H, d, furyl H-5), 8.40±8.45

(2H, m, o-Ar-H), 11.27 (1H, s, NH, reduced on D₂O

exchange), 11.32 (1H, s, NH, reduced on D₂O

exchange). m/z 278 (M^1z, 100%).

alcohol (50 cm³) under nitrogen. 3-Furonitrile (2.14 g,

23.0 mmol) was then added, stirring was continued

under re¯ux for 3 h, then at 258C for 24 h, during

which time a deep purple-red mixture gradually formed.

The mixture was added dropwise to a mixture of

methanol (90 cm³) and concentrated hydrochloric acid

(8 cm³) at 08C and the purple-red solid was ®ltered

off, washed with methanol and water, then dried in

vacuo. Yield 4.39 g (69%). This compound was not

obtained completely pure (Found: C, 68.7; H, 3.8; N,

9.1. C₁₆H₁₀N₂O₃requires C, 69.1; H, 3.6; N, 10.1%) but

gave the correct mass spectrum [m/z 278 (M^1z, 6%),

221 (7), 181 (13), 105 (29), 91 (100), 77 (12), 55

(13)] and was converted for full characterisation into

its di-Boc derivative (see below). n_max3138 (N±H),

1706, 1659, 1626 (CvO and N±H bending).

The 2,5-bis-t-butoxycarbonyl derivative was obtained by

stirring a mixture of compound 18a (0.25 g, 0.9 mmol),

Boc₂O (0.59 g, 2.7 mmol), DMAP (0.03 g, 0.2 mmol) and

tetrahydrofuran (20 cm³) at 258C for 19 h. The solvent was

evaporated under reduced pressure, and the residue mixed

with methanol (1 cm³), ®ltered off and washed with

methanol (1 cm³). The bright orange solid was dried in

vacuo. Yield 0.22 g (51%); decomposed without melting.

l_max455 (1 20842). d_H(CDCl₃) 1.39 (9H, s, OC(CH₃)₃),

1.57 (9H, s, OC(CH₃)₃), 6.70 (1H, dd, J1.9 and 3.6 Hz,

furyl H-4), 7.45±7.51 (3H, m, m-/p-Ar-H), 7.62 (1H, d, furyl

H-3), 7.70±7.75 (2H, m, o-Ar-H), 8.01 (1H, d, furyl H-5). In

view of this compound's lack of reactivity in the Diels±

Alder reaction (see below) complete characterisation was

not attempted.

The 2,5-bis-t-butoxycarbonyl derivative was obtained by

stirring a mixture of compound 18b (1.5 g, 5.4 mmol),

Boc₂O (2.67 g, 12.2 mmol), DMAP (0.13 g, 1.1 mmol),

tetrahydrofuran (100 cm³) and triethylamine (1.25 g,

12.4 mmol) at 258C for 3 h. Further Boc₂O (1.22 g,

5.6 mmol) was then added, stirring continued for 86 h,

then a ®nal portion of Boc₂O (1.26 g, 5.8 mmol) was

added and stirring maintained for 7 h more. The solution

was then concentrated under reduced pressure, and a light

yellow solid precipitated by addition of methanol (2 cm³);

this was ®ltered off and dried in vacuo. Yield 0.95 g (37%);

decomposed without melting. (Found: C, 64.3; H, 5.5; N,

5.6. C₂₆H₂₆N₂O₇requires C, 64.3; H, 5.5; N, 5.85%). d_H

(CDCl₃) 1.38 (9H, s, OC(CH₃)₃), 1.60 (9H, s, OC(CH₃)₃),

6.91 (1H, m, furyl H-4), 7.46±7.52 (3H, m, m-/p-Ar-H),

7.69±7.80 (3H, m, o-Ar-H and furyl H-5), 8.66 (1H, m,

furyl H-2).

3.1.29. 2,5-Dimethyl-3-(2-furyl)-6-phenyl-DPP 18c. A

mixture of 3-(2-furyl)-6-phenyl-DPP 18a (1.76 g,

6.3 mmol), potassium carbonate (1.76 g, 12.7 mmol), nitro-

benzene (50 cm³) and methyl toluene-p-sulfonate (3.06 g,

16.4 mmol) was stirred at 1508C for 3.5 h, further methyl

toluene-p-sulfonate (2.36 g, 12.7 mmol) was added and

heating continued for 2.5 h. After stirring for a further

15 h at 258C, the mixture was then added to water, extracted

with dichloromethane, dried (Na₂SO₄), concentrated and

dried in vacuo at 1008C. Recrystallisation from propan-2-

ol-tetrahydrofuran yielded red-orange crystals (1.19 g,

62%), mp 193±194.58C. (Found: C, 70.9; H, 4.6; N, 9.0.

C₁₈H₁₄N₂O₃requires C, 70.6; H, 4.6; N, 9.2%). d_H(CDCl₃)

3.40 (1H, s, NCH₃), 3.58 (1H, s, NCH₃), 6.72 (1H, dd, J1.6

and 3.6 Hz, furyl H-4), 7.47±7.57 (3H, m, m-/p-Ar-H), 7.68

(1H, d, furyl H-3), 7.88 (1H, dd, furyl H-5), 8.31 (2H, d,

o-Ar-H).

3.1.32. 3,6-Di-(3-furyl)-DPP 17. To a stirred solution of

sodium t-amyloxide (from sodium, 0.20 g, 8.7 mmol) in

dry t-amyl alcohol (15 cm³), at 958C and under nitrogen, a

mixture of diethyl succinate (0.60 g, 3.4 mmol), 3-furo-

nitrile (0.65 g, 7.0 mmol) and t-amyl alcohol (1 cm³) was

added during 10 min; a dark purple precipitate slowly

formed in a ¯uorescent yellow solution. Stirring was

continued at 55±608C for 2 h then the mixture was added

to an ice-cooled mixture of methanol (10 cm³) and concen-

trated hydrochloric acid (0.5 cm³). The purple precipitate

was ®ltered off, washed with methanol then water and

dried in vacuo. Yield 0.29 g (32%). d_H7.34 (2H, m, H-4),

7.87±7.88 (2H, m, H-5), 8.63 (2H, m, H-2), 11.07 (2H, s,

NH). m/z 268.0473 (M^1z, 100%; C₁₄H₈N₂O₄requires

268.0484).

3.1.30. 3,6-Di-(2-furyl)-DPP 16. A mixture of 2-furonitrile

(0.52 g, 5.6 mmol) and diethyl succinate (0.49 g, 2.8 mmol)

was added portionwise over 1.5 h to a solution of sodium

t-amyloxide (from sodium, 0.22 g, 9.6 mmol) in boiling dry

t-amyl alcohol (10 cm³). Stirring was continued for 0.5 h at

re¯ux, and the mixture was then added to an ice-cooled

mixture of methanol (35 cm³) and concentrated hydro-

chloric acid (1.5 cm³); the dark purple precipitate was

®ltered off, washed with methanol and water, then dried in

vacuo. Yield 0.46 g (61%). (Found: C, 62.8; H, 2.8; N, 10.2.

C₁₄H₈N₂O₄requires C, 62.7; H, 3.0; N, 10.4%). d_H

(200 MHz) 6.83 (2H, dd, J1.8 and 3.6 Hz, H-4), 7.67

(2H, d, H-3), 8.05 (2H, d, H-5), 11.19 (2H, s, NH). m/z

268 (M^1z, 86%).

3.2. Attempted Diels±Alder reactions

Only starting materials were detected (by ¹H NMR) after the

following attempted reactions:

(a) 3-(2-Furyl)-6-phenyl-DPP 18a with maleic anhydride

(large excess) in acetone at 258C for 16 h, then at re¯ux

(55±608C) for 8 h, and in the presence of zinc iodide at

258C for a further 16 h.

(b) 2,5-Bis-(t-butoxycarbonyl)-3-(2-furyl)-6-phenyl-DPP

with maleic anhydride (large excess) in acetone in the

presence of zinc iodide at 55±608C for 8 h, then at

3.1.31. 3-(3-Furyl)-6-phenyl-DPP 18b. The pyrroline-

carboxylate ester 3 (5.30 g, 22.9 mol) in t-amyl alcohol

(25 cm³) was added to a solution of sodium t-amyloxide

(from sodium, 1.64 g, 71.3 mmol) in boiling dry t-amyl

C. J. H. Morton et al. / Tetrahedron 58 (2002) 5547±5565

5561

258C for 48 h. [3-(2-Furyl)-6-phenyl-DPP was also

detected.]

an ice-cooled mixture of water (150 cm³) and concentrated

hydrochloric acid (6 cm³); the beige precipitate was ®ltered

off, recrystallised from propan-2-ol and dried in vacuo at

1008C. Yield 3.22 g (51%).

(c) 3,6-Di-(2-furyl)-DPP 16 with dimethyl acetylene-

dicarboxylate (large excess) in DMF at 958C for 4 days.

(d) The 3,6-di-(2-furyl)-DPP dianion with dimethyl

acetylenedicarboxylate (4 mol equiv.) in tetrahydrofuran

at 2788C for 1.5 h, then under re¯ux for 2 h and ®nally at

258C for 1 week.

(e) 3-(3-Furyl)-6-phenyl-DPP 18b with phenylacetylene

(3 mol equiv.) in 1:1 toluene±DMF at 1108C for 5 h, then

258C for 2 days, and in the presence of zinc iodide for a

further 12 days.

(b) Sodium hydride (60% w/w mineral oil dispersion,

0.36 g, 9 mmol) was added under nitrogen to a solution of

the pyrrolinecarboxylate ester 3 (1.0 g, 4.3 mmol) in tetra-

hydrofuran (70 cm³). The mixture was heated brie¯y to

re¯ux, then cooled to 258C, whereupon a white precipitate

formed. Methacrylonitrile (1.44 g, 21.5 mmol) was then

added, the mixture was then brie¯y reheated to boiling,

then stirred at 258C for 16 h, during which time the pre-

cipitate redissolved. The solution was added to ice,

extracted with tetrahydrofuran/diethyl ether, the extract

dried and the solvent evaporated; the colourless solid

residue was dried in vacuo and subjected to ¯ash chromato-

graphy (eluent, 5% methanol/dichloromethane then

methanol). Yield 1.02 g (65%).

(f) 3,6-Di-(3-furyl)-DPP 17 with phenylacetylene

(4.5 mol equiv.) in 1:1 toluene-DMF at 1008C for 39 h

in the presence of zinc iodide.

3.2.1. Reaction of acrylonitrile with sodium t-amyloxide.

Acrylonitrile (10.0 g) was added slowly, under nitrogen, to a

stirred solution of sodium t-amyloxide (from sodium (1.0 g,

43.5 mmol)) in t-amyl alcohol (40 cm³) at 60±658C. A

white precipitate rapidly formed. Stirring was continued at

308C for 3 h, and the mixture was then added to a mixture of

water (100 cm³) and concentrated hydrochloric acid

(5 cm³). The white solid was ®ltered off, washed with

water and dried in vacuo. Yield 7.13 g; mp .3008C. n_max

3342 (broad, water O±H), 2245 (CuN).

Compound 19b (mixture of diastereomers) had mp 211±

2138C (from propan-2-ol). (Found: C, 69.0; H, 6.5; N,

11.4. C₂₁H₂₃N₃O₃requires C, 69.0; H, 6.3; N, 11.5%).

n_max3222 (N±H), 2238 (CuN), 1739 and 1656

(2£CvO). d_H(CDCl₃) 1.10 (3H, t, J7.0 Hz, OCH₂CH₃),

1.29, 1.32 and 1.34 (3 overlapping d, total 6H, J6.9 Hz,

CH₃CHCN), 1.82±1.91, 2.11±2.36, 2.42±2.48 and 2.53±

2.72 (4£m, total 6H, CH₂CHCN and CH₂CHCN), 4.00±

4.22 (2H, m, OCH₂CH₃), 7.42±7.46 (2H, m, m-/p-Ar-H),

7.66±7.70 (2H, m, o-Ar-H), 7.82 (minor) and 8.07 (major)

(2£s, total 1H, NH). d_H(d₆-DMSO, 408C) 1.00±1.08 (3H,

m, OCH₂CH₃), 1.11±1.23 (6H, m, CH₃CHCN), 1.72±1.85,

1.98±2.15, 2.35±2.50 and 2.58±2.73 (4£m, total 6H,

CH₂CHCN and CH₂CHCN), 3.91±4.07 (2H, m,

OCH₂CH₃), 7.41±7.47 (3H, m, m-/p-Ar-H), 7.50±7.64

(2H, m, o-Ar-H), 10.94 (minor) and 11.01 (major) (2£s,

total 1H, NH). d_C(CDCl₃; provisional assignments, made

with the aid of DEPT): 13.7 (OCH₂CH₃); 18.9 and 19.6

(major), 19.1 and 19.4 (minor) (CH₂CHCN); 21.2 and

21.6 (major), 21.3 and 21.4 (minor) (CHCN); 40.5 and

40.7 (minor), 40.6 and 41.1 (major) (CH₂CHCN); 54.6

(major) and 55.3 (minor) (C-4); 60.2 (OCH₂CH₃), 107.8

(major) and 108.8 (minor) (C-3); 121.5, 121.7, 122.2 and

122.5 (CN); 128.1 and 128.9 (major) and 128.2 and 128.8

(minor) (o-/m-Ar-C); 129.8 (major) and 130.5 (minor)

(quat. Ar-C); 130.6 (major) and 130.8 (minor) (p-Ar-C);

151.9 (minor) and 153.4 (major) (C-2); 163.0 (major) and

163.2 (minor) (ester CvO); 180.8 (major) and 181.0

(minor) (C-5).

3.2.2. Ethyl 4,4-bis-(2-cyanoethyl)-4,5-dihydro-5-oxo-2-

phenylpyrrole-3-carboxylate 19a. The pyrrolinecarboxy-

late ester 3 (0.76 g, 3.3 mmol) and acrylonitrile (0.20 g,

3.8 mmol) were added successively to a stirred solution of

sodium t-amyloxide [from sodium (0.23 g, 10 mmol)] in

t-amyl alcohol (15 cm³) at 408C under nitrogen. The

mixture was stirred at 258C for 72 h and was then acidi®ed

to pH 5 with dilute (2 M) hydrochloric acid. The solution

upon concentration gave a brown solid which was redis-

solved in dichloromethane, and this solution was washed

with water, dried and re-concentrated. Compound 19a

(0.24 g, 37% based on acrylonitrile) formed beige crystals,

mp160±1618C. (from propan-2-ol). (Found: C, 67.6; H, 5.5;

N, 12.3. C₁₉H₁₉N₃O₃requires C, 67.6; H, 5.7; N 12.5%).

n

_max3249 (N±H), 2253 (CuN), 1735 and 1672 (2£CvO).

d_H(CDCl₃) 1.12 (3H, t, J7.1 Hz, OCH₂CH₃), 2.16 (2H,

app. dt, J13.8 and 6.9 Hz, 2£CH_ACH₂CN), 2.19±2.34

(4H, m, 2£CH₂CN), 2.41 (2H, dt, J13.8 and 7.1 Hz,

2£CH_BCH₂CN), 4.12 (2H, q, J7.1 Hz, OCH₂CH₃),

7.43±7.54 (3H, m, Ar-H), 7.59±7.62 (2H, m, Ar-H), 8.87

(1H, s, NH). d_C(assigned with the aid of DEPT), 12.7

(CH₂CN), 13.8 (CH₃), 31.3 (CH₂CH₂CN), 54.8 (C-4), 60.4

(OCH₂CH₃), 106.7 (C-3), 118.5 (CN), 128.1 and 128.7 (o-/

m-Ph-C), 129.1 (quat. Ph-C), 130.8 (p-Ph-C), 153.7 (C-2),

162.7 (ester CvO), 180.5 (C-5). m/z 337 (M^1z, 37%), 283

(100), 237 (52), 228 (9), 211 (25), 104 (28),77 (20).

3.2.4. 5-Cyano-4-hydroxy-3,6-diphenyl-2H-cyclopenta-

[c]pyrrol-1-one 24a. The pyrrolinecarboxylate ester 3

(17.90 g, 77.4 mmol) was added, under nitrogen, to a boil-

ing solution of sodium t-amyloxide (from sodium (5.66 g,

246.2 mmol)) in t-amyl alcohol (200 cm³). Cinnamonitrile

20a (10.02 g, 77.6 mmol) was then added portionwise over

30 min, during which time a purple-red solution formed.

Stirring was continued for 2 h under re¯ux, then for 15 h

at 258C, and the solution was then added to an ice-cooled

mixture of methanol (150 cm³) and concentrated hydro-

chloric acid (25 cm³). The dark red solid was ®ltered off,

washed thoroughly with methanol and water, then dried in

vacuo. Yield 7.39 g (31%), mp 273±2758C. (Found: C,

3.2.3. Ethyl 4,4-bis-(2-cyanopropyl)-4,5-dihydro-5-oxo-

2-phenylpyrrole-3-carboxylate 19b. (a) The pyrroline-

carboxylate ester 3 (4.0 g, 17.3 mmol) and methacrylonitrile

(6.0 g, 89.4 mmol) were added successively at 258C, under

nitrogen, to a stirred solution of sodium t-amyloxide [from

sodium (1.20 g, 52.2 mmol)] in t-amyl alcohol (50 cm³).

The mixture was heated under re¯ux for 3 h, then stirred

at 258C for 16 h. The red-brown solution was then added to

5562

C. J. H. Morton et al. / Tetrahedron 58 (2002) 5547±5565

77.1; H, 3.8; N, 8.9; m/z 312.1003. C₂₀H₁₂N₂O₂requires C,

76.9; H, 3.9; N, 9.0%; M, 312.0899). l_max457 (1 3946), 509

(2270). n_max3114 (strong, N±H or O±H), 2205 (CuN),

1667 (CvO), 1600. d_H7.45±7.57 (6H, m, m-/p-Ph-H),

8.23 (2H, dd, J1.5 and 8.0 Hz, o-Ph(6)-H), 8.33±8.36

(2H, m, o-Ph(3)-H), 11.01 (1H, s, NH, reduced on D₂O

exchange). m/z 312 (M^1z, 100%), 284 (25), 255 (37), 225

(25), 129 (20), 71 (32).

11.5. C₂₂H₁₇N₃O₂requires C, 74.4; H, 4.8; N, 11.8%). d_H

3.05 (6H, s, 2£CH₃), 6.83±6.86 (2H, m, Ar-H), 7.43±7.52

(3H, m, Ar-H), 8.24±8.33 (4H, m, Ar-H), 11.16 (1H, s, NH).

m/z 355 (M^1z, 19%), 324 (44), 169 (100), 91 (82), 77 (46),

with a trace amount of impurity giving m/z 379. l_max482 (1

6472), 583 (2829), unaffected by addition of triethylamine

(3 drops).

3.2.10. 5-Cyano-4-hydroxy-6-(3,4-methylenedioxy-

phenyl)-3-phenyl-2H-cyclopenta[c]-pyrrol-1-one 24h.

The following analogues of 24a were prepared similarly.

Obtained as for 24d, was dark red and had mp 296±

2988C.(dec., subl.) (Found: C, 70.5; H, 3.8; N, 7.8.

C₂₁H₁₂N₂O₄requires C, 70.8; H, 3.4; N, 7.9%.) d_H6.21

(3H, s, CH₂O₂), 7.14 (1H, d, J8.2 Hz, H-5⁰), 7.58±7.66

(4H, m, m- and p-Ph-H and OH), 8.07 (1H, dd, J8.2 and

1.8 Hz, H-6⁰), 8.14 (1H, d, J1.8 Hz, H-2⁰), 8.46 (2H, d,

J8.9 Hz, o-Ph-H), 10,80 (1H, s, NH). m/z 356 (M^1z, 88%),

344 (50), 288 (44), 149 (38), 135 (78), 105 (54), 77 (57), 57

(53), 43 (100).

3.2.5. 5-Cyano-4-hydroxy-3-phenyl-6-(p-tolyl)-2H-cyclo-

penta[c]pyrrol-1-one 24b. Dark red, yield 32%, mp 284±

2878C (dec.) (Found: C, 77.5; H, 4.4; N, 8.6. C₂₁H₁₄N₂O₂

requires C, 77.3; H, 4.3; N, 8.6%). n_max3114 (weak, N±H or

O±H), 2209 (CuN), 1668 (CvO). d_H2.37 (3H, s, CH₃),

7.31 (2H, half of AA⁰BB⁰, H-3 and -5 in 4-MeC₆H₄), 7.55±

7.57 (3H, m, m-/p-Ph-H), 8.15 (2H, half of AA⁰BB⁰, H-2

and -6 in 4-MeC₆H₄), 8.29±8.32 (2H, m, o-Ph-H), 11.04

(1H, s, NH).

3.2.11. 5-Cyano-4-hydroxy-6-(2-thienyl)-3-phenyl-2H-

cyclopenta[c]pyrrol-1-one 24i. Obtained as for 24d, was

dark red and had mp 285±2878C (dec., subl.) (Found: C,

67.7; H, 3.3; N, 8.5. C₁₈H₁₀N₂O₂S requires C, 67.9; H, 3.2;

N, 8.8%.) d_H7.40 (1H, dd, J5.0 and 3.8 Hz, Th-H-4),

7.45±7.80 (3H, m, m- and p-Ph-H), 7.97 (1H, d,

J4.6 Hz, Th-H-5), 8.2±8.6 (2H, br, o-Ph-H), 8.74 (1H,

d, J3.7 Hz, Th-H-3), 11.13 (1H, s, NH). m/z 318 (M^1z,

100%), 290 (29), 261 (32), 153 (98), 105 (37), 81 (55), 55

(40).

3.2.6. 6-(p-Chlorophenyl)-5-cyano-4-hydroxy-3-phenyl-

2H-cyclopenta[c]pyrrol-1-one 24c. The reagents were

added to the anion of 3 at 75±808C. Dark red; yield 54%,

mp 290±2928C. (Found: C, 69.0; H, 3.3; N, 7.8.

C₂₀H₁₁ClN₂O₂requires C, 69.3; H, 3.2; N, 8.1%). n_max

3370 (broad, N±H or O±H), 2208 (CuN), 1600 (CvO).

d_H7.51±7.58 (5H, m, Ar-H), 8.25±8.28 (2H, m, Ar-H),

8.33±8.36 (2H, m, Ar-H), 11.04 (1H, s, NH). l_max461 (1

14,872), 605 (7907), unaffected by addition of triethylamine

(3 drops). m/z 346/348 (M^1z, 100/43%), 318/320 (19/6), 311

(25), 289/291 (25/8), 255 (30), 225 (72), 104 (40), 77 (45).

Reaction of the pyrrolinecarboxylate ester

3 with

p-nitrocinnamonitrile 20e and sodium t-amyloxide under

the standard conditions produced only a light brown

intractable solid which was not suf®ciently soluble in

DMSO for NMR analysis and which was much less

intensely coloured than the other compounds in the series

24a±d and 24f±i.

3.2.7. 5-Cyano-4-hydroxy-6-(p-methoxyphenyl)-3-phen-

yl-2H-cyclopenta[c]pyrrol-1-one 24d. The reaction time

under re¯ux was extended to 3 h. Purple-red; yield 38%,

mp 286±2878C. (Found: C, 73.5; H, 3.9; N, 8.1; m/z

342.1009. C₂₁H₁₄N₂O₃requires C, 73.7; H, 4.1; N, 8.2%;

M, 342.1004). d_H3.84 (3H, s, OCH₃), 7.09 (2H, d,

J9.0 Hz, half of AA⁰BB⁰, H-3 and -5 in 4-MeOC₆H₄),

7.55±7.57 (3H, m, m- and p-Ph-H), 8.43 [4H, coincident

o-Ph-H (approx. d) and H-2 and -6 of 4-MeOC₆H₄(half of

AA⁰BB⁰)], 11.13 (1H, s, NH). l_max460 (1 13,309), 592

(5927); (11 drop conc. HCl) 492 (1 12,876). n_max3110

(N±H or O±H), 2208 (CuN), 1673 (CvO), 1611. m/z

342 (100%), 314 (13), 285 (10), 121 (14), 77 (9).

3.2.12. 2,5-Dimethyl-3,6-diphenyl-DPP. The dianion of

3,6-diphenyl-DPP was prepared as described above from

the pyrrolinecarboxylate ester 3 (1.02 g, 4.4 mmol), benzo-

nitrile (1.0 g, 9.7 mmol) and sodium t-amyloxide [from

sodium (0.33 g, 14.4 mmol)] in t-amyl alcohol (20 cm³).

After heating under re¯ux had been maintained for 5 h,

the mixture was cooled to 80±908C, methyl toluene-p-sul-

fonate (9.20 g, 49.4 mmol) was added portionwise, and

heating was continued for 45 min, during which time the

mixture turned ¯uorescent yellow. The product was isolated

by addition of the mixture to water (50 cm³) and extraction

with ethyl acetate. The orange-red product was ®nally

washed with methanol and dried in vacuo at 608C; it was

identical with the product obtained by the method of

Potrawa and Langhals.³³Yield 0.69 g (50%), mp 228±

2308C (from toluene; lit.,³³233±2348C).

3.2.8. 5-Cyano-4-hydroxy-6-(p-¯uorophenyl)-3-phenyl-

2H-cyclopenta[c]pyrrol-1-one 24f. Obtained (yield, 66%)

as for 24d, was dark red and had mp 274±2768C. (dec.,

subl.) (Found: C, 71.9; H, 3.1; N, 8.7. C₂₀H₁₁FN₂O₂requires

C, 72.7; H, 3.4; N, 8.5%.) d_H7.43 (2H, t, J9.0 Hz, Ar-H-3

and -5 in 4-FC₆H₄), 7.5 (1H, br s, OH), 7.55±7.70 (3H, m,

m-/p-PhH), 8.51 (2H, d, J10.0 Hz, o-PhH), 8.51 [4H, coin-

cident o-Ph (m) and Ar-H-2 and -6 in 4-FC₆H₄(dd, J9.0

and 5.6 Hz)], 10.73 (1H, s, NH).

d_H(200 MHz) 3.33 (6H, s, 2£CH₃), 7.50±7.54 (6H, m, m-/

p-Ar-H), 7.84±7.89 (4H, m, o-Ar-H). d_C29.9 (CH₃), 109.6

(C-3a and C-6a), 128.4 (quat. Ar-C), 129.3, 129.5, 131.7

(Ar-C), 149.0 (C-3 and C-6) and 163.0 (C-1 and C-4).

3.2.9. 5-Cyano-6-(p-dimethylaminophenyl)-4-hydroxy-3-

phenyl-2H-cyclopenta[c]-pyrrol-1-one 24g. The reagents

were added to the anion of 3 at 85±908C and the reaction

time under re¯ux was 1.5 h; purple-red, yield (impure)

0.81 g (20%). n_max3110 (weak, N±H or O±H), 2202

(CuN), 1657 (CvO), 1600. (Found: C, 72.5; H, 4.6; N,

3.2.13. 5-Cyano-4-methoxy-6-(p-methoxyphenyl)-2-

methyl-3-phenylcyclopenta[c]-pyrrol-1-one 26d. The

C. J. H. Morton et al. / Tetrahedron 58 (2002) 5547±5565

5563

dianion 25d was prepared as described above, from the

pyrrolinecarboxylate ester (2.56 g, 11.1 mmol),

vacuo. Yield 3.07 g (13%), mp 200±2028C. (Found: C,

78.0; H, 5.2; N, 7.8. C₂₄H₂₀N₂O₂requires C, 78.2, H, 5.5;

N, 7.6%). n_max2195 (CuN), 1694 (CvO), 1655. d_H

(200 MHz) 1.19 (3H, t, J7.1 Hz, CH₂CH₃), 1.29 (3H, t,

CH₂CH₃), 3.68 (2H, q, NCH₂CH₃), 4.55 (2H, q, OCH₂CH₃),

7.42±7.67 (8H, m, Ar-H), 8.22 (2H, dd, J2.2 and 8.2 Hz,

o-Ar-H). m/z 368 (M^1z, 100%), 340 (70), 325 (14), 311

(50), 283 (28), 255 (32), 240 (24), 227 (18), 104 (33),

77 (34).

3

p-methoxycinnamonitrile 20d (2.09 g, 13.1 mmol) and

sodium t-amyloxide (from sodium (0.79 g, 34.4 mmol)) in

t-amyl alcohol (25 cm³). After heating under re¯ux had been

maintained for 4 h, the dark purple solution was cooled to

408C, and methyl toluene-p-sulfonate (20.32 g, 0.1091 mol)

was added portionwise during 10 min. Heating under re¯ux

was resumed for 45 min, during which time the colour

changed to a bright orange-red. The mixture was cooled,

added to water (50 cm³), extracted with ethyl acetate, and

the extract washed with water then concentrated. The

orange-red product 26d was ®ltered off, washed with

methanol then petrol, dried in vacuo, and recrystallised

from 1,4-dioxan. Yield 0.97 g (24%), mp 253±2558C.

(Found: C, 74.7; H, 4.8; N, 7.4; m/z 370.1324.

C₂₃H₁₈N₂O₃requires C, 74.6; H, 4.9; N, 7.7%; M,

370.1317). n_max2200 (CuN), 1701 (CvO), 1607; d_H

3.19 (3H, s, NCH₃), 3.88 (3H, s, ArOCH₃), 4.20 (3H, s,

4-OCH₃), 7.00 (2H, d, J8.8 Hz, H-3 and -5 in

4-MeOC₆H₄), 7.54±7.62 (5H, m, Ph-H), 8.33 (2H, d,

J8.8 Hz, H-2 and 6 in 4-MeOC₆H₄). m/z 370 (100%),

355 (39), 314 (6), 185 (8), 118 (13), 77 (8).

3.2.16.

5-Cyano-4,5-dihydro-5-methyl-3,6-diphenyl-

cyclopenta[c]pyrrole-1,4-dione 28a. The dianion 25a

was prepared as described above, from the pyrrolinecar-

boxylate ester 2 (2.0 g, 8.6 mmol), cinnamonitrile 20a

(1.19 g, 9.2 mmol) and sodium t-amyloxide (from sodium

(0.60 g, 26.1 mmol)) in t-amyl alcohol (20 cm³); after 4.5 h

at the re¯ux temperature, the solution was cooled to 558C

and iodomethane (5.5 g, 38.7 mmol) was added. Heating

was continued at 408C for 1 h, then the mixture was added

to water, acidi®ed (10% HCl) and extracted with ethyl

acetate; the extract was dried (Na₂SO₄) and the solvent

evaporated off. Flash chromatography (eluent, petrol/ethyl

acetate (2:1)) yielded a bright orange solid (0.76 g, 27%),

mp 299±3018C (from propan-2-ol/tetrahydrofuran).

(Found: C, 77.3; H, 4.4; N, 8.4. C₂₁H₁₄N₂O₂requires C,

77.3, H, 4.3; N, 8.6%). n_max3167 (NH), 2365 (CuN),

1677 (CvO), 1607. d_H1.90 (3H, s, CH₃), 7.57±7.65 (6H,

m, m-/p-Ar-H), 8.41±8.51 (4H, m, o-Ar-H), 12.22 (1H, s,

NH) with trace impurity at 3.32 (!1H, s, NCH₃). m/z 326

(M^1z, 100%), 340 (14), 297 (13), 283 (4), 269 (9), 255 (95),

118 (10), 105 (12), 77 (14).

3.2.14. 5-Cyano-4-methoxy-2-methyl-3,6-diphenylcyclo-

penta[c]pyrrol-1-one 26a. This was prepared in a similar

manner, from the pyrrolinecarboxylate ester 2 (4.0 g,

17.3 mmol), cinnamonitrile 20a (4.46 g, 34.5 mmol) and

sodium t-amyloxide (from sodium (1.22 g, 53.1 mmol)) in

t-amyl alcohol (50 cm³); after 4 h at the re¯ux temperature,

methyl toluene-p-sulfonate (25.22 g, 135.4 mmol) was

added at 258C, and heating under re¯ux was then resumed

for 1 h. The mixture was cooled, added to water (100 cm³),

extracted with ethyl acetate, the extract dried (Na₂SO₄) then

concentrated; the orange-red product was puri®ed by dis-

solution in ethanolic sodium ethoxide solution and, after

18 h, reprecipitation by addition to water and dropwise acid-

i®cation (conc. HCl). Compound 26a (1.22 g, 21%) had mp

210±2128C (from propan-2-ol/tetrahydrofuran). (Found: C,

77.3; H, 4.7; N, 8.2. C₂₂H₁₆N₂O₂requires C, 77.6; H, 4.7, N,

8.2%.) n_max2197 (CuN), 1703 (CvO), 1677; d_H3.18 (3H,

s, NCH₃), 4.21 (3H, s, OCH₃), 7.43±7.66 (8H, m, Ar-H),

8.22 (2H, d, J6.6 Hz, Ar-H); m/z 340 (M^1z, 100%), 325

(76), 284 (12), 161 (21), 118 (15), 77 (15), 69 (18).

3.2.17. 5-Cyano-4,5-dihydro-2,5-dimethyl-3,6-diphenyl-

cyclopenta[c]pyrrole-1,4-dione 29a. The dianion 25a

was prepared as described above, from the pyrrolinecar-

boxylate ester 3 (10.0 g, 43.2 mmol), cinnamonitrile 20a

(5.6 g, 43.4 mmol) and sodium t-amyloxide (from sodium

(2.97 g, 129.2 mmol)) in t-amyl alcohol (80 cm³). After

3.5 h at re¯ux temperature and then 2 h at 258C, iodo-

methane (25.15 g, 177.2 mmol) was added and the mixture

was stirred at 258C for 6 days; it was then added to water

(200 cm³) and extracted with ethyl acetate. Flash chromato-

graphy of the dried (Na₂SO₄) and concentrated extract

(eluent, petrol/ethyl acetate (1:1)) afforded a bright orange

solid (5.12 g, 35%), mp 199±2008C (from propan-2-ol/

tetrahydrofuran). (Found: C, 77.3; H, 4.6; N, 7.9.

C₂₂H₁₆N₂O₂requires C, 77.6; H, 4.7; N, 8.2%). n_max2195

(CuN), 1694 and 1655 (2£CvO); d_H1.87 (3H, s, CCH₃),

3.32 (3H, s, NCH₃), 7.61±7.64 (6H, m, m-/p-Ar-H), 7.83±

7.87 (2H, m, o-H in 3-Ph), 8.50±8.53 (2H, o-H in 6-Ph). m/z

340 (M^1z, 100%), 325 (3), 312 (17), 311 (17), 283 (10), 254

(6), 240 (6), 156 (9), 127 (6), 118 (280), 105 (80), 91 (5), 77

(13).

3.2.15. 5-Cyano-4-ethoxy-2-ethyl-3,6-diphenylcyclopen-

ta[c]pyrrol-1-one 27a. This was prepared in a similar

manner, from the pyrrolinecarboxylate ester 3 (15.0 g,

64.9 mmol), cinnamonitrile 20a (8.4 g, 65 mmol) and

sodium t-amyloxide [from sodium (4.5 g, 0.196 mol)] in

t-amyl alcohol (80 cm³); after 1.5 h at the re¯ux tempera-

ture, a solution of ethyl toluene-p-sulfonate (52.5 g,

262 mmol) in dimethylformamide (20 cm³) was added to

the purple solution, and heating under re¯ux continued for

a further 1.5 h, during which time the colour changed to

orange and a colourless precipitate formed. The mixture

was cooled, added to water (250 cm³), then extracted with

ethyl acetate, the organic layer acidi®ed with 10% hydro-

chloric acid, washed with water, dried and the solvent

evaporated. The orange residue was dissolved overnight in

ethanolic sodium ethoxide solution, the solution set aside

overnight and the product reprecipitated by acidi®cation

(10% HCl), ®ltered off, washed with water and dried in

3.3. X-Ray crystallography

The intensity data for compounds 14, 15, 18c and 19b were

recorded at 293(1) K with a Rigaku AFC7S diffractometer

Ê

using graphite-monochromated Mo Ka (l0.7107 A), and

the structures in Figs. 2±4 were solved by direct methods

using SIR92³⁴and re®ned by full-matrix least squares on F,

using the TeXsan system 1.³⁵For crystals of compounds 15,

18c and 19b the systematic absences allowed unique

5564

C. J. H. Morton et al. / Tetrahedron 58 (2002) 5547±5565

assignment of all the space groups. All hydrogen atoms

were located from difference maps, and were included in

the re®nements as riding atoms in idealised positions with

isotropic displacement parameters; all non-hydrogen atoms

were re®ned anisotropically. In the case of compound 15,

the structure was disordered at two sites within the t-butoxy-

carbonyloxy group, and for clarity the structure shown

(Fig. 2) is simpli®ed to show the sites of maximum

occupancy.

Acknowledgements

We thank Professor G. Ferguson and Dr C. Glidewell for

valuable assistance with the solution of the X-ray crystal

structure of compound 14. For the solution of the structure

of compound 26d, we gratefully acknowledge the provision

of time on DARTS, the UK national synchrotron radiation

service at the CLRC Daresbury Laboratory. We also thank

Professors Abul Iqbal and I. A. Macpherson for helpful

discussions, Mrs S. Williamson for the microanalyses, Mr

C. Millar for the mass spectra, and Ciba Specialty

Chemicals Inc., Basel, for ®nancial support.

In the case of compound 14 (Fig. 1), the original `triclinic'

data set (4696 re¯ections) gives a very poor R_int(16%) on

merging to yield a `monoclinic' data set with 2228

re¯ections. The space group P2₁/c was chosen as being

the best option (two cell angles are 908 and the absences

do correspond with a monoclinic P2₁/c type cell). The Z

value of 2 in the cell demands that the molecule lie about

an inversion centre and thus have the phenyl and cyclo-

hexenyl moieties occupying the same site in the asymmetric

unit.

References

1. Hao, Z.; Iqbal, A. Chem. Soc. Rev. 1997, 26, 203±213 and

references therein.

2. Iqbal, A.; Jost, M.; Kirchmayr, R.; Pfenninger, J.; Rochat, A.;

Wallquist, O. Bull. Soc. Chim. Belg. 1988, 97, 615±643.

3. Mizuguchi, J.; Grubenmann, A.; Wooden, G.; Rihs, G. Acta

Crystallogr. 1992, B48, 696±700.

The structure solved relatively easily using SHELXS-97.³⁶

It was apparent at this `solution' stage that the phenyl/cyclo-

hexenyl site had six peaks, some of which were distended

normal to the plane. It was also obvious that the unique

t-butoxycarbonyl moiety was disordered unequally over

two sites. All the disorder was successfully modelled

using the available options in SHELXL-97.³⁶Using DFIX

and Free-variable options, the geometry of the cyclohexenyl

ring re®ned to yield a double-bond location consistent with

that anticipated, and the ®nal model has the phenyl and

cyclohexenyl rings, each with 0.5 occupancy, occupying

the same volume element in the crystal lattice. The

t-butoxycarbonyl geometry was controlled by the use of

various options in SHELXL-97.

4. (a) Rochat, A. C.; Cassar, L.; Iqbal, A. Eur. Pat. 94,911, 1983.

(b) Iqbal, A.; Pfenninger, J.; Rochat, A. C.; Babler, F. Eur. Pat.

181,290, 1986. (c) Surber, W.; Iqbal, A.; Stern, C. Eur. Pat.

302,018, 1989.

5. Pfenninger, J.; Iqbal, A.; Rochat, A. C.; Wallquist, O. US

Patent 4,778,899, 1986. Pfenninger, J.; Iqbal, A.; Rochat, A.

C. US Patent 4,749,795, 1986.

6. See, for example: Saunders, K. J. Organic Polymer Chemistry;

2nd ed; Chapman and Hall: London, 1987; p 16. Stevens, M. P.

Polymer Chemistry: An Introduction; Oxford University:

Oxford, 1990; pp 250±256, and references therein.

7. Bruson, H. A. Org. React. 1949, 5, 79±135. Bergmann, E. D.;

Ginsburg, D.; Pappo, R. Org. React. 1959, 10, 179±555 and

references therein.

For compound 26d, the intensity data were recorded at

291(2) K with a Siemens/Bruker SMART CCD diffract-

ometer, but with tuneable wavelengths (l0.68900 A)

8. Brion, F. Tetrahedron Lett. 1982, 23, 5299±5302.

9. Kienzle, F. Helv. Chim. Acta 1975, 58, 1180±1183.

10. Iqbal, A. Personal communication.

Ê

using the microcrystal diffraction facility on station 9.8³⁷

of the Synchrotron Radiation Source, CLRC Daresbury

Laboratory. Processing of the data used the SMART,

SAINT and SADABS^38,39programs, and the structure was

solved using SHELXTL.⁴⁰The intensity data for compound

29a were also recorded using a Siemens/Bruker SMART

diffractometer, with data again being integrated using the

SAINT and SADABS programs; the structure solved by

direct methods and re®ned by full-matrix least-squares

against F²(SHELXTL). All data were corrected for

Lorentz, polarisation and long-term intensity ¯uctua-

tions. Absorption effects were corrected on the basis

of multiple equivalent re¯ections or by semi-empirical

methods. All hydrogen atoms were assigned isotropic

displacement parameters and were constrained to idealised

geometries. Crystallographic data (excluding structure

factors) for compounds 14, 15, 18c, 19b, 26d and 29a

have been deposited with the Cambridge Crystallographic

Data Centre as supplementary publication numbers CCDC

176667, 176668, 176669, 176700, 176701 and 176702,

respectively. Copies of the data may be obtained, free of

charge, on application to CCDC, 12 Union Road,

Cambridge, CB2 1EZ, UK (fax: 144-1223-336033 or

e-mail: deposit@ccdc.cam.ac.uk).

11. (a) McKeown, N. B.; Chambrier, I.; Cook, M. J. J. Chem. Soc.,

Perkin Trans. 1 1990, 1169±1177. (b) Chambrier, I.; Cook,

M. J.; Cracknell, S. J.; McMurdo, J. J. Mater. Chem. 1993, 3,

841±849.

12. Wang, E.-C.; Lin, G.-J. Tetrahedron Lett. 1998, 39, 4047±

4050.

13. (a) Zambounis, J. S.; Hao, Z.; Iqbal, A. Nature 1997, 388, 131.

(b) Eur. Pat. 673,979, 1995.

14. Moon, M. W. J. Org. Chem. 1977, 42, 2219±2223. San

Feliciano, A.; Caballero, E.; Pereira, J. A. P.; Puebla, P.

Tetrahedron 1989, 45, 6553±6562.

15. Garst, J. E.; Wilson, B. J. J. Agric. Food Chem. 1984, 32,

1083±1087.

16. Charbonneau, G.-P.; Delugeard, Y. Acta Crystallogr. 1976,

B32, 1420±1423.

17. Bennes, R.; Philp, D.; Spencer, N.; Kariuki, B.; Harris,

K. D. M. Org. Lett. 1999, 1, 1087±1090.

18. Patrick, T. M. J. Org. Chem. 1952, 17, 1009±1016.

19. Boutagy, G.; Thomas, R. Chem. Rev. 1974, 74, 87±99.

20. Pastushak, N. O.; Stadniichuk, N. F.; Dombrovskii, A. V. Zh.

Obsh. Khim. 1963, 33, 2950±2952 Chem. Abstr. 1963, 60,

1639.

21. DiBiase, S. A.; Lipisko, B. A.; Haag, A.; Wolak, R. A.; Gokel,

G. W. J. Org. Chem. 1979, 44, 4640±4649.

C. J. H. Morton et al. / Tetrahedron 58 (2002) 5547±5565

5565

22. Butt, G.; Topsom, R. D. Spectrochim. Acta 1980, 36A, 811±

817.

FTNMR Spectra ; The Aldrich Chemical: Milwaukee, 1993

Spectrum 1-36B.

23. Schiemenz, G. P.; Engelhard, H. Chem. Ber. 1962, 95, 967±

970.

33. Potrawa, T.; Langhals, H. Chem. Ber. 1987, 120, 1075±1078.

34. Altomare, A.; Cascarano, G.; Giacovazzo, C.; Guagliardi, A.

J. Appl. Cryst. 1993, 26, 343±350.

24. Koelsch, C. F. J. Am. Chem. Soc. 1943, 65, 57±58.

25. Claisse, J. A.; Gregory, G. I.; Warburton, W. K. S. Afr. Pat.

68,01861, 1969; Chem. Abstr. 1970, 72, 21696.

26. Lippert, E.; LuÈder, W. J. Phys. Chem. 1962, 66, 2430±2434.

27. Mendes da Costa, R. Compt. Rend. Hebd. Acad. Sci. 1933,

196, 1815±1817.

35. TeXsan Crystal Structure Analysis Package, 1985 and 1992:

Molecular Structure Corporation, The Woodlands, TX77381,

USA.

È

36. Sheldrick, G. M. University of Gottingen, Germany.

37. Cernik, R. J.; Clegg, W.; Catlow, C. R. A.; Bushnell-Wye, G.;

Flaherty, J. V.; Greaves, G. N.; Burrows, I.; Taylor, D. J.; Teat,

S. J.; Hamichi, M. J. Synchrotron Rad. 1997, 4, 279±286.

38. SMART (control) and SAINT (integration) software, version

4, Bruker AXS Inc., Madison, Wisconsin, 1994.

28. Claisse, J. A.; Foxton, M. W.; Gregory, G. I.; Sheppard, A. H.;

Tiley, E. P.; Warburtion, W. K.; Wilson, M. J. J. Chem. Soc.,

Perkin Trans. 1 1973, 2241±2249.

29. Wah Chan, C.; Fawcett, A. H.; Mulemwa, J. N.; Chao-Eng,

Tan Polymer 1985, 26, 1268±1270.

39. Sheldrick, G. M. SADABS, program for scaling and correcion

of area detector data, University of Gottingen, 1997, based on

the method of Blessing, R. H. Acta Crystallogr., Sect. A 1995,

51, 33.

30. Olah, G. A.; Surya Prakash, G. K.; Arvanaghi, M.; Bruce,

M. R. Angew. Chem. Int. Ed. Engl. 1981, 20, 92±94.

31. Toland, W. G.; Ferstandig, L. L. J. Org. Chem. 1958, 23,

1350±1351.

40. Sheldrick, G. M. SHELXTL, version 5; Bruker AXS Inc.:

Madison, Wisconsin, 1994.

32. Pouchert, C. J.; Behnke, J. The Aldrich Library of ¹³C and ¹H

Article Doi

Synthetic studies related to diketopyrrolopyrrole (DPP) pigments. Part 1: The search for alkenyl-DPPs. Unsaturated nitriles in standard DPP syntheses: A novel cyclopenta[c]pyrrolone chromophore

DOI: 10.1016/S0040-4020(02)00443-X

Source and publish data:

Authors:

Article abstract of DOI:10.1016/S0040-4020(02)00443-X

Full text of DOI:10.1016/S0040-4020(02)00443-X

Products guided by the article

R&D Labs maybe for 469862-28-0

Relevant to this article

Hot Product