A facile route to pyrroles, isoindoles and hetero fused analogues

Article abstract of DOI:10.1039/b209255g

The decarboxylative cyclisation process where enamino acids derived from 1, 2-dimethylaminomethylene or 1, 2 hydroxymethylene-carbonyl compounds and amino acids gets converted into pyrroles, isoindoles and other fused pyrroles, was discussed. The cyclisat

Full text of DOI:10.1039/b209255g

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A facile route to pyrroles, isoindoles and hetero fused analogues
Christopher D. Gabbutt,a John D. Hepworth,b B. Mark Heron*a and Samantha L. Pugha
a Department of Colour Chemistry, The University of Leeds, Leeds, UK LS2 9JT
1
b James Robinson Ltd., PO Box B3, Hillhouse Lane, Huddersfield, UK HD1 6BU
Received (in Cambridge) 20th September 2002, Accepted 14th October 2002
First published as an Advance Article on the web 25th November 2002
Enamino acids derived from 1,2-dimethylaminomethylene- or 1,2-hydroxymethylene-carbonyl compounds and
amino acids undergo a decarboxylative cyclisation to pyrroles, isoindoles and other fused pyrroles. A two atom ring
expansion occurs preferentially with enamino acids from cyclohexane-1,3-diones and α-alkyl-α-amino acids leading
to oxocino[2,3-c]pyrroles.
Introduction
The pyrrole unit1 occurs in a range of naturally occurring
compounds, pharmaceutical products and polymers.2 The
synthesis of this ring system has been widely investigated and
has featured in a number of reviews.3,4 Nevertheless, ring
syntheses of pyrroles unsubstituted at the 2- and 5-positions
and routes which involve formation of the C-2–C-3 bond
are uncommon.4a Probably the single most convenient entry
to compounds of this type involves the condensation of
α,β-unsaturated ketones, esters and nitriles and nitroalkenes
with tosylmethyl isocyanide (TosMIC) and related com-
pounds.4b Several routes to pyrroles involve the reaction of 1,3-
dicarbonyl compounds and α-amino acids, but in all of these
examples a carboxylate function is retained in the pyrrole.5
Since its discovery in 1973 by Zav’yalov et al.6 the efficient
synthesis of pyrroles based on the acetic anhydride-promoted
cyclisation of the salt of an enamino acid (Scheme 1) has
Scheme 2 Reagents and conditions: (i) 1.05 eq. α-amino acid, 1.05 eq.
NaOAcؒ3H2O, aq. EtOH, ∆; (ii) Ac2O, Et3N, ∆.
ing triethylamine and this was accompanied by the vigorous
Scheme 1 Reagents and conditions: (i) Ac2O, ∆.
evolution of CO2 (lime water bubbler) as the internal reaction
temperature reached reflux. After ca. 30 minutes, the reaction
mixture was cooled and subjected to an aqueous work-up. TLC
examination of the crude reaction mixtures revealed the
presence of a fast running major component contaminated
with dark base line material rendering initial purification by
flash chromatography easy.
been rarely used.7 We now report the synthesis of some novel
substituted pyrroles and fused analogues through the applica-
tion of this methodology and describe a unique ring expansion
reaction that affords the oxocino[2,3-c]pyrrole system.
The cyclisation of the isomeric enamino acids 2a proceeded
with the expected regioselectivity of cyclisation on to the more
electrophilic ketonic carbonyl group rather than the ester
function to afford a single pyrrole, 3a, confirmed by the
Discussion
Dimethylaminomethylene carbonyl compounds 1a8 and 1b9
were obtained by standard protocols. Their addition–
elimination reaction with -2-phenylglycine and glycine in
aqueous ethanol containing sodium acetate gave the enamino
acids 2a–c in high yield (Scheme 2). The 1H NMR spectrum of
2a indicated that an unequal mixture (ca. 3 : 1) of E- and Z-
isomers had been isolated. In the former, the NH proton is
strongly H-bonded to the acetyl carbonyl resulting in a low field
signal (δ 11.68). In the Z-isomer intramolecular H-bonding is
weaker because of participation of the ester group as evidenced
by the upfield shift of this signal to δ 10.06.
1
presence of signals in its H NMR spectrum associated with
the ethyl ester moiety. The pyrrole ring proton resonates
significantly downfield at δ 7.93 as a consequence of the
adjacent ester function; the 4-methyl group and the N-acetyl
function are observed at δ 2.08 and δ 2.21, respectively.
Of particular note is the relatively efficient preparation
(ca. 40% overall yield) of the 2,5-unsubstituted pyrrole 3b.
Existing routes to compounds of this type are often laborious
1
and low yielding.3c,f,h,4a The H NMR spectrum of this com-
A deep red colour was instantaneously produced when the
enamino acids 2a–c were heated with acetic anhydride contain-
pound displayed the expected singlets at δ 7.25 and 7.78 for
5-H and 2-H respectively.
DOI: 10.1039/b209255g
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This journal is © The Royal Society of Chemistry 2002
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1
Cyclohexane-1,3-dione and dimedone were converted
according to literature procedures into the respective enamino
ketones 4a10 and 4b,11 which were reacted with a range of
α-amino acids according to the above method to afford the
enamino acids 5a–e (Schemes 3 and 4). The facile addition
although the H NMR spectrum of the product derived from
5b appeared to be in agreement with structure 8a. However,
HRMS and elemental analysis data did not support this struc-
ture, instead suggesting that the molecule contained an
additional CO2. The presence of a third low field signal between
δ 168–169 in the 13C NMR spectrum confirmed these data; this
chemical shift range is indicative of a carboxylate-type carbon.
Attempts to obtain a crystal structure of this compound were
unsuccessful since the compound decomposed during repeated
recrystallisation.
We next turned our attention to the product obtained from
the cyclisation of 5d. The 1H NMR spectrum of this compound
recorded at ambient temperature (24 ЊC) was uninformative
since many signals in the range δ 0.5–3.5 were poorly resolved
(Fig. 1), but a signal at δ 7.7, a chemical shift that is comparable
Scheme 3 Reagents and conditions: (i) 1.05 eq. α-amino acid, 1.05 eq.
NaOAcؒ3H2O, aq. EtOH, ∆; (ii) Ac2O, Et3N, ∆ (iii) AcOH, c. HCl, ∆.
and elimination of amino acids to 5,5-dimethyl-2-(dimethy-
aminomethylene)cyclohexane-1,3-dione 4b has been advocated
as an amino protection–deprotection sequence useful in solid
phase synthesis.12 The cyclisation of 5a–e was then investigated.
Heating the enamino acids derived from -2-phenylglycine
(5a and 5c) with acetic anhydride containing Et3N gave the
expected dihydroisoindoles 6a and 6b, respectively. The 1H
NMR spectra of these compounds displayed a singlet at ca. δ
7.1 for the pyrrole ring proton. The remaining carbonyl func-
tion of the starting dione had been converted to the enol acetate
as indicated by the presence of a signal at ∼δ 5.4 for the alkenic
proton and at ∼δ 2.2 for the OAc group. Compound 6a was
efficiently de-acetylated on heating in aqueous acetic acid con-
taining conc. HCl to afford 7 (92%). The presence of a broad
singlet at δ 9.7 for the pyrrole NH and the absence of the signal
for the alkenic proton associated with the enol acetate unit in
the 1H NMR spectrum of 7 indicated that both acetyl functions
had been removed. The 13C NMR of this compound displayed
a low field signal at δ 196.9 for the carbonyl group carbon.
In marked contrast to our observation noted for the cyclisa-
tion of the enamino acids 2a–c and 5a,c, only slight evolution
of CO2 was observed when enamino acids 5b,d, and e were
heated in acetic anhydride containing Et3N, suggesting that
some other reaction sequence had occurred (Scheme 4),
Fig.
1
Variable temperature 1H NMR spectra (δ 0.5–3.5) for
oxocinopyrrole 9b.
to that of 2-H in 3a–c, was clear. However, dramatic improve-
ments in resolution were achieved by recording the spectrum at
either elevated (55 ЊC) or reduced (Ϫ20 ЊC) temperature (Fig. 1)
indicating that the molecule is undergoing conformational
interconversion. Once again the 1H NMR spectrum of this
product appeared to suggest that isoindole 8b had been
isolated, though this data was again incompatible with other
spectroscopic evidence. The 13C NMR spectrum displayed a
signal for an additional carbon atom at ca. δ 169. Infrared
spectroscopy was inconclusive with only two bands present in
the C᎐O stretching region. However, X-ray crystallography of
᎐
this compound indicated the oxocino[2,3-c]pyrrole structure
9b.13 With the structure of 9b to hand, it is evident that the
product from the cyclisation of 5b is the related acetoxy
oxocinopyrrole 9a. It is noteworthy that the 1H NMR spectrum
of 9a is well resolved at ambient temperature as a consequence
of the rigidity imparted into the oxocine ring by the enol acetate
function. The absence of this structural feature in 9b allows
Scheme 4 Reagents and conditions: (i) Ac2O, Et3N, ∆.
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1
broadening of the signals in its H NMR spectrum as a con-
sequence of the oxocine ring existing in equilibrium between
several conformers.14
The low temperature H NMR spectrum of 9b merits some
1
further comment. The four methylene protons (3-C and 5-C)
are non-equivalent and each gives rise to a doublet with J 12.3
1
Hz. In order to confirm this coupling a H–1H COSY experi-
ment at Ϫ40 ЊC was recorded (Fig. 2). This revealed that the
1
Fig. 3 Low temperature (Ϫ40 ЊC) H NMR homo decoupling of the
doublet at δ 2.28 in oxocinopyrrole 9b.
Fig. 2 Low temperature (Ϫ40 ЊC) 1H–1H COSY spectrum for
oxocinopyrrole 9b.
Unfortunately the product derived from heating enamino
acid 5e, derived from 4b under the standard conditions,
decomposed on storage at room temperature.
12.3 Hz coupling was not due to a geminal interaction but was
instead a consequence of one of the 3-H protons coupling to
one of the 5-H protons, i.e. 4-bond coupling. The magnitude of
A possible mechanism for the formation of the isoindoles
8 and oxocinopyrroles 9 is outlined in Scheme 5. We favour
pathways involving the intermediacy of a ketene since their
formation via elimination from mixed anhydrides is especially
facile under basic conditions, many examples of this for N-
and O- linked alkanoic acids have been documented.16a The
acylation of N-substituted amino acids proceeds with cyclo-
dehydration to provide mesoionic 1,3-oxazolium-5-olates
(münchnones)16b and evidence has accrued that these are
tautomeric with N-acyl ketenes.16c The mesoionic heterocycle
10 may react by two distinct pathways to afford 8. We propose
that, when R = phenyl, the extended conjugation imparts
4
this coupling in 9b is quite unusual since J is typically 1–2
Hz.15a However, substantially larger 4J coupling constants have
been reported for rigid bicyclic systems where more than one
coupling pathway may operate.15b
In order to confirm this unexpected long-range relationship
between 3- and 5-H we selectively decoupled the doublet at
δ 2.28 (3-H). Whilst some loss of resolution of the doublet
at δ 2.38 was observed due to the decoupling pulse employed,
more significantly the signal at δ 2.93 resolved into a singlet
confirming the coupling arrangement (Fig. 3).
Scheme 5
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stability to the münchnone tautomer which then attacks the
proximal C᎐O group. The alkoxide species thus generated
᎐
forms the lactone 11 with concomitant oxazole ring cleavage.
Alternatively, cyclisation of the valence tautomer 12 (path a)
provides an oxazepine intermediate which contracts to 11. It
is pertinent to note that a similar dipolar species, a dioxepine,
has been invoked in the Ac2O-mediated cyclisation of
o-acylphenoxyalkanoic acids to benzofurans.16d Cycloreversion
of CO2 from 11 and subsequent O-acylation completes the
route to the dihydroisoindoles 8. Conversely, when R = alkyl,
the münchnone 10 undergoes ring–chain tautomerism to the
N-acyl ketene 12. Intramolecular acylation of the enamine
function affords the spirocycle 13 (path b). Oxetane ring form-
ation and subsequent ring cleavage of 14 effects the ring
expansion to the oxocinopyrrole system 9.
It was of interest to explore the versatility of this route for the
formation of other fused pyrrole containing systems. Thus
indan-1-one and indane-1,3-dione were readily converted into
the dimethylaminomethylene ketones 15a,17 b10 respectively.
Treatment with an ethanolic solution of an α-amino acid
containing sodium acetate gave the respective enamino acids
16a,b in high yield (Scheme 6). Unfortunately attempts to
Scheme 7 Reagents and conditions: (i) 1.05 eq. α-amino acid, 1.05 eq.
NaOAcؒ3H2O, aq. EtOH, ∆; (ii) Ac2O, Et3N, ∆.
Scheme 6 Reagents and conditions: (i) 1.05 eq. α-amino acid, 1.05 eq.
NaOAcؒ3H2O, aq. EtOH, ∆.
N-acetyl groups and a further singlet at δ 5.29 was assigned to
the methylene function of the O,S-acetal.
cyclise these compounds in the usual manner gave only tarry
multicomponent reaction mixtures from which no indeno[c]-
fused pyrroles 17 could be isolated. It is possible that the
postulated intermediate in the formation of 17, a tricyclic 5–5–4
system (cf. 11), is too strained to form thus preventing the
cycloreversion of the lactone ring that ultimately affords the
product.
We next explored the application of enamino acids 19f,g
derived from the tetralone homologue, 2-hydroxymethylene-1-
benzosuberone 18b,21 for the formation of further fused
pyrrroles (Scheme 7). Both 19f and 19g cyclised smoothly to
afford the expected pyrroles 20f,g in good yield.
From our research projects on chromanones and thio-
chromanones we had access to a range of 3-hydroxymethylene-
(thio)chromanones 18c–f.22,23 The enamino acids, 19h and 19i,
derived from glycine and the 3-hydroxymethylenebenzopyrans
18c and 18d respectively, cyclised to give the benzopyrano[3,4-
c]pyrroles 20h and i. The benzopyrano[3,4-c]pyrrole ring system
has recently been accessed by the photogeneration of radicals
from α-stannyl ethers and their conjugate addition to enones,24
through the displacement of the iron residue in 4-[η5-cyclopenta-
2-Hydroxymethylene-1-tetralone 18a is readily available by
the formylation of 1-tetralone.18 Treatment of this β-dicarbonyl
compound with glycine according to the above procedure gave
enamino acid 19a as bright yellow microcrystals in 74% yield.
Enamino acids 19b–e were similarly obtained from the
appropriate amino acids (Scheme 7). With the exception of
19a from which only a small amount of 1-tetralone could be
isolated from the tarry residue, the cyclisation of these enamino
acids proceeded smoothly to give the benzo[e]isoindoles 20b–e.
The cyclisation of 19d, derived from -methionine sulfox-
ide, yielded two products that were separated by elution from
silica. The less polar component was characterised as
acetoxymethylene-1-tetralone 21.19 The nitrogen containing
product was not the expected benzo[e]isoindole containing the
(CH2)2S(O)CH3 group but was instead 20d, arising from a
regiospecific Pummerer rearrangement20 of the (CH2)2S(O)CH3
function under the reaction conditions to provide the
dienyl(dicarbonyl)iron]-2H-chromene-3-carbaldehyde
with
primary amines25 and by the Fischer-Fink reaction of 4-chloro-
3-formylcoumarins with amino acid esters.26 The benzo-
pyrano[3,4-c]pyrrole unit has found application in photo-
crosslinkable polymers27 and as the structural unit in some
methine dyes.28 The enamino acids 19j–n, derived from hydroxy-
methylenethiochromanones 18e and f, gave mixed results on
heating in Ac2O–Et3N. Compounds 19l and m obtained from
the 2,2-dimethyl-3-hydroxymethylenethiochromanone 18f gave
the expected benzothiopyrano[3,4-c]pyrroles 20k and l in ca.
50% yield and constitutes the first synthesis of this ring system.
1
(CH2)2SCH2OAc side-chain. The H NMR spectrum of this
compound displayed singlets at δ 2.09 and 2.55 for the O- and
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However, we were unable to obtain any benzothiopyrano[3,4-c]-
pyrrole from the attempted cyclisation of enamino acid 19n
which was derived from -alanine and 18f. The enamino
acid 19j derived from glycine and the 3-hydroxymethylene-2-
methylthiochromanone 18e also failed to afford any isolable
pyrrole, although, that derived from 18e and -2-phenyl-
glycine (19k) gave the pyrrole 20j in a respectable 64% yield.
1-Dimethylaminomethylene-2-tetralone 22 was prepared
by heating 2-tetralone in N,N-dimethylformamide dimethyl
acetal.29 Subsequent reaction with -2-phenylglycine in
aqueous ethanol containing NaOAcؒ3H2O gave the enamino
acid 23 in 53% yield. Cyclisation of 23 using the standard
protocol gave the isomeric 3-phenylbenzo[e]isoindole 24 after
elution from silica in 56% yield.
Scheme 8 Reagents and conditions: (i) PhBr, ∆ (ii) PTAD, CH2Cl2, rt.
function and the alkenyl proton appeared at δ 6.83, typical for
such aminomethylene compounds.31 The more polar fraction
was characterised as 3-isopropenylchromone 28 and had
physical and spectroscopic properties comparable with
authentic material.22 The formation of 3-alkenyl- chromones22
and thiochromones23 by the rearrangement of 3-hydroxy-
methylene(thio)chromanones has been reported by us previ-
ously though in both instances the presence of acid was used to
effect the rearrangement. The alkenylchromone 28 was sub-
sequently reacted with 4-phenyl-1,2,4-triazoline-3,5-dione32
(PTAD) in dichloromethane at room temperature to afford the
novel fused tetracycle 29 in 92% yield. The 1H NMR spectrum
of 29 displayed an AB system for 5-H with J = 17.7 Hz. The
methine proton, 12a-H, appeared as a singlet at δ 6.83, a feature
that confirmed that the double bond had not migrated into the
pyran ring, a process that has been observed with cyclo-
additions to 2-styrylchromones.33 8-H resonates furthest
downfield of the aromatic signals due to its proximity to the
anisotropic carbonyl group at C-7.
In conclusion, this route to the pyrrole system is highly
versatile, since it offers potential for the formation of novel
2,5-unsubstituted pyrroles when glycine is employed as the
α-amino acid, is compatible with a range of α-amino acids and
α-hydroxy- and α-amino-methylene carbonyl compounds, is
applicable to the synthesis of 3-hydroxypyrrole derivatives,
isoindoles and fused pyrrole derivatives, and provides facile
access to the novel oxocino[2,3-c]pyrrole ring system by a two
atom ring expansion process.
The 1H NMR spectra of the fused pyrroles and isoindoles 20
merit some comment. For the 1-alkyl substituted compounds
20c,d,e and g the pyrrole ring proton (3-H) resonates at ca. δ
6.9. This signal is shifted downfield by ca. 0.3 ppm on replace-
ment of the alkyl group by a phenyl ring e.g. 20b,j and l. The
pyrrole ring proton (1-H) of the isomeric 3-phenyl substituted
isoindole 24 appears further downfield at δ 7.64. Noticeably
9-H resonates at δ 7.54 in 24 but is shifted significantly upfield
to δ 6.69 in 20b. It would appear that 9-H lies in the shielding
zone of the 1-phenyl substituent, suggesting that the disposition
of the phenyl ring must approach perpendicularity with respect
to the major plane of the molecule. A similar situation has been
previously noted for some related benzothiopyranopyrazoles.23
1
In the H NMR spectra of 20d and 20j 3-H appeared as a
doublet with J = 1.0 Hz as a result of allylic coupling to 4-H. In
the case of 1,3-unsubstituted fused pyrroles, (20a, 20f, 20h, 20i,
20k) the signals from 1-H and 3-H overlap with the aromatic
signals.
The generality of this pyrrole ring synthesis was investigated
further by reacting hydroxymethylene 18c with 2-amino-
acetonitrile which under routine conditions gave the enamino
nitrile 25 in high yield. However, attempts to cyclise this nitrile
to the pyrrolecarbonitrile 26 failed.
It is noteworthy that the formation of the pyrroles 3,
isoindoles 6 and the fused analogues 9, 20 and 24 is chemo-
selective, and in no instances did we observe the presence of
any α-amino ketones resulting from a Dakin–West reaction.30
Furthermore the formation of the oxocinopyrroles 9 only
occurs with the combination of an α-alkyl-α-amino acid and a
cyclohexane-1,3-dione; replacement of either one of these
components results in the formation of the pyrrole or isoindole.
We next explored the possibility of a thermal cyclisation of
enamino acid 19h. Heating 19h in bromobenzene effected the
gradual evolution of CO2 and resulted in the formation of two
products that were resolved by flash chromatography (Scheme
8). The less polar fraction was characterised as the 3-(methyl-
aminomethylene)chromanone 27 formed through decarboxyl-
ation of the glycine residue. In the 1H NMR spectrum of
this compound the NH proton resonated at δ 10.23 as a
consequence of intramolecular H-bonding to the carbonyl
Experimental
Melting points were determined in capillary tubes and are
uncorrected. Distillations were performed using a Kugelrohr
(Buchi GKR-50 Glass Tube Oven) and all boiling points
quoted relate to the oven temperature at which the distillation
commenced. Fourier transform infrared spectra were recorded
1
on a Mattson Polaris spectrophotometer. H and 13C NMR
spectra were recorded on either a Bruker WM 250 or Avance
400 MHz or a JEOL λ series 400 MHz instrument for solutions
in CDCl3 unless stated otherwise; coupling constants J are
given in Hz. Flash chromatographic separations were per-
formed on chromatography silica as supplied by Fluorochem
Ltd. (MPD 40–63µ) according to the published procedure.34
General method for the preparation of carboxymethylamino-
methylene derivatives
The dimethylamino- and hydroxy-methylene compound (15
mmol) was dissolved in ethanol (35 cm3) and a solution of the
amino acid (18 mmol) and sodium acetate trihydrate (18 mmol)
in the minimum volume of aqueous ethanol to effect complete
dissolution was added in a single portion. The resulting
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solution was refluxed for 4 h. and then reduced in volume
to ca. 25 cm3. The product was precipitated by the addition of
ice–water (40 cm3) and the pH of the solution adjusted to ∼6
with dilute hydrochloric acid (2 M, aq.). The precipitate was
collected by vacuum filtration, washed thoroughly with cold
water and air-dried. The following compounds were obtained
by this protocol.
2512, 1732, 1657, 1582, 1551 cmϪ1; δH 0.78–0.82 (6H, m,
CH(CH3)2), 1.00 (6H, s, 5-Me), 1.48–1.67 (3H, m,
CH2CH(CH3)2), 2.18 (2H, s, CH2), 2.22 (2H, s, CH2), 3.90
(1H, m, NCHCO2H), 6.82 (1H, vbr s, CO2H), 7.90 (1H, d,
J 14.1, alkenyl-H), 11.03 (1H, m, NH) (Found: C, 64.0; H,
8.1; N, 4.8. C15H23NO4 requires C, 64.0; H, 8.3; N, 5.0%).
8
DL-5,5-Dimethyl-2-(1-carboxy-2-methylpropylamino-
methylene)cyclohexane-1,3-dione 5e. From 4b and -valine as
off-white microcrystals from hexane and ethanol (yield 88%),
mp 184.0–188.0 ЊC (lit.12 mp 200–201 ЊC); νmax(KBr) 3438,
2508, 1730, 1656, 1591 cmϪ1; δH 1.05 (12H, m, 5-Me,
CH(CH3)2), 2.32 (1H, m, CH(CH3)2), 2.37 (2H, s, CH2), 2.40
(2H, s, CH2), 3.93 (1H, m, NCHCO2H), 8.12 (1H, d, J 14.2,
alkenyl-H), 10.91 (1H, br s, CO2H), 11.37 (1H, m, NH)
(Found: C, 62.8; H, 7.7; N, 5.0. C14H21NO4 requires C, 62.9; H,
7.9; N, 5.2%).
1
DL-(E )- and DL-(Z)-Ethyl 2-(1-carboxy-1-phenylmethyl-
aminomethylene)-3-oxobutanoate 2a. From 1a and -2-phenyl-
glycine as a pale yellow solid (yield 73%), mp 128–130 ЊC;
νmax(KBr) 3440, 2983, 2517, 1729, 1691 cmϪ1; δH (major E-
isomer) 1.22 (3H, t, J 7.1, CH2CH3), 2.45 (3H, s, Me), 4.12
(2H, q, J 7.1, CH2CH3), 5.14 (1H, d, J 6.9, NCHCO2H),
7.36–7.38 (5H, m, Ar–H), 7.94 (1H, d, J 13.9, alkenyl-H), 11.19
(1H, br s, CO2H), 11.68 (1H, m, NH); δH (minor Z-isomer) 1.32
(3H, t, J 7.2, CH2CH3), 2.39 (3H, s, Me), 4.24 (2H, q, J 7.2,
CH2CH3), 5.18 (1H, d, J 6.9, NCHCO2H), 7.34–7.36 (5H, m,
Ar–H), 8.19 (1H, d, J 13.8, alkenyl-H), 10.06 (1H, m, NH),
11.19 (1H, br s, CO2H) (Found: C, 61.7; H, 5.9; N, 4.7.
C15H17NO5 requires C, 61.8; H, 5.9; N, 4.8%).
9
2-(1-Carboxymethylaminomethylene)indanone 16a. From
15a and glycine, from hexane and ethanol as pale brown cubes
(yield 73%), mp 187.0–193.0 ЊC (decomp.); νmax(KBr) 3245,
1731, 1651, 1608 cmϪ1; δH (DMSO-d6) 3.52 (2H, s, 3-CH2), 4.09
(2H, d, J 6.1, NCH2CO2H), 7.19 (1H, d, J 12.8, alkenyl-H), 7.36
(1H, m, Ar–H), 7.49 (3H, m, Ar–H), 9.31 (1H, m, NH), 12.9
(1H, br s, OH) (Found: C, 66.3; H, 5.1; N, 6.4. C12H11NO3
requires C, 66.4; H, 5.1; N, 6.5%).
2
Diethyl 2-(1-carboxymethylaminomethylene)propane-1,3-
dicarboxylate 2b. From 1b and glycine as a fluffy off-white
solid (yield 69%), mp 138–140 ЊC; νmax(KBr) 3313, 2990, 1715,
1680, 1626 cmϪ1; δH 1.65 (6H, m, 2 × CH2CH3), 4.04 (6H, m,
2 × CH2CH3, NCH2CO2H), 7.80 (1H, d, J 14.2, alkenyl-H),
9.15 (1H, m, NH), 9.60 (1H, br s, CO2H) (Found: C, 49.1; H,
6.1; N, 5.7. C10H15NO6 requires C, 49.0; H, 6.2; N, 5.7%).
10 DL-2-(1-Carboxy-1-phenylmethylaminomethylene)-
indane-1,3-dione 16b. From 15b and -2-phenylglycine, from
ethanol as a fluffy yellow solid (yield 85%), mp 210.5–215.0 ЊC
(decomp.); νmax(KBr) 3273, 3068, 3032, 1727, 1702, 1651, 1605
cmϪ1; δH (DMSO-d6) 5.45 (1H, d, J 6.1, NCHCO2H), 7.19
(5H, m, Ar–H), 7.45 (4H, m, Ar–H), 7.63 (1H, d, J 14.3,
alkenyl-H), 9.77 (1H, dd, J 14.3, 7.2, NH), 13.2 (1H, br s, OH)
(Found: C, 70.3; H, 4.1; N, 4.3. C18H13NO4 requires C, 70.4; H,
4.3; N, 4.6%).
3
DL-Diethyl 2-(1-carboxy-1-phenylmethylaminomethylene)-
propane-1,3-dicarboxylate 2c. From 1b and -2-phenylglycine
as an off-white solid (yield 53%†); δH 1.25 (6H, m, 2 ×
CH2CH3), 4.12 (4H, m, 2 × CH2CH3), 5.06 (1H, d, J 6.7,
NCHCO2H), 7.29–7.33 (5H, m, Ar–H), 7.90 (1H, d, J 9.1,
alkenyl-H), 8.52 (1H, br s, CO2H), 9.90 (1H, m, NH).
11 2-(1-Carboxymethylaminomethylene)-1,2,3,4-tetrahydro-
naphthalen-1-one 19a. From 18a and glycine as yellow micro-
crystals from hexane and ethanol (yield 74%), mp 192.0–196.0
ЊC (decomp.); νmax(KBr) 3406, 2523, 1733, 1641, 1604, 1580
cmϪ1; δH (DMSO-d6) 2.50 (2H, m, CH2), 2.79 (2H, m, CH2),
4.02 (2H, d, J 7.7, NCH2CO2H), 7.02 (1H, d, J 12.6, alkenyl-H),
7.18–7.56 (3H, m, Ar–H), 7.81 (1H, d, J 7.6, 8-H), 9.92 (1H, br
m, NH), 12.9 (1H, br s, OH) (Found: C, 67.3; H, 5.6; N, 6.0.
C13H13NO3 requires C, 67.5; H, 5.7; N, 6.1%).
4
DL-2-(1-Carboxy-1-phenylmethylaminomethylene)cyclo-
hexane-1,3-dione 5a. From 4a and -2-phenylglycine as a
cream solid (yield 83%), mp 164–166 ЊC; νmax(KBr) 3446, 2551,
1730, 1665, 1580, 1557 cmϪ1; δH 1.92 (2H, m, 5-CH2), 2.47 (4H,
m, 2 × CH2), 5.22 (1H, d, J 6.8, NCHCO2H), 6.36 (1H, br s,
CO2H), 7.34–7.38 (5H, m, Ar–H), 8.18 (1H, d, J 14.2, alkenyl-
H), 11.95 (1H, m, NH) (Found: C, 65.9; H, 5.4; N, 5.0.
C15H15NO4 requires C, 65.9; H, 5.5; N, 5.1%).
5
DL-2-(1-Carboxy-3-methylthiopropylaminomethylene)-
12 DL-2-(1-Carboxy-1-phenylmethylaminomethylene)-
1,2,3,4-tetrahydronaphthalen-1-one 19b. From 18a and
-2-phenylglycine as a pale yellow solid (yield 74%), mp
cyclohexane-1,3-dione 5b. From 4a and -methionine as a
cream solid (yield 85%), mp 166–167 ЊC; νmax(KBr) 3424, 3212,
2571, 1724, 1657, 1608, 1581, 1544 cmϪ1; δH 1.95–2.65 (10H, m,
4,5,6-CH2, MeS(CH2)2), 2.13 (3H, s, SMe), 4.36 (1H, m, NCH-
CO2H), 5.07 (1H, br s, CO2H), 8.22 (1H, d, J 14.1, alkenyl-H),
11.31 (1H, m, NH) (Found: C, 53.0; H, 6.3; N, 5.1. C12H17NO4S
requires C, 53.1; H, 6.3; N, 5.2%).
104.0–107.0 ЊC; νmax(KBr) 3417, 2661, 1728, 1636, 1601 cmϪ1
;
δH (DMSO-d6) 2.48 (2H, m, CH2), 2.78 (2H, m, CH2), 5.29
(1H, d, J 7.8, NCH2CO2H), 7.04 (1H, d, J 12.5, alkenyl-H),
7.23–7.42 (8H, m, Ar–H), 7.82 (1H, d, J 7.8, 8-H), 10.64 (1H,
m, NH) (Found: C, 74.0; H, 5.3; N, 4.6. C19H17NO3 requires C,
74.2; H, 5.6; N, 4.6%).
6
DL-5,5-Dimethyl-2-(1-carboxy-1-phenylmethylamino-
methylene)cyclohexane-1,3-dione 5c. From 4b and -phenyl-
glycine as a pale yellow solid (yield 81%), mp 177–178 ЊC;
νmax(KBr) 3423, 2546, 1724, 1654, 1587, 1550 cmϪ1; δH 0.83 (6H,
s, 5-Me), 2.09 (2H, s, CH2), 2.17 (2H, s, CH2), 4.97 (1H, d, J 6.9,
NCHCO2H), 7.13–7.18 (5H, m, Ar–H), 7.83 (1H, d, J 14.1,
alkenyl-H), 9.54 (1H, br s, CO2H), 11.62 (1H, m, NH) (Found:
C, 67.5; H, 6.3; N, 4.6. C17H19NO4 requires C, 67.8; H, 6.4; N,
4.7%).
13 DL-2-(1-Carboxy-3-methylthiopropylaminomethylene)-
1,2,3,4-tetrahydronaphthalen-1-one 19c. From 18a and -
methionine as a bright yellow solid (yield 74%), mp 163.0–165.0
ЊC; νmax(KBr) 3417, 2494, 1712, 1632, 1601, 1577, 1499 cmϪ1; δH
(DMSO-d6) 1.99 (2H, m, CH2), 2.06 (3H, s, SMe), 2.53 (4H, m,
2 × CH2), 2.79 (2H, m, CH2), 4.14 (1H, m, NCHCO2H), 7.04
(1H, d, J 13.1, alkenyl-H), 7.20–7.36 (3H, m, Ar–H), 7.81 (1H,
d, J 7.8, 8-H), 10.13 (1H, m, NH) (Found: C, 62.8; H, 6.3; N,
4.4. C16H19NO3S requires C, 62.9; H, 6.3; N, 4.6%).
7
L-5,5-Dimethyl-2-(1-carboxy-3-methylbutylamino-
methylene)cyclohexane-1,3-dione 5d. From 4b and -leucine as a
pale yellow solid (yield 94%), mp 168–170 ЊC; νmax(KBr) 3444,
14 DL-2-(1-Carboxy-3-methylsulfinylpropylamino-
methylene)-1,2,3,4-tetrahydronaphthalen-1-one 19d. From 18a
and -methionine sulfoxide as a dull yellow solid (yield 67%),
mp 117.5–121.0 ЊC; νmax(KBr) 3423, 2479, 1712, 1631, 1600,
† Yield of crude material that was cyclised directly to 3c.
2804
J. Chem. Soc., Perkin Trans. 1, 2002, 2799–2808

View Article Online
1576, 1475, 1379 cmϪ1; δH (DMSO-d6) 2.30–3.00 (8H, br m, 4 ×
CH2), 2.69 (3H, s, S(O)Me), 4.18 (1H, m, NCHCO2H), 7.17–
7.50 (4H, m, Ar–H and alkenyl-H), 7.96 (1H, dd, J 8.0, 1.6, 8-
H), 10.30 (1H, m, NH) (Found: C, 59.5; H, 5.9; N, 4.3.
C16H19NO4S requires C, 59.8; H, 6.0; N, 4.4%).
76%), mp 157.0–160.0 ЊC (decomp.); νmax(KBr) 3471, 3219,
3055, 2960, 1717, 1635, 1590 cmϪ1; δH 1.39 (3H, d, J 6.7, 2-Me),
3.94 (1H, q, J 6.7, 2-H), 4.06 (2H, d, J 5.7, NCH2CO2H),
7.16–7.51 (4H, m, Ar–H and alkenyl-H), 7.70 (1H, br s, CO2H),
7.91 (1H, dd, J 8.0, 1.7, 5-H), 10.15 (1H, m, NH) (Found: C,
59.2; H, 4.9; N, 5.6; S, 12.0. C13H13NO3S requires C, 59.3; H,
5.0; N, 5.3; S, 12.2%).
15 L-2-[1-Carboxy-3-(methoxycarbonyl)propylamino-
methylene]-1,2,3,4-tetrahydronaphthalen-1-one 19e. From 18a
and -glutamic acid 5-methyl ester as a yellow solid (yield 78%),
mp 153.0–155.0 ЊC; νmax(KBr) 3418, 2949, 2841, 1733, 1642,
1602 cmϪ1; δH 2.21 (2H, m, CH2), 2.52 (4H, m, 2 × CH2), 2.85
(2H, m, CH2), 3.67 (3H, s, CO2Me), 3.98 (1H, m, NCHCO2H),
6.81 (1H, d, J 9.1, alkenyl-H), 7.18 (1H, d, J 7.4, 5-H), 7.33 (2H,
m, Ar–H), 7.86 (1H, br s, CO2H), 7.97 (1H, dd, J 7.8, 1.4, 8-H),
10.29 (1H, m, NH) (Found: C, 64.3; H, 6.0; N, 4.4. C17H19NO5
requires C, 64.3; H, 6.1; N, 4.4%).
22 DL-3-(1-Carboxy-1-phenylmethylaminomethylene)-2,3-
dihydro-2-methyl-4H-1-benzothiopyran-4-one 19k. From 18e
and -phenylglycine (yield 83%‡); δH (DMSO-d6) 1.36 (3H, d,
J 7.0, 2-Me), 3.93 (1H, q, J 7.0, 2-H), 4.05 (2H, d, J 5.9,
NCH2CO2H), 7.31 (5H, m, Ar–H, alkenyl-H and CO2H), 7.89
(1H, dd, J 8.4, 1.7, 5-H), 10.15 (1H, m, NH).
23 3-(Carboxymethylaminomethylene)-2,3-dihydro-2,2-
dimethyl-4H-1-benzothiopyran-4-one 19l. From 18f and glycine,
from ethyl acetate and methanol as bright yellow microcrytals
(yield 86%), mp 245.0–247.0 ЊC; νmax(KBr) 3400, 1720, 1635,
1590 cmϪ1; δH (DMSO-d6) 1.52 (6H, s, 2-Me), 3.73 (2H, d, J 5.1,
NCH2CO2H), 7.30 (4H, m, Ar–H and alkenyl-H), 7.91 (1H, dd,
J 8.7, 1.8, 5-H), 10.62 (1H, br m, NH) (Found: C, 60.3; H, 5.2;
N, 5.0. C14H15NO3S requires C, 60.6; H, 5.5; N, 5.1%).
16 DL-1-(1-Carboxy-1-phenylmethylaminomethylene)-
1,2,3,4-tetrahydronaphthalen-2-one 23. From 22 and -2-
phenylglycine as a bright yellow solid (yield 53%), mp 73.0–76.0
ЊC; νmax(KBr) 3422, 1728, 1639, 1599, 1565 cmϪ1; δH 2.54
(2H, m, CH2), 2.85 (2H, m, CH2), 5.18 (1H, d, J 6.1, NCH2-
CO2H), 6.99–7.46 (10H, m, (9-Ar–H), (alkenyl-H)), 8.04
(1H, br s, CO2H), 11.19 (1H, m, NH) (Found: C, 74.1; H, 5.5;
N, 4.4. C19H17NO3 requires C, 74.2; H, 5.6; N, 4.6%).
24 DL-3-(1-Carboxy-1-phenylmethylaminomethylene)-2,3-
dihydro-2,2-dimethyl-4H-1-benzothiopyran-4-one 19m. From
18f and -2-phenylglycine, from ethyl acetate as a bright
yellow solid (yield 73%), mp 120.0–121.5 ЊC; νmax(KBr) 3427,
1729, 1629, 1588, 1567 cmϪ1; δH (DMSO-d6) 1.07 (3H, s, 2-Me),
1.10 (3H, s, 2-Me), 4.61 (1H, d, J 7.0, NCHCO2H), 6.58 (1H, d,
J 12.6, alkenyl-H), 6.77–7.02 (8H, m, Ar–H), 7.61 (1H, d, J 8.5,
5-H), 10.86 (1H, br m, NH) (Found: C, 67.8; H, 5.1; N, 3.9.
C20H19NO3S requires C, 68.0; H, 5.4; N, 4.0%).
17 2-(1-Carboxymethylaminomethylene)-4,5-dihydro-3H-
benzocycloheptan-1(2H)-one 19f. From 18b and glycine as a
bright yellow solid (yield 58%), mp 181.0–184.0 ЊC (decomp.);
νmax(KBr) 3427, 2932, 1740, 1636, 1600 cmϪ1; δH 1.69 (2H, m,
CH2), 1.83 (2H, m, CH2), 2.47 (2H, m, CH2), 3.80 (2H, d, J 6.7,
NCH2CO2H), 6.49 (1H, d, J 13.9, alkenyl-H), 6.92 (1H, m,
Ar–H), 7.08 (2H, m, Ar–H), 7.34 (1H, dd, J, 7.8, 1.5, 9-H), 8.51
(1H, vbr s, CO2H), 9.93 (1H, m, NH) (Found: C, 68.2; H, 6.0;
N, 5.6. C14H15NO3 requires C, 68.5; H, 6.2; N, 5.7%).
25 DL-3-(1-Carboxyethylaminomethylene)-2,3-dihydro-2,2-
dimethyl-4H-1-benzothiopyran-4-one 19n. From 18f and
-alanine as bright yellow microcrystals from ethyl acetate
and hexane (yield 62%), mp 170.0–172.0 ЊC; νmax(KBr) 3423,
2561, 1718, 1635, 1589, 1566 cmϪ1; δH 1.58 (6H, s, 2-Me), 1.62
(3H, d, J 7.9, NCHCH3), 4.06 (1H, q, J 7.9, NCHCH3), 7.00
(1H, d, J 12.2, alkenyl-H), 7.19–7.35 (3H, m, Ar–H), 8.05 (1H,
d, J 8.0, 5-H), 8.16 (1H, br s, CO2H), 10.78 (1H, br m, NH)
(Found: C, 61.9; H, 5.9; N, 4.8; S, 10.8. C15H17NO3S requires C,
61.8; H, 5.9; N, 4.8; S, 11.0%).
18 DL-2-(1-Carboxy-3-methylthiopropylaminomethylene)-
4,5-dihydro-3H-benzocycloheptan-1(2H)-one 19g. From 18b
and -methionine as a bright yellow solid (yield 69%), mp
108.0–111.0 ЊC; νmax(KBr) 3417, 2533, 1717, 1635, 1601 cmϪ1
;
δH 1.88–2.10 (6H, m, 3 × CH2), 2.06 (3H, s, SMe), 2.65 (4H, m,
2 × CH2), 4.15 (1H, m, NCHCO2H), 6.79 (1H, d, J 13.8,
alkenyl-H), 7.14 (1H, m, Ar–H), 7.24–7.25 (2H, m, Ar–H), 7.57
(1H, d, J 8.2, 9-H), 8.46 (1H, br s, CO2H), 10.35 (1H, m, NH)
(Found: C, 63.9; H, 6.5; N, 4.2. C17H21NO3S requires C, 63.9; H,
6.6; N, 4.4%).
26 3-(1-Cyanomethylaminomethylene)-2,3-dihydro-2,2-
dimethyl-4H-1-benzopyran-4-one 25. From 18f and 2-amino-
acetonitrile as pale yellow cubes from ethyl acetate and hexane
(yield 79%), mp 140.0–141.0 ЊC; νmax(Nujol) 3280, 2220, 1648,
1605 cmϪ1; δH (DMSO-d6) 1.58 (6H, s, 2-Me), 4.16 (2H, d, J 5.9,
NCH2CN), 6.77 (1H, d, J 12.0, alkenyl-H), 6.88 (1H, d, J 7.9,
8-H), 6.99 (1H, m, 6-H), 7.39 (1H, m, 7-H), 7.85 (1H, dd, J 7.0,
1.4, 5-H), 10.20 (1H, m, NH) (Found: C, 69.5; H, 5.9; N, 11.6.
C14H14N2O2 requires C, 69.4; H, 5.8; N, 11.6%).
19 3-(Carboxymethylaminomethylene)-2,3-dihydro-2,2-
dimethyl-4H-1-benzopyran-4-one 19h. From 18c and glycine,
from methanol as lemon coloured cubes (yield 80%), mp 166–
168 ЊC (decomp.); νmax(Nujol) 3600–2400 (br), 1718, 1635, 1605
cmϪ1; δH (DMSO-d6) 1.51 (6H, s, 2-Me), 4.13 (2H, d, J 7.0,
NCH2CO2H), 6.80–7.84 (5H, Ar–H and alkenyl-H), 10.25
(1H, m, NH), 12.62 (1H, br s, CO2H) (Found: C, 64.3; H, 6.0;
N, 5.4. C14H15NO4 requires C, 64.3; H, 5.8; N, 5.4%).
General method for the cyclisation of the carboxymethylamino-
methylene derivatives
20 3-(Carboxymethylaminomethylene)-3,4-dihydrospiro-
[1-benzopyran-2,1Ј-cyclohexan]-4-one 19i. From 18d and glycine,
from methanol as a bright yellow solid (yield 73%), mp 186–187
ЊC (decomp.); νmax(Nujol) 3600–2400 (br), 1720, 1635, 1600
cmϪ1; δH (DMSO-d6) 1.55–2.08 (10H, m, -(CH2)5-), 4.13 (2H, d,
J 6.0, NCH2CO2H), 6.86 (1H, d, J 7.7, 8-H), 7.00 (1H, m, 6-H),
7.19 (1H, d, J 12.6, alkenyl-H), 7.39 (1H, m, 7-H), 7.73 (1H, dd,
J 7.7, 1.7, 5-H), 10.31 (1H, m, NH), 12.80 (1H, br s, CO2H)
(Found: C, 67.7; H, 6.4; N, 4.7. C17H19NO4 requires C, 67.8; H,
6.4; N, 4.7%).
The carboxymethylaminomethylene derivatives (10 mmol) and
triethylamine (10 cm3) were refluxed in acetic anhydride (30
cm3) until the vigorous evolution of CO2 (limewater bubbler)
ceased, after approximately 30 min, and then allowed to cool
to RT. The resulting dark red solution was poured into water
(400 cm3) and stirred for 1 h and extracted with CH2Cl2 (4 × 50
cm3). The combined organic extracts were washed with water
(2 × 100 cm3), saturated NaHCO3 solution (5 × 50 cm3) and
finally with water (100 cm3). Removal of the dried (Na2SO4)
solvent afforded a red–brown oil which either crystallised on
standing or was eluted from silica. The following compounds
were isolated by this protocol.
21 3-(1-Carboxymethylaminomethylene)-2,3-dihydro-2-
methyl-4H-1-benzothiopyran-4-one 19j. From 18e and glycine as
a bright yellow solid from ethyl acetate and methanol (yield
‡ Yield of crude material that was cyclised directly to 20j.
J. Chem. Soc., Perkin Trans. 1, 2002, 2799–2808
2805

View Article Online
1
Ethyl 1-acetyl-4-methyl-5-phenylpyrrole-3-carboxylate 3a.
CH2), 2.92 (2H, m, CH2), 6.69 (1H, d, J 8.2, 9-H), 6.88 (1H, m,
From 2a as a pale yellow solid after elution from silica with
30% EtOAc in hexane (yield 48%), bp 120 ЊC at 7 × 10Ϫ2
mmHg, mp 76.5–78.0 ЊC; νmax(KBr) 1714, 1701 cmϪ1; δH 1.36
(3H, t, J, 7.2, CH2CH3), 2.08 (3H, s, 4-Me), 2.21 (3H, s, N–Ac),
4.29 (2H, q, J 7.2, CH2CH3), 7.23–7.25 (2H, m, Ar–H), 7.36–
7.41 (3H, m, Ar–H), 7.93 (1H, s, 2-H); δC 10.6, 14.3, 24.7, 59.9,
118.0, 123.2, 125.7, 128.1, 128.2 (2 × C), 130.4 (2 × C), 131.6,
132.6, 164.4, 166.5 (Found: C, 70.8; H, 6.4; N, 5.1. C16H17NO3
requires C, 70.8; H, 6.3; N, 5.2%).
Ar–H), 7.05 (1H, m, Ar–H), 7.19 (1H, d, J 8.1, Ar–H), 7.22
(1H, s, 3-H), 7.46 (5H, m, Ar–H) (Found: C, 83.6; H, 5.9; N,
4.8. C20H17NO requires C, 83.6; H, 6.0; N, 4.9%).
7
2-Acetyl-4,5-dihydro-3-phenyl-2H-benzo[e]isoindole 24.
From 23 from light petroleum (bp 40–60 ЊC) after elution from
silica with 30% EtOAc in hexane (yield 56%), mp 61.5–63.5 ЊC;
νmax(KBr) 1728 cmϪ1; δH 2.27 (3H, s, N–Ac), 2.59 (2H, m, CH2),
2.86 (2H, m, CH2), 7.27 (3H, m, Ar–H), 7.31 (5H, m, Ar–H),
7.54 (1H, d, J 8.2, 9-H), 7.64 (1H, s, 1-H) (Found: C, 83.7; H,
6.0; N, 4.9. C20H17NO requires C, 83.6; H, 6.0; N, 4.9%).
2
Ethyl 4-acetoxy-1-acetylpyrrole-3-carboxylate 3b. From
2b as a colourless oil after elution from silica with 20% EtOAc
in hexane (yield 57%), bp 220 ЊC at 1 × 10Ϫ1 mmHg; νmax(KBr)
1745, 1710 cmϪ1; δH 1.32 (3H, t, J 7.3, CH2CH3), 2.30 (3H, s,
O–Ac), 2.54 (3H, s, N–Ac), 4.26 (2H, q, J 7.3, CH2CH3), 7.25
(1H, d, J 2.1, 5-H), 7.78 (1H, d, J 2.1, 2-H); δC 14.2, 20.5, 21.5,
60.3, 110.2, 113.3, 122.5, 138.2, 162.0, 166.8, 168.6 (Found: C,
54.9; H, 5.5; N, 5.7. C11H13NO3 requires C, 55.2; H, 5.5; N,
5.9%).
8
2-Acetyl-1-[2-(methylthio)ethyl]-4,5-dihydro-2H-benzo[e]-
isoindole 20c. From 19c from ethyl acetate and hexane after
elution from silica with 20% EtOAc in hexane (yield 46%), mp
113.0–114.0 ЊC; νmax(KBr) 1702 cmϪ1; δH 2.26 (3H, s, SMe), 2.56
(3H, s, N–Ac), 2.63 (2H, m, CH2), 3.89 (4H, m, 2 × CH2), 3.48
(2H, m, CH2), 6.87 (1H, s, 3-H), 7.24 (3H, m, Ar–H), 7.55 (1H,
dd, J, 8.4, 1.9, 9-H) (Found: Mϩ, 285.1187; C, 71.9; H, 6.8; N,
5.0; S, 11.3. C17H19NOS requires Mϩ, 285.1187(38); C, 71.5; H,
6.7; N, 4.9; S, 11.2%).
3
Ethyl 4-acetoxy-1-acetyl-5-phenylpyrrole-3-carboxylate
3c. From 2c as colourless needles from hexane and EtOAc after
elution from silica with 30% EtOAc in hexane (yield 51%), mp
122.0–124.0 ЊC; νmax(KBr) 1750, 1715, 1699 cmϪ1; δH 1.32 (3H,
t, J 7.1, CH2CH3), 2.17 (3H, s, Ac), 2.27 (3H, s, Ac), 4.28 (2H, q,
J 7.1, CH2CH3), 7.25–7.30 (2H, m, Ar–H), 7.37–7.41 (3H, m,
Ar–H), 7.90 (1H, s, 2-H) (Found: C, 64.6; H, 5.4; N, 4.3.
C17H17NO5 requires C, 64.7; H, 5.4; N, 4.4%).
9
2-Acetoxymethylene-1,2,3,4-tetrahydronaphthalen-1-one
21. From 19d from hexane as colourless needles (yield 24%), mp
129.5–131.5 ЊC; δH 2.26 (3H, s, O–Ac), 2.87–2.95 (4H, m, 2 ×
CH2), 7.23 (1H, d, J 7.8, 5-H), 7.35 (1H, m, Ar–H), 7.45 (1H, m,
Ar–H), 8.07 (1H, dd, J 7.6, 1.1, 8-H), 8.38 (1H, t, J 1.7, alkenyl-
H) and 1-[2-(acetoxymethylthio)ethyl]-2-acetyl-4,5-dihydro-
2H-benzo[e]isoindole 20d as colourless microcrystals from ethyl
acetate and hexane after elution from silica with 20% EtOAc in
hexane (yield 51%), mp 97.0–98.5 ЊC; νmax(KBr) 1741, 1704,
1696 cmϪ1; δH 2.09 (3H, s, Ac), 2.55 (3H, s, Ac), 2.63 (2H, m,
CH2), 2.81 (2H, m, CH2), 3.06 (2H, m, CH2), 3.51 (2H, m,
CH2), 5.29 (2H, s, AcOCH2S), 6.87 (1H, d, J 1.0, 3-H), 7.23
(3H, m, Ar–H), 7.52 (1H, dd, J 8.1, 1.6, 9-H) (Found: C, 66.4;
H, 6.2; N, 4.1; S, 9.4. C19H21NO3S requires C, 66.4; H, 6.2; N,
4.1; S, 9.3%).
4
4-Acetoxy-2-acetyl-6,7-dihydro-1-phenylisoindole
6a.
From 5a as pale yellow needles from light petroleum (bp 40–60
ЊC) and diethyl ether after elution from silica with 30% EtOAc
in hexane (yield 69%), mp 74.5–76.0 ЊC; νmax(KBr) 1751, 1713
cmϪ1; δH 2.17 (3H, s, Ac), 2.27 (3H, s, Ac), 2.46 (4H, m, 6,7-
CH2), 5.55 (1H, t, J 4.4, 5-H), 7.12 (1H, s, 3-H),7.25–7.42 (5H,
m, Ar–H) (Found: C, 66.9; H, 6.3; N, 5.9. C18H17NO3 requires
C, 66.9; H, 6.5; N, 6.0%).
A solution of the aforegoing isoindole 6a (4.0 mmol) in 80%
aqueous acetic acid (25 cm3) and conc. HCl (2 cm3) was main-
tained at 100 ЊC for 15 min. The cooled solution was poured
into water (200 cm3) and extracted with ethyl acetate (3 × 50
cm3). The combined extracts were washed with water (2 × 100
cm3), aqueous saturated NaHCO3 (4 × 50 cm3) and water (100
cm3). Removal of the dried (Na2SO4) ethyl acetate and elution
of the dark brown solid from silica with 40% EtOAc in hexane
gave 4-oxo-1-phenyl-4,5,6,7-tetrahydroisoindole 7 (92%), mp
167.0–173.5 ЊC (decomp.) as grey microcrystals from hexane
and ethyl acetate; δH 2.07 (2H, m, 6-CH2), 2.52 (2H, t, J 6.1,
7-CH2), 2.88 (2H, t, J 6.2, 5-CH2), 7.25–7.47 (6H, m, Ar–H,
3-H), 9.70 (1H, br s, NH); δC 22.6, 25.0, 39.1, 120.2, 123.1, 125.7
(2 × C), 126.5 (2 × C), 127.3, 128.8 (2 × C), 132.2, 196.9
(Found: Mϩ, 211.0997; C, 79.4; H, 6.2; N, 6.5. C14H13NO
requires Mϩ, 211.0997(14); C, 79.6; H, 6.2; N, 6.6%).
10 2-Acetyl-4,5-dihydro-1-[2-(methoxycarbonyl)ethyl]-2H-
benzo[e]isoindole 20e. From 19e as very pale brown needles
from ethyl acetate, hexane and light petroleum (bp 40–60 ЊC)
(yield 64%), mp 112.5–114.0 ЊC; νmax(KBr) 1734, 1702 cmϪ1; δH
2.53 (3H, s, N–Ac), 2.62 (2H, m, CH2), 2.81 (4H, m, 2 × CH2),
3.52 (2H, m, CH2), 3.68 (3H, s, CO2Me), 6.85 (1H, s, 3-H), 7.17
(1H, m, Ar–H), 7.25 (2H, m, Ar–H), 7.52 (1H, d, J 8.2, 9-H); δC
21.0, 23.5, 24.6, 30.9, 33.5, 51.6, 114.9, 122.9, 124.7, 124.9,
126.4, 126.9, 128.7, 129.5, 130.8, 137.6, 169.2, 173.4 (Found: C,
72.6: H, 6.6; N, 4.5. C18H19NO3 requires C, 72.7; H, 6.5; N,
4.5%).
11 2-Acetyl-2,4,5,6-tetrahydrobenzo[3,4]cyclohepta[1,2-c]-
pyrrole 20f. From 19f as a pale yellow oil (yield 57%), bp
180 ЊC at 1 × 10Ϫ1 mmHg; νmax(Nujol) 1707 cmϪ1; δH 2.08
(2H, m, 5-CH2), 2.49 (2H, m, CH2), 2.55 (3H, s, N–Ac), 2.68
(2H, m, CH2), 7.23–7.37 (6H, m, Ar–H, 1-H, 3-H) (Found: C,
79.8; H, 6.7; N, 6.4. C15H15NO requires C, 80.0; H, 6.7; N,
6.2%).
5
4-Acetoxy-2-acetyl-6,7-dihydro-6,6-dimethyl-1-phenyl
isoindole 6b. From 5c as colourless needles from hexane, light
petroleum (bp 40–60 ЊC) and ether (yield 72%), mp 89.5–92.0
ЊC; νmax(KBr) 1755, 1717 cmϪ1; δH 1.09 (6H, s, 6-Me), 2.18 (3H,
s, Ac), 2.25 (3H, s, Ac), 2.34 (2H, s, 7-CH2), 5.36 (1H, s, 5-H),
7.11 (1H, s, 3-H), 7.28–7.40 (5H, m, Ar–H); δC 20.9, 24.9, 28.8
(2 × C), 34.3, 34.6, 113.0, 118.0, 124.1, 125.3 (2 × C), 127.8,
128.2 (2 × C), 129.2 (2 × C), 132.9, 141.1, 168.5, 168.9 (Found:
C, 74.1; H, 6.5; N, 4.3. C20H21NO3 requires C, 74.3; H, 6.6; N,
4.3%).
12 2-Acetyl-2,4,5,6-tetrahydro-1-[2-(methylthio)ethyl]-
benzo[3,4]cyclohepta[1,2-c]pyrrole 20g. From 19g as colourless
crystals from light petroleum (bp 40–60 ЊC) and ethyl acetate
after elution from silica with 30% EtOAc in hexane (yield 64%),
mp 92.5–94.0 ЊC; νmax(KBr) 1707 cmϪ1; δH 2.00 (2H, m, 5-CH2),
2.03 (3H, s, SMe), 2.36 (2H, m, CH2), 2.56 (3H, s, N–Ac), 2.61
(2H, m, CH2), 2.78 (2H, m, CH2), 3.30 (2H, m, CH2), 6.87
(1H, s, 3-H), 7.23–7.29 (4H, m, Ar–H); δC 14.9, 21.9, 24.4, 27.0,
29.0, 32.1, 33.8, 115.8, 126.3, 126.6, 127.1, 128.2, 128.7, 129.3,
130.1, 134.2, 140.4, 168.8 (Found: Mϩ, 299.1344; C, 72.2; H,
7.1; N, 4.6; S, 10.8. C18H21NOS requires Mϩ, 299.1343(88); C,
72.2; H, 7.1; N, 4.7; S, 10.7%).
6
2-Acetyl-4,5-dihydro-1-phenyl-2H-benzo[e]isoindole 20b.
From 19b from hexane and ethyl acetate after elution from
silica with 30% EtOAc in hexane (yield 69%), mp 102.0–104.0
ЊC; νmax(KBr) 1718 cmϪ1; δH 2.17 (3H, s, N–Ac), 2.74 (2H, m,
2806
J. Chem. Soc., Perkin Trans. 1, 2002, 2799–2808

View Article Online
13 2-Acetyl-4,4-dimethyl-2H,4H-1-benzopyrano[3,4-c]-
pyrrole 20h. From 19h as a pale yellow solid from ethyl acetate
and hexane (yield 78%), mp 124.5–125.5 ЊC; δH 1.59 (6H, s,
4-Me), 2.55 (3H, s, N–Ac), 6.95 (2H, m, Ar–H), 7.12 (2H, m,
Ar–H), 7.43 (2H, m, Ar–H) (Found: C, 74.6; H, 6.2; N, 5.7.
C15H15NO2 requires C, 74.7; H, 6.2; N, 5.8%).
Thermolysis of 3-(1-carboxymethylaminomethylene)-2,3-
dihydro-2,2-dimethyl-4H-1-benzopyran-4-one 19h
A solution of 19h (5 mmol) in bromobenzene (25 cm3) was
refluxed until evolution of CO2 (limewater bubbler) ceased and
no starting material remained (TLC, 2.5 h). The bromobenzene
was removed under reduced pressure and the viscous brown
residue eluted with 40% EtOAc in hexane to afford two
fractions. Fraction 1. 2,3-Dihydro-2,2-dimethyl-3-(methylamino-
methylene)-4H-1-benzopyran-4-one 27, mp 128.5–129.0 ЊC,
from hexane (yield 32 %); νmax(Nujol) 3219, 1649 cmϪ1; δH 1.53
(6H, s, 2-Me), 3.03 (3H, d, J 5.2, N–Me), 6.79 (1H, d, J 8.1,
8-H), 6.83 (1H, s, alkenyl-H), 6.98 (1H, m, 6-H), 7.29 (1H, m,
7-H), 7.87 (1H, dd, J 8.3, 1.7, 5-H), 10.23 (1H, br s, NH);
δC 28.7 (2 × C), 35.4, 79.4, 107.0, 117.5, 120.6, 123.2, 126.1,
133.4, 150.4, 157.8, 181.4 (Found: C, 71.8; H, 7.0; N, 6.3.
C13H15NO2 requires C, 71.9; H, 7.0; N, 6.5%). Fraction 2.
3-Isopropenyl-4H-1-benzopyran-4-one 28 from light petroleum
(bp 40–60 ЊC) (yield 36%), mp 57.5–59.0 ЊC [lit.22 mp 57.0–59.0
ЊC]; νmax(Nujol) 1639 cmϪ1; δH 2.10 (3H, s, Me), 5.16 (1H, m,
isopropenyl-H), 5.45 (1H, m, isopropenyl-H), 7.37 (2H, m,
Ar–H), 7.60 (1H, m, Ar–H), 7.88 (1H, s, 2-H), 8.22 (1H, dd,
J 8.3, 1.9, 5-H).
14 2-Acetyl-2H-spiro[1-benzopyrano[3,4-c]pyrrole-4,1Ј-
cyclohexane] 20i. From 19i as pale brown crystals from ethyl
acetate and hexane (yield 62%), mp 145.5–147.0 ЊC; δH 1.28–
1.40 (10H, m, -(CH2)5-), 2.60 (3H, s, N–Ac), 6.80–7.60 (6H, m,
Ar–H) (Found: C, 76.8; H, 6.7; N, 4.8. C18H19NO2 requires C,
76.9; H, 6.7; N, 5.0%).
15 2-Acetyl-4-methyl-1-phenyl-2H,4H-1-benzothio-
pyrano[3,4-c]pyrrole 20j. From 19k from ethyl acetate and
hexane as pale brown microneedles (yield 64%), mp 182.0–
183.5 ЊC; νmax(Nujol) 1728 cmϪ1; δH 1.63 (3H, d, J 6.8, 4-Me),
2.12 (3H, s, N–Ac), 4.16 (1H, dq, J 1.0, 6.8, 4-H), 6.75 (2H, m,
Ar–H), 7.00 (1H, m, Ar–H), 7.24 (1H, d, J 1.0, 3-H), 7.39
(6H, m, Ar–H) (Found: C, 75.1; H, 5.3; N, 4.4; S, 10.4.
C20H17NOS requires C, 75.2; H, 5.4; N, 4.4; S, 10.0%).
A
solution of the aforegoing 3-isopropenyl-4H-1-
16 2-Acetyl-4,4-dimethyl-2H,4H-1-benzothiopyrano[3,4-c]-
pyrrole 20k. From 19l from ethyl acetate and hexane as pale
brown needles (yield 47%), mp 137.5–138.5 ЊC; νmax(Nujol)
1731 cmϪ1; δH 1.63 (6H, s, 4-Me), 2.57 (3H, s, N–Ac), 7.16 (4H,
m, Ar–H, 1-H, 3-H), 7.35 (1H, m, Ar–H), 7.57 (1H, m, Ar–H)
(Found: C, 70.1; H, 5.9; N, 5.4; S, 12.2. C15H15NOS requires C,
70.0; H, 5.9; N, 5.4; S, 12.5%).
benzopyran-4-one 28 (10 mmol) was dissolved in dichloro-
methane (25 cm3). PTAD [prepared according to the procedure
described by Moriarty et al.35] (10 mmol) in dichloromethane
(30 cm3) was added dropwise with stirring. The red colour of
the PTAD was instantly discharged and after stirring for 5 h the
precipitated cycloadduct was collected by vacuum filtration
and washed thoroughly with ether to afford analytically pure
6-methyl-2-phenyl-2,3,5,12a-tetrahydro-1H,7H-[1]benzopyrano-
[2,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3,7-trione
29
as
17 2-Acetyl-4,4-dimethyl-1-phenyl-2H,4H-1-benzothio-
pyrano[3,4-c]pyrrole 20l. From 19m from ethyl acetate and
hexane as colourless needles (yield 53%), mp 194.5–195.5 ЊC;
νmax(Nujol) 1729 cmϪ1; δH 1.65 (6H, s, 4-Me), 2.12 (3H, s,
N–Ac), 6.72–6.80 (2H, m, Ar–H), 7.01 (1H, m, Ar–H), 7.32
(1H, s, 3-H), 7.39–7.48 (6H, m, Ar–H) (Found: C, 75.5; H, 5.6;
N, 4.1; S, 9.3. C21H19NOS requires C, 75.6; H, 5.8; N, 4.2; S,
9.6%).
colourless microcrystals (yield 92%), mp 189.0–205.0 ЊC
(decomp.); νmax(Nujol) 1770, 1715, 1675, 1635 cmϪ1; δH
(DMSO-d6) 2.35 (3H, s, 6-Me), 4.41 (1H, d, J 17.7, 5-H),
4.62 (1H, d, J 17.7, 5-H), 6.83 (1H, s, 12a-H), 7.21 (1H, d, J 8.3,
11-H), 7.30 (1H, m, 9-H), 7.61 (5H, m, Ar–H), 7.70 (1H, m,
10-H), 7.96 (1H, dd, J 8.1, 1.3, 8-H) (Found: C, 66.3; H, 4.1;
N, 11.5. C20H15N3O4 requires C, 66.5; H, 4.2; N, 11.6%).
18 6-Acetoxy-8-acetyl-2,3,4,8-tetrahydro-9-(2-methylthio-
ethyl)-2-oxooxocino[2,3-c]pyrrole 9a. From 5b after elution
from silica with 30% ethyl acetate in hexane, as colourless cubes
from ethyl acetate and hexane (yield 45.4%), mp 151.5–152.5
ЊC, νmax(Nujol) 1759, 1717 cmϪ1, δH 2.15 (3H, s, SMe), 2.35
(3H, s, N–Ac), 2.47 (2H, m, S–CH2), 2.54 (3H, s, OAc), 2.68
(4H, m, 2 × CH2), 3.01 (2H, m, CH2), 5.50 (1H, t, J 4.6,
alkenic-H), 7.23 (1H, s, 7-H); δC 15.2, 19.2, 20.6, 23.5, 25.4,
28.3, 32.3, 100.8, 113.8, 116.1, 125.8, 134.6, 144.5, 168.2, 168.8,
168.9 (Found: C, 57.15; H, 5.85; N, 4.2; S, 9.8 %; MHϩ,
338.1060. C16H19NO5S requires C, 56.9; H, 5.7; N, 4.15; S, 9.5
%; MHϩ, 338.1062).
Acknowledgements
We thank the EPSRC for access to the mass spectrometry
service, University of Wales, Swansea, and the Worshipful
Company of Clothworkers of the City of London for a
Millennium grant for the purchase of a Bruker Avance 400
MHz NMR instrument.
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J 12.3, 3-CH2), 2.68 (1H, dd, J 13.9, 8.3,
CH2CH(CH3)2), 2.65 (3H, s, NAc), 2.81 (1H, dd, J 13.9, 8.3,
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J 12.3, 5-CH2), 7.70 (1H, s, 7-H); δC (299K) 22.1, 23.5,
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305.1627. C17H23NO4 requires C, 66.85; H, 7.60; N, 4.60 %; Mϩ
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