Synthetic studies related to diketopyrrolopyrrole (DPP) pigments. Part 2: The use of esters in place of nitriles in standard DPP syntheses: Claisen-type acylations and furopyrrole intermediates

Article abstract of DOI:10.1016/j.tet.2004.10.027

Ethyl 2-aryl-4,5-dihydro-5-oxopyrrole-3-carboxylates react with esters or acyl halides in the presence of a strong base to give 4-acyl derivatives, which exist predominantly as either E- or Z-enols. These are cyclised, either in solution at temperatures >200°C or by microwave irradiation, to 3,6-disubstituted 1H-furo[3,4-c]pyrrolediones which, after N-protection, are convertible by reaction with primary amines into novel N,N′-disubstituted DPP derivatives. Graphical Abstract.

Full text of DOI:10.1016/j.tet.2004.10.027

Tetrahedron 61 (2005) 727–738
Synthetic studies related to diketopyrrolopyrrole (DPP) pigments.
Part 2: The use of esters in place of nitriles in
standard DPP syntheses: Claisen-type acylations and
furopyrrole intermediates*
a
Colin J. H. Morton,a,b,† Richard L. Riggs,a David M. Smith,a, Nicholas J. Westwood,
*
Philip Lightfoota and Alexandra M. Z. Slawina
aSchool of Chemistry, University of St. Andrews, Purdie Building, St. Andrews, Fife KY16 9ST, Scotland, UK
bCiba Specialty Chemicals Inc., PO Box, CH-4002 Basel, Switzerland
Received 30 July 2004; revised 27 September 2004; accepted 7 October 2004
Available online 21 November 2004
Abstract—Ethyl 2-aryl-4,5-dihydro-5-oxopyrrole-3-carboxylates react with esters or acyl halides in the presence of a strong base to give 4-
acyl derivatives, which exist predominantly as either E- or Z-enols. These are cyclised, either in solution at temperatures O200 8C or by
microwave irradiation,0to 3,6-disubstituted 1H-furo[3,4-c]pyrrolediones which, after N-protection, are convertible by reaction with primary
amines into novel N,N -disubstituted DPP derivatives.
q 2004 Elsevier Ltd. All rights reserved.
The synthesis of 3,6-diaryl derivatives of the 2H,5H-
pyrrolo[3,4-c]pyrrole-1,4-dione (diketopyrrolopyrrole or
DPP) ring system, e.g. 1 (RZAr), is routinely accomplished
by reaction of ethyl 4,5-dihydro-5-oxo-2-phenylpyrrole-3-
carboxylate 2 with aromatic nitriles in the presence of a
strong base such as sodium t-amyloxide,1,2 and non-
aromatic nitriles react similarly with compound 2a to give
analogues of 1 where RZalkyl or cycloalkyl.3 In Part 1 of
this series1 we have described attempts to use a,b-
unsaturated nitriles in these processes: however, the
propensity of such nitriles to undergo conjugate rather
than ‘normal’ addition leads initially to the anions 3 and
thence to the novel cyclopenta[c]pyrrole derivatives 4
(Scheme 1). These products, although highly coloured,
appear to be of limited value as pigments, since when
incorporated into a PVC film, they show a tendency to
migrate out of the latter when it is placed in contact with a
second surface.
1. Results and discussion
The corresponding reactions of the pyrrolinecarboxylate
ester 2a with a,b-unsaturated esters were considered worthy
of investigation, in the expectation that the analogous
products 5 containing an ester group might have potential as
pigments. Reaction of the pyrrolinecarboxylate ester 2a
with ethyl cinnamate and sodium t-amyloxide under reflux
1
gave a bright orange product, the H NMR and infra-red
spectra of which confirmed the presence of both ethyl ester
and amide functionality. However, the mass spectrum
indicated a molecular mass of 361, which was not consistent
with the expected product 5 (molecular mass 359), and the
1H NMR spectrum indicated that the alkenic double bond of
the cinnamate had been retained in the product. An identical
product resulted from reaction of the pyrrolinecarboxylate
ester 2a with methyl cinnamate, indicating that the ester
group in the product originated in compound 2a rather than
the cinnamate. Structure 6 was therefore proposed for this
product, and the overall reaction was recognised as a
Claisen-type acylation (Scheme 2). Direct confirmation of
the structure 6 was sought using X-ray crystallography, but
suitable crystals could not be obtained; it is of course
conceivable that this solid consisted of a mixture of
crystalline tautomers: not only the keto isomer 6 but also,
for example, 6E and 6Z. However, in situ methylation of the
crude reaction product prior to the final acidification (the
* Part 1, see Ref. 1.
Keywords: Acylation; Cyclisation; Microwaves; Pigments; Pyrrolinones.
* Corresponding author. Fax: C44 1 334 463808;
e-mail: dms@st-and.ac.uk
† Present address: Ciba Specialty Chemicals Inc.
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.10.027

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C. J. H. Morton et al. / Tetrahedron 61 (2005) 727–738
Scheme 1.
method already described1 for the methylation of com-
pounds of type 4) gave an orange N-methyl derivative,
the structure of which was confirmed as the E-enol of 7 by
X-ray crystallography (Fig. 1). The coplanarity of the enol
and ester functions, and the relatively short distance
(2.51 A) between the enolic and ester carbonyl oxygens is
consistent with intramolecular hydrogen bonding between
these two functional groups.
9a, the 1H NMR spectrum (in CDCl3) shows the presence of
four ethoxy-groups, with an approximate integral ratio
70:14:5:11. The main product shows, unusually, the quartet
due to the ester methylene group at d 3.56, with the three
other methylene resonances at d 4.10, 3.75 and 3.45,
1
˚
respectively. In most other cases, the H NMR spectrum
contains one major and one minor methylene resonance, one
with d!4 and the other with dO4. Since compounds 6, 7, 8
and 9a are all sharp-melting solids, both by visual
observation and (in some cases) by differential scanning
calorimetry (DSC), it seems a reasonable supposition that in
each case the crystalline isomer isolated is likely to be
the principal isomer in solution; and that those with
d(CH2)!4 are Z-enols whereas those with d(CH2)O4
have the E-configuration.
Other alkyl and aryl esters react similarly with the
pyrrolinecarboxylate ester 2a. The reaction using ethyl
butanoate yielded an almost colourless solid, which was
sufficiently crystalline to be identified by X-ray crystal-
lography as the analogous E-enol 8E (Fig. 2); and the
corresponding reactions of the esters 2a with ethyl benzoate
and sodium t-amyloxide gave a beige-coloured enol, the
isolated crystal of which was, interestingly, the Z-enol 9aZ
(Fig. 3); in this molecule hydrogen bonding is apparent
The fact that some of these Claisen reaction products are
obtained in relatively low yield does not necessarily mean a
low conversion, but difficulty of isolation: for example the
‘one-pot’ preparation of the N-methyl compound 7 from 2a
by acylation followed by in situ methylation gives a higher
overall yield than the two-step sequence in which the
intermediate 6 is isolated and purified.
˚
(O/O distance 2.57 A) between the enolic hydrogen and
the oxygen of the pyrrolinone carbonyl group. Acylations of
the esters 2a and 2b using various acyl chlorides, with
sodium hydride as the base, give broadly similar results:
although this process is more convenient in practice, the
yields of the acylated products 9a–f are generally lower. The
results are tabulated below (Table 1); the zero yield in
several attempted preparations of the p-methoxybenzoyl
analogue 9d was unexpected.
Conversion of these enols into derivatives of DPP requires
three further steps. Rubin,3 Langhals4 and their co-workers
have previously shown that heating of dialkyl 2,3-
dibenzoylsuccinates to ca. 300 8C gives diketofurofurans
10, and that these fused dilactones are converted into N,N0-
diarylated DPPs, 11, by reaction with a primary aromatic
amine in the presence of N,N0-dicyclohexylcarbodiimide
and a catalytic amount of trifluoroacetic acid (Scheme 3(a)).
It is now shown that the aroylated pyrrolinone esters 9a–f
may be similarly cyclised to 3,6-diaryl-1H-furo[3,4-c]-
pyrrole-1,4(5H)-diones 12a–f (Scheme 3(b)), a process
The disparity in configuration between the various isolated
enols is not immediately explicable. It may be that the keto-
isomer and both E- and Z-enols are all present in solution,
and the compound which is isolated in each case is either the
most stable, or the least sterically hindered, or merely the
one which happens to be the least soluble under these
particular conditions. In the case of the benzoyl compound

C. J. H. Morton et al. / Tetrahedron 61 (2005) 727–738
729
Scheme 2.
which presumably involves Z/E isomerisation as the first
step. Heating to 240 8C in Dowthermw A for prolonged
periods gives moderate yields of the cyclised products, but
the yields may be significantly improved and the reaction
times greatly reduced when the cyclisations are carried out
in the cavity of a microwave reactor. The results are
tabulated below (Table 2). Unexpectedly the cinnamoyl and
butanoyl compounds 7 and 8, the principal isomer of which
already has the E-configuration and might have been
expected to undergo cyclisation more readily, underwent
only extensive decomposition under similar conditions, and
no furopyrrole was isolated. This behaviour is also
observable by DSC, where a broad exotherm occurs
immediately above the melting temperatures of both
compounds.
Conversion of the furopyrroles 12a–f into DPP derivatives
by adaptation of the above literature procedures3,4 appears
to require prior protection of the amido-nitrogen: methyl-
ation and benzylation are straightforwardly achieved
by standard procedures, and these derivatives (14 and
13, respectively) then undergo the ring-opening and

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C. J. H. Morton et al. / Tetrahedron 61 (2005) 727–738
˚
Figure 1. X-ray structure of compound 7. Selected bond lengths (A): C(1)–C(5), 1.383(4); C(3)–C(4), 1.370(4); C(5)–C(6), 1.448(5); C(6)–C(7), 1.331(5);
C(2)–O(2), 1.235(4); C(5)–O(1), 1.330(4). Selected interbond angles (8): C(4)–C(1)–C(5), 130.2(3); C(1)–C(2)–N, 105.9(3); C(4)–C(3)–N, 109.9(3); C(1)–
C(4)–C(21), 128.3(5); C(4)–C(21)–O(3), 124.7(3). Selected torsion angles (8): O(1)–C(5)–C(1)–C(4), 0.6(6); C(1)–C(4)–C(21)–O(3), K2.2(6); C(2)–C(1)–
˚
C(5)–O(1), 178.8(3); C(6)–C(7)–C(8)–C(9), K172.8(4); C(4)–(C3)–C(15)– are cts (A): O(1)/O(3), 2.51; O(3)/H(1), 1.70 (estimated).
ring-closure sequence, leading to the N5-protected 2,3,6-
triaryl-DPP derivatives 16 and 15.
2. X-ray crystallography
In the crystals selected for analysis, the enolic nature of each
of compounds 7, 8 and 9a is evident from the observed bond
lengths (see the data accompanying Figs. 1–3). In each case
the length of the carbon–carbon bond joining the acyl group
Langhals et al. had previously shown4 that the conversion
of the furofurans 10 into DPPs 11 required the presence of
N,N0-dicyclohexylcarbodiimide and a catalytic amount of
trifluoroacetic acid; in the absence of such reagents the ring-
closure step did not apparently occur, and the isolated
product3 from the reaction of 10 with aniline alone was
provisionally assigned the structure 17a or 17b, although
definitive proof of structure was lacking. In our series,
however, reaction of the N-methylated furopyrrole 14a with
aniline alone led to the enamine 18a, the structure of which
was established by X-ray crystallography (Fig. 4), and the
product from the corresponding reaction of 14c is the
analogue 18c. This suggests that ring-opening of
the furopyrroles 14 may involve nucleophilic attack by the
amine at C-3 (Scheme 4) rather than at C-1 as implied by the
intermediacy of amides such as 17.
˚
to the pyrroline ring is less than 1.4 A, indicative of
substantial double-bond character, whereas the acyl carbon–
˚
oxygen bond lengths (O1.3 A) are considerably longer than
expected for a normal C]O double bond, such as are found
˚
in the pyrrolinone carbonyl groups (1.23–1.26 A). In
compounds 7 and 8 the coplanar alignment of the enolic
hydroxyl and ester groups, together with the relatively short
distance between the enolic and carbonyl oxygen atoms (ca.
5
˚
2.5 A; well within the accepted range ) is taken as indicative
of intramolecular hydrogen bonding between these two
functionalities. By similar criteria, the crystal of compound
9a reveals a structure in which intramolecular hydrogen
bonding occurs between the enolic hydrogen and the
˚
Figure 2. X-ray structure of compound 8. Selected bond lengths (A): C(3)–C(14), 1.368(4); C(4)–O(1), 1.243(3); C(14)–O(4), 1.322(3); C(3)–C(4), 1.455(4);
C(2)–C(3), 1.477(4); C(1)–C(2), 1.368(4). Selected interbond angles (8): C(2)–C(3)–C(14), 132.2(3); C(3)–C(4)–N, 106.1(2); C(2)–C(1)–N, 109.3(3); C(3)–
C(2)–C(11), 125.4(3); C(2)–C(11)–O(2), 125.1(3). Selected torsion angles (8): O(4)–C(14)–C(3)–C(2), 0.0(5); O(2)–C(11)–C(2)–C(3), 4.9(5); C(4)–C(3)–
˚
C(14)–O(4), 177.8(3); C(2)–C(1)–C(5)–C(6), K133.7(4). Non-bonded contacts (A): O(2)/O(4), 2.52; O(2)/H(7), 1.64 (estimated).

C. J. H. Morton et al. / Tetrahedron 61 (2005) 727–738
731
pyrrolinone oxygen atom; interestingly both the phenyl
moiety of the benzoyl substituent and the ester group lie
significantly out of the plane of the heterocyclic ring. In the
enamine 18a, there is evidently intramolecular hydrogen
bonding between the anilino-NH and the pyrrolinone
oxygen.
3. Conclusion
Whereas reaction of the pyrrolinecarboxylate ester 2a with
nitriles leads directly to 3,6-disubstituted DPP derivatives,1
the corresponding reaction of 2a with esters proceeds in four
distinct stages; (a) C-acylation; (b) thermal cyclisation of
the acyl compounds, with or without the aid of microwaves,
to give furo[3,4-c]pyrroles; (c) N-protection and (d) ring-
opening of the furopyrroles, followed by ring-closure. This
sequence constitutes the first reliable general route to N5-
protected 2,3,6-triarylated DPPs.
4. Experimental
4.1. General
FT-IR spectra were recorded for Nujol mulls; frequencies
are expressed in cmK1. Unless otherwise indicated, UV–vis
spectra were recorded (wavelengths expressed in nm) for
1
solutions in dimethyl sulfoxide (DMSO), and H and 13C
NMR spectra were obtained at 300 and 75.4 MHz,
respectively, for solutions in DMSO-d6 (or, where indicated,
CDCl3). Chemical shifts (d) are expressed relative to SiMe4
(dHZdCZ0) and coupling constants (J) in Hz. Mass spectra
and accurate mass measurements were obtained using
electron impact (EI) ionisation at 70 eV, chemical ionisation
(CI) using a VG Autospec instrument, or electrospray
ionisation (ESI) with a Micromass LCT instrument. The
microwave reactor was a CEM Discovere model, with a
circular single mode cavity design and a maximum
operating power of 300 W; the samples were contained in
sealed glass tubes, whereby the pressure was allowed to
increase to a maximum of 2.07 MPa (300 psi).
Figure 3. X-ray structure of compound 9a. [View 3b shows the close
˚
proximity of the ester methylene protons (ca. 2.8 A) to the mean plane of
˚
the phenyl ring.] Selected bond lengths (A): C(3)–C(14), 1.372(4); C(4)–
O(1), 1.260(3); C(14)–O(4), 1.342(4); C(3)–C(4), 1.447(4); C(2)–C(3),
1.460(4); C(1)–C(2), 1.357(4). Selected interbond angles (8): C(3)–C(4)–
O(1), 127.8(3); C(4)–C(3)–C(14), 119.4(3); C(3)–C(14)–O(4), 118.9(3).
Selected torsion angles (8): C(1)–C(2)–C(11)–O(3), 123.4(3); C(3)–C(2)–
C(11)–O(2), 141.7(4); C(3)–C(14)–C(15)–C(16), 32.8(5); C(2)–C(1)–
C(5)–C(6), 132.5(4); C(4)–C(3)–C(14)–O(4), 6.3(5). Non-bonded contacts
2-Methylbutan-2-ol (t-amyl alcohol) was dried by heating
under reflux with sodium metal for several hours
˚
followed by distillation on to 4 A molecular sieves. Sodium
t-amyloxide solution was obtained by dissolving the
appropriate quantity of sodium, cut into small pieces, in
boiling t-amyl alcohol under nitrogen: this process normally
˚
(A): O(1)/O(4), 2.57; O(1)/H(17), 1.70 (estimated).
Table 1. Acylated derivatives of ethyl 2-aryl-4,5-dihydro-5-oxopyrrole-3-carboxylates 2
Compound
Yield (%), acylating agent
dH (OCH2CH3)
Isomer ratio (Z/E)
!1:10
RCO2Et
RCOCl
17
Major
Minor
3.57
6
7
59, 40
4.00
3.97
8
67
33
78
—
0
33
10
14
44
0
9a
9b
9c
9d
9e
9f
3.56
3.62
3.63
4.10
4.19
4.27
5:1
ca. 2.5:1
2:1
—
89
60
—
3.62
3.50
—
—
The empty cells in the table indicates that the reaction was not attempted or that the minor isomer was not detected.

732
C. J. H. Morton et al. / Tetrahedron 61 (2005) 727–738
Scheme 3.
Table 2. 3,6-Diaryl-1H-furo[3,4-c]pyrrole-1,4(5H)-diones 12 and their derivatives
Compound
Yield (%)
Visible absorption, lmax/nm (log 3 in brackets)
Conventional heating
Microwave heating
Parent compound 12 (in
DMSO)
N-Me deriv. 14 (in CH2Cl2)
12a
12b
12c
12e
12f
40
68
—
—
—
86, 70
—
94
87
19
455, 487 (4.41, 4.45)
463, 495 (4.47, 4.52)
461, 493 (4.45, 4.49)
487, 511 (4.38, 4.38)
457, 487 (4.02, 4.03)
453 (4.34)
454 (4.20)
482 (4.24)
The — in the ‘yield’ column indicates that the reaction was not attempted.
required several hours but could be accelerated by the
addition of a catalytic amount of anhydrous iron(III)
chloride.
carboxylate 2a was prepared according to the patented
procedure.6 The p-chlorophenyl analogue 2b was supplied
by Ciba Specialty Chemicals Inc. as an off-white solid of mp
198 8C, and was used without further purification. Solutions
were dried over anhydrous sodium sulfate or magnesium
sulfate.
‘Ether’ refers to diethyl ether and ‘petrol’ to the fraction of
bp 40–60 8C. Ethyl 4,5-dihydro-5-oxo-2-phenylpyrrole-3-
˚
Figure 4. X-ray structure of compound 18a. Selected bond lengths (A): C(2)–C(3), 1.356(2); C(4)–C(5), 1.456(2); C(5)–C(6), 1.382(2); C(4)–O, 1.2504(17),
C(6)–C(7), 1.481(2); C(6)–N, 1.3573(18); N–C(14), 1.4116(18); C(3)–C(20), 1.4632(19). Selected interbond angles (8): C(2)–C(5)–C(4), 106.39(12); C(4)–
C(5)–C(6), 123.25(13); C(3)–C(2)–C(5), 108.46(12); C(5)–C(6)–N, 118.89(13); C(5)–C(4)–O, 128.84(13). Selected torsion angles (8): C(4)–C(5)–C(6)–N,
K1.4(2); C(6)–C(5)–C(4)–O, K6.1(2); C(2)–C(3)–C(20)–C(21), 139.92(16); C(5)–C(6)–C(7)–C(8), K56.79(19); C(6)–N–C(14)–C(15), K23.4(2); N–C(6)–
˚
C(7)–C(8), 127.70(14); C(5)–C(2)–C(3)–N, 1.14(15). Non-bonded contacts (A): N/O, 2.7421(16).

C. J. H. Morton et al. / Tetrahedron 61 (2005) 727–738
733
Scheme 4.
4.1.1. Ethyl 4-cinnamoyl-4,5-dihydro-5-oxo-2-phenyl-
pyrrole-3-carboxylate 6. (a) Sodium (1.21 g, 52.6 mmol)
was added, with stirring and under nitrogen, to dried t-amyl
alcohol (70 cm3) and the mixture heated to reflux (105–
110 8C) until all the sodium dissolved. The solution was
cooled to 25 8C, then the pyrrolinecarboxylate ester 2a
(2.00 g, 8.6 mmol) and ethyl cinnamate (2.55 g, 14.5 mmol)
were added. The mixture was then heated to reflux for 2 h,
during which time an intense orange colour developed. The
cooled mixture was then added to an ice-cooled mixture of
methanol (20 cm3) and concentrated hydrochloric acid
(5 cm3) and the bright orange precipitate was filtered off,
washed with methanol and dried in vacuo at 40 8C. Yield
3.05 g (59%).
(b) The above method was repeated, using the pyrroline-
carboxylate ester 2a (2.00 g, 8.6 mmol), sodium t-amyl-
oxide [from sodium, (0.60 g, 26.1 mmol)] in dried t-amyl
alcohol (25 cm3) and methyl cinnamate (1.40 g, 8.6 mmol);
the mixture was heated to reflux for 2.5 h, then cooled and
added to an ice-cold mixture of methanol (10 cm3) and
water (20 cm3), and acidified dropwise with concentrated

734
C. J. H. Morton et al. / Tetrahedron 61 (2005) 727–738
hydrochloric acid (3 cm3). The orange precipitate was
filtered off, washed with methanol and water then dried in
vacuo. Yield 1.25 g (40%).
dried and concentrated under reduced pressure. Yield 0.43 g
(33%).
Compound 8 had mp 173–174 8C. (from ethanol or 1,4-
dioxan). (Found: C, 68.1; H, 6.6; N, 4.7. C17H19NO4
requires C, 67.8; H, 6.4; N, 4.7%). dH (CDCl3) 0.96 (3H, t,
JZ7.4 Hz, CH2CH2CH3), 1.03 (3H, t, JZ7.1 Hz,
OCH2CH3), 1.65–1.78 (2H, m, CH2CH2CH3), 3.04 (2H,
br t, JZ7.0 Hz, CH2CH2CH3), 4.10 (2H, q, JZ7.1 Hz,
OCH2CH3), 7.39–7.42 (5H, m, Ar-H), 8.85 (1H, br s, NH).
A minor signal occurred at d 3.73 (q, OCH2).
Compound 6 had mp 238–240 8C. (Found: C, 72.8; H, 5.3;
N, 3.8. C22H19NO4 requires C, 73.1; H, 5.3; N, 3.9%). m/z
361 (MC%, 100%), 315 (77), 238 (72). dH 0.88 (3H, t, JZ
6.6 Hz, OCH2CH3), 4.00 (2H, q, JZ6.6 Hz, OCH2CH3),
7.43–7.47 (8H, m, Ar-H), 7.59 (1H, d, JZ15.7 Hz,
CH]CHPh), 7.64–7.67 (2H, m, Ar-H), 8.62 (1H, d, JZ
15.7 Hz, CH]CHPh), 11.11 (1H, s, NH). A minor signal
occurred at d 3.57 (q, OCH2).
4.1.4. Ethyl 4-benzoyl-4,5-dihydro-5-oxo-2-phenylpyr-
role-3-carboxylate 9a. (a) The pyrrolinecarboxylate ester
2a (5.03 g, 21.8 mmol) and ethyl benzoate (3.27 g,
21.8 mmol) were added successively at 25 8C to a solution
of sodium t-amyloxide, prepared as above from sodium
(1.50 g, 65.2 mmol) and t-amyl alcohol (40 cm3), and the
mixture was then heated to reflux for 5.5 h. The resulting
orange solution was cooled and added to an ice-cooled
mixture of methanol (10 cm3) and water (50 cm3), then
acidified dropwise with concentrated hydrochloric acid
(3 cm3) and extracted with tetrahydrofuran/diethyl ether;
the extract was dried and concentrated, to give amber-
coloured crystals (2.38 g, 33%), mp 156–157 8C. (from
ethanol–water).
(c) The pyrrolinone ester 2a (2.00 g, 8.66 mmol) was added
to sodium hydride (1.73 g, 43.25 mmol) THF (200 cm3),
and the mixture was stirred for 30 min. Cinnamoyl chloride
(1.44 g, 8.66 mmol) was then added and the mixture stirred
at room temperature overnight, acidified (HCl), and
extracted with ethyl acetate. The dried extract on concen-
tration gave the enol 6 as an orange solid (523 mg, 17%), mp
247–250 8C, spectroscopically identical with the products
from (a) and (b).
4.1.2. Ethyl 4-cinnamoyl-4,5-dihydro-1-methyl-5-oxo-2-
phenylpyrrole-3-carboxylate 7. The dianion of the cinna-
moyl-pyrrolinecarboxylate ester 6 was prepared as above,
from the pyrrolinecarboxylate ester (5.00 g, 21.6 mmol),
ethyl cinnamate (3.88 g, 22.0 mmol) and sodium t-amyl-
oxide (from sodium, 1.51 g, 65.7 mmol) in t-amyl alcohol
(25 cm3). The orange solution was cooled to 25 8C, methyl
p-toluenesulfonate (15.88 g, 85.3 mmol) was added and the
mixture heated under reflux for 1 h, cooled, added to water
(30 cm3), extracted with ethyl acetate, and the extract dried
and concentrated. Recrystallisation (propan-2-ol–tetra-
hydrofuran) gave an orange solid (6.27 g, 77%), mp 190–
192 8C. (Found: C, 73.4; H, 5.6; N, 3.7. C23H21NO4 requires
C, 73.6; H, 5.6; N, 3.7%). m/z 375 (MC%, 100%), 329 (98).
dH (CDCl3) 0.75 (3H, t, JZ7.2 Hz, OCH2CH3), 2.97 (3H, s,
NCH3), 3.97 (2H, q, JZ7.2 Hz, OCH2CH3), 7.24–7.48 (8H,
m, Ar-H), 7.67–7.76 (3H, m, Ar-H and CH]CHPh), 8.76–
8.84 (1H, d, JZ15.5 Hz, CH]CHPh).
(b) The pyrrolinone ester 2a (1.50 g, 6.5 mmol) and benzoyl
chloride (0.91 g, 0.75 cm3, 6.5 mmol) were added success-
ively to sodium hydride (0.55 g, 27.75 mmol) in THF
(100 cm3), and the mixture stirred at room temperature
overnight, then added to water, acidified (HCl) and the
organic component extracted with ethyl acetate and dried.
Recrystallisation from ethanol gave the benzoylpyrrolinone
ester (100 mg, 9.5%), mp 157–158 8C, identical to the
product of method (a).
Found: C, 71.5; H, 5.2; N, 4.2. C20H17NO4 requires C, 71.6;
H, 5.1; N, 4.2%. nmax 3170 (NH), 2720 (H-bonded OH),
1720 (ester C]O), 1630 (lactam C]O), 1610 and 1600
(C]C). dH 0.60 (3H, t, JZ7.2 Hz, OCH2CH3—major),
0.95 (3H, t, JZ7.2 Hz, CH2CH3—minor), 3.56 (2H, q, JZ
7.2 Hz, CH2CH3—major), 4.10 (2H, q, JZ7.2 Hz,
CH2CH3—minor) 7.42–7.62 (6H, m, m/p-Ar-H), 7.62–
7.80 (4H, m, o-Ar-H), 9.52 (1H, br. s, NH). Other minor
signals (each OCH2, q) occur at d 3.75 and 3.45. dC 175.4
(lactam C]O), 170.7 (ester C]O), 165.0 (C]C(OH)Ph),
135.7 (Ph-C]C–CO2Et), 131.8 (Ar), 130.6 (quat. Ar),
130.2 (quat. Ar), 129.9 (Ar), 129.4 (Ar), 128.9 (2!C, Ar),
128.8 (2!C, Ar), 128.7 (Ar), 128.3 (Ar), 128.0 (Ar), 108.0
(Ph-C]C–CO2Et), 105.1 (C]C–C]C(OH)Ph), 61.0
(CH2), and 13.6 (CH3). m/z 335 (MC%, 54%), 289 (100),
261 (7), 105 (56).
4.1.3. Ethyl 4-butanoyl-4,5-dihydro-5-oxo-2-phenyl-
pyrrole-3-carboxylate 8. (a) The pyrrolinecarboxylate
ester 2a (2.00 g, 8.6 mmol) and ethyl butanoate (1.00 g,
8.6 mmol) were added successively, under nitrogen, at 80–
90 8C to a stirred solution of sodium t-amyloxide, prepared
as above from sodium (0.61 g, 26.5 mmol) in t-amyl alcohol
(25 cm3). The mixture was heated to reflux for 5 h, then
cooled and added to an ice-cold mixture of water (100 cm3)
and methanol (10 cm3). Dropwise acidificaton (conc. HCl)
gave a purple precipitate which was filtered off, washed with
methanol then water and decolourised in hot propan-2-ol
with charcoal, to yield almost colourless crystals (1.74 g,
67%).
4.1.5. Ethyl 4-(p-chlorobenzoyl)-4,5-dihydro-5-oxo-2-(p-
chlorophenyl)-pyrrole-3-carboxylate 9b. This compound
was prepared similarly to 9a, from the pyrrolinone ester 2b
(26.29 g, 99 mmol), ethyl p-chlorobenzoate (18.27 g,
99 mmol) and sodium t-amyloxide [from sodium, 6.82 g
(297 mmol) in t-amyl alcohol (230 cm3)], with the reactants
being added at 70 8C and the mixture being heated under
reflux for 22 h. The product was recrystallised from a
mixture of ethanol, propan-2-ol, and water; yield, 31.36 g
(b) The pyrrolinone ester 2a (1.00 g, 4.33 mmol) was added
to sodium hexamethyldisilazide (1 M solution in THF,
13.4 cm3), and the mixture was stirred for 30 min. Butanoyl
chloride (0.46 g, 0.45 cm3, 4.33 mmol) was then added and
the mixture stirred at room temperature overnight, then
acidified (HCl), extracted with ethyl acetate, and the extract

C. J. H. Morton et al. / Tetrahedron 61 (2005) 727–738
735
(78%). The alternative route, using p-chlorobenzoyl
chloride and sodium hydride as base, gave 9b in a yield of
only 14%.
After cooling to room temperature, water was added, and
the mixture acidified (HCl). The organic component was
extracted with ether, and a precipitate formed in the aqueous
layer. This precipitate was filtered off, the remaining
aqueous layer was evaporated to dryness and the organic
component was extracted with methanol. Evaporation of the
methanol gave the nicotinyl compound 9f as a yellow solid
(10.90 g, 89%), mp 194–197 8C (from ethanol). (Found: C,
67.6; H, 4.5; N, 8.2. C19H16N2O4 requires C, 67.85; H, 4.8;
N, 8.3%). dH 0.70 (3H, t, JZ6.5 Hz, OCH2CH3), 3.50 (2H,
q, JZ6.5 Hz, OCH2CH3), 7.31–7.41 (3H, m, 2! Ar-HC
Py-5-H), 7.43–7.53 (3H, m, Ar-H), 7.93 (1H, br dt, JZ7.9,
1.5 Hz, Py-4-H), 8.65 (1H, br d, JZ4.8 Hz, Py-6-H), 8.70
(1H, d, JZ1.5 Hz, Py-2-H) and 11.89 (1H, s, NH). m/z (ESI
Kve) 336 (22%, MC%), 335 [100, (MK1)]C.
Compound 9b had mp 170–172 8C. (Found: C, 59.4; H, 4.1;
N, 3.7; Cl, 17.4. C20H15Cl2NO4 requires C, 59.4; H, 3.7; N,
3.5; Cl, 17.5%). dH (CDCl3) 0.74 (3H, t, JZ7.2 Hz,
CH2CH3), 3.62 (2H, q, JZ7.2 Hz, CH2CH3), 7.40, 7.44,
7.55 and 7.59 (each 2H, 2!AA0BB0) and 8.63 (NH). [A
minor isomer showed resonances at d 1.05 (CH2CH3) and
4.19 (OCH2)].
4.1.6. Ethyl 4-(p-bromobenzoyl)-4,5-dihydro-5-oxo-2-
phenylpyrrole-3-carboxylate 9c. The pyrrolinone ester
2a (0.85 g, 3.69 mmol) was added to sodium hydride
(0.59 g, 14.75 mmol) in THF (40 cm3). After stirring for
30 min at room temperature, a solution of freshly prepared
p-bromobenzoyl chloride (0.81 g, 3.69 mmol) in THF
(10 cm3), and a catalytic amount (a few crystals) of
DMAP were added, and the mixture was stirred at room
temperature overnight, then acidified (dil. HCl) and
extracted with ether. Concentration of the dried extract in
vacuo gave the enol as a yellow crystalline solid (0.67 g,
44%), mp 189 8C (from ethanol). (Found: C, 58.4; H, 3.5; N,
3.3. C20H16BrNO4 requires C, 58.0; H, 3.9; N, 3.4%). dH
0.76 (3H, t, JZ7.2 Hz, CH2CH3), 3.63 (2H, q, JZ7.2 Hz,
CH2CH3), 7.43–7.52 (3H, m, ArH), 7.59–7.66 (4H, m,
ArH), 7.74–7.80 (2H, m, ArH) and 11.90 (1H, s, NH). m/z
(CI) 414/416 [96/100%, (MC1)C] A minor product showed
ethoxy-group resonances at dH 1.27 (t, CH2CH3) and 4.27
(q, OCH2); the ratio of the two products was ca. 2:1.
4.1.10. 3,6-Diphenyl-1H-furo[3,4-c]pyrrole-1,4(5H)-
dione 12a. (a) A mixture of compound 9a (10.00 g,
29.9 mmol) and Dowthermw A (200 cm3) was heated to
230–240 8C under nitrogen for 64 h. The solution was then
cooled to room temperature and added dropwise to petrol
(300 cm3); the fluorescent orange precipitate was filtered
off, washed with hexane and dried in vacuo. Yield 3.48 g
(40%).
(b) The benzoylpyrrolinone ester 9a was subjected to
flash vacuum pyrolysis (500 8C/8!10K3 Torr), on a very
small scale (50 mg) for ca. 45 min. The product from
this heating gave the desired furopyrrole 12a as a orange
solid.
(c) The benzoylpyrrolinone ester 9a (100 mg, 0.30 mmol)
was irradiated in a microwave reactor, without solvent,
heating to 250 8C for 10 min. The crude product was then
allowed to cool, methanol was added, and the solid filtered
off and washed with further methanol. This gave the
furopyrrole 12a (73 mg, 86%). On a larger scale, irradiation
of compound 9a (643 mg), heating to 180 8C. for 10 min,
gave the furopyrrole 12a (387 mg, 70%).
4.1.7. Compound 9d. Repeated attempts to prepare ethyl
4-(p-methoxybenzoyl)-4,5-dihydro-5-oxo-2-phenylpyrrole-
3-carboxylate 9d by either of the above acylation methods
were unsuccessful; in every case the only product isolated
was p-methoxybenzoic acid.
4.1.8. Ethyl 4-(p-nitrobenzoyl)-4,5-dihydro-5-oxo-2-
phenylpyrrole-3-carboxylate 9e. The pyrrolinone ester
2a (6.35 g, 27.5 mmol) was added to a mixture of sodium
hydride (2.00 g, 82.5 mmol) and THF (1 dm3), and this was
stirred at room temperature for 15 min. p-Nitrobenzoyl
chloride (5.50 g, 29.5 mmol) was then added, and the
mixture was stirred overnight. Methanol and then water
were added, and the mixture acidified (HCl). The organic
component was extracted with ether, the extract was dried,
the solvent evaporated, and the residue washed with
methanol to give the nitro compound as a yellow solid
(6.31 g, 60%), mp 254 8C (by DSC). (Found: C, 63.1; H,
4.15; N, 7.3. C20H16N2O6 requires C, 63.2; H, 4.2; N, 7.4%).
dH 0.75 (3H, t, JZ6.6 Hz, OCH2CH3), 3.62 (2H, q, JZ
6.6 Hz, OCH2CH3), 7.35–7.45 (3H, m, m/p-Ph-H), 7.50–
7.56 (2H, m, o-Ph-H), 7.84 and 8.30 (each 2H, AA0BB0,
Ar-H), and 11.95 (1H, s, NH); m/z (ESIKve) 380 (22%,
The benzoylpyrrolinone ester 9a (100 mg, 0.30 mmol) and
toluene (2 cm3) were irradiated in a microwave reactor,
heating up to 250 8C over 40 min. The solution was cooled,
and the precipitate filtered off and washed with methanol to
give the furopyrrole 12a as an orange solid (22 mg, 26%),
the remainder being unchanged starting material. Extension
of the reaction time to 1 h gave 12a in 48% yield.
Compound 12a had mp O300 8C (dec.) (broad DSC
endotherm at ca. 320 8C). (Found: C, 74.9; H, 4.2; N, 4.8.
C18H11NO3 requires C, 74.7; H, 3.8; N, 4.8%). nmax 1760
(ester C]O), 1670 (lactam C]O), 1625 (C]C). dH 7.48–
7.54 (6H, m, Ar-H), 8.12–8.17 (2H, m, Ar-H), 8.17–8.23
(2H, m, Ar-H) and 11.87 (1H, s, NH); dC 161.4 and 159.3
(2!C]O), 152.2 and 148.1 (2!quat.), 132.8, 132.6, 129.1
(2C), 128.0, 127.0 (all Ar-C–H), 126.8, 126.4, 115.8 and
102.8 (4!quat). m/z 289 (MC%, 100%), 204 (20), 105 (35),
77 (35).
M
C%), 379 [100, (MK1)]C.
4.1.9. Ethyl 4-nicotinyl-4,5-dihydro-5-oxo-2-phenyl-
pyrrole-3-carboxylate 9f. The pyrrolinone ester 2a
(8.43 g, 36.5 mmol) and methyl nicotinate (5.00 g,
36.5 mmol) were added successively to sodium t-amyloxide
[from sodium, 2.52 g (0.11 mol) in t-amyl alcohol
(100 cm3)], and the mixture heated to reflux overnight.
4.1.11. 3,6-Bis-(p-chlorophenyl)-1H-furo[3,4-c]pyrrole-
1,4(5H)-dione 12b. (a) A mixture of compound 9b
(15.00 g, 37 mmol) and Dowthermw A (300 cm3) was
heated to 205–210 8C during 48 h, then cooled and added

736
C. J. H. Morton et al. / Tetrahedron 61 (2005) 727–738
dropwise to petrol (1 l). The fluorescent purple solid was
filtered off, washed with further petrol and dried in vacuo.
Yield 8.95 g (68%), mp 387 8C (by DSC). (Found: C, 60.3;
H, 2.8; N, 3.9. C18H9Cl2NO3 requires C, 60.4; H, 2.5; N,
3.9%). dH 7.67, 7.73, 8.25, 8.34 (each 2H, 2!AA0BB0) and
12.25 (1H, br s, NH). m/z (EI) 357/359/361 (MC%, 95/63/
8%), 139/141 (100/35, ClC6H4CO), 111/113 (85/26,
ClC6H4), 75 (35).
1,4(5H)-dione 13a. Compound 12a (1.00 g, 3.4 mmol)
was added under nitrogen at 25 8C to a suspension of sodium
hydride (55–65% dispersion in mineral oil; 0.20 g) in
tetrahydrofuran (100 cm3), and the mixture heated briefly to
reflux during 5 min. The solution was cooled to room
temperature, benzyl bromide (0.70 g, 4.1 mmol) was added,
and the mixture heated under reflux for 19 h, then cooled.
Water (50 cm3) was added and the mixture extracted with a
mixture of tetrahydrofuran and ethyl acetate (1:1). The
extract was dried and concentrated, and the residue mixed
with petrol and immersed in an ultrasonic bath for 20 min.
The product 13a (0.97 g, 74%) was filtered off and dried
in vacuo: it had mp (DSC) ca. 213 8C (slow decomp.
O150 8C). (Found: C, 78.8; H, 4.9; N, 3.6. C25H17NO3
requires C, 79.1; H, 4.5; N, 3.7%). dH 5.09 (2H, s, CH2),
7.10–7.14 (2H, m, Ar-H), 7.19–7.50 (4H, m, Ar-H), 7.52–
7.64 (3H, m, Ar-H), 7.65–7.80 (4H, m, Ar-H) and 8.31–8.40
(2H, m, Ar-H). m/z (EI) 379 (MC%, 33%), 105 (50), 91
(100).
(b) The p-chlorobenzoylpyrrolinone ester 9b (58 mg,
0.14 mmol) was irradiated in a microwave reactor,
without solvent, heating to 200 8C over 10 min. The
crude product was then allowed to cool, methanol was
added, and the solid filtered off and washed with further
methanol. This gave the furopyrrole as a red solid (42 mg,
82%).
4.1.12. 3-(p-Bromophenyl)-6-phenyl-1H-furo[3,4-c]pyr-
role-1,4(5H)-dione 12c. The p-bromobenzoylpyrrolinone
ester 9c (154 mg, 0.37 mmol) was irradiated with micro-
wave radiation without solvent, heating to 250 8C for
10 min. The crude product was then allowed to cool,
methanol was added and the solid filtered off and
washed with methanol. This gave the furopyrrole as a red
solid (129 mg, 94%), mp 295 8C (subl., dec.) (Found: C,
58.9; H, 2.6; N, 3.7. C18H10BrNO3 requires C, 58.7; H 2.7;
N, 3.8%). dH 0 7.43–7.47 (3H, m, Ar-H), 7.66 and 7.98
(each 2H, AA BB0, p-BrC6H4), 8.13–8.17 (2H, m, Ar-H)
and 11.88 (1H, s, NH). m/z (CI) 368/370 [100/94%,
(MC1)C].
4.1.16. 2-Benzyl-3,5,6-triphenyl-DPP 15a. A mixture of
compound 13a (10.0 g, 26.4 mmol), N,N0-dicyclohexyl-
carbodiimide (13.5 g, 65.5 mmol), and aniline (5.0 g,
53.8 mmol) in dichloromethane (300 cm3) containing
trifluoroacetic acid (3 drops) was stirred under nitrogen at
40 8C for 16 h. Further portions of aniline (15.0 g) and N,N0-
dicyclohexylcarbodiimide (10.0 g) were then added, heating
was continued for a further 24 h and finally the solvent was
distilled off. The residue was recrystallised from 1,4-dioxan
and the fluorescent orange product 15a washed sequentially
with hot propan-2-ol, methanol and water. Yield 1.87 g
(16%), mp 270–272 8C. (Found: C, 81.9; H, 4.8; N, 6.2.
C31H22N2O2 requires C, 81.9; H, 4.9; N, 6.2%). dH (CDCl3)
5.05 (2H, s, PhCH2N), 7.16–7.24 (4H, m, Ar-H), 7.27–7.50
(12H, m, Ar-H), 7.66–7.70 (2H, m, Ar-H) and 7.74–7.79
(2H, m, Ar-H). m/z (EI) 454 (MC%, 100%), 363 (10), 335
(16), 292 (14), 180 (31), 91 (41). lmax (CH2Cl2) 468 (log 3
4.26).
4.1.13. 3-(p-Nitrophenyl)-6-phenyl-1H-furo[3,4-c]pyr-
role-1,4(5H)-dione 12e. The p-nitrobenzoylpyrrolinone
ester 9e (300 mg, 0.90 mmol) was irradiated with micro-
wave radiation without solvent, heating to 270 8C for
15 min. The crude product was then allowed to cool,
methanol was added and the solid filtered off and washed
with methanol. This gave the furopyrrole as a red solid
(230 mg, 87%), mp 340 8C (by DSC). (Found: C, 64.4; H,
2.9; N, 8.4. C18H10N2O5 requires C, 64.7; H, 3.0; N, 8.4%).
dH 7.58–7.69 (3H, m, m/p-Ph), 8.28–8.34 (2H, m, o-Ph),
8.38 (4H, s, p-O2NC6H4) and 12.15 (1H, s, NH). m/z (ESI
Kve) 334 (21%, MC%), 333 [100%, (MK1)]C.
4.1.17. 5-Methyl-3,6-diphenyl-1H-furo[3,4-c]pyrrole-
1,4(5H)-dione 14a. (a) Sodium hydride (55–65% dispersion
in mineral oil: 0.16 g) was added under nitrogen to a stirred
mixture of the furopyrrole 12a (0.99 g, 3.4 mmol) in dry
tetrahydrofuran (200 cm3) and the mixture heated to boiling
for ca. 5 min (until hydrogen evolution ceased), then cooled
to 25 8C. Iodomethane (1.46 g, 10.3 mmol) was added and
the mixture stirred at 25 8C for 16 h. Water (100 cm3) was
added and the mixture extracted several times with a
mixture of tetrahydrofuran and ethyl acetate (2:1). The
combined extracts were dried and concentrated, the residue
was redissolved in DMSO (20 cm3) and reprecipitated by
dropwise addition to water (200 cm3). The fluorescent
orange product was filtered off, washed with water and dried
in vacuo.
4.1.14. 6-Phenyl-3-(3-pyridyl)-1H-furo[3,4-c]pyrrole-
1,4(5H)-dione 12f. The nicotinylpyrrolinone ester 9f
(100 mg, 0.30 mmol) was irradiated with microwave
radiation without solvent, heating to 230 8C for 10 min.
The crude product was then allowed to cool, methanol was
added and the solid filtered off and washed with methanol.
This gave the furopyrrole 12f as a red solid (16 mg, 19%),
the remainder being an intractable black tar. Compound 12f,
mp 333 8C (by DSC), could not be obtained in analytical
purity (Found: C, 69.25; H, 3.5; N, 9.8. C17H10N2O3
requires C, 70.3; H, 3.5; N, 9.65%) but showed the correct
1H NMR and accurate mass: dH 7.63–7.74 (5H, m, Ph-H),
8.33–8.39 (1H, m, Py-5-H), 8.56 (1H, dt, JZ8.2, 1.9 Hz,
Py-4-H), 8.79 (1H, dd, JZ1.5, 4.8 Hz, Py-6-H), 9.41 (1H, d,
JZ1.9 Hz, Py-2-H) and 12.09 (1H, s, NH). m/z (ESI Kve)
290 (20%, MC%), 289.0618 [100%, (MK1)C; C17H9N2O3
requires 289.0613].
(b) A mixture of the furopyrrole 12a (1.19 g, 4.12 mmol),
methyl p-toluenesulfonate (1.15 g, 6.18 mmol), potassium
carbonate (1.14 g, 8.24 mmol) and DMF (40 cm3) was
stirred at room temperature overnight. Water was then
added, and the organic component extracted with dichloro-
methane. The extract was dried and the solvent was
removed; washing of the residue with water then methanol
4.1.15. 5-Benzyl-3,6-diphenyl-1H-furo[3,4-c]pyrrole-

C. J. H. Morton et al. / Tetrahedron 61 (2005) 727–738
737
gave the methylated compound 14a as a red solid (0.85 g,
68%), mp 198–200 8C.
255–256 8C. (Found: C, 65.4; H, 3.7; N, 6.2. C25H17BrN2O2
requires C, 65.7; H, 3.8; N, 6.1%). dH (CDCl3) 3.35 (3H, s,
NCH3), 7.07–7.12 (2H, m, Ar-H), 7.26–7.40 (5H, m, Ar-H),
7.43–7.49 (5H, m, Ar-H) and 7.83–7.88 (2H, m, Ar-H). lmax
(CH2Cl2) 479 (log 3 4.20).
(Found: C, 75.2; H, 4.5; N, 4.6. C19H13NO3 requires C, 75.3;
H, 4.3; N, 4.6%). nmax 1755 (ester C]O), 1700 (lactam
C]O) and 1625 (C]C). dH (CDCl3) 3.46 (3H, s, NCH3),
7.52–7.62 (6H, m, 2!m/p-Ph-H), 7.81–7.85 (2H, m, o-Ph-
H) and 8.39–8.43 (2H, m, o-Ph-H).
4.1.22. 2-Methyl-6-(p-nitrophenyl)-3,5-diphenyl-DPP
16e. A mixture of furopyrrole 12e (100 mg, 0.29 mmol),
aniline (53 mg, 0.57 mmol), DCC (118 mg, 0.57 mmol),
trifluoroacetic acid (2–3 drops) and dichloromethane
(25 cm3) was stirred at room temperature for 72 h. The
solvent was removed, and washing of the residue with
methanol gave the pyrrolopyrrole as a red solid (63 mg,
52%), mp 233–235 8C. (Found: C, 71.0; H, 3.7; N, 9.7.
C25H17N3O4 requires C, 70.9; H, 4.05; N, 9.9%). dH
(CDCl3) 3.45 (3H, s, NCH3), 7.15–7.20 (2H, m, o-Ph),
7.36–7.44 (3H, m, m/p-Ph), 7.55–7.60 (3H, m, m/p-Ph), 7.81
and 8.16 (each 2H, AA0BB0, p-C6H4NO2), and 7.93–7.98
(2H, m, o-Ph). m/z (ESI) 447 (28%, [MCNaC1]C), 446
(100%, [MCNa]C). lmax (CH2Cl2) 493 (log 3 4.15).
4.1.18.
3-(p-Bromophenyl)-5-methyl-6-phenyl-1H-
furo[3,4-c]pyrrole-1,4(5H)-dione 14c. A mixture of the
furopyrrole 12c (1.50 g, 4.08 mmol), methyl p-toluene-
sulfonate (1.14 g, 6.12 mmol), potassium carbonate (1.13 g,
8.16 mmol) and DMF (60 cm3) was stirred at room
temperature overnight. Water was then added, and the
organic component extracted with dichloromethane. The
extract was dried, the solvent was removed and the residue
washed with water then methanol, to give the methylated
compound as a red solid (0.83 g, 53%), mp 215–216 8C.
(Found: C, 59.6; H, 2.9; N, 3.6. C19H12BrNO3 requires C,
59.7; H, 3.2; N, 3.7%). dH (CDCl3) 3.38 (3H, s, NCH3),
7.50–7.54 (3H, m, m/p-Ph), 7.61 and 8.19 (each 2H,
AA0BB0, p-C6H4Br), 7.73–7.78 (2H, m, o-Ph). m/z (ESI)
404/406 (MCNa)C.
4.1.23. Z-1-Methyl-5-phenyl-3-[1-phenyl-1-(phenyl-
amino)methylidene]-2,3-dihydro-pyrrol-2-one 18a. A
solution of furopyrrole 14a (135 mg, 0.38 mmol) and aniline
(85 ml, 0.77 mmol) in toluene (3 cm3) was irradiated at
150 8C for 10 min. The solution was cooled, and the solvent
removed under reduced pressure. Recrystallisation from
ethanol gave the pyrrolinone as an orange solid (106 mg,
68%), mp 194.5–197.5 8C. (Found: C, 81.6; H, 5.4; N, 7.8.
C24H20N2O requires C, 81.8; H, 5.7; N, 8.0%). dH (CDCl3)
3.34 (3H, s, NCH3), 5.71 (1H, s, CH), 6.72–6.77 (2H, m,
o-PhN), 6.93–7.00 (1H, m, p-PhN), 7.07–7.15 (2H, m,
m-PhN), 7.28–7.34 (1H, m, Ar-H), 7.34–7.42 (9H, m,
Ar-H) and 11.82 (1H, s, NH). m/z (ESICve): 352 (100%,
4.1.19. 5-Methyl-3-(p-nitrophenyl)-6-phenyl-1H-furo-
[3,4-c]pyrrole-1,4(5H)-dione 14e. A mixture of furo-
pyrrole 12e (0.90 g, 2.7 mmol), methyl p-toluenesulfonate
(0.75 g, 4.04 mmol), potassium carbonate (1.00 g,
7.2 mmol) and DMF (40 cm3) was stirred at room
temperature overnight. Water was then added and the
organic component extracted with dichloromethane. The
extract was dried, solvent was removed and the residue
washed with water then methanol, to give the red
methylated compound 14e (0.65 g, 70%), mp 253–255 8C.
(Found: C, 65.4; H, 3.3; N, 7.8. C19H12N2O5 requires C,
65.5; H, 3.5; N, 8.0%). dH (CDCl3) 3.49 (3H, s, NCH3),
7.60–7.65 (3H, m, m/p-Ph-H), 7.84–7.88 (2H, m, o-Ph-H),
8.38 and 8.55 (each 2H, AA0BB0, p-O2NC6H4). m/z (ESI)
349 (100%, [MC1]C).
M
C%), 353 (44%, [MC1]C), 375 (92%, [MCNa]C), 376
(23%, [MCNaC1]C).
4.1.24. Z-3-[1-(p-Bromophenyl)-1-(phenylamino)methyl-
idene]-1-methyl-5-phenyl-2,3-dihydropyrrol-2-one 18c.
This was similarly prepared from furopyrrole 14c
(250 mg, 0.65 mmol) and aniline (119 ml, 1.31 mmol) in
toluene (5 cm3). The orange pyrrolinone (105 mg, 38%) had
mp 179.5–181.5 8C. (from ethanol). (Found: C, 67.15; H,
4.2; N, 6.4. C24H19BrN2O requires C, 66.8; H, 4.4; N,
6.5%). dH (CDCl3) 3.36 (3H, s, NCH3), 5.68 (1H, s, CH),
6.76–6.81 (2H, m, o-PhN), 6.97–7.05 (1H, m, p-PhN),
7.12–7.18 (2H, m, m-PhN), 7.28 and 7.52 (each 2H,
AA0BB0, p-BrC6H4), 7.30–7.45 (5H, m, Ar-H) and 11.80
(1H, s, NH).
4.1.20. 5-Methyl-2,3,6-triphenyl-DPP 16a. A solution of
the furopyrrole 14a0 (0.50 g, 1.65 mmol), aniline (1.54 g,
16.5 mmol), N,N -di-i-propylcarbodiimide (1.04 g,
1.29 cm3, 8.25 mmol) and trifluoroacetic acid (3 drops) in
dichloromethane (100 cm3) was stirred at room temperature
for 8 days. The solvent was distilled off and the residue
washed with methanol, to give the orange DPP (0.16 g,
25%), mp 267–269 8C. (Found: C, 79.4; H, 5.0; N, 7.3.
C25H18N2O2 requires C, 79.35; H, 4.8; N, 7.4%). nmax 1675
(C]O). dH 3.42 (3H, s, CH3), 7.15–7.20 (2H, m, Ar-H
o-Ph-H), 7.28–7.41 (6H, m, Ar-H), 7.51–7.56 (3H, m/p-Ph-
H), 7.62–7.68 (2H, m, Ar) and 7.91–7.95 (2H, m, Ar-H). m/z
(ESI-Cve) 402 (MCNaC1)C, 401 (MCNa)C. lmax
(CH2Cl2) 468 (log 3 4.11).
4.2. X-ray crystallography
The intensity data for compounds 7, 8 and 9a were recorded
at 293(1) K with a Rigaku AFC7S diffractometer using
˚
graphite-monochromated Mo-Ka radiation (lZ0.7107 A),
and the structures of 8 and 9a (Figs. 2 and 3) were solved by
direct methods using SIR927 and refined by full-matrix least
squares on F, using the TeXsan system 1.8 In the case of
compound 7, the structure refined with two independent
molecules in the asymmetric unit which are chemically
identical, and was solved using SHELXS-86.9 The intensity
data for compound 18a were recorded using a Siemens/
Bruker SMART diffractometer, with data being integrated
4.1.21. 6-(p-Bromophenyl)-2-methyl-3,5-diphenyl-DPP
16c. A mixture of furopyrrole 12c (300 mg, 0.79 mmol),
aniline (146 mg, 1.57 mmol), DCC (323 mg, 1.57 mmol),
trifluoroacetic acid (2–3 drops) and dichloromethane
(100 cm3) was stirred at room temperature for 6 days. The
solvent was removed and washing of the residue with
methanol gave the DPP as a red solid (173 mg, 55%), mp

738
C. J. H. Morton et al. / Tetrahedron 61 (2005) 727–738
using the SAINT10 and SADABS11 programs, the structure
solved by direct methods and refined by full-matrix least-
squares against F2 (SHELXTL12).
References and notes
1. Part 1: Morton, C. J. H.; Gilmour, R.; Smith, D. M.; Lightfoot,
P.; Slawin, A. M. Z.; MacLean, E. J. Tetrahedron 2002, 58,
5547–5565.
The systematic absences allowed unique assignment of all
the space groups. All hydrogen atoms were located from
difference maps, and were included in the refinements as
riding atoms in idealised positions with isotropic displace-
ment parameters; all non-hydrogen atoms were refined
anisotropically. All data were corrected for Lorentz,
polarisation and long-term intensity fluctuations. Absorp-
tion effects were corrected on the basis of multiple
equivalent reflections 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 7, 8, 9a and 18a have been deposited with the
Cambridge Crystallographic Data Centre as supplementary
publication numbers CCDC 243378, 243379, 243380 and
243381, respectively. Copies of the data may be obtained,
free of charge, on application to CCDC, 12 Union Road,
Cambridge, CB2 1EZ, UK [fax: C44-(0)1223-336033
or e-mail: deposit@ccdc.cam.ac.uk].
2. Iqbal, A.; Jost, M.; Kirchmayr, R.; Pfenninger, J.; Rochat, A.;
Wallquist, O. Bull. Soc. Chim. Belg. 1988, 97, 615–643.
3. Rubin, M. B.; Bargurie, M.; Kosti, S.; Kaftory, M. J. Chem.
Soc., Perkin Trans. 1 1980, 2670–2677.
4. Langhals, H.; Grundei, T.; Potrawa, T.; Polborn, K. Liebigs
Ann. Chem. 1996, 679–682.
5. Speakman, J. C. The Hydrogen Bond and other Intermolecular
Forces. Monographs for Teachers No. 27; The Chemical
Society: London, 1975; p 12.
6. 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.
7. Altomare, A.; Cascarano, G.; Giacovazzo, C.; Guagliardi, A.
J. Appl. Crystallogr. 1993, 26, 343–350.
8. TeXsan Crystal Structure Analysis Package, 1985 and 1992;
Molecular Structure Corporation: The Woodlands, TX 77381,
USA.
¨
9. Sheldrick, G. M. University of Gottingen, Germany, 1986.
10. SMART (control) and SAINT (integration) software, version 4;
Bruker AXS Inc.: Madison, Wisconsin, 1994.
Acknowledgements
11. Sheldrick, G. M. SADABS: program for scaling and correction
¨
of area detector data; University of Gottingen, 1997 (based on
We thank Mrs S. Williamson for microanalyses and DSC
measurements, Mrs C. E. R. Horsburgh (EI and CI) and Dr
C. H. Botting (ESI) for mass spectra, and Ciba Specialty
Chemicals Inc. (Basel) and the Royal Society (London) for
financial support (Fellowship to N.J.W.).
the method of Blessing, R. H. Acta Crystallogr. Sect. A 1995,
51, 33).
12. Sheldrick, G. M. SHELXTL, version 5; Bruker AXS Inc.:
Madison, Wisconsin, 1994.