Synthesis of Unsymmetrical Pyrrolo[3,2-b]pyrrole-2,5-diones

Article abstract of DOI:10.1055/s-2003-42095

The first unsymmetrical oxalic acid-bis(imidoyl)dichlorides were prepared and applied to the one-pot synthesis of the first unsymmetrical pyrrolo[3,2-b]pyrrole-2,5-diones and 2,2′-bis-quinazolin-4-ones.

Full text of DOI:10.1055/s-2003-42095

LETTER
2389
Synthesis of Unsymmetrical Pyrrolo[3,2-b]pyrrole-2,5-diones
Synthesisof
U
e
nsymmetri
t
e
b
]p
r
yrrole-2,5-dio
Lnes anger,* Falko Helmholz, Rita Schroeder
Institut für Chemie und Biochemie der Ernst-Moritz-Arndt-Universität Greifswald, Soldmannstr. 16, 17487 Greifswald, Germany
E-mail: Peter.langer@uni-greifswald.de
Received 14 July 2003
The reaction of commercially available ethyl 2-chloro-2-
oxoacetate with aniline (1a) gave the known amide 2a
(78%). The reaction of 2a with 2-anisidine afforded the
novel unsymmetrical oxalyl diamide 3a (78%). Treatment
of the latter with phosphorus pentachloride (PCl5) afford-
ed the unsymmetrical oxalic acid-bis(imidoyl) dichloride
4a (48%). The quality of PCl5, the reaction time (1 h, re-
flux), the absence of water and the conditions for recrys-
tallization (n-heptane) were important parameters during
the optimization of this transformation.9 The reaction of
the enolate of ethyl phenylacetate (5a), generated by
LDA, with 4a afforded the unsymmetrical pyrrolo[3,2-
b]pyrrole-2,5-dione 6a in 55% yield.10 During the optimi-
zation of this reaction, the stoichiometry (5a:4a = 2.3/1),
the reaction time (–78 to 20 °C, 14 h, then 20 °C, 36 h)
and the conditions for recrystallization (DMF or DMSO)
played an important role to isolate 6a in optimal yield.
Abstract: The first unsymmetrical oxalic acid-bis(imidoyl)dichlo-
rides were prepared and applied to the one-pot synthesis of the first
unsymmetrical pyrrolo[3,2-b]pyrrole-2,5-diones and 2,2¢-bis-
quinazolin-4-ones.
Key words: one-pot synthesis, unsymmetrical pyrrolo[3,2-b]pyr-
role-2,5-diones, dilactams of pulvinic acid
1,4-Dioxo-3,6-diphenylpyrrolo[3,4-c]pyrroles (DPP) rep-
resent formal dilactams of pentalene and are of consider-
able interest in the field of material sciences, due to their
optical properties.1 They have been used as key building
blocks of photo- and electroluminescent conjugated
polymers and dendritic structures.2 Pyrrolo[3,2-b]pyrrole-
2,5-diones, the positional isomers, can be regarded as di-
lactams of pulvinic acid – a natural pigment found in li-
chens.3
Pyrrolo[3,2-b]pyrrole-2,5-diones
represent
important optical materials;4 synthetic approaches to a
number of symmetrical derivatives have been reported.5,6
The synthesis of unsymmetrical derivatives is of consid-
erable interest for several reasons: a) the optical properties
can be more properly tuned; b) push-pull systems can be
prepared;7 c) the selective attachment of the heterocyclic
system to a polymeric or dendritic backbone requires the
presence of only one rather than two functional groups in
the molecule. Despite their potential importance, the syn-
thesis of unsymmetrical pyrrolo[3,2-b]pyrrole-2,5-diones
has not yet been realized.
To study the preparative scope of our methodology the
substituents of the starting materials were systematically
varied (Scheme 1, Table 1). The reaction of bis(imidoyl)
O
Cl
O
NEt3
EtO
O
O
N
EtO
+
R1
THF
R1 NH2
H
0 –20 °C
2
1
EtOH
reflux
R2 NH2
We have recently developed an efficient one-pot synthesis
of symmetrical pyrrolo[3,2-b]pyrrole-2,5-diones by reac-
tion of ester carbanions with oxalic acid-bis(imi-
doyl)dichlorides which can be regarded as aza-analogues
of oxalyl chloride.6,8 The scope of this method was severe-
ly limited by the fact that only symmetrical bis(imidoyl)
dichlorides were available. Herein, we wish to report the
synthesis of unsymmetrical oxalic acid-bis(imidoyl)
dichlorides. In addition, the application of these building
blocks to the synthesis of unsymmetrical pyrrolo[3,2-
b]pyrrole-2,5-diones and 2,2¢-bis-quinazolin-4-ones is re-
ported. Oxalic acid-bis(imidoyl) dichlorides have been
used for the synthesis of a great variety of heterocyclic
systems.8 Therefore, the unsymmetrical bis(imidoyl)
dichlorides reported herein should be of general interest.
H
N
PCl5
R2
N
Cl
R2
O
Cl
N
R1
Toluene
reflux
O
N
H
R1
3a–k
4a–k
O
2.6 equiv LDA
THF
20 °C, 14 h
20 °C, 36 h
R3
2.3
OEt
_
78
5
OEt
R3
NHR2
R1
R3
O
R1HN
N
O
O
R3
N
R2
R3
O
EtO
6a–m
SYNLETT 2003, No. 15, pp 2389–2391
0
1
.1
2
.2
0
0
3
Scheme 1 Synthesis of unsymmetrical oxalic acid-bis(imidoyl)
dichlorides 4 and pyrrolo[3,2-b]pyrrole-2,5-diones 6
Advanced online publication: 15.10.2003
DOI: 10.1055/s-2003-42095; Art ID: D17203ST
© Georg Thieme Verlag Stuttgart · New York

2390
P. Langer et al.
LETTER
Table 1 Products and Yields
3,4
a
a
b
b
c
6
a
b
c
d
e
f
R1
R2
R3
% (3)a
78
“
% (4)a
48
“
% (6)a
C6H5
2-(MeO)C6H4
C6H5
55
54
35
30
35
46
33
52
42
32
30
34
11
“
“
4-MeC6H4
C6H5
“
4-(MeO)C6H4
85
“
45
“
“
“
4-(MeO)C6H4
4-MeC6H4
C6H5
4-MeC6H4
C6H5
“
64
65
63
63
60
56
51
50
82
49
56
65
57
65
65
77
57
22
d
e
1-Naphthyl
g
h
i
“
2,4-Me2C6H3
4-MeC6H4
C6H5
f
4-MeC6H4
4-(MeO)C6H4
C6H5
“
g
h
i
“
4-MeC6H4
“
j
3,5-Me2C6H3
k
l
4-MeC6H4
4-(MeO)C6H4
4-(O2N)C6H4
“
C6H5
j
“
“
k
m
4-(MeO)C6H4
4-MeC6H4
a Yields of isolated products.
dichloride 4a with ethyl 4-tolylacetate afforded the pyr-
rolo[3,2-b]pyrrole-2,5-dione 6b. The unsymmetrical
bis(imidoyl) dichloride 4b was prepared from aniline and
4-anisidine in three steps via oxalyl diamide 3b. The cy-
clization of 4b with ethyl phenylacetate and ethyl 4-meth-
oxyphenylacetate gave the pyrrolo[3,2-b]pyrrole-2,5-
diones 6c and 6d. The reaction of bis(imidoyl) dichloride
4c, prepared from 4-toluidine and 4-anisidine, with ethyl
4-tolylacetate afforded 6e. The dione 6f was prepared
from ethyl phenylacetate and bis(imidoyl) dichloride 4d
which was prepared from aniline and 1-aminonaphtha-
lene. The bis(imidoyl) dichloride 4e was prepared from
aniline and 1-amino-2,4-xylene. The cyclization of 4e
with ethyl 4-tolylacetate afforded the pyrrolo[3,2-b]pyr-
role-2,5-dione 6g. Dichloride 4f was prepared from 4-
toluidine and 1-amino-2,4-xylene. The cyclization of 4f
with ethyl phenylacetate afforded 6h. Similarly, heterocy-
cle 6i was prepared from bis(imidoyl) dichloride 4g.
Bis(imidoyl) dichlorides 4j, 4h and 4l were prepared from
1-amino-3,5-xylene and aniline, 4-toluidine or 4-anisi-
dine, respectively. Starting with these dichlorides, the pyr-
rolo[3,2-b]pyrrole-2,5-diones 6j–l were prepared. The
push-pull substituted bis(imidoyl) dichloride 4k was pre-
pared from 4-nitroaniline and 4-anisidine. The cyclization
of 4k with ethyl 4-tolylacetate afforded the pyrrolo[3,2-
b]pyrrole-2,5-dione 6m.
O
O
N
OMe
NH2
R1
2
N
N
3.0 equiv NEt3
7
R1
N
Cl
N R2
N
THF, 68 °C
36 h
R2
+
O
8
Cl
4c
R1 = 4-MeC6H4 R2 = 4-(MeO)C6H4
Scheme 2 Synthesis of unsymmetrical 2,2¢-bis-quinazolin-4-ones
rical bis(imidoyl) dichloride 4c with 7 (Scheme 2). 2,2¢-
bis-Quinazolin-4-ones are of considerable pharmacologi-
cal relevance.11 The formation of 8 can be explained by
condensation of 7 (2 equiv) with 4c (1 equiv) to give an
open-chain intermediate and subsequent cyclization by
attack of the nitrogen atoms onto the ester groups.
References
(1) (a) Closs, F.; Gompper, R. Angew. Chem., Int. Ed. Engl.
1987, 26, 552; Angew. Chem. 1987, 99, 564. (b) Closs, F.;
Gompper, R.; Nöth, H.; Wagner, H.-U. Angew. Chem., Int.
Ed. Engl. 1988, 27, 842; Angew. Chem. 1988, 100, 875.
(c) Casser, L.; Iqbal, A.; Rochat, A. C. Eur. Pat. Appl., EP
98808, 1983; Ciba-Geigy.
(2) (a) Beyerlein, T.; Tieke, B. Macromol. Rapid Commun.
2000, 21, 182. (b) Beyerlein, T.; Tieke, B.; Forero-Lenger,
S.; Brütting, W. Synth. Metals 2002, 130, 115.
First results show that unsymmetrical 2,2¢-bis-quinazolin-
4-ones can be prepared by reaction of bis(imidoyl) dichlo-
rides with anthranilic ester. For example, the novel 2,2¢-
bis-quinazolin-4-one 8 was prepared from the unsymmet-
Synlett 2003, No. 15, 2389–2391 © Thieme Stuttgart · New York

LETTER
Synthesis of Unsymmetrical Pyrrolo[3,2-b]pyrrole-2,5-diones
2391
(3) (a) Rao, Y. S. Chem. Rev. 1976, 76, 625. (b) Pattenden, G.
Prog. Chem. Nat. Prod. 1978, 35, 133. (c) Knight, D. W.
Contemp. Org. Synth. 1994, 1, 287. (d) Schweppe, M.
Handbuch der Naturfarbstoffe; ecomed Verlagsgesellschaft:
Landsberg, 1992, 185. (e) Schweppe, M. Handbuch der
Naturfarbstoffe; ecomed Verlagsgesellschaft: Landsberg,
1992, 525.
(w), 1521 (m), 1666 (s), 3282 (s)cm–1. 1H NMR (200 MHz,
CDCl3): d = 2.23 (s, 3 H, CH3), 2.34 (s, 3 H,CH3), 6.94–7.66
(m, 8 H, Ar). 13C NMR (50 Hz, CDCl3): d = 17.83, 21.03,
118.65, 120.12, 120.35, 126.51, 126.73, 128.95, 129.74,
131.27, 136.47, 136.60, 142.01, 145.79. MS (EI, 70 eV):
m/z (%) = 305 (15) [M+], 269 (7), 166 (33), 138 (36), 77
(44), 28 (100). Anal. Calcd for C16H14Cl2N2 (305.06): C,
62.99; H, 4.58; N, 9.17. Found: C, 63.08; H, 4.96; N, 9.09.
All new compounds gave satisfactory spectroscopic and
analytical and/or high resolution mass data.
(4) Herbst, W.; Hunger, K. Industrial Organic Pigments; VCH:
Weinheim, 1993, 550.
(5) Selected symmetrical pyrrolo[3,2-b]pyrrole-2,5-diones have
been prepared in three steps from (N-phenylacetyl)-acetic
acid amino ester: (a) Bayer AG, a one step synthesis using
pulvinic acid proceeded under harsh conditions (autoclave
reaction, 140–180 °C: Fürstenwerth, H. Ger. Offen., DE
3,525,109 A1, 1987; Chem. Abstr. 1987, 106, 103815f.
(b) Ciba-Geigy: Rochat, A. C.; Iqbal, A.; Pfenninger, J.;
Casser, L. Eur. Pat. Appl., EP 016309, 1984. (c) See also:
Solberg, Y. Z. Naturforsch. 1977, 32c, 292. (d) Stachel, H.-
D. Arch. Pharm. Ber. Dtsch. Pharm. Ges. 1962, 295, 735.
(e) Mukai, T.; Konno, A.; Kumagai, T.; Satake, K. Chem.
Lett. 1985, 1809. (f) Stachel, H.-D.; Schorp, M.; Maier, L.;
Dandl, K. Liebigs Ann. Chem. 1994, 1121.
(10) General Procedure for the Synthesis of Unsymmetrical
Pyrrolo[3,2-b]pyrrole-2,5-diones (6). A THF solution of
LDA was prepared by addition of n-BuLi (5.15 mL, 7.92
mmol, solution in n-hexane) to a THF solution (6.1 mL) of
diisopropylamine (1.22 mL, 8.71 mmol) at 0 °C. After
stirring for 30 min a THF solution (33 mL) of ethyl 4-
tolylacetate (1.18 mL, 6.60 mmol) was added. The solution
was stirred for 1 h at 0 °C. The mixture was cooled to –78 °C
and a THF solution (18 mL) of 4c (967 mg, 3.00 mmol) was
slowly added. The solution was warmed to 20 °C during 14
h and was stirred for 36 h at 20 °C. The mixture was poured
into an aqueous solution of ammonium chloride (300 mL, 5
M). The addition of Et2O (200 mL) resulted in the formation
of a precipitate, which was washed with Et2O, dried in vacuo
and recrystallized from DMF. For some products DMSO
was used. The product 6e was obtained as an orange solid
(538 mg, 35%), mp 344 °C. IR (KBr): 977 (m), 1168 (m),
1252 (m), 1301 (w), 1415 (m), 1514 (s), 1612 (m), 1653 (s),
1735 (s), 3437 (m)cm–1. UV-Vis: 361 (4.33). 1H NMR (200
MHz, CDCl3): d = 2.27 (s, 6 H, CH3), 2.33 (s, 3 H, CH3),
3.79 (s, 3 H, OCH3), 6.77–7.09 (m, 16 H, Ar). 13C NMR (50
Hz, CDCl3): d = 21.12, 21.33 (CH3), 55.57 (OCH3), 104.72,
104.78 (C), 113.97 (CH), 125.23, 125.28 (C), 125.91 (CH),
126.83 (C), 127.42, 128.24, 128.32, 129.23, 129.69, 129.75
(CH), 131.28, 137.17, 137.18, 137.96, 137.97, 144.80,
145.06, 158.67 (C), 170.91, 171.05 (CO). MS (EI, 70 eV):
m/z (%) = 512 (100) [M+], 497 (11), 496 (10), 236 (10), 102
(36). Anal. Calcd for C34H28O3N2 (512.6): C, 79.66; H, 5.51;
N, 5.46. Found: C, 79.19; H, 5.86; N, 5.37.
(6) Langer, P.; Wuckelt, J.; Döring, M. J. Org. Chem. 2000, 65,
729.
(7) Push-pull substituted heterocycles are of considerable
importance. For a review, see: (a) Gompper, R.; Wagner,
H.-U. Angew. Chem., Int. Ed. Engl. 1988, 27, 1437; Angew.
Chem. 1988, 100, 1492. (b) See also: Effenberger, F.;
Schlosser, H.; Bäuerle, P.; Maier, S.; Port, H.; Wolf, H. C.
Angew. Chem., Int. Ed. Engl. 1988, 27, 281; Angew. Chem.
1988, 100, 274.
(8) Review: Langer, P.; Döring, M. Eur. J. Org. Chem. 2002,
221.
(9) General Procedure for the Synthesis of Unsymmetrical
Oxalic Acid-bis(imidoyl) dichlorides (4). Oxalic acid N-
phenyl-N¢-(2,4-dimethylphenyl)-bis(imidoyl) dichloride
(4e): A toluene solution (60 mL) of 3e (2.68 g, 10.0 mmol)
and of PCl5 (4.16 g, 20.0 mmol) was refluxed for 1 h. The
mixture was concentrated to 30 mL and stored at –20 °C to
give a yellow precipitate. The later was isolated by filtration
and recrystallized from n-heptane to give 4e as yellow
crystals (2.00 g, 65%), mp 148 °C. IR (KBr): 826 (m), 1443
(11) For symmetrical derivatives, see: Langer, P.; Wuckelt, J.;
Döring, M.; Görls, H. Eur. J. Org. Chem. 2001, 1503.
Synlett 2003, No. 15, 2389–2391 © Thieme Stuttgart · New York