Doubly N-confused calix[4]pyrrole prepared by rational synthesis

Article abstract of DOI:10.1081/SCC-120003153

Doubly N-confused calix[4]pyrrole 4 is prepared in high yield by the [3 + 1] condensation of tripyrrane 3 with 2,4-dihdoxymethylpyrrole 2 under acid-catalysed conditions.

Full text of DOI:10.1081/SCC-120003153

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DOUBLY N-CONFUSED CALIX[4]PYRROLE PREPARED BY
RATIONAL SYNTHESIS
Qingqi Chen a , Tianyu Wang b , Yi Zhang b , Qiuan Wang c & Jinshi Ma b
a Synapse Technologic Inc. , 6660 NW Marine Drive, Vancouver, BC, V6T V1Z4, Canada
b Center for Molecular Science , Institute of Chemistry , Chinese Academy of Sciences ,
Beijing, 100080, China
c College of Chemistry and Chemical Engineering , Hunan University , Changsha, 410082,
China
Published online: 21 Aug 2006.
To cite this article: Qingqi Chen , Tianyu Wang , Yi Zhang , Qiuan Wang & Jinshi Ma (2002) DOUBLY N-CONFUSED
CALIX[4]PYRROLE PREPARED BY RATIONAL SYNTHESIS, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 32:7, 1051-1058, DOI: 10.1081/SCC-120003153
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SYNTHETIC COMMUNICATIONS, 32(7), 1051–1058 (2002)
DOUBLY N-CONFUSED
CALIX[4]PYRROLE PREPARED BY
RATIONAL SYNTHESIS
Qingqi Chen,1, Tianyu Wang,2 Yi Zhang,2
*
Qiuan Wang,3 and Jinshi Ma2,
*
1Synapse Technologic Inc. 6660 NW Marine Drive,
Vancouver, BC, V6T V1Z4, Canada
2Center for Molecular Science, Institute of Chemistry,
Chinese Academy of Sciences, Beijing 100080, China
3College of Chemistry and Chemical Engineering,
Hunan University, Changsha 410082, China
ABSTRACT
Doubly N-confused calix[4]pyrrole 4 is prepared in high yield
by the [3 þ 1] condensation of tripyrrane 3 with 2,4-dihdoxy-
methylpyrrole 2 under acid-catalysed conditions.
Key Words: Dipyrrinone; Barton-Zard’s method; Pyrrole
Although known for over a century,1 calix [n]pyrroles I, the unconju-
gated cyclopolypyrroles prepared from the oligomerization of pyrrole
with ketone, have recently become the subject of intensive research targe-
ted at the development of novel receptors for anionic,2,3 neutral small
molecules,4 and transition metal ions.5 To improve their binding ability, a
*Corresponding authors. E-mail: qchen@synapse-tech.com
1051
Copyright & 2002 by Marcel Dekker, Inc.
www.dekker.com

1052
CHEN ET AL.
number of structurally modified calix[4]pyrroles such as monosubsitituted,6
functionalized,7 core modified,3a quinoxaline, anthracene, and ferrocene
conjugates,8 dimers,9 extended-cavity,10 have recently been prepared.
In spite of these successes, however, the need to prepare other new
systems for the study of molecule recognition, anion, neutral small molecule
and metal ion binding remains. We therefore wish to report here the rational
synthesis of a new class of calix[4]pyrrole: the doubly N-confused system 4,
which may be of importance as novel host systems.
Calix[4]pyrroles II, a cyclotetrapyrrole containing one N-confused
pyrrole ring, was isolated in 6–22% yields as a by-product from the con-
densation of pyrrole with hexanone under acid-catalysed conditions.11
A
doubly N-confused calix[4]pyrrole was also isolated in 1–36% yields from
the same reaction; however, the author was not able to characterize its
structure due to its extremely low solubility in common deuterium solvents.11
To synthesize doubly N-confused calix[4]pyrrole, we are attracted to
the [3 þ 1] condensation of a tripyrrane with a pyrrolic precusor since
this method has been extensively used to prepare prophyrins and their
analogues,12 core modified prophyrins,13 N-confused prophyrins,14 caraba-
chlorins,15 and calix[n]pyrroles.3a Our synthetic route, outlined as Scheme 1,
involves the synthesis of 2,4-bis[1-phenyl-1-(pyrrole-2-yl)methyl]pyrrole (3)
via acid-catalysed condensation of 2,4-bis[(1-hydroxy-1-phenyl)methyl]-
pyrrole (2) in the presence of excess of pyrrole. The 3 þ 1 condensation of
these two affords a new class of novel calix[4]pyrrole system, in which two
pyrrole rings are N-confused. The important starting material 2 is prepared
in two steps: first acylation16 of pyrrole with excess of benzoyl chloride to
give 2,4-dibenzoylpyrrole (1) in 62% in the presence of anhydrous alumi-
num chloride. Followed to convert 1 to the corresponding dihydroxy 2 in
methanol in the presence of sodium boronhydride.
The [3 þ 1] condensation of 3 with 2 affords in 20% yield a mixture
of regioisomers 4a and 4b. Due to their very close Rf values in different
solvent systems, it is not possible to isolate one of the isomers by common

DOUBLY N-CONFUSED CALIX[4]PYRROLE
1053
Scheme 1.
chromatographic purification procedures. Their MS, m/e 620, and combus-
tion analysis suggest a molecular formula of C44H36N4, which is consistent
with the [3 þ 1] condensation product of 3 with 2. The constitutional
structures are confirmed by the 1H NMR in DMSO-d6, which exhibits
8 : 1 ratio of the signals of meso-CH groups between 5.00–6.00 ppm and
the signals of pyrrolyl-CH, pyrrolyl-NH, and phenyl-CH groups between
6.60–7.50 ppm.
In summary, doubly N-confused calix[4]pyrroles are synthesized
by [3 þ 1] condensation of tripyrrane 3 with 2,4-dihydroxymethylpyrrole 2
under acid-catalysed conditions. Their binding abilities are currently under
study.
EXPERIMENTAL SECTION
Melting points were determined on a Yanaco MP-500 micro-melting
point apparatus and uncorrected. IR spectra were recorded on a BIO-RAD

1054
CHEN ET AL.
FT-165 IR spectrometer. NMR spectra were recorded on a Varian Gemini-
200 MHz instrument using tetramethylsilane as internal standard. UV–VIS
spectra were obtained on a Hitachi U-2001 spectrophotometer. Mass spec-
tra were obtained on VG TR10-200 spectrometer. Elemental analyses were
performed on Carlo Erba-120 elemental analyzer.
2,4-Dibenzoylpyrrole [1, C18H13NO2, FW 5 275]
A 2-l three-necked round-bottomed flask equipped with a reflux con-
denser and mechanic stirrer was charged with anhydrous aluminum chloride
(163 g, 1.20 mol, 2.40 equiv.) and dichloromethane (400 ml). The stirrer was
started, and a solution of pyrrole (35 ml, 0.5 mol) in dichloromethane (50 ml)
was added at 0ꢀC over a period of 10 min, followed by a solution of benzoyl
chloride (164 ml, 1.12 mol, 2.24 equiv.) in dichloromethane (100 ml) which
was added dropwise over a period of 60 min. The mixture was stirred at the
same temperature for another two days before pouring into a mixture of
ice–conc. hydrochloric acid (100 g ice plus 100 ml 35% hydrochloric acid).
The organic phase was separated, and the aqueous phase was extracted
with dichloromethane (3 Â 100 ml). The combined organic extracts were
successively washed with water (2 Â 200 ml), aqueous saturated sodium
bicarbonate (2 Â 200 ml), and brine (200 ml). After removal of the solvent
under vacuum, the residue was crystallized from methanol. The desired
compound was obtained (85.82 g, 62.4%). M.p. 136–138ꢀC (lit.16 140ꢀC),
1H NMR (200 MHz, CDCl3), d: 7.24–8.00 (m, 12H), 11.00 (brs, 1H,
NH) ppm. 13C NMR (CDCl3), d: 102.87, 120.27, 126.25, 128.48, 128.61,
128.94, 129.13, 130.70, 131.78, 132.67, 137.37, 139.08, 185.74 (C¼O),
190.49 (C¼O) ppm.
2,4-Bis(1-Phenyl-1-hydroxymethyl)pyrrole
[2, C18H17NO2, FW 5 279]
A 100-ml three-necked round-bottomed flask equipped with a mag-
netic stirrer bar and reflux condenser was charged with 1,3-dibenzoylpyrrole
(4.0 g, 14.5 mmol) and ethanol (50 ml). The mixture was stirred and sodium
boronhydride (1.38 g, 36.4 mmol, 2.5 equiv.) was added over a period of
20 min. The mixture was then stirred at 50ꢀC until TLC indicated that the
reduction was complete (about 4 h). The solvent was removed under
vacuum, and the oily residue was dissolved in dichloromethane (150 ml)
and partitioned by water (80 ml). The organic phase was separated and
the aqueous was extracted with dichloromethane (2 Â 50 ml). The combined

DOUBLY N-CONFUSED CALIX[4]PYRROLE
1055
organic extracts were successively washed with water (2 Â 100 ml), aqueous
saturated sodium bicarbonate (2 Â 200 ml), and brine (100 ml). After drying
over anhydrous sodium sulfate, and removing the solvent under vacuum,
a colorless oil product was obtained (3.65 g, 90%). NMR experiments
1
showed the product was a mixture of RR, SS, RS, SR isomers. H NMR
(200 MHz, CDCl3), d: 5.20 (brs, 1H, OH), 5.85 (s, 2H, 2CH), 6.40 (s, 1H, OH),
7.00–7.60 (m, 10H), 7.60–7.80 (m, 2H), 9.20 (brs, 1H, NH) ppm. 13C NMR
(50 HMz, CDCl3), d: 69.95 (CHOH), 83.45 (CHOH), 102.47, 102,89, 108.32,
113.86, 126.43, 128.18, 128.64, 128.88, 131.48, 135.70, 139.71, 141.54 ppm.
2,4-Bis[Phenyl-(Pyrrole-2-yl)methyl]pyrrole
[3, C26H23N3, FW 5 377]
A 500 ml three-necked round-bottomed flask equipped a magnetic
stirrer, a reflux condenser, and a nitrogen inlet was charged with 2,4-
bis(1-phenyl-1-hydroxymethyl)pyrrole 2 (0.3 g, 10.9 mmol) and dichloro-
methane (200 ml). The mixture was stirred and nitrogen was bubbled through
the solution. After 20 min, a solution of pyrrole (1.5 ml, 21.8 mmol, 2.0
equiv.) in dichloromethane (10 ml) was added followed trifluoroacetic acid
(2 ml). The mixture was stirred at room temperature for 3 days before
pouring into water (100 ml). The organic phase was separated and the aqu-
eous phase was extracted with dichloromethane (2 Â 50 ml). The combined
organic extracts were successively washed with water (2 Â 100 ml), aqueous
saturated sodium bicarbonate (2 Â 200 ml), and brine (100 ml). After drying
over anhydrous sodium sulfate, and passing through a flash silica gel chro-
matographic column, the solvent was removed under vacuum and the oily
product was obtained (3.3 g, 80%). 1H NMR (CDCl3, 200 MHz),
d ¼ 5.20–5.30 (m, 2H), 5.80–6.30 (m, 8H, 8 pyrrole-H), 7.20–7.60 (m, 10H,
10 phenyl-H), 7.80–8.10 (very broad, 3H, 3 NH) ppm. MS (EI) m/e
(%) ¼ 377 (Mþ, 5), 310 (Mþ-pyrrole, 16), 233 (12), 221 (15), 222 (100),
204 (5), 194 (6), 156 (40), 145 (900), 128 (5), 105 (6).
Tetraphenyl-Doubly N-Confused Calix[4]pyrrole
[4, C44H36N4, FW 5 620]
A 250-ml three-necked round-bottomed flask equipped with a
magnetic stirrer, a reflux condenser, and a nitrogen inlet, was charged
with 2,4-bis[phenyl-(pyrrole-2-yl)methyl]pyrrole (3, 2.73 g, 7.25 mmol), 2,4-
bis (1-phenyl-1-hydroxymethyl)pyrrole (2, 2.02 g, 7.25 mmol), and dichlor-
omethane (150 ml). The mixture was stirred and nitrogen was bubbled

1056
CHEN ET AL.
through the solution. After 30 min, trifluoroacetic acid (3 ml) was added at
once. The mixture was stirred at room temperature for three days under
nitrogen before pouring into water (100 ml). The organic phase was sepa-
rated and the aqueous was extracted with dichloromethane (2 Â 50 ml). The
combined organic extracts were successively washed with water (2 Â 100 ml),
aqueous saturated sodium bicarbonate (2 Â 200 ml), and brine (100 ml).
After drying over anhydrous sodium sulfate, and passing through a flash
silica gel chromatographic column, the solvent was removed under vacuum,
and the residue was crystallized from dichloromethane-hexane to yield the
1
expected compound (0.9 g, 20%) as colorless powder. H NMR (CDCl3,
200 MHz), d: 5.00–6.00 (m, 4H, 4CH), 6.60–7.50 (m, 32H, 4NH, 8 pyr-
role-H, 20 phenyl-H) ppm. MS DCI m/e (%) ¼ 620 (Mþ, 1), 553(2), 463
(70), 398 (60), 308 (70), 247 (30), 221 (20), 156 (100). Calcd. for C44H36N4,
required, C, 85.13; H, 5.84; N, 9.04. Found: C, 84.85; H, 5.44; N, 8.78.
ACKNOWLEDGMENTS
Q.C. thanks Professor David Dolphin (University of British Columbia),
in whose laboratory part of this work was initialized. J.M. thanks The 973
Project (G2000078100) and NSFC (20172055) and the National Key
Laboratory for Structural Chemistry of Unstable and Stable Species who
supported this work.
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Received in the USA March 29, 2001