A facile, highly efficient synthesis of fully N-confused calix[5]pyrrole

Article abstract of DOI:10.1081/SCC-120003152

Fully N-confused calix[5]pyrroles 3 are prepared in high yield by the oligomerization of 3-hydroxyphenylmethylpyrrole 2 under acid-catalysed conditions at room temperature.

Full text of DOI:10.1081/SCC-120003152

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A FACILE, HIGHLY EFFICIENT SYNTHESIS OF FULLY N-
CONFUSED CALIX[5]PYRROLE
Qingqi Chen a , Tianyu Wang b , Yi Zhang b , Qiuan Wang c & Jinshi Ma b
a Synapse Technologic Inc. , 6660 NW Marine Drive, Vancouver, V6T 1Z4, 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) A FACILE, HIGHLY EFFICIENT
SYNTHESIS OF FULLY N-CONFUSED CALIX[5]PYRROLE, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 32:7, 1041-1049, DOI: 10.1081/SCC-120003152
To link to this article: http://dx.doi.org/10.1081/SCC-120003152
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SYNTHETIC COMMUNICATIONS, 32(7), 1041–1049 (2002)
A FACILE, HIGHLY EFFICIENT
SYNTHESIS OF FULLY N-CONFUSED
CALIX[5]PYRROLE
Qingqi Chen,1, Tianyu Wang,2 Yi Zhang,2
*
Qiuan Wang,3 and Jinshi Ma2,
*
1Synapse Technologic Inc., 6660 NW Marine Drive,
Vancouver, V6T 1Z4, 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
Fully N-confused calix[5]pyrroles 3 are prepared in high yield
by the oligomerization of 3-hydroxyphenylmethylpyrrole 2
under acid-catalysed conditions at room temperature.
Key Words: Dipyrrinone; Barton-Zard’s method; Pyrrole
Although calix[n]pyrroles I have been known for over a century,1 their
intriguing properties as novel molecule recognition host systems to selec-
tively bind anions,2,3 neutral small molecules,4 and transition metal ions,5
are recently discerned and have attracted a lot of attention.
*Corresponding authors. E-mail: qchen@synapse-tech.com
1041
Copyright & 2002 by Marcel Dekker, Inc.
www.dekker.com

1042
CHEN ET AL.
To improve their binding ability so as to develop them as chemsensors
to selectively detect anions, small molecules, and metal ions, recent efforts
have been focused on preparing structurally modified calix[n]pyrroles, such
as monosubstituted,6 functionalized,7 quinoxaline, anthracene and ferrocene
conjugates,8 dimers,9 extended-cavity,10 cored modified and expanded cavity
calix[n]pyrrole.11
In this paper we report a new structurally modified calix[5]pyrroles III,
which may be of importance as novel host systems. They are cyclopenta-
pyrroles, in which the pyrrole rings are linked to each other by –CH2–
bridges at positions 2,40. In contrast, the pyrrole rings in calix[n]pyrroles I
are linked to each other through positions 2,20. We thus term III as fully N-
confused calix[5]pyrrole.
N-Confused calix[4]pyrroles II, a cyclotetrapyrrole containing one
N-confused pyrrole rings, was isolated in 6–22% yields as a by-product
from the condensation of pyrrole with hexanone under acid-catalysed
conditions.12 A doubly N-confused calix[4]pyrroles was also separated in
1–36% yields from the same reaction; however, the author was not able to
characterize its structure due to the extremely low solubility in common
deuterium solvents.12 Moreover, fully N-substituted N-confused calix[5]
pyrrole such as III was prepared by oligomerization of a N-substituted
3-hydroxymethylpyrrole under acid-catalysed condition under low tem-
perature.13 However, this molecule may not be a receptor with capacity
to bind anion or metal ion species since there are no any free NH groups.
Thus the N-unsubstituted N-confused calix[5]pyrroles III still remain
unknown.
Our synthetic route, as outlined in Scheme 1, involves cyclization of the
5-unsubstituted 3-hydroxyphenylmethylpyrrole 2 in the presence of p-tolue-
nesulfonic acid monohydrate with yields 60–75%. Compounds 2, prepared
in high yields by treating 3-benzoylpyrrole 1 sodium borohydride in tetra-

N-CONFUSED CALIX[5]PYRROLE
1043
Scheme 1.
hydrofurane, are not stable, and are used immediately without further pur-
ification. It is worth pointing out that attempts to convert 3c to
the corresponding fully N-confused calix[5]pyrrole 3b under standard depro-
tection procedure14 disappointedly failed.
The important starting material 1b was prepared by deprotection of
3-benzoyl-N-tosyl-pyrrole (1c). It is interesting to note that when treating 1c
with potassium hydroxide in dioxane, the expected product 1b was obtained
in 90%. However, when the same reaction was carried out in methanol, a
N-methyl-3-benzoyl-pyrrole (1a) was obtained in 60% (Scheme 2).
Scheme 2.
The structure of N-confused calix[5]pyrroles 3 followed the struc-
1
tures of their starting materials, 2, and was confirmed by H NMR, MS
spectra, and combustion analysis. Due to the possibility of cis- and trans-
arrangement of the five phenyl groups at meso-positions, the cyclization of 2
might produce a number of steroisomers of 3, which could be observed in
their 13CNMR spectra. Although the X-ray structure of 3 are currently not

1044
CHEN ET AL.
Figure 1. View of lowest-energy dominant conformation of 3b, generated by
HyperChemTM, Releases 6.0 for Windows. Upper: top view. Lower: side view. For
clarity, all hydrogen atoms are omitted.
available, the lowest-energy dominant conformation (Figure 1), generated
by HyperChem,15 showed that 3b adopts a 1,3-alternate conformation
wherein adjacent pyrrole rings are oriented in opposite directions just as is
true in the case of the reported calyx[4]pyrrole.2e This suggests that 3b
may be a novel host system for binding anions, neutral small molecules,
or metal ion.
In summary, a convenient and efficient route for the preparation
of fully N-confused calix[5]pyrroles 3 through the cyclization of 3-hydroxy-
phenylmethylpyrrole 2 is reported. Their binding properties 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 BIO-RAD
FT-165 IR spectrometer. NMR spectra were recorded on a Varian Gemini-
200 MHz instrument using tetramethylsilane as internal standard. UV-VIS

N-CONFUSED CALIX[5]PYRROLE
1045
spectra were obtained on a Hitachi U-2001 spectrophotometer. Mass
spectra were obtained on a VG TR10-200 spectrometer. Elemental analyses
were performed on a Carlo Erba-120 elemental analyzer.
3-Benzoyl-N-tosylpyrrole [1c, C18H15NO3S, FW 5 325]
A 1-l three-necked round-bottomed flask equipped with a reflux con-
denser and magnetic stirrer was charged with anhydrous aluminum chloride
(16 g, 0.12 mol, 1.20 mol equiv.), dichloromethane (250 ml) and N-tosylpyr-
role14 (22.1 g, 0.1 mol). The mixture was stirred, and a solution of benzoyl
chloride (14 ml, 0.12 mol, 1.20 mol equiv.) in dichloromethane (50 ml) was
added dropwise over a period of 5 min. The mixture was allowed to stir
another 10 min before pouring into an ice-concentration hydrochloric acid
mixture (100 g ice mixed with 50 ml 35% hydrochloric acid). The organic
phase was separated, and the aqueous phase was extracted with dichloro-
methane (3 Â 100 ml). The combined organic extracts were successively
washed with water (2 Â 200 ml), aqueous saturated sodium bicarbonate
(200 ml  2), and brine (200 ml). After removing the solvent under
vacuum, the crude product was crystallized from methanol. The desired
product was obtained (29 g, 89%) as gray needle crystal. M.p. 75–77ꢀC
[lit.14b 77ꢀC], 1H NMR (200 MHz CDCl3), d: 2.20 (s, 3H, CH3), 6.80
(d, J ¼ 2.56Hz, 1H, pyrr-H), 7.20–7.80 (m, 11H, 2 pyrr-H, 9 phenyl-H) ppm.
3-Benzoylpyrrole [1c]
N-Tosyl-3-benzoylpyrrole (42 g, 0.13 mol) was suspended in a solution
of dioxane (150 ml). The mixture was stirred at room temperature, then
a solution of aqueous potassium hydroxide (5 N, 150 ml) was added
at once. The mixture was stirred at reflux over a period of 12 h.
After removing all solvent under vacuum, the residue was taken up by
dichloromethane (200 ml), and partitioned by water (200 ml). The organic
phase was separated, and the aqueous phase was extracted by dichloro-
methane (3 Â 100 ml). The combined organic extracts were successively
washed with water (2 Â 200 ml), aqueous saturated sodium bicarbonate
(200 ml  2), and brine (200 ml). After removing the solvent under
vacuum, the title compound was obtained as white crystals after crystal-
lization for methanol (20.8 g, 94%). M.p. 98–100ꢀC[lit.
99ꢀC], H NMR
14b
1
(200 MHz, CDCl3), d: 6.80 (mm, 2H, 2 pyrrole-H), 7.20–7.80 (m, 5H,
phenyl-H), 9.20 (brs, 1H, NH) ppm. 13CNMR (CDCl 3), d: 102.86, 110.56,
119.83, 128.91, 124.44, 126.34, 128.91, 131.53, 139.97, 191.90 (C¼O) ppm.

1046
CHEN ET AL.
N-Methyl-3-benzoylpyrrole [1b]
A 250-ml three-necked round-bottomed flask equipped with a
magnetic stirrer bar and reflux condenser was charged with N-tosyl-3-
benzoylpyrrole (13 g, 40 mmol) and methanol (50 ml). The mixture was stir-
red and a solution of potassium hydroxide (20 g, 0.36 mol, 8.9 mol equiv.) in
water (50 ml) was added at once. The mixture was stirred at reflux, and was
monitored by TLC(dichloromethane/methanol, 97/3, v/v). After 10 h, the
reaction was completed. The solvent was removed under vacuum, and the
residue was taken up by 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 organic extracts were succes-
sively washed with water (2 Â 100 ml), aqueous saturated sodium bicarbonate
(200 ml  2), and brine (100 ml). After removing the solvent under vacuum,
the reside was crystallized from aqueous methanol (95%) to offer the
expected product as colorless crystalline (4.4 g, 60%). M.p. 127–129ꢀC.
1H NMR (200 MHz, CDCl3), d: 3.65 (s, 3H, CH3), 6.33 (m, 2H, 2 pyrrole-
H), 7.20 (s, 1H, pyrrole-H), 7.40 (m, 3H, 3 phenyl-H), 7.80 (m, 2H, 2 phenyl-
1
H) ppm. H NMR (200 MHz, dimethyl sulfoxide -d6) d: 3.65 (s, 3H, CH3),
6.52 (m, 1H, pyrrole-H), 6.91 (s, 1H, pyrrole-H), 7.41 (s, 1H, pyrrole-H), 7.65
(m, 3H, 3 phenyl-H), 7.80 (m, 2H, 2 phenyl-H) ppm. 13C NMR (CDCl3), d:
36.63 (CH3), 111.08, 123.11, 124.60, 128.12, 128.55, 131.23, 140.13, 190.54
(C¼O) ppm. MS (EI), m/e ¼ 185 (Mþ, 52%), 170 (Mþ-CH3, 5), 108 (Mþ-Ph,
100), 80 (Mþ-PhCO, 6), 77 (8), 53 (4). For C12H11NO, calcd C, 77.81; H, 5.99;
N, 7.56%. Found: C, 77.45; H, 6.12; N, 7.43.
General Procedure for Synthesis of 3
A 100 ml round-bottomed flask equipped with a magnetic stirrer bar
and a reflux condenser was charged with 3-benzoylpyrrole (3, 3.08 mmol),
dichloromethane (5 ml) and ethanol (50 ml). To this mixture, sodium
boronhydride (0.175 g, 4.6 mmol, 1.5 equiv.) was added. The mixture was
stirred at 50ꢀCuntil TLC(dichloromethane/methanol, 99/1, v/v) indicated
that the reaction was completed (about 3 h). The solvent was removed under
vacuum, and the residue was dissolved in dichloromethane (80 ml) and par-
titioned by water (50 ml). The organic phase was separated and the aqueous
phase was extracted with dichloromethane (2 Â 50 ml). The combined
organic extracts were successively washed with water (2 Â 50 ml), aqueous
saturated sodium bicarbonate (50 ml  2), and brine (50 ml). After drying
over anhydrous sodium sulfate, the resulting solution was transferred into a
100 ml round bottom flask, equipped with a magnetic stirrer, a reflux con-

N-CONFUSED CALIX[5]PYRROLE
1047
denser, and a nitrogen inlet. The stirrer was started and nitrogen was
bubbled through the solution. After 20 min, trifluoroacetic acid (1 ml) was
added. The mixture was allowed to stir 2 h under nitrogen protecting 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 50 ml), aqueous
saturated sodium bicarbonate (50 ml  2), and brine (50 ml). After drying
over anhydrous sodium sulfate, the solvent was removed under vacuum,
and the residue was dissolved in a minimum amount of dichloromethane,
and purified by flash chromatographic column (dichloromethane/methanol,
v/v, 97/3), and crystallized from methanol to yield the expected compound.
N-Tosyl N-Confused Calix[5]pyrrole [3c]
Yield: 60%, m.p. 205ꢀC(dec.). 1H NMR (CDCl3, 200 MHz), d: 2.20
(m, 15H, 5 CH3), 5.20–6.00 (m, 5H, 5CH), 6.90–8.00 (m, 55H, 10 pyrrolyl-
1
H, 45 phenyl-H) ppm. H NMR (DMSO-d6, 200 MHz), d: 1.80–2.00 (m,
15H, 5 CH3), 5.00–5.20 (m, 5H, 5CH), 6.20–7.20 (m, 55H, 10 pyrrolyl-H,
45 phenyl-H) ppm. MS(EI), m/e (%) ¼ 1546 (Mþ, 2), 1391 (Mþ-tosyl, 5),
1237 (32), 1083 (41), 927 (38), 773 (23), 619 (25), 551 (10), 465 (15), 310 (61),
244 (100). For C90H75N5O10S5, calcd C, 69.88; H, 4.89; N, 4.53%. Found:
C, 70.12; H, 4.67; N, 4.33%.
N-Methyl N-Confused Calix[5]pyrrole [3a]
Yield: 70%, m.p. 189ꢀC(dec.). 1H NMR (CDCl3, 200 MHz), d: 3.20
(m, 15H, 5 CH3), 5.20, 5.80 (mm, 5H, 5CH), 7.00–8.00 (m, 35H, 10 pyrrolyl-
H, 25 phenyl-H) ppm. MS(EI), m/e (%) ¼ 846 (Mþ, 2), 765 (5), 675 (23),
600 (5), 599 (15), 507 (49), 430 (15), 349 (10), 338 (100), 261 (74), 170 (25).
For C60H55N5, calcd C, 85.17; H, 6.55; N, 8.28. Found: C, 84.89; H, 6.23;
N, 8.01.
N-Confused Calix[5]pyrrole [3b, (C11H9N)n, n 3 155]
Yield: 75%, m.p. 195ꢀC(dec.). 1H NMR (CDCl3, 200 MHz), d:
5.00–5.30, 5.70 (mm, 5H, 5CH), 5.80–6.90, 7.00–7.80 (mm, 35H, 10 pyrro-
lyl-H, 25 phenyl-H), 7.90–8.00, 8.60–8.80 (brs, 5H, 5 NH) ppm. MS (EI)
at 200ꢀC, m/e (%) ¼ 775 (Mþ, 2), 708 (3), 620 (31), 553 (10), 532 (5), 479
(13), 465 (52), 402 (8), 398 (23), 309 (93), 244 (23), 233 (35), 156 (100).

1048
CHEN ET AL.
For C55H45N5, calcd C, 85.13; H, 5.84; N, 9.03%. Found: C, 84.85; H, 5.64;
N, 8.88%.
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