The pyrrole approach toward the synthesis of fully functionalized cup-shaped molecules

Article abstract of DOI:10.1021/ol047569f

(Chemical Equation Presented) A novel method for the synthesis of new highly functionalized cyclotrimers is described. The method consists of an original synthesis of β-dibromosubstituted pyrroles, metalation, cycloaddition, and cyclotrimerization. The se

Full text of DOI:10.1021/ol047569f

ORGANIC
LETTERS
2005
Vol. 7, No. 6
1003-1006
The Pyrrole Approach toward the
Synthesis of Fully Functionalized
Cup-Shaped Molecules
Cristiano Zonta,* Fabrizio Fabris, and Ottorino De Lucchi
Dipartimento di Chimica, UniVersita` Ca’ Foscari di Venezia,
Dorsoduro 2137, I-30123 Venezia, Italy
zontac@uniVe.it
Received November 26, 2004
ABSTRACT
A novel method for the synthesis of new highly functionalized cyclotrimers is described. The method consists of an original synthesis of
-dibromosubstituted pyrroles, metalation, cycloaddition, and cyclotrimerization. The sequence is highly compatible with common functional
â
groups and allows the construction of cup-shaped molecules functionalized both at the upper and bottom rim. This feature makes the newly
formed structures useful scaffolds for the development of supramolecular receptors.
The success of supramolecular chemistry in the recent years
has been characterized by the large number of original
systems which were developed to meet functional require-
ments.1 Calixarenes, crown ethers, resorcinarenes, just to cite
a few examples, have been major actors in the scene of
molecular recognition. All these systems possess common
characteristics such as the ease of synthesis, a certain level
of rigidity and most importantly the possibility to be
smoothly functionalized. For these reasons, it was possible
to use calixarenes as receptors, to bind them covalently on
gold surfaces, or to use them as scaffolds for the synthesis
of nanocapsules.2 In the recent years we have been working
in the synthesis of cup-shaped molecules using cyclo-
trimerization reactions. The synthesis of tris-annelated
structures allowed a practical synthesis of fullerene fragments
and of scaffolds with recognition properties.3,4 The general
approach consisted in synthesizing a vicinal halogen-metal
vinyl system, which undergoes cyclotrimerization in high
yield. However, this method did not appear to be applicable
if functionalities other than protected alcohols are present
in the substrates (Scheme 1a). For example, bromination
Scheme 1 a
a General conditions: (i) C2Cl4Br2, CCl4, hν; (ii) t-BuOK, THF,
rt; (iii) (1) LDA, THF, (2) Me3SnCl. P: protecting group.
(1) Steed, J. W.; Atwood J. L. Supramolecular Chemistry; John Wiley
& Sons: New York, 2000.
(2) (a) Gutsche, C. D. Calixarenes ReVisited in Monographs in Supramo-
lecular Chemistry; The Royal Society of Chemistry: London, 1998. (b)
Jasat, A.; Sherman, J. C. Chem. ReV. 1999, 99, 931-967. (c) Calixarenes
In Action; Mandolini, L., Ungaro, R., Eds.; Imperial College Press: London,
2000.
under ionic conditions of certain bicyclic systems leads to
the formation of undesired products due to Wagner-
Meerwein rearrangement while bromination under radical
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conditions in the presence of light caused decomposition of
some starting materials.5 Equally the use of strong bases in
the metalation or dehydrobromination steps excludes the
presence of base sensitive functional groups in the substrate.
To overcome these hurdles, we investigated the use of
protected aza-bicyclic systems, which could be obtained by
cycloaddition between 3,4-disubstituted pyrroles and electron
deficient dienophiles (Scheme 1b). In this approach, bromi-
nation and metalation are carried out on the starting pyrrole
before the cycloaddition step, allowing the presence of
diverse functionalities in the dienophile. Moreover, the
protected aza-bridge allows for further functionalization.
The basic knowledge for this approach is the widely
explored chemistry of pyrroles usually directed at the
synthesis of aza-bicycles included in alkaloids.6 Recently,
Tidwell et al. reported a method to prepare â-dibromo
substituted pyrroles which could be useful starting materials
for our approach.7 The method uses the steric properties of
triisopropylsilyl (TIPS) protected nitrogen to force the
formation of â-substituted compounds. Disappointedly, the
reaction of benzine on N-TIPS-3,4-dibromopyrrole failed to
afford the expected cycloadduct. These preliminary data
prompted us to investigate different N-protecting groups
aimed at favoring the cycloaddition step, focusing our
attention on electron-withdrawing groups, that are known
to diminish the aromatic character of pyrroles. From the
literature it is also known that R substituted N-protected
pyrroles rearrange at â position under acidic conditions due
to the higher thermodynamic stability of the â adducts.8 On
this basis, we submitted the N-tosyl-protected pyrrole 2
(prepared in multigram scale using a procedure described in
the literature for the benzene sulfonyl chloride) to 2-fold
bromination (Scheme 2).9,10 The tosyl group provides the
Several conditions for the bromination were used. The use
of a catalytic amount of trifluoro acetic acid in DCM with 1
or 2 equiv of bromine led to mixtures of monosubstituted
and disubstituted products. The selective dibromination in
R position using NBS at low temperatures and the subsequent
rearrangement with 10% of trifluoroacetic acid gave complex
mixtures.11 Better results were obtained using acetic acid as
solvent. Under these conditions, two equivalents of bromine
at reflux furnished mainly the desired product. GC-MS
analysis of the crude mixture revealed that in the course of
the reaction the R-R′ dibromide rearranges to the â-â′
isomer in 1 h under reflux. Filtration over silica and
subsequent recrystallization in DCM/Et2O gave 43% of 3
as a colorless solid.12,13 Possibly, the hydrobromic acid
produced under the reaction conditions led to a certain degree
of tosyl group deprotection.
Despite the moderate productivity, the procedure gives the
possibility to selectively synthesize and easily isolate mono-
and dibromo-substituted pyrroles starting from inexpensive
reagents.14
The synthesis of 4 was accomplished via metal-halogen
exchange with t-BuLi and subsequent quenching with
trimethyltin chloride in high yield (Scheme 3).15 Compounds
Scheme 3
Scheme 2
3 and 4 were then used in the Diels-Alder reaction with
dimethyl acetylene dicarboxylate (DMAD). They both
(9) Pleus, S.; Schwientek, M. Synth. Commun. 1997, 27, 2917-2930.
(10) Zelikin, A.; Shastri, V. R.; Langer, R. J. Org. Chem. 1999, 64,
3379-3380.
(11) Fu¨rstner, A.; Krause, H.; Thiel, O. R. Tetrahedron 2002, 58, 6373-
6380.
necessary electron-withdrawing feature and stability to the
acidic conditions.
(12) General Procedure for the Synthesis of 3. A solution of bromine
(7.4 mL, 0.14 mol) in acetic acid (80 mL) was slowly added to a solution
of 2 (13.5 g, 0.06 mol) in acetic acid (200 mL) over 30 min. After addition
was completed the mixture was heated to reflux for 1.5 h. The reaction
mixture was warmed to room temperature and the solvent removed under
reduced pressure. The black oil was filtered through a column of silica
using DCM as eluant. The resulting oil was recrystallised in a DCM/ether
mixture giving 3 (6.5 g) as colorless crystals. The remaining oil was then
purified using silica flash chromatography (DCM) affording further 3.5 g
of product with an overall yield of 43%.
(3) (a) Durr, R.; Cossu, S.; Lucchini, V.; De Lucchi, O. Angew. Chem.,
Int. Ed. 1998, 36, 22805-2807. (b) Borsato, G.; De Lucchi, O.; Fabris, F.;
Groppo, L.; Lucchini, V.; Zambon A. J. Org. Chem. 2002, 67, 7894-7897.
(4) (a) Zonta, C.; Cossu, S.; De Lucchi, O. Eur. J. Org. Chem. 2000,
1965-1971. (b) Sakurai, H.; Daiko, T.; Hirao, T. Science 2003, 301, 1878.
(5) (a) Tutar, A.; Taskesenligil, Y.; C¸ akmak, O.; Abbasogˇlu, R.; Balci,
M. J. Org. Chem. 1996, 61, 8297-8300. (b) Dowle, M. D.; Davies, D. I.
Chem. Soc. ReV. 1979, 171-197.
(6) (a) Chen, Z.; Trudell, M. L. Chem. ReV. 1996, 96, 1179-1193. (b)
Zhang, C.; Trudell, M. L. Tetrahedron 1998, 54, 8349-8354.
(13) Selected data for 3: 1H NMR (300 MHz, CDCl3, 25 °C) δ ) 7.80-
1
1
(7) Bray, B. L.; Mathies, P. H.; Naef, R.; Solas, D. R.; Tidwell, T. T.;
Artis, D. R.; Muchowaski, J. M. J. Org. Chem. 1990, 55, 6317-6328.
(8) (a) Choi, D.-S.; Huang, S.; Huang, M.; Barnard, T. S.; Adams, R.
D.; Seminario, J. M.; Tour, J. M. J. Org. Chem. 1998, 63, 2646-2655. (b)
Gilow, H. M.; Burton, D. E. J. Org. Chem. 1981, 46, 2221-2225.
7.75 (m, 2 H, /2 AB), 7.37-7.32 (m, 2 H, /2 AB), 7.19 (s, 2 H, H-2 and
H-5), 2.44 (s, 3 H); 13C NMR (CDCl3, 75 MHz) δ ) 146.4, 135.9, 130.8,
127.6, 120.4, 105.6, 22.1; IR (KBr, cm-1) 3137, 1594, 1520, 1455, 1376,
1172, 1057, 782. MS (EI+) m/z 379 (7) [M+], 155 (74) [C7H7O2S+], 91
(100) [C7H7+].
1004
Org. Lett., Vol. 7, No. 6, 2005

underwent cycloaddition smoothly using the dienophile as
solvent. Interestingly, the tin atom seems to offer d-
retrodonation favoring the reaction conditions. As expected,
compound 5 did not give metalation due to decomposition
of the starting cycloadduct.
The cyclotrimerization reaction was performed using
copper thiophenecarboxylate (CuTC)16 at -20 °C for 1 h
(Scheme 4).3 The reaction afforded the cyclotrimers anti-7
cycloddition of â-dibromopyrrole 3 and benzine generated
from anthranilic acid and isoamylnitrite.19 With the metalated
cycloadduct 9 in hands, the trimerization was performed
using standard conditions to obtain the trimers syn-10 and
anti-10 in a 1:3 statistical ratio.20,21 Both products were
separated using flash chromatography. Interestingly, the 1H
NMR spectrum for compound anti-10 shows unexpected
high field chemical shifts of the tosyl group protons (Figure
1). In the compound, the pocket formed by the two
Scheme 4
and syn-7 in 82% yield in 1:1.2 ratio. The two isomers were
isolated using column chromatography.17 The structures of
the syn-7 and anti-7 were assigned according to symmetry
consideration.18
To prove the viability of the method, the synthesis of
cyclotrimer 10 was performed (Scheme 5). The precursor
Scheme 5
1
Figure 1. Partial H NMR spectrum of the compound anti-10 in
acetone-d6 and MM2-minimized structure showing edge-to-face
interaction between the tosyl group and the aromatic cleft.
contiguous aromatic rings generates a cleft in which the
electron-poor tosyl group forms a double edge-to-face
interaction.22
To conclude, a new approach to the synthesis of cup-
shaped molecules has been developed. This method is based
on original synthesis of a â-dibromopyrrole, its metalation
and subsequent cycloaddition. The cyclotrimers represent
highly functionalized structures for future derivatization and
of the cyclotrimerization 9 was prepared by metalation of
the dibromo derivative 8, which in turn was obtained by
(19) Lautens, M.; Fagnou, K.; Zunic, V. Org. Lett. 2002, 4, 3465-
3468.
(14) One equivalent of bromine in the same condition led to the formation
of the â bromo isomer 11 in 72% yield.
(20) Selected data for syn-10: 1H NMR (300 MHz, CDCl3, 25 °C) δ
1
1
7.45-7.44 (m, 6 H, /2 AB), 7.12-7.08 (m, 6 H, /2 AB), 6.82-6.79 (m,
1
1
(15) Shum, P. W.; Kozikowski, A. P. Tetrahedron Lett. 1990, 31, 6785-
6 H, /2 AA′BB′), 6.63-6.59 (m, 6 H, /2 AA′BB′), 5.79 (s, 6 H), 2.32 (s,
9H); 13C NMR (CDCl3, 75 MHz) δ 144.8, 144.1, 134.5, 134.1, 130.0, 128.2,
126.7, 121.1, 66.4, 21.9.
6788.
(16) (a) Allred, G. D., Liebeskind, L. S., Sanford; S. J. Am. Chem. Soc.
1996, 118, 2748-2749. (b) Zhang, S.; Zhang, D.; Liebeskind, L. S. J. Org.
Chem. 1997, 62, 2312-2313.
(21) Selected data for anti-10: 1H NMR (300 MHz, CD3COCD3, 25 °C)
1
1
δ 7.60-7.56 (m, 2 H,
/ AA′BB′), 7.35-7.31 (m, 2 H, / AB), 7.29-
2 2
1
1
(17) Selected data for syn-7: 1H NMR (300 MHz, CDCl3, 25 °C) δ 7.59-
7.25 (m, 2 H, /2 AA′BB′), 7.13-7.08 (m, 8 H, /2 AB), 6.67-6.63 (m, 8
H, 1/2 AB), 6.20 (s, 2 H), 6.12 (s, 2 H), 6.05 (s, 2 H), 5.95-5.91 (m, 2 H,
1/2 AB), 2.87 (s, 3H), 2.83 (s, 6H); 13C NMR (CDCl3, 75 MHz) δ 146.8,
146.3, 146.0, 143.4, 142.4, 135.1, 135.0, 134.6, 134.5, 134.3, 129.7, 129.2,
127.7, 127.2, 126.8, 126.6, 126.4, 122.0, 121.9, 121.5, 66.6, 66.3, 66.0,
20.8, 20.7.
1
1
7.54 (m, 6 H, /2 AB), 7.29-7.24 (m, 6 H, /2 AB), 5.76 (s, 6 H), 3.65 (s,
18 H), 2.40 (s, 9 H); 13C NMR (CDCl3, 75 MHz) δ 161.6, 147.1, 145.1,
134.3, 133.6, 130.6, 128.3, 68.1, 52.7, 21.9.
(18) Selected data for anti-7: 1H NMR (300 MHz, CDCl3, 25 °C) δ 7.56-
1
1
7.46 (m, 2 H, /2 AB), 7.42-7.37 (m, 4 H, /2 AB), 7.17-7.12 (m, 6 H, 2
1/2 AB), 5.72 (s, 2 H), 5.66 (s, 4 H), 3.96 (s, 6 H), 3.76 (s, 6 H), 3.74 (s,
6 H), 2.34 (s, 3H), 2.34 (s, 6 H); 13C NMR (CDCl3, 75 MHz) δ 161.7,
161.6, 161.4, 147.9, 147.6, 145.3, 145.0, 134.3, 134.2, 134.0, 133.5, 133.4,
130.6, 130.3, 128.3, 128.0, 68.3, 68.1, 67.8, 53.3, 53.0, 52.9, 21.9 (2
carbons).
(22) (a) Hunter, C. A.; Lawson, K. R.; Perkins, J.; Urch, C. J. J. Chem.
Soc., Perkin Trans. 2 2001, 5, 651-669. (b) Carver, F. J.; Hunter, C. A.;
Livingstone, D. J.; McCabe, J. F.; Seward, E. M. Chem. Eur. J. 2002, 8,
2847-2859. (c) Chessari, G., Hunter, C. A.; Low, C. M. R.; Packer, M. J.;
Vinter, J. G.; Zonta, C. Chem. Eur. J. 2002, 8, 2860-2867.
Org. Lett., Vol. 7, No. 6, 2005
1005

application in supramolecular chemistry. Further function-
alizations of these molecules are under development.
Supporting Information Available: Experimental pro-
cedures and full characterization for compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
Acknowledgment. This work was co-founded by MURST
within the national project “Stereoselezione in Sintesi
Organica: Metodologie e Applicazioni”.
OL047569F
1006
Org. Lett., Vol. 7, No. 6, 2005