Microwave-Assisted Synthesis and Dynamic Behaviour of N 2 ,N 4 ,N 6 -Tris(1H-pyrazolyl)-1,3,5-triazine-2,4,6-triamines A ´ ngel Díaz-Ortiz, a Jose ´ Elguero, b Antonio de la Hoz, a * Agustín Jime ´ nez, a Andre ´ s Moreno, a Sergio Moreno a and Ana Sa ´ nchez-Migallo ´n a a Departamento de Química Inorga ´ nica, Orga ´nica y Bioquímica, Facultad de Ciencias Químicas, Universidad de Castilla-La Mancha, E-13071 Ciudad Real, Spain, Fax: þ 34926295411, Tel: þ 34926295318, E-mail: [email protected]b Instituto de Química Me ´dica (C.S.I.C.), Juan de la Cierva, 3, E-28006 Madrid, Spain, Fax: þ 34915644853, Tel: þ 34914110874, E-mail: [email protected]Dedicated to Juan Carlos del Amo, in memoriam (Madrid, 11.3.2004) Keywords: DNMR, Microwave, Pyrazolyltriazines, Solvent-free Received: June 29, 2004; Accepted: February 7, 2005 Abstract A series of N 2 ,N 4 ,N 6 -tris(1H-pyrazolyl)-1,3,5-triazine-2,4,6-triamines has been synthesised under microwave irradiation in solvent-free conditions. By reaction of pyrazolylamines with cyanuric chloride and 2-chloro-4,6-diamino-1,3,5-triazines under microwave irradiation, 1,3,5-triazine-2,4,6-triamies with symmetrical and asymmetrical substitution, respectively, can be obtained. In the latter case, the procedure can be easily adapted by addition of a small amount of Dimethyl Sulfoxide (DMSO) for the preparation of poly- mer-supported triazines, with application in supramolecular combinatorial synthesis. At low temperature, the presence of two or four conformers has been detected for symmet- rically and asymmetrically substituted derivatives respectively. 1D- and 2D-exchange spec- troscopy studies in various solvents and at different temperatures have been used to determine the equilibrium constants and the activation free energies of the restricted rotation about the amino – triazine bond. A plot of the activation free energy versus temperature shows a good linear correlation and confirms that the same process is present in all of the compounds under investigation. 1 Introduction Controlling structures using supramolecular interactions is an area of great interest in chemistry and biochemistry as well as in crystal engineering [1, 2]. Aminotriazines have been used in the formation of supramolecular structures using hydrogen bonds [3 – 6]. The importance of these sec- ondary interactions has also been thoroughly studied [7]. For instance, the interaction between cyanuric acid and melamine [8] is well documented and the stability of the resulting complexes has been used to obtain polymers in the solid state. Modification of the system formed by cya- nuric acid and/or melamine has allowed the synthesis of linear polymers [9, 10], the non-covalent synthesis of nano- structures with the assembly of up to 27 components with 144 hydrogen bonds [11 – 14], the chemoselective synthesis of dendrimers based on melamine [15], the construction of molecular tectonics from pentaerythritol derivatives [16], the preparation of electrooptic thin films by anchoring a melamine template to a cleaned glass or Si(100) substrate [17], the preparation of photoresponsive melamine – barbi- turate assemblies [18], as well as diastereoselective and enantioselective non-covalent synthesis of melamine – bar- biturate assemblies [19]. Tagged triazine libraries have also been used in forward chemical genetics as a powerful tool for novel drug candi- dates [20 – 21]. Since the advent of combinatorial chemis- try, several triazine-based libraries have been prepared both in solid phase and in solution [22]. An 8000-member library of trisamino and amino-oxy-1,3,5-triazines was pre- pared recently using a microwave-assisted nucleophilic substitution procedure with cellulose-membrane-bound monochlorotriazines [23]. Microwave-assisted organic synthesis is a high-speed methodology with clear benefits: significant rate enhance- ments and higher product yields are usually observed [24 – 28]. In several cases, the stereo- and/or regiochemical out- come of microwave-assisted reactions has been found to be different to that observed under classical heating [29, 30]. The combination of microwave-heating methodology and combinatorial chemistry provides an increase in speed and effectiveness in the synthesis of organic compounds, advantages that cannot be achieved by conventional heat- ing methods. Thus, in recent years, a considerable number QSAR Comb. Sci. 2005, 24 DOI: 10.1002/qsar.200420116 # 2005 WILEY-VCH Verlag GmbH &Co. KGaA, Weinheim 649 Full Papers
Transcript
Microwave-Assisted Synthesis and Dynamic Behaviour ofN2,N4,N6-Tris(1H-pyrazolyl)-1,3,5-triazine-2,4,6-triamines
Angel D'az-Ortiz,a Jose Elguero,b Antonio de la Hoz,a* Agust'n Jimenez,a Andres Moreno,a Sergio Morenoa andAna Sanchez-Migallona
a Departamento de Qu�mica Inorganica, Organica y Bioqu�mica, Facultad de Ciencias Qu�micas, Universidad de Castilla-La Mancha,E-13071 Ciudad Real, Spain, Fax: þ34926295411, Tel: þ34926295318, E-mail: [email protected]
b Instituto de Qu�mica Medica (C.S.I.C.), Juan de la Cierva, 3, E-28006 Madrid, Spain, Fax: þ34915644853, Tel: þ34914110874,E-mail: [email protected]
Dedicated to Juan Carlos del Amo, in memoriam (Madrid, 11.3.2004)
Received: June 29, 2004; Accepted: February 7, 2005
AbstractA series of N2,N4,N6-tris(1H-pyrazolyl)-1,3,5-triazine-2,4,6-triamines has been synthesisedunder microwave irradiation in solvent-free conditions. By reaction of pyrazolylamineswith cyanuric chloride and 2-chloro-4,6-diamino-1,3,5-triazines under microwaveirradiation, 1,3,5-triazine-2,4,6-triamies with symmetrical and asymmetrical substitution,respectively, can be obtained. In the latter case, the procedure can be easily adapted byaddition of a small amount of Dimethyl Sulfoxide (DMSO) for the preparation of poly-mer-supported triazines, with application in supramolecular combinatorial synthesis. Atlow temperature, the presence of two or four conformers has been detected for symmet-rically and asymmetrically substituted derivatives respectively. 1D- and 2D-exchange spec-troscopy studies in various solvents and at different temperatures have been used todetermine the equilibrium constants and the activation free energies of the restrictedrotation about the amino – triazine bond. A plot of the activation free energy versustemperature shows a good linear correlation and confirms that the same process ispresent in all of the compounds under investigation.
1 Introduction
Controlling structures using supramolecular interactions isan area of great interest in chemistry and biochemistry aswell as in crystal engineering [1, 2]. Aminotriazines havebeen used in the formation of supramolecular structuresusing hydrogen bonds [3 – 6]. The importance of these sec-ondary interactions has also been thoroughly studied [7].For instance, the interaction between cyanuric acid andmelamine [8] is well documented and the stability of theresulting complexes has been used to obtain polymers inthe solid state. Modification of the system formed by cya-nuric acid and/or melamine has allowed the synthesis oflinear polymers [9, 10], the non-covalent synthesis of nano-structures with the assembly of up to 27 components with144 hydrogen bonds [11 – 14], the chemoselective synthesisof dendrimers based on melamine [15], the construction ofmolecular tectonics from pentaerythritol derivatives [16],the preparation of electrooptic thin films by anchoring amelamine template to a cleaned glass or Si(100) substrate[17], the preparation of photoresponsive melamine – barbi-turate assemblies [18], as well as diastereoselective and
enantioselective non-covalent synthesis of melamine – bar-biturate assemblies [19].Tagged triazine libraries have also been used in forward
chemical genetics as a powerful tool for novel drug candi-dates [20 – 21]. Since the advent of combinatorial chemis-try, several triazine-based libraries have been preparedboth in solid phase and in solution [22]. An 8000-memberlibrary of trisamino and amino-oxy-1,3,5-triazines was pre-pared recently using a microwave-assisted nucleophilicsubstitution procedure with cellulose-membrane-boundmonochlorotriazines [23].Microwave-assisted organic synthesis is a high-speed
methodology with clear benefits: significant rate enhance-ments and higher product yields are usually observed [24 –28]. In several cases, the stereo- and/or regiochemical out-come of microwave-assisted reactions has been found tobe different to that observed under classical heating [29,30]. The combination of microwave-heating methodologyand combinatorial chemistry provides an increase in speedand effectiveness in the synthesis of organic compounds,advantages that cannot be achieved by conventional heat-ing methods. Thus, in recent years, a considerable number
of publications have described the preparation of diverselibraries using a combination of microwave and combina-torial chemistry methodologies [31 – 33].We planned the synthesis of several melamine deriva-
tives modified by attachment to azoles, in order to changethe nature of the intermolecular bonds and to allow inter-actions with other substrates. With the same purpose the
synthesis of cyanuric acid derivatives is under develop-ment. It is well known that reaction of amines with cyanu-ric chloride leads to the corresponding substitution prod-ucts. In this regard the substitution of two chloride atomsand consequently preparation of diaminotriazines occursunder mild conditions, at room temperature in the pres-ence of a base. Following this strategy we have recently de-
scribed the preparation of 2-chloro-4,6-bis-pyrazolylami-notriazines [34].In this paper we describe the synthesis both of N2,N4,N6-
tris((1H-pyrazol-1-yl)phenyl)-1,3,5-triazine-2,4,6-triamines1 – 3 and N2,N4,N6-tris(1-phenyl-1H-pyrazolyl)-1,3,5-tria-zine-2,4,6-triamines 4 – 5 by reaction of cyanuric chloridewith the corresponding amines, and of asymmetrically sub-stituted N2-(2-(1H-pyrazol-1-yl)phenyl)-N4,N6-bis(4-(1H-pyrazol-1-yl)phenyl)-1,3,5-triazine-2,4,6-triamine 6 andN2-(3-(1H-pyrazol-1-yl)phenyl)-N4,N6-bis(4-(1H-pyrazol-1-yl)phenyl)-1,3,5-triazine-2,4,6-triamine 7 by reaction ofthe corresponding amines with N4,N6-bis(4-(1H-pyrazol-1-yl)phenyl)-2-chloro-1,3,5-triazine-4,6-diamine 8 (Scheme 1).
2 Discussion
2.1 Synthesis of 1 – 7
Melamine derivatives have been usually prepared from cy-anuric chloride by sequential substitution with amines[35]; or by substitution of sulfones. [22] Recently a solvent-free procedure [36] and a microwave-assisted synthesis indioxane –Dimethylformamide (DMF) and basic condi-
tions has been described [37]. Although the first and sec-ond substitution can be performed at low temperature inthe presence of a base, the third substitution usually re-quires high temperatures and long reaction times.Derivatives 1 – 5 with symmetrical substitution patterns
were prepared by reaction of cyanuric chloride with thecorresponding amine using microwave irradiation in sol-vent-free conditions in only 10 min with moderate to highyields (42 – 62%) (Scheme 2). Six equivalents of theamine were required in order to neutralise the hydrogenchloride produced in the reaction. Similarly, derivatives6 – 7 with asymmetrical substitution patterns were pre-pared in excellent yield by reaction of N4,N6-bis(4-(1H-pyrazol-1-yl)phenyl)-2-chloro-1,3,5-triazine-4,6-diamine8 with two equivalents of the corresponding amine. Reac-tions were performed in a focused microwave reactorwith full control of the incident power and reaction tem-perature.It is remarkable that no reaction occurs by conventional
heating under comparable reaction conditions (tempera-ture and time). In order to obtain similar yields by conven-tional heating, reactions should be performed in Tetrahy-drofuran (THF) at reflux for five days in the presence ofdiisopropylethylamine (DIPEA) as base. However, even
Scheme 2. Reaction conditions and yield for the preparation of compounds 1 – 7.
Scheme 3. Reaction conditions and yield for the preparation of compound 8.
Microwave-Assisted Synthesis and Dynamic Behaviour of N2,N4,N6-Tris(1H-pyrazolyl)-1,3,5-triazine-2,4,6-triamines
under these conditions the formation of hindered com-pounds such as 1, 6 and 7 does not take place under con-ventional heating.Under these conditions, reaction of N4,N6-bis(4-(1H-pyr-
azol-1-yl)phenyl)-2-chloro-1,3,5-triazine-4,6-diamine 8with a polymer-supported benzylamine [aminomethylatedpoly(styrene-co-divinylbenzene)] does not afford the de-sired trisubstituted triazine because now the mixture is notpolar enough to be heated sufficiently under microwave ir-radiation. However, on the addition of a small amount of apolar solvent such as Dimethyl sulfoxide (DMSO) (1 mL/mmol of triazine) the reaction temperature rose to 130 8Cand produced complete conversion within 10 min(Scheme 3). This result opens the possibility of using thesepolymer-supported pyrazolyltriazines in supramolecularpolymer-supported synthesis taking advantage of the pos-sible interactions through hydrogen bond and/or coordina-tion with transition metals.
2.2 Structural Determination
Melamine derivatives show restricted rotations around thetriazine – nitrogen bond. This process has been studied insolution [34, 38] as well as in the solid state using NMRspectroscopy [39]. Compounds 1 – 5 can exist in two differ-ent conformations, a symmetrical conformation a with aC3 axis and an unsymmetrical conformation b, while com-pounds 6 – 7, due to their lower symmetry, present fourconformations, a –d (Scheme 4).At 298 K the 1H-NMR spectra of compounds 1 – 7 show
broad signals for all the NMR resonances. At 223 K thetwo different conformers of compounds 1 – 5 can be de-tected (Figure 1). For compounds 6 – 7 four different con-formers are expected while the lack of symmetry compli-cates the spectra.
At high temperature (363 – 393 K), a rapid rotation ofthe triazine – amino bond was observed and the NMR sig-nals could be assigned (Table 1). The only exception wascompound 4 that shows very broad signals in all solvents(CDCl3, DMF-d7, DMSO-d6) and along the whole range oftemperatures used (223 – 393 K). This effect can be ascri-bed to the presence of several tautomers due to the conju-gation of the pyrazole C¼N double bond with the NHgroup.Assignment of the NMR signals to the conformers was
performed at low temperature (Table 2), in symmetricallysubstituted compounds 1 – 5, considering the differentsymmetry of conformers a and b; in unsymmetrically sub-stituted compounds 6 – 7, the NMR spectra at low temper-ature were too complicated to assign the NMR signals tothe four different conformers.This permitted to determine the ratio of conformers. It
is remarkable that this ratio depends not only on the sub-stitution of the triazine ring but also on the solvent andtemperature, conformer a being favoured in apolar solventand at high temperature (Table 3).
2.3 Dynamic Behaviour of Compounds 1 –3 and 5
Using Dynamic NMR (DNMR) spectroscopy we studiedthe restricted rotation of triazines 1 – 3, 5. Multisite sys-tems that are not amenable to study by conventional meth-ods can be studied by 2D Exchange Spectroscopy (2DEXSY). More recently 1D-EXSY techniques have alsobeen introduced [40] as well as the application of Diffu-sion-ordered Spectroscopy (DOSY) for exchange [41]. Inthis work we used 1D- and 2D-EXSY techniques for thedetermination of the activation free energy of this process.In a first experiment 0.8 – 1-s mixing time was found to
be optimum. A second experiment with a 0.02-s mixing
Figure 1. NMR spectra of compound 2 in DMF-d7 solution: a) 223 K and b) 363 K.
Microwave-Assisted Synthesis and Dynamic Behaviour of N2,N4,N6-Tris(1H-pyrazolyl)-1,3,5-triazine-2,4,6-triamines
time was performed in order to obtain the pure diagonalpeaks without exchange cross-peaks. Experiments wereperformed at the temperature of the slow process in
DMF-d7 and CDCl3. Rate constants can be deduced fromthe spectra according to the following equation:
Table 2. 1H-NMR spectra of compounds 1 – 5, slow process, d [ppm], J [Hz] (see Scheme 1).
Table 2a
Compound 1 1 2 3 5
Solvent DMF-d7 CDCl3 DMF-d7 DMF-d7 DMF-d7Temp. [K] 213 203 223 223 223H-3 pyrazole d [a] 7.85 (s) 8.45 (s) 7.87 (s) 7.91 (s)H-4 pyrazole d 6.65 (s) 6.49 (s) 6.63 (s) 6.66 (s) –H-5 pyrazole d
J8.00 (s) 7.74 (s) 8.69 (s) 8.73 (d)
2.09.07 (s)
H-2’ dJ
– – 7.87 (s) 7.92 (d)9.0
7.89 (d)7.5
H-3’ dJ
7.63 (m) 7.5 – 7.1 (m) – 8.17 (d)9.0
7.60 (t)7.8
H-4’ dJ
7.28 (m) 7.5 – 7.1 (m) 8.04 (d)8.2
– 7.36 (d)7.4
H-5’ dJ
7.47 (m) 7.5 – 7.1 (m) 7.48 (t)8.1
8.17 (d)9.0
7.60 (t)7.8
H-6’ dJ
nda 8.39 (d)8.0
7.61 (d)8.2
7.92 (d)9.0
7.89 (d)7.5
NH d 10.14 (s) 9.70 (s) 10.45 (s) 10.40 (s) 10.33 (s)
Microwave-Assisted Synthesis and Dynamic Behaviour of N2,N4,N6-Tris(1H-pyrazolyl)-1,3,5-triazine-2,4,6-triamines
R¼� lnA/tm¼�X (lnL)X�1/tm (1)
where Aij¼ Iij/Mj, tm is the mixing time. Iij(tm)/Mj and Xare the square matrix of eigenvectors of Ai such thatX�1AX¼L¼diag (li), with li the i
th eigenvalue of A. Iijcan be deduced by measuring the volume of each peak in-tensity directly from the spectrum. Mj is the volume of thediagonal peak of the spectrum registered with a mixingtime close to 0 and without any chemical exchange.
Activation free energies for compounds 1 – 3, 5 were cal-culated (Table 4) from the rate constants according toSandstrçm [42].The calculated activation free energies correspond to
49 – 79 kJ mol�1 and they were determined in a wide rangeof temperatures (203 – 298 K); the representation of DG‡
versus temperature showed a linear plot with a good corre-lation constant, R2¼0.99 (Figure 2). This linear plot per-mitted the calculation of DH‡¼4.40 kJ mol�1 and DS‡¼�0.27 kJ mol�1 K�1. The DG‡ value was similar to thosemeasured for N-arylguanidines and related aminotriazines[38, 39, 43].
3 Conclusions
N2,N4,N6-Tris(1H-pyrazolyl)-1,3,5-triazine-2,4,6-triamineswith symmetrical and asymmetrical subtitution patternwere prepared in good yield under microwave irradiationunder solvent-free conditions in 10 min. Comparison withclassical heating shows that higher yields and shorter reac-tion times are observed under microwave irradiation. Withsterically hindered derivatives such as 1, 6 and 7, no reac-
tion occurs by conventional heating. The procedure wasadapted for the preparation of polymer-supported tria-zines with applications in combinatorial chemistry insupramolecular polymer-supported synthesis.The structures were determined in solution using NMR
spectroscopy. Conformers resulting from the restricted ro-tation about the amino – triazine bond were detected andidentified in solution and at low temperatures. The re-stricted rotation was studied by 1D and 2D EXSY. A plotof the calculated activation free energies versus tempera-ture showed a good correlation coefficient, indicating thata unique and similar process occurred in all the present tri-azines.The present study shows the interest of microwave irra-
diation and solvent-free conditions in organic synthesisand especially for preparing sterically hindered com-pounds. Also the importance of determining the molecularstructure in solution in order to gain an insight into possi-ble supramolecular interactions was shown.
4. Experimental Section
4.1 Apparatus
Microwave-assisted reactions were performed in a mono-mode microwave reactor PROLABO MAXIDIGESTMX350, modified with a mechanical stirrer and an infraredpyrometer. Incident power and temperature were control-led by computer using the software MPX-2 from PACAMElectronica. Melting points were determined using a SMP-3 melting-point apparatus and are uncorrected. The IRspectra were obtained with an FT-IR Nicolet-550 spectro-photometer. The mass spectra (electrospray ionisationmode, ESIþ ) were recorded on a HPLC-MSD flow-injec-tion analysis apparatus. Flash column chromatography wasperformed on silica gel 60 (Merck, 230 – 400 mesh).NMR spectra were recorded on a VARIAN INNOVA
500 spectrometer operating at 499.791 MHz for protonspecroscopy. Spectra were recorded at the temperature in-
dicated (�0.1 K) with a probe calibrated with methanol.The standard VARIAN pulse sequence was used (VNMR6.1B software). Samples were prepared by dissolving thetriazine (0.25 mmol) in DMF-d7, DMSO-d6 and CDCl3(0.6 mL) under argon atmosphere.The 2D exchange spectra (EXSY) were acquired in the
phase-sensitive mode using the States –Haberkorn meth-od [44]. Typically, a 3.1 kHz spectral width, 16 transients of2048 data points were collected for each 400 t1 increments.A 1-s relaxation delay, an 11-s (908) pulse width and a0.165-s acquisition time were used. The free induction de-cays were processed with square cosine-bell filters in bothdimensions and zero filling was applied prior to doubleFourier transition.The 1D exchange spectra (EXSY) were acquired using
the standard 1D NOESY pulse sequence with 512 transi-ents, a 0.8-s relaxation delay and a 1.892-s acquisition time.Determination of the kinetic parameters required two
experiments with mixing times of 1 s (optimised) for theexchange experiment and 0.02 s for the non-exchangespectra, respectively. The cross peak/diagonal ratio was de-termined by integrating the volume under the peaks.
4.2 Synthesis of N2,N4,N6-Tris(1H-pyrazolyl)-1,3,5-triazine-2,4,6-triamines 1 – 5
4.2.1 General Procedure
A mixture of cyanuric chloride (2 mmol, 0.373 g) and theappropriate amine (12 mmol, 1.906 g) was introduced in aPyrex flask and irradiated at 90 W (185 8C) for 10 min. Af-ter cooling, the crude mixture was extracted with the ap-propriate solvent and the corresponding triazines were pu-rified as described below.
From 1-(3-aminophenyl)pyrazole, temperature 185 8C:The crude was extracted with hot water (2�25 mL) andthe solid was filtered and purified by column chromatogra-phy using hexane/ethyl acetate (8 : 2) gradient (1 : 1). Yield
From 1-(4-aminophenyl)pyrazole, temperature 185 8C:The crude was extracted with hot water (2�25 mL) andthe solid was filtered and purified by column chromatogra-phy using hexane/ethyl acetate (1 :1) gradient ethyl ace-tate. Yield 0.555 g (50%), mp >298 8C. IR (KBr) nmax3284, 1618, 1587 cm�1. 13C-NMR (DMF-d7, 298 K) 165.21,141.10, 139.45, 135.57, 127.82, 121.35, 119.46, 107.97. MS(ESIþ ) m/z 553.2 (MþþH).
From 3-amino-1-phenylpyrazole, temperature 185 8C: Thecrude was extracted with water (4�25 mL) and the solidwas filtered and washed with diethyl ether (25 mL). Yield0.565 g (51%), mp 160 8C decomposes. IR (KBr) nmax 3415,1599, 1502 cm�1. MS (ESIþ )m/z 553.2 (MþþH).
From 4-amino-1-phenylpyrazole, temperature 185 8C: Thecrude was extracted with water (4�25 mL) and the solidwas filtered and washed with 0.01 m HCl (2�25 mL). Thecrude product was purified by column chromatography us-ing hexane/ethyl acetate (7 : 3) gradient (1 :1). Yield0.469 g (42 %), mp 259 – 261 8C. IR (KBr) nmax 3214, 1599,1395 cm�1. 13C-NMR (DMSO-d6, 393 K) 163.71, 139.55,133.80, 128.60, 124.97, 124.24, 117.55, 117.46. MS (ESIþ )m/z 553.2 (MþþH).
4.3 Synthesis of Triazines 6 and 7
4.3.1 General Procedure
A mixture of N4,N6-bis(4-(1H-pyrazol-1-yl)phenyl)-2-chlo-ro-1,3,5-triazine-4,6-diamine (8) (1 mmol, 0.43 g) and theappropriate amine (2 mmol, 0.32 g) was introduced into aPyrex flask and irradiated at 90 W for 10 min. After cool-ing, the crude mixture was extracted with a solution of0.01 m HCl (2�50 mL), the solid was filtered and washedwith water (5 mL) and ethyl ether (5 mL) to afford thepure product.
A mixture of poly(styrene-co-divinylbenzene) aminome-thylated 200 – 400 mesh, 4 mmol N/g (2 mmol, 0.500 g),N4,N6-bis(4-(1H-pyrazol-1-yl)phenyl)-2-chloro-1,3,5-tria-zine-4,6-diamine (8) (1 mmol, 0.429 g) and DMSO (1 mL)were introduced into a Pyrex flask and irradiated at 90 Wand for 10 min, temperature 130 8C. After cooling, thecrude mixture was washed with water (2�15 mL) the solidwas filtered and washed with ethanol (5 mL), then the sol-id was washed with ethyl acetate (2�15 mL) to afford0.856 g of resin. Loading of the resin (0.97 mmol/g of res-in). IR (KBr) nmax 1583, 1527, 1496, 1408.
Acknowledgements
Financial support from the DGICYT of Spain throughproject CTQ2004-01177 and from the Consejer�a de Cien-cia y Tecnolog�a JCCM through project PAI-02-019 isgratefully acknowledged. NMR spectra were recorded atthe Regional Institute of Applied Scientific Research.
References
[1] J. M. Lehn, Proc. Nat. Acad. Sci. 2002, 99, 4977 – 4982, andreferences therein.
[2] a) A. D. Burrows, C. W. Chan, M. M. Chowdhry, J. E.McGrady, D. M. P. Mingos, Chem. Soc. Rev. 1995, 329 – 339.b) M. D. Hollingsworth, Science 2002, 295, 2410 – 2413. c) B.Moulton, M. J. Zaworotko, Chem. Rev. 2001, 101, 1629 –1658. d) G. R. Desiraju, Chem. Commun. 1997, 1475 – 1482.e) G. R. Desiraju, Acc. Chem. Res. 2002, 35, 565 – 573.f) G. R. Desiraju, Nature 2001, 412, 397 – 400.
[3] a) E. A. Archer, H. Gong, M. J. Krische, Tetrahedron 2001,57, 1139 – 1159. b) M. Acedo, E. De Clercq, R. Eritja, J.Org. Chem. 1995, 60, 6262 – 6269. c) U. Von Krosigk, S. A.
Benner, J. Am. Chem. Soc. 1995, 117, 5361 – 5362. d) D. C.Sherrington, K. A. Taskinen, Chem. Soc. Rev. 2001, 30, 83 –93.
[4] R. Deans, G. Cooke, V. M. Rotello, J. Org. Chem. 1997, 62,836 – 839.
[5] A. Kraft, F. Osterod, R. Frçhlich, J. Org. Chem. 1999, 64,6425 – 6433.
[6] a) W. L. Jorgensen, J. Pranata, J. Am. Chem. Soc. 1990, 112,2008 – 2010. b) F. H. Allen, P. R. Raithby, G. P. Shields, R.Taylor, Chem. Commun. 1998, 1043 – 1044.
[7] a) L. J. Prins, D. N. Reinhoudt, P. Timmerman, Angew.Chem. Int. Ed. 2001, 40, 2382 – 2426. b) D. N. Reinhoudt, M.Crego-Calamas, Science 2002, 295, 2403 – 2407.
[8] Y. W. Cao, X. D. Chai, T. J. Li, J. Smith, D. Q. Li, Chem.Commun. 1999, 1605 – 1606.
[9] a) M. Mascal, J. Hansen, P. S. Fallon, A. J. Blake, B. R. Hey-wood, M. H. Moore, J. P. Turkenburg, Chem. Eur. J. 1999, 5,381 – 384. b) Y. W. Cao, X. D. Chai, T. J. Li, J. Smith, D. Li,Chem. Commun. 1999, 1605 – 1606.
[10] J. H. K. Ky Hirschberg, L. Brunsveld, A. Ramzi, J. A. J. M.Vekemans, R. P. Sijbesma, E. W. Meijer, Nature 2000, 407,167 – 169.
[11] V. Paraschiv, M. Crego-Calamas, R. H. Fokkens, C. J. Pad-berg, P. Timmerman, D. N. Reinhoudt, J. Org. Chem. 2001,66, 8297 – 8301.
[12] L. J. Prins, E. E. Neuteboom, V. Paraschiv, M. Crego-Cala-mas, P. Timmerman, D. N. Reinhoudt, J. Org. Chem. 2002,67, 4808 – 4820.
[13] V. Paraschiv, M. Crego-Calamas, T. Ishi-i, C. J. Padberg, P.Timmerman, D. N. Reinhoudt, J. Am. Chem. Soc. 2002, 124,7638 – 7639.
[14] V. Paraschiv, M. Crego-Calamas, R. H. Fokkens, C. J. Pad-berg, P. Timmerman, D. N. Reinhoudt, J. Org. Chem. 2001,66, 8297 – 8301.
[15] M. B. Steffensen, E. Simanek, Org. Lett. 2003, 5, 2359 –2361.
[16] H. Sauriat-Dorizn, T. Maris, J. D. Wuest, G. D. Enright, J.Org. Chem. 2003, 68, 240 – 246.
[17] P. Zhu, H. Kang, A. Facchetti, G. Evmenenko, P. Dutta,T. J. Marks, J. Am. Chem. Soc. 2003, 125, 11496 – 11497.
[18] S. Yagai, T. Karatsu, A. Kitamura, Chem. Commun. 2003,1844 – 1845.
[19] a) L. J. Prins, R. Hulst, P. Timmerman, D. N. Reinhoudt,Chem. Eur. J. 2002, 8, 2288 – 2301. b) L. J. Prins, J. J. Ve-rhage, F. de Jong, P. Timmerman, D. N. Reinhoudt, Chem.Eur. J. 2002, 8, 2302 – 2313.
[20] H.-S. Moon, E. M. Jacobson, S. M. Khersonsnsky, M. R. Lu-zung, D. P. Walsh, W. Xiong, J. W. Lee, P. B. Parikh, J. C.Lam, T.-W. Kang, G. R. Rosania, A. F. Schier, Y.-T. Chang,J. Am. Chem. Soc. 2002, 124, 11608 – 11609.
[21] S. M. Khersonsnsky, D.-W. Jung, T.-W. Kang, D. P. Walsh,H.-S. Moon, H. Jo, E. M. Jacobson, V. Shetty, T. A. Neubert,Y.-T. Chang, J. Am. Chem. Soc. 2003, 125, 11804 – 11805.
[22] J. T. Bork, J. W. Lee, S. M. Khersonsky, H.-S. Moon, Y.-T.Chang, Org. Lett. 2003, 5, 117 – 120, and references citedtherein.
[23] D. Scharn, H. Wenschuh, U. Reineke, J. Schneider-Merge-ner, L. Germeroth, J. Comb. Chem. 2000, 2, 361 – 369.
[24] A. Loupy, A. Petit, J. Hamelin, F. Texier-Boullet, P. Jac-quault, D. Mathe, Synthesis 1998, 1213 – 1234.
[25] P. Lidstrçm, J. Tierney, B. Wathey, J. Westman, Tetrahedron2001, 57, 9225 – 9283.
[26] R. S. Varma, Green Chem. 1999, 1, 43 – 55.[27] C. R. Strauss, Aust. J. Chem. 1999, 52, 83 – 96.[28] A. Loupy (Ed.), Microwaves in Organic Synthesis, Wiley-
VCH, Weinheim, Germany, 2002.[29] A. K. Bose, B. K. Banik, M. S. Manhas, Tetrahedron Lett.
1995, 36, 213 – 216.[30] F. Langa, P. de la Cruz, A. de la Hoz, E. Esp�ldora, F. P.
Coss�o, B. Lecea, J. Org. Chem. 2000, 65, 2499 – 2507.[31] C. O. Kappe, Curr. Opin. Chem. Biol. 2002, 6, 314 – 320.[32] M. Larhed, A. Hallberg, Drug Disc. Today 2001, 6, 406 –
416.[33] A. Lew, P. O. Krutzik, M. E. Hart, A. R. Chamberlin, J.
Comb. Chem. 2002, 4, 95 – 105.[34] A. D�az-Ortiz, J. Elguero, C. Foces-Foces, A. de la Hoz, A.
Moreno, S. Moreno, A. Sanchez-Migallon, G. Valiente Org.Biomol. Chem. 2003, 1, 4451 – 4457.
[35] P. de Hoog, P. Gamez, W. L. Driessen, J. Reedijk, Tetrahe-dron Lett. 2002, 43, 6783 – 6786.
[36] V. B. Kurteva, C. A. M. Afonso, Green Chem. 2004, 6, 183 –187.
[37] Y. Sha, Y. Dong, Synth. Commun. 2003, 33, 2599 – 2604[38] I. Ghiviriga, D. C. Oniciu, Chem. Commun. 2002, 2718 –
2719.[39] H. E. Birket, J. C. Cherryman, A. M. Chippendale, J. S. O.
Evans, R. K. Harris, M. James, I. J. King, G. J. McPherson,Magn. Reson. Chem. 2003, 41, 324 – 326.
[40] C. L. Perrin, R. E. Engler, J. Am. Chem. Soc. 1997, 119,585 – 591.
[41] E. J. Cabrita, S. Berger, Magn. Reson. Chem. 2002, 40,S122 – S127.
[42] J. Sandstrçm, in Dynamic NMR Spectroscopy AcademicPress, New York, 1982, p. 96.
[43] M. Oki, Applications of Dynamic NMR Spectroscopy to Or-ganic Chemistry, VCH, Weinheim, Germany, 1985, p. 360.
[44] D. J. States, R. A. Haberkorn, D. J. Ruben, J. Magn. Reson.1982, 48, 286 – 292.
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