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High-yielding synthesis of deepened cavitands bearing picolyl moieties on the upper rim
Tetrahedron 71 (2015) 2555e2560
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High-yielding synthesis of deepened cavitands bearing picolyl moieties on the upper rim n Nagymiha ly a, La szlo Kolla r a, b, * Zolta a b
gothai Research Center, PO Box 266, H-7624 P Department of Inorganic Chemistry, University of P ecs and Szenta ecs, Hungary g u. 6, H-7624 P sa MTA-PTE Research Group for Selective Chemical Syntheses, Ifju ecs, Hungary
a r t i c l e i n f o
a b s t r a c t
Article history: Received 22 December 2014 Received in revised form 19 February 2015 Accepted 3 March 2015 Available online 7 March 2015
Conventional high-yielding reactions (such as etherification, condensation reactions) and palladiumcatalysed aminocarbonylation served as highly efficient synthetic tools for the synthesis of novel cavitands bearing Schiff-base and carboxamide/2-ketocarboxamide functionalities, respectively. In this way, two families of deepened cavitands with related structures possessing 2-, 3- and 4-picolylamine moieties on the upper rim have been synthesised. Unexpectedly high chemoselectivities towards tetracarboxamides and tetrakis(2-ketocarboxamides) have been observed. The aminocarbonylation of tetraiodocavitand as an iodoaromatic substrate proved to be highly selective in two aspects: (i) no substantial formation of either the mono-, di- or trifunctionalized products was observed and (ii) no ‘mixed’ products possessing both carboxamide and 2-ketocarboxamide fragments, due to selective simple and double carbon monoxide insertion, were detected. Ó 2015 Elsevier Ltd. All rights reserved.
Keywords: Cavitand Schiff base Aminocarbonylation Carbon monoxide Palladium Carboxamide
1. Introduction 2-Methylresorcine-based cavitands1 with a conformationally rigid, bowl-shaped macrocyclic structure have been generating tremendous interest in the supramolecular community. In addition to cyclodextrins,2 calixarenes,3 calix-resorcinarenes4 and cucurbiturils,5 the well-known families of molecular hosts with exceptional molecular recognition ability, cavitands have also gained wide applications in ‘hosteguest’ chemistry. The size and shape of the cavitands are essential considering their potential applications as sensors, nanoreactors and drug delivery systems. Especially the peculiarities of the upper rim, i.e., that of the upper inlet of such molecular containers was brought into focus.6 Although deepening and enlarging the molecular pocket of cavitands was principally accomplished mainly by conventional organic reactions;7 some homogeneous catalytic reactions were sparsely employed.8 In one of our previous papers we described the upper rim functionalisation of a tetraidocavitand by various homogeneous catalytic reactions such as cross-coupling (Suzuki, Sonogashira, Stille) reactions and aminocarbonylation.9 Since the latter carboxamide-forming reaction serves as a keyreaction in the present work, it should be mentioned that carboxamide functionalities were previously introduced into the cavitand
r). * Corresponding author. E-mail address: [email protected] (L. Kolla http://dx.doi.org/10.1016/j.tet.2015.03.009 0040-4020/Ó 2015 Elsevier Ltd. All rights reserved.
skeleton by acylation of the corresponding aminocavitands.10 Palladium-catalysed carbonylations have become indispensable tools in organic chemistry.11 Among them, palladium-catalysed aminocarbonylation of organohalides (preferably iodoalkenes and iodoarenes) proved to be of high synthetic importance. The facile conversion of iodoalkenes or iodoarenes (as synthetic surrogates of the corresponding enol triflates and aryl triflates, respectively) to carboxamides by using carbon monoxide and various amines as Nnucleophiles, made these reactions of high synthetic importance.12 Various ‘preformed’ or in situ generated palladium(0) catalysts were used.13 As a part of our on-going research in the carbonylation reactions of iodoarenes and iodoalkenes, we turned our attention towards the systematic variation of the N-nucleophiles. It has to be added that in the case of various compounds with practical interest, the above catalytic reactions provide synthetic methods superior to conventional ones. Since several amines with picolyl substituents (especially 2-picolylamine (pam) and di-(2-picolyl)amine (dpa)) are favoured ligands in coordination chemistry (vide infra) their attachment to a cavitand backbone with potential host properties was considered. A wide application of pam as ligand in transition metal complexes such as Ir(III),14 Cu(II),15e17 Fe(II),18e21 Pd(II) and Pt(II),22 Cr(III)23e25 and Ni(II)26 has been described. 2-Picolylamine-based multidentate ligands have also been also used in Zn(II),27,28 Pt(II),29 Cu(II) and Mn(II)16,30 complexes. The coordination of the
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potentially N,N0 ,N00 -tridentate ligand dpa to Cu(II),31,32 Zn(II)33,34 and Ir(III)35 was also reported. The catalytic application of Ir-pam complexes36 and Os- and Ru-pam37 systems has been reported in CeH borylation and transfer hydrogenation, respectively. The high potential of picolyl moieties in binding properties as well as the molecular recognition properties of cavitands prompted us to combine the two functions in a family of novel cavitands, which proved to be available in high-yielding, facile reactions. 2. Results and discussion To synthesise multi-level (‘deepened’) cavitands with pyridyl groups on the upper rim, the tetrabromocavitand (1)38 was reacted with 4-hydroxybenzaldehyde under conventional etherification conditions in the first step yielding the tetraformyl derivative (2) in 87% yield. The condensation reaction of 2 with 2-, 3- or 4picolylamine (aec, respectively, Fig. 1) resulted in the highyielding formation (62e83%) of the corresponding Schiff-bases (3ae3c) (Scheme 1).
Fig. 1. Amines with pyridyl moieties used in this work.
To synthesise cavitands with similar structures, the aminocarbonylation reaction was chosen to introduce primary and secondary amines on the upper rim of the cavitand scaffold in the presence of Pd(OAc)2þ2PPh3 in situ catalytic systems (Scheme 2). Under the reaction conditions used, highly reactive, coordinatively unsaturated Pd(0) intermediates are formed39 enabling facile activation of the iodoaromatic substrate, carbon monoxide and amine nucleophile. Tetraiodocavitand (4), bearing four excellent leaving groups, served as a substrate for further extension of the cavitand structure as demonstrated in various coupling reactions before.9 In this study, we aimed to extend the scope of palladium-catalysed carbonylations using 4 as key-intermediate in this family of cavitands. The tetraiodocavitand (4) was synthesised from tetrabromocavitand (1) and 4-iodophenol by an improved methodology.9 Primary picolylamines (2-picolylamine (a), 3-picolylamine (b) and 4-picolylamine (c)) as well as secondary amines possessing picolyl substituent (4-(ethylaminomethyl)pyridine (d), di-(2picolyl)amine (e)) were employed as N-nucleophiles for the preparation of both novel carboxamidocavitands (5ae5d) and 2ketocarboxamides (6ae6e) in aminocarbonylation. That is, depending on the reaction conditions, the selective synthesis of carboxamides (5) and ketocarboxamides (6) can be accomplished (vide infra) via simple and double carbon monoxide insertion, respectively. Under ambient conditions (1 bar CO, 50 C) the formation of tetracarboxamides is highly favoured (Table 1, entries 1, 4, 8) when primary amines were used as N-nucleophiles. However, the use of secondary amine d provided a carboxamide/ketocarboxamide mixture of 40:60 (entry 11). The secondary amine e possessing two 4-pycolyl moieties, has shown decreased reactivity under 1 bar CO and no compound in isolable amount was formed (entry 13). It is
Scheme 1. Synthesis of cavitands with Schiff-base moieties on the upper rim.
Scheme 2. Synthesis of tetracarboxamidocavitands (5) and tetrakis(2-ketocarboxamido)cavitands (6) in palladium-catalysed aminocarbonylation.
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Table 1 Palladium-catalysed aminocarbonylation of 4a Entry
Amine
Molar equivalents of amine
p[CO] [bar]
Conversionb (%)
Chemoselectivityc (%)
Yieldd (%)
1 2 3 4 5 6 7 8 9 10 11 12 13 14
a a a b b be b c c c d d e e
8 8 8 8 8 2 8 8 8 8 8 8 8 8
1 40 60 1 40 40 90 1 40 90 1 40 1 40
>99 >99 <5 >99 >99 46 <2 >99 >99 <2 >99 >99 <5 >99
5a (>98), 6a (<2) 5a (<2), 6a (>98) n.d. 5b (>98), 6b (<2) 5b (<2), 6b (>98) 5b (<2), 6b (>98) n.d. 5c (>98), 6c (<2) 5c (<2), 6c (>98) n.d. 5d (40), 6d (60) 5d (<2), 6d (>98) n.d. 5e (<2), 6e (>98)
55 (5a) 69 (6a) n.d. 44 (5b) 54 (6b) 44 (6b) n.d. 50 (5c) 67 (6c) n.d. 24 (5d) 27 (6d) n.d. 42 (6e)
a b c d e
Reaction conditions: 1/Pd(OAc)2/PPh3/Et3N¼1:0.15:0.3:12, 60 C. (Moles of converted 4)/(Moles of initial 4)100. Determined on the crude reaction mixture by means of 1H and 13C NMR. Yield of isolated, analytically pure products. In case of selective tetrasubstitution observed the highest conversion that could be achieved is 50%.
worth noting that the extremely low reactivity of e is probably due to its strong tridentate coordination to palladium. We noticed, however, that higher CO pressure (40 bar) generated, as expected, a superior chemoselectivity towards 2ketocarboxamides (entries 2, 5, 9, 12 and 14 for 6a, 6b, 6c, 6d and 6e, respectively). It is important to note that neither the tetrakis(2ketocarboxamide) derivatives (6ae6e) nor tetracarboxamide derivatives (5ae5d) contained ‘mixed-substituted’ derivatives as minor components. That is, the cavitand derivatives show the simplest substitution pattern containing four identical ‘arms’. Either four carboxamide or four 2-ketocarboxamide arms were formed upon functionalisation of the parent tetraiodo compound. It was revealed by detailed NMR investigations carried out on the reaction mixtures that the total of the side-products (i.e., the total amount of the ‘mixed-substituted’ iodo-carboxamidocavitands or that of the carboxamido-ketocarboxamidocavitands) were less than 2%. The yields are strongly dependent on carbon monoxide pressure: practically no reaction was observed at 60e90 bar carbon monoxide pressure (entries 3, 7 and 10). Although no detailed mechanistic investigations are known, especially for this pressure range, it is generally accepted that the coordination of two or three carbonyl ligands to palladium(0) resulted in inactive catalytic species, that is, the oxidative addition of the iodoarene substrate is highly unfavoured. Even more surprisingly, when the molar equivalents of the amine reactants were decreased below 4, i.e., less than the stoichiometric amount of the N-nucleophile was used, only the same tetrafunctionalized products could be isolated along with unreacted starting tetraiodocavitand (4). For instance, carrying out aminocarbonylation at a 4/b molar ratio of ½ at 40 bar carbon monoxide pressure, 6b was formed and approximately half of the tetraiodo compound (4) was recovered (entry 6). Therefore, during the course of the reactions, the composition of the reaction mixtures was carefully checked both by in situ 1H and 13C NMR. Again, neither the formation of the diiodo-dicarboxamido-cavitand, that might be expected according to above molar ratios, nor that of the mono- or trifunctionalized products was observed. To find a reasonable explanation for the very high chemoselectivities towards tetrafunctionalized products, some novel catalytic features of the palladium-catalyst have to be supposed. It is worth noting, that various organic reactions have been applied for the introduction of appropriate functionalities using less than
4 M equiv of reactants related to cavitand. As expected, the application of these conventional synthetic reactions resulted in the generation of statistical mixtures of up to five partially substituted products.40 In contrast, we noticed unexpectedly high chemoselectivities towards tetrafunctionalized cavitands (vide supra) in palladiumcatalysed reactions. The rationalisation of the simple substitution patterns needs further investigations including mechanistic studies and the involvement of computational chemistry. 3. Conclusion Tetraiodocavitand served as a perfect platform for the highly selective synthesis of the corresponding tetrafunctionalised carboxamides and tetrakis(2-ketocarboxamides). The easily available primary and secondary amines make aminocarbonylation a powerful, switchable synthetic methodology for the functionalisation of deepened cavitands. Cavitands with similar sizes and upper rim groups have been synthesised via etherification/Schiff-base formation reaction. All of these deepened cavitands with 2-, 3- and 4pyridyl groups on the upper rim might serve as flexible binding pockets in ‘hosteguest’ chemistry. That is, instead of the conventional carboxylic acideacyl chlorideeamide route, the direct carbonylation of haloaromatics as well as those of the corresponding triflate surrogates can be used. We believe that the combination of high-yielding conventional reactions and chemo- and/or regioselective homogeneous catalytic reactions could serve as a powerful tool for the synthesis of novel supramolecular structures. 4. Experimental 4.1. General procedures All reagents and solvents were purchased from Aldrich and used as received. Toluene and THF was dried using traditional methods. 1 H and 13C NMR spectra were recorded at 25 C in CDCl3 (or in DMSO-d6) on a Bruker Avance III 500 spectrometer at 500 and 125.7 MHz, respectively. The 1H chemical shifts (d), reported in parts per million (ppm) downfield, are referenced to the residual protons (7.26 ppm for CDCl3 and 2.50 for DMSO-d6). The 13C chemical shifts are referenced to the carbon resonance of CDCl3 (77.00 ppm) or to that of DMSO-d6 (39.52 ppm), respectively.
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4.2. The synthesis of tetrakis(4-formylphenoxymethyl)cavitand (2) To the THF (15 mL) solution of 4-hydroxybenzaldehyde (0.5 g, 4.09 mmol), 1 M aqueous NaOH solution (5 mL) was added, and was left stirring for 30 min at room temperature. This solution was then slowly added to the THF (15 mL) solution of tetrakis(bromomethyl) cavitand (1.0 g, 1.04 mmol). The reaction mixture was stirred at 70 C for 24 h. The precipitating product was collected by filtration and washed with MeOH (25 mL) and dried in vacuo. Yield: 0.99 g (85%). 4.3. Synthesis of Schiff-base type cavitands (3) (condensation of 2 and the corresponding picolylamine (aec)) In a typical procedure, 2 (200 mg, 0.177 mmol), p-toluenesulfonic acid (2 mg, 0.011 mmol) and picolylamine (a, b or c) (146 mL, 1.42 mmol) were dissolved in dry THF (20 mL) under an inert atmosphere. The reaction mixture was stirred at 70 C for 24 h. The precipitating product was collected by filtration and washed with dry MeOH (25 mL) and dried in vacuo. 4.4. A typical procedure for aminocarbonylation experiments with tetrakis(4-iodophenoxymethyl)cavitand (4) 4.4.1. Method A (atmospheric aminocarbonylation). Compound 4 (250 mg, 0.164 mmol), Pd(OAc)2 (5.6 mg, 0.025 mmol) and PPh3 (13.1 mg, 0.05 mmol) were weighted and placed under an inert atmosphere into a 100 mL flask. Dry DMF (10 mL), NEt3 (275 mL, 1.968 mmol) and picolylamine (aee) (1.315 mmol) were added. The reaction mixture was then placed under atmospheric CO pressure. The reaction mixture was stirred at 60 C for 48 h under an inert atmosphere, the metallic palladium (‘palladium black’) was filtered off, and the filtrate was evaporated to dryness. The residue was treated with methanol (10 mL), the resulting precipitate was washed with methanol (10 mL) was collected by filtration and dried in vacuo. 4.4.2. Method B (high pressure aminocarbonylation). The same amount of catalyst, substrate and N-nucleophile as above (method A) were measured into a 100 mL stainless steel autoclave. The reaction mixture was then placed under 40 bar CO pressure. The reaction mixture was stirred at 60 C for 48 h, the metallic palladium was filtered, and the filtrate was evaporated to dryness. The residue was treated with methanol as above (method A). 4.5. Characterisations of the products 4.5.1. Cavitand 2. White powder (202 mg, 87%), mp >240 C (dec). Found: C, 72.20; H, 5.14%. C68H56O16 requires C, 72.33; H, 5.00%. IR (KBr, n (cm1)) 1696, 1600; dH (500.1 MHz, CDCl3): 1.87 (d, J 7.3 Hz, 12H, CH3CH), 4.64 (d, J 7.3 Hz, 4H, inner of OCH2O), 5.02 (s, 8H, ArCH2O), 5.11 (q, J 7.0 Hz, 4H, CHCH3), 5.78 (d, J 7.3 Hz, 4H, outer of OCH2O), 7.01 (d, J 8.2 Hz, 8H, Ar), 7.44 (s, 4H, Ar), 7.83 (d, J 8.2 Hz, 8H, Ar), 9.90 (s, 4H, ArCHO). dC (125.1 MHz, CDCl3): 16.1 (CH3CH), 31.3 (CH3CH), 61.0 (ArCH2O), 100.0 (OCH2O), 114.7, 121.0, 121.9, 130.4, 132.0, 139.1, 154.0, 163.4, 190.4 (ArCHO). 4.5.2. Cavitand 3a. Pale yellow powder (162 mg, 83%), mp >300 C (dec). Found: C, 74.01; H, 5.56; N, 7.30%, C92H80N8O12 requires C, 74.18; H, 5.41; N, 7.52%. nmax (KBr): 2965, 1642, 1594 cm1; dH (500.1 MHz, CDCl3): 1.87 (d, J 7.3 Hz, 12H, CH3CH), 4.66 (d, J 7.3 Hz, 4H, inner of OCH2O), 4.92 (s, 8H, NCH2Pyr), 4.97 (s, 8H, ArCH2O), 5.11 (q, J 7.0 Hz, 4H, CHCH3), 5.78 (d, J 7.3 Hz, 4H, outer of OCH2O), 6.96 (d, J 8.2 Hz, 8H, Ar), 7.17 (s, 4H, Ar), 7.26 (s, 4H, Ar), 7.66 (s, 4H, Ar), 7.75 (d, J 8.2 Hz, 8H, Ar), 8.39 (s, 4H, HC]
N), 8.57 (s, 4H, Ar). dC (125.1 MHz, CDCl3): 16.2 (CH3CH), 31.3 (CH3CH), 60.9 (ArCH2O), 66.7 (NCH2Pyr), 100.0 (OCH2O), 114.6, 120.7, 121.7, 121.9, 122.3, 126.2, 130.0, 136.6, 139.0, 149.2, 150.2, 154.0, 160.8, 162.1 (C]N). 4.5.3. Cavitand 3b. White powder (150 mg, 62%), mp 154 C. Found: C, 73.96; H, 5.30; N, 7.33%, C92H80N8O12 requires C, 74.18; H, 5.41; N, 7.52%. nmax (KBr): 2970, 1643, 1604 cm1; dH (500.1 MHz, CDCl3): 1.85 (d, J 7.2 Hz, 12H, CH3CH), 4.66 (d, J 7.2 Hz, 4H, inner of OCH2O), 4.77 (s, 8H, NCH2Pyr), 4.96 (s, 8H, ArCH2O), 5.11 (q, J 7.2 Hz, 4H, CHCH3), 5.79 (d, J 7.2 Hz, 4H, outer of OCH2O), 6.96 (d, J 8.5 Hz, 8H, Ar), 7.26e7.30 (m, 4H, Ar overlapping with CDCl3 signal), 7.42 (s, 4H, Ar), 7.67 (d, J 7.8 Hz, 4H), 7.72 (d, J 8.5 Hz, 8H, Ar), 8.35 (s, 4H, Ar), 8.53 (d, J 4.7 Hz, 4H, Ar), 8.60 (s, 4H, HC]N). dC (125.1 MHz, CDCl3): 16.2 (CH3CH), 31.2 (CH3CH), 60.6 (ArCH2O), 62.1 (NCH2Pyr), 100.1 (OCH2O), 114.6, 122.4, 123.4, 129.3, 130.0, 135.1, 135.4, 139.0, 148.4, 149.4, 154.0, 160.9, 161.7 (C]N). 4.5.4. Cavitand 3c. Pale yellow powder (155 mg, 80%), mp >300 C (dec). Found: C, 74.05; H, 5.50; N, 7.32%, C92H80N8O12 requires C, 74.18; H, 5.41; N, 7.52%. nmax (KBr): 2968, 1642, 1603 cm1; dH (500.1 MHz, CDCl3): 1.85 (d, J 7.3 Hz, 12H, CH3CH), 4.67 (d, J 7.3 Hz, 4H, inner of OCH2O), 4.75 (s, 8H, NCH2Pyr), 4.98 (s, 8H, ArCH2O), 5.10 (q, J 7.0 Hz, 4H, CHCH3), 5.78 (d, J 7.3 Hz, 4H, outer of OCH2O), 6.98 (d, J 8.2 Hz, 8H, Ar), 7.26e7.30 (m, 8H, Ar overlapping with CDCl3 signal), 7.43 (s, 4H, Ar), 7.73 (d, J 8.2 Hz, 8H), 8.33 (s, 4H, HC] N), 8.56 (s, 8H, Ar). dC (125.1 MHz, CDCl3): 16.2 (CH3CH), 31.3 (CH3CH), 60.8 (ArCH2O), 63.3 (NCH2Pyr), 100.1 (OCH2O), 114.6, 120.8, 122.4, 122.7, 129.3, 130.0, 139.0, 148.8, 149.8, 154.0, 160.9, 162.2 (C]N). 4.5.5. Cavitand 5a. White powder (112 mg, 55%), mp 195 C. Found: C, H, N, %, C92H80N8O16 requires C, 71.12; H, 5.19; N, 7.21%. nmax (KBr): 3402, 1658, 1596 cm1; dH (500.1 MHz, CDCl3): 1.84 (d, J 7.3 Hz, 12H, CH3CH), 4.61 (s, 8H, NCH2Pyr), 4.66 (d, J 7.3 Hz, 4H, inner of OCH2O), 5.02 (s, 8H, ArCH2O), 5.11 (q, J 7.0 Hz, 4H, CHCH3), 5.75 (d, J 7.3 Hz, 4H, outer of OCH2O), 6.96 (d, J 8.2 Hz, 8H, Ar), 7.15 (s, 4H, Ar), 7.20 (s, 4H, Ar), 7.31 (m, 4H, Ar overlapping with CDCl3 signal), 7.43 (s, 4H, Ar), 7.67 (d, J 8.2 Hz, 8H, Ar), 8.37 (s, 4H, HN), 8.56 (br s, 4H, Ar). dC (125.1 MHz, CDCl3): 16.1 (CH3CH), 31.2 (CH3CH), 44.4 (NCH2Pyr), 60.8 (ArCH2O), 100.1 (OCH2O), 114.3, 121.0, 121.9, 122.5, 126.8, 129.3, 133.9, 136.8, 139.1, 149.3, 154.0, 155.9, 162.8, 163.5 (C]O). 4.5.6. Cavitand 5b. White powder (120 mg, 44%), mp 184 C. Found: C, 70.98; H, 5.40; N, 7.02%. C92H80N8O16 requires C, 71.12; H, 5.19; N, 7.21%. nmax (KBr): 3390, 1659, 1598 cm1; dH (500.1 MHz, CDCl3): 1.83 (d, J 7.5 Hz, 12H, CH3CH), 4.14 (q, J 6.5 Hz, 8H, NCH2Pyr), 4.67 (d, J 7.2 Hz, 4H, inner of OCH2O), 4.92 (s, 8H, ArCH2O), 5.11 (q, J 7.2 Hz, 4H, CHCH3), 5.75 (d, J 7.2 Hz, 4H, outer of OCH2O), 6.96 (d, J 8.5 Hz, 8H, Ar), 7.26e7.30 (m, 4H, Ar overlapping with CDCl3 signal), 7.43 (s, 4H, Ar), 7.67 (d, J 7.8 Hz, 4H), 8.33 (d, J 8.5 Hz, 8H, Ar), 8.41e8.65 (m, 12H). dC (125.1 MHz, CDCl3): 16.2 (CH3CH), 31.2 (CH3CH), 41.3 (NCH2Pyr), 60.8 (ArCH2O), 100.2 (OCH2O), 114.3, 121.0, 122.0, 123.7, 126.6, 133.2, 133.9, 135.1, 139.6, 149.0, 154.0, 162.6, 163.6 (C]O). 4.5.7. Cavitand 5c. White powder (102 mg, 50%), mp >300 C (dec). Found: C, 71.23; H, 5.40; N, 7.07%, C92H80N8O16 requires C, 71.12; H, 5.19; N, 7.21%. nmax (KBr): 3392, 1660, 1599 cm1; dH (500.1 MHz, CDCl3): 1.85 (d, J 7.3 Hz, 12H, CH3CH), 4.56 (s, 8H, NCH2Pyr), 4.63 (d, J 7.3 Hz, 4H, inner of OCH2O), 5.04 (s, 8H, ArCH2O), 5.01 (q, J 7.0 Hz, 4H, CHCH3), 5.78 (d, J 7.3 Hz, 4H, outer of OCH2O), 6.96 (d, J 8.2 Hz, 8H, Ar), 7.23 (s, 8H, Ar), 7.44 (s, 4H, Ar), 7.87 (s, 4H, HN), 8.37 (d, J 8.2 Hz, 8H, Ar), 8.56 (s, 8H, Ar). dC (125.1 MHz, CDCl3): 16.2 (CH3CH), 31.2 (CH3CH), 40.9 (NCH2Pyr),
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60.8 (ArCH2O), 100.2 (OCH2O), 114.3, 121.0, 122.0, 123.7, 126.6, 134.0, 139.0, 139.1, 146.3, 149.0, 154.0, 162.8, 163.6 (C]O).
114.4, 120.8, 122.3, 122.7, 128.6, 139.3, 147.1, 150.0, 159.8, 163.9 (C] O), 189.5 (ArC]O).
4.5.8. Cavitand 5d. Pale brown powder (55 mg, 24%), mp 250 C (dec). Found: C, 76.88; H, 6.01; N, 6.55%, C100H96N8O16 requires C, 77.10; H, 5.81, N, 6.73%. nmax (KBr): 1705, 1602 cm1; dH (500.1 MHz, CDCl3): 1.14 (m, 12H, NCH2CH3), 1.85 (d, J 7.3 Hz, 12H, CH3CH), 3.45 (m, 8H, NCH2Pyr), 4.67 (d, J 7.3 Hz, 4H, inner of OCH2O), 4.95 (q, J 7.0 Hz, 4H, CHCH3), 5.03 (s, 8H, ArCH2O), 5.11 (s, 8H, NCH2CH3), 5.78 (d, J 7.3 Hz, 4H, outer of OCH2O), 6.93 (d, J 8.2 Hz, 8H, Ar), 7.29 (m, 4H, H-3(Pyr) overlapping with CDCl3 signal), 7.44 (s, 4H, Ar), 8.00 (m, 8H, Ar), 8.62 (s, 8H, H-4(Pyr)). dC (125.1 MHz, CDCl3): 12.4 (NCH2CH3)16.1 (CH3CH), 31.3 (CH3CH), 39.6 (NCH2CH3), 46.2 (NCH2Pyr), 60.8 (ArCH2O), 100.0 (OCH2O), 114.4, 120.8, 122.3, 122.7, 128.6, 139.3, 146.0, 150.0, 159.8, 171.8 (C]O).
4.5.13. Cavitand 6e. White powder (112 mg, 42%), mp 192 C. Found: C, 70.80; H, 5.13; N, 8.02%. C120H100N12O20 requires C, 70.99; H, 4.96; N, 8.28%. nmax (KBr): 1647, 1597 cm1; dH (500.1 MHz, CDCl3): 1.86 (d, J 7.3 Hz, 12H, CH3CH), 4.62 (m, 8H, NCH2Pyr), 4.69 (m, 4H, inner of OCH2O), 4.83 (m, 8H, NCH2Pyr), 5.02 (s, 8H, ArCH2O), 5.11 (q, J 7.0 Hz, 4H, CHCH3), 5.81 (d, J 7.3 Hz, 4H, outer of OCH2O), 7.02 (d, J 8.9 Hz, 8H, Ar), 7.13 (m, 4H, H5(Pyr)), 7.19 (m, 4H, H-5(Pyr)), 7.33 (m, 4H, H-3(Pyr)), 7.34 (m, 4H, H-3(Pyr)), 7.45 (s, 4H, Ar), 7.60 (m, 4H, H-4(Pyr)), 7.65 (m, 4H, H4(Pyr)), 8.12 (d, J 8.9 Hz, 8H, Ar), 8.42 (d, J 4.9 Hz, 4H, H-6(Pyr)), 8.54 (d, J 4.9 Hz, 4H, H-6(Pyr)). dC (125.1 MHz, CDCl3): 16.1 (CH3CH), 30.9 (CH3CH), 49.4 (NCH2Pyr), 53.1 (NCH2Pyr), 61.0 (ArCH2O), 100.0 (OCH2O), 114.5, 121.1, 121.9, 122.3, 122.5, 122.6, 122.7, 132.9, 136.8, 136.8, 139.2, 149.3, 149.4, 154.0, 155.5, 155.9, 163.6, 168.2 (C]O), 189.7 (ArC]O).
4.5.9. Cavitand 6a. White powder (149 mg, 69%), mp 186 C. Found: C, 69.10; H, 4.98; N, 6.50%, C96H80N8O20 requires C, 69.22; H, 4.84; N, 6.73%. nmax (KBr): 3327, 1660, 1596 cm1; dH (500.1 MHz, CDCl3): 1.84 (d, J 7.3 Hz, 12H, CH3CH), 4.61 (s, 8H, NCH2Pyr), 4.69 (d, J 7.3 Hz, 4H, inner of OCH2O), 5.02 (s, 8H, ArCH2O), 5.11 (q, J 7.0 Hz, 4H, CHCH3), 5.78 (d, J 7.3 Hz, 4H, outer of OCH2O), 6.96 (d, J 8.2 Hz, 8H, Ar), 7.22 (s, 4H, Ar), 7.26e7.30 (m, 4H, Ar overlapping with CDCl3 signal), 7.43 (s, 4H, Ar), 7.57 (s, 4H, Ar), 8.24 (s, 4H, HN), 8.38 (d, J 8.2 Hz, 8H, Ar), 8.56 (s, 4H, Ar). dC (125.1 MHz, CDCl3): 16.1 (CH3CH), 30.9 (CH3CH), 44.5 (NCH2Pyr), 60.8 (ArCH2O), 100.0 (OCH2O), 114.3, 120.9, 121.9, 122.5, 126.9, 129.3, 133.9, 136.8, 139.1, 149.3, 154.0, 155.9, 162.7, 163.4 (NC]O), 185.8 (ArC]O). 4.5.10. Cavitand 6b. White powder (120 mg, 44%), mp 190 C. Found: C, 69.11; H, 4.90; N, 6.68%. C96H80N8O20 requires C, 69.22; H, 4.84; N, 6.73%. nmax (KBr): 3390, 1659, 1598 cm1; dH (500.1 MHz, CDCl3): 1.84 (d, J 7.5 Hz, 12H, CH3CH), 4.56 (q, J 6.5 Hz, 8H, NCH2Pyr), 4.67 (d, J 7.2 Hz, 4H, inner of OCH2O), 5.01 (s, 8H, ArCH2O), 5.11 (q, J 7.2 Hz, 4H, CHCH3), 5.75 (d, J 7.2 Hz, 4H, outer of OCH2O), 6.94 (d, J 8.5 Hz, 8H, Ar), 7.26e7.30 (m, 4H, Ar overlapping with CDCl3 signal), 7.43 (s, 4H, Ar), 7.67 (d, J 7.8 Hz, 4H), 8.36 (d, J 8.5 Hz, 8H, Ar), 8.48e8.68 (m, 12H). dC (125.1 MHz, CDCl3): 16.2 (CH3CH), 31.2 (CH3CH), 40.9 (NCH2Pyr), 60.6 (ArCH2O), 100.1 (OCH2O), 114.3, 121.1, 122.0, 123.7, 127.0, 134.0, 135.7, 139.1, 149.1, 149.4, 154.1, 159.6, 162.6, 163.6 (NC]O), 185.4 (ArC]O). 4.5.11. Cavitand 6c. White powder (145 mg, 67%), mp 295 C (dec). Found: C, 69.10; H, 4.88; N, 6.57%. C96H80N8O20 requires C, 69.22; H, 4.84; N, 6.73%. nmax (KBr): 3384, 1669, 1599 cm1; dH (500.1 MHz, CDCl3): 1.85 (d, J 7.3 Hz, 12H, CH3CH), 4.56 (s, 8H, NCH2Pyr), 4.63 (d, J 7.3 Hz, 4H, inner of OCH2O), 5.01 (s, 8H, ArCH2O), 5.04 (q, J 7.0 Hz, 4H, CHCH3), 5.78 (d, J 7.3 Hz, 4H, outer of OCH2O), 6.96 (d, J 8.2 Hz, 8H, Ar), 7.23 (s, 8H, Ar), 7.44 (s, 4H, Ar), 7.87 (s, 4H, HN), 8.37 (d, J 8.2 Hz, 8H, Ar), 8.56 (s, 8H, Ar). dC (125.1 MHz, CDCl3): 16.1 (CH3CH), 31.3 (CH3CH), 42.2 (NCH2Pyr), 60.9 (ArCH2O), 100.0 (OCH2O), 114.4, 121.0, 121.9, 122.3, 126.6, 134.0, 139.0, 139.1, 146.3, 150.2, 154.0, 162.8, 163.7 (NC]O), 185.4 (ArC]O). 4.5.12. Cavitand 6d. Pale brown powder (62 mg, 27%), mp 282 C (dec). Found: C, 70.11; H, 5.50; N, 6.22%. C104H96N8O20 requires C, 70.26; H, 5.44; N, 6.30%. nmax (KBr): 1669, 1633 cm1; dH (500.1 MHz, CDCl3): 1.14 (m, 12H, NCH2CH3), 1.85 (d, J 7.3 Hz, 12H, CH3CH), 3.45 (m, 8H, NCH2Pyr), 4.67 (d, J 7.3 Hz, 4H, inner of OCH2O), 4.95 (q, J 7.0 Hz, 4H, CHCH3), 5.03 (s, 8H, ArCH2O), 5.11 (s, 8H, NCH2CH3), 5.78 (d, J 7.3 Hz, 4H, outer of OCH2O), 6.93 (d, J 8.2 Hz, 8H, Ar), 7.29 (m, 4H, H-3(Pyr) overlapping with CDCl3 signal), 7.44 (s, 4H, Ar), 8.00 (m, 8H, Ar), 8.62 (s, 8H, H-4(Pyr)). dC (125.1 MHz, CDCl3): 13.9 (NCH2CH3), 16.1 (CH3CH), 31.3 (CH3CH), 42.9 (NCH2CH3), 50.0 (NCH2Pyr), 60.8 (ArCH2O), 100.0 (OCH2O),
Acknowledgements The authors thank the Hungarian Scientific Research Fund (K113177) and Developing Competitiveness of Universities in the South Transdanubian Region (SROP-4.2.2.A-11/1/KONV-20120065) for the financial support and Johnson Matthey for the generous gift of palladium(II) acetate. References and notes 1. Cram, D. J.; Karbach, S.; Kim, H. E.; Knobler, C. B.; Maverick, E. F.; Ericson, J. L.; Helgeson, R. C. J. Am. Chem. Soc. 1988, 110, 2229e2237. 2. (a) Chen, G.; Jiang, M. Chem. Soc. Rev. 2011, 40, 2254e2266; (b) Del Valle, E. M. M. Process Biochem. 2004, 39, 1033e1046. €hmer, V. Angew. Chem., Int. Ed. Engl. 1995, 34, 713e745 and references cited 3. Bo therein. 4. Timmerman, P.; Verboom, W.; Reinhoudt, D. N. Tetrahedron 1996, 52, 2663e2704. 5. Masson, E.; Ling, X.; Joseph, R.; Kyeremeh-Mensah, L.; Lu, X. RSC Adv. 2012, 2, 1213e1247 and references cited therein. 6. Cram, D. J.; Cram, J. M. Container Molecules and Their Guests; Royal Society of Chemistry: Cambridge, UK, 1994. 7. (a) Moran, J. R.; Ericson, J. L.; Dalcanale, E.; Bryant, J. A.; Knobler, C. B.; Cram, D. J. J. Am. Chem. Soc. 1991, 113, 5707e5714; (b) Tucci, F. C.; Rudkevich, D. M.; Rebek, J., Jr. J. Org. Chem. 1999, 64, 4555e4559; (c) Li, X.; Upton, T. G.; Gibb, C. L. D.; Gibb, B. C. J. Am. Chem. Soc. 2003, 125, 650e651. 8. (a) Ma, S.; Rudkevich, D. M.; Rebek, J., Jr. J. Am. Chem. Soc. 1998, 120, 4977e4981; €y, C. B.; Schultheiss, N.; Desper, J. Org. Lett. 2006, 12, 2607e2610. (b) Aakero Kunsa k, Z.; Ke gl, T.; P nyi, L.; Varga, A.; gi-Ma te , S.; Koll 9. Cso arka ar, L. Supramol. Chem. 2011, 23, 710e719. 10. (a) Rudkevich, D. M.; Hilmersson, G.; Rebek, J., Jr. J. Am. Chem. Soc. 1998, 119, 9911e9912; (b) Rudkevich, D. M.; Hilmersson, G.; Rebek, J., Jr. J. Am. Chem. Soc. 1998, 120, 12216e12225; (c) Chang, T.-Y.; Paek, K. Bull. Korean Chem. Soc. 2008, 29, 1857e1859. 11. (a) Beller, M.; Bolm, C. Transition Metals for Organic Synthesis; Wiley-VCH: Weinheim, Germany, 1998, Vols. I and II; (b) Modern Carbonylation Methods; Koll ar, L., Ed.; Wiley-VCH: Weinheim, Germany, 2008. € ldes, R.; Koll 12. (a) Skoda-Fo ar, L. Curr. Org. Chem. 2002, 6, 1097e1119; (b) € hrer, A.; Neumann, H.; Beller, M. Angew. Chem., Int. Ed. 2009, 48, Brennfu 4114e4133; (c) Applied Homogeneous Catalysis with Organometallic Compounds; Cornils, B., Herrmann, W. A., Eds.; Wiley-VCH: Weinheim, Germany, 1996; (d) Transition Metals for Organic Synthesis; Beller, M., Bolm, C., Eds.; Wiley-VCH: Weinheim, Germany, 1998; Vols. I and II; (e) Arcadi, A. Carbonylation of Enolizable Ketones (Enol Triflates) and Iodoalkenes In Modern Carbonylation Methods; Koll ar, L., Ed.; Wiley-VCH: Weinheim, Germany, 2008; Chapter 9, pp 223e250. € ldes, R.; Kolla r, L. Lett. Org. Chem. 2010, 7, 621e633. 13. Skoda-Fo 14. Mastropietro, T. F.; Yadav, Y. J.; Szerb, E. I.; Talarico, A. M.; Ghedini, M.; Crispini, A. Dalton Trans. 2012, 41, 8899e8907. 15. Gaidamauskas, E.; Crans, D. C.; Parker, H.; Saejueng, K.; Kashemirov, B. A.; McKenna, C. E. New J. Chem. 2011, 35, 2877e2883. 16. Macias, B.; Villa, M. V.; Salgado, M.; Borras, J.; Gonzalez-Alvarez, M.; Sanz, F. Inorg. Chim. Acta 2006, 359, 1465e1472. 17. Barquin, M.; Garmendia, M. J. G.; Laminaga, L.; Pinilla, E.; Torres, M. R. Inorg. Chim. Acta 2009, 362, 2334e2340. 18. Shiota, Y.; Sato, D.; Juhasz, G.; Yoshizawa, K. J. Phys. Chem. A 2010, 114, 5862e5869. 19. Katz, B. A.; Strouse, C. E. J. Am. Chem. Soc. 1979, 101, 6214e6221.
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20. Greenaway, A. M.; Sinn, E. J. Am. Chem. Soc. 1978, 100, 8080e8085. 21. Gutlich, P.; Link, R.; Steinhauser, H. G. Inorg. Chem. 1978, 17, 2509e2514. 22. Rajkovic, S.; Zivkovic, M. D.; Kallay, C.; Sovago, I.; Djuran, M. I. Dalton Trans. 2009, 8370e8377. 23. Krause, R. A. J. Phys. Chem. 1978, 82, 2575e2581. 24. Ayres, D. J.; House, D. A.; Robinson, W. T. Inorg. Chim. Acta 1998, 277, 177e185. 25. Azzellini, M. A. D.; DeOliveira, M. D. P.; Iha, N. Y. M.; Osorio, V. K. M. Polyhedron 1996, 15, 4579e4584. 26. Tanase, S.; Farbinteanu, M.; Andruh, M.; Mathoniere, C.; Strenger, I.; Rombaut, G. Polyhedron 2000, 19, 1967e1973. 27. Brand, U.; Vahrenkamp, H. Inorg. Chem. 1995, 34, 3285e3293. 28. Tiwow, V.; Lawrence, G. A.; Maeder, M.; Jensen, P. J. Coord. Chem. 2011, 64, 3637e3651. 29. Hochreuter, S.; Puchta, R.; van Eldik, R. Inorg. Chem. 2011, 50, 8984e8996. 30. Wu, J. Z.; Bouwman, E.; Mills, A. M.; Spek, A. L.; Reedijk, J. Inorg. Chim. Acta 2004, 357, 2694e2702. 31. Zhang, X. L.; Jing, X.; Liu, T.; Han, G.; Li, H. Q.; Duan, C. Y. Inorg. Chem. 2012, 51, 2325e2332.
32. Choudhury, C. R.; Dey, S. K.; Mitra, S.; Gramlich, V. Dalton Trans. 2003, 1059e1060. 33. Ding, Y. B.; Zhu, W. H.; Xie, Y. S. Progr. Chem. 2011, 23, 2478e2488. 34. Xue, L.; Wang, H.-H.; Wang, X.-J.; Jiang, H. Inorg. Chem. 2008, 47, 4310e4318. 35. Lee, P.-K.; Law, W. H.-T.; Liu, H.-W.; Lo, K. K.-W. Inorg. Chem. 2011, 50, 8570e8579. 36. Roening, A. J.; Hale, L. V. A.; Squier, P. A.; Ringgold, M. A.; Wiederspan, E. R.; Clark, T. B. Org. Lett. 2012, 14, 3558e3561. 37. Putignano, E.; Bossi, G.; Rigo, P.; Baratta, W. Organometallics 2012, 31, 1133e1142. 38. Sorrell, T. N.; Pigge, F. C. J. Org. Chem. 1993, 58, 784e785. 39. (a) Amatore, C.; Jutand, A.; M’Barki, M. A. Organometallics 1992, 11, 3009e3013; (b) Amatore, C.; Carre, E.; Jutand, A.; M’Barki, M. A.; Meyer, G. Organometallics kai, Z.; Skoda-Fo € ldes, R.; Kolla r, L. Inorg. Chim. Acta 1995, 14, 5605e5614; (c) Csa 1999, 286, 93e97 and references cited therein. 40. (a) Boerrigter, H.; Verboom, W.; van Hummel, G. J.; Harkema, S.; Reinhoudt, D. N. Tetrahedron Lett. 1996, 37, 5167e5170; (b) Barrett, E. S.; Irwin, J. L.; Picker, K.; Sherburn, M. S. Aust. J. Chem. 2002, 55, 319e325.
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Tetrahedron journal homepage: www.elsevier.com/locate/tet
High-yielding synthesis of deepened cavitands bearing picolyl moieties on the upper rim n Nagymiha ly a, La szlo Kolla r a, b, * Zolta a b
gothai Research Center, PO Box 266, H-7624 P Department of Inorganic Chemistry, University of P ecs and Szenta ecs, Hungary g u. 6, H-7624 P sa MTA-PTE Research Group for Selective Chemical Syntheses, Ifju ecs, Hungary
a r t i c l e i n f o
a b s t r a c t
Article history: Received 22 December 2014 Received in revised form 19 February 2015 Accepted 3 March 2015 Available online 7 March 2015
Conventional high-yielding reactions (such as etherification, condensation reactions) and palladiumcatalysed aminocarbonylation served as highly efficient synthetic tools for the synthesis of novel cavitands bearing Schiff-base and carboxamide/2-ketocarboxamide functionalities, respectively. In this way, two families of deepened cavitands with related structures possessing 2-, 3- and 4-picolylamine moieties on the upper rim have been synthesised. Unexpectedly high chemoselectivities towards tetracarboxamides and tetrakis(2-ketocarboxamides) have been observed. The aminocarbonylation of tetraiodocavitand as an iodoaromatic substrate proved to be highly selective in two aspects: (i) no substantial formation of either the mono-, di- or trifunctionalized products was observed and (ii) no ‘mixed’ products possessing both carboxamide and 2-ketocarboxamide fragments, due to selective simple and double carbon monoxide insertion, were detected. Ó 2015 Elsevier Ltd. All rights reserved.
Keywords: Cavitand Schiff base Aminocarbonylation Carbon monoxide Palladium Carboxamide
1. Introduction 2-Methylresorcine-based cavitands1 with a conformationally rigid, bowl-shaped macrocyclic structure have been generating tremendous interest in the supramolecular community. In addition to cyclodextrins,2 calixarenes,3 calix-resorcinarenes4 and cucurbiturils,5 the well-known families of molecular hosts with exceptional molecular recognition ability, cavitands have also gained wide applications in ‘hosteguest’ chemistry. The size and shape of the cavitands are essential considering their potential applications as sensors, nanoreactors and drug delivery systems. Especially the peculiarities of the upper rim, i.e., that of the upper inlet of such molecular containers was brought into focus.6 Although deepening and enlarging the molecular pocket of cavitands was principally accomplished mainly by conventional organic reactions;7 some homogeneous catalytic reactions were sparsely employed.8 In one of our previous papers we described the upper rim functionalisation of a tetraidocavitand by various homogeneous catalytic reactions such as cross-coupling (Suzuki, Sonogashira, Stille) reactions and aminocarbonylation.9 Since the latter carboxamide-forming reaction serves as a keyreaction in the present work, it should be mentioned that carboxamide functionalities were previously introduced into the cavitand
r). * Corresponding author. E-mail address: [email protected] (L. Kolla http://dx.doi.org/10.1016/j.tet.2015.03.009 0040-4020/Ó 2015 Elsevier Ltd. All rights reserved.
skeleton by acylation of the corresponding aminocavitands.10 Palladium-catalysed carbonylations have become indispensable tools in organic chemistry.11 Among them, palladium-catalysed aminocarbonylation of organohalides (preferably iodoalkenes and iodoarenes) proved to be of high synthetic importance. The facile conversion of iodoalkenes or iodoarenes (as synthetic surrogates of the corresponding enol triflates and aryl triflates, respectively) to carboxamides by using carbon monoxide and various amines as Nnucleophiles, made these reactions of high synthetic importance.12 Various ‘preformed’ or in situ generated palladium(0) catalysts were used.13 As a part of our on-going research in the carbonylation reactions of iodoarenes and iodoalkenes, we turned our attention towards the systematic variation of the N-nucleophiles. It has to be added that in the case of various compounds with practical interest, the above catalytic reactions provide synthetic methods superior to conventional ones. Since several amines with picolyl substituents (especially 2-picolylamine (pam) and di-(2-picolyl)amine (dpa)) are favoured ligands in coordination chemistry (vide infra) their attachment to a cavitand backbone with potential host properties was considered. A wide application of pam as ligand in transition metal complexes such as Ir(III),14 Cu(II),15e17 Fe(II),18e21 Pd(II) and Pt(II),22 Cr(III)23e25 and Ni(II)26 has been described. 2-Picolylamine-based multidentate ligands have also been also used in Zn(II),27,28 Pt(II),29 Cu(II) and Mn(II)16,30 complexes. The coordination of the
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potentially N,N0 ,N00 -tridentate ligand dpa to Cu(II),31,32 Zn(II)33,34 and Ir(III)35 was also reported. The catalytic application of Ir-pam complexes36 and Os- and Ru-pam37 systems has been reported in CeH borylation and transfer hydrogenation, respectively. The high potential of picolyl moieties in binding properties as well as the molecular recognition properties of cavitands prompted us to combine the two functions in a family of novel cavitands, which proved to be available in high-yielding, facile reactions. 2. Results and discussion To synthesise multi-level (‘deepened’) cavitands with pyridyl groups on the upper rim, the tetrabromocavitand (1)38 was reacted with 4-hydroxybenzaldehyde under conventional etherification conditions in the first step yielding the tetraformyl derivative (2) in 87% yield. The condensation reaction of 2 with 2-, 3- or 4picolylamine (aec, respectively, Fig. 1) resulted in the highyielding formation (62e83%) of the corresponding Schiff-bases (3ae3c) (Scheme 1).
Fig. 1. Amines with pyridyl moieties used in this work.
To synthesise cavitands with similar structures, the aminocarbonylation reaction was chosen to introduce primary and secondary amines on the upper rim of the cavitand scaffold in the presence of Pd(OAc)2þ2PPh3 in situ catalytic systems (Scheme 2). Under the reaction conditions used, highly reactive, coordinatively unsaturated Pd(0) intermediates are formed39 enabling facile activation of the iodoaromatic substrate, carbon monoxide and amine nucleophile. Tetraiodocavitand (4), bearing four excellent leaving groups, served as a substrate for further extension of the cavitand structure as demonstrated in various coupling reactions before.9 In this study, we aimed to extend the scope of palladium-catalysed carbonylations using 4 as key-intermediate in this family of cavitands. The tetraiodocavitand (4) was synthesised from tetrabromocavitand (1) and 4-iodophenol by an improved methodology.9 Primary picolylamines (2-picolylamine (a), 3-picolylamine (b) and 4-picolylamine (c)) as well as secondary amines possessing picolyl substituent (4-(ethylaminomethyl)pyridine (d), di-(2picolyl)amine (e)) were employed as N-nucleophiles for the preparation of both novel carboxamidocavitands (5ae5d) and 2ketocarboxamides (6ae6e) in aminocarbonylation. That is, depending on the reaction conditions, the selective synthesis of carboxamides (5) and ketocarboxamides (6) can be accomplished (vide infra) via simple and double carbon monoxide insertion, respectively. Under ambient conditions (1 bar CO, 50 C) the formation of tetracarboxamides is highly favoured (Table 1, entries 1, 4, 8) when primary amines were used as N-nucleophiles. However, the use of secondary amine d provided a carboxamide/ketocarboxamide mixture of 40:60 (entry 11). The secondary amine e possessing two 4-pycolyl moieties, has shown decreased reactivity under 1 bar CO and no compound in isolable amount was formed (entry 13). It is
Scheme 1. Synthesis of cavitands with Schiff-base moieties on the upper rim.
Scheme 2. Synthesis of tetracarboxamidocavitands (5) and tetrakis(2-ketocarboxamido)cavitands (6) in palladium-catalysed aminocarbonylation.
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Table 1 Palladium-catalysed aminocarbonylation of 4a Entry
Amine
Molar equivalents of amine
p[CO] [bar]
Conversionb (%)
Chemoselectivityc (%)
Yieldd (%)
1 2 3 4 5 6 7 8 9 10 11 12 13 14
a a a b b be b c c c d d e e
8 8 8 8 8 2 8 8 8 8 8 8 8 8
1 40 60 1 40 40 90 1 40 90 1 40 1 40
>99 >99 <5 >99 >99 46 <2 >99 >99 <2 >99 >99 <5 >99
5a (>98), 6a (<2) 5a (<2), 6a (>98) n.d. 5b (>98), 6b (<2) 5b (<2), 6b (>98) 5b (<2), 6b (>98) n.d. 5c (>98), 6c (<2) 5c (<2), 6c (>98) n.d. 5d (40), 6d (60) 5d (<2), 6d (>98) n.d. 5e (<2), 6e (>98)
55 (5a) 69 (6a) n.d. 44 (5b) 54 (6b) 44 (6b) n.d. 50 (5c) 67 (6c) n.d. 24 (5d) 27 (6d) n.d. 42 (6e)
a b c d e
Reaction conditions: 1/Pd(OAc)2/PPh3/Et3N¼1:0.15:0.3:12, 60 C. (Moles of converted 4)/(Moles of initial 4)100. Determined on the crude reaction mixture by means of 1H and 13C NMR. Yield of isolated, analytically pure products. In case of selective tetrasubstitution observed the highest conversion that could be achieved is 50%.
worth noting that the extremely low reactivity of e is probably due to its strong tridentate coordination to palladium. We noticed, however, that higher CO pressure (40 bar) generated, as expected, a superior chemoselectivity towards 2ketocarboxamides (entries 2, 5, 9, 12 and 14 for 6a, 6b, 6c, 6d and 6e, respectively). It is important to note that neither the tetrakis(2ketocarboxamide) derivatives (6ae6e) nor tetracarboxamide derivatives (5ae5d) contained ‘mixed-substituted’ derivatives as minor components. That is, the cavitand derivatives show the simplest substitution pattern containing four identical ‘arms’. Either four carboxamide or four 2-ketocarboxamide arms were formed upon functionalisation of the parent tetraiodo compound. It was revealed by detailed NMR investigations carried out on the reaction mixtures that the total of the side-products (i.e., the total amount of the ‘mixed-substituted’ iodo-carboxamidocavitands or that of the carboxamido-ketocarboxamidocavitands) were less than 2%. The yields are strongly dependent on carbon monoxide pressure: practically no reaction was observed at 60e90 bar carbon monoxide pressure (entries 3, 7 and 10). Although no detailed mechanistic investigations are known, especially for this pressure range, it is generally accepted that the coordination of two or three carbonyl ligands to palladium(0) resulted in inactive catalytic species, that is, the oxidative addition of the iodoarene substrate is highly unfavoured. Even more surprisingly, when the molar equivalents of the amine reactants were decreased below 4, i.e., less than the stoichiometric amount of the N-nucleophile was used, only the same tetrafunctionalized products could be isolated along with unreacted starting tetraiodocavitand (4). For instance, carrying out aminocarbonylation at a 4/b molar ratio of ½ at 40 bar carbon monoxide pressure, 6b was formed and approximately half of the tetraiodo compound (4) was recovered (entry 6). Therefore, during the course of the reactions, the composition of the reaction mixtures was carefully checked both by in situ 1H and 13C NMR. Again, neither the formation of the diiodo-dicarboxamido-cavitand, that might be expected according to above molar ratios, nor that of the mono- or trifunctionalized products was observed. To find a reasonable explanation for the very high chemoselectivities towards tetrafunctionalized products, some novel catalytic features of the palladium-catalyst have to be supposed. It is worth noting, that various organic reactions have been applied for the introduction of appropriate functionalities using less than
4 M equiv of reactants related to cavitand. As expected, the application of these conventional synthetic reactions resulted in the generation of statistical mixtures of up to five partially substituted products.40 In contrast, we noticed unexpectedly high chemoselectivities towards tetrafunctionalized cavitands (vide supra) in palladiumcatalysed reactions. The rationalisation of the simple substitution patterns needs further investigations including mechanistic studies and the involvement of computational chemistry. 3. Conclusion Tetraiodocavitand served as a perfect platform for the highly selective synthesis of the corresponding tetrafunctionalised carboxamides and tetrakis(2-ketocarboxamides). The easily available primary and secondary amines make aminocarbonylation a powerful, switchable synthetic methodology for the functionalisation of deepened cavitands. Cavitands with similar sizes and upper rim groups have been synthesised via etherification/Schiff-base formation reaction. All of these deepened cavitands with 2-, 3- and 4pyridyl groups on the upper rim might serve as flexible binding pockets in ‘hosteguest’ chemistry. That is, instead of the conventional carboxylic acideacyl chlorideeamide route, the direct carbonylation of haloaromatics as well as those of the corresponding triflate surrogates can be used. We believe that the combination of high-yielding conventional reactions and chemo- and/or regioselective homogeneous catalytic reactions could serve as a powerful tool for the synthesis of novel supramolecular structures. 4. Experimental 4.1. General procedures All reagents and solvents were purchased from Aldrich and used as received. Toluene and THF was dried using traditional methods. 1 H and 13C NMR spectra were recorded at 25 C in CDCl3 (or in DMSO-d6) on a Bruker Avance III 500 spectrometer at 500 and 125.7 MHz, respectively. The 1H chemical shifts (d), reported in parts per million (ppm) downfield, are referenced to the residual protons (7.26 ppm for CDCl3 and 2.50 for DMSO-d6). The 13C chemical shifts are referenced to the carbon resonance of CDCl3 (77.00 ppm) or to that of DMSO-d6 (39.52 ppm), respectively.
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4.2. The synthesis of tetrakis(4-formylphenoxymethyl)cavitand (2) To the THF (15 mL) solution of 4-hydroxybenzaldehyde (0.5 g, 4.09 mmol), 1 M aqueous NaOH solution (5 mL) was added, and was left stirring for 30 min at room temperature. This solution was then slowly added to the THF (15 mL) solution of tetrakis(bromomethyl) cavitand (1.0 g, 1.04 mmol). The reaction mixture was stirred at 70 C for 24 h. The precipitating product was collected by filtration and washed with MeOH (25 mL) and dried in vacuo. Yield: 0.99 g (85%). 4.3. Synthesis of Schiff-base type cavitands (3) (condensation of 2 and the corresponding picolylamine (aec)) In a typical procedure, 2 (200 mg, 0.177 mmol), p-toluenesulfonic acid (2 mg, 0.011 mmol) and picolylamine (a, b or c) (146 mL, 1.42 mmol) were dissolved in dry THF (20 mL) under an inert atmosphere. The reaction mixture was stirred at 70 C for 24 h. The precipitating product was collected by filtration and washed with dry MeOH (25 mL) and dried in vacuo. 4.4. A typical procedure for aminocarbonylation experiments with tetrakis(4-iodophenoxymethyl)cavitand (4) 4.4.1. Method A (atmospheric aminocarbonylation). Compound 4 (250 mg, 0.164 mmol), Pd(OAc)2 (5.6 mg, 0.025 mmol) and PPh3 (13.1 mg, 0.05 mmol) were weighted and placed under an inert atmosphere into a 100 mL flask. Dry DMF (10 mL), NEt3 (275 mL, 1.968 mmol) and picolylamine (aee) (1.315 mmol) were added. The reaction mixture was then placed under atmospheric CO pressure. The reaction mixture was stirred at 60 C for 48 h under an inert atmosphere, the metallic palladium (‘palladium black’) was filtered off, and the filtrate was evaporated to dryness. The residue was treated with methanol (10 mL), the resulting precipitate was washed with methanol (10 mL) was collected by filtration and dried in vacuo. 4.4.2. Method B (high pressure aminocarbonylation). The same amount of catalyst, substrate and N-nucleophile as above (method A) were measured into a 100 mL stainless steel autoclave. The reaction mixture was then placed under 40 bar CO pressure. The reaction mixture was stirred at 60 C for 48 h, the metallic palladium was filtered, and the filtrate was evaporated to dryness. The residue was treated with methanol as above (method A). 4.5. Characterisations of the products 4.5.1. Cavitand 2. White powder (202 mg, 87%), mp >240 C (dec). Found: C, 72.20; H, 5.14%. C68H56O16 requires C, 72.33; H, 5.00%. IR (KBr, n (cm1)) 1696, 1600; dH (500.1 MHz, CDCl3): 1.87 (d, J 7.3 Hz, 12H, CH3CH), 4.64 (d, J 7.3 Hz, 4H, inner of OCH2O), 5.02 (s, 8H, ArCH2O), 5.11 (q, J 7.0 Hz, 4H, CHCH3), 5.78 (d, J 7.3 Hz, 4H, outer of OCH2O), 7.01 (d, J 8.2 Hz, 8H, Ar), 7.44 (s, 4H, Ar), 7.83 (d, J 8.2 Hz, 8H, Ar), 9.90 (s, 4H, ArCHO). dC (125.1 MHz, CDCl3): 16.1 (CH3CH), 31.3 (CH3CH), 61.0 (ArCH2O), 100.0 (OCH2O), 114.7, 121.0, 121.9, 130.4, 132.0, 139.1, 154.0, 163.4, 190.4 (ArCHO). 4.5.2. Cavitand 3a. Pale yellow powder (162 mg, 83%), mp >300 C (dec). Found: C, 74.01; H, 5.56; N, 7.30%, C92H80N8O12 requires C, 74.18; H, 5.41; N, 7.52%. nmax (KBr): 2965, 1642, 1594 cm1; dH (500.1 MHz, CDCl3): 1.87 (d, J 7.3 Hz, 12H, CH3CH), 4.66 (d, J 7.3 Hz, 4H, inner of OCH2O), 4.92 (s, 8H, NCH2Pyr), 4.97 (s, 8H, ArCH2O), 5.11 (q, J 7.0 Hz, 4H, CHCH3), 5.78 (d, J 7.3 Hz, 4H, outer of OCH2O), 6.96 (d, J 8.2 Hz, 8H, Ar), 7.17 (s, 4H, Ar), 7.26 (s, 4H, Ar), 7.66 (s, 4H, Ar), 7.75 (d, J 8.2 Hz, 8H, Ar), 8.39 (s, 4H, HC]
N), 8.57 (s, 4H, Ar). dC (125.1 MHz, CDCl3): 16.2 (CH3CH), 31.3 (CH3CH), 60.9 (ArCH2O), 66.7 (NCH2Pyr), 100.0 (OCH2O), 114.6, 120.7, 121.7, 121.9, 122.3, 126.2, 130.0, 136.6, 139.0, 149.2, 150.2, 154.0, 160.8, 162.1 (C]N). 4.5.3. Cavitand 3b. White powder (150 mg, 62%), mp 154 C. Found: C, 73.96; H, 5.30; N, 7.33%, C92H80N8O12 requires C, 74.18; H, 5.41; N, 7.52%. nmax (KBr): 2970, 1643, 1604 cm1; dH (500.1 MHz, CDCl3): 1.85 (d, J 7.2 Hz, 12H, CH3CH), 4.66 (d, J 7.2 Hz, 4H, inner of OCH2O), 4.77 (s, 8H, NCH2Pyr), 4.96 (s, 8H, ArCH2O), 5.11 (q, J 7.2 Hz, 4H, CHCH3), 5.79 (d, J 7.2 Hz, 4H, outer of OCH2O), 6.96 (d, J 8.5 Hz, 8H, Ar), 7.26e7.30 (m, 4H, Ar overlapping with CDCl3 signal), 7.42 (s, 4H, Ar), 7.67 (d, J 7.8 Hz, 4H), 7.72 (d, J 8.5 Hz, 8H, Ar), 8.35 (s, 4H, Ar), 8.53 (d, J 4.7 Hz, 4H, Ar), 8.60 (s, 4H, HC]N). dC (125.1 MHz, CDCl3): 16.2 (CH3CH), 31.2 (CH3CH), 60.6 (ArCH2O), 62.1 (NCH2Pyr), 100.1 (OCH2O), 114.6, 122.4, 123.4, 129.3, 130.0, 135.1, 135.4, 139.0, 148.4, 149.4, 154.0, 160.9, 161.7 (C]N). 4.5.4. Cavitand 3c. Pale yellow powder (155 mg, 80%), mp >300 C (dec). Found: C, 74.05; H, 5.50; N, 7.32%, C92H80N8O12 requires C, 74.18; H, 5.41; N, 7.52%. nmax (KBr): 2968, 1642, 1603 cm1; dH (500.1 MHz, CDCl3): 1.85 (d, J 7.3 Hz, 12H, CH3CH), 4.67 (d, J 7.3 Hz, 4H, inner of OCH2O), 4.75 (s, 8H, NCH2Pyr), 4.98 (s, 8H, ArCH2O), 5.10 (q, J 7.0 Hz, 4H, CHCH3), 5.78 (d, J 7.3 Hz, 4H, outer of OCH2O), 6.98 (d, J 8.2 Hz, 8H, Ar), 7.26e7.30 (m, 8H, Ar overlapping with CDCl3 signal), 7.43 (s, 4H, Ar), 7.73 (d, J 8.2 Hz, 8H), 8.33 (s, 4H, HC] N), 8.56 (s, 8H, Ar). dC (125.1 MHz, CDCl3): 16.2 (CH3CH), 31.3 (CH3CH), 60.8 (ArCH2O), 63.3 (NCH2Pyr), 100.1 (OCH2O), 114.6, 120.8, 122.4, 122.7, 129.3, 130.0, 139.0, 148.8, 149.8, 154.0, 160.9, 162.2 (C]N). 4.5.5. Cavitand 5a. White powder (112 mg, 55%), mp 195 C. Found: C, H, N, %, C92H80N8O16 requires C, 71.12; H, 5.19; N, 7.21%. nmax (KBr): 3402, 1658, 1596 cm1; dH (500.1 MHz, CDCl3): 1.84 (d, J 7.3 Hz, 12H, CH3CH), 4.61 (s, 8H, NCH2Pyr), 4.66 (d, J 7.3 Hz, 4H, inner of OCH2O), 5.02 (s, 8H, ArCH2O), 5.11 (q, J 7.0 Hz, 4H, CHCH3), 5.75 (d, J 7.3 Hz, 4H, outer of OCH2O), 6.96 (d, J 8.2 Hz, 8H, Ar), 7.15 (s, 4H, Ar), 7.20 (s, 4H, Ar), 7.31 (m, 4H, Ar overlapping with CDCl3 signal), 7.43 (s, 4H, Ar), 7.67 (d, J 8.2 Hz, 8H, Ar), 8.37 (s, 4H, HN), 8.56 (br s, 4H, Ar). dC (125.1 MHz, CDCl3): 16.1 (CH3CH), 31.2 (CH3CH), 44.4 (NCH2Pyr), 60.8 (ArCH2O), 100.1 (OCH2O), 114.3, 121.0, 121.9, 122.5, 126.8, 129.3, 133.9, 136.8, 139.1, 149.3, 154.0, 155.9, 162.8, 163.5 (C]O). 4.5.6. Cavitand 5b. White powder (120 mg, 44%), mp 184 C. Found: C, 70.98; H, 5.40; N, 7.02%. C92H80N8O16 requires C, 71.12; H, 5.19; N, 7.21%. nmax (KBr): 3390, 1659, 1598 cm1; dH (500.1 MHz, CDCl3): 1.83 (d, J 7.5 Hz, 12H, CH3CH), 4.14 (q, J 6.5 Hz, 8H, NCH2Pyr), 4.67 (d, J 7.2 Hz, 4H, inner of OCH2O), 4.92 (s, 8H, ArCH2O), 5.11 (q, J 7.2 Hz, 4H, CHCH3), 5.75 (d, J 7.2 Hz, 4H, outer of OCH2O), 6.96 (d, J 8.5 Hz, 8H, Ar), 7.26e7.30 (m, 4H, Ar overlapping with CDCl3 signal), 7.43 (s, 4H, Ar), 7.67 (d, J 7.8 Hz, 4H), 8.33 (d, J 8.5 Hz, 8H, Ar), 8.41e8.65 (m, 12H). dC (125.1 MHz, CDCl3): 16.2 (CH3CH), 31.2 (CH3CH), 41.3 (NCH2Pyr), 60.8 (ArCH2O), 100.2 (OCH2O), 114.3, 121.0, 122.0, 123.7, 126.6, 133.2, 133.9, 135.1, 139.6, 149.0, 154.0, 162.6, 163.6 (C]O). 4.5.7. Cavitand 5c. White powder (102 mg, 50%), mp >300 C (dec). Found: C, 71.23; H, 5.40; N, 7.07%, C92H80N8O16 requires C, 71.12; H, 5.19; N, 7.21%. nmax (KBr): 3392, 1660, 1599 cm1; dH (500.1 MHz, CDCl3): 1.85 (d, J 7.3 Hz, 12H, CH3CH), 4.56 (s, 8H, NCH2Pyr), 4.63 (d, J 7.3 Hz, 4H, inner of OCH2O), 5.04 (s, 8H, ArCH2O), 5.01 (q, J 7.0 Hz, 4H, CHCH3), 5.78 (d, J 7.3 Hz, 4H, outer of OCH2O), 6.96 (d, J 8.2 Hz, 8H, Ar), 7.23 (s, 8H, Ar), 7.44 (s, 4H, Ar), 7.87 (s, 4H, HN), 8.37 (d, J 8.2 Hz, 8H, Ar), 8.56 (s, 8H, Ar). dC (125.1 MHz, CDCl3): 16.2 (CH3CH), 31.2 (CH3CH), 40.9 (NCH2Pyr),
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60.8 (ArCH2O), 100.2 (OCH2O), 114.3, 121.0, 122.0, 123.7, 126.6, 134.0, 139.0, 139.1, 146.3, 149.0, 154.0, 162.8, 163.6 (C]O).
114.4, 120.8, 122.3, 122.7, 128.6, 139.3, 147.1, 150.0, 159.8, 163.9 (C] O), 189.5 (ArC]O).
4.5.8. Cavitand 5d. Pale brown powder (55 mg, 24%), mp 250 C (dec). Found: C, 76.88; H, 6.01; N, 6.55%, C100H96N8O16 requires C, 77.10; H, 5.81, N, 6.73%. nmax (KBr): 1705, 1602 cm1; dH (500.1 MHz, CDCl3): 1.14 (m, 12H, NCH2CH3), 1.85 (d, J 7.3 Hz, 12H, CH3CH), 3.45 (m, 8H, NCH2Pyr), 4.67 (d, J 7.3 Hz, 4H, inner of OCH2O), 4.95 (q, J 7.0 Hz, 4H, CHCH3), 5.03 (s, 8H, ArCH2O), 5.11 (s, 8H, NCH2CH3), 5.78 (d, J 7.3 Hz, 4H, outer of OCH2O), 6.93 (d, J 8.2 Hz, 8H, Ar), 7.29 (m, 4H, H-3(Pyr) overlapping with CDCl3 signal), 7.44 (s, 4H, Ar), 8.00 (m, 8H, Ar), 8.62 (s, 8H, H-4(Pyr)). dC (125.1 MHz, CDCl3): 12.4 (NCH2CH3)16.1 (CH3CH), 31.3 (CH3CH), 39.6 (NCH2CH3), 46.2 (NCH2Pyr), 60.8 (ArCH2O), 100.0 (OCH2O), 114.4, 120.8, 122.3, 122.7, 128.6, 139.3, 146.0, 150.0, 159.8, 171.8 (C]O).
4.5.13. Cavitand 6e. White powder (112 mg, 42%), mp 192 C. Found: C, 70.80; H, 5.13; N, 8.02%. C120H100N12O20 requires C, 70.99; H, 4.96; N, 8.28%. nmax (KBr): 1647, 1597 cm1; dH (500.1 MHz, CDCl3): 1.86 (d, J 7.3 Hz, 12H, CH3CH), 4.62 (m, 8H, NCH2Pyr), 4.69 (m, 4H, inner of OCH2O), 4.83 (m, 8H, NCH2Pyr), 5.02 (s, 8H, ArCH2O), 5.11 (q, J 7.0 Hz, 4H, CHCH3), 5.81 (d, J 7.3 Hz, 4H, outer of OCH2O), 7.02 (d, J 8.9 Hz, 8H, Ar), 7.13 (m, 4H, H5(Pyr)), 7.19 (m, 4H, H-5(Pyr)), 7.33 (m, 4H, H-3(Pyr)), 7.34 (m, 4H, H-3(Pyr)), 7.45 (s, 4H, Ar), 7.60 (m, 4H, H-4(Pyr)), 7.65 (m, 4H, H4(Pyr)), 8.12 (d, J 8.9 Hz, 8H, Ar), 8.42 (d, J 4.9 Hz, 4H, H-6(Pyr)), 8.54 (d, J 4.9 Hz, 4H, H-6(Pyr)). dC (125.1 MHz, CDCl3): 16.1 (CH3CH), 30.9 (CH3CH), 49.4 (NCH2Pyr), 53.1 (NCH2Pyr), 61.0 (ArCH2O), 100.0 (OCH2O), 114.5, 121.1, 121.9, 122.3, 122.5, 122.6, 122.7, 132.9, 136.8, 136.8, 139.2, 149.3, 149.4, 154.0, 155.5, 155.9, 163.6, 168.2 (C]O), 189.7 (ArC]O).
4.5.9. Cavitand 6a. White powder (149 mg, 69%), mp 186 C. Found: C, 69.10; H, 4.98; N, 6.50%, C96H80N8O20 requires C, 69.22; H, 4.84; N, 6.73%. nmax (KBr): 3327, 1660, 1596 cm1; dH (500.1 MHz, CDCl3): 1.84 (d, J 7.3 Hz, 12H, CH3CH), 4.61 (s, 8H, NCH2Pyr), 4.69 (d, J 7.3 Hz, 4H, inner of OCH2O), 5.02 (s, 8H, ArCH2O), 5.11 (q, J 7.0 Hz, 4H, CHCH3), 5.78 (d, J 7.3 Hz, 4H, outer of OCH2O), 6.96 (d, J 8.2 Hz, 8H, Ar), 7.22 (s, 4H, Ar), 7.26e7.30 (m, 4H, Ar overlapping with CDCl3 signal), 7.43 (s, 4H, Ar), 7.57 (s, 4H, Ar), 8.24 (s, 4H, HN), 8.38 (d, J 8.2 Hz, 8H, Ar), 8.56 (s, 4H, Ar). dC (125.1 MHz, CDCl3): 16.1 (CH3CH), 30.9 (CH3CH), 44.5 (NCH2Pyr), 60.8 (ArCH2O), 100.0 (OCH2O), 114.3, 120.9, 121.9, 122.5, 126.9, 129.3, 133.9, 136.8, 139.1, 149.3, 154.0, 155.9, 162.7, 163.4 (NC]O), 185.8 (ArC]O). 4.5.10. Cavitand 6b. White powder (120 mg, 44%), mp 190 C. Found: C, 69.11; H, 4.90; N, 6.68%. C96H80N8O20 requires C, 69.22; H, 4.84; N, 6.73%. nmax (KBr): 3390, 1659, 1598 cm1; dH (500.1 MHz, CDCl3): 1.84 (d, J 7.5 Hz, 12H, CH3CH), 4.56 (q, J 6.5 Hz, 8H, NCH2Pyr), 4.67 (d, J 7.2 Hz, 4H, inner of OCH2O), 5.01 (s, 8H, ArCH2O), 5.11 (q, J 7.2 Hz, 4H, CHCH3), 5.75 (d, J 7.2 Hz, 4H, outer of OCH2O), 6.94 (d, J 8.5 Hz, 8H, Ar), 7.26e7.30 (m, 4H, Ar overlapping with CDCl3 signal), 7.43 (s, 4H, Ar), 7.67 (d, J 7.8 Hz, 4H), 8.36 (d, J 8.5 Hz, 8H, Ar), 8.48e8.68 (m, 12H). dC (125.1 MHz, CDCl3): 16.2 (CH3CH), 31.2 (CH3CH), 40.9 (NCH2Pyr), 60.6 (ArCH2O), 100.1 (OCH2O), 114.3, 121.1, 122.0, 123.7, 127.0, 134.0, 135.7, 139.1, 149.1, 149.4, 154.1, 159.6, 162.6, 163.6 (NC]O), 185.4 (ArC]O). 4.5.11. Cavitand 6c. White powder (145 mg, 67%), mp 295 C (dec). Found: C, 69.10; H, 4.88; N, 6.57%. C96H80N8O20 requires C, 69.22; H, 4.84; N, 6.73%. nmax (KBr): 3384, 1669, 1599 cm1; dH (500.1 MHz, CDCl3): 1.85 (d, J 7.3 Hz, 12H, CH3CH), 4.56 (s, 8H, NCH2Pyr), 4.63 (d, J 7.3 Hz, 4H, inner of OCH2O), 5.01 (s, 8H, ArCH2O), 5.04 (q, J 7.0 Hz, 4H, CHCH3), 5.78 (d, J 7.3 Hz, 4H, outer of OCH2O), 6.96 (d, J 8.2 Hz, 8H, Ar), 7.23 (s, 8H, Ar), 7.44 (s, 4H, Ar), 7.87 (s, 4H, HN), 8.37 (d, J 8.2 Hz, 8H, Ar), 8.56 (s, 8H, Ar). dC (125.1 MHz, CDCl3): 16.1 (CH3CH), 31.3 (CH3CH), 42.2 (NCH2Pyr), 60.9 (ArCH2O), 100.0 (OCH2O), 114.4, 121.0, 121.9, 122.3, 126.6, 134.0, 139.0, 139.1, 146.3, 150.2, 154.0, 162.8, 163.7 (NC]O), 185.4 (ArC]O). 4.5.12. Cavitand 6d. Pale brown powder (62 mg, 27%), mp 282 C (dec). Found: C, 70.11; H, 5.50; N, 6.22%. C104H96N8O20 requires C, 70.26; H, 5.44; N, 6.30%. nmax (KBr): 1669, 1633 cm1; dH (500.1 MHz, CDCl3): 1.14 (m, 12H, NCH2CH3), 1.85 (d, J 7.3 Hz, 12H, CH3CH), 3.45 (m, 8H, NCH2Pyr), 4.67 (d, J 7.3 Hz, 4H, inner of OCH2O), 4.95 (q, J 7.0 Hz, 4H, CHCH3), 5.03 (s, 8H, ArCH2O), 5.11 (s, 8H, NCH2CH3), 5.78 (d, J 7.3 Hz, 4H, outer of OCH2O), 6.93 (d, J 8.2 Hz, 8H, Ar), 7.29 (m, 4H, H-3(Pyr) overlapping with CDCl3 signal), 7.44 (s, 4H, Ar), 8.00 (m, 8H, Ar), 8.62 (s, 8H, H-4(Pyr)). dC (125.1 MHz, CDCl3): 13.9 (NCH2CH3), 16.1 (CH3CH), 31.3 (CH3CH), 42.9 (NCH2CH3), 50.0 (NCH2Pyr), 60.8 (ArCH2O), 100.0 (OCH2O),
Acknowledgements The authors thank the Hungarian Scientific Research Fund (K113177) and Developing Competitiveness of Universities in the South Transdanubian Region (SROP-4.2.2.A-11/1/KONV-20120065) for the financial support and Johnson Matthey for the generous gift of palladium(II) acetate. References and notes 1. Cram, D. J.; Karbach, S.; Kim, H. E.; Knobler, C. B.; Maverick, E. F.; Ericson, J. L.; Helgeson, R. C. J. Am. Chem. Soc. 1988, 110, 2229e2237. 2. (a) Chen, G.; Jiang, M. Chem. Soc. Rev. 2011, 40, 2254e2266; (b) Del Valle, E. M. M. Process Biochem. 2004, 39, 1033e1046. €hmer, V. Angew. Chem., Int. Ed. Engl. 1995, 34, 713e745 and references cited 3. Bo therein. 4. Timmerman, P.; Verboom, W.; Reinhoudt, D. N. Tetrahedron 1996, 52, 2663e2704. 5. Masson, E.; Ling, X.; Joseph, R.; Kyeremeh-Mensah, L.; Lu, X. RSC Adv. 2012, 2, 1213e1247 and references cited therein. 6. Cram, D. J.; Cram, J. M. Container Molecules and Their Guests; Royal Society of Chemistry: Cambridge, UK, 1994. 7. (a) Moran, J. R.; Ericson, J. L.; Dalcanale, E.; Bryant, J. A.; Knobler, C. B.; Cram, D. J. J. Am. Chem. Soc. 1991, 113, 5707e5714; (b) Tucci, F. C.; Rudkevich, D. M.; Rebek, J., Jr. J. Org. Chem. 1999, 64, 4555e4559; (c) Li, X.; Upton, T. G.; Gibb, C. L. D.; Gibb, B. C. J. Am. Chem. Soc. 2003, 125, 650e651. 8. (a) Ma, S.; Rudkevich, D. M.; Rebek, J., Jr. J. Am. Chem. Soc. 1998, 120, 4977e4981; €y, C. B.; Schultheiss, N.; Desper, J. Org. Lett. 2006, 12, 2607e2610. (b) Aakero Kunsa k, Z.; Ke gl, T.; P nyi, L.; Varga, A.; gi-Ma te , S.; Koll 9. Cso arka ar, L. Supramol. Chem. 2011, 23, 710e719. 10. (a) Rudkevich, D. M.; Hilmersson, G.; Rebek, J., Jr. J. Am. Chem. Soc. 1998, 119, 9911e9912; (b) Rudkevich, D. M.; Hilmersson, G.; Rebek, J., Jr. J. Am. Chem. Soc. 1998, 120, 12216e12225; (c) Chang, T.-Y.; Paek, K. Bull. Korean Chem. Soc. 2008, 29, 1857e1859. 11. (a) Beller, M.; Bolm, C. Transition Metals for Organic Synthesis; Wiley-VCH: Weinheim, Germany, 1998, Vols. I and II; (b) Modern Carbonylation Methods; Koll ar, L., Ed.; Wiley-VCH: Weinheim, Germany, 2008. € ldes, R.; Koll 12. (a) Skoda-Fo ar, L. Curr. Org. Chem. 2002, 6, 1097e1119; (b) € hrer, A.; Neumann, H.; Beller, M. Angew. Chem., Int. Ed. 2009, 48, Brennfu 4114e4133; (c) Applied Homogeneous Catalysis with Organometallic Compounds; Cornils, B., Herrmann, W. A., Eds.; Wiley-VCH: Weinheim, Germany, 1996; (d) Transition Metals for Organic Synthesis; Beller, M., Bolm, C., Eds.; Wiley-VCH: Weinheim, Germany, 1998; Vols. I and II; (e) Arcadi, A. Carbonylation of Enolizable Ketones (Enol Triflates) and Iodoalkenes In Modern Carbonylation Methods; Koll ar, L., Ed.; Wiley-VCH: Weinheim, Germany, 2008; Chapter 9, pp 223e250. € ldes, R.; Kolla r, L. Lett. Org. Chem. 2010, 7, 621e633. 13. Skoda-Fo 14. Mastropietro, T. F.; Yadav, Y. J.; Szerb, E. I.; Talarico, A. M.; Ghedini, M.; Crispini, A. Dalton Trans. 2012, 41, 8899e8907. 15. Gaidamauskas, E.; Crans, D. C.; Parker, H.; Saejueng, K.; Kashemirov, B. A.; McKenna, C. E. New J. Chem. 2011, 35, 2877e2883. 16. Macias, B.; Villa, M. V.; Salgado, M.; Borras, J.; Gonzalez-Alvarez, M.; Sanz, F. Inorg. Chim. Acta 2006, 359, 1465e1472. 17. Barquin, M.; Garmendia, M. J. G.; Laminaga, L.; Pinilla, E.; Torres, M. R. Inorg. Chim. Acta 2009, 362, 2334e2340. 18. Shiota, Y.; Sato, D.; Juhasz, G.; Yoshizawa, K. J. Phys. Chem. A 2010, 114, 5862e5869. 19. Katz, B. A.; Strouse, C. E. J. Am. Chem. Soc. 1979, 101, 6214e6221.
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