| 28% |
With ammonium peroxydisulfate; sulfuric acid; silver nitrate; In water; at 80℃; for 0.5h; |
Example 1 - Procedure for Tri-directional Radical Alkylation (Minisci-type) Reaction[0059] The results demonstrated below are believed to represent the first success in preparing tri-podal compounds using a tridirectional Minisci-type radical alkylation reaction. Because this procedure provides functional organic molecules in a single step, it fulfills many criteria of an ideal synthesis.[0060] To a solution of 1,3,5-cyclohexane tricarboxylic acid (1 mmol) in 10%H2SO4 (5 ml) was added silver nitrate (0.6 mmol) and the N-heterocycle (10 mmol). The reaction mixture was heated to 80 0C. A saturated solution of ammonium persulfate (10 mmol) in water was added dropwise over 10 minutes to the reaction mixture with evolution of carbon dioxide (indicated by bubbling in the solution). After emission of carbon dioxide ceased, the reaction mixture was allowed to stir for an additional 20 min at 80 0C. The reaction mixture was then poured into ice and neutralized using saturated ammonium hydroxide solution (q.s). The resulting suspension was extracted with chloroform and the organic extract was washed with brine solution. Finally, the organic layer was dried over Na2SO4 and concentrated to yield crude product. The crude product was then purified using flash chromatography (appropriate proportions of methanol and dichloromethane). [0061] Initial trials employing pyridine (Figure 4) as the radical acceptor and c-l,3,5-cyclohexanetricarboxylic acid reacted under modified Minisci conditions (1.0 eq. triacid, 0.6 eq. AgNO3, 10 eq. NH4S2Os, 10 eq. heterocyclic base, excess H2SO4) produced inseparable mixtures of regioisomeric products. Since both the pyridine 2- and 4-positions are available for reaction with the intermediate secondary radical, this outcome was not altogether surprising. In contrast, reaction with pyrazine under analogous conditions produced the desired (2,2',2") trisubstituted compound 2 in 24% isolated yield as the major product (Figure 4). Yield of the major product was strongly dependent on the use of an excess of heterocyclic base in the reaction, and one could envision further improvements by employing an even larger amount. However, difficulty with separating unreacted starting material as well as the <n="18"/>expense of the reagent itself must be balanced against the desire to optimize yields, and it was discovered that a 10-fold excess represented a reasonable compromise. [0062] The scope of this reaction was then examined by varying the identity of the heterocyclic base while keeping the radical source constant. As shown in Figure 4, yields of major products were remarkably consistent for reaction with pyrimidine (affording Compound 3), ethyl isonicotinate (affording Compound 5), and ethyl nicotinate (affording Compound 6). In contrast, reaction with pyridazine (affording Compound 4) produced only a 5% yield of the desired product. No reaction was observed with triazine or benzoxazole. Like pyridine, reaction with quinoline produced only a complex mixture of inseparable products.[0063] Compound 7 was synthesized because it was expected that this compound would allow monitoring of carbohydrate binding by fluorescence spectroscopy (the quinoline moiety is a known fluorophore). The synthesis was effected in a similar way as that of Compound 12, where c-cyclohexane 1,3,5- tricarboxylic acid was reacted with 4-methylquinoline in a tri-directional Minisci reaction to obtain Compound 7 in 5% yield. Studies by Minisci and co workers demonstrated that radical alkylation of lepidine proceeds more rapidly in nonpolar solvent (Minisci et al., J. Org. Chem. 52:730-736 (1987), which is hereby incorporated by reference in its entirety), and it is possible that a similar change in solvent environment could improve the yield of Compound 7.[0064] Regioselectivity for the reaction with ethyl nicotinate was particularly interesting; Compound 6 was the only product isolated with a mixed (4,4',6") configuration. A minor product was also produced in this reaction, but could not be isolated in sufficient quantity to permit characterization. [0065] The obtained products 2-7 were characterized as set forth below:2,2',2"-cyclohexane-l,3,5-triyltripyrazine (2): yellow, amorphous solid; yield: 28%; mp 122-124 0C. IR (thin film from CHCl3): 2922, 1576, 1523, 1472, 1406, 1248, 1152, 1058, 1016, 843, 767 cm"1. 1H NMR (400 MHz, CDCl3): delta 8.57 (d, J=0.8 Hz, 3H), 8.51 (t, J=I.2 Hz, 3H), 8.43 (d, J=2.0 Hz, 3H), 3.28-3.21 (m, 3H), 2.32 (d, J=IO Hz, 3H), 2.12 (q, J=IO Hz, 3H). 13C NMR (400 MHz, CDCl3): delta 159.6, 144.1, 143.5, 142.9, 43.5, 37.0. HRMS: m/z calcd for C18Hi9N6 (M+H)+: 319.1671; found: 319.1679. |
| 24% |
With dihydrogen peroxide; iron(II) sulfate; In dichloromethane; water; at 0℃; for 0.5h;Product distribution / selectivity; |
Example 2 - Biphasic Variant of Tri-directional Minisci-type Reaction forSynthesis of 2,2 ',2"-cyclohexane-l,3,5-triyltripyrazine (Compound2); [0066] A biphasic variant of the traditional Minisci reaction, reported byHeinisch and Ltsch (Angew. Chem. Int. Ed. 24:692-693 (1985), which is hereby incorporated by reference in its entirety), was examined using pyrazine as the radical acceptor (Scheme 3; Figure 3). Cyclohexane tricarboxylic acid (leq.) was reacted with pyrazine (10 eq.) and ferrous sulfate heptahydrate (10 eq.) in a hydrogen peroxide (aq.) / dichlormethane biphasic solution at 00C for 15 minutes. After 15 min. of stirring, the resulting mixture was poured into ice, the phases were separated, and the aqueous phase was extracted with CH2Cl2 (3 times, 5 ml). After drying over anhydrous Na2SO4, the solvent was removed in vacuo to generate a yellow oil. This oil was directly applied to silica gel and eluted with a 5% MeOH/CH2Cl2 solution to afford the desired compound (2) in 24% yield. Increases in reaction time did not result in an increase in yield. |
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