Studies on the Chemistry and Reactivity of \xce\xb1-Substituted Ketones in Isonitrile-Based Multicomponent Reactions
Using the Passerini and Ugi reactions as representative tests, the utility of several \xce\xb1-substituted ketones R-CO-CH2-X (X= sulfonyloxy, acyloxy, azido, halo, hydroxy and sulfonyl) in isonitrile-based multicomponent reactions was explored. In a relative rate study (R= PhCH2CH2), each of the \xce\xb1-substituted ketones underwent Passerini condensation more rapidly than the parent ketone. Short, highly convergent routes to oxazoline, \xce\xb2-lactam, di-O-acylglyceramides, and other molecular frameworks were developed.
INTRODUCTION<!>Preparation of Substrates<!>Relative Rate Study of \xce\xb1-Substituted Ketones in the Passerini Reaction<!>Isonitrile-Based MCRs of Substituted Ketones<!>CONCLUSION<!>Compound 9a<!>Compound 11a<!>Compound 15a<!>Compound 20b<!>Compound 32d<!>Compound 33a
<p>The discovery in 1850 that α-amino acids could be prepared in one step from simple reactants using the Strecker reaction, the first reported example of a multicomponent reaction (MCR), launched a period of intensive synthetic chemical development that remains active today. Generally defined as one-pot processes that produce a desired target from the combination of three or more reactants,1 MCRs can create simple and convergent paths to structurally complex products in atom-economical2 fashion. With the advent of combinatorial chemistry and its widespread adoption by the pharmaceutical industry, MCR chemistry experienced a renaissance of interest in the past two decades, triggered initially by the demand for screening libraries in drug discovery programs, and stimulated more recently by efforts to assemble natural product-like scaffolds exhibiting specific pharmacological profiles.</p><p>To date, MCR reactions based on the chemistry of isonitriles have been particularly widely used in these endeavors, despite the well-known drawbacks to using this family of compounds. Besides their unpleasant olefactory properties, isonitriles have generally been limited in their commercial availability and have limited shelf stability. In recent years, however, versatile new syntheses of isonitriles have been developed,3 including routes to convertible isonitriles possessing pleasant aromas,4 that promise to expand the repertoire of known MCRs.</p><p>The Passerini and Ugi reactions, which represent the two most widely-employed isonitrile-based MCRs, also need simple carbonyl compounds as integral reactants. As part of our efforts to synthesize new molecular frameworks by using the "single reactant replacement" (SRR) strategy to evolve existing MCRs, we have investigated aldehydes and ketone surrogates that combine carbonyl electrophilic properties with additional embedded reactivity elements. For example, we recently discovered that replacing simple carbonyl compounds in the Passerini reaction with acyl cyanides made it possible to redirect the outcome to afford β-aminoacid diamides instead of the conventional α-acyloxyamides,5 and further empowered the assembly of densely-functionalized oxazoles and tetrazoles.6</p><p>We also investigated the use of α-diazoketones in isonitrile-based MCRs, finding them resistant to Passerini and Ugi reactions. However, by exploiting the reactivity of diazocarbonyls to Bronsted acids or transition metal catalysis, we recently achieved successful one-pot, four-component condensations that furnished substituted oxazolines via α-sulfonyloxyketones7 as well as substituted di-O-acylglyceramides from α-acyloxyketones.8 Following those communications, we now report a full account of our studies using α-substituted ketones as surrogates for simple carbonyl compounds in the Ugi and Passerini reactions.</p><p>The rationale for this study was to investigate SRR outcomes when reactive functionality was embedded at the α-position of the ketone. While several reactive α-substituents were of potential interest (sulfonyloxy, acyloxy, azido, halo, hydroxy and sulfonyl), almost nothing was known about their MCR chemistry, let alone relative reactivities. Prior to our own oxazoline-forming synthesis, there were no reports of Passerini or Ugi condensations on α-mesyloxy- or tosyloxyketones. Likewise, no examples of MCRs of α-azido-, α-hydroxy-, or α-sulfonylketones have been described in the literature. Enantioselective, copper-catalyzed Passerini reactions of alkoxy-substituted aldehydes have recently been described,9 but no examples of the corresponding alkoxyketones were included. Alpha-chloroketones have been reported to undergo the Passerini condensation, forming chloro-substituted acyloxyamides, which after subsequent base treatment were transformed into the corresponding acyloxy-β-lactams.10</p><p>It occurred to us that any pronounced rate differences between these various substituted ketones might make it possible to achieve selectivity when using mixtures of two or more carbonyl compounds, thus broadening the opportunities for incorporating novel functionality in MCRs. Anchimeric effects involving the neighboring α-substituent might also be exploited to produce new molecular frameworks. Here we report the relative rates of condensation of a representative series of α-substituted ketones in the Passerini condensation. That kinetic study provides useful new insights into the relative reactivity of each family and suggests additional directions for new work.</p><!><p>The starting material for all α-substituted ketones was the corresponding α-diazoketone 1 (Scheme 1), which could be conveniently prepared by reaction of the cognate acid chloride with diazomethane. Initially, the readily available 1-diazo-4-phenyl-2-butanone 1a (prepared from hydrocinnamoyl chloride) was used to synthesize a representative example of each family of substituted ketones. Reaction of 1a with methanesulfonic acid or toluenesulfonic acid furnished the mesyloxy and tosyloxyketones 2a and 3a, respectively.11 The corresponding acyloxyketone 4a (R2=CH3) was prepared from 1a by Cu(acac)2-catalyzed reaction with acetic acid.12 Chloroketone 5a was obtained from 1a by reaction with HCl in ether.13</p><p>Azidoketones 6 and arylsulfonylketones 7 were both prepared according to literature methods from the corresponding chloroketones 5. Thus, azidoketone 6a arose from the reaction of 5a with NaN3 in DMF.14 The synthesis of α-sulfonylketone 7a (Ar = Ph) was achieved by reaction of 5a with thiophenol and NaOH in the presence of oxone.15 A sample of the parent unsubstituted ketone, benzylacetone 8a, was obtained commercially and used as a control compound for the kinetic study.</p><!><p>Compounds 2a and 4a-8a were subjected to a representative Passerini condensation with acetic acid and t-butyl isonitrile (1.0 equiv each) under neat conditions at rt. Aliquots of each reaction mixture were removed for NMR analysis, and the progress of the reaction was monitored by the relative amounts of starting ketone (as judged by integration of the singlet resonance for the α-methylene carbon) and the Passerini product (as measured by the AB-quartet for the same methylene group). The results are tabulated in Figure 1.</p><p>As the data indicate, each of the α-substituted ketones underwent Passerini condensation more rapidly than the parent carbonyl compound 8a. Mesyloxyketone 2a was the most reactive carbonyl compound tested. Although tosylate 3a was not included in the rate study, independent side-by-side comparisons of 2a and 3a in other Passerini and Ugi condensations (vide infra) established that 3a displayed comparable reactivity in isonitrile-based MCRs. Chloroketone 5a and azidoketone 6a showed similar rate profiles, and were somewhat more reactive than acyloxyketone 4a. Sulfonylketone 7a was the least reactive of the substituted ketones tested, undergoing Passerini condensation only slightly faster than 8a. The kinetic data in Figure 1 were consistent with the expected enhancement of carbonyl electrophilicity caused by electronegative substituents, as judged by known Pauling atom or group electronegativity values for each of the substituents tested.16</p><p>Results with compounds 2a, 5a, and 6a suggested that selective Passerini condensations on these substances might be possible in the presence of a sulfonyl-substituted or unsubstituted ketone. As a preliminary test of this hypothesis, a 1:1 mixture of chloroacetone 5b (R1= CH3) and phenylsulfonylacetone 7b (R1= CH3) were reacted with 1 equiv each of acetic acid and t-butyl isonitrile (24 h, rt) to afford an 8:1 ratio of products from 5b and 7b, respectively.</p><!><p>Mesyloxy and tosyloxyketones 2 and 3 proved to be very good carbonyl components in the Passerini reaction, typically forming the expected products 9 and 10, respectively, in high yields (Scheme 2).</p><p>The results of a representative sampling of condensations using various carboxylic acids and isonitriles (1.1 equiv each) are summarized in Table 1.</p><p>Condensations of 2 and 3 were generally completed in 12-18 hours and successfully furnished the expected products in very good to excellent yields. Products 9 and 10 were readily purified by flash column chromatography. Furthermore, the possibility of directly converting the parent α-diazoketone to mesylate 9a was realized in a simple one-pot process by reacting a CH2Cl2 solution of diazoketone 1a with methanesulfonic acid (1.1 equiv, 10 min, 0 °C). After addition of NaOAc (0.5 equiv) to neutralize residual acid, the solution was treated with acetic acid and cyclohexyl isonitrile (rt 24 h) to afford 9a in 86% yield.</p><p>With their reactive sulfonate leaving groups, sulfonates 9 and 10 were also well-suited precursors for the synthesis of substituted β-lactams 11 (Scheme 3) following a procedure developed for cyclizations of the corresponding chloro compounds.10</p><p>Table 2 summarizes results obtained in our lab using this approach to substituted β-lactams from representative sulfonates 9 and 10. While the yields of 11a-e were generally comparable whether from the mesylate or tosylate precursor, the cyclization was noticeably more rapid in the case of mesylate 9c.</p><p>We also investigated Ugi reactions of sulfonyloxyketones 2 and 3. When using ammonia as the amine, the MCR led to a novel 4-component synthesis of substituted 2-oxazolines 13 (Scheme 4) by way of the intermediate diamides 12.7 Apparently the formation of imines derived from 2 or 3 was faster than ammonolysis of the mesylate or tosylate group, thus triggering the desired Ugi reaction to form 12. The fact that 12 cyclized spontaneously to 13 during the reaction finds precedent in the known biosynthesis of peptide-based oxazolines17 by cyclization of activated N-acylserine derivatives.18</p><p>Initial studies of this interesting transformation with 2a as a representative mesyloxyketone utilized methanol as solvent, a common medium for Ugi condensations, and also afforded significant quantities of the corresponding Passerini product 9. This byproduct could be effectively suppressed by replacing methanol with 2,2,2-trifluoroethanol, a solvent that was recently reported to improve Ugi reactions involving ammonia as the amine component.19 Overall, the new oxazoline synthesis, for which full experimental details on 14 examples have been reported,7 accommodated a broad range of sulfonyloxyketones, isonitriles and carboxylic acids.</p><p>Our initial communication noted that when NH3 was replaced with benzylamine, the MCR of 2a with acetic acid and cyclohexyl isonitrile afforded aminoester 15a (Scheme 5) as the exclusive product. Particularly characteristic was the strong ester carbonyl band (1740 cm-1) in the IR spectrum of 15a.</p><p>A mechanism of formation of 15a paralleling that of 13 could be envisioned in which hydrolysis of the oxazolinium intermediate 14a led to the observed product. Interestingly, 15a did not undergo 1,2-acyl shift, leading to the corresponding amidoalcohol 16a. Further confirmation of the structure of 15a was obtained by single crystal x-ray diffraction analysis.</p><p>Structures such as 16a embody the hydroxyethylene or hydroxyethyl structural unit found in transition state isosteres such as statine or norstatine, which have been developed as inhibitors of retroviral proteases.20 Given their potential biomedical significance, we have investigated this MCR further. As indicated in Table 3, several other primary amines and mesyloxyketones formed the corresponding amidoesters 15. In each case, only the amidoester isomer 15 (and none of the diamide 16) was detected.</p><p>To determine whether the products observed in each case were formed under kinetic control, aminoester 15a was subjected to basic (DBU-CH3CN, Et3N, NaH-DMF) equilibration conditions. However, no evidence for the formation of diamide 16a was obtained from these experiments.</p><p>The complementary equilibration experiment required an authentic sample of 16a, which we attempted to synthesize from acetoxyketone 4a in two steps using the Ugi reaction as shown below (Scheme 6). Little is known about Ugi condensations of such acyloxyketones. In fact, reaction of 4a with ammonia, acetic acid, and cyclohexyl isonitrile returned mostly starting ketoacetate 4a, along with the corresponding Passerini product (not shown) in 14% yield. However, replacing ammonia with benzylamine did afford the desired MCR product 17a in 67% yield.</p><p>Treatment of 17a with NH3-CH3OH was expected to furnish 16a by methanolysis of the more reactive acetate ester. Instead, two products were formed: aminoester 15a (20%) and aminoalcohol 18a (60% yield). Unfortunately, none of the hoped-for amidoalcohol 16a could be detected by IR.</p><p>In an alternative approach (Scheme 7), the known21 hydroxyketone 19 was subjected to the Ugi reaction with benzylamine, acetic acid and cyclohexyl isonitrile. Instead of the expected amidoalcohol 16a, the sole product of that reaction (56%) was aminoester 15a. Taken together, the results depicted in Schemes 6 and 7, while not conclusive, were consistent with the rapid conversion of 16a to 15a and its hydrolysis product 18a.</p><p>It became apparent from efforts to prepare 16a that Ugi condensations of acyloxyketones 4, while feasible, suffered certain limitations. Therefore, we decided to study the reactivity of acyloxyketones in the corresponding Passerini reactions. A recently published preliminary report summarized our findings in this area.8 Since acyloxyketones of general structure 4 were easily prepared by copper-catalyzed insertion of diazoketone 1 into a carboxylic acid,22 we were able to develop a versatile one-pot 4-component condensation in two stages leading to a new family of structurally diverse di-O-acylglyceric acid amides 20 (Scheme 8).</p><p>The initial insertion stage required heating of 1 with R2CO2H (30-60 min, toluene, 60-90 °C), usually in the presence of 1.0 mole-% Cu(acac)2. Once gas evolution ceased, the toluene was removed in vacuo and the crude acyloxyketone 4 was subjected to a Passerini condensation with R3NC and R4CO2H. Table 4 summarizes the range of new glyceramide diesters that could be synthesized using this method.</p><p>One advantage of the method over stepwise acylation of the vic-diol moiety in glyceramides is that it avoids the potential for ester interchange by competing O,O-acyl transfer side reactions. Moreover, by using one hydrophobic and one hydrophilic carboxylic acid (e.g. 20i), the approach depicted in Scheme 8 can be used to synthesize facially amphiphilic glyceramides for potential biomedical use, whether as cell-wall disrupting agents displaying antifungal activity or as encapsulating agents in micellar drug delivery. The method can be adapted to introduce different chain lengths in each ester group to fine-tune desired hydrophobic/hydrophilic properties.</p><p>The use of α-chloroketones 5 in isonitrile-based multicomponent reactions was also of interest in this investigation. Since Passerini reactions of 5 have already been described,10 we turned our attention to Ugi 4-component condensations of chloroacetone 5b (R= CH3) as a representative chloroketone using conditions optimized for the corresponding mesyloxyketones 2. Thus, reaction of 5b with ammonium acetate (4 equiv) and t-butyl isonitrile (1.1 equiv, rt, 24 h) in trifluoroethanol solvent afforded the normal Ugi product 21a in very good yield. Likewise, condensation of 2b with NH4OAc and cyclohexyl isonitrile also afforded the expected Ugi product 21b, along with small quantities of the corresponding Passerini product 22.</p><p>Using benzylamine instead of ammonia, the Ugi condensation of 5b took a different path, forming aminoester 15f (Scheme 10) in 74% yield, along with a small amount of the corresponding Passerini product (14%, structure not shown). As depicted in Scheme 10, the formation of aminoester 15f likely proceeded by an initial Ugi reaction leading to 23, followed by a rearrangement via 14f similar to that invoked for related structures 15a-e (Scheme 5).</p><p>Chloroketone-derived Ugi products like 21a and 21b would be particularly useful if they underwent cyclization to the corresponding acylamino-β-lactams 24 (Scheme 11), which embody the key structural element of penicillins, cephalosporins, and other β-lactam antibiotics at the forefront of modern antimicrobial chemotherapy.23 Not surprisingly, however, exposure of 21a to mild base instead formed the known17 oxazoline 13a.</p><p>We reasoned that replacing the acetamide group in 21a with a phthalimide would block the undesired formation of an oxazoline. Moreover, if the Ugi condensation of 5b using phthalic acid in combination with ammonia and t-butylisonitrile were successful, the initally-formed phthalimidic acid 25 (Scheme 12) might spontaneously dehydrate to the phthalimide 26 either during workup or upon standing, thus paving an approach to the desired β-lactam 27.</p><p>After testing the solubility of ammonium phthalate in various solvents, we chose methanol as the solvent for the Ugi reaction depicted in Scheme 11. Chloroketone 5b was added to a suspension of ammonium phthalate (4 equiv, 0 °C, 10 min), followed by t-butyl isonitrile (1.1 equiv, rt. 16 h). Extractive workup afforded acylaziridine 28 (Scheme 13) in 33% yield. However, when the Ugi reaction was repeated using the less nucleophilic trifluoroethanol as solvent, only traces of phthalimide 26 were detected by mass spectrometry. Instead, the major product was hydroxyamide 29, apparently the result of a 2-component Passerini condensation. The structure of 29 was confirmed by single crystal x-ray analysis (Figure 2).</p><p>The relatively rapid Passerini reaction of 6a (Figure 1) suggested that such azidoketones, although heretofore unstudied in isonitrile-based MCRs, would be good substrates for such complexity-generating processes. Furthermore, alkyl azides are particularly useful components in the synthesis of triazoles and tetrazoles by copper-catalyzed cycloadditions with alkynes using "click" chemistry.24 As shown in Scheme 14, representative Ugi condensations of 6a and 6d (R= CH3) with ammonium acetate and t-butyl isonitrile afforded the expected diamides 30 and 31 (Scheme 14) in reasonable yield.</p><p>We also investigated isonitrile-based MCRs of α-arylsulfonylketones having general structure 7. Unlike other representative α-substituted ketones in this study, sulfonylketones (also known as β-ketosulfones) are distinguished by their relatively acidic methylene hydrogens and have widespread applications, in the synthesis of disubstituted alkynes,25 alkenes,26 allenes,27 and heterocycles.28 Some β-ketosulfones function as aromatase inhibitors29 and also exhibit fungicidal activity.30</p><p>The Passerini condensation of phenylsulfonyl ketone 7a (Scheme 15) with acetic acid and t-butyl isonitrile (1 equiv each) reported in the kinetic study (Figure 1) proceeded smoothly (rt, 1 d) to afford the expected product 32a (46% yield) as an inseparable 1:1 mixture with 7a, based on NMR analysis.</p><p>The process seemed to be general, judging from the representative cases shown in Table 5, in which variations to the arylsulfonyl group and to the carbon framework of the ketone were introduced. Unlike 32a, products 32b-f were obtained pure after flash chromatography. Interestingly, using 2 equiv of acid and isonitrile shortened the overall reaction time, but failed to improve the yield of product.</p><p>A representative Ugi condensation using phenylsulfonyl ketone 7b with ammonium acetate and t-butyl isonitrile was performed as an initial reactivity test, and afforded the expected product 33a (Scheme 16, 54%). However, additional examples summarized in Table 6 defined a narrow scope of reactivity.</p><p>In entry 2, the low yield obtained of product 33b could not be improved by switching the solvent to the more commonly used methanol, and was apparently due to the poor solubility of benzoic acid in either solvent. Attempts to use benzylamine in place of ammonia produced complex mixtures in which neither the Ugi (expected) nor Passerini product could be identified. Generally, the reaction was successful with a number of isonitriles including t-butyl or n-butyl isonitrile as well as ethyl isocyanoacetate.</p><!><p>In conclusion, we have shown that numerous α-functionalized ketones having general structures 2-7 can serve as useful carbonyl components in isonitrile-based MCRs, occasionally with unexpected and surprising outcomes. The successful application of Passerini and Ugi condensations to families of ketones 2-7 enhances the utility of these two powerful name reactions, and adds another dimension to the structural complexity that can be achieved using multicomponent reactions.</p><!><p>To a sample of α-mesyloxyketone 2a (48 mg, 0.2 mmol) under N2 in a 5 mL roundbottom flask was added acetic acid (13 μL, 0.22 mmol, 1.1 equiv) and t-butyl isonitrile (25 μL, 0.22 mmol, 1.1 equiv). The resulting homogeneous solution was stirred at rt under N2 for 20 h. The product was purified by silica gel flash column chromatography ( 3:7 EtOAc:hexanes, Rf= 0.2) to afford 9a (68 mg, 88%) as a pale yellow oil.</p><!><p>To a suspension of freshly washed (pentane) sodium hydride (9 mg of 80% dispersion, 0.3 mmol, 1.5 equiv) in 4:1 CH2Cl2:DMF (3 mL) in a dry 25 mL roundbottom flask under N2 at 0 °C was added a solution of 9c (82 mg, 0.2 mmol) in 4:1 CH2Cl2:DMF (3 mL) dropwise. The reaction mixture was stirred at rt for 2 h. Saturated NH4Cl (6 mL) was then added and the mixture stirred for 30 min at rt. After separating the layers, the aqueous phase was extracted with CH2Cl2 (5 mL) and the combined organic layers were washed with H2O (5 mL) and saturated NaCl (5 mL), dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel flash column chromatography (3:7 ethyl acetate:hexanes, Rf= 0.3) to afford the desired product 11a as a pale yellow oil.</p><!><p>To a solution of α-mesyloxyketone 2a (48 mg, 0.2 mmol, 1 equiv) in anhydrous 2,2,2-trifluoroethanol (0.5 mL) at 0 °C was added benzylamine (178 μL, 0.8 mmol, 4.0 equiv) dropwise. The reaction mixture was stirred for 10 min at 0 °C, then acetic acid (23 μL, 0.4 mmol, 2.0 equiv) and cyclohexyl isonitrile (27 μL, 0.22 mmol, 1.1 equiv) were added via syringe with stirring. The reaction mixture was then warmed to rt and stirred for 18 h. After removing the solvent in vacuo, the residual oil was purified by silica gel flash column chromatography (3:7 ethyl acetate:hexanes, Rf= 0.3) to afford 15a as a white solid (57 mg, 71%).</p><!><p>A mixture of acetic acid (57 μL, 1.0 mmol) and Cu(acac)2 (2.6 mg, 0.01 mmol, 1 mol %) toluene (2 mL) in a 10 mL roundbottom flask was heated to 60 °C for 10 min under nitrogen. To it was added dropwise a solution of diazoketone 1a (226 mg, 1.3 mmol, 1.3 equiv) in toluene (2 mL). Once gas evolution was judged complete, the reaction mixture was stirred an additional 5 min, then cooled and concentrated in vacuo. The oily residue was blanketed in nitrogen, then treated with iso-butyric acid (140 μL, 1.5 mmol, 1.5 equiv) and t-BuNC (170 μL, 1.5 mmol, 1.5 equiv). The resulting reaction mixture was stirred at rt under N2 for 20 h. The product was purified by silica gel flash column chromatography (1:1 EtOAc:hexanes, Rf= 0.3) to afford 5b (338 mg, 90%) as a pale yellow oil.</p><!><p>To a stirred solution under N2 of freshly dried phenylsulfonylacetone 7b (67 mg, 0.34 mmol) in CH2Cl2 (0.02 mL, 19 M) was added isobutyric acid (37 μL, 0.37 mmol) followed by cyclohexylisonitrile (45.5 μL, 0.37 mmol). The reaction mixture was stirred at rt for four days, then volatile residues were removed under reduced pressure. After TLC analysis,31 the product was purified by silica gel flash chromatography (2:1 ethyl acetate:hexanes, Rf = 0.5) to furnish pure 32d (92 mg, 69%) as a colorless oil.</p><!><p>A solution of NH4OAc (101 mg, 1.31 mmol) and freshly dried phenylsulfonylacetone 7b (65 mg, 0.33 mmol) in anhydrous 2,2,2-trifluoroethanol (add vol, 0.4 M) under N2 was stirred at 0°C for 1 h. The, t-butyl isonitrile (41 μL, 0.36 mmol) was added and stirring at rt was continued for two days. Volatiles were removed under reduced pressure, and after TLC analysis,31 the crude oily product was purified by silica gel flash chromatography (10:1 ethyl acetate: hexanes, Rf 0.3) to furnish pure 33a (60 mg, 54% yield) as a white solid (mp 175-176 °C).</p>