2.9.1. Solid-Phase Organic Synthesis
Solid-phase organic synthesis (SPOS) exhibits several advantages compared with classical protocols in solution. Reactions can be accelerated and driven to completion by using a large excess of reagents, as these can easily be removed by filtration and subsequent washing of the solid support. In addition, SPOS can easily be automated by using appropriate robotics and applied to “split-and-mix” strategies, useful for the synthesis of large combinatorial libraries.208 However, SPOS also exhibits several shortcomings, as a result of the inherent nature of the heterogeneous reaction conditions; nonlinear kinetic behavior, slow reactions, solvation problems, and degradation of the polymer support, because of the long reaction times, are some of the problems typically experienced in SPOS. A technique such as microwave-assisted synthesis which is able to address some of these issues is therefore of considerable interest, particularly for research laboratories involved in high-throughput synthesis. As far as the polymer supports for microwave-assisted SPOS are concerned, the use of cross-linked macroporous or microporous polystyrene resins has been most prevalent. In contrast to the common belief that the use of polystyrene resins limits the reaction conditions to temperatures below 130 °C, it has recently been amply demonstrated, both in microwave-assisted SPOS and in the use of polymer-supported reagents and catalysts (see Section 2.9.4), that these resins can withstand microwave irradiation for short periods of time even at temperatures above 200 °C.
Early examples of SPOS under controlled microwave conditions12 typically involved the use of microwaves in one single step to either attach or cleave material onto or off the resin. A study published in 2001 demonstrated that high-temperature microwave heating (200 °C) can be effectively employed to attach aromatic carboxylic acids to chloromethylated polystyrene resins (Merrifield and Wang) by the cesium carbonate method (Scheme 43).209 Significant rate accelerations and higher loadings were observed when the microwave-assisted protocol was compared to the conventional thermal method. Reaction times were reduced from 12–48 hours with conventional heating at 80 °C to 3–15 minutes with microwave heating at 200 °C in NMP in open glass vessels. A comparison of the kinetics of the thermal coupling of benzoic acid to the chlorinated Wang resin at 80 °C with the microwave-assisted coupling at the same temperature demonstrated the absence of any microwave effects.
Peptide synthesis has long been one of the cornerstones of solid-phase organic synthesis, and attempts to speed up the rather time-consuming process by microwave heating were made as early as 1992.210 Erdélyi and Gogoll recently applied controlled microwave irradiation to the synthesis of a small tripeptide containing three of the most hindered natural amino acids (Thr, Val, Ile; Scheme 44).211
Scheme 44. Synthesis of a tripeptide. a) deprotection with piperidine at RT; b) coupling reagent, Fmoc-protected amino acid, iPr2NEt, DMF, MW, 110 °C, 20 min; c) TFA, RT, 2 h. Fmoc=9-fluorenylmethoxycarbonyl, TFA=trifluoroacetic acid.
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A variety of common coupling reagents have been investigated for the synthesis of this rather difficult peptide sequence on standard Rink polystyrene resin. The coupling of the activated amino acids under microwave conditions was completed in a few minutes (1.5–20 min) without the need for double or triple coupling steps as in conventional protocols. Most of the coupling reagents used showed increased coupling efficiency up to 110 °C, with O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU) being the most effective, and allowed complete coupling within 1.5 minutes at 110 °C. Decomposition of the reagents was indicated by a color change of the reaction mixtures above this temperature. However, no degradation of the solid support was observed. Furthermore, both LC-MS and 1H NMR spectroscopic analysis confirmed the absence of racemization during the high-temperature treatment, despite the presence of the diisopropylethylamine base.
The formation of a number of related peptide bonds have been reported under optimized microwave conditions.212 In fact, specialized equipment dedicated specifically to microwave-assisted solid-phase peptide synthesis is commercially available.36
As in solution-phase chemistry (see Sections 2.2 and 2.3), many transition-metal-catalyzed transformations have been conducted successfully on a solid phase by using microwave-assisted techniques. Examples include solid-phase Suzuki-,213 Stille-,213 and Sonogashira couplings,214 Negishi reactions,92 Mo-catalyzed allylic alkylations,117 aminocarbonylations,110 cyanation reactions,215 trifluoromethanesulfonations,82 Buchwald–Hartwig aminations,216 and Cu-catalyzed Ullmann-type C-N arylations.217
An interesting example of a transition-metal-mediated microwave-assisted SPOS involving either CuII- or PdII-mediated cyclizations of 2-alkynylanilides to indoles has been studied by Dai et al. (Scheme 45).218 The required alkynylanilide precursor 52 was constructed on Rink resin following standard SPOS procedures. The desired cyclization step 5253 was extremely sluggish under conventional thermal conditions and only partial ring closure was observed (80 °C, 4–5 h). In contrast, dielectric heating with microwaves for 10 minutes at 160 °C in THF in the presence of 20 mol % of [PdCl2(MeCN)2] afforded indole 53 (Ar=p-CF3C6H4, n=8) in 75 % yield and 94 % purity after cleavage. Alternatively, the equivalent CuII-mediated process (1 equiv of Cu(OAc)2, NMP, 200 °C, 10 min) also provided the desired indoles in similar yields and purities. The authors specifically note that no decomposition of the resin was observed even at 200 °C.
A related indole synthesis on Rink resin based on the Pd-catalyzed cyclization of propargylamines to iodoanilines was published by Berteina-Raboin and co-workers.219 In this case, open-vessel microwave technology was used for all the three steps of the synthesis (<15 min, <140 °C) as well as for the final cleavage reaction, which was carried out at room temperature. Higher yields of final products were achieved in much shorter reaction times by using the microwave protocol as compared to conventional heating.
An interesting multicomponent reaction is the Gewald synthesis of 2-amino-3-acylthiophenes. Earlier reports of the classical Gewald synthesis had described the rather long reaction times required by conventional heating and the laborious purification of the resulting thiophenes. In view of these issues, researchers from Morphochem investigated a “one-pot” microwave-assisted Gewald synthesis on a commercially available cyanoacetylated Wang resin as the solid support (Scheme 46).220 The overall two-step reaction procedure, including the acylation of the initially formed 2-aminothiophenes, could be performed in less than one hour. This process is an efficient route to 2-acylaminothiophenes which requires no filtration between the two reaction steps. Various aldehydes, ketones, and acylating agents have been employed to generate the desired thiophene products in high yields (81–99 %) and in generally good purities.
Kappe and co-workers have reported a multistep solid-phase synthesis of bicyclic pyrimidine derivatives by a Biginelli muticomponent reaction combined with multidirectional cyclative cleavage reactions (Scheme 47).221 This approach required the synthesis of the 4-chloroacetoacetate resin as the key starting material, which was prepared by microwave-assisted acetoacetylation of hydroxymethyl polystyrene resin. In analogy to earlier work,222 this transesterification was best carried out under open-vessel conditions in 1,2-dichlorobenzene (170 °C) to allow the formed methanol to be removed from the equilibrium (see also Scheme 20). This resin precursor was subsequently treated with urea and various aldehydes in an acid-catalyzed Biginelli multicomponent reaction (dioxane, 70 °C) to afford the corresponding resin-bound dihydropyrimidinones. The desired furo[3,4-d]pyrimidine-2,5-diones were obtained by cyclative release in DMF at 150 °C. Pyrrolo[3,4-d]pyrimidine-2,5-diones were also synthesized using the same pyrimidine resin precursor, which was first treated with a representative set of primary amines to substitute the chlorine atom. Subsequent cyclative cleavage was carried out at temperatures between 150 and 250 °C and led to the corresponding pyrrolopyrimidine-2,5-dione products in high purity. The synthesis of pyrimido[4,5-d]pyridazine-2,5-diones was carried out in a similar manner, by employing hydrazines for the nucleophilic substitution prior to cyclative cleavage. A number of related microwave-assisted cyclative-release protocols have been reported.223, 224
Apart from traditional cross-linked polystyrene resins a number of different supports and formats have been used in microwave-assisted SPOS. These include tentagel resins,117, 213, 214, 225 cellulose membranes (SPOT synthesis),226, 227 cellulose beads,228 and glass surfaces.229 Janda and co-workers have described the use of JandaJel as the support in the solid-phase synthesis of oxazoles (Scheme 48).230 In this case, resin-bound α-acylamino-β-ketoesters 54 were treated with Burgess reagent to form oxazoles 55, which were then cleaved from the resin by using a diversity-building amidation reaction. The conditions for the key cyclization step 5455 were carefully optimized with microwave dielectric heating and by monitoring the reaction by on-bead IR spectroscopy. The best conditions utilized 3.0 equivalents of the Burgess reagent and 20 equivalents of pyridine in chlorobenzene (100 °C, 15 min). Interestingly, conventional thermal heating at 80 °C for 4 hours was used for the production of the final library since it provided conversions as high as the 15 minutes microwave run.
One reason why microwave-assisted SPOS has not been as powerful a technique as it perhaps could be is the lack of suitable technology that would allow the combination of sealed-vessel microwave heating and bottom filtration (or related) methods for automated removal of excess reagents or solvents and for performing the required washing steps.231 Currently such vessel equipment is not generally available, and therefore the advantages of SPOS in conjunction with microwave technology can not be fully exploited. Additional examples of SPOS with controlled microwave heating are found in ref. 232.
2.9.2. Liquid-Phase Synthesis on Soluble Polymer Supports
Besides solid-phase organic synthesis (SPOS) involving insoluble cross-linked polymer supports, chemistry on soluble polymer matrices, sometimes called liquid-phase organic synthesis, has emerged as a viable alternative.233 Problems associated with the heterogeneous nature of the ensuing chemistry and on-bead spectroscopic characterization in SPOS have led to the development of soluble polymers as alternative matrices for the production of combinatorial libraries. Synthetic approaches that utilize soluble polymers couple the advantages of homogeneous solution chemistry (high reactivity, lack of diffusion phenomena, and ease of analysis) with those of solid-phase methods (use of excess reagents and easy isolation and purification of products). Separation of the functionalized matrix is achieved by either solvent or heat precipitation, membrane filtration, or size-exclusion chromatography.233
A variety of successful microwave-assisted transformations involving soluble polymers such as polyethylene glycol (PEG) have been reported since 1999,234 and most recently by Sun and co-workers using controlled open-vessel microwave conditions.235, 236 In the example shown in Scheme 49 polyethylene glycol of molecular weight 6000 (PEG 6000) was used as a support for the synthesis of a small library of thiohydantoins.235 In the first step Fmoc-protected amino acids (3.0 equiv) were loaded onto the support by standard peptide coupling with classical DCC/DMAP activation. The coupling was carried out in dichloromethane and required 14 minutes of microwave irradiation under open-vessel reflux conditions. Following deprotection with 10 % piperidine in dichloromethane at room temperature, various isothiocyanates (3.0 equiv) were introduced by heating under reflux conditions (7 min), again in the same solvent. The cyclization/traceless cleavage step was completed under mildly basic conditions (K2CO3) within 7 minutes and provided the desired thiohydantoins in high overall yield and purity. Although the authors did not report any reaction temperatures apart from “reflux conditions” they noted that control experiments under conventional reflux conditions required significantly longer reaction times, which would indicate the presence of a specific microwave effect (namely, a superheating effect at atmospheric pressure).
Scheme 49. Preparation of thiohydantoins on a PEG support. All microwave-assisted steps were carried out under open-vessel conditions.
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2.9.4. Polymer-Supported Reagents, Catalysts, and Scavengers
Apart from traditional solid-phase organic synthesis (SPOS), the use of polymer-supported reagents (PSR) has gained increasing attention from practitioners in the field of combinatorial chemistry.242 The use of PSRs combines the benefits of SPOS with many advantages of traditional solution-phase synthesis. The most important advantages of these reagents are the simplification of reaction work-up and product isolation, with the former being reduced to simple filtrations. In addition, PSRs can be used in excess without affecting the purification step. Reactions can be driven to completion more easily by using this technique than in conventional solution-phase chemistry.
The combination of MAOS and PSR technology is a rapidly growing field.243 An early example of microwave-assisted PSR chemistry published by Ley et al. involves the rapid conversion of amides into thioamides by employing a polystyrene-supported Lawesson-type thionating reagent.51 A range of secondary and tertiary amides was converted within 15 min with 3–20 equivalents of the PSR into the corresponding thioamides in high yield and purity by using microwave irradiation at 200 °C (Scheme 52). These thionation reactions showed a marked acceleration in the reaction rate compared to classical reflux conditions, with reaction times being reduced from 30 hours to 10–15 minutes. Interestingly, heating at these elevated temperatures caused no damage to the polymeric support. As toluene itself is a less than optimum solvent for absorption and dissipation of microwave energy (see Table 1), a small amount of ionic liquid (1-ethyl-3-methyl-1H-imidazolium hexafluorophosphate) was added to the reaction mixture to ensure an even and efficient distribution of heat.
Isonitriles represent an important class of monomers, and their unique reactivity in MCRs (see for, example, Scheme 26) have made them ideal targets for synthesis. Since the preparation and subsequent purification of the sometimes unstable isonitriles prepared by solution-phase methods is not trivial, a process allowing the rapid generation of isonitriles “on demand” is highly desirable. Two independent routes to isonitriles involving microwave-assisted PSR chemistry were reported in 2002 (Scheme 53).244–246 In the approach described by Ley and Taylor, a suspension of an isothiocyanate and a polymer-supported 1,3,2-oxazaphoshpholidine reagent (1.5–3.0 equiv) in toluene was heated under sealed-vessel microwave irradiation conditions at 140 °C. This method enabled the preparation of primary, secondary, tertiary and aromatic isocyanides in high yields and purities.244 In an alternative method presented by Bradley and co-workers,245 formamides (which themselves can be efficiently prepared by MAOS)246 were treated with a sulfonyl chloride resin (3.0 equiv) and pyridine (50 equiv) in dichloromethane. The optimum conditions involved heating the mixture at 100 °C for 10 minutes and provided the desired isonitriles in moderate to high yields.245, 246
Very recently, Porcheddu et al. described an attractive “resin capture and release” strategy for the preparation of libraries of 2,4,5-trisubstituted pyrimidines (Scheme 54).247 The key to the success of the “traceless” synthesis of the pyrimidines is the capturing of β-ketoesters or β-ketoamides on a solid-supported piperazine. Heating a mixture of the piperazine resin, N-formylimidazole dimethyl acetal, and the 1,3-dicarbonyl compound in DMF in the presence of 10 mol % camphersulfonic acid (CSA) at 80 °C for 30 minutes provided resin-bound enaminones in high yields. As in earlier examples described in this Review (see Schemes 20 and 47), it was found to be advantageous to work under open-vessel conditions to allow the removal of the formed methanol from the equilibrium. The desired pyrimidines were then released from the resin by heating the resin-bound enaminones in the presence of 1.0 equivalent of guanidinium nitrates (prepared by a MAOS method) at 130 °C for 10 minutes. A 39-member library of pyrimidines was prepared in excellent overall yields and purities. Related microwave-assisted capture and release strategies have been reported by Turner and co-workers.248 Some other applications of microwave-assisted PSR chemistry are summarized in Scheme 55.
Scheme 55. Examples of resin-bound reactions: synthesis of 1,3,4-oxadiazoles using Burgess reagent,249 Wittig reactions with triarylphosphanes,250 catalytic transfer reaction involving formate,251 O-alkylation with O-alkyl isoureas,252 and formation of amide bonds with carbodiimide.253 HOBt=1-hydroxybenzotriazole.
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A truly remarkable combination of polymer-bound reagents, catalysts, and scavengers was used by Ley and co-workers in their total synthesis of the natural product (+)-plicamine (Scheme 56).254 Microwave dielectric heating was used as the primary means of accelerating a number of slow reactions to maximize the quantities of intermediates that could be progressed through the synthetic sequence. The rapid optimization and screening of reaction conditions permitted by the adoption of automated microwave synthesis was crucial to the successful completion of this synthesis. Further details are found in the original references.254
The methodical examination of microwave-assisted scavenging techniques has only been explored recently. An appealing sequence of microwave-assisted synthesis and scavenging was reported by Ellman and co-workers (Scheme 57).255 The authors used microwave heating in the first step of their asymmetric synthesis of α-substituted amines to facilitate the formation of an imine intermediate from chiral 2-methylpropan-2-sulfinamide and an aldehyde precursor. Optimized conditions involved heating the sulfinamide with the aldehyde (1.2 equiv) in the presence of the Lewis acid and water scavenger Ti(OEt)4 (2.2 equiv) in dichloromethane at 90–110 °C for 10 minutes. Excess titanium reagent was removed by treatment of the crude mixture with water-saturated diatomaceous earth and subsequent filtration through silica gel. The nucleophilic addition of organomagnesium reagents to sulfinylimines proceeded with high diastereoselectivity at −48 °C. Finally, cleavage of the sulfinyl group with concomitant capture using a macroporous sulfonic acid resin in the presence of catalytic amounts of ammonium chloride (110 °C, 10 min) provided the desired amine tightly bound to the acidic ion-exchange resin. After washing the resin with methanol and dichloromethane, elution with ammonia furnished the chiral amines in high overall yield and purity.
A related, microwave-assisted scavenging process involving the rapid sequestration of amines by a high-loading Wang aldehyde resin was reported by Messeguer and co-workers,256 and a systematic kinetic study on microwave-assisted scavenging techniques involving various types of supports was published in 2003.257
A recent review has highlighted the growing importance of utilizing immobilized catalysts (namely, nanopalladium species) in conjunction with microwave dielectric heating.258