Resin-bound halides

Halogen-Magnesium Exchange of Resin-bound Halides... 

The second step introduces the side chain group by nucleophilic displacement of the bromide (as a resin-bound a-bromoacetamide) with an excess of primary amine. Because there is such diversity in reactivity among candidate amine submonomers, high concentrations of the amine are typically used ( l-2 M) in a polar aprotic solvent (e.g. DMSO, NMP or DMF). This 8 2 reaction is really a mono-alkylation of a primary amine, a reaction that is typically complicated by over-alkylation when amines are alkylated with halides in solution. However, since the reactive bromoacetamide is immobilized to the solid support, any over-alkyla-tion side-products would be the result of a cross-reaction with another immobilized oligomer (slow) in preference to reaction with an amine in solution at high concentration (fast). Thus, in the sub-monomer method, the solid phase serves not only to enable a rapid reaction work-up, but also to isolate reactive sites from... 

In aqueous DMF, the reaction can be applied to the formation of C-C bonds in a solid-phase synthesis with resin-bound iodobenzoates (Eq. 6.33).80 The reaction proceeds smoothly and leads to moderate to high yield of product under mild conditions. The optimal conditions involve the use of 9 1 mixture of DMF-water. Parsons investigated the viability of the aqueous Heck reactions under superheated conditions.81 A series of aromatic halides were coupled with styrenes under these conditions. The reaction proceeded to approximately the same degree at 400°C as at 260°C. Some 1,2-substituted alkanes can be used as alkene equivalents for the high-temperature Heck-type reaction in water.82... 

Preparation of Merrifield resin-bound nitro acetates, which is a suitable building block for the development of combinatorial solid phase synthesis, is reported.4 The anion of ethyl nitro acetate is generated in DMF by an electrochemical method using Pt cathode, magnesium rod anode, and tetrabutylammonium bromide as an electrolyte. Alkylaton of this anion with alkyl halides gives mono-alkylated products in 80% yield.5... 

Several palladium catalysts for formation of aryl sulfides from aryl halides have been investigated more recently. A combination of Pd2(dba)3 and DPEphos catalyzed the formation of a broad range of diaryl sulfides in the presence of 1 mol.% palladium and NaO-t-Bu base in toluene solvent.12,rThe highest yields of alkyl aryl sulfides were obtained from aryl triflates and n-butyl thiol catalyzed by a combination of palladium acetate and BINAP. However, these reactions contained 10 mol.% catalyst, were long, and required deactivated aryl triflates. A combination of Pd2(dba)3 and DPPF catalyzed the coupling of thiols with resin-bound aryl halides.121... 

The reactions were carried out in sealed Pyrex tubes employing a prototype single-mode microwave cavity. The reagents were added to the resin-bound aryl halide under a nitrogen atmosphere and irradiated for the time periods indicated (Scheme 7.14). Rather short reaction times provided almost quantitative conversions, with minimal degradation of the solid support. 

In a related study, Srivastava and Collibee employed polymer-supported triphenyl-phosphine in palladium-catalyzed cyanations [142]. Commercially available resin-bound triphenylphosphine was admixed with palladium(II) acetate in N,N-dimethyl-formamide in order to generate the heterogeneous catalytic system. The mixture was stirred for 2 h under nitrogen atmosphere in a sealed microwave reaction vessel, to achieve complete formation of the active palladium-phosphine complex. The septum was then removed and equimolar amounts of zinc(II) cyanide and the requisite aryl halide were added. After purging with nitrogen and resealing, the vessel was transferred to the microwave reactor and irradiated at 140 °C for 30-50 min... 

In a similar approach (Equation 53), the use of a resin-bound nitrile allowed access to the corresponding resin-bound amidoximes 274, which could be converted into 1,2,4-oxadiazoles 275 via acylation with either an appropriate acid halide/ anhydride in the presence of a base or a carboxylic acid in the presence of a coupling reagent followed by cyclization, where the latter step was performed by heating in pyridine or diglyme and could be accelerated by the use of a microwave oven. Cleavage from the resin was easily achieved by the use of TFA in dichloromethane <2000BML1431>. 

Several syntheses of l,3-dioxoperhydropyrrolo[l,2-c]imidazoles have been developed using different strategies. a-Substituted bicyclic proline hydantoins were prepared by alkylation of aldimines 135 of resin-bound amino acids with a,tu-dihaloalkanes and intramolecular displacement of the halide to generate cr-substituted prolines 136 and homologs (Scheme 18). After formation of resin-bound ureas 137 by reaction of these sterically hindered secondary amines with isocyanates, base-catalyzed cyclization/cleavage yielded the desired hydantoin products <2005TL3131>. 

The group of Williams has reported a DKR of halo a-bromo [33a] and a-chloro esters [33b]. In the latter case, the KR is catalyzed by commercially available cross-linked enzyme crystals derived from Candida cylindracea lipase. The racemization takes place through halide SN2 displacement. The DKR is possible because the racemization of the substrates is faster than that of the products (carboxylates). For the ester, the empty ( =0) orbital is able to stabilize the SN2 transition state by accepting electron density. However, the carboxylate is more electron-rich and therefore less able to facilitate an SN2 reaction. Racemization is performed by the use of a chloride source. The best results where obtained by using a resin-bound phosphonium choride (Scheme 5.17). 

In a similar way, Guiles and co-workers immobilized an aryl pinacol boronate on resin via an ester linkage, and then a small number of aryl halides were coupled to this (Scheme 31). The products were cleaved and immediately transformed into their methyl esters, presumably for ease of analysis and separation from unreacted boronate. The reaction was found to be slower than that of the opposite polarity (i.e., with the resin-bound iodide), and only moderate yields were obtained after as much as 48 h. Yields could be considerably improved upon a second round of coupling, but only one example was given of this. The aryl bromides were found to react only upon heating. 

A variety of conditions were tried for the coupling, and aqueous KOH in DME were found to be optimal. Although Pd(PPh3)4 and PdCl2(PPh3)2 worked equally well as catalysts, the latter was easier to handle, and this becomes an important issue when many reactions must be run to make a library. The resin-bound vinyl boronates 29, which would be produced if the order of addition of halides were different, were not stable with respect to deboration, and subsequent yields using this strategy were low. 

The same authors have also reported on the solid-phase synthesis of benzimidazolones 7 from resin-bound 4-fluoro-3-nitrobenzoic acid lb, amines, disuccinimidocarbonate (DSC), and alkyl halides (Scheme 14).10... 

Coupling of aryl halides with alkenyl stannanes promoted through palladium metal catalysis, otherwise known as the Stille coupling, has many applications,22 including solid-phase variants (see Chapter 2).3-5 One of these is featured in Nicolaou and co-workers solid-phase synthesis of (5)-zearalenone wherein a resin-bound alkenylstannane undergoes a Stille cycli-... 

Three different strategies are generally used for the attachment of carboxylic acids to resins as benzyl esters (a) acylation of resin-bound benzyl alcohols [38-40], (b) O-alkylation of carboxylates by resin-bound benzylic halides [4143], or (c) O-alkylation of carboxylic acids under Mitsunobu conditions [44,45] (Figure 3.3). These reactions are treated in detail in Section 13.4. 

As illustrated by the examples in Table 3.9, resin-bound 4-alkoxybenzylamides often require higher concentrations of TFA and longer reaction times than carboxylic acids esterified to Wang resin. For this reason, the more acid-sensitive di- or (trialkoxy-benzyl)amines [208] are generally preferred as backbone amide linkers. The required resin-bound, secondary benzylamines can readily be prepared by reductive amination of resin-bound benzaldehydes (Section 10.1.4 and Figure 3.17 [209]) or by A-alkyla-tion of primary amines with resin-bound benzyl halides or sulfonates (Section 10.1.1.1). Sufficiently acidic amides can also be A-alkylated by resin-bound benzyl alcohols under Mitsunobu conditions (see, e.g., [210] attachment to Sasrin of Fmoc cycloserine, an O-alkyl hydroxamic acid). 

Support-bound /V-sulfonyl carbamates, which can be prepared by N-sulfonylation of resin-bound carbamates, are susceptible to nucleophilic cleavage. These intermediates enable the solid-phase preparation of A-ary I- or /V-alkylsulfonamides using inexpensive hydroxymethyl polystyrene (Entries 8 and 9, Table 3.15). Polystyrene-bound carbamates can also be cleaved by treatment with acyl halides in the presence of Lewis acids (Entry 4, Table 3.16). 

Resin-bound triazenes with a free NH group can be acylated by treatment with acyl halides, or carbamoylated by treatment with isocyanates [342]. The resulting triazene derivatives are stable towards strong bases, but undergo acidolysis when treated with TFA or TMSC1, yielding amides and ureas, respectively (Entries 1 and 2, Table 3.16). Polystyrene-bound triazenes devoid of a free NH group or carbamates can be cleaved from the support by treatment with acyl halides to yield amides (Entries 3 and 4, Table 3.16). 

Because of the special structural requirements of the resin-bound substrate, this type of cleavage reaction lacks general applicability. Some of the few examples that have been reported are listed in Table 3.19. Lactones have also been obtained by acid-catalyzed lactonization of resin-bound 4-hydroxy or 3-oxiranyl carboxylic acids [399]. Treatment of polystyrene-bound cyclic acetals with Jones reagent also leads to the release of lactones into solution (Entry 5, Table 3.19). Resin-bound benzylic aryl or alkyl carbonates have been converted into esters by treatment with acyl halides and Lewis acids (Entry 6, Table 3.19). Similarly, alcohols bound to insoluble supports as benzyl ethers can be cleaved from the support and simultaneously converted into esters by treatment with acyl halides [400]. Esters have also been prepared by treatment of carboxylic acids with an excess of polystyrene-bound triazenes here, diazo-nium salts are released into solution, which serve to O-alkylate the acid (Entry 7, Table 3.19). This strategy can also be used to prepare sulfonates [401]. 

Illustrative examples of cleavage reactions of /V-arylbenzylaminc derivatives are listed in Table 3.25. Aromatic amines can be immobilized as /V-bcnzylanilincs by reductive amination of resin-bound aldehydes or by nucleophilic substitution of resin-bound benzyl halides (Chapter 10). The attachment of the amino group of 5-aminoin-doles to 2-chlorotrityl chloride resin has been reported [486]. Anilines have also been linked to resin-bound dihydropyran as aminals [487]. 

Phenols can be etherified with resin-bound benzyl alcohols by the Mitsunobu reaction [554,555], or, alternatively, by nucleophilic substitution of resin-bound benzyl halides or sulfonates [556,557], Both reactions proceed smoothly under mild conditions. Aliphatic alcohols have been etherified with Wang resin by conversion of the latter into a trichloroacetimidate (C13CCN/DCM/DBU (15 100 1), 0°C, 40 min), fol-... 

Both aliphatic alcohols and phenols have been immobilized as esters of support-bound carboxylic acids. The esterification can be achieved by treatment of resin-bound acids with alcohols and a carbodiimide, under Mitsunobu conditions, or by acylation of alcohols with support-bound acyl halides (see Section 13.4). 

In addition to the procedures listed in Table 3.38, further reactions have been used to generate halides upon cleavage. In Section 3.5.2, iodolactonization is presented as a method for the preparation of iodomethyl lactones from resin-bound pentenoic or hexenoic acid derivatives. Closely related to the iodolactonization is the iodine-mediated formation of 2-(iodomethyl)tetrahydrofurans from resin-bound isoxazoli-dines (Entry 9, Table 3.38 for the mechanism, see Figure 15.5). Nitriles can also be prepared by cleavage and simultaneous dehydration of amides RCONH2 from the Rink or Sieber linkers with TFA anhydride (Entry 10, Table 3.38). 

Nucleophilic substitutions offer a more versatile means of access to alkyl halides than oxidative halogenations. The most common starting materials for this purpose are resin-bound alcohols, which can be converted into halides either directly or via the intermediate formation of sulfonates [23]. Polystyrene-bound halides can also be... 

Table 6.2. Conversion of resin-bound benzylic and allylic alcohols into halides.

Polystyrene-bound aliphatic alcohols can be etherified with alkyl halides under strongly basic conditions (Table 7.10). Competing elimination is usually no concern, because a large excess of halide can be used and alkenes can be readily removed by filtration and washing of the support. Alternatively, the addition of resin-bound alco-... 

Sulfoxides and sulfones can be prepared on cross-linked polystyrene by oxidation of thioethers. The most commonly used reagent for this purpose is MCPBA in DCM [8,12,32,57,80-82] or dioxane [50,83] (Table 8.6), but other oxidants such as H2O2 in acetic acid [34], oxone (Entry 7, Table 8.6), or oxaziridines [84] have also been used. PEG-bound thioethers have been converted into sulfones by oxidation with MCPBA in DCM [52,54] or with Os04/NMO [85], The oxidation of thioethers to sulfoxides requires careful control of the reaction conditions to prevent the formation of sulfones. Sulfones have also been prepared by S-alkylation of polystyrene-bound sulfi-nates (Entries 8 and 9, Table 8.6), by a-alkylation of sulfones (BuLi, THF, alkyl halide [86]), and by addition of sulfinyl radicals to resin-bound alkenes or alkynes (Entry 11, Table 8.6). 

Because many more alcohols than alkyl halides are commercially available, the Mitsu-nobu reaction enables the synthesis of larger and more diverse compound arrays than alkylation with alkyl halides. A -AcyIsuIfonamides are strongly acidic and can be alkylated with diazomethane (Entry 6, Table 8.9) or trimethylsilyldiazomethane [137]. Resin-bound sulfonamides have been N-acylated by treatment with acyl halides, and N-carbamoylated by treatment with isocyanates [138]. 

Merrifield resin [33-37] and other support-bound benzyl halides [38] have also been used to alkylate amines (Entries 5-10, Table 10.2). Similarly, resin-bound allyl bromides react cleanly with aliphatic or aromatic amines (Entry 16, Table 10.2). Entry 15 in Table 10.2 is a rare example of the N-alkylation of an amine under the conditions... 

The Mitsunobu reaction is usually only suitable for the alkylation of negatively charged nucleophiles rather than for the alkylation of amines, and only a few examples of such reactions (mainly intramolecular N-alkylations or N-benzylations) have been reported (Entry 15, Table 10.2). Halides, however, are very efficiently alkylated under Mitsunobu conditions, and it has been found that the treatment of resin-bound ammonium iodides with benzylic alcohols, a phosphine, and an azodicarboxylate leads to clean benzylation of the amine (Entry 9, Table 10.3). Unfortunately, alkylations with aliphatic alcohols do not proceed under these conditions. The latter can, however, also be used to alkylate resin-bound aliphatic amines when (cyanomethyl)-phosphonium iodides [R3P-CH2CN+][r] are used as coupling reagents [62]. These reagents convert aliphatic alcohols into alkyl iodides, which then alkylate the amine (Entry 10, Table 10.3). 

Aryl ketones can also be prepared by C-acylation of support-bound arylstannanes with acyl halides (Entry 4, Table 12.1). The reaction conditions are mild and suitable for selective chemical transformations of polystyrene-bound intermediates. As an alternative, resin-bound arylstannanes can be converted into benzophenones by treatment with aryl halides and carbon monoxide ([(Pd(PPh3)4], DMSO, 80 °C, 18 h-3 d [8]). 

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