Nucleophilic additions and substitutions

Nucleophilic addition and substitution reactions, both aromatic and aliphatic, encompass a large number of synthetic transformations. Microwave irradiation has been used extensively to enhance nucleophilic aromatic substitutions40,110,379-387, Michael additions148,192,388-402, Mitsunobu reactions403, hydroacylations404, N-acylations41,42,90,405-422, acetylations422-424, carbon382,389,425-439 and heteroatom alkylations (N66,172,265,317,421,439-464,465-469, 53-54,134,179,351,380,425,464,470-485), Williamson etherifications4,10,11,223,486-491, esterifications56,423,492-506, transesterifications41,158,507,508, halogenations10,181,223,510-518, and 18F-radiolabeling519,520.

Nucleophilic aromatic substitution (SNAr) reactions play an important role in drug discovery. A large number of drug compounds contain multiple aromatic rings. SNAr allows an organic chemist a facile route to changing substituents on the ring systems. Classically, SNAr requires long reaction times and high temperatures and provide low to moderate product yields. Scheme 65 shows two different substitutions on 1-chloro-4-nitrobenzene. Route A shows a substitution to an amine with ammonia and copper(I) oxide.381 With microwave irradiation, this transformation is successfully completed in one hour with a 93% product yield. Likewise, in route B, replacing the chlorine substituent with an ethoxy group forms an ether quantitatively in only two minutes.382

Scheme 65

Scheme 66 exhibits a small library of heterocyclic compounds that were synthesized using SNAr.354 Starting from one common aromatic scaffold; different amines were added, individually, to yield a small family of eight compounds. Using microwave instrumentation, this entire library was achieved in less than 90 minutes, whereas with conventional methods, this could take many days to complete. Additionally, the yields of this reaction greatly increased from as high as 60% with conventional heating to quantitative yields with microwave irradiation.

The Michael reaction forms the basis for many synthetic transformations. It involves a conjugate 1,4-addition of a nucleophile to an α,β-unsaturated ketone, aldehyde, amide, nitrile, nitride, sulfoxide, or sulfone. Scheme 67 shows an example of a Michael addition reaction between two indoles.388 Bis(indole) molecules have recently been isolated from sponges and are known bioactive metabolites. In this particular reaction, both the nitrovinylindole and alkylindole are adsorbed on silica gel and then subjected to microwave irradiation for 7-10 minutes. Using conventional methods, these additions proceeded in considerably longer reaction times, 8-14 hours.

Scheme 66

Scheme 67

Mitsunobu reactions are powerful synthetic transformations that can invert stereochemical configurations. Microwave irradiation has been used to enhance these conversions, as classical methods usually require high temperatures and long reaction times. Scheme 68 exhibits the acetylation of (S)-sulcatol via microwave enhanced Mitsunobu conditions (triphenylphosphine/diisopropyl azodicarboxylate) with acetic acid followed by lithium aluminum hydride (LAH) reduction to (R)-sulcatol.403

Scheme 68

Acylations [-C(O)R] and acetylations [-C(O)Me] are useful synthetic methods for obtaining ketones, amides, and enol esters. In hydroacylation reactions, aldehydes and olefins yield ketones via C–H bond activation by transition metals. Scheme 69 shows an efficient synthesis to ketones utilizing both Wilkinson’s rhodium(I) catalyst and 2-amino-3-picoline.5 The aldimine intermediate undergoes cyclometallation with the rhodium catalyst, which is then followed by alkene coordination. Alkene insertion followed by reductive elimination yields a ketone.404 Thermal methods can take 24 hours, but those reaction times have been reduced to four hours with a benzoic acid catalyst. With microwave heating, the reaction proceeds in ten minutes with moderate to high product yields.

Scheme 69

Conversion of amines to amides is the most widely used protection method for amino groups. N-acylation of amines to maleimides is useful and can be enhanced with microwave heating (Scheme 70).405-410 Trifluoroacetylation is quite convenient in organic synthesis because of its facile cleavage. This acetylation is usually achieved with trifluoroacetic anhydride, but having trifluoroacetic acid as a byproduct causes one to look for alternative methods. The use of TiO(CF3CO2) provides a solution, as titanium oxide and water are the only byproducts. The use of this reagent on both primary and secondary amines, coupled with 5-10 minutes of microwave irradiation, gives trifluoroacetamides in excellent yields (Schemes 71 and 72).422 Use of conventional heating with the same reagents and reaction conditions takes at least 48 hours.

Scheme 70

Scheme 71

Scheme 72

Enol-acetylation of ketones is a valuable transformation in organic chemistry. The enol ethers that are formed are used extensively as intermediates in synthetic routes. Despite their popular usage, preparation methods are limited. A common procedure involves acetic anhydride with a basic or acid catalyst. These catalysts are very strong and can cause sensitive compounds to decompose. Scheme 73 shows a mild procedure that selectively acetylates six-membered cyclic ketones.423 With conductive heating, the cyclohexanone derivatives were refluxed in THF with acetic anhydride and iodine for 8 hours and gave very low product yields. Alternatively, quantitative yields were produced with microwave irradiation in only five to ten minutes.

Scheme 73

Carbon-alkylations are also important reactions in organic chemistry. The most common and well-known method is by deprotonating a carbon that is adjacent to an electron-withdrawing group (e.g. enolate formation). Scheme 74 shows alkyl addition to a substituted acetate.382 With microwave heating, this reaction proceeded in 3 minutes with high product yields. Another example of C-alkylation is the addition of a 2-nitropropane anion (A) with a heterocyclic electrophile (B) (Scheme 75). The solvent conditions determine whether the final product is C or D, which is formed from subsequent elimination of nitrous acid from C.426

Scheme 74

Scheme 75

Heterocyclic alkylation reactions also benefit from microwave irradiation. Saccharin can easily be alkylated with any alkyl halide under microwaves in only ten minutes (Scheme 76).445 The saccharin is first treated with base to form the sodium salt, which is then adsorbed on silica gel. This reaction is solvent-free and gives a 91% yield. Thiols can also be alkylated in near quantitative yield with alkyl halides via potassium carbonate on alumina (Scheme 77).450

Scheme 76

Scheme 77

Oxygen-alkylation of phenolic compounds is a versatile approach to aryl ethers. These compounds are the basis of many pharmaceutical templates that are used in drug discovery. With conductive heating, these reactions can take anywhere from one to seven days for completion. Microwave-enhanced transformations of a polymer-bound base (PTBD) with phenols occur in less than 30 minutes (Scheme 78).354

Scheme 78

The Williamson etherification reaction is another O-alkylation of alcohols, both alkyl and aromatic. Synthetically, it is a simple method to both symmetrical and asymmetrical ethers, but it can also be used in the protection of alcohols. Normally, with thermal heat, the reaction of alcohol with a primary alkyl halide and a base catalyst can take up to twelve hours before completion. With microwave irradiation, etherification of p-cresol is accomplished in three minutes (Scheme 79) and of sesamol in four minutes (Scheme 80).4,10,11,223

Scheme 79

Scheme 80

Esters are very important organic molecules in both the chemical and pharmaceutical industry. Esterification of carboxylic acids, alkylation of carboxylate anions, and transesterifications are the three types of methods for ester synthesis. Fisher esterification reactions are direct transformations of carboxylic acids in a sulfuric acid/alcohol mixture. With conventional heating, these conditions are harsh and can take anywhere from two hours to two days. Loupy et al. using microwave irradiation and p-toluenesulfonic acid (PTSA), provided esters in near quantitative yields in ten minutes or less (Scheme 81).507

Scheme 81

Alkylation of carboxylate anions is another routine transformation to esters. Once again, Loupy and colleagues have extensively examined this area of esterification.505-507 Both potassium acetate (R1 = Me) and potassium benzoate (R1 = Ph), first generated in situ with either potassium hydroxide or potassium carbonate, were mixed with different alkyl halides. Under thermal conditions, esters are achieved in five hours; however, microwave-driven substitutions proceeded in 5-15 minutes on alumina (Scheme 82). Loupy and co-workers have also investigated microwave irradiation in transesterifications reactions.507 These reactions can be catalyzed by either an acid or a base, with PTSA and K2CO3, respectively, providing the most quantitative results. As shown in Scheme 83, the methoxy group of methyl benzoate is replaced by an octoxy group, which yields octyl benzoate and methanol. This reaction is successfully completed in two minutes with microwave heating.

Scheme 82

Scheme 83

The Finkelstein halogen exchange reaction is another nucleophilic substitution reaction. Alkyl iodides can be prepared easily from alkyl chlorides or bromides. This reaction is successful because, unlike sodium iodide, both sodium chloride and sodium bromide are not soluble in acetone or MEK. When an alkyl chloride or bromide is treated with sodium iodide, sodium chloride precipitates out of the solution, and formation of the alkyl iodide is favored. These reactions can take anywhere from 30 minutes to 80 hours for completion with conductive heating. Microwave heating yields alkyl iodides in ten minutes with excellent yields (Scheme 84).10,223

Scheme 84

Another example of nucleophilic substitution reaction is radiolabeling. It is always a challenge to synthesize radiopharmaceuticals that are labeled with short-lived radionuclei. These reactions typically require long reaction times, and thus, have low radiochemical yields. The use of microwave irradiation provides shorter reaction times, and as a result, higher radiochemical yields.519,520 SNAr reactions, with 18F-fluoride anion (via cyclotron), were performed on nitrobenzenes (Scheme 85).519 Comparing conventional methods to that of microwave heating, the radiochemical yields, in most cases, more than doubled with the use of microwaves. Scheme 86 shows the synthesis of epi-[18F]-fluoromisonidazole, which has been used in suspected cases of myocardial infarction.520 Synthetically, the yields increased from 40% (conventional) to 65% overall with microwave irradiation. In addition, the entire route, including work-up, took less than 70 minutes with a 40% radiochemical yield.

Scheme 85

Scheme 86

Instruments

Discover 2.0

Microwave Synthesizer

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411. Kidwai, M.; Kumar, R. “Microwave-assisted synthesis of novel 1,3,4-thiadiazolyl-substituted-1,2,4-tetrazines, pyridazinones, 1,2,4-triazoles, 4-thiazolidinones, oxazoles, and thiazoles.” Gazz. Chim. Ital. 1997, 127, pp. 263-68.

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413. Marquez, H.; Plutin, A.M.; Rodriguez, Y.; Perez, E.; Loupy, A. “Efficient synthesis of 1-(4’-methylbenzoyl)-3,3-diethylthiourea under microwave irradiation using potassium fluoride on alumina.” Synth. Commun. 2000, 30, pp. 1067-74.

414. Kidwai, M.; Goel, Y.; Kumar, R. “Microwave-assisted synthesis and antifungal activity of 1,2,4-triazine, 1,2,4-triazole, tetrazole, and pyrazole derivatives.” Indian J. Chem. 1998, 37B, pp. 174-79.

415. Williams, L. “Thin layer chromatography as a tool for reaction optimisation in microwave assisted synthesis.” J. Chem. Soc., Chem. Commun. 2000, pp. 435-36.

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417. Gadhwal, S.; Dutta, M.P.; Boruah, A.; Prajapati, D.; Sandhu, J.S. “Zeolite-HY: a selective and efficient catalyst for the synthesis of amides under microwave irradiations.” Indian J. Chem. 1998, 37B, pp. 725-27.

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421. Kidwai, M.; Kumar, R.; Srivastava, A.; Gupta, H.P. “Microwave-assisted synthesis of novel 1,3,4-thiadi-azolyl-substituted-1,2,4-triazines as potential antitubercular agents.” Bioorg. Chem. 1998, 26, pp. 289-94.

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423. Kalita, D.J.; Borah, R.; Sarma. J.C. “A selective catalytic method of enol-acetylation under microwave irradiation.” J. Chem. Res. (S) 1999, 404-05.

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439. Almena, I.; Diaz-Ortiz, A.; Diez-Barra, E.; de la Hoz, A.; Loupy, A. “Solvent-free benzylations of 2-pyridone. Regiospecific N- or C-alkylation.” Chem. Lett. 1996, pp. 333-34.

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447. Sabitha, G.; Reddy, B.V.S.; Abraham, S.; Yadav, J.S. “Microwave promoted synthesis of aminoalcohols in dry media.” Green Chem. 1999, 1, pp. 251-52.

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