N- and O-Alkylations

Since the iridium(III) complex [(Cp )IrCl2]2 (Cp = pentamethylcyclo-pentadienyl) is an active catalyst for the p-alkylation of secondary alcohols with primary alcohols, a series of iridium(III) complexes 26-28 bearing a Cp unit tethered to an imidazolyhdene was synthesized (Equation (8.15)). These complexes displayed similar activities in the p-alkylation of secondary alcohols with primary alcohols as electrophiles (Equation (8.15)), and surpassed the performance of their parent compound [(Cp )IrQ2]2. Control of the reaction time was found to be crucial to avoid the undesirable dehydrogenation of the product (see Section 8.4.2 for further details). The sequence of catalytic reaction steps was thought to involve the oxidation of both alcohols and the formation of an iridium hydride species. Base-promoted cross-aldolization and elimination to form the ot-enone and hydrogenation of the C=C and C=0 bonds to regenerate an iridium-alkoxide species would complete the cycle. 

Peris and co-workers reported the benzylation of arenes using complex 26b as catalyst (0.1 or 1 mol%). Different benzylating agents such as benzyl alcohols, benzyl ethers or styrene derivatives were used in combination with toluene, xylenes, phenol and anisole (Equation (8.16)). Catalyst 26b displayed high activities, except for a few cases, but poor selectivities for both the ortho 

Alternatively, the cross-coupling between two alcohols to provide unsym-metrical ethers was catalyzed by 1 mol% of the bis-triflate complex 26b. Excellent conversions (generally 95%) as well as good selectivities for the unsymmetrical ether were generally obtained. An example using allyl alcohol is displayed in Equation (8.17). 

The (speculative) mechanism may first involve oxidative addition of an OH function to provide a Ir -H species which would behave as a Bronstedt acid towards the second alcohol and activate it for an nucleophilic attack at the C-O carbon atom. Displacement of water and release of the ether from the coordination sphere would regenerate the catalyst and close the cycle. 

For details on the [(NHC)Ir]-catalyzed A-alkylation processes, the reader is referred to Chapter 12. 

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Schwesingefs phosphazene base 2-tert-butylamino-2-diethylamino-l,3-dimethyl-perhydro-l,3,2-diazaphosphorine (PS-BEMP has a pKb = 27.5 in MeCN) has been immobilized and shown to have immense utility in the N- and O-alkylation of many weakly acidic heterocycles. Kim et al. has made extensive use of this reagent in the multi-step synthesis of a small collection of guanines possessing potential antiviral activity [90]. The generic procedure involved the direct alkylation of the purine moiety (20) (Scheme 2.64), promoted by PS-BEMP, resulting in a mixture... 

The reactions of alkyl halides with the silver salt of dinitroacetonitrile have been shown to be of limited use for the synthesis of polynitroaliphatic compounds. These reactions give a mixture of C-, N- and O-alkylation products with product distribution highly dependent on the nature of the substrate. ... 

Cyclic amino alcohols have been used in a Mitsunobu alkylation of 4-substituted phthalazin-l(2//)-ones <1996LA1477>. Mitsunobu alkylation has also been used to graft 6-chloropyridazin-3(2//)-one on a Wang resin. In this case competitive N- and O-alkylation is observed <2005JC0414>. 

The ambident nature of a hydroxyl group in an electrophilic position, and its strong preference for the oxo form, often leads to a mixture of N- and O-alkylated products. Generally soft electrophiles favor N-alkylation and harder electrophiles O-alkylation <1992ACS1219>, although the choice of solvent can also have an effect <2006T6848>. 

Willner and Halpern185 have described quantitative O-methylation of ac-ridone (119) under phase transfer conditions. But a more detailed study on alkylation of acridone under biphasic conditions by Galy et al.1 6 arrives at another conclusion the reaction gives a mixture of N- and O-alkylation products, with the N-alkyl derivative (120) predominating (65-100%). The yield of isolated N-alkyl derivative is 41-66%. 

Pyridone is O-alkylated more readily than normal amides, because the resulting products are aromatic. With soft electrophiles, however, clean N-alkylations can be performed (Scheme 1.7). The Mitsunobu reaction, on the other hand, leads either to mixtures of N- and O-alkylated products or to O-alkylation exclusively, probably because of the hard, carbocation-like character of the intermediate alkoxyphosphonium cations. Electrophilic rhodium carbene complexes also preferentially alkylate the oxygen atom of 2-pyridone or other lactams [20] (Scheme 1.7). 

Imides are sufficiently acidic to enable N-alkylation via the Mitsunobu reaction. As with amides, only cyclic imides are readily N-alkylated whereas acyclic imides tend to yield mixtures of N- and O-alkylated products or O-alkylated products exclusively when treated with an alkylating agent (Scheme 6.25). 

Attempted alkylation of 2-pyridones often leads to mixtures of N- and O-alkylated products with the selectivity dependent on the reaction conditions. Alkylation of the sodium salt of 2-pyridone often leads to iV-alkylation while alkylation of the silver salt results in O-alkylation. For example, /3-D-galactopyranose pentaacetate reacts with silver 2-pyridoxide in toluene under reflux to give the pyridylgalactopyranoside 100 in good yield (Equation 67) <2001T3267>. 

Hydroxythiadiazoles exhibit marked acid properties (see Section 4.26.2.8) and exist essentially in the hydroxy form (68AHC(9)107). Alkylation with alkyl halides or sulfates and base in dipolar aprotic solvents usually forms ethers. In media where the oxygen atom is screened by solvation or by formation of ion pairs, mixtures of N- and O -alkylation products are formed. The reaction of 3-chloro-4-hydroxy-l,2,5-thiadiazole with epichlorohydrin catalyzed by piperidine in the absence of a solvent gave a mixture of N- and O-alkylated products in about equal amounts (72JMC651). Treatment of 3 - hydroxy-4-(A - morpholino) -... 

The preparation and reaction of 1-alkylthioisoquinolinium salts with active methylene compounds was studied <02CPB225>. The selective N- and O-alkylation of 1-isoquinolones using Mitsunobu conditions was also studied <02JCS(P1)335>. Additionally, the oxidation of isoquinoline derivatives to the corresponding isoquinolones using iodosobenzene and catalytic tetrabuty(ammonium iodide was reported <02HCA1069>. 

O-Alkylation is also favored using more sterically hindered electrophiles such as secondary alkyl halides thus, alkylation of 2-pyridone with isopropyl iodide under mild conditions in the presence of cesium fluoride at room temperature leads to the formation of a mixture of N- and O-alkylated products in a 11 89 ratio <1995SL845>. 

Elimination of a formaldehyde molecule is an important fragmentation channel for iV-methoxymethyl 43a and iV-ethoxymethyl 43b sultams. The process is mediated by an ion neutral complex and it yields a mixture of N- and O-alkylated ions in various ratios <2005JMP331>. Fragmentations of 43a are shown in Scheme 5. 

The imide hydrogen atoms in barbituric acids take part in tautomerism (Section II,A) so that the alkylation of these compounds leads to a mixture of N- and O-alkyl derivatives. Levina thoroughly discussed the N-alkylation.4... 

Aminolysis of benzopyran 301 with ammonium acetate afforded the quinoline 302, which upon reaction with DMF diethyl acetal (DMFDEA) produced a mixture of the respective N- and O-alkylated derivatives 303 and 304. The latter compound was also prepared by chlorination of 302 with PCI5 followed by reaction with sodium ethoxide. Further treatment of 303 and 304 with DMFDEA in toluene at 180-200 °C resulted in C-alkylation to give 305 and 307, respectively. Column chromatography on silica gel resulted in the formation of 306 and 308, respectively with the recovery of the starting material 303 (91KGS86) (Scheme 57). 

The alkylation of pteridinones using reagents such as iodomethane or dimethyl sulfate in alkali usually results in A -alkylation, although sometimes mixtures of both N- and O-alkylated products are obtained. The use of diazomethane sometimes favours 0-methylation over N-methylation, but it is difficult to predict the outcome of such reactions, and mixtures of products are obtained in many cases. The best way of making alkoxypteridines is to use alkoxides and chloropteridines. However, in the case of pteridin-6(577)-ones and pteridin-7(8/f)-ones it is sometimes possible to use alcoholic hydrogen chloride to effect O-alkylation by a reaction similar to etherification of alcohols. For example 2,4-diaminopteridin-6(577)-one (1) can be converted to 6-methoxypteridine-2,4-diamine (2) by this process.166 Some other examples of the reaction have been reported, mostly using alkylated pteridines. 

There has been a longstanding controversy as to whether hydroxamic acids are NH or OH acids. The IR and UV evidence presented by ExnCT and coworkers indicated that they are NH acids in dioxane and aqueous alcohol solvents, and this conclusion has also been supported by a NMR study . However, other studies on meta- and para-substituted benzohydroxamic acids led to the conclusion that, in aqueous solution, RCONHO ions wctc at least as present as RCON(OH) ions. Mote recently, Crmnbliss and coworkCTs have concluded that, in an aqueous 2M NaNOs solution, aceto- and benzohydroxamic acids act as OH rather than NH acids. BordweU s group measured the equilibrium acidities in DMSO of aceto- and benzohydroxamic acids, as well as their N- and O-alkyl daivatives, and concluded that hydroxamic acids act as NH acids in non-HBD solvents, such as DMSO, DMF, CHjCN etc., but they may act primarily as OH acids in hydroxyUc solvents. 

The formulation of 2,l-benzisothiazolin-3-one as ketonic tautomers (see Vol. 3, p. 558) has been confirmed by the preparation of its N- and O-alkylated derivatives, by unambiguous routes, and examination of their u.v. spectra. The same conclusions have been reached about 5-chloro-2,l-benzisothiazolin-3-one. Other nucleophilic displacements of the 3-halogen in 3-chloro- and 3,5-dichloro-2,1-benzisothiazole have been reported the auxin analogue (72 R = CHgCOaH) was obtained in the course of this work. The results of a comparative study of the rates of A -methylation are included under isothiazoles (p. 344). 

The 0-acylhydroxamate (32a) (p Ta 6-7) reacts with benzyl alcohol, DEAD, and TPP to give N- and O-alkylated products, while the less acidic 0-alkylhydroxamaie (32b) (pXa 9-10) gives only the A7-alkyl product (eq 28). ... 

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