Amines with dimethyl sulfate

Methyl sulfate is not only of analytical interest as a counter ion of pharmaceutically relevant compounds. Rychtman [71] describes the trace analysis of this substance in pharmaceutical products that have been produced via alkylation with dimethyl sulfate. Tetraalkylammonium compounds, for example, may be synthesized by quatemation of tertiary amines with dimethyl sulfate ... 

Alkylation of l,2,4-triazin-3-amines with dimethyl sulfate was reported to yield the 1-methyl-1,2,4-triazinium salts 6 (R5 = Me).258 It was thought that alkylation of l,2,4-triazin-3-amines with iodomethane gave a 1 1 mixture of the 3-amino-l-methyl and the 3-amino-4-methyl-l,2,4-triazinium salts. However, reexamination of this reaction showed that Nl and N2 alkylated products 6 and 7 were isolated, but no 4-alkyl-l,2,4-triazinium salt.258 The formation of 2-substituted l,2,4-triazin-3-imines 8 during the alkylation of l,2,4-triazin-3-amines (R3 = H) has also been reported.257,26t> 264 When NR3R4 = NH2, the main products with methyl iodide are 2-methyl-l,2,4-triazin-3-imines 8 and the 1-methyl-1,2,4-triazinium salts 6 the minor products NR3R4 = NHMe affords predominantly the l-methyl-l,2,4-triazinium salts 6, and NR3R4 = NMe2 yields only the 1-methyl-l,2,4-triazinium salts 6.257... 

Methylation of 64 with ethereal diazomethane afforded the methyl ester 65, which was then reduced with amalgamated zinc and hydrochloric acid to give the amine 66. Methylation of the primary amine with dimethyl sulfate in the presence of potassium carbonate afforded a mixture of the monomethylamine 67 and the (hmethylamine 68, which were separated. Alkaline hydrolysis of 67 in methanol and subsequent column chromatognq>hy on Ambo lite IRA-120 completed the total synthesis of ( )-chanoclavine I acid (69). 

Other examples of esterification with trialkyloxonium salts have been reported.7,8 The present procedure offers the advantages that the reactive carboxylate ion is generated in sitv and that a low-boiling, nonaqueous solvent is employed, whereby the experimental procedure is considerably simplified. A related method has been reported which utilizes a hindered amine wdth dimethyl sulfate [Sulfuric acid, dimethyl csterj as the alkylating agent.9 The present procedure is carried out under somewhat milder conditions and avoids the use of highly toxic reagents. 

On the basis of fundamental experiments (see Section IV,A,2) some indenobenzazepine alkaloids have been efficiently synthesized from the corresponding protoberberines via 8,14-cycloberbines. For example, the cycloberbine 428 derived from the protoberberine 427 was heated with methanesulfonic acid in aqueous tetrahydrofuran to afford a 2 1 mixture of cis- and trans-indenobenzazepines 429 in 92% yield (Scheme 85). The mixture was methylated with methyl iodide to give the cts-N-methyl derivative 430 and the unchanged trans secondary amine (21%), which was very difficult to methylate and which gave the /V-methyl derivative only in 6% yield even on treatment with dimethyl sulfate for 43 hr. Contrary to the ordinary cases (Section IV,A,2), the trans derivative did not isomerize to the cis isomer 430 under various acidic conditions. Debenzylation of 430 by hydrogenolysis afforded fumarofine (417), which was converted to O-methylfumarofine (316) by methylation with diazomethane (215). 

Methyl 2,3-epoxypropanoate can be prepared by reaction of potassium glycidate with dimethyl sulfate and one equivalent of benzyltriethylammonium chloride in methylene chloride at room temperature (65% yield).14 The reactions of this ester with organolithium or organomagnesium reagents at low temperature afford optically pure epoxy ketones14 that may be transformed via reductive amination to anti amino epoxides.15... 

Aminocarbazoles are typical aromatic amines 3-aminocarbazoles, which are the most studied, form Schiff bases with aromatic aldehydes, and ketones. Use was made of such a benzaldehyde imine by methyla-tion with dimethyl sulfate and then by hydrolysis with acid to produce the mono-N-methylated amine. The dimethylated material was obtained via the trimethylammonium iodide, which gave 3-dimethylaminocarbazole on... 

Lactim ether formation from 2,3,4,5-tetrahydro-l//-l-benzazepin-2-one on reaction with dimethyl sulfate and triethyloxonium tetrafluoroborate has been described, and reactions of the lactim ether with a number of primary amines were reported <2003CHE344>. 

Yinylogous enamine dyes are obtained by reaction of aromatic amines with mucochloric acid (2,3-dichloro-4-oxo-2-butanoic acid), followed by condensation with quaternary quinaldine. After methylation of the enamine nitrogen atom with dimethyl sulfate, the dye 5 is obtained, which dyes bleached sulfite pulp red [15]. 

Diazotization, coupling, and methylation may be combined in a one-pot process by dissolving the aromatic amine and the heterocyclic methylene base in an organic acid and effecting the simultaneous diazotization and coupling by addition of sodium nitrite. The dye base is released by addition of alkali and is methylated with dimethyl sulfate to form the alkylarylhydrazone dye (e g., 11) [27]. 

Diazadimethinecyanine dyes are formed by coupling diazotized N-heterocyc-lic amines in the b-position to the nitrogen atom of other heterocycles followed by alkylation. The most important coupling agent is l-methyl-2-phenylindole. Reaction of this compound with diazotized 2-aminothiazole and subsequent methylation with dimethyl sulfate, yields 43, a dye that draws up very quickly on polyacrylonitrile and dyes it a lightfast red shade [102],... 

Even poor nucleophiles such as the amides 46 can react with azines in the presence of alkynes as activating agents [59, 60]. Various nucleophiles (including alkoxides, thiols, amines and nitrogen heterocycles) were recently employed in a related process with Ai-oxide azaindoles (Reissert-Henze reaction. Scheme 10). In the process, the oxygen is alkylated with dimethyl sulfate and, after the nucleophilic attack, methanol is released to aromatize the initial adduct [61,62]. Following similar mechanistic trends, V-heteroatom-activated azines afford the corresponding substituted adducts. Likewise, W-tosylated isoquinoline [63, 64] and W-fluoropyridinium salts [65] are also reactive substrates in Reissert-Henze type processes. 

Alkylation of imino or amidine nitrogen and subsequent hydrolysis give rise to amines. For instance, alkylation of imine esters (104a) or amidine esters (104b) with dimethyl sulfate or methyl triflate, fol-... 

Chlorobenzene is employed in the synthesis of certain amino-containing vat dye intermediates. When reacted with phthalic anhydride, the product is 2-chloroanthraquinone, which, with ammonia, is converted readily into 2-aminoanthraquinone (61). Other routes include replacement of halogen by amino groups, with ammonia or ammonium salts of urea, and alkyl- and aryl amines to afford secondary amines. Modification of the amino group by alkylation, with dimethyl sulfate, alkyl halides or esters of toluenesul-fonic acids, is of synthetic value. Arylation of the amino groups is of importance only in the reaction between aminoanthraquinones and nitro- or chloroanthraquinones to yield dianthraquinonylamines, or anthrimides48. For example, the reaction between 62 and 63 yields 64, which can then be converted into carbazole 65, Cl Vat Brown R (Scheme 14). Amination of haloanthraquinones such as l-amino-4-bromoanthraquinone-2-sulfonic acid (bromamine acid) (66), prepared from 1-aminoanthraquinone, is of industrial use. 

A general method for the preparation of unsymmetrical secondary amines involves alkylation of an N-ben/.ylidencamine such as (I) by mixing it with dimethyl sulfate In benzene, healing gently at lirst and then at reflux, ami decomposing the salt (21 with base. 

The 3-methyl ethers of the 4,6-0-benzylidene and 4,6-0-ethylidene derivatives of methyl 2-(A-benzyloxycarbonyl)amino-2-deoxy-a-n-gluco-pyranoside have been prepared by a sequence of reactions paralleling Neuberger s synthesis. The d anomer of the latter compound was obtained directly by methylation of 2-(A-benzyloxycarbonyl)amino-2-deoxy-4,6-0-ethylidene-D-glucose with dimethyl sulfate and alkali. Both anomers were transformed into the free amines by catalytic hydrogenolysis. ... 

This substance is prepared by alkylation of 1,8-diaminonaphthalene with dimethyl sulfate. Alder et al.1 report that it is a very strong base with pK 12.34. It is thus stronger than normal aliphatic amines. This strong basicity is due to the fact that l,8-bis(dimethylamino)naphthalene is very strained and the strain is relieved by protonation. On the other hand, it is only weakly nucleophilic. 

Esterification. Carboxylic acids can be converted into methyl esters in high yield with dimethyl sulfate in the presence of this base as the proton acceptor (10-20% excess amine).1 Ethyl esters can be prepared in the same way using diethyl sulfate. Dicyclohexylethylamine is equally elfective but is not available commercially. The method is simple and rapid and is useful when strongly acidic conditions must be avoided. 

A new type of ester amide as an alternative to diesterquats has gained attention in the personal care area in recent years. These ester amidoamines are prepared from diethanolamines and 2 mol of fatty acid. The hydroxyl group forms an ester function and the primary amine forms an amide bond. The resulting ester amidoamines are then quaternized with dimethyl sulfate or methyl chloride. These ester amidoamine dialkylquats are typically used as fabric softeners or in hair care formulations where they showed good hair softening and smoothing elfect [150] (Fig. 18). 

Carboxylic acids react with dimethyl sulfate in the presence of Dicyclohexyl(ethyl)amine (DICE) to afford methyl esters in high yield. The method is reported to be facile and particularly useful when ester formation using Diazomethane or... 

QuaterniZation. Quaternary ammonium compounds are formed by alkylation of alkyl, alkyl dimethyl, dialkyl, and dialkylmethyl fatty amines with methyl chloride, dimethyl sulfate, or benzyl chloride (1,3,7,12,29). 

The nitrogen of aHphatic and aromatic amines is alkylated rapidly by alkyl sulfates yielding the usual mixtures. Most tertiary amines and nitrogen heterocycles are converted to quaternary ammonium salts, unless the nitrogen is of very low basicity, eg, ia tn phenylamine. The position of dimethyl sulfate-produced methylation of several heterocycles with more than one heteroatom has been examined (22). Acyl cyanamides can be methylated (23). Metal cyanates are converted to methyl isocyanate or ethyl isocyanate ia high yields by heating the mixtures (24,25). 

SuIfona.tlon, Sulfonation is a common reaction with dialkyl sulfates, either by slow decomposition on heating with the release of SO or by attack at the sulfur end of the O—S bond (63). Reaction products are usually the dimethyl ether, methanol, sulfonic acid, and methyl sulfonates, corresponding to both routes. Reactive aromatics are commonly those with higher reactivity to electrophilic substitution at temperatures > 100° C. Tn phenylamine, diphenylmethylamine, anisole, and diphenyl ether exhibit ring sulfonation at 150—160°C, 140°C, 155—160°C, and 180—190°C, respectively, but diphenyl ketone and benzyl methyl ether do not react up to 190°C. Diphenyl amine methylates and then sulfonates. Catalysis of sulfonation of anthraquinone by dimethyl sulfate occurs with thaHium(III) oxide or mercury(II) oxide at 170°C. Alkyl interchange also gives sulfation. 

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