Nitrogen acids, sodium hydride

Nitrogen Acids. Sodium hydride in DMSO, HMPA, NMP, or... 

Nitrogen Acids. Sodium hydride can be used to achieve selective tV-alkylation of 2-hydroxycarbazole (eq 36). ... 

Acyl amino acids and peptides may be alkylated on nitrogen using sodium hydride, with noracemization (eq 9). A slight change of reaction conditions allows simultaneous esterification. ... 

Dimethylsulfoxide Acyl and aryl halides, boron compounds, bromomethane, nitrogen dioxide, magnesium perchlorate, periodic acid, silver difluoride, sodium hydride, sulfur trioxide... 

The imide proton N-3—H is more acidic than N-1—H and hence this position is more reactive toward electrophiles in a basic medium. Thus hydantoins can be selectively monoalkylated at N-3 by treatment with alkyl haUdes in the presence of alkoxides (2,4). The mono-A/-substituted derivatives (5) can be alkylated at N-1 under harsher conditions, involving the use of sodium hydride in dimethylform amide (35) to yield derivatives (6). Preparation of N-1 monoalkylated derivatives requires previous protection of the imide nitrogen as an aminomethyl derivative (36). Hydantoins with an increased acidity at N-1—H, such as 5-arylmethylene derivatives, can be easily monoalkylated at N-3, but dialkylation is also possible under mild conditions. 

A total of 3 g (0.13 moles) of sodium hydride is added to a solution consisting of 10 g of 17 -hydroxy-5a-androstan-3-one (36 mmoles) in 200 ml of benzene and 10 ml of ethyl formate. The reaction mixture is allowed to stand under nitrogen for 3 days followed by dropwise addition of 10 ml of methanol to decompose the excess of sodium hydride. The solution is then diluted with 300 ml water and the layers are separated. The basic aqueous solution is extracted with ether to remove neutral material. The aqueous layer is acidified with 80 ml of 3 A hydrochloric acid and the hydroxymethylene steroid is extracted with benzene and ether. The combined organic extracts are washed with water and saturated sodium chloride solution and then dried over magnesium sulfate and concentrated. The residue, a reddish-yellow oil, crystallized from 10 ml of ether to yield 9.12 g (83%) of 17 -hydroxy-2-hydroxymethylene-5a-androstan-3-one mp 162-162.5°. Recrystallization from chloroform-ether gives an analytical sample mp 165-165.5° [a]o 53° (ethanol) 2 ° 252 mjj. (g 11,500), 307 m u (e 5,800). 

Of the several syntheses available for the phenothiazine ring system, perhaps the simplest is the sulfuration reaction. This consists of treating the corresponding diphenylamine with a mixture of sulfur and iodine to afford directly the desired heterocycle. Since the proton on the nitrogen of the resultant molecule is but weakly acidic, strong bases are required to form the corresponding anion in order to carry out subsequent alkylation reactions. In practice such diverse bases as ethylmagnesium bromide, sodium amide, and sodium hydride have all been used. Alkylation with (chloroethyl)diethylamine affords diethazine (1), a compound that exhibits both antihista-minic and antiParkinsonian activity. Substitution of w-(2-chloroethyl)pyrrolidine in this sequence leads to pyrathiazine (2), an antihistamine of moderate potency. 

A 1.5 to 2 M solution of methylsulfinyl carbanion in dimethyl sulfoxide is prepared under nitrogen as above from sodium hydride and dry dimethyl sulfoxide. An equal volume of dry tetrahydrofuran is added and the solution is cooled in an ice bath during the addition, with stirring, of the ester (0.5 equivalent for each 1 equivalent of carbanion neat if liquid, or dissolved in dry tetrahydrofuran if solid) over a period of several minutes. The ice bath is removed and stirring is continued for 30 minutes. The reaction mixture is then poured into three times its volume of water, acidified with aqueous hydrochloric acid to a pH of 3-4 (pH paper), and thoroughly extracted with chloroform. The combined extracts are washed three times with water, dried over anhydrous sodium sulfate, and evaporated to yield the jS-ketosulfoxide as a white or pale yellow crystalline solid. The crude product is triturated with cold ether or isopropyl ether and filtered to give the product in a good state of purity. 

The hydrogeh atom bound to the amide nitrogen in 15 is rather acidic and it can be easily removed as a proton in the presence of some competent base. Naturally, such an event would afford a delocalized anion, a nucleophilic species, which could attack the proximal epoxide at position 16 in an intramolecular fashion to give the desired azabicyclo[3.2.1]octanol framework. In the event, when a solution of 15 in benzene is treated with sodium hydride at 100 °C, the processes just outlined do in fact take place and intermediate 14 is obtained after hydrolytic cleavage of the trifluoroacetyl group with potassium hydroxide. The formation of azabi-cyclo[3.2.1]octanol 14 in an overall yield of 43% from enone 16 underscores the efficiency of Overman s route to this heavily functionalized bicycle. 

Inclusion of basic nitrogen in the p-position is also compatible with antiinflammatory activity in this series. Nitration of phenylacetic acid (27) affords 28. Methyl iodide alkylation of the enolate prepared from 28 using two equivalents of sodium hydride gives 29. This appears to involve an Ivanov intermediate (28a). Catalytic reduction of the... 

B. Preparation of Cyclopropyldiphenylsulfonium Fluoroborate. A suspension of 118.7 g. (0.339 mole) of 3-chloropropyldiphenylsulfonium fluoroborate (Note 2) in 500 ml. of dry tetrahydrofuran (Note 12) is placed in a 2-1., one-necked flask equipped with a magnetic stirring bar and nitrogen inlet tube under nitrogen. Then 5-g. portions of 55% sodium hydride-mineral oil dispersion (15.2 g., 0.350 mole) are added in 30-minute intervals. The resulting mixture is stirred (Note 13) at room temperature for 24 hours. An aqueous solution of 25 ml. of 48% fluoroboric acid (Note 14), 15 g. of sodium fluoroborate (Notes 7, 15), and 400 ml. of water is added to the well-stirred reaction to destroy residual hydride and swamp out chloride ion (Note 16). After 5 minutes 300 ml. of methylene chloride is added, and the top methylene chloride layer is removed from the lower aqueous layer (Note 17). The methylene chloride solution is then extracted with 100 ml. of water. This water layer is combined with the first aqueous layer, and the combined water layers are extracted with an additional 100 ml. of methylene chloride. The methylene chloride portions are combined, dried over anhydrous sodium sulfate, and evaporated at reduced pressure until precipitation occurs. Addition of 1 1. of ether completes the precipitation of the salt. 

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