Nicotinic anhydride

Department of Chemistry, Duke University, Durham, North Carolina. This work was supported by the National Science Foundation. 

Submitted by Heinrich Rinderknecht and Morris Gutenstein 1 Checked by Walter K. Sosey, Wayland E. Noland, and William E. Parham 

Nicotinic acid (10 g., 0.081 mole) (Note 1) and anhydrous benzene (275 ml.) (Note 2) are placed in a 500-ml. three-necked, round-bottomed flask (Note 3) fitted with a sealed Hershberg 

Nicotinic acid supplied by Matheson, Coleman and Bell yielded a colorless anhydride tr.s.P. grade material gave a slightly buff-colored product. 

Benzene and cyclohexane are freshly distilled and stored over sodium wire or calcium hydride. 

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Nicotinic anhydride is extremely sensitive to moisture all glassware is therefore dried overnight in an oven at 200° before use. 

The present method is that described by Rinderknecht and Ma.3 4 It is equally applicable to a variety of other heterocyclic, aromatic, and aliphatic anhydrides.4,6 Nicotinic anhydride was first prepared by reaction of nicotinoyl chloride with sodium nicotinate,6,7 and more recently by reaction of potassium nico-tinate with oxalyl chloride in anhydrous benzene.2... 

Tndecanedione, 47, 95 Tnethylamine, 46, 18 dehydrobromination of o-bromo-y-butyrolactone with, 46, 23 dehydrobromination of or.a -dibromo-dibenzyl ketone, 47, 62 dehydrochlormation of cyclohexane-carbonyl chloride, 47, 34 in synthesis of nicotinic anhydride with phosgene, 47, 90 Tnethyl orthoformate, condensation with N,N diphenylethylene-diaminc, 47,14... 

Nicotinic anhydride, 47, 89 Nitration, of o-aminobiphenyl to o-amino-/> -nitrobiphenyl, 46, 86 of o-tolunitrile with nitronium tetra-fluorohorate, 47, 56... 

Although this is the classical method of anhydride formation it has been replaced to a large extent by the acylation of free carboxylic acids (method 341). The conditions employed and the solvents used in this reaction vary widely. Excellent directions are given for the preparations of nicotinic anhydride (89%) and acetic propionic anhydride (60%) from the respective potassium and sodium salts of the carboxylic acids. Silver salts of acids have also been used. The reaction has been extended to the preparation of mixed anhydrides of short- and long-chain fatty acidsbut has failed in the preparation of mixed anhydrides of substituted benzoic acids. ... 

Rinderknecht, H. and Gutenstein, M. 1967. Nicotinic anhydride. Organic Synthesis, 47 89. 

Anhydrides. The preparation of nicotinic anhydride by reaction of nicotinic ucid with phosgene has been published.1... 

The structure and absolute configuration of 7-0-nicotinoyl-strychnovo-line (66) were also established through semisynthesis. Treatment of strych-novoline (64) with nicotinic acid anhydride in the presence of 4-dimethylam-inopyridine gave 66, identical with the natural product (39). Similarly, when tetrahydrocantleyine (16) was treated with nicotinic anhydride, 7-O-nicotinoyl-tetrahydrocantleyine (67) was produced, identical with the natural product (39). 

Ester and amide synthesis. Nicotinic anhydride activates carboxyhc acids (by forming mixed anhydrides) to be transformed into esters and amides, with alcohols and amines, respectively (catalytic DMAP). 

A report of the synthesis of acid anhydrides using phosgene gas has also appeared in the literature [1040, 1041]. Nicotinic anhydride 1371 was prepared from nicotinic acid 1370 with phosgene in 87-93% yield, as described in a very detailed... 

The triethylamine hydrochloride cake was washed on the filter with warm (60 °C) benzene (3 x 25 mL). The combined filtrate and washings were transferred to a 500-mL round-bottomed flask and concentrated to dryness in a rotary evaporator at low temperature and pressure. The dry residue was gently boiled with anhydrous benzene (75 mL), and the mixture was again filtered while still hot. The triethylamine hydrochloride cake was washed with cold benzene (2x5 mL), and the combined filtrate and washings were left to stand at 20 °C for 2-3 h. The crystalline product was collected on a filter, washed with cold anhydrous benzene (2x4 mL), and dried in vacuo. The yield of nicotinic anhydride 1371, mp 122-125 °C, was 6.25 g (68%). The combined filtrate and washings were concentrated to dryness in a rotary evaporator. The residue was gently boiled with 175 mL of a mixture of benzene and cyclohexane (2 3), and a small amount of insoluble material was removed by filtration of the hot mixture. The filtrate was stored at 5 °C for 18 h the crystalline deposit obtained was collected, washed with 3 mL of a cold benzene/ cyclohexane mixture, and dried in vacuo. An additional 2.4 g (25%) of colorless product mp 122-123 °C, was thus obtained. The total yield of nicotinic anhydride 1371 was 8.05-8.65 g (87-93%). 

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