The synthesis of m-nitrobiphenyl serves as an example of an arylation reaction in which the arylation is accomplished by treating a triazine with benzene in the presence of a strong acid.

A stirred solution of 1-(m-nitrophenyl)-3,3-dimethyltriazine (58.2 g, 0.3 mol) in 1.25 liters of benzene is heated to reflux. To the reaction mixture is added dropwise over a period of 4.5 hours a solution of 94% p-toluenesulfonic acid (74 g, 0.4 mol) in 375 mL of benzene. The resulting solution is refluxed for an additional 1.5 hours. The reaction is allowed to cool and 400 mL of water is added with stirring. The aqueous layer is removed and the benzene layer is washed with water (2X250 mL), 5% aqueous sodium hydroxide (3X250 mL), and 250 mL of water. The organic layer is separated and treated with calcium chloride to remove water. The benzene is removed via distillation. After most of the benzene has been removed the residue is distilled and the m-nitrobiphenyl product is collected at 115-118 °C, .1 mm. The crude distillate can be purified via recrystallization from hot methanol to afford the title compound.

The following preparation is a good example of the standard laboratory procedure for converting a diazonium salt into a triazine. The reaction involves the simple nucleophilic attack of dimethyl amine at the remote nitrogen of the aryl diazonium salt. The reaction is performed in the presence of sodium carbonate which acts as a base to neutralize the hydrochloric acid generated.

Pulverized sodium carbonate monohydrate (435 g, 3.5 mol) is added in portions with rapid stirring to 1.25 liters of water. Crushed ice is added to the resulting suspension until the temperature has been lowered to 10 °C followed by the addition of a 25% solution of dimethyl amine (212 g, 1.18 mol). To the reaction mixture is then added with rapid stirring an ice cold solution of m-nitrobenzenediazonium chloride beneath the surface of the reaction mixture over a period of approximately 30 minutes. Ice is added throughout the addition in order to maintain the temperature at approximately 10 °C. The resulting mixture is then stirred for an additional 20 minutes.

The crude product is collected via filtration and the filter cake is washed with water with mixing (2X1.25 liters). The filter cake is then pressed to remove moisture and dissolved in 1 liter of boiling 95% ethanol. The resulting solution is cooled in a water bath and the resulting crystalline product is collected and washed with 95% ethanol (2X100 mL) to afford the title compound.

The synthesis of 1-(m-nitrophenyl)diazonium chloride from m-nitroaniline is a good example of the standard laboratory procedure for the transformation of an amine into a diazonium salt.

Concentrated hydrochloric acid (125 mL) and 250 mL of hot water are added to m-nitroaniline (138 g, 1.0 mol). The resulting solution is heated to 85 °C followed by the addition of 275 mL of concentrated hydrochloric acid. The reaction mixture is then cooled rapidly in a salt-ice bath. A solution of sodium nitrite (72 g, 1.05 mol) in 175 mL of water is then added slowly below the surface of the reaction mixture with stirring. The temperature of the reaction mixture is monitored to maintain the temperature below 0 °C. The resulting solution is then stirred for an additional 20 minutes followed by the slow addition of urea (5g) in 12.5 mL of water over 15 minutes to minimize foaming. The resulting solution of 1-(m-nitrophenyl)diazonium chloride is not isolated and should be kept cold until it used in a subsequent step.

The Baeyer-Villiger oxidation is a transformation in organic chemistry that inserts an oxygen atom between the carbonyl carbon of a ketone and an adjacent carbon atom:

The reaction is often performed using a peroxyacid such as mCPBA (meta-chloroperbenzoic acid). Other oxidants can be used under certain circumstances including hydrogen peroxide, peroxyacetic acid, peroxytrifluoroacetic acid, and other organic peroxy acids and peroxides.

Mechanism:

The mechanism involves the acid-promoted nucleophilic attack of the carbonyl carbon atom of the ketone starting material by the oxygen atom of the peroxy acid that is not bonded to carbon. This produces the tetrahedral intermediate known as the Criegee intermediate. A pair of electrons on the oxygen atom in the species formed is then used to form a carbon oxygen double bond, and one of the alkyl groups undergoes a 1,2 shift from the carbon atom of the carbonyl to the oxygen atom of the peroxy acid. The carboxylate analog of the peroxy acid is eliminated and the resulting ester product is formed.

Regio- and Stereochemistry:

The regiochemistry and stereochemistry of the reaction products are highly predictable. The group that migrates is the group that is best able to stabilize a developing positive charge in the transition state. Usually, but not always, the more highly substituted group will migrate. If one of the groups is particularly capable of stabilizing a positive charge, such as allyl or benzyl, it will usually migrate even if it is not the most highly substituted group. When the carbon atom that migrates is an asymmetric (i.e. chiral) center, the reaction usually proceeds with retention of configuration.

When aldehydes are subjected to the reaction conditions the hydrogen atom attached to the carbonyl carbon usually migrates and gives rise to the carboxylic acid. If the group attached to carbon is particularly well suited to stabilize a positive charge however, that group may undergo migration to produce the formic acid ester (i.e. formate).

References:

Baeyer, A.; Villiger, V. “Einwirkung des Caro’schen Reagens auf Ketone” (abstract). Ber. 1899, 32 (3): 3625–3633.

Burton, J.W.; Clark, J.S.; Derrer, S.; Stork, T.C.; Bendall, J.G.; Holmes, A.B. “Synthesis of Medium Ring Ethers. 5. The Synthesis of (+)-Laurencin” (Abstract). J. Am. Chem. Soc. 1997, 119 (32): 7483–7498.

M. A. Goodman, M. R. Detty. “Selenoxides as Catalysts for Epoxidation and Baeyer-Villiger Oxidation with Hydrogen Peroxide” Synlett, 2006, 1100-1104.

S. Murahashi, S. Ono, Y. Imada, Angew. “Asymmetric Baeyer-Villiger Reaction with Hydrogen Peroxide Catalyzed by a Novel Planar-Chiral Bisflavin” Chem. Int. Ed., 2002, 41, 2366-2368.

G. A. Olah, Q. Wang, N. J. Trivedi, G. K. S. Prakash. “Baeyer-Villiger Oxidation of Ketones to Esters with Sodium Percarbonate/Trifluoroacetic Acid”, Synthesis, 1991, 739-740.

Michael Renz, Bernard Meunier (1999). “100 Years of Baeyer-Villiger Oxidations”. European Journal of Organic Chemistry 1999 (4): 737–750.

While in its traditional form the Finkelstein reaction involves the transformation of an alkyl chloride or bromide to the corresponding alkyl iodide via treatment with sodium iodide in acetone, the name also refers to the conversion of alkyl sulfonates to alkyl iodides. Alkyl sulfonates are readily prepared from alcohols.

Procedure:

A solution of 5-hexen-1-ol (5.0 g, 0.050 mol) and triethylamine (7.6 g, 0.076 mol) in 250 mL of dichloromethane is cooled under inert atmosphere in an ice salt bath to ca. -5 °C. Methanesulfonyl chloride (4.7 mL, 0.06 mol) is added dropwise with stirring. After stirring for an additional hour at ca. -5 °C, the reaction is washed with cold water, cold 10% aqueous hydrochloric acid, a cold saturated aqueous solution of sodium bicarbonate, and a cold solution of brine using approximately 75 mL for each wash. The organic fraction is dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to afford the mesylate which is used in the next step without further purification.

To the flask containing the unpurified mesylate product are added 100 mL of dry acetone followed by anhydrous sodium iodide (9.3 g, 0.06 mol) with stirring under inert atmosphere. After stirring at reflux for 4 hours the reaction mixture is cooled to ambient temperature. The resulting solution is concentrated in vacuo and treated with 25 mL of pentane and 25 mL of 10 % aqueous sodium thiosulfate. The organic fraction is washed with 25 mL of brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting crude material is then passed through a plug of silica gel and eluted with pentane. The solution is then concentrated in vacuo to afford the title compound.

http://www.orgsyn.org/orgsyn/prep.asp?prep=v81p0121

This synthesis is a straightforward example of a laboratory procedure for the Mannich reaction. All of the reagents are combined together and the reaction is performed in a single pot. The electrophilic iminium ion is generated by the acid-promoted condensation of formaldehyde and dimethylamine in the presence of acetophenone and is consumed as it is formed.

A solution of acetophenone (30.0 g, 28.3 mL, 0.25 mol), dimethylamine hydrochloride (26.5 g, 0.33 mol), and paraformaldehyde (9.9 g, 0.11 mol) is treated with 0.5 mL of concentrated hydrochloric acid in 40 mL of 95% ethanol. The solution is heated to reflux for 2 hours followed by rapid filtration through a preheated funnel. The warm solution is treated with 100 mL of acetone and is then allowed to cool to room temperature slowly. After cooling for 12 hours at 0 °C, the solution is filtered to afford the title compound. Alternatively the crude material can be purified via column chromatography.

http://www.orgsyn.org/orgsyn/prep.asp?prep=cv3p0305

United States Patent Office.

3,120,529

Patented Feb. 4, 1964

10-ACYL DERIVATIVES OF APOYOHIMBINE AND PROCESS THEREFOR

John Shavel, Jr., Mendham, N.J., assignor to Warner-Lambert Pharmaceutical Company, Morris Plains, N.J., a corporation of Delaware

No Drawing. Filed Feb. 10, 1961, Ser. No. 88,307
4 Claims. (Cl. 260—287)

The present invention relates to new and novel 10-acyl derivatives of apoyohimbine of the formula:

[see figure]

wherein R is the acyl radical of an aliphatic carboxylic acid containing 1 to 6 carbon atoms and to the non-toxic acid addition and quaternary ammonium salts thereof. This invention also relates to a method of producing these compounds.

The compounds of this invention are derivatives of the alkaloid apoyohimbine of the yohimbane series. They have interesting pharmacological activity and are useful as analgesics, tranquilizers and hypotensive agents. In addition, they are valuable intermediates in the production of other compounds of the yohimbane series. Included within the scope of this invention are such 10-acyl derivatives of apoyohimbine as 10-acetylapoyohmibine, 10-propionylapoyobimbine, 10-butyrylapoyohimbine, 10-valerylapoyohimbine and the like.

It has now been found that the compounds of my invention of the above formula may be prepared by treating the known apoyohimbine at between +25° C. and — 40° C. with an acid anhydride or acyl halide having R acyl groups in the presence of a Friedel-Crafts catalyst. The reaction is one of acylation with an R acyl group being substituted at the 10-position of the apoyohimbine starting material. The reaction is carried out in the liquid phase under anhydrous conditions in the presence of a Friedel-Crafts catalyst such as boron trifluoride, aluminum chloride, aluminum bromide, stannic chloride, ferric chloride, ferric bromide, hydrofluoric acid, polyphosphoric acid, titanium tetrachloride, sulfuric acid and the like, with boron trifluoride being particularly effective. The reaction mixture may also contain a carboxylic acid or a carboxylic acid ester corresponding to the acid halide or acid anhydride, that is, a carboxylic acid of the formula ROH, or an ester of the formula ROR₁, wherein R₁ is a lower alkyl group.

In carrying out the reaction the acylating agent (acid anhydride or acyl halide), either with, or without the corresponding acid or ester, is initially saturated with catalyst at a temperature between about —20° C. and + 10° C. The temperature of the mixture is then adjusted to the desired reaction temperature and the apoyohimbine starting material is added, either as a solid or as a solution in the acylating agent or in an inert organic solvent, such as rnethylene chloride, dioxan, tetrahydrofuran and the like. The reaction mixture is then stirred at the reaction temperature to completion and the product is recovered therefrom by conventional techniques of extraction, crystallization and chromatography.

It is to be understood that the new and novel compounds of this invention may be used as the free base or may be converted into the corresponding pharmaceutically acceptable non-toxic acid addition and quaternary ammonium salts. Exemplary of non-toxic acid addition salts are those formed with maleic, fumaric, benzoic, ascorbic, succinic, bismethylensalicylic, methylsulfonic, ethanedisulfonic, acetic, propionic, tartaric, salicyclic, citric, gluconic, lactic, malic, mandelic, cinnamic, citraconic, stearic, palmitic, itaconic, glyolic, benzenesulfonic, hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric and nitric acids. The acid addition salts may be prepared in the conventional manner, for example, by treating a solution or suspension of the free base in an organic solvent with the desired acid, and then recovering the salt which forms by crystallization techniques. The quaternary salts are prepared by heating a suspension of the base in a suitable solvent with a reactive alkyl halide such as methyl iodide, ethyl bromide, n-hexyl bromide, benzyl chloride or a reactive ester such as methyl sulfate, ethyl sulfate or methyl p-toluene sulfonate.

For therapeutic use, the new and novel compounds of this invention, as the free base, or as their acid addition or quaternary ammonium salts, may be formulated with conventional pharmaceutical carriers into dosage unit forms, such as tablets, capsules, elixirs, suppositories, solution, suspensions and the like. The following example is included in order further to illustrate the present invention:

Example

45 A mixture of 25 ml. glacial acetic acid and 150 ml. acetic anhydride is saturated with boron trifluoride at —10° C. by passing boron trifluoride into the solution for 15 minutes. The resulting mixture is cooled to —20° C. and 25 g. apoyohimbine are added. The reaction mixture is agitated for two hours and then is poured onto crushed ice. The suspension formed is made basic with ammonium hydroxide and extracted with chloroform. The extract is dried over sodium sulfate, filtered and evaporated to dryness. The residue, an oil, is crystallized from methanol to yield 19.9 g. of crystals, which on two further recrystallizations from methanol yield pure 10-acetylapoyohimbine (as the hydrate), M.P. 204-206° C. (dec.), [α]_D²⁵ +38° (pyridine, c.= l.l).

Analysis.—Calc.: C, 69.67; H, 7.12; N, 7.07. Found: 60 C, 69.73; H, 7.43; N, 7.35. It is understood that the foregoing detailed description is given merely by way of illustration and that many variations may be made therein without departing from the spirit of my invention.

Having described my invention, what I desire to secure by Letters Patent is:

1. A member selected from the group consisting of compounds of the formula:

[see figure]

wherein R is the acyl radical of an unsubstituted saturated aliphatic carboxylic acid of 1 to 6 carbon atoms and the pharmaceutically acceptable non-toxic acid addition and quaternary ammonium salts thereof with a compound selected from the group consisting of methyl iodide, ethyl bromide, n-hexyl bromide, benzyl chloride, methyl sulfate, ethyl sulfate and methyl p-toluene sulfonate.

2. 10-acetylapoyohimbine.

3. A method of preparing a compound of the formula:

[see figure]

wherein R is the acyl radical of an unsubstituted saturated aliphatic carboxylic acid of 1 to 6 carbon atoms which comprises treating apoyohimbine with a member selected from the group consisting of a carboxylic acid anhydride (R)2O and a carboxylic acid halide R—X wherein X is halogen and R has the meaning above at a temperature between +25° C. and —40° C. in the presence of a Friedel-Crafts catalyst.

4. A method according to claim 3 wherein said Friedel- Crafts catalyst is boron trifluoride.

No references cited.

PDF of United States Patent Number 3120529

UNITED STATES PATENT OFFICE.

CHRISTIAN RUDOLPH, OF HOCHST-ON-THE-MAIN, GERMANY, ASSIGNOR TO FARBWERKE, VORMALS MEISTER, LUCIUS & BRUNING, OF SAME PLACE.

MANUFACTURE OF ARTIFICIAL INDIGO.

SPECIFICATION forming part of Letters Patent No. 262,695, dated August 15, 1882.
Application filed April 18, 1882. (Specimens.)

To all whom it may concern:

Be it known that I, CHRISTIAN RUDOLPH, a citizen of Germany, residing at Hochst-on-the-Main, Germany, have invented certain new and useful Improvements in the Production of Artificial Indigo; and I do hereby declare that the following is a full, clear, and exact description of the invention, which will enable others skilled in the art to which it appertains to make and use the same.

My invention relates to an improvement in the production of artificial indigo. It consists in producing artificial indigo from benzaldehyde in the manner hereinafter to be described.

In producing monobenzylidenacetone I use the simplest known method, which is that described by Schmidt Claisen in “Berichte der Deutschen Chemischen Gesellschaft,”(1881, pp. 2,472,) — viz., from benzaldehyde and acetone in a weak solution of caustic soda. The next step is the conversion of the monobenzylidenacetone into its orthonitromono substitution product, which is done as follows: one part monobenzylidenacetone is mixed with the quintuple quantity of sulphuric acid. Into this mixture I pour slowly the calculated quantity of nitric acid at a temperature of 32.59° Fahrenheit, (0.15° centigrade,) and having a specific gravity of 1.46, dissolved in the double quantity of sulphuric acid. After this operation is completed the nitro compounds which remain in solution in the sulphuric acid are separated by pouring this solution into a large quantity of water. Said nitro compounds are afterward collected on a filter, and after being carefully washed in water they are dissolved in one and a half time the quantity of alcohol. After this solution has been standing for several hours the paranitromonobenzylidenacetone will have separated almost completely. The residual liquor or nitrate contains the orthonitrobenzylidenacetone, which can be obtained by distilling off the alcohol or by adding to the residual liquor the triple to quadruple quantity of water. If, now, the orthonitrobenzylidenacetone be digested for some time in an alcoholic soda-lye, (one part of the nitrate, five parts alcohol, and three parts of soda-lye of ten per cent.,) it becomes converted into a new substance, which, after the acidulation of the solution, can be separated by washing it out with ether.

From this substance I obtain, by heating its aqueous solution, or, better still, by adding alkalies — such as soda or caustic soda — to the solution, a considerable quantity of artificial indigo, which may be obtained in a pure state by further washing the same with water and alcohol.

Having thus described my invention, what I claim as new, and desire to secure by Letters Patent, is—

1. The process of manufacturing an artificial indigo from benzaldehyde, which consists in first converting the same into monobenzylidenacetone by the ordinary well-known method, then converting said monobenzylidenacetone into its orthonitro substitution derivative, separating this orthonitro product from isomers by crystallization, filtration, and distillation, and finally converting it into the indigo-blue coloring- matter by digestion in a weak alkaline lye.

2. A blue coloring-matter or dye-stuff (an artificial indigo) prepared by the process herein set forth. In testimony that I claim the foregoing as my own I affix my signature in presence of two witnesses.

CHRISTIAN RUDOLPH.

Witnesses:
JOSEPH EUGEN REVERDY,
ALBERT FROSCHMANN.

An example of the experimental procedure of the Dieckmann condensation is exemplified by the synthesis of 3-quinuclidone hydrochloride. This preparation involves two steps. In the first step, 1-((ethoxycarbonyl)methyl)-4-carbethoxypiperidine is treated with potassium ethoxide in refluxing toluene leading to the formation of the bridgehead bicyclic system via the Dieckmann condensation. In the second step, the intermediate is decarboxylated via treatment with concentrated hydrochloric acid.

Experimental:

3-Quinuclidone hydrochloride

1. Dieckmann Condensation:

Freshly cut potassium (40 g, 1.03 mol) is added to 165 mL of dry toluene under inert atmosphere. The mixture is heated at reflux until the potassium has melted. Absolute ethanol (63 mL, 49.3 g, 1.07 mol) is then added over 30 minutes to the rapidly stirred solution at reflux. Upon the disappearance of the potassium metal, the temperature of the reaction mixture is raised to 130 °C and 1-((ethoxycarbonyl)methyl)-4-carbethoxypiperidine (100 g, 0.411 mol) in 250 mL of dry toluene is added dropwise over 2 hours.

After heating at 130 °C for an additional 3 hours, the reaction mixture is cooled to 0 °C followed by slow addition of 250 mL 10M hydrochloric acid. The resulting mixture is then extracted with 10M hydrochloric acid (2X125 mL).

2. Decarboxylation:

The combined aqueous fractions are heated at reflux for 15 hours followed by the addition of 5 g of activated charcoal. The resulting mixture is then filtered and evaporated to dryness in vacuo. The crude product is then dissolved in 150 mL of water and saturated aqueous potassium carbonate is added very slowly to avoid foaming until the solution has become basic. The resulting solution is then treated with solid potassium carbonate until a slurry is obtained, followed by extraction with diethyl ether (4X200 mL). The combined organic fractions are then treated with calcined potassium carbonate. After 60 minutes the mixture is filtered and concentrated in vacuo. The resulting solid is then treated with 75 g of ice and 10M hydrochloric acid (65 mL, 75 g) followed by evaporation to dryness. The resulting material is then purified via recrystallization from hot water and boiling isopropanol.

4-(Diethylamino)butan-2-one

The Mannich Reaction remains a popular tool in organic synthesis. It performs a one-carbon homologation and an amination in a single step and is involved in the biosynthetic pathways in the synthesis of many alkaloid natural products.

A very simple example of the reaction is the synthesis of 4-(diethylamino)butan-2-one. A solution of diethylamine hydrochloride (88.0 g, 0.80 mol), paraformaldehyde (34.0 g, 1.13 mol), acetone (300 mL, 4.1 mol), 40 mL of methanol, and 0.1 mL of concentrated hydrochloric acid is stirred at reflux using an oil bath for 12 hours. The reaction mixture is then allowed to cool to ambient temperature. A solution of sodium hydroxide (32.5 g) in 150 mL is then cooled to 0 °C and added to the reaction mixture. The resulting solution is extracted with diethyl ether (3X100 mL) and the combined organic fractions are washed with brine. The combined aqueous layers are then washed with diethyl ether (2X75 mL).

The combined organic fractions are dried over magnesium sulfate, filtered, and purified via vacuum distillation. The title compound is collected in fractions at approximately 63-67 °C at 15 mm of pressure.