Burgess Reagent Synthesis CAS 29684-56-8

Burgess Reagent Synthesis is usually done in these steps: First, chlorosulfonyl isocyanate (ClSO₂NCO) is reacted with anhydrous methanol at low temperatures (-78°C to 0°C) in anhydrous diethyl ether or dichloromethane to produce methyl chlorosulfonyl carbamate (ClSO₂NHCOOCH₃). This step requires strict control of moisture content; Next, triethylamine is added dropwise to the reaction system under an inert atmosphere, reacting with the intermediate to form a crystalline solid. The temperature must be maintained below 0°C to prevent side reactions; After the reaction is complete, the triethylamine hydrochloride salt is removed by filtration, and the filtrate is concentrated under reduced pressure to obtain a white to off-white solid crude product. Finally, high-purity Burgess reagent is obtained through recrystallization (commonly using a mixture of anhydrous ether and pentane as the solvent) or column chromatography purification. The entire synthesis process must be strictly protected from moisture, as this reagent is extremely sensitive to water. The yield typically ranges between 60–80%. Its structure can be characterized by ¹H NMR (δ 1.2–1.4 ppm for multiple peaks of triethylmethyl, δ 3.7 ppm for a single peak of methoxy) and IR (strong carbonyl absorption peak near 1720 cm⁻¹). This reagent is widely used as a strong dehydrating agent in organic transformation reactions such as the dehydration of alcohols to alkenes and the dehydration of amides to nitriles.

Melting point 76-79 ° C (lit.), Density 1.3023 (rough estimate), Refractive index 1.6300 (estimated), Storage conditions - 20 ° C, Solubility in organic solvents, Morphology crystal powder, Color slightly yellow, Sensitivity, BRN 1432131, InChIKeyYSHOWEKUVWPFNR-UHFFFAOYSA-N, Hazard symbol (GHS), GHS07, Warning word, Hazard description h315-h319-h335, Precautions p264-p280-p302 + p352 + p332 + P313 + p362 + p364-p305 + P351 + P338 + P337 + p313-p261-p305 + P351 + p338-p280a-p304 + p340-p405-p501a, Dangerous goods sign Xi, Hazard category code 36 / 37 / 38, Safety instructions 26-36-37 / 39, WGK Germany 3, F 10-21, TSCA No

The primary use of Burgess reagent is the dehydration of secondary and tertiary alcohols to form olefins. In the absence of other groups, alcohols are dehydrated to olefins. For example, in (+) - Narciclsine. In the total synthesis, RI gby synthesized advanced synthetic intermediates through a dehydrating agent. This method is also used by Nicolaou for the synthesis of efrotomycin, Uskokovic for the synthesis of pracastatin and Holton for the synthesis of taxol. Burgess is actually more used for the dehydration and cyclization of hydroxyamide or hydroxythioamide this year. For example, in the total synthesis of antibiotic (-) - madumycin II, Meyers constructed an oxazoline ring system with Burgess Reagent Synthesis, which was transformed into an oxazoline ring by dehydrogenation. Many complex natural products contain oxazole rings, which are mostly constructed by this method.

The name of this chemical comes from the contribution of a chemist named Edward Meredith Burgess, an American chemist, who named the chemical reagent after him. He specializes in organic chemistry, emphasizing methods, structure and photochemistry. His most famous is Burgess reagent, namely n - (triethylammonium sulfonyl) methylcarbamate, which is an internal salt of carbamates and is used as a dehydrating agent in organic chemistry. It is soluble in most organic solvents. Synthesis of Burgess reagent: it is prepared by the reaction of chlorosulfonyl isocyanate with methanol and triethylamine in.

Burgess reagent, also known as N - [(Dimethylamine) sulfonyl] metal] methane, is a compound with important application value in organic chemistry.
1. Dehydrating agent: The most common use is as a dehydrating agent for the preparation of nitrile compounds. Due to its ability to effectively remove moisture from amides and convert them into nitriles, it has important application value in organic synthesis.
2. Hydroxyl dehydration to prepare olefins: can be used in the reaction of hydroxyl dehydration to prepare olefins. Under appropriate conditions, alcohol compounds can undergo cis elimination dehydration reactions to generate corresponding olefins.
3. Dehydration of amides to prepare cyano groups: It can also be used in the reaction of dehydration of amides to prepare cyano groups. Through its reaction, amides can be converted into corresponding nitrile compounds.
4. Preparation of isocyanate from formamide: Under certain conditions, it can be used in the dehydration of formamide to prepare isocyanate. Isocyanide is an important intermediate in the synthesis of certain drugs and dyes.
5. Preparation of primary amine from amino acid esters: It can also be used in the reaction of preparing primary amine from amino acid esters. By reacting with it, carbamate can be converted into the corresponding primary amine.

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The detailed steps for synthesizing a Burgess reagent are as follows:

1. Prepare reagents and solvents: anhydrous methanol, anhydrous benzene, ClSO2NCO, anhydrous triethylamine, and anhydrous THF.

2. Heat a mixture of anhydrous methanol (19.2g, 0.6 mol) and anhydrous benzene (40 mL) under stirring until slightly boiling to remove any moisture.

3. Slowly add a mixture of anhydrous benzene (200 mL) and ClSO2NCO (85g, 52.3 mL, 0.6 mol) to a slightly boiling mixture of methanol and benzene within 30-40 minutes, controlling the temperature at 10-15 ℃. After adding, continue stirring at room temperature for 2 hours.

4. Add the above reaction solution to 1000 mL of anhydrous benzene and dilute to obtain a relatively dilute reaction solution.

5. Slowly add a mixture of 190 mL anhydrous triethylamine and 250 mL anhydrous benzene to the diluted reaction solution at 10-15 ℃, which takes about 40 minutes to complete. After adding, continue stirring at room temperature for 2 hours.

6. After the reaction, a large amount of solid precipitation was observed. Filter out the solid and wash it separately with anhydrous benzene (200 mL) and anhydrous THF (200 mL).

7. After concentrating the filtrate, add an appropriate amount of anhydrous THF to dissolve the solid. Then perform recrystallization operation to obtain Burgess reagent.

The following is the chemical equation for the above synthesis method:

Heating and dehydration of a mixture of methanol and benzene:

CH₃OH → CH₃ + H₂O

Reaction of ClSO2NCO with a mixture of methanol and benzene:

ClSO₂NCO+CH₃OH → CH₃NHSO₂Cl

ClSO₂NCO+C₆H₆ → C₆H₅NHSO₂Cl

Reaction between triethylamine and ClSO2NCO:

C₆H₅NHSO₂Cl + N (C₂H₅)₃ → C₆H₅NHSO₂N(C₂H₅) ₃+HCl

Recrystallization:

C₆H₅NHSO₂N (C₂H₅)₃ → C₆H₅NHSO₂N (C₂H₅)₃ · xH₂O

1. Selective reaction of alcohols
Burgess Reagent Synthesis is mainly used to convert secondary and tertiary alcohols with adjacent protons into olefins. However, the reaction effect on primary alcohols is not satisfactory. This may be due to the relatively difficult removal of hydroxyl hydrogen atoms from primary alcohols, resulting in slower reaction rates or lower yields. Therefore, when using Burgess reagents for alcohol dehydration reactions, it is necessary to consider the structure and properties of the alcohol in order to select appropriate reaction conditions and catalysts.

2. Security issues
Burgess reagent, as a chemical reagent, has certain toxicity. During use, relevant safety operating procedures should be followed, and appropriate protective equipment such as lab coats, gloves, goggles, etc. should be worn. At the same time, operations should be carried out in a well ventilated environment to avoid inhaling toxic gases or damaging the skin. In addition, the storage of Burgess reagents should also comply with relevant regulations, avoiding direct sunlight and high temperature environments.

3. Potential impact on the environment
The use of Burgess reagents may have potential environmental impacts. For example, the waste liquid and exhaust gas generated during the synthesis process may contain harmful substances that need to be properly treated to avoid harm to the environment and ecosystem. Therefore, when using Burgess reagents for organic synthesis, attention should be paid to raising environmental awareness and taking necessary measures to reduce the generation and emission of waste.

4. Interaction with other reagents
Burgess reagents may produce some unwanted side reactions when interacting with other reagents. For example, when reacting with compounds containing active hydrogen atoms, hydrogen atom transfer reactions may occur, leading to product complexity or reduced yield. In addition, Burgess reagents may decompose and produce toxic gases or explosive substances under certain conditions, so strict control of reaction conditions and operating steps is required during use.

5. Impact on human health
Long term exposure or inhalation of Burgess reagents may have adverse effects on human health. For example, it may cause respiratory irritation, skin inflammation, or allergic reactions. Therefore, when using Burgess reagents, staff need to receive professional safety training, understand the properties and hazards of the reagents, master the correct operating methods and emergency response measures. At the same time, regular health check ups should be conducted to promptly identify and address potential health issues.

Burgess reagent, also known as methyl N - (triethylammonium sulfate) carbamate, is an important organic synthesis reagent widely used in dehydration reactions, especially for converting alcohols to olefins and amides to nitriles. Its high reactivity and selectivity make it an important tool in modern organic chemistry. Before the discovery of Burgess reagents, chemists had already realized the importance of converting alcohols into olefins or amides into nitriles, but the dehydration methods at that time were often harsh, had many side reactions, or had low yields. Early chemists used strong acids (such as concentrated sulfuric acid) to catalyze the dehydration of alcohols, but this method had many side reactions and could easily lead to rearrangement or polymerization of carbocations.
P ₂ O ₅ (Phosphorus pentoxide) dehydration: Suitable for dehydration of certain alcohols, but the reaction is intense, difficult to control, and unfriendly to sensitive substrates.
POCl ∝ (phosphorus oxychloride) or SOCl ₂ (thionyl chloride): commonly used for chlorination of alcohols, but less efficient in dehydration reactions.
In the 1950s and 1960s, with the development of organic synthetic chemistry, chemists hoped to find a milder and more selective dehydration reagent to meet the synthesis needs of complex molecules such as natural products and pharmaceutical intermediates. This demand ultimately drove the discovery of Burgess reagents. The discovery of Burgess reagent is attributed to American chemist Edward M. Burgess (1932-2014), who systematically studied the reactivity of sulfonyl carbamate compounds in the 1970s and ultimately developed this highly efficient dehydration reagent. Burgess conducts organic chemistry research at Rutgers University and Ohio State University, focusing on the reactivity of amino esters and sulfonyl compounds. He noticed that certain sulfonyl protected amino acid esters can release isocyanates (R-N=C=O) when heated, and further studied their potential as dehydrating agents. In 1973, Burgess published a paper in the Journal of the American Chemical Society (JACS) reporting a novel dehydration reagent, methyl N - (triethylammonium sulfonyl) carbamate (now known as Burgess reagent).
This reagent can be synthesized through the following steps:

ClSO2​NCO+Et3​N→Et3​N+SO2​NCO−MeOH​Et3​N+SO2​NHCOOMe−
This reagent can efficiently achieve the conversion of alcohols to olefins and amides to nitriles under mild conditions (usually 0-25 ° C), with minimal by-products. Burgess proposed that the dehydration of the reagent may occur through the following steps: the reagent reacts with an alcohol (R-OH) to form a sulfonic acid ester intermediate. The intermediate undergoes beta elimination under heating or alkaline conditions, generating olefins and releasing SO ₂, CO ₂, and triethylamine.

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