Sulfonamides secondary

Phenols. Phenols are unreactive toward chloroformates at room temperature and at elevated temperatures the yields of carbonates are relatively poor (< 10%) in the absence of catalysis. Many catalysts have been claimed in the patent Hterature that lead to high yields of carbonates from phenol and chloroformates. The use of catalyst is even more essential in the reaction of phenols and aryl chloroformates. Among the catalysts claimed are amphoteric metals or thek haUdes (16), magnesium haUdes (17), magnesium or manganese (18), secondary or tertiary amines such as imidazole (19), pyridine, quinoline, picoline (20—22), heterocycHc basic compounds (23) and carbonamides, thiocarbonamides, phosphoroamides, and sulfonamides (24). 

NaAlH2(0CH2CH20CH3)2, benzene or toluene, reflux, 20 h, 65-75% yield. Note that LiAlH4 does not cleave sulfonamides of primary amines those from secondary amines must be heated to 120°. 

Amides can also be alkylated with diazo compounds, as in 10-49. Salts of sulfonamides (ArS02NH ) can be used to attack alkyl halides to prepare N-alkyl sulfonamides (ArS02NHR) that can be further alkylated to ArS02NRR. Hydrolysis of the latter is a good method for the preparation of secondary amines. Secondary amines can also be made by crown ether assisted alkylation of F3CCONHR (R = alkyl or aryl) and hydrolysis of the resulting F3CCONRR. ... 

Sulfonic esters are most frequently prepared by treatment of the corresponding halides with alcohols in the presence of a base. The method is much used for the conversion of alcohols to tosylates, brosylates, and similar sulfonic esters. Both R and R may be alkyl or aryl. The base is often pyridine, which functions as a nucleophilic catalyst, as in the similar alcoholysis of carboxylic acyl halides (10-21). Primary alcohols react the most rapidly, and it is often possible to sulfonate selectively a primary OH group in a molecule that also contains secondary or tertiary OH groups. The reaction with sulfonamides has been much less frequently used and is limited to N,N-disubstituted sulfonamides that is, R" may not be hydrogen. However, within these limits it is a useful reaction. The nucleophile in this case is actually R 0 . However, R" may be hydrogen (as well as alkyl) if the nucleophile is a phenol, so that the product is RS020Ar. Acidic catalysts are used in this case. Sulfonic acids have been converted directly to sulfonates by treatment with triethyl or trimethyl orthoformate HC(OR)3, without catalyst or solvent and with a trialkyl phosphite P(OR)3. ... 

The treatment of sulfonyl chlorides with ammonia or amines is the usual way of preparing sulfonamides. Primary amines give N-alkyl sulfonamides, and secondary amines give N,N-dialkyl sulfonamides. The reaction is the basis of the Hinsberg test for distinguishing between primary, secondary, and tertiary amines. N-Alkyl sulfonamides, having an acidic hydrogen, are soluble in alkali, while N,N-dialkyl sulfon-... 

Treatment with sodium hypochlorite or hypobromite converts primary amines into N-halo- or N,N-dihaloamines. Secondary amines can be converted to N-halo secondary amines. Similar reactions can be carried out on unsubstituted and N-substituted amides and on sulfonamides. With unsubstituted amides the N-halo-gen product is seldom isolated but usually rearranges (see 18-13) however, N-halo-N-alkyl amides and N-halo imides are quite stable. The important reagent NBS is made in this manner. N-Halogenation has also been accomplished with other reagents, (e.g., sodium bromite NaBr02) benzyltrimethylammonium tribromide (PhCH2NMe3 Br3"), and NCS. The mechanisms of these reactions involve attack by a positive halogen and are probably similar to those of 12-47 and 12-49.N-Fluorination can be accomplished by direct treatment of amines °° or... 

Saleh, M. and Pok, F., Separation of primary and secondary amines as their sulfonamide derivatives by reversed-phase high-performance liquid chromatography, /. Chromatogr. A, 763, 173, 1997. 

A-Protected amines were assembled on solid-phase via sulfonamide-based handle 58 (Scheme 27) [67]. Tertiary sulfonamides were generated upon reaction with allylic, benzylic and primary alcohols under Mitsu-nobu conditions. Secondary amines were released from the support using mild nucleophilic conditions such as treatment with thiophenol and potassium carbonate. 

The group of Caddick has described the synthesis of functionalized sulfonamides by microwave-assisted displacement of pentafluorophenyl (PFP) sulfonate esters with amines (Scheme 6.159) [306]. Their ease of handling due to their higher crystallinity, along with their long shelf-life and their ability to react under aqueous reaction conditions, makes these an attractive alternative to sulfonyl chlorides. The microwave-assisted reaction of alkyl PFP esters with amines is a facile process which proceeds cleanly and in good yields with a number of different amines, including primary, secondary, and sterically hindered amines, and anilines. Optimum condi-... 

There are examples of nucleophilic displacement of halide from halo-1,2,5-thiadiazoles by ammonia, primary alkylamines, secondary alkylamines, arylamines, sulfonamides, and phthalimide <1984CHEC(6)513, 1996CHEC-II(4)355>, but the reactions often require high temperatures and excess of the nucleophile. 

Dithiocarbamates have been prepared by the reaction of carbon disulfide with primary or secondary amines. The addition of DMF, cesium carbonate and a sulfonamide to the crude dithiocarbamate, give di-, tri- and tetra-substituted thioureas in 65-76% yields (Scheme 41).121... 

Although the ruthenium allenylidene complexes 2 have not yet been as comprehensively studied as their carbene counterparts, they also seem to exhibit a closely related application profile [6]. So far, they have proven to tolerate ethers, esters, amides, sulfonamides, ketones, acetals, glycosides and free secondary hydroxyl groups in the substrates (Table 1). 

N-Tosyl amides and lactams.2 DCC in combination with 4-pyrrolidinopyri-dine (4-PPy) effects condensation of carboxylic acids with secondary sulfonamides to provide N-tosyl amides in 75-90% yield. The intramolecular version of this reaction provides 4-, 5-, and 6-membered N-tosyl lactams in 60-90% yield. 

Sulfonyl chloride 2 is used to protect primary and secondary amines as the corresponding sulfonamide.8 The SES-protected amines are stable compounds that can be readily cleaved by fluoride sources to regenerate the parent amine. 

The next series of four preparations describe the synthesis and/or use of recently introduced reagents for functional group protection. The first in this series describes the preparation of 2-TRIMETHYLSILYLETHANE-SULFONYL CHLORIDE (SEC-C1), an effective reagent for protection of primary and secondary amines as the corresponding sulfonamide. The SES-protected amines are stable intermediates which can be readily purified treatment with CsF in DMF or TBAF in acetonitrile liberates the parent amine. The preparation of (l/S,2,S)-METHYL-30,40-(l, 2 -DIMETHOX YCYCLOHEXANE -l, 2 - DIYL) - a -d -M ANNOPYRANO-... 

Griffiths-Jones, C.M. and Hopkin, M.D. and Jbnsson, D. and Ley, S.V. and Tapolczay, D.J. and Vickerstaffe, E. and Ladlow, M. (2007). Fully Automated Flow-Through Synthesis of Secondary Sulfonamides in a Binary Reactor System. J. Comb. Chem., 9, 422-430. 

The instability of primary nitramines in acidic solution means that the nitration of the parent amine with nitric acid or its mixtures is not a feasible route to these compounds. The hydrolysis of secondary nitramides is probably the single most important route to primary nitramines. Accordingly, primary nitramines are often prepared by an indirect four step route (1) acylation of a primary amine to an amide, (2) A-nitration to a secondary nitramide, (3) hydrolysis or ammonolysis with aqueous base and (4) subsequent acidification to release the free nitramine (Equation 5.17). Substrates used in these reactions include sulfonamides, carbamates (urethanes), ureas and carboxylic acid amides like acetamides and formamides etc. The nitration of amides and related compounds has been discussed in Section 5.5. 

Tab. 10.6 summarizes the application of this transformation to a variety of racemic secondary allylic carbonates using the lithium anion of 4-methoxy-N-(p-toluidine)-benzene sulfonamide. The excellent regioselectivity obtained for this type of substitution provided an important advance in the synthesis of N-(arylsulfonyl)anihnes using the metal-catalyzed allyhc amination reaction. The allyhc alcohol derivatives examined... 

Amines may also behave as nucleophiles (Lewis bases). Primary amines are stronger nucleophiles than secondary amines, which, in turn, are stronger nucleophiles than tertiary amines. As nucleophiles, amines attack acid chlorides to form amides. Later in this chapter you see that they re important in the formation of sulfonamides. 

Secondary amines react to form an N,N-disubstituted sulfonamide (Figure 13-38). 

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