Nucleophilic secondary amines

The Pdl2 - KI system is an excellent catalyst also for promoting the oxidative monoaminocarbonylation of terminal alkynes, carried out in the presence of a nucleophilic secondary amine in 1,4-dioxane as the solvent (Eq. 49) [309],... 

In this section, emphasis is placed on reactions which are characteristic of the ring systems present and do not depend on the presence of particular substituents. In addition, the well-known and widely applied behavior of morpholine as a basic and nucleophilic secondary amine is not covered and neither is the aniline-like nucleophilic and basic behavior of dihydrobenzoxazines save for a few special examples. 

Vinyl substitution occurs with conjugated dienes as well as with alkenes, employing aryl-, vinyl-, methyl-, alkoxycarbonyl- or benzyl-mercury reagents and lithium tetrachloropalladate(II), but the products are usually rr-allylpalladium complexes if the reactions are carried out under mild conditions (equation 8).24,25 The ir-allylic complexes may be decomposed thermally to substituted dienes26 or reacted with nucleophiles to form allylic derivatives of the nucleophile. Secondary amines, for example, react to give tertiary allylic amines in modest yields, along with dienes and reduced dienes (equation 9).25... 

Considering functionalized olefins first, only three two-carbon reactants are listed above. Ethylene itself can give only terminal double bonds when elimination is facile and triethylamine functions as the base. If nucleophilic secondary amines are necessary, ethylene produces internal amines almost entirely. Aryl halides react well with ethylene to produce styrene derivatives. 

Strongly nucleophilic secondary amines may give to undesired side-reactions. Thus haloacetylenes bearing carbonyl groups react eagerly with secondary amines but the reaction cannot be arrested at the ynamine stage ketene N,N-acetals are formed instead (24) 48). 

Transamination of amide acetals is possible and of synthetic value if high boiling, strongly nucleophilic secondary amines are to be introduced. Ketene 0,iV-acetals add alcohols to yield amide acetals (468 equation 216). From tetrakis(dimethylamino)ethylene and methanol a mixture of amide acetals, e.g. (469) and (470 equation 217), is formed. Azavinylogous formamide acetals (471 equation 218) are accessible by the action of formide acetals on tris(formylamino)methane or form-amide. ... 

Insertions of vinylic palladium halides with olefins not conjugated with carbonyl groups is more complex. Rearrangement of the initial insertion product to a i-allyl-palladium derivative usually occurs as in Eq. (p). Since the a -allylic complexes are relatively stable, catalytic reactions to form dienes with tertiary amines as bases are slow and inefficient . A useful catalytic reaction occurs, however, if a nucleophilic secondary amine is used as base instead of the tertiary amine. The a-allylic palladium intermediates are attacked by the amine to form tertiary allylic amines and regenerate the catalyst ... 

Asymmetric reductive amination of a dialkyl ketone by an alkylamine, catalysed by (193), formed the diazepane ring (194) with >97% yield and >94% ee. Purging of the by-product CO2 resulted in increased rate and almost quantitative yield of the product which otherwise formed carbamates with CO2 an adverse effect on the equilibrium between Ru-hydride and Ru-formate (catalyst forms) was thereby avoided. The rate could also be accelerated by trapping with nucleophilic secondary amines. ... 

One of the earliest reports for hydroamination by Coulson [86] in 1971 was the hydroamination of ethylene with nucleophilic secondary amines using Rh and Ir salts as the metal catalyst These initial developments sparked intense investigation into this transformation, and while ample well-characterized examples of the stoichiometric addition of amines to ethylene complexes of late transition metals have been disclosed [159], advances in catalytic versions using ethylene as a substrate remains an unsolved problem. 

In a similar transformation, oxidative aminocarbonylation of alkyl- and aryl-substituted 1-alkynes is catalyzed by Pdl2/KI under relatively mild conditions to afford 2-ynamides 64 in good yield (Scheme 10.20) [60]. Nucleophilic secondary amines were required as amines of low basicity were unreactive and primary amines gave complex reaction mixtures. The key intermediate in the mono-aminocarbonylation was proposed to be an alkynyl palladium iodide that undergoes CO insertion followed by nucleophilic abstraction by amine to generate the product and Pd(0), which is reoxidized by iodine (2HI + I/2O2 = I2 + H2O). Small amounts of diaminocarbonylation product (maleic... 

Amines are powerful nucleophiles which react under neutral or slightly basic conditions with several electron-accepting carbon reagents. The reaction of alkyl halides with amines is useful for the preparation of tertiary amines or quaternary ammonium salts. The conversion of primary amines into secondary amines is usually not feasible since the secondary amine tends towards further alkylation. 

A special problem arises in the preparation of secondary amines. These compounds are highly nucleophilic, and alkylation of an amine with alkyl halides cannot be expected to stop at any specifle stage. Secondary amides, however, can be monoalkylated and lydrolyzed or be reduced to secondary amines (p. 11 If.). In the elegant synthesis of phenyl- phrine an intermediate -hydroxy isocyanate (from a hydrazide and nitrous acid) cyclizes to pve an oxazolidinone which is monomethylated. Treatment with strong acid cleaves the cyclic irethan. 

Based on the above-mentioned stereochemistry of the allylation reactions, nucleophiles have been classified into Nu (overall retention group) and Nu (overall inversion group) by the following experiments with the cyclic exo- and ent/n-acetales 12 and 13[25], No Pd-catalyzed reaction takes place with the exo-allylic acetate 12, because attack of Pd(0) from the rear side to form Tr-allyl-palladium is sterically difficult. On the other hand, smooth 7r-allylpalladium complex formation should take place with the endo-sWyWc acetate 13. The Nu -type nucleophiles must attack the 7r-allylic ligand from the endo side 14, namely tram to the exo-oriented Pd, but this is difficult. On the other hand, the attack of the Nu -type nucleophiles is directed to the Pd. and subsequent reductive elimination affords the exo products 15. Thus the allylation reaction of 13 takes place with the Nu nucleophiles (PhZnCl, formate, indenide anion) and no reaction with Nu nucleophiles (malonate. secondary amines, LiP(S)Ph2, cyclopentadienide anion). 

Hydroxylysine (328) was synthesized by chemoselective reaction of (Z)-4-acet-oxy-2-butenyl methyl carbonate (325) with two different nucleophiles first with At,(9-Boc-protected hydroxylamine (326) under neutral conditions and then with methyl (diphenylmethyleneamino)acetate (327) in the presence of BSA[202]. The primary allylic amine 331 is prepared by the highly selective monoallylation of 4,4 -dimethoxybenzhydrylamine (329). Deprotection of the allylated secondary amine 330 with 80% formic acid affords the primary ally-lamine 331. The reaction was applied to the total synthesis of gabaculine 332(203]. 

Ammonia can act as a nucleophile toward primary and some secondary alkyl halides to give primary alkylamines Yields tend to be modest because the primary amine IS itself a nucleophile and undergoes alkylation Alkylation of ammonia can lead to a mixture containing a primary amine a secondary amine a tertiary amine and a quaternary ammonium salt... 

Alkylation (Section 22 12) Amines act as nucleophiles toward alkyl halides Pri mary amines yield secondary amines secondary amines yield tertiary amines and tertiary amines yield quaternary ammonium salts... 

Primary cycloaUphatic amines react with phosgene to form isocyanates. Reaction of isocyanates with primary and secondary amines forms ureas. Dehydration of ureas or dehydrosulfuri2ation of thioureas results in carhodiimides. The nucleophilicity that deterrnines rapid amine reactivity with acid chlorides and isocyanates also promotes epoxide ring opening to form hydroxyalkyl- and dihydroxyalkylaniines. Michael addition to acrylonitrile yields stable cyanoethylcycloalkylarnines. 

Rifamycin S also undergoes conjugate addition reactions to the quinone ring by a variety of nucleophiles including ammonia, primary and secondary amines, mercaptans, carbanions, and enamines giving the C-3 substituted derivatives (38) of rifamycin SV (117,120,121). Many of the derivatives show excellent antibacterial properties (109,118,122,123). The 3-cycHc amino derivatives of rifamycin SV also inhibit the polymerase of RNA tumor vimses (123,124). 

Alkoxy-2,l-benzisoxazole-4,7-diones undergo ready nucleophilic displacement of the 3-alkoxy substituent, yielding 3-alkylamino and 3-dialkylamino derivatives with primary and secondary amines, respectively (67TL4313). In this instance the 4-carbonyl group apparently provides an activating effect. 

Secondary amines cannot form imines, and dehydration proceeds to give carbon-carbon double bonds bearing amino substituents (enamines). Enamines were mentioned in Chapter 7 as examples of nucleophilic carbon species, and their synthetic utility is discussed in Chapter 1 of Part B. The equilibrium for the reaction between secondary amines and carbonyl compounds ordinarily lies far to the left in aqueous solution, but the reaction can be driven forward by dehydration methods. 

Generally, isolated olefinic bonds will not escape attack by these reagents. However, in certain cases where the rate of hydroxyl oxidation is relatively fast, as with allylic alcohols, an isolated double bond will survive. Thepresence of other nucleophilic centers in the molecule, such as primary and secondary amines, sulfides, enol ethers and activated aromatic systems, will generate undesirable side reactions, but aldehydes, esters, ethers, ketals and acetals are generally stable under neutral or basic conditions. Halogenation of the product ketone can become but is not always a problem when base is not included in the reaction mixture. The generated acid can promote formation of an enol which in turn may compete favorably with the alcohol for the oxidant. 

Mononitration of a mixture of J- and 4 chlorobenzotnfluondes followed by nucleophilic substitution by hydroxide, ammonia, or a primary or secondary amine in dimethylformamide, leads to 5 chloro 2 nitrobenzotrifluoride The 4-chloro-3-nitro isomer selectively reacts and can be removed as a water-soluble phenoxide [19] (equation 16)... 

The addition of primary amines to fluoroolefins under anhydrous conditions yields imines The hexafluoropropene dimer, perfluoro-2-methyl-2-pcntcne, and ten butylamine react to yield a mixture of two compounds m a 9 4 ratio [4] (equation 3) rather than just the major keteiiimme-imine, as previously reported [5] It IS claimed that this result is possible by means of isomerization to the terminally unsaturated difluoromethylene isomer prior to nucleophilic attack Secondary amines add to fluoroolefins under anhydrous conditions to give fluonnated ternary amines m good yields If the fluoroolefin is added to the amine without cooling the reaction mixture, or if an excess of the secondary armne is used, there is a tendency toward dehvdrofluonnation of the ternary amine The products... 

Nucleophilic addition of amines to aldehydes and ketones (Sections 17.10, 17.11) Primary amines undergo nucleophilic addition to the carbonyl group of aldehydes and ketones to form carbinol-amines. These carbinolamines dehydrate under the conditions of their formation to give A/-substituted imines. Secondary amines yield enamines. 

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