Nitrogen nucleophiles,

Thiirane 1-oxide undergoes acid-catalyzed ring opening by ethanethiol to give ethyl 2-ethylthioethyl disulfide. Treatment of thiirane 1,1-dioxide with thiolate anions, sodium sulfide or thiourea gives /3-mercaptosulfinic acid derivatives (75S55). Thiiranium ions are attacked at carbon by most sulfur nucleophiles (79ACR282), but see Section 5.06.3.4.3 for exceptions. 

This will be important when we learn about carbohydrate chemistry in Chapter 24. Glucose, the major source of energy for the body, exists primarily as a cyclic hemiacetal  

14 Compound A has molecularfoimula C8H14O2. Upon treatment with catalytic acid, compound A is converted into the cyclic hemiacetal. Identify the structure of compound A. 

In mildly acidic conditions, an aldehyde or ketone will react with a primary amine to form an imine  

Imines are compounds that possess a C=N double bond and are common in biological pathways. Imines are also called Schiff bases, named after Hugo Schiff, a German chemist who first described their formation. A six-step mechanism for imine formation is shown in Mechanism 20.6. It is best to divide the mechanism conceptually into two parts (just as we did to conceptualize the mechanism of acetal formation) (1) The first three steps produce an intermediate called a carbinolamine and (2) the last three steps convert the carbinolamine into an imine  

Proton transfer Nucleophilic attack Proton transfer 

The alkylation of neutral amines by halides is complicated from a synthetic point of view by the possibility of multiple alkylation that can proceed to the quaternary ammonium salt in the presence of excess alkyl halide. 

Even with a limited amount of the alkylating agent, the equilibria between protonated product and the neutral starting amine are sufficiently fast that a mixture of products may be obtained. For this reason, when monoalkylation of an amine is desired, the reaction is usually best carried out by reductive amination, a reaction that is discussed in Chapter 5. If complete alkylation to the quaternary salt is desired, use of excess alkylating agent and a base to neutralize the liberated acid normally results in complete reaction. 

Amides are weakly nucleophilic and react only slowly with alkyl halides. The anions of amides are substantially more reactive. The classical Gabriel procedure for synthesis of amines from phthalimide is illustrative.58 

The enhanced acidity of the NH group in phthalimide permits formation of the anion, which is readily alkylated by alkyl halides or tosylates. The amine can then be liberated by reaction of the substituted phthalimide with hydrazine. 

It has been found that the deprotection phase of the Gabriel synthesis is accelerated by inclusion of NaOH.61 

CHAPTER 3 FUNCTIONAL GROUP INTERCONVERSION BY NUCLEOPHILIC SUBSTITUTION 

Conjugate additions of carbamates to a, P-unsaturated enones require - apart from metal halide - TMSC1 as a stoichiometric additive [96]. The addition of ethyl carbamate to cyclohexenone (41h) requires only 50mol% TMSC1, which was an exceptionally low amount compared with other Michael acceptors. With 10 mol% of the catalyst, the yield of 3-aminocyclohexenone derivative 66 was good (93%) [97], Aza-Michael reactions also proceed in aqueous media with good results if Co(II), 

Reaction of P-functionalized alkynyliodonium triflates, 11, with LiNPh2 results in various push-pull ynamines, 67, in 43-66% isolated yields [56] [Eq. (27)]. Treatment of alkynyliodonium tetrafluoroborates with Me3SiN3 in wet CH2CI2 results in the stereoselective formation of (Zy-P-azidovinyl iodonium salts 68 [Eq. (28)] in 50-91 % isolated yields [57]. 

Zinc azide bis-pyridine complex (the more stable form of zinc azide) behaves as an excellent nucleophile in the Mitsunobu reaction and furnishes (R)-azidoester 96 in high yield with complete inversion at C-2 [38]. 

The reaction of ethyl L-lactate with A -benzyloxycarbonylbenzamide under Mitsunobu conditions produces 109 stereospecifically. Removal of the Cbz protecting group under acidic conditions gives (R)-( — )-A -benzoylalanine ethyl ester (110) [39], A host of differentially A,A-diprotected (R)-alanines (111) can be prepared analogously by reaction of 2 with an imidodicarbonate or tosylcarbamate [40]. The enantiomeric excess in Mitsunobu products 111 exceed 95%. 

Lastly, phthaloyl-protected (R)-alanine 112 is formed in high yield by reaction of 2 with phthalimide [40]. Recently, polystyrene-supported methyl azodicarboxylate has been used as a replacement for the soluble dialkyl azodicarboxylates in the Mitsunobu reaction [41]. Yields generally are not as high as in the classical reaction (e.g., 2 112, 45% yield), but, purification can be expedited simply by filtration of the nonexplosive resin. 

DABCO salts of MBH adducts 288, generated in situ from the corresponding acetate or bromides,can be used for the synthesis of region-retentive allyl 

R = C6H5, 2-CIC6H4, 2-BtC6H4, 2-FC6H4,4-EWG = CN CIC6H4, MeC6H4,etc methanolic ammonia  

NuH = imidazole, isatin, benzotriazole, phthallmide, oxindole, barbituric acid (isomers are formed in the case of benzotriazole and oxindole) 

Ar = Ph, 4-MeOPh, 4-CIPh, 2-furyl, 3-MePh, 4-CIPh, 4-MeOPh 

Recently, Xia et al. have reexamined the reaction of MBH acetate with amines under both conventional stirring and ultrasound irradiation. They found the ultrasonic amination generally affords the target compounds in 

RNR2 + RNH2 RNR2 + RNH3 RNR2 + R —X — RNR3 + X- 

FIGURE 9.49 Clean monosubstitution of a-halocarboxylic acids by ammonia. 

FIGURE 9.51 Substitution using hexamethyiene tetramine as a proxy for ammonia—the Delepine reaction. 

FIGURE 9.53 Azide may also be used as a nucleophile in S l reactions. 

Many methods of reduction from azide to amine are available hydrogen with various metal catalysts, lithium aluminum hydride, or cobalt(II) chloride/sodium borohydride. 

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Most syntheses of nitrogen heterocycles involve substitution and/or condensation reactions of nitrogen nucleophiles with difunctional halides or carbonyl compounds. Common nitrogen reagents are ... 

Regioselectivity becomes important, if unsymmetric difunctional nitrogen components are used. In such cases two different reactions of the nitrogen nucleophile with the open-chain educt may be possible, one of which must be faster than the other. Hydrazone formation, for example, occurs more readily than hydrazinoLysis of an ester. In the second example, on the other hand, the amide is formed very rapidly from the acyl chloride, and only one cyclization product is observed. 

Carbamates are allylated in the presenee of strong bases in DMSO or HMPA[197], Phthalimide (320) and succimide are allylated with the allyl-isoureu 321 at room temperature or the allylic acetate 322 at 100 C[I98.I99], Di-/-butyl iminodicarbonate is used as a nitrogen nucleophile[200]. 

In acid the nitnle is protonated on nitrogen Nucleophilic addition of water yields an imino acid... 

The polymerization of ethyleneimine (16,354—357) is started by a catalyticaHy active reagent (H or a Lewis acid), which converts the ethyleneimine into a highly electrophilic initiator molecule. The initiator then reacts with nitrogen nucleophiles, such as the ethyleneimine monomer and the subsequendy formed oligomers, to produce a branched polymer, which contains primary, secondary, and tertiary nitrogen atoms in random ratios. Termination takes place by intramolecular macrocycle formation. 

Nitrogen nucleophiles used to diplace the 3 -acetoxy group include substituted pyridines, quinolines, pyrimidines, triazoles, pyrazoles, azide, and even aniline and methylaniline if the pH is controlled at 7.5. Sulfur nucleophiles include aLkylthiols, thiosulfate, thio and dithio acids, carbamates and carbonates, thioureas, thioamides, and most importandy, from a biological viewpoint, heterocycHc thiols. The yields of the displacement reactions vary widely. Two general approaches for improving 3 -acetoxy displacement have been reported. One approach involves initial, or in situ conversion of the acetoxy moiety to a more facile leaving group. The other approach utilizes Lewis or Brmnsted acid activation (87). 

Kinetic data on acetate displacement from C-3 using a number of sulfur and nitrogen nucleophiles in aqueous solution at near neutral pH demonstrate that the reaction proceeds by an 5 1 mechanism (B-72MI51004). The intermediate in this reaction is depicted as a dipolar allylic carbonium ion (9) with significant charge delocalization. Of particular significance in this regard is the observation that the free carboxylate at C-4 is required since... 

Formal replacement of one of the bulky halogens in polyhalogenofluoro-ethanes by nitrogen nucleophiles occurs through the intermediate formation of fluorinated olefins [91, 92] (see equation 47) (equation 79). 

The replacement of reactive aromatic fluonne by nitrogen nucleophiles is a well-known process for the preparation of aromatic amines The aromatic fluonne IS activated by the presence of electron-withdrawing substituents on the aromatic ring, especially in ortho and para positions [57 38, 39] (equations 25-27)... 

Reaction at position 4 of perfluotopyndme thus occurs readily with nitrogen nucleophiles, as exemplified by its reactions with sodium azide and with hydroxyl-amme [75, 76] (equation 39)... 

Phosphorus nucleophiles have received little attention compared with nitrogen nucleophiles in reactions with fluonnated systems Yields with phosphorus nucleophiles are sometimes low, but interesting materials are obtained [80, 81] (equations 42 and 43). 

In its overall design, this procedure is similar- to the Gabriel synthesis a nitrogen nucleophile is used in a carbon-nitrogen bond-fonning operation and then converted to an fflnino group in a subsequent transfor-mation. 

Amines can be prepared by means of Sn2 reactions involving alkyl halides and nitrogen nucleophiles. 

One potential problem with this procedure is that the product can sometimes act as a nitrogen nucleophile, and multiple substitutions may then occur. It is useful, therefore, to be able to distinguish the relative nucleophilicity of different amines. 

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