Nitrogen nucleophiles, 184 Table

Solution Ammonia is a nitrogen nucleophile (Table 6.1, entry 6). Since both reactants are neutral, the product has a positive charge (the formal +1 charge is on the nitrogen—check it out ). 

In an update [57, 58], of a 2002 report [59], Buchwald et al. described a very competitive catalytic system based on the use of 1,2-diamine ligand Lll for the coupling of aryl bromides with a very wide range of nitrogen nucleophiles (Table 1, entry 8). 

The use of a nitrogen nucleophile in the side chain (as an amide) also leads to an intramolecular 1,4-addition under the standard conditions for the palladium-catalyzed 1,4-oxidation reactions52. Nitrogen nucleophiles employed for this reaction comprise tosy-lamides, carboxamides, carbamates and ureas. The reactions are run in acetone-acetic acid with p-benzoquinone (BQ) as the oxidant. In most cases highly stereo- and regioselective reactions were obtained and some examples are given in Table 3. 

Ethoxymethylene)-2-phenyl-5(47/)-oxazolone 404, readily available from hippuric acid and triethyl orthoformate, has also been used as a starting material for other unsaturated oxazolones via addition-elimination reactions. Nitrogen nucleophiles are most commonly used and amines give rise to 4-(aminomethyl-ene)-2-phenyl-5(4//)-oxazolones 405 (Scheme 7.130 Table 7.37, Fig. 7.48) which, in many cases have been evaluated as antihypertensives. 

Electrophiles that have been used for the second alkylation of this tandem Michael addition -alkylation sequence are limited to primary iodoalkanes, (bromomethyl)benzenes and 3-bromo-propenes. Tables 9 and 10 provide details of the alkylations of enolate species prepared by 1,4-additions of -a,/j-unsaturated iron-acyl complexes by anionic carbon nucleophiles and anionic nitrogen nucleophiles, respectively. 

Fused ring heterocycles, prepared by cyclization of substrates with a tethered nitrogen nucleophile, have been used in the synthesis of amino sugars and aminocyclitols. The examples shown in Table 28 make use of imidate-type functionality (equation 101) to insure nucleophilic attack by nitrogen. The bro-mocyclization of N,W-dialkylaminomethyl ethers of 2-cyclohexen-l-ol to form bicyclic oxazolidine derivatives has been reported also.228b... 

Another aspect of regioselectivity with many nitrogen nucleophiles is the ambident nature of the nucleophile, which can lead to products of the same ring size through either N-cyclization or O-cyclization (see Scheme 12 for an example). As shown by entries 1 and 2 in Table 25, preferential N-cyclization to 3-lactams has been effected by use of sulfonyl or acyloxy substitution on nitrogen. However, these sub-... 

Phospha sugar nucleosides have not yet been shown to be naturally occurring. Some analogues of phospha sugar nucleosides (e.g., 118) are prepared from 2-bromo-3-hydroxyphospholanes 94 or 103 by nucleophilic substitution reaction with nitrogen nucleophiles (Schemes 35 and 36, and Table 8). However, the nucleophilic substitution reaction (or electrophilic substitution reaction in the presence of catalyst) of 2-bromo-3-hydroxyphospholanes 94... 

Reactions such as those just described, i.e., ones in which two molecules of starting material react to form one product molecule plus a by-product of considerably lower molecular weight are referred to as condensation reactions. Here, as in many other condensations, this by-product is H20. Table 9.2 summarizes the most important condensation reactions of nitrogen nucleophiles with carbonyl compounds, in which C=N double bonds are produced. 

As usual, the best strategy is to identify the nucleophile and the electrophile. This chapter introduced a new electrophile, the carbonyl carbon of an aldehyde or ketone. The nucleophiles are listed in Table 18.2. Hydride, water, HCN, and organometallic nucleophiles result in the addition of the nucleophile to the carbon and a hydrogen to the oxygen of the carbonyl group. Ylides and nitrogen nucleophiles result in the formation of a double bond between the carbonyl carbon and the nucleophile. And alcohols and thiols add two nucleophiles to the carbonyl carbon. 

Table 7.2. Condensation Reactions of Nitrogen Nucleophiles with Carbonyl Compounds through Which C=N Double Bonds Are Established—Mechanism and Scope...

When used in conjunction with nitrogen nucleophiles, a very high stereoselectivity is found yielding /1-amino, /i-nitro, /3-azido and / -pyrrolidino methylsulfenylated products (Table 3)39. 

This section focuses on those reactions of nitrogen nucleophiles with rr-allylpalladium complexes which proceed by stereoselective C-N bond formation. For the sake of brevity, the rr-allyl-palladium complexes involved as reactive intermediates in catalytic processes arc omitted in the diagrams and tables. If not explicitly mentioned otherwise, the depicted structures represent racemic mixtures. 

Orientation in electrophilic and nucleophilic reactions of aromatic compounds can be predicted with the aid of the reactivity index of MO theory. Electrophiles will attack positions of higher electron densities, larger superdelocalizability (electrophile), and the lower localization energy (electrophile). On the other hand, nucleophilic attack is preferred at positions of lower electron densities, larger superdelocalizability (nucleophile), and lower localization energy (nucleophile). Table XXIII shows reactivity indexes of some aromatic nitrogen cations. 

Table 19. Additions of nitrogen nucleophiles to alkynes, RC CR, to form acyclic adducts ... 

Whether one looks at C or X attack, the data given in Table 24 suggest that polarizability or the softness factor is important in determining nucleophilicity. Phosphorus nucleophiles appear to be more reactive than structurally similar nitrogen nucleophiles, e.g. with chlorophenylacetylene, A (Bu3P, DMF)/A (TED, MeCN) = 260 at 30 °C As compared with oxygen, sulphur compounds are... 

The precursor compound, phosphornitrilic chloride trimer, reacts with nitrogen and oxygen nucleophiles to form stable products [10]. Reaction of the trimeric phosphazene chloride with nitrogen nucleophiles, such as 3-aminopropyltriethoxysilane, facilitates the introduction of the silane component in a single step resulting in the modified compounds 13 and 14 in yields of about 90 % (Eq. 5 Table 3)... 

In the presence of a palladium catalyst, allyl epoxides (113) react with nitrogen nucleophiles at the al-kenic carbon atom remote from the oxirane ring to give 1,4-adducts (114)." In the absence of a palladium catalyst, azide ion attacks the oxirane ring affording 1,2-adducts (115 Scheme 52 and Table 2)." Vinyl epoxide (116) gave 1,2- and 1,4-azido alcohol in a ratio of 1 1.5 irrespective of the reaction system. " Intramolecular cyclization of vinyl epoxide (117) in the presence of a palladium catalyst afforded isoquinuclidine (118 Scheme 52). ... 

In other words, it is sometimes nucleophilic on carbon and sometimes on nitrogen nucleophiles like this are called ambident. The principle of hard and soft acids and bases helps us to classify and remember this pattern of reactivity. It tells us that the carbon atom will be the softer and the nitrogen atom the harder end of the nucleophile (since, other things being equal, as we have seen in the last section, hard nucleophiles are on the right in the periodic table). 

In the second study by Paneth and coworkers,88 the nitrogen incoming group and the secondary a-deuterium KIEs were determined for the Sn2 reactions between three para-substituted /V,/V-dimethylanilines and methyl iodide. The incoming group nitrogen KIEs (Table 15) decreased when a poorer nucleophile was used. This is consistent with a shorter N-Ca bond in the transition states with the poorer... 

Within a Period or row of the Periodic Table, the better nucleophile has the lower atomic number. This means that nitrogen nucleophiles such as ammonia and amines are better nucleophiles than the corresponding oxygen nucleophiles, water and alcohols. In fact, water and alcohols generally react too slowly to be of use, and often it is necessary to use their anionic forms HO or RO . 

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