With nucleophiles

With Nucleophiles.—Three-membered Rings. Base-catalysed racemization of 2,2-diphenylcyclopropylnitrile has been studied in different solvents. With sodium methoxide, the rate of racemization in 98.5 1.5 DMSO MeOH was 3.6 x 10 faster than that observed in methanol. This difference can be attributed to the presence of solvent-anion hydrogen bonds in MeOH which are absent in DMSO. Thus, the 

The temperature coefficient of the enthalpy of activation obtained from rate measurements of the solvolytic, disrotatory ring opening of cis- and trans-2-vinylcyclo-propyl bromides in water was unusual for both compounds (—27 and — 35 cal deg mol respectively). It was concluded from this fact that charge development at the transition state was low, a conclusion supported by the slightly inverse a-deuter-ium slope effect, k /kj = 0.994. 

Base-catalysed transformations in unsaturated terpenes containing three-membered rings have been examined,and the intermediacy of the anion (447) in the rearrangement of cyclopropindene (448) to (449) has been discussed.  

Isomerization kinetics of 1,3,3-trimethylcyclopropene and methylenecyclobutene, catalysed by alkali-metal t-butoxides, have been determined. The faster isomerization of the cyclopropene was attributed to strain factors.  

Evidence has been presented for the discrete existence of a bicyclo[4,l,0]hepta-2,4,7-triene, proposed as an intermediate in the arylcarbene-cycloheptatrienylidene interconversion. Treatment of the dichlorocyclopropene (450) with potassium butoxide in THF affords the product (452), and the intermediacy of (451) was demonstrated by its trapping as the dithioether (453) when (450) was treated with base in DMSO in the presence of methanethiol. 

With Nucleophiles.—Cyclopropane Derivatives. Simple cyclopropanes are normally resistant to nucleophilic attack, though cyclopropane itself gives a complex mixture of products in a photolytic reaction with tetrafluorohydra-zine. The isotope exchange rates in methanolic sodium methoxide of 1-deuterio- and 1-tritio-cyclopropanes with I-CF3, 1-CN, and l-S02Ph 

Although it has been usual to reduce dihalogenocyclopropanes with tri(n-butyl)tin hydride, it has recently been shown that lithium aluminium hydride reduces several bicyclic or caged dichloro- and dibromo-cyclopropanes in good yield and with moderate stereoselectivity.  

The tetrafluorocyclopropane residues of steroids (255) and (256) have been shown to be more susceptible to nucleophilic attack than the enol acetate groups. The initial reaction of both stereoisomers with sodium hydroxide 

The trans-spirocyclopropane (264) was reported earlier to react with hot, methanolic potassium hydroxide followed by hydrogen chloride, though the product was not properly characterized. The product has now been shown by chemical methods to be (265) and a probable mechanism involves initial proton 

Nucleophilic addition of diethyl sodiomalonate to (270) may also be either at C-2 or at the terminal vinyl carbon but in this case, unlike in radical addition, attack at C-2 predominates. When the nucleophile is pyrrolidine, it has been shown that the initial attack at C-2 of optically active (270) occurs with inversion of configuration.  

Wolff (1912) was the first to observe the ring expansion of phenyl azide, on thermolysis in aniline, to a compound he called dibenzamil (45). It was many years before this compound was shown to be 2-anilino-3if-azepine. This reaction was also found to take place on photolysis of aryl azides in primary and secondary aliphatic amines. The mechanism that was proposed and which has since been generally accepted involves nucleophilic attack by solvent on a benzazirine, that is believed to be in equilibrium with singlet arylnitrene. Nmr evidence has been advanced for the intermediacy of a 1/f-azepine (46) in related expansions which, as expected, rapidly isomerizes to the more stable tautomer. Spectroscopic evidence is still lacking for the aziridine intermediate 47, but this could simply be due to its short lifetime. On the other hand, the recent work of Chapman and Le Roux discussed in Section 1.4 has brought into question the intermediacy of benzazirine in phenyl 

The question now arises as to whether the Chapman mechanism is applicable to the decomposition of other aryl azides. Bicyclic aryl azides, for example, have a considerable degree of double-bond fixation in their aromatic rings. This might be expected to make them behave more like vinyl azides, which are known to give azirines on photolysis. It is therefore useful to compare the nature of the products formed on photolysis in nucleophilic solvents by a series of azides that have an increasing degree of vinyl azide character  

Phenyl azide itself undergoes ring expansion in the presence of nitrogen and oxygen nucleophiles, and hydrogen sulflde (in diethyl ether solution) but, in ethylmercaptan, 2-ethyImercaptoaniline, the product of rearomatization, is formed in preference to azepine. This rearomatization product can easily be accommodated by formation of an aziridine by initial attack on benzazirine and subsequent C-N bond fission of the aziridine  

Formation of the same product by attack on l-aza-l,2,4,6 cycloheptatetraene (13) appears more clumsy  

Rearomatization is much more common in bi- and tricyclic azides than ring expansion although ring expansion may be achieved employing sodium methoxide in methanol-dioxan as solvent. This dichotomy again may be resolved by invoking an aziridine intermediate vide supra). The formation of aminoketals from 2-azidoanthracene and 48 is of particular interest as similar products are commonly formed from aliphatic azirines on treatment with mildly basic methanol. At the moment, the intermediacy of benzazirine in phenyl azide photolysis at room temperature cannot be ruled out. In the case of bi- and tricyclic aromatic azides and azidouracil decompositions the nature of the products strongly supports azirine involvement. Only further experimental work will resolve this mechanistic dilemma. With this in mind, benzazirine intermediacy will be assumed for the purposes of this discussion. 

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In the synthesis of molecules without functional groups the application of the usual polar synthetic reactions may be cumbersome, since the final elimination of hetero atoms can be difficult. Two solutions for this problem have been given in the previous sections, namely alkylation with nucleophilic carbanions and alkenylation with ylides. Another direct approach is to combine radical synthons in a non-polar reaction. Carbon radicals are. however, inherently short-lived and tend to undergo complex secondary reactions. Escheirmoser s principle (p. 34f) again provides a way out. If one connects both carbon atoms via a metal atom which (i) forms and stabilizes the carbon radicals and (ii) can be easily eliminated, the intermolecular reaction is made intramolecular, and good yields may be obtained. 

Epoxide opening with nucleophiles occurs at the less substituted carbon atom of the oxlrane ting. Cataiytic hydrogenolysis yields the more substituted alcohol. The scheme below contains also an example for trons-dibromination of a C—C double bond followed by dehy-drobromination with strong base for overall conversion into a conjugated diene. The bicycKc tetraene then isomerizes spontaneously to the aromatic l,6-oxido[l0]annulene (E. Vogel, 1964). 

The benzylidene derivative above is used, if both hydroxyl groups on C-2 and C-3 are needed in synthesis. This r/vzns-2,3-diol can be converted to the sterically more hindered a-cpoxide by tosylation of both hydroxy groups and subsequent treatment with base (N.R. Williams, 1970 J.G. Buchanan, 1976). An oxide anion is formed and displaces the sulfonyloxy group by a rearside attack. The oxirane may then be re-opened with nucleophiles, e.g. methyl lithium, and the less hindered carbon atom will react selectively. In the following sequence starting with an a-glucoside only the 2-methyl-2-deoxyaltrose is obtained (S. Hanessian, 1977). 

Palladation of aromatic compounds with Pd(OAc)2 gives the arylpalladium acetate 25 as an unstable intermediate (see Chapter 3, Section 5). A similar complex 26 is formed by the transmetallation of PdX2 with arylmetal compounds of main group metals such as Hg Those intermediates which have the Pd—C cr-bonds react with nucleophiles or undergo alkene insertion to give oxidized products and Pd(0) as shown below. Hence, these reactions proceed by consuming stoichiometric amounts of Pd(II) compounds, which are reduced to the Pd(0) state. Sometimes, but not always, the reduced Pd(0) is reoxidized in situ to the Pd(II) state. In such a case, the whole oxidation process becomes a catalytic cycle with regard to the Pd(II) compounds. This catalytic reaction is different mechanistically, however, from the Pd(0)-catalyzed reactions described in the next section. These stoichiometric and catalytic reactions are treated in Chapter 3. 

All these intermediate complexes undergo various transformations such as insertion, transmetallation, and trapping with nucleophiles, and Pd(0) is regenerated at the end in every case. The regenerated Pd(0) starts the catalytic cycle again, making the whole process catalytic. These reactions catalyzed by Pd(0) are treated in Chapter 4. 

The most characteristic feature of the Pd—C bonds in these intermediates of both the stoichiometric and catalytic reactions is their reaction with nucleophiles, and Pd(0) is generated by accepting two electrons from the nucleophiles as exemplified for the first time by the reactions of 7r-allylpalladium chloride[2] or PdCl2-COD[3] complex with malonate and acetoacetate. It should be noted... 

TT-Allylpalladium chloride (36) reacts with the nucleophiles, generating Pd(0). whereas tr-allylnickel chloride (37) and allylmagnesium bromide (38) reacts with electrophiles (carbonyl), generating Ni(II) and Mg(II). Therefore, it is understandable that the Grignard reaction cannot be carried out with a catalytic amount of Mg, whereas the catalytic reaction is possible with the regeneration of an active Pd(0) catalyst, Pd is a noble metal and Pd(0) is more stable than Pd(II). The carbon-metal bonds of some transition metals such as Ni and Co react with nucleophiles and their reactions can be carried out catalytic ally, but not always. In this respect, Pd is very unique. 

TT-Aliylpalladium chloride reacts with a soft carbon nucleophile such as mal-onate and acetoacetate in DMSO as a coordinating solvent, and facile carbon-carbon bond formation takes place[l2,265], This reaction constitutes the basis of both stoichiometric and catalytic 7r-allylpalladium chemistry. Depending on the way in which 7r-allylpalladium complexes are prepared, the reaction becomes stoichiometric or catalytic. Preparation of the 7r-allylpalladium complexes 298 by the oxidative addition of Pd(0) to various allylic compounds (esters, carbonates etc.), and their reactions with nucleophiles, are catalytic, because Pd(0) is regenerated after the reaction with the nucleophile, and reacts again with allylic compounds. These catalytic reactions are treated in Chapter 4, Section 2. On the other hand, the preparation of the 7r-allyl complexes 299 from alkenes requires Pd(II) salts. The subsequent reaction with the nucleophile forms Pd(0). The whole process consumes Pd(ll), and ends as a stoichiometric process, because the in situ reoxidation of Pd(0) is hardly attainable. These stoichiometric reactions are treated in this section. 

The reaction of alkenyl mercurials with alkenes forms 7r-allylpalladium intermediates by the rearrangement of Pd via the elimination of H—Pd—Cl and its reverse readdition. Further transformations such as trapping with nucleophiles or elimination form conjugated dienes[379]. The 7r-allylpalladium intermediate 418 formed from 3-butenoic acid reacts intramolecularly with carboxylic acid to yield the 7-vinyl-7-laCtone 4I9[380], The /i,7-titisaturated amide 421 is obtained by the reaction of 4-vinyl-2-azetidinone (420) with an organomercur-ial. Similarly homoallylic alcohols are obtained from vinylic oxetanes[381]. 

The rather unreactive chlorine of vinyl chloride can be displaced with nucleophiles by the catalytic action of PdCb. The conversion of vinyl chloride to vinyl acetate (797) has been studied extensively from an industrial standpoint[665 671]. DMF is a good solvent. 1,2-Diacetoxyethylene (798) is obtained from dichloroethylene[672]. The exchange reaction suffers steric hindrance. The alkenyl chloride 799 is displaced with an acetoxy group whereas 800 and 801 cannot be displaccd[673,674]. Similarly, exchange reactions of vinyl chloride with alcohols and amines have been carried out[668]. 

Acyi halides are reactive compounds and react with nucleophiles without a catalyst, but they are activated further by forming the acylpalladium intermediates, which undergo insertion and further transformations. The decarbonyla-tive reaction of acyl chlorides as pseudo-halides to form the aryipalladium is treated in Section 1,1.1.1. The reaction without decarbonylation is treated in this section. 

Application of 7r-allylpalladium chemistry to organic synthesis has made remarkable progress[l]. As deseribed in Chapter 3, Seetion 3, Tt-allylpalladium complexes react with soft carbon nucleophiles such as maionates, /3-keto esters, and enamines in DMSO to form earbon-carbon bonds[2, 3], The characteristie feature of this reaction is that whereas organometallic reagents are eonsidered to be nucleophilic and react with electrophiles, typieally earbonyl eompounds, Tt-allylpalladium complexes are electrophilie and reaet with nucleophiles such as active methylene compounds, and Pd(0) is formed after the reaction. 

When the 7r-allylpalladium complexes are formed by the reaction of aikenes with PdCU and react with nucleophiles, the whole reaction constitutes the stoichiometric functionalization of alkenes[4,5]. 

Allylic nitro compounds form rr-allylpalladium complexes by displacement of the nitro group and react with nucleophiles, and allylation with the tertiary nitro compound 202 takes place at the more substituted side without rearrangement to give 203[8,9,128]. 

This equation, when applied to an ambident nucleophile with nucleophilic centers 1 and 2, becomes... 

Thiazole sulfonic acid reacts with nucleophiles leading to the corresponding 2-substituted compounds (140. 141, and 142) (Scheme 73) (39, 334). 

RELATIVE REACTIVITIES OF SOME HALO-AZA-ACTIVATED AROMATIC SUBSTRATES WITH NUCLEOPHILES ... 

Carbocations are strongly electrophilic (Lewis acids) and react with nucleophiles (Lewis bases)... 

The most common types of aryl halides m nucleophilic aromatic substitutions are those that bear o ox p nitro substituents Among other classes of reactive aryl halides a few merit special consideration One class includes highly fluormated aromatic compounds such as hexafluorobenzene which undergoes substitution of one of its fluorines on reac tion with nucleophiles such as sodium methoxide... 

Nitro substituted aromatic compounds that do not bear halide leaving groups react with nucleophiles according to the equation... 

The condensation leaves epoxy end groups that are then reacted in a separate step with nucleophilic compounds (alcohols, acids, or amines). Eor use as an adhesive, the epoxy resin and the curing resin (usually an aliphatic polyamine) are packaged separately and mixed together immediately before... 

Acrylamide, C H NO, is an interesting difiinctional monomer containing a reactive electron-deficient double bond and an amide group, and it undergoes reactions typical of those two functionalities. It exhibits both weak acidic and basic properties. The electron withdrawing carboxamide group activates the double bond, which consequendy reacts readily with nucleophilic reagents, eg, by addition. 

There are three general reactions of perfluoroepoxid.es pyrolyses (thermal reactions), electrophilic reactions, and by far the most important, reactions with nucleophiles and bases. 

Nucleophilic Reactions. The strong electronegativity of fluorine results in the facile reaction of perfluoroepoxides with nucleophiles. These reactions comprise the majority of the reported reactions of this class of compounds. Nucleophilic attack on the epoxide ring takes place at the more highly substituted carbon atom to give ring-opened products. Fluorinated alkoxides are intermediates in these reactions and are in equiUbrium with fluoride ion and a perfluorocarbonyl compound. The process is illustrated by the reaction of methanol and HFPO to form methyl 2,3,3,3-tetrafluoro-2-methoxypropanoate (eq. 4). 

Fluoropyridine is readily hydroly2ed to 2-pyridone in 60% yield by reflux in 6 Ai hydrochloric acid (383). It is quite reactive with nucleophiles. For example, the halogen mobiUty ratio from the comparative methoxydehalogenation of 2-fluoropyridine and 2-chloropyridine was 85.5/1 at 99.5°C (384). This labihty of fluorine has been utili2ed to prepare fluorine-free 0-2-pyridyl oximes of 3-oxo steroids from 2-fluoropyridine for possible use as antifertihty agents (385). 

Cyanuric fluoride is readily hydrolyzed to 2,4,6-thhydroxy-l,3,5-triaziae [108-80-5] (cyanuric acid). Cyanuric fluoride reacts faster with nucleophilic agents such as ammonia and amines than cyanuric chloride. 

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