Internal nucleophile addition

Acetal and hemiacetal groups are particularly common in carbohydrate chemistry. Glucose, for instance, is a polyhydroxy aldehyde that undergoes an internal nucleophilic addition reaction and exists primarily as a cyclic hemiacetal. 

Saczewski and Debowski reported the l,4-diaza-3-oxa-Cope rearrangement of N-cyanate anilides (equation 52). Prototropic rearomatization of 176 and internal nucleophilic addition afford the corresponding benzimidazolinone 177, usually in moderate yields (32-78%). A concerted [3,3]-sigmatropic rearrangement is proposed based on the absence of para rearrangement product that usually results from homolysis or heterolysis of the N—O bond followed by recombination of the two radicals or ions. 

Intermolecular anodic cyclizations often involve initial coupling of radical-cations followed by a chemical cyclization reaction. An alternative is cyclization by internal nucleophilic addition of some reactant to an intermediate derived by anodic oxidation. 

This internal nucleophilic addition introduces a new chiral centre into the molecule. The carbon of the new centre is known as the anomeric carbon and the two new stereoisomers formed are referred to as anomers. The isomer where the new hydroxy group and the CH2OH are on opposite sides of the plane of the ring is known as the alpha (a) anomer. Conversely, the isomer with the new hydroxy group and terminal CH2OH on the same side of the plane of the ring is known as the beta (P) anomer (Figure 1.12). 

Tandem Carbon-Carbon Bond Formation via Brook Rearrangement Takeda et al. have reported that the reactions of benzoyl- and crotonylsilanes with hthium enolates of methyl ketones produce 1,2-cyclopropanediol monosilyl ethers via the Brook rearrangement of the initial 1,2-adduct 158 and the subsequent internal nucleophilic addition (Scheme 10.225) [587]. No formation of the corresponding cyclopropanes with alkanoylsilanes implies fhat fhe Brook rearrangement is accelerated by the phenyl or vinyl group. 

The addition of electrophilic dienophiles to cyclo-octatetraene coordinated to — Fe(CO)3 or to — Ru(CO)s does not occur directly, since it is a thermally forbidden process. Rather, the dienophile co-ordinates to the metal, with subsequent transfer to the cycloalkene to give the observed 1 1 product. An analogue of the second stage of this mechanism is provided by the transfer of acetylacetone from platinum to the unsaturated ligand in the reaction (47) -> (48). This is internal nucleophilic addition of acetyl-... 

Cycloheptadienyliron complexes also frequently show examples of internal nucleophile addition [214,215,224—227]. Steric effects are conventionally cited to explain the tendency of cycloheptadienyl complexes to give internal addition products (whereas cydohexadienyl complexes react at the termini). There is kinetic evidence to support this, as cycloheptadienyl complexes have been shown to be less reactive than cydohexadienyl complexes [223]. The CH2 of the cydohexadienyl complexes, and the CHjCHj of the cydohepadienyl complexes fold out away from the metal in these structures, and in the cydoheptadienyl case, each CH2 blocks a terminus of the Jt system. NudeophUic attack is displaced to the internal positions, forming ij, r] products in competition with the 1 products from the normal addition pathway [214,215,224—230]. With larger metals [Ru(CO)3 and Os(CO)3], this effect becomes more pronounced, and the products can predominate [230,231]. The nature of the nudeophile can also influence the preferred pathway (see Section 14.4). With soft nudeophiles, cydoheptadienyl complexes show the terminal addition pathway, while hard nudeophiles add internally [232]. Further... 

The main purpose of this chapter is to discuss the directing effects of functional groups in these reactions. As one would expect, steric effects direct internal nucleophile addition to the less hindered of the electrophilic centers as in the formation of 49. With a C-1 OMe substituent, a addition has been proposed [235]. Internal nucleophile addition to the less hindered of the electrophilic centers has also been reported for 50 [236]. Other examples give mixtures [237]. On the other hand, 1,4-dimethyl substitution on the tj cydoheptadienyl ligand shows regiocon-trol dominated by the C-1 Me group (y selectivity ipso to the C-4Me group) [229]. 

Ring expansion of haloalkyloxiranes provides a simple two-step procedure for the preparation of azetidin-3-ols (Section 5.09.2.3.2(f)) which can be extended to include 3-substituted ethers and O-esters (79CRV331 p. 341). The availability of 3-hydroxyazetidines provides access to a variety of 3-substituted azetidines, including halogeno, amino and alkylthio derivatives, by further substitution reactions (Section 5.09.2.2.4). Photolysis of phenylacylamines has also found application in the formation of azetidin-3-ols (33). Not surprisingly, few 2-0-substituted azetidines are known. The 2-methoxyazetidine (57) has been produced by an internal displacement, where the internal amide ion is generated by nucleophilic addition to an imine. 

Reductive animations also occur in various biological pathways, fn the biosynthesis of the amino acid proline, for instance, glutamate 5-semjaldehyde undergoes internal imine formation to give 1-pyrrolinium 5-carboxylate, which is then reduced by nucleophilic addition of hydride ion to the C=N bond. 

Reactants with internal nucleophiles are also subject to cyclization by electrophilic sulfur reagents, a reaction known as sulfenylcyclization.92 As for iodolactonization, unsaturated carboxylic acids give products that result from anti addition.93... 

Mechanistically, the nucleophilic addition can occur either by internal ligand transfer or by external attack. Generally, softer more stable nucleophiles (e.g., malonate enolates) are believed to react by the external mechanism and give anti addition, whereas harder nucleophiles (e.g., hydroxide) are delivered by internal ligand transfer with syn stereochemistry.120... 

Vedejs developed an enantiocontrolled synthesis of aziridinomitosenes involving internal alkylation of the oxazole 132 to produce an oxazolium salt 133 followed by nucleophilic addition of cyanide providing the adduct 134 <00JA5401>. Electrocyclic ring opening of 134 to the azomethine ylide 135 with internal [2+3] trapping produces the tetracyclic product 137 via the pyrroline 136. 

The proposed mechanism involves the usual oxidative addition of the aryl halide to the Pd(0) complex affording a Pd(II) intermediate (Ar-Pd-Hal), subsequent coordination of allene 8 and migratory insertion of the allene into the Pd-C bond to form the jt-allylpalladium(II) species 123. A remarkable C-C bond cleavage of 123 leads by decarbopalladation to 1,3-diene 120 and a-hydroxyalkylpalladium species 124. /8-H elimination of 124 affords aldehyde 121 and the H-Pd-Hal species, which delivers Pd(0) again by reaction with base (Scheme 14.29). The originally expected cyclization of intermediate 123 by employment of the internal nucleophilic hydroxyl group to form a pyran derivative 122 was observed in a single case only (Scheme 14.29). 

Another rhodium vinylidene-mediated reaction for the preparation of substituted naphthalenes was discovered by Dankwardt in the course of studies on 6-endo-dig cyclizations ofenynes [6]. The majority ofhis substrates (not shown), including those bearing internal alkynes, reacted via a typical cationic cycloisomerization mechanism in the presence of alkynophilic metal complexes. In the case of silylalkynes, however, the use of [Rh(CO)2Cl]2 as a catalyst unexpectedly led to the formation of predominantly 4-silyl-l-silyloxy naphthalenes (12, Scheme 9.3). Clearly, a distinct mechanism is operative. The author s proposed catalytic cycle involves the formation of Rh(I) vinylidene intermediate 14 via 1,2-silyl-migration. A nucleophilic addition reaction is thought to occur between the enol-ether and the electrophilic vinylidene a-position of 14. Subsequent H-migration would be expected to provide the observed product. Formally a 67t-electrocyclization process, this type of reaction is promoted by W(0)-and Ru(II)-catalysts (Chapters 5 and 6). 

E. Addition of Alkoxide arul Cyanide Ions to ix-Halocarbonyl Compound —Epoxgdker and GlyoidonitrUes Internal nucleophilic displacement of a halogen with attendant epoxide ring closure has been utilized in the synthesis of epoxy ethers, according to the general transformation depicted in Eq. (209). 

It is of some interest to speculate briefly oonocming the nature of the peracid-imine reaction. It xb quite possible that this reaction is analogous to the epoxidation of olefins with peracids and involves a similar oydks transition state (X). An equally attractive if less obvious possibility is that the imine reaction proceeds through addition of the peracid to the azomethine followed by internal nucleophilic displace ment of the basic nitrogen atom on the peroxide bond. This reaction... 

Nucleophilic attack at tt- allylic complexes may also occur from (a) external trans addition or (b) internal cis addition, resulting in the formation of allylic oxidation products (equation 153).398,399... 

Backwall and coworkers have extensively studied the stereochemistry of nucleophilic additions on 7r-alkenic and ir-allylic palladium(II) complexes. They concluded that nucleophiles which preferentially undergo a trans external attack are hard bases such as amines, water, alcohols, acetate and stabilized carbanions such as /3-diketonates. In contrast, soft bases are nonstabilized carbanions such as methyl or phenyl groups and undergo a cis internal nucleophilic attack at the coordinated substrate.398,399 The pseudocyclic alkylperoxypalladation procedure occurring in the ketonization of terminal alkenes by [RCC PdOOBu1], complexes (see Section 61.3.2.2.2)42 belongs to internal cis addition processes, as well as the oxidation of complexed alkenes by coordinated nitro ligands (vide in/ra).396,397... 

Palladium(II) salts, in the form of organic solvent soluble complexes such as PdCl2(RCN)2, Pd(OAc>2 or Li2PdCU, are by far the most extensively utilized transition metal complexes to activate simple (unactivated) alkenes towards nucleophilic attack (Scheme 1). Alkenes rapidly and reversibly complex to pal-ladium(II) species in solution, readily generating alkenepalladium(II) species (1) in situ. Terminal monoalkenes are most strongly complexed, followed by internal cis and trans (respectively) alkenes. Geminally disubstituted, trisubstituted and tetrasubstituted alkenes are only weakly bound, if at all, and intermolecular nucleophilic additions to these alkenes are rare. 

Structurally related dienols and acyclic trienols, when reacted in fluorosulfuric acid, give tricyclic ether derivatives in kinetically controlled cyclization.810,811 The stereospecific product formation is rationalized by synchronous internal anti-addition via chair-like conformations of the protonated cyclohexene ring, resulting in ring closure with equatorial C-C bond formation and concomitant internal nucleophilic termination by anti-addition of the OH group [Eq. (5.294)]. Z/E isomerization may be competitive with cyclization. 

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