Cyclic tertiary amines addition

Many naturally occurring and synthetic drugs directed at biogenic amine receptors contain a basic tertiary amine center. It is common practice in the development of new central nervous system (CNS)-active pharma-ceuticals to incorporate pyrrolidino, piperidino, or morpholino moieties (in addition to dimethylamino) in structure-activity investigations. A significant number of cyclic tertiary amine drugs have thus appeared (and continue to appear) in the marketplace despite the fact that this structural construct appears to be especially... 

The Baylis-Hillman (also called Morita-Baylis-Hillman) (MBH) reaction (see Sect. 10.2.4 and Scheme 10.17) is the base-catalyzed addition of keto compounds to acrylic derivatives. The catalyst is a cyclic tertiary amine such as 1,4-diazabicyclo[2.2.2]octane (DABCO). Due to the generally poor yields observed, the reaction has not received sufficient attention despite the great synthetic value of the polyfunctional adducts. Among the various methods proposed to activate the reaction, pressure 107] and hydrophobic effects [70] have been used. Table 10.31 presents the results obtained in some Baylis-Hillman reactions carried out under pressure in aqueous solution [108]. 

Besides flrst moderating the oxonium end-group activity by reaction with cyclic tertiary amines followed by termination, the living CROP of tetrahydrofuran can be also directly terminated by the addition of carboxylic acid sodium salts [99], dithiocarbamic acid sodium salts... 

Titanium enolates can be prepared from lithium enolates by reaction withatrialkoxy-titanium(IV)chloride,suchasfra-(isopropoxy)titaniumchloride.21 Titanium enolates are usually prepared directly from ketones by reaction with TiCl4 and a tertiary amine.22 Under these conditions, the Z-enolate is formed and the aldol adducts have syn stereochemistry. The addition step proceeds through a cyclic TS assembled around titanium. 

The scope of Michael additions with catalysts containing cyclohexane-diamine scaffolds was broadened by Li and co-workers [95]. When screening for a catalyst for the addition of phenylthiol to a,p-nnsatnrated imides, the anthors fonnd that thiourea catalyst 170 provided optimal enantioselectivities when compared to Cinchon alkaloids derivatives (Scheme 41). Electrophile scope inclnded both cyclic and acyclic substrates. Li attributed the enantioselectivity to activation of the diketone electrophiles via hydrogen-bonding to the thiourea, with simultaneous deprotonation of the thiol by the tertiary amine moiety of the diamine (170a and 170b). Based on the observed selectivity, the anthors hypothesized that the snbstrate-catalyst... 

Initially, water can cause the hydrolysis of the anhydride or the isocyanate, Scheme 28 (reaction 1 and 2), although the isocyanate hydrolysis has been reported to occur much more rapidly [99]. The hydrolyzed isocyanate (car-bamic acid) may then react further with another isocyanate to yield a urea derivative, see Scheme 28 (reaction 3). Either hydrolysis product, carbamic acid or diacid, can then react with isocyanate to form a mixed carbamic carboxylic anhydride, see Scheme 28 (reactions 4 and 5, respectively). The mixed anhydride is believed to represent the major reaction intermediate in addition to the seven-mem bered cyclic intermediate, which upon heating lose C02 to form the desired imide. The formation of the urea derivative, Scheme 28 (reaction 3), does not constitute a molecular weight limiting side-reaction, since it too has been reported to react with anhydride to form imide [100], These reactions, as a whole, would explain the reported reactivity of isocyanates with diesters of tetracarboxylic acids and with mixtures of anhydride as well as tetracarboxylic acid and tetracarboxylic acid diesters [101, 102]. In these cases, tertiary amines are also utilized to catalyze the reaction. Based on these reports, the overall reaction schematic of diisocyanates with tetracarboxylic acid derivatives can thus be illustrated in an idealized fashion as shown in Scheme 29. 

Although there exist numerous ground state reactions, photochemically induci asymmetric radical additions can be very efficient and even highly stereoselectr [125]. Furthermore, no particular functionalization of the starting material is n< essary prior to the formation of a C-C bond. In this context, the photosensiti addition of alcohols, cyclic acetals, and tertiary amines to electron-deficient kenes has been particularly studied. This will be illustrated by a few exampli First attempts to induce chirality in the photoinduced addition of ket radicals (e.g., U) involved a, 3-usaturated carbonyl compounds such as 208 rived from carbohydrates (Scheme 56) [126]. With benzophenone as sensitizi these radicals could be added stereoselectively, and similar reactions were carri out with dioxolane and a, 3-usaturated nitropyranones [127]. 

The [3+2]-cycloaddition or [2+2]-cycloaddition of OSO4 and alkene followed by rearrangement forms the cyclic osmate ester. Tertiary amines (achiral ligand) such as 4-dimethyl-aminopyridine (DMAP) or pyridine (Py) accelerate the addition reaction (Scheme 7.24). 

On treatment of 221 with alkoxides having a bulky alkyl moiety, 224 was formed in addition to 223 (Nu = OR ) ". It was shown that l(>-12-membered cyclic chloroenamines (228) and succinimide (229) in the presence of a tertiary amine gave trans-bicyclic... 

While the addition of organometallic reagents to acyclic or cyclic imines (43) is often compromised by poor imine reactivity, these reagents readily condense with structurally diverse, more electrophilic imini-um salts (44), bearing a positive charge on the nitrogen atom, to provide substituted tertiary amines (45 Scheme 6). A review of the literature describing additions to cyclic iminium salts prior to 1966 is avail-... 

Another, and seemingly very powerful, reagent is the cyclic mixed anhydride (la), which is very readily opened by attack at phosphorus by alcohols or phenols even in the absence of base. The anion (lb), from dealkylation of (la) with a tertiary amine, is also an active phosphorylating agent for alcohols. Since the residual ketol group is easily removed, these compounds may prove to be useful additions to existing reagents. 

In order to enhance the reactivity of aluminum porphyrins (J ) especially towards C02 in the copolymerization with epoxide (Equation 4), the effect of addition of an amine or phosphine as a possible sixth ligand to the aluminum porphyrin was examined. The enhancement in reactivity by the addition of a tertiary amine such as N-methyl-imldazole was actually observed for the epoxlde-C02 reaction. The product, however, was a cyclic carbonate (JO), not a linear copolymer. On the other hand, J he addition of trlphenylphosphlne was very effective in the formation of an alternating copolymer from epoxide and... 

Boron or tin (II) Z-enolates are generated by reaction with the corresponding triflates with a carbonyl compound in the presence of tertiary amines like r-P NEt or. M-ethylpiperidine (except when using dicyclopentylboron triflate [407]). E-Enolates are prepared by using dicyclohexyl- or other cyclic chloroboranes in the presence of Et3N or Me NEt [407, 685, 686, 1246, 1247, 1248], Because enolization does not take place under such conditions with esters or aliphatic tertiary amides, thiophenyl esters RGH COSPh have been used as ester/amide substitutes. Furthermore, Z-boron enolates of ketones can be prepared by conjugate addition of acid derivatives of dialkylboranes to a-enones [687],... 

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