Addition-cyclization process

Trimethylsilylepoxides can be prepared by an addition-cyclization process. Reaction of chloromethyltrimethylsilane with sec-butyllithium at very low temperature gives an a-chloro lithium reagent that leads to an epoxide on reaction with an aldehyde or ketone.291... 

Scheme 2.123. Synthesis of indols via a domino carbolithiation/addition/cyclization process.

Scheme 10.14. Domino radical addition-cyclization process of oxime ethers.

Entropic contributions to the acceleration of first-order reactions by microwaves should be negligible (AS = = 0). When ionization (SN1 or E,) or intramolecular addition (cyclizations) processes are involved a microwave effect could be viewed as resulting from a polarity increase from GS to TS, because of the development of dipolar intermediates (Scheme 3.5). 

A tandem radical addition/cyclization process has been described for the formation of benzindolizidine systems from l-(2-iodoethyl)indoles and methyl acrylate <00TL10181>. In this process, sun-lamp irradiation of a solution of the l-(2-iodoethyl)ethylindoles 149 in refluxing benzene containing hexamethylditin and methyl acrylate effects intermolecular radical addition to the activated double bond leading to the stabilized radical 150. Intramolecular cyclization to the C-2 position of the indole nucleus then affords the benzindolzidine derivatives 151 after rearomatization of the tricyclic radical. 

A further addition-cyclization process that leads to complex fused-ring systems is the dicobalt octacarbonyl-mediated Pauson-Khand reaction which, applied to enynes 209 and 211, gives respectively and in modest yields the tricyclic cyclopentenones 210215 and 212.216... 

On the basis of this palladium-mediated Michael addition cyclization process, a novel two-step synthetic entry into functionalized furan derivatives 67 has also been devised (Scheme 28). Substitution of benzylidene (or alkyli-dene) malonates for their ethoxymethylene analog (65) as activating olefins gave rise to the formation of the corresponding 2-ethoxy-4-arylidene tetrahy-drofurans 66. An in situ addition of potassium ferf-buloxidc induced a decar-boxylative elimination reaction which was followed by an isomerization of the exocyclic double bond. The entire process successively involved a conjugate addition, a palladium-catalyzed cyclization-coupling reaction, a base-induced eliminative decarboxylation, and finally, a double bond isomerization [73]. 

Benzindolizidine systems 963 are generated in moderate yields by a hexabutylditin-mediated consecutive radical addition, cyclization, and oxidation process from easily accessible l-(2-iodoethyl)indoles 962 and methyl acrylate, in one step (Scheme 186) <2000TL10181>. l-(2-Iodoethyl)-l//-pyrrole-2-carbaldehyde was also subjected to the tandem radical addition-cyclization process, and the indolizidine derivative 964 was isolated in modest yield as the major product together with a small amount of starting material (Equation 229). 

Sibi et al. reported an elegant new tandem radical addition-cyclization process for the synthesis of oxacycles [122]. The method relies on the inter-molecular addition of alkyl radical to a doubly activated Michael acceptor moiety, followed by a cyclization step (Scheme 39). The outcome of the re-... 

Naito has also described analogous tandem radical addition-cyclization processes under iodine atom-transfer reaction conditions [16,32], Treatment of 186 with z-PrI (30 eq.) and triethylborane (3x3 eq.) in toluene at 100 °C gave, after cleavage from the resin, the desired lactam product 190 in 69% yield (Scheme 46). Similar reactions involving cyclohexyl iodide, cyclopentyl iodide, and butyl iodide were also reported as well as the reaction with ethyl radical from triethylborane [16,32], The relative stereochemistry of the products was not discussed. 

Mattay and coworkers reported that direct irradiation (2 > 300 nm) of 2-cyclohexene-l-one (251) in the presence of A, A -dimethylallylamine (252) leads to 2,4 y -dimethyl-ds-decahydro-S-isoquinolineone (253) in yields up to 20 % along with trace amounts of 254 (Scheme 60), depending on the polarity of the medium (Table 12) [307]. In polar solvents like acetonitrile containing 10 % water the PET promoted addition-cyclization process competes efficiently with the [2 + 2] cycloaddition pathway leading to dimers (Table 12). Irradiation in the presence of PET sensitizer such as dicyanonaphthalene (DCN) led to only trace amounts of products. 

The reaction of enantiopure cycUc nitrone 69 with alk5mylzinc reagents led to a tandem addition/cyclization process affording 2,3-dihydroisoxazole derivatives 72 in high yields and with complete diastereoselectivity <05EJO2694>. 

Hydroxylamine derivatives add to activated double bonds in the presence of a base to give aziridines where intermediates of the type illustrated above have not been isolated or observed. These reactions may proceed via stereospecific addition of nitrenoid intermediates to the double bonds. However, in some instances, both isomeric aziridines are produced and these are included in Table 21 of the Tabular Survey since the possibility exists that they are formed by a Michael addition/cyclization process. An example is shown in Eq. 172.495... 

Analogous condensations using lithium enolates of MA -diethyl-o-toluamide (149) have been described by Clark and Jahangir for the synthesis of 3,4-dihydro-l(2//)-isoquinolones (151 Scheme 31). It is fortunate that the enolate-imine addition-cyclization process occurs at low temperature, since warming the reaction mixture to room temperature, a common practice in many enolate-imine additions, leads to side reactions due to the instability of the 4-Iithiated derivative (150) formed by release of lithium diethylamide. The authors have exploited the in situ formation of (150) for the synthesis of 4-sub-stituted isoquinolones by trapping it with electrophiles. A cycloaddition mechanism via an... 

There are two conceivable mechanisms which can accommodate these results, v/z., (i) there are two competitive reactions which give a cyclic product (6) and an acyclic product (7) independently, where the cyclic product is formed via Diels-Alder cycloaddition while the acyclic product is yielded by a simple nucleophilic y-addition of VKSA (1), and (ii) there is a common intermediate complex for both the cyclic and acyclic products and 6 is formed through an addition-cyclization process. 

The reactions of 2-pyridineselenenyl- and tellurenyl chlorides with alkenes lead to the formation of products of a tandem electrophilic addition/cyclization process with the ring closure by the nitrogen atom of the pyridylchalcogeno moiety. 

In an elegant synthesis of the marine alkaloid flustramine B, MacMillan and coworkers have used catalyst 2 to promote the first organocatalytic addition/ cyclization process that allows the preparation of the chiral pyrroloindoline motif in a single step [82]. The transformation occurs between 6-bromotryptamine derivative 90 and acrolein via the intermediary formation of indolium ion 91, which is in turn readily trapped in an intramolecular way by the Boc-amino group, giving rise to intermediate 92 (Scheme 35.24). Then, six further additional steps were necessary to accomplish the synthesis of (—)-flustramine B. 

Bao et al. reported a cascade addition/cyclization process for preparing 2-heteroatom substituted benzimidazoles from o-haloarylcarbodiimides 72. Upon nucleophilic addition with amines, imidazoles and phenols, intermediates 75 might form, which in turn underwent intramolecular C-N bond formation to provide 2-amino benzimidazoles 73 and 2-aryloxy benzimidazoles 74 (Scheme 26) [58]. 

Thiazolo[3,2-a]pyridines (CaNS-CjN).— The established synthesis of thia-zolo[3,2-a]pyridines from pyridine-2-thiones and a-bromo-a -unsaturated carbonyl compounds (these Reports, Vol. 1, p. 432 Vol. 2, p. 698) has been further studied. The use of the isomeric a-bromocrotonic acids yields the expected bicyclic products (202), exclusively of the 2,3-trans-configuration, owing to the concurrent isomerization of the cis- to the trans-acid. Activated acetylenes undergo a comparable Michael-addition-cyclization process. Thus, acetylenedicarboxylic acid affords trans-2,3-dicarboxydi-hydrothiazolo[3,2-a]pyridinium salts (204). The intermediate vinyl... 

Another synthetic application starting with functionalized alkynes is the tandem addition-cyclization process. Such processes in the presence of radical initiators have been reported. The first metal-catalyzed version is exemplified by the following experiments [22] thus, when 1,6-heptadiyne is treated with HP(0)(0Me)2 in the presence of Pd(OAc)2 and dppben [l,2-bis(diphenylphosphino)benzene] at 130 C, cyclized product 8 is formed in 76% yield (Scheme 17). N, A -dipropargyl-p-tosylamide reacts similarly, but the major product is pyrrole derivative 9 due to extensive double bond isomerization. Extensimi to //-phosphinate and sec-phosphine oxide is also... 

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