Intramolecular Conjugate Additions

Both p-carbolines and the corresponding oxa analogs have been obtained by InBrs-catalyzed intramolecular addition reactions [294]. 

The cyclization of 103-A exhibits some enantioselectivity when conducted with a BINOL-phosphoric acid [295]. 

Similar a, (3-unsaturated aldehydes have been cyclized by iminium-type catalysis [296], 

Benzylidene malonate esters have also been subjected to enantioselective cyclization [297]. 

---

The success of intramolecular conjugate additions of carbon-centered radicals in multifunctional contexts is noteworthy. Compound 57 (see Scheme 10), prepared by an interesting sequence starting from meto-toluic acid (54) (see 54 > 55 > 56 > 57), can be converted to the highly functionalized perhydroindane 58 through an intramolecular conjugate addition of a hindered secondary radical.21-22 This radical cyclization actually furnishes a 6 1 mixture of perhydroindane diastereoisomers, epimeric at C-7, in favor of 58 (96 % total yield). It should be noted that a substantially less strained cis-fused bicyclo[4.3.0] substructure is formed in this cyclization. 

Scheme 2. Intramolecular conjugate addition for the construction of tetrahydropyrans affords the thermodynamically most stable isomer.

It will be recalled that one of the key operations in the synthesis of IJK ring system 86 is the intramolecular conjugate addition reaction (see 90—>89, Scheme 17b) to form ring J. In the context of compound 90, the electrophilic a,/ -unsaturated ester moiety and the potentially nucleophilic tertiary hydroxyl group reside in proximal regions of space, a circumstance that would seem to favor the desired cyclization evept (see Scheme 19). Indeed, exposure of a solution of 90 in THFto sodium hydride (1 equiv.) for one hour at 25 °C results in the formation of compound 89 in 92% yield. In... 

An example of intramolecular conjugate addition of aryllithium generated by halogen metal exchange reaction of 92 is illustrated in equation 7966. 

The tandem intramolecular conjugate addition to 99 followed by an intramolecular alkylation reaction leads to a bis-cyclized product in good yield (equation 80)66. 

Some examples of conjugate addition reactions of allylic silanes are given in Scheme 9.5. Entries 1 to 3 illustrate the synthesis of several (3-allyl ketones. Note that Entry 2 involves the creation of a quaternary carbon. Entry 4 was used in the synthesis of a terpenoid ketone, (+)-nootkatone. Entry 5 illustrates fluoride-mediated addition using tetrabutylammonium fluoride. These conditions were found to be especially effective for unsaturated esters. In Entry 6, the addition is from the convex face of the ring system. Entry 7 illustrates a ring closure by intramolecular conjugate addition. 

The intramolecular conjugate addition of either a 1 2 mixture of (E)- and (Z)-isomers or pure (Z)-isomer of 209 proceeded smoothly using KOBu between —58 and — 20°C and gave an 8 11 mixture of perhydropyrido[l,2-c] [l,3]oxazines 91 and 92 <1996SL100>. 

Finally in 2005, Hutt and Mander reported their strategy for the synthesis of nominine (Scheme 1.3) [29], The approach relies upon construction of the steroidal ABC carbocyclic ring structure followed by stepwise preparation of the fused aza-ring system. In the key sequence of the synthetic study, enone 50 was oxidized to dienone 51 with DDQ followed by Lewis acid-catalyzed intramolecular conjugate addition of the methylcarbamate to the newly formed dienone to deliver pyrrolidine 52. 

The intramolecular conjugate addition of ureas 129 to form quinazolinones 130 was reported by Xin and co-workers <00TL1147>. Ureas 129 were reported to be the major byproducts of Molina s carbodiimide methodology for making quinazolinones <94S1197>, which according to this work, can now be further transformed to the desired product. 

The sequential intramolecular conjugate addition of the oxime followed by intramolecular dipolar cycloaddition of the intermediate nitrone affords a... 

Enantiopure quinolizidinones and indolizidinones were obtained by Ma and Zhu in an intramolecular conjugate addition of the secondary amine of 293 to the alkynoate ester to provide the intermediate allenoate 294, which was subsequently trapped in a condensation reaction to afford 295 (Scheme 19.53) [62], In some instances, intermediate 296 was isolated, which could also be converted to 295. This quinolizidinone intermediate was then converted in a concise manner to lasubine II (297). 

This kind of reactivity turned out to be particularly attractive when applied to suitably functionalized terminal alkynes. Oxidative monoaminocarbonylation of 4-yn-l-ols led to the formation of tetrahydrofuran derivatives through intramolecular conjugate addition of -OH group to the triple bond of the initially formed 6-hydroxy-2-ynamide intermediates (Scheme 38) [310]. 

High levels of asymmetric induction can be achieved intramolecularly if the substrate functionality and the heteroatom ligand are contained in the same molecule. Chiral amido(a]kyl)cuprates derived from allylic carbamates [(RCH= CHCH20C(0)NR )CuR undergo intramolecular allylic rearrangements with excellent enantioselectivities (R = Me, n-Bu, Ph 82-95% ee) [216]. Similarly, chiral alkoxy(alkyl)cuprates (R OCuRLi) derived from enoates prepared from the unsaturated acids and trans-l,2-cyclohexanediol undergo intramolecular conjugate additions with excellent diasteroselectivities (90% ds) [217]. 

Takasu examined a series of five imidazolidinone catalysts in the intramolecular conjugate addition of amides to a,p-unsaturated aldehydes to prepare a series of tetrahydroisoquinolines [114]. Although yields were high for these organo-catalytic transformations (70-90%), enantiomeric excesses were low (18-53%) showing further optimisation with regards to the co-acid and solvent are necessary to bring this potentially useful transformation in line with other reactions of this class. 

Scheme 3.22 Rhodium-catalyzed asymmetric intramolecular conjugate addition-aldol reaction [40],...

N-alkinyldihydropyridone 72 yields bicyclic lactam 73 (92JA7292), and rhodium-complex-catalyzed intramolecular conjugate addition of vinylstan-nanes 74a and b (formed by aza-Diels-Alder reaction) leads to chiral piperidones 75a and b (08T3464). 

Intramolecular conjugate addition of allylic silanes can also be used to construct new rings, as illustrated by entry 6 in Scheme 9.5. 

Hydroxylation of 711 at C-2 can be achieved by an intramolecular conjugate addition of the benzamide to the enone system. The reaction takes place in high yield in the presence of a Lewis acid and affords direct hydroxylation with a syn relationship to the amide group via an intermediate 1,3-oxazoline (Scheme 7.223). " ... 

Lactone 86 undergoes an intramolecular conjugate addition reaction in the presence of cesium fluoride and tetraethyl orthosilicate to give furo[3,2- ]pyridine dione 87 (Equation 25). After 12 h, a 1 1 mixture of 3-ethyl epimers is found however, extending the reaction time to 72 h results in exclusively /3-ethyl isomer 87 in good yield <2005JOC384>. 

M. Hirama u. S. Ito, Heterocycles 28, 1229-1247 (1989) . .Asymmetric Induction in the Intramolecular Conjugate Addition of y- or d-Carbamoyloxy-a,/ -unsaturated Esters. A New Method for Diastcreo-selective Amination and Divergent Syntheses of 3-Amino-2,3,6-trideoxyhcxoscs". 

Intramolecular conjugate addition annotation of cyclohexenones.1 A new method of effecting carbocyclization involves conjugate addition to cyclohexenones mediated by an alkyltin(IV) reagent. An example is formulated in equation (1). 

Intramolecular conjugate addition occurs in the /3-sulfonylstyrenes (196) (72BCJ1893) and (197) (74JMC549) to give 1,2,4-thiadiazines. In the case of (197), subsequent elimination of HBr gave the fully unsaturated system. Similar intramolecular conjugate addition of oxygen and sulfur nucleophiles to sulfonylstyrenes and sulfonylalkynes also occurs. 

---