Cycloaddition of cyclohexenones

In the case of cycloalkenes, it is found that the size of the ring is an important factor in product distribution. Photo [2 -I- 2] cycloaddition of cyclohexenone derivatives (4) to carbomethoxy cyclobutene [47], cyclopentene [48], and cyclohexene [49] (see Scheme 5) demonstrates a gradual reversal of regioselectivity from head-to-head to head-to-tail adducts as indicated in Table 2 [50]. This result of head-to-tail products is not consistent with the dipole-dipole interaction theory. Stability of biradical intermediates is suggested to explain the reversed regioselectivity. 

Investigation of [2 -l- 2] photocycloaddition of enones to monosubstituted alkynes indicates that the reaction proceeds with an opposite regioselectivity compared to that of alkenes [71]. Generally, head-to-head adducts are major products except when the group substituted on the alkyne is -CO2R or -OR (see Scheme 17). Thus, methyl propynoate (60, R = CO2CH3) photoadds to cyclopentenone 59 to give 1 1 HH and HT products. Cycloaddition of cyclohexenone to 1-hexyne has also been studied and the HH HT ratio varies from 2 1 to 7 1 as a function of substituents at the enone 3-position. It... 

Cycloaddition of an enone with a cyclic alkene, such as 152, can occur with good stereoselectivity in favour of the thermodynamically more stable exo diastereoiso-mer (153 in this case) (3.108). Cycloaddition of cyclohexenone and Z-but-2-ene or -but-2-ene gave the same mixture of addition products in each case, suggesting that the reactions proceed in a stepwise manner through radical intermediates. Alkynes also add to enones on irradiation to form cyclobutenes. 

Photochemical cycloaddition of cyclohexenone Foturan glass microchannel reactor 300 W high-pressure mercury lamp [6]... 

Scheme 42.48 Chiral phosphoric acid-catalyzed [4+2] cycloaddition of cyclohexenone and aromatic aldimines via three-component methodology.

Conjugated cyclohexenones [6] have also been easily prepared by combining the cycloaddition of dimethylaminobutadiene 4 and several cyclic and acyclic dienophiles followed by the elimination of the amino group from the cycloadducts under acidic conditions. Scheme 2.3 summarizes some of these results. 

A broad study of aluminum chloride-induced cycloadditions of cyclopente-nones, cyclohexenones and cycloheptenones with 1,3-butadiene (1), isoprene... 

Highly uMtr-diastereofacial selective cycloaddition of isoprene (2) with 4-isopropyl-2-cyclohexenone allowed a short regiocontrolled and stereocon-trolled synthesis [13] of jS-cadinene and (y2-cadinene, Scheme 3.3). High anti-diastereofacial selectivity also occurs in the Diels-Alder reaction of optically active cyclohexenones 6-9 (Figure 3.2), readily available from the chiral pool, with open chain dienes [14-16]. Their cycloadducts are valuable intermediates in the synthesis of optically active sesquiterpenes in view of the easy conversion of the gem-dimethylcyclopropane and gem-dimethylcyclobutane in a variety of substituents. 

Similarly, cycloaddition of the cyclohexenone-like dienophile 40 with 2-tri-methylsilyloxy-1,3-butadiene (41) allowed [7] the regio- and stereoselective synthesis of tetracyclic compound 42, in high yield (Equation 5.5). 

An useful intermediate for the preparation of 1,4-cyclohexanediones is obtained by cycloaddition of 6-isopropyl-3-methyl-2-cyclohexenone to a cyclobutanediol derivative (4.59) 470>. 

Intramolecular [2 + 2]-cycloadditions of allenes and enones occur with fair to good site- and regioselectivities. Thus, cyclohexenone 40 bearing an allenic side-chain at the C3 position was irradiated and a single product 41 was isolated in 95% yield [45],... 

Carbonylative [5 + l]-cycloaddition of allenylcydopropanes was successfully achieved by use of an Ir(I) catalyst to yield (2-alkylidene)cyclohexenones in good yields (Scheme 16.43) [43]. No carbonylative [5 + l]-cycloaddition was observed in the case of an allenylcyclopropane lacking substituents at the allenic terminus. It can be deduced that the metal is too distant to open the cyclopropane ring, probably owing to the preferred -coordination at the allenic Jt-bond distal to the cyclopropyl group. 

Scheme 41 Mechanism of the aza-Diels-Alder-type reaction of cyclohexenone 2.3.12 1,3-Dipolar Cycloaddition...

In later work, Mioskowski and co-workers (320) used cyclohexenone 160 to prepare oxime 161 as part of a twofold nitrile oxide strategy to synthesize the basic taxol ring system. Cycloaddition of 161 was effected by means of sodium hypochlorite and gave tricyclic isoxazoline 162, which feamres rings A and C of taxol (320) (Scheme 6.79). Nagaoka and co-worker tried to apply a related intramolecular cycloaddition toward the synthesis of the taxane A/B ring but this approach failed, producing only the oxime derivative (248) (see Scheme 6.44, Section 6.3.1). 

Photochemical cycloaddition of ethene with racemic 4-/er -butyl-2-cyclohexenone yields three racemic diastereomers107. For configurational assignment, see pp 463 and 472. 

In principle, relative configurations can be determined directly by X-ray analysis (see Section A.4.2.). However, in cases where the compound of interest does not crystallize or does not give suitable crystals, it may be desirable to use crystals of a derivative. For example, photochemical cycloaddition of rac-4-tcrr-butyl-2-cyclohexenone and ethene yielded three stereoiso-meric products. The relative configuration of the (l, 55, 6 )-isomer (rac-6 on p 411) was determined by reduction and 4-bromobenzoate formation followed by an X-ray analysis107. 

If 2-methylenecyclobutanones, which themselves are not capable of this tautomerization and the following rearrangement, bear alkyl substituents with an a-hydrogen in the 3-position, still another rearrangement, a [1,3] shift, precedes the actual ring-enlargement step. This is important, because either 3-alkyl-2-methylene- or 2-alkylidenecyclobutanones or mixtures of both may be formed via [2 + 2] cycloaddition of allenes92 and can all be used as precursors for the same cyclohexenones. 

Occidentalol (628), a eudesmane-type sesquiterpene isolated from the wood of Eastern white cedar, was synthesized from a as-fused decalin system (627) prepared by cycloaddition of the a-pyrone (625) with 4-methyl-3-cyclohexenone (626 Scheme 140) (72TL4651). Derivatives of 2-pyrone have also been employed in syntheses of colchicine (629 Scheme 141) (59AG637) and barrelene (630 Scheme 142) (69JA2330). 

Cycloadditions can also be initiated by the CpFe(CO)2+ fragment, as demonstrated by Rosenblum s group in an early report where a CpFe (CO)2-CH2CH=CH2 complex reacts as the C3-component with the CpFe(CO)2+ adduct 49 of cyclohexenone to give the bicyclic product SO (Scheme 9.36) in very moderate yield of 10% [94],... 

Fukuyama, Ryu and coworkers reported intermolecular [2 + 2]-type cycloaddition of various cyclohexenone derivatives and alkenes using a micro reactor made entirely of glass, which was supplied by Mikroglas (Scheme 4.26) [39]. The device was equipped with a heat exchanger channel system through which water flowed to maintain isothermal reaction conditions. The remarkable photochemical efficiency of this device was manifested in rapid cycloaddition of vinyl acetate to cyclohex-2-enone. With this device, the desired product was obtained in 88% yield after 2 h, whereas the same reaction carried out in a Pyrex flask was very sluggish (only 8%... 

The photo-[4+2] cycloaddition of furan with Pummerer s ketone 102 [70,71] gives evidence for the intermediacy of the highly twisted enone intermediate 103, and a biradical cycloaddition pathway (Sch. 23). The structures of the endo and exo products 104 were confirmed by X-ray crystallography [72,73]. In a related comparison of cyclohexenone and cyclopentenone photochemistry, conditions that gave [4+2] adducts for the cyclohexenone produced only [2+2] adducts from cyclopentenone [74]. 

An additional example is a two-step approach to the preparation of 1,5-cyclo-decadiene. By a photochemical cycloaddition of a substituted cyclobutene and 2-cyclohexenone, a strained tricyclo[4.4.0.02,5]decane system is generated. Thermolysis of the tricycle gave 1,5-cyclodecadiene [52]. 

Cyclobutanones are obtained from cycloaddition of ketenes to enamines (see Section IV.A and Chapter 18)266. Such cycloadditions may be concerted or step-wise depending upon the amine moiety and the experimental conditions. Vinylketenes are especially interesting since these may undergo [2 + 2] or [4 + 2] cycloadditions to give after oxidation a vinylcyclobutanone or a cyclohexenone, respectively267,268. 

Ketals have also been used as an alternative to link the chiral inductor to the starting reagents. An important asymmetric induction was observed during the cycloaddition of ketals 94 having a C2 axis of symmetry, and a cyclopentenone or cyclohexenone derivative 95. Unfortunately, the observed chemical yields of 96 remain low (Scheme 22) [68]. With ketals of aliphatic enones, the selectivity decreases, and complex mixtures of isomers were observed [69]. 

Catalyst for DIels-Alder reaction of ynamlnes. A zero-valent iron species prepared by reduction of iron(III) chloride with isopropylmagnesium chloride serves as a unique catalyst for cycloaddition of butadiene and ynamines (1) to form 1,4-cyclohexadienamines (2). These products are hydrolyzed by mild acid treatment to (3,y-cyclohexenones (3), which are isomerized to either 4 or 5 by catalytic amounts of rhodium catalysts. 

The intramolecular 1,3-cycloaddition of azidoalkyl cyclohexenones occurred smoothly when the temperature range was between 80-110 °C, however, aziridines were obtained from the intermediate dihydrotriazoles il the correct substitution pattern and regiochemical arrangement were present, cf. formation of 13 and 14 vs. IS131,132. The reaction was applied to the formal total synthesis of ( )-desamylperhydrohistrionicotoxin132. Direct nitrene enone addition can not be ruled out when the reaction is performed in refluxing xylene. 

---