Cyclizations cyclobutanes

The alkylation of enamines with nitroolefins, which gives intermediates for reductive cyclization (6S2), also provided an example of a stable cycliza-tion product derived from attack of the intermediate imonium function by the nitro anion (683). A previously claimed tetrasubstituted enamine, which was obtained from addition of a vinylsulfone to morpholinocyclohexene (314), was shown to be the corresponding cyclobutane (684). Perfluoro-olefins also gave alkylation products with enamines (685). Reactions of enamines with diazodicarboxylate (683,686) have been used diagnostically for 6-substituted cyclohexenamines. In a reaction of 2-penten-4-one with a substituted vinylogous amide, stereochemical direction was seen to depend on solvent polarity (687). 

Larock has developed a new catalyst system for the Pd-catalyzed cyclization of olefinic tosylamides. Whereas typical conditions require either stoichiometric amounts of Pd(II) salts or catalytic amounts of Pd(II) in the presence of benzoquinone as a reoxidant, the new catalyst system utilizes catalytic Pd(OAc)2 under an atmosphere of O2 in DMSO with no additional reoxidant <96JOC3584>. Although o-vinylic tosylamides 76 can be cyclized to Af-tosylindoles 77 using this catalyst system, PdCla/benzoquinone is more effective for such cyclizations. Interestingly, in the case of o-allylic tosylanilides, the cyclization can be modulated to afford either dihydroindole or dihydroquinoline products. In a related approach involving a common 7i-aUyl Pd-intermediate, 2-iodoanilines were coupled with vinylic cyclopropanes or cyclobutanes in the presence of a Pd catalyst to afford dihydroindoles <96T2743>. 

The preparation of cyclobutanes via the catalytic conditions can be extremely efficient provided that the radical formed after epoxide opening is sterically shielded and cyclization promoted by the Thorpe-Ingold effect. It... 

It can be assumed that, upon irradiation, tautomer 5-40-II reacts with the alkene 5-41 in a highly regioselective [2+2] cycloaddition to give the cyclobutane 5-42 as an intermediate. Subsequent retro-aldol-type reaction and hemiacetal formation produces 5-44 via 5-43. After addition of the Lewis acid (BF3-Et20), cyclization takes place to give the desired products. It should be noted that the excess of alkene must be removed under reduced pressure before addition of the Lewis acid in order to avoid polymerization. 

The same type of bis-functionalization has been reported for the palladium-catalyzed borylstannylative carbocy-cyclization of 1,6-, 1,5-, 1,7-diynes, bis-propargylamine, and ether.377 It should be noted that even 1,2-dialkylidene cyclobutane can be obtained in reasonable yield. Ito has proposed the related silaborative reaction involving nickel(O) catalysis.378 This reaction has been performed in an intra- and intermolecular fashion. The intramolecular reaction allows the formation of cyclic dienes and the intermolecular process proceeds through a dimerization of alkynes to give acyclic dienes. 

Cleavage of the cyclobutane ring of (277) by Lewis acid followed by cyclization of the allylsilane (278), furnished the tricyclic compound (278)94). 

Dipolar species have been observed in the cycloaddition of polar intermediates. Thus cyclobutanes can be formed by non concerted processes involving zwitter ionic intermediates. The combination of an electron rich alkene (enamimes, enol ethers) and an alkene having electron withdrawing groups (nitro a cyano substituted alkenes) first gives a zwitter ion which can rotate about the newly formed bond before cyclization and gives both a cis and a trans adduct. 

The presence of hetero-atoms within the system, remote from the alkene double bonds, does not have an adverse influence on the SET processes that occur. Thus irradiation of the diene 33 in benzene solution with 1,4-dicyanonaphthalene as the electron-transfer sensitizer affords the cyclobutane 34 in 78% yield. Various examples of the reaction were described giving cyclobutane derivatives in 54-69% yield. Benzene, or an arene solvent, is vital for the success of the reaction. When acetonitrile is used, allylation of the sensitizer (akin to the photo-NOCAS reaction) results in the formation of the three products 35-3718. (2 + 2)-Cyclization of this type described for 33 is also seen with the dialkenyl ether 38. When 38 is irradiated using X > 350 nm or X > 450 nm in acetonitrile... 

The aryl groups of the styryl systems need not be unsubstituted, as has been illustrated before for the cyclizations encountered in the synthesis of naphthalenophanes from 120. Indeed cyclization to afford a cyclobutane derivative where methoxy groups are on the adjacent ring position to the vinyl moieties has also been studied. The irradiation of 138 affords the m-cyclophanes 139 and 14065. Further study has sought to evaluate the steric effect of o-methoxy groups in such molecules66. 

Bond constructions similar to those just discussed can be achieved using an alkylidene malonate which is tethered to an alkyl bromide [72]. Of particular interest in this context is the controlled potential reductive cyclization of 263. As illustrated, the method provides a reasonably facile and modestly efficient entry to cyclobutanes 264. Presumably, the process is initiated by reduction of the alkylidene malonate rather than the alkyl halide, since alkyl bromides are more difficult to reduce. The same substrate, when reduced with L-Selectride undergoes conjugate addition of hydride and a subsequent cyclization leading to the five-membered ring 265. The latter transformation constitutes an example of a MIRC reaction [71-73], a process which is clearly complementary to the... 

Recently it has been shown that radical anionic cyclization of olefinic enones effectively compete with intramolecular [2 -I- 2]-cycloaddition to form spirocy-clic compounds [205, 206], 3-Alkenyloxy- and 3-alkenyl-2-cyclohexenones 235 are irradiated in the presence of triethylamine. As depicted in Scheme 46 two reaction pathways may operate. Both involve electron transfer steps, either to the starting material (resulting in a direct cyclization) or to the preformed cyclobutane derivative 239, which undergoes reductive cleavage. The second... 

An alternate method for cyclizing ae./i-dihalobutanes is to use a controlled potential electrolytic reduction. 10 12 This method appears to be superior to the conventional reductive cyclization of 1,4-dihalobutanes with metals. Dibromides generally give better results than dichlorides in an aprotic solvent such as dimethylformamide or acetonitrile. Thus, a DC voltage of 1.8-3.0 V was applied for 6 hours to a solution of 1,4-dibromobutane (50 g) in dimethylformamide (1 L) in a cell consisting of a mercury cathode and a nichrome anode, to give cyclobutane and butane in 25 and 75 % yield, respectively.10,11 The experimental setup has been described in a detailed procedure.12... 

It has been shown that the cyclization step of 3-halopropylmalonic esters to give cyclobutane-1,1-dicarboxylatcs, e.g. 3. is rate-determining.4 A convenient synthesis of cyclobutyl derivatives via hydroboration has been reported.5 In this case, 4-tosyloxybut-1-yne was bishydroborated with 9-borabicyclo[3.3.1]nonane (9-BBN), and this was followed by treatment with methyllithi-um to give 9-cyclobutyl-9-BBN 4 in 65% yield.5 24... 

Somewhat surprisingly, cyclobutanes are formed in preference to cyclopentanes from the cyclization of an epoxynitrile as shown below. 

Intramolecular [2 + 2 + 2] cycloadditions belong to the same type of valence isomerization as those of 1,5-unsaturated compounds to cyclobutanes.70 The cobalt-mediated cyclization of l-en-5-ynes stereoselectively converts enediynes directly to bicyclo[4.2.0]hexa-l,3-dienes, as single diastereomers, when a stoichiometric amount of dicarbonyl(cyclopentadienyl)cobalt is used. This cyclization90 has a high efficiency (92%). An example is the synthesis of the protoilludane framework 23 from the enediyne precursor 22.71... 

Like many ionic cyclizations, the formation of cyclobutane rings by radical cyclizations is very slow, and powerful accelerating effects will be required for any synthetic applications (see Scheme 7).2 These cyclizations are again reversible, and, in the absence of any other effects, the equilibrium lies to the side of the open radical due to ring strain. The fragmentations of simple cyclobutyl carbinyl radicals are slow,... 

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