Disubstituted cyclobutanes

Cyclobutane adopts a puckered conformation in which substituents then occupy axial-like or equatorial-like positions. 1,3-Disubstituted cyclobutanes show small energy preferences for the cis isomer since this places both substituents in equatorial-like positions. The energy differences and the barrier to inversion are both smaller than in cyclohexane. 

The presence of a pyrrolidine unit in complex systems such as the azabicy-clo[2.1.1]hexane unit of 2,4-methanoproline (56) lends itself to synthesis pertaining to the 1,3-disubstituted cyclobutane part of the molecule. Thus two syntheses of 56 have been published, relying on the [2 + 2] photochemical synthesis of cyclobutanes. A nontrivial problem of the synthesis of these compounds is liberation of the target molecule from its protective groups (Scheme... 

With even-membered rings certain molecules show only geometric isomerism. Examples are afforded by 1, 3 disubstituted cyclobutanes. 

Phenyl vinyl ethers 1 undergo regiospecific but not stcreospecific dimerization to give a mixture of cisjtransA, 2-disubstituted cyclobutanes 2 and 3 on irradiation in the presence of dimethyl terephthalate in acetonitrile.5... 

Reductive rearrangement of alk-l-enyl alkyl acetals, promoted by triisobutylaluminum, stereoselectively gives 1,2-disubstituted cyclobutane derivatives. From the (S )-acetal 1, the (1. S,2.R)-cyclobulane derivative 2 is predominantly formed.39 However, the enantiomeric excess in this reaction is low because of competing racemization prior to the rearrangement. 

Semiempirical calculations on the 2+2 photocycloaddition between two propene molecules has suggested that there is a preference for a head-to-tail approach and a concerted pathway [7]. The authors suggest that intermolecular cycloaddition between alkenes with electron withdrawing groups should favor formation of the nms-l,3-disubstituted cyclobutane. 

Photocyclodimerization of electron-rich alkenes via photoinduced electron transfer is a useful method for preparation of cyclobutanes. A commonly accepted mechanism for this photoreaction is shown in Scheme 19. The radical cation of an alkene reacts with another neutral alkene to give a dimer radical cation. The dimer radical cation (1,4-radical cation) cyclizes, after one-electron reduction, to give a 1,2-disubstituted cyclobutane. 

The 2,4-disubstituted derivatives of the aforementioned 3-metallacyclobutanones allow for cis and trans isomers, much as for cyclobutanone and cyclobutane. It is found that the diphenyl species [Pt CHPhC(0)CHPh (PPh3)2] is synthesized with predominantly cis stereochemistry. This is consistent with stereochemical expectations—however, disconcertingly, there are no examples of disubstituted cyclobutanes (or derivatives) for which the enthalpy of formation of both the cis and trans isomers are both known to confirm this expectation. Gibbs free energy differences have been determined for the dimethyl , dichloro, dibromo and diiodo ° species, again in the expected order °. Indeed, the only case where the trans isomer is known to be more stable than the cis is the enigmatic bis-phenylsulfonyl species for which no explanation has been offered ... 

Styrene, butadiene and divinylacetylene similarly give [2 + 2] cycloadducts of head-to-head regiochemistry as mixtures of cis and trans 1,2-disubstituted cyclobutanes. The tetramethylene diradical... 

Lund and co workers [51] reported interesting stereochemical results in the reductive dimerization-cyclization of benzylidenemalononitrile, but the reaction pathway was not stereochemically clarified. Recently, it has been clearly demonstrated by some workers [51-54] that the reductive cyclodimerization of activated olefins in aprotic media affords the 1,2-disubstituted cyclobutanes as shown in Eq. (4). 

Compounds 7 and 8 (cyclobutanes are usually drawn in this style) are termed cis and trans, respectively. Further, 7 and 8 are diastereoisomers, though neither is chiral this is significant in that diastereoisomers encountered previously, e.g. (R, R) and meso tartaric acids, have at least one chiral member. Indeed, this observation is general for disubstituted saturated cyclic hydrocarbons provided that the number of carbon atoms in the ring, n, is even and that the substituents are located at carbon atoms 1 and 1 + nil). For cyclobutanes this corresponds to C(l) and C(3), and for cyclohexanes C(l) and C(4). The stereochemistry of 1,2-disubstituted cyclobutanes is analogous to that of cyclopropanes. 

Cis-1,4-dimethylcyclohexane, 25 and 26 collectively, is therefore a diastereoisomer of its trans- 1,4-dimethyl counterpart, 17 and 18, although neither is chiral. This relationship therefore parallels that previously mentioned in respect of 1,3-disubstituted cyclobutanes (Section 6.3). The six configurational possibilities are summarized in Table 6.1. 

Cyclobutane is not flat. Cis- and //v/m-l,3-disubstituted cyclobutanes are diastereoisomers, though neither is chiral. This unusual situation applies also to 1,4-disubstituted cyciohexanes, When the substituents are identical, a. v-l, 3-disubsti-tuted cyclopentanes and cis-1,3-disubstituted cyciohexanes are mesa the corresponding tram isomers are chiral. 

A. Compound 60 is of the same substitution pattern as dichloromethane, and the hydrogens Ha and Hb are homotopic. Compound 61 has the same pattern as ethanol here Ha and Hb are enantiotopic. In compound 62, Ha and Hb are homotopic here a in other homotopic examples, H and Hb lie astride a symmetry plane. In compound 63, Ha and Hb are diastereotopic. Separate replacement of Ha and Hb by D in 63 gives a pair of diastereoiso-mers (that is stereoisomers that are not enantiomers). In compound 64, Ha and Hb are diastereo topic this can be confirmed by separate replacement of Ha and Hb by D, to give a pair of diastereoisomers. Note that previously (Sections 6.3 and 6.5.2) we have shown that cis and trcms 1,3-disubstituted cyclobutanes and cis and tram 1,4-disubstituted cyclohexanes constitute a pair of achiral diastereoisomers. In compound 65, Ha and Hb are enantiotopic. In fused-ring molecules, substituents are often drawn where Ha/Hb are located in 65 however, anti-clockwise rotation by 120° around an axis through the bridgehead carbons puts Ha and Hb in a position where their enantiotopicity can be seen more easily. 

Regio- and stereoselective synthesis of aluminacyclopentanes from terminal alkenes or alkynes and ethylaluminum reagents is achieved with dichloro zirconocene as catalyst73 "19. The metal-lacyclic product can be converted to trans-l,2-disubstituted cyclobutanes in the presence of a palladium(II) catalyst74. 

Two conformations are possible for cyclobutanes, a flat planar structure or a puckered one. Cyclobutane itself has been determined to possess a puckered geometry in the gas phase by electron diffraction. A puckered conformation is also consistent with equilibration studies of 1,3-disubstituted cyclobutanes, which indicate that the ds-isomer is more stable than the trans. Such observations are consistent with the equatorial-like orientation of cis substituents in a nonplanar... 

Consider that cyclobutane exhibits a puckered geometry. Judge the relative stabilities of the 1,2-disubstituted cyclobutanes and of the 1,3-disubstituted cyclobutanes. (You may find it helpful to build handheld molecular models of representative compounds.)... 

A 1,3-disubstituted cyclobutane has also been utilized to prepare 9,11-methano-TXA2 (335). Thus the cyclobutanone (332) was transformed into the alcohol (333). lodoetherificat ion of (333)under carefully controlled conditions gave the bicyclic ether (334) and this compound was converted into the required TXA, analogue (335), using standard methodology (Scheme 48)... 

Cyclobutane adopts a puckered conformation. Substituents then occupy axial-like or equatorial-like positions. 1,3-Disubstituted cyclobutanes show small energy... 

Brown s book on organic synthesis via boranes, ° and reviews on sulphene chemistry, the use of activated metals in organic and organometallic chemistry, the Wolff rearrangement of a-diazocarbonyl compounds, and ring contractions and expansions of vicinally disubstituted cyclobutanes and cyclopropylmethyl compoundsare also of appreciable relevance to bridged carbocyclic chemistry. Other pertinent, but more specialized, reviews are recorded in the various sections of this chapter. 

Baran successfully employed a regioselective substrate-controlled sequential arylation strategy via Pd-mediated C—H functionalization toward the construction of the piperarborenine cyclobutane containing family of alkaloids (Scheme 3.31). At the time of publication this was the first example of sp hybridized arylation of the cyclobutane ring. Cw-disubstituted cyclobutane 36 underwent a regio- and completely diastereoselective sp C—H arylation with the listed aryl iodide to afford advanced intermediate 37. Epimerization of the resident amide followed by a successive sp C—H arylation afforded tetra-substituted cyclobutane 39. 

Cyclic Structures with Two Stereogenic Centers Disubstituted Cyclobutanes... 

Review "Ring Contractions and Expansions of Vicinally Disubstituted Cyclobutanes and Cyclopropylmethyl Compounds"... 

The bicyclo[3.2.0]heptanols obtained through this cycloaddition process can be exploited for the stereocontroUed synthesis of 1,2-disubstituted cyclobutanes. The concept is demonstrated by the synthesis of grandisol 53 (Scheme 16), the pheromone of the male cotton boU weevil Rosini et al. have described... 

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