Cyclopropenes nucleophilic addition

Reaction of cyclopropenes with bases such as alkoxide or amide ions often leads to a methylenecyclopropene by removal of an allylic hydrogen and reprotonation 6 9-71) though other reactions such as nucleophilic addition (see Section 5) or metallation at a vinylic position (see Section 2) may compete. Thus the ester (209) is isomerised by KOH to (210), and under more vigorous conditions to (211)144) ... 

The reaction of either cis- or trans-1 with potassium /-butoxide in tetrahydrofuran at 25 °C leads to a /-butyl ether (2), apparently arising by attack of /-butoxide ion on an intermediate l,4-di-/-butylmethylenecyclopropene. If the reaction is carried out at low temperature and the volatile materials are distilled directly into a cold trap, the cyclopropene can be trapped, albeit in low yield (10 %), by added cyclopentadiene or detected directly by low-temperature NMR23. In a related example, a l,l-dihalo-2-bromo-3-methylcyclopropane (2a) leads to products which are also apparently derived through an intermediate 1 -chloro-3-methylenecyclopropene which undergoes nucleophilic addition (See Ref. 80). 

The dichloride 17, R = H is dehydrohalogenated to a cyclopropene by addition of nucleophiles such as phenylthiolate but, in the absence of a trap, it ring-opens to a carbene which in turn is intercepted by insertion into the solvent36,37,85. In the case of related cyclopropanes e.g. 17, R = CH2CH2Ph, the carbene may be trapped in intramolecular reactions38 ... 

As further illustrated in Scheme 2, the 1-methyl- and 1,3,3-trimethylcyclopropene are rapidly metallated with organolithium reagents in ether to afford stable solutions of the 1-lithiocyclopropenes (18) In comparison, solutions of the metallocyclopropenes (16) are significantly less stable and even at — 40°C are observed to degrade slowly to a mixture of dimeric and trimeric products apparently formed by nucleophilic addition of 16 to the highly reactive cyclopropene n system L Alkylation of 18 (R=H or Me) with methyl iodide produced 1,2-dimethyl- and 1,2,3,3-tetramethylcyclopropene . The trimethyl derivative 18 (R = Me) has also been carbonated and acylated to afford the corresponding 2,3,3-trimethylcyclopropene carboxylic acid, methyl ketone and carboxaldehyde. 

Cyclopropenes, even unactivated ones, exhibit extraordinarily high reactivity in both electrophilic and nucleophilic addition reactions. They are also good dienophiles and react with a variety of conjugated dienes including acyclic 1,3-dienes, alicyclic 1,3-dienes, anthracenes and furans. An endo selectivity is usually observed. An alkyl or aryl substituent at the 3-position of cyclopropene sterically hinders the Diels-Alder addition and thus 3,3-dialkyl- and 3,3-diarylcyclopropenes exhibit a reduced dienophilicity (equation 131) . On the other hand, numerous Diels-Alder reactions have been reported for 3,3-dicyano- and 3,3-dihalocyclopropenes. The reactions of 3-monosubsti-tuted cyclopropenes with the diene take place stereoselectively from the less crowded side of the substrates (equation 132) °. 

A little-used route to stereoselectively labeled cyclopropanes is nucleophilic addition to the corresponding cyclopropene. Access to both labeled and unlabeled cyclopropenes from the corresponding 1-alkynes allows preparation of both diastereomers of the labeled product. This route is one of the few that would allow easy preparation of a 1,1-disubstituted-cyclopropane-2-d. Cyclopropanation of the corresponding alkene would in principle achieve the same goal but preparation of such alkenes with a label in a defined stereochemical position is not easy. An example of the approach is shown in Figure 10. ... 

Many cyclopropenes unsubstituted at C(3)are unstable and nucleophilic addition to the n bond often occurs. Cyclopropene esters 44 are not capable of isolation even when lithium dialkylamides are employed to effect the dehydrohalogenation reaction. Recent... 

Nucleophilic additions to the cyclopropene double bond are particularly well documented for strained and/or highly reactive derivatives " Thus bicyclo-[4.1.0]hept-l(7)-ene (139) can be trapped by oxygen, sulphur and carbon nucleophiles (equation 52) and the rapid reactions effect a syn-addition. Cyclopropenone dimethyl... 

Nucleophilic addition of t-butylisocyanide to cyclopropene 280 gives vinylketen-imines but the same cyclopropene with ynamines affords mixtures of furan 282 and... 

Formation of arylcyclopropanes also occurs when l-chlorotricyclo[3.1.0.0 ]hexane and 1-chlorotetracyclo[4.1.0.0 . 0 jheptane were reacted with phenyllithium. Both reactions involve formation of a strained cyclopropene by phenyllithium-promoted elimination and subsequent addition of the same organometallic species to the strained alkene. When the intermediate alkene is symmetric, such as tricyclo[3.1.0.0 ]hex-l(6)-ene (7), generated from 1-chlorotri-cyclo[3.1.0.0 ]hexane, the nucleophilic addition of phenyllithium leads to one product only, l-phenyltricyclo[3.1.0.0 ]hexane (8). However, when 4-chlorotetracyclo[4.1.0.0 ". 0 ]hept-ane was reacted with phenyllithium, the intermediate formed, tetracyclo[4.1.0.0 . 0 ]hept-3-ene, was unsymmetric and gave a 1 1 mixture of cis- and ra s-3-phenyltetracyclo-[4.1.0.0 . 0 ]heptane (9) in 90% yield when nucleophilic addition of phenyllithium to the double bond occurred.The cM-product can be regarded as the formation of one C-H and one C-C bond (Section 5.2.1.3.5). 

Attempted dehydrochlorination of (206) by potassium t-butoxide does not generate the expected spirene, but affords (209) instead. Cyclopropenes, a-elimination, and simple substitution have been excluded from the process, and the route is believed to involve (207), reacting from the preferred conformation by anti- and syn-elimination (see also p. 25), or (208). The cyclopentadienyl anion has also been implicated in the nucleophilic addition of 1,2,4-triazines to dimethyl 4,5,6,7-tetrachlorospiro[2,4]-hepta-1,4,6-triene-1,2-dicarboxylate. ... 

Additional methods for preparing non-heteroatom-substituted carbene complexes include nucleophilic or electrophilic additions to carbyne complexes (Section 3.1.4), electrophilic additions to alkenyl or alkynyl complexes (Section 3.1.5), and the isomerization of alkyne or cyclopropene complexes (Section 3.1.6). 

As already mentioned, treatment of dihalocyclopropanes with bases furnishes cyclopropenes. When nucleophilic reagents are present, these are added to the strained double bond, and the products thus formed correspond to the products of direct nucleophilic substitution of the substrate, i.e. the elimination/addition process is equivalent to an overall substitution. In fact, in some cases the instable chlorocyclopropene intermediates could be trapped as Diels-Alder adducts with cyclopen tadiene. 

It is rather difficult to generate donor-substituted carbenes (path b), and methylena-tion of push-pull-olefins (path c) is not very efficient due to the low reactivity of these alkenes. Therefore these two alternative [2 + l]-cycloadditions have been of relatively low importance so far. This is also true for the addition of suitable nucleophiles to cyclopropenes activated by electronwithdrawing substituents (path e). 

However, a respectable alternative to the direct [2 + l]-routes (a)-(c) is the variant using halo- or dihalocyclopropanes as precursors for the desired target molecules (path d). The cyclopropane ring is formed by addition of halocarbenes to the olefin and subsequent change of functionalities is achieved by treatment with nucleophiles. It is very unlikely that a direct substitution incorporates the donor-substituent. Instead an elimination/addition sequence with the intermediacy of a cyclopropene has to be assumed. 

However, the ready availability of halocyclopropanes has led to extensive studies of their 1,2-dehydrochlorination, and amines are now rarely used as cyclopropene precursors. Although the reaction of 1,1-dichlorocyclopropanes with strong base does in certain situations lead to cyclopropenes, it is frequently the case that the initially formed 1-halocyclopropene does not survive under the reaction conditions, undergoing either addition of a nucleophile to the alkene bond or prototropic shifts followed by further dehydrohalogenation. Two main variations on this method are available which proceed under conditions where further reaction does not, in general, occur, that is 1,2-dehalogenation and 1,2-dehalosilylation. Each of these three alternatives will be considered in turn. 

Because 1,1-dihalocyclopropanes are so readily available by carbene addition to alkenes, their dehydrohalogenation to 1-halocyclopropenes provides, in principle, one of the most attractive routes to functionalised cyclopropenes. However, most early studies of the reaction did not lead to the cyclopropenes themselves, but to products of their further reaction. The main problems arise when the 1-halocyclopropene (9) can undergo prototropic shifts by removal of a proton from C 2 or C3, or when the base used is also a good nucleophile and addition to the cyclopropene can occur ... 

The double bond of cyclopropenes is sufficiently reactive that in many cases attack of either electrophiles or nucleophiles can occur. 1,2-Addition to cyclopropenes can create up to three new chiral centres ... 

The addition of an electrophile to the cyclopropene double bond formally leads to a cyclopropyl cation this may be expected to undergo ring opening to an allyl ion unless it is rapidly trapped by a nucleophile. In some cases, however, electrophilic attack may occur at one of the a-bonds, leading directly to an allylic cation. 

The perfluorinated cyclopropenes (292, X = C(CF3)NH) may be prepared from (293) by 1,3-dipolar addition of diazomethane followed by desulphurisation with, triphenylphosphine to produce, (294), and then thermolysis. Addition of (292, X = C(CF3)0) to 2,3-dimethylbutadiene occurs predominantly in an endo-manner, the intermediate undergoing an intramolecular ene-reaction to produce (295). In the same way reaction with pyrrole leads to (296), in this case presumably by an intramolecular nucleophilic attack in the initially formed endo-adduct 237). 

The 7,7-dihalobicycloheptene route appears easily adaptable to the synthesis of 6n 5 atom cyclopropa[c]heteroarenes 61 as the three-membered ring is suitably located and the requisite precursors—the dichlorocarbene addition products of, for example, 2,5-dihydrofuran—are easily accessible. Unfortunately, treatment of halides 59 with r-BuOK fails to provide any evidence for sought after 61. Dehydrochlorination does occur but the strained 1,3-bridged cyclopropenes 60 ring expand to carbene or add a nucleophile faster than rearrangement and loss of a second molar equivalent of HCl. The precise outcome of these reactions is very dependent upon the nature of the ring system as the detailed studies show . ... 

Treatment of 3-chlorocyclopropenes with nucleophiles produces the substituted cyclopropenes presumably via successive addition-elimination steps . Perchlorocyclopropene gives the trisubstituted cyclopropenium salts (equation 134). 

As noted earlier (Section I V.A.5), the addition of nucleophiles to cyclopropenes relieves ring strain. Electrocyclic opening of the anion generated in this manner competes with capture by an ambient electrophile (E" ) (equation 85). Cyclopropene 278 reacts with... 

Cyclocodimerization and cyclooligomerization reactions of cyclopropenes catalyzed by nickel complexes require alkenes with electron-withdrawing substituents as reaction partners. In this respect, these reactions are complementary to the copper-catalyzed additions discussed in the previous section which do not proceed with electron-poor alkenes due to the low nucleophilicity of the copper-carbene complex. 

When halocyclopropanes react with an alkali metal alkoxide in an organic solvent, elimination-addition reactions take place and result in formation of alkoxycyclopropanes. In most cases the overall reaction can be regarded as a simple substitution of a halogen atom by an alkoxy group (see Section 5.2.1.1.11.2.2.), but in some cases a double substitution is observed. The latter reaction occurred when 6,6-dichloro-3-thiabicyclo[3.1.0]hexane was treated with potassium fcr/-butoxide and gave l-tcrt-butoxy-e r/o-6-chloro-3-thiabicyclo[3.1.0]hexane (1) in 68% yield. The reaction is believed to take place via a strained cyclopropene intermediate, which is trapped by nucleophilic attack of the ferr-butoxide or by reaction with furan if present.Other 1,1-dichlorocyclopropanes react analogously under similar conditions, 22-724 jjyj jien an excess of base is used, a second elimination-addition... 

Similarly, cyclopropyl anions 12, generated by addition of nucleophiles to l,2,3,3-tetrakis[4-(dimethylamino)pyridinium-l-yl]cyclopropene 11 opened to allylides 13. ... 

The addition of a range of nucleophiles to the fluorenyl-substituted cyclopropene 3 led to the formation of the products 4 resulting from ring opening. ... 

This contrasts with the addition of several nucleophiles to this and related cyclopropenes, which gives cyclopropanes by a Michael-type addition." ... 

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