Cyclopropyl substitution

Reaction of the cyclopropyl-substituted pivalate (25) with dimethyl benzylidenema-lonate in the presence of a palladium catalyst gave a mixture of alkylidenecyclo-propane (26) and vinylcyclopropane (27). The ratio of these two adducts is found to be quite sensitive to the choice of ligand and solvent. While triisopropyl phosphite favors the formation of the methylenecyclopropane (26), this selectivity is completely reversed with the use of the bidentate phosphite ligand dptp (12). Interestingly there was no evidence for any products that would have derived from the ring opening of the cyclopropyl-TMM intermediate (Scheme 2.8) [18]. 

The solvolysis of cyclopropyl-substituted vinyl halides, 154, was first investigated by Hanack and Bassler (145) and Bergman and Scherrod (146). 

Besides the carbocations mentioned above, numerous highly stable carboca-tions have been isolated as the salts of inorganic anions. Azulene analogues of triphenylmethylium ion [ll ]-[20 ], [21 j, [22 " ] and [23 j trisubsti-tuted cyclopropenylium ions [l" ] and [24 ]-p6 ] cyclopropyl-substituted tropylium ions [27 ]-[30 ] tropylium ions annelated with bicyclic frameworks [31 ]-[36 ] and [37 ]-[39 ] fulvene-substituted cyclopropenylium [40 ] and tropylium [41 ] ions a tropylium ion condensed with acenaphthylene [42 ] and a cation containing a 147t periphery [43 ] have... 

It is worth mentioning here that the spirocyclopropyl-substituted oxazoline-5-car-boxylates 2-172, as well as the corresponding thiazoline-4-carboxylates, can be transformed into cyclopropyl-substituted amino acids, which might act as potential enzyme inhibitors [93] and interesting building blocks for peptidomimetics [94]. 

Reaction of 2,3-dichloroquinoxaline 367 with sodium azide in ethanol has been used to synthesize bistetrazolo-[l,5- 5, l -c]quinoxaline 368 in 65% yield (Scheme 28) <1997JOC4082>. Similarly, reaction of 2,3-dichloroquinoxaline 367 with thiosemicarbazide 366 has been used to generate l,6-diamino-bis-l,2,4-triazolo[4,3- 3,4-f]quinoxaline 365 in 67% yield <2002AP389>. Condensation of cyclopropanecarboxylic acid hydrazide 369 meanwhile gives rise to the cyclopropyl-substituted tetracycle 370 in 93% yield in the presence of l,8-diazabicyclo[5.4.0]undec-7-ene (DBU) as base (Scheme 28) <2005JOC2878>. 

Cu(II) EPR signal in nitriles as solvent as well as by polarographic measurements 144>. Similarly, the EPR signal disappeared when Cu(OTf)2 was used for catalytic cyclo-propanation of olefins with diazoesters 64). In these cases, no evidence for radical-chain reactions has been reported, however. The Cu(acac)2- or Cu(hfacac)2-eatalyzed decomposition of N2CHCOOEt, N2C(COOEt)2, MeCOC(N2)COOEt and N2CHCOCOOEt in the presence of cyclopropyl-substituted ethylenes did not furnish any products derived from a cyclopropylcarbinyl - butenyl rearrangement128. These results rule out the possible participation of electron-transfer processes and radical intermediates which would arise from interaction between the olefin and a radical species derived from the diazocarbonyl compound. 

The allene 149 gave by reaction with maleic anhydride (entry 1) and N-phenylmaleimide (entry 2) the [2 + 2] adducts 155a, b as mixtures of two diastereoisomers [36], Nevertheless, their chemical yield was very low and competitive reactions, mostly [4 + 2] cycloadditions on a rearranged al-lylidenecyclopropane and on a primary 1 1 adduct derived from an ene reaction (see Sect. 2.1.2), prevailed. Allenes 149 and 563 cycloadded to tetracyano- and l,l-bistrifluoromethyl-2,2-dicyanoethylene (Table 45, entries 3-6) also selectively at the cyclopropyl substituted double bond in order to remove most of the ring strain [149a],... 

Surprising is the absence of evidence for additional stability of 85 over 83. Electron donation from the electron-rich a bonds of the cyclopropyl ring to the carbene s vacant p orbital is widely believed to stabilize cyclopropylcarbenes.4 One would therefore expect 85, with an additional cyclopropyl substituent, to react more slowly than either parent carbene 83 or dimethylcarbene, but all three lifetimes are comparable. The lifetimes of 83-85 need to be redetermined in inert (fluorocarbon) solvents in order to reveal their innate differences. Note, however, that the effect of cyclopropyl substitution is apparent upon comparison of 83 (r 24 ns) to MeCH (r < 0.5 ns).89110... 

More recently, the bis-cyclopropanation of dienyne 325 has also been investigated by Fensterbank, Malacria, and Marco-Contelles to construct highly strained cyclopropyl-substituted diquinane frameworks 327 in a completely diastereoselective manner (Scheme 84). 3 It is noteworthy that the formal metathesis product was also observed in these reactions, albeit as a minor product, and that a simple introduction of a methyl group to one of the two ene moieties substantially affects the reaction. 

The -conformation 13 is lower in energy than the Z-isomer 14. These are the smallest cyclopropyl substituted carbocations which can be investigated in solution by high resolution NMR. The corresponding primary cyclopropylmethyl cation 15 cannot directly be observed by high resolution NMR in solution because it is energetically less favorable than the bicyclobutonium ion 16 and thus only a minor isomer in the fast dynamic equilibrium of the cations 15 and 16. 13C- and H... 

A Ru-Josiphos catalyst was highly selective for the hydrogenation of an intermediate for an anthrax lethal factor inhibitor with a tetra-substituted C=C bond, as depicted in Figure 37.8 (Merck [44]). Rh-Josiphos (Lonza [42]) and Rh-Bo-Phoz (Eastman [45]) catalysts were effective for the hydrogenation of an exocy-clic and a cyclopropyl-substituted C=C bond. 

Oxidation by stoich. RuOyCCl of five xylofuranosides gave the corresponding 2- and 3-nloses (Table 2.3) [315], and that of 5-0-benzoyl-1,2-0-isopropylidene-a-D-xylofnranose by the reagent to the -a-D-e yt/iro-pentafuranos-3-ulose formed part of a synthesis of branched-chain 3 -C-methyladenosine [316, 322]. Likewise the cyclopropyl-substituted 4-C-cyclo-propyl-l,2-0-isopropyl-idene-D-xylo-tetrafuranose was converted to the 3-ulose [314]. 

Further reduction in R leads to the point Rc (Figure 3) at which the bond is fully formed and normal cyclopropyl substituent interactions occur. Homoconjugation ceases to be a relevant chemical factor at point Rc and the molecule can be adequately described in terms of a cyclopropyl substituted system. 

A series of cyclopropyl substituted carbyne complexes was photolyzed in order to follow the regio- and stereochemical outcome of the photooxidation. Irradiation of the deuterated molybdenum complex gave cyclopentenone exclusively labeled at C3 (equation 114). In the analogous tungsten complex only 90% of the deuterium resides on C3 the remaining 10% labeled the 2-position158. 

Ethynylcyclopropanes, like normal acetylenes, react with dicobalt octacarbonyl in ether to form stable dinuclear cluster-like hexacarbonyl complexes (equation 170)236. The complex with l-chIoro-2,2,3,3-tetramethylethynylcyclopropane reacts stereo- and regioselec-tively with norbomene in a typical Pauson-Khand reaction to give the exn-2-cyclopropyl substituted cyclopentenone (equation 171). Similarly, the reaction of 2-ethoxycyclo-propylacetylene with cyclopentene in the presence of Co2(CO)8 under CO gave 3-(2-ethoxycyclopropyl)-cw-bicyclo[3.3.0]oct-3-en-2-one (equation 172)242. 

CpCo(mcp)2, which in turn can be further transformed to the mono-complex CpCo(PPh3)(mcp) by exchange of one methylenecyclopropane ligand with PPhj (equation 312). Although both complexes are isolable crystals, they are thermally less stable than the analogous Feist s ester complexes. CpCo(mcp)2 readily undergoes thermal isomerization at 110 °C, to give cyclopropyl-substituted -butadiene complexes (see below). 

The dienylic cations 44 with cyclopropyl and phenyl groups were also prepared and characterized by the protonation of respective fulvenes74. Other cyclopropyl substituted allyl cations include acyclic 1,3- and 1,4-disubstituted allyl cations 45 and 46. The charge in these cations is localized mainly on the carbon adjacent to the cyclopropyl group. The rearrangement of these cations at higher temperatures was also studied76. 

However, the corresponding tertiary analogues, 2-methyl-, 2-phenyl- and 2-cyclopropyl substituted cations 97, have been prepared at low temperatures, and characterized by 13C NMR spectroscopy (equation 57). The cations were obtained by ionization of their corresponding alcohols with SbR/FSOjH in S02C1F102. 

The quaternary carbons of the tertiary cations 97 have chemical shifts of <5 l3C 69.2,61.1 and 58.8 for the Me, Ph and cyclopropyl substituted ions, respectively, which shows that progressively less charge is delocalized into the spirocyclopropyl ring going from methyl to phenyl to cyclopropyl. Consequently, the order of the stabilizing effects of the substituents on the cationic center is cyclopropyl > Ph > Me. 

Quantitative estimates of the thermodynamic stabilities of various phenyl and cyclopropyl substituted cyclopropenium ions were carried out by their pATR+ measurements18. The pKg+ values for 1,2,3-tricyclopropylcyclopropenium, l,2-dicyclopropyl-3-phenylcy-clopropenium ion and 1 -cyclopropyl-2,3-diphenylcyclopropenium ion were determined to be 10.0, 7.09 and 5.04, respectively. Thus, replacement of each phenyl group by a cyclopropyl group enhances the stability of the carbocation by two pATR+ units (2.74 kcal mol1). These results were also supported by the isodesmic reaction of equation 72 for which the energies were optimized at the HF/3-21G //HF/3-21G level18. 

A single product is also formed in the case of unsymmetrical ketones of the MeCOCHR R2 or RCH2COCHR R2 type, since for the Pfitzinger reaction to occur the ketone must contain either a methyl group or a methylene group next to the carbonyl group. For example, only one appropriate cyclopropyl-substituted acid 16 is formed from methyl cyclopropyl ketone 15 and isatins 9 [23, 24],... 

Cyclopropyl-substituted allenes open the door to yet another reaction mode. When treated with aryl iodides in the presence of a typical Heck-catalyst system and a dienophile, cyclohexene derivatives 77 were obtained (Scheme 11) [53,54]. Thus, the initially formed arylpalladium iodide car-bopalladates 72 to form a a-allylpalladium intermediate 73. It swiftly undergoes the cyclopropylcarbinyl to homoallyl rearrangement yielding the ho-moallylpalladium species 74 which finally suffers /1-hydride elimination. The thus formed 2-aryl-1,3,5-hexatrienes 75 are prone to undergo polymerization, but can be efficiently trapped by an appropriate dienophile at the least steri-... 

On the other hand, using cyclopropyl-substituted allylic trifluoroacetate 12 led to [5 + 2] cycloaddition product 13 after the temperature was raised to 80 °C (Scheme 8). Both procedures are experimentally simple since only a change in temperature is necessary to promote the second step of the sequential reactions. 

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