Showing papers on "Cyclopropane published in 2008"

Gold(I)-Catalyzed Intermolecular Addition of Carbon Nucleophiles to 1,5- and 1,6-Enynes

Abstract: Gold(I)-catalyzed addition of carbon nucleophiles to 1,6-enynes gives two different type of products by reaction at the cyclopropane or at the carbene carbons of the intermediate cyclopropyl gold carbenes. The 5-exo-dig cyclization is followed by most 1,6-enynes, although those bearing internal alkynes and alkenes react by the 6-endo-dig pathway. The cyclopropane versus carbene site-selectivity can be controlled in some cases by the ligand on the gold catalyst. In addition to electron-rich arenes and heteroarenes, allylsilanes and 1,3-dicarbonyl compounds can be used as the nucleophiles. In the reaction of 1,5-enynes with carbon nucleophiles, the 5-endo-dig pathway is preferred.

Cobalt-catalyzed asymmetric cyclopropanation of electron-deficient olefins

Abstract: The cobalt(II) complex of a D2-symmetric chiral porphyrin [Co(1)] is an effective catalyst for asymmetric cyclopropanation of electron-deficient olefins, including α,β-unsaturated esters, amides, ketones, and nitriles. Due to the absence of dimerization of diazo compounds, the catalytic reactions can be performed in one-pot protocol using olefins as the limiting reagent, forming the desired electrophilic cyclopropane derivatives in high yields and selectivities under mild conditions. In most cases, both excellent diastereo- and enantioselectivity were achieved.

Donor–Acceptor Cyclopropanes as Three‐Carbon Components in a [4+3] Cycloaddition Reaction with 1,3‐Diphenylisobenzofuran

Abstract: Substituted cyclopropanes have found broad application in modern organic synthesis owing to the unique reactivity of the cyclopropane moiety. Cyclopropanes can often be considered as three-carbon analogues of C=C bonds. For example, alkenes and cyclopropanes react with strong electrophiles and various radicals. Both undergo the addition of hydrogen and can be oxidized at the a position. The reactivity of cyclopropanes with electron-withdrawing substituents is similar to that of electron-deficient alkenes. However, the cycloaddition reactions of alkenes and cyclopropanes are quite different. In particular, the thermal reactions of alkenes are represented mainly by [1+2], [3+2], and [4+2] cycloaddition processes; thermal [2+2] cycloaddition occurs in very specific cases only. In contrast, the most well known type of cyclopropane cycloaddition is the [2p + 2s] reaction with alkenes. As this reaction yields cyclopentanes, it can also be considered as a [2+3] cycloaddition. The scope of such [2+3] cycloaddition reactions has been expanded significantly through the use of donor–acceptor cyclopropanes. The presence of both electron-donating and electron-withdrawing substituents on the cyclopropane ring enables cycloaddition to various multiple bonds, including C=C, C=O, C=N, and C N bonds. The [4+3] cycloaddition of cyclopropanes with dienes (Scheme 1) has not been reported previously, although this

Nucleophilic addition of phenol derivatives to methyl 1-nitrocyclopropanecarboxylates.

Abstract: Nucleophilic ring opening of methyl 1-nitrocyclopropanecarboxylates by phenol derivatives in the presence of Cs2CO3 is described. The reaction tolerates a variety of substituents on both the aromatic alcohol and the cyclopropane and affords the products in good yields (53−84%) and with complete preservation of the enantiomeric excess at C-4. The methodology was applied in an enantioselective synthesis of the norepinephrine reuptake inhibitor atomoxetine (Strattera).

trans‐Directing Ability of Amide Groups in Cyclopropanation: Application to the Asymmetric Cyclopropanation of Alkenes with Diazo Reagents Bearing Two Carboxy Groups

Abstract: Book: M. P. Doyle, M. A. McKervey, T. Ye Modern Catalytic Methods for Organic Synthesis with Diazo Compounds: From Cyclopropanes to Ylides; Wiley-VCH: New York, 1998. Comment: The authors propose an intriguing mechanistic pathways to explain the selectivity in the cyclopropanation with diazo reagents bearing two carboxy groups. It is proposed that the chiral rhodium complex preferentially binds to one face of 1, thereafter the amide substituent acts as a “trans-directing group” and promotes the formation of only one diastereomer. The enantioselectivity is shown to depend on both the ligand used and the substituents on the amide nitrogen. The yields are moderate to good for a variety of alkenes, although aliphatic olefins give poor results. Derivatizations of the resulting products, such as reduction, ring opening and esterification are demonstrated. R1 = OBu, Ph, Ar, Hetar, styryl R2 = H, Me 14 examples 24–92% yield 84–97% ee [Rh2(S-nttl)4] (1 mol%)

Gold- and silver-catalyzed tandem amination/ring expansion of cyclopropyl methanols with sulfonamides as an expedient route to pyrrolidines.

Abstract: An efficient synthetic route to pyrrolidines that relies on AuCl/AgOTf-catalyzed tandem amination/ring expansion of substituted cyclopropyl methanols with sulfonamides is reported herein. The reactions proceed rapidly at 100 degrees C with catalyst loadings as low as 2 mol % and produce the pyrrolidine products in yields of 30-95 %. The method was shown to be applicable to a broad range of cyclopropyl methanols, including unactivated ones, and sulfonamide substrates containing electron-withdrawing, electron-donating, and sterically-demanding substituents. The mechanism is suggested to involve activation of the alcohol substrate by the AuCl/AgOTf catalyst, followed by ionization of the starting material, which causes ring opening of the cyclopropane moiety and trapping by the sulfonamide nucleophile. The resultant aminated acyclic intermediate undergoes subsequent intramolecular hydroamination to give the pyrrolidine.

Synthesis of Cyclopentenones from Cyclopropanes and Silyl Ynol Ethers

Abstract: Five-membered carbocyclic rings appear in all classes of organic materials including pharmaceutical agents, polymers, natural products and catalysts. Accordingly, their preparation has challenged synthetic chemistry since the inception of the field.[1] In this regard, [3+2] cycloadditions - both concerted and stepwise - represent convergent strategies for the construction of the cyclopentane nucleus.[2] Dipolar cycloadditions, in particular, have proven especially successful, and of the various all-carbon dipoles available, donor-acceptor cyclopropanes (1) have proven especially versatile.[3] In the presence of Lewis acids, these materials undergo ring-opening to yield 1,3-dipoles. Pursuing a general interest in the reactivity of electron-rich alkynes,[4] we envisioned a cycloaddition between such dipoles and ynol ethers (2, Scheme 1). In analogy to Diels-Alder reactions involving Danishefsky’s diene[ 5 ] we postulated that the intermediate vinylogous acetal 3 might decompose to the cyclopentenone 4 during the reaction. While donor-acceptor cyclopropanes have been shown to combine with indoles,[6] enol ethers[7] and aryl acetylenes,[8] a condensation with ynol derivatives has not been documented. Indeed, these alkynes have hardly been explored in the context of [3+2] cycloadditions.[9] Scheme 1 Cycloaddition of ynol ethers with 1,3-dipoles derived from opening of donor-acceptor cyclopropanes. EWG = electron-withdrawing group. Exploratory studies examined the reaction of cyclopropane 1a (R1, R2 = H) with ynol ether 2a (R3 = n-Bu) which is prepared in a single step from n-hexyne.[10] Several Bronsted and Lewis acids, including Me3SiOTf (Tf = SO2CF3), HN(Tf)2 and BBr3, promoted the formation of cyclopentadiene 5aa and cyclopentenone 4aa in moderate yield. Despite substantial efforts to optimize the reaction conditions, however, we were never able to develop a protocol that returned the cycloadducts in synthetically useful yield. Our early experiments suggested similarly mediocre performance with Me2AlCl; therefore, when we reinvestigated this Lewis acid several months after our initial experiments, we were surprised to find that it promoted the cycloaddition cleanly and rapidly.[11] Our hope that the increase in yield reflected improved technique was quickly dispelled when we discovered substantial differences in reactivity between aged and freshly opened bottles of reagents. Reactions involving Me2AlCl from a new bottle required >24h to go to completion (Table 1, entry 1). Under otherwise identical conditions, reagent drawn from bottles that had been used for several months displayed markedly superior reactivity (entry 2). Reasoning that this observation could be accounted for by evaporation (solutions of Me2AlCl in hexanes were used) or adventitious air or water, we performed a series of control experiments. Modest changes to the charge of Me2AlCl had little effect on the rate of the reaction (not shown), and neither did small amounts of water (entry 3). In contrast, when dry air was bubbled through solutions containing the Lewis acid, we could recapitulate the phenomenon observed with aged bottles of reagent, and isolate 4aa in good yield (entry 4).[12] Table 1 Effects of Additives on the Al(III)-Mediated Reaction of Silyl Under optimized reaction conditions, air was bubbled through a solution of the Al reagent (1 equiv) at room temperature. At -78 °C, cyclopropane (1.3 equiv) and ynol ether (1 equiv) were added, and the solution was stirred until the reaction was complete (2-24 h). HF·pyridine was added, and, after aqueous workup, cyclopentenone 4 was purified by flash chromatography. In this way, a series of substituted donor-acceptor cyclopropanes combined with a range of ynol ethers to yield enones in generally good yields (Table 2). Silyl ynol ethers bearing olefins, alkynes, ethers, halides and aromatic rings all functioned effectively in the transformation (entries 1-12). Unfortunately, the ynol derived from phenyl acetylene was a poor substrate (entry 13). Cis- and trans-disubstituted cyclopropanes appear to behave equivalently (entry 1-2). Likewise, substitution at C3 (entries 14-16), C1 (entry 17), or both (entries 18-19) is accommodated in the cycloaddition. Thus, tri-, tetra-, and even penta-substituted cyclopentenones can be formed in good yields and in a convergent manner. Furthermore, both partners in the cycloaddition can be accessed in a single operation from readily available materials. Table 2 Synthesis of Cyclopentenes from Ynolates and Cyclopropanes.[a] The NMR spectrum of anaerobic solutions of Me2AlCl revealed one singlet at -0.31 ppm (CDCl3). After oxygenation, the same solution displays two upfield singlets at -0.39 and -0.43 ppm and two downfield resonances suggestive of a methoxide (3.87 and 3.85 ppm). We interpret these signals as arising from (MeO)AlMeCl, the product of aerobic oxidation of one methyl-aluminum bond. The two sets of signals (ca. 1:2 ratio) likely correspond to diastereomeric cyclic trimers.[ 13 ] Indeed, addition of 1 equiv of methanol to Me2AlCl yields a substance with substantially the same spectrum, and the reagent thus produced is a better Lewis acid for the cycloaddition than Me2AlCl (Table 1, entry 5). Interestingly, while the major products formed upon addition of methanol or air to Me2AlCl are the same, the reaction of methanol is noticeably messier: an unidentified precipitant is formed, and the 1H NMR spectrum of the filtrate contains several minor products. Perhaps as a consequence, the cycloadditions using this reagent are lower yielding and generate more side products. Thus aerobic oxidation of dialkyl alanes constitutes a clean and efficient method to generate a strong but selective Lewis acid. Finally, it is important to note that we observe no difference between the (MeO)AlMeCl generated from new versus aged bottles of Me2AlCl (Table 1, entries 4 vs. 6). With respect to the utility of the methodology described here, comparisons to two standard syntheses of cyclopentenones are appropriate. This cycloaddition is more direct than the Nazarov cyclization, and, in contrast to that cyclization, yields a single olefin positional isomer.[14] Likewise, while the Pauson-Khand reaction is generally limited to intramolecular cyclizations, the reactivity described above functions efficiently in an intermolecular context.[15] While (MeO)AlMeCl has been characterized previously, it has found infrequent use as a Lewis acid.[ 16 ] In the present transformation, it appears strong enough to activate the cyclopropane towards ring-opening and to mediate the decomposition of the vinylogous acetal (3), but mild enough to coexist with the ynol ether and the cyclopentenone. Whether this favorable reactivity profile extends to other classes of dipolar cycloadditions and, more broadly, other Lewis-acid promoted reactions remains the subject of future investigations.

Gold(I)-catalyzed cycloisomerization of 1,7- and 1,8-enynes: application to the synthesis of a new allocolchicinoid.

Abstract: Gold(I)-catalyzed cycloisomerization of 1,7- and 1,8-enyne propargylic acetates afforded cyclopropyl derivatives containing seven- and eight-membered rings, respectively. This reaction was used for the synthesis of a new allocolchicinoid having a cyclopropane ring fused to the B seven-membered ring at the C6-C7 positions.

Palladium-catalysed [3+2] cycloaddition of alk-5-ynylidenecyclopropanes to alkynes: A mechanistic DFT study

Abstract: The mechanism of the palladium-catalysed [3+2] intramolecular cycloaddition of alkylidenecyclopropanes to alkynes has been computationally explored at DFT level The energies of the reaction intermediates and transition states for different possible pathways have been calculated in a model system that involves the use of PH3 as a ligand The results obtained suggest that the most favourable reaction pathway involves the initial C--C oxidative addition of the cyclopropane to a Pd0 complex to give an alkylidenepalladacyclobutane, which isomerises to a methylenepalladacyclobutane intermediate Subsequent cyclisation by alkyne carbometallation, followed by reductive elimination affords the final product An alternative mechanism consisting of a palladaene-type rearrangement is less probable in terms of Gibbs energy, but cannot be fully discarded because it is competitive if one considers electronic energies For substrates that present an ester group at the terminal position of the triple bond we have found an alternative, more favourable mechanistic route that explains why the [3+2] cycloaddition of these types of systems does not lead to the expected cycloadducts

Lewis Acid Catalyzed Cascade Reactions of Diarylvinylidenecyclopropanes and 1,1,3‐Triarylprop‐2‐yn‐1‐ols or Their Methyl Ethers

Abstract: The reactions of vinylidenecyclopropanes 1 with 1,1,3-triarylprop-2-yn-1-ols or their methyl ethers 2 in the presence of a Lewis acid selectively produce 4-dihydro-1H-cyclopenta[b]naphthalene derivatives 3 or 1,2,3,8-tetrahydrocyclopenta[a]indene derivatives 4 depending on the substituents on the cyclopropane. Good to high yields are obtained under mild conditions. A plausible cascade Meyer-Schuster rearrangement and Friedel-Crafts reaction mechanism has been proposed. Moreover, novel functionalized methylenecyclobutene derivatives 5 could also be obtained in moderate to good yields under similar conditions when strongly electron-donating methoxy groups were introduced into the benzene rings of 2.

Homobenzene: homoaromaticity and homoantiaromaticity in cycloheptatrienes.

Abstract: Cycloheptatriene (C(s)) is firmly established to be a neutral homoaromatic molecule based on detailed analyses of geometric, energetic, and magnetic criteria. Substituents at the 7 (methylene) position, ranging from the electropositive BH2 to the electronegative F, favor the equatorial conformation but influence the aromaticity only to a small extent. By the same criteria, the planar transition state (C(2v)) for cycloheptatriene ring inversion is clearly antiaromatic. This is attributed to the involvement of the pseudo-2pi-electrons of the CH2 group with the 6pi-electrons of the ring to give an 8pi-electron system. Similarly, the participation of the CH2 groups into C(2v) cyclopentadiene and cyclononatetraene lead to significant 4n + 2 pi electron aromaticity. The cyclization of cycloheptatriene to norcaradiene proceeds via a highly aromatic transition structure, but norcaradiene itself is less aromatic than cycloheptatriene. An annelated cyclopropane ring does not function as effectively as a double bond in promoting cyclic electron delocalization.

Synthesis of methyl 3-bromomethylbut-3-enoate and its reactions with aldehydes and tributylchlorostannane in the presence of zinc

Abstract: Methyl 3-bromomethylbut-3-enoate smoothly reacted with prenal, β-ionylideneacetaldehyde, benzyloxyacetaldehyde, and tributylchlorostannane in the presence of zinc and aqueous ammonium chloride in tetrahydrofuran to give the corresponding δ-hydroxy-β-methylidenecarboxylic acid esters. In the absence of ammonium chloride, satisfactory yields of the products were obtained only in the reactions with prenal and benzyloxyacetaldehyde; these reactions involved lactonization of intermediate δ-hydroxy-β-methylidenecarboxylic acid esters, and the double carbon-carbon bond migrated to the conjugated position with the lactone carbonyl group. The condensation of β-ionylideneacetaldehyde with methyl 3-bromomethylbut-3-enoate was successfully used to obtain isotretinoin. Initial methyl 3-bromomethylbut-3-enoate was synthesized in a good yield from readily accessible ethyl 3,3-diethoxypropionate via cyclopropanation with ethylmagnesium bromide in the presence of titanium tetra(isopropoxide), oxidation of the acetal moiety to ester, and cleavage of the cyclopropane ring in intermediate methyl (1-methylsulfonyloxycyclopropyl)acetate.

Convergent Preparation of Enantiomerically Pure Polyalkylated Cyclopropane Derivatives

Abstract: Cyclopropane is a basic structural element in a wide range of naturally occurring compounds, and has been used as a versatile intermediate in the synthesis of more functionalized cyclic and acyclic alkanes. In the last few decades, most of the synthetic efforts have focused on the enantioselective synthesis of cyclopropanes, however, new and more efficient methods for the preparation of these entities in enantiomerically enriched form are still evolving. These methods can be divided into four types: the halomethylmetal-mediated cyclopropanation reaction, the transition-metal-catalyzed decomposition of diazo compounds, the nucleophilic addition/ring closure sequence, and the hydroand carbometalation reaction of strained cyclopropene derivatives. All of these methods are among the most powerful and innovative approaches, but they usually lead to functionalized cyclopropanes. To prepare nonfunctionalized, enantiomerically enriched disubstituted cyclopropanes (95% ee), we successfully reported the ( )-sparteine-catalyzed enantioselective carbolithiation of styrenyl derivatives which then undergo a 1,3-elimination reaction. These reactions were restricted to aryland vinyl-substituted cyclopropanes. To develop an even more general approach to the preparation of enantiomerically pure polyalkylated cyclopropanes (1; R, R, R = alkyl groups), we envisaged subjecting 2 to a combination of two consecutive selective sulfoxide/lithium exchanges, a transmetalation reaction, and then a reaction with an electrophile (Scheme 1). The sulfoxide/lithium exchange occurs when the reactive organometallic reagent reacts at the sulfur center of the sulfoxide, through an SN2 process, to generate a more stable organometallic leaving group. Alkylidene bis(p-tolylsulfoxides) (3) were recently used as highly versatile partners for asymmetric syntheses in the context of radical chemistry, polar Michael additions, and the Michael-initiated ring closure reaction which is used herein as the key step for the preparation of cyclopropane 2. Indeed, when the sulfur ylide, generated in situ by deprotonation of trimethyloxosulfonium iodide with NaH in DMSO, was reacted with alkylidene bis(p-tolylsulfoxides) 3a–c and corresponding bis(p-tolylsulfinyl)cyclopropanes 2a–c were obtained in good to excellent diastereoisomeric ratios (Scheme 2). Each of the products 2b and 2c were easily separated by column chromatography on silica gel to obtain each diastereoisomer as a pure isomer. The absolute configuration of 2a was determined by X-ray crystallographic analysis (see the Supporting Information) and by using the already established model.

A Convenient Route to Trifluoromethyl-Substituted Cyclopropane Derivatives

Abstract: A range of alkenes have been converted in a single step into the corresponding trifluoromethyl-substituted cyclopropanes by treatment with 2-diazo-l,l,l-trifluoroethane over metal catalysts. Application of the Gaspar-Roth procedure allowed the preparation of target compounds on a multi-gram scale. The practical utility of this reaction has been demonstrated by the synthesis of both diastereoisomers of the non-natural amino acid trifluoronorcoronamic acid in two steps.