Synthesis of 2‐silaoxane via 1,3‐ photocycloaddition

Irradiation of an aryl group with a silyl tethered alkene yields a tetracyclic 2‐silaoxane with high regiose‐lectivity. The multicyclic structure has been further modified to give an unstable tricyclic diol. Photocycloaddition between cyclopentene and phenylcyclopropane gave a single major cycloadduct without cyclopropyl ring opening, indicating that the putative radical intermediate involved in cycloaddition apparently has a very short lifetime if it exists at all.     

Design of a cyclopropyl quinone methide reductive alkylating agent. 2

A cyclopropyl quinone methide is formed by elimination of a leaving group from an appropriately functionalized hydroquinone. The presence of a carbon spacer results in the formation of a fused ring rather than the classic methide species. Discussed herein is cyclopropyl quinone methide formation from a pyrido[1,2-a]indole ring system. Both nucleophilic and electrophilic attack on the fused cyclopropane ring results in pyrido[1,2-a]indole and azepino[1,2-a]indole products. The stereoelectronic effect plays less a role in the relatively flexible pyrido[1,2-a]indole system compared to its role in the pyrrolo[1,2-a]-indole system. A 13C label on the fused cyclopropane ring permitted the rapid identification of complex rearrangement products observed in this study.     

Intramolecular electrophilic aromatic substitution of α-alkylcinnamaldehydes affording 1-alkoxy-2-alkylindenes

Treatment of α-alkylcinnamaldehydes with orthoesters, alcohols, or thiols in the presence of BF₃·OEt₂ induces an intramolecular electrophilic aromatic substitution reaction to afford 1-alkoxy-2-alkylindenes. The reaction mechanisms of the indene formation have been elucidated on the basis of the reaction behaviors of β-deuterated α-methylcinnamaldehyde and the NMR studies of the reaction mixture. The transformation process involves successive reactions, i.e., alkoxylation of the carbonyl carbon of α-alkylcinnamaldehydes to form acetals, elimination of alkoxide from the acetals to give alkoxycarbenium ion and γ-alkoxyallyl cation, and intramolecular electrophilic arylation to afford the indene ring structure.     

4‐[1‐(Phenylsulfonyl)indol‐3‐yl]‐3a,4,5,9b‐tetrahydro‐3H‐cyclopenta[c]quinoline

In the title compound, C₂₆H₂₂N₂O₂S, the tetra­hydro­pyridine ring has a conformation intermediate between half‐chair and sofa. The tetrahydroquinoline mean plane makes a dihedral angle of 73.3 (1)° with the cyclopentene ring, which adopts an envelope conformation, and an angle of 45.45 (4)° with the indole best plane. The dihedral angle between the benzene and pyrrole rings is 2.6 (1)°. The orientations of the phenyl ring on the sulfonyl group and of the indole are governed by weak C—H?O interactions. The packing of the mol­ecule in the solid state is stabilized by C—H?O and C—H?N hydrogen bonds.     

Domino carbocationic cyclization of functionalized cyclopropyl ketones: facile one-pot access to peri- and angularly fused polycyclic aromatic and heteroaromatic frameworks

Conjugate adducts obtained by base-induced 1,4-addition-elimination of various aryl/heteroaryl acetonitriles with 1-(2-arylcyclopropyl)-3,3-(bismethylthio)-2-propen-1-ones have been shown to undergo facile acid-induced domino carbocationic rearrangement yielding a variety of substituted tricyclic aromatic and heteroaromatic frameworks in high yields in a one-pot operation. The methodology provides efficient, high-yield routes for synthesis of novel substituted dihydrophenalenes, dihydrobenzo[d,e]anthracene, cyclopenta[a]naphthalene, and fused heteroaromatics such as substituted 4,5-dihydrobenzo[c,d]indole, dihydronaphtho[1,8-b,c]thiophene, dihydroindeno[5,4-b]- and -[4,5-b]-thiophenes, cyclopenta[a]carbazole, and dihydrocyclopenta[e]indazol-3-one derivatives. The probable mechanism of this interesting domino process appears to involve stepwise or concomitant acid-induced ring opening and intramolecular cyclocondensation of cyclopropyl ketones to give benzo-fused arene (or heteroarene) intermediates bearing a reactive benzylic carbocation that is captured intramolecularly either by a preexisting aromatic (or heteroaromatic) ring or by a newly formed benzene ring to give either peri-fused or angularly fused products, respectively. Thus, the overall domino process entails formation of two C-C bonds, a substituted benzene ring along with a peri-fused cyclohexane or angularly fused cyclopentane ring in a single operation.     

Structural Identification of Substituted C-1 Spiro Cyclopropyl Sugars.

ABSTRACT

Photolysis of peracetylated D-glucopyranosylidene diazide in the presence of acrylonitrile in excess leads to new isomeric spiro C-1 cyclopropanic sugars (65% combined yield). Such structures, thus readily accessible by a new route which probably involves the addition of carbenic intermediates to an electrophilic alkene, have been identified by NMR investigations. In particular, the ¹H NMR spectra show that the location and the orientation of the cyano substituent on the cyclopropyl ring can be easily established by way of the deshielding effect (0.2 - 0.3 ppm) which is induced on a sugar ring proton attached at C-2, C-3 or C-5. In order to unambiguously identify the obtained spirosugars, the crystal structure of one of them was determined by X-ray analysis. C₁₇H₂₁NO₉, orthorhombic P2₁2₁2₁, a=9.093(1), b=9.933(1), c=21.588(3) Å, Z=4, R=0.041 for 1645 unique observed reflexions.     

Cyclopropyl containing fatty acids as mechanistic probes for cytochromes P450

[reaction: see text] The mechanism of aliphatic hydroxylation by cytochromes P450 has been the subject of intense debate with several proposed mechanistic alternatives. Various cyclopropyl containing compounds (radical clocks), which can produce both unrearranged and ring opened products upon oxidation, have been key tools in these investigations. In this study, we introduce several cyclopropyl containing fatty acids 1a-4a with which to probe the mechanism of P450s capable of fatty acid hydroxylation. The probes are shown to be capable of distinguishing radical from cationic intermediates due to the rapid equilibration of isomeric cyclopropyl cations. Ring opening of a radical intermediate in an oxidative transformation is expected to yield a single rearranged alcohol, whereas a cation isomerizes prior to ring opening, leading to two isomeric homoallylic alcohols. Oxidation of these probes by P450(BM3) and P450(BioI) gives results consistent with a radical but not a cationic intermediate in fatty acid hydroxylation by these enzymes. Quantitation of the unrearranged and ring opened products gives remarkably homogeneous rates for oxygen rebound of (2-3) x 10(10) s(-1). The effects of introduction of a cyclopropane ring into a fatty acid upon the regiochemistry of hydroxylation are discussed.     

Direct cyclopropanation of 1-alkynylphosphonates by Cp2ZrCl2/2EtMgBr/2AlCl3 to afford cyclopropylmethylphosphonates

[reaction: see text] The reagent system Cp2ZrCl2/2EtMgBr/2AlCl3 converts 1-alkynylphosphonates into cyclopropylmethylphosphonates 3 in good isolated yields. Ethers, chlorides, and other cyclopropyl groups are compatible with the reaction conditions. Deuterium labeling is consistent with the formation of stable cyclopropylmethylbimetallic phosphonates by ring contraction of the corresponding aluminacyclopentenylphosphonate. Temperature is crucial; apparently, the cyclopropylmethylbimetallic phosphonates are in equilibrium with the aluminacyclopentenylphosphonates. Low temperature favors the former. We surmise that the negative charges of the intermediate are stabilized by the phosphonate group. Thus, diphenylacetylene and 3-hexyne failed to give cyclopropyl products under the same reaction conditions.     

REDUCTIVE REMOVAL OF HALOGEN BY THIOLATES FROM 1-HALOCYCLO-PROPYL SULFIDES

Abstract

Nucleophilic substitution of cyclopropyl halides or tosylates is often accompanied by ring rupture, but this can be prevented by the presence of an electron releasing substituent in α-position (NR₂, OR, SR). Alkylthio and arylthio groups are particularly effective in stabilizing intermediate cyclopropyl cations. These give with most nucleophiles e.g. alkoxide, azide, fluoride, in relatively rapid reactions good yields of substitution products.     

Density functional theory study on a missing piece in understanding of heme chemistry: the reaction mechanism for indoleamine 2,3-dioxygenase and tryptophan 2,3-dioxygenase

Indoleamine 2,3-dioxygenase (IDO) and tryptophan 2,3-dioxygenase (TDO) are heme-containing dioxygenases and catalyze oxidative cleavage of the pyrrole ring of L-tryptophan. On the basis of three recent crystal structures of these heme-containing dioxygenases, two new mechanistic pathways were proposed by several groups. Both pathways start with electrophilic addition of the Fe(II)-bound dioxygen concerted with proton transfer (oxygen ene-type reaction), followed by either formation of a dioxetane intermediate or Criegee-type rearrangement. However, density functional theory (DFT) calculations do not support the proposed concerted oxygen ene-type and Criegee-type rearrangement pathways. On the basis of DFT calculations, we propose a new mechanism for dioxygen activation in these heme systems. The mechanism involves (a) direct electrophilic addition of the Fe(II)-bound oxygen to the C2 or C3 position of the indole in a closed-shell singlet state or (b) direct radical addition of the Fe(III)-superoxide to the C2 position of the indole in a triplet (or open-shell singlet) state. Then, a radical-recombination or nearly barrierless charge-recombination step from the resultant diradical or zwitterionic intermediates, respectively, proceeds to afford metastable dioxetane intermediates, followed by ring-opening of the dioxetanes. Alternatively, homolytic O-O bond cleavage from the diradical intermediate followed by oxo attack and facile C2-C3 bond cleavage could compete with the dioxetane formation pathway. Effects of ionization of the imidazole and negatively charged oxyporphyrin complex on the key dioxygen activation process are also studied.     

Rapid access to halohydrofurans via Brønsted acid-catalyzed hydroxylation/halocyclization of cyclopropyl methanols with water and electrophilic halides

A one-pot, two-step method to prepare 3-halohydrofurans efficiently by TfOH-catalyzed hydroxylation/halocyclization of cyclopropyl methanols with H(2)O and N-halosuccinimide (NXS, X=1, Br, Cl) or Selectfluor is described. The reactions proceed rapidly under mild and operationally straightforward conditions with a catalyst loading as low as 1 mol % and afford the 3-halohydrofuran products in moderate to excellent yields and, in most cases, with preferential cis diastereoselectivity. The method was shown to be applicable to cyclopropyl methanols containing electron-withdrawing, electron-donating, and sterically demanding functional groups and electrophilic halide sources. The mechanism is suggested to involve protonation of the alcohol substrate by the Br?nsted acid catalyst and ionization of the starting material. This results in ring-opening of the cyclopropane moiety and in situ formation of a homoallylic alcohol intermediate, which undergoes subsequent intramolecular halocyclization on treating with the electrophilic halide source to give the halohydrofuran. The observed cis product selectivity is thought to be determined by the reaction proceeding through an in situ generated unsaturated alcohol intermediate that contains a (Z)-alkene moiety under the kinetically controlled conditions.     

Synthesis of iodo-indoloazepinones in an iodine-mediated three-component domino reaction via a regioselective 7-endo-dig iodo-cyclization pathway

An efficient and rapid synthetic strategy for the naturally occurring indoloazepinone scaffold via a three-component reaction of indole-2-carboxamides, 1,3-disubstituted propargyl alcohols, and I(2) is described. The strategy involves a C-H functionalization-alkyne activation-intramolecular hydroamidation-deprotonation domino sequence. The salient feature of this sequence is regioselective electrophilic 7-endo-dig iodo-cyclization during the intramolecular hydroamidation to afford a seven-membered azepinone ring annulated to the indole.     

Regioselective reactions of 1-alkylidene-2-oxyallyl cations with furan: control of [4 + 3] cycloaddition, [3 + 2] cycloaddition, and electrophilic substitution

The ring opening of alkylidenecyclopropanone acetal under acidic conditions produces the 1-alkylidene-2-oxyallyl cation as an intermediate, which reacts with furan to give the [3 + 2] and [4 + 3] cycloadducts as well as an electrophilic substitution product. The product distribution is controlled by the oxy substituents of the cation and by the solvent employed.     

The chemistry of the highly reactive 2,6‐bis(bromomethyl)‐4‐pyrone

Under basic conditions 2,6‐bis(bromomethyl)‐4‐pyrone 8 reacts with tetraethylene glycol to yield the unexpected macrocycle 9 , which is related to the antibiotic Kjellmanianone 10 . We propose that this ring transformation proceeds via the cyclopropyl intermediate d (Scheme 2), which undergoes a ring opening reaction comparable to the Favorskii rearrangement. Also, 8 reacts with methanol/sodium methoxide to yield the 3(2H)‐furanone derivative 11 , the formation of which is suggested to proceed via the intermediate k with a carbenium‐oxonium‐ion subunit (Scheme 3). The structure of the 3(2H)‐furanone derivative was confirmed by X‐ray analysis.     

Cyclopropyl alkynes as mechanistic probes to distinguish between vinyl radical and ionic intermediates

[reaction: see text] The reactions of (trans-2-phenylcyclopropyl)ethyne, 1a, (trans,trans-2-methoxy-3-phenylcyclopropyl)ethyne, 1b, and (trans,trans-2-methoxy-1-methyl-3-phenylcyclopropyl)ethyne, 1c, with either aqueous sulfuric acid or tris(trimethylsilyl)silane (or tributyltin hydride) and AIBN have been investigated. Protonation and addition of the silyl (or stannyl) radical occurred at the terminal position of the alkyne giving an alpha-cyclopropyl-substituted vinyl cation or radical, respectively. Under both reaction conditions, 1a yielded products derived from ring opening toward the phenyl substituent. Alkynes 1b and 1c, however, gave different products depending on whether radical or cationic conditions were used. When radical conditions were employed, products derived from regioselective ring opening toward the phenyl substituent were obtained. In contrast, when cationic conditions were employed, products derived from selective ring opening toward the methoxy substituent were isolated. The corresponding alpha-cyclopropyl-substituted vinyllithium derivatives were also synthesized and were found to be stable toward rearrangement. An estimate of the rate constants for ring opening of the alpha-cyclopropylvinyl cations was also made: values of 10(10)-10(12) s(-1) were found for the vinyl cations derived from protonation of the terminal carbon of alkynes 1a-c. Based on these results, cyclopropyl alkynes 1a-c can be classified as hypersensitive mechanistic probes for the detection of vinyl radical or cationic intermediates generated adjacent to the cyclopropyl ring and, in the case of 1b and 1c, the distinction between a radical or cationic intermediate is possible.     

Mechanism of the oxidation of sulfides by dioxiranes. 1. Intermediacy of a 10-S-4 hypervalent sulfur adduct

Earlier studies established that dimethyldioxirane (1a) reacts with sulfides 2 in two consecutive concerted electrophilic oxygen-transfer steps to give first sulfoxides 3 and then sulfones 4. The same sequential electrophilic oxidation model was assumed for the reaction of sulfides 2 with the strongly electrophilic methyl(trifluoromethyl)dioxirane (1b). In this paper we report on a systematic and general study on the mechanism of the reaction of simple sulfides 2 with DMDO (1a) and TFDO (1b) which provides clear evidence for the involvement of hypervalent sulfur species in the oxidation process. In the oxidation of sulfides 2a-c, diphenyl sulfide (2d), para-substituted aryl methyl sulfides 2e-i, and phenothiazine 2k with 1b, the major product was the corresponding sulfone 4, even when a 10-fold excess of sulfide relative to 1b was used. The sulfone:sulfoxide 4:3 ratio depends among other factors on the dioxirane 1a or 1b used, the sulfide substitution pattern, the polar, protic, or aprotic character of the solvent, and the temperature. The influence of these factors and also deuterium and (18)O tracer experiments performed allow a general mechanism to be depicted for these oxidations in which the key step is the reversible cyclization of a zwitterionic intermediate, 6, to form a hypervalent sulfur species, 7. The classical sequential mechanism which establishes that sulfides are oxidized first to sulfides and then to sulfones can be enclosed in our general picture of the process and represents just those particular cases in which the zwitterionic intermediate 6 decomposes prior to undergoing ring closure to afford the hypervalent sulfurane intermediate 7.     

Highly diastereoselective approach toward (+/-)-tetraponerine T6 and analogues via the double cycloisomerization-reduction of bis-alkynylpyrimidines

A new, short, and efficient approach toward tricyclic alkaloids, involving the double cycloisomerization-reduction of bis-alkynylpyrimidines 3a-m, has been developed. The requisite bis-alkynylpyrimidines 3a-m were readily prepared via regioselective sequential Sonogashira coupling reactions of dibromopyrimidines 1. Bis-alkynylpyrimidines 3a-m were converted into the 5-6-5 tricyclic heteroaromatic cores 4a-m via the Cu(I)-assisted double cycloisomerization reaction. The reaction proceeded stepwise, which was confirmed by the isolation of the mono-pyrrolization intermediate 5. The structure of 5 was assigned by 2D NMR and by independent synthesis. Cycloisomerization of 5 under standard conditions afforded tricyclic 4g in 89% yield. The PtO2-catalyzed hydrogenation of bis-pyrrolopyrimidines 4d, 4g, and 4i in acidic media afforded stable amidinium derivatives, 11a, 11b, and 11c. Further reduction of the latter with LiAlH4 allowed for the highly diastereoselective total synthesis of (+/-)-tetraponerine T6 and its analogues.     

Synthesis of pyrroles through a 4π-electrocyclic ring-closure reaction of 1-azapentadienyl cations

1-Azapenta-1,4-diene-3-ols 4a-m are easily accessible from 1-azapenta-1,4-dien-3-ones 3a-i and organolithium compounds. Treatment of the compounds 4a-m with strong acid (triflic acid) generates 1-azapentadienyl cations in situ upon protonation at the hydroxyl oxygen atom and subsequent water elimination. The intermediate cations undergo facile 4π-electrocyclization under ambient condition to give diversely substituted pyrroles 6a-m in moderate to good yield. The product pyrrole 6k could be characterized by X-ray diffraction. Quantum chemical calculations were performed to elucidate the mechanism of this reaction with respect to starting compounds, transition states, and products. They support the proposed mechanism of a 4π-conrotatory M?bius-type electrocyclic ring-closure reaction.     

Iridium- and ruthenium-catalysed synthesis of 2,3-disubstituted indoles from anilines and vicinal diols

A straightforward and atom-economical method is described for the synthesis of 2,3-disubstituted indoles. Anilines and 1,2-diols are condensed under neat conditions with catalytic amounts of either [Cp*IrCl(2)](2)/MsOH or RuCl(3)·xH(2)O/phosphine (phosphine = PPh(3) or xantphos). The reaction does not require any stoichiometric additives and only produces water and dihydrogen as byproducts. Anilines containing methyl, methoxy, chloro and fluoro substituents can participate in the cyclocondensation. Meta-substituted anilines give good regioselectivity for 6-substituted indoles, while unsymmetrical diols afford excellent regioselectivity for the indole isomer with an aryl or large alkyl group in the 2-position. The mechanism for the cyclocondensation presumably involves initial formation of the α-hydroxyketone from the diol. The ketone subsequently reacts with aniline to generate the α-hydroxyimine which rearranges to the corresponding α-aminoketone. Acid- or metal-catalysed electrophilic ring-closure with the release of water then furnishes the indole product.     

The fischer indolization of 4-acetonyl-2,6-piperidinediones

The PPA induced Fischer indolization of 4-acetonyl-2,6-piperidinediones 4 takes place both at the methylene and the methyl carbons, although the latter regioisomer (3) undergoes a further cyclization of the imide moiety upon the indole 3-position followed by ring-opening of the resulting intermediate 9 to give tetrahydrocarbazolone 8. Fragmentation of the two possible regioisomers 3 and 7 to 2-methylindole occurs at higher temperatures. This process is more pronounced when using 4-acetonyl-3,4-dihydro-2(1H)-pyridone 13 as the substrate for the indolization. The use of N-acetylphenylhydrazone derivatives leads to similar results as a consequence of the deacylation of the initially formed indole derivatives. In this case, an additional C-acylation of the indole ring also occurs.