Stereocontrolled synthesis of 5-azaspiro[2.3]hexane derivatives as conformationally “frozen” analogues of L-glutamic acid

• Beatrice Bechi,
• David Amantini,
• Cristina Tintori,
• Maurizio Botta and
• Romano di Fabio

Beilstein J. Org. Chem. 2014, 10, 1114–1120, doi:10.3762/bjoc.10.110

• rotation around the C3–C4 bond present in the azetidine derivative Ia by incorporating an appropriate spiro moiety. The cyclopropyl moiety was introduced by a diastereoselective rhodium catalyzed cyclopropanation reaction. Keywords: Amino acids; carbenes; cyclopropanation; rhodium; spiro compounds

• two different synthetic strategies: a) cyclopropanation of an α,β-unsaturated ester (compound III, Z = COOR); b) metal-catalyzed cyclopropanation of the corresponding terminal olefin derivative (compound III, Z = H) with a diazoacetate derivative. After having accomplished this key step, intermediate

• [28][29][30][31][32][33] cyclopropanation reaction were attempted (highlighted in Scheme 3). Regrettably, when these reactions were performed under different reaction conditions by changing the base, the solvent, the temperature and the reaction time, only trace amounts of final product 20 were

Site-selective covalent functionalization at interior carbon atoms and on the rim of circumtrindene, a C₃₆H₁₂ open geodesic polyarene

• Hee Yeon Cho,
• Ronald B. M. Ansems and
• Lawrence T. Scott

Beilstein J. Org. Chem. 2014, 10, 956–968, doi:10.3762/bjoc.10.94

• reactions and to probe the magnetic environment of the concave/convex space around the hydrocarbon bowl. For both classes of functionalization, computational results are reported to complement the experimental observations. Keywords: Bingel–Hirsch reaction; buckybowl; carbon nanomaterials; cyclopropanation

• unit. Representative synthetic reactions of fullerene C60 (2) include cyclopropanation [29][30], [3 + 2] cycloaddition [31][32], [4 + 2] cycloaddition [33], nucleophilic addition [34], and radical addition reactions [35]. Two of the earliest and most widely used reactions, the Bingel–Hirsch reaction

• behavior. Considering the similarity between the curved π-systems of circumtrindene and fullerene C60, we speculated that the Bingel–Hirsch reaction might occur with circumtrindene (6) in the same manner as it does with fullerene C60. Gratifyingly, the cyclopropanation of circumtrindene by the Bingel

Recent applications of the divinylcyclopropane–cycloheptadiene rearrangement in organic synthesis

• Sebastian Krüger and
• Tanja Gaich

Beilstein J. Org. Chem. 2014, 10, 163–193, doi:10.3762/bjoc.10.14

• alcohol to yield aldehyde 34. Addition of double deprotonated methyl acetoacetate gave β-ketoester 35. Diazotransfer followed by double protection resulted in the formation of compound 36. Rh-catalyzed intramolecular cyclopropanation of this compound gave bicycle 37. Selective removal of the secondary

• 82. Diazotransfer using p-ABSA [86] yielded diazoester 83. Selective rhodium-catalyzed cyclopropanation of the cis-double bond [87][88] of diene 84 [89] furnished cis-divinylcyclopropane 85, which underwent DVCPR upon Kugelrohr distillation at 140 °C to give bicyclic 86. Selective hydrogenation of

• ). Davies and co-worker [91][92] investigated the formal synthesis of the sequiterpene-hydroquinone derivative frondosin B (99, see Scheme 12) [93] via an enantioselective cyclopropanation of trans-piperylene and subsequent divinylcyclopropane rearrangement, to further demonstrate the versatility of their

Synthesis of five- and six-membered cyclic organic peroxides: Key transformations into peroxide ring-retaining products

• Alexander O. Terent'ev,
• Dmitry A. Borisov,
• Vera A. Vil’ and
• Valery M. Dembitsky

Beilstein J. Org. Chem. 2014, 10, 34–114, doi:10.3762/bjoc.10.6

New developments in gold-catalyzed manipulation of inactivated alkenes

• Michel Chiarucci and
• Marco Bandini

Beilstein J. Org. Chem. 2013, 9, 2586–2614, doi:10.3762/bjoc.9.294

• nucleophilic double bound of the allene, forming the intermediate 88. Finally, condensation of the alkylgold 88 onto the carbonyl group led to the bicyclic product 84 (Scheme 23). An interesting example of gold-catalyzed intramolecular cyclopropanation of olefins was recently documented by Maulide and

• -based electrophilc activation of the C=C, with consequent nucleophilic attack by the ylidic carbon onto the internal carbon of the double bond. Finally, the intermediate lactone 92 underwent cyclopropanation, delivering SPh2 as a leaving group (Scheme 24b). 5 Addition to allylic alcohols The use of

• benzoates. Intramolecular [Au(I)]-catalyzed cyclopropanation of alkenes. Stereospecificity in [Au(I)]-catalyzed hydroalkoxylation of allylic alcohols. Mechanistic investigation on the intramolecular [Au(I)]-catalyzed hydroalkoxylation of allylic alcohols. Mechanistic investigation on the intramolecular

Gold(I)-catalyzed enantioselective cycloaddition reactions

• Fernando López and
• José L. Mascareñas

Beilstein J. Org. Chem. 2013, 9, 2250–2264, doi:10.3762/bjoc.9.264

• with high diastereoselectivity. Moreover, the enantioselective cyclopropanation was not limited to arylated olefins (e.g. styrenes), but allyltrimethylsilane also participated in the process, producing the corresponding silylmethyl cyclopropane as a 5:1 mixture of cis:trans isomers with a good 78% ee

• (Scheme 1). In 2009, the same group extended the utility of this asymmetric cyclopropanation reaction to an intramolecular process that allows the enantioselective synthesis of polycarbocyclic products embedding seven or eight-membered rings [42]. Curiously, the catalytic system based on DTBM-Segphos

• eleven, gold has also demonstrated to be an efficient promoter of intermolecular carbene transfer reactions from diazo compounds to unsaturated systems such as alkenes or alkynes, resulting in cyclopropanation processes [44][45]. The development of an enantioselective variant of this type of reactions

Ethyl diazoacetate synthesis in flow

• Mariëlle M. E. Delville,
• Jan C. M. van Hest and
• Floris P. J. T. Rutjes

Beilstein J. Org. Chem. 2013, 9, 1813–1818, doi:10.3762/bjoc.9.211

• variety of reactions e.g. cyclopropanation, X–H insertion, cycloaddition and ylide formation [13][15], and more recently, in the synthesis of valuable compound classes such as β-keto esters [16] and β-hydroxy-α-diazocarbonyl compounds [17], we aimed to develop an inherently safe continuous-flow EDA

α-Bromodiazoacetamides – a new class of diazo compounds for catalyst-free, ambient temperature intramolecular C–H insertion reactions

• Åsmund Kaupang and
• Tore Bonge-Hansen

Beilstein J. Org. Chem. 2013, 9, 1407–1413, doi:10.3762/bjoc.9.157

• cycloaddition, ylide formation, cyclopropanation and C–H insertion reactions [1][2][3]. A generally useful modification of diazo compounds is the substitution of the α-hydrogen for an electrophile. This substitution can be effected in the presence of a base or starting from the metalated diazo compound, and

• dirhodium(II)-catalysed cyclopropanation, and C–H and Si–H insertion reactions [37][38][39]. There are, to the best of our knowledge, no reports in the literature of α-halodiazoacetamides as a substance class. Thus, we wished to expand the substrate scope of one of our published methodologies to encompass

• thermolysis of an α-bromodiazoketone was successfully employed in an intramolecular cyclopropanation reaction [62]. Historically, the thermolysis of diazocarbonyl compounds has been carried out under reflux [63][64][65][66], although examples of low temperature and ambient temperature thermolysis can be found

Synthesis of skeletally diverse alkaloid-like molecules: exploitation of metathesis substrates assembled from triplets of building blocks

• Sushil K. Maurya,
• Mark Dow,
• Stuart Warriner and
• Adam Nelson

Beilstein J. Org. Chem. 2013, 9, 775–785, doi:10.3762/bjoc.9.88

• unsaturated building blocks. The approach involved the iterative attachment of a propagating and a terminating building block to a fluorous-tagged initiating building block. Metathesis cascade chemistry was used to “reprogram” the molecular scaffolds. Remarkably, in one case, a cyclopropanation reaction

The chemistry of bisallenes

• Henning Hopf and
• Georgios Markopoulos

Beilstein J. Org. Chem. 2012, 8, 1936–1998, doi:10.3762/bjoc.8.225

• resulted from heating 24 and 193 together [134]. Finally, as shown by Lüttke and Heinrich, the cyclopropanation of the parent system 2 with diazomethane/Cu2Cl2 provided a mixture of twelve cyclopropanation products in very good yield (ca. 90%), from the mono adduct 195 to the dispiro compound 196, i.e. the

Alkenes from β-lithiooxyphosphonium ylides generated by trapping α-lithiated terminal epoxides with triphenylphosphine

• David. M. Hodgson and
• Rosanne S. D. Persaud

Beilstein J. Org. Chem. 2012, 8, 1896–1900, doi:10.3762/bjoc.8.219

• epoxides 8 by using hindered lithium amides, such as lithium tetramethylpiperidide (9, LTMP) [20], and have shown synthetically useful carbene reactivity (e.g., cyclopropanation [21][22], dimerization [23][24][25]). The reaction of carbenes and carbenoids with heteroatom lone pairs is a popular strategy to

Evaluation of a chiral cubane-based Schiff base ligand in asymmetric catalysis reactions

• Kyle F. Biegasiewicz,
• Michelle L. Ingalsbe,
• Jeffrey D. St. Denis,
• James L. Gleason,
• Junming Ho,
• Michelle L. Coote,
• G. Paul Savage and
• Ronny Priefer

Beilstein J. Org. Chem. 2012, 8, 1814–1818, doi:10.3762/bjoc.8.207

• cyclopropanation and Michael addition reactions. Although there was no increase in stereocontrol, upon computational evaluation using both M06L and B3LYP calculations, it was revealed that a pseudo six-membered ring exists, through H-bonding of a cubyl hydrogen to the copper core. This decreases the steric bulk

• evaluating this cubane-based ligand with cyclopropanation reactions. When no chiral ligand was added there was a 2.6:1 ratio of trans to cis products with no ee control. We then introduced our cubane-based chiral ligand 1 to our cyclopropanation protocol with four different copper sources (Table 1). The

• in obtaining high stereoselectivity, and thus we decided to switch to Michael addition with organomagnesium and organozinc reagents. Since the copper source that produced the highest ee value with the cyclopropanation above was Cu(I) triflate tetrakisacetonitrile, we decided to initially focus on

trans-2-(2,5-Dimethoxy-4-iodophenyl)cyclopropylamine and trans-2-(2,5-dimethoxy-4-bromophenyl)cyclopropylamine as potent agonists for the 5-HT₂ receptor family

• Adam Pigott,
• Stewart Frescas,
• John D. McCorvy,
• Xi-Ping Huang,
• Bryan L. Roth and
• David E. Nichols

Beilstein J. Org. Chem. 2012, 8, 1705–1709, doi:10.3762/bjoc.8.194

• than for DOI itself. Keywords: cyclopropanation; diazomethane; hallucinogen; 5-HT2A agonist; receptor probe; trans-2-phenylcyclopropylamines; Introduction Among the molecules that have proven very valuable to neuroscientists studying brain serotonin systems is the substituted phenethylamine

• sign of optical rotation [4]. The biological data are consistent with those configuration assignments. Chemistry We reasoned that a palladium-mediated cyclopropanation of the corresponding cinnamic acids would provide the required cyclopropanecarboxylic acid (Scheme 1); which could be readily converted

• chiral auxiliaries in the cyclopropanation step could directly afford the chiral cyclopropane acids [8], but time and resources did not allow us to pursue that approach. Conclusion In conclusion, our strategy to replace the ethylamine side chain of 1a (or 1b) with a cyclopropylamine moiety was successful

A quantitative approach to nucleophilic organocatalysis

• Herbert Mayr,
• Sami Lakhdar,
• Biplab Maji and
• Armin R. Ofial

Beilstein J. Org. Chem. 2012, 8, 1458–1478, doi:10.3762/bjoc.8.166

• is CH3CN unless otherwise mentioned, N values taken from [4][61]). Experimental and calculated rate constants k2 for the reactions of 17b and 17g with 3a and 3b in the presence of 2,6-lutidine in CH2Cl2 at 20 °C [61]. Comparison between experimental and calculated (Equation 1) cyclopropanation rate

Efficient and selective chemical transformations under flow conditions: The combination of supported catalysts and supercritical fluids

• M. Isabel Burguete,
• Eduardo García-Verdugo and
• Santiago V. Luis

Beilstein J. Org. Chem. 2011, 7, 1347–1359, doi:10.3762/bjoc.7.159

• the enantioselective cyclopropanation with supported copper–bisoxazoline (Cu–BOX) or copper-pyridineoxazoline (Cu–PyOX) complexes and related systems. The oxazoline ligands can be introduced in polystyrene–divinylbenzene (PS–DVB) matrices either by grafting, by reaction with chloromethyl groups of

• preformed resins, or by polymerization of the corresponding bisoxazolines or pyridineoxazolines containing polymerizable vinylic fragments [73][74]. The transformation of those BOX or PyOX moieties into the corresponding Cu complexes allows their use as catalysts for the enantioselective cyclopropanation of

• . Enantioselective hydroformylation of styrene. Enantioselective hydrovinylation of styrene. Enantioselective cyclopropanation of styrene catalyzed by supported Cu–BOX, Cu–PyOX and Rh–PyBOX catalysts. Continuous hydrogenation of acetophenone coupled with the kinetic resolution of the product. Kinetic resolution of

Recent developments in gold-catalyzed cycloaddition reactions

• Fernando López and
• José L. Mascareñas

Beilstein J. Org. Chem. 2011, 7, 1075–1094, doi:10.3762/bjoc.7.124

• )-catalyzed intermolecular (2 + 2) cycloaddition of alkynes with alkenes [62]. Metal-catalyzed cycloaddition of alkynes tethered to cycloheptatriene [65]. Gold-catalyzed cycloaddition of functionalized ketoenynes: Synthesis of (+)-orientalol F [68]. Gold-catalyzed intermolecular cyclopropanation of enynes

• with alkenes [70]. Gold-catalyzed intermolecular hetero-dehydro Diels–Alder cycloaddition [72]. Gold(I)-catalyzed stereoselective olefin cyclopropanation [74]. Reaction of propargylic benzoates with α,β-unsaturated imines to give azepine cycloadducts [77]. Gold-catalyzed (3 + 3) annulation of

Scalable synthesis of (1-cyclopropyl)cyclopropylamine hydrochloride

• Sergei I. Kozhushkov,
• Alexander F. Khlebnikov,
• Rafael R. Kostikov,
• Dmitrii S. Yufit and
• Armin de Meijere

Beilstein J. Org. Chem. 2011, 7, 1003–1006, doi:10.3762/bjoc.7.113

• cyclopropyl cyanide [3][4][5][6][7][8][9][10][11][12][13] by application of the Szymoniak–Kulinkovich reductive cyclopropanation procedure [14][15]. In our hands, however, this patented protocol [3][4][5][6][7][8][9][10][11][12][13] provided poor yields (15–20%) of impure 4 [16], which had to be purified by

When gold can do what iodine cannot do: A critical comparison

• Sara Hummel and
• Stefan F. Kirsch

Beilstein J. Org. Chem. 2011, 7, 847–859, doi:10.3762/bjoc.7.97

• the presence of an Au catalyst to afford the cyclopropanation product 70 with excellent diastereoselectivity. This is only one example where gold catalysts open the door to a realm of reactivity that traditional electrophiles can never reach. Conclusion This review was intended to demonstrate that

• cyclization modes for 1,5-enynes. Iodine-induced cyclization of 1,5-enynes. Diverse reactivity of 1,6-enynes. Iodocyclization of 1,6-enynes. Cyclopropanation of alkenes with 1,6-enynes. Cyclopropanation of alkenes with 1,6-enynes. Acknowledgements S. H. thanks the Erasmus programme for supporting her visit

High chemoselectivity in the phenol synthesis

• Matthias Rudolph,
• Melissa Q. McCreery,
• Wolfgang Frey and
• A. Stephen K. Hashmi

Beilstein J. Org. Chem. 2011, 7, 794–801, doi:10.3762/bjoc.7.90

• second option would be a classical cyclopropanation of an olefin. A third option would be trapping of intermediate A with an intramolecular hydroxy nucleophile [36]. Here we report our observations when trying to apply these principles to intermediates of type A or B. Results and Discussion

• in an intramolecular manner. Substrate 8 could potentially undergo three different modes of reaction (Scheme 4). After the initial step, the intermediate E would be produced (analogous to A). Cyclopropanation of the styrene subunit by the cyclopropyl carbenoid would deliver 9. If E rearranged to the

• vinylcarbenoid F, the two competing reactions would be the formation of the phenol 10 and cyclopropanation to form 11. The synthesis of 8 was possible by a short route (Scheme 5). Starting from the commercially available 2-bromostyrene (12), a halogen–metal exchange and subsequent formylation according to a

Synthetic applications of gold-catalyzed ring expansions

• David Garayalde and
• Cristina Nevado

Beilstein J. Org. Chem. 2011, 7, 767–780, doi:10.3762/bjoc.7.87

• . Cyclopropanes 85a are generated in situ by intermolecular cyclopropanation of enyne 84 and a carbene resulting from the rearrangement of propargyl ester 83. When tertiary propargyl esters are used, the 5-endo-dig cyclization generates the carbocation 89. Migration of the pivaloyloxy group affords the allylic

• -catalyzed synthesis of ventricos-7(13)-ene. 1,2- vs 1,3-Carboxylate migration. Gold-catalyzed cycloisomerization of vinyl alkynyl cyclopropanes. Proposed mechanism for the cycloisomerization of vinyl alkynyl cyclopropanes. Gold-catalyzed 1,2-acyloxy rearrangement/cyclopropanation/cycloisomerization cascades

When cyclopropenes meet gold catalysts

• Frédéric Miege,
• Christophe Meyer and
• Janine Cossy

Beilstein J. Org. Chem. 2011, 7, 717–734, doi:10.3762/bjoc.7.82

• nucleophilic addition with, e.g., alcohols, arenes or carbonyl groups, undergo self- or cross-carbene couplings and bring about the cyclopropanation of olefins. The first of these reaction types is often considered to be representative of cationic intermediates whereas the other two are best ascribed to

• in this review, these structural effects were found to have important consequences in terms of reactivity in the case of intermolecular olefin cyclopropanation promoted by gold carbenes generated from cyclopropenes. In fact, the first reports on gold-catalyzed reactions involving cyclopropenes

• cyclopropenes examined so far in this review have involved capture of the organogold intermediates, resulting from electrophilic activation and ring-opening, by an external or an internal nucleophile. Cyclopropanation of olefins, a reaction classically attributed to the carbene-like reactivity, will now be

Gold-catalyzed naphthalene functionalization

• Pedro J. Pérez,
• M. Mar Díaz-Requejo and
• Iván Rivilla

Beilstein J. Org. Chem. 2011, 7, 653–657, doi:10.3762/bjoc.7.77

• derivatives, formed by the cyclopropanation of one of the double bonds of the naphthalene ring. Later, Müller and co-workers [9] showed the effect of a series of Rh2(L-L)4 in the same transformation but with ethyl diazoacetate as the carbene source. A mixture of the products (2a–d) arising from

• cyclopropanation, ring opening and the formal insertion of CHCO2Et into the aromatic C–H bonds were observed, with 2a being by far the major product (Scheme 2). In the course of our research, focussed on the development of group 11 metal-based catalysts for carbene transfer reactions from diazo compounds [10], we

• formed, identified as ethyl 1a,7b-dihydro-1H-cyclopropa[a]naphthalene-1-carboxylate (2a), i.e., the product derived from the direct cyclopropanation of the naphthalene C–C double bond (Scheme 4a). By contrast, the use of the gold catalyst IPrAuCl (1b) under the same reaction conditions gave a mixture of

Ene–yne cross-metathesis with ruthenium carbene catalysts

• Cédric Fischmeister and
• Christian Bruneau

Beilstein J. Org. Chem. 2011, 7, 156–166, doi:10.3762/bjoc.7.22

• . This procedure has been successfully used to prepare C-aryl glycoside from C-alkynyl glycoside and ethylene according to an EYCM/Diels–Alder/oxidation sequence (Scheme 6) [52][53]. The selective cyclopropanation of the most electron deficient double bond of the unsymmetrical dienic system has been

Tandem catalysis of ring-closing metathesis/atom transfer radical reactions with homobimetallic ruthenium–arene complexes

• Yannick Borguet,
• Xavier Sauvage,
• Guillermo Zaragoza,
• Albert Demonceau and
• Lionel Delaude

Beilstein J. Org. Chem. 2010, 6, 1167–1173, doi:10.3762/bjoc.6.133

• ][13][14], ATRP [15][16][17][18], cyclopropanation [19], dihydroxylation [20], hydrogenation [21][22][23], hydrovinylation [24], isomerization [25][26][27][28], oxidation [29], or Wittig reactions [30], to name just a few [31]. In this contribution, we investigate the tandem catalysis of RCM/ATRC

α,β-Aziridinylphosphonates by lithium amide-induced phosphonyl migration from nitrogen to carbon in terminal aziridines

• David. M. Hodgson and
• Zhaoqing Xu

Beilstein J. Org. Chem. 2010, 6, 978–983, doi:10.3762/bjoc.6.110

• aziridinylphosphonate 3b in 79% yield (Table 1, entry 2). Aziridines 1c and 1d underwent migration smoothly without complications arising from potential allylic deprotonation [33], intramolecular cyclopropanation [11][12] or benzylic deprotonation (entries 3 and 4). Mixed results were obtained when the method was