C–H-Functionalization logic guides the synthesis of a carbacyclopamine analog

• Sebastian Rabe,
• Johann Moschner,
• Marina Bantzi,
• Philipp Heretsch and
• Athanassios Giannis

Beilstein J. Org. Chem. 2014, 10, 1564–1569, doi:10.3762/bjoc.10.161

• analog that still exhibits similar inhibitory activity on hedgehog-signaling. For the sake of brevity of the overall synthetic sequence we defined carbacyclopamine analog 2 (see Figure 1) as our primary target. Results and Discussion A retrosynthetic analysis identified diazo compound 3 as a key

• was thought to establish the C-nor-D-homo steroid system, and a gold-catalyzed amination/annulation/aromatization sequence was planned to install the pyridine F-ring. Diazo compound 3 originates from diene 4 through standard transformations, the latter being accessible from commercially available and

A tandem Mannich addition–palladium catalyzed ring-closing route toward 4-substituted-3(2H)-furanones

• Jubi John,
• Eliza Târcoveanu,
• Peter G. Jones and
• Henning Hopf

Beilstein J. Org. Chem. 2014, 10, 1462–1470, doi:10.3762/bjoc.10.150

• palladium catalysis afforded 4-substituted furanones in good to excellent yields. 4-Hydrazino-3(2H)-furanones could also be synthesized from diazo esters in excellent yields by utilising the developed strategy. We could also efficiently transform the substituted furanones to aza-prostaglandin analogues

• closure of the primary adduct to form the furanone. In this paper, we report our investigations that extend the reaction to heteroatom-containing electrophiles such as imines and diazo esters. Results and Discussion Following the work on nitrostyrenes, Yan et al. also reported a two-step asymmetric route

• entry 2 of Table 2 we can confirm that palladium catalyzes the reaction. The generality of the reaction was checked with different diazo esters 19a–c with 4-chloroacetoacetate esters 2a and 2b under the optimized conditions (diazo ester (1.0 equiv), 4-chloroacetoacetate (1.1 equiv), Pd(PPh3)4 (5 mol

Domino reactions of 2H-azirines with acylketenes from furan-2,3-diones: Competition between the formation of ortho-fused and bridged heterocyclic systems

• Alexander F. Khlebnikov,
• Mikhail S. Novikov,
• Viktoriia V. Pakalnis,
• Roman O. Iakovenko and
• Dmitry S. Yufit

Beilstein J. Org. Chem. 2014, 10, 784–793, doi:10.3762/bjoc.10.74

• ][17][18][19][20][21]. 2H-Azirines can react with ketenes both with cleavage and preservation of the three-membered ring [22][23][24][25][26]. It was found that acylketenes, which are generated in situ from diazo ketones, undergo cycloaddition with 3-mono- and 2,3-disubstituted-2H-azirines to afford 2

• application of the reaction is the nonselective mode of the Wolff rearrangement of the unsymmetrical diazo compounds. This generates a mixture of isomeric oxoketenes [27][28][29] and, as a result, a complex mixture of products is formed [22]. Moreover not all diazo compounds give oxoketenes easily [27][28][29

• ]. In particular, unsubstituted acylketenes, the reactivity of which towards azirines is until now unknown, cannot be generated from diazo compounds. An alternative source of acylketenes can be furan-2,3-diones, which have been used in reactions with nucleophiles and various cycloadditions [30][31][32

Use of activated enol ethers in the synthesis of pyrazoles: reactions with hydrazine and a study of pyrazole tautomerism

• Denisa Tarabová,
• Stanislava Šoralová,
• Martin Breza,
• Marek Fronc,
• Wolfgang Holzer and
• Viktor Milata

Beilstein J. Org. Chem. 2014, 10, 752–760, doi:10.3762/bjoc.10.70

• ), 1,3-dipolar cycloaddition with diazo compounds as a source of N–N linkage, degradation of fused pyrazoles or rearrangement of other monocyclic heterocycles under chemical, thermal or photochemical conditions [4]. Upon reaction of hydrazine with symmetrical enol ethers, only a single product is formed

Silver and gold-catalyzed multicomponent reactions

• Giorgio Abbiati and
• Elisabetta Rossi

Beilstein J. Org. Chem. 2014, 10, 481–513, doi:10.3762/bjoc.10.46

• been reported [59]. Preformed 2-(1-alkynyl)arylaldimines 27 have been used in a MCR involving tandem cyclization/three-component reactions with diazo compounds 37 and water or alcohols 38 in the presence of dirhodium acetate and silver triflate cooperative catalysis resulting in excellent yields of

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

• formal [4 + 3] cycloaddition [82]. Starting from 4-methoxyphenol (90) Friedel–Crafts acylation and cyclization provided bicycle 91. Wittig olefination furnished benzofuran 92. Diazotransfer using p-ABSA yielded the crucial diazo compound 93, which was used in the following enantioselective

• ethyl vinyl ether. The necessary diazo moiety was installed using tosylazide as a diazo-transfer reagent to yield 134. Copper catalyzed intramolecular cyclopropanation furnished bicycle 135. Reduction of the carbonyl moiety and protection of the resulting alcohol was followed by ether cleavage and

• -catalyzed cyclopropanation of silyl-enol-diazo compound 101 and Boc-protected pyrrole 147 resulted in the formation of intermediate cis-divinylcyclopropane 148, that rearranged under the reaction conditions to give the corresponding highly substituted bridged cycloheptadiene 149. Deprotection of the enolate

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

Less reactive dipoles of diazodicarbonyl compounds in reaction with cycloaliphatic thioketones – First evidence for the 1,3-oxathiole–thiocarbonyl ylide interconversion

• Valerij A. Nikolaev,
• Alexey V. Ivanov,
• Ludmila L. Rodina and
• Grzegorz Mlostoń

Beilstein J. Org. Chem. 2013, 9, 2751–2761, doi:10.3762/bjoc.9.309

• diazoalkanes, diazoesters and diazoketones [1][2][3][4]. Due to their high dipolarophilic reactivity thioketones were given the name ‘superdipolarophiles’ [3][4]. It might be expected that these highly reactive dipolarophiles could also easily react with the deactivated 1,3-dipoles of 2-diazo-1,3-dicarbonyl

• compounds takes place, but at room temperature the reaction proceeds very slowly [7][8]. Within the framework of our longstanding research interest in the synthesis of heterocycles by using diazo compounds [4][9][10][11][12][13], we have recently performed a comprehensive study of a variety of reactions of

• diazodicarbonyl compounds with arylsubstituted (aromatic) thioketones to establish their suitability for the preparation of 1,3-oxathioles and other sulfur-containing heterocycles [7][8]. The main goal of the present study was to investigate the scope and limitations of cycloaddition reactions of 2-diazo-1,3

Recent advances in transition metal-catalyzed Csp²-monofluoro-, difluoro-, perfluoromethylation and trifluoromethylthiolation

• Grégory Landelle,
• Armen Panossian,
• Sergiy Pazenok,
• Jean-Pierre Vors and
• Frédéric R. Leroux

Beilstein J. Org. Chem. 2013, 9, 2476–2536, doi:10.3762/bjoc.9.287

• sphere of the metal”. Indeed, the present radicals led to less side-reactions – in particular, oligomerization in the case of alkenes as substrates –, which shows that they exhibit “restricted reactivity” in comparison with “that of free radicals initiated by peroxides or diazo compounds and by

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

• 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

• -workers reported another example of a highly enantioselective gold-catalyzed cyclopropanation reaction by using diazo compounds as a source of gold carbenes. In particular, the authors demonstrated that the chiral bisgold complex Au6, derived from the spiroketal bisphosphine ligand, was a very efficient

The chemistry of isoindole natural products

• Klaus Speck and
• Thomas Magauer

Beilstein J. Org. Chem. 2013, 9, 2048–2078, doi:10.3762/bjoc.9.243

• Rh(II)-catalyzed C–H and OH insertion reactions (Scheme 4). The preparation of both enantiomeric furanose building blocks commenced with the Rh2(OAc)4-catalyzed OH insertion of 39, respectively 40 into the α-diazo-β-ketoester 40. A tandem [3,3]/[1,2]-rearrangement cascade, followed by reductive

Gold-catalyzed regioselective oxidation of propargylic carboxylates: a reliable access to α-carboxy-α,β-unsaturated ketones/aldehydes

• Kegong Ji,
• Jonathan Nelson and
• Liming Zhang

Beilstein J. Org. Chem. 2013, 9, 1925–1930, doi:10.3762/bjoc.9.227

• permits a safe and efficient access to α-oxo gold carbenes without resorting to the dediazotization strategy [3][4][5] using hazardous and potentially explosive diazo substrates (Scheme 1). Since then an array of versatile synthetic methods has been developed based on the general approach by us [2][6][7

• ratio of 5a-OAc and 5a-H in the gold-catalyzed oxidation of 4a (reaction conditions: 5 mol % gold catalyst, 1.5 equiv of 3, DCE, rt, 3 h). Natural charges at and the 13C chemical shifts of the alkynyl carbons in 4a. Generation of α-oxo gold carbenes via intermolecular oxidation of alkynes: a non-diazo

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

• conditions, a production yield of 20 g EDA day−1 was achieved using a microreactor with an internal volume of 100 μL. Straightforward scale-up or scale-out of microreactor technology renders this method viable for industrial application. Keywords: diazo compounds; diazotization; ethyl diazoacetate (EDA

• ); flow chemistry; microreactor technology; Introduction Diazo compounds are frequently used versatile building blocks in organic chemistry [1][2]. From this class of compounds diazomethane and ethyl diazoacetate (1, EDA) are arguably the synthetically most useful ones. Due to the potentially explosive

• nature of diazomethane and EDA [3][4][5], however, synthetic routes that involve large scale batchwise handling of such diazo compounds is generally avoided in industrial processes. With the advent of continuous processing over the past decade, new approaches have appeared to conceptually change the way

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

• cyclic amide side chains. Keywords: α-halo-β-lactam; diazo; halocarbonylcarbene; halogenation; thermolysis; Introduction Diazocarbonyl compounds are popular precursors for carbonylcarbenes and -carbenoids, the synthetic utility of which is thoroughly established through their successful employment in

• 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

• leaves the diazo function intact [4]. Among the reported transformations are substitutions of the diazomethyl hydrogen for electrophiles based on boron [5][6][7], nitrogen (NO2+) [8][9][10][11][12], silicon [13][14][15], phosphorous [16][17][18], sulfur [19][20][21] and halogens [10][22][23][24][25][26

Amyloid-β probes: Review of structure–activity and brain-kinetics relationships

• Todd J. Eckroat,
• Abdelrahman S. Mayhoub and
• Sylvie Garneau-Tsodikova

Beilstein J. Org. Chem. 2013, 9, 1012–1044, doi:10.3762/bjoc.9.116

• favorable pharmacokinetics in the brain with high uptake (3.42% ID/g at 2 min) and fast washout (0.53% ID/g at 60 min). The [125I]-labeled phenyldiazenyl benzothiazole 61 was prepared via a diazo coupling reaction between 79 and 80 to give 81 followed by installation of the radiolabel (Scheme 6E) [60

Substituent effect on the energy barrier for σ-bond formation from π-single-bonded species, singlet 2,2-dialkoxycyclopentane-1,3-diyls

• Jianhuai Ye,
• Yoshihisa Fujiwara and
• Manabu Abe

Beilstein J. Org. Chem. 2013, 9, 925–933, doi:10.3762/bjoc.9.106

• , 401.17071; found, 401.17041; Rf = 0.10 (EtOAc/hexane = 20/80). endo-2,3-Diazo-10,10-diaryloxy-1,4-diaryltricyclo[5.2.1.05,9]dec-2-ene (AZc–g) General procedure. To a solution of cyclopentadiene (1 mL) and pyrazole (2 mmol) in CH2Cl2 (2 mL) was added dropwise trifluoroacetic acid (1 mmol) in an ice bath

• purified by column chromatograph to give the product as colorless liquid (ca. 60%). The endo configuration was determined by NOE measurements. endo-2,3-Diazo-10,10-dibenzyloxy-1,4-diphenyltricyclo[5.2.1.05,9]dec-2-ene (AZc). IR (neat, cm−1): 3037, 2968, 2886, 1739, 1607, 1498, 1456, 1387, 1139, 1085, 1029

• -Diazo-10,10-bis(3,5-dimethoxybenzyloxy)-1,4-diphenyltricyclo[5.2.1.05,9]dec-2-ene (AZd). IR (neat, cm−1): 3022, 2966, 2844, 1751, 1603, 1473, 1326, 1162, 1072, 930, 844, 703; UV (MTHF) λmax 364 (ε 175.1); 1H NMR (500 MHz, CDCl3) δ 1.25–1.66 (m, 6H), 3.68 (s, 6H), 3.70 (t, J = 5.33 Hz, 2H), 3.75 (s, 6H

4-Pyridylnitrene and 2-pyrazinylcarbene

• Curt Wentrup,
• Ales Reisinger and
• David Kvaskoff

Beilstein J. Org. Chem. 2013, 9, 754–760, doi:10.3762/bjoc.9.85

• liquid N2 at −196 °C, or at 2092 cm−1 upon isolation in an Ar matrix at 10 K. The diazo compound is also formed on matrix photolysis of the triazole (Figure 1). Compound 22 can exist as s-Z and s-E conformers. One conformer dominates, absorbing strongly at 2092 cm−1; the other, minor absorption is at

• 2076 cm−1 (Figure 1). Warming the neat diazo compound to ca. −30 °C causes ring closure to triazole 24. Compound 24 can be isolated in up to 20% yield in preparative pyrolysis of 23 [16]. Further FVT of either 23 or 24 at ≥450 °C/10−3 mbar results in the formation of approximately equal amounts of the

• ) or triazole 24 in an Ar matrix at 7–10 K causes efficient ring expansion to the cyclic seven-membered ring ketenimine 20 as observed by IR spectroscopy (Figure 2). In the case of triazole 24, efficient ring opening to the diazo compound 22 happens first (Figure 1), so the latter is the immediate

3-Pyridylnitrene, 2- and 4-pyrimidinylcarbenes, 3-quinolylnitrenes, and 4-quinazolinylcarbenes. Interconversion, ring expansion to diazacycloheptatetraenes, ring opening to nitrile ylides, and ring contraction to cyanopyrroles and cyanoindoles

• Curt Wentrup,
• Nguyen Mong Lan,
• Adelheid Lukosch,
• Pawel Bednarek and
• David Kvaskoff

Beilstein J. Org. Chem. 2013, 9, 743–753, doi:10.3762/bjoc.9.84

• 21 → 20, with free energies of activation of 18–22 kcal/mol in solution, has been demonstrated for 1,2,3-triazolo[1,5-a]pyrimidines [24] but not for 1,2,3-triazolo[1,5-c]pyrimidines [25][26]. However, 7-benzyl-3-ethoxycarbonyl-1,2,3-triazolo[1,5-c]pyrimidin-5-ol and its diazo valence tautomer, 6-(2

A bisazobenzene crosslinker that isomerizes with visible light

• Subhas Samanta,
• Harris I. Qureshi and
• G. Andrew Woolley

Beilstein J. Org. Chem. 2012, 8, 2184–2190, doi:10.3762/bjoc.8.246

• -linked bisazobenzene derivative 2 was prepared by a double diazo-coupling reaction between the donor 1,4-diphenylpiperazine (7) and the acceptor 4-acetamido-3-sulfobenzenediazonium chloride (3), which was synthesized in situ by diazotization of sodium 2-acetamido-5-aminobenzenesulfonate (4) using sodium

Flow photochemistry: Old light through new windows

• Jonathan P. Knowles,
• Luke D. Elliott and
• Kevin I. Booker-Milburn

Beilstein J. Org. Chem. 2012, 8, 2025–2052, doi:10.3762/bjoc.8.229

Synthesis of trifunctional cyclo-β-tripeptide templates

• Frank Stein,
• Tahir Mehmood,
• Tilman Plass,
• Javid H. Zaidi and
• Ulf Diederichsen

Beilstein J. Org. Chem. 2012, 8, 1576–1583, doi:10.3762/bjoc.8.180

• . Residual solvent proton signals were used as an internal standard. Synthesis of compounds (S)-tert-Butyl(7-azido-1-diazo-2-oxoheptan-3-yl)carbamate. (S)-6-Azido-2-(tert-butoxycarbonylamino)hexanoic acid (7.38 g, 27.1 mmol, 1.00 equiv) was dissolved in dry THF (108 mL) under an argon atmosphere. The

• purification. DC (EtOAc/n-pentane 2:3 + 1% AcOH): Rf = 0.73. (S)-7-Azido-3-(tert-butoxycarbonylamino)heptanoic acid (3). A solution of silver trifluoroacetate (219 mg, 990 µmol, 0.110 equiv) in triethylamine (3.79 mL, 27.0 mmol, 3.00 equiv) was slowly added to a solution of (S)-tert-butyl 7-azido-1-diazo-2

N-Heterocyclic carbene-catalyzed direct cross-aza-benzoin reaction: Efficient synthesis of α-amino-β-keto esters

• Takuya Uno,
• Yusuke Kobayashi and
• Yoshiji Takemoto

Beilstein J. Org. Chem. 2012, 8, 1499–1504, doi:10.3762/bjoc.8.169

• migration of the N-acyl glycine derivatives [18]. The other consists of C–N bond-forming reactions, such as (c) a rhodium-catalyzed N–H insertion reaction with α-diazo-β-keto esters [19][20][21], and (d) α-oxidation of β-keto esters to the corresponding oximes and the subsequent hydrogenation [22]. However

Impact of cyclodextrins on the behavior of amphiphilic ligands in aqueous organometallic catalysis

• Hervé Bricout,
• Estelle Léonard,
• Christophe Len,
• David Landy,
• Frédéric Hapiot and
• Eric Monflier

Beilstein J. Org. Chem. 2012, 8, 1479–1484, doi:10.3762/bjoc.8.167

• , respectively) indicative of the deleterious role played by the diazo function on the inclusion phenomenon. In fact, two distinct parameters could be implicated to explain the low Kass values observed for 1 and 2. First, the hydrophilic diazo function had less affinity for the hydrophobic CD cavity than the

• biphenyl moiety. Additionally, the phosphane nonlinear geometry resulting from the zig-zag diazo structure also disfavored the recognition process between the phosphane and the CD cavity. The existence of phosphaneCD supramolecular complexes was confirmed by using a 2D NMR T-ROESY sequence sensitive to

• concentration range was narrow for aggregates constituted by diazo phosphanes 1 or 2 and rather broad for aggregates constituted by 3 or 4. Second, above a stoichiometric RAME-β-CD/phosphane ratio, the RAME-β-CD impact on aggregates became deleterious to the point that the aggregates were destroyed. Most of the

Cation affinity numbers of Lewis bases

• Christoph Lindner,
• Raman Tandon,
• Boris Maryasin,
• Evgeny Larionov and
• Hendrik Zipse

Beilstein J. Org. Chem. 2012, 8, 1406–1442, doi:10.3762/bjoc.8.163

• -position are significantly more effective than aryl substituents in stabilizing the pyridinium ions formed through acetyl cation addition. Photo-switchable 3,4-diaminopyridines including a diazo moiety are potentially useful as special-purpose catalysts. The azobenzene substituent itself is electron

• -withdrawing in nature and the calculation of ACA values can thus be used to optimize the design of these Lewis bases (Table 15). In terms of their overall architecture the pyridine bases presented in Table 15 fall into two different categories: The first of these attaches the diazo bridge to the C8-position

• of the pyridoquinoxaline framework and leads to a significant drop in ACA values (e.g., in compounds 411/412). In the second category, the diazo bridge connects to the 3,4-diaminopyridine amino nitrogen atoms through a phenyl spacer unit and leads to significantly larger ACA values as is best seen

Photochemistry with laser radiation in condensed phase using miniaturized photoreactors

• Elke Bremus-Köbberling,
• Arnold Gillner,
• Frank Avemaria,
• Céline Réthoré and
• Stefan Bräse

Beilstein J. Org. Chem. 2012, 8, 1213–1218, doi:10.3762/bjoc.8.135

• source, in a clean way, avoiding almost completely the formation of the undesired diazo derivatives 3. The side reaction is supposedly reduced due to a lesser effect of heating owing to the small bandwidth irradiation and minimized exposure time through the miniaturized flow setup. During these tests, it