Continuous gas/liquid–liquid/liquid flow synthesis of 4-fluoropyrazole derivatives by selective direct fluorination

• Jessica R. Breen,
• Graham Sandford,
• Dmitrii S. Yufit,
• Judith A. K. Howard,
• Jonathan Fray and
• Bhairavi Patel

Beilstein J. Org. Chem. 2011, 7, 1048–1054, doi:10.3762/bjoc.7.120

• hydrazine derivative. Water and ethanol are miscible with acetonitrile, thus enabling the cyclisation process to occur by efficient mixing of the two flow streams within the reactor channel. Similarly, fluoropyrazole derivatives 4b and 4c were prepared by reaction of 1a with fluorine and methyl hydrazine 3b

• derivatives were synthesised by sequential direct fluorination of appropriate 1,3-diketones and subsequent cyclisation of the in situ generated fluorodiketone with a hydrazine derivative. This represents the first example of a sequential, continuous flow gas/liquid–liquid/liquid process involving direct

Isotopic labelling studies for a gold-catalysed skeletal rearrangement of alkynyl aziridines

• Paul W. Davies,
• Nicolas Martin and
• Neil Spencer

Beilstein J. Org. Chem. 2011, 7, 839–846, doi:10.3762/bjoc.7.96

• the two isotopomers showed that a greater proportion of the 2,4-isomer formed from Path III was observed than with the other cyclisation precursors (Supporting Information File 1). Additionally, none of the 2,5-disubstituted pyrrole isomer, which would also result from B, was formed. In keeping with

• the deuterium labelling study using Ph3PAuCl/AgOTf. Supporting Information Supporting Information contains full experimental details for the preparation of the cyclisation precursors and their subsequent reactions. NMR spectra for the labelling studies are provided. Supporting Information File 74

Single enantiomer synthesis of α-(trifluoromethyl)-β-lactam

• Václav Jurčík,
• Alexandra M. Z. Slawin and
• David O'Hagan

Beilstein J. Org. Chem. 2011, 7, 759–766, doi:10.3762/bjoc.7.86

• -(trifluoromethyl)acrylic acid (2) which offered a commercially available source of the CF3 group. It was envisaged that conjugate addition of an enantiomerically pure amide such as (R)- or (S)-3 would generate the addition adducts, carboxylate salts 4, as a mixture of diastereoisomers. Cyclisation to the N

• nitrate (CAN) oxidation offered a milder deprotection method [15]. The aza-Michael reaction proved straightforward to generate 4b and then cyclisation again using thionyl chloride and triethylamine gave β-lactams 5b in a 40% de, presumably again a thermodynamically biased isomer ratio. The

• is reported which took advantage of an aza-Michael addition between (S)-α-(p-methoxyphenyl)ethylamine (3b) and α-(trifluoromethyl)acrylic acid (2). Cyclisation and then chromatographic resolution of the β-lactam diastereoisomers 5b, followed by deprotection with ceric ammonium nitrate generated the β

Asymmetric synthesis of tertiary thiols and thioethers

• Jonathan Clayden and
• Paul MacLellan

Beilstein J. Org. Chem. 2011, 7, 582–595, doi:10.3762/bjoc.7.68

• thioacetate in toluene proceeds faster at 55 °C (Scheme 4). The synthesis of the unnatural enantiomer of the natural product spirobrassinin has been achieved by substitution at a quaternary centre by a sulfur nucleophile [14]. Intramolecular cyclisation of a dithiocarbamate 13 allows isolation of 14 with

An overview of the key routes to the best selling 5-membered ring heterocyclic pharmaceuticals

• Marcus Baumann,
• Ian R. Baxendale,
• Steven V. Ley and
• Nikzad Nikbin

Beilstein J. Org. Chem. 2011, 7, 442–495, doi:10.3762/bjoc.7.57

• cyclisation. However, this problem could be avoided by using an acid-labile oxalate protected hydrazine 104 as depicted in Scheme 23. The yield of this step can be further improved up to 84% if the corresponding calcium oxalate is used. The Bischler–Möhlau reaction is an alternative indole synthesis employing

• established which gave the desired product in 90% overall yield (Scheme 33). Alternatively, glycine can be reacted with methyl pentanimidate 169 to form the corresponding amidine 171 in high yield. Cyclisation, followed by a Vilsmeier-type reaction then furnishes the key chloroimidazolyl building block 172 in

• . Alternatively, in order to circumvent the regioselectivity issue, other pyrazole syntheses have been used. For example, the substituted aryl hydrazine 237 can be reacted with trifluoromethyl butynone in a one pot reaction. A Michael addition/cyclisation sequence renders only the desired regioisomer of the

Aromatic and heterocyclic perfluoroalkyl sulfides. Methods of preparation

• Vladimir N. Boiko

Beilstein J. Org. Chem. 2010, 6, 880–921, doi:10.3762/bjoc.6.88

9,10-Dioxa-1,2-diaza-anthracene derivatives from tetrafluoropyridazine

• Graham Pattison,
• Graham Sandford,
• Dmitrii S. Yufit,
• Judith A. K. Howard,
• John A. Christopher and
• David D. Miller

Beilstein J. Org. Chem. 2010, 6, No. 45, doi:10.3762/bjoc.6.45

• phenoxide, to give intermediate 5a. At this point, we would expect cyclisation to occur at position 5 to give product 6, again by analogy to the outcome of reaction between 3 and excess phenoxide. However, since nucleophilic aromatic substitution reactions are frequently reversible [13], conversion of 6

Prins fluorination cyclisations: Preparation of 4-fluoro-pyran and -piperidine heterocycles

• Guillaume G. Launay,
• Alexandra M. Z. Slawin and
• David O'Hagan

Beilstein J. Org. Chem. 2010, 6, No. 41, doi:10.3762/bjoc.6.41

• . Keywords: 4-fluoropiperidine; 4-fluoropyran; heterocycles; organo-fluorine chemistry; Prins cyclisation; Introduction Selective incorporation of the C–F bond into organic molecules can impart useful and attractive properties to performance materials [1][2][3]. To this end there are a useful but relatively

• Prins reaction is a well established strategy for the synthesis of pyrans [5][6][7]. This cyclisation reaction, which occurs between a homoallylic alcohol and an aldehyde, is generally promoted by a Lewis acid. When BF3·OEt2 is used as the Lewis acid, then fluoride ion from the reagent can become

Bis(oxazolines) based on glycopyranosides – steric, configurational and conformational influences on stereoselectivity

• Tobias Minuth and
• Mike M. K. Boysen

Beilstein J. Org. Chem. 2010, 6, No. 23, doi:10.3762/bjoc.6.23

• (oxazoline) ligands [20][21]: Formation of bis(amide) 12 with dimethylmalonyl chloride, 3-O-acetylation and subsequent activation of the thioethyl moieties of 13 with NIS [30] for the double cyclisation step, led to benzylidene protected ligand 3-O-Ac alloBox 14 in excellent yield. As noted previously, the

• conformative effect is also in operation for allo-configured bis(oxazolines), we prepared ligand Ac alloBox 16 with acyclic 4,6-O-protection by the removal of the benzylidene groups from 12 under acidic conditions and per-O-acetylation in a one-pot reaction followed by NIS-mediated cyclisation of resulting bis

Fused bicyclic piperidines and dihydropyridines by dearomatising cyclisation of the enolates of nicotinyl-substituted esters and ketones

• Heloise Brice,
• Jonathan Clayden and
• Stuart D. Hamilton

Beilstein J. Org. Chem. 2010, 6, No. 22, doi:10.3762/bjoc.6.22

• : bicyclic; cyclisation; dearomatisation; enol ether; heterocycle; pyridine; quinoline; Introduction Oxidative [1][2][3] or reductive (nucleophilic) [4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21] dearomatising cyclisation reactions are effective strategies for rapidly building complexity

• carbocyclic ring by dearomatising cyclisation The study was initiated with the synthesis of the δ-nicotinyl ketone 7 as illustrated in Scheme 2. Ethyl benzoylacetate was alkylated with 3-(3-iodopropyl)pyridine 5 and the product 6 hydrolysed and decarboxylated to yield the pyridine 7 in moderate yield. On

• confirming the relative stereochemistry, and the assignment shown in Scheme 3 is on the basis that the benzoyl group of 8 is likely to lie on the exo face of the azadecalin system. We assume, in line with previous results [39], that cyclisation occurs only after the addition of the electrophilic trap (which

Benzyne arylation of oxathiane glycosyl donors

• Martin A. Fascione and
• W. Bruce Turnbull

Beilstein J. Org. Chem. 2010, 6, No. 19, doi:10.3762/bjoc.6.19

• synthesis of the key bicyclic intermediate was achieved starting from a simple thioglycoside 4 where the essential β-sulfur linkage was already installed, followed by a regio and stereoselective cyclisation onto the O-2 position to afford oxathiane glycosyl donor framework 5. The oxathiane ketal donor 5 is

Diastereoselective functionalisation of benzo-annulated bicyclic sultams: Application for the synthesis of cis-2,4-diarylpyrrolidines

• Susan Kelleher,
• Pierre-Yves Quesne and
• Paul Evans

Beilstein J. Org. Chem. 2009, 5, No. 69, doi:10.3762/bjoc.5.69

• Scheme 1, a Heck (Heck–Mizoroki) cyclisation [5][6][7][8][9] was employed to form the cyclic sulfonamide. Subsequently, it was shown that high stereofacial bias was achieved on hydrogenation, generating 2 as a single diastereoisomer. Treatment under dissolved metal reduction conditions afforded the cis

• and 6b which were used as substrates for the N–S and C–S bond cleavage forming arylsubstituted pyrrolidines [1][2][3]. In relation to this sequence attempts to achieve a reductive Heck cyclisation employing ammonium formate [12], gave only the product of bromine-hydrogen exchange 4c (where X = H

• ). Therefore, a one-pot method was developed based on recent reports which demonstrate that the residual palladium catalyst in Heck reactions may effectively mediate the addition of hydrogen to the newly substituted alkene [13][14][15]. Thus, following complete Heck cyclisation, as judged by TLC analysis, the

Three step synthesis of single diastereoisomers of the vicinal trifluoro motif

• Vincent A. Brunet,
• Alexandra M. Z. Slawin and
• David O'Hagan

Beilstein J. Org. Chem. 2009, 5, No. 61, doi:10.3762/bjoc.5.61

• (Scheme 5). Instead the fluorinated tetrahydrofuran 14 was isolated as a crystalline product in 33% yield and its structure and stereochemistry were established by X-ray structure analysis (Scheme 5). This deviant reaction was surprising not only because there was no trace of the analogous cyclisation

• product after treatment of 8b with HF/pyridine, but also because cyclisation had occurred with retention of configuration at C4. One explanation for this outcome is that the reaction proceeds via a bicyclic phenoxonium intermediate 13 generated after HF promoted epoxide ring opening. Fluoride ion

• the requisite α,β-epoxy alcohols 6b and 7b. Three step sequential fluorination from α,β-epoxy alcohols to eg. the vicinyltrifluoro tosylate 11. Unexpected cyclisation of 9b to furan 14 with HF·pyridine. An X-ray structure of 14 (CCDC 750309) reveals that the cyclisation proceeds with a retention of

2-Phenyl- tetrahydropyrimidine- 4(1H)-ones – cyclic benzaldehyde aminals as precursors for functionalised β²-amino acids

• Markus Nahrwold,
• Arvydas Stončius,
• Anna Penner,
• Beate Neumann,
• Hans-Georg Stammler and
• Norbert Sewald

Beilstein J. Org. Chem. 2009, 5, No. 43, doi:10.3762/bjoc.5.43

• acyclic resonance stabilised Schiff bases are preferentially formed. Consequently, one pot cyclisation protocols employing conditions such as KOH in protic solvents deliver the desired six-membered ring only in unsatisfactory yields [30][39]. An alternative approach to cyclise benzaldehyde-derived imines

• temperature. Despite the success in condensing 3 and benzaldehyde (dimethylacetal), all attempts to condense 3 with closely related acetophenone dimethylketal did not lead to any cyclisation product. To facilitate our selective ring opening concept, the N3-nitrogen of 4 had to be protected as a carbamate

• imidazolidinone rings [42]. Finally, enantiopure 2-phenyltetrahydropyrimidine-4(1H)-ones were successfully synthesised via a chiral pool approach by condensing Cbz-L-Asn-OAll (8) with benzaldehyde dimethylacetal (Scheme 4). Compared to the respective cyclisation reaction starting from 3, complete conversion of 8

Mitomycins syntheses: a recent update

• Jean-Christophe Andrez

Beilstein J. Org. Chem. 2009, 5, No. 33, doi:10.3762/bjoc.5.33

• -dimethoxyhydroquinone was then oxidized with silver(II) pinacolate (in poor yield) to give mitomycin K. 3.2. Naruta, Maruyama. Azide cycloaddition From a synthetic point of view, the intramolecular [1+4] cyclisation of a nitrene with a dienyl moiety gives a pyrrolizidine, the key structure found in mitomycins and many

• ]. With this substrate the subsequent cyclisation of azidodienylquinone 46 was performed with Cu(acac)2 as catalyst and afforded 48 with a high degree of diastereoselectivity. Thermal reaction led to the formation of the ring-contracted cyclopentendione derivative 54. The reaction was thought to proceed

• straightforward reactions then led to compound 80. As expected, the trans double bond in 80 prevented intramolecular alkylation of the amino group by the homoallylic bromide, thus explaining the somewhat surprising stability of this compound. The key step cyclisation was then carried out with the Nicolaou’s

Synthesis of new C^α-tetrasubstituted α-amino acids

• Andreas A. Grauer and
• Burkhard König

Beilstein J. Org. Chem. 2009, 5, No. 5, doi:10.3762/bjoc.5.5

• 327.2043. MF C17H29NO5. MW 327.42. Proposed reaction mechanism for the formation of Cα-tetrasubstituted tetrahydrofuran α-amino acids. Structure of compound 15 in the solid state determined by X-ray analysis [21]. Cyclisation reaction forming the tetrahydrofuran amino acid (TAA). Results of the reaction

Synthesis of chiral cyclohexanes and carbasugars by 6-exo-dig radical cyclisation reactions

• Rajeev K. Shrivastava,
• Elise Maudru,
• Gurdial Singh,
• Richard H. Wightman and
• Keith M. Morgan

Beilstein J. Org. Chem. 2008, 4, No. 43, doi:10.3762/bjoc.4.43

• gave mixtures of syn- and anti-alkynols 2a–2c which were separated following protection as methoxymethyl ethers. These were converted to the corresponding iodides which underwent 6-exo-dig radical cyclisation to afford chiral cyclohexanes and carbasugars. Oxidation of the primary alcohols 6a–b gave the

• corresponding aldehydes which on treatment with Grignard reagents afforded a mixture of alcohols. The corresponding iodides underwent similar 6-exo-dig cyclisation to give fully functionalised cyclohexanes. Keywords: carbasugars; cyclisation; cyclohexanes; 6-membered ring; stereoisomers; Introduction The use

• closure of a radical onto an alkyne [14]. In contrast there are fewer reports of the corresponding 6-exo-dig cyclisation to prepare fully functionalised cyclohexanes and carbasugars. The reason for this may be inferred from the observation that the formation of six-membered rings by a radical ring closure

Total synthesis of the indolizidine alkaloid tashiromine

• Stephen P. Marsden and
• Alison D. McElhinney

Beilstein J. Org. Chem. 2008, 4, No. 8, doi:10.1186/1860-5397-4-8

• centres on the stereoselective construction of the indolizidine core by capture of an electrophilic acyliminium species by a pendant allylsilane. The key cyclisation precursor is constructed using olefin cross-metathesis chemistry, which has the potential to facilitate both racemic and asymmetric

• approaches, depending upon the choice of the allylsilane metathesis partner. Results The use of the allyltrimethylsilane cross-metathesis approach enables the rapid construction of the key cyclisation precursor 3 (3 steps from commercial materials), which undergoes acid-induced cyclisation to give the

• -mediated reductive imide-olefin cyclisation [10]. Our own approach [14] utilises an intramolecular addition of an allylsilane to an N-acyliminium ion to deliver the [4.3.0]-azabicyclic (indolizidine) skeleton 2 (Scheme 1), wherein the pendant vinyl group acts as a handle to install the hydroxymethyl

Facile synthesis of two diastereomeric indolizidines corresponding to the postulated structure of alkaloid 5,9E- 259B from a Bufonid toad (Melanophryniscus)

• Angela Nelson,
• H. Martin Garraffo,
• Thomas F. Spande,
• John W. Daly and
• Paul J. Stevenson

Beilstein J. Org. Chem. 2008, 4, No. 6, doi:10.1186/1860-5397-4-6

• this intriguing transformation will be published elsewhere in due course. One-pot dehydration of the tertiary alcohol 3 was accomplished via the mesylate, and in situ elimination with triethylamine to give the diene 4 in 74% yield. Diene 4 smoothly underwent cyclisation to indolizidinone 5 when treated

Analogues of amphibian alkaloids: total synthesis of (5R,8S,8aS)-(−)-8-methyl- 5-pentyloctahydroindolizine (8-epi-indolizidine 209B) and [(1S,4R,9aS)-(−)-4-pentyloctahydro- 2H-quinolizin- 1-yl]methanol

• Joseph P. Michael,
• Claudia Accone,
• Charles B. de Koning and
• Christiaan W. van der Westhuyzen

Beilstein J. Org. Chem. 2008, 4, No. 5, doi:10.1186/1860-5397-4-5

• acylation of the chiral amine (−)-15, prepared as described in our prior work [13], with 5-bromopentanoyl chloride (obtained in two steps from δ-valerolactone) [27][28]. This afforded tert-butyl (3R)-[(5-bromopentanoyl)amino]octanoate (+)-25 in 98% yield (Scheme 3). However, subsequent cyclisation to the

• glacial acetic acid gave the free amine (−)-32 in quantitative yield. Treatment with 5-bromopentanoyl chloride as described above afforded the unstable bromoamide 33 as an orange oil in 89% yield. In this case, cyclisation of the crude intermediate to the lactam (+)-34 was most successfully effected by

• bromoacetate followed by treatment with triphenylphosphine and triethylamine in acetonitrile give the vinylogous urethane (+)-38 in 80% yield. Hydrolysis of the acetate with potassium carbonate in methanol then afforded the pivotal alcohol (+)-29 (70%). The scene was now set for cyclisation to the

Knorr- Rabe partial reduction of pyrroles: Application to the synthesis of indolizidine alkaloids

• Brendon S. Gourlay,
• John H. Ryan and
• Jason A. Smith

Beilstein J. Org. Chem. 2008, 4, No. 3, doi:10.1186/1860-5397-4-3

• (Scheme 3). The synthesis started with formation of the γ-pyrrolic ester 7 in high yield using an improved Clauson-Kaas synthesis [10], followed by boron tribromide mediated cyclisation to give the known bicyclic ketone 8 [11]. Upon subjection of this α-ketopyrrole 8 to the modified conditions reported by

Part 1. Reduction of S-alkyl- thionocarbonates and related compounds in the presence of trialkylboranes/air

• Jean Boivin and
• Van Tai Nguyen

Beilstein J. Org. Chem. 2007, 3, No. 45, doi:10.1186/1860-5397-3-45

• such as sugars.[3] On the other hand, iodides and S-alkylxanthates are useful compounds that easily produce carbon radicals involved in radical chain reactions (cyclisation, intermolecular addition onto an olefin, etc) in which trapping of the final radical results in the transfer of the iodine atom or

The tert- amino effect in heterocyclic chemistry: Synthesis of new fused pyrazolinoquinolizine and 1,4-oxazinopyrazoline derivatives

• Dipak Prajapati and
• Kalyan Jyoti Borah

Beilstein J. Org. Chem. 2007, 3, No. 43, doi:10.1186/1860-5397-3-43

• malononitrile and cyanoacetamide followed by cyclisation using anhydrous zinc chloride. Background The N-phenyl-3-substituted 5-pyrazolone derivatives are organic compounds that have been known since 1883; they are very useful as intermediates for pharmaceuticals and are used as anti-inflammatory agents and

• progress to understand the exact mechanism of the reaction. Conclusion In conclusion, we have demonstrated that N-phenyl-3-substituted pyrazolones can be used for the intramolecular alpha-cyclisation of tertiary amines [33] for the synthesis of pyrazolinoquinolizine and 1,4-oxazinopyrazoline derivatives in

The enantiospecific synthesis of (+)-monomorine I using a 5-endo- trig cyclisation strategy

• Malcolm B. Berry,
• Donald Craig,
• Philip S. Jones and
• Gareth J. Rowlands

Beilstein J. Org. Chem. 2007, 3, No. 39, doi:10.1186/1860-5397-3-39

• University, Private Bag 11 222, Palmerston North, New Zealand 10.1186/1860-5397-3-39 Abstract We have developed a general strategy for the synthesis of 2,5-syn disubstituted pyrrolidines that is based on the multi-faceted reactivity of the sulfone moiety and a 5-endo-trig cyclisation. This methodology was

• mode of cyclisation. [1][2][3][4][5][6] The methodology allows the conversion of epoxides (X = O) or aziridines (X = N-PG) (2) into the desired trisubstituted tetrahydrofurans or pyrrolidines (5) via a series of sulfone-mediated transformations (Scheme 1). Ring-opening 2 with the sulfone-stabilised

• anion of 1 forms the first C-C bond and furnishes 3. Modification of the work of Julia [7][8][9] then utilises the sulfone to facilitate stereocontrolled alkenylation to give the cyclisation substrate 4. Finally, 5-endo-trig cyclisation yields the desired heterocycles 5. Overall, the sulfone moiety

A convenient allylsilane- N-acyliminium route toward indolizidine and quinolizidine alkaloids

• Roland Remuson

Beilstein J. Org. Chem. 2007, 3, No. 32, doi:10.1186/1860-5397-3-32

• alkaloids ideal targets for total synthesis. We have developed a new method to generate bicyclic indolizidine and quinolizidine compounds based on an intramolecular cyclisation of acyliminium ions substituted by an allylsilyl side chain as an internal π-nucleophile (Scheme 1). [6] This reaction has proven

• and the important biological activities of the compound make this alkaloid an ideal target for total synthesis. [9][10][11][12][13][14][15][16] I 1.1 Intramolecular cyclisation We have found that intramolecular cyclisation of an allylsilane on an acyliminium ion constituted an excellent route to

• catalysed periodate oxidation of the olefinic bond of 6a and 6b led respectively to indolizidin-3-ones 7a and 7b. Upon treating an aqueous solution of 7a with 1N HCl the thermodynamically more stable indolizidinone 7b was obtained through a retro-Mannich fragmentation-cyclisation process. The last two steps