Baran Group Meeting Chemische Berichte 1960 Niklas Schöne

Origin of Papers Li/Hg – very most paper from Germany, from recognised Universities and Ni(CO)4 Cl recognized Professors 50 % Cl nearly – but also from Ahmadabad, Patna (India), Tokyo (Japan), Bucharest quant. (Romania), Warsaw (Poland), Sao Paulo (Brazil) – not from the US 1. O 3 1. O3 2. H , MeOH, 2 2. H2, MeOH, Main Topics Pd/CaCO 3 Pd/CaCO3 – sugars, lignin structural evidence: – all kinds of standard heterocycle syntheses with N, S – IR-spectra – steroids (no total syntheses) MeOC – UV-spectra – Stetter: Adamantane Chemistry MeOC COMe – elemental analyses O O COMe – melting point O Miscellaneous – NMR spectra O – reactions done on a very big scale (big apparati) Criegee: Chem. Ber. 1960, 93, 1553. – chiral products are derived from chiral starting material (no total synthesis) – paper chromatography to purify compounds AcOH/H+ OAc preparatively + HO CH2O AcO OAc Important Names and their Chemistry – p. 689: Criegee: First Isolation of a primary ozonide natural product synthesis 1. MeOH/HCl, !, 97 % – p. 775: Rosenmund: Contribution to the structure of strychnine 2. PhCHO, H+, 60 % – p. 809: Alder: Diels-Alder-reactions – p. 909: Hünig: acylation of 1-Morpholino cyclopentene Ph Ph – p. 1206: Bredereck: amendment of the structure of a purine base 1. TsCl O O – p. 1374: Treibs: allylic oxidation with Hg(OAc)2 in AcOH O O 2. NaI, 83 % 3. PPh , 88 % HO Ph3P 3 4. BuLi excess (CH2)n (CH2)n base (CH2)n structural evidence: HN Me N Me CHO – IR-spectra N 1. H Me – UV-spectra Cl 2. p-TsOH, MeOH, H2O 3. Ac2O AcO base: PhLi or NaNEt2 or NaNH2 or NaH yield: 88 % (n=2), 50 % (n=3), 67 % (n=5) OAc Centaur X Huisgen: Aryne chemistry: Chem. Ber. 1960, 93, 1496. Bohlmann: Chem. Ber. 1960, 93, 1945. 2 Baran Group Meeting Chemische Berichte 1960 Niklas Schöne

Improvement of the Natural product synthesis of Khellin: Preparation of 1,3-dicarbonyl compounds:

O O O O O 1. ClCH CO H – CO, –HBr 2 2 + Br POCl3 R'' Br Br R'' HO OH CCl4 O Ac O O R' OH 2. CaCO3 OH 2 R' OH NaOAc ROH – HBr AcOH Treibs: Chem. Ber. 1960, 93, 551. RNH2 AcO – HBr H2, PtO2, EtOAc, 90 % O O O O O OAc O OAc RO R'' RHN R'' OAc OAc R' R' Cl

CO2Me CCl4 + N2 Dioxan Me acetone 15 % 35 %

a) MeOH, K2CO3, acetone, b) EtOH, aq. NaOH, 82 % methyl ethyl ketone 17 % – cyclopentanone 22 % 55 % cyclohexanone 15 % 42 % HO C O 2 cycloheptanone (suberone) 10 % – 1. AcCl, HClO4, 85 % O O 2. aq. HBr, 94 % O O R'' R'' O OH H2O, HClO4 + H2O2 ON(SO K) R''' HO C 3 2 2 DMF/H O R' O R''' R' O H 2 O O buffer, 75 % ClO4 ClO4 H OMe O O O Balaban: Chem. Ber. 1960, 93, 599. – H2O

1. SO2, EtOH, 91 % O 2. Me SO , acetone O 2 4 O O R'' 70 % R'' R'' OMe O H R''' – H+ Khellin R''' R''' O O 48 % R' O R' O Dann: Chem. Ber. 1960, 93, 2829. R' O O Baran Group Meeting Chemische Berichte 1965 Niklas Schöne

Origin of Papers Recovering tertiary Phosphines from their Oxides with Silanes: – most paper again from Germany R PO + Ph3SiH R3P + Ph SiOH – but also from Budapest (Hungary), Cluj (Romania), Sofia (Bulgaria), 3 3 + Ph SiH Helsinki (Finland), Sao Paulo (Brazil), Rajasthan (India), Brussels 3 H + (Belgium), Strasbourg (France), Tempe (Arizona, USA!!!), Stanford 2 Ph3Si O SiPh3 (California, USA!!!), but both articles from German postdocs! :-) R3PO + Cl3SiH R3P + Cl3SiOH Main Topics – a little more inorganic chemistry: metal carbonyls, sandwich H2 " + SiCl4 HCl + (Cl2Si–O–)n ! complexes Cl3SiH – still all kinds of aromatic compounds, especially heterocycles Et3N – still sugars and steroids (no total synthesis) Et3N-method: yield: – dyes Ph3P 85 % Et3NHCl ! – Isolation of natural products and evidence of structure (p-MeO-C6H4)3P 65 % – Synthesis of peptides (with special protecting groups) and (C6H11)3P 75 % Fritzsche: Chem. Ber. 1965, 98, 171. nucleotides (n-C4H9)3P 93 %

Miscellaneous A Very Special Cycloaddition: – once tlc plates were printed for the control of a column chromatography O O O – in some cases still the same names and the same chemistry as in h# 1960 O + + Benzophenone O O Important Names and their Chemistry O 50 % O ~ 9 % – p. 451: Wittig: Question of Intermediary Appearance of Cyclobutyne O – p. 516: Beckmann: A New Ring Opening Reaction in the Bicyclo- Tetracyclooctane is not reacting with O3 or OsO4. [2.2.1] heptane series H – p. 650: Eistert: Convenient Synthesis of Cycloundecanon – p. 1081: Bredereck/Effenberger: Heterocycle synthesis CO2Me 300 ºC CO2Me – p. 1138: Huisgen: Click-Chemistry – p. 1246: Horner: New Mono- and Dihydronaphthochinones CO2Me CO2Me – p. 2221: Schöllkopf: Synthesis of Alkoxycyclopropanes Probably NOT a stepwise cyclo- – p. 2339: Criegee/Seebach: Valence Isomerizations of Cyclobutenes The following structure was not found as shown by spectral data: addition, because the author – p. 2701: Vögtle: Valence Isomerisations of double Schiff bases of didn't find intermediates like: 1,2-diamines O O – p. 2906: Schill: synthesis of catena compounds – p. 3170: Wanzlick: formation and reactivity of Bis[1,3-diphenyl- imidazolidin-2-ylidenes] O O – p. 3854: Schenk: four-membered ring synthesis through photo cyclo Askani: Chem. Ber. 1965, 98, 3618. addition of maleinic anhydrate and halogenated olefins O O Baran Group Meeting Chemische Berichte 1965 Niklas Schöne

(Total) Synthesis of Retamin H H H NC Br N N N BrCN Me3N NC Cyclic Diazo Compounds: N N N N Br H N N N H H N CHCl EtOH/ 3 acetone Very different in physical and Diazomethane Diazirine 7.32 g Lupanine often in chemical properties, but: both want to get rid of N2. O 6.8 g 8 g 1. MeOH/HCl Maybe with the loss of N2 the linear diazo compound is formed transiently. 2. basic ion Bohlmann/Winterfeld: MeOH/NH3, – 15 ºC H Chem. Ber. 1965, 98, 653. exchange resin O N N H2NOSO3H, 45 % AgNO , H O, aq. column filtration NH 3 2 N 3. 160 ºC, vacuum 1. O3, CHCl3, OH aq. H SO , – H NNH NaOH (Ag2O) CO Bn 2 4 2 2 OH OH 2 –58 ºC, 34 % CO2Bn PhNO2 ! HO CN ClCO2Bn NH N N 2. KCN, MeOH, dioxane/H2O Schmitz: Chem. Ber. 1965, 98, 2509. O + + AcOH, 95 % Na2CO3 97 % 2.7 g OH 1. aq. HCl, reflux OH O 5 % 21 % 73 % (100 % through 2. Pd, H2, AcOH/MeOH CCl acidic decomposition) 3. CH2N2 N 4 N pyridine O 4. !, 21 % O N N rt RNH2 LiAlH4, THF, OH C O OH N tBuOCl N OH O NH 36 % N R N N O separable, but both dia- RNHNH2 MeOH O stereomers are not Retamine N + O N MeOH aq. H2SO4 OH HN 0 ºC, 2 d 29 % 21 % OH OAc CN OAc CO2Et R 29 % 1. aq. NaOH, H2CO 1. EtOH, HCl 2. Ac O, 74 % 2. Ac O, 3. KCN 2 C-H-activation: Müller: Chem. Ber. 1965, 98, 3493. N 2 N (over last N 10 g Cl 3 steps) 2 H O H + h" OH NOCl C NO C N C N H O 1. Raney-Nickel, H2, 3.1 g 1. Ac O + Cl – HCl N 2 OH C H 2. 200 ºC OH CO2Et kat. HCl + H OH vacuum (cycl.) N NOH 1.4 g N EtO C N 2 NOH NOH N 10 g NOH N 3. LiAlH4, 0.5 g 4. separation, 4 g 80 % NOH O 2. EtOH, HCl 60 % (2:1) 37 % (1:1) (±)-Retamin (IR) chromatography, 30 mg Baran Group Meeting Chemische Berichte 1970 Niklas Schöne

Origin of Papers Synthesis of Aromatic Erythrina Alkaloids: – even fewer papers from outside germany O CO2Et CO2Et 1. H2O/MeOH – although some e. g. from Budapest (Hungary), Cluj (Romania), benzene, p-TsOH O O NaOH, 80 % Sofia (Bulgaria), Sheffield (England), Rehovot (Israel), Milan (Italy), Brussels (Belgium), Tsu (Japan) OH O 2. Xylenes, – H O HO 95 % 2 – again no contributions from the USA! :-( OH 67 % O Mondon: Chem. Ber. 1970, 103, 1512. MeO Main Topics O MeO H2N – still sugars, heterocycles, steroids, nucleosids 85 % H3PO4 H – still all kinds of aromatic compounds, especially heterocycles O O N 78 % N O O – a little bit more peptide synthesis: activation of carboxylic groups of O HCO2H amino acids, protecting groups, determinaton of racemization in H MeO DMF peptide synthesis O 76 % O – phenylenes, benzannulenes OM N MeO O e OMe Miscellaneous MeO for proof of identity they used: cis-15,16-Dimethoxy- IR, NMR, UV, mp, elemental – Bohlmann still isolates and synthesizes only natural products with the MeO erythrinane-1,8-dione analysis, mass spectra, same unsaturated side chains, isolated for example from bellis perennis L. (daisy), also Criegee and Stetter still do the same as well Clarification of results from Belleu and from Boekelheide by Mondon: – less interesting papers, less fun to get through – still no enantioselective or metal catalyzed reactions H H – one paper was only about a crystal structure to figure out the structure Cl O HN O + and relative configuration of a really boring molecule O H+ N N N O 100 ºC Important Names and their Chemistry – p. 339: Eicher: Reaction of Cyclopropenes with Diazoalkanes Why is the product not consistent with the one obtained by Mondons route? – p. 369: Dürr: Photochemistry with Small Rings Mondon repeated Belleus route and found the following: – p. 389: Simchen: A New Pyridine Synthesis H H – p. 426: Roth: Stereochemistry of Sigmatropic 1,5-H Shifts – p. 573: Viehe: Ynamine Addition to Imines: Ring Expansion of HN O O + Heterocycles by Two Carbon Atoms H N LiAlH4 N O – p. 1463: Regitz: Kinetic Study on the Mechanism of the Wolff 150 ºC rearrangement – p. 2598: Huisgen: Contributions to the Mechanism of the Dakin- mass difference determined West Reaction Mondon: Chem. Ber. 1970, 103, 3050. by mass spectra Baran Group Meeting Chemische Berichte 1970 Niklas Schöne

Chemistry of nucleophilic carbenes: Synthesis of Yndiamines via "onium" rearrangement:

Me Ph Ph H Cl LiNR2 Li Cl – LiCl LiNR N 2 N N H/D-exchange in F Cl R2N Cl H < H ? H 2-position as a F Cl – HNR2 F Cl – LiF N N N measure of Cl Cl Cl carbene stability HNR Me Ph Ph 20 % 2 Olofson Wanzlick Wanzlick R2N R N H 65 – LiNR2 or LiR, Et2O 2 R N NR Ph Ph 2 2 N Cl 89 % or NaNH , NH (lq.) R N Cl NaNH2, Et2O NH PhNCS N S R R 2 3 2 – HCl PhNH , 77 % EtO OEt 2 neat, 88 % HN EtO OEt EtO Ph Viehe: Chem. Ber. 1970, 103, 1209. OEt

!, 66 % conc. Application of Fischer Carbenes in a non-Dötz reaction HCl Ph Ph 50 % aq. HNO3 Ph 10 eq. mother liquor OMe CO2Me MeO MeO N N N Cr(CO) Ph + Ph treated with (OC) Cr 6 H + H S 5 + Cr? + Ph 90 ºC, 60 %,3 h CO2Me CO2Me N N MeOH, NaClO N ClO4 HSO4 4 37 % Ph 49 % Ph Ph Fischer/Dötz: Chem. Ber. 1970, 103, 1273.

Ph BaOAc H2O, 84 % the more nucleophilic the counter- Reduction of Carboxylic acid chlorides to aldehydes: N (an)ion, the faster the H/D-exchange H O O OR' N and: aromaticity also promotes + P(OR') OR' AcO 3 P + R'Cl Ph the H/D-exchange R Cl O Ph Ph Ph Ph aromatic and aliphatic HgCl2 acid chlorides both gave N N ClO N 4 Hg(OAc)2 DMSO N good yields after some pH 6 – 7 buffer NaBH4, MeOH/H2O Hg H Hg Cl Cl optimization N N DMSO N tBuOK N ClO4 95 % ClO OH Ph Ph Ph 4 61 % Ph O O OR' base OR' + P OR' P R H H OR' O The carbene itself was not isolable (adding only tBuOK) Wanzlick: Chem. Ber. 1970, 103, 1037. Horner: Chem. Ber. 1970, 103, 2984. Baran Group Meeting Chemische Berichte 1975 Niklas Schöne

A New Synthesis of the Eserin Skeleton Origin of Papers O 1. AcOH/HBr, 0 ºC, 98 % CN O – nearly no papers from outside Germany anymore OEt – although a few from e. g. Budapest, Szeged (Hungary), Bucharest OEt 2. KCN, EtOH/H2O, 75 ºC, 45 % (Romania), Lodz (Poland) – Leo A. Paquette (Columbus, Ohio, USA) published together with MeOH 1. PhNH(CH2)2NHPh, AcOH aq. HCl MeOH, Raney-Nickel, H Armin de Meijere :-) O 2 H2S 2. Et2O, aq. HCl CHO O OEt 1. MeOH, PhMeNNH2, 87 % Main Topics N 2. SnCl , EtOH, aq. HCl, 5 ºC OEt – still sugars, heterocycles (easy ones), steroids, nucleosids, peptides SnHCl3 2 – more and more papers on kinetic and reaction mechanisms O O O – for the first time a quantum chemical study MeOH, KOH RNH2, MeOH OEt O N – Electrochemistry N OH 50 ºC, 70 % R – in the few synthesis papers the authors write about pharmacologically N 50 ºC, 90 % N interesting propertes of their molecules for the first time Rosenmund: Chem. Ber. 1975, 108, 208. core strucure of Eserines (Physostigmines) Miscellaneous One Pot Procedure for a Nucleophilic Aminomethylation – Bohlmann does something new!! New molecules out of new plants! H H H But still publishes the most papers about the chemistry he makes O O O since 20 years. And he published a lot in 1975 H E N H N N E R R R R R R – once I saw Ät N instead of Et N – a very German paper! 3 3 Umpolung of Mannich type reactions: Seebach/Enders: H H Important Names and their Chemistry Chem. Ber. 1975, 108, 1293. N N N Nu – p. 88: Severin: 1,4-Dicarbonyl Compounds from ketones and R R R 2-Phenylhydrazonopropanal – p. 640: Günther/Vogel: Bridged [14]Annulenes with Anthracene R metallation R R Perimeter (NMR-Spectroscopy) N NO LDA, BuLi, PhLi N NO electrophile N NO – p. 1093: Spiteller: 16,17-Dihydroxy-9(11)-kauren-18-oic acid – R' R' R' A Compound of Roasted Coffee R'' H R'' Li R'' E R – p. 1182: Heesing: On the Mechanism of Friedel-Crafts Alkylation R N H with allyl alcohol nitrosation one pot N H denitrosation R' – p. 1321: Schmidbaur: Gold(I) Compounds of Simple Phosphorus Ylides H+, NaNO R' HCl, Et2O 2 R'' H – p. 2176: Conformation of protected Amino Acids: NMR and IR R'' E Investigations of Boc-L-!-Amino Acids R = alkyl, aryl; electrophiles = alkyl-, allyl-, benzylhalogenides, aldehydes, – p. 2598: Huisgen: Contributions to the Mechanism of the Dakin- ketones, acyl chlorides, CO2, Isocyanates West Reaction – p. 3141: Günther: The Cope rearrangement of 3,4-Homotropylidene For example: With CO2 the products are amino acid derivatives Baran Group Meeting Chemische Berichte 1975 Niklas Schöne

O Transformation of oximes into nitriles: Appel: Chem. Ber. 1975, 108, 1437. O Ph O BF #Et O CH N HO PPh 3 2 2 2 N 3 Ph O Ph3P !+ !" 70 % O Cl Et N + Ph P Cl CCl N 3 S S 3 3 R H R C N KCN MeO O CCl4 – HCCl R H – Ph3PO O Ph Ph 3 Ph AcOH + – Et3NHCl CH2Cl2, Et2O PPh3 2 OH O OMe HO Ph P R 55 % N 3 O Cl – Ph PO R2 CN S S N 3 N N S 65 % 14 % 1 2 CCl4 R R C toluene – H O Ac2O, Et3N – HCCl R1 R2 Cl 1 2 MeO OMe 3 R1 R Cl p-TsOH 59 % Ph DMAP, 70 % O Ph O H2O Ph $ 20 % more PPh3 should be used because of side reactions. 2 OAc Name of the reaction? Migratory Aptitude? 1 R C6H12, 78 % R N CN S OAc And peptide synthesis: Appel: Chem. Ber. 1975, 108, 2680. H S AcO OAc Ph 4 4 O R Ph P, CCl O R Ac2O, Et3N Ph H + 3 4 H $ N O Ph N O Ph DMAP, 90 % Z OH H N CN 2 Et N Z N Hofmann: CCl , 90 % 3 3 H 4 CN R O R3 O Chem. Ber. 1975, 108, 3596. S The Challenge in this time was to avoid racemisation: Good results with The Stereoselective Total Synthesis of Roxburghin D: All stereogenic centres these protecting groups, also good yields, but Ph3PO has to be removed. Also amino acids with functional groups in the side chain can be used were assigned, only C-19 had to be clarified by synthesis. without protecting these. Yields usually 80 to 90 %. I don't want to bother you with their determination of the mechanism... 1. F3CCO2H, 92 % (4.8 g) N 2. DME, DiBAl-H, –70 ºC O EtO OEt N HN O O OEt H O H H N2 OEt CN H H O C CN N O O O Xylenes MeO2C 140 ºC O O Apart from of ketene acetals can also be used: 33 % N O OEt N HN ketones, imines, nitriles H H H Me This reaction doesn't work with: O O CN H EtO2C CO2Et and EtO2C CO2Et N O MeO2C Stetter: Chem. Ber. 1975, 108, 3314. Winterfeld: Chem. Ber. 1975, 108, 248.