Chemo-enzymatic total synthesis: current approaches toward the integration of chemical and enzymatic transformations

• Ryo Tanifuji and
• Hiroki Oguri

Beilstein J. Org. Chem. 2024, 20, 1693–1712, doi:10.3762/bjoc.20.151

• enzyme SfmCy2, lead to saframycin S (95) [100][101]. To convert the labile hemiaminal moiety at C21 to a more stable aminonitrile, the extracts of the microorganism containing 95 were treated with KCN, allowing the isolation as saframycin A (5) [89]. A notable feature of this biosynthetic machinery is

• pentacyclic scaffolds. The designed and chemically synthesized substrate analog 96 was tolerated by the key NRPS module SfmC despite the structural modification (Scheme 10A). In vitro enzymatic conversion of 96 with tyrosine derivative 86 [103] followed by the addition of KCN concisely furnished the

BINOL as a chiral element in mechanically interlocked molecules

• Matthias Krajnc and
• Jochen Niemeyer

Beilstein J. Org. Chem. 2022, 18, 508–523, doi:10.3762/bjoc.18.53

• the formation of the desired chiral homocircuit [2]catenane (S,S)-5 in 21% yield. By treating (S,S)-5 with a large excess of aqueous KCN, demetalation occurred to give the corresponding [2]catenane (S,S)-6. Interestingly, the Cu-containing catenane (S,S)-5 shows a strong CD signal at wavelengths

Recent advances and perspectives in ruthenium-catalyzed cyanation reactions

• Thaipparambil Aneeja,
• Cheriya Mukkolakkal Abdulla Afsina,
• Padinjare Veetil Saranya and
• Gopinathan Anilkumar

Beilstein J. Org. Chem. 2022, 18, 37–52, doi:10.3762/bjoc.18.4

• . Commonly used metallic cyanating agents include K4Fe(CN)6, CuCN, KCN, NaCN, TMSCN etc. Ruthenium-catalyzed reactions have gained significant attention in recent times [26]. Ruthenium has the ability to show a large number of oxidation states, and thus a large number of complexes can be prepared using this

Synthesis of nonracemic hydroxyglutamic acids

• Dorota G. Piotrowska,
• Iwona E. Głowacka,
• Andrzej E. Wróblewski and
• Liwia Lubowiecka

Beilstein J. Org. Chem. 2019, 15, 236–255, doi:10.3762/bjoc.15.22

• . Reagents and conditions: a) MeOH, THF, KCN (cat.); b) MeOH, SiO2; c) t-BuMe2SiCl, imidazole, DMF; d) 0.01 M HCl; e) Jones reagent; f) CH2N2, ether; g) 6 M HCl, reflux. Synthesis of (2S,3R,4R)-4 from the orthoester 92. Reagents and conditions: a) OsO4, NMO, acetone/water, MeOH; b) Ac2O, pyridine; c) 1 M HCl

Reactions of 3-(p-substituted-phenyl)-5-chloromethyl-1,2,4-oxadiazoles with KCN leading to acetonitriles and alkanes via a non-reductive decyanation pathway

• Akın Sağırlı and
• Yaşar Dürüst

Beilstein J. Org. Chem. 2018, 14, 3011–3017, doi:10.3762/bjoc.14.280

• Akin Sagirli Yasar Durust Department of Chemistry, Faculty of Arts & Sciences, Bolu Abant Izzet Baysal University, Bolu, TR14030, Turkey 10.3762/bjoc.14.280 Abstract The present work describes an unfamiliar reaction of 5-(chloromethyl)-3-substituted-phenyl-1,2,4-oxadiazoles with KCN affording

• trisubstituted acetonitriles into alkanes by the incorporation of KCN with the association of in situ-formed HCN and most likely through the extrusion of cyanogen which could not be detected or isolated. In addition, the plausible mechanisms were proposed for both transformations. The structures of the title

• compounds were identified by means of IR, 1H NMR, 13C NMR, 2D NMR spectra, TOF–MS and X-ray measurements. Keywords: decyanation; KCN; 1,2,4-oxadiazole; Introduction Heterocyclic scaffolds bearing 1,2,4-oxadiazole rings have been the subject of an increasing and remarkable attention due to their various

Asymmetric synthesis of propargylamines as amino acid surrogates in peptidomimetics

• Matthias Wünsch,
• David Schröder,
• Tanja Fröhr,
• Lisa Teichmann,
• Sebastian Hedwig,
• Nils Janson,
• Clara Belu,
• Jasmin Simon,
• Shari Heidemeyer,
• Philipp Holtkamp,
• Jens Rudlof,
• Lennard Klemme,
• Alessa Hinzmann,
• Beate Neumann,
• Hans-Georg Stammler and
• Norbert Sewald

Beilstein J. Org. Chem. 2017, 13, 2428–2441, doi:10.3762/bjoc.13.240

• imine 5 against nucleophilic attack. Desilylation of N-sulfinyl propargylamine 6i with TBAF (GP-5) resulted in decomposition instead of formation of the free alkyne 7i. In order to obtain the free terminal alkyne 7i, a milder desilylation procedure was required. Therefore, AgNO3 and KCN (GP-7) were used

Mechanochemical synthesis of small organic molecules

• Tapas Kumar Achar,
• Anima Bose and
• Prasenjit Mal

Beilstein J. Org. Chem. 2017, 13, 1907–1931, doi:10.3762/bjoc.13.186

• aminonitriles are important synthons for the preparation of nitrogen-containing heterocycles and amino acids [119]. In 2016, Bolm and co-workers reported a mechanochemical synthesis of α-aminonitriles using benzaldehyde, benzyl amine, KCN and the milling auxiliary SiO2 to isolate 70–97% of α-aminonitriles as

• , aliphatic amines and sulfonamides worked smoothly under these conditions to obtain the desired product in 3 h. They have also extended the methodology for the synthesis of tetrahydroisoquinoline by using o-formyl phenethyl bromide with amine and KCN (Scheme 30) [120]. Since the discovery in 1890, the

Solvent-free sonochemistry: Sonochemical organic synthesis in the absence of a liquid medium

• Deborah E. Crawford

Beilstein J. Org. Chem. 2017, 13, 1850–1856, doi:10.3762/bjoc.13.179

• presence of KCN/Al2O3, is an example of organic synthesis employing ultrasound [17]. Interestingly, the conventional solution method results in the alkylation of the toluene aromatic ring, however, when sonication is employed, a reaction between benzyl bromide and KCN occurs producing PhCH2CN, indicating

Iodination of carbohydrate-derived 1,2-oxazines to enantiopure 5-iodo-3,6-dihydro-2H-1,2-oxazines and subsequent palladium-catalyzed cross-coupling reactions

• Michal Medvecký,
• Igor Linder,
• Luise Schefzig,
• Hans-Ulrich Reissig and
• Reinhold Zimmer

Beilstein J. Org. Chem. 2016, 12, 2898–2905, doi:10.3762/bjoc.12.289

• cyano group at the 5-position would lead to a push–pull system that could open new synthetic opportunities including the attack of nucleophiles at C-4. Metal cyanides such as KCN represent synthetically valuable C-1 building blocks that could efficiently be coupled by palladium catalysis to alkenyl

Economical and scalable synthesis of 6-amino-2-cyanobenzothiazole

• Jacob R. Hauser,
• Hester A. Beard,
• Mary E. Bayana,
• Katherine E. Jolley,
• Stuart L. Warriner and
• Robin S. Bon

Beilstein J. Org. Chem. 2016, 12, 2019–2025, doi:10.3762/bjoc.12.189

• cyanide (KCN) in hot DMSO under dilute conditions (Scheme 2A) [14][15]. However, this reaction is sluggish (partly because of the poor solubility of KCN in DMSO), requires elaborate extractive workups for the removal of DMSO (persistent traces of which are detrimental to purification) and gives low and

• variable yields (typically 30–50% in our hands). In addition, because DMSO can quickly penetrate the skin, working with KCN in DMSO requires substantial safety measures. Therefore, this route does not allow straightforward scale-up under laboratory conditions. Prescher and co-workers reported an

Multicomponent reactions: A simple and efficient route to heterocyclic phosphonates

• Mohammad Haji

Beilstein J. Org. Chem. 2016, 12, 1269–1301, doi:10.3762/bjoc.12.121

• the three-component reaction of 4-chlorobenzaldehyde (238), aminomethylphosphonate 239 and ynones 240 in 57% yield (Scheme 49). 7 Reissert-type multicomponent reactions The traditional Reissert reaction is a one-pot treatment of quinoline (242) with acid chlorides 243 and KCN to afford Reissert

• utilized in this reaction. For example, the one-pot reaction of isoquinoline (246) with KCN and chlorophosphates or chlorothiophosphates 247 has been described by Spatz and Popp. The corresponding N-phosphorylated isoquinolines 248 were obtained in 21–85% yields in CH2Cl2 at room temperature (Scheme 51

Regiodefined synthesis of brominated hydroxyanthraquinones related to proisocrinins

• Joyeeta Roy,
• Tanushree Mal,
• Supriti Jana and
• Dipakranjan Mal

Beilstein J. Org. Chem. 2016, 12, 531–536, doi:10.3762/bjoc.12.52

• afforded phthalide 23 in 61% yield. NBS bromination of 23 afforded the 3-bromophthalide [33], which on treatment with dioxane/water furnished phthalaldehydic acid 24 in 69% yield over two steps [34]. Treatment of 24 with KCN furnished 3-cyanophathalide 12 in 75% yield analogously as described in references

Stereochemistry of ring-opening/cross metathesis reactions of exo- and endo-7-oxabicyclo[2.2.1]hept-5-ene-2-carbonitriles with allyl alcohol and allyl acetate

• Piotr Wałejko,
• Michał Dąbrowski,
• Lech Szczepaniak,
• Jacek W. Morzycki and
• Stanisław Witkowski

Beilstein J. Org. Chem. 2015, 11, 1893–1901, doi:10.3762/bjoc.11.204

• compounds 6E and 10E were deacetylated (MeOH/KCN) [24] to give 8E and 12E. The samples 7Z, 8Z, 8E, and 12Z were subjected to acetylation (Py/Ac2O) to give 5Z, 6Z, 6E and 10Z, respectively. The acetates were directly characterized by GC–MS. Based on retention indices and literature data (MS spectra identity

Synthesis of nanodiamond derivatives carrying amino functions and quantification by a modified Kaiser test

• Gerald Jarre,
• Steffen Heyer,
• Elisabeth Memmel,
• Thomas Meinhardt and
• Anke Krueger

Beilstein J. Org. Chem. 2014, 10, 2729–2737, doi:10.3762/bjoc.10.288

• the deviation a deeper look into the mechanism of the formation of Ruhemann’s Blue is required. An important intermediate is hydrindantin, which is formed upon reduction using KCN (see Supporting Information File 1 for a complete reaction mechanism). Its role in the process is still under discussion

• and variable [28]. Although the amount of KCN in the standard protocol is taking this finding into account we suspected that nanodiamond itself could be adsorbing the intermediate species and thus hampering the further proceeding of the reaction. It is well known, that hydrophilic nanodiamond (and

• samples carrying amino groups count among these) is prone to unspecific adsorption of organic molecules via hydrogen bonding and other interactions [29]. Therefore it seems reasonable to assume that the rather low amounts of hydrindantin formed upon the addition of KCN can be adsorbed on the diamond

Syntheses of ¹⁵N-labeled pre-queuosine nucleobase derivatives

• Jasmin Levic and
• Ronald Micura

Beilstein J. Org. Chem. 2014, 10, 1914–1918, doi:10.3762/bjoc.10.199

• pathway of the hypermodified tRNA nucleoside queuosine (Que). The core structure of preQ1 is represented by 7-(aminomethyl)-7-deazaguanine (preQ1 base). Here, we report the synthesis of three preQ1 base derivatives with complementary 15N-labeling patterns, utilizing [15N]-KCN, [15N]-phthalimide, and [15N3

• was accessible by first synthesizing ethyl [15N]-2-cyanoacetate (11) from 2-bromoacetic acid (9) and potassium cyanide [15N]-KCN, followed by esterification (Scheme 3). All further steps were conducted in direct analogy as described for target 1, namely reaction with guanidine hydrochloride to furnish

• pyrrolo[2,3-d]pyrimidine ring system is based on the cyclocondensation reaction between α-bromoaldehydes and 2,6-diaminopyrimidin-4-ones and utilizes [15N]-KCN, [15N]-phthalimide, and [15N3]-guanidine for 15N sources to achieve three complementary labeling patterns that cover all five nitrogen atoms of

A practical synthesis of long-chain iso-fatty acids (iso-C₁₂–C₁₉) and related natural products

• Mark B. Richardson and
• Spencer J. Williams

Beilstein J. Org. Chem. 2013, 9, 1807–1812, doi:10.3762/bjoc.9.210

• . Alternatively, alcohol 12 could be intercepted and converted to the mesylate 13 using MsCl/Et3N [56] and thence the nitrile 14 (KCN in DMSO/THF). Finally, hydrolysis of the nitrile 14 with NaOH in H2O/EtOH afforded iso-C14 acid 3. The iso-C15–C17 fatty acids 4–6 were prepared from the readily available C15

• ; triethylsilane/BF3·Et2O [53] reduction gave 25; and KMnO4/Bu4NBr oxidation afforded iso-C18 acid 7 (Scheme 3). The iso-C19 acid 8 was readily prepared by a three-step homologation through intercepting the alcohol 25. Thus, mesylation of 25 (MsCl/Et3N [56]) afforded 26; substitution (KCN/DMSO) afforded the

• ). Reagents and conditions: (a) MeMgBr, THF, 98%; (b) BF3·Et2O, Et3SiH, CH2Cl2, 99%; (c) KMnO4, Bu4NBr, AcOH, H2O, 88% for 1, 96% for 2; (d) i) I2, NaBH4, THF, ii) H2O2, 95%; (e) MsCl, Et3N, CH2Cl2, 98%; (f) KCN, DMSO, THF, 72%; (g) aq NaOH, EtOH, 96%. Synthesis of iso-C15 4, iso-C16 5, and iso-C17 6 fatty

An organocatalytic route to 2-heteroarylmethylene decorated N-arylpyrroles

• Alexandre Jean,
• Jérôme Blanchet,
• Jacques Rouden,
• Jacques Maddaluno and
• Michaël De Paolis

Beilstein J. Org. Chem. 2013, 9, 1480–1486, doi:10.3762/bjoc.9.168

• substituted 2-heteroaromatic decorated N-arylpyrroles. Results and Discussion We first observed the unexpected formation of pyrrole 5a in 50% yield after treatment of pyrrolidine 4a with KCN in DMF (Scheme 2, conditions a). Although obtained in modest yield, we found the original and unique structure of the

• substituted pyrrole 5a interesting, especially with the 2-pyridylmethylene decoration. In an attempt to rationalize the formation of 5a, we hypothesized that KCN acted as a nucleophilic and weak base since the level of oxidation of 4a and 5a was the same. To improve the efficiency of the transformation, a

• the exo-enamine into the endo compound under basic treatment [26]. These observations suggest that DBU or KCN behave as base to promote the deconjugation of the acrylate moiety of 4a [27]. The resulting product 4a’ would lead under basic treatment to pyrroline 4a” from which aromatization to 5a would

Unusual behavior in the reactivity of 5-substituted-1H-tetrazoles in a resistively heated microreactor

• Bernhard Gutmann,
• Toma N. Glasnov,
• Tahseen Razzaq,
• Walter Goessler,
• Dominique M. Roberge and
• C. Oliver Kappe

Beilstein J. Org. Chem. 2011, 7, 503–517, doi:10.3762/bjoc.7.59

• procedure was developed. After considerable experimentation, we found that the use of a KCN/m-nitrobenzenesulfinic acid sodium salt mixture in water [68] at 80 °C effectively removes all Pd from the surface of the steel coils as these coils were not catalytically active in subsequent Mizoroki–Heck chemistry

• mixture of KCN (10 g/L) and m-nitrobenzenesulfinic acid sodium salt (10 g/L) in water. After processing of the 100 mL through the flow reactor (ca. 60 min), the inlet tubing was dipped back into a vial with distilled water and processed for a further 10 min. The process was repeated two more times with

• fresh 100 mL portions of KCN/m-nitrobenzenesulfinic acid sodium salt in water mixture before the reactor was finally washed with distilled water for 30 min to remove any remaining residues of the KCN/m-nitrobenzenesulfinic acid sodium salt in water mixture. Pressure dependence of nucleophilic aromatic

Kinetics and mechanism of vanadium catalysed asymmetric cyanohydrin synthesis in propylene carbonate

• Michael North and
• Marta Omedes-Pujol

Beilstein J. Org. Chem. 2010, 6, 1043–1055, doi:10.3762/bjoc.6.119

• asymmetric addition of TMSCN [26][27][28] and KCN [13] to aldehydes and are more enantioselective, but less reactive than the titanium based catalyst 1. Complexes 1 and 2 have been commercialized [10][29][30], immobilized to facilitate their recycling [31][32][33][34][35][36][37][38][39][40][41][42][43] and

Influence of spacer chain lengths and polar terminal groups on the mesomorphic properties of tethered 5-phenylpyrimidines

• Gundula F. Starkulla,
• Elisabeth Kapatsina,
• Angelika Baro,
• Frank Giesselmann,
• Stefan Tussetschläger,
• Martin Kaller and
• Sabine Laschat

Beilstein J. Org. Chem. 2009, 5, No. 63, doi:10.3762/bjoc.5.63

• similar manner, the cyanides 7 were prepared from the bromides 3. Treatment of the bromides 3c–e with KCN in EtOH/H2O at 110 °C for 12 h leads to the cyanides 7c–e in 72 to 97% yield. Since the yields of 3b were limited due to side reactions like elimination, the respective cyanide 7b was prepared by

• chromatography. General procedure 3 A solution of bromide 3 (0.50 mmol) and KCN (35.8 mg, 0.55 mmol) in 4 mL EtOH/H2O (3:1, v/v) was stirred at 110 °C for 12 h. After cooling to room temperature, 10 mL CH2Cl2 were added and the aqueous layer was extracted with CH2Cl2 (3 × 10 mL). The combined organic layers were

• 17.05. 5-[4-(6-Cyanohexyloxy)phenyl]-2-octylpyrimidine (7e) Prepared according to general procedure (3). Experiment: 224 mg (0.50 mmol) bromide 3e, 36.0 mg (0.55 mmol) KCN. Flash chromatography (PE/EtOAc, 4:1, v/v; Rf = 0.23) gave 142 mg (0.36 mmol, 72%) of 7e as a colourless crystalline solid. Mp: 68

Studies on polynuclear furoquinones. Part 1: Synthesis of tri- and tetra- cyclic furoquinones simulating BCD/ABCD ring system of furoquinone diterpenoids

• Faruk H. Shaik and
• Gandhi K. Kar

Beilstein J. Org. Chem. 2009, 5, No. 47, doi:10.3762/bjoc.5.47

• converted (KCN/DMF) to the nitrile derivative 5 which on hydrolysis (KOH/EtOH-H2O, reflux) followed by esterification with CH2N2 furnished methyl 2-(2-bromo-1-naphthyl)acetate 7 in overall good yield. The bromo ester was then subjected to Suzuki reaction with furan-2-boronic acid. Reaction of compound 7

• furoquinone 13. Assignment of chemical shifts (1H NMR and 13C NMR) of compound 13. Reagents and conditions: i) DDQ (1.5 equiv), dry benzene, reflux, argon atmosphere, 37 h, 83%. ii) NaBH4, EtOH, room temperature, 2 h, 94%. iii) PBr3, CCl4, 60 °C, 1 h, 82%. iv) KCN, DMF, room temperature, overnight then 1 h at

Asymmetric reactions in continuous flow

• Xiao Yin Mak,
• Paola Laurino and
• Peter H. Seeberger

Beilstein J. Org. Chem. 2009, 5, No. 19, doi:10.3762/bjoc.5.19

• delivering the cell lysate, KCN and citric acid (in situ HCN generation), one for the organic phase containing the aldehyde substrate and a third one at the end of the reactor channel as quenching inlet for deactivation of the enzyme. Under batch conditions, these reactions required vigorous stirring in

Cobalt(II) chloride catalyzed one-pot synthesis of α-aminonitriles

• Surya K. De

Beilstein J. Org. Chem. 2005, 1, No. 8, doi:10.1186/1860-5397-1-8

• has been extensively used as a mild catalyst for a plethora of organic transformations, [18][19][20] there are no examples of the use of cobalt(II) chloride as catalyst for the synthesis of α-aminonitriles. Results and discussion The treatment of benzaldehyde and aniline with KCN in the presence of a