Synthesis of aryl cyclopropyl sulfides through copper-promoted S-cyclopropylation of thiophenols using cyclopropylboronic acid

• Emeline Benoit,
• Ahmed Fnaiche and
• Alexandre Gagnon

Beilstein J. Org. Chem. 2019, 15, 1162–1171, doi:10.3762/bjoc.15.113

• thiophenols 14 through SN2 reaction with cyclopropyl bromide (15, Scheme 2a) [2][4] or by SNAr reaction between aryl fluorides 16 and cyclopropanethiol (17, (Scheme 2b) [6]. Although simple and attractive, these approaches usually require harsh conditions such as the presence of a strong base and high

Mechanistic investigations on multiproduct β-himachalene synthase from Cryptosporangium arvum

• Jan Rinkel and
• Jeroen S. Dickschat

Beilstein J. Org. Chem. 2019, 15, 1008–1019, doi:10.3762/bjoc.15.99

• formal syn-SN2’ reaction. This is an intriguing observation, since for other TSs a NPP-cyclisation by anti-SN2’ is usually described [40][45][46][47]. This cyclisation mechanism is thought to be the predominant case, giving rise to a more energetically favoured transition state, but occasionally also the

• of the commercial available products (Table S4–S8, Supporting Information File 1) clearly obeys the anti-SN2’ case (Figures S12–S14, Supporting Information File 1). The observation that 15 was obtained as a nearly racemic mixture contrasts the far more selective incorporation of deuterium into the

• ,10Si-cyclisation to E without major rotational changes and also reflects the short distance between HR and C-10 for the 1,3-hydride shift towards the 10Si face leading to F. Intriguingly, the unusual syn-SN2’ ring closure from (R)-NPP leads to the diphosphate moiety (OPP−) being located close to the

Stereochemical investigations on the biosynthesis of achiral (Z)-γ-bisabolene in Cryptosporangium arvum

• Jan Rinkel and
• Jeroen S. Dickschat

Beilstein J. Org. Chem. 2019, 15, 789–794, doi:10.3762/bjoc.15.75

• stereochemistry (anti-SN2’ reaction), which is favoured for a concerted process and is also discussed for other cyclisation mechanisms [24][25][26], the four theoretically possible options for the BbS cyclisation mechanism are narrowed down to two possibilities: Either the reaction takes place via (R)-NPP

Diastereo- and enantioselective preparation of cyclopropanol derivatives

• Marwan Simaan and
• Ilan Marek

Beilstein J. Org. Chem. 2019, 15, 752–760, doi:10.3762/bjoc.15.71

• reported on the reactivity of oxenoids [74][75][76][77], indicating that the reaction of a nucleophile with oxenoid proceeds through an SN2 process [74]. Following the carbocupration of cyclopropene 3 into cyclopropylcopper species, the subsequent oxidation with the amphiphilic lithiated hydroperoxide t

• ). The reaction proceeded for all R1 and R2 groups tested and determination of the stereochemistry confirmed that the oxidation reaction proceeds with pure retention of configuration at the metalated center (intramolecular SN2 reaction or 1,2-metalate rearrangement) [78][79][80]. It should be noted that

Study on the regioselectivity of the N-ethylation reaction of N-benzyl-4-oxo-1,4-dihydroquinoline-3-carboxamide

• Pedro N. Batalha,
• Luana da S. M. Forezi,
• Maria Clara R. Freitas,
• Nathalia M. de C. Tolentino,
• Ednilsom Orestes,
• José Walkimar de M. Carneiro,
• Fernanda da C. S. Boechat and
• Maria Cecília B. V. de Souza

Beilstein J. Org. Chem. 2019, 15, 388–400, doi:10.3762/bjoc.15.35

• resonance structures due to the adjacent carbonyl, being therefore, less stable (Scheme 5). Reaction paths analysis The paths for the SN2 N-alkylation reaction of both deprotonated species (oxoquinoline and carboxamide N–H units) using bromoethane were obtained. It is worth highlighting that for each of the

• the oxoquinoline, when compared to that of the carboxamide group. Because of this, the treatment with the base produces the reactive intermediate, the conjugate base resulting from the deprotonation of the oxoquinoline core, probably exclusively, which acts as the nucleophile in the SN2 reaction with

• bromoethane. These results are in agreement with the analysis of the reaction pathways from which we concluded that if the conjugate base of the carboxamide group were formed in the reaction medium, the SN2 reaction would most likely occur in this site, since this reaction would be the kinetic and

Sigmatropic rearrangements of cyclopropenylcarbinol derivatives. Access to diversely substituted alkylidenecyclopropanes

• Guillaume Ernouf,
• Jean-Louis Brayer,
• Christophe Meyer and
• Janine Cossy

Beilstein J. Org. Chem. 2019, 15, 333–350, doi:10.3762/bjoc.15.29

• addition of cyclopropenylmethylboronates to aldehydes was also reported [25]. A complementary strategy involves the addition of nucleophiles, in particular organometallic reagents, to cyclopropenylcarbinols or their derivatives E, which leads to alkylidenecyclopropanes F through a formal SN2’ process

• leading to zwitterronic intermediates 8 and 8’. This would result in an increase of conformational flexibility thereby facilitating the nucleophilic displacement of the ammonium by the phosphinite through transition states TS1 and TS2 (SN2-type process), respectively. Oxaphospholanium zwitterions 9 and 9

Silanediol versus chlorosilanol: hydrolyses and hydrogen-bonding catalyses with fenchole-based silanes

• Falco Fox,
• Jörg M. Neudörfl and
• Bernd Goldfuss

Beilstein J. Org. Chem. 2019, 15, 167–186, doi:10.3762/bjoc.15.17

• Nucleophilic substitution at silicon is already discussed with SN2 mechanism, following a backside attack opposite of the leaving group, as well as a front side attack near the leaving group [62][63][64][65][66][67][68]. A backside attack at the silicon in dichlorosilane 7 and monochlorosilanol 8 is blocked by

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

• with a CN− anion by a simple SN2 reaction. For this purpose, 5-chloromethyl-1,2,4-oxadiazole 1a was reacted with 10 equiv of KCN in CH3CN at reflux, after completion of the reaction on the basis of TLC, surprisingly we obtained a mixture of products 4 (major) and 3 (minor, Table 1, entry 1). This

• Cambridge Crystallographic Data Centre with the deposition numbers 1844118 and 1832133. We propose a plausible mechanism for the transformation of chloromethyloxadiazoles 1 into the title products 3 and 4. Accordingly, the reaction of 1 with a CN− anion gives cyanomethyloxadiazole by simple SN2 reaction

Generation of 1,2-oxathiolium ions from (arysulfonyl)- and (arylsulfinyl)allenes in Brønsted acids. NMR and DFT study of these cations and their reactions

• Stanislav V. Lozovskiy,
• Alexander Yu. Ivanov,
• Olesya V. Khoroshilova and
• Aleksander V. Vasilyev

Beilstein J. Org. Chem. 2018, 14, 2897–2906, doi:10.3762/bjoc.14.268

• and recyclization, rather than species C. Quenching of species Ba with water (high nucleophilicity) affords alcohol Z-4a. The formation of compound 4a in exclusively Z-configuration may indicate that cation Ba reacts with H2O in SN2 manner, keeping in mind that carbon C5 in Ba possesses a large

DABCO- and DBU-promoted one-pot reaction of N-sulfonyl ketimines with Morita–Baylis–Hillman carbonates: a sequential approach to (2-hydroxyaryl)nicotinate derivatives

• Soumitra Guin,
• Raman Gupta,
• Debashis Majee and
• Sampak Samanta

Beilstein J. Org. Chem. 2018, 14, 2771–2778, doi:10.3762/bjoc.14.254

• on the above experimental results as well as our previous report on DABCO-catalyzed reactions of cyclic sulfamidate imines with MBH carbonates of isatins [75], a plausible mechanism is presented and depicted in Scheme 2. For the first step, the nucleophilic Lewis base DABCO reacts with 2a in an SN2

• ' fashion to make a very reactive allyl ammonium intermediate 6. The latter further involves in the SN2' reaction with in situ generated carbanion intermediate 1a' forming SN2-adduct 3a. It undergoes an intramolecular aza-Michael reaction in the presence of DABCO, leading to tricyclic product 4a. For the

The design and synthesis of an antibacterial phenothiazine–siderophore conjugate

• Abed Tarapdar,
• James K. S. Norris,
• Oliver Sampson,
• Galina Mukamolova and
• James T. Hodgkinson

Beilstein J. Org. Chem. 2018, 14, 2646–2650, doi:10.3762/bjoc.14.242

• suitable position for PEG linker attachment [13]. From commercially available 2-(2-aminoethoxy)ethanol the amine functionality was Boc-protected under standard conditions to give compound 2 (Scheme 1). Under basic conditions 2 underwent an SN2 reaction with commercially available p-xylylene dichloride to

Design, synthesis and structure of novel G-2 melamine-based dendrimers incorporating 4-(n-octyloxy)aniline as a peripheral unit

• Cristina Morar,
• Pedro Lameiras,
• Attila Bende,
• Gabriel Katona,
• Emese Gál and
• Mircea Darabantu

Beilstein J. Org. Chem. 2018, 14, 1704–1722, doi:10.3762/bjoc.14.145

• from 4-(n-octyloxy)aniline, seven G-2 melamine-based dendrimers were obtained in 29–79% overall yields. Their iterative convergent- and chemoselective synthesis consisted of SN2-Ar aminations of cyanuric chloride and final triple N-acylations and Williamson etherifications (→ G-2 covalent trimers) or

• interested in the inclusion of 4-aminophenol, playing the role of peripheral unit, in G-0-2 dendritic melamines’ preparation, by applying the classic SN2-Ar amination of cyanuric chloride in iterative-convergent strategies. Depending on several factors such as (i) the variable π-deficiency of the s-triazine

• ascribed the low reactivity of G-1 dendrons D-Cl and D-N

  NH in our SN2-Ar amination conditions to the increased solvation of their (a–a)/(a–a) rotamers (+140–170%, i.e., more than double) compared to those of the (a–a) rotamers of G-0 3 and 2a. In addition to all the above, due to the steric

β-Hydroxy sulfides and their syntheses

• Mokgethwa B. Marakalala,
• Edwin M. Mmutlane and
• Henok H. Kinfe

Beilstein J. Org. Chem. 2018, 14, 1668–1692, doi:10.3762/bjoc.14.143

• ][83]. A single coupling product was obtained from the reaction of N-(trifluoroacetyl)glutathione dimethyl ester and triethylamine in methanol at 23 °C for 4 h in 80% yield, which occurred via SN2 displacement by nucleophilic sulfur at C-6. Selective hydrolysis of the trifluoroacetyl triester in a

Anomeric modification of carbohydrates using the Mitsunobu reaction

• Julia Hain,
• Patrick Rollin,
• Werner Klaffke and
• Thisbe K. Lindhorst

Beilstein J. Org. Chem. 2018, 14, 1619–1636, doi:10.3762/bjoc.14.138

• ][12]. The standard Mitsunobu reaction involves coupling of an alcohol and a nucleophile in a dehydrative SN2 process activated by a reactive combination of a triaryl- or trialkylphosphine as reducing agent and a dialkyl azodicarboxylate as oxidant. In a redox process, the phosphine species is oxidized

• anomerically modified carbohydrate with inversion of configuration at the anomeric center, according to a SN2 mechanism. Pathway A can also proceed through a SN1 mechanism when the intermediate glycosyloxyphosphonium ion is less stable. Then, it can decompose into the corresponding anomeric oxocarbenium ion

• -configured glycosyloxyphosphonium ions, which are in turn displaced by the nucleophile in the expected SN2 fashion, resulting in a respective anomeric mixture of products (cf. Scheme 2). In contrast to this, the yields of the obtained aryl sialosides strongly correlated with the pKa of the utilized phenols

Glycosylation reactions mediated by hypervalent iodine: application to the synthesis of nucleosides and carbohydrates

• Yuichi Yoshimura,
• Hideaki Wakamatsu,
• Yoshihiro Natori,
• Yukako Saito and
• Noriaki Minakawa

Beilstein J. Org. Chem. 2018, 14, 1595–1618, doi:10.3762/bjoc.14.137

• -thiosugar derivatives. We thus developed the first synthetic route accessing the 4-thiosugar derivative by way of bicyclic intermediate 8 from diacetoneglucose (5). Construction of the bicyclic ring of 8 was achieved by consecutive inter-/intramolecular SN2 reactions of the dimesylate derivative 7 obtained

• by intramolecular SN2 reaction at the 5-position by sulfur atom. Secondary, ring contraction from thiopyranose to thiofuranose occurred to produce 5-aldehyde 26. Finally, hydride reduction of 26 gave the 4-thiofuranose derivative 27. The Pummerer-type glycosylation reaction of 5-O-silylated sulfoxide

• reacted with a nucleobase, giving a mixture of α- and β-anomers since the reaction might occur by the simple SN2 reaction. Thus, the reaction proceeded through both paths a and b in method A, but path a was predominant in the reaction of method B [45] (Figure 3). Nishizono et al. applied the hypervalent

Cross-coupling of dissimilar ketone enolates via enolonium species to afford non-symmetrical 1,4-diketones

• Keshaba N. Parida,
• Gulab K. Pathe,
• Shimon Maksymenko and
• Alex M. Szpilman

Beilstein J. Org. Chem. 2018, 14, 992–997, doi:10.3762/bjoc.14.84

• -membered heterocycles such as thiophenes, furans, and pyrroles. Consequently, numerous multistep approaches to unsymmetrical 1,4-dicarbonyl compounds involving, e.g., SN2-type displacements [1] or highly functionalized substrates such as β-ketoesters [2][3] or β-ketosulfones [4] have been developed

Phosphodiester models for cleavage of nucleic acids

• Satu Mikkola,
• Tuomas Lönnberg and
• Harri Lönnberg

Beilstein J. Org. Chem. 2018, 14, 803–837, doi:10.3762/bjoc.14.68

• proceeds via a pentacoordinated species having the structure of a trigonal bipyramid. In case this species represents an energy maximum on a single barrier energy profile, as with SN2 displacement at carbon, the reaction is called concerted and the pentacoordinated species is a transition state. The

Enantioselective dioxytosylation of styrenes using lactate-based chiral hypervalent iodine(III)

• Morifumi Fujita,
• Koki Miura and
• Takashi Sugimura

Beilstein J. Org. Chem. 2018, 14, 659–663, doi:10.3762/bjoc.14.53

• proceed via an SN2 reaction of a cyclic intermediate such as I1, judging from the syn selectivity of the dioxytosylation [52][53]. The attack of the tosylate ion on I1 possibly takes place at the benzylic position or at the methylene carbon atom. The positive charge of I1 may be stabilized by the aryl

• styrene with 4a–e preferentially gave (S)-3, which forms via an electrophilic addition of the iodane toward the Si face of styrene, followed by an SN2 reaction with the tosylate ion. If an SN1 mechanism were involved in the oxytosylation of I1, the enantiomeric ratio of 3 would decrease owing to the

• planar structure of the benzylic cation. Thus, the tosylate ion may act as an effective nucleophile for the SN2 reaction of I1. The stereoface-differentiation in the dioxytosylation reaction using the lactate-derived aryl-λ3-iodanes is similar to that in preceding reactions [14], which include the

Synthesis of a sucrose-based macrocycle with unsymmetrical monosaccharides "arms"

• Karolina Tiara,
• Mykhaylo A. Potopnyk and
• Sławomir Jarosz

Beilstein J. Org. Chem. 2018, 14, 634–641, doi:10.3762/bjoc.14.50

• alternative way to the desired amine 12a, based on the SN2 reaction of the activated alcohol 13 [34][35] with benzylamine, also failed (Scheme 2). The Mitsunobu approach to convert the hydroxy group into an amine function was also unsuccessful. Although 13 reacted with phthalimide gave the desired product 13a

High-yielding continuous-flow synthesis of antimalarial drug hydroxychloroquine

• Eric Yu,
• Hari P. R. Mangunuru,
• Nakul S. Telang,
• Caleb J. Kong,
• Jenson Verghese,
• Stanley E. Gilliland III,
• Saeed Ahmad,
• Raymond N. Dominey and
• B. Frank Gupton

Beilstein J. Org. Chem. 2018, 14, 583–592, doi:10.3762/bjoc.14.45

• significant opportunity for optimization. While the recent improved route (Scheme 1b) by Li and co-workers [21] eliminates the protection–deprotection steps, its use of a complex multi-transition-metal-catalyst system to achieve direct SN2 substitution of the chlorine on 3 by amine 7, is sub-optimal [22][23

Stereochemical outcomes of C–F activation reactions of benzyl fluoride

• Neil S. Keddie,
• Pier Alexandre Champagne,
• Justine Desroches,
• Jean-François Paquin and
• David O'Hagan

Beilstein J. Org. Chem. 2018, 14, 106–113, doi:10.3762/bjoc.14.6

• an enantiopure isotopomer of benzyl fluoride to identify whether the reaction conditions favour a dissociative (SN1) or associative (SN2) pathway. [2H]-Isotopomer ratios in the reactions were assayed using the Courtieu 2H NMR method in a chiral liquid crystal (poly-γ-benzyl-L-glutamate) matrix and

• substantial F···HOR hydrogen bond interactions, rather than through electrostatic stabilisation only [3]. This stabilisation was suggested to lead to a purely associative bimolecular (SN2) mechanism. The authors also studied the C–F activated Friedel–Crafts reactions [6][7] using very strong hydrogen bond

• benzylic carbocation and a formal equivalent of HF (which behaves in an autocatalytic manner as a stronger hydrogen bond donor than HFIP or TFA). Overall, there are three possible mechanistic pathways that these C–F activation reactions could follow: SN1, SN2, and a mixed SN1/SN2 pathway. Typically

Conformational preferences of α-fluoroketones may influence their reactivity

• Graham Pattison

Beilstein J. Org. Chem. 2017, 13, 2915–2921, doi:10.3762/bjoc.13.284

• ; Introduction α-Halogenated ketones are widely used electrophiles in organic synthesis, being highly reactive in both nucleophilic addition to the carbonyl group and in SN2 nucleophilic displacements [1]. Our research group has recently been exploring the synthesis and reactivity of α-fluorinated ketones [2][3

• electrophiles available to synthetic chemists for SN2 substitution [5]. The orbital overlap in α-halogenated ketones also provides activation to the carbonyl group, making it more reactive towards nucleophilic addition than non-halogenated carbonyl compounds [6]. However, relatively little work has been

Acid-catalyzed ring-opening reactions of a cyclopropanated 3-aza-2-oxabicyclo[2.2.1]hept-5-ene with alcohols

• Katrina Tait,
• Alysia Horvath,
• Nicolas Blanchard and
• William Tam

Beilstein J. Org. Chem. 2017, 13, 2888–2894, doi:10.3762/bjoc.13.281

• reactions. The scope of the reaction was successfully expanded to include primary, secondary, and tertiary alcohol nucleophiles. Through X-ray crystallography, the stereochemistry of the product was determined which confirmed an SN2-like mechanism to form the ring-opened product. Keywords: acid catalysis

• compound 19 for the cleavage of the C–O bond (b) (Scheme 4). We initially anticipated that the SN2’ type ring-opening would occur which would lead to the formation of ring-opened product 27 (Scheme 5). However, in all cases tested, only the SN2 type ring-opened product 26 was formed. Results and Discussion

• cleavage of the C–O bond as seen in path A, the free carbocation 28 would form in an SN1-like manner. The nucleophile could therefore attack from either the top or the bottom, forming products 26a and 29. Alternatively, in path B the oxygen atom could be protonated and undergo an SN2-like mechanism with

Recent progress in the racemic and enantioselective synthesis of monofluoroalkene-based dipeptide isosteres

• Myriam Drouin and
• Jean-François Paquin

Beilstein J. Org. Chem. 2017, 13, 2637–2658, doi:10.3762/bjoc.13.262

• =CH]-Gly isosteres, a SN2’ reaction upon 3,3-difluoropropene substrates can be used, as shown by Taguchi’s group. The synthesis of monofluoroalkenes starting from 3,3-difluoropropenes and using trialkylaluminium reagents was developed. Using this methodology, they were able to prepare Boc-Nva-ψ[CF=CH

• ]-Gly isostere [26] via a SN2’ reaction (Scheme 3). The defluorinative allylic alkylation of terminal 3,3-difluoropropene 10 with triethylaluminium selectively provided the corresponding (Z)-monofluoroalkene 11. In this case, the use of Et3Al allowed access to a norvaline (Nva) isostere. Then, alcohol

• reacted easily in a SN2 reaction to give a more functionalized molecule. For example, treatment of the chlorinated monofluoroalkene with NaN3 provided the corresponding N3-containing monofluoroalkene. The azide group underwent a 1,3-dipolar cycloaddition to give a 1,2,3-triazole, which is also a peptide

Phosphonic acid: preparation and applications

• Charlotte M. Sevrain,
• Mathieu Berchel,
• Hélène Couthon and
• Paul-Alain Jaffrès

Beilstein J. Org. Chem. 2017, 13, 2186–2213, doi:10.3762/bjoc.13.219

• could consist in a nucleophilic substitution (SN2) involving chloride ions as nucleophilic species to produce the intermediate II. Then, a repetition of this mechanism yields phosphonic acid. The preponderant route is likely governed by the stability of the carbocation and the steric hindrance around

• avoid side reactions (from SN1 or SN2 mechanism) [204] that can involve the functional groups present in the amino acid or peptide. These conditions were applied to prepare the compound 82 from 81 [205][206] (Figure 24). 4. From dichlorophosphine (R–PCl2) or dichlorophosphine oxide (R–P=OCl2) Aryl- and