Direct synthesis of acyl fluorides from carboxylic acids using benzothiazolium reagents

• Lilian M. Maas,
• Alex Haswell,
• Rory Hughes and
• Matthew N. Hopkinson

Beilstein J. Org. Chem. 2024, 20, 921–930, doi:10.3762/bjoc.20.82

• Scheme 1, the reaction showed excellent functional group tolerance with a range of aromatic carboxylic acids 1, delivering the corresponding acyl fluorides 2 in very good 19F NMR yields above 75% for all substrates tested. Both electron-withdrawing and electron-donating substituents were tolerated while

• substituents could be present at the ortho-, meta- or para-positions. The heteroaromatic acyl fluoride 2h could be prepared efficiently while deoxyfluorination of representative olefinic and aliphatic carboxylic acids proceeded smoothly, affording cinnamoyl and decanoyl acyl fluorides 2i and 2j in 80% and 89

• of the desired amide 5a after 16 h at rt, which could be isolated in 80% yield after column chromatography. A survey of carboxylic acids 1 revealed that the one-pot approach is efficient for a variety of substitution profiles (Scheme 2). Aromatic acids bearing methyl substituents at the para-, ortho

Synthesis and properties of 6-alkynyl-5-aryluracils

• Ruben Manuel Figueira de Abreu,
• Till Brockmann,
• Alexander Villinger,
• Peter Ehlers and
• Peter Langer

Beilstein J. Org. Chem. 2024, 20, 898–911, doi:10.3762/bjoc.20.80

• substitution pattern on the phenyl groups and that the properties can be modulated by the choice of substituents. Conclusion In summary, we have developed a new, straightforward method for the synthesis of a series of new and hitherto unknown uracil derivatives. Different structural motifs could be obtained

• gives first insights into the optical properties. It was observed that the photophysical properties could be partially modulated by the chosen substituents. Experimental General information Nuclear magnetic resonance spectra (1H/13C/19F NMR) were recorded on a Bruker AVANCE 300 III, 250II, or 500. The

(Bio)isosteres of ortho- and meta-substituted benzenes

• H. Erik Diepers and
• Johannes C. L. Walker

Beilstein J. Org. Chem. 2024, 20, 859–890, doi:10.3762/bjoc.20.78

• benzenes are by now relatively well established. Cubanes [16][17], alkynes [18], and bicyclo[2.2.2]octanes [19] can all replicate the linear geometry of the para-substituents, but arguably the most well-investigated para-benzene bioisostere is bicyclo[1.1.1]pentane (BCP) [20][21][22][23] (Figure 1). The

• in exit vector analyses [25]. Here, the geometric relationship between the two substituents is measured and compared to those of the parent benzene. To compare physicochemical properties, the following indicators will generally be used: distribution coefficient (logD, desired range: 1–3 [26]) or

• Baran, Collins and co-workers and Anderson and co-workers showed that the substituent distance d of 3.5–4.0 Å and substituent angle φ1 of 89° inhabit a chemical space between ortho- and meta-substituted benzene (Figure 2) [26][27]. The 67° dihedral angle θ between the substituents differs significantly

Ortho-ester-substituted diaryliodonium salts enabled regioselective arylocyclization of naphthols toward 3,4-benzocoumarins

• Ke Jiang,
• Cheng Pan,
• Limin Wang,
• Hao-Yang Wang and
• Jianwei Han

Beilstein J. Org. Chem. 2024, 20, 841–851, doi:10.3762/bjoc.20.76

• , herein, we utilized a copper catalyst to activate the C–I bond of diaryliodonium salts in the generation of aryl radicals, thus resulting in an annulation reaction with naphthols and substituted phenols. This approach yielded a diverse array of 3,4-benzocoumarin derivatives bearing various substituents

• variety of 3,4-benzocoumarin derivatives. Our investigations commenced with 2-naphthol (1), and the results are presented in Table 2. Various substituted naphthols with a broad range of substituents on the naphthalene unit were well tolerated in the reaction, affording the corresponding products 3aa–aq in

• generally moderate to good yields of 22–83% (Table 2, entries 1–17). These substituents included halogen (Br), methyl, phenyl, aldehyde, ester, and methoxy groups, all of which were compatible with the reaction conditions. Notably, compounds 3ab, 3ah, 3aj, 3am and 3ap bearing bromine are very useful modules

Skeletal rearrangement of 6,8-dioxabicyclo[3.2.1]octan-4-ols promoted by thionyl chloride or Appel conditions

• Martyn Jevric,
• Julian Klepp,
• Johannes Puschnig,
• Oscar Lamb,
• Christopher J. Sumby and
• Ben W. Greatrex

Beilstein J. Org. Chem. 2024, 20, 823–829, doi:10.3762/bjoc.20.74

• , with the exo-hemiacetals favoured due to steric interactions between the substituents and alcohol, while the attempted preparation of 12b led only to complex mixtures (Scheme 2). The products of the reactions were characterised by 1D and 2D NMR, and X-ray crystallography of members from each class was

Synthesis of new representatives of A₃B-type carboranylporphyrins based on meso-tetra(pentafluorophenyl)porphyrin transformations

• Victoria M. Alpatova,
• Evgeny G. Rys,
• Elena G. Kononova and
• Valentina A. Ol'shevskaya

Beilstein J. Org. Chem. 2024, 20, 767–776, doi:10.3762/bjoc.20.70

• next studied the modification of the pentafluorophenyl substituents with carborane clusters via the SNAr substitution reaction with carborane nucleophiles [17][24][25][26][27]. These reactions are well studied for porphyrin 1 [17][24][25][26][27] to afford the corresponding carborane derivatives

• fluorophenylporphyrin substituents via the boron atom. At the same time the SNAr substitution reaction for the azido-substituted porphyrin 2 with mercaptocarborane 4 also afforded the amino-substituted porphyrin 5 in 32% yield (Scheme 2). During the reaction the reduction of the azide group under the action of

• the SNAr substitution reactions with 9-mercapto-m-carborane. As a result, tris(carboranyl)-substituted porphyrins containing pentafluorophenyl- or p-aminotetrafluorophenyl-substituents were synthesized and used in the reactions with a variety of thio- or amino-nucleophiles to form functionalized

Research progress on the pharmacological activity, biosynthetic pathways, and biosynthesis of crocins

• Zhongwei Hua,
• Nan Liu and
• Xiaohui Yan

Beilstein J. Org. Chem. 2024, 20, 741–752, doi:10.3762/bjoc.20.68

• , including common substituents of the crocetin skeleton. The pharmacological activity and mechanisms of action of crocins. Crocin biosynthetic pathways in C. sativus and G. jasminoides. Enzyme abbreviations are as follows: lycopene β-cyclase (LCYB), β-carotene hydrolase (BHY), carotenoid cleavage dioxygenase

• (CCD), aldehyde dehydrogenase (ALDH), uridine diphosphate glucosyltransferase (UGT). Structure of crocin and crocetin derivatives. A, SG, G, GB, and GT represent the common substituents of the crocin skeleton shown in Figure 1. Heterologous production of crocetin (1) and crocins. Acknowledgments We

SOMOphilic alkyne vs radical-polar crossover approaches: The full story of the azido-alkynylation of alkenes

• Julien Borrel and
• Jerome Waser

Beilstein J. Org. Chem. 2024, 20, 701–713, doi:10.3762/bjoc.20.64

• alkyne substituent. Arylalkynes are expected to perform well but in multiple cases alkyl substituents were reported to afford low yields or no reaction [35][36][37][38]. Finally, a radical-polar crossover (RPC) approach could be envisaged [39][40]. Instead of attempting to trap the C-centered radical

• work [45], and will be only shortly described in a summarized form (Scheme 3). Styrene substituted with a tert-butyl at the para position afforded 4b in 78% yield. Using a styrene bearing a sterically hindered aryl afforded 4c in a similar yield. Homopropargylic azides possessing oxygen substituents

• worked well in the transformation, affording homopropargylic azides 4n–q in 60–77% yield. The reaction appears to be sensitive to the steric hindrance of the nucleophile: addition of a mesitylalkyne only formed 33% of 4r. Pleasingly, heteroaryl substituents were tolerated, 4s bearing a thiophene was

Evaluation of the enantioselectivity of new chiral ligands based on imidazolidin-4-one derivatives

• Jan Bartáček,
• Karel Chlumský,
• Jan Mrkvička,
• Lucie Paloušová,
• Miloš Sedlák and
• Pavel Drabina

Beilstein J. Org. Chem. 2024, 20, 684–691, doi:10.3762/bjoc.20.62

• enantioselectivity and chemical yield. Next, the series of aromatic aldehydes with different substitutions were tested under the set reaction conditions. The yields decreased expectably in the range from aldehydes with electron-withdrawing substituents to that with electron-donating substituents. Thus, 4

Regioselective quinazoline C2 modifications through the azide–tetrazole tautomeric equilibrium

• Dāgs Dāvis Līpiņš,
• Andris Jeminejs,
• Una Ušacka,
• Anatoly Mishnev,
• Māris Turks and
• Irina Novosjolova

Beilstein J. Org. Chem. 2024, 20, 675–683, doi:10.3762/bjoc.20.61

• –tetrazole tautomeric equilibrium directs the nucleofugal sulfinate from the first step to replace chloride at the C2 position. This transformation is effective with quinazolines bearing electron-rich substituents. Therefore, the title transformations are demonstrated on the 6,7-dimethoxyquinazoline core

• reactions of substituted anilines VI, VII or N-arylamidines VIII are frequently employed for synthesizing C2-substituted quinazolines (Scheme 1), thereby influencing the spatial arrangement of the desired substituents [13][14]. Moreover, there have been recent advancements in efficient C–H activation

• out also with quinazoline derivatives 1b and 1c (Scheme 2), the structure features of which may slow-down the fast SNAr processes due to the substituents’ character. The desired products 4b and 4c were obtained in MeOH and isolated in 44 and 40% yields, respectively. Methanol is known to decrease

Palladium-catalyzed three-component radical-polar crossover carboamination of 1,3-dienes or allenes with diazo esters and amines

• Geng-Xin Liu,
• Xiao-Ting Jie,
• Ge-Jun Niu,
• Li-Sheng Yang,
• Xing-Lin Li,
• Jian Luo and
• Wen-Hao Hu

Beilstein J. Org. Chem. 2024, 20, 661–671, doi:10.3762/bjoc.20.59

• participated in this MCR, affording the products in moderate to good yields (6d–k, 43–73%). Then, the investigations of the scope of allenes demonstrated that the substrates possessing substituents at para-, meta-, and ortho-positions of the aromatic ring were also tolerated under our catalysis conditions

HPW-Catalyzed environmentally benign approach to imidazo[1,2-a]pyridines

• Luan A. Martinho and
• Carlos Kleber Z. Andrade

Beilstein J. Org. Chem. 2024, 20, 628–637, doi:10.3762/bjoc.20.55

• substituents at the aromatic aldehydes (both electron-withdrawing and electron-donating groups can be successfully used). The use of para-substituted aromatic aldehydes gave the corresponding products 4a–j in moderate to excellent yields (up to 99%). Aromatic aldehydes with electron-donating groups at the para

• -position gave moderate product yields (4c and 4d). Furthermore, cyclohexyl isocyanide gave higher yields compared to tert-butyl isocyanide. Ortho-substituted aromatic aldehydes were very efficient, regardless the type of substituents used, and good to excellent yields (74–99%) of products 4k–r were

A laterally-fused N-heterocyclic carbene framework from polysubstituted aminoimidazo[5,1-b]oxazol-6-ium salts

• Andrew D. Gillie,
• Matthew G. Wakeling,
• Bethan L. Greene,
• Louise Male and
• Paul W. Davies

Beilstein J. Org. Chem. 2024, 20, 621–627, doi:10.3762/bjoc.20.54

• (I) chloride in acetone led to the formation of the desired AImOxAuCl and AImOxCuCl metal chloride complexes 13 and 14, respectively (Scheme 2) [7]. The 1H NMR spectra of the resulting AImOx metal complexes show a loss of symmetry for the diisopropyl substituents, indicating restricted rotation about

• interatomic distances are between 3.53 and 3.66 Å leaving insufficient space for bond rotation about the C–N axis with the sulfonamide substituents being approximately perpendicular to the fused aromatic unit. A percentage buried volume of 44.6% was calculated from the crystal structure of 13 using Cavallo’s

Introduction of a human- and keyboard-friendly N-glycan nomenclature

• Friedrich Altmann,
• Johannes Helm,
• Martin Pabst and
• Johannes Stadlmann

Beilstein J. Org. Chem. 2024, 20, 607–620, doi:10.3762/bjoc.20.53

• “HNK-1” (from human natural killer cells) with sulfated glucuronic acid [47]. Annotating a structure like this requires some form of linear code and the addition of abbreviations for non-sugar substituents, in this case sulfate. Note that the hyphen binds the “su” to “Ga”, which in turn is hyphenated

• -vertebrates contain numerous “unusual” and remarkable structural features such as methylation, sulfation, and zwitterionic non-sugar substituents, again glucuronic acid and often unusual architectures such as substituted core-fucose just as an example [44][52]. While the methylated moss glycans are accessible

• to the proglycan systems (Figure 11) the extremely diverse and unusual structures found in invertebrates or algae demand IUPAC code or graphical representations [44][53][54][55]. Moss N‐glycans are included here to demonstrate the ability of the proglycan system to annotate nonsugar substituents

Entry to new spiroheterocycles via tandem Rh(II)-catalyzed O–H insertion/base-promoted cyclization involving diazoarylidene succinimides

• Alexander Yanovich,
• Anastasia Vepreva,
• Ksenia Malkova,
• Grigory Kantin and
• Dmitry Dar’in

Beilstein J. Org. Chem. 2024, 20, 561–569, doi:10.3762/bjoc.20.48

• carried out with different substituted propiolic acids 9 and DAS 1 are shown in Scheme 3. It can be noted that in the case of arylpropiolic acids, no significant influence of electronic effects of substituents in the aromatic ring was observed. In the case of the o-chloro derivative 2d the yield was

• isolate or otherwise identify any byproducts in this case. Recently, we have shown that this approach to the synthesis of spirocyclic butenolides can also be realized using allenic acids [40]. This opens up the possibility of obtaining target spiroheterocycles with substituents not only in the beta but

• presented in Scheme 5. As can be seen, the yields of the target compounds 4 vary from good to moderate per two steps of synthesis. The introduction of acceptor substituents in both the aniline and arylidene moieties of the DAS molecule leads to a decrease in the yield of the final spirocycle. The structure

Synthesis and biological profile of 2,3-dihydro[1,3]thiazolo[4,5-b]pyridines, a novel class of acyl-ACP thioesterase inhibitors

• Jens Frackenpohl,
• David M. Barber,
• Guido Bojack,
• Birgit Bollenbach-Wahl,
• Ralf Braun,
• Rahel Getachew,
• Sabine Hohmann,
• Kwang-Yoon Ko,
• Karoline Kurowski,
• Bernd Laber,
• Rebecca L. Mattison,
• Thomas Müller,
• Anna M. Reingruber,
• Dirk Schmutzler and
• Andrea Svejda

Beilstein J. Org. Chem. 2024, 20, 540–551, doi:10.3762/bjoc.20.46

• was not necessary to add a further base to activate the thiazoline nitrogen atom. Following the aforementioned two-step procedure, more than 15 unprecedented 2,3-dihydro[1,3]thiazolo[4,5-b]pyridines bearing different substituents were obtained for biological and biochemical tests. Converting the

• ]pyridine 7b had a higher water solubility of 173 mg/L and a lower LogP of 1.59 (pH 2.3). However, the lipophilicity of the new 2,3-dihydro[1,3]thiazolo[4,5-b]pyridines was highly dependent on the substituents. For example, the brominated analogs 13b and 13c showed considerably higher LogP values of 2.88

Switchable molecular tweezers: design and applications

• Pablo Msellem,
• Maksym Dekthiarenko,
• Nihal Hadj Seyd and
• Guillaume Vives

Beilstein J. Org. Chem. 2024, 20, 504–539, doi:10.3762/bjoc.20.45

• closely related tweezers based on a 2,6-bis(oxazolinyl)pyridine (Pybox) ligand with two 4-nitrophenylurea substituents as anion receptor 24 (Figure 14b) [56]. This ligand presents a “W” to “U”-shaped conformational change upon metal coordination similar to terpyridine but displays additional chirality

• hours). Another class of dissymmetric tweezers was later developed based on square planar Pt(II)-based hinges [85][86]. The heteroleptic Pt(II) complexes were directly obtained by coordination of two different phosphine thioether ligands with either aliphatic or aryl substituents. The hemi-opening of

Ligand effects, solvent cooperation, and large kinetic solvent deuterium isotope effects in gold(I)-catalyzed intramolecular alkene hydroamination

• Ruichen Lan,
• Brock Yager,
• Yoonsun Jee,
• Cynthia S. Day and
• Amanda C. Jones

Beilstein J. Org. Chem. 2024, 20, 479–496, doi:10.3762/bjoc.20.43

• observed rate was outside of one standard deviation from the average of 3 trials, confirming the overall reactivity trend. In hindsight, the ligand effect here may be expected to be small since the bisbiphenyl scaffold contains 2 of 3 identical substituents. Nevertheless, these comparisons confirm the

• -withdrawing substituents accelerate the reaction. Within the binary paradigm of gold-catalyzed mechanisms, where either π-activation or protodeauration is rate limiting, this electronic effect would suggest rate limiting π-activation [40], since protodeauration is fastest with strong donor ligands (tert

• maintained in DCM and MeOD. Our experiments show that alkene hydroamination is accelerated by simple hydrogen bonding additives (water and alcohols), acceptor ligands (arylphosphines with or without electron-withdrawing substituents) and demonstrates a continuum of primary deuterium isotope effects from

Mono or double Pd-catalyzed C–H bond functionalization for the annulative π-extension of 1,8-dibromonaphthalene: a one pot access to fluoranthene derivatives

• Nahed Ketata,
• Linhao Liu,
• Ridha Ben Salem and
• Henri Doucet

Beilstein J. Org. Chem. 2024, 20, 427–435, doi:10.3762/bjoc.20.37

• by successive palladium-catalyzed intermolecular and intramolecular C–H arylations using arenes activated by fluorine or chlorine substituents, or by combining a palladium-catalyzed intermolecular Suzuki coupling followed by an intramolecular C–H bond arylation, ii) on functional group tolerance for

• both synthetic routes for the introduction of substituents at the desired positions. Results and Discussion For our study, we selected 1,2,3,4-tetrafluorobenzene (1.5 equiv) and 1,8-dibromonaphthalene (1 equiv) as model substrates (Table 1). We first investigated the reaction outcome using a set of

• -aryl-8-bromonaphthalene A (Scheme 2). This catalytic cycle is followed by a second involving oxidative addition of 1-aryl-8-bromonaphthalene A, followed by intramolecular C–H coupling of the two aryl rings to give the fluoranthene derivative. Consequently, the use of arenes bearing substituents at the

Green and sustainable approaches for the Friedel–Crafts reaction between aldehydes and indoles

• Periklis X. Kolagkis,
• Eirini M. Galathri and
• Christoforos G. Kokotos

Beilstein J. Org. Chem. 2024, 20, 379–426, doi:10.3762/bjoc.20.36

• the corresponding BIMs in good to excellent yields (70–95%). It is important to mention that electron-withdrawing groups led to enhanced reaction rates and product yields, compared to their electron-donating substituents. However, aliphatic aldehydes and ketones displayed significantly lower

• electron-withdrawing substituents. The reaction mechanism is based on the activation of the carbonyl group by molecular I2, through the formation of a halogen bond, which lowers the LUMO of the carbonyl moiety, increasing its electrophilicity, and thus allowing the addition of the indole group (Scheme 7

• efficiency would not diminish even after 3 cycles [99]. Several substituted indoles, aldehydes and ketones reacted in good yields (74–98%), with ketones requiring longer reaction rates of 3 hours, due to their lower reactivity. The electron-donating or withdrawing effects of the substituents of the benzene

Facile approach to N,O,S-heteropentacycles via condensation of sterically crowded 3H-phenoxazin-3-one with ortho-substituted anilines

• Eugeny Ivakhnenko,
• Vasily Malay,
• Pavel Knyazev,
• Nikita Merezhko,
• Nadezhda Makarova,
• Oleg Demidov,
• Gennady Borodkin,
• Andrey Starikov and
• Vladimir Minkin

Beilstein J. Org. Chem. 2024, 20, 336–345, doi:10.3762/bjoc.20.34

• comprehensive reviews [18][19], but none is directly related to aromatic SNH reactions. The developed procedure was applied to the synthesis of compounds 4 and extended to arylamines with o-amino, o-hydroxy, and o-mercapto substituents, providing access to N-, O-, and S-containing heteropolycyclic structures

Elucidating the glycan-binding specificity and structure of Cucumis melo agglutinin, a new R-type lectin

• Jon Lundstrøm,
• Emilie Gillon,
• Valérie Chazalet,
• Nicole Kerekes,
• Antonio Di Maio,
• Ten Feizi,
• Yan Liu,
• Annabelle Varrot and
• Daniel Bojar

Beilstein J. Org. Chem. 2024, 20, 306–320, doi:10.3762/bjoc.20.31

• Fucα1-2Gal, likely due to steric clashes in the binding pocket. We thus conclude that the binding profile of CMA1 is distinct from that of the typical R-type lectin RCA1 and unusual for a R-type lectin in general. We also note that the flexibility of accommodated C2 substituents (from N-acetyl moieties

• to whole monosaccharides), could make CMA1 an interesting candidate for probing synthetically produced glycans with novel substituents. It is of course interesting to speculate about the physiological role of CMA1 in melons, yet this is hard to probe. It is noteworthy, however, that the glycan types

• no binding to unsubstituted galactose, we rather hypothesized the existence of specific interactions made with the C2-substituents, that did not exist in other R-type lectins such as RCA1. To determine this, we set out to resolve the detailed three-dimensional structure of CMA1 via X-ray

Synthesis of π-conjugated polycyclic compounds by late-stage extrusion of chalcogen fragments

• Aissam Okba,
• Pablo Simón Marqués,
• Kyohei Matsuo,
• Naoki Aratani,
• Hiroko Yamada,
• Gwénaël Rapenne and
• Claire Kammerer

Beilstein J. Org. Chem. 2024, 20, 287–305, doi:10.3762/bjoc.20.30

• sulfur extrusion [44]. It appeared that thiepines carrying sterically demanding substituents on the sulfur α-positions as well as annelated analogues show substantially increased lifetimes, owing to steric and electronic effects [45]. With these criteria in mind, a variety of thermally-stable annelated

• , Yamada, Fukui, Shinokubo and co-workers tackled the synthesis of perylene bisimide (PBI), a valuable n-type semiconductor, via a “precursor approach” based on the late-stage extrusion of S-based fragments [57]. Dinaphthothiepine bisimides 3a and 3b, bearing octyl- and butylimide substituents respectively

• ), it was non-scalable and displayed low modularity. Indeed, the imide groups along with their substituents were introduced at a rather early stage of the synthesis, with the ultimate synthetic step being the formation of the thiepine ring via a two-fold nucleophilic aromatic substitution by sodium

Synthesis of spiropyridazine-benzosultams by the [4 + 2] annulation reaction of 3-substituted benzoisothiazole 1,1-dioxides with 1,2-diaza-1,3-dienes

• Wenqing Hao,
• Long Wang,
• Jinlei Zhang,
• Dawei Teng and
• Guorui Cao

Beilstein J. Org. Chem. 2024, 20, 280–286, doi:10.3762/bjoc.20.29

• spiropyridazine-benzosultams. The electronic effects of substituents and the influence of steric hindrance on the reaction were explored. The configuration of the product was determined by X-ray single crystal diffraction. This method has the advantages of mild reaction conditions, wide substrate scope, and high

Substitution reactions in the acenaphthene analog of quino[7,8-h]quinoline and an unusual synthesis of the corresponding acenaphthylenes by tele-elimination

• Ekaterina V. Kolupaeva,
• Narek A. Dzhangiryan,
• Alexander F. Pozharskii,
• Oleg P. Demidov and
• Valery A. Ozeryanskii

Beilstein J. Org. Chem. 2024, 20, 243–253, doi:10.3762/bjoc.20.24

• , despite the presence of two pyridine nitrogen atoms, is extremely inert towards nucleophilic and oxidative amination reactions. Although molecule 5 does not explicitly contain deactivating electron-donating substituents such as alkoxy and dialkylamino (except for alkyl groups), the observed inertness may

• complexes due to the presence of 5(8) substituents, emerging from the plane of the π-system (see the previous section), and 3) acidification of the hydrogen atoms of the CH2 groups, which can facilitate their subsequent elimination. The analysis of the 1Н NMR spectrum not only confirmed the structure of

• structure of compound 15 was confirmed by a combination of spectral methods, in particular, the disappearance of a singlet from H-5,8 protons at 7.8–7.9 ppm in the starting material 5 during functionalization (nitration, bromination), unambiguously indicates the occurrence of substituents precisely in these