Directed ortho metalation-cross coupling strategies. N-cumyl arylsulfonamides. Facile deprotection and expedient route to 7- and 4,7-substituted saccharins

By using the powerful N-cumylsulfonamide directed metalation group (DMG), a series of 2-substituted derivatives were prepared according to the directed ortho metalation (DoM) tactic (Table 1). Mild conditions for N-decumylation and other simple transformations of the products have been achieved (Scheme 2). The 3-silyloxy sultam 12 undergoes further DoM to give formyl, thiomethyl, iodo, and amide derivatives 13a-g of potential value for saccharin synthesis (Table 2). An effective route to target 7-aryl saccharins via Suzuki cross coupling (Table 3) followed by further metalation-carbamoylation and cyclization (Table 5) is described. 4,7-Disubstituted saccharins have been obtained by similar sequences (Scheme 3). Mild TFA-mediated N-decumylation furnishes substituted primary arylsulfonamides (Table 4).     

New Results in the Synthesis of Styrylazulene Derivatives: Application of the ‘Anil synthesis’ to the preparation of azulenes substituted with styryl groups at the seven-membered ring

The synthesis of 4,6,8-trimethyl-1-[(E)-4-R-styryl]azulenes 5 (R=H, MeO, Cl) has been performed by Wittig reaction of 4,6,8-trimethylazulene-1-carbaldehyde ( 1 ) and the corresponding 4-(R-benzyl)(triphenyl)phosphonium chlorides 4 in the presence of EtONa/EtOH in boiling toluene (see Table 1). In the same way, guaiazulene-3-carbaldehyde ( 2 ) as well as dihydrolactaroviolin ( 3 ) yielded with 4a the corresponding styrylazulenes 6 and 7 , respectively (see Table 1). It has been found that 1 and 4b yield, in competition to the Wittig reaction, alkylation products, namely 8 and 9 , respectively (cf. Scheme 1). The reaction of 4,6,8-trimethylazulene ( 10 ) with 4b in toluene showed that azulenes can, indeed, be easily alkylated with the phosphonium salt 4b . 4,6,8-Trimethylazulene-2-carbaldehyde ( 12 ) has been synthesized from the corresponding carboxylate 15 by a reduction (LiAlH₄) and dehydrogenation (MnO₂) sequence (see Scheme 2). The Swern oxidation of the intermediate 2-(hydroxymethyl)azulene 16 yielded only 1,3-dichloroazulene derivatives (cf. Scheme 2). The Wittig reaction of 12 with 4a and 4b in the presence of EtONa/EtOH in toluene yielded the expected 2-styryl derivatives 19a and 19b , respectively (see Scheme 3). Again, the yield of 19b was reduced by a competing alkylation reaction of 19b with 4b which led to the formation of the 1-benzylated product 20 (see Scheme 3). The ‘anil synthesis’ of guaiazulene ( 21 ) and the 4-R-benzanils 22 (R=H, MeO, Cl, Me₂N) proceeded smoothyl under standard conditions (powered KOH in DMF) to yield the corresponding 4-[(E)-styryl]azulene derivatives 23 (see Table 4). In minor amounts, bis(azulen-4-yl) compounds of type 24 and 25 were also formed (see Table 4). The ‘anil reaction’ of 21 and 4-NO₂C₆H₄CH=NC₆H₅ ( 22e ) in DMF yielded no corresponding styrylazulene derivative 23e . Instead, (E)-1,2-bis(7-isopropyl-1-methylazulen-4-yl)ethene ( 27 ) was formed (see Scheme 4). The reaction of 4,6,8-trimethylazulene ( 10 ) and benzanil ( 22a ) in the presence of KOH in DMF yielded the benzanil adducts 28 to 31 (cf. Scheme 5). Their direct base-catalyzed transformation into the corresponding styryl-substituted azulenes could not be realized (cf. Scheme 6). However, the transformation succeeded smoothly with KOH in boiling EtOH after N-methylation (cf. Scheme 6).     

Directed ortho-metalation-cross-coupling strategies. One-pot Suzuki reaction to biaryl and heterobiaryl sulfonamides

A general synthesis of stable ortho-boropinacolato aryl and heteroaryl sulfonamides by directed ortho-metalation (DoM) and either MeOBPin or i-PrOBpin electrophile quench, 3 → 4, is described. A one-pot metalation-Suzuki cross-coupling procedure for the synthesis of biaryls and heterobiaryls, 3 → 5, and a complementary DoM-Ir-catalyzed boronation sequence (Scheme 6 ) are delineated.     

Regioselective synthesis of 7,8-dioxygenated-3,4-dihydroisoquinolinesby metalation of β-phenethylamines

A new, one-pot procedure for the synthesis of the title compounds isdescribed which is based on the thermodynamic metalation of thecorresponding β-(3,4-dialkoxyphenyl)ethylamine.     

A metalation strategy for the construction of functionalized naphthalenes: the first synthesis of guieranone A

The first synthesis of the natural product guieranone A is described, demonstrating a one-pot procedure for the synthesis of protected-1,3,6,8-tetraoxygenated naphthalenes and a subsequent directed metalation synthesis of 2-keto naphthalenes.     

Tandem oxidation processes for the regioselective preparation of 5-substituted and 6-substituted 1,2,4-triazines

α-Hydroxyketones undergo MnO₂-mediated oxidation, followed by in situ trapping with 2-pyridylamidrazone, to give 3-pyridyl-5-substituted 1,2,4-triazines in a one-pot procedure, which avoids the need to isolate the reactive α-ketoaldehyde intermediates. By modifying this procedure to allow condensation prior to oxidation, the corresponding 6-substituted 1,2,4-triazines were obtained. The preparation of a novel unsymmetrical 2,2′-bipyridine using one of the pyridyl 1,2,4-triazines prepared herein is also described.     

Cross‐Linked‐Polymer‐Supported N‐{2′‐[(Arylsulfonyl)amino][1,1′‐binaphthalen]‐2‐yl}prolinamide as Organocatalyst for the Direct Aldol Intermolecular Reaction under Solvent‐Free Conditions

A bottom‐up strategy was used for the synthesis of cross‐linked copolymers containing the organocatalyst N‐{(1R)‐2′‐{[(4‐ethylphenyl)sulfonyl]amino}[1,1′‐binaphthalen]‐2‐yl}‐D ‐prolinamide derived from 2 (Scheme 1). The polymer‐bound catalyst 5b containing 1% of divinylbenzene as cross‐linker showed higher catalyst activity in the aldol reaction between cyclohexanone and 4‐nitrobenzaldehyde than 5a and 5c . Remarkably, the reaction in the presence of 5b was carried out under solvent‐free, mild conditions, achieving up to 93% ee (Table 1). The polymer‐bound catalyst 5b was recovered by filtration and re‐used up to seven times without detrimental effects on the achieved diastereo‐ and enantioselectivities (Table 2). The catalytic procedure with polymer 5b was extended to the aldol reaction under solvent‐free conditions of other ketones, including functionalized ones, and different aromatic aldehydes (Table 3). In some cases, the addition of a small amount of H₂O was required to give the best results (up to 95% ee). Under these reaction conditions, the cross‐aldol reaction between aldehydes proceeded in moderate yield and diastereo‐ and enantioselectivity (Scheme 2).     

Regiospecific metalation of oligobromobenzenes

The metalation of selected oligobromobenzenes with lithium diisopropylamide (LDA) was investigated. 1,3-Dibromo-substituted benzenes were metalated without special precautions since the resultant 2,6-dibromophenyllithium intermediates are relatively stable under reaction conditions: corresponding benzaldehydes were obtained in good or moderate yields after subsequent quench with N,N-dimethylformamide (DMF). Aryllithium compounds derived from 1,4- and 1,2-dibromobenzene are much less stable, but they could be trapped by the in situ use of chlorotrimethylsilane. The one-pot metalation/disilylation of 1,4-dibromo- and 1,2-dibromobenzene afforded 1,4-dibromo-2,5-bis(trimethylsilyl)benzene and 2,3-dibromo-1,4-bis(trimethylsilyl)benzene, respectively.     

Condensation of laterally lithiated o-methyl and o-ethyl benzamides with imines mediated by (-)-sparteine. Enantioselective synthesis of tetrahydroisoquinolin-1-ones

The first asymmetric synthesis of tetrahydroisoquinolin-1-ones using a (-)-sparteine-mediated lateral metalation-imine addition sequence to furnish 3-phenyl tetrahydroisoquinolinones 3a with enantioselectivities up to 81% ee is described (Scheme 4). For amide 7b, imine addition products 10 and 11 have been obtained with high diastereoselectivities (91-97% de) and enantioselectivities (91-98% ee) (Scheme 8).     

通过硼氢化-原位再结晶提高二异松莰烷基硼烷光学纯度的简便方法

本文叙述了由国产低光学纯(43.6%e e)(-)-α-蒎烯通过硼氢化-原位再结晶, 制备高光学纯(97.2%ee)(+)-二异松茨烷基硼烷(diisopinocampheylborane, Ipc2BH)的简便新方法。     

Nucleosides and Oligonucleotides with Diynyl Side Chains: Base Pairing and Functionalization of 2′‐Deoxyuridine Derivatives by the Copper(I)‐Catalyzed Alkyne?Azide ‘Click’ Cycloaddition

Oligonucleotides containing the 5‐substituted 2′‐deoxyuridines 1b or 1d bearing side chains with terminal C?C bonds are described, and their duplex stability is compared with oligonucleotides containing the 5‐alkynyl compounds 1a or 1c with only one nonterminal C?C bond in the side chain. For this, 5‐iodo‐2′‐deoxyuridine ( 3 ) and diynes or alkynes were employed as starting materials in the Sonogashira cross‐coupling reaction (Scheme 1). Phosphoramidites 2b – d were prepared (Scheme 3) and used as building blocks in solid‐phase synthesis. T_m Measurements demonstrated that DNA duplexes containing the octa‐1,7‐diynyl side chain or a diprop‐2‐ynyl ether residue, i.e., containing 1b or 1d , are more stable than those containing only one triple bond, i.e., 1a or 1c (Table 3). The diyne‐modified nucleosides were employed in further functionalization reactions by using the protocol of the Cu^I‐catalyzed Huisgen–Meldal–Sharpless [2+3] cycloaddition (‘click chemistry’) (Scheme 2). An aliphatic azide, i. e., 3′‐azido‐3′‐deoxythymidine (AZT; 4 ), as well as the aromatic azido compound 5 were linked to the terminal alkyne group resulting in 1H‐1,2,3‐triazole‐modified derivatives 6 and 7 , respectively (Scheme 2), of which 6 forms a stable duplex DNA (Table 3). The Husigen–Meldal–Sharpless cycloaddition was also performed with oligonucleotides (Schemes 4 and 5).     

First general, direct, and regioselective synthesis of substituted methoxybenzoic acids by ortho metalation

New general methodology of value in aromatic chemistry based on ortho-metalation sites in o-, m-, and p-anisic acids (1-3) (Scheme 1) is described. The metalation can be selectively directed to either of the ortho positions by varying the base, metalation temperature, and exposure times. Metalation of o-anisic acid (1) with s-BuLi/TMEDA in THF at -78 degrees C occurs exclusively in the position adjacente to the carboxylate. On the other hand, a reversal of regioselectivity is observed with n-BuLi/t-BuOK. With LTMP at 0 degrees C, the two directors of m-anisic acid (2) function in concert to direct introduction of the metal between them while n-BuLi/t-BuOK removes preferentially the proton located ortho to the methoxy and para to the carboxylate (H-4). s-BuLi/TMEDA reacts with p-anisic acid (3) exclusively in the vicinity of the carboxylate. According to these methodologies, routes to very simple methoxybenzoic acids with a variety of functionalities that are not easily accessible by other means have been developed (Table 1).     

Efficient directed ortho metalation-based route to cytotoxic furanonaphthoquinone natural products

The naturally-occuring furanonaphthoquinone 1e have been synthesized in good overall yield by a route involving directed ortho metalation (Scheme 1, 1 → 2).     

A One‐Pot Tandem Ugi Multicomponent Reaction (MCR)/Click Reaction as an Efficient Protecting‐Group‐Free Route to 1H‐1,2,3‐Triazole‐Modified α‐Amino Acid Derivatives and Peptidomimetics

By a one‐pot tandem Ugi multicomponent reaction (MCR)/click reaction sequence not requiring protecting groups, 1H‐1,2,3‐triazole‐modified Ugi‐reaction products 6a – 6n (Scheme 1 and Table 2), 7a – 7b (Table 4), and 8 (Scheme 2) were synthesized successfully. i.e., terminal, side‐chain, or both side‐chain and terminal triazole‐modified Ugi‐reaction products as potential amino acid units for peptide syntheses. Different catalyst systems for the click reaction were examined to find the optimal reaction conditions (Table 1, Scheme 1). Finally, an efficient Ugi MCR+Ugi MCR/click reaction strategy was elaborated in which two Ugi‐reaction products were coupled by a click reaction, thus incorporating the triazole fragment into the center of peptidomimetics (Scheme 3). Thus, the Ugi MCR/click reaction sequence is a convenient and simple approach to different 1H‐1,2,3‐triazole‐modified amino acid derivatives and peptidomimetics.     

Versuche zur Synthese von Calicen aus trisubstituierten Cyclopropanen und Cyclopentenon

Attempted Synthesis of Calicene from Trisubstitued Cyclopropanes and Cyclopentenone The Li carbenoids 4 , prepared by treatment of substituted 1,1-dihalocyclopropanes with BuLi, are reacted with cyclopent-2-enone under thermodynamic and kinetic control (Scheme 1). In general, the latter procedure gives better yields of cyclopropylcyclopentenols 5a – e , but the reaction seems to be controlled mainly by the steric and electronic properties of the substituent Y. So, with 4b and 4e , the main reaction is the attack of the carbenoid at C(1) of cyclopent-2-enone, while 4a (Y = PhS) predominantly deprotonates the ketone (Scheme 4). Whereas 5d and 5e can easily be converted to the dihydrocalicenes 6d and 6e (Scheme 6), the attempted elimination of H₂O from 5a – c leads to the rearranged products 13 – 2 due to the opening of the cyclopropane ring (Scheme 5). Finally, the generation of the parent compound 2 from the silylated precursor 6d is attempted: treatment with MeO^? gives the addition products 18A/18B , while the reaction with Br₂ provides 19 by a bromination/dehydrobromination sequence (Scheme 7).     

Synthesis and Reactivity of π‐Electron‐Deficient (Arylsulfonyl)acetates

Different π‐electron‐deficient (arylsulfonyl)acetates 9 were synthesized (Scheme 1, Table 1), and their behavior as soft nucleophiles in the dialkylation reaction under phase‐transfer catalysis conditions was studied (Schemes 2 and 3, Tables 2 and 3). The [3,5‐bis(trifluoromethyl)phenyl]sulfonyl group was shown to be the best substituent for the stereoselective synthesis of (E)‐aconitates 18 via an alkylation hydro‐sulfonyl‐elimination integrated process under very mild phase‐transfer‐catalysis conditions (Scheme 5, Table 4). Sulfonylacetates 9h , i also underwent smooth Diels‐Alder reactions with acyclic and cyclic dienes via in situ formation of the appropriate dienophile through a Knoevenagel condensation with paraformaldehyde (Scheme 6). Reductive desulfonylation with Zn and NH₄Cl in THF was shown to be an efficient method for removal of the synthetically useful sulfonyl moiety (Scheme 7).     

Nonreductive Enantioselective Ring Opening of N-(Methylsulfonyl)dicarboximides with Diisopropoxytitanium α,α,α′,α′-Tetraaryl-1,3-dioxolane-4,5-dimethanolate

The bicyclic and tricyclic meso-N-(methylsulfonyl)dicarboximides 1a–f are converted enantioselectively to isopropyl [(sulfonamido)carbonyl]-carboxylates 2a–f by diisopropoxytitanium TADDOLate (75–92% yield; see Scheme 3). The enantiomer ratios of the products are between 86:14 and 97:3, and recrystallization from CH₂Cl₂/hexane leads to enantiomerically pure sulfonamido esters 2 (Scheme 3). The enantioselectivity shows a linear relationship with the enantiomer excess of the TADDOL employed (Fig.3). Reduction of the ester and carboxamide groups (LiAlH₄) and additional reductive cleavage of the sulfonamido group (Red-Al) in the products 2 of imide-ring opening gives hydroxy-sulfonamides 3 and amino alcohols 4 , respectively (Scheme 4). The absolute configuration of the sulfonamido esters 2 is determined by chemical correlation (with 2a,b ; Scheme 6), by the X-ray analysis of the camphanate of 3e (Fig. 1), and by comparative ¹⁹F-NMR analysis of the Mosher esters of the hydroxy-sulfonamides 3 (Table 1). A general proposal for the assignment of the absolute configuration of primary alcohols and amines of Formula HXCH₂CHR¹R², X = O, NH, is suggested (see 11 in Table 1). It follows from the assignment of configuration of 2 that the Re carbonyl group of the original imide 1 is converted to an isopropyl ester group. This result is compatible with a rule previously put forward for the stereochemical course of reactions involving titanium TADDOLate activated chelating electrophiles ( 12 in Scheme 7). A tentative mechanistic model is proposed ( 13 and 14 in Scheme 7).     

Lithiated 4-isopropyl-3-(methylthiomethyl)-5,5-diphenyloxazolidin-2-one: a chiral formyl anion equivalent for enantioselective preparations of 1,2-diols, 2-amino alcohols, 2-hydroxy esters, and 4-hydroxy-2-alkenoates

The heterocyclic compound specified in the title (and readily prepared from commercial precursors) has a sterically protected C==O group, so that direct lithiation by BuLi at the exocyclic CH(2) group is possible (3 --> Li-3). The lithiated N,S-acetal derivative (Li-3) adds diastereoselectively to aldehydes (Table 2), unsymmetrical ketones (Table 3), chalcone (1,4-addition, Scheme 2), and N-phosphinoyl- and N-sulfonylimines (Table 4). Protection of the newly formed OH groups (Scheme 3) and/or MeS/OH displacement by Hg(O(2)CCF(3))(2) in aqueous THF/acetonitrile converts the N,S-acetals into hemiaminals (--> 20) which, in turn, are readily cleaved to aldehydes, with recovery of the chiral auxiliary (1, Scheme 4). The aldehydes (especially those lacking alpha-carbonyl hydrogens) may be isolated, or they are trapped in situ by reduction to (selectively protected) diols or amino alcohols, by addition of Grignard or Li reagents, which provides diols with two stereogenic centers, by oxidation to give 2-hydroxy esters, or by olefination to provide 4-hydroxy-2-alkenoates (Scheme 5). The scope and limitations of the new, overall enantioselective transformation are determined, and the readily recovered chiral auxiliary used is compared with oxazolidinones of other substitution patterns (Scheme 7). The configuration of a number of products has been assigned by single-crystal X-ray diffraction (cf. Figure 5). These structures and similarities of NMR data led to configurational assignment of the other products (see formulas in the schemes and tables) by analogy. A simple mechanistic model for the stereochemical course of the addition of Li-3 to aldehydes and ketones is presented (Figure 6).     

Tetramethylheptalenes and Their Tricarbonylchromium Complexes: Synthesis,Structures, and Thermal Rearrangements

The thermal 4 : 1 equilibrium mixture of 1,3,5,6- and 1,3,5,10-tetramethylheptalene ( 13a and 13b , resp.) has been prepared, starting from the thermal equilibrium mixture of dimethyl 6,8,10-trimethylheptalene-1,2- and -4,5-dicarboxylate ( 6a and 6b , resp.; cf. Scheme 5). These heptalenes undergo double-bond shifts (DBS) even at ambient temperature. Treatment of the mixture 13a / 13b 4 : 1 with [Cr(CO)₃(NH₃)₃] in boiling 1,2-dimethoxyethane resulted in the formation of all four possible mononuclear Cr(CO)₃ complexes 19a – 19d of 13a and 13b , as well as two binuclear Cr(CO)₃ complexes 20a and 20b , respectively, in a total yield of 87% (cf. Scheme 7). The mixture of complexes was separated by column chromatography, followed by preparative HPLC (cf. Fig. 2). The structures of all complexes were established by X-ray crystal-structure analyses (complex 19b and 20b ; cf. Figs. 6 – 8) and extensive ¹H-NMR measurements (cf. Table 3). In 20b , the two Cr(CO)₃ groups are linked in a `syn'-mode to the highly twisted heptalene π-skeleton. The correspondence of the <sup>1</sup>H-NMR data of 20a with that of 20b indicates that the two Cr(CO)<sub>3</sub> groups in 20a also have a `syn'-arrangement. The thermal behavior of the mononuclear complexes 19a – 19d has been studied at 85° in hexafluorobenzene (HFB). At this temperature, all four complexes undergo rearrangement to the same thermal equilibrium mixture (cf. Table 8). The rates for the thermal equilibration of each complex have been determined by ¹H-NMR measurements (cf. Figs. 9 – 12) and analyzed by seven different kinetic schemes (Chapt. 2). The equilibration rates are in agreement with two different haptotropic rearrangements that take place, namely intra- and inter-ring shifts of the Cr(CO)₃ group, whereby both rearrangements are accompanied by DBS of the heptalene π-skeleton (cf. Scheme 9). All individual kinetic steps possess similar ΔG^≠ values in the range of 29 – 31 kcal⋅mol⁻¹ (cf. Table 8). The occurrence of inter-ring haptotropic migrations of Cr(CO)₃ groups has already been established for anellated aromatic systems (cf. Scheme 10); however, it is the first time that these rearrangements have been unequivocally demonstrated for Cr(CO)₃ complexes of non-planar bicyclic [4n]annulenes, such as heptalenes. The mechanism of migration may be similar to that proposed for aromatic systems (cf. Schemes 10 and 11).     

New Optically Active 2H‐Azirin‐3‐amines as Synthons for Enantiomerically Pure 2,2‐Disubstituted Glycines

The synthesis of novel 2,2‐disubstituted 2H‐azirin‐3‐amines with a chiral amino group is described. Chromatographic separation of the diastereoisomer mixture yielded the pure diastereoisomers (1′R,2R)‐ 4a – e and (1′R,2S)‐ 4a – e (Scheme 1, Table 1), which are synthons for the (R)‐ and (S)‐isomers of isovaline, 2‐methylvaline, 2‐cyclopentylalanine, 2‐methylleucine, and 2‐(methyl)phenylalanine, respectively. The configuration at C(2) of the synthons was determined by X‐ray crystallography relative to the known configuration of the chiral auxiliary group. The reaction of 4 with thiobenzoic acid, benzoic acid, and the dipeptide Z‐Leu‐Aib‐OH ( 12 ) yielded the monothiodiamides 10 , the diamides 11 (Scheme 2, Table 3), and the tripeptides 13 (Scheme 3, Table 4), respectively.