Asymmetric deprotonation-substitution of N-Pop-benzylamines using [RLi/(-)-sparteine]. Enantioselective sequential reactions and synthesis of N-heterocycles

Pop-directed asymmetric deprotonation of benzylic amines using [n-BuLi/(-)-sparteine] provides an efficient method for the synthesis of chiral NC alpha and NC alpha,alpha' derivatives with total selectivity with respect to competing allylic and ortho lithiation. The method described herein offers a straightforward route of accessing chiral N-Pop-protected nitrogen heterocycles.     

Syntheses of the first amine-dicarboxyboranes and their bis(methylester) and bis(N-ethylamide) derivatives

Amine-bis(N-ethylcarbamoyl)boranes [A.BH(CONHEt)(2), 3; A = trimethylamine (Me(3)N, a), quinuclidine (Q, b), pyridine (py, f), 4-picoline (pic, g)] have been prepared after deprotonation of [amine-bis(C-hydroxy-N-ethylimidate)hydroboron(2+)] cations (2), which were formed by the hydrolysis of [amine-bis(ethylnitrilium)hydroboron(2+)]tetrafluoroborates (1). Numerous representatives of 3 [A = diethylamine (Et(2)NH, c), piperidine (pip, d), pyrrolidine (pyrr, e), 4-aminopyridine (4-NH(2)-py, h), 4-(dimethylamino)pyridine (DMAP, i), imidazole (Him, j), 1-methylimidazole (Mim, k)] have been prepared by base exchange reactions from 3a. 3a-e are extremely stable in aqueous media, either acidic or alkaline, probably because of the considerable steric hindrance of possible reaction centers. However, they were transformed into amine-dicarboxyboranes [A.BH(COOH)(2), 4a-e] in acidic medium under vigorous conditions (100-130 degrees C). This transformation was accompanied by significant decomposition, probably owing to the protonation on the N atom, resulting in the rupture of the B-N bond. As an exception, 4b, where N atom in a rigid bicycle is not prone to attacks, could be isolated in very good yield. On the other hand, amine-bis(N-ethylcarbamoyl)boranes containing amines with sp(2)-hybridized N atoms (3f-k) undergo complete decomposition under similar conditions probably because of the increased hydridic character of the hydrogen adjacent to boron. Base exchange reactions starting from 4b resulted in the ammonium salts of 4c-e, h, i of composition [A.BH(COOH)(COO(-))][AH(+)], which in turn could be transformed into the diacids 4, except 4h, by protonation. As salt formation indicates, the 4 compounds are stronger acids as univalent acids than the corresponding A.BH(2)(COOH) complexes. 4a-e, i were readily esterified into amine-bis(methoxycarbonyl)boranes (5a-e, i) in methanol, employing a catalytic amount of HBr. 5a-e, i are stable in alkaline medium but are readily hydrolyzed in acidic medium. Hydrolysis of [amine-bis(C-methoxy-N-ethylimidate)hydroboron(2+)] cations did not give the corresponding bisesters 5 in alkaline, neutral, or acidic medium.     

Selective generation of lithiated benzonitriles: the importance of reaction conditions

Lithiated benzonitriles can be generated in high yields from reactions of bromobenzonitriles with n-BuLi in THF under standard cryogenic conditions (ca. -70 degrees C) provided the reverse addition mode is employed. The resultant aryllithiums are fairly stable at temperatures up to -60 degrees C. The formation of lithiated benzonitriles via Br/Li exchange under normal addition mode conditions is plagued by deprotonation and extensive CN-addition reactions. The generation of related aryllithiums from disilylated bromobenzonitriles is comparatively less sensitive to reaction conditions.     

Catalytic CN Bond Alkynylation of N‐Benzylic Sulfonamides with Terminal Alkynes

A new cross‐coupling reaction of N‐benzylic sulfonamides with terminal alkynes for the synthesis of internal alkynes is reported. In the presence of 5 mol% of (Tf)₂NH/Bi(OTf)₃ (1:1), a broad range of N‐benzylic sulfonamides react smoothly with arylacetylenes to afford structurally diverse internal alkynes in moderate to excellent yields. We reasoned that vinyl cations could be formed by the regioselective attack of terminal alkynes with benzyl cations generated in situ from N‐benzylic sulfonamides under acidic conditions, which then eliminated to form a carbon‐carbon triple bond.     

Metal triflate-catalyzed cationic benzylation and allylation of 1,3-dicarbonyl compounds

The rare earth metal and hafnium triflate-catalyzed secondary benzylation and allylation of 1,3-diketones, ketoesters, and ketoamides are described. The procedure was carried out under non-anhydrous conditions. Various 1-phenylethyl cations were generated from substituted 1-phenylethanols using 0.5 mol % of the metal triflates in CH3NO2. The cations reacted with 1,3-diketones and ketoesters to give benzylated products in high yields. Following the GC analysis, the reaction conditions were easily optimized by the selection of catalysts based on the Lewis acidity of the triflates and reaction temperature. A tertiary-alkylated diketone and a corresponding ketoester were also benzylated to afford products with a quaternary carbon atom in 57-84% yield. The ketoamide reactions required stronger Lewis acids than those used in the diketone and ketoester reactions. The reactions of benzylic alcohols possessing various substituents on the aromatic ring and dibenzoylmethane (2b) as a diketone were examined in the presence of Hf(OTf)4. Electron-rich benzylic alcohols reacted with 2b in 86-96% yield, and electron-deficient alcohol gave the desired product in 79-65% yield. Despite possessing a strong electron-withdrawing group, the reaction of 1-(4-nitrophenyl)ethanol gave the corresponding product in 61% yield. It was also possible to use allylic alcohols directly for the allylation of diketone 2b. The catalyst can be recovered by water extraction and reused up to five times.     

Reactivity and acid-base behavior of ring-methoxylated arylalkanoic acid radical cations and radical zwitterions in aqueous solution. Influence of structural effects and pH on the benzylic C-H deprotonation pathway

A product and time-resolved kinetic study of the one-electron oxidation of ring-methoxylated phenylpropanoic and phenylbutanoic acids (Ar(CH2)nCO2H, n = 2, 3) has been carried out at different pH values. Oxidation leads to the formation of aromatic radical cations (Ar.+(CH2)nCO2H) or radical zwitterions (Ar.+(CH2)nCO2-) depending on pH, and pKa values for the corresponding acid-base equilibria have been measured. In the radical cation, the acidity of the carboxylic proton decreases by increasing the number of methoxy ring substituents and by increasing the distance between the carboxylic group and the aromatic ring. At pH 1.7 or 6.7, the radical cations or radical zwitterions undergo benzylic C-H deprotonation as the exclusive side-chain fragmentation pathway, as clearly shown by product analysis results. At pH 1.7, the first-order deprotonation rate constants measured for the ring-methoxylated arylalkanoic acid radical cations are similar to those measured previously in acidic aqueous solution for the alpha-C-H deprotonation of structurally related ring-methoxylated alkylaromatic radical cations. In basic solution, the second-order rate constants for reaction of the radical zwitterions with (-)OH (k-OH)) have been obtained. These values are similar to those obtained previously for the (-)OH-induced alpha-C-H deprotonation of structurally related ring-methoxylated alkylaromatic radical cations, indicating that under these conditions the radical zwitterions undergo benzylic C-H deprotonation. Very interestingly, with 3,4-dimethoxyphenylethanoic acid radical zwitterion, that was previously observed to undergo exclusive decarboxylation up to pH 10, competition between decarboxylation and benzylic C-H deprotonation is observed above pH 11.     

Diastereoselective total synthesis of both enantiomers of epolactaene

A stereocontrolled total synthesis of both the (+)- and (-)-epolactaene ((+)- and (-)-1) enantiomers from tetrahydropyran-2-ol is described. The following reactions in this synthesis are particularly noteworthy: (1) the stereoselective construction of the conjugated (E,E,E)-triene by a combination of kinetic deprotonation and thermodynamic equilibration, (2) the E-selective Knoevenagel condensation of beta-ketonitrile 33 with a chiral 2-alkoxyaldehyde, (3) a diastereoselective epoxidation achieved using a bulky nucleophile (TrOOLi) and an appropriate protecting group, (4) the mild hydrolysis of an alpha-epoxy nitrile by silica gel on TLC facilitated by hydroxyl-mediated, intramolecular assistance.     

Acid-promoted reaction of trimethylsilylketene bis(ethylthio)acetal with imines. Synthesis of gamma,gamma-bis(ethylthio)allylamines

Acid-catalyzed reaction of silylketene dithioacetal 1 with iminium salts or imines 3b,d-h gave the corresponding gamma,gamma-bis(ethylthio)allylamines 2a-h or 5b,d-h in generally high yields. Similar reactions of 1 with (salicylidene)amines 6a-e afforded 4-amino-2,2-bis(ethylthio)chromans 8a-e in good to moderate yields.     

Asymmetric synthesis of anti-homopropargylic alcohols from aldehydes and chiral sulfonimidoyl substituted bis(allyl)titanium complexes through generation and elimination of novel chiral alkylidenecarbene (dimethylamino)sulfoxonium ylides

A new method for the asymmetric synthesis of anti-configured homopropargylic alcohols 1 is described, which features the addition of chiral sulfonimidoyl substituted bis(allyl)titanium complexes 3 to aldehydes, the methylation of sulfonimidoyl substituted homoallylic alcohols 2 at the N-atom, and the elimination of alkenyl (dimethylamino)sulfoxonium salts 7 with LiN(H)tBu. The reaction of isopropyl, cyclohexyl, and methyl substituted allylic titanium complexes 3a-c with benzaldehyde, p-bromobenzaldehyde, p-chlorobenzaldehyde, p-methoxybenzaldehyde, (E)-3-phenylpropenal, and phenylpropynal afforded with high regio- and diastereoselectivities the anti-configured sulfonimidoyl substituted homoallylic alcohols 2a-j, respectively. Only one allylic unit of the titanium complexes 3a-c was transferred in the case of unsaturated aldehydes, and the starting allylic sulfoximines 2a-g were recovered in approximately 50% yield. The methylation of the silyl protected alkenyl sulfoximines 6a-j with Me(3)OBF(4) gave in practically quantitative yields the (dimethylamino)sulfoxonium salts 7a-j, respectively. Salts 7a-e, 7g, 7h, and 7j delivered upon treatment with 2 equiv of LiN(H)tBu the enantio- and diastereomerically pure saturated and unsaturated alkynes 9a-e, 9g, 9h, and 9j, respectively, in high yields. Besides the alkynes the sulfinamide 8 (96% ee) was isolated. Aminosulfoxonium salts 9f and 9i, which carry a CC triple bond, also suffered an elimination under these conditions but did not yield the corresponding diynes. Elimination of salts 7a-e, 7g, 7h, and 7j proceeds most likely through deprotonation at the alpha-position with formation of the novel alkylidenecarbene aminosulfoxonium ylides 19a-e, 19g, 19h, and 19j, respectively. The ylides 19a-e, 19g, 19h, and 19j presumably eliminate sulfinamide 8 with generation of the chiral nonracemic (beta-siloxyalkylidene)carbenes 20a-e, 20g, 20h, and 20j, which suffer a 1,2-H-shift with formation of alkynes 9. Support for the formation of the putative alkylidenecarbenes 20 as intermediates comes from the elimination of the beta-methyl substituted aminosulfoxonium salt 24, which delivered the enantio- and diastereomerically pure 2,3-dihydrofuran derivative 28 upon treatment with LiN(H)tBu in high yield. Here, the putative (beta-siloxyalkylidene)carbene 26 suffers a 1,5-O,Si bond insertion rather than a 1,2-Me shift. Methylation of the alkenyl sulfoximine 6a at the alpha-position with formation of 13 was achieved through deprotonation of the former with formation of the alpha-lithioalkenyl sulfoximine 11a and its treatment MeI. Reaction of the alpha-methylated alkenyl aminosulfoxonium salt 14a with LiNiPr(2) at low temperatures gave the enantio- and diastereomerically pure anti-configured homoallenylic alcohol derivative 15, while reaction of the salt with LiNiPr(2) or LiN(H)tBu at higher temperatures afforded the enantio- and diastereomerically pure nonterminal homopropargylic alcohol derivative 17. Deprotonation of the alkenyl (dimethylamino)sulfoxonium salts 7a and 7b with nBuLi afforded the novel alkylidenecarbene aminosulfoxonium ylides 19a and 19b, respectively, which upon treatment with MeI yielded the methylated aminosulfoxonium salts 14a and 14b, respectively.     

Synthesis of new v-triazolopyrimidinium salts

New v-triazolo[1,5-α]- and v-triazolo[1,5-c]pyrimidinium salts 12a-e, 13a-c have been synthesized via oxidation (i.e. cyclodehydrogenation) of the appropriate pyrimidyl ketone arylhydrazones 3a-e, 6a-c using TBB (2,4,4,6-tetrabromocyclohexa-2,5-dien-1-one) as the reagent. The arylhydrazones were obtained by standard reactions; the Grignard reaction of 2-cyano- and 4-cyanopyrimidine 1a,b, 4a-c gave 2-pyrimidyl- and 4-pyrimidyl ketones 2a-e, 5a-c , which reacted with arylhydrazines to yield the desired ketone arylhydrazones 3a-e, 6a-c.     

Studies on tertiary amine oxides. LXVIII. . Reactions of aromatic N-oxides with 2-substituted 2-oxazolin-5-ones in the presence of acetic anhydride

Quinoline l-oxides 1a-f readily react with 2-phenyl- and 2-methyl-2-oxazolin-5-ones, 2a and 2b , in the presence of acetic anhydride to afford 2-substituted 4-(2-quinolyl)-2-oxazolin-5-ones 3a-h in good yields. Hydrolysis of 3a-f with 10% hydrochloric acid under refluxing conditions gives the corresponding 2-amino-methylquinoline dihydrochlorides 5a-e or monohydrochloride 5f also in good yields. Similar results are obtained from reactions of isoquinoline 2-oxide 9 with 2a,b under the same conditions.     

Aminolysis of Y-substituted phenyl X-substituted cinnamates and benzoates: effect of modification of the nonleaving group from benzoyl to cinnamoyl

A kinetic study is reported for reactions of Y-substituted phenyl X-substituted cinnamates (1a-e and 3a-g) and benzoates (2a-e and 4a-g) with a series of alicyclic secondary amines in 80 mol % H2O/20 mol % DMSO at 25.0 +/- 0.1 degrees C. Reactions of 2,4-dinitrophenyl X-substituted cinnamates (1a-e) and benzoates (2a-e) with amines result in linear Yukawa-Tsuno plots. The rho(X) values are much smaller for the reactions of 1a-e than for those of 2a-e. A distance effect and the nature of the reaction mechanism (i.e., a concerted mechanism for 1a-e) have been suggested to be responsible for the small rho(X) values. The Br?nsted-type plots for the reactions of 2,4-dinitrophenyl X-substituted cinnamates (1a, 1c, and 1e) with amines are curved with a decreasing betanuc value from 0.65 to 0.3-0.4. The reactions of Y-substituted phenyl cinnamates (3a-g) with morpholine also result in a curved Br?nsted plot, while the corresponding reactions of Y-substituted phenyl benzoates (4a-e) exhibit a linear Br?nsted plot. It has been concluded that the curved Br?nsted plots found for the reactions of the cinnamates (1a, 1c, 1e, and 3a-g) are not due to a change in the rate-determining step (RDS) but due to a normal Hammond effect for a concerted mechanism, that is, an earlier transition state (TS) for a more reactive amine or substrate.     

Bis

[formula: see text] The generation of (2-PyMe2Si)2CHLi was easily accomplished by the deprotonation of (2-PyMe2Si)2CH2 using n-BuLi in Et2O. Thus generated (2-PyMe2Si)2CHLi was found to react with a variety of aldehydes and ketones to give the corresponding vinylsilanes in extremely high yields with complete stereoselectivities.     

Effect of o-methyl group on rate, mechanism, and resonance contribution: aminolysis of Y-substituted phenyl X-substituted 2-methylbenzoates

Second-order rate constants have been determined spectrophotometrically for the reactions of 4-nitrophenyl X-substituted 2-methylbenzoates (2a-e) and Y-substituted phenyl 2-methylbenzoates (3a-e) with alicyclic secondary amines in 80 mol % H(2)O/20 mol % DMSO at 25.0 +/- 0.1 degrees C. The o-methyl group in the benzoyl moiety of 2a-e retards the reaction rate but does not influence the reaction mechanism. The Hammett plots for the reactions of 2a-e are nonlinear, while the corresponding Yukawa-Tsuno plots are linear with large r values (1.06-1.70). The linear Yukawa-Tsuno plots suggest that stabilization of the ground-state through resonance interaction between the electron donating substituent X and the carbonyl group is responsible for the nonlinear Hammett plots, while the large r values imply that the ground-state resonance interaction is significant. The reactions of 2a-e resulted in smaller rho(X) values but larger r values than the corresponding reactions of 4-nitrophenyl X-substituted benzoates (1a-e). The small rho(X) value for the reactions of 2a-e (e.g., rho(X) = 0.22) is suggested to be responsible for the large r value (e.g., r = 1.70). The reactions of 3a-e with piperidine are proposed to proceed in a stepwise manner with a change in the rate-determining step on the basis of the curved Br?nsted-type plot obtained. Microscopic rate constants associated with the reactions of 3a-e are also consistent with the proposed mechanism.     

Effect of solvent on the lithium-bromine exchange of aryl bromides: reactions of n-butyllithium and tert-butyllithium with 1-bromo-4-tert-butylbenzene at 0 degrees C

The outcome of reactions of 1-bromo-4-tert-butylbenzene (1), a representative aryl bromide, with n-BuLi or t-BuLi at 0 degrees C in a variety of solvent systems has been investigated. The products of reactions of 1 with n-BuLi vary significantly with changes in solvent composition: 1 does not react with n-BuLi in pure heptane; the exchange reaction to give (4-tert-butylphenyl)lithium, which is slow in pure diethyl ether, is virtually quantitative in heptane containing a small quantity of THF; and the reaction of 1 with n-BuLi in THF leads to considerable coupling. Lithium-bromine exchange is the virtually exclusive outcome of reactions of 1 with t-BuLi in every solvent studied except pure heptane: the presence of a small quantity of any of a variety of structurally diverse ethers (Et(2)O, THF, THP, MTBE) in the predominantly hydrocarbon medium affords (4-tert-butylphenyl)lithium, assayed as tert-butylbenzene, in yields exceeding 97%. The only side products observed from reactions of 1 with t-BuLi are small amounts of benzyne-derived hydrocarbons.     

Ring-closure reactions of 1,2-diaza-4,5-benzoheptatrienyl metal compounds: experiment and theory

2-Alkenylbenzylidene hydrazones 5a-m, which are accessible in good to excellent yields in a four-step synthesis, are converted into 1,2-diaza-4,5-benzoheptatrienyl metal compounds 1a-m by treatment with KO-t-Bu as base. These metal compounds undergo the various types of reactions in good yields and exclusively depending on the nature of substituents R(1) and R(3). Thus, metal compounds 1a-c carrying alkyl substituents R(1) and R(3) form 3H-benzodiazepines 6a-c after electrophilic quench of the intermediate cyclic anion 7 in a 7-endo-trig electrocyclic reaction with a mo?bius aromatic transition structure 1(-)-TS. Similarly, a benzothienyl derivative 5n is converted into diazepine 6d. Potassium compounds 1d-h, which are N-methyl and aryl substituted at R(3), form 1,2-dihydrophthalazines 8a-e in a predominantly charge-controlled 6-exo-trig cyclization reaction. In contrast, aryl-aryl-substituted systems 5i-m did not lead to cyclic products upon deprotonation, but the intermediate open-chain metal compounds 1i-m were trapped by acid chlorides at N1 to yield the hydrazides 10a-e. We interpret thermodynamics and kinetics of these reactions in the context of the Baldwin rules on the basis of quantum chemical calculations and discuss the transition structures considering the results of NICS and NBO-charge calculations. Examples of the products 6, 8, and 10 could be characterized by X-ray diffraction.     

DDQ-mediated direct oxidative coupling of amides with benzylic and allylic sp3 C–H bonds under metal-free conditions

A simple and efficient method for the direct oxidative coupling of amides with benzylic and allylic sp³ C–H bonds using DDQ as an oxidant is described. A range of amides including benzamide, benzyl carbamate, and substituted sulfonamides reacted efficiently with various benzylic and allylic substrates under metal free conditions to afford amidation products in good to excellent yields.     

Direkte und indirekte metallierung von endo-dicylopentadien. Sn- und C-NMR studie stannylierter folgeprodukte

endo-Dicyclopentadiene (1) can be metalated by use of simple procedures with good overall yields. The attack occurs at the various vinyl, rather than at the allyl, positions of 1 as was confirmed by trapping the carbanions with Me₃SnCl. When t-BuLi/TMEDA are used, the 8- and 9-stannyl derivatives (3 and 4) are formed, whereas an excess of n-BuLi/t-BuOK leads to doubly stannylated derivatives with Me₃Sn groups in position 4/8 (6), 4/9 (7), and 3/9 (8) in addition to 3 and 4. Furthermore the latter reaction yields 5,5-bis(trimethylstannyl)cyclopentadiene (5). With stoichiometric amounts of n-BuLi/t-BuOK the formation of 3 and 4 predominates over that of 5–8. 5 is obtained from 1 after deprotonation at the allyl position, followed by an extremely fast retro-Diels-Alder reaction and then by further deprotonation. This follows from two experiments: (1) exo- and endo-5-trimethylstannyl-endo-dicyclopentadiene (11 and 12) which are synthesized from 1 in three steps give cyclopentadienyllithium and 1 when treated with methyllithium at −78°C; (2) cyclopentadiene reacts with an excess of n-BuLi/t-BuOK and Me₃SnCl to give 5. When 12 is heated syn-10-trimethylstannyl-endo-dicyclopentadiene (13) is obtained. The eight stannyl derivatives of 1 are identified mainly from the following NMR parameters: δ(¹¹⁹Sn), δ(¹³C), δ(¹H), ⁿJ(^119/117Sn---¹³C), and ⁶J(¹¹⁹Sn---^119/117Sn). The ¹³C NMR satellite spectrum of 1 yields the isotope shifts ¹Δ¹³(i(¹³C(j)) and ¹J(¹³C---¹³C). The latter lead to the revision of earlier signal assignments.     

Synthesis, structures, and olefin polymerization capability of vanadium(4+) imido compounds with fac-N3 donor ligands

One-pot reactions of V(NMe2)4 with a range of primary alkyl- and arylamines RNH2 and Me3SiCl afforded the corresponding five-coordinate vanadium(4+) imido compounds V(NR)Cl2(NHMe2)2 [R = 2,6-C6H3(i)Pr2 (1a, previously reported), 2-C6H4(t)Bu (1b), 2-C6H4CF3 (1c), (t)Bu (1d), Ad (Ad = adamantyl, 1e)]. The crystal structures of 1b (two diamorphic forms) and 1c featured N-H...Cl hydrogen-bonded chains. Reaction of 1a-e with the neutral face-capping, N3 donor ligands TACN (TACN = 1,4,7-trimethyltriazacyclononane) or TPM [TPM = tris(3,5-dimethylpyrazolyl)methane] gave the corresponding six-coordinate complexes V(NR)(TACN)Cl2 (2a-e) and V(NR)(TPM)Cl2 (3a-e). The X-ray structures of 2b, 2c, 2d, 3b, 3c, and 3e were determined. When activated with methylaluminoxane, certain of the complexes V(NR)(TPM)Cl2 (3) formed moderately active ethylene polymerization catalysts, whereas none of the compounds V(NR)(TACN)Cl2 (2) were active.     

Ph2P(BH3)Li: from ditopicity to dual reactivity

A multinuclear NMR study shows that the deprotonation of diphenylphosphine-borane by n-BuLi in THF leads to a disolvated lithium phosphido-borane Ph(2)P(BH(3))Li of which Li(+) is connected to the hydrides on the boron and two THF molecules rather than to the phosphorus. This entity behaves as both a phosphination and a reducing agent, depending on the kinetic or thermodynamic control imposed to the reaction medium. Density functional theory computations show that H(2)P(BH(3))Li exhibits a ditopic character (the lithium cation can be in the vicinity of the hydride or of the phosphorus). It explains its dual reactivity (H- or P-addition), both routes going through somewhat similar six-membered transition states with low activation barriers.