Tosylamides, cyclization

The reaction can be done intramolecularly. N-Benzyl pent-4-ynamide reacted with tetrabutylammonium fluoride to an alkylidene lactam. Similar addition of a tosylamide-alkene, with a palladium catalyst, led to a vinyl Al-tosyl pyrrolidine. Similar cyclization reactions occur with tosylamide-alkynes. ... 

Larock has developed a new catalyst system for the Pd-catalyzed cyclization of olefinic tosylamides. Whereas typical conditions require either stoichiometric amounts of Pd(II) salts or catalytic amounts of Pd(II) in the presence of benzoquinone as a reoxidant, the new catalyst system utilizes catalytic Pd(OAc)2 under an atmosphere of O2 in DMSO with no additional reoxidant <96JOC3584>. Although o-vinylic tosylamides 76 can be cyclized to Af-tosylindoles 77 using this catalyst system, PdCla/benzoquinone is more effective for such cyclizations. Interestingly, in the case of o-allylic tosylanilides, the cyclization can be modulated to afford either dihydroindole or dihydroquinoline products. In a related approach involving a common 7i-aUyl Pd-intermediate, 2-iodoanilines were coupled with vinylic cyclopropanes or cyclobutanes in the presence of a Pd catalyst to afford dihydroindoles <96T2743>. 

Gyclization/hydrosilylation of enynes catalyzed by rhodium carbonyl complexes tolerated a number of functional groups, including acetate esters, benzyl ethers, acetals, tosylamides, and allyl- and benzylamines (Table 3, entries 6-14). The reaction of diallyl-2-propynylamine is noteworthy as this transformation displayed high selectivity for cyclization of the enyne moiety rather than the diene moiety (Table 3, entry 9). Rhodium-catalyzed enyne cyclization/hydrosilylation tolerated substitution at the alkyne carbon (Table 3, entry 5) and, in some cases, at both the allylic and terminal alkenyl carbon atoms (Equation (7)). 

Shibata and co-workers have reported an effective protocol for the cyclization/hydrosilylation of functionalized eneallenes catalyzed by mononuclear rhodium carbonyl complexes.For example, reaction of tosylamide 13 (X = NTs, R = Me) with triethoxysilane catalyzed by Rh(acac)(GO)2 in toluene at 60 °G gave protected pyrrolidine 14 in 82% yield with >20 1 diastereoselectivity and with exclusive delivery of the silane to the G=G bond of the eneallene (Equation (10)). Whereas trimethoxysilane gave results comparable to those obtained with triethoxysilane, employment of dimethylphenylsilane or a trialkylsilane led to significantly diminished yields of 14. Although effective rhodium-catalyzed cyclization/hydrosilylation was restricted to eneallenes that possessed terminal disubstitution of the allene moiety, the protocol tolerated both alkyl and aryl substitution on the terminal alkyne carbon atom and was applicable to the synthesis of cyclopentanes, pyrrolidines, and tetrahydrofurans (Equation (10)). 

Yu and co-workers have expanded upon Ojima s work through development of an effective Rh-catalyzed protocol for the cyclization/hydrosilylation of allenyl carbonyl compounds to form silylated vinylcycloalkanols and heterocyclic alcohols.For example, reaction of tosylamide 44 (X = NTs, R = H, n= ) and triethylsilane catalyzed by Rh(acac)(GO)2 (1 mol%) under GO (10 atm) at 70 °G for 8h gave the silylated vinyl pyrrolidinol 45 (X = NTs, R = H, n= ) in 74% yield with exclusive formation of the m-diastereomer (Equation (29)). The rhodium-catalyzed reaction was also effective for the cyclization of alleneones and for the formation of carbocycles, oxygen heterocycles, and six-membered cyclic alcohols (Equation (29)). However, Rh-catalyzed cyclization/hydrosilylation of allenyl carbonyl compounds that possessed substitution on an allenyl carbon atom was not established (Equation (29)). The efficiency of the Rh-catalyzed reaction of allenyl carbonyl compounds depended strongly on GO pressure. Reactions run under 10 atm GO were more efficient than were... 

The predominant formation of five-membered carbocydes or heterocycles 122 (Scheme 50) via a sequential conjugate addition-carbene insertion pathway is generally observed in the reactions of the appropriate alkynyliodonium salts 119 (R = long alkyl chain or other group with C-H bond available at C5) with various relatively hard nucleophiles. Typical nucleophiles used to initiate these selective cyclizations are enolate, azide, sulfinate, tosylamide, thioamide and some other anions. 

A similar intermolecular cyclization was recently utilized in the synthesis of highly substituted dihydropyrrole derivatives [133 -135]. In a specific example, the addition of pentadienyltosylamide derivatives 177 to propynyl(phenyl)iodo-nium triflate initiates a sequence of transformations that furnishes the complex, highly functionalized cyclopentene-annelated dihydropyrrole products 178 in moderate yields with complete stereoselection (Scheme 66). Under similar reaction conditions, the isomeric isoprene-derived tosylamide 179 reacts with propynyl(phenyl)iodonium triflate to give azabicyclo[3.1.0]hexane 180 as the final product [134]. 

A gold(I)-catalyzed domino reaction sequence involving pentenynyl tosylamides led to the formation of 2,3-disubstituted pyrroles containing a quaternary center in the 2-substituent <07OL3181>. The mechanism of the reaction involved a 5-endo-dig cyclization followed by an aza-Claisen rearrangement. 

Ten-membered. V,.V, ., -tris(tosyl)-l,4,7-triazacyclodecane 31 was obtained by Richman-Atkins reactions of fully tosylated iV,iV -bis(ethanol-2-yl)-l,3-diaminopropane with tosylamide in nearly quantitative yield (Scheme 1) <2001EJ04233>. Interestingly, reaction with benzylamine afforded the analogous macrocyclic product 32 in much lower yield (25%) <2001EJ04233>. Similar 10-membered triazamacrocycle 33 was obtained by the cyclization with propyleneglycol bis(triflate) in 33% yield (Scheme 1) <1999TL7687>. 

Principally, the same ring closure reactions as for tetraazacycles (Section 14.11.5.3) can be applied for preparation of larger polyazamacrocycles however, mostly tosylamide and peptide-like syntheses are employed. In addition, metal template or cyclization reactions between carbonyl compounds and amines (and reduction of intermediate Schiff base) are often utilized. 

For larger cycles, tosylamide or high-dilution amide condensations were mostly used. In addition, cyclization of amines and aldehydes to get Schiff bases (mostly for [2+2] or [3+3] cyclizations) is convenient. Metal template synthesis is useful only in special cases. Polycycles are conveniently prepared from appropriately protected cycles. 

Nagata s method. Reduction of the ketone with sodium borohydride stereoselec-tively led to the alcohol, which on repeated chromatography on basic alumina cyclized to the iminoether, 165. Its conversion into 14-oxodendrobine (97) was achieved by tosylation to the tosylamide and subsequent basic hydrolysis. The authors developed an alternative route from cyanoketone 164 to 14-oxodendrobine (97) by hydrolyzing the nitrile under acidic conditions. The acid formed was esterified with diazomethane and the ketone 166 was reduced stereoselectively with sodium borohydride. Subsequent saponification and acidic lactonization led to 14-oxodendrobine (97). Inubushi et al. also used Borch s method to convert 14-oxodendrobine (97) into dendrobine (82) via the lactimether 167 and reduction. 

The reaction of secondary sulfonamides with carboxylic acids in the presence of DCC and4-pyrrolidinopyridine affords N-tosylamides. Also intramolecular cyclization to lactames is achieved using DCC. 

Similar results were also obtained starting from 1,4-hexadiene in this case no trace of four-mem-bered heterocycles was observed. For example, when carbamates or tosylamides were reacted with 1,4- or 1,5-hexadiene by using mercury(II) nitrate as the electrophile in dichloromethane, the thermodynamically more stable civ-.V-substituted 2,5-dimcthylpyrrolidincs 8 were obtained after reductive cleavage. This result is ascribed to a double A1,2 strain in the cyclization which occurs under thermodynamic control90,91. 

The hydroamination reactions which are assisted or catalyzed by transition metal species can be utilized in the cyclization of unsaturated amines. Palladium(II) is not recommended for such transformations, since low yields were obtained even using stoichiometric amounts of palladium chloride47. Since an enamide is formed by /J-hydride elimination, a reduction step must be performed to obtain the saturated nitrogen heterocycle. A catalytic cyclization reaction, analogous to the Wacker process, was performed from /V-alkenyl tosylamides, such as 1, using... 

In 1992, Parker and Fokas reported the short step (11 steps) synthesis of racemic dihydroisocodeine, which completes a formal synthesis of codeine and morphine [58]. The key feature of their synthesis are (1) a construction of an aryl ether moiety (connection of the A and C rings) by Mitsunobu reaction, (2) a tandem radical cyclization of aryl bromide possessing the C-ring precursor to generate the A-B-C-E ring of morphine, and (3) a hydroamination for the construction of the D-ring by the reaction of a tosylamide with Li/NH3. In 2006, they reported the chiral version of the synthesis of dihydrocodeinone [59]. 

The thiazolium-catalyzed addition of an aldehyde-derived acyl anion with a Michael acceptor (Stetter reaction) is a well-known synthetic tool leading to the synthesis of highly funtionalized products. Recent developments in this area include the thiazolylalanine-derived catalyst 191 for asymmetric intramolecular Stetter reaction of a,P-unsaturated esters <05CC195>. However, these cyclizations proceed only in moderate enantioselectivities and yields even under optimized conditions. Thiazolium salt 191 has been used successfully for enantioselective intermolecular aldehyde-imine cross coupling reactions <05JA1654>. Treatment of tosylamides 194 with aryl aldehydes in the presence of 15 mol% of 191 and 2... 

Changing the metal carbonate also affected intramolecular cyclization to form the 10-membered macrocycle with three nitrogen atoms in the ring. Isolated yields were 0%, 21%, 75%, 75%, and 0% using lithium, sodium, potassium, cesium, and silver ions, respectively (Chavez and Sherry, 1989). This indicates that potassium and cesium carbonates are excellent bases for the deprotonation of the tosylamides in DMF and that a template effect is not the most important factor in this reaction. 

Cyclization reactions using tosylamides and ditosylates or dihalides is dependent on the base strength, as was pointed out by Chavez and Sherry (1989). If the base does not deprotonate the tosylamide, a reaction does not take place. It is also difficult to compare cyclization yields using various metal bases because of a concomitant decomposition of the ditosylate or dihalide coreactants in basic conditions at higher temperatures. This problem will be discussed again in the next chapter on the most common methods for the syntheses of the aza-crowns. 

The first use of a tosylamide in a cyclization reaction was reported nearly 100 years ago in German patents for the preparation of 1,4-ditosylpiperazine by Marckwald and Droste-Huelshoff (1898). Azetidine was also prepared by this process, as well as 1,5-diazacyclooctane using the appropriate halide and tosylamide (Bleier, 1899 Howard and Marckwald, 1899). A similar method was applied to macrocycles by Stetter and Roos (1954, 1955) when they reported the 2 2 cyclization reaction of an o ,(ij-dihalide with the dipotassium salt of an aromatic bis-sulfonamide as shown. Ring closure of an A-tosyl... 

Treatment of l,2-bis(2-iodoethoxy)ethane with the sodium salt of tosylamide gave the A-tosylaza-9-crown-3 (1 1 cyclization) and A,A -ditosyldiaza-18-crown-6 (2 2 cyclization) in 25% and 5% yields, respectively. Using the corresponding dichloro starting material, yields of 32% (9-crown-3) and 15% (18-crown-6) were realized. Rasshofer and Vogtle (1978) isolated only the diaza-18-crown-6 cycloadduct. Bis[2-(2-bromoethoxy)ethyl]cther gave only the A-tosylaza-12-crown-4 (1 1 cyclization) product. 

The reaction rate for the formation of small cyclic amines from open-chain precursors varies according to ring size as follows 5 members > 3 > 6 > 7 > 4 (Di Martino et al., 1985). This rule does not apply if four or more bonds are formed as in 2 2 and higher-order cyclizations (Juaristi and Madrigal, 1989). Thus, only a minimal yield of a 16-membered macrocycle was obtained when 1,3-dibromopropane was reacted with tosylamide. In a similar manner. 

Tandem cyclization. Using LHMDS as base the tetracycUc precursor of paieitropone is constructed from a biaryl. After addition of the tosylamide anion to an iodonioalky ne triple bond to generate an alkyUdenecarbene, addition across an aromatic ring follows. ... 

Azetidines and pyrrolidines. Base-promoted cyclization of epoxy tosylamides is sensitive to the structures of the substrates. Thus products having either a primary or a secondary hydroxyl group may be obtained. 

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