Amidation tosylamide

The conjugate hydrosilylation of a,/S-unsaturated amides can be carried out in high yields with PhSiH3/Mo(CO)6 (Eq. 297)450 or Ph2SiH2/ZnCl2/Pd(PPh3)4.436 Primary, secondary, and tertiary amides are equally reactive 450 The reduction of a J3 -tribu ty I s (annyl-a, /3 -unsaturatcd tosylamide is also reported 469... 

Intramolecularity was the next issue to be probed within the context of alkynyliodonium salt/nucleophile addition reactions.53 1 No prior history was available to guide us, and so the prospects for success remained uncertain. Of primary concern was the potential for iodonium salt/base destructive interactions in competition with the desired N-H deprotonation reaction. A substrate that bore some resemblance to key portions of the agelastatin precursor 33 was prepared (Scheme 6), compound 39. This species duplicated the alkynyliodonium/"amide" pairing of the real system, but it lacked the complex piperazine carbene trap of 33. The tosylimide (pre)nucleophile was proposed as a compromise between what we really wanted (an N-methyl amide) and what would likely work (a tosylamide). Simple treatment of 39 with mild base effected the desired bicyclization to afford the tosylimide product 41 in decent yield. A transition state model 40 for C-H insertion that features an equatorial phenyl unit might rationalize the observed sense of diastereoselectivity. So, at least for 39, no evidence for possible interference by iodonium/base reactions was detected. 

Feldman and co-workers developed a nicely designed intramolecular version of the MCI reaction [Eq. (108)] [190]. Treatment of the tosylamide-bearing alkynylstannane 118 with PhI(CN)OTf 19 gave via ligand exchange a labile alkynyliodane 119, which on exposure to a base undergoes an intramolecular tandem MCI reaction to afford the amide 120. Hydroxyalkynyl-A3-iodanes similarly undergo the intramolecular MCI reaction [191]. 

The transition metal catalyzed synthesis of arylamines by the reaction of aryl halides or tri-flates with primary or secondary amines has become a valuable synthetic tool for many applications. This process forms monoalkyl or dialkyl anilines, mixed diarylamines or mixed triarylamines, as well as N-arylimines, carbamates, hydrazones, amides, and tosylamides. The mechanism of the process involves several new organometallic reactions. For example, the C-N bond is formed by reductive elimination of amine, and the metal amido complexes that undergo reductive elimination are formed in the catalytic cycle in some cases by N-H activation. Side products are formed by / -hydrogen elimination from amides, examples of which have recently been observed directly. An overview that covers the development of synthetic methods to form arylamines by this palladium-catalyzed chemistry is presented. In addition to the synthetic information, a description of the pertinent mechanistic data on the overall catalytic cycle, on each elementary reaction that comprises the catalytic cycle, and on competing side reactions is presented. The review covers manuscripts that appeared in press before June 1, 2001. This chapter is based on a review covering the literature up to September 1, 1999. However, roughly one-hundred papers on this topic have appeared since that time, requiring an updated review. 

In an extension of the above studies involving oxygen atom transfer, Breslow and Gellman701 have carried out a related amidation involving tosylamidation of cyclohexane to yield iV-cyclohexyl-toluene-p-sulfonamide in the presence of [MnCl(TPP)] equation (19). 

In principle, any compound prepared by a ring-closure reaction in Section 14.11.5.3 and substituted with a removable substituent on ring nitrogen atoms can serve as a protected cycle. This is particularly true of a full range of the cyclic amides and sulfonamides (mostly tosylamides). Examples of the approach are 172 and 173 prepared by the tosylate method from tosylated and benzylated precursors <1995T1197>. Protected 16-membered tram 1,9-dibenzyl-l,5,9,13-tetraazacyclohexadecane was also obtained in this way <1998SC285>. 

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. 

Under identical reaction conditions by using CS2CO3 it was possible to isolate 7b in quantitative yield as an NMR pure product, whereas by application of Rb2C03 only an impure product in 70% yield was obtained (Table 3) [19]. By addition of other alkali metal carbonates, even after ten days of reaction time, only unsatisfactory yields below 10% could be obtained, whereas in the synthesis of the tris(amide) 11 applying K2CO3 as base the yields of the Cs procedure were reached [27]. This was attributed to the insufficient basicities of these carbonates, which did not allow complete deprotonation of these tosylamides [19]. 

Direct reductions of tosylamides were studied29,32,57 in both aprotic and protic media in order to control and understand the role and influence of the proton donor and its concentration in the catholyte on the product distribution. Table 7 demonstrates that the absence of a proton source leads to the recovery of approximately 50% of the starting tosylamide. It appears then that amide may play the role of a proton donor toward the electrogenerated base formed by the two-electron scission. Tosylamide deactivated by loss of a proton does not suffer any other electron transfer. 

Transacylation of amines. The effectiveness varies and good yields of products are obtained by using activated amides (imides, A -tosylamides). 4-Tosylaminobu-tanoylation " of amines with iV-tosylpyrrolidone proceeds much more smoothly. 

The allylic alcohol was subjected to an Eschenmoser-Claisen rearrangement with dimethylacetamide dimethylacetal to introduce the C14 substituent in a stereoselective manner. Reduction of the amide to the corresponding aldehyde with phenyl silane in the presence of Ti(0/Pr)4 was followed by an acid-promoted closure of the C-ring of codeine. In order to prevent N-oxidation, the amine was converted to the corresponding tosylamide, via debenzylation and treatment with tosyl chloride, before the allylic alcohol was introduced by the reaction of the alkene with selenium dioxide (65). The stereochemistry of the C6 hydroxy functionality was corrected by applying the well-known oxidation/reduction protocol [46, 60] before the benzylic double bond was reductively removed under Birch conditions. Codeine (2) was obtained in 17 steps with an overall yield of approximately 0.6%. 

Allylic silanes can be converted into allylic tosylamides by the reaction with PhINTs in the presence of copper salts. In particular, the copper(I)-catalyzed enantioselective amidation of the chiral ( )-crotylsilanes 659 (Scheme 3.263) has been used in the asymmetric synthesis of ( )-olefin dipeptide isosteres [806]. 

Aliphatic amines coordinate to electrophilic Pd(II) too strongly to undergo aminopalladation, and the aminopalladation is possible only in a special case. On the other hand, amides such as tosylamide, acetamide, and carbamates react more easily than free amines, because amidation reduces electron density and... 

Synonyms 4-Methylbenzenesulfonamide p-Methylbenzenesulfonamide PTSA p-Toluenesulfamine 4-Toluenesulfanamide p-Toluenesulfana-mide Toluene-4-sulfonamide p-Toluenesulfonylamide Tolylsulfona-mide p-Tolylsulfonamide To amide p-Tosylamide... 

Toluenesulfonamide/epoxy resin. See Tosylamide/epoxy resin Toluenesulfonamide/formaldehyde resin. See Tos amide/formaldehyde... 

Few examples of intramolecular additions of amines to alkenes catalyzed by late transition metals have been published more examples of the additions of amides, carbamates, and tosylamides to alkenes catalyzed by this type of complex have been reported. Addition of a secondary amine across a tethered olefin catalyzed by a simple platinum-halide complex is shown in Equation 16.65a. A more recent catalyst based on [Rh(COD)JBF and a biaryldialkylphosphine leads to cyclizations of aminoalkenes with greater scope (Equation 16.65b). These reactions occur to form five- and six-membered rings, with or without groups that bias the system toward cyclization. They also occur with both internal and terminal olefins and with both primary and secondary amines. 

The synthesis of ( )-Epibatidine 23b and analogs thereof was realized by regioselec-tive chloroacetoxylation of 2-aryl-l,3-cyclohexadiene.f" Subsequent stereoselective substitution of the chloro group by tosylamide with either retention or inversion provided both stereoisomers of the aminoalcohol derivative. Highly stereoselective hydrogenation of the allylic amides gave the requisite stereoisomers for synthesis of the exo- and endo-isomers (Scheme 16). 

Related with the previous synthesis, an FC aminoalkylation through a tosyliminium ion allowed the total synthesis of ( )-schefferine (Scheme 2.6) [7], which is a phenolic alkaloid isolated from Schefferomitra subaequalis, a liana climber found on rain forest trees. The known amidal 41 was treated at -78°C with 4-allyl-l,2-dimethoxybenzene (42) and BF Et O to regioselectively give 43 in 88% yield. The allylic chain of the aromatic ring was then modified to furnish alcohol 44, which after deprotection of the tosylamide was cyclized via a Mitsunobu reaction to give ( )-schefferine (46). 

The commonly used 2.2.2-cryptate is prepared by condensing triethylene glycol dichloride with tosylamide [49]. This affords the doubly N-protected macrocyclic aminoether 4. Detosylation yields the compound containing secondary nitrogen atoms (5). Double amide formation at high dilution affords the bicyclic structure 6 which can be reduced to the desired cryptate, 7. The sequence is formulated in equations 1.20-1.22. 

Aliphatic amine derivatives such as amides, carbamates and sulfonamides also participate in Pd - catalyzed intramolecular C-N bond formation. The relative reactivity of these amino nucleophiles toward cyclization has been evaluated in the PdCL-catalyzed cyclization of iV-protected 4-pentenylamines and 5-hexenylamines, and it was found to be urea > carbamate > tosylamide > benzamide. The PdCl2(CH3CN)2-catalyzed dehydrative cyclization of alkenyl urethanes bearing an allylic hydroxyl group has been elegantly applied to the synthesis of chiral piperidine alkaloids. The cyclization reaction occurs with complete stereocontrol in good yields in the presence of 15-20 mol % of catalyst without any reoxidant (eq 16). 

Nitrogen nucleophiles such as amines, and in intramolecular reactions amides and tosylamides, readily add to alkenes complexed to Pd derived from PdCl2 (RCN)2 with reactivity and regiochemi-cal features paralleling those observed for oxygen nucleophiles. Intramolecular nucleophilic attack by heteroatom nucleophiles also occurs in conjunction with other palladium-catalyzed processes presented in the following sections. 

In this manuscript we disclose new synthetic methodology to prepare a member of a class of tetrasubstituted imidazole p38 inhibitors. The optimal route involves a thiazolium catalyzed cross acyloin-type condensation of a pyridinealdehyde with an iV-acylimine. The pyridinealdehyde was prepared in 3 steps and 68% yield from 2-chloro-4-cyano pyridine. The tosylamide precursor to the iV-acyl imine was prepared in two steps and 93% yield from isonipecotic acid. We have demonstrated the scope and some preliminary mechanistic studies concerning this new reaction. The resulting a-keto-amide is then cyclized with methyl ammonium acetate to provide the desired tetrasubstituted imidazole. Cbz deprotection and formation of a pharmaceutically acceptable salt completes the synthesis in 6 steps and 38% overall yield. 

Carrying out the reaction of a distinct aldehyde (23) and tosylamide 21 in the presence of a completely differentiated keto-amide 35 provided only the product 24 from coupling of aldehyde 23 and tosyl amide 21 and not any of the components from the ketoamide 35 added at the start of the reaction. We performed this experiment several times and independently prepared samples of the crossover products and demonstrated that these were not present in these reactions. 

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