Richman Atkins

Cyclizations at moderate to low dilution. A series of A-tosylated (tosyl = p-toluenesulphonyl Ts) macrocycles may be readily prepared by direct means starting from pre-tosylated reactants (Richman Atkins, 1974). Equation [2.3] summarizes an example of this useful reaction type. Reasonable yields (often considerably better than 50%) of such cyclic tosylated products may be achieved in spite of the fact that such reactions are usually performed at moderate dilution. A number of procedures exist for detosylation of these products to yield the corresponding rings containing only secondary nitrogens a common method has been to treat the tosylated intermediate with hot concentrated sulfuric acid for several days. 

Scheme 3.17 Richman-Atkins synthesis of 1,4,7,10-tetraaza-cyclododecane followed by deprotection of the secondary amine groups (80 per cent yield, OTs = OSO2QH4CH3). 19...

The following procedure for the synthesis of the parent [18]-N402 macrocycle is representative of a direct [2 + 2] Richman-Atkins macrocyclisation.7... 

For the synthesis of aza-thia macrocycles, many of the methods that are available for the synthesis of aza cycles (Chapter 2) or aza-oxa crowns (Chapter 3) are also applicable. Thus the Richman-Atkins co-cyclisation of the ditoluenesulfonamide with an alkylditoluenesulfonate may be used for the synthesis of the [18]-N4S2 ring (Scheme 3.6). In this case, desulfonylation to afford the tetraamine 23 is best carried out with lithium in liquid ammonia.12... 

Developments in the chemistry of /V-tosyl heteronines and similar sulfonamides are connected with their easy accessibility through Richman-Atkins cyclization (Section 14.10.8.3) and synthetic utility through protection/depro-tection sequences. Selective cleavage of sulfonamides was a primary goal of many studies. 

Ditosyl derivative of 1,4,7-oxadiazonane was synthesized from /V,/V -ditosyl diaminoethane and diethylene glycol ditosylate (see Scheme 42, Section 14.10.7.5) <2004T5799> or with l-chloro-2-(2-chloroethoxy)ethane <1998JRM1448>. Similarly, Richman-Atkins cyclization of ditosyl-substituted ethylenediamine with ditosylate of iV,iV-bis(2-hydroxyethyl)-4-methylbenzenesulfonamide gave the functionalized triazonanes <2003OBC2357>. 

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>. 

Large symmetrical triazamacrocycles with 21, 24, and 27 atoms (1,8,15-triazacycloheneicosane, 1,9,17-triazacyclo-tetracosane, and 1,10,19-triazacycloheptacosane) were prepared by Richman-Atkins methodology with cyclization yields of 26 16% <1996JHC2013>. 

The Richman-Atkins tosylamide method also served as a method of choice for the synthesis of 22-membered... 

Tritopic cyclen- and isocyclam- (isocyclam = 1,4,7,11-tetraazacyclotetradecane) based ligands 121 and 122 were prepared according to Scheme 17. Tosylated tren derivative (tren = tris(2-aminoethyl)amine) was cyclized under Richman-Atkins conditions to give the fully tosylated amines in relatively high yield considering the [1+3] reaction <2002JOC9107>. 

A bicyclic azamacrocycle (127) has been prepared from [bisiV-(2-aminoethyl)-tacn)Cun] by reduction of the aminal formed with glyoxal (Scheme 30). The tricyclic ligands (128) and (129) formed by Richman-Atkins synthesis from tetrakis(3-aminopropyl)- and tetrakis(2-aminoethyl)-cyclam, respectively, form binuclear compounds.174... 

Scheme 1. Richman-Atkins type synthesis of the monomethyl-substituted ligand 16 accomplished in an overall yield of-4%.

The process can be repeated by hydrolysis with hydrazine, treatment with tosylchloride, and reaction again with 3-phthalimidopropyl tosylate to form the tripropylene-tetraamine-type compound as shown on the bottom of the sequence. In this way, polyamines with a few tetramethylene, trimethylene, and ethylene bridges can be constructed. The final products will have terminal tosylamines that can be ring-closed using the Richman-Atkins procedure. It is also possible to convert the terminal tosylamines to the tosylates as shown below (Iwata and Kuzuhara, 1985). 

It is interesting to note that replacement of the sodium cations by tetra-methylammonium ion in the Richman-Atkins procedure did not inhibit the reaction as one might expect in a template cyclization but only decreased the yield of the tetraaza-crown to about 50%. Gokel and coworkers suggested that the increase in the yield from 50% to 80% when tetramethylammonium was replaced by sodium does indicate a small template effect by the sodium ion (Gokel et al., 1982). Bogatskii and coworkers used phase-transfer con-... 

B. Ring Closure Using Sulfonamides (Often Called the Richman-Atkins Reaction) 123... 

B. RING CLOSURE USING SULFONAMIDES (OFTEN CALLED THE RICHMAN-ATKINS REACTION)... 

Richman and Atkins (1974) reported the generality of the sulfonamide method to prepare the polyaza-crowns. They used a ditosylate ester starting material rather than a dihalide. A similar reaction was reported at the same time by Cram (1977) in a patent filed in 1974. The so-called Richman-Atkins cyclization reaction is the reaction of the polysulfonamide or its disodium or dipotassium salt with a ditosylate or a dimesylate. The interior sulfonamide... 

Pertosylated peraza-crowns can be prepared by the Richman-Atkins procedure by many pathways depending on the size of the starting materials. 

The key step in the synthesis of macrocyclic chelators based on linear precursors is the cyclization. There are different strategies for this step. One common route is called the Richman-Atkins method (Richman and Atkins 1974). This method uses tosylated polyamines, reacting with dihalogenides or ditosylates. The yields have been reported to range between 40% and 90% for different sizes of macrocyclic polyamines. Later, an alternative route that uses cheaper starting materials for the synthesis of cyclen has been described (Weisman and Reed 1996). Starting from cyclen, the amines could be functionalized by carboxymethylation, which leads to DOTA or derivatives thereof... 

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