Relay processes

We used the radical relay process, chlorinating C-9 and then generating the 9(11) double bond, in a synthesis of cortisone 91 [158]. This is a substitute for manufacturing processes in which C-9 or C-ll are hydroxylated by biological fermentation. Also, with templates that directed the chlorination to C-17 of 3a-cholestanol, such as that in 90, we were able to remove the steroid sidechain [159-162]. Using an electrochemical oxidation process, we could direct chlorination by simple chloride ion with an iodo-phenyl template [163]. A general review of the processes with iodophenyl templates has been published [164]. 

The radical relay process also works with other template types. Thus, the thioether unit in 92 directed chlorination of C-14 by S02C12 [165]. Also, the sulfur in the thiox-anthone template of 93 directed the radical relay process to C-9 [166]. The thiophene sulfur in 94 was able to direct chlorination to C-9 in all three attached steroids [167]. In all these cases, an intermediate is formed with a chlorine atom bonded to sulfur. 

A chlorine atom could also coordinate to the nitrogen of the pyridine template in compound 95, directing chlorination to C-9 in a radical relay process [168]. Spectro-... 

PhICl2 is the chlorinating agent in the novel template directed radical relay process of remote regioselective chlorination of steroids introduced by Breslow. In this method a... 

The scope of the Cu-catalyzed cycloaddition between propargylamines and electron-deficient olefins in the presence of catalytic amounts of a copper salt was subsequently expanded to a one-pot, three-component coupling strategy involving phenols as third components [65]. In this case, reactive Michael acceptors such as ethyl 2-aryl- or alkylsulfonyl cinnamates 57 are involved in the process. This sequence leading to 3(4)-phenoxymethyl pyrrolidines 60 and their isomeric pyrrolidines 61 comprises of the relay process of... 

Diaiyl sulfide templates have also been used to direct chlorinations. The selectivities indicate that the chlorine atom is bound to the sulfur, but the yields are not as good as those with aryl iodide templates. The problem is that the sulfur gets oxidized under the reaction conditions. As expected, a thiophene ring is more stable to oxidation and its sulfur atom can still bind chlorine in a radical relay process." The best sulfur template so far examined is the thioxanthone system (Scheme 20). Thus with 3 equiv. PhICh compound (18) undergoes directed C-9 chlorination in 100% conversion, affording a 71% yield of the A iO-alkene sifter base treatment, along with some polar products from excessive chlorination. The thioxanthone template can be recovered unchanged. 

Ring closing and cross metathesis allow the rapid synthesis of simple cyclic and acyclic systems. The metathesis activity that is now possible using well-defined catalysts allows for the rapid generation of complexity from simple starting materials by relay processes and combinations of metathesis steps. Many of these reactions have been recognized only recently, are now beginning to be used in complex synthetic transformations. A few of these types of reactions will be outlined here to demonstrate the power of these multistep, relay processes. In these processes, an initial metathesis step leads to a new carbene that results in further transformations of the substrate. 

The dynamics of the rotor speed can be conveniently analysed and adjusted by feeding a signal from the rotor motion monitor (via an optical fibre) to a console ADC (Fig. 7). The corresponding spectra are shown in Fig. 8. The faster sweep clearly reduces K12, and to a lesser extent K13. Both direct complementary peaks (1-Kmn) and relayed peaks depend on the product of complementary transfer coefficients, and correlate well with the expected influence of the sweep rate variation. The observed relay process can be shorted by proton-driven spin diffusion. Consequently, efficient rotation-speed independent (or carefully synchronized) decoupling is required during the entire mixing period. 

Ingenious application of remote oxidation has opened the way to a novel and potentially useful degradation of 5a-cholestan-3a-ol to 3a-hydroxy-5a-androstan-17-one ( androsterone ). The radical relay process, whereby photolysis of an iodoaryl ester with iodobenzene dichloride introduces a chlorine atom or unsaturation into the steroid nucleus, has been adapted by use of the 3a-(4 -iodobiphenyl-3-carboxylate) (301). The size of this ester grouping allows the iodine atom to come... 

Arylamines undergo. V-contains titanium tetraisopn the amino group is unhinder Homoallyl alcohols. homoallylic alcohols in the three-component condensat moiety from allene and ary 1 indium. A relayed process tl intricacy of such a reaction... 

In this work a reagent, an aryl iodide dichloride, was directly attached to the substrate through a tether, but it had disadvantages. With such a scheme only stoichiometric amounts of the reagent could be used, and the reactions led to some recovered starting material. Thus we considered whether a new process was possible in which we would use both a tether and a template to direct halogenations. We decided to try to invent what we called a radical relay process. 

Since this study led to a number of extensions, it is desirable to explain why the process works, and what its advantages are. The rate advantage of a radical relay process is that the hydrogen abstraction is intramolecular, rather than the intermolecular abstraction that would occur without the relay by the template. However, this explains it only in part, since the relaying of a chlorine atom from the radical in solution to the iodine of the template is of course an intermolecular process. Why is the two-step sequence - intermolecular chlorine atom transfer, then intramolecular hydrogen abstraction - faster than an intermolecular hydrogen abstraction by the free radical in solution The answer is relat-... 

The practical advantages of the radical relay process over the use of a tethered arylio-dine dichloride reagent are several. First of all, an excess of the solution chlorinating agent can be used, so complete conversion of the substrate to product is achieved. Secondly, there is no need to premake an attached aryl dichloride by using CI2, so sensitive substrates can be used. Finally, other templates can be used that can capture and relay a chlorine atom but cannot themselves be converted to dichloride reagents. These will be described later. 

Some variants on the simple template-directed chlorination were also developed. For example, a steroid carrying a tethered iodophenyl group was chlorinated by electrolysis of a solution carrying chloride ion [54]. In this case, the electrolysis furnished CI2 in solution to carry a radical relay process and electrolysis also initiated the radical process by one-electron oxidation of the iodophenyl group. As another variant, the radical relay mechanism requires that it be a chlorine atom that attaches to the iodine or pyridine or sulfur to abstract hydrogen, since a complexed bromine atom is not reactive enough, but the new bond to the substrate does not have to be a carbon-chlorine link. That bond is formed by untemplated attack of the substrate carbon radical on a reagent in solution and, with an appropriate sequence of tandem reactions, other atoms can be linked to the substrate. 

The evidence that this relaying process occurs is that in some reactions the kinetic chain length is demonstrably considerable, while the average molecular w eight of the polymer formed is relatively much smaller than would correspond to it. 

In this chapter, we present unique aspects of the rearrangement with a focus on (1) the production of carbanions under mild conditions, (2) the generation of synthetically valuable enol silyl ethers that are often the products, (3) the potential for incorporation of die Brook rearrangement in tandem and sequential anion relay processes, and (4) the utility of the rearrangement in generating chiral, configurationally stable carbanions. 

As we have described elsewhere [9], we were able to use this radical relay process to complete a successful synthesis of cortisone. With another appropriate template we were able to achieve a selective chlorination at C-17 of the steroid, which permitted us to remove the steroid side chain [10]. Recent work in Germany [11] has resulted in a somewhat easier sequence for converting the 17-chloro steroid derivative to a useful intermediate in which the side chain has been removed. It remains to be seen whether the steroid reactions by which we can produce corticosteroids or remove steroid side chains and generate useful intermediates actually lead to practical transformations of industrial interest. These reactions are under active investigation in several companies. 

Scheme 26.16 Metal redox/organocatalytic addition relay processes.

Ar = 2,4,6-tri-isopropyl-phenyl Scheme 26.22 Gold-catalyzed alkyne addition/acid-catalyzed hydride transfer relay processes. 

The continuously analysis and control of the manufacturing process is the precondition for the obtaining of excellent products. The two established methods are quality control charts and the relayed process capability indices. Quality Control Charts (QCC) can be used without an exact knowledge of the characteristic distribution model and are useful in the analysis of manufacturing risks. QCCs show the mean and scattering of each product characteristic in relation to the given tolerance areas. Furthermore, alert and intervention limits can be adapted inside QCC, if needed. This method is an industrial standard, further explanations can be found in (Timischl 2002). It is possible... 

Two different metal-catalyzed cascade processes have also been reported. A recent example is the FeClj/PdClj-cocatalyzed coupling cyclization of 2,3-allenoates 41 with allylic bromides 42 (Scheme 5.25) [27], This protocol provides very concise access to P-allyUc-substituted butenolides 43. The key point for this catalyst relaying process is the in situ generation of sp carbon iron species A and its transmetallation with PdCl ... 

Relay RCM RCM can be used not only to build up a targeted framework in a direct manner but also to induce the desired metathesis through a relay process (Scheme 24.13). Such a relay RCM, which has been pioneered by Hoye et al., allows sluggish or even unsuccessful RCM to be performed by moving the site of catalytic initiation away from the point of steric hindrance and/or electronic deactivation. ... 

Recently, Lu s group reported almost the same P-lCD-catalyzed asymmetric MBH reaction of isatin derivatives with acrylates [41]. They also demonstrated that P lCD was an efficient catalyst for this reaction, affording 3-substituted 3-hydroxy-2-oxindoles 87 in good yields with high enantioselectivities (Scheme 31.27). They pointed out that the C6 -OH group of P-ICD probably facilitates the key proton transfer step in the MBH reaction, via an intramolecular proton relay process. 

Especially interesting are the computational results of Ceron-Carrasco et al. [72] who investigated the double proton-relay for the G-C complex with three intermolecular hydrogen bonds (Figure 6.6). The water molecules reside on the periphery of the complex and therefore cannot directly participate in the proton transfer for the middle hydrogen bond. The authors conclude that the double proton-relay process is sequential thus the above first proton-relay necessarily leads to the formation of a zwitterionic structure. 

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