Sequential Syntheses

Badger and coworkers devised a sequential synthesis of [ 18]annulene-l,4 7,10 l 3,16-trioxide which is formally the condensation product of three furan molecules and three ethylenes . The synthesis is illustrated below in Eq. (3.25). The [18]annulene trioxide was obtained as a red solid (mp 215—216 °d) whose proton nmr spectrum showed two peaks of equal area at 8.66 and 8.68 ppm. 

Although the first all-sulfur macrocycles were prepared many years ago " the first systematic study of such compounds was initiated by Busch and his coworkers , who were interested in the cation binding properties of such ligands. A sequential synthesis was utilized to produce 1,4,8,11-tetrathiacyclotetradecane [tetrathia-14-crown-4 (70)] . In the first step, 1,3-propanedithiol is metallated using sodium and alkylated with 2-chloroethanol. The diol was then treated with thiourea to form the dimercapto-dithioether compound 9. The latter was once again metallated with sodium and allowed to react with 1,3-dibromopropane. The yield of 70 in the ring closure step, conducted at high dilution in absolute ethanol, was 7.5% after recrystallization. The entire sequence is illustrated in Eq. (6.8) . ... 

Nickel catalysis has been used in a sequential synthesis of terphenyls, starting with 2-, 3-, or 4-bromophenyl neopentanesulfonates. Conventional Pd-catalyzed Suzuki conditions were used for the first step involving coupling of the bromide and then nickel catalysis was utilized for coupling the sulfonate. 

The issue of parallel versus sequential synthesis using multimode or monomode cavities, respectively, deserves special comment. While the parallel set-up allows for a considerably higher throughput achievable in the relatively short timeframe of a microwave-enhanced chemical reaction, the individual control over each reaction vessel in terms of reaction temperature/pressure is limited. In the parallel mode, all reaction vessels are exposed to the same irradiation conditions. In order to ensure similar temperatures in each vessel, the same volume of the identical solvent should be used in each reaction vessel because of the dielectric properties involved [86]. As an alternative to parallel processing, the automated sequential synthesis of libraries can be a viable strategy if small focused libraries (20-200 compounds) need to be prepared. Irradiating each individual reaction vessel separately gives better control over the reaction parameters and allows for the rapid optimization of reaction conditions. For the preparation of relatively small libraries, where delicate chemistries are to be performed, the sequential format may be preferable. This is discussed in more detail in Chapter 5. 

The issue of parallel versus sequential synthesis using multimode or monomode cavities, respectively deserves special comment. While the parallel setup allows for considerable throughput that can be achieved in the relatively short timeframe of a microwave-enhanced chemical reaction, the individual control over each reaction vessel in terms of reaction temperature and/or pressure is limited. In the parallel... 

Sequential hydrolysis, 10 536 Sequential modular approach, 20 730 Sequential polymerization, 24 704 Sequential proportioning, 26 249 Sequential substitution reactions, 16 361 Sequential synthesis film fabricatior, 17 447... 

All issues about the preparation of inorganic solid catalysts that we have discussed above apply for the rapid sequential synthesis of inorganic solids by automated methodologies. As for HTE - and combinatorial approaches in organic chemistry, technical solutions for compound synthesis can be obtained commercially for a number of synthetic problems [42-45] and it is beyond the scope of this chapter to discuss all the technical details. 

By way of comparison, the morphology of the sequential synthesis shows a much finer structure, the average domains being of the order of 300-600. Also, because of swelling restrictions, it was impossible to achieve materials having more than about 80% polystyrene (15). 

Piperazines and derivatives are archaetypical scaffolds and can be considered as efficient, however, structurally simple peptidomimics. The scaffolds combine conformational rigidity with peptide-like spacial placement of amino acid side chains or isosteres thereof. Moreover, piperazines can be used to confine compounds with beneficial properties such as water solubihty. Piperazines are therefore in the center of synthetic interest and many different synthetic pathways have been designed [16-19]. A preferred way to synthesize different piperazine scaffolds with plenty of variabihty provides MCR chemistry. Several piperazine scaffolds are currently only accessible by isocyanide-based MCR. Likely they could be assembled by sequential synthesis as well however, the synthetic efficiency, the diversity, and the size of the alternative chemical space will be inferior. The application of... 

Yoshida et al. [63] applied microreaction technology for the sequential synthesis and the disubstitution of o-bromophenyUithiuni (Scheme 28). Lithiation of o-dibromobenzene in batch leads to the formation of the highly reactive benzyne and to the further creation of various side products thus this reaction needs to be conducted at 100°C and below to avoid this problem. This reaction was optimized under microreactor conditions for the production of o-bromophenyUithium and for its further reaction with methanol to determine the yield of bromobenzene. Microreactors were set up of stainless steel tubes with an internal diameter of 250-1,000 pm. 

Scheme 3 illustrates retrosynthetic analysis of the E and F series of PGs. The widely used Corey synthesis (2) takes notice of the presence of the two olefinic bonds in the side chains of PGF2a. The actual synthesis consists of a two-fold Wittig-type chain extension of a chiral dialdehyde equivalent with four defined stereogenic centers derived from cyclopentadiene via a series of bicyclic intermediates. A similar sequential synthesis has been developed at Upjohn Co. (la). These chemical syntheses are much more economical than enzymatic methods and are used for commercial synthesis of certain PGs. An alternative pathway pioneered by Sih is the conjugate addition approach (3). Nucleophilic addition of an E-olefinic co side-chain unit to a cyclopentenone in which the a side chain is already installed leads directly to PGE-type compounds. Untch and Stork used an co chain unit with a Z-olefinic bond (4). The most direct and flexible synthesis is the convergent three-component coupling synthesis via consecutive linking of the two side chains to unsubstituted 4-hydroxy-2-cyclopentenone derivatives (5, 6). 

In Section 8.4 we discussed decomposition-based HEN synthesis approaches that feature three separate tasks to be performed sequentially (i) minimum utility cost, (ii) minimum number of matches, and (iii) minimum investment cost network configuration. Such a decomposition was motivated by the discovery of the pinch point on the one hand and by our inability in the 1980 s to address the HEN synthesis problem as a single task problem. Application of such sequential synthesis approaches in many case studies resulted in good quality networks with respect to the total annualized cost which is a strong indication of the clever decomposition scheme. 

The primary limitation however of sequential synthesis methods is that different costs associated with the design of HENs cannot be optimized simultaneously, and as a result the trade-offs are not taken into account appropriately. Early decisions in the selection of HRAT and partitioning into subnetworks affect the number of units and areas of the units in the HEN configuration. Therefore, sequential synthesis methods can often lead to suboptimal networks. 

Li J, Wang L, Liu S et al (2010) MCM-41 grafted quaternary ammonium salts as recyclable catalysts for the sequential synthesis of dimethyl carbonate from epoxides, C02, and methanol. Chem Lett 39 1277-1278... 

A sequential synthesis, starting from aminopropyl-modified MCM-41 and 2,6-diformyl-4-rm-butylphenol, was used to obtain the catalyst precursor 7h with the Mn-containing material, an ee of 89% was observed at 92% conversion in the epoxidation of styrene with NMO at 195 K (96) ... 

There are two principal approaches to forming sequential IPNs (1) form the first network, swell it with the second monomer, crosslinker and catalyst and then form the second network (2) blend the two monomers, crosslinkers and catalysts together and then crosslink them. Two different initiation processes (e.g. different temperatures) can be used in what is called in-situ sequential synthesis. Finally, an alternative consists in blending the monomers and then adding the catalysts and/or the crosslinkers sequentially. 

The difference in relative reactivity of aromatic iodides and triflates was exploited in this sequential synthesis of substituted terphenyls by repeated coupling with organozinc reagents. The more reactive iodide coupled at room temperature with palladium(O) and trio-fury]phosphine but warming to 65 °C was required for the triflate to participate in the second coupling. 

A particularly elegant application of DERA is the sequential synthesis of thermodynamically stable cyclic hemiacetal. Two DERA-catalyzed aldol reactions convert one equivalent of acceptor and two equivalents of acetaldehyde into this stable compound. A mild subsequent oxidation yielded the corresponding lactone in ex-... 

The enhanced reactivity of chelated amino acid esters towards attack by other nucleophiles has been used to advantage in the sequential synthesis of small peptides equation (4l).225 Formation of the amide bond takes only seconds to minutes at room temperature in DMSO as solvent, and the peptide can be easily recovered by reducing the metal to the Co" state. Recent studies have shown that the A and A diastereoisomeric reactants are selective in their couplings to (2 ) and (S) amino acid esters and that mutarotation at the asymmetric centre of the chelated ester reactant varies from 0-6%.226 Isied and coworkers have described the use of the Co(NH3)3+ as a C-terminal protecting group for the sequential synthesis of peptides (equation 42).227 This procedure has advantages over other methods in some cases. 

Microwave-assisted synthetic methodologies can also be divided into two main categories (a) methodologies in which the reactant(s) or reagent(s) are previously covalently linked to a solnble (e.g., polyethylene glycol) or nonsoluble (e.g., Wang resin, Merrifield resin, Tenta Gel, and cellulose) polymer support, and (b) parallel, simnltaneous or sequential synthesis without use of a polymer support. 

Parallel synthesis of combinatorial libraries is a synthetic sequence where the assembly of library is performed using an ordered array of spatially separated reaction vessels under the same reaction conditions. In sequential synthesis, the general reaction conditions can be modified for each building block combination according to the reactivity of the reagents in each reaction vessel. Parallel synthesis can be carried out with both conventional and MAOS and either in solid-phase or solntion-phase synthesis. 

---