General Synthetic Reactions

As the search for new synthetic methods continues, there has been a substantial increase in the number of papers reporting the use of monoterpenoids as model compounds. Some of the more significant examples of such synthetic methods provide the basis for the following discussion. 

The ene reaction (of, for example, the pinenes) with PhS02NS0 has been described, and the cyclization-induced [3,3] sigmatropic rearrangement of allylic carbamates e.g. linalyl A,A-dimethylcarbamate) catalysed by mercuric 

Recent reviews of interest to organic chemists are listed as a new regular feature in Journal of Organic Chemistry. For reviews published in 1977, see /. Org. Chem., 1978,43, 3085 a second list covering the first half of 1978 has appeared recently, viz. ibid., 1978, 43, 4397. 

Steglich, and H. Vorbriiggen, Angew. Chem. Internat. Edn., 1978,17, 569. 

Deleris, J. Kowalski, J. Dunogues, and R. Calas, Tetrahedron Letters, 1977, 4211 see also refs. 216, 498. 

Methods for oxidative transformations continue to receive attention. Nickel peroxide on graphite oxidizes geraniol to citral in 89% yield. Three groups report the oxidative rearrangement of tertiary vinyl carbinols. Linalool is con- 

Chabardes, E. Kuntz, and J. Varagnat, Tetrahedron, 1977,33,1775 see alsoT. Hosogai, T. Nishida, and K. Itoi, Jap. P. 48 608/1976 (Chem. Abs., 1976,85, 142 638). Last year s Report questioned that only E-citral was formed (Vol. 7, p. 17, ref. 190) the English translation of the full paper clarifies that E Z ratios vary during the course of the reaction. 

4-benzoquihone, halothiation as a method for oxidizing primary halides and terminal alkenes (e.g. jS-pinene low yield) to aldehydes, and the oxidation of secondary alcohols by trichloroacetaldehyde on alumina (e.g. menthol to menthone, plus some isomenthone) homogeneous catalytic oxidation of secondary alcohols with 02-PdCl2-Na0Ac fails in the presence of alkenes (e.g. p-menth-g-en-S-ol).  

Selective catalytic hydrogenation with chromium-promoted Raney nickel is reported (e.g. citral and citronellal to citronellol) NaHCr2(CO)io and KHFe(CO)4 reduction of a/3-unsaturated ketones (e.g. citral to citronellal) has been described (cf. Vol. 7, p. 7). The full paper on selective carbonyl reductions on alumina (Vol. 7, p. 7) has been published. Dehydrogenation of monoterpenoid alcohols over liquid-metal catalysts gives aldehydes and ketones in useful yields.  

Sensitized photo-oxidation of substituted cyclohexanone silyl enol ethers yields substituted cyclohex-2-enones. For example, menthone may yield (8 X=H) or (15) depending upon the direction of enolization the corresponding hydroxy- 

Catalytic transfer hydrogenation and the use of monoterpenoids as hydrogen donor compounds have been reviewed.34 

30 t Oritani and K. Yamashita, Agric. and Biol. Chem. (Japan), 1974, 38, 1961. 

Motl in Liquid Column Chromatography—A Survey of Modern Techniques and Applications , ed. Z. Deyl. K. Macek. and J. Janak, Elsevier, Amsterdam, 1975, p. 62.3. 

Reagents i, mesitoyl chloride ii, 03 iii, isopropenylMgBr iv, Ac20-py v, Bu Li-isopropyl-cyclohexylamine-THF, -78°C vi, HMPA-t-butyldimethylsilyl chloride-THF vii, hydrolysis viii, LiAlH4. 

Epoxidation of tetrahydropyranyl ethers e.g. isopentenyl tetrahydropyranyl ether) produces readily detonatable peroxides which are stable to many commonly used methods of destruction.  

Thermal and mercury(ii)-catalysed [3,3]sigmatropic rearangement of allylic trichloroacetimidates and allylic pseudo-ureas e.g. geraniol, linalool) are useful for the 1,3-transposition of hydroxy- and amino-groups the former is synthetically preferred. The [2,3]sigmatropic rearrangement of allylic sulphoxides has been used to effect an alkylative 1,3-carbonyl transposition of enones (e.g. carvone).  

Lund and P. E. Shaw, 172nd A.C.S. Meeting, San Francisco, August 1976, Abstracts ORGN, No. 169. 

Overman, J. Amer. Chem. Soc., 1976,98,2901 an earlier communication, ibid., 1974,96,597, was omitted from these Reports. 

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In Part A, the structural and mechanistic groundwork of organic chemistry was considered. Part B assumes that the student possesses a mastery of these areas and emphasizes the synthetic application of organic reactions. Mechanisms are discussed in sufficient detail to allow the student to understand the basis for the selectivity of the reaction and its stereochemistry, but fine points of mechanistic detail are not emphasized. Many of the most general synthetic reactions are illustrated by referenced examples included in the schemes. 

J. Tsuji, Pure Appl. Chem., 1986, 58, 869-878. New General Synthetic Reactions Catalyzed by Palladium Complexes. 

Table 1 Important Databa.ses for General Synthetic Reactions ...

This is a combined archival database with 171629 reactions originating predominantly from about 300 Journals and some patents. It comprises the Theilheimer databa.se (46785 reactions 1946-1980), the core database from the former ORAC system (about 65 000 reactions, mainly 1980-1991), and several databases produced by MDL (CLF Current Literature File 36600 general synthetic reactions 1983-1991. CHIRAS 13 200 asymmetric reactions 1975-1991. Metalysis 12000 metal-mediated reactions 1974-1991). Although the time coverage of RefLib does really start at 1946, the onset of Theilheimer, there are almost 4000 reactions with pre-1946 references (2600 with literature only before that year). 

The most general synthetic route to ketones uses the reaction of carboxylic acids (or their derivatives) or nitriles with organometallic compounds (M.J. Jorgenson, 1970). Lithium car-boxylates react with organolithium compounds to give stable gem-diolates, which are decom-... 

A more eflicient and general synthetic procedure is the Masamune reaction of aldehydes with boron enolates of chiral a-silyloxy ketones. A double asymmetric induction generates two new chiral centres with enantioselectivities > 99%. It is again explained by a chair-like six-centre transition state. The repulsive interactions of the bulky cyclohexyl group with the vinylic hydrogen and the boron ligands dictate the approach of the enolate to the aldehyde (S. Masamune, 1981 A). The fi-hydroxy-x-methyl ketones obtained are pure threo products (threo = threose- or threonine-like Fischer formula also termed syn" = planar zig-zag chain with substituents on one side), and the reaction has successfully been applied to macrolide syntheses (S. Masamune, 1981 B). Optically pure threo (= syn") 8-hydroxy-a-methyl carboxylic acids are obtained by desilylation and periodate oxidation (S. Masamune, 1981 A). Chiral 0-((S)-trans-2,5-dimethyl-l-borolanyl) ketene thioketals giving pure erythro (= anti ) diastereomers have also been developed by S. Masamune (1986). 

In spite of the diverse nature of alkaloid structures, two structural units, i.e. fused pyrrolidine and piperidine rings in different oxidation states, appear as rather common denominators. We therefore chose to give several examples for four types of synthetic reactions which have frequently been used in alkaloid total synthesis and which provide generally useful routes to polycyclic compounds with five- or six-membered rings containing one nitrogen atom. These are ... 

RTIX2 derivatives are covalent compounds, generally soluble in organic solvents. The aryl and vinyl derivatives are more stable than the corresponding alkyl compounds. This type of compound has been postulated to be an intermediate in many organic synthetic reactions involving thaUium(III) species. 

In 1959 Carboni and Lindsay first reported the cycloaddition reaction between 1,2,4,5-tetrazines and alkynes or alkenes (59JA4342) and this reaction type has become a useful synthetic approach to pyridazines. In general, the reaction proceeds between 1,2,4,5-tetrazines with strongly electrophilic substituents at positions 3 and 6 (alkoxycarbonyl, carboxamido, trifluoromethyl, aryl, heteroaryl, etc.) and a variety of alkenes and alkynes, enol ethers, ketene acetals, enol esters, enamines (78HC(33)1073) or even with aldehydes and ketones (79JOC629). With alkenes 1,4-dihydropyridazines (172) are first formed, which in most cases are not isolated but are oxidized further to pyridazines (173). These are obtained directly from alkynes which are, however, less reactive in these cycloaddition reactions. In general, the overall reaction which is presented in Scheme 96 is strongly... 

The procedure described is an example of a more general synthetic method for the direct conversion of ketones into cyanides. " The reaction has been carried out successfully with acyclic and cyclic aliphatic ketones, including numerous steroidal ketones and aryl-alkyl ketones. The conversion of diaryl or highly hindered ketones such as camphor and )3,j8-dimethyl-a-tetralone requires the use of a more polar solvent. The dimethoxyethane used in the present procedure should be replaced by dimethyl sulfoxide. ... 

A 17a-methyl in the product of ring D homo-annulation of 17-hydroxy-20-keto steroids may limit the general synthetic utility of the reaction. On the other hand, the 17a-hydroxyl group gives additional flexibility in planning further transformations. Moreover, by adjusting reaction conditions, the stereochemistry of the products can be changed. 

A variety of complexes of the thionyl imide anion [NSO] with both early and late transition-metal complexes have been prepared and structurally characterized. Since both ionic and covalent derivatives of this anion are readily prepared, e.g., K[NSO], McsMNSO (M = Si, Sn) or Hg(NSO)2, metathetical reactions of these reagents with transition-metal halide complexes represent the most general synthetic method for the preparation of these complexes (Eq. 7.10 and 7.11). ... 

The classical Vilsmeier-Haack reaction is one of the most useful general synthetic methods employed for the formylation of various electron rich aromatic, aliphatic and heteroaromatic substrates. However, the scope of the reaction is not restricted to aromatic formylation and the use of the Vilsmeier-Haack reagent provides a facile entry into a large number of heterocyclic systems. In 1978, the group of Meth-Cohn demonstrated a practically simple procedure in which acetanilide 3 (R = H) was efficiently converted into 2-chloro-3-quinolinecarboxaldehyde 4 (R = H) in 68% yield. This type of quinoline synthesis was termed the Vilsmeier Approach by Meth-Cohn. ... 

In general the reaction of an aldehyde with a ketone is synthetically useful. Even if both reactants can form an enol, the a-carbon of the ketone usually adds to the carbonyl group of the aldehyde. The opposite case—the addition of the a-carbon of an aldehyde to the carbonyl group of a ketone—can be achieved by the directed aldol reaction The general procedure is to convert one reactant into a preformed enol derivative or a related species, prior to the intended aldol reaction. For instance, an aldehyde may be converted into an aldimine 7, which can be deprotonated by lithium diisopropylamide (EDA) and then add to the carbonyl group of a ketone ... 

The reaction described is of general synthetic utility for the preparation of a variety of cyclic /3-keto esters from the corresponding ketones. Using this procedure the 2-carbethoxy-cycloalkanones have been prepared from cyclononanone, cyclo-decanone, and cyclododecanone in yields of 85%, 95%, and 90%, respectively. The procedure is simpler and gives much higher yields than other synthetic routes to these systems. 

From the point of view of general synthetic applicability, Table 10-6 shows clearly that there is no overall rationale in these cyclization reactions. The range of yields is enormous and, in addition, it is hardly possible to specify whether heterolytic or homolytic reaction conditions are preferred. 

In addition to the synthetic applications related to the stereoselective or stereospecific syntheses of various systems, especially natural products, described in the previous subsection, a number of general synthetic uses of the reversible [2,3]-sigmatropic rearrangement of allylic sulfoxides are presented below. Several investigators110-113 have employed the allylic sulfenate-to-sulfoxide equilibrium in combination with the syn elimination of the latter as a method for the synthesis of conjugated dienes. For example, Reich and coworkers110,111 have reported a detailed study on the conversion of allylic alcohols to 1,3-dienes by sequential sulfenate sulfoxide rearrangement and syn elimination of the sulfoxide. This method of mild and efficient 1,4-dehydration of allylic alcohols has also been shown to proceed with overall cis stereochemistry in cyclic systems, as illustrated by equation 25. The reaction of trans-46 proceeds almost instantaneously at room temperature, while that of the cis-alcohol is much slower. This method has been subsequently applied for the synthesis of several natural products, such as the stereoselective transformation of the allylic alcohol 48 into the sex pheromone of the Red Bollworm Moth (49)112 and the conversion of isocodeine (50) into 6-demethoxythebaine (51)113. 

Fischer-type carbene complexes, generally characterized by the formula (CO)5M=C(X)R (M=Cr, Mo, W X=7r-donor substitutent, R=alkyl, aryl or unsaturated alkenyl and alkynyl), have been known now for about 40 years. They have been widely used in synthetic reactions [37,51-58] and show a very good reactivity especially in cycloaddition reactions [59-64]. As described above, Fischer-type carbene complexes are characterized by a formal metal-carbon double bond to a low-valent transition metal which is usually stabilized by 7r-acceptor substituents such as CO, PPh3 or Cp. The electronic structure of the metal-carbene bond is of great interest because it determines the reactivity of the complex [65-68]. Several theoretical studies have addressed this problem by means of semiempirical [69-73], Hartree-Fock (HF) [74-79] and post-HF [80-83] calculations and lately also by density functional theory (DFT) calculations [67, 84-94]. Often these studies also compared Fischer-type and... 

A simple, high-yield procedure for the conversion of ArTlXj into ArjTlX compounds has recently been described 90). This symmetrization reaction, the mechanism of which is not known, can be effected by treatment of the ArTlX2 compound either with triethyl phosphite or with hot aqueous acetone. As a wide variety of ArTlXj compounds can now be easily prepared by electrophilic thallation of aromatic substrates with thallium(III) trifluoroacetate (q. v.), symmetrization represents the method of choice for the preparation of the majority of ArjTlX compounds. Only about twenty mixed compounds, RR TIX, have been prepared so far, and the only general synthetic procedure available consists of a disproportionation reaction between an RTIX2 species and another organometallic reagent [e.g., Eqs. (5)-(7)]. 

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