A series of reviews by leading specialists in their fields which gives systematic and comprehensive coverage of the progress in major areas of research.

General and Synthetic Methods Volume 1

A Review of the Literature Published During 1976

By G. Pattenden

The Royal Society of Chemistry

Copyright © 1978 The Chemical Society
All rights reserved.
ISBN: 978-0-85186-900-1

Contents

Chapter 1 Saturated and Unsaturated Acyclic Hydrocarbons By J. C. Saunders, B. P. Swann, and D. E. Tupper, 1,
Chapter 2 Aldehydes and Ketones By S. M. Roberts, 76,
Chapter 3 Carboxylic Acids and Derivatives By D. W. Knight, 111,
Chapter 4 Alcohols, Halogeno-compounds, and Ethers By R. C. F. Jones, 156,
Chapter 5 Amines, Nitriles, and Other Nitrogen-containing Functional Groups By E. F. V. Scriven, 184,
Chapter 6 Saturated Heterocyclic Ring Synthesis By N. F. Elmore, 197,
Chapter 7 Saturated Carbocyclic Ring Synthesis By M. Mellor and G. Pattenden, 288,
Chapter 8 Organometallics in Synthesis, 324,
Chapter 9 Strategy and Design in Synthesis By S. Turner, 382,
Chapter 10 Phase Transfer and Related Methods By R. C. F. Jones, 402,
Author Index, 429,

CHAPTER 1

Saturated and Unsaturated Acyclic Hydrocarbons

BY J. C. SAUNDERS, B. P. SWANN AND D. E. TUPPER

1 Saturated Hydrocarbons

Synthesis. — The radical anion from di-t-butylbiphenyl is found to be superior to lithium naphthalene for the reductive removal of halogen from alkyl chlorides (Table la). Alcohols are reduced directly to the corresponding hydrocarbon by the addition of a silane R3SiH to the alcohol in methylene chloride followed by addition of boron trifluoride gas. The reduction proceeds rapidly (<10 min) and is generally superior to the procedure which utilizes R3SiH in trifluoroacetic acid. The latter conditions often lead to both extensive decomposition of the silane and dehydration or rearrangement of the alcohol, whereas the R3SiH-BF3, combination enables even tertiary alcohols to be reduced without dehydration, although in some cases, such as octan-2-01, yields are low (ca. 50%); formation of non-volatile byproducts is possibly responsible for the lower yield since octane was the only product detected by g.1.c. An alternative procedure for primary and secondary alcohols involves prior conversion to the tosylate followed by treatment with sodium iodide and zinc powder in refluxing 1,2-dimethoxyethane. Yields are generally good but β-elimination can occur if the tosyl group site is hindered, leading to olefins (Scheme 1).

Aromatic aldehydes and ketones are reduced to the corresponding hydrocarbons in good yield by catalytic transfer reduction using cyclohexene or limonene as a donor, palladium-carbon as catalyst and a Lewis-acid promotor such as ferric chloride. The major competing reaction is decarbonylation, otherwise the reaction is straightforward and simply involves heating the catalyst, carbonyl compound, and donor under reflux for 3 — 5 h, furthermore the method is convenient and dispenses with elaborate equipment or potentially explosive hydrogen.

Alkyl halides react with superacids such as HF-TaF5, HCl-AlCI3, and HBr-AlBr3 initially to give the corresponding alkane via a hydride transfer. Naturally the reaction conditions detract from its synthetic utility. Readily available transition metal complexes such as Ni(acac)2 and Fe(acac)3 can be induced to react in an electrochemical system with alkyl halides to produce coupled hydrocarbon products. Low valency metal complexes are probably intermediates and these undergo reaction with alkyl halides to form ω-bonded alkyl transition metal intermediates, which then decompose by known pathways. The coupled products appear to arise from a free radical pathway, although the disproportionation products, alkane and alkene, may not be formed by this route. In particular organic halides having hydrogens on the carbon atom β- to the halide atom tend to yield alkanes and alkenes in addition to coupled products.

Reactions. — Alkanes can be oxidized by iodine tris(trifluoroacetate) to a mixture of mono and bis(trifluoroacetates). With certain alkanes, particularly those with tertiary carbon centres, the reaction can be of synthetic utility (Scheme 2). This is a further example of the parallel of the chemistry of iodine (III) and lead (IV) since lead tetra(trifluoroacetate) is reported to react similarly. Iodine tris(trifluoromethanesulphonate) is reported to be even more reactive. A similar type of functionalization can be carried out in superacid-S03ClF mixtures by addition of ozone. Mechanistic studies suggest that the active species is protonated ozone, 03H+ which undergoes electrophilic insertion into a σ-bond. Product analysis shows that oxygenation is followed by C -> O alkyl migration, analogous to the acid-catalysed cleavage and rearrangement reaction undergone by hydroperoxides. Direct amination of several acyclic and alicyclic alkanes can be effected with trichloramine-aluminium chloride. In general rearrangement and degradation of the hydrocarbon substrate occurs but isobutane and iso-octane give good yields of t-butylamine. Isoalkanes are brominated by dropwise addition of the isoalkane in sulphur dioxide at -80 °C to a solution of bromine in SbF5 or SbF5-FS03H in sulphur dioxide at -25 °C. Thus isopentane gives EtCBr(Me)CH2Br and isooctane gives a mixture of Me2CHCH2Br and Me2CBrCH2Br by a fragmentation–bromination sequence.

2 Olefinic Hydrocarbons

Synthesis. — Catecholborane offers a number of advantages over other boron hydrides for the reduction of αβ-unsaturated tosylhydrazones (1) to olefins. Only one equivalent of hydride is used and the conditions are mild. No alkane formation is observed. A study of the isomeric pulegone tosylhydrazones (2) and (3) and the role of stereochemistry upon the olefin formation has shown that the stereochemistry plays a critical role (Table lb). There would appear to be two decomposition routes, one of which is strongly stereochemically dependent, whereas the other has little, if any, dependence on tosylhydrazone stereochemistry. Suitable control quenching experiments show that the monoanions of the tosylhydrazones maintain their original stereochemistry. The exact mechanism has yet to be fully clarified. Treatment of ketone tosylhydrazones with a threefold excess of butyl-lithium provides a convenient route to vinyl-lithium reagents. The carbene (4), generated from the tosylhydrazone (5) fragments to give cis-1-allyl-2-ethynylcyclopropane, which readily rearranges to 1,2,5,7-octatetraene (6) in good yield (Scheme 3).

Several new reagents have been reported for dehydrating alcohols to olefins. Among these were the carbodimidium salt (7), methyltriphenoxyphosphonium iodine (8) in HMPT. and the use of dialkylcyanamides followed by a [3,3] sigmatropic rearrangement to ureas (9) and (10). Examples are shown in Scheme 4.

The use of vinyl and alkyl cuprates in organic synthesis shows no signs of abating. Amongst new examples which are useful in olefin synthesis are the cross-coupling of alkyl and arylcopper(1) reagents with (E)-2-iodo-l-alkenyl sulphones to give β-alkylated or β-arylated 2-alkyl-1-alkenyl sulphones, and the use of diphenylphosphate esters in the synthesis of olefins from ketones. The latter procedure involves conversion of the ketone to its enol phosphate via the regiospecifically generated anion, and displacement of the phosphate by a lithium dialkylcuprate, in parallel with work on the corresponding vinyl iodides. The final step involves three equivalents of lithium dialkylcuprate ; yields are only moderate (Scheme 5).

The fragmentation of simple β-lactones to carbon-carbon double bonds is a classic reaction in organic chemistry although little used in organic synthesis. Two examples appeared during 1976 illustrating the potential of this fragmentation reaction as shown in Scheme 6.

The combination of thionyl chloride-triethylamine is the reagent of choice for the elimination of β-hydroxy selenides to olefins. The reaction proceeds via stereospecific trans-elimination of the hydroxy and selenide moieties. An intermediate seleniranium ion is proposed, and these are now well-characterized species. The ease of formation of β-hydroxy selenides by addition of reagents such as phenylselenyl trifluoroacetate to double bonds followed by hydrolysis, makes it a possible protecting group for double bonds. A convenient route to substituted styrenes by a modified Wittig reaction involves addition of triphenyl substituted benzylphosphonium bromide to aqueous formaldehyde (40%) and dropwise addition of 50% sodium hydroxide. Yields in all cases (4-OMe to 4-N02) were above 85%. Iodinated popcorn polystyrene has been used for the photodimerization of olefins, and with substituted styrene derivaties the yields were moderate to good (Table 2). Trifluoroacetylation and trichloroacetylation proceeds very rapidly with ketene thioacetals or vinyl sulphides to give the corresponding acylated olefins in high yield. The reaction has an equivalence with enamine chemistry but does not occur with β-substituted olefins such as phenyl propenyl sulphide.

The introduction of the terminal isoprenoid 1,3-diene unit is feasible using pentadienyl anions. The symmetrical anion (11) gives almost exclusively one product, but the asymmetrical anion (12) gives rise to a mixture which can be separated by chromatography (Scheme 7). Isoprene can be readily converted into 4-bromo-3-methyl but-2-en-1 -01 from which the pure E-isomer can be isolated. This could be used as an attractive precursor for trisubstituted olefins using coupling conditions developed for the n-alkylcopper(I) reagents leading to stereospecific products (Scheme 8).

The reaction of 2-bromo-6-lithiopyridine (1 3) with trialkylboranes gives intermediate boron compounds which are versatile intermediates for the preparation of unsaturated nitriles (Scheme 9). A stereospecific synthesis of dehydronerol utilizes the dianion of 3-methylbut-2-enoic acid as an isoprene functionality (Scheme Lithium dianions from αβ-unsaturated acids generally undergo alkylation reactions at the α-carbon atom. In contrast the dicopper dianions undergo more selective γ-alkylation (62 — 99%) and this ratio is generally higher than with the corresponding esters. A study of various acids and their alkylation with ally1 electrophiles showed that allylic electrophiles unsubstituted at the γ-carbon react with the copper dienolates mainly in an SN2′ fashion giving products in which the allylic portion has been transposed. Those electrophiles which are y-substituted react exclusively by SN2 displacement whereas those with only one substituent give a mixture of SN2 and SN2′ attack. The y-selective alkylation of copper dienolates can be used as a convenient prenylogation process in natural product synthesis (Scheme 11). A full paper describing the quenching of the enolates of esters and ketones with dimethyl or diphenyldisulphide to give the α-sulphenylated products has appeared. Oxidation of these products to the sulphoxide followed by thermolysis (50 °C for Ph) gives the corresponding αβ-unsaturated products. In tetrahydrofuran only monosulphenylation occurs whereas in HMPT-tetrahydrofuran bis-sulphenylation takes place; these products can be converted into α-ketoesters, a transformation best performed via transketalization with iodine-methanol followed by ketal hydrolysis. Dipole–dipole effects are important in assessment of the regiospecificity of such eliminations (Scheme 12). A full paper has also appeared concerning the Claisen ester enolate rearrangement of allylic esters or the corresponding silylketene acetals. The products are the γ,δ -unsaturated acids (66 — 88 % yield). The mild conditions allow rearrangement of acid sensitive and thermally labile esters. Regioselectivity can also be controlled depending on the solvent used in the enolization process as illustrated for E-crotylpropanoate in Scheme 13.

Potassium hydroxide in acetonitrile solution with dicyclohexyl-18-crown-6 gives good yields of αβ-unsaturated nitriles from a variety of aldehydes and ketones, including benzophenone. One consequence of the rate enhancement of the [3,3] sigmatropic rearrangement of certain enolates reported last year by Evans is a new route to prenylated quinones (Scheme 14). A development in the synthesis of olefins by the boron mediated cross-coupling reaction is the use of the boronic ester (14). One advantage of this intermediate over the normal trialkylborane procedure is that the required group is fully utilized and no competition from blocking alkyl groups (such as thexyl) can occur, as can happen when mixed alkylboranes are used (Scheme 15). Metalation of 2-(alkylthio)-2-oxazolines (15) followed by addition of a variety of carbonyl compounds leads to thiirans in 60 — 70% yield. The process is also useful for the direct synthesis of alkenes and dienes by extrusion of sulphur. In many cases a high degree of stereoselectivity is observed in the alkene formation. A partial asymmetric synthesis of chiral thiirans has also been achieved. An extension of Meyers’ work on 2-substiluted 1,3-oxazines has utilized silyl substituents to stabilize the carbanion and leads to useful synthetic intermediates and transformations (Scheme 16).

The use of cuprous oxide and 2,2′-dipyridyl in quinoline has been shown to be superior to many other procedures for the bis-decarboxylation of vicinal dicarboxylic acids to olefins (Grob decarboxylation). The main drawback is the high temperature necessary (Scheme 17). γ-Chloroallyl sulphoxides undergo [2,3] sigmatropic rearrangement and fragmentation very readily to give αβ-unsaturated carbonyl compounds, and thus constitute a new synthon for this functional group (Scheme 18). Ester stabilized sulphonium ylides are readily prepared from sulphides and ethyl α-trifluoromethane sulphonylacetate. They readily fragment in dimethylformamide at 50 °C to yield olefins in variable amounts. The first example of regiospecific generation of isomeric olefins from two sulphoxides diastereoisomeric at sulphur is reported in the case of (R)- and (S)-3α-(1- adamantylsulphinyl)5α-cholestane. Thermolysis of the (R)-isomer at 110 °C gave 5α-cholest-3-ene whereas the (S)-isomer gave 5α-cholest-2-ene. In contrast, the corresponding steroidal derivatives from naphthalene, anthracene, or diphenylmethane, either gave unselective elimination or underwent stereomutation at sulphur.

The use of low valent titanium salts in olefin synthesis continues to be explored. Olah and Prakash report the coupling of various halogen substituted compounds to olefins and alkanes using titanium(II) in tetrahydrofuran. McMurry has developed a titanium(0) catalyst and has developed its use for the synthesis of tetrasubstituted olefins by a mixed coupling technique. Mixed coupling is particularly efficient for diaryl ketones and acetone since any tetramethylethylene formed is easily removed. The combination of titanium(III) and lithium aluminium hydride has been used on 1,4- and 1,6-diketones to give cyclic olefins in moderate yield, (Table 3). Interestingly the combination of titanium(IV) chloride and lithium aluminium hydride in ether was found to be a reasonable catalyst for the reduction of monosubstituted olefins to alkanes. Disubstituted alkenes were reduced more sluggishly. Terminal alkynes could be reduced all the way to the alkane, but it was impossible to obtain reasonable yields of the intermediate alkene; internal alkynes gave moderate yields of the trans-alkene. The reaction of the niobium and tantalum neopentylidene complexes (16) with carbonyl compounds gives the corresponding olefins and has parallels with phosphorus ylide chemistry.

Yields in the synthesis of homoallyl alcohols from allylic bromides can be substantially improved if a continuous flow procedure is employed. Percolation of a 1 : 1.5 mixture of the carbonyl component and allylic bromide in tetrahydrofuran down a column of granular zinc heated to just above the reflux temperature of the solvent was found to be the optimum condition. Allyltrimethylsilane (17) adds smoothly to carbonyl compounds, especially when catalysed by titanium tetrachloride. A typical procedure involves addition of the titanium tetrachloride under nitrogen to the carbonyl compound in methylene chloride, followed by the allylsilane (Scheme 19). After 1 minute, water is added and the alcohol isolated by chromatography. Prolonged stirring is less satisfactory because of polymerization of both the allyltrimethylsilane and the product, and other side reactions. With substituted allylsilanes such as Me3SiCH(Ph)CH = CH2 and Me3SiCH2CH = CHPh only one product is formed in each case indicating regiospecific transfer of the allylic group to the carbonyl function, whereas allylmagnesium halides give an isomeric mixture.

α-Silyl carbanions (18), generated by cleavage of the selenides (19) with butyl-lithium, react with ketones and aldehydes to give the alcohols (20) and thence the olefin by treatment with acid. The yields are only moderate but the method is general. β-Ketosilanes react with alkyl-lithium reagents to give predominantly one diastereoisomer of the two possible β-hydroxysilanes Work up by either acid or base conditions can be controlled to give mainly one or other of the trisubstituted ethylene stereoisomers (Scheme 20). Further work by the Cambridge group of Fleming, Warren, and co-workers has yielded new results in the synthesis of olefins and dienes utilizing diphenylphosphinoyl and trimethylsilyl functionalities to direct the regio and stereoselectivity. The results are summarized in Table 4.

(Continues…)Excerpted from General and Synthetic Methods Volume 1 by G. Pattenden. Copyright © 1978 The Chemical Society. Excerpted by permission of The Royal Society of Chemistry.
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