Cycloalkanones 3-substituted

One of the reactions extensively investigated is the heterolytic cleavage of the C(1),C(2) bond of cycloalkanones substituted in 2-position by an electron withdrawing group, Y, Scheme VII/23. 

Intramolecular nitrone-alkene cycloaddition. Reaction of cycloalkanones substituted by a 3-(2-propenyl) or a 3-(3-butenyl) side chain with alkylhydroxylamines with azeotropic removal of water results in a bridged bicycloalkane fused to an isoxazolidine ring. The transformation involves formation of a nitrone that undergoes intramolecular cycloaddition with the unsaturated side chain. 

Moreover, fermentation of various a-substituted cycloalkanone enol esters results in optically active six-, eight-, ten-, and twelve-membered ring ketones with 70—96% ee (84). Isolated enzymes catalyze similar transformations, bacillus coagulans and Candida glindracea]i 2Lse OF (Meito Sangyo) hydrolyze a number of cycHc and acycHc enol esters, giving ketones in 40—80% yield and 14—85% ee (85,86). 

The reaction conditions (neutral, acidic or basic) do have an affect on the regioselectivity of the reaction. Acidic reaction conditions have also been shown to preferentially provide one regioisomer over basic conditions for reactions of aryl hydrazines. Extensive studies with 2-perfluoroacylcycloalkanones and mono-substituted hydrazines were studied to determine the selectivity of various alkyl-, aryl-, and heteroaryl-substituted hydrazines. Reactions of the aryl hydrazine 21 with the trifluoromethyl-substituted cycloalkanone 22 under neutral conditions (methanol, reflux) gave a mixture of isomers 23 and 24, whereas the reaction of the pyridyl hydrazine 25 was shown to give exclusively 26. 

Notable examples of general synthetic procedures in Volume 47 include the synthesis of aromatic aldehydes (from dichloro-methyl methyl ether), aliphatic aldehydes (from alkyl halides and trimethylamine oxide and by oxidation of alcohols using dimethyl sulfoxide, dicyclohexylcarbodiimide, and pyridinum trifluoro-acetate the latter method is particularly useful since the conditions are so mild), carbethoxycycloalkanones (from sodium hydride, diethyl carbonate, and the cycloalkanone), m-dialkylbenzenes (from the />-isomer by isomerization with hydrogen fluoride and boron trifluoride), and the deamination of amines (by conversion to the nitrosoamide and thermolysis to the ester). Other general methods are represented by the synthesis of 1 J-difluoroolefins (from sodium chlorodifluoroacetate, triphenyl phosphine, and an aldehyde or ketone), the nitration of aromatic rings (with ni-tronium tetrafluoroborate), the reductive methylation of aromatic nitro compounds (with formaldehyde and hydrogen), the synthesis of dialkyl ketones (from carboxylic acids and iron powder), and the preparation of 1-substituted cyclopropanols (from the condensation of a 1,3-dichloro-2-propanol derivative and ethyl-... 

Lithiated areneacetonitriles react with a,/i-unsaturated ketones at low temperatures using short reaction times to give both 1,2- and 1,4-adducts. The 1,2-addition is reversible and under thermodynamic control (higher temperatures and longer reaction times) only the 1,4-adducts, i.e., <5-oxonitriles, arc obtained. When lithiated arylacetonitrile is added to 2-substituted 2-cy-cloalkenones in THF or in THF/HMPA mixtures at — 70-0°C, followed by protonation or alkylation under kinetically controlled conditions, predominantly cis- or fnms-2,3-disubstitut-ed cycloalkanones respectively, are obtained. 

The Michael additions of chiral cycloalkanone imines or enamines, derived from (FV l-l-phcnyl-ethanamine or (5)-2-(methoxymethyl)pyrrolidine, are highly diastereofacially selective reactions providing excellent routes to 2-substituted cycloalkanones. This is illustrated by the addition of the enamine of (S)-2-(methoxymethyl)pyrrolidine and cyclohexanone to 2-(aryl-methylene)-l,3-propanedioates to give, after hydrolysis, the (2 5,a.S )-oxodicstcrs in 35-76% yield with d.r. (2 S,aS)/(2 S,a/ ) 94 6- > 97 3 and 80-95% ee214. 

Trimethylsilylketene and acyl isocyanates generate 4-trimethylsiloxy-l,3-oxazin-6-ones 12 in situ, which smoothly react with the enamines of cycloalkanones to give bicyclic 2-pyridones 13 <96TL(37)4977>. The heterocycles 12 also undergo the Diels-Alder reaction with dimethyl acetylenedicarboxylate or methyl propiolate to furnish substituted 2-pyridones <96TL(37)4973>. 

The addition of a Ni-catalyst to an alkyne as 6/4-47 and a cyclic enone as 6/4-46 in the presence of the chiral ligand 6/4-49 followed by a methyl transfer using Me2Zn led to 3-substituted cycloalkanones as 6/4-48 in good to medium yield, with an ee-... 

Cycloalkenones are ubiquitous as reactive intermediates and bioactive materials. Modification of a simple cycloalkenone by addition of a carbon substituent at the o-position should be a useful transformation, but one that is not readily accomplished by conventional enone chemistry. a-Substituted cycloalkenones could of themselves be of interest, but perhaps, of more general importance would be their use as intermediates for the production of substituted cycloalkanones or a, 5-disubstituted cycloalkanones by a subsequent conjugate addition procedure.2 These strategies avoid many of the limitations attendant to the trapping of enolates with carbon electrophiles. The method of Kim involving treatment of enones with the combination of a dimethyl acetal, pyridine and trimethylsilyl triflates results in a-(1-methoxyalkyljenones.3 The metallation of a-bromoenones masked as ketals for [Pg.184]

In the first method, a dialkylzinc reagent bearing an acetal moiety at the d-posi-tion is used (Scheme 7.25(b)). The catalytic 1,4-addition is followed by acetal hydrolysis and aldol cyclization of the 4-substituted cycloalkanone, affording 6,6- (92), 6,7-, (93) and 6,8- (94) annulated ring systems with high enantioselectivities (>96% ees) [80]. In addition, dimethyl-substituted decalone 95, with a structure frequently found in natural products, is readily obtained in enantiomerically pure form. 

Recently, Corma et al. have patented a process of oxidizing cycloalkane with molecular oxygen to produce cycloalkanol and/or cycloalkanone in the presence of hydrotalcite-intercalated heteropoly anion [Co MnCo (H20)039] (M = W or Mo), which comprised one cobalt as a central atom and another as a substitute of a W=0 fragment in the Keggin structure [98]. At 130 °C and 0.5 MPa, 64 and 24% selectivity to cyclohexanone and cyclohexanol, respectively, was achieved at cyclohexane conversion about 5%. This catalytic system could be of practical importance provided a true heterogeneous nature of catalysis and good catalyst recyclability had been proved. Unfortunately, this information was lacking in [98]. 

Good yields of secondary amines are achieved using both the methods in the reactions of aromatic and aliphatic aldehydes as well as of diaUcyl ketones and cycloalkanones with aliphatic and alicyclic amines (and ammonia). Anilines give low yields, but when 2 equiv is used in the sodium hydrogen telluride method, the yields are improved. In the reaction of ammonia with aldehydes, symmetrical secondary amines are obtained, whereas glu-taraldehyde and amines lead to N-substituted piperidines. 

Of the many substituted and functionalized alkenes that have been combined with diazo dipoles to give A -pyrazolines or products derived from them (i.e., A -pyrazolines, pyrazoles, cyclopropanes), only a selection will be mentioned. These include ot-alkylidene-cycloalkanones (62), -flavanones, -thioflavanones, -chroma-nones, and thiochromanones (63,64) a-arylidene-indanones and -indolones (65) diarylideneacetones (66) l-benzopyran-2(77)-ones (coumarins) (67,68) 4-nitro-1,2-oxazoles (69) 2-alkylidene-2-cyanoacetates (70) dimethyl 2,3-dicyanofuma-rate (71) tetracyanoethylene (72) tetraethyl ethylenetetracarboxylate (72) 1,4-quinones (35,73-75) 2-X-l,l,l-trifluoro-2-propene [X = Br, (76), SPh, SOPh, S02Ph (77)] nitroalkenes (78) including sugar nitroalkenes (79) 1-diethoxyphos-phoryl-1-alkenyl-sulfoxides (80) methyl 2-(acetylamino)cinnamate and -acrylate... 

As alternatives to the 1,2-dihalocycloalkenes, l-halo-2-perfluoroalkanesulfonyloxycycloalkenes can also be favorably employed for twofold Heck reactions. Since they can be easily prepared from the corresponding ketones via the a-haloketones and subsequent sulfonylation of the enolate, this sequence provides a straightforward access to variously substituted 1,3,5-hexatrienes and cyclohexadiene-annelated cycloalkanes, essentially from cycloalkanones (Scheme 13). ... 

Enantlomerically pure B-suhstituted carbonyl compounds serve as useful intermediates in the synthesis of many chiral organic compounds. The enantloselective synthesis of acyclic 0-substituted carboxylic acids has been reported by Meyers, Mukaiyama, and Koga. However, no effective, general method for the enantio-controlled preparation of P-substituted cycloalkanones was available prior to the investigations by the submitters. For example, poor enantloselectivity was observed in conjugate additions of organometallic... 

Intramolecular acylation of thiophenes has been thoroughly examined and shown to provide a reasonable route to substituted cycloalkanones on desulfurization of the bicyclic products (53BSF62, 73BSF343). A variety of five-, six- and seven-membered ring systems have been constructed, e.g. (285) — (287). 

IntramolecularBarbier-type cyclization (12,429-430).1 Cyclizations of 2-(co-iodoalkyl)cyclopentanones induced with Sml2 result almost entirely in cw-fused products (equation I). ds-Fused bicyclic alcohols are also formed selectively from 2-substituted 2-(co-iodoalkyl)cycloalkanones (equation II). 

The fission of a bond on one side of a ketonic carbonyl group following photochemical excitation is known as a-cleavage. This type of reaction is quite general for cycloalkanones. Cleavage occurs preferentially between the carbonyl group and the more heavily substituted a-carbon. 

Chiral 3-substituted cycloalkanones. More recently Posner et al.s have found that the enantioselectivity of the conjugate addition to 2 can be controlled by changes in the experimental conditions. In the absence of a chelating metal, dialkylmagnesium species add predominantly to 2 to give, after desulfonylation, (R)-3-alkylcycloalka-nones (equation I). Zinc-chelated 2 on the other hand reacts with organometallic... 

Reduction of N-benzylimines.2 Borch reduction of imines (4, 450) to amines is not stereoselective, although reduction to equatorial amines is somewhat favored. Reductions with 1 and a number of dialkylcyanqborohydrides are much more stereoselective. Thus substituted cycloalkanone imines are reduced mainly to axial amines. However, highest selectivities are obtained with lithium tri-sec-butylborohy-dride (4, 312). 

The intermediate singlet 1,4-biradical can undergo hydrogen atom transfer to give products where only one C-C single bond has been formed, i.e., alkylated cycloalkanones 24 (Sch. 8). This is most often observed when the biradical has a gem-dimethyl substitution pattern, and is again favored, when the enone itself is easily reducible, e.g., for of-fluoro- or oc -trifluoromethylcycloalkenones [47]. 

Ring enlargement reactions also take place in 2-oxocycloalkane-l-carbonitri-les substituted in 1-position by an co-alkylester or ketone [17]. The introduction of cyano groups into the a-position of cycloalkanones can be carried out in CH2C12 with C1S02NC0 in dimethylformamide [18]. Two and three carbon atom ring expansion reactions are possible by this method. In most cases the yields are low, which is in contrast with the results of the lactonisation (compare... 

The 2-cyano-cycloalkanones are easy to prepare but only in moderate yields [18]. The introductions of nitro- [6] and sulfone- [5] [116] [117] groups are simpler than the cyano group, and the yields are better. Sulfone and cyano compounds are most suitable for the introduction of the side chain. Beside the Michael reaction [16] [97], and the Pd(O) catalyzed addition [15], and the reactions with alkyl halides [16] [17] proceed in good yields. In contrast to other compounds, 2-nitroketones generally do not undergo nucleophilic substitution with non-activated alkyl halides. However, Michael addition products [2], as well as products synthesized by Pd(O) catalyzed alkylation [118], are well known derivatives of 2-nitrocycloalkanones. 

R)-(-)-2,2-Diphenylcyclopentanol (1) is a highly effective chiral auxiliary in asymmetric synthesis. Hydrogenation of chiral 0-acetamidocrotonates derived from this alcohol has afforded the corresponding 0-amido esters with high diastereoselectivity (96% de).6 In addition, (R)-1 has been used as a chiral auxiliary in Mn(lll)-based oxidative free-radical cyclizations to provide diastereomerically enriched cycloalkanones (60% de).7 Our interest in (R)-(-)-2,2-diphenylcyclopentanol is its utility as a chiral auxiliary in Lewis acid-promoted, asymmetric nitroalkene [4+2] cycloadditions. The 2-(acetoxy)vinyl ether derived from alcohol (R)-1 is useful for the asymmetric synthesis of 3-hydroxy-4-substituted pyrrolidines from nitroalkenes (96% ee).8 In a similar fashion, a number of enantiomerically enriched (71-97% ee) N-protected, 3-substituted pyrrolidines have been prepared in two steps from 2-substituted 1-nitroalkenes and (R)-2,2-diphenyl-1-ethenoxycyclopentane (2) (see Table).9... 

---