Preparation of Unsaturated Ketones

Teles etal, US Patent 6,184,420 (February 6, 2001) Assignee BASF Aktiengesellschaft Utility Chemical Intermediate 

Approximately 90 ml of the catalyst from Step 1, 600 g hydro-hydrolinalool (1.30 mol), 306 g of an azeotropic mixture of 2-methoxypropene (3.9 mol) and methanol, and Ig dried and powdered KHSO4 were introduced into a pressure-resistant vessel. The mixture was heated to 140°C 20 minutes at a pressure of 5 bar, then heated an additional 2.5 hours at 120°C. The product yield was 249 g in 85% purity. 

The author also converted 3,7,ll-trimethyldodec-l-yn-3-ol into 6,10,14-pentadeca-4,5-diene-2-one, (I), using excess KHSO4 as illustrated in Eq. 1 and described below. 

A reactor was charged with 3,7,ll-trimethyldodec-7yl-3-ol (45 g), (I), (0.848 mol), 2-methoxypropene (2.78 mol), and KHSO4 (0.58 g in 1.74 g water). The reactor was sealed and heated 1 hour at 120°C whereupon an additional KHSO4 (0.58 g in 1.74 g water) added. The mixture was re-heated 1 hour at 120°C, products separated by distillation, and 6,10,14-pentadeca-4,5-diene-2-one, (II), and 6,10, 14-trimethylpentadeca-3,5-diene-2-one, (III), isolated in 65% and 7% yields, respectively. 

When KHSO4 was replaced by 75% phosphoric acid, the corresponding non-conjugated unsaturated ketone was obtained as illustrated in Eq. 2 described below. 

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The halogenation-dehydrohalogenation of ketones and their derivatives is the most widely applied method for the preparation of unsaturated ketones, and the different combinations of alternatives which exist for both steps extend the scope of this approach. Consequently, this route will be discussed in considerable detail. 

Fig. 16.29. Two-component variant (upper example) and three-component variant (lower example) of Stille reactions to be used for the preparation of unsaturated ketones. The phosphane ligand in the lower example is dppf [for bis(diphenylphosphino)fer-rocene], a diphosphane the structure of this ligand can be derived from the Formulas B-D.

Several protocols for the preparation of unsaturated ketones by the reaction of alkenyl- or alkynyl- metal derivatives with esters or with acid chlorides have been reported. Thus a,0-unsaturated... 

Takagaki, H. Sakai, M. Preparation of unsaturated ketone compounds. Jpn. Kokai Tokkyo Koho JP 04134037, 1992 Chem.Abstr. 1992,117, 171823. 

Numerous variants of the Claisen rearrangement are known which have increased its versatility and made it a powerful synthetic tool. Increased complexity in the vinyl ether portion can be tolerated. Claisen rearrangement using isopropenyl methyl ether in place of ethyl vinyl ether has been used in the preparation of unsaturated ketones as shown in entry 2. A version of the Claisen rearrangement that utilizes 3-methoxyisoprene as the alkyl vinyl ether has proved valuable as a method for introduction of isoprene units in the synthesis of natural products (entry 3). 

Halogenation of the double bond usually prevents the satisfactory preparation of vinylogous a-halo ketones by direct reaction of unsaturated ketones with... 

The preparation of enamine ketones by addition of a,jS-unsaturated ketones to enamines is described in Chapter 4. 

The dehydrogenative condensation of unsaturated ketones with methyl ketones was used for preparing various series of 2,4,6-tri-arylpyrylium salts not only by Dilthey, but also by Wizinger and co-workers (for combinations of phenyl, p-anisyl, and p-dimethyl-aminophenyl substituents), by Amoros-Marin and Carlin (combinations of phenyl and p-chlorophenyl), by Le Fevre and Le Fevre (for combinations of pbenyl and m- or p-nitrophenyl), and by others. ... 

Semmelhack et al. chose CuBr, together with either Red-Al or LiAl(OMe)3H in a 1 2 ratio, to afford presumed hydrido cuprates, albeit of unknown composition [llj. In THF, both the former Na complex and the latter Li complex are heterogeneous (and of differing reactivities), yet each is capable of 1,4-reductions of unsaturated ketones and methyl esters (Eq. 5.4). Commins has used a modified version, prepared from lithium tri-t-butoxy-aluminium hydride and CuBr (in a 3 4.4 ratio), to reduce a 3-substituted-N-acylated pyridine regioselectively at the a-site [12]. 

Claisen-Schmidt condensation org chem A reaction employed for preparation of unsaturated aldehydes and ketones by condensation of aromatic aldehydes with aliphatic aldehydes or ketones in the presence of sodium hydroxide. klas-on jshmit kand-on sa-shon ... 

Another synthetic method for the preparation of aziridinyl ketones involves the initial modification of unsaturated ketones, with formation of /3-methoxyamino derivatives, followed by treatment with either metal alcoholates [11, 28, 29, 30, 31], or hydroxylamine hydrochloride and then potassium hydroxide [32]. An obvious drawback of this approach is the possibility of obtaining an exclusively unsubstituted nitrogen atom for the aziridinyl ketones. Among the advantages are high yields for these reactions. For example, Jin et al. [31] recorded yields of aziridine 18 of 99%. In other publications the yields of target compounds were reported to be around 90%. 

Aldehydes may be prepared by selective hydrogenation of substituted acroleins in much the same manner as the selective reduction of unsaturated ketones (method 196) however, there are few examples adequately described. - ... 

Oxidations with manganese dioxide are well suited for the preparation of unsaturated and acetylenic ketones [524]. The yields depend on the method of preparation, dryness and particle size of the oxidant, and, to a smaller extent, on reaction temperatures and times [SOS] (equation 254). 

The best known and most widely used diazoalkane is diazomethane (95 equation 39). Preparative methods for diazomethane involve, in general, the nitrosation of a methylamine derivative (93), followed by cleavage under alkaline conditions. Methylamine derivatives used have included the urethanes, ureas,carboxamides, sulfonamides, guanidines and even the methylamine adducts of unsaturated ketones and sulfones. N-nitroso-N-methyl p-toluenesulfonamide (Diazald, Aldrich) is currently the most commonly used diazomethane precursor. Diazomethane is both toxic and explosive. Although in the past it has been purified by codistillation with ether, it is now usually generated, stored and used as an ether solution without distillation. 

The synthesis of the nonsteroidal anti-inflammatory drug nabumetone (9) was developed by Hoechst-Celanese [71]. It was prepared via a Heck coupling of 2-bromo-6-methoxy-naphthalene (1) with methyl vinyl ketone in the presence of palladium catalyst [71]. Further reduction of unsaturated ketone provided 9. Nabumetone was also obtained in a one-step coupling reaction of 2-bromo-6-methoxy-naphthalene with 3-buten-2-ol followed by isomerization of enol [72]. 

Formation of a double bond between carbon and a heteroatom or between two heteroatoms can be accomplished by a hetero retro-Diels-Alder reaction. Aldehydes, ketones and carboxylic esters can be obtain by this retrodiene process. A series of a,3-unsaturated aldehydes (152) was prepared by Funk using the facile bis-hetero retro-Diels-Alder reaction of 4-alkyl-4//-1,3-dioxins (151) as shown in equation (66). This retrodiene process involves exceptionally mild conditions, refluxing in toluene, in oMer to unmask the a, -unsaturated aldehyde. The diversity of this process is illustrated by the partial list of reactions shown.The same mild conditions can be used to prepare a, -unsaturated ketones by reflux-... 

Mannich bases are often valuable intermediates for preparation of unsaturated compounds. They are obtained by the action of formaldehyde and ammonia or a primary or secondary amine on compounds containing active hydrogen.77,78 When a Mannich base or its salt is heated, the amino group is split off and the unsaturated compound is formed. Unsaturated ketones,79 aldehydes,80 acids,77 and nitro compounds81 can all be thus prepared. 

The classification is unaffected by allylic, vinylic, or acetylenic unsaturation appearing in both starting material and product, or by increases or decreases in the length of carbon chains for example, the reactions f-BuOH f-BuCOOH, PhCHgOH PhCOOH, and PhCH=CHCH20H PhCH=CHCOOH would all be considered as preparations of carboxylic acids from alcohols. Conjugate reduction and alkylation of unsaturated ketones, aldehydes, esters, acids, and nitriles have been placed in Sections 74D and 74E (Alkyls from Alkenes), respectively. 

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