Lactams, preparation from ketones

Since oximes are obtained from condensation reactions of ketones with hydroxylamine, the single-pot preparation of amides and lactams directly from ketones and H2NOH.HCI was achieved via in situ generated oximes, by using the above catalyst in nitromethane under azeotropic conditions. 

Samarium(II) iodide also allows the reductive coupling of sulfur-substituted aromatic lactams such as 7-166 with carbonyl compounds to afford a-hydroxyalkylated lactams 7-167 with a high anti-selectivity [74]. The substituted lactams can easily be prepared from imides 7-165. The reaction is initiated by a reductive desulfuration with samarium(ll) iodide to give a radical, which can be intercepted by the added aldehyde to give the desired products 7-167. Ketones can be used as the carbonyl moiety instead of aldehydes, with good - albeit slightly lower - yields. 

Ketones, preparation from carboxylic acid, 66, 119 8-Lactams, 65, 140... 

With the procedure for constructing the quaternary carbon stereocenter in hand, the conversion of the ris-form to the trans form was explored in accordance with the synthetic plan shown in Scheme 9. The ketone moiety of the 1,4-conjugated adduct 61 was protected by an acetal group, followed by decarboxylation of compound 65 using sodium ethylthiolate to yield lactam trans-62 and cis-62 as an 8 1 diastereomixture [31]. The reason why the lactam trans-62 was obtained as a major product is that the subsequent protonation after decarboxylation proceeded kinetically. This assertion is supported by experimental results in which the trans- and cis-lactam diastereomixture (8 1) in ethanol was refluxed in the presence of potassium hydroxide to afford a 1 5 mixture [15,32,33]. The mixture of the lactam trans-62 and cis-62 was reduced with DIBALH, followed by treatment with sodium hydroxide to give bicyclic enamine 63. The kinetic iminium salt prepared from bicyclic enamine 63 with hydrochloric acid was reduced with sodium cyanoborohydride, leading to the frans-decahydroisoquinoline structure [22], The acetal moiety of the resultant 67 was removed to provide the objective ketones 68a and 2c. This method enabled the construction of the tra s-decahydroisoquinoline structure without an intermediate resembling the neurotoxic MPTP, and in fewer steps. 

Oxidative methanolysis of azetidinone 176 followed by hydrogenolysis of compound 177 afforded /3-lactam 178, which was protected to obtain the protected amine 179. The best conditions for rearrangement of 179 were found using TFA. Conversion of compound 180 to carbacephem 183 was accomplished by ketone reduction, alcohol protection, and elimination of methanol. Synthesis of carbacephem derivative 186 has been performed by rhodium(n)-catalyzed cycliza-tion of iodonium ylide 185 <1997TL6981> (Scheme 33). The iodonium ylide 185 was easily prepared from the corresponding /3-keto ester 184 and [(diacetoxy)iodo]benzene in good yield. 

Similarly, urea TV, 0-acetal 64 undergoes condensation reaction with weak carbon acids to afford acyclic 1,1-enediamines with the elimination of alcohol and amine42,95. A number of active methyl compounds such as an aliphatic ketone, acetophenone, imino ester and thioacetoamide has been successfully converted to 1,1-enediamines. Lactones, lactams and thiolactams condense with 64 to give enediamines 65 in moderate yields (equation 24). Very weakly activated methyl groups are also reactive towards urea A, 0-acetal 64, and 1,1-enediamines 66-71 are prepared from the corresponding reactants42,95. 

Isatin.—Furthermore, a di-ketone derivative of di-hydro indole-known as isatin is prepared from ortho-amino benzoyl formic acid as a lactam anhydride. 

Indium enolates, prepared conveniently by transmetalation of hfhium enolates with IriCl j, react wifh aldehydes to give fhe corresponding -hydroxy esters [80]. Ultrasound irradiation promotes fhe Reformatsky reaction of aldehydes and ethyl bromoacetate wifh indium [81]. Indium-mediated Reformatsky reaction of phenyl a-bromoalkanoates wifh ketones or aldehydes gives di-, tri-, and tetrasubstituted -lactones (Scheme 8.57) [82]. Indium-mediated reaction of imines with ethyl bromoacetate gives 3-unsubstituted -lactams (Scheme 8.58) [83]. An indium-Refor-matsky reagent prepared from 2-(chlorodifluoroacetyl)furan couples with aldehydes (Scheme 8.59) [84]. 

Ethoxybutadienylboronate 88 was prepared from a,j3-unsaturated acetal 87, and used for synthesis of phenyl 1-propenyl ketone (89) by S-MC and hydrolysis [82]. Similarly the 2-acyl-l,4,5,6-tetrahydropyridine 91 was prepared by the coupling of 90 with an alkenyl triflate, which was derived from the corresponding lactam [83]. 

As the first example of the application of our methodology, we picked yohimbine and alloyohimbine. The enamide was prepared from harmalane by acylation with p-methoxybenzoyl chloride and irradiated according to the established reductive photocyclization condition to afford the lactam with a methoxy-substituted dihydrobenzene moiety, which then underwent a facile hydrolytic cleavage to give the corresponding ketone. After reduction of the lactam carbonyl, acid treatment converted the enol ether into the 6,y -unsaturated ketone in good yield. 

Stork and Livingston have also employed a Michael reaction methodology in a concise synthesis of alloyohimbone 247 (Scheme 3.37). In this sequence, the Schilf base 243, prepared from tryptamine and 4-methoxybenzaldehyde, underwent sequential Birch reduction and acylation to afford the cyclo-hexadiene 244. Hydrolysis provided the corresponding a, ) -unsaturated ketone. Under basic conditions, the key Michael addition took place to yield the cis-fused bicyclic lactam 245. Decarboxylation and ketalization afforded 246 which underwent Bischler-Napieralski cyclization and subsequent deke-talization to afford alloyohimbone 247. All in all. Stork has shown that Michael addition methodologies can be successfully employed to construct the pentacyclic yohimbine alkaloid skeleton in an eflBcient stereoselective manner. 

Regioselective Beckmann rearrangements were used as key steps in the synthesis of phosphonoalkyl azepinones (Scheme 36) [43b] and in a formal total synthesis of the protein kinase C inhibitor balanol (Scheme 37) the optically active azide 197 derived from cyclohexadiene mono-oxide was converted into ketone 198 in several steps. After preparation of the oxime tosylates 199 (2.3 1 mixture), a Lewis acid mediated regioselective Beckmann rearrangement gave the lactams 200 and 201 in 66% and 9% yield, respectively. Lactam 201 underwent a 3-e im-ination to give additional 200, which served as a key intermediate in a balanol precursor synthesis (Scheme 37) [43 cj. 

The Baylis-Hillman reaction of TV-protected 3-substituted 4-formylazetidin-2-ones with methyl vinyl ketone has been used to prepare intermediates from which highly functionalised P-lactams fused to medium rings were obtained by radical, stereocontrolled methods <99CC1913>. 

The silyloxypyrrole 309 was prepared in 91% yield from the ,/3-unsaturated lactam 308 with TBDMSOTf and 2,6-lutidine (Equation 54) <1999TL2525>. Alternatively, the pyrrolo[l,2-f]oxazoles derivatives 311 were prepared by reaction between the stable bcnzotriazol-1 -yl(l //-pyrrol-2-yl)methanone 310 and various ketones (Equation 55) <2004JOC9313>. These two examples are the rare representatives of the pyrrolo[l,2-r ]oxazole ring system described in the literature to date. 

BC13 convert 0=0 groups of ketones, lactones, and lactams to G=S groups119 and H2S-Me3SiCl-i-Pr2NLi converts carboxylic esters to thiono esters.120 Carboxylic acids RCOOH can be converted directly to dithiocarboxylic esters RCSSR, 120a in moderate yield, with P4S, and a primary alcohol R OH.121 Thioketones can also be prepared by treatment of ketones with P4SI0,122 and from oximes or various types of hydrazone (overall conversion C=N------> C=S).123... 

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