Piperidines formylation

Stigmasterol from soy bean extracts can be selectively ozonolyzed on the side-chain double bond. The 20-formyl group formed is converted to the enamine with piperidine. This can be oxidized to progesterone. 

With malonic acid in a mixture of pyridine and piperidine 2-phenyl-4-formyl-5-chlorothiazole yields 2-phenyl-5-chloro-4-thiazoleacrylic acid (103). 

The enamine (191) from isobutyraldehyde on treatment with p-nitrophenyl-diazonium chloride, on the other hand, gave the p-nitrophenylhydrazone of acetone (192) and presumably N-formyl piperidine, although the latter was not isolated. 

Secondary amines such as dibenzylamine or 4-substituted piperidines are readily formylated in yields of up to 94% at room temperature by excess N,N-di-methylformamide (DMFj/MesSiCl 14/imidazole with formation of HCl and HMDSO 7 [32aj. 

A second convergent synthesis of haliclamine A (64) was achieved in a stepwise sequence from cyclopropyl(thiophen-2-yl)methanone (76) (Scheme 7) [37]. The protected thiophene 77 was condensed with formyl-piperidine to give 78, suitable for a Wittig olefination with 79. After desulfurization of the product 80, the deprotected alcohol 82 was subjected to homoallylic rearrangement using MesSiBr in the presence of ZnBr2. The re-... 

The very first report on the use of ionic liquids as soluble supports was presented by Fraga-Dubreuil and Bazureau in 2001 [102]. The efficacy of a microwave-induced solvent-free Knoevenagel condensation of a formyl group on the ionic liquid (IL) phase with malonate derivatives (E1CH2E2) catalyzed by 2 mol% of piperidine was studied (Scheme 7.89). The progress of the reaction could be easily monitored by 1H and 13C NMR spectroscopy, and the final products could be cleaved from the IL... 

The side-chain amino group of lysine is a strong nucleophile, the reactivity of which cannot be suppressed by protonation, so it must be protected at all times. Acyl groups such as formyl, which is stable to alkali, ammonia, and hydrogenation but sensitive to mild acid, and trifluoroacetyl (see Section 3.9), which is stable to piperidine and... 

CHj cho HjS/H3C - OH/wenig Piperidin 10-20", 30 min 2-A mino-3-formyl- /-methyl-indol 94 2... 

CH3 OHC CsHs H2S/H3C—OH/wenig Piperidin 10-20°, 30 min 5-Amino-4-formyl-l-me- thyl-3-phenyl-pyrazol 64 2... 

The ruthenium carbonyl complexes [Ru(CO)2(OCOCH3)] n, Ru3(CO)12, and a new one, tentatively formulated [HRu-(CO)s ] n, homogeneously catalyze the carbonylation of cyclic secondary amines under mild conditions (1 atm, 75°C) to give exclusively the N-formyl products. The acetate polymer dissolves in amines to give [Ru(CO)2(OCOCH3)(amine)]2 dimers. Kinetic studies on piperidine carbonylation catalyzed by the acetate polymer (in neat amine) and the iiydride polymer (in toluene-amine solutions) indicate that a monomeric tricarbonyl species is involved in the mechanism in each case. 

This paper summarizes our efforts to date and is concerned primarily with kinetic and mechanistic studies on the catalytic carbonylation of piperidine to N-formyl product using a ruthenium (I) -bridged acetate dicarbonyl polymer [Ru(CO)2(OCOCH3)] (6,7) and a less well-characterized polymeric hydridocarbonyl [HRu(CO)3]n (7). Kealy and Benson (8) noted the formation of N-cyclohexylformamide when car-bonylating cyclohexylamine in the presence of allene using Ru2(CO)9 [now known (9) to be Ru3(CO)i2] at high temperature and pressure. 

Adding N-formyl product (and other amides such as N,N-dimethyl-acetamide) decreases the carbonylation rate, and thus accumulation of product slowly poisons the catalyst. The rate for the piperidine system (Table I) after 70 hrs decreased to 0.4 X 10"5M sec1, and at this stage about 100 moles of amine were carbonylated per mole of ruthenium. Amine solutions of the dimers are quite stable at 75 °C for long periods in vacuo or under argon, and there is no trace of N-formylamine. 

The IR of the isolated crude complex also indicates some free formyl-piperidine, and chemical analyses are consistent with 80% HRu(CO)2-(pip) +20% Cr,H10 NCHO. 

Thus we tend to favor the mechanism outlined in Reactions 12 and 13 (followed by Reactions 7 and 8). The mechanisms as presented do not indicate how the N-formyl product is formed although formation of a Ru-CO-N moiety at some stage seems essential metal-assisted hydride shifts are a possibility. An alternative role of the attacking piperidine in Reaction 12 or 17 could be that of a proton acceptor as discussed by others (1, 13). For example, a plausible scheme would be the following (writing R2 for C5H10)... 

The stoichiometric carbonylation observed using [HRu(CO)3] and the proposed catalytic schemes all involve tricarbonyl species as the active catalyst the relatively high activity of Ru3(CO)i2 is consistent with this. The relative activity of the complexes for piperidine carbonylation is [HRu(CO)3L Ru3(CO)12 > [Ru(CO)2(OCOMe)]n. The major cause of the decrease in carbonylation rates is the accumulation of formyl product although the decrease in amine concentration is also a contributing factor. This catalyst poisoning is likely attributable to com-plexation to the ruthenium, presumably via the carbonyl grouping as commonly found for formamide ligands (26). The product could compete with either amine or CO for a metal coordination site. 

The synthesis of 3 was carried out as described above with the exception that Boc-Lys(Fmoc)-OH was used in the synthesis in place of Boc-Lys(CHO)-OH (Scheme 4). Following completion of the peptide synthesis, the peptide-bound resin 6 (250 mg) was treated with piperidine/DMF (20 80, 20 mL) for 20 min, the solvent removed by filtration, and the resin washed with CH2C12(3 x 20 mL). DMF (5mL) was added to the resin followed by a CH2C12 soln (5 mL) of formic anhydride, prepared as above, and DIPEA (350 xL, 1 mmol). The resin was shaken for 20 min, the solvent removed by filtration, and the formylation repeated by the addition to the resin of DMF (5 mL), a CH2CI2 soln of formic anhydride (5 mL), and DIPEA (350 pL, 1 mmol). The resin was shaken for 15 min, filtered, washed with CH2C12 (3 x 20 mL), and the resin dried under vacuum to yield 3. The peptide-resin was converted into 4 by treatment with HF as described above. 

Pyrrolo[2,1 -d][ 1,5]benzothiazepine-6-carboxylic acid (27) was obtained via base-catalyzed cyclization of pyrrole-2-carboxaldehydes 26 and 28, each synthesized by Vilsmeier-Haack formylation of their respective pyrroles 24 and 25, prepared in turn by condensation of 18, respectively, with ethyl bromoacetate and chloroacetonitrile in the presence of sodium ethylate at room temperature. When treated with piperidine in refluxing benzene for 48 hours, 26 and 28 afforded ester 29 and nitrile 31 from which, in an alkaline medium, acid 27 could be obtained. Under similar experimental conditions, acid 27 was also formed from amide 30 (Scheme... 

After standing at room temperature for 10 min, a solution of 710 mg of the 4b-methyl-ip-(2-formylethyl)-2p-formyl-2-(2-cyanoethyl)-4p,7a-dihydroxyperhydrophenanthrene 2p,4p-lactol methyl ether 7a-acetate in 5 ml of piperidine and 10 ml of benzene was heated at brisk reflux in a nitrogen atmosphere. After 3 h the solvents were removed under reduced pressure, leaving 820 mg of 4b-methyl-ip-[3-(l-piperidyl)-2-propenyl]-2p-formyl-2-(2-cyanoethyl)-4p,7a-dihydroxyperhydrophenanthrene 2p,4p-lactol methyl ether 7a-acetate as colorless oil. 

A benzene solution (5 ml) of 15 mg of the 4b-methyl-ip,2a-bis-(2-formylmethyl)-2p-formyl-4p,7a-dihydroxyperhydrophenanthrene 2p,4p-lactol 7a-acetate containing 3.4 mg of piperidine and 6.2 mg of acetic acid was heated at 60°C in slow stream of nitrogen with an azeotropic separator. After 1 h, half the solution was withdrawn, diluted with benzene, and washed with diluted aqueous hydrochloric acid and with aqueous sodium bicarbonate. The benzene extract dried over magnesium sulfate and concentrated to dryness under reduced pressure, giving 3a-acetoxy-17-formyl-16-etiocholen-lip-ol-18-one 1 ip, 18-lactol as colorless oil. 

Steroidal, alicyclic or aromatic annulated pyridines were prepared via a microwave-assisted, base-catalyzed Henry reaction of /1-formyl enamides and nitromethane on an alumina support [97]. Highly substituted tri- and tetrasubstituted pyridines were synthesized in a Bohlmann-Rahtz reaction from ethyl /3-amino crotonate and various alkynones. The reaction involved a Michael addition-cyclodehydration sequence and was effected in a single synthetic step under microwave heating conditions [98]. An alternative approach towards polysubstituted pyridines was based on a reaction sequence involving an inverse electron-demand Diels-Alder reaction between various enamines 45 and 1,2,4-triazines 44 (Sect. 3.6), followed by loss of nitrogen and subsequent elimination-aromatization. Enamines 45 were formed in situ from various ketones and piperidine under one-pot microwave dielectric heating conditions [99]. Furthermore, a remarkable acceleration of the reaction speed (from hours and days to minutes) was observed in a microwave-assisted cycloaddition. Unsymmetrically substituted enamines 45 afforded mixtures of regioisomers (Scheme 35). 

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