SYNTHESIS 2-methoxycarbonyl-2 -methyl

The first synthesis of a 3//-3-benzazepine, e.g. 65 (R1 = R2 = Me), was achieved by the condensation of phthalaldehyde with a bis[(alkoxycarbonyl)methyl]methylamine.24"25 With sodium methoxide as the base, A%V-bis[(methoxycarbonyl)methyl]pheiiylaniine condenses with the dialdehyde in a similar manner to give dimethyl 3-phenyl-3//-3-benzazepine-2,4-dicar-boxy late (65, Rl — Ph R2 — Me).99 However, replacement of methoxide by potassium tert-butoxide results in formation of 3-phenyl-3//-3-benzazepine-2,4-dicarboxylic acid (65, R1 = Ph R2 = H).25... 

Anderson, Goodman, and Baker employed an O-(methoxycarbonyl) protecting group in an analogous manner for their synthesis of methyl 2,3-anhydro-D-ribofuranoside (XLV). Treatment of 1,2-0-isopropylidene-D-xylofuranose (XLI) with methyl chloroformate in pyridine gave, by preferential esterification of the least-hindered alcohol group (at C5), predominantly 1,2-0-isopropylidene-5-0-(methoxycarbonyl)-D-xylofuranose (XLII) a small proportion of the 3,5-di-0-(methoxycarbonyl) derivative was separated by fractional recrystallization. Subsequently, the C3-hydroxyl was esterified with tosyl chloride, and the resulting 3-0-tosyl ester XLIII... 

Fu, Z.H. Ono, Y. Synthesis of methyl A-phenyl carbamate by methoxycarbonylation of aniline with dimethyl carbonate using Pb compounds as catalysts. J. Mol. Catal. 1994, 91, 399-405. 

Synthesis (S)-3-di(methoxycarbonyl)methyl-1-cyclohexanone from the Michael... 

SYNTHESIS OF (S)-3-DI(METHOXYCARBONYL)METHYL-1 -CYCLOPENTANONE FROM THE MICHAEL REACTION OF DIMETHYL MALONATE AND 2-CYCLOPENTEN-l-ONE CATALYSED BY Ru[(R,R)-TsDPEN](HMB)... 

H-Azepine, 2-methyl-1-methoxycarbonyl-rearrangement, 7, 504 1 //-Azepine, 3-methyl-1 -methoxycarbonyl-cycloaddition reactions, 7, 520 IH-Azepine, 1-phenyl-synthesis, 7, 542 1 H-Azepine, N-phthalimido-formation, 7, 508 IH-Azepine, N-sulfonyl-UV spectra, 7, 501 1 H-Azepine, tetrahydromethylene-synthesis, 7, 540 IH-Azepine, N-p-tosyl-protonation, 7, 509 synthesis, 7, 537 3H-Azepine, 3-acyl-2-alkoxy-synthesis, 7, 542-543 3H-Azepine, 3-acyl-2-methoxy-rearrangements, 7, 505 3H-Azepine, 2-alkoxy-hydrolysis, 7, 510... 

Azocin-2( 1H )-one, hexahydro- 1-phenyl-photochemical rearrangement, 7, 656 Azodn-2( 1H )-one, 1,2,7,8-tetrahydro-synthesis, 7, 662 Azocin-5-one IR spectra, 7, 16 transannular interactions, 7, 14 Azocin-5-one, l-(2,4-dimethylphenyl)-IR spectrum, 7, 657 Azocin-5-one, methoxycarbonyl-synthesis, 7, 657 Azocin-5-one, 1-methyl-IR spectrum, 7, 657 synthesis, 7, 657 Azodn-5-one, 1-p-tolyl-IR spectrum, 7, 657 Azocinones... 

Piperidine, l-(2-hydroxythiobenzoyI)-neutron diffraction, 2, 116 Piperidine, 4-hydroxy-2,2,6-trimethyI-as local anaesthetic, 1, 179 Piperidine, JV-methoxycarbonyl-electrolytic oxidation, 2, 374 Piperidine, 2-methyl-synthesis, 2, 524 Piperidine, 3-methyI-mass spectrometry, 2, 130 Piperidine, C-methyl-NMR, 2, 160 Piperidine, JV-methyl- C chemical shifts, 2, 15 catalyst... 

Pyran-2-one, 3,5-bis(methoxycarbonyl)-6-methyl-synthesis, 3, 789-790 Pyran-2-one, 3-bromo-synthesis, 3, 679 Pyran-2-one, 4,6-dialkoxy-reactions... 

Pyridinium iodide, l-ethyl-4-methoxycarbonyl-UV spectrum, 2, 127 Pyridinium iodide, 1-methyl-decomposition, 2, 300 Pyridinium iodide, 6-pterinylmethyl-synthesis, 3, 312... 

The synthetic utility of radical cyclization was used as the key step in a four-step synthesis of the natural product (d,0-epilupinine (134b, a quinolizidine alkaloid) (75CB1043) from methyl nicotinate (146). Thus, l-(4-bromobutyl)-3-methoxycarbonyl-l,4,5,6-tetrahydropyridine (140), obtained from methyl nicotinate (146), was cyclized to 141 (43%), which on reduction with LiAlH4 in THF provided 134b in 95% yield (89T5269). 

The synthesis of the E-ring intermediate 20 commences with the methyl ester of enantiomerically pure L-serine hydrochloride (22) (see Scheme 9). The primary amino group of 22 can be alkylated in a straightforward manner by treatment with acetaldehyde, followed by reduction of the intermediate imine with sodium borohydride (see 22 —> 51). The primary hydroxyl and secondary amino groups in 51 are affixed to adjacent carbon atoms. By virtue of this close spatial relationship, it seemed reasonable to expect that the simultaneous protection of these two functions in the form of an oxazolidi-none ring could be achieved. Indeed, treatment of 51 with l,l -car-bonyldiimidazole in refluxing acetonitrile, followed by partial reduction of the methoxycarbonyl function with one equivalent of Dibal-H provides oxazolidinone aldehyde 52. 

The method described for the preparation of 4-methoxycarbonyl-2-methyl-1,3-oxazole is that of Cornforth, and is widely applicable to the synthesis of 2-substituted 1,3-oxazole-4-carboxylates. The appropriate imidate hydrochloride required for step A is obtained from the reaction of a nitrile with an alcohol in the presence of hydrochloric add (eq. 1 ). A different synthesis of 2-substituted 1,3-oxazole-4-carboxylates employing rhodium-catalyzed heterocycloaddition of a diazomalonate to a nitrile has been described in Organic Syntheses by Helquist, but appears to be less general than the present route. 

Dihydrothieno[3,4-Z ]thiophene (131) was prepared by two methods. In the first (Scheme 8), chloromethylation of methyl thiophene-2-carboxylate (132) forms methyl 2,3-bischloromethyl-thiophene-5-carboxylate (133) (85%) cyclization of 133 with sodium sulfide in methanol yields (66%) methyl 4,6-dihydrothieno[3,4-i]-thiophene-2-carboxylate (134). Peroxide oxidation of 134 gives 2-methoxycarbonyl-4,6-dihydrothieno[3,4-h]thiophene 5,5-dioxide (135) and hydrolysis of 134 followed by metaperiodate oxidation furnishes the sulfoxide (91). Thienothiophene (131) was produced by hydrolysis and decarboxylation of 134. As indicated above, the sulfoxide (91) was used for the synthesis of thieno[3,4-6]thiophene (3). 

New pyrazolo[l,5-a]pyrimidine derivatives have been synthesized. These compounds are potent angiotensin-ll receptor antagonists <99CPB928>. Pyrazolot3,4-ri]dihydropyridazinone derivatives have been obtained by the reaction of 5-methyl-4-methoxycarbonyl-3-acetyl-1-phenylpyrazole with different hydrazines <99TL3891>. A direct synthesis of pyrazolo [3,4-b]pyridines 69 from pyrazole 67 and benzothiazole 68, through a Friendlander condensation, has been described <99SC655>. 

Similarly, Uneyama and Watanabe (91TL1459) have reported the synthesis of trifluoromethylated AI-aryl-1-azabutadienes by palladium-catalyzed coupling of trifluoroacetimidoyl iodides with alkenes as well as the transformation of the azadiene derived from methyl acrylate into the corresponding 4-methoxycarbonyl-2-trifluoromethylquinoline in quantitative yield. 

The Comforth synthesis of oxazoles is useful for the preparation of 4-methoxycarbonyl derivatives, which are found in many natural products (92CC1240). In this method, a glycine imidate is reacted with a strong base and methyl formate to give an enolate that cyclizes upon treatment with acetic acid (Scheme 32). 

A convenient asymmetric synthesis of a-hydroxyaldehydes begins with the addition of a Grignard reagent to the methoxycarbonyl aminal (238) prepared from methyl hydroxy-methoxyacetate and diamine (236) (79CL705). Treatment of the derived keto aminal (239) with a second Grignard reagent and hydrolysis of the resulting hydroxy aminal (240) yields the optically active a-hydroxyaldehyde (241). Enantiomeric excesses vary between 78 and... 

An approach to the synthesis of angularly substituted polycyclics through the Diels-Alder cycloaddition of dihydrothiophenes has been devised (69JA7780). The easily prepared 2,5-dihydro-4-methoxycarbonyl-2-thiopheneacetic acid methyl ester (316) was heated at 180 °C with excess butadiene to yield (317). Desulfurization and double bond reduction of the cycloadduct with W-5 Raney nickel gave (318) which was characterized by conversion to the corresponding diacid and comparison with an authentic sample. Dieckmann cyclization of (318) is known to lead to the 5-methyl-1-hydrindanone (319 Scheme 68). The use of other dienes in the [4 + 2] cycloaddition process will, of course, produce more highly functionalized hydrindanones. 

A convenient synthesis of thieno[2,3-6]quinoline (Scheme 111) (76ZN(B)1297,76ZN(B)1685, 77JCS(P1)2024) utilizes the readily available methyl 2-oxo-3-vinyl-l//-quinoIin-4-carboxylate (380) as starting material. Treatment of (380) with phosphorus oxychloride yields the chloroquinoline which on addition of bromine gives a trihalo compound. The cyclization to (381) is effected with thiourea in boiling ethanol. Elimination of the methoxycarbonyl group yields thieno[2,3-6]quinoline as colorless needles with m.p. 107-108 °C, which can be characterized as the picrate with m.p. 213-214 °C. 

More recently, Hoppe et all63 also reported a stereoselective synthesis of a P -amino-u -hydroxy enone and its transformation to a 1,2-dihydroxyethylene isostere (Scheme 29). The addition of dilithium dimethylcyanocuprate to the conjugated C=C bond proceeds smoothly to produce a Z-enolate. The C-methoxycarbonylation with methyl cyanoformate forms the epimeric mixture of the 3-oxo ester. The product is then reduced with sodium cyanobo-rohyde to provide a protected form of the 1,2-dihydroxyethylene isostere. 

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