Notes: Amination Reactions of cis-1,4-Dichloro-2-butene

Bobbitt, James M.; Amundsen, Lawrence H.; Steiner, Russell

doi:10.1021/jo01082a610

Cited by 41 publications

(20 citation statements)

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“…This analog was -5 times more active than DOX in inhibiting growth of the MCF-7 human breast cancer cell line in vitro. Synthesis was accomplished by reacting a 15-fold excess of cis-1,4-dichloro-2-butene (22) with DOX in the presence of an excess of tertiary base. The yield was 37% after purification by HPLC.…”

Section: Methodsmentioning

confidence: 99%

High yield conversion of doxorubicin to 2-pyrrolinodoxorubicin, an analog 500-1000 times more potent: structure-activity relationship of daunosamine-modified derivatives of doxorubicin.

Nagy¹,

Armatis²,

Schally³

1996

Proc. Natl. Acad. Sci. U.S.A.

106

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A convenient, high yield conversion of doxorubicin to 3'-deamino-3'-(2''-pyrroline-1''-yl)doxorubicin is described. This daunosamine-modified analog of doxorubicin is 500-1000 times more active in vitro than doxorubicin. The conversion is effected by using a 30-fold excess of 4-iodobutyraldehyde in anhydrous dimethylformamide. The yield is higher than 85%. A homolog of this compound, 3'-deamino-3'-(1'',3''-tetrahydropyridine-1''-yl)doxorubicin, was also synthesized by using 5-iodovaleraldehyde. In this homolog, the daunosamine nitrogen is incorporated into a six- instead of a five-membered ring. This analog was 30-50 times less active than its counterpart with a five-membered ring. A similar structure-activity relationship was found when 3'-deamino-3'-(3''-pyrrolidone-1''-yl)doxorubicin (containing a five-membered ring) and 3'-deamino-3'-(3''-piperidone-1''-yl)doxorubicin (with a six-membered ring) were tested in vitro, the former being 5 times more potent than the latter. To further elucidate structure-activity relationships, 3'-deamino-3'-(pyrrolidine-1''-yl)doxorubicin, 3'-deamino-3'-(isoindoline-2''-yl)doxorubicin, 3'-deamino-3'-(2''-methyl-2''-pyrroline-1''-yl)doxorubicin, and 3'-deamino-3'-(3''-pyrroline-1''-yl)doxorubicin were also synthesized and tested. All the analogs were prepared by using reactive halogen compounds for incorporating the daunosamine nitrogen of doxorubicin into a five- or six-membered ring. These highly active antineoplastic agents can be used for incorporation into targeted cytotoxic analogs of luteinizing hormone-releasing hormone intended for cancer therapy.

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Section: Methodsmentioning

confidence: 99%

High yield conversion of doxorubicin to 2-pyrrolinodoxorubicin, an analog 500-1000 times more potent: structure-activity relationship of daunosamine-modified derivatives of doxorubicin.

Nagy¹,

Armatis²,

Schally³

1996

Proc. Natl. Acad. Sci. U.S.A.

106

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“…In the case of hydrazine, the starting esters returned unchanged, although it is known [20][21][22]26] that adamantylated β-keto esters 19 and 21 could be transformed into the corresponding pyrazoles quite easily under these conditions. An attempt to obtain a pyridine structure according to the method previously developed for ethyl acetoacetate [29] by boiling phenyl ester 6 with cyanoacetamide in methanol in the presence of KOH resulted only in the formation of methyl ester 4 by interesterification. We could also not get the oxime of 22 by its reaction with hydroxylamine in the presence of various bases (NEt 3 , pyridine).…”

Section: Resultsmentioning

confidence: 71%

Self‐Acylation of 1‐Adamantylacetic Acid in Trifluoroacetic Anhydride Medium: A Route to 2,4‐Bis(1‐adamantyl)acetoacetic Acid and Its Derivatives

et al. 2010

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The self‐acylation of 1‐adamantylacetic acid (1) in trifluoroacetic anhydride, catalyzed by triflic acid, proceeds through the formation of the mixed 2,4‐bis(1‐adamantyl)acetoacetic–trifluoroacetic anhydride 2, and it was used as an efficient approach to previously unknown 2,4‐bis(1‐adamantyl)acetoacetic acid (3), its esters 4–6 and amides 7–11, and the sterically hindered 1‐adamantyl(1‐adamantylacetyl)ketene (12). The latter is stable in solution and can be isolated as a neat solid. Addition of methanol or primary amines to 12 gave the corresponding derivatives of acid 3. Acid 3 was decarboxylated to 1,3‐bis(1‐adamantyl)acetone (22), whereas theheterocyclization of phenyl ester 6 with thiourea gave two isomeric adamantylated thiouracils 23 and 24. The structures of N‐benzylamide 7 and thiouracil 23 were confirmed by single‐crystal X‐ray analysis. The utilization of the self‐acylation method for the conversion of some other aliphatic acids is discussed and preliminarily tested.

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“…-Tsuchiya® reduced 6 according to Knorr^, but contrary to his finding a mixture of about 68 % 5 and 32 % 4 arose in our hands ( J H-NMR spectroscopy). -Lehn et al 8 > synthesized N-methyl-A 3 -pyrroline for NMR-experiments without giving experimental details, condensing cisl,4-dichloro-2-butene with methylamine using Bobbitfs general approach 9 ) for N-alkylated A 3 -pyrrolines.…”

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confidence: 99%

Preparation and GC‐MS‐Identification of N‐Methyl‐Δ³‐pyrroline

Mahboobi

Fischer

Eibler

et al. 1988

Archiv der Pharmazie

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The preparation of N-methyl-A 3 -pyrroline by 1) reduction of N-methylpyrrole followed by gc-separation or by 2) condensation of cis-l,4-dichloro-2-butene with methylamine is described. The title compound is identified by GC-MS. Darstellung und GC-MS-Untersuchungen an N-Methyl-A -pyrrolinDie Darstellung von N-Methyl-A 3 -pyrrolin 1) durch Reduktion von NMethylpyrrol mit anschließender gc-Trennung und 2) durch Kondensation von cis-l,4-Dichlor-2-buten mit Methylamin wird beschrieben. Die Titelverbindung wird durch GC-MS identifiziert.In the course of our synthesis of rac. macrostomine (2) 1 ) the last step comprises a Pd/C-catalyzed dehydrogenation of the 3,4-dihydroisoquinoline 1 (solvent: tetralin). 1 lost unexpectedly the N-methylpyrrolidine group under formation of the 1-benzylisoquinoline 3 2) and minor amounts of 2.Later Kapil et al. In order to find out what had happened to the N-methylpyrrolidine moiety during the reaction mentioned above, we connected the reaction vessel containing 1, Pd/C, and tetrar lin to a special trapping device (Fig. 1) for collecting possible volatile components, e. g. N-methylpyrrolidine (4), N-methyl-A 3 -pyrroline (5), and/or N-methylpyrrole (6). For separation and identification of 4-6 we developed a GC-MS-procedure (Fig. 2). 4,5, and 6 proved to be stable under the pertinent conditions provided there is no Pd present (see below).GC-MS-analysis of the volatile components from the dehydrogenation of 1 (Scheme) indicated that a N-methyl- GC-MS-Separation pyrroline (M 4 " = m/z 83) and traces of 4 (M + * = m/z 85) had been formed. The quantity of the N-methylpyrroline was too small for ^-NMR spectroscopy. In the GC-EI-MS of this compound no loss of C 2 H 3 (27 mu) from (M-l) + was observed nor did we find the elimination of H 2 C = CH 2 from M + ' which is reported for molecules containing a A^pyrro-line increment^. So we assumed that N-methyl-A 3 -pyrroline (5) had been generated. For its identification we needed authentic 5.Various methods for the preparation of 5 are reported: Lukes et al.5) reduced 6 with Zn/HCl to a mixture of 5 and 4, which -as we found -contains components with M +> > m/z 85. This mixture was separated by prep. GC. -Tsuchiya® reduced 6 according to Knorr^, but contrary to his finding a mixture of about 68 % 5 and 32 % 4 arose in our hands ( J H-NMR spectroscopy). -Lehn et al. > synthesized N-methyl-A 3 -pyrroline for NMR-experiments without giving experimental details, condensing cisl,4-dichloro-2-butene with methylamine using Bobbitfs general approach 9 ) for N-alkylated A 3 -pyrrolines.After various trials this twofold condensation yielded 60-80 % 5 in our hands (cf. Exp. Part). 5 is extremely volatile, it is identical with the N-methylpyrroline obtained in the dehydrogenation of 1 (GC, MS).In order to find out whether 5 is stable under the conditions used for the dehydrogenation of 1 to 2 and 3, we treated 5 with Pd/C in tetralin at 190 °C and found some 6 besides the educt 5. Tetralin had been dehydrogenated to 1,2-dihydronaphthalene (7) and naphthalene...

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Notes: Amination Reactions of cis-1,4-Dichloro-2-butene

Cited by 41 publications

References 1 publication

High yield conversion of doxorubicin to 2-pyrrolinodoxorubicin, an analog 500-1000 times more potent: structure-activity relationship of daunosamine-modified derivatives of doxorubicin.

High yield conversion of doxorubicin to 2-pyrrolinodoxorubicin, an analog 500-1000 times more potent: structure-activity relationship of daunosamine-modified derivatives of doxorubicin.

Self‐Acylation of 1‐Adamantylacetic Acid in Trifluoroacetic Anhydride Medium: A Route to 2,4‐Bis(1‐adamantyl)acetoacetic Acid and Its Derivatives

Preparation and GC‐MS‐Identification of N‐Methyl‐Δ³‐pyrroline

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Notes: Amination Reactions of cis-1,4-Dichloro-2-butene

Cited by 41 publications

References 1 publication

High yield conversion of doxorubicin to 2-pyrrolinodoxorubicin, an analog 500-1000 times more potent: structure-activity relationship of daunosamine-modified derivatives of doxorubicin.

High yield conversion of doxorubicin to 2-pyrrolinodoxorubicin, an analog 500-1000 times more potent: structure-activity relationship of daunosamine-modified derivatives of doxorubicin.

Self‐Acylation of 1‐Adamantylacetic Acid in Trifluoroacetic Anhydride Medium: A Route to 2,4‐Bis(1‐adamantyl)acetoacetic Acid and Its Derivatives

Preparation and GC‐MS‐Identification of N‐Methyl‐Δ3‐pyrroline

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Preparation and GC‐MS‐Identification of N‐Methyl‐Δ³‐pyrroline