Amino Ketone Rearrangements. VI. Synthesis of 2-Alkylamino-2-phenylcyclohexanones<sup>1a</sup>

Stevens, Calvin L.; Ash, A. B.; Thuillier, André; Amin, Jahangir; Balys, Aldona; Dennis, William E.; Dickerson, James P.; Glinski, Ronald P.; Hanson, Harry T.; Pillai, Muriraj D.; Stoddard, John W.

doi:10.1021/jo01346a033

Cited by 34 publications

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“…This type of thermal rearrangement has been studied for almost half century first by Stevens [ 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 ] and later on by Compain [ 27 , 28 , 29 , 30 ], however the conditions needed for the reactions were not improved in those works. Interestingly, our starting compounds 4[a–g] , 5[a–g] for the thermal rearrangement were hypothesized (but not isolated) by Stevens (see Figure 2 , Figure 4 and Figure 5 ) as being the intermediates between the starting five member ring A and the product six member ring C isomers in his studies.…”

Section: Resultsmentioning

confidence: 99%

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Improved Methods for Thermal Rearrangement of Alicyclic α-Hydroxyimines to α-Aminoketones: Synthesis of Ketamine Analogues as Antisepsis Candidates

et al. 2012

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Ketamine is an analgesic/anesthetic drug, which, in combination with other drugs, has been used as anesthetic for over 40 years. Ketamine induces its analgesic activities by blocking the N-methyl-D-aspartate (NMDA) receptor in the central nervous system (CNS). We have reported that low doses of ketamine administrated to patients before incision significantly reduced post-operative inflammation as reflected by reduced interleukin-6 (IL-6) sera-levels. Our data demonstrated in a rat model of Gram-negative bacterial-sepsis that if we inject a low dose of ketamine following bacterial inoculation we reduce mortality from approximately 75% to 25%. Similar to what we have observed in operated patients, the levels of TNF-α and IL-6 in ketamine-treated rats were significantly lower than in septic animals not treated with ketamine. On the base of these results, we have designed and synthesized series of new analogues of ketamine applying a thermal rearrangement of alicyclic α-hydroxyimines to α-aminoketones in parallel arrays. One of the analogues (compound 6e) displayed high activity in down-regulating the levels of IL-6 and TNF-α in vivo as compared to ketamine.

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Section: Resultsmentioning

confidence: 99%

“… Hypothetical model (according to Stevens [ 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 ]) for inter-conversion between A, C and D by a thermal rearrangement. …”

Section: Resultsmentioning

confidence: 99%

Improved Methods for Thermal Rearrangement of Alicyclic α-Hydroxyimines to α-Aminoketones: Synthesis of Ketamine Analogues as Antisepsis Candidates

et al. 2012

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“…The use of more nucleophilic precursor reagents (N-methylhydrazine, 4-methoxybenzylamine) was also not successful. We therefore developed a new general route to many of these required norketamines, via the Neber (oxime to α-aminoketone) rearrangement [16] We initially sought to prepare the required new substituted norketamines by the published method for norketamine itself [13] that we had used previously [9], but this was not successful, probably due to the lower nucleophilicity of ammonia compared with methylamine in that process. The use of more nucleophilic precursor reagents (N-methylhydrazine, 4-methoxybenzylamine) was also not successful.…”

Section: Chemistrymentioning

confidence: 99%

“…However, few analogues of norketamine with substituents other than a 2-Cl in the aromatic ring have been reported; only the unsubstituted compound 21 [ 13 ] and the 4-Cl ( 22 ) and 4-Br ( 23 ) [ 14 ] analogues. The 3-OMe ( 25 ) and 3-OH ( 26 ) derivatives have also been characterised, but only as metabolites of methoxetamine ( 24 ) [ 15 ] ( Figure 2 ).…”

Section: Chemistry and Biologymentioning

confidence: 99%

“…We initially sought to prepare the required new substituted norketamines by the published method for norketamine itself [ 13 ] that we had used previously [ 9 ], but this was not successful, probably due to the lower nucleophilicity of ammonia compared with methylamine in that process. The use of more nucleophilic precursor reagents ( N -methylhydrazine, 4-methoxybenzylamine) was also not successful.…”

Section: Chemistry and Biologymentioning

confidence: 99%

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Structure-Activity Relationships for the Anaesthetic and Analgaesic Properties of Aromatic Ring-Substituted Ketamine Esters

et al. 2020

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A series of benzene ring substituted ketamine N-alkyl esters were prepared from the corresponding substituted norketamines. Few of the latter have been reported since they have not been generally accessible via known routes. We report a new general route to many of these norketamines via the Neber (oxime to α-aminoketone) rearrangement of readily available substituted 2-phenycyclohexanones. We explored the use of the substituents Cl, Me, OMe, CF3, and OCF3, with a wide range of lipophilic and electronic properties, at all available benzene ring positions. The 2- and 3-substituted compounds were generally more active than 4-substituted compounds. The most generally acceptable substituent was Cl, while the powerful electron-withdrawing substituents CF3 and OCF3 provided fewer effective analogues.

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The α‐Hydroxy Ketone (α‐Ketol) and Related Rearrangements†

Hofferberth

Paquette

2003

Organic Reactions

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Treatment of suitable alpha‐hydroxy aldehydes and ketones with a base, a Bronsted or Lewis acid, or simply with heat has long been know to induce the 1,2‐shift of an alkyl or aryl substituent to form an isomeric product. The synthetic utility of the process was considerably expanded when applied to steroidal D‐ring homoannulations, and has more recently encompassed novel ring expansion to numerous complex target ring systems. The classical alpha‐ketol rearrangement shares, in common with other base‐promoted ketogenic isomerizations, the property of advancing from an alkoxide to a carbonyl group as the migrating center relocates its bonding electrons to the adjacent trigonal center. A distinctive feature of the title reaction, however, is its reversibility, such that the more stable alpha‐hydroxy carbonyl isomer is favored. The process has sometimes been termed the acyloin rearrangement. This chapter focuses on the isomerization of alpha‐hydroxy ketones, aldehydes, and imines under various reaction conditions exclusive of photochemical activation. The literature coverage extends to 2000. Since many of the steroidal transformations were carried out in early days when products were not always adequately characterized; errors in structural assignment were occasionally made. Experimental detail was sometimes lacking. To alleviate this problem, we have included only experiments that lead to reasonably pure products of established structure.

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Amino Ketone Rearrangements. VI. Synthesis of 2-Alkylamino-2-phenylcyclohexanones^1a

Cited by 34 publications

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Improved Methods for Thermal Rearrangement of Alicyclic α-Hydroxyimines to α-Aminoketones: Synthesis of Ketamine Analogues as Antisepsis Candidates

Improved Methods for Thermal Rearrangement of Alicyclic α-Hydroxyimines to α-Aminoketones: Synthesis of Ketamine Analogues as Antisepsis Candidates

Structure-Activity Relationships for the Anaesthetic and Analgaesic Properties of Aromatic Ring-Substituted Ketamine Esters

The α‐Hydroxy Ketone (α‐Ketol) and Related Rearrangements†

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Amino Ketone Rearrangements. VI. Synthesis of 2-Alkylamino-2-phenylcyclohexanones1a

Cited by 34 publications

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Improved Methods for Thermal Rearrangement of Alicyclic α-Hydroxyimines to α-Aminoketones: Synthesis of Ketamine Analogues as Antisepsis Candidates

Improved Methods for Thermal Rearrangement of Alicyclic α-Hydroxyimines to α-Aminoketones: Synthesis of Ketamine Analogues as Antisepsis Candidates

Structure-Activity Relationships for the Anaesthetic and Analgaesic Properties of Aromatic Ring-Substituted Ketamine Esters

The α‐Hydroxy Ketone (α‐Ketol) and Related Rearrangements†

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Amino Ketone Rearrangements. VI. Synthesis of 2-Alkylamino-2-phenylcyclohexanones^1a