Chemoselective N-alkylation of 2-hydroxycarbazole as a model for the synthesis of N-substituted pyrrole derivatives containing acidic functions

Albanese, Domenico; Landini, Dario; Penso, Michele; Spano, Giulia; Trebicka, Artan

doi:10.1016/0040-4020(95)00232-w

Cited by 13 publications

(8 citation statements)

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“…A different reaction outcome was observed in THF (entry 3), in which the target product 2a was formed in low yield as the sole detectable product. This solvent was thus selected as the major component of specific solvating mixtures as illustrated in our preceding reports 3,4. The model reaction was operated in THF containing molar amounts of either DMF (2.6 mol DMF per mol 1a ) or DMSO (2.8 mol DMSO per mol 1a ) (entries 4–7).…”

Section: Resultsmentioning

confidence: 99%

“…These strategies can be summarized in three broad categories: (a) Protection of one specific functional group, (b) simultaneous transformation of all reactive centers, then restoration of one of the centers, or (c) activation of the target group and/or deactivation of groups that should remain unaltered 2a. Previously, we applied the activation/deactivation approach to the N ‐alkylation of substrates that contain nucleophilic N,O‐centers such as 2‐hydroxycarbazole,3 tyrosine,4,5 serine and threonine (2‐nitrobenzene)sulfonamido esters 6. Under the reaction conditions applied, both functions were deprotonated by an inorganic base, with formation of the corresponding dianion.…”

Section: Introductionmentioning

confidence: 99%

“…Under the reaction conditions applied, both functions were deprotonated by an inorganic base, with formation of the corresponding dianion. Following the empirical principle that “the anion derived from the weaker acid is the stronger nucleophile”,3,7 the aza‐anion was expected to preferentially react with the alkylating agent; actually, in most cases, a complex mixture of N ‐mono‐, O ‐mono‐, and N , O ‐bis‐alkylated products was formed. The chemoselectivity of the process was increased by carrying out the reactions in the presence of a coordinating non‐hydrogen‐bond donor (non‐HBD) solvent ( N , N ‐dimethylformamide (DMF), dimethyl sulfoxide (DMSO), diglyme, etc.…”

Section: Introductionmentioning

confidence: 99%

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Chemoselective Synthesis of N‐Protected Alkoxyprolines under Specific Solvation Conditions

et al. 2014

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N‐Protected hydroxyprolines (Hyp) were transformed chemoselectively into alkoxyproline derivatives by direct O‐alkylation. The starting Hyp was transformed into the corresponding dianion in a mixture of dimethyl sulfoxide and tetrahydrofuran (1:16 v/v) as solvent. Under these conditions, the carboxy‐anion showed reduced nucleophilicity because it was specifically solvated, and the more reactive oxy‐anion was selectively alkylated. N‐Protected trans‐4‐alkoxy‐, cis‐4‐alkoxy‐ and trans‐3‐alkoxyprolines were thus obtained in a single step in very high overall yields and with complete stability of the stereogenic center configuration.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Chemoselective Synthesis of N‐Protected Alkoxyprolines under Specific Solvation Conditions

et al. 2014

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“…We previously described the effect of specific solvation of the cationϪoxido-anion ion pair on the chemoselective Nalkylation of 2-hydroxycarbazole, [5] achieved by using a coordinating non-hydrogen-bonding donor (non-HBD) solvent, like DMF, DMSO or diglyme. Moreover, we found [a] Reaction conditions: 4 (10 mmol), NsCl (2a; 10 mmol), base (10 mmol), solvent (20 mL).…”

Section: Resultsmentioning

confidence: 99%

Specific Solvation as a Tool for the N‐Chemoselective Arylsulfonylation of Tyrosine and (4‐Hydroxyphenyl)glycine Methyl Esters

Penso¹,

Albanese²,

Landini³

et al. 2003

Eur J Org Chem

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The methyl esters of L-tyrosine and D-(4-hydroxyphenyl)glycine were directly transformed into the corresponding 2-arylsulfonamido esters with arylsulfonyl chlorides, without protecting the phenolic hydroxy group. The reaction is conducted in a THF/DMF (8:1) mixture as solvent, and using lyophilized solid sodium carbonate as base. The N-arylsulfonylation takes place with good yields (62−85%) in a chemoselective fashion, without racemization of the stereogenic carbon centers. The DMF (2.6 mol/mol amino ester) specific-

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“…N-Alkylation of aminophenols [48][49][50][51]. As illustrated by the examples shown in Scheme 6.13, astonishing selectivity can sometimes be achieved.…”

Section: Alkylation Of Anilinesmentioning

confidence: 99%

The Alkylation of Heteroatoms

Dörwald

2004

Side Reactions in Organic Synthesis

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Although carbon-heteroatom bonds are often easier to make than C-C bonds, and are therefore often chosen as retrosynthetic points of disconnection, some non-carbon nucleophiles can be difficult to alkylate. Problems can arise when the nucleophile is highly basic and hard, for these will preferentially attack (hard) protons and cause elimination instead of being alkylated [1]. Similarly, sterically demanding nucleophiles will also tend to attack protons faster than undergo alkylation. Ambident nucleophiles, such as amides, phenols, thiocyanate, or nitrite, can be a further cause of problems, because a variety of different products can be formed, depending on the type of electrophile chosen and on the precise reaction conditions [2]. Substrates with two or more similar nucleophilic groups, for example aminophenols or hydroxybenzoic acids, can often be alkylated with high chemoselectivity, but the outcome of these reactions can be difficult to predict. In the following sections the alkylation of the most common, trouble-causing non-carbon nucleophiles will be discussed.As for carbanions, the reactivity of anionic non-carbon nucleophiles depends on the cation. The nucleophilicity and basicity of a given anionic nucleophile will usually be enhanced if it does not form strong bonds either with the cation or with the solvent. Hard cations, for example Li + or Ti 4+ , will significantly reduce the reactivity of hard anions (RO -, R 2 N -, F -), whereas soft cations (Cs + , Cu + , Pd 2+ ) will form strong bonds with soft anions (RS -, I -, CN -, H -, R -) and thereby reduce their reactivity. 6.1 Alkylation of FluorideHydrogen fluoride (pK a 3.2 in water) is the hydrogen halide with the lowest acidity, and fluoride is, therefore, a rather strong base. Nucleophilic substitutions with fluoride do not usually proceed smoothly, despite the strength of the C-F bond, and alkenes are often obtained instead of alkyl fluorides if simple alkyl monohalides are treated with fluoride under basic reaction conditions. Eliminations occur particularly readily from alkyl fluorides with an electron-withdrawing group in the b position. Common reagents for displacing halides or related leaving groups by fluoride include AgF, KF, CsF, Bu 4 NF [3], HF, and SbF 5 , and suitable solvents are ethylene6 230 Scheme 6.1. Displacement of different leaving groups by fluoride [5-8].6.2 Alkylation of Aliphatic Amines groups is because of negative hyperconjugation between the (antibonding) r* C-F orbitals and the lone pairs on fluorine (see Section 3.4). Alkylation of Aliphatic AminesThe most conspicuous property of aliphatic amines, apart from their fishy smell, is their high basicity, which usually precludes N-alkylations under acidic reaction conditions (last reaction, Scheme 6.3). Hence, alkylation of amines with tertiary alkyl groups is not usually possible without the use of highly stabilized carbocations which can be formed under basic reaction conditions. Rare exceptions are N-alkylations of amines via radicals (Scheme 4.2), copper-catalyzed propar...

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Chemoselective N-alkylation of 2-hydroxycarbazole as a model for the synthesis of N-substituted pyrrole derivatives containing acidic functions

Cited by 13 publications

References 13 publications

Chemoselective Synthesis of N‐Protected Alkoxyprolines under Specific Solvation Conditions

Chemoselective Synthesis of N‐Protected Alkoxyprolines under Specific Solvation Conditions

Specific Solvation as a Tool for the N‐Chemoselective Arylsulfonylation of Tyrosine and (4‐Hydroxyphenyl)glycine Methyl Esters

The Alkylation of Heteroatoms

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