Selective monoalkylation

The imide proton N-3—H is more acidic than N-1—H and hence this position is more reactive toward electrophiles in a basic medium. Thus hydantoins can be selectively monoalkylated at N-3 by treatment with alkyl haUdes in the presence of alkoxides (2,4). The mono-A/-substituted derivatives (5) can be alkylated at N-1 under harsher conditions, involving the use of sodium hydride in dimethylform amide (35) to yield derivatives (6). Preparation of N-1 monoalkylated derivatives requires previous protection of the imide nitrogen as an aminomethyl derivative (36). Hydantoins with an increased acidity at N-1—H, such as 5-arylmethylene derivatives, can be easily monoalkylated at N-3, but dialkylation is also possible under mild conditions. 

FORSTER - DECKER Amine Synthesis Selective monoalkylation of primary amines via imines An altemativa method is the reaction ol 1 and 2 in the preserve of NaCNBH4 or tnaceloxyborohydride (Borch reduction)/... 

Selective monoalkylation of Cp2ZrCl2 to form Cp2Zr(R)Cl in which R is alkyl or alkenyl is best accomplished by hydrozirconation with [Cp2Zr(H)Cl]n (1). Most syn-thehc applications involve the use of terminal organozirconocene complexes. The hydrozirconahon reachon on carbon-carbon double or triple bonds with 1 is generally clean and gives high yields of essentially 100% cis addition products. 

Monoalkylation of a vic-glycol.1 Selective monoalkylation or monoacylation of the vic-glycol group of dimethyl L-tartrate is possible by conversion to the O-stannylene acetal (1) by reaction with dibutyltin oxide. The acetal is converted selectively to a mono derivative (3) by reaction with an alkyl halide or acyl chloride (excess) and CsF (about 2 equiv.). KF or Bu4NF are less effective than CsF. 

Selective monoalkylation of methyl aryl-acetates by alkylhalides is difficult with conventional bases. It may be achieved by application of the three-step procedure outlined above adding (33) to the methyl arylacetates at a low temperature... 

C). The substrate is deprotonated [pK(PhCH2COOMe) 22.7] and trapped by an alkyliodide (—78°C). This procedure leads selectively to mono a-alkylation (81-99%) [103]. Selective monoalkylation of 8-diketones in 70 to 95% yield was obtained by a similar procedure, and only in a few cases (bulky secondary alkylhalides) were the O-alkylated substrate found as a side product. Tetraalky-lammonium counter cations were necessary in stabilizing the enolate Na+ counter cations did not give selective C-alkylation [104]. 

Monoalkylation of isocyano amides can be accomphshed by a Michael reaction with an ot,p-unsaturated ketone in the presence of a catalytic amount of tetrabuty-lammonium fluoride (TBAF) in THF, as indicated by Ito in 1989 [31]. In addition, Zhu recently reported the selective monoalkylation of isocyano amides by using Cs0H-H20 (1.5 eq.) in MeCN at 0°C [32]. A slight excess of alkylating agent (1.2 eq.) can be used under the optimized conditions, which generates the mono-alkylated products for a wide range of primary halides (X = Br or 1) after 24 h. 

As an alternative to addition of anionic nucleophiles followed by reoxidation, rhodium(l)-catalyzed C-H activation allowed the nucleophilic addition of alkenes to the intermediate Rh(i) carbene complex <2002JA13964, 2004JOC7329>. Purine behaved anomalously compared to other heterocycles, for which selective monoalkylation was observed, and underwent sequential substitution first at C-8 and then at C-6 (Equation 8). Caffeine was monoalkylated at C-8 in low yield (15%). Selectivity for C-8-arylation was also observed in the palladium-catalyzed C-H activation of 6-phenyl-9-benzylpurine (aryl iodides, 0.05 equiv Pd(OAc)2, 3 equiv Cul, 2.5 equiv CS2CO3, DMF, 160 °C, 60 h, 48-95% yields) <2006OL5389>. 

Trimethyl orthoformate has been used as a solvent by Campbell and co-workers for site-selective monoalkylation in SPPSi1 % Trimethyl orthoformate was previously shown to be a highly efficient dehydrating solvent for the formation of imines. 112 Thus, dividing the reductive alkylation step into two separate substeps of (1) imine formation followed by solvent removal and (2) reduction, resulted in on-resin monoalkylation of various amino acids and dipeptides (Scheme 26). 

It was noted earlier that the lithium carbenoids on reaction with alkyl halides afford 1-alkyl-1-halo-cyclopropanes. It is possible to effect endo selective monoalkylation, as illustrated with a benzobarrelene... 

The Corey group used catalyst 8a in a selective monoalkylation of 35 with l-chloro-4-iodobutane to give the 4-chlorobutyl product (99% ee) (Chart 10.6). The intermediate product was reduced and then converted, by an A-alkylation and subsequent steps, into the (S)-pipecolic acid derivative 41 (77% overall chemical yield from 35, 99% ee, Chart 10.6) [21]. 

The selectivity of the Nafion-H catalyst for monoalkylation has been found to be generally high. With a molar ratio of benzene isopropyl chloride being 5 1, about 94% of the alkylate is monoalkylbenzene. This result is comparable to the highly selective monoalkylation reaction reported by Langlois.236 They alkylated benzene with propylene (5.2 1 molar ratio) over H3P04-quartz catalyst at --200 C and obtained cumene in 95% yield. 

Chiral salen-Cu(II) complex 39c also promoted selective monoalkylation of glycine derivative 20 to produce the corresponding a-amino acids (R)-42 with enantiomeric excesses in the range of 70 to 80% (Scheme 7.10) [32], The enantiomeric excess was... 

Grossman, R. B. Vamer, M. A. Selective monoalkylation of diethyl malonate, ethyl cyanoacetate, and malononitrile using a masking group for the second acidic hydrogen. 

Polyaminoheteroarenes have also been selectively monoalkylated by metalation and treatment with an electrophile. As illustrated by the examples shown in Scheme 6.13, astonishing selectivity can sometimes be achieved. 

Unlike 3-lactams, unsubstituted P-sultams can undergo selective monoalkylation at C4 or dialkylation at N2 and C4 when the dianion is treated with a large excess of the electrophile. 

Selective monoalkylation of organogembismetallics via an intramolecular nucleophilic substitution preparation of 4-allyl-3-iodo-2-methyl-undecane... 

The third possibility for a selective monoalkylation is provided by intramolecular Friedel-Crafts alkylations. There are no multiple alkylations simply because all electrophilic centers react most rapidly intramolecularly (i.e., only once). Friedel-Crafts alkylations of this type are ring closure reactions. 

Ensuring the selective monoalkylation of ketones [case (c)] is of special importance in synthetic practice and numerous approaches are elaborated for this purpose. This problem deserves special comment and will be considered later (Section 2.13). 

The selective monoalkylation of ketones at the a-position had no general solution for a long time. A classical approach to this problem, based upon the selective activation of this site via the introduction of additional electron withdrawing substituents e.g. alkoxycarbonyl group), is applicable only for symmetrical ketones. Non-symmetrical compounds react non-selectively in this auxiliary step. The synthetic importance of this problem triggered a thorough study of enolate chemistry in the 1960s and, as a result, at present the selective substitution at any of the a-positions of carbonyl compounds can be achieved via a number of routes. 

Chloro- and 3-bromo-quinolines and 2- and 4-chIoroisoquinoIines undergo Ni-catalyzed coupling with primary alkyl, allyl and cyclohexyl Grignard reagents selective monoalkylation in 4,5-dichloroiso-quinoline may be noted (equations 147-150). 44... 

Note the preferential reaction at the anomeric hydroxyl. The method is also effective for the protection of primary and secondary alcohols. A modification of this approach which uses f-Bu0C02CH2CH=CH2as the allyl source selectivity monoalkylates a tertiary hydroxyl in the erythronolide derivative. 

These complexes are stable to the conditions of the Sonogashira reaction, silica gel chromatography (EtOAc/Hex), dilute TEA, KF in DME, POCI3, PSCI3, MCPBA, MMPP, Arbuzov conditions (neat (EtO)3P, 110°C), and Nal/acetone. Reagents that release HCl will require an acid scavenger to prevent premature deprotection. The 9-BBN chelate of amino alcohols has been used to selectively monoalkylate primary amines, a process that is often problematic because of bisalkylation. ... 

Highly selective monoalkylated products of the side chain are formed at high aniline conversion levels with alkali exchanged Y zeolite. 

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