Boc protected amine

As another extension of this process, Davies et al. have developed highly regio-, diastereo- and enantioselective C-H insertions of methyl aryldiazoace-tates into cyclic A-Boc-protected amines catalysed by rhodium(II) S)-N- p-dodecylphenyl)sulfonylprolinate. The best results were obtained in the case of the C-H insertion of methyl aryldiazoacetates into A-Boc-pyrrolidine, which gave, in all cases, a diastereoselectivity and an enantioselectivity greater than 90% de and 90% ee respectively (Scheme 10.77). The synthetic utility of this method was demonstrated by means of a two-step asymmetric synthesis of a novel class of C2-symmetric amines. 

Researchers at Merck Co. [35] who, together with scientists from Solvias, had developed the enantioselective hydrogenation of unprotected enamine amides and esters [36], reported a more recent example of product inhibition. The product amine amide or ester was found to be an inhibitor of the catalyst, and indeed instances of catalyst poisoning by amines have been reported several times (see later). The authors also found an excellent solution to this problem the addition of BOC-anhydride to the hydrogenation reaction neatly reacts away all the amine to form the BOC-protected amine, whereas the enamine was left unreacted (Scheme 44.4). This addition resulted in a remarkable rate enhancement [35]. 

A synthetically important N-acylation reaction is the formation of Boc protected amines [129]. A rapid and simple method has been reported using sonication which allows this reaction to be effected in the absence of water using solid sodium hydrogen carbonate as the base in a methanol suspension (Eq. 3.29). 

Y. Yamamoto and co-workers used L-aspartic acid 4-methyl ester (108) as their starting material for the synthesis of preussin [64]. The ester was transformed in nine steps to the TBDPS-protected aminoalcohol 109 (Scheme 28). Allylation of the iST-Boc-protected amine using allyl bromide... 

In addition, iodine snccessfnlly catalyzed the electrophilic snbstitntion reaction of indoles with aldehydes and ketones to bis(indonyl)methanes [225], the deprotection of aromatic acetates [226], esterifications [227], transesterifications [227], the chemoselective thioacetalization of carbon functions [228], the addition of mercaptans to a,P-nnsatnrated carboxylic acids [229], the imino-Diels-Alder reaction [230], the synthesis of iV-Boc protected amines [231], the preparation of alkynyl sngars from D-glycals [232], the preparation of methyl bisnlfate [233], and the synthesis of P-acetamido ketones from aromatic aldehydes, enolizable ketones or ketoesters and acetonitrile [234],... 

Another cyclic imide that has been used as a protective group for primary amines is the dithiasuccinoyl group (Dts) [230,303,304]. This group is stable towards acids (e.g. during deprotection of Boc-protected amines), but can be cleaved with thiols under basic conditions (2-mercaptoethanol (0.2 mol/L), NEt3 (0.5 mol/L), DCM, 25 °C, 5 min [303]). 

C-H Insertion a to nitrogen is a useful process because it represents a direct method for the asymmetric synthesis of (3-amino esters. An especially attractive example of this is the reaction with N-Boc-protected amine 29 [26], Even though electronically functionalization at the benzylic position would be highly favored, this position is sterically too crowded and the reaction occurs cleanly at the N-methyl site. The resulting p-amino ester 30, formed in 96% ee, represents a potentially useful precursor to novel p-peptides. 

Curtius degradation.3 The reaction of the carboxylic acid 1 with this azide in t-butyl alcohol gives the Boc-protected amine 2 directly. 

Scheme 3.2.4 shows the synthetic route employed for the synthesis of linker-head intermediate 14 from half-sided Boc-protected amine 13 [28], via urea formation, mediated by 4-nitrophenyl chloroformate with 1-Cbz-piperazine, followed by hydrogenation of the Cbz group with palladium on carbon. 

Fig. 14.44. A one-pot diastereoselective degradation of a carboxylic acid to a Boc-protected amine via a Curtius rearrangement Boc refers to tert-butoxylcarbonyl. The mixed anhydride B is formed by a condensation of the phosphorus ) reagent with the carboxyl group. The anhydride B acylates the concomitantly generated azide ion forming the acyl azide A. A Curtius degradation converts A to C, and the latter reacts subse-guently with tert-butanol to the Boc-protected amine.

Figure 14.44 also shows how the Curtius degradation of an acyl azide can be combined with the addition of ferf-butanol to the initially obtained isocyanate. This addition gives a carbamate. In the present case a fert-butoxycarbonyl-protected amine ( Boc-protected amine ) is formed. 

As described in section 5.4, (-)-sparteine-directed lithiation of 86 yields diastereoisomerically pure complexes 87. The same reaction of the vinylogous Boc-protected amines 89 is also possible, giving 90, and the organolithiums 87 and 90 react stereospecifically with Michael acceptors to yield compounds such as 88 and 91.10... 

Fig. 11.40. A one-pot diastereoselective degradation of a carboxylic acid to a Boc-protected amine via a Curtius rearrangement Boc refers to fert-butoxylcarbonyl.

Urethanes analogous to the amides of the previous section undergo similar deprotonation followed by alkylation and condoisation reactions. For example, 2,4,6-tri-r-butylphenol may be converted into the corresponding urethane which can be further functionalized (equation 32). N-Carbomethoxy-3-pyrroline has been convoted into both the trail pheromone for the Pharaoh ant and gq)hyrotoxin 223 by using regiospecific alkylations (Scheme 3). ° Similar tqjproaches were used in the preparation of the natural product supinidine. Piperidines also have been alkylated via the r-BOC-protected amines. ... 

Protection of amino groups. Di-t.butyl dicarbonate called (Boc)20 (which is not made from the very unstable t.butyl chloroformate) is well known as the most popular reagent for the preparation of t.Boc protected amines, especially t.Boc-amino acids in peptide chemistry. 

Protected amines and phenols. Iminophosphoranes obtained from reaction of organic azides with BUjP are converted to the Boc-protected amines. Oxindoles also form Boc derivatives. ... 

Alternatively, it is also possible to use in situ generated N Boc imines as electro philes [117]. When a carbamoyl sulfones are treated under the rhodium catalyzed addition of arylboronic acids, the imine is formed in situ, and the nucleophilic addition proceeds smoothly to generate the N Boc protected amine (Scheme 1.34). 

Type of reaction protection Reaction condition solvent-free Keywords A-Boc protection, amine, iodine... 

Because of the very mild cleavage conditions required when using SASRIN- or HAL-resins, even Boc-protected amines remain unaffected during cleavage. Thus, further reactions such as head-to-tail cyclization or fragment condensations are possible, where protected reactive functions are required. 

Asymmetric oxidative alkylation of free tetrahydroisoquinolines 9 was recently described by Sodeoka and co-workers (Scheme 6) [22, 23]. Through the use of a chiral cationic palladium(II) species 10, The enantiopure alkylated BOC protected amines 11 were obtained with good yields and enantioselectivity. The alkylation is believed to occur through the initial protection of the amine with (Boc O, followed... 

Scheme 6 Palladium-catalyzed asymmetric oxidative alkylation of BOC protected amines...

Carbamates are one of the most widely used protecting groups for amines and the development of one-pot conversions of azides to carbamates such as Boc, Cbz, and allyl further expanded the scope of utility of the Staudinger reduction. Treatment of the Staudinger reaction iminophosphorane intermediate 26 with 1.05 equivalents of 2-t-(butoxycarbonyloximino)-2-phenylacetonitrile (Boc-on) led to Boc-protected amines 28 thru 32 in 87-100% overall yield.19 This process utilizes trimethylphosphine, which is more reactive than triphenylphosphine and provides an easier work-up because trimethylphosphine oxide is water soluble. It should be noted that the use of di-f-butyldicarbonate (B0C2O) has been investigated but leads to lower yields in comparison.20... 

---