Trichloroacetimidates from allylic alcohols

Allyl imidate esters undergo [3,3] sigmatropic rearrangements to A -allyl amides. Trichloroacetimidates can be easily made from allylic alcohols by reaction with trichloroacetonitrile. The rearrangement then provides trichloroacetamides of iV-allyl-amines.176 177... 

The Overman rearrangement, a thermal [3,3]-sigmatropic rearrangement of allylic trichloroacetimidates, is an attractive procedure for the preparation of ally] amines from allyl alcohols (Eq. (4)) [7]. 

The first step in this reaction is formation of the allyl trichloroacetimide 8 formed from allyl alcohol 3 by reaction with trichloroacetonitrile. The allyl amides 9 are formed by the [3,3]-sigmatropic rearrangement of 8, followed by hydrolysis. The reaction proceeds with good yield for primary and secondary amides however, for products where the amide nitrogen is bound to a tertiary carbon atom the yields are generally low. 

Acid-catalysed alkylation of an alcohol with O-alkyl trichloroacetimidate prepared from allyl alcohol and trichloroacetonitrile is readily accomplished Scheme 4.233]440 as previously discussed for the preparation of benzyl and tert-butyl ethers.311 However, these conditions are not compatible with many of the protecting groups employed in oligosaccharide synthesis. For such cases, two methods for 0-allylation under essentially neutral conditions have been devised. The first method takes advantage of the mild conditions and regioselectivity of stannylene alkylations (see section 4.3.3). The method is illustrated by the selective O-allylation of o-lactal, which began with stannylene formation on an 0.8 mole scale [Scheme 4.234].441... 

Nagashima, H., Wakamatsu, H., Ozaki, N., Ishii, T., Watanabe, M., Tajima, T., Itoh, K. Transition metal catalyzed radical cyclization new preparative route to y-lactams from allylic alcohols via the [3.3]-sigmatropic rearrangement of allylic trichloroacetimidates and the subsequent ruthenium-catalyzed cyclization of N-allyltrichloroacetamides. J. Org. Chem. 1992, 57, 1682-1689. 

Liebigs Ann Chem 654 180 1962]. It is readily converted into its trichloroacetimidate esters by reaction with ally lie alcohols in CH2CI2, in the presence of DBU at to ambient temperatures [Anderson Overman J Am Chem Soc 125 12412 2003, Kirsch et al. Org Lett 9 911 2007] similarly prepared trichloroacetimidates of allylic alcohols were shown to undergo ether-directed Pd(II)-catalysed aza-Claisen rearrangements [Jamieson Sutherland Tetrahedron 63 2132 2007], and bis-trichloroacetimidates from 2-aminopropane-l,3-diols yielded dihydrooxazines through an acid catalysed cychsation [Rondot et al. Org Lett 9 247 2007],... 

The synthesis of a fully functionalized cyclopentane core structure of pactamycin, a potent antitumor antibiotic, involves Overman rearrangement as a key reaction. Heating a mixture of potassium carbonate and the imidate derived from allylic alcohol 68 in p-xylene yields the desired trichloroacetamide 69 as a single isomer in 90% yield from 68. In this reaction, potassium carbonate is a crucial additive as no desired product is obtained when the same reaction is carried out without potassium carbonate. Trichloroacetimidate 69 has been elaborated into the tricyclic compound 70 which contains all the carbon atoms for the core cyclopentane of pactamycin,... 

Allyl alcohols readily react with trichloroacetonitrile to give the corresponding trichloroacetimidates 145. Activation of the double bond with electrophilic reagents results in ring closure to yield oxazolines 146. The most commonly employed electrophiles include iodine, iodine monochloride, phenylselenyl chloride, and mercuric trifluoroacetate. Other nitriles including cyanogen bromide and N,N-dimethylcyanamide can also be used. Since oxazolines readily hydrolyze to amides, the net effect of this reaction sequence is to produce p-amino alcohols 147 from an allyl alcohol. This strategy has been employed in numerous total syntheses of natural products. Examples are listed in Table 8.18 (Fig. 8.7 Scheme 8.43). ° ... 

Thermal rearrangements of allyltrichloroacetimidates to allylically transposed iV-(trichloro-acetyl)amines is a well-known method for the preparation of allylamines362,3b3. The rearrangement of trichloroacetimidates derived from secondary allylic alcohol results exclusively in E formation of the products363, e.g., formation of3362 364, 4365, 5362, 6362, 7362, 8 and 9362. Severe limitations, however, exist due to strong competition of elimination reactions especially at higher reaction temperatures. 

When simple aldehydes were converted to allylic alcohols, they could be transformed to the corresponding trichloroacetimidates and subjected to thermal rearrangement to provide aUyl amines. The aUyl amine functionality was also accessible from enantio-selective reduction of propargyl ketones followed by conversion to the phthalamide derivative and reduction of the triple bond. Ozonolysis of these substrates provided the corresponding a-amino methyl esters in good yield (eq 48). As with the allyl alcohols, optically active substrates were treated with ozone without loss of enantiopurity of the chiral center. 

Sigmatropic Rearrangement of Trichloroacetimidates The development of the asymmetric palladium(II)-catalyzed [3,3]-sigmatropic rearrangement of trichloroacetimidates has proven to be a powerful method for the generation of chiral amines from achiral allylic alcohols [12]. In particular, the cobalt oxazoline palladacycles, such as COP-Cl (4), have been shown to be particularly efficient for this transformation (Scheme 5.1) [13]. 

Electrophilic Cyclization of Trichloroacetimidates. Trichloroacetimidates derived from allylic " and homoallylic alcohols undergo electrocyclic ring closure when treated with a source of I" " (eq 5). Cyclization can also be triggered via the Lewis acid-mediated opening of epoxides. In at least one case the imidate proved more reactive than related reactions using carbamates. These are useful methods for the stereoselective introduction of nitrogen into cyclic and acyclic systems. 

The thermal rearrangement of O-allyl trichloroacetimidates 1 affords the corresponding 7V-allyl amides 31 2, which have been cyclized with the aim of obtaining amino diols or amino alcohols different to those from the cyclization of the trichloroacetimidates. Cyclization of these latter substrates 1 leads to 4,5-dihydro-4-(l-iodoalkyl)oxazoles 2, while treatment of unsaturated trichloroacetamides 3 with /V-iodosuccinimide3 in chloroform affords the corresponding 4,5-dihydro-5-(l-iodoalkyl)oxazoles 4 in high yield. These heterocyclic products are protected forms of the corresponding amino alcohols. 

Removal of protecting groups. A combination of DBU with a thiol can be used in the removal of an Fmoc group in a large scale process. Regeneration of alcohols from trichloroacetimidates is accomplished by treatment with DBU in MeOH (other methods involve acid-catalyzed hydrolysis and Zn dust reduction)." Alcohols temporarily protected as trichloroacetimidates permit their differentiation from others that are masked in acetonide, ester (acetate, benzoate, etc.), and ether (allyl, TBS, etc.) forms. 

In a similar manner, from alcohol 9, we performed the Overman rearrangement through the trichloroacetimidate 11 to give the trichloroacetamide 12 along with a small amount of the allylic chloride 13 [23,27]. 

The imidate can be prepared from the sodium alkoxide ion of benzyl alcohol and trichloroacetonitrile according to procedures based on those developed by Cramer in the late 1950s. Substituted benzyl ethers have also been prepared this way, for example using 4-methoxybenzyl trichloroacetimidate, 3,4-dimethoxybenzyl trichloroacetimidate, and 2,6-dichlorobenzyl trichloroacetimidate, and the method has also been applied for the synthesis of allyl and r-butyl ethers, as well as for 2-phenylisopropyl esters for peptide synthesis. The benzyl and 4-methoxybenzyl 2,2,2-trichloroacetimidates are available commercially. 

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