Isopropenyl chloroformate

M Jaouadi, C Selve, JR Dormoy, B Castro, J Martinez. Isopropenyl chloroformate in the chemistry of amino acids and peptides. III. Synthesis of active esters of A-protected amino acids. Tetrahedron Lett 26, 1721, 1985. 

N-Protected AAs were activated in situ with isopropenyl chloroformate to give an intermediate anhydride which reacted with Meldrum s acid in the presence of 4-dimethylaminopyridine (DMAP) to give the corresponding l,3-dioxane-4,6-dione. The reaction conditions are very stringent. Further transformation upon heating in an organic solvent yielded the pyrrole derivative (Scheme 15) [87JCS(P1)1177]. 

In the cases where optically active substrates were used as starting materials, chiral, saturated 5(47/)-oxazolones were obtained with good enantiomeric excesses (ee). Oxazolones derived from Al-formyl-a-amino acids are better prepared using isopropenyl chloroformate, rather than methyl chloroformate, in the presence of N-methylmorphohne. ... 

Boc-B-Ala-D-O-Leu-ODpm General Procedure for Depsipeptide Formation Using Isopropenyl Chloroform ate 1411... 

Solvolysis rates of isopropenyl chloroformate, CH2=C(Me)0C(0)Cl, were shown to be very similar to those for 4-nitrobenzoyl chloride in mechanism and reactivity.29 Stepwise mechanisms were observed in the aminolysis of aryl chloroformates by a series of substituted quinuclidines - which were more reactive than isobasic secondary alicyclic amines.30 The pH-independent hydrolysis of 4-nitrophenyl chloroformate in MeCN-H20 mixtures proceeded via a cyclic transition state containing the ester and two water molecules.15 Solvolyses of 2-furancarbonyl chloride in most... 

None of these methods has achieved popularity, but a unique variant of the carbonates provides a general method that is simple and efficient. Mixed carbonates 58 formed from isopropenyl chloroformate and substituted phenols or hydroxylamines react at room temperature with N -protected acids 23 in the presence of A-methylmorpholinet or a catalytic amount of 4-(dimethylammo)pyridinet giving active esters 24 in exceptionally high yield (see Table 13) with conconnitant liberation of acetone (Scheme 14). Compounds prepared using the non-aromatic base require purification on a silica gel column. 

Phosgene, when left in contact with acetone for about half an hour and then distilled, forms isopropenyl chloroformate according to the following equation, in which acetone is represented by its enohc formula ... 

Fluoroformates (Ref. 88) and phenyl iodoformate (Ref. 89) used here were prepared according to literature procedure (see also farther on in this section). The preparation of isopropenyl chloroformate, as well as 2,2-dichlorovinyl chloroformate will be presented in section 3-2-Z-4. 

Besides the severe difficulties encountered in the scaling up, this process was stymied by the impossibility of generalization to other 1-alkenyl chloroformates. For example in the same conditions, pyrolysis of the bischloro-formate of propylene glycol affords selectively the 1-pro-penyl chloroformate instead of the desired isopropenyl chloroformate as shown in scheme 88 (Ref. 111). 

In spite of numerous failures to prepare vinyl chlorofor-mate and Isopropenyl chloroformate by direct phosgenatlon of either acetaldehyde or acetone, we accepted the challenge to find economical routes to vinylic chloroformates and their derivatives, vinylic carbonates and carbamates. 

In the second step, the dried chloromercurials compounds are treated with phosgene at 80°C in nitrobenzene as the key solvent (Ref. 120). Vinyl chloroformate and isopropenyl chloroformate are isolated by simple distillation in 75-85 % yield [see scheme 93]. 

Scheme 93 Preparation of vinyl and isopropenyl chloroformates by the mercury process.

Alkenyl chloroformates, especially vinyl and isopropenyl chloroformates, as well as vinylic carbonates and carbamates have found number of valuable applications in various fields. 

More recently, a similar synthetic strategy was utilized to prepare the Dolastatin 15 via acylation of Meldrum s ester (156). In this work, isopropenyl chloroformate was found to give the best results of several mixed carbonic anhydrides derived from the required starting carboxylic acid when used in the presence of 5 molar equivalents of DMAP. Dolastatin proved to exhibit promising remarkable anticancer properties. 

In an obscure short paper published in 1934 (Ref. 114), Matuszak reported the first preparation of the previously unknown isopropenyl chloroformate. While working as a physical chemist at the US Bureau of Mines, he isolated this compound by microfractionation from a reaction mixture of 70 ml of acetone and 7 ml of liquid phosgene after half an hour at room temperature. 

Several chemists teams in the world, as well as researchers in our laboratories attempted to reproduce this exciting simple and cheap process. Unfortunately, whatever the conditions and catalysts used, all the carried out trials failed and the only products isolated were mesityl oxide and various chlorinated compounds. The conclusion of most investigators was that Matuszak did not isolate isopropenyl chloroformate but a mixture of chlorinated products. However, as shown in table 3-13, the properties given by Matuszak closely correspond to those of the isopropenyl chloroformate made by the mercury process (see farther on in this section). 

The phosgenation of the tributyltin enolate of acetone led to the same results although some trials performed at low temperature (below - 20°C) showed the possibility to obtain small amounts of isopropenyl chloroformate. It is noteworthy that, in a recent work devoted to a new synthesis of retinal (Vitamin A aldehyde), Bienayme from Rhone-Poulenc (Ref. 117), obtained isopropen-1-yI chloroformate in low yield through phosgenation of the reaction product of tributyltin methoxide with 1-acetoxy isoprene as depicted in scheme 92. 

To circumvent the difficulty, we attempted to start from other a-C-metallated keto compounds. Thus, we prepared acetonyltetracarbonylferrate by the reaction of disodium tetracarbonylferrate tCaution pyrophoric ) with chloroa-cetone in THF according to literature data (Ref. 121). Phosgenation in situ afforded isopropenyl chloroformate but in very variable and non-reproducible yields not exceeding 50 % as depicted in scheme 94 (Ref. 122). 

Scheme 94 Isopropenyl chloroformate through phosgenation of acetonyltetracarbonylferrate.

The studies in this area were not further pursued. However, it seems that several high-potential possibilities still remain untapped. To give just one example, the phosgenation of the reaction product of zirconium tetrachloride with acetone Cl3ZrCH2COCH3 described by Joseph and Blumenthal (Ref. 123), should yield, under selected conditions, isopropenyl chloroformate. 

Isopropenyl chloroformate (IPCF) has no value in amine protection but appears to be the most versatile chloroformate for acid activation. Thus, IPCF was proved... 

It is noteworthy that Takeda and coworkers (Ref. 154) recently proposed allyl isopropenyl dicarbonate made from isopropenyl chloroformate and sodium allyl carbonate as a convenient reagent for the preparation of allyl esters of carboxylic acids. Allyl isopropenyl dicarbonate reacts with carboxylic acids in the presence of DMAP under mild neutral conditions to give allyl esters in high yields. Allyl esters which could be deprotected by palladium catalysts are especially useful in the case of unstable compounds under acid or basic conditions, for example O-glycopeptides, penicillin derivatives, etc. 

The condensation of a chiral N-protected amino acid with Meldrum s acid in the presence of isopropenyl chloroformate and DMAP is the key for a stereospecific synthesis of N-protected Statine (Ref. 155). The novel route to Statine is depicted in scheme 106. 

Isobutyl chloroformate is most frequently applied in peptide chemistryfollowed by ethyl chloto-formate (see Table 1). The advantage of this method is that the mixed anhydride does not have to be isolated, and during work-up only carbonic acid half esters are formed, which decompose to an alcohol and carbon dioxide. Only in the case of sterically hindered amino acids does the opening of the anhydride at the undesired carbonyl occur in considerable amounts. Furthermore, short activation times (30 s) at low temperatures lead to peptides with minimal racemization. With isopropenyl chloroformate the mixed anhydride is prepared at room temperature, and during reaction only acetone and carbon dioxide are formed. 

Hg(CHjPh)Cl does not appear to react with phosgene at temperatures below which it decomposes to give PhCHjCHjPh [1020]. In contrast, treatment of Hg CH2C(0)H j with phosgene in thf yielded divinyl carbonate, CH j=C(H)0 2C=0 [1461a]. Similarly, treatment of either Hg CH jC(0)R Cl (R = H or Me) or Hg CHjC(0)R j with phosgene in a polar solvent (e.g. nitrobenzene, CHjClj or MeCN) at 20-60 C affords CHj=C(R)0C(0)Cl (i.e. vinyl or isopropenyl chloroformates for a review of their properties, see [61]) in excellent yields [1622]. The work was extended to include R = Ph, CMej or C3H3, and the synthesis of 1-cyclohexenyl chloroformate from mercury biscyclohexanone [1558]. 

RCH(NHPG)C02H, isopropenyl chloroformate, DMAP, CH2CI2, 0°C, R OH, 60-96%. 

Isopropenyl chloroformate, Me0C(,H4CH20H, DMAP, 0°C, CH2CI2, 91%. ... 

IPCF (-IPCC) isopropenyl chloroformate (isopropenyl chlorocarbonate)... 

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