Encyclopedia of Reagents for Organic Synthesis || Isobutyl Chloroformate
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ISOBUTYL CHLOROFORMATE 1 Isobutyl Chloroformate Cl O O [543-27-1] C 5 H 9 ClO 2 (MW 136.59) InChI = 1/C5H9ClO2/c1-4(2)3-8-5(6)7/h4H,3H2,1-2H3 InChIKey = YOETUEMZNOLGDB-UHFFFAOYAL (used for making mixed anhydrides which serve as active interme- diates for peptide synthesis; 1−3 used to block the 5 -hydroxy func- tion of deoxyribosides in oligonucleotide synthesis; 4 condensing reagent 5 ) Physical Data: bp 128.8 ◦ C; d 1.04 g cm −3 . Solubility: miscible with benzene, chloroform, ether. Form Supplied in: clear colorless liquid. Handling, Storage, and Precaution: gradually decomposed by water and alcohol; highly toxic; vapor irritates eyes and mucous membranes; stable on storage. 6,7 Use in a fume hood. Peptide Reagent. 1,3 Protected amino acids, such as the N- benzyloxycarbonyl (Cbz) derivatives, are brought into solution in toluene or THF by addition of enough Triethylamine to form the salt, and isobutyl chloroformate is added at 0 ◦ C to produce the mixed anhydride. A solution of an amino acid ester (or peptide ester) to be N-acylated is added in an inert solvent and the mixture is allowed to come to rt. Evolution of carbon dioxide begins im- mediately (eq 1). The isobutyl chloroformate is preferred to lower esters for preparation of peptides of moderate or high molecular weight; 6,7 ethyl chloroformate is preferred for synthesis of dipep- tides. CO 2 H R 1 NHCbz CO 2 – + NHEt 3 R 1 NHCbz CO 2 CO 2 -i-Bu R 1 NHCbz CONHCHR 2 CO 2 Me R 1 NHCbz H 2 NCHR 2 CO 2 Me + CO 2 + BuOH (1) Et 3 N i-BuOCOCl Boc-Gly-Gly-OEt and Boc-Gly-Gly-Gly-OEt have been suc- cessfully synthesized in reasonable yields (77% and 88%, respectively) via mixed anhydride derivatives from isobutyl chloroformate. 8 Previously it was reported 9 that considerable quantities of diacylated side products are formed in mixed an- hydride syntheses with glycine when ethyl chloroformate is used. 5 -Hydroxy Function Blocking Agent for Deoxyribosides. The reagent has been used to block the 5 -hydroxy function of deoxyribosides in oligonucleotide synthesis (eq 2). 4 The reagent shows good selectivity for the 5 -hydroxy group, as is evident in the high yield of (2). The blocking group is removed smoothly by alkaline hydrolysis to give (4). O N OH NH O O HO O N OH NH O O O O O i-Bu Ph 2 C Cl C 6 H 4 -p-OMe O N O NH O O O O O i-Bu Ph Ph OMe O N O NH O O HO Ph Ph OMe 5′ 3′ i-BuOCOCl, py 91% dioxane, NaOH (2) (3) (4) (2) (1) 96% 73% N-Protection. 10 In the synthesis of enantiomerically pure symmetric vicinal diamines involving chirality transfer from a single chiral source, 1,2-diphenylethane-1,2-diamine, hydrolysis of the bisacetamides to the corresponding vicinal diamines was attempted using a number of amide hydrolysis procedures. How- ever, the various base- and acid-catalyzed procedures did not result in a clean hydrolysis of the acetamide groups. This was achieved by converting amines into biscarbamate derivatives, followed by treatment with 30% HBr in acetic acid (eq 3). Cyclodehydration. 5 In the synthesis of 1,4-dihydro- pyran[3,4-b]indolones, the reagent was used along with triethy- lamine for cyclodehydration of hydroxymethylindoleacetic acid to produce the lactone (eq 4). Regioselective Arylation. 11 Arylation in the 4-position in pyridines results from 1:1 adduct formation between an aryltri- isopropoxytitanium reagent and an N-isobutyloxycarbonylpyridi- nium salt, and after successive 2,3-Dichloro-5,6-dicyano-1,4- benzoquinone dehydrogenation and cleavage of the 1-substituent (eq 5). N H H N Ph Ph NHCO 2 -i-Bu NHCO 2 -i-Bu NH 2 NH 2 1. i-BuOCOCl, py 30% HBr, HOAc · 2HBr (3) 2. Li, NH 3 80 °C Avoid Skin Contact with All Reagents
Transcript of Encyclopedia of Reagents for Organic Synthesis || Isobutyl Chloroformate
ISOBUTYL CHLOROFORMATE 1
Isobutyl Chloroformate
Cl O
O
[543-27-1] C5H9ClO2 (MW 136.59)InChI = 1/C5H9ClO2/c1-4(2)3-8-5(6)7/h4H,3H2,1-2H3InChIKey = YOETUEMZNOLGDB-UHFFFAOYAL
(used for making mixed anhydrides which serve as active interme-diates for peptide synthesis;1−3 used to block the 5′-hydroxy func-tion of deoxyribosides in oligonucleotide synthesis;4 condensing
reagent5)
Physical Data: bp 128.8 ◦C; d 1.04 g cm−3.Solubility: miscible with benzene, chloroform, ether.Form Supplied in: clear colorless liquid.Handling, Storage, and Precaution: gradually decomposed by
water and alcohol; highly toxic; vapor irritates eyes and mucousmembranes; stable on storage.6,7 Use in a fume hood.
Peptide Reagent.1,3 Protected amino acids, such as the N-benzyloxycarbonyl (Cbz) derivatives, are brought into solutionin toluene or THF by addition of enough Triethylamine to formthe salt, and isobutyl chloroformate is added at 0 ◦C to producethe mixed anhydride. A solution of an amino acid ester (or peptideester) to be N-acylated is added in an inert solvent and the mixtureis allowed to come to rt. Evolution of carbon dioxide begins im-mediately (eq 1). The isobutyl chloroformate is preferred to loweresters for preparation of peptides of moderate or high molecularweight;6,7 ethyl chloroformate is preferred for synthesis of dipep-tides.
CO2H
R1 NHCbz
CO2– +NHEt3
R1 NHCbz
CO2CO2-i-Bu
R1 NHCbz
CONHCHR2CO2Me
R1 NHCbz
H2NCHR2CO2Me+ CO2 + BuOH
(1)
Et3N i-BuOCOCl
Boc-Gly-Gly-OEt and Boc-Gly-Gly-Gly-OEt have been suc-cessfully synthesized in reasonable yields (77% and 88%,respectively) via mixed anhydride derivatives from isobutylchloroformate.8 Previously it was reported9 that considerablequantities of diacylated side products are formed in mixed an-hydride syntheses with glycine when ethyl chloroformate is used.
5′-Hydroxy Function Blocking Agent for Deoxyribosides.The reagent has been used to block the 5′-hydroxy function ofdeoxyribosides in oligonucleotide synthesis (eq 2).4 The reagentshows good selectivity for the 5′-hydroxy group, as is evident inthe high yield of (2). The blocking group is removed smoothly byalkaline hydrolysis to give (4).
ON
OH
NH
O
OHO
ON
OH
NH
O
OO
O
O
i-Bu
Ph2CCl
C6H4-p-OMe
ON
O
NH
O
OO
O
O
i-Bu
PhPh
OMe
ON
O
NH
O
OHO
PhPh
OMe
5′
3′
i-BuOCOCl, py
91%
dioxane, NaOH(2)
(3) (4)
(2)
(1)
96%
73%
N-Protection.10 In the synthesis of enantiomerically puresymmetric vicinal diamines involving chirality transfer from asingle chiral source, 1,2-diphenylethane-1,2-diamine, hydrolysisof the bisacetamides to the corresponding vicinal diamines wasattempted using a number of amide hydrolysis procedures. How-ever, the various base- and acid-catalyzed procedures did not resultin a clean hydrolysis of the acetamide groups. This was achievedby converting amines into biscarbamate derivatives, followed bytreatment with 30% HBr in acetic acid (eq 3).
Cyclodehydration.5 In the synthesis of 1,4-dihydro-pyran[3,4-b]indolones, the reagent was used along with triethy-lamine for cyclodehydration of hydroxymethylindoleacetic acidto produce the lactone (eq 4).
Regioselective Arylation.11 Arylation in the 4-position inpyridines results from 1:1 adduct formation between an aryltri-isopropoxytitanium reagent and an N-isobutyloxycarbonylpyridi-nium salt, and after successive 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone dehydrogenation and cleavage of the 1-substituent(eq 5).
NH
HNPh
Ph NHCO2-i-Bu
NHCO2-i-Bu
NH2
NH2
1. i-BuOCOCl, py 30% HBr, HOAc
· 2HBr (3)
2. Li, NH3 80 °C
Avoid Skin Contact with All Reagents
2 ISOBUTYL CHLOROFORMATE
NH
OHCO2H
NH
O
O
i-BuOCOCl(4)
Et3N, THF
N
i-BuOCOCl
N
CO2-i-Bu
N
Ph
CO2-i-Bu
N
Ph
H2O+
(5)
DDQ, PhH
THF. 20 °CCl–
PhTi(O-i-Pr)3
Isobutyl Sulfonate.12 With Silver(I) p-Toluenesulfonate,alkyl chloroformate forms sulfonic carbonic anhydride whichwhen heated liberates carbon dioxide, producing alkyl sulfonate.In order to find out the mechanism of the decomposition of themixed anhydride, reaction of isobutyl chloroformate and silverp-toluenesulfonate was investigated. If the free alkyl cation, i.e.isobutyl carbonium ion, is formed, the rearrangement to s-butyland t-butyl carbonium ion would be expected, finally resultingin the formation of s-butyl p-toluenesulfonate. t-Butyl p-toluene-sulfonate is unstable and is not expected to survive under the reac-tion conditions. In fact, decomposition gave a mixture of isobutyl
p-toluenesulfonate and s-butyl p-toluenesulfonate in a 0.8:1 molratio, with a quantity of isobutene and free p-toluenesulfonicacid. Isobutene was considered to be derived from the t-butylcation.
1. Boissonnas, R. A., Helv. Chim. Acta 1951, 34, 874; Helv. Chim. Acta1952, 35, 2229 and2237.
2. Vaughan, J. R., J. Am. Chem. Soc. 1951, 73, 3547; J. Am. Chem. Soc.1952, 74, 676 and6137; J. Am. Chem. Soc. 1953, 75, 5556; J. Am. Chem.Soc. 1954, 76, 2474.
3. Wieland, T.; Bernhard, H., Justus Liebigs Ann. Chem. 1951, 572, 190.
4. Ogilvie, K. K.; Letsinger, R. L., J. Org. Chem. 1967, 32, 2365.
5. Fray, E. B.; Moody, C. J.; Shah, P., Tetrahedron 1993, 49, 439.
6. Vaughan, J. R.; Osato, R. L., J. Am. Chem. Soc. 1952, 74, 676.
7. Anderson, G. W.; Zimmerman, J. E.; Callahan, F. M., J. Am. Chem. Soc.1966, 88, 1336. Anderson, G. W.; Zimmerman, J. E.; Callahan, F. M., J.Am. Chem. Soc. 1967, 89, 5012.
8. Hoffmann, J. A.; Tilak, M. A., Org. Prep. Proced. Int. 1975, 7, 215.
9. Kopple, K. D.; Renick, K. J., J. Org. Chem. 1974, 39, 660.
10. Nantz, M. H.; Lee, D. A.; Bender, D. M.; Roohi, A. H., J. Org. Chem.1992, 57, 6653.
11. Gundersen, L.; Rise, F.; Undheim, K., Tetrahedron 1992, 48, 5647.
12. Yamamoto, A.; Kobayashi, M., Bull. Chem. Soc. Jpn. 1966, 39,1283.
Tapan RaySandoz Pharmaceuticals, East Hanover, NJ, USA
A list of General Abbreviations appears on the front Endpapers
