[7087-68-5] · C8H19N · Diisopropylethylamine · (MW 129.24)
(hindered non-nucleophilic amine base used in alkylations, selective generation of enolates, aldol-like reactions, and eliminations)
Alternate Names: DIPEA; DIEA; Hünig's base.
Physical Data: bp 127 °C; d 0.742 g cm-3.
Solubility: sol most organic solvents.
Handling, Storage, and Precautions: corrosive and flammable liquid; flush containers with nitrogen or argon to prevent exposure to carbon dioxide; vapors are harmful; avoid absorption through the skin; use in a fume hood.
DIPEA can be used as a base in the palladium(0)-catalyzed alkoxycarbonylation of both allyl phosphates and acetates.1 Treatment of diethyl (E)-2-hexenyl phosphate with Tris(dibenzylideneacetone)dipalladium and Triphenylphosphine in the presence of 1 equiv of DIPEA in ethanol under 30 atm CO pressure leads to an 84:16 mixture of trans- and cis-ethyl heptenoates in 88% yield (eq 1). The base used neutralizes the phosphoric acid generated. Without DIPEA, the alkyl ester is not produced. Allyl acetates behave in a similar manner (eq 2). Use of other tertiary bases, such as triethylamine, leads to lower yields of products.
In an asymmetric variation of the Heck reaction,2 the sterically demanding DIPEA is used in combination with (R)-2,2´-Bis(diphenylphosphino)-1,1´-binaphthyl ((R)-BINAP) for generating enantiomerically enriched 2-aryl-2,3-dihydrofurans from aryl triflates.3 However, in a comparison study, the base 1,8-Bis(dimethylamino)naphthalene (proton sponge) was found to be superior in regards to enantiomeric purity for the arylation reaction (eq 3).4,5
This base, in combination with boryl triflates, is widely applied in the enolate generation of ketones for use in directed cross-aldol reactions.6 Reaction of 4-methyl-2-pentanone with DIPEA and Di-n-butylboryl Trifluoromethanesulfonate in ether at -78 °C produces the unisolated boron enolate. Subsequent treatment with hexanal yields the cross-aldol product in 70% yield as the sole regioisomer (eq 4).7 Reaction takes place at the methyl group of the ketone, while none of the ketone or aldehyde self-condensation products are observed. In a complementary fashion, substitution of 2,6-Lutidine for DIPEA and 9-Borabicyclononyl Trifluoromethanesulfonate (9-BBN triflate) for di-n-butylboryl triflate yields the opposite regioisomer as the sole product (eq 4).8
Proper choice of boron reagent, reaction solvent, and tertiary amine base influences the enolate geometry of ketones9 and esters.10 The use of dialkylboron triflates or dialkylboron halides, such as B-chloro-9-BBN, with DIPEA in ether at -78 °C favors the (Z)-enol borinates of ketones, while the more sterically demanding dialkylboron halides, such as dicyclohexylboron chloride (Chx2BCl), with Triethylamine favor the (E)-enol borinates (eq 5).9a,9b
Similar complementary methodologies exist for generating both the (E) and (Z) boron enolates of esters. The combination of chiral nonracemic bromoborane (1) and DIPEA in CH2Cl2 selectively converts trans-crotyl propionate into the (E)-boron enolate (2), which subsequently undergoes a highly enantioselective and diastereoselective Ireland-Claisen rearrangement to generate the threo product (3) in 75% yield and >97% ee. In comparison, use of triethylamine in a solvent mixture of toluene and hexane leads to a 90:10 mixture of (Z)- and (E)-boron enolates (4), which rearranges to generate the erythro product (5) as the major isomer in 65% yield and high enantiomeric excess (eq 6).10a,11
The stereoselective generation of silylketene acetals from alkyl esters and Triethylsilyl Perchlorate12 is quite effective using DIPEA as the base at -70 °C in a 1:1 solvent mixture of CH2Cl2 and CCl4 (see 2,2,6,6-Tetramethylpiperidine).
Phenols and enols can be O-methylated in moderate to good yields using Trimethylsilyldiazomethane with DIPEA in methanol-acetonitrile.13
Thioesters10c,10d and oxazolidones14 can also be selectively converted into dialkylboryl enolates using DIPEA as base and the appropriate boron triflates. The thioester enolates readily react with imines to generate b-amino thioesters (eq 7),10e whereas the oxazolidone boron enolates can undergo alkylation with acetoxyazetidinones (eq 8).14 S-t-Butyl bromothioacetate undergoes a highly stereospecific Darzens condensation with substituted benzaldehydes using Dicyclopentylboryl Trifluoromethanesulfonate and DIPEA at -78 °C to afford the trans-glycidic ester (eq 9).15
Aldol-like reactions between aldehydes and nitriles,16 alkylpyridines,17 2-methyloxazoles, 2-methylthiazoles,18 glycolates, and thioglycolates19 are possible in the presence of boryl triflates and DIPEA. Methyl-O-allyl glycolate tin(II) (or boron) enolates, prepared easily using DIPEA as base, undergo Wittig rearrangement to afford a-hydroxy esters with a high degree of diastereoselectivity (eq 10).20
Diisopropylethylamine also finds application in the preparation of titanium enolates from esters,21 aryl ketones,22 and oxazolidones.23
This sterically hindered amine is widely used in organic synthesis as a proton scavenger. Its lack of quaternization makes it an excellent choice of a base for use with very reactive alkylating agents.24 In the field of protecting group chemistry, DIPEA is a particularly useful base for protection of alcohols as substituted ethers.25 For example, the tertiary alcohol of mevalonic lactone can be protected as the p-methoxybenzyloxymethyl ether using an excess of DIPEA and 3 equiv of p-methoxybenzyl chloromethyl ether (eq 11).26
2,4-Disubstituted oxazolones are alkylated in high yields using alkyl halides with DIPEA as a base in DMF (eq 12).27 DIPEA can be used together with Triethyloxonium Tetrafluoroborate for the esterification of sterically hindered carboxylic acids.28
The alkylsulfination of diacetone-D-glucose with sulfinyl chlorides and DIPEA in toluene at -78 °C produces the (S)-sulfinates as the major products. Simply changing the base from DIPEA to pyridine and the solvent from toluene to THF results in a remarkable stereochemical reversal, affording the (R)-sulfinates as the major products (eq 13).29
The alkylation of protected uracils with alkyl halides using DIPEA in DMF or acetonitrile furnishes the alkylated uracils in good to moderate yields (eq 14). The alkylations involving ribofuranosyl bromides furnish the b-isomers as the sole products.30
Exposure of hydroxyl vinyl ethers to Trifluoromethanesulfonic Anhydride and DIPEA in CH2Cl2 at -78 °C results in a stereospecific cyclization to afford cyclic hemiacetals in near quantitative yield (eq 15).31
Addition of DIPEA to a mixture of phenylsulfenyl chloride and an unsaturated alcohol or carboxylic acid results in high yields of cyclic ethers or lactones, respectively.32 The presumed mechanism involves the intermediacy of an episulfonium ion (eq 16).
The eliminative deoxygenation of acetals into enol ethers is accomplished using Trimethylsilyl Trifluoromethanesulfonate and a slight excess of DIPEA (eq 17);33 similarly, treatment of 2-alkyloxazolidines with Chlorotrimethylsilane and DIPEA leads to N-(trimethylsilyloxyalkyl)enamines (eq 18).34 Thioacetals follow similar chemistry to furnish vinyl sulfides.35 Deoxygenation of sulfoxides with DIPEA and Iodotrimethylsilane produces vinyl sulfides.36
Diisopropylethylamine, as well as triethylamine, N-methylmorpholine, and other tertiary amines, find utility in the coupling of amino acids to prepare peptides.37 The basicity and steric nature of the tertiary amine utilized during the coupling reaction influences the degree of racemization.38
Minor dipeptide impurities, which sometimes are difficult to remove, can form during the N-acylation of amino acids. Acylation of alanine using benzoyl chloride and aqueous NaOH yields N-benzoylalanine (60%), which contains about 1.2% of the dipeptide impurity. Use of DIPEA nearly eliminates the impurity and results in a 72% yield of N-acylated product.39
The coupling of N-methylated amino acids is sometimes problematic. However, the combination of 3 equiv of DIPEA and 1 equiv of bromotris(dimethylamino)phosphonium hexafluorophosphate (BroP) in CH2Cl2 results in good yields of desired dipeptides. Methyl N-methylvalinate successfully couples with other amino acids using these reaction conditions. Epimerization during the coupling is not observed (eq 19).40
Kirk L. Sorgi
The R. W. Johnson Pharmaceutical Research Institute, Spring House, PA, USA