Diisopropylamine

i-Pr2NH

[108-18-9]  · C6H15N  · Diisopropylamine  · (MW 101.19)

(strong hindered base capable of catalyzing asymmetric protonation in photodeconjugation of a,b-unsaturated esters;1 deracemizes amino acids;2 forms quinquevalent cyclic phosphoranes with triflic anhydride;3 useful reagent in isocyanate synthesis;4 promotes thermal rearrangements of cyclopropylimines to pyrroles;5 in combination with HF, stereoselectively opens epoxides to trans-fluorohydrins6)

Physical Data: mp -61 °C; bp 83-84 °C; d 0.7178 g cm-3; n20D 1.3915; pKaH2O 11.13; pKaTHF 35.7.

Solubility: very sparingly sol H2O; sol most organic solvents.

Form Supplied in: neat colorless liquid; widely available.

Purification: can be dried over and distilled from fresh potassium hydroxide immediately before use.

Handling, Storage, and Precautions: highly flammable, corrosive liquid with a strong ammonia-like smell; irritating to eyes, respiratory system, and skin; use in a fume hood.

Diastereo- and Enantioselective Protonations.

Photodeconjugation of acyclic a,b-unsaturated esters, containing at least one hydrogen in the g-position, is a useful synthetic method for preparation of their thermodynamically less stable b,g-unsaturated isomers in high yield.7 It was proposed7b,7e that this process proceeded via photoenolization involving a pseudocyclic transition state, since cyclic esters were found to be completely inert to photochemical deconjugation.7b,7e,8 If the starting a,b-unsaturated ester is a-substituted, and either a chiral amino alcohol is added to the reaction mixture,9 or the ester group contains a chiral alcohol moiety,1 then photodeconjugation leads to enantio- or diastereoselective protonation, respectively.

In the latter case, diastereoselectivity of the protonation of the new asymmetric center is enhanced in the presence of 0.1 equiv of diisopropylamine in hexane at -40 to -70 °C (eq 1).1 Methanol, diethylamine, dibutylamine, N-ethylbenzylamine, (+)- and (-)-ephedrine, (+)-O-methylephedrine, and N-(2-hydroxy- and 2-methoxyethyl)benzylamines proved to be less effective additives, while dicyclohexylamine gave similar diastereoisomeric excess (de).

Deracemization of N-benzylidene methyl esters of racemic amino acids by a lithium amide, followed by asymmetric protonation by a chiral acid, yields optically active amino acids.10 The enantiomeric excess (ee) and yield are increased by an amine exchange involving diisopropylamine after the metalation step by Lithium Hexamethyldisilazide (LHMDS) and prior to the asymmetric protonation by means of (2R,3R)-Dipivaloyltartaric Acid (DPTA) (eq 2).2 By this method, the asymmetric induction exceeds or equals that obtained in the classical procedure using Lithium Diisopropylamide as the base, and the yield is somewhat higher. Use of other amines (e.g. ethylamine, Piperidine, chiral N-ethyl-a-methylbenzylamine), but not triethylamine, may enhance the asymmetric induction more than does diisopropylamine.

Synthesis of Cyclic Phosphoranes.

Quinquevalent cyclic phosphoranes can be prepared3 in good yields from readily available phosphine oxides by treatment with Trifluoromethanesulfonic Anhydride in dichloromethane at 0 °C, followed by an ether solution of diisopropylamine (2 equiv) and 1,2-diols or catechols at -78 °C (eq 3). Earlier, five-coordinate phosphoranes were prepared from tetravalent phosphorus compounds. Diisopropylammonium triflate can be readily precipitated by the addition of ether to the reaction mixture. This method could not be extended to cyclic phosphonates and phosphinates.

Isocyanate Synthesis.

General methods11 for the preparation of isocyanates include the dehydration of formamides by Phosgene,12 diphosgene,13 and Phosphorus Oxychloride14 in combination usually with tertiary amines. The replacement of Triethylamine by diisopropylamine enhances the average yields of the phosphoryl chloride method to the levels of the phosgene or diphosgene procedures.4 In addition, the isocyanates are often obtained in higher purity. Less bulky secondary amines, e.g. diethylamine, do not give any trace of the isocyanate. Phosphoryl chloride (1.1 equiv) is added dropwise to a dichloromethane solution of formamide and diisopropylamine (2.7 equiv) at 0 °C. In the case of simple alkylformamides, e.g. methyl N-formylaminoacetate, formamide is added to a mixture of phosphoryl chloride and diisopropylamine.

This method is considerably milder than the diphosgene method. It gives ferrocenylalkyl isocyanates in fair yields, whereas diphosgene/triethylamine fails to give isocyanates or leads to a mixture of isocyanate and cyanide. Chiral isocyanates derived from amino acids yield racemic isocyanates. With diisopropylamine, a combination of O-silylation and dehydration affords a one-pot preparation of the 2-siloxyphenyl isocyanate (eq 4).

Synthesis of N-Alkyl-2-chloropyrroles.

The thermolysis of N-t-alkyl-2,2-dichlorocyclopropylimines in N-methylpyrrolidine (NMP) gives 3-chloropyrroles in high yields via fission of the 1,3-bond (eq 5).4 When Lewis bases in ethyl phenyl ether are added, thermal ring opening via 1,2-bond cleavage is favored, yielding 2-chloro isomers (eq 5). Among the bases studied, diisopropylamine guided this reaction path most effectively;4 CaO and K2CO3 also facilitated this rearrangement, but to a lesser extent than diisopropylamine. In contrast to other cyclopropylimines, the ring transformation was not effected by NH4Cl or HBr additives.4,15

Synthesis of Fluorohydrins.

The addition of Hydrogen Fluoride to an oxirane is a synthetic method for the preparation of fluorohydrins.16 Diisopropylamine trihydrofluoride (Jullien's reagent6), prepared by lyophilization of a solution of a 1:3 mol ratio of diisopropylamine and 48% aqueous HF solution in a Nalgene polyethylene bottle,17 serves as an attenuated source of HF. It stereospecifically converts epoxides into trans-fluorohydrins (eq 6).

During the regioselective opening of epoxides, diisopropylamine trihydrofluoride initially donates a fluoride ion, and then HF donates a proton. Jullien's reagent can be stored in a desiccator at rt for periods longer than 6 months without noticeable decomposition,17 and can be used at 78-150 °C (typically at 110 °C) in an excess of 1.5-5 equiv for up to 30 h.6,17,18,19 Olah's reagent, Pyridinium Poly(hydrogen fluoride),20 employed below -5 °C for 15 min, gives somewhat lower yields of fluorohydrins with decreased regioselectivity (eq 7).

The regioselective ring opening of epoxides by Jullien's reagent is governed primarily by steric factors.17 trans-Epoxides afford a mixture of erythro isomers, while cis-epoxides yield threo isomers (eqs 8 and 9).6a

Other di- and trialkylamine trihydrofluorides6a,6b and diisopropylamine dihydrofluoride6a afford lower yields; use of HF in polar basic solvents, KF2, or boron trifluoride etherate with or without HF frequently results in polymerization or rearrangement of the products.16


1. (a) Awandi, D.; Henin, F.; Muzart, J.; Pete, J.-P. TA 1991, 2, 1101. (b) Mortezaei, R.; Awandi, D.; Henin, F.; Muzart, J.; Pete, J.-P. JACS 1988, 110, 4824.
2. Duhamel, L.; Fouquay, S.; Plaquevent, J.-C. TL 1986, 27, 4975.
3. Antczak, S.; Trippett, S. JCS(P1) 1978, 1326.
4. Obrecht, R.; Herrman, R.; Ugi, I. S 1985, 400.
5. Kagabu, S.; Kawai, I. CC 1990, 1393.
6. (a) Aranda, G.; Jullien, J.; Martin, J. A. BSF(2) 1965, 1890. (b) Aranda, G.; Jullien, J.; Martin, J. A. BSF(2) 1966, 2850. (c) Gardaix, R.; Jullien, J. BSF(2) 1969, 2721.
7. (a) Jorgenson, M. J. CC 1965, 137. (b) Rando, R. R.; Doering, W. E. JOC 1968, 33, 1671. (c) Kropp, P. J.; Krauss, H. J. JOC 1967, 32, 3222. (d) Lombardo, D. A.; Weedon, A. C. TL 1986, 27, 5555. (e) Duhaime, R. M.; Lombardo, D. A.; Skinner, I. A.; Weedon, A. C. JOC 1985, 50, 873. (f) Skinner, I. A.; Weedon, A. C. TL 1983, 24, 4299.
8. Majeti, S.; Gibson, T. W. TL 1973, 4889.
9. (a) Piva, O.; Henin, F.; Muzart, J.; Pete, J.-P. TL 1987, 28, 4825. (b) Piva, O.; Henin, F.; Muzart, J.; Pete, J.-P. TL 1986, 27, 3001. (c) Mortezaei, R.; Piva, O.; Henin, F.; Muzart, J.; Pete, J.-P. TL 1986, 27, 2997. (d) Mortezaei, R.; Henin, F.; Muzart, J.; Pete, J.-P. TL 1985, 26, 6079.
10. (a) Duhamel, L.; Duhamel, P.; Launay, J. C.; Plaquevent, J. C. BSF(2) 1984, 421. (b) Duhamel, L.; Plaquevent, J. C. BSF(2) 1982, 75.
11. Gogel, G.; Marquarding, D.; Hoffman, P.; Ugi, I. In Isonitrile Chemistry; Ugi, I., Ed.; Academic: New York, 1971; p 9.
12. Ugi, I.; Fetzer, U.; Eholzer, U.; Knupfer, H.; Offerman, K. AG 1965, 77, 492; AG(E) 1965, 4, 474.
13. Skorna, G.; Ugi, I. AG 1977, 89, 267; AG(E) 1977, 16, 259.
14. (a) Suzuki, M.; Nunami, K.; Matsumoto, K.; Yoneda, N.; Kasuga, O.; Yoshida, H.; Yamaguchi, T. CPB 1980, 28, 2374. (b) Nunami, K.; Suzuki, M.; Yoneda, N. S 1978, 840. (c) Hoppe, D.; Schöllkopf, U. In Reactions and Syntheses in the Organic Chemistry Laboratory; Tietze, L.-F.; Eicher, T., Eds; University Science Books; Mill Valley, CA, 1989; p 486. (d) Schöllkopf, U.; Schröder, R.; Stafforst, D. LA 1974, 44. (e) Van Leusen, A. M.; Wildeman, J.; Oldenziel, O. H. JOC 1977, 42, 1153. (f) Suzuki, M.; Nunami, K.; Moriya, T.; Matsumoto, K.; Yoneda, N. JOC 1978, 43, 4933.
15. (a) Stevens, R. V. ACR 1977, 10, 193. (b) Wasserman, H. H.; Dion, R. P. TL 1982, 23, 1413. (c) Pinnick, H. W.; Chang, Y.-H. TL 1979, 837. (d) Wasserman, H. H.; Dion, R. P. TL 1983, 24, 3409. (e) Celerier, J. P.; Haddad, C. M.; Jacoby, D.; Lhommet, G. TL 1987, 28, 6597.
16. Sharts, C. M.; Sheppard, W. A. OR 1972, 21, 125.
17. Muehlbacher, M.; Poulter, C. D. JOC 1988, 53, 1026.
18. Chaabuni, M. M.; Baklouti, A. BSF(2) 1989, 549.
19. Takano, S.; Yanase, M.; Ogasawara, K. CL 1989, 1689.
20. (a) Olah, G. A.; Meidar, D. Isr. J. Chem. 1978, 17, 148. (b) Ayi, A. I.; Remli, M.; Condom, R.; Guedj, R. JFC 1981, 17, 565.

István Hermecz

Chinoin, Budapest, Hungary



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