Author Topic: Amphs by Aminobromination of Phenylpropenes  (Read 3760 times)

0 Members and 1 Guest are viewing this topic.


  • Guest
Amphs by Aminobromination of Phenylpropenes
« on: October 06, 2003, 06:53:00 PM »
Direct aminobromination of propenylbenzenes, giving between 57-70% alpha-Bromoamphetamine HCl depending on if the cis or trans-propenylbenzene is used as a starting material. As the intermediate product is N-boc-alpha-Bromoamphetamine, performing an LAH reduction instead of hydrolyzing the carbamate will actually give the N-Methyl-Amphetamine in high yield, as LAH easily reduces carbamates to N-Methylamines and dehalogenates benzylic halides. It might even be possible to perform the reduction with sodium borohydride in diglyme! Any comments?

Formation of diastereomeric alpha-Bromoamphetamine HCl (12) from
(E)- and (Z)-1-phenylpropenes (trans- and cis-propenylbenzene)

Regioselective aminobromination of terminal alkenes
Anna Sliwinska and Andrzej Zwierzak

Tetrahedron 59, 5927–5934 (2003)




The addition of tert-butyl N,N-dibromocarbamate (BBC) to a variety of terminal alkenes has been studied. The reaction was spontaneously initiated and proceeded smoothly in refluxing dichloromethane. The N-bromo adducts, formed upon addition, could be reduced in situ with aqueous sodium sulfite to give the corresponding 2-bromo-N-Boc-amines. Immediate deprotection of these compounds with gaseous HCl or p-toluenesulfonic acid afforded 2-bromoamine hydrochlorides or tosylates in pure state and good overall yields.

2.5. Stereochemistry of BBC (3) addition to 1-phenylpropenes

Diastereomeric (E)- and (Z)-1-phenylpropenes7 were selected as model compounds for studying the stereochemical course of BBC 3 addition. Both crude BBC adducts to (E)- and (Z)-1-phenylpropene 11a and 11b have superimposable 1H-NMR spectra, suggesting that they are identical mixtures of erythro- and threo-isomers. Also, upon hydrolysis with HCl, both BBC adducts 11a and 11b gave an identical mixture of diastereomeric 2-bromoamine hydrochlorides 12.

Formation of diastereomeric 1-Bromoamphetamine HCl (12) from (E)- and
(Z)-1-phenylpropenes (trans- and cis-propenylbenzene)

3. Conclusion

In conclusion we have developed a simple, two-step, and efficient method for regioselective aminobromination of terminal alkenes using the new reagent tert-butyl N,N-dibromocarbamate (3). The procedure offers an operationally simple and convenient synthesis of 2-bromoamines. As a potential route to aziridines and N-Boc-aziridines it can successfully compete with other available protocols involving activation of the hydroxyl group in 2-aminoalcohols by converting into tosylates or mesylates and subsequent ring closure by means of strong bases.10

4. Experimental

4.1.1. Preparation of tert-butyl N,N-dibromocarbamate (BBC, 3).

Bromine (35.16 g, 0.22 mol) was added dropwise with efficient stirring for 40 min to a solution of crude tert-butyl carbamate4 (prepared in CH2Cl2, mp 90–93°C, yield ca. 100%, purity ~90%; 12.9 g, 0.11 mol) and K2CO3 (15.2 g, 0.11 mol) in water (200 mL) at room temperature. The resulting mixture was stirred for 2 h, CH2Cl2 (100 mL) was then added and stirring was continued for further 15 min. The organic layer was separated, and the aqueous phase was extracted with CH2Cl2 (3x30 mL). Combined extracts were washed with water (30 mL), dried (MgSO4), and the solvent evaporated in vacuo to give the title compound 3 (24.6 g, 90%) as an orange solid. Crude 3 was contaminated (1H-NMR) with ca. 9% of tert-butyl N-bromocarbamate. Analytically pure sample of 3 (prepared from pure tert-butyl carbamate, mp 107–108°C and washed with cold pentane) had mp 93–95°C.

4.2. Addition of BBC (3) to terminal alkenes.
General procedure

A solution of BBC (3) (1.38 g, 5 mmol) in CH2Cl2 (7 mL) was added dropwise with stirring to the solution of terminal alkene (5 mmol) in refluxing CH2Cl2 (7 mL) for 20 min. Stirring was then continued if necessary until pale-yellow coloration of the solution was obtained (ca. 2 h). The resulting solution was cooled to 5–10°C and 12% aqueous solution of sodium sulphite (5 mL) was added slowly at this temperature. Dichloromethane (15 mL) was then added, the organic layer was separated, washed with water (3x5 mL), dried (MgSO4) and the solvent evaporated in vacuo. The residual crude adducts  were purified by column chromatography using CH2Cl2 as eluent.

4.5. Deprotection of BBC adducts with hydrogen chloride.
General procedure

A solution of crude BBC adduct prepared as described above (Section 4.2) in CH2Cl2 (30 mL) was saturated with gaseous hydrogen chloride at 0°C and then left overnight at room temperature. The solvent was evaporated in vacuo and ether (30 mL) was added to the residue. Colorless crystals of the amine hydrochlorides obtained on refrigeration for 1 h were filtered off and washed with ether.

Addition of BBC (3) to (E)-1-phenylpropene followed by deprotection with HCl Addition and deprotection were carried out as described for other hydrocarbons. Yield 70%, colorless solid, mp 161–165°C (dec.).

Addition of BBC (3) to (Z)-1-phenylpropene followed by deprotection with HCl Addition and deprotection were carried out as described for other hydrocarbons. Yield 57%, colorless solid, mp 168–171°C (dec.).

5. References


J. Org. Chem. 28, 3421–3426 (1963)


tert-Butyl Carbamate

Trifluoroacetic acid (15.5 mL, 210 mmol) was added (fume hood!) slowly to a stirred mixture of tert-butyl alcohol (7.4g, 100 mmol) and sodium cyanate (13g, 200 mmol) in 25-100 mL of benzene (volumes of solvent significantly larger than this decreased the yield). A mildly exothermic reaction occurred arid some gas bubbled out of the system. The container was loosely stoppered, and the reaction mixture was stirred for 3 h (or overnight, the yield was the same). 15 mL of water was added and the organic layer was separated and dried: the solvent was removed in vacuo at a bath temp of 40-50°C. The residue solidified (92% yield, mp 98-101°C). Recrystallization from water gave an analytically pure product (8g, 69% yield), mp 107-108°C. This is similar to the prep in

Organic Syntheses.



J. Am. Chem. Soc. 75, 4094–4096 (1953)


Synlett 893–894 (1997)