N-Bromosuccinimide-Sodium Azide

(NBS)

[128-08-5]  · C4H4BrNO2  · N-Bromosuccinimide-Sodium Azide  · (MW 177.99) (NaN3)

[26628-22-8]  · N3Na  · N-Bromosuccinimide-Sodium Azide  · (MW 65.01)

(source of BrN3 in conversion of alkenes to b-bromoalkyl azides and, upon reduction, to aziridines)

Physical Data: for physical data see N-Bromosuccinimide and Sodium Azide.

Introduction.

Sodium azide-N-bromosuccinimide can transfer an azido group and a Br atom to C=C double bonds. Reduction of the resulting b-bromoalkyl azides with Lithium Aluminum Hydride produces aziridines. This combination has been used as an in situ source of bromine azide BrN3 and is a good substitute for the classical method of Hassner,1,2 which requires the synthesis of potentially explosive3 BrN3 in acetonitrile or pentane.

Scope and Limitations.

The reaction is usually carried out at temperatures around -5 °C, by adding NBS in small portions to a mixture (4/1 or 3/1) of organic solvent (DME, THF, or DMF) and water in which is dissolved an excess of NaN3 and the suspended alkene. It has been successfully carried out up to a molar scale.4 It is still unclear if BrN3 is effectively formed or if the azido anion reacts with the intermediate bromonium ion resulting from the interaction of the alkene with NBS. 1,1-Disubstituted,5 1,2-disubstituted,6 trisubstituted,6,7 and tetrasubstituted4,8 alkenes (eqs 1-5) as well as indenes (eq 6)9,10 and allylic alcohols (eq 7)10 are transformed in reasonably good yields (40-60%) to the corresponding b-bromoalkyl azides.

The reaction is difficult with less reactive C=C double bonds. For example, monosubstituted alkenes give poor yields of 1-bromoalkyl azides and bromohydrins are formed.6 This results from the reaction with HOBr, formed along with N2 by the decomposition of BrN3 in water. The same process is also observed with 7-methoxyindene (eq 6).9 Phenanthrene does not react11 and is recovered in high yield under these conditions. Again, decomposition of BrN3 by water is responsible for this failure, since preformed bromine azide in CH2Cl2 adds to the 9,10-C=C double bond (eq 8).11 In some cases, e.g. 9,9a-dihydro-3H-pyrrolo[1,2-a]indoles (eq 9)12 and 1,4,5,8,9,10-hexahydro-4a,9a-methanoanthracene and related derivatives (eq 5),4,8 aromatization totally or partially competes with the formation of the b-bromoalkyl azide. In some other cases, loss of HBr occurs during the purification of the crude mixture (eq 8)11 or even during the reaction (eq 10).13 In such cases the vinyl azides first generated are able to react further with BrN3 to produce b-bromo-a,a-bis(alkylazido)alkanes (eq 10).13

Regioselectivity (rs).

The addition is highly regiospecific with terminal5,6 and trisubstituted6 alkenes and produces the b-bromoalkyl azide in which the bromine atom is attached to the least substituted carbon atom (rs >95%; eqs 1-5). This is remarkable, since preformed BrN3 reacts in a nonregioselective manner with terminal alkenes in acetonitrile and leads to an 8/2 mixture of b-bromoalkyl azides, in which the product bearing the bromine atom at the least substituted carbon prevails (Markovnikov rules).6 The higher electronegativity of Br compared to that of I and probably to that of N3 explains why, under similar conditions, BrN3 possesses a much higher propensity than its iodo analog to react in a radical process.2 The high polarity of the medium in the NaN3-NBS reaction favors the ionic process.6 This reagent adds regioselectively to indenes (eq 6)9,10 and nonregioselectively to dialkyl substituted C=C double bonds bearing two different alkyl substituents (eqs 3 and 4)6 and to 2-cyclopenten-1-ol (eq 7).14

Stereoselectivity (ss).

The addition of the Br atom and N3 moiety is anti stereospecific (ss >98%) with tri- and tetrasubstituted alkenes (eqs 3 and 4) and, therefore, the whole process NaN3-NBS, LiAlH4 allows the highly stereoselective synthesis of aziridines which possess the same stereochemistry as their parent alkenes. This occurs6 with a much higher stereoselectivity than observed in the conventional BrN3, LiAlH4 method,2 due to the absence of radical reactions, and therefore more closely resembles the reaction IN3, LiAlH4.2

Asymmetric induction is very poor with 2-cyclopenten-1-ol (eq 7)14 but very high with 1,4,5,8,9,10-hexahydro-4a,9a-methanoanthracene (eq 5).8 In the latter case the ionic addition to the tetrasubstituted double bond is sterically controlled by the cyclopropane ring and, after reductive cyclization, affords a compound in which both three-membered rings are on the same face of the tricyclic derivative.14

Chemoselectivity.

NaN3-NBS proved to be more reactive toward tetra- than disubstituted double bonds (eq 5).4,8 It also reacts chemoselectively on the terminal nonfunctionalized C=C double bond of geranyl and farnesyl acetates as well as of squalene,7 which possess two, three, and six identically trisubstituted C=C double bonds, respectively (eqs 11 and 12). Presumably, the polyene is coiled in the highly polar medium used (DME-H2O) and presents its terminal double bond to the attack of the extensively solvated bromonium ion.7 A similar explanation was previously given to rationalize the high chemoselective addition of BrOH towards the same polyalkenes.15 Interestingly, the conventional BrN3 method7 as applied to geranyl and farnesyl acetates not only produces the corresponding b-bromoalkyl azides in very low yields but also shows very little terminal preference. Poor chemoselectivity is also observed if squalene is reacted with IN3 under conventional conditions.16

The NaN3-NBS, LiAlH4 method proved, for aziridine synthesis from alkenes, to be superior to the alternative method of epoxide ring opening by azide ion followed by reaction of the corresponding tosylate with LiAlH4.17

Related Reagents.

Bromine Azide; N-Bromosuccinimide; Iodine Azide; Sodium Azide.


1. Hassner, A.; Boerwinkle, F. JACS 1968, 90, 216.
2. Hassner, A. ACR 1971, 4, 9.
3. Spencer, D. A. JCS 1925, 127, 216.
4. Lange, W.; Tückmantel, W. CB 1989, 122, 1765.
5. Sasaki, T.; Eguchi, S.; Hirako, Y. T 1976, 32, 437.
6. Van Ende, D.; Krief, A. AG(E) 1974, 13, 279.
7. Van Ende, D.; Krief, A. AG(E) 1974, 13, 279-280.
8. Vogel, E.; Brocker, U.; Junglas, H. AG(E) 1980, 19, 1015.
9. Nguy, N. M.; Chiu, I.-C.; Kohn, H. JOC 1987, 52, 1649.
10. Chiu; I.-C.; Kohn, H. JOC 1983, 48, 2857.
11. Denis, J. N.; Krief, A. T 1979, 35, 2901.
12. Verboom, W.; Lammerink, B. H. M.; Egberink, R. J. M.; Reinhoudt, D. N.; Harkema, S. JOC 1985, 50, 3797.
13. Shin, C.; Yonezawa, Y.; Suzuki, K.; Yoshimura, J. BCJ 1978, 51, 2614.
14. Gibson, H. H.; Macha, M. R.; Farrow, S. J.; Ketchersid, T. L. JOC 1983, 48, 2062.
15. Van Tamelen, E. E.; Sharpless, K. B. TL 1967, 2655.
16. Avruch, L.; Oehlschlager, A. C. S 1973, 622.
17. Riddiford, L. M.; Ajami, A. M.; Corey, E. J.; Yamamoto, H.; Anderson, J. E. JACS 1971, 93, 1815.

Alain Krief

Facultés Universitaires Notre-Dame de la Paix, Namur, Belgium



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