Efficient synthesis of β-amino bromides

Article abstract of DOI:10.1016/S0040-4039(00)00330-0

β-Aminoalcohols were smoothly converted to β-amino bromides using thionyl bromide and DMF, which were easily isolated without any further purification. Participation by the β-amino group in brominations not only enhanced reaction rates but also promoted stereo- and regioselectivities. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00330-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 3011–3014
Efficient synthesis of β-amino bromides
Advait S. Nagle,a Ralph N. Salvatore,a Byong-Don Chong a and Kyung Woon Jung a,b,∗
aDepartment of Chemistry, University of South Florida, 4202 E. Fowler Avenue, Tampa, Florida 33620-5250, USA
bDrug Discovery Program, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida 33612-9497, USA
Received 19 January 2000; revised 18 February 2000; accepted 21 February 2000
Abstract
β-Aminoalcohols were smoothly converted to β-amino bromides using thionyl bromide and DMF, which were
easily isolated without any further purification. Participation by the β-amino group in brominations not only
enhanced reaction rates but also promoted stereo- and regioselectivities. © 2000 Elsevier Science Ltd. All rights
reserved.
Keywords: thionyl bromide; DMF; β-amino bromide; bromination; aziridinium salt.
β-Aminoalcohols and their derivatives have played seminal roles in peptidomimetic synthesis,1
while serving as important precursors for a variety of uses.2 During our synthesis of peptidomimetic
analogs,3 N,N-dibenzylamino bromides 2 emerged as key intermediates, which could be prepared from
the corresponding β-aminoalcohols 1 (Scheme 1). Surprisingly, an extensive literature search revealed
that few methods have been reported for the preparation of amino bromides. Reaction conditions were
typically harsh,4 and milder conditions gave low to moderate yields or rather unexpected products.5 Thus,
these methods lack in generality for the synthesis of amino bromides, prompting us to embark on a new
bromination protocol particularly suited for β-aminoalcohols.
Scheme 1.
N,N-Dibenzylamino ethanol 4 was smoothly converted to the desired bromide 5 in high yield by reac-
ting with thionyl bromide and DMF. The product was spectroscopically pure and no further purification
was needed.6 The addition of N,N-dimethylformamide as a catalyst was found to accelerate the reaction
∗
Corresponding author.
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00330-0
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significantly through a Vilsmeier–Haack type SOBr2–DMF complex. Cyclohexane was the solvent of
choice, and other nonpolar solvents (hexanes and petroleum ether) also worked well. Polar solvents
such as dichloromethane were avoided because undesired side reactions, including rearrangements,
occasionally took place and further purifications were required.
To attest our conjecture if the amino group plays a neighboring group participation role, comparative
studies were performed under the developed conditions (Table 1). Similarly to 2-aminoethanol, γ- and
δ-aminoalcohols underwent bromination efficiently (entries 1 and 2), whereas the reactions with higher
homologues or aliphatic alcohols (entries 3 and 4) proceeded at slower paces, often affording complicated
product mixtures. Other heteroatoms also facilitated brominations as shown in entries 5 and 6. These
results strongly indicate that the presence of the amino group enhances the rate of bromination.
Table 1
As delineated in Table 2, stereochemical elements were examined with regards to the influence
of the β-amino group. Bromination of (R)-1-dibenzylamino-2-propanol led to the formation of the
corresponding secondary bromide 19 with inversion at the C(2) center (entry 1).7 Likewise, complete
inversion was observed with nitrogen heterocycles such as 20 although the conversion was sluggish.
In the case of 1-dibenzylamino-2-cyclohexanol (entries 3 and 4),8 both diastereomers interestingly
Table 2

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gave the trans isomer 23 while the reaction rate was noticeably slow with the cis isomer 24.7 As
envisioned, aminoindanol 25 was also resistant to bromination, presumably due to lack of the amino
group participation.
This unusual set of results, coupled with the results in Table 1, lend further credence to the fact that
the neighboring amino group facilitates the reaction rates (Scheme 2). It is postulated that bromosulfite
ester 26 can be protonated by in situ generated HBr to form hydrobromide salt 27, which allows
internal delivery of the bromide nucleophile, accounting for rate enhancement as well as stereochemical
inversion. Conversely, when the dibenzylamino group is located at the secondary center, 26 would form
the aziridinium salt 29 perhaps to relieve the steric strain, resulting in the double inversion as observed
with the trans-aminocyclohexanol 22. With cis isomers in rigid systems (24 and 25), neither of these
internal assistance can be anticipated, where the intermolecular delivery of the bromide nucleophile is
expected to be sluggish and dependent on steric demand.
Scheme 2.
Next, our attention was directed towards bromination of aminoalcohols with the amino group at the
secondary center, which would allow translocation through aforementioned aziridinium salts (Table
3).7 Diprotected aminoalcohols including 30 and 32 led to the exclusive formation of the rearranged
amino bromides with complete stereochemical inversion at the secondary centers.9 Similar results were
observed for differently substituted aminoalcohols, even in the presence of ester functionality (entry 3)
and the prolinol derivative 36 underwent ring expansion to afford piperidine derivative 37 (entry 4). As
illustrated in entry 5, monoprotected aminoalcohol 38 also provided a rearranged product 39 exclusively.
On the contrary, in the absence of nitrogen protecting groups, a variety of aminoalcohols gave rise to
the exclusive formation of hydrobromide salts (entry 6), which were easily isolated from the reaction
media by simple filtration. Neither rearrangement nor aziridine ring formation was observed, implying
that rapid protonation would secure internal delivery of bromide prior to cyclization. Due to mild reaction
conditions, ester functionality was left intact to offer the desired bromide in high yield (entry 7).
In conclusion, we have developed a convenient and efficient protocol for the conversion of aminoal-
cohols to the corresponding bromides. Both primary and secondary alcohols were smoothly converted
to bromides in high yields, and purification processes were not necessary. Furthermore, the amino
group was found to facilitate the bromination of alcohols in their vicinity, thus offering high regio- and
stereoselectivities. In our laboratories, a variety of amino bromides have been synthesized, and their
applications will be reported in due course.
Acknowledgements
Financial support from the USF Research Council is gratefully acknowledged, as is support from the H.
Lee Moffitt Cancer Center & Research Institute. This project was also supported in part by the American
Cancer Society’s Institutional Research Grant #032.

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Table 3
References
1. For various examples, see: Ager, D. J.; Prakash, I.; Schaad, D. R. Chem. Rev. 1996, 96, 835 and references cited therein.
2. For comprehensive reviews on aminoalcohols and related compounds, see: (a) see Ref. 1. (b) Reetz, M. T. Chem. Rev. 1999,
99, 1121. (c) Sardina, F. J.; Rapoport, H. Chem. Rev. 1996, 96, 1825.
3. For our N-alkylation, see: Salvatore, R. N.; Nagle, A. S.; Schmidt, S. E.; Jung, K. W. Org. Lett. 1999, 1, 1893.
4. Cortese, F. Organic Syntheses; John Wiley: New York, 1943; Vol. II, pp. 91–93.
5. Chandrasekhar, S.; Mohanty, P. K.; Harikishan, M. K.; Sasmal, P. K. Org. Lett. 1999, 1, 877.
6. Representative experimental procedure: Into the opalescent solution of N,N-dibenzylaminoalcohol (1 mmol) in cyclohexane
(5 mL), N,N-dimethylformamide (0.5–0.6 mmol), and thionyl bromide (1.2 mmol), were added successively under a nitrogen
atmosphere. The yellow reaction mixture, separated into two layers, was then stirred for 3 h at ambient temperature. The
reaction suspension was diluted with dichloromethane until it became homogeneous, then the pale yellow solution was
neutralized with saturated NaHCO3 solution. The organic layer was washed with water (3×5 mL), dried over anhydrous
Na2SO4, filtered, and concentrated in vacuo to afford the desired N,N-dibenzylamino bromide as a yellow oil.
7. The stereochemistry of the bromides was elucidated by either proton NMR analysis or comparison with authentic samples.
Enantioselectivities and diastereoselectivities were confirmed through Mosher’s esters, which were prepared with (S)-MTPA
acid using our cesium base promoted O-alkylation techniques. For our O-alkylations, see: (a) Parrish, J. P.; Sundaresan, B.;
Jung, K. W. Synth. Commun. 1999, 29, 4423. (b) Dueno, E. E.; Chu, F.; Kim, S.-I.; Jung, K. W. Tetrahedron Lett. 1999, 40,
1843. (c) Chu, F.; Dueno, E. E.; Jung, K. W. Tetrahedron Lett. 1999, 40, 1847. (d) Kim, S.-I.; Chu, F.; Dueno, E. E.; Jung, K.
W. J. Org. Chem. 1999, 64, 4578.
8. cis-2-Aminocyclohexanol was prepared from the trans isomer. (a) Leffler, M. T.; Adams, R. J. Am. Chem Soc. 1937, 59,
2252. (b) McCasland, G. E.; Clark Jr., R. K.; Carter, H. E. J. Am. Chem. Soc. 1949, 71, 637.
9. Gmeiner, P.; Junge, D.; Kärtner, A. J. Org. Chem. 1994, 59, 6766.