A fast procedure for the preparation of vicinal azidoalcohols using polymer supported reagents

Article abstract of DOI:10.1016/j.tetlet.2005.05.023

Several vicinal azidoalcohols were prepared in good to high yield and purity, starting from aryl α-haloketones, using reagents supported on a macroporous ion exchange resin. This is a fast and new approach to aryl azidoalcohols.

Full text of DOI:10.1016/j.tetlet.2005.05.023

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 4531–4533
A fast procedure for the preparation of vicinal azidoalcohols
using polymer supported reagents
*
Eugenia Cristina Souza Brenelli, Jose Afranio Brenelli and
ˆ
´
Raquel Cristina Laranjeira Pinto
ˆ
´ ´ ˆ
Universidade Federal Fluminense, Campus Valonguinho, Instituto de Quımica, Departamento de Quımica Organica,
´
Outeiro de Sa˜o Joa˜o Batista s/n Centro, Niteroi-RJ, CEP 24020-150, Brazil
Received 30 March 2005; revised 9 May 2005; accepted 9 May 2005
Abstract—Several vicinal azidoalcohols were prepared in good to high yield and purity, starting from aryl a-haloketones, using
reagents supported on a macroporous ion exchange resin. This is a fast and new approach to aryl azidoalcohols.
Ó 2005 Published by Elsevier Ltd.
Solution-phase synthesis using solid-phase reagents or
scavengers has been termed Ôpolymer-assisted solution-
phaseÕ synthesis, and the developments in this field have
been subject of several reviews.1 The interest in this field
has caused a recent explosion in the number of scientific
papers describing the development of novel support-
bound reagents, catalysts and methods for purification.
Supported reagents are reactive species, which are asso-
ciated with a support material. The most important
advantage in using a polymer supported reagent in an
organic reaction is the simplification of reaction work-
up, i.e. product separation and isolation. In the case of
an insoluble polymeric reagent, filtration and repeated
washing with suitable solvents can be generally used at
the end of the reaction to isolate the product and there-
fore the need for complex chromatographic techniques
can be avoided.2 Monitoring the progress of the reac-
tions is easy by applying TLC, NMR or LC/MS tech-
niques. The use of an excess of reagent is also allowed
without the need for additional purification steps.3
Regeneration and reuse of the recovered polymer sup-
ported reagents are possible, thus providing an environ-
mentally benign system.4
of other functionalities, for example, amines via reduc-
tion, imines via rearrangement, triazoles and other het-
erocycles via cycloaddition. It is precisely for the
synthesis of such sensitive compounds that the use of
polymeric reagents, for example, azide anion, supported
on anion exchange resin (PS-azide) is ideally suited.5
Polymer supported borohydride exchange resin (PS-
BER) was first reported in 1977 by Gibson and Baily6
and differs from sodium borohydride in reactivity and
stability in alcoholic solvents and acidic solution. It
has been applied in solvent purification, generation of
volatile metal hydrides and reduction of metal ions,
some carbonyl compounds, acyl halides and unsaturated
nitroalkenes.7
Our research interests concerned the preparation of chi-
ral 1-aryl-2-azidoethanols through biotransformations
of corresponding a-azidoketones.8 These compounds
are precursors of important biologically active natural
compounds. We have been using conventional solution
phase chemistry to prepare racemic vicinal azidoalco-
hols for kinetic enzymatic resolution.9 In order to speed
up the preparation of such compounds we devised an
alternative procedure using polymer supported reagents
(Scheme 1).
Organic azides are thermally and photochemically labile
compounds but of considerable utility in the generation
Polymer supported azide resin was found to be a highly
effective reagent for the conversion of a-haloketones
into a-azidoketones10 (Table 1, product 2). These com-
pounds are most commonly prepared at low tempera-
tures (5–10 °C) using polar aprotic solvents;
Keywords: Azidoketones; Azidoalcohols; Polymer supported boro-
hydride; Polymer supported azide.
*
Corresponding author. Tel.: +55 (21) 26292230; fax: +55 (21)
26292135; e-mail: gqoecsb@vm.uff.br
0040-4039/$ - see front matter Ó 2005 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2005.05.023

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E. C. S. Brenelli et al. / Tetrahedron Letters 46 (2005) 4531–4533
O
OH
O
X
N3
N3
N3
CH2Cl2
30ºC
30 min
BH4
R1
R1
MeOH
R1
30ºC
R2
R2
R2
30 min
3
2
1
Scheme 1.
Table 1. a-Azidoketones and b-azidoalcohols prepared using polymer
supported reagents
Ed. 2001, 650–679; (d) Ley, S. V.; Baxendale, I. R.; Bream,
R. N.; Jackson, P. S.; Leach, A. G.; Longbottom, D. A.;
Nesi, M.; Scott, J. S.; Storer, R. I.; Taylor, S. J. J. Chem.
Soc., Perkin Trans. 1 2000, 3815–4195; (e) Thompson, L.
A. Curr. Opin. Chem. Biol. 2000, 324–337; (f) Parlow, J. J.;
Devraj, R. V.; South, M. S. Curr. Opin. Chem. Biol. 1999,
320–336; (g) Kaldor, S. W.; Siegel, M. G. Curr. Opin.
Chem. Biol. 1997, 101–106; (h) Ley, S. V.; Baxendale, I.
R.; Brusotti, G.; Caldarelli, M.; Massi, A.; Nesi, M. Il
Farmaco 2002, 321–330.
Entry
R1
R2
X
Yield/(%)a
2b
3c
1
H
H
Cl
Cl
95
90
90
88
2
F
H
3Cl
4
H
Cl
H
92
87
Br
I
Cl
Cl
Cl
Cl
Cl
Br
Br
90
89
93
91
89
85
96
88
5
H
2. Minghu, W.; Guichun, Y.; Zuxing, C. React. Funct.
Polym. 2000, 44, 97–100.
3. Nam, N.; Sardari, S.; Parang, K. J. Comb. Chem. 2003,
479–546.
6
Cl
Cl
H
7
Me
MeO
NO2
H
8
H
92(79)d
93(89)e
9
10
H
NO2
68
75
80
78
4. Togo, H.; Sakuratani, K. Synlett 2002, 1966–1975.
5. (a) Hassner, A.; Stern, M.; Gottlieb, H. E.; Frolow, F. J.
Org. Chem. 1990, 55, 2304–2306; (b) Liao, S.; Hruby, V. J.
Tetrahedron Lett. 1996, 37, 1563–1566; (c) Qian, X.;
Russel, K. C.; Boteju, L. W.; Hruby, V. J. Tetrahedron
1995, 51, 1033–1054; (d) Dharanipragada, R.; VanHulle,
K.; Bannister, A.; Bear, S.; Kennedy, L.; Hruby, V. J.
Tetrahedron 1992, 48, 4733–4748; (e) Lakshman, M.;
Nadkarni, D. V.; Lehr, R. E. J. Org. Chem. 1990, 55,
4892–4897; (f) Hassner, A.; Stern, M. Angew. Chem., Int.
Ed. Engl. 1986, 25, 478–479.
6. Gibson, H. W.; Baily, F. C. J. Chem. Soc., Chem.
Commun. 1977, 815.
7. Caiqin, Q.; Ling, X.; Yumin, D.; Xiaowen, S.; Jiawei, C.
React. Funct. Polym. 2002, 50, 165–171.
8. (a) Brenelli, E. C. S.; Carvalho, M.; Okubo, M. T.;
Marques, M.; Moran, P. J. S.; Rodrigues, J. A. R. Indian
J. Chem. 1992, 31B, 821–823; (b) Moran, P. J. S.;
Rodrigues, J. A. R.; Joekes, I.; Brenelli, E. C. S.; Leite,
R. A. Biocatalysis 1994, 9, 321–328.
a Crude yield. Purity was measured by 1H NMR.
b Using PS-azide ion exchange resin.
c Using PS-BER.
d Yield after recrystallization from ethyl acetate/hexanes.
e Yield after column chromatography.
frequently, an additional step of product extraction is
needed to obtain the desired a-azidoketone. Our results
showed that using PS-azide exchange resin at room tem-
perature and dichloromethane as solvent the a-azidoke-
tones were prepared in very good yields. The reaction
products can be obtained by simple filtration of the resin
and evaporation of the solvent without further
treatment.
The b-azidoalcohols were prepared starting from a-azido-
ketones using polymer supported borohydride exchange
resin11 and the results are summarized in Table 1 (prod-
uct 3). In all instances the b-azidoalcohols were formed
in high yield after a short reaction time. In the reaction
conditions PS-BER was very selective, reducing only the
ketone and leaving the azido and aromatic nitro func-
tionalities intact.
9. Brenelli, E. C. S.; Fernandes, J. L. N. Tetrahedron:
Asymmetry 2003, 14, 255–1259.
10. General procedure for preparation of a-azidoketones:
Polymer supported azide was prepared using a commercial
macroporous ion exchange resin, AmberliteÒ IRA 900 as
previously reported.5a,e In an Erlenmeyer flask the a-
haloketone (2.7 mmol) was dissolved in 25 mL of dichlo-
romethane and the azide resin (3.2 g) was added. The
reaction was carried out on a Dubnoff bath at 30 °C. The
progress of the reaction was followed by TLC. On
completion of the reaction, the resin was filtered off and
washed with dichloromethane. The solvent was removed
under reduced pressure. a-Azidoketones were identified by
comparison of their spectral data with those reported in
the literature.12 This material was sufficiently pure for use
in the next step without further treatment. If desired, the
a-azidoketone can be purified by recrystallization from
hexanes/ethyl acetate. Compound 2, entry 5, 2-azido-1-(4-
iodophenyl)ethanone: Yellowish solid, mp 89–91 °C. IR
In conclusion we have developed a new and efficient
procedure for the preparation of a-azidoketones and
b-azidoalcohols using polymer supported reagents. The
advantages of the present method in terms of ease of
manipulation, fast reaction rates and formation of clea-
ner products should make this protocol as a valuable
alternative to the existing methods.
References and notes
(KBr): 2097, 1689 cmÀ1 1H NMR (300 MHz, CDCl3) d
.
1. (a) Bhalay, G.; Dunstan, A.; Glen, A. Synlett 2000, 1846–
1859; (b) Shuttleworth, S. J.; Allin, S. M.; Wilson, R. D.;
Nasturica, D. Synthesis 2000, 1035–1074; (c) Kirschning,
A.; Monenschein, H.; Wittenberg, R. Angew. Chem., Int.
4.52 (s, 2H), 7.59–7.64 (dt, 2.1, 8.7 Hz, 2H), 7.86–7.90 (dt,
2.1, 8.7 Hz, 2H) ppm. 13C NMR (75 MHz, CDCl3) d 54.6,
102.1, 129.0, 133.4, 138.2, 192.0 ppm. Entry 9, 2-azido-1-
(4-nitrophenyl)ethanone: Brown solid, mp 79 °C dec. IR

E. C. S. Brenelli et al. / Tetrahedron Letters 46 (2005) 4531–4533
4533
1
(KBr): 2114, 1705, 1524, 1345 cmÀ1. H NMR (300 MHz,
CDCl3) d 4.61 (s, 2H), 8.07–8.11 (dt, 2.1, 9.0 Hz, 2H),
8.34–8.38 (dt, 2.1, 9.0 Hz, 2H) ppm. 13C NMR (75 MHz,
CDCl3) d 55.1, 124.0, 128.9, 138.5, 150.7, 191.9 ppm.
Entry 10, 2-azido-1-(3-nitrophenyl)ethanone: Orange
solid, mp 52–54 °C. IR (KBr): 2115, 1694, 1530,
ppm. 13C NMR (75 MHz, CDCl3) d 57.7, 72.6, 93.7 127.6
137.6 139.9 ppm. Entry 10, 2-azido-1-(3-nitrophenyl)eth-
anol: Yellow oil. IR (neat): 3434, 2105, 1526, 1348 cmÀ1
.
1H NMR (300 MHz, CDCl3) d 2.62 (br s, 1H), 3.46–3.53
(dd, 7.3, 12.6 Hz, 1H), 3.53–3.58 (dd, 4.2, 12.6 Hz, 1H),
4.98–5.02 (dd, 4.2, 7.3Hz, 1H), 7.57 (t, 8.1 Hz, 1H), 7.71–
7.75 (m, 1H), 8.16–8.20 (ddd, 1.2, 2.1, 8.1 Hz, 1H), 8.26–
8.28 (m, 1H) ppm. 13C NMR (75 MHz, CDCl3) d 58.0,
72.5, 121.3, 123.4, 129.9, 132.3, 142.9 148.6 ppm.
12. (a) Ackrell, J.; Muchowski, J. M. J. Org. Chem. 1986, 51,
3374–3376; (b) Takeuchi, H.; Yanagida, S.; Ozaki, T.;
Hagiwara, S.; Eguchi, S. J. Org. Chem. 1989, 54, 431–434;
(c) Patonay, T.; Hoffman, R. V. J. Org. Chem. 1994, 59,
2902–2905; (d) Suzuki, H.; Kawaguchi, T.; Takaoka, K.
Bull. Chem. Soc. Jpn. 1986, 59, 665–666.
1357 cmÀ1 1H NMR (300 MHz, CDCl3) d 4.63(s, 2H),
.
7.75 (t, 8.1 Hz, 1H), 8.25–8.29 (ddd, 1.2, 1.8, 7.8 Hz, 1H),
8.48–8.51 (ddd, 1.2, 2.2, 8.1 Hz, 1H), 8.73(t, 1.8 Hz, 1H)
ppm. 13C NMR (75 MHz, CDCl3) d 54.9, 122.7, 128.2,
130.2, 133.3, 135.3, 148.3, 191.3 ppm.
11. General procedure for preparation of b-azidoalcohols:
Polymer supported borohydride was prepared using
AmberliteÒ IRA 900 as previously described.14 The b-
azidoalcohol was prepared using the same procedure
above described changing the azide resin for borohydride
resin. It was used 2.23mmol of a-azidoketone, 0.75 g of
borohydride resin in 25 mL of methanol. The products
were characterized by their spectral data, which were
identical to those in the literature.13 Compound 3, entry 5,
2-azido-1-(4-iodophenyl)ethanol: Yellow oil. IR (neat):
13. (a) Yadav, J. S.; Reddy, P. T.; Hashim, S. R. Synlett 2000,
1049–1051; (b) Guy, A.; Doussot, J.; Ferroud, C.; Gar-
reau, R.; Godefroy-Falguieres, A. Synthesis 1992, 821–
822; (c) Cho, B. T.; Kang, S. K.; Shin, S. H. Tetrahedron:
Asymmetry 2002, 13, 1209–1217; (d) Spelberg, J. H. L.;
Vlieg, J. E. T. van H.; Tang, L.; Janssen, D. B.; Kellogg,
R. M. Org. Lett. 2001, 3, 41–43.
3385, 2106 cmÀ1. H NMR (300 MHz, CDCl3) d 2.35 (br
1
s, 1H), 3.42–3.44 (m, 2H), 4.81–4.85 (t, 6.0 Hz, 1H), 7.10–
7.15 (dt, 2.1, 8.7 Hz, 2H), 7.68–7.73(dt, 2.1,8.7 Hz, 2H)
14. Yoon, N. M.; Sim, T. B. Bull. Korean Chem. Soc. 1993, 14,
749–752.