ZnI2/NaCNBH3 as an Efficient Reagent for Regioselective Ring Opening of the Benzylic Epoxide Moiety

Article abstract of DOI:10.1081/SCC-120028362

In the presence of zinc iodide, sodium cyanoborohydride was found to produce regioselective ring opening of benzylic epoxides in mild reaction conditions.

Full text of DOI:10.1081/SCC-120028362

This article was downloaded by: [Umeå University Library]
On: 23 September 2013, At: 04:20
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered office: Mortimer
House, 37-41 Mortimer Street, London W1T 3JH, UK
Synthetic Communications: An International Journal
for Rapid Communication of Synthetic Organic
Chemistry
Publication details, including instructions for authors and subscription information:
http://www.tandfonline.com/loi/lsyc20
ZnI2/NaCNBH3 as an Efficient Reagent for
Regioselective Ring Opening of the Benzylic Epoxide
Moiety
L. M. Finkielsztein a , J. M. Aguirre b , B. Lantaño a , E. N. Alesso a & G. Y. Moltrasio
Iglesias a
a Departamento de Quínica Orgánica, Facultad de Farmacia y Bioquímica, Universidad de
Buenos Aires, Junín 956, (1113), Buenos Aires, Argentina
b Departamento de Ciencias Básicas, Universidad Nacional de Luján, Luján, Argentina
Published online: 20 Aug 2006.
To cite this article: L. M. Finkielsztein , J. M. Aguirre , B. Lantaño , E. N. Alesso & G. Y. Moltrasio Iglesias (2004)
ZnI2/NaCNBH3 as an Efficient Reagent for Regioselective Ring Opening of the Benzylic Epoxide Moiety, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry, 34:5, 895-901, DOI:
10.1081/SCC-120028362
To link to this article: http://dx.doi.org/10.1081/SCC-120028362
PLEASE SCROLL DOWN FOR ARTICLE
Taylor & Francis makes every effort to ensure the accuracy of all the information (the “Content”) contained
in the publications on our platform. However, Taylor & Francis, our agents, and our licensors make no
representations or warranties whatsoever as to the accuracy, completeness, or suitability for any purpose of
the Content. Any opinions and views expressed in this publication are the opinions and views of the authors,
and are not the views of or endorsed by Taylor & Francis. The accuracy of the Content should not be relied
upon and should be independently verified with primary sources of information. Taylor and Francis shall
not be liable for any losses, actions, claims, proceedings, demands, costs, expenses, damages, and other
liabilities whatsoever or howsoever caused arising directly or indirectly in connection with, in relation to or
arising out of the use of the Content.
This article may be used for research, teaching, and private study purposes. Any substantial or systematic
reproduction, redistribution, reselling, loan, sub-licensing, systematic supply, or distribution in any
form to anyone is expressly forbidden. Terms & Conditions of access and use can be found at http://
www.tandfonline.com/page/terms-and-conditions

SYNTHETIC COMMUNICATIONSw
Vol. 34, No. 5, pp. 895–901, 2004
ZnI2/NaCNBH3 as an Efficient Reagent for
Regioselective Ring Opening of the
Benzylic Epoxide Moiety
L. M. Finkielsztein,1 J. M. Aguirre,2 B. Lantan˜o,1
E. N. Alesso,1 and G. Y. Moltrasio Iglesias1,
*
1
´ ´ ´
Departamento de Quınica Organica, Facultad de Farmacia y Bioquımica,
Universidad de Buenos Aires, Buenos Aires, Argentina
´
´
Lujan, Argentina
2
´
Departamento de Ciencias Basicas, Universidad Nacional de Lujan,
ABSTRACT
In the presence of zinc iodide, sodium cyanoborohydride was found to
produce regioselective ring opening of benzylic epoxides in mild reaction
conditions.
Key Words: Sodium cyanoborohydride; Zinc iodide; Benzylic epoxide;
a-Chloroketone; b-Chlorohydrin.
*
´ ´
Correspondence: G. Y. Moltrasio Iglesias, Departamento de Quınica Organica,
´ ´
Facultad de Farmacia y Bioquımica, Universidad de Buenos Aires, Junın 956, (1113),
Buenos Aires, Argentina; E-mail: gmoltra@ffyb.uba.ar.
895
DOI: 10.1081/SCC-120028362
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com
Copyright # 2004 by Marcel Dekker, Inc.

ORDER
REPRINTS
896
Finkielsztein et al.
Figure 1. Synthetic pathway of alcyopterosins.
In an attempt to find a synthetic route to the natural occurring sesquiter-
penes named alcyopterosins,[1] we needed to reduce a-chloroketone 1 to the
indanic compound 2 (Fig. 1). To this end, we chose sodium cyanoborohydride
in the presence of zinc iodide. This system afford reductive deoxygenation of
aryl aldehydes and ketones[2] and benzylic alcohols[3] to the corresponding
hydrocarbons.
When the reaction was carried out with zinc iodide/sodium cyanoboro-
hydride at room temperature, compound 1 cleanly furnished the corresponding
halohydrin 3 in good yield, but when the reaction was performed under reflux
conditions, the main product isolated was alcohol 4. To generalize this
reaction, several examples were performed, and results are given in Table 1.
The obtention of alcohols 4, 9, and 13 prompted us to consider the
possibility of in situ epoxide formation, whereby the epoxide would be opened
by attack of the hydride moiety to afford the primary alcohol.
To test this hypothesis, we synthesized several epoxides, which were then
treated with ZnI2/NaCNBH3 in the same conditions used for reductive
deoxygenation reaction. It was found that this mixture of reagents is able to
perform ring opening of the epoxide moiety to render, in all examples, the less
substituted alcohol in an efficient manner (see Table 2), better than when the
starting material was the a-chloroketone or b-chlorohydrin. The presence of a
Lewis acid is required to activate the epoxide toward nucleophilic attack, since
this moiety is essentially inert to sodium cyanoborohydride. Hydride is
trapped at the site best able to accommodate a carbonium ion, and thus the less
substituted alcohol is preferentially obtained.
When the reaction was carried out starting from either a-chloroketone or
b-chlorohydrin at reflux conditions, an iododerivative was also obtained in all
cases. In an early publication, Lau et al.[2] proposed the formation of a spiro
cyclopropyl intermediate when 4-methoxyphenethyl alcohol was treated with
ZnI2/NaCNBH3. Such an intermediate, favored by the electron donor effect of
the methoxyl group, is then attacked by an iodide anion to produce 4-
methoxyphenethyl iodide. Our results would seem to indicate that the
production of the iododerivative is not entirely due to the formation of this
intermediate. As the epoxide is formed, starting from the b-chlorohydrin or

ORDER
REPRINTS
ZnI2/NaCNBH3 as Efficient Reagent
897
b
a
a

ORDER
REPRINTS
898
Finkielsztein et al.
Table 2. Ring opening of benzylic epoxides with ZnI2/
NaCNBH3.
Epoxide
Producta
Yield (%)b
76c
81c
85c
79c
82c
80d
aReaction time: 16 h.
bYields refer to isolate and chromatographically pure
products. All the products exhibited spectral data consistent
with their structures carried out.
cReaction carried out in dichloroethane under reflux
conditions.
dReaction carried out in dichloroethane at room tempera-
ture.
a-chloroketone, the former is rapidly cleaved to render the corresponding
alcohol. When epoxide formation is more difficult, as in the case of compound
12 and 16, required reaction times are greater. In such conditions, the
substitution of the alcohol by the iodide occurs, thus leading to the iodo-
derivative. In support, when phenethyl alcohol was treated in the same
conditions used for compound 16, the corresponding iododerivative was
obtained (yield: 91%). Throughout, the progress of the reaction was monitored
by tlc.
In conclusion, the combination of ZnI2 and NaCNBH3 is capable of
achieving the formation and cleavage of epoxides starting from a-chloro-

ORDER
REPRINTS
ZnI2/NaCNBH3 as Efficient Reagent
899
ketones and b-chlorohydrins. The mixture of reagents proves also a
convenient and efficient method for ring opening of benzylic epoxides. The
reaction is invariably regioselective and proceeds in mild conditions. Due to,
the ease in handling and inertness toward other functional groups, this method
is recommended when chemoselectivity is crucial. Full investigation of ring
opening of diverse classes of epoxides, with this reagent, are under way.
EXPERIMENTAL
The epoxides used were prepared from the corresponding alkenes and m-
chloroperbenzoic acid in CHCl3.[4] 1H and 13C NMR spectra were recorded
with a Bruker AC-300 spectrometer with CDCl3 as solvent, employing Me4Si
as internal standard (d: 0.00), J values are given in Hz. Mass spectra were
obtained by direct injection of the sample as chloroform solution by using
Shimadzu GCQP 1000 mass spectrometer operating at an ionizing electron
energy of 70 eV. Elemental analysis was carried out in our laboratories with a
Colleman Analyser. Melting point (uncorrected) was obtained with a Thomas
Hoover apparatus. Preparative thin layer chromatography (p-tlc) was
performed on a 20 Â 20 cm glass coated with silica gel 60 F254 (0.50 mm).
General Procedure for Reaction of ZnI2/NaCNBH3 with
a-Chloroketones, b-Chlorohydrins and Epoxides
To a solution of a-chloroketone, b-chlorohydrin or epoxide (2 mmol) in
ethylene dichloride (10 mL) at room temperature were added zinc iodide
(3 mmol) and sodium cyanoborohydride (15 mmol). The reaction mixture was
stirred at room temperature or refluxed and, after completion of the reaction
(monitored by tlc), the mixture was then cooled and poured onto a solution of
6N HCl (40 mL). Lastly, the mixture was extracted with dichloromethane
(20 mL) and the organic extract was washed with water (15 mL), dried over
anhydrous magnesium sulfate, filtered and evaporated to dryness. The residue
obtained was chromatographed using hexane–ethyl acetate (4 : 1) as eluent.
General Procedure for the Preparation of a-Chloroketones
To a magnetically stirred cold solution of corresponding aromatic
compound (2 mmol) and chloroacetyl chloride (2.5 mmol) in carbon disulfide
(10 mL) was added AlCl3 (15 mmol) in small portions. The reaction mixture
was then refluxed for 30 min, cooled to room temperature, and carefully
poured onto ice. The product was extracted into dichloromethane (25 mL) and

ORDER
REPRINTS
900
Finkielsztein et al.
then washed with water (15 mL). The organic layer was dried over anhydrous
magnesium sulfate, filtered and the solvent removed in vacuo. The crude
product was purified by p-tlc using hexane-ethyl acetate (4 : 1) as eluent.
2-Chloro-1-(2,2,6-trimethylindan-5-yl)ethan-1-one 1
1
White solid, m.p. 61–638C. H NMR d 1.14 (s, 6H), 2.49 (s, 3H), 2.72
(s, 4H), 4.64 (s, 2H), 7.09 (s, 1H), 7.43 (s, 1H). 13C NMR d 22.3, 29.3, 41.1,
47.7, 48.4, 48.6, 125.8, 129.9, 133.2, 138.6, 141.9, 149.8, 194.5. MS (m/z):
236 (9, Mþ), 237 (2, Mþ þ 1), 238 (3, Mþ þ 2), 187 (100, Mþ 2 CH2Cl).
Calcd. for C14H17ClO: C, 71.03; H, 7.24; Cl, 14.98. Found: C, 71.24; H, 7.18;
Cl, 15.09.
2-Chloro-1-(2,2,6-trimethyl-5-yl)ethan-1-ol 3
Oil. 1H NMR d 1.11 (s, 3H), 1.15 (s, 3H), 2.30 (s, 3H), 2.60–2.69 (m, 4H),
3.59 (dd, J: 9.2, J: 11.4, 1H), 3.68 (dd, J: 3.0, J: 11.4, 1H), 5.07 (dd, J: 3.0, J:
9.2, 1H), 6.96 (s, 1H), 7.31 (s, 1H). 13C NMR d 19.7, 29.5, 40.9, 48.1, 50.8,
71.8, 122.3, 127.5, 133.1, 136.3, 142.5, 144.4. MS (m/z): 238 (11, Mþ), 239
(2, Mþ þ 1), 240 (4, Mþ þ 2), 189 (100, Mþ 2 CH2Cl). Calcd. for
C14H19ClO: C, 70.43; H, 8.02; Cl, 14.85. Found: C, 70.39; H, 7.88; Cl, 15.02.
2-(2,2,6-Trimethylindan-5-yl)ethan-1-ol 4
Oil. 1H NMR d 1.15 (s, 6H), 2.30 (s, 3H), 2.68 (s, 4H), 2.86 (t, J: 6.8, 2H),
3.82 (t, J: 6.8, 2H), 6.92 (s, 2H). 13C NMR d 20.1, 29.5, 29.6, 37.1, 40.8, 48.1,
63.4, 126.6, 127.3, 134.6, 142.0, 142.6. MS (m/z): 204 (19, Mþ), 205 (3,
Mþ þ 1), 173 (100, Mþ 2 CH2OH). Calcd. for C14H20O: C, 82.30; H, 9.87.
Found: C,82.46; H, 9.73.
5-(2-Iodoethyl)-2,2,6-trimethylindane 5
Oil. 1H NMR d 1.13 (s, 6H), 2.27 (s, 3H), 2.64 (s, 2H), 2.67 (s, 2H), 3.11–
3.19 (m, 2H), 3.23–3.29 (m, 2H), 6.95 (s, 1H), 6.98 (s, 1H). 13C NMR d 5.1,
19.8, 29.5, 39.1, 40.9, 48.1, 48.2, 126.0, 127.5, 134.0, 137.6, 142.3, 143.2. MS
(m/z): 314 (10, Mþ), 315 (2, Mþ þ 1), 187 (100, Mþ 2 I). Calcd. for
C14H19I: C, 53.52; H, 6.10; I, 40.39. Found: C, 53.45; H, 6.22; I, 40.65.

ORDER
REPRINTS
ZnI2/NaCNBH3 as Efficient Reagent
901
5-Ethyl-2,2,6-trimethylindane 6
1
´
Oil. H NMR o 1.15 (s, 6H), 1.21 (t, J: 7.5, 3H), 2.28 (s, 3H), 2.60 (q, J:
7.5, 2H), 2.68 (s, 4H), 6.96 (s, 1H), 6.98 (s, 1H). 13C NMR d 15.3, 19.8, 26.9,
29.7, 40.8, 48.2, 124.9, 127.0, 134.0, 140.7, 141.6, 141.9. MS (m/z): 188 (53,
Mþ), 189 (8, Mþ þ 1), 173 (81, Mþ 2 CH3), 159 (100, Mþ 2 CH2CH3).
Calcd. for C14H20: C, 89.30; H, 10.17. Found: C, 89.17; H, 10.81.
ACKNOWLEDGMENTS
This research was supported by grants from Consejo Nacional de
´
Investigaciones Cientıficas (CONICET) and Universidad de Buenos Aires.
REFERENCES
´
1. Palermo, J.A.; Rodrıguez Brasco, M.F.; Spagnuolo, C.; Seldes, A.M.
Illudalane sesquiterpenoids from the soft coral Alcyonium paessleri: the
first natural nitrate esters. J. Org. Chem. 2000, 65 (15), 4482–4486.
´
´ ´
2. Lau, C.K.; Dufresne, C.; Belanger, P.C.; Pietre, S.; Scheigetz, J. Reductive
deoxygenation of aryl aldehydes and ketones and benzylic, allylic, and
tertiary alcohols by ZnI2-NaCNBH3. J. Org. Chem. 1986, 51 (15),
3038–3043.
3. Alesso, E.N.; Bianchi, D.E.; Finkielsztein, L.M.; Lantan˜o, B.; Molt-
rasio, G.Y.; Aguirre, J.M. Reductive deoxygenation of indan-1-ols by
ZnI2/NaCNBH3. Tetrahedron Lett. 1995, 36 (19), 3299–3302.
4. Fieser, L.; Fieser, M. Reagents for Organic Synthesis; Wiley: New York,
1967; Vol. 1, 135.
Received in the USA October 3, 2003

Request Permission or Order Reprints Instantly!
Interested in copying and sharing this article? In most cases, U.S. Copyright
Law requires that you get permission from the article’s rightsholder before
using copyrighted content.
All information and materials found in this article, including but not limited
to text, trademarks, patents, logos, graphics and images (the "Materials"), are
the copyrighted works and other forms of intellectual property of Marcel
Dekker, Inc., or its licensors. All rights not expressly granted are reserved.
Get permission to lawfully reproduce and distribute the Materials or order
reprints quickly and painlessly. Simply click on the "Request Permission/
Order Reprints" link below and follow the instructions. Visit the
U.S. Copyright Office for information on Fair Use limitations of U.S.
copyright law. Please refer to The Association of American Publishers’
Fair Use in the Classroom.
(AAP) website for guidelines on
The Materials are for your personal use only and cannot be reformatted,
reposted, resold or distributed by electronic means or otherwise without
permission from Marcel Dekker, Inc. Marcel Dekker, Inc. grants you the
limited right to display the Materials only on your personal computer or
personal wireless device, and to copy and download single copies of such
Materials provided that any copyright, trademark or other notice appearing
on such Materials is also retained by, displayed, copied or downloaded as
part of the Materials and is not removed or obscured, and provided you do
not edit, modify, alter or enhance the Materials. Please refer to our
Website
User Agreement for more details.
Request Permission/Order Reprints
Reprints of this article can also be ordered at
http://www.dekker.com/servlet/product/DOI/101081SCC120028362