Hydrazine sulphate: a cheap and efficient catalyst for the regioselective ring-opening of epoxides. A metal-free procedure for the preparation of β-alkoxy alcohols

Article abstract of DOI:10.1016/j.tetlet.2007.12.121

An efficient and general procedure for the regioselective ring opening of epoxides with alcohols to afford the corresponding β-alkoxy alcohols, using hydrazine sulphate as catalyst, is described. This new metal-free process was found to be highly versatile allowing the use of primary, secondary and tertiary alcohols as nucleophiles and a large variety of epoxides, including 5α,6α-, 5β,6β- and 2α,3α-epoxysteroids, as substrates.

Full text of DOI:10.1016/j.tetlet.2007.12.121

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 1694–1697
Hydrazine sulphate: a cheap and efficient catalyst for the
regioselective ring-opening of epoxides. A metal-free procedure
for the preparation of b-alkoxy alcohols
b
a
Alcino J. L. Leitao a, Jorge A. R. Salvador b, , Rui M. A. Pinto , M. Luısa Sa e Melo
*
´
´
˜
a
ˆ ˆ
´ ´ ´
Centro de Estudos Farmaceuticos, Laboratorio de Quımica Farmaceutica, Faculdade de Farmacia,
Universidade de Coimbra, Coimbra 3000-295, Portugal
ˆ
´
Laborato´rio de Quı´mica Farmaceutica, Faculdade de Farmacia, Universidade de Coimbra, Coimbra 3000-295, Portugal
b
Received 5 December 2007; accepted 21 December 2007
Available online 8 January 2008
Abstract
An efficient and general procedure for the regioselective ring opening of epoxides with alcohols to afford the corresponding b-alkoxy
alcohols, using hydrazine sulphate as catalyst, is described. This new metal-free process was found to be highly versatile allowing the use
of primary, secondary and tertiary alcohols as nucleophiles and a large variety of epoxides, including 5a,6a-, 5b,6b- and 2a,3a-epoxy-
steroids, as substrates.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: Hydrazine sulphate; Metal-free catalysis; Epoxides; Steroids; b-Alkoxy alcohols
Ring opening of epoxides with nucleophilic reagents is an
useful tool for the preparation of several 1,2-disubstituted
products.1 b-Alkoxy alcohols are important intermediates
for the preparation of a-alkoxy ketones and a-alkoxy acids
as well as for the synthesis of compounds with pharmaceu-
tical interest.2,3
The most common and simple protocol for the synthesis
of b-alkoxy alcohols is the ring opening of epoxides with
an appropriate alcohol under strongly acidic4 or basic5
conditions. Commercially available Woelm 200 neutral
chromatographic alumina,6 Nafion-H, a perfluorinated sul-
fonic acid resine7 and organotin phosphate condensates8
have been applied as heterogeneous reagents for the alco-
holysis of epoxides. However, the fact that these reagents
have to be prepared prior to their use plus the large amounts
needed to perform these reactions led to the development of
more convenient processes. The use of one-electron transfer
catalysts, such as 2,3-dichloro-5,6-dicyano-p-benzoquinone
(DDQ),9 tetracyanoethylene (TCNE)10 and ceric(IV)
ammonium nitrate (CAN)11 as well as electron deficient
metalloporphyrins12 has been reported for this reaction.
Alternatively, procedures that use metal salts in stoichio-
metric amounts13 or Lewis acid catalysts under homo-
geneous14 or heterogeneous conditions15 have also been
described. Quite recently, heteropolyoxometalates16 were
introduced as heterogeneous catalysts for this reaction
and Robinson and co-workers reported the alcoholysis of
epoxides promoted by a mesoporous aluminosilicate cata-
lyst.17 Despite the fact that these methods generally lead
to high yields with good regioselectivity, the handling of
toxic and/or expensive reagents, intolerance to highly sensi-
tive groups, unwanted by-products and relatively limited
scope of the application of some of the methods restricts
their widespread applicability.
The development of metal-free synthetic methods
is an area of great interest. This approach avoids the
use of toxic and expensive metals and is particularly
attractive for the preparation of compounds that do not
*
Corresponding author. Tel.: +351 239 859900; fax: +351 239 827126.
E-mail address: salvador@ci.uc.pt (J. A. R. Salvador).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.12.121

A. J. L. Leita˜o et al. / Tetrahedron Letters 49 (2008) 1694–1697
1695
Table 1
The success of this first set of experiments using
NH2NH2ÁH2SO4 (10 mol %) as a catalyst encouraged us
to enlarge the scope of the reaction to other epoxides.
Thus, the alcoholysis of a-epoxyketone 2, the 3-phenylgly-
cidate derivatives 3–5 and epoxysteroids 6–8 with MeOH
and EtOH afforded the corresponding b-alkoxy alcohols
2a–8a in high yields (Table 2). For substrates 2–5, the reac-
tions were also regioselective with the nucleophilic attack
occurring invariably at the benzylic position (Table 2,
entries 1–8). The reactions performed using MeOH (Table
2, entries 1, 3, 5 and 7) gave shorter reaction times than the
ones with EtOH (Table 2, entries 2, 3, 6 and 8). The b-
alkoxy alcohols 2a–5b were obtained as mixtures of anti-
and syn-isomers in a ratio ranging from 1:1 to 4:1 (Table
2, entries 1–8).
Hydrazine sulphate-catalyzed alcoholysis of styrene oxidea
Entry
R
Temp (°C)
Time (h)
Productb
Yieldc (%)
1
2
3
4
5
6
7
8
9
a
Med
Me
Et
rt
rt
rt
rt
50
50
50
50
50
90
3
5
1a
1a
1b
1b
1a
1b
1c
1d
1e
Traces
87
94
96
92
96
93
86
63
Ete
5
Me
Et
n-Pr
i-Pr
t-Bu
0.25
0.5
1
4
4
The hydrazine sulphate-catalyzed alcoholysis of the
epoxysteroids 6–8 was not only regioselective but also
stereoselective as result of the trans-diaxial ring opening
of these substrates (Table 2, entries 9–13). Treatment
Reaction conditions: 0.2 M solution of styrene oxide in the appropri-
ated alcohol; 10 mol % of catalyst.
b
All products 1a–1e gave satisfactory analytical data according to the
literature.14g,21
c
of 5a,6a-epoxy-17-oxoandrostan-3b-yl acetate
6 with
Isolated yield after flash column chromatography.
d
Reaction performed in the absence of NH2NH2ÁH2SO4.
NH2NH2ÁH2SO4 (10 mol %) in MeOH or EtOH afforded
the corresponding 5a-hydroxy-6b-alkoxy derivatives 6a
and 6b in 75% and 70% yield, respectively (Table 2,
entries 9 and 10), whereas 5b,6b-epoxide 7 gave the 5a-
alkoxy-6b-hydroxy products 7a and 7b, in 81% and 80%
yield, respectively (Table 2, entries 11 and 12). It is impor-
tant to note that under these reaction conditions the acet-
oxy functions remained intact. The structure and
stereochemistry of the new steroid compounds 6b and
7b were established based on the related literature23 and
analysis of NMR data. For both compounds 6b and 7b,
the multiplicity of the 3a-H signal (a broad multiplet),
which indicates a trans-fused (5a,10b)-steroid structure,
and the coupling pattern observed for 6-H (triplet,
J = 2.6 and J = 2.8 Hz, respectively), which suggests
equatorial–equatorial and equatorial–axial couplings con-
sistent with a 6b-substitution, confirm the trans-diaxial
nature of the epoxide ring opening. For the 5a-hydroxy-
6b-ethoxy derivative 6b, the chemical shift value of the
6a-H (3.08 ppm) is consistent with a 6b-OEt group whilst
the value of 3.95 ppm for the 6a-H of the 5a-ethoxy-6b-
hydroxy product 7b is in accordance with a 6b-OH
function. The hydrazine sulphate-catalyzed ring
opening of 2a,3a-epoxy-5a-pregnan-20-one 8 with EtOH
resulted in the formation of the 2b-ethoxy-3a-hydroxy
steroid 8a, in 90% yield, after 30 h of reaction (Table 2,
entry 13).
e
Reaction performed using the recovered catalyst after filtration.
tolerate metal contamination, such as pharmaceutical
products.18
As part of our ongoing project on the application of
hydrazine and hydrazine salts as non-metallic reagents in
organic chemistry,19 we report in this Letter the use of
hydrazine sulphate20 as an efficient catalyst for the synthe-
sis of b-alkoxy alcohols.
Our initial studies showed that NH2NH2ÁH2SO4 is an
adequate catalyst for the ring opening of styrene oxide 1
with primary, secondary and tertiary alcohols (Table 1).
No significant reaction occurred in the absence of
NH2NH2ÁH2SO4 (Table 1, entry 1). The reaction was ini-
tially screened using stoichiometric amounts of NH2NH2Á
H2SO4 but it rapidly became evident that the reaction pro-
ceeds well using 10 mol % of catalyst at rt (Table 1, entries 2
and 3). The ring opening of styrene oxide 1 occurred at the
benzylic position, as expected, and the b-alkoxy alcohols 1a
and 1b were obtained on the reactions performed with
MeOH and EtOH, in 87 and 94% yield, respectively (Table
1, entries 2 and 3). Due to its very low solubility in alcohols,
NH2NH2ÁH2SO4 can be almost quantitatively recovered
and reused without the need for further activation or loss
of activity (Table 1, entry 4). In fact, from a practical point
of view, not only is the possibility of recovery and reuse
noteworthy, but also the work-up procedure becomes
easier.22 The ring opening of styrene oxide 1 with MeOH
and EtOH was then performed at 50 °C and significantly
shorter reaction times were observed (Table 1, entries 5
and 6). Thus, we considered the use of this temperature
for studying the process. The hydrazine sulphate-catalyzed
ring opening of styrene oxide 1 with n-PrOH, i-PrOH and
t-BuOH afforded the corresponding b-alkoxy alcohols
1c–1e, in 63–93% yield (Table 1, entries 7–9).
In conclusion, we developed an efficient metal-free pro-
cess for the ring opening of epoxides, including several
epoxysteroids, with a wide set of representative alcohols.
This method takes place under relatively mild conditions
and relies simply on the use of catalytic amounts of the
cheap and commercially available hydrazine sulphate.
Other important features such as the stability of ester
groups, high yields, easy work-up and high regioselectivity
make this new process an attractive alternative to current
methodologies.

1696
A. J. L. Leita˜o et al. / Tetrahedron Letters 49 (2008) 1694–1697
Table 2
Reaction of epoxides with alcohols (ROH) using hydrazine sulphate as a catalysta
Entry
Epoxide
R–OH
Time (h)
Productb/yieldc (%)
1
2
3
4
5
6
7
8
2d: R1 = R2 = H; R3 = Ph
2d: R1 = R2 = H; R3 = Ph
3d: R1 = R3 = OMe; R2 = H
3d: R1 = R3 = OMe; R2 = H
4e: R1 = R2 = H; R3 = OEt
4e: R1 = R2 = H; R3 = OEt
5e: R1 = H; R2 = Me; R3 = OEt
5e: R1 = H; R2 = Me; R3 = OEt
R = Me
R = Et
R = Me
R = Et
R = Me
R = Et
R = Me
R = Et
5
24
1
12
16
48
20
48
2a/93 (anti/syn = 3.2/1)
2b/93 (anti/syn = 5.7/1)
3a/91 (anti/syn = 2/1)
3b/90 (anti/syn = 1.6/1)
4a/87 (anti/syn = 3.8/1)
4b/85 (anti/syn = 4/1)
5a/91 (anti/syn = 1/1)
5b/90 (anti/syn = 1/1)
9
10
R = Me
R = Et
24
30
6a/75
6b/70
11
12
R = Me
R = Et
10
36
7a/81
7b/80
13
R = Et
30
8a/90
a
Reaction performed at 50 °C using 10 mol % of NH2NH2ÁH2SO4.
b
Analytical data for compounds 2a,24a 3a,24b 4a,24c 4b,24c 5a,24d 6a,23 7a23 and 8a24e are in accordance with the literature. For compounds 2b, 3b, 5b, 6b
and 7b see selected analytical data.25
c
Isolated yield after flash column chromatography.
The racemic trans-isomer was used.
A mixture of cis- and trans-isomers was used.
d
e
4. Battistini, C.; Crotti, P.; Damiani, D.; Macchia, F. J. Org. Chem.
1979, 44, 1643–1647.
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J.A.R.S. thanks Universidade de Coimbra for financial
support. M.L.S.M. and A.J.L.L. thank Fundaßcao para a
˜
Cieˆncia e Tecnologia (FCT) through POCI (FEDER).
R.M.A.P. also thanks FCT for financial support (SFRH/
BD/18013/2004).
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1
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1476; (b) Yarapathi, R. V.; Reddy, S. M.; Tammishetti, S. React.
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European Medicines Agency, Pre-authorisation Evaluation of Medi-
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SWP/QWP/4446/00; http://www.emea.europa.eu/.
3474, 3062, 2976, 1682, 1598, 1402, 1098 cmÀ1; H NMR (300 MHz,
CDCl3) d 1.05 (t, J = 7.0 Hz, 3H), 3.24–3.41 (m, 2H), 3.89 (s, 1H);
4.55 (d, J = 4.8 Hz, 1H), 5.33 (d, J = 4.8 Hz, 1H), 7.15–7.87 (m, 10H);
13C NMR (75 MHz, CDCl3) d 14.8, 64.7, 76.0, 83.5, 127.3, 127.9,
128.3, 128.6, 133.5, 135.1, 137.1, 199.9.
Compound 3b: Colourless liquid; IR (film) 3490, 2973, 1745, 1612,
1440, 1250, 1094 cmÀ1 1H NMR (300 MHz, CDCl3) d 1.15 (t,
;
J = 7.1 Hz, 3H), 2.48 (s, 1H), 3.29–3.51 (m, 2H), 3.78 (s, 3H), 3.80 (s,
3H), 4.23 (d, J = 3.4 Hz, 1H), 4.62 (d, J = 3.4 Hz, 1H), 6.90 (d,
J = 8.8 Hz, 2H), 7.30 (d, J = 8.8 Hz, 2H); 13C NMR (75 MHz,
CDCl3) d 15.0, 52.4, 55.2, 64.6, 75.3, 81.2, 113.7, 128.4, 129.7, 159.4,
172.6.
19. Salvador, J. A. R.; Leitao, A. J. L.; Melo, M. L. S.; Hanson, J. R.
˜
Compound 5b (anti/syn = 1/1): Colourless liquid; IR (film) 3504,
3059, 2979, 1732, 1447, 1391, 1105; 1H NMR (300 MHz, CDCl3) d
1.03 (t, J = 7.1 Hz, 3H), 1.20 (t, J = 7.0 Hz, 3H), 1.69 (s, 3H), 2.70 (s,
1H), 3.16–3.30 (m, 1H), 3.42–3.47 (m, 1H), 3.96–4.08 (m, 2H), 4.16 (s,
1H), 7.30–7.36 (m, 5H); 13C NMR (75 MHz, CDCl3) d 13.8, 13.9,
15.5, 18.7, 20.1, 58.1, 58.3, 60.9, 61.0, 78.4, 78.5, 80.4, 80.6, 126.5,
126.9, 127.4, 127.6, 128.0, 128.1, 140.9, 141.3, 171.6, 172.0.
Compound 6b: mp 179–181 °C (n-hexane/acetone); IR (film) 3477,
Tetrahedron Lett. 2005, 46, 1067–1070.
20. Despite some concern related to its toxicity, hydrazine sulphate has
been used in clinical practice for the treatment of cachexia associated
with cancer. See: Ernst, E.; Cassileth, B. R. Eur. J. Cancer 1999, 35,
1608–1613.
21. Salehi, P.; Dabiri, M.; Zolfigol, M. A.; Fard, M. A. B. Phosphorus,
Sulfur Silicon Relat. Elem. 2004, 179, 1113–1121.
22. Typical procedure: to a solution of 5b,6b-epoxy-17-oxoandrostan-3b-
yl acetate 7 (346.5 mg, 1.0 mmol) in EtOH (20 mL), NH2NH2ÁH2SO4
(13 mg, 0.1 mmol) was added. After 30 h under magnetic stirring at
50 °C the reaction was completed as verified by TLC control. The
reaction mixture was filtered, the catalyst was recovered (11 mg, 85%)
and the filtrate was concentrated under reduced pressure. The
resulting residue was purified by flash column chromatography to
afford 5a-ethoxy-6b-hydroxy-17-oxoandrostan-3b-yl acetate 7b as a
white solid (314.0 mg, 80% yield).
2939, 1735, 1026 cmÀ1 1H NMR (300 MHz, CDCl3) d 0.88 (s, 3H,
;
18-CH3), 1.14 (s, 3H, 19-CH3), 1.17 (t, J = 6.8 Hz, 3H, OCH2CH3),
2.04 (s, 3H, CH3COO), 3.08 (t, J = 2.6 Hz, 1H, 6a-H), 3.29 and 3.59
(2m, 2H, OCH2CH3), 5.14 (m, 1H, 3a-H); 13C NMR (75 MHz,
CDCl3) d 65.5 (OCH2CH3); 71.1 (C-3); 75.9 (C-5); 83.2 (C-6); 170.9
(CH3COO); 221.3 (C-17); EI-MS m/z (%): 392(14) M+, 314 (26), 270
(100), 232 (42), 179 (82), 151 (29), 91 (36), 79 (40).
Compound 7b: mp 202–204 °C (acetone); IR (film) 3523, 2941, 1731,
1023 cmÀ1; 1H NMR (300 MHz, CDCl3) d 0.88 (s, 3H, 18-CH3), 1.16
(t, J = 6.9 Hz, 3H, OCH2CH3), 1.22 (s, 3H, 19-CH3), 2.03 (s, 3H,
CH3COO), 3.29 and 3.54 (2m, 2H, OCH2CH3), 3.95 (t, J = 2.8 Hz,
1H, 6a-H), 4.86 (m, 1H, 3a-H); 13C NMR (75 MHz, CDCl3) d 55.2
(OCH2CH3); 69.9 (C-6); 71.1 (C-3); 78.5 (C-5); 170.8 (CH3COO);
221.4 (C-17); EI-MS m/z (%): 392(6) M+, 346 (8), 299 (7), 286 (90),
268 (100), 253 (26), 123 (31), 91 (41).
23. Boynton, J. A.; Hanson, J. R.; Uyanik, C. J. Chem. Res., Synop. 1995,
334–335.
24. (a) Plietker, B. Eur. J. Org. Chem. 2005, 1919–1929; (b) Hashiyama,
T.; Watanabe, A.; Inoue, H.; Konda, M.; Takeda, M.; Murata, S.;
Nagao, T. Chem. Pharm. Bull. 1985, 33, 634–641; (c) Chai, W.;
Takeda, A.; Hara, M.; Ji, S. J.; Horiuchi, C. A. Tetrahedron 2005, 61,