Efficient regioselective opening of epoxides by nucleophiles in water under simultaneous ultrasound/microwave irradiation

Article abstract of DOI:10.1055/s-2007-984891

Epoxide cleavage by nucleophiles in aqueous media may suffer from competition by water itself, yielding the diol as byproduct. However, when the reaction was carried out under high-intensity ultrasound or microwaves, attack by the nucleophile was strongly promoted and water no longer reacted. Best results were achieved under simultaneous ultrasound/microwave irradiation: a series of mono-, di- and trisubstituted oxiranes reacted rapidly with sodium azide or 1-(3-chlorophenyl)piperazine, usually leading to the corresponding more substituted alcohols in acceptable to high yields. This catalyst-free, greener protocol achieves a much faster cleavage of epoxides with a high regioselectivity. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-984891

LETTER
2041
Efficient Regioselective Opening of Epoxides by Nucleophiles in Water under
Simultaneous Ultrasound/Microwave Irradiation
Efficient
R
egiose
l
i
O
o
pening of
E
v
poxides anni Palmisano,a Silvia Tagliapietra,b Alessandro Barge,b Arianna Binello,b Luisa Boffa,b Giancarlo Cravotto*b
a
Dipartimento di Scienze Chimiche e Ambientali, Università degli Studi dell’Insubria, Via Valleggio 11, 22100 Como, Italy
b
Dipartimento di Scienza e Tecnologia del Farmaco, Università degli Studi di Torino, Via Giuria 9, 10235 Torino, Italy
Fax +39(011)6707687; E-mail: giancarlo.cravotto@unito.it
Received 14 May 2007
N-(2,3-epoxypropyl)phthalimide, 1,2-epoxyoctane, cy-
clohexene oxide, (+)-limonene 1,2-epoxide] with sodium
azide (A, Table 1) and 1-(3-chlorophenyl)piperazine7 (B,
Table 1) in water at neutral pH, without any metal catalyst
Abstract: Epoxide cleavage by nucleophiles in aqueous media may
suffer from competition by water itself, yielding the diol as byprod-
uct. However, when the reaction was carried out under high-inten-
sity ultrasound or microwaves, attack by the nucleophile was
strongly promoted and water no longer reacted. Best results were added. We compared four different methods: 1) conven-
achieved under simultaneous ultrasound/microwave irradiation: a
tional heating at 50 °C under high-speed magnetic stirring
series of mono-, di- and trisubstituted oxiranes reacted rapidly with
(24–36 h), i.e. the typical ‘on water’ conditions described
sodium azide or 1-(3-chlorophenyl)piperazine, usually leading to
by Sharpless; 2) under MW irradiation (open vessel, 100
the corresponding more substituted alcohols in acceptable to high
W, at 50 °C) in a multimode professional oven (Micro-
yields. This catalyst-free, greener protocol achieves a much faster
synth, Milestone); 3) under US (20.3 kHz, 70 W at 45 °C),
using a titanium probe;8 4) under simultaneous US/MW
irradiation (at 45 °C),9 achieved by introducing in the
same MW oven a probe equipped with a horn made of
PEEK®.10 Both US and MW dramatically accelerated the
reaction, that went to completion in 0.5–2 hours whereas
it took at least one day under stirring and conventional
heating. Products were readily isolated by silica gel
column chromatography after evaporation of the solvent.
Results are gathered in Table 1. Reactions carried out un-
der these conditions are completely anti stereoselective,
as shown by the exclusive formation of the anti products
in reactions of cyclic epoxides (entries 4, 5; Table 1). As
regards the regiochemistry of ring opening for unsym-
metrical epoxides (entries 2, 3, 5), reactions are regio-
selective, the attack of the N-nucleophiles (A, B) taking
place on the less hindered epoxide carbon (b), except for
2-phenyloxirane (entry 1). The reverse regioselectivity
observed for 1A,B is typical of benzylic substrates in
accordance with the soft-base properties11 of our nucleo-
philes (Figure 1).
cleavage of epoxides with a high regioselectivity.
Key words: epoxide opening, ultrasound, microwave, reaction in
water, one-pot reaction
Epoxides are widespread in nature, standing at crossroads
of several metabolic pathways; they also are useful
building blocks for organic syntheses. Ring opening of
epoxides by nucleophiles is one of the most versatile reac-
tions among ‘click chemistry’ protocols, that often feature
water as the solvent of choice.1 The reaction with amines
affords b-amino alcohols, important intermediates for car-
bohydrate and nucleoside synthesis.2 It usually requires
long reaction times and the use of a metal catalyst (e.g.,
Cu, Al, Sn, or Bi triflates, ZrCl4).3 An alternative route to
the same products is the azidolysis of epoxides followed
by reduction; side products, however, are often formed by
this procedure and reaction times are not much shorter. In
–
aqueous media competition between N3 and water is pH-
and temperature-dependent, as is the regioselectivity.4
Microwave-assisted cleavage of epoxides by amines is
described in the literature, however, the metal catalyst was
required in all reported instances.5
OH
N
Cl
OH
Cl
N
N
Aiming to develop an efficient, greener protocol for the
regioselective opening of epoxides by nucleophiles, we
studied the catalyst-free reaction in water under high-in-
tensity ultrasound (US), microwaves (MW) and simulta-
neous US/MW irradiation.6 We found that these means of
physical activation induced a regioselectivity that was the
reverse of that observed by Fringuelli et al., working at
acidic pH under conventional conditions.4
α
β
N
1Aβ
1Aα
Figure 1 Regioisomers from the reaction of 2-phenyloxirane with
1-(3-chlorophenyl)piperazine
Under nonconventional conditions (procedures 2–4),
competition between water and the nucleophile did not
occur; as shown in Table 1, the diol was never detected.
On the contrary, reactions carried out under conventional
heating were prone to nucleophilic attack by water, al-
though Saidi et al. did not isolate the diols in the aminol-
ysis of epoxides in water.12 Trisubstituted oxiranes
showed a modest reactivity. Under conventional heating
We reacted a series of commercially available oxiranes
with different degrees of substitution [2-phenyloxirane,
SYNLETT 2007, No. 13, pp 2041–2044
1
3
.0
8
.2
0
0
7
Advanced online publication: 12.07.2007
DOI: 10.1055/s-2007-984891; Art ID: G15107ST
© Georg Thieme Verlag Stuttgart · New York

2042
G. Palmisano et al.
LETTER
(+)-(1R,2S,4R)-cis-limonene 1,2-epoxide (entry 5),13 bined US/MW irradiation markedly improved yields
gave exclusively the trans-diaxial diol when reacted with (51% unoptimized yields) and cut down reaction times.
1-(3-chlorophenyl) piperazine, while its azidolysis exclu-
sively led to azidohydrin 5Bb, albeit in low yields. Com-
Table 1 Reaction Times and Yields for Epoxide Opening by Methods 1–414
Entry
Epoxide
Nua
Method
Time (h)
Selectivity a/b/diolb
(isolated yields, %)
Conversion (%)
1. Oil bath
2. MW
24
2
12:19:29
16:20:0
25:45:0
28:61:0
88:0:0
90:0:0
91:0:0
95:0:0
0:24:55
0:78:0
0:80:0
0:86:0
0:25:0
0:34:0
0:40:0
0:61:0
0:20:51
0:40:0
0:43:0
0:59:0
0:35:13
0:55:0
0:61:0
0:79:0
10:31
26:0
60
36
70
89
88
90
91
95
79
78
80
86
25
34
40
61
71
40
43
59
48
55
61
79
41
26
30
56
25
27
32
50
A15,16
3. US
2
O
4. US/MW
1. Oil bath
2. MW
0.5
24
1
1
B
3. US
0.5
0.5
24
1
4. US/MW
1. Oil bath
2. MW
A17
3. US
1
O
N
4. US/MW
1. Oil bath
2. MW
1
2c
O
24
0.5
0.5
0.5
30
1.5
1.5
1.5
30
1.5
1.5
1.5
30
1.5
1.5
1.5
36
0.5
0.5
0.5
O
B
3. US
4. US/MW
1. Oil bath
2. MW
A18
3. US
4. US/MW
1. Oil bath
2. MW
O
3
B
3. US
4. US/MW
1. Oil bath
2. MW
A19
3. US
30:0
4. US/MW
1. Oil bath
2. MW
56:0
4
O
25:0
27:0
B
3. US
32:0
4. US/MW
50:0
Synlett 2007, No. 13, 2041–2044 © Thieme Stuttgart · New York

LETTER
Efficient Regioselective Opening of Epoxides
2043
Table 1 Reaction Times and Yields for Epoxide Opening by Methods 1–414 (continued)
Entry
Epoxide
Nua
Method
Time (h)
Selectivity a/b/diolb
(isolated yields, %)
Conversion (%)
1. Oil bath
2. MW
30
2.5
3
0:0:35
n.d.
35
<3
<3
39
20
11
15
51
A20
3. US
n.d.
O
4. US/MW
1. Oil bath
2. MW
2
0:39:0
0:20:0
0:11:0
0:15:0
0:51:0
5
30
2
B21
3. US
2
4. US/MW
1.5
a Nucleophiles: A = 1-(3-chlorophenyl)piperazine, B = sodium azide.
b a: Less-substituted alcohol, b: more-substituted alcohol.
c The amount of 0.8 mL of BMIMBF4 (3-butyl-1-methylimidazolium tetrafluoroborate) was added as a co-solvent.
By applying a combination of 1D and 2D NMR experi- In conclusion, here we disclose an efficient, catalyst-free
1
1
1
ments (i.e., H–13C HMQC, H–1H COSY and H–1H synthetic procedure for a regioselective opening of
NOESY) we were able to unambiguously determine the epoxides by some N-nucleophiles in water. This result
1R,2R,4R stereochemistry of 5Bb (Figure 2).
was achieved under US or MW irradiation, or, better still,
under simultaneous US/MW irradiation that strongly
accelerated the cleavage with a high regioselectivity.
Interestingly, 2-azido-2-phenylethanol was prepared in a
one-pot manner in high yield from styrene.
H
4
H
H-2 / H-3a
H-3a / H-4
1
OH
Ha
2
3
N3
Hb
Acknowledgment
Figure 2 NOE correlations for 5Bb
The combined US/MW reactor has been developed in collaboration
with Danacamerini sas (Torino, Italy). MIUR-FIRB 2003 and the
University of Torino are gratefully acknowledged for financial sup-
port.
Efficient cooling by circulation of a refrigerated fluid that
was inert to MW ensured temperature control, a crucial
feature when working in water under combined US/MW
irradiation. The device illustrated in Figure 3 made the
one-pot alkene → epoxide → azide reaction sequence
feasible. Scheme 1 shows the preparation of 2-azido-2-
phenylethanol from styrene; sodium azide was added after
five minutes US/MW irradiation at 15 °C.
References and Notes
(1) Kolb, H. C.; Finn, M. G.; Sharpless, K. B. Angew. Chem. Int.
Ed. 2001, 40, 2004.
(2) Sekar, G.; Singh, V. K. J. Org. Chem. 1999, 64, 287.
(3) (a) Ollevier, T.; Lavie-Compin, G. Tetrahedron Lett. 2004,
45, 49. (b) Chakraborti, A. K.; Kondaskar, A. Tetrahedron
Lett. 2003, 44, 8315. (c) Fringuelli, F.; Pizzo, F.; Tortoioli,
S.; Vaccaro, L. J. Org. Chem. 2004, 69, 7745. (d) Sekar,
G.; Singh, V. K. J. Org. Chem. 1999, 64, 287.
(4) Fringuelli, F.; Piermatti, O.; Pizzo, F.; Vaccaio, L. J. Org.
Chem. 1999, 64, 6094.
(5) (a) Mojtahedi, M. M.; Saidi, M. R.; Bolourtchian, M.
J. Chem. Res., Synop. 1999, 128. (b) Eshghi, H.;
Rahimizadeh, M.; Shoryabi, A. Synth. Commun. 2005, 35,
791. (c) Rodríguez-Escrich, S.; Popa, D.; Jimeno, C.; Vidal-
Ferran, A.; Pericàs, M. A. Org. Lett. 2005, 7, 3829.
(6) Cravotto, G.; Cintas, P. Chem. Eur. J. 2007, 13, 1902.
(7) The use of 1-(3-chlorophenyl)piperazine refers to the work
of: Narayan, N.; Muldoon, J.; Finn, M. G.; Fikin, V. V.;
Kolb, H. C.; Sharpless, K. B. Angew. Chem. Int. Ed. 2005,
44, 3275.
Figure 3 Typical setup for US/MW irradiation, showing the
cooling system
N3
MCPBA, H2O, NaHCO3,
15 °C, 5 min US/MW
OH
(8) Cravotto, G.; Omiccioli, G.; Stevanato, L. Ultrason.
Sonochem. 2005, 12, 213.
(9) Cravotto, G.; Boffa, L.; Bia, M.; Bonrath, W.; Curini, M.;
Heropoulos, G. A. Synlett 2006, 2605.
+ NaN3, 45 °C,
30 min US/MW
90%
Scheme 1 Scheme of the one-pot reaction
Synlett 2007, No. 13, 2041–2044 © Thieme Stuttgart · New York

2044
G. Palmisano et al.
LETTER
(10) Cravotto, G.; Buffa, C.; Omiccioli, G. TO patent application
A000766, 2006.
(11) HSAB theory: Huyskens, P.; Sobczyk, L.; Majerz, I. J. Mol.
Struct. 2002, 615, 61.
3 H, H-2¢¢¢, -4¢¢¢, -6¢¢¢), 4.21 (m, 1 H, H-2¢), 3.50 (m, 2 H, H-
1¢a,b), 2.57 (m, 2 H, H-3¢a,b), 2.90–2.40 (m, 8 H, H-2¢¢a,b,
H-3¢¢a,b, H-5¢¢a,b, H-6¢¢a,b). MS (CI, isobutane): m/z = 400
[MH]+.
(12) Azizi, N.; Saidi, M. R. Org. Lett. 2005, 7, 3649.
(13) (a) Newhall, W. F. J. Org. Chem. 1964, 29, 185.
(b) Steiner, D.; Ivison, L.; Goralski, C. T.; Appell, R. B.;
Gojkovic, J. R.; Singaram, B. Tetrahedron: Asymmetry
2002, 13, 2359. (c) Davis, C. E.; Bailey, J. L.; Lockner, J.
W.; Coates, R. M. J. Org. Chem. 2003, 68, 75.
(18) 1-[4-(3-Chlorophenyl)piperazin-1-yl]octan-2-ol (3Ab): pale
yellow oil; Rf = 0.40 (hexane–EtOAc, 7:3). IR (film): 3460,
1595, 1487, 1234, 1153, 987, 837, 769 cm–1. 1H NMR (300
MHz, CDCl3): d = 7.10 (t, J = 8.1 Hz, 1 H, H-2¢¢), 6.85–6.50
(m, 3 H, H-4¢¢, -5¢¢, -6¢¢), 3.70 (m, 1 H, H-2), 3.10 (m, 4 H,
H-3¢a,b, H-5¢a,b), 2.75 (m, 2 H, H-2¢a,b), 2.50 (m, 2 H, H-
6¢a,b), 2.30 (m, 2 H, H-1a,b), 1.50–1.00 (m, 10 H, H-3a,b, H-
4a,b, H-5a,b, H-6a,b, H-7a,b), 0.95 (br s, 3 H, CH3). MS (CI,
isobutane): m/z = 325 [MH]+.
(19) trans-2-[4-(3-Chlorophenyl)piperazin-1-yl]cyclohexanol
(4A): pale yellow oil; Rf = 0.13 (PE–EtOAc, 8:2). IR (film):
3462, 1597, 1495, 1263, 1105, 1014, 954, 771, 681 cm–1. 1H
NMR (300 MHz, CDCl3): d = 7.02–6.77 (m, 4 H, H-2¢¢, -4¢¢,
-5¢¢, -6¢¢), 4.16 (m, 1 H, H-1), 3.43 (m, 1 H, H-2), 3.23–3.19
(m, 4 H, H-3¢a,b, H-5¢a,b), 2.88 (m, 2 H, H-2¢a,b), 2.58 (m,
2 H, H-5¢a,b), 2.40–1.15 (m, 8 H, H-3,a,b, H-4a,b, H-5a,b,
H-6a,b). MS (CI, isobutane): m/z = 295 [MH]+.
(20) (1R,2R)-2-[4-(3-Chlorophenyl)piperazin-1-yl]-1-methyl-4-
(prop-1-en-2-yl)cyclohexanol (5Ab): pale yellow oil; Rf =
0.62 (hexane–EtOAc, 7:3). IR (film): 3462, 2361, 1595,
1450, 1238, 1126, 987, 767 cm–1. 1H NMR (300 MHz,
CDCl3): d = 7.17 (t, J = 8.1 Hz, 1 H, H-2¢¢¢), 6.87 (m, 3 H, H-
4, -5, -6), 4.96 (m, 1 H, H-9a), 4.87 (m, 1 H, H-9b), 3.47 (m,
1 H, H-2), 3.22 (m, 4 H, H-3¢¢a,b, H-5¢¢a,b), 2.90 (m, 2 H, H-
2¢¢a,b), 2.68 (m, 2 H, H6¢¢a,b), 2.5 (br s, 1 H, OH). MS (CI,
isobutane): m/z = 349 [MH]+.
(21) (1R,2R,4R)-2-Azido-1-methyl-4-(prop-1-en-2-yl)cyclo-
hexanol (5Bb): colorless oil; Rf = 0.24 (CHCl3–MeOH,
19:1). IR (film): 3450, 2094, 1645, 1454, 1261, 1032, 891
cm–1. 1H NMR (300 MHz, CDCl3): d = 4.8 (m, 2 H, H-9a,b),
3.55 (br s, 1 H, H-2), 2.20 (m, 1 H, H-4), 2.00 (m, 1 H, H-
3a), 1.85 (m, 1 H, H-3b), 1.73 (m, 3 H, H-10, CH3), 1.45 (br
s, 1 H, OH), 1.40 (m, 3 H, H-7, CH3). MS (CI, isobutane):
m/z = 196 [MH]+.
(14) General Procedure
In a 50 mL two-necked round-bottomed flask (equipped
with an optical-fiber thermometer for reactions under MW
or combined US/MW) the epoxide (2.5 mmol), the amine (or
NaN3, 2.5 mmol), and H2O (15 mL) were mixed and
subjected to procedures 1–4.
(15) 2-[4-(3-Chlorophenyl)piperazin-1-yl]-2-phenylethanol
(1Aa): pale yellow oil; Rf = 0.56 (CHCl3–MeOH, 19:1). IR
(film): 3584, 1595, 1452, 1238, 1028, 954, 765 cm–1. 1H
NMR (300 MHz, CDCl3): d = 7.37–7.22 (m, 5 H, H-2¢, -3¢,
-4¢, -5¢, -6¢), 7.14 (t, J = 8.1 Hz, 1 H, H-5¢¢¢), 6.83–6.72 (m, 3
H, H-2¢¢¢, -4¢¢¢, -6¢¢¢), 4.03 (m, 1 H, H-2), 3.74 (m, 2 H, H-2,
-3), 3.20 (m, 4 H, H-3¢¢a,b, H-5¢¢a,b), 2.74–2.54 (m, 4 H, H-
2¢¢a,b, H-6¢¢a,b). MS (CI, isobutane): m/z = 317 [MH]+.
(16) 2-[4-(3-Chlorophenyl)piperazin-1-yl]-1-phenylethanol
(1Ab): pale yellow oil; Rf = 0.43 (CHCl3–MeOH, 19:1). IR
(film): 3400, 1595, 1566, 1481, 1244, 1057, 947, 777 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.46–7.38 (m, 5 H, H-2¢, -
3¢, -4¢, -5¢, -6¢), 7.22 (t, J = 8.1 Hz, 1 H, H-5¢¢¢), 6.94–6.83
(m, 2 H, H-2¢¢¢, -4¢¢¢, -6¢¢¢), 4.86 (m, 1 H, H-1), 3.31 (m, 4 H,
H-3¢¢a,b, H-5¢¢a,b), 2.95–2.92 (m, 2 H, H-2¢¢a,b), 2.70–2.56
(m, 4 H, H-2, -3, H-6¢¢a,b). MS (CI, isobutane): m/z = 317
[MH]+.
(17) 2-{3-[4-(3-Chlorophenyl)piperazin-1-yl]-2-hydroxypropyl}
isoindoline-1,3-dione (2Ab): pale yellow oil; Rf = 0.39
(CHCl3–MeOH, 19:1). IR (film): 3327, 1626, 1576, 1437,
1244, 893 cm–1. 1H NMR (300 MHz, CDCl3): d = 7.87–7.81
(m, 4 H, H-3, -4, -5, -6,), 7.17 (m, 1 H, H-5¢¢¢), 6.80–6.65 (m,
Synlett 2007, No. 13, 2041–2044 © Thieme Stuttgart · New York

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