Facile synthesis of aminoalcohols by ring opening of epoxides under solvent free conditions

Article abstract of DOI:10.1081/SCC-120039493

The convenient cleavage of symmetrical and unsymmetrical epoxides with either aromatic or aliphatic amine under solvent free conditions is reported. The reactions were carried out in a sealed ampoule at 90°C to give regioselectively the corresponding β-amino alcohol in one pot in high yields.

Full text of DOI:10.1081/SCC-120039493

This article was downloaded by: [Fondren Library, Rice University ]
On: 16 October 2012, At: 12:43
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
Facile Synthesis of
Aminoalcohols by Ring
Opening of Epoxides Under
Solvent Free Conditions
Gloria Huerta a , Guadalupe Contreras‐Ordoñez a ,
C. Alvarez‐Toledano a , Víctor Santes b , Elizabeth
Gómez a & Rubén A. Toscano a
a Instituto de Química‐UNAM, Circuito Exterior,
Ciudad Universitaria, Coyoacán, C. P. 04510,
México, DF, México
b Instituto Mexicano del Petróleo, Programa de
Tratamiento de Crudo Maya, Col. San Bartolo
Atepehuacan, México, DF, México
Version of record first published: 10 Jan 2011.
To cite this article: Gloria Huerta, Guadalupe Contreras‐Ordoñez, C.
Alvarez‐Toledano, Víctor Santes, Elizabeth Gómez & Rubén A. Toscano (2004):
Facile Synthesis of Aminoalcohols by Ring Opening of Epoxides Under Solvent
Free Conditions, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 34:13, 2393-2406
To link to this article: http://dx.doi.org/10.1081/SCC-120039493
PLEASE SCROLL DOWN FOR ARTICLE

Full terms and conditions of use: http://www.tandfonline.com/page/terms-
and-conditions
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.
The publisher does not give any warranty express or implied or make any
representation that the contents will be complete or accurate or up to
date. The accuracy of any instructions, formulae, and drug doses should
be independently verified with primary sources. The publisher shall not
be liable for any loss, actions, claims, proceedings, demand, or costs or
damages whatsoever or howsoever caused arising directly or indirectly in
connection with or arising out of the use of this material.

SYNTHETIC COMMUNICATIONSw
Vol. 34, No. 13, pp. 2393–2406, 2004
Facile Synthesis of Aminoalcohols by
Ring Opening of Epoxides Under
Solvent Free Conditions
Gloria Huerta,1 Guadalupe Contreras-Ordon˜ez,1
1
C. Alvarez-Toledano, Vıctor Santes,
2
´
Elizabeth Gomez, and Ruben A. Toscano
1,
1
*
´
´
1
´
Instituto de Quımica-UNAM, Circuito Exterior, Ciudad Universitaria,
´ ´
Coyoacan, Mexico, DF, Mexico
´
Instituto Mexicano del Petroleo, Programa de Tratamiento de
Crudo Maya, Col. San Bartolo Atepehuacan,
´
2
´ ´
Mexico, DF, Mexico
ABSTRACT
The convenient cleavage of symmetrical and unsymmetrical epoxides
with either aromatic or aliphatic amine under solvent free conditions is
reported. The reactions were carried out in a sealed ampoule at 908C to
*
´ ´
Correspondence: Elizabeth Gomez, Instituto de Quımica-UNAM, Circuito Exterior,
´
´
´
Ciudad Universitaria, Coyoacan, C. P. 04510, Mexico DF, Mexico; Fax: þ52-55-
56162217; E-mail: eligom@servidor.unam.mx.
2393
DOI: 10.1081/SCC-120039493
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com
Copyright # 2004 by Marcel Dekker, Inc.

2394
Huerta et al.
give regioselectively the corresponding b-amino alcohol in one pot in
high yields.
Key Words: b-Aminoalcohols; Epoxide; Aromatic amines; Facile syn-
thesis; Regioisomers.
INTRODUCTION
The ring opening of epoxides is an attractive and easy route to achieve the
synthesis of b-amino alcohols, which are of special interest in the fields of
drugs and pharmaceuticals; they are also widely used in asymmetric synthesis
as chiral auxiliaries.[1–7] The most common approach to accomplish the
cleavage of epoxides involves the use of an epoxide in the presence of an
excess of amine as nucleophile and of protic solvents.[8,9] Common routes
for the ring opening epoxides described so far include Lewis acids[10]
metal salts,[10–14] lanthanide halides,[15–17] triflates,[18,19] boranes,[20]
heterogeneous catalysis,[21] fluoroalkyl alcohols,[22] ionic liquids,[23] and
alumina.[24] On the other hand, the use of microwave irradiation has been
recently reported for the epoxides opening either in the absence of catalyst[25]
or in the presence of Montmorillonite K10 clay as catalyst.[26] However, most
of these synthetic methods present different disadvantages such as the excess
of amines, low yields by using deactivated aromatic amines, and lack of regio-
and stereoselectivity when highly substituted epoxides are used. Additionally,
many of the catalysts commonly employed are quite expensive. As part of our
interest in the condensation reactions of b-amino alcohols with 1,2-dicarbo-
nyls, we have reported the preparation and characterization of five- and six-
membered heterocycles derived of b-amino alcohols and their application
in the synthesis of optically pure piperazines.[27–29] In continuation with
our studies we herein describe an efficient one pot preparation of amino alco-
hols by ring opening of a series of epoxides using aromatic and aliphatic
amines as nucleophiles under solvent free conditions.
RESULTS AND DISCUSSION
The syntheses were achieved by treating equimolar ratios of 2-aminophe-
nol, 2-aminothiophenol, or ethanolamine with a variety of epoxides. The reac-
tions were carried out either in a sealed ampoule or in a Parr reactor at 908C
under solvent free conditions to yield the corresponding amino alcohols.
The reaction of 2-aminophenol and 2-aminothiophenol with styrene oxide
afforded as main products the regioisomers 2a and 3a, respectively (Sch. 1).

Facile Synthesis of Aminoalcohols
2395
Scheme 1. (a) 2-Aminophenol or 2-aminothiophenol and (b) ethanolamine.
For the reaction with o-aminophenol, however, the NMR spectrum of the
crude mixture reaction showed signals for the two possible regioisomers in
a 9 : 1 molar ratio which, after purification by crystallization from methylene
chloride/hexane, led to the regioisomer 2a as unique product. In both reac-
tions the main product resulted from the attack of the amine at the more
hindered carbon of the styrene oxide, which is in accordance with the
literature.[11] On the other hand, the reaction with ethanolamine yielded a
3 : 1 mixture of regioisomers 4a and 4b. The major regioisomer 4a was formed
by the attack of ethanolamine at the benzylic carbon. Compound 4a was also
isolated by crystallization from methylene chloride/hexane.
The ring opening of trans-stilbene oxide with 2-aminophenol or ethanol-
amine under the above-mentioned conditions yielded, respectively, the amino
alcohol 6a or 7a regioselectively in good yield (90–99%, Sch. 2). Crystalline
amine hydrochloride of 7a was obtained by adding HCl which in turn allowed
us to establish the relative stereochemistry of 7a by the x-ray diffraction analy-
sis. Figure 1 shows its molecular perspective, and it is observed that the phenyl
groups are syn orientated to each other. Unit cell parameters and basic
information about data collection and structure refinement are summarized
in Experimental section.

2396
Huerta et al.
Scheme 2. (a) 2-Aminophenol and (b) ethanolamine.
Cyclohexene oxide reacted with 2-aminophenol, 2-amino-5-methyl-phenol,
2-amino-5-chloro-phenol, ethanolamine, and 2-amino-5-chlorobenzyl alcohol
to give, respectively, the amino alcohols 9a–13a in high yield (Sch. 3). All
compounds showed the trans configuration as evidenced by JH–H spin–spin
coupling constants values. This selectivity is in accordance with previous
Figure 1. Molecular perspective for compound amine hydrochloride of 7a.

Facile Synthesis of Aminoalcohols
2397
Scheme 3. (a) 2-Aminophenol, 2-amino-5-methyl-phenol, or 2-amino-5-chloro-
phenol, (b) ethanolamine, and (c) 2-amino-5-chlorobenzyl alcohol.
reports.[11–15,21,26] In addition, the structure of compound 9a was analyzed by
x-ray diffraction. Figure 2 shows a molecular perspective of 9a in a chairlike
conformation confirming the trans stereochemistry. It is also observed that the
phenyl amine moiety and the hydroxyl group are in equatorial positions.
Moreover, the cleavage of ethylene and propylene oxides with 2-amino-
phenol was also carried out affording the corresponding aminoalcohols 14 and
15. For the reaction with ethylene oxide a single compound 14a was obtained
in 99% yield (Sch. 4) whereas for propylene oxide a 3 : 1 mixture of regio-
isomers 15a and 15b was isolated. NMR data allowed to establish that the
major product resulted from the attack of 2-aminophenol at the less substituted
carbon.
In order to explore the stereoselectivity using a chiral inductor we treated
R-(2)-2-phenylglycinol with trans-stilbene oxide for 12 hr at 908C (Sch. 5).
Under these conditions the reaction was not stereoselective and gave a mixture
Figure 2. Molecular perspective of compound 9a.

2398
Huerta et al.
Scheme 4. (a) 2-Aminophenol.
of 16a and 16b in 99% yield (1H NMR). Eventually, compound 16a was
isolated by crystallization from methylene chloride/hexane and its structure
was established by x-ray diffraction (Fig. 3). The molecular perspective of
16a shows that phenyl groups are on the same side and the relative confi-
guration at C1 and C2 are R and S, respectively. Otherwise, compound 16b
was isolated and purified by addition of HCl giving the corresponding
amine hydrochloride of 16b.
In summary, we have described the convenient cleavage of symmetrical
and unsymmetrical epoxides using aliphatic and aromatic amines under
solvent free conditions. This novel synthetic method offers a convenient
entry to b-aminoalcohols in high yield. The most important point of this
study is that catalysts, amine excesses, or solvents are not required. The sim-
plicity makes this approach interesting for further studies, and investigations
with other chiral aminoalcohols are in progress.
EXPERIMENTAL
Amines and epoxides were obtained from Aldrich Chemical Co. 1H NMR
and 13C NMR spectra were recorded on a JEOL Eclipse þ 300 spectrometer.
Chemical shifts (ppm) are relative to (CH3)4Si. Coupling constants are quoted
in Hz. Melting points were measured on Melt Temp II apparatus and are
Scheme 5. R-(2)-2-phenylglycinol.

Facile Synthesis of Aminoalcohols
2399
Figure 3. Molecular perspective of compound 16a.
uncorrected. Elemental microanalyses were performed by Galbraith Labora-
tories, Inc. Mass spectra were obtained with a JEOL JMS-AX505 HA mass
spectrometer. Optical rotations were measured on a JASCO DIP-360 digital
polarimeter [a]2D0 values are given in deg cm22 g21. The x-ray crystallographic
studies were done on
a Bruker Smart Apex CCD diffractometer
˚
l(Mo–Ka) ¼ 0.71073 A, graphite monochromator, T ¼ 293 K, v22u scan,
range 1.5 , u , 258. Corrections were done for Lorentz and polarization
effects. The structures were solved by direct methods (Shelxs 86); all
nonhydrogen atoms were refined anisotropically, by full least squares,
(SHELXL-97)[30] Hydrogen atoms bound to carbon atoms were inserted at
calculated position with isotropic temperature factor 1.2 times the Uiso of
the parent carbon atom. Crystallographic data for the structural analysis
have been deposited with the Cambridge Crystallographic Data Centre,
CCDC nos. 225262, 225263, and 225264 for compounds 7a, 9a, and 16a,
respectively.
Crystal data: Compound 7a (C16H20ClNO2). MW ¼ 293.78, a ¼ 7.945
˚
˚
˚
(1) A, b ¼ 6.821 (1) A, c ¼ 28.561 (2) A, b ¼ 95.604 (2)8, V ¼ 1540.4
(3) A , space group P21/n, Z ¼ 4, rcalc ¼ 1.267 g/cm3, 11,989 reflections
3
˚
collected, 2727 independent reflections, No. of variables 193, final
R ¼ 0.037, Rw ¼ 0.081.

2400
Huerta et al.
˚
Crystal data: Compound 9a (C12H17NO2). MW ¼ 227, a ¼ 10.4 17 (1) A,
3
˚
˚
˚
b ¼ 10.607 (1) A, c ¼ 20.652 (1)A, a ¼ b ¼ g ¼ 908, V ¼ 2281.9 (3) A ,
space group Pbcn, Z ¼ 8, rcalc ¼ 1.207g/cm3, 17,399 reflections collected,
2017 independent reflections, No. of variables 145, final R ¼ 0.051, Rw ¼ 0.087.
˚
Crystal data: Compound 16a (C22H23NO2). MW ¼ 333, a ¼ 11.817 (1) A,
3
˚
˚
˚
b ¼ 5.818 (1) A, c ¼ 14.109 (1) A, b ¼ 108.946 (2)8, V ¼ 917.2 (2) A , space
group P21, Z ¼ 2, rcalc ¼ 1.207 g/cm3, 7611 reflections collected, 3245 inde-
pendent reflections, No. of variables 318, final R ¼ 0.039, Rw ¼ 0.047.
General Procedure
The corresponding amine and the appropriate epoxide were heated at
908C either in a type Parr reactor or in a sealed ampoule for the time indicated
for each compound. After completion of the reaction, the reaction mixture was
cooled and extracted with methylene chloride (3 ꢀ 30 mL), the solvent was
removed, and the oil residue was crystallized from a mixture hexane–
methylene chloride.
2-(2-Hydroxy-1-phenyl-ethylamino)-phenol (2a).[31] From 2g (18.4mmol)
of 2-aminophenol and 2.2 g (18.8 mmol) of styrene oxide, 2.36 g (55%), yellow
pale solid, mp 142–1458C; time 3 hr; 1H NMR (300 MHz, DMSO-d6) d:
3.4–3.5 (1H, m, CH2) 3.6–3.7 (1H, m, CH2), 4.2–4.3 (1H, m, CH), 6.1 (1H,
dd, J ¼ 1.3, 7.5, H-8), 6.4 (2H, m, H-6, H-7), 6.7 (1H, dd, J ¼ 1.5, 7.4, H-5),
7.3–7.4 (4H, m, H-arom); 13C NMR: (74MHz, DMSO-d6) d: 59.6 (C-1), 66.0
(C-2), 111.7 (C-8), 113.9 (C-5), 116.7 (C-6), 119.9 (C-7), 127.3 (C-m), 127.4
(C-p), 128.8 (C-o), 137.3 (C-3), 142.6 (C-i), 144.9 (C-4); MS m/z (%): [Mþ 229
(10)], 198 (100), 120 (10), 109 (5); IR nmax (KBr): 3485 (NH), 3370 (OH) cm21
.
2-(2-Mercapto-phenylamino)-2-phenyl-ethanol (3a). From 1.16 g
(9.32 mmol) of 2-aminothiophenol and 1.06 g (9.32 mmol) of styrene oxide,
2.36 g (85%), yellow solid, mp 1528C; time 3 hr; 1H NMR (300 MHz,
DMSO-d6) d: 3.64–3.70 (1H, m, H-2a), 3.70 (1H, m, H-2b), 4.06 (1H, t,
J ¼ 7.4, H-1), 6.44 (1H, td, J ¼ 7.5, 1.5, H-6), 6.72 (1H, d, J ¼ 8.0, H-8),
7.18 (1H, td, J ¼ 7.5, 1.5, H-7), 7.10 (1H, d, J ¼ 7.7, H-5), 7.26 (5H, m,
H-arom); 13C NMR (74 MHz, DMSO-d6) d: 54.4 (C-1), 64.5 (C-2), 114.9
(C-8), 115.2 (C-4), 116.8 (C-6), 127.6 (C-p), 128.7 (C-m, C-o), 130.4 (C-7),
137.0 (C-5), 140.8 (C-i), 150.7 (C-3); MS m/z (%): [Mþ þ 1, 245 (38)],
215 (25), 125 (100); IR nmax (KBr): 3366 (NH), 3251 (OH). Anal. calcd.
for C14H15NOS: C, 68.60; H, 6.12; N, 5.71; S, 13.04. Found: C, 68.14; H,
6.15; N, 5.67; S, 13.28.
2-(2-Hydroxy-ethylamino)-2-phenyl-ethanol (4a). From 0.5 mL (8.8 mmol)
of ethanolamine and 1 mL (8.8 mmol) of styrene oxide, 1.58 g (99%, 3 : 1);
1
time 3 hr; H NMR (300 MHz, CDCl3) d: 2.3 (2H, bs, OH), 2.8 (4H, m,

Facile Synthesis of Aminoalcohols
2401
H-2, H-4), 3.7 (2H, t, J ¼ 5.1, H-3), 4.7 (1H, dd, J ¼ 3.7, 8.8, H-1), 7.2 (5H, m,
H-arom); 13C NMR (74 MHz, CDCl3) d: 51.1 (C-1), 57.1 (C-3), 64.9 (C-4),
72.1 (C-2), 126.4 (C-m), 127.3 (C-p), 128.5 (C-o), 145.1 (C-i); MS m/z
(%): [Mþ þ 1, 182 (2)], 132 (8), 105 (8), 91 (5), 74 (100). IR nmax (CDCl3):
3607, 3443 cm21. Anal. calcd. for C10H16NO2Cl: C, 65.93; H, 8.79; N,
7.69. Found: C, 65.13; H, 8.25; N, 8.04.
2-(2-Hydroxy-ethylamino)-1-phenyl-ethanol (4b). White solid, mp
1
948C; time 3 hr; H NMR (300MHz, CDCl3) d: 2.79 (4H, m, H-1, H-3), 3.6
(2H, t, J ¼ 5.1, H-4), 4.8 (1H, dd, J ¼ 4.2, 11.01, H-2), 7.4 (5H, m, H-arom);
13C NMR (74 MHz, CDCl3) d: 49.0 (C-3), 60.7 (C-1), 64.7 (C-4), 66.8 (C-2),
125.9 (C-m), 127.5 (C-p), 128.7 (C-o), 140.0 (C-i); MS m/z (%): [Mþ þ 1, 182].
2-(2-Hydroxy-1,2-diphenyl-ethylamino)-phenol (6a). From 2 g (18.4
mmol) of 2-aminophenol and 3.7 g (18.8 mmol) of trans-stilbene oxide,
5.13 g (90%), yellow pale solid, mp 1308C; time 5 hr; 1H NMR
(300 MHz, DMSO-d6) d: 4.6 (1H, d, J ¼ 4.5, H-1), 5.1 (1H, d, J ¼ 4.7,
H-2), 6.4 (1H, m, H-8), 6.6-6.7 (3H, m, H-7, H-6, H-5), 7.1–7.3 (10H,
m, H-arom); 13C NMR (74 MHz, DMSO-d6) d: 64.5 (C-1), 77.3 (C-2),
114.6 (C-8), 114.8 (C-5), 118.9 (C-6), 121.4 (C-7), 126.8 (C-m0), 127.7
(C-p0), 128.0 (C-m), 128.1 (C-p), 128.3 (C-o0), 128.4 (C-o), 135.4 (C-i0),
138.6 (C-3), 140.0 (C-i), 144.7 (C-4); MS m/z (%): [Mþ þ 1, 305 (1)],
198 (100), 120 (20); IR nmax (CHCl3): 3603 (NH), 3411 (OH). Anal.
calcd. for C20H19NO2: C, 78.68; H, 6.22; N, 4.59. Found: C, 77.10; H,
6.42; N, 4.47.
2-(2-Hydroxy-ethylamino)-1,2-diphenyl-ethanol (7a). From 0.77 mL
(12.7 mmol) of ethanolamine and 2.5 g (12.7 mmol) of trans-stilbene oxide,
3.25 g (99%), white solid, mp 1008C; time 3 hr; 1H NMR (300 MHz,
DMSO-d6) d: 2.30 (1H, bs, NH), 2.56–2.59 (2H, m, H-3) 3.50–3.54 (2H,
m, H-4), 3.85 (1H, d, J ¼ 5.8, H-1), 4.82 (1H, d, J ¼ 5.8, H-2), 7.14–7.24
(10H, m, H-arom); 13C NMR (74 MHz, DMSO-d6) d: 48.9 (C-3), 61.4
(C-4), 68.7 (C-1), 77.1 (C-2), 126.9 (C-p), 127.7 (C-m0), 127.8 (C-p), 128.2
(C-o), 128.3 (C-o0), 139.2 (C-i0), 140.7 (C-i); MS m/z (%): [Mþ þ 1, 258
(2)], 198 (5), 178 (5), 165 (7), 150 (100) 132 (10), 118 (18), 105 (30), 91
(28); IR nmax (CDCl3): 3607 (NH), 3443 (OH). Anal. calcd. for C16H19NO2:
C, 74.70; H, 7.39; N, 5.44. Found: C, 74.51; H, 7.51; N, 5.38.
2-(2-Hydroxycyclohexylamino)-phenol (9a).[32] From 2 g (18.4 mmol)
of 2-aminophenol and 1.85 mL (18.8 mmol) of cyclohexene oxide, 3.46 g
(90%), pale yellow solid, mp 1278C; time 3 hr; 1H NMR (300 MHz,
DMSO-d6) d: 1.05–1.33 (4H, m, H-cyclohex), 1.55–1.68 (2H, m, H-cyclo-
hex), 1.85–1.88 (2H, m, H-cyclohex), 2.91 (1H, ddd, J ¼ 4.3, 9.2, 12, H-1),
3.30 (1H, ddd, J ¼ 3.5, 9.2, 12, H-2), 6.58–6.71 (4H, m, H-arom); 13C
NMR (74 MHz, DMSO-d6) d: 24.4 (C-10), 24.5 (C-11), 31.5 (C-9), 34.6
(C-12), 58.8 (C-1), 72.4 (C-2), 110.7 (C-8), 113.9 (C-5), 116.1 (C-6), 120.1

2402
Huerta et al.
(C-7), 137.8 (C-3), 144.7 (C-4); MS m/z (%): [Mþ 207 (90)], 148 (100), 120
(50), 109 (25).
2-(2-Hydroxy-5-methyl-cyclohexylamino-phenol) (10a). From 1 g
(8.12 mmol) of 2-amino m-cresol and 0.8 mL (8.12 mmol) of cyclohexene
oxide, 1.54 g (86%), yellow pale solid, mp 1408C; time 3 hr; 1H NMR
(300 MHz, CDCl3) d: 1.0–1.1 (1H, m, H-cyclohex), 1.25–1.40 (4H, m,
H-cyclohex), 1.67–1.78 (2H, m, H-cyclohex) 2.06–2.24 (3H, m, H-cyclo-
hex), 2.25 (3H, s, –CH3), 2.99 (1H, ddd, J ¼ 4.3, 9.2, 12, H-1), 3.37 (1H,
ddd, J ¼ 3.5, 9.2, 12, H-2), 4.14 (bs, NH), 6.15–6.61 (4H, m, H-arom); 13C
NMR (74 MHz, CDCl3) d: 21.5 (C-13), 24.4 (C-10, C-11), 32.2 (C-9), 34.7
(C-12), 58.8 (C-1), 72.4 (C-2),111.6 (C-8), 113.8 (C-5), 116.3 (C-6), 128.5
(C-7), 136.7 (C-3), 142.0 (C-4); MS m/z (%): [Mþ, 221 (100)], 162 (82),
134 (78), 123 (48). Anal. calcd. for C13H19NO2: C, 70.58; H, 8.59; N, 6.33.
Found: C, 69.79; H, 8.70; N, 6.20.
2-(5-Chloro-2-hydroxy-cyclohexylamino)-phenol (11a). From 1 g
(6.8 mmol) of 4-chloro 2-aminephenol and 0.8 mL (6.8 mmol) of cyclohexene
1
oxide, 1.17 g (65%), brown oil; time 3 hr; H NMR (300 MHz, CDCl3) d:
1.0–1.07 (1H, m, H-cyclohex), 1.24–1.37 (4H, m, H-cyclohex), 1.65–1.75
(2H, m, H-cyclohex), 1.95–2.12 (3H, m, H-cyclohex), 3.01 (1H, ddd,
J ¼ 4.3, 9.2, 12.0, H-1), 3.37 (1H, ddd, J ¼ 3.5, 9.2, 12.0, H-2), 5.26 (1H,
bs, NH), 6.46 (2H, m, H-7, H-8), 6.63 (1H, s, H-5); 13C NMR (74 MHz,
CDCl3) d: 24.3, 24.9, 31.2, 33.4, 60.0 (C-1), 74.3 (C-2), 113.1 (C-8), 115.7
(C-5), 117.8 (C-6), 125.6 (C-7), 137.0 (C-3), 143.5 (C-4); MS m/z (%):
[Mþ, 256 (90)].
2-(2-Hydroxy-ethylamino)-cyclohexanol (12a).[33] From 1.2 mL
(19.8 mmol) of ethanolamine and 2 mL (19.8 mmol) of cyclohexene oxide,
1
3.1 g (99%), yellow oil; time 3 hr; H NMR (300 MHz, CDCl3) d: 0.9–1.1
(4H, m, H-cyclohex), 1.1–1.5 (2H, m, H-cyclohex), 1.82–1.97 (2H, m,
H-cyclohex), 2.58–2.61 (2H, m, H-3), 3.60–3.64 (2H, m, H-4), 2.81 (1H,
ddd, J ¼ 4.3, 9.2, 12.0, H-1), 3.60 (1H, ddd, J ¼ 3.5, 9.2, 12.0, H-2), 5.2
(1H, bs, NH); 13C NMR (74 MHz, CDCl3) d: 24.6 (C-6, C-7) 29.9 (C-5),
34.2 (C-8), 48.2 (C-3), 60.8 (C-4), 63.1 (C-1), 73.28 (C-2); MS m/z (%):
[Mþ, 159 (10)], [Mþ þ 1, 160 (18)], 128 (100), 110 (45), 100 (85), 81 (40);
IR nmax (CHCl3): 3370 (NH), 3250 (OH), 2932, 2859 (CH2).
2-(5-Chloro-2-hydroxymethyl-phenylamino)-cyclohexanol (13a). From
0.53 g (3.36 mmol) of 2-amino-4chloro-benzylalcohol and 0.34 mL
(3.36 mmol) of cyclohexene oxide, 0.70 g (80%), white solid, mp 908C;
1
time 3 hr; H NMR (300 MHz, CDCl3) d: 1.00–1.15 (1H, m, cyclohex),
1.20–1.41 (4H, m, cyclohex), 1.62–1.80 (2H, m, cyclohex), 2.00–2.12
(3H, m), 3.09 (1H, ddd, J ¼ 3.5, 9.0, 12.5, H-1,) 3.37 (1H, ddd, J ¼ 3.7,
9.0, 12.5, H-2), 4.50 (2H, s, H-13), 6.69 (1H, d, J ¼ 6.0, H-8), 6.99 (2H,
dd, J ¼ 2.3, 8.7, H-5, H-7); 13C NMR: (74 MHz, CDCl3) d: 24.3 (C-11),

Facile Synthesis of Aminoalcohols
2403
24.8 (C-10), 31.5 (C-9), 33.5 (C-12), 59.6 (C-13), 63.9 (C-1), 74.5 (C-2),
113.3 (C-8), 117.2 (C-6), 121.5 (C-4), 126.3 (C-5), 128.9 (C-7), 146.0
(C-3). Anal. calcd. for C13H18NO2Cl: C, 61.08; H, 6.69; N, 5.51. Found: C,
59.42; H, 6.81; N, 6.04.
2-(2-Hydroxy-ethylamino)-phenol (14a). From 2 g (18.3 mmol) of
2-aminophenol and 0.9 mL (18.3 mmol) of ethylene oxide, 2.9 g (99%),
1
brown oil; time 1 hr; H NMR (300 MHz, CDCl3) d: 3.03 (2H, m, H-1),
3.50 (2H, m, H-2), 5.70 (1H, bs, NH), 6.79–6.87 (2H, m, H-6, H-8),
6.99–7.08 (2H, m, H-5, H-7); 13C NMR (74 MHz, CDCl3) d: 57.4 (C-1),
59.6 (C-2), 115.7 (C-8), 120.3 (C-5), 123.4 (C-6), 126.5 (C-7), 137.0 (C-3),
153.5 (C-4); IR nmax (CHCl3): 3339 (OH), 2952 (CH2).
2-(2-Hydroxy-propylamino)-phenol (15a). From 1.70 g (15.6 mmol) of
2-aminophenol and 1.1 mL (15.6 mmol) of propylene oxide, yield 99%, white
1
solid; time 1 hr; H NMR (300 MHz, CDCl3) d: 1.11 (3H, d, J ¼ 1.8, CH3),
2.69 (1H, dd, J ¼ 10.6, 13.4, H-1a), 3.13 (1H, dd, J ¼ 12.0, 13.6, H-1b),
3.85 (2H, m, H-2), 6.90 (m, H-arom); 13C NMR (74 MHz, CDCl3) d: 20.2
(CH3), 64.8 (C-1) 66.2 (C-2), 116.3 (C-8), 119.9 (C-5), 122.2 (C-6), 125.8
(C-7), 137.4 (C-3), 152.8 (C-4); MS m/z (%): [Mþ, 167], 155 (15), 133
(13), 122 (100), 95 (20); IR nmax (CHCl3): 3602 (NH), 3424 (OH). Anal.
calcd. for C9H13NO2: C, 64.67; H, 7.78; N, 8.38. Found: C, 64.00; H, 8.59;
N, 8.20.
2-(2-Hydroxy-1-methyl-ethylamino)-phenol (15b). Yellow solid 1H
NMR (300 MHz, CDCl3) d: 1.07 (3H, d, J ¼ 1.8, CH3), 2.93 (1H, dd,
J ¼ 9.6, 13.2, H-2a), 3.03 (1H, dd, J ¼ 9.6, 13.0, H-2b), 3.8 (1H, m, H-1),
7.07 (5H, m, H-Ar); 13C NMR (74 MHz, CDCl3) d: 20.7 (CH3), 62.0 (C-1),
65.3 (C-2), 116.0 (C-8), 120.6 (C-5), 124.2 (C-6), 126.7 (C-7), 138.3 (C-3),
153.7 (C-4); MS m/z (%): [Mþ 167].
(10R,1S,2R)-2-(20-Hydroxy-10-phenyl-ethylamino)-1,2-diphenyl-etha-
nol (16a). From 1 g (7.28 mmol) of (R)-(2)-2-phenylglycinol and 1.43 g
(7.28 mmol) of trans-stilbene oxide, white solid, mp 1408C, [a]D20
¼
1
20.064 (C ¼ 2.24, CHCl3); time 12 hr; H NMR (300 MHz, CDCl3) d: 3.54
(1H, dd, J ¼ 4.4, 10.4, H-3), 3.68–3.75 (2H, m, H-4), 3.91 (1H, d J ¼ 5.1,
H-1), 4.98 (1H, d, J ¼ 5.1, H-2), 7.0–7.59 (H-arom); 13C NMR (74 MHz,
CDCl3) d: 61.6 (C-3), 66.0 (C-4), 66.2 (C-1), 75.9 (C-2), 126.7, 127.2,
127.5, 127.6, 127.7, 128.0, 128.1, 128.3, 128.7, 139.4 (C-i), 140.1 (C-i),
140.9 (C-i); MS m/z (%): [Mþ þ 1, 334 (2)], 302 (10), 284 (5), 256 (100),
194 (12), 121 (15), 106 (78); IR nmax (film): 3064 (NH), 3033 (OH). Anal.
calcd. for C22H27NO2: C, 79.20; H, 6.90; N, 4.20. Found: C, 78.74; H, 7.02;
N, 4.12.
(10R,1R,2S)-2-(20-Hydroxy-10-phenyl-ethylamino)-1,2-diphenyl-ethanol
hydrochloride (16b). [a]2D5 ¼ 2 0.013 (C ¼ 1.8, MeOH); 1H NMR
(300 MHz, CDCl3) d: 3.92 (1H, dd, J ¼ 4.4, 10.4, H-3), 4.11 (3H, m, H-4,

2404
Huerta et al.
H-1), 5.43 (1H, d, J ¼ 5.1, H-2), 6.91–7.45 (15H, H-Ar); 13C NMR (74 MHz,
CDCl3) d: 61.1 (C-3), 65.4 (C-4), 66.9 (C-1), 77.6 (C-2), 127.2, 127.4, 127.5,
127.6, 127.7, 128.0, 128.1, 128.3, 128.7, 139.3 (C-i), 139.9 (C-i), 140.9 (C-i);
IR nmax (film): 3064 (NH), 3033 (OH).
ACKNOWLEDGMENTS
Financial support from DGAPA (IN 207103) is grateful acknowledged.
´
Authors thank Francisco Javier Perez, Luis Velasco, Myrian Adaya and
´
Rocıo Patin˜o for technical support.
REFERENCES
1. Anger, D.J.; Prakash, I.; Schaad, D.R. 1,2-Amino alcohols and their hetero-
cyclic derivatives as chiral auxiliaries in asymmetric synthesis. Chem.
Rev. 1996, 96 (2), 835–875.
2. Iida, T.; Yamamoto, N.; Sasai, H.; Shibasaki, M. New asymmetric reac-
tions using a gallium complex: a highly enantioselective ring opening of
.
.
epoxides with thiols catalyzed by a gallium lithium bis(binapthoxide)
complex. J. Am. Chem. Soc. 1997, 119 (20), 4783–4784.
3. Wu, M.H.; Jacobsen, E.N.J. Asymmetric ring opening of meso epoxides
with thiols: enantiomeric enrichment using a bifunctional nucleophile.
Org. Chem. 1998, 63 (15), 5252–5254.
4. Buono, G. On the beneficial effect of ortho-methoxy groups in the asym-
metric ring opening of meso epoxides with silicon tetrachloride catalyzed
by chiral ortho-methoxyphenyldiazaphosphonamide Lewis bases.
Angew. Chem. Int. Ed. 2001, 40 (24), 4536.
5. Adams, H.; Bell, R.; Cheung, Y.-Y.; Jones, D.N.; Tomkinson, N.C.O. The
cleavage of meso-epoxides with homochiral thiols: synthesis of (þ)- and
(2)-trans-1-mercaptocyclohexan-2-ol. Tetrahedron: Asymmetry 1999,
10 (21), 4129–4142.
6. Wu, J.; Hou, X.-L.; Dai, L.-X.; Xia, L.-J.; Tang, M.-H. Enantioselective
ring opening of meso-epoxides with thiols catalyzed by a chiral (salen)
Ti(IV) complex. Tetrahedron: Asymmetry 1998, 9 (19), 3431–3436.
7. Rogers, G.A.; Parsons, Anderson, D.C.; Nilsson, L.M.; Bahr, B.A.;
Kornreich, W.D.; Kaufman, R.; Jacobs, R.S.; Kirtman, B. Synthesis, in
vitro acetylcholine-storage-blocking activities, and biological properties
of derivatives and analogues of trans-2-(4-phenylpeperidino)cyclohexa-
nol (vesamicol). J. Med. Chem. 1989, 32 (6), 1217–1230.

Facile Synthesis of Aminoalcohols
2405
´ ´
8. Mousseron, M.; Jullien, J.; Jolchine, Y. Obtention et proprietes d’amines
´
substitutees. Bull. Soc. Chim. Fr. 1952, 757–766.
9. Deyrup, J.A.; Moyer, C.L. 1,2,3-Oxathiazolidines. Heterocyclic system.
J. Org. Chem. 1969, 34 (1), 175–179.
10. Chini, M.; Crotti, C.; Macchia, F. Metal salts as new catalysts for mild and
efficient aminolysis of oxiranes. Tetrahedron Lett. 1990, 31 (32),
4661–4664.
11. Chini, M.; Crotti, P.; Macchia, F. Regioalternatig selectivity in the metal
salt catalyzed aminolysis of styrene oxide. J. Org. Chem. 1991, 56 (20),
5939–5942.
12. Ollevier, T.; Lavie-Compin, G. An efficient method for the ring opening
of epoxides with aromatic amines catalyzed by bismuth trichloride.
Tetrahedron Lett. 2002, 43 (44), 7891–7893.
13. Swamy, R.N.; Kondaji, G.; Nagaiah, K. Bi3þ catalyzed regioselective
ring opening of epoxides with aromatic amines. Synth. Commun. 2002,
32 (15), 2307–2312.
14. Chandrasekhar, S.; Ramachandar, S.; Prakash, J.S. TaCl5 catalysed clea-
vage of epoxides with aromatic amines. Synthesis 2000, (13), 1817–1818.
15. Fu, X.L.; Wu, S.H. A regio and stereoselective synthesis of b-amino
alcohols. Synth. Commun. 1997, 27 (10), 1677–1683.
16. Weghe, P.; Collin, J. Ring opening reactions of epoxides catalyzed by
samarium iodides. Tetrahedron Lett. 1995, 36 (10), 1649–1652.
17. Reddy, L.R.; Reddy, M.A.; Bhanumathi, N.; Rao, K.R. Cerium chloride
catalysed cleavage of epoxides with aromatic amines. Synthesis
2001,(6), 831–832.
18. Chini, M.; Crotti, P.; Favero, L.; Macchia, F.; Pineschi, M. Lanth-
anide(III) trifluoromethanesulfonates as extraordinarily effective new
catalysts for the aminolysis of 1,2-epoxides. Tetrahedron Lett. 1994,
35 (3), 433–436.
19. Sekar, G.; Singh, V.K. An efficient method for cleavage of epoxides with
aromatic amines. J. Org. Chem. 1999, 64 (1), 287–289.
20. Chandrasekhar, S.; Reddy, C.R.; Babu, B.N.; Chandrashekar, G. Highly
efficient cleavage of epoxides catalyzed by B(C6F5)3. Tetrahedron Lett.
2002, 43 (21), 3801–3803.
21. Currini, M.; Epifano, F.; Marcotullio, M.C.; Rosati, O. Zirconium sulfo-
phenyl phosphonate as a heterogeneous catalyst in the preparation of
b-amino alcohols from epoxides. Eur. J. Org. Chem. 2001, (21),
4149–4152.
´
´
22. Das, U.; Crousse, B.; Kesavan, V.; Bonnet-Delpon, D.; Begue, J.P. Facile
ring opening of oxiranes with aromatic amines in fluoro alcohols. J. Org.
Chem. 2000, 65 (20), 6749–6751.

2406
Huerta et al.
23. Yadav, J.S.; Reddy, B.V.S.; Basak, A.K.; Narsaiah, A.V. [Bmim]BF4
ionic liquid: a novel reaction medium for the synthesis of b-amino
alcohols. Tetrahedron Lett. 2003, 44 (5), 2721–1050.
24. Harrak, Y.; Pujol, M.D. Mild cleavage of aliphatic epoxides with substi-
tuted anilines on alumina. Tetrahedron Lett. 2002, 43 (5), 819–822.
¨
25. Lindstrom, B.; Olofsson, B.; Somfai, P. Microwave-assisted aminolysis
of vinylepoxides. Tetrahedron Lett. 1999, 40 (52), 9273–9276.
26. Mojtahedi, M.M.; Saidi, M.R.; Bolourtchian, M. Microwave-assisted
aminolysis of epoxides under solvent-free conditions catalyzed by Mont-
morillonite clay. J. Chem. Res. (S) 1999, 128–129.
´
´
´
´
27. Santes, V.; Gomez, E.; Jimenez, G.; Santillan, R.; Gutierrez, A.; Farfan, N.
Syntheses and study of new 2-hydroxy-5,6-dihydro-2H-1,4-oxazines by
NMR and X-ray crystallography. Synth. Commun. 2000, 30 (15),
2721–2734.
´
´
28. Santes, V.; Gomez, E.; Santillan, R.; Farfan, N. Facile deuteration of
chiral N,N0-substituted piperazines. Synthesis 2001,(2), 235–238.
´
´
´
29. Santes, V.; Gomez, E.; Zarate, V.; Santillan, R.; Farfan, N.;
Rojas-Lima, S. Synthesis of new homochiral 2,3-dialkylpiperazines
derived fron (R)-(2)-phenylglycinol. Tetrahedron: Asymmetry 2001,
12 (2), 241–247.
30. Sheldrick, G.M. SHELXL-97, Program for Refinement of Crystal Struc-
¨
tures. University of Gottingen: Germany.
¨
31. Hoffmann, D.; Meyer, J.F. Uberfu¨hrung der 1-4-Benzoxazinone-(2) in
Phermorpholone (2) and N-Substituierte Aminoalkohole. Chem. Ber.
1961, 94, 1676–1682.
32. Brown, D.W.; Ninan, A.; Sainsbury, M. The synthesis of reduced phenox-
azines as potential chain-breaking antioxidants. Synthesis 1997, (8),
895–898.
33. Mousseron, M.; Granger, R. Etude des amino-alcohols. Bull. Soc. Chim.
Fr. 1947, 850–868.
Received in the USA March 2, 2004