Synthesis of β-amino alcohols by regioselective ring opening of arylepoxides with anilines catalyzed by cobaltous chloride

Article abstract of DOI:10.1016/j.tetlet.2004.09.023

CoCl₂ has been used as a mild and effective catalyst for regioselective ring opening of oxiranes with anilines to synthesize β-amino alcohols in good yields.

Full text of DOI:10.1016/j.tetlet.2004.09.023

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 8253–8256
Synthesis of b-amino alcohols by regioselective ring opening of
arylepoxides with anilines catalyzed by cobaltous chloride
Govindarajan Sundararajan,a,* Kari Vijayakrishnaa and Babu Vargheseb
aDepartment of Chemistry, Indian Institute of Technology Madras, Chennai 600 036, India
bSophisticated Analytical Instrument Facility, Indian Institute of Technology Madras, Chennai 600 036, India
Received 18 June 2004; revised 27 August 2004; accepted 2 September 2004
Available online 21 September 2004
Abstract—CoCl2 has been used as a mild and effective catalyst for regioselective ring opening of oxiranes with anilines to synthesize
b-amino alcohols in good yields.
ꢀ 2004 Elsevier Ltd. All rights reserved.
b-Amino alcohols are key intermediates to many organic
compounds, mainly in biologically active natural and
synthetic products1 and are chiral auxiliaries for asym-
metric synthesis.2 The classical synthetic approach
towards b-amino alcohols involves aminolysis of epox-
ides in protic solvents.3 There are many limitations to
this classical approach such as the requirement for ele-
vated reaction temperatures for less nucleophilic
amines and lower reactivity for sterically crowded
amines/epoxides. In addition, as a rule, these reactions
are accompanied by poor regioselectivity of ring open-
ing. Several activators/promoters have been used in
order to overcome these problems. These include the
use of metal salts4 (lithium, sodium, magnesium and cal-
cium), metal amides (lithium,5a magnesium,5b lead,5c
tin,5d and amide cuprate5e), metal alkoxides (DIPAT,6a
Ti(OiPr)46b), metal triflates (lithium,7a lantha-
nides(III),7b,c Ph4SbOTf7d), alumina,8a,b microwave
assisted solvent-free montmorillonite clay,9 transition
metal halides (TaCl5,10a ZrCl4,10b,c VCl3,10d ZnCl210e),
rare earth metal halides (SmI2(THF)2,11a CeCl3Æ
7H2O11b), transition metal salts under solvent-free con-
ditions,12 ionic liquids,13 and Bi(OTf)3 and Bi(TFA)3
under microwave irradiation.14 Some of these methods
suffer one or more limitations such as the use of costly
chemicals, refluxing temperatures, inert atmosphere con-
ditions, less regioselectivity, side reactions, etc. Hence
there is a demand for cost effective regioselective syn-
thetic routes to b-amino alcohols at ambient
temperature.
Herein, we discuss CoCl2-catalyzed regioselective syn-
thesis of various b-amino alcohols. First, we tried to
ring-open styrene oxide with the sterically bulky 2,6-
diisopropylaniline in the presence of CoCl2 catalyst at
room temperature in acetonitrile. Upon work-up, two
regioisomers 1A and 1B were produced in moderate
yields with selectivity favouring the latter (Table 1, entry
1).16,17
The structure of the regioisomer 1B was established un-
equivocally by single crystal X-ray analysis and the
solved structure is given in Figure 1.18 The observed reg-
ioselectivity in this reaction is contrary to that reported
earlier.15 In order to generalize the observed regioselec-
tivity, we investigated the reactions of several epoxides
with various amines. We realized that CoCl2 catalyzes
the ring opening of oxiranes with anilines both regio-
selectively as well as chemoselectively. In these CoCl2
catalyzed reactions, styrene oxide undergoes regioselec-
tive addition of the anilines to the most substituted car-
bon (benzylic carbon) yielding amino alcohols B
predominantly. The regioselective formation of amino
alcohols B ranges from 88 to 98.5% (entries 1–5). In gen-
eral we found that there was very little change in the
Keywords: b-Amino alcohols; Epoxides; Anilines; Ring opening;
Regioselectivity.
*
Corresponding author. Tel.: +91 44 22578254; fax: +91 44
22578241; e-mail: gsundar@iitm.ac.in
0040-4039/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.09.023

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G. Sundararajan et al. / Tetrahedron Letters 45 (2004) 8253–8256
Table 1. CoCl2 catalyzed ring opening of oxiranes with anilines
Entry Oxirane
Aniline
Time (h) Products
Yield (%)a A:Bb
O
HO
OH
H
H
N
Ph
Ph
N
1
NH2
24
76
12:88
Ph
+
1B
1A
HO
OH
O
O
O
H
H
N
N
2
3
4
3
7
98
74
76
5:95 (24:76)c
+
NH2
Ph
2A
2B
HO
OH
Ph
H
N
H
N
1.5:98.5
NH2
+
Ph
3A
3B
HO
OH
Ph
H
H
N
N
24
3.5:96.5 (26:74)c
MeO
NH2
Ph
+
MeO
MeO
4A
4B
HO
O
H
N
OH
H
N
Cl
5
7
4
60
96
19:81
95:5
NH2
NH2
+
Cl
5A
5B
Cl
OH
OH
H
H
N
N
O
6
6B
6A
a Isolated yields.
b % of regioisomers were calculated using 1H NMR.
c Corresponding ratio of regioisomers obtained via the classical synthesis (aminolysis of styrene oxide in ethanol at room temperature).
long reaction periods with only trace amounts of the
expected product amino alcohols being observed.
Shortly after the addition of benzylamine to the CoCl2
solution, a white precipitate formed. We suspect that
this may be due to prior complexation of the highly
basic benzylamine and other aliphatic amines with the
catalyst system. Similar behaviour has been reported
with TaCl5,10a CeCl3
and metal triflates systems.7
11b
1
The H NMR spectrum of this crude reaction product
was too complex to offer any meaningful clues to the
course of the reaction.
We also discovered that anilines act as superior ring-
opening reagents even when the reactions were per-
formed with CoCl2Æ6H2O or under aerobic conditions
thereby ruling out the possibility of the mediation by
free radicals. Therefore we speculate that an ionic proc-
ess occurs, which explains the regioselectivity of the
reaction (Scheme 1).
Figure 1. ORTEP diagram of amino alcohol 1B.
regioselectivity of the products when anilines containing
different substituents were used. With electron-with-
drawing groups such as Cl, in the aromatic ring of the
oxirane there was a slight decrease in reactivity (entry
5) as well as in regioselectivity. In strict contrast, the ali-
phatic oxirane gave the major product with the opposite
regiochemistry (entry 6). Benzylamine and other ali-
phatic amines failed to ring open the oxirane even after
Thus we suggest that CoCl2 coordinates with the oxi-
rane oxygen to promote nucleophilic attack of the ani-
lines leading to two regioisomers A and/or B. Attack
of the nucleophile is governed by the nature of the oxi-
rane and the stability of the incipient carbonium ion. In

G. Sundararajan et al. / Tetrahedron Letters 45 (2004) 8253–8256
8255
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Scheme 1. The ionic intermediate in the ring-opening reaction medi-
ated by CoCl2.
the case of metal coordinated styrene oxide, the positive
charge on oxygen appears to be localized on the more
highly substituted benzylic carbon. Thus the nucleophile
attacks the benzylic carbon of the styrene oxide leading
to amino alcohol B.10a,b,11b This suggestion is supported
by the lower reactivity of p-chlorostyrene oxide towards
ring opening under these conditions. To explain the
reversal of stereochemistry in the ring opening of 1-hex-
ene oxide, where the rate of formation of the less stable
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General procedure: To a solution of anhydrous CoCl2
(1mmol) in acetonitrile (10mL), styrene oxide (10mmol)
and aniline (10mmol) were added. The reaction mixture
was stirred at room temperature for the required time
(Table 1). After completion of the reaction, the solvent
was removed under reduced pressure; the reaction mix-
ture was diluted with water and extracted with diethyl
ether (3 · 20mL). The organic extracts were washed
with aqueous NaHCO3, water, dried over anhydrous
Na2SO4 and evaporated under reduced pressure to pro-
vide the crude product, which was purified by column
chromatography (60–120mesh silica gel) to give a mix-
ture of A and B. Preparative HPLC of the mixture
yielded pure components. CoCl2Æ6H2O also promotes
the reaction in similar manner.
8. (a) Posner, G. H.; Rogers, D. Z. J. Am. Chem. Soc. 1977,
99, 8208–8214; (b) Harrak, Y.; Pujol, M. D. Tetrahedron
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Synthesis 2000, 22, 1817–1818; (b) Chakraborti, A. K.;
Kondaskar, A. Tetrahedron Lett. 2003, 44, 8315–8319; (c)
Swamy, N. R.; Goud, T. V.; Reddy, S. M.; Krishnaiah, P.;
Venkateswarlu, Y. Synth. Commun. 2004, 34, 727–734; (d)
Sabitha, G.; Reddy, G. S. K. K.; Reddy, K. B.; Yadav, J.
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1649–1652; (b) Reddy, L. R.; Reddy, M. A.; Bhanumathi,
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In summary, CoCl2 has been used as a mild and effective
catalyst for regioselective ring opening of oxiranes with
anilines to synthesize b-amino alcohols in good yields.
Here, styrene oxides undergo regioselective addition of
anilines at the highly substituted carbon to yield regio-
isomers B, predominantly.
15. Iqbal, J.; Pandey, A. Tetrahedron Lett. 1990, 31, 575–576.
16. Regioisomers B gives a base peak at m/z (M+À31) after
losing CH2OH. In the 1H NMR spectrum the benzylic
protons of the regioisomer B resonate upfield compared to
A. Thebenzylicprotonsof Aresonateataround4.9ppmand
those of B resonate at around 4.5ppm. See Refs. 4a and 10b.
17. Spectral data for new compounds, entry 1, 1A: viscous
Acknowledgements
We thank the Department of Science and Technology,
New Delhi (Project no. CHY/00-01/143/DST/GSUN)
for financial support.
1
liquid, H NMR (400MHz, CDCl3): d 7.42–7.06 (m, 8H,
ArH), 4.95 (dd, 1H, J = 7.9, 3.7Hz), 3.24–3.05 (m, 4H),
1.25–1.19 (AB quartet, 6H each, J = 5.9, 6.4Hz, 4CH3).
13C NMR (100MHz, CDCl3): d 142.7, 142.2, 142.1, 128.5,
127.8, 125.8, 124.1, 123.6, 73.4, 58.8, 27.5, 24.2. IR (neat)/
cmÀ1: 3392, 2960, 1590. MS (m/z): 297, 190 (base peak),
175, 160, 107. HRMS calculated for (M+H) = 298.2171,
found = 298.2195. Compound 1B: white solid, mp = 54–
References and notes
1. (a) Corey, E. J.; Zhang, F. Angew. Chem., Int. Ed. 1999,
38, 1931–1934; (b) Punniyamurthy, T.; Iqbal, J. Tetrahe-
dron Lett. 1997, 38, 4463–4466; (c) Chng, B. L.; Ganesan,
A. Bioorg. Med. Chem. Lett. 1997, 7, 1511–1514; (d)
Johannes, C. W.; Visser, M. S.; Weatherhead, G. S.;
Hoveyda, A. H. J. Am. Chem. Soc. 1998, 120, 8340–
8347.
1
55ꢁC, H NMR (400MHz, CDCl3): d 7.31–7.03 (m, 8H,
ArH), 4.10–3.85 (m, 3H), 3.13 (septet, 2H, J = 0.17Hz),
1.19 and 1.00 (2d, 6H each, J = 0.17Hz, 4CH3). 13C NMR
(100MHz, CDCl3): d 142.1, 141.1, 140.5, 128.6, 127.6,
127.0, 123.5, 65.9, 65.3, 27.5, 24.0. IR (neat)/cmÀ1: 3392,
2960, 1587. MS (m/z): 297, 266 (base peak), 190, 175,
160, 91. HRMS calculated for (M+H) = 298.2171,
found = 298.2149.
2. Ager, D. J.; Prakash, I.; Schaad, D. R. Chem. Rev. 1996,
96, 835–875.

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G. Sundararajan et al. / Tetrahedron Letters 45 (2004) 8253–8256
˚
C21.5H30.5NO, M = 318.97, triclinic, a = 11.370(8)A,
18. Crystallographic data for the structure of 1B has been
deposited with the Cambridge Crystallographic Data
Centre as supplementary publication number CCDC
248686. Crystal data for 1B: intensity data were collected
on an Enraf Nonius CAD4 diffractometer with graphite
˚
˚
b = 13.812(7)A, c = 14.395(7)A, a = 107.49(9)ꢁ, b =
3
˚
ꢀ
99.57(9)ꢁ, c = 106.39(9)ꢁ, V = 1989(2)A , space group P1,
Z = 4, dcalcd = 1.065g/cm3, 6978 reflections measured,
4443 reflections [I > 2r(I)] were used in all calculations,
˚
monochromated MoKa radiation (k = 0.71069A)
using the x À 2h technique to a maximum 2h of 49.94ꢁ.
R1 = 0.0620, wR2 = 0.1412,
R1 = 0.1059, wR2 = 0.1619.
R
indices (all data)