A powerful, practical and chemoselective synthesis of 2-anilinoalkanols catalyzed by Bi(TFA)3 or Bi(OTf)3 in the presence of molten TBAB

Article abstract of DOI:10.1016/j.tetlet.2004.02.139

A facile and efficient synthesis of β-amino alcohols by ring opening of epoxides with anilines in good to excellent yields in the presence of catalytic amounts of Bi(TFA)₃ or Bi(OTf)₃ via the use of molten tetrabutylammonium bromide

Full text of DOI:10.1016/j.tetlet.2004.02.139

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 3525–3529
A powerful, practical and chemoselective synthesis
of 2-anilinoalkanols catalyzed by Bi(TFA)3 or Bi(OTf)3
in the presence of molten TBAB
Mohammd M. Khodaei,* Ahmad R. Khosropour* and Kazem Ghozati
Department of Chemistry, Faculty of Science, Razi University, Kermanshah 67149, Iran
Received 13 October 2003; revised 9February 2004; accepted 20 February 2004
Abstract—A facile and efficient synthesis of b-amino alcohols by ring opening of epoxides with anilines in good to excellent yields in
the presence of catalytic amounts of Bi(TFA)3 or Bi(OTf)3 via the use of molten tetrabutylammonium bromide (TBAB) as an ionic
liquid is described. In addition, the observed chemoselectivity can be considered as a noteworthy advantage of this method.
ꢀ 2004 Elsevier Ltd. All rights reserved.
Epoxides are versatile intermediates in organic chemis-
try and their reactions with different nucleophiles have
been the subject of extensive studies. Ring opening of
epoxides with excess amounts of amines is the most
common method for the synthesis of b-amino alcohols,
which are an important class of compounds in phar-
maceutical and organic chemistry. Some of these com-
pounds are used as starting materials for the preparation
of oxazolines, which have been widely explored as pro-
tecting groups.1 These amino alcohols are also used as
insecticidal agents and as chiral ligands in asymmetric
synthesis.2 Recently, Cho et al. proposed the formation
of the 2-anilinoalkanol as an intermediate in the ruthe-
nium-catalyzed synthesis of indoles.3 Furthermore,
b-amino alcohols are a major functional group in nat-
ural products such as sphingosine that demonstrate
physiological activities.4 Thus the development of facile
and environmentally friendly synthetic methods towards
b-amino alcohols, constitutes an active area of investi-
gation in organic synthesis.
conium sulfophenyl phosphonate,8 CeCl3,9 diisoprop-
11
oxyaluminium trifluoroacetate,10 TaCl5 and LiOTf12
have been reported as catalysts. Recently, it has been
found that epoxides can be converted into b-amino
alcohols using anilines in the presence of [Bmim]BF4 as
an ionic liquid.13 However, these methods often involve
the use of expensive reagents,4;8;11;13 extended reaction
times,6;13 drastic reaction conditions,11 give mixtures of
regioisomers,6;7;9 unsatisfactory yields,7 especially with
aliphatic epoxides and entail undesirable side reactions
due to polymerization or rearrangement of oxir-
anes.6;10;11 Acid-catalyzed ring opening of epoxides with
anilines is limited and requires careful control of the
acidity to prevent side reactions. Therefore, the intro-
duction of new and efficient methods for this transfor-
mation is still in demand.
Because of the volatile and toxic nature of many organic
solvents, ionic liquids are emerging as effective solvents
for ‘green’ processes.14 These solvents are nonflamma-
ble, nonvolatile, easy to handle and possess high thermal
stability.15 However, the high cost of most conventional
room temperature ionic liquids and apprehension about
their toxicity13 have led us to explore the use of more
benign salts in the molten state as practical alternatives.
Recently, molten tetrabutylammonium bromide was
used as a low toxic and cost-effective ionic liquid in a
number of useful synthetic transformations.16 In addi-
tion, the applications of Bi(TFA)3 and Bi(OTf)3 as
environmentally friendly reagents for organic synthesis
have been extensively investigated.17 Due to our interest
in the use of Bi(III) salts,18 we have reported that
Although, aminolysis reactions of epoxides are typically
catalyzed by transition metal salts,5 new catalytic sys-
tems are continuously being explored in the search for
improved efficiencies and cost effectiveness. In this
context, Lewis acids such as Ca(OTf)2,6 alumina,7 zir-
Keywords: Ionic liquid; Anilines; Ring opening; Epoxides; Chemo-
selectivity; Epoxides; Bi(III) salts.
* Corresponding authors. Tel./fax: +98-831-4223306; e-mail addresses:
mmkhoda@razi.ac.ir; arkhosropour@razi.ac.ir
0040-4039/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.02.139

3526
M. M. Khodaei et al. / Tetrahedron Letters 45 (2004) 3525–3529
O
Bi(OTf)3 or Bi(TFA)3
R2
R2
R2
NHCH CHR1
NHCHCH2OH
R1
NH2
+
+
2
molten TBAB
70 o
R1
OH
C
Scheme 1.
Bi(TFA)3 and Bi(OTf)3 are extraordinarily efficient
catalysts for the conversion of epoxides to thiiranes19
and 1,3-dioxolanes.20 Unlike many Lewis acids,
Bi(TFA)3 and Bi(OTf)3 are relatively stable, nontoxic,
easy to handle and insensitive to air and moisture. We
now report a facile and efficient method for the ring
opening of epoxides with anilines catalyzed by Bi(TFA)3
or Bi(OTf)3 in molten tetrabutylammonium bromide at
70 ꢁC (Scheme 1).
Different classes of epoxides carrying activated and
deactivated groups were reacted with aniline, p-methyl-
aniline and p-bromoaniline in molten TBAB in the
presence of catalytic amounts of the Bi(III) salts. These
reactions were performed under moderate conditions to
produce the corresponding b-amino alcohols in good to
excellent yields. The results are shown in Table 1. The
high reactivity and selectivity are similar to those
observed in the case of strong Lewis acids.8–11
Table 1. Ring opening of epoxides with aromatic amines and Bi(TFA)3 or Bi(OTf)3 in the presence of molten TBAB
Entry
Productsa Yield (%)b/mmol of Bi(III) salt/time (min)
Bi(TFA)3
Bi(OTf)3
NHC6H5
1
68/0.05/45
70/0.05/55
78/0.02/45
OH
NHC6H4-p-CH3
2
76/0.02/35
OH
NHC6H4-p-Br
3
4
5
6
67/0.07/55
90/0.03/15
93/0.03/15
90/0.04/15
80/0.03/60
96/0.01/15
95/0.01/15
92/0.01/15
OH
NH
NH
HOCH2CH
Ph
CH3
Br
HOCH CH
2
Ph
HOCH CH
NH
2
Ph
7
82/0.05/30
86/0.05/20
90/0.06/20
84/0.05/45
80/0.05/45
78/0.06/45
81/0.06/45
84/0.02/15
90/0.01/15
92/0.02/25
85/0.02/25
80/0.01/20
79/0.02/45
86/0.03/60
PhOCH2CH(OH)CH2NH
8
PhOCH2CH(OH)CH2NH
CH3
Br
9
PhOCH2CH(OH)CH2NH
10
11
12
13
CH2=CHCH2OCH2CH(OH)CH2NH
CH2=CHCH2OCH2CH(OH)CH2NH
CH3
Br
CH2=CHCH2OCH2CH(OH)CH2NH
NH
CH3(CH2)5CH(OH)CH2

M. M. Khodaei et al. / Tetrahedron Letters 45 (2004) 3525–3529
3527
Table 1 (continued)
Entry
Productsa
Yield (%)b/mmol of Bi(III) salt/time (min)
Bi(TFA)3
83/0.06/60
Bi(OTf)3
CH3
14
15
NH
87/0.02/60
CH3(CH2)5CH(OH)CH2
Br
78/0.07/60
80/0.05/45
85/0.05/45
80/0.06/45
83/0.05/50
90/0.05/45
80/0.06/60
82/0.03/60
90/0.02/45
88/0.02/30
83/0.03/55
86/0.02/45
93/0.02/30
85/0.03/60
NH
CH3(CH2)5CH(OH)CH
2
16
17
18
19
20
21
CH3(CH2)2CH2OCH2CH(OH)CH2NH
CH3(CH2)2CH2OCH2CH(OH)CH2NH
CH3
Br
CH3(CH2)2CH2OCH2CH(OH)CH2NH
ClCH2CH(OH)CH2NH
CH3
ClCH2CH(OH)CH2NH
ClCH2CH(OH)CH2NH
Br
a All products were characterized by 1H NMR, 13C NMR, IR and mass spectroscopy.
b Isolated yields.
The reactions of cyclohexene oxide as a model com-
pound with anilines in the presence of these catalysts
proceeded readily in short times (35–60 min) and with
good yields (Table 1, entries 1–3).
and ketals were stable under these reaction conditions
(Table 2, entries 3 and 4). Furthermore, in this com-
petitive reaction aliphatic amines and p-nitroaniline did
not give the desired product and were completely
recovered. Such selectivity has not been reported pre-
viously and could be considered as a useful practical
achievement in epoxide ring opening reactions.
The reactions of styrene oxide with aromatic amines
(Table 1, entries 4–6) under acidic conditions gave the
corresponding b-amino alcohols, in which the aromatic
amines in contrast to the other oxiranes attack the a-
carbon of the epoxide ring in high yield and excellent
regioselectivity.
In conclusion, the present procedure demonstrates the
successful use of TBAB as a reaction media for the
regio- and chemoselective ring opening of epoxides with
anilines using 1–3 mol % of bismuth(III) triflate or 3–
7 mol % of bismuth(III) trifluoroacetate as catalysts. The
notable features of this procedure are clean reaction
profiles, improved yields, enhanced rates and simplicity
in operation, which make it a useful and attractive
process for the synthesis of b-amino alcohols. Moreover,
nonhydroscopic, inexpensive and nontoxic catalysts and
solvents for this transformation are other noteworthy
advantages of this method. The highly catalytic nature
of these reagents and their wide applicability should
make this procedure an attractive alternative to existing
methods for the preparation of b-amino alcohols.
A variety of epoxides were converted to the products
with high efficiency and chemoselectivity in the presence
of functional groups such as PhO–, RO–, ClCH2– and
allyl ether. The presence of weak electron-donating or
electron-withdrawing groups such as CH3 or Br on the
aromatic ring of aniline did not make any difference in
this reaction. Furthermore, stronger examples such as
p-nitroaniline and 1,2-diaminobenzene or aliphatic
amines did not produce the corresponding b-amino
alcohols under the same reaction conditions. This may
be due to the weaker nucleophilicity of p-nitroaniline or
high basicity and strong complexation of the amines
with these catalysts. This type of behavior was also
previously reported with metal triflates as catalysts.5a;b;12
Also it was found that Bi(OTf)3 (0.01–0.03 mmol) was a
more effective catalyst than Bi(TFA)3 (0.03–0.07 mmol).
General procedure: To a mixture of epoxides (1 mmol)
and anilines (1 mmol) in molten TBAB (0.5 mmol) was
added Bi(TFA)3 (0.03–0.07 mmol) or Bi(OTf)3) (0.01–
0.03 mmol). The reaction mixture was stirred at 70 ꢁC
for the appropriate time according to Table 1. The
progress of the reaction was followed by GLC or TLC.
After completion, the reaction was washed with 0.5 N
HCl (25 mL) and extracted. The mixture was extracted
with CH2Cl2 (3 · 10 mL) and the combined organic
In order to evaluate the intermolecular chemoselectivity
of the reagents, competitive reactions were carried out
and the results are summarized in Table 2. It is inter-
esting to note that acid-sensitive groups such as acetals

3528
M. M. Khodaei et al. / Tetrahedron Letters 45 (2004) 3525–3529
Table 2. Competitive ring opening of epoxides with aromatic amines in the presence of Bi(TFA)3–TBAB and Bi(OTf)3–TBAB
Entry
Epoxide
Anilines
Products
Yield (%)/Time (min)
Bi(TFA)3
Bi(OTf)3
90(20)b
O
HOCH2CHNHPh
82(25)a
100
Ph
Ph
O
1
O
NH2
100
ClCH2
ClCH2
O
80(25)a
100
88(25)b
100
HOCH2CHNHPh
Ph
Ph
2
3
NH2
O
O
O
O
O
HOCH2CHNHPh
Ph
82(30)a
100
86(25)b
100
Ph
NH2
O
O
O2N
O2N
O
O
O
76(45)c
100
81(25)d
100
PhOCH2CH(OH)CH2NHPh
PhO
4
NH2
O
CH3O
O
CH3O
O
O
O
O
PhOCH2CH(OH)CH2NHPh
H2NCH2CH2CH2CH3
77(45)c
100
80(25)d
100
NH2
O
5
6
PhO
H2NCH2CH2CH2CH3
69(65)c
73(45)d
NHC6H4-p-CH3
NH2
NO2
CH3
H2N
O
OH
100
100
NO2
H2N
a 0.03 mmol of Bi(TFA)3.
b 0.01 of Bi(OTf)3.
c 0.05 mmol of Bi(TFA)3.
d 0.02 of Bi(OTf)3.
2. (a) Takehara, J.; Hashiguchi, S.; Fujii, A.; Inoue, S. I.;
Ikaria, T.; Nayori, R. Chem. Commun. 1996, 233; (b)
Ager, D. J.; Prakash, I.; Schaad, D. Chem. Rev. 1996, 96,
835; (c) Auvin-Guette, C.; Rebuffat, S.; Prigent, Y.; Bodo,
B. J. Am. Chem. Soc. 1992, 114, 2170.
layers dried with Na2SO4. The solvent was evaporated
and the crude product purified by chromatography on a
silica-gel plate or silica-gel column to afford the pure b-
amino alcohols in 68–96% yields.21
3. Cho, C. S.; Kim, J. H.; Heung-Jin Choi, H.; Kim, T.;
Shim, S. C. Tetrahedron Lett. 2003, 44, 2975.
4. Carter, H. E.; Glick, F. J.; Norris, W. P.; Phillips, G. E.
J. Biol. Chem. 1947, 170, 285.
Acknowledgements
We are grateful to the Razi University Research Council
for partial support of this work.
5. (a) Sekar, G.; Singh, V. K. J. Org. Chem. 1999, 64, 287; (b)
Chini, M.; Crotti, P.; Favero, L.; Macchia, F.; Pinesch, M.
Tetrahedron Lett. 1994, 35, 433; (c) Meguro, M.; Asao, N.;
Yermamoto, Y. J. Chem. Soc., Perkin Trans. 1 1994, 2597;
(d) Fujiwara, M.; Imada, M.; Baba, A.; Matsuda, H.
Tetrahedron Lett. 1989, 30, 739.
References and notes
ꢀ
ꢁ
ꢁ ꢁ
6. Cepanec, I.; Litvic, M.; Mikuldas, H.; Bartolincic, A.;
ꢀ
1. Jnaneshwara, G. K.; Deshpande, V. H.; Lalithambika,
M.; Ravindranathan, T.; Bedekar, A. V. Tetrahedron Lett.
1998, 39, 459.
Vinkovic, V. Tetrahedron 2003, 59, 2435.
7. Harrak, Y.; Pujol, M. D. Tetrahedron Lett. 2002, 43,
819.

M. M. Khodaei et al. / Tetrahedron Letters 45 (2004) 3525–3529
3529
8. Curini, M.; Epifano, F.; Marcotullio, M. C.; Rosati, O.
Eur. J. Org. Chem. 2001, 4149.
Wieland, L. C.; Mohan, R. S. Tetrahedron 2002, 58,
8373.
9. Rajender Reddy, L.; Arjun Reddy, M.; Bhanumathi, N.;
Rama Rao, K. Synthesis 2001, 831.
10. Rampalli, S.; Chandhari, S. S.; Akamanchi, K. G.
Synthesis 2000, 78.
11. Chandrasekhar, S.; Ramachandar, T.; Jaya Prakash, S.
Synthesis 2000, 1817.
18. (a) Khosropour, A. R.; Khodaei, M. M.; Kookhazadeh,
M. Tetrahedron Lett. 2004, 45, 1725; (b) Khodaei, M. M.;
Khosropour, A. R.; Hoseini, J. J. Chem. Res. (S) 2003,
10, 638; (c) Mohammadpoor-Baltork, I.; Aliyan, H.;
Khosropour, A. R. Tetrahedron 2001, 57, 5851; (d)
Mohammadpoor-Baltork, I.; Khosropour, A. R.; Aliyan,
H. J. Chem. Res. (S) 2001, 7, 780.
19. Mohammadpoor-Baltork, I.; Khosropour, A. R. Mole-
cules 2001, 6, 996.
20. Mohammadpoor-Baltork, I.; Khosropour, A. R. Synth.
Commun. 2001, 22, 3411.
12. Auge, J.; Leroy, F. Tetrahedron Lett. 1996, 37, 7715.
13. Yadav, J. S.; Reddy, B. V. S.; Basak, A. K.; Venkat
Narsaiah, A. Tetrahedron Lett. 2003, 44, 1047.
14. (a) Harjani, J. R.; Nara, S. J.; Salunkhe, M. M. Tetrahe-
dron Lett. 2002, 43, 1127; (b) Namboodiri, V. V.; Varma,
R. S. Chem. Commun. 2002, 342; (c) Sheldon, R. Chem.
Commun. 2001, 2399; (d) Wasserscheid, P.; Keim, W.
Angew. Chem., Int. Ed. 2000, 39, 3773; (e) Welton, T.
Chem. Rev. 1999, 9 9 .
15. (a) Ganchegui, B.; Bouquillon, S.; Henin, F.; Muzart, J.
Tetrahedron Lett. 2002, 43, 6641; (b) Ranu, B. C.; Das, A.;
Samanta, S. J. Chem. Soc., Perkin Trans. 1 2002, 1520; (c)
Selvakumar, K.; Zapt, A.; Beller, M. Org. Lett. 2002, 4,
3031; (d) Amantini, C.; Fringuelli, F.; Pizzo, F.; Vaccaro,
L. J. Org. Chem. 2001, 66, 6734; (e) Smietana, M.;
Mioskowski, C. Org. Lett. 2001, 3, 1037.
16. (a) Ranu, B. C.; Dey, S. S. Tetrahedron Lett. 2003, 44,
2865; (b) Ranu, B. C.; Dey, S. S.; Hajra, A. Tetrahedron
2003, 2417.
17. (a) Yadav, J. V.; Reddy, B. V. S.; Reddy, P. N.; Rao, M.
S. Synthesis 2003, 1387; (b) Mohammadpoor-Baltork, I.;
Khosropour, A. R. Monatsh. Chem. 2002, 133, 189; (c)
Repichet, S.; Zwick, A.; Vendier, L.; Le Roux, C.; Dubac,
J. Tetrahedron Lett. 2002, 43, 993; (d) Leonard, M. N.;
21. Selected spectroscopy data: Compound 2 (Table 1, entry
2): viscous liquid, IR (NaCl, cmꢀ1) 3618–3104 (NH and
1
OH), 1603, 1502, H NMR (CDCl3, 200 MHz) d 1.09(m,
1H), 1.47 (m, 3H), 1.72 (m, 2H), 2.09(m, 2H), 2.33 (s, 3H),
3.14 (ddd, 1H, J ¼ 11:2, 11.2, 6.2 Hz), 3.31–3.53 (m, 1H),
3.89(br s, 2H), 6.78–7.02 (m, 4H, Ar–H), 13C NMR
(CDCl3, 50 MHz) d 24.7, 25.4, 31.4, 31.8, 33.6, 60.9, 74.8,
115.2, 119.3, 129.8, 147.7. Anal. Calcd for C13H19NO: C,
76.06; H, 9.33; N, 6.82. Found: C, 76.35; H, 9.11; N, 6.61.
Compound 10 (Table 1, entry 10): viscous liquid; IR
(NaCl, cmꢀ1) 3510–3115 (NH and OH), 3009, 1598, 1500,
1068, 1H NMR (CDCl3, 200 MHz) d 3.15 (dd, J ¼ 9:9,
10 Hz, 2H), 3.26 (dd, J ¼ 5:1, 7.2 Hz, 2H), 3.52 (m, 2H),
3.81 (br s, 1H), 4.08 (d, J ¼ 9:1 Hz, 2H), 5.23 (d,
J ¼ 12:4 Hz, 2H), 5.98 (m, 1H), 6.62 (d, J ¼ 10:2 Hz,
2H), 7.15 (d, J ¼ 10:04 Hz, 2H), 13C NMR (CDCl3,
50 MHz) d 47.4, 69.4, 72.8, 73.9, 113.9, 117.9, 118.5,
129.7, 134.7, 142.7. Anal. Calcd for C12H17NO2: C, 69.54;
H, 8.27; N, 6.76. Found: C, 69.30; H, 8.39; N, 6.68.