Facile Ring Opening of Oxiranes with Aromatic Amines in Fluoro Alcohols

Full text of DOI:10.1021/jo000031c

J . Org. Chem. 2000, 65, 6749-6751
6749
Sch em e 1
F a cile Rin g Op en in g of Oxir a n es w ith
Ar om a tic Am in es in F lu or o Alcoh ols
Udayan Das, Benoit Crousse, Venkitasamy Kesavan,
Danie`le Bonnet-Delpon, and J ean-Pierre Be´gue´*
Laboratoire BIOCIS associe´ au CNRS,
Centre d’Etudes Pharmaceutiques, Rue J . B. Cle´ment,
92296 Chaˆtenay-Malabry, France
jean-pierre.begue@cep.u-psud.fr
Received J anuary 10, 2000
Ta ble 1. Rin g Op en in g of Cycloh exen e Oxid e (1) w ith
Ar om a tic Am in es
â-Amino alcohols are an important class of organic
compounds1 and are of considerable use in medicinal
chemistry.2 The most practical and widely used route to
the synthesis of these compounds is the direct aminolysis
of 1,2-epoxides;1 however, these reactions, which are
usually carried out with a large excess of ammonia or
amines at elevated temperatures, often fail when poorly
nucleophilic amines are concerned. Several useful modi-
fications of the classical procedures have been reported:
thus metal amides (Al, Mg, Li, Pb, and Si)3 have been
successfully employed in several cases although many
functional groups are potentially incompatible with their
use. To avoid drawbacks due to the basic medium, a
variety of activators such as Lewis acids or metal salts
can be introduced to effect the ring opening at room
temperature.4
entry
product
durationa
yield (%)b
1.
2.
3.
4.
5.
2a
2b
2c
2d
2e
4
4
2.5
3
2.5
84
86
92
87
88
a
b
Duration in hours. Isolated yields.
2-propanol, by hydrogen bonding. We report here the
reaction of amines with epoxides in those solvents.
Resu lts a n d Discu ssion
Initially ring opening of cyclohexene oxide 1 was
investigated with aniline in trifluoroethanol (TFE). Cy-
clohexene oxide was treated with 1.1 equiv of aniline at
room temperature, and no reaction was observed. Ring
opening of epoxide with aniline failed even at reflux
temperature. Since hexafluoro-2-propanol (HFIP) is more
acidic (pKa ) 9.3) than trifluoroethanol (pKa ) 12.8), ring
opening was tried out in the former. Cyclohexene oxide
(1 mmol) was treated with aniline (1.1 mmol) at room
temperature in HFIP (1 mL). After 48 h, there was
formation of 65% of amino alcohol 2a . When the reaction
was performed at reflux, 84% of amino alcohol 2a was
obtained after 4 h. The trans-configuration of 2a was
assigned by J H-H coupling constants (ddd, J ) 10.7, 9.4,
Due to the electron-withdrawing character of fluoro-
alkyl groups, fluoroalkyl alcohols have a high ability to
form hydrogen bonds.5 In our interest for the use of
fluorous medium in organic synthesis,6 we investigated
the possible activation of oxirane ring opening by fluo-
roalkyl alcohols such as trifluoroethanol and hexafluoro-
(1) (a) Moller, F. Methoden der Organische Chemie (Houben-Weyl),
4th ed.; Thieme Verlag: Stuttgart, 1957; Vol 11/1, pp 311-326. (b)
Mousseron, M.; J ullien, J .; J olchine, Y. Bull. Chem Soc. J pn. 1952,
757.
(2) (a) Rogers, G. A.; Parsons, S. M.; Anderson, D. C.; Nilsson, L.
M.; Bahr, B. A.; Kornreich, W. D.; Kaufman, R.; J acobs, R. S.; Kirtman,
B. J . Med. Chem. 1989, 32, 1217. (b) Cheng, B.-L.; Ganesan, A. Bioorg.
Med. Chem. Lett. 1997, 7, 1511.
(3) (a) Carre´, M. C.; Houmounou, J . P.; Caube`re, P. Tetrahedron
Lett. 1985, 26, 3107. (b) Kissel, C. L.; Rickborn, B. J . Org. Chem. 1972,
37, 2060. (c) Overman, L. E.; Flippin, L. A. Tetrahedron Lett. 1981,
22, 195. (d) Yamada, J .-I.; Yumoto, M.; Yamamoto, Y. Tetrahedron Lett.
1989, 30, 4255. (e) Fiorenza, M.; Ricci, A.; Taddei, M.; Tassi, D.; Seconi,
G. Synthesis 1983, 640.
(4) (a) Fu, X.-L.; Wu, S.-H. Synth. Commun. 1997, 27, 1677. (b) Van
de Weghe, P.; Collin, J . Tetrahedron Lett. 1995, 36, 1649. (c) Chini,
M.; Crotti, P.; Macchia, F. J . Org. Chem. 1991, 56, 5939. (d) Iqbal, J .;
Pandey, A. Tetrahedron Lett. 1990, 31, 575. (e) Papini, A.; Ricci, A.;
Taddei, M.; Seconi, G.; Dembech, P. J . Chem. Soc., Perkin Trans 1
1984, 2261. (f) Sekar, G.; Singh, V. K. J . Org. Chem. 1999, 64, 287. (g)
Posner, G. H.; Rogers, D. Z. J . Am. Chem. Soc. 1977, 99, 8208. (h)
Augy, J .; Leroy, F. Tetrahedron Lett. 1996, 37, 7715. (i) Meguro, M.;
Asao, N.; Yamamoto, Y. J . Chem. Soc., Perkin Trans. 1 1994, 2597. (j)
Fujiwara, M.; Imada, M.; Baba, A; Matsuda, H. Tetrahedron Lett. 1989,
30, 739.
(5) (a) Eberson, L.; Hartshorn, M. P.; Persson, O.; Radner, F. J .
Chem. Soc. Chem. Commun. 1996, 2105. (b) Richard, J . P. Tetrahedron
1995, 51, 1535.
(6) (a) Ravikumar, K. S.; Barbier, F.; Be´gue´, J . P.; Bonnet-Delpon,
D. Tetrahedron 1998, 54, 7457. (b) Ravikumar, K. S.; Be´gue´, J . P.;
Bonnet-Delpon, D. Tetrahedron Lett. 1998, 39, 3141. (c) Ravikumar,
K. S.; Zhang, Y. M.; Be´gue´, J . P.; Bonnet-Delpon, D. Eur. J . Org. Chem.
1998, 2937, 7. (d) Ravikumar, K. S.; Barbier, F.; Be´gue´, J . P.; Bonnet-
Delpon, D. J . Fluorine. Chem. 1999, 95, 123. (e) Kesavan, V.; Bonnet-
Delpon, D.; Be´gue´, J . P. Synthesis 2000, 2, 223.
1
3.8 Hz) at 3.14 ppm for CH-NH in H NMR spectrum.
When the reaction was carried out in 2-propanol no
reaction occurred, clearly showing the activating effect
of HFIP (Scheme 1, Table 1).
The reaction could be generalized to various aromatic
amines. As shown in Table 1, the reaction was also
efficient with the secondary N-methylaniline. Steric
hindrance of the aromatic amine does not have any
profound effect on their reactivity toward ring opening
of epoxide. Cyclohexene oxide underwent a ring opening
reaction at reflux in HFIP with o-methylaniline and
R-naphthylamine to afford the amino alcohols 2c4f and
2d ,4f respectively, in high yields (Scheme 1, Table 1).
However, the reaction failed with p-nitroaniline. With
other cyclic epoxides, 3 and 5, ring opening could also be
achieved with aromatic amines in good yields (Scheme
2, Table 2).
When 1-dodecene oxide 7, a terminal epoxide, was
subjected to ring opening with the N-methylaniline, a
mixture of both regioisomers 8b and 9b were obtained
in the ratio of 90:10, the major product resulting from
the attack of nucleophile at the less-substituted carbon
10.1021/jo000031c CCC: $19.00 © 2000 American Chemical Society
Published on Web 09/14/2000

6750 J . Org. Chem., Vol. 65, No. 20, 2000
Notes
Sch em e 2
experiment indicates that interaction between HFIP and
piperidine resulted in two effects: HFIP deactivates
piperidine toward ring opening and piperidine decreases
the activating interaction between HFIP and the oxirane.
Since 1 mL of HFIP corresponds to 10 equiv, this cannot
be explained only by neutralization but by modified
physical properties of HFIP in the presence of piperidine.5a
A large amount of HFIP (5 mL) was required to obtain
72% conversion into 2a after 9 h, and no product of
reaction with piperidine was observed (Scheme 4). In
2-propanol the reaction occurred with piperidine, afford-
ing, after 30 h at reflux, the amino alcohol 12 in good
yield with no traces of 2a . Thus it seems that there are
competitive effects of HFIP depending on the nucleophi-
licity of amines: an activation of the oxirane through
hydrogen bonding, and a deactivation of amines.
Ta ble 2. Ep oxid e Rin g Op en in g w ith Ar om a tic Am in es
entry
substrate
product
durationa
yield (%)b
6
7
8
9
3
4a
4b
6a
6b
9
6
38
52
88
81
70c
68c
5
Duration in hours. Isolated yields. c Some starting materials
a
b
were recovered.
To summarize, epoxide ring opening with aromatic
amines was achieved by using HFIP as the solvent
without any catalyst under neutral conditions, leading
to high yields of the corresponding amino alcohols.
Conversely, HFIP deactivates more-nucleophilic amines
(alkylamines) toward oxirane ring opening.
(Scheme 3). The regioisomers were separated by column
chromatography. This selectivity is similar to that of
reactions catalyzed by metal salts and triflates.4f-i Ring
opening of styrene oxide with aniline resulted in an
inextricable mixture. However, when the reaction was
performed at room temperature, it afforded after 3 h the
regioisomer 11a (∼50%) accompanied by an unidentified
mixture. The facile nature of the styrene ring opening
prompted us to perform the reaction in the less acidic
CF3CH2OH. After 6 h at room temperature, the reaction
was complete and afforded 80% of 11a as the single
regioisomer. These high reactivity and selectivity are
similar to that observed in the case of metal salts and
strong Lewis acids.4c
An interesting feature of this method is that the
aliphatic amines such as diethylamine, n-butylamine,
benzylamine, and pyrrolidine failed to effect the ring
opening under the similar reaction conditions even after
4 days at reflux. This is in sharp contrast with ring
opening reactions facilitated with metal salts,4a-e but has
already been observed in the case of Cu(OTf)2-catalyzed
reactions.4f Conversely, when the reaction was carried
out in 2-propanol, without any promotor, no conversion
was observed with aniline, but piperidine, which is more
nucleophilic, underwent reaction to afford the corre-
sponding amino alcohol 12. Even though we do not have
any support for the mechanism, we assume that HFIP
forms an association with nucleophilic amines and de-
activates them toward reaction with the epoxide. In
contrast, in the case of less nucleophilic amines such as
aniline, HFIP activates the epoxide ring probably through
hydrogen bonding. To explore further, the following
experiment was carried out: cyclohexene oxide was
treated with an equimolar mixture of piperidine and
aniline at reflux in HFIP (1 mL). Only product 2a was
formed after 10 h, but the conversion was only 40%. This
Exp er im en ta l Section
Amines and epoxides were obtained from Aldrich Chemical
Co. and used as such. Products were characterized by compari-
son of their physical data with those of known samples. 1H NMR
spectra were performed at 200 MHz with CDCl3 solutions. All
yields refer to isolated products. TLC were performed on 0.25
mm Merck precoated silica plates (60F-254). Compounds 2a -
e,4f 4a -4bc,4f 6a -6bc,4f 8a ,4f 8b,4f 9b,4f 11a ,4c,7 and 128 were
known.
Typ ica l Exp er im en ta l P r oced u r e for Ep oxid e Rin g
Op en in g w ith Ar om a tic Am in es. To a solution of epoxide (1
mmol) in HFIP (1 mL) was added aromatic amine (1.1 mmol).
The solution was kept at reflux under argon atmosphere. The
completion of the reaction was ascertained by GC. At the end of
the reaction, HFIP was recovered by distillation, and the crude
product was purified by column chromatography using 3-5%
EtOAc in petroleum ether.
tr a n s-2-(P h en ylam in o)cycloh exan ol (2a): white solid (0.168
g, 84%); mp: 59-61 °C (lit4f: 58-59 °C); Rf 0.3 (10% EtOAc in
petroleum ether); 1H NMR δ 1.0 (m, 1H), 1.35 (m, 3H), 1.75 (m,
2H), 2.1 (m, 2H), 3.15 (ddd, J ) 10.7, 9.8, 3.8 Hz, 1H), 3.3 (ddd,
J ) 9.9, 9.8, 4.4 Hz, 1H), 6.75 (m, 3H), 7.1 (m, 2H).
tr a n s-2-(N-Meth yl-N-p h en yla m in o)cycloh exa n ol (2b):4f
viscous liquid (0.76 g, 86%); Rf 0.5 (10% EtOAc in petroleum
ether); 1H NMR δ 1.27 (m, 2H), 1.4 (m, 2H), 1.75 (m, 2H), 2.2
(m, 2H), 2.75 (s, 3H), 3.4 (ddd, J ) 10.8, 9.7, 3.7 Hz, 1H), 3.65
(ddd, J ) 10.3, 9.7, 4.7 Hz, 1H), 6.95 (m, 3H), 7.25 (m, 2H).
tr a n s-2-(2-Meth ylp h en yla m in o)cycloh exa n ol (2c):4f liq-
1
uid (0.190 g, 92%); Rf 0.3 (10% EtOAc in petroleum ether); H
NMR δ 1.1 (m, 1H), 1.4 (m, 3H), 1.8 (m, 2H), 2.15 (m, 2H), 2.2
(s, 3H), 3.2 (ddd, J ) 10.9, 9.4, 3.8 Hz, 1H), 3.4 (ddd, J ) 10.5,
9.4, 4.8 Hz, 1H), 6.7 (m, 1H), 6.8 (d, J ) 7.9 Hz, 1 H), 7.1 (m,
2H).
tr a n s-2-(r-Na p h th yla m in o)cycloh exa n ol (2d ): white solid
(0.210 g, 87%); mp: 83-85 °C (lit4f: 84-85 °C); Rf 0.7 (10% EtOAc
Sch em e 3

Notes
J . Org. Chem., Vol. 65, No. 20, 2000 6751
ether); 1H NMR δ 1.6-2.1 (m, 6H), 2.80 (s, 3H), 3.95 (m, 1H),
4.2 (m, 1H), 6.7-6.9 (m, 3H), 7.2 (m, 2H).
Sch em e 4
tr a n s-2-(P h en yla m in o)cycloh ep ta n ol (6a ): white solid
(0.140 g, 70%); mp: 58-60 °C (Lit4f: 59-60 °C); Rf 0.3 (10%
EtOAc in petroleum ether); 1H NMR δ 1.2-1.8 (m, 9H), 2.0 (m,
1H), 3.2 (ddd, J ) 10.6, 9.3, 3.3, 1H), 3.4 (ddd, J ) 9.6, 9.3, 3.6
Hz, 1H), 6.7 (m, 3H), 7.2 (m, 2H).
tr a n s-2-(N-Meth yl-N-p h en yla m in o)cycloh ep ta n ol (6b):
4f colorless liquid (0.147 g, 68%); Rf 0.4 (10% EtOAc in petroleum
1
ether); H NMR δ 1.38-1.80 (m, 9H), 2.1 (m, 1H), 2.74 (s, 3H),
3.5 (ddd, J ) 10.6, 9.3, 2.4, 1H), 3.6 (ddd, J ) 9.5, 9.3, 3.6 Hz,
1H), 6.85-7.0 (m, 3H), 7.26 (m, 2H).
1-(N-m eth yl-N-p h en yla m in o)d od eca n -2-ol (8b):4f colorless
liquid, Rf 0.5 (10% EtOAc in petroleum ether); 1H NMR δ 0.9 (t,
J ) 6.9 Hz, 3H), 1.3 (bs, 16H), 1.5 (m, 2H), 1.57 (m, 1H), 2.9 (s,
3H), 3.2 (m, 2H), 3.9 (m, 1H), 6.75-6.9 (m, 3H), 7.3 (m, 2H).
2-(N-m eth yl-N-p h en yla m in o)d od eca n -1-ol (9b):4f colorless
liquid, Rf 0.45 (10% EtOAc in petroleum ether); 1H NMR δ 0.88
(t, J ) 6.9 Hz, 3H), 1.2 (bs, 17H), 1.5 (m, 1H), 2.7 (s, 3H), 3.6
(m, 2H), 3.95 (m, 1H), 6.7-6.9 (m, 3H), 7.2 (m, 2H).
2-P h en yla m in o-2-p h en ylet h a n ol (11a )7 (reaction per-
formed in trifluoroethanol at room temperature): colorless liquid
(0.115 g, 80%); Rf 0.5 (10% EtOAc in petroleum ether); 1H NMR
δ 3.75 (dd, 1J ) 11.0 Hz, 2J ) 7.0 Hz, 1H), 3.95 (dd, 1J ) 11.0
Hz, 2J ) 4.0 Hz, 1H), 4.5 (dd, 2J ) 7.0 Hz, 2J ) 4.0 Hz, 1H),
6.6-7.4 (m, 10H).
in petroleum ether); 1H NMR δ 1.15 (m, 4H), 1.4 (m, 2H), 1.8
(m, 2H), 2.2 (m, 2H), 3.4 (ddd, J ) 10.9, 9.3, 3.9 Hz, 1H), 3.55
(ddd, J ) 9.6, 9.3, 4.2 Hz, 1H), 6.8 (dd, J ) 6.3, 0.9 Hz, 1H), 7.3
(m, 2H), 7.45 (m, 2H), 7.8 (m, 2H).
tr a n s-2-(4-Meth oxyph en ylam in o)cycloh exan ol (2e): white
solid (0.192 g, 88%); mp: 59-61 °C (lit4f: 58-59 °C); Rf 0.4 (10%
EtOAc in petroleum ether); 1H NMR δ 1.0 (m, 1H), 1.3 (m, 3H),
1.72 (m, 2H), 2.1 (m, 2H), 3.0 (ddd, J ) 10.9, 9.3, 3.8 Hz, 1H),
3.3 (ddd, J ) 9.5, 9.3, 3.9 Hz, 1H), 3.7 (s, 3H), 6.7 (d, J ) 8 Hz,
2H), 6.8 (d, J ) 8 Hz, 2H).
tr a n s-2-(P h en yla m in o)cyclop en ta n ol (4a ): white solid
(0.156 g, 88%); mp: 54-56 °C (lit4f: 54-55 °C); Rf 0.3 (10% EtOAc
in petroleum ether); 1H NMR δ 1.4 (m, 1H), 1.6 (m, 1H), 1.8 (m,
2H), 2.1 (m, 2H), 3.6 (m, 1H), 4.0 (m, 1H), 6.7 (m, 3H), 7.2 (m,
2H).
tr a n s-2-(P ip er id in -1-yl)cycloh exa n ol (12):8 colorless oil
1
(0.150 g, 82%); bp 150-152 °C (1 mmHg, Kugelrohr); H NMR
δ 1.02-1.34 (m, 6H), 1.62-1.84 (m, 8H), 2.12 (m, 1H), 2.12 (m,
1H), 2.48 (ddd, J ) 11.0, 9.5, 3.3 Hz, 1H), 2.54 (m, 2 H), 2.68
(m, 2H), 3.45 (ddd, J ) 9.6, 9.5, 2.8 Hz, 1H).
tr a n s-2-(N-Meth yl-N-p h en yla m in o)cyclop en ta n ol (4b):
Ackn owledgm en t. Financial support from CEFIPRA
and COST D12 action (Group working 98/012) are
gratefully acknowledged. U.D. and V.K. thank CEFIPRA
for a position of research associate. We thank Central
Glass Co. for the generous supply of HFIP.
4f colorless liquid (0.154 g, 81%); Rf 0.4 (10% EtOAc in petroleum
(7) (a) Barluenga, J .; Fananas, F. J .; Yus, M. J . Org. Chem. 1979,
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J O000031C