Highly regioselective microwave-assisted synthesis of enantiopure C3-symmetric trialkanolamines

Article abstract of DOI:10.1016/S0040-4039(02)00306-4

Enantiopure, C₃-symmetric trialkanolamines can be efficiently and rapidly obtained on a gram scale via one pot or step-wise microwave-assisted epoxide ring opening with ammonia in high yields (up to 89%) and regioselectivity up to 100%.

Full text of DOI:10.1016/S0040-4039(02)00306-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 2581–2584
Highly regioselective microwave-assisted synthesis of enantiopure
C -symmetric trialkanolamines
3
a
b
a,
Laura Favretto, William A. Nugent and Giulia Licini *
a
Universit a` di Padova, Dipartimento di Chimica Organica, CMRO del CNR, via Marzolo 1, 35131 Padova, Italy
b
Bristol-Myers Squibb Pharma Co., P.O. Box 269, Deepwater, NJ 08023, USA
Received 17 January 2002; revised 11 February 2002; accepted 13 February 2002
Abstract—Enantiopure, C -symmetric trialkanolamines can be efficiently and rapidly obtained on a gram scale via one pot or
3
step-wise microwave-assisted epoxide ring opening with ammonia in high yields (up to 89%) and regioselectivity up to 100%.
©
2002 Elsevier Science Ltd. All rights reserved.
The discovery of new stereoselective catalytic processes
is a major task in chemistry and this is a field under
continuous development. In this context chiral ligands
process and complete conversion into the products can
be obtained only after 4–6 days at 50–60°C. The reac-
tion occurs with complete control of the regiochemistry
when alkyl epoxides are employed, while with aryl
epoxides (e.g. styrene oxide) the regioselectivity
decreases significantly and at least two of the four
possible regioisomers are obtained. In the case of 1b,
chromatographic separation of the products is required.
1
play a major role and many efforts have been made for
2
finding new families of chiral ligands, both via rational
3
4
ligand design and via combinatorial screening. How-
ever, despite the intrinsic behavior of a specific ligand,
its availability via simple, efficient and highly selective
procedures is a necessary condition for its practical use.
Therefore, the development of efficient syntheses of
enantiopure ligands is of fundamental importance in
stereoselective catalysis.
The chromatography is not straightforward and further
crystallizations are needed to obtain the pure homochi-
9
ral ligands with an 18–40% yield in purified product.
In order to have the trialkanolamines more easily avail-
able we decided to further investigate their synthesis.
An improved trialkanolamine preparation must over-
come two major problems: (1) the intrinsic low reactiv-
ity of ammonia as nucleophile; and (2) the limited
regioselectivity of the nucleophilic attack of the amines
on 2-aryl epoxides (e.g. styrene oxide). Both problems
are expected to become less critical as the reaction
proceeds due to the increasing reactivity of the nucleo-
phile as well increasing steric hindrance along the series
Recently we reported a new class of Ti(IV) and Zr(IV)/
C trialkanolamine complexes that efficiently catalyze
3
stereoselective processes such as meso-epoxide ring
5
6
opening, halohydrin synthesis and sulfoxidation of
7
,8
aryl alkyl sulfides. The trialkanolamine ligands 1 are
obtained via stereospecific ring opening of enantiopure
epoxides by anhydrous ammonia (Scheme 1). Nucleo-
10
9
philic attack of ammonia on the epoxides is a slow
NH <NH R<NHR . Consequently, the first addition
step (addition of ammonia to the epoxide) is the most
critical.
R
1a R=Me (73%)
1b R=Ph (18-40%)
1c R=t-Bu (83%)
3
3
2
2
O
MeOH
+
NH3
N
OH
r.t. 1 day;
0°-60°C, 6 days
R
5
Here we report that microwave (MW) induced heating
can be effectively used for the synthesis of enantiopure
C trialkanolamines. Compared with traditional heat-
3
Scheme 1. Stereospecific synthesis of enantiopure trialka-
nolamines.
ing, much faster reactions (one-three hours versus six
days) could be obtained affording high yields of prod-
ucts. Furthermore, a significant increase of the regiose-
lectivity in the synthesis of (R,R,R)-tris(2-phenyl)-
ethanolamine 1b was obtained allowing a considerable
Keywords: enantiopure trialkanolamines; chiral ligands; microwaves;
microwave assisted synthesis; epoxide ring opening.
*
Corresponding author. Tel.: +39 049 8275289; fax: +39 049 827
239; e-mail: giulia.licini@unipd.it
5
0
040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00306-4

2
582
L. Fa6retto et al. / Tetrahedron Letters 43 (2002) 2581–2584
enhancement of the chemical yields together with a
much easier purification procedure.
(ethyl acetate: toluene 20:80) afforded (R,R,R)-1b in
43% yield. In the previously reported procedure,
(
R,R,R)-1b could be obtained in yields up to 40 only
9
Reactions of dry ammonia in methanol (2.0 M) with
three equiv. of (S)-propylene oxide or (R)-styrene oxide
were performed in closed Teflon reactors at 130°C upon
irradiation with microwaves (240 W). Microwave irra-
diation has been applied with success in organic synthe-
sis because reaction rates can be greatly increased by
after more than one chromatographic separation.
Therefore, notwithstanding the formation of solvolysis
products, a significant improvement in the regioselectiv-
ities and purification procedure of the desired C tri-
alkanolamine (R,R,R)-1b were obtained also in this
3
case (Table 1, entries 3 and 4).
11
heating induced by microwaves.
As far as the preparation of (R,R,R)-1b is concerned, a
very noticeable improvement could be obtained per-
forming the synthesis step-wise (Scheme 2).
Addition of ammonia to (S)-propylene oxide was com-
12
plete after only 90 min. Not only was reaction time
diminished compared with the standard procedure, but
also ligand 1a was obtained as a single regioisomer in
higher yields (92%, 89% after crystallization from tolu-
ene, Table 1, entries 1 and 2). Reaction with styrene
oxide required longer reaction times for completion (3
hours). Compared with the reaction of (S)-propylene-
oxide, much lower regioselectivities were obtained
In order to stop the synthesis at the level of amino
alcohols, despite the increased nucleophilicity of the
amines produced, the reactions were performed in
ammonium hydroxide (28% in water) in large excess
12
using microwave induced heating (Table 2).
[
(R,R,R)-1b: (R,R,S)-3b=58:42] and in addition to the
In fact, a similar approach was recently used in the
vinyl epoxide ring opening by ammonium hydroxide
with subsequent acceleration of the reaction and
decreasing of production of side products. The reac-
tion performed under conditions comparable to the one
trialkanolamines, two other products derived from
solvolysis of (R)-styrene-oxide were also recovered:
1
3
(
R)-2-methoxy-1-phenylethanol
4b
and
(S)-2-
14
15
methoxy-2-phenylethanol 5b
(20%, 41:59 ratio).
Purification via flash chromatography over silica gel
Table 1. One pot microwave-assisted synthesis of enantiopure (S,S,S)-triisopropanolamine 1a and (R,R,R)-tris(2-phenyl)-
a
ethanol amine 1b
R
OH
OH
HO
+
HO
R
MeO
R
O
MeOH, MW HO
N
R
R
NH3 + 3
N
+
+
o
R
1
30 C
R
R
OMe
OH
R
OH
OH
(
(
S)-2a R=Me
R)-2b R=Ph
1
3
4
5
Yield,%b
D.e. (1), %
c
1:3:4:5d
Yields (1), %
e
Ref.
Entry
Substrate
R
Temperature
time)
Pressure (bar)
(
f
1
2
(S)-2a
(S)-2a
Me 130°C (90 min)
Me r.t. (1 day) then
7
–
92
98
97
94
\100:1:1:1
\100:1:1:1
89
72
9
5
0°C (5 days)
f
3
4
(R)-2b
(R)-2b
Ph
Ph
130°C (180 min)
r.t. (15 h) then
4
–
80
n.d.
n.d.
n.d.
46:34:8:12
n.d.
43
18–40
9
60°C (5 days)
a
Reaction conditions: see Ref. 12.
b
c
Yields in trialkanolamines after removal of the solvent, without further purification.
D.e. of (S,S,S)-1a over (R,S,S)-1a were determined on the crude reaction product via 13C NMR as described in Ref. 9. The amount of
diastereoselection observed depends on the enantiopurity of the reagent (S)-2a.
d
e
Determined via 1H NMR on the reaction mixture.
Yields after purification [(S,S,S)-1a crystallization (toluene), (R,R,R)-1b chromatography (silica gel, ethyl acetate: toluene: triethylamine=
2
0:80:5)].
f
Present work.
(
R)-Styrene oxide
(2 equiv, 4.0M)
O
NH4OH, 130°C
OH
(R,R,R)-1b
NH2
Ph
MW, 13 min
Ph
MeOH, 130°C,
MW, 35 min
(R)-6
Scheme 2. Stereospecific step-wise synthesis of (R,R,R)-tris(2-phenyl)ethanolamine 1b.

L. Fa6retto et al. / Tetrahedron Letters 43 (2002) 2581–2584
2583
a
Table 2. Microwave-assisted synthesis of (R)-2-amino-1-phenylethanol 6 and (S)-2-amino-2-phenylethanol 7
OH
NH2
O
MW
+
NH4OH
NH2
+
OH
1
30°C Ph
Ph
Ph
(R)-2b
(R)-6
(S)-7
b
Yields, %c
d
d
Entry
[2b], M
[NH OH]/[2b]
Solvent
Pressure, bar
Ratio 6:7
(R)-6, %
(S)-7, %
4
1
2
3
4
5
6
7
0.03
0.10
0.17
0.27
0.68
0.36
0.18
430
143
86
54
21
–
–
–
–
–
12
12
12
12
12
12
12
80:20
80:20
80:20
77:23
75:25
81:19
91:9
\98
\98
\98
97
92
\98
\98
–
80
–
–
20
–
–
–
48
60
74
11
11
7
21
25
Dioxane (45%)
Dioxane (68%)
a
Reaction conditions: see Ref. 12.
b
c
Determined via 1H NMR on the reaction mixture.
After filtration and solvent removal.
After chromatography (silica gel, ethyl acetate:methanol:triethylamine=12:2:1).
d
1
5
reported in the literature for vinyl epoxides afforded
the two-regioisomeric alcohols (R)-6 and (S)-7 in good
ratio (80:20) and in quantitative yield, (Table 2, entry
6 and 7). Indeed no decomposition of the starting
material was observed anymore and the formation of
products of further substitution was also minimized.
Under the condition reported in entry 7 a regioisomeric
ratio of 91:9 was obtained and amino alcohol (R)-6 was
1
2
1
). Because of the very diluted reaction conditions
and the high cost of ammonium hydroxide, more con-
centrated solutions of styrene oxide were also tested.
17
obtained in 74% yield after chromatography.
Comparable results were obtained up to [(R)-2b] =0.17
o
M, while at higher concentrations (up to 0.68 M, Table
The addition of amino alcohol (R)-6 to (R)-styrene
oxide was then studied. The influence of the concentra-
tion of the reagents and the nature of the solvent were
explored and the reactions were performed under
microwave induced heating also in this case (Table 3).
Only the reactions performed in methanol and iso-
propanol yielded to products (Table 3, entries 1–5) and
two of the three possible regioisomers were obtained. In
this case the purification of the products was particu-
larly easy and the two regioisomeric trialkanolamines
1b and 3b could be separated in a quantitative way by
2, entry 5) a decrease of the regioselectivities (75:25)
and amino diol yields (59%) was observed. The lower
efficiency of the system originates from the formation
of higher substitution products (amino diols) and from
16
a partial decomposition of the reagent/products. In
order to verify if the decomposition was due to hetero-
geneous nature of the reaction mixture because styrene
oxide is poorly soluble in ammonium hydroxide at such
high concentrations, increasing amounts of dioxane
were added to homogenize the system (Table 2, entries
a
Table 3. Microwave-assisted synthesis of (R,R,R)-tris(2-phenyl)ethanolamine 1b
Ph
OH
OH
HO
Ph
HO
+
HO
Ph
MeO
O
MW
HO
N
Ph
Ph
+
2
N
+
+
Ph
o
Ph
NH2
130 C
Ph
Ph
OMe Ph
OH
OH
OH
(R,R,R)-1b
(R)-6 b
(R,R,S)-3b
(R)-4b
(S)-5b
b
c
c
c
Entry
Solvent
[(R)-6], M
Time, min
Pressure, bar
Ratio 1b:3b
(R,R,R)-1b, %
(R,R,S)-3b, %
4b+5b, %
1
2
3
4
5
6
7
8
MeOH
MeOH
MeOH
i-PrOH
i-PrOH
t-BuOH
0.07
0.16
2.00
0.16
2.00
0.16
0.16
0.16
95
95
35
155
125
35
100
63
5
5
5
3
3
6
2
3
89:11
92:08
80:20
80:20
73:27
–
55
67
80
73
72
–
7
6
20
21
27
–
39
28
0
–
–
–
–
–
CH CN
–
–
–
–
–
–
3
THF
a
Reaction conditions: see Refs 12 and 17.
b
c
Determined via 1H NMR on the reaction mixture.
After chromatography (silica gel, ethyl acetate:toluene:triethylamine=20:80:5).

2
584
L. Fa6retto et al. / Tetrahedron Letters 43 (2002) 2581–2584
flash chromatography over silica gel (eluent toluene:
ethyl acetate: triethylamine=80:20:5).
2. Brunner, H.; Zettlmeier, W. Handbook of Enantioselective
Catalysis with Transition Metal Compounds; VCH: Wein-
heim, 1993; Vol. II.
The reactions performed in methanol (the solvent nor-
mally used in the one pot trialkanolamine synthesis)
afforded the products in very short reaction times (30–
3. Reetz, M. T. Angew. Chem. Int. Ed. 2001, 40, 284 and
reference cited therein.
4. Trost, B. M. Acc. Chem. Res. 1996, 29, 355.
5. Nugent, W. A. J. Am. Chem. Soc. 1992, 114, 2768.
90 min) and with very good regioselectivities (Table 3,
entries 1–3). The results reported indicate that the
concentration of the reagents plays an important role.
In fact the reactions performed at lower substrate con-
centrations (Table 3, entries 1 and 2) besides the tri-
alkanolamines 1b and 3b afforded also the solvolysis
products (R)-4 and (S)-5. However, at higher reagent
concentration (2.0 M) the solvent does not compete in
the nucleophilic attack and (R,R,R)-1 could be
obtained in high yield (80%) and a good regioisomeric
ratio: (R,R,R)-1: (R,R,S)-3=80:20.
6
7
. Nugent, W. A. J. Am. Chem. Soc. 1998, 120, 7139.
. Di Furia, F.; Licini, G.; Modena, G.; Motterle, R.;
Nugent, W. A. J. Org. Chem. 1996, 61, 5175.
. Bonchio, M.; Licini, G.; Di Furia, F.; Mantovani, S.;
Modena, G.; Nugent, W. A. J. Org. Chem. 1999, 64,
8
1
326.
. Nugent, W. A.; Harlow, R. L. J. Am. Chem. Soc. 1994,
16, 6142.
0. An improved synthetic procedure for the synthesis of
R,R,R)-tris(2-phenyl)ethanolamine 1b was particularly
9
1
1
(
necessary because this is the ligand that affords the best
performances in the Ti(IV) and Zr(IV) catalyzed stereose-
lective sulfoxidations (Refs 7 and 8).
In order to overcome problems due to the solvolysis,
the use of other, less nucleophilic solvents was also
examined. The reactions performed in isopropanol
afforded high yields of trialkanolamines but with lower
regioisomeric ratio and required longer reaction times
1
1. (a) Mingos, D. M. P.; Baghurst, D. R. Chem. Soc. Rev.
1991, 20, 1; (b) Caddick, S. Tetrahedron 1995, 51, 10403;
(
c) Varma, R. S. Green Chemistry 1999, 1, 43.
(
Table 3, entries 4 and 5). Use of tert-butanol as
1
2. The reactions were performed by placing the reagents in
the solvent of choice (10 ml total volume) in a close
reactor (HPR-1000/10S, Milestone) equipped with pres-
sure and temperature control units and irradiating inside
the cavity of a MW Ethos-1600 Lab Station (Milestone)
accordingly with the following parameters: initial power,
solvent resulted in extensive decomposition of the reac-
tion mixture while acetonitrile and THF did not afford
any products and the starting materials were quantita-
tively recovered.
In conclusion an improved protocol for the regioselec-
300 W, 5 min; final power 240 W; Tmax=130°C. After
tive and stereospecific synthesis of enantiopure, C -sym-
3
cooling the reaction to r.t., the solvent was removed
under vacuum and the products were purified by chro-
matography or crystallization. Reactions could be run on
metric (S,S,S)-triisopropanolamine 1a and (R,R,R)-
tris(2-phenyl)-ethanol amine 1b has been developed.
Compared with the previous procedure the new method
affords much faster reactions and higher chemical
yields and regioselections allowing an easy preparation
of the derivatives in multi-gram scale.
2.0 M scale on up to six reactors at the same time,
allowing the synthesis of 0.03 mol of ligand. All the
products gave satisfactory analytical data.
1
1
1
1
3. Terfort, A.; Brunner, H. J. Chem. Soc., Perkin Trans. 1
1
996, 1467.
4. Moberg, C.; R a` kos, L.; Tottie, L. Tetrahedron Lett. 1992,
3, 2191.
Acknowledgements
3
5. Lindstr o¨ m, U. M.; Olofsson, B.; Somfai, P. Tetrahedron
Lett. 1999, 40, 9273.
This work was supported by the University of Padova
Progetti di Ateneo 1999, CNR and DuPont Aid to
Education program. It was carried out under the aegis
of COST, Action D12 (D12/0018/98). We thank Dr.
Francesca Santin for preliminary experiments.
6. After running the reaction under the same conditions, in
the colorless reaction solution the presence of dark flakes
was detected. After filtration, the usual work up was used
for the isolation and purification of the products.
7. The two amino alcohols can be easily and quantitatively
separated by flash chromatography on silica gel (eluent:
ethyl acetate: methanol: triethylamine=12:2:1) after
removal of the solvent under vacuum. Recently (R)-6
became also commercially available.
1
References
1. Ojima, I. Catalytic Asymmetric Synthesis; Wiley-VCH:
New York, 2000.