Microwave-assisted highly diastereoselective synthesis of oxazolidines derived from ketones and aminoalcohols

Article abstract of DOI:10.1016/j.tetlet.2008.09.063

A number of oxazolidines derived from ketones and aminoalcohols have been prepared in excellent yields using microwave irradiation. In most cases, conventional reflux failed to provide any of the desired products.

Full text of DOI:10.1016/j.tetlet.2008.09.063

Tetrahedron Letters 49 (2008) 6951–6954
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Microwave-assisted highly diastereoselective synthesis of
oxazolidines derived from ketones and aminoalcohols
b
b
Philip C. Bulman Page a, , Genna A. Parkes , Benjamin R. Buckley ,
*
Harry Heaney b, Mostafa Gholizadeh c, J. Steven Wailes d
a School of Chemical Sciences and Pharmacy, University of East Anglia, University Plain, Norwich, Norfolk NR4 7TJ, UK
b Department of Chemistry, Loughborough University, Loughborough, Leicestershire LE11 3TU, UK
c Department of Chemistry, Tarbiat Moallem University of Sabzevar, Sabzevar, Iran
d Syngenta, Jealott’s Hill International Research Centre, Bracknell, Berkshire RG42 6EY, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 28 July 2008
Revised 27 August 2008
Accepted 12 September 2008
Available online 17 September 2008
A number of oxazolidines derived from ketones and aminoalcohols have been prepared in excellent yields
using microwave irradiation. In most cases, conventional reflux failed to provide any of the desired
products.
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
at dC 96–99 ppm and is diagnostic. For example, when pseudoe-
phedrine 1 was treated with isopropyl methyl ketone 2 (1.0 equiv),
The synthesis of oxazolidines derived from aminoalcohols and
aldehydes is well documented, but oxazolidines derived from ke-
tones have only been reported infrequently, presumably as a result
of the slow rate at which they are formed.1 They are also easily
hydrolysed as a result of the additional stabilization of the incipi-
ent iminium ion in the ring-opened tautomer. Recent interest in
the use of oxazolidines as ligands and as organocatalysts,2 coupled
with several ongoing projects in our laboratories, has prompted us
to investigate the synthesis of oxazolidines derived from ketones
and aminoalcohols.3
We have recently reported the use of scandium triflate in the
presence of carefully dried 4 Å molecular sieve to mediate oxazol-
idine synthesis from aminoalcohols and ketones. Reactions were
carried out initially in dichloromethane (DCM) at room tempera-
ture or reflux, and later in 1,2-dichloroethane (DCE) at reflux, and
were monitored by 1H and 13C NMR spectroscopy; the 13C NMR
chemical shift at position 2 in the oxazolidine products is observed
scandium triflate (10 mol %) and molecular sieve, the oxazolidine 3
was formed in almost quantitative yield, and only one diastereo-
isomer could be detected by 1H NMR spectroscopy (Scheme 1);
the stereochemistry was determined by NOE analysis. The reac-
tions were very clean; products were isolated after stirring the
reaction mixtures with anhydrous sodium hydrogen carbonate in
order to remove adventitious protic acid and the Lewis acid.
The use of microwave-assisted reactions has, over the past dec-
ade, increased dramatically, and we have exploited this technology
for Mannich reactions involving tetraalkoxyresorcin[4]arenes.4
Experiments were carried out using a CEM Discover focused micro-
wave apparatus; we observed that reactions could be carried out
with much reduced reaction times and that improved yields and
cleaner products could be obtained. Following this work and
noting the long reaction times required for oxazolidine formation
(ca. 1–14 days),3 we decided to investigate the formation of
oxazolidines from ketones using microwave irradiation.
Sc(OTf)3 (10 Mol%)
4 Å mol sieve
Ph
O
Ph
O
N
CH2Cl2 , r.t., 2 weeks or
C2H4Cl2, reflux 12 h
99% yield; >99:1 dr
NH OH
1
2
3
Scheme 1.
* Corresponding author. Tel.: +44 0 1603 591061; fax: +44 0 1603 593008.
E-mail address: p.page@uea.ac.uk (P. C. Bulman Page).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.09.063

6952
P. C. Bulman Page et al. / Tetrahedron Letters 49 (2008) 6951–6954
Table 1
Screening of various acids for the synthesis of oxazolidines 5 and 6a
Ph
O
Ph
O
Ph
O
Lewis acid
OH
NH
N
N
μw
1
4
5
6
Acid
Temperatureb (°C)
Solvent
Time
d.r. [5:6]c
Yield (%)
Sc(OTf)3
—
83 (reflux)d
100
100
100
100
100
120
100
100
DCE
12 h
5.7:1
—
—
4:1
4:1
—
88
<5
<5
51
Neat
Neat
DCE
2 Â 5 min
2 Â 5 min
2 Â 5 min
2 Â 10 min
30 min
5 min
5 min
5 min
5 min
5 min
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
BF3ÁEt2O
BF3ÁEt2O
TiCl4
Neat
Neat
Neat
Neat
Neat
Neat
Neat
Neat
54
Dec.
Dec.
91e
86e,f
20
—
4:1
4:1
3.1:1
3.4:1
3.3:1
100
100
100
p-TsOH
CSA
75
89
5 min
a
Reaction conditions: pseudoephedrine (1.0 mmol), butan-2-one (1.5 mmol), acid (10 mol %), CEM discover microwave set at a maximum of 300 W with cooling activated.
b
c
d
e
f
Microwave instrument temperature indication except for conventional reflux experiments.
Major diastereoisomer determined by NOE analysis.
Conventional reflux in solution.
Average yield of two runs.
Reaction carried out on a 12 mmol scale.
Table 2
The synthesis of several oxazolidines from ephedrine and pseudoephedrinea
R1
Me
Me
R2
R1
Me
N
R2
N
O
Me
H
OH
R4
R3
(1S,2R)-Ephedrine: R1= Ph, R2 = H
(1S,2S)-Pseudoephedrine : R1= H, R2 = Ph
Ketone
b-Aminoalcohol
Lewis acid
Conditions, temperatureb (°C)
Solvent
Reaction time
d.r.
Yield (%)
Ephedrine
Sc(OTf)3
Sc(OTf)3
BF3ÁEt2O
BF3ÁEt2O
Sc(OTf)3
Sc(OTf)3
BF3ÁEt2O
BF3ÁEt2O
Sc(OTf)3
BF3ÁEt2O
Reflux, 83
DCE
12 h
2:1
2:1
2:1
2:1
5.7:1
4:1
4:1
94
52
38
78
88
51
91
O
Microwave, 100
Microwave, 100
Microwave, 100
Reflux, 83
Microwave, 100
Microwave, 100
Neat
Neat
Neat
DCE
Neat
Neat
2 Â 5 min
5 min
2 Â 5 min
12 h
Pseudo-ephedrine
2 Â 5 min
5 min
O
O
Ephedrine
Pseudo-ephedrine
Microwave, 100
Microwave, 100
Microwave, 100
Neat
Neat
Neat
2 Â 5 min
2 Â 5 min
5 min
2:1
9:1
9:1
67
65
88
Ephedrine
Sc(OTf)3
BF3ÁEt2O
BF3ÁEt2O
Sc(OTf)3
BF3ÁEt2O
Reflux, 83
DCE
Neat
Neat
DCE
Neat
7 d
97:1
95
26
30
96
95
Microwave, 100
Microwave, 100
Reflux, 83
5 min
10 min
2 d
5.6:1
5.6:1
97.5:1
97.5:1
Pseudo-ephedrine
O
O
Microwave, 100
5 min
Ephedrine
Pseudo-Ephedrine
BF3ÁEt2O
Sc(OTf)3
BF3ÁEt2O
Microwave, 100
Reflux, 83
Microwave, 100
Neat
DCE
Neat
2 Â 5 min
2 d
5 min
6:1
97.5:1
97.5:1
54
88
87
Ephedrine
Sc(OTf)3
BF3ÁEt2O
Sc(OTf)3
BF3ÁEt2O
Reflux, 83
Microwave, 80
Reflux, 83
DCE
Neat
DCE
Neat
14 d
10 min
7 d
—
—
97.5:1
5.7:1
NR
NR
55
90
Pseudo-
ephedrine
Microwave, 100
5 min
O
O
Ephedrine
Pseudo-Ephedrine
BF3ÁEt2O
BF3ÁEt2O
Microwave, 100
Microwave, 100
Neat
Neat
2 Â 5 min
3:2
6:1
77
78
5 min
N
Ephedrine
Pseudo-ephedrine
BF3ÁEt2O
BF3ÁEt2O
Microwave, 100
Microwave, 100
Neat
Neat
2 Â 5 min
1.3:1
3.7:1
85
93
5 min
a
Reaction conditions: aminoalcohol (1.0 mmol), ketone (1.5 mmol), acid (10 mol %), CEM Discover Microwave set at a maximum of 300 W with cooling activated.
Microwave instrument temperature indication except for conventional reflux experiments.
b

P. C. Bulman Page et al. / Tetrahedron Letters 49 (2008) 6951–6954
6953
Table 3
The synthesis of several oxazolidines from 1,2,3,4-tetrahydroisoquinolin-3-yl methanol 7a
OH
NH
O
N
R2
R1
7
Ketone
Lewis acid
Conditions, temperatureb (°C)
Solvent
Reaction time
d.r.
Yield (%)
Sc(OTf)3
Sc(OTf)3
BF3ÁEt2O
Reflux, 83
Microwave, 100
Microwave, 100
DCE
Neat
Neat
12 h
1.5:1
1.5:1
1.5:1
42
40
53
O
2 Â 5 min
5 min
O
O
Sc(OTf)3
BF3ÁEt2O
Microwave, 100
Microwave, 100
Neat
Neat
2 Â 5 min
4:1
4:1
51
58
5 min
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
BF3ÁEt2O
BF3ÁEt2O
Reflux
Reflux
DCE,
DCE,
Neat
Neat
Neat
3 d
7 d
10 min
5 min
5 min
11:1
—
11:1
11:1
11:1
43
Dec.
57
25
50
Microwave, 120
Microwave, 100
Microwave, 100 + 4 Å mol sieves
Sc(OTf)3
Sc(OTf)3
BF3ÁEt2O
Reflux
Microwave, 100
Microwave, 100
DCE,
Neat
Neat
3 d
10 min
5 min
20:1
20:1
20:1
33
38
40
O
a
Reaction conditions: 1,2,3,4-tetrahydroisoquinolin-3-yl methanol 7, (1.0 mmol), ketone (1.5 mmol), acid (10 mol %), CEM Discover Microwave set at a maximum of 300 W
with cooling activated.
b
Microwave instrument temperature indication except for conventional reflux experiments.
We initially ran a range of reactions using scandium triflate, as
this Lewis acid had shown the best reaction profile, in terms of
yield and diastereoselectivity, for our previously published process
using classical reflux conditions.3 We were, however, unable to at-
tain the level of yield or diastereoselectivity obtained when using
the scandium triflate/dichloroethane/reflux conditions. We there-
fore screened a range of Lewis and protic acids with the most reac-
tive aminoalcohol and ketone (pseudoephedrine and butan-2-one
4) (Table 1).
We observed that in the absence of acid no oxazolidine was
formed; on addition of Sc(OTf)3, however, we saw a much reduced
reaction time, although we were unable to increase the yield from
54% without decomposition products being formed. A range of
other acids were tested, and BF3ÁEt2O appears to be the catalyst
of choice, affording 91% of the desired oxazolidines 5 and 6 in just
5 min. This is remarkable when considering that reaction times for
the corresponding reaction under classical reflux conditions were
at least 12 h. We were also able to conduct the reaction on a larger
scale (12 mmol) and were delighted to observe similar high yields.
Having established the optimum conditions, we conducted several
further reactions to produce a range of oxazolidines from various
ketones and ephedrine or pseudoephedrine (Table 2).
2. Typical experimental procedure
2.1. (+)-(2S,4S,5S)-2-Isopropyl-5-phenyl-2,3,4-trimethyl-
oxazolidine
Pseudoephedrine (0.50 g, 3.0 mmol) and 3-methylbutanone
(0.26 g, 3.0 mmol) were added to a CEM Discover microwave reac-
tion tube containing a Teflon stirrer bar. The vial was capped,
purged with N2 and BF3ÁEt2O (0.4 mL, 0.3 mmol) was added drop-
wise. The reaction mixture was transferred to the microwave and
irradiated at a fixed temperature of 100 °C for 5 min with cooling
activated. The mixture was diluted with dichloromethane
(5.0 mL) and copper sulfate solution (1.0 mL, 5%), and stirred for
10 min at room temperature. The aqueous phase was extracted
with dichloromethane (10 mL), and the combined organic layers
washed with saturated aqueous Rochelle salt (5.0 mL) and dried
(MgSO4). The solvents were removed under reduced pressure to af-
ford the product as a colourless oil (0.67 g, 95%). [
a]D +39.0 (c 1.00,
CCl4);
m
max (neat)/cmÀ1 3130, 2924, 2761, 1459, 1373, 1326, 1189,
1135; dH (250 MHz; CDCl3) 0.95 (3H, d, J 2.8 Hz), 0.98 (3H, d, J
2.8 Hz), 1.01 (3H, d, J 6.0 Hz), 1.25 (3H, s), 1.70–1.86 (1H, m),
2.20 (3H, s) 2.41–2.50 (1H, m), 4.30 (1H, d, J 8.9 Hz), 7.22–7.40
(5H, m); dC (100 MHz; CDCl3) 7.7, 14.4, 14.6, 33.7, 36.4, 65.1,
85.4, 98.6, 126.2, 126.7, 127.0, 127.7, 140.4; m/z 234.1801;
C15H24NO (M++H) requires 234.1799.
Following our success in the synthesis of oxazolidines from
pseudoephedrine and ephedrine, we next turned our attention to
the synthesis of oxazolidines derived from 1,2,3,4-tetrahydroiso-
quinolin-3-yl methanol 7, as these products would provide
valuable intermediates for other projects within our laboratories
(Table 3).
Acknowledgements
Formation of the oxazolidines from 7 proved more problematic
than from ephedrine or pseudoephedrine. In each case the yield
was slightly improved when using the microwave reactor, but
any further attempts to optimize the system beyond 60% yield
proved unsuccessful. One possible explanation for this arises from
the relative lack of stability of the oxazolidine products.
In summary, we have developed a useful procedure for the
rapid formation of oxazolidines derived from ketones and amino-
alcohols, with reaction times being dramatically reduced when
compared to traditional heating conditions (1–14 days reduced to
10 min). In each case the yield of the reaction was also increased
when using microwave irradiation.
This investigation has enjoyed the support of Loughborough
University, the EPSRC and Syngenta. We also acknowledge the
support of The Royal Society (PCBP: Industry Fellowship). We are
indebted to the EPSRC Mass Spectrometry Unit, Swansea.
References and notes
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Nadelson, J.; Simpson, R.; Smith, H. C. J. Med. Chem. 1998, 41, 4556.

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