Diisopropoxyaluminium trifluoroacetate: A new promoter for aminolysis of epoxides

Article abstract of DOI:10.1055/s-2000-6235

Aminolysis of symmetrical as well as unsymmetrical epoxides using various amines in the presence of diisopropoxyaluminium trifluoroacetate (DIPAT) as a new promoter gave 1,2-amino alcohols in excellent yields at room temperature with good to excellent selectivities.

Full text of DOI:10.1055/s-2000-6235

78
SHORT PAPER
Diisopropoxyaluminium Trifluoroacetate: A New Promoter for Aminolysis of
Epoxides
Sriram Rampalli, Sachin S. Chaudhari, Krishnacharya G. Akamanchi*
Pharmaceuticals and Fine Chemicals Division, Department of Chemical Technology, University of Mumbai, Matunga, Mumbai-400 019.
India
Fax: +91(22)4145614; E-mail: kga@pharma.udct.ernet.in
Received 19 August 1999
Lewis acidity of DIPAT in comparison to aluminium iso-
Abstract: Aminolysis of symmetrical as well as unsymmetrical ep-
propoxide (AIP).
oxides using various amines in the presence of diisopropoxyalumin-
ium trifluoroacetate (DIPAT) as a new promoter gave 1,2-amino
alcohols in excellent yields at room temperature with good to excel-
lent selectivities.
AIP was used as a promoter in epoxide opening reactions
with nucleophiles like azides.7 However, to the best of our
knowledge, it has not been used in epoxide opening with
amines as nucleophiles. Initially, to evaluate AIP as a pro-
moter, we carried out aminolysis of cyclohexene oxide
with diisopropylamine in the presence of AIP. The reac-
tion was extremely slow and remained incomplete (yields:
~38%) even after stirring at room temperature for three
days. This may be attributed to its moderate Lewis acidity
and consequently low oxophilicity. We reasoned that with
increased Lewis acidity, DIPAT could make a better pro-
moter. The above aminolysis reaction was carried out re-
placing AIP with DIPAT. As expected, the reaction
occurred comparatively faster and went to completion
(yields: 84%) in two days at room temperature. To study
generality and selectivities of the reaction, cyclohexene
oxide and styrene oxide were chosen as representative
symmetrical and unsymmetrical epoxides, respectively.
These underwent aminolysis readily with a variety of pri-
mary, benzylic, secondary, and tertiary amines. The re-
sults are summarized in Tables 1 and 2. All reactions were
carried out by the general procedure (experimental).
Key words: diisopropoxyaluminium trifluoroacetate, Lewis acid,
epoxides, 1,2-amino alcohols
Aminolysis of epoxides is becoming a powerful tool in the
field of synthetic organic chemistry.1 1,2-Amino alcohols
constitute an important class of well-known compounds
that has a unique place and importance in natural products
and medicinal chemistry.2,3
Classically, 1,2-amino alcohols were synthesized by ami-
nolysis of epoxides with an excess of amines. This method
has some significant limitations arising out of low nucleo-
philicity, steric factors in the case of sterically bulky
amines, and in some cases low boiling points. The reac-
tions require elevated temperatures, which is not only det-
rimental to certain functional groups, but also to the
control of regioselectivities.4 To obviate these problems,
many varieties of activators/promoters have been devel-
5a
oped and used.5 These include COCl2, Ti(O-i-Pr)4,5b
SmI2,5c basic metal amides,5d SmCl3,5e and metal triflates
such as Sn(OTf)2,5f Cu(OTf)2,5f LiOTf,5g Yb(OTf)3,5h
Ln(OTf)3,5i and Pb4SbOTf.5j Although a wide choice of
promoters is available many are associated with one or
other drawback. These include requirement of an excess
of reagents and reflux temperature, and sluggish reac-
tions. Moreover, a major drawback associated with metal
amides is that the epoxides frequently undergo rearrange-
ment to give allyl alcohols as the major product.5d Primary
amines show almost no regioselectivity in the case of ba-
sic metal amide salts.5d Benzylic and aliphatic amines do
not react under the COCl2 catalysed opening of ep-
oxides.5a Hence, there is a need for newer versatile meth-
ods which could be of great benefit.
Table 1 Aminolysis of Cyclohexene Oxide using DIPAT with
Aminesa
Com-
pound
R1
R2
Time
(h)
Yield
(%)b,c
1a
1b
1c
1d
1e
1f
CH3(CH2)3-
(CH3)3C-
PhCH2-
Ph-
(CH3)2CH-
H
H
H
H
2.5
6
3
80
80
85
85
84
86
88
We have recently reported a new “off the shelf” alkoxide
type reducing agent DIPAT, which can easily be
prepared6a and used. The reagent has dramatically accel-
erated Meerwein−Ponndorf−Verely reduction6a and it is
also effectively used in Oppenauer oxidation in the pres-
ence of a hydride acceptor.6b This enhancement in the re-
activity observed could be attributed to the increased
5
(CH3)2CH-
55
1.1
1
piperidine
morpholine
1g
a All reactions were carried out according to the general procedure.
bYields refer to isolated pure compounds after column chromatogra-
phy (Silica gel, 20% Hexane/EtOAc).
c Structures were confirmed by IR, 1H NMR, mp/bp.
Synthesis 2000, No. 1, 78–80 ISSN 0039-7881 © Thieme Stuttgart · New York

SHORT PAPER
Diisopropoxyaluminium Trifluoroacetate: A New Promoter for Aminolysis of Epoxides
79
Table 2 Aminolysis of Styrene Oxide using DIPAT with Aminesa,b
Com-
pound
R1
R2
RA
RB
Time Yield
(h)
(%)c,d
2a
2b
2c
2d
2e
2f
CH3(CH2)3-
(CH3)3C-
PhCH2-
H
H
H
H
20
30
0
80
1
85
70
100
100
40
53
67
4.5 80
1.5 86
2.5 90
12
1.3 90
Ph-
0
(CH3)2CH-
piperidine
morpholine
(CH3)2CH- 60
80
47
33
2g
1
90
IR spectra were recorded on a single beam Buck Scientific M500 in-
strument in KBr pellets (solids) and CHCl3 or neat (liquids). H
a All reactions were carried out as per the general procedure.
1
b Ratio of the regioisomers were determined from 1H NMR of the
crude mixture.
NMR spectra were recorded on Varian EM360L (200 MHz) and
Brucker AMX (500 MHz) using CDCl3 as solvent and TMS as an
internal standard. MeCN was dried by the standard technique. Mps
and bps were recorded by standard techniques and are uncorrected.
Na2SO4 was used as a drying agent in all workup procedures. The
required epoxides were acquired from local manufacturers.
c Yields refer to the mixture of crude products.
d Structures were confirmed by IR, 1H NMR, mp/bp.
From the results (Table 1) it is evident that aminolysis of
cyclohexene oxide gave exclusively the corresponding Compounds 1a-g and 2a-g; General Procedure
The appropriate epoxide (5.1mmol) was added to a solution of DI-
trans-1,2-amino alcohols in good yields. In all cases, the
reactions were complete within 6 hours, except in the case
of diisopropylamine, a bulky amine, where the reaction
took a longer time (Table 1, 1e).
PAT (1.316 g, 5.1mmol) in 20 mL of MeCN, and the mixture was
stirred for 5 min at r.t. Then, the desired amine (5.1mmol) was add-
ed and stirring was continued at r.t. until the reaction was complete
(monitored by TLC). The reaction was quenched with H2O and the
precipitate was filtered off. The filtrate was subjected to distillation
under reduced pressure to remove MeCN. The viscous mass that re-
mained was diluted with CH2Cl2 (25 mL). The organic layer was
washed with H2O (2 x 15 mL), passed through anhyd Na2SO4 and
the solvent was distilled off to give the respective 1,2-amino alco-
hols. These were further purified by column chromatography (silica
gel, 20% hexane/EtOAc). Physical properties of the 1,2-amino al-
When styrene oxide was used two regioisomers RA and
RB were formed. As expected, the regioselectivity was to-
wards regioisomer RB with all the amines except diisopro-
pylamine. This observed reverse regioselectivity towards
the regioisomer RA with diisopropylamine could be attrib-
uted to steric factors. The bulkier diisopropylamine pref-
erentially attacks the less hindered position of the epoxide cohols thus obtained were in good agreement with reported data.5h,k
Spectral data of some of the representative compounds are given be-
low.
ring. It is noteworthy that the reactions with aniline and
benzylamine gave exclusively one regioisomer. It is re-
trans-2-(N,N-Diisopropylamino)cyclohexanol (1e)
ported that these amines do not show any regioselectivity
in the case of metal salts5d and they do not react at all un-
der COCl2 catalysed aminolysis.5a
Liquid (Lit.,5h liquid), yield: 0.85 g (84%).
IR (neat): ν = 3500−3100 cm-1.
1H NMR (200 MHz, CDCl3): δ = 0.90−2.10 (m, 8H, CH2), 1.06 (m,
12H, CH3), 2.30−2.41 (m, 1H, Ha), 3.00−3.30 (m, 3H, Hb, and CH).
The scope of this reaction was demonstrated through the
synthesis of aryloxypropanolamine type β-blockers tak-
ing atenolol analogue (Scheme) as one example. The re- trans-2-(Benzylamino)cyclohexanol (1c)
Colourless oil (Lit.,5h colourless oil), yield: 0.88 g (85%).
IR (neat): ν = 3500−3100 cm-1.
1H NMR (200 MHz, CDCl3): δ = 1.00−2.40 (m, 8H, CH2), 2.50−
2.80 (m, 1H, Ha), 3.20−3.40 (m, 1H, Hb), 3.90 (d, 1H, J = 11.5 Hz,
benzylic CH2), 4.10 (d, 1H, J = 11.5 Hz, benzylic CH2), 4.50 (br s,
2H, NH, -OH, D2O exch.), 7.20−7.50 (m, 5H ArH).
action was complete within 1.5 hours and gave only 1,2-
amino alcohol 4 from epoxide 3 in good yields (1.17 g,
82%) after purification.
Aminolysis of cyclohexene oxide with benzylamine was
attempted using a catalytic amount of DIPAT (20 mol%).
It was found that the reaction was incomplete (TLC) even
after stirring for 3 days at room temperature.
trans-2-(Morpholin-4-yl)cyclohexanol (1g)
Oily liquid, yield: 0.83 g (88%).
In conclusion, we have demonstrated that DIPAT is an ef-
ficient promoter for aminolysis of epoxides and shows ex-
cellent regioselectivities with a range of amines as
nucleophiles. Moreover, this new methodology appears to
have valuable synthetic applications, which could make
DIPAT a preferred promoter over others, previously de-
scribed.
IR (neat): ν = 3500−3100 cm-1.
1H NMR (200 MHz, CDCl3): δ = 1.20−2.10 (m, 8H, CH2), 2.30−
2.60 (m, 5H, Ha, CH2-N-CH2), 3.00−3.80(m, 5H, Hb, CH2-O-CH2).
2-(Benzylamino)-2-phenylethanol (2c, RB)
Yellow oil, yield: 0.99 g (86%).
IR (CHCl3): ν = 3500−3100 cm-1.
Synthesis 2000, No. 1, 78–80 ISSN 0039-7881 © Thieme Stuttgart · New York

80
S. Rampalli et al.
SHORT PAPER
(3) a) Rich, D. H. J. Med. Chem. 1985, 28, 263.
1H NMR (200 MHz, CDCl3): δ = 2.35 (br s, 2H, NH, OH, D2O
exch.), 3.40−3.95 (m, 5H, Ha, Hb, Hc, benzylic CH2), 7.20−7.40 (m,
10H, ArH).
b) Gorzynski Smith, J. Synthesis 1984, 629.
c) Corey, E. J.; Zhang, F. Angew. Chem. Int. Ed. 1999, 38,
1931.
2-(N-Phenylamino)-2-phenylethanol (2d, RB)
Viscous yellow liquid, yield: 0.98 g (90%).
IR (CHCl3): ν = 3500−3100 cm-1.
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1H NMR (200 MHz, CDCl3): δ = 1.70 (2H, br s., NH and OH, D2O
exch.), 3.70 (dd, 1H, Jba = 6.8 Hz, Jbc = 10.8 Hz, Hb), 3.90 (dd, 1H,
Jca = 4.2 Hz, Jcb = 10.8 Hz, Hc), 4.50 (dd, 1H, Jac = 4.2 Hz, Jab = 6.8
Hz, Ha), 6.50−7.45 (m, 10H, ArH).
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2-[p-2-Hydroxy-3-(n-butylamino) propoxy] phenylacetamide
(4)
Semisolid, yield: 1.17 g (82%).
IR (CHCl3): ν = 3500−3100 cm-1.
1H NMR (500 MHz,DMSO-d6): δ = 0.92 (m, 3H, CH3), 1.28−1.45
(m, 2H, CH2CH3), 1.47−1.52 (m, 2H, CH2CH2CH3), 2.58−2.63 (m,
2H, NH-CH2), 2.72 (dd, 1H, Jba = 12.6 Hz, Jbc = 3.2 Hz, Hb), 2.81
(dd, 1H, Jab = 12.6 Hz, Jac = 5.0 Hz, Ha), 3.55 (s, 2H, CO-CH2-),
3.93−3.98 (m, 2H, OCH2CH), 4.02–4.07 (m, 1H, Ha), 6.13 (br s, 1H,
NH-CH2, D2O exch.), 6.48 (br s, 1H, OH, D2O exch.), 6.90 (m, 2H,
ArH), 7.20 (m, 2H, ArH), 8.10 (br s, 2H, CO-NH2).
Acknowledgement
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We are grateful to DST and UGC, and the Government of India for
fellowships to SR and SSC, respectively.
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Article Identifier:
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Synthesis 2000, No. 1, 78–80 ISSN 0039-7881 © Thieme Stuttgart · New York