Lanthanide triflate catalysed reactions of acetals with primary amines and cascade cyclisation reactions

Article abstract of DOI:10.1055/s-1998-1734

The formation of imines from acetals and primary amines can be carried out at significantly lower temperatures using scandium or lanthanide triflates as catalysts, than in the absence of a catalyst: the intermediate aminol ethers can also take part in cascade cyclisation reactions, for example using tryptamine and ethyl tryptophanate.

Full text of DOI:10.1055/s-1998-1734

640
LETTERS
SYNLETT
Lanthanide Triflate Catalysed Reactions of Acetals with Primary Amines and Cascade
Cyclisation Reactions
a
a
a
b
Harry Heaney, * Michael T. Simcox, Alexandra M.Z. Slawin, Robert G. Giles
a
Department of Chemistry, Loughborough University, Loughborough, Leicestershire, LE11 3TU
Fax +44 (1509) 223925; E-mail h.heaney@lboro.ac.uk
b
SmithKline Beecham Pharmaceuticals, Old Powder Mills, Leigh, Tonbridge, Kent, TN11 9AN
Received 24 March 1998
Abstract: The formation of imines from acetals and primary amines can
be carried out at significantly lower temperatures using scandium or
lanthanide triflates as catalysts, than in the absence of a catalyst: the
intermediate aminol ethers can also take part in cascade cyclisation
reactions, for example using tryptamine and ethyl tryptophanate.
5 mol% of scandium (III) triflate we obtained the expected imine (2) in
88% yield after purification. In a control experiment we showed that no
imine was formed in the absence of scandium triflate.
The use of Lewis acids to promote imine formation of hindered and
1
unreactive ketones, such as aromatic ketones is well known. Examples
2a
2b
of imine formation catalysed by zinc chloride, thallium acetate and
titanium tetrachloride
2c,d
have all been reported. However, Lewis acid
chlorides have some disadvantages. In addition to being difficult to
handle, they also require the use of more than a stoichiometric amount
of the acid chloride and that requires the disposal of substantial
Scheme 1
3
Thus the reaction shown in Scheme 1 using scandium triflate is truly
catalytic whereas reactions using zinc chloride, thallium acetate and
titanium tetrachloride
acids. Other representative examples of the method are given in the
Table. We note that the new protocol gave a significant improvement in
the yield of the imine derived from benzophenone and (R)-(+)-α-
methylbenzylamine as compared to the 45-60% yields reported using
titanium (IV) chloride. The yield of the product of the reaction of 4-
aminopyridine with benzophenone dimethylacetal was reported to be
quantities of insoluble residues. We observed difficulties in obtaining
2a
2b
reproducible yields of some imines from carbonyl compounds that
carried other potentially reactive functionalities when using established
protocols. The use of rare earth salts, including scandium triflate, has
been developed recently in a number of important synthetic operations
2c,d
require stoichiometric amounts of the Lewis
4
and a number of the mentioned disadvantages are thereby avoided.
5
More recent applications include Friedel-Crafts alkylation reactions,
14
6
Michael reactions, including enantioselective examples, reactions
7
8
involving aldimines, and the formation of enamino esters. Three
component coupling reactions catalysed by rare earth triflates have also
been studied and include reactions of aldehydes, hydroxylamines, and
12c
32% when the two reactants were heated in a sealed tube for 96h. Our
method gave more than double that. We also carried out reactions using
lanthanum, ytterbium, and copper(II) triflates in addition to those
reported below. We conclude that there is little to choose between the
various triflates in the reactions that we studied.
9a
alkenes that result in the formation of isoxazolidines and reactions of
aldehydes, N-benzoylhydrazine and silylenolates that give precursors to
9b
10
pyrazolones. The formation of a number of N-benzylguanidines by
the addition of benzylamine to carbodiimide derivatives and trans
11
acetalisation reactions were both found to be catalysed by scandium
triflate. These transformations suggested the use of lanthanide triflates
in imine formation. We now report herein the use of scandium(III) and
some lanthanide triflates in reactions of acetals with primary and
secondary amines and some cascade reactions of primary amines with
methyl 2-(1,1-dimethoxyethyl)benzoate.
Our initial studies involved imine formation from ketones and primary
amines using scandium triflate (5 mol%) in toluene where the water was
removed by azeotropic distillation. Whereas benzylamine gave the
imine with benzophenone in 67% yield after purification, a number of
other reactions gave the products in disappointing yields. Reports that
imines can be prepared from acetals have been published over a long
12
period of time. The yields varied from poor to very good (10-95%) but
it was invariably found that temperatures in the region of 180-200 °C
were required to effect the transformation.
We presumed that the reactions proceed via aminol ethers that result
from the capture of methoxycarbenium ions by the primary amines and
therefore that the reactions could be adapted to take part in a cascade
sequence leading to isoindoloisoquinoline derivatives. Although the
conversion of 2-acetylbenzoic acid into its methyl ester gives almost
We prepared the range of dimethyl acetals of ketones that we required in
excellent yields using methyl orthoformate adsorbed on montmorillonite
clay K-10. Although the efficiency of scandium triflate is not reduced
by the presence of alcohols we carried out reactions of primary amines
under Dean-Stark conditions with 4 Å molecular sieves in the trap. We
found that when a solution of benzylamine and benzophenone dimethyl-
acetal (1) were heated under reflux for 16h in toluene in the presence of
13
15
quantitative yields using diazomethane, conventional Fischer-Speier
procedures were reported to give mixtures that were not separated but in
16
which the pseudo-acid predominated. In our hands, using methanol

June 1998
SYNLETT
641
Scheme 2
and sulfuric acid, we obtained the pseudo ester in 65% yield together
with methyl 2-acetylbenzoate in 29% yield after separation using flash
chromatography. However, we found that when the dry potassium salt
from 2-acetylbenzoic acid was dissolved in DMSO and methylated with
methyl iodide, methyl 2-acetylbenzoate was isolable in 86% yield.
Conversion into the related dimethyl acetal, methyl 2-(1,1-
dimethoxyethyl)benzoate (3) was achieved in 78% yield by using the
methyl orthoformate - montmorillonite clay K-10 method.
In an experiment using acetal 3 together with 3,4-dimethoxy-β-
phenylethylamine we obtained the anticipated cascade product 6 in 54%
yield together with 3-methyleneisoindol-1-one derivative 7 in 16%
yield. It is possible in this case that the compound 7 is an intermediate
involved in the cascade sequence. We found that when the compound 7
was heated under reflux in xylene for 16h in the presence of 10 mol% of
scandium triflate we isolated the compound 6 in 81% yield. As
expected, replacement of the more nucleophilic arylethylamines by β-
phenylethylamine did not lead to the final cascade product in the
presence of scandium triflate; the product 8 was isolated in 75% yield.
On the other hand the final cyclisation product 9 was obtained in 67%
yield when the 3-methyleneisoindol-1-one 8 was heated in the presence
of orthophosphoric acid.
We had previously shown that imines derived from methyl 2-formyl-
benzoate undergo base catalysed rearrangement reactions that lead to
acyliminium ion precursors and hence cyclised to isoindoloisoquinoline
17
derivatives, for example using titanium tetrachloride. We argued that
acetals derived from esters of 2-acylbenzoic acids should undergo
cascade sequences with suitable primary amines in the presence of mild
Lewis acids. We therefore heated a solution of tryptamine and acetal 3
in toluene for 16 h in the presence 10 mol% of scandium triflate and 4Å
18
molecular sieves. We isolated the β-carboline derivative 4 in 91%
yield, presumably as a result of the sequence of reactions shown in
Scheme 2. Although the ethyl ester of tryptophane is less basic than
tryptamine we investigated the reaction with the acetal 3. The compound
5 which was isolated as a single diastereomer in 36% yield. In one
experiment methyl 2-acetylbenzoate was also recovered in 48% yield
after an aqueous work-up. An X-ray crystal structure determination
showed that both the ethyl ester and methyl groups occupy axial
Typical Experimental Procedure
Trimethyl orthoformate (5 ml, 46 mmol), montmorillonite clay K-10
(3g), and methyl 2-acetylbenzoate (1.5g, 8 mmol) gave, after stirring for
16 h, methyl 2-(1,1-dimethoxyethyl)benzoate (3) (1.48g 78%) as a
19
positions on the same face of the molecule.
20
colourless oil. Scandium triflate (0.12g, 0.25 mmol) was added to a
solution of methyl 2-(1,1-dimethoxyethyl)benzoate (0.56g, 2.5 mmol)
and 3,4-dimethoxy-β-phenylethylamine (0.45g, 2.5 mmol) in xylene (30
ml). The reaction mixture was heated under reflux using a Dean-Stark
trap containing activated molecular sieves (4Å) for 16 h, filtered and the
solvent evaporated under reduced pressure. Chromatography on silica
gel, eluting with ethyl acetate : light petroleum (2 : 1), gave the
21
22
compounds 6 (0.415g, 54%), a yellow solid, m.p. 197-200 °C, and 7
(0.12g, 16%), a pale yellow solid, m.p. 138-141 °C.
Acknowledgements. We thank the EPSRC and SmithKline Beecham
for a CASE award (to MTS) .

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LETTERS
SYNLETT
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3
2
2
55.8 (OMe), 56.3 (OMe), 63.6 (C), 109.5 (CH), 112.0 (CH), 122.2
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7
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