Acetoacetoxy ethyl methacrylate (AAEM) resin, a new scavenger for primary amines in the presence of secondary amines

Article abstract of DOI:10.1016/S0040-4039(00)01590-2

Preliminary results on a new type of polymer scavenger, acetoacetoxy ethyl methacrylate (AAEM) resin, are reported. AAEM resin can selectively remove primary amines in the presence of secondary amines. Its application in a solution library synthesis is demonstrate. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01590-2

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 8963–8967
Acetoacetoxy ethyl methacrylate (AAEM) resin, a new
scavenger for primary amines in the presence of secondary
amines
Zhanru Yu,a Sonia Alesso,a David Pears*,b Paul A. Worthington,c Richard W. A. Luked
and Mark Bradleya,*
aDepartment of Chemistry, University of Southampton, Southampton SO17 1BJ, UK
bAvecia, PO Box 42, Hexagon House, Blackley, Manchester M9 8ZS, UK
cZeneca Agrochemicals, Jealott’s Hill Research Station, Bracknell, Berkshire RG42 6ET, UK
dAstraZeneca Pharmaceuticals, Alderley Park, Macclesfield, Cheshire SK10 4TG, UK
Received 17 July 2000; accepted 14 September 2000
Abstract
Preliminary results on a new type of polymer scavenger, acetoacetoxy ethyl methacrylate (AAEM)
resin, are reported. AAEM resin can selectively remove primary amines in the presence of secondary
amines. Its application in a solution library synthesis is demonstrated. © 2000 Elsevier Science Ltd. All
rights reserved.
Keywords: combinatorial chemistry; reductive alkylation; polymer scavenger; amines.
Over the past few years, the exploration and utilisation of combinatorial chemistry as a
pharmaceutical drug discovery technology has rapidly evolved. The field of combinatorial
chemistry has expanded to include not only solid- and solution-phase methods for expedited
compound synthesis, but also hybrid approaches which combine the purification advantages of
solid-phase synthesis with the flexibility of solution-phase synthesis.1 Inherent in any approach
to produce chemical libraries is the need to rapidly purify, isolate, and manipulate chemical
library members during their preparation. Polymer scavenging reagents2,3 have thus emerged as
useful tools for combinatorial synthesis, specifically, for solution-phase chemical library
synthesis.
Secondary amines are important pharmacophores in many biologically active compounds.
They are often prepared by reductive alkylation of primary amines with aldehydes or ketones,4
although overalkylation readily occurs.5 In order to overcome overalkylation, excess primary
* Corresponding authors.
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01590-2

8964
amine is usually used, thus, generating the problem of how to purify the secondary amine
obtained or to remove selectively the primary amine in the presence of the secondary.
Traditional distillation and chromatographic methods are unsuitable for chemical library
synthesis, and thus it is desirable to develop and use polymer scavenging reagents for selective
removal of the primary amines in the presence of the secondary.
In this area, benzaldehyde resins (Fig. 1, A) have been reported,2 but are not particularly
stable and may be oxidised in air. Herein, we wish to report preliminary results on a new kind
of polymer, acetoacetoxy ethyl methacrylate (AAEM) resin (3.0 mmol/g, available from Avecia
Ltd) (Fig. 1, B) as a scavenger for primary amines in the presence of secondary amines.
Figure 1. Benzaldehyde resin (A) and acetoacetoxy ethyl methacrylate (AAEM) resin (B)
In order to optimise the reaction conditions, two pairs of amines: benzylamine (BnNH2)/N-
benzylmethylamine (BnNHMe) and benzylamine/dibenzylamine were selected as model com-
pounds to test the new AAEM resin. HPLC was used as the analytical tool.6 The two pairs of
amines were treated with AAEM resin in different solvents, 2-propanol (2-PrOH) or tetra-
hydrofuran (THF) at different temperatures.7 The results are shown in Figs. 2 and 3. The
primary amine, benzylamine, was removed at ambient temperature, although the rate of removal
was accelerated at slightly elevated temperature (40°C) (Fig. 2). The secondary amines, N-ben-
zylmethylamine or dibenzylamine showed little loss under the same conditions even at higher
temperature (40°C) (Fig. 3). 2-Propanol was much more effective than tetrahydrofuran. These
results indicated that AAEM resin had high selectivity for the primary amine, benzylamine.
Figure 2. Removal of benzylamine

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Figure 3. Removal of secondary amines
The data in Table 1 show the effect solvent has on the removal of benzylamine from a mixture
of benzylamine and N-benzylmethylamine. Benzylamine could be selectively removed in all the
solvents utilised. 2-Propanol gave much better results than methanol, while a mixture of
2-propanol and tetrahydrofuran or dichloromethane (DCM) gave slightly better purities for the
secondary amine, N-benzylmethylamine.
Table 1
a
Effects of solvent on the removal of BnNH2 from a mixture of BnNHMe/BnNH2
Solvents
Purity (%, HPLC)b
Recovery of BnNHMe (%)
MeOH
MeOH/DCM (1:1)
2-PrOH
2-PrOH/DCM (1:1)
2-PrOH/THF (1:1)
93
95
96
100
100
41
71
72
65
69
a Conditions. Solvent: 4.0 ml; 2 molar equiv. of AAEM resin relative to benzylamine; time: 48 hours; room
temperature; BnNH2/BnNHMe (80 mg/140 mg).
b Ratio of BnNHMe/(BnNHMe+BnNH2).
Having obtained these results, secondary amines were prepared by reductive alkylation, as
shown in Scheme 1.8 Benzaldehyde was selected as the carbonyl component, while the primary
amines used were benzylamine, 2-furylmethylamine, 2-phenylethylamine, 1-naphthylmethyl-
amine, 2,2-diphenylethylamine and diphenylmethylamine. The results obtained are given in
Table 2.

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Scheme 1. (a) 2-PrOH or MeOH, 2 h; (b) 2-PrOH or MeOH, 24 h, Amberlite IRA 400 borohydride resin (2 equiv.);
(c) 2-PrOH/THF or MeOH/CH2Cl2 (1:1, v/v), 36 h, AAEM resin (2 equiv.)
Table 2
Results of reductive alkylation
R1
Solvents
Step ca
Compound
Purity (%)
Yield (%)
Step a+b
Phenyl
2-Furyl
Benzyl
1-Naphthyl
Benzhydryl
Diphenyl
Phenyl
2-Furyl
Benzyl
2-PrOH
2-PrOH
2-PrOH
2-PrOH
2-PrOH
2-PrOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
2-PrOH/THF
3
3
3
3
3
3
4
4
4
4
4
4
100b
100b
100b
100b
98b
60
68
70
56
54
63
81
88
87
72
69
80
2-PrOH/THF
2-PrOH/THF
2-PrOH/THF
2-PrOH/THF
2-PrOH/THF
MeOH/DCM
MeOH/DCM
MeOH/DCM
MeOH/DCM
MeOH/DCM
MeOH/DCM
97b
100c
100b
100c
100b
93b
1-Naphthyl
Benzhydryl
Diphenyl
87b
a Ratio 1/1 (v/v).
1
b Purity obtained by H NMR.
c Purity obtained by HPLC.
Initially, 2-propanol and tetrahydrofuran were used as solvents, benzaldehyde being converted
to the corresponding imines (3) with the primary amines. However, polymer supported
borohydride9 failed to reduce these imines (3) to the corresponding secondary amines; the
starting imines (3) were instead recovered. It is known10 that the rate of reduction of carbonyl
compounds, with sodium borohydride, is solvent dependent with reductions in methanol being
much more rapid than in 2-propanol. Thus, methanol and dichloromethane were chosen as
solvents in the second test. In this solvent system benzaldehyde yielded the corresponding pure
secondary amines (4) by reductive amination, as shown in Scheme 1. It is very interesting that
the polymer supported borohydride showed such high selectivity for imines in these different
solvents.

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In summary, we have shown that the new acetoactoxy ethyl methacrylate (AAEM) resin can
be used as a scavenging reagent for primary amines in the presence of secondary amines. Its
application in library synthesis has been demonstrated.
Acknowledgements
We would like to thank the Royal Society for a university research fellowship (M.B.),
AstraZeneca PLC for a research fellowship SRF (Z.Y.) and a studentship (S.A.) and Avecia Ltd
for supply of resins and technical support.
References
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6. HPLC System: Hewlett Packard Chemstation: HP series 1100. Column: Prodigy 5m ODS3, 150×3 mm,
Phenomenex; UV Detector: 254 nm. Mobile phase: gradient from water (0.1% TFA) to MeCN (0.042% TFA) in
20 min. Flow rate: 0.5 ml/min. Benzylamine (6.9 min), N-benzylmethylamine (7.2 min) and dibenzylamine (9.7
min).
7. Procedure: To a solution of 1.5 mmol of benzylamine and 2.6 mmol of secondary amine (N-benzylmethylamine
or dibenzylamine) in 8.0 ml of solvent (see notes in Figures) was added 1.0 g (3.0 mmol) of AAEM resin at
different temperatures. A sample (10 ml) of the solution was taken from the suspension and diluted to 1.0 ml of
acetonitrile. The sample was analysed by HPLC.
8. Procedure: To a solution of 0.5 mmol of benzaldehyde in 1.5 ml of solvent (2-PrOH or MeOH) was added 0.8
mmol of benzylamine. The resulting solution was shaken for 2 h at room temperature to allow for imine
formation, and then 0.4 g of Amberlite IRA 400 borohydride resin (2.5 mmol NaBH4/g resin, 1.0 mmol) was
added to the solution. The resulting suspension was shaken for 24 h at room temperature. 1.5 ml of solvent (THF
or dichloromethane) was added. 0.2 g of AAEM resin was added to the suspension. The resulting suspension was
shaken for 36 h at room temperature. The resin was filtered off and the solution was evaporated to give the
corresponding products (see Table 2).
9. Amberlite IRA 400 borohydride exchange resin, purchased from Aldrich Chemical Company.
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