A novel traceless solid phase tertiary amine synthesis based on Merrifield resin

Article abstract of DOI:10.1016/S0040-4039(00)02251-6

Substitution of Merrifield resin by a secondary amine gives a resin-bound tertiary amine which is then quaternised with an alkyl halide to provide a resin-bound quaternary ammonium salt. Cleavage of the ammonium salt with morpholine delivers a tertiary am

Full text of DOI:10.1016/S0040-4039(00)02251-6

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 1383–1385
A novel traceless solid phase tertiary amine synthesis based on
Merrifield resin
Jiaqiang Cai* and Bernard Wathey
Lead Discovery Unit, Organon Laboratories Ltd, Newhouse, Lanarkshire ML1 5SH, Scotland, UK
Received 30 October 2000; revised 27 November 2000; accepted 6 December 2000
Abstract—Substitution of Merrifield resin by a secondary amine gives a resin-bound tertiary amine which is then quaternised with
an alkyl halide to provide a resin-bound quaternary ammonium salt. Cleavage of the ammonium salt with morpholine delivers
a tertiary amine in high yield and purity. © 2001 Elsevier Science Ltd. All rights reserved.
Solid phase tertiary amine synthesis has been the sub-
ject of several recent publications.1–10 In our laborato-
ries we have developed the REM linker1,2 for the
production of tertiary amines. This methodology is
based on an addition–quaternisation–elimination se-
quence. Michael addition of a secondary amine to the
resin-bound a,b-unsaturated ester provides a resin-
bound tertiary amine. Quaternisation of the resin-
bound tertiary nitrogen with an excess of an alkyl
halide gives a resin-bound quaternary ammonium salt,
which when treated with a base1,6,7 effects a Hofmann
elimination and provides the desired tertiary amine in
high purity. Although this methodology has been suc-
cessfully applied to the preparation of libraries for
HTS, it has some limitations: firstly, only reactive alkyl
halides, such as methyl iodide, allyl and benzyl bro-
mides, can give a meaningful yield of final product;
secondly, the linker itself is not stable under all reaction
conditions. Several modifications of this method have
been recently published3–7 in an attempt to extend the
utility of this methodology and to overcome some of
these limitations. As part of our effort to develop a
reliable method suitable for making novel combinato-
rial tertiary amine screening libraries, we discovered
that, in solution, quaternary ammonium salts can be
dequaternised with high selectivity by heating in neat
morpholine11 at 110°C. Under these conditions, deben-
zylation and deallylation are highly favoured over
demethylation which itself is much more favoured over
the loss of other alkyl groups, such as n-butyl and
Scheme 1.
Scheme 2. (a) 3.5 equiv. of R1R2NH, 1 equiv. of NaI, N-methylpyrrolidin-2-one (8–10 ml/g resin), 65 h, 100%; (b) 20 equiv. of
R3X, DMF (8 ml/g resin), 58°C,15 60 h, 64–100%; (c) morpholine (8 ml/g resin), 70–110°C, 10–20 h.
Keywords: tertiary amine; traceless linker; solid phase synthesis.
* Corresponding author. E-mail: j.cai@organon.nhe.akzonobel.nl
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)02251-6

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J. Cai, B. Wathey / Tetrahedron Letters 42 (2001) 1383–1385
Table 1. Results from the solid phase tertiary amine synthesis18
3-phenylpropyl (Scheme 1). This selectivity opened up
the possibility for the development of a resin bound
approach to tertiary amine synthesis, particularly as
benzyl was one of the best leaving groups and could be
easily derived from Merrifield resin.
proceeded smoothly, other alkyl iodides were slow at
room temperature. The almost quantitative yield can
only be achieved with heating at 55–60°C for up to 60
hours. Under these conditions, less reactive alkyl
halides, such as 3-phenylpropyl bromide, also give a
useful yield (64–70%). Attempts to increase the yield of
the quaternisation step by raising the temperature to
100°C were found to be detrimental and led to slow
dequaternisation and premature cleavage off the resin.16
The desired dequaternisation and cleavage of the resin-
bound quaternary ammonium salt with morpholine17 at
110°C proceeded very smoothly and delivered the
desired tertiary amine 4 in high purity and very good
overall yield (Table 1). When a lower temperature
(70°C) was used for the dequaternisation reaction, it was
found that the reaction generally requires much longer
reaction times.18
Although several dequaternisation reagents have been
reported,12 we believe that this is the first application of
these conditions to solid phase synthesis. In this letter we
disclose a novel traceless13 methodology for solid phase
tertiary amine synthesis which is based on an SN2–
quaternisation–SN214 reaction sequence (Scheme 2).
The solid phase route starts with high loading Merrifield
resin 1. Substitution of the resin-bound benzylic chlorine
by a secondary amine using sodium iodide as catalyst
afforded a resin-bound tertiary amine 2. Quaternisation
of this resin-bound tertiary nitrogen with an alkyl halide
in DMF gave the resin-bound quaternary ammonium
salt 3. Although the quaternisation with methyl iodide
To demonstrate further the usefulness of this methodol-
ogy, a 3D library of compounds was synthesised in
Scheme 3. (a) 10 equiv. of bisamines, 1 equiv. of NaI, DMF (5 ml/kan), 60 h; (b) 5 equiv. of R2COCl, DCM/pyridine (5:1) (5
ml/kan), rt, 5 h; (c) 20 equiv. of MeI, rt, 60 h; (d) morpholine (4 ml/kan), 100°C, 10 h.
Figure 1. Building blocks.

J. Cai, B. Wathey / Tetrahedron Letters 42 (2001) 1383–1385
1385
Table 2. Results from 3D library
Bisamines (R1)
R2COCl
Yield (%)
Puritya (%)
MWtb (MS)
1
2
3
4
5
6
7
5
5
5
5
6
7
8
9
10
11
12
10
10
10
80
52
70
75
77
6
90
>95
90
>95
>95
90
234 (235 MH+)
273 (273 MH+)
248 (249 MH+)
254 (255 MH+)
287 (287 MH+)
301 (301 MH+)
275 (275 MH+)
59
>95
a Yields are based on purified product by prep-HPLC; purity determined by LC–MS.
b Atomic mass of chlorine was taken as 35.5.
IRORI™ macrokans using the chemistry depicted in
Scheme 3. Four bisamines, four acyl chlorides and one
alkyl halide (Fig. 1) were combined to give a library of
16 compounds. A representative sample of the results
are shown in Table 2.
12. NaTeH (a) Barton, D. H. R.; Fekih, A.; Lusinchi, X.
Tetrahedron Lett. 1985, 26, 6197–6200; Ph3P (b) Ho,
T.-L. Synth. Commun. 1973, 3, 99–100; PrSLi/HMPA (c)
Hutchins, R. O.; Dux, F. J. J. Org. Chem. 1973, 38,
1961–1962; PhSNa (d) Kametani, T.; Kikasawa, K.;
Hiiragi, M.; Wagatsuma, N.; Wakisaka, K. Tetrahedron
Lett. 1969, 35, 635–638; PhSeNa (e) Simanek, V.; Klasek,
A. Tetrahedron Lett. 1969, 35, 3039–3040; lithium tri-
ethylborohydride (f) Cooke, Jr., M. P.; Parlman, R. M. J.
Org. Chem. 1975, 40, 531–532; DABCO (g) Ho, T.-L.
Synthesis 1972, 12, 702; ethanolamine (h) Hunig, S.;
Baron, W. Chem. Ber. 1957, 90, 395–402 and 403–413.
13. This can be regarded as a safety catch method.
14. Quaternisation is also an SN2 reaction. The dequaternisa-
tion might be more complicated than a simple SN2 reac-
tion. For Ph3P as reagent see: Deady, L. W.; Korytsky,
O. L. Tetrahedron Lett. 1979, 5, 451–452.
In conclusion, a novel traceless solid phase tertiary
amine synthesis based on Merrifield resin has been
developed. This method should offer a much more
versatile stable linker that permits a wider range of
functional group transformations to be effected on the
resin. We are currently searching for a high throughput
cleavage method. One possibility is to use a nucle-
ophilic counter-ion such as hydroxide or fluoride in an
assisted solvent free thermal cleavage. The findings
from these studies will be reported in due course.
15. Methyl iodide quaternises at room temperature.
16. Wilson, N. D. V.; Joule, J. A. Tetrahedron 1968, 24,
5493–5497.
Acknowledgements
17. Chosing morpholine for this reaction is due to its ideal
resin swelling property.
We would like to thank ACRN, Newhouse for their
assistance with analysis and R. Morphy and Z.
Rankovic for useful discussion.
18. All tertiary amine products gave satisfactory 400 MHz
1H NMR spectra and LC–MS. A typical experimental
procedure is as follows: Merrifield resin (5 g; 9.55 mmol,
Polymer Laboratories; 1.91 mmol/g) was added to a 100
ml conical flask. N-Methylpyrrolidin-2-one (50 ml) and
sodium iodide (1.5 g; 10 mmol) were added, followed by
1-bis(4-fluorophenyl)methylpiperazine (10 g; 34.7 mmol).
The flask was shaken at rt on an orbital shaker for 65 h.
The resin was cross-washed with MeOH (5×100 ml),
water (5×100 ml), N-methylmorpholine (10% in DCM,
3×100 ml), DCM (5×100 ml), ether (100 ml) and was
dried in vacuo (7.4 g; 100%; equivalent to 1.29 mmol/g).
A portion of the resin (1.0 g; 1.29 mmol) was swollen
with a mixture of DMF (7 ml) and n-butyl iodide (3 ml;
26 mmol) and was heated with slow stirring at 58°C for
60 h. The resin was cross-washed with MeOH (5×10 ml),
DCM (5×10 ml) and ether (10 ml) and dried in vacuo
(1.221 g, calculated yield: 1.237 g; 93%; equivalent to 0.99
mmol/g). A portion of the resin (0.5 g; 0.49 mmol) was
swollen with morpholine (4 ml), and heated at 70°C for
20 h. The resin was washed with MeOH (2×3 ml) and the
filtrate was evaporated. The resulting solid was parti-
tioned between DCM (2 ml) and 5% aqueous sodium
carbonate (2 ml). The organic layer was removed and the
aqueous layer washed with DCM (2×2 ml). The com-
bined organic washings were dried and evaporated to give
125 mg of product (74% for cleavage step; 69% overall
yield based on Merrifield resin; >95% purity).
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