Soluble polymer-supported synthesis of tertiary amines

Article abstract of DOI:10.1081/SCC-120016315

The synthesis of tertiary amines on a modified soluble polymer, poly(ethylene glycol) (PEG), is described. The PEG-bound quaternary intermediates were assembled via Michael addition reaction, followed by alkylation. Cleavage from the soluble polymer support was induced by insoluble weak basic resin, to afford the target tertiary amines in excellent purity.

Full text of DOI:10.1081/SCC-120016315

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Soluble Polymer-Supported Synthesis of Tertiary
Amines
a
a
a
Zuxing Chen , Guichun Yang & Zhaojun Zhang
a
Faculty of Chemistry and Material Science , Hubei University , Wuhan, Hubei, P.R. China
Published online: 17 Aug 2006.
To cite this article: Zuxing Chen , Guichun Yang & Zhaojun Zhang (2003) Soluble Polymer-Supported Synthesis of Tertiary
Amines, Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry, 33:5,
729-734, DOI: 10.1081/SCC-120016315
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Õ
SYNTHETIC COMMUNICATIONS
Vol. 33, No. 5, pp. 729–734, 2003
Soluble Polymer-Supported Synthesis of
Tertiary Amines
Zuxing Chen,* Guichun Yang, and Zhaojun Zhang
Faculty of Chemistry and Material Science,
Hubei University, Wuhan, Hubei, P.R. China
ABSTRACT
The synthesis of tertiary amines on a modified soluble polymer,
poly(ethylene glycol) (PEG), is described. The PEG-bound quater-
nary intermediates were assembled via Michael addition reaction,
followed by alkylation. Cleavage from the soluble polymer support
was induced by insoluble weak basic resin, to afford the target
tertiary amines in excellent purity.
Key Words: Tertiary amine; Soluble polymer; Support; Synthesis.
*
Correspondence: Zuxing Chen, Faculty of Chemistry and Material Science,
Hubei University, Wuhan, Hubei 430062, P.R. China; Fax: 86 27 8866343;
E-mail: chzux@163.net.
7
29
DOI: 10.1081/SCC-120016315
Copyright & 2003 by Marcel Dekker, Inc.
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com

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7
30
Chen, Yang, and Zhang
It is known that tertiary amines are an extremely important class of
compounds from the drug discovery perspective. Indeed more than a
[
1]
quarter of registered drugs are tertiary amines. Insoluble polymer-
supported synthesis of tertiary amines based on the classical Michael
[
2]
addition and Hofmann elimination reactions has been described.
However, the insoluble polymer hampers routine reaction monitoring.
Hofmann elimination reaction itself requires tertiary amine which
increases the difficulty of removal of the unwanted triethylamine hydro-
bromide or iodide salts and needs long reaction time at high temperature
[3]
in the elimination step.
Organic synthesis on soluble polymer-supports is currently receiving
[4,5]
a great deal of attention
and has the potential to combine the best
aspects of both solid-phase chemistry and solution-phase chemistry.
As a continuation of our efforts to utilize soluble polymer-supported
[
6]
systems in organic synthesis, we now first report in this article the
synthesis of tertiary amines using PEG as soluble polymer-supports,
insoluble weak basic resin I as base and scavengers. The synthetic
route is illustrated in Sch. 1, i.e., utilizing PEG derivatized as the acrylate
ester II. Michael addition reaction of a secondary amine III to II affords
the PEG-bound tertiary amine IV. Quaternization of the tertiary amine
IV with an alkyl halide V to give VI introduces another site of diversity
and activates the linker for cleavage by a facile Hofmann elimination
reaction. During the course of preparing IV and VI, the reaction can
take place homogeneously for II and IV which can dissolve in DMF.
At the end of reactions, precipitation of IV and VI by adding icy-cold dry
Et O (10 folds of the solution) to the solution, filtering and washing the
2
PEG-bound productby icy-cold dry Et O affords IV and VI. TLC (silica
2
gel, acetone/petroleum ether ¼1:4 as eluent) showed that the polymer
contained no secondary amine or alkyl halide. Afterwards, the tertiary
amine VIII was liberated from VI utilizing insoluble weak basic resin I at
Scheme 1.

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Tertiary Amines
731
room temperature and regenerated II. Filtration of the mixture gave
excessive I, VII and a solution of II and VIII in CH Cl . Separation of
II and VIII can be easily realized by precipitating II using icy-cold Et O.
2
2
2
Finally, VIII was obtained in 95–98% purity.
It is worth being mentioned that, in each step of the sequence, the
PEG-bound products were precipitated selectively and the excess low
molecular reagents and the by-products were removed by simple filtration
and were easily detected by TLC which was used to confirm the complete
removal of the reagent in excess and the soluble by-products, the PEG-
bound intermediates were easily analyzed to confirm the structure with
routine analytical methods (UV, IR, H NMR) without following cleave-
[
7]
&
-analyze technique or spectral analyze technique. During the course
[
8]
of preparing II and VIII, use of I as base and scavengers largely
simplified the purification procedure and facilitated spectral analysis of
the PEG-bound products and final products comparing with the reported
methods, in which polar trialkylamine hydrochloride or iodide was
difficult to be disposed of during reaction work-up. Addition of the
mixture of I and VII t o 1 M NaCO in water regenerated I which
2
3
can be reused. II recycled in Hofmann elimination reaction can also be
reused.
Table 1 shows the representative tertiary amines that have been
prepared by this route. The purity of the products is excellent, which
may be due to the fact that only the desired PEG-bound quaternized
amine VI was susceptible to the cleavage conditions by use of the
insoluble weak basic resin. The very low yields (21%, 23%) obtained
for two of the transformations in Table 1 were thought to be owing to
poor quaternization of ethyl bromide.
In conclusion, use of PEG as the soluble polymer support provided a
facile method for the synthesis of tertiary amines. Insoluble weak basic
resin simplified the purification. Further explorations for extending the
application of this method to the synthesis of focused libraries are being
developed and will be reported in due course.
EXPERIMENTAL
All organic solvents were dried by standard methods. All PEG
ꢀ
samples were melted at 80 C in vacuum for 30 min before use to remove
traces of moisture. After reaction, products were purified by evaporation
of the reaction solvent in vacuum, followed by addition of the residue
dissolved in a few of CH Cl t o EtO, stirred and cooled for 20–30 min
2
2
2

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Chen, Yang, and Zhang
Table 1. Synthesis of tertiary amines using PEG as soluble polymer-supports.
1 2
R R NH (III)
3
R X (V)
a
Product (VIII)
b
c
Yield (purity ) (%)
3
R -NEt
H-NEt2
CH3I
65 (97)
21 (95)
70 (98)
2
C
CH
2
H
5
Br
=CHCH Br
2
2
7
8 (97)
CH
3
I
68 (95)
C
2
H
5
Br
23 (97)
74 (95)
CH =CHCH Br
2
2
7
1 (98)
a
The structure of the obtained tertiary amines was confirmed through the IR and
H NMR and also by comparison with authentic samples.
1
b
Crude overall yield calculated based on the capacity of PEG.
Determined by GC.
c
ꢀ
at0 C. The obtained suspension was filtered and the solid was repeatedly
washed with cold Et O. Melting points were determined on an
2
electrothermal melting point apparatus and were uncorrected. GC was
recorded on Shimadzu 16A instrument. IR spectra were recorded using
1
KBr pellets on an IR-Spectrum One (PE). H NMR spectra were
recorded on Brucker Ac-80 instrument using CDCl as solvents and
3
TMS as internal standard.
Preparation of PEG-Bound Acrylate (II)
Dry PEG (4.0 g), insoluble weak basic resin I (8.0 g) [Nankai
University Chemical Corporation, ꢁ4.3 mmol/g], and acryloyl chloride
ꢀ
(1.6 mL, 20 mmol) were stirred in DMF (30 mL) for 5 h at 20 C. Then,
the mixture was filtered under aspirator pressure using a fritted funnel
and washed with DMF (3 ꢂ 5mL). The solution was concentrated in
vacuum and precipitated by adding icy-cold Et O (10 folds of the left
2
solution). The PEG-bound product was then filtered and washed 3 times
with Et O. The crude PEG-bound productwas redissolved, precipi ta te d
once and dried in vacuum to give II.
2

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Tertiary Amines
733
General Procedure for the Preparation of PEG-Bound
Tertiary Amines (IV)
A portion of the PEG-bound product II (2.8 g) was dissolved in a
mixture of DMF (15 mL) and amines III (2.0 mL) and agitated for
ꢀ
overnightat20 C. The solution was precipitated by icy-cold Et O. The
2
polymer was filtered, redissolved in DMF (4 mL), precipitated once and
dried in vacuum to give IV.
General Procedure for the Preparation of PEG-Bound
Quaternary Ammonium Salts (VI)
The PEG-bound product IV (1.9 g) was dissolved in a mixture of
DMF (15 mL) and alkyl halide (16.0 mmol) and agitated for 15 h at
ꢀ
20 C. The solution was precipitated by icy-cold Et O. The polymer was
filtered, redissolved with CH Cl (4 mL), precipitated once and dried in
2
2
2
vacuum to give VI.
General Procedure for the Preparation of
Tertiary Amines (VIII)
The PEG-bound product VI (1.7 g) and resin I (1.0 g, 4.3 mmol) were
ꢀ
added to CH Cl (15 mL) and agitated for 18 h at 20 C. The resin I was
2
2
filtered and washed with CH Cl (3 ꢂ 4mL). The filtrate was concentrated
2
2
and precipitated by addition of icy-cold Et O. The PEG product II
2
was then filtered and washed 3 times with Et O. The polymer was filtered,
2
redissolved in CH Cl (4 mL), precipitated once and dried in vacuum
2
2
for reuse. The crude PEG-bound product II was also redissolved,
precipitated once and dried in vacuum for reuse. The combined filtrate
was dried to afford crude product. The purity of this compound
was determined to be 98% by GC and could be illustrated by IR
1
and H NMR.
ACKNOWLEDGMENT
Financial supports were provided by Education Department of
Hubei Province and Hubei University.

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34
Chen, Yang, and Zhang
REFERENCES
1
2
. This estimate was obtained by searching the World Drugs Index
Derwent Information Ltd.) for compounds with a tradename
containing a tertiary amine group.
(
. Morphy, J.R.; Rankovic, Z.; Rees, D.C. Tetrahedron Lett. 1996, 37,
3209.
3. Cai, J.Q.; Wathey, B. Tetrahedron Lett. 2001, 42, 1383.
4. Parrick, H.Y.; Kim, D.J. Acc. Chem. Res. 2000, 33, 546.
5. Chen, Z.X.; Zhang, Z.J.; Yang, G.C. Chin. J. Org. Chem. 2001, 21, 263.
6. Chen, Z.X.; Yang, G.C.; Zhang, Z.J. Synthesis 2001, 1483.
7. Luo, Y.; Ouyang, X.H.; Robert, W.A. Murphy, M.M. J. Org. Chem.
1998, 63, 8719.
8. Parlow, J.J. Tetrahedron Lett. 1996, 37, 5257.
Received in Japan November 13, 2001