PS-IIDQ: An efficient polymer-supported amide coupling reagent

Article abstract of DOI:10.1039/b414889d

Polystyrene-IIDQ is a polymer-supported coupling reagent that couples carboxylic acids to amines in good yields and high purity without the requirement of a pre-activation step. Importantly the order of addition of the amine, acid or coupling agent makes no difference to the efficiency of the coupling reaction and the reagent can be readily regenerated. The Royal Society of Chemistry 2005.

Full text of DOI:10.1039/b414889d

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PS-IIDQ: an efficient polymer-supported amide coupling reagent
Eric Valeur and Mark Bradley*
Received (in Cambridge, UK) 27th September 2004, Accepted 19th November 2004
First published as an Advance Article on the web 17th January 2005
DOI: 10.1039/b414889d
addition of isobutanol yielding the expected PS-IIDQ.{ The
presence of a tertiary amine base was essential as the reaction failed
in the presence of K2CO3 or NaHCO3, while organic bases such as
pyridine did not work.
Polystyrene-IIDQ is a polymer-supported coupling reagent that
couples carboxylic acids to amines in good yields and high
purity without the requirement of a pre-activation step.
Importantly the order of addition of the amine, acid or
coupling agent makes no difference to the efficiency of the
coupling reaction and the reagent can be readily regenerated.
The MAS-1H NMR spectra of polymer supported quinoline
(Fig. 1b) and the supported IIDQ (Fig. 1c) were compared to the
1H NMR spectra of IIDQ (Fig. 1a). 1H–1H COSY spectra
confirmed the correlation between the protons H-12 (and H-16)
and the proton H-13 (and H-17 respectively) of the supported
IIDQ and clearly showed that polymer-supported quinoline and
polymer-supported IIDQ were successfully synthesised. This was
confirmed by the characteristic absorption band of the carbamate
moiety in the IR spectra at 1709 cm21. The loading of the resin
obtained was evaluated by coupling benzylamine to phenylacetic
Many coupling reagents have been reported since the 1960’s and
used with varying degrees of success.1 Classical methods using a
variety of carbodiimides have been supplemented with a range of
additives such as HOBt2 and HOAt,3 which enhance coupling
efficiency and reduce racemisation. Newer reagents are often based
on these additives and uronium or phosphonium salts, and include
PyAOP,4 PyBOP,5 HATU,6 HBTU.7 Some work very efficiently
with unhindered substrates but many have issues with stability,8
and many of these newer agents give unwanted guanidinium
species. Other coupling reagents such as those based on the
generation of acid chlorides or bromides have therefore been
synthesised such as PyBroP9 or BOP-Cl10 but have the major
drawback of giving high racemisation rates. Recently some
coupling agents have been made available on solid supports,
including a number of supported carbodiimides.11 Reagents such
as polymer supported TBTU have also been attached to the resin
via resin immobilised HOBt,12 although the mode of action of
these coupling agents means that by-products from the coupling
agent will end up in solution. Other coupling agents can be used
and include reagents which generate mixed anhydrides as the
active coupling species. Among this family of coupling reagent is
acid and the isolated yield gave a loading of 1.6 mmol g21
,
corresponding to a conversion of 86% from Merrifield resin into
the polymer-supported IIDQ.
The coupling conditions for PS-IIDQ were first optimised by
coupling benzylamine to phenylacetic acid and DCM gave the best
results. However the choice of DCM was not optimal because too
many carboxylic acids were not soluble in this solvent and it was
too volatile for parallel synthesis use and thus acetonitrile was
chosen. Only 2 equiv. of PS-IIDQ were necessary to ensure high
conversion and an excessive coupling time of 24 h was used in
order to enable difficult substrates to react. This contrasts with
many coupling reagents, which although often having a very high
intrinsic reactivity are unstable in solution, with most of the
reagent (or active HOBt ester) having degraded after an hour, a
characteristic which is unsuitable for hindered substrates or if the
coupling is slow. Considering this problem, PS-IIDQ offers a good
balance between reactivity and stability.
IIDQ
(2-isobutoxy-1-isobutoxycarbonyl-1,2-dihydroquinoline)
which has long been used in solution-phase synthesis,13 although
it has seen limited use in parallel synthesis. IIDQ however has
several advantages over other coupling agents that include: the
order of addition of the amine, acid and IIDQ makes no difference
to the efficiency of coupling (no pre-activation step is needed); no
guanidinium species can be obtained in contrast to the uronium
based coupling reagents and IIDQ is stable in the presence of base.
With these issues in mind a polymer-supported equivalent of IIDQ
was targeted.
PS-IIDQ was tested on a small library of 3 amines and 3
carboxylic acids (Table 1)§ and the yields and purities were
compared to IIDQ in solution. This library followed a short study
Polymer-supported IIDQ was successfully synthesised in three
steps as shown in Scheme 1. 6-Hydroxyquinoline was coupled
onto Merrifield resin using potassium carbonate (in excess) in
DMA at reflux for 6 h (DMF should be avoided as this undergoes
decomposition into primary amines that reacts with Merrifield
resin).{ By nitrogen and chlorine combustion elemental analysis
conversion was 98%. PS-Quinoline was treated with isobutyl
chloroformate in the presence of Hu¨nig’s base at 0 uC for 3 h,
yielding a highly reactive intermediate which was quenched by the
*mb14@soton.ac.uk
Scheme 1 Synthesis of PS-IIDQ.
1164 | Chem. Commun., 2005, 1164–1166
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Table 1 Coupling using PS-IIDQ or IIDQ
PS-IIDQ
IIDQ
Entry
Amine
Acid
Yield (%)a
Purity(%)b
Yield (%)a
Purity (%)b
1
2
3
4
5
6
7
8
9
a
4-tBu-aniline
Benzylamine
H-PhG-OMe
4-tBu-aniline
Benzylamine
H-PhG-OMe
4-tBu-aniline
Benzylamine
H-PhG-OMe
b
Boc-Aib-OH
Boc-Aib-OH
Boc-Aib-OH
Phenylacetic acid
Phenylacetic acid
Phenylacetic acid
Benzoic acid
69
66
64
60
80
61
89
85
75
100
100
100
100
100
99
100
100
99
81
92
89
83
74
84
78
85
81
91
98
98
98
96
96
93
96
94
Benzoic acid
Benzoic acid
Isolated yield. Purity determined by ELSD. PhG 5 Phenylglycine.
Although PS-IIDQ was targeted for general amide bond
formation, possible racemisation by epimerisation was evaluated
with the Anteunis’s test.14 Thus coupling between Z-Gly-Phe-OH
and H-Val-OMe gave the expected tripeptide with no epimerisa-
tion (limit of detection by 1H NMR at 400 MHz), thus making PS-
IIDQ a suitable reagent for coupling amino-acids.
In conclusion PS-IIDQ is an efficient polymer-supported
coupling reagent for general amide bond formation, including
hindered substrates. PS-IIDQ proved to be stable under general
laboratory storage, with no degradation noticed after 2 months. In
addition PS-IIDQ was easily regenerated, intensive washing
followed by reaction with isobutyl chloroformate{ yielded a
recycled polymer-supported IIDQ with an efficiency similar to the
original material. The resin (30 g) was recycled twice with little
variation observed in the loading (1.5 to 1.6 mmol g21 ) and no
changes in synthetic efficiency.
The authors thank the supporting partners of the Southampton
Combinatorial Centre of Excellence for financial support. The
authors are grateful to Neil Wells for performing the MAS-NMR,
and John Langley and Julie Herniman for assistance in MS.
Eric Valeur and Mark Bradley*
Combinatorial Centre of Excellence, School of Chemistry, University of
Southampton, Southampton, UK SO17 1BJ. E-mail: mb14@soton.ac.uk
Fig. 1 NMR spectra at 400 MHz showing evidence of the synthesis of
Notes and references
PS-IIDQ.
{ Procedure for synthesising PS-Quinoline: Merrifield resin (20 g,
3.99 mmol g21, 1 equiv.) was swollen in DMA (250 mL). 5 Equiv. of
K2CO3, 2.5 equiv. of 6-hydroxyquinoline and a catalytic amount of KI
were added and the reaction was heated at reflux for 6 h. The resin was
filtered and washed successively with THF–H2O (1 : 1), THF, DCM,
MeOH, DCM, MeOH, Et2O. Loading determined by Nitrogen Elemental
Analysis: 2.74 mmol g21 (98%).
on the efficiency of IIDQ in solution, which proved that this
coupling reagent was more efficient for general amide bond
formation than many classic agents (HATU, BOP-Cl, PyBOP),
when adding all the reactants at the same time. Synthesis
comparing PS-IIDQ and IIDQ was carried out using the
optimised conditions and, after reaction, a quick aqueous work-
up was carried out in order to remove the unreacted amine and
carboxylic acid.
{ PS-Quinoline (25 g, 2.74 mmol g21, 1 equiv.) was swollen in dry DCM
(300 mL). 3 Equiv. of dry DIPEA were added and the mixture was shaken
and cooled to 0 uC. 3 Equiv. of isobutyl chloroformate were added to the
reaction mixture. After 3 h, isobutanol (150 mL) was added, the mixture
allowed to warm up and shaken overnight. The resin was then filtered and
washed successively with 3 cycles of DCM, DCM–Et2O, Et2O. Loading
evaluated by the yield of the coupling between benzylamine and
The different amides were in most cases obtained in acceptable
yield and very high purity. The coupling with sterically hindered
building blocks phenylglycine (entries 3, 6 and 9) was successful
even when coupling to hindered Boc-aminoisobutyric acid.
Interestingly, coupling using an aniline succeeded in good yield
(entries 1, 4 and 7). Generally results were slightly better in terms
of purity when using PS-IIDQ. This illustrates the advantage of
PS-IIDQ over the classic solution-phase reagent IIDQ, where an
intensive work up is necessary to remove all the quinoline
generated during the coupling.
phenylacetic acid: 1.6 mmol g21
.
§ Typical procedure for using PS-IIDQ as coupling reagent: PS-IIDQ
(1.60 mmol g21, 2 equiv.) was swollen in acetonitrile. The carboxylic acid
(1 equiv.) and the amine (1 equiv.) were added and the reaction mixture
was shaken for 24 h. The resin was filtered and washed with 3 cycles of
DCM and MeOH. The filtrates were collected and concentrated in vacuo.
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1166 | Chem. Commun., 2005, 1164–1166
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